dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022131 1 necrobiotic xanthogranuloma as sign of monoclonal gammopathy claudio conforti1, iris zalaudek1 1 dermatology clinic, maggiore hospital, piazza dell’ospitale 1, university of trieste, trieste, italy citation: conforti c, zalaudek i. necrobiotic xanthogranuloma as sign of monoclonal gammopathy. dermatol pract concept. 2022;12(4):e2022131. doi: https://doi.org/10.5826/dpc.1204a131 accepted: january 9, 2022; published: october 2022 copyright: ©2022 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, hospital maggiore, trieste, italy. phone number: +39 3335441549, e-mail address: claudioconforti@yahoo.com case presentation a 52-year-old woman referred to our skin cancer unit for the presence of yellow periorbital plaques that enlarged over the past decade. based on the clinical and dermoscopic presentations (figure 1), a clinical diagnosis of necrobiotic xanthogranuloma (nx) was suspected. a  full laboratory workup was performed including skin and bone marrow biopsy, ct scan of the orbital region and urine examination. tests revealed an igg paraproteinemia without bone involvement and, based on skin biopsy, the diagnosis of nx braf wild type was confirmed. figure 1. (a) clinical appearance of necrobiotic xanthogranuloma showing eyelid and periorbital yellow plaques. (b) dermoscopic features of xn showing yellow structureless areas that correspond to the presence of histiocytes in the dermis. (c) h&e histological detail showing foamy histiocytes in the dermis. 2 image letter | dermatol pract concept. 2022;12(4):e2022131 teaching point necrobiotic xanthogranuloma is a rare  manifestation of non-langerhans histiocytosis and it is often associated with monoclonal gammopathy. references 1. spicknall ke, mehregan da. necrobiotic xanthogranuloma. int j dermatol. 2009;48(1):1-10. doi: 10.1111/j.1365-4632. 2009.03912.x. pmid: 19126043 dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022139 1 dermatology practical & conceptual a case of melanoma in a patient with psoriasis highlighting the importance of dermatoscopy and inflammoscopy sarah benton1, lori ann fiessinger1, juan pablo jaimes1 1 department of dermatology, university of minnesota medical school, minneapolis, minnesota, usa citation: benton s, fiessinger la, jaimes jp. a case of melanoma in a patient with psoriasis highlighting the importance of dermatoscopy and inflammoscopy. dermatol pract concept. 2022;12(3):e2022139. doi: https://doi.org/10.5826/dpc.1203a139 accepted: december 27, 2021; published: july 2022 copyright: ©2022 benton et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: juan p jaimes, md, ms, department of dermatology, university of minnesota medical school, 516 delaware st se suite 4-240, minneapolis, mn 55455, usa e-mail: jaim0004@umn.edu case presentation a male patient in his fourth decade of life presented to the clinic for evaluation of psoriasis. dermatoscopy of a lesion on the right posterior upper arm that clinically resembled a psoriasiform papule showed numerous polarizing-specific white lines and polymorphous vessels (figures 1, a-c). dermatoscopy of nearby papules and plaques of psoriasis revealed white scale on a background of randomly distributed dotted and coiled vessels (figure 1d). the lesion in figure 1a was sent for histological analysis and found to be a malignant melanoma with a breslow depth of 0.7 mm, occurring in association with a nevus. teaching point though clinically the melanoma resembled a psoriatic papule, under dermatoscopy the lesion appeared very different from other psoriatic lesions and had features of melanoma. this highlights the importance of dermatoscopy and inflammoscopy in the diagnosis of neoplasms and inflammatory conditions. the most common dermatoscopic pattern of psoriasis is erythematous background with evenly distributed red dots and white scale [1]. polarizing specific white lines and polymorphous vessels, clues that can be seen in melanoma, would not be expected in psoriasis [2]. 2 image letter | dermatol pract concept. 2022;12(3):e2022139 figure 1. (a) clinical image of the patient right upper arm with scattered pink papules and plaques with overlying white scale. (b) close-up image of the patient right upper posterior arm showing an 8 mm erythematous papule with white scale. (c) dermatoscopic view showing many polarizing-specific white lines and polymorphous vessels (polarized dermatoscopy). (d) dermatoscopic view of nearby psoriasis showing white scale on a background of randomly distributed dotted and coiled vessels (polarized dermatoscopy). informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. sgouros d, apalla z, ioannides d, et al. dermoscopy of common inflammatory disorders. dermatol clin. 2018;36(4): 359-368. doi: 10.1016/j.det.2018.05.003. pmid: 30201145. 2. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67(2):194. e1-194.e8. doi: 10.1016/j.jaad.2011.04.039. pmid: 22030020. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022158 1 dermoscopic findings of the evolving pigmented spitz nevus in a child joanna pogorzelska-dyrbuś1, beata bergler-czop2 1 “estevita” specialist medical practice, tychy, poland 2 school of medicine in katowice, medical university of silesia in katowice, department of dermatology, katowice, poland citation: pogorzelska-dyrbuś j, bergler-czop b. dermoscopic findings of the evolving pigmented spitz nevus in a child. dermatol pract concept. 2022;12(4):e2022158. doi: https://doi.org/10.5826/dpc.1204a158 accepted: january 27, 2022; published: october 2022 copyright: ©2022 pogorzelska-dyrbuś et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: joanna pogorzelska-dyrbuś md, phd specjalistyczna praktyka lekarska “estevita”, pasaz europejski 8/1 street, 43-100 tychy, silesia, poland, telephone: +48604542643 e-mail: jpogorzelskadyrbus@gmail.com case presentation a 12-year-old girl presented for a routine examination with a 4-mm oval-shaped dark brown papule on the right temple which slowly grew since her early childhood ( figure  1a). dermoscopy showed a homogenous half-blue and half-brown presentation (figure 1b 20x, fotofinder gmbh). the lesion has changed subtly within two years (figure 1c). after three years, the lesion displayed a uniform blue-brown color with streaks distributed at the periphery (figure 1d). the high magnification dermoscopy revealed peripherally distributed brown roundish cells [1] (figure 1e, f, 400x, fotofinder gmbh). the patient underwent excision of the lesion and histopathological diagnosis of spitz nevus was established. the consent to publish data has been obtained from the patient’s parents. teaching point typical for children spitz nevi usually occur as a solitary, rapidly growing, pink nodule on the face [2]. this case represents a less common presentation of spitz nevus in childhood, with changes extremely extended in time. references 1. cinotti e, tognetti l, campoli m, et al. super-high magnification dermoscopy can aid the differential diagnosis between melanoma and atypical naevi. clin exp dermatol. 2021;46(7):1216-1222. doi: 10.1111/ced.14566. pmid: 33486758. 2. lallas a, apalla z, ioannides d, et al. update on dermoscopy of spitz/reed naevi and management guidelines by the international dermoscopy society. br j dermatol. 2017;177(3):645-655. doi: 10.1111/bjd.15339. pmid: 28118479. 2 image letter | dermatol pract concept. 2022;12(4):e2022158 figure 1. (a) the clinical presentation of the nevus a 4-mm oval-shaped dark brown papule. (b) dermoscopic image of the nevus at the first visit with a homogenous half-blue and half-brown presentation. (c) subtle changes in dermoscopic features of the nevus after two years, with streaks appearing in the upper left quadrant (claret asterisks). (d) dermoscopic image of the nevus after three years with uniform blue-brown color with streaks distributed at the periphery (green asterisks). (e and f) high magnification dermoscopic image of the lesion revealed blue-grey background with distinctive brown oval structures corresponding to the hair follicles (blue arrows) and peripherally distributed brown roundish cells corresponding to peripheral streaks (red arrows). dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022200 1 cobblestone-like skin laura macca1, luca di bartolomeo1, claudio guarneri2 1 department of clinical and experimental medicine, section of dermatology, university of messina, messina, italy. 2 department of biomedical and dental sciences and morphofunctional imaging, section of dermatology, university of messina, messina, italy. citation: macca l, di bartolomeo l, guarneri c. cobblestone-like skin. dermatol pract concept. 2022;12(4):e2022200. doi: https://doi.org/10.5826/dpc.1204a200 accepted: march 2, 2022; published: october 2022 copyright: ©2022 macca et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: claudio guarneri, md, department of biomedical and dental sciences and morphofunctional imaging, section of dermatology, university of messina, messina, italy c/o a.o.u.p. “gaetano martino”, via consolare valeria, 1 – 98125 messina (italy); phone number: +390902212894. fax number: +390902927691. e-mail: cguarneri@unime.it case presentation a 55-year-old caucasian man who was positive for obesity, hypertension and congestive heart failure presented for a sixteen-months history of recurrent lower limbs swelling with progressive thickening of the skin. clinical examination revealed lymphedema with deformed fibrotic enlargement of the extremities. brownish pigmentation, with generalized lichenification (figure 1a) and cobblestone-like papules and nodules on the lower two thirds of both legs were also notable (figure 1b). swabs from some ulcerated lesions of the left pretibial area were obtained, but cultures did not show any pathogens growth. histological examination of a nodular lesion showed hyperkeratosis, parakeratosis, and acanthosis of the epidermis, as well as edema and dilated lymphatic spaces in the papillary and reticular dermis. no neoplastic changes were found. diagnosis of elephantiasis nostras verrucosa (env) was made upon clinical and histopathological findings. teaching point env is an uncommon dermatological disorder characterized by hyperkeratotic, verrucous, and papillomatous projections [1]. keong described it as “a non-filariasis chronic lymphedema, causing disfigurement of the extremities, and it will lead to recurrent infections and disabilities” [2]. the diagnosis is based on anamnesis and peculiar skin modifications  [1]. differential diagnosis includes venous stasis dermatitis, pretibial myxedema and filariasis [1]. several therapeutic options have been described in literature such as skin care, weight reduction, compressive medications and physiotherapy [2]. oral retinoids, surgery, and antimicrobials for super infections have also been used [1]. the unique target of the therapy is represented by restoring function and reducing physical disability. as chronic lymphedema could be the antechamber of lymphangiosarcoma, long-term follow-up is highly recommended [2]. 2 image letter | dermatol pract concept. 2022;12(4):e2022200 references 1. guarneri c, vaccaro m. cobblestone-like skin. cmaj. 2008;179(7):673-674. doi:10.1503/cmaj.080642. pmid: 18809899. pmcid: pmc2535733. 2. kar keong n, siing ngi at, muniandy p, voon fei w. elephantiasis nostras verrucosa: a rare complication of lower limb lymphoedema. bmj case rep. 2017;2017:bcr2017221492. doi:10.1136/bcr-2017-221492. pmid: 28847994. pmcid: pmc5624055. figure 1. (a) lymphedema of the lower extremities, with brownish pigmentation and generalized thickening of the pretibial skin. (b) close view of cobblestone-like papules and nodules on the lower two-thirds of left leg. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022088 1 natalizumab-induced pustular psoriasis of palms and soles bengisu ozarslan1, teresa russo2, giuseppe argenziano2, vincenzo piccolo2 1 dermatology unit, doku medical center, istanbul, turkey 2 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: natalizumab, psoriasis, pustular, palmo-plantar citation: ozarslan b, russo t, argenziano g, piccolo v. natalizumab-induced pustular psoriasis of palms and soles. dermatol pract concept. 2022;12(2):e2022088. doi: https://doi.org/10.5826/dpc.1202a88 accepted: september 18, 2021; published: april 2022 copyright: ©2022 ozarslan et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, md, c/o ii policlinico, building 9, first floor, via pansini 5 80131 napoli, italy. e-mail: piccolo.vincenzo@gmail.com introduction psoriasis and multiple sclerosis (ms) are both autoimmune t-cell mediated diseases that share a possible common genetic linkage [1]. natalizumab is a recombinant humanized monoclonal antibody targeting the cell adhesion molecule α4 integrin and is labeled to treat ms. it is known that biological agents induce cutaneous adverse drug reactions. although there is not a defined link between natalizumab and psoriasis, there are case reports describing a possible relationship [2]. here, we report on a patient with ms who developed pustular psoriasis of palms and soles after natalizumab treatment. case presentation a 50-year-old woman presented with multiple millimetric pustules and scaling sited on erythematous plaques on the palms and soles (figure 1a). personal and familiar history for psoriasis was negative. she has been treated with natalizumab for 6 months for ms. dermoscopy revealed yellow globules and crusts along with the dotted vessels (figure 1b). the patient was diagnosed with pustular psoriasis of palms and soles. discussion data on whether natalizumab can induce or aggravate psoriasis are limited. in literature, 2 of the cases developed plaque psoriasis while 1 patient had new-onset psoriatic arthritis during natalizumab treatment. family history of psoriasis was positive in all patients. one patient affected by mild psoriasis had a severe flare-up after several natalizumab infusions [2]. our patient, on the other hand, differs from those cases due to the absence of family history and the development of localized pustular psoriasis. although there are pieces of evidence showing common pathophysiological pathways in psoriasis and ms, it has been observed that treatment of one condition did not provide a parallel improvement in the other one. t helper 17 (th17) cells are involved in the inflammation stage of both disease [1]. the pathophysiological mechanism between 2 research letter | dermatol pract concept. 2022;12(2):e2022088 psoriasis and natalizumab remains unclear but natalizumab has been associated with paradoxical activation of autoimmune disorders by pathologically stimulating the production of il17 and increased activation of th17 cells [2]. conclusions we highlight that a new onset of palmoplantar pustular psoriasis may also be a rare side effect of natalizumab. there is not enough data yet to make a recommendation regarding the consideration of psoriasis history in the patient or in the family when deciding for natalizumab treatment. more research is needed to understand the relationship between natalizumab and psoriasis. references 1. kwok t, loo wj, guenther l. psoriasis and multiple sclerosis: is there a link? j cutan med surg. 2010;14(4):151-155. doi: 10.2310/7750.2010.09063. pmid: 20642982. 2. lambrianides s, kinnis e, leonidou e, pantzaris m. does natalizumab induce or aggravate psoriasis? a case study and review of the literature. case rep neurol. 201818;10(3): 286-291. doi: 10.1159/000492891. pmid: 30323758. pmcid: pmc6180259. figure 1. (a) multiple pustules and crusting over the palm. (b) dermoscopic image demonstrates yellow globules and crusts along with the dotted vessels. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2013;3(4):10 41 the patient a 36-year-old female with no previous history of melanoma presented for a routine mole check. a small, slightly raised lesion was discovered on the left side of her back (figures 1, 2). what is your provisional diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a complimentary copy of the book, dermoscopy: the essentials, 2nd ed. [elseviersaunders, 2012]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. dermoscopy: what is your diagnosis? viji narayanan1 1 general practitioner, seasons skin clinic, auckland, new zealand citation: narayanan v. dermoscopy: what is your diagnosis? dermatol pract conc. 2013;3(4):10. http://dx.doi.org/10.5826/dpc.0304a10. copyright: ©2013 narayanan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: dr. viji narayanan, seasons skin clinic, 26/2 bishop dunn place, flatbush, auckland, new zealand. email: moledoctor@gmail.com. figure 1. small, raised shiny lesion about 4 x 3 mm on the left flank of a 36-year-old woman. [copyright: ©2013 narayanan et al.] figure 2. dermoscopy of the lesion taken with dermlite dl3. [copyright: ©2013 narayanan et al.] ies, which represent the molluscum bodies or henderson-paterson bodies [1]. in our case, the diagnosis was unequivocal and histopathology was not required. infection with mcv is self-limited and will usually resolve spontaneously within weeks to months, but patients are considered contagious until all mc lesions have disappeared. therapeutic options for refractory lesions include topical tretinoin, topical cantharidin, surgical tape, light cryotherapy, topical trichloracetic acid, topical sodium nitrite with salicylic acid, or curettage [1]. we have also seen favorable results with topical cidofovir and ingenol mebutate. references 1. james wd, berger tg, elston dm. andrews’ diseases of the skin. 10th ed. philadelphia, pa: elsevier/saunders, 2006. 2. pierard-franchimont c, legrain a, pierard ge. growth and regression of molluscum contagiosum. j am acad dermatol. 1983;9(5):669-72. 3. shelley wb, burmeister v. demonstration of a unique viral structure: the molluscum viral colony sac. br j dermatol.1986;115(5): 557-62. 4. ianhez m, cestari sda c, enokihara my, seize mb. dermoscopic patterns of molluscum contagiosum: a study of 211 lesions confirmed by histopathology. an bras dermatol. 2011;86(1):74-9. 5. morales a, puig s, malvehy j, zaballos p. dermoscopy of molluscum contagiosum. arch dermatol. 2005;141(12):1644. congratulations to dr. jan lapins, who was the first to send us the correct answer! 42 quiz | dermatol pract concept 2013;3(4):10 july 2013 quiz—answer and discussion the correct answer to the dermatoscopy quiz in the july 2013 issue is molluscum contagiosum. (http://dx.doi.org/10.5826/ dpc.0303a07) molluscum contagiosum (mc) is a cutaneous infection caused by various types of the poxvirus, molluscum contagiosum virus (mcv)-1 to -4, with mcv-1 being the most common [1]. the virus is spread by direct skin-to-skin contact with lesions and typically occurs in young children, sexually active adolescent and adults, and immunosuppressed individuals. after viral entry, mcv replicates in the lower layers of the epidermis for an incubation period of 14 days to 6 months [2]. with active infection, the epidermis hypertrophies and extends into the dermis. molluscum bodies begin to form within cells of the stratum spinosum, causing further enlargement of individual cells. the basal cell layer replaces the spinosa layer, projecting the hypertrophied spinosa cells towards the stratum corneum, forming the characteristic small (3 to 5 mm in diameter), smooth, pink-red, dome-shaped, umbilicated lesions [3]. the most commonly affected areas are the face, trunk, extremities, and genitals [1]. the diagnosis of mc is typically clinical. unlike herpes viruses, mc is not routinely cultured. for challenging cases, the use of a dermatoscope may aid in diagnosis by allowing the clinician to visualize the characteristic white-yellow clods and surrounding vessels (molluscum bodies) [4,5]. histopathology yields the final diagnosis in clinically unequivocal cases, demonstrating numerous characteristic inclusion boddermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022073 1 dermatology practical & conceptual introduction grafts-versus-host disease (gvhd) is a severe systemic complication most commonly occurring after allogeneic hematopoietic stem cell transplantation (hsct). we would like to share our clinical experience with a patient who developed a grade 4 hyperacute gvhd after haploidentical hsct for acute myelogeneous leukemia (aml). case presentation a 18 year-old woman with a history of haploidentical hsct was consulted for palmoplantar erythematous rash and severe mucositis. twelve days prior to the consultation, she had allogeneic haploidentical hsct from her younger sister for aml. three days after hsct, the patient developed neutropenic feverand intractable diarrhea; intravenous (iv) meropenem, teicoplanin and metronidazole were initiated. there was no bacterial growth in blood and urine cultures. however, abdominal computed tomography revealed findings compatible with typhlitis. twelve days after hsct, she was referred to our clinic due to severe mucocutaneous eruption. dermatological examination showed diffuse hemorrhagic-crusted plaques on her lips and neck and dusky-edematous plaques involving volar areas (figure 1). our initial diagnoses were stevens johnson syndrome (sjs), hyperacute grade 4 gvhd and paraneoplastic pemphigus. a skin biopsy was taken from the neck which showed mild lymphocytic hyperacute graft-versus-host disease mimicking stevens-johnson syndrome in a patient with allogeneic hematopoietic stem cell transplantation ecem bostan1, duygu gulseren1, deniz ates ozdemir2, ibrahim haznedaroglu3, sibel ersoy-evans1 1 department of dermatology and venereology, hacettepe university, faculty of medicine, ankara, turkey 2 department of pathology, hacettepe university, faculty of medicine, ankara, turkey 3 department of hematology, hacettepe university, faculty of medicine, ankara, turkey key words: graft versus host disease, pathology, skin, stevens-johnson syndrome citation: bostan e, gulseren d,ozdemir da, haznedaroglu i, ersoy-evans s. hyperacute graft-versus-host disease mimicking stevens johnson syndrome in a patient with allogeneic hematopoietic stem cell transplantation.dermatol pract concept. 2022;12(2):e2022073. doi: https://doi.org/10.5826/dpc.1202a73 accepted: september 7, 2021; published: april 2022 copyright: ©2022 bostan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: ecem bostan, hacettepe university, faculty of medicine, department of dermatology and venereology, ankara, turkey. e-mail: bostanecem@gmail.com 2 research letter | dermatol pract concept. 2022;12(2):e2022073 inflammation and vacuolar change at the epidermal-dermal junction, dyskeratosis in basal layer keratinocytes (figure 2). direct immunofluorescence assay was negative. she continued to have intractable diarrhea and gradually increasing levels of acute phase reactants, alkaline phosphatase (alp), gamma-glutamyl transferase (ggt) and of total/direct bilirubin levels. anti-skin specific antibodies were negative. with clinical, laboratory and histopathological findings, as the diagnosis was hyperacute grade 4 gvhd (the beginning of the rash was within the first week of hsct) according to consensus grading of hyperacute/acute gvhd [1]. iv methylprednisolone was started as maintenance treatment. cyclosporine and mycophenolate mofetil were switched to tacrolimus. since sjs was could not be excluded on clinical grounds, recently administered antibiotic drugs teicoplanin and meropenem were changed to cefepime. however, she succumbed to death 5 weeks after hsct. discussion gvhd is a severe systemic complication most commonly occurring after allogeneic hsct even though gvhd cases have also been reportedin association with solid organ transplantation and non-irradiated blood product transfusion. dermatological presentation may range from maculopapular eruption to generalized erythroderma and epidermal sloughing mimicking toxic epidermal necrolysis [1]. this severe dermatological presentation is accepted as stage 4 and grade 4 figure 2. (a) biopsy shows hyperkeratinization and basal membrane irregularity (h&e, 40x). (b) basal keratinocytes show vacuolar degeneration due to mild lymphocytic infiltrate (h&e, 100x). (c) higher power reveals damaged basilar keratinocytes which show hydropic degeneration with eosinophilic cytoplasm and single cell necrosis (arrows) (h&e, 200x). figure 1. (a) initial dermatologic examination at the first consultation revealed diffuse hemorrhagic encrusting of the lips spreading beyond the vermillion border, diffuse ulcerative-hemorrhagic crusted plaques covering entire anterolateral neck. (b) diffuse plantar erythema and edema. (c) acral and palmar peeling along with erythema. research letter | dermatol pract concept. 2022;12(2):e2022073 3 gvhd [1]. schultz et al reported a case of grade 4 gvhd who developed extensive macular rash along with mucosal ulceration within weeks of liver transplantation [1]. similar to the letter by klein et al, our patient developed severe mucocutaneous eruption with epidermal sloughing within the second week of hsct [2]. distinctively, she had diarrhea and progressive elevation in bilirubin, alp and ggt levels favoring the gastrointestinal involvement of acute gvhd. conclusions in all patients with a prior history of allogeneic hsct, hyperacute/acute gvhd should be considered in the differential diagnosis when severe mucositis, palmoplantar involvement, and epidermal detachment similar to sjs are observed. references 1. schulz jt 3rd, sheridan rl. severe desquamating disorder after liver transplant: toxic epidermal necrolysis or graft versus host disease? j burns wounds. 2006 jan 28;5:e1.pmid: 16921414. pmcid: pmc1687152. 2. klein b, kolm i, nair g, nägeli mc. ten-like acute cutaneous gvhd in a stem cell recipienta diagnostic dilemma. j eur acaddermatolvenereol. 2021;35(9):e585-e587. . doi: 10.1111/ jdv.17310. pmid: 33914967. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022083 1 dermatology practical & conceptual a case of adult-onset facial cutaneous mastocytoma: clinical and dermoscopic findings matteo megna1, massimiliano scalvenzi1, sonia sofía ocampo garza1,2, gabriella fabbrocini1, elisa camela1 1 section of dermatology department of clinical medicine and surgery, university of naples federico ii, naples, italy 2 universidad autónoma de nuevo león, university hospital ¨dr. josé eleuterio gonzález¨, dermatology department, monterrey, nuevo león, méxico key words: solitary mastocytoma, adult, cutaneous mastocytoma, mastocytosis, facial citation: megna m, scalvenzi m, ocampo garza ss, fabbrocini g, camela e. a case of adult-onset facial cutaneous mastocytoma: clinical and dermoscopic findings. dermatol pract concept. 2022;12(3):e2022083. doi: https://doi.org/10.5826/dpc.1203a83 accepted: october 17, 2021; published: july 2022 copyright: ©2022 megna et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: elisa camela, md, department of dermatology, university of naples federico ii, via pansini, 5 80131 napoli, italy, tel: +39 081 -7462457 fax: +39 081 – 7462442, e-mail: elisacamela@gmail.com introduction cutaneous mastocytoma is a form of mastocytosis that usually affects newborns and children, representing an uncommon finding in adults [1]. clinically, it presents with up to 3 yellowish, brown, or red nodular lesions mainly located on the trunk and extremities [1]. the most common dermoscopic feature is a yellow-orange blot pattern [1]. we report the unusual case of an adult-onset facial cutaneous mastocytoma, arising on the forehead, and describe a new dermoscopic pattern. case presentation a 36-year-old woman came to our dermatology department for the presence of an asymptomatic erythematous plaque on the forehead, of two-month-duration (figure 1). the patient was in good health and did not refer systemic symptoms; her medical and pharmacological history was unremarkable. dermoscopic evaluation revealed an irregular vascular pattern characterized by irregular linear vessels, some of which serpiginous, of steady caliber, on a pink-red background and perifollicular scar-like white areas (figure 2). incisional biopsy displayed the presence of a diffuse and homogeneous pan-dermal infiltrate of mast cells, with some perivascular and peri-adnexal lymphocytes and plasma cells in the upper dermis. to rule out systemic mastocytosis, routine blood tests as well as serum tryptase (st) were performed resulting unremarkable. based on clinical, dermoscopic and histologic findings along with normal st levels and absence of systemic involvement, a diagnosis of cutaneous mastocytoma was made. the patient was started on topical tacrolimus with progressive subsiding of clinical manifestations. conclusions adult-onset cutaneous mastocytoma is a rare entity described in less than 20 patients so far [1]. its diagnosis is 2 research letter | dermatol pract concept. 2022;12(3):e2022083 figure 1. clinical aspect of facial cutaneous mastocytoma: an erythematous plaque of the forehead. figure 2. dermoscopy of facial cutaneous mastocytoma: irregular vascular pattern with linear vessels, some of which serpiginous, showing steady caliber; pink-red background; perifollicular scar-like white areas. research letter | dermatol pract concept. 2022;12(3):e2022083 3 challenging as it may be confused with a vast spectrum of diseases according to its clinical presentation. indeed, it may appear as a macule, papule, plaque or nodule and vary in color from yellow to brown, to red [2]. dermoscopically, cutaneous mastocytoma has been reported to present a yellow-orange blot pattern [2]. anyway, in our case, an irregular vascular pattern exclusively characterized by irregular linear and serpiginous vessels of steady caliber, on a pink-red background and perifollicular scar-like white areas were observed. more data are needed since reported dermoscopic descriptions are very scant. given that the onset of cutaneous mastocytosis in adults is frequently associated with systemic disease, it has been recommended that the initial diagnostic work-up should include blood tests ( complete blood cell count, serum chemistries with liver function tests, and st levels), and also bone marrow biopsy (bmb) [2]. if there is no systemic involvement, all the above-mentioned investigations apart from bmb, should be repeated yearly [2]. in our case, due to the absence of systemic symptoms and normal st, bmb was not performed. concerning treatment, surgical excision is the most employed one, followed by topical or intralesional corticosteroids [2]; other treatments comprise pimecrolimus and pulsed dye laser therapy [2]. we reported the unusual case of adult-onset facial mastocytoma, arising on the forehead, and described new dermoscopic findings. although the strength of our observation is limited by the single patient, we believe that enriching literature with new information may contribute to improve diagnosis of unusual manifestations. informed consent: written informed consent was obtained from the patient for publication of this case report and any accompanying images. references 1. vano-galvan s, álvarez-twose i, de las heras e, et al. dermoscopic features of skin lesions in patients with mastocytosis. arch dermatol. 2011;147(8):932-940. doi:10.1001/archdermatol. 2011.190. pmid: 21844452. 2. cohen p. solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment. dermatol pract concept. 2016;6(3):31-38. doi:10.5826/dpc.0603a07. pmid: 27648381. pmcid: pmc5006550. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022105 1 do pd-1/pdl-1 inhibitors play a triggering or causative role in the development of paraneoplastic dermatomyositis? michela starace1, francesca pampaloni2, miriam anna carpanese1, andrea sechi1, francesca bruni1, aurora alessandrini1 1 dermatology -irccs policlinico di sant’orsola department of experimental, diagnostic and specialty medicine (dimes) alma mater studiorum university of bologna, italy 2 dermatology unit, department of medicine, university of padova, italy key words: pd-1 inhibitors, dermatomyositis, paraneoplastic, breast cancer, immune-related adverse events citation: starace m, pampaloni f, carpanese ma, et al. do pd-1/pdl-1 inhibitors play a triggering or causative role in the development of paraneoplastic dermatomyositis? dermatol pract concept. 2022;12(3):e2022105. doi: https://doi.org/10.5826/dpc.1203a105 accepted: october 25, 2021; published: july 2022 copyright: ©2022 starace et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: carpanese miriam anna, md, dermatology -irccs policlinico di sant’orsola department of experimental, diagnostic and specialty medicine (dimes) alma mater studiorum university of bologna, via massarenti, 1, 40138 bologna, italy, phone: +390512143677 fax: +390512144867 e-mail: miriam.carpanese@gmail.com introduction the use of immune checkpoint inhibitors therapy in cancers is widely diffuse but the dermatologic immune-related adverse events (iraes) are not completely characterized. we present the first case of paraneoplastic dermatomyositis triggered by atezolizumab. case presentation a 53-year-old woman affected by ductal infiltrative breast cancer underwent mastectomy and lymphadenectomy, followed adjuvant chemotherapy. later she started paclitaxel weekly and atezolizumab after 2 months. at the fifth infusion of atezolizumab she developed a skin rash attributed to drug. dermatologic examination revealed marked butterfly-facial edema with periocular swelling, erythematous-violaceous plaques of the face, upper chest and back. (figure 1a). erythematous papules coalescing into plaques of the metacarpophalangeal and proximal interphalangeal joints were detected (figure 1b). hemorrhagic onycholysis and periungual erythema were detected by capillaroscopy that revealed capillary loss, tortuosity, ramified, enlarged capillaries, and microhemorrhages (figure 1, c and d). a  skin biopsy from a papule of the back of the hand showed an interface dermatitis and focal mucin deposition in the dermis. laboratory testing revealed positive ana (1:320), normal cpk (212 u/l), mild increased serum aldolase (15.5 u/l), normal transaminases. given the clinical presentation, capillaroscopy, histopathology and ana positivity 2 research letter | dermatol pract concept. 2022;12(3):e2022105 conclusions pd-1/pdl-1 inhibitor immunotherapy represents a successful treatment for advanced malignancies; it can be associated with lots of iraes, among which dermatomyositis. guidelines recommend temporary or permanent drug we made the diagnosis of dermatomyositis. between myositis-specific antibodies requested anti-tif ƴ antibodies were significantly positive (negative anti-ro and anti-jo). systemic prednisone 50 mg daily and intravenous immunoglobulins were prescribed with improvement of the clinical signs (figure 2). figure 1. (a) facial butterfly-edema, with periocular swelling, erythematous-to-slightly-violaceous plaques sparing the frontal region and the submental area. (b) erythematous discrete papules coalescing into plaques of the metacarpophalangeal and proximal interphalangeal joints. (c) capillaroscopic examination: capillary loss, tortuosity, ramified, enlarged and giant capillaries, and microhemorrhages 50x magnification. (d) 70x magnification figure 2. the same patient after the therapy with intravenous immunoglobulin: evident improvement on face (a) and hands (b). research letter | dermatol pract concept. 2022;12(3):e2022105 3 this case adds new findings to the literature regarding dermatomyositis associated with pd-1/pdl-1 inhibitors. pd-1/pdl-1 inhibitors could have a triggering role rather than a causative role in the development of dermatomyositis. clinicians should be aware that facing a patient affected by metastatic cancer treated with pd-1/pdl-1 inhibitors, cutaneous adverse events such dermatomyositis may be not related to the treatment but also to the underlying disease, preventing the interruption of safety treatments. references 1. messer a, drozd b, glitza ic, lu h, patel ab. dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature. dermatol online j. 2020;26(8):13030/qt4c21b068. pmid: 32941716. 2. didona d, fania l, didona b, eming r, hertl m, di zenzo g. paraneoplastic dermatoses: a brief general review and an extensive analysis of paraneoplastic pemphigus and paraneoplastic dermatomyositis. int j mol sci. 2020;21(6):2178. doi: 10.3390/ijms21062178. pmid: 32245283; pmcid: pmc7139382. interruption according to the severity of the skin reaction  [1]. besides being drug-induced, dermatomyositis is a well described paraneoplastic disease in ovarian and breast cancer. the patient described in our report had the exposure to atezolizumab and breast cancer, which are both risk factors for the development of dermatomyositis. at the beginning we believed that dermatomyositis could be drug induced, due to the latency between the drug infusion and the onset of the reaction, and the strong association between antipd-1/pdl-1 therapy and dermatomyositis. nevertheless, the worsening after drug discontinuation suggested that the antipd-1/pdl-1 was only a triggering factor for a classical paraneoplastic dermatomyositis. paraneoplastic origin was supported by the presence of all the criteria proposed for the diagnosis of paraneoplastic dermatoses. the disease was near the beginning of the cancer and following the same course, moreover dermatomyositis is rare in the general population but strictly associated to tumors, as cancer occur in 14.8% of dermatomyositis patients [2]. the detection of anti-tif ƴ antibodies, that are positive in 42%-100% of paraneoplastic dermatomyositis, confirmed our diagnosis [1]. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023075 1 rapid progression of localized morphea to disseminated plaque-type morphea following covid-19 infection hoda rahimi1, leila rezaie shirmard2, mehrdad ashayer1, sajjad barin3 1 skin research center, shahid beheshti university of medical sciences, tehran, iran 2 department of pharmaceutics, school of pharmacy, ardabil university of medical sciences, ardabil, iran 3 department of pathology, ardabil university of medical sciences, ardabil, iran key words: covid-19, morphea, plaque, autoimmune disorders citation: rahimi h, rezaie shirmard l, ashayer m, barin s. rapid progression of localized morphea to disseminated plaque-type morphea following covid-19 infection. dermatol pract concept. 2023;13(2):e2023075. doi: https://doi.org/10.5826/dpc.1302a75 accepted: june 20, 2022; published: april 2023 copyright: ©2023 rahimi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: mehrdad ashayer, md, dermatologist, skin research center, shahid beheshti university of medical sciences, tehran, iran. shohada-e tajrish hospital, shahrdari st, 1989934148, tehran, iran. tel: +98-2122744394 e-mail: m.ashayer@yahoo.com introduction since the emerging of the sars-cov-2 pandemic, different covid‐19‐associated manifestations have been reported, involving nervous, hematologic, and endocrine systems [1]. as the largest organ of the body, the skin has not been an exception and is reported to be involved in covid-19 patients with diverse manifestations, including maculopapular, vesicular, lichenoid, urticarial, vasculitis, and chilblain-like lesions [2,3]. herein, we report a stable case of localized morphea which progressed rapidly to disseminated morphea following covid-19 infection. case presentation a 45-year-old female patient was referred to our dermatology clinic due to asymptomatic bilateral sclerotic cutaneous lesions on the trunk and lower extremities. the patient reported a single small lesion on her trunk from 1 year ago (which was neither enlarged nor distributed), so she did not visit a physician. seven months later, she was infected with the sars-cov-2 virus, presenting with mild symptoms (including myalgia, headache, and sore throat) without any lung involvement, which was confirmed by reverse transcriptase–polymerase chain reaction (rt-pcr). she received palliative treatment in addition to azithromycin 250mg/d for 1 week, and her symptoms were resolved without any sequel. after 2 months, her cutaneous lesion spread rapidly involving her trunk and lower extremities. she did not have any systemic signs or symptoms. her familial and personal history was negative for any autoimmune disease. the physical examination revealed several brownish and violaceous plaques with firm ivory centers. the lesions showed symmetrical and bilateral distribution, which tend to coalescence with islands of sparing normal skin (figure 1). 2 research letter | dermatol pract concept. 2023;13(2):e2023075 figure 1. (a,b) violaceous plaques with firm ivory centers tend to coalescence with islands of sparing normal skin on the trunk (a) and the leg (b) of the patient. figure 2. thickening of dermal collagen bundles running parallel to the skin surface (a) (h&e x4), with scattered, perivascular, and periadnexal lymphoplasmacytic infiltration which extended into the hypodermis. some eccrine glands appeared atrophic with few surrounding adipocytes (b,c) (h&e x40). research letter | dermatol pract concept. 2023;13(2):e2023075 3 a biopsy from one of her new leg lesions revealed thickening of dermal collagen bundles running parallel to the skin surface with scattered, perivascular, and periadnexal lymphoplasmacytic infiltration, which extended into the hypodermis. some eccrine glands appeared atrophic with few surrounding adipocytes, confirming the diagnosis of morphea (figure 2). narrow-band uvb therapy started for the patient, but she did not return for follow-up. conclusions during the recent sars-cov-2 pandemic, different covid‐19‐associated cutaneous disorders have been reported [2]. as infections have long been known as the most important environmental trigger in the complex pathophysiology of autoimmune diseases, it is not surprising that many of these systemic or cutaneous covid‐19‐mediated diseases are autoimmune disorders [1]. among autoimmune connective tissue disorders, several cases of new onset or deterioration of systemic lupus erythematosus were reported as a consequence of covid-19 [1]. however, to date, there are only 2 cases of morphea reported in association with this infection. pigliacelli et al reported the onset of limited plaque morphea following sars-cov-2 infection for the first time [4]. the other case was reported by lotfi et al as pansclerotic morphea in a patient with lung cancer and covid-19 infection [5]. however, in this case, due to the presence of a malignant neoplasm, the correlation between morphea and covid-19 remains questionable. to the best of our knowledge, there is no report of the evolution of localized-type morphea to disseminated plaque-type morphea following covid-19 infection in the literature. references 1. yazdanpanah n, rezaei n. autoimmune complications of covid-19. j med virol. 2022;94(1):54-62. doi: 10.1002 /jmv.27292. pmid: 34427929. pmcid: pmc8661629. 2. rahimi h, tehranchinia z. a comprehensive review of cutaneous manifestations associated with covid-19. biomed res int. 2020;2020:1236520. doi: 10.1155/2020/1236520. pmid: 32724793. pmcid: pmc7364232. 3. tehranchinia z, asadi-kani z, rahimi h. lichenoid eruptions with interface dermatitis and necrotic subepidermal blister associated with covid-19. dermatol ther. 2020;33(6):e13828. doi: 10.1111/dth.13828. pmid: 32542925. pmcid: pmc7323232. 4. pigliacelli f, pacifico a, mariano m, et al. morphea induced by sars-cov-2 infection: a case report. int j dermatol. 2021;61(3):377-378. doi: 10.1111/ijd.15983. pmid: 34783020. pmcid: pmc8653008. 5. lotfi z, haghighi a, akbarzadehpasha a, et al. pansclerotic morphea following covid-19: a case report and review of literature on rheumatologic and non-rheumatologic dermatologic immune-mediated disorders induced by sars-cov-2. front med (lausanne). 2021;;8:728411. doi: 10.3389/fmed.2021.728411. pmid: 34746174. pmcid: pmc8564069. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):4 23 dermatology practical & conceptual www.derm101.com introduction while dermoscopy has become standard procedure in the diagnosis and management of patients with skin lesions, clinical and dermoscopic photographic documentation of lesions scheduled for biopsy are only infrequently performed in everyday practice [1-7]. herein we present a case of a young woman who developed a re-pigmentation within the scar of an excised primary melanoma and highlight the importance of pre-surgical clinical photography in her management. case presentation a 23-year-old woman with multiple nevi presented because of a brown, sharply demarcated plaque on her left shoulder (figure 1a arrow), which she recently the value of pre-surgical photography in the management of melanoma iris zalaudek1,teresa deinlein1, nora woltsche1, romana kupsa1, christina ambros-rudolph2 1 department of dermatology and venereology, medical university of graz, austria 2 private practice, graz, austria key words: melanoma, preventive medicine, photography, dermoscopy citation: zalaudek i, deinlein t, woltsche n, kupsa r, ambros-rudolph c. the value of pre-surgical photography in the management of melanoma. dermatol pract concept. 2017;7(2):4. doi: https://doi.org/10.5826/dpc.0702a04 received: december 15, 2016; accepted: january 14, 2017; published: april 30, 2017 copyright: ©zalaudek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. irb statement: it was waived, because we did no studies in humans. patient consent: the explicit written informed consent of the patient for publication was given. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: iris zalaudek, md, non-melanoma skin cancer unit, department of dermatology, medical university of graz, auenbruggerplatz 8 8036 graz, austria. tel. 0043 316 385 80542; fax. 0043 316 385 16827. email: iris.zalaudek@medunigraz.at figure 1. (a) clinical picture showing a well-defined, roundish, brown macula on the left shoulder. (b) dermoscopy reveals irregular brown globules varying in size at the periphery and a dark-brown structereless area in the center of the lesion. [copyright: ©zalaudek et al.] a b noticed. upon dermoscopy the lesion exhibited irregularly sized brown globules and a central dark-brown structureless area (figure 1b). based on this pattern, a diagnosis of melanoma was suspected and the lesion was excised. mailto:iris.zalaudek@medunigraz.at 24 observation | dermatol pract concept 2017;7(2):4 only be made because review of the presurgical images revealed the presence of a small pigmented nevus at the side, at which the re-excision of the primary melanoma had been performed. in fact, the clinically suspected diagnosis of persisting nevus within a scar was further confirmed by digital monitoring revealing no canges over a follow-up period of one year. hence, we suggest that pre-surgical digital photography become a routine procedure in the management of patients with skin tumors. however, before excision, a clinical overview of her back, a digital dermoscopic image of the lesion, as well as some of the surrounding nevi was performed. histopathology confirmed the clinical suspect and revealed a melanoma (0.5 mm tumor thickness, mitosis < 1/ mm2). imaging examinations were unremarkable and re-excision with 1 cm safety margins was performed. histopathology of the re-excision showed no further tumoral evidence. at follow-up 6 months later, a linear brown pigmentation extending from the lower border into the scar of the primary tumor was noticed. dermoscopically, a structureless brown to gray pigmentation was observed (figure 2b arrow). side-by-side review of the clinical overview image taken at baseline and at the current visit (figure 3) revealed a small pigmented nevus in about 1 cm distance at the lower area of the primary melanoma (figure 3a red arrow). based on this observation, a diagnosis of an incompletely removed nevus during the surgical procedure of the re-excision of the primary melanoma was made and the lesion was scheduled for digital follow-up. at follow-up 6 and 12 months later, the lesions remained completely unchanged. conclusion ferrara et al. showed that the addition of clinical information including presurgical images improves the diagnostic accuracy and confidence of pathologists when dealing with melanocytic skin tumors that are difficult to interpret. moreover, bauer and coworkers reported that review of dermoscopic images can help in avoiding sampling errors in histopathology [1-7]. our case adds further support to the value of pre-surgical photographic documentation of the clinical management of patients with pigmented skin lesion. in our patient, the diagnosis of an incompletely removed nevus could references 1. ferrara g, argenyi z, argenziano g, et al. the influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms. plos one. 2009;4:e5375. 2. bauer j, metzler g, rassner g, garbe c, blum a. dermatoscopy turns histopathologist’s attention to the suspicious area in melanocytic lesions. arch dermatol. 2001;1371338-1340. 3. ferrara g, argenziano g, soyer hp, et al. dermoscopic an histopathological diagnosis of equivocal melanocytic lesions. an interdisciplinary study on 107 cases. cancer. 2002;95:1094-1100. figure 2. (a) linear homogenous brown pigmentation extending from the lower border into the scar of the primary tumor. (b) structureless brown to gray pigmentation dermoscopically. [copyright: ©zalaudek et al.] a b figure 3. side-by-side review of the follow-up (b) and baseline image (a) revealed a small pigmented nevus at a distance of about 1 cm from the lower area of the primary melanoma (a, red arrow). [copyright: ©zalaudek et al.] a b observation | dermatol pract concept 2017;7(2):4 25 logical diagnosis of cutaneous melanoma and other pigmented skin lesions. j clin oncol. 1996;14:1218-1223. 6. farmer er, gonin r, hanna mp. discordance in the histopathological diagnosis of melanoma and melanocytic nevi be4. ferrara g, argenziano g, cerroni l, et al. a pilot study on combined dermoscopicpathological approach to the telediagnosis of melanocytic skin neoplasms. j telemed telecare. 2004;10:34–38. 5. corona r, mele a, amini m, et al. interobserver variability on the histopathotween expert pathologists. hum pathol. 1996;27:528-531. 7. soyer hp, kenet ro, wolf ich, kenet bj, cerroni l. clinicopathological correlation of pigmented skin lesions using dermoscopy. eur j dermatol. 2000;10(1):22-8 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2013;3(3):3 7 case presentation a 56-year-old man presented with a 12-month history of tingling ulcers on both feet (figure1a). he was otherwise well. on examination there were ulcers on both feet, 1-1.5 cm in diameter with a macerated edge. skin-colored to redbrown papules were noted on both knees (figure 1b) as well as irregular red circles on both calves. skin biopsies taken from knee papules and red circles on the lower leg showed extravascular eosinophilic deposits in the dermis (figure 1c), which stained positive with pas, igm (figure 1d) and kappa stains, but negative with congo red. investigations are summarised here: serum kappa free chains, 85.9 mg/l (normal 3.3-19.4 mg/l); serum lambda free chains, 17 mg/l (normal 7.7-26.3 mg/l); serum free kappa chains /free-lambda chains ratio, 5.05 (normal 0.26-1.65); serum electrophoresis, elevated ig m gradient; serum immunofixation, monoclonal ig m/kappa-type immunoglobulin; urine immunofixation, monoclonal kappa-free chain; bone marrow microscopy, infiltrate of lymphoplasmocytic cells (15%) (most cd20 and cd138 positive) with preferential expression for igm. discussion the cutaneous manifestations of waldenström macroglobulinaemia have been classified as either infiltration by neoplastic cells or those related to the paraproteinaemia, such as immunoglobulin deposition, cryoglobulinaemia or blood hyperviscosity. a number of other nonspecific cutaneous presentations have been reported. approximately 5% of patients with waldenström macroglobulinaemia develop cutaneous manifestations, with neoplastic infiltration being the least common. skin signs may either precede or follow the diagnosis. prognosis does not appear to be influenced by the presence or absence of cutaneous disease [1]. waldenström macroglobulinaemia presenting as tingling ulcers on the feet isabelle fischer,1 delwyn dyall-smith,1 birgit peters,1 wilhelm stolz,1 brigitte coras-stepanek1 1 department of dermatology, klinikum schwabing, munich, germany key words: peripheral neuropathy, storage papules, macroglobulinaemia cutis citation: fischer i, dyall-smith d, peters b, stolz w, coras-stepanek b. waldenström macroglobulinaemia presenting as tingling ulcers on the feet. dermatol pract conc. 2013;3(3):3 . http://dx.doi.org/10.5826/dpc.0303a03. received: may 1, 2013; accepted: june 1, 2013; published: july 31, 2013 copyright: ©2013 fischer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: b. coras-stepanek, m.d., department of dermatology, klinikum schwabing, koelner platz 1, 80804 munich, germany. tel. 0049 89 3068; fax . 0049 89 3068 3918. email: brigitte.coras@klinikum-muenchen.de. a 56-year-old man presented with tingling ulcers on the feet. on further skin examination, papules on the knees were observed. biopsies revealed extravascular eosinophilic deposits of igm, and waldenström macroglobulinaemia was diagnosed. the skin manifestations have resolved with chemotherapy. peripheral neuropathy and storage papules are rare manifestations of waldenström’s macroglobulinaemia. abstract 8 observation | dermatol pract concept 2013;3(3):3 showed a leukocytoclastic vasculitis with a neutrophilic infiltrate. storage papules were present on the knees and perianal skin. another report described igm dermal deposits that presented as painful hyperkeratotic papules on the soles of the feet that were not ulcerated [5]. on further examination, our patient had the papules of macroglobulinosis. storage papules, also known as macroglobulinaemia cutis, are rare but well described and are usually found on the knees or other extensor surfaces. they are usually skin-coloured, red-brown or translucent, and may be umbilicated, crusted or haemorrhagic. biopsy shows dermal eosinophilic hyaline material, which is igm. our patient was treated with six cycles of bendamustine infusions. after five cycles the lower limb ulceration and neurological symptoms had resolved, although the blood igm level did not change. conclusion waldenström macroglobulinaemia is a low-grade lymphoplasmacytoid lymphoma that usually presents with nonspecific systemic symptoms, but cutaneous changes may be the initial manifestation and hence may present first to a dermatologist. although our patient presented with tingling ulcers, the diagnosis was reached after skin biopsy from knee papules demonstrated dermal immunoglobulin deposition. references 1. libow lf, mawhinney jp, bessinger gt. cutaneous waldenström’s macroglobulinemia: report of a case and overview of the spectrum of cutaneous disease. j am acad dermatol. 2001; 45(6 suppl): s202-6. 2. abdallah-lotf m, bourgeois-droin c, perronne v, et al. cutaneous manifestations as initial presentation of waldenstrom’s macroglobulinemia. eur j dermatol. 2003;13(1):90-2. 3. silberman j, lonial s. review of peripheral neuropathy in plasma cell disorders. hematol oncol. 2008;26(2):55-65. 4. del olmo j, españa a, idoate ma, panizo c. waldenström macroglobulinemia associated with cutaneous lesions and type i cryoglobulinemia. actas dermosifiliogr. 2008;99(2):138-44. 5. harnalikar m, pande s, kharkar v, khopkar u. keratotic vascular papules over the feet: a case of waldenström’s macroglobulinaemia-associated cutaneous macroglobulinosis. clin exp dermatol. 2010;35(3):278-81. neoplastic cell infiltrates present as red or purple patches and plaques. in one case the patient presented with a burning red face which was initially diagnosed as rosacea but with time the more typical purple infiltration developed [2]. peripheral neuropathy is a well recognised presentation of dysproteinaemias, particularly igm [3]. in waldenström macroglobulinaemia the neuropathy is typically sensorimotor, initially with paraesthesias and numbness in the feet and hands. motor symptoms, such as weakness or foot drop, develop later. the possible mechanisms in waldenström macroglobulinaemia include microangiopathy, direct infiltration of nerves, endoneural deposition of igm protein or amyloidosis, hyperviscosity or immunoglobulin deposit in blood vessels. the tingling ulcers in our patient are probably an example of this and, although biopsies were not taken from the ulcers, may have been due to igm deposition given he also had macroglobulinaemia cutis. there has been only one other case reported, to our knowledge, of ulcers on the sides of the feet [4]. these developed in areas of hyperkeratosis and were associated with dysaesthesia and a burning sensation. however, the biopsy figure 1a. the patient presented with tingling ulcers on the feet. [copyright: ©2013 fischer et al.] figure 1b. on further examination, papules were noted on the knees. [copyright: ©2013 fischer et al.] figure1c. biopsy from a knee papule showed homogeneous extravascular eosinophilic hyaline deposits throughout the papillary and reticular dermis (h&e 40x). [copyright: ©2013 fischer et al.] figure 1d. igm stain demonstrates the extravascular igm deposits in the dermis (40x). [copyright: ©2013 fischer et al.] dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(1):e2023021 1 dermoscopy of infectious dermatoses: is it time to replace the terms “entodermoscopy” and “entomodermoscopy” with “infectiouscopy”? enzo errichetti 1 1 institute of dermatology, “santa maria della misericordia” university hospital, udine, italy citation: errichetti e. dermoscopy of infectious dermatoses: is it time to replace the terms “entodermoscopy” and “entomodermoscopy” with “infectiouscopy”? dermatol pract concept. 2023;13(1):e2023021. doi: https://doi.org/10.5826/dpc.1301a21 accepted: april 13, 2022; published: january 2023 copyright: ©2023 errichetti. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: enzo errichetti, institute of dermatology, “santa maria della misericordia” university hospital. piazzale santa maria della misericordia, 15. 33100-udine, italy. tel: (+39) 0432559822. e-mail: enzoerri@yahoo.it besides the classical use in the oncological setting, dermoscopy has showed to be helpful to assist the recognition of several non-neoplastic dermatoses (general dermatology), including inflammatory and infectious conditions [1]. the initial applications in this regard date back to 1997 and concerned parasitic infections (scabies and larva migrans), afterwards several papers on the use of dermoscopy in the field of general dermatology have progressively published, with 305 dermatoses (including relevant disease variants typified by dermoscopic peculiarities) showing at least a dermoscopic description at the end of 2020 [2]. over the time, the terms “inflammoscopy” and “entodermoscopy” (or “entomodermoscopy”) have gradually spread in the scientific community to refer to dermoscopy of inflammatory and infectious diseases, respectively, as their roots link the fields of inflammatory diseases and entomology with dermoscopy [3-4]. however, while the former denomination is still appropriate, there is a need to update the latter. in fact, the terms “entodermoscopy”/“entomodermoscopy” were initially conceived to refer to the study of parasitic dermatoses (including arthropod bites and stings) [3-4] based on the etymology of the word “entomology” (from ancient greek ἔντομον (entomon) “insect”, and -λογία (-logia) “study of”), [5] yet nowadays the use of dermoscopic assessment has expanded to many non-parasitic infections [2]. in detail, according to a literature overview about the applications of dermoscopy in general dermatology updated to the end of 2020, a total of 25 parasitoses and arthropod bites/stings turned out to have at least one dermoscopic description, which was remarkably lower than the sum of non-parasitic infections (51, with 11, 21, 19 being viral, bacterial and fungal, respectively) (a complete list is reported in table 1) [2]. interestingly, whereas the review showed only a little increase in the publication trend about parasitoses over recent times, it displayed a significant leap of articles dealing with dermoscopy of non-parasitic infections in the last few years (36 vs 9 addressing parasitoses in the time span between 2016 and 2020 – table 1), thus making this topic a promising research field in the coming future [2]. based on the foregoing, when talking about dermoscopy of infectious dermatoses, it would be reasonable to think to replace the terms “entodermoscopy” and “entomodermoscopy”, which include a limited part of the infectious spectrum of skin diseases, with “infectiouscopy”, that is an “umbrella” term as its root refers to all infectious dermatoses. 2 commentary | dermatol pract concept. 2023;13(1):e2023021 table 1. list of both parasitic and non-parasitic infections whose dermoscopic findings have been described in the literature. parasitic dermatoses* (year of first description) n=25 non-parasitic infections (year of first description) n=51 • scabies (1997) • cutaneous larva migrans (1997) • nodular scabies (2001) • tungiasis (2004) • spider leg spines skin reaction (2006) • furuncular myiasis (2007) • cutaneous leishmaniasis (2009) • phthiriasis (2009) • bullous scabies (2010) • crusted scabies (2010) • demodicosis (2010) • tick bite (2010) • trombiculiasis (2014) • wasp (hymenoptera, vespidae) stings (2014) • pediculosis corporis (2014) • dermanyssus gallinae mite cutaneous infestation (2015) • thaumetopoea pityocampa cutaneous reactions (2016) • bed bug (cimex lectularius) bites (2016) • acute cutaneous leishmaniasis (2017) • wound myiasis (2017) • disseminated strongyloidiasis (2018) • cutaneous loxoscelism (2018) • post-kala-azar dermal leishmaniasis (2018) • cydnidae pigmentation (2019) • infectious folliculitis (parasitic) (2019) • tinea nigra (2001) • tinea corporis (2004) • plane warts (2004) • common folliculitis (2004) • molluscum contagiosum (2004) • epidermodysplasia verruciformis (2006) • genital warts (2008) • verruca vulgaris (2008) • plantar warts (2009) • lupus vulgaris (2009) • pitted keratolysis (2010) • trichobacteriosis axillaris (2012) • mycetoma (2014) • cutaneous blastomycosis (2015) • pityriasis versicolor (2015) • achromic pityriasis versicolor (2016) • condylomata lata (2016) • tinea manuum (2016) • tinea of vellus hair (2016) • white piedra (2016) • pseudomonas folliculitis (2016) • contagious ecthyma (orf) (2016) • tinea incognito (2016) • staphylococcal scalded skin syndrome (2016) • disseminated cryptococcosis with cutaneous involvement (2017) • chromoblastomycosis (2017) • peruvian wart (2017) • milker’s nodule (2017 • borderline tuberculoid leprosy (2017) • syphilis (palmar syphiloderm) (2017) • histoid leprosy (2017) • pityrosporum folliculitis (2018) • sporotrichosis (2018) • tinea manuum (2018) • candidal balanitis (2018) • mycobacterium marinum skin infection (2019) • majocchi’s granuloma (2019) • infectious folliculitis (fungal) (2019) • infectious folliculitis (viral) (2019) infectious folliculitis (bacterial) (2019) • talaromyces (penicillium) marneffei infection • tuberculoid leprosy (2019) • borderline lepromatous leprosy (2019) • lepromatous leprosy (2019) • type 1 lepra reaction (2019) • type 2 lepra reaction (2019) • tuberculosis verrucosa cutis (2020) • lichen scrofulosorum (2020) • focal epithelial hyperplasia (2020) • chilblain-covid-19-like skin lesions (2020) • syphilis (penile annular syphiloderm) (2020) *including arthropod bites and stings commentary | dermatol pract concept. 2023;13(1):e2023021 3 references 1. errichetti e, zalaudek i, kittler h, et al. standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (non-neoplastic dermatoses): an expert consensus on behalf of the international dermoscopy society. br j dermatol 2020; 182:454-67. 2. errichetti e. dermoscopy in general dermatology (non-neoplastic dermatoses): the journey so far. dermatol ther (heidelb) 2021; 11:1871-7. 3. errichetti e. dermoscopy of inflammatory dermatoses (inflammoscopy): an up-to-date overview. dermatol pract concept 2019; 9:169-80. 4. tschandl p, argenziano g, bakos r, et al. dermoscopy and entomology (entomodermoscopy). j dtsch dermatol ges 2009; 7:589-96. 5. entomology. available at: https://en.wikipedia.org/wiki/entomology (last accessed 19 february 2022) dermatology: practical and conceptual 56 quiz | dermatol pract concept 2018;8(1):13 dermatology practical & conceptual www.derm101.com whitish halo on a papular pigmented lesion martina lambertini1, barbara corti2, carlotta baraldi1, maria lucia tardio2, michelangelo la placa1 1 dermatology division, university of bologna, bologna, italy 2 section of pathology, s. orsola-malpighi university hospital, bologna, italy citation: lambertini m, corti b, baraldi c, tardio ml, la placa m. whitish halo on a papular pigmented lesion. dermatol pract concept. 2018;8(1):56-58. doi: https://doi.org/10.5826/dpc.0801a13 received: february 20, 2017; accepted: november 11, 2017; published: january 31, 2018 copyright: ©2018 lambertini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. michelangelo la placa, dermatology division, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138 bologna, italy. tel. +39-051-2143880; fax +39-051-347847. e-mail: michelangelo. laplaca@unibo.it a 49-year-old healthy caucasian woman presented with a sudden change in a lesion on her abdomen. at the time of our consultation, we observed a pigmented papular lesion, 1.5 cm in diameter, surrounded by an incomplete whitish halo with two dark rounded blotches at its top (figure 1a). the patient had a fair skin phototype and chronic photoaging, characterized by atrophic skin, wrinkling, and diffuse solar elastosis, especially on the sun-exposed areas. dermoscopy showed a brownish irregularly oval plaque with a few dotted vessels and regular globules. on top of the lesion, two heavily asymmetric and pigmented blotches were visible: on the left, it was bluish and on the right side reddish (figure 1b). histopathological examination revealed a compound, predominantly intradermal melanocytic nevus with congenital features adjacent to a focal scar, suggestive of a previous trauma or surgical procedure (figure 2a). within the lesion, an expanding dermal nodule was detected, characterized by nests of epithelioid melanocytes. no nuclear cell atypia, pleomorphism, mitosis, or pagetoid spread into the epidermis was observed (figure 2b). the nodule was characterized by large melanocytes with minimal pleomorphism, without evidence of necrosis (figure 2c). the periphery of the nodule showed maturation of the melanocytes blending with the surrounding nevus. cells of the congenital nevus and cells of the dermal nodule were positive for s-100 protein and negative for hmb45. the ki-67 proliferation index was low in the congenital nevus but moderately high in the nodule, while p-16 was negative in the nodule, but positive in the remainder of the nevus. bap-1 immunohistochemistry revealed bap-1 nuclear staining (figure 2d). what is your diagnosis? figure 1. (a) clinical presentation. papular pigmented lesion measuring 1.5 cm in diameter, surrounded by an incomplete whitish halo and areas of hyperpigmentation on its top. (b) dermoscopic images revealed a regular pigmented network with two hyperpigmented blotches on its top, one bluish and one reddish, surrounded by an asymmetric vitiligoid halo. [copyright: ©2018 lambertini et al.] a b quiz | dermatol pract concept 2018;8(1):13 57 tochemical analysis was also performed in order to evaluate the loss of bap-1 expression [8-10]. in our case, ki-67 was moderately high in the pn and negative in the remaining congenital nevus, while p-16 was negative in the nodule, but positive in the remainder of the nevus. the presence of melanocyte maturation with symmetrical architecture and the presence of p-16 in the lower part surrounding the nodule did not support the criteria for malignant melanoma. bap-1 immunohistochemistry revealed bap-1 nuclear staining in the proliferative nodule, supporting the benign nature of the melanocytic proliferation [8-10]. our case is remarkable because of the patient’s age and the unusual clinical and dermoscopic features, characterized by an incomplete whitish halo corresponding to the focal scar and the reddish blotch on its top corresponding to the proliferative nodule on the left. it is possible, however, that her lesion had started primarily as a nodule, and the sudden occurrence of the depigmentation prompted the patient to seek medical advice. in conclusion, pns are typically found in childhood but may develop in much older individuals, and every rapid change on a cmn should always lead to surgical excision. figure 2. histological findings. (a) junctional and dermal melanocytic congenital nevus with a dermal nodule (hematoxylin-eosin, 4x). (b) dermal nodule with nests of typical epithelioid cells. the periphery of the nodule showed gradual loss of cell density and blended with the surrounding nevus (hematoxylin-eosin 10x). (c) high power view. large melanocytes with minimal pleomorphism and without necrosis (hematoxylin-eosin 40x). (d) bap-1 immunostaining. strong and diffuse nuclear staining in the proliferative nodule. [copyright: ©2018 lambertini et al.] answer proliferative nodule in a small congenital melanocytic nevus explanation proliferative nodules (pns) are rare melanocytic neoplasms arising in congenital melanocytic nevi (cmns) that usually have a very good prognosis but can mimic malignancy in the rapid onset and clinical features [1]. nevertheless, histological analysis can be difficult and every new proliferation arising on a cmn poses a challenge to determine the differential diagnosis from a malignant melanoma [2-6]. except for one case in a 17-year-old girl, pn proliferation has been described exclusively in newborns or during childhood [2-3]. despite the worrisome clinical morphology, characterized by a nodular or papular consistency that slowly regresses, the majority of these neoplasms are benign, confirming the extreme rarity of melanoma in infancy [2-6]. sometimes immunohistochemical analyses can be helpful, using the melanocytic markers s-100, hmb-45 or melan a and other antibodies against ki-67 and p-16 [7]. immunohis58 quiz | dermatol pract concept 2018;8(1):13 6. vergier b, laharanne e, prochazkova-carlotti m, et al. proliferative nodules vs. melanoma arising in giant congenital melanocytic nevi during childhood. jama dermatol. 2016;152(10):11471151. 7. herron md, vanderhooft sl, smock k, zhou h, leachman sa, coffin c. proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. am j surg pathol. 2004;28(8):1017-1025. 8. piris a, mihm mc jr, hoang mp. bap1 and brafv600e expression in benign and malignant melanocytic proliferations. hum pathol. 2015;46(2):239-245. 9. uguen a, uguen m. about braf mutations and p16 expression in melanomas associated with blue nevi or mimicking cellular blue nevi. am j surg pathol. 2016;40(6):857. 10. busam kj, sung j, wiesner t, von deimling a, jungbluth a. combined braf(v600e)-positive melanocytic lesions with large epithelioid cells lacking bap1 expression and conventional nevomelanocytes. am j surg pathol. 2013 feb;37(2):193-199. references 1. bastian bc, xiong j, frieden ij, et al. genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. am j pathol. 2002;161(4):1163-1169. 2. lowes ma, norris d, whitfeld m. benign melanocytic proliferative nodule within a congenital naevus. austral j dermatol. 2000;41(2):109-111. 3. kiyohara t, sawai t, kumakiri m. proliferative nodule in small congenital melanocytic naevus after childhood. acta derm venereol. 2012;92(1):96-97. 4. nguyen tlt, theos a, kelly dr, busam k, andea aa. mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall. am j dermatopathol. 2013;35(1):e16-21. 5. christou em, chen ac, sugo e, barbaric d, wargon o. proliferative nodules of undifferentiated spindle cells arising in a large congenital melanocytic nevus. austral j dermatol. 2014;55(2):e24e28. https://www.ncbi.nlm.nih.gov/pubmed/?term=vergier%20b%5bauthor%5d&cauthor=true&cauthor_uid=27486690 https://www.ncbi.nlm.nih.gov/pubmed/?term=laharanne%20e%5bauthor%5d&cauthor=true&cauthor_uid=27486690 https://www.ncbi.nlm.nih.gov/pubmed/?term=prochazkova-carlotti%20m%5bauthor%5d&cauthor=true&cauthor_uid=27486690 https://www.ncbi.nlm.nih.gov/pubmed/?term=bastian%20bc%5bauthor%5d&cauthor=true&cauthor_uid=12368190 https://www.ncbi.nlm.nih.gov/pubmed/?term=xiong%20j%5bauthor%5d&cauthor=true&cauthor_uid=12368190 https://www.ncbi.nlm.nih.gov/pubmed/?term=frieden%20ij%5bauthor%5d&cauthor=true&cauthor_uid=12368190 dermatology: practical and conceptual opinion | dermatol pract concept. 2023;13(1):e2023013 1 virtual resident education with the dermatologic society of greater new york during the covid-19 pandemic shweta shukla1, jason cohen2, george han3, roger ho4, vitaly terushkin5, shari r. lipner5 1 suny downstate medical center, brooklyn ny, usa 2 dermpath diagnostics, white plains ny, usa 3 mount sinai hospital, manhattan ny, usa 4 new york university, manhattan ny, usa 5 department of dermatology, weill cornell medicine, new york, usa citation: shukla s, cohen j, han g, ho r, terushkin v, lipner sr. virtual resident education with the dermatologic society of greater new york during the covid-19 pandemic. dermatol pract concept. 2023;13(1):e2023013. doi: https://doi.org/10.5826/dpc.1301a13 accepted: may 2, 2022; published: january 2023 copyright: ©2023 shukla et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: shari r. lipner md, phd, new york university 1305 york avenue, 9th floor, manhattan, ny 10021, 646-962-3376 e-mail: shl9032@med.cornell.edu technology has grown exponentially in this past decade, with a plethora of virtual communities for socializing, emotional support, online purchases, but few opportunities for virtual medical education [1]. prior to the covid-19 pandemic, dermatology continuing medical education opportunities for both residents and board-certified dermatologists had been predominantly in-person experiences, limited to those with the time and means to attend these events. conferences for major dermatology organizations had always been held in-person until recently. many residents were previously unable to attend educational conferences due to limited academic time, clinical coverage, and cost. however, due to covid-19, many groups, including the dermatologic society of greater new york (dsgny), have been forced to adapt to the changing landscape. the covid-19 pandemic has resulted in far-reaching changes in resident education. in a survey-based study, 60% of dermatology residents reported that covid-19 had negatively impacted their education, with cancelled or postponed lectures and reduced patient volume in clinic [2]. in a survey-based study performed during the pandemic, 80% of residents reported high levels of anxiety regarding the american board of dermatology (abd) certification examination and employment opportunities [3]. on the other hand, in a nationwide survey-based study, 99% of dermatology residents reported that virtual didactics were beneficial during the peak of the pandemic in april 2020 [4]. thus, covid-19 has brought about a unique opportunity to dramatically transform resident education and the dsgny was one of the first dermatology societies to embrace that change. dermatopathology education may pose the greatest obstacle to remote learning. prior to the pandemic, residents typically learned at the microscope by observing dermatopathology signouts [5]. however, with many residents having 2 opinion | dermatol pract concept. 2023;13(1):e2023013 limited rotations in dermatopathology, there have been significant disruptions due to the pandemic. in 2020, the abd changed the testing format from utilizing microscopic slides to digital slides for the dermatopathology component on the boards. since residents had been traditionally taught at the microscope, many residents felt unprepared for digital dermatopathology. in spring 2020, dsgny was one of the first organizations to create a free recurring dermatopathology resident education series with dr. jason cohen, a dermatopathologist at dermpath diagnostics in white plains, new york. during each session, dr. cohen reviewed 15 unknown slides with residents in an interactive format and reinforced a methodical and algorithmic approach to approaching dermatopathology slides. the group regularly reviewed high-yield diagnoses including benign adnexal neoplasms, acantholytic disorders, autoimmune blistering disease, and infections. residents asked for clarification on specific histologic findings or differentiating specific diagnoses either verbally or via chat. the residents who participated found these lectures incredibly helpful for their overall education and dermatopathology board review. over 90 residents have participated thus far. we do not know the impact of this series on board pass rates or promoting dermatology residents’ interests in pursuing dermatopathology, and these topics merit further study. our dsgny dermatopathology series highlights the benefits of virtual education. residents with limited dermatopathology didactics at their own residency programs or who wanted additional training could participate in these sessions free of cost, which is helpful on a tight resident budget. furthermore, residents who are less comfortable asking questions in real-time may feel more comfortable doing so via a virtual platform. our lecture series is scheduled weekly to monthly and thus shorter lectures may help to circumvent mental fatigue sometimes experienced at lengthy in-person conferences. residents with children who struggle with childcare are able to attend these lectures from home. our virtual dermatopathology didactics are now expanding to include additional speakers, facilitating new teaching opportunities for dermatologists not directly tied to academic institutions, and giving residents different perspectives. these lecture series are open to dermatology residents from across the united states, allowing for a unique opportunity for interactions among residents from different programs and opening the door for collaborations. residents can learn from others’ experiences and questions during teaching sessions. residents may utilize these virtual sessions as a platform for communication and inform one another of additional teaching sessions or grand rounds at their home institutions. these interactions may pave the way for cross-institutional research collaborations and dissemination of the newest findings in dermatology relevant to clinical care. it is also interesting to note that this may help residents pick up different approaches to dermatologic differential diagnosis, and gain exposure to approaching different patient populations from those which they are already familiar with. however, virtual learning does raise concerns about the negative implications of limited human contact. the practice of dermatology is highly team-based, and collegiality is an essential aspect of dermatology education and patient care. virtual learning experiences make it more difficult to have exchanges about shared patient experiences. while social distancing is necessary, we recommend that virtual networking events have small group breakouts. we are also promoting virtual one-on-one mentorship experiences between residents and attending dermatologists which will transition to in-person meetings when the time permits. thus, residents who have had limited mentoring opportunities may be able to find a mentor through our structured program. virtual dermatology education does raise privacy concerns as care must be taken to utilize online platforms that prohibit downloading of patient photos. the dsgny has played an important role in promoting resident education during this pandemic. we will continue our virtual education series for new york city dermatology residents and encourage residents from across the country to attend. we hope that this model and spirit of service may lead to similar programs nationwide, all in the interest of improving dermatology resident education. references 1. hilburg r, patel n, ambruso s, biewald ma, farouk ss. medical education during the covid-19 pandemic: learning from a distance. advances in chronic kidney disease. 2020 jun 23.2. 2. stewart cr, lipner sr. experiences of resident dermatologists during the covid‐19 pandemic: a cross‐sectional survey. dermatologic therapy. 2020 nov 24. 3. adusumilli nc, eleryan m, tanner s, friedman aj. third-year dermatology resident anxiety in the era of covid-19. journal of the american academy of dermatology. 2020 sep 1;83(3):969-71. 4. li ym, galimberti f, abrouk m, kirsner rs. us dermatology resident responses about the covid-19 pandemic: results from a nationwide survey. southern medical journal. 2020 sep 1;113(9):462-5 5. ko ln, chen st, huang jt, mcgee js, liu kj. rethinking dermatology resident education in the age of covid‐19. international journal of dermatology. 2020 dec;59(12):1539. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):6 35 dermatology practical & conceptual www.derm101.com case report a 34-year-old male patient with no relevant medical history presented at the hospital with facial erythema and desquamation accompanied by a pruritic sensation that had appeared two years before. he had been treated with topical corticosteroids and pure aloe vera for a long time. physical examination revealed facial keratotic scaly changes with a faint erythematous background on both cheeks and the frontotemporal area (figures 1,2). at polarized-light dermoscopy, demodex tails and demodex follicular openings, erythema and non-specific scales were observed (figures 3, 4, 5). we performed a cyanoacrylate standardized skin surface biopsy (sssb) in the cheek involved, and the microscopic examination confirmed the presence of multiple viable demodex mites (figure 6). topical steroids were tapered, and aloe vera was discontinued. the patient was given ivermectin 1% cream at night, and a significant improvement was seen after two weeks (figures 7, 8). based on the clinical presentation, positive sssb examination, and positive response to anti-demodex therapy, we concluded this was a case of topical steroid induced-demodicosis. comments human demodicosis (dd) is a skin disease of the pilosebaceous units associated with human demodex, a widely usefulness of dermoscopy in the diagnosis and monitoring treatment of demodicidosis paula friedman1, emilia cohen sabban 1, horacio cabo 1 1 dermatology department, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina key words: dermoscopy, demodicidosis, standardized skin surface biopsy citation: friedman p, cohen sabban e, cabo h. usefulness of dermoscopy in the diagnosis and monitoring treatment of demodicidosis. dermatol pract concept. 2017;7(1):6. doi: https://doi.org/10.5826/dpc.0701a06 received: august 13, 2016; accepted: october 17, 2016; published: january 31, 2017 copyright: ©2017 friedman et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: paula friedman, md, 2562 arcos st, 2nd floor, buenos aires, argentina. tel. +0541158406476. email: paufriedman@gmail.com demodicidosis is a common infestation and should be considered in the differential diagnosis of recurrent or recalcitrant perioral dermatitis or rosacea-like eruptions of the face. we report on a 34-year-old male, who presented with facial erythema and desquamation accompanied by a pruritic sensation. dermoscopic examination revealed demodex tails and demodex follicular openings, both specific features of this entity. microscopically, standardized skin surface biopsy test was pathogenic and the patient had positive response to anti-demodectic drugs. to our knowledge, a few reports of the dermatoscopic features of demodicidosis have been published in the literature. dermoscopy offers a potential new option for a real-time validation of demodex infestation and a useful tool for monitoring treatment. abstract 36 observation | dermatol pract concept 2017;7(1):6 follicles become heavily infested, or when the mites penetrate the dermal tissue [1,2]. clinical manifestations include a group of eruptions known ectoparasitic mite, involving mainly the face and head. although it is controversial, this mite is thought to play a pathogenic role in humans. symptoms may develop when the figure 6. standardized skin surface biopsy. microscopic visualization of demodex folliculorum (original magnification 40x). [copyright: ©2017 friedman et al.] figure 1. facial spinulosis (roughness) over an erythematous background. [copyright: ©2017 friedman et al.] figure 2. facial erythema and desquamation on both cheeks and frontotemporal area. [copyright: ©2017 friedman et al.] figure 3.  dermoscopic picture: demodex ‘‘tails” (arrow), demodex ‘‘follicular openings” (star), filaments protruding out of follicular openings (circle), erythema and non-specific scales. [copyright: ©2017 friedman et al.] figure 4.  dermoscopic picture: demodex ‘‘tails” (arrow), demodex ‘‘follicular openings” (star) and non-specific scales. [copyright: ©2017 friedman et al.] figure 5. dermoscopic picture: demodex ‘‘tails” (arrow), demodex ‘‘follicular openings” (star). [copyright: ©2017 friedman et al.] observation | dermatol pract concept 2017;7(1):6 37 applying topical corticosteroids for a long period, so we concluded this was a case of secondary dd due to topical steroid therapy [3]. the most important differential diagnoses are papulopustular or erythematotelangiectatic rosacea and seborrheic dermatitis (table 2). folliculitis, perioral dermatitis, contact dermatitis and acne can also be included [4,5]. our case is an example of how dermoscharacterized by variable degrees of spinulosis (roughness of the skin), erythema, papules, and pustules, usually accompanied by a burning or pruritic sensation. primary dd is characterized by the absence of preexisting or concurrent inflammatory dermatoses. an abnormal increase of demodex mites in patients with other known dermatoses or diseases can be classified as secondary dd (table 1). our patient had been copy could have helped in demodicidosis recognition, since the patient was incorrectly treated with topical steroids possibly with the diagnosis of seborrheic dermatitis. however, when we evaluated the patient, dermoscopy did not reveal what would be expected for seborrheic dermatitis (dotted vessels in a patchy distribution and fine yellowish scales), but revealed, instead, features associated with demodicidosis (‘‘demodex tails’’ and ‘‘demodex follicular openings’’). the diagnosis of dd should be made based on three major criteria: the specific clinical presentation, the microscopic observation of a high density of mites and a positive response to antidemodectic drugs [6]. under dermoscopy, we observed non-follicular and perifollicular gelatinous threads or filaments protruding out of follicular openings known as “demodex tails.” they account for the presence of the mite itself. demodex follicular openings were also identified as dilated follicular openings containing round, amorphic, grayish/light brown plugs surrounded by an erythematous halo. they are both specific features of dd. the density of demodex mites can be studied by sssb, potassium hydroxide examination, skin biopsy, or a combination of these. sssb is considered to be the gold standard for diagnosis; with this method, the superficial parts of the horny follicle layer are collected and live mites can be observed on microscopic examination. a density of more than 5 mites/ follicles or 5 mites/cm2 of sssb specimen is considered to be pathogenic [7]. various therapeutic regimens have been proposed to treat dd, including acaricides— ivermectin, permethrin, crotamiton, lindano—and adjuvants, such as systemic and topical metronidazole, salicylic acid, gamma benzene hexachloride, sublimed sulfur and benzyl benzoate. both effectiveness and optimal dosage still remain to be determined. our patient was treated with ivermectin 1% cream at night for two weeks, and both physical and dermoscopic examination improved. figure 8. dermoscopic pictures before (a) (b) (c) and after treatment (d). [copyright: ©2017 friedman et al.] a b c d figure 7. (a) (c) secondary demodicosis induced by topical corticosteroid treatment. (b) (d) rash resolved after two weeks of ivermectin 1% cream at night and a gradual tapering of topical steroid therapy. [copyright: ©2017 friedman et al.] a b c d 38 observation | dermatol pract concept 2017;7(1):6 3. chen w, plewig g. human demodicosis: revisit and a proposed classification. br j dermatol. 2014;170(6):1219-1225. 4. kaur t, jindal n, bansal r. facial demodicidosis: a diagnostic challenge. indian j dermatol. 2012;57(1):72-73. 5. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6:471. 6. segal r, mimouni d, feuerman h. dermoscopy as a diagnostic tool in demodicidosis. int j dermatol. 2010;49(9):1018-1023. 7. aşkın ü, seckin d. comparison of the two techniques for measurement of the density of demodex folliculorum: standardized skin surface biopsy and direct microscopic examination. br j dermatol. 2010;162(5):1124-1126. conclusion dermoscopy may serve as a useful and non-invasive tool for the real-time identification of demodex infestation, evaluation and follow-up. references 1. donnelly a, kenney a, dicaudo d. demodicosis: clinical, dermatoscopic, and microscopic correlation. [abstract]. j am acad dermatol. 2013;68(4):suppl 1,ab117. 2. hsu ck, hsu mm, lee jy. demodicosis: a clinicopathological study. j am acad dermatol. 2009;60:453-462. table 1. secondary demodicosis associations. [copyright: ©2017 friedman et al.] acne perioral dermatitis papulopustular rosacea seborrheic dermatitis calcineurin inhibitors topical corticosteroids epidermal growth factor receptor inhibitors phototherapy melanocytic nevi eyelid basal cell carcinoma mycosis fungoides systemic diseases (chronic renal failure) leukemia hiv infection table 2. differential diagnosis for demodicosis—dermoscopic clues. [copyright: ©2017 friedman et al.] demodicidosis seborrheic dermatitis rosacea ‘‘demodex tails’’ ‘‘demodex follicular openings’’ dotted vessels in a patchy distribution fine yellowish scales erythematotelangiectatic rosacea linear vessels characteristically arranged in a polygonal network papulopustular rosacea linear vessels characteristically arranged in a polygonal network follicular pustules dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual or educational note | dermatol pract concept 2014;4(2):5 29 introduction gross and microscopic criteria are morphologic and thus subjectivity abounds for the pathologist in the diagnosis of benign and malignant melanocytic proliferations [1]. the state-of-the-art criteria, often touted to be definitive, delineates between benign and malignant conditions clinically and histopathologically. this issue becomes murky, however, when the same criteria, on occasion, are present in both benign and malignant entities. this twist of fate is commonly referred to as overlapping criteria. this is exemplified frequently in benign melanocytic proliferations, i.e., melanocytic nevus and its variants (so-called combined nevus, spitz’s nevus, juvenile melanoma, dysplastic nevus, atypical nevus, nevus with architectural disorder and sever/moderate cytologic atypia, deep penetrating nevus, reed’s nevus, spindle-cell tumor, pre-melanoma, borderline melanoma, and recurrent/persistent melanocytic nevus, all of which are nothing more than a benign melanocytic nevus with findings focal common to those of the infamous melanoma. overlapping criteria in benign and malignant melanocytic proliferations are well known and expected findings [1-3]. because of the confusion that overlapping criteria create, it is essential to separate those proliferations truly benign from those that are in fact malignant. furthermore, it is important, if not imperative, to recognize the degree of criteria, i.e., mild, moderate or extensive. in other words, is the criterion or criteria, an occasional finding, focal, isolated, or diffuse? what is the degree of criteria? is it just happenstance, and does it matter? this is the question. the assessment of the degree of criteria is of the essence in order to arrive at an accurate diagnosis and avoid a misdiagnosis. discussion the spectrum of criteria to differentiate a melanocytic nevus from melanoma is variable. clinically, the criteria are few in number and include asymmetry, border, color, and diameter. however, many of the acknowledged criteria for the clinical diagnosis for melanoma may be found in other benign or malignant proliferations, such as melanocytic nevus, seborrheic keratosis, hemangioma, adnexal proliferations, basal and squamous-cell carcinoma, and lymphoma, to mention but a few. however, microscopically the criteria for melanoma are diverse and at times perplexing. they include asymmetry, poor circumscription, cellular/nuclear jumbling or crowding, atypia, pleomorphism, nuclear hyperchromatic and heterochromasia, increased small and/or large nuclei, large nucleoli, mitoses (typical and atypical), lack of maturation of solitary melanocytes and aggregations of melanocytes with progressive descent into the dermis, single cells predominate over aggregates of melanocytes within the epidermis, scatter of melanocytes within the upper spinous layer, atypical and typical pagetoid cells, pagetoid cells in pagetoid pattern, aggregates of melanocytes with bizarre shapes and confluence with pseudoacantholysis. the above criteria alone are not definitive for a diagnosis of melanocytic nevi and melanoma: overlapping criteria—the degree is the key robert m. hurwitz1, larry j. buckel1, don-john summerlin1 1 cutaneous and maxillofacial pathology laboratory, pc, indianapolis, in, usa citation: hurwitz rm, buckel lj, summerlin dj. melanocytic nevi and melanoma: overlapping criteria—the degree is the key. dermatol pract concept. 2014;4(2):5. http://dx.doi.org/10.5826/dpc.0402a05 copyright: ©2014 hurwitz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. robert m. hurwitz, m.d., larry j. buckel, m.d., and don-john summerlin, d.m.d., contributed significantly to this publication. corresponding author: robert m. hurwitz, md, cutaneous and maxillofacial pathology laboratory, pc, 9292 north meridian street, suite 210, indianapolis, in 46260, usa. tel. 317-403-7572. email: bobbyhur@aol.com. mailto:bobbyhur@aol.com 30 practical, conceptual or educational note | dermatol pract concept 2014;4(2):5 melanoma because on occasion, if not repeatedly, they may be found in some benign melanocytic nevi. therefore, it is crucial to consider the degree of the findings. in other words, the finding of a single, isolated criterion, which may occur in figure 1. melanocytic nevus on the back of a 22-year-old female. (a & b) (h&e) there are nests of melanocytes with relatively small roundoval nuclei, some with prominent pale staining cytoplasm, typical pagetoid cells, within the epidermis at the dermoepidermal junction and within the thickened papillary dermis. focally, there is a scatter of solitary melanocytes within the upper spinous layer of the epidermis above the dermoepidermal junction, as well as maturation of melanocytes from the epidermis and dermis of typical pagetoid cells with loss of its prominent cytoplasm. (c & d) melan a outlines the solitary and nested melanocytes. focally there are scattered solitary melanocytes above the dermoepidermal junction within the upper spinous layer. [copyright: ©2014 hurwitz et al.] a b c figure 2. melanocytic nevus on the back of a 60 year-old male. (a) (h&e) there are round and elongated confluent nests of melanocytes along with crowded solitary melanocytes with monomorphous small, round-oval nuclei with paltry cytoplasm, at the dermoepidermal junction and upper spinous layers of the infundibulum and surface epidermis. (b) melan a outlines solitary, crowded and nested melanocytes, some confluent, as well as focally scattered solitary, monomorphous small round-oval melanocytes with paltry cytoplasm within the upper spinous layer of the epidermis and infundibulum. [copyright: ©2014 hurwitz et al.] a b d practical, conceptual or educational note | dermatol pract concept 2014;4(2):5 31 melanocytic nevus, or extensive criteria in multiple locations, which commonly occur in a melanoma, allows for the differentiation of melanocytic nevus from melanoma (figures 1, 2, 3). nonetheless, a melanocytic nevus biopsied shortly after birth is well known to have criteria consonant with melanoma. in addition, a specific anatomic site of a melanocytic proliferation is referred to as a special site. melanocytic nevi on special sites may have histopathologic finding similar to those of a melanoma. special sites include areas such as the palm and sole, genitalia, perianal, buttocks, umbilicus, breast, ear, scalp, and regions intertrigenous. to boot, traumatized melanocytic nevi and persistent melanocytic nevi commonly and often regularly have comparable criteria to a melanoma. oftentimes, the criteria on special sites, traumatized and persistent melanocytic nevi are present in a mild, moderate or widespread degree, e.g., focal and/or diffuse scatter of solitary and/or nested melanocytes above the dermoepidermal within the upper spinous layers, nuclear crowding with atypia in areas especially with excoriation, ulceration, scale-crust, or scarring. accordingly, in view of the foregoing, it is essential to be knowledgeable of special sites, persistent melanocytic nevi, as well as the effects of trauma on a melanocytic nevus, to avoid a misdiagnosis. furthermore, it is worthy to acknowledge that, without a doubt, the relevance of subjectivity of the diagnosis by pathologists, especially in controversial melanocytic lesions, results in part in the totality of our attitudes and emotions. we are personally influenced, in addition to our degree of diagnostic threshold, by our indoctrination into the various aspects of controversial melanocytic neoplasia. the influence, of course, is predicated upon our enthusiasm and bias, as well as that of our mentors. during and after formal training, one’s mentor may emphasize or diminish subjective morphologic findings, which influence and prejudice our acceptance or rejection of one criterion over another, especially over the degree of criteria. the result, at times, may be the over-diagnosis or the misdiagnosis of melanoma. this event is painfully evident in those thorny, demanding, controversial and problematical melanocytic lesions, which as a consequence of the foregoing, for sure, are expected to be logically and understandably a b c d figure 3. melanoma on the cheek of a 94 year-old female. (a) (h&e) there are nested and solitary crowded atypical melanocytes with small and large round hyperchromatic nuclei, some with increased pale cytoplasm, scattered within the spinous layer at and above the dermoepidermal junction of the hyperplastic epidermis and infundibulum that houses scale-crust. (b) melan a outlines solitary and nested, crowded, confluent, atypical melanocytes. (c) (h&e) crowded solitary and nested confluent atypical melanocytes within the ulcerated and crusted surface epidermis and infundibulum overlying dermal severe solar elastosis, patchy lymphocytes and numerous melanophages. (d) melan a outlines confluent nests of crowded solitary atypical melanocytes within infundibulum and epidermis. [copyright: ©2014 hurwitz et al.] 32 practical, conceptual or educational note | dermatol pract concept 2014;4(2):5 defensible, especially and regularly in medico-legal issues [5]. to be precise, overlapping criteria and the various range of degree of criteria, as a consequence, expose the practice of medicine and pathology for what they are: an ever changing, imperfect as well as a vexing science. certainly, our individual concepts, views, beliefs and bias formed during and after our formal educational process (which by the way never ends) are significantly affected and powerfully influenced by our own and our mentor’s interest and zeal, and how! summary summing up, the concept of the degree of criteria is the key to overlapping subjective criteria in melanocytic proliferations. this is the lesson to be learned. although criteria that are used to come to a diagnosis of melanoma are well known and as a whole accepted, it is the degree or number or quantity of criteria, that is a few or many, that are vitally important, and at times crucial to arrive at the correct diagnosis of melanocytic nevus or melanoma. until the time when there is a definitive litmus test to differentiate a melanocytic nevus from a melanoma with absolute certainty, the degree of overlapping criteria will remain essential, even though misdiagnoses will, from time to time, continue to occur. fittingly, the words of the late a. bernard ackerman, m.d., who during his career was incredibly unrestrained and exceptionally passionate on the subject of melanocytic neoplasia, are to the point: “the effort here at characterization accurate of the changes is defensible, but not verifiable! it being subjective, as are all judgments predicated on observations morphologic” [6]. references 1. ackerman ab, cerroni l, kerl h. pitfalls in histopathologic diagnosis of malignant melanoma. lea & febiger, philadelphia, 1994. 2. hurwitz rm, atypical or typical pagetoid cell: a subtle clue to differentiate a melanoma from a melanocytic nevus. dermatol pract concept. 2013;3(2):3. 3. hurwitz rm, buckel lj. superficial congenital compound melanocytic nevus. another pitfall in the diagnosis of malignant melanoma. dermatol surg. 1997;23:897-900. 4. ackerman ab, elish d, shami s. “spitz’s nevus”: reassessment critical, revision radical. new york city: ardor scibendi, ltd., 2007. 5. hurwitz rm, summerlin dj. malpractice. has the rage become an inquisition? j drugs dermatol. 2007;6(10):977. 6. “quiz 648”. derm101.com. website. accessed november 19, 2013. http://www.derm101.com/quiz/quiz-648/study-by-case/1/ dermatology: practical and conceptual observation | dermatol pract concept 2017;7(3):10 47 dermatology practical & conceptual www.derm101.com introduction merkel cell carcinoma (mcc) is a highly malignant and uncommon neuroendocrine tumor of the skin. polyomavirus infection and ultra-violet light exposure are known etiological factors in this cutaneous malignancy [1]. mcc has an aggressive behavior with early metastases and frequent recurrences [2]. it often develops on chronically sun-damaged skin, particularly on the head and neck of elderly patients [3]. mcc commonly presents clinically as a rapidly growing shiny erythematous or violaceous papule, plaque or nodule. due to its non-specific clinical appearance, mcc is frequently overlooked or misdiagnosed and it is not uncommon that the histopathologic diagnosis of mcc takes the dermatologist by surprise [3]. dermoscopic assessment of vascular structures in solitary small pink lesions—differentiating between good and evil shamir geller1, melissa pulitzer2, mary sue brady3, patricia l. myskowski1 1 dermatology service, department of medicine memorial sloan kettering cancer center and weill cornell medical college, new york, ny, usa 2 department of pathology, memorial sloan kettering cancer center and weill cornell medical college, new york, ny, usa 3 department of surgery, memorial sloan kettering cancer center and weill cornell medical college, new york, ny, usa key words: dermoscopy, merkel cell carcinoma citation: geller s, pulitzer m, brady ms, myskowski pl. dermoscopic assessment of vascular structures in solitary small pink lesions— differentiating between good and evil. dermatol pract concept 2017;7(3):10. doi: https://doi.org/10.5826/dpc.0703a10 received: february 27, 2017; accepted: april 11, 2017; published: july 31, 2017 copyright: ©2017 geller et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part through the nih/nci cancer center support grant p30 ca008748. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: shamir geller, md, dermatology service, memorial sloan kettering cancer center, 16 east 60th street, new york, ny 10022, usa. tel. 646 888 6032. email: shamirgeller@gmail.com the diagnosis of a single small pink papule poses a real challenge to the clinician, as the differential diagnosis of such lesions includes benign entities such as a neurofibroma or hemangioma, as well as aggressive and potentially fatal skin malignancies such as amelanotic melanoma or merkel cell carcinoma (mcc). the absence of a benign vascular pattern and the presence of atypical vascular features under dermoscopy direct the clinician to proceed to histologic evaluation in order to rule out a malignant process in such lesions. the diagnosis of mcc is particularly problematic, given that this tumor usually lacks specific clinical diagnostic features. low clinical suspicion for mcc may result in delayed diagnosis and poor outcomes. the dermoscopic features of mcc are also non-specific, most commonly including milky-red areas and linear irregular vessels. we report a patient who presented with two discrete pink papules on different digits that appeared three years apart. dermoscopy helped to diagnose a harmless hemangioma in the first lesion, and a mcc in the latter. the malignant tumor was diagnosed and excised expeditiously, with no evidence of metastatic spread. abstract https://doi.org/10.5826/dpc.0703a10 mailto:shamirgeller@gmail.com 48 observation | dermatol pract concept 2017;7(3):10 three years later, the patient returned for another followup visit at which time she pointed out a new red papule on the dorsal middle digit of her left hand. three months earlier she had noticed a small red “dot” on her finger that gradually grew in size to a 3 mm papule. on physical exam, an erythematous shiny red papule was identified. dermoscopic examination of the papule showed linear irregular blood vessels (figure 1b). the rest of the patient’s skin was of normal appearance, and no lymphadenopathy was present. a biopsy of the lesion demonstrated a cutaneous neuroendocrine (merkel cell) carcinoma (figure 2). immunohistochemical stains were positive for ck20 and merkel cell polyomavirus, supporting the diagnosis. the patient was referred for a complete excision of the digital tumor and a sentinel lymph node biopsy. at resection there was no evidence of residual or metastatic disease, demonstrating early (stage ia) disease [13]. discussion the diagnosis of a single pink papule can be extremely challenging for the clinician. most pink papules are banal benign skin lesions. rapid growth, ulceration, or pain are several studies have aimed to characterize the dermoscopic appearance of mcc, however no specific pattern has been identified [4-8]. atypical vascular structures were found to be of the most diagnostic significance in mcc, most commonly linear irregular vessels and milky-red areas [6]. these dermoscopic findings are not specific and can be found in other types of cutaneous malignancies such as hypomelanotic / amelanotic melanoma [9] and melanoma metastasis [10], skin metastases from solid tumor [11], and other skin tumors [7]. case report a 74-year-old caucasian female has been followed by our clinic for more than ten years after a diagnosis in 2005 of a cd4+ small/medium pleomorphic t-cell lymphoma. in 2013 the patient presented with an erythematous papule on the second finger of her right hand. dermoscopic examination of the lesion revealed red-purple lacuna suggestive of a hemangioma [12] (figure 1a). because of the patient’s history of cutaneous t-cell lymphoma, a skin biopsy was performed, and the diagnosis of hemangioma was confirmed histologically. the lesion completely regressed after the biopsy was taken. figure 1. clinical presentation (upper pictures) and dermoscopic appearance (lower pictures) of two digital pink papules appearing three years apart. (a) a solitary pink papule on the lateral aspect of the second digit on the right hand with red-purple lacunes under dermoscopic examination, compatible with a hemangioma. (b) a pink solitary papule on the dorsal aspect of the third finger on the left. dermoscopy shows linear irregular blood vessels with a diffuse milky-white background. [copyright: ©2017 geller et al.] observation | dermatol pract concept 2017;7(3):10 49 structures on dermoscopy as the only clue of the alarming diagnosis [9]. a linear irregular vascular pattern consists of straight vessels of irregular shape, size, and distribution. it is a wellknown dermoscopic feature in skin tumors and has been described in multiple cutaneous malignancies that appear as pink or skin-colored lesions [7,9,11]. linear irregular vessels correlate with small diameter, abnormally structured and heterogeneously dense blood vessels that are seen in the context of tumor angiogenesis [15]. in amelanotic and hypomelanotic melanoma, a predominance of linear irregular vessels on dermoscopy has been reported to have a sensitivity of 34% and a specificity of 80% for melanoma [9]. vascular structures also predominate the appearance of amelanotic cutaneous melanoma metastases under dermoscopy, in which irregular linear vessels are identified in 45% of lesions [10]. similarly, cutaneous metastases of solid tumors often present with a vascular dermoscopic pattern, with linear irregular vessels seen in 77% [11]. linear irregular vessels can also be identified in other uncommon skin tumors such as adnexal tumors as well as in mcc [7,8]. clinical features that suggest a malignant process, though such clues are not always present. dermoscopy is a useful diagnostic aid in approaching such lesions, as it elucidates the morphology and distribution of blood vessels and other features such as white shiny structures that may focus the differential diagnosis [14]. in small pink lesions such as a hemangioma, the diagnosis can be made by identifying the dominant vascular components of red lacunae, pale septae and milky-red areas that form a specific and diagnostic dermoscopic pattern. in other pink lesions, the presence of non-dominant, even subtle vascular structures seen on dermoscopy, when integrated with the overall morphologic appearance, may suggest a possible diagnosis. for example, the presence of glomerular vessels in an erythematous scaly lesion is suggestive of bowen’s disease [12]. in some cases, neither the gross morphology nor the dermoscopic features are diagnostically specific. in these cases, the presence of atypical blood vessels may prompt the clinician to perform a biopsy in order to rule out malignancy. amelanotic melanoma may present as an unremarkable pink papule that may show predominantly linear irregular and dotted vascular figure 2. histopathology of the two lesions on the fingers: (a) pink papule on the right hand (see figure 1a) shows large numbers of dilated vessels within the dermis compatible with capillary hemangioma. (b) pink papule on the 3rd finger left hand (see figure 1b) reveals dermal nodular infiltrate of small blue round-oval cells. a cluster of dilated blood vessels were noted on the upper periphery of the dermal tumor correlating with the focal linear irregular vessels seen under dermoscopy (hematoxylin and eosin stain). [copyright: ©2017 geller et al.] 50 observation | dermatol pract concept 2017;7(3):10 with guidelines for multidisciplinary management. cancer. 2007;110(1):1-12. 3. heath m, jaimes n, lemos b, et al. clinical characteristics of merkel cell carcinoma at diagnosis in 195 patients: the aeiou features. j am acad dermatol. 2008;58(3):375-381. 4. dalle s, parmentier l, moscarella e, phan a, argenziano g, thomas l. dermoscopy of merkel cell carcinoma. dermatology. 2012;224(2):140-144. 5. harting ms, ludgate mw, fullen dr, johnson tm, bichakjian ck. dermatoscopic vascular patterns in cutaneous merkel cell carcinoma. j am acad dermatol. 2012;66(6):923-927. 6. jalilian c, chamberlain aj, haskett m, et al. clinical and dermoscopic characteristics of merkel cell carcinoma. br j dermatol. 2013;169(2):294-297. 7. lallas a, moscarella e, argenziano g, et al. dermoscopy of uncommon skin tumours. australas j dermatol. 2014;55(1):53-62. 8. suárez al, louis p, kitts j, et al. clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (scc)/neuroendocrine [merkel cell] carcinoma (mcc). j am acad dermatol. 2015;73(6):968-975. 9. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-1127. 10. jaimes n, halpern ja, puig s, et al. dermoscopy: an aid to the detection of amelanotic cutaneous melanoma metastases. dermatol surg. 2012;38(9):1437-1444. 11. chernoff ka, marghoob aa, lacouture me, deng l, busam kj, myskowski pl. dermoscopic findings in cutaneous metastases. jama dermatol. 2014;150(4):429-433. 12. marghoob aa, usatine rp, jaimes n. dermoscopy for the family physician. am fam physician. 2013;88(7):441-450. 13. edge sb. american joint committee on cancer. ajcc cancer staging manual. 7th ed. new york: springer; 2010. 14. zalaudek i, kreusch j, giacomel j, ferrara g, catricala c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377-386. 15. nishida n, yano h, nishida t, kamura t, kojiro m. angiogenesis in cancer. vasc health risk manag. 2006;2(3):213-219. 16. ng l, beer tw, murray k. vascular density has prognostic value in merkel cell carcinoma. am j dermatopathol. 2008;30(5):442445. 17. stokes jb, graw ks, dengel lt, et al. patients with merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. j clin oncol. 2009;27(23):37723777. the dermoscopic features of mcc have been assessed in several small case series, each involving ten to 12 mcc lesions [4-6]. the most consistent dermoscopic features in these studies were milky-red areas and linear irregular blood vessels [6]. these dermoscopic vascular features are not specific to mcc and they can be found in amelanotic melanoma and other malignant skin tumors as described above. increased vascular density has been shown to be significantly associated with a worse prognosis in mcc as in melanoma [16]. while the clinical and dermoscopic identification of scale over a pink lesion with milky-red areas and linear irregular blood vessels could indicate a component of squamous differentiation in mcc [8], other attempts to correlate mcc dermoscopic features with other histopathologic components have failed [5]. however, in our case we show the correlation of linear irregular vessels noted on dermoscopy with the histopathological finding of clustered dilated vessels at the periphery of the tumor (figure 2). our case demonstrates that dermoscopic examination of mcc may provide subtle but crucial clinical clues enabling the early diagnosis of this aggressive tumor. in mcc, early detection enables expeditious treatment, and may prevent tumor progression and lead to improved survival [17]. in conclusion, dermoscopy is a helpful diagnostic tool that helps distinguish between benign and malignant tumors in patients with non-specific solitary pink lesions. the presence of linear irregular vessels in a solitary pink lesion should prompt a biopsy in order to prevent delayed diagnosis in aggressive amelanotic skin malignancies. acknowledgments: dr. shamir geller is a recipient of a supplemental grant from the american physicians and friends for medicine in israel (apf). references 1. rockville merkel cell carcinoma group. merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. j clin oncol. 2009;27(24):4021-4026. 2. bichakjian ck, lowe l, lao cd, sandler hm, bradford cr, johnson tm, wong sl. merkel cell carcinoma: critical review dermatology: practical and conceptual research | dermatol pract concept 2015;5(4):4 13 dermatology practical & conceptual www.derm101.com oral and written counseling is a useful instrument to improve short-term adherence to treatment in acne patients: a randomized controlled trial cristián navarrete-dechent1, maximiliano curi-tuma1, claudia nicklas1, consuelo cárdenas1, maría luisa pérez-cotapos1, claudia salomone1 1 department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile key words: treatment, adherence, acne, counseling, randomized controlled trial citation: navarrete-dechent c, curi-tuma m, nicklas c, cárdenas c, pérez-cotapos ml, salomone c. oral and written counseling is a useful instrument to improve short-term adherence to treatment in acne patients: a randomized controlled trial. dermatol pract concept 2015;5(4):4. doi: 10.5826/dpc.0504a04 received: july 17, 2015; accepted: september 23, 2015; published: october 31, 2015 copyright: ©2015 navarrete-dechent et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication: the acquisition, analysis, and interpretation of data, drafting and revision of the article, and final approval for publication. corresponding author: claudia salomone, md, department of dermatology, facultad de medicina, pontificia universidad católica de chile, av. vicuña mackenna 4686, macul, santiago, chile. tel. +(56 2) 354 8659 ; fax. +(56 2) 552 9974. e-mail: csalomon@uc.cl background: therapeutic success in acne patients not only depends on the appropriate selection of drugs but also on the patient’s treatment adherence or compliance. lack of adherence is an important problem both in general medicine and in dermatologic practice. objective: to evaluate the impact of oral and written counseling on treatment adherence among acne patients. patients and methods: eighty patients were randomized into two groups of 40 patients each. the intervention group received a patient information leaflet (apart from oral counseling), and instructions were reinforced by a telephone call within 15 days of treatment onset. the second group (control group) received treatment indications as usual (oral counseling in-office only). both groups were followed up with a phone call, evaluating adherence to treatment according to self-reporting of patients at 30, 60, 90 days, and 6 months. results: better adherence to treatment was observed in the intervention group. this difference was significant only within the first month of treatment (80% versus 62%, p = 0.043). the beneficial effect of written counseling plus a phone call decreased in subsequent months. conclusion: written counseling significantly improves adherence within the first month of treatment. these results suggest that it is reasonable to spend time and resources in written counseling in order to optimize adherence to treatment. abstract mailto:csalomon@uc.cl 14 research | dermatol pract concept 2015;5(4):4 to remind patients about treatment, give counseling, and give a chance to answer questions. the evaluation of results was done with a telephone survey, without blinding, at 30, 60, 90 days, and 6 months after the first evaluation. this survey evaluated patient self-report of treatment adherence in four categories: (1) used every day, (2) used almost every day, (3) sometimes used, and (4) never used treatment. they were again rearranged into two categories: (a) good adherence: category 1 and (b) poor adherence: categories 2, 3 and 4. intervention effect was evaluated as “rate of good-adherence” (treatment used every day). at the 6-month follow-up, an elective control was offered to all patients to evaluate efficacy of treatment. a blind evaluator did analysis by intention to treat (itt). the spss (version 16.0.1) program and the mann-whitney u nonparametric test were used for statistical analysis. p-value < 0.05 was considered significant. results forty patients were included in cg, and 40 patients in the ig. seventy-one patients completed the study and 9 patients were lost from follow-up: 5 from the ig and 4 from the cg. groups had similar baseline characteristics (age, sex, severity and type of acne, site of involvement, type of treatment (topical vs systemic) and acne duration) (table 1). educational level was also similar in both groups. at 1-, 2-, 3and 6-month follow-up an overall of 70%, 51%, 46% and 34%, respectively, of patients reported good adherence. ig verintroduction acne has similar negative effects as chronic systemic diseases on mental, social health and on the patient’s quality of life [1]. therapeutic success not only depends on the appropriate selection of drugs, but also on the patient’s treatment adherence or compliance [2]. adherence is defined as the extent to which a patient’s medication use and behavior matches or is consistent with the physician’s prescriptions or whether the patient uses his/her treatment according to the assigned regimen [2]. lack of adherence is an important problem both in general medicine and in dermatologic practice [3,4]. despite this, few studies are available to evaluate a patient’s adherence to treatments or prescriptions. we evaluated the impact of oral and written counseling on acne patients’ adherence to treatment. methods a randomized controlled trial was done between november 2008 and february 2009 in our department. we included 80 patients referred for evaluation and treatment of acne that agreed to participate in the study. they were randomized into two groups with a blind sequence of codes in a 1:1 proportion. the control group (cg) received oral counseling: education about pathophysiology of acne, treatment details and emphasis in treatment adherence. the intervention group (ig) received the same oral counseling, a patient information leaflet, and a phone call at day 15 after treatment initiation table 1. clinical and demographic characteristics of the study population [copyright: ©2015 navarrete-dechent et al.] intervention group control group p-value age (years) 17.2 (3.91) 18.23 (4.78) p=0.756 sex (male) 20 (50%) 25 (56%) p=0.148 acne severity: p=0.107 comedogenic 9 (22.5%) 4 (10%) mild inflammatory 21 (52.5%) 18 (45%) moderately inflammatory 8 (20%) 17 (42.5%) severe inflammatory 2 (5%) 1 (2.5%) site of involvement: face 39 (97%) 38 (95%) p=0.5 thorax anterior 14 (35%) 15 (37%) p=0.5 back 22 (55%) 22 (55%) p=0.589 treatment modality: topical treatment 38 (95%) 38 (95%) p=0.692 systemic treatment 15 (37%) 16 (40%) p=0.5 acne duration (years): 2.5 (1.93) 2.98 (2.9) p=0.459 research | dermatol pract concept 2015;5(4):4 15 similar to what is described in the literature with an overall 34% treatment adherence at 6-month follow-up, with no differences between ig and cg. however, these results should be interpreted with caution: there is a possibility of information bias, as the study outcome was not assessed blindly to the exposure. also, we observed a tendency to an improvement in adherence at the 2and 3-month follow-up in the ig compared to the cg. despite this, the results were not statistically significant. good adherence could help to obtain more effective treatments [9]. in our study, the patients reporting good adherence had better follow-up attendance, higher perception of improvement and a better quality of life. this data should be read carefully, as this is another potential source of bias: the evaluation of the therapeutic response included subjects that attended “electively” their follow-up visits and did not include all the subjects included in the study. it is probable that patients attending this “elective” visit were those who had greater improvement, tolerance, and probably better adherence than those who did not attend this final follow-up visit. in order to decrease the risk of bias, future investigations should include all patients in the study in the follow-up visit. another drawback of our study is that the evaluation of adherence (main outcome) was based exclusively on patients’ “self-report.” new ways of evaluating adherence to treatments include electronic monitors (automatic indicators located in pill boxes or cream dispensers with memory/ records on how many times they were opened or “squeezed”). nolan and friedman elegantly described how patients may tell us how they used their medicines (“i used it religiously”); however, it is usually overstated, as comparing the patient’s diary with the electronic devices monitoring real adherence in research studies show [10]. some examples include the medication event monitoring system cap (mems, aardex group, sion, switzerland) that has the ability to record the sus cg reported good adherence at 1-, 2-, 3and 6-month follow-up was 80% versus 62% (p=0.043); 56% versus 51% (p=0.41); 56% versus 38% (p=0.087); and 37% versus 32% (p=0.4), respectively (figure 1). good adherence was associated with use of oral treatments (p=0.021); attending regular follow up visits (p=0.021); increased perception of adverse events: mainly erythema (p=0.046); and a high perception of acne improvement (p=0.064). this high perception of acne improvement was associated to less “feelings of shame” (p=0.001); less use of coverage cosmetics and clothes (p=0.046); and less changes in social life (p=0.03). twenty-two out of the 80 patients (27.5%) attended the 6-month elective follow-up visit, with an overall rate of 73% clinical improvement, without significant differences between groups (p=0.583). patients who reported “good adherence” at the first month had a tendency for a greater improvement of their acne: 86% compared with a 43% improvement in the group reporting “poor adherence” at the first month (p=0.064). the patients’ main reason for poor adherence was, according to them, “forgetfulness and desertion” (50%; figure 2). discussion adherence to medical prescriptions is essential for a treatment’s success. treatment adherence in acne patients has been reported as ranging from 12.5 to 65% [5]. interventions to improve adherence to treatment in acne patients are not well defined [6,7,8]. in our study, treatment adherence was significantly higher in the first month in the ig compared to the cg (80% vs. 60% respectively), supporting our hypothesis that adherence could be improved with clinical interventions such as patient information leaflets and a phone counseling. nevertheless, this effect seemed to decrease over time, with a 56% of good adherence at 3-month follow-up in the ig, figure 1. reported good adherence percentages in the three months of follow-up (reported as everyday use of treatment); “*” indicates statistically significant differences (p < 0.05). [copyright: ©2015 navarrete-dechent et al.] figure 2. patient self-reported causes of “poor of adherence.” [copyright: ©2015 navarrete-dechent et al.] 16 research | dermatol pract concept 2015;5(4):4 moderate or severe atopic dermatitis on maintenance therapy: the conda-sat study. actas dermosifiliogr 2013;104:409-17. pmid: 23665434 doi: 10.1016/j.adengl.2013.04.004 4. puig l, carrascosa jm, belinchón i, et al. adherence and patient satisfaction with topical treatment in psoriasis, and the use, and organoleptic properties of such treatments: a delphi study with an expert panel and members of the psoriasis group of the spanish academy of dermatology and venereology. actas dermosifiliogr 2013;104:488-96. pmid: 23395400 doi: 10.1016/ j.ad.2012.12.005 5. jones-caballero m, pedrosa e, peñas pf. self-reported adherence to treatment and quality of life in mild to moderate acne. dermatology 2008; 217:309-14. pmid: 18714158 doi: 10.1159/00015144 6. koch pe, ryder hf, dziura j, njike v, antaya rj. educating adolescents about acne vulgaris: a comparison of written handouts with audiovisual computerized presentations. arch dermatol 2008;144:208-14. pmid: 18283177 10.1001/archdermatol. 2007.35 7. yentzer ba, gosnell al, clark ar, et al. a randomized controlled pilot study of strategies to increase adherence in teenagers with acne vulgaris. j am acad dermatol 2011;64:793-5. pmid: 21414505 doi: 10.1016/j.jaad.2010.05.008 8. boker a, feetham hj, armstrong a, purcell p, jacobe h. do automated text messages increase adherence to acne therapy? results of a randomized, controlled trial. j am acad dermatol 2012;67:1136-42. pmid: 22521201 doi: 10.1016/j.jaad. 2012.02.031 9. macedo o. “got sick, got a gift”: a new tool for optimizing adherence to acne therapy [abstract]. j am acad dermatol 2011; 64:ab13. 10. nolan bv, friedman sr. adherence, the fourth dimension in the geometry of dermatological treatment. arch dermatol 2009;145:1319-21. pmid: 19917965 doi: 10.1001/archdermatol. 2009.259 date and time of every opening/closing of the medication cap and that can be attached to any cream tube for studies [8]. we encourage clinicians to use written counseling during follow-up visits. “phone counseling” is also an effective alternative for improving a patient’s treatment adherence. these two interventions seem very reasonable, given the fact that “forgetfulness and desertion” are the main reasons for “poor adherence” as reported by our patients. as adherence improvement decreases over time, new strategies to maintain the patient’s compliance are needed. we agree with nolan and friedman about the concept that adherence is the “fourth dimension” in dermatologic treatment and that improving it may help us to understand better treatment outcomes and make effective interventions to improve these outcomes [10]. acknowledgements we would like to thank camila downey, md, for her assistance with english language and comments that greatly improved this manuscript. references 1. mallon e, newton jn, klassen a, et al. the quality of life in acne: a comparison with general medical conditions using generic questionnaires. br j dermatol 1999;140:672-6. pmid: 10233319 doi: 10.1046/j.1365-2133.1999.02768.x 2. nolan bv, feldman sr. adherence, the fourth dimension in the geometry of dermatological treatment. arch dermatol 2009;145:1319-21. pmid: 19917965 doi: 10.1001/archdermatol. 2009.259 3. torrelo a, ortiz j, alomar a, et al. health-related quality of life, patient satisfaction, and adherence to treatment in patients with dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):7 39 dermatology practical & conceptual www.derm101.com case 1 a 55-year-old female patient with clinical diagnosis of ocaia and a personal history of two thin amelanotic melanomas (breslow thickness <1 mm) presented with multiple nonpigmented nevi. clinically, these lesions were pink macules and papules. on dermoscopy, all the lesions exhibited a light pink background with regularly distributed dotted and comma-like vessels (figure 1). the predominant vascular pattern in macular lesions was dotted vessels. in contrast, papular lesions showed predominantly comma-like vessels. none of the lesions were different from the signature pattern, and all of them were stable on time. case 2 a 38-year-old male patient with clinical diagnosis of ocaia presented multiple pinkish nevi. dermatoscopically, some nevi exhibited a pink background with regularly distributed comma-like and dotted vessels, (figure 2 and 3) and others presented a homogeneous light brown, yellowish pattern associated with predominantly comma-like vessels (figure 4). we did not identify any lesion without the mentioned signature patterns. the digital videodermoscopy follow-up showed no changes on these lesions. proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type ia rosario peralta1, emilia cohen sabban2, paula friedman1, carolina marcucci1, luis a. bollea garlatti1, gastón galimberti3, horacio cabo2 1 dermatology, buenos aires, argentina 2 dermatology department, school of medicine, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina 3 dermatology deparment, school of medicine, hospital italiano, buenos aires, argentina key words: dermoscopy, digital follow-up, reflectance confocal microscopy, nevi, oculocutaneous albinism, melanoma citation: peralta r, cohen sabban e, friedman p, marcucci c, bollea garlatti la, galimberti g, cabo h. proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type ia. dermatol pract concept. 2017;7(1):7. doi: https:// doi.org/10.5826/dpc.0701a07 received: october 2, 2016; accepted: october 3, 2016; published: january 31, 2017 copyright: ©2017 peralta et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rosario peralta, md, 12 prefecto furnillo st, puerto madryn, chubut, argentina. tel. 0542804190759. email: rosarioperalta@yahoo.com albino patients are at great risk for developing cutaneous neoplasms, including melanomas. in this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type ia (oca-ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. we propose managing these patients with dermoscopy, using the comparative approach, digital follow up (dfu), and reflectance confocal microscopy as a complementary tool for difficult cases. abstract https://doi.org/10.5826/dpc.0701a07 https://doi.org/10.5826/dpc.0701a07 mailto:rosarioperalta@yahoo.com 40 observation | dermatol pract concept 2017;7(1):7 in oca-ia patients. these features were also seen in our patients’ nevi. due to reduced or absent protection from melanin, skin cancers are common in patients with albinism and the majority of these consist of squamous cell carcinoma. although rare, melanoma has also been reported [5-8]. we want to highlight that oca-ia patients’ nevi present a vascular pattern similar to that described for amelanotic melanoma, for which it is sometimes challenging to make a differential diagnosis—even for trained physicians. we propose three steps to manage and follow up these kinds of nevi using dermoscopy evaluation with a comparative approach, follow-up with digital dermoscopy and reflectance confocal microscopy as complementary tools for difficult cases. the first step is the clinical and dermoscopic evaluation using a comparative approach. it is important to evaluate all lesions in oca-ia patients who have multiple red clark nevi in order to verify similar vascular patterns and colors of these nevi. if a different lesion is noticed, biopsy is mandatory. clinical discussion oculocutaneous albinism (oca) is a group of rare autosomal recessive disorders of pigmentation. it consists of absence or reduction of melanin in the skin, hair, and eyes due to a partial or total deficit in the activity of tyrosinase, with a normal melanocyte number and structure. the clinical spectrum of oca varies, with oca-ia being the most severe type, characterized by a complete lack of melanin production, while the milder forms oca-ib, oca-ii, oca-iii and oca-iv show some pigment accumulation over time. clinically, it is possible to distinguish the most severe form (oca-ia), but as to the others, it is necessary to obtain a molecular diagnosis [1-4]. clinically our patients were clearly oca-ia type. to date and to our knowledge, only two reports of dermoscopic nevi features of this disease have been published in the literature [2-3]. caldarola et al. [2] found a dermoscopic pattern represented by a homogeneous light brown, yellowish pattern associated with comma-like and dotted vessels predominantly figure 1. nevus on back. homogeneous light-pink background with regularly distributed dotted vessels and scarce comma-like vessels. clinically it was a flat lesion. [copyright: ©2017 peralta et al.] figure 2. nevus on left leg. pink background with regularly distributed dotted vessels and scarce comma-like vessels. clinically it was a macular lesion. [copyright: ©2017 peralta et al.] figure 3. nevus on right lower limb. light pink background with regularly distributed comma-like and dotted vessels. clinically it was a papular lesion. [copyright: ©2017 peralta et al.] figure 4. nevus on back. homogeneous light brown, yellowish pattern associated with predominantly comma-like vessels. clinically it was a papular lesion. [copyright: ©2017 peralta et al.] observation | dermatol pract concept 2017;7(1):7 41 milky-red globules, with or without white shiny structures or reticular depigmentation is highly suggestive of invasive melanoma. thus, excision of melanocytic tumors showing melanoma pattern is mandatory [16]. we did not observe reticular depigmentation or linear irregular vessels in our patients’ lesions. the second step is follow-up with total-body photography and digital dermoscopy. if a change is noticed, biopsy should be done. the combined use of total-body photography and digital dermoscopy called “the two-step method of digital follow-up (dfu)” in a selected population at high risk demonstrated the early detection of melanomas with a low rate of excisions. the first step is a total-body mapping, for clinical examination of the patient and total-body mapping with digital images; and the second step, a digital dermoscopy, for clinical and dermoscopic examination in real-time of all individual lesions. digital storage of dermoscopy images of each lesion showing atypical features is recommended for later follow-up [17]. this dual modality is useful not only for the detection of melanoma with few dermoscopic criteria by dfu of dermoscopy records, but also for the detection of melanoma either presenting as new lesions or arising from nevi that were not monitored by dermoscopy. in a high-risk population, longterm follow-up is required to allow the detection of slowgrowing melanomas [17,18]. patients generally are scheduled for follow-up in 3, 6 or 12 months according to the judgment of the professional who performed the evaluation. short-term follow-up (3 months) is considered for individual suspicious melanocytic lesions that do not satisfy the dermoscopic criteria for the diagnosis of melanoma, while medium and long-term (6 and 12) is considered for the surveillance of patients with high or moderate risk respectively [17]. we suggest dfu for oca-ia patients with multiple nevi because it is the most reliable and efficient approach in detecting incipient melanoma, and dfu should be maintained in time. the third step is to practice a rcm (reflectance confocal microscopy) as a useful complementary tool in difficult cases in order to find structures compatible with nevi or melanoma. rcm is of value as a third-step examination of clinical, dermoscopic, equivocal melanocytic lesions, because in this subset of tumors specificity is superior [19,20]. guitera et al. [19] demonstrated that diagnosis based on pure morphology is often not sufficient in the context of pink tumors and that combining dermoscopy and rcm evaluation is most likely to provide the correct diagnosis of these difficult cases. several studies have shown that rcm may improve the accuracy in the differentiation of benign and malignant melanocytic lesions as an adjuvant technique to dermoscopy, evaluation of these lesions can be difficult given the lack of pigmentary patterns, both under normal illumination and by dermoscopy. one way to approach patients with numerous nevi is to identify the ‘‘ugly duckling’’ sign (ud). when one lesion can be identified as being different from a patient’s other moles, it is called the ud sign. melanomas generally appear with a ud sign [9-10]. another is to identify the signature nevus (sn), with signature nevi defined as the predominant group of nevi in individuals that share a similar clinical appearance [9]. the type of sn oca-ia patients is uniformly pink in color, seen also in those individuals with skin phototype i or ii. the identification of the ud requires recognition of the sn, these two methods actually being interrelated, and they will allow the physician to more efficiently focus diagnostic methods, such as dermoscopy and biopsy, on melanocytic lesions that are of greater concern [9]. scope et al. [11] found that individuals tend to have one to three predominant dermoscopic nevus global patterns and defined a dominant global dermoscopic pattern, if global pattern, color and specific structures were seen in 40% or more of the patient´s nevi. patients could also have minor patterns, defined as occurring in 20 to 39% of the nevi. later, argenziano et al. [12] showed the importance of the dermoscopic comparative approach (to evaluate the lesions in the context of other nevi from the same patient) versus the morphologic approach (to evaluate individual lesions based only on morphologic structure) in patients with multiple nevi, concluding that the evaluation of equivocal lesions in the context of a patient’s other nevi results in a lower rate of excision recommendations (a decrease from 55.1% to 14.1%) compared with evaluation of individual lesions based on morphologic structure alone. therefore, we consider it crucial to perform total-body skin examinations; to observe the dermoscopic nevus global pattern(s); and to use the dermoscopic morphologic and comparative approach in order to find any suspicious lesion. because of the lack of pigment on nevi of oca-ia patients, dermoscopy may aid in diagnosis by the evaluation of vascular structures. zalaudek et al. [13] described that comma, dotted and linear irregular vessels are suggestive of melanocytic skin tumors. dermal nevi are typically characterized by a regular distribution of comma-like vessels. dotted vessels are highly predictive for melanocytic skin tumors in general. dotted vessels in red clark nevi are loosely arranged throughout the lesion and are often associated with a few comma-like vessels, as we observed in our patients [13,14]. on the other hand, it is important to consider that regularly distributed dotted vessels over a pink background associated with a reticular depigmentation is suggestive of nonpigmented spitz nevus, but early amelanotic melanoma must be ruled out [13-15]. additionally, the combination of dotted and linear irregular vessels over a milky red background, 42 observation | dermatol pract concept 2017;7(1):7 4. ortonne jp. trastornos pigmentarios. in: bolognia jl, jorizzo jl, rapini rp. dermatology. 1st ed. spain: elsevier; 2004:955-956. 5. perry pk, silverberg nb. cutaneous malignancy in albinism. cutis. 2001;67:427-430. 6. streutker cj, mccready d, jimbow k, from l. malignant melanoma in a patient with oculocutaneous albinism. j cutan med surg. 2000;4:149-152. 7. wu cy, gao hw, chiang cp. malignant amelanotic melanoma developing from an intradermal naevus in a patient with oculocutaneous albinism. clin exp dermatol. 2009;34:590-593. 8. zalaudek i, argenziano g, mordente i, et al. nevus type in dermoscopy is related to skin type in white persons. arch dermatol. 2007;143: 351–356. 9. suh ky, jean l, bolognia jl. signature nevi. j am acad dermatol. 2009;60:508-514. 10. scope a, dusza sw, halpern ac, et al. the “ugly duckling” sign: agreement between observers. arch dermatol. 2008;144:58-64. 11. scope a, burroni m, agero al, et al. predominant dermoscopic patterns observed among nevi. j cutan med surg 2006;10:170-4. 12. argenziano g, catricalà c, ardigo m, et al. dermoscopy of patients with multiple nevi: improved management recommendations using a comparative diagnostic approach. arch dermatol. 2011;147:46-49. 13. zalaudek i, kreusch j, giacomel j, et al. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part i. melanocytic skin tumors. j am acad dermatol. 2010;63:361-374. 14. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144:1120-1127. 15. carrera c, palou j, malvehy j, et al. early stages of melanoma on the limbs of high-risk patients: clinical, dermoscopic, reflectance confocal microscopy and histopathological characterization for improved recognition. acta derm venereol. 2011;91:137-146. 16. zalaudek i, kittler h, hofmann-wellenhof r, et al. “white” network in spitz nevi and early melanomas lacking significant pigmentation. j am acad dermatol. 2013;69:56-60. 17. salerni g, carrera c, lovatto l, et al. benefits of total body photography and digital dermatoscopy (“two-step method of digital follow-up”) in the early diagnosis of melanoma in patients at high risk for melanoma. j am acad dermatol. 2012;67:17–27. 18. puig s, malvehy j. monitoring patients with multiple nevi. dermatol clin. 2013;31:565-577. 19. guitera p, menzies sw, argenziano g, et al. dermoscopy and in vivo confocal microscopy are complimentary techniques for the diagnosis of difficult amelanotic and light colored skin lesions. br j dermatol. 2016;175(6):1311-1319. 20. carrera c, puig s, malvehy j. in vivo confocal reflectance microscopy in melanoma. dermatol ther. 2012;25:410-422. and three main algorithms have been developed to apply in equivocal lesions [20]. in hypopigmented and amelanotic melanoma when dermoscopy is not able to show specific findings, rcm may render clear findings of melanoma due to the refractivity of melanoma cells, even if they are non-pigmented. melanocytic lesions present a large number of characteristic findings visible in the upper parts of tumors, such as in the case of melanoma: pagetoid roundish or dendritic cells in superficial epidermis, atypical nests at the dermoepidermal junction, non-edged papillae and atypical nucleated cells in papillary dermis [20]. the advantage of in vivo observation of the tumor in real-time, at the bedside, is opening the clinical applications of rcm in the evaluation of melanocytic lesions, in the study of amelanotic melanomas, among others [20]. conclusion in conclusion, dermoscopy can be helpful to evaluate characteristics of melanocytic lesions in oca-ia patients, with special relevance in the vascular structures. nevi of these patients present a vascular pattern similar to that described for amelanotic melanoma, for which it is sometimes challenging to make a differential diagnosis—even for trained physicians. therefore, we consider crucial for the management of these patients the combination of periodic physician-based totalbody skin examinations with dermoscopy, using the comparative approach, dfu with both total-body photography and digital dermoscopy, and rcm in equivocal lesions because it has been proven to improve accuracy in early detection of melanoma in high-risk patients and reduces the number of excisions of benign lesions in these kind of patients. references 1. grønskov k, ek j, brondum-nielsen k. oculocutaneous albinism. orphanet j rare dis. 2007;2:43. 2. caldarola g, fania l, fossati b, et al. dermoscopy of melanocytic lesions in patients affected by oculocutaneous albinism: a case series. dermatology. 2013;226:358–361. 3. bakos rm, argenziano g, zalaudek i, et al. dermatoscopy of pigmented melanocytic nevi in patients with oculocutaneous albinism. j am acad dermatol. 2009;60:487–489. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):9 45 case report a 44-year-old female patient presented to a dermatologist in blanquefort, france for a routine check of her moles. there was no family or personal history of cutaneous malignancy and there was no history of any significant health problems or of any symptoms of disease. there had been a previous examination by the same dermatologist one year earlier, and nothing of concern had been noticed. examination revealed that the patient had skin of fitzpatrick photo-type 3, with multiple ephelides as evidence of previous sun exposure. on the skin over her right scapula a raised, smooth, shiny, yellow and skin-colored lesion was observed (figure 1). a dermatoscopic examination was performed (figure 2), and the lesion was noted to be structureless, predominantly yellow. there was evidence of light melanin pigmentation with some areas of structureless gray interspersed between the dominant yellow areas and present non-choroidal yellow melanoma showing positive staining with sudan black consistent with the presence of lipofuscin: a case report marie hélène jegou penouil1, jean-yves gourhant2, catherine segretin3, david weedon4, cliff rosendahl5 1 cabinet de dermatologie, blanquefort, france 2 centre de dermatologie, nemours, france 3 cabinet d’anatomopathologie, talence, france 4 sullivan nicolaides pathology, brisbane, australia 6 school of medicine, the university of queensland, australia keywords: dermatoscopy, dermoscopy, dermatopathology, yellow melanoma, hypomelanotic melanoma, lipofuscin, sudan black citation: jegou penouil mh, gourhant j-y, segretin c, weedon d, rosendahl c. non-choroidal yellow melanoma showing positive staining with sudan black consistent with the presence of lipofuscin: a case report. dermatol pract concept. 2014;4(2):9. http://dx.doi. org/10.5826/dpc.0402a09 received: september 9, 2013; accepted: october 8, 2013; published: april 30, 2014 copyright: ©2014 jegou penouil et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, phd, po box 734, capalaba, queensland, 4157australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com a case of a predominantly yellow primary superficial spreading melanoma arising on the back of a 44-year-old woman is presented. possible causes of the clinical and dermatoscopic yellow color are discussed. staining with the histochemical stain, sudan black, revealed a differential uptake compared to a closely matched control melanoma. we speculate that the clinical and dermatoscopic yellow color could be due to the presence of increased amounts of the pigment lipofuscin, which is known to produce subtle orange color in some choroidal melanomas. abstract mailto:cliffrosendahl@bigpond.com 46 observation | dermatol pract concept 2014;4(2):9 6a), which was also verified by masson fontana stain that confirmed significant melanin extending to the base of the melanocytic proliferation. evidence of a pre-existing nevus was present as a sheet of mature nevomelanocytes at the base of the lesion (figure 6d). the diagnosis was rendered melanoma, superficial spreading subtype with a dominant nodule comprising the great majority of the lesion, breslow thickness 2.4 mm with 4 mitoses per high power field. following this, in an attempt to clarify the cause of yellow color, two further stains were performed. a pearl’s stain confirmed the absence of hemosiderin. to test for the presence of the pigment lipofuscin, new sections were cut from the paraffin block, five microns in thickness and stained with sudan black. when this appeared to stain heavily, new sections of the same thickness were also cut from the paraffin block of another melanoma as a control and stained with sudan black. the control melanoma was a heavily pigmented superficial spreading melanoma, also with a dominant (pigmented) nodule, with a breslow thickness of 2.2 mm, 2 mitoses per mm2, and no ulceration. figure 7 is a composite image of both the melanoma reported here (upper image) and the control (lower image), both stained with sudan black. both images are taken at with the same 4x objective and with identical exposure and white-balance settings. apart from cropping and identical resizing for publication, there has been no photo manipulation. it can be seen that there is difat one end of the lesion but not the other producing asymmetry of color. polymorphous linear vessels (serpentine, looped and curved) were arranged randomly and densely over the surface of the lesion and there were a small number of dot vessels. immediate excision biopsy was performed. dermatopathologically (figures 3-7) the lesion presented as a nodular, well circumscribed proliferation of melanocytes (figure 3). there was a proliferation of cytologically abnormal melanocytes and some confluent nests of melanocytes at the dermoepidermal junction (figure 5), and the junctional proliferation did extend beyond the dermal proliferation for more than three rete ridges at one location at the periphery of the nodular component. in the dermis sheets of abnormal melanocytes, most as spindle cells (figures 5, 6a & b) and others with plump oval nuclei, prominent nucleoli and abundant clear cytoplasm (figure 6a, b, c, d), extended throughout the dermis with both nesting and evidence of melanin production all the way to the base of the lesion (figures 4 and 6). melanin was seen on hemotoxylin and eosin staining (figure figure 1. close-up image (pentax ds camera, pentax ricoh, tokyo, japan) of a nodular lesion over the right scapular area of a 44-yearold female patient. irregular dominant yellow color is apparent. [copyright: ©2014 jegou penouil et al.] figure 2. dermatoscopy image (heine delta 20 dermatoscope [heine, optotechnic, gmbh, hersching, germany] manually coupled to a panasonic lumix dmc zx1 camera [panasonic corp., kadoma, japan]) of the lesion shown in figure 1. the pattern is structureless, predominantly yellow, with an eccentric structureless pink area (upper pole of image) and evidence of light melanin pigmentation with some areas of structureless gray interspersed between the dominant yellow areas but absent at the upper pole of the image with resulting asymmetry. polymorphous linear vessels (serpentine, looped and curved) are arranged randomly and densely over the surface of the lesion. there are a small number of dot vessels. [copyright: ©2014 jegou penouil et al.] figure 3. dermatopathologic overview of the lesion shown in figures 1 and 2. significant nodular morphology is apparent although close examination of additional dermatopathology sections revealed that strict criteria for the classification as nodular subtype were not met. [copyright: ©2014 jegou penouil et al.] observation | dermatol pract concept 2014;4(2):9 47 [1], amelanotic/hypomelanotic melanomas (ahm) typically present with minimal clues due to melanin structures on which to base a diagnostic analysis [2]. the particular challenge, where a melanoma presents clinically as a hypomelanotic nodule, has been described as that of evaluating a rapidly enlarging pink tumor [3]. the melanoma reported here was a hypopigmented superficial spreading melanoma ferential staining with sudan black in the upper image (case subject to this report) compared to the control. conclusions while pigmented melanomas usually display dermatoscopic disorganization and clues related to their chaotic evolution figure 4. medium high power dermatopathologic view of the lesion shown in figure 3. nesting is apparent at the base of the lesion. [copyright: ©2014 jegou penouil et al.] figure 5. higher power dermatopathologic view of the lesion shown in figure 3 showing a proliferation of melanocytes at the dermoepidermal junction both as single cells and confluent nests with some clefting. a limited amount of pagetoid spread is seen. sheets of spindle-shaped cells fill the dermis. [copyright: ©2014 jegou penouil et al.] figure 6. (a) medium high power dermatopathologic view of the center of the lesion shown in figure 3. two distinct cell types are apparent, including spindle-shaped cells on one hand and cells with plump oval nuclei, prominent nucleoli and abundant clear cytoplasm (balloon cells) on the other. (b) high power view of spindle shaped cells and (c) balloon cells. (d) high power view of the base of the lesion shown in figure 3. a sheet of mature nevomelanocytes can be seen beneath the nests of abnormal melanocytes, consistent with the contiguous presence of a nevus. [copyright: ©2014 jegou penouil et al.] figure 7. (upper image) dermatopathologic view of the lesion shown in figure 3 stained with sudan black. (lower image) dermatopathologic image of a control melanoma of similar breslow thickness and mitotic rate but with heavy melanin pigmentation. both lesions had 5 micron thick sections stained with sudan black and the images were taken with the same exposure and white-balance settings. there has been no photo manipulation apart from cropping and identical resizing for publication. the case being reported here (upper image) is seen to stain differentially consistent with the possible presence of the pigment lipofuscin. [copyright: ©2014 jegou penouil et al.] 48 observation | dermatol pract concept 2014;4(2):9 [15]. sebum consists primarily of a complex mixture of lipids [17]. ideally staining for lipids is performed on fresh unfixed tissue with stains such as oil red o. in this case all tissue had been fixed in formalin and blocked in paraffin. subtle orange pigment, attributed to the pigment lipofuscin, a derived lipid which is an accumulation of lysosomes [18], is described as one of the features that can help differentiate choroidal melanoma from choroidal nevus [19]. the histochemical stain sudan black can be used on formalinfixed, paraffin-processed tissue to detect some phospholids and also lipofuscin [18]. the melanoma reported here showed significant staining with sudan black compared to staining by a similar but deeply pigmented melanoma. this increased staining was present in varying intensity and uneven distribution throughout the dermal component of the melanoma consistent with the uneven presence of dermatoscopic structureless yellow (figure 2). the possible presence of the pigment lipofuscin in this melanoma is supported by positive staining by sudan black, and we speculate that the structureless yellow color displayed clinically and dermatoscopically may be due to the pigment lipofuscin, a pigment which has been previously described as a clue to choroidal melanoma. references 1. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—“chaos and clues.” aust fam physician. 2012 jul;41(7):482–7. 2. chamberlain aj, fritschi l, kelly jw. nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection. j am acad dermatol. 2003 may;48(5):694–701. 3. moloney fj, menzies sw. key points in the dermoscopic diagnosis of hypomelanotic melanoma and nodular melanoma. j dermatol. 2011 jan;38(1):10–5. 4. steglich rb, meotti cd, ferreira ms, lovatto l, de carvalho ave, de castro cgc. dermoscopic clues in the diagnosis of amelanotic and hypomelanotic malignant melanoma. an bras dermatol. 2012 dec;87(6):920–3. 5. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual 2007;13:3. 6. kittler h, rosendahl c, cameron a, tschandl p. dermatoscopy. vienna, austria: facultas.wuv, 2011. 7. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008 sep;144(9):1120–7. 8. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011 jun;64(6):1068–73. 9. berk dr, bayliss sj. milia: a review and classification. j am acad dermatol. 2008 dec;59(6):1050–63. 10. changchien l, dusza sw, agero alc, et al. ageand site-specific variation in the dermoscopic patterns of congenital melanocytic nevi: an aid to accurate classification and assessment of melanocytic nevi. arch dermatol. 2007 aug;143(8):1007–14. (ssm) with a dominant nodule, which was notable because of its dominant structureless yellow color. in one series of four cases of ahm with dermatoscopic images, all cases had significant pink or red color and none had any yellow color [4]. although this lesion fulfilled the definition of ahm, according to revised pattern analysis (rpa), the presence of any pigment should lead to a diagnostic analysis based on pigmented structures [5,6]. applying the rpa algorithmic method for pigmented lesions, “chaos and clues” [1] this lesion was asymmetric by color and therefore was regarded as exhibiting chaos (defined as asymmetry of structure and/ or color), and it had the clue of blue or gray structures so excision biopsy was indicated. in addition to these pigment clues, there were vascular dermatoscopic clues including an eccentric structurless pink area (figure 2 upper pole) and a random arrangement of polymorphous vessels. both milky red pink areas and linear irregular vessels are described as clues to ahm by menzies et al. [7], and an eccentric structureless area (any color except skin color, including pink) and polymorphous vessels have been evaluated as clues to malignancy in rpa [8]. dermatoscopic yellow color has also been attributed to keratin as seen in seborrheic keratosis [9] and congenital type nevus [10]. in a study of 400 bccs bellucci et al. found that 10% displayed yellow structures either as milia-like cysts (7.75%) or lobular structures (4.2%) [11], also presumably due to keratin. there was no accumulation of keratin to explain the yellow color in the melanoma reported here. structureless dermatoscopic yellow color has also been attributed to ulceration with surface serum exudate [6], and dermatoscopic structureless yellow color was described in the first case report of a balloon cell melanoma (bcm) with dermatoscopy [12], being attributed by the authors to ulceration. considering the possibility that it may actually have been the balloon cells that caused the yellow color, the only other reported bsm with dermatoscopic images was a partially pigmented lesion with a dominant structureless white area and without any yellow color [13]. the case we report here did have two cell populations, including one with large cells with vacuolated cytoplasm resembling balloon cells (figures 6 a, c, d), but it did not meet the criteria for diagnosis as a bcm which requires that the melanoma contain more than 50% of balloon cells, [14] and in fact the sheets of balloon cells were only present focally. with respect to ulceration as a reported cause of structureless yellow in one melanoma [12], there was no evidence of ulceration either clinically, dermatoscopically or dermatopathologically in the case reported here. another published cause of dermatoscopic yellow is the presence of sebaceous structures in sebaceous hyperplasia [15], nevus sebaceous and sebaceous adenoma [16]. bryden et al. attributed the yellow color in sebaceous hyperplasia to sebum accumulation by proliferation of sebaceous glands observation | dermatol pract concept 2014;4(2):9 49 15. bryden am, dawe rs, fleming c. dermatoscopic features of benign sebaceous proliferation. clin exp dermatol. 2004 nov;29(6):676–7. 16. enei ml, paschoal fm, valdés g, valdés r. basal cell carcinoma appearing in a facial nevus sebaceous of jadassohn: dermoscopic features. an bras dermatol. 2012 aug;87(4):640-2. 17. mcmahon a, lu h, butovich ia. the spectrophotometric sulfophospho-vanillin assessment of total lipids in human meibomian gland secretions. lipids. 2013 may;48(5):513–25. 18. bancroft j, stevens a. bancroft’s theory and practice of histological techniques. 2nd ed. edinburgh: churchill livingstone, 2012. 19. shields cl, furuta m, berman el, et al. choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. arch ophthalmol. 2009;127(8):981-7. 11. bellucci c, arginelli f, bassoli s, magnoni c, seidenari s. dermoscopic yellow structures in basal cell carcinoma. j eur acad dermatol venereol. epub 2013 jan 18. 12. inskip m, magee j, barksdale s, weedon d, rosendahl c. balloon cell melanoma in primary care practice: a case report. dermatol pract concept. 2013;3(3):6. 13. maher j, cameron a, wallace s, acosta-rojas r, weedon d, rosendahl c. balloon cell melanoma: a case report with polarized and non-polarized dermatoscopy and dermatopathology. dermatol pract conc. (in press) 14. kao gf, helwig eb, graham jh. balloon cell malignant melanoma of the skin. a clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations. cancer. 1992 jun 15;69(12):2942–52. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023035 1 attitudes towards artificial intelligence among dermatologists working in saudi arabia fatima al-ali1, sam polesie2,3, john paoli2,3, mohammed aljasser4, 5, louai a salah6 1 department of internal medicine, king hamad university hospital, muharraq, bahrain 2 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 3 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 4 college of medicine, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia 5 division of dermatology, king abdulaziz medical city, ministry of national guard health affairs, riyadh, saudi arabia 6 dermatology department, east jeddah general hospital, ministry of health, jeddah, saudi arabia key words: dermatologists, artificial intelligence, attitudes citation: al-ali f, polesie s, paoli j, aljasser m, salah la. attitudes towards artificial intelligence among dermatologists working in saudi arabia. dermatol pract concept. 2023;13(1):e2023035. doi: https://doi.org/10.5826/dpc.1301a35 accepted: june 17, 2022; published: january 2023 copyright: ©2023 al-ali et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: louai a salah, dermatology department, east jeddah hospital, 2277 king abdullah rd, al sulaymaniyah, jeddah 22253, makkah, saudi arabia. tel: 012 232 7555 e-mail loai.salah@gmail.com introduction: artificial intelligence (ai) and its applications are among the most discussed modern technologies today. despite the rapidly expanding use of ai in medicine, and specifically in dermatology, only a few studies have studied the attitude of physicians toward ai. objective: to recognize the attitudes towards ai among dermatologists in the kingdom of saudi arabia. methods: a cross-sectional survey was done among dermatologists in saudi arabia. questionnaires were distributed through several online channels. results: overall, 103 dermatologists filled out the survey. the majority saw very strong or strong potential for ai in the automated detection of skin diseases based on dermatological clinical images (50.9%), dermoscopic images (66.6%) and within dermatopathology (66.6%). in regard to results of attitudes towards ai, 56.6% and 52. 8% agreed that ai will revolutionize medicine and dermatology, respectively. however, many of the respondents disagreed that ai will replace physicians (41.5%) and human dermatologists (39.6%) in the future. age did not impact the overall attitude of dermatologists. conclusion: dermatologists in saudi arabia showed an optimistic attitude towards ai in dermatology and medicine. however, dermatologists believe that ai will not replace humans in the future. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023035 introduction with the current advancement of technology, algorithms have taken on a huge role in the field of medicine and displaced much of the work of physicians. artificial intelligence (ai) and its application in various fields are considered one of the most talked about modern technologies today. experts in medicine have described ai as the stethoscope of the 21st century [1]. ai is a revolution that can help optimize any job. a recent review showed a promising impact on the sensitivity and accuracy in the screening of skin lesions and skin cancer detection [2]. multiple recent studies demonstrated the benefits of ai. worldwide, there is an increasing number of impressive attempts at the rapid leveraging of this technology in dermatology [3]. with the rapidly expanding use of ai in medicine and specifically in dermatology, there are only a few studies that discussed the attitude of physicians towards ai. in order to understand the attitudes, an online survey was prepared. objective the goal of the current study is to understand the attitudes towards ai among dermatologists in the kingdom of saudi arabia. to our knowledge, this topic has never been investigated through research in saudi arabia. materials and methods a cross-sectional survey was prepared. survey forms were disseminated electronically through the saudi society of dermatology and dermatologic surgery mailing group and a saudi dermatologists’ whatsapp group during the months of september 2020, march and july 2021. included in the study were dermatologists (consultants and specialists) working or having worked in saudi arabia at the time of the survey and who had online access. the survey was adapted from the form used in an original study by two of the authors [4]. it contained 30 questions including socio-demographic data (gender, age, main practice setting, and years of working in saudi arabia), their background knowledge and sources of ai and, lastly, their feelings and attitudes towards ai in dermatology. analysis and data management were done using ibm spss software version 23 (ibm corp., armonk, n.y., us). results were presented as counts and percentages for categorical variables while numerical variables were presented by mean and standard deviations. also, the general linear regression model (glrm) was used to determine the relation of sex and group with attitudes using scores for the answers. p-values <0.05 were considered statistically significant. results among the 103 dermatologists who responded to the survey, 87 (84.5%) were practicing dermatology in saudi arabia and 9 (9.4%) were not, at the time of the study (table 1). the majority of the respondents were male (n=33, 67.3%), mostly between the ages of 31 to 40 years old (n=17, 34.7%) and had 6-10 years (n=14, 28.6%) experience in dermatology. in regards to their main practice setting, most of the table 1. socio-demographic characteristics of respondents in the study (n = 103). variables n percentage(%) practicing in saudi arabia yes 87 84.5 no 9 8.7 skipped 7 6.7 distribution of answers to the questions below: answered 49 47.6 skipped 54 52.4 gender female 16 32.6 male 33 67.4 age 21-30 years 2 4.1 31-40 years 17 34.7 41-50 years 7 14.3 51-60 years 8 16.3 61-70 years 15 30.6 main practice setting university hospital 12 24.5 military hospital 5 10.2 public teaching hospital 8 16.3 public non-teaching hospital 8 16.3 private clinic 10 20.4 private hospital 4 8.2 other 2 4.1 years of working in dermatology 0-5 years 5 10.2 6-10 years 14 28.6 11-15 years 6 12.2 16-20 years 4 8.2 21-25 years 8 16.3 26-30 years 2 4.1 31-35 years 5 10.2 36-40 years 4 8.2 40 above years 1 2 original article | dermatol pract concept. 2023;13(1):e2023035 3 respondents practiced in university hospitals (n=12, 24.5%) followed by private clinics (n=10, 20.4 %), public teaching hospitals (n=8, 16.3%) and public non-teaching hospitals (n=8, 16.3%). answers regarding background knowledge in ai revealed that 46 (63.9%) knew about ai as a topic in dermatology. however, 11.1% (n=8) had excellent knowledge when it comes to ai in dermatology and the majority (n=20, 27.8%) had only heard about it but not more (table 2). meanwhile, when asked about their source of ai information, 68.8%, 65.6%, 42.2% and 32.8% heard about ai from social media, media, friends, and lectures, respectively (table 3). in regard to potential applications of ai in dermatology, respondents believed that ai has a strong potential in the automated detection of skin diseases based on clinical dermatological images (n=20, 35.1%), on dermatoscopic images (n=28, 49.1%) and on dermatopathology images (n=23, 40.4%) (table 4). more than half of the respondents considered themselves as well-educated regarding the use of modern technology (n=28, 52.8%). the majority of respondents had read medical publications regarding ai within dermatology (n=25, 51%) while most had not used ai as a diagnostic aid in real life (n=34, 69.4%) (table 5). results of attitudes towards ai revealed that age did not affect the attitudes of dermatologists toward ai overall. in general, 56.6% (n=30) and 52.8% (n=28) agreed that ai will generally revolutionize medicine and dermatology, respectively. twenty-six (49.1%) agreed that dermatology and medicine become more exciting to them with the increased use of ai. more than half agreed that ai will improve dermatology (n=30, 56.6%) and medicine in general (n=27, 50.9%) and almost half (n=24, 45.3%) agreed that ai must be part of medical training. however, most respondents expressed disagreement regarding ai replacing physicians table 2. distribution of answers regarding background knowledge of artificial intelligence. count percent (%) ai is a topic that has become of interest to the dermatology community. were you already aware of this topic in dermatology? yes 46 63.9 no 26 36.1 which degree of knowledge would you say you have when it comes to ai within dermatology? excellent knowledge 8 11.1 good knowledge 14 19.4 basic knowledge 19 26.4 i have heard about it, but not more 20 27.8 i have never heard about it 11 15.3 *72 (69.9.%) participants answered this part table 3. distribution of answers regarding sources of knowledge on artificial intelligence. sources count percent (%) media yes 42 65.6 no 22 34.4 social media yes 44 68.7 no 20 31.2 lectures yes 21 32.8 no 43 67.2 friends yes 27 42.2 no 37 57.8 *64 (62.1%) participants answered this part table 4. distribution of answers regarding the potential of artificial intelligence in dermatology*. question choices very strong potential strong potential moderate potential low potential no potential i don’t know automated detection of skin diseases based on dermatological clinical images? 9(15.8%) 20(35.1%) 16(28.1%) 10(17.5%) 1(1.7%) 1(1.7%) automated detection of skin diseases based on dermatoscopic images? 10(17.5%) 28(49.1%) 13(22.8%) 5(8.8%) 0(0%) 1(1.7%) automated detection of skin diseases based on dermatopathology images? 15(26.3%) 23(40.3%) 11(19.3%) 6(10.5%) 0(0.%) 2(3.5%) *57 (55.3%) participants answered this part 4 original article | dermatol pract concept. 2023;13(1):e2023035 table 5. distribution of answers regarding attitudes towards artificial intelligence among dermatologists in saudi arabia. section 1* question choices strongly agree agree neither agree nor disagree disagree strongly disagree i don’t know ai will revolutionize medicine in general. 16(30.2%) 30(56.6%) 4(7.5%) 2(3.8%) 0(0.0%) 1(1.9%) ai will revolutionize dermatology 16(30.2%) 28(52.8%) 4(7.5%) 3(5.7%) 0(0.0%) 0(0.0%) ai will revolutionize dermatology more than other medical specialties in general. 6(11.3%) 15(28.3%) 16(30.2%) 10(18.9%) 2(3.8%) 4(7.5%) in the foreseeable future, all physicians will be replaced by ai. 2(3.8%) 4(7.5%) 5(9.4%) 22(41.5%) 17(32.1%) 3(5.7%) the human dermatologist will be replaced by ai in the foreseeable future. 2(3.8%) 3(5.7%) 5(9.4%) 21(39.6%) 18(34%) 4(7.5%) a development with an increased use of ai in dermatology frightens me. 3(5.7%) 6(11.3%) 9(17%) 23(43.4%) 12(22.6%) 0(0.0%) a development with an increased use of ai in dermatology makes dermatology more exciting to me. 14(26.4%) 26(49.1%) 12(22.6%) 1(1.9%) 0(0.0%) 0(0.0%) a development with an increased use of ai makes medicine in general more exciting to me. 13(24.5%) 26(49.1%) 11(20.7%) 1(1.9%) 2(3.8%) 0(0.0%) ai will improve dermatology. 15(28.3%) 30(56.6%) 5(9.4%) 1(1.9%) 2(3.8%) 0(0.0%) ai will improve medicine in general. 16(30.2%) 27(50.9%) 7(13.2%) 1(1.9%) 1(1.9%) 1(1.9%) ai should be part of medical training. 21(39.6%) 24(45.3%) 5(9.4%) 2(3.8%) 0(0.0%) 1(1.9%) section 2** strongly agree agree neither agree nor disagree disagree strongly disagree i don’t know i consider myself well informed about the use of modern technology, especially computers. 13(26.5%) 28(52.8%) 3(6.1%) 5(10.2%) 0(0.0%) 0(0.0%) yes no would you consider yourself to be someone who enjoys technology? 47(95.9%) 2(4.1%) have you read any medical publications regarding ai within dermatology? 25(51.1%) 24(49%) have you used ai as a diagnostic aid in real life within dermatology? 15(30.6%) 34(69.4%) *53 (51.5%) participants answered this part ** 49 (47.6) participants answered this part (n=22, 41.5%) and human dermatologists (n=21, 39.6%) in the future. in addition, 43.4% (n=23) were not frightened about the increased use of ai. the majority of respondents were neutral regarding the proposal that “ai will revolutionize dermatology more than other medical specialties” (n=16, 30.2%). discussion in this cross-sectional study, dermatologists in saudi arabia showed a positive attitude towards ai. most of the respondents had not used ai in diagnosis in real settings but generally agreed that ai will revolutionize dermatology and medicine. while 63,9% of the respondents were aware of ai as a topic in dermatology, the majority of them had only heard about it (n=20, 27.8%) and only 11.1% had excellent knowledge. although the awareness of ai among dermatologists was lower compared to the report of polesie et al. [4], respondents viewed ai as having strong potential in the detection of skin diseases. dermatologists saw a stronger potential of ai in detection using dermatoscopic images and within dermatopathology than with dermatological clinical images [4]. original article | dermatol pract concept. 2023;13(1):e2023035 5 in our study, although respondents were optimistic about the increased use of ai in the development of dermatology and medicine in general, the majority (n=21, 39.6%) disagreed that ai will replace doctors. only 3.8% strongly agreed while 5.7% agreed with this hypothesis. this is consistent with other studies about ai. polesie et al. reported similar results in which only 5.5% of the participants agreed that human doctors will be displaced by ai [4]. krittanawong also concluded that although ai may become more effective in diagnosis and image recognition, it cannot replace physicians [5]. in a 2017 survey in the united states, the majority of the respondents were worried about computers replacing humans in the future [6]. this was not the case in korea, in which only 35.4% of the participants agreed that ai will displace physicians in the future [7]. in this study, the relationship between sex and age was determined and examined. the findings revealed that dermatologists’ attitudes toward ai were unaffected by their age. similar results were found in the study of polesie et al. [4]. the current study has some limitations. first, since this is a cross-sectional survey, selection bias and social desirability biases are possible. due to the selected method of distributing the survey, the response rate could not be calculated. participants may be more optimistic than those who did not participate. second, not all the questions in the survey were answered by the participants, some were skipped, resulting also in possible selection bias. conclusion dermatologists in saudi arabia showed an overall positive attitude towards ai in dermatology. overall, age did not affect the attitudes of dermatologists about ai. furthermore, results showed that most dermatologists were aware of the potential of ai in the automated detection of skin diseases using dermatoscopic, histopathological and clinical dermatological images. moreover, they agreed that ai will revolutionize dermatology and the development of ai within our specialty seemed exciting to them. however, most participants believed that ai will not replace physicians in the future. references 1. mesko b. the role of artificial intelligence in precision medicine. expert rev precis meddrug dev. 2017 2017/09/03;2(5):239241. doi: 10.1080/23808993.2017.1380516. 2. de a, sarda a, gupta s, et al. use of artificial intelligence in dermatology. indian j dermatol. 2020 sep-oct;65(5):352-357. doi: 10.4103/ijd.ijd_418_20. pubmed pmid: 33165383; pubmed central pmcid: pmcpmc7640800. eng. 3. negnevitsky m. artificial intelligence. 2nd ed. essex, england: addison-wesley; 2002. 4. polesie s, gillstedt m, kittler h, et al. attitudes towards artificial intelligence within dermatology: an international online survey. br j dermatol. 2020 jul;183(1):159-161. doi: 10.1111/ bjd.18875. pubmed pmid: 31953854; eng. 5. krittanawong c. the rise of artificial intelligence and the uncertain future for physicians. eur j intern med. 2018 feb;48:e13-e14. doi: 10.1016/j.ejim.2017.06.017. pubmed pmid: 28651747; eng. 6. smith a, anderson m. americans’ attitudes toward a future in which robots and computers can do many human jobs 2017 [14 nov 2021]. available from: https://www.pewresearch.org/internet/2017/10/04/americans-attitudes-toward-a-future-in-which -robots-and-computers-can-do-many-human-jobs/ 7. oh s, kim jh, choi sw, et al. physician confidence in artificial intelligence: an online mobile survey. jmir. 2019 mar 25;21(3):e12422. doi: 10.2196/12422. pubmed pmid: 30907742; pubmed central pmcid: pmcpmc6452288. eng. dermatology: practical and conceptual research | dermatol pract concept 2016;6(3):5 17 dermatology practical & conceptual www.derm101.com introduction dermoscopy is gaining popularity in the diagnosis of inflammatory dermatoses. polarized dermoscopes are widely used due to their better visualization of the deeper epidermis and papillary dermis [1]. a granulomatous disorder is a pathological description of a variety of conditions that have different etiologies but dermoscopy could be useful in differentiating sarcoidosis from necrobiotic granulomas even after treatment with systemic steroids shahira ramadan1, dalia hossam1, marwah a. saleh1 1 dermatology department cairo university, cairo, egypt key words: cutaneous sarcoidosis, dermoscopy, necrobiotic granuloma, steroids, treatment citation: ramadan s, hossam d, saleh ma. dermoscopy could be useful in differentiating sarcoidosis from necrobiotic granulomas even after treatment with systemic steroids. dermatol pract concept 2016;6(3):5. doi: 10.5826/dpc.0603a05 received: august 2, 2015; accepted: may 24, 2016; published: july 31, 2016 copyright: ©2016 ramadan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: marwah adly saleh, md, phd, department of dermatology, cairo university school of medicine, kasr al ainy hospital, po 11956, cairo, egypt. tel. +201223132773. email: salehmarwah@kasralainy.edu.eg background: diagnosing cutaneous sarcoidosis and necrobiotic granulomas is challenging. objective: assessing the value of dermoscopy in differentiating cutaneous sarcoidosis from necrobiotic granulomas and evaluating whether their dermoscopic features will be altered after treatment. methods: nineteen cutaneous sarcoidosis and 11 necrobiotic granuloma patients (2 necrobiosis lipoidica, 4 granuloma annulare and 5 rheumatoid nodule) were included in this study. the diagnosis was confirmed by skin biopsy. the lesions were examined using non-contact polarized dermoscope (dermlite 2 hr-pro; 3gen, san juan capistrano, ca). results: ten out of 19 cutaneous sarcoidosis patients and 7/11 necrobiotic cases group were receiving treatments (topical, intralesional or systemic steroids ± chloroquine) but still have cutaneous lesions. treatment duration in the sarcoidosis group ranged from 2 months to 10 years (median 3 years) and in the necrobiotic cases group ranged from 3 months to 16 years (median 2 years). pink homogenous background, translucent orange areas, white scar-like depigmentation and fine white scales were significantly associated with the cutaneous sarcoidosis compared to necrobiotic cases group. on the other hand mixed pink, white and yellowish background was significantly associated with the necrobiotic cases group. no significant difference in the dermoscopic findings was detected between treated and non-treated patients. conclusion: some dermoscopic findings are shared between the cutaneous sarcoidosis group and the necrobiotic cases group, yet dermoscopy could be a useful aid in differentiating them even after treatment. abstract mailto:salehmarwah@kasralainy.edu.eg 18 research | dermatol pract concept 2016;6(3):5 was represented using the terms sensitivity, specificity, +ve predictive value, -ve predictive value, and overall accuracy. p values less than 0.05 was considered statistically significant. all statistical calculations were done using computer program spss (statistical package for the social science; spss inc., chicago, il, usa) release 15 for microsoft windows (2006). 2.2 accuracy calculations sensitivity = t(+)ve ÷ [t(+)ve + f(-)ve] specificity = t(-)ve ÷ [t(-)ve + f(+)ve] positive predictive value = t(+)ve ÷ [t(+)ve + f(+)ve] negative predictive value = t(-)ve ÷ [t(-)ve + f(-)ve] overall accuracy = [t(+)ve + t(-)ve] ÷ all sample results the demographic data of the patients are summarized in table 1. nineteen cutaneous sarcoidosis cases and 11 necrobiotic cases groups (2 necrobiosis lipoidica, 4 granuloma annulare and 5 rheumatoid nodule) were included in this study. the number of examined lesions in the cutaneous sarcoidosis group ranged from 1 to 16 lesions (median=3). the number of examined lesions in the necrobiotic cases group (necrobiosis lipoidica, granuloma annulare and rheumatoid nodule) ranged from 1 to 14 lesions (median=2). ten out of 19 cutaneous sarcoidosis cases and 7/11 of the necrobiotic cases group were receiving treatments but still had cutaneous lesions. the cutaneous sarcoidosis patients received systemic steroids and chloroquine. one patient received adjuvant intralesional steroids. three patients from the necrobiotic cases group received topical steroids, 1 patient received systemic steroids, 2 patients received systemic steroids and methotrexate and 1 patient received systemic steroids, methotrexate and chloroquine. the dermoscopic findings are summarized in table 2. the results showed that pink homogenous background, translucent orange areas, white scar-like depigmentation and fine white scales (figure 1) were significantly associated with cutaneous sarcoidosis compared to the necrobiotic share granuloma formation pathologically. a granuloma is an organized collection of epithelioid histiocytes with variable number of multinucleated giant cells [2]. granulomas include sarcoidal, foreign body granuloma and necrobiotic granuloma [3]. necrobiotic granulomas include granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, rheumatoid fever nodules and foreign body reactions. the diagnosis of cutaneous sarcoidosis is challenging due to the variety of clinical presentations of the disease [4]. moreover, differentiating cutaneous sarcoidosis from necrobiotic granulomas is sometimes difficult [5], and the existence of both conditions in the same patient was already reported [6]. in this work we aimed to assess the value of dermoscopy in differentiating cutaneous sarcoidosis from necrobiotic granulomas. patients and methods this is a cross sectional study that was conducted between january and november 2014 in our department. all patients diagnosed as cutaneous sarcoidosis or necrobiotic granulomas during this period were included in this study. patients were subjected to history taking, clinical examination, and skin biopsy to confirm the diagnosis and dermoscopic examination using polarized dermoscope (dermlite 2 hr-pro). this study was approved by the ethical committee of the dermatology department and was conducted according to the declaration of helsinki principles. 2.1 statistical analysis data were statistically described in terms of mean ± standard deviation (± sd), median and range, or frequencies (number of cases) and percentages when appropriate. comparison of numerical variables between the study groups was done using mann-whitney u test for independent samples. for comparing categorical data, chi square (χ2) test was performed. exact test was used instead when the expected frequency was less than 5. correlation between various variables was done using spearman’s rank correlation equation. accuracy table 1. demographic data of the patients [copyright: ©2016 ramadan et al.]   cutan cutaneous sarcoidosis (n=19) eous sarcoidosis (n=19) necrobiotic cases group (n=11) females 16 8 males 3 3 age (mean) 25-62 (45±9.8) 18-69 (37.7±17.1) fitzpatrick’s skin type (number) iv (18), v (1) iv (7), v (2), vi (2) disease duration range (median) 2 months-10 years (3 years) 3 months16 years (2 years) total number of examined lesions (range, median) 1-16 (3) 1-14 (2) research | dermatol pract concept 2016;6(3):5 19 table 2. summary of the dermoscopic findings [copyright: ©2016 ramadan et al.] cutaneous sarcoidosis (n=19) necrobiotic cases group p value granuloma annulare (n=4) necrobiosis lipoidica (n=2) rheumatoid nodule (n=5) background color pink homogenous background 14 0 0 3 *0.018 mixed pink and white homogenous background 0 1 0 1 0.298 mixed pink, white and yellowish background 0 2 2 0 *0.012 mixed pink and orange background 5 0 0 0 0.082 translucent orange globules and areas translucent orange globules 4 0 0 0 0.141 translucent orange areas 12 0 0 0 *0.001 blood vessels arborizing vessels 5 0 2 1 0.637 short linear blood vessels 9 0 2 1 0.245 pigmentation hypopigmented areas 0 2 0 0 0.367 scar like depigmentation 7 0 0 0 *0.025 reticulate pigmentation 1 1 2 1 *0.047 scales fine white scales 9 0 0 0 *0.006 *p value <0.05 is significant figure 1. dermoscopic picture of cutaneous sarcoidosis cases showing (a) arborizing blood vessels (black arrow) (no treatment); (b) translucent orange areas (black arrow) (treatment for 3 years); (c) scar-like depigmentation (black arrow) (no treatment); (d) white scales (black arrow) (no treatment). [copyright: ©2016 ramadan et al.] 20 research | dermatol pract concept 2016;6(3):5 discussion the spectrum of inflammatory diseases that can be diagnosed using a dermoscope has markedly increased. granulomatous skin diseases are a group of inflammatory dermatoses that are characterized pathologically by granuloma formation. few studies evaluated the use of dermoscopy in diagnosing cutaneous sarcoidosis; the largest of which was using 7 cases [7]. in this work we aimed to assess the value of the dermoscope in diagnosing cutaneous sarcoidosis using a larger number of patients. moreover, we tried to evaluate whether receiving cases group. p values were 0.018, 0.001, 0.025 and 0.006 respectively. on the other hand, mixed pink, white and yellowish background was significantly associated with the necrobiotic cases group; p value was 0.012 (figure 2). we tried to evaluate whether receiving treatment affected the dermoscopic findings. we compared the dermoscopic findings of the patients who were receiving treatment with those who had not started any treatment. however, the results were not significant in all the dermoscopic findings (table 3) (figure 3). figure 2. dermoscopic picture of necrobiotic cases group (a) necrobiotic granuloma showing mixed pink, white and yellowish background and arborizing blood vessels (black arrow) (no treatment); (b) granuloma annulare showing hypopigmented areas (black arrow) (no treatment); (c) rheumatoid nodule showing mixed pink and white background and short linear vessels (black arrow) (treatment for 2 years). [copyright: ©2016 ramadan et al.] table 3. comparison between dermoscopic findings in treated and untreated cases [copyright: ©2016 ramadan et al.]   cutaneous sarcoidosis (n=19) necrobiotic cases group (n=11)   untreated cases (9) treated cases (10) p value untreated cases (4) treated cases (7) p value background color pink homogenous background 5 9 0.119 0 3 0.212 mixed pink and white homogenous background 0 0 0 2 0.382 mixed pink, white and yellowish background 0 0 3 1 0.088 mixed pink and orange background 4 1 0.119 0 0 translucent orange globules and areas translucent orange globules 1 3 0.333 0 0 translucent orange areas 7 5 0.22 0 0 blood vessels arborizing vessels 4 1 0.119 1 2 0.721 short linear blood vessels 4 5 0.586 1 2 0.721 pigmentation hypopigmented areas 0 0 2 0 1 scar like depigmentation 2 5 0.22 0 0 reticulate pigmentation 0 1 0.526 2 2 0.47 scales fine white scales 5 4 0.414 0 0 research | dermatol pract concept 2016;6(3):5 21 authors stated that arborizing blood vessels were detected in necrobiosis lipoidica while linear vessels were detected in sarcoidosis. nonetheless, we detected arborizing blood vessels in 5 (26.3%) cases of cutaneous sarcoidosis. those arborizing blood vessels might be shorter with fewer branches in sarcoidosis than necrobiosis lipoidica. necrobiosis lipoidica is a rare disease. bakos et al. [12], pellicano et al. [11] and lallas et al. [13] all reported the presence of arborizing vessels on yellowish background in necrobiosis lipoidica, and our results confirm their findings. hairpin like structures were detected by bakos et al. in necrobiosis lipoidica; although we did not detect any hair pin like structures, we noticed that short linear blood vessels can be seen in necrobiosis lipoidica patients. lallas et al [13]reported the dermoscopic findings of granuloma annulare in 47 lesions of 24 patients. they found that the dermoscopic findings in granuloma annulare are heterogeneous. the background color is a combination of red and white in 42.6%, dotted vessels in 40.4%, short linear vessels in 21% and arborizing vessels in 14.9% of the lesions. in this work we found mixed pink and white background in 1 patient. interestingly we found hypopigmented areas in 2/4 granuloma annulare patients and mixed pink white and yellow background in 1 patient. some dermoscopic features of inflammatory lesions are lost after treatment with steroids, which makes their diagnosis difficult [14]. regarding lichen planus, wickham’s striae and peripheral homogenous vascular pattern disappeared after 4 weeks of treatment with topical steroids [14]. interestingly, our results showed that the dermoscopic findings of cutaneous sarcoidosis and necrobiotic cases group remained even after several years of treatment. some possible explanations are that topical and systemic steroids may not be effective in treating all patients [15] or that more time may be needed for these lesions to disappear. in addition to that, different drugs with different mechanisms of action may be responsible for different dermoscopic modifications after treatment. treatment affected the dermoscopic findings of cutaneous sarcoidosis and necrobiotic granulomas. pellicano et al. [7] reported that scar-like depigmentation and translucent orange globules were suggestive of cutaneous sarcoidosis. they detected scar-like depigmentation in 5 cases and translucent orange globules in 7 cases of cutaneous sarcoidosis. the translucent orange globules were thought to be equivalent to the apple jelly color in diascopy [8]. our results showed that scar-like depigmentation was detected in 7/19 (36.8%) cutaneous sarcoidosis cases, which was statistically significant in differentiating cutaneous sarcoidosis from necrobiotic granuloma; p value was 0.025. in our results, translucent orange globules were found in 4/19 (21.1%) cutaneous sarcoidosis cases. although they were not detected in any necrobiotic granuloma, they were not significant in differentiating cutaneous sarcoidosis from the necrobiotic cases group. on the other hand, our results added that translucent orange areas were significant in differentiating cutaneous sarcoidosis from the necrobiotic cases group; p value was 0.001. translucent orange areas were 100% specific and 63.16% sensitive in differentiating cutaneous sarcoidosis from necrobiotic granulomas. however, in spite of their significance, they might not be specific for sarcoidosis. translucent orange areas were reported before in lupus vulgaris [9]. interestingly, differentiating sarcoidosis from lupus vulgaris clinically and pathologically is challenging. therefore it is not surprising that they have the similar dermoscopic features. vazquez-lopez et al. [10] reported the presence of vascular globules in 2 cutaneous sarcoidosis cases. vascular globules were not detected in this work. moreover, pellicano et al. and vazquez-lopez et al. reported that linear vessels were associated with sarcoidosis. in this work we detected short linear vessels in 9 (47%) cutaneous sarcoidosis cases and in 3 (27%) of the necrobiotic group. however, the results were not significant. arborizing blood vessels were the main clue to differentiate necrobiosis lipoidica from sarcoidosis according to pellicano et al. [11] and lallas et al. [8]. those figure 3. treatment did not affect the dermoscopic findings of cutaneous sarcoidosis. translucent orange areas in the forehead of a non-treated male (a) and a treated female for 3 years with systemic steroids (b). [copyright: ©2016 ramadan et al.] 22 research | dermatol pract concept 2016;6(3):5 systemic sarcoidosis. ann dermatol 2012;24:74-6. pmid: 22363160. doi: 10.5021/ad.2012.24.1.74. 6. igawa k, maruyama r, satoh t, et al. necrobiosis lipoidica-like skin lesions in systemic sarcoidosis. j dermatol 1998;25:653-6. pmid: 9830264. doi: 10.1111/j.1346-8138.1998.tb02475.x. 7. pellicano r, tiodorovic-zivkovic d, gourhant jy, et al. dermoscopy of cutaneous sarcoidosis. dermatology 2010;221:51-4. pmid: 20375489; doi: 10.1159/000284584. 8. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol 2014;170:514-26. pmid: 24266695. doi: 10.1111/bjd.12685. 9. brasiello m, zalaudek i, ferrara g, et al. lupus vulgaris: a new look at an old symptom—the lupoma observed with dermoscopy. dermatology 2009;218:172-4. pmid: 19060460. doi: 10.1159/000182255. 10. vazquez-lopez f, palacios-garcia l, gomez-diez s, argenziano g. dermoscopy for discriminating between lichenoid sarcoidosis and lichen planus. arch dermatol 2011;147:1130. pmid: 21931067. doi: 10.1001/archdermatol.2011.278. 11. pellicano r, caldarola g, filabozzi p, zalaudek i. dermoscopy of necrobiosis lipoidica and granuloma annulare. dermatology 2013;226:319-23. pmid: 23797090. doi: 10.1159/000350573. 12. bakos rm, cartell a, bakos l. dermatoscopy of early-onset necrobiosis lipoidica. j am acad dermatol. 2012;66:e143-4. pmid: 22421129. doi: 10.1016/j.jaad.2011.01.028. 13. lallas a, zaballos p, zalaudek i, et al. dermoscopic patterns of granuloma annulare and necrobiosis lipoidica. clin exp dermatol 2013;38:425-7. pmid: 23495727 doi: 10.1111/ced.12126. 14. gungor s, topal io, goncu ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept. 2015;5(2): 45-53. pmid: 26114051. doi: 10.5826/dpc.0502a06. 15. katoh n, mihara h, yasuno h. cutaneous sarcoidosis successfully treated with topical tacrolimus. br j dermatol. 2002;147:1546. pmid: 12100200. 10.1046/j.1365-2133.2002.04727.x. some limitations of this work should be highlighted: dermoscopic features before and after treatment have not been compared; the limited number of patients, especially in the necrobiotic cases group; and most of the patients were fitzpatrick’s skin type iv skin phototype. in conclusion, some dermoscopic findings are shared between the cutaneous sarcoidosis and necrobiotic cases group. however, translucent orange areas, white scar-like depigmentation and white scales may be more suggestive of cutaneous sarcoidosis, while mixed pink, white and yellowish background may be more suggestive of necrobiotic granuloma. the dermoscopic features of cutaneous sarcoidosis might remain even after receiving treatment. acknowledgment the authors acknowledge dr. magdy ibrahim, professor of obstetrics and gynecology at cairo university for his help with statistics. references 1. marghoob aa, usatine rp, jaimes n. dermoscopy for the family physician. am fam physician 2013;88:441-50. pmid: 24134084. 2. weedon d, strutton g, rubin ai, weedon d (eds). weedon’s skin pathology. 3rd ed. london: churchill livingstone, 2010. 3. hawryluk eb, izikson l, english jc, 3rd. non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. am j clin dermatol 2010;11:171-81. pmid: 20184390. doi: 10.2165/11530080-000000000-00000. 4. katta r. cutaneous sarcoidosis: a dermatologic masquerader. am fam physician 2002;65:1581-4. pmid: 11989634. 5. chiba t, takahara m, nakahara t, et al. cutaneous sarcoidosis clinically mimicking necrobiosis lipoidica in a patient with dermatology: practical and conceptual research | dermatol pract concept 2017;7(3):1 1 dermatology practical & conceptual www.derm101.com performance of the “if in doubt, cut it out” rule for the management of nodular melanoma elvira moscarella1,2, aimilios lallas3, caterina longo2, iris zalaudek4, stefano caccavale1, alessio gambardella1, amalia lupoli1, roberto alfano5, giuseppe argenziano1 1 dermatology unit, university of campania, naples, italy 2 dermatology and skin cancer unit, arcispedale santa maria nuova irccs, reggio emilia, italy 3 first department of dermatology, aristotle university, thessaloniki, greece 4 department of dermatology, non-melanoma skin cancer unit, medical university of graz, graz, austria 5 department of anesthesiology, surgery and emergency, second university of naples, naples, italy key words: nodular melanoma; number needed to excise; skin cancer; dermatoscopy citation: moscarella e, lallas a, longo c, zalaudek i, caccavale s, giambardella a, lupoli a. alfano r, argenziano g. performance of the “if in doubt, cut it out” rule for the management of nodular melanoma. dermatol pract concept 2017;7(3):1. doi: https://doi. org/10.5826/dpc.0703a01 received: january 6, 2017; accepted: march 4, 2017; published: july 31, 2016 copyright: ©2017 moscarella et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, dermatology unit, university of campania, nuovo policlinico, via pansini 5, 80131. tel. +39.335.1727229. email: elvira.moscarella@gmail.com background: the recognition of nodular melanoma is clinically challenging, and the diagnostic accuracy of dermoscopy and confocal microscopy is lower than for superficial spreading melanoma. objectives: to test a management strategy consisting in the excision of any nodular lesion that cannot be confidently and precisely classified as a benign tumor after clinical and dermoscopic examination. methods: clinical and dermoscopic images of excised nodular lesions were retrospectively collected and evaluated. the evaluators were asked to record the level of diagnostic confidence for each lesion, by declaring if they were confident or doubtful about the given diagnosis. the nne (number needed to excise) value was used to evaluate the efficacy of the proposed method. results: a total of 1,319 excised nodular lesions formed the study set. the nne for any malignancy was 3.9 (634/164), while the nne for melanoma was 13.2 (634/48). nne for hypo and amelanotic melanoma was 27.3 (327/12). conclusions: excising doubtful nodular lesions seems to be an effective management strategy not to miss nodular melanoma, resulting in an acceptable rate of unnecessary excision of benign lesions. abstract 2 research | dermatol pract concept 2017;7(3):1 will are not routinely performed at our referral centers, but all excisions are performed to rule out malignancy. the inclusion criteria for the current study were the availability of clinical and dermoscopic images of a nodular lesion that was excised and histopathologically diagnosed. nodularity was evaluated on clinical images, in which a ruler was available. pure nodular and flat palpable lesions with a nodular component were included. we did not select lesions based on the histopathologic diagnosis; thus, both benign and malignant lesions were included for evaluation. the study period was 2008 to 2014. clinical images were acquired using a highresolution digital camera. dermoscopic images were captured using non-polarized dermoscopes (dermlite foto, 3gen llc, dana point, ca). all images were evaluated by two residents in dermatology with an average expertise in dermoscopy. the evaluators were blinded to the final histopathologic diagnosis. the presence of pigmentation was assessed on the dermoscopic images, and a lesion was classified as pigmented when pigmentation was involving 50% or more of the lesion surface, hypopigmented when pigmentation was present in less than 50% of the lesion surface, and amelanotic when no pigmentation was detected at all. the evaluators were asked to provide a diagnosis based on the clinical and dermoscopic aspects of the lesion. to serve the main aim of our study, the evaluators were also asked to record the level of diagnostic confidence for each lesion, by declaring if they were confident or doubtful about the given diagnosis. the nne (number needed to excise) value was used to evaluate the efficacy of the proposed method [20-22]. this was obtained by dividing the total number of doubtful lesions excised to the number of those histopathologically proven to be malignant. nne values were calculated for all malignancies (nne total) and for melanoma diagnosis in particular. results in all, 1,319 excised nodular lesions formed the study set. of these, 747 (56.6%) were malignant and 572 (43.4%) were benign. the study sample included: hemangioma (27; 2.0%), angiocheratoma (3; 0.2%), angioleiomioma (1; 0.1%), clear cell acanthoma (5; 0.4%), angiosarcoma (2; 0.2%), basal cell carcinoma (283; 21.4%), squamous cell carcinoma (205; 15.5%); merkel cell carcinoma (3; 0.2%), cylindroma (2; 0.2%), epidermal cyst (20; 1.5%), dermatofibroma (60; 4.5%), pyogenic granuloma (24; 1.8%), kaposi sarcoma (12; 0.9%), melanoma (199; 15.0%), metastasis from internal tumors (2; 0.2%), melanocytic nevi (342; 25.9%), other benign lesions (88; 6.7%), and other malignant lesions (41; 3.1%). on clinical-dermoscopic evaluation, 685 of 1,319 lesions (51.9%) were assessed as surely malignant and 634 (48.1%) as doubtful. of 685 lesions clinically/dermoscopically judged introduction nodular melanoma (nm) is a very aggressive subtype of melanoma lacking a significant superficial spreading phase and, consequently, being thicker at diagnosis as compared with other melanoma subtypes [1]. although nm accounts only for 9 to 15% of melanomas, it is responsible for 43% of melanoma deaths, according to a population-based study in australia [2]. because of its peculiar clinical characteristics, the abcd clinical criteria are usually of no help for nm recognition [3-5]. the tumor typically develops as a rapidly growing, firm papule or nodule. these clinical characteristics have been summarized by the egf rule (elevation, growth, firmness), which has been proposed to facilitate the recognition of nm by patients and clinicians [6,7]. the introduction of noninvasive diagnostic tools in dermatology, such as dermoscopy and confocal microscopy, has significantly improved melanoma diagnostic accuracy [5,8-18]. despite these advances, the recognition of nm remains a challenge, because its clinical and dermoscopic features may be similar to benign nodular lesions, such as hemangioma, pyogenic granuloma, seborrheic keratosis, dermatofibroma, and dermal nevi. several studies have investigated the accuracy of dermoscopic criteria in the diagnosis of nm, reporting sensitivity, specificity, and predictive values lower than those for superficial spreading melanoma (ssm) [8]. reflectance confocal microscopy (rcm), a recently introduced diagnostic tool allowing skin evaluation at a quasi histologic level, has been tested for the diagnosis of nodular lesions in a retrospective study [17]. however, the use of rcm is limited by its cost and availability. moreover, the presence of hyperkeratosis and ulceration may prevent the deeper evaluation of the tumor structures and render rcm of limited value in nm [17]. when taking into consideration the limitations of clinical, dermoscopic and confocal diagnosis, a practical management strategy has been suggested so as not to miss nm [8,19]. according to this approach, any nodular lesion that cannot be confidently and precisely classified as a benign tumor after clinical and dermoscopic examination should be histopathologically diagnosed [19]. however, one might argue that applying this strategy would result in a high number of excisions of benign lesions. the aim of this study was to evaluate the effectiveness of this strategy, by evaluating the number needed to excise (nne) when applying the rule of excising any doubtful nodular lesion. material and methods clinical and dermoscopic images of excised nodular lesions were retrospectively collected from the databases of two pigmented lesion clinics in naples and reggio emilia, italy. as a general rule, excision for cosmetic concern or patient research | dermatol pract concept 2017;7(3):1 3 doubtful and histopathologically malignant. in the subgroup of hypoor amelanotic lesions, the nne for any malignancy was 2.8 (327/116). a subset of 33 melanomas consisted of hypoor amelanotic lesions. of these, 12 lesions were judged doubtful; thus, the nne for hypo and amelanotic melanoma was 27.3 (327/12). the majority of histopathologically benign lesions that were judged to be doubtful under clinical and dermoscopic examination were melanocytic nevi (279 lesions, 44.0%), including spitz nevus (102; 16.1%), compound nevus (86; 13.6%), dermal nevus (24; 3.8%), blue nevus (16; 2.5%), clark nevus (15; 2.4%), congenital nevus (14; 2.2%), and 22 (3.5%) other nevi, not specified. dermatofibroma accounted for 50 (7.9%) of the benign doubtful lesions, whereas 32 (5.0%) were angiomas, 22 (3.5%) pyogenic granulomas, and 15 (2.4%) epidermal cysts. as surely malignant, 583 were indeed malignant histopathologically (85.1%), and 102 (14.9%) were histopathologically benign. of 634 clinically/dermoscopically doubtful lesions, 164 (25.9%) were histopathologically malignant, including 48 melanomas. thus, the nne for any malignancy was 3.9 (634/164), while the nne for melanoma was 13.2 (634/48). two hundred eighty-three bcc were included in the study set, and of these 238 were judged “sure malignant,” and 45 clinically doubtful. two hundred five scc were included in the study set, and 154 were judged clinically “sure malignant,” and 34 clinically doubtful. of the 199 melanomas, 151 were clinically “sure malignant,” and 48 were clinically doubtful. regarding pigmentation, 755 lesions were hypo or amelanotic and, of these, 509 were malignant. three hundred twenty-seven lesions were hypo or amelanotic and clinically/ dermoscopically doubtful. of these, 116 lesions were judged figure 1. clinical presentation of 4 nodular lesions excised to rule out melanoma. (a) a red-purple-to-black nodule, arising on the leg of a 72-year-old woman. the patient reported recent onset and sudden change in color. the lesion was excised and histopathologically diagnosed as angioma. (b) a large amelanotic nodule, arising on the leg of 80-year-old woman. three smaller papules were visible in the surrounding skin (white arrows). the patient was unaware of the time duration of the lesions. a biopsy was taken, and a final diagnosis of clear cell acanthoma with satellites was given. (c) an 8 mm diameter amelanotic, ulcerated nodule arising on the abdomen of a 40-year-old man. the lesion was noticed three months before and was rapidly growing in size. histopathologic examination revealed a melanoma 2.5 mm breslow thickness. (d) a 6 mm nodule (white arrow) arising on the chest of a 64-year-old man with a prior history of multiple primary melanomas. color variegation and presence of central bluish hue prompted excision. histopathology revealed a dermal nevus. [copyright: ©2017 moscarella et al.] 4 research | dermatol pract concept 2017;7(3):1 benign lesions are excised to find one malignancy [20-22]. the nne depends on both the expertise of the clinician and the prevalence of the disease. usually, nne values for melanoma diagnosis vary between 4 and 30, with lower values achieved in specialized or referral centers [23]. our results are in line with previous studies, confirming that diagnosing nodular melanoma can be challenging. when considering malignant lesions overall, including bcc, scc, and others, an nne value of 3.9 was achieved. in simple words, when applying the rule of excising doubtful nodular lesions, 1 out of 4 will be proven to be malignant. this result highlights that applying this approach results in an acceptable number of excisions of benign lesions. within the group of clinically doubtful benign lesions, the great majority were melanocytic nevi (44%), with spitz, compound and dermal nevi accounting for 16.1%, 13.6 and 3.8% of excisions, respectively. apart from spitz nevi that are well-known simulators of melanoma, compound, and dermal nevi are usually easy to recognize both clinically and dermodiscussion when facing nodular lesions, clinicians are asked to provide one of two mutually exclusive management recommendations, namely, excision or “no action” [19]. follow-up of nodular lesions is not an option, because of the possibility of missing a nodular melanoma, which may result in worsened prognosis given the high growth rate of the tumor [1,19]. to address this problem, a practical management strategy has been suggested, namely to recommend surgical excision of all nodular lesions for which a confident and specific diagnosis of a benign tumor is not feasible after clinical and dermoscopic examination [19]. however, one could argue that applying this rule in daily practice could result in a high number of unnecessary excisions of benign lesions. our results suggest that the aforementioned strategy is effective, resulting in an nne of 13.2 for the diagnosis of melanoma. the number needed to excise is a value indicating the accuracy of a screening strategy, measuring how many figure 2. corresponding dermoscopy image of the four excised nodular lesions (thrombosed hemangioma, clear cell acanthoma, nodular melanoma and dermal nevus). (a) asymmetric lesion, with red-to-purple background, purple globules and two areas of structureless blue pigmentation. (b) a symmetric amelanotic lesion, with multiple dotted vessels in a chain-like distribution, the so-called “string of pearls.” (c) an amelanotic nodule displaying central ulceration, scaling, and peripheral short linear vessels over a pink background. (d) asymmetric nodular lesion, with brown globules and short linear vessels. a central area of structureless white-blue pigmentation is visible. [copyright: ©2017 moscarella et al.] research | dermatol pract concept 2017;7(3):1 5 8. menzies sw, moloney fj, byth k, et al. dermoscopic evaluation of nodular melanoma. jama dermatol. 2013;149(6):699-709. 9. argenziano g, longo c, cameron a, et al. blue-black rule: a simple dermoscopic clue to recognize pigmented nodular melanoma. br j dermatol. 2011;165(6):1251-1255. 10. kalkhoran s, milne o, zalaudek i, et al. historical, clinical, and dermoscopic characteristics of thin nodular melanoma. arch dermatol. 2010;146(3):311-318. 11. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-1127. 12. cavicchini s, tourlaki a, bottini s. dermoscopic vascular patterns in nodular “pure” amelanotic melanoma. arch dermatol. 2007;143(4):556. 13. menzies sw, ingvar c, crotty ka, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):1178-1182. 14. pizzichetta ma, kittler h, stanganelli i, et al. italian melanoma intergroup. pigmented nodular melanoma: the predictive value of dermoscopic features using multivariate analysis. br j dermatol. 2015 jul;173(1):106-114. 15. carli p, de giorgi v, palli d, et al. patterns of detection of superficial spreading and nodular-type melanoma: a multicenter italian study. dermatol surg. 2004;30(11):1371-1375. 16. segura s, pellacani g, puig s, et al. in vivo microscopic features of nodular melanomas: dermoscopy, confocal microscopy, and histopathologic correlates. arch dermatol. 2008;144(10):13111320. 17. longo c, farnetani f, ciardo s, et al. is confocal microscopy a valuable tool in diagnosing nodular lesions? a study of 140 cases. br j dermatol. 2013;169(1):58-67. 18. longo c, farnetani f, moscarella e, et al. can noninvasive imaging tools potentially predict the risk of ulceration in invasive melanomas showing blue and black colors? melanoma res. 2013;23(2):125-131. 19. lallas a, zalaudek i, apalla z, et al. management rules to detect melanoma. dermatology. 2013;226(1):52-60. 20. english dr, del mar c, burton rc. factors influencing the number needed to excise: excision rates of pigmented lesions by general practitioners. med j aust. 2004; 80:16–19. 21. hansen c, wilkinson d, hansen m, argenziano g. how good are skin cancer clinics at melanoma detection? number needed to treat variability across a national clinic group in australia. j am acad dermatol. 2009;61:599–604. 22. ahnlide i, nielsen k, bjellerup m.diagnosis of pigmented skin tumours in a dermatological setting: different aspects of the number needed to excise as a measure of efficiency. acta derm venereol. 2014;94(6):683-686. 23. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10-year multicenter survey. j am acad dermatol. 2012;67(1):54-59. scopically. however, sometimes their morphologic characteristics might not allow a confident diagnosis. as shown by our results, such morphologically atypical nevi should be removed when applying the rule of excising doubtful nodular lesions. (figures 1 and 2) however, given that the nne remains absolutely acceptable, sacrificing a small number of nevi to avoid missing nodular melanoma seems a reasonable compromise. with a value of 2.8 lesions to excise to find one malignancy, our results highlight that the rule of excising doubtful nodular lesions is particularly effective for hypoor nonpigmented tumors. among nonmelanocytic lesions, the most problematic in our series were dermatofibroma, hemangioma, and pyogenic granuloma, accounting for 16.4% of doubtful lesions. this confirms that benign nonmelanocytic lesions represent a consistent proportion of the lesions to be considered in the differential diagnosis of nodular melanoma. one limitation of our study was the retrospective design, which did not allow us to evaluate prospectively the factors prompting excision of a given lesion. however, as a general rule, at our referral centers, all excisions are performed to rule out malignancy. in conclusion, excising doubtful nodular lesions seems to be an effective management strategy not to miss nodular melanoma, resulting in an acceptable rate of unnecessary excision of benign lesions. references 1. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol. 2006;142(12):1551–1558. 2. mar v, roberts h, wolfe r, english dr, kelly jw. nodular melanoma: a distinct clinical entity and the largest contributor to melanoma deaths in victoria, australia. j am acad dermatol. 2013;68(4):568-575. 3. rigel ds, friedman rj, kopf aw, polsky d. abcde: an evolving concept in the early detection of melanoma. arch dermatol. 2005;141(8):1032-1034. 4. lin mj, mar v, mclean c, wolfe r, kelly jw. diagnostic accuracy of malignant melanoma according to subtype. australas j dermatol. 2014;55(1):35-42. 5. rigel ds, russak j, friedman r. the evolution of melanoma diagnosis: 25 years beyond the abcds. ca cancer j clin. 2010;60(5):301-316. 6. kelly jw, chamberlain aj, staples mp, mcavoy b. nodular melanoma: no longer as simple as abc. aust fam physician. 2003;32(9):706-709. 7. kelly jw. nodular melanoma: how current approaches to early detection are failing. j drugs dermatol. 2005;4(6):790-793. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023131 1 a practical algorithm for the management of superficial folliculitis of the scalp: 10 years of clinical and dermoscopy experience michela starace1,2, joão paulo yamagata3, rita fernanda cortez de almeida3, simone frattini4, francesca bruni1,2, aurora alessandrini1,2, matilde iorizzo5, daniel fernandes melo3, iria neri 1,2,bianca maria piraccini1,2 1 dermatology irccs azianda ospedaliero-universitaria di bologna, bologna, italy 2 department of medical and surgical sciences, university of bologna, bologna, italy 3 department of dermatology, state university of rio de janeiro – uerj, rio de janeiro – rj, brazil 4 mental health department, guelph general hospital, guelph, on, canada 5 private dermatology practice, bellinzona/lugano, switzerland key words: folliculitis, scalp, dermoscopy, rosacea, seborrheic dermatitis citation: starace m, yamagata jp, cortez de almeida rf, et al. a practical algorithm for the management of superficial folliculitis of the scalp: 10 years of clinical and dermoscopy experience . dermatol pract concept. 2023;13(3):e2023131. doi: https://doi.org/10.5826/dpc.1303a131 accepted: january 17, 2023; published: july 2023 copyright: ©2023 starace et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: joão paulo yamagata, department of dermatology, state university of rio de janeiro – uerj, rio de janeiro – rj, brazil. e-mail: jpyamagata@gmail.com introduction: superficial folliculitis of the scalp (sfs) is a common complaint in clinical practice, and initial presentation may be difficult to differentiate as they may appear very similar to each other. objectives: the aim of this thesis is to describe the pathologies that occur clinically as folliculitis of the scalp, identify their causes and characteristics and create a standardized classification. methods: this is a retrospective clinical, dermoscopic and histopathological study over 10 years of dermatologic consultations. only individuals with a confirmed diagnosis of sfs (updated diagnostic criteria or biopsy) were included. results: in this review, we describe the various clinical features of different causes of sfs in ninety-nine cases and divided into infectious due to fungus, bacteria, or virus and inflammatory conditions such as rosacea, acneiform eruption and ofuji syndrome. conclusions: the clinician must differentiate sfs from other underlying scarring disorders to prevent poorer outcomes. we created an algorithm to help the clinician reach a proper diagnosis. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023131 introduction folliculitis means the presence of inflammatory cells in the wall and lumen of a hair follicle. superficial folliculitis of the scalp (sfs) is a frequent disorder and describes inflammatory infiltrate in the upper portion [1]. sfs is characterized by erythema, pustules and/or vesicles typical of the acute phase, with possible chronic evolution into perifollicular hyperkeratosis and keratin plugs. the course is chronic-recurrent, interspersed with acute phases sometimes difficult to manage [1]. despite several types of sfs reported in the literature, there is no official classification yet. usually, the one by herman et al, a modification of ackerman one, is the most widely known and identifies 2 major groups: superficial folliculitis (infectious and noninfectious forms) and perifolliculitis [1,2]. a classification based on the histopathological characterization of the inflammatory process (neutrophilic, lymphocytic, eosinophilic, or mixed) is also possible, which is reasonable to identify the etiological agent and the best corresponding therapeutic option [2]. objectives with this paper, we aimed to report 10 years of out-patients experience with sfs, showing the most common clinical pictures and dermoscopy patterns. besides, according to their age, we created a practical algorithm for managing sfs. methods we performed a retrospective medical record review of patients with a confirmed diagnosis of sfs over 10 years of dermatologic consultations. chart review and evaluation of clinical, dermoscopic and histopathological images from the dermatology electronic medical records were conducted, and only those individuals with a confirmed diagnosis of sfs (updated diagnostic criteria or biopsy) were included. the cases were divided into infectious due to fungus, bacteria, or virus and inflammatory conditions such as rosacea, acneiform eruption and ofuji syndrome. results between 2010 and 2020, 58 males and 41 females, aged between 1 and 80 years (mean 35 years), were referred to our attention due to sfs (table 1). according to our findings, we divided sfs into 9 groups as following. dermatophytes tinea capitis was diagnosed in 28 patients, 17 caucasian and 11 afro-descendant ones, respectively. a fungal search (microscopic and culture) was performed in all cases to confirm the clinical diagnosis and allow an etiological differentiation, important to set the most appropriate treatment. in 16 caucasian patients, the etiologic agent was microsporum canis, while in the others, the culprit came from the  tricophyton family (violaceum, soudanense, tonsurans). dermoscopy was fundamental to support the clinical suspicion (figure 1a), enlightening the presence of typical hair shaft abnormalities. however, three patients still needed a confirmatory biopsy due to an atypical clinical presentation with diffuse alopecia and crusts on an erythematous base. candida folliculitis due to candida albicans was diagnosed in an 84-year-old caucasian male with an itchy scalp. table 1. numbers of superficial folliculitis of the scalp cases observed in 10 years (2010 – 2020) of dermatologic consultations. diagnosis cases males females average age biopsy inflammatory infiltrate infective dermatophytes 28 13 15 16 3 mixed candida spp. 1 1 84 1 mixed malassezia spp. 13 8 5 40 2 mixed bacteria 21 11 10 10 1 neutrophilic herpes zoster virus 3 3 75 neutrophilic pox virus 4 4 5 4 neutrophilic non-infective acneiform rash 23 17 6 35 5 mixed rosacea 5 3 2 57 5 mixed ofuji syndrome 1 1 1 1 eosinophilic total 99 58 41 35 22 original article | dermatol pract concept. 2023;13(3):e2023131 3 multiple whitish pinpoint folliculitis could be seen on an erythematous-squamous background. however, the clinical and dermoscopic aspects were atypical, and only histological examination confirmed the diagnosis. malassezia at dermoscopy, the typical arborized vessels were always present, as well as scales. around the pustules were also evident dotted vessels (figure 1b). dermoscopy facilitated the diagnosis in 11 cases, while 2 needed histopathological examination. bacteria primary impetigo of the scalp is relatively rare, whereas it is much more common to see secondary forms where bacteria colonize the scalp after scratching due to itch. the most frequently isolated bacteria in our group were staphylococcus aureus and streptococcus pyogenes. all cases were primary form. physical examination, facilitated by dermoscopy, always allowed the diagnosis except for 1 patient. at dermoscopy, single exudative to crusted yellowish -colored lesions, sometimes trapping tufts of hair, and surrounded by erythema with sparsely dotted vessels, were clearly visible. herpes zoster virus all patients reported during the vesicular phase evolved into a crusty phase subsequently. the associated neuritis helped define the diagnosis. a confirmatory pcr was, however, made in all patients. pox virus molluscum contagiosum was diagnosed in 4 children. two presented whitish papules of a few mm in diameter visible to the naked eyes but better defined at dermoscopy [5]. despite the evident presence of molluscum body after curettage, pathology was required to make the differential diagnosis with scalp nodules. acneiform eruption pustules and follicular crusts are generally observed on an erythematous base, sometimes accompanied by pain or accidental bleeding with minimal trauma. the culture was always negative for bacteria. in milder cases, a biopsy was performed to support the differential diagnosis with seborrheic dermatitis (sd) due to dilated and arborized capillaries. at dermoscopy, pustular lesions were clearly visible as distributed on top of the follicular ostium. the roof of the pustular lesions is very fragile, and easily ruptures with leakage of serum material (figure 1c). rosacea the presence of demodex folliculorum (tails) was identified in five patients referred for red and itchy scalp. skin biopsy was performed in all cases as the clinical picture and dermoscopy pattern did not provide a conclusive diagnosis despite the presence of diffuse erythema, branching vessels and small dry scales (figure 1d). in some areas of the scalp, the most sun-exposed, we have also identified a diffuse vascular figure 1. (a) dermoscopic image of tinea capitis (kerion). culture of the lesion confirmed the presence of microsporum canis. (b) dermoscopic image of dilated and arborizing vessels with dotted vessels around the pustule, which are typical of seborrheic dermatitis. (c) dermoscopic image of folliculitis during the acute phase of a histologically confirmed acneiform eruption. (d) dermoscopic image of scalp rosacea: erythematous round lesions with a central yellowish area. 4 original article | dermatol pract concept. 2023;13(3):e2023131 instrumental techniques, helps determine the correct diagnosis. also, very much important is not to miss another underlying and potentially scarring disorder. etiological agents such as malassezia, demodex, etc, are common commensals of our scalp and live in the follicular infundibulum. when in excess, they can act as trigger factors, stimulating a perifollicular inflammatory reaction comprised of lymphocytes, neutrophils, and, occasionally, multinucleated histiocytes [10]. they can be treated but not removed. malassezia is implicated in the pathogenesis of sd. in the presence of significant refractory inflammation, folliculitis appears. because of the intense itch, scratching the pustules can frequently lead to bacterial superinfection and yellow crusts [4]. folliculitis in tinea capitis is generally present in acute stages and presents as a follicular micro papule that progresses centrifugally to form a round or polycyclic plaque 5-6 cm in diameter with hair shafts trapped inside [3]. ofuji syndrome is characterized by four clinical signs and symptoms: 1. sterile pustules in seborrheic areas, 2. intermittent outbreaks accompanied by leukocytosis and eosinophilia, 3. primary follicular eosinophilic pustules, 4. good response to small and prolonged doses of corticosteroids. post-inflammatory hyperpigmentation might follow as a sequela [9]. from the data that emerged in this study, we created an algorithm (figure 2) based on the clinical and dermoscopic picture, to help reach the correct diagnosis. table 2 summarizes the main clinical, dermoscopic and histopathological alteration, characterized by round lesions, frankly erythematous and flat, painful if of recent onset, and with a central yellowish area, as reported in the literature [6,7]. the color of these spots turns brownish over time. all patients were classified as rosacea third stage due to a stable phase of vasodilation. a variant of rosacea named glandular form, characterized by edematous papules, large pustules, nodulocystic lesions, marked inflammation and hyperseborrhea has been described in the literature but never found in our practices [8]. eosinophilic pustular folliculitis (ofuji syndrome) a 1-year-old child presented us with small scalp pustules that tended to confluence and form an annular or polycyclic plaque. yellow crusts were also present, possibly due to scratching. at dermoscopy, pustules and the erythematous base were more evident, as well as crusts and dilated vessels. biopsy was, however, mandatory, and the pathology report confirmed eosinophilic pustular folliculitis. cytology was also important to reveal the presence of eosinophils and to allow differential diagnosis with infective forms. discussion an early diagnosis of sfs is sometimes difficult as, initially, they may appear very similar to each other. an accurate clinical history, with careful physical examination and figure 2. suggested algorithm to follow when dealing with superficial folliculitis of the scalp sfs = superficial folliculitis of the scalp. original article | dermatol pract concept. 2023;13(3):e2023131 5 table 2. clinical, dermoscopic and histopathological features of sfs. clinical features dermoscopy histopathology dermatophytes follicular micropapule. comma, broken and corkscrew hair, black dots and pustules with or without trapped hair. superficial and deep mixed perifollicular infiltrate. positive pas staining. candida from small pustules to painful papules, nodules and pustules with the presence of itching. multiple whitish pinpoint pustules, scattered throughout the scalp. peripheral erythematous halo with small dilated capillaries. dense perifollicular mixed-type infiltrate, edema, abscesses at the follicular epithelium and pas-positive staining. malassezia folliculitis with small whitish scales on the scalp, erythematousdesquamative plaques with greasy appearance and seborrhea with greasy and opaque hair. furfuraceous scales, arborized vascular and atypical reticular dilatations, small whitish folliculitis, centered by the hair and a small crust secondary to itching. mild to moderate lymphocytic inflammatory infiltrate at the infundibular, peri-infundibular and peri-isthmic level, mild fibroplasia, abscesses, dilation of the infundibulum with laminated orthokeratosis and focal parakeratosis of the epidermis. bacteria a single lesion with a tuft of hair. yellowish-whitish pustule with perifollicular erythema, yellow-brownish crusts, painful perifollicular papular lesions with peripheral erythema. a crusty thickened exudative lesion, yellowish in color, with a central tuft and peripheral erythema; brownish yellow background with an aflegmasic alopecia, atrophy, and absence of follicular openings. collection of neutrophils and bacteria in the epidermis with dilated vessels, edema, and mild-moderate mixed type -infiltrate in the papillary and middle dermis. herpes zoster multiple vesicles and subsequent pustules following the innervation, with neuritis of the scalp. herpetic polymorphism: vesicles, pustules and crusts at the same time and peripheral erythema with numerous dilated and superficial capillaries, scabs and scarring lesions. intraepidermal vesicles containing multinucleated keratinocytes with a nucleus of grayish color, marginal chromatin, ballooning cytoplasm and acantholysis. a moderatedense perivascular and interstitial inflammatory infiltrate of mixed-type fibrosis and destruction of the adnexal structures. pox virus hemispherical and roundish papules, in palepink color, 2-3 mm in diameter, with a central navel and a smooth regular surface. central umbilicated papule surrounded by yellowish-white polylobed amorphous structures. crown vessels known as “red corona” emerge from the periphery of the lesion and radiate towards the center, rarely crossing each other. rounded basophilic bodies present among the keratinocytes are observed, grouped in a “crater” and in the infundibular hyperplastic areas of the granular and spinous layer of the epidermis. acneiform eruption papules, pustules or follicular crusts on erythematous skin, pain with possible bleeding or leakage of pus. central pustular lesions, intensely erythematous with dilated capillaries in the periphery, crusts of variable colors from intense red to yellowish-brown, dilated vessels with a lattice appearance throughout the scalp. suppurative folliculitis in the superficial dermis with a neutrophilic inflammatory infiltrate, dilated sebaceous glands and hyperkeratinization of the intrainfundibular epithelium and retention of lamellae, plugs. rosacea diffuse erythema of the scalp with small dry scales, painful flat erythematous round lesions, and facial involvement. branching vessels with a yellowish central area that turns brownish over time. vasodilation of the vessels of the subpapillary plexus and a polymorphic inflammatory infiltrate, non-caseous granulomatous infiltrate in the perifollicular and perivascular areas, and the presence of demodex folliculorum. ofuji syndrome plaque of small erythematous-edematous, sterile pustules in seborrheic areas. central folliculitis with dilated capillaries in the periphery and yellowish crust. massive mixed-type inflammatory infiltrates, microabscesses, epithelial necrosis and intercellular edema. 6 original article | dermatol pract concept. 2023;13(3):e2023131 2. ackerman ab. folliculitis and perifolliculitis. en histologic diagnosis of inflammatory skin diseases. a method by pattern analysis. philadelphia: lea&febiger ed, 1978:641-713. 3. golińska j, sar-pomian m, rudnicka l. diagnostic accuracy of trichoscopy in inflammatory scalp diseases: a systematic review. dermatology. 2022;238(3):412-421.  doi: 10.1159/000517516. pmid: 34265772. 4. meza-romero r, navarrete-dechent c, downey c. molluscum contagiosum: an update and review of new perspectives in etiology, diagnosis, and treatment. clin cosmet investig dermatol. 2019;12:373-381.  doi: 10.2147/ccid.s187224. pmid: 31239742. pmcid: pmc6553952. 5. vázquez-herrera ne, zamora-benze dm, garza-chapa ji, rodríguez-baca ab, tosti a. scalp rosacea: rethinking peripilar scaling. skin appendage disord. 2021;7(5):382–386. doi: 10.1159/000514565. pmid: 34604328;. pmcid: pmc8436626. 6. miguel-gomez l, fonda-pascual p, vano-galvan s, carrillo gijon r, muñoz-zato e. extrafacial rosacea with predominant scalp involvement. indian j dermatol venereol leprol. 2015;81(5):511-513. doi: 10.4103/0378-6323.162340. pmid: 26261148. 7. williams j, eichenfield l, burke b, barnes-eley m, friedlander s. prevalence of scalp scaling in prepubertal children. pediatrics. 2005; 115(1):e1-6. doi: 10.1542/peds.2004-1616. pmid: 15629960. 8. naldi l. diphoorn j. seborrhoeic dermatitis of the scalp. bmj clin evid. 2015;27:1713. pmid: 26016669. pmcid: pmc4445675. 9. meneses om, donati a, silva fo, mimiça mj, machado cj, veasey j. trichoscopy patterns of tinea capitis and their correlation with mycological culture results. j am acad dermatol. 2023;88(1):166-167. doi: 10.1016/j.jaad.2021.12.010. pmid: 34906665. 10. nervi sj, schwartz ra, dmochowski m. eosinophilic pustular folliculitis: a 40-year retrospect. j am acad dermatol. 2006;55(2):285-289. doi: 10.1016/j.jaad.2006.02.034. pmid: 16844513. features of sfs. when dealing with a pediatric patient with sfs, the first step is to classify the presence of a single lesion with tufted hair or multiple diffuse lesions. in single lesions, if dermoscopy shows a crusty/exudative yellowish area with a central tuft, the diagnosis of scalp impetigo is the most probable. in cases with multiple diffuse lesions on the scalp, when dermoscopy presents with typical hair shaft abnormalities such as comma, broken or corkscrew hairs and pustules with or without trapped hairs, tinea capitis should be suspected, and a confirmatory culture requested. when dermoscopy is not typical for tinea capitis, a biopsy is recommended. in adult patients with sfs, the main point is to assess the presence of itching. when there is pruritus, associated with dilated arborizing vessels, the diagnosis of rosacea (when there is concomitant facial involvement) or sd should be considered. in cases without pruritus, a thorough clinical history and dermoscopy help differentiating the diagnosis of acneiform eruption or candida. in conclusion, this article suggests an algorithm containing these main differential diagnoses to guide dermatologists in clinical practice. from our algorithm, in a pediatric patient, folliculitis generally occurs with impetigo or tinea capitis. in adults, the main reason for sfs is probably sd. symptoms such as pain or discomfort may suggest an acneiform rash – if non-itchy – or scalp rosacea – if itching, and in both conditions facial involvement is present. references 1. herman le, harawi sj, ghossein ra, kurban ak. folliculitis. a clinicopathologic review. pathol annu. 1991;26pt2:201-246. pmid: 1861886. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023083 1 evaluation of flexibility and thickness of cleft lip scars after treatment with microneedling technique: a cohort trial mohamad alghazzawi1, yasser almodalal2 1 department of oral and maxillofacial surgery, university of damascus dental school, damascus, syria 2 oral and maxillofacial surgery, university of damascus dental school, damascus, syria key words: cleft lip, scar, scar management, scar treatment, microneedling citation: alghazzawi m, almodalal y. evaluation of flexibility and thickness of cleft lip scars after treatment with microneedling technique: a cohort trial. dermatol pract concept. 2023;13(2):e2023083. doi: https://doi.org/10.5826/dpc.1302a83 accepted: september 20, 2022; published: april 2023 copyright: ©2023 alghazzawi et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: mohamad alghazzawi, phd student, department of oral and maxillofacial surgery, university of damascus dental school, damascus, syria. e-mail: d.ghazawy86@gmail.com mobile: +963988359129 introduction: the early surgical treatment of the cleft lip led to a postoperative scar formation which may affect the physiological and psychological aspects of the patient. objectives: evaluating the improvement rate of thescar flexibility and thickness of the cleft lip scar after treatment with the microneedling. methods: sixteen patients (12 females and 4 males), aged 16-30 years who had a cleft lip scare were included in the current study. all patients suffered from a visible defective scar in the upper cleft lip. all patients were treated with a microneedling pen device combined with topical application of oil-based hyaluronic acid. the procedure was performed in 4 sessions with 3-week intervals between sessions. the scars were assessed by the patient and an external observer using the patient and observer scar assessment scale. results: thickness of the scar was improved according to the patient and observer opinions (67.28% and 61.55% respectively). flexibility was improved according to the patient observer opinion (65.57% and 60.25% respectively). conclusions: microneedling treatment can be considered as an effective method for the treatment of the defective scars resulting from the cleft lip plastic surgery. the microneedling technique is a simple, easy, safe, non-invasive, and low-cost procedure. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023083 introduction the cleft lip is a congenital development defect caused by the lack of connection of the upper lip tissues during the embryonic period [1]. the cleft lip defect has an influence on the normal facial appearance and functions such as feeding and speech, which affect the child psychosocial development negatively [2]. the surgical treatment of the cleft lip allows to secure continuity of the lip tissues. it is usually performed at the age of 2 to 6 months. there are many surgical techniques for the primary repair of cleft lip. unfortunately, these techniques are associated with a postoperative scar formation [3]. the scar often undergoes contracture and hypertrophy, due to the repeated movements related to facial expressions and basic life activities, which adversely affect the postoperative wound healing process [4]. the scar tends to be raised above the skin surface and is hyperpigmented more than the normal skin [5]. the scar tissue leads to the creation of some secondary deformities, such as deformed philtrum, cupid’s bow asymmetry, tight upper lip, whistle deformity, and irregularities in the function of orbicularis oris muscle [6,7]. the scar of the upper lip may restrict the growth and development of the maxilla, leading to a skeletal class iii malocclusion [8]. a mature cutaneous scar usually consists of a large amount of collagen fibers (80%-90% type i, the rest type iii) [9]. the collagen fibers within the scar are arranged in bundles parallel to the surface of the skin. on the other hand, the collagen fibers in the normal skin are arranged in a nonparallel ‘‘basket-weave’’ orientation [10]. the basement membrane of the epidermis that develops over the scar tissue is flatter than the normal skin tissue because the scar does not contain the rete pegs that penetrate the dermis [9]. in addition, the cutaneous scar does not contain dermal appendages such as hair follicles, sebaceous glands, and stem cells [5,11]. the extracellular matrix (ecm) of the scar tissue contains less elastin than normal skin, resulting in decreased elasticity in the scar [12]. clinically and cosmetically, a favorable scar has an imperceptible fine line and is parallel to skin creases and folds, similar in color and contour to the surrounding skin, and within the level of the skin [13]. many methods were proposed for treating the scar of cleft lip including surgery, steroids injection, botulinum toxin type a injection, silicone gel sheeting, fractional ablative lasers, and microneedling [14,15]. the microneedling procedure is also called the percutaneous needle collagen induction technique (pci). the pci was firstly introduced by orentreich and orentreich [16] who used the needles in order to stimulate the production of collagen in the treatment of depressed scars and wrinkles. the mechanism of action is mainly based on the rupture and removal of the damaged subepidermal collagen followed by substitution for new collagen and elastin fibers. the microneedling treatment stimulates collagen production without removing the epidermis, and the tissue regeneration time is commonly shorter than the ablative techniques, which substantially reduces the risk of adverse effects when benchmarked. as well, the skin becomes more resistant and thicker [15]. objectives the current study aimed to evaluate the efficacy of microneedling in improving the flexibility and thickness of the cleft lip scar as one of the conservative techniques in the management of postoperative scars. methods trial design this study was a cohort study. the current trial was achieved at the department of maxillofacial surgery at the faculty of dentistry, damascus university, syria between august 2019 and september 2021. ethical approval was obtained from the local ethics research committee at the university of damascus, dental school (reference number: 25223102017-den). participants and eligibility criteria the sample consisted of 18 scars in 16 patients (14 unilateral clefts, 2 bilateral clefts). the distribution was as following: 2 males (3 scars) and 14 females (15 scars) of cleft lip and palate patients who completed their lip repair surgeries. the age of patients ranged from 16-35 years. all patients had a visible defective scar and the desire to perform cosmetic procedures in order to improve the general appearance of the lip. all individuals were able to follow the stages of treatment. microneedling intervention the automated microneedling tchnique was performed using an automated micro needling dermapen (beijing hye technology co) which is considered an advanced technology for vertical pricking of the skin through several needles that puncture the skin with an automatic percussion function. the device consists of a handpiece, equipped with an electric motor and a head consisting of 12 needles, 33 gauges are attached to a disposable rod (figure 1). the needles move up and down from 0.25 mm to 2.5 mm entering depth. the speed of movements ranges from 1 to 7 pricks per second. the entry depth and speed are adjusted depending on the scare area via private keys. original article | dermatol pract concept. 2023;13(2):e2023083 3 the treatment was divided into 4 sessions with an interval of 3 weeks. the surface of scar was cleaned well with 0.10 ml hexamidine solution, then a local anesthetic cream (emla) was applied for 20 minutes. after that an oil-based hyaluronic substance with a concentration of 3.5% and formulated from a mixture of hyaluronic acid of non-cross-linked biotechnological origin was applied to the skin surface. the dermapen was applied to the scar with a prick depth of 2-2.5 mm and speed of 5 pricks per second, depending on the device instructions for the treatment of scars. finally, the surface of the scar was cleaned with a piece of sterilized gauze soaked in saline solution and a steri-strip bandage was applied (figures 2 and 3). additional images for clinical cases were treated in the current study have been included in figures 4 and 5. all patients were informed that a redness can be seen after treatment and may last for 2-3 days after the procedure. all of them were also asked to apply a cold compress to the workplace for the first couple of hours. outcome assessment the thickness and flexibility of the cleft scar were assessed before treatment and one month after the last treatment session by both the patient and three external observers from the oral and maxillofacial surgery residents using the patient and observer scar assessment scale (posas) [17]. comparisons have been made between the baseline data (before treatment) and after one month of treatment. thickness: the distance between the surface of the scar and the adjacent skin surface. flexibility: it is measured by the flexibility of the scar between the index finger and thumb. the evaluated items consist of a 10-point scale where 1 indicates the best scar that matches the adjacent healthy skin and the number increases as the scar worsens as 10 indicates the worst scar.figure 1. the automated microneedling dermapen. figure 2. (a) topical anesthesia; (b) application of hyaluronic acid; (c) the microneedling process; (d) steri-strip dressing. 4 original article | dermatol pract concept. 2023;13(2):e2023083 figure 4. clinical case 2. (a) before treatment; (b) immediately after microneedling; (c) after 1 month of the final microneedling process. figure 3. clinical case 1. (a) before treatment; (b) immediately after microneedling; (c) after 1 month of the final microneedling process. figure 5. clinical case 3. (a) before treatment; (b) immediately after microneedling; (c) after 1 month of the final microneedling process. statistical analysis all statistical analyses were performed using spss software (version 20; ibm)). the paired sample t-test was applied to assess the differences in the thickness and flexibility of the cleft lip scar before and after treatment with microneedling. results the percentage of improvement for both the thickness and elasticity of the scar was assessed, according to the opinions of both the patient and the observers with the posas, according to the following equation: the improvement percentage = (the amount of the improvement after treatment / pre-operative rate) * 100 (table 1). the thickness of the scar was improved according to the patient’s and observer’s opinions (67.28% and 61.55% respectively). flexibility was improved according to the patient’s and observer’s opinion (65.57% and 60.25% respectively). the thickness and flexibility were improved significantly after the pci according to the patient and outer observer reports (p < 0.05) (table 2). according to the patient opinion, the mean improvement rate was 4.899 and 5.791 for thickness and flexibility of the scare respectively. according to the observer opinion the mean improvement rate was 4.548 and 4.963 for thickness and flexibility of the scar respectively. conclusions aesthetics is a science, practice and experience. it is developing rapidly due to the entry of new technologies and devices original article | dermatol pract concept. 2023;13(2):e2023083 5 scare. in the current trial, the microneedling treatment and hyaluronic acid application were combined together. lee et  al combined the microneedling treatment with a human stem cell conditioned medium [20]. the same findings were observed by aust et al who conducted a study to evaluate the effectiveness of microneedling in improving the appearance of post-burn scars [21]. finally, the lack of number of the patients in the current study and the short duration of the follow-up period are the main limitations of this trial. in conclusion, the cleft lip scar management should be considered as a principal element of the treatment plan in cleft patients. in the case of patients with secondary cleft lip deformities, surgical correcting methods should be considered taking into account that any surgical intervention leads to new scars formation. therefore, it is necessary to implement nonsurgical methods to prevent the scar hypertrophy. microneedling therapy can be considered an effective modality for the treatment of surgical cleft lip scars in patients. microneedling treatment is a simple and cost-effective technique in the treatment of the facial scars. damascus dental school (reference number: 25223102017-den). references 1. silva hpvd, arruda tts, souza ksc, et  al. risk factors and comorbidities in brazilian patients with orofacial clefts. braz oral res. 2018;32: e24. doi: 10.1590/1807-3107bor-2018. vol32.0024. pmid: 29641641. in this field. on the other hand, aesthetics has a principal role in people social and professional life. this study was conducted to evaluate the efficacy of microneedling with hyaluronic acid therapy in the management of postoperative cleft lip scars resulting from primary and secondary repair surgeries in cleft lip patients. the elasticity and thickness of the scar were assessed according to the opinion of the patient and external observers. in the current study, the flexibility of the scar was improved to reach as close as the surrounding natural skin with an average improvement percentage of 65.57% and 60.25% for the patient and observer respectively. the same findings were observed in the thickness of scar. the level of scare (thickness) also improved to become very similar to the surrounding natural skin with an average improvement percentage of 67.28% and 61.55% for patient and observer respectively. these results were similar to what was reported by lakshmi et al who evaluated the pci efficacy in treating the scars resulting from trauma, surgery, or cleft lip. lakshmi et al reported that the scar improvement rate after microneedling was 100% [18]. this percentage was higher than the current results. this dissimilarity may be due to the involvement of many types of scares not only the scars resulting from postoperative clef lip scars. el-domyati et al demonstrated that the treatment with microneedles enhances the growth of type i, iii, and vii collagen and tropoelastin [19]. lee et al found that the microneedling combined with other substances is effective in the enhancement of cleft lip table 1. the descriptive values in both the thickness and elasticity of the scar. studied item the resident before after the amount of improvementa improvement percentage thickness patient 7.281 2.382 -4.899 67.28% observer 7.389 2.841 -4.548 61.55% flexibility patient 8.831 3.040 -5.791 65.57% observer 8.237 3.274 -4.963 60.25% a the amount of improvement = post-operative rate value – pre-operative rate value. table 2. comparison of the thickness and flexibility of the lip scar before and after the microneedling operation. variable assessor time n mean ± sd t-test value p valueb thickness patient before 18 7.28±1.36 15.149 <0.001a after 18 2.38±1.17 observer before 18 7.38±0.99 23.795 <0.001a after 18 2.84±0.79 flexibility patient before 18 8.83±1.58 5.57 <0.001a after 18 3.04±1.14 observer before 18 8.23±0.74 30.233 <0.001a after 18 3.27±0.67 a p <0.05 significant difference; b paired t test was applied sd = standard deviation. 6 original article | dermatol pract concept. 2023;13(2):e2023083 2. chen g, li mx, wang hx, et al. identification of key genes in cleft lip with or without cleft palate regulated by mir-199a-5p. int j pediatr otorhinolaryngol. 2018; 111:128-137. doi: 10.1016/j.ijporl.2018.06.005. pmid: 29958595. 3. de korte cl, van hees n, lopata rg, weijers g, katsaros c, thijssen jm. quantitative assessment of oral orbicular muscle deformation after cleft lip reconstruction: an ultrasound elastography study. ieee trans med imaging. 2009;28(8):1217-1222. doi: 10.1109/tmi.2009.2013461. pmid: 19211342. 4. soltani am, francis cs, motamed a, et  al. hypertrophic scarring in cleft lip repair: a comparison of incidence among ethnic groups. clin epidemiol. 2012; 4:187-191. doi: 10.2147/clep. s31119. pmid: 22879780. pmcid: pmc3413167. 5. baum cl, arpey cj. normal cutaneous wound healing: clinical correlation with cellular and molecular events. dermatol surg. 2005;31(6):674-686; discussion 686. doi: 10.1111/j.15244725.2005.31612. pmid: 15996419. 6. cohen m. residual deformities after repair of clefts of the lip and palate. clin plast surg. 2004;31(2):331-345. doi: 10.1016/ s0094-1298(03)00133-0. pmid: 15145673. 7. stal s, hollier l. correction of secondary cleft lip deformities. plast reconstr surg. 2002;109(5):1672-1681; quiz 1682. doi: 10.1097/00006534-200204150-00031. pmid: 11932617. 8. zhang h, deng f, wang h, huang q, zhang y. early orthodontic intervention followed by fixed appliance therapy in a patient with a severe class iii malocclusion and cleft lip and palate. am j orthod dentofacial orthop. 2013;144(5):726-736. doi: 10.1016/j.ajodo.2012.11.028. pmid: 24182589. 9. monaco jl, lawrence wt. acute wound healing an overview. clin plast surg. 2003;30(1):1-12. doi: 10.1016/s00941298(02)00070-6. pmid: 12636211. 10. van zuijlen pp, ruurda jj, van veen ha, et al. collagen morphology in human skin and scar tissue: no adaptations in response to mechanical loading at joints. burns. 2003;29(5):423-431. doi: 10.1016/s0305-4179(03)00052-4. pmid: 12880721. 11. hu ms, maan zn, wu jc, et al. tissue engineering and regenerative repair in wound healing. ann biomed eng. 2014;42(7):14945107. doi: 10.1007/s10439-014-1010-z. pmid: 24788648. pmcid: pmc4144830. 12. amadeu tp, braune as, porto lc, desmoulière a, costa am. fibrillin-1 and elastin are differentially expressed in hypertrophic scars and keloids. wound repair regen. 2004;12(2):169-174. doi: 10.1111/j.1067-1927.2004.012209. x. pmid: 15086768. 13. watson d, reuther ms. scar revision techniques-pearls and pitfalls. facial plast surg. 2012;28(5):487-491. doi: 10.1055/s0032-1325642. pmid: 23027214. 14. zhang c, yin k, shen ym. efficacy of fractional carbon dioxide laser therapy for burn scars: a meta-analysis. j dermatolog treat. 2021;32(7):845-850. doi: 10.1080/09546634.2019.1704679. pmid: 31865824. 15. lima e, lima m. pci and transcutaneous drug delivery. percutaneous collagen induction with microneedling. springer. 2021;185195. isbn : 3-030-57541-1. 185-193.pp346. 16. orentreich ds, orentreich n. subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. dermatol surg. 1995;21(6):543-549. doi: 10.1111/j.15244725.1995.tb00259.x. pmid: 7773602. 17. fearmonti r, bond j, erdmann d, levinson h. a review of scar scales and scar measuring devices. eplasty. 2010;10:e43. pmid: 20596233. pmcid: pmc2890387. 18. vijaya lakshmi y, swetha reddy l, naga neelima devi k, et al. evaluation of microneedling therapy in management of facial scars. j craniofac surg. 2020;31(2):e214-e217. doi: 10.1097/ scs.0000000000006145. pmid: 31977699. 19. el-domyati m, barakat m, awad s, medhat w, el-fakahany h, farag h. multiple microneedling sessions for minimally invasive facial rejuvenation: an objective assessment. int j dermatol. 2015;54(12):1361-1369. doi 10.1111/ijd.12761. pmid: 26096653. 20. lee hj, lee eg, kang s, sung jh, chung hm, kim dh. efficacy of microneedling plus human stem cell conditioned medium for skin rejuvenation: a randomized, controlled, blinded split-face study. ann dermatol. 2014;26(5):584-591. doi: 10.5021/ ad.2014.26.5.584. pmid: 25324650. pmcid: pmc4198585. 21. aust mc, fernandes d, kolokythas p, kaplan hm, vogt pm. percutaneous collagen induction therapy: an alternative treatment for scars, wrinkles, and skin laxity. plast reconstr surg. 2008;121(4):1421-1429. doi: 10.1097/01. prs.0000304612.72899.02. pmid: 18349665. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022197 1 the hunt for baby melanomas: a prospective study of the dermoscopy features on 100 small melanoma cases with in vivo surface diameters up to a maximum of 6 mm john h pyne1, sarah macdonald1, susan m beale1, esther myint1, wei w huang1, simon paul clark1, andrew trang1 1 faculty of medicine, the university of new south wales, sydney, australia key words: early small melanoma, dermoscopy, confocal microscopy, pigmented hair follicles, pseudopods citation: pyne jh, macdonald s, beale sm, et al. the hunt for baby melanomas: a prospective study of the dermoscopy features on 100 small melanoma cases with in vivo surface diameters up to a maximum of 6mm. dermatol pract concept. 2022;12(4):e2022197. doi: https://doi.org/10.5826/dpc.1204a197 accepted: march 27, 2022; published: october 2022 copyright: ©2022 pyne et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: john pyne, associate professor, faculty of medicine, the university of new south wales, sydney, 131 ellesmere rd gymea bay nsw australia. ph +61 414 750 625. fax +61 2 9525 3193. e-mail: j.pyne@uq.edu.au introduction: early diagnosis can improve melanoma prognosis. dermoscopy can enhance early melanoma recognition. objectives: examine the dermoscopy features of early melanoma up to a maximum surface diameter of 6 mm. methods: consecutive melanoma cases were collected from two medical practices in sydney, australia 2019-2021. dermoscopy features were recorded for melanomas by maximum surface diameter, to the nearest 0.1 mm, to a limit of 6 mm. results: total cases numbered 100; with males (n = 48) and females (n = 52), melanoma in situ (mis,  n = 96) and invasive (n = 4). the most frequent anatomic sites on both males and females were back (males n = 20, females n = 16) then knee or leg (males n = 8, females n = 12). minimum respective mis diameters for males/females was 1.2/2.0 mm and for invasive cases 2.0/3.4 mm. highest frequency dermoscopy features were: light brown, dark brown, gray and asymmetric melanoma shape. brown pigment in hair follicles were more frequent on legs compared to other anatomic sites (odds ratio [or] 14.6; 95% ci 1.29-165.17, p 0.03). pseudopods were substantially increased in frequency comparing diameters less than 4 mm with 4 up to 6 mm (or 8.81; 95% ci 1.05-73.9, p  0.004). structureless area cases recorded increased gray (or 7.08; 95% ci 1.61-31.11, p=0.01). abstract 2 original article | dermatol pract concept. 2022;12(4):e2022197 or greater were excluded. cases with known previous topical or ablative therapies, any previous partial biopsy or adjacent scars were also excluded. each case was an attempted full excision with a 2mm dermoscopy identified margin. a dermoscopy image for each case was submitted along with each tissue specimen to the reporting pathologists. further, representative vivascope 1500 confocal images were also available to the reporting pathologists for difficult to diagnose cases. excised tissue was examined routinely with hematoxylin and eosin staining followed with sox 10 and prame stains if required. inclusion of each case required an independent histopathological diagnosis of melanoma from each of two experienced dermato-histopathologists. cases where only one of two dermato-histopathologists reported melanoma were also excluded. atypical vessels were defined as dermoscopy identified vessels within the melanoma “footprint” displaying a different morphology or increased number of vessels per unit area compared to vessels in the adjacent background skin out to 10 mm from the edge of the melanoma, an example is displayed in figure 5b. asymmetric shape relates to the silhouette of the melanoma. atypical network was defined when the width of lines forming a reticular brown network exceeded the diameter of the adjacent dermal papillae, see  figure 5c. polygons were angular lines in polygonal shapes [8], see figure 6b. structureless areas displayed no distinct features within the area concerned and had to occupy at least 20% of the melanoma “footprint”, see figure 5a. results all cases presented as macules with no overt surface elevation. patients had predominately northern european ancestry with fair skin and were typically australian born. following histopathologic diagnostic confirmation, a total of 100 melanoma cases were collected. cases on males numbered 48 (mean age 56) and on females 52 (mean age also  56), see table 1. study cases by anatomic site and sex are set out in table 2. no cases were recorded on the following sites on either sex: scalp, eyelid, chin, cutaneous or mucosal lip, hand, fingers or toes. females had an increased frequency of introduction primary cutaneous melanoma prognosis is optimal when early diagnosis leads to prompt effective intervention. however, small diameter early melanoma cases are often feature poor and may be difficult to recognize. the use of dermoscopy has been shown to enhance diagnostic accuracy for melanoma [1-3]. some recent publications have addressed the dermoscopy features of small early melanoma [4,5]. additional evidence collated with the dermoscopy features of smaller melanomas may facilitate diagnosing these early cases [6]. recent commentary has questioned the value of diagnosing melanoma with small diameters and suggested suspicious pigmented lesions not be biopsied if less than 6mm diameter [7]. objectives the main purpose of this study was to quantify the dermoscopy features of melanoma cases with an in vivo maximum horizontal diameter of up to and including 6 mm. a second aim was to record how these dermoscopy features varied by the surface diameters in 1mm increments for melanomas presenting with a surface diameter of 6 mm or less. methods consecutive melanoma cases were prospectively collected from routine workflow in 2 medical practices in sydney, australia over 28 months from 2019 until 2021. one practice was a referral practice with vivascope 1500 confocal capability. the second practice was a primary care designated skin cancer clinic. ethics approval was provided by the university of queensland, brisbane australia (2016001221). all patients in the study provided informed consent for their data to enter the study. there were no exclusions based on patient age or anatomic site. dermoscopy using either a heine ic1 or vivacam dermatoscope recorded each case in vivo maximum horizontal diameter, measured in 0.1 mm increments, up to and including 6.0 mm. cases with a maximum surface diameter 6.1mm melanomas with edge angulation were noted in 20%-50% of cases across diameters 1-6 mm, less frequent were pigmented circles and polygons. conclusions: watch out! mis presented with a surface diameter of just 1.2 mm and invasive melanoma 2.5 mm. pseudopods were a strong clue to melanomas with a surface diameter less than 5mm. we found melanomas on leg sites displayed more frequent pigmented hair follicles. original article | dermatol pract concept. 2022;12(4):e2022197 3 male case recorded a mitotic count: 1 per mm2 from the case on the back. the only invasive melanoma on a female was on the upper arm with a breslow of 0.4 mm and 0 mitotic count. there was no microscopic evidence of tumor induced ulceration on all four invasive cases. no cases of acral, nodular or desmoplastic melanoma were recorded in this study. when using dermoscopy the colors identified within the melanoma with the highest percentage presence in descending order were: light brown, dark brown and gray, see figure  1. figure 1 also displays these dermoscopy features with a typical frequency range from 50% up to 100% across the recorded range of diameters. in comparison, other dermoscopy identified features with moderate prevalence (frequency of feature from 15% up to 50%) are set out in figure 2. lower prevalence features (frequency at or below 25% of cases) are displayed in figure 4. although low in frequency, typically less than 10% of cases, polygons were recorded in cases over 2 mm diameter. melanomas on the upper arm compared to males: odds ratio [or] 4.16, 95% ci 0.836-20.7, p 0.08. for knee combined with leg sites females also had more melanomas compared to males: or 1.49, 95% ci 0.5454.05, p 0.44. males recorded more melanomas on the back compared to females: or 1.61, 95% ci 0.707-3.67, p 0.26. however, none of these anatomic site differences reached statistical significance. melanoma in situ was reported in 96 cases. the average surface diameter for the melanoma in situ cases was 3.9 mm (n = 96) and for the invasive melanoma cases 3.6 mm (n = 4). on males the smallest recorded surface diameter for a melanoma in situ case was 1.2 mm (chest) and for invasive cases 2.5 mm (back). in comparison, on females the smallest diameter melanoma in situ case was 2.0 mm (thigh) and the single invasive case 3.4 mm (upper arm). three invasive melanoma cases were recorded on males: one with a breslow of 0.4 mm (thigh) the other two cases both had a breslow of 0.5 mm (abdomen and back), again see table 2. only one table 1. patient characteristics by sex and in vivo melanoma surface diameter. male (n = 48) female (n = 52) age (years) range (min, max) 18-78 29-90 mean 56 56 iqr 45-66 42-69 diameter of lesion (mm) < 2.0 5 0 2.0-3.0 13 15 3.1-4.0 8 13 4.1-5.0 13 16 5.1-6.0 9 8 iqr = interquartile range. table 2. number of melanoma cases by sex and anatomic site. anatomic site male (n = 48) female (n = 52) ear 1 2 forehead 1 0 nose 1 0 neck 1 1 chest 6 6 back 20 (1 invasive 0.5 mm) 16 upper arm 2 8 (1 invasive 0.4 mm) forearm 3 3 abdomen 2 (1 invasive 0.5 mm) 0 thigh 2 (1 invasive 0.4 mm) 3 knee or leg 8 12 foot 1 1 number of melanoma cases by sex and anatomic site. all cases were melanoma in situ except four invasive cases. these 4 invasive cases are identified by site and respective breslow invasion depth. 4 original article | dermatol pract concept. 2022;12(4):e2022197 p 0.02. finally, structureless areas were associated with an increased presence of gray within the whole melanoma “footprint” (or 7.08, 95% ci 1.61-31.11, p 0.01). conclusions nearly all cases in this study were detected by pattern analysis involving attention to features dominated by melanin pigment. predominant color pink with scant minimum brown was observed in only one case. there were no cases displaying all pink without brown. there may be a selection bias favoring brown pigment cases. amelanotic melanoma cases: those without clinical or dermoscopy evidence of brown pigment, may be underrepresented. we integrated and combined all the relevant clinical, dermoscopy and confocal features to facilitate diagnosis as previously described to minimize the risk of missing a melanoma [9]. in equivocal cases all relevant information was readily available to the reporting histopathologists. this may have increased our diagnostic “pick up” rate compared to other studies. we found very similar mean surface diameters for melanoma in situ (3.9 mm) and invasive melanoma (3.6 mm). previous studies have reported melanoma in situ and invasive melanomas with diameters up to and including 3 mm [10], all colors identified (light and dark brown, gray and pink) within the melanoma rose in frequency as the diameters increased from 1 to 6 mm, again se figure 1. the exception to this rise in frequency of color was black which had frequencies 20% to 40% over the full range of diameters, see  figure 2. other dermoscopy features also increased in frequency as diameters increased: asymmetric melanoma shape (30 to 65%), atypical network (20 to 57%), grey circles (0  to  25%) and polygons (0 to 12%). atypical vessels fell from 20 to zero then increased to 12%. angles at the edge of the melanoma increased then decreased with an overall range of frequencies from 20% to 47%. a striking finding in this study was how focal pseudopods (11% of all cases, n = 11/100) can facilitate very small diameter melanoma recognition, see figure 3. when comparing smaller melanomas with a surface diameter less than 4.0 mm to larger diameter 4.0 to 6.0 mm inclusive cases the presence of pseudopods was substantially increased (or  8.81, 95% ci 1.05-73.9, p 0.004). brown pigment within hair follicle infundibula were recorded in a total of eight cases (8%, 8/100). on the leg (3 out of these 8 cases) pigment in follicles were more frequent compared to other sites (or 14.6, 95% ci 1.29-165.17, p 0.03). pink occurred more frequently on non-leg sites (n = 40) out of all other sites combined (n = 43), or 4.72, 95% ci 1.22-18.2, figure 1. dermoscopy features with high prevalence by in vivo melanoma surface diameter. 100 90 80 70 60 50 40 p er c en ta g e o f c a se s w it h f ea tu r e 30 20 10 0 1 2 light brown dark brown grey pink assymetric shape 3 surface diameter of melanoma (mm) 4 5 6 n = 17n = 29n = 21n = 28n = 5 original article | dermatol pract concept. 2022;12(4):e2022197 5 p er c en ta g e o f c a se s w it h f ea tu r e n = 5 n =28 n = 21 n = 29 n = 17 1 0 10 20 30 40 50 60 70 80 90 100 2 3 4 5 6 atypical networkdotspseudopods surface diameter of melanoma (mm) figure 3. dermoscopy features with progressive variation in prevalence by in vivo melanoma surface diameter. figure 2. dermoscopy features with moderate prevalence by in vivo melanoma surface diameter. 100 90 80 70 60 50 p er c en ta g e o f c a se s w it h f ea tu r e 40 30 20 10 0 1 n = 5 n = 28 n = 21 n = 29 n = 17 2 3 surface diameter of melanoma (mm) black structureless angle at edge of melanoma 4 5 6 6 original article | dermatol pract concept. 2022;12(4):e2022197 figure 5. (abc) displaying pseudopods, structureless area, atypical vessels, atypical network and angular edge of melanoma. figure 4. dermoscopy features of melanoma with low prevalence over all surface diameters. polygonsatypical vesselsclodspigmented hair follicle openingcircles p er c en ta g e o f c a se s w it h f ea tu r e surface diameter of melanoma (mm) n = 5 n =28 n = 21 n = 29 n = 17 1 0 10 20 30 40 50 60 70 80 90 100 2 3 4 5 6 original article | dermatol pract concept. 2022;12(4):e2022197 7 later in development rather than originating or appearing up out of infundibula in earlier stage development. our finding increased grey associated with structureless areas in the melanoma may indicate increased melanin at the level of the papillary dermis following a host immune response. this finding could be substantiated with further investigation. atypical vessels noted in this study were typically an increase in dot vessels per unit area within the melanoma. these dot vessels may represent increased perfusion in the superficial dermal vessels as previously described [12] rather than true tumor induced neovascularization. clinicians and pathologists need to be vigilant with small suspicious cases displaying melanoma associated features presenting with diameters much less than 6 mm. we found the lowest recognition threshold diameter for melanoma in situ was 1.2 mm and for invasive melanomas 2.5 mm. in descending order, we found the following colors present in melanomas with a maximum surface diameter up to 6 mm: light brown, dark brown, grey, pink then black. other dermoscopy features which were clues to these small early melanomas include: asymmetric macule shape, angulation on the edge of the melanoma, pseudopods, pigmented follicular infundibula, structureless areas, atypical network and pigmented circles. (n = 23, invasive cases n = 19). these findings sound a warning to both clinicians and pathologists that macules with an in vivo diameter of 6 mm or even substantially less require vigilance for melanoma diagnosis and even early metastatic potential. only 5 of our cases had a maximum surface diameter less than 2 mm. except for the presence of pseudopods the lack of distinctive features in these very small cases may account for such a low detection rate. a dermoscopy image of each case was submitted to the reporting pathologists at the same time as the tissue submission. confocal microscopy images were also available to enhance diagnostic certainty for some cases as this has been demonstrated [11]. future investigation could quantify the contribution of this additional information in small size cases compared to just examining the histology slides and the routine notes supplied by the clinician on the pathology request documentation. one explanation of brown pigment within a hair follicle infundibulum is melanocytes producing melanin at this site. we found melanomas in our study with a diameter three mm or less did not display brown pigment in hair follicule infundibula. pigment was found in larger melanomas with diameters over 3 mm, see figure 3. this finding suggests melanin producing melanocytes spread down into the infundibula figure 6. (abc) displaying pigmented hair follicular opening, polygons and circles. 8 original article | dermatol pract concept. 2022;12(4):e2022197 7. welch hg, mazer bl, adamson as. the rapid rise in cutaneous melanoma diagnoses n engl j med. 2021;384:72-79. doi: 10.1056/nejmsb2019760. pmid: 33406334. 8. gamo-villegas r, pampín-franco a, floristán-murúzabal u, garcía-zamora e, pinedo-moraleda f, lópez-estebaranz jl. key dermoscopic signs in the diagnosis and progression of extrafacial lentigo maligna: evaluation of a series of 41 cases. australas j dermatol. 2019;60(4):288-293. doi: 10.1111/ajd.13051. pmid: 30997681. 9. argenziano g, briatico g, brancaccio g, alfano r, moscarella e, lallas a. clinical clues to avoid missing melanoma when morphology is not enough. dermatol pract concept. 2021; 11(4):e2021143. doi: 10.5826/dpc.1104143. pmid: 3463 1275. pmcid: pmc8480449. 10. bono a, tolomio e, trincone s, bartoli c, tomatis s, carbone a, santinami m. micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm. br j dermatol. 2006;155(3):570-573. doi: 10.11 11 /j.1365-2133.2006.07396.x. pmid: 16911283. 11. stanganelli i, longo c, mazzoni l, et al. integration of reflectance confocal microscopy in sequential dermoscopy follow-up improves melanoma detection accuracy. br j dermatol. 2015;172(2):365-371. doi: 10.1111/bjd.13373. pmid: 25154446. 12. kreusch jf. vascular patterns in skin tumours. clin dermatol. 2002; 20(3):248-254. doi: 10.1016/s0738-081x(02)00227-4. pmid: 12074860. references 1. argenziano g, albertini g, castagnetti f, et al. early diagnosis of melanoma: what is the impact of dermoscopy? dermatol ther. 2012;25(5):403-409. doi: 10.1111/j.1529-8019.2012.01482.x. pmid: 23046019. 2. dinnes j, deeks jj, chuchu n, et al. dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. cochrane database syst rev. 2018;12(12):cd011902. doi: 10.1002/14651858.cd011902.pub2. pmid: 30521682. pmcid: pmc6517096. 3. borsari s, pampena r, benati e, et al. in vivo dermoscopic and confocal microscopy multistep algorithm to detect in situ melanomas. br j dermatol. 2018l;179(1):163-172. doi: 10.1111/ bjd.16 364. pmid: 29355898. 4. otero c, podlipnik s, carrera c, et al. dermoscopic, confocal and histopathologic characteristics of small-diameter melanomas (minimelanoma): a cross sectional study. australas j dermatol. 2021;62(2):e256-e261. doi: 10.1111/ajd.13562. pmid: 3366 7318. 5. akay bn, okcu heper a, clark s, erdem c, rosendahl co, kittler h. dermatoscopy of a melanoma less than one millimeter in diameter.  int j dermatol.  2017;56(12):1498–1499. doi: 10.1111/ijd.13728. pmid: 28857145. 6. kittler h. evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma.  dermatol pract concept. 2021;11 (suppl 1):e2021163s. doi: 10.5826/dpc.11s1a163s. pmid: 3444 7612. pmcid: pmc8366309. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022183 1 evaluating the perception of mycosis fungoides patients about their disease before and after educating them maryam nasimi1, robabeh abedini1, yousef fakour 2, shideh shahabi1, yasamin kalantari1, ifa etesami1 1 department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 2 deputy of research, moh of iran, ministry of health, tehran, iran key words: mycosis fungoides, illness perception, illness perception questionnaire-revised, cutaneous t-cell lymphomas citation: nasimi m, abedini r, fakour y, shahabi s, kalantari y, etesami i. evaluating the perception of mycosis fungoides patients about their disease before and after educating them. dermatol pract concept. 2022;12(4):e2022183. doi: https://doi.org/10.5826/dpc.1204a183 accepted: january 31, 2022; published: october 2022 copyright: ©2022 nasimi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ifa etesami, department of dermatology, razi hospital, vahdat-eeslami square, tehran university of medical sciences, tehran, iran, 1199663911, fax number: 021 55634461 e-mail: ifa.etesami@gmail.com introduction: patient-held beliefs are important for disease management and few studies have evaluated illness perception of mycosis fungoides (mf) patients. objectives: here, we aimed to determine the effect of educating mf patients on their perception of their disease. methods: patients with diagnosed mf were asked to fill the illness perception questionnaire-revised (ipq-r) once before education and once 3 months later. results: fifty-five patients, 41 men and 14 women, with a mean age of 45.5 ± 13.9 years were enrolled. regarding the main etiologic factor, most patients cited anxiety (91%). after education, the most significant changed belief on disease etiology was immune system dysfunction and the change was twenty-six percent which was observed more in patients with higher educational levels, shorter disease duration, and lower mf stages. regarding the most prevalent clinical manifestations, most patients mentioned erythema (86%). after education, the greatest change in symptom perception was related to lymphadenopathy (32%) which was significantly associated with less disease duration and those treated with phototherapy. before education, the mean perception score about the disease chronicity was 23.67 ± 3.549 that increased to 27.71 ± 1.66 (p < 0.001). this change was more observed in men (p = 0.03), those with less disease duration, and those treated with phototherapy. abstract 2 original article | dermatol pract concept. 2022;12(4):e2022183 introduction mycosis fungoides (mf) is the most common type of cutaneous t-cell lymphomas (ctcl). the annual incidence of mf is estimated at approximately 6:1,000,000 [1-3]. the common age of onset is 55-60 years, and the prevalence of the disease in men is reported to be 2 times higher than in women [2-4]. the most common clinical manifestations of mf are slowly progressive patches and plaques on the trunk that might be scaly or pruritic [5,6]. due to the long course of the disease, patients with mf will experience annoying symptoms such as pain and itch for a considerable period of time, and their skin lesions may lead to social anxiety, embarrassment, and isolation [7]. also, currently available treatments do not cause long-lasting remission of the disease which can have financial, emotional, and functional burdens for patients [8]. the concept of illness perception is based on leventhal self-regulatory model and deals with the relationship between the nature of the disease, the patient concern about the disease, coping processes, and health outcomes [9,10]. patient-held beliefs are very important for the clinical management of their disease. also, it has been proved that acquiring more knowledge about the disease is associated with a better understanding of the illness and more personal and treatment control [11]. in previous studies on mf, patients illness perception was assessed in a one-time examination or in two-time assessments without any educational intervention regarding the disease between the two evaluations. hence, the data in this area is lacking. objectives since mf patient interpretation and perception can affect different aspects of their lives, this study aimed to determine the effect of educating mf patients on their perception of their disease. methods participants, questionnaire, and data collection an analytical, cross-sectional study was conducted in razi dermatology hospital, tehran, iran from march 2020 to july 2020. the study was approved by the ethical committee of tehran university of medical sciences (ir.tums. medicine.rec.1399.266). information about the study was given to all participants and each participant signed a form of consent for taking part in our study. sixty patients with mf diagnosed based on both clinical and histopathological studies aged between 19 and 74 years were enrolled in the study. a checklist including demographic and clinical characteristics of participants was filled out for each patient. afterward, the patients were asked to fill the illness perception questionnaire-revised (ipq-r) once before educating them on their disease characteristics and once 3 months after the education. the given education included patient-oriented information about mf etiology, prevalence, clinical manifestations, diagnosis, treatment, and the prognosis given in the format of an educational catalog. the educational material was first explained to all patients by a dermatologist and then given to them for further reading. of 60 participants who completed the ipq-r questionnaire in the first assessment, 5 did not complete the questionnaire in the second round. the ipq-r had been previously translated to the persian language and its validity and reliability were confirmed [12]. the ipq-r evaluates patients’ perspectives across seven subscales: timeline acute/chronic, timeline-cyclical, consequences, personal control, treatment control, illness coherence, and emotional representations. moreover, a checklist of clinical symptoms was shown to patients and they were asked to choose the most important factors causing their disease from a checklist of possible etiologic factors (supplementary file 1). data analysis statistical analysis was performed by using ibm spss statistics 26. frequency and percentage were reported for qualitative variables, and mean and standard deviation for quantitative variables. to compare the mean scores between discrete independent variables, independent t-test and one-way anova test was used. also, the pearson correlation coefficient was used to evaluate the correlation between continuous variables. a p of less than 0.05 was considered as significant. results sociodemographic characteristics a total of fifty-five patients, 41 (74.5%) men and 14 (25.5%) women, with the mean age of 45.5 ± 13.9 years (range 19-74) were enrolled in the study. the demographic data are conclusions: generally, mf patients hold favorable perspectives about their disease and educating them positively improves their illness perception. patients with higher educational levels and lower stages of the disease showed more significant changes in various aspects of illness perception. hence, early education is recommended in patients with lower educational levels. original article | dermatol pract concept. 2022;12(4):e2022183 3 shown in table 1. considering the stage of the disease, the most prevalent stages among 55 patients were stage ia in 18 (32.7%) and stage ib in 14 (25.5%), respectively (table 1). beliefs about the cause of the disease before educating the patients, the most common etiologic factors associated with their disease based on patients beliefs were stress and anxiety (91%), familial worries and problems (82%), and emotional states (76%). while after educating the patients, the most prevalent etiologic factors were stress and anxiety (94%), familial worries (83%), and immune system dysfunction (73%). after educating the patients, the most significant change in the mean score of perception about the disease etiology was related to immune system dysfunction (26%), smoking and drug abuse (20%), and hereditary factors. this change was reported more in patients with higher educational levels, lower stages of the disease, and shorter illness duration. beliefs about illness coherence before training, the achieved score about patients illness coherence was 13.82 ± 3.65 and after the training, this score was 17.80 ± 2.81 (range 5-25). this proves that most patients had an acceptable knowledge about their disease and after the training, their knowledge improved (p < 0.001). after educating the patients, the educational level had a positive relationship with illness coherence (p < 0.001) and with the changes in patients’ beliefs about illness coherence (p = 0.019). also, there was a negative relationship between patients age and their beliefs about illness coherence (p = 0.004). beliefs about the symptoms before educating the patients, the most common reported symptoms were erythema (86%), pruritus (75%), and scaling (68%). in the second assessment, the first three common symptoms were again erythema (100%), pruritus (92%), and scaling (84%), but they were different from those in table 1. sociodemographic characteristics of the patients. characteristic age, years, mean ± sd 45.5 ± 13.9 gender, n (%) male 41 (74.5%) female 14 (25.5%) marital status, n (%) single 16 (29.1%) married 39 (70.9%) education level, n (%) under high school diploma 20 (36.4%) high school diploma and associate degree 14 (25.5%) bachelor and masterdegree 17 (30.9%) doctorate and more 4 (7.3%) duration of the disease, n (%) less than 2 years 20 (36.4%) 2-) years 23 (41.81%) 4-6 years 6 (10.90%) 6-8 years 4 (7.27%) 8-10 years 2 (3.63%) stage of the disease, n (%) stage ia 18 (32.7%) stage ib 14 (25.5%) stage iia 7 (12.7%) stage iib 9 (16.4%) stage iiia 4 (7.3%) stage iva 3 (5.5%) skin lesions, n (%) patch 23 (41.8%) plaque 18 (32.7%) cutaneous tumor 10 (18.2%) generalized erythema 4 (7.3%) palpable lymph nodes, n (%) no 37 (67.3%) yes 18 (32.7%) type of treatment, n (%) phototherapy 39 (70.9%) phototherapy with additional treatment 16 (29.1%) 4 original article | dermatol pract concept. 2022;12(4):e2022183 about the negative consequences of their illness and this attitude increased after the training (p = 0.005). after the training, the stage of the disease had a positive relationship with beliefs about consequences (p > 0.001). beliefs about cure and control the achieved score before and after the training was 20.69 ± 3.82 and 23.71 ± 2.85, respectively (p < 0.001) indicating that most of the patients were aware of their role in controlling their disease and this increased significantly after the training. also, comparing the scores of their beliefs about treatment control before (18.60 ± 3.010) and after (22.45 ± 1.74) the training showed that most patients believed that treatment has an acceptable role in controlling the disease and improving the clinical symptoms (p < 0.001). moreover, the educational level had a positive relationship with the changes in beliefs about treatment control (p = 0.011). beliefs about emotional representation before the training, most patients complained about the negative effects of this illness on their emotions (22.35 ± 5.372). after the training, this amount increased significantly (24.00 ± 3.03;p = 0.004). there was a positive relationship between negative effects on emotions and stages of the disease after the training (p = 0.047). moreover, after educating the patients, as the educational level increased, negative effects on emotions enhanced (p = 0.025) (table 2). conclusions mf is the most common type of ctcl and can influence various aspects of patients lives. the results of our study the first assessment regarding their frequency. after instructing the patients about their illness, the greatest change in terms of symptom perception was related to lymphadenopathy (32%), pruritus (17%), and scaling (16%). the change in patients beliefs was more pronounced in patients with shorter disease duration, patients with patches and plaques type lesions, and those receiving phototherapy. beliefs about chronicity and recurrence before informing the patients, the mean perception score about the disease chronicity was 23.67 ± 3.549; after educating the patients, this score was 27.71 ± 1.66 (range 6-30). the given scores show that most patients accepted that their disease is a chronic situation and this attitude increased significantly after training (p < 0.001). regarding the disease timeline-cyclical, before and after training, the scores were 13.00 ± 2.40 (range 4-20) and 16.31 ± 1.78 (range 4-20), respectively. this shows that most patients consider their illness as a recurrent situation and this belief increased significantly after the training (p < 0.001). beliefs about the disease chronicity changed significantly after the training in both genders and it was more prominent in men (p = 0.03). after educating the patients, as the educational level increased, the awareness about the disease chronicity increased (p < 0.001). after the training, the stage of the disease had a positive relationship with beliefs about the chronicity of the disease (p < 0.001). beliefs about consequences comparing the patients beliefs scores about their disease consequences between the first (18.53 ± 3.681) and the second (19.55± 3.66) assessments shows that patients knew table 2. perception modalities before and after educating the patients. mean number standard deviation p timeline-acute/chronic 1 23.67 55 3.549 < 0.001 timeline-acute/chronic 2 27.71 55 1.663 consequences 1 18.53 55 3.681 0.005 consequences 2 19.55 55 3.366 personal control 1 20.69 55 3.829 < 0.001 personal control 2 23.71 55 2.859 treatment control 1 18.60 55 3.010 < 0.001 treatment control 2 22.45 55 1.741 illness coherence 1 13.82 55 3.657 < 0.001 illness coherence 2 17.80 55 2.811 timeline-cyclical 1 13.00 55 2.404 < 0.001 timeline-cyclical 2 16.31 55 1.783 emotional representation 1 22.35 55 5.372 0.004 emotional representation 2 24.00 55 3.031 1= before; 2= after. original article | dermatol pract concept. 2022;12(4):e2022183 5 physicians do not educate patients about it. after educating them, the greatest change in the amount of knowledge about the mf clinical signs was observed in those with less disease duration, those who manifested patches or plaques and those who were being treated with phototherapy. this finding can be suggestive of the fact that educating those who are only treated with medications does not result in a desirable change in their illness perceptions in comparison to therapies such as phototherapy that requires more visits by the physicians. our study shows that mf patients have an acceptable knowledge about the chronic and recurrent nature of their disease that significantly increases after training especially in men, those with less disease duration, and those who were only treated with phototherapy. as seen in fortune et al that investigated 162 patients with psoriasis and observed that a vast majority of patients believed their disease was more likely to be chronic or recurrent, while only a short number of them considered their condition to be temporary [16]. regarding the beliefs about the disease negative consequences, after the education, patients had a better understanding of their diseases’ negative consequences, especially in those with higher stages of mf. mf has a severe negative emotional impact on patients that significantly increases after educating them. although a negative perception about the consequences of illness is not the equivalent of having a psychiatric disorder, it may increase the likelihood of developing the disorder [16]. the greatest change regarding the negative emotional feelings toward the disease was observed in those with less disease duration and those who had lower stages of mf. since the greatest changes in patients illness perception were observed among patients with less disease duration and lower stages of the disease, it is important to educate patients in the early stages of their illness. most of our patients believed that they have an important role in controlling their illness that significantly improved after educating them. the greatest change in this belief was observed in those with higher educational levels. notably, in eder et al study, it was observed that patients had limited belief in personal control, but a strong belief in treatment control which was attributed to their sample consisting of patients with long disease duration [8].in general, mf patients hold favorable perspectives about their disease and educating them positively improves their views about their illness. also, patients with higher educational levels and lower stages of the disease showed more significant changes in various aspects of illness perception. hence, early education is recommended in patients with lower educational levels. more research on increasing mf patients understanding of their illness should be done, since correcting patients misconceptions is associated with increased follow-up and improved treatment outcomes. indicate that mf patients have an acceptable understanding of their disease, its causing factors, and clinical manifestations associated with their disease which significantly increases after training them. the fact that patients have an acceptable perception of their illness has been confirmed in previous studies on various dermatologic diseases including vitiligo and skin cancers and is consistent with our study [13-15]. a study by topal et al on 100 vitiligo patients using ipq suggested that patients had good knowledge about their disease and were highly aware of the etiologic factors [14]. despite the low prevalence of mf, the patients in our study had a good knowledge about their disease which significantly increased after educating them. the opposite results were observed in a study done by eder et al that believed patients with ctcl have a poor understanding of their disease. this poor knowledge was attributed to the low prevalence of the disease and the unknown cause of ctcl [8]. our study showed that educating mf patients cause significant changes in beliefs about different factors such as the etiologic factors, clinical manifestations, disease chronicity and recurrency, emotional impacts, illness consequences, personal control, and treatment control. these changes indicate that educating mf patients help them to have a better knowledge about their illness. generally, changes in patients perception about the clinical manifestations, consequences, and emotional representations were more notable than other variables after the education. regarding the main etiologic factor, the results of our study showed that most patients with mf cited stress and anxiety as the main causing factor for their illness. the same results were also found in firooz et al study which assessed 80 vitiligo patients using ipq and observed that a total of 62.5% of patients believed that stress was a major factor in causing their disease [13]. after the education, the greatest change in the knowledge of patients in etiology was observed in patients with higher educational levels, shorter disease duration, and lower stages of mf. this indicates that educating mf patients as early as possible may have a better influence on patients perception of their disease. it is worth mentioning that after the education, patients with lower educational levels did not show significant changes regarding the etiologic factors which highlight the point that more efforts should be made in educating these groups of patients and different means of education rather than a single brochure should be considered for them. in terms of clinical manifestations, most of our patients mentioned erythema, pruritus, and scaling as the most prevalent clinical manifestations. after instructing the patients about their illness, the greatest change in terms of symptom perception was related to lymphadenopathy meaning that lymphadenopathy might not be noticed by patients if the 6 original article | dermatol pract concept. 2022;12(4):e2022183 references 1. criscione vd, weinstock ma. incidence of cutaneous t-cell lymphoma in the united states, 1973-2002. arch dermatol. 2007;143(7):854-859. doi: 10.1001/archderm.143.7.854. pmid: 17638728. 2. sant m, allemani c, tereanu c, et al. incidence of hematologic malignancies in europe by morphologic subtype: results of the haemacare project. blood. 2010;116(19):3724-3734. doi: 10.1182/blood-2010-05-282632. pmid: 20664057. 3. korgavkar k, xiong m, weinstock m. changing incidence trends of cutaneous t-cell lymphoma. jama dermatol. 2013;149(11):12951299. doi: 10.1001/jamadermatol.2013.5526. pmid: 24005876. 4. bradford pt, devesa ss, anderson wf, toro jr. 2009. cutaneous lymphoma incidence patterns in the united states: a population-based study of 3884 cases. blood. 2009;113(21):50645073. doi: 10.1182/blood-2008-10-184168. pmid: 19279331. pmcid: pmc2686177. 5. pimpinelli n, olsen ea, santucci m, et al. defining early mycosis fungoides. j am acad dermatol. 2005;53(6):1053-1063. doi: 10.1016/j.jaad.2005.08.057. pmid: 16310068. 6. kazakov dv, burg g, kempf w. clinicopathological spectrum of mycosis fungoides. j eur acad dermatol venereol. 2004;18(4):397415. doi: 10.1111/j.1468-3083.2004.00937.x. pmid: 15196152. 7. olsen e, vonderheid e, pimpinelli n, et al. revisions to the staging and classification of mycosis fungoides and sezary syndrome: a proposal of the international society for cutaneous lymphomas (iscl) and the cutaneous lymphoma task force of the european organization of research and treatment of cancer (eortc). blood. 2007;110(6):1713-1722. doi: 10.1182/ blood-2007-03-055749. pmid: 17540844. 8. eder j, kammerstatter m, erhart f, mairhofer-muri d, trautinger f. illness perception in primary cutaneous t-cell lymphomas: what patients believe about their disease. acta derm venereol. 2016;96(3):381-385. doi: 10.2340/00015555-2245. pmid: 26392387. 9. leventhal h, nerenz dr, steele ds. illness representations and coping with health threats. in: baum, a., taylor, s.e. and singer, j.e. eds., handbook of psychology and health, volume iv: social psychological aspects of health, erlbaum, hillsdale, nj:219-252. 10. leventhal hby, brownlee s, diefenbach m, leventhal e, patrick-miller l, robitaille c. illness representations: theoretical foundations. in: petrie kj, weinman j, editors. perceptions of health and illness: current research and applications amsterdam, harwood academic publishers, london. 1997:19–45. 11. husson o, thong ms, mols f, oerlemans s, kaptein aa, van de poll franse lv. illness perceptions in cancer survivors: what is the role of information provision? psychooncol. 2013;22(3):490-8. doi: 10.1002/pon.3042. pmid: 22307579. 12. bazzazian s, besharat ma. reliability and validity of a farsi version of the brief illness perception questionnaire. procedia social and behavioral sciences. 20105:962-965. doi: 10.1016/j. sbspro.2010.07.217. 13. firooz a, bouzari n, fallah n, ghazisaidi b, firoozabadi mr dy. what patients with vitiligo believe about their condition? int j dermatol. 2004;43(11):811-814. doi: 10.1111/j.13654632.2004.02059.x. pmid: 15533062. 14. topal io, duman h, goncu oek, durmuscan m, gungor s, ulkumen pk. knowledge, beliefs, and perceptions of turkish vitiligo patients regarding their condition. an bras dermatol. 2016;91(6):770-775. doi: 10.1590/abd1806-4841.20165060. pmid: 28099599. pmcid: pmc5193188. 15. abedini r, nasimi m, nourmohammad pour p, etesami i, al-asiri s, tohidinik hr. skin cancer awareness and sun protection behavior before and following treatment among skin cancer-treated patients. j cancer educ. 2019;34(2):285290. doi: 10.1007/s13187-017-1299-z. pmid: 29143268. 16. fortune dg, richards hl, main cj, griffiths ce. what patients with psoriasis believe about their condition? j am acad dermatol. 1998;39(2 pt 1):196-201. doi: 10.1016/s01909622(98)70074-x. pmid: 9704828. dermatology: practical and conceptual review | dermatol pract concept. 2023;13(3):e2023132 1 a practical approach to the diagnosis of lymphedema: a narrative review lauren banner1, alexa cohen1, viral patel1, neda nikbakht1 1 department of dermatology and cutaneous biology, thomas jefferson university, philadelphia, pennsylvania, usa key words: lymphedema, meige syndrome, diagnosis, lymphedema praecox citation: banner l, cohen a, patel v, nikbakht n. a practical approach to the diagnosis of lymphedema: a narrative review. dermatol pract concept. 2023;13(3):e2023132. doi: https://doi.org/10.5826/dpc.1303a132 accepted: january 4, 2023; published: july 2023 copyright: ©2023 banner et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: neda nikbakht, md, phd, faad, assistant professor of dermatology director, cutaneous lymphoma clinic, department of dermatology and cutaneous biology thomas jefferson university, 233 s. 10th street, rm 409, philadelphia, pa 19107 e-mail: neda.nikbakht@jefferson.edu introduction: lymphedema often presents as progressive, unremitting swelling and skin changes that are extremely distressing to patients. hereditary lymphedema (hl) constitutes a type of primary lymphedema that is passed down through generations. objectives: the primary aims of this narrative review are to illustrate a framework to distinguish lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from each other. results: a literature search was undertaken using relevant search terms. the articles were evaluated to generate a diagnostic algorithm to approach the swelling of an extremity using clinical and laboratory data. first, the stemmer sign should be evaluated. if it is negative, other causes should be considered. history and additional physical exam findings suggest either a primary or secondary cause of lymphedema. conclusions: the hereditary lymphedemas have been classified by age of onset and then stratified by clinical criteria and genetic testing. abstract 2 review | dermatol pract concept. 2023;13(3):e2023132 introduction lymphedema is a manifestation of lymphatic dysfunction presenting primarily as swelling of an extremity due to the accumulation of lymphatic fluid [1]. the diseased lymphatic system slows uptake and decreases flow of interstitial fluid resulting in buildup of lymphatic fluid [2]. as the disorder progresses, the skin thickens and hardens [1]. the often progressive and unremitting swelling and skin changes can be extremely distressing to patients. primary lymphedema refers to processes that result from intrinsic damage to lymphatic structures [1]. hereditary lymphedema (hl) constitutes a type of primary lymphedema that is passed down through generations [1]. one of the known etiologies of its pathogenesis is primarily driven by dysfunctions in the vegfr-3 signaling axis, which is involved in lymphangiogenesis [2]. secondary or acquired lymphedema indicates an underlying pathology that damages the lymphatic tissue [1]. while secondary lymphedema is more common, affecting 200 million people in the world, hl has an estimated prevalence of 0.001% [1]. hl has been classified in various ways since it appeared in the medical literature. until recently, lymphedema present at birth was designated milroy disease, and adolescent onset lymphedema was referred to as meige disease [3]. given the reported heterogeneity of these syndromes and new advances in analyzing genetic data, subsequent articles characterized lymphedema by age of onset: congenital (before age 1 year), praecox (ages 2-35 years), and tarda (after 35 years) [1] and specific diseases were assigned to each of these groups. lymphedema congenita and praecox can be either syndromic and non-syndromic [1]. lymphedema tarda is thought to be triggered by prior infection or trauma [1]. it is also important to consider the complications of chronic lymphedema such as skin changes, infections, malignancies and psychological effects. elephantiasis nostra verrucosa (env), for example, is a severe edematous skin change resulting from longstanding lymphedema [4,5]. this can negatively impact the quality of life of patients as the limb disfiguration is uncomfortable, functionally challenging, and cosmetically unpleasant. additionally, both congenital and acquired lymphedema have been associated with benign vascular neoplasms such as spindle cell hemangioma (sch) and malignant angiosarcoma [6-10]. unfortunately, there is no curative treatment for primary lymphedema, only palliative strategies [11,12]. lymphedema and its sequelae provide diagnostic challenges, as they are rare and have several challenging differential diagnoses. objectives there is a clear need for a systematic diagnostic approach that considers the current classifications of lymphedema. while lymphedema tends to be a clinical diagnosis, awareness of genetic studies can provide additional information. we present a narrative review of hl with primary aims of illustrating a framework to distinguish lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from one another. methods literature search relevant articles were included regardless of the date published. using pubmed and the omim genetic library. english language was a criterion for inclusion. the primary interests were the genetic basis and clinical manifestations of hl. specific reviews and cohort studies on the diagnostic workup were included if they provided useful additional evidence. the initial search was narrowed based on titles and abstracts given their relevance to research questions. cited articles within these identified manuscripts were also considered. within the pubmed database (1935-2022), there were 4,465 manuscripts in the literature that pertained to the diagnosis of hereditary lymphedema. the initial search was narrowed to 1,089 results to focus on manuscripts published in the last five years. articles were preliminarily omitted if the focus was on treatment, cancer, or post-operative lymphedema. thirty-nine relevant articles and their references were initially identified and reviewed to generate the backbone for the diagnostic algorithm. we also searched for lymphedema praecox which yielded 66 results of which 14 relevant articles and their references were interrogated. in addition, the omim database was searched for the primary hereditary lymphedemas: milroy or milroy-like lymphedema, hereditary lymphedema 1b, meige lymphedema, hereditary lymphedema type 1c, lymphedema-distichiasis syndrome, yellow nail syndrome, primary lymphedema with myelodysplasia or emberger syndrome, hypotrichosis-lymphedema telangiectasia syndrome which yielded 72 references. in total, 120 articles were considered in this work. results diagnostic approach to swelling of an extremity ruling out other causes of edema lymphedema is often misdiagnosed due to its mimicry of other conditions. a decision tool was developed by the authors to assist in diagnosing swelling in an extremity (figure 1). lymphedema is more likely in patients with a positive stemmer sign, which is the inability to pinch the skin on the dorsum of the second toe [13]. a study on the stemmer sign showed the sensitivity to be high at 92% and the review | dermatol pract concept. 2023;13(3):e2023132 3 specificity to be moderate at 57% for accurately detecting lymphedema [13]. other causes of edema such as lipedema, venous disease, hypoalbuminemia, myxedema, infection, and morbid obesity can also be ruled out with a thorough history including familial conditions and laboratory results such as cbc, albumin, and tsh [1,11]. a blood smear to detect microfilaria may have utility if the patient has traveled to an endemic area [11]. if there is no other obvious cause of extremity swelling and suspicion for lymphedema is high even with a negative stemmer sign, lymphoscintigraphy may be considered, but it may have limited clinical utility [1,11,14]. other diagnostic studies include magnetic resonance imaging, ultrasonography, and bioimpedance spectroscopy [11,14]. while bioimpedance spectroscopy is a non-invasive technique that has resulted in early detection of breast cancer related lymphedema, it is not widely available because it is considered investigational [11]. a recent study evaluated the diagnostic workup in diagnosing 49 adolescents with lymphedema praecox with clinical exam alone, doppler ultrasound, mri, lymphoscintigraphy, and x-ray either alone or combined [14]. the diagnosis of lymphedema praecox did not change with additional imaging including lymphoscintigraphy [14]. however, an ultrasound of the swollen extremity may be recommended to rule out a deep vein thrombosis [14]. categorization and genetic basis of lymphedema once the diagnosis of lymphedema is established, the type of lymphedema should be determined. secondary causes of lymphedema such as infection, malignancy, podoconiosis, and morbid obesity can be revealed via careful history and physical examination [1,11]. the hereditary lymphedemas can be categorized into age of onset: congenital (age < 2), praecox (ages 2-35), and tarda (age > 35) [1]. these divisions can be further subdivided. in congenital lymphedema, there are three non-syndromic types and a multitude of syndromes that are beyond the scope of this paper [1,2]. the three congenital non-syndromic lymphedema syndromes are milroy lymphedema (hl1a), milroy-like lymphedema (hl1d), and hereditary lymphedema 1b (hl1b) [1]. milroy lymphedema is caused by either a missense or inactivation mutation of vascular endothelial growth factor receptor 3 (vegfr3) tyrosine kinase [15,16]. it may be inherited in an autosomal dominant (ad), autosomal recessive (ar), or genetic testing milroy lymphedema hereditary lymphedema ���� 1b milroy like lymphedema vegfcneithervegfr3 meige disease lymphedema tarda lymphedema negative primary lymphedema history and physical exam findings infection, malignancy, silica microparticle exposure, obesity lipedema, venous disease, obesity, ccbs, hypoalbuminemia, myxedema consider other causes yesstemmer sign swelling of an extremity secondary causes onset > 35 years positive onset 2-35 years yellow nail syndrome yellow nails lymphedemadistichiasis syndrome primary lymphedema w/ myelodysplasia hereditary lymphedema type 1c hypotrichosislymphedema telangiectasia hypotrichicosis all 4 limbs a�e cted aml / mds distichiasis features lymphedema praecox congenital lymphedema syndromic? congential syndromic lymphedema i.e. noonan syndrome. tuberous sclerosis, turner syndrome, cholestasis lymphedema syndrome etc. yesyes yes yes yes yes yes no no no no no history and physical exam findings syndromic? figure 1. approach to swelling of an extremity. 4 review | dermatol pract concept. 2023;13(3):e2023132 remarked on the heterogeneity of the disease with features such as distichiasis, ptosis, and yellow nails [28]. in the last two decades, the lymphedema syndromes of pubertal onset have been separated by genetic and clinical features [1,12,23]. meige disease classically presents with bilateral lower extremity lymphedema in the absence of other syndromic features [1,23]. unilateral lymphedema may also occur [23]. like all lymphedemas, meige disease may be complicated by infections such as cellulitis or erysipelas [1]. the pathogenesis of the delayed onset has been proposed to be due to either a secondary infection or trauma, exposing the underlying lymphatic defect, or attributed to a hormonal effect, as symptoms predominately begin occurring in pubescent or pregnant females [29]. while genetic testing is not needed to distinguish the praecox syndromes, it may have a role in confirming the diagnosis or for research purposes. lds is typically inherited in an ad or de novo manner with variable penetrance and is due to a loss of function (lof) mutation in foxc2 [2022]. hl1c is an ad missense mutation in gjc2 [19]. hlts is an ad or ar lof mutation in sox18 [24,25]. yns is sporadically inherited; however, the mutation is unknown.22 emberger syndrome is either an ad or de novo lof mutation in gata2 [26,31].the gene foxc2 has been ruled out as the cause of meige disease [23]. while no gene has been explicitly determined as the cause of meige disease, celsr1 was proposed to be implicated in hereditary lymphedema [32-34]. a 2016 case report found that a rare early inactivating mutation in celsr1 caused non-syndromic hereditary lymphedema in seven individuals spanning three consecutive generations [32]. another study analyzed 95 probands for the celsr1 gene [33].ten patients had a loss of function mutation. four patients had progressive or relapsing lymphedema with no other symptoms reported [33]. one patient’s presentation was consistent with noonan syndrome [33]. the remaining five had no phenotypic of lymphedema. in all but one case, the age of onset was prior to 35 years [33]. based on the two studies, the inheritance pattern appears to be autosomal dominant with incomplete penetrance and variable expressivity [32, 33]. in the second study, five out of six females with the celsr1 gene developed lymphedema, but only one out of four males developed lymphedema and did so later in life [33]. a third manuscript supported the female driven penetrance of the gene. all females with the variant had lymphedema, and all males with the variant served as carriers with none developing lymphedema [34]. this inheritance pattern is consistent with the higher predominance of lymphedema praecox in females [23]. further studies are needed to provide a convincing link between this gene and meige disease specifically. de novo fashion [15]. the onset of swelling is at birth, and the lymphedema is confined to the lower extremities, which contain wide caliber veins. secondary changes include deep creases within toes, curved and brittle toenails, papillomatosis, chronic venous ulcers, hydrocele, and cellulitis [16]. hl1d has similar features to hl1a; however, the mutation is vegf-c rather than vegfr [17]. hl1b is clinically similar to hl1a and hl1d with a few key differences. the location of the associated gene has been narrowed to loci 6q16.2 – q22.1; however, a candidate gene foxo3 was not implicated in the disease based on a 2008 study [18]. hl1b is distinct, progressing from the onset of lymphedema at birth to papillomas and itching in childhood and early adolescence, shrunken papillomas and scarring with keratinized hairless skin in adulthood, and finally, reduction in lymphedema in ages 40-45 [18]. these non-syndromic congenital lymphedemas are most definitively differentiated with genetic testing. there are six currently identified conditions that constitute lymphedema praecox. of the six, only meige disease is non-syndromic. hereditary lymphedema type ic (hlic), lymphedema-distichiasis syndrome (lds), yellow nail syndrome (yns), primary lymphedema with myelodysplasia (emberger syndrome), and hypotrichosis-lymphedema telangiectasia syndrome are the five syndromes which can be differentiated by their distinct features [1]. the presence of edema in all four limbs suggests hlic [19]; ptosis and secondary eyelash formation leading to corneal abrasions are seen in lds [20,21]; and yellow nails and respiratory tract symptoms indicates yns [22]. the triad of yellow nails, respiratory symptoms, and lymphedema is only present in 27-60% of patients, and the complete triad of yns may not be present at once, increasing the diagnostic difficulty [22]. the color of the nails in yns is yellow/green with increased curvature, onycholysis, shedding, cross-ridging, and loss of lunulae and cuticles [23]. the nails grow thicker but less rapid longitudinally [22]. this is distinct from the yellow discoloration seen in many lymphedema syndromes. as any form of lymphedema may have yellow nails as a nonspecific feature, the specific appearance of the yellow nails must be observed to definitively diagnose yns [23]. another lymphedema praecox syndrome is hypotrichosis-lymphedema telangiectasia syndrome (hlts). it is associated with vascular malformations including aortic dilation, cutaneous telangiectasias, and defects in hair follicle development; however, lymphedema is not always present [24,25]. finally, emberger syndrome is the presence of myelodysplasia with or without congenital deafness in patients with lymphedema [26]. non-syndromic meige disease (hereditary lymphedema type ii), the most common form of primary lymphedema, was first written about in 1898 [27]. subsequent reports of the disease defined it as pubertal onset lymphedema and review | dermatol pract concept. 2023;13(3):e2023132 5 4. duckworth al, husain j, deheer p. elephantiasis nostras verrucosa or "mossy foot lesions" in lymphedema praecox: report of a case. j am podiatr med assoc. 2008;98(1):66-69. doi: 10.7547/0980066. pmid: 18202337. 5. sisto k, khachemoune a. elephantiasis nostras verrucosa: a review. am j clin dermatol. 2008;9(3):141-146. doi: 10.2165/00128071-200809030-00001. pmid: 18429642. 6. fletcher cd, beham a, schmid c. spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. histopathology. 1991;18(4):291-301. doi: 10.1111/j.1365-2559.1991. tb00849.x. pmid: 2071088. 7. farzaliyev f, hamacher r, steinau professor hu, bertram s, podleska le. secondary angiosarcoma: a fatal complication of chronic lymphedema. j surg oncol. 2020;121(1):85-90. doi: 10.1002/jso.25598. pmid: 31236970. 8. janssens p, dekeuleneer v, van damme a, et al. angiosarcoma arising from congenital primary lymphedema. pediatr dermatol. 2018;35(6):e382-e388. doi: 10.1111/pde.13664. pmid: 30216524. 9. tronnier m, vogelbruch m, kutzner h. spindle cell hemangioma and epithelioid hemangioendothelioma 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lymphedema type 1a) flt4 (vegfr3) non-syndromic congenital lymphedema primary hereditary lymphedema type 1b unknown non-syndromic. disease occurs in four stages milroy-like lymphedema (hereditary lymphedema type 1d) vegfc non-syndromic congenital lymphedema syndromes varies specific to syndrome meige disease (hereditary lymphedema type ii) unknown non-syndromic lymphedema praecox lymphedema distichiasis syndrome foxc2 ptosis, secondary eyelash formation and corneal abrasions primary lymphedema with myelodysplasia (emberger syndrome) gata2 myelodysplasia, congenital deafness may be present hereditary lymphedema type 1c gjc2 lymphedema in 4 limbs hypotrichosis-lymphedematelangiectasia sox18 vascular malformations including aortic dilation and cutaneous telangiectasias, hypotrichosis yellow nail syndrome unknown triad of yellow/green nails, respiratory symptoms, and lymphedema lymphedema tarda n/a obesity n/a secondary infection n/a malignancy n/a microparticles n/a n/a = not applicable. 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mansour s, connell f, steward c, et al. emberger syndrome primary lymphedema with myelodysplasia: report of seven new cases. am j med genet a. 2010;152a(9):2287-2296. doi: 10.1002/ajmg.a.33445. pmid: 20803646. 27. online mendelian inheritance in man, omim®. johns hopkins university, baltimore, md. mim number: 153200: 01/10/2019: available from https://www.omim.org/entry/153200?search =153200&highlight=153200 28. wheeler es, chan v, wassman r, rimoin dl, lesavoy ma. familial lymphedema praecox: meige's disease. plast reconstr surg. 1981;67(3):362-364. doi: 10.1097/00006534-198103000 -00016. pmid: 7232571. 29. kerchner k, fleischer a, yosipovitch g. lower extremity lymphedema update: pathophysiology, diagnosis, and treatment guidelines. j am acad dermatol. 2008;59(2):324-331. doi: 10.1016/j.jaad.2008.04.013. pmid: 18513827. 30. bell r, brice g, child ah, et al. analysis of lymphoedema distichiasis families for foxc2 mutations reveals small insertions and deletions throughout the gene. hum genet. 2001;108(6): 546-551. doi: 10.1007/s004390100528. pmid: 11499682. 31. ostergaard p, simpson ma, connell fc, et al. mutations in gata2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (emberger syndrome). nat genet. 2011;43(10):929-931. doi: 10.1038/ng.923. pmid: 21892158. 32. gonzalez-garay ml, aldrich mb, rasmussen jc, et al. a novel mutation in celsr1 is associated with hereditary lymphedema. vasc cell. 2016;8:1. doi: 10.1186/s13221-016-0035-5. pmid: 26855770. pmcid: pmc4743364. 33. maltese pe, michelini s, ricci m, et al. increasing evidence of hereditary lymphedema caused by celsr1 loss-of-function variants. am j med genet a. 2019;179(9):1718-1724. doi: 10.1002/ajmg.a.61269. pmid: 31215153. 34. erickson rp, lai lw, mustacich dj, bernas mj, kuo ph, witte mh. sex-limited penetrance of lymphedema to females with celsr1 haploinsufficiency: a second family. clin genet. 2019;96(5):478-482. doi: 10.1111/cge.13622. pmid: 31403174. lymphedema. am j dermatopathol. 2006;28(3):223-227. doi: 10.1097/00000372-200606000-00010. pmid: 16778491. 10. eltorky m, mcc chesney t, sebes j, hall jc. spindle cell hemangioendothelioma. report of three cases and review of the literature. j dermatol surg oncol. 1994;20(3):196-202. doi: 10.1111/j.1524-4725.1994.tb00466.x. pmid: 8151034. 11. grada aa, phillips tj. lymphedema: diagnostic workup and management. j am acad dermatol. 2017;77(6):995-1006. doi: 10.1016/j.jaad.2017.03.021. pmid: 29132859 12. connell fc, gordon k, brice g, et al. the classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. clin genet. 2013;84(4): 303-314. doi: 10.1111/cge.12173. pmid: 23621851. 13. goss ja, greene ak. sensitivity and specificity of the stemmer sign for lymphedema: a clinical lymphoscintigraphic study. plast reconstr surg glob open. 2019;7(6):e2295. doi: 10.1097/gox.0000000000002295. pmid: 31624689. pmcid: pmc6635205. 14. shah aa, petrosyan m, nizam w, roberson j, guzzetta p. resource overutilization in the diagnosis of lymphedema praecox. j pediatr surg. 2020;55(7):1363-1365. doi: 10.1016/j.jpedsurg. 2019.09.014. pmid: 31706604. 15. ghalamkarpour a, morlot s, raas-rothschild a, et al. hereditary lymphedema type i associated with vegfr3 mutation: the first de novo case and atypical presentations. clin genet. 2006;70(4):330-335. doi: 10.1111/j.1399-0004.2006.00687.x. pmid: 16965327. 16. balboa-beltran e, fernández-seara mj, pérez-muñuzuri a, et al. a novel stop mutation in the vascular endothelial growth factor-c gene (vegfc) results in milroy-like disease. j med genet. 2014;51(7):475-478. doi: 10.1136/jmedgenet-2013-102020. pmid: 24744435. 17. gordon k, schulte d, brice g, et al. mutation in vascular endothelial growth factor-c, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy like primary lymphedema. circ res. 2013;112(6):956-960. doi: 10.1161/circresaha.113.300350. pmid: 23410910. 18. malik s, grzeschik kh. congenital, low penetrance lymphedema of lower limbs maps to chromosome 6q16.2-q22.1 in an inbred pakistani family. hum genet. 2008;123(2):197-205. doi: 10.1007/s00439-007-0458-4. pmid: 18193458. 19. ostergaard p, simpson ma, brice g, et al. rapid identification of mutations in gjc2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. j med genet. 2011;48(4):251-255. doi: 10.1136/jmg.2010.085563. pmid: 21266381. 20. zhu ll, lv yn, chen hd, gao xh. a chinese pedigree of lymphoedema-distichiasis syndrome with a novel mutation in the foxc2 gene. clin exp dermatol. 2014;39(6):731-733. doi: 10.1111/ced.12389. pmid: 24984567. 21. fang j, dagenais sl, erickson rp, et al. mutations in foxc2 (mfh-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. am j hum genet. 2000 dec;67(6):1382-1388. doi: 10.1086/316915. pmid: 11078474. pmcid: pmc1287915. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022074 1 follicular becker nevus: an unusual clinical and dermoscopic manifestation li-wen zhang1, xue shen1, lei xu1, hai-peng shi2, tao chen1 1 department of dermatovenereology, chengdu second people’s hospital, chengdu, sichuan, china 2 department of pathology, chengdu second people’s hospital, chengdu, sichuan, china key words: becker nevus, follicular, dermoscopy, papule citation: zhang l, shen x, xu l, shi h, chen t. follicular becker’s nevus: an unusual clinical and dermoscopic manifestation. dermatol pract concept. 2022;12(2):e2022074. doi: https://doi.org/10.5826/dpc.1202a74 accepted: september 8, 2021; published: april 2022 copyright: ©2022 zhang et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: tao chen, department of dermatovenereology, chengdu second people’s hospital, 165 caoshi street, chengdu 610017, sichuan, china. e-mail: 13980427003@163.com introduction becker nevus (bn) is characterized by a unilateral, hairy, pigmented macule usually involving the chest or scapular region. we hereby reported a specific case of follicular bn presenting follicular macules and maculopapules, and described its dermoscopic manifestation. case presentation a 20-year-old female presented with a 12-year history of multiple clustered asymptomatic brown macules and maculopapules affecting the inside of the left upper arm (figure 1a). the pigmented lesions gradually increased in the initial phase and then stabilized. no other accompanied systemic abnormality was found. familiar and medical histories were unremarkable. the dermoscopy revealed multiple brown round perifollicular macules with thicker hairs in the follicles (figure 1b). the histopathological examination showed hyperkeratosis, acanthosis, and darkly pigmented basal cell layer (figure 1c). a diagnosis of follicular bn was made. discussion bn, also called pigmented hairy epidermal nevus, is characterized by a unilateral, hairy, pigmented macule usually involving the upper chest or the scapular region, a few cases present multiple or bilateral. the pathogenesis is still unclear. the plausible explanations for bn include mosaicism and an androgen-dependent lesion [1]. bn has male predilection, with a 2:1 to 5:1 predominance of men over women [1]. bn commonly appears during adolescence and some cases are congenital. the lesions usually present as an asymptomatic well-demarcated, irregular, brown macule with a geographic or block-like configuration. however, manchanda et al first reported an unusual clinical manifestation of bn in 2020, which presented follicular lesions [2]. they speculated that some bn might begin from perifollicular lesions and follicular epithelium might hold a significant role in the etiopathogenesis. the mechanism of follicular bn and the pathogenesis of bn remain to be further studied. bn usually do not require treatment, and some potential therapeutic options were taken due to cosmetic requirement, 2 research letter | dermatol pract concept. 2022;12(2):e2022049 including electrolysis, waxing, makeup, laser treatment, and topical therapy. currently, no consensus has yet been reached in the literature regarding which treatment is preferred and success with each treatment varies widely. conclusions follicular bn is an unusual clinical variant. the dermatologist should be aware of the unusual clinical manifestation of bn, which could permit to quickly solve the clinical doubts and reassure the patient. references 1. danarti r, konig a, salhi a, bittar m, happle r. becker’s nevus syndrome revisited. j am acad dermatol. 2004;51(6):965-969. doi: 10.1016/j.jaad.2004.06.036. pmid: 15583590. 2. manchanda y, khaitan bk, ramam m, das s, al-mutairi n. follicular becker’s nevus: a new clinical variant. indian j dermatol. 2020;65(2):130-132. doi: 10.4103/ijd.ijd_476_18. pmid: 32180599. pmcid: pmc7059461. figure 1. (a) multiple clustered brown follicular macules and maculopapules affecting the inside of the left upper arm. (b) the dermoscopy revealed multiple brown round perifollicular macules with thicker hairs in the follicles. (c) the histopathology showed hyperkeratosis, acanthosis, and darkly pigmented basal cell layer (h&e staining; ×200 magnification). dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):7 31 dermatology practical & conceptual www.derm101.com case report an otherwise healthy 60-year-old man was referred to our department with a one-year history of recurrent pruritic vesiculo-pustular lesions on both axillae and groin. the lesions improved after topical application of steroids but reappeared and gradually spread to trunk and extremities. the patient was not receiving any medications. examination revealed a symmetric eruption on the proximal extremities and trunk with prominent involvement of the axillae and groin. it was composed of grouped vesiculo-pustular lesions mostly on well-circumscribed erythematous patches (figure 1). mucous membranes were not involved. nikolsky’s sign was negative. bacterial cultures from representative pustules were all negative. histological examination of a biopsy specimen revealed subcorneal neutrophilic pustules with few acantholytic cells. there were also numerous neutrophils infiltrating the epidermis (figure 2). direct immunofluorescence microsiga pemphigus showing iga antibodies to desmoglein 1 and 3 salama hegazy1, sana bouchouicha1, aida khaled1, lilia laadher2, maryem kallel sellami2, faten zeglaoui1 1 department of dermatology, charles nicolle hospital, tunis, tunisia 2 department of immunology, rabta hospital, tunis, tunisia key words: pemphigus, iga pemphigus, desmoglein citation:hegazy s, bouchouicha s, khaled a, laadher l, kallel sellami m, zeglaoui f. iga pemphigus showing iga antibodies to desmoglein 1 and 3.dermatolpract concept 2016;6(4):7.doi: 10.5826/dpc.0604a07 received: august 20, 2016; accepted: august 24, 2016; published: october 31, 2016 copyright: ©2016 hegazy et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: salama hegazy, md. email: dr_salama_86@hotmail.com background: iga pemphigus is a rare autoimmune vesiculo-pustular skin disease. only approximately 70  cases have been reported to date. we report a case of iga pemphigus with iga antibodies to desmoglein 1 (dsg1) and desmoglein 3 (dsg3). case report: we report the case of an 60-year-old man with intraepidermal neutrophilic iga pemphigus with iga antibodies to dsg1 and dsg3. histologic examination revealed subcorneal neutrophilic pustules with few acantholytic cells. the disease was not effectively controlled by conventional therapeutic regimens (colchicine, dapsone). systemic treatment with isotretinoin 25 mg/d and prednisone 20 mg/d achieved only a slight effect after six months. conclusions: our case confirmed the recalcitrant nature of iga pemphigus in response to distinct therapies, indicating that further research focusing on therapeutic approaches for this type of pemphigus is needed.physicians should keep iga pemphigus in mind when approaching patients with bullous eruption. abstract 32 observation | dermatol pract concept 2016;6(4):7 into two subtypes,namely,subcorneal pustular dermatosis (spd) and intraepidermal neutrophilic dermatosis (ien) types [1,2]. clinically, as seen in our patient, both subtypes of iga pemphigus present with small blisters and pustules overlaying well-circumscribed erythemas [2]. a herpetiform appearance has also been reported [2]. the whole body can be involved,with a predilection for flexures, such as axilla, groin and submammary area [1]. mucosa is usually copy (dif) of perilesional skin detected intercellular deposits of iga throughout the epidermis (figure 3). igg-elisa for desmogleins (dsg) showed no igg antibodies to either dsg1 or dsg3. igaelisa for dsgs was then performed and the results indicated that the patient’s serum was positive for iga anti-dsg1 and anti-dsg3 antibodies. there was no monoclonal iga gammapathy on immunoelectrophoresis. based on immunopathological data, intraepidermal neutrophilic dermatosis type iga pemphigus was diagnosed. colchicine, 0.5 mg 3 times daily was begun, but this had no effect after one month so it was substituted by dapsone 100 mg/d, which also failed to produce any improvement and his disease remained active. subsequently, isotretinoin 25 mg/d and prednisone 20 mg/d were initiated achieving only a slight effect after six months. conclusions based on pathology and dif findings, iga pemphigus can be further divided figure 2. histopathological findings:subcorneal neutrophilic pustules, few acantholytic cells and numerous neutrophils infiltrating the epidermis. [copyright: ©2016 hegazy et al.] figure 1. vesiculo-pustular lesions mostly on well-circumscribed erythematous patches on the axillae. [copyright: ©2016 hegazy et al.] free of lesions [2]. while spd-type iga pemphigus shows subcorneal pustules, the ien type is characterized by pustule formation throughout the entire epidermis [1,2,3]. in dif, spd-type iga pemphigus involves cell surface iga binding only in the upper epidermis, where as ien-type iga pemphigus shows binding throughout the epidermis [1]. although the histological features of our case are consistent with those of the spd type of iga pemphigus, ienfigure 3. dif of perilesional skin: intercellular deposits of iga throughout the epidermis. [copyright: ©2016 hegazy et al.] observation | dermatol pract concept 2016;6(4):7 33 mofetil, have also been reported to be useful in treating iga pemphigus [2]. our case confirmed the recalcitrant nature of iga pemphigus in response to distinct therapies, indicating that further research focusing on therapeutic approaches for this type of pemphigus is needed. references 1. hashimoto t. immunopathology of iga pemphigus. clin dermatol 2001; 19:683-9. pmid: 11705676. 2. tsuruta d, ishii n, hamada t, et al. iga pemphigus. clin dermatol 2011;29:437-42. pmid: 21679872. doi: 10.1016/j.clindermatol.2011.01.014. 3. tajima m, mitsuhashi y, irisawa r, et al.iga pemphigus reactingexclusively to desmoglein 3. eur j dermatol 2010; 20(5):626-9. pmid: 20605770. doi: 10.1684/ejd.2010.1021. 4. moreno ac, santi gg, gabbi tv, et al. iga pemphigus: case serieswithemphasis on therapeuticresponse. j am acad of dermatol 2014; 70(1)200-1. pmid: 24355273. doi: 10.1016/j. jaad.2013.09.037. 5. hodak e, lapidoth m, david m. effect of colchicine in the subcorneal pustular dermatosis type of iga pemphigus. j am acad dermatol 1999;40:91-4. pmid: 9922018. type iga pemphigus was diagnosed in the present patient because of iga deposits throughout the epidermis. desmocollin 1 has recently been identified as the target antigen of the spd type [3]. in contrast, in the ien type no reactivity of auto antibodies with desmocollin 1, 2, and 3 has been found [3],whereas desmoglein 1 and 3 were suggested as putative target antigens of ien type in single case reports [2,3].the result of immunoelectron microscopic study revealed that the antigen of ien type may not be a desmosomal component [1]. in our patient, iga-elisa for dsgs showed reactivity with dsg1 and dsg3, suggesting that his pemphigus most likely belongs to the ien type. iep should be performed because iga pemphigus has been reported to be associated with monoclonal iga gammapathy [2]. treatments of iga pemphigus are performed based on the disease pathomechanism and on anecdotal reports. dapsone is commonly the drug of choice due to its effect in suppressing neutrophilic infiltration [2]. acitretin or isotretinoin are alternatives when dapsone cannot be used [1,2,4]. furthermore, both types of iga pemphigus have been described as responding to colchicines [5]. recently, adalimumab and mycophenolate dermatology: practical and conceptual review | dermatol pract concept 2017;7(2):1 1 dermatology practical & conceptual www.derm101.com introduction epidemiology, translated from greek, literally means “the study of population.” the main aims of epidemiology include the description of disease patterns in human populations, as well as the identification of causes of diseases. epidemiology provides essential data for the management, evaluation and planning of services for prevention, control and therapeutic management of diseases [1]. skin cancer represents the most common group of malignant neoplasms in the white population. the incidence rate of melanoma and non-melanoma skin cancer (nmsc) is increasing worldwide [2]. therefore, studying and understanding their current epidemiological trends is considered crucial in order to achieve early and adequate control of the disease. melanoma melanoma is much more common in whites than in other ethnic groups. overall, the lifetime risk of developing melanoma is about 2.4% in caucasians, 0.1% in blacks, and 0.5% in hispanics [3]. the risk of melanoma increases with age. the average age at the time of diagnosis is about 60. melanoma is approximately 1.5 times more frequent in males than females. it has been shown that the incidence rate does not significantly differ until the age of 40, however, after age 75, the incidence becomes almost three times higher in males compared to females [4,5]. in addition, the frequency of its occurrence is closely associated with the constitutive color of the skin and depends on the geographical zone [6]. cumulative epidemiologic data from europe [7-10], canada [11] and the united states [12-14] indicate a continuous epidemiological trends in skin cancer zoe apalla1, aimilios lallas1, elena sotiriou1, elizabeth lazaridou1, demetrios ioannides1 1 first department of dermatology, medical school, aristotle university of thessaloniki, greece key words: skin cancer, melanoma, non-melanoma skin cancer, epidemiology citation: apalla z, lallas a, sotiriou e, lazaridou e, ioannides d. epidemiological trends in skin cancer. dermatol pract concept. 2017;7(2):1. doi: https://doi.org/10.5826/dpc.0702a01 received: september 4, 2016; accepted: january 19, 2017; published: april 30, 2017 copyright: ©2017 apalla et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: zoe apalla, md, phd, delfon 124, 54643, thessaloniki, greece. tel. +302313308882. e-mail: zoimd@yahoo.gr skin cancer, including melanoma and non-melanoma skin cancer (nmsc), represents the most common type of malignancy in the white population. the incidence rate of melanoma is increasing worldwide, while the associated mortality remains stable, or is slightly decreasing. on the other hand, the incidence for nmsc varies widely, with the highest rates reported in australia. in the current review, we highlight recent global trends in epidemiology of skin cancer. we discuss controversial issues raised in current epidemiological data, we analyze the most important risk factors associated with the development of melanoma and nmsc and the impact of skin cancer on health care services. furthermore, we underline the pressing need for improved registration policies, especially for nmsc, and lastly, we refer to the ongoing primary and secondary prevention strategies and their outcomes so far. abstract 2 review | dermatol pract concept 2017;7(2):1 indeed, very recent epidemiological studies indicate that melanoma in situ, with an annual increase of 9.5%, occupies a disproportionately high percentage of the overall melanoma increase. however, the combined melanoma incidence (including both invasive and in situ melanoma) was also found to increase by 2.6% per year [20], justifying that the incidence increase also considers tumors with metastatic potential. from the dermatopathologic point of view, this is not surprising, since there are studies suggesting a current trend towards reclassification of prior non-malignant diagnoses as melanoma [21]. furthermore, in a population-based study correlating number of skin biopsies and incidence of melanoma, the investigators noted that there was an in parallel increase during a 15-year period, suggesting that the melanoma “epidemic” is possibly attributed to scrutiny and increased number of biopsies, too [21]. on the other hand, studies exploring the incidence of melanoma based on tumor thickness and demographic factors have suggested that increased screening and biopsy alone cannot account for the dramatic increase in the incidence. the authors’ chief argument is that incidence increases independently of socioeconomic status, which functions as a surrogate marker for access to care and screening [24]. the latter suggestion is in agreement with the findings of shaikh et al. in their study they used a validated imputation method for missing thickness data, in order to characterize melanoma thickness and survival trends among men and women in the surveillance epidemiology and end results (9 registries included) between 1989-2009. according to their results, an increasing incidence was observed in all thickness groups. in addition, thickness increased in t3/t4 tumors, and nodular melanomas. these observations coupled together “suggest that the melanoma epidemic is real and not simply an artifact of increased detection pressure of earlier-stage t1/ t2 lesions” [25]. what does the future hold concerning melanoma incidence? whiteman et al used age-period cohort models to describe current trends and project future incidence rates. they analyzed three decades of registry data (1982-2011) from six populations with moderate-to-high melanoma incidence (us whites, united kingdom, sweden, norway, australia, new zealand). statistical analysis showed that melanoma rates in the us, uk, sweden and norway increased more than 3% annually. future projections indicate that the rates will keep on rising until at least 2022. on the other hand, in australia melanoma incidence has been declining since 2005, whilst in new zealand, even though it is currently increasing, it is and dramatic increase in incidence during the last decades. the highest incidence rates have been reported in new zealand with 50 cases per 100,000 persons and australia with 48 cases per 100,000 persons (59 for males and 39 for females in 2011), followed by the us (21.6 new cases per year per 100,000 in 2012) and europe (13.2 and 13.1 new cases per year, per 100,000 for men and women, respectively) [15-17]. the wide variation in incidence rates is not observed only among different continents. data from the european cancer observatory suggest significant variability among european countries, too. scandinavian countries (especially sweden, with an estimated incidence of 23.9 in 2012), switzerland and great britain report the highest rates (>16.9 per 100,000 for 2012), whilst the balkan countries, moldova and bosnia and herzegovina, are standing at the lower incidence levels (<5.3 per 100,000 for 2012) [17]. the latter deviation is not only associated with the different risk factors characterizing different european populations. it may also be connected to weaknesses or discrepancies in the national registration systems among different countries. as an example, in austria the reports by the national cancer registry showed that there was an underestimation of the true melanoma burden. the observed divergence is not surprising, given that private practice and non-hospital-based pathology laboratories are not legally obliged to report cancer cases in austria [18]. the melanoma epidemic: is it real? as described above, the continuous increase of melanoma incidence is supported by several epidemiologic data from different countries. however, the real nature of this increase has become a controversial issue [19]. specifically, the issue in question is whether the incidence increase should be interpreted as a real melanoma “epidemic,” or if it represents the result of intense screening [20,21], improved diagnostic ability of clinicians, increased biopsies [22], or changes in histologic criteria [23] that allow us to diagnose melanomas that previously remained unrecognized. the controversy deepens by the recently introduced concept of “overdiagnosis” in cancer, which refers to the increased sensitivity of diagnostic techniques to detect “cancers” that would otherwise not progress enough to cause significant morbidity or death. in the melanoma family, the subtype that could fit the concept of “overdiagnosis” is melanoma in situ, since one could argue that some of these melanomas, especially those developing in elderly individuals, would not have the time to invade the dermis and acquire a metastatic potential. this argument might be supported by data suggesting that some melanomas (mainly—but not exclusively—of the lentigo maligna subtype) grow very slowly and might need years or even decades to become invasive. review | dermatol pract concept 2017;7(2):1 3 keratinocyte carcinoma increases with age [2]. with regards to the gender, there is a slight male predilection, which also increases with age [2]. concerning lifetime risk of developing a nmsc (for a child born in l994 in rhode island, usa), it was estimated to be 28-33% for bcc and 7-11% for scc [2]. the most well recognized exogenous factor implicated in the pathogenesis of nmsc is the ultraviolet radiation (uvr). in western societies, tan-seeking behavior, including sunbathing and indoor tanning, outdoor activities without adequate sun protection, clothing style and ozone depletion are among the parameters contributing to the increased uvrexposure [2]. future projections about nmsc: why should we worry? future expectations, as reported by the dutch national institute for public health and the environment, suggest a possible increase in the overall number of extra cancer cases related to environmental factors and increased uvr by 2060 [36]. apart from environmental changes, another crucial reason for a further future increase of the nmsc incidence is the prolonged life expectancy. data from the population division of the department of economic and social affairs of the united nations underline that population ageing, as recorded since 1950, is unprecedented, and it is estimated that within the next four decades, will be even more rapid. by 2050, it is expected that 32% of the world population will be above the age of 60. given the predilection of keratinocyte cancers for the elderly, it is reasonable that nmsc will follow this age increase [37]. besides the the uv exposure and the increased life expectancy, other possible reasons contributing to the incidence increase during the last decades of life may include improved registration procedures and improved diagnostic tools [6]. the economic burden of nmsc increasing incidence together with high prevalence translates into significantly higher costs, which has become a considerable economic burden for public health services. the quantifiable financial cost consists of the direct costs, resulting from medical care, and indirect costs, associated to loss of potential life-years and productivity [38]. in australia (population: 23.13 million), the estimated total cost, including diagnosis, therapeutic management and histopathology, reached $511 million in 2010, and it is projected to increase up to $703 million by 2015 [39]. similarly, in the us (population: 318.9 million), the estimated total annual expenditure for nmscs’ medical care reached $650 million [40]. concerning cost efficacy of differexpected to decline soon. in regards with the number of new melanoma cases, it is estimated that they will rise in all the studied populations because of the increasing longevity and the high age-specific rate of melanoma in the elderly. the latter highlights the rigorous need for adequate melanoma control [26]. non-melanoma skin cancer or keratinocyte carcinomas under the umbrella of nmsc we describe all the non-melanoma malignant neoplasms affecting the skin. however, especially epidemiologically, the term nmsc practically refers to keratinocyte carcinomas, namely basal (bcc) and squamous cell carcinoma (scc), since they account for the 99% of the tumors in this group [27]. the incidence of nmsc is 18-20 times higher than that of melanoma [28]. however, compared to melanoma, the epidemiology of nmsc is understudied. there are significant limitations in the investigation of nmsc incidence, mainly attributed to its marked geographic variability, as well as to the fact that large cancer registries usually exclude nmsc from their records, or the records are incomplete. even secondary data analyses are rather limited [29]. the low mortality rate together with the practical difficulties in ascertaining the large number of cases may represent possible reasons for this gap in nmsc recording. indeed, the metastatic potential and mortality rates of nmsc are low. the incidence of metastatic bcc and scc ranges between 0.00281-0.05% and 0.5-16%, respectively, whilst the age-adjusted mortality rate is estimated to be 0.12 per 100,000 for bcc and 0.3 per 100,000 for scc [30-32]. however, despite its relatively low malignant potential, nmsc is associated with a remarkable morbidity and substantial cost [33,34]. the lack of national cancer registries for nmsc restricts our ability to estimate and establish definite and comparable incidence rates. looking at the map of keratinocyte carcinomas, it is evident that the worldwide incidence varies widely. australia is by far at the top of the rate, with more than 1,000 per 100,000 person-years for bcc (2,448/100.000, 2011), followed by europe (129.3 in men, and 90.8 in women per 100,000 person-years, european standard) and the us (450 per 100.000 person-years, 2010). prevalence was estimated to be 2.0% (2002), 1.4% and 0.7%, for australia, europe and the us, respectively [35,2]. during the last 30 years, the incidence of scc has been rising 3–10% per year [29]. for the same period, it is estimated that bcc incidence rate has risen between 20-80% in the us [29]. bcc is more common than scc, with a standardized ratio being roughly 4:1.2 [6]. the risk for development of a 4 review | dermatol pract concept 2017;7(2):1 melanoma and nmsc: prevention strategies prevention strategies are divided twofold: primarily to encourage behavioral changes to lower subsequent skin cancer risk, and secondarily, to enhance early detection. primary prevention is considered efficient when it succeeds in reducing incidence over the years. to achieve this goal it must be focused on interventions that reduce sun exposure, reinforce the use of adequate sun protection and discourage intensive tanning [47]. approaching different age groups is sometimes tricky. as an example, it seems that in teen girls emphasizing the risk-toappearance, by correlating sun damage and premature wrinkling, works better, while in teen boys, shifting the emphasis from long-term risk of nmsc to protection of painful burns is more efficient [48]. stratification of the parents as models of sun protection is also efficient. introduction of sun protection policy guidelines for primary/secondary schools is also a promising policy [49]. implementation of mass media campaigns for public education is considered a significant intervention for achieving behavioral modification. the benefit-cost ratio of three skin cancer campaigns held in australia between 2006-2013 was found to be 3.85, meaning that for every $1 invested, there is a return of $3.85. based on this finding, the authors concluded that public education in mass media campaigns are beneficial, taking into account the likelihood of resulting reduced morbidity, mortality and economic burden of skin cancer [50]. on the other hand, the aim of secondary prevention is to reduce morbidity and mortality, mainly through early recognition of skin cancer. some big steps towards early diagnosis include screening of the high-risk population, skin self-examination with the assistance of a partner, as well as physicians’ surveillance [51,52]. the benefits of dermatoscopy [53] and total body skin examination are well known, especially when we deal with the population at high risk, such as young individuals with many nevi and elderly people with sun damage [54]. conclusion taking into account the worldwide epidemiologic trends of skin cancer, it becomes obvious that there is a rigorous need to control increasing incidence and subsequent socioeconomic burden. efforts towards this aim include optimization of the registration standards and development of efficient primary and secondary prevention strategies. references 1. australasian epidemiological association website. http://www. aea.asn.au/about-us/what-is-epidemiology. accessed june 3, 2016. ent care settings, mudigonda et al found out that physicianoffice settings are characterized by the lowest cost per episode of care and represent the most popular choice of care. the latter is in agreement with data in the recent literature that evaluated the financial burden of bcc and reported higher costs in the hospital compared to physician-office treatment setting. in the same study, investigators concluded that in descending order, cost of different treatment modalities is as follows: radiotherapy, mohs surgery, standard excision, destruction (electrodessication and curettage, cryotherapy), imiquimod and 5-fluoruracil [41]. this information is essential, since it indicates that investment in optimization of the already existing, and development of new, physician-office based treatments is clinically relevant and may contribute to the control of the overall cost. nmsc: risk factors elaboration of efficient prevention strategies requires good knowledge of the risk factors. regarding nmsc, these are divided into personal and environmental. age, gender and genetic susceptibility are the most dominant risk factors of the former group, while uvr exposure represents the most dominant environmental risk factor [38]. the incidence of scc increases more rapidly with age than bcc. in younger ages, the incidence of nmsc is similar for both sexes; however after the age of 45, men develop keratinocyte carcinomas 2-3 times more frequently than women. genetic susceptibility is mainly attributed to the melanin content of the skin and ability to tan [6]. while scc is strongly related to long-term, cumulative sun exposure [42], the relationship between exposure to uvr and the risk of bcc is more complex. it seems that a history of excessive/intermittent sun exposure and sunburn in childhood and adolescence are responsible for its development [43]. this observation is also in agreement with findings from histopathological studies, investigating the association of scc and bcc with sun-damage alterations in the perilesional skin. according to their results, presence of actinic damage at the perilesional skin is five times more frequent in scc than in bcc [44]. a very worrisome finding in epidemiological studies is the substantial increase of bcc among younger women. this has raised concerns about the role of sunbathing and indoor tanning behaviors, which may contribute to this increase [45]. indeed, despite the intense warnings of the harmful effects of indoor tanning, there are studies reporting that in western countries it is very common, especially among young individuals [46]. these findings contribute to the growing body of evidence on the harm of indoor tanning and on the support of public health campaigns and regulation to reduce exposure and alter this modifiable risk factor [47]. http://www.aea.asn.au/about-us/what-is-epidemiology http://www.aea.asn.au/about-us/what-is-epidemiology review | dermatol pract concept 2017;7(2):1 5 22. weyers w. the ‘epidemic’ of melanoma between underand overdiagnosis. j cutan pathol. 2012;39:9-16. 23. linos e, swetter sm, cockburn mg, colditz ga, clarke ca. increasing burden of melanoma in the united states. j invest dermatol. 2009;129: 1666-1674. 24. shaikh wr, dusza sw, weinstock ma, et al. melanoma thickness and survival trends in the united states, 1989 to 2009. j natl cancer inst. 2015;108(1). 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2014;810:120-140. 3. american cancer society. http://www.cancer.org/cancer/skin cancer-melanoma/detailedguide/melanoma-skin-cancer-keystatistics. accessed june 3, 2016. 4. rastrelli m, tropea s, rossi c, alaibac m. melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification. in vivo. 2014;28:1005-1011. 5. chen st, geller ac, tsao h. update on the epidemiology of melanoma. curr dermatol rep. 2013;2:24-34. 6. leiter u, garbe c. epidemiology of melanoma and nonmelanoma skin cancer—the role of sunlight. adv exp med biol. 2008;624:89-103. 7. de vries e, coebergh jw. cutaneous malignant melanoma in europe. eur j cancer. 2004;40:2355–2366. 8. lasithiotakis k, leiter u, gorkievicz r, et al. the incidence and mortality of cutaneous melanoma in southern germany: trends by anatomic site and pathologic characteristics, 1976 to 2003. cancer. 2006;107:1331–1339. 9. mansson-brahme e, johansson h, larsson o, rutqvist l, ringborg u. trends in incidence of cutaneous malignant melanoma in a swedish population 1976–1994. acta oncol. 2002;41:138– 146. 10. stang a, pukkala e, sankila r, söderman b, hakulinen t. time trend analysis of the skin melanoma incidence of finland from 1953 through 2003 including 16,414 cases. int j cancer. 2006;119:380–384. 11. ulmer mj, tonita jm, hull pr. trends in invasive cutaneous melanoma in saskatchewan 1970–1999. j cutan med surg. 2003;7:433–442. 12. dennis l. analysis of the melanoma epidemic, both apparent and real: data from the 1973 through 1994 surveillance, epidemiology, and end results program registry. arch dermatol. 1999;135:275– 280. 13. geller ac, miller dr, annas gd, demierre mf, gilchrest ba, koh hk. melanoma incidence and mortality among us whites, 1969–1999. jama. 2002;288:1719–1720. 14. hall hi, miller dr, rogers jd, bewerse b. update on the incidence and mortality from melanoma in the united states. j am acad dermatol. 1999;40:35–42. 15. australian government, cancer australia. http://melanoma. canceraustralia.gov.au/. accessed june 3, 2016. 16. national cancer institute, surveillance epidemiology, and end results program. http://seer.cancer.gov/. european cancer observatory http://eco.iarc.fr/eucan. accessed june 3, 2016. 17. monshi b, vujic m, kivaranovic d, et al. the burden of malignant melanoma—lessons to be learned from austria. eur j cancer. 2016;56:45-53. 18. erickson c, driscoll ms melanoma epidemic: facts and controversies. clin dermatol. 2010;28:281-286. 19. higgins hw 2nd, lee kc, galan a, leffell dj. melanoma in situ: part i. epidemiology, screening, and clinical features. j am acad dermatol. 2015;73:181-190. 20. frangos je, duncan lm, piris a, et al. increased diagnosis of thin superficial spreading melanomas: a 20-year study. j am acad dermatol. 2012;67: 387-394. 21. welch hg, woloshin s, schwartz lm. skin biopsy rates and incidence of melanoma: population based ecological study. bmj. 2005;331:481. http://www.rivm.nl/dsresource?objectid=rivmp:9586&type=org&disposition=inline&ns_nc=1 http://www.rivm.nl/dsresource?objectid=rivmp:9586&type=org&disposition=inline&ns_nc=1 http://www.rivm.nl/dsresource?objectid=rivmp:9586&type=org&disposition=inline&ns_nc=1 http://www.un.org/en/development/desa/population/publications/pdf/ageing/worldpopulationageing2013.pdf http://www.un.org/en/development/desa/population/publications/pdf/ageing/worldpopulationageing2013.pdf http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics http://melanoma.canceraustralia.gov.au/ http://melanoma.canceraustralia.gov.au/ http://eco.iarc.fr/eucan 6 review | dermatol pract concept 2017;7(2):1 47. olson al, gaffney ca, starr p, dietrich aj. the impact of an appearance-based educational intervention on adolescent intention to use sunscreen. health educ res. 2008;23:763-769. 48. reeder ai, jopson ja, gray a. sun protection policies and practices in new zealand primary schools. n z med j. 2012;125:7082. 49. doran cm, ling r, byrnes j, et al. benefit cost analysis of three skin cancer public education mass-media campaigns implemented in new south wales, australia. plos one. 2016;11:e0147665. 50. robinson jk, mallett ka. the duty to inspect the skin and counsel those at risk to develop melanoma. jama. 2009;301:1702-1704. 51. weinstock ma, risica pm, martin ra, et al. melanoma early detection with thorough skin self-examination: the “check it out” randomized trial. am j prev med. 2007;32:517-524. 52. zalaudek i, lallas a, moscarella e, longo c, soyer hp, argenziano g. the dermatologist’s stethoscope—traditional and new applications of dermoscopy. dermatol pract concept. 2013;3:6771. 53. argenziano g, zalaudek i, hofmann-wellenhof r, et al. total body skin examination for skin cancer screening in patients with focused symptoms. j am acad dermatol. 2012;66:212-219. 39. mudigonda t, pearce dj, yentzer ba, williford p, feldman sr. the economic impact of non-melanoma skin cancer: a review. j natl compr canc netw. 2010; 8(8):888-896. 40. wu x, elkin ee, marghoob aa. burden of basal cell carcinoma in usa. future oncol. 2015;11:2967-2974. 41. gallagher rp, hill gb, bajdik cd, et al. sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. ii. squamous cell carcinoma. arch dermatol. 1995;131:164-169. 42. rubin ai, chen eh, ratner d. basal-cell carcinoma. n engl j med. 2005;353:2262-2269. 43. apalla z, calzavara-pinton p, lallas a, et al. histopathological study of perilesional skin in patients diagnosed with nonmelanoma skin cancer. clin exp dermatol. 2016;41:21-25. 44. flohil s, seubring i, van rossum mm, coebergh jw, de vries e, nijsten t. trends in basal cell carcinoma incidence rates: a 37-year dutch observational study. j invest dermatol. 2013;133:913-918. 45. wehner mr, chren mm, nameth d, et al. international prevalence of indoor tanning: a systematic review and meta-analysis. jama dermatol. 2014;150:390-400. 46. wehner mr, shive ml, chren mm, han j, qureshi aa, linos e. indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. bmj. 2012;345:e5909. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022079 1 dermatoscopic features of a metastatic eccrine porocarcinoma arising on lymphedema dimitrios sgouros1, eleni routsi1, zannis almpanis2, athanasios korogiannos3, alexander katoulis1 1 second department of dermatology-venereology, attikon general university hospital, national and kapodistrian university of athens, medical school, athens, greece 2 department of pathology, 251 hellenic air force general hospital of athens, athens, greece 3 third oncology clinic, herny dunant hospital, athens, greece key words: eccrine porocarcinoma, metastatic eccrine porocarcinoma, malignant eccrine poroma, sweat gland tumor citation: sgouros d, routsi e, almpanis z, korogiannos a, katoulis a. dermatoscopic features of a metastatic eccrine porocarcinoma arising on lymphedema. dermatol pract concept. 2022;12(2):e2022079. doi: https://doi.org/10.5826/dpc.1202a79 accepted: september 15, 2021; published: april 2022 copyright: ©2022 sgouros et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dimitrios sgouros, 2nd department of dermatology-venereology, “attikon” general university hospital, 1 rimini str, 12462, chaidari, athens, greece. e-mail: disgo79@gmail.com introduction eccrine porocarcinoma (epc) is a rare type of skin cancer arising from the intraepidermal portion of eccrine sweat glands or acrosyringium and comprises of 0.005% of all malignant epithelial tumors with an equal prevalence in both sexes and a predominance of elderly patients. the reported incidence may be underestimated because epc can also mimic clinically and dermatoscopically several other benign or malignant cutaneous tumors (eg seborrheic keratosis, bowen disease, melanoma, etc.) typically presenting as an asymptomatic, painless and solitary nodule with ulcerated surface also developing in former sites of irradiation, lymphedema, and trauma [1,2]. epc represents a tumor with aggressive biologic behavior and a tendency for local recurrence and regional lymph nodes metastatic potential (about 20% in both scenarios). the mortality rate of 67% in patients with lymph node metastases poses epc as a life-threatening cutaneous neoplasm [2]. herein we report a rare case of metastatic epc with a zosteriform development on the right lower extremity. case presentation an 85-year-old woman, fitzpatrick phototype iv, presented with 1-year history of multiple violaceous-black diffuse papules on the right thigh and a plaque on the mons pubis. she had no symptoms or any discharge such as pain, itch or other. of note, the patient suffered from a stable lymphedema of unknown origin in the right lower extremity for 3 years while there was a preexisting scar on the right thigh due to a previously excised epc 2 years ago with clear resection margins. previous dermatological history included bowen disease on the left leg presenting 1 year ago. her 2 research letter | dermatol pract concept. 2022;12(2):e2022079 squamoid differentiation ( figure  1). diagnostic work-up with a computed tomography revealed infiltration of homolateral inguinal lymph nodes. concerning vascularity our findings are in contrast to published literature since epc as well as its benign counterpart, eccrine poroma, mostly present with polymorphous vessels imitating amelanotic melanoma  [1]. our observation could be partially explained by the presence of lymphedema that might had caused suppression of vascular structures. in line with current evidence pink-whitish round areas seem to be a common finding among epcs correlating with edematous sub-epidermal stroma reaction [2]. past medical history also included arterial hypertension and diabetes mellitus. the general examination showed no other abnormal findings. dermoscopy revealed black coloration correlated with crusts covering areas of erosions. structureless pink-whitish background and a lack of apparent vasculature were additional dermatoscopic findings, as well. fine scaling surrounding sites of erosions was also evident in all lesions. moreover, few papules exhibited pink-whitish ovoid areas. two papules with such dermatoscopic characteristics were excised and histopathological examination showed an invasive, welldifferentiated porocarcinoma with focal epidermal attachments and partial figure 1. (a) multiple violaceous-to-black papules coalescing into a plaque on the mons pubis. (b) dermoscopy reveals that black coloration is associated with crusts surrounded by a structureless dark pink-to-purple background. (c) multiple papules of a 5 mm of maximum diameter are diffusely arranged on a lymphedematous right thigh. a scar due to a former excision of an epc can be detected on the upper external part of the extremity (black arrow). (d,e) a hint of fine scaling around areas of erosions and crusts (black arrows) and dermatoscopically evident pink-to-white ovoid structures (white arrow) can be observed. (b, d, e) lack of apparent vasculature is also prominent in all dermatoscopic images. (f) malignant neoplastic cells extended from the epidermis into the dermis with infiltrative growth pattern (black arrow) and were composed of large, basaloid and atypical neoplastic cells with hyperchromatic nuclei. depletion of vessels and lymphatic vascular ectasia due to lymphedema (red arrow) are also prominent in histological images. (g) eccrine porocarcinoma usually composed of basaloid cells and many times it may show squamoid features (black arrow), resembles squamous cell carcinoma, but has sweat ducts or duct-like structures (red arrow). research letter | dermatol pract concept. 2022;12(2):e2022079 3 conclusions epc represents a rare malignant cutaneous adnexal tumor with non-specific clinical and dermatoscopic features. history of previously excised epc and lymphedema constitute risk factors for the development of metastatic cutaneous disease. dermatoscopically observed pink-to-white ovoid structures and whitish fine scaling surrounding areas of erosions over a vague pinkish background may be of help for the early detection of this life-threatening neoplasm. consent: patient has provided written consent for her data publication references 1. sgouros d, piana s, argenziano g, et al. clinical, dermoscopic and histopathological features of eccrine poroid neoplasms. dermatology. 2013;227(2):175–179. doi: 10.1159/000354152. pmid: 24080919. 2. edamitsu t, minagawa a, koga h, uhara h, okuyama r. eccrine porocarcinoma shares dermoscopic characteristics with eccrine poroma: a report of three cases and review of the published work. j dermatol. 2016;43(3):332–335. doi:  10.1111/13468138.13082. pmid: 26333057. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022226 1 dermoscopic changes in nevi during an atopic dermatitis flare-up sara pilar herrero-ruiz1, anastasia alejandra garrido-ríos1, helena álvarez-garrido1, laura fernández de la fuente1, begoña echeverría-garcía1, jesús borbujo1 1 department of dermatology, hospital universitario de fuenlabrada, madrid, spain citation: herrero-ruiz sp, garrido-ríos aa, álvarez-garrido h, fernández de la fuente l, echeverría-garcía b, borbujo j. dermoscopic changes in nevi during an atopic dermatitis flare-up. dermatol pract concept. 2022;12(4):e2022226. doi: https://doi.org/10.5826/ dpc.1204a226 accepted: march 29, 2022; published: october 2022 copyright: ©2022 herrero ruiz et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sara pilar herrero ruiz, md, department of dermatology, hospital universitario de fuenlabrada, 2 molino street, fuenlabrada, madrid, spain 28942. e-mail: sarapilar.herrero@salud.madrid.org case presentation a 34-year-old male with a personal history of atopic eczema attended his annual digital dermoscopic control with a three-week flare-up of atopic dermatitis. on examination, he had scaly erythematous and eczematous plaques at the back and the flanks. comparing the dermoscopic images we observed a global attenuation of the reticular pattern, even close to disappearance in some areas, and a pink-reddish coloration background in several nevi (figure 1). we appreciated these changes in nevi located in areas affected with the atopic dermatitis flare-up but also in nevi in healthy skin. teaching point the meyerson phenomenon consists of an eczematous halo surrounding a melanocytic lesion [1]. the dermoscopic features in this phenomenon have been reported as the pigmented pattern reticular and/or globular encircled by dotted vessels associated with crust, without changes in the dermoscopic features of the involved melanocytic lesions [2]. however, in our patient the dermoscopic changes affected all the surface of the nevi and not all of them had clinical eczema. these changes are not consistent with previous descriptions of the meyerson nevi. it is known that in the reticular pattern, the pigmented lines correlate with the inter-papillar ridges and the holes of the network correspond to the dermal papillae. thus, these dermoscopic findings may be explained by the histopathologic changes found in atopic dermatitis. acute lesions of dermatitis show epidermal spongiosis and a perivascular infiltrate around vessels in the papillary dermis. these changes may be responsible for the attenuation of the reticular pattern and the pink-reddish background coloration. 2 image letter | dermatol pract concept. 2022;12(4):e2022226 references 1. panagou e, heelan k. meyerson nevus. j cutan med surg. 2018;22(1):84. doi: 10.1177/1203475417721426. pmid: 29309239. 2. oliveira a, arzberger e, massone c, fink-puches r, zalaudek i, hofmann-wellenhof r. dermoscopy, reflectance confocal microscopy and immunohistochemical analysis in melanocytic lesions with meyerson’s phenomenon. dermatology. 2014;229(4):297-305. doi: 10.1159/000365657. pmid: 25472722. figure 1. three examples of the dermoscopic findings in nevi before (a, c, e) and during (b, d, f) the atopic dermatitis episode. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022206 1 dermatologic manifestations of thymoma-associated multiorgan autoimmunity (tama) syndrome: cutaneous signs of an immune dysregulation luigi rossiello1, amalia lupoli2, giuseppe cicala1, gianfranco de dominicis3, vittorio tancredi2, stefano caccavale2 1 department of dermatology, a.o.r.n. “a. cardarelli”, naples, italy. 2 department of dermatology, “luigi vanvitelli” university of naples, italy. 3 department of pathology, a.o.r.n. “a. cardarelli”, naples, italy. key words: tama syndrome, myastenia gravis, gvhd, thymoma citation: rossiello l, lupoli a, cicala g, de dominicis g, tancredi v, caccavale s. dermatologic manifestations of thymoma-associated multiorgan autoimmunity (tama) syndrome: cutaneous signs of an immune dysregulation. dermatol pract concept. 2022;12(4):e2022206. doi: https://doi.org/10.5826/dpc.1204a206 accepted: february 25, 2022; published: october 2022 copyright: ©2022 rossiello et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vittorio tancredi, md, dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy; phone: +39 3313919797; fax: +39 0815468759; e-mail: tancredivittorio@ymail.com introduction thymoma-associated multiorgan autoimmunity (tama) syndrome is the consequence of auto-reactive t-cells activation developing in the setting of a thymoma, which mediates graft-versus-host-disease (ghvd)-like reactions in several tissues, including skin [1]. case presentation a 61-year-old man was admitted in our dermatology department for a skin rash appearing concomitantly to a nodal relapse of a malignant thymoma. cutaneous examination revealed a confluent erythematous and papulo-squamous eruption involving most of his face, trunk, bilateral upper and lower extremities. his palms and soles presented confluent pink tender papules. moreover, multiple chronic painful erosions affected the oral mucosa (figure 1). the patient reported general malaise with deep asthenia and an abundant chronic diarrhea. a skin biopsy was performed and histologic examination revealed an interface and perivascular dermatitis in the dermis. epidermis showed psoriasiform hyperplasia, diffuse parakeratosis and spongiosis, hypogranulosis, necrotic keratinocytes with intense eosinophilic cytoplasm (figure 2). although several differential diagnoses (including drug reaction, viral exanthema, pityriasis lichenoid, and sub-erytrodermic psoriasis) were considered, relying on 2 research letter | dermatol pract concept. 2022;12(4):e2022206 figure 1. erythematous and scaly papulosquamous eruption. figure 2. (a) histology showing epidermal hyperplasia (h&e, 40x). higher magnification highlights parakeratosis, epidermal spongiosi , hypogranulosis and some apoptotic keratinocytes characterized by intensely eosinophilic cytoplasm. (b) the underlying dermis contains few infiltrates of lymphocytes (h&e, 200x). anamnesis, histology and literature, a gvhd-like reaction occurring in the setting of a malignant thymoma was finally diagnosed. in addition, our patient developed a progressive muscle weakness. a thymoma-related myasthenia gravis was diagnosed after the detection of autoantibodies directed against research letter | dermatol pract concept. 2022;12(4):e2022206 3 acetylcholine receptor and electrophysiological evaluation of neuromuscular junctions. after three months our patient died as a result of the rapidly progressive clinical deterioration and the hypoxemic respiratory failure consequent to a lung infection and myasthenia gravis. myasthenia gravis is the most typical paraneoplastic syndrome associated with thymoma; it does not always develop at diagnosis, but it has a high impact of morbidity and mortality [2]. gvhd-like reactions are rare immune response that occur particularly at level of skin, intestine, or liver, which resemble gvhd on histopathology, except for graft lymphocytes [3]. the diagnosis requires the exclusion of the main causes of a real ghvd, such as hematopoietic stem cell transplantation (hsct) and transfusion of non-irradiated blood. being not associated to hsct, waldhera et al decided to collect the gvhd-like reactions occurred in the setting of a thymoma under the umbrella name of tama syndrome [1]. first described cases were characterized by a constant colon involvement; subsequently, tama reactions were detected in multiple organs, including not only gastrointestinal tract, but also skin, thyroid and liver [4]. conclusions we remark the uniqueness and interest of this case, since tama syndrome is a very rare disorder and with few cases reported in literature to date. the dermatologic manifestations of tama syndrome consist of diffuse papulo-squamous rash, often involving palms and soles, with possible lesions of oral mucosa. tama syndrome should be always kept in mind on a thymoma background when these specific skin signs are associated with systemic manifestations, first of all diarrhea. references 1. waldhera a, maverakis e, mitisiades n, lara pn,  fung ma, lynch pj. thymoma associated multiorgan autoimmunity: a graft-versus-host-like-disease. j am acad dematol. 2007; 57(4):683-689. doi: 10.1016/j.jaad.2007.02.027. pmid: 17433850. 2. tian w, li x, sun y, wang j, jiang g, tong h. myasthenia gravis affects overall survival in patients with thymoma: an analysis of multicentre database using propensity score matching. interact cardiovasc thorac surg. 2021;33(2):250-257. doi: 10.1093/ icvts/ivab074. pmid: 34151968. pmcid: pmc8691723. 3. holder j, north j, bourke j, colloby p, fletcher a, graham-brown r, whaley k. thymoma-associated cutaneous graft-versus-hostlike reaction. clin exp dermatol. 1997;22(6):287-290. pmid: 9604457. 4. warren s, nehal k, querfeld c, wong r, huang j, pulitzer m. graft-versus-host disease-like erythroderma: a manifestation of thymoma-associated multiorgan autoimmunity. j cutan pathol. 2015;42(10):663-668. doi: 10.1111/cup.12642. pmid: 26509934. pmcid: pmc5072282. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023147 1 dermoscopic and cytological findings in scleromyxedema tuğba tehçi1, elif burcu şenyurt2, murat durdu3, enzo errichetti4 1 department of dermatology, university of health sciences -adana health practice and research center, adana, turkey 2 department of pathology, university of health sciences -adana health practice and research center, adana, turkey 3 department of dermatology, başkent university faculty of medicine, adana dr. turgut noyan application and research center, adana, turkey 4 department of dermatology, university hospital “santa maria della misericordia”, udine, italy citation: tehçi t, şenyurt eb, durdu m, errichetti e. dermoscopic and cytological findings in scleromyxedema. dermatol pract concept. 2023;13(3):e2023147. doi: https://doi.org/10.5826/dpc.1303a147 accepted: december 4, 2022; published: july 2023 copyright: ©2023 tehçi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: murat durdu, department of dermatology, başkent university faculty of medicine, adana dr. turgut noyan application and research center, adana, turkey. tel: +90 2422406710 fax: +90 2422496040 email: sivandr@hotmail.com case presentation a 63-year-old male presented with pruritic, firm, domeshaped, skin-colored/whitish papules mainly located over the forehead, neck, elbows, hands and feet (figure 1a) that had progressively increased in number over the last year; skin induration of the trunk without papular lesions was also evident on palpation. dermoscopic  examination of the papules showed round/oval, homogenous, white-ivory structureless areas similar to “rice grains” with no vessels (figure 1b) [1], while cytological assessment of slit-skin smear taken from the lesions revealed round fibrotic collagen structures and mucinous materials (figures 1, c and d). based on clinical, dermoscopic and cytological findings, a possible diagnosis of scleromyxedema was made, and a biopsy was taken for histological examination, that confirmed this hypothesis by revealing fibroblast proliferation, collagen deposition, perivascular lymphoplasmocytic infiltration, and mucin  deposition in the dermis (figures 1, e and f). laboratory tests showed monoclonal gammopathy, while no systemic involvement was detected on further examination. intravenous immunoglobulin therapy (2 g/kg dose for 5 consecutive days per month) was started, with significant improvement after three cycles of treatment. teaching point scleromyxedema is a form skin mucinosis with possible extra-cutaneous involvement, including neurological, renal, hematological, and rheumatological, that may carry a poor prognosis if not treated timely [2]. diagnosis is generally clinical, yet in initial phases/incomplete instances it may be challenging to differentiate from similar conditions (eg lichen planus, lichen amyloidosis, papular lichen simplex chronicus, papular granuloma annulare, multiple follicular adnexal tumors) that, however, show a different 2 image letter | dermatol pract concept. 2023;13(3):e2023147 figure 1. (a) dome-shaped, firm, small papules on the nape are similar as seen on clinical examination. (b) dermoscopy reveals round and oval-shaped white-ivory homogenous areas similar to rice grains (magnification x10) [1]. (c,d) cytology shows round fibrotic collagen structures and mucinous materials (may-grünwald giemsa x1000). (e) histopathological examination displays increased mucin deposition in the superficial dermis and stellated fibroblasts between collagen fibers (h&e x200). (f) fragmented elastic fibers are also evident (alcian blue stain x200). image letter | dermatol pract concept. 2023;13(3):e2023147 3 dermoscopic and cytological patterns [3]. therefore, the use of such techniques may increase the index of suspicion for scleromyxedema with consequent prompt treatment. references 1. mendes bastos p, borges as, cardoso jc, oliveira a. dermoscopy and reflectance confocal microscopy for the diagnosis of scleromyxedema. jaad case rep. 2019;5(5):451-453. published 2019 may 8. doi:10.1016/j.jdcr.2019.03.005 2. ferreli c, gasparini g, parodi a, cozzani e, rongioletti f, atzori l. cutaneous manifestations of scleroderma and scleroderma-like disorders: a comprehensive review. clin rev allergy immunol. 2017;53(3):306-336. doi: 10.1007/s12016 -017-8625-4. pmid: 28712039. 3. lallas a, errichetti e, ioannides d. dermoscopy in general dermatology. crc press, boca raton, fl, 2018. dermatology: practical and conceptual quiz | dermatol pract concept 2017;7(1):3 19 dermatology practical & conceptual www.derm101.com report of cases case 1: a man in his fifties with a history of hodgkin lymphoma treated 20 years prior with the stanford v protocol and mantle field radiation (total dose: 36 gray) presented for skin examination. a 3 mm pedunculated pink papule was found on the right chest within the prior radiation field (figure 1a). the lesion was asymptomatic and of unknown duration. there was no history of change, bleeding, or itching. polarized dermoscopy of the papule revealed irregular linear and looped branching vessels that terminated in a semicircular or circular fashion, also termed “cherry-blossom” vessels (figure 2a). histopathologic examination revealed a pedunculated well-circumscribed nodular epithelial tumor composed of uniform cuboidal cells with round basophilic monomorphic nuclei. multiple broad cords of the anatomizing tumor epithelium connected to the overlying epidermis, surrounding characteristic sclerotic well-vascularized stroma (figure 3a). case 2: a woman in her fifties with a history of basal cell carcinoma and b-cell acute lymphoblastic leukemia status post two allogenic hematopoietic stem cell transplants (total body irradiation induction dose of: 13.75 gy) presented for skin examination. a new, asymptomatic 2 mm pedunculated pink papule was found on the presternal chest (figure 1b). polarized dermoscopy of the lesion revealed semicircular/ circular branching vessels originating from a common stem vessel (figure 2b). histopathological examination revealed a polypoid epithelial tumor comprised of broad downgrowths of cuboidal epithelium clearly demarcated from overlying epidermis amidst a background of hyalized/sclerotic highly vascular stroma. small ducts with a pink cuticle were noted within epithelial bands (figure 3b). what is the diagnosis? isolated pink papule on the chest zachary wolner1, melissa p. pulitzer2, michael a. marchetti1 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 2 dermatopathology service, memorial sloan kettering cancer center, new york, ny, usa citation: wolner z, pulitzer mp, marchetti ma. isolated pink papule on the chest. dermatol pract concept. 2017;7(1):3. doi: https://doi. org/10.5826/dpc.0701a03 copyright: ©2017 wolner et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: michael a. marchetti, md, 16 east 60th street, new york, ny 10022, usa. tel. 646-888-6016. email: marchetm@ mskcc.org figure 1. non-pigmented eccrine poroma. a) clinical image showing a pink papule on the right upper chest. b) clinical image showing a pink papule on the presternal chest. [copyright: ©2017 wolner et al.] a b figure 2. non-pigmented eccrine poroma. polarized, non-contact dermoscopy images of a pedunculated pink papule with irregular branching vessels that terminate in circular and semi-circular structures. a is from case 1 and b is from case 2. [copyright: ©2017 wolner et al.] a b mailto:marchetm@mskcc.org mailto:marchetm@mskcc.org 20 quiz | dermatol pract concept 2017;7(1):3 the dermoscopic features of nonpigmented eccrine poromas are variable (table 1). a “polymorphous” vascular pattern consisting of hairpin, glomerular, and irregular linear vessels in a single lesion has been frequently described [3,5-15]. the most common features include a structureless pink-white background (48%), hairpin (loop) vessels (47%), “frog-egg appearance” (39%), glomerular vessels (35%), red lacunae (27%), ulcers (24%), linear-irregular vessels (23%), and leaf-like or cherry-tree vessels (21%). the cases described herein showed irregular branching and looped vessels that terminated in semicircular or circular structures, which raised the suspicion for eccrine poroma [7,11]. these vascular structures may correlate with localization of proliferative vessels within the curved “canals” of tumor stroma. variation among dermoscopic characteristics reported in the literature can depend on whether contact and/or polarized dermoscopy was used, the location of the lesion, or variation in the angles of the tumor and the dermatoscope [10]. larger studies are needed to determine the sensitivity and specificity of the dermoscopic criteria for eccrine poroma. answer eccrine poroma discussion eccrine poromas are benign cutaneous adnexal neoplasms with terminal eccrine duct differentiation. in 2016, ito et al reviewed 376 lesions and found that eccrine poromas occur most frequently on the lower extremities (44.4%), followed by the scalp (16.2%), trunk (11.7%), upper extremities (11.4%), face (9.8%), and neck (3.7%) [1]. typically eccrine poromas appear as solitary plaques, papules, or nodules, but multiple tumors can be seen. poromas commonly contain highly vascularized stroma but can uncommonly have pigmentation [2]. the differential diagnosis of a non-pigmented papule arising in the field of prior radiotherapy should include amelanotic melanoma, squamous cell carcinoma, adnexal neoplasm, and basal cell carcinoma. interestingly, eccrine poromas have been associated with radiotherapy and hematologic malignancy [3,4]. figure 3. a) non-pigmented eccrine poroma: photomicrograph showing an exophytic, well-circumscribed nodular epithelial tumor with uniform cuboidal cells, round basophilic monomorphic nuclei, and sclerotic vascularized “poroma stroma” (hematoxylin-eosin stain, original magnification x20). b) non-pigmented eccrine poroma: photomicrograph showing a pedunculated epithelial proliferation characterized by sharply demarcated broad epithelial downgrowths of cuboidal cells and characteristic sclerotic and vascular stroma (hematoxylin-eosin stain, original magnification x20). [copyright: ©2017 wolner et al. a b quiz | dermatol pract concept 2017;7(1):3 21 ta b le 1 . a l it er at u re s ea rc h i d en ti fi ed e le ve n c as e re p o rt s an d s er ie s id en ti fy in g d er m o sc o p ic c h ar ac te ri st ic s o f n o n p ig m en te d e cc ri n e p o ro m as [ 3 ,5 -1 5 ] a u th o r/ y e a r c a se s n h a ir p in o r lo o p v e ss e ls n ( % ) d o tt e d v e ss e ls n ( % ) li n e a rir re g u la r v e ss e ls n ( % ) v a sc u la r b lu sh n ( % ) c o m e d o -l ik e o p e n in g s n ( % ) m il ia -l ik e cy st s n ( % ) u lc e r n ( % ) c h e rr y b lo ss o m v e ss e ls n ( % ) s tr u ct u re le ss p in k w h it e a re a s n ( % ) g lo m e ru la r v e ss e ls n ( % ) r e d la cu n a e n ( % ) fr o g e g g o r re d d is h / w h it e g lo b u le s w / in te rl a ci n g w h it e co rd s n ( % ) w h it e -t o p in k h a lo n ( % ) sh al o m e t al ( 2 0 1 2 ) 1 9 9 ( 4 7 % ) – – 1 2 (6 3 % ) – – 8 ( 4 2 % ) 8 ( 4 2 % ) 1 5 ( 7 9 % ) 1 0 ( 5 3 % ) 2 ( 1 1 % ) 9 ( 4 7 % ) – e sp in o sa e t al ( 2 0 1 2 ) 1 3 5 ( 3 8 % ) – 3 ( 2 3 % ) – – – 3 ( 2 3 % ) 4 ( 3 1 % ) 9 ( 6 9 % ) 2 ( 1 5 % ) 9 ( 6 9 % ) 5 ( 3 8 % ) – m in ag aw a et a l (2 0 1 0 ) 1 0 4 ( 4 0 % ) 3 ( 3 0 % ) 2 ( 2 0 % ) – 1 ( 1 0 % ) 1 ( 1 0 % ) 1 ( 1 0 % ) – – – – 9 ( 9 0 % ) – f er ra ri e t al ( 2 0 0 9 ) 7 5 ( 7 1 % ) – 3 ( 4 3 % ) – – – 1 ( 1 4 % ) – 5 ( 7 1 % ) 5 ( 7 1 % ) – 1 ( 1 4 % ) 5 ( 7 1 % ) l al la s et a l (2 0 1 5 ) 6 2 ( 3 3 % ) 2 ( 3 3 % ) 2 ( 3 3 % ) – 1 ( 1 7 % ) – 1 ( 1 7 % ) – – 1 ( 1 7 % ) 1 ( 1 7 % ) – 2 ( 3 3 % ) a vi lé s– iz q u ie rd o e t al (2 0 0 9 ) 2 2 (1 0 0 % ) – 2 (1 0 0 % ) – – – – – – 2 ( 1 0 0 % ) 2 (1 0 0 % ) – – d o s sa n to s (2 0 1 5 ) 1 – 1 ( 1 0 0 % ) – – – – – – – – 1 (1 0 0 % ) – 1 ( 1 0 0 % ) a yd in go z (2 0 0 9 ) 1 – – – – – – – 1 (1 0 0 % ) – – – – – n ic o li n o e t al ( 2 0 0 7 ) 1 – – 1 (1 0 0 % ) – – – – – – 1 ( 1 0 0 % ) 1 (1 0 0 % ) – 1 ( 1 0 0 % ) a lt am u ra e t al ( 2 0 0 5 ) 1 1 (1 0 0 % ) 1 ( 1 0 0 % ) 1 (1 0 0 % ) – – – 1 ( 1 0 0 % ) – – – 1 (1 0 0 % ) – – sg o u ro s et a l (2 0 1 3 ) 1 1 (1 0 0 % ) – 1 (1 0 0 % ) – – – – – 1 ( 1 0 0 % ) 1 ( 1 0 0 % ) – – – t o t a l 6 2 2 9 (4 7 % ) 7 ( 1 1 % ) 1 5 (2 4 % ) 1 2 (1 9 % ) 2 ( 3 % ) 1 ( 2 % ) 1 5 ( 2 4 % ) 1 3 ( 2 1 % ) 3 0 ( 4 8 % ) 2 2 ( 3 5 % ) 1 7 (2 7 % ) 2 4 ( 3 9 % ) 9 ( 1 5 % ) 22 quiz | dermatol pract concept 2017;7(1):3 m, lazaro-ochaita p. [dermoscopic features of eccrine poroma]. actas dermosifiliogr. 2009;100(2):133-136. 9. minagawa a, koga h, takahashi m, sano k, okuyama r. dermoscopic features of nonpigmented eccrine poromas in association with their histopathological features. br j dermatol. 2010;163 (6):1264-1268. 10. shalom a, schein o, landi c, marghoob a, carlos b, scope a. dermoscopic findings in biopsy-proven poromas. dermatol surg. 2012;38(7 pt 1):1091-1096. 11. espinosa aed, ortega bc, venegas rq, ramírez rg. dermoscopy of non-pigmented eccrine poromas: study of mexican cases. dermatol pract concept. 2013;3(1):25-28. 12. sgouros d, piana s, argenziano g, et al. clinical, dermoscopic and histopathological features of eccrine poroid neoplasms. dermatology. 2013;227(2):175-179. 13. dos santos bs. clinical and dermoscopic features of eccrine poroma. indian j dermatol venereol leprol 2015;81(3):308-309. 14. nicolino r, zalaudek i, ferrara g, et al. dermoscopy of eccrine poroma. dermatology. 2007;215(2):160-163. 15. lallas a, chellini pr, guimaraes mg, et al. eccrine poroma: the great dermoscopic imitator. j eur acad dermatol venereol. 2016;30(10):e61-e63. references 1. ito k, ansai si, fukumoto t, anan t, kimura t. clinicopathological analysis of 384 cases of poroid neoplasms including 98 cases of apocrine type cases. j dermatol. may 14 2016. [epub ahead of print] 2. bolognia j, jorizzo jl, schaffer jv. dermatology. philadelphia: elsevier saunders; 2012. 3. miura t, yamamoto t. eruptive poromatosis following radiotherapy. am j dermatopathol. 2013;35(5):615-617. 4. mahlberg mj, mcginnis ks, draft ks, fakharzadeh ss. multiple eccrine poromas in the setting of total body irradiation and immunosuppression. j am acad dermatol. 2006;55(2 suppl):s46-49. 5. altamura d, piccolo d, lozzi gp, peris k. eccrine poroma in an unusual site: a clinical and dermoscopic simulator of amelanotic melanoma. j am acad dermatol. 2005;53(3):539-541. 6. ferrari a, buccini p, silipo v, et al. eccrine poroma: a clinicaldermoscopic study of seven cases. acta derm venereol. 2009;89 (2):160-164. 7. aydingoz ie. new dermoscopic vascular patterns in a case of eccrine poroma. j eur acad dermatol venereol. 2009;23(6):725726. 8. aviles-izquierdo ja, velazquez-tarjuelo d, lecona-echevarria dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022101 1 can immunofluorescence on skin/mucosal scraping smear for pemphigus diagnosis substitute direct immunofluorescence on skin biopsy? mohammad shahidi dadras 1, zahra asadi kani 1, behnaz hamedani 1, sahar dadkhahfar 1, nazy rastgoo1, nikoo mozafari 1,2 1 skin research center, shahid beheshti university of medical sciences, tehran, iran. 2 department of dermatology, loghman hakim hospital, shahid beheshti university of medical sciences, tehran, iran. key words: pemphigus, direct immunofluorescence, sensitivity, specificity, smear citation: shahidi dadras m, asadi kani z, hamedani b, dadkhahfar s, rastgoo n, mozafari n. can immunofluorescence on skin/ mucosal scraping smear for pemphigus diagnosis substitute direct immunofluorescence on skin biopsy? dermatol pract concept. 2022;12(3):e2022101. doi: https://doi.org/10.5826/dpc.1203a101 accepted: october 24, 2021; published: july 2022 copyright: ©2022 shahidi dadras et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: nikoo mozafari, md, tajrish sq, skin research center, shohada-e-tajrish hospital, shahrdari st, tehran, iran telephone number: (98) 21-22741507. e-mail address: nikoo_md@yahoo.com introduction: few studies have been conducted on the use of direct immunofluorescence (dif) on skin/mucosal scraping smear for diagnosis of pemphigus disease; however, the diagnostic value of dif on the smear has not been fully evaluated. objectives: the present study was carried out to assess the sensitivity and specificity of dif on skin/ mucosal smear for diagnose of pemphigus in the patients presenting with mucocutaneous erosive lesions. methodology: a total of 89 patients including 40 males and 49 females aged between 23 and 80 years old with various bullous disorders were enrolled in the study. for definite diagnosis, all the patients were subjected to lesional biopsy for pathological studies and perilesional biopsy for dif studies. in all the cases, skin/mucosal scraping smears were prepared from the perilesional healthy skin/mucosa and were stained with immunofluorescence conjugated anti-igg. results: of 89 patients, 56 (63%) patients were diagnosed with pemphigus. immunodeposits favoring the pemphigus were demonstrated in the 46 smears of 56 cases of pemphigus (sensitivity of 82%). no case with other types of bullous disease had positive dif on the smear (specificity of 100%). conclusion: the findings of the study showed that the sensitivity of dif on the smear is not high enough to allow us replacing the conventional dif with smear-dif for diagnosis of pemphigus, while the specificity of 100% would allow the unequivocal identification of a subset of patients with pemphigus. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022101 introduction pemphigus as a rare autoimmune blistering disease is characterized by the widespread flaccid blisters and erosions on the skin and mucous membranes [1]. the hallmark of pemphigus is finding the immunoglobulin g (igg) autoantibodies against the cell surface of keratinocytes. pemphigus is classified into subtypes based on the main autoantigen involved in the pathogenesis of disease [1]. detection of igg autoantibodies raised against the cell surface of keratinocytes is considered as the gold standard for diagnosis of pemphigus. pemphigus can be differentiated from other vesiculobullous or pustular diseases through detection of these autoantibodies [2]. direct immunofluorescence (dif) examination is the most reliable and sensitive diagnostic test used for all forms of pemphigus. dif is able to show the igg and c3 deposition around the epithelial cells, confirming the diagnosis of pemphigus [3]. durdu et al have demonstrated that the keratinocyte cells obtained by tzanck smear can be used as a substrate for dif studies [4]. obtaining the tzanck smears is less invasive than skin or mucosal biopsy and would be useful in the pemphigus patients with conjunctiva involvement or inaccessible oral lesions that cannot be biopsied easily [5]. in this technique, preparation of the samples is much more rapid than the conventional dif and there is no need for specialized equipment such as the cryostat. objectives the current study was performed to investigate the usefulness of dif on skin scraping smears obtained from intact perilesional skin in the patients with bullous/erosive disorders in order to evaluate the use of skin/mucosal smears as an alternative to skin or mucosal biopsies for diagnosis of pemphigus. methods patients the study protocol was approved by the institutional ethics committee and an informed written consent was obtained from all the patients. a total of 89 consecutive patients with erosive, vesicular, bullous or pustular skin, or mucosal lesions were included in this study. demographic, clinical and laboratory data including patients age, gender, and lesion location were recorded using a questionnaire. for definite diagnosis, all the patients were subjected to lesional biopsy for pathological studies and perilesional biopsy for dif studies. in all the cases, smears were prepared from the perilesional healthy skin/mucosa and were stained with immunofluorescence conjugated anti-igg. preparation of the smears and application of dif on the samples for preparing the smears, the perilesional skin or mucosa adjacent to the fresh blister or erosion was first anesthetized through the intradermal lidocaine injection and then, they were gently scraped using the small curette. then, the obtained cellular materials were spread as a thin layer onto at least two glass slides and were air-dried. the prepared smears were sent to the department of pathology for staining. smears were incubated with fluorescein isothiocyanate (fitc)-conjugated goat antihuman igg (cedarlane, lot number: 7201111401) for 30 minutes in a moist chamber at 37degree temperature. the sections were then washed in phosphate-buffered saline (pbs) (2washes of 15 min each), mounted in buffered glycerol, and examined under fluorescent microscope. detection of the ring-shaped deposition of igg on the individual acantholytic cells or the net-like intercellular fluorescence pattern when sheet of cells were present was considered positive for diagnosis of pemphigus (figure 1). the immunofluorescence (if)-stained samples were studied independently by 2 of the authors. they were unaware of the results of the conventional dif. calculation of the diagnostic value of if -stained skin/mucosal scraping smears the parameters including sensitivity (ie the percentage of patients with positive conventional dif whose if-stained smear was positive), specificity (ie the percentage of patients with negative conventional dif whose if-stained smear was negative), positive predictive value (ppv) (ie the percentage of patients with positive if-stained smear whose conventional dif was also positive) ,and negative predictive value (npv) (ie, the percentage of patients with negative if-stained smear whose conventional dif was also negative) were calculated to determine the diagnostic value of the if-stained smear (table 1). kappa coefficient was calculated to evaluate the concordance of the if-stained smear and conventional dif, and the p value of less than 0.05 was considered as statistically significant. results totally, 89 patients (40 males and 49 females) aged between 2380 years were included in this study. table1 shows the characteristics of the patients and their diagnosis based on the histopathological and conventional dif results. classical suprabasal acantholysis at the lesional biopsy and immune original article | dermatol pract concept. 2022;12(3):e2022101 3 figure 1. positive direct immunofluorescence examination of skin scraping smear in a patient with pemphigus vulgaris shows immunoglobin g deposition around the individual acantholytic cells (a) and those in groups (b) (400×). table 1. characteristics of patients with bullous/erosive lesion age, years mean ±sd, range 46.60±12.16, (23-80) gender, n(%) female 49 (55%) male 40 (45%) diagnosis diagnose of patient with bullous disease based on histopathology of lesional samples, n intraepidermal positive dif on perilesional punch biopsy sample n(%) positive dif on perilesional scraping smear n(%) pemphigus 56 56 (100%) 46 (82%) vulgaris 54 54 44 folliaceous 2 2 2 bullous pemphigoid 6 0(0%) 0(0%) ten 3 0(0%) 0(0%) erythema multiforme 3 0(0%) 0(0%) fixed drug eruption 7 0(0%) 0(0%) herpes zoster 3 0(0%) 0(0%) chicken pox 3 0(0%) 0(0%) bullous impetigo 2 0(0%) 0(0%) bite reaction 1 0(0%) 0(0%) acute eczema 3 0(0%) 0(0%) sweet syndrome 1 0(0%) 0(0%) pustular psoriasis 1 0(0%) 0(0%) site of obtaining smear or biopsy for if study n(%) oral mucosa 19 (21%) 16 12 extremities 9 (10%) 2 2 trunk 40 (45%) 18 14 scalp 21 (24%) 20 18 dif = direct immunofluorescence; if = immunofluorescence; sd = standard deviation; ten = toxic epidermal; necrolysis. deposition compatible with the diagnosis of pemphigus (intercellular lattice-like pattern) were demonstrated in the igg–stained perilesional biopsies of 56 cases. if on the smear was positive in 46 (82%) patients with pemphigus. if on the smear had a sensitivity of 0.82 (95% confidence interval [ci] 0.72-0.92), a specificity of 1.00 4 original article | dermatol pract concept. 2022;12(3):e2022101 table 2. distribution of frequency of dif on tzank smear and conventional dif on skin/mucosa biopsy in patients with bullous/erosive lesions. result of conventional dif (golden criteria for pemphigus diagnosis) results of dif on tzank smear positive, n(%) negative, n(%) total, n(%) positive, n(%) 46 (82%) 0 (0%) 46(55%) negative, n(%) 10 (18%) 33 (100%) 43(45%) total n(%) 56 (100%) 33 (100%) 89 (100%) kappa = 0.773 p < 0.001 dif = direct immunofluorescence. (95% ci 1.00-1.00), a ppv of 1.00 (95% ci 1.00-1.00), and a npv of 0.77 (95% ci 0.64-0.89). a significant concordance was found between the results of if-stained smears and those prepared by the conventional dif for diagnose of pemphigus (kappa= 0.773, p <0.001). table 2 presents the data on if-stained smears and those prepared by the conventional dif. conclusions lesional skin/mucosal scraping called tzanck smear is generally used for diagnosis of the herpes simplex virus infections [6]. the presence of acantholytic cells accompanied by multinucleated giant cells is a characteristic cytological finding for diagnosis of herpetic infections [6]. this method has also been suggested as a simple and rapid technique to be used in diagnosis of pemphigus disease [6]. cytological examination of the smears obtained from scraping of floor of the blisters in the pemphigus patients has shown the presence of typical acantholytic cells (or tzanck cells). these cells are not pathognomonic for the pemphigus and are commonly observed in other types of bullous disease such as hailey-hailey disease and herpetic infections [4,6]. the cyto-diagnosis is not extensively used due to low specificity of this technique in diagnosis of the pemphigus. positivity of acantholytic cells in the cases with pemphigus has been reported by 96.7%-100% while, the specificity of acantholytic cells for pemphigus has been reported by 43.3%-60% [4,7]. this means that, if we rely on the use of tzanck smear alone, 40%-60% of the cases presented with erosive and bullous eruptions would falsely be diagnosed as pemphigus. then, for definite diagnosis of pemphigus, autoantibodies raised against the epithelial cell membrane have to be detected by applying the dif staining [3]. dif analysis of the perilesional skin biopsy is the most accurate approach for diagnosis of pemphigus , showing igg deposits on the surface of keratinocytes [3] . the direct immunofluorescence test on tzanck smears has been proposed as a simple alternative to skin biopsy for diagnosis of pemphigus [4]. dif examination of a tzanck smear shows bright green fluorescence at the cell margins of single acantholytic cell or in the intercellular region in the case of cell clumps, compatible with positive if pattern of pemphigus [4]. although, the if examination of skin scraping smear seems a simple and practical cytological technique for diagnosis of pemphigus, there is a limited evidence on the relative sensitivity and specificity of dif on the smear compared to the dif on skin biopsy as a gold standard. according to the review of the literature, there are a few related studies with divergent results in this context. durdu et al have reported about the typical igg deposit around the acantholytic keratinocytes in the tzanck smears of all (100%) the 20 patients with pemphigus [4]. nonetheless, aithal et al have shown that among 12 pemphigus patients with positive dif on the skin biopsy, only 6 of them (50%) had positive dif on the tzanck smear [8]. in the current study, the result of dif examination on the smear was positive in 46 (82%) of the pemphigus patients (out of 56 patients). ten patients had negative results. the larger sample size or technical issue in the if staining of the smears might explain observing these 10 false negative results. it also could be attributed to the fact that the smears were taken from the healthy perilesional skin and not from the blister floor. in scraping of the intact skin, collected keratinocytes are mostly from the superficial epidermal layers where immune depositions are partly or completely absent in the subset of patients with pemphigus vulgaris. in pemphigus vulgaris, due to the difference in the relative amount of desmoglein 3 in the epidermal layers, occasionally the fluorescence may be limited to or more intense in the lower levels of the epidermis [2]. according to the results, the sensitivity and specificity of dif on skin/mucosal smear for diagnosis of pemphigus were equal to 82% and 100%, respectively. this sensitivity was not high enough to allow us replacing the conventional dif on skin biopsy with dif on skin/mucosal smear, for diagnosis of pemphigus. in other words, approximately 20% of pemphigus patients would be missed if we rely on if staining on the smear alone. nonetheless, the observed specificity of 100% allows an extremely high level of confidence to diagnose the pemphigus in the case of positive dif on the smear. original article | dermatol pract concept. 2022;12(3):e2022101 5 one limitation of this study is that the only dif was used as a gold standard to differentiate pemphigus cases from other vesiculobullous diseases. because of resource limitation anti desmoglein antibodies were not measured. then we were unable to compare the diagnostic value of dif on skin/ mucosal smears with enzyme-linked immunosorbent assay for detecting anti-desmoglein 1 and 3. given that, dif on the smear is a less invasive and much cheaper procedure compared to the dif on biopsy, a plausible approach is that when a clinically suspicious pemphigus patient presents with the bullous lesions first, the dif examination on the skin scraping smear is performed, and if it is positive then, the diagnose of pemphigus is confirmed while if, it is negative then, a biopsy must be taken for conventional dif studies. references 1. kasperkiewicz m, ellebrecht ct, takahashi h, et al. pemphigus. nat rev dis primers. 2017;3:17026. doi: 10.1038/ nrdp.2017.26. pmid: 28492232. pmcid: pmc5901732. 2. mutasim df, adams bb. immunofluorescence in dermatology. j am acad dermatol. 2001;45(6):803-822; quiz 822-4. doi: 10.1067/mjd.2001.117518. pmid: 11712024. 3. giurdanella f, diercks g, jonkman m, pas h. laboratory diagnosis of pemphigus: direct immunofluorescence remains the gold standard. br j dermatol. 2016;175(1):185-186. doi: 10.1111/ bjd.14408. pmid: 26798993. 4. durdu m, baba m, seçkin d. the value of tzanck smear test in diagnosis of erosive, vesicular, bullous, and pustular skin lesions. j am acad dermatol. 2008;59(6):958-964. doi: 10.1016/j. jaad.2008.07.059. pmid: 18929431. 5. yavuzekinci ü, özcan d, seçkin d. non‐oral mucosal involvement of pemphigus vulgaris: t zanck smear test as a handy diagnostic tool. int j dermatol. 2015;54(8):e325-e326. doi: 10.1111/ijd.12872. pmid: 26147466. 6. ruocco e, brunetti g, del vecchio m, ruocco v. the practical use of cytology for diagnosis in dermatology. j eur acad dermatol venereol. 2011;25(2):125-129. doi: 10.1111/j.14683083.2010.03740.x. pmid: 20553359. 7. zhou t, fang s, li c, hua h. comparative study of indirect immunofluorescence, enzyme‐linked immunosorbent assay, and the tzanck smear test for the diagnosis of pemphigus. j oral pathol med. 2016;45(10):786-790. doi: 10.1111/jop.12439.. pmid: 27005471. 8. aithal v, kini u, jayaseelan e. role of direct immunofluorescence on tzanck smears in pemphigus vulgaris. diagn cytopathol. 2007;35(7):403-407. doi: 10.1002/dc.20657. pmid: 17580352. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com editorial/commentary dpc | dermatol pract concept 2014;4(2):10 51 in this issue, rosendahl and colleagues report a case of non-choroidal melanoma that shows a strikingly unusual dermatoscopic aspect, namely, structureless yellow color. the authors correlate the yellow color to the presence of lipofuscin using tissue staining with sudan black. upon dermatoscopy, colors are important because they allow the estimation of different types of chromophores located at different levels of the skin. the most important chromophore in melanocytic tumors is melanin, which gives rise to black, brown, gray or blue color depending on its location in the skin. hemoglobin is the major source of colors in vascular tumors and appears dermoscopically either ink black, bright red, purple or blue. instead, yellow color has been linked to keratin or lipids, and accordingly, it is commonly seen in keratinizing tumors including seborrheic keratosis and squamous cell carcinoma or in tumors with sebaceous differentiation, but also in juvenile xanthogranuloma or granulomatous skin diseases [1]. it is more surprising that recent dermatoscopic observations report on yellow color in both melanocytic nevi and melanoma [2,3]. herein we would like to add an additional observation of melanoma dermatoscopically characterized by yellow color. yellow color upon dermatoscopy does not exclude melanoma! caterina longo1, margherita raucci1, simonetta piana2, iris zalaudek1,3 1 dermatology and skin cancer unit, arcispedale santa maria nuova (istituto di ricovero e cura a carattere scientifico-irccs), reggio emilia, italy 2 pathology unit, arcispedale santa maria nuova (istituto di ricovero e cura a carattere scientifico-irccs), reggio emilia, italy 3 department of dermatology, medical university of graz, graz, austria citation: longo c, raucci m, piana s, zalaudek i. yellow color upon dermatoscopy does not exclude melanoma! dermatol pract concept. 2014;4(2):10. http://dx.doi.org/10.5826/dpc.0402a10. copyright: ©2014 longo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: iris zalaudek, m.d., medical university of graz, graz, austria. email: dpc@derm101.com figure 1. (a) clinical picture of a solid hypopigmented nodule located on the left cheek of a 76-year-old woman. (b) dermatoscopy reveals the presence of a central structureless yellow-pink area expanding to the edge of the lesion, and a gray colored area (arrow). [copyright: ©2014 longo et al.] 52 editorial/commentary dpc | dermatol pract concept 2014;4(2):10 a 76-year-old woman was referred to our skin cancer unit because of the presence of a recently developed and growing nodule located on her left cheek. clinically, the lesion appeared as a dome-shaped yellow to reddish nodule with well-defined borders that was surrounded by a collarette-like scale (figure 1a). the nodule was firm on palpation. based on the clinical appearance, the differential diagnosis included an epidermal cyst or a sebaceous tumor. the dermatoscopic examination revealed mainly structureless yellow to pink areas and some dotted vessels. however, at the base and the figure 2. (a) reflectance confocal microscopy portrays the presence of a nodular proliferation. (b) high magnification image shows the presence of atypical melanocytic nests (red square). [copyright: ©2014 longo et al.] figure 3. (a) on histology, the melanoma is nodular and extends to the subcutaneous adipose tissue. (b, c) at higher magnification, discrete areas composed of large epithelioid melanocytes, with abundant foamy cytoplasm, are evident. [copyright: ©2014 longo et al.] editorial/commentary dpc | dermatol pract concept 2014;4(2):10 53 periphery of the nodule, additional gray color in the form of small dots was observed, which has been recently suggested to represent an important dermatoscopic clue for the diagnosis of lentigo maligna (figure 1b) [4]. to further assess whether the nodule was a melanocytic tumor, we performed reflectance confocal microscopy, which revealed a nodular proliferation with atypical melanocytic nests (figure 2). based on these features, a suspect of melanoma was raised and the nodule was immediately excised. histopathologic examination showed an amelanotic nodular melanoma infiltrating the subcutaneous adipose tissue, with a 5 mm breslow thickness, 8 mitosis per square millimeter and no ulceration (figure 3). the neoplastic cells were mostly spindle shaped; focally, discrete areas composed of large epithelioid melanocytes, with abundant foamy cytoplasm, were noted (figure 3b, c). both the populations were diffusely immunoreactive with s100 and mart-1, confirming their melanocytic origin. however, the origin of the yellow color in our case remains speculative, as we did not observe intracellular material as described by rosendahl and colleagues in their article in this issue. comment the widespread use of dermatoscopy opens new insights into the microscopic world of skin lesion and allows not only for significant improvements in the diagnosis of melanoma but also permits the identification of peculiar characteristics among distinct histiogenetic melanoma subtypes. it is remarkable that after nearly three decades of dermatoscopy, new details are still being discovered. until further research provides novel knowledge on the frequency and histopathological correlates of colors and structures in dermatoscopy, we like to conclude that yellow color upon dermatoscopy should not lead clinicians to exclude a diagnosis of melanoma. references 1. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology. 2006;212(1):7-18. 2. jaimes n, braun rp, stolz w, busam kj, marghoob aa.white globules correlate with balloon cell nevi nests. j am acad dermatol. 2011 oct;65(4):e119-20. 3. inskip m, magee j, barksdale s, weedon d, rosendahl c. balloon cell melanoma in primary care practice: a case report. dermatol pract concept. 2013 jul 31;3(3):25-9. 4. longo c, zalaudek i, argenziano g, pellacani g. new directions in dermatopathology: in vivo confocal microscopy in clinical practice. dermatol clin. 2012 oct;30(4):799-814. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023159 1 docetaxel-induced nail bed purpura arunachalam narayanan1, devinder mohan thappa1, balasundaram mithin kumar1 1 department of dermatology and std, jipmer, puducherry, india citation: narayanan a, thappa dm, mithin kumar b. docetaxel-induced nail bed purpura. dermatol pract concept. 2023;13(3):e2023159. doi: https://doi.org/10.5826/dpc.1303a159 accepted: december 15, 2022; published: july 2023 copyright: ©2023 narayanan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. arunachalam narayanan, md, senior resident, department of dermatology and std, jipmer, puducherry-605006. e-mail id: narayanan359@gmail.com case presentation a 57-year-old male patient presented to our outpatient clinic with reddish discoloration of the nail plates. he was a known case of moderately differentiated adenocarcinoma of the stomach and was on treatment with docetaxel-based chemotherapy (docetaxel 75 mg/m2 and oxaliplatin 130 mg/m2 on day 1 followed by capecitabine 1000 mg/m2 orally twice daily on days 2-14) for the last 2 months. examination of his nails revealed subungual onycholysis of his bilateral great toes along with nail bed purpura over the third right toe and multiple fingernails (figure 1a). dermatoscopy revealed presence of circumscribed red homogenous blotches on multiple fingernails (figure 1b). based on the above features, we made a diagnosis of docetaxel-induced nail bed purpura and subungual onycholysis. teaching point docetaxel is a semisynthetic analogue of paclitaxel that acts by binding to beta tubulin subunit of microtubule resulting in its disassembly. nail changes seen post-treatment with docetaxelbased chemotherapy include onychomadesis, onycholysis, beau’s lines, paronychia, and nail bed purpura [1]. the direct toxic insult to the nail bed epithelium results in the formation of hemorrhagic bulla and onycholysis [2]. secondary infection of the collected blood can also be present, which may present as intense pain due to pressure effect. under dermatoscopy, hemorrhages would appear as presence of globules of varying colors including purple, violet, and red. management includes antibiotics for the treatment of paronychia. nail bed purpura resolves spontaneously after treatment is stopped. references 1. capriotti k, capriotti ja, lessin s, et al. the risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta-analysis. br j dermatol. 2015;173(3):842-845. doi: 10.1111/bjd.13743. pmid: 25704465. 2. roh mr, cho jy, lew w. docetaxel-induced onycholysis: the role of subungual hemorrhage and suppuration. yonsei med j. 2007;48(1):124-126. doi: 10.3349/ymj.2007.48.1.124. pmid: 17326255. pmcid: pmc2628000. 2 image letter | dermatol pract concept. 2023;13(3):e2023159 figure 1. (a) nail bed purpura over fingernails. (b) dermatoscopy revealing presence of circumscribed red homogenous blotches on fingernails. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4):e2021145 1 janus kinase inhibitors for the treatment of atopic dermatitis: focus on abrocitinib, baricitinib, and upadacitinib miguel nogueira1, tiago torres1,2 1 department of dermatology, centro hospitalar universitário do porto, porto, portugal 2 instituto de ciências biomédicas abel salazar, university of porto, porto, portugal key words: atopic dermatitis, treatment, janus kinase inhibitors, abrocitinib, baricitinib, upadacitinib citation: nogueira m, torres t. janus kinase inhibitors for the treatment of atopic dermatitis: focus on abrocitinib, baricitinib, and upadacitinib. dermatol pract concept. 2021;11(4):e2021145. doi: https://doi.org/10.5826/dpc.1104a145 accepted: october 15, 2021; published: october, 2021 copyright: ©2021 nogueira et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: miguel nogueira has received grants and/or consulting fees from abbvie, leo pharma. tiago torres has received research grants and/or consulting fees from abbvie, almirall, amgen, arena pharmaceuticals, biocad, boehringer ingelheim, bristol-myers squibb, celgene, eli lilly, janssen, leo pharma, msd, novartis, pfizer, samsung-bioepis, sandoz and sanofi. authorship: all authors have contributed significantly to this publication. corresponding author: tiago torres, department of dermatology, centro hospitalar universitário do porto, porto, portugal. email: torres.tiago@outlook.com atopic dermatitis (ad) is a clinically heterogenous, inflammatory skin condition with a high impact on patients’ daily activities that remains difficult to treat. the knowledge acquired over the last decade on ad pathophysiology and disease burden led to the development of new targeted therapeutic options that enable clinicians to better manage ad patients. the jak/stat signaling pathway modulates several immune pathways (t helper (th)1, th2, th17, and th22 cells) that have been found to be involved in ad pathogenesis. for this reason, jak inhibitors emerged as a possible therapy for ad. baricitinib, upadacitinib, and abrocitinib are the three oral jak inhibitors already approved or in advanced clinical development for this purpose. the results showed that this drug class is highly effective achieving symptomatic relief (itch control) in the short term, as well as improving disease severity in abstract this article is part of a series of reviews dedicated to atopic dermatitis, guest edited by prof. anna balato. guest editor prof. anna balato, md, phd associate professor of dermatology, dermatology unit, university of campania, naples, italy 2 review | dermatol pract concept. 2021;11(4):e2021145 introduction atopic dermatitis (ad) is a chronic, relapsing, clinically heterogeneous, and difficult-to-treat disorder, also known for being the most prevalent inflammatory skin disease in developed countries with a lifetime prevalence of up to 20% [1,2]. ad was originally labeled as an early childhood disease. however, it is now known that despite the incidence peak during infancy – onset of the disease occurs before 6 years of age in 80% of patients -, the proportion of patients with adult-persistent or adult-onset forms of ad is nonnegligible [2–4]. the disease is clinically associated with a variety of features ranging from minimal eczema on flexural folds or hands to erythroderma [2–4]. cutaneous manifestations and associated symptoms/signals, such as redness, peeling, lichenification, and itchiness markedly interfere with daily activities and may lead to sleep loss and diminished self-esteem, having a high impact on social interactions and school/work performance [2–4]. consequently, ad is an important health concern worldwide, occupying the top position on the list of the causes of non-fatal disease burden of skin disorders [3]. the pathophysiology of ad is thought to be a result of the interaction between various critical factors, such as epidermal barrier disruption, genetic susceptibility, activation of distinct subsets of t-cells, environmental triggers, and dysbiosis of commensal skin microbiota [2,5]. the strongest identified risk factor for ad is a positive family history of atopy which may result in a 3 or 5-fold increased risk for developing ad when one or both parents are affected, respectively [2]. in the last decade, major advances were made in understanding the molecular bases behind ad, which also allowed the development of new targeted strategies for the management of the disease [2,6,7]. in addition to the classic treatment approaches – including avoiding environmental triggers, topical therapies and traditional immunosuppressants – several targeted drugs (biologic or small molecules) were introduced as new treatment options for ad. dupilumab, an il-4 receptor α inhibitor that blocks the activity of both il-4 and il-13, was the first non-traditional immunomodulator agent approved for the treatment of moderate-to-severe ad in patients with 6 years of age or older. however, the development of new treatments for ad is crucial, as a considerable number of patients are non-responders to the available regimens. currently, several small molecules are already approved or under evaluation in clinical trials for treating patients with ad [4,6–9]. janus kinase (jak)/signal transducer and activator of transcription (stat) signaling pathway in atopic dermatitis the jak/stat signaling pathway has been associated with the development of ad as it modulates several immune pathways that are involved in its pathogenesis, such as those associated with t helper (th)1, th2, th17, and th22 cells [10, 11]. briefly, this pathway involves a circulating cytokine, such as an interferon (ifn) or an interleukin (il), that binds to its cell membrane receptor triggering a conformational change with subsequent jaks recruitment and activation [12]. two activated and combined jaks have the ability to further phosphorylate stat proteins, inducing their dimerization and subsequent translocation into the cell nucleus. once in the nucleus, stat proteins can affect gene expression [12]. there are four different jak proteins (jak1, jak2, jak3, and tyk2) and seven distinct stat proteins (stat1, stat2, stat3, stat4, stat5a, stat5b, and stat6) [12]. jak1 and jak3 seem to be responsible for mediating the signaling of cytokines from the γc family, including il-4, a cytokine known for its relevant role in ad cascade [10,11]. il-31-induced signaling pathway, particularly through jak1, is also thought to play an important role in inducing chronic pruritus [11,13]. stat6 activation, which occurs mainly through jak1 and jak3 activation after il-4 and il-13 bind their receptors, have also been implicated in ad development [10,11,14,15]. on the other hand, jak2 and tyk2 interact to stat4 and seem to mediate th1 differentiation, as well as il-12 signaling [10,11]. systemic jak inhibitors in atopic dermatitis over the last decade, the marked advances that have been made in understanding the impact of jak/stat signaling pathway on the pathogenesis of ad encouraged the use of jak inhibitors as a therapeutic alternative for this disease [10,11,16]. although jak inhibitors safety profile had already been evaluated this class of drugs is already approved for the treatment of other immune mediated diseases such as rheumatoid arthritis – several clinical trials were conducted to assess the performance of these drugs in the specific context of ad[10,11]. the short and medium term. however, their efficacy should be balanced with possible side effects, that have been reported in clinical trials. more data on the long-term efficacy and safety, as well as from head-to-head comparisons and from real-world setting will be crucial to position oral jak inhibitors in the ad therapeutic armamentarium. review | dermatol pract concept. 2021;11(4):e2021145 3 in the following review, we will focus on the results of the available phase iii clinical trials of oral jak inhibitors used in ad patients after their positive data on safety and efficacy in phase i and ii studies, namely baricitinib, upadacitinib and abrocitinib (table 1). baricitinib baricitinib is a small molecule that selectively inhibits both jak1 and jak2 proteins [10,11]. this drug is approved by the european medicines agency (ema) for treating moderate-to-severe atopic dermatitis in adult patients, but table1. results from phase iii clinical trials of oral jak inhibitors used for ad patients: baricitinib, upadacitinib and abrocitinib. drug name main jak inhibition trial name patients, n. study duration (co)primary endpoint(s) most important side effects associated to jak inhibitors baricitinib jak1 and jak2 breezead1 [18] 624 16 wks viga-ad 0/1 at week 16 baricitinib 2mg: 11.4% baricitinib 4mg: 16.8% placebo: 4.8% increased blood cpk, nasopharyngitis, headache, herpes simplex breezead2 [18] 615 16 wks viga-ad 0/1 at week 16 baricitinib 2mg: 10.6% baricitinib 4mg: 13.8% placebo: 4.5% increased blood cpk, nasopharyngitis, headache breezead3 [19] 221 total/ partial responders (16 wks from previous enrollment in breeze-ad1 or breeze-ad2) plus 52 wks viga-ad 0/1 at week 16, 36 and 52 published results at week 52: baricitinib 2mg: 59.3% baricitinib 4mg: 47.1% nasopharyngitis, headache, increased blood cpk and diarrhea breezead4 [20] 463 16 wks easi75 at week 16 baricitinib 2mg+tcs: 27.6% baricitinib 4mg+tcs: 31.5% placebo+tcs: 17.2% nasopharyngitis, headache, upper tract respiratory infections breezead7 [21] 329 16 wks viga-ad 0/1 at week 16 baricitinib 2mg+tcs: 24.0% baricitinib 4mg+tcs: 31.0% placebo+tcs: 15.0% nasopharyngitis, folliculitis, herpes simplex infection, upper respiratory tract infection, acne, diarrhea, and back pain upadacitinib jak1 measure up 1 [24] 847 16 wks easi75 at week 16 upadacitinib 15mg: 69.6% upadacitinib 30mg: 79.9% placebo: 16.3% viga-ad 0/1 at week 16 upadacitinib 15mg: 48.1% upadacitinib 30mg: 62.0% placebo: 8.4% acne, upper respiratory tract infections, nasopharyngitis, headache and increased blood cpk measure up 2 [24] 836 16 wks easi75 at week 16 upadacitinib 15mg: 60.1% upadacitinib 30mg: 72.9% placebo: 13.3% viga-ad 0/1 at week 16 upadacitinib 15mg: 38.8% upadacitinib 30mg: 52.0% placebo: 4.7% acne, upper respiratory tract infections, nasopharyngitis, headache and increased blood cpk ad up [25,26] 901 52 wks easi75 at week 16 upadacitinib 15mg+tcs: 64.6% upadacitinib 30mg+tcs: 77.1% placebo+tcs: 26.4% viga-ad 0/1 at week 16 upadacitinib 15mg+tcs: 39.6% upadacitinib 30mg+tcs: 58.6% placebo+tcs: 10.9% acne, nasopharyngitis, increased blood cpk, upper respiratory tract infection, herpes simplex infection heads up [27] 692 24 wks easi75 at week 16 upadacitinib 30mg: 71.0% dupilumab: 61.1% acne, upper respiratory tract infections, nasopharyngitis, increased blood cpk table1 continues 4 review | dermatol pract concept. 2021;11(4):e2021145 drug name main jak inhibition trial name patients, n. study duration (co)primary endpoint(s) most important side effects associated to jak inhibitors abrocitinib jak1 jade mono-1 [28] 387 12 wks easi75 at week 12 abrocitinib 100mg: 40.0% abrocitinib 200mg: 63.0% placebo: 12.0% iga 0/1 at week 12 abrocitinib 100mg: 24.0% abrocitinib 200mg: 44.0% placebo: 8.0% nausea, nasopharyngitis, headache, upper respiratory tract infection jade mono-2 [29] 391 12 wks easi75 at week 12 abrocitinib 100mg: 45.0% abrocitinib 200mg: 61.0% placebo: 10.0% iga 0/1 at week 12 abrocitinib 100mg: 28.0% abrocitinib 200mg: 38.0% placebo: 9.0% nausea, nasopharyngitis jade compare [30] 838 16 wks easi75 at week 12 (vs. placebo) abrocitinib 100mg+tcs: 58.7% abrocitinib 200mg+tcs: 70.3% dupilumab: 58.1% placebo+tcs: 27.1% iga 0/1 at week 12 (vs. placebo) abrocitinib 100mg+tcs: 36.6% abrocitinib 200mg+tcs: 48.4% dupilumab: 36.5% placebo+tcs: 14.0% nausea, nasopharyngitis, upper respiratory tract infection, headache, acne, herpes zoster, thrombocytopenia jade regimen [31] 1233 (798 after a 12-week induction period with abrocitinib 200mg) 52 wks proportion of patients that did not loss easi50 and had iga score <3 at week 52 abrocitinib 100mg: 57.4% abrocitinib 200mg: 81.1% placebo: 19.1% nausea, nasopharyngitis, acne, upper respiratory tract infections, increased blood cpk jade teen [32] 285 12 wks easi75 at week 12 abrocitinib 100mg+tcs: 68.5% abrocitinib 200mg+tcs: 72.0% placebo+tcs: 41.5% iga 0/1 at week 12 abrocitinib 100mg+tcs: 41.6% abrocitinib 200mg+tcs: 46.2% placebo+tcs: 24.5% nausea, upper respiratory tract infections, headache, and nasopharyngitis cpk = creatine phosphokinase; easi = eczema area and severity index; easi-50 = improvement of 50% in easi compared to baseline; easi-75 = improvement of 75% in easi compared to baseline; iga 0/1 = investigator global assessment score of 0 or 1; jak = janus kinase; tcs = topical corticosteroids; viga-ad 0/1 = validated investigator’s global assessment for atopic dermatitis score of 0 or 1; wks = weeks table1. results from phase iii clinical trials of oral jak inhibitors used for ad patients: baricitinib, upadacitinib and abrocitinib. (continued) is currently waiting for the approval of food and drugs administration (fda) [17]. the recommended dosage is 4 mg once daily. half dosage schemes (2 mg) may be considered in patients aged 75 years or older, in those with a history of chronic or recurrent infections, or in those who have achieved a sustained control of disease as a dose tapering strategy [17]. as these are the recommended dosage regimens, data on the usage of 1 mg dosage schemes will not be discussed. two independent multicentric double-blinded 16-week phase iii clinical trials (breeze-ad1 and breeze-ad2) compared baricitinib monotherapy (2 mg and 4 mg) with placebo in adult patients with moderate-to-severe ad [18]. the results of both trials revealed that the primary endpoint [validated investigator’s global assessment for ad (viga-ad) score of 0 (clear) or 1 (almost clear)] was achieved with both baricitinib 2 mg and 4 mg once daily dosing-regimens [breeze-ad1: n = 624, baricitinib 2 mg 11.4 %, baricitinib 4 mg 16.8 % vs. placebo 4.8 % (p < 0.05 and p < 0.001, respectively); breeze-ad2: n = 615, baricitinib 2 mg 10.6 %, baricitinib 4 mg 13.8 % vs. placebo 4.5 % (p < 0.05 and p = 0.001, respectively)]. however, the same was not verified for secondary endpoints, as only baricitinib 4 mg consistently met the key secondary endpoints. although improvements in ad-associated symptoms (skin pain and review | dermatol pract concept. 2021;11(4):e2021145 5 night awakenings) were achieved at week 1 for both dosing regimens, the same was not verified for itchiness it improved at week 1 with baricitinib 4 mg, but patients receiving baricitinib 2 mg only registered improvements at week 2, making the first dosing regimen superior. treatment-emergent adverse events were observed in 54 to 58 % of the patients, predominantly mild-to-moderate. the most reported adverse events included increased blood creatine phosphokinase (cpk), nasopharyngitis and headache. herpes simplex infection was more frequent with baricitinib compared to placebo in breeze-ad1 (baricitinib 2 mg 3.3 %, baricitinib 4 mg 7.2 % vs. placebo 1.2 %), but the same was not verified in breeze-ad2. no venous thromboembolic events, significant hematological abnormalities, cardiovascular events, or death were observed in any of the baricitinib groups. after a 16-week period, adults receiving baricitinib 4 mg or 2 mg that were responders or partial responders (viga-ad score ≤ 2) in breeze-ad1 and breeze-ad2 trials were analyzed in a long-term extension study (breeze-ad3) [19]. the proportion of patients receiving baricitinib 2 mg and 4 mg that achieved a viga-ad of 0 or 1 at week 16 (breeze-ad3 study baseline) was 46.3 % and 45.7 %, respectively. at week 68, those numbers improved to 59.3 % and 47.1 %, with a similar safety profile, thus showing the sustained long-term efficacy and safety of baricitinib in these patients. the combination of baricitinib (2 mg and 4 mg) with topical corticosteroids was evaluated in two distinctive phase iii clinical trials (breeze-ad4 [20] and breeze-ad7 [21]) that included adult patients with moderate-to-severe ad. in these trials, only baricitinib 4 mg met the primary endpoint [an improvement of 75 % in eczema area and severity index (easi) compared to baseline (easi75) in breeze-ad4, and a viga-ad score of 0/1 in breeze-ad7] at week 16. at the mentioned timepoint, a total of 31.5 % of patients receiving baricitinib 4 mg achieved easi75 (baricitinib 2 mg 27.6 %; placebo 17.2 %) in breeze-ad4, while 31.0 % achieved viga-ad score of 0/1 (baricitinib 2 mg 24.0 %; placebo 15.0 %) in breeze-ad7. the symptomatic relief (improvement in itch scores) was verified in all patients receiving baricitinib – when comparing to placebo, a higher response of itch improvement with baricitinib 4 mg was achieved as early as on day 4 of treatment. regarding side effects, infections and increased blood cpk were the most common reported ones. a pulmonary thromboembolic event in a patient receiving baricitinib 4 mg was reported in breeze-ad7. the impact of the combined therapy in the health-related quality of life and productivity of ad patients, as well as the improvement in patient-reported outcomes were also assessed in breeze-ad7 [22]. both dosing regimens (2 mg and 4 mg) of baricitinib plus topical corticosteroids induced a rapid – before week 2 – and significant improvement in several of the evaluated scores (dermatology life quality index, work productivity and activity impairment, patient-reported outcomes measurement information system itch and sleep) when compared to placebo plus topical corticosteroids in the same timepoints. upadacitinib upadacitinib is a small molecule that selectively inhibits jak1 [23]. the drug is approved by the ema for the treatment of moderate-to-severe ad in patients aged 12 years or older [23]. similarly to baricitinib, upadacitinib is currently under fda evaluation. the recommended dose is 15 mg or 30 mg once daily, according to the disease burden and age of the patient [23]. two 16-week phase iii clinical trials (measure up 1 and measure up 2) compared upadacitinib monotherapy with placebo in patients aged 12 to 75 years with moderate-tosevere ad [24]. a total of 847 patients in measure up 1 and 836 patients in measure up 2 were randomly (1:1:1 ratio) assigned to receive either upadacitinib 15 mg, upadacitinib 30 mg, or placebo. the coprimary endpoints at week 16 (easi75 and viga-ad score of 0/1) were achieved in all upadacitinib groups in both measure up 1 [easi75: upadacitinib 15 mg 69.6 %, upadacitinib 30 mg 79.9 % vs. placebo 16.3 % (p < 0.0001); viga-ad score of 0/1: upadacitinib 15 mg 48.1 %, upadacitinib 30 mg 62.0 % vs. placebo 8.4 % (p < 0.0001)] and measure up 2 [easi75: upadacitinib 15 mg 60.1 %, upadacitinib 30 mg 72.9 % vs. placebo 13.3 % (p < 0.0001); viga-ad score of 0/1: upadacitinib 15 mg 38.8 %, upadacitinib 30 mg 52.0 % vs. placebo 4.7 % (p < 0.0001)]. the secondary endpoints at week 16 were also met in both upadacitinib groups. there was a similar incidence of serious adverse events and adverse events leading to study dropout between groups. acne, upper respiratory tract infections, nasopharyngitis, headache, and increase in serum cpk levels were the most frequently reported adverse events. regarding herpes zoster, the rates of infection in the groups receiving upadacitinib were low (< 2 %). a 52-week phase iii trial (ad up) evaluated the efficacy and safety of combining upadacitinib with topical corticosteroids in patients aged 12 to 75 years old [25,26]. in a 1:1:1 ratio randomization, 901 patients were assigned to receive topical corticosteroids plus either upadacitinib 15 mg, upadacitinib 30 mg or placebo [25,26]. the coprimary endpoints at week 16 (easi75 and viga-ad score of 0/1) were achieved in the two upadacitinib groups [easi75: upadacitinib 15 mg 64.6 %, upadacitinib 30 mg 77.1 % vs. placebo 26.4 % (p < 0.0001); viga-ad score of 0/1: upadacitinib 15 mg 39.6 %, upadacitinib 30 mg 58.6 % vs. placebo 10.9 % (p < 0.0001)], and both upadacitinib groups achieved higher response rates than placebo for all key secondary endpoints [25]. not only upadacitinib (both doses) demonstrated 6 review | dermatol pract concept. 2021;11(4):e2021145 to have a higher efficacy, but also a rapid onset of action, with differences observed as early as week 2 [25]. although similar rates of herpes zoster infections were observed across groups (1 to 2 %), eczema herpeticum was only registered in patients receiving upadacitinib [25]. no new safety findings were reported at week 16 [25]. for all endpoints, efficacy of both dosing regimens of upadacitinib were maintained through week 52 [26]. no new relevant safety events were reported in the extended period [26]. upadacitinib was also tested in a 24-week head-to-head phase iii clinical trial (heads up) [27]. a total of 692 adult patients with moderate-to-severe ad were randomized (1:1 ratio) to receive either upadacitinib 30 mg once daily or dupilumab 300 mg every other week (600 mg as initial loading dose). at week 16, 71.0 % patients in the upadacitinib group achieved easi75, compared to 61.1 % in the dupilumab one (p = 0.006). in addition, upadacitinib demonstrated to have a faster onset of action when compared to dupilumab: 43.7 % of patients receiving upadacitinib achieved easi75 at week 2, compared to 17.4 % of those receiving dupilumab. no new safety-related events were registered compared to the already available data for both drugs. it was verified a higher rate of serious infections, herpes zoster, eczema herpeticum, and laboratory adverse events in the group of patients receiving upadacitinib whereas rates of conjunctivitis and injection-site reactions were higher in the dupilumab group. one treatment-emergent death occurred in the upadacitinib group due to a viral bronchopneumonia. abrocitinib abrocitinib is a jak1 selective inhibitor that, differently from the previous drugs, has neither received fda or ema approval yet. fda is now reviewing the new drug application for abrocitinib, and a decision is expected soon after. two 12-week similarly designed phase iii trials (jade mono-1 and jade mono-2) [28,29] compared abrocitinib monotherapy (100 mg and 200 mg once daily) with placebo in a total of 778 patients with moderate-to-severe ad aged 12 years or older. both dosing regimens of abrocitinib met the coprimary endpoints at week 12 (easi75 and investigator global assessment (iga) score of 0 or 1) in both jade mono-1 [easi75: abrocitinib 100 mg 40 %, abrocitinib 200 mg 63 % vs. placebo 12 % (p < 0.0001); iga score of 0/1: abrocitinib 100 mg 24 %, abrocitinib 200 mg 44 % vs. placebo 8 % (p = 0.0037 and p <0.0001, respectively)] and jade mono-2 [easi 75: abrocitinib 100 mg 45 %, abrocitinib 200 mg 61 % vs. placebo 10 % (p < 0.001); iga score of 0/1: abrocitinib 100 mg 28 %, abrocitinib 200 mg 38 % vs. placebo 9 % (p < 0.001)]. regarding safety, treatment-emergent adverse events were more frequently registered in patients receiving abrocitinib in both trials (69 78 % in abrocitinib groups and 57 % in placebo group in jade mono-1; 63 66 % in abrocitinib groups and 42 % in placebo group in jade-mono-2), but there was a similar rate of serious adverse events with abrocitinib when comparing to the placebo group. despite the low rates, herpes simplex infection was only observed in patients receiving abrocitinib. nausea, nasopharyngitis, and headache were the most commonly reported adverse events, but there was also a relevant mention to dose-dependent acne after abrocitinib. no deaths occurred. patients that completed 16 weeks of treatment in jade mono-1 and jade mono-2 were invited to enroll an ongoing phase iii long-term extension study (jade extend – nct03422822) including 92 weeks of treatment with abrocitinib (100 mg or 200 mg) with or without concomitant topical corticosteroids. an active-controlled 16-week phase iii clinical trial (jade compare) enrolled a total of 838 adult patients with moderate-to-severe ad and compared the efficacy and safety of abrocitinib (100 mg or 200 mg) with dupilumab 300 mg every other week (600 mg of initial loading dose) and placebo [30]. in this study, all patients received concomitant topical corticosteroids. easi75 was achieved by 58.7 % of patients in abrocitinib 100 mg group, 70.3 % in abrocitinib 200 mg group, 58.1 % in dupilumab group, and 27.1 % in placebo group. the goal of an iga score of 0/1 was achieved by 36.6 % in the abrocitinib 100 mg group, 48.4 % in the abrocitinib 200 mg group, 36.5 % in the dupilumab one, and 14.0 % in the placebo group (p < 0.001 for both abrocitinib groups compared to placebo). abrocitinib 200 mg (but not abrocitinib 100 mg) was superior to dupilumab in achieving the itch-relief-scores at week 2. however, at week 16, none of abrocitinib groups differed significantly from the dupilumab one regarding other key secondary endpoints. in what concerns to safety questions, herpes zoster only occurred in patients receiving abrocitinib, while eczema herpeticum developed in 2 patients, one from the abrocitinib 100 mg group, and the other from the placebo group. no new safety-related events were noted. patients that completed this trial were also invited to enroll the jade extend (nct03422822). in a 52-week phase iii clinical trial (jade regimen), patients with moderate-to-severe ad aged 12 years or older that responded positively (achieved easi75 and iga score of 0/1) to a 12-week induction period of an open-label treatment with abrocitinib 200 mg once daily, were randomly assigned to receive blinded abrocitinib (100 mg or 200 mg) or placebo for 40 weeks [31]. a total of 1233 patients started at week 0, 798 (64.7 %) responded to the 12-week induction period and were randomly assigned to the abovementioned groups. the primary endpoint – proportion of patients that did not loss easi50 and had iga score < 3 (mild) – was achieved by 57.4 % in abrocitinib 100 mg group, 81.1 % patients in abrocitinib 200 mg group, and 19.1 % in placebo group, with statistically superiority of abrocitinib 200 mg compared review | dermatol pract concept. 2021;11(4):e2021145 7 to abrocitinib 100 mg. regarding safety, treatment-emergent adverse events (abrocitinib 100 mg 54.0 %, abrocitinib 200 mg 63.2 %) and adverse events leading to drug discontinuation (abrocitinib 100 mg 1.9 %, abrocitinib 200 mg 6.0 %) were higher with abrocitinib. a total of 285 adolescents aged 12 to 17 years with moderate-to-severe ad were enrolled in a 12-week phase iii placebo-controlled study (jade teen) and randomized to receive either once daily abrocitinib 100 mg, abrocitinib 200 mg, or placebo, in combination with topical corticosteroids [32]. the coprimary endpoints (easi75 and iga score of 0/1) were achieved in both abrocitinib groups [easi75: abrocitinib 100 mg 68.5 %, abrocitinib 200 mg 72.0 % vs. placebo 41.5 % (p < 0.05); iga score of 0/1: abrocitinib 100 mg 41.6 %, abrocitinib 200 mg 46.2 % vs. placebo 24.5 % (p < 0.05)]. adverse events were observed in 52.0 % to 63.0 % of the patients among all groups, and the most reported were nausea, upper respiratory tract infections, headache, and nasopharyngitis. herpes simplex infection was uncommon (1.1 %). no new safety-related events were noted when compared to the available data from previous studies. conclusion the results of the aforementioned trials revealed that jak inhibitors are an effective therapeutic option for ad. not only they were able to induce short and medium-term cutaneous improvement, but also to induce symptomatic relief, confirmed by their impact on itch control and on patients’ daily activities previously affected by ad. another important-to-mention finding was the rapid onset of action of jak inhibitors, able of inducing their benefits after just 1 to 2 weeks of treatment. these findings support the fact that an improvement in ad patients goes beyond the sole cutaneous improvement. additionally, available data on head-to-head comparisons suggested that jak inhibitors might be an important option in ad armamentarium, with a slightly numerical superiority in efficacy when compared to the already fda and ema approved dupilumab. however, their potential side effects must be considered when opting for these drugs. in fact, jak/stat signaling pathway has been shown to play a role in several crucial physiological regulatory processes, that potentially increases their risk of side effects. although most of them are mild-to-moderate, they include infections – including infection by opportunistic agents such as mycobacterium tuberculosis or herpes zoster –, thromboembolic events, malignancies, lipid disturbances (increased total, lowand high-density lipoprotein cholesterol and increased triglycerides), and hematologic abnormalities (neutropenia, anemia, thrombocytopenia), and transient increases of liver enzymes, creatine phosphokinase (cpk), or creatinine [10,11]. although hematologic disturbances have also been reported after the use of jak1 inhibitors – by a mechanism that is not completely understood -, they are more commonly observed after using jak2 inhibitors as jak2 interferes with erythropoietin and other colony-stimulating factors (csf) function [10,11]. regarding lipid abnormalities, they have been mostly reported after the use of jak1 inhibitors, however more data is needed to better clarify this interaction as some reports suggest that lipid disturbances may be related to inflammation and not to jak1 pathway itself [10,11]. over the last decade, knowledge on ad pathophysiology and its impact in quality of life has expanded, which promoted the pursuit for new targeted therapeutic options that enable clinicians to better manage their ad patients. dupilumab was the first biological agent approved for moderate-to-severe ad, and data from clinical trials and real-world setting studies have been extensively analyzed and discussed in the recent years [33]. however, targeted therapy continued to evolve, and the emergence of small molecules, such as the jak inhibitors baricitinib, upadacitinib, and abrocitinib, is increasing the range of options for dermatologists to treat their patients. jak inhibitors seem to have a faster onset of action than alternative agents, such as dupilumab, although the latter have a more favorable safety profile with no requirements of blood monitoring. despite the efficacy and safety profile that jak inhibitors demonstrated in clinical trials, some questions remain, including their long-term efficacy (rate of flares), long-term safety events, head-to-head comparisons, and data on the efficacy and safety of the drug in a real-world setting. in summary, the improvement on the knowledge of the pathophysiology of ad is allowing the targeting of the treatment of patients on a molecular basis [11,34–37]. new emergent drugs are allowing a smoother balance between efficacy and side 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baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial. jama dermatol. 2020;156(12):1333-1343. doi:10.1001/ jamadermatol.2020.3260. pmid: 33001140 . pmcid: pmc7527941. 22. wollenberg a, nakahara t, maari c, et al. impact of baricitinib in combination with topical steroids on atopic dermatitis symptoms, quality of life and functioning in adult patients with moderate-to-severe atopic dermatitis from the breezead7 phase 3 randomized trial. j eur acad dermatol venereol. 2021;35(7):1543-1552. doi:10.1111/jdv.17278. pmid: 33834521. pmcid: pmc8251919. 23. european medicines agency. rinvoq® (upadacitinib): epar product information. https://www.ema.europa.eu/en/documents/ product-information/rinvoq-epar-product-information_en.pdf. published 2021. accessed july 27, 2021. 24. guttman-yassky e, teixeira hd, simpson el, et al. once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (measure up 1 and measure up 2): results from two replicate double-blind, randomised controlled phase 3 trials. lancet. 2021;397(10290):2151-2168. doi:10.1016/s0140-6736(21)00588-2. 25. reich k, teixeira hd, de bruin-weller m, et al. safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (ad up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. lancet. 2021;397(10290):2169-2181. doi:10.1016/s0140-6736(21)00589-4 26. silverberg ji, de bruin-weller m, bieber t, et al. upadacitinib plus topical corticosteroids in atopic dermatitis: week-52 ad up study results. j allergy clin immunol. august 2021. doi:10.1016/j. jaci.2021.07.036. pmid: 34403658. 27. blauvelt a, teixeira hd, simpson el, et al. efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial. jama dermatology. 2021;157(9):1047-1055. doi:10.1001/jamadermatol.2021.3023. pmid: 34347860. pmcid: pmc8340015. 28. simpson el, sinclair r, forman s, et al. efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (jade mono-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. lancet. 2020;396(10246):255-266. doi:10.1016/s01406736(20)30732-7 29. silverberg ji, simpson el, thyssen jp, et al. efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. jama derreview | dermatol pract concept. 2021;11(4):e2021145 9 matol. 2020;156(8):863-873. doi:10.1001/jamadermatol.2020.1406. pmid: 32492087. pmcid: pmc7271424. 30. bieber t, simpson el, silverberg ji, et al. abrocitinib versus placebo or dupilumab for atopic dermatitis. n engl j med. 2021;384(12):1101-1112. doi:10.1056/nejmoa2019380. pmid:33761207. 31. blauvelt a, silverberg ji, lynde cw, et al. abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: results from the jak1 atopic dermatitis efficacy and safety (jade) regimen phase 3 trial. j am acad dermatol. august 2021. doi:10.1016/j. jaad.2021.05.075. pmcid: pmc7788316. 32. eichenfield lf, flohr c, sidbury r, et al. efficacy and safety of abrocitinib in combination with topical therapy in adolescents with moderate-to-severe atopic dermatitis: the jade teen randomized clinical trial. jama dermatol. 2021:e212830. doi:10.1001/jamadermatol.2021.2830. pmid: 34406366. pmcid: pmc8374743. 33. seegräber m, srour j, walter a, knop m, wollenberg a. dupilumab for treatment of atopic dermatitis. expert rev clin pharmacol. 2018;11(5):467-474. doi:10.1080/17512433.2018.1449642. pmid: 29557246. 34. thyssen jp, thomsen sf. treatment of atopic dermatitis with biologics and janus kinase inhibitors. lancet. 2021;397(10290):21262128. doi:10.1016/s0140-6736(21)00717-0. 35. chovatiya r, paller a. jak inhibitors in the treatment of atopic dermatitis. j allergy clin immunol. august 2021. doi:10.1016/j. jaci.2021.08.009. pmid: 34437922. 36. melo a, carrascosa jm, torres t. baricitinib for the treatment of atopic dermatitis. j dermatolog treat. august 2021:1-10. doi:1 0.1080/09546634.2021.1967268. pmid: 34379541. 37. singh r, heron ce, ghamrawi r, strowd lc, feldman sr. emerging role of janus kinase inhibitors for the treatment of atopic dermatitis. immunotargets ther. 2020;9:255-272. doi:10.2147/ itt.s229667. pmid: 33204661. pmcid: pmc7667501. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023052 1 telemedicine evaluation of pediatric acral dermatitis in covid-19 era: a real-life experience on covid-19 toes versus pool palms and review of the literature on juvenile palmar dermatitis laura cristina gironi1, andrea guala2, francesca zottarelli1, francesca graziola1, elisa zavattaro1, elia esposto1, giovanni damiani3,4, paola savoia5 1 aou maggiore della carità di novara, novara, italy 2 department of pediatrics, castelli hospital, verbania, italy 3 clinical dermatology, irccs istituto ortopedico galeazzi, milan, italy 4 department of biomedical, surgical and dental sciences, university of milan, milan, italy 5 department of health sciences, university of eastern piedmont, novara, italy key words: acral dermatitis, covid-19, covid-19 toes, pool palms, teledermatology citation: gironi lc, guala a, zottarelli f, et al. telemedicine evaluation of pediatric acral dermatitis in covid-19 era: a real life experience on covid-19 toes versus pool palms and review of the literature on juvenile palmar dermatitis. dermatol pract concept. 2023;13(1):e2023052. doi: https://doi.org/10.5826/dpc.1301a52 accepted: april 24, 2022; published: january 2023 copyright: ©2023 gironi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: laura cristina gironi, aou maggiore della carità, c.so mazzini 18, 28100 novara, italy. phone: +39 03213733269. fax: +39 03213733117. e-mail address: gironi.laura@gmail.com orcid id: 0000-0002-7298-4446 introduction pediatric acral dermatitis represents a diagnostic challenge, as it can have various origins [1], including sars-cov-2 infection [2], that can cause acro-ischemic lesions, also called pseudo-chilblain or pernio-like lesions, or “covid toe”. due to the mild systemic symptoms, the role of dermatologists is fundamental in the early recognition of the infection and the consequent pandemic containment [2]. we described our real-life experience with teledermatology management of 6 pediatric acral dermatites during the first covid-19 pandemic. telemedicine-assisted consultations were conducted to collect anamnestic history and perform skin examination; skin lesions images were independently analyzed by three different dermatologists (glc, ze, gf). cases presentation case 1: a 6-year-old boy with asymptomatic and symmetrical shiny erythematous-edematous plaques on the toe pads and the fingertips of both hands (figure 1, a-e). the child had no signs or symptoms and frequented a private pool. case 2: a 13-year-old girl with partially exulcerated erythematous-edematous plaques on the toes, fingertips and palms (figure 1, f-g). lesions were mildly painful, bilateral 2 research letter | dermatol pract concept. 2023;13(1):e2023052 figure 1. clinical aspect of case 1 (a-e, 6-year-old child) and 2 (f-g, 13-year-old girl): redness and edema symmetrically involving the palmar (a,b,f) and plantar (c,d,e,g) surface of all the distal phalanges of the feet and hands, with the sole exception of the fifth toe; the palms of the hands and feet, in correspondence with the metacarpophalangeal and metatarsophalangeal joints, are also partially affected in case 1. vesicle-bullous evolution is possible in areas subject to friction on rough pool surfaces (g). clinical aspect of case 3 (h-l, 13and 15-yearold girls) and 4 (m-o, 3-year-old girl): chilblain‐like edematous and erythematous lesions involving the feet, on the dorsal surface (h-i-l), or both on the palmar-plantar and dorsal side (m-n-o). note the presence of exulcerations on the third and fourth toes (h, l). research letter | dermatol pract concept. 2023;13(1):e2023052 3 and symmetric. the girl attended the family private pool, with a 12 years-old cousin who showed identical lesions. case 3: two 13and 15-year-old girls, with chilblain‐like burning-aching edematous and erythematous lesions asymmetrically involving the feet, that completely resolved in about 3 weeks. case 4: a 3-year-old girl with bilateral and asymmetrical, painful and burning erythemato‐violaceous and edematous macules involving the toes and fingers, both on the palmar-plantar and dorsal side (figure 1, m-o) without systemic symptoms. sars-cov-2 igg antibodies were positive in both cases 3 and 4. all 3 dermatologists agreed on the diagnosis of pool palms (pm), also named “juvenile palmar dermatitis of swimming pools” in cases 1 and 2. otherwise, in cases 3 and 4 all dermatologists hypothesized covid-19-related skin lesions, subsequently confirmed by laboratory investigations. pm is a benign acquired acral dermatosis, typically occurring during childhood (mean age of 6.4 years) [3], probably frequently misdiagnosed with bilateral and symmetrical hand involvement. table 1 reviews all the 15 pm cases published [3-6]. pm is characterized by erythematous edematous violaceous asymptomatic lesions with a smooth surface, generally non-infiltrated; in some cases, a painful vesicular-bullous evolution has been described [3-5]. this mechanical dermatosis is caused by repeated rubbing of the palmar and/or plantar skin with the hard and rough walls of the swimming pool. consequently, the convex areas of the palmar and plantar surface are more affected [3-5]. it is mostly seen in subjects who are learning to swim and so who tend to cling to the pool walls. the dermatosis typically is self-limiting with the interruption of exposure to the pool environment [3-5]. table 1. clinical findings of all reported pm cases, since the first description, dated in 1992* reference age, sex anatomical sites involved symptoms geographical origin morgado-carrasco et al. 2019 pmid: 31921496 5-year-old, f palmar surface of the fingers** painful lesions spain novoa et al. 2016 pmid: 26424817 5-year-old, f palmar surface of the fingers** asymptomatic lesions spain 4-year-old, f plantar surface of the fingers, toe pads and heels** martin jm et al. 2009 pmid: 19709557 6-year-old, f palm and palmar surface of the fingers** asymptomatic lesions spain lopez-neyra et al. 2009 pmid: 19951653 6-year-old, m palmar surface of the fingers** asymptomatic lesions spain wong et al. 2007 pmid: 17300665 5-year-old, f palmar and plantar surface of the fingers** not specified australia sassolas et al. 1996 pmid: 9033728 10-year-old, m palmar surface of the fingers and palms and toe pads** painful lesions france 8-year-old, m 4-year-old, m lacour et al. 1995 pmid: 8687057 6-year-old, m palmar surface of the fingers and palms** not specified france 4-year-old, f asymptomatic lesions blauvelt et al. 1992 pmid: 1619059 12-year-old, f palmar surface of the fingers and palms** asymptomatic lesions u.s.a. 11-year-old, f 3 ½-year-old, m age not specified, m notes: * we performed a systematic review in medline using the following keywords: “pool palms”, “juvenile palmar dermatitis of swimming pools” and “dermatite palmaire juvenile des piscines”. every reference cited in all the articles included has also been verified. every article that met the search criteria was analyzed, regardless of language (english, italian, spanish and french). gray literature, any document that hasn’t gone through peer review for a publication and conference abstracts were excluded. **lesions present bilaterally and symmetrically 4 research letter | dermatol pract concept. 2023;13(1):e2023052 2. molaee h, emadi sn, m'imunya jmn, davoudi-monfared e, mohammed a, razavi z. chilblain or perniosis-like skin lesions in children during the covid-19 pandemic: a systematic review of articles. dermatol ther. 2022 jan 3:e15298. doi: 10.1111/dth.15298. 3. morgado-carrasco d, feola h, vargas-mora p. pool palms. dermatol pract concept. 2019;10(1):e2020009. doi: 10.5826 /dpc.1001a09. 4. martín jm, martín jm, ricart jm. lesiones eritematovioláceas en las palmas. diagnóstico: palmas de piscina [ erythematous-violaceous lesions on the palms]. actas dermosifiliogr. 2009;100(6):507-8. pmid: 19709557 5. novoa a, klear s. pool palms. arch dis child. 2016;101(1):41. doi: 10.1136/archdischild-2015-309633. 6. wong lc, rogers m. pool palms. pediatr dermatol. 2007;24(1):95. doi: 10.1111/j.1525-1470.2007.00347.x. conclusions in the pre-covid-19 era, allergic contact dermatitis and atopic pulpitis were the main differential diagnoses suggested by several authors [3]. we report the first pm cases reported during the covid-19 pandemic, proposing a possible potentially underestimated differential diagnosis among childhood acral dermatosis. pm may indeed present clinical features like the acral lesions observed in mild covid-19 patients; nevertheless, an accurate clinical and anamnestic evaluation can properly orient clinicians (figure 2). references 1. caccavale s, ruocco e. acral manifestations of systemic diseases: drug-induced and infectious diseases. clin dermatol. 2017 jan-feb;35(1):55-63. doi: 10.1016/j.clindermatol.2016.09.008. pool palms simmetric hands and/or feet, palmoplantar surface childhood (mean 7.1 yrs) no systemic symptoms skin lesions mostly asymptomatic pain or itch in 75% of cases covid19 toes preadolescence (mean 13.5 yrs) mild systemic symptoms asimmetric toes and feet, dorsal surface figure 2. diagnostic algorithm for the differential diagnosis between pool palms and covid-19 toes dermatoses. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023087 1 erysip eloid presentation of cutaneous leishmaniasis of the scalp awatef kelati1, mouna rimani2 1 dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco 2 department of pathological anatomy hassan, rabat, morocco citation: kelati a, rimani m. erysipeloid presentation of cutaneous leishmaniasis of the scalp. dermatol pract concept. 2023;13(2):e2023087. doi: https://doi.org/10.5826/dpc.1302a87 accepted: september 14, 2022; published: april 2023 copyright: ©2023 kelati et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: kelati awatef, dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco. e-mail: akelati@um6ss.ma case presentation a 39-year-old man from the area of tinghir in morocco, was referred to the dermatology consultation with a 6-month history of mild itchy skin lesions of the forehead. the physical examination showed an extensive erythematous infiltrated plaque of the forehead and the fronto-temporal area. dermoscopy revealed perifollicular scales, yellow dots, follicular keratotic plugs, and branching vessels on an erythematous orange background (figure 1). after a negative slit-skin smear, which was performed because of the high frequency of leishmaniasis in that endemic area of morocco, and because of the suggestive dermoscopic appearance especially the yellow dots and plugs on an orange-erythematous background. skin biopsy showed diffuse tuberculoid granulomatous infiltrate without caseous or fibrinoid necrosis, with the presence of leishman bodies (figure 1), which confirmed the  diagnosis of granulomatous cutaneous leishmaniasis. the  identification of parasite species by pcr was not performed. meglumine antimoniate was out of stock at that period, so, we prescribed doxycycline and aureomycine ointment for 12 weeks, with a significant amelioration, then the patient received intramuscular  injection of glucantime for 20  days because of the persistence of a slight erythema, a complete remission was then achieved. teaching points cutaneous leishmaniasis (cl) can have atypical clinical presentations with sometimes a negative slit-skin smear, especially in chronic granulomatous presentations, however, cl could be highly suspected on dermoscopy. follicular keratotic plugs, generalized erythema with vascular structures are the most common dermoscopic features [1]. the diagnosis confirmation relies on the skin smear or histopathology findings [2]. 2 image letter | dermatol pract concept. 2023;13(2):e2023087 figure 1. (a) cutaneous leishmaniasis. extensive erythematous infiltrated plaque of the forehead and the fronto temporal area. (b) dermoscopy revealed perifollicular witish scales and erythema (green arrow), yellow dots ( yellow arrows), follicular keratotic plugs (gray circle), and branching vessels (red arrow) on an erythematous orange background. histopathology (c, h&e) and giemsa stain (d): diffuse tuberculoid granulomatous infiltrate without caseous or fibrinoid necrosis, with the presence of leishman bodies. magnification x 400. references 1. serarslan g, ekiz ö, özer c, sarıkaya g. dermoscopy in the diagnosis of cutaneous leishmaniasis. dermatol pract concept. 2019;9(2):111-118. doi:  10.5826/dpc.0902a06. pmid: 31106013. pmcid: pmc6502294. 2. garcias-ladaria j, lópez-brito k, pascual-lópez m, rocamora v. an itching plaque. dermatol pract concept. 2015;5(1):51-53. doi:  10.5826/dpc.0501a09. pmid: 25692083. pmcid: pmc4325692. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com tufted hemangioma: clinical case and literature review viktoryia kazlouskaya1, bohdan lytvynenko2, elen blochin1 1 ackerman academy of dermatopathology, new york, ny, usa 2 “euroderm” clinic, kyiv, ukraine keywords: tufted hemangioma, hemangioma, histopathology citation: kazlouskaya v, lytvynenko, blochin e. tufted hemangioma: clinical case and literature review. dermatol pract concept. 2014;4(2):6. http://dx.doi.org/10.5826/dpc.0402a06 received: november 5, 2013; accepted: january 11, 2014; published: april 30, 2014 copyright: ©2014 kazlouskaya et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: viktoryia kazlouskaya, m.d., ph.d., ackerman academy of dermatopathology, 145 e 32 st, fl 10, new york, ny 10016, usa. e-mail: viktoriakozlovskaya@yahoo.com observation a 26-year-male patient presented with a brownish plaque in the flank area. it appeared one year after birth and was partially excised shortly after. histopathological examination was not performed at that time. over the past several years the lesion has gradually enlarged with the appearance of new smaller lesions in the vicinity of the main lesion (figure 1). the patient is otherwise healthy. a biopsy revealed a vascular proliferation with round and poorly defined collections of epithelioid and spindle cells. dilated slit-like vascular spaces, resembling those of lymphatic vessels, were seen in the sclerotic stroma (figures 2-4). cracked irregular spaces were seen between the cells in the proliferation (figure 5). scarring from the previous excision was evident (figure 2 and 3). the vascular proliferation was positive for cd31, cd34, d2-40 and negative for hhv8. ki-67 rate was low (figure 6). the diagnosis of tufted hemangioma was established on the basis of clinical presentation, history and histopathological presentation. discussion tufted hemangiomas are relatively rare benign vascular proliferations. although initially described in the european and japanese literature, the term “tufted hemangioma” was introduced in 1989 by jones and orkin [1] along with the description of the largest group of 20 patients. they usually appear during the first years of life and are congenital in up to 50% of cases [2]. review | dermatol pract concept 2014;4(2):6 33 tufted hemangiomas are relatively rare benign vascular proliferations that are congenital or appear during the first years of life. herein we present an additional case of tufted hemangioma that appeared one year after birth and discuss its histopathological criteria and differential diagnosis with malignant vascular proliferations including sarcoma kaposi, angiosarcoma and kaposiform hemangioendothelioma. abstract mailto:viktoriakozlovskaya@yahoo.com 34 review | dermatol pract concept 2014;4(2):6 sometimes present on the surface of plaques or surrounding the lesions. in children the lesions may be painful. histopathologically the lesions are characterized by collections of vessels in small tufts with a cannonball distribution, encircled by empty cleft-like vessels and often surrounded by sclerotic dermis. tufts are composed of epithelioid and spindle cells with slit-like spaces resembling kaposi sarcoma. hyaline globules may be seen within the tufts [2]. widened vessels, resembling lymphatic ones, are often a source of potential diagnostic mistakes if the biopsy is taken at the periphery of the lesion [4]. tufted hemangiomas express endothelial and lymphatic vascular markers cd31, cd34, vegf-a and d2-40. mitotic rate is usually low. the differential diagnosis of tufted hemangioma is with a variety of vascular tumors. although kaposi sarcoma resembles tufted hemangioma histopathologically, it rarely affects children. clinical data (hiv status, immunodeficiency, and african or mediterranean origin) and positivity for hhv8 allow distinguish both entities with certainty. presence of tufted hemangiomas predominantly affect males and are located on the trunk, neck or extremities [1,2]. they clinically present as patches or plaques, although subcutaneous masses may be seen [3]. hypertrichosis and hyperhidrosis are figure 1. large vascular lesion present since infancy (with the scar from the previous biopsy) and smaller lesions in the flank area. [copyright: ©2014 kazlouskaya et al.] figure 2. vascular lesion with ill-defined vascular proliferations in a sclerotic stroma. hematoxylin and eosin stain, x40. [copyright: ©2014 kazlouskaya et al.] figure 3. ill-defined and round vascular proliferations in a sclerotic stroma. hematoxylin and eosin stain, x100. [copyright: ©2014 kazlouskaya et al.] figure 4. rounded collections of epithelioid cells surrounded by slitlike vascular lumina. small hyaline globules are noted. hematoxylin and eosin stain, x600. [copyright: ©2014 kazlouskaya et al.] figure 5. collections of epithelioid cells with cracked spaces. hematoxylin and eosin stain, x200. [copyright: ©2014 kazlouskaya et al.] review | dermatol pract concept 2014;4(2):6 35 siform hemangioendotheliomas (known as kasabach-merritt syndrome) may be a grave consequence of both conditions. the phenomenon is explained by entrapment and adhesion of the thrombocytes to the endothelial cells of the hemangioma. subsequent activation of the thrombocytes leads to coagulopathy. large hemangiomas may lead to congestive heart failure [7]. osio et al. described a clinical variant of tufted hemangiomas with chronic coagulopathy, but without thrombocytopenia [2]. there are no standard guidelines for the treatment of tufted hemangiomas. if the lesion is not associated with kasabach-merritt syndrome no treatment is usually necessary. kasabach-merritt syndrome is aggressively treated with corticosteroids, vincristine or interferon-a7. excision or laser modalities may be implemented for cosmetic reasons. references 1. jones ew, orkin m. tufted angioma (angioblastoma). a benign progressive angioma, not to be confused with kaposi’s sarcoma or low-grade angiosarcoma. j am acad dermatol. 1989;20:214-25. 2. osio a, fraitag s, hadj-rabia s, et al. clinical spectrum of tufted angiomas in childhood: a report of 13 cases and a review of the literature. arch dermatol. 2010;146:758-63. 3. herron md, coffin cm, vanderhooft sl. tufted angiomas: variability of the clinical morphology. pediatr dermatol. 2002;19:394401. 4. sadeghpour m, antaya rj, lazova r , ko cj. dilated lymphatic vessels in tufted angioma: a potential source of diagnostic confusion. am j dermatopathol. 2012;34:400-3. 5. arai e, kuramochi a, tsuchida t, et al. usefulness of d2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma. j cutan pathol. 2006;33:492-7. 6. le huu ar, jokinen ch, rubin bp, et al. expression of prox1, lymphatic endothelial nuclear transcription factor, in kaposiform hemangioendothelioma and tufted angioma. am j surg pathol. 2010;34:1563-73. 7. rodriguez v, lee a, witman pm, anderson pa. kasabach-merritt phenomenon: case series and retrospective review of the mayo clinic experience. j pediatr hematol oncol. 2009;31:522-6. spindle cells, formation of new vessels around the preexisting cutaneous structures (“promontory sign”), variable cellular polymorphism may help in the diagnosis of kaposi sarcoma. angiosarcomas usually affect elderly patients and have a predilection for the scalp. multiple mitotic figures and marked atypia are the hallmarks of angiosarcomas. the differential diagnosis of kaposiform hemangioendothelioma and tufted hemangioma is challenging. some authors consider both to be within the spectrum of the same condition. tufted hemangiomas tend to be located more superficially compared to superficial kaposiform hemangoenothelioma which may affect subcutis and retroperitoneum, invade the internal organs and is characterized by aggressive growth. podoplanin (d2-40) was proposed as a useful marker for the differential diagnosis of tufted hemangioma and kaposiform hemangioendothelioma by arai et al [5]. in their study d2-40 was positive in small capillaries in the kaposi sarcoma-like part of the proliferation and was negative in the widened superficial vessels in kaposiform hemangioendothelioma. in contrast, in tufted hemangiomas, d2-40 labeling was seen in the widened superficial vessels and was negative or patchy in the capillaries of the cannonball vessels [5]. other studies, as well as our case report, showed inconsistency of these findings and demonstrated that d2-40 may also be positive in the small capillaries in tufted hemangiomas [4]. infantile hemangiomas are seen only in newborns and usually involute. they appear mostly commonly on the face and neck. prox1 has been recently described as a potential useful marker for the differential diagnosis of tufted hemangiomas/kaposiform hemangioepitheliomas versus infantile hemangiomas and pyogenic granuloma [6]. it is usually positive in tufted hemangiomas/ kaposiform hemangioendotheliomas, but is not expressed in infantile hemangiomas and pyogenic granulomas. the clinical course of tufted hemangiomas is variable. more often the lesions gradually progress. cases of spontaneous involution have been reported [2]. about 30% of patients may develop thrombocytopenia. thrombocytopenia and coagulopathy in patients with tufted hemangiomas and kapofigure 6. (a) d2-40 positivity in the small and large dilated vessels in the superficial dermis, x100. (b) expression of cd31 in the small vessels, x200. (c) sparse cells expressing ki-67, x200. [copyright: ©2014 kazlouskaya et al.] dp0303a09_r1 dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2013;3(3):9 31 review by puja k. puri, m.d. neoplastic mimics in dermatopathology is part of the pathology of neoplastic mimics series, which includes thoracic and cardiovascular pathology and genitourinary pathology. forthcoming volumes include breast pathology, gastrointestinal and liver, gynecologic pathology, head and neck pathology and bone and soft tissue pathology. i had not had the opportunity to read any of these books until now; therefore, i cannot provide a comparison within the series. neoplastic mimics in dermatopathology is well organized. it starts with a concise, basic overview, and then is divided into five sections addressing imitators of epithelial tumors; regressed and regressing melanocytic neoplasms; mesenchymal lesions; neurocutaneous rests and ectopias; and lymphoreticular infiltrates. the final section of the book provides a table of “pseudo-pseudotumors” and the lesions they mimic. pseudo-pseudotumors are the more common review of neoplastic mimics in dermatopathology, by mark r. wick and james w. patterson reviews by puja k. puri and mark a. hurt citation: puri pk, hurt m. review of neoplastic mimics in dermatopathology, by mark r. wick and james w. patterson. new york: demos medical, 2013. print. dermatol pract conc. 2013;3(3):9. http://dx.doi.org/10.5826/dpc.0303a09. copyright: ©2013 puri et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr, maryland heights, mo 63043, usa. tel. 314.99.4470. email: markhurt@ aol.com. figure 1. wick mr, patterson jw. neoplastic mimics in dermatopathology. new york: demos medical, 2013. isbn 978-1-62070-0129; upc 9781620700129; $160. malignant neoplasms than imitate benign and reactive proliferations. the book is 155 pages with appropriate references (pages 157-187) and an index (pages 189-194). the text is concise and easy to follow, which made it a quick read. there are many useful tables outlining neoplastic and pseudoneoplastic lesions with corresponding imitators. many high quality photomicrographs are included, comparing tumors and their mimics. some clinical photos are also present. this book is ideal for residents or fellows, as it highlights histopathologic clues and immunohistochemical stains that can be used to distinguish between entities. it describes the difficulties in establishing various diagnoses including desmosplastic melanoma, cutaneous lymphoma, angiosarcoma, kaposi’s sarcoma, and squamous cell carcinoma. general pathologists who do not interpret dermatopathology slides regularly would also derive benefit from this book. additionally, it is a wonderful tool for dermatologists as it describes specific situations where clinical information can help the dermatopathologist provide a more definitive diagnosis. for example, pathologists are familiar with pseudoepitheliomatous (pseudocarcinomatous) hyperplasia and how it can mimic squamous cell carcinoma. while the authors give histopathologic features distinguishing between the entities, they point out that sometimes it is difficult to be definitive, especially when examining a superficial biopsy specimen. another example is the discussion of verrucous carcinoma, where macroscopic information may be critical for an accurate diagnosis. this book is meant to be an easy-to-use reference and it serves this purpose well. it compactly describes histopathologic characteristics that distinguish entities from one 32 book review | dermatol pract concept 2013;3(3):9 while the authors have done a great job with creating this reference, i have a few recommendations should there be a second edition. the authors mention that bcl-2 does not offer much in the assistance of cutaneous b-cell infiltrates. i do not agree with this statement and would appreciate if the authors would re-consider this statement or further support this statement. bcl-2 can be helpful in diagnosing primary cutaneous marginal zone lymphoma, which is usually positive for this marker. it helps to distinguish it from primary cutaneous follicle center lymphoma, which is typically negative for bcl-2. additionally, reactive germinal centers are also typically bcl-2 negative. it is important to note that nodal follicle center lymphoma, secondary cutaneous follicle center lymphoma and primary cutaneous large b-cell lymphoma, leg type are usually positive for bcl-2. however, the latter typically has a different histomorphology, and the other lymphomas mentioned can be excluded by clinical work-up. the authors discuss reactive and malignant angioendotheliomatosis (i.e., angioendotheliomatosis proliferans systemisata). given the differences is the histopathology, they suggest using the term “intravascular lymphomatosis” for the malignant variant of this non-hodgkin lymphoma. i think they should consider using the term “intravascular large b-cell lymphoma” which is current classification of this disorder according to the world health organization (who). additionally, it should be noted that rare cases of t-cell and nk cell phenotypes have been described, but should be considered different entities according to the who. additionally, there is movement toward dropping ”s” from entities termed by proper names. for example, kaposi’s sarcoma, should now be called kaposi sarcoma and paget’s disease should be termed paget disease, etc. i would suggest updating these terms. finally, an index of acronyms would be useful. while i use acronyms heavily, there were some of which i was not aware, such as ing (isolated necrobiotic granuloma). i found myself searching the text to find the initial acronym many times. also, some of the acronyms were different from the ones that i use. for instance, pscn is a post-operative spindle cell nodule within the text; whereas, i know it as pigmented spindle cell nevus of reed. it was a bit difficult to re-learn the new acronym, as i found myself reading the acronym the way i learned it, which did not make sense. considering this is my major critique, i think the authors can commend themselves on a job well done. my last recommendation is to create an electronic application for mobile devices for residents and fellows to use when learning dermatopathology. having a list (and such great photomicrographs) of microscopic differential diagnoses for neoplastic mimics at our fingertips would be useful to many practicing physicians, as well as to pathologists in training. another. it is not intended to include comprehensive discussions of difficult entities. instead, readers are provided references to textbooks devoted to such topics, such as cutaneous lymphoma. that said, i think there could have been some expansion or a short table describing other mimics for some lesions such as epidermal nevi. the authors point out that these lesions imitate seborrheic keratosis. in the absence of clinical information, additional considerations include acanthosis nigricans, terra ferma forme dermatosis and acrokeratosis verruciformis of hopf. as a relatively young pathologist (practicing dermatopathology for 5 years), i was aware of most of the entities and mimics discussed. however, i did learn some new facts and was reminded of some tidbits of information, as well as differential diagnoses, in conditions that i do not see commonly in my practice. for example, the authors discuss “der wulst” to describe a condition for which i had used the term “central facial folliculcentric basaloid proliferation.” additionally, i thought i knew all of the terms for pseudolymphoma, but learned of another: spiegler-fendt sarcoid. i typically do not use p53 immunohistochemical stain, and was pleasantly reminded that p53 is positive in acantholytic actinic keratoses while re-epithelialized bullae and warty dyskeratoma are negative, and paget disease is variably positive. in my practice, clinical information is often scarce. for cases that look like scar, i typically call the clinician to find out if a prior biopsy was performed, and if so, what the initial lesion was. if i am told there was no prior biopsy, i typically order an s-100 to rule out desmoplastic melanoma. however, drs. wick and patterson have reminded me that ordering an hhv-8 to exclude kapsoi sarcoma also may be prudent. additionally, they provided a photomicrograph of a keloidal kaposi sarcoma mimicking keloid, and i will from now on think of this entity in the back of my mind when looking at mundane keloids. some other facts that i learned or which i was reminded include the following: rosai dorfman disease can mimic regressed malignant melanoma. angiokeratoma is not a true hemangioma and is thought to represent reactive telangiectasias. (from a philosophical standpoint, drs. patterson and wick have done a thorough job categorizing and considering many entities such as this.) epithelioid sarcoma does not express the ini1 gene product, while isolated necrobiotic granuloma retains it. rhabdomyomatous mesenchymal hamartoma should be distinguished from adult or fetal-type rhabdomyoma. i do not think about these entities very often. the histopathologic features described by drs. patterson and wick are useful. book review | dermatol pract concept 2013;3(3):9 33 including the authors, will disagree with me, but this lesion looks nothing like a sebaceoma, which is the only authentic sebaceous adenoma in the skin. these criticisms aside, the authors make relevant points about ductal proliferations, monsel’s reaction simulating sarcomatoid squamous cell carcinoma, and certain bullous diseases that can simulate solar keratoses and acantholytic squamous carcinomas. in chapter 3, the authors present a series of conditions that can mimic partially or fully regressed melanocytic lesions. these include fixed drug reactions, lupus, lichen planus, and erythema multiforme. the authors include destombes-rosai-dorfman disease in this differential, but i think it is somewhat spurious, as this condition is uncommon and not usually in the differential of melanocytic lesions. lichenoid keratosis, however, is in this differential commonly, and it is not mentioned in this chapter. as a practical matter, one must be ever vigilant when using melan-a to find the “hidden” melanocytic lesion in lichenoid inflammation. as the authors aver, regressed melanoma is regressed melanoma; one will not find evidence of it, and it is an impossible diagnosis. only when a residual melanoma is in the field can one repeatedly and reliably make such a diagnosis. the pseudoneoplastic mesenchymal lesions (chapter 4) is a very strong and useful compilation of a myriad of mesenchymal lesions hyperplasias, hamartomas, and malformations that confound many a reviewer of sections of skin lesions. most of the photographs are of high quality, with minor exception. moreover, there is a good mixture of clinical, scanning, and medium to high-power photomicrographs in this section. chapter 5 consists of a number of unusual proliferations that dermatopathologists encounter only rarely: meningotheliomatous hamartomas and cutaneous glial heterotopias. the photography is excellent throughout, and the discussion of the differential diagnosis includes fibrohistiocytic and vascular proliferations. chapter 6 addresses lymphoid hyperplasias that mimic lymphomas. “pearls” are given, such as the situation in which there are nodular or diffuse mononuclear lymphoid infiltrates expressing cd20 and cd43 as suggestive of b-cell lymphoma. another example that suggests lymphoma is the predominance of >75% of b-cells that label with cd20, cd79a, or pax5. other interesting and important mimics of malignancy include reactive angioendotheliomatosis and intralymphatic histiocytosis. the fact that most of the conditions cited are rare and in the differential diagnosis of lymphoma underscores their importance to the histopathologist; it is a credit to the authors for providing a sound discussion of them. the final chapter, chapter 7, is but a single page; it is packed with a table of pseudo-pseudoneoplasms, meaning that they are really neoplastic. dr. puri is co-director of dermatopathology and director of immuno pathology-diagnostics at laboratory corporation of america, 1912 tw alexander dr, research triangle park, nc 27709, usa. tel: (919) 361-7160. contact her at purip@labcorp.com. drs. wick and patterson respond we are grateful to dr. puri for her careful review of our monograph, and for helpful comments that can be applied in the future. we are pleased that she found our book to be a worthy effort! m!"# w$%# & j!'() p!**(")+, review by mark a. hurt, md this is a book about cutaneous non-neoplastic proliferations that mimic neoplastic ones. as the authors note in the preface: … with particular reference to this monograph, it is also possible for nonneoplastic proliferations to assume the guises of neoplasms at a macroscopic level, a microscopic, one or both…. there are 7 chapters, which are as follows: 1. neoplastic mimics: overview 2. pseudoneoplastic mimics of epithelial tumors in the skin 3. imitators of regressing and regressed melanocytic neoplasms 4. pseudoneoplastic mesenchymal lesions 5. pseudoneoplastic neurocutaneous rests and ectopias 6. pseudoneoplastic lymphoreticular infiltrates of the skin 7. “pseudo-pseudoneoplasms” of the skin there is an index preceded by all references in one location rather than after each chapter. in chapter 1, the authors lay the groundwork for what is to follow. they layout a number of scenarios by which pseudoneoplasms mimic actual neoplasms based on cause rather than morphology: reparative/post-traumatic, developmental, “functional”, iatrogenic, and infectious. this is followed by a detailed list of specific non-neoplastic cellular proliferations sorted by anatomic location. pseudoneoplastic mimics of epithelial tumors in the skin presents the basic problem of hyperplasia versus neoplasm versus hamartoma versus malformation. again, there are detailed tables of specific lesions, not all of them epithelial. i take issue with some of the diagnoses in the photographs presented. for instance figure 2.40, which is presented as a “basaloid follicular hamartoma” i think is a variation of basal cell carcinoma of the infundibulocystic type. i don’t think it is a hamartoma, as it consists of germinative cells, which are not mature, maturity being the template for a hamartoma. furthermore, i think that figure 2.44 is a sebaceous carcinoma, not an adenoma. i understand that most readers of this review, 34 book review | dermatol pract concept 2013;3(3):9 ance when errors are made in either direction, so it is important to be right. i believe this book will aid its readers to move in the right direction. dr. hurt is the book review editor for dermatology practical and conceptual. he practices dermatopathology in st. louis, mo, at cutaneous pathology, wcp laboratories. contact him at markhurt@aol.com. i recommend enthusiastically this book for all who practice pathology, especially dermatopathology. there is a lot of valuable material presented here, and it is presented well. i hope the authors consider expanding this work in a second edition, as every dermatopathologist i know, including this one, fears the mimic he or she might misdiagnose as benign when malignant, and and vice versa. lives hang in the baldermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023106 1 cryotherapy unmasks umbilication in molluscum contagiosum camilo arias-rodriguez1, julia nowowiejska2, giuseppe argenziano3, vincenzo piccolo3 1 department of dermatology, universidad pontificia bolivariana, medellín, colombia 2 department of dermatology and venereology, medical university of bialystok, bialystok, poland 3 dermatology unit, university of campania, naples, italy citation: arias-rodriguez c, nowowiejska j, argenziano g, piccolo v. cryotherapy unmasks umbilication in molluscum contagiosum. dermatol pract concept. 2023;13(2):e2023106. doi: https://doi.org/10.5826/dpc.1302a106 accepted: september 17, 2022; published: april 2023 copyright: ©2023 arias-rodriguez et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: julia nowowiejska, md, phd, department of dermatology and venereology, medical university of bialystok, poland. tel: +48857409572 e-mail: julia.nowowiejska@umb.edu.pl case presentation molluscum contagiosum (mc) is a viral skin disease caused by the molluscum contagiosum virus [1]. the virus is characterized by high infectious potential and may be transmitted via direct contact, using fomites, or due to autoinoculation [1]. clinically, mc usually manifests as multiple pearl-whitish shiny papules with the umbilicated center, although solitary lesions may be observed [1]. on dermoscopy, typical features can be seen, mainly a central white-yellowish amorphous areas, surrounded by blurry crowned vessels on the periphery [2]. solitary lesions represent a clinical challenge, especially in cases where umbilication is not evident (figure 1a), and in cases with confusing dermoscopic findings. what else can aid diagnosis in these cases, apart from histopathological examination? teaching point cryotherapy is a practical and cost-effective solution to this problem. after administration of a short cycle of liquid nitrogen to a lesion with an inconspicuous umbilicated center, the concavity appears instantly, confirming the diagnosis of molluscum contagiosum (figure 1b). cryotherapy is widely available in every dermatology department, moreover, it is a non-invasive technique and it does not require much time to perform or to recover after the procedure. hence, in doubtful monolesional non-umbilicated cases, it improves the diagnostic efficacy. 2 image letter | dermatol pract concept. 2023;13(2):e2023106 references 1. meza-romero r, navarrete-dechent c, downey c. molluscum contagiosum: an update and review of new perspectives in etiology, diagnosis, and treatment. clin cosmet investig dermatol. 2019;12:373–381. doi: 10.2147/ccid.s187224. pmid: 31239742. pmcid: pmc6553952. 2. piccolo v. update on dermoscopy and infectious skin diseases. dermatol pract concept. 2019;10:e2020003. doi: 10.5826 /dpc.1001a03. pmid: 31921490 pmcid: pmc6936624. figure 1. molluscum contagiosum. (a) a solitary, non-umbilicated lesion before administration of treatment. (b) on the right: umbilicated center appears after administration of cryotherapy. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023026 1 two new dermoscopic features of trichostasis spinulosa and its reflectance confocal microscopic appearance xuemei lan1, jianfang sun1, yiqun jiang1, xiaopo wang1 1 department of pathology, chinese academy of medical sciences & peking union medical college hospital of skin diseases and institute of dermatology, jiangsu, china key words: trichostasis spinulosa, dermoscopy, reflectance confocal microscopy citation: lan x, sun j, jiang y, wang x. two new dermoscopic features of trichostasis spinulosa and its reflectance confocal microscopic appearance. dermatol pract concept. 2023;13(1):e2023026. doi: https://doi.org/10.5826/dpc.1301a26 accepted: april 7, 2022; published: january 2023 copyright: ©2023 lan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: yiqun jiang, emails: yiqunjiang@qq.com; xiaopo wang, emails: 13770757675@163.com. department of pathology, chinese academy of medical sciences & peking union medical college hospital of skin diseases and institute of dermatology, 12 jiangwangmiao street, nanjing, jiangsu, 210042, china. introduction trichostasis spinulosa (ts) is a relatively common yet unrecognized follicular disorder characterized by the retention of numerous vellus hairs surrounded by a hyperkeratotic dilated hair follicle [1]. the main dermoscopic structures of ts have been identified previously [2]. herein, we identify two new dermoscopic features of ts and report its reflectance confocal microscopy (rcm) characteristics for the first time. case presentation a 25-year-old woman complained of progressive multiple, black-colored keratotic lesions with mild pruritus involving her trunk for 2 years. her medical history was otherwise unremarkable. physical examination revealed numerous black, firm, discrete, 0.2-0.5 mm follicular keratotic papules on the abdomen and back (figure 1, a and b). histopathology revealed hyperkeratosis with follicular plugging, a dilated infundibulum containing multiple vellus hairs enveloped in keratinous material (figure 1c). the microscopic examination illustrated a cluster of vellus hairs embedded in keratinous material from an extracted plug (figure 1d). dermoscopy demonstrated a bundle of vellus hairs projecting together (figure 2a) and keratotic plugs in some dilated follicles. in addition, dark concentric hair forming a circle under the horny layer (circle hair) and hairs rolled in spiral with peripilar casts (rolled hair) were also seen (figure 2, b and c). rcm showed dilated follicular openings were consisted of moderaterefractive keratotic substitutes and/or hyper-refractive numerous vellus hairs (figure 2, d and e). based on the above findings, the diagnosis was consistent with ts. 2 research letter | dermatol pract concept. 2023;13(1):e2023026 conclusions two clinical variants of ts have been proposed, namely nonpruritic and pruritic type [3]. we present a patient classified as pruritic type which usually affects young adult characterized by multiple itchy follicular papules mainly on the trunk and upper limbs. the diagnosis of ts is usually based on clinical presentation, microscopy and sometimes on histopathology. however, dermoscopy is the most helpful tool in clinical practice. the main dermoscopic characteristics of ts, including tufts of short, vellus hairs emerging together and keratotic plugs of some follicular openings, were noticed in our patient as previously described [2]. furthermore, we observed two new dermoscopic findings of ts: circle hair and rolled hair. circle hair is almost exclusively found incidentally on the trunk and upper legs of overweight men, where they are interspersed with normal hairs [4]. rolled hair is associated with many conditions such as ichthyosis, keratosis pilaris, xerosis, neurodermatitis, and palmoplantar keratoderma [5]. some authors attributed rolled hair to mechanical trauma resulting from repeated and vigorous rubbing. rcm is a high-resolution imaging technique which allows in vivo visualization of upper layers of skin structures. however, the rcm characteristics of ts have not been described so far. in this study, we observed rcm features as moderate-refractive and hyper-refractive structures among figure 1. (a,b) multiple dark-brownish keratotic follicular papules distributed on the abdomen and back. (c) histopathology revealed several vellus hairs in follicular plugging (h&e x100); (d) microscopic examination showed several hair shafts blocked in one follicle (x100). research letter | dermatol pract concept. 2023;13(1):e2023026 3 figure 2. (a-c) dermoscopy demonstrated tufts hairs (black arrows), rolled hairs (red arrows), circle hairs (blue arrows), and blackhead-like structures (yellow arrows) (x10). (d-e) reflectance confocal microscopy illustrated an oval-shaped moderate-refractive structure (red arrows) in the epidermis and hyper-refractive piliform structures (blue arrows) among dilated follicular openings (basic image, 0.5mm × 0.5mm). 4 research letter | dermatol pract concept. 2023;13(1):e2023026 study of 306 patients. skin appendage disord. 2018;4(4): 291-295. doi: 10.1159/000486541. pmid: 30410899. pmcid: pmc6219231. 3. kositkuliorn c, suchonwanit p. trichostasis spinulosa: a case report with an unusual presentation. case rep dermatol. 2020;12(3): 178-185. doi: 10.1159/000509993. pmid: 33250734. pmcid: pmc7670378. 4. esteves alv, serafini nb, lemes lr, et al. circular hairs: nomenclature and meanings. an bras dermatol. 2017;92(6):874-876. doi: 10.1590/abd1806-4841.20176487. pmid: 29364454. pmcid: pmc5786412. 5. panchaprateep r, tanus a, tosti a. clinical, dermoscopic, and histopathologic features of body hair disorders. j am acad dermatol. 2015;72(5):890-900. doi: 10.1016/j.jaad.2015.01.024. pmid: 25748313. dilated follicular openings, corresponding well to histologic horny follicular plugs and tufts vellus hairs, respectively. in conclusion, we have proposed two new dermoscopic signs of ts and its rcm features. these techniques, combined with the clinical findings, may be useful to diagnosis of ts, possibly limiting the need for skin biopsy. references 1. goldust m, wollina u, bhargava s, et al. trichostasis spinulosa misdiagbosed as alopecia areata. dermatol ther. 2020; 33(4):e13513. doi:10.1111/dth.13513. pmid: 32372429. 2. kelati a, aqil n, mernissi fz. dermoscopic finding and their therapeutic implications in trichostasis spinulosa: a retrospective dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2013;3(4):12 51 “a transition” dear readers of the book reviews, it is now some 10 years since i became the book review editor of dermatopathology: practical & conceptual. when that journal closed and became dermatology practical & conceptual, i stayed on as the editor of the book reviews. it has been quite a run; i have edited some 40 reviews across both journals, and i hope it has kept you, the reader and the central purpose of this journal, engaged intellectually. i have certainly been challenged, and i have appreciated the opportunity to engage with all of you. now it is time for me to retire from being the editor of the book reviews. i appreciate all of the help provided me by the staff of derm101.com and especially the guidance of the late bernie ackerman, his successor, almut böer, and her successor, harald kittler. now as iris zalaudek takes on of the role of editor-inchief of dermatology practical & conceptual, i wish her everything good for the continued high academic standards that have been established from the roots of the journal, which go back to 1995. i know it will be a challenge for her. all the best to her and all of you, from mark a. hurt, m.d. review by mark a. hurt in this second edition of practical dermatopathology, dr. rapini’s mission is the same as in his prior version: “a practical approach to skin biopsies is presented to supplement existing books of dermatopathology.” this second edition is review of practical dermatopathology by ronald p. rapini review by mark a. hurt, m.d. citation: hurt ma. review of practical dermatopathology by r rapini. dermatol pract conc. 2013;3(4):12. http://dx.doi.org/10.5826/ dpc.0304a12. copyright: ©2013 hurt. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr, maryland heights, mo 63043, usa. tel. 314.99.4470. email: markhurt@ aol.com. rapini rp. practical dermatopathology. second edition. edinburgh: elsevier-saunders. 2012; 450 pp with index and web access. isbn 978-0-32306658-7. ~$150. much more extensive than the prior edition (which contained a cd-rom) in that it provides also a code that one can use to gain access to the “expert consult” website, which contains all of the information in the book but provides also enhanced searching, some hypertext, and additional photographs (those in the book plus additional photographs only on the website). in the introduction, the publisher highlights the website features specifically, as follows: “website features • consult the book from any computer at home, in your office, or at any practice location. • instantly locate the answers to your clinical questions via a simple search query. • quickly find out more about any bibliographical citation by linking to its medline abstract. • images: browse a library of all book images. easily select, organize, and download your images into a presentation. 52 book review | dermatol pract concept 2013;3(4):12 intertriginous eruptions (see axilla 1.10 or groin 1.55)” the numbers to the right of the listed conditions refer to subsequent chapters to which the reader can refer to “drill down” to specific findings. the website version of the book recapitulates this almost exactly, but one downside on the website is that it does not provide hyperlinks to each condition listed above, which would have been a great enhancement. as it is, it is similar to the book but even easier to navigate. the beauty of dr. rapini’s method of orientation is that it provides an “in the moment” experience for anyone who is sitting a microscope and attempting to solve a diagnostic problem. do you see “pale epidermis”? if so, go to chapter 1, and there is an item by that name. here is what it says: “1.99 pale epidermis (see also vacuolization of epidermis 1.144, clear cell neoplasms 1.22, pagetoid cells 1.37) acrodermatitis enteropathica (17.1) hartnup’s disease (2.1) necrolytic migratory erythema (3.2) pellagra (8.19) psoriasis (2.8) radiodermatitis (9.2) syphilis (2.13)” of course, if you don’t like the idea of using an empirical findings list like those in chapter 1, there is a 20-page index, mostly in small print. the website also has the index hyperlinked to the sections in the book where the item(s) are found. similar to the prior version, the subsequent chapters are organized by topic and contain highlighted “p” areas that provide bullet points of key histopathological findings. the photographs are generally of high quality and are labeled with lines that show and list the specific findings, which is a great help to someone who is just beginning in the field. additionally, the photographs can be downloaded from the website for use in lectures, etc. in sum and in short, don’t walk, run out to get this second edition of “rapini.” it is a terrific, useful, and enjoyable book to use every day at the microscope. i believe that residents and fellows in dermatopathology will find it useful, especially when combined with the website, which one can use at any computer or on an ipad. this ~$150 investment is well worth it. dr. hurt is a dermatopathologist who practices in maryland heights, mo, usa, and he is the book review editor of dermatology practical & conceptual. contact him at markhurt@aol.com • online-only images: browse a library of the additional online-only images. easily select, organize, and download your images into a presentation. • review questions: test yourself, in either study or assessment mode, on these review questions.” in 2006, i reviewed the first edition of this book with these opening words: “dr. rapini’s book is intriguing; it is a relatively concise 395 pages with few references to books or articles from the literature (153 total), but he does not hesitate to reference articles from this journal, much to his credit. the book is organized as clues (chapter 1) and as chapters (the remaining chapters) on specific categories of clinical findings or specific diseases, concluding with a chapter on special stains. the conditions are presented, mostly, as brief statements, often in numbered lists, about the specific clue or condition in question, which is without doubt a culmination of dr. rapini’s many years of experience in practice, teaching, and writing about dermatopathology.” the second edition is somewhat larger than the first edition, it containing 55 additional pages. the basic structure of the book is similar to the 1st edition, the chapter titles are identical, and, like the previous edition (as well as a good film or a good novel), one must read the preface and the first chapter to understand what dr. rapini is attempting to achieve. in that chapter, dr. rapini lays the groundwork for the remainder of the book. it serves as the point of orientation for the reader who is looking to solve a diagnostic dilemma, as it provides differential diagnostic lists. for instance, if one identifies interstitial dermatitis under the microscope, he needs to turn only to chapter 1, page 20, that headlines that condition. there, it states the following: “1.65 interstitial dermatitis this is defined as the unimpressive presence of inflammatory cells scattered in the spaces between collagen bundles in the dermis, as opposed to the more common perivascular dermatitis (1.109). it is not as dense as nodular and diffuse dermatitis (1.91) or lichenoid dermatitis (1.72). of course, many of these other patterns may have a few interstitial inflammatory cells, but the list here primarily includes those where interstitial inflammation is the major finding. cellulitis (12.3) erythema marginatum (3.1 and 12.2) granuloma annulare (7.1) interstitial drug reaction (3.5) interstitial mycosis fungoides (24.1) sweet’s syndrome (3.7, usually more diffuse) urticaria (3.1) well’s syndrome (3.8, usually more diffuse) dermatology: practical and conceptual 204 letter | dermatol pract concept 2018;8(3):11 dermatology practical & conceptual www.derm101.com digital dermatoscopy as a useful tool for evaluating therapeutic efficacy in a patient with eruptive keratoacanthomas ruzica jurakic toncic1, sandra jerkovic gulin2, jaka rados1, daska stulhofer buzina1, kresimir kostovic1, giuseppe argenziano3 1 department of dermatology and venereology, university hospital centre zagreb, zagreb school of medicine, zagreb, croatia 2 department of infectious diseases, dermatology, and venereology, general hospital sibenik, sibenik, croatia 3 dermatology unit, university of campania, naples, italy key words: digital dermoscopy follow-up, keratoacanthoma, eruptive keratoacanthomas, treatment response to acitretin citation: jurakic toncic r, jerkovic gulin s, rados j, stulhofer buzina d, kostovic k, argenziano g. digital dermoscopy as useful tool for evaluating therapeutic efficacy in a patient with eruptive keratoacanthomas. dermatol pract concept. 2018;8(3):204-207. doi: https:/ doi.org/10.5826/dpc.0803a11 received: september 25, 2017; accepted: march 7, 2018; published: july 31, 2018 copyright: ©2018 jurakic toncic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, department of dermatology and venereology, university hospital centre zagreb, salata 4, 10000, zagreb, croatia. email: rjtoncic@gmail.com. introduction digital dermoscopy follow-up (ddfu) has proved its place in the monitoring of patients with multiple moles. the main indications for ddfu are a large number of nevi, a personal/ familial history of melanoma, and patients with lesions where excision would lead to disfiguring scars. ddfu includes short-term (3-6 months) and long-term (6-12 months) followup strategies [1,2]. keratoacanthoma (ka) is a relatively common, rapidly growing low-grade tumor that originates in the pilosebaceous glands and closely resembles squamous cell carcinoma (scc) [3]. some authors regard ka as a variant of scc [4]. ka rapidly grows within few weeks/months, followed by spontaneous resolution within few months. rarely, cases of ka progressing to invasive/metastatic carcinoma have been reported. trauma, human papilloma virus, genetic factors, immunosuppression, professional exposure to carcinogens, and some drugs have been considered in etiology of ka [3,5]. infrequently, ka presents as multiple tumors, and there are few described syndromes with multiple kas including grzybowski syndrome (generalized eruptive ka; hundreds of papules in middle-aged adults) [6], muirtorre/lynch syndrome (skin tumors in association with visceral cancer) [7], ferguson-smith syndrome (rare autosomal dominant disorder characterized by the sudden appearance of multiple self-healing recurrent skin tumors resembling welldifferentiated scc/ka in young age) [8], and ka centrifugum marginatum [9]. authors speculate that multiple ka might belong to the spectrum of keratinocytes maturation abnormalities, giving a clue for acitretin therapy [10]. case presentation we report a case of a 78-year-old man with multiple eruptive ka-like tumors generalized on the body. face, palms, soles, letter | dermatol pract concept 2018;8(3):11 205 and mucosa were spared. the patient reported the occurrence of tumors within 3 months before the first visit. his family members did not present with skin tumors. physical examination revealed the presence of up to 50 welldemarcated, dome-shaped nodules with a rolled, mildly erythematous border and central hyperkeratotic plug (figure 1). most of the lesions were less than 0.5 cm in diameter with only a few more than 1 cm in diameter. dermatoscopy revealed a central mass of yellow-white keratin with some hemorrhages, peripheral arrangement of hairpin vessels, linear vessels, and, less commonly, glomerular vessels. biopsy of several lesions was done, and in most we confirmed ka and in just 4 cases we confirmed scc (figure 2). all histologically proven scc underwent complete surgical excision. after surgery, acitretin  50  mg/ day was administered, subsequently reduced to 30 mg/day after a month due to nonspecific bone/muscle pain. figure  1. clinical findings. (a) a large number of well-demarcated, dome-shaped nodules with a rolled, mildly erythematous border and central hyperkeratotic plug on the back (before the treatment). (b) the total count of lesions was reduced and signs of regression were present, resulting in loss of palpability. [copyright: ©2018 jurakic toncic et al.] figure  2. histopathology of lesions before and during acitretin treatment. (a) and (b) lesions excised before acitretin treatment. well-differentiated squamous cell carcinoma (medium power photomicrograph, hematoxylin and eosin [h&e] stain ×4), intradermal tumor islands of pleomorphic keratinocytes at the base of tumor accompanied by a marked inflammatory infiltrate with eosinophils (high-power photomicrograph, h&e stain ×20). (c) lesions excised before acitretin treatment. small and well-demarcated lesion with characteristic crateriform architecture with symmetrical overhanging edges of epidermal hyperplasia and central keratin plug (h&e stain ×2). (d) regressing/resolving phase of keratoacanthoma under treatment. histopathology revealed flattening of cup shape of the lesion, irregular hyperplastic epidermis without atypia of keratinocytes, solitary dyskeratotic keratinocytes, fibrosis, and angioplasia with mixed infiltrate of inflammatory cells reminiscent on scar tissue (medium power photomicrograph, h&e stain ×4). biopsy was done during the treatment. [copyright: ©2018 jurakic toncic et al.] 206 letter | dermatol pract concept 2018;8(3):11 upon submission of the article, acitretin treatment was still ongoing, and the patient was being closely monitored, dermoscopically and clinically, with dermoscopic documentation completed every 2 months. detailed diagnostic investigations had been excluded visceral malignancy until now. at the time of submission, the patient was on a regimen of acitretin 25 mg/day, but with few new lesions observed. we decided to keep the patient on this dosage because he could not stand the pain that came with a higher dosage. the complete duration of the therapy was 6 months at the time of submission of the article. the patient was monitored from the aspect of skin and visceral tumors, an excellent therapeutic response was seen very quickly, after only 10 days of therapy, with good resolution of all tumors after 2 months. resolution of the lesion was histologically proven (figure 2). full-body photography and dermoscopic images of most of the lesions were taken before the treatment. at the 2-month follow-up, an excellent treatment response was observed. observation found no new lesions and signs of regression in all lesions, resulting in loss of palpability, loss of atypical vessels, loss of keratin structures, and the presence of melanophages/peppering structures (figure 3). this is comparable to the finding seen in histology report of the regressed lesion (figure 2). figure  3. dermatoscopic images taken with digital dermoscopy system visiomed microderm d120, equipped with full-body documentation system with slr camera canon eos 1200 d. (a), (c), and (e) lesions before the acitretin treatment. (a) hyperkeratotic, verrucous lesion with nonspecific vessels with the adjunction of seborrheic keratosis in the lower part. atypical vessels and hyperkeratotic lesions are present in other lesions before treatment. (b), (d), and (f) the same lesions at 2-month follow-up, during treatment. almost complete regression of the lesions along with loss of nodularity and signs of regression (peppering sign and nonspecific erythema) are observed. loss of atypical vessels, loss of keratin structures, and the presence of melanophages/peppering structures present phenomena detected in other lesions after the treatment. [copyright: ©2018 jurakic toncic et al.] and the examinations were repeated on a 6-month basis. conclusions ddfu has proven efficacy in the followup of patients with multiple nevi. in our case, ddfu proved to be very useful because it allowed documentation of the efficacy of acitretin therapy, regression of the previously observed lesions, and follow-up of the possible occurrence of new lesions. as the patient developed new lesions on a lowered dose, we suggest that ddfu can also be used as an additional tool for finding the lowest and most optimal dose that might be used to prevent the development of new lesions. references 1. moscarella e, tion i, zalaudek i, et al. both short-term and long-term dermoscopy monitoring is useful in detecting melanoma in patients with multiple atypical nevi. j eur acad dermatol venereol. 2017;31(2):247-251. doi: 10.1111/ jdv.13840. 2. longo c, borsari s, benati e, moscarella e, alfano r, argenziano g. dermoscopy and reflectance confocal microscopy for monitoring the treatment of actinic keratosis with ingenol mebutate gel: report of two cases. dermatol ther (heidelb). 2016;6(1):81-87. doi: 10.1007/s13555016-0094-9. 3. kwiek b, schwartz ra. keratoacanthoma (ka): an update and review. j am acad dermatol. 2016;74(6):1220-1233. doi: 10.1016/j.jaad.2015.11.033. 4. ogita a, ansai si, misago n, anan t, fukumoto t, saeki h. histopathological diagnosis of epithelial crateriform tumors: keratoacanthoma and other epithelial crateriform tumors. j dermatol. 2016;43(11):1321-1331. doi: 10.1111/1346-8138.13390. 5. sinha r, larkin j, gore m, fearfield l. cutaneous toxicities associated with vemurafenib therapy in 107 patients with braf v600e mutation-positive metastatic melanoma, including recognition and management of rare presentations. br j dermatol. 2015;173(4):1024-1031. doi: 10.1111/bjd.13958. letter | dermatol pract concept 2018;8(3):11 207 treated with acitretin. clin exp dermatol. 2010;35(4):e100-e102. doi: 10.1111/j.1365-2230.2009.03668.x. 9. divers ak, correale d, lee jb. keratoacanthoma centrifugum marginatum: a diagnostic and therapeutic challenge. cutis. 2004;73(4):257-262. 10. farro p, zalaudek i, ferrara g, et al. unusual association between acrokeratosis verruciformis of hopf and multiple keratoacanthomas. successful therapy with acitretin. j dtsch dermatol ges. 2004;2(6):440-442. 6. laaff h, mittelviefhaus h, wokalek h, schöpf e. grzybowski type eruptive keratoacanthomas and ectropion. a therapeutic problem. hautarzt. 1992;43(3):143-147. 7. hartig c, stieler w, stadler r. muir-torre syndrome. diagnostic criteria and review of the literature. hautarzt. 1995;46(2):107113. doi: 10.1007/s001050050218. 8. robertson sj, bashir sj, pichert g, robson a, whittaker s. severe exacerbation of multiple self-healing squamous epithelioma (ferguson-smith disease) with radiotherapy, which was successfully dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023043 1 the relative frequency of small vessel cerebrovascular disease and brain atrophy in mri of patients with psoriasis sahar dadkhahfar1, mozhdeh gheisari2, zahra mahboubi-fooladi3, mohammad shahidi dadras1 1 skin research center, shahid beheshti university of medical sciences, tehran, iran 2 department of radiology, shahid beheshti university of medical sciences, tehran, iran 3 department of radiology, school of medicine, shahid beheshti university of medical sciences, tehran, iran key words: psoriasis, svcd, mta, gca, fazekas citation: dadkhahfar s, gheisari m, mahboubi-fooladi z, shahidi dadras m. the relative frequency of small vessel cerebrovascular disease and brain atrophy in mri of patients with psoriasis. dermatol pract concept. 2023;13(1):e2023043. doi: https://doi.org/10.5826/ dpc.1301a43 accepted: may 19, 2022; published: january 2023 copyright: ©2023 dadkhahfar et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: zahra mahboubi-fooladi, department of radiology & medical imaging center, shohada tajrish hospital – tajrish square, tehran, iran (shaheed beheshti university of medical sciences tehran – iran.) e-mail: mahboubiz@sbmu.ac.ir introduction: psoriasis is a systemic autoimmune disease that is associated with numerous comorbidities. objective: this study aimed to compare the prevalence of small vessel cerebrovascular disease (svcd) and atrophic brain changes in mri of patients with psoriasis and normal subjects. methods: this case-control study was performed on 27 patients with psoriasis and 27 normal individuals who were referred to shohada-e-tajrish hospital, tehran, iran during 2019 and 2020. basic demographic and clinical information of participants were recorded. brain mri was performed for all individuals to examine the medial temporal atrophy (mta) score, global cortical atrophy (gca) score, and fazekas scale. finally, the relative frequencies of each parameter between the two groups were compared. results: there was no significant difference in the frequency of the fazekas scale, gca, and mta scores between the two groups. however, a mild trend was found for a higher frequency of fazekas scale, gca, and mta scores in controls in comparison with the case group. while there was no significant relationship between the fazekas scale and disease duration (p=0.16), a significant and positive correlation was found between disease duration and gca and mta scores [p<0.001). there was no significant relationship between fazekas, gca and mta status and other parameters. conclusions: the increase in disease duration was significantly associated with an increase in the incidence of cerebral atrophy, which may suggest the need for screening in terms of cns involvement in psoriasis patients. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023043 introduction psoriasis is a polygenic immune-inflammatory skin disease [1]. a variety of environmental factors may elicit disease in predisposed individuals. it affects 0.6-5% of the general population in different communities [2]. psoriasis affects about 8 million adults in the united states, and its overall prevalence in developed countries is about 2% to 3% [3]. the incidence of psoriasis in iran has been reported between 1.3% and 2.5% (4, 5]. about 75% of psoriasis patients have at least one comorbidity such as dyslipidemia, hypertension, diabetes, cardiovascular disease, uveitis, inflammatory bowel disease, osteoporosis and bone involvement, and obstructive pulmonary disease [6]. some studies have described various neurological and psychiatric involvement such as seizure, stroke, guillain-barré syndrome, migraine, and myasthenia gravis in patients with psoriasis. additionally, there seems to be a higher incidence of cardiovascular and cerebrovascular disease in patients with psoriasis even after eliminating confounding risk factors of vascular disease such as stroke[7]. small vessel cerebrovascular disease (svcd) is caused by damage to cerebral microcirculation and often affects the white matter of the brain [8]. about 45% of dementia is caused by svcd and it accounts for approximately 20% of all strokes worldwide [9, 10]. clinically, these lesions can range from silent disease to evidence of lacunar infarction, vascular dementia, and other distinct neurological symptoms [11]. radiological findings include subcortical infarcts, and in advanced stages can be characterized as white matter hyperintensities (wmh), enlargement of the perivascular spaces, lacunae, cerebral microbleeds and atrophy [8, 12]. depression, cognitive impairment and gait problems, stroke, dementia, and mood disturbance are also commonly found in patients who suffer from svcd[8]. to the best of our knowledge, no study has examined the extent and the incidence of csvd in conventional brain mri of patients with psoriasis. therefore, we designed and conducted a study to compare the prevalence of svcd and atrophic changes in conventional mri of patients with psoriasis in comparison with the control group using medial temporal atrophy (mta) score, global cortical atrophy (gca) score and fazekas scale. materials and methods this case-control study was conducted on 27 patients with psoriasis and 27 healthy individuals aged 18-60 years old who had been referred to the dermatology department of shohadaye tajrish hospital (tehran, iran) between 2019 and 2020. healthy controls were age and sex-matched individuals who were referred to the dermatology clinic for cosmetic concerns. they also had no considerable history of dermatological disease or previous medical diseases. the control subjects were matched to patients by age and sex. both groups did not declare past medical history of neurological disease. this case-control study was approved by the institutional review board and ethical committee of shahid beheshti university of medical sciences. written informed consent forms were signed by all individuals, including case and control participants. demographic data of all patients, including gender and age, as well as their medical history, habitual history (including smoking habit), disease duration, nail involvement, and other comorbidities were recorded. brain mri was performed for all patients and controls with the following setting: tr = 9.8 ms; te = 4.6 ms; flip angle = 8; section thickness = 1.2 mm; number of sections = 120; no section gap; whole-brain coverage; fov = 224 mm; matrix = 192; reconstruction matrix = 256. finally, the mta score, gca score and fazekas scale were calculated by an assistant professor of diagnostic radiology with 4 years of experience, to estimate the frequency of brain atrophy and small vessel cerebrovascular disease in each group. the radiologist was blind to whether the images belonged to the case or control group. mta is a score from 0 to 4 for the assessment of cognitive impairment. the gca scale is a qualitative rating system from 0 to 3 established to measure cerebral atrophy. the fazekas scale is used to quantify high signal lesions on t2-weighted imaging in deep white matter and periventricular regions that are usually attributed to chronic small vessel disease (figure 1) [13]. statistical analysis the results were presented as mean ± standard deviation (sd) for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. categorical variables were compared using chi-square test or fisher’s exact test. quantitative variables were also compared with t-test or mann u test. in this study, p<0.05 was considered statistically significant. the spss software (ibm, version 19) was applied for the analysis of data. results a total number of 27 consecutive patients with psoriasis and a mean age of 48.14 ± 5.41 years old were entered into the study. the majority of cases (17 out of 27 (63%)) were males. the basic demographic and disease characteristics of all patients are summarized in table 1. most patients (74.1%) had nail involvement. approximately 33% of patients exhibited arthritis and exacerbation. the mean disease duration and pasi score were 10.59 years and 13.74 respectively. comparison of the fazekas scale, gca and mta scores between study participants are shown in table 2. there was original article | dermatol pract concept. 2023;13(1):e2023043 3 no significant difference in the frequency of the fazekas scale, gca and mta scores between the two groups. however, a mild trend was found for a higher frequency of fazekas, gca and mta with normal status in controls than case group. the relationships between the fazekas scale, gca and mta scores with other parameters are shown in table 3. while there was no significant relationship between the fazekas scale and disease duration (p=0.16), a significant and positive correlation was found between disease duration with gca and mta scores (p<0.001). there was no figure 1. magnetic resonance imaging of 51-year-old male known case with 16 years involvement with psoriasis. mild periventricular and subcortical t2-weighted hyper signal lesions are seen due to small vessel disease (arrows) table 1: the basic demographic and clinical characteristics of patients. variables results age (years) 48.14 ± 5.41 gender male (%) 17 (63%) female (%) 10 (37%) smoking yes (%) 4 (14.8%) no (%) 23 (85.2%) underlying diseases no (%) 23 (85.2%) hyperlipidemia (%) 1 (3.7%) hyper tg (%) 1 (3.7%) diabetes (%) 2 (7.4%) nail involvement yes (%) 20 (74.1%) no (%) 7 (25.9%) arthritis yes (%) 9 (33.3%) no (%) 18 (66.7%) exacerbation yes (%) 10 (37%) no (%) 17 (63%) disease duration (year) 10.59 ± 7.91 pasi score 13.74 ± 4.42 drug therapy methotrexate (month) 27.7 ± 17.65 phototherapy (session) 15.23 ± 8.3 cyclosporin (month) 14.48 ± 6.5 acitretin (month) 2.3 ± 0.4 sinora (month) 15.7 ± 3.4 table 2: comparison of the fazekas, gca and mta between patients and control. control case p-value fazekas scale 0 15 (55.5%) 14 (51.8%) 0.13 1 7 (25.9%) 9 (33.3%) 2 5 (18.5%) 5 (18.5%) 3 0 (0.0%) 0 (0.0%) gca scale 0 24 (88.9%) 20 (74.1%) 0.75 1 3 (11.1%) 4 (14.8%) 2 0 (0.00%) 2 (7.4%) 3 0 (0.00%) 1 (3.7%) mta scale 0 25 (92.6%) 25 (92.6%) 0.87 1 2 (7.4%) 2 (7.4%) 2 0 (0.00%) 0 (0.00%) 3 4 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 4 original article | dermatol pract concept. 2023;13(1):e2023043 case-control design revealing that psoriasis significantly associates with impaired cognitive function. similarly, brown et al. [13], reported that psoriasis may be associated with increased cognitive impairment in these patients. in another study, innamorati et al., [14] evaluated the association between psoriasis and cognitive impairment in 50 patients with psoriasis and 50 normal individuals. they found that patients with psoriasis had more prominent cognitive impairment, anxiety, depression as well as poorer quality of life. recently, najafi et al., [15] examined the anatomical and functional status of the brain in 14 patients with psoriasis and 15 healthy individuals. they also found that chronic psoriasis could alter brain anatomy. the results of this study are closely consistent with the findings of our research emphasizing that psoriasis could affect brain structures. as in our study, they showed an increased risk of cerebral atrophy in patients with long-term psoriasis. highlighting the significance of cns investigation in patients with relevant history and symptoms. conversely, in a recent population-based study, elena pezzolo et al.[4] found that cognitive test scores and volumetric, microstructural, focal measures on brain mri did not differ between psoriasis and non-psoriasis participants. they concluded that in this population-based study, psoriasis was not associated with preclinical markers or higher dementia risk. this study differs from our study in terms of the method of white matter evaluation since we subjectively illustrated the white matter changes by fazekas score. limitations one of the limitations of this study was the small sample size, which probably affected the comparative results between the control and patient groups to achieve significant differences. therefore, another study with larger sample size, as well as a long-term cohort can be performed to investigate the association of psoriasis with these parameters. conclusions results from the current case-control study support that psoriasis patients are at risk of developing brain atrophy evaluated by fazekas score. our study showed that the disease duration in psoriasis patients exhibited a significant relationship with cerebral atrophy. an increase in the disease duration was significantly associated with an increase in the incidence of cerebral atrophy, which can confirm the importance of follow-up for these patients. significant relationship between the fazekas scale, gca and mta scores with other parameters such as age, gender, smoking, nail involvement, pasi score, and gca. discussion in this study, the relative frequency of brain atrophy and small vessel cerebrovascular disease in brain mri of patients with psoriasis and normal subjects was compared to age and sex-matched normal individuals. our results showed that there was no significant difference in chronic small vessel disease measured by fazekas score. additionally, the indices of gca (referring to brain atrophy) and mta (referring to cognitive impairment) were not significantly different among the case and control groups. according to our results, age, sex, smoking, disease severity (measured by pasi score) and nail involvement did not have an impact on gca, mta scales and fazekas score. interestingly, brain atrophy and cognitive impairment measured by gca and mta scales respectively were found to significantly correlate with the disease duration in psoriasis patients. longer duration of the disease was significantly associated with an increase in cerebral atrophy. this finding can be associated with the fact that chronic plaque psoriasis is an immune-mediated inflammatory skin disease that is strongly associated with the clinical features of metabolic syndrome, and metabolic syndrome can cause alteration in the brain [2, 3]. to the best of our knowledge, the current investigation was the first to reveal an association between psoriasis and increased risk of cerebral atrophy. several studies have reported the association between psoriasis and other brain disorders, including cognitive disorders. for example, gisondi et al.[2], examined the association between psoriasis and cognitive impairment in a table 3: the relationship between fazekas, gca and mta with other parameters. fazekas gca mta age 0.37 0.29 0.41 gender 0.64 0.26 0.69 smoking 0.72 0.28 0.41 underlying diseases 0.28 0.3 0.47 nail involvement 0.42 0.23 0.28 arthritis 0.52 0.67 0.39 exacerbation 0.35 0.29 0.45 pasi score 0.54 0.46 0.54 disease duration 0.16 <0.001 <0.001 original article | dermatol pract concept. 2023;13(1):e2023043 5 this study provides new insight into comorbidities associated with psoriasis and the necessity of screening psoriasis patients for neurological manifestations. references 1. bazsó a, szodoray p, szappanos á, korda j, pálfi p, kiss e, et al. systemic autoimmune, rheumatic diseases and coinciding psoriasis: data from a large single-centre registry and review of the literature. mediators of inflammation. 2015;2015:657907. 2. gisondi p, fostini ac, fossà i, girolomoni g, targher g. psoriasis and the metabolic syndrome. clinics in dermatology. 2018;36(1):21-8. 3. lu r, aziz na, diers k, stöcker t, reuter m, breteler mmb. insulin resistance accounts for metabolic syndrome-related alterations in brain structure. human brain mapping. 2021;42(8):2434-44. 4. pezzolo e, mutlu u, vernooij mw, dowlatshahi ea, gisondi p, girolomoni g, et al. psoriasis is not associated with cognition, brain imaging markers, and risk for dementia: the rotterdam study. journal of the american academy of dermatology. 2021;85(3):671-80. 5. engin b, keçici as, uzun a, yalçın m. psychiatric comorbidity, depression, and anxiety levels and quality of life of the patients with mycosis fungoides. dermatologic therapy. 2020:e13922. 6. goldman l, wilson rg, hornby p, meyer rg. radiation from a q-switched ruby laser. effect of repeated impacts of power output of 10 megawatts on a tattoo of man. the journal of investigative dermatology. 1965;44:69-71. 7. chowdri na, mattoo mma, darzi ma. keloids and hypertrophic scars: results with intra-operative and serial postoperative corticosteroid injection therapy. australian and new zealand journal of surgery. 1999;69(9):655-9. 8. wolfe f, michaud k. the effect of methotrexate and anti–tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. arthritis & rheumatism. 2007;56(5):1433-9. 9. fung ma, sharon vr, ratnarathorn m, konia th, barr kl, mirmirani p. elastin staining patterns in primary cicatricial alopecia. j am acad dermatol. 2013;69(5):776-82. 10. frank o, nestle m, daniel h, kaplan m, barker j. mechanisms of disease: psoriasis. n engl j med. 2009;361:496-509. 11. stern rs, nijsten t, feldman sr, margolis dj, rolstad t, editors. psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. journal of investigative dermatology symposium proceedings; 2004: elsevier. 12. chen g, chen zm, fan xy, jin yl, li x, wu sr, et al. gut-brain-skin axis in psoriasis: a review. dermatology and therapy. 2020. 13. brown g, koo j. severe plaque psoriasis may have associated cognitive impairment. dermatology. 2020. 14. innamorati m, et al. cognitive impairment in patients with psoriasis: a matched case-control study. journal of psychosomatic research. 2018. 15. najafi p, et al. functional and anatomical brain connectivity in psoriasis patients and healthy controls: a pilot brain imaging study after exposure to mentally-induced itch. jeadv. 2020;34:2557-65. dermatology: practical and conceptual letter to the editor | dermatol pract concept. 2022;12(4):e2022187 1 unilateral rosacea in a patient with multiple sclerosis mariem tabka1, rima gammoudi1, refka frioui1, nadia fetoui1, sana mokni1, amina ounallah1, colondane belajouza1, mohamed denguezli1 1 department of dermatology, farhad hachad hospital of sousse, sousse, tunisia citation: tabka m, gammoudi r, refka f, et al. unilateral rosacea in a patient with multiple sclerosis. dermatol pract concept. 2022;12(4):e2022187. doi: https://doi.org/10.5826/dpc.1204a187 accepted: march 17, 2022; published: october 2022 copyright: ©2022 tabka et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: refka frioui, md, department of dermatology, farhat hachad hospital, ibn jazzar,4000 sousse, tunisia. phone: +216 29320235; email: rafkouna1993@gmail.com written consent from the patient: the authors certify that they have obtained all appropriate patient consent forms, in which the patient gave his consent for images and other clinical information to be included in the journal. the patient understands that his name and initial will not be published and due effort will be made to conceal his identity, but that anonymity cannot be guaranteed. introduction rosacea is a common and chronic inflammatory skin condition of clinical heterogeneity and intriguing pathophysiological mechanisms. herein, we report a case of unilateral rosacea in a patient with multiple sclerosis. case presentation a 37-year-old woman presented to the dermatology department with a 2-year history of facial unilateral redness and paroxysmal pain. over the last 2 years, she received multiple treatments, such as ivermectin cream, doxycycline and metronidazole gel, without any benefit. her facial dermatosis presented as unilateral persistent erythema with multiple papules and pustules strictly confined to the right side (figure 1). the skin biopsy revealed a perivascular and perifollicular inflammatory infiltrate consisting of lymphocytes, neutrophils with the presence of demodex mites, compatible with rosacea. the unilateral distribution of the dermatosis was suggestive of pre-existing neurological lesion. we referred the patient for additional testing, including an mri of the brain, which demonstrated a demyelinating plaque at the trigeminal root entry zone consistent with trigeminal neuralgia secondary to multiple sclerosis (figure 2). she was put on natalizumab and bolus steroid therapy. the pain has decreased. however, the rosacea got worse, probably because of corticosteroids. conclusion despite its high prevalence, the underlying pathophysiology of rosacea remains unclear. this observation highlights the complexity of the disease contributing mechanisms. indeed, it describes a distinct variant of the disease denominated neurogenic rosacea, presented with unilateral arrangement and associated with an autoimmune disease. the pathophysiological mechanisms implicated in the development of 2 letter to the editor | dermatol pract concept. 2022;12(4):e2022187 rosacea include dysregulation of the innate immune system, imbalance of commensal skin microbiota, and abnormal neurovascular signaling [1]. neurogenic rosacea, a recently described rosacea subtype, demonstrates the role of local neural-associated mediators dysregulation in the pathophysiology of the dermatosis [2]. moreover, it occurs more often in patients with neurological or neuropsychiatric conditions, including complex regional pain syndrome, essential tremor, depression and obsessive-compulsive disorder [2]. dysesthesia secondary to neuronal injury was commonly reported and was associated with classical rosacea signs [2]. it is well known that patients suffering from rosacea have an increased of developing a number of auto-immune diseases, including multiple sclerosis. yet, it is also important to notice that trigeminal neuralgia, attributed to multiple sclerosis, may explain the neurogenic inflammation leading to such skin condition as well as the unilateral arrangement of the lesions. our case may also reflect a regional destabilization of the neuroimmunocutaneous system induced by multiple sclerosis. this hypothesis fully represents the concept of immuno-compromised district (icd) [3,4]. icd, a newly introduced pathogenic concept, stipulates that several different factors are likely to create a privileged cutaneous district, which explains the segmental presentation of many skin disorders, including bullous pemphigoid, pemphigus, lichen planus, discoid lupus erythematosus, drug eruptions and acne [4-6]. trigeminal neuralgia attributed to multiple sclerosis, in analogy with the aforementioned facial nerve palsy, could locally alter the immune response and induce the occurrence of rosacea following the neurologically impaired facial side. regardless of the etiopathogenic mechanisms of rosacea, the interaction between the skin and the immune and nervous systems is currently well established, with rosacea being one of the established examples involving these various systems. the systematized arrangement of a dermatosis that is strictly confined to a specific area may refer to figure 1. (a) unilateral rosacea confined to the right hemiface. (b) right lateral aspect evidencing erythema and papulopustules. (c)_slight erythema on the left side. figure 2. neuroimaging findings in our patient with gadolinium-enhanced t1-weighted image on the axial plane that shows a hyperintense pontine lesion at the right trigeminal nerve zone. letter to the editor | dermatol pract concept. 2022;12(4):e2022187 3 the “immunocompromised district” concept, and thus promoting investigations into possible immunocompromising factors. further research is clearly needed to better describe the underlying patho-physiologic characteristics and to identify additional effective treatment methods”. acknowledgment: we thank the patient for granting permission to publish this information (the patient in this manuscript has given written informed consent to publication of her case details). we are also indebted to badreddine sriha, md, phd, department of pathology, farhat hached hospital, university of sousse, for his interpretation of the skin biopsies. he received no compensation for his contributions. references 1. choi je, di nardo a. skin neurogenic inflammation. semin immunopathol. 2018;40(3):249-259. doi: 10.1007/s00281018-0675-z. pmid: 29713744. pmcid: pmc6047518. 2. scharschmidt tc, yost jm, truong sv, steinhoff m, wang kc, berger tg. neurogenic rosacea: a distinct clinical subtype requiring a modified approach to treatment. arch dermatol. 2011;147(1):123-126. doi: 10.1001/archdermatol.2010.413. pmid: 21242409. pmcid: pmc3692271. 3. egeberg a, hansen pr, gislason gh, thyssen jp. clustering of autoimmune diseases in patients with rosacea. j am acad dermatol. 2016;74(4):667-672.e1. doi: 10.1016/j.jaad.2015.11.004. pmid: 26830864. 4. ruocco v, ruocco e, piccolo v, brunetti g, guerrera lp, wolf r. the immunocompromised district in dermatology: a unifying pathogenic view of the regional immune dysregulation. clin dermatol. 2014;32(5):569-576. doi: 10.1016/j.clindermatol.2014.04.004. pmid: 25160098. 5. piccolo v, russo t, baroni a. unilateral bullous pemphigoid in hemiplegic patients: an instance of immunocompromised district. j dermatol. 2013;40(1):64-65. doi: 10.1111/j.13468138.2012.01647.x. pmid: 22901292. 6. piccolo v, ruocco v, russo t, ruotolo f, piccolo s, baroni a. unilateral rosacea in patients with facial nerve palsy: a mere example of immunocompromised district. j dermatol. 2013;40(10):850. doi: 10.1111/1346-8138.12208. pmid: 239 57626. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023115 1 benign keratosis: a useful term? rebecca scott1, amanda oakley2,3 1 university of aberdeen, waikato hospital, hamilton, new zealand 2 waikato district health board, hamilton, new zealand 3 university of auckland, faculty of medical and health science medical school, waikato campus, auckland, new zealand key words: benign keratosis, seborrhoeic keratosis, lichen planus-like keratosis, solar lentigo, dermoscopy citation: scott r, oakley a. benign keratosis: a useful term? dermatol pract concept. 2023;13(2):e2023115. doi: https://doi .org/10.5826/dpc.1302a115 accepted: november 9, 2022; published: april 2023 copyright: ©2023 scott et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: amanda oakley, waikato district health board, pembroke street, 183 pembroke street, hamilton, new zealand 3204. university of auckland, faculty of medical and health science medical school, waikato campus. email: amanda.oakley@waikatodhb.health.nz; amanda.oakley@me.com introduction: seborrheic keratosis (sk), lichen planus-like keratosis (lplk), and solar lentigo (sl) are common benign skin lesions. these lesions are frequently seen adjacent to each other or can arise from one another. they can sometimes be difficult to differentiate despite having distinct histopathological features. objectives: we evaluated dermoscopic images of 80 skin lesions to confirm the term ‘benign keratosis’ is useful for an undifferentiated sk/lplk/sl where there are overlapping clinical and dermoscopic characteristics. methods: clinical and dermoscopic images were sourced from a teledermoscopy service database of 13,000 lesions in 7,000 patients. the database was queried for sk, sl or lplk in sun-exposed sites. each lesion was evaluated based on specific dermoscopic criteria and the results analyzed. results: lesions were identified with mixed clinical and dermoscopic criteria of sk and sl, and in some, dermoscopic criteria for lplk were also present. conclusions: this study highlights the relationship between these lesions. we confirm the term ‘benign keratosis’ is useful for mixed lesions or for those that are difficult to classify. abstract introduction seborrheic keratosis (sk), solar lentigo (sl) and lichen planus-like keratosis (lplk, also known as lichenoid keratosis), can be difficult to differentiate although each has defined clinical and dermoscopic characteristics [1]. the histopathological features of sk, lplk and sl differ but as they are benign, only those suspicious of melanoma are subjected 2 original article | dermatol pract concept. 2023;13(2):e2023115 to biopsy. an sk can arise from an sl and an lplk can arise from an sl or from an sk. there is limited research linking these three lesions [2]. the international skin imaging collaboration (isic) aims to improve early melanoma detection [3]. isic has hosted challenges since 2016 covering lesion segmentation, detection of clinical diagnostic patterns, and lesion classification with the purpose of developing computer-based image analysis tools. the 2019 isic challenge classified pigmented lesions into 9 diagnostic categories including ‘benign keratosis’ (seborrheic keratosis, solar lentigo, and lichen planus-like keratosis) [4]. the isic public-access archive includes more than one thousand dermoscopic images classified as ‘benign pigmented keratosis’ [5]. however, the term ‘benign keratosis’ is not well known by dermatologists. the classification of these entities by clinical terminology tools is inconsistent. • icd-11 (version 09/2020) lists all three entities within the benign squamous cell neoplasm category (seborrheic keratosis xh0949, solar lentigo xhb58, lichen planus-like keratosis xh63l8), and includes a separate entry for benign keratosis, nos (xh0s03). • icd-11 also lists seborrheic keratosis and lichen planus-like keratosis within benign keratinocytic acanthoma (2f21) and solar lentigo within photoaging of the skin (ej20) [6]. • the snomed international snomed ct browser (31 january 2021 edition) does not link seborrheic keratosis (disorder code sctid: 394726009) and solar lentigo (disorder code sctid: 72100002), and lichenoid keratosis is classified as lichenoid actinic keratosis (sctid: 403198004) [7]. sk is a common benign epidermal age-related proliferation of keratinocytes [8]. sk can occur anywhere on the body sparing the mucous membranes, palms and soles. there are several histological subtypes which often overlap; they are characterized by acanthosis, papillomatosis, hyperkeratosis and the presence of pseudocysts [9]. sl is a macular hyperpigmented lesion linked to chronic sun exposure. typical histological features are acanthosis with elongated epidermal ridges with accompanying actinic elastosis [10]. lplk, also known as lichenoid keratosis, is thought to represent an inflammatory regressive response to a pre-existing cutaneous lesion. the pathogenesis is not completely understood, however most literature suggests lplk is a regressive form of benign epithelial neoplasm such as an sk or sl [11-13]. lplk lesions can be seen in multiple regressive stages and therefore can often be confused with other skin tumors including basal cell carcinoma and melanoma [14]. histological features are lichenoid lymphocytic infiltrate, hyperkeratosis with focal parakeratosis, variable hypergranulosis and focal acanthosis. eosinophils and plasma cells with civatte bodies are also noted [15]. a link between sl and sk was supported by histological evidence of transformation in 50 cases, and histological sl was documented at the periphery of 50 specimens of lplk [16]. biopsies taken from a solitary lesion 5 years apart reported the evolution of a sl into a solitary lplk [17]. in a series of 100 cases of lplk evaluated by histology, 28% had an adjacent skin lesion, most commonly sk (8.4%), sl (7%) and actinic keratosis (5.6%) [18]. a further clinicopathologic review of lplk cases confirmed the most frequently seen adjacent lesions were sl (73%) and sk (6.5%) [2]. gene mutations (fgfr3 and pik3ca) have been identified in sl and sk to support a link between them [14]. objectives the main objective of the study was to confirm the term ‘benign keratosis’ is useful, by comparing the clinical and dermoscopic features of typical sk,sl, lplk and lesions in which overlapping features were present. methods clinical and dermoscopic images were sourced from a teledermoscopy service database of 13,000 lesions in 7,000 patients [19]. the database was queried for sk, sl or lplk in sun exposed sites (scalp, ears, face) (table 1). non-randomized lesions were selected that had good quality clinical images typical for sk (n=20), sl (n=20), lplk (n=20) or having mixed clinical features (n=20), ie sk+sl+/-lplk), matched for anatomical area and camera (3gen dermlitecam v1). lesions identified as clinically ‘benign’ were not formally excised, therefore histopathological findings were not available. each lesion was evaluated using specific dermoscopic criteria for sk, sl, and lplk (1) (table 2). results the 80 lesions evaluated were associated with 440 macroscopic, polarized and nonpolarized dermoscopic images (table 3). dermoscopic criteria of seborrheic keratosis (table 4) analysis of sks revealed that: • sks exhibited an average of 3.3 sk criteria. • three or more of the five sk criteria were present in 17/20 sks. • ‘sharply demarcated border’ and ‘lines curved and thick (cerebriform)’ were each present in 19/20 sks. original article | dermatol pract concept. 2023;13(2):e2023115 3 table 2. dermoscopic criteria for seborrheic keratosis, solar lentigo, and lichen planus-like keratosis. seborrheic keratosis solar lentigo lichen planus-like keratosis • sharply demarcated border • dots or clods white clustered or disseminated • clods brown-yellow or orange (rarely black) • lines curved and thick • lines brown curved parallel thin • sharply demarcated • scalloped border • homogenous brown pigmentation • homogenous and structureless pigmentation • faint reticulation • fine parallel lines • fine parallel lines • ink spot lentigo excluded • fine scale • polymorphous vessels • dotted vessels • gray dots • diffuse gray dotted pattern • color (white, pink, red, orange, purple, blue-gray, black, light brown, dark brown) • color red excluded table 3. average number of dermoscopic criteria present in sk/sl/lplk lesion group. lesion type sk criteria sl criteria lplk criteria sk 3.3/5 (66%) 1.8/6 (31%) 0.0/5 (0%) sl 2.0/5 (40%) 5.3/6 (88%) 1.0/5 (2%) lplk 0.6/5 (12%) 2.4/6 (34%) 1.8/5 (35%) mixed 3.75/5 (75%) 4.4/6 (73%) 0.6/5 (12%) lplk = lichen-planus like keratosis; sk = seborrheic keratosis; sl = solar lentigo. table 1. original database collection with patient demographics. • ‘clods brown-yellow or orange (rarely black)’ were present in 16/20 sks. • ‘dots or clods white clustered or disseminated’ and ‘lines brown curved parallel thin’ were present in 6/20 sks. sk criteria were less common in sls with the exception of ‘sharply demarcated border’ seen in 18/20, a shared characteristic of sl lesions. ‘lines curved and thick (cerebriform)’ and ‘lines brown curved parallel thin’ were seen in 8/20 and 10/20 sl lesions consecutively. 4 original article | dermatol pract concept. 2023;13(2):e2023115 sl criteria were less common in the sk group except for ‘sharply demarcated border’, which was present in 19/20 sl lesions. ‘faint reticulation’ and ‘scalloped border’ were seen in 4/20 and 7/20 sk lesions consecutively. certain sl criteria were high in lplk lesions. ‘structureless (amalgamate of homogenous and structureless pigmentation)’ was present in in 18/20 and ‘scalloped border’ in 14/20 lplk lesions. ‘homogenous brown pigmentation’ and ‘fine lines parallel’ were present in none of the lplks. all mixed lesions had three or more sl criteria. none had ‘homogenous brown pigmentation’. ‘scalloped border’ was present in 19/20 and ‘structureless’ in 17/20 of mixed lesions. • the mixed lesion group had an average of 73% sl criteria. • the sl and lplk groups had an average of 88% and 34% sl criteria respectively. dermoscopic criteria of lichen planus-like keratosis (table 6) • lplks exhibited an average of 1.75 lplk criteria: • ‘diffuse gray dotted pattern’ was present in all 20 lplk lesions. • ‘gray dots’ were present in 10/20 lplk lesions. • there were no ‘polymorphous vessels’ in lplk lesions and ‘fine scale’ was present in only 1/20 lplk lesions. no lplk criteria were present in sk lesions. sl findings were less common also with 3 out of the 5 criteria having sk features were present to a lesser degree in lplk lesions. a ‘sharply demarcated border’ was present in 6/20 lplks, ‘lines curved and thick (cerebriform)’ in 4/20 and ‘clods brown-yellow or orange (rarely black) were present in 2/20. no lplks had ‘dots or clods white clustered or disseminated’ or ‘lines brown curved parallel thin’. all 5 sk criteria were present in 6/20 of the mixed lesions; 19/20 had a ‘sharply demarcated border’ and ‘dots or clods white clustered or disseminated’, ‘clods brown-yellow or orange (rarely black)’ and ‘lines brown curved parallel thin’ were commonly seen. • the mixed lesion group had an average of 75% sk criteria. • the sl and lplk groups had an average of 40% and 12% sk criteria respectively. dermoscopic criteria of solar lentigo (table 5) analysis of sls revealed that: • sls exhibited an average of 5.28 sl criteria. • four or more of the sl criteria were present in 19/20 sl lesions. • ‘faint reticulation’ and ‘scalloped border’ were each present in all 20 sl lesions. • ‘homogenous brown pigmentation’ was present in 17/20 sl lesions. • ‘structureless (amalgamate homogenous and structureless pigmentation)’ was present in 16/20 lesions and ‘fine lines parallel’ was present in 14/20 lesions. table 4. dermoscopic criteria for seborrheic keratosis in various clinically diagnosed lesions. lesion type sharply demarcated border dots or clods white clustered or disseminated clods brown, yellow or orange (rarely black) lines curved and thick (cerebriform) lines brown curved parallel thin sk 19/20 (95%) 6/20 (30%) 16/20 (80%) 19/20 (95%) 6/20 (30%) sl 18/20 (90%) 2/20 (10%) 2/20 (10%) 8/20 (40%) 10/20 (50%) lplk 6/20 (30%) 0/20 (0%) 2/20 (10%) 4/20 (20%) 0/20 (0%) mixed 19/20 (95%) 11/20 (55%) 17/20 (85%) 16/20 (80%) 12/20 (60%) lplk = lichen-planus like keratosis; sk = seborrheic keratosis; sl = solar lentigo. table 5. dermoscopic criteria for solar lentigo in various clinically diagnosed lesions. lesion type sharply demarcated border homogenous brown pigmentation structureless (~10%) faint reticulation (criss-cross network) scalloped border fine lines parallels sk 19/20 (95%) 2/20 (10%) 0/20 (0%) 4/20 (20%) 7/20 (35%) 4/20 (20%) sl 18/20 (90%) 17/20 (85%) 16/20 (80%) 20/20 (100%) 20/20 (100%) 13/20 (65%) lplk 6/20 (30%) 0/20 (0%) 18/20 (90%) 9/20 (45%) 14/20 (70%) 0/20 (0%) mixed 19/20 (95%) 0/20 (0%) 17/20 (85%) 16/20 (80%) 19/20 (95%) 15/20 (75%) lplk = lichen-planus like keratosis; sk = seborrheic keratosis; sl = solar lentigo. original article | dermatol pract concept. 2023;13(2):e2023115 5 table 6. dermoscopic criteria for lichen planus-like keratosis in various clinically diagnosed lesions. lesion type fine scale polymorphous vessels dotted vessels (small red dots) gray dots diffuse gray dotted pattern sk 0/20 (0%) 0/20 (0%) 0/20 (0%) 0/20 (0%) 0/20 (0%) sl 0/20 (0%) 0/20 (0%) 0/20 (0%) 1/20 (5%) 1/20 (5%) lplk 1/20 (5%) 2/20 (10%) 2/20 (10%) 10/20 (50%) 20/20 (100%) mixed 3/20 (15%) 0/20 (0%) 0/20 (0%) 4/20 (20%) 4/20 (20%) lplk = lichen-planus like keratosis; sk = seborrheic keratosis; sl = solar lentigo. figure 1. mixed lesion displaying appearance of sk arising from sl. lesion id 15040477. dermoscopy features —sharply demarcated border, dots or clods white clustered or disseminated, clods brown yellow or orange (rarely black), lines curved and thick (cerebriform), lines brown curved parallel thin, faint reticulation (criss-cross network), scalloped border, fine lines parallels. figure 2. seborrhoeic keratosis classical lesion. lesion id 35110201. dermoscopy features — sharply demarcated border, dots or clods white clustered or disseminated, clods brown-yellow or orange (rarely black), lines curved and thick (cerebriform), lines brown curved parallel thin. figure 3. solar lentigo classical lesion. lesion id 44740194. dermoscopy features — sharply demarcated border, homogenous brown pigmentation, structureless (approx. 10%), faint reticulation (criss-cross network), scalloped border, fine lines parallel. 6 original article | dermatol pract concept. 2023;13(2):e2023115 lowest positive result for sk criteria had a thick scale reducing dermoscopic feature detail. the sl criterion ‘scalloped border’ was present in all 20 sl and mixed lesions. ‘faint reticulation’ was seen in 16/20 mixed lesions. lplk lesions also displayed sl features. a high percentage of classic lplk lesions displayed specific sl criteria including ‘structureless’ (18/20), ‘scalloped border’ (14/20) and ‘faint reticulation (criss-cross network)’ (9/20). lplk may arise from an sl with sections of the lesion representing regressive structures of sl. ‘faint reticulation’ and ‘scalloped border’ were seen in all 20 sl lesions confirming that these criteria have high specificity to sl. ‘homogenous brown pigmentation’ showed high specificity in sl lesions and was uncommonly observed in other lesion groups. this is a classical feature of an sl; the mixed lesions had a combination of features and therefore could not be classified as ‘homogenous’. the key dermoscopic features in the lplk lesions were ‘diffuse gray dotted pattern ‘in all 20 classic lplk lesions and ‘gray dots’ in 10/20. lplk lesions are most easily clinically recognised in the late regressive stage as early phase lesions are nonspecific. only 2/20 lplk lesions in our selective sample displayed ‘polymorphous vessels’ and ‘dot vessels’. ‘fine scale’ was not displayed within any lplk lesions however was noted in 3/20 mixed lesions. fine scale was difficult to detect on the clinical and dermoscopic images as a contact fluid had been applied. the largest color variation group seen in lplk was ‘light brown/grey’ in 11/20 lplk lesions and reflects the classic regressive features in this sample of lplk lesions. ‘light brown/dark brown were most common in the sk, sl and mixed groups. few lplk features were present in classic sl or sk lesions, however sk and sl features were displayed in lplk lesions. sl criteria were more common with an average of 2.4/6 (34%) features present. sk features were also seen with ‘lines curved and thick (cerebriform) seen in 4/20 lesions and the common sl/sk feature of ‘sharply demarcated border’ seen in 6/20 lesions. this indicates overlap between these lesions. a 0/20 result. ‘gray dots’ and ‘diffuse gray dotted pattern’ were present in no sl lesions. lplk criteria were more common in the mixed lesions compared to classic sl and sk. ‘diffuse gray dotted pattern’ and ‘gray dots’ were seen in 4/20 mixed lesions. conclusions analysis of the lesions selected for this study confirms that the specific dermoscopic criteria suggested in dermoscopedia for sk, sl and lplk can be observed in the other clinically diagnosed lesions [1]. our clinically selected sl and mixed lesions displayed the highest number of listed dermoscopic criteria followed by sk and lplk lesions. we found that dermoscopic criteria for clinically typical sl and sk overlap. ‘sharply demarcated border’ was found in 19/20 (95%) of sks and 18/20 (90%) of sls. the sk features, ‘lines curved and thick (cerebriform)’ and ‘lines brown curved parallel thin’ were commonly seen in sl. sl features of ‘faint reticulation’ and ‘scalloped border’ were found in otherwise typical sk. ‘sharply demarcated border’ was present in 19/20 of the mixed group which correlates with these lesions being predominantly sl or sk. the mixed lesions displayed significant findings for both sk and sl criteria, and lplk criteria were less common. sk criteria had the highest result with an average of 3.4/5 (74%) of mixed lesions displaying sk criteria. three out of five sk criteria had higher overall findings in mixed lesions than in the sk group. sl criteria were also common with an average of 4.4/6 (73%) of mixed lesions. mixed lesions chosen had less lplk criteria at 0.6/5 (12%). ‘dots or clods white clustered or disseminated’ are typical of sk but in our sample, this feature was present in 11/20 mixed lesions and in fewer sk lesions (6/20). it may be a less common characteristic of sk or reflect the small sample size. as expected, few lplk lesions exhibited sk criteria. a ‘sharply demarcated border’ was seen in 30% of lplks. we noted that 2/20 of the clinically typical sk lesions with the figure 4. lichen planus-like keratosis classical lesion. lesion id 46600410. dermoscopy features — structureless (approx. 10%), faint reticulation (criss-cross network), scalloped border, grey dots, diffuse grey dotted pattern. original article | dermatol pract concept. 2023;13(2):e2023115 7 7. snomed international -medical terminology.available from:. https://browser.ihtsdotools.org/. accessed july 24, 2021 8. greco mj, bhutta bs. seborrheic keratosis. in:  statpearls. treasure island (fl): statpearls publishing. available from https:// www.ncbi.nlm.nih.gov/books/nbk545285/. accessed august 11, 2021. 9. hafner c, vogt t. seborrheic keratosis. j dtsch dermatol ges. 2008;6(8):664-677. doi:10.1111/j.1610-0387.2008.06788.x. pmid: 18801147 10. ortonne jp, pandya ag, lui h, hexsel d. treatment of solar lentigines. j am acad dermatol. 2006;54(5 suppl 2):s262-s271. doi:10.1016/j.jaad.2005.12.043. pmid: 16631967. 11. watanabe s, sawada m, dekio i, ishizaki s, fujibayashi m, tanaka m. chronology of lichen planus-like keratosis features by dermoscopy: a summary of 17 cases. dermatol pract concept. 2016;6(2):29-35. doi:10.5826/dpc.0602a06. pmid: 27222769. pmcid: pmc4866624. 12. nagrani n, jaimes n, oliviero mc, rabinovitz hs. lichen planus-like keratosis: clinical applicability of in vivo reflectance confocal microscopy for an indeterminate cutaneous lesion. dermatol pract concept. 2018;8(3):180-183. doi:10.5826 /dpc.0803a06. pmid: 30116660. pmcid: pmc6092072. 13. bugatti l, filosa g. dermoscopy of lichen planus-like keratosis: a model of inflammatory regression. j eur acad dermatol venereol. 2007;21(10):1392-1397. doi:10.1111/j.1468-3083 .2007.02296.x. pmid: 17958847. 14. liopyris k, navarrete-dechent c, dusza sw, et al. clinical and dermoscopic features associated with lichen planus-like keratoses that undergo skin biopsy: a single-center, observational study. australas j dermatol. 2019;60(2):e119-e126. doi:10.1111 /ajd.12955. pmid: 30450536. pmcid: pmc6520177. 15. zaballos p, blazquez s, puig s, et al. dermoscopic pattern of intermediate stage in seborrhoeic keratosis regressing to lichenoid keratosis: report of 24 cases. br j dermatol. 2007;157(2):266-272. doi:10.1111/j.1365-2133.2007.07963.x. pmid: 17553042. 16. mehregan ah. lentigo senilis and its evolutions. j invest dermatol. 1975;65(5):429-433. doi:10.1111/1523-1747.ep12608175. pmid: 127813. 17. goldenhersh ma, barnhill rl, rosenbaum hm, stenn ks. documented evolution of a solar lentigo into a solitary lichen planus-like keratosis.  j cutan pathol. 1986;13(4):308-311. doi:10.1111/j.1600-0560.1986.tb01527.x. pmid: 3771875. 18. prieto vg, casal m, mcnutt ns. lichen planus-like keratosis. a clinical and histological reexamination.  am j surg pathol. 1993;17(3):259-263. doi:10.1097/00000478-199303000-00006. pmid: 8434706. 19. lim d, oakley am, rademaker m. better, sooner, more convenient: a successful teledermoscopy service.  australas j dermatol. 2012;53(1):22-25. doi:10.1111/j.1440-0960.2011.00836.x. pmid:  22309326. mixed lesions displayed evidence of end-stage regressive lplk features with the commonest features present being ‘gray dots’ (4/20) and ‘diffused gray dotted pattern’ (4/20). other features were infrequent. mixed lesions displayed a high proportion of sl/sk criteria alongside these regressive lplk findings. this points to a relationship between the evolution of these lesions as previously documented in the literature. benign keratoses arise in most older people. lesions we had clinically diagnosed as sk had overlapping dermoscopic criteria for sl, and others we diagnosed as sl had dermoscopic criteria for sk. we identified some lesions with mixed clinical and dermoscopic criteria of sk and sl, and in some, dermoscopic criteria for lplk were also present. this study highlights the relationship between these lesions. we can confirm that the term ‘benign keratosis’ would be useful for mixed lesions or for those that are difficult to classify. this would include lesions with overlapping sl and sk features and those with features of intermediate or end-stage regressive lplk features wherein the features of origin are characteristic of a primary sl or sk. references 1. braun r, nouveau s. solar lentigines/ seborrhoeic keratoses/ lichen planus-like keratosis dermoscopedia. in dermoscopedia. available from: https://dermoscopedia.org/w/index.php?title =solar_lentigines&oldid=16362. accessed april 23, 2021. 2. vincek v. lichen planus-like keratosis: clinicopathological evaluation of 1366 cases.  int j dermatol. 2019;58(7):830-833. doi:10.1111/ijd.14358. pmid: 30565224. 3. international skin imaging collaboration (isic) overview. available from: https://www.isicarchive.com/#!/topwithheader/ tightcontenttop/about/aboutisicoverview. accessed april 23, 2021. 4. international skin imaging collaboration (isic) archive, 2019 challenge. available from: https://challenge2019.isic-archive. com/. accessed april 23, 2021. 5. isic archive, pigmented benign keratosis gallery. available from: https://www.isic-archive.com/#!/topwithheader/onlyhead er top/gallery?filter=%5b%22meta.clinical.diagnosis%7cpig men ted%20benign%20keratosis%22%5d. accessed april 25, 2021. 6. icd-11 for mortality and morbidity statistics. available from: https://icd.who.int/browse11/l-m/en. accessed july 24, 2021. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022106 1 dermatology practical & conceptual case presentation a 66-year-old male presented with pigmented lesions that he had for a few months. diagnosis of erythema dyschromicum perstans was made based on clinical appearance (asymptomatic, blue-grayish patches of varying sizes, some with erythematous borders, distributed on the face, arms, shoulders and trunk) (figure 1 a-d), histopathology (atrophic epidermis, superficial and perivascular lymphocytic infiltrate and pigment incontinence in the dermis) (figure 1e) and dermoscopy (gray-bluish small dots over a bluish base) (figure 1f). teaching points in everyday practice and for every skin lesion, the use of dermoscopy as a supportive tool is highly recommended. in a case of erythema dyschromicum perstans (edp), there are a case of erythema dyschromicum perstans ana ravić nikolić1,2, vesna miličić1,2, bojana jovović dagović2, slobodanka mitrović3,4 1 department of dermatovenereology, faculty of medical sciences, university of kragujevac, kragujevac, serbia 2 department of dermatology, university clinical center kragujevac, kragujevac, serbia 3 department of pathology, faculty of medical sciences, university of kragujevac, kragujevac, serbia 4 department of pathology, university clinical center kragujevac, kragujevac, serbia citation: ravić nikolić a, miličić v, jovović dagović b, mitrović s. a case of erythema dyschromicum perstans. dermatol pract concept. 2022;12(2):e2022106. doi: https://doi.org/10.5826/dpc.1202a106 accepted: november 4, 2021; published: april 2022 copyright: ©2022 ozarslan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ana ravić nikolić, md, phd, department of dermatovenereology, faculty of medical sciences, university of kragujevac, kragujevac, serbia. e-mail: anaravic74@gmail.com significant clinical, histological and dermoscopic similarities between edp and other acquired dermal macular hyperpigmentations-pigmented contact dermatitis and lichen planus pigmentosus [1]. viney et al reported that severity of pigmentation by dermoscopy is comparable with severity of clinical and histological findings but there are no specific dermoscopic differences to differentiate these diseases [1,2]. four dermoscopic grades were observed: 1) discrete pigment dots without any pattern; 2) pigment dots and globules arranged in broken net pattern; 3) pigment dots and globules in a wellformed net-like pattern and 4) diffuse pigment dots, globules and blotches, sparing only gland openings [1]. according to the given classification, first grade corresponds to our case. presence of dots, globules and blotches in edp differs from other hyperpigmentations, such as melasma where pseudo-reticular network is observed or in the case of nevus ota where slate-gray structureless areas are present [1]. 2 image letter | dermatol pract concept. 2022;12(2):e2022106 references 1. vinay k, bishnoi a, kamat d, chatterjee d, kumaran ms, parsad d. acquired dermal macular hyperpigmentation: an update. indian dermatol online j. 2021;12(5):663-673. doi: 10.4103/ idoj.idoj_881_20. pmid: 34667751. pmcid: pmc8456249. figure 1. (ad). blue-grayish patches of varying sizes, some with erythematous borders localized on the face, arms, shoulders and trunk. (e) atrophic epidermis, superficial and perivascular lymphocytic infiltrate and pigment incontinence in the dermis (h&e x100). (f) dermoscopic image: gray-bluish small dots over a bluish base (dermatoscope heine delta 20 led plus). 2. sasidharanpillai s, govindan a, ajithkumar k, et al. histological evaluation of acquired dermal macular hyperpigmentation. indian dermatol online j. 2019;10(5):542-546. doi: 10.4103/ idoj.idoj_426_18. pmid: 31544073. pmcid: pmc6743398. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022096 1 dermatology practical & conceptual a particular bicentric structure in dermoscopic demonstration of degos disease anqi li1, rouyu fang1, qiuning sun1 1 department of dermatology, peking union medical college hospital, chinese academy of medical sciences and peking union medical college, beijing, china citation: li a, fang r, sun q. a particular bicentric structure in dermoscopic demonstration of degos disease. dermatol pract concept. 2022;12(3):e2022096. doi: https://doi.org/10.5826/dpc.1203a96 accepted: october 30, 2021; published: july 2022 copyright: ©2022 li et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this research was supported by sedimentation integration fund of peking union medical college hospital (zc201902245). competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: qiuning sun, peking union medical college hospital, department of dermatology no.1 shuaifuyuan, dongcheng district, beijing, china. tel: +86 13910318639, e-mail: doctorjenny1@126.com case presentation a 38-year-old woman suffered recurrent abdominal pain and rashes for 1 year. physical examination showed multiple red papules with porcelain-white centers over her trunk and limbs (figure 1a). dermoscopic imaging demonstrated 2 yellow-white structureless centers of different sizes with telangiectasia, similar  to a bicentric structure (figure 1b). histopathology showed intravascular thrombosis in the dermis (figure 1c). abdominal ct scanning confirmed small bowel perforation and abdominal adhesion. a diagnosis of degos disease was made. figure 1. clinical, dermoscopic, and histopathological figures (a) red papules with porcelain-white atrophic centers (b) two yellow-white structureless centers in different sizes with telangiectasia (c) epidermis atrophy, vacuolar degeneration  of  basal  layer, increased collagen fibers, and intravascular thrombosis of the dermis. 2 image letter | dermatol pract concept. 2022;12(3):e2022096 teaching point degos disease is characterized by unusual chronic thrombo-obliterative vasculopathy that affects small vessels. the histopathology of degos disease is inconsistent, so dermoscopy may be helpful in making  a  definite  diagnosis. the dermoscopic character of degos disease is a homogeneous yellow-white structureless area in the center, surrounded by a circular hairpin-like small vessel [1,2]. apart from the features mentioned previously, we noticed a particular bicentric structure, which is related to avascular  necrosis caused by thrombosis. references 1. darwich e, guilabert a, mascaró jm jr, et al. dermoscopic description of a patient with thrombocythemia and factor v leiden mutation-associated degos’ disease. int j dermatol. 2011;50(5):604-6. doi: 10.1111/j.1365-4632.2010.04539.x. pmid: 21506980. 2. anker jp, kaminska-winciorek g, lallas a, et al. the dermoscopic variability of degos disease at different stages of progression. dermatol pract concept. 2014;4(3):59-61. doi: 10.5826/ dpc.0403a11. pmid: 25126461. pmcid: pmc4132001. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022117 1 application of an interactive diagnosis ranking algorithm in a simulated vignette-based environment for general dermatology antonia wesinger1, elisabeth riedl1, harald kittler1, philipp tschandl1 1 department of dermatology, medical university of vienna, vienna, austria key words: logic, diagnosis, algorithm, ranking, human-computer interaction citation: wesinger a, riedl e, kittler h, tschandl p. application of an interactive diagnosis ranking algorithm in a simulated vignette-based environment for general dermatology. dermatol pract concept. 2022;12(3):e2022117. doi: https://doi.org/10.5826/dpc.1203a117 accepted: november 24, 2021; published: july 2022 copyright: ©2022 wesinger et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this research was supported by a grant of the austrian research promotion agency (ffg = forschungsförderungsgesellschaft). the investigation is part of the ffg-project: “a novel decision support tool for training and diagnosis in dermatology” (project number: 840281). the development of the cdra was realized by the medical university of vienna, and its project partners, the vienna university of technology and emergentec biodevelopment gmbh. competing interests: pt reports fees from silverchair, grants from metaoptima technology inc. and lilly, and speaker honoraria from lilly, fotofinder and novartis, all outside the submitted work. er is currently an employee and minor stockholder of eli lilly and company. hk reports royalties or licenses from casio, barco and metaoptima, speaker honoraria from fotofinder, and receipt of equipment for testing from fotofinder, 3gen, dermamedicalsystems, heine and casio; all outside the submitted work. authorship: all authors have contributed significantly to this publication. corresponding author: philipp tschandl, md, phd, department of dermatology medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria e-mail: philipp.tschandl@meduniwien.ac.at dermatology practical & conceptual introduction: diagnostic algorithms may reduce noise and bias and improve interrater agreement of clinical decisions. in a practical sense, algorithms may serve as alternatives to specialist consultations or decision support in store-and-forward tele-dermatology. it is, however, unknown how dermatologists interact with algorithms based on questionnaires. objectives: to evaluate the performance of a questionnaire-based diagnostic algorithm when applied by users with different expertise. methods: we created 58 virtual test cases covering common dermatologic diseases and asked five raters with different expertise to complete a predefined clinical questionnaire, which served as input for a disease ranking algorithm. we compared the ranks of the correct diagnosis between users, analyzed the similarity between inputs of different users, and explored the impact of different parts of the questionnaire on the final ranking. results: when applied by a board-certified dermatologist, the algorithm top-ranked the correct diagnosis in the majority of cases (median rank 1; interquartile range: 1.0; mean reciprocal rank 0.757). the median rank of the correct diagnosis was significantly lower when the algorithm was applied by four dermatology residents (median rank 2-5, p < 0.01). the lowest similarity between inputs of the residents and the board-certified dermatologist was found for questions regarding morphology. sensitivity analysis showed the highest deterioration in performance after omission of information on morphology and anatomic site. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022117 introduction skin diseases have a profound impact on public health as they are estimated to account for a large fraction of all primary care visits [1,2]. skin diseases are the fourth most common form of illness and affect almost one-third of the world population at any time [3,4]. furthermore, because of the rising incidence of skin cancer in most countries, accurate diagnosis and treatment of cutaneous neoplasms are required to maintain a high standard of care in the future. recent developments in the field of artificial intelligence (ai) propelled machine learning algorithms in the center of image-based diagnostic dermatology [5,6], but this development was also the target of substantial critique [7-9]. the main points of critique include lack of robustness and interpretability of current machine learning algorithms as well as failure to include relevant diagnostic information beyond what is captured in images. a more complete view of the patient including contextual information may lead to better and more robust diagnoses for neoplastic and inflammatory diseases [10,11]. attempts to incorporate multimodal information in machine learning models for automated diagnosis are emerging slowly [12-17]. only a few digital tools employ a bottom-up approach starting with the description of the appearance and distribution of primary lesions and additional symptoms [18,19]. objectives we recently described an interactive diagnosis ranking algorithm based on high-level, symbolic representations of structured descriptions of dermatologic conditions by human readers [20]. herein, we want to assess this algorithm in a vignette-based study simulating a potential application in tele-dermatology decision support. the major goals of this pilot study were to assess the baseline performance of such an algorithm and to explore typical problems of human-computer interaction. methods a reasoning based clinical diagnosis-ranking algorithm (cdra) was used as an example for an interactive diagnostic system based on high-level, human readable, symbolic logic [20]. five physicians with varying experience in clinical dermatology independently rated 58 consecutive patient vignettes (virtual test cases). the raters input consisted of structured descriptions of the dermatologic conditions presented in the vignettes. the  descriptions were entered into the software via a simple multiple-choice questionnaire, resulting in ranked lists of differential diagnoses. clinical diagnostic ranking algorithm the cdra uses a custom dermatological knowledge database, containing 620 different dermatologic diagnoses at the time of conducting the study, as described recently [20]. briefly, it provides probability-ranked differential diagnoses through a reasoning component, based on computational logic. the user interface in this study was a simple questionnaire that allowed users to enter the following information: 1) basic epidemiologic information (patient sex, age, skin type, number of lesions); 2) arrangement of lesion(s) (information regarding multiplicity, distribution and arrangement of the lesions); 3) localization of lesion/s in anatomic areas (including special sites such as sun-exposed areas); 4) morphology of lesion(s); 5) color of lesions; 6) timing and onset of the disease; 7) additional non-cutaneous signs and symptoms. the participants did not receive any additional information or exemplar cases of primary lesions. after completing the input, the algorithm creates a ranked list of all 620 diagnoses in the background. the software generates up to 8 “top-ranked” diagnoses and an arbitrary number of “excluded diagnosis”. no correction of data entry after the first submission was permitted or possible, and users did not see ranked lists at any point. rater characteristics and training four dermatologists-in-training and 1 board-certified dermatologist from a single center served as independent raters (supplementary table 1). dermatologists in-training were ranked by post-graduate years (pgy-1 to pgy-4). before entering any study-specific information, all raters were trained on the technical data entry process of the software. raters received individual user access for the software and a pdf-file containing all virtual patients in random order. every rater had a separate computer workstation and no time constraints for entering the information into the cdra. conclusions: a simple questionnaire-based disease ranking algorithm provides accurate ranking for a wide variety of dermatologic conditions. when applied in clinical practice, additional measures may be needed to ensure robustness of data entry for inexperienced users. original article | dermatol pract concept. 2022;12(3):e2022117 3 vignettes the convenience sample was collected from educational material of the medical university of vienna, and contained 58 virtual patient cases including common dermatologic diseases but also more rare conditions, if they seemed relevant for a primary care setting. fitzpatrick skin types, as assessed by a single author based on digital images, were 93.1% i-ii (n = 54), 5.2% iii-iv (n = 3), and 1.7% v-vi (n = 1). a complete list of diagnoses alongside basic patient information is shown in supplementary table 2. vignettes included a brief medical history covering only the main points, and between one and four representative clinical images involving overviews of different body parts and, if necessary, close-up images of individual skin lesions. the views were selected to allow evaluation of morphologic features of the primary lesions as well as their distribution, arrangement and color. the 58 vignettes covered a range of different disease categories including allergic, autoimmune, benign neoplastic, exogenous, hereditary, infections, inflammatory, malignant neoplastic, and other diseases like melasma or amyloidosis). of the 58 vignettes, 31 contained information about non-cutaneous signs and symptoms. statistical analysis a single correct diagnosis served as the ground truth for each vignette. we used the median correct ranking position and the mean reciprocal rank (mrr) to estimate the ranking ability of the algorithm. the reciprocal rank is defined as 1/k, where k is the rank position of the correct diagnosis as predicted by the cdra. the mrr is the mean across all cases. we calculated the sørensen-dice-coefficient (dice) to measure the similarity between descriptions. paired comparisons of rank positions were performed with the wilcoxon signed-rank test. confidence intervals (ci) and interquartile range (iqr) are reported where applicable. we used r statistics (version 4.1.0) for all statistical analyses and applied a bonferroni-holm correction to all p-values [21,22]. a twosided p value < 0.05 indicates statistical significance. plots were created using ggplot2 [23]. results fifty-eight vignettes described by five raters, with one entry of rater pgy-2 missing through a technical error, resulted in 289 probability-ranked diagnosis lists. for all raters, the correct diagnosis was top-1 ranked in most vignettes (figure 1). while most rankings following inputs of more experienced users fell into the top-8 ranks, inputs by younger participants (pgy-1 & pgy-2) frequently resulted in a very low ranking of the correct diagnosis (> 128; figure 1). the mean reciprocal rank of the algorithm was 0.757 when applied by the board-certified dermatologist, and significantly lower when applied by residents (table 1). the highest mrr was measured for benign (0.68; 95% ci: 0.35-1.01) and inflammatory (0.68, 95% ci: 0.46-0.90), the lowest for autoimmune (0.39; 95% ci: 0.020.76) and exogenous (0.43; 95% ci: 0.30-0.56) diseases. similarity of data entry the vignettes’ descriptions of the four residents were compared with those of the board-certified dermatologist for similarity. the median dice-score ranged from 0.64 (95% ci: 0.60-0.67; pgy-2) to 0.74 (95% ci: 0.71-0.77; pgy-3; suppl. figure 1). furthermore, we analyzed the similarities table 1. performance of the cdra with different users. mrr: mean reciprocal rank. p-value denotes paired wilcoxon signed-rank test, comparing the diagnosis ranks of a dermatology resident to those of a board-certified dermatologist (reference). rater median rank position of the correct diagnosis mrr p pgy-1 2.00 (iqr: 21.50) 0.514 < 0.001 pgy-2 5.00 (iqr: 239.00) 0.355 < 0.001 pgy-3 2.00 (iqr: 2.75) 0.597 0.003 pgy-4 2.00 (iqr: 4.00) 0.557 0.003 board-certified 1.00 (iqr: 1.00) 0.757 reference iqr = interquartile range; pgy = post-graduate year of dermatology residency. table 2. similarity of descriptions of residents compared to the corresponding descriptions of a board-certified dermatologist according to subsections. results are pooled over all users and cases, lowest values are highlighted in bold. questionnaire section dice (mean) arrangement 0.75 (95% ci: 0.72-0.79) color 0.75 (95% ci: 0.71-0.79) epidemiology 0.96 (95% ci: 0.94-0.97) localization 0.72 (95% ci: 0.69-0.75) morphology 0.57 (95% ci: 0.54-0.60) signs and symptoms 0.85 (95% ci: 0.81-0.89) time 0.62 (95% ci: 0.58-0.65) ci = confidence interval 4 original article | dermatol pract concept. 2022;12(3):e2022117 30 p g y -1 p g y -2 p g y -3 p g y -4 b o a r d -c er tified 20 10 0 20 15 10 5 0 30 20 n u m b er o f c a se s 10 0 30 20 10 0 40 30 20 10 0 1 top predicted rank of the correct diagnosis less probable excluded 2 4 8 16 32 64 123 256 512 figure 1. histogram of ranking positions of the correct diagnosis. black color denotes the categorization as a highly relevant differential diagnosis, the brightest gray as “excluded”. between the pooled ratings of the residents and the board-certified dermatologist for different subsections of the questionnaire. inputs for the sections “epidemiology” and “signs & symptoms” obtained the highest average similarity between residents and the board-certified dermatologist (dice 0.96, [95% ci: 0.94-0.97] and 0.85 [95% ci: 0.81-0.89], respectively). we observed the lowest dice scores for descriptions of morphology, arrangement and time (table 2). similarity of inputs regarding morphology and time descriptions for primary lesions (“elevation”, “plane”, “even”) and surface changes (“crust”, “erosion”) were used consistently, whereas descriptions of consistency (“firm”, “soft”, “indurated”) were more ambiguous (supplementary figure 2a). regarding the section of time and disease course (suppl. figure 2 b), the terms “recurrent” and “progressive” were used consistently, while the similarity of inputs for the terms “limited”, “self-limited”, and “transient” was rather low. influence of users input on performance of the algorithm complete omission of subsections of the questionnaire deteriorated ranking results. the decrease in performance was most pronounced for the subsections on anatomic site and morphology (figure 3; supplementary table 3). in a small pgy.4 a ll er g ic a u to im m u n e b en ig n ex o g en o u s h er ed it a r y in fe c ti o n s in fl a m m a to r y m a li g n a n t o th er epidemiology arrangement localization similarity dice 1.00 0.75 0.50 0.25 0.00 morphology color time signs and symptoms cases pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 pgy.4 pgy.3 pgy.2 pgy.1 figure 2. similarity of descriptions of residents with the corresponding descriptions of a board-certified dermatologist according to subsections. columns denote a single case, column groups denote grouping of cases to a diagnostic category. row groups denote description groups within the data entry form. original article | dermatol pract concept. 2022;12(3):e2022117 5 for primary care and in the setting of store-and-forward tele-dermatology [18,25]. we further demonstrate that human understandable symbolic ai fed by human inputs could be a worthwhile alternative to deep learning algorithms for image based diagnostic dermatology. in contrast to deep learning, the rules of symbolic ai are derived from expert knowledge, which facilitates explainability. aside from that, the rules can be easily adjusted, if errors occur. the disadvantage of this approach, however, is the reproducibility of human inputs. to better pin down potential sources of noise and bias introduced by user inputs, we studied the impact of user expertise on ranking and the similarity of user inputs for corresponding cases. finally, we also performed a sensitivity analysis to test the robustness of rankings if parts of the clinical description are either missing or misleading. in this respect, we found that the algorithm is most vulnerable to omissions of sections regarding morphology and localization. we further found that the rank of the correct diagnosis significantly decreased if less experienced users were responsible for the input. in some cases, the correct diagnosis was subgroup of vignettes, omission of inputs on morphology and color from novices improved the rankings. conclusions in this pilot study we conducted an experimental validation of a simple diagnosis ranking algorithm based on comprehensive and structured clinical descriptions provided by physicians. if applied by an experienced user, the algorithm top-ranked the correct diagnosis in the majority of cases. the median rank of the correct diagnosis was not below the fifth position even for the least experienced participant (figure 1). this means that in a typical use case the correct diagnosis will be included in the first eight ranked diagnoses. the measured accuracy of our approach outperformed similar algorithms in general medicine, in which the top-5 results included the correct diagnosis in about 50% of cases [24]. our results are in line with other promising reports of clinical decision support systems for dermatology and provide further evidence that a logic-based, interactive diagnosis ranking algorithm may be a useful tool in clinical practice, especially 512 novices (pgy1 pgy2) experienced (pgy3 board certified) 256 128 64 32 16 8 4 2 c h a n g e o f r a n k in g (c o r r ec t d ia g n o si s) 0 -2 -4 -8 -16 -32 -64 -128 ep id em io lo gy ar ra ng em en t lo ca li za ti on m or ph ol og y co lo r ti m e si gn s s ym pt om s ep id em io lo gy omitted questionnaire section ar ra ng em en t lo ca li za ti on m or ph ol og y co lo r ti m e si gn s s ym pt om s figure 3. rank changes after omission of specific subsections of the questionnaire. participants were grouped according to experience into novices (left panel; pgy-1 and pgy-2) and experienced users (right panel; pgy-3, pgy-4 and board-certified dermatologist). dots denote change of rank of the correct diagnosis for one query of one user, boxplots denote median and iqr. the green area highlights changes to a better position, the red area to a worse position. iqr = interquartile range; pgy = post-graduate year of dermatology residency. 6 original article | dermatol pract concept. 2022;12(3):e2022117 even excluded (figure 1). as the cdra is structured in sections simulating a bottom-up dermatologic work-up starting with descriptions of primary lesions, we were able to decipher the reasons for these errors in most cases. considering the inputs of the board-certified dermatologist as the reference standard, the residents’ descriptions were most similar to the reference standard for questions regarding epidemiology, age group, skin type, and additional symptoms (figure 2). not unexpectedly, the most ambiguous parts of the questionnaire were the subsections covering morphology and timing. haptic elements such as induration were used inconsistently, which can be easily explained by the virtual setting which makes palpation impossible (supplementary figure 2a). follow-up studies with live patients will be necessary to determine whether such elements should be entirely removed from the algorithm or omitted only in image-based case presentations. analysis of user inputs referring to timing demonstrated that terms describing the course of the disease (“recurrent”, “progressive”, “chronic”; supplementary figure 2b) were used rather consistently, but not terms related to resolution (“transient duration”, “self-limited”, “limited”). the explanation may be that experienced users will already know the correct diagnosis and may fabricate a description that is in line with the correct diagnosis, even if the information given in the vignette or by the patient is ambiguous. this points to a limitation of our study since we did not compare diagnostic rankings of users with and without support by the algorithm. the aims of this pilot study, however, were to investigate whether the algorithm is principally feasible for clinical use and to improve the logic of the algorithm and the composition of the questionnaire upon the results of this small-scale experiment, if necessary. our results show that the performance of the algorithm will depend on the quality of user inputs. to improve the evolution of this and similar algorithms, developers need to focus not only on machine learning issues but also on the user interface and how to minimize noise and bias. the results of our study indicate that it is crucial to select variables that are equally robust and relevant. the number of variables and the time spent for data input will significantly impact the user friendliness of the interface. poor user friendliness and time efficacy constitute important barriers for deploying such systems in primary care [26]. furthermore, we learnt from this pilot study that the number of variables and the granularity of descriptions were probably too high, which had the adverse effect of increasing noise while decreasing accuracy. this was a small-scale pilot study using a convenience sample and vignettes instead of live consecutive patients. the study included only dermatologists, either board-certified dermatologists or dermatology residents, and did not include main target users such as primary care physicians or nurses. because of the small number of raters included, especially quantitative findings should be verified in larger follow-up studies. as baseline accuracy of raters was not measured, applicability and added value in a clinical setting could not be estimated. the range of skin types of patients in the vignettes was biased towards lighter skin and skin of color was underrepresented, which may limit the generalizability of our findings [27]. in conclusion, we demonstrated that our previously described clinical diagnosis ranking algorithm performed well across a wide range of dermatologic. in our small rater group, we found inconsistent input from inexperienced users, who are an important target population of this algorithm, introduced noise and bias and decreased its performance. acknowledgements we want to thank the residents that participated in this study, arno lukas from emergentec biodevelopment gmbh for the help in creating the initial graphical user interface of the algorithm, and gernot salzer as well as rodriguez dominguez rosa maría for the algorithm testing tool. ethics approval the study was reviewed and approved by the institutional review board of the medical university of vienna, austria (protocol-no: 1758/2013), and conducted in accordance with the helsinki declaration of 1975, as revised in 1983. patient consent not required. references 1. lowell ba, froelich cw, federman dg, kirsner rs. dermatology in primary care: prevalence and patient disposition. j am acad dermatol. 2001;45(2):250-255. doi: 10.1067/ mjd.2001.114598. pmid: 11464187. 2. verhoeven ewm, kraaimaat fw, van de kerkhof pcm, et al. prevalence of physical symptoms of itch, pain and fatigue in patients with skin diseases in general practice. british journal of dermatology. 2007;156(6):1346-1349. doi:10.1111/j.13652133.2007.07916.x. pmid: 17535233. 3. hay rj, johns ne, williams hc, et al. the global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. j invest dermatol. 2014;134(6):1527-1534. doi: 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pmcid: pmc7745523. 26. burke md, savard lb, rubin as, littenberg b. barriers and facilitators to use of a clinical evidence technology in the management of skin problems in primary care: insights from mixed methods. j med libr assoc. 2020;108(3):428-439. doi: 10.5195/ jmla.2020.787. pmid: 32843874. pmcid: pmc7441913. 27. groh m, harris c, soenksen l, et al. evaluating deep neural networks trained on clinical images in dermatology with the fitzpatrick 17k dataset. in: proceedings of the ieee/cvf conference on computer vision and pattern recognition. 2021;1820-1828. doi: 10.48550/arxiv.2104.09957. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e202308 1 mortality of malignant melanoma in central serbia, in the period 1999-2015 milica pantovic1, ognjen djordjevic2, svetlana radevic3, dragic bankovic4, katarina parezanovic ilic5, snezana radovanovic3 1 clinical hospital center zemun, belgrade, serbia 2 department of hygiene and ecology, faculty of medical sciences, university of kragujevac, kragujevac, serbia 3 department of social medicine, faculty of medical sciences, university of kragujevac, kragujevac, serbia 4 faculty of science, university of kragujevac, kragujevac, serbia 5 university of kragujevac, serbia, faculty of medical sciences, department of physical medicine and rehabilitation key words: malignant melanoma, mortality, risk factors, serbia citation: pantovic m, djordjevic o, radevic s, bankovic d, parezanovic ilic k, radovanovic s. mortality of malignant melanoma in central serbia, in the period 1999-2015. dermatol pract concept. 2023;13(1):e202308. doi: https://doi.org/10.5826/dpc.1301a8 accepted: june 20, 2022; published: january 2023 copyright: ©2023 pantovic et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: svetlana radevic, phd, department of social medicine, faculty of medical sciences university of kragujevac, svetozara markovica 69, 34000 kragujevac, serbia. tel: +381 34 306 800 ext 217 fax: + 381 34 306 800 e-mail: cecaradevic@yahoo.com introduction: malignant melanoma is one of the rarest forms of skin cancer but it is the most deadly. objective: the objective of this paper was to analyze the epidemiological characteristics and trends of mortality from malignant melanoma in the population of central serbia in the period 1999-2015. methods: the study was designed as a retrospective descriptive epidemiological study. standardized mortality rates were used in statistical data processing. a linear trend model and regression analysis were used to examine trends in malignant melanoma mortality. results: in serbia, malignant melanoma mortality shows an increasing trend. the overall age-adjusted melanoma death rate was 2.6 per 100,000 with a higher death rate among men (3.03 per 100,000) than among women (2.1 per 100,000). malignant melanoma mortality rates increase with age in both sexes and are highest in the age group of 75 and older. the highest increase in mortality in men is recorded in the 65-69 age group, with an average percentage increase of 21.33 (95% ci, 8.40 51.05), while in women the largest increase in mortality was recorded in the 35-39 age group, with an average percentage increase of 31.4 and in the 70-74 age group, 12.9. conclusions: the trend of increasing mortality from malignant melanoma in serbia is similar to those in most developed countries. education and improvement of awareness in the general population and among health professionals are vital to reducing melanoma mortality in the future. abstract 2 original article | dermatol pract concept. 2023;13(1):e202308 introduction malignant melanoma accounts for 4% of all skin cancers and 1,7% of all cancers [1]. although it still accounts for less than 5% of all skin malignancies, melanoma causes about 80% of skin cancer deaths [2]. the incidence of cutaneous melanoma has increased sharply in recent years in all parts of the world, with a steady increase in incidence among the white population, while the mortality associated with it remains stable [3-5]. it should also be noted that the incidence of melanoma has increased due to better education and improvement of awareness among patients and due to the development of dermatoscopy [6]. according to globocan data from 2018, the total number of deaths from malignant melanoma in the world was 60,712, which ranks it 22nd in the structure of mortality from malignant tumors of all localizations [7]. mortality rates in different populations of the world multiple vary depending on the level of development, so mortality is almost 5 times higher in developed countries than in developing countries [8,9]. worldwide, the highest mortality rates are registered in regions such as north america, northern europe, australia and new zealand, while lower rates are commonly found in south american and african countries. for 2018, global data on skin melanoma revealed age-standardized mortality rates of approximately 0.63 deaths per 100,000 inhabitants (0.78 deaths per 100,000 inhabitants for men and 0.50 for women) [7]. epidemiological studies show that melanoma is more common in older adults than in younger people and is more common in men than in women, but the ratio of these rates between the sexes varies with age [10, 11]. for example, the incidence rate is three times higher in men aged 80 and older than in women of the same age [12]. although the incidence of melanoma is lower in people under the age of 40, it is one of the most common cancers diagnosed among adolescents and young adults [13]. although the etiology of melanoma has not been fully elucidated, the findings of studies indicate the importance of the interaction between genetic, biological, and environmental factors.  several meta-analyses have identified key risk factors such as: family history of melanoma, age, history of sunburn and exposure to ultraviolet (uv) radiation, fair-skinned people, increased number of nevi, dysplastic nevi, genetic factors (cdkn2a, cdk4, mc1r genes, tyrp1) [14,15]. the most important and potentially modifying environmental risk factor for the development of malignant melanoma is exposure to ultraviolet (uv) rays due to their genotoxic effects [10,16,17]. according to the latest iarc estimations (2018), the estimated mortality rate in serbia is 2.5 / 100,000 inhabitants [18].  compared to other countries, although serbia has lower mortality rates than the highest estimated in the world, it is in the group of countries with a higher risk of disease. unless additional efforts in prevention are made, the number of melanoma cases is projected to increase in serbia over the next 15 years, with a concomitant increase in healthcare costs. the aim of the research is to analyze the epidemiological characteristics and trends of mortality from malignant melanoma in the population of central serbia in the period 1999-2015. materials and methods the study was designed as a retrospective descriptive epidemiological study. the research used data from the cancer registry of central serbia, formed on the basis of reports of malignant diseases for the period 1999-2015. the population register for cancer was established in serbia in 1970 and since 1998, the cancer registry of central serbia has been admitted to the international (iacr) and european association of cancer registries (encr). in the registers, due to numerous data sources and the need for their verification and analysis, the usual time period for data collection is two years, after which the report is published, which is the reason why the last published data from 2015 will be used. standardized mortality rates were used in statistical data processing. mortality rates were calculated based on data on deaths from malignant melanoma in the cancer registry of central serbia.  all reported melanoma deaths were coded according to the international classification of disease, 10th revision (code s43.0).  the cases were grouped by gender into 5-year age groups. the size and composition of the population by age and sex were obtained by the 1991, 2002, and 2011 censuses. the population of central serbia by age and sex in the years between the censuses were estimated based on natural increase and migration. age-adjusted mortality rates were calculated by direct standardization, using the world’s population and presented per 100,000 inhabitants. a linear trend model and regression analysis were used to examine trends in malignant melanoma mortality. the percentage of the change in the mortality rate was calculated as the percentage of the difference between the adjusted rates for two consecutive years, and then as the average value of these changes over the entire observation period. confidence intervals (ci) for average age-adjusted and age-specific mortality rates were estimated with 95% probability.  bilateral p values have been reported and are considered to show statistical significance if they are lesser than 0.05. data were processed using the statistical package for social sciences, version 19.0 (spss inc, chicago, il, usa). original article | dermatol pract concept. 2023;13(1):e202308 3 results in 2015, a total of 195 melanoma deaths occurred in central serbia, which constitutes 1.3% of the total number of cancer deaths and ranks 17th in the structure of cancer mortality of all localizations.  during the 17-year observation period, there was a significant decrease in the total mortality of the population (y = -8,7001x + 582.67; p = 0.001; % change = 8.83) (figure 1), with a significant increase in mortality from all malignant tumors in total (y = 0.6343x + 115.13; p = 0.004; % change = + 0.27) and in both sexes (figure 2). in the same period, mortality from malignant melanoma recorded an increasing trend (y = 0.0194x + 1.3682; p = 0.009; % change = + 1.94). observed by gender, there is a significant trend of increasing mortality in men (y = 0.0486x + 1.5494; p = 0.036; % change = + 6.26), while in women there is a trend of declining mortality from malignant melanoma (y = -0, 0124x + 1.3282; p = 0.088; % change = + 0.43. (figure 3). the overall age-adjusted melanoma death rate was 2.6 per 100,000 with a higher death rate among men (3.03 per 100,000) than among women (2.1 per 100,000). malignant melanoma mortality rates increase with age in both sexes and are highest in the age group of 75 and older (10.15 per 100,000 for men; 8.32 per 100,000 for women) (table 1). low mortality rates have been reported in men and women under the age of 30. the largest increase in mortality in men was recorded in the 65-69 age group, with an average percentage increase of 21.33 (95% ci, 8.40 51.05), while in women the largest increase in mortality was recorded in the 35-39 age group, an average percentage increase of 31.4 (95% ci, 23.10 85.91) and in the 70-74 age group, 12.9 (95% ci, 14.41 40.14). discussion mortality from malignant melanoma in serbia records an upward trend and mortality rates for malignant melanoma in serbia remain among the highest in the world. similar trends are being observed around the world despite numerous efforts to improve primary prevention and early detection, and these increasing rates are affecting public health and the economic burden of the disease [11, 19]. melanoma mortality rates have increased marginally among fair-skinned populations.  mortality rates are highest in australia and new zealand (3.4 per 100,000) and northern europe (2.0 per 100,000), while the lowest rates are recorded in south central asia and eastern asia (0.19) [7]. trends in melanoma mortality are variable and are affected by latitude, ethnicity, age, and gender [20-22]. in high-risk regions, the mortality rate increased historically until the 1980s, peaking between 1988 and 1990, and then gradually maintained a slow increase. over the last decade, the death rate has been growing steadily by 1.5% in the most of observed countries, such as new zealand and australia [10]. mortality rates in northern european countries (norway, sweden, netherlands) are among the highest in the world.  thus, according to the latest data from globocan, in norway in 2018, the total number of deaths from malignant melanoma was 13.2% of cancer of all localizations, which ranks it 7th in the structure of cancer mortality of all localizations. for the same period, in sweden, the number of deaths from malignant melanoma accounted for 2.4% of cancer deaths of all localizations, which ranks it 12th, the standardized mortality rate is 2.5 per 100,000 inhabitants. the total number of deaths from malignant melanoma in the netherlands in 2018 presents 2.0%, of deaths from cancer of all localizations, which ranks it 17th in the structure of cancer mortality of all localizations [7]. differences in skin type, length, and sun exposure patterns may partly explain the lowest mortality rates recorded in some middle eastern countries (qatar 0.04 per 100,000 inhabitants, saudi arabia 0.10 per 100,000 inhabitants, and yemen 0.11 per 100,000 inhabitants), africa (egypt 0.13 per 100,000 inhabitants; libya 0.14 per 100,000 inhabitants); asian countries (india 0.16 per 100,000 inhabitants, china 0.18 per 100,000 inhabitants and vietnam 0.08 per 100,000 inhabitants), some central american countries (barbados 0.0 per 100,000 inhabitants and haiti 0.16 per 100,000 inhabitants) and europe (albania 0.53 per 100,000 inhabitants; montenegro 0.89 per 100,000 inhabitants) [18]. the results of our study showed that mortality from malignant melanoma is higher in men than in women, which is in line with most published studies [11, 23]. the average standardized mortality rate for men in the world was 0.78 per 100,000 in 2018, and 0.50 per 100,000 for women in 2018. in terms of the global distribution of malignant melanoma, the standardized malignant melanoma mortality rate expressed on 100,000 inhabitants is higher for men than for women in all regions of the world: australia and new zealand (men 5.9; women 2.4); northern europe (men 2.5; women 1.6), north america (men 2.6; women 1.2), western europe (men 2; women 1.3). less significant differences in mortality rates are present in less developed regions of the caribbean (men 0.3, women 0.2), west africa (men 0.5; women 0.3); east asia (men 0.4; women 0.3); southeast asia (men 0.3; women 0.2); north africa (men 0.2; women 0.2), central asia (men 0.2; women 0.1) [7]. in europe, the standardized mortality rate of malignant melanoma for men is 3.2 per 100,000, and for women 1.9 per 100,000, with differences varying between regions of europe: western europe (3.3 men and 1.9 women) in central and eastern europe (3.0 and 2.0) in northern europe 4 original article | dermatol pract concept. 2023;13(1):e202308 poland (4.0 and 2.4 per 100,000 inhabitants), slovakia (4.8 and 3.2 per 100,000 inhabitants), finland (4.4 and 1.7  per 100,000 inhabitants), norway (6.3 and 4.1 per 100,000 inhabitants) and the netherlands (4.6 and 3.1 per 100,000 inhabitants) [24]. men are approximately 1.5 times more likely to develop melanoma than women. the incidence of melanoma is higher in women than in men until they reach the age of 40, however, from the age of 75, the incidence is almost three times higher in men than in women [25]. mortality from (3.8 and 2.2) in southern europe (2.7 and 1.6).  the estimated standardized mortality rate for malignant melanoma for men and women in 2018 in europe is the lowest in albania (0.8 and 0.6 per 100,000 inhabitants), montenegro (1.2 and 1.3 per 100,000 inhabitants), romania (1.9 and 1.4 per 100,000 inhabitants), spain (1.9 and 1.3 per 100,000 inhabitants). on the other hand, the highest values for men and women are in croatia (4.6 and 2.5 per 100,000 inhabitants), north macedonia (4.0 and 2.2 per 100,000 inhabitants), slovenia (4.8 and 3, 2 per 100,000 inhabitants), table 1. the average age-specific mortality rates and linear trend of melanoma malignum in central serbia, in 1999–2015. age (years) age-specific rates* (per 100,000) linear trend r2 p average annual percentage change (95% ci) male † 0-4 0.00 † 5-9 0.00 † 10-14 0.00 † 15-19 0.00 † 20-24 0.27 † 25-29 0.42 † 30-34 1.07 † 35-39 1.69 † 40-44 2.03 † 45-49 3.33 † 50-54 4.95 † 55-59 7.99 † 60-64 4.15 y = 5,26 + 0.21·x 0.274 0.031 7,93 (-9.16 – 24.97) 65-69 4.85 y = 5.87 + 0.46·x 0.321 0.018 21.33 (-8,40 – 51,05) 70-74 7.68 y = -6.23 +0.56·x 0.620 < 0.0005 10.84 (-8.73 – 30.41) 75+ 10.15 y = 7.16 + 0.83·x 0.669 < 0.0005 10,96 (-9.59 – 31.51) female 0-4 0.00 † 5-9 0.00 † 10-14 0.00 † 15-19 0.00 † 20-24 0.16 † 25-29 0.42 † 30-34 0.88 † 35-39 1.48 y = 2.28 0.10·x 0.273 0.032 31.41 (-23,10 – 85.91) 40-44 1.80 † 45-49 2.34 † 50-54 2.82 † 55-59 3.56 † 60-64 3.45 † 65-69 3.42 70-74 5.42 y = 2.90 + 0.32·x 0.430 0.004 12.86 (-14.41 – 40.14) 75+ 8.32 † original article | dermatol pract concept. 2023;13(1):e202308 5 when age is taken into account, adolescents and young adult women are more susceptible to melanoma than men [20]. this could be partly due to the widespread use of tanning beds among women, which is associated with an increased risk of melanoma [11]. however, after the age of 40, the incidence rate of melanoma among men is higher than among women [25]. some believe that this increased sensitivity in men may be partly influenced by androgens [26]. malignant melanoma begins to rise sharply in men aged 4044 and is especially high in those over 60 years of age. in women, a sharp increase was also observed at the age of 40-44, while the rate is especially high between the ages of 55 and 59. in some countries, the increase in the standardized mortality rate for those over the age of 85 is twenty times higher than for those at the age of 40-44 (australia 42.65 per 100,000 and 2.62 per 100,000) [18]. y = -8.7001x + 582.67; р=0.001; % change =8.83 y = 0.6341x + 115.13; p=0.004; %change=+0.27 y = 0.0194x + 1.3682; p=0.375; %change=+197 0 100 200 300 400 500 600 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 a g e st an d ar d iz ed ra te s (p er 1 00 .0 00 ) all causes all malignant tumors malignant melanoma figure 1. trends of age-adjusted mortality rates for all causes of death, all malignant tumors and malignant melanoma in central serbia in the period 1999-2015. y = 0.6342x + 115.13 p=0.004; % change=+0.27 y = 0.4255x+ 144.37; p=0,04; % change = +0.51 y = 0.2038x + 93.92; p=0.106; % change=+0.08 40 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 60 80 100 120 140 160 180 a g e st an d ar d iz ed ra te s (p er 1 00 .0 00 ) both males females figure 2. trends of age-adjusted mortality rates all malignant tumors in central serbia by sex, in the period 1999-2015. 6 original article | dermatol pract concept. 2023;13(1):e202308 many authors state that melanoma is more common in the elderly [30,31].  the results of our study also confirmed that age is a significant risk factor for malignant melanoma.  mortality rates are highest in people aged 75 and older in both sexes, with the highest percentage increase in mortality recorded in the 35-39 age group in women, and in the oldest age groups in men (65-69, 70-74, and 75 and older). similar to our results, a study conducted by karimkhani et al found that malignant melanoma mortality rates are highest in the 75-79, 70-74, and 80 and older age groups [30]. in america, the percentage share of individual age groups in the total number of deaths shows the highest percentage (23.9%) in the 75-84 age group [32]. older adults have more cumulative sun exposure than younger ones, and each additional decade of intense sun exposure increases the risk of melanoma [33,34]. the results of epidemiological research show that high sun exposure in the first 10 years of life more than doubles the risk of melanoma, while intense, occasional sun exposure during each decade until the age of 29 increases the risk of melanoma by more than 1.5 times [35]. more than five sunburns double the risk of melanoma for both those under 15 and those over 15 years of age.  however, other studies have found that the number of sunburns before the age of 30 significantly increased the risk of melanoma, and the positive connection with the risk of melanoma is weaker in burns that occurred in those older than 30 years [36]. higher survival rates in women are also attributed to biological differences such as oxidative stress response, sex hormones or vitamin d metabolism and other influencing factors that have yet to be explored [27]. speculation about the link between steroid hormones and melanoma arose when population studies found that women had a higher survival rate than men, which was evident between 1973 and 1997 when men had a death rate from melanoma that was twice as high as in women [28]. furthermore, the history of malignant melanoma in women is rare before puberty and then increases sharply during the reproductive period and decreases during the menopausal years, which implies the involvement of estrogen. this phenomenon has led to the suggestion that hormones play an important role in melanoma.  however, the results of epidemiological studies that assess the risk of melanoma in relation to hormonal and reproductive factors, such as the use of oral contraceptives, pregnancy and menopause, are contradictory; some studies did not show a causeand-effect relationship, while others found an increased risk of melanoma [26,29]. thus, the existence of a link between hormones and melanoma remains uncertain. other authors believe that these gender differences may be partly due to low rates of sun protection and more time spent outdoors during life compared to women. in addition, men are less likely to use sunscreen compared to women and are less aware of the importance of preventive measures, so melanoma is usually detected when the disease is present at an advanced stage, while women are more willing to seek medical help earlier and thus to detect changes in the earlier stage of the disease [5]. y = 0.0194x + 1.3682 ; p=0.009; % change=+1.94 y = 0.0486x + 1.5494 ; p=0.036; % change = +6.26 y = -0.0124x + 1.3282; p=0.088; % change=+0.43 0 0.5 1 1.5 2 2.5 3 3.5 19992000200120022003200420052006200720082009201020112012201320142015 a g e st an d ar d iz ed r at es (p er 1 00 .0 00 ) both males females figure 3. trends of age-adjusted malignant melanoma mortality rates in central serbia, by sex, in the period 1999-2015. original article | dermatol pract concept. 2023;13(1):e202308 7 7. globocan 2020. cancer incidence and mortality worldwide. accessed march 19, 2020. available from: http:// https://gco. iarc.fr/ 8. boyers ln, karimkhani c, naghavi m, et al. global mortality from conditions with skin manifestations. j am acad  dermatol. 2014; 2. pii: s0190-9622(14)01869-6. doi: https://doi. org/10.1016/j.jaad.2014.08.022 9. lin l, yan l, liu y, yuan f, li h, ni j. incidence and death in 29 cancer groups in 2017 and trend analysis from 1990 to 2017 from the global burden of disease study.  j hematol oncol. 2019;12(1):96. doi: 10.1186/s13045-019-0783-9 10. sneyd mj, cox b. a comparison of trends in melanoma mortality in new zealand and australia: the two countries with the highest melanoma incidence and mortality in the world.  bmc cancer. 2013;13:372. doi: 10.1186/1471-2407-13-372 11. ghazawi fm, le m, lagacé f, et al. incidence, mortality, and spatiotemporal distribution of cutaneous malignant melanoma cases across canada.  j cutan med surg. 2019;23(4):394-412. doi: 10.1177/1203475419852048 pmid: 31132871 12. jemal a, saraiya m, patel p, cherala ss, barnholtz-sloan j, kim j, et al. recent trends in cutaneous melanoma incidence and death rates in the united states, 1992-2006. j am acad dermatol. 2011; 65: e17. doi: 10.1016/j.jaad.2011.04.032 pmid: 22018063 13. iannacone mr, youlden dr, baade pd, aitken jf, green ac. melanoma incidence trends and survival in adolescents and young adults in queensland, australia.  int j cancer. 2015;136(3):603-609. doi: 10.1002/ijc.28956 pmid: 24806428 14. puig-butille ja, escámez mj, garcia-garcia f, et al. capturing the biological impact of cdkn2a and mc1r genes as an early predisposing event in melanoma and non melanoma skin cancer.  oncotarget. 2014;5(6):1439-1451. doi:10.18632/ oncotarget.1444 15. gandini s, sera f, cattaruzza ms, et al. meta-analysis of risk factors for cutaneous melanoma: iii. family history, actinic damage and phenotypic factors. eur j cancer. 2005;41(14):2040-2059. doi: 10.1016/j.ejca.2005.03.034 pmid: 16125929 16. leiter u, garbe c. epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight. adv exp med biol 2008;624:89103. doi: 10.1007/978-0-387-77574-6_8 pmid: 18348450 17. leiter u, eigentler t, garbe c. epidemiology of skin cancer. adv exp med biol. 2014;810:120-140. doi: 10.1007/978-1-49390437-2_7 pmid: 25207363 18. international agency for research on cancer. cancer mortality database. accessed march 9, 220. available from: https://wwwdep.iarc.fr/whodb/whodb.htm 19. whiteman dc, green ac, olsen cm. the growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. j investig dermatol.  2016;136(6):1161–71. doi:10.1016/j. jid.2016.01.035 pmid: 26902923 20. watson m, geller ac, tucker ma, guy gp jr, weinstock ma. melanoma burden and recent trends among non-hispanic whites aged 15–49 years, united states. prev med. 2016;91:294–8. doi: 10.1016/j.ypmed.2016.08.032 pmid: 27565055 21. garbe c, leiter u. melanoma epidemiology and trends. clin dermatol. 2009;27(1):3–9. doi: 10.1016/j.clindermatol.2008.09.001 pmid: 19095149 conclusion the trend of increasing mortality from malignant melanoma in serbia is similar to those in most developed countries. due to the high incidence of malignancies and their high mortality rates, the prevention of malignant diseases has a huge public health potential and represents the most effective approach to the control of malignant diseases. given the strong and continuous trend of demographic aging and the growing burden of the disease, it is estimated that a significant number of new cases of melanoma could be prevented by implementing effective prevention measures ranging from primary, targeted to reducing outdoor and indoor sunbathing exposure in order to reduce the exposure to ultraviolet (uv) radiation, to secondary methods of prevention such as whole-body visual examinations of the skin. education and improvement of awareness in the general population and among health professionals are vital to reducing melanoma mortality in the future. the results of this research can be used as a starting point in creating strategies at the community level, as well as for the development of prevention programs aimed at vulnerable and high-risk categories of the population such as children, adolescents and their parents, which would significantly reduce health care costs and total disease burden. references 1. globocan 2020. cancer incidence and mortality worldwide. accessed march 19, 2020. available from: http:// https://gco. iarc.fr/ 2. gutiérrez-gonzález e, lópez-abente g, aragonés n, et al. trends in mortality from cutaneous malignant melanoma in spain (1982-2016): sex-specific age-cohort-period effects. j eur acad dermatol venereol. 2019;33(8):1522-1528. doi: 10.1111/ jdv.15565 3. mckenna mr, stobaugh dj, deepak p. melanoma and non-melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-α inhibitor monotherapy and in combination with thiopurines: analysis of the food and drug administration adverse event reporting system. j gastrointestin liver dis. 2014;23:267-271. doi: 10.15403/ jgld.2014.1121.233.mrmk 4. nikolaou v, stratigos aj. emerging trends in the epidemiology of melanoma.  br j dermatol.  2014;170(1):11–19. doi: 10.1111/ bjd.12492 pmid: 23815297 5. guy gp jr, thomas cc, thompson t, watson m, massetti gm, richardson lc. vital signs: melanoma incidence and mortality trends and projections – united states, 1982–2030.  mmwr morb mortal wkly rep. 2015;64(21):591–6.) pmid: 26042651 6. kaminska-winciorek g, wydmanski j, gajda m, tukiendorf a. melanoma awareness and prevalence of dermoscopic examination among internet users: a cross-sectional survey. postepy dermatol alergol. 2016;33(6):421-428. doi:10.5114/ pdia.2016.63297 8 original article | dermatol pract concept. 2023;13(1):e202308 22. aitken jf, youlden dr, baade pd, soyer hp, green ac, smithers bm. generational shift in melanoma incidence and mortality in queensland, australia, 1995-2014. int j cancer. 2018;142(8):1528-1535. doi: 10.1002/ijc.31141 pmid: 29105744 23. khosrotehrani k, dasgupta p, byrom l, youlden dr, baade pd, green ac. melanoma survival is superior in females across all tumour stages but is influenced by age. arch dermatol res. 2015;307(8):731–40. doi:  10.1007/s40487-020-00109-1 pmid: 32700073 24. ferlay j, colombet m, soerjomataram i, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries and 25 major cancers in 2018. eur j cancer. 2018;103:356-387. doi: 10.1016/j.ejca.2018.07.005 pmid: 30100160 25. weir hk, marrett ld, cokkinides v, barnholtz-sloan j, patel p, tai e, et al. melanoma in adolescents and young adults (ages 15–39 years): united states, 1999–2006. j am acad dermatol. 2011;65(5) suppl 1:s38–49. doi: 10.1016/j.jaad.2011.04.038 pmid: 22018066 26. li wq, cho e, weinstock ma, mashfiq h, qureshi aa. epidemiological assessments of skin outcomes in the nurses’ health studies. am j public health. 2016;106(9):1677–83. doi: 10.2105/ajph.2016.303315 pmid: 27459457 27. erdei e, torres sm. a new understanding in the epidemiology of melanoma.  expert rev anticancer ther. 2010;10(11):18111823. doi: 10.1586/era.10.170 pmid: 21080806 28. schmidt a, nanney lb, boyd as, king le, ellis dl. oestrogen receptor-β expression in melanocytic lesions. exp dermatol. 2006;15:971–980. doi: 10.1111/j.1600-0625.2006.00502.x pmid: 17083364 29. koomen er, joosse a, herings, et al. estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case–control study. ann oncol. 2009;20(2):358–364. doi: 10.1093/annonc/ mdn589 pmid: 18725391 30. karimkhani c, green ac, nijsten t, et al. the global burden of melanoma: results from the global burden of disease study 2015. br j dermatol. 2017;177(1):134-140. doi: 10.1111/ bjd.15510 pmid: 28369739 31. lasithiotakis kg, petrakis ie, garbe c. cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. melanoma res. 2010;20(3):163-70. doi: 10.1097/ cmr.0b013e328335a8dd pmid: 20375923 32. national cancer institute surveillance, epidemiology, and end results program. cancer stat facts: melanoma of the skin. available from: https://seer.cancer.gov/statfacts/html/melan .html. 33. veierod mb, adami ho, lund e, armstrong bk, weiderpass e. sun and solarium exposure and melanoma risk: effects of age, pigmentary characteristics, and nevi. cancer epidemiol biomarkers prev. 2010;19(1):111-120. doi: 10.1158/1055-9965. epi-09-0567 pmid: 20056629 34. armstrong bk. how sun exposure causes skin cancer: an epidemiological perspective in: hill d, elwood jm, english d. prevention of skin cancer. dordrecht, the netherlands: kluwer academic publishers, 2004: 89-116. 35. kricker a, armstrong bk, goumas c, et al. ambient uv, personal sun exposure and risk of multiple primary melanomas. cancer causes control 2007;18(3):295-304. doi: 10.1007/ s10552-006-0091-x pmid: 17206532 36. pfahlberg a, kölmel kf, gefeller o; febim study group. timing of excessive ultraviolet radiation and melanoma: epidemiology does not support the existence of a critical period of high susceptibility to solar ultraviolet radiationinduced melanoma. br j dermatol. 2001;144(3):471-475. doi: 10.1046/j.13652133.2001.04070.x pmid: 11260001 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022052 1 dermoscopic findings of recurrent herpetic whitlow in a child ishan agrawal1, bhabani bhabani singh tarini prasad singh1, bikash ranjan kar1 1 department of dermatology, ims and sum hospital, siksha ‘o’ anusundhan university, bhubaneswar, india key words: dermoscopy, herpetic whitlow, viral infection, hsv, vesicular lesion. citation: agrawal i, singh bstp, kar br. dermoscopic findings of recurrent herpetic whitlow in a child. dermatol pract concept. 2022;12(2):e2022052. doi: https://doi.org/10.5826/dpc.1202a52 accepted: august 5, 2021; published: april 2022 copyright: ©2022 agrawal et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ishan agrawal, department of dermatology, ims and sum hospital, soa university, bhubaneswar, india – 751003. e-mail: ishanagrawal1995@gmail.com learning points 1. herpetic whitlow can have ambiguous presentation and is commonly misdiagnosed. 2. dermoscopic description of herpetic whitlow is characteristic and may help to avoid biopsy or serological test in children. 3. specific diagnosis is made by pcr, can be aided by cytology. introduction hsv-1 and 2 infections in children commonly present with fever and gingivostomatitis [1]. infection of the fingers and toes, due to autoinoculation from asymptomatic salivary carriers, is known as herpetic whitlow. classically, it presents as deep seated, tender, non-purulent, swollen, vesico-ulcerative lesions on the finger, usually preceded by a prodrome of numbness, tingling or itching of the affected site [1]. however, atypical presentations may be often misdiagnosed. timely diagnosis of the condition helps prevent secondary bacterial infection. we report this case to emphasize the dermoscopic features of herpetic whitlow which has never been previously reported. case presentation a 10-year-old girl presented with a 4 day history of redness, swelling and blistering of 2 fingers of the left hand. patient gave a history of similar episode 2 years back over the same location. there was no history of fever, trauma, new medication, friction over the fingertips or any contact with other infectious lesions. on examination there were tense, clear, fluid-filled vesicles arranged linearly over the palmar side of the left thumb and index finger (figure 1). draining lymph nodes were not palpable. there were no coexisting mucocutaneous vesiculation. a clinical diagnosis of herpetic whitlow was made. on dermoscopic evaluation, the lesions were longitudinally oriented and the primary lesions rested on a pale base with surrounding bright erythema. the primary lesions appeared as relatively pale rings circumscribed by a rim of red dots. the pale lobulated appearance is explained by the formation of intraepidermal bullae due to pathogenic ballooning degeneration of keratinocytes and acantholysis. the pallor is also partly due to the presence of vesicular fluid. the red dots 2 research letter | dermatol pract concept. 2022;12(2):e2022052 differential diagnosis of herpetic whitlow includes bacterial infective whitlow, friction blister, suction blister, bullous impetigo, erythema multiformae, coxsackie virus infection [1]. herpetic whitlow is a self-limiting infection and incision and drainage are not indicated, as they are done in bacterial paronychia, due to the risk of viremia and secondary bacterial infection. treatment with antiviral decreases the duration of symptoms of viral shedding. conclusions diagnosis of herpetic infection is often made clinically. however, it resembles many other infectious and non-infectious dermatoses [1]. our report documents the dermoscopic features of herpetic whitlow, which has never been previously reported and can aid in early diagnosis. consent: a written consent was taken from the guardian for using the image and other clinical information to be reported in the journal. the patient understand that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. references 1. lieberman l, castro d, bhatt a, guyer f.  case report: palmar herpetic whitlow and forearm lymphangitis in a 10-year-old female. bmc pediatr. 2019;19(1):450. doi:10.1186/s12887-0191828-5. pmid: 31752766. pmcid: pmc6868856. 2. hoyt b, bhawan j. histological spectrum of cutaneous herpes infections. am j dermatopathol. 2014;36(8):609–619. doi: 10.1097/dad.0000000000000148. pmid: 25051039. figure 2. (a,b) primary lesion over a pale base and surrounding erythema. pale rings circumscribed by rim of red dots and a central red hue, with no loss of dermatoglyphics. figure 1. clear, fluid-filled vesicles over an erythematous base arranged in a linear fashion over the thumb and index finger. are due to erythrocyte extravasation seen histopathologically [2]. the thickness of stratum corneum over the palms and soles and the subepidermal location of the vesicle explain why dermatoglyphics are not lost ( figure 2, a and b). tzanck smear of blister fluid showed multinucleated giant cells. gram stain did not reveal any bacterial colonies. pcr assay was positive for hsv-1 virus, confirming the diagnosis. the patient was started on oral acyclovir 200 mg 5 times a day and patient completed a course of 5 days of therapy with complete resolution of skin lesions. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022089 1 dotted vessels in a reticular arrangement florentina silvia delli1, despina noukari1, zoe apalla2, aimilios lallas3 1 state hospital for skin and venereal diseases thessaloniki, hippokratia hospital, thessaloniki, greece 2 second department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece 3 first department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece citation: delli fs, noukari d, apalla z, lallas a. dotted vessels in a reticular arrangement. dermatol pract concept. 2022;12(2):e2022089. doi: https://doi.org/10.5826/dpc.1202a89 accepted: september 26, 2021; published: april 2022 copyright: ©2022 delli et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: florentina silvia delli, dermatologist, md, phd, state hospital for skin and venereal diseases thessaloniki, hippokratia hospital, 124 delfon street, 546 43, thessaloniki greece. e-mail: delliflorentina@ymail.com case presentation we report a case of a 56-year-old male patient who presented for evaluation of a tumor on his right lower back ( figure  1a). he reported that he observed the lesion for the first time 3 years earlier and, since then, it gradually increased in size and was sporadically traumatized. dermoscopy revealed glomerular and dotted vessels with a reticular arrangement at the periphery of the lesion (white circles, figure 1b), but also linear mixed and hairpin-like vessels (white arrows, figure 1b) irregularly distributed in the center and eccentrically. white structureless areas were also focally present (figure 1b). although reticularly arranged dotted vessels are suggestive of a clear cell acanthoma (cca) (1), the uneven distribution of vessels in the lesion and the co-existence of other morphologic vessel types did not allow a confident clinical diagnosis. therefore, the lesion was excised with a clinical differential diagnosis including cca, non-pigmented eccrine poroma (2), amelanotic melanoma and poorly differentiated squamous cell carcinoma. histopathology confirmed the diagnosis of cca. teaching point dotted vessels in a reticular arrangement (“string of pearls” in the metaphoric terminology) are strongly indicative of cca. however, excisional biopsy and histopathological examination is mandatory for any nodular lesions that will express only in part the dermoscopic criteria for clear cell acanthoma. references 1. cunha dg, kassuga-roisman lebp, silveira lkcb, macedo fc. dermoscopic features of clear cell acanthoma. an bras dermatol. 2018;93(3):449–450. doi:10.1590/abd1806–4841.20186977. pmid: 29924237. pmcid: pmc6001098. 2. chessa ma, patrizi a, baraldi c, fanti pa, barisani a, vaccari s. dermoscopic-histopathological correlation of eccrine poroma: an observational study. dermatol pract concept. 2019;9(4):283–291. doi:10.5826/dpc.0904a07. pmid: 31723462. pmcid: pmc6830555. 2 image letter | dermatol pract concept. 2022;12(2):e2022089 figure 1. (a) nodular and pink skin lesion measuring 23 mm on patient right lower back. (b) glomerular and dotted vessels with a reticular arrangement at the periphery of the lesion (white circles), linear mixed and hairpin-like vessels (white arrows irregularly distributed in the center and eccentrically. white structureless areas were also focally present. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022205 1 white rosettes as a new dermoscopic finding in acute cutaneous lupus erythematosus patient with unilateral erythema fangyan zhou1, shisheng chen1 1 department of dermatology, the second affiliated hospital and yuying children’s hospital of wenzhou medical university wenzhou, zhejiang, china citation: zhou f, chen s. white rosettes as a new dermoscopic finding in acute cutaneous lupus erythematosus patient with unilateral erythema. dermatol pract concept. 2022;12(4):e2022205. doi: 10.5826/dpc.1204a205 accepted: march 21, 2022; published: october 2022 copyright: ©2022 zhou et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: shisheng chen, m.s., department of dermatology, the second affiliated hospital and yuying children’s hospital of wenzhou medical university, no.109 west college road, wenzhou, zhejiang, p.r. china 325027. email: chshsh168@163.com case presentation a 65-year-old female presented with a 2-week history of swelling erythema (10 cm × 8 cm) on her left cheek, without pruritus, pain, or systemic complaints (figure 1a). dermoscopy showed some whitish scales, mixed vascular pattern, and remarkable white rosettes on a pinkish reddish background (figure 1b). skin biopsy of the lesion revealed epidermal atrophy in addition to follicular plugging, obviously vacuolar degeneration of the basal layer, and remarkable superficial and deep perifollicular lymphocytic inflammatory infiltrate (figure 1c). after treatment of 200  mg hydroxychloroquine daily, the lesion was relieved entirely in the eighth week. we have obtained informed consent from this patient. teaching point acute cutaneous lupus erythematosus (acle) is a subcategory of le-specific skin disease, which is usually diagnosed based on typical lesions. because the acle has less cutaneous involvement, it is essential to identify such lesions early for appropriate interventions promptly. white rosettes are not lesion-specific and were reported in many lesions, including discoid lupus erythematosus (dle) [1], while there are few reports of white rosettes in acle in the literature. in our case, lots of white rosettes with the same size, shape, and orientation angle are observed in the same field of view. 2 image letter | dermatol pract concept. 2022;12(4):e2022205 figure 1. (a) unilateral swelling erythematosus patch on the patient’s left face without contralateral involvement. (b) dermatoscopy of a target lesion (the site highlighted in (a)) shows some whitish scales, mixed vascular pattern (black triangle), and remarkable white rosettes (black circle) with some white shiny structures (black square) on a pinkish reddish background. (c) histopathological of the skin biopsy showing follicular plug, superficial and deep perifollicular lymphocytic infiltrate (h&e×100). (d) vacuolar degeneration of the basal layer and (e) remarkable superficial and deep perivascular and periadnexal lymphocytic infiltrate at higher magnification from the sites highlighted in (c) respectively (h&e×200). references 1. ankad bs, shah sd, adya ka. white rosettes in discoid lupus erythematosus: a new dermoscopic observation. dermatol pract concept. 2017;7(4):9-11. doi:10.5826/dpc.0704a03. pmid:29214102. pmcid: pmc5718119. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023028 1 various colors of presentation of pseudochromhidrosis a case series priyadarshini sahu1, disha chakraborty1, surabhi dayal1, meenakshi sachdeva1 1 department of dermatology, venereology and leprosy, pt b.d. sharma, university of health sciences, rohtak, haryana, india key words: pseudochromhidrosis, red, black, pink citation: sahu p, chakraborty d, dayal s, sachdeva m. various colors of presentation of pseudochromhidrosis a case series. dermatol pract concept. 2023;13(1):e2023028. doi: https://doi.org/10.5826/dpc.1301a28 accepted: june 8, 2022; published: january 2023 copyright: ©2023 sahu et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: priyadarshini sahu, department of dermatology, venereology and leprosy, pt. b. d. sharma, university of health sciences, rohtak, haryana, india. pin-124001 tel: +91-9416536159 e-mail: priyadarshini.sahu.9@gmail.com introduction colored sweat is a sporadic disorder, which can be due to apocrine, true eccrine and pseudo-ecrrine chromhidrosis [1]. pseudo-chromhidrosis is characterized by excretion of normal colorless sweat, which becomes colored following contact with products of chromogenic microbial or extrinsic chemicals on the skin surface [2]. there are very few case reports of pseudo-chromhidrosis [1-4]. hereby, we present three sporadic case of red, black and pink pseudo-chromhidrosis. case presentation case 1. an apparently healthy 10-year-old female presented with reddish discoloration of both palms for last 7 days. her brother was also suffering from the similar complaint. clinical examination revealed palmar creases with reddish secretion (figure 1). skin biopsy was negative for lipofuscin granules around eccrine orifices which ruled out apocrine chromhidrosis. clinical diagnosis of pseudo-chromhidrosis was made. case 2. a 7-year-old boy presented with progressive darkening of both the palms since last 5 days. skin biopsy was performed which supported the diagnosis of pseudo-chromhidrosis. case 3. a 36-year-old female, known case of rheumatoid arthritis presented with 10 days history of pink discoloration of both palms which aggravated with exertion. she did not give consent for biopsy. clinical diagnosis of pseudo-chromhidrosis was made. in all the three cases, color fade on rubbing with absolute alcohol. all patients denied intake of food, vitamin supplements, use of cosmetics or dyes that could have caused such discoloration. there was no specific odor or bleeding from any site. psychological assessment was normal and family history was insignificant for all patients. routine biochemical tests, gram staining, fungal scrapping and staining revealed no abnormality. all patients were prescribed oral erythromycin and topical clindamycin which resulted in complete relief with no recurrence for all patients. 2 research letter | dermatol pract concept. 2023;13(1):e2023028 figure 1. pre-treatment and post-treatment photographs of patients of red pseudo-chromhidrosis. figure 2. pre-treatment and post-treatment photographs of patients of pink pseudo-chromhidrosis. conclusions chromhidrosis, ie colored sweat can be produced by eccrine and apocrine glands. eccrine chromhidrosis due to intrinsic factors is known as true eccrine chromhidrosis and secondary to extrinsic factors is known as pseudo-chromhidrosis. in pseudo-chromhidrosis, sweat produced is colorless but it becomes colored because of chromogen, which include chromogenic bacteria, chemicals, paints, dyes and self-tanning products [2]. apocrine chromhidrosis is due to presence of increased amount of lipofuscin granules in apocrine glands and their excretion in sweat produces colored sweat [5]. while the diagnosis of eccrine chromhidrosis depends on detailed patient history and exclusion of ingestion of pigments, diagnosis of pseudo-chromhidrosis is based on exclusion of chromhidrosis and successful treatment with antibiotics or antiseptic scrub in this case. thus, it is very important to distinguish between apocrine or eccrine chromhidrosis and pseudo-chromhidrosis as there is difference in management with different types. pseudo-chromhidrosis can be treated with topical or systemic antibiotics and cessation of offending agents. although, pseudo-chromhidrosis does not constitute a health issue, it may cause psychological stress and social embarrassment. thus, dermatologist must be aware of the various colors of chromhidrosis in order to determine its actual cause as pseudo-chromhidrosis is easily treatable with antiseptic scrub, topical, systemic antibiotics [2]. on detail literature scan, red pseudo-chromhidrosis has never been reported on palms and pink pseudo-chromhidrois has been once been reported in the literature. references 1. nair pa, kota rk, surti nk, diwan ng, gandhi ss. yellow pseudochromhidrosis in a young female. indian dermatol online j. 2017;8(1):42-44. doi: 10.4103/2229-5178.198778. pmid: 28217472. pmcid: pmc5297270. s4c highlight au: figure 2 citation is missing in text. kindly confirm. research letter | dermatol pract concept. 2023;13(1):e2023028 3 2. koley s, mandal rk. red and black pseudochromhidrosis. indian j dermatol. 2016;61(4):454-457. doi: 10.4103/0019 -5154.185733. pmid: 27512200. pmcid: pmc4966413. 3. lefeber wp, golitz le. green foot.   pediatr dermatol. 1984;2(1):38-40. doi: 10.1111/j.1525-1470.1984.tb00439.x. pmid: 6438617. 4. mapare a, tapre v, khandelwal a. apocrine chromhidrosis over dorsum of foot. journal of dental and medical sciences. 2012;2(3):33-34. 5. singal a, thami gp. red pseudochromhidrosis of the neck. clin exp dermatol. 2004;29(5):548-549. doi: 10.1111/j.1365 -2230.2004.01567.x. pmid: 15347348. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023053 1 significant association between obsessive-compulsive disorder and atopic dermatitis – a retrospective population-based case-control study sofia åkerlund1, oliver seifert2,4, johan assarsson3, sandra gulin jerkovic2,4 1 department of dermatology and venereology, höglandssjukhuset nässjö, region jönköping county, sweden 2 division of cell biology, department of biomedical and clinical sciences, linköping university, linköping, sweden 3 jönköping county council, sweden 4 department of dermatology and venereology, ryhov county hospital, jönköping, sweden key words: atopic dermatitis, obsessive-compulsive disorder, comorbidities citation: åkerlund s, seifert o, assarsson j, gulin jerkovic s. significant association between obsessive-compulsive disorder and atopic dermatitis – a retrospective population-based case-control study. dermatol pract concept. 2023;13(1):e2023053. doi: https://doi. org/10.5826/dpc.1301a53 accepted: june 27, 2022; published: january 2023 copyright: ©2023 åkerlund et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sandra gulin jerkovic, department of dermatology and venereology, ryhov county hospital, sjukhusgatan, 55305 jonkoping, sweden, jonkoping, sweden. e-mail: sandrajerkovicgulin@rjl.se; sandra.jerkovic.gulin@liu.se introduction: atopic dermatitis (ad) is a global health problem. there are no data on the association of ad with obsessive-compulsive disorder (ocd). objectives: this study aimed to map a wide spectrum of different diseases among patients with atopic dermatitis compared to healthy controls in the region of jönköping county, sweden with special focus on ocd. methods: we conducted a retrospective case control study from january 1st 2013 until december 31st 2021 using an electronic medical records database covering the entire population of the county of jönköping. icd-10 codes were used to identify patients with ad. individuals without ad served as controls. a total number of 398,874 citizens under the age of 90 was included in this study and among these 2,946 individuals were diagnosed with ad. regression analysis was performed to describe the risk for comorbidities in patients with ad compared to controls, adjusted for age and gender. results: we found an association between obsessive-compulsive disorder (ocd) in patients with ad (adjusted odd ratio 2.0, 95% confidence interval 1.5-2.7, p<0.001). other results are in the line with other studies. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023053 introduction atopic dermatitis (ad) is a chronic inflammatory disease with a lifetime prevalence of up to 20% [1]. the disease is associated with an impaired skin barrier, elevated levels of total immunoglobulin e (ige) and immune dysregulation. genetic predisposition and environmental triggers are likely involved in causing the disease [2]. treatment strategies usually involve moisturizing regimes, topical anti-inflammatory preparations, phototherapy and, in severe cases systemic therapy [3, 4]. ad usually develops in children as part of the atopic march, thus frequently occurs together with asthma and allergic rhinitis in the same individual [5). different subtypes of hand eczema are additional conditions that have well-established associations with ad [6]. several studies have indicated that the burden of comorbidity reaches well beyond the atopic march and hand dermatitis [7-9]. previous studies have shown that patients with ad have an increased risk of bacterial, viral and fungal infections [9-12]. several studies have detected a positive association between ad and allergic and autoimmune diseases. furthermore, alopecia areata has been shown to increase the risk of ad [8]. most recently, a large population-based study conducted in sweden has indicated significant autoimmune comorbidity of adults with ad, pointing to autoimmune dermatological, gastrointestinal and rheumatological diseases [13]. an association between overweight/obesity and ad has been significantly observed in north america and asia, but not in europe [14]. data has shown a greater risk for congestive heart failure and coronary artery disease in adults with ad, while results on increased risk in ad for myocardial infarction and stroke have varied [15]. the association between ad and cancer is the subject of several previous studies but results are ambiguous. [8, 16]. depression, suicidality and anxiety are more frequently occurring in patients with ad compared to the non-ad population [17, 18]. several studies show that atopic disease and atopic eczema correlate to an increased risk of developing attention deficit/hyperactivity disorder (adhd) and autism spectrum disorder later in life [19-21]. data is limited when it comes to the association between ad and obsessive-compulsive disorder (ocd). two studies examined the association of ocd in mothers of children with ad where results showed that having a child with ad does not influence their mothers in terms of ocd and health-related quality of life [21, 22]. objectives establishing comorbidity seen in ad can help to further understand the complex pathogenesis of ad, contribute to finding improved treatment strategies, and thus improve quality of life in ad patients. consequently, studies investigating comorbidities related to ad are of great importance in order to screen for and treat them as early as possible. this study aimed to determine the association between ad and selected diagnoses, including ocd, in the population of the region jönköping, sweden. methods in this retrospective population-based case-control study, patients and controls were identified from cosmic r8; the electronic medical record (emr) used by the regional healthcare provider. all registered citizens of the region jönköping under the age of 90 were included from january 1, 2013, until december 31, 2021, also including those who had never contacted a regional state facility. the case group included all individuals with one of the following icd-10 diagnoses; l209 atopic dermatitis, unspecified; l208a atopic dermatitis in children without food allergy; l208b atopic dermatitis in children with food allergy; l208g atopic dermatitis in adult; registered in the dermatology and venereology clinic or in the pediatric clinic. the control group included all citizens of the region who had never been diagnosed with one of the mentioned l20diagnoses in one of the two clinics. for each individual, data was collected about gender and age. in the case group, age was defined as the patients’ age the first time they acquired an ad diagnosis and for controls as their age on december 31, 2021. ethical approval for this study was obtained by swedish ethical review authority (dnr 2022-00212-01). a literature search was performed in pubmed on articles exploring atopic dermatitis and comorbidities and resulted in an arbitrary selection of 82 comorbidity diagnoses. each individual, both cases and controls, was matched with each comorbidity in cosmic r8 and it was registered if they had received one of the diagnoses during the test period. the data conclusion: pointing to previous studies, the cause of ad and ocd share several gene-environmental mechanisms and this association should be further studied on larger populations. the results of the present study underline the need for dermatologists to be aware of ocd and to screen for this condition in ad patients because early diagnosis and treatment may improve outcome. original article | dermatol pract concept. 2023;13(1):e2023053 3 was coded so that the person performing the analysis was blinded to personal information about the subjects. data were processed into a statistical package for the social sciences (ibm spss version 27.0) data sheet for statistical analysis. continuous data were described as mean±sd. to estimate the risk of comorbidity the odds ratio (or) presented with a 95% confidence interval (ci) was calculated using a binominal logistic regression and ors were adjusted for age and sex and presented as such unless stated otherwise. results the study included all 398,874 citizens of jönköping county under the age of 90 that were registered in cosmic r8 and were alive on december 31, 2021. among these, 2,946 (0.7%) were included in the case group and 395,928 (99.3 %) in the control group. there were 1,229 males and 1,717 females in the case group and 201,732 males and 194,196 females in the control group. the mean age in the case group was 23.2 years and most patients (34.6 %) were seen in the age groups 0-9. the control group had a more homogenous distribution between the age groups and a mean age of 40.5 years. (table 1) our results showed that patients with atopic dermatitis had an increased risk for several comorbidities including ocd (or = 2.0; 95% ci =1.5-2.7), anxiety disorders (or = 1.5; 95% ci = 1.4-1.7), depressive episodes and sleep disorders (or = 1.4, 95% ci = 1.3-1.6; or = 1.8, 95% ci = 1.6-2.0) (table 2). further, adhd was significantly increased in ad. furthermore, our result indicated a positive association between ad and autoimmune disorders such as vitiligo (or =3.5; 95% ci = 2.2-5.4), alopecia areata (or =3.9; 95% ci = 2.8-5.5), crohn’s disease (or = 3.4; 95% ci = 2.4-4.9) as well as ulcerative colitis (or = 2.2; 95% ci = 1.5-3.2). positive associations were seen among infections: other bacterial intestinal infections (or =2.4; 95% ci = 1.7-3.4), erysipelas (or = 3.4; 95% ci =2.8-4.2), streptococcus and staphylococcal infection (or =5.9; 95% ci = 4.6-7.4), herpes viral infections (or = 3.3; 95% ci = 2.8-3.9), viral infections (or = 1.6; 95% ci = 1.5-1.7), dermatophytosis (or =2.5; 95% ci = 2.2-2.8), candidiasis (or = 2.1; 95% ci = 1.8-2.4), lyme disease (or = 1.7, 95% ci = 1.4-2.0) and impetigo (or = 4.9; 95% ci = 4.5-5.4) and streptococcal sepsis were significantly associated with ad (or = 3.9; 95% ci = 1.3-12.3). significantly increased risk of having cardiovascular disorders for patients with ad was found for hypertension (or = 2.2; 95% ci = 1.9-2.6), dyslipidaemia (or = 1.8, 95% ci = 1.5-2.2), atherosclerosis (or = 3.5; 95% ci = 1.9-6.2), cerebral infarction (or = 3.0; 95% ci = 2.0-4.6), angina pectoris (or =1.9; 95% ci = 1.3-2.8) and chronic ischemic heart disease (or = 2.0; 95% ci = 1.5-2.8). the diagnosis z72 problems related to lifestyle was significantly increased in the ad group (or = 1.5, 95% ci = 1.3-1.8). the diagnoses include the sub-diagnoses z72.0 tobacco use, table 1. table showing patients demographics patients with atopic dermatitis and controls. atopic dermatitis controls n 2946 % 0.7 m 1229 f 1717 n 395928 % 99.3 m 201732 f 194196 age mean (±sd) 23.2 (20.6) 19.9 (20.5) 25.6 (20.3) 40.5 (23.8) 39.9 (23.5) 41.0 (24.1) 0-9 989 34.6 535 454 45012 11.4 23106 21906 10-19 531 18.0 217 314* 46627 11.8 23916 22711 20-29 474 16.1 138 336** 54388 13.7 28376 26012 30-39 319 10.8 92 227# 55676 14.1 29045 26631 40-49 228 7.7 98 130% 45980 11.6 23725 22255 50-59 189 6.4 78 111& 48409 12.2 24908 23501 60-69 123 4.2 41 82a 41034 10.4 20813 20221 70-79 78 2.7 27 51b 38717 9.8 19093 19624 80-89 15 0.5 3 12 20085 5.1 8750 11335 n = number, m = male, f = female * or for females to develop eczema is 1.517 (95% ci 1.277-1.801) ** or for females to develop eczema is 2.635 (95% ci 2.163-3.210) # or for females to develop eczema is 2.677 (95% ci 2.102-3.409) % or for females to develop eczema is 1.412 (95% ci 1.087-1.834) & or for females to develop eczema is 1.506 (95% ci 1.128-2.011) a or for females to develop eczema is 2.054 (95% ci 1.413-2.987) b or for females to develop eczema is 1.836 (95% ci 1.152-2.925) 4 original article | dermatol pract concept. 2023;13(1):e2023053 ta b le 2 . n u m b er , f re q u en cy a n d o d d s ra ti o ( o r ) fo r co m o rb id c o n d it io n s o f p at ie n ts w it h a to p ic d er m at it is b et w ee n 2 0 1 3 a n d 2 0 2 1 c o m p ar ed t o c o n tr o ls . c o m o rb id it y ic d -1 0 -c o d e a to p ic d e rm a ti ti s (n = 2 9 4 6 ) n ( % ) o r ( 9 5 % c i) a d ju st e d o r # (9 5 % c i) s ig n ifi ca n ce l e v e l # # p re d o m in an tl y al le rg ic a st h m a j4 5 .0 1 7 7 ( 6 .0 ) 8 .6 ( 7 .3 -1 0 .1 ) 6 .4 ( 5 .5 -7 .5 ) * * * v as o m o to r an d a ll er gi c rh in it is j3 0 8 9 7 ( 3 0 .4 ) 4 .0 ( 3 .7 -4 .4 ) 4 .2 ( 3 .8 -4 .5 ) * * * a cu te a to p ic c o n ju n ct iv it is h 1 0 .1 5 3 0 ( 1 8 .0 ) 6 .4 ( 5 .8 -7 .0 ) 5 .6 ( 5 .1 -6 .2 ) * * * v it il ig o l 8 0 2 1 ( 0 .7 ) 2 .9 ( 1 .8 -4 .4 ) 3 .5 ( 2 .2 -5 .4 ) * * * a lo p ec ia a re at a l 6 3 3 5 ( 1 .2 ) 3 .8 ( 2 .7 -5 .4 ) 3 .9 ( 2 .8 -5 .5 ) * * * c ro h n d is ea se k 5 0 2 9 ( 1 .0 ) 2 .5 ( 1 .7 -3 .5 ) 3 .4 ( 2 .4 -4 .9 ) * * * u lc er at iv e co li ti s k 5 1 2 7 ( 0 .9 ) 1 .5 ( 1 .0 -2 .3 ) 2 .2 ( 1 .5 -3 .2 ) * * * e ss en ti al h yp er te n si o n i1 0 2 8 0 ( 9 .5 ) 0 .5 ( 0 .4 -0 .5 ) 2 .2 ( 1 .9 -2 .6 ) * * * a th er o sc le ro si s i7 0 1 2 ( 0 .4 ) 0 .7 ( 0 .4 -1 .2 ) 3 .5 ( 1 .9 -6 .2 ) * * * c er eb ra l in fa rc ti o n i6 3 2 5 ( 0 .8 ) 0 .7 ( 0 .5 -1 .1 ) 3 .0 ( 2 .0 -4 .6 ) * * * a n gi n a p ec to ri s i2 0 3 1 ( 1 .1 ) 0 .5 ( 0 .3 -0 .7 ) 1 .9 ( 1 .3 -2 .8 ) * * * d is o rd er s o f li p o p ro te in m et ab o li sm a n d o th er l ip id em ia s e 7 8 1 6 7 ( 5 .7 ) 0 .4 ( 0 .4 -0 .5 ) 1 .8 ( 1 .5 -2 .2 ) * * * o b es it y e 6 6 2 5 3 ( 8 .6 ) 1 .1 ( 0 .9 -1 .2 ) 1 .6 ( 1 .4 -1 .9 ) * * * p ro b le m s re la te d t o l if es ty le z 7 2 1 3 8 ( 4 .7 ) 0 .9 ( 0 .8 -1 .1 ) 1 .5 ( 1 .3 -1 .8 ) * * * d ep re ss iv e ep is o d e f 3 2 3 6 4 ( 1 2 .4 ) 1 .1 ( 0 .9 -1 .2 ) 1 .4 ( 1 .3 -1 .6 ) * * * o th er a n x ie ty d is o rd er s f 4 1 5 0 2 ( 1 7 .0 ) 1 .3 ( 1 .1 -1 .4 ) 1 .5 ( 1 .4 -1 .7 ) * * * o b se ss iv eco m p u ls iv e d is o rd er f 4 2 4 2 ( 1 .4 ) 2 .3 ( 1 .7 -3 .1 ) 2 .0 ( 1 .5 -2 .7 ) * * * n o n -o rg an ic s le ep d is o rd er f 5 1 2 9 6 ( 1 0 .0 ) 0 .9 ( 0 .8 -0 .9 ) 1 .5 ( 1 .4 -1 .8 ) * * * sl ee p -d is o rd er s g 4 7 2 5 6 ( 8 .7 ) 0 .9 ( 0 .9 -1 .1 ) 1 .8 ( 1 .6 -2 .0 ) * * * o th er b ac te ri al i n te st in al i n fe ct io n s a 0 4 3 1 ( 1 .1 ) 1 .7 ( 1 .2 -2 .4 ) 2 .4 ( 1 .7 -3 .4 ) * * * e ry si p el as a 4 6 9 5 ( 3 .2 ) 1 .5 ( 1 .2 -1 .8 ) 3 .4 ( 2 .8 -4 .2 ) * * * l ym e d is ea se a 6 9 .2 1 4 0 ( 4 .8 ) 1 .1 ( 0 .9 -1 .3 ) 1 .7 ( 1 .4 -2 .0 ) * * * h er p es s im p le x i n fe ct io n s b 0 0 1 4 5 ( 4 .9 ) 3 .2 ( 2 .7 -3 .8 ) 3 .3 ( 2 .8 -3 .9 ) * * * v ir al i n fe ct io n o f u n sp ec ifi ed s it e b 3 4 9 7 7 ( 3 3 .2 ) 2 .1 ( 2 .0 -2 .3 ) 1 .6 ( 1 .5 -1 .7 ) * * * d er m at o p h yt o si s b 3 5 2 3 6 ( 8 .0 ) 1 .8 ( 1 .5 -2 .0 ) 2 .5 ( 2 .2 -2 .8 ) * * * c an d id ia si s b 3 7 2 5 3 ( 8 .6 ) 1 .7 ( 1 .5 -1 .9 ) 2 .1 ( 1 .8 -2 .4 ) * * * st re p to co cc u s an d s ta p h yl o co cc u s as t h e ca u se o f d is ea se s cl as si fi ed t o o th er c h ap te rs b 9 5 7 5 ( 2 .5 ) 2 .6 ( 2 .1 -3 .3 ) 5 .9 ( 4 .6 -7 .4 ) * * * original article | dermatol pract concept. 2023;13(1):e2023053 5 c o m o rb id it y ic d -1 0 -c o d e a to p ic d e rm a ti ti s (n = 2 9 4 6 ) n ( % ) o r ( 9 5 % c i) a d ju st e d o r # (9 5 % c i) s ig n ifi ca n ce l e v e l # # im p et ig o l 0 1 5 8 5 ( 1 9 .9 ) 8 .0 ( 7 .3 -8 .8 ) 4 .9 ( 4 .5 -5 .4 ) * * * r es is ta n ce t o m et h ic il li n u 8 2 .1 2 1 ( 0 .7 ) 3 .7 ( 2 .4 -5 .7 ) 2 .9 ( 1 .9 -4 .5 ) * * * t o b ac co u se z 7 2 .0 6 6 ( 2 .2 ) 0 .9 ( 0 ,7 -1 .1 ) 1 .5 ( 1 .2 -2 .0 ) * * * c er eb ra l at h er o sc le ro si s i6 7 .2 1 ( 0 .0 ) 3 .9 ( 0 .5 -2 8 .9 ) 1 5 .3 ( 2 .1 -1 1 4 .1 ) * * c h ro n ic i sc h em ic h ea rt d is ea se i2 5 4 8 ( 1 .6 ) 0 .4 ( 0 .3 -0 .5 ) 2 .0 ( 1 .5 -2 .8 ) * * sc ab ie s b 8 6 3 7 ( 1 .3 ) 2 .2 ( 1 .6 -3 .1 ) 1 .6 ( 1 .2 -2 .2 ) * * o th er s p ec ifi ed b ac te ri al a ge n ts a s th e ca u se o f d is ea se s cl as si fi ed t o o th er c h ap te rs b 9 6 2 9 ( 1 .0 ) 0 .7 ( 0 .5 -0 .9 ) 1 .7 ( 1 .2 -2 .5 ) * * a rt h ri ti s m 0 5 -m 0 9 3 2 ( 1 .1 ) 1 .0 ( 0 .7 -1 .5 ) 2 .0 ( 1 .4 -2 .8 ) * * c o el ia c d is ea se k 9 0 .0 3 4 ( 1 .2 ) 1 .7 ( 1 .2 -2 .5 ) 1 .7 ( 1 .2 -2 .4 ) * * l ac k o f p h ys ic al e x er ci se z 7 2 .3 1 2 ( 0 .4 ) 1 .4 ( 0 .8 -2 .4 ) 2 .1 ( 1 .2 -3 .8 ) * * h yp er k in et ic d is o rd er f 9 0 1 2 5 ( 4 .2 ) 1 .8 ( 1 .5 -2 .2 ) 1 .3 ( 1 .1 -1 .5 ) * * e at in g d is o rd er s f 5 0 3 6 ( 1 .2 ) 2 .5 ( 1 .8 -3 .4 ) 1 .6 ( 1 .1 -2 .2 ) * * st re p to co cc al s ep si s a 4 0 3 ( 0 .1 ) 1 .4 ( 0 .4 -4 .3 ) 3 .9 ( 1 .3 -1 2 .3 ) * m en in go co cc al i n fe ct io n a 3 9 1 ( 0 .0 ) 9 .0 ( 1 .2 -6 7 .9 ) 1 2 .9 ( 1 .6 -1 0 1 .7 ) * p n eu m o n ia d u e to s tr ep to co cc u s p n eu m o n ia j1 3 4 ( 0 .2 ) 1 .3 ( 0 .5 -3 .6 ) 3 .2 ( 1 .2 -8 .5 ) * t yp e 1 d ia b et es m el li tu s e 1 0 3 2 ( 1 .1 ) 0 .9 ( 0 .6 -1 .3 ) 1 .5 ( 1 .1 -2 .2 ) * t yp e 2 d ia b et es m el li tu s e 1 1 7 1 ( 2 .4 ) 0 .4 ( 0 .3 -0 .5 ) 1 .3 ( 1 .0 -1 .7 ) * o th er s ep si s a 4 1 9 ( 0 .3 ) 0 .6 ( 0 .3 -1 .2 ) 2 .0 ( 1 .0 -3 .9 ) * e o si n o p h il ic e so p h ag it is k 2 0 9 a 2 ( 0 .1 ) 2 .9 ( 0 .7 -1 2 .0 ) 3 .9 ( 0 .9 -1 5 .9 ) n s a u ti sm f 8 4 .0 /f 8 4 .1 4 0 ( 1 .4 ) 1 .9 ( 1 .4 -2 .6 ) 1 .2 ( 0 .9 -1 .6 ) n s m u lt ip le s cl er o si s g 3 5 3 ( 0 .1 ) 0 .5 ( 0 .2 -1 .5 ) 0 .7 ( 0 .2 -2 .2 ) n s sy st em ic l u p u s er yt h em at o su s m 3 2 2 ( 0 .1 ) 0 .9 ( 0 .2 -3 .5 ) 1 .3 ( 0 .3 -5 .1 ) n s a cu te m yo ca rd ia l in fa rc ti o n i2 1 1 0 ( 0 .3 ) 0 .3 ( 0 .2 -0 .5 ) 1 .1 ( 0 .6 -2 .1 ) n s su b se q u en t m yo ca rd ia l in fa rc ti o n i2 2 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s c er ta in c u rr en t co m p li ca ti o n s fo ll o w in g ac u te m yo ca rd ia l in fa rc ti o n i2 3 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s o th er a cu te i sc h ae m ic h ea rt d is ea se i2 4 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s sm o k in g z 7 2 .0 a 4 3 ( 1 .5 ) 0 .7 ( 0 .5 -0 .9 ) 1 .3 ( 0 .9 -1 .7 ) n s a lc o h o l u se z 7 2 .1 3 ( 0 .1 ) 0 .9 ( 0 .3 -3 .0 ) 2 .0 ( 0 .6 -6 .3 ) n s t ab le 2 c o n ti n u es 6 original article | dermatol pract concept. 2023;13(1):e2023053 c o m o rb id it y ic d -1 0 -c o d e a to p ic d e rm a ti ti s (n = 2 9 4 6 ) n ( % ) o r ( 9 5 % c i) a d ju st e d o r # (9 5 % c i) s ig n ifi ca n ce l e v e l # # sc h iz o p h re n ia f 2 0 2 ( 0 .1 ) 0 .3 ( 0 .1 -1 .1 ) 0 .5 ( 0 .1 -2 .0 ) n s o th er s ex u al ly t ra n sm it te d c h la m yd ia l d is ea se a 5 6 6 0 ( 2 .0 ) 1 .7 ( 1 .4 -2 .3 ) 1 .2 ( 0 .9 -1 .5 ) n s t u b er cu lo si s o f sk in a n d s u b cu ta n eo u s ti ss u e a 1 8 .4 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s h u m an i m m u n o d efi ci en cy v ir u s (h iv ) d is ea se r es u lt in g in in fe ct io u s an d p ar as it ic d is ea se b 2 0 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s c yt o m eg al o vi ra l d is ea se b 2 5 3 ( 0 .1 ) 2 .5 ( 0 .8 -7 .8 ) 2 .8 ( 0 .9 -8 .7 ) n s a n o ge n it al h er p es vi ra l (h er p es s im p le x ) in fe ct io n a 6 0 1 8 ( 0 .6 ) 1 .6 ( 1 .0 -2 .5 ) 1 .4 ( 0 .9 -2 .2 ) n s o th er d is ea se s ca u se d b y ch la m yd ia e a 7 4 1 0 ( 0 .4 ) 1 .2 ( 0 .6 -2 .1 ) 0 .9 ( 0 .5 -1 .8 ) n s g o n o co cc al i n fe ct io n a 5 4 2 ( 0 .1 ) 1 .6 ( 0 .4 -6 .5 ) 1 .5 ( 0 .4 -5 .9 ) n s v ir al a ge n ts a s th e ca u se o f d is ea se s cl as si fi ed t o o th er ch ap te rs b 9 7 5 ( 0 .2 ) 1 .3 ( 0 .5 -3 .1 ) 1 .4 ( 0 .6 -3 .3 ) n s t ic k -b o rn e vi ra l en ce p h al it is a 8 4 0 ( 0 .0 ) 0 .0 ( 0 .0 -0 .0 ) 0 .0 ( 0 .0 -0 .0 ) n s h ep at it is b 1 5 -b 1 8 5 ( 0 .2 ) 0 .4 ( 0 .2 -0 .9 ) 0 .5 ( 0 .2 -1 .2 ) n s m al ig n an t m el an o m a o f sk in c 4 3 8 ( 0 .3 ) 0 .6 ( 0 .3 -1 .1 ) 1 .5 ( 0 .7 -3 .0 ) n s o th er m al ig n an t n eo p la sm s o f sk in c 4 4 2 8 ( 1 .0 ) 0 .4 ( 0 .2 -0 .5 ) 1 .3 ( 0 .9 -1 .9 ) n s l ym p h o m as c 8 1 -c 8 6 4 ( 0 .1 ) 0 .7 ( 0 .3 -1 .9 ) 1 .9 ( 0 .7 -5 .2 ) n s # o d d s ra ti o a d ju st ed f o r ag e gr o u p a n d s ex # # s ig n if ic an ce l ev el o f ad ju st ed o d d s ra ti o ( * p < 0 .0 5 ; * * p < 0 .0 1 ; * * * p < 0 .0 0 1 ; n s p > 0 .0 5 ). ta b le 2 . n u m b er , f re q u en cy a n d o d d s ra ti o ( o r ) fo r co m o rb id c o n d it io n s o f p at ie n ts w it h a to p ic d er m at it is b et w ee n 2 0 1 3 a n d 2 0 2 1 c o m p ar ed t o c o n tr o ls . ( co n ti n u ed ) original article | dermatol pract concept. 2023;13(1):e2023053 7 with ad. furthermore, if microbes can trigger autoimmunity that leads to ocd, it is not irrelevant to consider increased skin infection in ad as a possible risk factor for ocd. a  total-population-based swedish study found a significant association between ocd and several autoimmune diseases including psoriasis vulgaris (32%). however, ad was not included in the study. the authors evaluated the risk of 40 autoimmune diseases in people with ocd and their relatives and found an increased risk for autoimmune disease in first-degree relatives to patients with ocd compared to secondand third-degree relatives. their results suggest a potential genetic link between ocd and autoimmune diseases[34]. similar studies could be performed with ocd and ad to see if there are indications of genetic linkage between the two diseases. in conclusion, the two conditions likely share several common gene-environmental pathways. optimized treatment of ad to restore the skin barrier and prevent skin infections might be of great importance in order to prevent ocd. for future research, larger populations should be included and it should be investigated if those with both ad and ocd also have been diagnosed with pandas and if they have other autoimmune diseases or infections in close temporal association with the onset of ocd. the connection should be adjusted for comorbidity diagnoses shared between ad and ocd, such as anxiety disorder and depression. studies to see if ocd and ad share genetic material/ activated gene sequences could also be interesting. depression and anxiety occurred more frequently in patients with ad compared to the control population, which was in line with earlier findings. sleep disturbance was increased in ad patients in this study. sleep disturbance, pruritus, stigma, social isolation and poor quality of life are associated with ad and might contribute to this correlation [9, 35, 36]. pruritus and inflammation as part of ad can lead to sleep disturbances which in turn may cause depression and anxiety [9]. the systemic inflammation seen in ad is another possible explanation for the connection since inflammatory proteins are elevated in depressed patients in blood and cerebrospinal fluid [37-39]. cytokines can affect neurotransmission and behaviors and emotions associated with both sickness and depression [40]. this study found that adhd was significantly increased in the ad group which is in line with previous studies [41, 42]. most of these studies however include only children or analyze children and adults separately [19-21]. buske-kirschbaum et al propose three different explanations for the association between ad and adhd: 1) allergic inflammation and psychologic stress due to chronic disease leads to the release of inflammatory cytokines that interfere with the maturation of prefrontal cortex regions and neurotransmission involved in ahdh pathology; 2) elevated stress z72.1 alcohol use, z72.2 drug use, z72.3 lack of physical exercise, z72.4 inappropriate diet and eating habits, z72.5 high-risk sexual behaviour, z72.6 gambling and betting, z72.8 other problems related to lifestyle and z72.9 problems related to lifestyle, unspecified. none of the studied malignant diagnoses were significantly increased in the ad population (table 2). to our knowledge, this is the first large population-based study describing a significant association between ocd and ad. there are only two previous studies analyzing the association between ad and ocd, but the authors studied symptoms of ocd in mothers of children with ad and found that ad in the child did not influence their mothers in terms of ocd [22, 23]. however, our study only included 42 patients diagnosed with ocd which makes studies on additional and preferably larger populations essential to further investigate the association. ocd is characterized by recurrent thoughts, urges or images that lead to repetitive behavior or mental acts, causing distress and anxiety. these are severely time-consuming and/ or cause impairment in social, occupational or other important situations [24]. the estimated one-year prevalence of ocd is 1.2% and the estimated lifetime prevalence is 2.3%, with an onset usually seen before the age of 30 [25]. during our test period of nine years, 1.4% of the ad patients were diagnosed with ocd, which correlates somewhat with the global prevalence, but it was significantly less prevalent in the control group (0.6%). the reason for the generally lower prevalence of ocd in the population of jönköping compared to the global population cannot easily be explained and further studies are needed on large groups. the comorbidities most often seen with ocd are additional psychiatric disorders [26]. previous studies and reviews investigated the role of the immune system in the pathophysiology of ocd [27-29]. there is some evidence that persistent low-grade inflammation is seen in ocd patients [28]. specifically, the cytokines il-4 and il-17 are elevated in both ad and ocd [30-32]. autoantibodies against the basal ganglia are almost five times more likely to be detected in patients with ocd compared to controls. in some cases of ocd infectious agents, such as streptococcus, other bacteria, viruses and parasites are seen as triggers of autoimmunity [28]. in some children, the onset or exacerbation of ocd is seen in association with streptococcus a infection. the condition is named pediatric autoimmune neuropsychiatric disorder associated with group a streptococci (pandas). hypothetically, streptococcus a triggers an autoimmune reaction that interacts with neurons in the basal ganglia and causes ocd [33]. the above-mentioned studies suggest that a dysregulated inflammatory response might contribute to the occurrence of ocd and this could potentially explain the association 8 original article | dermatol pract concept. 2023;13(1):e2023053 this study has several strengths. we used an electronic medical record for the collection of all data. these records allowed easy access to data that was required for the analysis. this furthermore enabled a large study population. we chose to only include patients in the study group that received their ad diagnosis in the dermatology or pediatric clinic. at these clinics, physicians have more specialized competence to correctly recognize these conditions than in other clinics. understandably, this means that those with an ad diagnosis from another clinic were included in the control group rather than the study group, as were those who received an ad diagnosis before and not during the test period. most probably, the patients in our study group have a moderate to severe degree of disease and most of the ad diagnoses included in the control group have mild symptoms. this can affect the results in different ways. it might make significant associations between ad and the different comorbidity more difficult since those with one of the examined comorbidities in the control group might have ad. if that is the case, then that would mean that their exclusion from the control group would make our results even more significant. on the other hand, it could be speculated that comorbidity is mostly seen in moderate to severe ad, which strengthens the choice of inclusion criteria. a limitation of this study was that we did not specify the degree of ad symptoms, so we are not able to analyze disease severity and how it correlates to comorbidity. another limitation is that we initially only adjusted for age and gender. as discussed above, metabolic diseases share risk factors with some common comorbidity in ad. unless we adjust for those risk factors nothing can be said about a causal association between cardiovascular comorbidity and ad. the connection between ad and ocd should be adjusted for shared comorbidity. in agreement with the current literature, we found an increased risk for allergic rhinitis, allergic asthma and atopic conjunctivitis in ad patients. this is in line with previous knowledge and can be used as validation of the diagnostic code for ad [5]. we did not choose to validate every comorbidity diagnosis since this study was intended as a screening for multiple comorbidities in order to detect interesting correlations. conclusions our results strengthen the knowledge that a wide spectrum of comorbidity is seen in ad. we found an increased risk between ad and ocd. these findings are essential for clinicians seeing patients with ad. early detection and treatment of ocd are crucial for optimal treatment of ad and the quality of life of ad patients. future nationwide studies are needed to confirm our results. levels in adhd trigger ad or 3) the conditions are separate but have shared risk factors (eg. genetics, prenatal stress) that increase the risk of developing both disorders [43]. similar to previous studies we saw increased risk for a number of infections and autoimmune diseases in the ad group. somewhat surprisingly, we found an increase in lyme disease in the ad group which logically cannot be explained by a default skin barrier. literature is scarce on the area and future studies on the connection and potential co-factors, such as neuroborreliosis, could be interesting. the positive association between ad and crohn’s disease, ulcerative colitis, celiac disease, alopecia areata and vitiligo detected in this study, correlates well with previous study results [8, 13, 44]. inflammatory bowel disease, psoriasis and alopecia areata share several genetic risk loci with ad [45-47]. a german cohort study showed an increased risk of rheumatoid arthritis and inflammatory bowel disease (and a decreased risk for type 1 diabetes) in combination with ad, independent of known risk alleles [48]. elevated levels of th1, th2 and th17 responses are present in the pathogenesis of both inflammatory bowel disease and atopic dermatitis [10, 49]. we found a significant association with several comorbidities that can be categorized as cardiovascular disease. four well-known risk factors for cardiovascular disease were also increased in the ad group, e.g. hyperlipidemia, obesity, hypertension and diabetes. poor health behavior is often seen in patients with ad. they have a higher incidence of smoking, drinking alcohol at a young age and have reduced physical activity. children with ad participate less in sports and play more videogames [50, 51]. this was to some extent reflected in our results. these combined increased cardiovascular risk factors, as well as the aforementioned frequent sleep disturbance in patients with ad, likely play an important role in the development of cardiovascular disease in the ad population [7]. the systemic inflammation seen in ad and to some extent in cardiovascular disease as well as in some of the cardiovascular risk factors might be one reason for the association, as well as genetic factors [52, 53]. two studies however found an increased risk for cardiovascular disease and stroke in ad patients initially but not after adjusting for cardiovascular risk factors, which suggests that poor health behavior and cardiovascular risk factors are the major reason for increased cardiovascular disease in ad patients, rather than systemic inflammation [54, 55]. we did not choose to adjust for cardiovascular risk factors when analyzing the odds ratio for cardiovascular disease. thus this study does not contribute to deeper insight into the mechanism for the connection between such conditions and ad. generally, cardiovascular risk factors are seen less often in association with ad compared to psoriasis [56]. original article | dermatol pract concept. 2023;13(1):e2023053 9 18. thyssen jp, hamann cr, linneberg a, dantoft tm, skov l, gislason gh, et al. atopic dermatitis is associated with anxiety, depression, and suicidal ideation, but not with psychiatric hospitalization or suicide. allergy. 2018;73(1):214-20. 19. chen mh, su tp, chen ys, hsu jw, huang kl, chang wh, et al. is atopy in early childhood a risk factor for adhd and asd? a longitudinal study. j psychosom res. 2014;77(4):316-21. 20. schmitt j, buske-kirschbaum a, roessner v. is atopic disease a risk factor for attention-deficit/hyperactivity disorder? a systematic review. allergy. 2010;65(12):1506-24. 21. strom ma, fishbein ab, paller as, silverberg ji. association between atopic dermatitis and attention deficit hyperactivity disorder in u.s. children and adults. br j dermatol. 2016;175(5):920-9. 22. gunduz s, usak e, ozen s, gorpelioglu c. obsessive compulsive symptoms and quality of life in mothers of children with atopic dermatitis. actas dermosifiliogr. 2017;108(5):432-7. 23. olivera pueyo j. mothers of children with atopic dermatitis are not more prone to obsessive-compulsive symptoms. actas dermosifiliogr. 2017;108(5):392. 24. substance abuse and mental health services a. cbhsq methodology report. impact of the dsm-iv to dsm-5 changes on the national survey on drug use and health. rockville (md): substance abuse and mental health services administration (us); 2016. 25. ruscio am, stein dj, chiu wt, kessler rc. the epidemiology of obsessive-compulsive disorder in the national comorbidity survey replication. mol psychiatry. 2010;15(1):53-63. 26. brady cf. obsessive-compulsive disorder and common comorbidities. j clin psychiatry. 2014;75(1):e02. 27. marazziti d, mucci f, fontenelle lf. immune system and obsessive-compulsive disorder. psychoneuroendocrinology. 2018;93:39-44. 28. gerentes m, pelissolo a, rajagopal k, tamouza r, hamdani n. obsessive-compulsive disorder: autoimmunity and neuroinflammation. curr psychiatry rep. 2019;21(8):78. 29. attwells s, setiawan e, wilson aa, rusjan pm, mizrahi  r, miler l, et al. inflammation in the neurocircuitry of obsessive-compulsive disorder. jama psychiatry. 2017;74(8): 833-40. 30. şimşek ş, yüksel t, çim a, kaya s. serum cytokine profiles of children with obsessive-compulsive disorder shows the evidence of autoimmunity. int j neuropsychopharmacol. 2016;19(8). 31. klonowska j, gleń j, nowicki rj, trzeciak m. new cytokines in the pathogenesis of atopic dermatitis-new therapeutic targets. int j mol sci. 2018;19(10). 32. rao np, venkatasubramanian g, ravi v, kalmady s, cherian a, yc jr. plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder. psychiatry res. 2015;229(3):949-52. 33. snider la, swedo se. pandas: current status and directions for research. mol psychiatry. 2004;9(10):900-7. 34. mataix-cols d, frans e, pérez-vigil a, kuja-halkola r, gromark c, isomura k, et al. a total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and tourette’s/chronic tic disorders. mol psychiatry. 2018;23(7):1652-8. 35. silverberg ji, gelfand jm, margolis dj, boguniewicz m, fonacier  l, grayson mh, et al. patient burden and 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dermatol. 2015;72(6):992-1002. 17. yu sh, silverberg ji. association between atopic dermatitis and depression in us adults. the journal of investigative dermatology. 2015;135(12):3183-6. 10 original article | dermatol pract concept. 2023;13(1):e2023053 46. paternoster l, standl m, waage j, baurecht h, hotze m, strachan dp, et al. multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. nat genet. 2015;47(12):1449-56. 47. ellinghaus d, baurecht h, esparza-gordillo j, rodríguez e, matanovic a, marenholz i, et al. high-density genotyping study identifies four new susceptibility loci for atopic dermatitis. nat genet. 2013;45(7):808-12. 48. schmitt j, schwarz k, baurecht h, hotze m, fölster-holst r, rodríguez e, et al. atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. j allergy clin immunol. 2016;137(1):130-6. 49. geremia a, biancheri p, allan p, corazza gr, di sabatino a. innate and adaptive immunity in inflammatory bowel disease. autoimmun rev. 2014;13(1):3-10. 50. silverberg ji, greenland p. eczema and cardiovascular risk factors in 2 us adult population studies. j allergy clin immunol. 2015;135(3):721-8.e6. 51. strom ma, silverberg ji. associations of physical activity and sedentary behavior with atopic disease in united states children. j pediatr. 2016;174:247-53.e3. 52. nastałek m, wojas-pelc a, undas a. plasma fibrin clot properties in atopic dermatitis: links between thrombosis and atopy. j thromb thrombolysis. 2010;30(2):121-6. 53. silverberg ji, becker l, kwasny m, menter a, cordoro km, paller as. central obesity and high blood pressure in pediatric patients with atopic dermatitis. jama dermatol. 2015;151(2):144-52. 54. drucker am, li wq, cho e, li t, sun q, camargo ca, jr., et al. atopic dermatitis is not independently associated with nonfatal myocardial infarction or stroke among us women. allergy. 2016;71(10):1496-500. 55. andersen ymf, egeberg a, gislason gh, hansen pr, skov l, thyssen jp. risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. j allergy clin immunol. 2016;138(1):310-2.e3. 56. radtke ma, schäfer i, glaeske g, jacobi a, augustin m. prevalence and comorbidities in adults with psoriasis compared to atopic eczema. j eur acad dermatol venereol. 2017;31(1):151-7. of life in atopic dermatitis in us adults: a population-based cross-sectional study. ann allergy asthma immunol. 2018;121(3):340-7. 36. silverberg ji, garg nk, paller as, fishbein ab, zee pc. sleep disturbances in adults with eczema are associated with impaired overall health: a us population-based study. the journal of investigative dermatology. 2015;135(1):56-66. 37. ford de, erlinger tp. depression and c-reactive protein in us adults: data from the third national health and nutrition examination survey. arch intern med. 2004;164(9):1010-4. 38. tiemeier h, hofman a, van tuijl hr, kiliaan aj, meijer j, breteler mm. inflammatory proteins and depression in the elderly. epidemiology. 2003;14(1):103-7. 39. levine j, barak y, chengappa kn, rapoport a, rebey m, barak v. cerebrospinal cytokine levels in patients with acute depression. neuropsychobiology. 1999;40(4):171-6. 40. raison cl, capuron l, miller ah. cytokines sing the blues: inflammation and the pathogenesis of depression. trends immunol. 2006;27(1):24-31. 41. danielson ml, bitsko rh, ghandour rm, holbrook jr, kogan md, blumberg sj. prevalence of parent-reported adhd diagnosis and associated treatment among u.s. children and adolescents, 2016. j clin child adolesc psychol. 2018;47(2):199-212. 42. fayyad j, de graaf r, kessler r, alonso j, angermeyer m, demyttenaere k, et al. cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. br j psychiatry. 2007;190:402-9. 43. buske-kirschbaum a, schmitt j, plessow f, romanos m, weidinger s, roessner v. psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. psychoneuroendocrinology. 2013;38(1):12-23. 44. mohan gc, silverberg ji. association of vitiligo and alopecia areata with atopic dermatitis: a systematic review and meta-analysis. jama dermatol. 2015;151(5):522-8. 45. weidinger s, willis-owen sa, kamatani y, baurecht h, morar n, liang l, et al. a genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. hum mol genet. 2013;22(23):4841-56. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2013;3(4):11 43 introduction the halo split skin graft (hssg) was first described by sharad paul in 2010, with a series of 28 procedures, as a novel method for surgically managing non-melanoma skin cancer (nmsc) lesion defects on the leg (lower limb below the knee to the ankle) [1]. this technique eliminated the need for two separate surgical sites, both requiring local anesthetic and the halo split skin graft in the management of non-melanoma skin cancer of the leg: a retrospective study danika fietz1, graham sivyer2, denis o’brien1, cliff rosendahl2 1 mermaid beach medical centre, mermaid beach, gold coast, australia 2 school of medicine, the university of queensland, brisbane, australia key words: skin cancer, halo graft, non-melanoma skin cancer, nmsc, leg citation: fietz d, sivyer g, o’brien d, rosendahl c. the halo split skin graft in the management of non-melanoma skin cancer of the leg: a retrospective study. dermatol pract conc. 2013;3(4):11. http://dx.doi.org/10.5826/dpc.0304a11. received: june 24, 2013; accepted: september 1, 2013; published: october 31, 2013 copyright: ©2013 fietz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, po box 734, capalaba, queensland, 4157, australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com background: the purpose of this study was to compare the results of the halo split skin graft (hssg) by two primary care skin cancer practitioners at one clinic at the gold coast, queensland, australia, to the results of the only previous study while adding to the body of evidence regarding use of the hssg following excision of non-melanoma skin cancer on the leg. method: a retrospective review of the notes (jan 2010-aug 2012) was performed of all cases of nonmelanoma skin cancer (nmsc) excisions in which split skin graft (ssg) closure with the hssg was utilized on the leg. results: there were a total of 68 hssgs included over the 31 months of the study. average lesion size was 19.4 mm (range 9-75 mm) and the average age of patients was 78 years (range 49-95 years) with 49% of patients being male. the average healing time was 4 weeks with 35/68 (51%) healing within 14 to 21 days. the overall infection rate was 8/68 (11.8%), which decreased to 4/53 (7.5%) when the ankle grafts were excluded. the graft failure rate was 7/68 (10%) with 3/68 (4.4%) having both infection and graft failure. limitations: this was a retrospective study. conclusion: the hssg confines the surgical wounds to a single site, does not require specialized equipment and it is an economical and effective option for managing nmsc on the leg in situations where skin graft is indicated. abstract 44 research | dermatol pract concept 2013;3(4):11 the demographics of the patient population treated at the clinic reflected the popularity of the region with people at retirement age. many of these patients had multiple comorbidities including one or more of cardiovascular disease, peripheral arterial disease, diabetes mellitus, chronic renal impairment, chronic venous insufficiency and cognitive impairment. a proportion of them were consequently on multiple medications including, of significance to surgery, immunosuppressant therapy, anticoagulants and anti-platelet medications. the hssg cases were compiled by the researcher via a search of the medicare billing item-numbers and then crosschecked via a manual search of the surgery booking system. the researcher entered the data collected into the excel program (excelmicrosoft corporation, redmond, wa, usa) for further analysis. wound healing time was estimated using a surrogate marker being the number of weekly dressing changes. the patients were routinely seen after one week (i.e., 5-7 days post-surgery) by the registered nurse (rn) who worked exclusively in the skin cancer clinic as well as by the practitioner who had performed the surgery. the patients continued to attend the clinic approximately every seven days thereafter for wound review and dressing changes (again seen by both the rn and practitioner involved). this routine was altered and more frequent visits were made in the case of complications such as infection. the marker of wound healing was taken from the weekly visit that either the foam dressing was changed to a dry dressing or when the wound was left open or when a notation was made that complete wound healing had taken place. patients that were either lost to follow-up or had their wound care carried out by nursing staff at residential facilities (where healing assessment could not be made by the investigator) were excluded from the study. the actual size of the lesions was included for the purpose of this study and where size had not been recorded in the notes it was determined from the histopathology report. surgical margins were marked prior to excision of the lesions according to those recommended in the clinical guidelines [6] with a minimal margin of 3 mm for clinically favorable bccs and keratoacanthomas and 5 mm for clinically favorable sccs. pre-operative biopsy was routinely performed to establish the diagnosis and histological characteristics. all cases of hssg included had healed within the time period of the study. the hssg protocol the practitioners followed a similar protocol to paul [1] with some minor modifications with respect to the harvesting instrument and the dressing protocol. both practitioners chose to use a flexible shave biopsy blade (biopsiblade—kai medical, honolulu, usa) as they felt that it enabled a thinpost-operative management. paul also reported decreased healing times and reduced donor site pain. because no hospitalization or specialized instruments were required, this procedure was described as cost effective. despite the results of his study supporting these statements, a literature search has not revealed any further publications to replicate or add to the findings made by paul in his original article. there has however been a small replication study (12 hssg) which remains unpublished but which was presented at a mohs surgery meeting [2]. although that presenter described a healing rate of between 5.3-16 weeks (average 9 weeks), he remained impressed by the results and argued that the healing was much faster than wound healing via secondary intention. split skin grafts (ssg) have been in use since the 19th century. conventional methods of harvesting ssg involve the use of specialized equipment such as a weck blade (pilling, weck surgical, north carolina, usa), or power dermatome, following which the graft is sutured or stapled into place [3]. the hssg is a type of ssg where the donor skin is harvested from the periphery of the initial circular excision. after familiarizing themselves with the hssg technique as published by paul, two skin cancer primary care practitioners at one clinic commenced using the hssg technique for nmsc surgery on the leg. they selected their patients for this procedure by choosing those lesions, which were unable to be treated by either primary or flap closure (employing either a keystone island flap [4] or a rom flap [5]). previously they would have referred these patients to hospital for admission in order to have excision and ssg using the traditional methods. the purpose of this study was to compare the results of the hssg performed by the two practitioners at this clinic to the results of paul [1] while contributing to the body of evidence regarding use of the hssg after excision of nmsc on the leg. methods a retrospective review of the medical records was performed of all cases of nmsc (including squamous cell carcinoma (scc), keratoacanthoma (ka) and basal cell carcinoma (bcc) excisions by two skin cancer practitioners at a primary care clinic at the gold coast, queensland, australia, in which ssg closure with the hssg was utilized on the leg, including the ankle. the time period chosen was from january 2010, when the practitioners began using the technique, until august 2012. the procedures included in this study were on nmsc on the leg (from below the knee to the ankle) as well as on nmsc that were sited both at the ankle and just distal to the ankle including the achilles tendon area and also the dorsum of the foot immediately adjacent to the ankle. this group of lesions both at and just distal to the ankle were grouped together and allocated to the ‘ankle’ for the purpose of this study. research | dermatol pract concept 2013;3(4):11 45 annulus (see figure 1b). for the majority of the study time, small bleeding areas in both the donor site and the wound bed were electrically cauterized, however a change was made later in the study period to using aluminum chloride 35% for hemostasis to the donor area only, while still using cautery to achieve hemostasis in the wound bed. no aluminum chloride was used on the wound bed at any time. the wound was dressed with paraffin-like impregnated gauze (cuticerin-smith & nephew, london, uk), covered by a hydrocellular foam dressing (allevyn non-adhesive— smith & nephew, london, uk) and then secured firmly into place with adhesive stretchable woven tape (fixomul—bsn medical, hamburg, germany). a cotton ball was strategically placed under the tape over the center of the wound to provide support to the graft. tubular bandage (tensogrip—bsn medical, hamburg, germany) was then placed over the lower limb for most patients. occasionally, for those patients with a tendency towards leg edema, a primary layer of cohesive bandage (handy gauze cohesive—bsn medical, hamburg, germany) was placed over the limb and dressing prior to the tubular external bandage. patients were given both verbal and written instructions by the rn with regards to the aftercare plan which included gentle mobilization as well as and limb elevation when sitting. patients were instructed to keep the dressings dry until they were informed that the wound had completely healed. patients were routinely instructed to continue taking their anticoagulants or antiplatelet medications prior to surgery. prophylactic antibiotics were only prescribed when it was perceived that there was a high risk of infection although there was no formal protocol in this regard. figure 1 shows images of an scc marked out for excision (a), immediately after harvesting and placement of the graft (b) and at one week (c) and six months (d) post-operatively. results there were a total of 76 hssg performed on the leg and ankle during the 31 months of the study. eight were excluded due to lack of clarity in the notes or because the patients were lost to follow up leaving 68 cases of hssg which were included in the study (scc=45, bcc=16, ka=7). all analyzed details of all of the 68 cases are displayed in table 1. overall, 36/68 (51%) of the patients were female and the average age of patients was 78 years (range 49-95 years). the average age for females was 79 years and for males 77 years. the average lesion size was 19.4 mm (range 9-75 mm). all lesions in this study were excised down to at least the subcutaneous tissue plane. there were 2/68 (2.9%) cases in which the histopathology report stated that a margin was positive for tumor and 3/68 (4.4%) where margins were ner graft than that of the no. 22 scalpel blade that was used by paul [1]. the protocol adopted required that patients wash at home in triclosan 1% (phisohex—sanofi-aventis, paris, france) body wash for 1 week prior to the surgery. at the time of presentation for surgery, the lesion and the clinical surgical margins were marked on the skin after which the annulus, from which the graft would be harvested, was marked around the central lesion (see figure 1a). this was measured slightly differently to the method described by paul [1]. the radius of the actual lesion plus the surgical margin was measured then multiplied by 1.5 to reveal the new radius (i.e., radius of the lesion including the surgical margin and the annulus). povidone iodine 10% (betadine—catalent pharma solutions, new jersey, usa) skin preparation was used. if the patient was allergic to povidone, chlorhexidine aqueous 0.1% (pfizer) was used instead. the procedure was performed under local anesthetic (lignocaine 1% with adrenaline) then after excision of the lesion including the surgical margin, a flexible shave biopsy blade was utilized to take thin shavings of skin of variable sizes (approximately 10 x 10 mm each) from the annulus. these shavings were carefully placed in a mosaic fashion over the central defect until full coverage was achieved. small bridges of intact skin were left between the donor areas of the figure 1. (a) clinical image of a squamous cell carcinoma of the leg marked up for surgery. the inner circle indicates the planned excision margins. the annulus between the two circles is the planned donor-site. the radius of the outer circle is approximately 1.5 times the radius of the inner circle. (b) skin has been harvested from the donor site and laid in mosaic pattern on the surgical defect. (c) appearance of the surgical site at the time of the first dressing change seven days after surgery. (d) appearance of the surgical site six months after surgery. [copyright: ©2013 fietz et al.] 46 research | dermatol pract concept 2013;3(4):11 table 1. results of all data analyzed in this study age sex size (mm) site histology dressing (weeks) post op bleed margins positive margins inadequate graft failure infection tumour recurrence 1 83 f 23 leg scc 4             2 76 m 20 leg scc 2 yes           3 84 f 30 ankle scc 7             4 79 m 24 leg bcc 3             5 77 m 22 leg bcc 4             6 81 f 14 ankle scc 4         yes   7 75 f 32 ankle scc 6       yes yes   8 80 f 11 leg scc 2             9 76 m 25 ankle bcc 4 yes           10 90 f 25 leg scc 7             11 83 f 20 leg scc 3             12 83 f 19 ankle scc 2             13 67 m 12 leg bcc 3             14 77 f 23 leg iec 5 yes           15 74 f 10 leg bcc 3             16 58 f 14 leg scc 2             17 77 f 15 leg ka 3             18 72 f 17 leg scc 3           yes 19 77 f 23 leg scc 7     yes       20 75 m 12 leg scc 3             21 79 f 16 ankle bcc 3             22 80 f 14 leg ka 3             23 84 f 25 leg iec 6             24 70 f 12 leg ka 2             25 85 m 18 leg scc 4             26 92 f 23 leg scc 4             27 87 m 14 leg bcc 3             28 80 f 25 leg scc 3             29 88 f 16 ankle bcc 4             30 79 f 13 leg scc 3             31 81 f 12 ankle scc 4     yes   yes   32 84 f 25 leg scc 3     yes       33 71 m 17 leg bcc 3             34 59 m 20 leg scc 3 yes           35 84 m 30 ankle scc 3             36 68 m 11 leg scc 3             37 91 m 17 ankle bcc 3             38 91 m 15 leg bcc 4             39 91 m 19 leg iec 4             40 83 f 23 leg scc 3             41 81 f 20 leg scc 3             42 74 f 22 leg scc 5             43 79 f 20 leg ka 3             44 77 m 40 ankle scc 3             45 49 f 20 leg scc 4             46 69 m 14 leg scc 3             47 69 m 20 leg bcc 3             48 77 m 15 leg bcc 3             research | dermatol pract concept 2013;3(4):11 47 flap-closure, the hssg does not require sutures which is arguably an advantage in the elderly where flap closure requiring any significant tension causes a risk of ‘pull-through’ of suture material in the often friable, fragile skin of the leg. a ssg is generally more likely than a full thickness skin graft to survive under suboptimal conditions and can be used to cover larger defects [3] which make the hssg procedure arguably well suited to the leg. compared to the study by paul [1] this study involved a larger group of patients (68 compared to 28) with a greater range of ages and an older mean age (78 compared to 71). while the average size of the lesion was smaller (19.4 mm compared to 31 mm), the size range was greater (9-75 mm compared to 20-45 mm). this result in this study may have been skewed by the inclusion of histopathological macro measurements (which are usually under-estimated due to specimen shrinkage in formalin) of the lesions in cases where specimen size was not stated in the pre-operative notes. first-day post-operative bleeding occurred in 4 cases. this occurred only in graft procedures that were performed earlier in the study prior to the change to the use of aluminum chloride 35% as a hemostatic agent to the donor site. this would be an area where further research with respect to risks and benefits of using aluminum chloride as a hemostatic agent for this type of wound would be useful. the number of lesions that did not have clear margins at the time of surgery was 2/68 (2.9%) (one bcc and one scc). potentially inadequate due in each case to the deep surgical margin having tumor clearance of less than 1mm. tumor recurrence occurred in 1/68 (1.5%) and this was in spite of the fact that the histopathological report had stated that the surgical margins were clear. the average healing time was 4 weeks. the healing times were as follows: 6/68 (8.8%) by week 2, 35/68 (51.4%) by week 3, 51/68 (75%) by week 4, 54/68 (79.4%) by week 5, 60/68 (88.2%) by week 6, 63/68 (92.6%) by week 7 and 67/68 (98.5%) by week 8. the last patient (1.5%) did not heal until week 20 and was therefore considered to have had a graft failure. the overall infection rate was 8/68 (11.8%) and this consisted of 4/15 (26.7%) ankle grafts and 4/53 (7.5%) leg grafts. the graft failure rate was 7/68 (10%) and three of these were co-infected. five of the infected grafts did not fail (see table 1). post-operative bleeding on the first day occurred in 4/68 (5.9%), but bleeding did not result in infection or graft failure in any of these cases. discussion the hssg procedure supports the concept of early mobilisation after a ssg procedure, which is known to reduce postoperative complications such as deep vein thrombosis while showing a similar outcome in healing times when compared to the traditional post-ssg bed rest protocols [7,8]. in contrast to age sex size (mm) site histology dressing (weeks) post op bleed margins positive margins inadequate graft failure infection tumour recurrence 49 78 m 26 leg scc 4             50 65 f 15 ankle scc 8       yes     51 80 m 15 leg scc 6             52 82 f 15 leg scc 3             53 71 f 23 leg scc 8         yes   54 76 m 19 leg bcc 3             55 89 m 30 leg bcc 20       yes yes   56 75 m 10 leg bcc 2             57 83 m 17 leg scc 5             58 78 m 16 leg bcc 8   yes     yes   59 79 m 9 leg scc 4             60 95 f 35 leg scc 4   yes     yes   61 95 f 21 leg scc 3             62 68 m 11 leg scc 4             63 77 m 23 ankle bcc 6       yes yes   64 77 m 25 leg scc 4             65 65 m 21 leg scc 8       yes     66 81 f 15 leg ka 3             67 78 m 35 ankle bcc 6       yes     68 78 m 15 ankle scc 6       yes     abbreviations used: scc: squamous cell carcinoma; bcc: basal cell carcinoma; ka: 48 research | dermatol pract concept 2013;3(4):11 ciency and diabetes. the older population of this study may be relevant in that regard. graft failure was declared in any wound that took more than 8 weeks to heal or which was described in the notes as having had a graft failure. while the infection rate was 8/68 and the graft failure rate similar at 7/68, there were 5 infected grafts that did not fail. ankle hssg however were over-represented with five of the graft failures involving ankle grafts. post-operative bleeding, which occurred in 4/68 cases, was not associated with either infection or graft failure (see table 1). it is not known whether the slight deviations in surgical method or the difference in dressing protocol to that described by paul [1], contributed to the graft failure rate. however it is clear that the hssg at the ankle were not always successful. there have been arguments expressed against using this technique for any skin cancer due to the concept of fieldcancerization, which refers to the potential for the donor skin to contain cancer cells which may cause tumor to arise at the graft site. in response to this it is a fact that flap closure also places skin from tumor margins over the surgical defect. a recurrence did occur once during this study despite the margins having been reported as clear in the histopathology report. although this may have been an example of field cancerization it could also have been due to limitations of histopathology methodology when assessing margins using standard techniques. specifically, paul maintains that the hssg is not suitable for wound closure after melanoma excision because of the risk of field cancerization [1] and hssg was not employed in this study after melanoma excision. the authors of this study agree with the subjective observations made by paul comparing the hssg compared to traditional ssg where he stated that the contour gradient was smaller, the color and texture match to surrounding skin was superior and the reported patient pain levels were less [1]. objective measurement of these characteristics is an area of potential future research. a major limitation of this study is that it was retrospective. it was totally reliant on the comprehensiveness of the notes that were taken by the practitioners and the nursing staff at the time of treatment and the subsequent interpretation of those notes by the researcher. overall, this study highlights a number of areas in which more research is desirable. a prospective randomized study of patients allocated to a traditional ssg procedure or a hssg procedure, would be a useful future study. conclusion the results of this study suggest that the hssg is a reasonable choice for wound management after excision of nmsc on the leg when primary closure or skin-flap closure is not posthese cases were not routinely re-excised but were assessed on an individual basis taking into account the patient’s morbidity at the time and in fact they were both managed by ongoing surveillance. in addition, margins assessed as inadequate according to current guidelines [6] occurred in another 3/68 (4.4%) of the cases (all sccs) and similarly these cases were managed by observation rather than re-excision. it is acknowledged that the hssg procedure is unique in that the skin from the surgical margin is placed over the defect in contrast to traditional ssg procedures where the skin from a remote site is used. it is also acknowledged that this is done in a non-oriented manner. for this reason it would appear to be advisable to respond to a positive margin with a hssg procedure by total removal of the graft, in contrast to the situation where a traditional skin graft or skin flap procedure has been employed where orientation of the specimen permits targeted re-excision if a margin is positive. although there was no clear protocol followed for positive or inadequate margins in the practice, which is the subject of this retrospective observational study, there is a good argument for establishing a protocol for dealing with these in the future. one such protocol could include delaying ssg closure of wounds by 24-48 hours while awaiting pathology results regarding histological margins, in order to establish that clear margins have been obtained. while mohs surgery would be optimal prior to closure, it is not affordable for most patients. the average time taken for wound healing was longer in this study compared to that of paul (28 days compared to 17). it is acknowledged that the deviation from the protocol of paul may have influenced slower healing rates although this is not the explanation in the opinion of the authors. the estimation of healing time on a weekly basis using a surrogate marker as described is likely to have produced an overestimation but it was the only method available in this retrospective study. the infection rate was higher in this study (11.8% of all leg and ankle hssgs compared to 0% by paul [1]), which may have also contributed to the overall increased time taken to heal. it is known that wounds on the lower leg have a higher rate of infection than wounds on some other sites of the body, with an increased infection rate with a more distal location from the knee [9,10]. this is reflected in this study with the infection rate for ankle grafts being proportionately higher than that for the leg (26.7% vs. 7.5%). it is also possible that the infection rate in this study was overestimated by the researcher due to the methods used to collect the data, by which all instances of antibiotic prescribing were classified as due to wound infection if they occurred after the time of surgery and if an alternative reason for the prescription was not clear. other potential causes of the higher wound infection rate and slower healing times are the warmer and more humid climate of the region [10] and patient co-morbidities such as peripheral vascular disease, chronic venous insuffiresearch | dermatol pract concept 2013;3(4):11 49 4. behan fc. the keystone design perforator island flap in reconstructive surgery. anz j surgery. 2003;73:112-20. 5. dixon aj, dixon mp. reducing opposed multilobed flap repair, a new technique for managing medium sized low leg defects following skin cancer surgery. dermatol surg. 2004;30:1406–11. 6. basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in australia. cancer council australia and australian cancer network, sydney, 2008. 7. luczak b, ha j, gurfinkel r. effect of early and late mobilisation on split skin graft outcome. australas j dermatol. 2012;55(1): 19-21. 8. tallon b, oliver g. comparison of inpatient bed rest and home convalescence following split skin grafting to the lower leg. australas j dermatol. 2007;48(1):11-15. 9. dixon aj, dixon mp, askew da, wilkinson d. prospective study of wound infections in dermatologic surgery in the absence of prophylactic antibiotics. dermatol surg. 2006;32(6):819-26. 10. heal c, buettner p, browning s. risk factors for wound infection after minor surgery in general practice. med j aust. 2006 sep 4;185(5):255-8. sible. it allows patients to remain out of hospital, to continue to mobilize and to convalesce at home. it also confines the surgical wounds, and thus local anesthetic infiltration, surgical healing and wound dressing to a single site. the authors of this study agree with paul that the hssg is a technique that does not require specialized equipment and that it is an economical and effective procedure for managing nmsc on the leg when ssg is indicated. references 1. paul sp. ‘halo’ grafting: a simple and effective technique of skin grafting. dermatol surg. 2010;36:115-9. 2. parker t. (april 2011) halo grafts: why you don’t need to dread skin cancers on the lower leg anymore. presentation at american academy of dermatology, 43rd annual meeting of american college of mohs surgery, las vegas, usa. 3. robinson j, hanke w, siegel, d, fratila a. surgery of the skin, 2nd ed. philadelphia: mosby elselvier, 2010. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023146 1 phenotypic and genetic features that differ between hereditary and sporadic melanoma: results of a preliminary study from a single center from turkey aysel cakir¹, gonca elcin¹, saadettin kilickap², özay gököz³, zihni ekim taskiran4, i̇smail celik² 1 hacettepe university faculty of medicine, department of dermatology and venerology, ankara, turkey 2 hacettepe university faculty of medicine, department of medical oncology, ankara, turkey 3 hacettepe university faculty of medicine, department of medical pathology, ankara, turkey 4 hacettepe university faculty of medicine, department of medical genetics, ankara, turkey key words: melanoma, hereditary melanoma, sporadic melanoma, cdkn2a, mc1r citation: cakir a, elcin g, kilickap s, gököz ö, taskiran ze, celik i̇ phenotypic and genetic features that differ between hereditary and sporadic melanoma: results of a preliminary study from a single center from turkey. dermatol pract concept. 2023;13(3):e2023146. doi: https://doi.org/10.5826/dpc.1303a146 accepted: january 12, 2023; published: july 2023 copyright: ©2023 cakir et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this study was supported by the hacettepe university faculty of medicine, scientific search projects support unit (project number: 16087). competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: aysel cakir, lokman hekim akay hospital, büklüm cad. no: 4, 06700 kavaklıdere/çankaya/ankara telephone: +905301023765 e-mail: drayselcakir@hotmail.com introduction: most melanoma patients under our supervision lack characteristic phenotypic features for melanoma. in contrast, history of cancers other than melanoma and early age at onset were common. this observation was in favor of hereditary melanoma. objectives: to search for the phenotypic and genetic features that differ between sporadic and hereditary melanomas. methods: in order to reveal phenotypic features, detailed physical exam was conducted to all melanoma patients (n = 43) and for genetic features. cdkn2a and mc1r mutations were detected with sanger sequencing method. assignment to hereditary and sporadic groups was done according to the “melanoma cancer syndrome assessment tool”. patients who were diagnosed before the age of 50 were also assigned to the hereditary melanoma group. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023146 introduction cutaneous melanoma is a malignant solid tumor that arises from melanocytes in the skin. melanoma accounts for approximately 2-5% of all skin cancers, but is the most common cause of skin cancer-related deaths. if melanoma is diagnosed early, it can be treated by simple excision, thus cancer-related morbidity and mortality may be prevented [1]. therefore, it is important to identify groups at high risk for melanoma development. three main risk factors namely, environmental factors, phenotypic features and genetic features and intermittent intense sun exposure play role in melanoma development. the most common environmental risk factor for the development of melanoma is intermittent intense sun exposure [2]. fair skin, fair hair and eye color, freckles, multiple solar lentigines, tendency to sunburn and inability to tan are the best-known phenotypic risk factors. approximately 5-10% of melanomas develop due to genetic factors and this type of melanomas are called hereditary melanomas [3]. genes associated with melanoma range from rare but high-penetrating tumor suppressor genes such as cyclin-dependent kinase inhibitor 2a (cdkn2a), to very common but medium-penetrating genes such as the melanocortin 1 receptor gene (mc1r). the first gene described as a risk factor for hereditary melanoma is cdkn2a. germline mutations in the cdkn2a gene are responsible for 40% of the hereditary melanoma patients [4,5]. mc1r normally determines the hair and skin color and can lead to melanoma development through both pigment-related and non-pigment-related pathways [6]. mc1r increases the penetration of cdkn2a from 50% to 84% thus called the "melanoma modifier gene" [7]. leachman et al suggested that in addition to melanoma-dominant pattern of inheritance like cdkn2a gene mutations, melanoma can also be a part of other cancer syndromes like hereditary breast ovarian cancer syndrome, li fraumeni syndrome, xeroderma pigmentosum, phosphatase and tensin homolog (pten) hamartoma syndrome. they suggested that patients with a family history of pancreatic cancers, neurologic cancers, renal cell carcinoma and/or mesothelioma should rise suspicion for these cancer syndromes  [8]. this overlap might likely to have major implications for genetic testing. it is possible that families that fail to meet the genetic testing criteria for a melanoma-dominant syndrome, still may carry an increased risk for melanoma cancer syndromes. leachman et al. offered a comprehensive cancer gene assessment tool for families with a hereditary pattern of cancer that includes melanoma [8]. the incidence of melanoma in turkey according to the ministry of health unified database in 2014 is 1.8 per 100000 in men and 1.2 per 100000 in women which might be considered as quite low when compared with the incidence of melanoma in europe where it ranges from 2.2 to 19.2 per 100000 people [9,10]. interestingly, we have observed that most of the melanoma patients under our supervision had dark hair, darker skin color and had less sun exposure than expected for melanoma development. in contrast, we have realized that most of them had personal and/or family history of cancers other than melanoma and/or were diagnosed before 50 years of age. thus, we have hypothesized that, in our patient group genetic risk factors rather than phenotypic features may play a more important role at the development of cancer/melanoma. objectives the aim of this study was to define the phenotypic and genetic features that differentiate hereditary melanomas from sporadic melanomas. methods after the approval of the ethics committee, 43 histologically confirmed patients with cutaneous melanoma were recruited for this prospective study between february 2017 and october 2017 at the department of dermatology, university of hacettepe faculty of medicine, ankara, turkey. a face-to-face questionnaire was applied to all patients. after the dermatological examinations of the patients were completed, a whole-body nevus examination was performed results: thirty-one patients were assigned to the hereditary group and 12 to the sporadic group. fair eye color was statistically significantly higher in the sporadic group (p = 0.000). cdkn2a was detected in only 1 patient in the hereditary group. mc1r mutations were found in 12 out of 13 (92.3%) in the hereditary group with a score ≥3 points, 13 out of 18 (72.2%) in the early age at onset group and 5 out of 12 (41.7%) in the sporadic group (p = 0.024). conclusions: incidence of cdkn2a mutations in our hereditary group is in accordance with the reported incidences from mediterranean countries. the difference between the hereditary and sporadic groups in terms of mc1r mutations supports the idea that mc1r genetic testing might help to determine patients with higher risk for hereditary melanoma. original article | dermatol pract concept. 2023;13(3):e2023146 3 using the dermlite® hand dermatoscope, and then the nevi were recorded using the fotofinder® universe version 2.0.39.3(x64) digital dermatoscope. sociodemographic features (age, sex, occupation, place of birth, place of current residence, phenotypic features (hair color, eye color, skin phototype and presence of freckles), treatments taken before to the diagnosis of melanoma (whether the patients received immunosuppressive therapy and/or any phototherapy such as narrowband ultraviolet b, psoralen ultraviolet a (puva) and /or local puva therapy), sun exposure (the patients history of working outdoors and its duration, whether they participated in outdoor sports and similar activities, the habit and duration of vacation in sunny holiday resorts, the habit and duration of sunbathing, the history and age of second-degree sunburns, the history and age of indoor tanning, the characteristics of sun protection habits, including using sunscreen), genetic factors (the personal history and family history including the presence of melanoma and other cancers in the individual and/or their first and second degree relatives) were questioned and recorded in the questionnaire form. the stage of melanoma at diagnosis, anatomical location of melanoma, histopathological features of melanoma (breslow thickness, presence of ulceration, presence and number of mitoses, presence of lymphocytic infiltration, late regression, presence of lympho-vascular invasion) were noted on a separate sheet, namely the examination form. the presence of re-excision after diagnosis and/or sentinel lymph node biopsy were recorded at the examination form. total number of nevi, anatomic location of the nevi, number of typical and atypical nevi, number and size of giant congenital melanocytic nevi, number of actinic keratosis, presence of solar lentigo, presence of photo aging, presence and number of pigmented lesions in the iris on inspection were recorded on the examination form. body mass index was calculated for each patient. additional findings such as benign skin tumors (eg cherry angiomas) were also recorded. assignment of patients to subgroups as shown in figure 1 the assignment of patients into hereditary or sporadic melanoma subgroups was done according age >50 (n = 12) age = <50 (n = 18) leachman score ≥3 (n = 13) age at onset hereditary (n = 30) utilization of melanoma cancer assessment tool all patients (n = 43) le achman score <3 (n = 30) sporadic (n = 12) figure 1. assignment of melanoma patients into sporadic and hereditary subgroups. 4 original article | dermatol pract concept. 2023;13(3):e2023146 was performed with the qiaquick pcr purification kit (qiagen gmbh) according to the manufacturer protocol. for the sequencing of the pcr products, the sequence reaction consisting of purified pcr product, distilled water, primer and bigdye® terminator mixture was prepared and allowed to react in the thermal cycler. for the sequencing reaction of pcr products forward and reverse primers were used when necessary. finally, after pre-sequence purification with zr® dna sequencing clean-up kit (zyno research), samples were abi 3500 genetic analyzer (applied biosystems) and analyzed using sequencing analysis software. statistics spss 23.0 (ibm) was used to analyze the data. descriptive statistics were calculated with data. the accordance of the quantitative data for normal distribution was evaluated by the shapiro-wilk test. the difference between the two groups of normally distributed independent variables was compared with the significance test of the difference between the two means. the variables not showing normal distribution were compared with mann-whitney u test. qualitative variables were evaluated by chi-square test by cross tables. all analyses were tested at the 0.05 significance level. to the “melanoma cancer syndrome assessment tool” [8]. as shown in table 1 according to this tool 13 patients received ≥3 points (leachman score ≥3) and were assigned to the hereditary melanoma group. in addition, in this study patients who received <3 points, but who were diagnosed before the age of 50 were also assigned to the hereditary melanoma group. sporadic melanoma group consisted of 12 patients who scored less than 3 points and who were diagnosed after age 50. cdkn2a and mc1r germline gene mutations were detected with sanger sequencing method in laboratories of hacettepe university faculty of medicine, department of medical genetics. dna sequence analysis with sanger method polymerase chain reaction (pcr) was performed, including the exon and exon-intron junction points of cdkn2a and mc1r genes. primer sequences required for amplification were designeed using the perlprimer program. gotaq® (thermus aquaticus) dna polymerease enzyme (promega) was used for the pcr reaction. the pcr reaction was completed under the amplification conditions specified in the veriti thermal cycler device (thermo fischer scientific), and the products were checked. following the amplification, the purification of pcr products table 1. details of leachman scores of 13 patients who received ≥3 points with the utilization of melanoma cancer syndrome assessment tool. patient number cancer type occurrence in the first or second degree relative leachman score 1 melanoma breast cancer prostate cancer mother, maternal uncle, melanoma proband, aunt and sister father and paternal uncle 6.5 2 pancreatic cancer renal cell carcinoma paternal grandfather father 4.5 3 melanoma colon cancer paternal uncle daughter 4 4 breast cancer colon cancer 2 sisters maternal uncle 3.5 5 breast cancer over cancer sister melanoma proband 3.5 6 breast cancer prostate cancer aunt paternal uncle uncle and grandfather 3.5 7 pancreatic cancer aunt 3 8 pancreatic cancer sister 3 9 pancreatic cancer brother 3 10 second melanoma pancreatic cancer melanoma proband father 3 11 melanoma sister 3 12 melanoma sister 3 13 renal cell carcinoma father 3 original article | dermatol pract concept. 2023;13(3):e2023146 5 in outdoor sports and/or similar activities (p = 1.000), history of summer vacation in sunny resorts (p = 0.672), time spent on summer vacation in sunny resorts (p = 0.497), sunbathing (p = 1.000), second degree sunburn (p = 0.497), protection with clothing (p = 0.311) and using sunscreen (p = 0.159). the histopathological features of melanoma were not statistically different in both group in terms of breslow thickness (p = 1.000), presence of ulceration (p = 1.000), presence of mitosis (p = 1.000), lymphocytic infiltration (p = 0.721), late regression (p = 1.000) and/or sentinel lymph node biopsy (p = 1.000). mutational analysis cdkn2a mutation was detected in only 1 patient in the hereditary melanoma group (1/31); whereas no patient in the sporadic melanoma group (0/12) had cdkn2a mutation. the only cdkn2a mutation positive patient belonged to the leachman score ≥3 subgroup of hereditary melanoma (1/13). as shown in figure 2 the mutation found was cdkn2a heterozygous a118v. mc1r mutations were found in 25 out of 31 (80.6%) patients in the hereditary melanoma group; whereas 5 out of 12 (41.7%) patients in the sporadic melanoma group (p = 0.024) (odds ratio=5.833). among the 13 patients with leachman score ≥3, 12 had mc1r mutations (92.3%) whereas, 13 out of 18 patients (72.2%) who scored <3  points but were diagnosed before 50 years of age had mc1r mutations. the most common mc1r variant in all patients was the v60l variant. the distribution of different variants of mc1r mutations observed in hereditary and sporadic results patients and melanoma characteristics twenty-seven (62.6%) of 43 patients were female and 16 (37.2%) were male. the mean age of patients was 50.72±12.21 years (22-75 years). the mean age at diagnosis was 48.95±12.13 years (range 22-70 years). there were 10 patients diagnosed before the age of 40. of 10 patients diagnosed before age 40, 7 were female and 3 were male. there were 22 patients diagnosed before the age of 50. regarding the phenotypic features, the only phenotypic feature that differed in the hereditary and sporadic melanoma groups was the fair eye color, which was more common in the sporadic melanoma group (p = 0.000). all 12 patients (12/12) assigned in the sporadic melanoma group had fair eye color. whereas 13 out of 31 patients assigned to the hereditary melanoma group had fair eye color. all other sociodemographic data, features related to sun exposure and clinical characteristics questioned and/ or examined in this study displayed similar distributions namely; gender (p = 0.092), hair color (p = 1.000), skin phototype (p = 0.091), presence of freckles (p = 0.719), number of nevi (p = 0.565), number of nevi in the head and neck region (p = 0.208), number of nevi in the upper extremity (p = 0.342), number of nevi on the trunk (p = 0.690), number of nevi in the lower extremity (p = 0.650), number of atypical nevi (p = 0.837), number of lesions excised from the skin (p = 0.316), presence of solar lentigines (p = 0.507), presence of cherry angioma (p = 1.000), ≥1 pigmented lesions in the iris (p = 0.052), history of working outdoors (p = 0.453), outdoor-working time (p = 1.000), participating figure 2. heterozygous cdkn2a c.353c>t p.a118v. mutation 6 original article | dermatol pract concept. 2023;13(3):e2023146 study, cdkn2a mutation was detected in only 1 out of 43 patients. this 1 patient belonged to the hereditary melanoma group with leachman score ≥3 points (n=13). although the sample size in our study is small, the incidence of cdkn2a in the hereditary melanoma group with leachman score ≥3 was 1/13 (7.7%), which is in accordance with rates recorded from italy. unfortunately, hereditary melanoma definition is not straight forward and differs from study to study. because melanoma incidence is quite low in our country, we have decided to keep the criteria for the “hereditary melanoma” as wide as possible in the current study in order not to miss any patients with relevant clues for a hereditary disease. typical features of true hereditary melanoma/cancer syndromes include features such as unilateral lineage, multi-generational inheritance, multiple primary lesions and early onset of disease [3]. patients who exhibit all of these features are in fact quite rare. a score ≥ 3 in the leachman scoring system helps to differentiate patients with predisposition for hereditary cancers. however, age is not used as a criterion in leachman scoring system and we believe “early age at diagnosis” is a very strong predictor for any disease that is hereditary. this was the reason for a second category in our study as “leachman score <3 and age at onset <50 years”. our results with mc1r genetic testing confirm that adding "age" had an impact on the differentiation between the sporadic and the hereditary melanoma patients. as shown in table 2, mc1r variant positivity was highest in “leachman score ≥ 3” subgroup of patients, intermediate in the early age at onset subgroup of hereditary melanoma patients and melanoma groups did not show a statistically significant difference. mc1r gene variants, red hair color (rhc) and nonred hair color (non-rhc) variants are listed in table 2. conclusions the aim of this study was to determine the phenotypic and genetic features that differ among the hereditary and sporadic melanoma groups. in regard to the phenotypic features, results show that fair eye color was the only statistically significantly different feature among all phenotypic features examined in this study. all 12 patients assigned to the sporadic melanoma group in this study had fair eye color, namely blue, green or hazel. in accordance with this finding and taking into consideration that a greater percentage of our population has dark eye color, we suggest that fair eye color should be the alarming sign for dermatologist for a detailed whole body skin examination and a detailed explanation of sun protection to these patients. cdkn2a mutations were found in 40% of melanoma families worldwide [4]. however, this rate varies geographically. for example, this rate was 20% in australia where melanoma is very common in contrast, it was 45% in north america and 57% in europe [11]. regarding the mediterranean area in europe cdkn2a mutations were found in 7.2% of melanoma families in north-eastern italy and 8.3% for italy in general [12,13]. in spain, a total of 30% of the melanoma kindred studied were carriers of cdkn2a variant [14]. in another study conducted in spain cdkn2a mutation was found in 15 of 87 families (17.2%) [15]. in our table 2. mc1r gene variants in hereditary and sporadic melanoma patients. mc1r gene variants n (%) hereditary melanoma n=31 (%) sporadic melanoma (n=12) (%)rhc variants leachman score ≥3 (n=13) (%) <50 years of age (n=18) (%) r160w 7 (16.7) 4 (23.5) 1 (5) 2 (40) r151c 3 (7.1) 2 (10) 1 (20) r142h 2 (4.8) 1 (5.9) 1 (5) non-rhc variants v60l 9 (21.4) 5 (29.4) 3 (15) 1 (20) r163q 8 (19) 3 (17.6) 5 (25) c.942a>g 5 (11.9) 2 (11.8) 3 (15) k278e 2 (4.8) 1 (5.9) 1 (5) c35y 1 (2.4) 1 (5.9) v59l 1 (2.4) 1 (5) r67q 1 (2.4) 1 (5) v92m 1 (2.4) 1 (5) i120t 1 (2.4) 1 (20) c.699a>g 1 (2.4) 1 (5) original article | dermatol pract concept. 2023;13(3):e2023146 7 references 1. jemal a, siegel r, ward e, et al. cancer statistics, 2008. ca cancer j clin.  2008;58(2):71-96. doi: 10.3322/ca.2007.0010. pmid: 18287387. 2. gandini s, sera f, cattaruzza ms, et al. meta-analysis of risk factors for cutaneous melanoma: ii. sun exposure. eur j cancer. 2005;41(1):45-60.  doi: 10.1016/j.ejca.2004.10.016 . pmid: 15617990. 3. leachman sa, carucci j, kohlmann w, et al. selection criteria for genetic assessment of patients with familial melanoma. j am acad dermatol. 2009;61(4):677.e1-e14.  doi: 10.1016/j .jaad.2009.03.016. pmid: 19751883. pmcid: pmc3307795. 4. goldstein am, chan m, harland m, et al. high-risk melanoma 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vries e, bailey ee, geller ac. melanoma incidence and mortality in europe: new estimates, persistent disparities. br j dermatol. 2012;167(5):1124-1130. doi: 10.1111/j.1365-2133.2012.11125.x.  pmid: 22759278. 10. turkish ministry of health-public health institution. cancer statistics of turkey (türkiye kanser istatistikleri). 2017:1-48. https://hsgm.saglik.gov.tr/tr/kanser-istatistikleri/yillar/2017 -turkiye-kanser-i-statistikleri.html 11. goldstein am, chan m, harland m, et al. features associated with germline cdkn2a mutations: a genomel study of melanoma-prone families from three continents. j med genet. 2007;44(2):99-106.  doi: 10.1136/jmg.2006.043802. pmid: 16905682. pmcid: pmc2598064. 12. landi mt, kanetsky pa, tsang s, et al. mc1r, asip, and dna repair in sporadic and familial melanoma in a mediterranean population. j natl cancer inst. 2005;97(13):998-1007.  doi: 10.1093/jnci/dji176. pmid: 15998953. 13. pellegrini c, maturo mg, martorelli c, et al. characterization of melanoma susceptibility genes in high-risk patients from central italy. melanoma res. 2017;27(3):258-267.  doi: 10.1097 /cmr.0000000000000323. pmid:  28146043. pmcid: pmc 7050442. 14. de torre c, garcia-casado z, martínez-escribano ja, et al. influence of loss of function mc1r variants in genetic susceptibility of familial melanoma in spain. melanoma res. 2010;20(4):342-348.  doi: 10.1097/cmr.0b013e32833b159d. pmid: 20539244. lowest in the patients assigned for sporadic melanoma group and the difference between the sporadic and hereditary groups were statistically significant. the difference between the two groups in terms of mc1r mutations supports the idea that mc1r genetic testing might help to determine patients with higher risk for hereditary melanoma. in our patient group the presence of mc1r variants was not associated with hair colour, eye color, skin phototype, presence of solar lentigines, presence of freckles or the number of nevi. this data is in agreement with the fact that most of our patients had dark hair (85.7%) and approximately 50% had skin phototype iii and above. this finding strengthens our hypothesis that genetic features may account for the majority of melanomas in our study group rather than phenotypic features or environmental factors. studies have reported that mc1r mutations increase the risk of developing melanoma 2-4 times in individuals with both familial and sporadic melanoma [12,16]. it is also reported that this risk was particularly high in individuals with darker skin colour and/or a lower number of nevi [12]. we know that one person can have more than one mc1r variant. to date more than 80 mc1r variants have been identified in caucasians [6]. the variants and the frequencies of the variants monitored vary according to the geographical regions and prevalence of melanoma. as the variant number of mc1r increases, the risk of new melanoma development increases [12]. it has been reported that the most common variant among mc1r variant in caucasians is v60l [12,13,16–20]. in our study, in accordance with the literature, the most common variant was also v60l. our data is consistent with the current literature. in conclusion, in turkey, there was no previous data on the cdkn2a and mc1r germline gene mutations in individuals with neither hereditary nor sporadic melanoma. our study gives at least an estimation of the occurrence of cdkn2a and mc1r germline gene mutations in melanoma patients in turkey. located at the capital city our hospital drains patients from all over turkey and has a wide range of different patient profiles. the small sample size of this study may also be a reflection of the low incidence of melanoma in our country. for those countries where melanoma is rare and where the majority of the population has dark skin, we suggest using “early age at onset” as an additional criterion to melanoma cancer syndrome assessment tool for a more precise detection of hereditary cancer/melanoma cases. acknowledgements: the patients in this manuscript have given written informed consent to publication of their case details. this study was supported by the hacettepe university faculty of medicine, scientific search projects support unit (project number: 16087). 8 original article | dermatol pract concept. 2023;13(3):e2023146 18. casula m, muggiano a, cossu a, et al. role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from south italy. bmc cancer. 2009;9:352.  doi: 10.1186/1471-2407-9-352. pmid:  19799798. pmcid: pmc 2763007. 19. koulermou g, shammas c, vassiliou a, et al. cdkn2a and mc1r variants found in cypriot patients diagnosed with cutaneous melanoma. j genet. 2017;96(1):155-160. doi: 10.1007/ s12041-017-0742-6. pmid: 28360400. 20. müller c, wendt j, rauscher s, et al. characterization of patients at high risk of melanoma in austria. br j dermatol.  2016; 174(6):1308-1317. doi: 10.1111/bjd.14407. pmid: 26800492. 15. huertas c, garcia-casado z, bañuls j, et al. characteristics of familial melanoma in valencia, spain, based on the presence of cdkn2a mutations and mc1r variants. acta derm venereol. 2018;98(5):512-516.  doi: 10.2340/00015555-2898. pmid: 29405243. 16. stratigos aj, dimisianos g, nikolaou v, et al. melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern european population. j invest dermatol. 2006;126(8):1842-1849.  doi: 10.1038/sj.jid.5700292. pmid: 16601669. 17. gerstenblith mr, goldstein am, fargnoli mc, peris k, landi mt. comprehensive evaluation of allele frequency differences of mc1r variants across populations. hum mutat. 2007;28(5):495-505.  doi: 10.1002/humu.20476. pmid: 172 79550. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023133 1 evaluation of the incidence of anal fissures in patients who systemic isotretinoin therapy for acne hamza aktas1, zeynep şener bahçe2 1 private memorial hospital, department of dermatology, diyarbakır, turkey 2 private memorial hospital, department of general surgery, diyarbakır, turkey key words: acne vulgaris, isotretinoin, adverse events, anal fissure, constipation citation: aktaş h, şener bahçe z. evaluation of the incidence of anal fissures in patients who systemic isotretinoin therapy for acne. dermatol pract concept. 2023;13(3):e2023133. doi: https://doi.org/10.5826/dpc.1303a133 accepted: january 11, 2023; published: july 2023 copyright: ©2023 aktaş et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: hamza aktaş, private memorial hospital, department of dermatology, fırat bulvarı peyas mahallesi no:12, 21080 kayapınar/diyarbakır, turkey. tel: 0505 6685239 fax: +90 0412 314 66 17 e-mail: drhamzaaktas21@gmail.com introduction: isotretinoin is an effective drug widely used in the treatment of severe acne. in this study, we tried to evaluate the incidence of anal fissures with clinical and laboratory side effects associated with isotretinoin. methods: the study evaluated 210 patients who received systemic isotretinoin treatment. especially patients with constipation and anal bleeding were evaluated by the general surgery clinic to arrange appropriate treatments. results: of 210 patients included in the study, 138 (65.7%) were female and 72 (34.3%) were male, with a mean age of 23.7 years. the most common adverse event was dry lips in 206 (98.1%) patients. the mucocutaneous side effects were constipation 36 (17.1%), anal bleeding 18 (8.6%), mucosal erosion 10 (4.7%), anal fissure 7 (3.3%). treatment was discontinued due to elevated liver function tests in 5 patients (2.3%), and because anal bleeding could not be controlled in 1 patient. conclusions: isotretinoin is the most effective acne medicine used today. clarification of the patients about the rarely seen side effects such as dryness, erosion, fissure and bleeding in the anal mucosa in addition to the common mucocutaneous side effects will ensure that patients are more cautious and increase their tolerance to the treatment. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023133 introduction acne vulgaris is a multifactorial disease of the pilosebaceous unit that affects millions of people around the world to varying degrees. it affects about 85% of the young population. although it is primarily a disease of the adolescent period, we observe it in neonatal and infancy periods, as well as prepubertal period and advanced age patients [1-3]. primary pathogenic factors of acne are increased sebum production, changes in keratinization process, follicular colonization with the natural immune activation of propionibacterium acnes and increased inflammation. lesions of various variations such as come done, papule, pustule, nodule and rarely cyst, characterize acne [4]. the distribution of acne lesions is often the face, back, chest and shoulder areas where sebaceous glands are densely located. treatment of acne vulgaris varies based on the type, extent and severity of the lesions. while topical antibiotics and retinoid are the first choice in the treatment of mild acne, systemic antibiotics and anti-androgenic agents are used in moderate to severe acne [5,6]. the most effective treatment method for severe acne is systemic isotretinoin. isotretinoin is an agent that suppresses sebum production and is effective on all pathogenic factors that play a role in the formation of acne and has been used in the usa since 1982 in the treatment of severe nodulocystic and persistent acne. however, as antibiotic resistance is increasing worldwide, antibiotic monotherapy has begun to be used less frequently in acne treatment. classically used for nodulocystic acne, isotretinoin has become the drug of choice by dermatologists for moderate acne. it can also be used in seborrheic dermatitis, acne rosacea, and perioral dermatitis resistant to classical treatment [7-9]. treatment protocol recommended in clinical applications is the use of 0.5-1 mg/kg/day over a period of 4-12 months to reach a total dose of 120-150 mg/kg [10]. the most common side effects observed during isotretinoin use are mucocutaneous side effects. mucocutaneous side effects develop secondary to a decrease in sebum production, thinning of the stratum corneum and changes in skin barrier functions, among which the most common side effect observed is cheilitis. almost all patients have cheilitis with varying severity. other common side effects of systemic isotretinoin are nosebleeds, generalized muscle aches, malaise, and dry eyes. the most important side effect of the drug is its teratogenic effect [11,12]. another system in which side effects of isotretinoin are seen is the gastrointestinal system (gis). regarding the side effects of gis, martin et al. have been the first to report a case of proctosigmoiditis in 1987. afterwards, a few more cases have been reported on isotretinoin-related inflammatory bowel disease (ibd) [13,14]. objectives isotretinoin can also dry the anal mucosa, triggering fissure formation. in this study, we evaluated the side effects and especially the development of anal fissures, mucosal damage and rectal bleeding in patients receiving systemic isotretinoin therapy. methods the study included all patients who applied to dermatology clinic between 2018-2019 and received systemic isotretinoin therapy. the data were evaluated retrospectively (the local ethics committee confirmed that formal approval was not required for this retrospective audit of practice). patients with missing data were excluded from the study. participants were informed about the study. adolescents who agreed to participate in the study provided signed informed consent forms. before treatment, all patients and their families were questioned for hyperlipidemia and atherosclerosis. patients’ demographic data such as age and gender as well as body weight, duration of the disease and the medications used were recorded. before treatment, after treatment and at intervals during treatment, the following laboratory values were examined: hemoglobin, hematocrit, leukocyte, platelet count, erythrocyte sedimentation rate (esr), alkaline phosphatase (alp), lactate dehydrogenase (ldh), aspartate aminotransferase (ast), alanine aminotransferase (alt), cholesterol (low density cholesterol (ldl) high density cholesterol (hdl), very low density cholesterol (vldl), triglyceride, creatine kinase (ck), and monthly beta-human chorionic gonadotropin (b-hcg) in female patients. in the monthly follow-ups, all side effects were questioned in detail. especially, patients with gastrointestinal system complaints were referred to the general surgery clinic. the data of the patients, whose detailed examinations were performed here, were recorded on the follow-up form. the treatment of patients who could not tolerate side effects and had abnormal laboratory findings was terminated. the data obtained were statistically analyzed using the software program spss 22.0. continuous variables were expressed as mean ± standard deviation, and variables indicated by count were expressed as percentages. chi-square tests were used in comparisons. results of 210 patients included in the study, 138 (65.7%) were female and 72 (34.3%) were male, with a mean age of 23.7 (16-59). mean body weight of the patients was 62.1 (38-105) kg. the dose of isotretinoin ranged from 20 to 70 mg/day. original article | dermatol pract concept. 2023;13(3):e2023133 3 the treatment was regulated in such a way that 59.2% of our patients received 30 mg/kg/day and 36% received 40/mg/kg/day. the average duration of drug use by patients was detected to be 5.36 months. the most common adverse event of isotretinoin was dry lips in 206 (98.1%) patients. then, dry eye 87 (41.4%), nosebleed 73 (34.7%), muscle pain 58 (27.6%), malaise 56 (26.6%), facial erythema 39 (18.5%), itching 36 (17.1%), constipation 36 (17.1%), xerosis 30 (14.2%), sun sensitivity 21 (10%), joint pain 17 (8.9%), anal bleeding 18 (8.6%), headache 18 (8.6%), hair loss 15 (7.1% ), mucosal erosion 10 (4.7%), mental change 9 (4.2%), menstrual irregularity 8 (3.8%) and anal fissure 7 (3.3%) were observed, respectively (table 1). no patient experienced abdominal pain. five of the patients who developed anal fissure were female and 2 were male, and all had fissure with constipation and anal bleeding. only 2 of 10 patients with mucosal erosion had constipation. in patients with fissure and mucosal erosion, the isotretinoin dose ranged from 30-70 mg/day. it was determined that 8 of 36 cases with constipation already had constipation before treatment. the comparison between gender and anal bleeding revealed that anal bleeding was more common in women (p = 0.029). in addition, no statistically significant difference was observed between gender and constipation (p = 0.226), drug dose given and constipation (p = 0.067), drug dose given and anal bleeding (p = 0.290) and drug dose given and fissure formation (p = 0.835). there was no history of ibd in patients or their families. in 12 of the 210 patients (5.7%) enrolled in the study, elevations in liver function tests were identified, while 7 patients (3.3%) had triglycerides and 3 patients had high cholesterol (1.4%). treatment was discontinued due to elevated liver function tests in 5 patients (2.3%), and because anal bleeding could not be controlled in 1 patient. patients with constipation and anal bleeding were examined in detail by the general surgery clinic. medical treatment, topical moisturizers and appropriate diet were recommended to patients with fissure and mucosal erosion. the dose of isotretinoin was reduced in three patients. in the controls, symptoms were observed to improve except for one patient. conclusions acne vulgaris is a chronic inflammatory disease that primarily concerns adolescents. this condition, which affects 85% of people, is mostly seen in young girls and boys aged [15,16]. acne vulgaris is treated with the use of topical treatments alone or topical and systemic treatments in combination, depending on the severity of the disease [5,6,16,17]. isotretinoin, which is a synthetic retinoid, has been used for many years to treat nodulocystic acne. today, it is used in the treatment of moderate to severe acne, severe seborrheic dermatitis, pyoderma faciale and gram-negative folliculitis, unresponsive to other treatments, including oral antibiotics. isotretinoin is the only drug effective on all factors involved in the pathogenesis of acne vulgaris and is the most effective treatment tool in the treatment of acne vulgaris with a remission rate of up to 70%-89% [18-20]. the most common side effects related to the use of isotretinoin have mucocutaneous characteristics. many of these symptoms are tolerable, treatable, and dose-dependent  [19]. cheilitis, dry nasal, dry eyes are the most common finding and occurs in almost all patients. apart from these side effects, facial erythema, muscle aches, itching, malaise, joint pain and headache are other common side effects [21-25]. many studies have been conducted on gis side effects of systemic isotretinoin. first, martin et al reported a case of isotretinoin-related proctosigmoiditis in 1987 [13]. several other cases of isotretinoin-related ibd have been reported afterwards. this suggests that isotretinoin affects the intestinal mucosa [13,14,17,26]. passier et al thought that three patients receiving isotretinoin with gastrointestinal system complaints might have ibd, and in the colonoscopy examination, ulcerative colitis was detected in two patients and crohn disease in one [27]. however, in recent large-scale studies, no relationship between isotretinoin and ibd could be demonstrated [28-31]. among the rarer gis, side effects of isotretinoin include appendicitis, esophagitis, anorexia and weight loss [32]. table 1. prevalence of adverse effects. adverse effect patients, n (%) dry lip dry eyes nose bleeds (epistaxis) muscle aches (myalgias) tiredness facial erythema itching of the skin constipation xerosis sun sensitivity headaches anal bleeding joint aches (arthralgias) hair loss mood change heavy menstrual periods anal fissure herpes simplex abdominal pain 206 (98.1%) 87 (41.4%) 73 (34.7%) 58 (27.6%) 56 (26.6%) 39 (18.5%) 36 (17.1%) 36 (17.1%) 30 (14.2%) 21 (10%) 18 (8.6%) 18 (8.6%) 17 (8.1%) 15 (7.1%) 9 (4.2%) 8 (3.8%) 7 (3.3%) 2 (1%) 0 (0%) 4 original article | dermatol pract concept. 2023;13(3):e2023133 develop accordingly can be prevented. however, further case-controlled studies with low dose or fixed-dose are needed in order to clarify the relationship between systemic isotretinoin therapy and anal mucosal dryness, constipation, anal fissure, and rectal bleeding. references 1. zaenglein al, thiboutot dm. acne vulgaris. in bolognia jl, jorizza jl, rapini rp, editors. dermatology. 2nd ed. spain, mosby elsevier inc 2008:495-508. 2. rapp da, brenes ga, feldman sr, et al. anger and acne: implications for quality of life, patient satisfaction and clinical care. br j dermatol. 2004;151(1):183-189. doi: 10.1111/j.1365 -2133.2004.06078.x. pmid: 15270889. 3. tom wl, friedlander sf. acne through the ages: case-based observations through childhood and adolescence. clin pediatr (phila). 2008;47(7):639-651. doi: 10.1177/0009922808315444. pmid: 18698096. 4. zanglein al, graber me, thiboutot dm, strauss js. acne vulgaris and acneiform eruptions. in wolff k, goldsmith la, katz si, gilchrest ba, paller as, leffell dj, editors. fitzpatrick’s dermatology in general medicine. 7th ed. new york, mcgraw hill. inc 2008:690-703. 5. olutunmbi y, paley k, english jc 3rd. adolescent female acne: etiology and management. j pediatr adolesc gynecol. 2008;;21(4):171-176. doi: 10.1016/j.jpag.2007.07.004. pmid: 18656070. 6. rigopoulos d, larios g, katsambas ad: the role of isotretinoin in acne therapy: why not as first-line therapy? facts and controversies. clin dermatol.;28(1):24-30. doi: 10.1016/j.clindermatol.2009.03.005. pmid: 20082946. 7. hodgkiss-harlow cj, eichenfield lf, dohil ma. effective monitoring of isotretinoin safety in a pediatric dermatology population: a novel “patient symptom survey” approach. j am acad dermatol. 2011; 65(3):517-524. doi: 10.1016/j .jaad.2010.06.040. pmid: 21632153. pmcid: pmc4336191. 8. lowenstein eb, lowenstein ej: isotretinoin systemic therapy and the shadow cast upon dermatology’s downtrodden hero. clin dermatol. 2011; 29(6):652-661. doi: 10.1016/j.clindermatol .2011.08.026. pmid: 22014987. 9. habeshian ka, cohen ba. current issues in the treatment of acne vulgaris. pediatrics. 2020;145(suppl 2):s225-s230. doi: 10.1542/peds.2019-2056l. pmid: 32358215. 10. cunliffe wj, van de kerkhof pc, caputo r, et al. roaccutane treatment guidelines: results of an international survey. dermatology. 1997;194(4):351-357. doi: 10.1159/000246134. pmid: 9252756. 11. borovaya, a, dombrowski y, zwicker s, et al. isotretinoin therapy changes the expression of antimicrobial peptides in acne vulgaris. archives of dermatological research. 2014;306(8):689-700. doi: 10.1007/s00403-014-1477-3. pmid: 24916439. 12. li w, liu y, luo q, li x-m, zhang x-b. off-label uses of retinoids in dermatology. our dermatol online. 2012;3(suppl. 1): 259-278. doi: 10.7241/ourd.20124.62. 13. martin p, manley pn, depew wt, blakeman jm. isotretinoin-associated proctosigmoiditis. gastroenterology. 1987;93(3):606-609. doi: 10.1016/0016-5085(87)90925-5. pmid:3475230. isotretinoin can affect the anal mucosa, and this can promote mucous dryness, leading to mucosal erosion and fissure formation. anal fissure is a tear in the anoderm distal to the dentate line. the diagnosis of an anal fissure is made with the evaluation of the medical history, preferably on the proctology table, and basically through inspection. with a thorough assessment of pain in the anal fissure, diagnosis can be made with approximately 100% accuracy as early as at the stage of taking a medical history [33]. one of the most popular theories about anal fissure is that mucosal rupture and anal fissure develop after anal canal trauma secondary to constipation and hard stools. in addition, in patients with xerosis of the anal mucosa, hard stools due to constipation may traumatize the mucosa during the passage, causing fissure and pain and bleeding as a result [34,35]. several cases of isotretinoin-related anal fissure and rectal bleeding have been reported in the literature [36,37]. in a study from our country, gastrointestinal side effects were detected in four patients (2.6%) [38]. in 1 of these, anal fissure developed in the first month of the treatment, rectal bleeding in the third month of treatment in 2 patients, and constipation in the fourth month of treatment in 1 patient. other than these, several other cases with isotretinoin-related anal fissures and rectal bleeding have been reported in the literature [15,36,37]. again, in different studies from our country and abroad [19,21,39], gis side effects were found to be between 0.19%-0.3%. however, it has not been reported in detail whether these side effects are ibd or anal fissures. in our study, the number of patients with constipation was 36. anal fissures were detected in 7 patients with constipation. anal bleeding was another accompanying finding in all patients with fissure. however, constipation was detected in only 2 of 10 patients with mucosal erosion. this was a condition that supported isotretinoin causing dryness in the anal mucosa. medical treatment and topical moisturizer were recommended by general surgery clinic to patients complaining with fissure, rectal bleeding and constipation. in addition, the dose of isotretinoin was reduced in 3 patients. after treatment, there was an improvement in complaints in patients except for 1 patient. in conclusion, frequent mucosal dryness in patients using systemic isotretinoin due to severe acne may also be encountered in the anal mucosa. therefore, in addition to starting moisturizer to prevent cheilitis, dry eye and epistaxis in patients with whom we started isotretinoin treatment, topical moisturizers can also be added to the treatment of anal area dryness and an appropriate diet can be recommended. presence of constipation and rectal bleeding should be investigated during patient controls. in the case of their presence, treatment should be arranged by the relevant clinics. thus, possible fissure and severe mucosal erosion and subsequent rectal bleeding that may original article | dermatol pract concept. 2023;13(3):e2023133 5 28. alhusayen ro, juurlink dn, mamdani mm, morrow rl, shear nh, dormuth cr. isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study. j invest dermatol. 2013; 133(4):907-912. doi: 10.1038/jid.2012.387. pmid: 23096714. pmcid: pmc3728031. 29. etminan m, bird st, delaney ja, bressler b, brophy jm. isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data. jama dermatol. 2013;149(2):216-220. doi: 10.1001/jamadermatol.2013.1344. pmid: 23426479. 30. rashtak s, khaleghi s, pittelkow mr, larson jj, lahr bd, murray ja. isotretinoin exposure and risk of inflammatory bowel disease. jama dermatol. 2014;150(12):1322-1326. doi: 10.1001/jamadermatol.2014.1540. pmid: 25207875. 31. bernstein cn, nugent z, longobardi t, blanchard jf. isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study. am j gastroenterol. 2009;104(11):2774-2778. doi: 10.1038/ajg.2009.417. pmid: 19623167. 32. brito mde f, sant’anna ip, galindo jc, rosendo lh, santos jb. evaluation of clinical adverse eff ects and laboratory alterations in patients with acne vulgaris treated with oral isotretinoin. a bras dermatol. 2010;-85(3):331-337. doi: 10.1590/s0365 -05962010000300006. pmid: 20676466. 33. menteş b, leventoğlu s. anal fissür. in: menteş b, leventoğlu a, eds. anorektal bölgenin selim hastalıkları. i̇stanbul; türk kolon ve rektum cerrahisi derneği. 2011:37-53. 34. schlichtemeier s, engel a. anal fissure. aust prescr. 2016;39(1):14-17. doi: 10.18773/austprescr.2016.007. pmid: 27041801. pmcid: pmc4816871. 35. kenny se, irvine t, driver cp, et al. double blind randomised controlled trial of topical glyceryl trinitrate in anal fissure. arch dis child. 2001;85(5):404-407. doi: 10.1136/adc.85.5.404. pmid: 11668104. pmcid: pmc1718983. 36. erpolat s, gorpelioglu c, sarifakioglu e. isotretinoin associated anal fissure and rectal bleeding: a rare complication. int j dermatol. 2012;51(3):358-359. doi: 10.1111/j.1365 -4632.2010.04556.x. pmid: 22348579. 37. güngör s, gökdemir g. anal fissure and rectal bleeding as a complication of systemic isotretinoin therapy: dermatologists know this side-effect, what about proctologists? colorectal dis. 2013;15(9):1187-1188. doi: 10.1111/codi.12294. pmid: 23701373. 38. karadağ as, çalka ö, akdeniz n. evaluation of side effects of isotretinoin in 150 patients with acne vulgaris. turkderm-turk arch dermatol venereol. 2011;45(1):37-42. doi: 10.4274 /turkderm.45.09. 39. çıkım aç, muammer seyhan m. efficiency and side effects of isotretinoin usage in the treatment of acne vulgaris. türkderm. 2008;42:51-55. 14. brodin mb. inflammatory bowel disease and isotretinoin. j am acad dermatol. 1986;14(5 pt 1):843. doi: 10.1016/s0190 -9622(86)80535-7. pmid: 2940270. 15. radmanesh m. anal fissure, rectal bleeding and proctitis as complications of systemic isotretinoin therapy: report of two cases. j eur acad dermatol venereol. 2006;20(10):1394. doi: 10.1111/j.1468-3083.2006.01759.x. pmid: 17062102. 16. james wd, berger tg, elston dm. andrews’ diseases of the skin: clinical dermatology, (11th ed.). philadelphia, elsevier, 2011:228e34. 17. dubeau mf, iacucci m, beck pl, et al. drug-induced inflammatory bowel disease and ibd-like conditions. inflamm bowel dis. 2012;19(2):445-456. doi: 10.1002/ibd.22990. pmid: 22573536. 18. bremner jd, shearer kd, mccaffery pj: retinoic acid and affective disorders: the evidence for an association. j clin psychiatry. 2012; 73(1):37-50. doi: 10.4088/jcp.10r05993. pmid: 21903028. pmcid: pmc3276716. 19. rademaker m. adverse effects of isotretinoin: a restrospective review of 1743 patients started on isotretinoin. australas j dermatol. 2010;51(4):248-253. doi: 10.1111/j.1440-0960.2010.00657.x. pmid: 21198520. 20. katsambas a, papakonstantinou a. acne: systemic treatment. clin dermatol. 2004; 22(5):412-418. doi: 10.1016/j.clindermatol.2004.03.014. pmid: 15556728. 21. brzezinski p, borowska k, chiriac a, smigielski j. adverse effects of isotretinoin: a large, retrospective review. dermatol ther. 2017;30(4). doi: 10.1111/dth.12483. pmid: 28295859. 22. prevost n, english jc. isotretinoin: update on controversial issues. j pediatr adolesc gynecol. 2013; 26(5):290-293. doi: 10.1016/j.jpag.2013.05.007. pmid: 24147278. 23. landis mn. optimizing isotretinoin treatment of acne: update on current recommendations for monitoring, dosing, safety, adverse effects, compliance, and outcomes. am j clin dermatol. 2020;21(3):411-419. doi: 10.1007/s40257-020-00508-0. pmid: 32107726. 24. neudorfer m, goldshtein i, shamai-lubovitz o, chodick g, dadon y, shalev v. ocular adverse effects of systemic treatment with isotretinoin. arch dermatol. 2012;148(7):803-808. doi: 10.1001/archdermatol.2012.352. pmid: 22508771. 25. kaymak y, ilter n. the results and side effects of systemic isotretinoin treatment in 100 patients with acne vulgaris. dermatol nurs. 2006;18(6):576-580. pmid: 17286159. 26. crockett sd, porter cq, martin cf, sandler rs, kappelman md. isotretinoin use and the risk of inflammatory bowel disease: a case-control study. am j gastroenterol. 2010;105(9):19861993. doi: 10.1038/ajg.2010.124. pmid: 20354506. pmcid: pmc3073620. 27. passier jl, srivastava n, van puijenbroek ep: isotretinoin-induced inflammatory bowel disease. neth j med. 2006;64(2):52-54. pmid: 16517990. dermatology: practical and conceptual letter to the editor | dermatol pract concept. 2022;12(4):e2022171 1 lymphadenopathy after covid-19 vaccine mimicking lymph-node progression in a patient with metastatic melanoma julia verdaguer-faja1, josé luis manzano2, sofía españa2, paula cecilia notta3, raul vicente rodriguez iniesta4, aram boada1,5 1 dermatology department. hospital universitari germans trias i pujol. universitat autònoma de barcelona. badalona, barcelona, españa. 2 medical oncology department. hospital universitari germans trias i pujol. universitat autònoma de barcelona. badalona, barcelona, españa. 3 nuclear medicine-pet department. hospital universitari de bellvitge. universitat de barcelona. hospitalet de llobregat, barcelona, españa. 4 radiology department. hospital universitari germans trias i pujol. universitat autònoma de barcelona. badalona, barcelona, españa. 5 institut investigació germans trias i pujol (igtp). badalona, barcelona, españa. citation: verdaguer faja j, manzano jl, españa s, notta pc, rodriguez iniesta rv, boada a. lymphadenopathy after covid-19 vaccine mimicking lymph node progression in a patient with metastatic melanoma. dermatol pract concept. 2022;12(4):e2022171. doi: https://doi.org/10.5826/dpc.1204a171 accepted: february 19, 2022; published: october 2022 copyright: ©2022 verdaguer faja et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: julia verdaguer faja, md, dermatology department. hospital universitari germans trias i pujol. carretera de canyet s/n. 08916. badalona (barcelona), spain. phone: 0034934978813, e-mail: verdaguer.ju@gmail.com introduction covid-19 vaccination has been rapidly implemented worldwide, especially among patients with cancer. local reactions with ipsilateral lymphadenopathy are among the most common side effects. a few cases of falsepositive 18-fluorodeoxyglucose (18fdg) pet/computed tomography (ct) scan after covid-19 vaccination have been reported [1,2]. this is especially important in oncologic patients, such as in cutaneous melanoma, where these findings might pose difficulties during their follow-up and management. case presentation a 47-year-old male with braf mutant melanoma of the back and right axillar adenopathies underwent wide excision and lymphadenectomy and started adjuvant treatment with nivolumab. one month later, he presented disease relapse with satellitosis and a contralateral adenopathy in the left axilla, the latter detected by pet-ct. treatment was changed to targeted therapy (dabrafenib and trametinib), reaching complete remission. an fdgpet/ct from february 2021 showed no active disease. in may 2021, after eight months of targeted therapy, a 2 letter to the editor | dermatol pract concept. 2022;12(4):e2022171 routine fdg-pet/ct showed substantial 18f-fdg avidity in the left axilla, with multiple malignant-appearing lymph nodes; no other foci were identified (figure 1a). given this finding, up to two ultrasound-guided biopsies were performed on the left axilla, describing at least one clearly malignant-appearing adenopathy in the ultrasound examination (figure 1, b and c), and showing histologically lymphoid hyperplasia with no evidence of microscopic disease. further questioning of the patient revealed that he had received the second dose of the covid-19 mrna vaccine (moderna) in the left deltoid muscle 5 days prior to the routine pet/ct scan. finally, a new pet/ct was performed 4 months later and revealed complete resolution of the hypermetabolic left axillary nodes (figure 2), suggesting the diagnosis of reactive lymphadenopathy due to covid-19 vaccine. figure 1. imaging tests performed in may 2021. (a-d) routine ¹⁸f-fdg-pet/tc: hypermetabolic lymphadenopathy in the left axillary region, the largest and with most metabolism of 13 mm (suvmax: 3.9), suggestive of malignancy. (e) sonographic exam of the left axilla after pet/ct findings: left axillary lymphadenopathy of rounded morphology with displacement of the central fatty hilum at the expense of great hypoechoic cortical thickening, sonographically suspicious. core needle biopsy was taken from it. figure 2. (a-d) 4-month control 18f-fdg-pet/tc, september 2021: normalization of hypermetabolic lymphadenopathies in the left axillary region: resolution of the pathologic nodal uptake. letter to the editor | dermatol pract concept. 2022;12(4):e2022171 3 discussion transient fdg uptake in normal or enlarged lymph nodes (mainly axillary, supraclavicular and cervical nodes) has already been described after administration of several types of vaccines [3,4]. this issue has also been observed now with the covid-19 vaccination [1,2], being more frequently seen in patients vaccinated with moderna, compared to pfizer-biontech (72% versus 43%), and more intensely after the booster administration. furthermore, it has been most frequently seen on day 1–7 after vaccination (71% of patients) and showed a negative correlation with time after vaccination [2]. this fdg avid axillary lymphadenopathy may confound interpretation in oncologic patients and change patient management (eg excessive follow-up imaging studies, unnecessary biopsies, treatment delays), besides causing additional patient anxiety [2]. this is the case of cutaneous melanoma, where misinterpretation in tumor staging or disease response during treatment may lead to deeply important differences in terms of disease prognosis and treatment algorithm. in order to avoid misinterpretation, it is therefore important in oncologic patients to perform vaccination contralateral to the tumor expected nodal drainage, to ask patients about recent vaccination, and to perform fdg pet/ct before or at least 2 weeks after (optimally 4–6 weeks after) vaccine administration, if possible [2,4,5]. conclusions as covid-19 vaccination has been rapidly implemented worldwide, clinicians should be aware of the transient appearance of hypermetabolic regional lymph nodes after its injection. keeping this etiology in mind and following some recommendations for scheduling the pet-ct is especially important when evaluating oncologic patients to avoid misinterpretation. references 1. cohen d, krauthammer sh, wolf i, even-sapir e. hypermetabolic lymphadenopathy following administration of bnt162b2 mrna covid-19 vaccine: incidence assessed by [18f]fdg pet-ct and relevance to study interpretation. eur j nucl med mol imaging. 2021;48(6):1854-1863. doi: 10.1007/s00259-021-05314-2. pmid: 33774684. pmcid: pmc8003894. 2. skawran s, gennari ag, dittli m, et al. [18f]fdg uptake of axillary lymph nodes after covid-19 vaccination in oncological pet/ ct: frequency, intensity, and potential clinical impact. eur radiol. 2022;32(1):508-516. doi: 10.1007/s00330-021-08122-2. pmid: 34156552. pmcid: pmc8217971. 3. thomassen a, lerberg nielsen a, gerke o, johansen a, petersen h. duration of 18f-fdg avidity in lymph nodes after pandemic h1n1v and seasonal influenza vaccination. eur j nucl med mol imaging. 2011;38(5):894-898. doi: 10.1007/s00259-011 -1729-9. pmid: 21340453. 4. mcintosh lj, bankier aa, vijayaraghavan gr, licho r, rosen mp. covid-19 vaccination-related uptake on fdg pet/ct: an emerging dilemma and suggestions for management. am j roentgenol. 2021;217(4):975-983. doi: 10.2214/ajr.21.25728. pmid: 33646823. 5. mcintosh lj, rosen mp, mittal k, et al. coordination and optimization of fdg pet/ct and covid-19 vaccination; lessons learned in the early stages of mass vaccination. cancer treat rev. 2021;98:102220. doi: 10.1016/j.ctrv.2021.102220. pmid: 34029956. pmcid: pmc8110324. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023088 1 elastic stain in pseudopelade of brocq: a helpful histopathological diagnostic clue gloria baeza-hernández1, mercedes isabel jaquero-valero2, ricardo francisco rubio-aguilera1, luis carlos araya-umaña2, celia horcajada-reales1, amalia moreno-torres2 1 dermatology department, hospital universitario de fuenlabrada, madrid, spain 2 pathology department, hospital universitario de fuenlabrada, madrid, spain citation: baeza-hernández g, jaquero-valero mi, rubio-aguilera rf, araya-umaña lc, horcajada-reales c, moreno-torres a. elastic stain in pseudopelade of brocq: a helpful histopathological diagnostic clue. dermatol pract concept. 2023;13(2):e2023088. doi: https://doi.org/10.5826/dpc.1302a88 accepted: october 6, 2022; published: april 2023 copyright: ©2023 baeza-hernández et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gloria baeza-hernández, servicio de dermatología hospital de fuenlabrada, camino del molino 2, 28942 fuenlabrada, madrid. e-mail: gloria.baeza@salud.madrid.org case presentation a 50-year-old caucasian woman presented to the dermatology clinic complaining of hair loss over at least 5 years, without itching or redness. a 4 mm punch biopsy fixed in 10% buffered formalin was sent to our laboratory and then vertically bisected for analysis (figure 1). it showed features of scarring alopecia, with a syringomatous proliferation in a fibrous zone; with orcein stain dense elastic fibers could be observed within a fibrous tract that extended below and above the insertion of the arrector pili muscle. the network of elastic fibers in the dermis was preserved. a diagnosis of pseudopelade of brocq was made with clinicopathological correlation: the patient had reduced hair density with a scarred background on the interparietal area, towards the vertex, with no signs of inflammation. teaching point elastic stains like verhoeff-van giesson and orcein are part of an alopecia histopathological routine study and can aid in the differential diagnosis of scarring alopecias. elastic fibers are characteristically preserved and thickened in central centrifugal cicatricial alopecia and pseudopelade 2 image letter | dermatol pract concept. 2023;13(2):e2023088 of brocq, while other types of scarring alopecias like lupus erythematosus or lichen planopilaris show loss or absence of elastic fibers [1,2]. histology needs to be correlated with clinical history and examination. while the existence of pseudopelade of brocq as an independent clinical entity is still under debate, it being a diagnosis of exclusion, some recent molecular studies have begun to shed light in its distinction from lichen planopilaris [1,2]. further research is still needed to clear up this long-standing controversy. references 1. bernárdez c, molina-ruiz am, requena l. histologic features of alopecias: part ii: scarring alopecias. actas dermosifiliogr. 2015;106(4):260-270. doi:10.1016/j.ad.2014.06.016. pmid: 25439143. 2. ramos-e-silva m, pirmez r. disorders of hair growth and the pilosebaceous unit: facts and controversies. clin dermatol. 2013;31(6):759-763. doi:10.1016/j.clindermatol.2013.06.003. pmid: 24160282. figure 1. (a, b) pseudopelade of brocq: h-e x10 (a) and elastic stain-orcein x10 (b). the dermal elastic network is intact. dense elastic fibers can be observed along a band of fibrous tissue which stretches below and above the preserved arrector pili muscle. syringomatous hyperplasia can be observed (on the right). dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023033 1 dermoscopic features of external ear melanoma: a case series rosario peralta1, horacio cabo2, emilia cohen sabban1, gabriel salerni3, virginia mariana gonzález4 1 dermatology department, instituto de investigaciones médicas “a. lanari”, university of buenos aires, buenos aires, argentina 2 dermatology deparment, university of buenos aires, buenos aires, argentina 3 dermatology department, hospital provincial del centenario de rosario, rosario, argentina 4 dermatology department, hospital alemán, buenos aires, argentina key words: melanoma, dermoscopy, ear citation: peralta r, cabo h, cohen sabban e, salerni g, gonzález vm. dermoscopic features of external ear melanoma: a case series. dermatol pract concept. 2023;13(1):e2023033. doi: https://doi.org/10.5826/dpc.1301a33 accepted: june 1, 2022; published: january 2023 copyright: ©2023 peralta et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: peralta rosario, md, 3150 combatientes de malvinas, cp 1427, ciudad autónoma de buenos aires, argentina. tel: (+54) 011-5287-3788, email: rosarioperalta@yahoo.com introduction external ear melanoma (eem) is a rare condition, corresponding to 1%-4% of all cutaneous melanomas. it affects mainly individuals in the sixth decade of life, being predominantly observed in white men, in the auricular helix. the most common subtype that have been reported is the superficial spreading melanoma (40.1%), followed by the lentigo maligna (33.7%) [1]. eem usually exhibits the classical features of facial or extra-facial melanoma, both clinically and dermoscopically [2]. the majority of these melanomas are diagnosed in early stages, when the breslow thickness is less than 2 mm, in 75% of patients [1]. we report eight clinical cases of eem and their dermoscopic findings, diagnosed at an early stage, emphasizing the importance of the routine clinical examination of the ears in the dermatological consultation. case presentation eight patients (7 men and 1 woman) with biopsy-proven diagnosis of melanoma were analyzed. the median age was 68 years (range, 54–82 years). two were located on the right helix, 3 on the left helix, 1 on the right lobe, 1 on the left antihelix and 1 on the left antitragus. all of them presented as a single lesion and only two patients noticed its appearance before consultation. clinically, they were pigmented brown macules, with the exception of one that presented as a multicolored, slightly raised lesion. most of them showed asymmetrical shape. upon dermoscopy, in 6 out of 8 lesions, we found features of lentigo maligna, such as asymmetric pigmented follicular openings, rhomboidal structures and dark brown homogeneous areas without obliterated hair follicles (figure1, a-f), 1 lesion presented dark brown homogeneous areas with obliterated hair follicles (figure 1g) and 1 exhibited criteria for superficial 2 research letter | dermatol pract concept. 2023;13(1):e2023033 figure 1. clinical and dermoscopic images of external ear melanomas. dermoscopic examination developed. (a,b) asymmetric pigmented follicular openings, and concentric circles. (b) zig-zag pattern (black arrows) and some rhomboidal structures (black asterisk). (c) annular-granular pattern. (d,e) rhomboidal structures. (f) dark brown homogeneous areas without obliterated hair follicles. (g) dark brown homogeneous areas with obliterated hair follicles. (h) multicomponent pattern with multiple colors, atypical pigment network, negative network, irregular blotches and dotted and linear irregular vessels distributed peripherally (white arrow). spreading melanoma with a multicomponent pattern with atypical pigment network, negative network, irregular blotches and atypical vessels (figure 1h). clinical and demographic data, dermoscopic findings and histopathologic result are detailed in table 1. conclusions in the dermoscopic findings of this eem case series we achieved similar results to those in previous reports, showing classical dermoscopic features of facial and extra-facial melanomas. research letter | dermatol pract concept. 2023;13(1):e2023033 3 face-specific dermoscopic criteria of melanoma are asymmetric pigmented follicular openings, concentric circles, annular-granular pattern, rhomboidal structures, and homogeneous areas. extra facial melanoma features in general include atypical pigment network, angulated lines, irregular dots and/ or globules, irregular streaks/ pseudopods, irregular blotches, regression structures, blue-white veil, negative network, shiny white structures, milky-red areas, and atypical vascular pattern [3]. concerning melanoma subtype, unlike previous reports, lentigo maligna was more frequent than superficial spreading melanoma in our series. 6 out of 8 cases were melanomas in situ, the other 2 were invasive melanomas (breslow thickness 0.6 and 1.2 mm, respectively). to conclude, the importance of routine clinical examination of the ears during dermatological consultations is reinforced, recommending the use of the dermatoscope when evaluating single lesions in this location, in order to recognize an early melanoma. early diagnosis of eem directly impacts on survival and dermoscopy has been shown to aid in the correct diagnosis. references 1. fiorio lm, diniz lm, spelta k, badaró ba. ear melanoma: a four-case series. an bras dermatol. 2021;96(1):64-67. doi: 10.1016/j.abd.2020.08.003. pmid: 33281007. pmcid: pmc7838110. 2. deinlein t, blum a, schulter g, et al. clinical and dermoscopic features of melanocytic lesions on the face versus the external ear. dermatol pract concept. 2021;11(4):e2021124. doi: 10.5826/dpc.1104a124. pmid: 34631268. pmcid: pmc7838110. 3. kittler h, marghoob aa, argenziano g, et al. standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy.  j am acad dermatol.  2016;74(6):1093–1106. doi:  10.1016/j.jaad.2015.12.038.  pmid: 26896294. pmcid: pmc5551974. table 1. clinical and demographic data, dermoscopic findings and histopathological subtype of external ear melanoma patients. patient # age (years) sex anatomical site single lesion (yes/no) dermoscopic findings histopathological subtype 1 57 m right helix yes asymmetric pigmented follicular openings, concentric circles lentigo maligna 2 70 f right lobe yes asymmetric pigmented follicular openings, zig-zag pattern, rhomboidal structures lentigo maligna 3 55 m left antihelix yes annular-granular pattern, rhomboidal structures lentigo maligna 4 54 m left antitragus yes annular-granular pattern, rhomboidal structures, dark brown homogeneous areas without obliterated hair follicles lentigo maligna 5 74 m right helix yes gray color, annular-granular pattern, rhomboidal structures lentigo maligna 6 73 m left helix yes asymmetric pigmented follicular openings, rhomboidal structures, dark brown homogeneous areas without obliterated hair follicles lentigo maligna 7 82 m left helix yes annular-granular pattern, rhomboidal structures, dark brown homogeneous areas with obliterated hair follicles lentigo maligna melanoma, breslow 0,6 mm 8 65 m right helix and auricle yes multicomponent pattern with atypical pigment network, negative network, irregular blotches and atypical vessels superficial spreading melanoma, breslow 1,2 mm dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022185 1 dermoscopy of diabetic dermopathy montserrat navarro-gilo1, nuria alberti-masalleras2, mercedes de gea-fernández1, anna domingo3, marc sagristà3 1 eap, pineda de mar, spain 2 eap, tordera, spain 3 sant jaume de calella hospital, calella, spain citation: navarro-gilo m, alberti-masalleras n, de gea-fernández m, domingo a, sagristà m. dermoscopy of diabetic dermopathy. dermatol pract concept. 2022;12(4):e2022185. doi: https://doi.org/10.5826/dpc.1204a185 accepted: march 23, 2022; published: october 2022 copyright: ©2022 navarro-gilo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: marc sagristà, department of dermatology and venereology, sant jaume de calella hospital, c/sant jaume, 209-217. calella, spain. e-mail address: marc_sagrista@yahoo.es figure 1. (a) clinical picture. (b) dermoscopic image shows two central areas (inside blue dotted-line) surrounded by an ill-defined brown peripheral rim. (c) high magnification dermoscopic image. “ring-like” globular structures can be identified in the brown peripheral rim (black arrows). fine scarcely branching linear vessels (white arrows) are separated by blurred grayish-white streaks (*) which look like dusky wickham striae. case presentation a 43-year-old man presented with asymptomatic multiple, bilateral, small, brown macules on pretibial areas which had been present for the last 3 years (figure 1a). the patient was diagnosed with type 2 diabetes 18 years ago, with associated retinopathy and nephropathy. 2 image letter | dermatol pract concept. 2022;12(4):e2022185 dermoscopic evaluation of the lesions revealed a distinctive pattern which was characterized by a one or multiple central area/s surrounded by an ill-defined brown peripheral rim (figure 1b). “ring-like” globular structures could be identified in the brown peripheral rim. finally, central areas dermoscopically demonstrated several fine scarcely branching linear vessels separated by blurred greyish-white streaks which resembled dusky wickham striae (figure 1c). the diagnosis of diabetic dermopathy was confirmed by histopathological assessment. these dermoscopic features show an excellent correlation with histologic findings [1,2]. thus, the greyish-white color of the central area probably corresponds to increased collagen density and fibroblastic proliferation, and the fine branching vessels probably are telangiectasias in the papillary dermis underlying an atrophic epidermis. the brown peripheral rim can be explained by hemosiderin deposition in dermis and increased melanin of basal cells. teaching point dermoscopic features of diabetic dermopathy (as described above) are different from other diseases that can also present with pretibial pigmented patches, such as early lesions of necrobiosis lipoidica, pigmented purpuric dermatosis or lichen planus. references 1. morgan aj, schwartz ra. diabetic dermopathy: a subtle sign with grave implications. j am acad dermatol. 2008;58(3):447-451. doi: 10.1016/j.jaad.2007.11.013. pmid: 18155320. 2. naik pp, farrukh sn. clinical significance of diabetic dermatopathy. diabetes metab syndr obes. 2020;13: 4823-4827. doi: 10.2147/dmso.s286887. pmid: 33324080. pmcid: pmc7733392. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023036 1 the effect of covid-19 on the hair diseases observed in health care providers: analysis of 513 participants ecem bostan1, aysel cakir2 1 cihanbeyli state hospital, dermatology and venereology clinic, konya, turkey 2 lokman hekim atay hospital, dermatology and venereology clinic, ankara, turkey key words: covid-19, hair diseases, surveys, questionnaires citation: bostan e, cakir a. the effect of covid-19 on the hair diseases observed in health care providers: analysis of 513 participants. dermatol pract concept. 2023;13(1):e2023036. doi: https://doi.org/10.5826/dpc.1301a36 accepted: june 17, 2022; published: january 2023 copyright: ©2023 bostan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ecem bostan, dermatology and venereology clinic, cihanbeyli state hospital, atceken avenue, hastane street, cihanbeyli/konya, 42850, turkey. telephone: +90 0332 673 40 93 e-mail: bostanecem@gmail.com introduction: the covid-19 pandemic has been shown to have major acute and chronic impacts on the skin. various studies reported that there has been an increase in the number of patients referred to outpatient dermatology clinics with the complaint of variable hair diseases during the era of covid-19. hair seems to be substantially affected by both the infection itself and anxiety/stress provoked by the pandemic. therefore, understanding the impact of covid-19 on the clinical course of variable hair diseases has become a major concern in dermatology practice. objectives: to examine the frequency and types of various hair diseases, both new-onset and ingravescent, observed in healthcare providers. methods: a web-based questionnaire related to the hair diseases seen in healthcare providers both prior to the covid-19 pandemic and after the start of the pandemic was created. the type of both new-onset and pre-existing hair diseases and ongoing hair diseases observed during covid-19 were investigated. results: a total number of 513 participants were included in the study. one hundred seventy cases were diagnosed with covid-19. during the covid-19 pandemic, 228 reported having at least one hair disease; the most common one being telogen effluvium, followed by hair greying and seborrheic dermatitis. there was a statistically significant relationship between the presence of a new-onset hair disease during the pandemic and being diagnosed with covid-19 (p=0.004). conclusion: our study shows that covid-19 infection has a significant impact on the emergence of new-onset hair diseases. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023036 introduction the covid-19 pandemic has been shown to have a negative influence on both skin diseases and the dermatological life quality of healthcare providers (hcps) [1]. skin serves as one of the first-line-of-defense components of the body against numerous pathogens by forming a physical barrier [2]. continuous use of personal hygiene equipment impairs the skin barrier, causing skin problems such as drying, lichenification and itching further aggravating a previously-existing dermatological disease or resulting in the development of a new-onset skin disorder [1]. hair is a skin appendage whose cycle is frequently affected by various external factors including nutritional deficiencies, endocrinopathies, major surgical operations and systemic diseases [3]. in a normal hair cycle, approximately 90% of the hairs are in the anagen phase [4]. the catagen phase begins when the anagen phase ends and approximately 5% of all hair shafts are in the catagen phase at any given time [4]. in the anagen phase, hair follicles continue to grow whereas in the catagen phase, hair follicles start to dwindle and hair growth stops [5]. the telogen phase or ‘resting phase’ lasts about three months and 10-15% of all hairs are in the telogen phase in a normal hair cycle [4,5]. following the telogen phase, hair shafts fall out. telogen effluvium (te) presents itself in the form of excessive hair shedding resulting from the rapid entry of anagen hairs into the telogen phase [3]. the normal cycle of hair growth is influenced and disrupted by various internal and external factors including severe systemic infections such as covid-19 [6]. covid-19-induced mild and severe te cases have continued to be reported in increasing numbers from the start of the pandemic [6,7]. alopecia areata (aa), an autoimmune hair disorder; seborrheic dermatitis (sd), a chronic inflammatory skin disease; trichotillomania, a psychodermatologic hair disorder are some other entities that are increasingly observed in the era of covid-19 [8-10]. both adverse psychosocial effects of the pandemic and cytokine storm induced in the setting of covid-19 infection are implicated in the development of these hair diseases [6]. in our study, we aimed to investigate the frequencies and types of both new-onset and pre-existing variable hair diseases observed in hcps during the covid-19 pandemic. methods local ethics committee approval was obtained for the present study (the date and decision number: november 19 2021, 2021/028). a web-based survey consisting of 22 questions (supplementary file 1) was created using google forms. the survey included four sections: (i) personal information; (ii) covid-19 infection; (iii) hair diseases seen prior to the onset of the covid-19 pandemic; (iv) hair diseases observed during the covid-19 pandemic. the online questionnaire was carried out among hcps and a virtual snowball sampling method was used. ibm spss for windows version 20.0 was used for the statistical analysis. for descriptive analysis, numerical variables were given as mean ± standard deviation (range: minimum-maximum) and categorical variables were shown as percentages and frequencies. chi-square test was used to analyze the relationships between the categorical variables. p values of <0.05 were considered statistically significant. results a total number of 513 hcps were included in the study. the mean age was 34.84 ± 8.90 years (minimum:19, maximum:66). three hundred fifty-eight (69.8%) of the participants were female whereas 155 (30.2%) were male. two hundred forty-one (47%) respondents reported having covid-19 related symptoms; whereas 272 (53 %) didn’t exhibit any symptoms. three hundred twenty-nine (63.2%) participants had a history of close contact with someone with a confirmed diagnosis of covid-19. covid-19 real-time polymerase chain reaction test (rt-pcr) was performed on 445 (86.7 %) respondents; 156 (35.1%) cases tested positive, whereas 289 (64.9%) tested negative. additionally, 14 cases who did not give rt-pcr test or tested negative, were diagnosed with covid-19 via radiological imaging. so, a total of 170 cases were accepted to have a confirmed diagnosis of covid-19. only 12 patients were required to be hospitalized for severe covid-19 infection. during the online questionnaire, participants were asked if they had any other contributing factors during the covid-19 pandemic that might have played a role in the development or worsening of their hair diseases. thirty-six (7%) cases had a pregnancy, one (0.2%) respondent was receiving chemotherapy, 21 (4.1%) were dieting, 12 (2.3%) had a major surgical operation, 20 (3.9%) had intentional/ unintentional loss of more than 5% of their own weight in a period of 6 months during the covid-19 pandemic. lastly, 162 (31.6%) participants reported feeling stressed, which had a major impact on their lives during the covid-19 pandemic. two hundred fifty-four (49.5%) respondents had at least one hair disease prior to the start of the covid-19 pandemic. the frequencies and percentages of different types of hair diseases observed in the pre-covid-19 era are shown in table 1. of 513 patients, only 40 patients had new-onset hair disease that developed during the covid-19 pandemic. out of 40  patients, 25 (62.5%) had new-onset te, 12 (30%) reported increased hair greying, 6 (15%) had new-onset original article | dermatol pract concept. 2023;13(1):e2023036 3 female-pattern hair loss (fphl), 3 (7.5%) had new-onset male-pattern hair loss (mphl), 4 (10%) reported trichodynia, 2 (5%) reported new-onset sd, 2 (5%) reported new-onset trichotillomania and 1 (2.5%) reported new-onset scalp psoriasis. of these 40 patients, only 20 (50%) were diagnosed with covid-19. the mean duration between the emergence of the new-onset hair disease and covid-19 diagnosis was 1.24 ± 0.83 months (minimum: 0.25, maximum:3). of 25 patients with new-onset te during the covid-19 pandemic, 22 (88 %) had been tested for sars-cov-2 infection. fourteen (63.6%) out of 22 patients had a positive rt-pcr result. for these patients, the mean time interval between the diagnosis of covid-19 and the approximate commencement of the acute te was 1.13 ± 0.66 months (minimum: 0.3, maximum:3). during the era of covid-19, 228 (44.4 %) reported having any hair disease (including pre-existing, ongoing and new-onset ones); the frequencies and percentages of different types of hair diseases observed in the covid-19 era are shown in table 1. of 228 individuals with a history of any hair disease during covid-19, 34 (14.9%) had been diagnosed by a physician. participants who had the same hair disease prior to the covid-19 pandemic and during the covid-19 pandemic were asked to express their opinion about the course of the hair disease during the covid-19 pandemic. out of 259 respondents, 129 (49.8 %) indicated that there was no change, 121 (46.7%) reported an increase in the sign and symptoms of the specified hair disease whereas 9 (3.5 %) claimed that the severity of the hair disease decreased. of 121 patients who reported an increase in the severity of the pre-existing hair disease during the covid-19 pandemic, 51 (42.1%) had te, 37 (30.6%) had hair greying, 29 (24%) were diagnosed with sd, 16 (13.2%) had symptoms of trichodynia, 16  (13.2%) had fphl, 12 (9.9 %) were diagnosed with mphl, 7 (5.8%) had trichotillomania, 5 (4.1%) were suffering from scalp psoriasis, 2 (1.7 %) had aa and only 1 (0.8 %) patient had alopecia totalis. again, of 121 individuals who reported an increase in the severity of the hair disease and 40 who had new-onset hair disease during the covid-19 pandemic, 138 (85.7%) thought that stress and anxiety played a role either in the development of the new-onset hair disease or deterioration of the pre-existing disease. a statistically significant relationship was found between covid-19 rt-pcr positivity and the presence of any hair disease during the covid-19 pandemic (p=0.009) (table 2). in addition, a statistically significant relationship was present between covid-19 rt-pcr positivity and the presence of any new-onset hair disease during the covid-19 pandemic (p=0.002). the distribution of covid-19 rt-pcr results in relation to the presence of any new-onset hair disease during the covid-19 pandemic is shown in figure 1. the distribution of covid-19 infection status in relation to the presence of any hair disease during the covid-19 pandemic is shown table 1. frequencies and percentages of different types of hair diseases in the pre-covid-19 and covid-19 pandemic eras. type of hair disease pre-covid-19 (n, %) covid-19 (n,%) male pattern hair loss 36 (13.9) 29 (12.7) alopecia areata 13 (5) 3 (1.3) female pattern hair loss 30 (11.6) 33 (14.5) alopecia totalis 1 (0.4) 1 (0.4) telogen effluvium 108 (41.7) 111 (48.7) seborrheic dermatitis 63 (24.3) 52 (22.8) scalp psoriasis 9 (3.5) 9 (3.9) trichodynia 35 (13.5) 32 (14) trichotillomania 18 (6.9) 16 (7) increased hair greying 72 (27.8) 71 (31.1) total 259 (100) 228 (100) table 2. statistically significant relationship was found between the covid-19 rt-pcr positivity and having at least one hair disease during the covid-19 pandemic (p=0.009). covid-19 rt-pcr results presence of any hair disease during covid-19 pandemic total n (%)not present n (%) present negative 169 (70.4) 120 (58.5) 289 (64.9) positive 71 (29.6) 85 (41.5) 156 (35.1) total 240 (100) 205 (100) 445 (100) 4 original article | dermatol pract concept. 2023;13(1):e2023036 difference between developing new-onset hair disease and having at least one contributing factor that may be related to the pathogenesis of the new-onset hair disorder (p=0.119). discussion from the start of the covid-19 pandemic, numerous cutaneous manifestations of the infection itself along with the occupational skin problems which result from the continuous use of personal protective equipment have been reported in the literature [11,12]. urticaria, maculopapular eruption, angioedema, vesicular eruption, pityriasis rosea, erythema in figure 2. a statistically significant relationship was found between being diagnosed with covid-19 and having any specific hair disease during the covid-19 pandemic (p=0.011). again, there was a statistically significant relationship between the presence of any new-onset hair disease and the diagnosis of covid-19 (p=0.004). the distribution of covid-19 infection status in relation to the presence of any new-onset hair disease is shown in table 3. the distribution of having a new-onset hair disease with regard to the presence of one or more contributing factors for hair disease development (supplementary file 1question 13) is shown in table 4. there was no statistically significant 140 negative rt-pcr result not present present positive rt-pcr result 132 c o v id -1 9 r tp c r r es u lt s presence of any new-onset hair disease during covid-19 pandemic 49 17 19 120 100 80 60 40 20 0 figure 1. the distribution of covid-19 rt-pcr results in relation to the presence of any new-onset hair disease during the covid-19 pandemic. 250 204 81 139 89 not diagnosed with covid-19 not present present c o v id -1 9 in fe c ti o n s ta tu s presence of any hair disease during covid-19 pandemic diagnosed with covid-19 by rt-pcr testing or radiological imaging 200 150 100 50 0 figure 2. the distribution of covid-19 infection status in relation to the presence of any hair disease during the covid-19 pandemic. original article | dermatol pract concept. 2023;13(1):e2023036 5 relationship with hair cortisol concentration as a biomarker of stress was sought. in a study population of 234 hcps, 40% showed hair cortisol concentration outside of the normal range  [16]. in this study, positive correlation between hair cortisol concentration versus perceived stress and direct correlation between hair cortisol concentration versus emotional exhaustion were also found [16]. this study again underlies the fact that hcps are exposed to emotional stress and burnout syndrome during the pandemic and hair is largely influenced by the psychosocial impacts of covid-19. in correlation with this research, in our study of 161 participants who either reported an increase in the severity of the pre-existing hair disease or had new-onset hair disease during the covid-19 pandemic, 138 (85.7%) thought that stress and anxiety contributed to the development of the new-onset hair disease or progression of the pre-existing disease. cases of te and trichodynia have been observed to increase in number from the start of the pandemic [6,17]. rizzetto et al [6] reported three cases of te observed after severe sars-cov-2 infection. furthermore, mieczkowska et al [18] described a case series consisting of 10 women who were diagnosed with covid-19 via rt-pcr and antibody test. these patients didn’t have any other triggering factor that would induce te and te started 3 to 7 months after covid-19 infection. in another retrospective study by cline et al [19], it is found that there was a >400 % increase in the number of patients diagnosed with te between july and august 2020 when compared to the number of patients diagnosed with te between november 2019 and february 2020. in another multi-centered study, 214 patients who were diagnosed with acute te after sars-cov-2 infection were multiforme, chilblain-like acral lesions and cutaneous small vessel vasculitis are among the reported cutaneous manifestations of covid-19 infection [11]. hcps have worked so hard to provide effective and adequate care for patients with covid-19 infection. since effective health care requires optimum protection, continual use of personal protective equipment such as gloves, goggles, masks and hand disinfectants has become an irrevocable rule for all hcps. besides the skin diseases observed in the setting of hyperinflammation and immune system activation, occupational skin problems including irritant/allergic contact dermatitis, acne, itching, xerosis, pressure-related skin injuries, skin erythema, retroauricular dermatitis and secondary cutaneous infections continue to be a major concern, especially for hcps [11,12]. hair is a part of the integumentary system which has its own growth cycle and this cycle is greatly influenced by intrinsic and extrinsic factors. diverse drugs, stress, anxiety, chronic illnesses, high fever, extreme loss weight, smoking and iron deficiency may all disrupt the normal hair cycle and cause the hair shafts to enter the telogen phase prematurely which results in excessive hair shedding [13]. although all humanity is likely to be largely affected by a chaotic emergency situation such as a pandemic, those who work on the front lines to fight against the infection and struggle to provide the utmost care for the patients are more likely to have unfavorable psychosocial impacts [14]. during the era of covid-19, hcps have been shown to exhibit signs of post-traumatic stress disorder, depression, anxiety, insomnia, burnout syndrome and somatization [15]. in a study by ibar et al [16], chronic stress and anxiety among health workers during the covid-19 pandemic were examined and the table 3. the distribution of covid-19 infection status in relation to the presence of any new-onset hair disease during the covid-19 pandemic. diagnosed with covid-19 by rt-pcr testing or radiological imaging presence of any new-onset hair disease during covid-19 pandemic total n (%)not present n (%) present no 156 (72.9) 20 (50) 176 (69.3) yes 58 (27.1) 20 (50) 78 (30.7) total 214 (100) 40 (100) 254(100) table 4. the distribution of having a new-onset hair disease with regard to the presence of one or more contributing factors for hair disease development. presence of any new-onset hair disease during covid-19 pandemic presence of at least one precipitating factor linked to hair disease total n (%)not present n (%) present not present 145 (86.8) 69 (79.3) 214 (84.3) present 22 (13.2) 18 (20.7) 40 (15.7) total 167 (100) 87 (100) 254 (100) 6 original article | dermatol pract concept. 2023;13(1):e2023036 and/or increased grey hair prior to the pandemic. out of 37 patients, only 5 required hospitalization for covid-19. aa is an autoimmune, inflammatory, non-cicatricial alopecia which is characterized by relapsing and recurring episodes of patchy or diffuse hair loss. in the hyperinflammatory state of covid-19, plasma levels of tumor necrosis factorα, interferonγ, interleukin-2 and interleukin-1β which are also involved in the pathogenesis of aa, rise substantially [27]. in a study by rudnicka et al [28], 32 patients with mild-to-moderate aa were evaluated 1-6 weeks before covid-19 infection and 3 months after the infection [28]. it was found that covid-19 infection didn’t have any negative impact on the clinical course of aa [28]. in another study with 392 aa patients, 42.5 % had disease relapse about 2  months after covid-19 infection whereas disease relapse was observed in 12.5 % of all participants without a confirmed diagnosis of sars-cov-2 infection [29]. in our study, no new-onset aa was identified, but only 2 (15.4%) out of 13 patients with a pre-existing diagnosis of aa reported an increase in the severity of symptoms. sd is a chronic inflammatory skin disorder characterized by erythema, greasy scaling and itching which most commonly occurs in the scalp, eyebrows, ears and face [30]. a study by veraldi et al [30], showed that disease severity increased in 46.5 % of the patients diagnosed with sd. these patients reported wearing anti-covid-19 masks for 6 to 10 hours a day and 35 % of the patients with worsening sd were health workers [30]. it was asserted that the high temperature and humidity induced by the use of face masks cause abnormalities in microbiota and enhance sweating, thereby provoking an irritant reaction and itching [30]. in line with the results of this study, 29 (90.6%) out of 32 participants with a previous diagnosis of sd, reported an increase in the severity of symptoms of the disease during the pandemic. the higher percentage of participants in our study is not surprising since we have included only hcps in our study. trichotillomania is characterized by repetitive urges to pull out hair from the scalp, eyebrows or other parts of the body [31]. low self-confidence, social anxiety, major depression and psychosocial dysfunction are associated with trichotillomania [31]. in a study by pathoulas et al [32], 460 patients presented with a self-reported diagnosis of body-focused repetitive behaviors, 181 patients had a hair-pulling disorder, whereas 141 reported both hair-pulling and skin-picking disorders. a majority of the patients reported an increase in their symptoms during covid-19 [32]. our results showed that 38.9% of the individuals with a diagnosis of trichotillomania prior to the pandemic reported having incremental symptoms during covid-19. in conclusion, if we were to look at the results of our study altogether, we want to highlight that a statistically significant relationship exists between being diagnosed with evaluated [20]. the mean age was 47.4 years and 78.5 % of all patients were female, 86.4 % developed a fever during the infection. additionally, 20.8 % of patients required hospitalization and the mean time interval between the covid-19 diagnosis and significant hair shedding was 57.1 days [20]. in our study cohort, only 40 patients developed new-onset hair disease during the covid-19 pandemic and the most frequently observed new-onset hair disease was te. of these 25 patients with te, 22 were tested for sars-cov-2 infection. fourteen out of 22 patients had been diagnosed with covid-19. in our research, the mean time interval between the diagnosis of covid-19 and the start of hair shedding was found to be 1.13 ± 0.66 months. trichodynia is defined as a painful sensation in the scalp often accompanied by te [21]. di landro et al [17] observed 39 patients who presented with te after covid-19 infection. of 39 patients, 7 patients also suffered from severe trichodynia. in this study, the mean age was 64.6 years and both the excessive hair shedding and trichodynia resolved within 2 to 4 months. the authors argued that the hyperinflammatory environment developing in the setting of sars-cov-2 infection, was the most probable cause of te and trichodynia since interleukin-6, interleukin-1ß and tumor necrosis factor-α were shown to induce transition to the catagen phase in hair follicles [17,22]. in our research, 4 newonset trichodynia cases were detected whereas 16 participants reported exacerbation in trichodynia symptoms during the covid-19 pandemic. mphl is a common hair disease which is characterized by patterned, progressive thinning of hair, seen in genetically susceptible men. the presence of mphl is thought to be correlated with severe covid-19 infection [23]. the priming of sars-cov-2’s spike protein requires transmembrane protease, serine 2 (tmprss2) activity [23]. tmprss2 gene transcription is dependent upon androgen receptor activity, so it seems plausible that men are more vulnerable to sars-cov-2 infection and fatality rates are rare before puberty [23]. lee et al [24] evaluated 1605 patients who tested negative for covid-19 and 336 patients who were diagnosed with covid-19. the two groups didn’t have any difference in terms of mean age and body mass index [24]. in this study, it was shown that covid-19 positivity correlated with the increasing baldness score (determined by the hamilton-norwood scale) [24]. in another study, 41 caucasian males who were hospitalized with a diagnosis of sarscov-2 pneumonia were evaluated [25]. twenty-nine (71%) had clinically evident androgenetic alopecia (hamilton norwood scale > 2) and 12 (29%) patients had a hamilton norwood scale of 1 or 2 [25]. in another study by muller ramos et al [26], it was proven that alopecia and grey hair are correlated with covid-19 severity. in our study, of 170 patients diagnosed with covid-19, 21.8 % reported having mphl original article | dermatol pract concept. 2023;13(1):e2023036 7 10. alpalhão m, gaibino n, filipe p. seborrheic dermatitis in covid-19: a case report. int j dermatol. 2020;59(12):15431544. doi: 10.1111/ijd.15256. pmid: 33095515. 11. mawhirt sl, frankel d, diaz am. cutaneous manifestations in adult patients with covid-19 and dermatologic conditions related to the covid-19 pandemic in health care workers. curr allergy asthma rep. 2020;20(12):75. doi: 10.1007/s11882-02000974-w. pmid: 33047260; pmcid: pmc7549735. 12. wilcha rj. does wearing a face mask during the covid-19 pandemic increase the incidence of dermatological conditions in health care workers? narrative literature review. jmir dermatol. 2021;4(1):e22789. doi: 10.2196/22789. pmid: 34028470; pmcid: pmc8104277. 13. rossi a, magri f, sernicola a, et al. telogen effluvium after sars-cov-2 infection: a series of cases and possible pathogenetic mechanisms. skin appendage disord. 2021;21(5):1-5. doi: 10.1159/000517223. pmid: 34373830; pmcid: pmc8339054. 14. rodríguez bo, sánchez tl. the psychosocial impact of covid-19 on health care workers. int braz j urol. 2020;46(suppl.1):195-200. doi: 10.1590/s1677-5538.ibju.2020.s124. pmid: 32618464; pmcid: pmc7719993. 15. salazar de pablo g, vaquerizo-serrano j, catalan a, et al. impact of coronavirus syndromes on physical and mental health of health care workers: systematic review and meta-analysis. j affect disord. 2020;275:48-57. doi: 10.1016/j.jad.2020.06.022. pmid: 32658823; pmcid: pmc7314697. 16. ibar c, fortuna f, gonzalez d, et al. evaluation of stress, burnout and hair cortisol levels in health workers at a university hospital during covid-19 pandemic. psychoneuroendocrinology. 2021;128:105213. doi: 10.1016/j.psyneuen.2021.105213. pmid: 33845387; pmcid: pmc8015376. 17. di landro a, naldi l, glaser e, paus r, tosti a. pathobiology questions raised by telogen effluvium and trichodynia in covid-19 patients. exp dermatol. 2021;30(7):999-1000. doi: 10.1111/exd.14352. pmid: 33838048; pmcid: pmc8250761. 18. mieczkowska k, deutsch a, borok j, et al. telogen effluvium: a sequela of covid-19. int j dermatol. 2021;60(1):122-124. doi: 10.1111/ijd.15313. pmid: 33226117; pmcid: pmc7753411. 19. cline a, kazemi a, moy j, safai b, marmon s. a surge in the incidence of telogen effluvium in minority predominant communities heavily impacted by covid-19. j am acad dermatol. 2021;84(3):773-775. doi: 10.1016/j.jaad.2020.11.032. pmid: 33310111. 20. moreno-arrones om, lobato-berezo a, gomez-zubiaur a, et al. sars-cov-2-induced telogen effluvium: a multicentric study. j eur acad dermatol venereol. 2021;35(3):e181-e183. doi: 10.1111/jdv.17045. pmid: 33220124; pmcid: pmc7753386. 21. rebora a. trichodynia: a review of the literature. int j dermatol. 2016;55(4):382-4. doi: 10.1111/ijd.13204. pmid: 26696219. 22. hussain n, agarwala p, iqbal k, et al. a systematic review of acute telogen effluvium, a harrowing post-covid-19 manifestation. j med virol. 2022;94(4):1391-1401. doi: 10.1002/ jmv.27534. pmid: 34931698. 23. wambier cg, goren a. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection is likely to be androgen mediated. j am acad dermatol. 2020;83(1):308-309. doi: 10.1016/j. jaad.2020.04.032. pmid: 32283245; pmcid: pmc7151476. 24. lee j, yousaf a, fang w, kolodney ms. male balding is a major risk factor for severe covid-19. j am acad dermatol. 2020;83(5):e353-e354. doi: 10.1016/j.jaad.2020.07.062. covid-19 and having at least one specific hair disease during the covid-19 pandemic. additionally, there seems to be a statistically significant relationship between having a new-onset hair disease during the pandemic and being diagnosed with covid-19. our study indicates that hair is vulnerable to the direct effects of sars-cov-2 infection and indirect effects of the pandemic (psychosocial impacts, skin problems resulting from the use of personal protective equipment etc.). we believe that the underlying etiopathological mechanisms of the trichological effects of covid-19 are also possibly related to other pre-existing, ongoing and new-onset (post-covid-19) systemic as well as dermatological manifestations. our research has some limitations since not all the participants were diagnosed by a dermatologist. the severity of the hair disease was not directly evaluated by a physician using a score or scale, so the results might have been subjective. prospective, randomized-controlled studies with larger sample sizes are needed to confirm our results. references 1. daye m, cihan fg, durduran y. evaluation of skin problems and dermatology life quality index in health care workers who use personal protection measures during covid-19 pandemic. dermatol ther. 2020;33(6):e14346. doi: 10.1111/dth.14346. pmid: 32985745; pmcid: pmc7536955. 2. toncic rj, jakasa i, hadzavdic sl, et al. altered levels of sphingosine, sphinganine and their ceramides in atopic dermatitis are related to skin barrier function, disease severity and local cytokine milieu. int j mol sci. 2020;21(6):1958. doi: 10.3390/ ijms21061958. pmid: 32183011; pmcid: pmc7139865. 3. asghar f, shamim n, farooque u, sheikh h, aqeel r. telogen effluvium: a review of the literature. cureus. 2020;12(5):e8320. doi: 10.7759/cureus.8320. pmid: 32607303; pmcid: pmc7320655. 4. harland dp. introduction to hair development. adv exp med biol. 2018;1054:89-96. doi: 10.1007/978-981-10-8195-8_8. pmid: 29797270. 5. stenn ks, paus r. controls of hair follicle cycling. physiol rev. 2001;81(1):449-494. doi: 10.1152/physrev.2001.81.1.449. pmid: 11152763. 6. rizzetto g, diotallevi f, campanati a, et al. telogen effluvium related to post severe sars-cov-2 infection: clinical aspects and our management experience. dermatol ther. 2021;34(1):e14547. doi: 10.1111/dth.14547. pmid: 33190397; pmcid: pmc7744849. 7. abrantes tf, artounian ka, falsey r, et al. time of onset and duration of post-covid-19 acute telogen effluvium. j am acad dermatol. 2021;85(4):975-976. doi: 10.1016/j. jaad.2021.07.021. pmid: 34302903; pmcid: pmc8294706. 8. fivenson d. covid-19: association with rapidly progressive forms of alopecia areata. int j dermatol. 2021;60(1):127. doi: 10.1111/ijd.15317. pmid: 33226118; pmcid: pmc7753616. 9. öner ü. children with trichotillomania in covid-19 outbreak. j cosmet dermatol. 2021;20(7):1967-1968. doi: 10.1111/ jocd.14200. pmid: 33950551; pmcid: pmc8242538. 8 original article | dermatol pract concept. 2023;13(1):e2023036 erratum in: j am acad dermatol. 2021 ;85(3):799. pmid: 32707256; pmcid: pmc7373684. 25. goren a, vaño-galván s, wambier cg, et al. a preliminary observation: male pattern hair loss among hospitalized covid-19 patients in spain a potential clue to the role of androgens in covid-19 severity. j cosmet dermatol. 2020;19(7):1545-1547. doi: 10.1111/jocd.13443. pmid: 32301221. 26. müller ramos p, ianhez m, amante miot h. alopecia and grey hair are associated with covid-19 severity. exp dermatol. 2020;29(12):1250-1252. doi: 10.1111/exd.14220. pmid: 33098701. 27. zhong j, tang j, ye c, dong l. the immunology of covid-19: is immune modulation an option for treatment? lancet rheumatol. 2020;2(7):e428-e436. doi: 10.1016/s2665-9913(20)30120-x. pmid: 32835246; pmcid: pmc7239618. 28. rudnicka l, rakowska a, waskiel-burnat a, kurzeja m, olszewska m. mild-to-moderate covid-19 is not associated with worsening of alopecia areata: a retrospective analysis of 32 patients. j am acad dermatol. 2021;85(3):723-725. doi: 10.1016/j. jaad.2021.05.020. pmid: 34051315; pmcid: pmc8149466. 29. rinaldi f, trink a, giuliani g, pinto d. italian survey for the evaluation of the effects of coronavirus disease 2019 (covid-19) pandemic on alopecia areata recurrence. dermatol ther (heidelb). 2021;11(2):339-345. doi: 10.1007/s13555-021-00498-9. pmid: 33580408; pmcid: pmc7880634. 30. veraldi s, angileri l, barbareschi m. seborrheic dermatitis and anti-covid-19 masks. j cosmet dermatol. 2020;19(10):24642465. doi: 10.1111/jocd.13669. pmid: 32790897; pmcid: pmc7436393. 31. diefenbach gj, tolin df, hannan s, crocetto j, worhunsky p. trichotillomania: impact on psychosocial functioning and quality of life. behav res ther. 2005;43(7):869-84. doi: 10.1016/j. brat.2004.06.010. pmid: 15896284. 32. pathoulas jt, olson sj, idnani a, farah rs, hordinsky mk, widge as. cross-sectional survey examining skin picking and hair pulling disorders during the covid-19 pandemic. j am acad dermatol. 2021;84(3):771-773. doi: 10.1016/j. jaad.2020.11.011.pmid: 33279648; pmcid: pmc7711196. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022209 1 five synchronous melanomas: role of dermoscopy as a triage tool to manage melanoma during the covid-19 pandemic carla tubau1, lluís rusiñol1, guillermo sánchez-rodríguez1, helena iznardo1, victoria amat-samaranch1, oriol yélamos1 1 department of dermatology, hospital de la santa creu i sant pau, universitat autònoma de barcelona, barcelona, spain key words: covid-19, dermoscopy, management, in situ melanoma, synchronous melanomas citation: tubau c, sánchez-rodríguez g, iznardo h, amat-samaranch v, yélamos o. five synchronous melanomas: role of dermoscopy as a triage tool to manage melanoma during the covid-19 pandemic. dermatol pract concept. 2022;12(4):e2022209. doi: https://doi. org/10.5826/dpc.1204a209 accepted: january 5, 2022; published: october 2022 copyright: ©2022 tubau et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: oy has received honoraria from bms (speakers honoraria), and msd (speakers honoraria). the other authors declare no conflicts of interest. authorship: all authors have contributed significantly to this publication. corresponding author: carla tubau, md, department of dermatology, hospital de la santa creu i sant pau, universitat autònoma de barcelona, mas casanovas 90, 08041 barcelona, spain, phone: (+34) 935537007, fax (+34) 935537008. e-mail: ctubau@santpau.cat introduction multiple meta-analyses have shown that dermoscopy is more accurate than the naked eye in melanoma diagnosis [1]. since dermoscopy has direct histopathological correlates, it can be used to triage and manage pigmented lesions [2]. certain colors under dermoscopy such as blue over raised areas are indicators of deep melanin, whereas on flat surfaces may indicate regression [2]. furthermore, certain structures indicate melanoma invasion such as shiny white streaks or blue-whitish veil [2]. hence, when large lesions are challenging to be excised completely, these areas suspicious for invasion under dermoscopy such as raised blue-gray areas could be sampled in order to maximize the histologic results. moreover, dermoscopy also allows the identification of small invasive melanomas thus improving its management. during our daily practice, currently in the middle of the covid-19 pandemic, we face challenging cases that need to be managed with fewer visits than usual. case presentation an 89-year-old man with multiple comorbidities, ecog 3, was referred for evaluation of a nasal pigmented lesion. previous biopsies did not reveal malignancy but he referred enlargement over time. a brown-black 2.5 cm-patch with ill-defined borders covered patient’s central nasal dorsum ( figure 1a). dermoscopy showed asymmetric pigment around follicles, peppering, angulated lines, and areas of follicle invasion ( figures 1, b, c and d). a complete cutaneous examination was performed identifying four further suspicious lesions. one black 2.1 x 1 cm macule on the chest (figure  2a) showing peripheral streaks asymmetrically distributed and a central blue-whitish veil on dermoscopy ( figure 2b). one elongated 2 research letter | dermatol pract concept. 2022;12(4):e2022209 figure 1. (a) clinical image of the nasal dorsum pigmented lesion consisting of a brown-black 2.5cm patch with ill-defined borders that covers the central nasal dorsum. (b-d) dermoscopy images showing asymmetric pigmented follicular openings (arrows), angulated or polygonal lines (arrowheads), blue-gray dots or peppering (asterisk), and areas of follicle invasion (circles). figure 2. (a) clinical image of the 2.2 x 2 cm macule on the chest. (b) dermoscopic image showing peripheral streaks asymmetrically distributed and central blue-whitish veil. (c) clinical image of the pigmented lesion on the neck, which presented as an elongated brown-black macule of 1.4 x 0.8 cm. (d) dermoscopy of the neck lesion where atypical pigmented network and an irregular black blotch at the periphery can be observed. (e) clinical image of the upper dorsum brown to black 0.5 x 0.3 cm macule. (f) upper dorsum lesion dermoscopy showing an atypical brown network. (g) clinical image of the pigmented lesion on the right shoulder presented as a brown-black 0.7 x 0.6 cm macule. (h) atypical brown network and inferior-left homogeneous brown area on dermoscopy of the shoulder lesion. research letter | dermatol pract concept. 2022;12(4):e2022209 3 brown to black 1.4 x 0.8 cm macule on the neck (figure 2c), with an atypical pigmented network and an irregular black blotch on dermoscopy (figure 2d). a brown to black 0.5 x 0.3  cm macule on the upper dorsum showing an atypical brown network on dermoscopy (figures 2, e and f). ultimately, a brown to black 0.7 x 0.6 cm macule on his right shoulder, with an atypical brown network and an inferior-left homogenous brown area on dermoscopy (figures 2, g and h). given the number of lesions suggesting melanoma and considering the patient comorbidities, a shave-excision was performed during the same initial appointment of the smaller lesions suspected to be in situ by dermoscopy (atypical network with absence of blue-gray color, shiny white structures or vessels): the shoulder and upper dorsum lesions. the patient was scheduled for complete excision of the chest and neck lesions, due to suspicion of invasion (blue-whitish veil on dermoscopy) on the former, and due to a larger size and irregular shape on the latter. regarding the nasal lesion, although no signs of invasion were suspected, due to its large size and the potentially complex reconstruction, a dermoscopy-targeted punch biopsy was performed on the brown area, and not on the blue-gray area which may have only revealed regression. results from histologic examination yielded four in situ melanomas, and an invasive melanoma with a 0.6 mm breslow index (chest lesion). wide local excision was later performed in all lesions according to the current guidelines. the patient is alive with no signs of active disease. conclusions we present an unusual case of a man with five synchronous primary melanomas, whose management was streamlined thanks to dermoscopy. hence, by using dermoscopy we could simplify the patient flow and minimize the number of appointments, especially useful in the current context of covid-19 pandemic. references 1. dinnes j, deeks jj, chuchu n, et al. dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. cochrane database syst rev. 2018;12(12):cd011902. doi: 10.1002/14651858.cd011902. pmid: 30521682. pmcid: pmc6517096. 2. yélamos o, braun rp, liopyris k, et al. dermoscopy and dermatopathology correlates of cutaneous neoplasms. j am acad dermatol. 2019;80(2):341–363. doi: 10.1016/j.jaad.2018.07.073. pmid: 30321581. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):11 55 case presentation we report the case of an 8-year-old girl who was referred to our pigmented lesions clinic exhibiting a pale pink lesion (almost 1 cm in diameter) with a soft, lobulated surface (figure 1). this lesion had been present on the neck of the child for a year but during the previous six months had enlarged. the personal and family history of the patient was negative for the presence of other similar lesions. the dermoscopic examination, performed at that time with a handheld dermatoscope (dermlite ii hr pro by 3gen), revealed a translucent white background with blue-gray globules at the periphery and very subtle arborizing vessels (figure 2). these features could not exclude the possibility of basal cell carcinoma (bcc) although that would have been a very unlikely diagnosis in an 8-year-old child. the lesion was surgically excised. the histopathologic examination undoubtedly established the diagnosis of trichoepithelioma (te) and was characterized by the following findings: lobules of basaloid cells were arranged within the lamina propria, with no connection to the epidermis (figure 3). at the periphery of the lobules, the neoplastic cells displayed characteristic palisadsolitary trichoepithelioma in an 8-year old child: clinical, dermoscopic and histopathologic findings elizabeth lazaridou1, christina fotiadou1, aikaterini patsatsi2, anastasia fotiadu3, eirini kyrmanidou1, christina kemanetzi1, demetrios ionnides1 1 first department of dermatology/venereology, aristotle university medical school, thessaloniki, greece 2 second department of dermatology/venereology, aristotle university medical school, thessaloniki, greece 3 laboratory of diagnostic histopathology, thessaloniki, greece key words: trichoepithelioma, basal cell carcinoma, diagnosis, dermoscopy, histopathology citation: lazaridou e, fotiadou c, patsatsi a, fotiadu a, kyrmanidou e, kemanetzi c, ionnides d. solitary trichoepithelioma in an 8-year-old child: clinical, dermoscopic and histopathologic findings. dermatol pract concept. 2014;4(2):11. http://dx.doi.org/10.5826/ dpc.0402a11 received: july 9, 2013; accepted: december 26, 2013; published: april 30, 2014 copyright: ©2014 fotiadou et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: christina fotiadou, first department of dermatology/venereology, aristotle university medical school, delfon 124 st, 54643, thessaloniki, greece. tel. +3069 7728 0280 email: cifotiadou@hotmail.com solitary trichoepithelioma (te) is a rare, benign tumor of follicular origin that in certain cases is difficult to differentiate from basal cell carcinoma (bcc). we report the case of an 8-year-old girl with a pale pink, soft lesion on the neck. the clinical image of the lesion was equivocal, while some dermoscopic findings—blue-gray globules and arborizing vessels—could not exclude the presence of bcc from the differential diagnosis, although that would have been a very unlikely case considering the age of the patient. the histopathologic examination established the diagnosis of te. given the occasion of this challenging case we try to list the key clinical, dermoscopic and histopathological characteristics of te and bcc in order to elucidate the differential diagnosis of these two entities. abstract 56 observation | dermatol pract concept 2014;4(2):11 discussion te is a rare, benign dermal tumor of follicular origin [1]. three major variants have been described in the literature, namely solitary, multiple and desmoplastic te [1] the solitary subtype is commonly found in young adults. it is usually located on the central face and on the perinasal area in particular. this site predilection could be attributed to the high concentration of pilosebaceous units in this area. however, on rare occasions te can acquire a diameter of ≥1 cm and can be situated on the neck, scalp or trunk [2]. sometimes, te can closely resemble bcc. the occurrence of te and/or bcc in childhood, although it has been reported in anecdotal cases, is very uncommon [3]. the key clinical, dermoscopic and histopathologic characteristics of te and bcc are summarized in table 1. ing, while in central areas small keratinous cysts were seen (figure 4). focally, there was prominent fibroplastic stroma with moderate cellularity (figure 5). figure 1. clinical image of the lesion. [copyright: ©2014 fotiadou et al.] figure 2. dermoscopic image of the lesion showing blue-gray dots at the periphery (black arrows), subtle arborizing vessels (white arrows) and white-translucent background (dermlite ii hr pro by 3gen). [copyright: ©2014 fotiadou et al.] figure 3. histopathologic image of the lesion (hematoxylin & eosin x20) showing lobules of basaloid cells not connected to the epidermis. [copyright: ©2014 fotiadou et al.] figure 4. small keratin cysts and peripheral palisading are characteristic features of the tumor cell lobules (h&e x400). [copyright: ©2014 fotiadou et al.] figure 5. a conspicuous perilobular connective tissue sheath is present focally (h&e x100). [copyright: ©2014 fotiadou et al.] observation | dermatol pract concept 2014;4(2):11 57 the diagnosis of te by revealing the following characteristics: abundance of stroma relative to the neoplastic aggregates, lack of connection between the tumor lobules and the surface epithelium, presence of keratinous cysts, and finally absence of ulceration and mitoses. in conclusion, histopathology remains the gold standard method for the differential diagnosis between te and bcc [3,4]. the dermatoscopic criteria for te need further investigation since only a small case series has been published until now [2]. moreover, dermatoscopic findings must always be interpreted in light of important clinical information, such as the age of the patient and the natural history of the lesion. in that sense, our case shows that dermatoscopic criteria suggestive of the diagnosis of bcc, such as blue-gray globules and fine arborizing vessels, can also be seen in some cases of te. references 1. ackerman ab, reddy vb, soyer p. neoplasms with follicular differentiation. 2nd ed. new york city: ardor scribendi, ltd., 2001. in this case the clinical presentation of the lesion was in favor of te mainly due to its soft surface and to the absence of central erosion or ulceration, which usually develops in enlarging bccs. moreover, the young age of the patient almost excludes the diagnosis of bcc, although the relatively rapid enlargement of the lesion (6 months to 1 year) is not characteristic for te. the dermatoscopic examination revealed several findings that could be attributed to bcc, such as some blue-gray globules and fine arborizing vessels. however these vessels, in contrast to the arborizing vessels commonly found in a nodular bcc, were very thin, few in number and were not “in focus” under dermatoscopy. the presence of blue-gray globules, which were not very evident to the clinical eye, probably corresponds on histopathology to presence of melanin within the neoplastic aggregates found in the dermis. all the above criteria taken together with the absence of other well-known dermatoscopic clues for the diagnosis of bcc, such as leaf-like structures and spokewheel areas, do not coincide with the typical findings in bcc. finally, the histopathologic examination undoubtedly proved table 1. clinical, dermoscopic and histopathologic characteristics of trichoepithelioma and basal cell carcinoma. trichoepithelioma basal cell carcinoma (nodular) natural history and clinical picture young patients usually very slow enlargement solitary or multiple translucent skincolored papules sometimes show slight surface telangiectasia middle aged or older individuals gradual but notable enlargement a translucent papule, yellow or pink or with a pearly appearance telangiectatic vessels are often evident as the lesion enlarges, central erosion or ulceration develops dermoscopic findings thin arborizing vessels pearl-white background throughout the lesion (especially in the desmoplastic variant) sometimes multiple milia-like cysts are seen arborizing vessels blue -gray ovoid nests multiple blue-gray globules leaf-like structures and spoke wheel areas histopathological features1 discrete aggregations of germinative cells in a cribriform pattern papillary mesenchymal body with hair bulb formation pale fibrocytic stroma the epithelial—connective tissue units may be surrounded by a cleft large basaloid aggregations of varying shape and size form a relatively circumscribed mass aggregations may have a jagged outline and large zones of necrosis clefts between the germinative cells at the periphery and the adjacent altered stroma stroma retraction artifact with mucin deposits 58 observation | dermatol pract concept 2014;4(2):11 4. arits a, parren l, van marion a, et al. basal cell carcinoma and trichoepithelioma: a possible matter of confusion. int j dermatol. 2008;47 (suppl. 1): 13-17. 2. ardigo m, zieff j, scope a, et al. dermoscopic and reflectance confocal microscope findings of trichoepithelioma. dermatology. 2007; 215: 354-8. 3. lichtenstein d, taijbee s, carr r. trichoepithelioma, not basal call carcinoma in an 8-year-old child. pediatr dermatol. 2013; 30: 276-8. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):7 37 longterm digital monitoring in the diagnosis and management of congenital nevi of the nail apparatus showing pseudo-hutchinson’s sign mizuki sawada1, sumiko ishizaki1, ken kobayashi1, itaru dekio1, masaru tanaka1 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan keywords: hutchinson’s sign, nevus of the nail apparatus, congenital, dermoscopy, periungual pigmentation, longterm digital monitoring citation: sawada m, ishizaki s, kobayashi k, dekio i, tanaka m. longterm digital monitoring in the diagnosis and management of congenital nevi of the nail apparatus showing pseudo-hutchinson’s sign. dermatol pract concept. 2014;4(2):7. http://dx.doi.org/10.5826/ dpc.0402a07 received: december 16, 2013; accepted: january 25, 2014; published: april 30, 2014 copyright: ©2014 sawada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: masaru tanaka, m.d., department of dermatology, tokyo women’s medical university medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel. +81 3 3810 1111; fax. +81 3 3894 1441, e-mail: tanaka.twmu@gmail.com introduction congenital nail apparatus nevi often show substantial enlargement and wide involvement and greatly concern parents of a child as well as dermatologists. the differential diagnosis from melanoma is critical. the biopsy of the nail matrix is very traumatic and a fearful experience for a child. therefore, a longterm careful follow-up with digital monitoring is very important and should be the first choice of management. ronger et al. [1] reported that only three cases of melanoma showed micro-hutchinson’s sign in 148 cases of melanonychia. however, similar findings are also observed in congenital nevus of the nail apparatus. we report three cases of congenital or early-onset nevus of the nail apparatus with minute periungual regular pigmentation found on dermoscopy. we used the terms, “hutchinson’s sign” and “pseudohutchinson’s sign” based on the original descriptions [2, 3]. baran and kechijian [3] originally defined the term, pseudohutchinson’s sign, for three conditions, including 1) benign pigmentation of the nailfolds, 2) pigmentation of the nailfolds due to malignant but non-melanoma tumors, 3) pigmentation seen through translucent nailfolds. case presentations case 1 a 10-year-old japanese boy presented with pigmentation of the nail of the right ring finger. the lesion was noticed at birth. physical examination showed melanonychia of the fingernail. he had been followed up for eight years. dermoscopy showed regular dark brown lines and a brown band (figure 1a–f). dermoscopy performed from 2008 to 2012 also showed several blue-gray dots along the brown lines. these blue-gray dots disappeared on the dermoscopy performed in 2013. there was a regular minute fibrillar pattern on the proximal nailfold and subtle pigmentation on the lateral nailfold. the minute fibrillar pattern was also observed under the distal nail edge, namely the hyponychium. these minute periungual pigmentations were not noticed at the initial clinical examination (figure 1g). the follow-up revealed that the dark brown lines were gradually decreasing and the mailto:tanaka.twmu@gmail.com 38 observation | dermatol pract concept 2014;4(2):7 blue-gray dots were subsiding. a possibility of melanoma has been ruled out because of scarce change through the followup for eight years. case 2 an 11-year-old japanese boy presented with pigmentation of the nail of the right middle finger. the lesion was noticed when he was 7 years old. physical examination showed melanonychia of the fingernail. he had been followed up for three years. dermoscopy showed regular dark brown lines and a brown band (figure 2a–c). the brown background band slightly widened compared with previous dermoscopy results, however, the dark brown lines on the band were gradually decreasing. there were also blue-gray dots along the brown lines, which also seemed to be gradually decreasing. there was a regular minute fibrillar pattern on the proximal nailfold, which was not noticed at the clinical examination. a possibility of melanoma has been ruled out because of scarce change through the follow-up for three years. figure 1. dermoscopy of case 1. dermoscopy showed regular dark brown lines and a brown background band (a–f), and dermoscopy from 2008 (b) to 2012 (e) also showed several blue-gray dots along the brown lines. there was a regular minute fibrillar pattern on the proximal nailfold and hyponychium and subtle pigmentation on the lateral nailfold. the clinical picture disclosed prominent nail pigmentation, but periungual pigmentation was too subtle to notice (g). [copyright: ©2014 sawada et al.] g case 3 a 12-year-old japanese boy presented with pigmentation of the nail of the right third toe. the lesion was noticed at birth. the amount of pigmentation increased after 3 years. physical examination showed melanonychia of the fingernail. he had been followed up for three years. dermoscopy showed regular dark brown lines and a brown band (figure 3a–c). there was regular fibrillar minute periungual pigmentation, which was not noticed at the clinical examination (figure 3d), on the proximal nailfold, lateral nailfold, and hyponychium. the pigmentation on the hyponychium observed in 2007 seemed to have been decreasing. a possibility of melanoma has been ruled out because of scarce change through the follow-up for three years. observation | dermatol pract concept 2014;4(2):7 39 recommend using a simple term “periungual pigmentation” or “periungual minute pigmentation” and to describe the distribution of the pigmentation as either regular or irregular fibrillar pigmentation. although congenital nevus often shows periungual pigmentation, resulting in increased concern on the part of the clinician and therefore necessitating biopsy, we would like to discussion the brown-black periungual pigmentation seen in melanoma is known and described as hutchinson’s sign [2]. however, such periungual pigmentation could be found not only in melanoma but also in various benign conditions such as congenital nevus, laugier-hunziker-baran syndrome, subungual hematoma, and nonmelanoma skin cancer such as bowen’s disease, or in the pigmentation observable through the translucent nailfolds [3]. ronger et al. described the minute periungual pigmentation in melanomas as micro-hutchinson’s sign, which is difficult to find with the naked eye but could be observed on dermoscopy. they reported that micro-hutchinson’s sign was observed only in three cases of nail apparatus melanoma, but not in nevi from 148 melanonychia cases [1]. as we noted similar minute periungual pigmentation in congenital nevus of the nail apparatus, we presented three such cases. our follow-up observation revealed that congenital or early-onset nevus of the nail apparatus also showed minute periungual pigmentation. therefore, we described and named them as “pseudo-micro-hutchinson’s sign.” however, as this term seems to describe several different conditions, we figure 2. dermoscopy of case 2. dermoscopy showed regular dark brown lines and a brown background band (a–c). the brown background band slightly widened, but the dark brown lines on the band is gradually decreasing. there was a regular minute fibrillar pattern on the proximal nailfold. [copyright: ©2014 sawada et al.] d figure 3. dermoscopy of case 3. dermoscopy showed regular dark brown lines and a brown band (a–c). there was regular fibrillar minute periungual pigmentation on the proximal nailfold, lateral nailfold, and hyponychium. cilinical picture disclosed prominent nail pigmentation, but periungual pigmentation was too subtle to notice (d). [copyright: ©2014 sawada et al.] figure 4. “neumatic” pattern resembling the notation of the gregorian chant. the dots and lines in the regressing melanonychia show a “neumatic” pattern. [copyright: ©2014 sawada et al.] 40 observation | dermatol pract concept 2014;4(2):7 important because it would help explain to the patient’s family that the melanonychia might disappear in the future. we would also like to emphasize the importance of the longterm follow-up of the melanonychia in children rather than histopathological examination, which could leave permanent nail deformity, to rule out melanoma. these cases were presented at the 65th western division meeting of the japanese dermatological association. references 1. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138:1327-33. 2. kopf aw. hutchinson’s sign of subungual malignant melanoma. am j dermatopathol. 1981;3:201-2. 3. baran r, kechijian p. hutchinson’s sign: a reappraisal. j am acad dermatol. 1996;34:87-90. 4. murata y, kumano k. dots and lines: a dermoscopic sign of regression of longitudinal melanonychia in children. cutis. 2012;90:293-6. propose that a biopsy is not necessarily applicable. instead, if dermoscopic features are regular in lines, longterm followup is important to rule out melanoma. in our opinion, all the nevi in children would increase in size for certain periods at the beginning and then decrease in pigmentation. one of the signs for regression is the “neumatic notation”-like blue-gray dots, as murata and kumano reported [4]. when this sign is observed, we would wait and expect that the nail pigmentation might disappear. therefore, we think that it is more important to follow up on the changes of the nevus rather than to biopsy it. a biopsy of nail matrix would result in permanent nail deformity; additionally, the procedure of a biopsy is a fearful experience for children in this age. the blue-gray dots are a sign of regression of melanonychia in children [4]. this finding would correspond to transepithelial elimination of melanin or apoptotic melanocytes in the nail plate. as originally described by murata and kumano, these dots appear like the neumatic notation of the gregorian chant (figure 4). knowledge about this feature is dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022143 1 habits of using social media and the internet in psoriasis patients melek aslan kayıran1, ayşe serap karadağ2, i̇lteriş oğuz topal3, esra adışen4, sevilay kılıç5, nuray keskin4, asude kara polat6, bengü çevirgen cemil7, mualla polat8, oğuz yılmaz9, hilal ayvaz10, filiz topaloğlu demir11, sezgi sarıkaya solak12, derya uçmak13, mehmet salih gürel1, sema aytekin14, algün polat ekinci15, kübra nursel bölük15, neslihan şendur16, tuğba özkök akbulut17, günseli öztürk18, ayda acar18, erkan alpsoy9 1 i̇stanbul medeniyet university, göztepe prof dr. süleyman yalçın city hospital, department of dermatological and venereal diseases 2 ataşehir memorial hospital, department of dermatological and venereal diseases 3 health sciences university, prof. dr. cemil taşçıoğlu hospital, department of dermatological and venereal diseases 4 gazi university, faculty of medicine, department of dermatological and venereal diseases 5 çanakkale 18 mart university, faculty of medicine, department of dermatological and venereal diseases 6 health sciences university, i̇stanbul training and research hospital, department of dermatological and venereal diseases 7 health sciences university, dışkapı yıldırım beyazıt training and research hospital, department of dermatological and venereal diseases 8 bolu abant i̇zzet baysal university, faculty of medicine, department of dermatological and venereal diseases 9 akdeniz university, faculty of medicine, department of dermatological and venereal diseases 10 süleyman demirel university, faculty of medicine, department of dermatological and venereal diseases 11 i̇stanbul medipol university, faculty of medicine, department of dermatological and venereal diseases 12 trakya university, faculty of medicine, department of dermatological and venereal diseases 13 dicle university, faculty of medicine, department of dermatological and venereal diseases 14 health sciences university, haydarpaşa training and research hospital faculty of medicine, department of dermatological and venereal diseases 15 i̇stanbul university, i̇stanbul faculty of medicine, department of dermatological and venereal diseases 16 adnan menderes university, faculty of medicine, department of dermatological and venereal diseases 17 health sciences university, haseki training and research hospital, department of dermatological and venereal diseases 18 ege university, faculty of medicine, department of dermatological and venereal diseases key words: psoriasis, social media, internet, habit citation: aslan kayıran m, karadağ as, oğuz topal i, et al. habits of using social media and the internet in psoriasis patients. dermatol pract concept. 2022;12(3):e2022143. doi: https://doi.org/10.5826/dpc.1203a143 accepted: december 9, 2021; published: july 2022 copyright: ©2022 aslan kayıran et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: melek aslan kayıran, md, eğitim mah, kadıköy, i̇stanbul, 34722, e-mail: melekaslan@gmail.com 2 original article | dermatol pract concept. 2022;12(3):e2022143 introduction psoriasis is a chronic systemic inflammatory disease seen at a rate of 1-3% across the world [1]. sufferers may experience itching, burning and pain sensation, and restrictions in social life, which reduce their quality of life [2]. social media (sm) comprises internet-based communication tools that have entered people lives very quickly [3]. it is utilized for many different purposes, such as accessing educational tools and creating educational resources, creating campaigns to reach the public, and even inviting patients to participate in clinical trials or online surveys [3]. today, access to information through technology tools has become extremely easy and fast. as in every subject, the internet has become almost the first source of reference for health problems. although there are a few studies related to the use of sm and the internet conducted with patients presenting to dermatology outpatient clinics, there is no research specifically focusing on psoriasis patients [4,5]. psoriasis affects the quality of life of patients due to recurrent nature of the disease, long-term and sometimes laborious treatment processes, accompanying symptoms including pain, itching, and xerosis, and involvement of visible areas such as the face or intimate parts of the body such as the genitals [6]. this prompts patients to explore different treatment options, seek different physicians and hospitals, and reach other patients and various medical organizations. in this respect, the internet and sm provide patients with a wide range of sources and fast access to information. objectives this study aimed to explore the habits of patients with psoriasis related to their use of sm and the internet to obtain information about their disease, methods they used, whether they followed programs concerning the disease available on media outlets, whether they read related brochures, and their recommendations to dermatologists and dermatological associations concerning the use of sm related to psoriasis. methods patients the study included voluntary literate psoriasis patients over the age of 18 years and who were followed in the psoriasis-specialized outpatient clinics of 18 different dermatology departments located in seven regions of turkey between january 1, 2020, and july 1, 2020. each researcher had to enroll at least 75 patients in the study [7]. although part of the study coincided with the pandemic period, dermatology outpatient clinics were actively working in hospitals due to the regulations of the health authority. procedure this is a non-interventional, cross-sectional multicenter study. approval for the study was obtained from the ethics committee of the university (id 25.12.2019/0527). the survey questions were prepared by the researchers. information on the patients clinical findings and the psoriasis area severity index (pasi) scores were noted by their physicians. the introduction: psoriasis significantly affects the patients quality of life, which often leads patients to seek online information about this disease. objectives: to explore the habits of patients with psoriasis related to their use of social media (sm) and the internet to obtain information about their disease. methods: 1,520 patients completed the survey and the dermatology life quality index (dlqi) questionnaire. the psoriasis area severity index scores (pasi) and clinical data of the patients were recorded by their physicians. results: of the 1,114 patients that reported using sm and internet, 48.38% regularly and 31.14% sometimes resorted to obtain information about psoriasis. the use of sm and internet for psoriasis was statistically significantly higher among young people (p = 0.000), those with university or higher education (p = 0.009), higher dlqi (p = 0.000) and pasi (p = 0.011) scores, facial (p = 0.050), scalp (p = 0.032), hand (p = 0.048), genital (p = 0.001) and inverse (p = 0.000) involvement, and arthralgia/arthritis (p = 0.006). the participants mostly used the google (86%) and facebook (41%). more than half of the participants (62.8%) expected dermatologists to inform society that psoriasis is not contagious. conclusions: internet and sm being widely available and offering substantial information to be easily accessed make it very attractive for patients to use these platforms to investigate diseases, including psoriasis. if what is presented on sm conflicts with what the physician says, patients mostly trust the latter, but at the same time, they tend not to share the results of their online inquiries with their physicians. abstract original article | dermatol pract concept. 2022;12(3):e2022143 3 patients were asked to complete the survey (supplementary table 1) and the dermatology life quality index (dlqi) questionnaire without any time limitation [8,9]. statistical analysis data obtained were analyzed using spss ibm software package at the 95% confidence level, ie, 5% margin of error. descriptive statistics concerning the survey results were given as frequencies and percentages. in continuous measurements showing a normal distribution, paired-group comparisons were undertaken with the independent-samples t-test while three groups were compared using analysis of variance (anova). in cases where there was a significant difference in anova, the groups that caused the significant difference were examined using the least significant difference test as a post-hoc method. in continuous measurements that did not show a normal distribution, two groups were compared using the mann-whitney u test and three-group comparisons were undertaken with the kruskal-wallis h test. the test statistics for the comparison of two or more groups were obtained using the chi-squared test. results a total of 1,520 participants (709 women and 811 men) were included in the study and all of them agreed to participate. of the participants, 51.40% stated that they used sm and the internet regularly, 21.90% sometimes used them, and 26.70% never used them. in addition, of the participants who stated that they used sm and the internet, 48.38% regularly and 32.14% sometimes made inquiries about psoriasis on these platforms while 19.48% did not consult online platforms for this purpose. the use of sm and the internet for psoriasis was significantly higher in young people, those with university or higher education levels. although there was no significant difference between smokers and non-smokers, the smoking pack years were significantly higher in sm users than non-sm users (11±23 pack years, 9±14 pack years; p = 0.027, respectively). social media and internet use in psoriasis patients were found not significantly associated with gender, marital status, alcohol use, and monthly family income (table 1). the use of the internet and sm for psoriasis-related inquiries was higher in marmara region where the education level and the rate of working population are high, as well as in central anatolia where the capital of turkey is located. social media and internet use was significantly higher in those with higher dlqi and pasi scores, those with facial, scalp, hand, genital and inverse involvement, and those with arthralgia/arthritis. nail involvement, family history of psoriasis, and disease duration were not found associated with sm and internet use (table 2). there was no difference between psoriasis subtypes in terms of sm and internet usage. sm tools used by the participants to investigate psoriasis are shown in figure 1. most participants (86%) reported using google for this purpose. the participants most frequently (76%) sought information about the disease itself, followed table 1. social media and internet use according to demographic characteristics. frequency of social media use yes no sometimes overall p n % n % n % n % gender female 238 45.9% 122 23.5% 159 30.6% 519 46.6% 0.136 male 274 46.1% 165 27.8% 155 26.1% 594 53.4% marital status married 356 45.6% 211 27.0% 214 27.4% 781 70.1% 0.336single 144 48.5% 67 22.6% 86 29.0% 297 26.7% divorced 13 36.1% 9 25.0% 14 38.9% 36 3.2% smoking status non-smoker 277 44.2% 161 25.7% 188 30.0% 626 56.3% 0.193 smoker 236 48.7% 126 26.0% 123 25.4% 485 43.7% ex-smoker no 473 46.6% 253 24.9% 290 28.5% 1016 91.4% 0.173 yes 39 41.1% 32 33.7% 24 25.3% 95 8.6% alcohol no 404 45.7% 228 25.8% 252 28.5% 884 79.4% 0.918regularly 13 54.2% 6 25.0% 5 20.8% 24 2.2% social drinker 96 46.8% 53 25.9% 56 27.3% 205 18.4% monthly income level* 300$ and below 96 41.4% 69 29.7% 67 28.9% 232 20.8% 0.376 300-650$ 277 47.7% 135 23.2% 169 29.1% 581 52.2% 650-1,300$ 110 45.1% 70 28.7% 64 26.2% 244 21.9% above 1,300$ 29 51.8% 13 23.2% 14 25.0% 56 5.0% table1 continues 4 original article | dermatol pract concept. 2022;12(3):e2022143 table 2. social media and the internet use according to disease involvement. frequency of social media use yes no sometimes overall p n % n % n % n % joint pain/involvement arthralgia 120 45.1% 55 20.7% 91 34.2% 266 25.0% 0.006arthritis 73 52.9% 27 19.6% 38 27.5% 138 12.9% absent 287 43.4% 197 29.8% 178 26.9% 662 62.1% nail involvement absent 310 47.9% 167 25.8% 170 26.3% 647 58.1% 0.205 present 203 43.5% 120 25.7% 144 30.8% 467 41.9% scalp involvement absent 217 43.3% 148 29.5% 136 27.1% 501 45.0% 0.032 present 296 48.3% 139 22.7% 178 29.0% 613 55.0% facial involvement absent 402 44.4% 244 26.9% 260 28.7% 906 81.3% 0.050 present 111 53.4% 43 20.7% 54 26.0% 208 18.7% hand involvement absent 324 46.0% 196 27.8% 184 26.1% 704 63.2% 0.048 present 189 46.1% 91 22.2% 130 31.7% 410 36.8% genital involvement absent 382 44.2% 246 28.4% 237 27.4% 865 77.6% 0.001 present 131 52.6% 41 16.5% 77 30.9% 249 22.4% inverse involvement absent 375 43.5% 249 28.9% 239 27.7% 863 77.5% 0.000 present 138 55.0% 38 15.1% 75 29.9% 251 22.5% pasi 6.8 ± 9 5.7 ± 9.7 6.8 ± 9.5 6.5 ± 9.4 0.011 dlqi 10.3 ± 8.7 6.6 ± 7.1 9.7 ± 8.4 9.1 ± 8.4 0.000 disease duration 14 ± 10 15 ± 11 15 ± 11 14 ± 10 0.217 family history of psoriasis absent 188 44.0% 111 26.0% 128 30.0% 427 38.8% 0.560 present 315 46.7% 176 26.1% 183 27.2% 674 61.2% dlqi = dermatology life quality index scores; pasi = the psoriasis area severity index scores. frequency of social media use yes no sometimes overall p n % n % n % n % education level literate** 2 11.1% 10 55.6% 6 33.3% 18 1.6% 0.009 primary-middle school 156 43.8% 99 27.8% 101 28.4% 356 32.0% high school-college 208 46.3% 102 22.7% 139 31.0% 449 40.4% university 129 50.0% 66 25.6% 63 24.4% 258 23.2% post-graduate (masters-phd) 17 56.7% 9 30.0% 4 13.3% 30 2.7% age, years, mean ± standard deviation 39 ± 13 43 ± 15 40 ± 13 41 ± 14 0.000 *calculated based on the exchange rate at the time of the study. **refers to participants that have no formal education but know how to read and write. table 1. social media and internet use according to demographic characteristics. (continued) by medication and treatment options (62%), physicians (40%), and other patients posts (43%). of the respondents, 9.9% were members of sm groups related to psoriasis, 3.1% were former members, and 87% stated that they had never joined such a group. the platforms used for patient groups were facebook for 80.3% of the participants, instagram for 21.4%, whatsapp for 10.3%, twitter for 2.6%, and other platforms for 12%. when asked about their views on what was discussed in these groups, 35.7% of the respondents reported that they read the posts if they caught their attention, 23.6% looked for further information on what was discussed, 20.7% just read the posts, 22.2% felt relieved to see others with similar problems, and 8.4% thought that a physician or product was advertised in these online groups. we determined that 78.7% of the participants did not ask their physician about the accuracy of information obtained from sm and the internet (figure 2a). in case of contradiction between their findings in internet search and their physicians’ original article | dermatol pract concept. 2022;12(3):e2022143 5 900 800 700 600 n u m b er o f pa r ti c ip a n ts 500 400 300 200 100 0 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% n % 771 google facebook youtube instagram patient blogs twitter other 364 295 33% 280 31% 172 19% 72 8% 58 6%41%86% figure 1. social media and internet platforms on which the participants sought information about psoriasis. figure 2. (a) the answers to the question “do you ask your physician about the accuracy of information obtained from social media?”. (b) the answers to the question “in case of contradiction between the sm and your physician, who would you trust?”. recommendations, 84.6% of the participants stated that they would trust their physicians (figure 2b). of the participants, 19.4% stated that they used sm to try to contact dermatologists to ask questions about their disease. when online platforms were used for this purpose, 14.2% of the participants considered that physicians should answer patients’ questions, 13.6% stated that only physicians working in private hospitals should answer such questions, 32.8% thought that physicians should respond politely even if they were not obliged to answer, and 43.6% believed that physicians did not have to answer. the participants stated that they most frequently (66.7%) tried to contact physicians by personal or clinic phone (figure 3a). of those that tried to contact via sm, they mostly used facebook (49.3%) (figure 3b). when they reached physicians, they mostly asked questions about their treatment (41.4%) and disease (31.1%). furthermore, 8.7% stated that they sent physicians photographs of their symptoms in order to ask for their advice, 12% asked for help to get hospital appointments, and the remainder asked for advice on other skin diseases or the health problems of relatives. the majority of the participants that tried to contact physicians on sm (77.9%) added that they did not receive a response, while most of those that obtained a response (61.8%) mentioned that they followed physicians’ recommendations, 21.2% sometimes followed these recommendations, and 17% did not do what was recommended. when the participants were asked whether they would trust a physician’s answer if they directed him/her a question accompanied by a photograph, 56.6% responded as no, 11.4% as yes, and 32% as yes but they would still visit a physician for an examination. 6 original article | dermatol pract concept. 2022;12(3):e2022143 of the participants, 36.9% did not like the television and radio programs on psoriasis, 29% considered that such programs only aimed to promote physicians or advertise products, 31.7% wanted to be given information, and 22.8% stated that it was a relief to see other psoriasis patients. while 52.5% of the participants did not follow such programs, 14.5% followed them regularly and 33% sometimes watched them. most of the respondents (83.9%) reported that they did not apply what they saw on television, and 9.1% always and 7% sometimes tried them. in addition, the participants made further inquiries about what they saw on television by consulting the internet (27.4%), a physician (18.4%), a pharmacist (7%), and other patients (8.2%). among these participants, 13.6% sought further information if what was presented on television appeared logical while 46.3% did not make any further inquiries. only 0.2% of the respondents contacted the television or radio program to ask questions. of the participants, 75.2% stated that they never asked their physicians about what they saw on television programs while 10.6% asked such questions implicitly and 14.2% openly. when asked whether they had read a book/brochure about psoriasis, 5.8% of the participants stated that they had, 71.7% had not, and 22.5% were not aware of such publications. furthermore, 62.7% of the respondents wanted seminars on psoriasis to be given by physicians and 30.3% by official institutions, and 21.9% stated that they would attend such events if they were free, 9% would be willing to pay a fee, and 19.3% were not interested. more than half the participants (56.5%) reported that hospitals or physicians did not give them educational brochures while 26.9% were provided such publications and read them, and 16.6% were presented such materials but did not read them. table 3 summarizes the participants responses concerning their recommendations for dermatologists and dermatological associations. the respondents most frequently (62.8%) wanted the public to be informed that psoriasis was not contagious. secondly (62%), the patients wanted the dermatologists and the dermatology associations to prepare the publications and information shown in sm and the figure 3. (a) the patients answers to the question “how do you try to contact your physician?”. (b) the social media platforms which they use to communicate their physician. table 3. recommendations of the participants to dermatologists and dermatological associations concerning the use of social media and internet related to psoriasis recommendation n % society should be made aware that the disease is not contagious. 955 62.8% these publications should be prepared by the authorities in this area. 942 62.0% sharing false information should not be allowed. 831 54.7% society should be made aware that treatment is available for the disease. 752 49.5% only dermatologists should discuss the disease. 670 44.1% seminars should be organized in places easily accessible to the public. 573 37.7% associations should file a criminal complaint if inaccurate information is present. 494 32.5% books-booklets should be prepared and distributed. 449 29.5% more media programs should be made available to present introductory information about the disease. 402 26.4% patient schools should be organized in hospitals. 353 23.2% more information should be shared on the internet. 302 19.9% total percentage exceeds 100 since the participants were allowed to choose more than one option original article | dermatol pract concept. 2022;12(3):e2022143 7 difference, but internet and sm users had a mean lower age and higher education level. this can be explained by the higher internet and sm usage among young adults and those with a higher education level [18]. furthermore, the more people quality of life was, the more likely they would look for a solution to their disease. in addition, it has been shown that the involvement of the visible parts of the body such as the face and hands and intimate parts such as the genitals and skin folds, as well as the presence of accompanying painful conditions, including arthralgia/arthritis are more likely to have negative psychosocial effects on patients and result in higher dlqi scores [6]. unsurprisingly, in the presence of such involvements, patients tend to make more online inquiries concerning their disease. in the usa, the rate of individuals referring to facebook to obtain information about health was found to be 38% [19]. in a study conducted with dermatology patients, it was shown that the patients obtained information about their physicians through sm 9.7 times more frequently compared to traditional media sources [11]. the source of this information was mostly twitter (44.5%), followed by instagram (27.9%), and facebook (2.8%). however, the authors did not include search engines such as google in their study [11]. in another study, the patients most frequently used google (42.3%), followed by youtube (34.6%) and facebook (22.3%) for their medical searches[5]. in our study, 86% of the patients used google for this purpose, while 41% used facebook, 33% youtube, 31% instagram, and 8% twitter. since google is globally the most used search engine as in our country, it is natural for patients to seek information about their diseases using this engine. facebook is the most frequently used sm tool for adults using the internet [20]. however, sm habits can change over time. some websites/ applications may lose popularity while others may become more popular or their popularity may fluctuate. in addition, sm applications can be expected to vary according to geographical regions [21]. one of the interesting findings of our study is that 19% of the participants used patient blogs to obtain information. in addition, 22.8% stated that it was a relief seeing patients with psoriasis like themselves on traditional media programs such as television. in general, patients express that they feel comfortable and less embarrassed when they meet people with the same disease and exchange views about their disease [22]. the findings from our study indicate that patients are interested in what other patients with the same disease experience and they may even compare their experiences to others, and it is comforting for them to realize that there are others that suffer from the same problems. our participants reported that they mostly consulted the internet to seek information about their disease, followed by treatment options and physicians. patients motivations to internet. they (54.7%) also did not want to see false information about psoriasis on sm and the internet. conclusions our study showed that 80.5% of the patients with psoriasis had the habit of regularly or sometimes using sm and the internet to seek information about their disease. this behavior was more common in young people, those with university or higher education levels, those with higher dlqi and pasi scores, those with facial, scalp, hand, genital and inverse involvement, and those with arthralgia/arthritis. the most commonly used search engine was google (86%) and the most commonly used sm platform was facebook (41%). while it is known that globally, 4.5% of online inquiries was related to health in the 2000s, this rate has gradually increased, reaching 79% today [4,10,11]. patients resort to sm and the internet to obtain information about their diseases and treatments, communicate with other patients and physicians, and look for organizations related to their diseases [12]. a previous study conducted in the united states of america (usa) reported that 80% of internet users consulted the internet to access information about at least one disease throughout their lifetimes [13]. however among the studies conducted for this purpose, especially those related to internet use on a disease basis have not yet become widespread, and research on the general use of the internet about diseases has only accelerated in the last few years. our study is the first to investigate the internet and sm use of patients with psoriasis and includes data obtained from 1,520 patients participating from different regions of turkey. in a study conducted with 460 patients who presented to a general dermatology outpatient clinic, the rate of those consulting sm was found to be 80% [14]. in another study conducted with patients who presented to the dermatology outpatient clinic in saudi arabia, this rate was found to be 47% [4]. in a general surgery study, the rate of patients referring to online research before hernia surgery was reported to be 67% [15]. in our study, 80.5% of the patients with psoriasis stated that they resorted to the internet or sm to obtain information about their disease. the difference in this rate seems to be due to our research focusing on a specific chronic disease. the rate of online medical inquires is also reported to be higher among women, people with higher income, those with higher education levels, and those more affected by the disease [5,14-16]. similarly, in our study, we observed that the use of sm and the internet for psoriasis was statistically significantly higher in young people and highly educated individuals. in dietetic studies, the use of sm was found to be higher in women and in young adults aged 18 to 35 years [17]. in the current study, there was no gender 8 original article | dermatol pract concept. 2022;12(3):e2022143 and comments, it is inevitable that some of the shared information is false. our study showed that a high rate of patients with psoriasis consulted online sources to seek information about their disease. they most frequently used google, facebook, and youtube channels to obtain information about the disease, treatment options, and doctors. however, although they consulted the internet and sm to seek information, most stated that they had greater trust in the information given by physicians. they also followed patient blogs and were relieved to see the presence of other patients suffering from psoriasis. they expressed their discomfort with the misbelief of a section of society without the disease that psoriasis is contagious, and they recommended dermatologists and dermatological associations to educate the public in this regard. as dermatologists, we have great responsibility in sharing accurate information about psoriasis on sm and the internet, as well as raising the awareness of society. references 1. ljubenovic m, lazarevic v, golubovic m, binic i. integrative approach to psoriasis vulgaris. holist nurs pract. 2018;32(3): 133– 139. doi: 10.1097/hnp.0000000000000180. pmid: 29261515. 2. oji v, luger ta. the skin in psoriasis: assessment and challenges. clin exp rheumato.l 2015;33(5 suppl 93):s14–s19. pmid: 26472560. 3. grajales fj 3rd, sheps s, ho k, novak-lauscher h, eysenbach g. sm: a review and tutorial of applications in medicine and health care. j med internet res. 2014;16(2):e13. doi: 10.2196 /jmir.2912. pmid: 24518354. pmcid: pmc3936280. 4. alghamdi km, moussa na. internet use by the public to search for health-related information. int j med inform. 2012;81(6):363–373. doi: 10.1016/j.ijmedinf.2011.12.004. pmid: 22217800. 5. gantenbein l, navarini aa, maul lv, brandt o, mueller sm. internet and sm use in dermatology patients: search behavior and impact on patient-physician relationship. dermatol ther. 2020;33(6):e14098. doi: 10.1111/dth.14098. pmid: 32725746. 6. alpsoy e, polat m, fettahlıoglu-karaman b, et al. internalized stigma in psoriasis: a multicenter study. j dermato. l 2017;44(8):885–891. doi: 10.1111/1346-8138.13841. pmid: 28407292. 7. scala e, megna m, amerio p, et al. patients’ demographic and socioeconomic characteristics influence the therapeutic decision-making process in psoriasis. plos one. 2020;15(8):e0237267. doi: 10.1371/journal.pone.0237267. pmid: 32785291. pmcid: pmc7423114. 8. finlay ay, khan gk. dermatology life quality index (dlqi)--a simple practical measure for routine clinical use. clin exp dermatol. 1994;19(3):210–216. doi: 10.1111/j.1365-2230.1994. tb01167.x. pmid: 8033378. 9. oztürkcan s, ermertcan at, eser e, sahin mt. cross validation of the turkish version of dermatology life quality index. int j dermatol. 2006;45(11):1300–1307. doi: 10.1111/j.13654632.2006.02881.x. pmid: 17076710. resort to sm and the internet to obtain information about their diseases can be listed as understanding the disease, exploring personal diagnosis-treatment methods and alternative treatments, and obtaining information about doctors and hospitals. however, they still consider physicians as the most trustworthy source [14]. in our study, 84.6% of the participants stated that even if they conducted online searches, they would trust the physician in the presence of conflicting information. as a more interesting finding, 56.6% of the participants stated that even if they had been given the opportunity to obtain information about their disease by sending photographs to their physician, they would have not trusted the physician response and 32% would still go to a physician for an examination. this shows that although the patients trusted physicians’ knowledge, they would still prefer to be personally examined by a physician and exchange ideas. in this study, 78.7% of the respondents stated that they did not share with their physicians what they inquired about on the internet related to their disease, which is in agreement with previous studies.14 this can be interpreted as patients not being willing to disclose to their physicians that they consult online sources and they may even be concerned about their physicians reaction. when asked about their recommendations to dermatologists and dermatological associations regarding the use of sm, internet and traditional media, most of the participants (62.8%) stated that society should be informed that psoriasis is not contagious. in addition, they stated that informative publications and broadcasts should be prepared by the authorities in the field, such as dermatologists (62%) and that false information about the disease should not be allowed to spread (54.7%). it is now widely known that psoriasis is not contagious, but even today patients with lesions, especially in visible areas still express that other people refrain from touching them or shaking hands [23,24]. in this respect, it is very important that three out of every five participants in the current study recommended that the public should be informed about the non-contagious nature of the disease. it is clear that this situation affects the social relationships of patients. the main limitations of our study are that the data were collected through a survey, and therefore they were based on the self-reported statements of the patients and a part of the study period coincided with the ongoing pandemic. during the first months of the pandemic, working from home may make the patients access sm frequently. a comparison with another chronic skin disease or with a control group may be done for further studies. however, this study is important due to being the first in this area, multicenter design involving the whole country, and inclusion of a large patient series. although sm comprises many favorable characteristics, such as allowing for the mutual exchange of information original article | dermatol pract concept. 2022;12(3):e2022143 9 10. eysenbach g, kohler c. what is the prevalence of healthrelated searches on the world wide web? qualitative and quantitative analysis of search engine queries on the internet. amia annu symp proc. 2003;225–229. pmid: 14728167. pmcid: pmc1480194. 11. albeshri m, alharithy r, altalhab s, alluhayyan ob, farhat am. the influence of modern sm on dermatologist selection by patients. cureus. 2020;12(12) e11822. doi: 10.7759/cureus.11822. pmid: 33409064. pmcid: pmc7781535. 12. reich j, guo l, groshek j, et al. sm use and preferences in patients with inflammatory bowel disease. inflamm bowel dis. 2019;25(3):587–591. doi: 10.1093/ibd/izy280. pmid: 30203036. 13. kardeş s. seasonal variation in the internet searches for psoriasis. arch dermatol res. 2019;311(6):461–467. doi: 10.1007 /s00403-019-01921-0. pmid: 31025101. 14. yousaf a, hagen r, delaney e, davis s, zinn z. the influence of sm on acne treatment: a cross-sectional survey. pediatr dermatol. 2020;37(2):301–304. doi: 10.1111/pde.14091. pmid: 31944359. pmcid: pmc7453954. 15. miller mp, arefanian s, blatnik ja. the impact of internet-based patient self-education of surgical mesh on patient attitudes and healthcare decisions prior to hernia surgery. surg endosc. 2020;34(11):5132–5141. doi: 10.1007/s00464-019-07300-0. pmid: 31832857. 16. bender jl, hueniken k, eng l, et al. internet and sm use in cancer patients: association with distress and perceived benefits and limitations. support care cancer. 2021;29(9):5273-5281. doi: 10.1007/s00520-021-06077-0. pmid: 33651181. 17. dumas aa, lapointe a, desroches s. users, uses, and effects of sm in dietetic practice: scoping review of the quantitative and qualitative evidence. j med internet res. 2018;20(2):e55. doi: 10.2196/jmir.9230. pmid: 29463487. pmcid: pmc5840482. 18. perrin a. social networking usage: 2005-2015. pew research center. 2015. available from: http://www.pewinternet. org/2015/10/08/2015/social-networking-usage-2005-2015 /[last accessed: august 27, 2021]. 19. fox s. health information online. pew research center 2005. available from: https://www.pewresearch.org/ internet/2005/ 05/17/health-information-online/ [last accessed: august 27, 2021]. 20. greenwood s, perrin a, duggan m. sm update 2016. pew research center 2016. available from: https://www.pewresearch. org/internet/2016/11/11/social-media-update-2016/ [last accessed: august 27, 2021]. 21. niu z, willoughby j, zhou r. associations of health literacy, sm use, and self-efficacy with health information-seeking intentions among sm users in china: cross-sectional survey. j med internet res. 2021;23(2):e19134. doi: 10.2196/19134. pmid: 33629955. pmcid: pmc7952238. 22. zhao j, han h, zhong b, xie w, chen y, zhi m. health information on sm helps mitigate crohn's disease symptoms and improves patients' clinical course. comput human behav. 2021;115:106588. doi: 10.1016/j.chb.2020.106588. 23. kim wb, jerome d, yeung j. diagnosis and management of psoriasis. can fam physician. 2017;63(4):278–285. pmid: 28404701. pmcid: pmc5389757. 24. russo pa, ilchef r, cooper aj. psychiatric morbidity in psoriasis: a review. australas j dermatol. 2004;45(3):155–159. doi: 10.1111/j.1440-0960.2004.00078.x. pmid: 15250891. 10 original article | dermatol pract concept. 2022;12(3):e2022143 supplementary table 1. survey questions directed to the participants are you actively using social media and the internet? are you using social media and the internet to obtain information about psoriasis? if yes, which social media/internet platforms are you using? what subjects are you inquiring about concerning your disease? are you a member of any online patient groups? if yes, which social media groups? are you following/writing posts in these groups? what do you think about these groups? would you share with your physician what you have seen on online about your disease? if the information on social media conflicts what your physician says, which would you trust? if you consult a dermatologist with a photograph of your disease on social media, would you trust his/her answer? are you trying to contact physicians using social media? if yes, on which platforms? when you contact a physician online, do you think he/she is obliged to answer your questions about your disease? what do you ask physicians that you contact online? do you trust their answers? do you follow their recommendations? what do you think about the health programs on television/radio concerning your disease? do you follow these programs? do you further investigate what you see in these programs? would you consult your physician about the information presented in these programs? have you ever applied the recommendations you have seen in these programs to relieve your disease? do you read books/brochures on psoriasis? do you read information booklets provided by physicians? would you like educational seminars to be organized on psoriasis? do you have any recommendations to dermatologists and dermatological associations concerning the use of social media/media related to psoriasis? dermatology: practical and conceptual 78 letter | dermatol pract concept 2018;8(2):3 dermatology practical & conceptual www.derm101.com an 18-year-old caucasian patient presented with an asymptomatic skin eruption on his trunk. the patient stated the lesions have been present for 15 years and that the lesions were more prominent and more extensive in childhood. however, the size and number of lesions decreased with time. the past medical history was remarkable for beta thalassemia minor. he had not received any treatment for the skin lesions or thalassemia previously. dermatologic examination revealed erythematous, hyperpigmented papules and plaques on the neck, chest and upper back (figure  1). darier sign was present. a skin biopsy was performed to reach a definitive diagnosis. histopathologic evaluation revealed a massive mast cell infiltration and eosinophils in the dermis (figure 2). the diagnosis of urticaria pigmentosa was made based on clinical and histopathologic features. laboratory tests, including complete blood count, chemistry panel, complete urinalysis, thyroid-stimulating hormone (tsh), serum iron, ironbinding capacity, ferritin, folate, vitamin b 12 , sedimentation, c-reactive protein (crp) and abdominal ultrasonography were performed to rule out systemic involvement. the chemistry panel, urine test, tsh, serum iron, iron-binding capacity, ferritin, folate, vitamin b 12 , sedimentation, crp and abdominal ultrasonography were all within normal limits. the complete blood count was normal except for slightly decreased mean platelet volume (5.98 fl, range: 6.4 –11 fl) and slightly elevated eosinophil percentage (7.8%, range: 0%-7%). unfortunately, further diagnostic tests such as serum tryptase level, tryptase in bone marrow blood, histamine and metabolites in a 24-hour urine analysis were not performed. the patient refused bone marrow biopsy due to fear of pain. therefore, the patient was informed about the triggers of mast cell activation and it was recommended to him that he make regular follow-up appointments. urticaria pigmentosa is a form of cutaneous mastocytosis that is characterized by excessive mast cell infiltration of the superficial dermis [1]. it presents with hyperpigmented macules, papules or nodules on the trunk and extremities [2]. thalassemia minor is a common genetic disorder that is characterized by a mutation in one chain of β-globin for hemoglobin. the patients with thalassemia minor are usually asymptomatic. blood tests may reveal mild anemia or normal hemoglobin levels [3]. urticaria pigmentosa may progress to systemic mastocytosis in 4.5%–10% of cases [1]. systemic involvement is more common in adults than in children [1]. in these patients, increased histamine levels due to mast coexistence of urticaria pigmentosa and thalassemia minor in a young adult funda tamer1, haldun umudum2 1 department of dermatology, ufuk university school of medicine, ankara, turkey 2 department of pathology, ufuk university school of medicine, ankara, turkey key words: urticaria pigmentosa, thalassemia, mastocytosis, young adult citation: tamer f, umudum h. coexistence of urticaria pigmentosa and thalassemia minor in a young adult. dermatol pract concept. 2018;8(2):78-79. doi: https://doi.org/10.5826/dpc.0802a03 received: september 26, 2017; accepted: november 22, 2017; published: april 30, 2018 copyright: ©2018 tamer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: funda tamer, md, assistant professor, department of dermatology, ufuk university school of medicine, mevlana bulvari (konya yolu), no 86-88, 06510, balgat, ankara, turkey tel.+903122044151. email: fundatmr@yahoo.com letter | dermatol pract concept 2018;8(2):3 79 a sensitive marker of systemic mastocytosis [5]. urticaria pigmentosa may be associated with hematologic abnormalities and malignancies. ogg et al reported a 44-year-old male with an eight-year history of urticaria pigmentosa who developed multiple myeloma and renal failure [2]. jappe et  al reported on a 5-year-old male with urticaria pigmentosa and thrombocytosis. they suggest that thrombocytosis may precede systemic mastocytosis [1]. other diseases cell proliferation can lead to diarrhea, bronchospasm, arthralgia, weight loss, and flushing [2]. elevated serum tryptase level, peripheral blood eosinophilia, skin biopsy, biopsy of the suspected involved organ such as colon or liver, kit d816v mutation, cd2 and cd25 expression of the bone marrow or affected tissue may be helpful in the diagnosis of systemic mastocytosis in adults [4]. furthermore, proelss et al suggest that elevated levels of tryptase in the bone marrow may be figure 1. (a) hyperpigmented papules on the neck and chest. urticarial plaque indicates a positive darier’s sign. (b) hyperpigmented macules and papules on the upper back. [copyright: ©2018 tamer et al.] a b figure 2. (a) dense mast cell infiltration with some eosinophils in the dermis (h&e x40). (b) numerous mast cells in the dermis (metachromatic staining with toluidine blue x100). [copyright: ©2018 tamer et al.] a b that coexist with urticaria pigmentosa are polycythemia vera [6], acute lymphoblastic leukemia [7], and massive peripheral eosinophilia [8]. hodgkin’s disease, lymphocytic lymphoma and chronic lymphocytic leukemia have also been associated with urticaria pigmentosa [2]. the case we described is unique in that the patient had both urticaria pigmentosa and thalassemia minor simultaneously. thalassemia may be considered as a hematologic disorder that can occur in patients with urticaria pigmentosa. however, further studies are required to explain possible common etiological mechanisms. references 1. jappe u, aumann v, mittler u, gollnick h. familial urticaria pigmentosa associated with thrombocytosis as the initial symptom of systemic mastocytosis and down’s syndrome. j eur acad dermatol venereol. 2003;17(6):718-722. 2. ogg gs, rosbotham jl, macdonald dm. urticaria pigmentosa coexisting with multiple myeloma. clin exp dermatol. 1996;21(5):365-366. 3. choudhry vp. thalassemia minor and major: current management. indian j pediatr. 2017;84(8):607-611. 4. scherber rm, borate u. how we diagnose and treat systemic mastocytosis in adults. br j haematol. 2017. epub ahead of print. 5. proelss j, wenzel j, ko y, bieber t, bauer r. tryptase detection in bone-marrow blood: a new diagnostic tool in systemic mastocytosis. j am acad dermatol. 2007;56(3):453-457. 6. guevara bek, guillano vp, dayrit jf. urticaria pigmentosa with concomitant polycythaemia vera in a 3-year-old boy. clin exp dermatol. 2017;42(6):696-698. 7. lewis hm, winter e, darbyshire p, yoong a, marsden jr, moss c. urticaria pigmentosa and acute lymphoblastic leukaemia. j r soc med. 1995;88(9):530-531. 8. stern rl, manders sm, buttress sh, heymann wr. urticaria pigmentosa presenting with massive peripheral eosinophilia. pediatr dermatol. 1997;14(4):284-286. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022135 1 eccrine porocarcinoma arising from an eccrine poroma: a case report ingrid silveira1, gabriela siliprandi lorentz sartori1, andré da silva cartell1,2, thaís corsetti grazziotin1 1 department of dermatology, hospital são lucas, pontifícia universidade católica do rio grande do sul (pucrs) 2 department of pathology, universidade federal do rio grande do sul (ufrgs) porto alegre, brazil keywords: eccrine porocarcinoma, eccrine poroma, dermoscopy, sweat gland, tumor citation: silveira i, siliprandi lorentz sartori g, da silva cartell a, corsetti grazziotin t. eccrine porocarcinoma arising from an eccrine poroma: case report. dermatol pract concept. 2022;12(3):e2022135. doi: https://doi.org/10.5826/dpc.1203a135 accepted: december 21, 2021; published: july 2022 copyright: ©2022 silveira et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: thais corsetti grazziotin, pontifícia universidade católica do rio grande do sul (pucrs). email thais.grazziotin@ pucrs.br dermatology practical & conceptual introduction eccrine porocarcinoma (epc) is the malignant counterpart of eccrine poroma (ep) and is mostly found on the lower extremities in elderly adults [1]. epc may develop as a primary tumor or from a benign long-standing ep with malignant transformation. dermoscopy is used increasingly to facilitate clinical diagnosis [2]. in this report, we describe a case of an invasive epc originating in an eccrine poroma and associated with an adjacent satellite lesion of eccrine poroma. case presentation a 68-year-old woman referred a vegetative lesion in the right plantar region with one year of evolution. she reports that the lesion appeared after local trauma caused by sandals and complains of pain. on physical examination, it presented as an ulcerated, vegetative, bulky exophytic tumor associated with a satellite small plaque (figure 1a). dermoscopy of the lesion showed predominantly round-to-oval shaped pink white structureless areas surrounded by white-to-pink halo and polymorphous vessels including coiled and branched vessels with rounded ending (flower-like vessels) (figure 1b). ulcerated areas presented polymorphous vascular pattern with linear irregular and dotted vessels with splinter hemorrhage (figure 1c). histopathology showed that the main lesion was compatible with ulcerated porocarcinoma, in association with an eccrine poroma, invading the inferior reticular dermis, without vascular and perineural invasion (figure 2, a and b). the satellite lesion was diagnosed as eccrine poroma. there were no signs of postoperative recurrence or metastasis after 6 months of follow-up. conclusions ep is a benign tumor of the sweat gland that arises from acrosyringium. epc is a rare malignant skin tumor that usually appears in the lower limbs of elderly people as nodule, plaque or papule pink to red, sometimes with ulceration [1]. epc may arise de novo or can originate from malignant transformation of an ep [2]. an ep that shows changes, as sudden growth, ulceration and spontaneous bleeding turns 2 research letter | dermatol pract concept. 2022;12(3):e2022135 figure 1. clinical and dermoscopic findings. (a) clinical presentation of an ulcerated, exophytic tumor in the right plantar region associated with a satellite small plaque in the metatarsal region. (b) dermoscopy of the non-ulcerated component showing round-to-oval shaped pink white structureless areas surrounded by white-to-pink halo (blue asterisks) and polymorphous vessels including coiled and branched vessels with rounded ending (blue arrows). (c) dermoscopy of ulcerated areas presented polymorphous vascular pattern with linear irregular and dotted vessels (black arrows) with splinter hemorrhage (black asterisks). figure 2. histopathological findings. (a) histology of eccrine poroma showing epidermis with hyperkeratosis and cuboidal poroid nests with small cuboidal cells in closer examination. (b) infiltrative tumor with proliferation of epidermis and tumor cells forming ductal lumina. closer examination reveals atypical neoplastic cells and some mitotic figures of porocarcinoma. on the red flag for an arising epc. in our case the patient had both tumors, ep and epc, and it seems probable that the epc originated from the ep. according to previously reported, dermoscopic features may overlap between epc and ep, such as pink white structureless areas and white-to-pink halo, although in epc they are present focally in the tumor and do not comprise the entirety of nodules, such as in ep [1]. vascular pattern is often polymorphous in epc, usually combining hairpin, dotted and linear irregular vessels, while coiled, glomerular and the typical flower, leaf-like vessels are less frequently found [1]. in the histopathological examination the usual findings include nuclear atypia, increased mitotic activity rate and necrosis. in the clinical examination, infiltrated borders, bleeding, growth and ulceration are important features that may indicate malignancy in ep-like lesions [2]. since epc shares multiple features with other tumors and is a rare skin neoplasm, diagnosis is a challenge. anatomopathological signs of invasion and cellular pleomorphism in an eccrine tumor are clues to the definitive diagnosis [2]. treatment is necessary due to the aggressive nature of the tumor, and surgery is the first option. references 1. edamitsu t, minagawa a, koga h, uhara h, okuyama r. eccrine porocarcinoma shares dermoscopic characteristics with eccrine poroma: a report of three cases and review of the published work. j dermatol. 2016;43(3):332-335. doi: 10.1111/1346-8138.13082. 2. uchiyama j, jardim m, valente n, camargo mf. the transition between a poroma and a porocarcinoma evidenced by the dermoscopy. an. bras. dermatol. 2019;94(2):230-232. doi: 10.1590/abd1806-4841.20197280. pmid: 31090833; pmcid: pmc6486063. dermatology: practical and conceptual note | dermatol pract concept 2017;7(3):14 63 dermatology practical & conceptual www.derm101.com the increased incidence of pediatric atopic dermatitis (ad) has resulted in more studies to determine whether ad can be prevented [1,2]. the following editorial serves as an update on the role of breastfeeding, weaning timeline, dietary restrictions, and maternal antigen avoidance in ad. numerous studies have concluded that exclusive breastfeeding is not an identifiable risk or protective factor in the development of ad in children [3,4,5]. contrary to these findings, concurrent studies have found that breastfeeding during the first four months of life may result in a 33% reduction in the incidence and severity of ad in high-risk patients (those with a first degree relative with atopy) [6-9]. new evidence from a 2016 cohort study now suggests that breastfeeding itself may be a risk factor. the study proposes that the breastfeeding timeline might be crucial in determining whether it prevents or incites the development of ad in all children regardless of risk. breastfeeding for one to six weeks and beyond six months was associated with an increased risk of developing ad at both 9 months and 5 years of age compared to those started on breast milk and subsequently maintained on an exclusive breast milk diet for six weeks to six months or less than one week [10]. these results are summarized in figure 1. along with breastfeeding, introduction of other foods during the neonatal period should be considered. the odds of developing ad were found to be higher in infants who were started on solid foods at less than four months of age [10]. additionally, in support of exclusive breastfeeding for at least four months, a separate matched case-control study on physician-diagnosed ad concluded that weaning at 4 to 5 months of age was associated with a lower risk of developing ad [11]. consequently, taking all current study evidence into consideration, exclusive breastfeeding for four to six months with weaning initiated at exactly 4 to 5 months may provide the lowest risk for developing ad [6-11]. introduction of cow’s milk before 9 months was associated with a small increased risk for ad [10]. previous studies found that maternal dietary antigen avoidance during the prenatal and postnatal period was of no benefit [12-15], and maternal dietary modification during pregnancy offered little protective effect [14-19]. new studies indicate that slight dietary modifications may be beneficial. a 2014 analysis of 42 studies suggest that a maternal diet rich in fruits, vegetables, fish, and vitamin d is associated with a lower risk of ad in children [20]. furthermore, adding a probiotic to the maternal diet, specifically lactobacillus, has been found to have a small effect on preventing pediatric ad [21,22]. in conclusion, more extensive studies are needed to provide stronger evidence in making recommendations. however, at this time, the following suggestions would likely most reduce the risk for developing pediatric ad. maternal antigen avoidance does not reduce the risk of ad in children and although dietary modification should not be recommended, a diet rich in fruits, vegetables, fish, vitamin d, and probiotics should be encouraged. breastfeeding during the first four months of life has been shown to modestly reduce the incidence of ad in infants at high risk, while exclusive breastfeedupdate: can breastfeeding and maternal diet prevent atopic dermatitis? colleen little1, collin m. blattner2, john young iii2 1 university of colorado, denver, colorado, usa 2 silver falls dermatology, salem, oregon, usa citation: update: can breastfeeding and maternal diet prevent atopic dermatitis? dermatol pract concept 2017;7(3):14. doi: https://doi. org/10.5826/dpc.0703a14 copyright: ©2017 little c, blattner cm, young j. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: colleen little, do, university of colorado, denver, colorado, usa. email: colleen.little@ucdenver.edu 64 note | dermatol pract concept 2017;7(3):14 7. laubereau b, brockow i, zirngibl a, et al. effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life—results from the gini-birth cohort study. j pediatr. 2004; 144:602-607. 8. schoetzau a, filipiak-pittroff b, franke k, et al. effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. pediatr allergy immunol. 2002;13:234-242. 9. von berg a, koletzko s,, grübl s, et al. the effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the german infant nutritional intervention study, a randomized double-blind trial. j allergy clin immunol. 2003;111:533-540. 10. taylor-robinson dc, williams h, pearce a, law c, hope s. do early life exposures explain why more advantaged children get eczema? findings from the u.k. millennium cohort study. br j dermatol. 2016;174: 569-578. 11. turati f, bertuccio p, galeone c, et al. early weaning is beneficial to prevent atopic dermatitis occurrence in young children. allergy. 2016;71: 878-888. 12. kramer ms, kakuma r. maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. cochrane database syst rev. 2012a; 9: cd0001333. 13. appelt gk, chan-yeung m, watson wta, et al. breastfeeding and food avoidance are ineffective in preventing sensitization in high-risk children. j allergy clin immunol. 2004;113:s99. 14. fälth-magnusson k, kjellman ni. allergy prevention by maternal elimination diet during late pregnancy—a 5-year follow up of a randomized study. j allergy clin immunol. 1992;89:709-713. ing for four to six months with weaning initiated at exactly 4 to 5 months may provide the lowest risk for developing ad in all children [10,11]. references 1. deckers ia, mclean s, linssen s, mommers m, van schayck cp, sheikh a. investigating international time trends in the incidence and prevalence of atopic eczema 1990-2010: a systemic review of epidemiological studies. plos one. 2012:7:e39803. 2. blattner cm, murase je. a practice gap in pediatric: does breastfeeding prevent the development of infantile atopic dermatitis? j am acad dermatol. 2014;71:405-406. 3. kramer ms, kakuma r. optimal duration of exclusive breastfeeding. cochrane database syst rev. 2012b;8:cd003517. 4. yang yw, tsai cl, lu cy. exclusive breastfeeding and incident atopic dermatitis in childhood: a systematic review and metaanalysis of prospective cohort studies. br j dermatol. 2009;161:373383. 5. flohr c, nagel g, weinmayr g, et al. lack of evidence for a protective effect of prolonged breastfeeding on childhood eczema: lessons from the international study of asthma and allergies in childhood (isaac) phase two. br j dermatol. 2011;165:12801289. 6. gdalevich m, mimouni d, david m, mimouni m. breastfeeding and the onset of atopic dermatitis in childhood: a systemic review and meta-analysis of prospective studies. j am acad dermatol. 2001;45:520-527. figure 1. relationship between a child developing atopic dermatitis at 9 months and 5 years of age in relation to length of time the child was breastfed after birth. [copyright: ©2017 little et al.] note | dermatol pract concept 2017;7(3):14 65 20. makrides m, middleton pf, netting mj. does maternal diet during pregnancy and lactation affect outcomes in offspring? a systematic review of food-based approaches. nutrition. 2014;30:1225-1241. 21. doege k, grajecki d, zyriax bc, et al. impact of maternal supplementation with probiotics during pregnancy on atopic eczema in childhood—a meta-analysis. br j nutr. 2012;107:1-6. 22. blattner cm, crosby ms, goedken m, murase je. update: do probiotics prevent or treat pediatric atopic dermatitis? pediatr allergy immunol. 2016;27(4):425-428. 23. hanke w, jerzynska j, ligocka d, et al. the effect of prenatal exposure to phthalates on food allergy and early eczema in inner city children. allergy asthma proc. 2015;36:72-78. 24. barbarot s, futamura m, madhok v, et al. what’s new in atopic eczema? an analysis of systematic reviews published in 2012 and 2013. part 2. treatment and prevention. clin exp dermatol. 2015;40:349-354. 15. fälth-magnusson k, kjellman ni. development of atopic disease in babies whose mothers were receiving exclusion diet during pregnancy-a randomized study. j allergy clin immunol. 1987;80:868-875. 16. fälth-magnusson k, oman h, kjellman ni. maternal abstention from cow milk and egg in allergy risk pregnancies. effect on antibody production in the mother and the newborn. allergy. 1987;42:64-73. 17. björksten b, kjellman ni, hattervig g, et al. natural history of food allergy. ann allergy. 1988;61:83-87. 18. hampton sm, lovegrove ja, morgan jb. the immunological and long-term atopic outcome of infants born to women following a milk-free diet during late pregnancy and lactation: a pilot. br j nutr. 1994;71:223-238. 19. hampton sm, lovegrove ja, morgan jb. dietary factors influencing levels of food antibodies and antigens in breast milk. acta paediatr. 1996;85:778-784. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022084 1 dermatology practical & conceptual dermoscopic view of papular acantholytic dyskeratosis of the genitocrural region dua cebeci1, i̇lkay can2, i̇brahim kobat3 1 famagusta state hospital dermatology and venerology department, famagusta, cyprus 2 balıkesir state hospital dermatology and venerology department, balıkesir, turkey 3 famagusta state hospital pathology department, famagusta, cyprus key words: acantholytic dyskeratosis, genital region, domed papules citation: cebeci d, can i̇, kobat i̇. dermoscopic view of papular acantholytic dyskeratosis (pad) of the genitocrural region. dermatol pract concept. 2022;12(3):e2022084. doi: https://doi.org/10.5826/dpc.1203a84 accepted: october 21, 2021; published: july 2022 copyright: ©2022 cebeci et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dua cebeci, famagusta stat hospital, famagusta, cyprus, telephone number : 05488586367 e-mail : perolidua@gmail.com introduction papular acantholytic dyskeratosis (pad), also known as acantholytic dermatosis of the vulvocrural (or anogenital) region is a rare skin disorder reported more common in women than men. recent studies have revealed that mutations in the atp2c1 gene, typically seen in hailey-hailey disease, are also detected in papular acantholytic dermatosis of the anogenital region [1]. we report a case of a 49-year-old female with pruritic papular eruptions over the vulvocrural area. histology of lesions revealed focal acantholysis with presence of dyskeratotic cells resembling corps ronds and grains.  case presentation a 49-year-old female patient presented with persistent pruritic papular rash in both inguinal regions for 6 months. the patient applied to the obstetrics clinic with similar complaints and was referred to the dermatology clinic considering as condyloma. she had no history or family history of any skin disorder. physical examination revealed multiple whitish pruritic papules with underlying erythematous patches in both inguinal regions (figure 1a). no lesions were found at other locations and her nails were normal. koh test was negative. skin biopsy showed numerous typical acantholytic dyskeratotic cells in the stratum corneum and spinosum. there was also hyperkeratosis and irregular acanthosis in the epidermis and lymphocytic infiltration in the underlying dermis and no evidence of viral infection, dysplasia or malignancy (figure 2). dermoscopic examination (×10 magnification in polarized mode) showed an irregular star-shaped (circled) brown pigmentation and globular domed brown papules (figure 1b). direct immunofluorescence or genetic studies were not performed. clinical and histopathological pad was present. 0.1% topical mometasone furoate and topical tacrolin 0.1 cream were started on the patient. the patient showed a minimal improvement and is still being following up. constent form was obtained from the patient. 2 research letter | dermatol pract concept. 2022;12(3):e2022084 figure 2. (a) low-power view of a papule showing suprabasal cleft, dyskeratosis, and acantholytic cells (h&e, ×10). (b) high-power view of dyskeratotic acantholytic cells (corps ronds, h&e, ×40). figure 1. (a) multiple shiny whitish papules 2 mm to 3 mm in diameter in a cobblestone pattern on the medial aspect of the thigh, on the perineum, and in the perianal region. (b) dermoscopic image showing brown pigmentation and globular domed brown papules. conclusions localized pad to the genitocrural area is a rare and distinct clinical entity that was first described by bernard ackerman in 1972 as focal acantholytic dyskeratosis. the dermoscopic features of hailey-hailey and darier disease been described before in several studies but the dermoscopic features of the reported cases of pad have not been experienced. in hailey-hailey disease, the combination of pink and white areas was more prominent. minor erosions and ulcerations may also accompany it. in contrast, polygonal, star-like, roundish-oval, whitish, yellowish areas with peripheral halos have been described in dariers disease [2]. in this report, brown to gray hyperpigmented domed papules with a central hypopigmented core were the main dermoscopic findings. by reporting the dermoscopy of this case pad, we would like to point out the usefulness of such dermoscopy in assisting the recognition of this entity. references 1. al-muriesh m, abdul-fattah b, wang x, zhao m, chen s, huang c. papular acantholytic dyskeratosis of the anogenital and genitocrural area: case series and review of the literature. j cutan pathol. 2016;43(9):749-758. doi: 10.1111/cup.12736. pmid: 27161553. 2. kadiri s, bay bay h, chaoui r, douhi z, elloudi s, mernissi fz. dermoscopy of hailey hailey disease: is it useful? our dermatol online. 2020;11(e):e50.1-e50.2. doi: 10.7241/ ourd.2020e.50. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2013;3(3):7 23 the patient a healthy 2-year-old girl presented with a rash on her shoulder of 6 months’ duration. physical examination revealed a solitary 5 mm erythematous dome-shaped papule surrounded by numerous smaller similar lesions (figure 1). dermatoscopy visualized numerous central white and skincolored clods with vessels arranged radially to the clods (figure 2). what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a complimentary copy of the book, dermoscopy: the essentials, 2nd ed. [elsevier-saunders 2012]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. answer to the april 2013 quiz the correct answer to the dermatoscopy quiz in the april 2013 issue (http://dx.doi.org/10.5826/dpc.0302a12) is psoriasis. congratulations to dr. john stretch, who was the first to send us the correct answer! dermoscopy: what is your diagnosis? barry ladizinski1, marigdalia k. ramirez-forte2, david j. elpern3 1 johns hopkins bloomberg school of public health, baltimore, maryland, usa 2 center for clinical studies, houston, texas, usa 3 the skin clinic, williamstown, massachusetts, usa citation: ladizinski b, ramirez-forte mk, elpern dj. dermoscopy: what is your diagnosis? dermatol pract conc. 2013;3(3):7. http:// dx.doi.org/10.5826/dpc.0303a07. copyright: ©2013 ladizinski et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: david j. elpern, m.d., the skin clinic, 12 meadow st, williamstown, ma 01267, usa. email: djelpern@gmail. com. figure 1. a solitary 5 mm erythematous dome-shaped papule on the right shoulder of a 2-year-old girl. [copyright: ©2013 ladizinski et al.] figure 2. dermoscopy showed numerous central white and skincolored clods with vessels arranged radially to the clods. [copyright: ©2013 ladizinski et al.] mailto:dpc@derm101.com http://dx.doi.org/10.5826/dpc.0302a12 dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023009 1 dermal amyloid deposits: a possible misleading pathologic finding serena giacalone1,2, carlo alberto maronese1,2, giovanni genovese1,2, marco cusini1, angelo valerio marzano1,2 1 uoc dermatologia, fondazione irccs ca’ granda ospedale maggiore policlinico, milan, italy 2 dipartimento di fisiopatologia medico-chirurgica e dei trapianti, università degli studi di milano, milan, italy key words: amyloid deposits, drug eruption, systemic amyloidosis, cutaneous involvement citation: giacalone s, maronese ca, genovese g, cusini m, marzano av. dermal amyloid deposits: a possible misleading pathologic finding. dermatol pract concept. 2023;13(1):e2023009. doi: https://doi.org/10.5826/dpc.1301a9 accepted: may 9, 2022; published: january 2023 copyright: ©2023 giacalone et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: serena giacalone, md, unità operativa di dermatologia, fondazione irccs ca’ granda, ospedale maggiore policlinico, via pace 9, milan, italy. telephone: +390255034718 fax: +390255033562 e-mail: serenagiacalone92@gmail.com introduction amyloid is a highly organized fibrillar substance resistant to macrophage degradation. it can originate from more than 27 misfolded proteins. extracellular amyloid deposition may result from several pathophysiological processes: abnormal protein production, excessive presence of normal proteins or senescence. recently, reclassification of amyloidosis based on protein type led to the identification of subgroups with different etiology (acquired or inherited), clinical manifestations, and prognosis [1]. some forms are localized while others involve multiple organs. dermal amyloid deposits can be detected in both cases. cutaneous localized amyloidosis includes keratinic and nodular amyloidosis. in the first case the macular and lichenoid lesions correspond to subtle deposits limited to the upper dermis, in the second case plaque and nodules are secondary to deep dermal and subcutis deposits. the spectrum of cutaneous involvement in systemic amyloidosis encompasses a wide variety of lesions that reflect localization and abundance of amyloid deposits. generally, amyloid deposition affects dermal blood vessels, that easily rupture upon minimal trauma, with subsequent appearance of petechiae, purpura and ecchymoses, mostly located on body folds. profuse infiltration of amyloid within the dermis and the subcutis can manifest also as papules, plaques, nodules, bullae, and even scleroderma-like lesions. amyloid infiltration in or about sweat glands, sebaceous glands, and hair follicles can result in anhidrosis and alopecia [2]. curiously, amyloid deposits have been demonstrated in all of the aforementioned sites, also in clinically uninvolved skin [3]. here, we present a case of massive dermal amyloid deposit both in involved and uninvolved skin that mislead clinical diagnosis. case presentation a 53-year-old man presented with a pruritic, non-confluent, maculopapular eruption of one month duration, consisting of discrete 5-10 mm lesions, symmetrically distributed on his 2 research letter | dermatol pract concept. 2023;13(1):e2023009 trunk, arms and upper thighs ( figure 1 ). his medical history was significant for multiple myeloma and systemic amyloid light-chain (al) amyloidosis with cardiac, gastric and bone marrow involvement. he had been treated with allogenic bone marrow transplantation followed by bortezomib, endoxaban and dexamethasone without any adverse cutaneous reaction. the patient received pomalidomide ten days before the onset of the rash and the drug was promptly discontinued. he complained of xerostomia and development of hematomas after mild trauma. histological examination revealed presence of multiple hyaline deposits in the superficial dermis, with perivascular, peri-adnexal, and interstitial arrangement ( figure 2a ). congo-red staining positivity along with apple-green birefringence under polarized light was consistent with amyloid ( figure 2b ). immunohistochemical typing of amyloid revealed lambda light chain accumulation ( figure 2c ). a course with prednisone 25 mg daily tapered over three weeks quickly led to clinical resolution of the eruption. however, 3 days following pomalidomide reintroduction, sudden reappearance of the same monomorphous lesions was observed. two additional punch biopsies were performed, on lesional and non-lesional areas, respectively. the former showed diffuse vacuolar change in the basal layer of the epidermis with scattered necrotic keratinocytes and a band-like superficial inflammatory infiltration. amyloid deposits were detected in both specimens. finally, a diagnosis of lichenoid drug eruption in the setting of systemic al amyloidosis with concomitant massive dermal amyloid deposits was made. conclusions globally, mucocutaneous lesions have been described in 30% of all cases of systemic amyloidosis, and in up to 50% those with al type [4]. although the dermatologist may have a crucial role in the prompt diagnosis of systemic amyloidosis [5], massive presence of cutaneous amyloid, as in our case, could mislead both the dermatologist and the pathologist involved in the diagnostic process, masking other concurrent disorders. indeed, detection of amyloid deposits in normal-appearing skin has been widely demonstrated in literature: in the past, several studies proposed to perform biopsy on uninvolved skin to confirm systemic cases figure 1 . non-confluent, maculopapular eruption of discrete 5-10 mm lesions on patient lower back (a), right arm (b) and right forearm (c). figure 2 . histopathology showing diffuse vacuolar change in the basal layer of the epidermis with scattered necrotic keratinocytes and a band-like superficial inflammatory infiltration. (a) h&e x200 notice dermal amyloid deposit (black arrows). (b) congo red stain highlighting dermal perivascular, peri-adnexal, and interstitial infiltration of amyloid. (c) immunohistochemical typing of amyloid revealing lambda light chain accumulation. research letter | dermatol pract concept. 2023;13(1):e2023009 3 of amyloidosis [3]. however, even if type of dermatological findings depends on amyloid localization, the exact amount of deposit capable to trigger clinical modification has not yet been identified. in systemic amiloidosis, the presence of deposits in uninvolved sites enforces the idea that detection of amyloid in cutaneous lesions should not lead to hasty diagnostic conclusions. although the possible cutaneous manifestations of systemic amyloidosis are protean, clinical confirmation bias should always be considered and avoided. references 1. muchtar e, dispenzieri a, magen h, et al. systemic amyloidosis from a (aa) to t (attr): a review. j intern med. 2021;289(3):268-292. doi: 10.1111/joim.13169. pmid: 32929754. 2. schreml s, szeimies rm, vogt t, landthaler m, schroeder j, babilas p. cutaneous amyloidoses and systemic amyloidoses with cutaneous involvement. eur j dermatol. 2010;20(2):152-160. doi: 10.1684/ejd.2010.0842. pmid: 20071301. 3. rubinow a, cohen as. skin involvement in generalized amyloidosis. a study of clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. ann intern med. 1978;88(6):781-785. doi: 10.7326/0003-4819-88-6-781. pmid: 666134. 4. flores-bozo lr, echevarría-keel j, domínguez-cherit j, esquivel-pedraza l, méndez-flores s. mucocutaneous manifestations in systemic amyloidosis a retrospective analytical study in a tertiary care center. int j dermatol. 2019;58(9):1062-1068. doi: 10.1111/ijd.14443. pmid: 30941743. 5. wu b, pak dm, smith kd, shinohara mm. utility of abdominal skin punch biopsy for detecting systemic amyloidosis. j cutan pathol. 2021;48(11):1342-1346. doi: 10.1111/cup.14070. pmid: 34075607. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022176 1 the use of dermoscopy in the delineation of basal cell carcinoma for mohs micrographic surgery: a systematic review with meta-analysis noureddine litaiem1,2, faten hayder1,2, imene benlagha1,2, manel karray1,2, chadli dziri2,3, faten zeglaoui1,2 1 department of dermatology, charles nicolle hospital, tunis, tunisia 2 university of tunis el manar, faculté de médecine de tunis, tunis, tunisia; 3 director of honoris medical simulation center, tunisia key words: mohs micrographic surgery, slow mohs, dermoscopy, dermatoscopy, basal cell carcinoma citation: litaiem n, hayder f, benlagha i, karray m, dziri c, zeglaoui f. the use of dermoscopy in the delineation of basal cell carcinoma for mohs micrographic surgery: a systematic review with meta-analysis. dermatol pract concept. 2022;12(4):e2022176. doi: https://doi.org/10.5826/dpc.1204a176 accepted: february 18, 2022; published: october 2022 copyright: ©2022 litaiem n et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: noureddine litaiem, department of dermatology, charles nicolle hospital, tunis, tunisia. e-mail: noureddine.litaiem@gmail.com introduction: several studies investigated the use of dermoscopy in the delineation of basal cell carcinoma (bcc) for mohs micrographic surgery (mms) with conflicting results. objectives: the purpose of this systematic review with meta-analysis was to evaluate the effectiveness of the use of dermoscopy-guided mms in the treatment of bcc. methods: we included all comparative studies. cases of bcc treated using dermoscopy-guided mms (or slow mms) were compared to those treated with curettage-guided mms or “standard” mms. results: a total of 6 studies including 508 bccs were reviewed. there was no statistically significant difference in the proportion of total margin clearance on the first mms stage between bccs removed using dermoscopy-guided mms and those that had curettage or visual inspection. however, lateral margin involvement was significantly lower in bccs that had dermoscopy-guided mms. conclusions: dermoscopy allows visualization of structures up to 1mm into the dermis. therefore, it is rational to use it for lateral margin evaluation. currently, there are two comparative studies showing the efficacy of dermoscopy for lateral margin evaluation during mms. future studies are required to develop an evidence-based recommendation regarding the utility of dermoscopy in mms. abstract 2 review | dermatol pract concept. 2022;12(4):e2022176 introduction basal cell carcinoma (bcc) is the most prevalent skin cancer worldwide [1]. the overall incidence has been steadily rising in the last decade throughout the world due to a burgeoning aging population and increased surveillance and diagnosis [2]. the biological behavior of bcc depends on the tumor subtype [1,2]. undiagnosed and untreated bcc could lead to extensive local destruction and increase both functional and cosmetic morbidity making the treatment and repair approach challenging for the physician. the national comprehensive cancer network (nccn) has established guidelines of care for bccs [3]. high-risk bccs include recurrent bcc, tumors with ill-defined borders, located on high-risk mask area of the face, arising on sites of prior radiation therapy or harboring aggressive histological features [3]. there are multiple treatment options for bcc such as ablative laser, photodynamic therapy, curettage, cryosurgery, imiquimod, and sonic hedgehog pathway inhibitors [12,2]. however, surgical excision remains the gold standard for treatment of most bccs [1]. standard excision is performed with a predefined clinical margin in order to achieve low recurrence rates. mohs micrographic surgery (mms) is a specialized surgical technique that combines surgery with pathology. mms uses horizontal frozen sections to obtain complete margin control resulting in minimal tissue removal with low recurrence rates  [1]. mms proved to be superior to standard excision for high-risk bcc [1]. slow mohs is a variant of mms using formalin-fixed paraffin-embedded sections with similar outcome [4]. dermoscopy, also known as dermatoscopy or epiluminescence microscopy, is a non-invasive imaging technique widely employed for the diagnosis of skin cancers. some specific dermoscopic patterns are helpful in the diagnosis of bcc [5]. the use of dermoscopy in the demarcation of surgical margins is another scope of its application. for instance, the use of dermoscopy in mms might help reduce the number of mohs stages and achieve surgical margin control within the 1st mohs stage [4,6-11]. many studies investigated the effectiveness of dermoscopy in tumor delineation for mms but with varying outcomes [4,6-11]. while some  suggested that dermoscopy could help reduce the number of mohs stages and therefore shorten operative time and cost [4,9,11], others argued against the usefulness of this approach [6,12]. the ambiguity of these findings is further hampered by the lack of randomized studies and systematic reviews. objectives the purpose of this systematic review with meta-analysis was to evaluate the effectiveness of the use of dermoscopy-guided mms in the treatment of bcc. methods search strategy this systematic review with meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [13]. we searched the pubmed and scopus databases from inception up to january 26, 2022 to identify eligible studies. we aimed to identify all relevant studies published in english language. we used the following search algorithm: (“basal cell carcinoma”) and (“mohs surgery” or “slow mohs” or “micrographic surgery” or ”3‐d histology” or “microscopically controlled surgery”) and (“dermoscopy” or “dermatoscopy” or “epiluminescence microscopy”). the pubmed and scopus search strategies are available as supplementary material. inclusion and exclusion criteria of studies two review authors (nl and fh) independently screened titles and abstracts for eligible studies. eligible articles were identified on the basis of the following inclusion criteria: (i) comparative studies having at least a group of bccs treated with dermoscopy-guided mms, (ii) studies that used a control group of bccs treated with visual inspection and/or curettage-guided mms, (iii) articles published in english language. for eligible studies, full articles were retrieved in full and analyzed by two independent authors (nl and fh). any discrepancy between the two investigators was resolved by consensus. pico(s): populations, interventions, comparison, outcome measures, types of studies we included all comparative observational as well as randomized clinical trials (rct). participants with bcc regardless of the clinical and histological subtype of the tumor were eligible for inclusion. cases of bcc treated using dermoscopy-guided mms (or slow mms) were compared to those treated with curettage-guided mms or “standard” mms. the latter uses visual inspection alone to delineate the tumors. all types of dermoscopy techniques were eligible, regardless of the polarization mode (polarized vs. nonpolarized mode) and the device type (hand-held dermoscopy or video dermoscopy). the main outcome measure was the proportion of total margin clearance on the first mms stage. the secondary outcome measures included the: (i) number of mohs stages required to achieve complete margin control, (ii) the lateral margin involvement rate, and (iii) the recurrence rate. if one or more outcome measures were missing, we contacted the corresponding author at least twice (with at least one-week interval) to ask whether full data were available. if the contact was unsuccessful, the corresponding article was excluded from the analysis. review | dermatol pract concept. 2022;12(4):e2022176 3 assessment of the risk of bias two review authors (nl and fh) independently assessed the quality of consistency and the risk of bias in the eligible studies. any disagreement was resolved by discussion or by consensus with a third author (cd). minors score was used for observational studies [14]. rct were evaluated using the jadad score [15] . data synthesis and statistical analysis results were reported as odds ratio (or) with 95% confidence intervals (cis) for dichotomous data (proportion of total margin clearance on the first mms stage, lateral margin involvement, and recurrence rates) and standardized mean difference with standard error of the mean for continuous data (number of mohs stages). a random-effects model was used. forest plots summarized the data. funnel plot was used to investigate the existence of publication bias. strategies for addressing heterogeneity included performing a random-effects meta-analysis and subgroup analyses. we performed all calculations using comprehensive meta-analysis 3.0 package. we investigated heterogeneity using cochran q test. evaluation of the percentage of variation between the sample estimates was performed using the higgins i2 statistic. results results of the search the literature search identified 289 articles (figure 1). after removing duplicates, 69 articles were screened for eligibility. fifty-five records were excluded, including not relevant articles (n = 30), papers not published in english (n = 3), editorials and commentary (n = 11), review articles (n = 10) and book chapters (n = 2). fourteen full-text articles were assessed for eligibility. among these, 4 were excluded (case reports and noncomparative studies) [16-19]. three research letters were excluded [11,20,21]. among these research figure 1. flow diagram. 4 review | dermatol pract concept. 2022;12(4):e2022176 the mean number of mohs stages in each study group was specified in 5 articles [4,6-9]. however, related standard deviations were only available in 3 articles [4,6,7]. contact with the corresponding authors of these studies was unsuccessful. therefore, we did not have the required data to carry out the up-mentioned analysis for these articles [4,6,7]. only two studies reported the number of positive lateral margins after the first mohs stage [4,10]. relapse rates were described in 2 articles [4,9], ranging between no relapse and 4%, after a follow-up period of 10 ± 5 and more than 62.5 months respectively. assessment of risk of bias in included studies for rct [6,7], the jadad scale was 1 and 2. overall, the methodological quality was poor. there was no disagreement between the review authors (nl and fh) about the studies quality. for non-randomized studies [4,8-10], the minors index ranged between 14 and 16. effects of interventions when comparing dermoscopy-guided vs. standard mms for bcc treatment, there was no statistically significant difference in the proportion of total margin clearance on the first mms stage (or 0.86, 95% ci 0.41 to 1.15; five studies [4,7-10]) (figure 2). there was no statistically significant difference in the number of mohs stages when comparing dermoscopy-guided and standard mms (the standardized mean difference -0.17, 95% ci -0.51 to 0.17; three studies [4,6,7]) (figure 3). for this outcome measure, we found heterogeneity (tau2 = 0220 et i2 = 70.334%). subgroup analysis was performed based on the technique used for mohs surgery (frozen sections versus formalin-fixed paraffin-embedded sections). after subgroup analysis, including studies using mms [6,7], there was no heterogeneity (tau2 = 0.000), the pooled standard difference in means showed no statistically significant difference. only one study reported the number of mohs stages in patients treated using slow mohs [4]. since iterative mohs sessions rely on histopathological examination of excised tissue, it is possible that the type of tissue processing technique (frozen sections in mms vs formalin-fixed paraffin-embedded sections in slow mohs) is responsible for heterogeneity regarding the outcome measure (number of mohs stages). a significantly lower proportion of positive lateral margins was obtained with dermoscopy-guided mms compared with standard mms based on visual inspection (or 0.16, 95% ci 0.06 to 0.83; 2 studies [4,10]) (figure 4). with regards to recurrence rates, available data was insufficient for meta-analysis. two studies reported the number of recurrences after mms [4-9]. one of these letters, two compared dermoscopy to naked eye examination in bcc margin evaluation but the number of mohs stages in each study group expressed in mean with standard deviation was not available [11,20]; and one article included only bcc evaluated using dermoscopy prior to mms [21]. a randomized open-label study comparing visual inspection, curettage, and dermoscopy in tumor delineation for mms was excluded because no outcome measure was available for each study group [12]. contact with the corresponding authors of this study was unsuccessful. six articles were ultimately included in the present systematic review. of these, 2 studies were from asia-pacific region, 1 from north america, 1 from south america, 1 from europe, and 1 from africa (table 1) [4,6-10]. description of included studies of the 6 included studies, 2 were rcts [6,7], and four were observational studies [4,8-10]. there was no randomized controlled study available for the present systematic review. all included studies were conducted in university‐setting centers [4,6-10]. these studies had no funding support and corresponding authors declared no conflicts of interest [4,6-10]. the number of bccs evaluated ranged from 40 to 197 bccs per study. the total number of evaluated bccs was 508. suzuki et al included both bcc (n = 40) and squamous cell carcinomas (n = 6). the latter were excluded from the analysis. three studies specified bcc subtypes [6,7,9]. asilian and momeni included only nodular bcc [6], and gurgen and gatti only infiltrative bcc [7]. dika et al included various bcc subtypes including nodular (n = 40) and morpheiform bccs (n = 40) [9]. recurrent bccs were excluded in three studies [4,6,7]. one study included only recurrent bcc following ablative laser treatment [10]. two studies enrolled both primary and recurrent bcc (table 1) [8,9]. four studies compared 2 interventions for mms: tumor delineation using naked eye examination versus dermoscopy-guided margin assessment [4,7,8,10]. one of the studies compared dermoscopy-guided mms to curettage-guided mms [9]. asilian and momeni compared 3 groups: tumor demarcation using naked eye examination (n = 20), dermoscopy (n = 20) and curettage (n = 20) [6]. for the primary outcome “total margin clearance on the first mms stage”, we assumed that bccs that underwent more than one mohs stage showed at least one positive margin. thereby, the number of bccs showing total margin clearance on the first mms stage was extracted from 5 articles [4,7-10]. the secondary outcomes included the mean number of mohs stages, the recurrence rate, and the number of positive lateral margins after the first mohs stage. ta b le 1 . su m m ar y o f in cl u d ed s tu d ie s. a u th o r y e a r c o u n tr y s tu d y o b je ct iv e s tu d y d e si g n c o v e ra g e p e ri o d in te rv e n ti o n g ro u p s b c c s u b ty p e s in e a ch g ro u p r e cu rr e n t b c c b e fo re m o h s su rg e ry c a se s in cl u d e d in t h e m e ta -a n a ly si s fo ll o w -u p (m o n th s) a si li an a n d m o m en i [6 ] 2 0 1 2 ir an t o c o m p ar e th re e w ay s (n ak ed e ye ex am in at io n , d er m o sc o p y, a n d cu re tt ag e) f o r d et er m in in g tu m o r ex te n si o n b ef o re in it ia ti o n o f m m s, r c t 2 0 1 1 2 0 1 2 3 g ro u p s: tu m o r d em ar ca ti o n u si n g n ak ed e ye ex am in at io n (n = 2 0 ), d er m o sc o p y (n = 2 0 ) an d cu re tt ag e (n = 2 0 ) n o d u la r b c c i n a ll in cl u d ed c as es n o t in cl u d ed i n th e st u d y 4 0 n d g u rg en a n d g at ti [ 7 ] 2 0 1 2 u n it ed st at es t o c o m p ar e th e fi n al n u m b er o f m m s st ag es p er fo rm ed u si n g d er m o sc o p y an d vi su al i n sp ec ti o n o f in fi lt ra ti ve b as al ce ll c ar ci n o m a r c t n d 2 g ro u p s: d er m o sc o p y gr o u p ( n = 2 0 ) vi su al in sp ec ti o n gr o u p ( n = 2 0 ) in fi lt ra ti ve b c c i n al l ca se s n o t in cl u d ed i n th e st u d y 4 0 n d su zu k i et a l [8 ] 2 0 1 4 b ra zi l t o a ss es s th e im p ac t o f d er m o sc o p y o n th e d em ar ca ti o n o f su rg ic al m ar gi n s fo r m m s an d a sc er ta in w h et h er t h e u se o f th is m et h o d c an sh o rt en o p er at iv e ti m e o b se rv at io n al st u d y 2 0 0 9 -2 0 1 1 2 g ro u p s: g ro u p 1 : m o h s su rg er y (n = 2 1 ) g ro u p 2 : m o h s su rg er y w it h d er m o sc o p ygu id ed m ar gi n s (n = 2 3 ) n d g ro u p 1 : 3 /2 1 g ro u p 2 : 4 /2 3 4 4 n d t ab le 1 c o n ti n u es 6 review | dermatol pract concept. 2022;12(4):e2022176 a u th o r y e a r c o u n tr y s tu d y o b je ct iv e s tu d y d e si g n c o v e ra g e p e ri o d in te rv e n ti o n g ro u p s b c c s u b ty p e s in e a ch g ro u p r e cu rr e n t b c c b e fo re m o h s su rg e ry c a se s in cl u d e d in t h e m e ta -a n a ly si s fo ll o w -u p (m o n th s) d ik a et a l [9 ] 2 0 1 7 it al y to e va lu at e th e ro le o f vi d eo d er m o sc o p y an d c u re tt ag e in m s fo r a b et te r m ar gi n e va lu at io n in tr ao p er at iv el y o b se rv at io n al st u d y 2 0 0 5 -2 0 1 0 2 g ro u p s: g ro u p 1 : p at ie n ts t re at ed w it h v id eo d er m o sc o p y gu id ed m o h s su rg er y (n = 1 0 2 ) g ro u p 2 : p at ie n ts t re at ed w it h c u re tt ag egu id ed m o h s su rg er y (n = 9 5 ) g ro u p 1 : n o d u la r b c c s (n = 2 1 ) p ig m en te d b c c s (n = 2 8 ) m o rp h ei fo rm b c c s (n = 2 0 ) g ro u p 2 : n o d u la r b c c s (n = 1 9 ) p ig m en te d b c c s (n = 2 8 ) m o rp h ei fo rm b c c s (n = 2 0 ) su b ty p es o f p ri m ar y tu m o rs ( n o d u la r, p ig m en te d , o r m o rp h ei fo rm b c c s) w er e eq u al ly d is tr ib u te d i n t h e 2 g ro u p s (p ri m ar y b c c i n g ro u p a 7 1 g ro u p b 6 9 ) g ro u p 1 (3 1 /1 0 2 ) g ro u p 2 (2 6 /9 5 ) 1 9 7 g ro u p 1 (8 2 .6 ) g ro u p 2 (6 2 .5 ) sh in e t al [1 0 ] 2 0 2 0 k o re a t o e va lu at e th e u se fu ln es s o f d er m o sc o p y in d et er m in in g m m s su rg ic al m ar gi n s o f b c c s w it h a h is to ry o f ab la ti ve la se r tr ea tm en t. o b se rv at io n al st u d y 2 0 0 9 2 0 1 6 2 g ro u p s: c li n ic al s u rg ic al m ar gi n (n = 6 9 ) d er m o sc o p ic su rg ic al m ar gi n (n = 6 4 ) n d a ll c as es w er e re cu rr en t b c c (p re vi o u sl y tr ea te d b y ab la ti ve l as er ). r ec u rr en t ca se s af te r ra d io th er ap y o r su rg ic al re se ct io n w er e ex cl u d ed . 1 3 3 n d ta b le 1 . su m m ar y o f in cl u d ed s tu d ie s. ( co n ti n u ed ) review | dermatol pract concept. 2022;12(4):e2022176 7 a u th o r y e a r c o u n tr y s tu d y o b je ct iv e s tu d y d e si g n c o v e ra g e p e ri o d in te rv e n ti o n g ro u p s b c c s u b ty p e s in e a ch g ro u p r e cu rr e n t b c c b e fo re m o h s su rg e ry c a se s in cl u d e d in t h e m e ta -a n a ly si s fo ll o w -u p (m o n th s) l it ai em et a l [4 ] 2 0 2 0 t u n is ia t o e va lu at e th e u se o f d er m o sc o p y in th e d em ar ca ti o n o f su rg ic al m ar gi n s in sl o w m o h s su rg er y. o b se rv at io n al st u d y 2 0 1 6 2 0 1 9 2 g ro u p s: g 1 : tu m o r d em ar ca ti o n u si n g n ak ed e ye ex am in at io n (n = 2 8 ) g 2 : tu m o r d em ar ca ti o n u si n g n ak ed e ye ex am in at io n + d er m o sc o p y (n = 2 6 ) n d n o t in cl u d ed i n th e st u d y 5 4 1 0 ± 5 b c c = b as al c el l ca rc in o m a; n d = n o t d es cr ib ed ; r c t = r an d o m iz ed c li n ic al t ri al . 8 review | dermatol pract concept. 2022;12(4):e2022176 figure 2. comparison of the proportion of positive margins after the first mohs stage using dermoscopy-guided vs. standard or curettage guided mms for bcc treatment meta analysis (outcome: positive margins) (q test) p=0,164 i2: 38,4% funnel plot of standard error by log odds ratio log odds ratio 0,8 0,0-0,5-1,0-1,5 0,5 1,0 1,5 2,0-2,0 st a n d a r d e r r o r standard and curettage-guided mmsdermoscopy-guided mms statistics for each study 1,222 0,372 4,018 0,741 0,521 0,295 0,921 0,01 0,1 1 10 100 0,958 0,463 1,983 0,909 0,025 0,247 0,079 0,769 0,016 0,686 0,409 1,150 0,153 1,238 0,343 4,464 0,744 odds ratio p-value lower limit upper limit odds ratio and 95% ci gurgen and gatti, 2012 dika et al., 2017 shin et al, 2020 litaiem et al, 2020 suzuki et al., 2014 study name 0,6 0,2 0,0 0,4 studies reported a recurrence rate of 3% in bccs treated with dermoscopy-guided mms and of 5.2% in those treated with curettage-guided mms (p = 0.48; fisher exact test) after a follow-up period of 82.6 and 62.5 months respectively [9]. in the second study, both study groups showed no recurrence after a mean follow-up period of 10 ± 5 months [4]. conclusions in the present study, we aimed to assess the effectiveness of dermoscopy as an ancillary tool for mms. six studies were included: 2 rcts [6,7], and 4 observational studies [4,810]. the total number of evaluated bccs was 508. three studies specified the subtypes of evaluated bccs [6,7,9]. three studies excluded recurrent bcc [4,6,7], while one study included only recurrent bcc following ablative laser [10]. of the included studies, pooling of the data was feasible for 3 evaluated outcomes. there was no statistically significant difference in the proportion of total margin clearance on the first mms stage between bccs removed using dermoscopy-guided mms and those that had curettage or visual inspection. however, lateral margin involvement was significantly lower in bccs that had dermoscopy-guided mms. to the best of our knowledge, no systematic review addressed the question of whether dermoscopy is useful for delineating bcc margins for mms. que published a comprehensive narrative review on noninvasive imaging technologies used for the delineation of bcc in the setting of review | dermatol pract concept. 2022;12(4):e2022176 9 funnel plot of standard error by std diff in means st a n d a r d e r r o r std diff in means -2,0 0,4 0,3 0,2 0,1 0,0 -1,5 -1,0 -0,5 0,0 0,5 1,0 1,5 2,0 meta analysis (outcome: number of mohs sessions) (q test) p=0,034 -i2: 70,3% standard or curettage-guided mmsdermoscopy-guided mms study name statistics for each study standard error upper limit lower limit p-value std diff in means std diff in means and 95% ci asilian momeni 2012 gurgen gatti 2012 litaiem 2020 0,200 0,191 -0,130 -0,739 0,317 0,317 0,323 0,281 0,317 0,317 0,323 -2,00 -1,00 0,00 1,00 2,00 0,281 -0,421 -0,430 -0,764 -1,290 0,821 0,812 -0,503 -0,187 figure 3. comparison of the number of mohs stages using dermoscopy-guided vs. standard or curettage mms for bcc treatment statistics for each study odds ratio and 95% cistudy name litaiem 2020 shin 2020 odds ratio p-value 0,001 0,012 0,000 0,429 0,703 0,385 0,034 0,061 0,066 0,120 0,206 0,159 lower limit upper limit standard and curettage-guided mmsdermoscopy-guided mms 0,01 0,1 1 10 100 meta analysis (outcome: positive lateral margins after the first mohs sessions) (q test) p=0,550 i 2 : 0% figure 4. comparison of the proportion of positive lateral margins after the first mohs stage using dermoscopy-guided vs. standard or curettage guided mms for bcc treatment 10 review | dermatol pract concept. 2022;12(4):e2022176 not indicated in all included studies. this may hinder the interpretation of findings and undermine their accuracy. finally, both dermoscopy and mms are operator-dependent procedures [4]. thus, controlled, consistent and reproducible results are not readily attainable. despite these limitations, this systematic review is a comprehensive summary on the reported use of dermoscopy for bcc delineation in mms to date. overall, our data suggest that dermoscopy could improve lateral margin assessment within the first mohs stage. future randomized clinical trials are required to develop an evidence-based recommendation regarding the utility of dermoscopy in mms. references 1. cameron mc, lee e, hibler bp, et al. basal cell carcinoma: contemporary approaches to diagnosis, treatment, and prevention. j am acad dermatol. 2019;80(2):321-339. doi:10.1016/j. jaad.2018.02.083. pmid: 29782901. 2. rogers hw, weinstock ma, feldman sr, coldiron bm. incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the us population, 2012. jama dermatology. 2015;151(10):1081-1086. doi:10.1001/jamadermatol .2015.1187. pmid: 25928283. 3. danesh mj, menge td, helliwell l, mahalingam m, waldman a. adherence to the national comprehensive cancer network criteria of complete circumferential peripheral and deep margin assessment in treatment of high-risk basal and squamous cell carcinoma. dermatol surg. 2020;46(12):1473-1480. doi:10.1097/dss.0000000000002354. pmid: 32149872. 4. litaiem n, karray m, jones m, rammeh s, zeglaoui f. effectiveness of dermoscopy in the demarcation of surgical margins in slow mohs surgery. dermatol ther. published online 2020;33(6):e14196. doii:10.1111/dth.14196. pmid: 32798257. 5. rosendahl c, marozava a, eds. dermatoscopy and skin cancer: a handbook for hunters of skin cancer and melanoma. 1st edition. scion publishing; 2019:276-284. 6. asilian a, momeni i. comparison between examination with naked eye, curretage and dermoscopy in determining tumor extension before mohs micrographic surgery. adv biomed res. 2013;2:2. doi: 10.4103/2277-9175.107961. pmid: 23930247. pmcid: pmc3732882. 7. gurgen j, gatti m. epiluminescence microscopy (dermoscopy) versus visual inspection during mohs microscopic surgery of infiltrative basal cell carcinoma. dermatologic surg. 2012;38 (7 part 1):1066-1069. doi:10.1111/j.1524-4725.2012.02424 .x. pmid: 22676346. 8. suzuki hs, serafini sz, sato ms. utility of dermoscopy for demarcation of surgical margins in mohs micrographic surgery. an bras dermatol. 2014;89(1):38-43. doi:10.1590/abd18064841.20142400. pmid: 24626646. pmcid: pmc3938352. 9. dika e, fanti pa, christman h, ravaioli gm, patrizi a. videodermoscopy and curettage: the value of simple procedures during mohs surgery. dermatologic surg. 2017;43(12):1411-1417. doi:10.1097/dss.0000000000001247. pmid: 28858922. mms [22]. three technologies were discussed: dermoscopy, confocal microscopy, and optical coherence tomography. only the number of mohs stages was evaluated as an outcome measure in relation to dermoscopy. que stated that dermoscopy did not prove to decrease the number of mohs stages. in our systematic review, there was no statistically significant difference in the number of mohs stages between the use of dermoscopy or visual inspection for mms (the standardized mean difference -0.17, 95% ci -0.51 to 0.17; three studies [4,6,7]). a hypothesis to explain this finding is that dermoscopy utility is limited to the first mohs stage. subsequent stages would only rely on the surgeon’s skills and experience. in the present systematic review, there was no significant association between the use of dermoscopy and the proportion of total margin clearance on the first mms stage. surgical margin assessment includes both deep and lateral margin evaluation. a dermoscope is a magnifying instrument that enables visualization of pigmented structures and vessels up to 1mm into the dermis and therefore would not allow for deep margin evaluation [5]. hence, it is rational to use it for lateral margin evaluation [4,10]. there are several potential implications for both practice and research. relapsing bccs and bccs bearing aggressive histopathological features may exhibit a subclinical extension of their lateral margins [23]. this could result in recurrences and incomplete surgical excision [23]. further studies assessing lateral margin involvement are needed. in addition, future research is warranted to investigate the utility of dermoscopy for tumor delineation in high‐risk bcc. combining two imaging techniques is beyond the scope of the present systematic review. recently, lupu et al evaluated whether bcc lateral excision margins could be precisely evaluated preoperatively through the use of dermoscopy and reflectance confocal microscopy [23]. in this study, 18 patients (20 bccs, mostly were nodular: 12/20) were included. the authors concluded that dermoscopy served as an accurate guide during reflectance confocal microscopy [23]. the global accuracy of the procedure was 93.1% (95% ci 0.77–0.99) [23]. the present systematic review sought to summarize the existing data on the possible use of dermoscopy for tumor delineation in mms. however, certain limitations apply to the results depicted herein. first, our sample size was limited by the scarcity of research on this subject in the literature. only two included studies evaluated the use of dermoscopy for lateral margin assessment. therefore, these results should be interpreted with caution. second, some studies had missing data on outcome measures and hence were excluded from the data analysis. third, the histopathological subtype of bcc, which can act as a confounding factor, was review | dermatol pract concept. 2022;12(4):e2022176 11 17. jawed si, goldberg lh, wang sq. dermoscopy to identify biopsy sites before mohs surgery. dermatologic surg. 2014;40(3): 334-337. doi:10.1111/dsu.12422. pmid: 24447179. 18. hidalgo l, donoso f, guzmán m, et al. multiple aggregated yellow-white (may) globules, a dermoscopic sign to be considered in the presurgical evaluation in mohs surgery. dermatol ther. 2022;35(4):e15333. doi:10.1111/dth.15333. pmid: 35080119. 19. coleman aj, penney gp, richardson tj, et al. automated registration of optical coherence tomography and dermoscopy in the assessment of sub-clinical spread in basal cell carcinoma. comput aided surg. 2014;19(1-3):1-12. doi:10.3109/10929088.20 14.885085. pmid: 24784842. pmcid: pmc4075257. 20. jayasekera psa, dodd j, oliphant t, langtry jaa, lawrence cm. dermoscopy prior to mohs micrographic surgery does not improve tumour margin assessment and leads to fewer mohs stages. br j dermatol. 2018;178(2):565-566. doi:10.1111 /bjd.15903. pmid: 28851098. 21. cerci fb, kubo em, werner b, tolkachjov sn. dermoscopy accuracy for lateral margin assessment of distinct basal cell carcinoma subtypes treated by mohs micrographic surgery in 368 cases. int j dermatol. 2022;61(4):e139-e141. doi: 10.1111/ ijd.15655. pmid: 34013989. 22. que skt. research techniques made simple: noninvasive imaging technologies for the delineation of basal cell carcinomas. j invest dermatol. 2016;136(4):e33-e38. doi:10.1016/j .jid.2016.02.012. pmid: 27012561. 23. lupu m, voiculescu vm, caruntu a, tebeica t, caruntu c. preoperative evaluation through dermoscopy and reflectance confocal microscopy of the lateral excision margins for primary basal cell carcinoma. diagnostics. 2021;11(1):120. doi:10.3390/diagnostics11010120. pmid: 33466602; pmcid: pmc7828674. 10. shin k, kim h-sh-jh, ko h, kim b, kim m-b, kim h-sh-jh. dermoscopy-guided mohs micrographic surgery in post-laser basal cell carcinomas: is dermoscopy helpful for demarcation of the surgical margin? j dermatolog treat. 2020;0(0):1-12. doi:1 0.1080/09546634.2020.1762839. pmid: 32345116. 11. yeom sd, lee sh, ko hs, et al. effectiveness of dermoscopy in mohs micrographic surgery (mms) for nonmelanoma skin cancer (nmsc). int j dermatol. 2017;56(6):e136-e139. doi:10.1111 /ijd.13501. pmid: 28247925. 12. guardiano ra, grande dj. a direct comparison of visual inspection, curettage, and epiluminescence microscopy in determining tumor extent before the initial margins are determined for mohs micrographic surgery. dermatologic surg. 2010;36(8):1240-1244. doi:10.1111/j.1524-4725.2010.01616.x. pmid: 20666811. 13. liberati a, altman dg, tetzlaff j, et al. the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. bmj. 2009;339. doi:10.1136/bmj.b2700. pmid: 19622552. pmcid: pmc2714672. 14. slim k, nini e, forestier d, kwiatkowski f, panis y, chipponi j. methodological index for non-randomized studies (minors): development and validation of a new instrument. anz j surg. 2003;73(9):712-716. doi:10.1046/j.1445-2197.2003.02748.x. pmid: 12956787. 15. jadad ar, moore ra, carroll d, et al. assessing the quality of reports of randomized clinical trials: is blinding necessary? control clin trials. 1996;17(1):1-12. doi:10.1016/0197-2456(95) 00134-4. pmid: 8721797. 16. terushkin v, wang sq. mohs surgery for basal cell carcinoma assisted by dermoscopy: report of two cases. dermatologic surg. 2009;35(12):2031-2035. doi:10.1111/j.1524-4725.2009.01329 .x. pmid: 19758353. 12 review | dermatol pract concept. 2022;12(4):e2022176 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com letter | dermatol pract concept 2013;3(4):13 53 case a 25-year-old male patient without significant personal or family medical history was admitted to the dermatology department suffering from primary syphilis. he was a heterosexual man and the infective sexual contact was approximately five weeks before hospitalization. he started the specific treatment with benzathine penicillin 2.400.000 iu followed by the discharge from the hospital, as he tolerated the first doses of penicillin very well, without jarish-herxheimer reaction following the initiation of the antibiotic. he received advice to continue the treatment with penicillin as an outpatient. after ten days the patient returned to the emergency department having an altered general condition, low-grade fever, loss of appetite, vomiting, oliguria, generalized edema, and lumbar pain. during the medical examination we noticed pale skin, renal type generalized edema, dull pain radiating to the flanks, tender kidneys on palpation, and left side inguinal lymphadenopathy. the urine volume during 24 hours was of 900 ml. we established the diagnosis of acute glomerulonephritis with nephrotic syndrome [1]. the investigations revealed the following abnormalities: erythrocyte sedimentation rate 100 mm/h, fibrinogen 720 mg/ dl, positive reactive c protein; hypoproteinemia 5 g/dl; hypercholesterolemia 371 mg/dl; hyperlipidemia 1,168 mg/dl; renal impairment: urea 64 mg/dl and creatinine 1.87 mg/dl; hepatic cytolysis: aspartate transaminase 77 iu/l; alanine transaminase 75 iu/l with increase of alkaline phosphatase 324 iu/l; a rare case of syphilis associated with renal and hepatic involvement alin laurentiu tatu1, maria popescu2, radu rotarescu3, sanda dorina popescu4 1 faculty of medicine and pharmacy, dunarea de jos university, galati, romania 2 internal medicine department, emergency hospital of galati, galati, romania 3 dermatology department, mid staffordshire nhs foundation trust, stafford, staffordshire, united kingdom 4 dermatology department, university hospital of north stafffordshire, staffordshire, united kingdom key words: syphilis, membranous glomerulonephritis, nephrotic syndrome, hepatic involvement citation: tatu al, popescu m, rotarescu r, popescu sd. a rare case of syphilis associated with renal and hepatic involvement. dermatol pract conc. 2013;3(4):13. http://dx.doi.org/10.5826/dpc.0304a13. received: june 4, 2013; accepted: july 1, 2013; published: october 31, 2013 copyright: ©2013 tatu et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. alin laurentiu tatu, faculty of medicine and pharmacy dunarea de jos university, strada al.i.cuza nr 39 galati, jud galati cod 800101,romania. tel. + 0336 130 217. email: dralin_tatu@yahoo.com we present an unusual case of syphilis that despite starting treatment with penicillin has evolved with renal complications. due to glomerulonephritis with nephrotic syndrome the case required shared care between the renal physician and dermatologist. doctors of different specialties need to keep in mind that early syphilis can have visceral involvement and patients might need prompt, specific therapeutic intervention. abstract 54 letter | dermatol pract concept 2013;3(4):13 cific syphilis serological tests were also improved, vdrl ++ (dilution1/2) and tpha +++. after the patient was discharged from the hospital, he continued the treatment with benzathine penicillin 2.400.000 iu/week (for two weeks) and prednisone in reducing doses with regular monitoring of the urine and renal tests. at 2-month follow-up the proteinuria was absent. at 6-month follow-up vdrl was negative and tpha ++ had improved, remaining positive. the serological and urine tests monitoring continued every three months in the first year and every six months in the second year. after two years tpha ++ was still positive but vdrl and rpr remained negative. discussion this rare case is interesting from the nephrologic point of view due to the rare systemic involvement of the kidneys during the syphilis infection, leading to the presentation of membranous glomerulonephritis [1,2,3]. for dermatologists, it is important to keep in mind the possibility of early and multiple visceral involvement of syphilis that sometimes can be severe but with a rapid favorable evolution with supportive treatment [4]. references 1. mora mora mt, gallego domínguez ms, castellano cerviño mi, et al. membranous glomerulonephritis in a patient with syphilis. nefrologia. 2011;31(3):372-3. 2. hunte w, al-ghraoui f, cohen rjsecondary syphilis and the nephrotic syndrome. j am soc nephrol. 1993;3(7):1351-5. 3. soehardy z, hayati sn, rozita m, et al. subclinical acquired syphilis masquerading as membranous glomerulonephritis. med j malaysia. 2006;61(4):484-6. 4. koenig m, duband s, thibaudin d, cathébras p. rash and nephrotic syndrome: consider syphilis. presse med. 2005;4;34(9):657. circulating immune complexes 42 iu/l. the urine examination showed proteinuria 12 g/24h, microscopic hematuria with dysmorphic red blood cells, and cylindruria hyaline cylinders. the hiv, and hepatitis b and c screenings were negative. due to the recent history of syphilis infection, a dermatologic consultation was requested. examination showed in the coronal sulcus presence of ulceration with indurated basis and satellite inguinal lymphadenopathy. the clinical examination was completed by the specific serological investigations that were intensely positive: vdrl++++ (venereal disease research laboratory) (dilution 1/4), positive rpr (rapid plasma reagin), and tpha++++ (treponema pallidum hemagglutination assay). the ophthalmologic and the neurologic examinations showed no change. ultrasound revealed moderate hepatomegaly, ascites and kidneys increased in size. the final and reviewed diagnosis was made: early secondary syphilis with the persistence of the primary chancre, associated with syphilitic glomerulonephritis with nephrotic syndrome and hepatic involvement [1,2]. since the secondary stage of syphilis starts around ninth week after infection and as our patient had visceral involvement, although no exanthemas or enanthemas had been found clinically, we felt that this was an early stage of secondary syphilis and that the persistence of ulcus durum would be consistent with this stage. treatment with penicillin 2.400.000 iu/day was started with oral steroid therapy, prednisone 1 mg/kg/day, and correction of the hypoproteinemia (human albumin perfusions) and diuretics (furosemide and spironolactone) were initiated. after the first 10 days of treatment we noticed a favorable clinical progress: improvement of the general condition, the disappearance of the low-grade fever and of the edema, the normalization of urine volume, the remission of lymphadenopathy, and the epithelialization of the primary chancre. at the time of discharge from the hospital we noted proteinuria < 0.5 g/24h without hematuria, the acute renal impairment had disappeared, hepatic tests had settled, and that the speuntitled observation | dermatol pract concept 2015;5(3):12 53 dermatology practical & conceptual www.derm101.com the patient a 15-year-old, otherwise healthy boy presented with 2-yearhistory of swelling and thickening localized to the lateral aspects of his fingers. dermatological examination revealed fusiform soft tissue swelling on the lateral and medial aspects of the second to fourth proximal interphalangeal (pip) joints of both hands (figure 1). there was no arthralgia or limited range of motion. rheumatological examination was otherwise normal. there was no history of repetitive trauma, tick-like habits or any mental disorders. laboratory tests, including routine biochemistry, thyroid function tests, and rheumatologic markers, disclosed no abnormalities. an mri and x-ray examination was normal except for soft tissue hypertrophy around the affected joints (figure 2). what is your diagnosis? symmetrical fusiform swellings around the proximal interphalangeal joints merve hatun saricam1, andac salman2, ayse deniz yucelten3 1 merve hatun saricam, marmara university, school of medicine, department of dermatology, istanbul, turkey 2 andac salman, marmara university, school of medicine, department of dermatology, istanbul, turkey 3 ayse deniz yucelten, marmara university, school of medicine, department of dermatology, istanbul, turkey key words: fibromatosis, pachydermodactyly citation: saricam mh, salman a, yucelten ad. symmetrical fusiform swellings around the proximal interphalangeal joints.dermatol pract concept 2015;5(3):12. doi: 10.5826/dpc.0503a12 received: may 16, 2015; accepted: june 16, 2015; published: april 30, 2015 copyright: ©2015 saricam et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: andac salman, md, marmara universitesi pendik egitim ve arastirma hastanesi, dermatoloji anabilim dali fevzi cakmak mah, mimar sinan cad. no:41, 34899 pendik, istanbul, turkey. tel. +902166570606, ext 4649; fax: +902165970052. e-mail: asalmanitf@gmail.com figure 1. fusiform, soft tissue swelling on the lateral and medial aspects the proximal interphalangeal joints of the second to fourth fingers. [copyright: ©2015 saricam et al.] figure 2. x-ray examination shows soft tissue swelling around the affected joints without any osseous changes. [copyright: ©2015 saricam et al.] 54 observation | dermatol pract concept 2015;5(3):12 any articular or osseous changes. ultrasonography also confirms the presence of soft tissue hypertrophy without hypervascularization and the absence of joint disease. similarly, magnetic resonance imaging (mri) reveals only soft tissue swelling without synovitis or tendinitis [3]. though histopathology is not routinely necessary in clinical practice, it shows epidermal acanthosis, increase in dermal collagen and mucin deposits in dermis [1-3]. there is no effective treatment for pdd. avoidance of mechanical trauma may result in improvement. intralesional corticosteroid injections and localized resection of subcutaneous tissue were reported to be effective in some cases [2-5]. however, given to its benign nature, non-invasive treatment options are recommended for pdd [2]. in conclusion, recognition of this rare, or under-reported, benign condition is crucial to prevent patients from unnecessary or expensive laboratory tests and improper treatment with immunosuppresive agents. references 1. kamino h, reddy vb, pui j. fibrous and fibrohistiocytic proliferations of the skin and tendons. in: bolognia jl, jorizzo jl, schaffer jv, eds. dermatology. 3rd ed. china: elsevier, 2012:1961-77. 2. beltraminelli h, itin p. pachydermodactyly—just a sign of emotional distress. eur j dermatol 2009;19:5-13. 3. dallos t, oppl b, kovacs l, et al. pachydermodactyly: a review. curr rheumatol rep 2014;16:442-9. 4. ulusoy h, tas np, akgol g, et al. unusual unilateral presentation of pachydermodactyly: a case report. rheumatol int 2012;32:174750. 5. bardazzi f, neri i, raone b, et al. pachdermodactyly: seven new cases. ann dermatol venereol 1998;125:247-50. answer pachydermodactyly. clinical course although a treatment with intralesional corticosteroids was planned, the patient was lost to follow-up. discussion pachydermodactyly (pdd), is an uncommon, benign form of superficial digital fibromatosis [1]. it is characterized by asymptomatic, periarticular soft tissue swelling of the pip joints. the disease is most commonly seen in young, otherwise healthy males [1-3]. while pdd usually affects the pip joints symmetrically, involvement of distal interphalangeal (dip) joints and metacarpophalangeal (mcp) joints or unilateral disease can also be seen [4]. in the transgradient form of pdd, both mcp and pip joints are affected [3]. the etiology of pdd is not fully understood but repetitive minor traumas (occupational, habitual or compulsive) are thought to be the major contributing factor [1,2]. pdd was reported to be associated with obsessive-compulsive disorder, asperger syndrome, ehlers-danlos syndrome and tuberous sclerosis [3]. pdd may resemble juvenile idiopathic arthritis, rheumatoid arthritis, knuckle pads, pachydermoperiostosis or acromegaly [3]. the diagnosis of pdd is usually made with typical clinical findings. laboratory tests and radiographic examination may be helpful in exclusion of the differential diagnosis. x-ray imaging shows soft tissue swelling without dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):11 51 dermatology practical & conceptual www.derm101.com introduction pedunculated basal cell carcinoma (bcc) is a rare bcc variant. there have been limited cases reported in the pubmed database [1-6]. dermoscopic features were reported in only one of them [6] and not one described reflectance confocal microscopy (rcm) features. case a 7 x 5 mm slight brown-gray pigmented pedunculated lesion was detected on the right post-auricular region on the routine skin examination of a 60-year-old woman. she had a history of multiple bccs due to radiotherapy for the treatment of lymphoma in childhood. the lesion displayed arborizing vessels, multiple blue-gray globules and ovoid nests on dermoscopy (figure 1). on rcm, at the epidermal layer, polarization (streaming) and some dendritic cells and at the dermoepidermal junctional level, and multiple tumor islands with different sizes were observed. in addition, there were many canalicular vessels all throughout the lesion (vivascope 3000 handheld, mavig gmbh, munich, germany). a pedunculated nodular bcc was diagnosed with the large basaloid tumor islands with peripheral palisading and retraction artifact and dilated vascular spaces on histopathology (figure 2). the differential diagnosis of pigmented pedunculated lesion may sometimes be challenging and include an acrochordon, seborrheic keratosis, condyloma, dermal nevus, bcc, eccrine poroma or trichoblastoma. moreover, a pedunculated melanoma should also be excluded. thus, in vivo diagnostic techniques such as dermoscopy and rcm may play a crucial role in the differential diagnosis. dermoscopy and reflectance confocal microscopy in pedunculated basal cell carcinoma seda yildiz1, isil karaarslan1, banu yaman2, fezal ozdemir1 1 department of dermatology, faculty of medicine, university of ege, izmir, turkey 2 department of pathology, faculty of medicine, university of ege, izmir, turkey key words: dermoscopy, reflectance confocal micoscopy, basal cell carcinoma citation: yildiz s, karaarslan i, yaman b, ozdemir f. dermoscopy and reflectance confocal microscopy in pedunculated basal cell carcinoma. dermatol pract concept. 2017;7(2):11. doi: https://doi.org/10.5826/dpc.0702a11 received: january 9, 2017; accepted: january 14, 2017; published: april 30, 2017 copyright: ©2017 seda et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: seda yildiz, md, department of dermatology, faculty of medicine, university of ege, 35100, bornova, izmir, turkey. tel. +902323902698; fax: +902323399702. email: yildizsda@gmail.com there have been limited cases of pedunculated basal cell carcinoma (bcc) reported in the literature. the dermoscopic features were described in only one of them. however, not one of them described the confocal microscopy features. in this report we presented a case of pedunculated basal cell carcinoma (bcc) with dermoscopic and reflectance confocal microscopy features. abstract 52 observation | dermatol pract concept 2017;7(2):11 there have been rare cases of pedunculated bcc reported in the literature. dermoscopic features were mentioned in only one report describing multiple acrochordon-like bccs in a patient with gorlin-goltz syndrome [6]. in that case, the dermoscopic features observed were multiple or isolated gray-blue globules and/or telangiectases of different caliber and number of branches. other dermoscopic features of bcc, such as ulceration, maple leaf-like areas, or spokewheel areas, were not detected. the dermoscopic features observed in the present case were similar to those findings. on the other hand, rcm findings were not described in any of the cases in the literature. in the present case, observing the typical rcm criteria for bcc helped in making a more confident preoperative diagnosis. to our knowledge, this is the first rcm description of a pedunculated bcc. references 1. megahed m. polypoid basal cell carcinoma: a new clinicopathological variant. br j dermatol. 1999;140(4):701-703. 2. misago n, suzuki y, miura y, narisawa y. giant polypoid basal cell carcinoma with features of fibroepithelioma of pinkus and extensive cornification. eur j dermatol. 2004;14(4):272-275. 3. misago n, narisawa y. polypoid basal cell carcinoma on the perianal region: a case report and review of the literature. j dermatol. 2004;31(1):51-55. 4. azzam c, arrese je, jacquemin d, calteux n, piérard ge. pedunculated and pigmented basal cell carcinoma: an unusual presentation]. rev med liege. 2006;61 (9):614-616. 5. repertinger sk, stevens t, markin n, et al. fibroepithelioma of pinkus with pleomorphic epithelial giant cells. dermatol online j. 2008;14(12):13. 6. feito-rodríguez m, sendagorta-cudós e, moratinos-martínez m, et al. dermatoscopic characteristics of acrochordonlike basal cell carcinomas in gorlin-goltz syndrome. j am acad dermatol. 2009; 60(5):857-861. figure 1. (a, b) slight brown-gray pigmented pedunculated lesion. (c, d) arborizing vessels, multiple blue-gray globules and ovoid nests on dermoscopy. [copyright: ©2017 seda et al.] a b c d figure 2. (a) bright tumor island (red arrows). (b) epidermal polarization. (c) tumor island and canalicular vessels. (d) atrophic epidermis, large basaloid tumor islands and melanophages (h&ex40) (inset: pedunculated nodular bcc [h&ex20]). [copyright: ©2017 seda et al.] a b c d dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023160 1 can cemiplimab become a life-changer in xeroderma pigmentosum? maria boziou1, dimitrios dionyssiou2, dimitrios dionyssopoulos3, elizabeth lazaridou1, aimilios lallas4, zoe apalla1 1 second dermatology department, school of medicine, faculty of health sciences, aristotle university of thessaloniki, thessaloniki, greece 2 department of plastic surgery, school of medicine, faculty of health sciences, aristotle university of thessaloniki, thessaloniki, greece 3 department of medical oncology, faculty of medicine, school of health sciences, aristotle university of thessaloniki, thessaloniki, greece 4 first dermatology department, school of medicine, faculty of health sciences, aristotle university of thessaloniki, thessaloniki, greece key words: immune checkpoint inhibitors, cemiplimab, xeroderma pigmentosum, squamous cell carcinoma, melanoma citation: boziou m, dionyssiou d, dionyssopoulos d, lazaridou e, lallas a, apalla z. can cemiplimab become a life-changer in xeroderma pigmentosum?. dermatol pract concept. 2023;13(3):e2023160. doi: https://doi.org/10.5826/dpc.1303a160 accepted: december 9, 2022; published: july 2023 copyright: ©2023 boziou et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maria boziou, md, agiou pavlou 76, thessaloniki, greece tel:+302313323274 e-mail: mariaboziou@gmail.com introduction xeroderma pigmentosum (xp) is a rare inherited autosomal recessive disease, resulting in defective repair of the ultraviolet radiation induced dna damage. prognosis of xeroderma pigmentosum (xp) is unfavorable, with most patients dying from metastatic skin cancer before the age of 30. management is extremely challenging and includes strict avoidance of sun exposure, close monitoring and early therapeutic interventions. cemiplimab is an anti-programmed cell death 1 (pd-1) antibody, approved for advanced nonmelanoma skin cancers (nmscs) and tested also for melanoma. taking into account the spectrum of malignancies appearing in the context of xp, anti-pd-1 antibodies may represent the ideal treatment choice [1-8]. case presentation a 29-year-old female with xp was referred to our onco dermatology, multidisciplinary unit for management. the patient had undergone numerous surgical excisions in the past. upon clinical examination, apart from extensive freckling and numerous actinic keratoses, we identified two atypical melanocytic lesions compatible with melanoma and multiple basal (bcc) and squamous cell carcinomas (scc) (figure 1). ct scan of chest, upper/lower abdomen and brain mri were unremarkable. we decided to proceed with an “en-bloc” resection of the skin of the forehead, due to the extreme cancer burden, plus resection of the second atypical melanocytic lesion of the lower face. histologic examination of the forehead skin 2 research letter | dermatol pract concept. 2023;13(3):e2023160 showed a fully regressed melanoma, two sccs and nine bccs. the second melanocytic lesion was diagnosed as tumoral melanosis. breslow thickness could not be defined due to full regression. a combination of photodynamic therapy(pdt), sequentially to 5% imiquimod cream, plus 10mg of daily oral acitretin, as a prophylactic modality, were used. however, the locally advanced scc of the eyelid that invaded the conjunctiva posed a serious therapeutic dilemma, since its surgical removal would inevitably lead to eye loss. considering the limitations of the surgery, the concomitant presence of a second large scc involving the right nasolabial fold and the overall nmscs burden in the cancerized areas, we decided to set the patient under treatment with cemiplimab. after 1.5 year of systemic treatment with cemiplimab, there is a remarkable response (figure 2), with excellent tolerance and the treatment is still ongoing. conclusions xp is an ideal model for studying effectiveness of immune checkpoint inhibitors (icis) on skin malignancies, especially when i0074 comes to the treatment of advanced sccs and bccs, coexisting with melanoma. carrying out a literature review, we retrieved eight individuals with xp treated with icis, with only one of them receiving cemiplimab (table 1). overall, as in our patient, individuals receiving icis demonstrated a constant response of locally advanced and metastatic tumors of both origins, epithelial and melanocytic. tolerability and safety were satisfactory as in our patient. the particularity of the current case is the concomitant presence of unresectable nmscs and two melanomas, which is a common scenario in the context of xp. icis, due to their dual therapeutic effect on both, epithelial and melanocytic skin cancers, may open a new therapeutic horizon, changing the so far unfavorable fate of xp patients. figure 1. extreme photodamage, with multiple freckles, two melanomas (arrows) and numerous nonmelanoma skin cancers on the face, including two advanced squamous cell carcinoma, one at the right lower eyelid and one at the right nasolabial fold. figure 2. the patient after 1.5 year of cemiplimab initiation. we observe complete clinical response, not only of the unresectable squamous cell carcinoma (scc) of the right lower eyelid, but also of the non-resected scc involving the right nasolabial fold, as well as of the multiple smaller nonmelanoma skin cancers of the facial skin. research letter | dermatol pract concept. 2023;13(3):e2023160 3 ta b le 1 . o u tc o m es o f u se o f im m u n e ch ec k p o in t in h ib it o rs i n x er o d er m a p ig m en to su m p at ie n ts r e fe re n ce s a g e / s e x tu m o r (i c is t a rg e t) s it e ic i u se d o u tc o m e o f ta rg e t tu m o r o u tc o m e o f co e x is ti n g tu m o rs ic i d e ri v e d a e s a d d it io n a l tr e a tm e n t r u b at to e t al [ 1 ] 1 9 /f n o n o p er ab le , m et as ta ti c sc c r ig h t o rb it al a n d n as al c av it y w it h l ym p h n o d e m et as ta si s c em ip li m ab 3 5 0 m g ev er y 3 w ee k s p ar ti al r es p o n se r eg re ss io n o f n m sc s, a k d ia rr h ea r ad io th er ap y a m er i et a l [2 ] 1 8 /f n o n o p er ab le s c c l im b u s o f ri gh t ey e p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s c o m p le te re sp o n se n o r es p o n se o f fa ci al b c c s a m er i, et  a l [2 ] 1 9 /m n o n o p er ab le s c c r ig h t o rb it al a n d n as al c av it y p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s p ar ti al r es p o n se a m er i et a l [2 ] 2 0 /f i) m et as ta ti c m el an o m a ii ) n o n o p er ab le sc c i) m u p ii ) m ax il la ry s in u s i) ip il im u m ab 1 0 m g/ k g ev er y 3 w ee k s ii ) p em b ro li zu m ab 1 4 0 m g/ m o n th i) n o ta b le re sp o n se ii ) n o ta b le re sp o n se t il l ra d io gr ap h ic p ro gr es si o n h au sc h il d e t al [ 3 ]. 3 5 1 /m m et as ta ti c m el an o m a l ef t ch ee k w it h m u lt ip le p u lm o n ar y, l ym p h n o d e an d ri gh t in fr ao rb it al m et as ta se s p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s 9 0 % r eg re ss io n o f th e la rg es t lu n gm et as ta si s. c o m p le te re gr es si o n o f th e o th er s. r eg re ss io n o f al m o st a ll n m sc s, a k r ed d is h sw el li n g o f th e ri gh t o rb it a, in fl am m at o ry ra sh i n s u n d am ag ed s k in , m il d i tc h in g d ei n le in e t al [ 4 ] 4 8 /f m et as ta ti c sc c l ef t ti gh t w it h a b d o m in al , in gu in al a n d l ef t su p ra cl av ic u la r ly m p h n o d e m et as ta se s p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s si gn ifi ca n t re gr es si o n o f al l m et as ta se s n o im p ro ve m en t o n so la r le n ti gi n es m et as ta ti c su p ra cl av ic u la r ly m p h ad en ec to m y c h am b o n e t al [ 5 ] 6 /f i) sa rc o m at o id ca rc in o m a ii )s c c sc al p w it h b o n e ly ti c le si o n s, va sc u la r, m en in ge al c o n ta ct an d s u p er io r sa gi tt al s in u s in vo lv em en t i) n iv o lu m ab 3 m g/ k g ev er y 2 w ee k s ii ) n iv o lu m ab m o n th ly & c et u x im ab 2 5 0 m g/ m 2 /w ee k , 3 w ee k s o u t o f 4 6 5 % r eg re ss io n o f th e sa rc o m at o id ca rc in o m a. n o re sp o n se t o s c c a p p ea ra n ce o f tw o i n va si ve m el an o m as o n th e sc al p . m u lt ip le cu ta n eo u s, l ip , to n gu e tu m o rs c h em o th er ap y (5 f u , c is p la ti n ), su rg er y t ab le 1 c o n ti n u es 4 research letter | dermatol pract concept. 2023;13(3):e2023160 r e fe re n ce s a g e / s e x tu m o r (i c is t a rg e t) s it e ic i u se d o u tc o m e o f ta rg e t tu m o r o u tc o m e o f co e x is ti n g tu m o rs ic i d e ri v e d a e s a d d it io n a l tr e a tm e n t sa lo m o n e t al [ 6 ] 1 7 /m m et as ta ti c m el an o m a sc al p w it h l iv er a n d p u lm o n ar y m et as ta se s p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s p ar ti al re sp o n se o f al l m et as ta se s, l o n g la st in g d is ea se st ab il iz at io n r eg re ss io n o f n m sc s, a k v it il ig o id d ep ig m en ta ti o n o n s u n -e x p o se d ar ea s st ei n ec k e t  al [ 7 ]7 7 /f m et as ta ti c sc c r ig h t si d e o f th e fa ce sp re ad in g to t h e ri gh t sp h en o id b o n e, t h e ca ve rn o u s si n u s, t h e ri gh t ca ro ti d a rt er y, th e su rr o u n d in g ti ss u es , th e ly m p h n o d es & t h e le p to m en in ge al p em b ro li zu m ab 2 m g/ k g ev er y 3 w ee k s r ed u ct io n o f tu m o r si ze , re so lu ti o n o f le p to m en in ge al sp re ad , l o n g la st in g d is ea se st ab il iz at io n r es p o n se o f m o st o f th e o cu lo cu ta n eo u s le si o n s. m il d p ro gr es si o n o f a ri gh t co rn ea l sc c m o m en e t al [ 8 ] 3 2 /m c u ta n eo u s an gi o sa rc o m a l ef t ey eb ro w w it h m et as ta ti c p u lm o n ar y, p er ic ar d ia l, m ed ia st in al , p le u ra l, su b m an d ib u la r, h ep at ic & b o n e d is ea se p em b ro li zu m ab 2 0 0 m g/ k g ev er y 3 w ee k s c o m p le te re sp o n se o f th e p u lm o n ar y & b o n e m et as ta se s, al m o st c o m p le te re sp o n se o f th e ca rd ia c & p er ic ar d ia l d is ea se , re gr es si o n o f th e h ep at ic , su b m an d ib u la r & p le u ra l le si o n s r ad io th er ap y a e s = a d ve rs e ev en ts ; a k = a ct in ic k er at o se s; b c c = b as al c el l ca rc in o m a; f = f em al e; i c i = i m m u n e ch ec k p o in t in h ib it o r; m = m al e; m u p = m el an o m a o f u n k n o w n p ri m ar y; n m sc s = n o n -m el an o m a sk in ca n ce rs ; sc c = s q u am o u s ce ll c ar ci n o m a. ta b le 1 . o u tc o m es o f u se o f im m u n e ch ec k p o in t in h ib it o rs i n x er o d er m a p ig m en to su m p at ie n ts ( co n ti n u ed ) research letter | dermatol pract concept. 2023;13(3):e2023160 5 references 1. rubatto m, merli m, avallone g, et al. immunotherapy in xeroderma pigmentosum: a case of advanced cutaneous squamous cell carcinoma treated with cemiplimab and a literature review. oncotarget. 2021;12(11):1116-1121. doi: 10.18632/oncotarget.27966. pmid: 34084285. pmcid: pmc8169062. 2. ameri ah, mooradian mj, emerick ks, et al. immunotherapeutic strategies for cutaneous squamous cell carcinoma prevention in xeroderma pigmentosum. br j dermatol. 2019;181(5):10951097. doi: 10.1111/bjd.18144. pmid: 31102460. 3. hauschild a, eichstaedt j, möbus l, et al. regression of melanoma metastases and multiple non-melanoma skin cancers in xeroderma pigmentosum by the pd1-antibody pembrolizumab. eur j cancer. 2017;77:84–87. doi: 10.1016/j.ejca.2017.02.026. pmid: 28365530. 4. deinlein t, lax sf, schwarz t, giuffrida r, schmidzalaudek k, zalaudek i. rapid response of metastatic cutaneous squamous cell carcinoma to pembrolizumab in a patient with xeroderma pigmentosum: case report and review of the literature. eur j cancer. 2017;83:99–102. doi: 10.1016/j.ejca.2017.06.022. pmid: 28734147. 5. chambon f, osdoit s, bagny k, moro a, nguyen j, réguerre y. dramatic response to nivolumab in xeroderma pigmentosum skin tumor. pediatr blood cancer. 2018;65(2). doi: 10.1002/ pbc.26837. pmid: 28988442. 6. salomon g, maza a, boulinguez s, et al. efficacy of anti programmed cell death-1 immunotherapy for skin carcinomas and melanoma metastases in a patient with xeroderma pigmentosum. br j dermatol. 2018;178(5):1199-1203. doi: 10.1111 /bjd.16270. pmid: 29274233. 7. steineck a, krumm n, sarthy jf, et al. response to pembrolizumab in a patient with xeroderma pigmentosum and advanced squamous cell carcinoma. jco precis oncol. 2019;3:po.19.00028. doi: 10.1200/po.19.00028. pmid: 32923855. pmcid: pmc7446378. 8. momen s, fassihi h, davies hr, et al. dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease. cold spring harb mol case stud. 2019;5(5):a004408. doi: 10.1101 /mcs.a004408. pmid: 31645345. pmcid: pmc6824248. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):7 35 dermatology practical & conceptual www.derm101.com case report a 29-year-old male presented with a two-day history of rash after taking the nonsteroidal anti-inflammatory drug, diclofenac, for pain. on examination there were multiple erythematous macules all over the trunk (figure 1). polarized dermoscopy revealed milky globules on a uniform reddish background sparing the follicles (figure 2). a diagnosis of acute generalised exanthematous pustulosis (agep) was made. discussion acute generalized exanthematous pustulosis (agep) is a rare severe cutaneous reaction pattern that in the majority of cases non-follicular milky globules— dermoscopy saves the day abhijeet k. jha1, sidharth sonthalia2, aimilios lallas3 1 department of skin and vd, patna medical college & hospital, patna, bihar, india 2 skinnocence: the skin clinic, gurgaon, india 3 first department of dermatology, aristotle university, thessaloniki, greece key words: dermoscopy; milky globules; acute generalized exanthematous pustulosis citation: jha ak, sonthalia s, lallas a. non-follicular milky globules—dermoscopy saves the day. dermatol pract concept. 2017;7(2):7. doi: https://doi.org/10.5826/dpc.0702a07 received: december 19, 2016; accepted: december 28, 2016; published: april 30, 2017 copyright: ©2017 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & vd, patna medical college & hospital, patna, bihar, india. email: drabhijeetjha@gmail.com acute generalized exanthematous pustulosis (agep) is a rare severe cutaneous adverse reaction caused mostly by medication. early diagnosis is important as initiation of supportive treatment and avoidance of drug is of prime importance. a young male presented with an erythematous rash after taking diclofenac for pain. polarized dermoscopy revealed milky globules on a uniform reddish background sparing the follicles, which confirmed the diagnosis of agep. abstract figure 1. multiple erythematous macules all over the trunk. [copyright: ©2017 jha et al.] 36 observation | dermatol pract concept 2017;7(2):7 ing to nonfollicular subcorneal pustules, a pinkish-reddish background, consistent with dermal inflammation [7]. no distinct vascular structure was evident. dermoscopy may help in diagnosis at an early stage, as awaiting histopathology reports may prolong the treatment. references 1. sidoroff a, halevy s, bouwes bavinck jn, vaillant l, roujeau jn. acute generalized exanthematous pustulosis (agep)—a clinical reaction pattern. j cutan pathol. 2001;28:113-119. 2. cohen ad, cagnano e, halevy s. acute generalized exanthematous pustulosis mimicking toxic epidermal necrolysis. int j dermatol. 2001;40:458-461. 3. roujeau jc, bioulac-sage p, bourseau c, et al. acute generalized exanthematous pustulosis. analysis of 63 cases. arch dermatol. 1991;127:1333-1338. 4. vassallo c, derlino f, brazzelli v, d’ospina rd, borroni g. acute generalized exanthematous pustulosis: report of five cases and systematic review of clinical and histopathological findings. g ital dermatol venereol. 2014;149:281-290. 5. rawlin m. exanthems and drug reactions. aust fam physician. 2011;40:486-489. 6. roujeau jc. clinical heterogeneity of drug hypersensitivity. toxicology. 2005;209:123-129. 7. errichetti e, pegolo e, stinco g. dermoscopy as an auxiliary tool in the early differential diagnosis of acute generalized exanthematous pustulosis (agep) and exanthematous (morbilliform) drug eruption. j am acad dermatol. 2016;74(2):e29-31. is related to medication administration [1-3]. early diagnosis of agep is of paramount importance, as it necessitates a more aggressive therapeutic approach because it carries a worse prognosis [4,5]. the cutaneous manifestations of agep are usually associated with fever and leukocytosis, mostly due to blood neutrophil count above 7000/mcl. mild eosinophilia may be present in about one-third of the patients [3]. internal organ involvement is relatively rare and the mortality rate is approximately 5% [6]. in this patient, agep mainly showed small, milky, roundish globules, histologically correspondfigure 2. dermoscopy (polarized 10x) showing milky globules on a uniform reddish background sparing the follicles. [copyright: ©2017 jha et al.] dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023117 1 dermatoscopy of bednar tumor: new case and review of literature vincenzo maione1, giuseppe la rosa1,2, laura miccio1,2, claudia zambelli3, piergiacomo calzavara-pinton1,2 1 division of dermatology, asst spedali civili di brescia, brescia, italy 2 division of dermatology, department of clinical and experimental sciences, university of brescia, brescia, italy 3 division of pathology, asst spedali civili di brecia, brescia, italy key words: bednar tumor, dermoscopy, dermatofibrosarcoma, pigmeted dermatofibrosarcoma citation: maione v, la rosa g, miccio l, zambelli c, calzavara-pinton p. dermatoscopy of bednar tumor: new case and review of literature. dermatol pract concept. 2023;13(2):e2023117. doi: https://doi.org/10.5826/dpc.1302a117 accepted: november 23, 2023; published: april 2023 copyright: ©2023 maione et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. vincenzo maione, division of dermatology, spedali civili, piazzale spedali civili 1, brescia, italy. phone +39 0303995300, fax +39 0303995015 e-mail: maionevincenzo@gmail.com introduction bednar tumor is a rare variant of dermatofibrosarcoma. we report a new case with its dermatoscopic features, comparing them with findings of literature. case presentation a 14-year-old female patient presented because of the onset of a bluish plaque on the right forearm five months before (figure 1a). dermoscopy displayed blue-whitish areas with white streaks. a pigmented network was evident at the periphery of the lesion and in some areas appeared linearly stretched. blurry branching vessels were distributed on the entire lesion (figure 2). histological exam showed a mesenchymal neoplastic proliferation of pigmented spindle cells, with a storiform pattern, interposed with scattered thin-walled vessels ( figure 1b). immunochemistry was positive for cd34+ and fluorescence in situ hybridization displayed a rearrangement of col1a1/ pdgfb genes, confirming the diagnosis of pigmented dermatofibrosarcoma protuberans. the patient underwent surgical resection with wide margins and removal of the fascia. no recurrence was detected so far. conclusions pigmented dermatofibrosarcoma protuberans (also called bednar tumor), accounts for less than 5% of all dermatofibrosarcoma protuberans (dfsp), and it is characterized by the presence of melanin-containing dendritic cells within the tumor [1]. diagnosis is insidious, as it may be easily mistaken for other skin tumors, and for these reasons, dermoscopy can assist in the diagnosis. classic dermatofibrosarcoma displays 6 dermatoscopic patterns: thin regular pigmented network, reticular vessels, structureless light-brown areas, white streaks, pink background coloration, and structureless hypo\depigmented 2 research letter | dermatol pract concept. 2023;13(2):e2023117 areas [2]. only a few reports described the dermatoscopic features of its pigmented counterpart. in a study of bernard et al among 15 patients with dfsp, only one had a histological confirmed diagnosis of bednar tumor and displayed all six dermoscopic patterns described above [2] meada et al reported a case of bednar tumor in which dermoscopy displayed only blue whitish veil [3]. the same feature was present in a case of pigmented dermatofibrosarcoma described by ehara et al [4]. lastly, almeida et al described another case of bednar tumor which showed pigmented network, whitish-blue veil, blurry branching vessels and white streaks as principal dermoscopic patterns [5]. the pathologic features of pigmented dermatofibrosarcoma easily correlate to these aforementioned dermatoscopic findings: blue-whitish veil is due to pigmented spindle cells while white streaks are caused by altered collagen fibers. arborizing vessels, generally unfocused, may correlate with the depth of the tumor and its major need for vascularization. moreover, peripheral pigmented network may correspond to pigmented basal keratinocytes, as in dermatofibroma. in different areas this network appeared linearly stretched and this feature could be determined by changes in the rete-ridges induced by exuberant tumor growth. besides the potential value of each single dermoscopic criterion, the presence of all these described features could help in differentiating bednar tumor from the other simulators as basal cell carcinoma, melanoma or hematoma. the diagnosis results more challenging in presence of bluish veil as unique dermatoscopic pattern. we present a case of bednar tumor and report the presence of a new dermatoscopic finding in addition to those previously reported. to confirm these assumptions further evidence is needed. figure 1. (a) presence of bluish indurated plaque of right arm. (b) diffuse proliferation of spindle cells in a storiform pattern. some cells contain abundant melanin. (h&e x4). figure 2. (a,b) diffuse white-bluish pigmentation associated to white streaks (black square). arborizing vessels are present over the entire lesion and are not focused (white square). at periphery, a pigmented network is evident (black arrow). in some part of the lesion this network appears linearly stretched (black circle). research letter | dermatol pract concept. 2023;13(2):e2023117 3 references 1. ishida m, okabe h. fibrosarcomatous pigmented dermatofibrosarcoma protuberans: a case report with review of the literature. oncol lett. 2012;4(3):390-392. doi: 10.3892 /ol.2012.765. epub 2012 jun 19. pmid: 23741240. pmcid: pmc3673649. 2. bernard j, poulalhon n, argenziano g, debarbieux s, dalle s, thomas l. dermoscopy of dermatofibrosarcoma protuberans: a study of 15 cases. br j dermatol. 2013;169(1):85-90. doi: 10.1111/bjd.12318. pmid: 23496114. 3. maeda t, watabe y, yanagi t, et al. dermoscopic features of bednar tumor: report of a case. j dermatol. 2018;45(7):e179-e180. doi: 10.1111/1346-8138.14232. pmid: 29341231. 4. ehara y, yoshida y, shiomi t, yamamoto o. pigmented dermatofibrosarcoma protuberans and blue naevi with similar dermoscopy: a case report. acta derm venereol. 2016;96(2):272-273. doi: 10.2340/00015555-2204. pmid: 26258458. 5. almeida ft, carvalho sd, pereira t, brito c. when a bruise gets important: bednar tumour. bmj case rep. 2019;12(2):e228446. doi: 10.1136/bcr-2018-228446. pmid: 30755432. pmcid: pmc6381944. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023148 1 “stretching dermoscopy” to delineate the margins of basal cell carcinoma on photodamaged telangiectatic skin felipe b. cerci1-3, mara lynda zehnder4, aimilios lallas5, betina werner2,6,7, stanislav nickolaevich tolkachjov8-11 1 mohs curitiba, clínica cepelle. curitiba, brazil 2 post-graduate program – internal medicine and health sciences, universidade federal do paraná, curitiba, brazil 3 dermatology service, hospital universitário evangélico mackenzie, curitiba, brazil 4 department of dermatology, university hospital basel, basel, switzerland 5 first department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece 6 dermatology service, hospital de clínicas da universidade federal do paraná, curitiba, brazil 7 department of pathology, hospital de clínicas da universidade federal do paraná, curitiba, brazil 8 epiphany dermatology, dallas, texas, usa 9 texas a&m college of medicine, dallas, texas, usa 10 department of dermatology, the university of texas at southwestern medical center, dallas, texas, usa 11 division of dermatology, baylor scott & white, dallas, texas, usa key words: dermoscopy, basal cell carcinoma, mohs micrographic surgery, skin cancer, surgical margins citation: cerci fb, zehnder ml, lallas a, werner b, tolkachjov sn. “stretching dermoscopy” to delineate the margins of basal cell carcinoma on photodamaged telangiectatic skin. dermatol pract concept. 2023;13(2):e2023148. doi: https://doi.org/10.5826/ dpc.1302a148 accepted: november 4, 2022; published: april 2023 copyright: ©2023 cerci et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: stanislav n. tolkachjov, md, 1640 fm 544. suite 100 the colony, tx 75056 phone: 972-961-7869 e-mail: stan.tolkachjov@gmail.com introduction dermoscopy is widely used in clinical practice for basal cell carcinoma (bcc) diagnosis and has been shown to accurately predict the tumor subtype [1]. furthermore, dermoscopy was shown to enhance the clinical preoperative assessment of peripheral margins, especially for pigmented bccs [2]. in non-pigmented, the topographic evaluation of the vessels may be an important way to assess the tumor margins. commonly, dermoscopy of non-superficial bcc reveals large linear ramified (arborizing) vessels that are usually well focused and bright red, and superficial bcc displays thinner and shorter vessels, the so-called superficial fine telangiectasias [1]. in contrast, telangiectatic vessels from chronic sun damage are smaller, less focused and dull-red. however, when bcc develops on severely sun-damaged skin with numerous telangiectasias, it might be challenging to discriminate them from tumoral vessels and delineate the tumor [3]. stretching the skin around the tumor has been proposed to improve the assessment of its margins by enhancing the 2 research letter | dermatol pract concept. 2023;13(2):e2023148 macroscopic visualization of the opalescent color that corresponds to the stromal alterations of bcc (figure 1) [4]. although it can be reasonably hypothesized that combining skin stretching with dermoscopy might offer additional information and further improve the assessment of bcc margins, this is not supported by evidence up to date. case presentation we present a case that aims to suggest that combining both techniques might be superior to using each technique alone to delineate bcc margins prior to surgical removal in areas with a telangiectatic background. figure 1a shows an ill-defined infiltrative bcc on the upper cutaneous lip of a 63-year-old female patient and figure 1b depicts the same lesion after skin stretching. in the standard non-contact polarized dermoscopic evaluation, tumor is evaluated without stretching the surrounding skin (figure 2a). in “stretching dermoscopy,” the skin adjacent to the tumor is stretched during dermoscopic examination (figure 2b). with this maneuver, the opalescent white structureless area of the bcc becomes more evident. in addition, the blood flow of the smaller vessels surrounding the tumor is reduced without compromising the larger arborizing vessels of the tumor, enhancing, thus, the discrimination between them (figure 2). the pressure applied with contact dermoscopy can also achieve compression of uv-induced telangiectasias, but it may also compress the tumoral vessels, which are important for the diagnosis. dermoscopy alone has been used for preoperative margin delineation of bcc during classic surgery and also to reduce the number of stages in mohs micrographic surgery (mms), but data on the latter are controversial {5,6]. similarly, skin traction by itself has been described as an important preoperative step to maximize the contrast between bcc and surrounding normal skin during naked eye examination [4]. in the present case, the tumor was cleared after one stage of mms. conclusions we suggest that combining both techniques might be a simple and inexpensive way to enhance the preoperative examination in classic surgery or the first stage of mms. however, our hypothesis needs to be evaluated by further studies assessing whether stretching dermoscopy allows for less incomplete excisions during classic surgery or reduced number of stages in mms. acknowledgment: the patient has given written informed consent to the publication of her case details. figure 1. clinical presentation. (a) 63-year-old female patient, presenting with an ill-defined plaque on the upper cutaneous lip and signs of photodamaged skin as lentigines and telangiectasias in all sun-exposed areas of the face. (b) view when stretching the surrounding skin. research letter | dermatol pract concept. 2023;13(2):e2023148 3 references 1. reiter o, mimouni i, dusza s, halpern ac, leshem ya, marghoob aa. dermoscopic features of basal cell carcinoma and its subtypes: a systematic review. j am acad dermatol. 2021;85(3):653-664. doi: 10.1016/j.jaad.2019.11.008.pmid: 31706938. pmcid: pmc9366765. 2. hurley ar, totty jp, pinder rm. dermoscopy as an adjunct to surgical excision of nonmelanoma skin lesions: a systematic review and meta-analysis. j clin aesthet dermatol. 2022;15(9):45-49. pmid: 36213603. pmcid: pmc9529075. 3. cerci fb, kubo em, werner b, tolkachjov sn. dermoscopy accuracy for lateral margin assessment of distinct basal cell carcinoma subtypes treated by mohs micrographic surgery in 368 cases. int j dermatol. 2022;61(4):e139-e141. doi: 10.1111/ ijd.15655. pmid: 34013989. 4. shalom a, westreich m, schein o, hadad e. stretch test: effectiveness in identifying basal cell carcinoma borders. ann plast surg. 2012;68(1):72-73. doi: 10.1097/sap.0b013e3182119126. pmid: 21629104. 5. yeom sd, lee sh, ko hs, et al. effectiveness of dermoscopy in mohs micrographic surgery (mms) for nonmelanoma skin cancer (nmsc). int j dermatol. 2017;56(6):e136-e139. doi: 10.1111/ijd.13501. pmid: 28247925. 6. jayasekera psa, dodd j, oliphant t, langtry jaa, lawrence cm. dermoscopy prior to mohs micrographic surgery does not improve tumour margin assessment and leads to fewer mohs stages. br j dermatol. 2018;178(2):565-566. doi: 10.1111/ bjd.15903. pmid: 28851098. figure 2. stretching dermoscopy. (a) non-contact polarized dermoscopy of a basal cell carcinoma on the upper cutaneous lip, with a telangiectatic background. (b) dermoscopy after stretching the surrounding tissue. note how the basal cell carcinoma is better visualized contrasting with the surrounding telangiectatic background. (c) the tumor margins as assessed after stretching dermoscopy. (d) demarcation of the tumor boundary before excision. the excision was performed at the outer margin of the black ink. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022172 1 atypical spitz nevus: dermoscopic, confocal microscopic and histopathological correlation rita bouceiro mendes1, camila scharf2, eugenia veronica di brizzi2, andrea ronchi3, giuseppe argenziano2, elvira moscarella2 1 dermatology unit, north lisbon university hospital centre, lisbon, portugal. 2 dermatology unit, university of campania l. vanvitelli, naples, italy. 3 pathology unit, university of campania l. vanvitelli, naples, italy. citation: bouceiro mendes r, scharf c, di brizzi ev, ronchi a, argenziano g, moscarella e. atypical spitz nevus: dermoscopic, confocal microscopic and histopathological correlation. dermatol pract concept. 2022;12(4):e2022172. doi: https://doi.org/10.5826/ dpc.1204a172 accepted: january 14, 2022; published: october 2022 copyright: ©2022 bouceiro mendes et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: rita bouceiro mendes, north lisbon university hospital centre, dermatology department, piso 5, av. prof. egas moniz, 1649-035 lisboa. phone: 00351 969928106, e-mail: rita.bouceiro.mendes@gmail.com case presentation a 12-year-old girl was observed for a new asymmetric pink and black papule on her back. dermoscopy revealed a multicomponent pattern with pink pigmentation, and blue-white veil. by reflectance confocal microscopy (rcm) overall asymmetry was noted. irregular honeycomb pattern of the epidermis and compact dermal nests, matching the pink pigmentation area were evident while, in the blue-white veil dermoscopic area, multiple superficial dendritic cells and an irregular meshwork pattern at the dermal-epidermal junction were seen. considering these findings, surgical excision was performed. histopathological examination disclosed an asymmetric compound proliferation of melanocytic epithelioid cells. its junctional element was predominantly nested, whereas the dermal aspect was highly cellular with fascicles of slightly pleomorphic epithelioid cells throughout the entire dermis. these findings favored the diagnosis of atypical spitz nevus. teaching point atypical spitz nevi represent an intermediate category of melanocytic lesions whose differentiation from melanoma is difficult because of overlapping features [1]. rcm represents a noninvasive diagnostic add-on, but rcm features of atypical spitz tumors are not well characterized [1,2]. confocal features that may help to differentiate spitz nevi from melanoma have already been identified [2]; however, a study from guida et al stated that rcm was not useful in lesions with multicomponent or unspecific dermoscopic patterns since many “malignant” features were shared between both entities [1]. we are able to overcome this gap if we consider the patient age when evaluating a spitzoid lesion. besides that, this case illustrates the rcm features of an atypical spitz nevus with an impressive dermoscopic and histopathological correlation. 2 image letter | dermatol pract concept. 2022;12(4):e2022172 references 1. guida s, pellacani g, cesinaro am, et al. spitz naevi and melanomas with similar dermoscopic patterns: can confocal microscopy differentiate? the br j dermatol. 2016;174(3):610-616. doi: 10.1111/bjd.14286. pmid: 26554394. 2. pellacani g, longo c, ferrara g, et al. spitz nevi: in vivo confocal microscopic features, dermatoscopic aspects, histopathologic correlates, and diagnostic significance. j am acad dermatol. 2009;60(2):236-247. doi: 10.1016/j.jaad.2008.07.061. pmid: 19091443. figure 1. spitz nevus. (a) clinical picture: asymmetric 1cm diameter papule with uneven pink and black color. (b) dermoscopy picture: multicomponent pattern with irregular brown and pink pigmentation, and blue-white veil. (c) confocal microscopy picture: c1 epidermal honeycombed structures and thin dermal papillae; c2 irregular meshwork pattern at the dermal-epidermal junction and associated areas of totally disarranged papillary contours owing to multiple bright fusiform cells with dendrites (white asterisks). (d) histopathological pictures: d1 overall asymmetric polypoid-like melanocytic compound proliferation with an important deep component. the junctional element of the lesion is predominantly nested while the dermal aspect is highly cellular (white asterisk) (h&e, x25). d2 higher magnification showing the cellular dermal component of slightly pleomorphic epithelioid cells organized in fasciles. these cells immunostaining for hmb-45 was positive throughout the entire dermis (h&e, x100). dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023126 1 inverse gottron papules in dermatomyositis maria-elena gimeno-ribes1, daniel morgado-carrasco1 1 dermatology department, hospital clínic de barcelona, universitat de barcelona, barcelona, spain citation: gimeno-ribes me, morgado-carrasco d. inverse gottron papules in dermatomyositis. dermatol pract concept. 2023;13(2):e2023126. doi: https://doi.org/10.5826/dpc.1302a126 accepted: september 26, 2022; published: april 2023 copyright: ©2023 gimeno-ribes et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, dermatology department, hospital clínic de barcelona, spain. tel. (+34) 935 464 710 fax (+34) 935 464 729 e-mail: morgadodaniel8@gmail.com case presentation an otherwise healthy 40-year-old woman, working as a secretary, presented to our clinic complaining of photosensitivity and muscle weakness. physical examination revealed facial erythematous desquamative plaques, and non-tender pale hyperkeratotic papules over the palmar aspect of the interphalangeal joints (figure 1). she was sent to the rheumatology department, where a muscle biopsy was performed, confirming the diagnosis of dermatomyositis. an autoimmunity panel showed positivity for antimi2 antibodies. all other autoantibodies were negative. no malignancies were found on imaging tests. a high-resolution computed tomography of the lungs showed no pathologic findings. prednisone 30 mg/day, methotrexate 15 mg/week and hydroxychloroquine 400 mg/day were started, with resolution of muscular symptomatology after 2 months. facial cutaneous manifestations and photosensitivity showed only partial response. palmar papules persisted during the follow-up (12 months), and antimi2 antibodies remained positive. teaching point dermatomyositis can be associated with a wide range of cutaneous manifestations. inverse gottron papules are keratotic papules located on the flexor aspects of the fingers (distal and proximal interphalangeal joints, and metacarpophalangeal joints), and are an infrequently reported clinical sign of dermatomyositis [1,2]. in some case series, an association between inverse gottron papules and antimda5 antibodies or juvenile dermatomyositis has been reported, and figure 1. inverse gottron papules. pale hyperkeratotic papules over the palmar aspect of interphalangeal joints. 2 image letter | dermatol pract concept. 2023;13(2):e2023126 patients with this clinical sign might have an increased risk of developing interstitial lung disease, and a worse prognosis [1,2]. however, there is scarce literature regarding this manifestation, and clinical implications remain unclear and should be further assessed. regarding physiopathology, inverse gottron papules may be induced by keratinocyte damage secondary to mechanical injury [1]. inverse gottron papules are an infrequent manifestation of dermatomyositis. recognizing this clinical sign can help in the diagnosis of this disorder. references 1. irie k, matsumura n, hoshi m, yamamoto t. inverse gottron’s papules in patients with dermatomyositis: an underrecognized but important sign for interstitial lung disease. int j dermatol. 2021;60(2):e62-e65. doi: 10.1111/ijd.15204. pmid: 32970839. 2. anjani g, govindarajan s, sudhakar m, chaudhary h, rawat a, kumar jindal a. catch the thief by its marks: inverse gottron papules, interstitial lung disease, anti mda-5 antibody positivity in juvenile dermatomyositis. rheumatology. 2021;60(2):e56– e58. doi: 10.1093/rheumatology/keaa433. pmid: 32888028. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e202297 1 a solitary nodule over the chest gitesh sawatkar1, nisha meshram2, keshavamurthy vinay3 1 department of dermatology and venereology, all india institute of medical sciences (aiims), nagpur, india 2 department of pathology, all india institute of medical sciences (aiims), nagpur, india 3 department of dermatology, venereology and leprology, postgraduate institute of medical education and research; chandigarh, india citation: sawatkar g, meshram n, vinay k. a solitary nodule over the chest. dermatol pract concept. 2022;12(3):e202297. doi: https://doi.org/10.5826/dpc.1203a97 accepted: october 26, 2021; published: july 2022 copyright: ©2022 sawatkar et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: dr. keshavamurthy vinay, department of dermatology, venereology and leprology postgraduate institute of medical education and research, sector 12, chandigarh 160012, india. tel: +91-8872993222 e-mail: vinay.keshavmurthy@gmail.com case presentation a 35-year-old male presented with an asymptomatic, subcutaneous mass with an overlying firm, red-brown nodule and shiny stretched skin (figure 1a). on dermoscopy, an accentuated pigment network over background of pinkish color was seen. a few structureless focal white areas were present (figure 1b). histopathology revealed a poorly circumscribed dermal tumor with a clear grenz zone. the tumor consisted of monomorphic spindle cells with elongated hyperchromatic nuclei arranged in fascicles forming a storiform pattern (figure 1c). clinical, dermoscopic and histopathological features confirmed the diagnosis of dermatofibrosarcoma protuberans (dfsp). teaching point dermatofibrosarcoma protuberans presents as an asymptomatic, slowly progressive indurated plaque that subsequently develops nodules. dermoscopic features suggestive of dfsp are: delicate pigment network, vessels, structureless light brown areas, shiny white streaks, pink background coloration, and structureless hypoor depigmented areas [1]. mohs micrographic surgery remains the treatment of choice. imatinib and sorafenib can be employed for unresectable and metastatic dfsp [2]. this report reinstitutes the importance of keen clinical and dermoscopic examination with histopathological correlation for timely diagnosis of this dermal tumor. 2 image letter | dermatol pract concept. 2022;12(3):e202297 references 1. bernard j, poulalhon n, argenziano g, debarbieux s, dalle s, thomas l. dermoscopy of dermatofibrosarcoma protuberans: a study of 15 cases. br j dermatol. 2013;169(1):85-90. doi: 10.1111/bjd.12318. pmid: 23496114. 2. allen a, ahn c, sangueza op. dermatofibrosarcoma protuberans. dermatol clin. 2019;37(4):483-488. doi: 10.1016/j. det.2019.05.006. pmid: 31466588. figure 1. (a) red-brown nodule with overlying shiny stretched skin present over right side of chest. (b) dermatoscopy (dermlite™ dl3 3gen under contact polarized mode) showing pinkish red background and unfocussed vessels (yellow arrow), accentuated pigment network (green arrowhead) and focal white areas (black arrow head). (c) sections shows epidermis with grenz zone and underlying dermal tumor in storiform pattern. entrapped adnexal structure and adipose tissue seen (h&e, 4x). dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(1):e2023006 1 lichen striatus post-covid-19 infection: clinical and dermoscopic presentations filippo chersi1, claudio conforti1, iris zalaudek1, nicola di meo1 1 dermatology clinic of trieste, maggiore hospital, university of trieste, trieste, italy key words: lichen striatus, covid-19, infection, rash citation: chersi f, conforti c, zalaudek i, di meo n. lichen striatus post-covid-19 infection: clinical and dermoscopic presentations. dermatol pract concept. 2023;13(1):e2023006. doi: https://doi.org/10.5826/dpc.1301a6 accepted: april 23, 2022; published: january 2023 copyright: ©2023 chersi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic of trieste, maggiore hospital, university of trieste, trieste, italy. phone: +390403992056 e-mail: claudioconforti@yahoo.com case presentation a 24-year-old female with classic symptoms for covid-19 underwent a rhino-pharyngeal swab test in october 2020 that confirmed the infection. she had been previously vaccinated with two pfitzer vaccine doses in july. nine days after the positive rhino-pharyngeal swab test, the patient came in consultation with small, 1-2 mm elevated pinkish papules that joined together in a slightly scaly, irregular, linear band of about 20 cm following blaschko lines on the medial portion of the left leg (figure 1, a and b). the patient reported that the rash had appeared 2 days after covid-19 symptoms started and that it caused her moderate pruritus. dermoscopy showed a slight erythematous pinkish background and confluent areas of telangiectatic vessels, ruling out other diseases (eg ilven, linear psoriasis or linear darier disease) (figure 1, c and d). a 4-mm punch confirmed the clinical suspicion of ls. ls has a self-limiting nature, with an expected complete recovery. however, because this patient sought treatment, a short course of topical steroids together with antihistamines were prescribed to treat the itch and dryness of the skin. after 6 weeks the patient had no more signs of active disease, and no post-inflammatory hypopigmentation was observed. usually relapses of this condition are uncommon. teaching point few papers have reported ls after covid-19 vaccination [1], but this case shows that also covid-19 infection could be a trigger, although pathophysiological mechanisms and causes underlying this condition are still not completely understood. being a benign self-limiting condition, usually no treatment is required, although low doses of systemic corticosteroids or topical corticosteroids can contribute to provide some benefits in symptomatic patients [2]. 2 image letter | dermatol pract concept. 2023;13(1):e2023006 references 1. conforti c, dianzani c, agozzino m, et al. cutaneous manifestations in confirmed covid-19 patients: a systematic review.  biology (basel). 2020;9(12):449. doi:10.3390/biology9120449. pmid: 33291502. pmcid: pmc7762103. figure 1. (a,b) clinical presentation of lichen striatus post-covid-19 infection: elevated pinkish papules of 1-2 mm joining together in a slightly scaly, irregular, linear band that follows the blaschko lines on the medial portion of the left leg. (c,d)  dermoscopy shows a slight erythematous pinkish background with confluent areas of telangiectatic vessels. 2. charifa a, jamil rt, ramphul k. lichen striatus. in: statpearls. treasure island (fl): statpearls publishing; october 12, 2021. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):12 59 introduction primitive non-neural granular-cell tumor (pngct) is a rare tumor of uncertain lineage. it was first described by le boit et al. [1] as “primitive polypoid granular cell tumor” after analysis of four cases. since then various other names have been proposed. lazar et al. called it “primitive non-neural granular cell tumor” [2] and chaudhry et al. coined the term “dermal non-neural granular cell tumor” [3]. unlike conventional granular cell tumor, pngct is not of neural or schwannian lineage, and the precise line of differentiation is still unclear [2,3]. herein we describe a case of this rare and intriguing entity in which the clinical and dermoscopic pattern guided the management for excision although only histological and immunohistochemical evaluation allowed to make the correct diagnosis. case report a 20-year-old man presented with a small reddish papule on the abdomen, measuring about 2 x 3 mm, surrounded by a faint erythematous halo. the asymptomatic lesion had appeared 4-5 months earlier and had gradually grown in size (figure 1a). it had been bleeding spontaneously for the last 2 weeks. dermoscopic examination revealed diffuse red color, subtle linear vessels and weak whitish striae (figure 1b). clinical examination did not reveal any other nodules or skin lesions. the patient denied any recent weight loss, fatigue or abdominal pain. because of the unspecific clinical and dermoscopic presentation, the lesion was excised for histological and immunohistochemical examination. histological examination revealed a growth consisting of oval and spindle cells with granular cytoplasm (figure 2). a case of primitive non-neural granular cell tumor presenting as a single painless bleeding nodule luca feci1, clelia miracco2, michele fimiani1, pietro rubegni1 1 dept. clinical medicine and immunological sciences, dermatology section, university of siena, siena, italy 2 dept. of oncology, pathology section, university of siena, siena, italy keywords: primitive non-neural granular-cell tumor, dermoscopy, immunohistochemistry citation: feci l, miracco c, fimiani m, rubegni p. a case of primitive non-neural granular cell tumor presenting as a single painless bleeding nodule. dermatol pract concept. 2014;4(2):12. http://dx.doi.org/10.5826/dpc.0402a12. received: november 2, 2013; accepted: december 28, 2013; published: april 30, 2014 copyright: ©2014 feci et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. pietro rubegni, dept. of clinical medicine and immunological science dermatology section, policlinico “le scotte” viale bracci 53100 siena, italy. tel. +39 0577 40190. e-mail: rubegni@unisi.it primitive non-neural granular cell tumor is a rare tumor of uncertain lineage that clinically presents as a solitary painless nodule most typically on the extremity or trunk of an adult. we report the case of a 20-year-old man with a small reddish papule on the abdomen, measuring about 2 x 3 mm, surrounded by a faint erythematous halo. dermoscopy examination shows diffuse red color and weak whitish striae. however, only histological and immunohistochemical evaluation allowed us to perform the correct diagnosis. abstract 60 observation | dermatol pract concept 2014;4(2):12 and factor xiiia and negative for cd31, cd34, desmin, hhf35, s-100, melan a, hmb45, mitf, synaptophysin and cd57 (figure 3). these features confirmed the diagnosis of primitive non-neural granular-cell tumor (pngct). a computer tomographic total body scan was performed to rule out systemic involvement. the patient refused sentinel thickness was about 15 mm. one mitotic figure was observed per mm2 of field; none of the figures were atypical. there was no evidence of junctional component or melanin pigmentation. a panel of immunohistochemical stains was performed. the tumor cells were positive for cd10, cd68, d2-40 figure 1. (a) small red nodule on the abdomen; (b) diffuse structureless red color, fine linear vessels and whitish striae at dermoscopy examination. [copyright: ©2014 feci et al.] figure 2. histological examination showing prominent dermal nodule consisting of oval and spindle cells (original magnification: x50 in h&e). [copyright: ©2014 feci et al.] figure 3. immunohistochemistry showing positivity for: (a) f xiiia (original magnification: x200); (b) d2-40 (original magnification: x200); (c) mib1 (original magnification: x100); (d) cd10 (original magnification: x50); (e) cd68 (original magnification: x200). [copyright: ©2014 feci et al.] observation | dermatol pract concept 2014;4(2):12 61 ma-like dermal melanocytic tumor (s-100+, melanin a+ and hmb45+). although local recurrence has been reported in rare cases and secondary lymph node localizations in 2/30 cases, these tumors are thought to pursue a benign clinical course, and complete excision is currently the recommended treatment. in our case, after the complete excision of the lesion, a computer tomographic total body scan was performed to rule out systemic involvement. the patient refused sentinel lymph node biopsy. twelve months after diagnosis, there was no evidence of local recurrence or systemic disease. acknowledgements dr. luca feci and prof. clelia miracco provided substantial contributions to concept and design, to acquisition of data, and analysis and interpretation of data. dr. luca feci and prof. pietro rubegni drafted the article and revised it critically for intellectual content. prof. michele fimiani provided final approval of the version to be published. references 1. le boit pe, barr rj, burall s, et al. primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin. am j surg pathol. 1991;15(1):48–58. 2. lazar aj, fletcher cd. primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases. am j surg pathol. 2005;29(7):927–34. 3. chaudhry ih, calonje e. dermal non-neural granular cell tumor (so-called primitive polypoid granular cell tumour): a distinctive entity further delineated in a clinicopathological study of 11 cases. histopathology. 2005;47(2):179–85. 4. habeeb aa, salama s. primitive nonneural granular cell tumor (so-called atypical polypoid granular cell tumor). report of 2 cases with immunohistochemical and ultrastructural correlation. am j dermatopathol. 2008;30(2):156–9. 5. zaballos p, carulla m, ozdemir f, et al. dermoscopy of pyogenic granuloma: a morphological study. br j dermatol. 2010;163(6):1229-37. 6. g i a c o m e l j, z a l a u d e k i . p i n k l e s i o n s . d e r m a t o l c l i n . 2013;31(4):649-78. 7. sbano p, nami n, grimaldi l, rubegni p. true amelanotic melanoma: the great masquerader. j plast reconstr aesthet surg. 2010; 63(3):307-8. 8. rubegni p, lamberti a, mandato f, perotti r, fimiani m. dermoscopic patterns of cutaneous melanoma metastases. int j dermatol. 2013 [epub ahead of print] 9. sgambato a, zalaudek i, ferrara g, et al. adnexal tumors: clinical and dermoscopic mimickers of basal cell carcinoma. arch dermatol. 2008; 144(3):426. 10. yeh i, tran dt, davis tl, argenyi zb. an infiltrative variant of non-neural granular cell tumor: a case report. j cutan pathol. 2009. oct;36 suppl 1:46-51. 11. wright na, thomas cg, calame a, cockerell cj. granular cell atypical fibroxanthoma: case report and review of the literature. j cutan pathol. 2009;37(3):380. lymph node biopsy. twelve months after diagnosis, there was no evidence of local recurrence or systemic disease. conclusions pngcts have been reported in a wide age range (5–83 years), with slight female predominance [3,4]. clinically, it presents as a solitary painless nodule, typically on an extremity or the trunk of adults [2]. the reported size range is 0.2–2.8 cm (median 0.5–0.8 cm). configuration is on the whole papulonodular or polypoid and may be ulcerated [2,3]. this makes differential diagnosis with other malignant and benign skin growths particularly difficult. as shown by our single case, dermoscopy does not allow for a correct diagnosis as it reveals unspecific pattern that have been reported in a range of tumors including pyogenic granuloma, amelanotic melanoma, non-pigmented melanoma metastases or other rare adnexal tumors [5-9]. further reports are needed to improve the knowledge about the clinical and dermoscopic variability of this rare tumor. currently a provisional clinical-dermoscopic diagnosis must be sustained by histological examination and immunohistochemistry. microscopically, these lesions do not tend to be encapsulated and are relatively circumscribed dermal nodules without any associated grenz zone. pseudocarcinomatous hyperplasia, which is commonly associated with conventional granular-cell tumors, is generally absent, but epithelial hyperplasia with collarette formation is common [2]. cytologically, the tumors are composed of spindle, oval and polygonal cells with abundant granular eosinophilic cytoplasm. some cases may be cytologically atypical with hyperchromatic nuclei and nucleoli [2]. the mitotic index averages 1—3 per mm2 with occasional atypical forms. cytological atypia and increased mitotic index do not seem to imply a more aggressive clinical course [4]. pngct is a rare tumor and awareness of it is important to avoid misdiagnosis with more sinister entities, leading to over-treatment and unnecessary patient anxiety. in fact, granular changes due to lysosome accumulation can be observed in a variety of neoplasms, including conventional granular-cell tumor, melanocytic neoplasms, smooth muscle neoplasms, dermatofibromas, epithelioid cell histiocytomas, dermatofibrosarcoma protuberans, fibrous papules, basal cell carcinomas, atypical fibroxanthomas, angiosarcomas, malignant fibrohistiocytomas, perineuromas and metastatic carcinomas [10,11]. this granular cell change usually involves only part of the lesion, allowing differentiation by conventional morphological and immunohistochemical criteria [3]. immunohistochemistry is fundamental for differential diagnosis with conventional granular cell tumors (s-100+), epithelioid cell histiocytoma (cd68-) and paragangliohttp://www.ncbi.nlm.nih.gov/pubmed?term=zaballos p%5bauthor%5d&cauthor=true&cauthor_uid=20846306 http://www.ncbi.nlm.nih.gov/pubmed?term=carulla m%5bauthor%5d&cauthor=true&cauthor_uid=20846306 http://www.ncbi.nlm.nih.gov/pubmed?term=ozdemir f%5bauthor%5d&cauthor=true&cauthor_uid=20846306 http://www.ncbi.nlm.nih.gov/pubmed/20846306 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http://www.ncbi.nlm.nih.gov/pubmed?term=perotti r%5bauthor%5d&cauthor=true&cauthor_uid=24320196 http://www.ncbi.nlm.nih.gov/pubmed?term=fimiani m%5bauthor%5d&cauthor=true&cauthor_uid=24320196 http://www.ncbi.nlm.nih.gov/pubmed/24320196 http://www.ncbi.nlm.nih.gov/pubmed/24320196 http://www.ncbi.nlm.nih.gov/pubmed?term=sgambato a%5bauthor%5d&cauthor=true&cauthor_uid=18347310 http://www.ncbi.nlm.nih.gov/pubmed?term=zalaudek i%5bauthor%5d&cauthor=true&cauthor_uid=18347310 http://www.ncbi.nlm.nih.gov/pubmed?term=ferrara g%5bauthor%5d&cauthor=true&cauthor_uid=18347310 http://www.ncbi.nlm.nih.gov/pubmed/18347310 http://www.ncbi.nlm.nih.gov/pubmed/18347310 http://www.ncbi.nlm.nih.gov/pubmed?term=yeh i%5bauthor%5d&cauthor=true&cauthor_uid=19187104 http://www.ncbi.nlm.nih.gov/pubmed?term=davis tl%5bauthor%5d&cauthor=true&cauthor_uid=19187104 http://www.ncbi.nlm.nih.gov/pubmed?term=argenyi zb%5bauthor%5d&cauthor=true&cauthor_uid=19187104 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022087 1 dermatology practical & conceptual introduction verrucous epidermal nevus (ven) is hamartoma characterized by hyperplasia of keratinocytes. some cases of secondary tumors developing in ven have been reported, but adnexal tumors are infrequent, especially coexistence of more than one type of adnexal tumors. we report a case of syringocystadenoma papilliferum (scap) and multiple eccrine poromas (ep) arising in a ven, and the dermoscopic and ultrasonic features of these lesions. case presentation a 28-year-old woman had the band-like, light-brown verrucous plaque on her right leg since birth, with no symptoms. syringocystadenoma papilliferum and eccrine poroma arising in verrucous epidermal nevus: a case report and multidimensional skin imaging evaluation shan zhang1, jie liu1 1 department of dermatology, state key laboratory of complex severe and rare diseases, peking union medical college hospital, chinese academy of medical science and peking union medical college, national clinical research center for dermatologic and immunologic diseases, beijing, china key words: verrucous epidermal nevus, syringocystadenoma papilliferum, eccrine poroma, dermoscopy, high-frequency ultrasound citation: zhang s, liu j. syringocystadenoma papilliferum and eccrine poroma arising in verrucous epidermal nevus: a case report and multidimensional skin imaging evaluation. dermatol pract concept. 2022;12(2):e2022087. doi: https://doi.org/10.5826/dpc.1202a87 accepted: october 4, 2021; published: april 2022 copyright: ©2022 zhang et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this work is supported by grants from national natural science foundation of china (no. 82173449) and the non-profit central research institute fund of chinese academy of medical sciences (no. 2019xk320024). competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: jie liu, department of dermatology, state key laboratory of complex severe and rare diseases, peking union medical college hospital, chinese academy of medical science and peking union medical college, national clinical research center for dermatologic and immunologic diseases, no.1 shuaifuyuan wangfujing dongcheng district, beijing, china 100730. e-mail: liujie04672@pumch.cn four years ago, a hemispherical nodule, with erosion and bleeding recurrently, and multiple pink to violaceous papules gradually developed on the preexisting lesion. clinical examination revealed a band-like, light-brown plaque, extending from the middle of the right thigh to the dorsum of the right foot. on the popliteal fossa, there was a black-brown verrucous hyperplastic plaque of 10 cm in length, without erosion or exudation (figure 1a). skin biopsy revealed ven. on the right medial malleolus, there was a red nodule of 1.5 cm in diameter with erosions and yellowish crusts (figure 1b). dermoscopy revealed pinkish-white ulcerated areas, polymorphic vessels and yellow crusts (figure 1c). ultrasound showed a superficial dermal lesion with regular shape, well-defined margin and heterogeneous internal echo, 2 research letter | dermatol pract concept. 2022;12(2):e2022087 and superficial hyperechoic focus (figure 1d). histopathologic examination revealed endophytic tumor extended from the epidermis with intraluminal papillary fronds, which were lined by a bilayer. dense infiltrate of lymphocytes and plasma cells and decapitation secretion could be seen (figure 1, e and f). it was consistent with scap. on the medial of the right lower leg and knee, there were 3 pink to violaceous papules (figure 2, a and b). under dermoscopy, white streaks, short linear, coiled and looped vessels with yellow background were observed (figure 2c). ultrasound showed well-defined, oval-shaped dermal lesions with heterogeneous internal echo and hyperechoic spots (figure 2d). these papules had a similar appearance under microscopy. well-circumscribed dermal neoplasms continuous with the epidermis. ductal differentiation was noted. (figure 2, e and f). the diagnosis of ep was made. the tumors were resected and the patient was still under follow-up. discussion ven derive from hyperplasia of keratinocytes, unlike organoid epidermal nevi, secondary tumor is relatively infrequent, and most of them are epithelial tumors [1,2]. however, scap and ep are both benign adnexal neoplasms, which are quite rare in ven. to the best of our knowledge, the case of scap and ep successively developed in a ven has not been documented previously. we applied non-invasive skin imaging techniques in the diagnosis. we observed the dermoscopic feature of polymorphous vascular pattern, a sign of malignancy. it indicated a biopsy should be performed. the ultrasound showed the lesions were in the superficial dermal with well-defined margin, which indicated that they tended to be benign conditions and helped assess the excision extension. conclusions we reported a quite rare case of scap and ep arising in a ven. we applied dermoscopy and high-frequency ultrasound in the evaluation, and demonstrated the multidimensional skin imaging features of scap and ep. figure 1. (a) clinical presentation: light-brown plaques extending from the middle of the right thigh to the right foot. (b) clinical presentation: a red nodule of 1.5 cm in diameter on the right medial malleolus with erosions and yellowish crusts. (c) dermoscopically, polymorphic vessels were seen within the pinkish-white ulcerated areas, with yellow crusts. (d) high-frequency ultrasound showed a superficial dermal lesion with regular shape, well-defined margin and heterogeneous internal echo, and superficial hyperechoic focus (white circle) (50 mhz). (e) histopathology showed papillomatosis of the epidermis. endophytic tumor extended from the epidermis with intraluminal papillary fronds (h&e staining; original magnification, ×40). (f) the fronds are lined by double-layered epithelium, with basal cuboidal cells and apical columnar apocrine cells. dense infiltration of lymphocytes and plasma cells in the cores of fronds and decapitation secretion were noted (h&e staining; original magnification, ×100). research letter | dermatol pract concept. 2022;12(2):e2022087 3 figure 2. (a,b) clinical presentation: 2 violaceous papules on the medial of the right knee, and one pink papule on the lower leg (black arrows). (c) dermoscopy showed white streaks, short linear, coiled and looped vessels, with yellow background. (d) ultrasound revealed a well-defined, oval-shaped dermal lesion with heterogeneous internal echo and hyperechoic spots (50 mhz). (e) epitheliomatous hyperplasia of the epidermis, well-circumscribed dermal neoplasms continuous with the epidermis. inflammatory cells infiltrated in the superficial dermis (h&e staining; original magnification, ×40). (f) ductal differentiation was noted (h&e staining; original magnification, ×100). references 1. yarak s, machado ty, ogawa mm, almeida ml, enokihara mm, porro am. squamous cell carcinoma arising in a multiple verrucous epidermal nevus. an bras dermatol. 2016;91(5 suppl 1):166-168. doi:10.1590/abd1806-4841.20164506. pmid: 28300931. pmcid: pmc5325030. 2. jeon j, kim jh, baek ys, kim a, seo sh, oh ch. eccrine poroma and eccrine porocarcinoma in linear epidermal nevus. am j dermatopathol. 2014;36(5):430-432. doi:10.1097/ dad.0000000000000012. pmid: 24803063. dermatology: practical and conceptual cutaneous squamous cell carcinoma: an update on diagnosis and treatment table of contents risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio, giulia briatico, cristina pellegrini, tea rocco, elvira moscarella, maria concetta fargnoli surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez, francisca silva-clavería, almudena fernández-orland, noemí eiris, andrés ruiz de casas, lara ferrándiz radiotherapy in the adjuvant and advanced setting of cscc paolo muto and francesco pastore immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh, daniel morse, jigar patel, michael r. migden treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi, luigi lorini mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples, italy guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s2):e2021167s 1 surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez1, francisca silva-clavería1, almudena fernández-orland1, noemí eiris1, andrés ruiz de casas1, lara ferrándiz1 1 department of medical-&-surgical dermatology. university hospital virgen macarena. medicine school, university of sevilla. seville, spain. key words: cutaneous squamous cell carcinoma, surgery, oncologic surgery, mohs surgery, nodal surgery, nodal metastases citation: moreno-ramírez d, silva-clavería f, fernández-orland a, eiris n, ruiz de casas a, ferrándiz l. surgery for cutaneous squamous cell carcinoma and its limits in advanced disease. dermatol pract concept. 2021; 11(s2):e2021167s. doi: https://doi.org/10.5826/ dpc.11s2a167s. accepted: september 8, 2021; published: october, 2021 copyright: ©2021 moreno-ramírez et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: david moreno-ramírez, md, prof. chairman of the department of medical-&-surgical dermatology, professor of dermatology. university hospital virgen macarena medicine school, university of sevilla. seville, spain. email: dmoreno@us.es this article is part of the dpc journal special issue cutaneous squamous cell carcinoma: an update on diagnosis and treatment guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. surgery remains the first-line therapeutic option for most patients with cutaneous squamous cell carcinoma (cscc). however, in the current therapeutic landscape, surgery must attempt to the complete tumor resection (r0 resection) with the lowest risk of surgical complications. this double aim is usually accomplished through standard excision with clinical margins in patients with low-risk tumors or by some of the micrographically controlled surgery procedures for patients with tumors at high-risk of local recurrence and metastasis. surgery is also a first-line treatment for nodal metastases of cscc abstract 2 review | dermatol pract concept. 2021; 11(s2):e2021167s surgery: still the front-line treatment for cutaneous squamous cell carcinoma the therapeutic landscape for non-melanoma skin cancer has evolved significantly in recent years. however, surgery remains the first-line therapeutic option for most patients with non-melanoma skin cancer, which includes basal cell carcinoma and cutaneous squamous cell carcinoma (cscc) [1,2]. although no clinical trial or systematic reviews have addressed the effectiveness of surgery for cscc, most primary tumors can be safely approached through surgical excision [2]. surgical excision offers high-cure rates and long-term control of primary cscc and is indeed the treatment of choice for most patients with cscc, as also recommended by international guidelines [2-4,6]. given the leading role of surgery for cscc and the need for individualized approaches for patients, this article addresses the surgical issues that are under debate in the literature and in multidisciplinary tumor boards. what is appropriate surgical excision? aims of cscc surgery and appropriate surgery for primary tumors r0 surgery, that is the clinical and complete microscopic resection of the tumor, is the main goal of oncologic surgery. with the current availability of non-surgical therapeutic options for cancer, however, this goal should be adapted based on the oncologic effectiveness and the patient’s acceptance in terms of morbidity. thus, appropriate surgery for cscc has the objective to achieve r0 resection but also to preserve function and quality of life as much as possible [5]. if all these criteria cannot be met via surgical procedure, alternative therapies, such as radiation therapy and systemic therapy, should be considered. decisions on the most appropriate surgery for cscc should start with a comprehensive assessment of the tumor’s clinical and pathological features. these tumor features, in addition to other patient-related characteristics, provide information on the risk of local recurrence and metastasis, helping to classify tumors into low-risk and high-risk groups (table 1) (figure 1) [2,4,6]. the optimal surgical procedure for patients with cscc will fit the tumor’s risk profile, and the therapeutic goals (r0 surgery) can be accomplished through standard surgical resection with clinical margins, or through micrographically controlled surgery (mcs) (figure 1) [2-4]. standard excision with clinical margins standard excision with clinical margins and a postoperative pathological evaluation of the margins are recommended for primary cscc without high-risk features and for patients with high-risk tumors who are not suitable for or cannot access mcs [3, 4, 7]. in general, retrospective analyses, prospective observational studies and pooled analysis of observational studies on standard surgery with clinical margins of head and neck cscc, have reported 5-year recurrence-free survival rates above 90% and recurrence rates below 6% [8, 9]. the appropriate clinical margins to be applied have been explored in various studies assessing the cure rates of a variety of margin thresholds based on tumor risk features. accordingly, 95% of tumors < 2 cm with well-defined borders have been reported to be successfully managed with 4 mm clinical margins, whereas tumors > 2 cm require clinical margins of at least 6 mm to achieve histologically clear margins in 95% of cases [4]. if additional high-risk features are present, the clinical margins can increase up to 9 mm. in general, the larger the tumor the higher the number of tumor risk factors (eg, poor differentiation, high-risk location, perineural invasion), and the wider the clinical margin to be applied. the european association of dermato-oncology (eado) guidelines recommend clinical margins of 5 mm for low-risk cscc and 6–10 mm for those tumors with accepted high-risk features, provided that mcs is unsuitable or unavailable [3]. the national comprehensive center networks guidelines recommend 4–6-mm clinical margins and postoperative margin assessment for low-risk tumors, whereas wider margins are preferred for high-risk tumors. however, these guidelines do not specify the clinical margins to be applied for high-risk tumors due to the variability that these tumors encompass and therefore recommend individualized margins adapted to tumor and patient-related factors [11]. table 2 shows a summary of these recommendations. in contrast to lateral clinical margins, the current guidelines offer no concrete recommendations for managing deep margins beyond including the subcutaneous tissue while sparing the perichondrium or periosteum, provided that there as well as an option to consider in patients who develop recurrences while receiving immunotherapy, or as a palliation procedure in patients with advanced tumors. neoadjuvant immunotherapy, that is the use of a medical treatment before surgery, is under investigation in patients with cscc. the decision-making process and guidelines recommendations regarding cscc surgery are reviewed in this manuscript. review | dermatol pract concept. 2021; 11(s2):e2021167s 3 table 1. clinical and pathological criteria for the definition of cutaneous squamous cell carcinoma at high-risk of recurrence eado guidelines [6] • tumor diameter > 20 mm • localization on temple, ear, lip area • thickness > 6 mm or invasion beyond subcutaneous fat • poor grade of differentiation • desmoplasia • microscopic, symptomatic, or radiological perineural invasion • bone erosion • immunosuppression nccn guidelines [4] • size 2 cm to < 4 cm on the trunk, extremities • head, neck, hands, feet, pretibial, and anogenital (any size) • poorly defined • recurrent tumor • immunosuppression • site of prior radiation therapy or chronic inflammatory process • rapidly growing tumor • neurologic symptoms • histologic features: acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtype • perineural involvement • very high-risk: • ≥ 4 cm (any location) • poor differentiation • > 6 mm or invasion beyond subcutaneous fat • desmoplastic scc • tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥ 0.1 mm • lymphatic or vascular involvement patient with cutaneous squamous cell carcinoma consider nonsurgical options staging low-risk tumor2 yes yes no no high-risk tumor2 micrographically controlled surgery (mcs)3 standard resection with 10 mm clinical margins standard resection with 4-6mm clinical margins incomplete resection (r1)4 re-excision complete resection (r0) consider rt innonsurgical candidates follow-up • patient suitable for surgery1. • tumor resectable and amenable to r0 resection. • surgical procedure acceptable by the patient. • radiation therapy • cemiplimab • clinical trials • others • ct-scan or mri, for local assessment (deep, perineural, or vascular invasion). ct-scan preferred for suspicion of bone invasion. mri preferred for suspicion of perineural invasion. • ct-scan and regional ultrasound for regional lymph assessment. • ct-scan or pet scan if suspicion of extensive or at distance disease. • consider adjuvant rtif microscopic or clinical perineural invasion r0 resection suitable for reconstruction through linear closure, second intention, grafting surgical defect expected to require a flap mcs techniques not available figure 1. decision algorithm for the surgical management of patients with primary cutaneous squamous cell carcinoma. (a) ecog-ps 0-2, acceptable overall condition, lack of non-controlled major cardiovascular or hematologic morbidities. (b) assessment of accepted high-risk criterion (table 1). (c) micrographically controlled surgery always preferred as first option in high-risk tumors. intraoperative frozen-section assessment or paraffin-embedded sections with delayed closure techniques based on tumor-, patient-related features, and availability of the procedures. (d) for definition of incomplete resection see the text. 4 review | dermatol pract concept. 2021; 11(s2):e2021167s table 2. guidelines recommendations concerning surgery of primary cutaneous squamous cell carcinoma (cscc) patients eado guidelines [3, 6] • low-risk cscc should be excised with a clinical safety margin of 5 mm. • high-risk cscc should be excised with a clinical safety margin of 6-10 mm or by mms/ mcs. this margin should fall within the 6to 10 -mm range and be based on individual risk assessment and a constellation of tumorand patient-related characteristics. • as long as an r0 resection is not histologically confirmed, wound closure with local tissue movements (flaps) should be avoided. • in case of positive margins, a re-excision shall be done, for operable cases. nccn guidelines [4] low-risk cscc: • standard excision with 4to 6-mm clinical margins and postoperative margin assessment and second intention healing, linear repair, or skin graft. • closures like adjacent tissue transfers, in which significant tissue rearrangement occurs, are best performed after clear margins are verified • positive margins: mohs micrographic surgery (mms) or other forms of ccpdma. standard re-excision if clinically feasible. • negative margins: follow-up. high-risk or very-high-risk cscc: • mms or other forms of ccpdma (preferred for very high risk). • standard excision with wider surgical margins and postoperative margin assessment and linear or delayed repair. due to the wide variability of clinical characteristics that may define a high-risk tumor, it is not feasible to recommend a defined margin for standard excision of high-risk cscc. • positive margins: re-resect, mms or other forms of ccpdma, if feasible. • negative margins: if extensive perineural, large, or named nerve involvement, or if other high-risk features consider adjuvant radiation therapy. mms=mohs micrographic surgery; mcs= micrographically controlled surgery; ccpdma=complete circumferential peripheral and deep margin assessment. is no clinical involvement of the aforementioned structures. [3]. this recommendation applies to ear cscc. if the perichondrium is not clinically involved, the structure should be kept untouched, representing the deepest margin of resection. subcutaneous tissue should be resected, particularly when dealing with ear and scalp tumors, up to the periosteum or perichondrium level, sparing these structures if not clinically involved. however, a recent study analyzing the rate of incomplete excision in cscc showed that residual disease was located at the depth of the surgical specimen rather than in the lateral resection margins [7]. in this study, the overall incomplete excision rate was 7.6%, with 94% of incomplete excisions involving the deep margin. these results led the authors to suggest that if intraoperative frozen sections are not performed, superior deep clearance can be achieved by excising an extra deep fascial plane of tissue, even in the presence of a macroscopically clear deep plane [7]. micrographically controlled surgery micrographically controlled surgery (mcs) involves the intraoperative examination of the tumor’s resection borders through frozen sections. this is done to confirm, the tumor’s complete removal, prior to the incision closure [12]. mcs also avoids the unnecessary removal of uninvolved tissue, which is important for tumors located in critical anatomical sites [3,12] mohs micrographic surgery (mms) was the first technique developed to meet the aims of ensuring complete tumor removal and avoiding the unnecessary excision of healthy tissue [13]. since its introduction, mms has been considered the first-line surgical procedure for locally invasive, high-risk skin cancers’ removal. mms is especially useful when maximal preservation of unaffected tissue is essential. classic mms is a day surgery procedure performed under local anesthesia and involves the following steps: mapping the procedure, debulking the primary tumor, tissue layers’ excision, frozen section processing and analysis, re-excisions of further tissue from involved areas, and reconstruction of the surgical defect. the most common cancers treated with mms are basal cell carcinoma and cscc, although mms is also employed to remove other skin cancers such as dermatofibrosarcoma protuberans, merkel cell carcinoma, and lentigo maligna. with respect to cscc, a prospective multicenter case series showed a 5-year recurrence rate after mms of 3.9%. the recurrence rate was 2.6% in patients with primary scc and 5.9% for patients with previously recurrent scc (p < 0.001). in view of this low 5-year recurrence rate, the authors emphasized the importance of margin-controlled excision for scc. a recent retrospective cohort study of patients with a scc treated with mms or standard excision also showed an review | dermatol pract concept. 2021; 11(s2):e2021167s 5 8% recurrence risk after standard excision, higher than the 3% after mms, and a higher cumulative incidence of recurrence for standard excision than for mms during the entire follow-up period. carcinomas treated with mms were at a 3-fold lower risk of recurrence than those treated with standard excision when adjusted for tumor size and deep tumor invasion (adjusted hazard ratio (hr) 0.31, 95% confidence interval 0.12–0.66) [13, 14, 15]. in cscc, however, tumor extensions can be better assessed in paraffin sections, and there is the likelihood of false-negative results in frozen sections. paraffin-embedded section assessment with deferred closure has therefore been favored for patients with high-risk cscc, using techniques that allow for complete circumferential peripheral and deep circumferential margin assessment (ccpdma or 3d surgery) [4, 12, 16, 17]. these procedures are also particularly appropriate for patients with tumors requiring general anesthesia. table 2 provides a summary of the recommendations for mms and other mcs, ccpdma and 3d surgery for cscc. surgical defect reconstruction another essential issue after conventional cscc surgery is the reconstruction procedure. appropriate closure after cscc resection provides proper tissue coverage of the surgical defect, restores the function and cosmetic appearance of the anatomical region, and allows for early detection of potential local recurrence. these are particularly relevant issues for tumors removed through conventional surgery with clinical margins, a procedure that, as mentioned, cannot ensure the complete removal of the tumor. consequently, any reconstruction technique that involves tissue movement or rearrangement, particularly rotation, or that provides thick coverage of the surgical defects should be avoided if clear resection margins are not histologically confirmed [3]. after standard surgery with clinical margin resection and linear closure, second intention healing and thin skin grafting are the preferred closure procedures [3,4]. if local flaps or more complex reconstruction techniques are expected, an intraoperative surgical margin assessment is essential (table 2). when primary cscc surgery fails management of r1 tumor resection standard resection with clinical margins and postoperative microscopic control of the margins entails the major risk of incomplete resection. depending on the study, incomplete excision (r1 resection) has been defined for the standard vertical bread-loaf technique as follows: the presence of tumor cells at the surgical lateral or deep margin, the presence of residual tumor within 0.5–1 mm or “close to” the margins of the excised specimen, or a tumor-free margin ≤ 2 mm [14, 19, 20]. a recent systematic review showed an overall incomplete excision rate of 13% for cscc on head and neck, and other body locations [20]. head-and-neck locations, tumor depth and size, invasive growth, and re-excision were indicated as the risk factors for incomplete excision [20]. another study identified perineural invasion due to subclinical spread below and beyond the cutaneous margin as a predictor of incomplete resection [19]. the need for re-excision of incompletely excised non-melanoma skin cancers has been a matter of debate. incomplete excision of cscc leads to an increased risk of local recurrence, deep subclinical progression, and metastasis, prompting current guidelines to recommend re-excision of those csccs with positive resection margins, particularly with deep margin involvement, except for patients unwilling or unfit to undergo another surgical procedure [3,4]. re-excision of incompletely resected tumors often yields clean margins. re-excision specimen might however not contain tumor cells and still, there is evidence for up to 5% of patients with negative re-excisions who developed local recurrence [18-20]. due to the methodological issues related to the heterogeneous concept of incomplete excisions, the rate of residual tumor cells in re-excision specimens ranges from 29% to 100% [19, 20]. additionally, there is evidence of a lower degree of differentiation in re-excision histology reports compared to the primary excision specimen [19]. as with primary surgery, cscc should also be adapted to the tumor’s risk profile. regardless of the tumor’s risk, however, an mcs procedure with frozen or permanent sections is preferred as the surgical option for incompletely resected cscc. if not available or if the patient is unsuitable, patients with low-risk tumors can be managed through standard re-excision with postoperative margin assessment. appropriate clinical margins for these re-excisions have not been defined but should be based on the extension of the primary specimen’s margin involvement, after considering tissue shrinkage during the process [3,4]. patients with incompletely resected high-risk tumors should always undergo an intraoperative or delayed mcs procedure (table 2). surgery beyond primary cscc surgical management of lymph node metastasis of cscc in patients with cscc, regional nodal disease represents a major event in up to 4% and 6% of patients overall, a rate that increases if the primary tumor is at high risk and is in an advanced stage [21, 22]. however, the survival of patients with nodal metastases is not necessarily poor. five-year disease-specific survival for patients with low-burden single nodal metastasis (stage i) is approximately 90%, a survival rate that falls to 75% and 42% for patients with multiple and large-burden metastases (stage ii and iii, respectively) [21]. given that these results have been classically achieved through lymph node dissections, it appears that regional 6 review | dermatol pract concept. 2021; 11(s2):e2021167s lymph node surgery still plays a role in the routine management of nodal regional disease. however, most of the available literature related to nodal surgery of cscc refers to head-and-neck tumors, with few references to tumors in other body sites. there is a lack of high-quality studies, randomized clinical trials, and large prospective cohort studies. recommendations on managing regional nodal basins are therefore mostly based on low-tomedium levels of evidence [3]. sentinel lymph node biopsy in patients with cscc: is it worth performing? to date, there have been no randomized clinical trials that have assessed the role of sentinel lymph node biopsy (slnb) in patients with cscc in terms of survival, regional control, or any other outcome. the available evidence comes from a number of small prospective series and systematic reviews of retrospective studies that have reported a positive slnb rate of 12%–17% [23-26], rates below the rates of positive sentinel lymph nodes in patients with melanoma and intermediate thickness tumors (16%–20%), a subgroup of patients with melanoma for whom slnb is the standard of care and a widely recommended procedure [27, 28]. in terms of survival outcomes, the reported results on the prognostic ability of slnb for patients with cscc are also conflicting, with a number of studies showing improved disease-specific survival in slnb-negative patients, whereas other series have failed to demonstrate any survival benefit in patients without microscopic nodal disease when compared with those with positive slnb [24, 29, 30]. slnb eligibility for patients with cscc is usually determined by 2 additional clinical features that frequently coincide in these patients: age and anatomical location. between 75% and 90% of these tumors originate at the level of the head and neck, an anatomical location where surgeons faced specific challenges when compared with, for instance, trunk and limbs. head and neck tumors usually have more complicated lymphatic drainage patterns, with a high frequency of bilateral and contralateral drainage. in this region, lymph nodes are more often tiny and usually overlap each other. this makes anatomical and gammagraphic inspection/identification more difficult compared with other anatomical locations [31]. head and neck melanomas, for instance, are well known to be associated with the non-visualization of sentinel lymph nodes (slns) on lymphoscintigraphy, higher false negative slnb rates, and lower slnb positivity [32]. moreover, the surgical anatomy of the neck is challenging, and, in the case of the parotid gland where 70% of head and neck sccs drain, its relationship with facial and accessory nerves requires a thorough analysis of the risk-benefit balance. the literature on slnb in patients with melanoma has also shown that increasing age is related to lower slnb positivity rates, slower lymphatic drainage, and greater surgical risk related to the poorer performance status of elderly patients [31, 33]. for all these reasons, the currently available results, the poor evidence, and other technical and clinical issues, the current guidelines do not recommend slnb as a routine procedure for managing cscc patients, except for clinical trial settings (table 3). complete lymph node dissection: an opportunity to preserve when left untreated, nodal disease is necessarily progressive and can become distressing and life-threatening for cscc patients. accordingly, the guidelines definitely recommend performing therapeutic lymph node dissection as a routine procedure in patients with nodal recurrence, detected either clinically or by imaging [3,4]. evidence supporting this recommendation is not outstandingly strong, as this is based on a single prospective series, several retrospective studies, and systematic reviews of these studies, all of which analyzed exclusively cutaneous head and neck tumors [35, 36]. nevertheless, skin cancer clinics should focus their efforts on the early detection of lymph node metastases for possible surgery of low-burden metastatic disease, with the expectedly lower surgical morbidity. close follow-up of regional table 3. guidelines recommendations concerning lymph node surgery of cutaneous squamous cell carcinoma (cscc) patients eado guidelines [3,6] • slnb is currently not recommended in the management of cscc outside of the setting of clinical trials. • a regional therapeutic lymph node dissection should be performed in clinically or radiologically detected lymph node metastasis that is confirmed with cytology or biopsy. • the extent of surgical resection is determined by the surgeon in collaboration with the interdisciplinary tumour board. nccn guidelines [4] • discuss and consider slnb for patients with very-high-risk csccs that are recurrent or have multiple risk factors placing them in very-high-risk group and have normal exam of draining nodal basin. • palpable regional lymph node(s) or abnormal lymph nodes identified by imaging studies: lymph node dissection in operable disease. slnb=sentinel lymph node biopsy. review | dermatol pract concept. 2021; 11(s2):e2021167s 7 basins using ultrasound has gained interest as a routine imaging procedure for the early detection of nodal metastasis (figure 2-3) [4]. another issue for patients with nodal metastasis is the appropriate extent of the dissection. patients with cscc and nodal involvement have usually undergone complete radical lymph node dissections of the involved regional basin, which involves the 3 levels of the axillar basin, the superficial and deep groin nodes, and the 5 levels of the neck. additionally, complete dissections in the neck are often completed with superficial parotidectomy if the parotid gland is affected. however, over the last decade, a trend towards the consideration and offer of less extensive and more selective lymph node dissections has developed, with cscc patients. the few available studies on selective neck dissections have shown regional control and survival rates of 85%–100%, rates similar to those reported for conventional radical and modified radical neck dissections [37, 38]. thus, selective neck dissection appears to provide an oncologically effective and safe surgical procedure for those patients with clinically positive nodes in the neck and with no other high-risk clinical feature. this also applies to patients with low or intermediate nodal burden, non-fixed or with no muscles or major vessel invasion, although these features should unfailingly lead to radical and complete neck dissection. to date, there are still no studies on selective groin or axillary dissections in patients with cscc. in any case, the extent of lymph node dissections should be discussed and determined by the surgical team in the context of an interdisciplinary tumor board and after a thorough assessment of tumor-related (aggressiveness, involved regional basin, tumor burden, etc.), surgical (potential complications, morbidity, etc.), and patient-related features (overall condition, performance status, preferences, expectations, etc.). table 3 shows a summary of the recommendations for the surgical management of lymph node regions. when not to operate. the limits of surgery for patients with cscc in 2021 surgery for patients with advanced cscc in line with the famous quote “the best surgeons are those who know when not to operate”, major and radical procedures causing major anatomic mutilation or physical disfiguration, in an attempt to achieve oncological results, should no longer be first-line options for cscc patients [39]. thus, if figure 2. lymph node metastasis of cutaneous squamous cell carcinoma on the right arm. (a) regional ultrasound shows a 17 mm hypoecoic structure also identified in the pet-ct scan. (b) the patient undewent right axillary lymph node dissection. figure 3. lymph node metastasis of cutaneous squamous cell carcinoma from a primary tumor on the right sole. (a) ct-scan shows a well defined 20 mm nodule on the right superficial groin (white asterisk). (b) regional ultrasound showed an anecoic rounded structure. the patient underwent a groin lymph node dissection. 8 review | dermatol pract concept. 2021; 11(s2):e2021167s there is a clinical situation in which the role of surgery needs to be revisited, such as for other skin cancer types, it is that of patients with advanced disease. advanced cscc usually encompasses the following 2 clinical contexts: 1) unresectable primary, recurrent, or metastatic tumors due to a large tumor burden, invasion of major vessels, neural or bone underlying structures hampering r0 resection, and 2) tumors or metastasis for which complete resection unfailingly entails a major anatomical defect, or a functional or cosmetic impairment that is unbearable for the patient (figure 4). these clinical contexts usually present in patients with additional conditions, favoring the tumor growth over long periods before seeking the needed care (neglected patients, lack of caregivers, etc.), or render patients more prone to aggressive invasion due to immunosuppression (organ recipients, lymphoproliferative conditions, etc.), genetic disorders (ie xeroderma pigmentosum), or local factors (ie previous radiation therapy and burns) (figure 5). considering the current therapeutic landscape, the presence of these criteria for advanced cscc should be accepted as the real limit for surgery as front-line therapy for patients with cscc. accordingly, the current recommendations on these clinical settings indicate radiation therapy, systemic therapy with the recently approved anti-pd1 antibody cemiplimab, and clinical trials as first-line therapeutic options for patients with advanced cscc [3,4]. however, there are still 3 situations for patients with advanced cscc in which surgery is likely to play a significant role. the first is when the patients are undergoing immunotherapy or other systemic therapies and develop further resectable recurrences. determining the appropriate therapy for those cancers for which immunotherapy is available should be a dynamic process far from the classical binary figure 4. advanced cutaneous squamous cell carcinoma (cscc). a 70-year old man with unresectable lymph node metastasis on the groin from a previously resected high-risk cscc arising on a previously radiated area on the left heel. figure 5. advanced cutaneous squamous cell carcinoma (cscc). (a) a 32-year old man with dystrophic epidermolysis bullosa who developed an unresectable cscc over a chronic wound on the left hand stump. the patient underwent amputation. (b) a 50-year old man with polyomelitys who developed an unresectable cscc over a chronic ulcer on the right sole. the patient refused radiation therapy and systemic immunotherapy and a lower leg transtibilial amputation was carried out. (c) a 70 year-old woman who developed a neglected 10-year history ulcer on the right leg tha was considered unresectable. radiation therapy achieved partial response and knee disarticulation had to be performed. (d) a 70-year old man immunosuppresed due to kidney grafting who developed fast-growing ulcer on the right hand. systemic immunotherapy and radiation therapy did not achieved clinical response and consequently the patient underwent major amputation. review | dermatol pract concept. 2021; 11(s2):e2021167s 9 approach based on deciding between surgery versus chemotherapy. the experience gained with other tumor types treated effectively with immunotherapy (eg malignant melanoma) provides insight into the capability of surgery to completely remove recurrences (mainly regional), while keeping distal disease under control through systemic immunotherapy. although a survival benefit is not expected from surgery for these patients with recurrent disease, it might help the patients restore impaired function and quality of life. the second situation is when surgery may be considered in the palliative setting, although as a last resort. major resections, including major limb amputations, might be acceptable and are still performed from time to time on patients with untreatable and unbearable pain and unmanageable bleeding. the only aim of surgery in this clinical situation is to reduce the symptoms. surgery should therefore not be offered if these symptoms can be controlled through other non-surgical options. however, in the case on minor amputations (ie finger or toe amputations) this radical surgical approach may leave the patient free of disease, providing long recurrence-free and overall survival. finally, the use of systemic immunotherapy in an attempt to reduce tumoral burden, thereby allowing for a less extensive surgery (neoadjuvant therapy), is being assessed in ongoing clinical trials on advanced cscc. a recently published phase ii pilot trial of neoadjuvant immunotherapy with cemiplimab has shown pathologically complete responses in 70% of the patients [40]. although these results were obtained from patients with advanced but resectable tumors, it can be hypothesized that the same neoadjuvant approach can be applied to borderline resectable or even unresectable advanced cscc in the future. improving the results of surgery adjuvant radiation therapy for primary and metastatic cscc the risk of residual disease after inadequate or incomplete surgery of high-risk primary tumors and lymph node metastases is usually managed through adjuvant radiation therapy. the benefits and indications of adjuvant radiation therapy for patients with cscc is beyond the scope of this article. for patients with primary or nodal metastasis with high-risk features, however, surgery may be maintained or enhanced by postoperative radiation therapy. therefore, for those patients with incompletely resected primary high-risk cscc and those with completely excised but aggressive nodal metastasis (eg large burden, extracapsular extension), or incompletely excised involved nodes that are not suitable for further surgery, radiation therapy should be discussed and offered [3,4]. this essential part of cscc management will be comprehensively addressed elsewhere in this monograph. conclusions appropriate surgery for patients with cscc represents a challenge in terms of oncological outcomes, postoperative function, and quality of life. successfully accomplishing this task is not just a matter of surgeon expertise or technical procedural aspects. oncologically successful surgery for patients with cscc requires timeliness, proper surgical procedures based on guidelines and tailored to the patient’s clinical condition and the tumor’s particular features and, above all, requires to be acceptable to the patient. skin cancer clinics and multidisciplinary tumor boards should strive to meet the requirements for cscc proper surgery procedures. if the criteria are met, surgery coupled with the recent breakthroughs in systemic immunotherapy is likely to offer patients with cscc the best standard of management, proving longer survival and greater quality of life. references 1. 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cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. j am acad dermatol. 2018;78(2):249-261. doi:10.1016/j. jaad.2017.08.058. pmid: 29332705. 23. systematic review of the prevalence of nodal metastases and the prognostic utility of sentinel lymph node biopsy in cutaneous squamous cell carcinoma pubmed. accessed august 13, 2021. https://pubmed.ncbi.nlm.nih.gov/29701281/ 24. lhote r, lambert j, lejeune j, et al. sentinel lymph node biopsy in cutaneous squamous cell carcinoma series of 37 cases and systematic review of the literature. acta derm venereol. 2018;98(7):671-676. doi:10.2340/00015555-2942. pmid: 29648676. 25. navarrete-dechent c, veness mj, droppelmann n, uribe p. highrisk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: a literature review. j am acad dermatol. 2015;73(1):127-137. doi:10.1016/j.jaad.2015.03.039. pmid: 26089049. 26. schmitt ar, brewer jd, bordeaux js, baum cl. staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymph node biopsy results: meta-analysis of american joint committee on cancer criteria and a proposed alternative system. jama dermatol. 2014;150(1):19-24. doi:10.1001/jamadermatol.2013.6675. pmid: 24226651. 27. chang jm, kosiorek he, dueck ac, et al. stratifying sln incidence in intermediate thickness melanoma patients. am j surg. 2018;215(4):699-706. doi:10.1016/j.amjsurg.2017.12.009. pmid: 29502857. 28. morton dl, cochran aj, thompson jf, et al. sentinel node biopsy for early-stage melanoma: accuracy and morbidity in mslt-i, an international multicenter trial. ann surg. 2005;242(3):302-311; discussion 311-313. doi:10.1097/01.sla.0000181092.50141.fa. pmid: 16135917. 29. sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the english literature pubmed. accessed august 14, 2021. https://pubmed.ncbi.nlm.nih. gov/17083582/ 30. sentinel node biopsy for high-risk cutaneous squamous cell carcinoma pubmed. accessed august 14, 2021. https://pubmed.ncbi. nlm.nih.gov/24953417/ 31. conway wc, faries mb, nicholl mb, et al. age-related lymphatic dysfunction in melanoma patients. ann surg oncol. 2009;16(6):1548-1552. doi:10.1245/s10434-009-0420-x. pmid. 19277787. 32. gurney b, newlands c. management of regional metastatic disease in head and neck cutaneous malignancy. 1. cutaneous squamous cell carcinoma. br j oral maxillofac surg. 2014;52(4):294300. doi:10.1016/j.bjoms.2014.01.015. pmid: 24559975. 33. radu s, han d, fowler g, han g, fortino j, vetto jt. relationship of patient age to tumor factors and outcomes among patients undergoing sentinel node biopsy for melanoma. am j surg. 2020;219(5):836-840. doi:10.1016/j.amjsurg.2020.03.013. pmid: 32184009. 34. jol j a. d, van velthuysen mlf, hilgers fjm, keus rb, neering h, balm ajm. treatment results of regional metastasis from cutaneous head and neck squamous cell carcinoma. eur j surg oncol. 2003;29(1):81-86. doi:10.1053/ejso.2002.1330. pmid: 12559082. 35. schmidt c, martin jm, khoo e, plank a, grigg r. outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. head neck. 2015;37(12):1808-1815. doi:10.1002/hed.23843. pmid: 24995842. 36. smith ja, virk s, palme ce, et al. age is not a predictor of prognosis in metastatic cutaneous squamous cell carcinoma of the head review | dermatol pract concept. 2021; 11(s2):e2021167s 11 and neck. anz j surg. 2018;88(4):e273-e277. doi:10.1111/ ans.13757. pmid: 29611361. 37. rodrigo jp, grilli g, shah jp, et al. selective neck dissection in surgically treated head and neck squamous cell carcinoma patients with a clinically positive neck: systematic review. eur j surg oncol. 2018;44(4):395-403. doi:10.1016/j.ejso.2018.01.003. pmid: 29395434. 38. wang jt, palme ce, wang ay, morgan gj, gebski v, veness mj. in patients with metastatic cutaneous head and neck squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not influence outcome. j laryngol otol. 2013;127 suppl 1:s2-7. doi:10.1017/s0022215112002101. pmid: 23046820. 39. knowing when not to operate. bmj. 1999;318(7180):a. doi: 10.1136/bmj.318.7180.0a. 40. ferrarotto r, amit m, nagarajan p, et al. pilot phase ii trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. clin cancer res. published online june 29, 2021. doi:10.1158/1078-0432.ccr-21-0585. pmid: 34187851. dermatology: practical and conceptual research | dermatol pract concept 2017;7(2):9 39 dermatology practical & conceptual www.derm101.com triage amalgamated dermoscopic algorithm (tada) for skin cancer screening tova rogers1, maria marino1, stephen w. dusza1, shirin bajaj1, michael a. marchetti1, ashfaq marghoob1 1 dermatology service, department of medicine, memorial sloan kettering cancer center, new york, new york key words: dermoscopy, dermoscopy algorithm, melanoma, basal cell carcinoma, squamous cell carcinoma citation: rogers t, marino m, dusza sw, bajaj s, marchetti ma, marghoob a. triage amalgamated dermoscopic algorithm (tada) for skin cancer screening. dermatol pract concept. 2017;7(2):9. doi: https://doi.org/10.5826/dpc.0702a09 received: january 30, 2016; accepted: february 19, 2017; published: april 30, 2017 copyright: ©2017 rogers et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part through the nih/nci cancer center support grant p30 ca008748. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ashfaq a. marghoob, md, dermatology service, department of medicine, memorial sloan kettering cancer center, 16 e 60th street, new york 10065, usa. email: marghooa@mskcc.org importance: dermoscopic triage algorithms have been shown to improve beginners’ abilities for identifying pigmented skin lesions requiring biopsy. objective: to estimate the diagnostic accuracy of the triage amalgamated dermoscopic algorithm (tada) for pigmented and nonpigmented skin cancers. secondarily, to compare tadas performance to those of existing triage algorithms for the identification of pigmented skin cancers. design: cross-sectional, observational, reader study that took place at a beginner and intermediate level dermoscopy course. participants: two hundred medical professionals of various specialties attended the course and 120 voluntarily joined the study (60% participation rate). exposures: after receiving basic dermoscopy training, participants evaluated 50 polarized, dermoscopic images of pigmented (22 benign, 18 malignant) and nonpigmented (1 benign, 9 malignant) skin lesions using tada. pigmented lesions were also evaluated using the three-point checklist and ac rule. with tada, participants first determined if a lesion was an unequivocal angioma, dermatofibroma, or seborrheic keratosis, which would exclude it from further evaluation. all other lesions were assessed for architectural disorder, starburst pattern, blue-black or gray color, shiny white structures, negative network, ulcer/erosion, or vessels. any one feature indicated suspicion for malignancy. results: most participants were dermatologists (n=64, 53.3%) or primary care physicians (n=41, 34.2%), and many lacked previous dermoscopy training (n=52, 43.3%). tada’s sensitivity and specificity for all skin cancers was 94.6% (95% ci=93.4-95.7%) and 72.5% (95% ci=70.1-74.7%), respectively. for pigmented skin cancers, the sensitivity and specificity were 94.0% (95% ci=92.995.0%) and 75.5% (95% ci=73.8-77.2%). this compared to 71.9% (95%ci=69.8-73.9%) and 81.4% (95%ci=79.7-83.0%) for the three-point checklist and 88.6% (95%ci=87.1-89.9%) and 78.7% (95%ci=76.9-80.3%) for the ac rule. conclusions: these results suggest that tada compares favorably to existing triage algorithms and might be a useful triage tool with high sensitivity and specificity for pigmented and nonpigmented skin cancers. further studies are needed to validate these preliminary observations. abstract mailto:marghooa@mskcc.org 40 research | dermatol pract concept 2017;7(2):9 white color) and the ac rule (asymmetry, color variation), have demonstrated the feasibility of this approach by quickly improving novices’ abilities to recognize pigmented lesions requiring biopsy [11,12]. a limitation of both methods is that they were designed for subsets of pigmented skin cancers. the triage amalgamated dermoscopic algorithm (tada) was designed to identify common pigmented and nonpigmented skin cancers (figure 1). although tada does not ask users to preselect and apply the algorithm to exclusively pigmented lesions, it does require that users first determine if a lesion is a dermoscopically unequivocal example of one of three commonly encountered benign neoplasms (angioma, dermatofibroma, seborrheic keratosis). if a lesion is determined to be one of these three neoplasms, it is excluded from further evaluation. if not, it is then evaluated for architectural disorder (i.e., disorganized or asymmetric distribution of colors and/or structures)—a robust criterion that is strongly associated with malignancy and has good interobserver agreement, making it easier to teach and learn and lending itself to the inclusion in a triage algorithm [13,14]. to improve sensitivity for organized and symmetric skin cancers, including certain melanomas (e.g., spitzoid, desmoplastic, nodular, and amelanotic) as well as non-melanoma skin cancers, tada includes six additional criteria (starburst, blue-black or gray color, shiny white structures, negative network, ulcer/erosion, introduction dermoscopy allows skilled observers to more accurately identify pigmented skin cancers compared to clinical exam alone [1-3]. in some cases, it can also help identify nonpigmented malignancies [4]. despite the potential for improved skin cancer detection, a number of barriers are preventing many dermatologists, dermatology residents, and other medical professionals interested in skin cancer management from adopting dermoscopy. lack of training has been cited as a major hindrance [5,6]. nonetheless, the use of dermoscopy is increasing [7], and with it, interest in educational materials that provide novices an entry point into dermoscopy [8]. teaching beginners the numerous and often nuanced dermoscopic patterns and structures required for diagnosis can be daunting. this has led some authors to suggest that triage and not diagnosis be the goal of the dermoscopic evaluation when performed by non-experts [9,10]. triage in the context of skin lesion evaluations requires the examiner to determine if a lesion is suspicious for malignancy, thus requiring a biopsy or specialist referral; it does not require that a specific diagnosis be made. triage algorithms may be easier to teach, learn, and implement by allowing for the nonspecific identification of concerning lesions using limited dermoscopic criteria. the validation of two triage algorithms, the three-point checklist (asymmetry, atypical network, bluefigure 1. the triage amalgamated dermoscopic algorithm (tada)—illustrated diagram outlining tadas step-wise approach to evaluating and managing pigmented and nonpigmented skin lesions. [copyright: ©2017 rogers et al.] research | dermatol pract concept 2017;7(2):9 41 powershot g16; canon inc., tokyo, japan) and a dermoscopy lens attachment (dermlite foto system; 3gen inc., san juan capistrano, ca, usa). dermoscopy training: the study was conducted during the latter half of the second day of a three-day dermoscopy course. on day one of the course, participants were lectured on basic dermoscopic criteria of common benign and malignant skin lesions. participants were also introduced to the idea of dermoscopy algorithms as part of a lecture on dermoscopic teaching methodologies. on the morning of day two, participants reviewed the material covered on day one via unknown lesion identification sessions with feedback. instruction on how to apply the three-point checklist, ac rule, and tada algorithms occurred during a 30-minute training session immediately prior to the study. evaluation of study lesions: dermoscopic images were displayed in powerpoint® and projected onto two large screens. participants used worksheets to evaluate the study lesions. the worksheets separately listed the dermoscopic criteria included in the three algorithms. for the three-point checklist, the criteria evaluated were asymmetry (monoaxial or biaxial), atypical network, and blue-white color, with two of the three being required for biopsy. for the ac rule, the criteria evaluated were asymmetry and color variation, which were ranked on a scale of 1 to 10. based on the evaluation of these two criteria, users then determined if a lesion was suspicious for malignancy (yes or no) [22]. for tada, participants were first asked to determine if a lesion was an unequivocal angioma, dermatofibroma, or seborrheic keratosis. if the lesion was determined to be one of these three, they were instructed to stop filling out the worksheet and wait for the next case. otherwise, participants assessed the lesion for architectural disorder. lesions demonstrating this feature were considered to be suspicious for malignancy without need for further evaluation for the remaining tada criteria. lesions lacking architectural disorder (i.e., organized, symmetric lesions) were evaluated further for the presence of starburst pattern, blue-black or gray color, shiny white structures, negative network, ulcer/erosion, or vessels, with the presence of any one feature indicating suspicion for malignancy. lesions lacking all tada criteria were considered equivocal and required monitoring for morphological changes or symptoms (i.e., itching, bleeding). clinical images were not provided. however, information regarding textural features (i.e., firm, keratotic, smooth, dimpling) was given. the lesions were displayed in random order. statistical analysis: descriptive statistics were used to describe the study participants, study lesions, and participant evaluations. three separate dichotomous outcome measures were created with the data to reflect the participants’ lesion evaluations for tada, the three-point checklist, and ac rule. the primary independent variable for these analyses vessels) previously validated to be associated with different subtypes of melanoma and non-melanoma skin cancers and are independent predictors of malignancy [15-21]. the presence of any one feature included in tada warrants a biopsy or specialist referral. since shiny white structures can only be seen with polarized light, tada requires the use of polarized dermoscopy. tada was not tested on facial, mucosal, volar, or nail lesions. the aim of this study was to determine the sensitivity and specificity of tada for the detection of common skin cancers (melanoma, basal cell carcinoma, squamous cell carcinoma). a secondary aim was to compare the performance of tada, the three-point checklist, and ac rule when identifying pigmented study lesions. materials and methods study design: this was a cross-sectional, observational study performed in an experimental setting. participants: this study was approved by the memorial sloan kettering cancer center institutional review board without requirement of written informed consent in accordance with the helsinki declaration. the study was performed on august 14, 2015, at a dermoscopy course for beginner and intermediate level dermoscopy users. all registered attendees were invited to participate. participation was voluntary. there was no compensation or inducement. participant characteristics (age, sex, medical specialty, prior dermoscopy training, cumulative dermoscopy experience) were recorded on data collection forms. image selection: the image records of aam were retrospectively and sequentially reviewed, starting from the most recent dermoscopic image on file, to identify an approximately equal proportion of representative examples of common benign and malignant skin lesions. facial, mucosal, volar, and nail lesions were excluded. sixty-two skin neoplasms were selected, of which twelve were excluded due to image quality or lack of polarized dermoscopic images. the resulting 50 lesions included 27 malignant (16 melanomas, 7 basal cell carcinomas, and 4 squamous cell carcinomas) and 23 benign neoplasms (8 nevi, 5 angiomas, 5 seborrheic keratoses, 4 dermatofibromas, and 1 clear cell acanthoma). all but one of the 16 melanomas measured less than 0.5 mm thick (nodular melanoma >1mm). ten of the 50 lesions (20%) were clinically and dermoscopically nonpigmented (2 melanomas, 5 basal cell carcinomas, 2 squamous cell carcinomas, and 1 clear cell acanthoma). all malignant lesions were pathologically verified. benign lesions were either evaluated pathologically or were required to be unchanged compared to baseline images. images were captured with contact polarized dermoscopy (x10 magnification factor) using a digital camera (canon 42 research | dermatol pract concept 2017;7(2):9 96% of which were correctly classified (n=411). angioma had a false positive rate (malignant lesions erroneously identified as angioma) of 0.2% (n=13). of the 458 dermatofibroma diagnoses made (31.7% of the 1,443 lesion evaluations in step one), 94% (n=431) were correct. the false positive rate for dermatofibroma was 1% (n=29). the diagnosis of seborrheic keratosis was made on 558 occasions (38.7% of the 1,443 is the benign or malignant nature of the lesion based on histologic evaluation. separate cross-classifications of the benign/malignant nature of a lesion by participant algorithm outcome were created and used to calculate overall estimates of diagnostic accuracy. since study participants evaluated multiple study lesions, a general estimating equations approach was used to estimate model-based diagnostic accuracy measures while evaluating the effect of participant characteristics, such as previous dermoscopy training and/or years practicing dermatology. separate models were independently used to estimate sensitivity and specificity. algorithm performance comparisons of sensitivity, specificity and area under the receiver operating characteristic (roc) curve were made. for the three-point checklist and ac rule, only participants’ responses for pigmented study lesions were recorded and used for statistical analysis. all statistical analyses were performed with stata v14.1 (stata corporation, college station, tx). results two hundred individuals attended the dermoscopy course and 120 (60%) participated in the study. participant characteristics, including age, sex, medical specialty, previous dermoscopy training, and years of dermoscopy experience, are indicated in table 1. in total, 5,646 lesion evaluations were performed, 3,036 malignant (53.8%) and 2,610 benign (46.2%), with a mean of 47 evaluations per participant (out of a possible 50). in the first step of tada, 25.6% (n=1,443/5,646) lesion evaluations resulted in the diagnosis of angioma, dermatofibroma, or seborrheic keratosis (figure 2). of these lesions, 94% (n=1,357) were histologically benign and 90% (n=1,301) were one of the three, above-named, benign lesions. the diagnosis of angioma was made on 427 evaluations (29.6% of the 1,443 lesion evaluations in step one), table 1. characteristics of study participants (n=120). [copyright: ©2017 rogers et al.] variable coding n (%) age <20 7 (5.8) 21-30 28 (23.3) 31-40 25 (20.8) 41-50 37 (30.8) 51-60 15 (12.5) 61-70 4 (3.3) 71-80 0 (0.0) >81 0 (0.0) did not respond 4 (3.3) sex male 52 (43.3) female 64 (53.3) did not respond 4 (3.3) specialty dermatology 64 (53.3) internal medicine 22 (18.3) family medicine 19 (15.8) emergency medicine 2 (1.7) general surgery 2 (1.7) pathology 1 (0.8) dentistry 1 (0.8) instrumental physics 1 (0.8) medical student 1 (0.8) did not respond 7 (5.8) previous dermoscopy training yes 63 (52.5) no 52 (43.3) did not respond 5 (4.2) years of previous dermoscopy experience 0 28 (23.3) ≤1 24 (20.0) 2-5 35 (29.2) 6-10 18 (15.0) >10 9 (7.5) did not respond 6 (5.0) lesion evaluations in step one). of these, 82% (n=459) were correctly classified. seborrheic keratosis had a false positive rate of 1.4% (n=44). among the 3,036 evaluations of histologically malignant lesions, 2,950 were performed in the second step of tada, denoting that 97% of malignant study lesions were correctly triaged in step one. participants performed 4,203 lesion evaluations (74.4%) in step two of research | dermatol pract concept 2017;7(2):9 43 ing, are listed in table 2. in order to compare the diagnostic performance of tada to the three-point checklist and ac rule, nonpigmented study lesions (n=10) were excluded from the analysis. in this evaluation, tada performed with the highest sensitivity (94.0%, 95% ci: 92.9%-95.0%), followed by the ac rule (88.6%, 95% ci: 87.1%-89.9%) and the three-point checklist (71.9%, 95% ci: 69.8%-73.9%). the three-point checklist had the highest specificity (81.4% (95% ci: 79.7%-83.0%), followed by the ac rule (78.7%, 95% ci: 76.9%-80.3%) and tada (75.5%, 95% ci: 73.8%77.2%). roc curves for the three algorithms highlight these results (figure 3). discussion in this pilot study, we tested a novel triage algorithm to determine its sensitivity and specificity for common skin cancers. a significant proportion of study participants lacked tada, of which 3,590 (85.4%) were identified as suspicious for malignancy based on the presence of any single tada criterion. eighty percent of these lesions were true malignancies. the features that most strongly discriminated benign and malignant study lesions were disorganized architecture, ulcers/erosions, and shiny white structures. disorganized architecture was identified in 57% of histologically malignant lesions versus 21% of benign lesions (p<0.001). ulcers/erosions were identified in 29% versus 11% of malignant and benign lesions, respectively (p<0.001). shiny white structures were identified in 25% versus 11% of malignant and benign lesions, respectively (p<0.001). of the 613 lesion evaluations lacking any tada criteria (14.6% of the 4,203 lesion evaluations in step two), 87% were truly benign. tada had a sensitivity of 94.6% and a specificity of 72.5% for all malignant study lesions. sensitivity and specificity estimates for the individual study lesions, as well as for participants with and without previous dermoscopy trainfigure 2. breakdown of participants’ responses for tada step 1 and step 2—results of the 5,646 lesion evaluations performed by study participants as a function of the true diagnoses of study lesions. benign lesions correctly identified in tada step 1 are classified as “true benign” and are further broken down into either “correctly classified,” for lesions with true diagnoses of angioma, dermatofibroma, or seborrheic keratosis, or “incorrectly classified,” for all other benign lesions. malignant study lesions incorrectly identified as benign in tada step 1 are classified as “false benign.” lesions identified as malignant in tada step 2 (positive for any one criteria) are classified as either “true malignant,” for lesions with true malignant diagnoses, or “false malignant,” for lesions with true benign diagnoses. lesions identified as not malignant, or equivocal, in tada step 2 (negative for all criteria) are either classified as “true benign,” for lesions with true benign diagnoses, or “false benign,” for lesions with true malignant diagnoses. abbreviations: df, dermatofibroma; sk, seborrheic keratosis; cca, clear cell acanthoma; amm, amelanotic melanoma; bcc, basal cell carcinoma; mm, malignant melanoma; nm, nodular melanoma; scc, squamous cell carcinoma [copyright: ©2017 rogers et al.] 44 research | dermatol pract concept 2017;7(2):9 laypersons, respectively [11,12]. our study population also compares favorably to the participant profile in a study that reevaluated the three-point checklist, of which 24 individuals (14%) lacked previous dermoscopy experience.9 the three-point checklist was also evaluated in a prospective trial with 73 primary care physicians; however, the previous dermoscopic experience or training of participants was not previous dermoscopy training (43%, n=52) and/or experience (23%, n=28). this allowed us to evaluate the potential utility of tada as a skin cancer detection aid for inexperienced dermoscopists, who comprise our target audience. our study population had a greater sample of beginners than the pilot studies for the three-point checklist and ac rule, which included 6 inexperienced dermoscopists and 17 table 2. model-based estimates of sensitivity and specificity for tada for all study lesions. [copyright: ©2017 rogers et al.] variable sensitivity variable specificity coding estimate (95% ci) p-value coding estimate (95% ci) p-value overall 94.6 (93.4—95.7) — overall 72.5 (70.1—74.7) — diagnosis amm 95.6 (91.5 -99.8) 0.942 diagnosis angioma 76.4 (72.6—80.4) <0.001 bcc 95.2 (92.9 -97.6) 0.651 cca 39.1 (37.0—41.4) <0.001 mm 94.4 (92.3 -96.6) 0.251 df 93.6 (90.0—98.1) <0.001 nm 91.6 (88.2 -95.1) 0.020 nevus 69.4 (67.0—71.9) — scc 95.7 (93.8 -97.7) — sk 82.9 (79.2—86.7) <0.001 previous dermoscopy training no 93.6 (91.8—95.5) — previous dermoscopy training no 69.0 (64.6—73.7) — yes 95.4 (94.8—99.6) 0.14 yes 73.2 (71.4—84.5) 0.450 abbreviations: amm, amelanotic melanoma; bcc, basal cell carcinoma; mm, malignant melanoma; nm, nodular melanoma; scc, squamous cell carcinoma; cca, clear cell acanthoma; df, dermatofibroma; sk, seborrheic keratosis figure 3. receiver operating characteristic (roc) curves for tada, the three-point checklist, and ac rule—roc curves demonstrate the diagnostic performance of the three algorithms compared for the identification of pigmented skin lesions. [copyright: ©2017 rogers et al.] research | dermatol pract concept 2017;7(2):9 45 ficities ranging from 91.0% to 96.3% and 32.8% to 71.9%, respectively, for the identification of pigmented melanoma and basal cell carcinoma [9,11]. the ac rule has reported sensitivities and specificities of 94% and 62%, respectively, for pigmented melanoma.12 two of the three criteria used in the three-point checklist are for pigmented lesions and at least two of these criteria must be present for a lesion to warrant a biopsy. this greatly decreases the likelihood that the algorithm will identify nonpigmented malignancies. regarding the ac rule, the final determinant of whether or not a lesion requires a biopsy is the user’s level of suspicion, which reflects the presence of one or both of the algorithms criteria. one of these criteria, asymmetry, is not specific to pigmented lesions. the ac rule thus might be applicable for nonpigmented lesions, however, only those with disorganized architecture. similarly, the algorithm might miss organized, homogenously pigmented skin cancers, such as some nodular melanomas. when comparing the results of tada to that of the threepoint checklist and ac rule for the detection of pigmented lesions, we found that tada performed with the highest sensitivity by as much as 22%. the fact that the sensitivity estimates for tada were the same on the entire data set and on the subset of pigmented lesions (94.6% vs. 94.0%) might reflect the inclusion of sufficient dermoscopic criteria for the identification of both pigmented and nonpigmented skin cancers. regarding specificity, we found that all three algorithms performed well. the specificity seen with tada was slightly lower than for the other two algorithms. certain features included in tada, such as vessels of any morphology, will invariably lead to biopsies of some benign lesions, like clear cell acanthomas or some intradermal nevi. tada knowingly sacrifices this specificity for simplicity and sensitivity. additional training in the identification of certain benign lesions would likely increase tadas specificity. the results of this study suggest that tada might be a useful triage tool by providing a simplified dermoscopic method with high sensitivitity for common skin cancers. however, our study population consisted of individuals attending a dermoscopy course and were thus a motivated group with an interest in learning dermoscopy. as such, our results might not be generalizable to all novices. to make definitive statements about the efficacy of tada in clinical practice, our findings would need confirmation with a greater number of inexperienced dermoscopists evaluating a larger and more diverse sample of neoplasms with a more balanced proportion of pigmented and nonpigmented lesions. this would ideally be achieved with a prospective study. since clinical-dermoscopic correlation can be crucial for certain diagnoses, the addition of gross images would more closely correlate to the clincal scenerio. our use of clinical descriptives (i.e., firm, keratotic) could have introduced an informaindicated [23]. a limitation of our study is that non-participant characteristics were not recorded and we are unable to report on any differences between participants (n=120) and non-participants (n=80). the overall sensitivity of tada for pigmented and nonpigmented skin cancers was 94.6%. this value was marginally influenced by participants’ previous dermoscopy training (95.4% vs. 93.6%). the first criterion included in tada is architectural disorder, which is not an objective criterion in that it cannot be defined by any given shape or color. it is rather the result of the overall impression, or gestalt, of an asymmetric or chaotic lesion. the subjective interpretation of disorganization within a lesion has been shown to have better interobserver agreement than most objectively defined criteria [13]. it has also been shown to be one of the dermoscopic criteria with the highest discriminatory power [13-15]. indeed in the present study, architectural disorder allowed for the correct identification of greater than 50% of malignant study lesions. in order to identify malignancies with ordered and symmetric appearances, participants needed to be able to recognize six additional features, three of which (blue-black or gray color, ulcer/erosion, and vessels of any morphology) are colors and structures not specific to dermoscopy and, in our experience, beginners have been able to quickly recognize. facial, acral, nail, and mucosal lesions were not evaluated and the algorithm states that tada cannot be used for lesions on these sites. while our results for non-melanoma skin cancer can likely be generalized to facial lesions, more robust studies across multiple ages and skin color cohorts are needed to validate the dermoscopic features of early special sites melanomas. notably, untrained participants achieved an overall specificity of 69% using tada. additionally, the specificities for the three types of benign lesions included in the algorithm ranged from 76% to 94%. this finding substantiates our view that beginners can be quickly trained to accurately identify classic examples of certain benign lesions. in many instances, these benign neoplasms can have dermoscopic characteristics attributable to malignant lesions, such as the blue, black, or gray colors commonly observed in seborrheic keratoses or the shiny white structures or scar-like areas seen in dermatofibromas [24,25]. however, when these features are viewed in the context of the global lesion pattern as a whole, the diagnosis can become apparent. additionally, the frequency with which these lesions are encountered in clinical practice can allow one to rapidly gain experience in their identification. while requiring users to gain additional dermoscopic knowledge in order to identify these lesions is arguably a limitation of tada, it also seemed to strengthen the algorithm, as indicated by the high specificities achieved for these lesions. pre-selection of lesions is not something unique to tada. the three-point checklist has reported sensitivities and speci46 research | dermatol pract concept 2017;7(2):9 12. luttrell mj, mcclenahan p, hofmann-wellenhof r, fink-puches r, soyer hp. laypersons’ sensitivity for melanoma identification is higher with dermoscopy images than clinical photographs. br j dermatol. 2012;167:1037-1041. 13. carrera c, marchetti ma, dusza sw, et al. validity and reliability of dermoscopic criteria used to differentiate nevi from melanoma: a web-based international dermoscopy society study. jama dermatol. 2016;152(7):798-806. 14. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64:1068-1073. 15. henning js, dusza sw, wang sq, et al. the cash (color, architecture, symmetry, and homogeneity) algorithm for dermoscopy. j am acad dermatol. 2007;56:45-52. 16. lallas a, moscarella e, longo c, et al. likelihood of finding melanoma when removing a spitzoid-looking lesion in patients aged 12 years or older. j am acad dermatol. 2015;72:47-53. 17. argenziano g, longo c, cameron a, et al. blue-black rule: a simple dermoscopic clue to recognize pigmented nodular melanoma. br j dermatol. 2011;165:1251-1255. 18. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67:194.e1-8. 19. bassoli s, ferrari c, borsari s, et al. negative pigment network identifies a peculiar melanoma subtype and represents a clue to melanoma diagnosis: a dermoscopic study of 401 melanomas. acta derm venereol. 2013;93:650-655. 20. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010; 62:67-75. 21. pizzichetta ma, talamini r, stanganelli i, et al. amelanotic/ hypomelanotic melanoma: clinical and dermoscopic features. br j dermatol. 2004;150:1117-1124. 22. luttrell mj, hofmann-wellenhof r, fink-puches r, soyer hp. the ac rule for melanoma: a simpler tool for the wider community. j am acad dermatol. 2011;65:1233-1234. 23. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24:1877-1882. 24. braun rp, rabinovitz hs, krischer j, et al. dermoscopy of pigmented seborrheic keratosis: a morphological study. arch dermatol. 2002;138:1556-1560. 25. zaballos p, puig s, llambrich a, malvehy j. dermoscopy of dermatofibromas: a prospective morphological study of 412 cases. arch dermatol. 2008;144:75-83. 26. pagnanelli g, soyer hp, argenziano g, et al. diagnosis of pigmented skin lesions by dermoscopy: web-based training improves diagnostic performance of non-experts. br j dermatol. 2003;148:698-702. tion bias not reproducible in clinical settings, however, this limitiation would have more relevance to a study evaluating teladermoscopy. further, in the present study, all participants received standardized training. randomizing participants to various levels and durations of training would allow us to determine if the teaching modality for tada can be streamlined. an upcoming study will address the latter limitation and also determine if the inclusion of step one (identifying common benign lesions) truly strengthens the algorithm. references 1. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159-165. 2. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137:1343-1350. 3. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159:669-676. 4. argenziano g, albertini g, zalaudek i. commentary: improved detection of nonpigmented skin tumors. dermatol surg. 2012;38:1445-1447. 5. nehal ks, oliveria sa, marghoob aa, et al. use of and beliefs about dermoscopy in the management of patients with pigmented lesions: a survey of dermatology residency programmes in the united states. melanoma res. 2002;12:601-605. 6. engasser hc, warshaw em. dermatoscopy use by us dermatologists: a cross-sectional survey. j am acad dermatol. 2010;63:412419. 7. terushkin v, oliveria sa, marghoob aa, halpern ac. use of and beliefs about total body photography and dermatoscopy among us dermatology training programs: an update. j am acad dermato.l 2010;62:794-803. 8. anderson rt, dziak k, mcbride j, camacho f, hege ac, torti fm. demand for continuing medical education programs on cancer care among primary care physicians in north carolina. n c med j. 2004;65:130-135. 9. zalaudek i, argenziano g, soyer hp, et al. three-point checklist of dermoscopy: an open internet study. br j dermatol. 2006;154:431-437. 10. robison s, kljakovic m, barry p. choosing to biopsy or refer suspicious melanocytic lesions in general practice. bmc fam pract. 2012;13:78. 11. soyer hp, argenziano g, zalaudek i, et al. three-point checklist of dermoscopy. a new screening method for early detection of melanoma. dermatology. 2004;208:27-31. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022177 1 sexually transmitted infections during the covid-19 pandemic in a swedish healthcare region without lockdown: a focus on gonorrhea and syphilis maria pissa1, sandra jerkovic gulin1 1 department of dermatology and venereology, ryhov county hospital, jonkoping, sweden key words: syphilis, covid-19, sars-cov-2, gonorrhea citation: pissa m, gulin jerkovic s. sexually transmitted infections during the covid-19 pandemic in a swedish healthcare region without lockdown: a focus on gonorrhea and syphilis. dermatol pract concept. 2022;12(4):e2022177. doi: https://doi.org/10.5826/dpc.1204a177 accepted: january 11, 2022; published: october 2022 copyright: ©2022 pissa et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sandra jerkovic gulin, md, phd, msc, department of dermatology and venereology, ryhov county hospital, sjukhusgatan, 55305 jonkoping, sweden, jonkoping, sweden, e-mail: sandrajerkovicgulin@rjl.se introduction in late december 2019, the first case of infection with sarscov-2 was reported [1]. in march 2020, the pandemic was declared and led to the collapse of the health care functioning [2]. the normal access to specialist care was not always guaranteed in many countries around the world. in march 2020 the pandemic reached sweden and the public health agency of sweden issued recommendations to people aged from 70 years or older and risk groups including physical distancing. the incidence of syphilis and gonorrhea in the covid-19 pandemic in sweden has not been studied yet in contrast to several other countries. several studies reported a decrease in early syphilis and gonorrhea cases and one from the czech republic showed an initial decrease of early syphilis followed by a significant increase during the pandemic (march 2020 – february 2021)[3-6]. case presentation we aimed to compare the incidence of gonorrhea and syphilis in region jonkoping county healthcare region in sweden during the 18-month covid-19 period with the non-pandemic period. this was a retrospective, observational cohort study done in the three hospitals (ryhov county hospital, highland hospital of nassjo, and varnamo hospital) in region jonkoping county (rjc), which is part of the southeast healthcare region in sweden providing a healthcare for approximately 360,000 inhabitants. the study was a quality review study approved by the operations manager and head of department of dermatology at ryhov county hospital in jonkoping county region according to section 31 of the health and medical services act, which was published in lakartidningen (2015; 112: c9cl). 2 research letter | dermatol pract concept. 2022;12(4):e2022177 we analyzed monthly cases of gonorrhea and syphilis at our three hospitals. we have observed a significant increase in syphilis cases during the pandemic (april 1, 2020  – september 31, 2021) compared to non-pandemic period (october 1, 2018 – march 31, 2020). the difference in the number of gonorrhea cases during pandemic versus non pandemic was not significant. twenty-five cases of syphilis were reported during the pandemic and only 10 syphilis cases during the non-pandemic period (p = 0.0143, 95% ci 1.20-5.20, rr 2.49). forty-four gonorrhea cases were reported under the pandemic period and 52 gonorrhea cases under the non-pandemic period (figure 1). conclusions the effect of the pandemic on sexually transmitted diseases (stds) frequency is difficult to explain due to differences in pandemic social restriction measures worldwide. the implementation of the measures was expected to reduce not only the spread of covid-19 but also stds. the incidence of syphilis and gonorrhea decreased during the pandemic according to reports from several countries with lockdown [3–5]. one study reported an increase in the incidence of syphilis when social measures were subsequently relaxed [6]. on contrary, the access to healthcare was not affected with the pandemic in sweden, and the tracking of cases and partner notification was functioning as during the time before the pandemic. the increase in newly diagnosed syphilis cases during pandemic might be explained not only by light covid-19 restrictions and poor compliance with recommendations for social distancing but also rising stds trend. references 1. huang c, wang y, li x, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet. 2020;395(10223):497-506. doi 10.1016/s0140-6736(20)301835. pmid: 31986264. pmcid: pmc7159299. 2. who director-general’s opening remarks at the media briefing on covid-19 11 march 2020. available from https://www.who. int/director-general/speeches/detail/who-directorgeneral-s-openingremarks-at-the-media-briefing-on-covid-19---11-march-2020; accessed 5 oct 2021. 3. apalla z, lallas a, mastraftsi s, et al. impact of covid-19 pandemic on stis in greece. sex transm infect. 2021;97:319. doi:10.1136/sextrans-2021-054965 4. crane ma, popovic a, stolbach ai, et al. reporting of sexually transmitted infections during the covid-19 pandemic. sex transm infect. 2021;97:101–102. doi:10.1136/sextrans-2020-05 4805 5. rodríguez i, hernández y. sexually transmitted diseases during the covid-19 pandemic: a focus on syphilis and gonorrhoea in cuba. public health pract (oxf). 2021;2:100072. doi: 10.1016/j.puhip.2020.100072. pmid: 33521735. pmcid: pmc78 34305.. 6. bížová b, rob f, hercogová jt. increase of early syphilis cases during the covid-19 pandemic in the czech republic. sex transm infect. 2021. doi:10.1136/sextrans-2021-055098. 1 2 3 4 5 6 7 8 9 monthly average n u m b er o f c a se s n u m b er o f c a se s monthly average 10 11 12 13 14 15 16 17 18 0 1 2 3 4 5 6 7 8 9 gonorrhea syphilis pandemic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 1 2 3 4 5 6 pandemic figure 1. number of cases of gonorrhea (by culture or nucleic acid testing) and early syphilis (by serology or nucleic acid testing) during pandemic (april 1, 2020 – september 31, 2021) and non-pandemic period (october 1, 2018 – march 31, 2020). dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023089 1 tacrolimus in solution as an option to inflammatory conditions of the scalp camila scharf1, gaetano licata2, giulia briatico1, sebastiano pellerone1, giuseppe argenziano1, caterina mariarosaria giorgio1 1 dermatology unit, university of campania l.vanvitelli, naples, italy 2 dermatology unit, san antonio abate hospital, trapani, italy key words: tacrolimus, lichen planus pilaris, discoid lupus, frontal fibrosing alopecia, folliculitis decalvans citation: scharf c, licata g, briatico g, pellerone s, argenziano g, giorgio c. tacrolimus in solution as an option to inflammatory conditions of the scalp. dermatol pract concept. 2023;13(2):e2023089. doi: https://doi.org/10.5826/dpc.1302a89 accepted: september 22, 2022; published: april 2023 copyright: ©2023 scharf et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: camila scharf, md, university of campania l. vanvitelli, naples, italy. e-mail: kmischarf@gmail.com introduction: several dermatological diseases lead to inflammatory conditions of the scalp. most of these afflictions are recalcitrant and require long term maintenance treatment. objectives: we present a case series where topical tacrolimus was used in a solution vehicle for these conditions. methods: a total of 22 patients (aged 24-90 years) with confirmed diagnosis of lichen planus pilaris (lpp), discoid lupus (dl), frontal fibrosing alopecia (ffa), erosive pustulosis of the scalp (eps) or folliculitis decalvans (fd) were evaluated and treated with tacrolimus solution (0.1%) applied twice daily for 1 month, then once daily for another month and alternate days for 4 months. efficacy was evaluated by an investigator global assessment, clinical and dermoscopic evaluation at weeks 4, 8 and 24. the safety assessment included monitoring of all adverse events. results: the study included 13 patients with lpp, 2 with dl, 2 with fd, 2 with eps and 3 with aff. after 1 month, 14 patients (63.6%) had a good response and 7 (31.8%) had excellent response. after 2 months, 16 patients (72.7%) had excellent response, and this response was persistent after 6 months of treatment. conclusions: tacrolimus in solution, even if not yet commercially available, was an effective and well tolerated alternative for the maintenance treatment of inflammatory conditions of the scalp. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023089 introduction several dermatological diseases may lead to inflammatory conditions of the scalp.  hyperkeratosis, pruritus, alopecia, and inflammatory signs (such as erythema and purulence) are common symptoms of scalp disorders and therefore a significant overlap in clinical  symptomatology can be seen. most of these afflictions are recalcitrant conditions, and corticosteroids have been widely used, in spite of its well-known side effects of atrophy and rebound [1,2]. treatment of these conditions varies accordingly to the disease itself, as the pathogenic principles are also different, however, the large amount of hair follicles and intense production of sebum in the region presents a challenge for topical therapies. the most common conditions are lichen planus pilaris (lpp), discoid lupus (dl), frontal fibrosing alopecia (ffa), erosive pustulosis of the scalp (eps) and folliculitis decalvans (fd). among the drugs that can be used as an alternative to corticosteroids, tacrolimus is a valid option. tacrolimus is a metabolite of the fungus streptomyces tsukubaensis, developed as an anti-t-cell immunosuppressor. it acts by inhibiting the production of interleukins, such as il-2, il-3, il-4, tnfα, and gm-csf, being more effective and with slightly fewer secondary effects than cyclosporine [1]. it is available commercially for oral, intravenous and topical use, being the latter commercialized as creams, ointment or ophthalmologic drops. topical immunomodulators (such as tacrolimus and pimecrolimus) have been originally developed for the treatment of atopic dermatitis but their safety profiles and excellent efficacy as anti-inflammatory agents make them attractive candidates to treat many other skin disorders. in this context, these drugs have been extensively studied in dermatology for not only atopic dermatitis but also allergic contact dermatitis, erosive mucosal lichen planus, seborrheic dermatitis, and pyoderma gangrenosum [2]. objectives in this article, we discuss the use of tacrolimus in solution, which even if not commercially available can be prepared in a compounding pharmacy, as an alternative for different inflammatory conditions of the scalp that typically require steroids for long-term treatment. we present a case series where it has been used as an alternative for maintenance treatment. methods this study was conducted at a referral dermatology unit in italy, under open-label conditions. were enrolled patients aged 24–90 years, from both genders (13 females and 9 males), with confirmed histologic diagnosis of lpp, dl, ffa, fd or epf. histological diagnosis had been recorded on patients charts, after a 4 mm punch biopsy and analyzed by an experienced dermatopathologist. patients were informed of the potential benefits and risks of topical application of tacrolimus and had agreed to apply as indicated and signed the informed consent. patients who did not complete the 24-week follow-up were excluded from the study. assessment included the patients age, gender, clinical and dermoscopical images, past therapies and adverse events. all patients after enrolment were subsequently followed-up and assessed by the same 3 dermatologists at 4-week intervals until 24 weeks, and related data and information regarding improvement were recorded. an investigator global assessment (iga) score of poor, good or excellent response was stablished in every visit. the response rate was graded as excellent (>75% of hair regrowth or absence of inflammatory signs), good (>50 to 75% of hair regrowth or improve of inflammatory signs), poor (>0 to 25%), and no response. the effective rate = (good + excellent cases number)/total cases number) was calculated. additionally, local adverse reactions, including erythema, atrophy, telangiectasia, pigment changes, and folliculitis were observed throughout the study period. tacrolimus solution 0.1% (tacrolimus  monohydrate 0.5-mg/ml in syrspend™ sf solution, ph 4, fagron) was prepared by the same pharmacist, as it is not commercially available, and was applied twice daily for one month, then once daily for another month and alternate days for 4 months. safety parameters included symptoms and objective findings. patients were required not to apply other medications during the study period. results baseline demographics of the 22 patients enrolled were recorded, including 13 women and 9 men, with ages ranging from 24 to 90 years. of these 22, 13 patients had a diagnosis of lpp, 2 of dl, 2 of fd, 2 of eps and 3 of ffa, all with previous punch biopsies that confirmed histologically the diagnosis. the average course of disease was of 8 ± 3 months. the overall effective rate, defined as some degree of hair regrowth and cessation of inflammation (good or excellent response), was of 95,4% and 86% after 1 and 6 months respectively. table 1 presents the results for each condition. mild redness and scratch occurred in one patient. no serious local adverse reactions were detected. one patient with lpp did not respond to the therapy and two patients with lpp lost response after 6 months of therapy. figures 1-4 show clinical and tricoscopic results before and after treatment. original article | dermatol pract concept. 2023;13(2):e2023089 3 table 1. results age gender diagnosis iga 1 month iga 2 months iga 6 months 62 female lpp 2 3 3 24 male lpp 3 2 1 52 male lpp 2 2 1 75 female lpp 2 2 2 72 female lpp 2 3 3 73 female lpp 2 2 3 63 female lpp 2 3 3 36 male lpp 2 3 2 61 male lpp 0 0 0 40 female lpp 3 3 3 70 female lpp 2 3 3 54 female lpp 2 3 3 51 female lpp 3 3 2 90 male eps 3 2 2 84 male eps 2 3 3 77 female dl 2 3 2 74 male dl 3 3 3 40 male fd 3 3 3 53 male fd 2 3 3 62 female ffa 2 3 3 64 female ffa 2 2 2 47 female ffa 3 3 3 iga: investigators global assessment (1: poor / 2: good / 3: excellent); lpp: lichen planus pilaris, fd: folliculitis decalvans; eps: erosive pustulosis of the scalp; dl: dyscoid lupus; ffa: fibrosing frontal alopecia figure 1. (a) clinical presentation at first visit of a 68-year-old female with dyscoid lupus. an erythematous and desquamative plaque of the vertex. (b) trichoscopy (20x) showing squamation, prominent arborizing blood vessels and brown scattered pigmentation. (c) clinical presentation after 1 month of treatment. (d) trichoscopy showing no more signs of inflammation. 4 original article | dermatol pract concept. 2023;13(2):e2023089 figure 2. (a) clinical image of a scarring alopecia of the vertex with signs of inflammation, histologically compatible with folliculitis decalvans. (b) trichoscopy showing follicular hyperkeratosis, perifollicular erythema, tufted hairs, and cicatricial white patches. (c) clinical image of a scarring alopecia of the vertex without signs of inflammatory activity. (d) trichoscopy of a scarring alopecia. figure 3. (a) clinical image of a scarring alopecia of the vertex with signs of desquamation, histologically compatible with lichen planus pilaris. (b) trichoscopy reveals absent follicles, white dots, tubular perifollicular scale and perifollicular erythema, follicular inflammation and fibrosis. (c) clinical image of a scarring alopecia of the vertex without signs of inflammatory activity. (d) trichoscopy of a spent scarring alopecia. original article | dermatol pract concept. 2023;13(2):e2023089 5 figure 4. (a) clinical image of a scarring frontotemporal alopecia histologically compatible with frontal fibrosing alopecia. (b) trichoscopy showing follicular hyperkeratosis, perifollicular erythema, lonely hair and cicatricial white patches. (c) clinical image of repilation after 6 months without signs of inflammatory activity. (d) trichoscopy revealing discreet follicular hyperkeratosis and repilation. conclusions in this case series we discussed the use of tacrolimus in a solution for different inflammatory conditions of the scalp. even if those conditions differ in pathology and have different approaches regarding therapy, topical steroids are usually the first line of therapy for lp, dl, ffa and eps and antibiotics for fd. sometimes, however, corticosteroids might not be completely effective and these conditions when left untreated might evolve into scarring alopecia. literature review did not show any results for the use of tacrolimus in solution instead of ointment or cream as an alternative treatment for inflammatory conditions of the scalp [10-18]. the majority of studies available consider the treatment of lp and dl as the same regarding all anatomic sites, except for oral mucosa, being the use of topical or systemic corticosteroids the first line therapy [10,11]. however, most patients eventually relapsed, since the corticosteroid treatment could not be maintained for longer periods. ffa has been extensively studied in the more recent years, and current consensus recommends topical treatments including corticosteroids, minoxidil, and calcineurin inhibitors and/or systemic treatments including 5α-reductase inhibitors, hydroxychloroquine, and retinoids [13]. intralesional triamcinolone acetonide has also been described, with different response rates and recurrence levels. fd, even though several publications are available regarding the treatment, most studies evaluated had small sample size, lacked control groups, and randomization, and in these studies combination of clindamycin and rifampicin were the most commonly referred [14]. nevertheless, we agree initial treatment with antibiotics is required, most patients recur after the treatment, so maintenance with tacrolimus solution is a viable option. a study that evaluated 4 patients with fd with tacrolimus in ointment showed that these patients significantly controlled their condition, stopping inflammatory lesions and progression of the disease, although alopecia and tufted hairs remained unchanged and the discontinuation of the therapy produced rapid relapses in all cases [19]. calcineurin inhibitors have already been described in the literature as a good choice for inflammatory conditions of the scalp. some case reports showed only limited improvement in lpp (total number of patients: 12; global response rate: 23.1% (2 of 12); response rate in monotherapy: 11.1%) [15]. regarding eps, tacrolimus has recovered skin atrophy both during and after treatment and also led to 40–50% regrowth of hair after 2 months of therapy [16]. 6 original article | dermatol pract concept. 2023;13(2):e2023089 j dermatol. 2021;60(7):818-828. doi: 10.1111/ijd.15365. pmid: 33319363. 6. strazzulla lc, avila l, lo sicco k, shapiro j. novel treatment using low-dose naltrexone for lichen planopilaris. j drugs dermatol. 2017;16(11):1140-1142. pmid: 29141063. 7. esteban-lucía l, molina-ruiz am, requena l. update on frontal fibrosing alopecia. actas dermosifiliogr. 2017;108(4):293-304. doi: 10.1016/j.ad.2016.11.012. pmid: 28117051. 8. otberg n, kang h, alzolibani aa, shapiro j. folliculitis decalvans. dermatol ther. 2008;21(4):238-244. doi: 10.1111/j.15298019.2008.00204.x. pmid: 18715292. 9. elewski be. clinical diagnosis of common scalp disorders. j investig dermatol symp proc. 2005;10(3):190-193. doi: 10.1111/j.1087-0024.2005.10103.x. pmid: 16382661. 10. sharma a, białynicki-birula r, schwartz ra, janniger ck. lichen planus: an update and review. cutis. 2012;90(1):17-23. pmid: 22908728. 11. walling hw, sontheimer rd. cutaneous lupus erythematosus: issues in diagnosis and treatment. am j clin dermatol. 2009;10(6):365-381. doi: 10.2165/11310780-00000000000000. pmid: 19824738. 12. gupta s, jawanda mk. oral lichen planus: an update on etiology, pathogenesis, clinical presentation, diagnosis and management. indian j dermatol. 2015;60(3):222-229. doi: 10.4103/0019-5154.156315. pmid: 26120146. pmcid: pmc4458931. 13. iorizzo m, tosti a. frontal fibrosing alopecia: an update on pathogenesis, diagnosis, and treatment. am j clin dermatol. 2019;20(3):379-390. doi: 10.1007/s40257-019-00424-y. pmid: 30659454. 14. rambhia ph, conic rrz, murad a, atanaskova-mesinkovska n, piliang m, bergfeld w. updates in therapeutics for folliculitis decalvans: a systematic review with evidence-based analysis. j am acad dermatol. 2019;80(3):794-801.e1. doi: 10.1016/j. jaad.2018.07.050. pmid: 30092322. pmcid: pmc6363910. 15. errichetti e, figini m, croatto m, stinco g. therapeutic management of classic lichen planopilaris: a systematic review. clin cosmet investig dermatol. 2018;11:91-102. 16. karanfilian km, wassef c. erosive pustular dermatosis of the scalp: causes and treatments. int j dermatol. 2021;60(1):25-32. doi: 10.1111/ijd.14955. pmid: 32516510. 17. kuhn a, gensch k, haust m, et al. efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: a multicenter, randomized, double-blind, vehicle-controlled trial. j am acad dermatol. 2011; 65(1):54–64, 64.e1–e2. doi: 10.1016/j. jaad.2010.03.037. pmid: 21501887. 18. strazzulla lc, avila l, li x, et al. prognosis, treatment, and disease outcomes in frontal fibrosing alopecia: a retrospective review of 92 cases. j am acad dermatol. 2018;78:203–205. doi: 10.1016/j.jaad.2017.07.035. pmid: 29241787. 19. bastida j, valerón-almazán p, santana-molina n, medina-gil c, carretero-hernández g. treatment of folliculitis decalvans with tacrolimus ointment. int j dermatol. 2012;51(2):216-220. doi: 10.1111/j.1365-4632.2011.05212.x. pmid: 22250634. one randomized double-blind study of 38 individuals, 14 with dle, found significant improvement in those treated with 0.1% tacrolimus ointment applied twice daily for 3 months compared to vehicle [17]. in a study on 92 patients with ffa, patients treated with 0.3% tacrolimus were significantly more likely to stabilize in 3 months compared with patients treated with clobetasol/ betamethasone (p 0.0297), but with longer median time of stabilization [18]. these studies current limitation are small simple size and the lack of comparison between regular treatment with tacrolimus in cream/ointment, because most patients did not comply on applying the cream on the scalp, making the comparison of outmost difficulty. on our study, a good compliance was observed and most patients had a satisfactory response for their conditions. limitation of this study is that, as a case series, it does not have a control group, and further studies should address individually each condition in a controlled trial. still, tacrolimus as solution remained a viable option particularly for a long-term maintenance treatment. our case series showed tacrolimus as solution could be an interesting alternative, as it is not related to atrophy if used for long periods and therefore can be of great use for inflammatory conditions that are usually prone to recurrences. moreover, this vehicle is more comfortable for patients on the scalp than ointment, especially female patients where the cosmetic aspect of the hair is usually taken into consideration when complying with a therapy. further long-term comparative studies are required for better understanding. references 1. rallis e, korfitis c, gregoriou s, rigopoulos d. assigning new roles to topical tacrolimus. expert opin investig drugs. 2007;16(8):1267-1276. doi: 10.1517/13543784.16.8.1267. pmid: 17685874. 2. nasr is. topical tacrolimus in dermatology. clin exp dermatol. 2000;25(3):250-254. doi 10.1046/j.1365-2230.2000.00628.x. pmid: 10844509. 3. hordinsky m.  cicatricial alopecia: discoid lupus erythematosus.  dermatol ther. 2008;21(4):245-248. doi: 10.1111/j.15298019.2008.00205.x. pmid: 18715293. 4. suchonwanit p, udompanich s, thadanipon k, chanprapaph k. trichoscopic signs in systemic lupus erythematosus: a comparative study with 109 patients and 305 healthy controls. j eur acad dermatol venereol. 2019;33(4):774-780. doi: 10.1111/ jdv.15421. pmid: 30633418. 5. żychowska m, żychowska m. dermoscopy of discoid lupus erythematosus – a systematic review of the literature. int dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(1):e2023025 1 eruptive xanthoma as a sign of underlaying severe metabolic disorder jordana rigolon de lara1, gabriela momente miquelin2, jan lapins4, elizabeth leocadia fernades3 1 university of mogi das cruzes (umc), brazil 2 university of mogi das cruzes (umc); brazilian society of dermatology, brazil 3 dermatoscopy and melanoma clinic at unitau; brazilian society of dermatology; international dermoscopy society, brazil 4 departament of dermatology, karolinska university hospital and karolinska institutet, sweden keywords: eruptive xanthoma, hypertriglyceridemia, dermoscopy, xanthomatosis citation: rigolon de lara j, momente miquelin g, lapins j, leocadia fernades e. eruptive xanthoma as a sign of underlaying severe metabolic disorder. dermatol pract concept. 2023;13(1):e2023025. doi: https://doi.org/10.5826/dpc.1301a25 accepted: may 1, 2022; published: january 2023 copyright: ©2023 rigolon de lara et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: jordana rigolon de lara, av. prefeito carlos ferreira lopes, 635, apto 172, zip code: 08773-490, mogi das cruzes sp, brazil. e-mail: jordanarigolon@gmail.com case presentation a 40-year-old woman presented with a 2 year history of multiple asymptomatic yellow-erythematous papules and plaques on the upper limbs, extending to the trunk and lower limbs. dermatoscopy showed aggregates of white to yellow clods on a structureless pink background. history of type 2 diabetes mellitus. laboratory abnormalities occurred: triglycerides 6137 mg/dl (0-149 mg/dl), glucose 317 mg/dl (65-99 mg/dl). histopathological examination revealed xanthomatous cells with immunohistochemistry: cd68+ in numerous histiocytes, compatible with eruptive xanthoma. teaching point eruptive xanthomas develop in cases of pronounced and abrupt onset hypertriglyceridemia and are characterized by small, yellow, cutaneous papules, 1-4 mm in diameter, with an erythematous halo around the base. they appear suddenly in crops over pressure points and extensor surfaces of the arms, legs, and buttocks. these forms of xanthomas develop exclusively in the presence of lactescent plasma and severe hypertriglyceridemia [1]. hypertriglyceridemia causes morbidity and mortality by significantly increasing the risk of atherosclerosis, cardiovascular disease and stroke. in addition, there is an increased risk of acute pancreatitis [2]. it is therefore very important to recognize the clinical and dermatoscopic features of the cutaneous presentation of this severe metabolic disease and request adequate laboratory workup and initiate appropriate treatment. 2 image letter | dermatol pract concept. 2023;13(1):e2023025 references 1. parker f. xanthomas and hyperlipidemias.  j am acad dermatol. 1985;13(1):1-30. doi:10.1016/s0190-9622(85)70139-9. pmid: 4031142. figure 1. (a, b) multiple yellow-erythematous papules and plaques. (c) dermatoscopy showed aggregates of white to yellow clods on a structureless pink background. 2. nessel ta, kerndt cc, bills ja, sikorski l. eruptive xanthomas: a warning sign of future hyperlipidemia complications. int j res dermatol. 2020;6:579-583. doi:10.18203/ issn.2455-4529. dermatology: practical and conceptual 184 observation | dermatol pract concept 2018;8(3):7 dermatology practical & conceptual www.derm101.com subcutaneous scalp nodule as the presenting symptom of systemic light-chain amyloidosis joseph tadros1, stacey goodman2,3, eric r. tkaczyk2,3,4 1 university of cincinnati college of medicine, cincinnati, oh, usa 2 vanderbilt university medical center, nashville, tn, usa 3 department of veterans affairs, tennessee valley health system, nashville, tn, usa 4 department of biomedical engineering, vanderbilt university, nashville, tn, usa key words: nodular amyloidosis, systemic al amyloidosis, pilar cyst, subcutaneous nodule citation: tadros j, goodman s, tkaczyk er. subcutaneous scalp nodule as the presenting symptom of systemic light-chain amyloidosis. dermatol pract concept. 2018;8(3):184-187. doi: https://doi.org/10.5826/dpc.0803a07 received: october 1, 2017; accepted: november 21, 2017; published: july 31, 2018 copyright: ©2018 tadros et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: eric tkaczyk, md, phd, director, vanderbilt cutaneous imaging clinic, 719 thompson lane, suite 26300, nashville, tn 26300 usa. email: eric.tkaczyk@vanderbilt.edu. case presentation an 81-year-old man with a history of carpal tunnel syndrome, diabetes mellitus, and nonmelanoma skin cancer presented with a 1-year history of an asymptomatic 4 mm diameter subcutaneous nodule on the right anterior scalp. a pilar cyst was suspected and an excisional biopsy was performed. microscopic examination revealed extensive dermal infiltration by amorphous hyaline and fibrillary material (figures 1-3) revealing the diagnosis of amyloidosis. initial laboratory workup revealed normal protein gap, unremarkable complete blood counts (cbc), and comprehensive metabolic panel. however, further laboratory investigation confirmed systemic light-chain (al) amyloidosis involving several organ systems. hematopoietic system involvement was characterized by an elevated serum free lambda light chain of 152 mg/l (range 5.71-26.30 mg/l), moderate serum lambda bence-jones protein, and faint urinary faint lambda bence-jones protein as measured by serum protein and urine protein electrophoresis. cardiac involvement was evidenced by a right bundle branch block on electrocardiogram and moderate left ventricular hypertrophy with increased interventricular thickness and moderate diastolic dysfunction on echocardiogram. an underlying plasma cell dyscrasia was evidenced by findings on a bone marrow biopsy of a lambda-restricted increase in plasma cells (15%-20%) on immunohistochemistry and flow cytometry. fortunately, a skeletal survey was negative, indicating no bony involvement. additionally, autoimmune titers were within normal limits for antinuclear antibody (ana), anti-ro/ssa, and anti-la/ we present a case of subcutaneous nodular amyloidosis mimicking a pilar cyst. further evaluation led to the diagnosis of malignant systemic light-chain amyloidosis. the epidemiology and histopathological features of light-chain amyloidosis with cutaneous involvement are reviewed, as well as current recommendations for initial evaluation. abstract observation | dermatol pract concept 2018;8(3):7 185 of 290 plca cases at initial diagnosis, only 4 went on to develop systemic amyloidosis [3]. in their own retrospective institutional study identifying cases of localized nodular amyloidosis, 0 of the 20 patients went on to develop systemic disease over a 7.6-year mean follow-up period [3]. though it can be plca, which is relatively benign and requires only routine monitoring, nodular amyloidosis can also be the presenting sign of a serious systemic pathology, such as systemic al amyloidosis in this case. systemic al amyloidosis has a reported incidence of only 3 to 5 cases per million population, correlating to roughly 1 750 to 3 200 new cases annually in the united states [8,9]. cutaneous involvement occurs in up to 29% to 40% of cases [10]. histopathological examination of nodular amyloidosis is characterized by amyloid deposits, which appear as amorphous, acellular, fissured, eosinophilic material in the papilssb autoantibodies. diagnosis of systemic primary lambda light-chain amyloidosis with cutaneous manifestations was made. a cardiac mri was obtained to further characterize the cardiac involvement. treatment with cyclophosphamidebortezomib-dexamethasone was initiated with subsequent outpatient follow-up. discussion amyloidosis is not just one disease but a rare group of diseases resulting from the extracellular deposition of misfolded proteins in various tissues as toxic amyloid aggregates. amyloidosis is characterized based on the subtype of amyloid fibril protein as well as the mechanism of deposition. cutaneous amyloidosis may be organized into one of 3 groups: primary localized cutaneous amyloidosis (plca), secondary localized cutaneous amyloidosis, or systemic al amyloidosis with cutaneous involvement [1]. among the plca group, lichen, macular, biphasic, and nodular forms are recognized. the most encountered type of plca, lichen amyloidosis, presents clinically as multiple hyperpigmented, clustered, pruritic papules on the lower extremities [2]. macular amyloidosis presents darkly pigmented macules with a rippled surface. both lichen and macular types are derived from cytokeratins [2]. the biphasic form is simply a mix of the macular and lichen amyloidoses. nodular amyloidosis, accounting for 1.5% of plca cases, presents as either single or multiple lesions and is derived from immunoglobulins, commonly lambda light chain. there have been less than 100 cases of primary localized nodular amyloidosis reported to date [2-5]. some studies suggest that nodular amyloidosis may be associated with systemic disease in 7% to 50% of patients [6,7]. however, a literature review conducted by biewend et al found that figure 1. amyloid deposition from excisional skin biopsy specimen (hematoxylin and eosin [h&e] staining, original magnification ×4). [copyright: ©2018 tadros et al.] figure  2. amyloid deposition from excisional skin biopsy specimen (h&e staining, original magnification ×40). congo red stain revealed abundant eosinophilic, amorphous material exhibiting dermal apple-green birefringence with polarization, consistent with amyloid deposition (figure 3). [copyright: ©2018 tadros et al.] figure  3. amyloid deposition on excisional skin biopsy specimen (congo red, original magnification ×40). [copyright: ©2018 tadros et al.] 186 observation | dermatol pract concept 2018;8(3):7 biopsy is done to monitor for monoclonal plasma cells and if present, requires further evaluation to determine whether the patient has active multiple myeloma [15]. aspiration of subcutaneous tissues of the abdominal wall or of an involved organ (in our patient, the skin) is required to definitively confirm the diagnosis of systemic amyloidosis [16]. because primary nodular amyloidosis has a significant association with sjögren syndrome, serology for ana, anti-ro/ssa, and anti-la/ssb may also be considered, which in this case were unremarkable [17-19]. conclusions subcutaneous nodules, which may appear clinically benign, should not be ignored; physicians must consider the patient’s history when assessing these lesions. the incidental finding of amyloid deposition on biopsy of a subcutaneous nodule in an asymptomatic, healthy individual warrants further evaluation to better determine if it represents localized amyloidosis or the initial manifestation of a systemic process. although a rare initial presentation, cutaneous manifestations of systemic al amyloidosis may pose as the first clue toward successful diagnosis. acknowledgement dr. tkaczyk is grateful for the support from nih k12 ca 090625. references 1. schucht k, schröder j, siegmund h, grafe c, schreml s. nodular cutaneous amyloidosis at the temple. case rep dermatol. 2016;8(2):193-196. doi: 10.1159/000447234. 2. weidner t, illing t, elsner p. primary localized cutaneous amyloidosis: a systematic treatment review. am j clin dermatol. 2017;18(5):629-642. doi: 10.1007/s40257-017-0278-9. 3. kaltoft b, schmidt g, lauritzen af, gimsing p. primary localised cutaneous amyloidosis—a systematic review. dan med j. 2013;60(11):a4727. 4. biewend ml, menke dm, calamia kt. the spectrum of localized amyloidosis: a case series of  20  patients and review of the literature. amyloid. 2006;13(3):135-142. doi: 10.1080/13506120600876773. 5. nguyen tu, oghalai js, mcgregor dk, janssen nm, huston dp. subcutaneous nodular amyloidosis: a case report and review of the literature. hum pathol. 2001;32(3):346-348. doi: 10.1053/ hupa.2001.22742. 6. brownstein mh, helwig eb. the cutaneous amyloidoses. i. localized forms. arch dermatol. 1970;102(1):8-19. doi: 10.1001/ archderm.1970.04000070010002. 7. woollons a, black mm. nodular localized primary cutaneous amyloidosis: a long-term follow-up study. br j dermatol. 2001;145(1):105-109. doi: 10.1046/j.1365-2133.2001.04291.x. 8. wechalekar ad, gillmore jd, hawkins pn. systemic amyloidosis. lancet. 2016;387(10038):2641-2654. doi: 10.1016/s01406736(15)01274-x. lary and reticular dermis as well as in the subcutaneous fat [11]. flattened rete ridges may be observed in the overlying epidermis. amyloids stained with congo red display applegreen birefringence under polarized light. because nodular amyloid is produced by plasma cell infiltration, specimens may stain with immunohistochemical stains for kappa or lambda chains [11]. it is common for cysts to be falsely diagnosed based on appearance alone. one retrospective analysis aimed to see if histological findings correlated with clinical diagnosis. the authors found that 13 of 295 cases were positive for calcium deposition, described as calcinosis cutis, on histology [12]. these findings compromised all the cases under the deposition category: no cases of amyloid deposition were evident. this highlights the rarity of nodular amyloidosis mimicking a cystic lesion. investigation of a benign-appearing subcutaneous nodule as the initial presentation for asymptomatic al amyloidosis in a relatively healthy patient is atypical, as the diagnosis is often made after workup of unexplained cardiomyopathy, proteinuria, neuropathy, or hepatomegaly. it is difficult to determine the precise occurrence of this presentation given the limited number of cases in the literature. importantly, since nodular primary cutaneous amyloidosis is so rare, biopsy-confirmed amyloid lesions warrant further workup as immunoglobulin light-chain amyloid fibrils may be a complication of systemic and multiple myeloma-associated amyloidosis [13]. therefore, evaluation for systemic involvement at the time of diagnosis is recommended. plasma cell disorders are diagnosed by quantitative immunoglobulin assays, serum and urine free light chains, and serum protein electrophoresis or urine protein electrophoresis with immunofixation. serum calcium and creatinine as well as a skeletal survey and bone marrow biopsy are used to better characterize the plasma cell dyscrasias. the diagnosis of active multiple myeloma requires greater than 10% clonal plasma cells on bone marrow biopsy plus one or more multiple myeloma defining events based on the crab criteria: hypercalcemia, renal failure, anemia, or lytic bone lesions. in this context, our patient had inactive myeloma-associated al amyloidosis. presenting clinical symptoms of systemic al amyloidosis varies based on the organ system affected. cardiac involvement may manifest as a new av or bundle branch block; renal involvement by albuminuria from glomerular injury; gi involvement by nausea, vomiting, or diarrhea; autonomic dysfunction by symptoms of orthostasis or gi dysmolity; and neurologic involvement by peripheral neuropathy. initial workup for systemic amyloidosis may include cbc, chemistries, serum free light chains, serum and urine protein electrophoresis with immunofixation, and urinary bence-jones protein [14]. the presence of a monoclonal protein is found in 80% to 90% of serum and urine immunochemistry studies in patients with primary amyloidosis [15]. bone marrow observation | dermatol pract concept 2018;8(3):7 187 15. wei a, juneja s. bone marrow immunohistology of plasma cell neoplasms. j clin pathol. 2003;56(6):406-411. doi: 10.1136/ jcp.56.6.406. 16. van gameren ii, hazenberg bp, bijzet j, van rijswijk mh. diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. arthritis rheum. 2006;54(6):2015-2021. doi: 10.1002/ art.21902. 17. vitali c, bombardieri s, jonsson r, et al; european study group on classification criteria for sjögren’s syndrome. classification criteria for sjögren’s syndrome: a revised version of the european criteria proposed by the american-european consensus group. ann rheum dis. 2002;61(6):554-558. doi: 10.1136/ ard.61.6.554. 18. brown aj, spicknall ke, mutasim df. multiple lesions of primary cutaneous nodular amyloidosis in sjögren syndrome. j am acad dermatol. 2012;67(6):e267-e268. doi: 10.1016/j. jaad.2012.05.012. 19. butler j. sjögren syndrome–associated localized cutaneous nodular amyloidosis. j am acad dermatol. 2013;68(4)(suppl 1):ab72. 9. falk rh, comenzo rl, skinner m. the systemic amyloidoses. n engl j med. 1997;337(13):898-909. doi: 10.1056/ nejm199709253371306. 10. steciuk a, dompmartin a, troussard x, et al. cutaneous amyloidosis and possible association with systemic amyloidosis. int j dermatol. 2002;41(3):127-132; discussion 133-124. doi: 10.1046/j.1365-4362.2002.01411.x. 11. borrowman ta, lutz me, walsh js. cutaneous nodular amyloidosis masquerading as a foot callus. j am acad dermatol. 2003;49(2):307-310. doi: 10.1067/s0190-9622(03)00433-x. 12. ring cm, kornreich da, lee jb. clinical simulators of cysts. j am acad dermatol. 2016;75(6):1255-1257. doi: 10.1016/j. jaad.2016.07.013. 13. breathnach sm. the cutaneous amyloidoses. pathogenesis and therapy. arch dermatol. 1985;121(4):470-475. doi: 10.1001/ archderm.1985.01660040054011. 14. musbahi e, hameed o, lateo s. a case presentation of nodular primary localized cutaneous amyloidosis: learning points and update. j am acad dermatol. 2015;72(5)(suppl 1):ab36. doi: 10.1016/j.jaad.2015.02.155. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023029 1 the psychosocial impact of chronic facial dermatoses in adults yunus ozcan1, mehmet ali sungur2, begum yaman ozcan3, yavuz eyup4, emin ozlu5 1 department of dermatology, duzce ataturk state hospital, duzce, turkey 2 department of biostatistics, duzce university faculty of medicine, duzce, turkey 3 department of psychiatry, duzce university faculty of medicine, duzce, turkey 4 department of dermatology, unye state hospital, unye/ordu, turkey 5 associate professor of dermatology, private practice, duzce, turkey key words: acne, anxiety, depression, rosacea, seborrheic dermatitis citation: ozcan y, sungur ma, yaman ozcan b, eyup y, ozlu e. the psychosocial impact of chronic facial dermatoses in adults. dermatol pract concept. 2023;13(1):e2023029. doi: https://doi.org/10.5826/dpc.1301a29 accepted: april 16, 2022; published: january 2023 copyright: ©2023 ozcan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: yunus ozcan, department of dermatology, duzce ataturk state hospital, duzce, turkey. e-mail: yunusozcan18@gmail.com introduction: skin diseases have negative psychological and social consequences, especially when they are chronic and affect a visible area of the body, such as the face. objectives: the purpose of this study is to investigate and compare the psychosocial impact of three common chronic dermatoses of the face: acne, rosacea, and seborrheic dermatitis. methods: the dermatology life quality index (dlqi), hospital anxiety and depression scale (hads), and social appearance anxiety scale (saas) were used to compare acne, rosacea, and seborrheic dermatitis patients and healthy controls. the relationships between dlqi, hads, and saas results were investigated, as well as their associations with disease duration and severity. results: the study included 166 acne patients, 134 rosacea patients, 120 seborrheic dermatitis patients, and 124 controls. the patient groups had significantly higher dlqi, hads, and saas scores than the control group. rosacea patients had the highest dlqi and saas scores, as well as the highest anxiety prevalence. patients with seborrheic dermatitis had the highest rate of depression. the dlqi, hads, and saas results were moderately correlated with each other, but their relationship with disease duration and severity was insignificant or weak at best. conclusions: chronic facial dermatoses have a detrimental impact on mood and quality of life. although patients with acne, rosacea, and seborrheic dermatitis have distinct lesions, the outcomes in terms of quality of life, anxiety, and depression are largely similar. furthermore, these patients report similar levels of social anxiety as a result of their overall appearance. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023029 introduction healthy skin shields the organism from the outside. however, in its absence, a person becomes not only vulnerable to the physical environment but also suffers from psychological and social problems. while it is easier to conceal pathologies in certain areas, concealing the face is often more difficult. one’s social, economic, and romantic opportunities are shaped by one’s face. thus, facial dermatoses may be more likely to have negative consequences. acne, rosacea, and seborrheic dermatitis are chronic skin diseases that primarily affect the face. although each of these diseases is well known to be associated with poor quality of life, anxiety, and depression, no study has been conducted to compare the psychosocial burden of these diseases. in this study, we examined acne, rosacea, or seborrheic dermatitis patients who presented to a dermatology outpatient clinic with facial complaints. we hoped to use the findings to better identify patients who might benefit from psychosocial support in addition to dermatological care, as well as to strengthen patient compliance. the patients’ quality of life as well as the frequency and severity of anxiety and depression were compared. also, the social anxiety caused by patients’ overall appearances—which extended beyond their facial appearance—was compared. objectives the purpose of this study was to compare the quality of life, anxiety, and depression levels in adult acne, rosacea, and seborrheic dermatitis patients and healthy controls. we also compared the social anxiety caused by overall appearance (rather than just the face) between these groups. methods study design, participants and ethics this cross-sectional study included patients between the ages of 18 and 65 who presented to the duzce university hospital dermatology clinic with acne, rosacea, or seborrheic dermatitis between october 2020 and july 2021. patients who presented with more than one of these diagnoses, as well as patients with other facial dermatoses, scarring, or dysmorphia, were excluded from the study. patients who were pregnant or breastfeeding, patients with comorbidities that could cause neurological or psychiatric symptoms, and those who had used central nervous system-influencing medications in the previous 6 months (including systemic isotretinoin) were all excluded from the study. hospital employees were chosen as healthy controls. the study protocol was reviewed and approved by the duzce university ethics committee (07.09.2020–2020/199). all participants in the study provided written consent. sociodemographic and clinical characteristics all participants’ ages, genders, and bmis, as well as the severity and duration of illness for patient groups, were recorded. global acne grading system[1] for acne patients, rosacea clinical scorecard[2] for rosacea patients, and seborrheic dermatitis area severity index[3] for seborrheic dermatitis patients were used to assess the severity of illness, and only the scores obtained from the facial area were used. the dermatology quality of life index (dqli) this scale, created by finlay[4] and adapted by ozturkcan[5], aims to measure and compare data across all skin diseases. questions are answered based on the previous week. the higher the final score, the greater the decrease in quality of life. the outcomes are graded as follows: 0 – 1 no effect at all on patient’s life 2 – 5 small effect on patient’s life 6 – 10 moderate effect on patient’s life 11 – 20 very large effect on patient’s life 21 – 30 extremely large effect on patient’s life it is further divided into six subscales to determine the focus of the impact on quality of life: questions 1&2: symptoms, feelings questions 3&4: daily activities questions 5&6: leisure question 7: work/school questions 8&9: personal relationships question 10: treatment the hospital anxiety and depression scale (hads) the hospital anxiety and depression scale was created to screen for the presence of anxiety and depression in patients with physical illnesses who presented to non-psychiatric clinics[6]. half of the 14-question scale investigates anxiety, while the other half investigates depression. it is answered based on the previous week. in 1993, aydemir et al. adapted it, and cut-off scores indicating the presence of anxiety and depression were determined[7]. an anxiety subscale score of 11 or higher indicates the presence of anxiety, whereas a depression subscale score of 8 or higher indicates the presence of depression[7]. the results also reflect the severity of anxiety and depression, allowing them to be used in comparisons or patient follow-up[6]. the social appearance anxiety scale (saas) the social appearance anxiety scale was developed by hart et al. in 2008[8] and later adapted by dogan et al. in 2010[9]. it was created to assess fear in situations where the person’s original article | dermatol pract concept. 2023;13(1):e2023029 3 overall external appearance can be evaluated. the appearance is assessed in a broader context, rather than focusing on a specific feature such as hair, nose, or chest size. its primary purpose is to assess the components of social anxiety. the scale consists of 16 questions with no cut-off point. as the score rises, so does the person’s anxiety about his or her appearance. statistics baseline demographic and clinical characteristics in acne, rosacea, seborrheic dermatitis, and control groups were described using mean (standard deviation), median (interquartile range), frequencies, and percentages. the pearson chi-square test was used to compare the categorical variable (sex). the continuous variables (age, bmi, and duration of illness) were initially evaluated using the kolmogorov-smirnov test, and then compared using the kruskal-wallis test because they did not have a normal distribution. pairwise comparisons were analyzed using the mann-whitney u test with bonferroni correction. the distribution of the dlqi, hads, and saas results in the acne, rosacea, seborrheic dermatitis, and control groups was analyzed using the kolmogorov-smirnov test. because the data did not have a normal distribution, the kruskal-wallis test was performed to compare the results. pairwise comparisons were analyzed using the mann whitney u test, with bonferroni correction applied in cases where the difference was found to be significant. furthermore, quade’s non-parametric analysis of covariance (ancova) was employed to account for differences in baseline demographic factors, including age, gender, and bmi. scheffe’s method was employed as a post-hoc test. categorical variables were evaluated using pearson’s chi-square, fisher’s exact test, or fisher-freeman-halton test, depending on the expected value principle. pearson or spearman correlation analysis was used to examine correlations between continuous variables, depending on the distribution of the data. an ordinal logistic regression model was designed to analyze the relationship between acne, rosacea, seborrheic dermatitis, control groups, and dlqi outcomes using the previously described five outcome grades of the scale. for saas, an ordinal logistic regression model was also created, and the final scale score was employed as the response variable. the binary logistic regression models for anxiety and depression subscales were created using the previously defined cut-off values. the healthy controls served as the reference group. age, gender, and bmi were included as covariates in all regression models, and the results were reported as adjusted odds ratios with 95% confidence intervals. the spss 26.00 package program was used to analyze the data. statistical significance was defined as .05 or less. results participants the study enrolled 166 acne, 134 rosacea, and 120 seborrheic dermatitis patients, along with 124 healthy volunteers. rosacea patients had the highest mean age, bmi, and longest duration of illness. acne patients had the lowest mean age and bmi of any group. the majority of patients with acne and rosacea were female, while the majority of patients with seborrheic dermatitis were male (table 1). table 1. the baseline demographic and clinical features of the participants. acne rosacea seborrheic dermatitis control p n (%) 166 (30.5) 134 (24.6) 120 (22.1) 124 (22.8) — age1 mean (sd) 22.8 (5.3) 37.9 (12.9) 31.9 (12.2) 31.7 (11.1) < .001* median (iqr) 21.5 (6) 36 (22) 28 (13) 27.5 (15) [min.–max.] [18 – 55] [18 – 65] [18 – 65] [20 – 65] sex, n (%) male 51 (30.7) 29 (21.6) 89 (74.2) 64 (51.6) < .001**female 115 (69.3) 105 (78.4) 31 (25.8) 60 (48.4) bmi1 mean (sd) 22.3 (3.4) 28.8 (6.1) 25.3 (4.7) 24.8 (4.5) < .001* median (iqr) 21.6 (4) 28 (7.5) 24.6 (6.1) 24.4 (6.6) [min.–max.] [16 – 40.4] [17.5 – 53.1] [15.4 – 39.4] [16.4 – 41.5] duration of illness2, years mean (sd) median (iqr) [min. – max.] 4.7 (4.1) 4 (4.5) [0 – 20] 8.4 (9.5) 5 (10) [0 – 40] 4.9 (6.5) 3 (5) [0 – 50] 0 0 0 .003* *kruskal-wallis test **pearson chi-square pairwise comparisons are significant at p <.05 for: 1 acne vs. rosacea, seborrheic dermatitis, control; rosacea vs. seborrheic dermatitis, control 2 acne vs. rosacea; rosacea vs. seborrheic dermatitis 4 original article | dermatol pract concept. 2023;13(1):e2023029 134.513, p <.001]. the adjusted odds ratio for acne patients was 8.78 (95% ci 5.24–14.72, p <.001), for rosacea patients was 13.04 (95% ci 7.44–22.86, p <.001), and for the seborrheic dermatitis patients was 8.17 (95% ci 4.80–13.88, p <.001). the hospital anxiety and depression scale hads results suggested the presence of anxiety in 30 (18.1%) acne patients, 50 (37.3%) rosacea patients, 31 (25.8%) seborrheic dermatitis patients, and 10 (8.1%) subjects from the control group (table 3). using the previously reported cut-off points in the hads, a binary logistic regression model was used to investigate the relationship between the acne, rosacea, seborrheic dermatitis, and control groups, and the presence of anxiety. age, gender, and bmi were identified as confounders and were adjusted for. the healthy controls served as the reference group. the logistic regression model was statistically significant [χ2(6) = 37.542, p <.001]. the presence of anxiety was associated with an adjusted odds ratio of 2.59 (95% ci 1.18–5.69, p =.017) in acne patients, 5.90 (95% ci 2.73–12.73, p <.001) in rosacea patients, and 4.01 (95% ci 1.84–8.73, p <.001) in seborrheic dermatitis patients. in terms of anxiety severity, patients with rosacea scored the highest, with a mean of 8.49 (4.7). seborrheic dermatitis patients had a mean of 7.92 (4.19), acne patients had a mean of 7.32 (3.99), and the control group had a mean of 5.73 (3.52). after controlling for age, gender, and bmi, we discovered that the dermatology life quality index acne, rosacea, and seborrheic dermatitis patients (p <.001) had a significantly lower quality of life than the control group when the results were interpreted as grades (figure 1). the negative impact on quality of life was similar across acne, rosacea and seborrheic dermatitis patients. acne patients had a higher mean and median score than seborrheic dermatitis patients and a lower mean and median score than rosacea patients [dlqi, mean (sd) = acne: 5.5 (5.1); rosacea: 6.3 (5.8); seborrheic dermatitis: 4.3 (4); control: 1.3 (1.8)]. the only statistically significant difference after adjusting for age, gender, and bmi was found in pairwise comparisons between the patient groups and the healthy controls (table 2). acne patients had higher average scores on the “symptoms and feelings” and “treatment” subscales, whereas rosacea patients had higher impairment in “daily activities,” “leisure,” “work and school,” and “personal relationships.” but the only significant result was obtained when comparing patients with rosacea and seborrheic dermatitis on the subscale concerning daily activities (mean (sd): rosacea: 1.13 (1.6) – seborrheic dermatitis: .48 (.92); p = .002). ordinal logistic regression was performed to evaluate the likelihood of being in a higher dlqi grade in acne, rosacea, and seborrheic dermatitis patients, with healthy controls serving as the reference group. age, gender, and bmi were identified as confounders and were adjusted for. the logistic regression model was statistically significant [χ2(6) = 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 21,7% 22,4% 34,3% 23,1% 17,9% 10% 17,5% 47,5% 25% 72,6% 24,2% 3,2% 36,7% 26,5% 13,3% 1,8% 2,2% 0% acne rosacea seborrheic dermatitis control extremely large effectvery large effectmoderate effectsmall effectno effect figure 1. the negative impact of skin disease on quality of life. original article | dermatol pract concept. 2023;13(1):e2023029 5 in rosacea patients, and 3.53 (95% ci 1.89–6.59, p <.001) in seborrheic dermatitis patients. in terms of depression severity, rosacea patients received the highest scores, with a mean of 6.51 (3.73). this was followed by seborrheic dermatitis with a mean of 6.31 (3.62), acne with a mean of 5.66 (3.54), and the control group with a mean of 4.59 (2.89).  after controlling for age, gender, and bmi, it was found that acne, rosacea, and seborrheic dermatitis patients experienced more severe depression than healthy controls, but there was no significant difference between the patient groups (table 3). the social appearance anxiety scale according to the results of the saas, rosacea patients had the highest mean score of 38.51 (16.37). acne patients had a mean of 36.86 (14.24), seborrheic dermatitis patients had a mean of 33.83 (13.67), and the control group had a mean of patients with acne, rosacea, and seborrheic dermatitis experienced more severe anxiety than healthy controls, but there was no significant difference across the patient groups (table 3). the depression subscale suggested the presence of depression in 46 (27.7%) of the acne patients, 51 (39.5%) of the rosacea patients, 49 (41.5%) of the seborrheic dermatitis patients, and 19 (16.1%) of the control group (table 3). to examine the association between the acne, rosacea, seborrheic dermatitis, and control groups and the presence of depression, a binary logistic regression model was created using the depression cut-off points in the hads. age, gender, and bmi were identified as confounders and were adjusted for. the healthy controls served as the reference group. the logistic regression model was statistically significant [χ2(6) = 25.227, p <.001]. the presence of depression was associated with an adjusted odds ratio of 2.16 (95% ci 1.15–4.04, p =.016) in acne patients, 3.35 (95% ci 1.76–6.37, p <.001) table 2. comparison of dermatology life quality index (dlqi) scores by group. acne rosacea seborrheic dermatitis control median (iqr) 4 (5) 5 (7) 3 (5) 1 (2) [min.-max.] [0-26] [0-27] [0-16] [0-10] mean (sd) 5.5 (5.1) 6.3 (5.8) 4.3 (4) 1.3 (1.8) sem .399 .501 .372 .165 p* < .001 < .001 < .001 ref. p value for kruskal-wallis test < .001 * mann-whitney u test. after controlling for age, gender, and bmi, pairwise comparisons are significant (p <.05) for: acne vs. control; rosacea vs. control; seborrheic dermatitis vs. control. table 3. comparison of the frequency and severity of anxiety and depression by group. acne rosacea seborrheic dermatitis control p participants, n (%) 166 (30.5) 134 (24.6) 120 (22.1) 124 (22.8) anxiety yes, n (%) 30 (18.1) 50 (37.3) 31 (25.8) 10 (8.1) < .001* median (iqr) [min.max.] 7 (5) [0-19] 9 (7) [0-19] 7 (6) [0-19] 6 (4) [0-20] < .001** mean (sd) 7.32 (3.99) 8.49 (4.7) 7.92 (4.19) 5.73 (3.52) sem .31 .407 .382 .317 depression yes, n (%) 46 (27.7) 51 (39.5) 49 (41.5) 19 (16.1) < .001* median (iqr) [min.max.] 5 (5) [1 – 18] 6 (5) [0 – 19] 6 (6) [0 – 14] 4 (4) [0 – 14] < .001** mean (sd) 5.66 (3.54) 6.51 (3.73) 6.31 (3.62) 4.59 (2.89) sem .275 .323 .331 .260 * pearson chi-square ** kruskal-wallis test after controlling for age, gender, and bmi, pairwise comparisons are significant (p <.05) for: anxiety: acne vs. control; rosacea vs. control; seborrheic dermatitis vs. control. depression: acne vs. control; rosacea vs. control; seborrheic dermatitis vs. control 6 original article | dermatol pract concept. 2023;13(1):e2023029 with seborrheic dermatitis. these associations were found to be significant but weak, with the strongest link being found between the severity of seborrheic dermatitis and the dlqi results [r (120) =.446, p =.000]. there was no significant relationship between illness duration and dlqi, hads, or saas outcomes in the patient groups (table 5). in all patient groups, the dlqi, hads, and saas outcomes had significant and positive correlations with each other (table 6). the strongest correlation was seen between the hads anxiety and depression subscales, which were moderately correlated with each other. there was also a moderate association between the dlqi and the saas outcomes in acne patients [r (166) =.659, p =.000]. discussion acne, rosacea, and seborrheic dermatitis patients’ quality of life was found to be significantly lower when compared to healthy people. these patients reported having more negative feelings about themselves as a result of their skin illnesses, and they had more difficulty with their daily and leisure time activities, work and school lives, and personal relationships. 26.37 (8.4). in paired comparisons, acne, rosacea, and seborrheic dermatitis patients’ scores were significantly higher than the control group after controlling for age, gender, and bmi. the pairwise comparisons of the patient groups revealed no significant differences (table 4). an ordinal logistic regression model was created to explore the relationship between the acne, rosacea, seborrheic dermatitis, and control groups and the saas results. age, gender, and bmi were identified as confounders and were adjusted for. the healthy controls served as the reference group. the logistic regression model was statistically significant [χ2(6) = 54.586, p <.001]. the adjusted odds ratio for receiving a higher score on the scale was 3.14 (95% ci 2.05– 4.81, p <.001) for acne patients, 4.05 (95% ci 2.54–6.48, p <.001) for rosacea patients, and 2.46 (95% ci 1.57–3.83, p <.001) for seborrheic dermatitis patients. correlations there was a positive relationship between disease severity and the dlqi, hads, and saas scores in acne and rosacea patients. similarly, a positive relationship was found between disease severity and the dlqi and saas scores in patients table 4. comparison of social appearance anxiety scale (saas) scores between groups. acne rosacea seborrheic dermatitis control median (iqr) 35 (22) 35 (26) 32 (23) 24 (12) [min.-max.] [16 – 75] [16 – 79] [16 – 67] [16 – 50] mean (sd) 36.86 (14.24) 38.51 (16.37) 33.83 (13.67) 26.37 (8.4) sem 1.106 1.414 1.249 .754 p* < .001 < .001 < .001 ref. p value for kruskal-wallis test < .001 * mann-whitney u test. after controlling for age, gender, and bmi, pairwise comparisons are significant (p <.05) for: acne vs. control; rosacea vs. control; seborrheic dermatitis vs. control. table 5. the correlations between severity and duration of illness with the dermatology quality of life index, anxiety and depression scores, and the social appearance anxiety scale in patient groups. dlqi anxiety subscale depression subscale saas r r r r severity of illness acne .271** .172* .206* .241* rosacea .354** .290** .272* .308** seborrheic dermatitis .446** .173 .198 .262* duration of illness acne -.022 .071 -.002 -.007 rosacea -.144 -.108 -.122 .003 seborrheic dermatitis -.053 .018 -.036 .070 dlqi: dermatology life quality index, saas: social appearance anxiety scale, r: correlation coefficient. * significant at p < .05 ** significant at p < .001 original article | dermatol pract concept. 2023;13(1):e2023029 7 triggers such as the sun, weather, stress, emotional state, and various foods may cause patients to develop an avoidance behavior, either consciously or unconsciously. patients may refrain from participating in outdoor activities to avoid being exposed to triggers such as the sun, hot or cold air, wind, and social gatherings to avoid emotional triggers. this can result in introversion, social isolation, depression, and anxiety. a lack of sunlight is linked to an increased risk of depression[12,13]. anxiety and other psychological stressors contribute to this cycle by exacerbating rosacea symptoms through the release of proinflammatory cytokines[14]. another intriguing finding is the high rate of depression in seborrheic dermatitis patients. seborrheic dermatitis is frequently linked to neurological conditions such as parkinson’s disease[15,16], tardive dyskinesia[17], or spinal damage[18]. there is also a link between seborrheic dermatitis and psychiatric illnesses. according to the literature, those with mood disorders are more likely to develop seborrheic dermatitis[19], and those with seborrheic dermatitis are more likely to develop depression[20]. parkinson’s disease is characterized by a decrease in dopamine, and dopamine receptor blockage results in tardive dyskinesia. recently, the importance of dopamine has been emphasized in addition to serotonin and noradrenaline in the pathophysiology of depression[21]. although our study was observational in nature and was not intended to establish a cause-effect relationship, it is worth noting that seborrheic dermatitis is frequently seen in conjunction with diseases in which dopamine plays a prominent role in the pathophysiology. our findings show that the severity of psychosocial impact in patients with acne, rosacea, and seborrheic dermatitis is unrelated to the duration or severity of symptoms. the literature shows that even when different measurement methods are used, the results are similar. acne[22,23], rosacea[24,25], and seborrheic dermatitis[26] severity and duration have been reported to be insignificant or significant but furthermore, anxiety and depression were both more common and severe in these individuals. they experienced more intense social anxiety as a result of their beliefs that their appearance would be judged negatively, and the source of this anxiety extended beyond the facial area to overall negative body image thoughts (not being attractive, being overweight, hair color, nose shape, body shape). rosacea patients had the most negative impact on their quality of life, followed by acne and seborrheic dermatitis patients, respectively. there was also a statistically significant difference between rosacea and seborrheic dermatitis patients. this difference, however, was eliminated after controlling for age, sex, and bmi. similarly, the severity of social anxiety caused by overall appearance was highest in rosacea patients, second in acne patients, and third in seborrheic dermatitis patients, but the differences were not statistically significant. a study comparing acne and seborrheic dermatitis found that acne patients had a higher rate and severity of anxiety and depression[10]. a study in lithuania comparing acne and rosacea patients aged 18-70 found that acne patients had higher anxiety and rosacea patients had higher depression[11]. the fact that these studies were completed with a smaller number of patients is a limitation. our study included a larger number of participants, comparing patients with acne, rosacea, and seborrheic dermatitis simultaneously. according to our data, anxiety rates were highest in rosacea patients, followed by seborrheic dermatitis and acne patients, respectively. depression rates were highest in patients with seborrheic dermatitis, followed by rosacea and acne patients, respectively. the severity of anxiety and depression, on the other hand, was comparable in acne, rosacea, and seborrheic dermatitis patients after controlling for age, sex, and bmi. rosacea patients’ physical symptoms, such as burning, stinging, redness, and flushing, may explain why the negative impact on quality of life is greater. common rosacea table 6. correlations of the dermatology quality of life index, anxiety and depression scores, and the social appearance anxiety scale by groups. dlqi and anxiety subscale dlqi and depression subscale dlqi and saas anxiety and depression subscales anxiety subscale and saas depression subscale and saas r r r r r r acne .468** .473** .659** .564** .413** .339** rosacea .354** .338** .487** .671** .400** .437** seborrheic dermatitis .275* .182* .401** .593** .304** .374** control .255* .204* .154 .330** .333** .039 dlqi: dermatology life quality index, saas: social appearance anxiety scale, r: correlation coefficient. * significant at p < .05 ** significant at p < .001 8 original article | dermatol pract concept. 2023;13(1):e2023029 is not only a symptom of illness; it is also one of its causes, and it can lead to suicidal ideation during vulnerable times in one’s life. identifying vulnerable patients and breaking the disease-stress cycle in both steps might improve patient compliance and treatment efficacy. references 1. doshi a, zaheer a, stiller mj. a comparison of current acne grading systems and proposal of a novel system. int j dermatol. 1997;36(6):416-418. doi:10.1046/j.1365-4362.1997.00099.x 2. wilkin j, dahl m, detmar m, et al. standard grading system for rosacea: report of the national rosacea society expert committee on the classification and staging of rosacea. j am acad dermatol. 2004;50(6):907-912. doi:10.1016/j. jaad.2004.01.048 3. baysal v, yildirim m, ozcanli c, ceyhan am. itraconazole in the treatment of seborrheic dermatitis: a new treatment modality. int j dermatol. 2004;43(1):63-66. doi:10.1111/j.1365-4632.2004.02123.x 4. finlay ay, khan gk. dermatology life quality index (dlqi)- a simple practical measure for routine clinical use. clin exp dermatol. 1994;19(3):210-216. doi:10.1111/j.1365-2230.1994. tb01167.x 5. oztürkcan s, ermertcan at, eser e, sahin mt. cross validation of the turkish version of dermatology life quality index. int j dermatol. 2006;45(11):1300-1307. doi:10.1111/j.1365 -4632.2006.02881.x 6. zigmond as, snaith rp. the hospital anxiety and depression scale. acta psychiatr scand. 1983;67(6):361-370. doi:10.1111/j.1600-0447.1983.tb09716.x 7. aydemir ö, güvenir t, küey l, kültür s. hastane anksiyete ve depresyon ölçeği türkçe formunun geçerlilik ve güvenilirlik çalışması. reliability and validity of the turkish version of hospital anxiety and depression scale. türk psikiyatr derg. 1997;8(4):280-287. https://www.researchgate.net /publication/301778685_hastane_anksiyete_ve_depresyon_olcegi_turkce_formunun_gecerlilik_ve_guvenilirlik_ calismasi_reliability_and_validity_of_the_turkish_version_of_ hospital_anxiety_and_depression_scale 8. hart ta, flora db, palyo sa, fresco dm, holle c, heimberg  rg. development and examination of the social appearance anxiety scale. assessment. 2008;15(1):48-59. doi:10.1177/1073191107306673 9. doğan t. sosyal görünüş kaygısı ölçeği’nin (sgkö) türkçe uyarlaması: geçerlik ve güvenirlik çalışması. hacettepe üniversitesi eğitim fakültesi derg. 2010;(39):151-159. 10. pärna e, aluoja a, kingo k. quality of life and emotional state in chronic skin disease. acta derm venereol. 2015;95(3):312-316. doi:10.2340/00015555-1920 11. lukaviciute l, ganceviciene r, navickas p, navickas a, grigaitiene j, zouboulis cc. anxiety, depression, and suicidal ideation amongst patients with facial dermatoses (acne, rosacea, perioral dermatitis, and folliculitis) in lithuania. dermatology. 2020;236(4):314-322. doi:10.1159/000506627 12. kim sy, bang m, wee jh, et al. shortand long-term exposure to air pollution and lack of sunlight are associated with an increased risk of depression: a nested case-control weakly related to psychosocial outcomes. this suggests that patients with a new-onset or mild disease may be severely impacted. on the other hand, despite having a severe or long-term disease, some patients can maintain their mental health. this implies that what matters is not the biological process itself, but the meaning ascribed to one’s own illness. another intriguing aspect is the correlation between the dlqi, had, and saas results. the negative effects observed by these scales are significantly related to each other in all patient groups, with anxiety and depression having the most pronounced relationship. mental symptoms caused by a physical illness, particularly chronic diseases, can lead to other mental problems and loss of function over time. yazici et al. used the same measurement methods in their study on acne patients and found results that were similar to ours in terms of the relationship between quality of life and anxiety and depression[27]. because of the nature of observational studies, cause-and-effect relationships cannot be established, and results may differ across cultures, time periods, or measurement methods. furthermore, some selection bias is unavoidable, particularly when recruiting the control group. therefore, we concentrated mostly on comparing patient groups to one another. the patient groups are made up of those who sought treatment, and it is reasonable to assume that those who have been severely impacted by the negative psychological and social consequences will seek treatment more frequently. as a result, those who have the disease but lack the motivation to seek treatment might be underrepresented in the study. therefore, we can speculate that if similar studies were conducted with a general population sample, the psychosocial impact on the subjects would be less severe. acne, rosacea, and seborrheic dermatitis lead to a number of psychosocial consequences, but also vice versa. sebocytes, which play a key role in the pathogenesis of acne, have functional receptors for molecules involved in the stress response, such as crh, melanocortin, betaendorphin, vasoactive intestinal polypeptide, neuropeptide y, and calcitonin gene-related peptide[28]. it has been established that stress-induced reactive oxygen derivatives, antimicrobial peptides, and neuropeptides cause inflammation by activating various cytokine and chemokine networks in the formation of rosacea’s characteristic histopathology[29]. observational studies have shown that patients with seborrheic dermatitis have more frequent and severe attacks during stressful times[30,31]. breaking the disease-stress cycle in both steps may improve treatment outcomes. a thorough skin examination should be complemented by a brief assessment of the patient’s mental state. chronic skin diseases impose a significant psychosocial burden, which may be exacerbated if they are visible to others. stress original article | dermatol pract concept. 2023;13(1):e2023029 9 23. sood s, jafferany m, vinaya kumar s. depression, psychiatric comorbidities, and psychosocial implications associated with acne vulgaris. j cosmet dermatol. 2020;19(12):3177-3182. doi:10.1111/jocd.13753 24. haber r, el gemayel m. comorbidities in rosacea: a systematic review and update. j am acad dermatol. 2018;78(4):786-792. e8. doi:10.1016/j.jaad.2017.09.016 25. wu y, fu c, zhang w, li c, zhang j. the dermatology life quality index (dlqi) and the hospital anxiety and depression (hads) in chinese rosacea patients. psychol health med. 2018;23(4):369-374. doi:10.1080/13548506.2017.1361540 26. cömert a, akbaş b, kılıç ez, et al. psychiatric comorbidities and alexithymia in patients with seborrheic dermatitis: a questionnaire study in turkey. am j clin dermatol. 2013;14(4):335-342. doi:10.1007/s40257-013-0019-7 27. yazici k, baz k, yazici ae, et al. disease-specific quality of life is associated with anxiety and depression in patients with acne. j eur acad dermatol venereol. 2004;18(4):435-439. doi:10.1111/j.1468-3083.2004.00946.x 28. zouboulis cc, böhm m. neuroendocrine regulation of sebocytes – a pathogenetic link between stress and acne. exp dermatol. 2004;13 suppl 4(4):31-35. doi:10.1111/j.1600 -0625.2004.00254.x 29. gerber pa, buhren ba, steinhoff m, homey b. rosacea: the cytokine and chemokine network. j investig dermatology symp proc. 2011;15(1):40-47. doi:10.1038/jidsymp.2011.9 30. peyrí j, lleonart m, grupo español del estudio sebderm. [clinical and therapeutic profile and quality of life of patients with seborrheic dermatitis]. actas dermosifiliogr. 2007;98(7):476-482. doi:10.1016/s1578-2190(07)70491-2 31. misery l, touboul s, vinçot c, et al. [stress and seborrheic dermatitis]. ann dermatol venereol. 2007;134(11):833-837. doi:10.1016/s0151-9638(07)92826-4 study using meteorological data and national sample cohort data. sci total environ. 2021;757(2):143960. doi:10.1016/j. scitotenv.2020.143960 13. o’hare c, o’sullivan v, flood s, kenny ra. seasonal and meteorological associations with depressive symptoms in older adults: a geo-epidemiological study. j affect disord. 2016;191:172-179. doi:10.1016/j.jad.2015.11.029 14. oussedik e, bourcier m, tan j. psychosocial burden and other impacts of rosacea on patients’ quality of life. dermatol clin. 2018;36(2):103-113. doi:10.1016/j.det.2017.11.005 15. mastrolonardo m, diaferio a, logroscino g. seborrheic dermatitis, increased sebum excretion, and parkinson’s disease: a survey of (im)possible links. med hypotheses. 2003;60(6):907-911. doi:10.1016/s0306-9877(03)00094-x 16. barbeau a. dopamine and disease. can med assoc j. 1970; 103(8):824-832. http://www.ncbi.nlm.nih.gov/pubmed/4248929 17. sandyk r. melanocyte-stimulating hormone and persistent tardive dyskinesia: a hypothesis. int j neurosci. 1990;51(1-2):45-52. doi:10.3109/00207459009000507 18. reed wb, pidgeon j, becker sw. patients with spinal cord injury. clinical cutaneous studies. arch dermatol. 1961;83:379-385. doi:10.1001/archderm.1961.01580090029002 19. maietta g, fornaro p, rongioletti f, rebora a. patients with mood depression have a high prevalence of seborrhoeic dermatitis. vol 70.; 1990. doi:10.2340/0001555570432434 20. oztas p, calikoglu e, cetin i. psychiatric tests in seborrhoeic dermatitis. acta derm venereol. 2005;85(1):68-69. doi:10.1080/00015550410021574 21. dunlop bw, nemeroff cb. the role of dopamine in the pathophysiology of depression. arch gen psychiatry. 2007;64(3):327-337. doi:10.1001/archpsyc.64.3.327 22. bhate k, williams hc. epidemiology of acne vulgaris. br j dermatol. 2013;168(3):474-485. doi:10.1111/bjd.12149 dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):11 55 dermatology practical & conceptual www.derm101.com case presentation a 23-year-old woman with recently diagnosed invasive melanoma of the back presented with an asymmetric, dark brown papule measuring 7 x 5 mm in the right axilla (figure 1). dermoscopy revealed a homogenous globular pattern at the center with brown to gray-bluish pigmentation and slight vascular blush, while at the periphery there were regular globules (figure 2). the leading diagnosis was irritated melanocytic nevus, while the possibility of melanoma was considered, given the patient’s history of melanoma as well as the lesion’s variegation of color and increased vascularity. an rcm examination showed enlarged junctional nests of cells with marked dermoscopic and confocal features of an axillary “special site” nevus riana dutt1, harold s. rabinovitz2, rajendra singh1, alon scope3 1 department of dermatology and pathology, icahn school of medicine at mount sinai, new york ny, usa 2 department of dermatology, university of miami school of medicine, miami fl, usa 3 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel citation: dutt r, rabinovitz, singh r, scope a. dermoscopic and confocal features of an axillary “special site” nevus. dermatol pract concept. 2017;7(1):11. doi: https://doi.org/10.5826/dpc.0701a11 received: november 13, 2016; accepted: november 26, 2016; published: january 31, 2017 copyright: ©2017 dutt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajendra singh, md, icahn school of medicine at mount sinai, annenberg building, 15th floor, room 5, 1468 madison avenue, new york, ny 10029, usa. tel. 212-241-6064; fax. 212-241-7832. email: rajendra.singh@mountsinai.org “nevi of special sites” is a term that denotes melanocytic nevi presenting in specific anatomic locations including the scalp, genital area, flexural sites, and acral sites [1]. nevi from these anatomic sites display at times histopathologic features that may lead the reading pathologist to recommend re-excision of these benign nevi. reflectance confocal microscopy (rcm) is a noninvasive imaging tool that allows for visualization of epidermal, dermal-epidermal junctional (dej), and superficial dermal tissue structures at cellular level resolution. rcm features of special site nevi have not been previously described in the literature. defining the rcm characteristics of special site nevi may increase diagnostic accuracy and assist in ruling out melanoma. here, we report a case of a pigmented lesion appearing in the axilla of a patient with a recently diagnosed melanoma. dermoscopic and histopathologic results were consistent with the diagnosis of nevus in flexural anatomic sites. in this case, rcm showed a regular honeycomb pattern of epidermal keratinocytes and enlarged, non-homogenous, discohesive nests at the dej, a pattern that corresponded well with the histopathologic findings. larger studies are needed to establish rcm features of special site nevi in order to reliably rule out melanoma and lower the rate of unnecessary excisions of these benign nevi. abstract mailto:rajendra.singh@mountsinai.org 56 observation | dermatol pract concept 2017;7(1):11 discussion flexural nevi that fit criteria for “special site” nevi may be clinically indistinguishable from other types of melanocytic nevi [2]. they are usually greater than 6 mm and have an irregular border [3]. the axillary nevus in the present case exhibited regular, uniform globules, but with variegated pigmentation pattern on dermoscopy. while specific dermoscopic features of flexural nevi have only been identified in a few case reports, some authors have categorized axillary lesions with those of differences in size and shape. within the nests, there was diminished cohesion of melanocytes (figure 3a). the surface of the skin showed a papillomatous contour, and at the level of the spinous and granular layers, a regular honeycomb pattern was seen (figure 3b). there was complete absence of reflective cells in pagetoid pattern. the rcm findings rendered the diagnosis of melanoma unlikely. histopathologic analysis confirmed the diagnosis of a nevus. the presence of enlarged junctional nests with discohesive cell clusters (figure 4) were consistent with the recent histopathologic descriptions of nevi in flexural sites. figure 1. clinical photograph of a pigmented axillary papule measuring 7 x 5 mm. [copyright: ©2017 dutt et al.] figure 2. dermoscopic image, under contact polarized light, depicts a globular homogenous pattern with variegated color. [copyright: ©2017 dutt et al.] figure 3. (a) rcm at the level of the dermal-epidermal junction shows enlarged junctional nests with diminished cohesion of melanocytes. (b) rcm at the spinous granular level reveals a regular honeycomb pattern. [copyright: ©2017 dutt et al.] a b observation | dermatol pract concept 2017;7(1):11 57 cytologic atypia that rarely raises concern, and another with irregular nests and uniform junctional cytologic atypia that the pathologist may, at times, find to be more concerning for melanoma [12]. a study of the histopathologic characteristics of 40 cases of nevi on flexural sites such as the axilla, umbilicus, and inguinal creases showed a primarily “nested and discohesive” pattern [13]. this junctional nested pattern correlates well with the histopathology of our patient’s axillary nevus, although cellular atypia was not observed in this case. in high-risk patients, such as the individual in this case, it is important to achieve a balance between careful surveillance of lesions for any clinical or dermoscopic concern and prevention of unnecessary excisions. the consistency between rcm and histopathologic features of the special site nevus described in this case report support the possibility of diagnosing such nevi less invasively in the future. larger studies are needed to define specific criteria required to distinguish special site nevi from melanoma when the clinical and dermoscopic features are indeterminate. references 1. mason ar, mohr mr, koch lh, hood af. nevi of special sites. clin lab med. 2011;31(2):229-242. 2. buonaccorsi jn, lynott j, plaza ja. atypical melanocytic lesions of the thigh with spitzoid and dysplastic features: a clinicopathologic study of 29 cases. ann diagn pathol. 2013;17(3):265-269. 3. hofmann-wellenhof r. special criteria for special locations: scalp, mucosal, and milk line. dermatol clin. 2013;31(4):625636. 4. massi g, leboit pe. polypoid nevus of pregnancy and milk line nevi. in: histological diagnosis of nevi and melanoma. darmstadt: steinkopff verlag; 2004:329-336. 5. merkel ea, martini mc, amin sm, lee cy, gerami p. evaluation of dermoscopic features for distinguishing melanoma from special site nevi of the breast. j am acad dermatol. 2016;75(2):1-7. the breast and other locations along the “milk line” due to their overlapping histopathologic features and the possible contribution of embryologic and hormonal influence [3,4]. a retrospective study of the dermoscopic features of 104 nevi and 13 melanomas from the breast and chest found the presence of atypical pigment network and irregular globules did not discriminate well between nevi and melanoma [5]. this is in contrast to studies that were not “site-specific,” in which atypical pigment network and irregular globules were sensitive and specific for melanoma [6,7]. this discrepancy indicates that the when evaluating the dermoscopic characteristics needed to differentiate nevi from melanoma, the anatomic site should be taken into consideration. thus, ancillary diagnostic methods that can assist to exclude, reliably and reproducibly, melanoma in “special” anatomic locations are warranted. rcm is a noninvasive tool that utilizes differences in refractivity of skin structures to visualize the epidermis, dermal-epidermal junction, and dermis at the cellular level [8]. while there exists a considerable amount of data on rcm features of melanoma and nevi [9,10] rcm features specific to flexural or other special site nevi have not yet been elucidated. the well-conserved honeycomb pattern of keratinocytes visualized at the spinous and granular levels in this case is more consistent with rcm findings of nevi [11]. in contrast, the rcm finding of enlarged, discohesive junctional nests with variability in shape, size, and spacing may elicit concern for melanoma, but have also been described in an rcm study of nevi, denoted by the authors as dysplastic nevi, from nonspecial anatomic sites [9]. absence of large, bright pagetoid cells in the epidermis and cytologic atypia at the basal layer were criteria supporting the diagnosis of a nevus [11]. two histopathologic patterns have been observed in flexural nevi; one with a papillomatous epidermis and mild figure 4. histopathologic images (h&e) confirm the diagnosis of a nevus showing enlarged, discohesive, junctional nests. [copyright: ©2017 dutt et al.] a b 58 observation | dermatol pract concept 2017;7(1):11 9. pellacani g, farnetani f, gonzalez s, et al. in vivo confocal microscopy for detection and grading of dysplastic nevi: a pilot study. j am acad dermatol. 2012;66(3):e109-e121. 10. pellacani g, guitera p, longo c, avramidis m, seidenari s, menzies s. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759-2765. 11. carrera c, marghoob aa. discriminating nevi from melanomas: clues and pitfalls. dermatol clin. 2016;34(4):395-409. 12. hosler ga, moresi jm, barrett tl. nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. j cutan pathol. 2008;35(10):889-898. 6. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-693. 7. annessi g, bono r, sampogna f, faraggiana t, abeni d. sensitivity, specificity, and diagnostic accuracy of three dermoscopic algorithmic methods in the diagnosis of doubtful melanocytic lesions. the importance of light brown structureless areas in differentiating atypical melanocytic nevi from thin melanomas. j am acad dermatol. 2007;56(5):759-767. 8. grant-kels jm, pellacani g, longo c. reflectance confocal microscopy clinical applications: the skin from inside. dermatol clin. 2016;34(4):xiii-xiv. dermatology: practical and conceptual cutaneous squamous cell carcinoma: an update on diagnosis and treatment table of contents risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio, giulia briatico, cristina pellegrini, tea rocco, elvira moscarella, maria concetta fargnoli surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez, francisca silva-clavería, almudena fernández-orland, noemí eiris, andrés ruiz de casas, lara ferrándiz radiotherapy in the adjuvant and advanced setting of cscc paolo muto and francesco pastore immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh, daniel morse, jigar patel, michael r. migden treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi, luigi lorini mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples, italy guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s2): e2021168s 1 radiotherapy in the adjuvant and advanced setting of cscc paolo muto1, francesco pastore2 1 radiation oncology unit, istituto nazionale tumori irccs fondazione g. pascale – naples, italy 2 radiation oncology, fondazione muto onlus emicenter – naples, italy key words: radiotherapy, squamous cell carcinoma, brachytherapy. citation: muto p, pastore f. radiotherapy in the adjuvant and advanced settings of cscc. dermatol pract concept. 2021; 11(s2): e2021168s. doi: https://doi.org/10.5826/dpc.11s2a168s accepted: september 22, 2021; published: october, 2021 copyright: ©2021 muto and pastore. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: francesco pastore, radiation oncology, fondazione muto onlus emicenter – naples, italy. email: fr.pastore@libero.it this article is part of the dpc journal special issue cutaneous squamous cell carcinoma: an update on diagnosis and treatment guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. introduction: the use of radiotherapy for cutaneous squamous cell carcinoma (cscc) has solid historical roots. it is used with patients who are not suitable for surgery, with patients with high-risk histological features in the adjuvant setting, and in palliative care. objectives: the aim of this article is to summarize and provide a radiation therapy overview on the indications, effectiveness, and potential adverse events of radiotherapy in the adjuvant and advanced setting of cscc. methods: we performed a comprehensive literature review on pubmed, adopted as our biomedical literature database. articles were selected based on their date of publication (in the last 30 years) and relevance. abstract 2 review | dermatol pract concept. 2021; 11(s2): e2021168s introduction cutaneous squamous cell carcinoma (cscc) is the second most common type of non-melanoma skin cancer (nmsc) after basal cell carcinoma (cbcc). it arises most commonly in sun-exposed areas of the body and originates from keratinocytes in the epidermis through a carcinogenesis process [1]. as the world’s population ages, the incidence of both types of nmsc (scc and bcc) is dramatically increasing and disease implications on public health are vastly underestimated in terms of morbidity and treatment costs. these costs are unavoidably going to rise [2]. cscc can arise from precancerous precursor lesions such as actinic keratosis or can grow de novo, in particular on chronically inflamed skin and consequently more exposed to pro-carcinogenetic stimuli [3]. invasive cscc (histologically characterized by the presence of infiltrating cells crossing the basement membrane) has the ability to relapse and metastasize to regional lymph nodes or distant organs and, if left untreated or if inadequately treated, can lead to extensive tissue destruction up to massive patterns of tumour infiltration. even though the ability of cscc to metastasize is limited, the presence of distant metastases in cscc patients is associated with poor prognosis and a median survival of less than 2 years. for this reason, it is fundamental to perform a careful clinical and surgical evaluation, that goes hand in hand with a correct early management of all cases. multidisciplinary management is essential in order to guide the patient towards the best possible treatment options [4]. the ultimate scc treatment goals are complete removal of the tumor or, when this is not possible, tumor debulking, and the minimization of functional and aesthetic impairment that often, for particular anatomical areas, can be a very central issue. [1]. surgery with adequate margins is the most common treatment option for most csccs, but radiation therapy (rt) can be an effective non-surgical option in the definitive (inoperable patients), adjuvant (high postoperative risk), and palliative (cytoreductive, pain-relieving) setting. rt is also a tissue-preserving modality that might offer a better cosmetic and functional outcome than surgery [4]. a variety of radiation therapy techniques have been used to treat epithelial skin tumors. nmsc have historically been among the first to be irradiated since discovery of radioactivity. the appropriate radiation therapy technique depends on multiple factors, including the primary tumor’s location, the neoplasm size, the scar length (in the adjuvant setting) which may be difficult to cover with radiation planning, the surrounding anatomy (presence of organs at risk that must be preserved), and the presence of disease-affected lymph nodes that deserve to be included in the radiation field [5]. surface electrons are typically used for primary lesions or tumor beds > 5 mm or deeper, because of their unique physical penetration features. electrons are produced by modern linear accelerators and have a dose distribution with a peak dose near the skin surface and a rapid dose drop beyond the target. this allows adequate coverage of the disease or surgical bed and the ability to minimize side effects. superficial x-rays, or photons, have greater physical penetration compared with surface electrons and have been used to treat deep cscc or more advanced diseases (with or without positive nodes) [6]. this article aims to summarize the effectiveness, potential adverse events, and indications of rt in the adjuvant, advanced, and palliative setting of cscc, performed through a thorough and broad literature review. when is radiotherapy recommended? rt is recommended as adjuvant therapy in high-risk cscc or when surgery is excluded due to cosmetic or functional reasons [6]. rt allows treatment of anatomic sites that are difficult to manage surgically, and to achieve a good cosmetic result. this applies in particular to the head and neck (h/n) region. rt is also preferred for elderly patients (> 60 years) [7]. the dose of rt can be delivered with external beams (external beam radiation therapy (ebrt)) and by direct results: radiotherapy (rt) can safely be used to manage non-surgical patients and high-risk patients in the advanced cscc setting. the remarkable progress of delivery techniques has greatly improved the effectiveness and toxicity profile of rt treatments. from 2d techniques to intensity modulated radiation therapy (imrt), and brachytherapy, all rt techniques have greatly advanced. to improve acute and chronic side effects, a deeper care has been used. as regards cscc, several dose fractionations and schedules have been suggested, in line with the patient’s age and medical conditions. conclusions: rt is a fundamental and constantly evolving therapeutic option in the treatment of cscc, to minimize the risk of recurrence and metastases in the adjuvant setting and in the exclusive treatment for non-surgical patients. patients’ selection is crucial, together with and a collaborative team working approach among the specialists involved in disease management in the perspective of the best multidisciplinary assessment. review | dermatol pract concept. 2021; 11(s2): e2021168s 3 application using brachytherapy (brt). ebrt is delivered via photon or electron beams and can be superficial or deeply penetrating, depending on the megavoltage of the different energy sources [8]. rt can be delivered to fields of different sizes and with different complex shapes. highly conformal rt, such as tomotherapy or volumetric modulated arc therapy (vmat), allows delivery of relatively superficial rt to complex and often irregular targets, while limiting the dose to adjacent organs at risk (oars) [9, 10]. radiation therapy can be administered via different techniques, several fractionations, and total doses. the aim is to match the tumor and spare healthy tissues from radiation. rt delivery has greatly improved, starting from a better visualization of the target with ever-improving imaging techniques, through precise contouring and treatment planning systems. many quality-control checks have been added in the intraand inter-fraction assurance. the choice of the technique is certainly influenced by the type of tumor, treatment setting (radical, adjuvant, or palliative), tumor depth, and location of the tumour that can be particularly unfavorable and close to sensitive organs at risk. high-energy radiation therapy, delivered by a linear accelerator, has greater penetration capacity and is therefore useful to treat deeper malignant tumors while largely sparing the skin. low-energy radiation (kilovoltage and orthovoltage) is preferred to treat skin lesions where deep penetration is not necessary and skin preservation is the main concern [11, 12]. rt is usually a well-tolerated treatment with specific acute and late toxicities and documented advantages and disadvantages compared with surgery. the most striking limits of radiation therapy are adverse effects and contraindications. skin reactions triggered by radiation therapy are called radiation therapy-induced dermatitis or radiodermatitis. they can be acute (up to 6 months after the end of treatment) or delayed. they are related to the dose delivered and the anatomical location. acute reactions lasts several weeks, patients may experience skin changes (ranging from faint erythema and desquamation to skin necrosis) and ulceration, depending on the severity of the reaction. delayed reactions usually appear months or years after treatment and are more common with higher treatment doses. the most common late reactions are hypopigmentation and hyperpigmentation, telangiectasia, epidermal atrophy, skin fragility, sebaceous gland atrophy, alopecia, fibrosis, necrosis, and an increased risk of certain cancers, such as angiosarcoma. rt contraindications include young age (for cscc is a minor concern), verrucous scc, cancer-predisposing genodermatoses, and immunodepression (essential cost-benefits analysis) [13]. radiotherapy in the adjuvant setting the goal of adjuvant radiation therapy is to reduce the risk of local or regional recurrence after surgical excision. in general, adjuvant radiation therapy is offered when the risk of recurrence is high or the likelihood of successful salvage surgery is relatively low [11]. risk factors to look out for in cscc include male sex, recurrent disease, neoplasms located at the center of the face, poor histologic differentiation, and deep subclinical extension. other high-risk factors for cscc include tumor location (lip or ear), tumors arising from scarring tissues, size > 2 cm, depth > 4 mm or clark level ≥ iv, invasion beyond subcutaneous tissues, rapidly growing lesions, perineural invasion, desmoplasia, poor differentiation, and infiltrative margins [14]. adjuvant radiation therapy is recommended after extensive surgical excision with close or positive margins (only if the tumor cannot be re-excised) or in the presence of high-risk factors, including perineural invasion (pni), invasion of bone or nerves, or in case of recurrent disease after previous surgical excision or other medical therapy [15]. the rate of positive margins after excision in cscc ranges from 5.8% to 17.6% and is influenced by the adopted technique [16,17]. positive margins after surgery have been reported as prognostic in a study [18]. indeed, csccs with a close or positive surgical margin have an increased risk of local recurrence and locoregional metastasis [19]. postoperative rt is a treatment option for tumors with margins that are not completely excised or cannot be completely resected. in a study of cscc of the lower lip that included tumors with a close or positive margin, the local recurrence rate was 64% for tumors with positive margins that were not subsequently excised versus a 6% rate for those treated with postoperative rt [20]. pni is an important risk factor because it has been shown to be associated with a higher risk of recurrence and a higher incidence of lymph node metastasis [18]. pni occurs in between 2.5% and 14% of csccs, usually found as an incidental histologic finding. it has been linked to poor prognosis and a higher rate of metastasis and disease-specific death [14,21,22]. extensive pni is an indication for postoperative rt according to nccn guidelines [23]. postoperative rt has also been recommended for high-risk tumors. historically, the definition of high risk has been a matter of debate. guidelines agree on the definition of high risk as a disease characterized by diameter > 2 cm, a thickness > 2 mm (and especially 6 mm), poor differentiation, ear or lip location, pni, recurrence, and immunosuppression [24]. most of the evidence regarding the role of postoperative rt in the other risk is derived from a 2009 systematic review indicating that prognosis is generally excellent as long as margins are negative and pni is not observed, and therefore postoperative rt is not necessary if no such findings occur [25]. cscc with cranial nerve invasion, on the other hand, represents a possible criterion for choosing to perform postoperative rt [26]. several rt schedules have been used for adjuvant treatment of cscc. briefly, the proposed algorithm by the nccn includes doses of 60-64 gy over 6 to 7 weeks or 50 gy over 4 weeks [23]. 4 review | dermatol pract concept. 2021; 11(s2): e2021168s radiotherapy in the definitive setting definitive primary rt represents a curative and alternative treatment strategy to surgery for cscc. rt may be considered as primary treatment in patients who are not candidates for surgery (eg locally advanced cscc, comorbidities, or refusal of surgery) or in cases where surgery is not feasible. this may occur when the surgical approach could result in poor functional outcomes or be disfiguring, as in large cscc lesions located on the face (eg eyelids, nose, and lips) or large lesions on the ear, forehead, or scalp [13]. no prospective randomized trials comparing the efficacy of primary rt in local tumor control and patient survival compared with other local therapy modalities are available. a mean local recurrence rate of 6.4% was reported in a meta-analysis analyzing 1018 csscs, including 14 observational rt studies [1]. also in the exclusive setting, rt dose can be delivered as either ebrt or brt. ebrt can use both photons and electrons, with deeply penetrating energies in the range of 4-10 mv. treatment can be administered to a small surface area (eg the nasal wing) or a large complex volume (eg the entire scalp or base of the skull). the total prescribed dose and fractionation should reflect differences in radiobiologic efficacy between radiation modalities. briefly, doses of 45-50 gy in fractions of 2.5-3 gy are recommended for tumors < 2 cm and doses of 60-66 gy in fractions of 2 gy or 50-60 gy in fractions of 2.5 gy for tumors > 2 cm [1]. rt is an overall safe procedure, although it can be associated with both acute and late toxicities. the most frequent acute toxicity may consist of acute, often erosive dermatitis, while late onset chronic depigmentation and telangiectasias are more often seen. moreover, rt should not be recommended in younger (< 60 years old) patients because chronic toxicity becomes more visible with age. higher doses per fraction lead to higher rates of late toxicity [27]. therefore, accelerated fractionation schemes (acceleration means radiation treatment in which the total dose of radiation is given over a shorter period of time compared to standard radiation therapy) should be reserved for elderly and frail patients, or when the cosmetic outcome is less important. the volume to be irradiated in csccs represents the visible disease gross tumor volume (gtv) associated with microscopic disease and possible leakage pathways. the prescribed dose should therefore include all visible tumors plus an appropriate variable margin (clinical target volume), sparing surrounding healthy structures as much as possible [28,29]. dosimetry and technical details should be monitored by a certified radiation oncologist, for some difficult anatomical sites there is the risk to undertreat some cscc. rt may be combined with systemic therapies including chemotherapy (chemoradiation) or cetuximab in more advanced cases (for h/n tumours). age is a very important issue for dose/fractionation decisions: as mentioned above, there are multiple dose fractionation schedules, but in patients < 50 years old rt fraction sizes of 2-2.5gy are delivered over a period of 4-5 weeks, with the aim of achieving the best long-term results (heal and cosmetic outcome) [30]. when deciding on the number of fractions to prescribe for an appropriate course of radiotherapy, age must be considered together with the patient’s medical co-morbidity, performance status, and preference. in older (70-80 years old) patients it could be useful to decrease the total duration of treatment using daily rt fraction sizes of 3-4gy over a period of 2-3 weeks (40-45gy in 10-15 fractions). in elderly patients (>80 years old) less frequent (1 to 3 times per week) and larger fraction sizes are recommended, such as 5-7gy in 5 to 6 fractions [31]. hypofractionated rt delivered 2-3 times a week or once weekly is a highly effective option with tolerable treatment-related toxicity (figures 1 and 2). two recent systematic reviews of hypofractionated rt reported durable local control rates of over 90% and acceptable side effects [32]. in a systematic review comprising 40 relevant publications (external beam rt and brachytherapy included) of over 12 000 nmsc (24% scc), local recurrence rates did not exceed 7.9%. the authors concluded that hypofractionated rt does not confer no obvious disadvantage in local control when compared with traditional more protracted rt schedules [33]. rt could have also an important role in palliative setting for bleeding tumors, to reduce disfiguring or symptomatic neoplasms: the most used schedules are 30 gy in 10 daily fractions or 20 gy in 5 fractions. brachytherapy brachytherapy for cutaneous neoplasms has solid historical roots (with the first documented cases in 1896) [34]. interest in the use of brachytherapy for skin cancers has decreased with the development of better surgical techniques such as mohs surgery, and its application in skin cancer has declined figure 1. pre rt treatment for a cscc. review | dermatol pract concept. 2021; 11(s2): e2021168s 5 significantly over the years. the introduction of the highdose-rate afterloading technique and electronic brachytherapy has renewed interest in the role of brachytherapy in cscc. compared with external beam rt, high-dose-rate brachytherapy demonstrates some advantages, such as delivery of a high dose of radiation in the clinical target volume/ planning target volume, rapid dose decrease at the periphery of the target, optimal sparing of normal tissue in sensitive structures, shorter treatment time, and use of a hypofractionated pathway. cutaneous brachytherapy is advantageous especially in curved surfaces and should be considered instead of external beam radiation therapy (if surgical excision is not possible) in areas of poor vascularization, such as the back of the hands or feet or lower legs. it can be administered, for example, in a superficial technique using dermal applicators with 192iridium [35]. interstitial brachytherapy is another option to deliver high dose radiation rate in thicker (above 5 mm) skin lesions with catheters to be inserted under anaesthesia directly into the lesion or surgical bed in the adjuvant setting [36]. electronic brachytherapy is a new technique of rt based on a miniaturised x-ray source that allows to treat small and flat surfaced cscc [37, 38] and has attracted considerable interest in recent years in the management of cscc [39]. although preliminary data on the use of electronic brachytherapy in cscc are promising, there is a lack of scientific work designed for direct comparison with external beam rt or radionuclide brachytherapy. because this is a relatively new scientific scenario, long-term follow-up data are also missing. the american brachytherapy society consensus statement does not endorse the use of electronic brachytherapy outside of prospective clinical studies. [40]. rt planning the main treatment planning modality in a modern radiation therapy department is based on computed tomography. computed tomography is used to define the clinical target and organs at risk in photon and electron treatment (figures 3 and 4). integration with mri imaging (for increased figure 2. post rt treatment for a cscc. figure 3. treatment electron planning for a cscc. figure 4. treatment electron planning for a cscc. 6 review | dermatol pract concept. 2021; 11(s2): e2021168s reliability for soft tissue) or pet (for biological assessment of disease) is often necessary. radiation therapy results depend on accurate coverage of a target volume with appropriate margins. margins that are too narrow can lead to local failure and margins that are too wide can increase radiation therapy-related morbidity. delineating a target volume could be challenging, particularly in superficial and small cscc, where the spatial resolution of computed tomography limits the visualization of any skin lesions. multidisciplinary evaluation with the dermatologist (dermoscopic imaging) or surgeon (for surgical scar margins) is essential for the assessment of such targets [41]. in skin rt, the use of computed tomography-based planning is also linked to cases of larger and deeply invading cscc, nodal basin rt, skin brachytherapy planning and in select palliative settings. after the clinical target and organs at risk delineation, a personalized plan is built up by the certified radiation oncologist in synergy with the medical physicist, respecting the dose limits of any organ at risk to minimize the side effects of radiation treatment. conclusions radiotherapy could be an optimal therapeutic option for cscc. it could be used for non-surgical candidates as exclusive therapy, in adjuvant high risk patients or to decrease pain and bleeding. several dose schedules and techniques have been proposed both for ebrt (external beam radiotherapy) than for brt (brachytherapy). multidisciplinary assessment is a main issue in this subset of patients. references 1. lansbury l, bath-hextall f, perkins w, stanton w, leonardi-bee j. interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. bmj. 2013;34: f6153. doi: 10.1136/bmj.f6153. pmid: 24191270. 2. lomas a, leonardi-bee j, bath-hextall f. a systematic review of worldwide incidence of nonmelanoma skin cancer. br j dermatol. 2012;166(5):1069–1080. doi: 10.1111/j.13652133.2012.10830.x. pmid: 22251204. 3. kallini jr, hamed n, khachemoune a. squamous cell carcinoma of the skin: epidemiology, classification, management, and novel trends. int j dermatol.2015;54(2):130–140. doi: 10.1111/ ijd.12553.pmid: 25428226. 4. veness mj, delishaj d, barnes ea, bezugly a, rembielak a. current role of radiotherapy in non-melanoma skin cancer. clin oncol (r coll radiol).2019; 31(11): 749–758. doi: 10.1016/j. clon.2019.08.004.pmid: 31447088. 5. 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r et al. electronic brachytherapy for superficial and nodular basal cell carcinoma: a report of two prospective pilot trials using different doses. j contemp brachytherapy. 2016;8(1):48–55. doi: 10.5114/jcb.2016.57531. pmid: 26985197. 39. ramachandran p. new era of electronic brachytherapy. world j radiol. 2017;9(4):148–154. doi: 10.4329/wjr.v9.i4.148. pmid: 28529679. 40. tom mc et al. the american brachytherapy society consensus statement for electronic brachytherapy. brachytherapy. 2019;18(3):292–298.doi: 10.1016/j.brachy.2018.10.006. pmid: 30497939. 41. khan l et al. recommendations for ctv margins in radiotherapy planning for non melanoma skin cancer. radiother oncol. 2012;104(2):263–266. doi: 10.1016/j.radonc.2012.06.013. pmid: 22857860. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4):e2021146 1 atopic dermatitis: epidemiology and clinical phenotypes annunziata raimondo1, serena lembo1 1 department of medicine, surgery and dentistry, “scuola medica salernitana”, university of salerno, salerno, italy key words: atopic dermatitis, epidemiology, phenotypes, clinical features citation: raimondo a, lembo s. atopic dermatitis: epidemiology and clinical phenotypes. dermatol pract concept. 2021;11(4):e2021146. doi: https://doi.org/10.5826/dpc.1104a146 accepted: october 14, 2021; published: october, 2021 copyright: ©2021 raimondo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: serena lembo, md, phd, department of medicine, surgery and dentistry, “scuola medica salernitana”, university of salerno, italy. email: slembo@unisa.it atopic dermatitis (ad) is a chronic, lifelong, relapsing condition. the wide spectrum of the possible clinical presentations, depending on patient’ s age, age of onset of disease, topography and morphology of dermatitis, limits the epidemiologic information on its prevalence and incidence. a clear definition of the different clinical ad phenotypes and epidemiology is essential for an appropriate patient’s treatment and management, in particular for adults. this review summarizes the most recent epidemiologic data from the 21st century, on ad prevalence and incidence rates either in children or adults, with a special focus on their trends in europe. moreover, an effort to categorize diverse ad clinical expressions, has been made, aiming to facilitate differential diagnosis and speed up the start of the correct therapy. abstract this article is part of a series of reviews dedicated to atopic dermatitis, guest edited by prof anna balato. guest editor prof. anna balato, md, phd associate professor of dermatology, dermatology unit, university of campania, naples, italy 2 review | dermatol pract concept. 2021;11(4):e2021146 epidemiology of atopic dermatitis: data from the 21st century updated prevalence and incidence data of ad, across different age groups and countries, increase our understanding of the disease burden. it is well established that in most cases (approximately 80%) ad onset occurs during the first years of life, with frequent remissions in adolescence (approximately 60% of individuals). recently, some studies have reported an adult-onset ad, even if epidemiological and clinical features of this adult form need to be further clarified [1-4]. ad incidence and prevalence register a stable plateau in europe and north america, while they are increased in other continents, such as asia. there are few recent studies on the incidence of ad. most of them have been conducted in europe (eu) and usa [5]. limited information on the prevalence and incidence of ad among adults suggest the wide variability that may be dependent by the population, disease definitions, diagnostic criteria, presence or not of disease register, and lack of a universally accepted index for disease severity. future studies with more standardized methods need to be conducted to assess epidemiology of ad, especially for adults: they are important to improve healthcare planning and patient management. ad in children: prevalence and incidence the point prevalence (the proportion of the population that has the disease at a specific point in time) ranged from 0% (nigeria) to 18.2% (turkey) [6,7]. the 1-year period prevalence (the proportion of the population presenting the disease for 1 year) ranged from 4.1% to 22.7%. the 1-year prevalence of doctor diagnosed (the proportion of the population with the disease diagnosed by a doctor in 1 year) ranged from 0.96% to 22.6%, and the lifetime symptom prevalence (the proportion of population that has the disease symptoms at least once in a lifetime) ranged from 4.4% to 17.7% assessed at age 7–15 years [8-12]. the 1-year incidence (the annual incidence, the probability of the disease occurrence in the population) in children ranged from 10.2 per 1,000 person years in italy (95% confidence interval (ci), 9.9–10.6) to 95.6 per 1,000 person years in scotland (ci 93.4–97.9 %). many studies reported that the highest incidence of ad occurred during infancy, with a disease onset by the age of 7 years [1,13,14]. the incidence was also high in early childhood during the first 18 months of life [13,15]. ad in adults: prevalence and incidence in the overall population, the 1-year adult prevalence of ad was 4.9% (95% ci: 4.6% 5.2%) in the us, 3.5% (95% ci: 3.1%-3.9%) in canada, and 4.4% (95% ci: 4.2%-4.6%) in europe (eu) [16,17]. the 1-year prevalence of diagnosed ad ranged from 1.2% (asia) to 17.1% (eu) [8,9,18]. the lifetime symptom prevalence ranged from 3.0% to 17.7% [8,9,12]. the point prevalence of adult ad was reported to be 2.9% in japan, with 1-year rate of 3.0% and lifetime prevalence of 3.3% [19]. a significant incidence was also reported during adolescence and adulthood. studies recorded an incidence rate of ad in adults of 7.41 per 1,000 person years (6.27–8.74) [20], and a proportion of adult onset of 8.0% in germany at age 28–30 years [16,21,22-25]. trends of prevalence by sex both the 1-year prevalence and lifetime prevalence of diagnosed ad were higher in females (range 0.6–24.3%; 1.0–35.5%, respectively) than in males (range 0.8–17.6%; 1.4–37.3%, respectively), except for the uk, where the prevalence was the same (2.5%), and the us, where prevalence was numerically, but not significantly, higher in males (5.1% vs 4.6%) [5,26]. spotlight on ad epidemiology in europe european trends seem to be in-line with those reported from global studies: ad is more prevalent in children compared to adults, and in overcrowded urban areas [27]. the prevalence in adolescent group is between 1.5% (lithuania) and 15% (bulgaria, denmark, finland, and hungary). epidemiology in adult group remains a challenge. an international, cross sectional, web-based survey was performed in 2018 [26]. it reported 1-year adult prevalence of ad in eu of 4.4% (95% ci: 4.2%-4.6%) with country ranges from 2.2% (95% ci: 1.9%-2.5%) in germany to 8.1% (95% ci: 7.5%-8.6%) in italy. italy and spain reported a higher point adult prevalence respect to other countries. the prevalence in females was significantly enhanced in spain (9.3% females vs 5.1% males, p < .05). france, italy, and spain had more mild forms of adult ad compared with the ones reported in uk and germany. italy had an important regional variability, showing higher adult prevalence rates in mediterranean regions [28]. the reasons of this variability are many: genetic, behavioral or cultural components, socioeconomic conditions, and climatic factors [29]. in general, mild, or moderate severity were the most common clinical presentations, with low proportions of severe form. the thousand faces of ad: the wide spectrum of clinical phenotypes the heterogeneous and intriguing clinical aspects of ad reflects the complex nature of this lifelong disease. traditionally, clinical lesions are classified as “acute”, characterized by oozing, edema, and erythema, or “chronic”, with prevalent xerosis, lichenification, and dyspigmentation. however, as chronic relapsing condition, both types of lesions can coexist in the same individual, especially during flares. the main hallmark of ad is pruritus, responsible for excoriations and skin lichenification. a clear definition of the different clinical review | dermatol pract concept. 2021;11(4):e2021146 3 ad phenotypes (table 1) is essential to improve its treatment and management, passing from a “one-size-fits-all” to a personalized approach based on differentiation of ad clinical expressions. age-related clinical phenotype many clinical pictures of ad have been described based on the age of the patient: infantile ad (3 months/2 years), childhood ad (2-12 years), adolescent/adult ad (12-60 years), and table1. clinical phenotypes of ad and related-differential diagnosis. phenotype clinical features differential diagnosis age-related clinical phenotype infantile (0-2 years) eczematous lesions typically affect scalp, checks, neck, and extensor parts of the extremities with edematous papulo-vesicles, oozing, and crusting. seborrheic dermatitis, psoriasis, scabies, ichthyosis vulgaris, phenylketonuria genetic syndromes: di george syndrome, netherton syndrome, wiskott-aldrich syndrome. childhood (2-12 years) eczematous lesions typically affect popliteal and antecubital fossa, hand, and foot, with edematous papulo-vesicles, oozing, crusting, and lichenification. impetigo, psoriasis, tinea manuum, pedis. adolescent/ adult (12-60 years) eczematous lesions prevalently affect head, neck and flexural areas, with xerosis, lichenification, and depigmentation. in females they also involve periorbital and nipple areas. acd, psoriasis, cutaneous t-cell lymphoma, pityriasis rubra pilaris, pityriasis rosea, asteatotic eczema. elderly (>60 years) extensive eczematous lesions, including flexural areas, up to erythrodermic aspect. acd, psoriasis, cutaneous t-cell lymphoma, pityriasis rubra pilaris, pityriasis rosea, asteatotic eczema. topography-related clinical phenotypes head and neck scalp erythema, scaling, crusting, lichenification, excoriation, and scarring. psoriasis, seborrheic dermatitis, acd, icd, tinea capitits. face erythema, oozing, edema, xerosis, lichenification, dyspigmentation, and excoriation. acd, icd, psoriasis, seborrheic dermatitis, impetigo. eyes erythema, scaling, crusting, lichenification, depigmentation, and scarring. acd, icd, psoriasis, infectious conjunctivitis. lips erythema, xerosis, lichenification, fissuration, and dyspigmentation. acd, icd, psoriasis, infectious cheilitis. flexures erythema, edema, excoriation, lichenification, oozing, and crusting. psoriasis, seborrheic dermatitis, acd, icd, infectious intertrigo, scabies. nipples erythema, scaling, crusting, lichenification, excoriation, and scarring. psoriasis, acd, jogger’s nipple, paget’s disease. hand and foot erythema, xerosis, lichenification, scaling, crusting, fissuration, and dyspigmentation. psoriasis, acd, icd, tinea manuum, tinea pedis. morphology-related clinical phenotypes nummular circinate and ovoid plaques with central clearing and peripheral extension of papules and papulo-vesicles. acd, tinea corporis, psoriasis, pityriasis rosea, asteatotic eczema. prurigo nodularis excoriated hyperkeratotic and intensely itchy nodules. scabies, cutaneous t-cell lymphoma, psoriasis bullous pemphigoid, paraneoplastic manifestations. erythrodermic phenotype erythema on >90% of the body surface area. cutaneous t-cell lymphoma, psoriasis, bullous pemphigoid, lyell syndrome, paraneoplastic manifestations. lichenified skin is thick with accentuated creases and a leathery appearance. psoriasis, cutaneous t-cell lymphoma, acd. follicular/ papular papular-lichenoid lesions. lichen ruber planus, psoriasis, pityriasis rubra pilaris. acd = allergic contact dermatitis; icd = irritant contact dermatitis. 4 review | dermatol pract concept. 2021;11(4):e2021146 elderly ad (> 60 years). pruritus remains the hallmark in all stages, except for very initial disease onset (< 3 months). in the infantile form, eczematous lesions typically affect scalp, cheeks, neck, and extensor parts of the extremities with edematous papulo-vesicles, oozing, and crusting. in the childhood stage both acute and chronic lesions are present. popliteal, antecubital fossa and hand are predilected areas involved. in adolescents and adults, eczematous lesions prevalently affect flexural areas, neck, and head. periorbital areas are also involved, mainly in females. sometimes, an erythrodermic status could occur. elderly ad is an underestimated clinical phenotype characterized by extensive eczematous lesions, also presenting with erythrodermic aspect. three forms of elderly-type ad have been recognized: elderly onset, relapsing, and continuous subtype. elderly ad phenotype poses many problems of differential diagnosis that might mimic ad, such as allergic contact dermatitis or cutaneous-t cell lymphoma, and it needs to be deeply investigated to avoid misdiagnosis. topography-related clinical phenotypes head and neck dermatitis. recently, a specific topographical form of ad has been investigated: it is the head and neck dermatitis (hnd), also called “portrait dermatitis”, characterized by erythematous and scaly plaques localized on the face and neck [30,31]. there are many other possible causes for hnd, including allergic contact dermatitis to topical products, topical corticosteroid withdrawal syndrome, aeroallergen sensitization, rosacea, seborrheic dermatitis, and sensitization to malassezia furfur. interestingly, all these potential causes may coexist with ad in the same patient. reports show that elevated serum levels of malassezia-specific ige in hnd, and positive response to systemic antifungals, may support the clinical diagnosis. scalp. it is frequently involved with xerotic, scaly, erythematous, and sometimes lichenified plaques. facial dermatitis. it is very common in ad in all stages, from infants to adults. in many cases this is the only clinical presentation of the disease. eyelids. eyelids of ad patients are characterized by lichenification, depigmentation, and loss of lashes, accompanied by itch and burn. moreover, ad is associated with ocular diseases, including conjunctivitis and cataracts. ad lips. when lips are affected by ad, these appear red and dry. sometimes, a median fissure of the lower lip and angular cheilitis with alongside lateral fissures are visible. flexural involvement. this is characterized by erythema, edema, excoriation, lichenification, oozing, and crusting. usually, affected flexural areas are neck, cubital and popliteal fossae, wrists, and ankles. it is more prevalent in adolescent and adult caucasian patients with a chronic persisting course. nipple dermatitis. nipples and areolas involvement is found in 11-23% of ad patients. it is frequent in post-puberal girls and young adults, and it can be triggered or aggravated by breast-feeding. nipple dermatitis is typically symmetrical. its specificity as minor diagnostic feature of ad remains to be clarified. hand and foot ad. this form appears with xerotic, scaly, lichenified, and fissured skin, notably on the dorsal part. this phenotype is more common in adulthood, especially in females. conditions, such as juvenile palmoplantar dermatitis or dermatitis plantaris sicca, have been described in children, with a possible link to atopic diathesis. the risk of hand dermatitis was greater in children with persistent or severe ad. dyshidrotic eczema may be a clinical phenotype of hand and foot ad that manifests as vesicles and blisters on the palms and soles. morphology-related clinical phenotypes nummular phenotype. the term derives from the coin like appearance of the lesions. indeed, they are typically circinate and ovoid plaques with central clearing and peripheral extension of papules and papulo-vesicles. lower extremities are predominantly affected. it is the most common morphologic variant of ad, and it is more prevalent in children and adult-onset forms. however, if nummular eczema is ad in all cases needs to be deeply clarified. prurigo nodularis phenotype. in some ad patients the morphology of lesions is characterized by multiple excoriated hyperkeratotic and intensely itchy nodules. a condition defined prurigo nodularis secondary to ad. it is more common in adults. also, for this morphologic variant an accurate differential diagnosis must be considered. erythrodermic phenotype. it is the presence of erythema on > 90% of the body surface area. this form is frequent in adolescents and adults, especially in those with a life-long disease. lichenified phenotype. in this variant the skin is thick with accentuated creases and a leathery appearance. it is more common in adolescents and adults from south-east asia or africa than in caucasian patients. follicular/papular phenotype. it is a morphological subtype more frequent in dark skin, characterized by papular-lichenoid lesions. conclusions and open questions ad is a heterogeneous disease that can be classified according to many and different criteria, based on morphology, topography, severity, age at onset, or disease course. the difficulty in identifying ad, for the lack of validated universal diagnostic criteria as well as for the variegated clinical phenotypes, is responsible for the approximation of the epidemiology of this disease. in fact, ad clinical phenotypes and epidemiology clarification are current challenges for dermatologists. it will be useful to realize a practical review | dermatol pract concept. 2021;11(4):e2021146 5 guide to 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his history revealed that, on advice of his parents, he had been using an electric heater for the past four winter months to keep his legs warm, prior to appearance of the rash. he had no leg pain, abdominal pain, or any history of recurrent fever. there was no history of systemic disease, and physical examination with cbc was within normal limits. a reticular pigmented rash on the lower leg karan lal1, saurabh malhotra2, viktoryia kazlouskaya2, dirk m. elston2 1 new york college of osteopathic medicine, new york, ny, usa 2 ackerman academy of dermatopathology, new york, ny, usa citation: lal k, malhotra s. kazlouskaya v, elston d. a reticular pigmented rash on the lower leg. dermatol pract conc. 2013;3(3):6. http://dx.doi.org/10.5826/dpc.0303a06. copyright: ©2013 lal et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: viktoryia kazlouskaya m.d., ph.d., ackerman academy of dermatopathology, 145 e 32nd street, fl 10, new york, ny, usa. tel. 800.553.6621. e-mail: viktoriakozlovskaya@yahoo.com. figure 1. reticular pigmented rash at the lower right leg. [copyright: ©2013 lal et al.] a final diagnosis of heater-induced erythema ab igne was made. keeping the leg in close proximity to the heater for prolonged periods of time was responsible for the reticulated lesion on his leg. discussion erythema ab igne is a reticular rash that is caused by prolonged close exposure to heat. it is more common in older 22 quiz | dermatol pract concept 2013;3(3):6 malignancies in longstanding lesions. squamous cell carcinoma is one of the most common malignancies caused by thermal radiation. its development after heat exposure has been described in different cultures. examples are kang cancer (carcinoma caused by sleeping on hot bricks) and kengri cancer (seen only in the kashmir region of india and caused by wearing a heater pot under the clothes). cases of merkel cell carcinoma and marginal zone lymphoma have also been described with these lesions [7, 8]. however there have been no cases of malignancy development reported in the pediatric population within these lesions. the diagnosis of erythema ab igne is usually straightforward and is based on the carefully collected anamnesis. the differential diagnosis includes cutis marmorata, livedo vasculitis and poikiloderma. in problematic cases, biopsy may be recommended to exclude the underlying pathology. treatment is usually based on avoiding the use of heating devices, although longstanding cases may be resistant to this avoidant therapy. use of q-switched laser has been described in a single case report [9]. corticosteroids and photodynamic therapy are also described to be helpful. references 1. bachmeyer c, bensaid p, bégon e. laptop computer as a modern cause of erythema ab igne. j eur acad dermatol venereol. 2009;23(6):735-6. 2. arnold aw, itin ph. laptop computer–induced erythema ab igne in a child and review of the literature. pediatrics. 2010; 126(5):e1227-30. 3. mok dw, blumgart lh. erythema ab igne in chronic pancreatic pain: a diagnostic sign. j r soc med. 1984;77(4):299-301. 4. fischer j, rein k, erfurt-berge c, de zwaan m. [three cases of erythma ab igne (eai) in patients with eating disorders]. neuropsychiatr. 2010;42:141-3. 5. finlayson g, sams w, smith j. erythema ab igne: a histolopathological study. j invest dermatol. 1966;46(1):104-9. 6. cavallari v, cicciarello r, torre v, et al. chronic heat-induced skin lesions (erythema ab igne): ultrastructural studies. ultrastruct pathol. 2001;25(2):93-7. 7. hewitt jb, sherif a, kerr km, stankler l. merkel cell and squamous cell carcinomas arising in erythema ab igne. br j dermatol. 1993;128(5):591-2. 8. wharton j, roffwarg d, miller j, sheehan dj. cutaneous marginal zone lymphoma arising in the setting of erythema ab igne. j am acad dermatol. 2010;62(6):1080-1. 9. cho s, jung jy, lee jh. erythema ab igne successfully treated using 1,064-nm q-switched neodymium-doped yttrium aluminum garnet laser with low fluence. dermatol surg. 2011;37(4):551-3. adults, females more than males, although cases in children have also been reported. recurrent exposure to various sources of heat, such as hot water bottles, heating pads, cell phones, radiators, sauna belts, and furniture with heating devices cause the appearance of lesions. the heat is in the range 45-470 c, which is usually insufficient to cause a burn. in rural areas of the world, the lesion is traditionally caused by sitting or cooking near an open fire. laptops are becoming one of the most frequent causes of this entity in the industrialized world [1]. lesions caused by laptop exposure tend to be located on the anterior thighs. the age of patients with erythema ab igne caused by laptops is getting younger. so far, a 12-year-old patient has been the youngest described with laptop induced erythema ab igne [2]. patients with chronic pain such as, for example in chronic pancreatitis, neuropathies or cancer, may use heating devices for pain relief [3]. prolonged use of heat may also be seen in patients with certain personality disorders [4]. the rash tends to be erythematous at the beginning but becomes more pigmented over time. pain or pruritus is not usually noted by the patients. rare forms of bullous erythema ab igne have been described. the pathophysiology of the erythema ab igne development is not completely understood, but it has some similarities with actinic skin damage. it results from damage to superficial blood vessels, which causes angiogenesis and hemosiderin deposition within the dermis. finlayson et al hypothesized that the macroscopic and histological changes present in erythema ab igne are due to a process known as labilization of lysosomes within the dermal cells which is a result of heat rays entering the dermis and causing rupture of lysosomes, thereby allowing degradative enzymes to disperse within the dermis [5]. the released enzymes digest the various fibrous components of the dermis and facilitate accumulation and compacting of elastic fibers producing elastosis. histopathological examination of erythema ab igne in the early stages of the development may be nonspecific. slight atrophic changes within the epidermis, apoptotic keratinocytes, increased melanin deposition, hyperkeratosis, and mononuclear infiltrate at the dermo-epidermal junction may be seen. it has also been proposed that changes in elastic fibers occur [6]. ultrastructural studies have shown welldeveloped tonofilaments and increased number of melanosomes and melanophages within cells [5]. although erythema ab igne is mainly a self-limited condition, some reports have shown possible development of dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023102 1 “dot in a circle”: a useful ultrasound finding for a rapid diagnosis of mycetoma vincenzo maione1, chiara cozzi1, marina venturini1, angela napolitano2, piergiacomo calzavara-pinton1 1 department of dermatology, spedali civili, university of brescia, brescia, italy 2 department of neuroradiology, asst papa giovanni xxiii, bergamo, italy citation: maione v, cozzi c, venturini m, napolitano a, calzavara-pinton p. “dot in a circle”: an useful ultrasound finding for a rapid diagnosis of mycetoma. dermatol pract concept. 2023;13(2):e2023102. doi: https://doi.org/10.5826/dpc.1302a102 accepted: september 25, 2022; published: april 2023 copyright: ©2023 maione et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo maione, department of dermatology, spedali civili, university of brescia, brescia, italy. tel +39 030 3995301 fax +39 0303995015 e-mail: maionevincenzo@gmail.com case presentation a 65-year-old man from senegal presented to our clinic with a 15-year history of a nodular enlarging mass on his left foot. clinical examination revealed a large painless lesion with crusting and purulent discharge (figure 1a). the lesion gradually enlarged, leading to deformity and walking impairment. before biopsy, we performed an ultrasonography which showed hypoechoic areas containing hyperechoic foci, a typical “dot in a circle” sign (figure 1b). a  subsequent mri of the foot confirmed ultrasound findings, revealing well-defined hyperintense lesions with peripheral hypointense rim and central hypointensities, confirming our hypothesis of mycetoma. in addition an underlying osteomyelitis was diagnosed (figure 1c). after a first negative culture, we collected new skin samples under ultrasound guidance which resulted positive for staphylococcus caprae and bacillus pumilus. the patient was treated with ampicillin, after a surgical debulking. teaching point madura foot or mycetoma is endemic disease in tropical regions and takes its name from the indian city of madurai, where it was described for the first time. its clinical presentation, typified by sinuses, subcutaneous nodules and 2 image letter | dermatol pract concept. 2023;13(2):e2023102 purulent discharge, is due to a granulomatous reaction to fungal hyphae (eumycetoma) or bacteria (actinomycetoma) aggregates the “grains” [1]. these pathological findings can be assessed with different diagnostic tools. for instance, dermoscopy displays multiple papules, disappearance of skin furrows and fistulous tracts extruding grains. in additional other dermoscopic features include blood spots, erosions, orange-yellowish structureless areas [2]. ultrasonography seem to be more specific showing a peculiar aspect called “dot in a circle” [3], which correlates directly with the presence of grains. microbiological culture from skin biopsy is necessary to confirm diagnosis but often results difficult, delaying treatment. ultrasound is rapid and low-cost technique – available also in dermatology clinicswhich assists early diagnosis and helps appropriate specimen collection for culture, avoiding multiple surgical interventions. references 1. verma p, jha a. mycetoma: reviewing a neglected disease. clin exp dermatol. 2019;44(2):123-129. doi: 10.1111/ced.13642. pmid: 29808607. 2. errichetti e, ankad b, chatterjee m, calzavara-pinton p, maione v, chauhan p. mycosis. in: dermoscopy in general dermatology for skin of color. errichetti e, lallas a (eds) 1th ed. 2022:132-133. doi: 10.1201/9780367816483. 3. petscavage jm, richardson ml. madura foot masquerading as a hemangioma. radiol case rep. 2015;5(1):355. doi: 10.2484 /rcr.v5i1.355. pmid: 27307847. pmcid: pmc4898212. figure 1. (a) painless mass of the plantar surface of the left foot with a purulent discharge. (b) ultrasound (14-20 mhz us transducer – mylabtmone, esaote) evidenced a hypoechoic area containing hyperechoic foci, due to granulomatous reaction to bacteria grains. (c) sagittal t2 weighted stir mri confirms the presence of “dots in a circle sign” associated to osteomyelitis. dermatology: practical and conceptual 6 observation | dermatol pract concept 2017;7(3):2 dermatology practical & conceptual www.derm101.com introduction eosinophilic dermatosis of hematologic malignancy was first reported in 1965 and thought to be a hypersensitivity reaction to insect bites in patients with chronic lymphocytic leukemia (cll) [1]. subsequent reports noted that most patients failed to recall insect bites; thus, the term “insect bite-like reaction” was established [2]. byrd et al. later dubbed the process eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: report in a woman with chronic lymphocytic leukemia and review of the literature omar bari1, philip r. cohen2 1 university of california san diego school of medicine, la jolla, ca, usa 2 department of dermatology, university of california san diego, la jolla, ca, usa key words: chronic, dermatosis, eosinophilic, hematologic, infection, leukemia, lymphocytic, malignancy, varicella, zoster citation: bari o, cohen pr. eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: report in a woman with chronic lymphocytic leukemia and review of the literature. dermatol pract concept 2017;7(3):2. doi: https://doi.org/10.5826/ dpc.0703a02 received: december 1, 2016; accepted: april 29, 2017; published: july 31, 2017 copyright: ©2017 bari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md, department of dermatology, university of california san diego, la jolla, ca, usa. email: mitehead@gmail.com eosinophilic dermatosis of hematologic malignancy is a rare papulovesicular eruption that presents in patients with hematoproliferative disorders, particularly chronic lymphocytic leukemia. a 59-year-old woman with chronic lymphocytic leukemia who developed eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection is described. pubmed database was searched with the key words: chronic, dermatosis, eosinophilic, hematologic, infection, leukemia, lymphocytic, malignancy, varicella, zoster. the papers generated by the search and their references were reviewed. the patient presented, on more than 20 occasions, with a dermatomal vesicular eruption. her oncologist, based on the clinical presentation, treated each episode as recurrent varicella zoster virus infection. a complete workup of the patient not only demonstrated negative viral studies but also revealed pathologic changes consistent with eosinophilic dermatosis of hematologic malignancy on lesional skin biopsy. the recurrence of the patient’s dermatosis was less frequent when her malignancy was under better control. eosinophilic dermatosis of hematologic malignancy may mimic other reactive dermatoses. the morphology of our patient’s recurrent dermatosis resembled varicella zoster virus infection. disseminated zoster virus infection with dermatomal and non-dermatomal distribution should be added to the clinical differential diagnosis of eosinophilic dermatosis of hematologic malignancy. abstract observation | dermatol pract concept 2017;7(3):2 7 infection outbreaks. cutaneous examination showed dermatomal (figure 1) and non-dermatomal (figure 2) lesions with similar morphology on her back and flanks. vesicles ranging from 2 mm to 5 mm, within areas of erythema, were present. initial evaluation included viral cultures for herpes simplex virus and varicella zoster virus; vesicular fluid was sent for direct fluorescent antibody to these viruses. in addition, biopsies were performed for both routine staining and direct immunofluorescence to rule out autoimmune bullous diseases. the viral cultures and direct fluorescent antibody studies were negative. microscopic examination of the skin biopsy showed an intraepidermal vesicle with eosinophils, eosinophilic spongiosis, and an accompanying diffuse and dense perivascular and periadnexal lymphocytic infiltrate with numerous eosinophils (figure 3). direct immunofluorescence and enzyme-linked immunosorbent assay (elisa) studies were negative for bullous pemphigoid antigen-1 and bullous pemphigoid antigen-2. correlation of the clinical history, morphology, pathologic changes, and laboratory studies established the diagnosis of eosinophilic dermatosis of hematologic malignancy. initial management included twice daily application of betamethasone dipropionate 0.05% cream, which provided relief and eventual resolution of the lesions. two weeks later, the patient had recurrence of her lesions (figure 4) and another skin biopsy showed similar pathologic changes. the patient was receiving investigational systemic therapy for her cll; oral and other systemic therapies were prohibited. she continued her topical treatment. the frequency of relapsing skin lesions was markedly reduced during periods in which the patient’s hematologic malignancy was under better control. recently, she had an exacerbation of her cll and antineoplastic therapy was altered. subsequently, she has had less frequent flares of her dermatosis after being placed on obinutuzumab. eosinophilic dermatosis of myeloproliferative disease [3], though farber et al. favor the term eosinophilic dermatosis of hematologic malignancy to better encompass the numerous hematologic malignancies associated with this cutaneous eruption [4,5]. we describe a woman with cll whose lesions resembled varicella zoster virus infection and review the literature on eosinophilic dermatosis of hematologic malignancy. case report a 59-year-old woman with cll presented for evaluation of vesicular eruptions thought to be recurrent varicella zoster virus infection. she was diagnosed with cll in 2003 but experienced several recurrences of her leukemia. shortly after the first recurrence of cll in 2009, she developed skin lesions that appeared in a dermatomal distribution on her back. these lesions reappeared several times, and her oncologist treated her for presumptive herpes zoster virus infection with an appropriate dosage of acyclovir on more than 20 occasions. the patient had no definitive prior history of herpes zoster virus infection; varicella zoster virus infection had never been objectively confirmed with biopsy, viral culture, or pcr amplification. however, the patient did have several complete blood counts drawn. eosinophil percentages ranged from 1-10%, though most frequently were 4-5% (normal range 0-7%); however, absolute eosinophil count never exceeded 500 cells per ml (normal range 0-500 cells per ml). serum ige level was assessed and found to be 2 international units (iu) per ml (normal range 0-99 iu/ml). her cll therapy initially included fludarabine, cyclophosphamide, and rituximab but later included alemtuzumab, lenalidomide, venetoclax, and obinutuzumab. she presented to the dermatologist for evaluation of a new onset of her skin lesions; these were similar to those that her oncologist had previously treated as varicella zoster virus figure 1. distant views of vesicles on an erythematous base corresponding to the left t6 dermatome presenting below the breast (a), and extending to involve the upper abdomen and mid-back (b). [copyright: ©2017 bari et al.] a b 8 observation | dermatol pract concept 2017;7(3):2 the pathogenesis of this condition is poorly understood [4]. it has been hypothesized that there is an excess of interleukin-4 and interleukin-5; this imbalance may lead to a proliferation of neoplastic b cells, which have been considered a major driver of the eruption [3,4,9]. this hypothesis is supported by the fact that interleukin-5 is the major eosinophilrecruiting cytokine [4]. alternatively, it has been thought that neoplastic b cells drive a hypersensitivity reaction [3]. several therapeutic options to treat eosinophilic dermatosis of hematologic malignancy have been reported. they include antibiotics, antihistamines, chemotherapy, dapsone, interferon alpha, intravenous immunoglobulin, phototherapy, and radiation [2,4,10]. though some patients report favorable responses to therapy, overall the results have been disappointing [4]. the poor response underscores the lack of clarity of this condition’s pathogenesis [4]. in regards to prognosis, eosinophilic dermatosis of hematologic malignancy may be associated with an aggressive course of cll [4]; our patient lends support to this observation, given her repeat recurrences of cll. reported complications in patients with cll and eosinophilic dermatosis of hematologic malignancy include richter transformation and malignant clone expansion [2,10]. an underlying state of immunosuppression is postulated as the cause for these occurrences. conclusion our patient’s recurrent skin lesions of eosinophilic dermatosis of hematologic malignancy were clinically interpreted by her oncologist to be varicella zoster virus infection because they were frequently dermatomal. however, the likelihood of over 20 episodes of herpes zoster would be unique and unexpected; hence, we were prompted to evaluate her skin lesions and exclude the diagnosis of either a viral infection or discussion patients with cll usually present with eosinophilic dermatosis of hematologic malignancy between 40 to 60 years of age [4]. table 1 offers a review of this condition [1-25]. the eruption often occurs concurrently with or months to years after the diagnosis of the associated hematologic malignancy. however, the condition has also been reported to present prior to the cancer diagnosis [4]. eosinophilic dermatosis of hematologic malignancy occurs most often with cll. it has also been associated with acute lymphoblastic leukemia, acute monocytic leukemia, large cell lymphoma, mantle cell lymphoma, multiple myeloma, and myelofibrosis [4,6,7]. eosinophilic dermatosis of hematologic malignancy has a polymorphic presentation. the condition may manifest as erythema, papules, nodules, urticaria, or vesicles [4,9]. the eruption is usually indurated and erythematous but can also be tender [4]. the clinical differential diagnosis includes arthropod assault, dermatitis herpetiformis, drug reaction, eosinophilic cellulitis, eosinophilic folliculitis, infection, leukemia cutis, papular urticaria, scabies, and urticarial stage of bullous pemphigoid [4,9]. histologically, this condition displays a superficial and deep dense perivascular infiltrate of lymphocytes and eosinophils [2,4]. vesicles or bullae may also present due to intraepidermal or subepidermal edema [4]. flame figures in the dermis have also been reported [5]. a figure 2. distant (a) and close (b) views of an isolated, non-dermatomal, erythematous-based vesicle appears on the lower left flank. [copyright: ©2017 bari et al.] b observation | dermatol pract concept 2017;7(3):2 9 autoimmune bullous disease. it is conceivable that our patient may have initially had zoster sine herpete, which manifests as radicular pain without rash [26]. with a background of zoster sine herpete, the patient plausibly could have developed an immunocompromised zone and therefore displayed wolf’s isotopic response, in which a new skin disorder occurs at the site of a previously healed skin disease [27]. however, our investigation established the diagnosis of eosinophilic dermatosis of hematologic malignancy. based on our patient’s a b c d figure 3. microscopic examination of a low magnification view showing a large vesicle (a). intermediate magnification views (b and c) of the lateral aspects of the vesicle demonstrating that it is intraepidermal and contains serosanguinous fluid with eosinophils. the base of the blister shows eosinophilic spongiosis (d); the spaces between keratinocytes are filled with eosinophils. in the underlying dermis, there is edema and a dense infiltrate that is not only diffuse but also perivascular and periadnexal; the infiltrate consists of lymphocytes and numerous eosinophils (d and e) (hematoxylin and eosin; a = x4; b = x20; c = x20; d = x20; and e = x40). [copyright: ©2017 bari et al.] e 10 observation | dermatol pract concept 2017;7(3):2 morphologic presentation of eosinophilic dermatosis of hematologic malignancy, we add disseminated zoster infection with dermatomal and non-dermatomal distribution to the differential diagnosis of this condition. a b c figure 4. distant (a) and closer (b and c) views of a linear presentation of erythematous-based vesicles of eosinophilic dermatosis of hematologic malignancy corresponding to the left l4 dermatome. [copyright: ©2017 bari et al.] observation | dermatol pract concept 2017;7(3):2 11 table 1. summary of eosinophilic dermatosis of hematologic malignancy [copyright: ©2017 bari et al.] author, year number of cases associated malignancy age; sex clinical manifestation histology management edhm course ref weed, 1965 8 cll 40-76; nr erythematous, indurated, and pruritic lesions in areas of recent mosquito bites or areas with central punctum subepidermal edema with dense dermal infiltrate of eosinophils and lymphocytes cll was treated with chlorambucil or prednisone in most patients lesions resolved spontaneously within weeks 1 rosen, 1986 10 cll 57-82; 7 m, 3 w erythematous and pruritic bullae, nodules, and papules at various locations superficial and deep, perivascular, periadnexal, and interstitial infiltrate of eosinophils and lymphocytes treatments for cll included prednisone, vincristine, cyclophosphamide, and chlorambucil nr 11 kolbusz, 1989 1 cll 51; w recurrent eruptions of erythematous urticarial patches on the extremities and trunk lymphohistiocytic infiltrate with eosinophils diphenhydramine for skin lesions initial outbreaks were self-limited with no treatment; later eruptions improved with diphenhydramine 12 davis, 1998 8 cll 51-69; 6 m, 2 w papular and vesiculobullous lesions in various locations all biopsies revealed lymphohistioctic infiltrate and eosinophils in the dermis chemotherapy, ivig, and glucocorticoids 3 patients experienced improvement with chemotherapy for cll; 1 patient improved with ivig; 4 patients responded to oral glucocorticoids 10 barzilai, 1999 8 all, aml, cll (3 patients), mcl, lcl, mf 42-72; 4 m, 4 w recurrent erythematous, pruritic papules and plaques at various locations superficial and deep perivascular and interstitial infiltrate of eosinophils and lymphocytes topical antipruritic agents, topical and systemic corticosteroids, systemic antihistamines no improvement with any agent except systemic corticosteroids, though lesions recurred when steroids were tapered 2 blum, 2001 1 cll 49; m admitted to the hos pi tal after second cycle of chemotherapy with vesicles and hemorrhagic bullae on the extremities, face, and trunk superficial and deep perivascular dermatitis with interstitial eosinophils systemic corticosteroids lesions improved with steroids but recurred with tapered dose 13 byrd, 2001 4 aml, cll (2 patients), mds 53-81; 4 m recurrent eruptions of erythematous, pruritic nodules and papules at various locations perivascular and periadnexal infiltrate with lymphocytes and eosinophils antibiotics, antifungals, antihistamines, colchicine, dapsone, hydroxyurea, hydroxychloroquine, isotretinoin, systemic and topical steroids, and uv-b phototherapy for skin lesions; chemotherapy started for malignancy 2 patients’ lesions resolved during chemotherapy but recurred once it was complete, and chemotherapy was re-started to control skin lesions in these patients; 2 patients experienced improvement with phototherapy 3 asakura, 2004 1 cll 46; w pruritic, erythematous bullae on the extremities in the site of prior mosquito bites nr cyclophosphamide and prednisolone for cll skin lesions were self-limited 14 cocuroccia, 2004 1 cll 65; m 4-month history of recurrent pruritic bullae and papules on the extremities epidermal spongiosis, edema in papillary dermis, with superficial and deep, perivascular and interstitial infiltrate of eosinophils and neutrophils antihistamines and topical corticosteroids for skin lesions improvement after 10 days with mild recurrence after 2 weeks; no further lesions at 6-month follow-up 15 (continued next page) 12 observation | dermatol pract concept 2017;7(3):2 author, year number of cases associated malignancy age; sex clinical manifestation histology management edhm course ref dodiuk-gad, 2004 2 mcl 61, 64; 2 m patient 1 with 6-month duration of pruritic, erythematous nodules and papules on the extremities; patient 2 with 2-year history of pruritic, erythematous nodules, papules, and plaques on the extremities patient 1 with epidermal spongiosis and microvesicles with eosinophils, along with an upper dermal infiltrate of eosinophils; patient 2 with dense infiltrate of eosinophils and neutrophils in the dermis antipruritic agents, topical and oral steroids for skin lesions in patient 1; patient 2 started on chop and rituximab patient 1 improved with oral prednisone but lesions continued to recur; patient 2 improved with chemotherapy 16 khamaysi, 2005 6 cll (3 patients) and mcl (3 patients) 56-74; 3 m, 3 w pruritic and erythematous nodules, papules, plaques, and vesicles superficial and deep perivascular and interstitial infiltrate with eosinophils and mononuclear cells nr nr 17 vassallo, 2005 5 cll (3 patients), nhl (2 patients) nr; nr erythematous, pruritic bullae, papules, and plaques superficial and deep perivascular and interstitial infiltrate of eosinophils and lymphocytes antihistamines and systemic steroids for skin lesions improvement in skin lesions but flares continued to recur 18 yoon, 2005 1 nmzl 46; m 6-year history of recurrent papulovesicular eruptions at various locations epidermal spongiosis with focal necrosis, edema in the papillary dermis, and perivascular, periadnexal, and interstitial infiltrate of eosinophils, lymphocytes, and neutrophils 6 courses of chop improvement in skin lesions with residual scar 19 walker, 2007 1 cll 69; w 18-month history of pruritic, erythematous plaques on the extremities spongiotic vesiculation and infiltrate of eosinophils in the papillary dermis antibiotics, fexofenadine, ibuprofen, oral prednisolone, promethazine, and topical betamethasone for skin lesions; rituximab for cll poor response to all agents except ibuprofen and prednisolone, which reduced severity of outbreaks; once patient was switched to rituximab, she experienced less frequent flares 20 rodríguezlojo, 2010 1 cll 63; m 1-year history of recurrent urticarial nodules on the extremities and trunk infiltrate of eosinophils that involved fat lobules; later biopsies revealed dermal eosinophilic infiltrate with flame figures systemic steroids, topical steroids, and dapsone for skin lesions; chop for cll recurrences were reduced with therapy for skin lesions; eruptions stopped when cll was controlled 21 bairey, 2012 48 cll 33-82; 25 m, 23 f erythematous and pruritic macules, nodules, papules, and vesicles at various locations superficial and deep, interstitial and perivascular infiltrates of eosinophils and mononuclear cells antibiotics, antihistamines, dapsone, oral and topical steroids, phototherapy 60% of eruptions resolved with treatment, 24% improved, and 14% had no response to therapy 22 farber, 2012 1 cll 73; m 4-year history of recurrent erythematous, pruritic nodules and papules on the extremities, face, neck, scalp, and trunk dense superficial and deep perivascular infiltrate of eosinophils and lymphocytes doxycycline, hydroxyzine, and prednisone taper for skin lesions; chemotherapy started for cll eruptions improved when chemotherapy started but recurred once it was completed; number of lesions and intensity of pruritus decreased but complete resolution was not achieved 4 table 1. summary of eosinophilic dermatosis of hematologic malignancy (continued) (continued next page) observation | dermatol pract concept 2017;7(3):2 13 author, year number of cases associated malignancy age; sex clinical manifestation histology management edhm course ref mitteldorf, 2012 1 cll 71; f pruritic, erythematous papulovesicular eruptions on the face and trunk focal epidermal spongiosis, edema within the papillary dermis, and superficial and deep perivascular and interstitial infiltrate of eosinophils and lymphocytes prednisolone for skin lesions; rituximab and bendamustine started for cll no cutaneous improvement from chemotherapy; steroids led to complete resolution of skin lesions 23 qiao, 2013 1 cll 67; w 9-month history of recurrent pruritic eruptions of bullae, papules, plaques, and vesicles on the extremities, face, and trunk prominent subepidermal blisters with diffuse infiltrate of eosinophils and flame figures in the dermis prednisone lesions improved within 10 days of prednisone but eruption recurred with steroid taper 5 butzmann, 2014 1 cll 60; w 6-month history of lesions on the extremities; presented with excoriated papules and vesicles intraepidermal vesicle with eosinophils; dermis with dense perivascular lymphocytic infiltrate with eosinophils topical corticosteroids and oral antihistamines reduced recurrence rate and intensity of new lesions 24 two, 2014 1 mm 50; m 3-month history of pruritic vesicles on the extremities and trunk superficial and deep mixed perivascular infiltrate of eosinophils and lymphocytes topical corticosteroids for skin lesions; bortezomib, carfilzomib, and dexamethasone for mm vesicles disappeared at 6-week follow-up after stopping topical steroids though mm was undergoing continued therapy 6 liu, 2015 1 cll 45; w 5-year history of recurrent pruritic blisters, papules, and plaques on the extremities and face subepidermal edema with dense nodular and interstitial infiltrate of eosinophils and lymphocytes in the dermis and subcutaneous tissue prednisolone for 12 months lesions continued to recur 25 penn, 2015 1 dlbcl 56; w pruritic papular eruptions on the extremities superficial and deep perivascular infiltrate of eosinophils and lymphocytes antihistamines, intralesional glucocorticoids, and topical glucocorticoids for skin lesions; rituximab and bendamustine for cll eruptions improved with systemic therapy for malignancy along with regimen of antihistamines and steroids 7 jayasekera, 2016 1 cll 51; m several week history of papules and plaques on the extremities epidermal spongiosis and interstitial infiltrate of eosinophils topical betamethasone, dapsone, oral prednisolone with topical clobetasol; idelalisib and rituximab for cll failed topical steroids; rash flared once oral prednisolone was tapered 9 martires, 2016 1 cll 68; w 5-month history of recurrent pruritic bullae on the extremities and face epidermal spongiosis with superficial and deep mixed infiltrate of eosinophils, lymphocytes, and neutrophils methylprednisolone, prednisone, and high-potency topical glucocorticoids for skin lesions rate of resolution increased but lesions continued to recur 8 table 1. summary of eosinophilic dermatosis of hematologic malignancy (continued) (continued next page) 14 observation | dermatol pract concept 2017;7(3):2 13. blum rr, phelps rg, wei h. arthropod bites manifesting as recurrent bullae in a patient with chronic lymphocytic leukemia. j cutan med surg. 2001;5(4):312-314. 14. asakura k, kizaki m, ikeda y. exaggerated cutaneous response to mosquito bites in a patient with chronic lymphocytic leukemia. int j hematol. 2004;80(1):59-61. 15. cocuroccia b, gisondi p, gubinelli e, girolomoni g. an itchy vesiculobullous eruption in a patient with chronic lymphocytic leukaemia. int j clin pract. 2004;58(12):1177-1179. 16. dodiuk-gad rp, dann ej, bergman r. insect bite-like reaction associated with mantle cell lymphoma: a report of two cases and review of the literature. int j dermatol. 2004;43(10):754-758. 17. khamaysi z, dodiuk-gad rp, weltfriend s, et al. insect bite-like reaction associated with mantle cell lymphoma: clinicopathological, immunopathological, and molecular studies. am j dermatopathol. 2005;27(4):290-295. 18. vassallo c, passamonti f, cananzi r, et al. exaggerated insect bite-like reaction in patients affected by oncohaematological diseases. acta derm venereol. 2005;85(1):76-77. 19. yoon ty, kim yg, kim jw, kim mk. nodal marginal zone lymphoma in association with hydroa vacciniforme-like papulovesicular eruption, hypersensitivity to mosquito bites and insect bite-like reaction. br j dermatol. 2005;153(1):210-212. 20. walker p, long d, james c, marshman g. exaggerated insect bite reaction exacerbated by a pyogenic infection in a patient with chronic lymphocytic leukaemia. australas j dermatol. 2007;48(3):165-169. 21. rodríguez-lojo r, almagro m, piñeyro f, et al. eosinophilic panniculitis and insect bite-like eruption in a patient with chronic lymphocytic leukaemia: a spectrum of the same entity. dermatol res pract. 2010;2010:263827. 22. bairey o, goldschmidt n, ruchlemer r, et al. insect-bite-like reaction in patients with chronic lymphocytic leukemia: a study from the israeli chronic lymphocytic leukemia study group. eur j haematol. 2012;89(6):491-496. 23. mitteldorf c, tronnier m, merz h, et al. insect bite-like reactions in a patient with b-cell chronic lymphocytic leukaemia: fluorescence in situ hybridization analysis revealed neoplastic b cells within the skin infiltrate. br j dermatol. 2012;167(4):944-946. references 1. weed ri. exaggerated delayed hypersensitivity to mosquito bites in chronic lymphocytic leukemia. blood. 1965;26:257-268. 2. barzilai a, shpiro d, goldberg i, et al. insect bite-like reaction in patients with hematologic malignant neoplasms. arch dermatol. 1999;135(12):1503-1507. 3. byrd ja, scherschun l, chaffins ml, fivenson dp. eosinophilic dermatosis of myeloproliferative disease: characterization of a unique eruption in patients with hematologic disorders. arch dermatol. 2001;137(10):1378-1380. 4. farber mj, la forgia s, sahu j, lee jb. eosinophilic dermatosis of hematologic malignancy. j cutan pathol. 2012;39(7):690-695. 5. qiao j, sun ce, zhu w, zhu d, fang h. flame figures associated with eosinophilic dermatosis of hematologic malignancy: is it possible to distinguish the condition from eosinophilic cellulitis in patients with hematoproliferative disease? int j clin exp pathol. 2013;6(8):1683-1687. 6. two am, li c, hata t. a case of eosinophilic dermatosis of hematologic malignancy in a patient with multiple myeloma. dermatol online j. 2014;20(1):21256. 7. penn l, ahern i, mir a, meehan sa. eosinophilic dermatitis of hematologic malignancy. dermatol online j. 2015;21(12). 8. martires k, callahan s, terushkin v, brinster n, leger m, soter n. eosinophilic dermatosis of hematologic malignancy. dermatol online j. 2016;22(12). 9. jayasekera ps, bakshi a, al-sharqi a. eosinophilic dermatosis of haematological malignancy. clin exp dermatol. 2016;41(6):692695. 10. davis md, perniciaro c, dahl pr, randle hw, mcevoy mt, leiferman km. exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: a clinical, histopathologic, and immunopathologic study of eight patients. j am acad dermatol. 1998;39(1):27-35. 11. rosen lb, frank bl, rywlin am. a characteristic vesiculobullous eruption in patients with chronic lymphocytic leukemia. j am acad dermatol. 1986;15(5 pt 1):943-950. 12. kolbusz rv, micetich k, armin ar, massa mc. exaggerated response to insect bites. an unusual cutaneous manifestation of chronic lymphocytic leukemia. int j dermatol. 1989;28(3):186187. author, year number of cases associated malignancy age; sex clinical manifestation histology management edhm course ref bari and cohen, 2017 1 cll 59; w 5-year history of dermatomal and non-dermatomal distribution of vesicles on the back and flanks eosinophilic spongiosis, intraepidermal vesicle with eosinophils, and perivascular and periadnexal lymphocytic infiltrate with eosinophils acyclovir, topical betamethasone for skin lesions; cll was treated with many agents but most recently the patient was started on obinutuzumab acyclovir was not efficacious, though topical betamethasone led to temporary resolution of skin lesions; patient experienced fewer recurrences after obinutuzumab was started cr abbreviations: all, acute lymphocytic leukemia; aml, acute monocytic leukemia; chop, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone; cll, chronic lymphocytic leukemia; cr, current report; dlbcl, diffuse large b cell lymphoma; edhm, eosinophilic dermatosis of hematologic malignancy; ivig, intravenous immunoglobulin; lcl, large cell lymphoma; m, man; mcl, mantle cell lymphoma; mds, myelodysplastic syndrome; mf, myelofibrosis; mm, multiple myeloma; nhl, non-hodgkin lymphoma; nmzl, nodal marginal zone lymphoma; nr, not reported; ref, reference; uv-b, ultraviolet-b phototherapy; w, woman table 1. summary of eosinophilic dermatosis of hematologic malignancy (continued) observation | dermatol pract concept 2017;7(3):2 15 24. butzmann cm, kern js, stanislawski g, meiss f. insect bite-like reaction in a patient with chronic lymphocytic leukemia. j dtsch dermatol ges. 2014;12(8):734-737. 25. liu kc, hsu ck, lee jy. insect bite-like reaction in association with chronic lymphocytic leukemia. int j dermatol. 2015;54(10):1191-1193. 26. gilden d, cohrs rj, mahalingam r, nagel ma. neurological disease produced by varicella zoster virus reactivation without rash. curr top microbiol immunol. 2010;342:243-253. 27. wolf r, wolf d, ruocco e, brunetti g, ruocco v. wolf’s isotopic response. clin dermatol. 2011;29(2):237-240. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):4 23 dermatology practical & conceptual www.derm101.com case report the case presents a caucasian female, who had been consulting dermatology for nine years for asymptomatic lesions on the central thorax, present from the first days of life. on physical examination, multiple brown and skin-colored papules were observed 2-3 mm in size (figure 1). with dermoscopy (polarized light), the lesions showed an agminated homogeneous blue pattern (figure 2) and a pore, through which brown material was seen (figure 3). multiple agminated lesions with homogeneous blue pattern on dermoscopy belén lozano-masdemont1, monserrat franco-muñoz1, mónica garcía-arpa1, claudia ramos-rodríguez2 1 department of dermatology, hospital general de ciudad real, ciudad real, spain 2 department of pathology, hospital general de ciudad real, ciudad real, spain citation: lozano-masdemont b, franco-muñoz m, garcía-arpa m, ramos-rodriguez c. multiple agminated lesions with homogeneous blue pattern on dermoscopy. dermatol pract concept. 2017;7(1):4. doi: https://doi.org/10.5826/dpc.0701a04 copyright: ©2017 lozano-masdemont. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: belén lozano masdemont, md, department of dermatology. hospital general de ciudad real, obispo rafael torija s/n, 13005, ciudad real, spain. tel. +34 926 278 000. email: belenmasdemont@gmail.com figure 1. clinical image. multiple brown and skin-colored papules on the anterior chest. [copyright: ©2017 lozano-masdemont.] figure 2. dermoscopy (polarized light). agminated homogeneous blue pattern resembling a bunch of grapes (bunch of grapes sign) and a schematic representation of the image. [copyright: ©2017 lozano-masdemont.] mailto:belenmasdemont@gmail.com 24 observation | dermatol pract concept 2017;7(1):4 copy, common acne shows yellowish or brownish follicular plugging and inflammation [1]. dermoscopy may be a useful tool in the diagnosis of these lesions, especially at atypical locations or ages, besides being a safe technique, which could have been used in this patient since birth. references 1. alfaro-castellón p, mejía-rodríguez sa, valencia-herrera a, ramírez s, mena-cedillos c. dermoscopy distinction of eruptive vellus hair cysts with molluscum contagiosum and acne lesions. pediatr dermatol. 2012;29(6):772-3. 2. gencoglan g, karaarslan ik, akalin t, ozdemir f. trichilemmal cyst with homo-geneous blue pigmentation on dermoscopy. australas j dermatol. 2009;50(4):301-2. 3. panasiti v, curzio m, roberti v, et al. ectopic hidradenoma papilliferum dermo-scopically mimicking a blue nevus: a case report and review of the literature. int j dermatol. 2014;53(2):e103-6. discussion a biopsy, covering three lesions, showed three cystic formations in the middle dermis, covered by squamous epithelium, the interior of which contained laminated keratin and multiple vellus hairs (figures 4, 5). the diagnosis of eruptive vellus hair cyst (evhc) was established. evhc are asymptomatic skin-colored papules, erythematous or bluish, typically located in the anterior portion of the chest, axillae and buttocks. it usually occurs in children, even from birth, as in the case presented, which is postulated to be a hamartomatous entity. histologically, they are characterized by dermal cystic formations of squamous epithelium, laminated keratin and multiple vellus hairs. the dermoscopic characteristics of evhc have been described only twice, with different findings. alfaro-castellón et al describe them as round or oval yellowish structures, with occasional erythematous halos [1]. in our case, the lesions show a homogeneous blue pattern, agminated, so the dermoscopic image resembles a bunch of grapes (bunch of grapes sign). the main differential diagnoses of the homogeneous blue pattern are blue nevus and melanoma metastasis, although in recent years other lesions, mostly adnexal, are being described with this pattern, caused by the tyndall effect. trichilemmal cysts may show a erythematous periphery, besides the homogeneous blue pattern [2]. ectopic hidradenoma papilliferum may present large vessels in the periphery [3]. eccrine acrospiroma is surrounded by a discrete pigment network [4], like some dermatofibromas [5]. oiso et al [6] observed another dermatoscopic sign: cystic openings in the epidermis, a feature that can also be seen in figure 3 of this case. these or puncta barely visible to the naked eye can also be observed in epidermal cysts, although these do not exhibit the characteristic bluish agminated structures (figure 3b) or clinical location. finally, with dermosfigure 3. dermoscopy (polarized light). (a) isolated pore (keratinfilled orifice). (b) a pore and a papule with homogeneous blue pattern (arrow). [copyright: ©2017 lozano-masdemont.] figure 4. histopathologic image. a cystic formation in the middle dermis covered by squamous epithelium, the interior of which contained trichilemmal keratinization and multiple vellus hairs (hematoxylin and eosin, 20x). [copyright: ©2017 lozano-masdemont.] figure 5. histopathologic image. detail (hematoxylin and eosin, 40x). [copyright: ©2017 lozano-masdemont.] observation | dermatol pract concept 2017;7(1):4 25 6. oiso n, matsuda h, kawada a. eruptive vellus hair cysts of the labia majora: detection of openings of the cysts to the epidermis by dermoscopy. eur j dermatol. 2013;23(3):417-8. 4. gatti a, di meo n, trevisan g. dermoscopy of eccrine acrospiroma masquerading as nodular malignant melanoma. acta dermatovenerol alp pannonica adriat. 2010;19(4):23-5. 5. ozdemir f, kilinc i, akalin t. homogeneous blue pigmentation in dermatofibroma simulating a blue naevus. j eur acad dermatol venereol. 2006;20(6):733-4. pmid: 1683506. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023037 1 an unexpected dermatophyte? two remarkable cases of tinea barbae by trichophyton benhamiae gloria baeza-hernández1, maría de la soledad vallejo-ruiz1, ricardo francisco rubio-aguilera1, alberto romero-maté1, cristina martínez-morán1 1 dermatology department, hospital de fuenlabrada. fuenlabrada, madrid, spain key words: trichophyton benhamiae, arthroderma benhamiae, tinea barbae, dermatophytosis, terbinafine citation: baeza-hernández g, de la soledad vallejo-ruiz m, rubio-aguilera rf, romero-maté a, martínez-morán c. an unexpected dermatophyte? two remarkable cases of tinea barbae by trichophyton benhamiae. dermatol pract concept. 2023;13(1):e2023037. doi: https://doi.org/10.5826/dpc.1301a37 accepted: june 13, 2022; published: january 2023 copyright: ©2023 baeza-hernández et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gloria baeza-hernández, servicio de dermatología, hospital de fuenlabrada, camino del molino 2, 28942 fuenlabrada, madrid, spain. e-mail: gloria.baeza@salud.madrid.org introduction trichophyton (t.) benhamiae is considered an emergent zoophilic dermatophyte, with more cases being reported from various countries around the world. we hereby present two cases of tinea barbae by t. benhamiae. case presentation case 1. a 48-year-old man attended the emergency department with a 1-month history of facial lesions treated with ciclopirox and mupirocin ointment. he had a healthy pet dog. on examination, he had extensive impetiginized crusts all over the nasolabial triangle. removal of the crusts revealed erythematous, vegetating plaques on the nasolabial folds (figure 1). case 2. another 50-year-old man, owner of a healthy dog, came to the outpatient clinic complaining of a two-week facial rash previously treated with topical clobetasol and gentamicin without improvement. on examination he had an erythematous plaque on his chin, with some pustules and erosions covered by serous-hematic crust, and a 2-3 cm nodule in the plaque’s border (figure 2). some of his closest family members were being treated for tinea corporis. scales were gathered for fungal culture. in both cases, t. benhamiae was identified by maldi-tof (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry analysis. terbinafine 250 mg daily for three months completely cleared the lesions in both patients. conclusions t. benhamiae, previously known as arthroderma (a.) benhamiae, is nowadays a species on its own according to the latest dermatophyte taxonomy, based on the analysis of the internal transcribed spacer (its) ribosomal dna region [1,2]. every year, more cases of t. benhamiae are being reported worldwide particularly among children. this zoophilic dermatophyte is mainly transmitted by guinea pigs, 2 research letter | dermatol pract concept. 2023;13(1):e2023037 and seldom by other infected animals like rabbits, cats, dogs and even a fox [3]. our patients were both adults and only had contact with their pet dogs, which were apparently unaffected; however, we have no information about their veterinary evaluation. retrospectively our patients couldn’t remember being near a guinea pig, which can be silent carriers of t.  benhamiae [4]. we haven’t found studies about t. benhamiae colonization in dogs. clinically, it usually causes highly inflammatory tinea corporis and faciei which can be confused with impetigo, delaying a correct diagnosis [5]. there are scattered reports of kerion celsi and onychomycosis [3,5]. to the best of our knowledge, only one case of tinea barbae by t. benhamiae has been previously reported by braun et al in 2013, a 24-year-old male in which the authors identified a. benhamiae by pcr in the patient and in his guinea pig [6]. identification of t. benhamiae requires molecular methods due to its similarity to other fungal species in standard cultures. yellow subtype of this fungus grows in colonies that may be diagnosed as microsporum canis, and the unusual white subtype is usually identified as t. mentagrophytes. polymerase chain reaction (pcr) of the its region and maldi-tof both allow for a correct diagnosis [7]. treatment is akin to that of other dermatophyte infections. if the infection covers an extensive area or hair follicles are affected, oral treatment is preferred, terbinafine being the first choice [3,5]. tinea barbae by t. benhamiae seems to be rare. previous contact with animals, especially guinea pigs, and inflammatory lesions on physical examination should prompt the diagnosis of t. benhamiae infection. molecular diagnostic methods like pcr and maldi-tof are necessary to ensure correct identification of this emergent dermatophyte. references 1. shiraki y, hiruma m, matsuba y, et al. a case of tinea corporis caused by arthroderma benhamiae (teleomorph of tinea mentagrophytes) in a pet shop employee. j am acad dermatol. 2006;55(1):153-154. doi:10.1016/j.jaad.2005.05.048. pmid: 16781312. 2. de hoog gs, dukik k, monod m, et al. toward a novel multilocus phylogenetic taxonomy for the dermatophytes. mycopathologia. 2017;182(1-2):5-31. doi:10.1007/s11046016-0073-9. pmid: 27783317. pmcid: pmc5283515. 3. tan j, liu x, gao z, yang h, yang l, wen h. a case of tinea faciei caused by trichophyton benhamiae: first report in china. bmc infect dis. 2020;20(1):1-5. doi:10.1186/s12879-0204897-z. pmid: 32087692. pmcid: pmc7036192. 4. berlin m, kupsch c, ritter l, stoelcker b, heusinger a, gräser y. german-wide analysis of the prevalence and the propagation factors of the zoonotic dermatophyte trichophyton benhamiae. j fungi. 2020;6(3):1-11. doi:10.3390/jof6030161. pmid: 32899171. pmcid: pmc7558194. 5. nenoff p, uhrlaß s, krüger c, et al. t trichophyton species of arthroderma benhamiae a new infectious agent in dermatology.  j dtsch dermatol ges. 2014;12(7):571-581. doi:10.1111 /ddg.12390. pmid: 24981469. 6. braun sa, jahn k, westermann a, bruch-gerharz d, reifenberger j. tinea barbae profunda durch arthroderma benhamiae. der hautarzt. 2013;64(10):720-722. doi:10.1007/s00105-0132646-6. pmid: 24150818. 7. sabou m, denis j, boulanger n, et al. molecular identification of trichophyton benhamiae in strasbourg, france: a 9-year retrospective study. med mycol. 2018;56(6):723-734. doi:10.1093 /mmy/myx100.  pmid: 29165673. figure 1. case 1: clinical image of tinea barbae caused by trichophyton benhamiae. erythematous vegetating plaques on the nasolabial folds, devoid of hair in some areas. figure 2. case 2: clinical picture of tinea barbae caused by trichophyton benhamiae. erythematous plaques in the chin and right cheek, with erosions and pustules, with a 2-3 cm nodule in the chin plaque border. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022090 1 dermatology practical & conceptual case presentation an 80-year-old man was referred for a new eyelid papule in proximity of a scar from a previously excised basal cell carcinoma (bcc) (figure 1). based on naked-eye examination, recurrent bcc was suspected, and surgery was performed. the histopathological features were consistent with apocrine hidrocystoma (ah). teaching point ah is a benign cystic lesion of the apocrine glands usually found on the head and neck, particularly periocular [1]. when arising in or around scars of patients with previous bcc, diagnosis becomes challenging. dermoscopy might be a helpful tool. our patient prior bcc showed eyelash destruction, in-focus arborizing telangiectasias2 and blotches and strands on dermoscopy (figure 1, a and b) [2]. ah, on the other hand, was clinically similar but on dermoscopy it had translucent homogenous areas, linear whitish structures, and no eyelash involvement, as previously reported in literature (figure 1, b-f) [1,2]. dermoscopy might help differentiate recurrent bcc from other adnexal tumors, potentially avoiding unnecessary procedures. dermoscopy as an aid in the differentiation of recurrent eyelid basal cell carcinoma versus apocrine hidrocystoma leonel hidalgo1, eugenia abusleme2, cristián navarrete-dechent1,3, álvaro abarzúa-araya1,3 1 department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 2 department of ophthalmology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 3.melanoma and skin cancer unit, escuela de medicina, pontificia universidad católica de chile, santiago, chile citation: hidalgo l, abusleme e, navarrete-dechent c, abarzúa-araya a. dermoscopy as an aid in the differentiation of recurrent eyelid basal cell carcinoma versus apocrine hidrocystoma. dermatol pract concept. 2022;12(2):e2022090. doi: https://doi.org/10.5826/ dpc.1202a90 accepted: october 12, 2021; published: april 2022 copyright: ©2022 hidalgo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: álvaro abarzúa-araya, md, ifaad, department of dermatology, escuela de medicina, pontificia universidad católica de chile, diagonal paraguay 362, 6th floor, santiago, chile 8330077. e-mail: alvaroabarzuaaraya@gmail.com 2 image letter | dermatol pract concept. 2022;12(2):e2022090 references 1. zaballos p, banuls j, medina c, salsench e, serrano p, guionnet n. dermoscopy of apocrine hidrocystomas: a morphological study. j eur acad dermatol venereol. 2014;28(3):378-381. doi: 10.1111/jdv.12044. pmid: 23198900. 2. williams nm, navarrete-dechent c, marghoob aa, abarzua-araya a, salerni g, jaimes n. differentiating basal cell carcinoma from intradermal nevi along the eyelid margin with dermoscopy: a case series. j am acad dermatol. 2021;84(1):173175. doi: 10.1016/j.jaad.2020.04.059. pmid: 32330634. pmcid: pmc8442835 figure 1. a 80-year-old man referred for a new eyelid papule in proximity of a scar from a previously excised basal cell carcinoma. (a) pearly papule with eyelash destruction. histopathology confirmed a basal cell carcinoma. (b) dermoscopy showing eyelash destruction, in-focus arborising telangiectasias, and blotches and strands (polarized dermoscopy, x10). (c) homogeneous skin colored papule near previous scar. histopathology confirmed an apocrine hidrocystoma. (d) dermoscopy showing no eyelash involvement and linear whitish structures (polarized dermoscopy, x10). (e) dermoscopy showing translucent homogenous area and no eyelash involvement (non-polarized dermoscopy, x10). (f) surgery of the new eyelid papule. histopathology confirmed an apocrine hidrocystoma. dermatology: practical and conceptual letter to the editor | dermatol pract concept. 2023;13(3):e2023178 1 efficacy of cemiplimab in a patient affected by cutaneous squamous cell carcinoma and myelodysplastic syndrome ilaria proietti1, ersilia tolino1, nicoletta bernardini1, marco di fraia1, nevena skroza1, concetta potenza1 1 department of medico-surgical sciences and biotechnologies, polo pontino, sapienza university of rome, italy citation: proietti i, tolino e, bernardini n, di fraia m, skroza n, potenza c. efficacy of cemiplimab in a patient affected by cutaneous squamous cell carcinoma and myelodysplastic syndrome. dermatol pract concept. 2023;13(3):e2023178. doi: https://doi.org/10.5826/dpc.1303a178 accepted: february 28, 2023; published: july 2023 copyright: ©2023 proietti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: di fraia marco, md, department of medico-surgical sciences and biotechnologies, polo pontino, sapienza university of rome, corso della repubblica, 79, 04100, latina (lt), italy. e-mail: marco.difraia@uniroma1.it dear editor, we have read with interest the article by michela lai et al entitled “cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature” [1]. cutaneous squamous cell carcinoma (cscc) is the second most common malignant neoplasm of the skin. immunosuppressed patients can develop cscc more frequently than average population, and these cancers seem to behave more aggressively with a lower degree of differentiation [2]. naturally, hematologic patients have an immunosuppressed status due to their disease and to its treatment. immunotherapy (it) is assuming an important role in the treatment of cscc: cemiplimab, an inhibitor of programmed death receptor-1 (pd-1) has been approved for patients affected by cscc, not eligible to curative surgery and radiotherapy. however, the use of immunotherapy in hematologic patients with cscc is still under study, for this population is often excluded from clinical trials [3]. herein we present the case of a hematologic patient affected by cscc treated with cemiplimab. a 73-year-old man showed a painful, ulcerated firm nodule of the lower left hemilip (figure 1a) and a nodular ulcerated lesion in the submental region (figure 1b). the patient also complained about remarkable fatigue. he has been suffering from myelodysplastic syndrome (mds) for around two years. a diagnosis of a type 2 refractory anemia with excess of blasts (raeb-2) was made after bone marrow aspiration (2016 who classification). the patient was under treatment with systemic antibiotics and 5-azacytidine. excisional (free margins) skin biopsy of the labial lesion revealed a g3 cscc, with skeletal muscle and bone invasion (pt3 according to ajcc staging system). no biopsy was performed for the ulcerated lesion of the submental region. the patient underwent a positron emission computed 2 letter to the editor | dermatol pract concept. 2023;13(3):e2023178 tomography (pet/ct) with 18-fluorodeoxyglucose that showed two areas of pathologic tracer uptake in the lower left hemilip, extended to the jaw, and in the submental region. in addition, the exam documented mildly increased tracer uptake in the humeral and femoral diaphyses, referable to the mds, and some pathologic cervical adenopathies. thus, the patient started treatment with cemiplimab, 350 mg every three weeks. after five administrations, marked clinical improvement of the submental region was observed (figure 2) while there was no local relapse in the labial region. moreover, the patient reported notable pain and fatigue reduction. results of laboratory tests performed before starting cemiplimab and after 15 weeks of therapy are reported in table 1. the pd-1/pd-l1 axis is involved in the pathogenesis of many hematological malignancies. for this reason, anti-pd1 drugs might have a promising role for their treatment. in chronic lymphocytic leukemia (cll), pd-1 is expressed on cd4+  and cd8+  t cells, and proliferation of these cells is associated with a negative prognosis. in fact, patients with advanced cll stage have an increased number of pd1+ cd4+ t cells in the peripheral blood. pd-1 blockade has also shown a significant benefit in cll patients with richter syndrome [3]. concerning mds pathogenesis, pathological medullary progenitor cells (cd34+), show an increased expression of checkpoint molecules, including pd1, which interfere with an effective t-cell-receptor (tcr) signaling and correct presentation of the antigens to t-lymphocytes. because of this, the use of immunotherapy is suggested in association with demethylating agents, such as azacytidine [4]. these agents increase the expression of molecules such as cancer/testis antigens, which are highly immunogenic. this synergistic effect might elicit an increased immune response against the pathologically altered bone marrow progenitor cells of mds. phase 2 trials regarding the association of demethylating agents with various types of immunotherapies, including nivolumab (an anti-pd-1) are ongoing, and preliminary results seem promising [5]. in our case, cemiplimab was successful for cscc treatment, as expected. moreover, we suppose that cemiplimab in combination with 5-azacytidine improved mds control. references 1. lai m, pampena r, cornacchia l, et al. cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature. int j dermatol. 2022;61(5):548557. doi: 10.1111/ijd.15813. pmid: 34351635. pmcid: pmc 9290486. 2. tam s, yao cmkl, amit m, et al. association of immunosuppression with outcomes of patients with cutaneous squamous cell carcinoma of the head and neck. jama otolaryngol head neck surg. 2020;146(2):128-135 doi: 10.1001/jamaoto .2019.3751. pmid: 31804658. pmcid: pmc6902183. 3. ding w, laplant br, call tg, et al. pembrolizumab in patients with cll and richter transformation or with figure 1. (a) lower left hemilip lesion before excisional biopsy. (b) submental lesion. table 1. results of laboratory tests performed before starting cemiplimab (w0) and after 15 weeks (w15) of therapy. w0 w15 hemoglobin 8.6 g/dl 10.7 g/dl neutrophils 0.4 x103/µl 0.5 x103/µl lymphocytes 0.2 x103/µl 0.7 x103/µl. platelets 50 x103/µl 74 x 103/µl figure 2. submental region after cemiplimab treatment. letter to the editor | dermatol pract concept. 2023;13(3):e2023178 3 relapsed cll. blood. 2017;129(26):3419-3427. doi: 10.1182 /blood-2017-02-765685. pmid: 28424162. pmcid: pmc 5492091. 4. wong kk, hassan r, yaacob ns. hypomethylating agents and immunotherapy: therapeutic synergism in acute myeloid leukemia and myelodysplastic syndromes. front oncol. 2021 feb 25;11:624742 doi: 10.3389/fonc.2021.624742. pmid: 33718188. pmcid: pmc7947882. 5. jelinek t, mihalyova j, kascak m, duras j, hajek r. pd-1/pdl1 inhibitors in haematological malignancies: update 2017. immunology. 2017;152(3):357-371. doi: 10.1111/imm.12788. pmid: 28685821. pmcid: pmc5629439. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022075 1 features of skin cancer in black individuals: a single-institution retrospective cohort study rachel n manci1,2, megan dauscher1, michael a marchetti1, richard usatine3, veronica rotemberg1, stephen w dusza1, ashfaq a marghoob1 1 dermatology service, department of medicine, memorial sloan kettering cancer center, new york, ny, usa 2 cooper medical school of rowan university, camden, nj, usa 3 university of texas health, san antonio, tx, usa key words: skin cancer, skin of color, ethnic skin, dermoscopy citation: manci r, dauscher m, marchetti ma et al. features of skin cancer in black individuals: a single-institution retrospective cohort study. dermatol pract concept. 2022;12(2):e2022075. doi: https://doi.org/10.5826/dpc.1202a75 accepted: october 8, 2021; published: april 2022 copyright: ©2022 manci et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: supported in part by memorial sloan kettering cancer center’s nih/national cancer institute cancer center support grant p30 ca008748. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ashfaq marghoob, m. dermatology service, department of medicine, memorial sloan kettering cancer center, new york, ny, usa. e-mail: marghooa@mskcc.org introduction: minimal knowledge exists regarding skin cancers in black individuals, which may adversely affect patient care. objectives: to describe clinical features and risk factors of skin cancers in black individuals. methods: retrospective study of black individuals diagnosed with skin cancer between january 2000 and january 2020 at our institution. results: 38,589 patients were diagnosed with skin cancer, of which 165 were black individuals. one-hundred-thirteen of these black individuals were diagnosed with melanoma, 35 with squamous cell carcinoma (scc), and 17 with basal cell carcinoma (bcc). most melanomas (80.0%, n = 90) were of the acral subtype; 75% (6 of 8 cases with dermoscopic images) displayed a parallel ridge pattern (prp). the surrounding uninvolved background skin was visible in 7 cases, all demonstrating a prp. this disappeared adjacent to most of the melanoma lesions (n = 4, 57.1%). creating a peripheral hypopigmented “halo”. the nonmelanoma skin cancers were pigmented and had similar dermoscopic features as reported in predominantly white populations. most sccs (n = 5, 71.4%) had a hypopigmented “halo” and most bccs (n = 10, 55.6%) had an accentuated reticular network adjacent to the lesions. conclusions: skin cancers are pigmented in black individuals. in both acral melanomas and sccs, we noted a peripheral rim of hypopigmentation between the lesions and the surrounding uninvolved background skin, while bccs had accentuation of the background pigmentation adjacent to the lesions. most acral melanomas displayed a prp, which was also seen in surrounding uninvolved background skin. abstract 2 original article | dermatol pract concept. 2022;12(2):e2022075 introduction skin cancer is the most common malignancy worldwide and its incidence is expected to increase [1,2]. although much is known about the presentation of skin cancer in fair skin individuals, there is a paucity of data regarding disease morphology and contributing risk factors among those with darker skin [2-5]. this is likely secondary to the relatively higher incidence of skin cancer in those with fair skin, as well as disparities related to systemic racism in healthcare systems. it is essential for healthcare providers to assess skin lesions with consideration of skin types. experience has shown that skin cancer risk factors and morphology are not the same across all skin types, but there have been few studies specifically examining black individuals [6,7]. this void increases the risk of missed diagnoses, and simultaneously may increase morbidity through the unnecessary biopsies of benign skin lesions. objectives to address these knowledge gaps, we sought to describe the clinical and dermoscopic features of skin cancers in black patients that were seen at memorial sloan kettering cancer center (mskcc). additionally, we identified skin cancer risk factors and features of early disease. methods this study was approved by the institutional review board at mskcc and adhered to the helsinki declaration. we conducted a retrospective review of black patients with biopsy-confirmed basal cell carcinoma (bcc), squamous cell carcinoma (scc), or melanoma seen at mskcc between january 1st, 2000, and january 1st 2020. we identified patients with billing record icd diagnostic codes for these skin cancers (n = 38,948). at our institution, race/ethnicity information is collected from all patients, and we selected those who self-identified as black (n = 359). racial information was missing from 344 cases and these were excluded. we screened medical records and included black patients who received treatment for skin cancers at our institution (n = 165). we conducted a review of medical records through january 2020 and recorded demographic information, medical history, and skin cancer risk factors, including a history of cancer genetic syndromes, large congenital nevi, hpv infection, trauma, burns, and immunocompromised states. additionally, we recorded the pathology diagnosis and anatomic location of each cancer. we excluded those who did not receive treatment at our institution (n = 194) since they did not have complete reports within our medical record system. all lesions selected for biopsy by the dermatology service undergo clinical and dermoscopic imaging. thus, we cross-referenced all 165 cases with our image database to conduct a subset analysis on available images. most patients (n = 146) were referred to mskcc after a biopsy was performed by a community-based practitioner, and therefore did not have images in our database. there were clinical and dermoscopic images of 37 lesions from 19 patients (11 melanomas from 11 patients, 8 sccs from 3 patients, and 18 bccs from 5 patients). we evaluated images for standard dermoscopic features [8-13]. we also evaluated the surrounding uninvolved background skin to identify dermoscopic structures or patterns present in this surrounding skin. to analyze melanoma cases, we utilized the world health organization melanoma classification algorithm as a basis for subtype classification [14]. frequencies, relative frequencies, means, standard deviations (sd), and ranges were used to describe the distribution of characteristics and dermoscopic features of skin cancers. results overall results our search yielded a total of 165 black patients diagnosed with bcc, scc, or melanoma between january 1st, 2000 and january 1st, 2020. the average age at diagnosis was 58.9 years (sd = 3.2) and 59% (n = 96) were female. one hundred and thirteen patients (68.5%) were diagnosed with melanoma, 35 (21.2%) with scc, and 17 (10.3%) with bcc. acral lentiginous melanomas (alm) the majority of melanomas were acral (80.0% of all melanoma cases, n = 90), with 83.4% (n = 75) occurring on plantar surfaces, 13.3% (n = 12) in nail units, and 3.3% (n = 3) on palmar surfaces. the average age at diagnosis was 61.7 years (sd = 13.0) and 52.2% (n = 47) were male. most plantar alms were invasive (table 1) and half of these cases were classified as ajcc 8th edition stage iv melanoma at the time of initial biopsy. all dermoscopic images (n = 8) had structureless areas with multiple colors and most had a parallel ridge pattern (prp) (table 2). the surrounding uninvolved background skin was visible in 7 of these cases, all demonstrating a prp and most also demonstrating a fibrillar pattern (figure 1). four of these cases (57.1%) demonstrated a peripheral hypopigmented “halo” (figure 1). additionally, diffuse plantar lentigines were found in 5 of these cases (71.4%). half of the nail unit alms were invasive (table) and two-thirds (n = 8) were classified as ajcc 8th edition stage iv melanoma at time of initial biopsy. there were dermoscopic images of 3 nail-unit melanomas, all of which were heavily pigmented (table 2). the melanoma-in-situs original article | dermatol pract concept. 2022;12(2):e2022075 3 table 1. melanoma characteristics melanoma subtype in-situ versus invasive depth of invasion (mm) mean (median, range) ulceration y/n mitotic index (mit/ mm2) mean (sd) n (%) in-situ n (%) invasive n (%) yes n (%) no plantar alm (n=75) 27 (36.00) 48 (64.00) 5.84 (4, 0.75-55) 37 (49.33) 38 (50.67) 5.03 (5.91) nail-unit alm (n=12) 6 (50.00) 6 (50.00) 3.15 (2.9, 1.6-5) 4 (33.33) 8 (66.67) 4.00 (4.30) palmar alm (n=3) 1 (33.33) 2 (66.67) 5.25 (5.25, 3.5-7) 1 (33.33) 2 (66.67) 1.50 (0.71) other melanomas on non-acral and non-mucosal surfaces (n=19) 1 (5.26) 18 (94.74) 7.31 (4.5, 0.4-20) 3 (15.79) 16 (84.21) 5.25 (6.70) the pathologic characteristics of the melanomas observed in our black patient population. alm = acral lentiginous melanoma (n = 2) demonstrated micro-hutchinson sign and brown to black parallel lines on the nail plate with irregular spacing, thickness, and disruption of parallelism (figure 2). the invasive melanoma (n = 1) demonstrated hutchinson sign, pigmentation of the entire nail plate, and nail dystrophy (figure 2). there were only 3 palmar alms, 2 of which were invasive (table 1) and classified as ajcc 8th edition stage iv melanoma at the time of initial biopsy. there were no dermoscopic images of these alms. none of these patients had a family history of melanoma or had received testing for germline mutations increasing melanoma risk. melanomas, not otherwise specified nineteen (16.8%) melanoma cases were on non-acral cutaneous surfaces, and the average age at diagnosis was 54.7 years (sd = 18.2). twelve (63.2%) of these patients were female. two-thirds of these cases presented as ajcc 8th edition stage iv melanoma (table 1). table 2. dermoscopic features of melanomas dermoscopic features prevalence: n (%) acral lentiginous melanoma cases on the soles (n=8) structureless areas with multiple shades of brown, blue, black, and pink colors 8 (100.00) parallel ridge pattern 6 (75.00) ulceration 2 (25.00) atypical fibrillar pattern 2 (25.00) parallel ridge pattern of surrounding skin* 7 (100.00) fibrillar pattern of surrounding skin* 4 (57.14) peripheral hypopigmentation* 4 (57.14) diffuse plantar lentigines* 5 (71.43) acral lentiginous melanoma cases on the nail-unit (n=3) hutchinson sign (pigmentation of the nail fold) 3 (100.00) brown-to-black parallel lines on the nail plate with irregular spacing, thickness, and disruption of parallelism 3 (100.00) band involving more than 2/3 of the nail plate 2 (66.67) nail dystrophy 1 (33.33) 4 original article | dermatol pract concept. 2022;12(2):e2022075 figure 2. nail melanoma cases. (a,b) the dermoscopic images of two melanoma-in-situ cases that demonstrate micro-hutchinson sign and brown to black parallel lines on the nail plate with irregular spacing, thickness, and disruption of parallelism. (c) the clinical image of an invasive melanoma case that demonstrates and easily visible hutchinson sign, diffuse pigmentation of the whole nail plate, and nail dystrophy. figure 1. acral melanoma on the sole of the foot. the normal background skin surrounding the acral melanomas had noticeable pigmentation demonstrating a parallel ridge pattern (solid oval). there was loss of the pigmentation and dermoscopic patterns surrounding the lesion itself, generating a hypopigmented “halo” around the acral lentiginous melanoma on the plantar surface. this “halo” was seen in 57.1% (n = 5) of plantar melanoma cases and was most evident in cases with the most heavily pigmented surrounding skin. most cases occurred on the lower extremities (31.6%, n = 6) and back (26.3%, n = 5). the most common subtype was spindle cell and/or epithelioid (36.8%, n = 7). one patient developed a dermal primary melanoma within a giant congenital nevus and no other risk factors were identified. there were no clinical or dermoscopic images. other melanoma subtypes included mucosal (n = 8, 7.1%), ocular (n = 4, 3.5%), and metastatic with unknown primary lesion (n = 6, 5.3%). mucosal melanomas were located on the anus (n = 3), nasopharynx (n = 2), vagina (n = 2), and vulva (n = 1). no clinical or dermoscopic images were available. squamous cell carcinomas there were 29 black individuals with 35 sccs, and the average age at diagnosis was 56 years (sd = 16). most cases (71.4%, n = 25) were invasive. most sccs were located on anogenital surfaces (n = 11), lower extremities (n = 7), or the head and neck (n = 6). known scc risk factors were identified in 80% of patients (n = 28), including active hiv infection (n = 11), chronic wounds (n = 4), prior radiation to the area (n = 2), psoriasis (n = 2), hidradenitis suppurativa (n = 1), and lichen simplex chronicus (n = 1). hpv testing was conducted in 8 total cases, of which 7 were positive for high-risk hpv, located on the anogenital region (n = 3) and nail unit (n = 4). there were dermoscopic images of 8 sccs, many of which were heavily pigmented (table 3). in the surrounding uninvolved background skin, half had a pigmented reticular network and an associated “halo” effect (figure 3); the other half had patchy hyperpigmentation. original article | dermatol pract concept. 2022;12(2):e2022075 5 dermoscopic images were available for 18 bccs (from 5 patients), all of which were pigmented (table 3). the surrounding uninvolved background skin was assessed in 15 cases. all cases had a pigmented reticular network, and 11 cases (73.3%) had an accentuated network adjacent to the lesion (figure 4). conclusions over a 20-year period, only a small proportion of our skin cancer patients were black individuals; this is likely due to basal cell carcinomas there were 15 black individuals with 17 bccs that were diagnosed and treated at our institution and the average age at diagnosis was 54.4 years (sd = 21.6). most lesions were located on the head and neck (n = 12). pigmentation was noted on the pathology report of 6 cases (35.3%). pathologic subtypes included combined nodular and infiltrative (n = 6), micronodular (n = 3), nodular (n = 3), superficial (n = 1), and combined superficial and nodular (n = 1). two patients had gorlin syndrome, and no other risk factors were observed. table 3. dermoscopic features of non-melanoma skin cancers (basal cell carcinomas and squamous cell carcinomas). dermoscopic features prevalence: n (%) pigmented squamous cell carcinoma cases (n=3) adherent scales with pigment 3 (100.00) peripheral hypopigmentation, loss of pigmented network seen in surrounding skin 3 (100.00) white circles 1 (33.33) milky-red areas 1 (33.33) non-pigmented squamous cell carcinoma cases (n=4) adherent white scale 4 (100.00) white circles 3 (75.00) ulceration 3 (75.00) peripheral hypopigmentation, loss of pigmented network seen in surrounding skin 2 (50.00) dotted vessels 2 (50.00) serpentine vessels 1 (25.00) shiny white strands 1 (25.00) peripheral islands of hyperpigmentation 1 (25.00) nail unit squamous cell carcinoma case (n=1) heavy pigmentation of the nail plate 1 (100.00) nail dystrophy 1 (100.00) subungual hyperkeratosis 1 (100.00) basal cell carcinoma cases (n=18) loss of normal background pigmentation and network 13 (72.22) milky red area 12 (66.67) accentuated normal background pigmentation network surrounding the lesion itself 10 (55.56) leaf-like areas 9 (50.00) blue-gray ovoid nests 9 (50.00) multiple blue-gray dots and globules 9 (50.00) shiny white blotches and strands 9 (50.00) central hypopigmentation 6 (33.33) spoke-wheel like structures 4/18 (22.22) scale and/or crust 2/18 (11.11) may globules 1/18 (5.56) milky white areas 1/18 (5.56) ulceration 1/18 (5.56) peripheral hypopigmentation 1/18 (5.56) 6 original article | dermatol pract concept. 2022;12(2):e2022075 that mskcc is a tertiary cancer center and therefore it is more likely to see advanced cases. it is interesting to note that 90.6% (n = 102) of melanomas in our population were alm, mucosal, or ocular subtypes, all of which have not been associated with ultraviolet radiation (uvr) exposure. superficial spreading and lentigo maligna melanomas are most closely associated with uvr exposure; these subtypes accounted for only 2 of our cases (1.8%), suggesting that uvr likely plays little to no role in the pathogenesis of melanoma in black individuals [20-22]. as suggested by a recent systematic review, photoprotection will likely provide minimal benefit [20]. we were unable to identify any major risk factors in black individuals. benign pigmented macules and mottled hyperpigmentation on acral surfaces are suggested risk factors, but approximately 50% of black individuals have these features [23-25]. while many of our patients had diffuse pigmented macules on the plantar surfaces, it is unlikely that this is a risk factor given the high prevalence of this finding and the low prevalence of melanoma in black individuals [23,25]. the prp has been suggested to have high sensitivity and specificity for early alm in caucasian and asian populations, but it has not been validated in individuals of other races/ethnicities [26]. while the majority of our plantar melanoma cases demonstrated the prp, these individuals also had the prp in surrounding uninvolved background skin. a limitation of this finding is that the clinically uninvolved skin displaying the prp was not biopsied. therefore, it is possible the overall low incidence of skin cancer in this population and also secondary to disparities in access to healthcare facilities [15]. reports have suggested that skin cancers are found at more advanced stages in black people compared to white individuals – possibly due to differences in screening, skin cancer knowledge, healthcare access, or cancer types across populations [16,17]. however, before recommending for or against screening or public education efforts to possibly address these disparities, it is imperative to discern the features of skin cancers in black patients and determine whether these features can differentiate benign from malignant lesions in asymptomatic black individuals. it has been reported that melanomas in black individuals are diagnosed at locally advanced stages with higher rates of metastases [18]. while overarching gross statistics reveal that melanoma thickness is greater in blacks compared to whites, the difference narrows when the comparison focuses on alms, the most common subtype in blacks [18,19]. an analysis of the seer database revealed that the average depth across all subtypes for caucasians and african americans was 1.09 mm and 2.02 mm, respectively; when stratifying for subtype, the average depth of alms was 2.05 mm and 2.28 mm, respectively [19]. our review revealed a high proportion of advanced cases, but it is important to underscore figure 4. accentuated pigmented network surrounding the basal cell carcinoma lesion. the pigmentation network observed in the normal skin (dashed oval) was accentuated surrounding the basal cell carcinoma lesion itself (solid oval). this was observed in 55.6% (n = 10) of the basal cell carcinoma cases. figure 3. loss of normal pigmented network surrounding the squamous cell carcinoma lesion. note the pigmented network seen in the normal skin surrounding the pigmented squamous cell carcinoma (solid ovals) and the loss of network just adjacent to the lesion (dashed ovals). this was observed in 4 cases (57.1%). original article | dermatol pract concept. 2022;12(2):e2022075 7 to be more sensitive to uvr. there is a known association between skin tone and bcc risk, of which black individuals with lighter complexions are more likely to develop bccs [35]. two of our patients had gorlin syndrome, but no other risk factors were observed. pigmented bccs are quite rare overall but are the most prevalent type in black populations [34,36]. all of our dermoscopy images were heavily pigmented, and the features were consistent with those known for pigmented bccs. we observed reticular pigmentation in the surrounding uninvolved background skin, and 55.6% (n = 10) of cases had a hyperpigmented network adjacent to the lesion. central hypopigmentation was seen in 33.3% (n = 6) of cases. these features are not to be confused with those of a dermatofibroma, a pigment network and central scar-like white patch [37]. it is important to note that no cases were associated with significant morbidity. our study is limited since it is a retrospective analysis of a single tertiary cancer center. referral bias is likely the reason for the high proportion of advanced disease cases. it is also important to consider other socioeconomic limitations that may hinder the ability of some black patients to seek care at mskcc. we observed that bccs and sccs are pigmented and demonstrate similar dermoscopic features to those reported in predominately white populations. our study brings into question the ability of the prp to distinguish alm from benign acral lesions. it has been reported that the prp can be present in benign pigmented macules on volar surfaces, and we also observed this pattern in the surrounding uninvolved background skin, brining into question the reliability of this feature for differentiating benign and malignant lesions in black patients. future research is needed to elucidate whether the rim of peripheral hypopigmentation that we observed around the alms can assist in the differentiation of alms and benign pigmented macules. black individuals deserve equal care, which does not necessarily mean the same care. instead, it means that black individuals deserve customized care based on the features most useful at discriminating benign from malignant lesions. towards this end, a better understanding of the clinical, morphologic, and dermoscopic features of skin cancers in those with darker skin is required. references 1. gordon r. skin cancer: an overview of epidemiology and risk factors. semin oncol nurs. 2013;29(3):160-169. doi: 10.1016/j.soncn.2013.06.002. pmid: 23958214. 2. gloster hm jr, neal k. skin cancer in skin of color. j am acad dermatol. 2006;55(5):741-764. doi: 10.1016/j. jaad.2005.08.063. pmid: 17052479. 3. buster kj, stevens ei, eelmets ca. dermatologic health disparities. dermatol clin. 2012;30(1):53-viii. doi: 10.1016/j. det.2011.08.002. pmid: 22117867. pmcid: pmc3742002. that this prp may represent subclinical extension of the melanomas, though we believe this is unlikely since the prp was diffusely present in the surrounding uninvolved background skin in the majority of our cases. additionally, the prp has been described in benign ethnic pigmented macules [27,28]. therefore, this knowledge adds credence that the prp may lack discriminatory power in black individuals; if used, it may lead to an escalation of unnecessary biopsies [29]. future studies analyzing the prp in black individuals may benefit from acquiring dermoscopy images of contralateral volar surfaces. regarding other dermoscopic features observed in our alm cases, the presence of structureless areas with multiple colors proved most useful, but this was not helpful in differentiation of in-situ and invasive disease, since cases of all stages exhibited this feature. a novel feature we identified was a hypopigmented “halo” surrounding 57.1% (n = 4) of the plantar melanoma lesions, all of which were melanoma in-situ cases. further studies with larger sample sizes would be helpful in identifying whether this is a sensitive and specific feature for early diagnosis. early detection also remains a challenge for nail-matrix melanomas, since patients of color often have benign pigmented nail bands [30]. to better understand how to differentiate these benign from malignant lesions, we need data comparing ethnic pigmented nail bands and nail-matrix melanomas. while we await such studies, reassuring factors include the involvement of multiple nails and stability over time. regarding the other melanoma subtypes, no identifiable risk factors were found. one patient developed a dermal melanoma within a giant congenital nevus; dermoscopy will not be useful in the early identification of these dermal lesions. regarding squamous cell carcinomas (scc), uvr exposure is the most common risk factor for the development of scc in those with fair skin, but trauma and inflammatory processes predominate the pathogenesis in black populations, a trend also observed in our population [1,2,31-33]. most black patients had sccs on non-sun exposed areas, which is consistent with other literature reports, suggesting photoprotection will likely have little to no benefit [31,32]. sccs in black individuals are often superficial, discrete, hard lesions arising from an indurated, rounded, elevated base [31,32]. the dermoscopic features observed in our images were similar to those described in white individuals, but there was a higher incidence of pigmented variants [8,10,31,33]. we observed a similar “halo” pattern as was described for plantar alms, but a larger study is needed to validate the predictive importance of this result. finally, in terms of our basal cell carcinomas (bcc), the majority of bccs (70.6%) occurred on the head and neck region, suggesting uvr may play some role in the pathogenesis [34]. the low incidence of bcc in black individuals suggests that other factors must predispose certain individuals 8 original article | dermatol pract concept. 2022;12(2):e2022075 18. cormier jn, xing y, ding m, et al. ethnic differences among patients with cutaneous melanoma.  arch intern med 2006; 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quiz 178. pmid: 19691228. pmcid: pmc2757062. 32. alam m, ratner d. cutaneous squamous-cell carcinoma.  n engl j med. 2001;344(13):975-983. doi: 10.1056/ nejm200103293441306. pmid: 11274625. 33. morais pm, schettini apm, rocha ja, silva júnior rcd. pigmented squamous cell carcinoma: case report and importance of differential diagnosis.  an bras dermatol. 2018;93(1):96-98. doi: 10.1590/abd1806-4841.20186757. pmid: 29641705. pmcid: pmc5871370. 34. gupta r, gordon sl, council ml, hurst ea. clinical characteristics of basal cell carcinoma in african americans: a 10-year retrospective review at a single academic institution.  dermatol surg. 2019;45(5):660-665. doi: 10.1097/ dss.0000000000001744. pmid: 30614839. 35. beckenstein ms, windle bh. basal cell carcinoma in black patients: the need to include it in the differential diagnosis.  ann plast surg. 1995;35(5):546-548. doi: 10.1097/00000637199511000-00020. pmid: 8579279. 36. nouri k. skin cancer. new york, ny, usa: mcgraw-hill medical; 2008. 37. kelati a, aqil n, baybay h, gallouj s, mernissi fz. beyond classic dermoscopic patterns of dermatofibromas: a prospective research study. j med case rep. 2017;11(1):266. doi: 10.1186/ s13256-017-1429-6. pmid: 28927449. pmcid: pmc5605998. dermatology: practical and conceptual letter to editor | dermatol pract concept. 2023;13(2):e2023128 1 multiple pigmented trichoepitheliomas: a case report stefano caccavale1, carmine fiorentino1, maria pia boccellino1, francesca pagliuca2, ruzica jurakic toncic3, giuseppe argenziano1 1 dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, naples, italy 2 division of pathology, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, naples, italy 3 department of dermatology and venereology, university of zagreb, zagreb, croatia citation: caccavale s, fiorentino c, boccellino mp, pagliuca f, jurakic toncic r, argenziano g. multiple pigmented trichoepitheliomas: a case report. dermatol pract concept. 2023;13(2):e2023128. doi: https://doi.org/10.5826/dpc.1302a128 accepted: november 2, 2022; published: april 2023 copyright: ©2023 caccavale et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: stefano caccavale, md, dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy; phone: +39 3336365526; fax: +39 0815468759; e-mail: stefano85med@libero.it dear editor, trichoepitheliomas are uncommon benign tumors with infundibulocystic differentiation. they most often occur in women, presenting themselves as translucent round papules or nodules mainly localized at the face or scalp [1]. they may appear as solitary or multiple lesions in non-familial or familial forms (including multiple familial trichoepitheliomas, brooke-spiegler syndrome and familial cylindromatosis) [1,2]. familial forms are often due to mutations in cyld gene, on chromosome 9, with autosomal dominant transmission. this gene has incomplete penetration in males, so the prevalence of familial forms is higher in women. in these cases, the onset of trichoepitheliomas is earlier compared to sporadic forms. to the best of our knowledge, we report the first case of multiple pigmented trichoepitheliomas discussed in literature so far. a 70-year-old-man, fitzpatrick photo-type 4, presented to our attention for zoon balanitis. during the clinical examination of the total body surface we found multiple nodular pigmented lesions of the face, trunk and lower limbs. we identified 5 pigmented, non-ulcerated, smooth, brown/blue papules and nodules of 0.5-0.7 cm of diameter. two lesions were localized on the head, respectively at the superciliary arch and the occiput. the other three lesions were localized at the posterior thigh, the superior back and the chest. on dermoscopy (figure 1, a-f), the lesions were highly pigmented and showed basalioma-like features, such as brown-blue globules and nests, blue-black blotches and leaf-like areas together with  less specific patterns (shiny-white lines, milia-like cysts and gray-blue veil). four of them presented bright vessels. the lesion localized at the posterior thigh presented a blue lacunar-like pattern. 2 letter to editor | dermatol pract concept. 2023;13(2):e2023128 since the  dermoscopic  clues were suggestive for pigmented basal cell carcinomas, we decided to excise all lesions. the histopathology of the biopsy samples showed islands and nests of follicular germinative cells, without stromal retraction spaces, immersed in a conspicuous fibrocytic stroma, with high cellularity. the well-circumscribed tumors were focal connected with the overlying epidermis. in addition, multiple horn cysts were detected in some lesions. all these features suggested overall the diagnosis of trichoepitheliomas and not of basal cell carcinomas. due to the presence of multiple pigmented trichoepitheliomas, a dna analysis to exclude a possible genetic etiology was proposed to the patient, but he refused. in conclusion,  this was the first case of multiple pigmented trichoepitheliomas described so far in literature to our knowledge. these lesions are clinically and dermoscopically very difficult to distinguish from pigmented basal cell carcinomas, similarly to non-pigmented ones. at date, the histopathological examination still represents the gold standard to the final diagnosis. more studies will be needed to understand if there may be a correlation between the photo-type and predisposition to develop pigmented rather than non-pigmented trichoepitheliomas. references 1. karimzadeh  i, namazi mr,  karimzadeh  a. trichoepithelioma: a comprehensive review.  acta  dermatovenerol  croat. 2018; 26(2):162-165. pmid: 29989874. 2. supekar bb, rambhia kd, tomar ss, singh rp, multiple familial trichoepithelioma with varied malignancies. indian j dermatol. 2021;66(2):226.  doi: 10.4103/ijd.ijd_647_18. pmid: 34188306. pmcid: pmc8208248. figure 1. (a-f) clinical presentation on admission (a,c,e). dermoscopic images (b,d,f) revealed: bright vessels (red arrows in b,d,f), milia-like cyst (blue arrow in b), leaf-like areas  (d), brown-blue globules and nests (d), lacunar-like pattern  (f), shiny white lines (f), blue-white veil (b,f), brown-blue blotches (b,f). dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2014;4(2):13 63 the patient a 61-year-old white man presented with an asymptomatic brown-red nodular lesion located on his back. the patient reported the lesion had been present for years (figure 1). he had no previous skin cancers and there was no family history of melanoma. on dermoscopy, the lesion showed a multicomponent pattern, characterized by blue-gray dots, globules and a network disposed centrifugally at the periphery with a polymorphous vascular pattern and chrysalis structures centrally (figure 2). an excisional biopsy was performed with 2 mm margins. the diagnoses proposed to the pathologist included basal cell carcinoma and melanoma. an atypical pigmented lesion claudia costa1, franco palmisano1, massimiliano scalvenzi1 1 department of dermatology, university of naples federico ii, naples, italy citation: costa c, palmisano f, scalvenzi m. an atypical pigmented lesion. dermatol pract concept. 2014;4(2):13. http://dx.doi. org/10.5826/dpc.0402a13. copyright: ©2014 costa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: massimiliano scalvenzi, via pansini 5, 80129 naples. italy. email: scalvenz@unina.it figure 1. figure 2. mailto:scalvenz@unina.it 64 quiz | dermatol pract concept 2014;4(2):13 what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. the morphological field (figure 3) shows a neoplasia with dermal dislocation, composed of a well-defined nodule in the middle surrounded by small nests in which multiple keratinic cysts can be identified (red arrows). some of them are locus of dystrophic calcification (green arrows). the neoplasia is composed of basaloid cells with mild cytology without acceptable mitotic activity. figure 3. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023015 1 clinical efficacy of medical dextrose tincture liquid in the treatment of facial photoaging yuexing song1, qiuhui liu2, yihan zhang2, huina zhang3, bin li2 1 department of cosmetic dermatology, xi’an evercare medical beauty hospital, xi’an, china 2 department of cosmetic dermatology, beijing evercare medical beauty hospital, beijing, china 3 beijing evercare medical technology group co., ltd, beijing, china key words: medical dextran tincture liquid, facial photoaging, clinical efficacy citation: song y, liu q, zhang y, zhang h, li b. clinical efficacy of medical dextrose tincture liquid in the treatment of facial photoaging. dermatol pract concept. 2023;13(1):e2023015. doi: https://doi.org/10.5826/dpc.1301a15 accepted: may 5, 2022; published: january 2023 copyright: ©2023 song et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: bin li, beijing evercare medical beauty hospital, building a, no.3 east third ring north road, chaoyang district, beijing, 100027 china. tel: 86-010-82037778 email: binli1228@163.com introduction: exogenous aging mainly refers to photo-aging, which is caused by environmental factors including ultraviolet exposure. dextran is a homopolysaccharide composed of glucose as monosaccharide, and glucose units are connected by glycosidic bonds. objectives: the purpose of this study was to explore the clinical efficacy of medical dextrose tincture liquid (medical dextrose tincture) in the treatment of facial photoaging. methods: thirty-four volunteers were included in the randomized double-blind study. according to the random number table method, the subjects were randomized into control and treatment groups. the subjects in the control and treatment groups were treated with medical hyaluronic acid gel and medical dextrose tincture, respectively. they received mesotherapy therapy three times with an interval of 28 days between treatments. video image acquisition was performed before treatment and 28 days after treatment. skin moisture content, glossiness, heme content, collagen density, and elasticity were tested. the subjective evaluations of subjects and doctors before and after treatment were compared. results: compared with the pre-treatment baseline, medical dextran tincture significantly increased skin moisture retention, skin gloss, and skin collagen density (p<0.001). additionally, the skin retraction time was significantly reduced, and the skin retraction time was also markedly decreased after treatment with medical dextran tincture (p<0.001). the effects of medical dextran tincture were more significant in comparison with medical hyaluronic acid gel (p<0.05). the subjective evaluation results abstract 2 original article | dermatol pract concept. 2023;13(1):e2023015 introduction skin is the largest organ of the human body, and its aging is a complex process caused by a variety of endogenous and exogenous factors [1]. endogenous aging is inherent, that is, natural aging that develops over time. exogenous aging mainly refers to photo-aging, which is caused by environmental factors including ultraviolet (uv) exposure. the clinical manifestations of naturally aging skin are decreased skin thickness, dryness and fine wrinkles [2]. however, the clinical manifestations in the skin caused by photoaging are deep wrinkles, roughness, relaxation, spotted pigmentation, telangiectasia and various skin tumors [3]. exogenous aging damage caused by skin exposure to ultraviolet light (uv) is slow. uv radiation can affect skin pigment metabolism [4]. the immediate response is an increase in the reactive synthesis of melanin and its redistribution, and the delayed response is an increase in the number and vitality of melanocytes [4]. uv can upregulate the expression level of vascular endothelial growth factor (vegf), resulting in the proliferation and expansion of capillaries [5]. at the same time, uv has an autoimmune inhibitory effect, resulting in the changed number and vitality of immune cells, and the expression of related cytokines [6]. the most relevant feature of photoaging caused by uv is the changes in the proportion, quality and function of the dermal extracellular matrix [7]. the main components of the dermal extracellular matrix are the collagen fiber network, elastic fiber network and proteoglycan [8]. the elastic fiber network provides elasticity to the skin, while proteoglycan plays a role in moisturizing and biological signal transduction. in exogenously damaged skin, these three components have undergone specific changes. dextran is a homopolysaccharide composed of glucose as monosaccharide, and glucose units are connected by glycosidic bonds [9]. according to the type of glycosidic bond, dextran can be divided into α-dextran and β-dextran. dextrose is a kind of widely studied and used α-dextran. in animal models, dextran materials showed good soft tissue filling effect and biocompatibility [10,11]. however, there are no relevant reports on clinical research on the therapeutic effects of dextrose on cosmetic dermatology and facial photoaging. therefore, the purpose of this study was to explore the clinical efficacy of medical dextrose tincture liquid in the treatment of facial photoaging. subjects and methods subjects all volunteers were informed of the purpose of the study in detail and signed the informed consent documents. a total of 34 volunteers were included in the randomized double-blind study. inclusion criteria: (1) those whose face had symptoms of photo-aging, including dryness, dullness, lack of elasticity, etc.; (2) non-smokers; (3) individuals aged more than 18 years old. exclusion criteria: (1) women who were menstruating, pregnant or breastfeeding; (2) those with a history of food or drug allergies and ethical contraindications; (3) those who had taken corticosteroids, antibiotics, tretinoin or other anti-acne medications two weeks before treatment; (4) those who had used hormone drugs and immunosuppressant in the past month; (5) those with obvious damage, redness, scars, active skin diseases, inflammation, or infection on the face; (6) those with symptoms of colds, headaches and fever on the day of the test; (7) those who were allergic to injection materials or certain ingredients in injection preparations; (8) those who had injected unknown fillers into the face that had not gone away before treatment. informed consent has been obtained from all the participants. this study was approved by the ethics committee of xi’an evercare medical beauty hospital (no. 20200501). treatment medical hyaluronic acid gel (huaxi furuida biomedical co., ltd., jinan, china) was marked as product a, and medical dextrose tincture liquid (ningxia miaolang biotechnology co., ltd., ningxia, china) was marked as product b. according to the random number table method, the subjects were randomized into control and treatment groups (n = 17). each volunteer randomly selected product a and product b. the volunteers in the control and treatment groups were treated with medical hyaluronic acid gel and medical dextrose tincture, respectively. they received mesotherapy three times with an interval of 28 days. the steps of mesotherapy were as follows. volunteers cleaned their faces of doctors showed that after 84 days of treatment, the overall skin photoaging score was significantly reduced (p<0.001). the subjective evaluation results of volunteers showed that the various skin problems of more than 50% of volunteers were improved after treatment. conclusion: medical dextran tincture has obvious effects of moisturizing, increasing luster, improving skin redness, increasing skin collagen content and enhancing skin elasticity. original article | dermatol pract concept. 2023;13(1):e2023015 3 with mild soap. after topical anesthesia for 20-30 min, the face was cleaned again. iodophor solution is used for disinfection and deiodination. the whole face was injected with the mesotherapy instrument, the injection depth was 0.8-12 mm, and the skin punctate hemorrhage  was the standard. after treatment, the facial treatment area was covered with a sterile facial pack for 20-30 min. image analysis on the 0th, 28th, 56th and 84th day of treatment, visual images of the face were collected by visia image acquisition as previously described [13]. skin detection and analysis on the 0th, 28th, 56th and 84th day of treatment, skin moisture content test, skin gloss test, skin heme content test, skin collagen density test and skin elasticity test were carried out by mpa10 skin tester (ck, germany) and dermalab skin tester (cortex, denmark). the effects of those two products on skin moisture content, skin gloss, skin tone, and anti-aging were assessed through the changes in those indexes. the test environment was 20.0℃-22℃, with a humidity of 40.0%rh-60.0%rh. at the junction of the middle line of the left eye and the nasal wing, the moisture content of the stratum corneum, skin gloss and skin heme were measured. the skin collagen density and skin elasticity were measured at the junction of the middle line of the right eye and the nasal wing. subjective evaluation for subjective evaluation by doctors, two dermatologists scored the degree of facial photoaging before treatment and after a course of treatment according to the visia image. the scoring standard was shown in table 1. for subjective evaluation by volunteers, volunteers rated themselves in terms of skin color, wrinkles, luster, elasticity and moisturizing on the 28th day after each treatment. 0 points for deterioration, 1 point for ineffectiveness, 2 points for slight improvement, 3 points for obvious improvement and 4 points for complete improvement. evaluation indexes on the 0th, 28th, 56th and 84th day of treatment, the visual images of the face were analyzed. the moisture content of the stratum corneum, skin gloss and skin heme, skin collagen density and skin elasticity were analyzed. skin subjective evaluation of doctors and volunteers was also assessed after treatment. statistical analysis ibm spss statistics 22 was used to make descriptive statistics on the measured values and the subjective evaluation scores. the measurement data were expressed as means ± standard deviation (sd). the count data were expressed as a percentage. for the intra-group comparison before and after treatment, the measured values at different time points were compared with the initial values. if the data were normally distributed, t-test was used for statistical analysis. if the data were not normally distributed, t-test was used for statistical analysis. results general information a total of 34 people completed this study. there were 17 volunteers in group a, including 1 man and 16 women, with an average age of 29.59 ± 1.05 years. there were 17 volunteers in group b, including 3 males and 14 females, with an average age of 31.35 ± 1.05 years. there were no significant differences in general information such as gender and age between the two groups (p < 0.05). comparison of skin moisture content between the two groups after 28, 56 and 84 days of treatment, the skin moisture contents in group a were significantly increased by 18.0%, table 1. overall score of photoaging. scores descriptions 0 the whole face is smooth, without obvious fine wrinkles and uneven pigment in any part of the cheek, forehead and eyes. 1 there is obvious roughness, uneven pigment (pigmentation or hypopigmentation) or fine wrinkles on one of the above three parts of the whole face. 2 there are obvious roughness, uneven pigment or fine wrinkles on two of the above three parts of the face, or rough, uneven pigment and fine wrinkles in one part at the same time. 3 there are obvious roughness, uneven pigment or fine wrinkles on the above three parts of the face, or rough, uneven pigment and fine wrinkles in two parts at the same time. 4 there is any situation heavier than 3 points on the face. 4 original article | dermatol pract concept. 2023;13(1):e2023015 comparison of skin erythema index between the two groups in group a, there was no significant difference in the changes in skin erythema index after 28 days, 56 days and 84 days of treatment in comparison with those before treatment (p > 0.05), indicating that product a had no significant change in skin heme contents (erythema index). in group b, the average skin heme content (erythema index) of volunteers before treatment, 28 days, 56 days and 84 days after treatment were 351.8 ± 15.2, 332.9 ± 13.4, 313.4 ± 112 and 303.01 ± 18.0, respectively. compared with that before treatment, the changes in skin erythema after treatment with product b were statistically reduced by 4.8%, 10.0% and 13.1% (p < 0.001, figure 3). taken together, product b can significantly reduce skin erythema index and improve skin redness. comparison of skin collagen density between the two groups although skin collagen density after treatment with product a was higher than that before treatment, the effect of 31.4% and 47.0% in comparison with those before treatment, respectively (p < 0.001). after 28, 56 and 84 days of treatment, the skin moisture contents in group b were also notably increased by 23.9%, 33.2% and 53.6% compared with those before treatment (p < 0.001, figure 1). taken together, both products a and b had a moisturizing effect, which can significantly improve the moisture content of cheek cuticles. particularly, the effect of product b was more obvious than product a. comparison of skin gloss between the two groups after 28, 56 and 84 days of treatment, skin gloss in group a was markedly increased by 8.4%, 18.3% and 30.3% in comparison with that before treatment, respectively (p < 0.001). after 28, 56 and 84 days of treatment, skin gloss in group b was also significantly increased by 11.0%, 20.4% and 33.7% compared with that before treatment, respectively (p < 0.001, figure 2). in conclusion, both products a and b can significantly increase skin gloss. 80.00 *** *** *** *** *** *** a group a group b 70.00 60.00 50.00 40.00 30.00 20.00 sk in m o is tu re c o n te n t (a .u .) 10.00 0.00 day 0 day 28 day 56 experimental check (days) day 84 b group a group b 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% r at e o f c h an g e vs . d ay 0 (% ) experimental check (days) day 28 day 56 day 84 figure 1. changes in skin moisture content before and after treatment. (a) skin moisture content; (b) rate of change vs. day 0. ***p<0.001; **p<0.01; *p<0.05 vs. day0. 14.00 a 12.00 * * *** *** *** *** 10.00 8.00 sk in g lo ss 6.00 4.00 2.00 0.00 group a group b day 0 day 28 experimental check (days) day 56 day 84 b group a group b 40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% r at e o f c h an g e vs . d ay 0 (% ) 5.0% 0.0% day 28 experimental check (days) day 56 day 84 figure 2. changes in skin gloss before and after treatment. (a) skin gloss; (b) rate of change vs. day 0. ***p<0.001; **p<0.01; *p<0.05 vs. day0. original article | dermatol pract concept. 2023;13(1):e2023015 5 4.4% and 5.4% respectively. after 28, 56 and 84 days of treatment, the skin retraction time in group b was decreased by 9.5%, 11.2% and 14.8% respectively in comparison with that before treatment (p < 0.001, figure 5). as described above, product b can significantly reduce skin retraction time and enhance skin elasticity. the effect of product b on skin elasticity was significantly earlier than that of product a, and the effect of improving skin relaxation was better than that of product a. comparison of subjective assessments of doctors and volunteers between the two groups the lower the score of comprehensive skin improvement, the better the effect of the product on improving skin photoaging. before treatment, the skin scores in group a and group b were 2.14 ± 0.1 and 2.30 ± 0.1, respectively (p > 0.05). after three instances of treatment, the doctor’s score was significantly lower than that before treatment (p < 0.01). according to the doctor’s score, after 84 days of treatment, product a and product product a on skin collagen density showed significant differences after 56 and 84 days of treatment, with an increase of 26.4% and 44.9%, respectively (p < 0.001). after 28, 56 and 84 days of treatment, skin collagen density after treatment with product b was increased by 10.6%, 30.9% and 52.5% respectively compared with that before treatment (p < 0.001, figure 4). in short, both products a and b can significantly increase skin collagen density, and the effect of product b on skin collagen density was significantly earlier than that of product a. comparison of skin elasticity between the two groups skin retraction time is one of the indicators to measure skin elasticity. it refers to the time required for the skin to fully lift and retract to 33% of the peak height. the shorter the retraction time, the better the elasticity of the skin. after 56 and 84 days of treatment, compared with before treatment, the skin retraction time of product a group decreased by 400.00 a group a group b * *** *** p <0.05 350.00 300.00 250.00 sk in h em e co n te n t 200.00 150.00 100.00 50.00 0.00 day 0 day 28 day 56 day 84 experimental check (days) b group a group b 1.0% -1.0% r at e o f c h an g v s. d ay 0 (% ) -3.0% -5.0% -7.0% -9.0% -11.0% -13.0% -15.0% day 28 day 56 day 84 experimental check (days) figure 3. changes in skin heme content before and after treatment. (a) skin heme content; (b) rate of change vs. day 0. ***p<0.001; **p<0.01; *p<0.05 vs. day0. 35.00 a 30.00 25.00 20.00 15.00 10.00 sk in c o lla g en c o n te n t 5.00 0.00 day 0 day 28 group a group b experimental check (days) day 56 day 84 *** *** *** *** *** 60.0% b 50.0% 40.0% 30.0% r at e ch an g e vs . d ay 0 (% ) 20.0% 10.0% 0.0% day 28 day 56 experimental check (days) day 84 group a group b figure 4. changes in skin collagen density before and after treatment. (a) skin collagen density; (b) rate of change vs. day 0. ***p<0.001 vs. day0. 6 original article | dermatol pract concept. 2023;13(1):e2023015 the skin color became brighter, the pores narrowed and the gloss increased. figure 8b showed a case of skin redness and uneven complexion improvement (volunteer no. 25, visia standard light source mode). after three instances of treatment with product b, the volunteer’s skin turned red, and the uneven skin color was significantly improved. the skin color was uniform, and the skin became bright and white. figure 8c showed a case of skin redness and uneven complexion improvement (volunteer no. 25, visia standard light source mode). figure 8c showed a case of skin redness improvement (volunteer no. 38, visiared areas light source mode photo). after three instances of treatment with product b, the volunteer’s skin redness was significantly improved, the color of erythema became lighter, the red area became smaller, and skin inflammation was decreased. figure  8d showed a case of skin redness and roughness improvement (volunteer no. 8, visia standard light source mode). after three instances of treatment with product b, the volunteer’s skin dullness and roughness were significantly improved, the skin color became brighter, the pores narrowed and the gloss increased. discussion water light therapy is the accurate injection of nutrients or drugs into specific layers of the skin through hollow microneedles, which can effectively supplement nutrients, such as hyaluronic acid and vitamins [13]. moreover, it can stimulate collagen production, make the skin moist and shiny, effectively delay skin aging and improve skin quality [14]. it can also treat diseases by injecting drugs [15]. the common drugs and components used in water light therapy can be divided into simple use of hyaluronic acid, non-crosslinked hyaluronic acid as carrier, matching with different nutrients, collagen preparation, mixed growth factor series, cocktail formula with multiple components or focusing on one component, polydeoxynucleoside, etc. [16]. b improved the skin condition of 53% and 76% of volunteers, respectively (p > 0.05, figure 6). volunteers subjectively evaluated the treatment effect according to the improvement of skin color, wrinkles, elasticity, gloss and moisture contents. the higher the percentage of positive feedback, the more satisfied volunteers were. the clinical results were assigned and scored, and the higher the score, the better the treatment effect. after three treatments, the total score and positive response percentage of product b were higher than those of product a in the dimensions of skin color, wrinkles, elasticity, gloss and moisture contents (fig. 7a, 7b). representative image of the treatment effect of product b fig. 8a is a case of improvement of dull and rough skin (volunteer no. 21, visia standard light source mode). after three instances of treatment with product b, the dullness and roughness of the volunteer’s skin were significantly improved. 300.00 a group a group b 250.00 200.00 150.00 100.00 sk in r et ra ct io n t im e (m s) 50.00 0.00 day 0 day 28 day 56 experimental check (days) day 84 p < 0.01 *** * *** * *** p < 0.05 0.0% b group a group b -2.0% -4.0% -6.0% -8.0% -10.0% -12.0% -14.0% -16.0% day 28 day 56 experimental check (days) day 84 r at e o f c h an g e vs . d ay 0 (% ) figure 5. changes in skin retraction time before and after treatment. (a) skin retraction time; (b) rate of change vs. day 0. ***p<0.001 vs. day0. 100.00% 90.00% 80.00% 70.00% 60.00% 50.00% pe rc en ta g e o f s u b je ct s 40.00% 30.00% 20.00% 10.00% 0.00% group a group b 76.0% 24.0% 47.0% improvement no improvement 53.0% figure 6. the percentage of volunteers who showed improvement and those who did not show improvement in the subjective evaluation score of doctors. original article | dermatol pract concept. 2023;13(1):e2023015 7 of treatment. it showed that medical dextran can significantly improve the roughness of the skin and increase the moisture content of the skin stratum corneum. in terms of moisturizing and improving skin gloss, medical dextran has the same improvement effect as sodium hyaluronate. compared with that before treatment, medical dextran treatment significantly reduced skin erythema and redness. however, sodium hyaluronate had no significant effect in improving skin erythema. compared with that before treatment, medical dextran treatment significantly increased skin collagen density, stimulated collagen production, and has an anti-aging effect. particularly, the significant difference in the effect of medical dextran on skin collagen density appeared earlier than that of sodium hyaluronate, indicating that medical dextran can start and promote collagen regeneration faster. compared with that before treatment, medical dextrose treatment can significantly reduce the skin retraction time, indicating that it can improve skin sagging problems, and the effect was significantly better than with sodium hyaluronate. the subjective evaluation results of doctors showed that after 84 days of treatment with medical dextran and sodium dextran is a kind of branched dextran polymer with molecular weight ranging from 1 kda to 2000 kda. the side chain degree of dextrose differs according to molecular weight [17]. the smaller the molecular weight, the lower the side chain degree. the closer the molecular weight distribution is, the different application emphases of different molecular weights are different [18]. compared with other polymer materials, dextran has the advantages of good water solubility, biodegradability, small antigenicity and high safety, and it has been used as a plasma substitute in clinics [19, 20]. therefore, dextran with the above characteristics has important application value in the field of skin rejuvenation treatment. the cross-linked dextran filler (lipen de, cheonghwa medipower corporation, jangseoung, korea) was approved by the korean food and drug administration in 2012. shin and his team have confirmed that it has a filling effect for more than six months for the treatment of nasolabial folds [21]. in this study, we explored the therapeutic effect of medical dextran as a new type of water-light injection material on skin photoaging. our results showed that compared with that before treatment, medical dextran significantly increased skin moisture retention and skin gloss after 84 days 100.00% b complete improvement obvious improvement slight improvement no improvement 80.00% 60.00% 40.00% 20.00% 0.00% 11.8% 52.9% 35.3% 23.5% 70.6% 5.9% 5.9% 5.9% 5.9% 5.9% 5.9% 5.9% 64.7% 23.5% 5.9% 5.9% 11.8% 64.7% 29.4% 47.1% 17.7% 5.9% 41.2% 47.1% 5.9% 17.7%17.7% 70.6% 5.9% 64.7% 29.4% 5.9% 52.9% 35.3%47.1% 47.1% a skin color wrinkles elasticity gloss moisture retention b a b a b a b a b figure 7. efficacy evaluation after treatment. (a) results obtained from the questionnaire completed by volunteers after 84 days of treatment with product a and product b. the results are expressed as the total score of each volunteer’s questionnaire. complete improvement = 4 points, obvious improvement = 3 points, slight improvement = 2 points, no improvement = 1 point, deterioration = 0 points. the higher the score, the better the skin state; (b) after treatment, the percentage of each item in the volunteers’ questionnaire. 8 original article | dermatol pract concept. 2023;13(1):e2023015 primary human dermal fibroblasts and ex vivo human skin. biomed pharmacother. 2021;145:112461. 2. chung jh, eun hc. angiogenesis in skin aging and photoaging. j dermatol. 2007;34(9):593-600. 3. kosmadaki mg, gilchrest ba. the role of telomeres in skin aging/photoaging. micron. 2004;35(3):155-159. 4. kim hm, oh s, yang jy, et al. evaluating whether radiofrequency irradiation attenuated uv-b-induced skin pigmentation by increasing melanosomal autophagy and decreasing melanin synthesis. int j mol sci. 2021;22(19):10724. 5. hartono sp, bedell vm, alam sk, et al. vascular endothelial growth factor as an immediate-early activator of ultraviolet-induced skin injury. mayo clin proc. 2021;s0025-6196(21):00643-1. 6. vechtomova yl, telegina ta, buglak aa, kritsky ms. uv radiation in dna damage and repair involving dna-photolyases and cryptochromes. biomedicines. 2021;9(11):1564. 7. fernando ips, heo sj, dias mkhm, et al. (-)-loliolide isolated from sargassum horneri abate uvb-induced oxidative damage in human dermal fibroblasts and subside ecm degradation. mar drugs. 2021;19(8):435. 8. lin s, he x, he y. co-culture of ascs/epcs and dermal extracellular matrix hydrogel enhances the repair of full-thickness skin wound by promoting angiogenesis. stem cell res ther. 2021;12(1):129. 9. zeng y, zhang x, lin d, et al. a lysosome-targeted dextran doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia. j hematol oncol. 2021;14(1): 189. hyaluronate, the overall score of the volunteers’ photoaging was significantly reduced in comparison with that before treatment, indicating that they can significantly improve skin photo-aging problems, including skin roughness, dryness, lack of elasticity, etc. from the subjective evaluation results of volunteers, as the time of treatment increased, the percentage of positive responses from volunteers in various aspects, such as dry skin, skin gloss, uneven skin tone and dullness, skin elasticity, and skin wrinkles, gradually increased. especially for gloss and elasticity, the overall improvement with medical dextran is better than with sodium hyaluronate. conclusion in conclusion, medical dextran has obvious effects of increasing moisture content, increasing luster, improving skin redness, increasing skin collagen and enhancing skin elasticity. medical dextrose is superior to hyaluronic acid in improving skin redness and skin relaxation. references 1. klinngam w, rungkamoltip p, thongin s, et al. polymethoxyflavones from kaempferia parviflora ameliorate skin aging in figure 8. representative images of improvement of dull, rough, reddish skin and uneven skin color. (a) representative images of improvement of dull and rough; (b) representative images of improvement of reddish skin and uneven skin color; (c) representative images of improvement of reddish skin; (d) representative images of improvement of reddish skin and rough. original article | dermatol pract concept. 2023;13(1):e2023015 9 injection (water light therapy). qiong journal of practical dermatology. 2018;11 (2). 16. chun j, bao f, pei l, sun l. application status, efficacy and prospect of aesthetic formula in the field of skin rejuvenation. chinese cosmetic medicine. 2018;27(10):21-25. 17. trandel ma, johanningsmeier s, schultheis j, gunter c, perkins-veazie  p. cell wall polysaccharide composition of grafted ‘liberty’ watermelon with reduced incidence of hollow heart defect. front plant sci. 2021;12:623723. 18. wang x, zhao b, pan b. application research and prospect of glucan as a new medical dressing. china tissue engineering research. 2017;21(26):4252-4257. 19. kleinveld djb, simons ddg, dekimpe c, et al. plasma and rhadamts13 reduce trauma-induced organ failure by restoring the adamts13-vwf axis. blood adv. 2021;5(17):3478-3491. 20. darras a, peikert k, rabe a, et al. acanthocyte sedimentation rate as a diagnostic biomarker for neuroacanthocytosis syndromes: experimental evidence and physical justification. cells. 2021;10(4):788. 21. shin sj, her y, yu ds, kim cw, kim ss. twenty-four-week multicenter, evaluator-blinded clinical study of the efficacy and safety of a dextran filler in the treatment of nasolabial folds. dermatol surg. 2014;40(6):652-657. 10. goldberg dj. breakthroughs in us dermal fillers for facial soft tissue augmentation. j cosmet laser ther. 2009;11(4):240-247. 11. lemperle g, morhenn v, charrier u. human histology and persistence of various injectable filler substances for soft tissue augmentation. aesthetic plast surg. 2020;44(4):1348-1360. 12. yang f, zhou z, guo m, zhou z. the study of skin hydration, anti-wrinkles function improvement of anti-aging cream with alpha-ketoglutarate. j cosmet dermatol. 2021;10.1111/ jocd.14635. 13. wanitphakdeedecha r, iamphonrat t, phothong w, eimpunth s, manuskiatti w. local and systemic effects of low-level light therapy with light-emitting diodes to improve erythema after fractional ablative skin resurfacing: a controlled study. lasers med sci. 2019;34(2):343-351. 14. yang g, xiang lf, gold mh. 5-aminolevulinic acid-based photodynamic intense pulsed light therapy shows better effects in the treatment of skin photoaging in asian skin: a prospective, single-blinded, controlled trial. j clin aesthet dermatol. 2010;3(3):40-43. 15. skin laser medical cosmetology group of dermatology and venereology branch of chinese medical association, laser sub-committee of cosmetology and plastic surgeons branch of chinese medical association. expert consensus on electronic untitled practical, conceptual & educational note | dermatol pract concept 2015;5(3):13 55 dermatology practical & conceptual www.derm101.com patient’s question “doctor, please wait before rushing off. i have a question for you. do i have cancer? please be direct and honest with me, and explain to me the truth about what you know about cancer in a manner that i, as a layman, will be able to understand what you tell me. most importantly, what is cancer, and what causes cancer? if i have cancer, how long will i live, and will i have just a little or significant pain? and lastly, is there any chance of a cure”? doctor’s answer “i don’t know! no one knows the answers to your questions with absolute certainty. you must now excuse me i have other patients to see.” discussion cancer is a general term frequently used to describe a variety of malignant altercations, most of which manifest invasiveness and metastasize to multiple sites, resulting in progressive illness and death [1]. for centuries, the causes of a variety of malignant conditions and cancer were unknown; some cases even were considered mythical, such as “the black plague,” which was attributed at one time to an ethnic group, i.e., the jews. this mythical concept, for example, resulted in the extermination of an enormous number of jews. only decades later did this mythical misconception prove false, and not surprisingly, found to be caused by infectious gram negative bacteria, yersinia pestis, by selman waksman [2] and his protégé albert schatz, in the 1940s and early 1950s. the black plague was easily and quickly controlled and minimized by the use of streptomycin, a gray secreted substance from an actinomyces, actinomyces griseus (gray). interestingly, my first and only experience with the black plague was at the young age of 27 in march 1969 while in the united states navy, 3rd medical battalion of the 3rd marine division, where i treated an epidemic of plague in the village of pho hoi, viet nam. i documented 38 men, women and children with classic signs and symptoms of plague including prominent buboes, which were treated and resolved with a combination of streptomycin and tetracycline. it was hard for me to believe that the life-saving drug streptomycin had been available for only 25 years. complete clearing of the plague was ensured in days after treatment was instituted. not surprisingly, the only ones that were exterminated then were the carrier rodents. although melanoma is considered an unquestionable malignant growth, i.e., a cancer, its etiology to date remains undefined or uncertain, although sun exposure is considered strongly [3]. to support uvr exposure to some melanomas, there are a variety of unpredictable chemotherapeutic and immunotherapeutic treatment regimens such a dacarbazine (dtic) and interleukin-2 (hdil-2 of interferon). “novel and emerging therapies for melanoma” [4] acknowledges variable responses and unfortunately significant toxicity. other therapies in use and under investigation include targeted immunotherapy and or immunotherapy, vemurafenib and ipilimumab. infectious cancers robert m. hurwitz1 1 dermatopathology, indianapolis, indiana, usa key words: cancer, infectious, cancer, myth, melanoma citation: hurwitz rm. infectious cancers. dermatol pract concept 2015;5(3):13. doi: 10.5826/dpc.0503a13 copyright: ©2015 hurwitz. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. acknowledgement: thanks to steven a. hurwitz, ms, mba, for his active support and assistance. corresponding author: robert m. hurwitz, md, 1829 box elder court, indianapolis, in, 46260 usa. email: bobbyhur@aol.com mailto:bobbyhur@aol.com 56 practical, conceptual & educational note | dermatol pract concept 2015;5(3):13 • r. palmer beasley (hepatitis b and liver cancer) • harald zur hausen (human papillomavirus hpv 16 and cervical squamous cell carcinoma) • barry marshall and robin warren (h. pylori gastric ulcer and gastric cancer) • patrick s. moore and yuan chang (merkel cell cancer with the polyomavirus) • yuan chang, ethel cesarman, and melissa s. pessin (aids/ kaposi sarcoma, now considered by some to be a hyperplasia) • ludwik gross, paul ewald, cynthia l. sears, robert holt (stealth and colonic infection and cancer; “fusobacterium bacterimia nucleatium”) an interesting twist to the infectious etiology of cancers concerns the fact that the same infectious agent may be implicated and proliferates in a variety of clinical expressions. some presentations included those simulating an inflammatory reaction. for example, lymphomatoid papulosis is an inflammatory variation of a cd 30 lymphoma, other infectious agents often prove to be viral or bacterial organisms such as the human papillomavirus (hpv), epstein-barr virus (herpes virus (infectious mononucleosis, and lymphoma), and hiv and lymphoma, hepatitis b virus and liver cancer, herpes virus, bartonella henselae, and borrelia (spirochete). similarly, inflammatory hiv, viral hepatitis, vaccines, and drugs such as tnf-α inhibition, gold and/or interferon injection may result in clinical inflammatory reactions such as granuloma annulare as well as lymphoproliferative/hematopoietic malignancies [9]. it is common knowledge that it is usual for an infectious agent to alter its normal mechanisms of a molecular cellular proliferation, and/or its molecular pathway. on the other hand, there are significant genomic and molecular studies in progress showing alternation of chromosomes and altered genetic pathways in both benign and malignant conditions. the question becomes just what alteration an infectious organism may assume. just because an organism may or may not be identifiable per se by culture or electron microscopy, or any other investigative mechanism, does not necessarily purport that they are present or not present, active and/or out of action. understanding that some cancers have been found to be associated with an infectious agent is in reality a fact, and not only for the classification of cancers. in brief summary, there are numerous cancers such as ovarian, breast, brain, pancreatic and melanoma with unknown etiologies, and yet today there are many progressive inflammatory and neoplastic diseases of known infectious etiology. as a consequence, an infectious etiology must continue to be a main concern. some conditions on the other hand, might well be expected to be infectious, such as amyotrophic lateral sclerosis (lou gehrig’s disease) and alzheimer’s disease, which as yet are undetermined. to date, none of these modalities appear to be directly related to an infectious organism or directly eliminate or cure a melanoma. interestingly, today many believe emphatically that the sun with its ultraviolet rays is the offending agent; even though melanoma is not uncommonly present in non-sun-exposed areas of the body, including the genitalia, oral/nasal mucosa, perianal, palm/soles, and regions subungual. in addition, even the renowned abcd’s (asymmetry, border, color and diameter), once considered diagnostically infallible for a diagnosis of melanoma clinically are now breaking down among those arched backers, who now recognize numerous benign and malignant melanocytic proliferations, as well as pigmented and non pigmented and non melanocytic proliferations that simulate the abcd’s. frequent strong and obnoxious comments have been expressed commonly by colleagues towards dr. a. bernard ackerman’s views, especially on the subject of melanoma. as quoted in the sun and the “epidemic” of melanoma: myth on myth! ackerman [3] responded straightforwardly, honestly, unswervingly, directly and poignantly from the film breaker morant, “scientists are human; they do not wait for proof; many devote their professional lives to seeking evidence for hypotheses (especially well-funded hypotheses) they’ve chosen to believe.” [5] an extraordinary, informative and exceptionally brilliant must read book is the emperor of all maladies: a biography of cancer, by siddhartha mukherjee [6]. in his work, mukherjee attacks cancer and outlines the morbid history in detail and the unbelievable events that physicians, investigators and researchers had to deal with in their study of cancer. for a decade, from 2003-2013, clifton leaf conducted an extensive investigation and introspection on the war on cancer, which is published in his book the truth in small doses: why we’re losing the war on cancer—and how to win it [7]. he understood that science determines the limits of the possible and that engineering allows us to reach them. he was well aware of the difficulty to secure funding in an atmosphere of competition overriding collaboration. his investigations extended to include, among others, the tribulations of denis burkitt, the epstein-barr virus, and the complexities of oncogenes. recently, in claudia cornwall’s [8], catching cancer: the quest for its viral and bacterial causes, there were astonishing, hard to believe, incredible accounts of the individual trials and tribulations that researchers were forced to go through to prove their theories that an infectious agent was the cause of the cancer at hand. funding was nearly out of the question to obtain. one such group (marshall and warren) drank a bacterial impregnated liquid to prove their point that h. pylori bacteria resulted in gastric ulcers (and later gastric carcinoma). there were successful investigators who associated an infectious agent with cancer, who included the likes of: • denis p. burkitt (burkitt’s lymphoma) practical, conceptual & educational note | dermatol pract concept 2015;5(3):13 57 3. ackerman ab. the sun and the “epidemic” of melanoma: myth on myth! contrary view on behalf of patients, 2nd ed. new york, ny: ardor scribendi, ltd., 2008. 4. novel and emerging therapies for melanoma. targetedonc. com. march 5, 2014. intellisphere llc. accessed march 11, 2015. http://www.targetedonc.com/articles/novel-and-emergingtherapies-for-melanoma/1 5. jenkins hw jr. “the science of gore’s nobel”. the wall street journal, december 5, 2007. 6. mukherjee s. the emperor of all maladies. a biography of cancer. new york, ny: simon & schuster, 2011. 7. leaf c. the truth in small doses: why we’re losing the war on cancer—and how to win it. new york, ny: simon & schuster, 2013. 8. cornwall c. catching cancer: the quest for its viral and bacterial causes. lanham, md: rowman & littlefield publishers, 2013 9. shinkai k, rosenbach m, wintroub b, berger g. therapeutic strategies in dermatology: granuloma annulare. derm101.com. accessed march 11, 2015. http://www.derm101.com/therapeutic/ granuloma-annulare-2/key-points/ 10. jansen g, gatenby r, aktipis ca. opinion: control vs. eradication: applying infectious disease treatment strategies to cancer. pnas 2015;112:937-8. doi: 10.1073/pnas1420297111. 11. srivastava a, shirwan h. armed with the right adjuvant system, vaccines are poised to tackle on of the world’s most intractable diseases. the-scientist.com. march 31, 2015. labx media group. http://www.the-scientist.com/?articles.view/articleno/42563/title/ opinion—making-cancer-vaccines-work/ 12. pagano hs, blasner m, buedia ma, et al. infectious agents and cancer: criteria for a causal relation. semin cancer biol 2004;14(6):453-71. during the past decade there has been a surge in the literature strongly associating infectious agents with cancers of various types, as previously described. some therapeutic modalities have been found to be effective in eliminating some cancers completely, or at least minimizing the consequences from the cancer. new and sophisticated therapeutic modalities, specifically attacking the infectious agent or their consequences have been and are being discovered and used to affect the infectious agent directly and to minimize their secondary effects: “cancer-control measures . . . avoid attempting to completely eradicate tumor cells, by aiming to (i) limit essential resources to cancer cells, (ii) disrupt cooperation among cancer cells; and (iii) prevent host damage.” [10] in the meantime, study of neoplastic infections agents will continue to illuminate molecular oncogenic processes. both known and unidentified infectious agents have yet to be implicated in human cancer. when all is said and done and all things considered, the future looks bright, but infectious etiology must not be ignored or overlooked. we can and should expect a proliferation of new therapeutic agents, e.g., vaccines, [11] in association with one cancer or another [12]. references 1. stedman’s medical dictionary. baltimore, md: the williams & wilkins company, 1961. 2. heynick f. jews and medicine: an epic saga. hoboken, nj: ktav publishing house, inc., 2002. http://www.derm101.com/therapeutic/granuloma-annulare-2/key-points/ http://www.derm101.com/therapeutic/granuloma-annulare-2/key-points/ dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2022; 12(1):e2022080 1 clinical and dermoscopic approaches to diagnosis of frontal fibrosing alopecia: results from a multicenter study of the international dermoscopy society michela starace1, gloria orlando2, matilde iorizzo3, aurora alessandrini1, francesca bruni1, victor desmond mandel4,5, kelati awatef6, horacio cabo7, gabriella fabbrocini13, baybay hanane8, sven lanssens9, alejandro lobato-berezo10, fatima zahra mernissi8,  john paoli11,12, angela patrí13, emilia noemi cohen sabban7, martyna sławińska14, michał sobjanek14, oscar zaar11,12, giovanni pellacani4,15, bianca maria piraccini1 1 department of experimental, diagnostic, and specialty medicine-division of dermatology, university of bologna, bologna, italy 2 department of medicine dimed, dermatology unit, university of padova, italy 3 private dermatology practice, bellinzona, lugano, switzerland 4 dermatology unit, surgical, medical, and dental department of morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, modena, italy 5 dermatology unit, department of clinical and experimental medicine, university of parma, parma, italy 6 dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco 7 dermatology division of the instituto de investigaciones médicas alfredo lanari, university of buenos aires (uba), argentina 8 dermatology department, uhc hassan ii. fez, morocco 9 dermatologie maldegem – maldegem, belgium 10 department of dermatology, hospital del mar-parc de salut mar, barcelona, spain 11 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 12 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 13 department of clinical medicine and surgery, section of dermatology, university of naples federico ii 14 department of dermatology, venereology and allergology, faculty of medicine, medical university of gdańsk, poland 15 dermatologic unit, department of clinical internal, anesthesiological and cardiovascular sciences, sapienza university of rome, rome, italy key words: frontal fibrosing alopecia, trichoscopy, diagnosis, non-invasive, techniques citation: starace m, orlando g, iorizzo m, et al. clinical and dermoscopic approaches to diagnosis of frontal fibrosing alopecia: results from a multicenter study of the international dermoscopy society. dermatol pract concept. 2022; 12(1):e2022080. doi: https://doi .org/10.5826/dpc.1201a80 accepted: october 18, 2021; published: january 2022. copyright: ©2022 starace et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gloria orlando, dermatology unit, department of medicine dimed, university of padova, italy. e-mail: gloriaorlando@gmail.com 2 review | dermatol pract concept. 2022; 12(1):e2022080 introduction: frontal fibrosing alopecia (ffa) is a form of primary lymphocytic scarring alopecia characterized by a progressive recession of the fronto-temporal hairline. although the clinical presentation of ffa is very typical, biopsy for histopathological examination is still recommended to confirm the diagnosis. currently, a growing number of skin and mucosal inflammatory diseases are diagnosed with modern noninvasive techniques such as dermoscopy without the necessity of a biopsy. objectives: the international dermoscopy society (ids) aimed to test the ability of its members to diagnose classic ffa through clinical and dermoscopic parameters and to compare acquired data to the largest cohort studies published since 1994. methods: this is an observational, cross-sectional study describing patient demographics, clinical presentation and diagnostic tools used in a sample of ffa patients collected by ids members. a literature search was then performed using pubmed to review studies reporting more than 100 cases. results: ids members submitted 188 cases demonstrating a predominant female population (98.4%). in 71.8% of the cases, the clinical presentation and the trichoscopic findings allowed for the diagnosis. out of 24 revised studies, 13 showed that clinical and trichoscopic features were decisive for the diagnosis in almost all cases. conclusions: demographic and clinical data of our cohort were mostly comparable to previous reported data on ffa. the relevant role of the clinical and trichoscopic features in diagnosing ffa was confirmed by our study and the reviewed literature. trichoscopy could be considered a worldwide-acknowledged non-invasive technique for the diagnosis of ffa. abstract introduction frontal fibrosing alopecia (ffa), first described by kossard in 1994 [1,2] is a form of primary lymphocytic scarring alopecia characterized by a progressive band-like recession of the fronto-temporal hairline and, in 50-75% of cases, by a partial or complete alopecia of the eyebrows. whether ffa is only a form of lichen planopilaris (lpp) or a more complex disorder is still a matter of debate [3-5]. thousands of cases have been described to date, with increasing incidence of the disease worldwide. postmenopausal women are still those primarily affected, but women with childbearing potential and males can also present with this disease [6-8]. scalp ffa can also present in atypical forms such as linear, diffuse, zig-zag, and pseudo-fringe patterns [9]. hair follicles on the occipital scalp and sideburns can also be involved as well as eyelashes, beard, axillae, limbs and pubis [10-12]. lichen planus pigmentosus, facial papules and facial erythema have also been described in patients with ffa indicating that this is not necessarily a disease limited to the scalp and eyebrows [13-15]. the real incidence of ffa is unknown, but the important increase in the reported cases in recent years has led some authors to refer to it as an epidemic disease [16]. the etiopathogenesis and the reason for the increasing incidence of ffa are still unknown. the fact that ffa develops later in life suggests that triggering environmental factors might play a role in the development of the disease. a genetic basis has also been hypothesized since ffa has been diagnosed in siblings and members of the same family [17, 18]. although ffa is thought to be a variant of lpp, there is no reported association with hla-dr1. a recent genome-wide association study showed that ffa correlates with the hla-b*07:02 allele [19]. lastly, it has been speculated that the disease was present even before kossard’s first description, but somehow passed unnoticed [20]. due to the lack of randomized clinical trials and lack of a control group in previous clinical studies, treatment of ffa is not evidence-based [21]. lack of evidence doesn’t mean, however, lack of effectiveness. disease control might be achieved with topical, intralesional and oral treatments, often combined together. the treatment aim is always to stop disease progression [22]. at present, although the clinical picture of ffa is very typical in most cases, a biopsy for histopathological confirmation is still recommended to administer the correct treatment [23]. in cases not involving the scalp, a biopsy is mandatory. scarring might be subtle and the fibrous tracts so thin that the loss of follicular ostia might be missed. thus, ffa can be mistaken for a nonscarring alopecia, particularly alopecia areata (aa) and androgenic alopecia (aga). moreover, due to the presence of the disease in cosmetically sensitive areas, patients do not always accept biopsy even if it is a 2-mm punch biopsy [24]. for these reasons, modern noninvasive techniques including dermoscopy [25-27], reflectance confocal microscopy [28] and optical coherence tomography [29] are increasingly used to diagnose several skin and mucosal inflammatory diseases. the goal is to perform a diagnosis without the necessity of a biopsy and to reserve it only for early stages, doubtful cases and/or uncommon presentations. therefore, the international dermoscopy society (ids) aimed to test the ability of its members to diagnose typical or classic ffa through clinical and dermoscopic parameters and compare the acquired data to the largest cohort studies published since 1994. review | dermatol pract concept. 2022; 12(1):e2022080 3 methods the study was launched by the ids via an online call for contributions published on the ids website (www.dermoscopy-ids.org). from march 2018 to march 2020, ids members were invited to submit cases of ffa. high quality clinical and dermoscopic images of the clinical presentations were mandatory. information on patient demographics and lesion characteristics were also required including age, gender, involved skin/scalp areas, time at onset, subjective symptoms and trichoscopic features. furthermore, information regarding the diagnostic methodologies were also mandatory. the study was conducted in accordance with ethical guidelines, and irb approval was obtained. all data were collected and analyzed. a literature search for “frontal fibrosing alopecia” was then performed on pubmed and returned 502 items (april 2021). only papers reporting more than 100 cases were considered and revised. for each paper the year of publication, the number of patients, the origin of the population, the type of diagnostic methodology was collected. results after the initial call, 206 ffa cases from 10 different centres were collected, but 18 cases were excluded from analysis due to misdiagnosis (8.7%). the clinical and trichoscopic data of all 188 included cases are presented in table 1. the mean age of the studied population was 62 years (range 40–84) with a predominant female population (98.4%) and only 3 male patients. the great majority of the female population were post-menopausal (88.1%) with an average age of climacteric onset at 44.3 years. the mean age at onset of the disease was 58.6 years, on average 11.2 years after menopause. however, the disease was diagnosed up to 35 years after menopause. regarding the degree of disease at diagnosis, 51.6% of the patients already showed grade 2 disease at that timepoint. when the frontal scalp was involved, the mean recession of the hairline was 2.35 cm (0-10 cm) and the distance between the glabella and the forehead was 7.57 cm (range 5-15 cm). ffa also affected the parietal regions in 70.2% of cases (132/188), while the occipital region was involved in 11.7% of cases (22/188). the sideburns were not affected in any of the patients. reduction or complete loss of eyebrows was reported in 85.6% of patients with partial loss in 104 patients (55.3%) and total loss in 56 patients (29.8%). the beard was involved only in one male patient, whereas involvement of eyelashes, armpits and pubis were reported in 52 (27.6%), 80 (42.5%) and 68 (36.1%) patients, respectively. in all cases with an extra-scalp involvement, the eyebrows were also compromised at the same time. non-inflammatory facial papules were observed in 56 patients (29.8%). in 48 patients, they table 1. clinical and trichoscopy data from 188 patients affected by ffa and collected through the international dermoscopy society online call characteristics age (range) female patients 62 (40-84) years 98.4% (185/188) post-menopausal patients 88.1% (163/185) menopause onset, mean age (range) 44.3 (40-61) years ffa family history 10.1% (19/188) aga family history 42% (79/188) aga personal history 38.8% (73/188) ffa onset, mean age (range) 58.6 (15-84) years disease duration, mean (range) 4.4 (2 months – 30 years) years clinical severity grade 1 37 (19.6%) grade 2 97 (51.6%) grade 3 45 (23.9%) grade 4 7 (3.7%) grade 5 2 (1%) clinical data recession 2.35 (0-10) cm glabella-hairline distance 7.57 (5-15) occipital area involvement 11.7% (22/188) parietal area involvement 70.2% (132/188) eyebrows involvement 85.6% (161/188) eyelashes involvement 27.6% (52/188) body hairs involvement 47,3% (89/188) armpits hairs involvement 42.5% (80/188) pubis hairs involvement 36.1% (68/188) beard (*men only*) 33.3% (1/3) facial papules 29.8% (56/188) scalp symptoms pruritus 65.9% (124/188) trichodynia 22.9% (43/188) trichoscopy empty follicles 93.6% (176/188) absence of follicular ostia 92% (173/188) perifollicular erythema 63.8% (129/188) follicular hyperkeratosis 60.1% (113/188) lonely hairs 54.8% (103/188) clinical associations aga 38.8% (73/188) lichen planopilaris 18.6% (35/188) lichen planus (skin/mucosae/nails) 5.3% (10/188) diagnostic methods dermoscopy 71.8% (135/188) biopsy 28.2% (53/188) ffa=frontal fibrosing alopecia; aga= androgenetic alopecia 4 review | dermatol pract concept. 2022; 12(1):e2022080 were localized on the face, in 6 patients on the limbs and in 2 patients simultaneously on the face, limbs and trunk. concomitant signs of lpp on the scalp were present in 35 patients (18.6%). five of them showed diffuse hair thinning in the crown area associated with trichoscopic and histopathological features of lpp and were diagnosed with fibrosing alopecia in a pattern distribution (fapd). ten out of 188 patients (5.3%) had lichenoid changes on the skin, mucous membranes and/or nails. the concomitant presence of aga was found in 73 patients (38.8%). a family history of ffa was reported in 19 patients (10.1%) with a mean age of onset at 56.4 years, while it was 59.6 years in patients without a family history (p = 0.9). trichoscopy reports showed signs of cicatricial alopecia in all patients, with empty follicles in 93.6% of cases and absence of follicular ostia in 92% of cases. the presence of inflammatory signs such as perifollicular erythema and perifollicular hyperkeratosis were present in 129 (63.8%) and 113 (60.1%) of the patients, respectively. one hundred and three patients (54.8%) presented lonely hairs. trichoscopic signs were not associated with the degree of disease, but clinical signs of inflammation such as perifollicular erythema and perifollicular hyperkeratosis were associated with the presence of pruritus (p = 0.049). indeed, 124 patients (65.9%) complained of itching and 43 (22.9%) reported concomitant trichodynia. in most cases (71.8%), the characteristic clinical presentation (figure 1) and the typical trichoscopic findings (figure 2) made it possible to make the diagnosis of ffa without resorting to the use of invasive diagnostic techniques. only 53 patients required a histopathological diagnosis. table 2. data of published studies on ffa reporting more than 100 cases number of patients sex m/f population type of diagnosis data collected pindado-ortega c et al 2021 [30] 224 2/222 spain clinical (histopathological when needed) retrospective observational study on effectiveness of dutasteride in ffa muller ramos p et al 2021 [31] 451 18/433 brazil na multicenter case-control study on risk factors for ffa grassi s et al 2021 [32] 119 8/111 italy na retrospective observational monocentric study on epidemiology, clinical and trichoscopic features and comorbidities in ffa patients trager mh et al 2021 [33] 173 14/159 colombia and usa clinical and histopathological retrospective cohort study on medical comorbidities and gender distribution among patients with lpp and ffa mcsweeney sm et al 2020 [34] 711 0/711 uk clinical (histopathological when needed) descriptive cross-sectional study on clinical phenotype in women from ffa uk gwas cohort figure 1. clinical presentation of a female with frontal fibrosing alopecia. figure 2. trichoscopy of a female affected by frontal fibrosing alopecia. the literature search identified a total of 24 papers (all published between 2014 and 2021) with more than 100 included cases (table 2) [19, 25-27, 30-49]. during 2014, 2015, and 2016 only one study was published per year [25,48,49]. two and 5 studies were published in 2017 and table 2 continues review | dermatol pract concept. 2022; 12(1):e2022080 5 number of patients sex m/f population type of diagnosis data collected anzai a et al 2019 [27] 151 0/151 brazil/italy histopathological retrospective and prospective study on trichoscopic findings of ffa of the eyebrows papanikou s et al 2019 [35] 100 0/100 greece na observational study on the influence of social status on the prognosis of ffa in female patients mulinari brenner f et al 2019 [36] 227 na brazil na observational study on reported cases of ffa in a tertiary center vañó-galván et al 2019 [37] 306 na australia, brazil, chile, colombia, italy, mexico, norway, poland, portugal, south africa, spain, switzerland, usaand uk na retrospective multicenter study on frequencies of alopecia types at 22 specialized hair clinics kanti v et al 2019 [38] 490 25/465 france and germany clinical (histopathological when needed) observational cross-sectional descriptive study on demographic and clinical characteristics associated with the severity of ffa moreno-arrones om et al 2019 [39] 278 0/278 spain clinical (histopathological when needed) multicenter cross-sectional study on factors influencing ffa severity tziotzios c et al 2019 [19] 1016 0/1016 greece and uk na genome-wide association study on ffa moreno-arrones om et al 2019 [40] 335 20/315 spain na multicenter case-control study on risk factors associated with ffa cranwell wc et al 2019 [41] 130 0/130 australia na case-control questionnaire study on exposure to sunscreen or facial skin care products and their association with ffa buendia-castano d et al 2018 [42] 104 0/104 spain clinical (histopathological when needed) case-control study on hormonal and gynecological risk factors for ffa imhof rl et al 2018 [43] 148 0/148 usa clinical (histopathological when needed) retrospective study on clinicopathological findings, comorbidities and treatment outcomes in women with ffa saceda-corralo d et al 2018 [44] 103 0/103 spain clinical (histopathological when needed) descriptive cross-sectional study on patients diagnosed with both ffa and lpp cervantes j et al 2018 [26] 108 na usa clinical (histopathological when needed) retrospective study on trichoscopic features of sideburns in ffa compared to fronto-temporal scalp pindado ortega c et al 2018 [45] 103 0/103 spain clinical (histopathological when needed) descriptive cross-sectional study on relationship between ffa and rosacea donati a et al 2017 [46] 149 na france clinical (histopathological when needed) retrospective analysis on the use of direct immunofluorescence in ffa table 2 continues table 2. data of published studies on ffa reporting more than 100 cases (continued). 6 review | dermatol pract concept. 2022; 12(1):e2022080 number of patients sex m/f population type of diagnosis data collected moreno arrones om et al 2017 [47] 242 0/242 spain clinical (histopathological when needed) retrospective single-centre observational study on clinical and prognostic classification of ffa aldoori n et al 2016 [48] 105 0/105 uk clinical case-control study on the role of leave-on facial skin care products and sunscreen in ffa fernandezcrehuet p et al 2015 [25] 249 11/238 spain clinical and histopathological descriptive retrospective observational multicenter study on trichoscopic features of ffa vañó-galván et al 2014 [49] 355 12/343 spain clinical (histopathological when needed) retrospective multicenter study on epidemiology, comorbidities, clinical presentation, diagnostic findings, and therapeutic choices in ffa ffa = frontal fibrosing alopecia; f = females; m = ales; na=not applicable. table 2. data of published studies on ffa reporting more than 100 cases (continued). 2018, respectively [26,42-47]. nine studies were released in 2019 [19,27,35-41] and 5 studies were published in 2020 and 2021 [30-34]. in 13 studies, clinical and trichoscopic features were decisive for the diagnosis in almost all ffa cases [26,30,34,39,42-49]. invasive biopsies for histopathological examinations were reserved for doubtful cases and confirmed the diagnosis in all cases. conclusions since its first description in 1994, ffa has shown a significant increase in incidence all over the world. in 2014, vañó-galván et al published the first large cohort of patients diagnosed with ffa [49]. subsequently, as confirmed by our review of the literature, the number of published large cohort studies have increased over time, in particular during the last 3 years. of note, tziotzios et al published the largest cohort study in 2019, reporting more than 1,000 patients from greece and uk [19]. here, we report an additional large cohort of patients diagnosed with ffa collected through ids members who responded to our online call. the mean age at onset of the disease in our sample was 58.6 years, which is comparable to the previously reported data on ffa. the results support the current theory that the disease mainly affects postmenopausal women (88.1%), but also documents that it can be found in younger women (11.9%). the youngest patient was 15 years old at the onset of symptoms. our sample also included 3 male subjects supporting the fact that ffa can affect males as well. cases of ffa within multiple members of the same family have been reported in 5-8% of the cases [49, 50], a result that is a very similar to the percentage observed in our study (10.1%). navarro belmonte et al reported that the age at onset of the disease in cases with relatives affected by ffa appears to be lower than in isolated cases [51]. our study also showed an earlier onset of about 3 years in subjects with a positive family history. however, the difference between the two groups was not significant in our cases. in accordance with other small studies [8,52], our study reported an association between ffa and lpp (18.6% of cases) including 5 patients with fapd. this observation supports the theory that ffa could actually represent a clinical variant of lpp despite the different symptoms. although this association was not reported in larger studies, it is possible that it is under-reported. consistent with previous studies [53,54], the presence of aga was recorded in 38.8% of patients suggesting that aga may be at the root of a fibrotic process leading to ffa or that ffa and aga may have a similar underlying pathogenetic mechanism, for example a hormonal basis. the role of hormones is however still uncertain and debated as well as the link between ffa, lpp and aga. one retrospective study associated ffa with androgen deficiency, while lpp was more frequently associated with androgen excess [54]. furthermore, no association with lupus and aa was reported in our group of patients. interestingly, the diagnosis of ffa in our cohort was made on average 4.4 years after the onset of the disease and in 51.6% of cases already presented as grade 2 of severity with a mean frontal hairline recession of 2.35 cm, which in some cases reached 10 cm. this underlines the importance of awareness and education on this disease, not only among patients but also among health professionals, in order to diagnose and treat ffa at an earlier stage to stop the scarring process. review | dermatol pract concept. 2022; 12(1):e2022080 7 alopecia of the eyebrows, found in 85.6% of cases, was confirmed as the most frequent sign of the disease, while the loss of eyelashes and axillary, pubic and/or body hair was documented with a lower rate. some authors have raised the doubt that the peripheral involvement of the disease could actually be simply a consequence of menopause and/or aging [55]. in this regard, we compared patients of childbearing age with menopausal patients and found overlapping percentages of body hair involvement in both age groups (86.4% versus 87.1%). therefore, these observations seem to confirm the frequent involvement of various anatomical regions of ffa. in particular, eyebrow involvement could play a significant role in early diagnosis since, in many cases, thinning or loss of the eyebrows precedes the recession of the fronto-temporal hairline. eyebrows and body hair reduction/loss are often confused with age-related loss and seldom reported by patients themselves. thus, awareness of this sign possibly indicating ffa is important when considering differential diagnoses such as aa or aging [56]. moreover, the finding of non-inflammatory facial papules was described in 29.8% of patients, suggesting that this sign should always be sought in cases of suspected ffa. even if the clinical diagnosis is most often easy to perform, trichoscopy is a valid aid in milder cases and in evaluation of facial/body hair loss. trichoscopy is also a valid aid in the differential diagnosis with other diseases such as aga, traction alopecia or aa in which there is no scarring. interestingly, trichoscopic cicatricial signs were absent in a small percentage of patients, suggesting that ffa could likely begins as a non-scarring process. consequently, early treatment could partially recover damaged follicles. the presence of inflammatory signs such as perifollicular erythema and perifollicular hyperkeratosis were present in 63.8% and 60.1% of patients, respectively, and were associated with the presence of dysaesthetic sensations such as trichodynia and pruritus (p = 0.049). previous studies report that up to one-third of patients with ffa may have itching and, less frequently, trichodynia. however, our series revealed higher percentages of symptomatic subjects with 65.9% of patients complaining of itching and 22.9% reporting concomitant trichodynia. in most 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al. trichoscopic features of frontal fibrosing alopecia: results in 249 patients. j am acad dermatol. 2015;72(2):357-359. doi: 10.1016/j. jaad.2014.10.039. pmid: 25592346. 26. cervantes j, miteva m. distinct trichoscopic features of the sideburns in frontal fibrosing alopecia compared to the frontotemporal scalp. skin appendage disord. 2018;4(1):50-54. doi: 10.1159/000479116. pmid: 29457017; pmcid: pmc5806192. 27. anzai a, pirmez r, vincenzi c, fabbrocini g, romiti r, tosti a. trichoscopy findings of frontal fibrosing alopecia on the eyebrows: a study of 151 cases. j am acad dermatol. 2021;85(5):11301134. doi: 10.1016/j.jaad.2019.12.023. pmid: 31857108. 28. kurzeja m, czuwara j, walecka i, olszewska m, rudnicka l. features of classic lichen planopilaris and frontal fibrosing alopecia in reflectance confocal microscopy: a preliminary study. skin res technol. 2021;27(2):266-271. doi: 10.1111/srt.12940. pmid: 32743819. 29. vazquez-herrera ne, eber ae, martinez-velasco ma, et al. optical coherence tomography for the investigation of frontal fibrosing alopecia. j eur acad dermatol venereol. 2018;32(2):318-322. doi: 10.1111/jdv.14571. pmid: 28859221. 30. pindado-ortega c, saceda-corralo d, moreno-arrones óm, et al. effectiveness of dutasteride in a large series of patients with frontal fibrosing alopecia in real clinical practice. j am acad dermatol. 2021;84(5):1285-1294. doi: 10.1016/j.jaad.2020.09.093. pmid: 33038469. 31. ramos pm, anzai a, duque-estrada b, et al. risk factors for frontal fibrosing alopecia: a case-control study in a multiracial population. j am acad dermatol. 2021;84(3):712-718. doi: 10.1016/j.jaad.2020.08.076. pmid: 32835739. 32. mcsweeney sm, christou eaa, dand n, et al. frontal fibrosing alopecia: a descriptive cross-sectional study of 711 cases in female patients from the uk. br j dermatol. 2020;183(6):1136-1138. doi: 10.1111/bjd.19399. pmid: 32652611. 33. trager mh, lavian j, lee ey, et al. medical comorbidities and sex distribution among patients with lichen planopilaris and frontal fibrosing alopecia: a retrospective cohort study. j am acad dermatol. 2021;84(6):1686-1689. doi: 10.1016/j.jaad.2020.08.015. pmid: 32781188. 34. grassi s, tadiotto cicogna g, et al. frontal fibrosing alopecia and genital lichen sclerosus: single-center experience. j cosmet dermatol. 2021;20(2):615-620. doi: 10.1111/jocd.13573. pmid: 32590887. 35. papanikou s, xydeas-kikemenis a, nicolaidou e, et al. social status may interfere in the prognosis of frontal fibrosing alopecia in female patients: an observational study. skin appendage disord. 2019;5(6):355-358. doi: 10.1159/000501888. pmid: 31799262; pmcid: pmc6883467. 36. brenner fm, oldoni c. frontal fibrosing alopecia: epidemic? an bras dermatol. 2019;94(4):482. doi: 10.1590/abd18064841.20198300. pmid: 31644628; pmcid: pmc7007025. 37. vañó-galván s, saceda-corralo d, blume-peytavi u, et al. frequency of the types of alopecia at twenty-two specialist hair clinics: a multicenter study. skin appendage disord. 2019 aug;5(5):309-315. doi: 10.1159/000496708. pmid: 31559256; pmcid: pmc6751437. 38. kanti v, constantinou a, reygagne p, vogt a, kottner j, blume-peytavi u. frontal fibrosing alopecia: demographic and clinical characteristics of 490 cases. j eur acad dermatol venereol. 2019;33(10):1976-1983. doi: 10.1111/jdv.15735. pmid: 31179579. 39. moreno-arrones om, saceda-corralo d, rodrigues-barata ar, et al. factors influencing frontal fibrosing alopecia severity: a multicentre cross-sectional study. j eur acad dermatol venereol. 2019;33(9):e315-e316. doi: 10.1111/jdv.15590. pmid: 30895660. 40. moreno-arrones om, saceda-corralo d, rodrigues-barata ar, et al. risk factors associated with frontal fibrosing alopecia: a multicentre case-control study. clin exp dermatol. 2019;44(4):404410. doi: 10.1111/ced.13785. pmid: 30259544. 41. cranwell wc, sinclair r. sunscreen and facial skincare products in frontal fibrosing alopecia: a case-control study. br j dermatol. 2019;180(4):943-944. doi: 10.1111/bjd.17354. pmid: 30367472. 42. buendía-castaño d, saceda-corralo d, moreno-arrones om, et al. hormonal and gynecological risk factors in frontal fibrosing alopecia: a case-control study. skin appendage disord. 2018;4(4):274-276. doi: 10.1159/000484210. pmid: 30410895; pmcid: pmc6219213. 43. imhof rl, chaudhry hm, larkin sc, torgerson rr, tolkachjov sn. frontal fibrosing alopecia in women: the mayo clinic experience with 148 patients, 1992-2016. mayo clin proc. review | dermatol pract concept. 2022; 12(1):e2022080 9 2018;93(11):1581-1588. doi: 10.1016/j.mayocp.2018.05.036. pmid: 30392542. 44. saceda-corralo d, fernández-crehuet p, fonda-pascual p, pindado-ortega c, moreno-arrones om, vañó-galván s. clinical description of frontal fibrosing alopecia with concomitant lichen planopilaris. skin appendage disord. 2018;4(2):105-107. doi: 10.1159/000479799. pmid: 29765970; pmcid: pmc5939712. 45. pindado-ortega c, saceda-corralo d, buendía-castaño d, et al. frontal fibrosing alopecia and cutaneous comorbidities: a potential relationship with rosacea. j am acad dermatol. 2018;78(3):596-597.e1. doi: 10.1016/j.jaad.2017.09.004. pmid: 29447678. 46. donati a, gupta ak, jacob c, cavelier-balloy b, reygagne p. the use of direct immunofluorescence in frontal fibrosing alopecia. skin appendage disord. 2017;3(3):125-128. doi: 10.1159/000469665. pmid: 28879188; pmcid: pmc5582472. 47. moreno-arrones om, saceda-corralo d, fonda-pascual p, et al. frontal fibrosing alopecia: clinical and prognostic classification. j eur acad dermatol venereol. 2017;31(10):1739-1745. doi: 10.1111/jdv.14287. pmid: 28426907. 48. aldoori n, dobson k, holden cr, mcdonagh aj, harries m, messenger ag. frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study. br j dermatol. 2016;175(4):762-767. doi: 10.1111/ bjd.14535. pmid: 26987767. 49. vañó-galván s, molina-ruiz am, serrano-falcón c, et al. frontal fibrosing alopecia: a multicenter review of 355 patients. j am acad dermatol. 2014;70(4):670-678. doi: 10.1016/j. jaad.2013.12.003. pmid: 24508293. 50. dlova nc. jordaan hf, skenjane a,, khoza n, tosti a. frontal fibrosing alopecia: a clinical review of 20 black patients from south africa. br j dermatol. 2013;169(4):939-941. doi: 10.1111/ bjd.12424. pmid: 23647261. 51. navarro-belmonte mr, navarro-lópez v, ramírez-boscà a, et al. case series of familial frontal fibrosing alopecia and a review of the literature. j cosmet dermatol. 2015;14(1):64-9. doi: 10.1111/jocd.12125. pmid: 25614294. 52. ranasinghe gc, piliang mp, bergfeld wf. prevalence of hormonal and endocrine dysfunction in patients with lichen planopilaris (lpp): a retrospective data analysis of 168 patients. j am acad dermatol. 2017;76(2):314-320. doi: 10.1016/j. jaad.2016.05.038. pmid: 28088992. 53. samrao a, chew al, price v. frontal fibrosing alopecia: a clinical review of 36 patients. br j dermatol. 2010;163(6):1296-300. doi: 10.1111/j.1365-2133.2010.09965.x. pmid: 20698851. 54. moreno-ramírez d, camacho martínez f. frontal fibrosing alopecia: a survey in 16 patients. eur acad dermatol venereol. 2005;19(6):700-705. doi: 10.1111/j.1468-3083.2005.01291.x. pmid: 16268874. 55. ladizinski b, bazakas a, selim ma, olsen ea. frontal fibrosing alopecia: a retrospective review of 19 patients seen at duke university. j am acad dermatol. 2013;68(5):749-755. doi: 10.1016/j.jaad.2012.09.043. pmid: 23375454. 56. waśkiel-burnat a, rakowska a, kurzeja m, et all. the value of dermoscopy in diagnosing eyebrow loss in patients with alopecia areata and frontal fibrosing alopecia. j eur acad dermatol venereol. 2019;33(1):213-219. doi: 10.1111/jdv.15279. pmid: 30290016. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023134 1 investigation of the pd-1/pd-l1 expression in the lesional skins of patients with psoriasis selma emre1, nuran süngü2, yıldız hayran3, d deniz demirseren4, akın aktas1, tuce özkara duman1 1 yildirim beyazit university, medical school, department of dermatology, ankara, turkey 2 yildirim beyazit university, medical school, department of pathology, ankara, turkey 3 ministry of health, ankara city hospital, department of dermatology, ankara, turkey 4 university of health science, ankara city hospital, department of dermatology, ankara, turkey key words: autoimmunity, immunohistochemistry, pd1, pdl-1, psoriasis citation: emre s, süngü n, hayran y, demirseren dd, aktas a, duman tö. investigation of the pd-1/pd-l1 expression in the lesional skins of patients with psoriasis. dermatol pract concept. 2023;13(2):e2023134. doi: https://doi.org/10.5826/dpc.1302a134 accepted: november 17, 2022; published: april 2023 copyright: ©2023 emre et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: selma emre, yildirim beyazit university, medical school, department of dermatology, ankara city hospitals, orthopedics and neurology hospital, cankaya, ankara, turkey. orcid number: 0000-0001-5963-8939 e-mail: dr_semre@yahoo.com introduction: psoriasis is an immune-mediated, chronic and inflammatory disease whose pathogenesis is affected by the interactions of several immune cells and cytokines. pd-1 is an inhibitor receptor that is expressed to a large extent in t lymphocytes and responsible for regulating autoimmunity and self-tolerance. objectives: in this study, we aimed to investigate the expression of pd-1/pd-l molecules in the lesioned skins of psoriasis patients. methods: the study included 30 psoriasis patients, and 15 healthy volunteers as the control group. anti pd-1 and pd-l1 antibodies were applied to the skin biopsy samples that were collected from the patient and control groups. cytoplasmic and membranous staining of pd-1 and pd-l1 were considered positive. the number of stained immune cells that was examined for each case. results: the percentage of the tissues with high pd-1 (+) and pdl-1 (+) immune cell counts were significantly higher in the psoriasis patients compared to healthy controls (p values = 0.004 and 0.002, respectively). a negative and statistically significant correlation was detected between pdl-1(+) immune cell numbers and pasi scores (p = 0.033, r=-0.57). conclusions: in the lesioned skin samples of psoriasis patients, the pd-1 and pd-l1 expressions were significantly higher in immune cells than that in the skin samples of the healthy controls. this study was the first investigation of the expression of pd-1/pd-l molecules in the immune cells in found the lesioned skins of psoriasis patients. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023134 introduction psoriasis is an immune-mediated, chronic and inflammatory disease whose pathogenesis is affected by the interactions of several immune cells and cytokines. over the last two decades, highly significant advancements have been achieved regarding the pathogenetic mechanisms of psoriasis where t helper 1 (th1) and th 17 lymphocytes play a major role [1].1 recently, new molecules and pathways responsible for regulating autoimmunity and tolerance have been defined. one of these molecules, programmed death-1 (pd-1) (cd279) is an immune check point that sends inhibitor signals to the immune system to maintain a balance between t cell activation and self-tolerance in peripheral tissues. pd-1 is an inhibitor receptor in the form of a transmembrane glycoprotein that belongs to the cd28/ctla-4 family with the weight of 50-55 kda. pd-1 is expressed in active t cells, b cells, thymocytes, natural killers (nk) and double negative thymocytes (cd4ˉcd8ˉ). pd-1 has two ligands: inhibitor signals are achieved by the bonding of pd-1 to its ligands – pd-1 ligand 1 (pd-l1) and pd-1 ligand 2 (pd-l2). while pd-l1 is widely expressed in t cells, b cells, macrophages and dendritic cells, pd-l2 is expressed in active macrophages and dendritic cells. the pd-1/pd-l pathway participates in the pathogenesis of autoimmune diseases. signals that are generated by pd-1 and its ligands, pd-l1 and pd-l2, regulate central and peripheral tolerance by means of several mechanisms [2-4]. in experimental autoimmunity and pathogenic polymorphism models, it was seen that a decrease in the expression of pd-1 and its ligands is associated with some autoimmune disorders such as type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and encephalomyelitis [2,3]. regulatory t-cells (treg) is a t-cell subtype responsible for suppressing the immune response and maintaining immune tolerance. pd-1 surface molecules on the surface of treg cells play a key role in immune tolerance. pd-1 binds to pd-l1, inhibiting the function of the effector t-cells and supporting the treg cells activity. likely to be dysfunctional in psoriatic patients, t-cell surface molecules are unable to inhibit the activity of the inflammatory cells [4,5]. in addition, the pd-1 and pdl-1 pathways are among the most important mechanisms in tumor cells escape from the immune system. pd-l1 expression of tumors is a key determinant of the response to immune check point inhibitors. it was reported that, in patients treated with anti-pd-1 molecules, eczema, lichenoid dermatoses, vitiligo and psoriasis lesions emerged, or previously existing psoriasis became more severe [7-9]. the fact that anti-pd-1/pd-l1 antibodies trigger psoriasis suggests that pd-1 and pd-l1 pathways are somehow involved in the pathogenesis of psoriasis. few studies have investigated the expression of pd-1 and pd-l in the t lymphocytes of the peripheral blood of psoriasis patients. even fewer studies investigate the expression of pd-1 and pd-l1 in the lesional skins of psoriatic patients. objectives in this study, we aimed to investigate the expression of pd-1/pd-l molecules in the lesional skins of psoriasis patients. methods thirty psoriasis patients aged between 18 and 70 years who were admitted to the dermatology outpatient clinic were included in the study. skin biopsy specimens of the patients who were histopathologically diagnosed with psoriasis, and had the appropriate characteristics for the study, were included in the immunohistochemical study. those who had another autoimmune disease such as type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, vitiligo, alopecia areata or encephalomyelitis were excluded. none of the patients included in the study, had any malignity or was being treated with anti-pd-1 molecules for malignity. intact skin biopsy samples of healthy volunteers aged 19 to 60 years who did not have any disease were included in the study as the control group. all participants were informed about the study and their written consent was obtained prior to their enrollment in the study. before starting the study, approval was received from the local ethics board of our hospital with the decision date 05.03.2018 and number 52. the skin biopsy samples collected from the patients were put into formalin solutions. after formaldehyde fixation, the tissues were embedded in paraffin. four cross-sections were taken from the paraffin blocks. one of the cross-sections was stained with h&e. the diagnosis of psoriasis was histopathologically confirmed by the h&e cross-sections. immunohistochemical study procedure all cases were applied, a 1/250 dilution rate of anti pd-1 antibody (ab137132, abcam), 1/200 dilution rate of anti pd-l1 antibody (ab205921, abcam) and 1/100 dilution rate of anti pd-l2 antibody (ab200377, abcam). from the formalin-fixed paraffin blocks, 3-4-μ-thick sections were prepared on slides coated with poly-l-lysine. the cross-sections were left overnight in a stove at 37-40 °c, and in the morning, they were kept in a stove at 65 °c for 45 minutes so that the paraffin could melt. the cross sections were then kept in xylol for 20 minutes to deparaffinize. they were rehydrated in alcohol and hydrated in distilled water. original article | dermatol pract concept. 2023;13(2):e2023134 3 in the immunohistochemical staining process that was carried out using a leica bond-max automated immunohistochemical staining device, the slides were boiled in water containing a citrate buffer (ph 6.0) solution at 95-99 °c for 10 minutes to recover the antigen before applying the antibody. they were then left to cool at room temperature for 15-20 minutes. the slides were washed with distilled water, treated with 3% hydrogen peroxide for 15 minutes at room temperature to block endogenous peroxidase activity, and put in distilled water once more. superblock was dripped on the cross-sections which were washed with pbs (0.01 m phosphate buffer saline) and left for 3-5 minutes. then, primary antibodies were dripped on the cross sections, which were left for 30-45 minutes. following the pbs washing process, the cross-sections were kept at room temperature for 20 minutes by dripping biotinylated secondary antibodies, and then, washed with pbs for 5 minutes. conjugated streptavidin enzyme was dripped on the cross-sections, which were kept at room temperature for 10 minutes, and washed again with pbs. later, dam chromogen was dripped, and the cross-sections were washed with distilled water. following a preliminary staining with harris hematoxylin for 10 seconds, and washing with distilled water, the slides were dried by dipping into alcohol and coated with balm. analysis of the immunohistochemical study results anti pd-1 and pd-l1 antibodies were applied on the cross-sections obtained from the prepared paraffin blocks. cytoplasmic and membranous staining of pd-1 and pd-l1 was considered positive. the number of the stained immune cells was examined, counted and recorded for each case. additionally, tissues were divided into two groups according to their pd-1 and pd-l1 positive immune cell counts: tissues with low pd-1 and pd-l1 (+) immune cell counts (number of pd-1 and pd-l1 positive immune cell <10) and tissues with high pd-1 and pd-l1 (+) immune cell counts (number of pd-1 and pd-l1 positive immune cells ≥10) statistical analyses all statistical analyses were conducted using ibm statistical package for the statistical package for the social sciences (spss) version 23.0 (ibm spss corp.). categorical variables were presented as frequency and percentage. visual methods, kolmogorov–smirnov test and shapiro-wilk test were used to evaluate if the numerical variables were normally distributed. normally distributed variables were presented as mean (standard deviation, sd) and continuous variables which were not normally distributed were presented as median (interquartile range, iqr). categorical variables were analyzed using chi-squared test or fischer exact and numerical variables were analyzed using student t-test or mann–whitney u test. spearman and pearson tests were used to evaluate the correlations of continuous variables. the level of statistical significance was accepted as p < 0.05. results among the patients in the study, 22 were male, 8 were female. among the individuals in the control group, 13 were female, 2 were male. the mean age of the patients was 40.07 ± 16.99, the mean age of the control group was 44.13 ± 12.35, and there was no significant difference between the groups in terms of age (p = 0.415) (table 1). for all the samples studied, only the immune cells in the dermis showed positive staining with pd-1 and pdl-1. epidermis did not show any staining. 86.7% of the psoriasis patients had high pd-1 (+) immune cell counts (figure 1). in the control group, 40% of the tissues had high pd-1 (+) immune cell counts, which was significantly lower than the table 1. basic characteristics of patient and control groups, comparison of pd-1 and pdl-1 results. patients (n = 30) controls (n = 15) p age (years, mean ± sd) 40.07±16.99 41.13±12.35 0.415 gender (n (%)) female male 8 (26.7) 22 (73.3) 13 (86.7) 2 (13.3) <0.001 pasi (median (iqr)) 5.4 (4.6-6.9) disease duration (years, median (iqr)) 2 (1.5-9) pd-1 positive cell number (n (%)) low (<10) high (≥10) 4 (13.3) 26 (86.7) 9 (60) 6 (40) 0.004 pdl-1 positive cell number (n (%)) low (<10) high (≥10) 17 (56.7) 13 (43.3) 15 (100) 0 (0) 0.002 iqr = interquartile range; pasi: psoriasis area and severity index; sd = standard deviation. 4 original article | dermatol pract concept. 2023;13(2):e2023134 while stimulation of the pd-1 pathway inhibited the th-1/ th17-mediated cutaneous reactions [6,11]. high-affinity anti-pd-1 or anti-pd-l1 monoclonal antibodies that block the pd-1 and pd-l1 interaction may eliminate the control mechanism over t cells by reversing the immune control point. in recent years, anti-pd-1 antibodies have been used in cancer treatment, controlling tumor progression and mobilizing the immune system. using anti-pd-1 antibodies for treatment has brought about some side effects. skin toxicity is the most frequently observed side effect encountered in anti-pd-1 treatments. some skin diseases such as vitiligo, photosensitivity, lichenoid eruption and psoriasis were triggered in patients, on whom the anti-pd-1 antibody was used. in the literature, lichenoid reactions, eczema, pruritus and vitiligo are reported as the most frequently encountered cutaneous side effects [7,9,12,13]. psoriasis is a well-established side effect secondary to pd-1 and pdl1 blockade, and the number of anti-pd-1-induced psoriasis cases in the literature continues to increase [8,14-17]. how the pd-1/pd-l1 pathway affects psoriasis or other skin diseases is unknown. in patients receiving anti-pd-1 therapy, pd-1 blockade may be inducing a pro-inflammatory th-1/th-17 response by increasing interferon-gamma, tumor necrosis factor-alpha (tnf-alpha), and il-2, il-6, and il-17 [17]. psoriasis patients (p = 0.004). similarly, the percentage of the tissues with high pdl-1 (+) immune cell counts was significantly higher in the psoriasis patients compared to healthy controls (43.3% versus 0%, p = 0.002) (figure 2). the median pasi score was calculated as 5.4 (iqr: 4.6-6.9) and the median disease duration was 2 years (iqr: 1.5-9). a negative and statistically significant correlation was detected between pasi scores and pdl-1 (+) immune cell counts (p = 0.033, r = -0.57). there was no significant correlation between pasi scores and pd-1 (+) immune cell counts (p = 0.51, r = -0.19). disease duration did not correlate with the pd-1 (+) immune cell counts or pdl-1 (+) immune cell counts (p = 0.43, r = 0.29; p = 0.61, r = 0.19, respectively). among psoriasis patients, one patient had pustular psoriasis, one had guttate and one had palmoplantar psoriasis. all three patients had high pd-1 (+) immune cell counts however pdl-1 (+) immune cell counts differed with subtype. patient with pustular psoriasis had high pdl-1 (+) immune cell counts whereas patients with guttate and palmoplantar psoriasis had low pdl-1 (+) immune cell counts. conclusions pd-1 is an inhibitor receptor that is highly expressed in t lymphocytes. when the pd-1 pathway is activated, its inhibiting effect on the immune system emerges [10]. it was reported in previous studies that the pd-1 signal pathway regulates the production of cytokines such as inf, il-2, il-17, and tnf-α, thus regulating the axes of pd-1, th1, and th17. in murine models, pd-1 deficiency induced psoriasiform dermatitis figure 1. positive staining of more than 10 cells is present in the immune cells in the upper dermis under the epidermis (pd-1, x400). figure 2. positive staining is present in more than 10 cells in the immune cells of the upper dermis under the epidermis (pd-l1, x400). original article | dermatol pract concept. 2023;13(2):e2023134 5 in our study, we examined pd-1 and pd-l1 expression in the immune cells in the epidermis and dermis. there was no pd-l1 and pd-1 expression in the keratinocytes in psoriatic skin and healthy controls. in patient group, we found the pd-1 and pd-l1 expression in the immune cells in the dermis of psoriatic skin to be significantly higher in comparison to the healthy controls. since pd-1 is an inhibitor co-receptor in the immune system, it may seem unreasonable that its expression increases in autoimmune diseases, whereas studies in autoimmune diseases including sle and rheumatoid arthritis show that the pd-1/pd-l1 pathway is modulated under the permanent chronic inflammation conditions [5]. it is reported that t-cells express higher amounts of pd-1 in autoimmune diseases, neoplasms and chronic infections, limiting the protective immunity. in addition, since pd-1 is also a marker of the t-cell activation, it is not surprising to see that it is increased in psoriatic lesions [23]. in this study, we also evaluated the association of clinical features such as disease duration and pasi scores of psoriasis patients with pd-1 and pd-l1 expressions. our results showed a significant negative correlation between pdl-1 (+) immune cell counts and pasi. pdl-1 (+) immune cell counts did not correlate with disease duration. pd-1 (+) immune cell counts did not correlate with pasi or disease duration. few studies investigated the association of clinical features with pd-1 and pd-l1 expressions. in the study by peled et al, no statistically significant correlation was shown among the percentage of pd-1 expressing t cells and pasi scores of patients but the percentage of pd-1 expressing t cells negatively correlated with psoriatic arthritis articular disease activity [10]. jung et al showed that psoriasis patients with high epidermal pd-1 expression had higher pasi scores and longer disease durations [20]. however, dermal pd-1 expression and disease duration had an opposite relationship. psoriasis patients with lower pd-1 expressions had longer disease durations. dermal pd-1 expression did not correlate with pasi. these differences between the results of the studies may be due to the small number of patients included in the studies, the fact that the presence of psoriatic arthritis was not considered in every study, different sides of the pd-1 and pdl-1 positivity (epidermal or dermal area), and the low pasi scores of the patients included in the studies. this study showed that, the pd-1 and pd-l1 expressions in immune cells in the lesioned skin samples of psoriasis patients are significantly higher than that in the skin samples of healthy controls. previous studies and our study are preliminary studies with small numbers of patients with psoriasis. to the best of our knowledge, the present study is one the first investigations of the expression of pd-1/pd-l molecules in the immune cells in the lesioned skins of psoriasis patients. the role that the degradation of the pd-1/pd-l1 axis plays in psoriatic patients is backed by evidence. however, there is a few studies have been conducted to investigate pd-1 and pd-l1 expression in the t lymphocytes in the peripheral blood of psoriasis patients. bartosinska et al examined the pd-1 expressions in the cd4+ and cd8+ t-cells in the peripheral blood samples of the patients with psoriasis and psoriatic arthritis [18]. they concluded that the pd-1 expression in the cd4+ and cd8+ t lymphocytes of the patient group was significantly lower than the controls. the authors argued that reduced pd-1 expression may be responsible for immune dysregulation in the pathogenesis of psoriasis. in a later study of theirs, bartosinska et al reported that there was no difference between psoriatic patients with and without psoa in terms of cd4+ and cd8+ t lymphocytes pd-1 in peripheral blood, and both groups had lower cd4+ and cd8+ pd-1 levels than the healthy controls [19]. the authors stated that, regardless of the clinical type, mutual inflammatory pathways and mediators play a role in psoriasis. in contrast, peled et al reported that the pd-1 expression in the t lymphocytes in the peripheral blood of psoriatic arthritis patients was significantly higher than the healthy controls [10]. they showed that this was correlated with the activity of arthritis. the authors argued that pd-1 could be a marker that shows psoriatic arthritis activity. bommarito et al showed that rheumatoid arthritis (ra) and psoriatic arthritis (psoa) patients had an increased expression of pd1 on their cd4+ and cd8+ t cells in their peripheral blood and sinovial fluids [20]. the authors showed that il-1β, il-6, and tnf-α raised the soluble pd-1 levels, and that increased expression of soluble pd-1 interfered with the pd-1/pd-l1 pathway. few studies investigate the pd-1 and pd-l1 expression in the lesional skins of psoriatic patients and reported variable results. kim et al showed that the pd-l1 expression in keratinocytes in psoriatic epidermis was significantly reduced compared to normal skin, pityriasis rosea, liken planus and allergic contact dermatitis epidermis samples [21]. the authors suggested that t cell activation was not suppressed due to the reduced pd-l1 and 2 in psoriasis. on the other hand, jung et al. [20] reported that among the chronic plaque-type psoriatic patients, the group with a higher pd-1 in epidermis had a higher pasi score and more typical histopathological changes than the lower pd-1 expression group. authors suggested that epidermal pd-1 upregulation in chronic plaque psoriasis is correlated with a more chronic and severe disease. they showed that guttate psoriatic patients with a longer disease duration had a lower dermal pd-1 expression than those with a shorter disease duration, and downregulated dermal pd-1 expression is correlated with a poorer prognosis in guttate psoriasis. çetinözman, et al also found increased levels of pd-1 in the cd8+ t-cells in the epidermis and dermis of the skin biopsies taken from the lesions of 6 patients with psoriatic erythroderma [22]. 6 original article | dermatol pract concept. 2023;13(2):e2023134 11. fujiwara h, maeda y, kobayashi k, et al. programmed death-1 pathway in host tissues ameliorates th17/th1-mediated experimental chronic graft-versus-host disease. j immunol. 2014;193(5):2565-2573. doi: 10.4049/jimmunol.1400954. pmid: 25080485. 12. hwang sje, carlos g, wakade d, et al. cutaneous adverse events (aes) of anti-programmed cell death (pd)-1 therapy in patients with metastatic melanoma: a single-institution cohort. j am acad dermatol. 2016;74(3):455-461.e1. doi: 10.1016/j. jaad.2015.10.029. pmid: 26793994. 13. sibaud v. dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. am j clin dermatol. 2018;19(3):345-361. doi: 10.1007/s40257-017-0336-3. pmid: 29256113. 14. voudouri d, nikolaou v, laschos k, et al. anti-pd1/pdl1 induced psoriasis. curr probl cancer. 2017;41(6):407-412. doi: 10.1016/j.currproblcancer.2017.10.003. pmid: 29096940. 15. kato y, otsuka a, miyachi y, kabashima k. exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. j eur acad dermatol venereol. 2016;30(10):e89-e91. doi: 10.1111/jdv.13336. pmid: 26388113. 16. elousa-gonzalez m, pampin-franco a, mazzuchelli-esteban r, et al. a case of de novo palmoplantar psoriasis with psoriatic arthritis and autoimmune hypothyroidism after receiving nivolumab therapy. dermatol online j. 2017;23(8):13030/qt12n4m6pm. pmid: 29469753. 17. ellis s, vierra at, millsop jw, lacouture me, kiuru m. dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features. j am acad dermatol. 2020;83(4):1130-1143. doi: 10.1016/j.jaad.2020.04.105. pmid: 32360716. pmcid: pmc7492441. 18. bartosinska j, zakrzewska e, raczkiewicz d, et al. suppressed programmed death 1 expression on cd4+ and cd8+ t cells in psoriatic patients. mediators inflamm. 2017;2017:5385102. doi: 10.1155/2017/5385102. pmid: 29180838. pmcid: pmc5664337. 19. bartosinska j, zakrzewska e, purkot j, et al. decreased blood cd4+pd-1+ and cd8+pd-1+ t cells in psoriatic patients with and without arthritis. postepy dermatol alergol. 2018;35(4):344-350. doi: 10.5114/ada.2018.75609. pmid: 30206445. pmcid: pmc6130132. 20. jung cj, yang hj, bang sh, et al. clinicoprognostic and histopathological features of guttate and plaque psoriasis based on pd-1 j clin med. 2021;10(21):5200. doi: 10.3390/ jcm10215200. pmid: 34768720. pmcid: pmc8584888. 21. kim ds, je jh, kim sh, et al. programmed death-ligand 1, 2 expressions are decreased in the psoriatic epidermis. arch dermatol res. 2015 aug;307(6):531-8. doi: 10.1007/s00403-0151588-5. epub 2015 jul 2. pmid: 26133691. 22. çetinözman f, jansen pm, willemze r. expression of programmed death-1 skin biopsies of benign inflammatory vs. lymphomatous erythroderma. br j dermatol. 2014;171(3):499-504. doi: 10.1111/bjd.12934. pmid: 24601935. 23. bommarito d, hall c, taams ls, corrigall vm. inflammatory cytokines compromise programmed cell death-1 (pd-1)-mediated t cell suppression in inflammatory arthritis through up-regulation of soluble pd-1. clin exp immunol. 2017;188(3):455-466. doi: 10.1111/cei.12949. pmid: 28245522. pmcid: pmc5422858. not ample evidence and the results of the present study are not sufficient for a thorough understanding of the subject matter. for a better understanding of this subject, it is necessary to investigate the pd-1 and pd-l1 expressions in psoriasis patients with reference to the studies conducted with more patients and employing more detailed research designs. we believe that this may unearth new pathways in the pathogenesis of psoriasis. in the future, medications modulating the function of the pd-1/pd-l1 pathway may emerge as a promising option in the treatment of psoriasis. pd-1 and pd-l1 expressions in the immune cells in the psoriatic skin are significantly higher in comparison to the healthy controls. increased immune system activity in the psoriatic lesions may trigger pd-1 and pd-l1 expression in the immune cells of the lesioned skin. references 1. mahil sk, capon f, barker jn. update on psoriasis immunopathogenesis and targeted immunotherapy. semin immunopathol. 2016;38(1):11-27. doi: 10.1007/s00281-015-0539-8. pmid: 26573299. pmcid: pmc4706579. 2. zamani rm, aslani s, salmaninejad a, javan mr, rezaei n. pd-1/pd-l and autoimmunity: a growing relationship. cell immunol. 2016;310:27-41. doi: 10.1016/j.cellimm.2016.09.009. pmid: 27660198. 3. keir me, liang sc, guleria i, et al. tissue expression of pd-l1 mediates peripheral t cell tolerance. j exp med. 2006;203(4):883-895. doi: 10.1084/jem.20051776. pmid: 16606670. pmcid: pmc2118286. 4. hamza a, roberts d, su s, weber rs, bell d, ferrarotto r. pd-l1 expression by immunohistochemistry in salivary duct carcinoma. ann diagn pathol. 2019;40:49-52. doi: 10.1016/j.anndiagpath.2019.04.001. pmid: 30978575. pmcid: pmc6599643. 5. adamczyk m, krasowska d. pd1/pd-l1 pathway in psoriasis and psoriatic arthritis: a review. postepy dermatol alergol. 2021;38(6):925-930. doi: 10.5114/ada.2021.112274. pmid: 35125995. pmcid: pmc8802966. 6. sharpe ah, pauken ke. the diverse functions of the pd1 inhibitory pathwaynat rev immunol. 2018;18(3):153-167. doi: 10.1038/nri.2017.108. pmid: 28990585. 7. belum vr, benhuri b, postov ma, et al. characterisation and management of dermatologic adverse to events to agents targeting the pd-1 receptor. eur j cancer. 2016;60:12-25. doi: 10.1016/j. ejca.2016.02.010. pmid: 27043866. pmcid: pmc4998047. 8. bonigen j, raynaud-donzel c, hureaux j, et al. anti-pd1-induced psoriasis: a study of 21 patients. j eur acad dermatol venereol. 2017;31(5):e254-e257. doi: 10.1111/jdv.14011. pmid: 27739129. 9. sibaud v, meyer n, lamant l, vigarios e, mazieres j, delord jp. dermatologic complications of anti-pd-1/pd-l1 immune checkpoint antibodies. curr opin oncol. 2016;28(4):254-263. doi: 10.1097/cco.0000000000000290. pmid: 27136138. 10. peled m, strazza m, azoulay-alfaguter i, mor a. analysis of programmed death-1 in patients with psoriatic arthritis. inflammation. 2015;38(4):1573-1579. doi: 10.1007/s10753015-0132-2. pmid: 25663558. dermatology: practical and conceptual letter to editor | dermatol pract concept. 2023;13(1):e2023005 1 high-risk genital-mucosal human papilloma virus types 58 and 59 associated with solitary angiokeratoma on the elbow geeti khullar1, mithilesh chandra2, deepti agarwal2, aradhana bhargava1 1 department of dermatology and sexually transmitted diseases, vardhman mahavir medical college and safdarjung hospital, new delhi, india 2 pathology consultancy services, uttar pradesh, india key words: human papilloma virus 58, human papilloma virus 59, high-risk, genital-mucosal, angiokeratoma citation: khullar g, chandra m, agarwal d, bhargava a. high-risk genital-mucosal human papilloma virus types 58 and 59 associated with solitary angiokeratoma on the elbow. dermatol pract concept. 2023;13(1):e2023005. doi: https://doi.org/10.5826/dpc.1301a5 accepted: april 25, 2022; published: january 2023 copyright: ©2023 khullar et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: geeti khullar, department of dermatology and sexually transmitted diseases, vardhman mahavir medical college and safdarjung hospital, new delhi-110029, india. phone+91-9592818474 e-mail: geetikhullar@yahoo.com to the editor, human papilloma viruses (hpvs) are associated with a wide spectrum of cutaneous and mucosal infections and neoplasms. though angiokeratoma can clinically mimic warts, koilocytes and presence of high-risk hpv dna have not been reported in angiokeratoma. we describe a case of extragenital solitary angiokeratoma associated with high-risk types of hpv in a child. a 10-year-old girl presented with two-year history of an asymptomatic bluish-black plaque on the left elbow. there was no history of preceding trauma, bleeding from the lesion or immunosuppression. cutaneous examination revealed a well-circumscribed dark blue to black colored verrucous plaque of size 2.5 x 1.5 cm on the left elbow (figure 1a). dermatoscopic examination showed dark blue, violaceous and black colored round to ovoid lacunae with bluish-white veil (figure 1b). excisional biopsy revealed hyperkeratosis, hypergranulosis, acanthosis and papillomatosis. numerous keratinocytes with raisinoid nuclei and perinuclear halo, characteristic of koilocytes were seen in stratum spinosum. multiple thin-walled dilated vascular channels filled with erythrocytes were noted in papillary dermis (figures 1c, 1d). hpv genotyping was performed with extracted dna from biopsy tissue using applied biosystem 7500 fast dx real-time polymerase chain reaction (pcr) instrument. target dna was amplified for identifying either high-risk hpv (hpv types 16/ 18/ 31/ 33/ 35/ 39/ 45/ 51/ 52/ 56/ 58/ 59/ 66 and 68) or low-risk hpv genotypes (hpv 6/11) respectively. test results identified hpv high-risk genotypes in the sample. trupcr high risk genotyping kit designed to qualitatively detect dna of high-risk hpv of 14 genotypes by amplifying e6/ e7 region by primers and probes specific for the particular genotype by real time pcr confirmed the presence of hpv-58 and hpv-59 genotypes (cycle threshold values 30.32 and 25.94 respectively), with a cut off value of 36 (figures 2 a and b). 2 letter to editor | dermatol pract concept. 2023;13(1):e2023005 the role of hpv in the pathogenesis of non-melanoma skin cancers was initially described in epidermodysplasia verruciformis and transplant recipients. high-risk types, mainly hpv 16, are strongly linked with anogenital carcinomas and among cutaneous lesions, implicated in bowen’s disease and squamous cell carcinoma (scc) [1]. high-risk genital-mucosal hpv 58 and hpv 59 are risk factors for cervical carcinoma and uncommonly detected in cutaneous lesions [2-4]. hpv 58 has been identified in cutaneous premalignant and malignant lesions including, bowen disease on the fingers and elbow, scc and keratoacanthoma [2,3]. hpv 59 genome is most closely figure 1. (a) well-circumscribed bluish-black verrucous plaque of size 2.5 x1.5 cm. (b) dermoscopic examination revealed dark blue, violaceous and black round to ovoid lacunae with bluish-white veil (dermlite 4, original magnification x10). (c) there is marked hyperkeratosis, hypergranulosis, acanthosis and papillomatosis. papillary dermis shows thin-walled dilated vascular channels impinging onto the overlying epidermis (h&e, x100). (d) stratum spinosum showing koilocytes characterized by raisinoid nuclei and perinuclear halo (h&e, x200). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 34 36 37 38 39 40 internal control hpv 58 hpv 59 1.000e+007 1.000e+006 1.000e+005 1.000e+004 1.000e+003 1.000e+002 1.000e+001 1.000e+000 cycle number d el ta r n a figure 2. (a) real-time polymerase chain reaction amplification plot showing curves of 14 high risk genotypes, with hpv-58 and hpv-59 dna amplification curves above the cycle threshold value. (b) cycle threshold (ct) values for 14 high risk genotypes (cut-off value = 36) obtained by performing real-time polymerase chain reaction of dna isolated from skin biopsy sample letter to editor | dermatol pract concept. 2023;13(1):e2023005 3 related to hpv 18, and has been reported in bowen disease [4]. hpv infection associated with angiokeratoma has been described in a case presenting on vulva with coexisting positivity for hpv-6 [5]. high-risk genital-mucosal hpv types have not been associated with angiokeratoma. hpv proteins may promote cell proliferation through many signal transduction pathways. the reactive inflammation associated with viral infection results in tumor necrosis factor (tnf)-α production, which in turn stimulates the release of nf-ϗb. the latter induces production of vascular endothelial growth factor, causing vascular ectasia [6]. our patient had angiokeratoma on elbow, without any present or past history of anogenital lesions. interestingly, koilocytes were noted and pcr demonstrated hpv-58 and hpv-59 genotypes. the mode of acquisition of hpv infection in our case could be close contact with some family member having hpv infection. the limitation of this report is we did not assess the presence of hpv in healthy samples of perilesional and distant skin. it remains to be determined, whether hpv merely occurs as a commensal infection due to ubiquitous presence or is related to disease pathogenesis in angiokeratoma. nonetheless, detection of high-risk hpv types warrants close follow-up for malignant transformation. references 1. aoki r, clanner-engelshofen bm, charnowski s, ruzicka t, reinholz m. distribution of high-risk alpha-genus human papillomavirus genotypes impacts cutaneous neoplasms. j eur acad dermatol venereol. 2019;33(7):1304-1311. doi: 10.1111/jdv.15547. epub 2019 apr 10. pmid: 30835882. 2. mitsuishi t, kawashima m, matsukura t, sata t. human papillomavirus type 58 in bowen’s disease of the elbow. br j dermatol. 2001;144(2):384–386. doi: 10.1046/j.1365-2133.2001.04033.x. pmid: 11251579. 3. kobayashi k, tanese k, kubo a, et al. identification of a human papillomavirus type 58 lineage in multiple bowen’s disease on the fingers: case report and published work review. j dermatol. 2018;45(10):1195-1198. doi: 10.1111/1346-8138.14574. pmid: 30035309. 4. murao k, kubo y, fukuhara k, matsumoto k, arase s. three cases of bowen’s disease on the lower abdomen associated with high-risk types 16, 33, and  59  of  human  papillomavirus. j am acad dermatol. 2005;52(4):723-724. doi: 10.1016/j.jaad.2004.11.042. pmid: 15793544. 5. baruah j, roy kk, rahman sm, kumar s, pushparaj m, mirdha ar. angiokeratoma of vulva with coexisting human papilloma virus  infection: a case report. arch gynecol obstet. 2008;278(2): 165-167. doi: 10.1007/s00404-007-0539-6. pmid: 18193251. 6. molho-pessach v, lotem m. viral carcinogenesis in skin cancer. curr probl dermatol. 2007;35:39-51. doi: 10.1159/000106409. pmid: 17641489. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022132 1 lymphoma developing in a patient with long-term antitumor necrosis factor therapy giovana serrão fensterseifer1, andré carvalho2, ana letícia boff3, joel schwartz4 1 dermatologist at private practice, dermatologist at dermatology department at hospital são lucas da pucrs, porto alegrebrazil 2 dermatologist at private practice, dermatologist at hospital moinhos de vento, porto alegrebrazil 3 pathologist at private practice, pathologist at dermatology department at santa casa de misericórdia de porto alegre, porto alegrebrazil 4 dermatologist at private practice, porto alegrebrazil key words: lymphoma, antitnf, adalimumab, psoriasis citation: fensterseifer gs, carvalho a, boff al, schwartz j. lymphoma developing in a patient with long-term antitumor necrosis factor therapy. dermatol pract concept. 2022;12(3):e2022132. doi: https://doi.org/10.5826/dpc.1203a132 accepted: december 6, 2021; published: july 2022 copyright: ©2022 fensterseifer et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: giovana serrão fensterseifer, md, rua professor langendonck, 117. porto alegrebrazil, +55 51 99240-4660, e-mail: gfensterseifer@gmail.com dermatology practical & conceptual introduction some studies have shown that tumor necrosis factor (tnf) alfa inhibitor therapy may increase the risk of lymphomas [1]. it is historically known that psoriasis can also increase the risk of cutaneous lymphomas. here we present a case of a primary cutaneous anaplastic large cell lymphoma in a patient under treatment with adalimumab for psoriasis and psoriatic arthritis. case presentation patient presented to the clinic with a shallow one-month ulcerative lesion, with infiltrated borders on the buttock. the patient had been on adalimumab for, approximately, the last 10 years due to psoriasis and psoriatic arthritis (figure 1). a biopsy was performed for histopathology and immunohistochemistry analysis. the report showed cohesive sheets of large cd30-positive anaplastic cells confirming the figure 1. ulcer on the buttock. 2 research letter | dermatol pract concept. 2022;12(3):e2022132 diagnosis of cd30+ anaplastic t-cell lymphoma. staging determined a cutaneous primary lymphoma with no other organs involved. the patient is currently under treatment for the disease (figure 2). conclusions studies have shown that the most common lymphoma subtype associated with anti-tnf therapy is non-hodgkin b-cell lymphoma [1]. in the other hand, it is known that psoriasis itself can increase the risk of cutaneous lymphoma. in this case, t-cell lymphoma is the most associated lymphoma subtype, mainly mycosis fungoides. our patient presented a primary cutaneous anaplastic large cell lymphoma. this subtype of cutaneous t-cell lymphoma usually presents as a solitary nodule that often develops ulceration, as presented in this case. the prognosis is usually favorable with extracutaneous dissemination occurring in approximately 10% of the patients. radiotherapy is usually the initial choice of treatment, but chemotherapy could also be considered. more recently, a study by langley et al stated that longer-term (≥ 12 months) treatment with a tnf alfa inhibitor, but not shorter-term treatment, was associated with increased risk figure 2. (a) histopathology shows (x10) an acanthotic epidermis and a diffuse infiltrate of lymphocytes and some neutrophils on the dermis. (b) histopathology shows (x40) a diffuse lymphocyte infiltrate with irregularly shaped nuclei, prominent nucleoli and abundant cytoplasm. (c) immunohistochemistry shows cd3 positive lymphocytes. (d) immunohistochemistry shows diffuse and strong positivity for cd30 on neoplastic cells. for malignancy [2]. the patient presented here had been under treatment for, approximately, 10 years. in conclusion, studies are controversial regarding if there is an increased risk of malignancy due to anti-tnf alfa therapy, with a tendency of relating it to the duration of the treatment. we presented a case of a patient with a longterm treatment with adalimumab for psoriasis and psoriatic arthritis who developed a cutaneous lymphoma. further studies are needed to determine the risk of lymphomas in patients with long term anti-tnf therapy, but physicians should remain aware of this possibility when following patients under this treatment. references 1. wong ak, kerkoutian s, said j, rashidi h, pullarkat st. risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies. clin rheumatol. 2012;31(4):631-636. doi: 10.1007/ s10067-011-1895-y. pmid: 22147207.2. fiorentino d, ho v, lebwohl mg, et at. risk of malignancy with systemic psoriasis treatment in the psoriasis longitudinal assessment registry. j am acad dermatol. 2017;77(5):845-854. doi: 10.1016/j. jaad.2017.07.013. pmid: 28893407. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2013;3(4):14 55 introduction the desmogleins are a family of cadherins cell-cell adhesion molecules consisting of proteins dsg1, dsg2, dsg3, and dsg4. they play a role in the formation of desmosomes, which form the major types of intercellular adhesive junctions. dsgs are currently thought to be involved in autoimmune diseases, infectious diseases, and inherited diseases. patients with pemphigus, an autoimmune blistering disease of the skin and mucous membranes, carry igg autoantibodies directed against dsg1 and dsg3 [1]. pemphigus vulgaris antigen is also considered a tissue-specific type of desmoglein [1]. case presentation a 67-year-old japanese woman noted an erosive lesion on the median side of the soft palate four months earlier and was referred to the department of oral surgery for suspected pemphigus vulgaris. physical examination showed slightly elevated erosive lesion measuring approximately 3 cm in diameter on the central soft palate, with a clear demarcated border (figure 1). no enanthema were seen in other areas of squamous cell carcinoma of the soft palate associated with autoantibodies to desmoglein 1 and 3 yoshifumi maumi1, reiko suzaki1, naoko ito1, mizuki sawada1, sumiko ishizaki1, mariko fujibayashi2, motohiko aiba2, hiroyuki kaneko3, masaru tanaka1 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of pathology, tokyo women’s medical university medical center east, tokyo, japan ¶ 3 department of oral surgery, tokyo women’s medical university medical center east, tokyo, japan key words: desmoglein, squamous cell carcinoma, mucous membrane, soft palate, autoantibody citation: maumi y, suzaki r, ito n, sawada m, ishizaki s, fujibayashi m, aiba m, kaneko h, tanaka m. squamous cell carcinoma of the soft palate associated with autoantibodies to desmoglein 1 and 3. dermatol pract conc. 2013;3(4):14. http://dx.doi.org/10.5826/ dpc.0304a14. received: june 4, 2013; accepted: july 1, 2013; published: october 31, 2013 copyright: ©2013 maumi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: masaru tanaka, m.d., department of dermatology, tokyo women’s medical university, medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: tanaka.twmu@gmail.com. figure 1. clinical finding: erosive lesion measuring approximately 3 cm in diameter on the central part of the soft palate. [copyright: ©2013 maumi et al.] 56 observation | dermatol pract concept 2013;3(4):14 fluorouracil (5-fu)] combined with tegafur, gimeracil, and oteracil potassium (tgo). the treatment resulted in a significant fall in anti-dsg antibody titer (dsg1: 10, dsg3: 5) by elisa. discussion to our knowledge, there are no reports of primary squamous cell carcinoma associated with anti-dsg antibody, although there is a case of pemphigus foliaceus developing after metastasis of cutaneous squamous cell carcinoma to regional lymph nodes [2]. recently, a possible role of dsg3 in the process of squamous cell carcinogenesis has been hypothesized [3]. there are several recent studies reporting the overexpression of dsg3 in head and neck squamous cell carcinoma [4] or conversely decrease in expression of desmocollin 3 and dsg3 in oral squamous cell carcinoma [5] especially when the tumor is poorly differentiated. there is also a study describing decrease of desmoplakin, plakophillin and dsg1 in dysplasia and oral squamous cell carcinoma [6]. furthermore, dsg3 is reported as a biomarker for occult lymph node metastasis in oral cancer [7]. it was assumed in the present case that the increase in anti-dsg antibody titer was secondary in response to tumor cells, which might be overexpressing dsg1 and dsg3, although no evidence of autoimmune disease was available. interestingly, surgical treatment followed by cddp/5-fu and tgo resulted in normalization of autoantibody titer by elisa. the findings suggest that anti-dsg antibodies could be potentially used to screen for tumor relapse or metastasis in this patient. the oral cavity. anti-dsg antibodies were positive (dsg1: 42, dsg3: 25) by elisa, and a biopsy was taken from the soft palate. histopathological examination of the biopsy showed proliferation of atypical epithelial cells and invasion into the lamina propria mucosa by tumor cells (figure 2). these cells showed wide variation in size and mitoses of the nucleus in the mucous membrane. the lamina propria mucosa showed prominent cell infiltration mainly composed of lymphocytes and plasma cells (figure 3). immunostaining for mib1 (ki67) showed positive staining in approximately 80% of tumor cells (figure 4). there were no features of acantholysis, suggesting the histopathological diagnosis of pemphigus. direct immunofluorescence staining demonstrated no deposition of igg or c3 on the epithelial cell surface or basement membrane zone. the final diagnosis of squamous cell carcinoma was established. treatment included complete excision of the tumor on june 6, 2007, followed by chemotherapy [cisplatin (cddp)/5 figure 2. histopathological examination of hematoxylin-eosin stained tissue biopsy showed invasion of the lamina propria mucosa by tumor cells. magnification, 20x. [copyright: ©2013 maumi et al.] figure 3. histopathological examination of hematoxylin-eosin stained tissue biopsy under high magnification confirmed the diagnosis of undifferentiated squamous cell carcinoma. the subepithelial tissue shows marked inflammatory reaction with a mixture of lymphocytes and plasma cells. magnification, 200x. [copyright: ©2013 maumi et al.] figure 4. immunohistochemical staining for mib1 (ki67) showed nuclear staining in approximately 80% of tumor cells. magnification, 200x. [copyright: ©2013 maumi et al.] observation | dermatol pract concept 2013;3(4):14 57 5. wang l, liu t, wang y, et al. altered expression of desmocollin 3, desmoglein 3, and beta-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation. virchows arch. 2007;451(5);959-66. 6. narayana n, gist j, smith t, et al. desmosomal component expression in normal, dysplastic, and oral squamous cell carcinoma. dermatol res pract. 2010:649731. 7. patel v, martin d, malhotra r, et al. dsg3 as a biomarker for the ultrasensitive detection of occult lymph node metastasis in oral cancer using nanostructured immunoarrays. oral oncol. 2013;49(2);93-101. references 1. amagai m, klaus-kovtun v, stanley jr. autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. cell. 1991;67(5);869-77. 2. inaoki m, kaji k, furuse s, et al. pemphigus foliaceus developing after metastasis of cutaneous squamous cell carcinoma to regional lymph nodes. j am acad dermatol. 2001;45(5);767-70. 3. alaibac m. targeting dsg3: from pemphigus to squamous cell carcinoma. expert opin ther targets. 2013;17(5);477-9. 4. chen yj, chang jt, lee l, et al. dsg3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of oncogenesis. oncogene. 2007;26(3);467-76. dermatology: practical and conceptual review | dermatol pract concept 2017;7(1):1 1 dermatology practical & conceptual www.derm101.com introduction patients with hair loss often inquire whether nutritional supplements can help restore hair growth or prevent further hair loss. in fact, many will start dietary supplements without consultation in the hope that the supplements will help. the unregulated supplement industry also capitalizes on this population’s vulnerability. while hair follicles are among the most metabolically active in the body, and hair growth may be impacted by calorie and protein malnutrition as well as micronutrient deficiency, the links are complex. nutritional deficiency may impact both hair structure and hair growth. effects on hair growth include acute telogen effluvium (te), a well-known effect of sudden weight loss or decreased protein intake [1], as well as the diffuse alopecia seen in niacin deficiency [2]. studies have also reported potential associations between nutritional deficiency and chronic te, androgenetic alopecia (aga), female pattern hair loss (fphl), and alopecia areata (aa) [3,4]. given this well-recognized link, many patients seeking treatment for hair loss ask about dietary recommendations. specifically, is it necessary to test for nutrient deficiency in a patient presenting with hair loss? are there risk factors that should prompt testing? in the absence of such risk factors, is there any evidence to support the use of micronutrient supplementation? physicians must be prepared to answer these questions. hair loss is common, with close to 50% of men and women diet and hair loss: effects of nutrient deficiency and supplement use emily l. guo1, rajani katta2 1 baylor college of medicine, houston, tx, usa 2 department of dermatology, houston methodist hospital, houston, tx, usa key words: hair loss, alopecia, diet, nutrition, supplementation citation: guo el, katta r. diet and hair loss: effects of nutrient deficiency and supplement use. dermatol pract concept. 2017;7(1):1. doi: http://dx.doi.org/10.5826/dpc.0701a01 received: august 16, 2016; accepted: november 25, 2016; published: january 31, 2017 copyright: ©2017 guo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajani katta, md, 6800 west loop south, suite 180, bellaire, tx 77401, usa. tel. 281-501-3150; fax. 832-8100072. email: info@kattamd.com patients presenting with hair loss should be screened by medical history, dietary history and physical exam for risk factors for nutrient deficiency. if warranted, laboratory studies may be performed. in patients with no risk factors, further laboratory evaluation searching for nutritional deficiencies is not warranted. for patients with nutritional deficiencies, it is clear that those deficiencies should be corrected. further research is required to determine whether any benefit exists for nutrient supplementation in the absence of documented deficiency. at this time, patients must be informed that such research is lacking and that in fact some supplements carry the risk of worsening hair loss or the risk of toxicity. abstract mailto:info@kattamd.com 2 review | dermatol pract concept 2017;7(1):1 vegans and vegetarians are also at higher risk for id, as their requirements for dietary iron are considered to be 1.8 times higher than for meat consumers [18]. non-heme iron, found in plants, has a lower bioavailability than heme iron, found in meat and fish [19]. patients with more advanced id develop iron deficiency anemia and require replacement. id may also result in a reduction of storage iron, measured by serum ferritin. a normal ferritin level does not exclude id, however, as it is an acute phase reactant. although multiple research studies have been conducted, it is unknown if a deficiency of storage iron contributes to hair loss, as conflicting results have been noted. some studies have found that low serum ferritin is more prevalent in patients with chronic te, fphl, aga, and aa. other studies have found no such link. two excellent review articles have summarized these results and note considerable variations in study design, controls, and id definitions [16,20]. there are few intervention trials, and they are limited by small numbers, lack of controls in some, and variable ferritin levels. these have utilized different interventions, including iron alone [21], iron with l-lysine [8,22], and iron with spironolactone [23]. one study used a control population that excluded patients at risk for id [24] and found no statistically significant increase in the prevalence of id in premenopausal or postmenopausal women with chronic te or fphl. at this time, there are no definitive answers. patients must be approached on a case-by-case basis. in the aforementioned review articles, the researchers present their approach. both groups test patients with iron studies, including serum ferritin. both recommend treatment of id, with or without anemia, with dietary sources and oral iron supplementation when necessary, with a goal of ferritin levels above 50 μg/l [16] or 70 μg/ml, respectively [20]. patients are monitored to measure their response—an important point. patients who take iron supplements without monitoring are at risk for potentially severe complications, as iron supplementation leading to iron overload can cause toxicity. this can occur even at low levels if taken over a long period [25]. zinc zinc is an essential mineral required by hundreds of enzymes and multiple transcription factors that regulate gene expression [26]. while the exact mechanism of action is unclear, one possibility centers on zinc’s role as an essential component of numerous metalloenzymes important in protein synthesis and cell division [27]. another possibility is zinc’s role in the hedgehog signaling pathway [28], a critical component in the pathways that govern hair follicle morphogenesis [29]. zinc deficiency may be either inherited or acquired and affected by pattern hair loss by age 50 [5]. many nutritional supplements are marketed as hair loss treatments. a search of the keywords “hair loss” within the vitamins & dietary supplements section of amazon.com, which sells supplements via internet sales, yields 923 products [6]. many are composed of differing formulations. the u.s. food and drug administration (fda) does not have the authority to review dietary supplements for safety and effectiveness before they are marketed, and it is therefore the responsibility of manufacturers [7]. given the marketing efforts directed to consumers, physicians must be able to respond with a review of the known evidence. one point to emphasize is that such supplements are not without risks. in the absence of deficiency, supplementation may actually prove harmful to hair. over-supplementation of certain nutrients, including selenium, vitamin a, and vitamin e, has actually been linked to hair loss [4,8-11]. it is therefore surprising that the best-selling hair supplement on amazon. com contains both vitamin a and vitamin e [12], while the next contains selenium, vitamin a, and vitamin e [13]. while such products contain a variety of nutrients, review of the medical literature finds a notable lack of evidence supporting their use. much of what is known about nutrient effect on hair loss is based on disease states that result in deficiency. there is currently a lack of literature regarding the effects of supplementation in individuals without nutrient deficiency. in this paper, we review the available literature on nutrient deficiencies that result in hair loss, detail the risk factors for these deficiencies, and review the available evidence of the effects of supplementation, both beneficial and adverse, on hair loss. iron iron deficiency (id) is the world’s most common nutritional deficiency and is a well-known cause of hair loss. what remains unclear is what degree of id may contribute to hair loss. while the mechanism of action by which iron impacts hair growth is not known, hair follicle matrix cells are some of the most rapidly dividing cells in the body, and id may contribute to hair loss via its role as a cofactor for ribonucleotide reductase, the rate-limiting enzyme for dna synthesis [14]. in addition, multiple genes have been identified in the human hair follicle [15], and some may be regulated by iron [16]. in a mouse model, reversal of id led to restoration of hair growth [17]. certain populations are at higher risk for id, and a medical and dietary history may reveal risk factors. premenopausal women are at higher risk due to menstrual blood loss, while postmenopausal women and men may present due to gastrointestinal blood loss. other risk factors include malabsorption disorders (such as celiac disease) as well as achlorhydria or the use of h2 blockers, as iron requires an acidic ph for absorption. review | dermatol pract concept 2017;7(1):1 3 in a review of the literature, no studies regarding niacin levels in patients presenting only with hair loss were identified. fatty acids deficiency of the polyunsaturated essential fatty acids linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) can result from inappropriate parenteral nutrition and malabsorption disorders such as cystic fibrosis. hair changes include loss of scalp hair and eyebrows as well as lightening of hair [3,4]. unsaturated fatty acids may modulate androgen action by inhibition of 5α-reductase, similar to the drug finasteride [42]. additionally, arachidonic acid, an omega-6 fatty acid, may promote hair growth by enhancing follicle proliferation [43]. however, limited information is available on supplementation. in one patient with essential fatty acid deficiency, topical application of safflower oil, high in linoleic acid, resulted in growth of hair [44]. while results from a trial utilizing a supplement were reported, limited conclusions may be drawn, as this supplement combined multiple fatty acids and antioxidants [45]. selenium selenium is an essential trace element that plays a role in protection from oxidative damage as well as hair follicle morphogenesis. rats deficient in selenium display sparse hair growth [46], while knockout mice lacking specific selenoproteins exhibit progressive hair loss after birth [47]. risk factors for deficiency include living in areas with low selenium soil content (particularly in parts of china, tibet, and siberia), long-term hemodialysis, hiv, and malabsorption disorders [48]. there is limited research on selenium deficiency and alopecia in humans. one case report in a child described sparse hair, which improved after dietary supplementation [49]. given the lack of human research, it is surprising that some hair loss supplements are marketed as containing selenium. this is concerning, as selenium toxicity from nutritional supplementation is well documented [9-11]. toxicity can result in generalized hair loss, as well as blistering skin lesions, gastrointestinal symptoms, and memory difficulties. vitamin d data from animal studies suggests that vitamin d plays a role in hair follicle cycling [50]. in a study of mice treated to model vitamin d-dependent rickets, the resultant animals developed hair loss [51]. in vitro studies have shown increase in vitamin d receptor expression in the outer root sheath keratinocytes during the growing phases of the hair cycle [52]. may affect multiple organ systems. patients may experience diarrhea, immunological effects, and delayed wound healing. abnormalities in taste and smell may occur. cutaneous effects include acral and periorificial dermatitis, while hair changes include te and brittle hair. the autosomal recessive disorder, acrodermatitis enteropathica, results in decreased absorption of zinc, while acquired zinc deficiency may occur in malabsorption syndromes, such as inflammatory bowel disease [30] or following gastric bypass surgery. other groups at risk include patients with malignancy, those with liver or renal dysfunction, pregnant women [31], and patients with alcoholism [32]. drugs that can affect zinc levels include valproic acid [33] and certain antihypertensives [34]. dietary risk factors include vegetarianism, as bioavailability of zinc is lower in vegetables than meat [35]. additionally, vegetarians typically consume more legumes and whole grains, which contain phytates that bind to zinc and inhibit absorption [35]. serum zinc, the most commonly measured index of zinc status, may be impacted by several variables, and the functional effects of deficiency may be observed before serum levels decrease below normal [36]. screening in those with risk factors is indicated, as hair loss due to zinc deficiency can be reversed. a case series demonstrated reversal of hair loss following oral supplementation in five patients with te and zinc deficiency [37]. a study of 312 patients with aa, male pattern hair loss (mphl), fphl, or te showed that all groups had statistically lower zinc concentrations as compared to 30 healthy controls [38]. in patients with aa and low serum zinc levels, supplementation has been shown to have therapeutic effects [39]. however, there is currently limited information on the effects of zinc supplementation on hair growth in those without documented deficiency. one report described a single patient with alopecia, without clear deficiency, who experienced improvement following oral zinc therapy [40]. a major point when considering supplementation in the absence of known deficiency is that zinc toxicity can occur with excess supplementation. acute adverse effects include pain, vomiting, and diarrhea, while chronic effects include interaction with iron and reduced immune function [18]. niacin pellagra, due to a deficiency of niacin, results in the wellknown triad of photosensitive dermatitis, diarrhea, and dementia. alopecia is another frequent clinical finding [2]. pellagra became rare in many developed countries after niacin fortification of food was introduced. alcoholism is now considered the most common cause of pellagra in developed countries [41]. other causes include malabsorption disorders or drug-induced cases, such as with isoniazid [41]. 4 review | dermatol pract concept 2017;7(1):1 no significant difference in serum folate levels was seen in 91 patients with diffuse hair loss as compared to controls [58]. in fact, another study of 200 women with chronic te showed 28.5% had elevated serum folic acid, although methodology of the study was not included and therefore limited conclusions may be drawn [8]. biotin biotin, or vitamin h, serves as a cofactor for carboxylation enzymes. in isolated sheep hair follicles, incubation in biotincontaining solutions resulted in increased dna concentration and protein synthesis [59]. symptoms of deficiency include eczematous skin rash, alopecia, and conjunctivitis [60]. one study of an infant fed with a formula lacking sufficient biotin content reported manifestations of periorificial dermatitis and patchy alopecia, both of which resolved with daily oral supplementation of biotin [61]. biotin deficiency is rare, as intestinal bacteria are typically able to produce adequate levels of biotin. deficiency is seen in cases of congenital or acquired biotinidase or carboxylase deficiency, antibiotic use disrupting the gastrointestinal flora, and antiepileptic use. deficiency can occur from excessive ingestion of raw egg whites due to binding by avidin. no clinical trials have shown efficacy in treating hair loss with biotin supplementation in the absence of deficiency. despite this, biotin is found in multiple supplements marketed to consumers for hair loss. this marketing approach may have been chosen as biotin has shown positive effects in the treatment of brittle fingernails and onychoschizia [62-63]. amino acids and proteins protein malnutrition, such as in kwashiorkor and marasmus, can result in hair changes that include hair thinning and hair loss [64]. one study examined the role of l-lysine, an essential amino acid that may play a role in iron and zinc uptake. addition of l-lysine to iron supplementation resulted in a significant increase in mean serum ferritin concentration in some women with chronic te who failed to respond to iron supplementation alone [8]. although interesting, there is limited data available, and the role of l-lysine should be investigated further. in terms of other amino acids and proteins, no clear conclusions may be drawn about the role of supplementation in hair loss. while trials of amino acid and protein supplements have been published, they are formulated with a variety of nutrients, and therefore it is unclear what role, if any, is played by amino acid and protein supplementation in the absence of known deficiency. risk factors for vitamin d deficiency include inadequate sun exposure, dark skin, obesity, gastric bypass, and fat malabsorption [53]. one study of eight females with te or fphl showed that serum vitamin d2 levels were significantly lower than in controls. furthermore, vitamin d2 levels decreased with increased disease severity [54]. however, data on the effects of vitamin d supplementation in hair loss is lacking. vitamin a vitamin a is a group of compounds including retinol, retinal, retinoic acid, and provitamin a carotenoids. in murine studies, dietary vitamin a has been shown to activate hair follicle stem cells [55], although its role is recognized as complex and “precise levels of retinoic acid are needed for optimal function of the hair follicle” [56]. while deficiency has not been linked to hair loss, high levels of vitamin a have. in fact, one study found that in a mouse aa model, reduction of vitamin a in the diet actually delayed hair loss onset [56]. in humans, hypervitaminosis a may result from oversupplementation and has a strong known link to hair loss with other effects such as skin, vision, and bone changes [4,8]. vitamin e tocotrienols and tocopherols are members of the vitamin e family and are potent antioxidants. deficiency results in hemolytic anemias, neurologic findings, and skin dryness. vitamin e deficiency is rare, but may occur with fat malabsorption disorders. minimal information in the literature exists regarding benefits of vitamin e supplementation on hair loss. one study of 21 volunteers who received tocotrienol supplementation (100 mg of mixed tocotrienols daily) showed significant increase in hair number as compared to a placebo group [57]. however, excess supplementation may result in hypervitaminosis e, which can increase the risk of bleeding and decrease thyroid hormone production. additionally, there is some evidence for an adverse effect on hair growth, as seen in volunteers taking 600 iu per day for 28 days, a dosage around 30 times the daily recommended intake [8]. this group had significant decreases in thyroid hormone levels [8]. folic acid folic acid is found in leafy greens and many foods are fortified with folic acid, making deficiency uncommon. deficiency mainly results in megaloblastic anemia, without manifestation of hair loss. review | dermatol pract concept 2017;7(1):1 5 table 1. effects of nutrient deficiency and supplement use on hair loss. [copyright: ©2017 guo et al.] nutrient effect of deficiency on hair loss studies of supplementation iron • chronic diffuse telogen hair loss with iron deficiency anemia [20]. • in the absence of anemia, studies are not clear whether there is a significant link between id and hair loss [16,20,24]. • insufficient evidence to recommend iron supplementation to all hair loss patients with iron deficiency in the absence of anemia [20]. approach on a case-by-case basis. • excess supplementation can cause hemochromatosis [25]. zinc • statistically lower serum zinc concentrations in a study of 312 patients with aa, mphl, fphl, or te compared to 30 healthy controls [38]. • a case series demonstrated reversal of hair loss following oral supplementation in five patients with te and zinc deficiency [37]. • limited information on effects of zinc supplementation improving hair growth in the absence of deficiency. • one case report with a patient with dry brittle hair and alopecia, without clear zinc deficiency, who experienced improvement in alopecia following oral zinc therapy [40]. • excess supplementation can cause acute toxic effects including epigastric pain, nausea, vomiting diarrhea, and headache and chronic toxic effects including reduced copper status, interaction with iron, reduced immune function, and decreased concentrations of hdl cholesterol [18]. niacin (vitamin b3) • diffuse hair loss with pellagra due to severe deficiency [2]. • no known studies regarding serum niacin levels in patients with hair loss. • limited information on effects of niacin supplementation improving hair growth in absence of deficiency. fatty acids • loss of scalp and eyebrow hair [3-4]. • limited information on effects of fatty acid supplementation improving hair growth in absence of deficiency. selenium • in animal studies, rats deficient in selenium display sparse hair growth [46], while knockout mice lacking specific selenoproteins exhibit progressive hair loss after birth, ultimately leading to almost total alopecia [47]. • one case report of selenium deficiency in a young child reported clinical manifestations of dry skin and sparse, light-colored hair, improving after supplementation [49]. • limited information on effects of selenium supplementation improving hair growth in absence of deficiency. • toxicity from excess supplementation is well documented and can cause generalized hair loss [9-11]. vitamin d • serum vitamin d2 levels in a study of eight females with either te or fphl were shown to be significantly lower than in 40 agematched female controls, with decreased levels correlating to increased disease severity [54]. • limited information on effects of vitamin d supplementation improving hair growth in absence of deficiency. vitamin a • deficiency has no known link to hair loss. • limited information on effects of vitamin a supplementation improving hair growth in absence of deficiency. • toxicity from excess supplementation has a strong known link to hair loss, as well as other effects on skin, vision, and bone [4,8]. (continued next page) 6 review | dermatol pract concept 2017;7(1):1 oxidative stress may have an important role in the balding phenotype and development of aga [72]. additionally, in a study of endogenous antioxidant enzymes and lipid peroxidation in the scalps of patients with aa, excessive free radical generation was shown to occur in the scalps of patients with aa accompanied by high levels of antioxidant enzymes that were unable to protect against the ros [73]. while dietary antioxidants play a key role in reinforcing our endogenous antioxidant system, high doses of exogenous antioxidants may actually disrupt the balance between oxidation and antioxidation [71]. in vitro studies have shown that while polyphenols have antioxidant properties at low concentrations, they can potentiate ros generation at higher concentrations [71, 74-75]. compounds within plant foods, such as from fruits, vegetables, and grains, may be safer and healthier compared to isolated, high doses present in supplements [71]. conclusion while multiple nutrient deficiencies may result in hair loss (table 1), screening for such deficiencies must be guided by the one trial included l-cysteine, a constituent of keratin, in combination with medicinal yeast and pantothenic acid [65]. other trials have evaluated supplements containing marine proteins in conjunction with multiple other nutrients [66-69]. however, it is difficult to evaluate the results of these trials, as the composition of these nutritional supplements is not disclosed. marketing materials accessed from one product’s website describe the composition as including “vitamins and minerals for hair growth, including iron, zinc, biotin, niacin, vitamin c and an exclusive marine complex derived from fish proteins” [70]. antioxidants antioxidants are compounds that are able to neutralize reactive oxygen species (ros), preventing oxidative damage. many substances can be classified as antioxidants, including zinc, selenium, and vitamins a and e, as described previously in this article, as well as vitamin c and polyphenols [71]. oxidative stress has been linked to hair loss. in vitro studies of dermal papilla cells from male aga patients have shown that table 1. (continued) nutrient effect of deficiency on hair loss studies of supplementation vitamin e • deficiency has no known link to hair loss. • limited information on effects of vitamin e supplementation improving hair growth in absence of deficiency. • supplementation in one study of twenty-one volunteers suffering from hair loss has showed significant increase in hair number compared to placebo [57]. • toxicity from excess supplementation can result in risk of bleeding problems, decreased thyroid hormones, and decreased activity of vitamin k. additionally, there is some evidence for adverse effect on hair growth with excess supplementation [8]. folic acid • no significant difference in serum folate levels in a study of 91 patients with diffuse hair loss and 74 healthy controls [58]. • limited information on effects of folic acid supplementation improving hair growth in absence of deficiency. biotin • deficiency can result in alopecia, eczematous skin rash, conjunctivitis, and candidiasis [60]. • limited information on effects of biotin supplementation improving hair growth in absence of deficiency. amino acids and proteins • protein malnutrition can result in hair loss [64]. • l-lysine supplementation in addition to iron supplementation has been shown to significantly increase mean serum ferritin concentration in some women with chronic te who failed to respond to iron supplementation alone [8]. • limited information on effects other amino acids and proteins improving hair growth in absence of deficiency. key of abbreviations: alopecia areata – aa; androgenic alopecia – aga; female pattern hair loss – fphl; high density lipoprotein – hdl; iron deficiency – id; male pattern hair loss – mphl; telogen effluvium te. review | dermatol pract concept 2017;7(1):1 7 history and physical exam. nutrient deficiencies may arise due to genetic disorders, medical conditions, or dietary practices. if risk factors are identified (table 2), then laboratory screening for nutrient deficiency may be indicated. in patients with hair loss, but without any known risk factors for nutrient deficiency, laboratory testing for nutrient deficiency is not required. an area that requires further research is the role of supplementation. it is clear that nutrient deficiencies must be corrected. what is unclear is the ideal range of micronutrient levels to prevent or correct hair loss. in id and anemia, supplementation is required, but patients with id in the absence of anemia must be approached on a case-by-case basis. some authors believe that raising levels of storage iron may improve hair loss, although the research is not conclusive. all patients receiving iron supplementation must be monitored due to toxicity risk. for other nutrients, such as zinc, supplementation in deficient patients has resulted in hair growth, although, again, patients must be monitored due to toxicity risk (table 3). there is very limited research on the role of nutrient supplementation in the absence of deficiency. despite this, patients often seek nutrient supplements as a treatment for hair loss. in fact, direct-to-consumer advertising promotes the use of supplements for hair loss, and many such products, containing a wide variety of formulations, are easily available for purchase. table 2. medical and dietary history risk factors that can cause nutritional deficiencies contributing to hair loss. [copyright: ©2017 guo et al.] medical or dietary history risk factor nutrient deficiency history of blood loss (menstrual in premenopausal women, gi in postmenopausal women and men) iron malabsorption disorders multiple vitamin deficiencies pregnancy iron, folic acid, zinc alcoholism folic acid, zinc, niacin malignancy iron, zinc, can depend on type of malignancy renal dysfunction selenium, zinc h2 blocker use iron antiepileptics biotin, zinc antihypertensives zinc prolonged antibiotic use biotin isoniazid niacin inadequate sun exposure vitamin d living in parts of china, tibet, and siberia selenium vegans/vegetarians iron, zinc excessive ingestion of raw egg whites biotin malnutrition multiple vitamin deficiencies table 3. potential toxicities of supplements. [copyright: ©2017 guo et al.] supplement in excess signs and symptoms of toxicity iron acute • gi bleeding • abdominal pain • metabolic acidosis chronic • hemochromatosis zinc acute • abdominal pain • vomiting • diarrhea chronic • interaction with iron • immune dysfunction selenium • hair loss • blistering skin lesions • gastrointestinal symptoms • memory difficulties vitamin a • hair loss • skin, vision, and bone changes • increased intracranial pressure vitamin e • increased risk of bleeding • decreased thyroid hormone production • possible adverse effect on hair growth 8 review | dermatol pract concept 2017;7(1):1 14. kantor j, kessler lj, brooks dg, cotsarelis g. decreased serum ferritin is associated with alopecia in women. j invest dermatol. 2003;121(5):985-988. 15. ohyama m, terunuma a, tock cl, et al. characterization and isolation of stem cell-enriched human hair follicle bulge cells. j clin invest. 2006;116(1):249-260. 16. st pierre sa, vercellotti gm, donovan jc, hordinsky mk. iron deficiency and diffuse nonscarring scalp alopecia in women: more pieces to the puzzle. j am acad dermatol. 2010;63(6):1070-1076. 17. du x, she e, gelbart t, et al. the serine protease tmprss6 is required to sense iron deficiency. science. 2008;320(5879):10881092. 18. institute of medicine (us) panel on micronutrients. dietary reference intakes for vitamin a, vitamin k, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. washington (dc): national academy press (us); 2001. 19. camaschella c, schrier sl. regulation of iron balance. uptodate website. www.uptodate.com. updated november 11, 2015. accessed june 27, 2016. 20. trost lb, bergfeld wf, calogeras e. the diagnosis and treatment of iron deficiency and its potential relationship to hair loss. j am acad dermatol. 2006;54(5):824-844. 21. hard s. non-anemia iron deficiency as an etiologic factor in diffuse loss of hair of the scalp in women. acta derm venereol. 1963;43:562-569. 22. rushton dh, norris mj, dover r, busuttil n. causes of hair loss and the developments in hair rejuvenation. int j cosmet sci. 2002;24(1):17-23. 23. sinclair r. there is no clear association between low serum ferritin and chronic diffuse telogen hair loss. br j dermatol. 2002;147(5):982-984. 24. olsen ea, reed kb, cacchio pb, caudill l. iron deficiency in female pattern hair loss, chronic telogen effluvium, and control groups. j am acad dermatol. 2010;63(6):991-999. 25. coates td, carson s, wood jc, berdoukas v. management of iron overload in hemoglobinopathies: what is the appropriate target iron level? ann n y acad sci. 2016;1368(1):95-106. 26. ogawa y, kawamura t, shimada s. zinc and skin biology. arch biochem biophys. [epub june 2016]. 27. macdonald rs. the role of zinc in growth and cell proliferation. j nutr. 2000;130(5s suppl):1500s-8s. 28. ruiz i altaba a. gli proteins and hedgehog signaling: development and cancer. trends genet. 1999;15(10):418-425. 29. st-jacques b, dassule hr, karavanova i, et al. sonic hedgehog signaling is essential for hair development. curr biol. 1998;8 (19):1058-1068. 30. valberg ls, flanagan pr, kertesz a, bondy dc. zinc absorption in inflammatory bowel disease. dig dis sci. 1986;31(7):724-731. pmid: 2873002. 31. caulfield le, zavaleta n, shankar ah, merialdi m. potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. am j clin nutr. 1998;68(2 suppl):499s-508s. 32. dinsmore w, callender me, mcmaster d, todd sj, love ah. zinc absorption in alcoholics using zinc-65. digestion. 1985;32(4):238-242. 33. yilmaz y, tasdemir ha, paksu ms. the influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. eur j paediatr neurol. 2009;13(5):439-443. physicians must counsel their patients on the lack of research supporting these products. since supplements are not regulated by the fda, it is up to the physician and the consumer to review the efficacy and safety of supplements. websites such as the natural medicines comprehensive database [76] or the national institutes of health office of dietary supplements’ pubmed dietary supplement subset [77] and dietary supplements ingredient database [78] may be of help in this exploration. equally important is a discussion of the potential toxicity of some of these supplements. over-supplementation of some nutrients may result in multiple toxicities, while over-supplementation of certain nutrients, including vitamin a, vitamin e, and selenium, may actually result in hair loss. references 1. mubki t, rudnicka l, olszewska m, shapiro j. evaluation and diagnosis of the hair loss patient: part i. history and clinical examination. j am acad 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alpha-reductase by specific aliphatic unsaturated fatty acids. biochem j. 1992;285(pt 2):557562. 43. munkhbayar s, jang s, cho a-r, et al. role of arachidonic acid in promoting hair growth. ann dermatol. 2016;28(1):55-64. 44. skolnik p, eaglstein wh, ziboh va. human essential fatty acid deficiency: treatment by topical application of linoleic acid. arch dermatol. 1977;113(7):939-941. 45. le floc’h c, cheniti a, connétable s, piccardi n, vincenzi c, tosti a. effect of a nutritional supplement on hair loss in women. j cosmet dermatol. 2015;14(1):76-82. 46. bates jm, spate vl, morris js, st germain dl, galton va. effects of selenium deficiency on tissue selenium content, deiodinase activity, and thyroid hormone economy in the rat during development. endocrinology. 2000;141(7):2490-2500. 47. sengupta a, lichti uf, carlson ba, et al. selenoproteins are essential for proper keratinocyte function and skin development. plos one. 2010;5(8):e12249. 48. selenium dietary supplement fact sheet. 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demonstration of the ambivalent redox character of polyphenols. biochim biophys acta. 2009;1787(12):1425-1432. 75. wätjen w, michels g, steffan b, et al. low concentrations of flavonoids are protective in rat h4iie cells whereas high concentrations cause dna damage and apoptosis. j nutr. 2005;135(3):525-531. 76. natural medicines comprehensive database website. http:// naturaldatabase.therapeuticresearch.com. accessed november 7, 2016. 77. pubmed dietary supplement subset. national institutes of health office of dietary supplements website. https://ods.od.nih.gov/ research/pubmed_dietary_supplement_subset.aspx. accessed november 7, 2016. 78. dietary supplements ingredient database. national institutes of health office of dietary supplements website. https://dietarysupplementdatabase.usda.nih.gov/. accessed november 7, 2016. 70. vitamins and minerals for healthier hair. viviscal website. http:// www.viviscal.com/vitamins-and-minerals-for-healthier-hair. accessed june 2, 2016. 71. bouayed j, bohn t. exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. oxid med cell longev. 2010;3(4):228-237. 72. upton jh, hannen rf, bahta aw, farjo n, farjo b, philpott mp. oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia. j invest dermatol. 2015;135(5):1244-1252. 73. akar a, arca e, erbil h, akay c, sayal a, gür ar. antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata. j dermatol sci. 2002;29(2):85-90. 74. de marchi u, biasutto l, garbisa s, toninello a, zoratti m. quercetin can act either as an inhibitor or an inducer of the dermatology: practical and conceptual 38 research | dermatol pract concept 2017;7(3):8 dermatology practical & conceptual www.derm101.com background dermoscopy is an in vivo, non-invasive technique utilized when examining the skin. a dermatoscope is a handheld device, which allows illumination and 10-14 times magnification of the area being analyzed. the dermatoscope allows clinicians to not only magnify skin lesions, but also helps visualize subsurface features. dermoscopy is effective in evaluation of both melanocytic and non-melanocytic skin lesions, as well as rashes and infectious dermatoses [4-7]. dermoscopy improves the diagnostic accuracy for melanoma detection by up to 50% in comparison to unaided visual inspection, but only in examiners experienced with the use of dermoscopy [6,8]. for some non-melanocytic neoplasms, visualization of analysis of dermoscopy teaching modalities in united states dermatology residency programs yun an chen1, joanne rill2, elizabeth v. seiverling3 1 penn state college of medicine, hershey, pa, usa 2 department of dermatology, penn state hershey medical center, hershey, pa, usa 3 department of dermatology & department of family and community medicine, penn state hershey medical center, hershey, pa, usa key words: dermoscopy training, dermatology residency, medical education citation: chen ya, rill j, seiverling ev. analysis of dermoscopy teaching modalities in united states dermatology residency programs. dermatol pract concept 2017;7(3):8. doi: https://doi.org/10.5826/dpc.070308 received: march 25, 2017; accepted: may 15, 2017; published: july 31, 2017 copyright: ©2017 chen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elizabeth v. seiverling, md, assistant professor of dermatology & family and community medicine, department of dermatology, penn state hershey medical center, hershey, pa, usa. email: eseiverling@pennstatehealth.psu.edu the use of dermoscopy in dermatology residency programs is on the rise (over 94% of chief residents reported using a dermatoscope in 2013) [1]. despite increased use (100% of our surveyed residents reported using a dermatoscope), dermoscopy training is one of the aspects of united states dermatology residency training with the lowest resident satisfaction [2]. diagnostic accuracy with dermoscopy is highly correlated with the amount of dermoscopy training the user has undertaken [3]. we sought to analyze dermoscopy use in us dermatology residencies to better understand resident dermoscopy utilization and teaching modalities. we found residents learn dermoscopy via multiple teaching modalities. the most commonly reported dermoscopy teaching modality was didactic lectures, followed by time in clinic with a dermoscopy expert. of the different teaching modalities, time in the clinic with a dermoscopy expert was reported to be the most effective. we also found that the majority of dermatology residents receive didactic dermoscopy lectures and clinical dermoscopy training on the differentiation of benign nevi from melanoma using dermoscopy, the detection of basal cell carcinoma, and the identification of seborrheic keratosis. however, few residents receive dedicated training on the use of dermoscopy in the evaluation of inflammatory dermatoses and skin infections despite dermoscopy’s demonstrated value in both areas [4-7]. abstract research | dermatol pract concept 2017;7(3):8 39 curriculum, (7) the analytical methods used when performing dermoscopy, and (8) opinion regarding inclusion of dermoscopy as an accredited council for graduate medical education (acgme) dermatology core competency (table 1). descriptive statistics, such as frequency distribution and percentages, were calculated to quantify the survey responses. results study participants forty dermatology residents from 16 different us dermatology residency programs completed the survey. seventy-seven different us dermatology residency programs were asked to participate, thereby yielding a 21% representation rate of all the us dermatology residency programs as identified by apd as being receptive to receiving surveys. use of dermoscopy in resident clinical practice all surveyed residents reported using dermoscopy in their clinical practice. the top three reported reasons for using dermoscopy were: (1) helps detect melanoma (97%), (2) helps detect basal cell carcinoma, squamous cell carcinoma, and/ or actinic keratoses (87%), and (3) leads to fewer biopsies and reduces patient anxiety (79%). the majority of respondents believed that dermoscopy is useful in: (1) diagnosis of melanoma (85%), (2) evaluation of patients with clinically atypical/dysplastic nevi (77%), and (3) diagnosis of basal cell carcinoma (72%). while the majority of respondents believed that dermoscopy was not useful in: (1) evaluation of inflammatory dermatoses (85%), (2) diagnosis of actinic keratosis (77%), (3) evaluation of skin infections (74%), and (4) diagnosis of squamous cell carcinoma (72%). dermoscopy education and training the most commonly reported dermoscopy teaching modality was didactic lecture: 88% of respondents reported having dermoscopy lectures as part of their residency curriculum. an average of two hours of dermoscopy lectures per academic year were reported. the most common topics discussed in lectures were: (1) differentiation of benign nevi from melanoma, (2) detection of basal cell carcinoma, and (3) detection of seborrheic keratosis, angiomas, or angiokeratomas. lectures on the use of dermoscopy in the evaluation of inflammatory dermatoses and skin infections were rare. dermoscopy teaching also occurred in a clinical setting: 59% of the residents reported working with a dermoscopy expert in clinic. the average time spent with the expert was four hours per week. similarly to dermoscopy lectures, inflammatory dermatoses and skin infections were not topics commonly addressed in clinical dermoscopy training, while differentiation of benign nevi from melanoma and detection of basal cell carcinoma were frequently taught (figure 1). dermatoscopic structures is 100% specific (i.e. spoke wheels seen in pigmented basal cell carcinoma) [9]. additionally, there are dermatoscopic structures with a very high specificity for psoriasis [10]. despite its demonstrated value, dermoscopy is not uniformly being taught to dermatology residents. in 2002, 50% of us dermatology residents were using dermoscopy for melanocytic lesion evaluation [11]. by 2011, 88% of chief residents in us dermatology programs were using dermoscopy to aid in melanoma detection [12], and by 2013, 94% of chief residents were doing so [1]. despite the increase in use, dermoscopy training was one of the aspects of us dermatology residency training with the lowest resident satisfaction [2]. furthermore, while there is an abundance of literature addressing the use and education of dermoscopy in the diagnosis of melanocytic lesions, to our knowledge, there has been no published study investigating whether dermoscopy is being utilized and taught in us dermatology residency programs for evaluation of non-melanocytic neoplasms, skin infections, or inflammatory dermatoses. objective the goal of this study is to analyze current dermoscopy training modalities in us dermatology residency programs and to determine if dermoscopy is being taught for purposes other than evaluation of melanocytic growths, such as nonmelanocytic neoplasms, skin infections, and inflammatory dermatoses. methods institutional review board approval was obtained from the penn state hershey medical center (study00002833). anonymous surveys were sent to all us dermatology residency program directors as identified by the association of professors of dermatology (apd) listserv on august 17, 2015. the survey was administered through surveymonkey® and dispensed to dermatology residency program directors, who were asked to dispense the survey link to all the dermatology residents at their institution, regardless of post-graduate year. the survey link was resent to program directors on three separate occasions to elicit more responses. the survey was closed on october 1, 2015. informed consent was obtained by survey responder’s acceptance of participation as elicited on the cover letter of the survey. questions regarding dermoscopy training within the responder’s current residency program addressed: (1) quantity of dermoscopy education and training, (2) dermoscopy teaching modalities, (3) topics addressed in dermoscopy lectures, (4) aspects of clinical dermoscopy training, (5) effectiveness of dermoscopy teaching modalities, (6) deficiencies within the dermoscopy 40 research | dermatol pract concept 2017;7(3):8 table 1. survey questions and possible responses. [copyright: ©2017 chen et al.] do you use dermoscopy in your clinical practice? 4 yes 4 no what are your reasons for dermoscopy use? (check all that apply) 4 helps detect melanoma 4 helps detect bcc, scc, and/or ak 4 helps differentiate between inflammatory dermatoses and skin growths 4 helps with evaluation of infectious skin conditions (i.e. scabies, molluscum) 4 leads to fewer biopsies 4 reduces cost of care through early diagnosis 4 reduces patient anxiety 4 documentation for medical liability do you believe dermoscopy is useful in: (check all that apply) 4 diagnosis of melanoma 4 patients with clinically atypical/dysplastic nevi 4 diagnosis of bcc 4 diagnosis of scc 4 diagnosis of ak 4 evaluation of inflammatory dermatoses 4 evaluation of skin infections are dermoscopy lectures part of your resident education curriculum? 4 yes 4 no do your dermoscopy lectures address: (check all that apply) 4 differentiation of benign nevi from melanoma 4 detection of bcc 4 detection of scc 4 detection of ak 4 detection of sk 4 detection of angiomas or angiokeratomas 4 evaluation of inflammatory dermatoses 4 evaluation of skin infections approximately how many hours of dermoscopy lectures does your department provide during an academic year? (please specify) do you have dermoscopy “unknown” sessions? 4 yes 4 no do you utilize other dermoscopy training resources? 4 yes 4 no what are these other resources? (check all that apply) 4 online dermatology lectures 4 online dermoscopy quizzes 4 dermatology textbooks have you attended a dermoscopy conference at a regional or national dermatology meeting? 4 yes 4 no (continued next page) research | dermatol pract concept 2017;7(3):8 41 did your institution/residency program provide you with a dermatoscope? 4 yes 4 no what analytic method(s) do you use when performing dermoscopy? (check all that applies) 4 pattern analysis or revised pattern analysis 4 abcd rule of dermoscopy 4 menzies method 4 7-point score or checklist 4 cash algorithm (i.e. colors architecture symmetry homogeneity) do you work with a dermoscopy expert in a clinical setting? 4 yes 4 no approximately how many hours per week do you work with a dermoscopy expert in a clinical setting? (please specify) in a clinical setting, are you taught how to use dermoscopy for: (check all that apply) 4 differentiation of benign nevi from melanoma 4 detection of bcc 4 detection of scc 4 detection of ak 4 detection of sk 4 detection of angiomas or angiokeratomas 4 evaluation of inflammatory dermatoses 4 evaluation of skin infections which method of teaching dermoscopy do you find most effective? (check all that applies) 4 structured lectures 4 “unknown” sessions 4 time in clinic with a dermoscopy expert are you satisfied with the dermoscopy education you receive as part of your residency program? 4 yes 4 no do you feel dermoscopy training should be an acgme (accreditation council for graduate medical education) dermatology core competency? 4 yes 4 no *bcc=basal cell carcinoma, scc=squamous cell carcinoma, ak=actinic keratosis, sk=seborrheic keratoses table 1. survey questions and possible responses. (continued) other reported forms of dermoscopy education were: attending dermoscopy conferences (15% of respondents) and dermoscopy “unknown sessions (23% of respondents). fiftyfour percent of respondents supplement with other dermoscopy training resources, with dermatology textbooks being the most commonly utilized other resource. of the different dermoscopy teaching modalities, time in clinic with a dermoscopy expert was reported to be the most effective modality for learning dermoscopy (72% of respondents reported this method to be effective), followed by structured lectures (61%), and “unknown” sessions (36%). eighty-nine percent of the residents were taught pattern analysis, which has the highest diagnostic accuracy for detecting melanoma [8], as the main analytical approach when using dermatoscopes, followed by 53% who were also taught the abcd rule of dermoscopy. forty-two percent of residents felt dissatisfied with the dermoscopy training they receive in their residency program. lastly, the majority (78%) of the respondents felt dermoscopy training should be an acgme dermatology core competency. conclusions dermoscopy is widely used in us dermatology residency programs (100% dermoscopy use in our study). in 2010, 42 research | dermatol pract concept 2017;7(3):8 found in dermoscopy training in the clinical setting (with a dermoscopy expert): 97% of residents reported being taught how to differentiate benign nevi from melanoma with a dermatoscope, but only 31% and 11% were taught how to use dermoscopy in the evaluation of skin infections and inflammatory dermatoses, respectively (figure 1). lack of training in the full capacity of dermoscopy might account for the following: while the majority (85%) of our participants considered dermoscopy useful in the diagnosis of melanoma, the majority (85%) did not consider dermoscopy to be useful in the evaluation of inflammatory dermatoses, diagnosis of actinic keratosis (77%), evaluation of skin infections (74%), and diagnosis of squamous cell carcinoma (72%). the benefits of dermoscopy for detection of melanoma are well documented; however, there is an expanding body of literature supporting dermoscopy use in evaluating non-melanocytic tumors, skin infections, and inflammatory dermatoses [5,7,9,10]. an increased number of hours of structured dermoscopy lectures and increased clinic time with a dermoscopy expert may allow for more dermoscopy topics to be addressed in resident education. additionally, inclusion of dermoscopy as an acgme dermatology core competency, which 78% of the surveyed residents favored, might allow for standardization of resident dermoscopy education. in summary, resident satisfaction with their dermoscopy training is low and resident dermoscopy teaching is limited mostly to the evaluation of skin neoplasms, specifically melanoma and basal cell carcinoma. increased resident clinic time with a dermoscopy expert, more structured dermoscopy lectures, and inclusion of dermoscopy as a dermatology acgme core competency has the potential to increase dermoscopy despite high rates of use by us dermatology residents, only 48% of practicing us dermatologists were using dermoscopy. the main reason reported by the practicing us dermatologists for not using a dermatoscope was lack of training [13]. european literature has shown that resident dermoscopy training is highly correlated with dermoscopy use for melanoma detection [14]. little is published on european dermoscopy teaching modalities for residents. in our us-based study, we found that residents learn dermoscopy through a variety of teaching modalities. of these, the most common dermoscopy teaching modality is didactic lecture, followed by clinic time with a dermoscopy expert. time in clinic with a dedicated dermoscopy expert was reported to be the most effective way residents learn dermoscopy. however, only 59% of the residents in our study had the opportunity to work with a dermoscopy expert in a clinical setting. prior research supports this finding: dedicated time in clinic with a “pigmented lesion specialist” is one of the most effective ways to learn dermoscopy [1]. therefore, program directors should strive to have residents spend more time in clinic with a dermoscopy expert. structured lectures were reported to be the second most effective modality for learning dermoscopy. while 88% of residents in our study reported having formal dermoscopy lectures, making it the most commonly reported modality for learning dermoscopy, the residents only receive an average of two hours of dermoscopy lectures per year. of the residents who had dermoscopy lectures, all of them received lectures addressing dermoscopy in the differentiation of benign nevi from melanoma, but only 27% and 18% received lectures on using dermoscopy to evaluate skin infections and inflammatory dermatoses, respectively. the same pattern was figure 1. dermoscopy topics addressed. [copyright: ©2017 chen et al. ] research | dermatol pract concept 2017;7(3):8 43 5. dupuy a, dehen l, bourrat e, lacroix c, et al. accuracy of standard dermoscopy for diagnosing scabies. j am acad dermatol. 2007;56(1):53-62. 6. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. 7. lacarrubba f, verzi ae, dinotta f, et al. dermatoscopy in inflammatory and infectious skin disorders. g ital dermatol venereol. 2015;50(5):521-531. 8. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. 9. popadic m. statstical evaluation of dermoscopic features in basal cell carcinomas. dermatologic surgery. 2014;40(7):718724. 10. pan y, chamberlain aj, bailey m, et al. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268274. 11. nehal ks, oliveria sa, marghoob aa, et al. use of and beliefs about dermoscopy in the management of patients with pigmented lesions: a survey of dermatology residency programmes in the united states. melanoma res. 2002;12(6):601-605. 12. terushkin v, oliveria sa, marghoob aa, et al. use of and beliefs about total body photography and dermatoscopy among us dermatology training programs: an update. j am acad dermatol. 2010;62(5):794-803. 13. engasser hc, warshaw em. dermatoscopy use by us dermatologists: a crosssectional survey. j am acad dermatol. 2010;63(3): 412-419, 419.e1-2. 14. forsea am, tschandl p, del marmol v, et al. factors driving the use of dermoscopy in europe: a pan-european survey. br j dermatol. 2016;175(6):1329-1337. use for non-melanocytic conditions, including inflammatory dermatoses and skin infections, and increase resident satisfaction with their dermoscopy training. limitations our study was limited by our number of responses: this data represents 21% of the us dermatology residency programs as identified by apd as being receptive to receiving surveys. we used the apd listserv to identify program directors and asked the program directors to distribute the survey to their residents. distribution of the survey using a different modality, targeting individual residents as opposed to program directors, may have allowed for inclusion of more us dermatology residents and programs. references 1. wu tp, newlove t, smith l, et al. the importance of dedicated dermoscopy training during residency: a survey of us dermatology chief residents. j am acad dermatol. 2013;68(6): 1000-1005. 2. freeman sr, greene re, kimball ab, et al. us dermatology residents’ satisfaction with training and mentoring: survey results from the 2005 and 2006 las vegas dermatology seminars. arch dermatol. 2008;144(7):896-900. 3. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137:1343–1350. 4. errichetti e, lacarrubba f, micali g, et al. differentiation of pityriasis lichenoides chronica from guttate psoriasis by dermoscopy. clin exper dermatol. 2015;40:804-806. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):9 39 dermatology practical & conceptual www.derm101.com introduction lichen planus (lp) is a common inflammatory disease affecting the skin, the mucous membranes, the genitalia, the nails and the scalp [1]. prevalence of lichen planus in the general population ranges from 0.1 to 4 % and it is more common in females, especially in the perimenopausal period [1,2]. pathophysiology of lp involves an immune-mediated reaction, in which an antigen is processed to t-lymphocytes and they, subsequently, attack basal keratinocytes, leading to apoptosis of the cells [3]. several factors have been suggested as possible antigens, including viruses, bacterials and drugs [3,4]. the typical clinical manifestations of lp are purple to violaceous polygonal papules with sharp borders, usually pruritic, most commonly developing on the extremities and the trunk. less frequently the disease affects the genital area, mucous membranes, palms and soles and nails [1,5]. mucosal lesions are typified by the presence of reticular white lines, known as wickham striae. the disorder has several clinical variations: annular, hypertrophic, atrophic, ulcerative, bullous, erythrodermic, inverse, linear, follicular, pemphigoides, pigmentosus, follicularis decalvans and actinic lp [3]. the diagnosis of lp is usually established clinically based on the characteristic morphology of the lesions and the coexisting intense pruritus. however, atypical presentations requiring histopathologic confirmation of the diagnosis do exist [1]. dermoscopy allows the visualization of structures located in the epidermis, dermo-epidermal junction and papillary dermis that cannot be seen with the naked eye [6]. initially, dermoscopy was almost exclusively used to evaluate skin atypical case of lichen planus recognized by dermoscopy chrysoula papageorgiou1, zoe apalla1, elizabeth lazaridou1, elena sotiriou1, efstratios vakirlis1, demetrios ioannides1, aimilios lallas1 1 first department of dermatology, aristotle university, thessaloniki, greece key words: lichen planus; dermoscopy; psoriasis; wickham striae; eczema citation: papageorgious c, apalla z, lazaridou e, sotiriou e, vakirlis e, ioannides d, lallas a. atypical case of lichen planus recognized by dermoscopy. dermatol pract concept 2016;6(4):9. doi: 10.5826/dpc.0604a09 received: august 8, 2016; accepted: august 23, 2016; published: october 31, 2016 copyright: ©2016 papageorgiou et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: chrysoula papageorgiou, md, first department of dermatology, aristotle university, thessaloniki, 124 delfon str, 54643, thessaloniki, greece. tel.: 00302313308882; fax: 00302310277979. email: xrysapapageorgiou@gmail.com lichen planus (lp) is an inflammatory disease that affects the skin—mainly the extremities and the trunk—the mucous membranes, the genitalia, the nails and the scalp. the diagnosis of lp is usually established clinically based on the typical morphology and distribution of the lesions in conjunction with the associated itch. we report a patient with lp manifesting highly psoriasiform lesions, that could only be correctly assessed after the application of dermoscopy, which revealed lp-specific findings. abstract mailto:xrysapapageorgiou@gmail.com 40 observation | dermatol pract concept 2016;6(4):9 the dorsal surfaces of the feet and hands. clinical examination revealed hyperkeratotic plaques on the dorsal surface of the feet and hands and erythematous hyperkeratotic, partially erosive plaques on the soles. as shown in figure 1, the overall clinical presentation was highly suggestive of psoriasis. surprisingly, application of dermoscopy did not reveal the expected psoriatic pattern of regularly distributed dotted vessels and white scales (figure 2). instead, white crossing lines (the so-called wickham striae) were dermoscopically evident, along with dotted and short linear vessels and yellow scales. since the dermoscopic presence of wickham striae is considered highly specific of lp, the dermoscopic findings prompted us to perform a biopsy for histopathologic assessment. histopathology, as shown in figure 3, revealed hyperkeratosis, dense hypergranulosis, vacuolar degeneration of basal cell keratinocytes, band-like lymphocytic infiltration in the upper dermis, as well as presence of colloid bodies, justifying the diagnosis of lp. tumors [7,8]. however, cumulative evidence suggests that dermoscopy is also meaningful for the evaluation of inflammatory and infectious skin disorders [7,9]. in the field of papulosquamous dermatoses, dermoscopy has been shown to enhance the differential diagnosis among psoriasis, dermatitis, lp and pityriasis rosea [7,10]. particularly for lp, dermoscopy brought to light that white crossing lines do not characterize only mucosal lesions, but cover virtually every cutaneous papule of active lp [7]. in this report we present a characteristic example of a patient with misleading clinical manifestations of lp resembling psoriasis. application of dermoscopy was the key point guiding to the accurate diagnosis [11]. clinical presentation a 61-year-old woman visited our department for evaluation of a three-month, mildly pruritic eruption on the soles and figure 1. lichen planus. erythematous plaques covered by silvery-whitish scales. both the clinical morphology and the distribution of the skin lesions are indicative of psoriasis. [copyright: ©2016 papageorgiou et al.] observation | dermatol pract concept 2016;6(4):9 41 arranged dotted vessels and yellow scales were compatible with eczema [7,14,15], the prevailing dermoscopic features were the white crossing lines, corresponding to the so-called wickham striae, which is known as a highly specific criterion of lp [7,10,11]. clinical examination is undoubtedly the cornerstone of diagnosis in everyday dermatology practice, and in the majority of our patients, the macroscopic morphology is already enough to establish an accurate diagnosis. this is especially true for widespread inflammatory diseases, where the combination of clinidiscussion in the current case, clinical manifestations on the dorsal hands and plantar surfaces were highly suggestive of psoriasis, with eczema and lp included in the differential diagnosis. however, application of dermoscopy significantly influenced our diagnostic thoughts. this was because the lesion deviated from the standard dermoscopic pattern of psoriatic lesions, which are composed of regularly distributed dotted vessels and white-colored scales [7,12,13]. although the presence of irregularly figure 2. lichen planus. dermoscopy revealed dotted and short linear vessels and yellowish scales. however, the most prominent dermoscopic finding are the white crossing lines (wickham striae). [copyright: ©2016 papageorgiou et al.] cal history, morphology and distribution often points towards a specific diagnosis [14]. lp and psoriasis are two characteristic examples, representing entities routinely diagnosed straightforward. however, equivocal clinical manifestations do exist in everyday practice, posing diagnostic doubts and often prompting clinicians to perform diagnostic biopsies [12]. it has been demonstrated that coupling clinical examination with dermoscopy significantly improves the diagnostic performance of clinicians [7]. however, in order to maximize the benefit from dermoscopy in differentiation of inflammatory dermatoses, clinicians have to virtually use their dermatoscope on every lesion. in daily routine, dermoscopy often confirms and strengthens our clinical suspicion. furthermore, as shown in the current case, it may change our diagnostic thoughts, saving us from misdiagnosis and potential inappropriate management. references 1. usatine rp, tinitigan m. diagnosis and treatment of lichen planus. am fam physician 2011;84(1):53-60. pmid: 21766756 2. zakrzewska jm, chan es, thornhill mh. a systematic review of placebocontrolled randomized clinical trials of treatments used in oral lichen planus. br j dermatol 2005;153(2):336-41. pmid: 16086745. doi: 10.1111/j.13652133.2005.06493.x. 3. wagner g, rose c, sachse mm. clinical variants of lichen planus. j dtsch dermatol ges 2013;11(4):309-19. pmid: 23320493. doi: 10.1111/ddg.12031. 4. lehman js, tollefson mm, gibson le. lichen planus. int j dermatol 2009;48(7): 682-94. pmid: 19570072. doi: 10.1111/ j.1365-4632.2009.04062.x. 5. katta r. lichen planus. am fam physician 2000;61(11):3319-24. pmid: 10865927 6. russo t, piccolo v, lallas a, argenziano g. recent advances in dermoscopy. f1000res 2016;5. pmid: 26949523. doi: 10.12688/f1000research.7597.1 7. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen figure 3. lichen planus. histopathology revealed hyperkeratosis, dense hypergranulosis, vacuolar degeneration of basal cell keratinocytes, band-like lymphocytic infiltration in the upper dermis, as well as presence of colloid bodies, justifying the diagnosis of lichen planus. [copyright: ©2016 papageorgiou et al.] 42 observation | dermatol pract concept 2016;6(4):9 12. lallas a, apalla z, tzellos t, lefaki i. photoletter to the editor: dermoscopy in clinically atypical psoriasis. j dermatol case rep 2012;6(2):61-62. pmid: 22826724. doi: 10.3315/ jdcr.2012.1102. 13. lallas a, apalla z, karteridou a, lefaki i. photoletter to the editor: dermoscopy for discriminating between pityriasis rubra pilaris and psoriasis. j dermatol case rep 2013;7(1):20-2. pmid: 23580911. doi: 10.3315/jdcr.2013.1131. 14. lallas a, argenziano g, apalla z, et al. dermoscopic patterns of common facial inflammatory skin diseases. j eur acad dermatol venereol 2014;28(5):609-614. pmid: 23489377. doi: 10.1111/ jdv.12146. 15. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol venereol 2013;27(5):61721. pmid: 22404051. doi: 10.1111/j.1468-3083.2012.04499.x. planus and pityriasis rosea. br j dermatol 2012;166(6):1198-1205. pmid: 22296226. doi: 10.1111/j.1365-2133.2012.10868.x. 8. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol 2003;48(5):679-93. pmid: 12734496. doi: 10.1067/mjd.2003.281. 9. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology 2006;212(1):7-18. pmid: 16319467. doi: 10.1159/000089015. 10. vázquez-lópez f, manjón-haces ja, maldonado-seral c, raya-aguado c, pérez-oliva n, marghoob aa. dermoscopic features of plaque psoriasis and lichen planus: new observations. dermatology 2003;207(2):151-6. pmid: 12920364. doi: 10.1159/000071785. 11. friedman p, sabban ec, marcucci c, peralta r, cabo h. dermoscopic findings in different clinical variants of lichen planus. is dermoscopy useful? dermatol pract concept 2015;5(4):51-5. pmid: 26693092. doi: 10.5826/dpc.0504a13. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022144 1 dermatology practical & conceptual comparison of early and late onset psoriasis (eop and lop) regarding systemic inflammatory comorbidities: lop is a more rapid subtype of psoriasis leyla huseynova terzi1, sibel dogan gunaydin1,2 1 hacettepe university, faculty of medicine, department of dermatology and venereology, ankara, turkey 2 hacettepe university, graduate school of medical sciences, department of pediatric basic sciences, immunology, ankara, turkey key words: psoriasis, comorbidity, early onset psoriasis, late onset psoriasis, inflammation citation: huseynova terzi l, dogan gunaydin. comparison of early (eop) and late onset psoriasis (lop) regarding systemic inflammatory comorbidities: lop is a more rapid subtype of psoriasis. dermatol pract concept. 2022;12(3):e2022144. doi: https://doi.org/10.5826/ dpc.1203a144 accepted: november 28, 2021; published: july 2022 copyright: ©2022 tognetti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: leyla huseynova terzi, md, hacettepe university, faculty of medicine, department of dermatology and venereology 9. entrance, 06100 sıhhiye, ankara, turkey, +90 312 305 17 0417 06, fax: +90 312 880 58 08, e-mail: leyla.huseynova@ymail.com introduction: early onset psoriasis (eop) and late onset psoriasis (lop) differ regarding genetic background, clinical presentation and course of disease. objectives: in this study, comparison of eop and lop regarding systemic inflammatory comorbidities which are frequently seen in psoriasis and determination of possible differences is aimed. methods: a total of 160 plaque psoriasis patients (121 with eop and 39 with lop) were enrolled for the study. data was collected with face-to-face questionnaire and patients medical chart evaluation. collected data included medical and family history, clinical features and parameters indicating severity of psoriasis, results of laboratory work-up, physical and dermatological examination findings, presence of joint and nail involvement and associated inflammatory systemic comorbidities such as cardiovascular diseases (cvd), diabetes mellitus (dm), hypertension (ht), metabolic syndrome (ms), obesity. results: nail involvement and psa occurred more rapidly in lop compared to eop (p < 0.01, p < 0.01). compared frequencies in lop and eop were 7.7% versus 0.8% for cvd, 38.5% versus 14% for ht, 33.3% versus 9.9% for dm and 44.7% versus 24.8% for ms, respectively. cvd, ht, dm and ms were significantly more frequent in lop compared to eop (p = 0.045, p = 0.001, p < 0.01, p = 0.022). results of multivariate analysis performed taking into account the age, gender, severity parameters of disease, alcohol consumption, smoking habits and other concurrent systemic comorbidities revealed lop to be an independent risk factor for cvd and dm (p < 0.01, r2: 0.036, p < 0.01, r2: 0.077). conclusions: lop seems to interact with systemic comorbidities hence generates more severe inflammatory burden and shows a more rapid course. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022144 introduction psoriasis is a chronic, multifactorial inflammatory skin disease with a polygenic background and variable clinical presentations. nowadays, it is more frequently referred as “psoriatic disease” due to its association with systemic comorbidities such as psoriatic arthritis (psa), obesity (ob), cardiovascular diseases (cvd), diabetes mellitus (dm), hypertension (ht), metabolic syndrome (ms) and inflammatory bowel diseases (ibd). psoriasis is classified based upon phenotypic presentation, association with human leukocyte antigen (hla) and age at onset [1]. henseler and christophers have observed that clinical characteristics of psoriasis differ according to the age of onset [2]. in patients who developed psoriasis before age 40, psoriasis tends to be more severe, recurrent and resistant to treatment. thus, they offered new classification of psoriasis based upon the age of onset; psoriasis which developed before 40 years was accepted as early onset psoriasis (eop) and psoriasis which developed after 40 years as late onset psoriasis (lop). although this cut-off point have been used by several authors, others have used a wide range of cut-off point (30-50 years), thus limiting comparisons between studies [1,3–6]. differences in the clinical characteristics and course of the disease, response to treatment, genetic predisposition and psychosocial effects in eop and lop have been reported in previous studies. eop have been shown to be more severe and pose recurrent flares, positive family history, koebner phenomenon and association with hla-c [3–5,7–9]. eop was also claimed to have more prominent psychosocial effect and requirement for systemic treatment is usually more frequent [1,7,10]. epidemiologic studies have demonstrated association of psoriasis with systemic inflammatory diseases, but to our knowledge there is only one report comparing eop and lop regarding concomitant systemic inflammatory comorbidities, which found ob to be more frequent in lop than eop [1]. objectives based on previous literature and lack of data in this aspect, we aimed to compare inflammatory comorbidities along with clinical characteristics and severity of psoriatic disease and possibly determine differences in eop and lop in this study. methods patients data was collected by a face-to-face questionnaire and medical chart evaluation. patients older than 18 years of age with plaque psoriasis who were on follow-up at our department of dermatology between 1st october 2018 and 1st march 2019 were enrolled for the study. patients with disease onset before age of 40 years were accepted as eop and patients with disease onset equal or after 40 years were considered to have lop. the study was approved by the ethic committee of non-invasive clinical studies of hacettepe university (id go 18/1057-30). methods questionnaire the face-to-face questionnaire consisted of 5 main sections: (1) patient demographics; (2) psoriasis characteristics; (3) concurrent comorbidities; (4) physical and dermatological examination; (5) laboratory studies. patient demographics age, gender, place of birth, place of residence was recorded. psoriasis characteristics age of onset of the disease, existence of nail involvement, age at the onset of nail involvement, type of nail involvement, existence of concomitant psa, age at the onset of psa, family history of psoriasis and psa and age at the onset of psoriasis and psa of the family member, received treatment regimens and duration of the treatment were recorded. duration of active psoriatic disease was also required to be evaluated. to make this assessment; active psoriatic disease was defined as existence of cutaneous psoriatic lesions affecting more than 3% of body surface area with or without given treatments and was calculated for each patient. hospitalizations due to psoriasis and any existed erythroderma attacks were also recorded. existent or previous psoriatic nail involvement including onycholysis, pitting, subungual hyperkeratosis and oil-drop sign were questioned in detail and recorded. joint involvement was questioned based on the previous diagnosis of psa established by a rheumatologist. all patients were also filled out rheumatologic screening questionnaire (rsq) regarding existence of psa. rsq included 5 items: (i) existence of joint and muscle pain at rest, (ii) existence of neck, waist or back pain awakening at nights, (iii) existence of pain, edema and tenderness in hands or feet joint, (iv) history of morning stiffness lasting for more than 20 minutes, and (v) existence of tenderness while stepping on heels in the mornings [11]. patients were also consulted to rheumatology department based on the suspicion of psa according to rsq (patients with one or more positive answers to 5 items were consulted) and consultation results were added to the study data. concurrent comorbidities any previous diagnosis of concurrent systemic inflammatory comorbidities comprising ht, dm, nash, cvd, dlp, ms, original article | dermatol pract concept. 2022;12(3):e2022144 3 ob was noted. patients who had physical examination and/ or laboratory findings indicative of definite disease according to below mentioned criteria despite lack of previous diagnosis, they were referred to concordant specialist for further evaluation, the results of this consultations were also added to this study data. ht was accepted as having systolic blood pressure ≥ 150 mmhg and diastolic blood pressure ≥ 90 mmhg in patients ≥ 60 years and systolic blood pressure ≥ 140 mmhg and diastolic blood pressure ≥ 90 mmhg in patients < 60 years [12]. fasting blood glucose ≥ 126 mg/dl and random blood glucose ≥ 200 mg/dl was accepted as dm [13]. dlp was defined as total cholesterol levels > 200 mg/dl, ldl cholesterol > 100 mg/ dl, hdl cholesterol < 40 mg/dl, tg >150 mg/dl and non-hdl cholesterol > 130 mg/dl, as proposed by american endocrinology association [14]. ms was accepted as having any three of the following five criteria: 1. obesity: waist circumference ≥ 102 cm in men and ≥ 88 cm in women; 2. dyslipidemia: tg > 150 mg/dl or having pharmacologic treatment (rx); 3. dyslipidemia (second, separate criteria): hdl cholesterol < 40 mg/dl in men and hdl cholesterol < 35 mg/dl in women or rx; 4. ht: systolic blood pressure ≥ 130 mmhg and diastolic blood pressure ≥ 85, or rx; 5.hyperglycemia fasting blood glucose ≥ 100 mg/dl or rx [15]. cvd included history of mi, coronary artery by-pass surgery, balloon angioplasty or coronary artery stent, cerebrovascular accident or peripheral atherosclerotic vascular disease. ob was defined bmi ≥ 30 [16]. physical and dermatologic examination physical and dermatological examination findings obtained during examination in the last 6 months were noted. physical examination findings included blood pressure, height, weight and waist circumference. obtained dermatologic examination results comprised pasi score and affected body surface area (bsa). the severity of psoriasis was classified as mild (bsa ≤ 10; pasi ≤ 10) or moderate-to-severe (bsa > 10 and pasi > 10). systemic treatment regimen, duration of systemic treatment, duration of active disease (both under treatment and without any treatment), number of erythroderma attacks and hospitalization due to psoriasis were also collected to assess the severity of psoriasis. laboratory studies obtained laboratory test results conducted during the last 6 months including complete blood count, fasting blood glucose, c-reactive protein (crp), total cholesterol (tc), high density lipoprotein cholesterol (hdl), low density lipoprotein cholesterol (ldl), triglycerides (tg), blood urea nitrogen (bun) were recorded. statistical analysis statistical analysis was performed using statistical package for the social science (spss) version 20.0. patient group data were presented as mean ± standard deviation (sd) or median (range), as appropriate and compared with adjustments using fisher exact tests (for categorical variables) and student two-sample t tests or wilcoxon rank-sum tests (for continuous variables), subject to normality assumptions being satisfied. associations between the age at the time of diagnosis and binary comorbidity outcomes were evaluated using multiple logistic regression adjusted for age and other relevant confounders. results demographic data and disease characteristics in eop and lop data of 160 patients; 75.62% (n = 121) with eop and 24.38% (n = 39) with lop was analyzed and shown in table 1. family history of psoriasis was more frequent in eop significantly. family history of psoriasis was most frequently positive in the first-degree relatives in eop and lop: 23.1%, n = 28 and 10.3%, n = 4, respectively. assessment of severity of psoriasis in eop and lop severity of psoriasis was accessed depending on bsa percentage, pasi score, active duration of the disease without any treatment and under treatment, history of hospitalizations due to psoriasis and number of erythroderma attacks and no statistically significant difference was found in any parameters between eop and lop (table 2). physical examination findings in eop and lop physical examination findings in eop and lop are shown in table 3. indicative findings of comorbidities such as ht and ob, eg systolic and diastolic blood pressure and bmi were significantly higher in lop than eop statistically (p = 0.005, p = 0.047 and p = 0.020). laboratory studies in eop and lop laboratory work-up findings of the patients are shown in table 4. parameters indicating increased systemic inflammation, eg red cell distribution width (rdw), c-reactive protein (crp) and erythrocyte sedimentation rate (esr) were statistically higher in lop than in eop respectively (p = 0.017, p = 0.006, p = 0.001). fasting blood glucose was also higher in lop (p = 0.002). systemic treatments in eop and lop duration of systemic treatment was 42.09 ± 44.41 months in all patients, 44.41 ± 45.76 in eop and 34.91 ± 39.65 months in lop showing no significant difference (p = 0.158). 4 original article | dermatol pract concept. 2022;12(3):e2022144 table 1. demographics and family history of psoriasis in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p gender 0.144male, n (%) 90 (56.3) 72 (59.5) 18 (46.2) female, n (%) 70 (43.8) 40 (40.5) 21 (53.8) age, years, 44.73 ± 13.66 40.46 ±12.24 57.95±8.40 <0.01 mean±sd (range) (18-75) (18-65) (41-75) age at onset of psoriasis, years, 27.24±15.06 20.07±8.45 49.49±7.20 <0.01 mean±sd (range) (4-67) (4-38) (41-67) family history of psoriasis, n (%) 64 (40) 57 (47.1) 7 (17.9) 0.001 eop = early onset psoriasis; lop = late onset psoriasis; sd = standard deviation. table 2. comparison of disease severity in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p bsa, % 3.50 ± 8.65 3.34 ± 8.58 3.99 ± 8.96 mean±sd (range) (0-74.5) (0.1-74.7) (0-37.8) 0.636 pasi 3.46 ± 6.42 3.16 ± 6.07 4.37 ± 7.43 mean±sd (range) (0-53.10) (0.2-53.10) (0-36) 0.460 active disease without rx, months 24.46 ± 49.59 28.62 ± 55.26 11.54 ± 20.57 mean±sd (range) (0-360) (0-360) (0-96) 0.083 active disease with rx, months 28.29 ± 68.68 33.78 ± 77.57 11.26 ± 18.32 mean±sd (range) (0-492) (0-492) (0-72) 0.334 history of hospitalization number of positive history, n (%) 28 (17.5) 24 (19.8) 4 (10.3) 0.171 number of hospitalizations 0.38 ± 1.25 0.35 ± 0.90 0.49 ± 1.99 mean±sd (range) (0-12) (0-5) (0-12) 0.380 history of erythroderma number of positive history, n (%) 12 (7.5) 11 (9.1) 1 (2.6) 0.296 number of erythroderma 0.13 ± 0.55 0.16 ± 0.61 0.05 ± 0.32 mean±sd (range) (0-5) (0-5) (0-2) 0.187 bsa = body surface area; eop = early onset psoriasis; lop = late onset psoriasis; pasi = psoriasis area and severity index; rx = systemic treatment; sd = standard deviation. table 3. physical examination findings in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p systolic bp, mm/hg 118.17 ± 13.39 116.24 ± 12.46 124.18 ± 14.55 mean±sd (range) (90-160) (90-150) (100-160) 0.005 diastolic bp, mm/hg 79.31 ± 10.94 78.14 ± 10.02 82.95 ± 12.86 mean±sd (range) (50-120) (50-100) (60-120) 0.047 bmi, kg/m2 28.02 ± 4.93 27.62 ± 5.16 29.27 ± 3.94 mean±sd (range) (16.67-46.90) (16.67-46.90) (21.39-39.40) 0.020 waist circumference/men, cm 102.07 ±13.55 101.13 ±13.97 105.83 ±11.31 mean±sd (range) (76-143) (76-143) (79-129) 0.190 waist circumference/women, cm 99.80 ± 13.29 98.67 ±14.62 102.42 ± 9.29 mean±sd (range) (76-149) (76-149) (84-127) 0.282 bmi = body mass index; bp = blood pressure; eop = early onset psoriasis; lop = late onset psoriasis; sd = standard deviation. original article | dermatol pract concept. 2022;12(3):e2022144 5 nail involvement in eop and lop psoriatic nail involvement was compared in eop and lop, and results are shown in table 5. the duration of disease between onset of psoriasis and nail involvement was statistically significantly shorter in lop than eop (p < 0.01). duration of active psoriatic disease in patients with nail involvement was also significantly shorter in lop than in eop (p < 0.01, p < 0.01). the most frequent psoriatic nail involvement was seen as pitting, observed in 14% (n = 17) of eop and 12.8% (n = 5) in lop. subungual hyperkeratosis was only observed in 5% (n = 6) of eop, distal onycholysis was observed in 5% (n = 6) and 10.3% (n = 4), oil-drop sign was observed in 5% (n = 6) and 2.3 % (n = 1) of eop and lop, respectively. psa in eop and lop data regarding prevalence of psa, age at onset of psa, duration between onset of psoriasis and psa, and active disease duration of patients with psa with and without treatment are shown in table 6. duration between onset of psoriasis and psa was significantly shorter in lop than eop (p < 0.01). duration of active disease in psa patients with or without systemic treatments was also significantly shorter in lop than eop respectively (p = 0.002, p < 0.01). rsq revealed morning stiffness in 10.7% (n = 13) of eop and 5.1 % (n = 2) of lop. muscle-joint complaints was observed in 9.1% (n = 11) and 10.3% (n = 4), small joints complaints were found in 9.1% (n = 11) and 5.1% (n = 2), enthesis complaints were found in 14% (n = 17) and 12.8% (n = 5) and axial complaints were noted in 14.9 % (n = 18) and 20.5% (n = 8) of eop and lop patients respectively. none of the patients referred to rheumatologic consultations were diagnosed with psa. concurrent systemic inflammatory comorbidities in eop and lop prevalence and age at onset of systemic inflammatory comorbidities in eop and lop are shown in table 7. cvd, ht, dm and ms were found significantly more frequent in lop compared to eop (p = 0.045, p = 0.001, p < 0.01, p = 0.022). in order to evaluate the effect of psoriasis subtype to the development of concurrent systemic inflammatory comorbidities, multivariate regression analysis was performed; age, gender, severity parameters of disease, alcohol consumption, smoking habits and other concurrent systemic comorbidities were taken into account (table 8). based on this analysis, lop was found as an independent risk factor for cvd and dm (p < 0.01, r2: 0.036; p < 0.01, r2: 0.077). risk of cvd, dm, ht and ms were increased accordingly with decades of psoriasis onset (p = 0.036, p = 0.007, p = 0.001, p = 0.003). nash, dlp and ob development risk was not found to be showing this relationship with psoriasis onset (p = 0.194, p = 0.158, p = 0.644). conclusions as it was aimed, comparison of disease characteristics and concurrent inflammatory comorbidities enabled us to spot the peculiar differences in eop and lop; we were also able table 4. laboratory findings in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p hemoglobin, gr/dl 14.71 ± 1.46 14.85 ± 1.43 14.28 ± 1.48 mean±sd (range) (9.6-17.6) (9.6-17.6) (11.0-17.2) 0.035 wbc, x103/µl 7069 ± 1716.37 6973 ±1701.75 7364 ± 1750.11 mean±sd (range) (3800-13400) (3900-11800) (3800-13400) 0.222 platelets, x103/µl 230597±60028.87 227699 ±58982.59 239589 ± 63101.30 mean±sd (range) (24600-424000) (24600-381000) (137000-424000) 0.283 rdw, % 13.99±1.64 13.84 ± 1.33 14.46 ± 2.34 mean±sd (range) (12-27) (12-20.1) (12.5-27.1) 0.017 fasting blood glucose, mg/dl 97.75 ± 25.77 94.84 ± 22.37 106.65 ± 32.92 mean±sd (range) (68-260) (68-203) (77-260) 0.002 crp, mg/l 0.52 ± 0.81 0.45 ± 0.59 0.76 ± 1.28 mean±sd (range) (0.02-7.90) (0.02-5.59) (0.15-7.99) 0.006 esr, mm/hour 11.61 ± 9.52 10.30 ± 8.58 16.56 ± 11.30 mean±sd (range) (2-54) (2-37) (2-54) 0.001 crp = c-reactive protein; eop = early onset psoriasis; esr = erythrocyte sedimentation rate; lop = late onset psoriasis; mcv = mean corpuscular volume; mpv = mean platelet volume; nlr = neutrophil lymphocyte ratio; rdw = red cell distribution width; sd = standard deviation; wbc = white blood cells. 6 original article | dermatol pract concept. 2022;12(3):e2022144 table 6. psa characteristics in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p psa, n (%) 41 (25.6) 33 (27.3) 8 (20.5) 0.057 age at psa onset, years 38.98 ± 11.64 37.0 ± 11.49 47.13 ± 8.77 mean±sd (range) (10-71) (10-63) (37-71) 0.025 duration between ps and psa, years 12.80 ± 11.46 15.72 ± 10.36 0.75 ± 7.36 -a, < 0,01b mean±sd (range) (15-34) (1-34) (1-15) active ps duration in psa patients with rx, months 28.34 ± 9.2 34 ± 20.1 6 ± 8.3 0.761 a, 0.002 b mean±sd active ps duration in psa patients without rx, months 27.98 ± 10.3 33 ± 15.1 9 ± 18.1 0.803 a, < 0.0 b mean±sd eop = early onset psoriasis; lop = late onset psoriasis; ps = psoriasis; psa = psoriatic arthritis; rx = systemic treatment; sd = standard deviation. pa: patients with psoriasis; pb: between eop and lop table 5. psoriatic nail involvement in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p nail involvement, n (%) 87 (54.3) 68 (56.1) 19 (48.7) 0.415 age at nail involvement onset, years 34.29 ± 12.93 29.51 ± 10.23 49.85 ± 7.33 mean±sd (range) (10-70) (10-62) (37-70) < 0.01 disease duration between ps and nail involvement, years 7.4 ± 8.1 9.06 ± 8.5 2.1 ± 3.0 a, < 0.01b mean±sd (range) (4-37) (0-37) (4-9) concurrent nail involvement and psa, n (%) 28 (17.5) 8 (6.6) 5 (12.8) 0.072 a, 0.041 b active disease duration in patients with nail involvement and rx, months 30.63 ± 9.1 35 ± 48.32 16 ± 19.3 0.639 a, < 0.01 b mean±sd active disease duration in patients with nail involvement without rx, months 30.22 ± 9.8 34 ± 50.1 17 ± 18.2 0.027a, < 0.01 b mean±sd eop = early onset psoriasis; lop = late onset psoriasis; ps = psoriasis; psa = psoriatic arthritis; rx = systemic treatment; sd = standard deviation. p a: patients with psoriasis; pb: between eop and lop to evaluate the sole contribution of psoriasis subtype (lop) to the developmental risk of certain comorbidities determined as cvd and dm. psoriasis is proven to cause serious systemic inflammation however the exact tools to monitor the inflammatory burden is yet to be discovered. reports in literature concerning the severity of psoriasis subtypes comparing eop and lop are few and contradictory. in these data, authors mostly used pasi score, bsa and duration of systemic treatment to evaluate severity of psoriasis. although some researches did not find significant difference in the severity of psoriasis between eop and lop , others found eop to be more severe than lop [1,3,4,7,17]. in this study, evaluation of psoriatic inflammation was assessed by severity parameters along with calculations made for active disease duration and duration of time between onset of psoriasis and concurrent inflammatory comorbidities. although traditional markers of psoriasis severity such as pasi scores and bsa did not show any difference between eop and lop, we found that lop was associated with rapid development of psoriatic nail involvement and psa in statistically significantly shorter periods of time despite shorter active disease durations with and without treatment. lop was also found to associate with higher levels of inflammatory serum markers like crp, esr and rdw. as a whole, our results strongly support that lop poses heavier and rapid inflammatory burden. accordingly, we prioritize the determination of the disease subtype as eop or lop and suggest exploring the duration of time between original article | dermatol pract concept. 2022;12(3):e2022144 7 table 7. prevalence and age at onset of psoriatic comorbidities in eop and lop variables total patients (n = 160) eop (n = 121) lop (n = 39) p cvd, n (%) 4 (2.5) 1 (0.8) 3 (7.7) 0.045 age at cvd onset, years 50.75 ± 2.36 51 50.67 ± 1.67 0.929 mean±sd (range) (49-54) 51 (49 -54) ht, n (%) 32 (20) 17 (14) 15 (38.5) 0.001 age at ht onset, years 44.28 ± 8.23 41.53 ± 5.37 47.40 ± 9.87 mean±sd (range) (33-70) (33-53) (39-70) 0.165 dm, n (%) 25 (15.6) 12 (9.9) 13 (33.3) < 0.01 age at dm onset, years 42.68 ± 9.79 37.75 ± 7.70 47.23 ± 9.53 0.004 mean±sd (range) (28-65) (28-57) (38-65) nash, n (%) 29 (18.1) 22 (18.2) 7 (17.9) 0.974 age at nash onset, years 39.21 ± 8.20 37.48 ± 8.34 44.43 ± 5.38 0.045 mean±sd (range) (20-59) (20-59) (38-53) dlp, n (%) 99 (61.9) 72 (59.5) 27 (69.2) 0.392 ms, n (%) 47 (29.6) 30 (24.8) 17 (44.7) 0.022 ob, n (%) 46 (28.7) 36 (29.8) 10 (25.6) 0.622 cvd = cardiovascular disease; dlp = dyslipidemia; dm = diabetes mellitus; eop: early onset psoriasis; ht = hypertension; lop = late onset psoriasis; ms = metabolic syndrome; nash = non-alcoholic steatohepatitis; ob = obesity; sd = standard deviation. table 8. multivariate regression analysis of impact of psoriasis subtype on concurrent systemic inflammatory comorbidities ht dm ibd nash cvd dlp ms ob rx duration disease duration ht 0.158 -0.249 0.225 0.177 dm 0.167 0.235 ibd 0.217 nash 0.219 0.249 cvd dlp -0.231 0.557 -0.194 ms 0.402 0.309 0.632 ob 0.220 pasi bsa ps subtype 0.168 0.248 -0.747 gender -0.265 -0.163 0.182 0.101 duration of rx 0.236 0.250 age 0.403 0.224  1.009 0.663 disease duration  -0.516 duration of active disease without rx.  0.156 duration of active disease with rx 0.123 0.188 smoking r2 value 0.288 0.237 0.056 0.200 0.133 0.451 0.538 0.115 0.325 0.620 p value 0.000 0.000 0.003 0.000 0.000 0.000 0.000 0.000 0.000 0.000 bsa = body surface area; cvd = cardiovascular disease; dlp = dyslipidemia; dm = diabetes mellitus; ht = hypertension; ibd = inflammatory bowel disease; ms = metabolic syndrome; nash = nonalcoholic steatohepatitis; ob = obesity; pasi = psoriasis area and severity index; ps = psoriasis; rx = systemic treatment. 8 original article | dermatol pract concept. 2022;12(3):e2022144 onset of psoriatic involvements and comorbidities (psoriatic nail, psa, cvd, dm, ht, ms) and active disease duration for evaluating inflammation and its consequences in psoriasis. we believe that the alltogether analysis of these parameters with the traditional clinical severity scores may create a new concept of approach for psoriasis follow-up. nail involvement is observed in 13%-50% of psoriasis patients and this rate increases to 80%-90% by age [18]. reports on nail involvement in eop and lop differ; some report more frequent nail involvement in eop, others found that lop more frequently affect nails [3,5,10,17]. there are also studies showing no difference in nail involvement between eop and lop [1,4,7]. we did not observe statistically significant difference in both nail involvement and type of nail involvement, neither. but interestingly, nails were found to be affected in significantly shorter duration in lop in comparison with eop. similar to the findings observed in psoriatic nail involvement, psa was found to develop in significant shorter periods of time in eop. generally, psa is observed in 5-30% of patients with psoriasis [19]. most researches did not find difference in concurrent psa between eop and lop [3,4,7]. heredi et al have demonstrated that the psa was more frequent in eop and risk of development of psa decreases by increasing age and this risk completely disappears after age 75 [1]. in this study, there was no difference between eop and lop for associating psa prevalence. rsq responses were also similar in two disease subtypes. as it leads to psa faster than eop, lop can be accepted to generate a rapid inflammatory course and cause damage target organs such as nails, ligaments, tendons and joints. increased frequencies of systemic comorbidities such as cvd, dm, ht and ms in lop compared to eop were detected in this study. bmi, systolic and diastolic blood pressure values, fasting blood glucose, bun, crp, esr, rdw levels were also higher in lop. these findings suggest that concomitant inflammatory comorbidities may increase the amount and speed of psoriatic inflammation. to our knowledge there are no reports comparing the laboratory indicatives of systemic inflammation in eop and lop, but these parameters have been shown to be higher in psoriasis patients in comparison to general population [20,21]. rdw and crp levels have also been suggested as reliable markers of inflammation in psoriasis [20,21]. besides, elevated levels of crp have been shown to be an independent risk factor for development of cvd in psoriasis and may be associated with increased risk of ms [21]. however, there is again few data of psoriasis subtype and its contribution to these concurrent comorbidities. heredi et al did not found difference in the risk of development of cvd between eop and lop [1]. despite our low number of cases in the study, lop was able to be shown as an independent risk factor for cvd and dm. this risk must be kept in mind in lop and on time referral and adequate anti-psoriatic treatment choice is mandatory and is lately recommended in psoriasis guidelines [22]. eop and lop are two different types of psoriasis with different etiologies, clinical characteristics, laboratory indicatives and concurrent systemic comorbidities. despite similar treatment regimens and shorter duration of active disease, lop causes faster nail and joint involvement in a shorter period of time and is more frequently associated with systemic inflammatory comorbidities such as cvd, dm, ht and ms. lop was also found to be independent risk factor for development of cvd and dm. from this aspect, we prioritize the determination of the disease subtype as eop or lop and suggest lop to be closely monitored for potential development of end-organ inflammatory comorbidities. lop must be considered as the more rapid and aggressive type of psoriasis which provokes development of inflammatory comorbidities in 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and attention to comorbidities. j am acad dermatol. 2019;80(4):1073–1113. doi: 10.1016/j. jaad.2018.11.058. pmid: 30772097. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023067 1 international dermoscopy society (ids) criteria for skin tumors: validation for skin of color through a delphi expert consensus by the “imaging in skin of color” ids task force balachandra s ankad1, biswanath behera2, aimilios lallas3, bengu nisa akay4, yasmeen j bhat 5, payal chauhan6, nkechi anne enechukwu7, shamir geller8, abhijeet kumar jha9, feroze kaliyadan10, kayitesi kayitenkore11, awatef kelati12, keshavamurthy vinay13, jennifer stein14, ibrahima traoré15, richard p usatine16, enzo errichetti17 1 department of dermatology, venereology and leprosy, sn medical college, bagalkot, karna-taka, india 2 department of dermatology and venereology, aiims, bhubaneswar, india 3 first department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece 4 department of dermatology, school of medicine, ankara university, ankara, turkey; 5 department of dermatology, venereology and leprology, government medical college, university of kashmir, srinagar, jammu and kashmir, india 6 department of dermatology, all india institute of medical sciences (aiims), bilaspur, himachal pradesh, india 7 nnamdi azikiwe university/nnamdi azikiwe teaching hospital nnewi, anambra state, nigeria; 8 division of dermatology, tel aviv sourasky medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel 9 department of dermatology & std, patna medical college & hospital, patna, india 10 department of dermatology, sree narayana institute of medical sciences, ernakulum, india 11 university of rwanda, kigali, rwanda 12 dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco 13 department of dermatology, venereology and leprology, postgraduate institute of medical education and research, chandigarh, india 14 the ronald o. perelman department of dermatology, new york university school of medicine, new york, ny, usa 15 dermatological clinic, conakry, guinea 16 department of dermatology and cutaneous surgery, department of family and community medicine, university of texas health san antonio, san antonio, tx, usa 17 institute of dermatology, “santa maria della misericordia” university hospital, udine, italy key words: dermoscopy, neoplasias, neoplastic dermatoses, skin of color, tumors citation: ankad bs, behera b, lallas a, et al. international dermoscopy society (ids) criteria for skin tumors: validation for skin of color through a delphi expert consensus by the “imaging in skin of color” ids task force. dermatol pract concept. 2023;13(1):e2023067. doi: https://doi.org/10.5826/dpc.1301a67 accepted: november 17, 2022; published: january 2023 copyright: ©2023 ankad et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: enzo errichetti, institute of dermatology, “santa maria della misericordia” university hospital, piazzale santa maria della misericordia, 15. 33100-udine, italy. tel: (+39) 0432559822. e-mail: enzoerri@yahoo.it 2 original article | dermatol pract concept. 2023;13(1):e2023067 introduction dermoscopy has nowadays become an invaluable tool for the dermatologist’s daily practice as it allows to highlight relevant findings corresponding to key histological changes that are not visible to the naked eye, thus increasing diagnostic accuracy in the field of both neoplastic and non-neoplastic skin conditions [1,2]. importantly, to make dermoscopic examination as reproducible as possible it is of utmost importance to follow a systematic analytical approach, with a standardized set of parameters to evaluate and a uniform terminology to use [3-5]. however, over time, many authors employed an arbitrary approach with the use of different terms, even to refer to the same dermoscopic finding, with a consequent heterogeneous semeiology generating confusion among users [4]. in order to face such an issue, the international dermoscopy society (ids) has released two consensus documents encompassing basic dermoscopic variables to assess with the corresponding vocabulary to adopt, one for skin neoplasms and one for non-neoplastic dermatoses (inflammatory, infectious, and infiltrative diseases) [4,5]. notably, these guidelines were issued considering the literature evidence on light phototypes, with consequent possible limitations if used in dark skin [4,5]. indeed, it has been shown that dermoscopic patterns of skin disorders may remarkably vary (especially for phototypes v/vi) because of the different color backgrounds as well as specific reaction patterns typical of darker phototypes (e.g., lability of pigment and greater tendency to follicular or sclerotic reactions) [6,7]. for these reasons, the ids supported a validation process of its consensus document on non-neoplastic dermatoses for use in dark skin, yet such a procedure has not been performed with regard to neoplastic disorders [8]. this document was promoted by the “imaging in skin of color” ids task force with the aim of validating the dermoscopic criteria/terminology provided by the ids for skin tumors for the use in skin of color by a consensus process involving a panel of experts routinely dealing with dark-skinned patients (phototypes iv, v, and vi). materials and methods the consensus was performed according to the two-round “delphi method”, with an iterative process including two rounds of email questionnaires starting from a list of preselected items (i.e., dermoscopic criteria provided by the ids)  [5]. notably, differently from the “modified delphi method”, the delphi process makes it possible to gain expert consensus on variable issues by using at least two rounds of questionnaires and involving at least 5-10 participants, without the need for an in-person discussion [9-11]. so, similarly to the validation process for skin of color carried out for non-neoplastic dermatoses [8], we chose to avoid a face-to-face meeting in order to reduce decisional biases because of group interaction [9-11]. introduction: a structured set of eight basic dermoscopic parameters (lines, clods, dots, circles, pseudopods, structureless, else, and vessels) including a total of 77 variables with corresponding descriptive and metaphoric vocabulary has been released for evaluation of skin tumors by the international dermoscopy society (ids). objectives: to validate the aforementioned criteria for the use in darker phototypes (phototypes iv-vi) via an expert consensus. methods: the two-round “delphi method” was adopted, with an iterative process including two rounds of email questionnaires. potential panelists were asked to take part in the procedure via email on the basis of their expertise in the dermoscopy of skin tumors in dark phototypes. results: a total of 17 participants were involved. all the original variables of the eight basic parameters reached agreement during the first round, except for “pink small clods” (“milky red globules”) and “structureless pink zone” (“milky red areas”). moreover, during the first round, panelists proposed a change of three existing items and the introduction of four new items, i.e., “black, small clods” (“black globules”), “follicular plugs”, “erosions/ulcerations”, and “white color around vessels” (“perivascular white halo”). all such proposals achieved agreement, thus being included in the final list, for a total of 79 items. there was consistency between the descriptive and metaphoric approaches in terms of scoring. conclusions: albeit most of the original items were considered applicable even for skin of color, there are some points of differences that physicians need to know. no significant preference was found between descriptive and metaphoric terminology among panelists. abstract original article | dermatol pract concept. 2023;13(1):e2023067 3 panel selection panel selection was performed by sending an e-mail invitation from the coordinators of the process (e.e. and b.s.a.) to experts in the field of dermoscopy in skin of color (phototypes iv, v, and vi) across the world. in detail, all the members of the “imaging in skin of color” ids task force were invited to join the panel, along with researchers who had published at least five peer-reviewed articles or book chapters on such a topic as either the first or last author. in total, 22 international experts were invited as panel members; participants’ assessments were blinded and anonymity was maintained during the entire process of consensus. round 1 the dermoscopic criteria provided by the ids [5] were tabulated (table 1) and shared with all the panelists via emails, including eight basic dermoscopic parameters with a total of 77 items. as per the original consensus, descriptive terminology and corresponding metaphoric vocabulary for each dermoscopic parameter were included in the validation process. instructions and aims of the consensus process were also circulated. panelists were asked to judge on a 5-point scale the level of agreement on the relevance of each variable (descriptive and metaphoric) for the use in dark-skinned patients (1, no agreement; 2, low agreement; 3, moderate agreement; 4, agreement; and 5, strong agreement). in case of disagreement/ poor agreement (score 1-3) on any of the items, participants were invited to justify their choice and provide (optional) suggestions to improve them. experts were also given the chance to propose additional variables not included in the original list. each item was considered appropriate for the use in skin of color in case of achievement of a score of 4 or 5 out of 5 by more than 80% of the experts. the agreement threshold of 80% was selected based on the literature guidance on delphi consensus [10]. parameters which had not attained 80% agreement would be modified in accordance with suggestions (if any) given by the participants and redistributed, along with new possible proposed items, to the panel of experts for round 2. round 2 in round 2, panelists were asked to assess the modified and new parameters (if any) resulting from round 1, following the same methodology as the previous round. at the end of round 2, a comparison between the rating of descriptive and metaphoric terminology for each of the eight basic dermoscopic parameters was carried out. data were expressed as means ± sd and analysis was performed using microsoft excel 2016 (microsoft corporation, redmond, wa, usa) by the unpaired, two-tailed student’s t-test, with p-value of <0.05 deemed statistically significant. results a total of 17 participants were involved in both rounds of the consensus. with regard to descriptive terminology, all the items received agreement in round 1 except for “pink small clods” and “structureless pink zone”, which reached a mean score of 3.94 and 3.95, respectively. similarly, corresponding metaphoric terms for such variables (i.e., “milky red globules” and “milky red areas”) did not achieve agreement too, with a mean score of 3.98 and 3.86, respectively. four new items were proposed during the first round, i.e., (i) “black, small clods” (black globules) for parameter 2 (“clods”); (ii) follicular plugs and (iii) erosions/ulcerations for parameter 7 (“else”); and (iv) white color around vessels (perivascular white halo) for parameter 8 (“vessels”). moreover, the group of experts suggested changing three items when it comes to descriptive terminology, including (i) “clods, brown or blue, concentric (clod within a clod)” to “clods, brown, blue or black, concentric (clod within a clod)”; (ii) “dots, gray” to “dots, gray, blue or black”; and (iii) “dots, gray and circles, gray” to “dots, gray, blue or black and circles, gray, blue or black”. all such proposals were rated during the second round and achieved agreement, thus being included in the final list. therefore, at the end of the validation process, a total of 79 items were identified (72 out of the 77 proposed by the ids plus seven added in the course of the consensus procedure). table 1 displays details on agreement rates and mean scores for rounds 1 and 2. figures 1-4 depict schematic illustrations of the new/changed items and examples of skin tumors typified by such structures. moving to the comparative analysis between descriptive and metaphoric terms of the eight basic parameters, although for the majority of them the mean score was higher for the descriptive counterpart, no statistically significant differences were observed (p-values >0.05). discussion this expert consensus underlines that the whole set of dermoscopic criteria proposed by the ids for the evaluation of skin tumors may also be used when assessing dark phototypes, apart from “clods, pink and small” and “structureless zone, pink” (and corresponding metaphoric terms, i.e., “milky-red globules” and “milky-red areas”) as “pink”/“milky-red” hue is more difficult to detect in skin of color because of the pigmented background [6, 12]. in general, most of the variables included from the original ids list (considering both descriptive and metaphoric 4 original article | dermatol pract concept. 2023;13(1):e2023067 ta b le 1 . r es u lt s o f th e va li d at io n p ro ce ss f o r th e u se o f th e id s d er m o sc o p ic c ri te ri a (i n cl u d in g b o th d es cr ip ti ve a n d m et ap h o ri c te rm in o lo gy ) fo r n eo p la st ic d er m at o se s in s k in o f co lo r w it h c o rr es p o n d in g ag re em en t ra te s (p er ce n ta ge o f ex p er ts g iv in g a sc o re o f 4 o r 5 ) an d m ea n s co re s fo r ea ch r o u n d d e rm o sc o p ic p a ra m e te r (d e sc ri p ti v e t e rm in o lo g y ) i r o u n d * ii r o u n d * d e rm o sc o p ic p a ra m e te r (m e ta p h o ri c te rm in o lo g y ) i r o u n d * ii r o u n d * 1 l in es l in es , r et ic u la r 1 0 0 ( 4 .8 3 ) p ig m en t n et w o rk 1 0 0 ( 4 .9 1 ) l in es , r et ic u la r an d t h ic k 1 0 0 ( 4 .7 5 ) b ro ad en ed n et w o rk 1 0 0 ( 4 .9 1 ) l in es , r et ic u la r an d t h in 1 0 0 ( 4 .5 8 ) d el ic at e n et w o rk 1 0 0 ( 4 .7 5 ) l in es , r et ic u la r an d t h ic k o r re ti cu la r li n es t h at v ar y in co lo r 1 0 0 ( 4 .6 6 ) a ty p ic al p ig m en t n et w o rk 1 0 0 ( 4 .9 1 ) l in es , r et ic u la r, w h it e 8 5 ( 4 .2 5 ) l in es , r et ic u la r, h yp o p ig m en te d , a ro u n d b ro w n c lo d s 9 2 ( 4 .4 1 ) n eg at iv e p ig m en t n et w o rk 1 0 0 ( 4 .3 3 ) l in es , w h it e, p er p en d ic u la rl y* * * 1 0 0 ( 4 .6 6 ) sh in y w h it e st re ak s* * * 8 4 .6 ( 4 .6 6 ) l in es , b ra n ch ed 1 0 0 ( 4 .7 5 ) b ra n ch ed s tr ea k s 1 0 0 ( 4 .6 6 ) l in es , r ad ia l (a lw ay s at p er ip h er y) 1 0 0 ( 4 .8 3 ) st re ak s 1 0 0 ( 4 .8 3 ) l in es , r ad ia l an d s eg m en ta l 1 0 0 ( 4 .8 3 ) r ad ia l st re am in g 1 0 0 ( 4 .6 6 ) l in es , r ad ia l, co n n ec te d t o a c o m m o n b as e 1 0 0 ( 4 .7 5 ) l ea fl ik e ar ea s 1 0 0 ( 4 .8 3 ) l in es , r ad ia l, co n ve rg in g to a c en tr al d o t o r cl o d 1 0 0 ( 4 .9 1 ) sp o k e w h ee l ar ea 1 0 0 ( 4 .7 5 ) l in es , c u rv ed a n d t h ic k 1 0 0 ( 4 .6 6 ) c er eb ri fo rm p at te rn 1 0 0 ( 4 .8 3 ) l in es , b ro w n , c u rv ed , p ar al le l, th in 1 0 0 ( 4 .6 6 ) f in ge rp ri n ti n g 1 0 0 ( 4 .8 3 ) l in es , c u rv ed a n d t h ic k , i n c o m b in at io n w it h c lo d s 1 0 0 ( 4 .7 5 ) c ry p ts 1 0 0 ( 4 .8 3 ) l in es , p ar al le l, sh o rt , c ro ss in g ri d ge s (v o la r sk in ) 1 0 0 ( 4 .8 3 ) f ib ri ll ar p at te rn 1 0 0 ( 4 .8 3 ) l in es , p ar al le l, th ic k , o n t h e ri d ge s (v o la r sk in ) 1 0 0 ( 4 .8 3 ) p ar al le l ri d ge p at te rn 1 0 0 ( 4 .7 5 ) l in es , p ar al le l, th in , i n t h e fu rr o w s an d c ro ss in g th e ri d ge s (v o la r sk in ) 1 0 0 ( 4 .8 3 ) l at ti ce -l ik e p at te rn 1 0 0 ( 4 .7 5 ) l in es , p ar al le l, th in , i n t h e fu rr o w s (v o la r sk in ) 1 0 0 ( 4 .8 3 ) p ar al le l fu rr o w s p at te rn 1 0 0 ( 4 .7 5 ) l in es , a n gu la te d o r p o ly go n al ( fa ci al s k in ) 9 2 ( 4 .5 8 ) r h o m b o id s/ zi gza g p at te rn 9 2 ( 4 .5 0 ) l in es , a n gu la te d o r p o ly go n al ( n o n -f ac ia l sk in ) 9 2 ( 4 .5 0 ) a n gu la te d l in es /p o ly go n s 9 2 ( 4 .5 2 ) 2 c lo d s c lo d s, s m al l, ro u n d o r o va l 1 0 0 ( 4 .7 5 ) g lo b u le s 1 0 0 ( 4 .5 0 ) c lo d s, b ro w n , c ir cu m fe re n ti al 9 2 ( 4 .5 8 ) r im o f b ro w n g lo b u le s 9 2 ( 4 .5 1 ) original article | dermatol pract concept. 2023;13(1):e2023067 5 d e rm o sc o p ic p a ra m e te r (d e sc ri p ti v e t e rm in o lo g y ) i r o u n d * ii r o u n d * d e rm o sc o p ic p a ra m e te r (m e ta p h o ri c te rm in o lo g y ) i r o u n d * ii r o u n d * c lo d s, b ro w n , y el lo w , o r o ra n ge ( ra re ly b la ck ) 9 2 ( 4 .5 2 ) c o m ed o -l ik e o p en in gs 9 2 ( 4 .4 1 ) c lo d s, b ro w n o r b lu e, c o n ce n tr ic ( cl o d w it h in a c lo d ) 8 5 ( 4 .1 6 ) c o n ce n tr ic g lo b u le s 9 2 ( 4 .4 2 ) c lo d s, b ro w n , b lu e o r b la ck , c o n ce n tr ic ( cl o d w it h in a cl o d )* * 1 0 0 ( 4 .5 3 ) c o n ce n tr ic g lo b u le s 1 0 0 ( 4 .4 2 ) c lo d s, b ro w n o r sk in c o lo re d , l ar ge a n d p o ly go n al 1 0 0 ( 4 .5 8 ) c o b b le st o n e p at te rn 1 0 0 ( 4 .5 0 ) c lo d s, b lu e, l ar ge , c lu st er ed 1 0 0 ( 4 .5 2 ) b lu egr ay o vo id n es ts 1 0 0 ( 4 .7 5 ) c lo d s, b lu e, s m al l 1 0 0 ( 4 .4 1 ) b lu e gl o b u le s 1 0 0 ( 4 .4 1 ) c lo d s, b la ck , s m al l 1 0 0 ( 4 .5 3 ) b la ck g lo b u le s 1 0 0 ( 4 .5 3 ) c lo d w it h in a c lo d ( co n ce n tr ic c lo d s) 8 5 ( 4 .2 5 ) v ar ia n t o f sp o k e w h ee l ar ea 8 5 ( 4 .3 0 ) c lo d s, w h it e, s h in y* * * 1 0 0 ( 4 .6 6 ) sh in y w h it e b lo tc h es a n d s tr an d s* * * 1 0 0 ( 4 .5 6 ) c lo d s, p in k a n d s m al l 7 2 ( 3 .9 4 ) m il k yre d g lo b u le s 7 2 ( 3 .9 8 ) c lo d s, r ed o r p u rp le 9 2 ( 4 .4 1 ) r ed l ac u n ae 9 2 ( 4 .2 3 ) 3 d o ts * * * * d o ts , a n y co lo r 1 0 0 ( 4 .8 3 ) g ra n u la ri ty o r gr an u le s 9 2 ( 4 .5 4 ) d o ts , g ra y 1 0 0 ( 4 .8 3 ) p ep p er in g 9 2 ( 4 .5 2 ) d o ts , g ra y, b lu e o r b la ck * * 1 0 0 ( 5 .0 ) p ep p er in g 1 0 0 ( 4 .5 2 ) d o ts , g ra y an d c ir cl es , g ra y 1 0 0 ( 4 .6 6 ) a n n u la rgr an u la r p at te rn 1 0 0 ( 4 .5 8 ) d o ts , g ra y, b lu e o r b la ck a n d c ir cl es , g ra y, b lu e o r b la ck * * 1 0 0 ( 4 .5 3 ) a n n u la rgr an u la r p at te rn 1 0 0 ( 4 .5 8 ) d o ts o r cl o d s, w h it e, c lu st er ed o r d is se m in at ed 9 2 ( 4 .5 8 ) m il ia -l ik e cy st , c lo u d y o r st ar ry 1 0 0 ( 4 .7 5 ) d o ts , w h it e, f o u r ar ra n ge d i n a s q u ar e* * * 1 0 0 ( 4 .5 1 ) r o se tt es * * * 9 2 ( 4 .6 6 ) d o ts , p er ip h er al , a rr an ge d i n l in es 1 0 0 ( 4 .5 3 ) l in ea r d o ts 8 5 ( 4 .5 2 ) d o ts , b ro w n , c en tr al ( in t h e ce n te r o f h yp o p ig m en te d sp ac es b et w ee n r et ic u la r li n es ) 9 2 ( 4 .4 8 ) t ar ge to id d o ts 9 2 ( 4 .3 2 ) 4 c ir cl es c ir cl es , w h it e 9 2 ( 4 .5 8 ) c ir cl es , c o n ce n tr ic 9 2 ( 4 .1 6 ) c ir cl e w it h in a c ir cl e 9 2 ( 4 .1 6 ) c ir cl es , i n co m p le te 9 2 ( 4 .3 3 ) a sy m m et ri c p ig m en te d f o ll ic u la r o p en in gs 1 0 0 ( 4 .1 2 ) 5 p se u d o p o d s p se u d o p o d s, c ir cu m fe re n ti al o r li n es , r ad ia l, ci rc u m fe re n ti al 1 0 0 ( 4 .6 6 ) st ar b u rs t p at te rn 1 0 0 ( 4 .6 6 ) t ab le 1 c o n ti n u es 6 original article | dermatol pract concept. 2023;13(1):e2023067 d e rm o sc o p ic p a ra m e te r (d e sc ri p ti v e t e rm in o lo g y ) i r o u n d * ii r o u n d * d e rm o sc o p ic p a ra m e te r (m e ta p h o ri c te rm in o lo g y ) i r o u n d * ii r o u n d * 6 s tr u ct u re le ss st ru ct u re le ss z o n e, b ro w n o r b la ck 1 0 0 ( 4 .7 5 ) b lo tc h 1 0 0 ( 4 .7 5 ) st ru ct u re le ss z o n e, b lu e 1 0 0 ( 4 .5 8 ) b lu ew h it is h v ei l 1 0 0 ( 4 .6 6 ) st ru ct u re le ss z o n e, p in k 7 5 ( 3 .9 5 ) m il k yre d a re as 7 2 ( 3 .8 6 ) st ru ct u re le ss z o n e, w h it e 1 0 0 ( 4 .8 3 ) sc ar -l ik e d ep ig m en ta ti o n 1 0 0 ( 4 .7 5 ) st ru ct u re le ss z o n e, w h it e, c en tr al 1 0 0 ( 4 .8 3 ) c en tr al w h it e p at ch 1 0 0 ( 4 .6 6 ) st ru ct u re le ss z o n e, p o ly ch ro m at ic 8 5 ( 4 .3 3 ) r ai n b o w p at te rn 9 2 ( 4 .4 1 ) st ru ct u re le ss , r ed , i n te rr u p te d b y fo ll ic u la r o p en in gs 8 2 ( 4 .1 6 ) st ra w b er ry p at te rn 8 5 ( 4 .2 3 ) st ru ct u re le ss , b ro w n ( ta n ), e cc en tr ic 1 0 0 ( 4 .5 8 ) st ru ct u re le ss , a n y co lo r 1 0 0 ( 4 .7 5 ) h o m o ge n eo u s p at te rn 1 0 0 ( 4 .8 3 ) st ru ct u re le ss , b ro w n , i n te rr u p te d b y fo ll ic u la r o p en in gs (f ac ia l sk in ) 1 0 0 ( 4 .6 6 ) p se u d o n et w o rk 1 0 0 ( 4 .6 6 ) 7 e ls e sh ar p ly d em ar ca te d , s ca ll o p ed b o rd er 1 0 0 ( 4 .6 6 ) m o th -e at en b o rd er 1 0 0 ( 4 .7 5 ) f o ll ic u la r p lu gs 9 2 ( 4 .6 9 ) e ro si o n s/ u lc er at io n s 1 0 0 ( 4 .8 4 ) 8 v es se ls 8 .1 m o rp h o lo gy d o ts 1 0 0 ( 4 .7 5 ) c lo d s 1 0 0 (4 .3 8 ) r ed -p u rp le l ac u n es 1 0 0 ( 4 .4 6 ) l in ea r 1 0 0 ( 4 .7 5 ) c o il ed 1 0 0 ( 4 .5 8 ) g lo m er u la r 1 0 0 ( 4 .5 0 ) l o o p ed 1 0 0 ( 4 .6 6 ) h ai rp in 1 0 0 ( 4 .7 5 ) se rp en ti n e 1 0 0 ( 4 .5 0 ) l in ea r ir re gu la r 1 0 0 ( 4 .5 8 ) h el ic al 1 0 0 ( 4 .5 0 ) c o rk sc re w 1 0 0 ( 4 .5 8 ) c u rv ed 1 0 0 ( 4 .4 4 ) c o m m a 1 0 0 ( 4 .4 1 ) m o n o m o rp h o u s 9 2 ( 4 .4 1 ) p o ly m o rp h o u s 1 0 0 ( 4 .7 5 ) ta b le 1 . r es u lt s o f th e va li d at io n p ro ce ss f o r th e u se o f th e id s d er m o sc o p ic c ri te ri a (i n cl u d in g b o th d es cr ip ti ve a n d m et ap h o ri c te rm in o lo gy ) fo r n eo p la st ic d er m at o se s in s k in o f co lo r w it h c o rr es p o n d in g ag re em en t ra te s (p er ce n ta ge o f ex p er ts g iv in g a sc o re o f 4 o r 5 ) an d m ea n s co re s fo r ea ch r o u n d ( co n ti n u ed ) original article | dermatol pract concept. 2023;13(1):e2023067 7 d e rm o sc o p ic p a ra m e te r (d e sc ri p ti v e t e rm in o lo g y ) i r o u n d * ii r o u n d * d e rm o sc o p ic p a ra m e te r (m e ta p h o ri c te rm in o lo g y ) i r o u n d * ii r o u n d * 8 .2 a rr an ge m en t r ad ia l 1 0 0 ( 4 .6 6 ) c ro w n v es se ls 9 2 ( 4 .5 0 ) se rp ig in o u s 1 0 0 ( 4 .6 6 ) st ri n g o f p ea rl s 1 0 0 ( 4 .6 6 ) b ra n ch ed 1 0 0 ( 4 .7 8 ) a rb o ri zi n g ve ss el s 1 0 0 ( 4 .8 3 ) c lu st er ed 1 0 0 ( 4 .8 3 ) c en te re d d o ts 1 0 0 ( 4 .6 1 ) t ar ge to id v es se ls 1 0 0 ( 4 .6 3 ) 8 .3 w h it e co lo r ar o u n d v es se ls 1 0 0 ( 4 .5 3 ) p er iv as cu la r w h it e h al o 1 0 0 ( 4 .6 1 ) * a gr ee m en t ra te ( m ea n s co re ) – a gr ee m en t ra te i s m ea su re d f ro m 0 % t o 1 0 0 % , m ea n s co re i s m ea su re d f ro m 0 t o 5 ; * * t h is p ar am et er r ep la ce s th e p re vi o u s o n e. * * * o n ly v is ib le b y p o la ri ze d d er m o sc o p y. * * * * d o ts a n d c lo d s ca n b e b es t d if fe re n ti at ed i f th ey a p p ea r as a p at te rn . m u lt ip le d o ts h av e th e sa m e si ze a n d s h ap e (t h ey a re a ll s m al l an d r o u n d ), m u lt ip le c lo d s va ry i n s iz e an d s h ap e. i n g en er al d o ts a re n o t la rg er t h an t h e d ia m et er o f a te rm in al h ai r. 7 8 original article | dermatol pract concept. 2023;13(1):e2023067 change in the morphology of some structures (e.g., “incomplete” may become “complete” pigmented circles). this is in line with evidence from the literature. for example, blurred vascular structures and “reticular white lines”/“lines, reticular, hypopigmented, around brown clods” (negative pigment network), commonly found respectively in dermal nevi and dermatofibromas in light phototypes, have been reported less frequently in skin of color [13-15]. on the other hand, homogeneous pigmentary findings (excluding concentric and polychromatic items) and white structures were generally rated high (> 4.5). this is easily explained as diagnosis of skin tumors in dark-skinned patients mainly relies on the prevalence and combination of such features [16]. additionally, some vessel shapes/arrangements also reached a high score, especially dotted/linear morphologies and clustered/branched distribution patterns, likely resulting from the significant prevalence of these findings in bowen’s disease and basal cell carcinoma also in skin of color [17, 18]. besides dermoscopic items included in the original list of the ids, panelists also proposed and agreed on the introduction of four new variables for the assessment of skin tumors in dark phototypes, including “clods, black, small” (black terminology) received a high mean rate (between 4.5 and 5), with only a few of them reaching agreement with a lower score (< 4.5). in detail, the latter group included the following descriptive items: “reticular white lines” and “lines, reticular, hypopigmented, around brown clods” in the “lines” category; “clods, brown or blue, concentric (clod within a clod)”, “clods, blue, small”, “clod within a clod (concentric clods)” and “clods, red or purple” in the “clods” parameter; “dots, brown, central (in the center of hypopigmented spaces between reticular lines)” in the “dots” category; “circles, concentric” and “circles, incomplete” when it comes to the “circles” parameter; “structureless zone, polychromatic” and “structureless, red, interrupted by follicular openings” considering the “structureless” category; and “clods”, “curved” and “monomorphous” morphology in the “vessels” parameter. the reasons underlying a lower scoring for such variables mainly include the higher melanin content and the greater tendency to pigmentary incontinence typical of darker phototypes [6] that may result in lower optical contrast (needed to optimally see concentric, polychromatic or pigmented structures) or the partial obscuration of some findings (e.g., red/purple structures, smaller/thinner vessels, or hypopigmented lines) as well as figure 1. schematic representation of newly-introduced dermoscopic parameters to use in skin of color: black, small clods (black globules) (a); follicular plugs (b); erosions/ulcerations (c); and white color around vessels (perivascular white halo) (d). original article | dermatol pract concept. 2023;13(1):e2023067 9 figure 2. examples of skin tumors in dark-skinned patients (phototypes v/vi) typified by the newly-introduced dermoscopic structures: black, small clods (black globules) in a seborrheic keratosis (arrows) (a); follicular plugs in an actinic keratosis (arrows) (b); erosions in a basal cell carcinoma (arrows) (c); and white color around vessels (perivascular white halo) in a squamous cell carcinoma (d). figure 3. schematic representation of modified dermoscopic parameters to use in skin of color: “clods, brown, blue or black, concentric” (clod within a clod) (a); “dots, gray, blue or black” (peppering) (b); and “dots, gray, blue or black and circles, gray, blue or black” (annular-granular pattern) (c). figure 4. examples of skin tumors in dark-skinned patients (phototypes v/vi) typified by the modified dermoscopic parameters: black/ brown concentric clods (black clod within a brown clod) in a basal cell carcinoma (arrows) (a); “blue/black dots” (blue/black peppering) in a melanoma (arrows) (b); and “blue/black dots and circles” (blue/black annular-granular pattern) in a lentigo maligna (arrows) (c). 10 original article | dermatol pract concept. 2023;13(1):e2023067 intended to be the starting point to fill the existing knowledge gap in the field of dermoscopy of skin tumors in skin of color as it might help facilitate the interpretation of reported findings and increase the reproducibility of the studies. limitations the present validation process was based on the delphi technique, which relies on the opinion of a group of experts, so the results represent the point of view of a limited number of evaluators. additionally, albeit all the included panelists routinely deal with dark-skinned patients, an interobserver variability does exist in terms of the proportions of each phototype. references 1. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb) 2016;6:471-507. 2. fee ja, mcgrady fp, rosendahl c, hart nd. training primary care physicians in dermoscopy for skin cancer detection: a scoping review. j cancer educ 2020;35:643-50. 3. errichetti e. dermoscopy of inflammatory dermatoses (inflammoscopy): an up-to-date overview. dermatol pract concept 2019;9:169-80. 4. errichetti e, zalaudek i, kittler h, et al. standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (non-neoplastic dermatoses): an expert consensus on behalf of the international dermoscopy society. br j dermatol 2020;182:454-67. 5. kittler h, marghoob aa, argenziano g, et al. standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy. j am acad dermatol 2016;74:1093-106. 6. errichetti e, ankad bs, sonthalia s, et al. dermoscopy in general dermatology (non-neoplastic dermatoses) of skin of colour: a comparative retrospective study by the international dermoscopy society. eur j dermatol 2020;30:688-98. 7. errichetti e. dermoscopy of common papulosquamous dermatoses varies between dark (iii and iv) and very dark (v and vi) skin phototypes. dermatol ther 2021;34:e14757. 8. errichetti e, ankad bs, jha ak, et al. international dermoscopy society criteria for non-neoplastic dermatoses (general dermatology): validation for skin of color through a delphi expert consensus. int j dermatol 2022;61:461-71. 9. hasson f, keeney s, mckenna h. research guidelines for the delphi survey technique. j adv nurs 2000;32:1008-15. 10. lynn mr. determination and quantification of content validity. nurs res 1986;35:382-5. 11. graefe a, armstrong js. comparing face-to-face meetings, nominal groups, delphi and prediction markets on an estimation task. int j forecasting 2016;27:183-95. 12. ankad bs, sakhare ps, prabhu mh. dermoscopy of non-melanocytic and pink tumors in brown skin: a descriptive study. indian j dermatopathol diagn dermatol 2017;4:41-51. 13. lallas a, reggiani c, argenziano g, et al. dermoscopic nevus patterns in skin of colour: a prospective, cross-sectional, morphological study in individuals with skin type v and vi. j eur acad dermatol venereol 2014;28:1469-74. globules), follicular plugs, erosions/ulcerations, and white color around vessels (perivascular white halo), histologically related to melanin deposits/melanocytes in the epidermis, follicular hyperkeratosis, loss of epidermis/dermis, and acanthosis, respectively. this was due to their significant diagnostic relevance (e.g., follicular plugs are a key clue in actinic keratosis/scc as they often show a pigmentary pattern similar to lentigo maligna/melanoma – see figures  2b,4c) but also to the higher prevalence of such structures in skin of color (as the result of a greater tendency to darker pigmentation and follicular/ulcerative reactions as well as a greater contrast between the perivascular white halo and surrounding pigmented skin) [6, 19]. moreover, during the consensus process a change of three existing parameters (i.e., “dots”, “clod within a clod”, and “dots and circles”) was also included, with darker colors (blue/black) being listed as a possible additional hue for the aforementioned structures, still due to the higher tendency to have more prominent pigmentation in dark phototypes [6, 19]. finally, the comparative analysis between descriptive and metaphoric terminology highlighted no relevant differences in terms of mean score for each of the eight basic parameters, thereby underlying that both of them are useful and might be complementary. in fact, the metaphoric approach is more related to “blink” (quick) diagnoses (e.g., “arborizing” vessels are a quick hint for a basal cell carcinoma), while descriptive assessment is extremely helpful when “blink” fails in describing a lesion and a more analytical process is needed for a correct dermoscopic diagnosis [20, 21]. the lack of a clear predominance between the two approaches is also emphasized by the consistency observed in the present consensus process when considering the rating of each descriptive item and corresponding metaphoric counterpart (<4.0; 4÷4.5; >4.5), with the only exception of “comedo-like openings”. indeed, this item was rated lower than the corresponding descriptive terminology, likely because it has a weaker correspondence from a morphological point of view in skin of color as the lower optical contrast typical of dark phototypes often makes epidermal invaginations filled with keratin look like darkly pigmented globules rather than “comedo-like openings” [12]. conclusions to conclude, the present validation process provides structured dermoscopic criteria for the assessment of skin tumors in dark phototypes based on parameters proposed by the ids. albeit most of the original items were considered applicable even for skin of color, there are some points of differences that physicians need to know. notably, no significant preference was found between descriptive and metaphoric terminology. the set of criteria validated in this consensus is original article | dermatol pract concept. 2023;13(1):e2023067 11 18. behera b, kumari r, thappa dm, gochhait d, srinivas bh, ayyanar p. dermoscopy of bowen’s disease: a case series of five patients. indian j dermatol venereol leprol 2021; 87:576-80. 19. neema s, patil s, pol d. basic principles of dermoscopy. in: iadvl atlas of dermoscopy (ankad bs, bhat yj, rambhia kd, eds), 1 edn. new delhi: jaypee brothers medical publishers, 2022:6-18. 20. giacomel j, zalaudek i, marghoob aa. metaphoric and descriptive terminology in dermoscopy: lessons from the cognitive sciences. dermatol pract concept 2015; 5:69-74. 21. blum a, argenziano g. metaphoric and descriptive terminology in dermoscopy: combine “blink” with “think”. dermatol pract concept 2015; 5:23. 14. sarma n, das a, gupta a. melanocytic nevus and nevoid disorders. in: dermoscopy histopathology correlation (ankad bs, mukherjee ss, nikam bp, eds), 1st edn. singapore: springer publications, 2021:15-46. 15. kelati a, aqil n, baybay h,  et al.  beyond classic dermoscopic patterns of dermatofibromas: a prospective research study. j med case reports 2017;11:266.s 16. ezenwa e, stein ja, krueger l. dermoscopic features of neoplasms in skin of color: a review. int j womens dermatol 2021;7:145-51. 17. vinay k, ankad bs, narayan vr, et al. a multicentric study on dermoscopic patterns and clinico-dermoscopic-histological correlates of basal cell carcinoma in indian skin. clin exp dermatol 2022 jul 22. doi: 10.1111/ced.15337. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023071 1 acquired bilateral nevoid telangiectasia induced by tamoxifen irene navarro-navarro1, alejandro ortiz-prieto1, gonzalo gallo-pineda1, myriam viedma-martínez1, david jiménez-gallo1, mario linares-barrios1 1 unidad de gestión clínica de dermatología médico-quirúrgica y venereología, hospital universitario puerta del mar, cádiz, españa key words: bilateral nevoid telangiectasia, tamoxifen citation: navarro-navarro i, ortiz-prieto a, gallo-pineda g, viedma-martínez m, jiménez-gallo d, linares-barrios m. acquired bilateral nevoid telangiectasia induced by tamoxifen. dermatol pract concept. 2023;13(2):e2023071. doi: https://doi.org/10.5826/dpc.1302a71 accepted: july 5, 2023; published: april 2023 copyright: ©2023 navarro-navarro et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: irene navarro navarro, md, hospital universitario puerta del mar. unidad de gestión clínica de dermatología, 2ª planta. avenida ana de viya 21, 11009, cádiz, spain phone: +34629924839 e-mail: irenen.navarro@gmail.com introduction unilateral nevoid telangiectasia (unt) is a superficial telangiectasia of the upper body characterized by showing a unilateral dermatomal distribution, typically affecting dermatomes from c3 to t3 [1]. although the exact cause is unknown, the association with hyperestrogenic states has been described [2]. bilateral nevoid telangiectasia (bnt) is a rare variant of unt affecting both sides of the body. we present a case of bnt in relation with tamoxifen treatment. case presentation a 41-year-old female attended our dermatology department due to the appearance of asymptomatic cutaneous lesions on the upper trunk and arms. she had a history of ductal cancer of the right breast stage ia with positivity for estrogen and progesterone receptors, treated with surgery, radiotherapy and tamoxifen. she did not have any other drug history. the cutaneous lesions had appeared several weeks after finishing radiotherapy and starting tamoxifen treatment. physical examination showed symmetric purpuric linear macules on the inner arms, chest and upper back (figure 1). the macules had a dermatomal distribution following the t1 dermatome (figure 2). she was interrogated for extracutaneous manifestations such as digestive bleeding or epistaxis, without reporting any systemic symptoms. a skin biopsy showed dilated blood vessels in the upper dermis with mild perivascular inflammation and normal number of mastocyte cells. immunohistochemistry showed positivity to estrogen receptors in fibroblastic cells. blood tests including biochemistry, blood count, coagulation study, estrogen and progesterone levels and viral hepatitis serology were normal or negative. stool blood test was negative. she was diagnosed with bnt secondary to tamoxifen. conclusions bnt, although bilateral in its presentation, is analogous to unt in that it follows the characteristic dermatomal 2 research letter | dermatol pract concept. 2023;13(2):e2023071 distribution of the telangiectasias. however, this variant seems to be less frequent. over a hundred cases of unt have been described in the literature, and only twenty-four cases of bnt [3]. although both entities are similar in their presentation, some epidemiological differences have been described between the two variants. bnt is more frequent in male patients whereas unt occurs predominantly in women. patients with bnt are usually older than those with unt, with a later onset of presentation, and higher association with underlying diseases such as liver diseases, diabetes and smoking [4]. the association of unt with hyperestrogenic states has been proposed, owing to the high prevalence in patients during puberty and pregnancy [5]. tamoxifen is a selective estrogen receptor modulator used in breast cancer with positivity for hormonal receptors. this therapy has an antagonist effect on breast tissue, but an agonist effect on bone, liver, skin and endometrium. association between unt and other drugs, such as chemotherapy agents, has also been proposed [6]. we hypothesize that tamoxifen led to an increase of estrogen receptors on the dermatomal skin of our patient, which may have been the cause for the presentation of bnt in this case. this is the first case reported, to our knowledge, of nevoid telangiectasia (unt or bnt) in relation with tamoxifen. this contributes to the hypothesis that hyperestrogenic states may be important not only for the pathogenesis of unt but also for bnt. however, more studies directed to explain the underlying mechanisms causing unt and bnt are needed to validate our observations. references 1. duong mh, raymond cp. unilateral dermatomal superficial telangiectasia. can med assoc j. 1983;129(10):1117-1118. pmid: 6627172.pmcid: pmc1875470. 2. uhlin sr, mccarty ks jr. unilateral nevoid telangiectatic syndrome. the role of estrogen and progesterone receptors. arch dermatol. 1983;119(3):226-228. doi: 10.1001/archderm.119.3.226. pmid: 6824361. 3. jee h, kim tg, kim ds, kim dy, lee mg. acquired bilateral nevoid telangiectasia: report of 9 cases. eur j dermatology. 2013;23(5):736-737. doi: 10.1684/ejd.2013.2141. pmid: 24211825. 4. kim ej, park hs, yoon hs, kim kh, cho s. demographic and clinical differences between unilateral and bilateral forms of naevoid telangiectasia: a retrospective study with review of the literature. br j dermatol. 2015;172(6):1651-1653. doi: 10.1111/bjd.13615. pmid: 25495722. 5. sánchez conejo-mir j, ortega resina m cmf. unilateral nevoid telangiectasia syndrome. study of cutaneous estrogen receptors. med cutan ibero lat am. 1984;12(6):469-475. pmid: 6397668. 6. rodríguez-martín m, sáez m, carnerero a, et al. unilateral naevoid telangiectasia in a young man after chemotherapy: a simple coincidence or a new clinical association? j eur acad dermatology venereol. 2006;20(8):1001-1002. doi: 10.1111/j.1468-3083.2006.01593.x. pmid: 16922953. figure 1. clinical image of bilateral nevoid telangiectasia. symmetric purpuric linear macules on the arms and chest following the t1 dermatome. figure 2. clinical image of bilateral nevoid telangiectasia. linear purpuric – brownish macules following the t1 dermatome. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022147 1 dermatology practical & conceptual “oak-leaf-like” loop vessels in super-high magnification dermoscopy of basal cell carcinoma joanna pogorzelska-dyrbuś1 1“estevita” specialist medical practice, tychy, poland citation: pogorzelska-dyrbuś j. “oak-leaf-like” loop vessels in super-high magnification dermoscopy of basal cell carcinoma. dermatol pract concept. 2022;12(3):e2022147. doi: https://doi.org/10.5826/dpc.1203a147 accepted: december 17, 2021; published: july 2022 copyright: ©2022 pogorzelska-dyrbuś. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: joanna pogorzelska-dyrbuś md, phd specjalistyczna praktyka lekarska “estevita”, pasaz europejski 8/1 street, 43-100 tychy, silesia, poland, telephone: +48604542643 e-mail: jpogorzelskadyrbus@gmail.com case presentation an 81-year-old patient presented with a 5-mm red firm ulcerated nodule of the skin on his back. dermoscopy revealed ulceration in the center and linear irregular vessels distributed on the lesion’s periphery (figure 1a). optical super-high magnification dermoscopy (oshmd) revealed looped vessels with extremely branched loops resembling oak leaves, which were distributed throughout the entire lesion (figure 1b). the patient underwent excision of the lesion and diagnosis of nodular basal cell carcinoma (bcc) was established. a 49-year-old patient presented with a 4-mm plaque on the abdomen. dermoscopy (figure 1c) showed an image typical for bcc. oshmd showed surprisingly numerous loop vessels in form of “oak leaves“, distributed across the entire lesion as well as in the previous case (figure 1d). the established diagnosis was superficial bcc. the consent to publish data has been obtained from the patients. teaching point in some cases, the diagnosis of bcc can be challenging. therefore, the detailed dermoscopy, including analysis of morphology of the vessels is of the greatest importance. according to the literature, arborizing vessels are the most common type of vessels followed by the short fine tele-angiectasias, while the looped vessels are a minor vascular feature of bcc [1,2]. i have found looped vessels and named them “oak-leaf-like” because of their striking similarity to an oak leaf. as each of the images concerned a different subtype of bcc, it might be presumed that such complicated vessels do not depend on the thickness of the lesion. 2 image letter | dermatol pract concept. 2022;12(3):e2022147 references 1. micantonio t, gulia a, altobelli e, et al. vascular patterns in basal cell carcinoma.  j eur acad dermatol venereol. 2011;25(3):358–361. doi:10.1111/j.1468–3083.2010.03734.x. pmid: 20561131. 2. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study.  arch dermatol. 2004;140(12):1485–1489. doi:10.1001/archderm.140.12.1485. pmid: 15611426. figure 1. dermoscopy and super-high magnification dermoscopy images of basal cell carcinoma cases presented in the manuscript. (a) ulceration in the center of the lesion and linear irregular vessels distributed on the red homogenous background on the periphery of the lesion (20x magnification). (b) super high magnification dermoscopy (400x magnification) demonstrating looped vessels with extremely branched loops resembling “oak leaves”. (c) arborizing vessels and short fine telangiectasias with a blue-gray globule (20x magnification). (d) numerous loop vessels in the form of “oak leaves“ (400x magnification). all images taken by the foto finder gmbh. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022188 1 theory-based approaches to support dermoscopic image interpretation education: a review of the literature tiffaney tran1, niels k ternov2, jochen weber3, catarina barata4, elizabeth g berry5, hung q doan1, ashfaq a marghoob3, elizabeth v seiverling6, shelly sinclair7, jennifer a stein8, elizabeth r stoos5, martin g tolsgaard9, maya wolfensperger10, ralph p braun10, kelly c nelson1 1 department of dermatology, the university of texas md anderson cancer center, houston, tx, usa 2 department of plastic surgery, herlev hospital, herlev, denmark 3 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 4 institute for systems and robotics; instituto superior técnico, university of lisbon, lisbon, portugal 5 department of dermatology, oregon health & science university, portland, or, usa 6 division of dermatology, maine medical center, portland, me, usa; department of dermatology, tufts university school of medicine, boston, ma,usa 7 department of biology, davidson college, davidson, nc, usa 8 the ronald o. perelman department of dermatology, new york university school of medicine, new york, ny, usa 9 copenhagen academy for medical education and simulation; department of obstetrics, copenhagen university hospital rigshospitalet, copenhagen, denmark 10 department of dermatology, university hospital of zürich, university of zürich, zürich, switzerland key words: dermoscopy education, image interpretation education, pattern recognition, educational theory, container model citation: tran t, ternov nk, weber j, et al. theory-based approaches to support dermoscopic image interpretation education: a review of the literature. dermatol pract concept. 2022;12(4):e2022188. doi: https://doi.org/10.5826/dpc.1204a188 accepted: february 1, 2022; published: october 2022 copyright: ©2022 tran et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: kelly c. nelson, md, department of dermatology, the university of texas md anderson cancer center, 1400 pressler street, unit 1452, houston, tx 77030, usa, telephone: 713-745-1113, fax: 713-745-3597, e-mail: kcnelson1@mdanderson.org introduction: efficient interpretation of dermoscopic images relies on pattern recognition, and the development of expert-level proficiency typically requires extensive training and years of practice. while traditional methods of transferring knowledge have proven effective, technological advances may significantly improve upon these strategies and better equip dermoscopy learners with the pattern recognition skills required for real-world practice. abstract 2 review | dermatol pract concept. 2022;12(4):e2022188 healthcare providers estimated that at least six years of experience may be necessary to develop a sufficient level of competency [1]. the container model embodies a traditional instructional approach centered on the idea that the acquisition of knowledge is comparable to filling one mind, or one mental filing cabinet, with as many facts and concepts as possible [2,3]. this learning theory was developed on the metaphor of our minds acting as containers capable of accumulating and retaining different items, whether real or metaphorical [4]. using this metaphor, knowledge is regarded as a commodity to be transferred from one medium to another [3]. the expectation that diagnostic concepts can be placed in a fixed cognitive “container,” where they can then be easily accessed, is misleading, especially in the setting of medical education. the successful recall of knowledge in the real-world context seems to be strongly influenced by the learning context [5]. however, knowledge acquired using the container model is usually isolated from its context and thus static and inflexible. in practice, knowledge, even if highly case-specific, is not a readily available object to retrieve but something to reconstruct and adapt when faced with different situations [2]. thus, opponents to the container model point out that in solving new problems, learners who have diligently absorbed declarative knowledge (eg facts and concepts that can be verbalized) under the container model may still fail to appropriately retrieve and apply that knowledge [6]. alternatively, learners may be able to successfully adapt their knowledge in the problem-solving process, but this successful retrieval and application may require a high cognitive load [6]. the cognitive load theory is an instructional theory derived from current understanding of cognitive architecture [7]. the term cognitive load refers to the learner introduction as a visual specialty, dermatology relies on the recognition of characteristic features and patterns within clinical and dermoscopic images of skin lesions. other fields in medicine, such as radiology and pathology, also rely on pattern recognition to formulate diagnoses and plans of care. in these fields, experts are distinguished from novices by their speed and accuracy in interpreting medical images and completing diagnostic tasks. while analyzing images of skin lesions, viewers may perform global interpretation, which encompasses holistic processing with immediate pattern recognition. viewers may also perform feature search, which involves the identification of specific features (eg, dermoscopic criteria) associated with normalcy or pathology. experts and novices differ in the order that they perform these mental processes during medical image analysis. novices usually start by attempting to search deliberately for features and comparing their findings with their prior, albeit limited, knowledge and experiences. in contrast, experts typically reach a diagnostic conclusion relatively quickly through global interpretation and then seek to justify their conclusion with an efficient feature search. visual diagnostic skills at the expert level require the ability to perform global interpretation—or efficient pattern recognition without deliberate search strategies. traditional educational methods that primarily drill declarative knowledge (e.g., specific features) have been largely ineffective in teaching novices the pattern recognition skills required for real-world practice. with these conventional training modalities, expert-level proficiency in dermoscopy has typically required extensive training and years of practice. a diagnostic accuracy study performed among medical students and objectives: a narrative review of the literature was performed to explore emerging directions in medical image interpretation education that may enhance dermoscopy education. this article represents the first of a two-part review series on this topic. methods: to promote innovation in dermoscopy education, the international skin imaging collaborative (isic) assembled a 12-member education working group that comprises international dermoscopy experts and educational scientists. based on a preliminary literature review and their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. for each approach, literature searches were performed for relevant articles. results: through a consensus-based approach, the group identified a number of emerging directions in image interpretation education. the following theory-based approaches will be discussed in this first part: whole-task learning, microlearning, perceptual learning, and adaptive learning. conclusions: compared to traditional methods, these theory-based approaches may enhance dermoscopy education by making learning more engaging and interactive and reducing the amount of time required to develop expert-level pattern recognition skills. further exploration is needed to determine how these approaches can be seamlessly and successfully integrated to optimize dermoscopy education. review | dermatol pract concept. 2022;12(4):e2022188 3 objectives this article represents the first of a two-part review series on novel instructional approaches in image interpretation education that could translate to dermoscopic educational interventions. in this first part, we will present a collection of theory-based approaches —such as whole case learning, microlearning, perceptual learning, and adaptive learning— that could enhance dermoscopic image interpretation education. while these emerging directions may also apply to general dermatology education, the scope of this series is limited to dermoscopy education. methods to promote innovation in dermoscopy education, the international skin imaging collaborative (isic) assembled a 12-member education working group that comprises international dermoscopy experts and educational scientists. for this initiative, the group convened virtually on a regular basis to discuss novel methods in medical image interpretation education that could be translate to dermoscopy training programs. based on a preliminary literature review as well as their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. for each approach, literature searches were performed in the pubmed and google scholar databases for relevant english-language articles. search strategies included terms for concepts of dermoscopy education, image interpretation education, and health science education in addition to the instructional approach under investigation. articles published since 2000 were preferred for inclusion, but articles published before 2000 were also considered, especially when seeking to understand the historical and theoretical underpinnings of some approaches. additional articles were identified among the references of retrieved articles and through discussions with educational scientists. relevant literature findings on the educational theories, methods, and concepts identified during the consensus process are presented in this review series. the theory-based approaches described in the first part of this series include: whole-task learning, microlearning, perceptual learning, and adaptive learning. results whole-task learning (4-c/id) overview whole-task learning is a time-efficient instructional design in medical education that teaches complex skill development mental bandwidth to complete tasks [7]. it is based on the idea that working memory—where information is stored temporarily—has limited capacity to store and use new information [7]. as a result, if the amount of new information exceeds mental capacity, further learning and accurate decision making will be impaired [8]. it is important for educators to consider cognitive load when designing instructional materials to maintain the overall load within the optimal range for learning and performance. for difficult tasks, learners may primarily rely on deliberate and purposeful thinking, and this process may strain their working memory, negatively affecting their ability to complete the tasks. in cognitive psychology, the dual process theory recognizes two thought systems: slow (deliberate) thinking and fast (automatic) thinking [9]. for medical image interpretation, the dual process theory manifests as a two-component diagnostic strategy in which the fast system facilitates pattern recognition and the slow system facilitates analytical reasoning [10]. within a medical simulation, accessing relevant knowledge and skills while assessing the simulated clinical environment may create a high extraneous cognitive load for learners, causing poor performance [8]. the high cognitive load experienced by learners in medical simulations may be explained by their extensive use of slow thinking as opposed to fast thinking, the former requiring considerable mental effort and use of mental resources. fast thinking, or non-analytical reasoning, is a key component of expert performance for diagnostic tasks that rely on pattern recognition, such as skin lesion classification in dermatology and x-ray interpretation in radiology [11]. for image interpretation education, an important goal is for novices to gradually develop a degree of automaticity in pattern recognition, which translates to a low cognitive load [10]. traditional teaching methods based on the container model have been generally ineffective in both teaching flexible knowledge and training automaticity in novices. in dermoscopy education, educators who use the container model usually provide instruction to passive learners on a defined set of diagnostic features, adding to their “containers.” in teaching learners to detect the relative presence or absence of a feature, this approach in effect requires real-world stimuli to likewise fit a binary interpretation (eg  present/absent, melanoma/non-melanoma). however, real-world stimuli frequently present on a continuum, or a sliding scale, where concerning features may be completely non-existent, obviously present, or extremely subtle. dermoscopy education requires instructional approaches that transfer flexible knowledge on the continuous nature of features and their clinically relevant contexts. this review seeks to explore an array of emerging theory-based approaches in image interpretation education that may displace the container model and enhance dermoscopy training programs. 4 review | dermatol pract concept. 2022;12(4):e2022188 applications in dermoscopy education in whole-task learning, authentic scenarios, structured in a way to facilitate skill transfer to clinical encounters, serve as the framework for learning. this approach contrasts with conventional teaching models that focus on didactic lectures, which are then supported by hypothetical scenarios. wholetask learning could be applied to dermoscopy education to promote problem-solving skills and foster professional independence. learning tasks may involve addressing skin complaints in hypothetical patient encounters. learners then receive instruction on the dermoscopic appearance of common dermatologic diagnoses (supportive information). dermoscopic training programs that involve casebased learning could be adapted to whole-task learning by re-structuring the curriculum with cases at the forefront and re-imagining each case as a series of learning tasks [17]. for example, dermoscopic cases are introduced prior to receiving instruction. as they navigate through cases, learners may receive further information on specific dermoscopic features and management approaches in the form of didactic lectures, multimedia content, or other teaching materials [18]. after completing the didactic portion, learners may then engage in repetitive practice to develop task automaticity and efficiency. microlearning overview microlearning is an instructional approach that involves segmenting the curriculum into short bursts, or small bites, of learning [19]. in contrast to traditional training sessions with “massed” practice, microlearning sessions may involve spaced review and distributed practice, increasing on-task attention and decreasing mind wandering [20]. according to the “forgetting curve,” memory retention declines over time as learners tend to forget much of their learned material within hours or days [19]. microlearning seeks to address this trend by introducing and re-introducing lessons in short bursts. through distributed practice, microlearning promotes the transfer of information from short-term to longterm memory storage [19]. with the microlearning approach, learners experience low cognitive load since working memory does not become overstrained, and this maintains learning capacity [21]. in reducing mental fatigue, this strategy increases learning retention and efficiency [19]. while microlearning lessons are usually self-paced, learners tend to complete them faster given their high level of engagement [19]. applications in medical education in recent years, microlearning modules have become more readily available to learners with the emergence of through authentic clinical scenarios [12]. for learners, spontaneous transfer of knowledge from the learning situation to the clinical environment is challenging [13]. through incorporation of real-life problems and fragmentation of instruction, whole-task learning aims to teach foundational knowledge in a way that fosters the “transfer out” of knowledge to actual practice. this approach also seeks to facilitate skill transfer in a manner that attends to cognitive load [12]. a specific whole-task learning strategy is four-c omponent instructional design (4-c/id). the four components in 4-c/id are: (1) learning tasks, (2) supportive information, (3) justin-time information, and (4) part-task practice [12]. learning tasks, which function as the backbone of 4-c/id, are authentic tasks sequenced from simple to complex in terms of difficulty and organized into “task classes.” supportive information may be presented at the beginning of a task class and provide foundational knowledge. just-in-time information may be provided right when the learner needs it for a specific task. part-task practice is an optional component in which the learner is given the opportunity to practice a specific task in order to develop a degree of automaticity. by shifting the focus of learning from lectures to clinical scenarios, learners may better appreciate the educational content and its relevance to their professional roles [14]. whole-task learning is similar to case-based learning in that both emphasize realistic clinical situations in the instructional design. in case-based learning, learners engage in group-based discussions of authentic patient cases and receive guidance and feedback from instructors [15]. learners are usually expected to prepare on their own through selfdirected learning in advance of the case-based learning sessions [15]. in whole-task learning, learners are presented with authentic clinical scenarios prior to receiving formal instruction. as learners navigate the scenarios, they are provided further information relevant to the scenarios in a structured delivery format. applications in medical education task-based learning has been applied in surgical education in recent years. a randomized controlled study conducted among surgical interns implemented task-based learning in an inanimate surgical skills laboratory setting [16]. compared to the control group, the intervention group performed better on post-intervention assessments and required less time to complete the clinical procedure [16]. another qualitative study evaluated the feasibility and efficacy of whole-task learning in a web-based doctoral-level pharmacotherapy course and garnered positive results [14]. learners expressed that by posing authentic scenarios, the complex delivery format provided them an opportunity to identify with their future health profession [14]. 5 education, a microlearning module in which learners exclusively practice diagnosing seborrheic keratosis (sks) would result in blocked practice, while one requiring a learner to distinguish between sks, benign nevi, and melanomas, presented in a random order, would result in interleaved practice. in a before-and-after study for a dermoscopy training program, blocked practice for benign lesions resulted in high specificity for benign lesions but poor sensitivity for malignant lesions in that participants would frequently categorize melanomas as, for instance, sks [28]. sensitivity for malignant lesions subsequently improved with the adoption of interleaved practice [28]. by segmenting complex tasks into smaller units, microlearning represents a powerful teaching tool for dermoscopy education. it may enable an efficient transfer of expert-level pattern recognition skills to novices, especially when implemented through technology tools such as smartphone apps. in bridging the gap between formal and informal learning, the use of microlearning technology may enhance learner engagement and motivation as well as knowledge retention [29]. microlearning modules may also be suitable for gamification in which game design principles are applied to enhance the learning experience and activate intrinsic reward pathways. perceptual learning overview perceptual learning is a learning method that challenges the container model theory by promoting the idea of experience as fundamental to developing expertise [30]. in neuropsychology, perceptual learning refers to the changes that occur in neural circuitry as a result of experience, resulting in the development of sensory discrimination [31]. this phenomenon explains how we learn to discriminate between faces, speech sounds, and musical pitches. for visual discrimination training, this approach relies on repeated exposures to numerous stimuli (eg visual features) so that one learns to perceive subtle differences between the stimuli. the concept of perceptual learning may be applied to visual specialties in which the educator teaches key diagnostic features and then creates opportunities for learners to practice recognizing these features with feedback. for medical image interpretation education, the two components of perceptual learning are discovery and fluency [6]. in the discovery phase, students learn to identify new information relevant to the diagnostic task by ignoring less relevant information and extracting the more salient points. using inattentional selectivity, learners may process a large amount of information from a case. fluency comes with practice and refers to the student ability to efficiently recognize the information needed for diagnostic tasks. multimedia content that can be easily accessed via personal devices. in a dutch non-randomized study involving medical and biomedical university students, investigators employed an open-source mobile application (or “app”) to teach circulation and respiration using microlearning and spaced review [22]. for a month before the exam, learners used the app to complete training modules with practice assessments that reviewed educational content and provided feedback. intensive app users performed significantly better on the final exam compared to moderate users and non-users, though these results may also be correlated with increased time spent learning [23]. applications in dermoscopy education in dermoscopy education, a real-life example of microlearning can be found in a telementoring framework model called project echo (extension for community health outcomes) [24]. as an effective alternative to on-site mentoring, tele-mentoring allows learners to process the cases with real-time guidance from dermoscopy experts [25]. in project echo, teaching sessions occur on a monthly basis and pair a didactic micro-lecture with learner presentations of real-life challenging cases encountered during patient care. a before-and-after study among primary care providers demonstrated that echo attendance increased participants’ ability to interpret dermoscopic images of skin cancer [25]. another example of microlearning in dermoscopy can be found in the educational webcasts posted by the international dermoscopy society (ids). these webcasts include short youtube videos of 5 to 10 minutes in length organized into disease-based learning (level 1), morphology-based learning (level 2), and context-based learning (level 3) as well as case-based learning [26]. to facilitate conceptual understanding, these webcasts could be expanded by posting dermoscopic images with practice questions plus key points in a microlearning format on a weekly or monthly basis. since microlearning can be applied to drill certain topics or specific skills, educators may consider whether to implement “blocked” or “interleaved” practice. many programs involve “blocked” practice in which the learner practices specific skills (eg a, b, c) one at a time in isolation (eg aaa bbb ccc) [27]. an alternative to “blocked” practice is “interleaved” practice in which learners practice multiple different skills in an intermixed order (eg abc bca cab). in interleaved practice, the amount of practice devoted to a specific skill becomes spaced, or distributed, across the learn-ing session [27]. by continuously exposing learners to multiple relevant topics, interleaved practice may be more effective in preparing learners for real-life applications. in dermoscopy review | dermatol pract concept. 2022;12(4):e2022188 6 review | dermatol pract concept. 2022;12(4):e2022188 students may have different starting points for a given topic, or they may learn at different paces based on their individual abilities and the instructional method being used. adaptive approaches represent a solution to these problems: by responding to the learner response times and accuracy rates, adaptive algorithms can repeat content, or adapt content difficulty, to optimize the learning process [36]. adaptive response time-based sequencing (arts) is an example of an adaptive learning approach that customizes the learning sequence based on performance data [37]. once the algorithm has detected mastery of a specific concept according to objective learning criteria, it can retire that concept and shift to focus on the learner weaker areas. learning criteria should correlate with a given level of proficiency and could involve a number of accurate responses provided within a specified amount of time, correlating with a degree of automaticity. training is considered complete when all criteria are met. applications in medical education adaptive algorithms have been successfully applied in teaching transesophageal echocardiography (tee) image interpretation. like dermoscopic image interpretation, tee interpretation involves recognition of diagnostic patterns. in one teaching method, an algorithm modified the sequence of and time intervals between different tee cases to suit each learner needs [38]. it evaluated both response speed and accuracy to determine whether to retire or re-sequence a specific concept. this method proved effective in improving response time and accuracy and optimizing performance for tee learners. for electrocardiography (ekg) interpretation, adaptive learning has also been successful in promoting content mastery. reading an ekg, like evaluating a skin lesion in dermoscopy, requires pattern recognition skills that novices are expected to obtain via experiential learning [30]. with arts, the pace of learning was adapted for each ekg learner based on response time and accuracy. as with the previous example, a concept was retired only if the learner achieved the target response time while maintaining accuracy. if both measures were not achieved, the concept was re-sequenced into the learning sequence. applications in dermoscopy education for dermoscopy education, adaptive algorithms may gradually increase the difficulty of dermoscopic images based on learner performance to generate faster improvements in performance. alternatively, if a learner repeatedly fails to recognize a specific dermoscopic feature, additional images containing the feature may be shown until the learner starts to “see” the feature. since learners encounter new content according to a personalized training schedule, demotivation applications in medical education through perceptual learning, learners receive exposure to real-life examples, engage in repetitive practice, and gradually learn to recognize important diagnostic features quickly and accurately. perceptual learning has been applied to radiology and electrocardiogram (ekg) image interpretation training, where learners have demonstrated gains in accuracy and fluency [6,30]. more recently, perceptual learning has been applied to dermatology education, where learners classify clinical images of rashes and skin lesions by morphology, configuration, and distribution [32]. through perceptual learning, learners demonstrated the ability to quickly and accurately identify skin lesion characteristics at a level comparable to that of expert dermatologists. applications in dermoscopy education in a dermoscopy training program for primary care providers, educators applied a heuristic training approach that resembled the discovery phase of the perceptual learning approach [33]. in the heuristic strategy, learners are expected to devise their own heuristics, or mental shortcuts, for future decision-making based on their experiences. following an introductory didactic training session on classical dermoscopic features, learners in the heuristic training arm were provided the opportunity to view a series of dermoscopic images with minimal guidance from instructors. labeled with the diagnosis only, these images did not contain further annotation or description, and learners were expected to discover salient features on their own. on post-intervention assessments, learners in the heuristic training arm performed as well as learners who had received feedback on the salient features in those images. adaptive learning overview adaptive learning is an educational approach that optimizes learning for the individual learner through innovative technology tools [6]. this approach features an adaptive algorithm that tailors the individual learning sequence according to their strengths and weaknesses. adaptive algorithms resemble an automated form of the deliberate practice strategy commonly used to achieve expert performance in music and sports. in deliberate practice, a teacher evaluates student performance and recommends practice activities (training tasks) and practice objectives (training goals) based on the teacher prior experiences and the student needs [34]. students follow teachers recommendations, practice with full concentration, and receive or self-generate immediate feedback [34]. in traditional medical education, pre-determined lecture or training schedules could not be easily adapted or modified to accommodate the individual student needs [35]. review | dermatol pract concept. 2022;12(4):e2022188 7 we envision a hypothetical dermoscopy training program that combines the strengths of each approach presented in this article. in this program, learning concepts, such as a specific dermoscopic diagnoses, would be organized as their own unit. each unit may be prefaced by a real-world clinical scenario that promotes whole-task learning. educational content on the dermoscopic diagnosis (eg clinical presentation, dermoscopic appearance) could then be presented via microlearning modules that deliver instruction in small segments to minimize extraneous cognitive load. each microlearning module may also include multiple example images of each diagnostic feature plus new cases for perceptual learning. these example images and cases could be hosted on a user-friendly application that contains elements of game design and provides immediate feedback to learners. adaptive learning algorithms built into the application would either re-sequence or retire cases according and mental fatigue may be reduced [39]. adaptive learning ensures that each student acquires the knowledge needed, in whatever sequence and at whatever pace, to reach their desired level of mastery. in addition, innovative technologies with user interface interactions may enable performance tracking and personalized modifications for efficient learning. conclusions a summary of the instructional approaches explored in the first part of this review series is included in table 1. in general, training programs that apply microlearning modules, perceptual learning cases, and/or adaptive learning algorithms may enable novices to acquire expert-level knowledge in an effective manner. meanwhile, whole-task learning equips learners for real-life clinical situations using hypothetical clinical scenarios. table 1. summary of the educational theories presented in the first part of this review series plus examples of existing or potential applications in dermoscopy education. educational theory description application(s) in dermoscopy education container model • learners receive passive instruction and fill their mental “container” with as many facts and concepts as possible. • acquired knowledge is usually static and inflexible because it is isolated from its context. existing applications • didactic lectures • rules-based algorithms whole-task learning • curriculum design is based on authentic clinical scenarios and comprises 4 components: (1) learning tasks, (2) supportive information, (3) just-in-time information, and (4) part-time practice. potential application • curriculum design: structured as a series of clinical scenarios based on real-life cases micro-learning • educational content is segmented into short bursts, or small bites, of learning that may be spaced apart. • this approach is expected to enhance engagement, increase knowledge retention, and decrease mental fatigue. existing application • project echo, developed by dermatology faculty at mainehealth perceptual learning • for medical image interpretation, fine visual discrimination skills are developed through repeated exposures to numerous examples of important visual features. • with feedback and practice, novices may learn to efficiently extract important features and ignore irrelevant ones. existing applications • youdermoscopy, created and developed by meeter congressi potential applications • library of training cases: learners classify hundreds of images and receive feedback on performance adaptive learning • adaptive algorithms respond to the individual performance data and make personalized modifications to the training schedule. • each individual training schedule is tailored to his/her strengths and weaknesses in order to optimize learning outcomes. potential applications • learning modules: learners complete assessments; adaptive algorithms retire specific learning concepts based on objective mastery criteria echo = extension for community healthcare outcomes. 8 review | dermatol pract concept. 2022;12(4):e2022188 9. kahneman d. thinking, fast and slow. new york, ny, us: farrar, straus and giroux; 2011. 10. gronchi g, giovannelli f. dual process theory of thought and default mode network: a possible neural foundation of fast thinking. front psychol. 2018;9:1237. doi: 10.3389/fpsyg.2018.01237. pmid: 30065692. pmcid: pmc6056761. 11. norman g, young m, brooks l. non-analytical models of clinical reasoning: the role of experience. med educ. 2007;41(12): 1140-1145. doi: 10.1111/j.1365-2923.2007.02914.x. pmid: 1800 4990. 12. daniel m, stojan j, wolff m, et al. applying four-component instructional design to develop a  case presentation curriculum. perspect med educ. 2018;7(4):276-280. doi: 10.1007/s40037018-0443-8. pmid: 29992438. pmcid: pmc6086819. 13. castillo j-m, park ys, harris i, et al. a critical narrative review of transfer of basic science knowledge in health professions education. med educ. 2018;52(6):592-604. doi: 10.1111/ medu.13519. pmid: 29417600. 14. pittenger al, olson-kellogg b. leveraging learning technologies for collaborative writing in an online pharmacotherapy course. distance educ. 2012;33(1):61-80. doi: 10.1080/0158 7919.2012.667960 15. bi m, zhao z, yang j, wang y. comparison of case-based learning and traditional method in teaching postgraduate students of medical oncology. med teach. 2019;41(10):1124-1128. doi: 10.1080/0142159x.2019.1617414. pmid: 31215320. 16. velmahos gc, toutouzas kg, sillin lf, et al. cognitive task analysis for teaching technical skills in an inanimate surgical skills laboratory. am j surg. 2004;187(1):114-119. doi: 10.1016/j. amjsurg.2002.12.005. pmid: 14706600. 17. sherbino j, dore kl, wood tj, et al. the relationship between response time and diagnostic accuracy. acad med. 2012;87(6):785-791. doi: 10.1097/acm.0b013e318253acbd. pmid: 22534592. 18. janssen-noordman am, merrienboer jj, van der vleuten cp, scherpbier aj. design of integrated practice for learning professional competences. med teach. 2006;28(5):447-452. doi: 10.1080/01421590600825276. pmid: 16973459. 19. shail ms. using micro-learning on mobile applications to increase knowledge retention and work performance: a review of literature. cureus. 2019;11(8):e5307. doi: 10.7759/cureus.5307. pmid: 31511813. pmcid: pmc6716752. 20. metcalfe j, xu j. people mind wander more during massed than spaced inductive learning. j exp psychol learn mem cogn. 2016;42(6):978-984. doi: 10.1037/xlm0000216. pmid: 26618908. 21. raman m, mclaughlin k, violato c, rostom a, allard jp, coderre  s. teaching in small portions dispersed over time enhances  long-term knowledge retention. med teach. 2010;32(3): 250-255. doi: 10.3109/01421590903197019. pmid: 20218841. 22. lameris al, hoenderop jg, bindels rj, eijsvogels tm. the impact of formative testing on study behaviour and study performance of (bio)medical students: a smartphone application intervention study. bmc med educ. 2015;15:72. doi: 10.1186/ s12909-015-0351-0. pmid: 25889923. pmcid: pmc4404663. 23. thijssen dhj, hopman mte, van wijngaarden mt, hoenderop jgj, bindels rjm, eijsvogels tmh. the impact of feedback during formative testing on study behaviour and performance of (bio)medical students: a randomised controlled study. bmc med educ. 2019;19(1):97. doi: 10.1186/s12909-019-1534-x. pmid: 30943962. pmcid: pmc6446354. to learner performance, indicated by response time and accuracy. upon completion of all microlearning modules for the unit, learners are offered the opportunity to revisit the clinical scenario from the beginning of that unit. to evaluate the impact of these educational approaches on dermoscopic image interpretation skills, educators may assess learner performance at multiple time points using validated instruments that measure both fluency and accuracy in diagnosing lesions. investigators may also perform prospective audits of clinical diagnoses versus histopathological diagnoses among participants in the training program. with the container model, learners were taught to interpret images using a given set of diagnostic features and/ or rule-based algorithms. however, learners often struggled with manipulating and applying acquired knowledge to new images. compared to traditional methods, emerging approaches in image interpretation education are more interactive and learner-centered. these approaches may improve learning outcomes by grounding learning in real-life clinical scenarios (whole-task learning) or delivering instruction in short segments (microlearning). for dermoscopic training, perceptual learning and adaptive learning may be especially valuable in that they provide immediate feedback and adapt the pace of learning to learner performance, respectively. the second part of this series will continue exploring instructional strategies and methods in image interpretation education that could also support dermoscopy education. references 1. ternov nk, vestergaard t, hölmich lr, et al. reliable test of clinicians’ mastery in skin cancer diagnostics. arch dermatol res. 2021;313(4):235-243. doi: 10.1007/s00403-020-02097-8. pmid: 32596742. 2. bereiter c, scardamalia m. beyond bloom’s taxonomy: rethinking knowledge for the knowledge age. in: hargreaves a, lieberman a, fullan m, hopkins d, eds. international handbook of educational change. vol 5. dordrecht: springer; 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radiotherapy. topical treatment with 5-fluorouracil or imiquimod is also suggested for superficial bcc (sbcc) [1]. case presentation a 100-year-old woman was visited in her home. she suffered from senile dementia with low mobility and lived permanently in bed. she had a large flesh-colored nodule on the left cheek that was eroded and covered by crusts (figure 1). an incisional biopsy was performed, and histology confirmed the diagnosis of nodular bcc (nbcc). as the patient’s situation did not lend itself toward surgical excision of the tumor or other physical therapies (curettage and cautery, cryosurgery, pdt, radiotherapy), treatment with topical ingenol mebutate nodular basal cell carcinoma of the face successfully treated with ingenol mebutate 0.015% gel silvia s. iannazzone1, vito ingordo2 1 outpatient department of dermatology, benevento north-east district, local health unit benevento, benevento, italy 2 outpatient department of dermatology, district n. 6, local health unit taranto, taranto, italy key words: ingenol mebutate, nodular basal cell carcinoma, non-melanoma skin cancer, therapy citation: iannazzone ss, ingordo v. nodular basal cell carcinoma of the face successfully treated with ingenol mebutate 0.015% gel. dermatol pract concept. 2018;8(2):129-131. doi: https://doi.org/10.5826/dpc.0802a12 received: october 5, 2017; accepted: november 16, 2017; published: april 30, 2018 copyright: ©2018 iannazzone et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: vito ingordo, md, via pupino, 7, 74123 taranto, italy. email: vito.ingordo@gmail.com surgical excision is the first-choice treatment for basal cell carcinoma (bcc). other treatments with topical agents such as 5-fluorouracil or imiquimod have also been suggested for use in superficial bcc (sbcc). ingenol mebutate (im) is a novel agent employed in the treatment of superficial actinic keratoses. the drug has been also successfully used in the treatment of sbcc. a case of large nodular bcc (nbcc) of the face in a 100-year-old inoperable woman is described. im 0.015% gel was applied once daily for three consecutive days. this dose regimen was repeated for seven rounds within 11 months, with complete cure of the tumor. mild local skin reactions, which were tolerated well, were observed. selected cases of nbcc could be treated with im gel, but the optimal concentration of the drug and the standard dose regimen of treatment are yet to be determined. abstract 130 observation | dermatol pract concept 2018;8(2):12 (im) 0.015% gel was chosen. the gel was applied in the morning and washed after eight hours for three consecutive days. this dosing regimen was repeated once monthly for three consecutive months, and the tumor size progressively reduced (figure 2). after six months the same dosing regimen was repeated four times (once monthly) until complete disappearance of the lesion was achieved (figure 3). six months later no relapse was observed. a local inflammatory response was observed after every application, consisting of erythema, scaling, and crusting. these skin reactions were tolerated well. discussion im is a novel agent extracted from the sap of the plant euphorbia peplus, which has a dual mechanism of action consisting of rapid induction of primary necrosis followed by neutrophil-mediated, antibody-dependent cellular cytotoxicity of residual disease cells; the latter is partly mediated by protein kinase c activation [2]. this drug is registered in italy for topical treatment of superficial actinic keratoses. im gel was first employed in the therapy of sbcc in a randomized phase iia trial, using concentrations of drug of 0.0025%, 0.01%, and 0.05%. two arms of treatment were started. the drug was applied on days 1 and 2 in the first arm and on days 1 and 8 in the second arm. the histologic figure 1. clinical picture before treatment. [copyright: ©2018 iannazzone et al.] figure 2. clinical picture after 3 months of treatment. [copyright: ©2018 iannazzone et al.] figure 3. clinical picture after 13 months of treatment. [copyright: ©2018 iannazzone et al.] observation | dermatol pract concept 2018;8(2):12 131 in conclusion, selected cases of nbcc could be treated with im gel, but the optimal concentration of the drug and the standard dose regimen of treatment are yet to be determined. more studies on larger series of cases are needed to confirm our hypotheses. acknowledgements we wish to thank andrea g. tortora, md, for revision of the manuscript. references 1. trakatelli m, morton c, nagore e, et al. bcc subcommittee of the guidelines committee of the european dermatology forum. update of the european guidelines for basal cell carcinoma management. developed by the guideline subcommittee of the european dermatology forum. eur j dermatol. 2014;24(3):31229. 2. siller g, rosen r, freeman m, welburn p, katsamas j, ogbourne sm. pep005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase iia trial. australas j dermatol. 2010;51(2):99-105. 3. cantisani c, paolino g, cantoresi f, faina v, richetta ag, calvieri s. superficial basal cell carcinoma successfully treated with ingenol mebutate gel 0.05%. dermatol ther. 2014;27:352-354. 4. stieger m, hunger re. ingenol mebutate treatment in a patient with gorlin syndrome. dermatology. 2016;232 (suppl 1):29-31. 5. jung ys, lee jh, bae jm, kim gm. superficial basal cell carcinoma treated with two cycles of ingenol mebutate gel 0.015%. ann dermatol. 2016;28(6):796-797. 6. izzi s, sorgi p, piemonte p, carbone, frascione p. successfully treated superficial basal cell carcinomas with ingenol mebutate 0.05% gel: report of twenty cases. dermatol ther (heidelb). 2016;29:470-472. 7. bettencourt ms. treatment of superficial basal cell carcinoma with ingenol mebutate gel, 0.05%. clin cosmet investig dermatol. 2016;9:205-209. 8. monfrecola g, scalvenzi m, costa c, cantelli mt, fabbrocini g. ingenol mebutate for pigmented superficial basal cell carcinomas: evaluation by confocal microscopy. g ital dermatol venereol. 2016; jun 10. 9. diluvio l, bavetta m, di prete m, orlandi a, bianchi l, campione e. dermoscopic monitoring of efficacy of ingenol mebutate in the treatment of pigmented and non-pigmented basal cell carcinomas. dermatol ther (heidelb). 2017;30:e12438. 10. del rosso jq. ingenol mebutate topical gel. a status report on clinical use beyond actinic keratosis. j clin aesthet dermatol. 2016;9 (11 suppl 1):s3-s11. clearance was 0%, 14% and 71% with the first dose regimen and 13%, 11% and 33 % with the second dose regimen [2]. im 0.05% gel was therefore used in the treatment of sbcc in single case reports, applied for two consecutive days and obtaining complete remission of lesions [3,4]. it was also used successfully at concentrations of 0.015% in a single case of sbcc, with two courses of four daily applications [5]. the concentration of 0.05% with the dose regimen of two daily applications was employed in treatment of sbcc in a 20-case series, achieving complete disappearance of the lesions in 100% of tumors. no recurrence was observed after six months [6]. bettencourt also treated nine sbccs using im 0.05% gel, with occlusion by adhesive bandage in six lesions and no occlusion in three lesions. a lesion was treated for two days, two lesions were treated for four days, and all other lesions were treated for seven days. all sbccs were clinically cured on short-term follow-up at 2-4 weeks. biopsy of six of the nine lesions confirmed histologic clearance in all biopsy samples. no clinically suspicious lesion in any patients on subsequent follow-up evaluations at 3-month intervals was observed [7]. im 0.05% gel was also used in three pigmented bcc and the lesions were examined by dermoscopy and confocal microscopy before, during, and after the treatment [8]. diluvio et al treated seven sbcc: two were treated with im 0.015% gel for three consecutive days and five with im 0.05% gel for two consecutive days. all the lesions were examined by dermoscopy before and after therapy, and dermoscopic patterns of bcc had disappeared. the clearance of tumors was also confirmed by histology [9]. finally, a 2.5 cm nbcc in a patient with multiple major medical problems was treated with im gel 0.015% once daily applied on three consecutive days, resulting in the complete disappearance of the lesion [10]. conclusion according to the existing literature, this is the second case of nbcc successfully treated with im gel. as the lesion was located on the face, we used a 0.015% concentration regimen. the therapy was well tolerated, but the length of treatment was long and several applications were needed due the low concentration of the drug. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2014;4(2):14 67 below find the answer and discussion to the quiz by savoia et al. presented in the previous issue of dermatology practical & conceptual (http://dx.doi.org/10.5826/dpc.0401a12). diagnosis pigmented cutaneous squamous cell carcinoma (pcscc). clinical course the patient had no evidence of local recurrence or metastasis during 12 months of follow-up. answer and explanation pcscc is a variant of invasive squamous cell carcinoma, with less than 20 cases reported, to our knowledge, in the english literature [1,2]. pcscc had been more often reported to occur in the oral mucosa and conjunctiva [3]. pigmentation is probably due to cytokines secreted by tumoral cells that stimulate melanocytes to produce melanin [4]. in some cases, pcscc may be the malignant progression of a pigmented actinic keratosis or a pigmented bowen’s disease [4]. the clinical appearance of pcscc is considered nonspecific, with differential diagnoses including other benign and malignant skin lesions such as melanoacanthoma, seborrheic keratosis, melanoma, pigmented basal cell carcinoma, pigmented basosquamous carcinoma and pigmented adnexal tumors [3,5]. the dermatoscopic features of our case were unspecific and no algorithm was useful for a correct diagnosis [6,7]. as previously reported by rosendahl and colleagues, malignancy was considered on the basis of the “chaos and clues” algorithm: there was “chaos” (asymmetry, structureless global pattern) and the clues of “few discrete blue-grey blotches with rather ill-defined edges (blue)” and “atypical vessels” [6,7]. indeed, the scaly center and the pink-white halo were suggestive of a keratotic lesion, even though the diagnosis of pcscc was not initially considered. on the basis of our and previous reports, pcscc should be considered when dealing with a pigmented lesion characterized by an unspecific dermoscopic pattern with the features of diffuse blue-gray pigmentation, scaling, polymorphic vessels and radial structures [1,6,8,9]. congratulations to dr. paschal dsouza, who was the first to send us the correct answer! references 1. yoshida y, yamasaki a, shiomi t, et al. ulcerative pigmented squamous cell carcinoma in a 101-year-old japanese woman. j dermatol. 2009;36(4):241-4. 2. vargas tj, campos cm, coutinho rb. case for diagnosis: pigmented squamous cell carcinoma. [article in portuguese.] an bras dermatol. 2009;84(3):293-5. an atypical pigmented lesion on the nose—answer francesco savoia1, giuseppe gaddoni1, vincenzo albano1, vera tengattini2, lorenza ricci2, annalisa patrizi2, emilia crisanti3 1 unit of dermatology, ausl ravenna, italy 2 department of specialized, diagnostic and experimental medicine, division of dermatology, university of bologna, italy 3 unit of pathologic anatomy, ausl ravenna, italy citation: savoia f, gaddoni g, albano v, tengattini v, ricci l, patrizi a, crisanti e. an atypical pigmented lesion on the nose—answer. dermatol pract concept. 2014;4(1):12. http://dx.doi.org/10.5826/dpc.0402a14 copyright: ©2014 savoia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: dr. vera tengattini, department of specialized, diagnostic and experimental medicine, division of dermatology, university of bologna, via massarenti, 1, 40138 bologna, italy. tel. +390516364198; fax. +390516363091. email: vera.tengattini@ hotmail.com 68 quiz | dermatol pract concept 2014;4(2):14 3. satter ek. pigmented squamous cell carcinoma. am j dermatopathol. 2007;29(5):486-9. 4. terada t, yamagami j, fugimoto a, tanaka k, sugiura m. pigmented squamous cell carcinoma of the cheek skin probably arising from solar keratosis. pathol int. 2003;53(7):468-72. 5. giacomel j, lallas a, argenziano g, et al. dermoscopy of basosquamous carcinoma. br j dermatol. 2013;169(2):358-64. 6. rosendahl c, cameron a, bulinska a, weedon d. cutaneous pigmented invasive squamous cell carcinoma: a case report with dermatoscopy and histology. dermatol pract concept. 2011;1(1):7. 7. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068-73. 8. zalaudek i, citarella l, soyer hp, hofmann-wellenhof r, argenziano g. dermoscopy features of pigmented squamous cell carcinoma: a case report. dermatol surg. 2004;30(4 pt 1):539-40. 9. de giorgi v, alfaioli b, papi f, et al. dermoscopy in pigmented squamous cell carcinoma. j cutan med surg. 2009;13(6):326-9. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023022 1 regression of multiple melanocytic nevi in two patients on nivolumab for metastatic melanoma gloria baeza-hernández1, ricardo francisco rubio-aguilera1, anastasia alejandra garrido-ríos1, helena álvarez-garrido1, cristina martínez-morán1, jesús borbujo1 1 department of dermatology. hospital universitario de fuenlabrada, madrid, spain key words: nivolumab, regression, melanocytic nevi, melanoma, dermoscopy citation: baezahernández g, rubio-aguilera rf, garrido-ríos aa, álvarez-garrido h, martínez-morán c, borbujo j. regression of multiple melanocytic nevi in two patients on nivolumab for metastatic melanoma. dermatol pract concept. 2023;13(1):e2023022. doi: https://doi.org/10.5826/dpc.1301a22 accepted: may 26, 2022; published: january 2023 copyright: ©2023 baezahernández et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gloria baeza-hernández, servicio de dermatología, hospital de fuenlabrada, camino del molino 2, 28942 fuenlabrada, madrid. e-mail: gloria.baeza@salud.madrid.org introduction immunotherapy (anti-pd1 and anti-ctla4) has been described to achieve complete regression of non-metastatic melanoma, assessed by reflectance confocal microscopy; however, their effects on benign melanocytic lesions have not been thoroughly studied and may be underreported [1]. herein we report 2 patients with regression of multiple nevi while on treatment with nivolumab for metastatic melanoma. case presentation two patients, suffering from metastatic melanoma treated with nivolumab (table 1), attended our outpatient clinic for their annual digital dermoscopic monitoring. they were not aware of any changes or new melanocytic lesions. on physical examination, no new lesions were detected since their last visit one year before; with dermoscopy several of their benign melanocytic nevi had lightened and no atypical or malignant lesions were observed (figures 1 and 2). both patients had experienced disease progression despite anti-pd1 treatment. conclusions benign melanocytic nevi regression is an emerging secondary effect of anti-pd1 drugs nivolumab and pembrolizumab. although these drugs are used on other cancer treatments, this secondary effect seems to be more frequent in patients undergoing treatment for melanoma [2]. in an observational study published in 2017, 11 patients treated 2 research letter | dermatol pract concept. 2023;13(1):e2023022 with anti-pd1 for metastatic melanoma (10 with pembrolizumab and 1 with nivolumab) had more lightened nevi than controls during follow-up (49% versus 19%); nevertheless, differences were not statistically significant [3]. lightening without halo is a known phenomenon, especially in patients treated with pembrolizumab [4,5]. there are few reports regarding regression of melanocytic nevi in patients treated with nivolumab: one similar to our patient, with no inflammation or halo, and another patient who experimented inflammation before regression, with no halo [6,7]. though some articles suggest that regression of melanocytic nevi may be related to the therapeutic effect of the anti-pd1 drug and could be interpreted as a sign of good therapeutical response, our patients both experimented progression despite nivolumab treatment; therefore, more studies are required to shed light on this matter [2,5,7]. one of our patients also had vitiligo-like phenomenon, which has been suggested to be associated with a better prognosis [2]. furthermore, some other questions remain still unanswered: it could be asked why some patients experience only lightening without halo, while others have vitiligo-like reactions and halo nevi, and whether the underlying mechanism is the same [3]; why some patients have clinical inflammation but most of them do not according to the literature. lastly, it is debatable whether regression of nevi with anti-pd1 is as rare as it seems today, for it may be an unnoticed secondary effect in other cancer patients (lung, table 1. patient characteristics. metastatic melanoma patient 1 patient 2 sex male male age, years 50 60 location abdomen back mutation braf v600e/e2/d treatment before/after nivolumab before: dabrafenib-trametinib, which was stopped because metastases spread to his lungs and inguinal and retroperitoneal lymph nodes (lymphadenectomy was performed) no nivolumab start and end dates/doses mg/weeks 2021 – ongoing/ 240 mg every 2 weeks 2020-2021/ 480 mg every 4 weeks lightening of nevi observed with digital dermoscopy 2021: > 80% of his nevi. (previous digital monitoring: 2020) 2022: > 60% of his nevi. (previous digital monitoring: 2021) nivolumab secondary effects yes, vitiligo-like lesions yes, nivolumab-induced thyrotoxicosis and subsequent hypothyroidism disease progression while on nivolumab yes, new lymph node metastases near his melanoma scar on the abdomen and small bowel metastases (2022) yes, dermal melanoma metastases on the back (2021) second melanoma while on treatment yes, melanoma in situ on his back while on dabrafenibtrametinib (2020). yes, melanoma on his right leg (breslow thickness 3.4 mm) while on nivolumab (2021). both were detected in the annual digital dermoscopy monitoring visit. other a lung adenocarcinoma was diagnosed while on nivolumab (2021) and later excised. he has developed mediastinal lymph node metastases, awaiting treatment. research letter | dermatol pract concept. 2023;13(1):e2023022 3 figure 1. clinical images of patient 1: 2020 (left) and 2021 (right). three examples of lesions registered in digital monitoring of patient 1. (a1-c1) first row shows these benign melanocytic in 2020. (a2-c2) second row shows the same lesions one year later in 2021, 6 months after starting treatment with nivolumab. kidney, head, and neck, etc.) who are not followed up in a dermatology clinic. one may well wonder about the utility of digital monitoring of patients with metastatic melanoma undergoing treatment with immune checkpoint inhibitors (ici). in a recent single-center retrospective cohort study 42 patients (1.9%) with metastatic melanoma who received treatment with ici developed new melanomas; thus, prospective studies with longer follow-up are needed to draw a solid conclusion [8]. while on ici, both of our patients had a second melanoma that was detected in the digital follow-up; we want to highlight that in case 1, with longer digital monitoring, melanoma was detected in situ, in line with the findings of lallas et al where almost 70% of second primary melanomas detected during surveillance were in situ [9]. we think that, when available and feasible, monitoring with digital dermoscopy and total body photography should be offered to all melanoma patients, as it helps in the early diagnosis of melanoma, with some lesions being only diagnosed by dermoscopic changes in the absence of melanoma-specific criteria [9]. regression of multiple nevi is a scarcely reported secondary effect of nivolumab we should be aware of, especially in dermoscopic monitoring. it may be an overlooked effect because patients treated with anti-pd1 for cancers other than melanoma are not usually examined by a dermatologist. its prognostic meaning is still unclear. 4 research letter | dermatol pract concept. 2023;13(1):e2023022 4. wolner zj, marghoob aa, pulitzer mp, postow ma, marchetti ma. a case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma. br j dermatol. 2018;178(1):265-269. doi:10.1111/bjd.15354. pmid: 28132411. pmcid: pmc5533648. 5. mauzo sh, tetzlaff mt, nelson k, et al. regressed melanocytic nevi secondary to pembrolizumab therapy: an emerging melanocytic dermatologic effect from immune checkpoint antibody blockade. int j dermatol. 2019;58(9):1045-1052. doi:10.1111 /ijd.13833. pmid: 29152725. 6. vazquez b, velasco r, martin jm, gonzalez i, ramon md. regression  of multiple melanocytic nevi associated with nivolumab treatment  for metastatic melanoma. int j dermatol. 2019;58(11):1331-1333. doi:10.1111/ijd.14340. pmid: 30536371. 7. nakamura y, fujino t, kagamu h, et al. induction of immune reaction in benign melanocytic nevi without halo during nivolumab therapy in a patient with melanoma. jama dermatology. 2017;153(8):832-834. doi:10.1001/jamadermatol.2017.0615. pmid: 28492864. references 1. navarrete-dechent c, cordova m, postow ma, et al. evaluation of the response of unresectable primary cutaneous melanoma to immunotherapy visualized with reflectance confocal microscopy. jama dermatology. 2019;155(3):347. doi:10.1001/jamadermatol.2018.3688. pmid: 30624578. pmcid: pmc6440283. 2. farinazzo e, zelin e, agozzino m, et al. regression of nevi, vitiligo-like depigmentation and halo phenomenon may indicate response to immunotherapy and targeted therapy in melanoma. melanoma res. 2021;31(6):582-585. doi:10.1097 /cmr.0000000000000776. pmid: 34433200. 3. zhao cy, hwang sje, wakade d, carlos g, anforth r, fernández-peñas p. melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: an observational study. australas j dermatol. 2017;58(4):292-298. doi:10.1111/ajd.12645. pmid: 28707403. figure 2. clinical images of patient 2: 2021 (left) and 2022 (right). three lesions registered in digital monitoring of patient 2. (d1-f1) first row shows these benign melanocytic nevi in 2021, while on nivolumab treatment. (d2-f2) second row displays the same lesions one year later in 2022, 6 months after finishing treatment with nivolumab. research letter | dermatol pract concept. 2023;13(1):e2023022 5 9. lallas a, apalla z, kyrgidis a, et al. second primary melanomas in a cohort of 977 melanoma patients within the first 5  years of monitoring. j am acad dermatol. 2020;82(2):398-406. doi:10.1016/j.jaad.2019.08.074. pmid: 31499156. 8. nanda jk, dusza sw, navarrete-dechent c, liopyris k, marghoob aa, marchetti ma. incidence of new primary cutaneous melanoma in patients with metastatic melanoma treated with immune checkpoint inhibitors. jama dermatology. 2021;157(1):79. doi:10.1001/jamadermatol.2020.3671. pmid: 32936222. pmcid: pmc7495326. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023002 1 a case of metastatic basosquamous basal cell carcinoma treated with carboplatin and paclitaxel chryssoula papageorgiou1, zoe apalla1, eleni timotheadou2, konstantia loga2, elizabeth lazaridou1, dimitrios dionysopoulos2 1 second dermatology department, medical school, faculty of health sciences, aristotle university of thessaloniki, thessaloniki, greece 2 department of medical oncology, school of medicine, faculty of health sciences, papageorgiou hospital, aristotle university of thessaloniki, thessaloniki,greece key words: basal cell carcinoma, vismodegib, chemotherapy, carboplatin, metastatic citation: papageorgiou c, apalla z, timotheadou e, loga k, lazaridou e, dionysopoulos d. a case of metastatic basosquamous basal cell carcinoma treated with carboplatin and paclitaxel.dermatol pract concept. 2023;13(1):e2023002. doi: https://doi.org/10.5826 /dpc.1301a2 accepted: april 28, 2022; published: january 2023 copyright: ©2023papageorgiouet al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: chryssoula papageorgiou, md, second dermatology department, aristotle university, 76 agiou pavlou, pavlos melas, 564 29, thessaloniki, greece. tel. +302313323873, fax: +302310991473 e-mail: xrysapapageorgiou@gmail.com introduction basal cell carcinoma (bcc) is the most common type of skin cancer. however, it rarely metastasizes. herein, we present a case of metastatic bcc treated with chemotherapy following vismodegib treatment failure. case presentation an 82-year-old man visited our clinic for regular follow up due to a personal history of cutaneous bcc which was located on the face. the primary tumor was excised with clear margins 16 months ago and the histopathology report indicated a nodular bcc. physical examination revealed a swollen lymph node in the right anterior neck. the fine needle aspiration of the lymph node demonstrated the presence of basosquamous bcc (bsc). due to the presence of headaches, lacrimation and tinnitus, a head mri and later a pet-ct scan were performed. the latter revealed bones involvement (figure 1a). following these findings, vismodegib treatment was initiated. a new pet-ct was performed 3 months later that indicated disease progression (figure 1b, figure 2a). therefore, switch to carboplatin and paclitaxel-based chemotherapy was decided. one month after treatment initiation, the patient did not longer suffer from the symptoms mentioned above. accordingly, three months later, a new pet-ct was performed, which revealed complete response of the bcc (figure 2b). conclusions although bccs are very common neoplasms, it is by nature extremely rare to metastasize. 2 research letter | dermatol pract concept. 2023;13(1):e2023002 in our patient, the primary tumor was histologically diagnosed as a nodular bcc, whilst histology of the lymph node mass indicated a bsc, which is considered a more aggressive form of bcc. this discrepancy may be attributed to sectioning limitations, not always allowing examination of all the areas of the tumor, in conjunction with the possible coexistence of different areas of differentiation within the tumor mass. mixed histology is a common scenario, especially in large bccs. recent introduction of line-field confocal optical coherence tomography for the in-vivo diagnosis of keratinocyte tumors has improved bcc subtype recognition and its aggressive variants like basosquamous carcinoma. thus, it could serve as a very helpful tool for clinicians even in such cases to overcome this discrepancy [1,2]. surgical excision with clear margins is the gold standard of treatment of all bccs. in contrast, in locally advanced and metastatic bccs the therapeutic management seems to be limited to the so-called sonic hedgehog pathway inhibitors (hhi), namely vismodegib and sonidegib. however, their use remains controversial in the case of bscs. specifically, several studies in the past demonstrated squamatization of bcc in the setting of acquired drug resistance during hhi therapy [3,4]. on the other hand, recent studies have reported complete responses of locally advanced bscs with vismodegib  [5]. in figure 1. metastatic bcc. (a) pet-ct at baseline displaying bone involvement and a mass of soft tissue in the skull base invading the clivus, both petrosal bones and the right sphenoid bone. an additional mass of soft tissue is seen to protrude back of the right sphenoid bone to the right sinus. (b) 3 months after vismodegib administration indicating progression of the disease (black arrow). figure 2. comparative pet-cts (a) before and (b) after 3 months treatment with carboplatin combined with paclitaxel (150 mg and 120 mg were administered per week, respectively) revealing complete response and disappearance of the tumor brain metastases. research letter | dermatol pract concept. 2023;13(1):e2023002 3 our patient, vismodegib treatment was not beneficial. however, 3-month treatment with carboplatin and paclitaxel led to radiologically confirmed, complete response of the tumor. this is in line with previous evidence suggesting that cisplatin-based chemotherapy may be associated with rapid symptomatic responses [6]. however, despite the brilliant response to the systemic therapy, long term followup will be of crucial importance to evaluate the real efficacy of the therapy. this case report illustrates the clinical challenge of managing patients with metastatic bcc with squamous differentiation and, subsequently, highlights the need of a multidisciplinary approach among the clinicians involved for the patient benefit. references 1. cappilli s, dejonckheere g, hajjar n, et al. line-field confocal optical coherence tomography: a case on the importance of full-lesion examination for basal cell carcinoma. int j dermatol. 2022;61(7):e248-e250. doi: 10.1111/ijd.15930. pmid: 34591332. 2. cappilli s, cinotti e, lenoir c, et al. line-field confocal optical coherence tomography of basosquamous carcinoma: a case series with histopathological correlation. j eur acad dermatol venereol. 2022;36(8):1214-1218.. doi: 10.1111/jdv.18038. pmid: 35224784. 3. iarrobino a, messina jl, kudchadkar r, sondak vk. emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. j am acad dermatol. 2013;69(1):e33-e34. doi: 10.1016/j.jaad.2013.01.023. pmid: 23768306. 4. bancalari b, llombart b, serra-guillén c, et al. histologic changes during treatment with vismodegib in locally advanced basal cell carcinoma: a series of 19 cases. am j dermatopathol. 2019;41(10):711-717. doi: 10.1097/dad .0000000000001384. pmid: 31436575. 5. apalla z, giakouvis v, gavros z, et al. complete response of locally advanced basosquamous carcinoma to vismodegib in two patients. eur j dermatol. 2019;29(1):102-104. doi: 10.1684 /ejd.2018.3482. pmid: 30998204. 6. jefford m, kiffer jd, somers g, daniel fj, davis id. metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel. anz j surg. 2004;74(8):704-705. doi: 10.1111/j.1445-1433.2004.03130.x. pmid: 15315581. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023120 1 dermatologists communication skills and performance from point of view of patients nasim farajtabar nashli1, parvaneh hatami1, zeinab aryanian1, 2, abbas rahimi foroushani³, reza robati4,5, azadeh goodarzi6,7, masoud assadi8,9, narges ghandi1,10 1 autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran 2 department of dermatology, babol university of medical sciences, babol, iran 3 department of epidemiology and biostatistics, school of public health, tehran university of medical science, tehran, iran 4 skin research center, shahid beheshti university of medical sciences, tehran, iran 5 department of dermatology, loghman hakim hospital, shahid beheshti university of medical sciences, tehran, iran 6 department of dermatology, rasool akram medical complex clinical research development center, school of medicine, iran university of medical sciences, tehran, iran 7 skin and stem cell research center, tehran university of medical sciences, tehran, iran 8 health research institute, babol university of medical sciences, babol, iran 9 department of medical ethics, school of traditional medicine, shahid beheshti university of medical sciences, tehran, iran 10 department of dermatology, razi hospital, tehran niversity of medical sciences, tehran, iran key words: communication skills, calgarycambridge observation guide, ccog, dermatology, persian citation: farajtabar nashli n, hatami p, aryanian z, et al. dermatologists’ communication skills and performance from point of view of patients. dermatol pract concept. 2023;13(2):e2023120. doi: https://doi.org/10.5826/dpc.1302a120 accepted: november 16, 2022; published: april 2023 copyright: ©2023 farajtabar nashli et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: narges ghandi, md, autoimmune bullous diseases research center,razi hospital ,tehran university of medical sciences, tehran, iran tel: +98(912)3276640 e-mail: nghandi@tums.ac.ir introduction: effective communication is an important issue in patient-doctor interaction which is even more important regarding chronic disorders which need a strong relationship between patient and clinician for better compliance and optimal control disease. objectives: this study was aimed to develop the best cultural adapted persian version of the 28-item calgarycambridge observation guide (ccog) questionnaire. methods: in this descriptive-analytic study, data collected from 400 patients attending the outpatient dermatology clinics of 3 major hospitals in tehran using the modified persian version of ccog questionnaire, both before and after being visited by dermatologists. results: the difference of ccg scores for all of questions, except for questions number 1,16 and 22, was statistically significant. the highest score, both before and after visiting, attained by question regarding being respectful. the lowest scores for necessary behavior and the adequate amount of exabstract 2 original article | dermatol pract concept. 2023;13(2):e2023120 introduction effective communication is an important issue in patient-doctor interaction and has been proved to be associated with positive health-related outcomes [1-4]. hence, finding the appropriate tools to assess communication skills in medical staffs, seems to be essential and also challenging. mostly, some checklists for performance comparison and feedback are used [5]. one of the most useful checklists in this regard is calgarycambridge observation guide (ccog) which is a 28-item questionnaire derived from calgarycambridge process guides and consists of six blocks/ domains with a 3-point scale (yes/ yes, but and no) and has been previously shown to have adequate psychometric properties [5]. since many of dermatologic disorders are chronic conditions which need a long-lasting patient-doctor interaction, effective communication is essential to provide a better patient’s compliance and adherence to treatment which is an even more important issue for optimal control of chronic disorders. objectives this study was aimed to develop a persian version of the 28-item ccog questionnaire and try to reach the best cross-cultural adapted form of it to assess medical communication skills in dermatology clinics via a validated persian questionnaire. methods we conducted this study based on previous recommendations [6] via the following stages: translation, review by a committee of specialists and pretesting for assessing its validity. initially, two bilingual translators provided two persian versions of the questionnaire, independently. these forms were sent to an expert committee consisting of five associated professors of dermatology to check its reliability. they checked the contents, provided some changes and suggestions and tried to merge two forms into a complete, final version, ready for pre-testing. after reaching a consensus, the final version was applied to 15 patients coming to the razi dermatology hospital, affiliated to tehran university of medical sciences (tums). the patients visited a dermatologist at a baseline visit and two weeks later and were asked to fill out the questionnaire. all doubts and concerns regarding the questionnaire were discussed and patients were guided through the process in case they encountered any difficulty. the translated form of questionnaire is available in the appendix. the statistical analysis was performed using spss, version 20. we estimated the cronbach’s alpha coefficient and the spearman correlation coefficient to assess the internal consistency of each domain and the correlation between the domains. after confirming the validity of questionnaire, it was filled out by 400 patients attending the outpatient dermatology clinics of 3 major hospitals in tehran (razi hospital, rasoul-e-akram hospital and shohadaye tajrish hospital). for questions regarding necessity of performing a behavior by clinician, the answers were scored as follows: below (1), at (2) or above (3) the expected level. about the adequate amount of implementing that behavior by clinician, the answers were again scored as follows: no (0), somehow (1) and yes (2). then, sum of the scores per each question was calculated and final scores for each question was calculated using this formula: sum of scores × 100/800 inferential statistics were performed using paired t-test, chi-square and mann-whitney tests, where appropriate. a significant p value was considered less than 0.05. results based on spearman ratio and cronbach alfa of 0.838 (95% ci: 0.82 -0.86), the translated questionnaire was proved to be valid (data was not shown). demographic and socioeconomic characteristics of participants are shown in table 1. the participants were mainly female (67% versus 33%) with a mean age of 37.5 ± 5.6 years, ranged from 12 to 73 years. table 2 shows ccgs before and after a dermatology visit. as shown above, the difference of ccg scores for all of questions, except for questions number 1,16 and 22, was statistically significant. ecution were related to questions number 3 (introducing self) and 4 (introducing role), respectively. age and educational level of patients were significantly correlated with their expectations regarding communication skills of clinician. conclusions: this study showed the acceptable validity of modified persian version of ccog-24 item questionnaire. our findings also demonstrated that there was a significant difference between what patients expected from a dermatologist and the manner they actually were treated regarding physician communication skills. original article | dermatol pract concept. 2023;13(2):e2023120 3 table 1. demographic and socioeconomic characteristics of participants. number % hospital razi 300 75 shohadaye tajrish 60 15 rasoule akram 40 10 gender male 132 33 female 268 67 education level under diploma 77 19 diploma 121 30 associate 35 9 bachelor 103 26 master or above 64 16 occupation employee 123 30.8 self-employed 96 24 worker 7 1.8 housewife 115 28.8 collegian 35 8.8 student 24 6 residential area tehran 310 77.5 other cities 85 21.3 rural area 5 1.3 reason of attendance dermatologic disease 299 74.8 cosmetic problems 42 10.5 both 59 14.8 number of attendance first visit 141 35.3 second visit or more 259 64.7 table 2. mean ccg scores before (necessity of execution of behavior) and after (the actual amount of execution of behavior) visiting by dermatologist. n question mean necessity of execution mean actual amount effect size p value 1 greeting patient 1.51 1.55 0.094 0.061 2 asking patient name 1.10 0.97 0.11 0.028 3 introducing self 1.07 0.63 0.38 <0.001 4 introducing role 1.29 0.45 0.69 <0.001 5 behave patient respectfully 1.91 1.59 0.16 0.002 6 encourage patient to tell the problem 1.86 1.84 0.4 <0.001 7 does not interrupt or direct patient statements 1.89 1.55 0.33 <0.001 8 uses understandable questions without any professional vocabulary 1.79 1.67 0.24 <0.001 9 establishes dates and sequence of events 1.79 1.67 0.13 0.001 10 exploring patient worries regarding problems discussed 1.60 1.07 0.52 <0.001 11 encourage patient to express feelings 1.34 0.83 0.45 <0.001 12 pays enough attention to patient behaviors 1.72 1.37 0.38 <0.001 13 makes a note of important issues 1.54 1.40 0.13 0.011 14 appropriate time management of interview 1.74 1.50 0.26 <0.001 15 appropriate coping with patient 1.57 1.16 0.41 <0.001 table2 continues 4 original article | dermatol pract concept. 2023;13(2):e2023120 our findings demonstrated that there was a significant difference between what patients expected from a dermatologist and the manner they actually were treated regarding physician communication skills evaluated by the ccg questionnaire. overall, mean general score for necessitation of communication skills was 81% and the most important issues in this regard were “being respectful” and “presenting complete and adequate data”. contrary, “introducing self and role” was considered the least important item by patients. these results are in line with afkham et al study in which the main priority of patients was acquisition of adequate and complete data [8]. athari et al showed the importance of being respectful in a review published in 2010 which is congruent with our results [9]. from the point of view of our patients, criteria regarding “gathering information” and “initiating the session” were the most and the least important items, respectively. these findings are against the results of previous studies conducted in some western countries in which initiation of the session and introducing the clinician seems to be very important for patients [3]. this discrepancy in results could be explained by cultural differences. in fact, iranian patients do not expect the clinician to introduce her/his self or encourage them to express their feelings. hence, culture building in this regard seems to be necessary among iranian patients. we found that older patients compared to young ones emphasized more on the necessity of communication skills, especially regarding criteria related to initiating the session and understanding the patient’s perspective. this indicates the significance of implementing these skills of older people. the study also highlighted the relationship between educational level and some gcg criteria including “understanding the patient perspective”,” building relationship” and “closing the session”. in fact, patients with higher educational level were more likely to be understood by physician and have a summary at the end of the session. the highest score both before and after a visit was attained by question number 5 which was about being respectful (92% and 85%, respectively). the lowest scores for necessary behavior and the adequate amount of execution were related to questions number 3 (introducing self) and 4 (introducing role), respectively (table 2). based on our results, questions number 5 and 7 were noted to be more important for patients and items number 6 and 16 were the most executed behavior by dermatologists (table 2). several subgroup analyses were performed to peruse the correlation of various characteristics of participants with gcc scores. the results showed that age and educational level of patients were significantly correlated with their expectations regarding communication skills of clinician, as follows: the answers to questions number 1,2,3,4,11,13,15 and 21 were correlated to age of participants (p values: 0.04, 0.032, 0.016, <0.001, 0.001, 0.004, 0.04 and 0.013, respectively). educational level of subjects affected the response to questions number 7,11,12,14,15,18,19,21 and 22 (p values: 0.045, 0.023, <0.001, 0.006, 0.008, 0.025. 0.037, <0.001 and 0.001, respectively). regarding adequate execution of skills by clinicians, educational level of patients was the only factor that affected their opinions: answers to the questions number 5,8,9,14,16,17 and18 were significantly correlated with educational level of patients (p values: 0.036, 0.010, 0.022, 0.001, 0.009, 0.002 and 0.019, respectively). conclusions the reliability coefficient of questionnaire was 0.84 in our study which was in the acceptable range of 0.8 to 0.9 [7]. hence, this study showed the acceptable validity of modified persian version of ccog-24 item questionnaire. n question mean necessity of execution mean actual amount effect size p value 16 appropriate self-confidence 1.842 1.79 0.08 0.081 17 present complete and appropriate data 1.91 1.67 0.36 <0.001 18 repeats medical advice in order to help to a better understanding by patient 1.57 1.067 0.39 <0.001 19 shares decision making process with patient 1.58 1.24 0.33 <0.001 20 final check if patient has any question or other items to discuss 1.54 0.93 0.54 <0.001 21 summarizes patient information at the end of visit 1.51 0.90 0.55 <0.001 22 scheduling for next visit 1.77 1.56 0.094 0.061 table 2. mean ccg scores before (necessity of execution of behavior) and after (the actual amount of execution of behavior) visiting by dermatologist. (continued) original article | dermatol pract concept. 2023;13(2):e2023120 5 the mean score for executing the communication skills by clinicians was 65%. the highest and lowest scores in this regard were attained by “being respectful” and “introducing role” (92% and 23%, respectively). the rate of patient satisfaction among whom attending to outpatient dermatology clinic was shown to be 60% in previous studies [10] which is somehow similar to our results regarding communication skills. finally, we found that our dermatologists were relatively weaker on criteria related to initiating the session, coping with patients and caring for their feelings which mandates future changes in their educational curriculum in this regard. however, other potential reasons could be a higher number of patients in clinics of educational hospitals and the absence of enough time for visiting patients as well as a relatively higher workload and exhaustion of physicians in this setting. this study had some limitations: firstly, illiterate patients could not participate in the study and secondly, the questionnaire was only about physicians, but other medical staffs might be as important as clinicians and might lead to patient’s dissatisfaction as well. future studies for evaluating the behavior of other medical staffs are needed to enhance the satisfaction level of patients. references 1. dwamena f, holmes-rovner m, gaulden cm, et al. interventions for providers to promote a patient-centred approach in clinical consultations. cochrane database syst rev. 2012;12:cd003267. doi: 10.1002/14651858.cd003267.pub2. pmid: 23235595. 2. smith sm, soubhi h, fortin m, hudon c, o'dowd t. interventions for improving outcomes in patients with multimorbidity in primary care and community settings. cochrane database syst rev. 2012;(4):cd006560. doi: 10.1002/14651858.cd006560. pub2. pmid: 22513941. 3. poitras me, maltais me, bestard-denommé l, stewart m, fortin m. what are the effective elements in patient-centered and multimorbidity care? a scoping review. bmc health serv res. 2018;18(1):446. doi: 10.1186/s12913-018-3213-8. pmid: 29898713. pmcid: pmc6001147. 4. moore pm, rivera s, bravo-soto ga, olivares c, lawrie ta. communication skills training for healthcare professionals working with people who have cancer. cochrane database syst rev. 2018;7(7):cd003751. doi: 10.1002/14651858.cd003751. pub4. pmid: 30039853. pmcid: pmc6513291. 5. wool ms. teaching and learning communication skills in medicine (2e). health expect. 2005;8(4):363–365. doi: 10.1111/j.1369-7625.2005.00351.x. pmcid: pmc5060313. 6. dohms mc, collares cf, tiberio ic. brazilian version of calgary-cambridge observation guide 28-item version: cross-cultural adaptation and psychometric properties. clinics (sao paulo). 2021 14;76:e1706. doi: 10.6061/clinics/2021/ e1706. pmid: 34133477. pmcid: pmc8183315. 7. streiner dl. being inconsistent about consistency: when coefficient alpha does and doesn’t matter. j pers assess. 2003;80(3):217-222. doi: 10.1207/s15327752jpa8003_01. pmid: 12763696. 8. ebrahimi a, esfahani n, saghafi m. patients’ expectations and satisfaction with their treating physician. rjms.2004;(41)11:367-375. 9. athari m., anbari a. relashinship of physician and patient. daneshvar medicine. 2010;17(85)17:71-80. available from https://www.sid.ir/fa/journal/viewpaper.aspx?id=110177. 10. renzi c, abeni d, picardi a, et al. factors associated with patient satisfaction with care among dermatological outpatients. br j dermatol. 2001;145(4):617-623. doi: 10.1046/j.13652133.2001.04445.x. pmid: 11703289. untitled editorial | dermatol pract concept 2015;5(2):3 27 dermatology practical & conceptual www.derm101.com editorial in this edition pyne et al have described a dermatoscopic pattern as a clue to infiltrative basal cell carcinoma (bcc), defined as: a geometric star-shaped pattern, extending outwards from the circumferential peripheral edge of the tumor, and identified by white lines, vessels or uneven skin surface morphology. they found this clue present in 34/107 infiltrating bccs and in 37/634 non-infiltrating bccs giving it a sensitivity of 31.7% and a specificity of 94.1% in their test series [1]. is this a useful clue for the entity “infiltrative bcc” and will it influence patient management in any significant way? infiltrative bcc is arguably the most elusive subtype and as such is the most likely subtype to invade widely and deeply before it is discovered and treated [2]. this explains why it is over-represented in bccs that are more likely to recur after treatment and more likely to cause significant functional and cosmetic morbidity [2]. in assessing the impact of this clue the important question to consider is whether the presence of a stellate pattern will make infiltrative bcc more likely to be discovered, just as much as whether it will facilitate distinction from other bcc subtypes. the former has arguably the more important impact, as it could lead to earlier cure, whereas distinction from other bcc subtypes is more relevant to method of treatment than to outcome. dermatoscopic features can be divided into patterns and clues [3]. patterns apply to the global appearance on the lesion and can lead to a differential diagnosis whereas clues are finer details that assist in reaching a provisional diagnosis [3]. some dermatoscopic methods employ metaphoric terminology to describe patterns and colors [4-6] whereas others prefer geometric terminology [7]. the proponents of geometric terminology argue that in all other fields of medicine, description clearly precedes diagnosis, except in that science of dermatoscopy, which employs metaphoric terminology. a potential problem with using a metaphor to describe this pattern in infiltrative bcc is the risk of applying a metaphor-based preconceived diagnostic implication at the time of lesion description. the feature which pyne et al describe is a pattern constructed by one of, or a combination of, three different dermatoscopic features: white radial lines, vessels in a radial pattern or 3-dimensional skin-folds in a radiating pattern. although only one of the three features was needed for the pattern to be rated, the pattern was only significant with respect to differentiating infiltrative bcc from other subtypes if two or three of the features were present [1, table 4]. the authors discuss possible causes of this dermatoscopic sign. the images they display all show central ulceration, a known cause of a radial arrangement of vessels in bcc [8]. they found that both 50% of infiltrative bcc and 45% of nodular bcc, with stellate pattern, had central ulceration. taking into account that ulceration in bcc can heal and therefore not be apparent dermatoscopically, ulceration, presregarding a dermatoscopic pattern for infiltrating basal cell carcinoma cliff rosendahl1 1 school of medicine, the university of queensland, australia citation: [editorial] regarding a dermatoscopic pattern for infiltrating basal cell carcinoma. dermatol pract concept 2015;5(2):3. http:// dx.doi.org/10.5826/dpc.0502a03 copyright: ©2015 rosendahl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: cliff rosendahl, mbbs, phd, po box 734, capalaba, queensland, 4157, australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com 28 editorial | dermatol pract concept 2015;5(2):3 references 1. pyne jh, fishburn p, dicker a, david m. infiltrating basal cell carcinoma: a stellate peri-tumor dermatoscopy pattern as a clue to diagnosis. dermatol pract concept 2015;5(2):2. 2. hendrix jd, parlette hl. duplicitous growth of infiltrative basal cell carcinoma: analysis of clinically undetected tumor extent in a paired case-control study. dermatol surg 1996;22(6):535–9. 3. pehamberger h, steiner a, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol 1987;17(4):571–83. 4. argenziano g, fabbrocini g, carli p, et al. epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. comparison of the abcd rule of dermatoscopy and a new 7-point checklist based on pattern analysis. arch dermatol 1998;134:1563–70. 5. menzies sw, ingvar c, crotty k, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol 1996;132:1178–82. 6. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol 2003;48(5):679–93. 7. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—‘chaos and clues.’ aust fam physician 2012;41(7):482–7. 8. rosendahl c, cameron a, tschandl p, bulinska a, zalaudek i, kittler h. prediction without pigment: a decision algorithm for nonpigmented skin malignancy. dermatol pract concept 2014;4(1):9. ent or past, would be a plausible explanation for stellate pattern. the authors acknowledge the need for further studies, with dermatopathological correlation, to investigate this [1]. what we know from this study is that in a test series of known bccs, the presence of a stellate dermatoscopy pattern will be present in approximately one third of the bccs that have an infiltrative component, and in only approximately 6% of bccs that do not [1]. simply because of the prevalence of bcc, any flat, non-pigmented malignant lesion is most likely to be a bcc. therefore it could appear reasonable to proceed to primary excision of any such lesion, without prior biopsy, if a stellate pattern is present, selecting excision margins appropriate for an aggressive bcc subtype. on the other hand, because it is not known what proportion of stellate-pattern lesions are benign, presumable scars, such a recommendation to proceed to excision without biopsy, currently lacks a compelling evidence base. more importantly, if recognition of this stellate dermatoscopic pattern can be shown to improve the diagnostic sensitivity of infiltrative bcc in the clinical setting, so that lesions are detected that otherwise would have been missed, the recognition of this dermatoscopic pattern will have a significant practical benefit. further studies to clarify these issues are appropriate. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022141 1 erythema multiforme: a clinico dermoscopic-histopathological correlation of evolving targetoid lesions shreya deoghare1, devayani pol1 1 department of dermatology, venerology and leprosy, patil medical college and hospital & research centre, pune, india citation: deoghare s, pol d. erythema multiforme: a clinico-dermoscopic-histopathological correlation of evolving targetoid lesions. dermatol pract concept. 2022;12(4):e2022141. doi: https://doi.org/10.5826/dpc.1204a141 accepted: march 7, 2022; published: october 2022 copyright: ©2022 deoghare et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: shreya deoghare, department of dermatology, venerology and leprosy, dr. d. y. patil medical college and hospital & research centre, sant tukaram nagar, pimpri, pune, india – 411018 ph no: +919325307311, e-mail: shreyadeoghare@yahoo.co.in case presentation a 32-year-old male was diagnosed with recurrent erythema multiforme secondary to orolabial herpes. dermoscopy ( polarised light, dermlite dl4) of evolving targetoid lesions is shown in figure 1. teaching point the central ruptured vesicle is seen as a central circular yellowish-pink area on dermoscopy and correlates with subepidermal split on histopathology. the black pigmentation is seen as brown-black colored dots and clods on dermoscopy and correlates with necrotic keratinocytes along dermo-epidermal junction on histopathology. a well-defined urticaria-like erythematous plaque is seen on dermoscopy as structureless homogenous pink-white area obliterating the normal pigment network and correlates with papillary oedema on histopathology. we discovered that, in the absence of treatment, the size of individual lesions increases as the time since the onset of the lesion increases. this is associated with dermoscopic feature of increase in the number and density of black-brown dots and clods, that we have termed as "splash of ink" appearance in fully evolved targetoid lesions, which could indicate ongoing damage to basal keratinocytes and melanocytes and thus disease activity. dermoscopy can be used to determine the relative age of targetoid lesions. the size of the targetoid 2 image letter | dermatol pract concept. 2022;12(4):e2022141 lesion and the size of “splash of ink” appearance indicates the evolution of the individual lesion. targetoid lesions with the earliest onset will have largest size and “splash of ink” appearance and vice-versa. we believe that regardless of the cause of em, its morphological appearance will be consistent in all cases, and treatment will result in fading of “splash of ink” appearance. however, further studies are needed to validate this. references 1. trayes kp, love g, studdiford js. erythema multiforme: recognition and management. am fam physician. 2019;100(2):82-88. pmid: 31305041. 2. kaliyadan f. dermoscopy of erythema multiforme. indian dermatol online j. 2017;8:75. doi: 10.4103/2229-5178.198771. pmid: 28217488. pmcid: pmc5297286. figure 1. (a) a 32-year-old male presented with erythema multiforme presented with multiple targetoid lesions (white arrow) and post-inflammatory hyperpigmented patches (green arrow). dermoscopy (polarised light, dermlite dl4) of targetoid lesions of erythema multiforme: newest lesion onset one day back (b), onset two days back (c) and oldest lesion onset three days back (d). yellow arrow: central circular yellowish-pink area, black arrow: brown-black colored dots and clods clustered regularly at center with irregular distribution at periphery, red arrow: structureless homogenous pink-white area obliterating normal pigment network, blue arrow: pigmented reticular lines (pigment network) of normal skin. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023038 1 basal cell carcinomas presenting as flat pigmented macules on the face mimicking lentigo maligna on dermoscopy: a case series. cristian navarrete-dechent1,2, pablo uribe1,2, harold rabinovitz3, alvaro abarzua-araya1,2, harald kittler4 1 melanoma and skin cancer unit, department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 2 department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 3 department of dermatology, medical college of georgia, augusta, ga, usa 4 department of dermatology, medical university of vienna, vienna, austria key words: dermoscopy, dermatoscopy, basal cell carcinoma, lentigo maligna, melanoma, face citation: navarrete-dechent c, uribe p, rabinovitz h, abarzua-araya a, kittler h. basal cell carcinomas presenting as flat pigmented macules on the face mimicking lentigo maligna on dermoscopy: a case series. dermatol pract concept. 2023;13(1):e2023038. doi: https://doi.org/10.5826/dpc.1301a38 accepted: april 24, 2022; published: january 2023 copyright: ©2023 navarrete-dechent et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: cristian navarrete-dechent, md, department of dermatology, escuela de medicina, pontificia universidad catolica de chile, diagonal paraguay 362, 6th floor, santiago, chile 8330077 phone: +56-2-2435 3574 email: ctnavarr@gmail.com introduction basal cell carcinoma (bcc), the most common type of skin cancer, can usually be diagnosed with dermoscopy with high accuracy [1]. we noted, however, that certain pigmented bccs (pbccs) are more difficult to diagnose than others. these challenging pbccs usually appear as flat, pigmented lesions on the face and mimic lentigo maligna (lm). to better characterize these types of pbccs, we retrospectively collected typical cases of this clinical presentation and reevaluated the dermoscopic findings. case presentation cases were selected retrospectively from databases from austria, chile, and the united states. cases were included if they were clinically pigmented and flat. most cases were submitted for biopsy with lm in the differential diagnosis. we analyzed both pbcc and lm dermoscopic criteria by two independent investigators (cnd and hk). a third reviewer helped solving disagreements (pu or .aa). for reflectance confocal microscopy (rcm) images, we used a wide-probe rcm (vivascope 1500). biopsy reports were obtained from clinical records and reviewed by expert dermatopathologists. finally, we analyzed the dermoscopic images with a previously validated convolutional neural network (cnn) (https://dermonaut.meduniwien.ac.at/ypsono) and recorded the top-1 and top-3 accuracy rates [2]. we found 10 cases of bccs that mimicked lms. the mean age at diagnosis was 73 years (range: 44-87 years) and 6 of the 10 patients were females. all bccs presented as flat pigmented macules on sun-exposed areas of the face 2 research letter | dermatol pract concept. 2023;13(1):e2023038 (table 1). on dermoscopy, the main feature was a pattern of angulated lines without obliteration of the follicular openings, in all cases (figure 1 and 2). this pattern mimicked the rhomboidal or ‘zig-zag’ pattern of lm. additionally, all cases had pink areas and lacked the typical vascular pattern of bcc. shiny white blotches and strands were seen in 4 out of 10 (40%). one case was examined by rcm and showed classic bcc features such as tumor nodules and cords with table 1. demographic and tumor characteristics of included cases. case # age (y) gender subtype location 1 45 f superficial nose 2 72 m superficial forehead 3 44 f superficial nose 4 54 m superficial forehead 5 83 m infiltrative cheek 6 74 f superficial cheek 7 87 f superficial and nodular nose 8 77 f superficial and nodular forehead 9 83 f nodular, multifocal nose 10 42 m superficial cheek m = male; f = female. figure 1. basal cell carcinoma presenting as flat pigmented macules. (a) clinical features of a flat pigmented macule on the nasal supratip. (b) dermoscopic features showing rhomboidal structures (arrow) and a pink background (asterisk) (polarized light dermoscopy, original magnification x10). inset shows reflectance confocal microscopy features showing tumor nodules with palisading and clefting (original magnification x30). (c) clinical features of a flat pigmented macule on the right cheek. (d) dermoscopic features showing rhomboidal structures (arrow), pink background, and shiny white blotches and strands (asterisk) (polarized light dermoscopy, original magnification x10). research letter | dermatol pract concept. 2023;13(1):e2023038 3 figure 2. basal cell carcinoma presenting as flat pigmented macules. (a) clinical features of a flat pigmented macule on the right nasal tip. (b) dermoscopic features showing rhomboidal structures (black arrow) and a pink background with shiny white blotches and strands (asterisk) (polarized light dermoscopy, original magnification x10). (c) clinical features of a flat pigmented macule on the left nasal tip. d. dermoscopic features showing rhomboidal structures (black arrow) and a pink background (asterisk) (polarized light dermoscopy, original magnification x10). palisading and clefting. with regard to histopathologic subtype, six were superficial, two mixed (superficial and nodular), one had an infiltrative component, and one was nodular bcc. the top-1 and top-3 accuracy rates of the cnn were 0% (0 out of 10) and 60% (6 out of 10), respectively. the most common top-1 predictions of the cnn were pigmented actinic keratosis (pak), melanoma, and solar lentigo. the patients in this manuscript have given written informed consent to publication of their case details. conclusions we characterized a previously undescribed presentation of facial pbccs mimicking lm. the common confounding feature seen in all cases was angulated lines (ie ‘rhomboidal’, ‘zig-zag’) without involvement of hair follicles. although all cases were typified by pink structureless areas, none displayed the typical serpentine and branching vessels of bcc. in our experience, lm only rarely displays pink areas, which could be a clue for the correct diagnosis of bcc. shiny white blotches and strands also rarely appear on lms [3]. the poor performance of a previously validated cnn underlines that these pbccs are difficult to diagnose [2]. limitations of this study are (1) that we were not able to estimate the frequency of this type of pbcc in clinical practice, (2) that we did not include a control group of other flat pigmented lesions such as pak or lm, which is the main mimicker, (3) cases were not consecutive and there might be selection and recall bias, (4) no histopathological correlation of the angulated lines in bccs was available, and (5) no pathology slides review was performed for bcc histopathological subtypes; however, all cases were initially signed by expert dermatopathologists. in summary, when evaluating flat pigmented lesions on the face, pbcc should be included in the differential diagnosis [4]; especially when seeing angulated lines amidst pink areas with or without shiny white blotches and strands. references 1. reiter o, mimouni i, gdalevich m, et al. the diagnostic accuracy of dermoscopy for basal cell carcinoma: a systematic review and meta-analysis. j am acad dermatol. 2019;;80(5):1380-1388. doi: 10.1016/j.jaad.2018.12.026. pmid: 30582991. 4 research letter | dermatol pract concept. 2023;13(1):e2023038 blotches and strands with nonpigmented basal cell carcinoma: evaluation of an additional dermoscopic diagnostic criterion. jama dermatol. 2016;;152(5):546-552. doi: 10.1001/jamadermatol.2015.5731. pmid: 26792406. pmcid: pmc5037958. 4. tschandl p, rosendahl c, kittler h. dermatoscopy of flat pigmented facial lesions. j eur acad dermatol venereol. 2015;29(1):120-127. doi: 10.1111/jdv.12483. pmid: 24661420. 2. tschandl p, codella n, akay bn, et al. comparison of the accuracy of human readers versus machine-learning algorithms for pigmented skin lesion classification: an open, web-based, international, diagnostic study. lancet oncol. 2019;20(7):938-947. doi: 10.1016/s1470-2045(19)30333-x. pmid: 31201137. pmcid: pmc8237239. 3. navarrete-dechent c, bajaj s, marchetti ma, rabinovitz h, dusza sw, marghoob aa. association of shiny white dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023143 1 real-life safety and effectiveness of dupilumab in patients with concomitant malignancies: a case series luigi gargiulo1,2, carlo alberto vignoli1,2, andrea cortese1,2, luciano ibba1,2, antonio costanzo1,2, alessandra narcisi1,2 1 department of biomedical sciences, humanitas university, pieve emanuele, italy 2 dermatology unit, irccs humanitas research hospital, rozzano, italy citation: gargiulo l, vignoli ca, cortese a, ibba l, costanzo a narcisi a. real-life safety and effectiveness of dupilumab in patients with concomitant malignancies: a case series. dermatol pract concept. 2023;13(3):e2023143. doi: https://doi.org/10.5826/ dpc.1303a143 accepted: december 12, 2022; published: july 2023 copyright: ©2023 gargiulo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: antonio costanzo has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, galderma, boehringer, novartis, pfizer, sandoz, and ucb. alessandra narcisi has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, boehringer, novartis, pfizer and ucb. luigi gargiulo, carlo alberto vignoli, andrea cortese and luciano ibba have nothing to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: carlo alberto vignoli, department of biomedical sciences, humanitas university, via rita levi montalcini 4, pieve emanuele (mi), 20090, italy. e-mail: c.alberto.vignoli@gmail.com ethics / patient consent statement: all included patients had provided written consent for retrospective study of data collected during routine clinical practice. introduction dupilumab is a human monoclonal antibody which targets the alpha subunit of the interleukin (il)-4-receptor, blocking the signaling of both il-13 and il-4 and it is the first biologic drug approved for moderate-to-severe atopic dermatitis [1]. according to a systematic review from braddock et al [2], data on the role of il-13 and il-4 in carcinogenesis are conflicting and there is paucity of evidences regarding the use of dupilumab in patients with concomitant malignancies [3]. we report our experience with 10 patients with previous history of cancer and 4 patients who developed a malignancy during treatment with dupilumab, from january 2019 to june 2022. case presentation ten patients started dupilumab after receiving a diagnosis of cancer (table 1): • three patients had previously undergone partial thyroidectomy for papillary thyroid carcinoma (4, 6 and 29 years before receiving dupilumab, respectively). • two women had a history of ductal breast cancer: one received chemotherapy 12 years before the start of dupilumab, while the second patient underwent surgery 6 years before. • two patients had a diagnosis of prostatic cancer: one started dupilumab 4.5 years after the prostatectomy, while 2 research letter | dermatol pract concept. 2023;13(3):e2023143 ta b le 1 . d em o gr ap h ic d at a an d c h ar ac te ri st ic s o f th e m al ig n an ci es o f p at ie n ts w it h h is to ry o f ca n ce r b ef o re th e st ar t o f d u p il u m ab a n d p at ie n ts w h o d ev el o p ed c an ce r af te r th e st ar t o f d u p il u m ab n ° s e x a g e ty p e o f c a n ce r c a n ce r tr e a tm e n t d a te o f c a n ce r d ia g n o si s d a te o f d u p il u m a b tr e a tm e n t s ta rt t im e b e tw e e n c a n ce r d ia g n o si s a n d d u p il u m a b (m o n th s) e a s i a t b a se li n e p -n r s a t b a se li n e d a te o f la st o b se rv a ti o n e a s i a t la st o b se rv a ti o n p -n r s a t la st o b se rv a ti o n 1 m 2 6 p ap il la ry t h yr o id c ar ci n o m a su rg er y ja n -1 6 ju l2 0 5 5 2 8 9 f eb -2 2 3 ,5 5 2 f 3 2 p ap il la ry t h yr o id c ar ci n o m a su rg er y ja n -1 6 ja n -2 2 7 3 2 4 9 m ay -2 2 0 0 3 f 8 8 p ap il la ry t h yr o id c ar ci n o m a su rg er y ja n -9 3 ju n -2 2 3 5 8 2 8 ,2 1 0 n /a n /a n /a 4 f 4 6 d u ct al b re as t c an ce r c h em o th er ap y ja n -0 8 f eb -2 0 1 4 7 2 6 1 0 ju n -2 2 2 3 5 f 6 6 d u ct al b re as t c an ce r su rg er y ja n -1 6 m ar -2 2 7 5 2 4 1 0 ju l2 2 3 9 6 m 7 4 p ro st at ic a d en o ca rc in o m a su rg er y d ec -1 6 m ay -2 1 5 4 2 4 1 0 ju l2 2 0 3 7 m 5 9 p ro st at ic a d en o ca rc in o m a r ad io th er ap y + h o rm o n al t h er ap y m ay -2 1 m ay -2 2 1 2 2 4 8 n /a n /a n /a 8 m 7 0 l u n g a d en o ca rc in o m a su rg er y ja n -1 6 ja n -2 0 4 9 2 4 9 a p r2 2 2 4 9 m 9 2 sq u am o u s ce ll c ar ci n o m a su rg er y ju n -1 3 ju n -2 0 8 5 2 6 9 m ay -2 2 3 3 1 0 f 7 4 o va ri an c an ce r c h em o th er ap y ja n -0 9 ju n -2 0 1 3 9 2 6 9 m ay -2 2 2 7 n ° s e x a g e ty p e o f c a n ce r c a n ce r tr e a tm e n t d a te o f d u p il u m a b tr e a tm e n t s ta rt d a te o f d u p il u m a b tr e a tm e n t s ta rt t im e b e tw e e n c a n ce r d ia g n o si s a n d d u p il u m a b (m o n th s) e a s i a t b a se li n e p -n r s a t b a se li n e d a te o f la st o b se rv a ti o n e a s i a t la st o b se rv a ti o n p -n r s a t la st o b se rv a ti o n 1 m 7 4 m el an o m a su rg er y m ay -2 1 d ec -2 1 7 2 4 1 0 ju l2 2 0 3 2 m 7 5 m el an o m a su rg er y ju n -1 9 ja n -2 0 7 2 7 9 a p r2 2 0 0 3 m 6 1 p ro st at ic a d en o ca rc in o m a su rg er y + h o rm o n al t h er ap y m ay -2 1 m ay -2 1 2 2 5 9 ju l2 2 1 1 4 m 7 1 sq u am o u s c el l c ar ci n o m a su rg er y ju n -1 9 ja n -2 0 7 2 6 1 0 m ay -2 2 0 0 e a si =   e cz em a a re a an d s ev er it y in d ex ; p -n r s = p ru ri tu sn u m er ic al r at in g sc al e. research letter | dermatol pract concept. 2023;13(3):e2023143 3 the other received dupilumab one year after radiotherapy and hormonal therapy. • one woman had history of ovarian cancer, treated with chemotherapy 11 years before starting dupilumab. • one patient underwent pulmonary lobectomy for a lung adenocarcinoma 4 years before dupilumab. • one patient was diagnosed with multiple squamous cell carcinomas (sccs). all patients are currently undergoing a specific oncologic follow-up, according to guidelines from the italian association of medical oncology. overall, 4 patients started dupilumab less than 5 years after the cancer diagnosis. one patient received dupilumab one year after completing radiotherapy. six patients have already completed one year of treatment with dupilumab, without any cancer progressions or recurrences. among our patients treated with dupilumab, 4 developed malignancies during therapy (table 1). after 7 months of therapy, two patients were diagnosed with a melanoma in situ and a pt1a melanoma respectively, both completely excised. another patient was diagnosed with a scc. another patient was diagnosed with prostatic carcinoma two months after starting dupilumab; he is currently receiving hormonal therapy after prostatectomy. all of these patients never interrupted dupilumab and they are still on treatment, completing one year of follow-up. conclusions the role of il-4 and il-13 in carcinogenesis is still unclear. a systematic review did not show a higher risk of malignancy when specifically targeting the il-13 and il-4 pathway [2]. in literature, several case series on patients with concomitant malignancies have been described, showing no elevated risk of cancer recurrences or relapses [4-5]. in our experience, three of the four cancers diagnosed during treatment with dupilumab were cutaneous malignancies. the fourth patient was diagnosed with a prostatic adenocarcinoma two months after the start of dupilumab: considering his age (61 years old) and the short timespan between the diagnosis and the start of the treatment, no causal effect could be observed. finally, none of our patients experienced cancer progressions or relapses during treatment. we have described a case series of patients with concomitant malignancies treated with dupilumab. larger prospective studies with longer follow-up are needed to further assess this topic. larger prospective studies with longer follow-up are needed to further assess this topic. references 1. costanzo a, amerio p, asero r, et al. long-term management of moderate-to-severe adult atopic dermatitis: a consensus by the italian society of dermatology and venereology (sidemast), the association of italian territorial and hospital allergists and immunologists (aaiito), the italian association of hospital dermatologists (adoi), the italian society of allergological, environmental and occupational dermatology (sidapa), and the italian society of allergy, asthma and clinical immunology (siaaic). ital j dermatol venerol. 2022;157(1):1-12. doi:10.23736/s2784-8671.21.07129-2. pmid: 34929995. 2. braddock m, hanania na, sharafkhaneh a, colice g, carlsson m. potential risks related to modulating interleukin-13 and interleukin-4 signalling: a systematic review.  drug saf. 2018; 41(5):489-509. doi:10.1007/s40264-017-0636-9. pmid: 2941 1337. pmcid: pmc5938313. 3. shirley m. dupilumab: first global approval.  drugs. 2017; 77(10):1115-1121. doi:10.1007/s40265-017-0768-3. pmid: 28547386. 4. siliquini n, giura mt, viola r, et al. atopic dermatitis, dupilumab and cancers: a case series.  j eur acad dermatol venereol. 2021;35(10):e651-e652. doi:10.1111/jdv.17264. pmid: 33797094. 5. fowler e, rosen j, lev-tov h, yosipovitch g. two cancer patients receiving dupilumab for treatment of atopic dermatitis.  acta derm venereol. 2019;99(10):899-900. doi:10.2340 /00015555-3201. pmid: 31037315. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022114 1 dermatology practical & conceptual dermoscopy for facial leukotrichia in vitiligo: an important step for a better treatment decision mohammed ibrahim aljasser1,2 1 division of dermatology, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia 2 king abdullah international medical research center, riyadh, saudi arabia citation: aljasser mi. dermoscopy for facial leukotrichia in vitiligo: an important step for a better treatment decision. dermatol pract concept. 2022;12(3):e2022114. doi: https://doi.org/10.5826/dpc.1203a114 accepted: november 16, 2021; published: july 2022 copyright: ©2022 aljasser. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: mohammed i. aljasser mbbs frcpc, associate professor, division of dermatology, king saud bin abdulaziz university for health sciences, p.o. box 3660, riyadh 11481, saudi arabia, tel: +966-11-4299999 ext. 95211, fax: +966-11-429 9999 ext. 95148, e-mail: jasserm@ksau-hs.edu.sa; mj_derma@hotmail.com case presentation a 14-year-old female with stable generalized vitiligo (body surface area 1%) was being treated with excimer laser and tacrolimus 0.1% ointment. she showed some re-pigmentation in some body sites such as the knees. however, facial patches showed very minimal re-pigmentation despite receiving many sessions of excimer laser. dermoscopy showed leukotrichia affecting the whole vitiliginous facial areas (figure 1). the patient was therefore advised to undergo melanocyte transplantation. topical and laser therapy were discontinued. teaching point leukotrichia within vitiligo is known to be associated with poor response to medical and light therapy. therefore, it is important to identify leukotrichia in order to predict response to treatment within a given body site. it is often difficult to detect leukotrichia clinically especially in areas with fine vellus hair such as the face. dermoscopy has recently emerged as a valuable tool in the assessment of vitiligo, especially for disease activity [1,2]. we find dermoscopy very helpful in detecting leukotrichia that cannot be seen clinically by the naked eye, especially for facial patches. 2 image letter | dermatol pract concept. 2022;12(3):e2022114 references 1. jha ak, sonthalia s, lallas a. dermoscopy as an evolving tool to assess vitiligo activity. j am acad dermatol. 2018;78(5):1017– 1019. doi: 10.1016/j.jaad.2017.12.009. pmid: 29229577. 2. kumar jha a, sonthalia s, lallas a, chaudhary rkp.. dermoscopy in vitiligo: diagnosis and beyond. int j dermatol. 2018;57(1):50–54. doi: 10.1111/ijd.13795. pmid: 29076154. figure 1. (a) facial vitiligo with minimal response to many sessions of excimer laser. (b) polarized dermoscopy clearly demonstrate multiple white vellus hairs within vitiliginous skin . leukotrichia was difficult to appreciate with the naked eye. dermatology: practical and conceptual review | dermatol pract concept. 2023;13(1):e2023010 1 melanocytic lesions with peripheral globules: proposal of an integrated management algorithm simone cappilli1,2, simone ribero3, luigi cornacchia1,2, silvia catapano1,2, laura del regno1, laura quattrini1,2, alessandra d’amore1,2, francesco federico4, paolo broganelli3, ketty peris1,2, alessandro di stefani1,2 1 uoc di dermatologia, dipartimento di scienze mediche e chirurgiche, fondazione policlinico universitario a. gemelli irccs, rome, italy 2 dermatologia, dipartimento di medicina e chirurgia traslazionale, università cattolica del sacro cuore, rome, italy 3 dermatology clinic, department of medical sciences, university of turin, turin, italy 4 patologia, dipartimento di scienze della vita e sanità pubblica, fondazione policlinico universitario a. gemelli irccs, rome, italy key words: melanoma, reflectance confocal microscopy, diagnostic imaging, dermoscopy citation: cappilli s, ribero s, cornacchia l, et al. melanocytic lesions with peripheral globules: proposal of an integrated management algorithm. dermatol pract concept. 2023;13(1):e2023010. doi: https://doi.org/10.5826/dpc.1301a10 accepted: may 18, 2022; published: january 2023 copyright: ©2023 cappilli et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: simone cappilli, md, dermatologia, dipartimento di medicina e chirurgia traslazionale, università cattolica del sacro cuore, rome, italy. largo a. gemelli 8, 00168, rome, italy. tel.: +39 06-30154227 fax: +39 06-30154919 email: simo.cappilli@ gmail.com introduction: a peripheral rim of globules represents a marker of the horizontal growth phase in nevi and is a common feature in children and adolescents. the observation of melanocytic lesions with peripheral globules (mlpgs) in adulthood deserves more attention, since melanoma may exhibit this feature, albeit rarely. risk-stratified management recommendations considering a global clinical approach are still missing. objectives: to analyze current knowledge on mlpgs and propose an integrated management algorithm stratified for age groups. methods: we conducted a narrative review of current published data on mlpgs, analyzing clinical dermoscopic and confocal distinguishing features of melanoma from benign nevi. results: the risk of finding a melanoma when removing an mlpg increases with age, especially in people >55 years old, and is significantly higher in the extremities, head/neck and in case of a single asymmetrical lesion, ≥6 mm in diameter. dermoscopic features associated with melanoma diagnosis include atypical peripheral globules, asymmetrical distribution, multiple rims as well as the reappearance of globules after prior loss. in addition, wide blue-grey regression areas, atypical networks, abstract 2 review | dermatol pract concept. 2023;13(1):e2023010 introduction a dermoscopic subset of melanocytic lesions is characterized by the presence of round to oval globules regularly distributed at the edge of the lesion, representing a marker of the horizontal enlargement with a mean growth rate of 0.25mm2/month [1,2]. a decreased density or a complete disappearance of peripheral globules has been associated with a stabilization of nevi, with an estimated median time of growth cessation of 58.6 months (4-5 years) [1,3]. enlargement of nevi is commonly observed in children and adolescents with a linear age-related prevalence reduction [3,4]. the common approach towards melanocytic lesions with peripheral globules (mlpgs) in patients younger than 35 years is conservative, not requiring interventions, as regards their benign clinical behavior [2,3]. the occurrence of mlpgs in adulthood and the elderly is infrequent and requires a cautious approach, since change over time represents a suspicious feature [3]. furthermore, peripheral globules may also be detected, albeit rarely, in melanoma [3,5]. in 2007, the international dermoscopic society recommended that mlpgs exhibiting asymmetry of structures within the lesion should be closely monitored or excised, regardless of age [6]. afterwards, it has been suggested to monitor mlpgs in the absence of other dermoscopic melanoma-specific criteria beyond the age of 30, considering instead surgical excision or close follow-up for those over 50 [3]. reflectance confocal microscopy (rcm) allowed the accurate definition of globules as junctional clusters of melanocytes protruding into dermal papillae, or widening the interpapillary space, at the edge of the lesions with a perfect correspondence to histology [7]. consecutive confocal evaluations of mlpgs in adults supported the dynamic evolution of this process, through an eccentric elongation of junctional clusters with narrowing of their shape, associated with a centrifugal extension [7]. recent studies have been focused on the clinical approach to mlpgs, providing further insights into mlpgs, however heterogeneous management strategies have been proposed and common practical indications are still missing [5, 8-12]. objectives the main aim of this manuscript is to critically review the current published data on mlpgs and to provide an integrated clinical, dermoscopic and confocal management algorithm stratified for age groups, resulting in a more appropriate and individualized management strategy. methods search strategy to identify eligible studies, a comprehensive search was conducted using pubmed electronic database with the following terms: “dermoscopy (mesh)”, “dermatoscopy (mesh)”, “confocal microscopy (mesh), “melanocytic lesions (mesh)”, “melanoma (mesh)” and any one of the terms “peripheral clods (mesh)”, “peripheral globules (mesh)” published in english. the main search and the screening of titles and abstracts were completed independently by two reviewers (sc and lc). the manual search was concluded by the perusal of the reference sections of all relevant articles. all studies identified as relevant were analyzed and included. case reports aiming to describe singular observations or written in non-native english language were excluded. results search results we completed a literature review by searching the electronic database pubmed until 1 december 2021, for all relevant records. a total of 125 articles were retrieved in the data synthesis: 120 were excluded due to being duplicated (among mesh terms), not written in english, and not relevant (not related to melanocytic lesions). finally, a total number of 5 studies were included and analyzed, and their main features are summarized in table 1. age and clinical data the impact of patient age on clinical decision-making for mlpgs is well acknowledged but different thresholds and suggestions have been proposed [5,8-11]. williams et al eccentric blotches, tan structureless peripheral areas and vascularization are atypical dermoscopic features. confocal worrisome findings are represented by pagetoid cells within the epidermis, architectural disarrangement and atypical cells of the dermo-epidermal junction with irregular peripheral nests. conclusion: we proposed a multi-step age-stratified management algorithm integrating clinical, dermoscopic and confocal findings that may increase the early recognition of melanoma and avoid surgical excision of benign nevi. review | dermatol pract concept. 2023;13(1):e2023010 3 observed all confirmed cases of melanoma (4/99, 4.0% of mlpgs) in adulthood, specifically in individuals aged 30, 35, 40 and 55, without difference in the proportion of malignancy, when dichotomizing by age 50 (5.3% vs 3.9%, p=1.0) [11]. conversely, ribero et al observed 9.8% of mlpgs (45/457) being melanomas (age ranged from 35 to 85 years) with a dramatic increase of frequency in patients >55 years old (10/69, 15%) [5]. two other studies found a positive trend between histologically proven dysplastic nevi and melanoma with patients’ ages, even though without statistical significance [9,10]. in particular, reiter et al. reported a diagnosis of melanoma for 39.2% (115/293) of total mlpgs with an average age of 50 years old (range 20-85 years old), and more than half of cases (68%) being younger than 60 years old [9]. a lower percentage of melanoma (1.9%, 3/154 mlpgs) was observed by pampínfrancoin et  al with 49.5 years old estimated as the median age of malignancy in high-risk patients, defined as patients under digital dermoscopic surveillance for atypical mole syndrome and/or personal or familial history of melanoma [10]. in a similar selected population of high-risk adults, carbone et al reported a higher rate of malignancy with 19 melanomas in 135 mlpgs (14%) with a mean age of 49.8 years old and 10% of cases occurring even in patients under 30 years old [8] (table 1). concerning the anatomic site of mlpgs, the most common location was the torso and especially the back [5,8-10], while the risk of finding a melanoma when removing an mlpg resulted significantly higher in the extremities and head/neck [5,9]. a gender prevalence of mplgs was largely not reported except for two studies with controversial results [5, 8-11]. in addition, pampìn-francoin et al. reported an average size of mlpgs of 4.1 mm with a significant association with the diagnosis of melanoma in lesions ≥6mm in diameter, as well as in mlpgs showing asymmetry in two axes [10]. moreover, the authors highlighted that multiple mlpgs in a single patient were statistically less likely to be diagnosed as melanoma [10] (table 2). dermoscopy the morphology and distribution of peripheral globules along with the presence of additional atypical features in mlpgs was recently investigated, with the objective to identify specific structures indicating a diagnosis of melanoma [8-11]. dermoscopic findings that support a diagnosis of melanoma included atypical globules (irregular in shape, size or color) and/or their asymmetrical distribution. completely circumferential atypical globules are reported to have the highest risk of being melanoma, followed by focal circumferential atypical globules and focal circumferential typical globules [9]. globules distributed in more than a single rim (tiered) and departing within the edge of a lesion were found to be more frequently observed in melanoma rather than nevi, as were peripheral globules covering less than 25% of the entire circumference (especially in case of <1-history) [9,10]. in addition, the reappearance of peripheral globules after their previous disappearance has been also related to a diagnosis of melanoma, and this finding is in contrast with the expected evolution of mlpgs [2,10]. other relevant diagnostic clues suggesting melanoma were the presence of blue-grey regression areas (especially when involving a large part of an mlpg, >50%) and atypical table 1. included studies on melanocytic lesions with peripheral globules. study study design participant’s age no. of cases williams et al. 2020 retrospective study >20 yo 95 nevi 4 mm ribero et al. 2020 retrospective study 35-85 yo (median age 49) 412 nevi 45 mm 19 in situ 26 invasive reiter et al. 2021 cross-sectional, retrospective study 285 yo (median age of mm=50 yo, median age of nevi=34 yo ) 178 nevi 115 mm pampín-franco et al. 2021 prospective study, high risk patients 19-73 yo (median age 42 yo) 151 nevi 3 mm 3 invasive carbone et al. 2021 prospective study, high-risk patients 16-79 yo (median age 41 yo) 116 nevi 19 mm 5 in situ 14 invasive mm= malignant melanoma, yo= years old 4 review | dermatol pract concept. 2023;13(1):e2023010 papillary dermis were seen either in benign nevi or in melanomas [10]. proposal of an integrated management algorithm herein we propose a flowchart algorithm for individualized management of mlpgs considering clinical, dermoscopic and confocal criteria, with the aim to identify melanomas at an early stage and to reduce as much as possible the unnecessary surgical excision of benign nevi (figure 1). the proposed algorithm is outlined to provide risk stratification and includes the following steps: mlpgs in patients <35 years old: regular dermoscopic monitoring is recommended for lesions showing an organized rim of globules with a reticular, globular, or mixed central pattern. a decreased density of peripheral globules resulting in total disappearance, in an overall period of 4-5 years, is expected. this clinical evolution allows the interruption of follow-up surveillance at the end of the process. we suggest performing rcm in mlpgs when at least two atypical dermoscopic structures are detected, as we still consider the very low percentage of melanoma exhibiting this pattern in patients younger than 35 years old. in the absence of cyto-architectural atypia a dermoscopic follow-up can be extended whereas in presence of confocal melanoma-specific criteria, surgical excision is recommended (figure 2). mlpgs showing ≥2 new-onset atypical dermoscopic structures during dermoscopic surveillance should be further investigated by means of rcm and follow the same recommendations. mlpgs in patients 35-55 years old: in this age group, mlpgs should be managed with more caution, with a careful assessment of dermoscopic features: if any atypical networks [10]. eccentric blotches, tan structureless peripheral areas and vascularization were also considered worrisome features [10,11]. in presence of a regular distribution of peripheral globules, at least two melanomaspecific criteria were considered indicative of malignancy by reiter et al, while for williams et al a single melanoma specific-structure was sufficient, although such circumstance was observed in more than half of nevi and in all melanoma cases (table 2) [9,11]. remarkably, the risk of an mlpg being a melanoma remains not negligible even for lesions that exhibit only peripheral regular globules without additional worrisome dermoscopic criteria [5]. confocal microscopy in-vivo confocal evaluation of mlpgs, with a detailed analysis of global architecture and cytological aspects, was performed in two studies [8,10]. classical melanoma-specific findings were detected in 100% of malignant mlpgs [8,10]. in detail, the presence of intraepidermal pagetoid cells (roundish or dendritic in shape) was strongly related to the diagnosis of melanoma [10]. moreover, architectural disarray of the dermo-epidermal junction (dej), unspecific pattern or non-edged dermal papillae, and atypical junction thickening represented confocal findings more frequently observed in malignant lesions. atypical cells at the dej, especially when multiple, along with the presence of irregular and sparse peripheral nests with an evident cleft, were also reported as being associated with histologically proven melanomas (table 2) [8,10]. no lesions showed true cerebriform nets. inflammatory cells and melanophages at the table 2. clinical, dermoscopic and confocal criteria associated with the diagnosis of melanoma showing peripheral globules. clinical data dermoscopy rcm extremities and head/neck single lesion rather than multiple mlpg ≥6 mm diameter asymmetry in two axes regular pg with at least 2 melanoma-specific structures or ≥2 of the following findings pg in less than 25% of the circumference with 1 year history reappearance of pg pg irregular in size, shape, or color atypical and/or asymmetric distribution of pg blue-grey regression structures involving >50% of the lesion vascularization off-center blotches peripheral tan structureless areas epidermis pagetoid cells (roundish or dendritic) dej unspecific pattern non-edged dermal papillae architectural disarrangement atypical thickenings atypical cells peripheral dense irregular (sparse) nests rcm= reflectance confocal microscopy, mlpg= melanocytic lesions with peripheral globules, pg= peripheral globules, dej= dermal-epidermal junction review | dermatol pract concept. 2023;13(1):e2023010 5 <35 yo dermoscopy atypical structures ≥2 excision yes dermoscopy onset of new criteria rcm melanoma specific criteria no <2 dermoscopy onset of new criteria 35–55 yo >55 yo yes yes rcm melanoma specific criteria dermoscopy atypical structures reqular follow-up until stabilization excision excision no no reqular follow-up until stabilization figure 1. our proposed algorithm for the clinical management of melanocytic lesions with peripheral globules, including dermoscopic and confocal findings in different age groups. figure 2. invasive melanoma (breslow 0.9 mm) on the upper back of a 33-years old man: dermoscopy (a), rcm (b,c) and histology (d). irregular blotches, shiny white streaks and blue-whitish veils are observed at dermoscopy beyond a regular distribution of peripheral globules (a). a confocal section of the dermal-epidermal junction displays dendritic cells and sparse nests (blue squares) (b, low magnification; c, high magnification) corresponding to the epidermal spreading of melanocytes and discohesive nests seen on histology (d) [haematoxylin and eosin stain, original magnification x200]. 6 review | dermatol pract concept. 2023;13(1):e2023010 warning signal and the chance of an mlpg being a melanoma exhibiting only organized peripheral globules without other worrisome dermoscopic features represents a concrete risk after 55 years old [5]. limitations a limitation of this work is the inclusion of different studies with heterogeneous methodological cohorts and interventions, with no age-group standardisation. in addition, it should be considered that non-proven histologic mlpgs were not considered in the studies, and this may have contributed to a realistic underestimation of benign nevi exhibiting peripheral globules. this scenario may be due to the most common approach of favoring a surveillance program of mlpgs over time, under 35 years old in daily practice. lastly, data synthesising dermoscopic and confocal criteria were retrieved from a small number of studies, and larger prospective datasets are needed to validate the utility of the proposed algorithm. the suggested management indications should be interpreted with caution and individualized for every single patient. dermoscopic structure is detected, surgical excision is recommended. in addition, we suggest performing rcm evaluation also in the absence of melanoma-specific dermoscopic criteria (figure 3). confocal cyto-architectural irregular features require surgical excision of the lesion, while a regular follow-up is suggested in case of reassuring findings. during the follow-up period, surgery is recommended where new atypical dermoscopic criteria are observed. the decision to perform rcm in the range of 35-55 years old, even in presence of reassuring dermoscopic criteria, is due to the still not negligible risk of a regular mlpg being a melanoma. indeed, 50 years old was assessed as the median age of patients with a proven histological diagnosis of melanoma in different studies [9,10] and confocal evaluation has been demonstrated to disclose irregular/atypical findings with a 100% sensitivity for the diagnosis of mm [8,10]. mlpgs in patients >55 years old: in this age group, the suggested management is surgical excision in all cases. while growth markers of melanocytic lesions are expected in young adults, the observation of mlpgs in the elderly represents a figure 3. nevus on the right leg of a 46-year-old woman: dermoscopy (a), rcm (b,c) and histology (d). peripheral globules are symmetrically organized at the edge of the lesion (a), corresponding to dense melanocytic nests (blue squares) located at the dermal-epidermal junction and papillary dermis upon confocal view at low (b) and high (c) magnification. a ringed pattern composed of edged dermal papillae is observed in the central area (b). junctional melanocytic nests are observed at histopathology (d) [haematoxylin and eosin stain, original magnification x200]. review | dermatol pract concept. 2023;13(1):e2023010 7 6. bowling j, argenziano g, azenha a. et al. dermoscopy key points: recommendations from the international dermoscopy society. dermatology. 2007;214(1):3-5. doi: 10.1159/000096904. pmid: 17191039 7. pellacani g, scope a, ferrari b. et al. new insights into nevogenesis: in vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy. j am acad dermatol. 2009 ;61(6):1001-13. doi: 10.1016/j.jaad.2009.04.018. pmid: 19833408 8. carbone a, persechino f, paolino g et al. enlarging melanocytic lesions with peripheral globular pattern: a dermoscopy and confocal microscopy study. ital j dermatol venerol. 2021;156(4):467-472. doi: 10.23736/s2784-8671.19.06471-x. pmid: 31760729 9. reiter o, chousakos e, kurtansky n. et al. association between the dermoscopic morphology of peripheral globules and melanocytic lesion diagnosis. j eur acad dermatol venereol. 2021;35(4):892-899. doi: 10.1111/jdv.17035. pmid: 33205467 10. pampín-franco a, gamo-villegas r, floristán-muruzábal u, pinedo-moraleda fj, pérez-fernández e, lópez-estebaranz jl. melanocytic lesions with peripheral globules: results of an observational prospective study in 154 high-risk melanoma patients under digital dermoscopy follow-up evaluated with reflectance confocal microscopy. j eur acad dermatol venereol. 2021;35(5): 1133-1142. doi: 10.1111/jdv.17105. pmid: 33428272 11. williams nm, navarrete-dechent c, marchetti ma de bedout v, jaimes n. diagnostic utility of circumferential peripheral globules under dermoscopy in adults. j am acad dermatol. 2021;85(5):1300-1302. doi: 10.1016/j.jaad.2020.08.107. pmid: 32891776 12. lazaridou e, fotiadou c, apalla z. melanocytic lesions with peripheral globules: still a pitfall in the differential diagnosis of melanoma. j eur acad dermatol venereol. 2021;35(5):1040. doi: 10.1111/jdv.17239. pmid: 33885195 conclusions mlpgs are frequently seen in daily practice and represent a clinical challenge requiring the most appropriate management for individual patients. herein we propose a multi-step and age-based management algorithm based on current published data integrating clinical, dermoscopic and confocal findings, in order to increase the early recognition of melanoma and avoid surgical excision of benign lesions. references 1. kittler h, seltenheim m, dawid m, pehamberger h, wolff k, binder m. frequency and characteristics of enlarging common melanocytic nevi.  arch dermatol. 2000;136(3):316-20. doi: 10.1001/archderm.136.3.316. pmid: 10724192 2. bajaj s., dusza sw, marchetti ma. et al. growth-curve modeling of nevi with a peripheral globular pattern. jama dermatol.2015;151(12):1338-1345.doi: 10.1001/ jamadermatol .2015.2231. pmid: 26287475 3. zalaudek i, schmid k, marghoob aa. et al. frequency of dermoscopic nevus subtypes by age and body site: a cross-sectional study. arch dermatol. 2011;147(6):663-70. doi: 10.1001 / archdermatol.2011.149. pmid: 21690528 4. zalaudek i, conforti c, guarneri f. et al. clinical and dermoscopic characteristics of congenital and noncongenital nevus-associated melanomas. j am acad dermatol. 2020;83(4):1080-1087. doi: 10.1016/j.jaad.2020.04.120. pmid: 32360715 5. ribero s, argenziano g, di stefani a. et al. likelihood of finding melanoma when removing a melanocytic lesion with peripheral clods. j eur acad dermatol venereol. 2020;34(12):e812-e814. doi: 10.1111/jdv.16674. pmid: 32458482 dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022076 1 dermatology practical & conceptual apremilast survival and reasons for discontinuation in psoriasis: five-year experience from a greek tertiary care centre elena sotiriou1, aikaterini tsentemeidou1, nikolaos sideris1, aimilios lallas1, nikolaos kougkas2, dimitrios ioannides1, efstratios vakirlis1 1 first department of dermatology and venereology, school of medicine, aristotle university, thessaloniki, greece 2 fourth department of internal medicine, aristotle university of thessaloniki, greece. key words: psoriasis, apremilast, survival, discontinuation, greece citation: sotiriou e, tsentemeidou a, sideris n, et al. apremilast survival and reasons for discontinuation in psoriasis: five-year experience from a greek tertiary care centre. dermatol pract concept. 2022;12(2):e2022076. doi: https://doi.org/10.5826/dpc.1202a76 accepted: december 7, 2021; published: january 2022 copyright: ©2022 sotiriou et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. irb approval: ethics committee of the hospital of venereal and dermatologic diseases of thessaloniki, greece. authorship: all authors have contributed significantly to this publication corresponding author: aikaterini tsentemeidou, ms. first department of dermatology and venereology, school of medicine, aristotle university, thessaloniki, greece. email: ktsenteme@gmail.com introduction: drug survival is an indirect measure of efficacy and safety and its post-marketing assessment using real-life data is invaluable. objectives: to investigate the survival of apremilast in a cohort of psoriasis patients treated with apremilast in a greek hospital. methods: a retrospective cross-sectional study examined adult psoriasis patients receiving apremilast (march 2016 to january 2021). primary endpoint was the cumulative survival probability at 52 weeks. kaplan-meier analysis was used to calculate survival probability. cox regression analysis was performed to investigate potential risk factors for apremilast discontinuation. results: one hundred and two patients (29.4% females) with a mean age of 55.9 years (standard deviation 15.21) were included. sixty-five patients (63.7%) had discontinued treatment by lock date: 19 (18.6%) due to lack of efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to adverse reactions, and 7 (6.9%) due to other reasons. cumulative survival probability at 52 weeks was 52.1%. median survival time for all reasons for discontinuation was 58 weeks (95% confidence interval 40.02, 75.98). conclusions: approximately half of patients remained on apremilast after 1 year of treatment. secondary drug failure was the most common reason for discontinuation. abstract 2 original article | dermatol pract concept. 2022;12(2):e2022076 introduction apremilast (otezla®, amgen) is an orally administered pde4 inhibitor, whose efficacy and tolerability for the treatment of moderate-to-severe plaque psoriasis was investigated in the esteem phase iii trials [1,2]. psoriasis treatment with biologics and small-molecule agents is of finite duration, most often due to efficacy-related reasons [3] the probability that psoriasis patients will stay on a biologic treatment for ≥3 years is 53%-58% [4]. anti-drug antibodies, genomic and transcriptomic parameters as well as non-compliance could possibly explain this phenomenon [4,5]. forty-five of 382 (11.78%) esteem 2 participants, who received apremilast, discontinued treatment due to lack of efficacy by week 52 [2]. long-term (≥156 weeks) pooled data from the two esteem trials showed that 34.7% of participants receiving apremilast discontinued treatment due to lack of efficacy, which was the most common reason for treatment cessation [6]. drug survival – time from initiation to discontinuation of treatment – can be used as a surrogate measure for drug efficacy and tolerability [4]. as everyday practice may differ from the setting of clinical trials, real-world data is invaluable. objectives this study was conducted to investigate the survival of apremilast in a cohort of patients treated for psoriasis in a real clinical setting. methods a retrospective cross-sectional study was performed. data was retrieved from the psoriasis archives of the 1st dermatology department, aristotle university, thessaloniki, greece. all adult patients with any type of psoriasis, who had received at least one dose of apremilast from march 2016 until january 2021, were eligible for inclusion in the study. dosing followed summary of product characteristics. primary endpoint was cumulative survival probability at 52 weeks. secondary endpoints were cumulative survival probability at weeks 24, 104, 156, and 208, percentage of patients achieving 75% reduction in their baseline psoriasis area severity index (pasi) score (pasi75) at weeks 16, 24, 52, 104 and 156 as well as mean/median drug survival for all reasons for discontinuation and stratified for specific reason (lack of and loss of efficacy, adverse events, other). gender, age, body mass index (bmi, kg/m2), presence of scalp and nail psoriasis, presence of psoriatic arthritis, diabetes, hyperlipidaemia, hypertension and cardiovascular disease, as well as previous treatment with biologics were tested as potential predictors for drug discontinuation. treatment was considered discontinued if patients stopped receiving apremilast tablets. reasons for discontinuation were primary drug failure (no ≥50% improvement in baseline pasi – pasi50 – by week 24), secondary drug failure (loss of achieved efficacy at two consecutive visits), adverse events and personal/other reasons. patients lost to follow-up were considered to have discontinued treatment. sequential recruitment of all eligible treated patients was performed to limit selection bias. the study protocol adhered to the declaration of helsinki and was approved by the ethics committee of the first dermatology department, aristotle university, thessaloniki, greece. signed informed consent was obtained by all participating patients. spss software version 25 (ibm corp.) was used to perform all statistical analyses. qualitative variables were described through relative frequencies. we used shapiro-wilk test to check for normal distribution of quantitative variables. mean, standard deviation (sd) and 95% confidence interval (ci) were used in case of normal distribution, whereas median and interquartile range were used in the opposite case. a two-tailed significance level of <0.05 was set. kaplan-meier analysis was used to calculate survival probability. study event was drug discontinuation due to any reason or loss to follow-up. patients still on treatment were censored at the last available follow-up visit. univariate and multivariate cox regression analysis were performed to investigate potential risk factors for apremilast discontinuation (hazard ratio, significance level set at p ≤0.05). akaike information criterion was used to choose the best-fitting model for survival prediction. results out of 2313 psoriasis patients registered in the psoriasis archives, 110 patients were potentially eligible for inclusion. six take-home message • psoriasis treatment with biologics and small-molecule agents is of finite duration, most often due to efficacy-related reasons. • apremilast survival was investigated in a real-life setting. cumulative survival probability at 24, 52 and 208 weeks was 69.3%, 52.1% and 28.1%, respectively. nineteen (18.6%), 24 (23.5%) and 15 (14.7%) patients discontinued apremilast due to lack of efficacy, loss of efficacy and adverse reactions, respectively. original article | dermatol pract concept. 2022;12(2):e2022076 3 patients did not give consent for study participation and 2 patients were excluded due to incompletely recorded data. we included 102 patients in our analysis (29.4% females, 70.6% males) with various types of psoriasis and a mean age of 55.94 years (sd 15.21). patient baseline characteristics are presented in table 1. patients were followed-up for a total of 26,826 patient-weeks. sixty-five patients (63.7%) had discontinued treatment by lock date: 19 (18.6%) due to lack of efficacy, 24 (23.5%) due to loss of efficacy, 15 (14.7%) due to adverse reactions, 3 (2.94%) due to other/personal reasons, while 4 (3.92%) were lost to follow-up. cumulative survival probability at 24, 52, 104, 156, and 208 weeks was 69.3%, 52.1%, 39.8%, 31.2%, and 28.1%, respectively (figure 1). mean survival time per reason for discontinuation and pasi75 achievement rates are presented in table 1. median survival time for all reasons for discontinuation was 58 weeks (95% ci 40.02, 75.98). the only covariate found able to predict drug survival was the combination of cardiovascular disease and diabetes, which was associated with 78% less likelihood of apremilast discontinuation (hazard ratio 0.22, p = 0.035). table 1. patient demographic characteristics and apremilast survival female male sex†, n (%) 30 (29.4) 72 (70.6) age‡, years( 57.1 (12.89, 57.1 – 52.29) 55.17 (16.06, 51.37 – 58.97) bmi§ (kg/m2) 27.11 (8.01) 27.68 (6.63) psoriasis duration§ (years) 9 (14) 13 (14) baseline pasi§ 11 (5.4) 11.7 (7.4) psoriatic arthritis† 5 (16.7) 15 (20.8) scalp psoriasis† 28 (93.3) 55 (76.4) nail psoriasis† 13 (43.3) 35 (48.6) smoking† 15 (50.0) 44 (61.1) comorbidities hypertension† 11 (36.7) 23 (31.9) diabetes† 6 (20.0) 11 (15.3) hyperlipidemia† 9 (30.0) 18 (25.0) obesity† 9 (30.0) 24 (33.3) cardiovascular disease† 5 (16.7) 15 (20.8) median survival time (all reasons for discontinuation) 58 weeks 95%ci (40.02, 75.98) mean survival time in weeks (95% confidence interval) all reasons for discontinuation 96.75 (78.34, 115.15) due to lack of efficacy 178.06 (159.41, 196.72) due to loss of efficacy 152.35 (130.53, 174.17) due to adverse events 190.59 (174.45, 206.73) due to other reasons (including loss to follow-up) 211.06 (199.08, 223.05) week 16 week 24 week 52 week 104 week 156 pasi75¶ 20.80% 46.00% 45.74% 30.33% 13.20% †number (percentage). ‡mean (standard deviation, 95% confidence interval). §bmi: body mass index, median (interquartile range). ¶pasi75: percentage of patients having achieved 75% reduction in their baseline psoriasis area severity index score. 4 original article | dermatol pract concept. 2022;12(2):e2022076 figure 1. cumulative survival probability of apremilast (kaplan-meier survival curve) for all reasons of drug discontinuation. event: drug discontinuation due to any reason or loss to follow-up. patients still on treatment were censored at the last available follow-up visit. 1.0 apremilast survival all reasons for discontinuation 0.8 0.6 0.4 0.2 0.0 0 weeks of apremilast treatment until january 2021 p r o b a b il it y o f r em a in in g o n d r u g 50 100 150 200 250 0.5 survival function censored conclusions according to our results, approximately half of psoriasis patients treated with apremilast remained on treatment after one year and a little more than a quarter of them were still receiving the drug after 4 years of treatment. the most common reason for discontinuation was secondary drug failure. patients suffering from both diabetes and cardiovascular disease were significantly less likely to discontinue apremilast. limitations of our study are its retrospective nature, lack of a control group and absence of subgroup analysis of patients having received concurrent topical treatment. according to real-world evidence, median apremilast survival ranges from 12.5 to 65 weeks, while 52-week survival probability ranges from 40.7% to 53.4% [7–11]. two-year survival probability was 37.4% in a japanese study [7]. median time to drug discontinuation was 23 weeks for primary drug failure, 63 weeks for secondary failure and 8 weeks for adverse events [12]. lunder et al found that apremilast had the lowest survival comparing to ustekinumab, adalimumab, etanercept, ixekizumab, infliximab and secukinumab, with ustekinumab having the longest duration in all examined psoriasis patients [3]. patients on apremilast were more likely to discontinue treatment compared to patients on methotrexate in a nationwide french study [11]. in a cohort of patients with palmoplantar pustulosis, however, apremilast was associated with the longest survival (65 weeks) comparing to classic systemic treatments, such as cyclosporine, acitretin plus puva, methotrexate, acitretin, alitretinoin and fumaric acid esters [13]. primary treatment failure was the most common reason for apremilast discontinuation in a usa study comparing various biologics and apremilast as well as in a smaller austrian study [5,10]. loss of efficacy was the main reason for apremilast cessation in a japanese study (46.4%) [9]. apremilast survival was significantly reduced in patients with scalp psoriasis (p = 0.001) in a small spanish study [12]. the results of this study are comparable to other real-life apremilast survival data. median apremilast survival at 52 weeks was found less than that of other systemic treatments for psoriasis, as presented in various real-life reports. references 1. papp k, reich k, leonardi cl, et al. apremilast, an oral phosphodiesterase 4 (pde4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase iii, randomized, controlled trial (efficacy and safety trial evaluating the effects of apremilast in psoriasis [esteem] 1). j am acad dermatol. 2015;73(1):37–49. doi: 10.1016/j.jaad.2015.03.049. pmid: 26089047. original article | dermatol pract concept. 2022;12(2):e2022076 5 2. paul c, cather j, gooderham m, et al. efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase iii, randomized controlled trial (esteem 2). br j dermatol. 2015;173(6):1387– 1399. doi: 10.1111/bjd.14164. pmid: 26357944. 3. lunder t, zorko ms, kolar nk, et al. drug survival of biological therapy is showing class effect: updated results from slovenian national registry of psoriasis. int j dermatol. 2019;58(6):631– 641. doi: 10.1111/ijd.14429. pmid: 30973647. 4. yiu zzn, mason kj, hampton pj, et al. drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis: a prospective cohort study from the british association of dermatologists biologics and immunomodulators register (badbir). br j dermatol. 2020;183(2):294–302. doi: 10.1111/ bjd.18981. pmid: 32124442. 5. zeb l, mhaskar r, lewis s, et al. real-world drug survival and reasons for treatment discontinuation of biologics and apremilast in patients with psoriasis in an academic center. dermatol ther. 2021;34(2):e14826. doi: 10.1111/dth.14826. epmid: 33527682. 6. crowley j, thaçi d, joly p, et al. long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (esteem 1 and 2). j am acad dermatol. 2017;77(2):310-317. e1. doi: 10.1016/j.jaad.2017.01.052. pmid: 28416342. 7. saruwatari h. real-world experiences of apremilast in clinics for japanese patients with psoriasis. j dermatol. 2019;46(12):1166– 1169. doi: 10.1111/1346-8138.15104. pmid: 31587350. 8. lee eb, amin m, wu jj. drug survival of apremilast in patients treated for psoriasis in a real-world setting. j am acad dermatol. 2018;79(4):760–761. doi: 10.1016/j.jaad.2018.03.028. pmid: 29588246. 9. kishimoto m, komine m, kamiya k, sugai j, ohtsuki m. drug survival of apremilast in a real-world setting. j dermatol. 2019;46(7):615-617. doi: 10.1111/1346-8138.14943. pmid: 31180150. 10. vujic i, herman r, sanlorenzo m, et al. apremilast in psoriasis – a prospective real-world study. j eur acad dermatology venereol 2018;32(2):254–259. doi: 10.1111/jdv.14598. pmid: 28925560. 11. sbidian e, billionnet c, weill a, maura g, mezzarobba m. persistence of apremilast in moderate-to-severe psoriasis: a real-world analysis of 14 147 apremilastand methotrexate-naive patients in the french national health insurance database. br j dermatol. 2020;182(3):690-697. doi: 10.1111/bjd.18047. pmid: 31021438. 12. sahuquillo-torralba a, de unamuno bustos b, rodríguez serna m, monte boquet e, botella estrada r. treatment persistence and safety of apremilast in psoriasis: experience with 30 patients in routine clinical practice. actas dermosifiliogr (engl ed). 2020;111(5):415418. doi: 10.1016/j.ad.2018.10.031. pmid: 32423533.s 13. kromer c, wilsmann-theis d, gerdes s, et al. drug survival and reasons for drug discontinuation in palmoplantar pustulosis: a retrospective multicenter study. j dtsch dermatol ges. 2019;17(5):503–516. doi: 10.1111/ddg.13834. pmid: 30994260. pmcid: pmc6850581. dp0303a04_r1 dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2013;3(3):4 9 introduction nail plate microscopic analysis in pas stained slides, also known simply as nail clipping, is an established test used in the diagnosis of onychomycosis [1-7], and in one study it proved to have a role in discovering clinically unapparent nail fungal infection [8]. its application in evaluating causes of onychodystrophy other than fungal infection is reported to a very small extent, though [2,9,10]. because we believe microscopic evaluation of nail clippings may be a potential microscopic examination of normal nail clippings betina werner1, andre antunes 2 1 dermatopathologist, department of pathology, universidade federal do paraná, curitiba, brazil 2 graduate student, universidade tuiuti do paraná, curitiba, brazil key words: nails, normality, nail clipping, microscopy, histotechnology citation: werner b, antunes a. microscopic examination of normal nail clippings. dermatol pract conc. 2013;3(3):4. http://dx.doi. org/10.5826/dpc.0303a04. received: may 1, 2013; accepted: june 1, 2013; published: july 31, 2013 copyright: ©2013 werner et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. dr. betina werner and mr. andre antunes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. all authors have contributed significantly to this publication. corresponding author: betina werner, m.d., ph.d., rua dr. nelson de souza pinto, 759. cep 82200-060, curitiba, pr, brazil. tel. (41) 9116 0525. e-mail: betina.werner@gmail.com. background: nail clipping analysis for diagnosing causes of onychodystrophy other than onychomycosis is investigated to a very small extent. in order to achieve acceptance as a diagnostic method for any kind of nail abnormalities, normal microscopic parameters have to be established first. in most reported cases, nail plates were fixed in formalin with processing of the specimens with routine automated histotechnique. methodology: fifteen pairs of normal nails were studied. one nail fragment was placed in a container with formalin, and the other was kept dry in a proper receptacle. fixed specimens were submitted to standard automated tissue processing (formalin group) and dry specimens were directly embedded in paraffin (dry group). several microscopic parameters were analyzed. results: nail plate thickness ranged from 0.25 to 0.50 mm (mean 0.36 mm) and subungual region from 0 to 0.31 mm (mean 0.11 mm). forty-one percent of cases presented onychokaryosis, and hypereosinophilic nuclear shadows were detected in 63%, statistically more frequent in the dry group (p=0.002). parakeratosis was present in 86% of nails varying from 1 to 13 layers (mean 5.6). none of the nails presented fungi, neutrophils, and blood or serum collections. bacteria were seen in 60% of specimens. both groups yielded adequate microscopic preparations for analysis with no statistical difference in the dryness or hardness of specimens or difficulty in cutting the paraffin blocks (p=1). conclusion: these microscopic findings of a normal population can be used as parameters for evaluating any cause of onychodystrophy. the dry method is faster and cheaper and yields adequate slide preparations for microscopic analysis of nail clippings. abstract 10 research | dermatol pract concept 2013;3(3):4 the statistical analysis of quantitative variables was performed with descriptive statistics, such as the mean, median, standard deviation, minimum and maximum. in order to compare the two microscopic processing methods used, nonparametric wilcoxon test for quantitative variables, non-parametric mcnemar test for dichotomous categorical variables, and sign test for ordinal categorical variables were applied. p values < 0.05 were considered statistically significant. results there were 13 male and two female subjects enrolled in the study yielding 15 pairs of nails. ages varied from 20 to 62 years (mean 36, median 33, sd +/-11.4 years). because one fragment of each individual was randomly selected for one of the methods tested, we examined 15 formalin-fixed specimens and submitted to standard automated tissue processing (formalin group), and 15 specimens kept dry and directly embedded in paraffin (dry group). nail specimens measured from 9 to 14 mm in length (mean 10.7, median 10, sd +/-1.3 mm) and from 1 to 3 mm in width (mean 1.8, median 2, sd +/-0.65 mm). formalin and dry groups were statistically similar regarding length and width of nail fragments (p=0.62 and 0.27, respectively). all microscopic preparations were done by one of the authors (aa), on the same day. there was no statistical difference in the feeling of dryness or in difficulty in cutting of the specimens among the groups (p=1 in both variables). both pas and h&e in the formalin and dry groups were adequate for analysis and showed two readily discernable areas: plate (external) and subungual region (internal) (figure 1a and 1b). the corners or extremities of nails had a wavy configuration in the subungual region in contrast with tool in investigation of nail dystrophies of any cause, not only mycotic but also inflammatory and traumatic, we considered necessary to establish normal microscopic parameters first. furthermore, in order to make the diagnostic test of nail clippings easier and quicker, we propose a method of microscopic preparation without fixation with formalin and automated tissue processing. we will compare that method with an alternative one, in which nail fragments are placed directly in paraffin, without fixation and automated microscopic tissue processing. materials and methods volunteers were asked to donate nail clippings from two fingers. inclusion criteria: healthy adults with no visible nail abnormality and without any local or systemic disease that could interfere with nail growth. exclusion criteria: manicure or nail biting habits. the subjects were oriented in such a way so as to obtain a full-thickness nail sample with nail clippers or scissors (as far proximally as possible without discomfort) from the distal part of both annular fingers nail plates. randomly, one nail fragment was placed in a container with 10% formalin, and the other was put in a dry sealed receptacle. the samples were coded to allow blinded paraffin block sectioning, slide preparation/staining and microscopic interpretation. cassettes with formalin-fixed specimens were submitted to standard automated tissue processing, and cassettes with dry specimens were directly immersed in melted paraffin (68o c) for 50 minutes. for paraffin embedment, in all specimens, the long axis of the nail fragment was oriented in a way that would allow microtomy to be achieved at a right angle to the microtome blade. once all paraffin blocks were ready for sectioning, each block was trimmed with caution to only expose the nail down to a level where a representative section could be obtained. the cut faces of the blocks were kept facing an icy cold surface (approximately 1o c) with 10% ammonium hydroxide solution for 30 minutes, prior to microtomy. paraffin sections were cut at 2 microns and placed on meyer albumin coated slides. two slides from each block were obtained, one subjected to staining with hematoxylin and eosin (h&e) and the other with pas with digestion (pas). the h&e-stained slides were evaluated for the following microscopic features: nail plate and subungual region thickness (measured using a microscopic ruler), and the presence or absence of neutrophils, bacteria, parakeratosis, onychokaryosis (name given for the retention of nuclei in the nail plate) and hypereosinophilic nuclear shadows (name given for the apparent staining of the ”nuclei ghosts” of onychocytes). the pas-stained slides were evaluated for fungi. both h&e and pas-stained sections were examined using the light microscope by the dermatopathologist (bw) blinded to the processing method used. figure 1. (a) nail from the formalin group and (b) nail from the dry group. two regions are readably discernable: nail plate (above) and subungual region (below). h&e x100 (original magnification). [copyright: ©2013 werner et al.] research | dermatol pract concept 2013;3(3):4 11 discussion microscopic examination of nail clippings immediately involves two discernable regions: the nail plate itself and the subungual region. nail plate and subungual region analysis reflects nail matrix and nail bed status, respectively [11-13]. although the nail plate shows a subtle and subjective difference in the superior and inferior parts (superior onychocytes are smaller than inferior onychocytes), we were not able to separate those two regions with confidence. nonetheless, an a smoother surface in the center of the fragment (figure 2). nail plate thickness ranged from 0.25 to 0.50 mm (mean 0.36, median 0.37, sd +/-0.06 mm) and subungual region thickness from 0 to 0.31 mm (mean 0.11, median 0.08, sd +/-0.07 mm); those measures were not statistically different among the groups tested (p=0.59 e 0.91, respectively). the contours of cells from nail plate (onychocytes) were better seen with pas staining; cells increased in size closer to the subungual region (figure 3). in 12 instances (41% of cases) nail plates presented few basophilic fusiform nuclei (onychokaryosis), usually in the outer aspect of the plate, and that finding was much more evident in the dry group (figure 4). the presence of hypereosinophilic nuclear shadows was a common finding, detected in 63% of specimens, also more prominent in the dry group (figure 4). in half of cases that finding was observed in the inferior/internal aspect of the plate (figure 5), statistically more frequent in the dry group (p=0.002). nuclei in the subungual region (parakeratosis) were present in 86% of nails, and thickness varied from 1 to 13 layers of nuclei thick (mean 5.6, median 4, sd +/-3.5 layers) (figure 6). none of the nails examined presented fungi, neutrophils, and blood or serum collections. bacteria were seen in 60% of specimens in foci of the subungual region, usually in the corners, and in small amounts (figure 7). figure 2. panoramic view of nail from the formalin group. in several instances the corners or extremities of nails had a wavy configuration in the subungual region. h&e x40 (original magnification). [copyright: ©2013 werner et al.] figure 3. nail from the formalin group. onychocytes borders are better seen in the pas staining. pas x400 (original magnification). [copyright: ©2013 werner et al.] figure 4. nail from the dry group showing several hypereosinophilic nuclear shadows and onychokaryosis. insert: one fusiform basophilic nucleus (upper half) and several hypereosinophilic ”stains” in the center of onychocytes. h&e x100 and x400 (original magnification). [copyright: ©2013 werner et al.] figure 5. nail of the dry group showing prominent hypereosinophilic nuclear shadows in the inferior/internal aspect of the plate. h&e x400 (original magnification). [copyright: ©2013 werner et al.] 12 research | dermatol pract concept 2013;3(3):4 the nail tell of standing disease (and also either topical or systemic treatment influences) that the patient had several months before the time clipping was performed. as mentioned before, in the literature, nail clipping has an established role only for the diagnosis of onychomycosis [1-8]. apart from that, nail-clipping microscopy was superficially studied in psoriasis [2], but in comparison to fungal infection; alopecia areata [9], a light and electron microscopic study in only nine patients; and in onychomatricoma [10], a case report. as far as we are concerned, the study of laporte and co-workers [9] in alopecia areata was the first publication that used the microscopic examination of nail clipping as an investigation tool for a disease, in 1988 [9]. they analyzed nails from nine patients with alopecia areata and found architectural disorder of the corneocyte arrangement, parakeratosis of variable intensity, disintegration and little depressions in the upper part of the plate, and noted that the subungual keratin was spared. neither those authors showed frequency or intensity in their microscopic findings, nor did they compare to normal controls. on the other hand, mahler and colleagues, in 1998 [2], sought for microscopic differences in nail clippings between dystrophic changes due to psoriasis and onychomycosis, compared to normal controls. they examined four cases of onychomycosis, 14 cases of psoriasis and five normal controls. in nails with psoriasis they concluded: “the psoriatic nails were dystrophic with foci of parakeratosis and frequently scattered neutrophils in the residual nail bed”, without giving a full account of those findings. and about the nails without dystrophy they commented: “the normal nail cases were uniform and demonstrated only compact hyperkeratosis”, without any further details. in the present normal population that we studied, we found that nail plates and subungual regions measured around 0.37 and 0.08 mm in thickness, respectively, and nuclei in the subungual region (parakeratosis) was a common finding (86%), the numbers of layers varying from 1 ultrastructural study of normal nails permitted the definition of three regions of nail apparatus: upper and lower parts of the plate, and what is called hyponychium (subungual region) [14]. the border between the two parts of the nail plate were not easily discernable, however, cells at the upper part of the nail plate were more flattened when compared to ones at the lower part [14]. so, they also demonstrated progressive thickening of the plate cells from the nail surface to the subungual region limit. furthermore, the authors found that onychocytes of the upper part of nail plates were joined laterally by sparse and deep digitations, in contrast to onychocytes from the lower part of the plate which had membranes showing a different pattern: the digitations were regular and numerous, but shallow [14]. similar to the present microscopic study, the ultrastructural investigation of parent and colleagues [14] showed that the limit between the plate and the subungual region was clearly discernible because different sizes, morphology, and staining affinities of the cells in the two regions existed. therefore, the microscopic separation of the nail in three regions, namely, superior part of nail plate, inferior part of nail plate and subungual region, has the potential of taking the nail clipping analysis to a higher level. the dorsal aspect of nail plate (superior half) yields information about the proximal nail matrix, the ventral aspect of nail plate, immediately above the subungual region (inferior half), reveals facts concerning the distal nail matrix, and the subungual region reflects what is going on the nail bed. that approach could be very useful if nail-clipping examination is used to investigate nail diseases that affect one or other part of nail apparatus, in particular. or, to the contrary, microscopic examination of nail clippings could indicate where in the nail apparatus disease is more prominent. one has to keep in mind that microscopic examination of nail plates can be compared to looking at the starry sky at night: one is observing the past, because the distal part of the nail that is clipped off was formed around six months previously [11,15]. therefore, microscopic findings seen in figure 6. nuclei in the subungual region (parakeratosis) in a nail of the formalin group. h&e x400 (original magnification). [copyright: ©2013 werner et al.] figure 7. bacteria in subungual region in a nail of the formalin group. h&e x400 (original magnification). [copyright: ©2013 werner et al.] research | dermatol pract concept 2013;3(3):4 13 in the present study we tried to compare the more conventional method of microscopic slides preparations for nails, i.e., fixing nail fragments in formalin and processing the specimens as done in routine histotechnique, with the less widespread procedure in which nail clippings are placed directly in paraffin without fixation and automated microscopic tissue preparation. both techniques yielded adequate microscopic preparations and no difference was detected either in cutting the paraffin block or in preparing and staining the slide. it seems that the main vantage of not using formalin fixation followed by standard histotechnology with overnight processing, is that the dry specimens allow a faster microscopic slide preparation of the nail clippings and is a less expensive technique. however, the microscopic aspect of the slides on h&e and pas differ between the methods. the dry specimens delivered more “busy” sections, where nuclei and hypereosinophilic stains were more often seen in nail plates, when compared to the formalin-fixed ones. that microscopic difference between techniques must be kept in mind when dystrophic nails are analyzed using one or the other method of slide preparation. in conclusion, we believe nail clippings are a valuable source of information when considering inflammatory and traumatic onychodystrophy. we here delineate microscopic findings of a normal population used as basis for evaluating any cause of nail abnormalities under the microscope. the alternative method of not using formalin fixation and overnight automated processing is faster and less expensive and yields adequate slide preparations stained with h&e and pas for microscopic analysis of nail clippings. references 1. suarez sm, silvers dn, scher rk, pearlstein hh, auerbach r. histologic evaluation of nail clippings for diagnosing onychomycosis. arch dermatol. 1991;127(10):1517-9. 2. machler bc, kirsner rs, elgart gw. routine histologic examination for the diagnosis of onychomycosis: an evaluation of sensitivity and specificity. cutis. 1998;61(4):217-9. 3. lawry ma, haneke e, strobeck k, et al. methods for diagnosing onychomycosis: a comparative study and review of the literature. arch dermatol. 2000;136(9):1112-6. 4. gianni c, morelli v, cerri a, et al. usefulness of histological examination for the diagnosis of onychomycosis. dermatology. 2001;202(4):283-8. 5. barak o, asarch a, horn t. pas is optimal for diagnosing onychomycosis. j cutan pathol. 2010;37(10):1038-40. 6. wilsmann-theis d, sareika f, bieber t, schmid-wendtner mh, wenzel j. new reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis. j eur acad dermatol venereol. 2011;25(2):235-7. 7. mayer e, izhak ob, bergman r. histopathological periodic acidschiff stains of nail clippings as a second-line diagnostic tool in onychomycosis. am j dermatopathol. 2012;34(3):270-3. 8. walling hw. subclinical onychomycosis is associated with tinea pedis. br j dermatol. 2009;161(4):746-9. to 13 layers of nuclei thick (mean 5.6). the external surface of all specimens was smooth, and no depressions were observed. those parameters can be easily used for comparison with dystrophic nails. what we called onychokaryosis (nuclei in nail plate) was seen in 12 nails examined (41%), particularly in the superior part of nail. what we named hypereosinophilic nuclear shadow was a common finding (63% of nails examined), and was observed in the inferior/ internal part of the plate statistically more frequent in the dry group (p=0.002). both onychokaryosis and hypereosinophilic nuclear shadow were more easily perceived in the specimens pertaining to the dry group, in general. that feature gave the dry group a “busier” look when compared to the formalin group. the meaning of these two findings and why they are sometimes present in normal nails, though, remains to be investigated further. it would be very interesting to evaluate these two parameters in dystrophic nails, to see whether nuclear retention (onychokaryosis) or some sort of cell maturation (hypereosinophilic nuclear shadow) would be increased or decreased. fungi, neutrophils, and blood or serum collections were not seen in any case examined, and the presence of those features may indicate nail disease. on the contrary, as expected, bacteria were seen in the subungual region (60% of nails analyzed), but usually in the corners of nails and in small amounts. for that reason, the presence of bacteria should not be taken as an abnormal finding itself, although variations in the amount and localization of those organisms could have a meaning in nail abnormality investigation. although nail fragments are easily obtainable specimens, a nail plate specimen is very difficult to cut for microscopic preparations, due to its hardness. probably that is one of the reasons why microscopic analysis of nail clippings is not a widespread technique in onychodystrophy investigations. a good microscopic slide is usually time consuming to make and is totally dependent upon an experienced histotechnologist. the techniques described in the literature for nail processing vary, though. the majority of nail clipping studies fix the specimens in formalin [1-8, 10,17], some apply substances for softening of the nail plate, like chitin-softening solution [1,10] and tween solution [5]. several articles mentioned using traditional routine histologic examination for nail processing [1,2,3,7,10], few studies applied what seemed to be a diverse microscopic processing only with a series of ethanol [4,6], and a few did not use any microscopic processing at all after fixing with formalin and before paraffin embedding [5,8]. one study obtained good histologic preparations without using a fixative and immersed nail fragments in a solution of liquid hand soap and distilled water followed by a process in a routine overnight cycle [16], and in only two reports the samples examined were immediately wrapped in paraffin without using a fixative liquid [9,17]. 14 research | dermatol pract concept 2013;3(3):4 13. magalhães mg, succi icb, sousa maj. subsídios para estudo histopatológico das lesões ungueais. an bras dermatol. 2003;78:49-61. 14. parent d, achten g, stouffs-vanhoof f. ultrastructure of the normal human nail. am j dermatopathol. 1985;7(6):529-35. 15. yaemsiri s, hou n, slining mm, he k. growth rate of human fingernails and toenails in healthy american young adults. j eur acad dermatol venereol. 2010;24(4):420-3. 16. mondragon g. histotechnologist to histopathologist: a method for processing specimens of nails. dermatopathology: practical conceptual. 1996;2:41-2. 17. fillus neto j, tchornobay am. how the nail clipping helps the dermatologist. an bras dermatol. 2009;84(2):173-6. 9. laporte m, andré j, stouffs-vanhoof f, achten g. nail changes in alopecia areata: light and electron microscopy. arch dermatol res. 1988;280 suppl:s85-9. 10. miteva m, de farias dc, zaiac m, romanelli p, tosti a. nail clipping diagnosis of onychomatricoma. arch dermatol. 2011;147 (9):1117-8. 11. ackerman ab, böer a, bennin b, gottlieb gj. embryologic, histologic, and anatomic aspects of the nail. in: histologic diagnosis of inflammatory skin diseases. an algorithmic method based on pattern analysis. 3rd ed. new york: ardor scribendi, ltd., 2005. available at: http://www.derm101.com. 12. baran r. the nail in the elderly. clin dermatol. 2011;29(1):5460. dermatology: practical and conceptual dermatology practical & conceptual editorial | dermatol pract concept. 2021;11(4):e2021147 1 a journey into atopic dermatitis: 5 experts’ reviews appearing in dpcj next issues anna balato1 1 unit of dermatology – university of campania “luigi vanvitelli”, naples, italy citation: balato a. a journey into atopic dermatitis: 5 experts’ reviews appearing in dpcj next issues. dermatol pract concept. 2021;11(4):e2021147. doi: https://doi.org/10.5826/dpc.1104a147 accepted: october 21, 2021; published: october, 2021 copyright: ©2021 balato. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: anna balato, md, phd. associate professor of dermatology, dermatology unit, university of campania, naples, italy. email: anna.balato@unicampania.it this editorial article is dedicated to a series of reviews dedicated to atopic dermatitis, appearing in the next issues of dpcj and guest edited by prof. anna balato. in the last decade, our understanding of atopic dermatitis (ad) pathogenesis made significant steps forward leading to the development of multiple game-changer therapies. although we can say that the horizon is now a little brighter, we cannot argue that “all the job” is done. we are currently witnessing a translational revolution in the treatment and management of ad. breakthroughs in the understanding of the immunology and the genetics of ad have been translated into highly effective targeted therapies. unraveling the importance of the il-4 and il-13/th2 immune response and associated signaling pathways have directly led to the development of some of the most effective treatments of ad to date. the aim of this “journey” is to provide further insights into ad, collecting dedicated article reviews by experts in the field. it is now well established that immunological response has a leading role in the pathogenesis of ad, so “lessons from immunology” will be one of the steps in this journey. over the last years, dermatology has greatly expanded its field of research, going beyond the focus on skin, with an eye winked at immunology research. in this specific review, the scientific pathogenetic rationale that stands beneath the mechanisms of action of modern drugs will be addressed. even if it is true that dermatology has gone through a radical transformation in its approach, it is fundamental to mention that dermatology was born as a morphologic science, and as such, the clinical approach could not miss. in particular, all clinical manifestations and attempts to harmonize clinical criteria for ad classification will be discussed in the review on “epidemiology and clinical phenotypes”. in this translational revolution process, we could not help but to consider updating on “the new era of biologics in ad” and on the “jak inhibitors in the treatment of ad”. anyhow, we asked ourselves a question: “have topical and conventional systemic treatments in ad gone out of fashion?”. these important themes will be discussed in separate reviews in order to provide a very recent update to help to better understand this disease and improve the management of ad patients. enjoy the reading! dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023049 1 silicone models for dermatological education: assessment of a new teaching tool by dermatologists leonie frommherz1, pascal hering1, pia-charlotte stadler1, benjamin m. clanner-engelshofen1, markus reinholz1 1 department of dermatology and allergy, university hospital, lmu munich, germany key words: dermatological education, teaching tool, silicone models, 3d models, evaluation citation: frommherz l, hering p, stadler pc clanner-engelshofen bm, reinholz m. silicone models for dermatological education: assessment of a new teaching tool by dermatologists. dermatol pract concept. 2023;13(1):e2023049. doi: https://doi.org/10.5826/ dpc.1301a49 accepted: april 21, 2022; published: january 2023 copyright: ©2023 frommherz et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: markus reinholz, md, ph.d. department of dermatology and allergy, university hospital, lmu munich, frauenlobstr. 9-11, 80337 munich, germany. tel: +49 (0)89 4400-56010 fax: +49 (0)89 4400-56389 email: markus.reinholz@med. unimuenchen.de introduction: the coronavirus pandemic forced universities to transfer academic curricula into the digital realm and calls for the introduction of new teaching methods to adequately compensate for the limited in-patient training. especially in the field of dermatology, the use of 3d models presents an interesting opportunity to maintain the teaching of diagnostically essential sensory and haptic characteristics of primary lesions. objectives: we developed a prototype silicone model and presented it to the medical service of the department of dermatology of the ludwig-maximilians university for evaluation. methods: silicone models demonstrating primary skin lesions were produced by using negative 3d-printed molds and different types of silicone. an online survey obtained evaluations from a group of dermatologists regarding the quality of previously supplied silicone 3d models and their potential use in medical education. data from 58 dermatologists were collected and analyzed. results: the majority of the participants rated the models overall as positive and innovative, providing constructive feedback for additional modifications, and recommended further implementation into the regular curriculum as an additional tool after the end of the pandemic. conclusions: our study underlined the possible advantages of using 3d models as a supplement in educational training even after the end of the sars-cov-2 pandemic. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023049 introduction at the beginning of 2020, the pandemic outbreak of the coronavirus sars-cov-2 necessitated a quick shutdown of most public life in germany to contain dissemination. accordingly, universities were confronted with new challenges to continue providing high-quality education. for most faculties, this entailed a drastic transition into the digital realm. however, a couple of specialist fields depending on physical practices could not properly substitute essential courses. medical education in particular is heavily reliant on face-to-face contact with patients both to learn clinical pictures as well as to improve important communication skills. different approaches already aimed to expand learning and teaching strategies beyond traditional methods even before the pandemic urged educators to revise their formerly established curriculum. case discussions and inverted classroom courses incentivize a more active engagement of students, whereas websites and a range of mobile learning applications, e.g. for dermatological education, encourage auto-didactic learning[1-3]. furthermore, patientorientatedcommunication courses use actors to simulate true-to-life clinical situations. however, these approaches are still not able to substitute the in-patient examination of haptic manifestations of symptoms, the lack of which constitutes a major disadvantage of currently used teaching methods[4,  5]. therefore, other medical fields have already implemented the use of 3d models in training and education, for example in anatomy, dentistry and surgical preparations[6, 7]. expanding on this idea, we created colored 3d silicone models with texturized surface areas to emulate common primary skin lesions. since visual and haptic examination of the skin plays a major role in dermatological differential diagnosis[8], this model should be especially useful in times of restricted patient access and possibly as a general learning tool as well. in this study, an early version of our 3d-printed model of primary skin lesions was shown to a group of dermatologists to evaluate the quality of the model and state their opinion on incorporating 3d models into dermatological education in general. methods silicone models our study object was a silicone model demonstrating primary skin lesions. the silicone models were produced using negative molds made from polylactide (pla) using martz pla matt filament (igo3d gmbh, hannover, germany) on the 3d printer anycubic i3 mega s printer (shenzhen anycubic  technology co., ltd, shenzhen, guangdong, china). the layer height was adjusted to 0.1 mm without any support structures or attachment layers. the platform temperature was set at 60° c with an extrusion temperature of 200°c. subsequently, a cotton swab soaked in tetrahydrofuran (sigma aldrich, steinheim, germany) was repeatedly used to smooth the molds. tinkercad online software (autodesk, inc, san rafael, california, usa) was applied for designing the molds. the slicing software used was ultimaker cura (version 4.8, ultimaker bv, utrecht, netherlands). next, after degassing for 1 minute using a vacuum pump (diaphragm vacuum pump, vacuubrand gmbh+co., wertheim, germany), we poured silicone rubber (equal amounts of part a and b) according to the lesion properties (suppl. file 1), polymerized overnight at room temperature and applied normal skin as the last layer on the second day (all materials: kaupo plankenhorn e.k., spaichingen, germany). after another overnight polymerization period, the silicone model was stripped off and stuck onto a postcard sized (approximately 10.5  cm  ×  14.8  cm) overhead transparency (figure 1a). finally, to obtain a matt surface finish our models were powdered with household starch. survey in february 2021, we performed a longitudinal study using an online survey addressed to dermatologists of the ludwig-maximilian-university (lmu) in munich/germany to use their knowledge and dermatological expertise in the assessment of silicone models in medical teaching. questions were answered using a grading from strongly agree, agree, neutral, disagree to strongly disagree. the survey was in german language and carried out completely anonymously (translated version suppl. file 1). participants were asked about their work experience, acquired knowledge about moulages and their opinion about the study object, possible benefits for students and suggestions for improvement. statistics statistical calculations were done using spss statistics 26.0 (ibm corp., released 2019, armonk, ny/usa), visualizations were performed using graphpad prism version 9.0.0 (graphpad software, la jolla, ca). metric variables were indicated as mean values ± standard deviation (sd). p value was calculated by using the mann-whitney test. significance level was set at p<.05. the data were evaluated descriptively. ethical approval was obtained from the committee of the lmu (project kb 20/031). results study population fifty-eight dermatologists participated in the survey. thirty-eight participants were female (65.5%), and twenty original article | dermatol pract concept. 2023;13(1):e2023049 3 figure 1. a: study object (silicone model): upper row illustrating patch (macula), plaque (plaque) and wheal (urtica), lower row depicting papule (papula), nodulus (nodulus), nudule (nodus), pustule (pustula) and vesicle (vesicula) (left to right, respectively; latinized german terms in brackets). b: age and gender distribution of all participants (left panel). experience with moulages depending on working experience (right panel). c: exemplary represented assessment (from “strongly agree” to “strongly disagree”) for different evaluation criteria. macula a papula nodulus nodus pustula vesicula plaque urtica macula plaque urtica papula nodulus nodus pustula vesicula a g e male female 0 10 20 30 40 50b experience with moulages yes no > 10 y 5 10 y < 5 y participants 0 10 20 30 40 50 y ea r s o f w o r k in g e x p er ie n c e % o f pa r ti c ip a n ts strongly agree strongly disagree innovative surface feel size quality 0 20 40 60 80 100c 4 original article | dermatol pract concept. 2023;13(1):e2023049 however, 61.8% (34/55) of the participants strongly agreed that the models should be expanded to include secondary lesions or dermatological clinical pictures as well. over a quarter (27.3%, 15/55) answered “agree” and 10.9% (6/55) answered “neutral, disagree or strongly disagree”. to evaluate possible benefits of the 3d-printed models, the participants were asked if they would deem the silicone moulages advantageous over the more traditional, usually wax-based models, to which almost two-thirds (65.5%, 36/55) strongly agreed, while 25.5% (14/55) answered “agree” and 9.1% (5/55) answered “neutral”. finally, the participants were asked to rate the general idea of teaching with silicone moulages on a scale ranging from very good (1) to poor (5), to which 72.7% (40/55) answered “very good”, while 20% (11/55) answered “good” and only 7.3% (4/55) answered “moderate or poor”. additionally, the participants had the opportunity to comment on their perceived shortcomings and their general opinion of the silicone moulages in two open-ended questions. constructive criticism involved suggestions to modify color, haptics and size to improve resemblance to actual clinical cases. however, one comment stated that the models are, although nice to have, rather irrelevant since students have always been able to correctly identify primary lesions without additional teaching methods. almost all of the participants gave positive feedback, complimenting the resourcefulness and good realization, as well as describing the model as a great supplement to the traditional teaching methods and long-distance teaching tool, especially in times of limited patient contact due to covid-19 restrictions. discussion in the medical field, providing the best possible education and preparation of students for clinical practice at any given time is of paramount concern. usually, this is accomplished by connecting the knowledge obtained by lectures and textbooks with actual clinical pictures via bedside teaching. however, times of limited patient access impose the need for alternative substitutional methods. physical 3d models have already found their way into various medical fields to better illustrate spatial visualization of anatomical features and pathologies, rendering them a suitable candidate for a contactless teaching experience[6]. various studies reported improvements in students’ self-perceived knowledge and confidence following an auto-didactic study session[9]. furthermore, studies have shown an objective increase in knowledge acquisition[10, 11], even proving to be superior in direct comparison with cadaveric material[12], ct scans or 3d computer simulations[13, 14]. all aforementioned studies additionally received positive feedback from participants were male (34.5%). the current mean age was 34.6 years (range 25 – 64 years). among all participants, thirty-eight (65.5%) were dermatological residents with less than five years of working experience. nine doctors were attending physicians (15.5%) and worked between five and ten years in the field of dermatology and eleven (mainly advanced attending physicians) (19.0%) worked for more than ten years as dermatologists. overall, fifty-one doctors (89.5%) stated that they have not worked or taught students by using moulages while six participants (10.5%) have already gained experience by using them. doctors who already used moulages provided a significantly higher working experience (p=.003) (figure 1b). survey to review the true-to-life properties of the silicone models, the participants were asked if they would assess the moulage as realistic in terms of sensory and haptic perception. almost two-thirds (62.5%, 35/56) answered “strongly agree”, a quarter (25%, 14/56) answered “agree” and 12.5% (7/56) answered “neutral or strongly disagree”. subsequently, when asked whether the model was representative of the clinical picture regarding haptic properties, 50.9% (28/55) answered “strongly agree” 34.5% (19/55) answered “agree” and 14.6% (8/55) answered “neutral or disagree”. furthermore, 65.5% (36/55) answered “strongly agree” when asked if the models are of good quality regarding their elaboration, 29.1% (16/55) answered “agree” and 5.4% (3/55) answered “neutral or disagree”. more than three-quarters (76,4%, 42/55) of the participants strongly agreed that the model was sufficient in size, while 18.2% (10/55) agreed and the rest (5.4%, 3/55) answered “neutral or disagree”. additionally, when asked if the model was of a handy size, 80% (44/55) answered “strongly agree”, 18.2% (10/55) answered “agree” and only one participant (1.8%, 1/55) answered “neutral”. subsequent questions regarded the use of models as learning/teaching tools. therefore, participants were asked if they considered the training with models as innovative regarding the current situation. over two-thirds (69.1%, 38/55) answered “strongly agree”, 27.3% (15/55) answered “agree” and 3.6% (2/55) answered “disagree or strongly disagree” (figure 1c). additionally, when asked if they would expect the moulages to facilitate the student’s learning approach, 74.5% (41/55) answered “strongly agree”, 20% (11/55) answered “agree” and 5.4% (3/55) answered “neutral or disagree”. more than two-thirds (67.3%, 37/55) of the dermatologists strongly agreed that they consider the moulages a good supplement to in-patient teachings even after the end of the pandemic. almost a quarter (23.6%, 13/55) answered “agree” and 9% (5/55) answered “neutral, disagree or strongly disagree”. original article | dermatol pract concept. 2023;13(1):e2023049 5 chances. journal of the european academy of dermatology and venereology, 2020. 34(5): p. e214-e216. 2. moszkowicz, d., et al., daily medical education for confined students during coronavirus disease 2019 pandemic: a simple videoconference solution. clinical anatomy, 2020. 33(6): p. 927-928. 3. brewer, a.c., et al., mobile applications in dermatology. jama dermatology, 2013. 149(11): p. 1300-1304. 4. dedeilia, a., et al., medical and surgical education challenges and innovations in the covid-19 era: a systematic review. in vivo, 2020. 34(3 suppl): p. 1603-1611. 5. bączek, m., et al., students’ perception of online learning during the covid-19 pandemic: a survey study of polish medical students. medicine, 2021. 100(7). 6. dawood, a., et al., 3d printing in dentistry. british dental journal, 2015. 219(11): p. 521-529. 7. coelho, g., et al., multimaterial 3d printing preoperative planning for frontoethmoidal meningoencephalocele surgery. child’s nervous system, 2018. 34(4): p. 749-756. 8. rosendahl, c., et al., dermatoscopy in routine practice:’chaos and clues’. australian family physician, 2012. 41(7): p. 482. 9. smerling, j., et al., utility of 3d printed cardiac models for medical student education in congenital heart disease: across a spectrum of disease severity. pediatric cardiology, 2019. 40(6): p. 1258-1265. 10. garg, a., h.-l. haley, and d. hatem, modern moulage: evaluating the use of 3-dimensional prosthetic mimics in a dermatology teaching program for second-year medical students. archives of dermatology, 2010. 146(2): p. 143-146. 11. fleming, c., et al., effectiveness of three-dimensionally printed models in anatomy education for medical students and resident physicians: systematic review and meta-analysis. journal of the american college of radiology, 2020. 12. lim, k.h.a., et al., use of 3d printed models in medical education: a randomized control trial comparing 3d prints versus cadaveric materials for learning external cardiac anatomy. anatomical sciences education, 2016. 9(3): p. 213-221. 13. preece, d., et al., “let’s get physical”: advantages of a physical model over 3d computer models and textbooks in learning imaging anatomy. anatomical sciences education, 2013. 6(4): p. 216-224. 14. knoedler, m., et al., individualized physical 3-dimensional kidney tumor models constructed from 3-dimensional printers result in improved trainee anatomic understanding. urology, 2015. 85(6): p. 1257-1262. 15. jones, d.b., et al., three-dimensional modeling may improve surgical education and clinical practice. surgical innovation, 2016. 23(2): p. 189-195. 16. schaefer, i., et al., prevalence of skin diseases in a cohort of 48,665 employees in germany. dermatology, 2008. 217(2): p. 169-172. students, who expressed wishes to incorporate the 3d models into the regular curriculum. correspondingly, medical experts also reported their satisfaction with the models and emphasized their usefulness in medical education[15]. these findings concur with our own results, as the idea of 3d models generally yielded a very positive response, and the majority of questioned dermatologists found the silicone models to be innovative and to facilitate learning of primary lesions. although it was noted that 3d models cannot fully encapsulate the visual and sensory representation of primary lesions and are therefore not able to replace the clinical picture, the models primarily attempt to create a basic understanding in students with little to no clinical dermatological experience. this is especially crucial since dermatological problems are numerous and often occur as comorbidities in a variety of medical domains[16]. additionally, the restricted ability to replicate the clinical picture in complete detail should not be seen as a limitation, considering the model an auxiliary teaching tool rather than a replacement for in-patient training once the pandemic subsides. for this application, our study yielded almost universal approval among participants. improvement suggestions stated in the open-ended questions regarded slight modifications of color, size and haptic characteristics. since the nature of the silicone models allows for quick and easy incorporation of feedback, our prototype model can be constantly upgraded utilizing these suggestions at a fairly low price point (approximately 50 eurocent (0.5 €) per model). conclusions in conclusion, experts approved the utilization of silicone 3d-printed models as a highly promising method in dermatological education in times of restricted in-patient contact and further recommended the incorporation of the models as an additional tool into the regular curriculum. references 1. reinholz, m. and l. french, medical education and care in dermatology during the sars‐cov2 pandemia: challenges and dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023118 1 the use of new hematological markers in the diagnosis of alopecia areata gulhan aksoy sarac1, onur acar 2, tufan nayır3, pınar hararcı yıldırım1, didem dinçer rota1 1 ufuk university faculty of medicine department of dermatology, ankara, turkey 2 ağrı provincial health directorate, republic of turkey, ministry of health, ağrı, turkey 3 turkish ministry of health, ankara, turkey key words: alopecia areata, monocyte lymphocyte ratio (mlr), roc analysis, marker citation: aksoy sarac g, acar o, nayir t, hararcı yıldırım p, dinçer rota d. the use of new hematological markers in the diagnosis of alopecia areata. dermatol pract concept. 2023;13(2):e2023118. doi: https://doi.org/10.5826/dpc.1302a118 accepted: november 16, 2022; published: april 2023 copyright: ©2023 aksoy sarac et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: onur acar, md, ağrı provincial health directorate, republic of turkey, ministry of health, ağrı, turkey. tel: +90 5062341595 orcid id: https://orcid.org/0000-0003-3561-3192 e-mail: dronuracar@yandex.com introduction: alopecia areata (aa) is a non-cicatricial inflammatory and autoimmune hair loss disease. in recent studies, it has been reported that hematological parameters can be used as oxidative stress markers in the diagnosis of many inflammatory diseases due to their low cost and widespread use. objectives: in this study, it was aimed to reveal the significant cut-off points of hematological inflammatory markers in aa that can guide clinicians in clinical practice and determine how many times they increase the risk of disease. methods: the present study is retrospective case-control type. seventy patients with aa and seventy healthy controls were included in the study. the hematological parameters in both groups were evaluated retrospectively. results: hemoglobulin, monocyte, platelet, monocyte high-density lipoprotein cholesterol (hdl-c) ratio (mhr), monocyte lymphocyte ratio (mlr), platelet lymphocyte ratio (plr) were high in patients with aa, while the number of lymphocytes was low. in roc analysis, the optimal cut-off values for the diagnosis of aa were as follows: mlr 0.216, mhr 0.010, and plr 111.715. in regression analysis, being above the following values of mlr 0.216, mhr 0.010, and plr 111.715 increased the risk of developing aa by 6.3, 3.8, and 2.7 times, respectively. conclusions: it was seen that mhr and plr, especially mlr, can significantly increase the risk of developing the disease in aa and can also be used as diagnostic markers. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023118 introduction alopecia areata (aa) is an inflammatory and autoimmune disease clinically ranging from small, round, well-defined hair loss patch to its complete disappearance on the body and scalp [1]. the incidence of aa, which is a non-scarring disease in which the hair follicle is preserved, is 2% [2]. the mean age at diagnosis of aa, which can be seen in all age groups without any difference between genders, is 30-39 years [3]. the etiopathogenesis of aa has not yet been fully elucidated. although genetics and immunity are seen as the factors that cause the most disease, many factors such as melanocyte anomalies, keratinocyte degeneration, neurological factors, and emotional stress have also been blamed [4-6]. the disease develops as a result of t cell-mediated cytotoxic damage to the hair follicle. since il-17a, il17f, il21, il22, il6, and tnf alpha levels are elevated in aa patients, these cytokines are thought to play a role in the pathogenesis [7]. in recent studies, it has been discussed that the whole blood parameters can be used as an oxidative stress and diagnostic marker in many diseases associated with inflammatory processes. in clinical practice, these markers are important for objective and quantitative evaluation of the disease process and response to treatment, as well as the diagnosis [8]. red-cell distribution width (rdw), monocyte high-density lipoprotein ratio (mhr), monocyte lymphocyte ratio (mlr), platelet lymphocyte ratio (plr), neutrophil-lymphocyte ratio (nlr) and mean platelet volume (mpv) are investigated in many dermatological diseases such as psoriasis, rheumatological diseases of dermatology, cutaneous vasculitis, atopic eczema, pityriasis rosea, behçet disease, recurrent aphthous stomatitis, and pemphigus vulgaris [9-12]. although there are many studies on these dermatological diseases in the literature, studies investigating the relationship between aa and these inflammatory markers are limited. in addition, no studies have been found showing at which cutoff point these significant inflammatory markers start to be significant and how many times they increase the risk of developing the disease. objectives in this study, it was aimed to compare the levels of rdw, mpv, mhr, mlr, nlr, plr between patients with aa and healthy controls, and to reveal the significant cut-off points that can guide clinicians in clinical practice and determine how many times they increase the risk. methods study design and patient selection this study was conducted as a retrospective case-control study with patients with aa who applied to the dermatology outpatient clinic between june 2020 and june 2021 and healthy controls with no previous history of aa. ethics committee approval of the study was received from local ethics committee. demographic characteristics and laboratory values were obtained from the database of the health center for both the case and control groups. demographic data include age, gender, duration of illness (months). laboratory data include the levels of white blood cell (wbc: k/µl), hemoglobin (hb: g/dl), platelets (plt: k/µl), rdw, mpv (k/µl), neutrophils (ne: k/µl), lymphocytes (ly: k/µl), monocytes (mn: k/µl), high-density lipoprotein cholesterol (hdl-c: mg/dl), nlr, plr, mhr, and mlr. disease severity in patients with aa was evaluated according to the classification made by kavak et al and classified as mild (3 or fewer patches with a diameter of 3 cm or less, or involvement limited to eyebrows and eyelashes), moderate (more than 3 alopecic patches or involvement of more than 3 cm without alopecia totalis or alopecia universalis), severe (alopecia totalis or alopecia universalis) [13]. patients with aa who had an active infection, malnutrition, anemia, immunodeficiency, chronic inflammatory skin disease, rheumatological disease, heart disease, and drug use were excluded from the study. the laboratory values of the patients with aa at the application date were included. laboratory values of the patients with aa regarding the follow-up and treatment couldn’t be included because they were absent in the hospital record. healthy controls were comprised of individuals without active infection, systemic or dermatological disease, and drug use. both of two groups don’t include members who got covid-19 infection in recent six months. statistical analysis the data of the study were analyzed using spss 20 (statistical package for social sciences). descriptive statistics were given as numbers, percentages, mean and standard deviation. the relationship between continuous variables was evaluated with the pearson correlation test. the t-test was used for continuous variables between two independent groups. significant cut-off points were determined using roc ( receiver operating characteristic) analysis for markers with significant differences between the two groups in the t-test. the odds ratios of the cut points that were found to be causing high activity aa were analyzed using the logistic regression model. all findings were evaluated at a 95% confidence interval (ci) and 5% significance level (p). results seventy patients with aa and 70 healthy controls were included in this study. the mean age was 31.57 ± 9.92 years in the patient group and 31.51 ± 7.37 years in the control group. original article | dermatol pract concept. 2023;13(2):e2023118 3 there was no significant difference between the groups according to age (p = 0.969). the mean age of patients with aa was 29.78 ± 8.58 years in men and 33.47 ± 10.98 years in women, and the difference was not statistically significant. the gender distribution was the same in the patient and control groups, with 36 (51.4%) men and 34 (48.6%) women. while the mean duration of disease was 1.22 ± 2.21 months in men and 3.05 ± 5.43 months in women, it was 2.11 ± 4.17 months in the whole aa group, and there was no significant difference between the genders. of the patients with aa, 41 (58.6%) had mild, 12 (17.1%) had moderate, and 17 (24.3%) had severe alopecia. the laboratory findings of the patient and control groups are shown in table 1. the mean of hb (p = 0.004), mn (p < 0.001), plt (p = 0.042), mhr (p < 0.001), mlr (p < 0.001) and plr (p < 0.001) was higher in patients with aa compared to the control group, while the number of lymphocytes was lower (p = 0.005). table 2 shows the effect of laboratory parameters on disease duration in patients with aa. while the increase in hdl-c (r = 0.324, p = 0.013), mpv (r = 0.239, p = 0.046) and plr (r = 0.297, p = 0.013) in patients with aa increased the duration of the disease (positive correlation); the increase in hb (r = -0.301, p = 0.011), ly (r = -0.269, p = 0.024) and mhr (r = -0.289, p = 0.015) was a factor reducing disease duration (negative correlation). when classified according to disease severity, for those who have severe aa disease the increase in hdl-c (r = 0.620, p = 0.008) led to increasing the duration of the disease (positive correlation). also the increase in hb (r = -0.505, p = 0.039) led to decreasing the duration of the disease (negative correlation). while there was a positive correlation between disease severity and rdw (r = 0.242, p = 0.044) and plr (r = 0.315, p = 0.008); a negative correlation between wbc (r = -0.236, p = 0.049), hb (r = -0.285, p = 0.017), mn (r = -0.270, p = 0.024) and mhr (r = -0.356, p = 0.002) was present. there was a positive, weak and very significant correlation between disease duration and disease severity in patients with aa (r = 0.494, p < 0.001). table 3 and figure 1 show the optimal value of laboratory parameters to diagnose aa using roc analysis. in roc analysis, it was found that mlr (p < 0.001), mhr (p < 0.001) and plr (p = 0.001) values could be used as a diagnostic test in aa. the cut-off values of mlr 0.216 value (auc = 0.873, good usefulness, 85.7% sensitivity and 70% specificity), mhr 0.010 value (auc = 0.759, moderate useful, 82.9% sensitivity and 58.6% specificity), plr 111.715 value (auc = 0.727, moderate useful, 75.7% sensitivity and 58.6% specificity) were found to be useful as diagnostic tests. table 4 shows how many times the parameters found to be significant in diagnosing aa in the roc analysis increase table 1. comparison of laboratory values of patients and controls using t-test. group n mean sd p value wbc patient 70 7.26 1.80 0.115 control 70 7.67 1.16 hb (g/dl) patient 70 14.91 1.65 0.004 control 70 14.15 1.37 rdw (%) patient 70 11.95 1.67 0.026 control 70 12.44 0.76 mn(k/µl) patient 70 0.57 0.17 <0.001 control 70 0.38 0.66 hdl-c (mg/dl) patient 70 52.49 10.83 0.252 control 70 50.31 11.62 ne (k/µl) patient 70 4.27 1.26 0.062 control 70 4.63 0.95 plt (k/µl) patient 70 248.81 57.91 0.042 control 70 229.87 50.94 ly (k/µl) patient 70 2.21 0.80 0.005 control 70 2.56 0.62 mpv (k/µl) patient 70 8.06 1.22 0.252 control 70 8.26 0.76 mhr patient 70 0.011 0.004 <0.001 control 70 0.007 0.001 mlr patient 70 0.281 0.111 <0.001 control 70 0.158 0.050 nlr patient 70 2.140 0.986 0.127 control 70 1.921 0.674 plr patient 70 121.461 34.492 <0.001 control 70 94.805 29.309 hb = hemoglobin; hdl-c = high-density lipoprotein cholesterol; ly = lymphocytes; mn = monocytes; mhr = monocyte high-density lipoprotein cholesterol ratio; mlr = monocyte lymphocyte ratio; mpv = mean platelet volume; ne = neutrophils;nlr = neutrophil lymphocyte ratio; plr = platelet lymphocyte ratio; plt = platelets; rdw = red-cell distribution width; wbc = white blood cell. 4 original article | dermatol pract concept. 2023;13(2):e2023118 table 2. correlation analysis between disease duration and alopecia areata group parameters. variables disease duration (months) disease severity mild&moderate patients (n = 53) severe patients (n = 17) all patients (n = 70) r p r p r p r p wbc 0.054 0.703 -0.223 0.390 -0.205 0.089 -0.236 0.049 hb -0.010 0.946 -0.505 0.039 -0.301 0.011 -0.285 0.017 rdw (%) -0.128 0.361 0.201 0.440 0.113 0.351 0.242 0.044 mn (k/µl) 0.012 0.931 -0.179 0.492 -0.230 0.055 -0.270 0.024 hdl-c (mg/dl) 0.117 0.405 0.620 0.008 0.324 0.013 0.227 0.059 ne (k/µl) 0.024 0.865 0.375 0.138 0.193 0.110 0.083 0.496 plt (k/µl) 0.304 0.027 -0.264 0.306 -0.065 0.593 0.044 0.715 ly (k/µl) -0.013 0.926 -0.482 0.050 -0.269 0.024 -0.182 0.132 mpv (k/µl) -0.150 0.284 0.312 0.222 0.239 0.046 0.195 0.106 mhr -0.079 0.574 -0.355 0.161 -0.289 0.015 -0.356 0.002 mlr -0.002 0.989 0.219 0.399 0.048 0.691 -0.064 0.601 nlr 0.024 0.865 0.375 0.138 0.193 0.110 0.083 0.496 plr 0.167 0.231 0.366 0.149 0.297 0.013 0.315 0.008 hb = hemoglobin; hdl-c = high-density lipoprotein cholesterol; ly = lymphocytes; mn = monocytes; mhr = monocyte high-density lipoprotein cholesterol ratio; mlr = monocyte lymphocyte ratio; mpv = mean platelet volume; ne = neutrophils; nlr = neutrophil lymphocyte ratio; plr = platelet lymphocyte ratio; plt = platelets; rdw = red-cell distribution width; wbc = white blood cell. table 3. findings of the roc analysis. variables auc (p value) 95% ci co sen (%) spe (%) plr nlr mlr 0.873 (<0.001) 0.8150.931 0.216 85.7 70.0 2.85 0.20 mhr 0.759 (<0.001) 0.6790.840 0.010 82.9 58.6 2 0.29 plr 0.727 (<0.001) 0.6430.810 111.715 75.7 58.6 1.82 0.41 auc = area under curve; ci = confidence interval; co = cutoff value; mhr = monocyte high-density lipoprotein cholesterol ratio; mlr = monocyte lymphocyte ratio; nlr = negative likelihood ratio; plr = platelet lymphocyte ratio; plr = positive likelihood ratio; roc = receiver operating characteristic; sen = sensitivity; spe = specifity. the probability of catching aa at the determined cut-off values in the established logistic regression model. according to the logistic regression analysis result, an mlr value of 0.216 and above increases the risk of developing aa by 6.30 times (95% ci: 2.41-16.45 p < 0.001), an mhr value of 0.010 and above by 3.87 times (95% ci: 1.54-9.73 p = 0.004) and a plr value of 111.715 and above by 2.76 times (95% ci:1.06-7.17 p = 0.037). conclusions in this study, the relationship between complete blood count and biochemical parameters, which can be easily used by clinicians in routine, and aa disease is shown in detail. there is a limited number of studies on the subject in the literature, and it has not been investigated yet at what values hematological and inflammatory markers are diagnostic for the disease and how much they increase the risk of disease in these diagnostic values. this study is a pioneering study in terms of answering these questions that are not yet available in the literature. aa is a non-cicatricial, autoimmune, inflammatory hair loss disease that has many factors in its etiology and has various clinical manifestations [1]. there is no significant difference between genders in terms of incidence. however, it was emphasized that the most common age of onset of the disease was between 50-59 years of age in women and 30-39 years in men and that the average age of diagnosis was older in women than in men (36.2 versus31.5 years) [14]. in this study, the mean age of patients with aa was 29.78 ± 8.58 years in men and 33.47 ± 10.98 years in women, which is consistent with the literature. whole blood parameters are a low-cost test and are widely used by clinicians. it provides important information about systemic inflammation. in this study, hb, mn, plt, mhr, mlr, and plr values were higher in patients original article | dermatol pract concept. 2023;13(2):e2023118 5 and hdl-c, mpv, and plr, and a negative correlation between hb, ly, and mhr. but, when correlation analysis included only severe aa patients, there was a positive with aa compared to the control group, while the number of lymphocytes was found to be lower. in addition, there was a positive correlation between aa durations table 4. logistic regression results. variables or 95% ci p value mlr 0.216 and above 6.309 2.41916.456 <0.001 below 0.216 1 (reference) mhr 0.010 and above 3.879 1.5469.732 0.004 below 0.010 1 (reference) plr 111.715 and above 2.761 1.0627.174 0.037 below 111.715 1 (reference) ci = confidence interval; mhr = monocyte high-density lipoprotein cholesterol ratio; mlr = monocyte lymphocyte ratio; plr = platelet lymphocyte ratio; or = odds ratio. roc curve se n si ti v it y 1 specificity diagonal segments are produced by ties. 0,0 0,0 0,2 0,4 0,6 0,8 1,0 0,2 0,4 0,6 0,8 1,0 source of the curve mlr mhr plr reference line figure 1. roc curve. mhr: monocyte high-density lipoprotein cholesterol ratio mlr monocyte lymphocyte ratio plr: platelet lymphocyte ratio 6 original article | dermatol pract concept. 2023;13(2):e2023118 2. pratt ch, king le, messenger ag, christiano am, sundberg jp. alopecia areata. nat rev dis primer. 2017;3:17011. doi:10.1038/nrdp.2017.11. pmid: 28300084. pmcid: pmc5573125. 3. safavi kh, muller sa, suman vj, moshell an, melton lj. incidence of alopecia areata in olmsted county, minnesota, 1975 through 1989. mayo clin proc. 1995;70(7):628-633. doi:10.4065/70.7.628. pmid: 7791384. 4. darwin e, hirt pa, fertig r, doliner b, delcanto g, jimenez jj. alopecia areata: review of epidemiology, clinical features, pathogenesis, and new treatment options. int j trichology. 2018;10(2):51-60. doi:10.4103/ijt.ijt_99_17. pmid: 29769777. pmcid: pmc5939003. 5. gilhar a, etzioni a, paus r. alopecia areata. n engl j med. 2012;366(16):1515-1525. doi:10.1056/nejmra1103442. pmid: 22512484. 6. simakou t, butcher jp, reid s, henriquez fl. alopecia areata: a multifactorial autoimmune condition. j autoimmun. 2019;98:74-85. doi: 10.1016/j.jaut.2018.12.001. pmid: 30558963. 7. islam n, leung psc, huntley ac, gershwin me. the autoimmune basis of alopecia areata: a comprehensive review. autoimmun rev. 2015;14(2):81-89. doi: 10.1016/j.autrev.2014.10.014. pmid: 25315746. 8. rashmi r, rao ksj, basavaraj kh. a comprehensive review of biomarkers in psoriasis. clin exp dermatol. 2009;34(6):658-663. doi:10.1111/j.1365-2230.2009.03410.x. pmid: 19558584. 9. asahina a, kubo n, umezawa y, honda h, yanaba k, nakagawa h. neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and mean platelet volume in japanese patients with psoriasis and psoriatic arthritis: response to therapy with biologics. j dermatol. 2017;44(10):1112-1121. doi:10.1111/1346-8138.13875. pmid: 28493493. 10. kridin k, shihade w, zelber-sagi s. mean platelet volume in pemphigus vulgaris. angiology. 2018;69(4):303-307. doi:10.1177/0003319717718329. kpmid: 28681645. 11. pancar gs, eyupoglu o. red cell distribution width and mean platelet volume in patients with pityriasis rosea. j clin med res. 2016;8(6):445-448. doi:10.14740/jocmr2535w. pmid: 27222672. pmcid: pmc4852777. 12. turkmen d, altunisik n, sener s. investigation of monocyte hdl ratio as an indicator of inflammation and complete blood count parameters in patients with acne vulgaris. int j clin pract. 2020;74(12):e13639. doi:10.1111/ijcp.13639. pmid: 32741037. 13. kavak a, baykal c, ozarmağan g, akar u. hla in alopecia areata. int j dermatol. 2000;39(8):589-592. doi:10.1046/ j.1365-4362.2000.00921.x. pmid: 10971726. 14. mirzoyev sa, schrum ag, davis mdp, torgerson rr. lifetime incidence risk of alopecia areata estimated at 2.1% by rochester epidemiology project, 1990-2009. j invest dermatol. 2014;134(4):1141-1142. doi:10.1038/jid.2013.464. pmid: 2420223. pmcid: pmc3961558. 15. ozlu e, karadag as, toprak ae, et al. evaluation of cardiovascular risk factors, haematological and biochemical parameters, and serum endocan levels in patients with lichen planus. dermatol basel switz. 2016;232(4):438-443. doi:10.1159/000447587 opmid: 27508489. 16. sirin mc, korkmaz s, erturan i, et al. evaluation of monocyte to hdl cholesterol ratio and other inflammatory markers in patients with psoriasis. an bras dermatol. 2020;95(5):575-582. correlation between aa durations and hdl-c, and a negative correlation between aa durations and hb. in many studies in the literature, the relationship between dermatological diseases and these hematological markers has been investigated. in a study conducted by ozlu et al wbc and mhr were found to be high and mpv was found to be low in patients with lichen planus [15]. it was shown that patients with psoriasis have higher levels of mhr and nlr compared to healthy controls [16]. similarly, while there was a positive relationship between mhr, nlr, plr, and mlr and disease duration in psoriasis, it has been reported that there was a negative relationship between nlr, plr, and disease duration in vitiligo [17,18]. however, there are also studies stating that there is no significant relationship between aa and these hematological markers [19]. monocytes are one of the cornerstones of the immune system that take on important tasks. they play a role in inflammatory processes in many diseases involving many systems such as rheumatologic, endocrine, dermatological, oncologic, and cardiovascular [20-23]. in this study, mlr, mhr, and plr values were found to be good and moderately useful diagnostic tests for aa. the values that are above 0.216 for mlr, 0.010 for mhr, and 111.715 for plr as cut-off increase the risk of alopecia areata by 6.3, 3.8, and 2.7 times, respectively. in a study by yayla et al.; it has been reported that high nlr increases the risk of systemic sclerosis by 3.49 times [24]. in the study by cosansu et al, it was stated that the mlr value of 0.192 was a moderately useful test in the diagnosis of patients with psoriasis, and similarly, mhr and mlr values were significant markers in the diagnosis of vitiligo [25,18]. there are some limitations to this study. firstly, since it was in a retrospective style, the laboratory values of the patients at the time of application were included and no evaluation could be made regarding the follow-up data. secondly, the fact that it is a single-center study, and third, the relatively small number of patients and controls may cause differences in findings. fourth, it may assess as another limitation that the severity of alopecia tool score wasn’t used when classifying the severity. in conclusion, in this study, mhr and plr values, especially mlr, were shown to be low-cost and fast-accessible oxidative stress markers in the diagnosis of aa. it is believed that our results may provide important information for further studies on the use of hematological markers in aa. references 1. strazzulla lc, wang ehc, avila l, et al. alopecia areata: disease characteristics, clinical evaluation, and new perspectives on pathogenesis. j am acad dermatol. 2018;78(1):1-12. doi:10.1016/j.jaad.2017.04.1141. pmid: 29241771. original article | dermatol pract concept. 2023;13(2):e2023118 7 doi:10.1016/j.abd.2020.02.008. pmid: 32711928. pmcid: pmc7562997. 17. aktaş karabay e, demir d, aksu çerman a. evaluation of monocyte to high-density lipoprotein ratio, lymphocytes, monocytes, and platelets in psoriasis. an bras dermatol. 2020;95(1):40-45. doi:10.1016/j.abd.2019.05.002. pmid: 31889591. pmcid: pmc7058861. 18. demirbaş a, elmas öf, atasoy m, türsen ü, lotti t. can monocyte to hdl cholesterol ratio and monocyte to lymphocyte ratio be markers for inflammation and oxidative stress in patients with vitiligo? a preliminary study. arch dermatol res. 2021;313(6):491-498. doi:10.1007/s00403-020-02129-3. pmid: 32816078. 19. i̇slamoğlu zgk, demirbaş a. evaluation of complete blood cell and inflammatory parameters in patients with alopecia areata: their association with disease severity. j cosmet dermatol. 2020;19(5):1239-1245. doi:10.1111/jocd.13131. pmid: 31502748. 20. ji h, li y, fan z, et al. monocyte/lymphocyte ratio predicts the severity of coronary artery disease: a syntax score assessment. bmc cardiovasc disord. 2017;17(1):90. doi:10.1186/s12872017-0507-4. jpmid: 28359298. pmcid: pmc5374608. 21. kang y, zhu x, lin z, et al. compare the diagnostic and prognostic value of mlr, nlr and plr in crc patients. clin lab. 2021;67(9). doi:10.7754/clin.lab.2021.201130. pmid: 34542964. 22. yue s, zhang j, wu j, teng w, liu l, chen l. use of the monocyte-to-lymphocyte ratio to predict diabetic retinopathy. int j environ res public health. 2015;12(8):10009-10019. doi:10.3390/ijerph120810009. pmid: 26308022. pmcid: pmc4555325. 23. zawada am, rogacev ks, rotter b, et al. supersage evidence for cd14++cd16+ monocytes as a third monocyte subset. blood. 2011;118(12):e50-61. doi:10.1182/blood-2011-01-326827. pmid: 21803849. 24. yayla me, i̇lgen u, okatan i̇e, et al. association of simple hematological parameters with disease manifestations, activity, and severity in patients with systemic sclerosis. clin rheumatol. 2020;39(1):77-83. doi:10.1007/s10067-019-04685-0. pmid: 31317426. 25. cosansu nc, dikicier bs, yaldiz m, solak b. is there any association between the monocyte/lymphocyte ratio and the presence and severity of the disease in patients with psoriasis? sak tıp derg. 2020;10(3):430-436. doi: 10.31832/smj.719980. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2013;3(3):1 1 editorial it is a great pleasure for me to write this editorial in my role as the new editor of dermatology practical & conceptual. with this new role i face, equally, a challenge and an honor, given that i follow the footsteps of the esteemed personalities of the former editors, a. bernard ackerman, who founded the journal under the name dermatopathology practical & conceptual, succeeded by almut böer-auer and then harald kittler, who renamed the journal dermatology practical & conceptual. i wish to give special mention to harald kittler, who i personally know, not only as an outstanding and brilliant researcher and clinician, but who i consider a true and unique friend. thanks to harald’s efforts and passion, dermatology practical & conceptual has turned out to be a modern, innovative and dynamic journal. he always respected the historical fundamentals and basis of this journal, namely clinical morphology. his own respect for clinical morphology is reflected in the changes that the journal underwent during his editorship. when harald took over the editorship three years ago, he decided to change the title. the change of only that one word in the title of the journal encompassed the broader aims and scope of it. in this way, he opened the journal to all aspects of morphology, including macroscopic morphology, morphology related to new non-invasive diagnostic tools and to traditional microscopic histopathology. but harald did much more for the journal. during his editorship, dermatology practical & conceptual became an open-access online journal, offering free access to both readers and authors. moreover, dermatology practical & conceptual became the official journal of the international dermoscopy society, which accounts currently for more than 6700 members all over the world and which promotes research, education and advancement of dermoscopy. most exciting, thanks to his efforts and those of the production team of derm101 and the valuable contributions of researchers and the editorial team, the journal has succeeded in being included to pubmed central. all articles published starting with the first issue of dermatology practical & conceptual appear in full in the u.s. national institutes of health (nih) digital archive of biomedical and life sciences journal literature, also known as pubmed central (pmc). this also means that pmc submits a citation to pubmed as soon as the article is live in pmc. besides his passion for the journal and clinical morphology, i would also like to point another aspect of harald’s personality, which can be described as unconventional. it is not surprising that he earned, not only the plaudits of his colleagues, but also severe criticism for his work. with regard to this aspect of harald’s character, i would like to cite the words of our friend geppi argenziano, who described the need for outliers like harald, especially after bernie’s death, as follows: “bernie ackerman was the charismatic and loud critical voice in the dermatologic establishment. we are fortunate to have harald among us, who continues to represent a critical voice in dermatology.” i cannot but fully agree with this statement. as the new editor of dermatology practical & conceptual, i will do my best to guarantee sufficient space for critical thought and unconventional viewpoints in clinical dermatology. that being said, clinical morphology will continue to represent the traditional aim of the journal. however, as we foresee that the number of article submissions increasing welcome, readers! iris zalaudek, m.d. citation: zalaudek i. welcome, readers! dermatol pract conc. 2013;3(3):1. http://dx.doi.org/10.5826/dpc.0303a01. copyright: ©2013 zalaudek. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: iris zalaudek, m.d., division of dermatology, medical university of graz, auenbruggerplatz 8, 8036 graz, austria. email: dpc@derm101.com. 2 editorial | dermatol pract concept 2013;3(3):1 i also want to express my thanks to alon scope and jeff keir for their exceptional past work on the journal and for having accepted to continue collaborating with us in the future. alon will continue as section editor for diagnostic imaging and dermatoscopy and jeff as section editor of dermatology in primary care. i would also like to thank mark hurt, who is responsible for the book reviews of the journal, as well as the many colleagues of the editorial board, who collaborated so well in the past and, hopefully, will continue their work also in the future. all section editors are not only renown experts in their fields, but they are all outstanding critical thinkers who will guarantee and maintain the critical spirit of the journal. i am proud to be part of this wonderful team. finally, what would be the value of a journal without its contributors? i thank all past and current contributors for sharing their scientific work with the dermatological community. in the spirit of a young and modern journal, we see it as an obligation to support, especially, young researchers and thus we invite them to actively contribute to the future content of the journal. iris zalaudek, m.d. editor-in-chief dermatology practical & conceptual because of its inclusion in pubmed, i think that the journal should be also open to evolving fields linked to clinical morphology, such as translational clinical and molecular dermatology, dermato-oncology, dermatologic surgery and cosmetic and aesthetic dermatology. these are relevant fields in clinical dermatology and i believe that dermatology practical & conceptual can only benefit from being open to some of these, perhaps not traditionally morphological, but still closely related dermatologic subspecialties. as the rapidly and continuously growing knowledge in these different fields of clinical dermatology cannot be followed by a single person, i plan to work with a team of section editors in order to guarantee a high scientific standard and timely peer-review process for all submitted manuscripts. it is my great pleasure to introduce in this issue the new sections and section editors, to whom i am grateful for their willingness to contribute with their knowledge to the future directions of dermatology practical & conceptual. i am happy to welcome, in alphabetic order, maria gonzalez, athanassis kyrgidis, aimilios lallas, vito di lernia, elvira moscarella, john paoli, michael skerlev and alex stratigos as the new section editors for cosmetic and aesthetic dermatology, statistics, general dermatology, autoimmune and blistering diseases, pediatric dermatology, dermatologic surgery, mycosis and sexually transmitted diseases and dermato-oncology, respectively. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022119 1 dermatology practical & conceptual iridescent changes observed during dynamic cross-polarized dermoscopy john paoli1,2, lykke barck1,2, eva johansson backman1,2, ashfaq marghoob3, sam polesie1,2 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 3 department of dermatology, memorial sloan kettering cancer center, new york, ny, usa citation: paoli j, barck l, backman ej, marghoob a, polesie s. iridescent changes observed during dynamic cross-polarized dermoscopy. dermatol pract concept. 2022;12(3):e2022119. doi: https://doi.org/10.5826/dpc.1203a119 accepted: november 24, 2021; published: july 2022 copyright: ©2022 paoli et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: john paoli, m.d., ph.d, department of dermatology and venereology, sahlgrenska university hospital, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gröna stråket 16, 413 45, gothenburg, sweden tel: +46(0) 730 40 40 44, e-mail: john.paoli@gu.se case presentation a 60-year-old male with skin phototype iv from africa and a history of kaposi sarcoma on his foot presented with a rapidly growing, 6.5-mm, bluish-purple nodule on his back. cross-polarized dermoscopy using a dermlite dl4 (3gen) coupled with an iphone xs max (apple) revealed a ‘rainbow pattern’ on a structureless red background. by rotating the dermoscope without moving the smartphone during imaging, also known as dynamic cross-polarized dermoscopy, the color distribution within the rainbow pattern changed substantially (figure 1, supplementary video 1). the lesion was excised and histopathologically confirmed as kaposi sarcoma. teaching point the metaphoric term ‘rainbow pattern’ is used to describe polychromatic structureless areas only seen with polarized dermoscopy. it has been described in several different skin tumors (eg kaposi sarcoma, hemosiderotic dermatofibroma, angiokeratoma, aneurysmal atypical fibroxanthoma, melanoma and basal cell carcinoma) and other skin conditions (eg stasis dermatitis, lichen planus and scars) [1]. it is surmised that polarized light passing through slits created by parallelly aligned collagen bundles or vessels may cause the light to separate into different wavelengths [2]. although the exact structures that actually cause the optical interference are unknown, the observed phenomenon is called iridescence. by applying dynamic cross-polarized dermoscopy, we demonstrate that the iridescence changes with the angle of polarization. this angular dependence of cross-polarized light has also been demonstrated previously by marghoob et al on shiny white lines, which are only visible with the dermoscope positioned at specific angles. 2 image letter | dermatol pract concept. 2022;12(3):e2022119 references 1. elmas of, mayisoglu h, celik m, kilitci a, akdeniz n. dermoscopic rainbow pattern: a strong clue to malignancy or just a light show? north clin istanb. 2020;7(5):494–498. doi: 10.14744/ nci.2020.32656. pmid: 33163886. pmcid: pmc7603844. 2. draghici c, vajaitu c, solomon i, voiculescu vm, popa mi, lupu m. the dermoscopic rainbow pattern a review of the literature. acta dermatovenerol croat. 2019;27(2):111–115. pmid: 31351506. figure 1. (a) clinical presentation of a case of kaposi sarcoma. (b) iridescence or ‘rainbow pattern’ observed during cross-polarized dermoscopy at a specific angle. (c) modified iridescence shown after rotating the dermoscope 90°. supplementary video legend supplementary video 1. the iridescence or ‘rainbow pattern’ changes substantially while rotating the dermoscope relative to the smartphone camera (dynamic cross-polarized dermoscopy), thus demonstrating the angular dependence of polarization. https://mattiolihealth.com/wp-content/uploads/2022/08/dp1203a119s1.mp4 dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023129 1 interstitial granulomatous dermatitis and palisaded neutrophilic granulomatous dermatitis: retrospective clinicopathological analysis of 16 cases ebru sarıkaya tellal1, dilara ilhan erdil1, muge gore karaali2, ayse esra koku aksu1, erdemir va3, asude kara polat1, cem leblebici4 1 department of dermatology, university of health science (hsu) istanbul training and research hospital, istanbul, turkey 2 department of dermatology, irmet international hospital, tekirdag, turkey 3 department of dermatology, göztepe training and research hospital, medeniyet university, istanbul, turkey 4 department of pathology, university of health science (hsu) istanbul training and research hospital, istanbul, turkey key words: granulomatous dermatitis, interstitial granulomatous dermatitis, palisaded neutrophilic and granulomatous dermatitis, reactive granulomatous dermatitis citation: sarıkaya tellal e, ilhan erdil d, gore karaali m, et al. interstitial granulomatous dermatitis and palisaded neutrophilic granulomatous dermatitis: retrospective clinicopathological analysis of 16 cases. dermatol pract concept. 2023;13(3):e2023129. doi: https://doi.org/10.5826/dpc.1303a129 accepted: december 1, 2022; published: july 2023 copyright: ©2023 sarıkaya tellal et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: muge gore karaali, md, irmet international hospital, tekirdag, turkey. tel: +9005303093328 e-mail: mugegore@hotmail.com introduction: reactive granulomatous dermatitis (rgd) is a new entity, which is highly associated with systemic disorders. there is scarce data regarding interstitial granulomatous dermatitis (igd) and palisaded neutrophilic granulomatous dermatitis (pngd). objectives: we aimed to evaluate clinical and histopathological characteristics of igd and pngd as unified entities under the term of rgd. methods: observational, retrospective, single-center study of patients diagnosed with igd and pngd between 2012 and 2021 were included in the study. results: of 16 patients (14 females and 2 males) with rgd, 13 had igd and 3 had pngd with a mean age of 62.5 years. the most common clinical presentation was plaques 37.5% (n=6), followed by patches 25% (n=4). the most common localization of involvement was lower extremity 75% (n=12), followed by trunk and upper extremity. multiple localization of involvement was determined in 75% (n=12) of patients. none of the patients had rope sign. associated comorbidities such as abstract 2 original article | dermatol pract concept. 2023;13(3):e2023129 introduction interstitial granulomatous dermatitis (igd) and palisaded neutrophilic granulomatous dermatitis (pngd) are reactive granulomatous inflammatory skin disorders which were recently proposed to be unified under the term of reactive granulomatous dermatitis (rgd). they are highly associated with systemic disorders with only few and recent large patient population studies regarding the concept of rgd [1,2]. igd and pngd are uncommon clinicopathological entities with a wide spectrum of clinical manifestations, and also it can be difficult to establish clinical and pathological correlations of these diseases. igd usually presents with erythematous to violaceous patches or plaques symmetrically located on the upper trunk or proximal limbs, and pngd with plaques/papules/nodules sometimes painful with central ulceration or crust distributed on the extensor limbs [3,4]. despite of initial reporting of classical presentation of igd with rope sign (linear subcutaneous cords), it is seen rarely in the current reports [2]. histopathologically a diffuse, interstitial and perivascular, superficial and deep inflammatory infiltrate composed mainly of lymphocytes and histiocytes surrounding foci of collagen degeneration in the dermis with a limited number of neutrophils and eosinophils have been determined. scarce interstitial mucin deposition can be present. igd usually does not have leukocytoclastic vasculitis (lv). on the other hand, despite overlapping histopathological findings with igd, pngd biopsies are characterized by more intense neutrophilic infiltration, karyorrhexis, more degenerated collagen in dermis, palisading granuloma with or without lv compared with igd. interstitial granulomatous drug reaction is also a form of igd can mimic pngd and igd both clinically and histologically with prominent eosinophilic infiltration [2]. associated comorbidities of rgd include autoimmune diseases (as the most common cause), malignancy and infections. it is reported in the literature that there are not any associated comorbidities at the time of the diagnose in up to 25% of patients however, concomitant disease may also occur after the diagnosis and so follow up is required [2,4]. objectives to analyze the clinicopathological findings and the disease associations of rgd. methods we conducted an observational, retrospective study for clinical and histopathological analysis of 16 patients diagnosed with igd and pngd between the years 2012 and 2021 by searching the database of the pathology and dermatology departments of a tertiary center. the study has been approved by the institutional review board of the hospital. previously defined histopathological criteria, including presence of histiocytic and lymphocytic infiltration through the dermis and surrounding with foci of degenerated collagen was used in the current study [2]. the presence of a “floating sign” was noted, which is the visible clefting in abnormal collagen by the clusters of histiocytes. mucin deposits should be absent or moderate. patients who did not meet these criteria, and who had alternative diagnosis (necrobiosis lipoidica, granuloma annulare, interstitial granulomatous drug reaction) were excluded from the study. for clinical analysis, sex, age at the diagnosis, localization, characteristics of the cutaneous lesions, associated symptoms, medical comorbidities, medication use, laboratory values and treatments were recorded. results clinical findings this study included 16 patients (14 females; 2 males, female:male ratio of 7:1) aged between 42 and 81 years (mean 62.5±11.1 years). symptom duration ranged from 1 month to 30 months (mean 7.0 ± 8.3 months). the most common autoimmune diseases and malignancies were detected in 68.7% (n=11) of patients. in majority of biopsies (87.5%; n=14), there were lymphohistiocytic cell infiltration. other accompanying cells were scarce neutrophils 31.2% (n=5) and eosinophils 31.2% (n=5). all of the biopsies had interstitially located lymphohistiocytic cell infiltration surrounding with swollen and degenerated collagen. palisaded pattern was determined in 18.7% (n=3) of patients and floating sign was seen in 18.7% (n=3) of biopsies. conclusions: rgd is a rare entity and most patients with rgd had associated disorders such as autoimmunity or malignancy. there is overlapping between igd and pngd, therefore supporting the usage of umbrella term as reactive granulomatous dermatitis is compatible with the literature. original article | dermatol pract concept. 2023;13(3):e2023129 3 presentation was isolated plaques 37.5%, followed by only patch 25%, papules and plaques in 12.5% patients, one patient with papule and one patient with macule, papule, purpura. “rope sign” was not present in any of the patients. all lesions were violaceous and/or erythematous in color (figure  1). most common localization was lower extremity (mainly medial thigh region) 75%, followed by trunk 50%, upper extremity 43.7%. multiple site involvement was seen in 75% of patients. one patient had face and neck involvement. mycosis fungoides (56.2%) was the most commonly differential diagnosis of igd/pngd. igd/pngd were among the pathological pre-diagnoses in only 25% of the patients. associated autoimmune systemic disease or malignancy was observed in 12 patients (68.7%). associated diseases of pngd were autoimmune hepatitis in one patient, sjögren syndrome in one patient, lung cancer and churg strauss syndrome in one patient. in a single patient igd occurred as wolf isotopic response after herpes zoster (patient #13). comorbidities of patients with igd and pngd were listed in table 1. the drugs used by the patients for their associated diseases were listed in table 1. all of these drugs were used by the patients for many years. in 31.2% of patients there were no associated disease despite of clinical and laboratory evaluation for an underlying disorder; 12.5% of patients, had both ana positivity and arthralgia. rheumatoid factor (rf) positivity was seen in 18.7% of patients and c-anca was positive in a single patient. during the follow-up, one of the patients diagnosed with sjogren syndrome and the other patient with history of thyroiditis was diagnosed with rheumatoid arthritis. patients with rgd were treated with topical corticosteroids and also underlying systemic diseases were treated. all the lesions resolved completely with topical therapy in about six months without recurrency in a mean of 39.8 month follow up. the clinical features of the 16 patients are summarized in table 1. histopathological findings epidermis was preserved in 82.7% of the biopsies. others had hyperkeratosis, parakeratosis, acanthosis and mild increased pigmentation. in all biopsies, there were lymphohistiocytic cell infiltration. other accompanying cells were scarce neutrophils (31.2%), eosinophils (31.2%) and plasmocytes (12.5%). all of the biopsies had interstitially located lymphohistiocytic cell infiltration surrounding with swollen and degenerated collagen. palisaded pattern with combination of interstitial pattern was observed in 18.7% of patients. floating sign was detected in 18.7% of biopsies. none of the biopsies had dermal fibrosis. alcian blue staining demonstrated interstitial minimal mucin in 56% of the biopsies and moderate mucin in one case, remaining biopsies did not reveal mucin formation. nuclear debris was seen in 31.2%, vasculitic changes such as fibrinoid figure 1. some clinical presentations of the patients. (a) erythematous papules and plaques on the anterolateral abdomen. (b) violaceous papules extending from inframammary region to lateral trunk. (c) violaceous macules on the arm. (d) violaceous plaque on the inner thigh. 4 original article | dermatol pract concept. 2023;13(3):e2023129 table 1. clinical features of 16 patients diagnosed with interstitial granulomatous dermatitis (igd) and palisaded neutrophilic granulomatous dermatitis (pngd). patient nr. sex age (year) time to lesion lesion characteristics localization of lesions associated diseases/drugs (if available) final diagnosis 1 f 77 2 mo erythematous plaques trunk, lower extremity hypertension (calcium channel blockers) igd 2 f 42 2 mo violaceous papules and plaques upper extremity rheumatoid arthritis (non-steroid antiinflammatory drugs) igd 3 f 58 1,5 mo erythematous to violaceous papules and plaques face,neck, upper extremity autoimmune hepatitis (azathioprine) pngd 4 f 66 9 mo violaceous plaques trunk, lower extremity hypertension (thiazide diuretic+ angiotensin receptor blocker) igd 5 f 58 4 mo erythematous to violaceous plaques upper extremity, lower extremity thyroiditis, type 2 diabetes mellitus (levothyroxine) igd 6 f 58 24 mo violaceous macules, papules and petechies lower extremity sjögren syndrome pngd 7 f 58 6 mo violaceous plaques upper extremity, trunk, lower extremity tubulovillous adenoma with high dysplasia igd 8 f 81 12 mo erythematous plaques upper and lower extremity thyroiditis (levothyroxine) igd 9 f 71 3 mo erythematous patches trunk, lower extremity hypertension (thiazide diuretic+ angiotensin receptor blocker) igd 10 f 68 2 mo violaceous patches lower extremity hypertension (angiotensin-receptor blocker) igd 11 m 44 3 mo erythematous plaques upper extremity, trunk rheumatoid arthritis (colchicine) igd 12 f 58 30 mo erythematous patches trunk, lower extremity behçet disease (colchicine) igd 13 f 69 1 mo violaceous papules trunk rheumatoid arthritis igd 14 f 50 6 mo erythematous patches trunk, lower extremity none igd 15 m 71 1 mo erythematous patches, plaques and nodules upper and lower extremity lung adenocarcinoma, churg strauss syndrome pngd 16 f 71 6 mo erythematous plaques and patches trunk, lower extremity thyroiditis, hypertension (levothyroxine, thiazide diuretic) igd igd = interstitial granulomatous dermatitis; mo = months; pngd = palisaded neutrophilic granulomatous dermatitis. necrosis was seen in 12.5%, leukocytoclasis in 12.5% of patients. leukocytoclastic vasculitis was determined in 12.5% of patients. histopathological information of the 16 biopsies is summarized in table 2 and some examples are shown in figure 2. conclusions rgd is an umbrella term for igd and pngd, which are rarely seen dermatosis with a wide clinical spectrum. igd and pngd have overlapping clinical and histopathological original article | dermatol pract concept. 2023;13(3):e2023129 5 ta b le 2 . h is to p at h o lo gi ca l fe at u re s o f 1 6 p at ie n ts d ia gn o se d w it h i n te rs ti ti al g ra n u lo m at o u s d er m at it is a n d p al is ad ed n eu tr o p h il ic g ra n u lo m at o u s d er m at it is . p a ti e n t e p id e rm a l in v o lv e m e n t ly m p h o h is ti o cy ti c ce ll i n fi lt ra ti o n fl o a ti n g si g n m u ci n p a li sa d in g p a tt e rn fi b ri n o id n e cr o si s v a sc u li ti s le u k o cy to cl a si a n u cl e a r d e b ri s n e u tr o p h il e o si n o p h il 1 + + m in im al 2 + m in im al + + + 3 a + + + + + + 4 + + m in im al 5 + + + 6 a + + + 7 + m in im al 8 + m in im al 9 + 1 0 + m o d er at e 1 1 + m in im al + + + + + + 1 2 + + + 1 3 + 1 4 + m in im al 1 5 a + + m in im al + + + + + 1 6 + m in im al + p n g d = p al is ad ed n eu tr o p h il ic g ra n u lo m at o u s d er m at it is .a p at ie n ts w it h p n g d . 6 original article | dermatol pract concept. 2023;13(3):e2023129 and/or malignancy (lung adenocarcinoma) were accompanied in all (100.0%) pngd patients, in 7 of 13 (53.8%) patients with igd had autoimmunity and 1 (7.7%) had malignancy (tubulovillous adenoma with high dysplasia). neutrophilic infiltration was determined in all patients with palisading pattern and all of them were associated with autoimmunity or malignancy. however, we could not detect any clinical and/or histopathological data that can definitely distinguish between these two entities due to a small number of pngd patients and overlapping features of igd and pngd. for this reason, the term proposed as rgd in the current studies will be appropriate. comorbidities associated with our patients were similar to the literature (60-76%) [1,2,4]. in one 69-year-old female patient with a history of herpes zoster, igd developed in the same localization after one month. we evaluated this patient as wolf’s isotopic response. one patient with wolf isotopic response was reported in the literature. this patient was an 11-year-old boy diagnosed with igd possibly to herpes zoster [11]. autoimmune hepatitis associated with igd was previously reported [3,12,13]. in our series, the patient with findings. therefore, more extensive reports on these diseases are needed. reported clinical presentations of rgd in the previous studies are annular plaques, erythematous-violaceous papules or nodules [4,5], non-scaly annular plaques (similar to most of our patients) [4,6,7], linear-shaped plaques [8,9] and arciform-non scaly nodules [10]. most of our patients presented with mf like, erythematous to violaceous plaques on the sun-protected sites such as axilla, lateral chest or inner thighs. since rgd is a rare disease, this diagnosis can be underestimated by clinicians, thus in only 25% of the patients in our study, pre-diagnosis of igd/pngd was possible due to a wide spectrum of presentations. according to our results rgd should be considered in the differential diagnosis of plaque lesions on sun-protected areas. it has been reported that the rope sign is rarely seen in studies, similar to these studies, this finding was not found in any of the patients in our study, despite of initial reporting of classical presentation of igd with rope sign [2]. due to possible accompanying diseases, correct and early diagnosis of rgd is important. in our study, autoimmunity figure 2. some histopathological examination of the skin of patients. (a) interstitial lymphohistiocytic infiltrate with collagen degenerationinterstitial granulomatous dermatitis subtype (h&e, ×100). (b) collagen degeneration and “floating sign” with lymphohistiocytic infiltrate (h&e, ×200). (c) palisading granulomas accompanied by neutrophils, lymphohistiocytic infiltration, collagen degeneration (h&e, ×200). (d) palisading granulomas accompanied by neutrophils, lymphohistiocytic infiltration, collagen degeneration (h&e, ×400). original article | dermatol pract concept. 2023;13(3):e2023129 7 palisaded neutrophilic and granulomatous dermatitis: a study of 52 patients. j eur acad dermatol venereol. 2021;35(4):988-994. doi: 10.1111/jdv.17010. pmid: 33098595. 3. rosenbach m, english jc 3rd. reactive granulomatous dermatitis: a review of palisaded neutrophilic and granulomatous dermatitis, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, and a proposed reclassification. dermatol clin. 2015;33(3):373-387. doi: 10.1016/j .det.2015.03.005. pmid: 26143420. 4. coutinho i, pereira n, gouveia m, cardoso jc, tellechea o. interstitial granulomatous dermatitis: a clinicopathological study. am j dermatopathol. 2015;37(8):614-619. doi: 10.1097/dad.0000000000000288. pmid: 25830722. 5. veronez is, dantas fl, valente ny, kakizaki p, yasuda th, cunha tdo a. interstitial granulomatous dermatitis: rare cutaneous manifestation of rheumatoid arthritis. an bras dermatol. 2015;90(3):391-393. doi: 10.1590/abd1806-4841.20153263. pmid: 26131871. pmcid: pmc4516102. 6. altemir a, iglesias-sancho m, sola-casas mlá, novoa-lamazares l, fernández-figueras m, salleras-redonnet m. interstitial granulomatous dermatitis following tocilizumab, a paradoxical reaction? dermatol ther. 2020;33(6):e14207. doi: 10.1111 /dth.14207. pmid: 32816393. 7. wang y, wu y, zheng z, bai y, cui y. interstitial granulomatous dermatitis associated with primary biliary cirrhosis. j dermatol. 2018;45(1):112-113. doi: 10.1111/1346-8138.13778. pmid: 28225148. 8. kim ys, lee jh, lee jy, park ym. interstitial granulomatous dermatitis associated with rheumatoid arthritis. ann dermatol. 2016;28(3):395-397. doi: 10.5021/ad.2016.28.3.395. pmid: 27274645. pmcid: pmc4884723. 9. verneuil l, dompmartin a, comoz f, pasquier cj, leroy d. interstitial granulomatous dermatitis with cutaneous cords and arthritis: a disorder associated with autoantibodies. j  am acad dermatol. 2001;45(2):286-291. doi: 10.1067 /mjd.2001.114577. pmid: 11464193. 10. rato m, gil f, monteiro af, aranha j, tavares e. interstitial granulomatous dermatitis in a patient with chronic hepatitis c and mixed cryoglobulinemia. dermatol online j. 2018;24(1):13030/ qt3x33s9m7. pmid: 29469770. 11. takenoshita h, yamamoto t. granulomatous isotopic response possibly to herpes zoster in childhood. j dermatol. 2014;41(7):651-652. 12. lee kj, lee es, lee dy, jang kt. interstitial granulomatous dermatitis associated with autoimmune hepatitis. j eur acad dermatol venereol. 2007;21(5):684-685. doi: 10.1111/j.1468 -3083.2006.01982.x. pmid: 17447986. 13. szepetiuk g, lesuisse m, piérard ge, quatresooz p, piérard franchimont c. autoimmunity-related granulomatous dermatitis in association with hepatitis. case rep dermatol. 2012;4(1):80-84. doi: 10.1159/000337894. pmid: 22649335. pmcid: pmc3362185. 14. corneli p, di meo n, zalaudek i, et al. interstitial granulomatous dermatitis as primary manifestation of marginal zone lymphoma. int j dermatol. 2020;59(11):e412-e414. doi: 10.1111 /ijd.14981. pmid: 32662885. 15. kim sm, cho sh, lee jd, kim hs. interstitial granulomatous dermatitis in a patient with prostate cancer. ann dermatol. pngd was accompanied by autoimmune hepatitis. in literature, other diseases which may accompany were autoimmune disorders such as; rheumatoid arthritis [3,4], systemic lupus erythematosus [1,3,4,16], autoimmune thyroiditis, primary biliary cirrhosis [7], malignancies such as hematological or solid cancers [14,15], infections such as hcv and related cryoglobulinemia [10], coccidiomycosis [17] or medications [4,5]. in 31.2% of patients, there were no associated autoimmunity or malignancy despite of clinical and laboratory evaluation for an underlying disorder. due to high association with systemic disorders, follow-up of the patient for the possible development of autoimmunity or malignancy is important despite of having no associated features at time of diagnosis. in addition to reported comorbidities, we had a patient with behçet disease and igd in our case series. when we search for the literature, behçet’s disease accompanies only two patients with pngd [18,19]. kim et al. reported a 32-year-old female with papular lesions on legs [18]. shin et al. reported a 60-year-old female with also popular lesions on extremities, buttocks, and ear lobes [19]. in our study the patient with igd and behçet disease was 58-year-old female, and her lesions were erythematous patches on her trunk and legs. angiotensin receptor antagonists, thiazide diuretics, calcium channel blockers are thought to be associated with interstitial granulomatous drug reaction [3]. like mentioned in methods, interstitial granulomatous drug reaction was excluded from the study. however, when the drugs used by the patients, especially the antihypertensive drugs were evaluated, they were not considered to be associated with igd development in this study, as the duration of the drugs were more than four years in our study. rgd is a rare clinicopathological entity. this is one of the larger case series presenting new disease associations. since there is a high association with systemic disorders, follow up of patients is required. due to overlapping features between igd and pngd, the term proposed as rgd in the current studies will be appropriate. references 1. bangalore kumar a, lehman js, johnson ef, et al. reactive granulomatous dermatitis as a clinically relevant and unifying term: retrospective review of clinical features, associated systemic diseases, histopathology, and treatment for a series of 65 patients at mayo clinic. j eur acad dermatol venereol. 2022. doi: 10.1111/jdv.18203 pmid: 35535506. 2. rodríguez-garijo n, bielsa i, mascaró jm jr, et al. reactive granulomatous dermatitis as a histological pattern including manifestations of interstitial granulomatous dermatitis and 8 original article | dermatol pract concept. 2023;13(3):e2023129 18. kim sk, park ck, park yw, jun jb, yoo dh, bae sc. palisaded neutrophilic granulomatous dermatitis presenting as an unusual skin manifestation in a patient with behçet’s disease. scand j rheumatol. 2005;34(4):324-327. doi:10.1080/03009740510015195. pmid: 16195168. 19. shin yb, jo jw, yoon tj. palisaded neutrophilic and granulomatous dermatitis in a patient with behçet’s disease: a case report. ann dermatol. 2021;33(1):73-76. doi:10.5021 /ad.2021.33.1.73. pmid: 33911815.. 2017;29(3):337-340. doi: 10.5021/ad.2017.29.3.337. pmid: 28566913. pmcid: pmc5438943. 16. jandali b, uthman i, abbas o. interstitial granulomatous dermatitis associated with systemic lupus erythematosus: case report and review of the literature. lupus. 2016;25(2):209-213. doi: 10.1177/0961203315604908. pmid: 26385222. 17. dicaudo dj, connolly sm. interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. j am acad dermatol. 2001;45(6):840-845. doi: 10.1067/mjd.2001.117522. pmid: 11712027. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023153 1 onychoheterotopia kethini ramadas ram kumar1, arunachalam narayanan1, sivaranjini ramassamy1 1 department of dermatology and std, jipmer, puducherry, india citation: ram kumar kr, narayanan a, ramassamy s. onychoheterotopia. dermatol pract concept. 2023;13(2):e2023153. doi: https://doi.org/10.5826/dpc.1302a153 accepted: november 18, 2022; published: april 2023 copyright: ©2023 ram kumar et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sivaranjini ramassamy, md, associate professor, department of dermatology and std, jipmer, puducherry-605006 e-mail: sivaranjini11@gmail.com case presentation a 53-year-old farmer visited our outpatient clinic with an asymptomatic, slow-growing, hard, keratotic nail-like structure growing from the dorsal aspect of his left index finger (figure 1) for 40 years following a penetrating injury. on examination, a 5 x 3 mm rectangular nail plate-like structure, with a smooth surface, was located 7 mm proximal to the proximal nail fold. folds of skin, similar to proximal and distal nail folds of a normal nail, were seen surrounding it. the cuticle was not visible. other nails were normal. no functional disability was noted. radiographic examination didn`t reveal any hypoplasia or thinning of the phalanx. based on the above features, a diagnosis of onychoheterotopia was made. teaching point ectopic nail or onychoheterotopia is characterized by nail plate growth in regions other than the normal nail bed due to the presence of an ectopic nail matrix. it is classified into two types: congenital and acquired ectopic nail [1]. although the pathogenesis is unclear, it is hypothesized to occur due to the presence of ectopic germ cells, an underlying subclinical polydactyly, or traumatic inoculation of nail matrix cells [2]. figure 1. a slow-growing, hard, keratotic nail-like structure growing from the dorsal aspect of his left index finger with proximal and lateral nail folds. 2 image letter | dermatol pract concept. 2023;13(2):e2023153 diagnosis of ectopic nail is made based on its clinical findings and is supported by histopathological evaluation. treatment includes surgical excision of the nail and its entire matrix to prevent recurrence followed by primary closure of the defect. we present this uncommon condition which has differential diagnosis of cutaneous horn, foreign body reactions, and rudimentary polydactyly, and is likely to be missed by dermatologists. references 1. chatterjee k, chaudhuri a, chatterjee g. onychoheterotopia: a unique case. indian j dermatol. 2013;58(2):150-115. doi: 10.4103/0019-5154.108064. pmid: 23716811. pmcid: pmc3657221. 2. fleury cm, nasser js, aivaz m, et al. pediatric ectopic nail formation following fingertip trauma: a case report and literature review. plast reconstr surg glob open. 2020;8(12):e3291. doi: 10.1097/gox.0000000000003291. pmid: 33425603. pmcid: pmc7787327. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022178 1 various application of tofacitinib and ruxolitinib (janus kinase inhibitors) in dermatology and rheumatology: a review of current evidence and future perspective sara sadeghi1, azadeh goodarzi1,2 1 rasool akram medical complex clinical research development center (rcrdc), iran university of medical sciences, tehran, iran 2 department of dermatology, faculty of dermatology, rasool akram medical complex clinical research development center (rcrdc), school of medicine, iran university of medical sciences, tehran, iran key words: tofacitinib, ruxolitinib, janus kinase inhibitors, skin, mucosa citation: sadeghi s, goodarzi a. various application of tofacitinib and ruxolitinib (janus kinase inhibitors) in dermatology and rheumatology: a review of current evidence and future perspective. dermatol pract concept. 2022;12(4):e2022178. doi: https://doi.org/10.5826/dpc.1204a178 accepted: february 1, 2022; published: october 2022 copyright: ©2022 sadeghi et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: azadeh goodarzi, md, department of dermatology, associate professor of dermatology, rasool akram medical complex clinical research development center (rcrdc), school of medicine, iran university of medical sciences, tehran, iran. e-mail: azadeh_goodarzi1984@yahoo.com, goodarzi.a@iums.ac.ir introduction: janus kinase inhibitors (jaki) are anti-inflammatory medications suppressing janus kinase-signal transducer and activator of transcription (jak-stat) pathway by inhibiting various cytokines receptors on the membrane of cells. mutations and polymorphisms on jak and stat proteins can cause dysregulation in the balance of immune system, and ultimately result in autoimmune disorders. objectives: to record and summarize the overall efficacy and safety of jaki in various autoimmune conditions such as alopecia areata (aa), psoriasis vulgaris (pv), psoriatic arthritis (psa), atopic dermatitis (ad), vitiligo, hidradenitis suppurative (hs), lichen planus (lp), and pyoderma gangrenosum (pg). methods: a thorough review of articles was performed across pubmed and google scholar on meta-analyses, systematic reviews, clinical trials and case studies evaluating the treatment of autoimmune disorders such as aa, pv, psa, ad, vitiligo, lp, hs, and pg with jaki. duplicated data and animal experiments or in vitro/ex vivo studies were excluded. results: all the reviewed articles reported beneficial effects of tofacitinib and ruxolitinib application in the treatment of disorders mentioned above with the autoimmune predisposition. abstract 2 review | dermatol pract concept. 2022;12(4):e2022178 introduction the janus kinase inhibitors are a category of anti inflammatory medications, targeting jak-stat pathways. many inflammatory cytokines function through the jakstat pathways in the human body [1,2]. cytokines are crucial molecules working on the immune system regulation, and their dysregulation might be important in the pathogenesis of autoimmune disorders [3]. genetic polymorphisms and different mutations can occur within jak-stat pathways, resulting in several forms of malignancies and autoimmune disorders, ie polymorphisms of jak2 and stat3 are involved in psoriasis [4]. jaki medications provide us with the possibility of shutting down the impaired jak-stat pairs. ruxolitinib and tofacitinib are the prototypes of jaki. ruxolitinib is a jak1/2 selective inhibitor; it affects several parts of the innate and adaptive immune system, including natural killer cells (nkc), dendritic cells, t-helpers, and regulatory t-cells [5]. tofacitinib preferentially blocks jak1/3 and, to some degree, jak2 and tyk2 [6]. jaki, like other medications, have adverse effects (aes) on the human body. jaki suppress the immune system at some levels, and their consumption increases the risk of some infections such as herpes zoster (hz). vaccination against hz prior to the treatment with tofacitinib is recommended. non-hz opportunistic infections, including cytomegalovirus, cryptococcus, histoplasmosis and clostridium difficile are also reported in jaki recipients [5,7]. there is a potential risk of increasing venous thromboembolism (vte) events following the treatment with jaki so it is recommended to avoid prescribing jaki in patients with age >50, previous vte, hypercoagulability, smoking, cardiovascular disease (cvd), long-term immobilization, recent trauma or surgery, paralysis, malignancy, obesity, frequent long flights, and hormonal therapy. a further consideration is required to either avoid or prescribe jaki with extra caution in patients with a history of cancer; however, there is not enough evidence and data about the carcinogenicity of jaki. other aes include anemia, reversible hyperlipidemia and minimal elevation in liver transaminases and creatine phosphokinase (cpk) [7,8]. objectives the development of jaki in dermatology and rheumatology is still in the early stage; however, there is favorable evidence about the utility of jaki in treating some of the autoimmune disorders. to prevent extensive efforts collecting data from different studies to answer specific inquiries about such disorders and medications, we performed a narrative review to summarize all the available evidence on the utility of jaki in treating aa, pv and psa, ad, vitiligo, lp, hs, and pg. methods a thorough search was performed on pubmed, and google scholar using combinations of the following mesh terms: “tofacitinib,” “ruxolitinib,” “jak inhibitors,” “janus kinase inhibitors,” “alopecia areata,” “psoriasis vulgaris,” “psoriasis arthritis,” “atopic dermatitis,” “vitiligo,” “hidradenitis suppurative,” “pyoderma gangrenosum,” “lichen planus,” “ lichen planopilaris.” a total of 672 publications were found. after removing duplicates and non-suitable publications, we focused on the most recent and available pooled studies such as systematic reviews and meta-analyses and then available clinical trials, observational and case studies. results alopecia areata alopecia areata is a non-cicatricial alopecia with an autoimmune etiology, affecting approximately 2% of the general population. histopathology assessment on the involved skin showed lymphocytic infiltration around the hair follicles at the level of bulb or lower [9]. immune system dysregulation results in hair follicles damage by t-cells and nkc. moreover, auto-reactivation of immune cells upregulates ifn-γ and cytokines and cause further cellular damage and inflammation [10]. excessive activation of jak-stat has a major effect on maintaining the activation of cd8+ t-cells and nkc. additionally, a low level of t-regulatory cells identified in aa patients, makes it impossible to suppress excessive amounts of cytokines. these complexes of immune dysregulations contribute to hair follicles damage [10,11]. conclusions: tofacitinib and ruxolitinib showed potential efficacy in treating several autoimmune disorders. based on records in the reviewed studies, both medications had acceptable safety profiles; however, physicians are recommended to outweigh the risks and benefits of such treatments for each specific condition. review | dermatol pract concept. 2022;12(4):e2022178 3 yu et al reviewed 12 studies with 346 patients. in this review 288 participants received oral tofacitinib and 58 received oral ruxolitinib. the outcome measurement was reported with the severity of alopecia tool50 (salt50), showing 66% overall improvement in all patients. there was no statistically difference when studies categorized by sex, age and subtypes of aa (p = 0.81, p = 0.37 and p =  0.91, respectively). the salt50 rates were lower in patients who received a shorter length of treatment but was not statistically significant (p = 0.25). the reported aes were upper respiratory tract infections (urti), urinary tract infections (uti), herpes simplex and herpes zoster infections, alteration of blood cells count, the elevation of liver aminotransaminase and lipids; moreover, there were no fatal aes [12]. in another meta-analysis, hamilton et al reviewed ten different studies on the systemic and topical tofacitinib and ruxolitinib in children and teenage populations (age 1 – 17 years). the review affirmed success for jaki in children and teens with higher numbers of complete responders and smaller numbers of poor responders compared to adults. aes were small and limited to mild infections, diarrhea and reversible lab abnormalities [13]. in addition, guo et al conducted a meta-analysis on 14 studies with 275 patients treating with oral and topical tofacitinib. a complete response in 54.0% and partial response in 26.1% of patients were reported. the aa relapse rates were 24.0% in the pooled results, and the main reason was medication discontinuation. a 7.2% of patients presented aes, and the most common ae was urti [14]. psoriasis vulgaris psoriasis is a chronic autoimmune inflammatory disease with the prevalence of 2% worldwide. psoriasis has several subtypes, including plaque, guttate, inverse, and pustular. overactivation of dendritic cells is responsible for the initial phase of psoriasis and unbalanced elevated levels of cytokines such as il-17, il-21 and il-22 (mostly th17 and il-23 driven [15]) for the maintenance phase of inflammation. medications such as tofacitinib and ruxolitinib targeting tnf-α, il-23 and il-17 and jak/stat pathways can be effective in treating pv [16]. kvist-hansen et al conducted a systematic review on five clinical trials (phase two and three trials) utilizing oral tofacitinib to treat moderate to severe forms of pv. the effectiveness was calculated based on pasi75 (psoriasis area & severity index 75% reduction). in the phase two studies, the effectiveness of tofacitinib was reported 25% with 2 mg/bid, 40.8% with 5 mg/bid, and 66.7% with 15 mg/bid compared to 2% efficacy in placebo. in the phase three studies, the effectiveness was reported 39.5% – 54.3% with 5 mg/bid and 59.2% 81.1% with 10 mg/bid compared to 5.6% 12.5% for the placebo recipients at weeks 16 24. moreover, clinical efficacy was reported based on dermatology life quality index (dlqi) and nail psoriasis severity index (npsi). aes such as hyperlipidemia, cpk elevation, anemia and lymphopenia were observed in some patients [17]. tian et al meta-analyzed seven randomized clinical trials (rcts) about oral tofacitinib in chronic plaque psoriasis. physician global assessment (pga) and pasi 75 (4 studies reported pasi 90) showed denoting difference between the group of tofacitinib 5 mg/bid users and control group (p <  0.00001). the effectiveness of tofacitinib 10 mg/ bid was also significantly distinct from the control group (p < 0.00001). moreover, 5 mg/bid of tofacitinib showed less efficacy than 10 mg/bid. even though, there was no statistically significant difference in aes between 5 and 10 mg tofacitinib, more aes were related to 10 mg/bid dosage [18]. further, it is recommended to conduct clinical trials on topical types of jaki in treating pv. psoriatic arthritis approximately 19.4% of patients with psoriasis present joints involvement [19]. psa manifestations include peripheral arthritis, enthesitis, axial disease, dactylitis, and skin characteristics [20]. no serology markers are available to distinguish psa from psoriasis; however, hyperlipidemia, gout, axial spondylopathy or allergic rhinitis are more common in psa [19]. companaro et al systematically reviewed three rcts studying oral tofacitinib. in these studies, 947 patients treated with tofacitinib and those who only received 5 mg/bid were assessed in the review. the results at week 16 revealed a significant higher acr20 (number of patients who achieved ≥20% response rate to the treatment based on the american college of rheumatology index) response than placebo. moreover, tofacitinib also presented statistically higher acr50, acr70 and pasi75 response rates compared to placebo, and health assessment questionnaire-disability index (haq-di) score and post-treatment fatigue assessment showed lower rate, which means better response. serious aes were greater in the treatment group than the control group; however, it was not proved statistically [21]. paik et al reviewed tofacitinib efficacy in two well-designed parallel rcts (phase 3) in psa patients: the opal broaden with 442 patients for 12 months and the opal beyond with 394 patients for six months. patients received tofacitinib 5 or 10 mg/bid or placebo (or adalimumab 40 mg/sc combined with a csdmard instead of placebo in opal broaden) in both trials. the efficacy of tofacitinib over placebo was evaluated with acr20, acr50, acr70, haq-di and pasi75. after three months, tofacitinib 5 mg/bid recipients achieved statistically significant acr20 or acr50 and haq-di 4 review | dermatol pract concept. 2022;12(4):e2022178 patients received oral tofacitinib 5 – 10 mg/bid for 12 – 40 weeks; 11 patients received topical tofacitinib 2% bid + uvb phototherapy for 12 weeks, 21 patients received topical ruxolitinib 1.5% bid for 12 – 38 weeks (in one study uvb phototherapy was also added), and one patient received oral ruxolitinib 20 mg/bid for 20 weeks. efficacy was assessed with vitiligo area and severity index (vasi) and facial vitiligo area and severity index (fvasi). overall effectiveness in the jaki-alone recipients was reported as 57.8% good response, 22.2% partial and 20% none or minimal response. moreover, the response to the treatment with concurrent uvb phototherapy was statistically higher than jaki alone (p < 0.001). the improvement turned more significant (fvasi reduction) in facial vitiligo than other body sites (p < 0.001) when the studies were sub-grouped based on specific body areas. no significant difference was observed between different routes of jaki administration (p = 0.1). aes were erythema, transient acne, hyperpigmentation, transient hyperlipidemia, urtis, weight gain and joint pain [27]. in a case report, komnitski et al presented a 40-year-old lady with vitiligo and rheumatoid arthritis receiving 5 mg oral tofacitinib twice daily. after 2 years of the treatment without being sun-exposed, complete re-pigmentation of the frontal and peri-labial were observed. further, partial improvement in the back of the neck and upper chest were also noted. no aes were reported during the treatment in this case [28]. lichen planus lichen planus is a chronic inflammatory disorder that can involve derma, mucous, nail and hair follicles. the etiology of lp seems to be autoimmune with the incidence rate of 2% – 3% [30]. the overactivation of cd8+ t-call lymphocytes and dysregulation of cd4+ t-cells have been observed to play a major role in the pathogenesis of lp [30]. damsky et al 2020 evaluated the benefit of oral tofacitinib in a case series of three patients with erosive lichen planus (elp). treatment with oral tofacitinib 5 mg/bid was initiated for all patients. additional therapy with methotrexate and prednisolone was added to the therapeutic regimen of patient #1 due to the refractory course of his condition. all patients showed dramatic improvements and complete or near-complete remission while they were on tofacitinib. discontinuation of tofacitinib in patient #1 resulted in elp relapse even when he continued methotrexate and prednisolone. re-initiation of tofacitinib 5 mg/bid resulted again in improvement in patient #1. tofacitinib was tolerated well with no reported aes in any of the cases [31]. another case series by yang et al reported the effectiveness of oral tofacitinib in ten patients with refractory lichen planopilaris (lpp). treatment with tofacitinib 5 mg/ bid for 8 patients and 5 mg/tds for the other 2 patients, scores than placebo in both trials, and in the opal broaden study, significantly more patients treated with 5 mg/bid tofacitinib achieved pasi75 score than placebo. after 12 months, minimal disease activity was attained in 37% of tofacitinib 5 mg recipients. a minimal progression in radiography was reported in the opal broaden trial, and more than 90% of patients showed non-progression criteria [22]. all reviewed studies reported favorable safety and efficacy profiles of oral tofacitinib and ruxolitinib. atopic dermatitis atopic dermatitis is the most common chronic inflammatory skin disease with 3% – 10% prevalence in adults and 15% – 25% in children. moderate-to-severe ad can alter the health-related quality of life (hrqol) because of sleep disturbance, purities and comorbid mental conditions. multiple inflammatory pathways and cytokines are involved in the pathogenesis of ad, and they can be considered as therapeutic targets [15,23]. tsai et al conducted a meta-analysis on 15 rcts and reviewed the efficacy and safety of jaki in treating ad. among 4,367 participants, 69 patients received topical tofacitinib 2% bid for 4 weeks, and 307 patients received topical ruxolitinib 0.15%, 0.5%, or 1.5% once daily, or 1.5% bid for 8 weeks. in the tofacitinib study, efficacy was evaluated by investigator global assessment (iga), eczema area and severity index (easi-75%) and body surface area (bsa) response. there were statistically significant higher rates of achievement to iga, easi-75%, and bsa responses in the treatment group compared to the control group. in assessing topical ruxolitinib among 307 patients, efficacy was evaluated by pruritus numerical rating scale (pruritus-nrs) response. participants in the treatment group disclosed statistically greater rates of achieving pruritus-nrs response than placebo recipients. additionally, safety was reported with treatment-emergent adverse events (teaes), showing a higher rate of aes in the treatment groups that was directly related to the length of treatment (24). further, it is suggested that topical jaki are rational modalities in treating refractory ad; however, more clinical trials are required to evaluate the long-term safety. vitiligo vitiligo is an autoimmune skin disease with acquired loss of function in epidermal melanocytes, resulting in depigmented white patches of skin. the unregulated activity of t-helper1 and high levels of ifn-γ, il-9 and il-10 seem to be the leading cause of autoimmunity in vitiligo, and treatments aiming to lower the levels of ils seem to be rationale [25,26]. phan et al meta-analyzed data from nine case reports and case series to assess the pooled results about the efficacy and safety of jaki in the treatment of vitiligo. twenty-three review | dermatol pract concept. 2022;12(4):e2022178 5 including adalimumab, tacrolimus, prednisolone, and rituximab. treatment was transitioned to oral tofacitinib 5 mg/bid: significant improvement was observed after two weeks, and 95% improvement and sustained remission were reported at three months post-treatment [42]. another case report was conducted by kochar et al presenting three patients with refractory pg. the first two patients were treated with 5 mg of tofacitinib twice daily, and no signs of disease activity and aes were reported after 12 months. the third patient commenced on tofacitinib 5 mg/bid and concomitant steroid, and his pg lesions were improved but not healed entirely within a month. then steroid was stopped, and tofacitinib up-titrated to 10 mg/bid and improvement continued [43]. reviewed studies indicated the effectiveness of oral tofacitinib in the treatment of pg; however, more studies with larger scales are needed to assess the accuracy of this allegation. conclusions tofacitinib and ruxolitinib showed potential efficacy in the treatment of several autoimmune disorders. based on a thorough review of the literature, it is concluded that both medications have acceptable safety profiles; however, physicians are recommended to outweigh the risks and benefits of the treatment for each specific condition. further, there are not enough data and studies about the benefit and safety of tofacitinib and ruxolitinib in treating disorders such as hs, pg, and lp. we predict that jaki will be utilized more broadly in treating autoimmune disorders, and future reviews can be a paradigm guideline helping clinicians to treat their patients. acknowledgement the authors would also like to express their gratitude to zeena amini, for an extraordinary helpful comments during the review process, and to the authorities of rasool akram medical complex clinical research development center (rcrdc)or their technical assistance. references 1. choy eh. clinical significance of janus kinase inhibitor selectivity. rheumatology (oxford). 2019;58(6):953-962. doi: 10.1093/rheumatology/key339. pmid: 30508136. pmcid: pmc6532440. 2. damsky w, king ba. jak inhibitors in dermatology: the promise of a new drug class. j am acad dermatol. 2017;76(4):736-744. doi 10.1016/j.jaad.2016.12.005. pmid: 28139263. pmcid: pmc6035868. 3. o’shea jj, kontzias a, yamaoka k, tanaka y, laurence a. janus kinase inhibitors in autoimmune diseases. ann rheum dis. 2013;72 suppl 2(0 2):ii111-ii115. doi: 10.1136/ with more severe disease, was commenced and continued for 2 – 19 months. disease activity assessed by lpp activity index ( lppai), and showed statistically significant improvement compared to pre-treatment (p = 0.0014). one patient reported hair loss upon treatment discontinuation (due to weight gain), which stabilized when medication was re-started with a 5 mg/bid dosage [32]. a significant efficacy and low aes were reported in the reviewed case series. large-scale and long-term studies are required to assess the safety and efficacy of the treatment. hidradenitis suppurativa hidradenitis suppurativa is a chronic inflammatory disorder in 1% of general population [33,34]. pathogenesis of hs starts with cutaneous changes around hair follicles and dysregulation of innate and adaptive immunity: elevated levels of ils following the overactivity of t-helpers, ultimately affect neutrophils, macrophages and plasma cells. these changes result in a vicious cycle of inflammation, pain, purulence, tissue destruction, and disfiguring scars [33-36]. jaki suppress the impacts of ils, and thus they can be a potential treatment for hs; however, limited studies aim to prove the benefit of jaki in treating hs. savage et al reported two cases of hs treating with oral tofacitinib 5 mg/bid: a patient treated for one year and the other patient for three years. both patients showed favorable results: patient #1 was pain and drainage free after 11 months. upon discontinuation at 12 months, the modest disease activity was observed, and tofacitinib re-treatment directed the disease to full remission. patient #2 experienced gradual remission over 3 years of treatment. at this time, localized herpes zoster infection was reported which was controlled with intravenous valacyclovir. no other aes were reported in either of the two patients [35]. pyoderma gangrenosum pyoderma gangrenosum is a rare, ulcerative and painful dermatological condition with a multifactorial pathogenesis. diagnosis of pg is 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am. beyond ruxolitinib: fedratinib and other emergent treatment options for myelofibrosis. cancer manag res. 2019;11:10777-10790. doi: 10.2147/cmar.s212559. pmid: 31920387. pmcid: pmc6935287. 9. pratt ch, king le, messenger ag, christiano am, sundberg jp. alopecia areata. nat rev dis primers. 2017;3:17011. doi: 10.1038/nrdp.2017.11. pmid: 28300084. pmcid: pmc5573125. 10. dillon kl. a comprehensive literature review of jak inhibitors in treatment of alopecia areata. clin cosmet investig dermatol. 2021;14:691-714. doi: 10.2147/ccid.s309215. pmid: 34211288. pmcid: pmc8242127. 11. hordinsky mk. overview of alopecia areata. j investig dermatol symp proc. 2013;16(1):s13-s15. doi: 10.1038/ jidsymp.2013.4. pmid: 24326541. 12. yu d-a, kim ye, kwon o, park h. treatment outcome of oral tofacitinib and ruxolitinib in patients with alopecia areata: a systematic review and meta-analysis. indian j dermatol venereol leprol. 2021;87(5):621-627. doi: 10.25259/ijdvl_975_19. pmid: 34379968. 13. hamilton ce, craiglow bg. jak inhibitors for the treatment of pediatric alopecia areata. j investig dermatol symp proc. 2020;20(1):s31-s36. doi: 10.1016/j.jisp.2020.04.005. pmid: 33099381. 14. guo l, feng s, sun b, jiang x, liu y. benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis. j eur acad dermatol venereol. 2020;34(1):192-201. doi: 10.1111/jdv.15937. pmid: 31494993. 15. he h, guttman-yassky e. jak inhibitors for atopic dermatitis: an update. am j clin dermatol. 2019;20(2):181-192. doi: 10.1007/s40257-018-0413-2. pmid: 30536048. 16. rendon a, schäkel k. psoriasis pathogenesis and treatment. int j mol sci. 2019;20(6):1475. doi: 10.3390/ijms20061475. pmid: 30909615. pmcid: pmc6471628. 17. kvist-hansen a, hansen pr, skov l. systemic treatment of psoriasis with jak inhibitors: a review. dermatol ther (heidelb). 2020;10(1):29-42. doi: 10.1007/s13555-019-00347-w. pmid: 31893355. pmcid: pmc6994544. 18. tian f, chen z, xu t. efficacy and safety of tofacitinib for the treatment of chronic plaque psoriasis: a systematic review and meta-analysis. j int med res. 2019;47(6):2342-2350. doi: review | dermatol pract concept. 2022;12(4):e2022178 7 33. sabat r, jemec gbe, matusiak ł, kimball ab, prens e, wolk k. hidradenitis suppurativa. nat rev dis primers. 2020;6(1):18. doi: 10.1038/s41572-020-0149-1. pmid: 32165620. 34. savage kt, santillan mr, flood ks, charrow a, porter ml, kimball ab. tofacitinib shows benefit in conjunction with other therapies in recalcitrant hidradenitis suppurativa patients. jaad case rep. 2020;6(2):99-102. doi: 10.1016/j.jdcr.2019.10.010. pmid: 31993474. pmcid: pmc6974699. 35. zouboulis cc, frew jw, giamarellos-bourboulis ej, jemec gbe, del marmol v, marzano av, et al. target molecules for future hidradenitis suppurativa treatment. exp dermatol. 2021;30 suppl 1:8-17. doi: 10.1111/exd.14338. pmid: 34085329. 36. miller j, yentzer ba, clark a, jorizzo jl, feldman sr. pyoderma gangrenosum: a review and update on new therapies. j am acad dermatol. 2010;62(4):646-654. doi: 10.1016/j.jaad.2009.05.030. pmid: 20227580. 37. crowson an, mihm mc, jr., magro c. pyoderma gangrenosum: a review. j cutan pathol. 2003;30(2):97-107. doi: 10.1034/j.16000560.2003.00024.x. pmid: 12641787. 38. ruocco e, sangiuliano s, gravina ag, miranda a, nicoletti g. pyoderma gangrenosum: an updated review. j eur acad dermatol venereol. 2009;23(9):1008-1017. doi: 10.1111/j.14683083.2009.03199.x. pmid: 19470075. 39. braswell sf, kostopoulos tc, ortega-loayza ag. pathophysiology of pyoderma gangrenosum (pg): an updated review. j am acad dermatol. 2015;73(4):691-698. doi: 10.1016/j.jaad.2015.06.021. pmid: 26253362. 40. alavi a, french le, davis md, brassard a, kirsner rs. pyoderma gangrenosum: an update on pathophysiology, diagnosis and treatment. am j clin dermatol. 2017;18(3):355-372. doi: 10.1007/s40257-017-0251-7. pmid: 28224502. 41. choi aw, abuav r, rabizadeh sm, ansari r, marsch af. recalcitrant and severe pyoderma gangrenosum attributable to levamisole-adulterated cocaine and treated successfully with oral tofacitinib. jaad case rep. 2020;6(9):939-941. doi: 10.1016/j. jdcr.2020.07.035. pmid: 32923571. pmcid: pmc7475066. 42. kochar b, herfarth n, mamie c, navarini aa, scharl m, herfarth hh. tofacitinib for the treatment of pyoderma gangrenosum. clin gastroenterol hepatol. 2019;17(5):991-993. doi: 10.1016/j.cgh.2018.10.047. pmid: 30404036. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023014 1 demographics of skin cancer knowledge among middle and high schoolers in texas dina h. zamil1, shangyi fu1, zahra majd2, emily powell3, jenna h. zamil4, zeena y. nawas5, ida f. orengo5 1 baylor college of medicine, school of medicine, houston, tx, us 2 university of houston college of pharmacy, department of pharmaceutical health outcomes and policy, houston, tx, us 3 integrated dermatology of ponchatoula, los angeles, ca, us 4 university of houston, department of biology and biochemistry, houston, tx, us 5 baylor college of medicine, department of dermatology, houston, tx, us key words: melanoma, education, adolescents, knowledge, demographics citation: zamil dh, fu s, majd z, et al. demographics of skin cancer knowledge among middle and high schoolers in texas. dermatol pract concept. 2023;13(1):e2023014. doi: https://doi.org/10.5826/dpc.1301a14 accepted: july 4, 2022; published: january 2023 copyright: ©2023 zamil et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: a grant was provided for this study by the texas medical association alliance. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: dina h. zamil, baylor college of medicine, 1 baylor plaza houston, tx 77030. phone: 713-798-4951 e-mail: dina.zamil@bcm.edu introduction: adolescents, an age group that can reduce sun exposure early, may benefit from school-based skin cancer education programs. literature regarding the demographics of melanoma knowledge is sparse. objectives: this study sought to evaluate melanoma knowledge among students in texas viewing john wayne cancer foundation block the blaze (jwcfbtb) presentations and identify group differences with regard to sociodemographic factors. methods: before jwcfbtb presentations delivered in houston and dallas by health professions students, a pre-presentation melanoma knowledge quiz was distributed. this survey was adapted from a 2000 study evaluating melanoma knowledge in middle and high schoolers in houston and dallas. respondents were also asked to provide their gender, age, grade, race, parent education level, and whether they are first-generation american. anova and tukey tests were used to evaluate demographic group differences in scores. logistic regression models determined predictors of answering selected true/false questions correctly. results: one-way anova tests showed statistically significant group differences in pre-test scores for all demographic factors evaluated. females, whites/caucasians, students whose parents hold graduate degrees, and older students had higher scores. black students and non-first-generation americans were more likely to answer selected commonly missed questions correctly. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023014 introduction accounting for 4% of cancers in adolescents, melanoma of the skin is a common preventable cancer in the united states [1]. adolescents can reduce sun exposure early, and thus particularly benefit from sun-protective practices [2]. this age group also tends to engage in intentional tanning and may not actively avoid uv exposure [3]. countries such as australia have implemented state government and non-governmental organization skin cancer awareness programs, which emphasize childhood prevention, since the 1980s [4]. a  20-year study found that one of these programs, sunsmart, likely contributed to a reduced incidence of melanoma among younger australians [5]. additionally, a 2015 review found skin cancer prevention initiatives to be costeffective and even cost-saving [6]. as such, skin cancer and melanoma awareness initiatives for adolescents in the united states warrant further investigation. previous studies have evaluated adolescent knowledge and attitudes towards skin cancer and the efficacy of various school-based interventions. as early as 1992, a chicago study found that high schoolers spend significant amounts of time in the sun and that a 45-minute intervention increased students’ knowledge of skin cancer [7]. another study from 2001 found that texas teenagers under 16 indicated they would limit sun exposure following a melanoma educational quiz exercise [8]. later research investigated different populations and methods of intervention. disparities in skin cancer awareness and sun-safe behaviors were found among white hispanic and white non-hispanic students in florida  [9]. among utah high school students, skin cancer presentations, sunscreen efficacy demonstrations, and distribution of personalized uv damage photos at schools significantly increased sun-protective behaviors in a 1-month follow-up [3]. finally, medical students have been described as an asset to skin cancer awareness programs for teens; they can offer cost-effective, enthusiastic, and informative melanoma education that can help identify and prevent melanoma [10]. while the literature has extensively investigated attitudes towards and knowledge of skin cancer and melanoma in adults [11–14], few studies have specifically focused on adolescents [15], and even fewer studies have examined school-based interventions addressing knowledge gaps in the us. moreover, literature regarding adolescents of varying socioeconomic backgrounds or adolescents of racial minorities is sparse [16]. such knowledge would help identify sociodemographic subgroups that may specifically benefit from more education. this will be essential to targeting skin cancer education programs to the grade levels, age groups, and geographic areas in which they will be most effective. the john wayne cancer foundation block the blaze (jwcfbtb) program, based in california, delivers skin cancer education presentations to youth in 16 states [17]. the texas branch of the program includes presentations offered at middle and high schools by baylor college of medicine medical and physician assistant students. texas has a high uv index for most of the year [18] and ranks fourth in the nation for estimated new cases of melanoma of the skin in 2020 [1]. texas is also the second most populous state in the us [19], where people enjoy spending time outside. thus, early melanoma education in texas is essential for prevention. objectives as part of jwcfbtb presentations, anonymous surveys are distributed. these include true/false pre-presentation melanoma knowledge quizzes and post-presentation surveys evaluating program efficacy. the objective of this study was to assess the current knowledge of high school students regarding melanoma and skin cancer and examine group sociodemographic group differences in knowledge using pre-presentation survey responses. methods this was a cross-sectional survey study. the pre-presentation true/false melanoma knowledge quizzes and post-presentation surveys utilized in this study were adapted from a previously published study of melanoma knowledge among texas teenagers [8]. surveys also collected information on race, parent education level, age, grade, gender, and whether the student is a first-generation american. middle and high schools in the greater houston area and dallas were contacted via email, and 46 virtual jwcfbtb presentations conclusions: results from 2000 and 2020-2021 indicate older students from higher grade levels know more about melanoma, suggesting adolescents may benefit from earlier skin cancer education. racial minorities and individuals of low socioeconomic status, who suffer from disparities in melanoma treatment and mortality, showed poorer melanoma knowledge. targeting skin cancer education to disadvantaged schools may help remedy such gaps. original article | dermatol pract concept. 2023;13(1):e2023014 3 were offered at the 12 schools that responded and scheduled presentations. survey data was collected between october 14, 2020, and may 25, 2021. due to the covid-19 pandemic, jwcfbtb presentations took place virtually, and a link to the survey was sent to all middle and high school students in texas ( houston and dallas) watching the presentations. anonymous responses were collected in a secure spreadsheet. students were given the option to enter a gift card raffle upon completion of both pre-presentation and post-presentation surveys. to maintain the anonymity of survey responses, students were redirected to a separate link to enter the raffle following survey completion. the g-power 3.1 statistical software was used for sample size estimation [20]. it was estimated that a total sample of 352 subjects will be needed to provide 80% power to detect significance with a 0.3 effect size for a two-tail analysis t-test at 0.05 α-level. a total of 305 subjects will be needed to provide 80% power to detect significance with a 0.2 effect size for an anova analysis at a 0.05 α-level. a total of 308 students will be needed for a two-tail analysis using logistic regression at a 0.05 α-level, 0.10 β-level (80% power), and for a 1.5 odds ratio. we planned to recruit a minimum of 500 subjects which provides sufficient power for the proposed analysis. scores on the melanoma knowledge pre-test were summarized as means and standard deviation overall and stratified by race, parent education level, age, grade, gender, and whether the student is a first-generation american. anova and tukey tests were used to evaluate group differences in scores. logistic regression models were carried out to determine predictors of answering the following true/false questions correctly, selected from the most missed questions on the survey: 1. without sun exposure, my body will not produce vitamin d. 2. melanoma is usually flat, not raised like a mosquito bite or a pimple. the outcome variable in the logistic regression models was correct versus incorrect response to each of the questions. independent variables in these models included all sociodemographic variables collected in the study (race, parent education level, age categories, grade categories, gender, and whether the student is a first-generation american). age categories were organized as pairs between adjacent ages (12-13, 14-15, 16-17, 18+). grade-level categories were also created in this way (5-6, 7-8, 9-10, 11-12). all statistical analyses were carried out using sas software version 9.4 (sas institute, cary, nc) at an a priori significance level of 0.05 for two-sided tests. the study was approved by the institutional review board of baylor college of medicine. results the jwcfbtb presentations were offered to 1279 students in texas, of which 1154 completed the pre-presentation survey, providing a response rate of approximately 90.3%. the overall average score on the pre-presentation melanoma knowledge test was 64.6%, with a standard deviation of 0.121, a median of 65.6%, and a range of 24.13% to 96.6%. one-way anova tests showed statistically significant group differences in melanoma knowledge pre-test scores for all demographic factors evaluated, including gender (f2,1151 = 21.74; p<.001), race (f5,1148 = 6.10; p<.001), parent educational level (f5,1148 = 3.92; p= .002), age (f4,1149 = 7.70; p<.001), and grade level (f3,1150 = 10.82; p<.001). for gender (male, female, or other), the tukey post-hoc test showed higher test scores among females compared to males (η2=0.050; 95% ci, 0.032-0.068; tukey honestly significant difference (hsd), p<0.05). individuals of multiracial or biracial background scored higher than individuals of black/african american race (η2=0.059; 95% ci, 0.007-0.112; tukey hsd, p<0.05) and other (native american/alaskan native, ethnicity not listed, prefer not to answer) race (η2=0.064; 95% ci, 0.002-0.126; tukey hsd, p<0.05). whites/caucasians also had higher pre-test scores than hispanics/latinos (η2=0.031; 95% ci, 0.003-0.059; tukey hsd, p<0.05), blacks/african americans (η2=0.052; 95% ci, 0.017-0.087; tukey hsd, p<0.05), and individuals of other race (η2=0.057; 95% ci, 0.009-0.104; tukey hsd, p<0.05). with regards to parent education level, significant differences were only found between two categories: students who answered graduate degree (master’s, md, phd, etc.) had higher scores than those selecting prefer not to answer (η2=0.055; 95% ci, 0.008-0.102; tukey hsd, p<0.05). students aged 12-13 scored lower than students aged 14-15 (η2=0.043; 95% ci, 0.015-0.071; tukey hsd, p<0.05) and 16-17 (η2=0.060; 95% ci, 0.028-0.091; tukey hsd, p<0.05). students in grades 9-10 tended to outperform students in grades 5-6 (η2=0.052; 95% ci, 0.018-0.087; tukey hsd, p<0.05) and 7-8 (η2=0.039; 95% ci, 0.014-0.065; tukey hsd, p<0.05). students in grades 11-12 also scored higher than students in grades 5-6 (η2=0.060; 95% ci, 0.023-0.098; tukey hsd, p<0.05) and 7-8 (η2=0.047; 95% ci, 0.017-0.077; tukey hsd, p<0.05). table 1 summarizes the logistic regression results for selecting the correct versus incorrect answer for the true/false statement “without sun exposure, my body will not produce vitamin d.” black/african american students were at a greater odd of answering this question correctly than white/caucasian students (aor=1.56; 95% ci, 1.03-2.37; p-value=0.007). additionally, eleventh and twelve graders were at significantly greater odds of answering this question correctly than fifth or sixth graders (aor=3.41; 95% ci, 1.24-9.37; p-value= 0.04). 4 original article | dermatol pract concept. 2023;13(1):e2023014 and increase early diagnosis [21]. while this highlighted the importance of melanoma education, a pubmed search of “melanoma education” showed that there are only 23 results since 1983, as of august 2021, underscoring the lack of melanoma awareness education programs and research analyzing its efficacy. in this study, we implemented a melanoma education program designed by the john wayne cancer foundation in middle and high schools, with presentations delivered by health professions student volunteers. this study uses surveys adapted from a school-based melanoma education study that took place in houston and dallas in 2000, which found that students aged 16 and older scored 11 percentage points higher, on average, than those between 12-15 years on the melanoma pre-test [8]. the present study found table 2 summarizes the logistic regression results for selecting the correct versus incorrect answer for the true/false statement “melanoma is usually flat, not raised like a mosquito bite or a pimple.” students who were first-generation americans were less likely to select the correct answer, as compared to students who were not first-generation americans (aor=0.71; 95% ci, 0.55-0.92; p-value= 0.009). discussion a web-based education resource in switzerland gathered data on melanoma knowledge in association with disease development over 10 years, and found that education programs can statistically prevent melanoma, reduce mortality, table 1. multivariable logistic regression for selecting the correct versus incorrect answer for the true/false statement “without sun exposure, my body will not produce vitamin d.” variable aora (95% cib) p-value age 12-13 vs under 12 0.89 (0.35-2.28) 0.82 14-15 vs under 12 0.72 (0.24-2.16) 0.43 16-17 vs under 12 0.68 (0.20-2.28) 0.35 18+ vs under 12 0.98 (0.23-4.14) 0.70 gender male vs female 0.92 (0.70-1.20) 0.45 other vs female 0.49 (0.13-1.87) 0.33 race asian or pacific islander vs white or caucasian 1.20 (0.85-1.72) 0.15 black or african american vs white or caucasian 1.56 (1.03-2.37) 0.007* hispanic or latino vs white or caucasian 1.00 (0.70-1.44) 1.00 multiracial or biracial vs white or caucasian 0.86 (0.48-1.54) 0.53 other vs white or caucasian 0.62 (0.33-1.16) 0.06 first-generation american yes vs no 0.83 (0.64-1.07) 0.15 grade 11-12 vs 5-6 3.41 (1.24-9.37) 0.04* 7-8 vs 5-6 2.09 (1.03-4.27) 0.76 9-10 vs 5-6 2.19 (0.93-5.14) 0.58 highest parent education level bachelor’s degree vs low education 0.91 (0.56-1.48) 0.56 graduate degree (master’s, md, phd, etc.) vs low educationc 0.93 (0.59-1.48) 0.66 prefer not to answer vs low educationc 0.89 (0.46-1.73) 0.68 high educatione vs low educationc 1.04 (0.62-1.73) 0.72 intermediated education vs low educationc 1.14 (0.70-1.87) 0.31 aaor = adjusted odds ratio bci = confidence interval clow education includes the following categories: no schooling, some elementary school, completed elementary school, some middle school, some high school, some trade/vocational school, completed trade/vocational school dintermediate education includes the following categories: completed high school, associate degree ehigh education includes the following categories: some college, some graduate school *indicates statistical significance (significance level p < 0.05) original article | dermatol pract concept. 2023;13(1):e2023014 5 although melanoma of the skin is more prevalent among non-hispanic whites, survival has been poorer among ethnic minorities since the 1990s, and gaps are worsening over time. across all minorities, the disparity is growing in patients with localized disease. in patients with distant or regional disease, the disparity is increasing among hispanic patients  [23]. our study showed white/caucasian students tended to score higher than minorities such as hispanics/ latinos and blacks/african americans on the melanoma knowledge pre-test. similar findings were reported from a survey of boston adults, in which white race positively correlated with melanoma knowledge. additionally, immigrants and hispanics could less often define melanoma [24]. these results are corroborated by the present study, in which a similar trend: students aged 12 to 13 tended to score lower than students who were between 14 and 17 years old. grade level followed the same pattern as high school students (9th-12th grade) scored better than middle school students (5th-8th grade). on one of the most missed true/false questions, “without sun exposure, my body will not produce vitamin d,” eleventh and twelfth graders were nearly three and a half times more likely than fifth and sixth graders to answer this question correctly. this trend of increasing performance with age, found in houston and dallas both in 2000 and 2020-2021, suggests melanoma education programs should target younger students [8]. as sun exposure is cumulative [22], it is essential to expose students to information regarding skin cancer early and to bridge the knowledge gap between younger and older students. table 2. multivariable logistic regression for selecting the correct versus incorrect answer for the true/false statement “melanoma is usually flat, not raised like a mosquito bite or a pimple.” variable aora (95% cib) p-value age 12-13 vs under 12 2.10 (0.90-4.92) 0.12 14-15 vs under 12 1.46 (0.53-4.05) 0.99 16-17 vs under 12 1.26 (0.41-3.89) 0.50 18+ vs under 12 1.72 (0.43-6.80) 0.67 gender male vs female 1.07 (0.82-1.39) 0.62 other vs female 1.56 (0.49-5.00) 0.49 race asian or pacific islander vs white or caucasian 0.97 (0.69-1.37) 0.89 black or african american vs white or caucasian 0.90 (0.59-1.37) 0.58 hispanic or latino vs white or caucasian 1.08 (0.75-1.54) 0.54 multiracial or biracial vs white or caucasian 1.04 (0.59-1.81) 0.83 other vs white or caucasian 0.95 (0.54-1.67) 0.86 first-generation american yes vs no 0.71 (0.55-0.92) 0.009* grade 11-12 vs 5-6 1.06 (0.41-2.80) 0.57 7-8 vs 5-6 0.80 (0.42-1.56) 0.41 9-10 vs 5-6 0.84 (0.38-1.88) 0.58 highest parent education level bachelor’s degree vs low educationc 0.62 (0.38-0.99) 0.17 graduate degree (master’s, md, phd, etc.) vs low educationc 0.82 (0.52-1.28) 0.38 prefer not to answer vs low educationc 0.54 (0.28-1.03) 0.16 high educatione vs low educationc 0.80 (0.48-1.31) 0.61 intermediate educationd vs low educationc 0.75 (0.46-1.22) 0.91 aaor = adjusted odds ratio bci = confidence interval clow education includes the following categories: no schooling, some elementary school, completed elementary school, some middle school, some high school, some trade/vocational school, completed trade/vocational school dintermediate education includes the following categories: completed high school, associate degree ehigh education includes the following categories: some college, some graduate school *indicates statistical significance (significance level p < 0.05) 6 original article | dermatol pract concept. 2023;13(1):e2023014 milbrey parke, louisa liu, tiffaney tran, hanqing shang, joanne jacob, rohit gupta, tejas joshi, and xiaoman yu for their role in data collection. funding for the inaugural chapter of john wayne cancer foundation’s block the blaze program at baylor college of medicine was provided by the texas medical association alliance. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin. 2020;70(1):7–30. pmid: 31912902. 2. paulson kg, gupta d, kim ts, et al. age-specific incidence of melanoma in the united states. jama dermatol. 2020;156(1):57–64. pmid: 31721989. 3. wu yp, parsons bg, nagelhout e, et al. a four-group experiment to improve western high school students’ sun protection behaviors. transl behav med. 2019;9(3):468–79. pmid: 31094440. 4. mccarthy wh. the australian experience in sun protection and screening for melanoma. journal of surgical oncology. 2004;86(4):236–45. doi: 10.1002/jso.20086. 5. tabbakh t, volkov a, wakefield m, dobbinson s. implementation of the sunsmart program and population sun protection behaviour in melbourne, australia: results from cross-sectional summer surveys from 1987 to 2017. plos medicine. 2019;16(10):e1002932. doi: 10.1371/journal.pmed.1002932. 6. gordon lg, rowell d. health system costs of skin cancer and cost-effectiveness of skin cancer prevention and screening: a systematic review. eur j cancer prev. 2015;24(2):141–9. pmid: 25089375. 7. mermelstein rj, riesenberg la. changing knowledge and attitudes about skin cancer risk factors in adolescents. health psychol. 1992;11(6):371–6. pmid: 1286656. 8. lucci a, citro hw, wilson l. assessment of knowledge of melanoma risk factors, prevention, and detection principles in texas teenagers. j surg res. 2001;97(2):179–83. pmid: 11341796. 9. ma f, collado-mesa f, hu s, kirsner rs. skin cancer awareness and sun protection behaviors in white hispanic and white non-hispanic high school students in miami, florida. arch dermatol. 2007;143(8):983–8. pmid: 17709656. 10. kamell jm, rietkerk w, lam k, et al. medical students educate teens about skin cancer: what have we learned? j cancer educ. 2011;26(1):153–5. pmid: 20422477. 11. gillespie hs, watson t, emery jd, lee aj, murchie p. a questionnaire to measure melanoma risk, knowledge and protective behaviour: assessing content validity in a convenience sample of scots and australians. bmc med res methodol. 2011;11:123. pmid: 21867531. 12. seité s, del marmol v, moyal d, friedman aj. public primary and secondary skin cancer prevention, perceptions and knowledge: an international cross-sectional survey. j eur acad dermatol venereol. 2017;31(5):815–20. pmid: 28045207. 13. maarouf m, zullo sw, decapite t, shi vy. skin cancer epidemiology and sun protection behaviors among native americans. j drugs dermatol. 2019;18(5):420–3. pmid: 31141849. 14. kelati a, baybay h, atassi m, et al. skin cancer knowledge and attitudes in the region of fez, morocco: a cross-sectional study. bmc dermatology. 2017;17(1):2. doi: 10.1186/ s12895-017-0055-8. first-generation americans were less likely to answer the true/false statement “melanoma is usually flat, not raised like a mosquito bite or a pimple” correctly. one unique finding in the present study was that black/african american students were more likely to answer the true/false statement “without sun exposure, my body will not produce vitamin d” correctly, as compared to white students. research has shown greater melanoma mortality rates among individuals of low socioeconomic status due to a lack of access to care and early detection [25,26]. however, group differences in scores between students stratified by parental education level were not as pronounced as other demographic factors. nonetheless, remediation of generally poorer melanoma outcomes and general knowledge among disadvantaged populations and minorities may benefit from school-based education programs to increase awareness of melanoma and sun-protective behaviors. with regards to gender, females outperformed males on the melanoma knowledge pre-test. as women are at a lower odds of developing skin cancer than men in the us, males may especially benefit from skin cancer education in schools [27]. although this study did not feature a large sample size of gender minorities, literature has shown a disproportionate skin cancer burden among gender and sexual minorities, as well as unique risk factors for skin cancer in these populations [28,29]. conclusions overall, on a melanoma education knowledge test given to middle and high schoolers before a skin cancer awareness presentation, this study found lower scores among racial minorities and students of younger ages and lower grade levels. students who were black, older, or who were not first-generation americans were more likely to select the correct answer on a subset of the most missed questions on the test. limitations of this study include self-reported data by the students and general cross-sectional design limitations, as well as a sample limited to schools where baylor college of medicine students were able to offer presentations. future directions include analyzing the results of the post-presentation surveys from the same educational program to determine program efficacy. acknowledgements we would like to thank dr. anthony lucci, lauren fraga, mayra de la cruz, yasmin khalfe and the john wayne cancer foundation for their guidance and support in conducting this study. we would also like to acknowledge kristiana nasto, amna bashir, rujman khan, sahifah ansari, rachel stroh, nicole walters, ebubechi adindu, ruth mizu, original article | dermatol pract concept. 2023;13(1):e2023014 7 23. qian y, johannet p, sawyers a, et al. the ongoing racial disparities in melanoma: an analysis of the surveillance, epidemiology, and end results database (1975–2016). j am acad dermatol. 2021;84(6):1585–93. pmid: 32861710. 24. sanchez dp, maymone mbc, mclean eo, et al. racial and ethnic disparities in melanoma awareness: a cross-sectional survey. j am acad dermatol. 2020;83(4):1098–103. [pmid: 32380221]. 25. sitenga jl, aird g, ahmed a, walters r, silberstein pt. socioeconomic status and survival for patients with melanoma in the united states: an ncdb analysis. int j dermatol. 2018;57(10):1149–56. pmid: 29736922. 26. abdel-rahman o. prognostic impact of socioeconomic status among patients with malignant melanoma of the skin: a population-based study. j dermatolog treat. 2020;31(6):571–5. pmid: 31418320. 27. singer s, tkachenko e, hartman ri, mostaghimi a. gender identity and lifetime prevalence of skin cancer in the united states. jama dermatol. 2020;156(4):458–60. pmid: 32049307. 28. yeung h, braun h, goodman m. sexual and gender minority populations and skin cancer-new data and renewed priorities. jama dermatol. 2020;156(4):367–9. [pmid: 32049300]. 29. marks dh, arron st, mansh m. skin cancer and skin cancer risk factors in sexual and gender minorities. dermatol clin. 2020;38(2):209–18. pmid: 32115130. 15. robinson jk, rademaker aw, sylvester ja, cook b. summer sun exposure: knowledge, attitudes, and behaviors of midwest adolescents. prev med. 1997;26(3):364–72. pmid: 9144761. 16. nagelhout es, parsons bg, haaland b, et al. differences in reported sun protection practices, skin cancer knowledge, and perceived risk for skin cancer between rural and urban high school students. cancer causes control. 2019;30(11):1251–8. pmid: 31522321. 17. block the blaze. john wayne cancer foundation content site. accessed july 17, 2021. https://johnwayne.org/pages/ block-the-blaze. 18. us environmental protection agency. sun safety monthly average uv index. us environmental protection agency. 2015. accessed 14 october 2020. https://www.epa.gov/sunsafety /sun-safety-monthly-average-uv-index. 19. population clock. the united states census bureau. accessed 17 july 2021. https://www.census.gov/popclock/. 20. faul f, erdfelder e, lang a-g, buchner a. g*power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. behav res methods. 2007;39(2):175–91. pmid: 17695343. 21. meyer sr, rudzki-senet a, emde n-l, et al. results of a 10-year web-based health promotion campaign against skin cancer in switzerland. eur j dermatol. 2021. pmid: 34405807. 22. sample a, he y-y. mechanisms and prevention of uv-induced melanoma. photodermatol photoimmunol photomed. 2018;34(1): 13–24. pmid: 28703311. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022133 1 dermatology practical & conceptual dermoscopy as a supportive tool to differentiate lichen amyloidosus from clinical mimickers emilia n. cohen sabban1, enzo errichetti2, horacio a. cabo1, esteban maronna3 1 dermatology department “instituto de investigaciones médicas a. lanari”, university of buenos aires, argentina 2 institute of dermatology, “santa maria della misericordia” university hospital, udine, italy 3 histopathology department, hospital f.j. muñiz, buenos aires, argentina citation: sabban enc, errichetti e, cabo ha, maronna e. dermoscopy as a supportive tool to differentiate lichen amyloidosus from clinical mimickers. dermatol pract concept. 2022;12(3):e2022133. doi: https://doi.org/10.5826/dpc.1203a133 accepted: december 2, 2021; published: july 2022 copyright: ©2022 sabban et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: emilia n. cohen sabban, dermatology department “instituto de investigaciones médicas a. lanari”, university of buenos aires, argentina, e-mail: emicohensabban@gmail.com case presentation a 52-year-old woman presented with a 5-year history of itchy hyperkeratotic brownish papules on the legs (figure 1a) dermoscopically typified by central brown globules surrounded by a pigmented halo (figure 1b). histology showed compact ortho-hyperkeratosis, irregular acanthosis, and amorphous eosinophilic material in the upper dermis which displayed positive congo red staining and a green fluorescence under polarized microscopy (figure 1c), consistently with a diagnosis of lichen amyloidosis. teaching point dermoscopy may be of aid in recognizing lichen amyloidosis by showing a peculiar pigmentary pattern resulting from the presence of melanin granules within amyloid deposition in dermal papilla (central globule) and basal layer hyperpigmentation/dermal pigment incontinence (peripheral pigmentation) [1]. indeed, such dermoscopic clues are different from those visible in similar conditions, ie, pretibial pruritic papular dermatitis (dotted/globular vessels over a pinkish-white background) (figure 1d), lichen myxedematous (white structureless areas) (figure 1e), and lichen planus (wickham striae) (figures 1f) [1,2]. 2 image letter | dermatol pract concept. 2022;12(3):e2022133 references 1. errichetti e, lallas a. other infiltrative conditions. in: lallas a, errichetti e, ioannides d, eds. dermoscopy in general dermatology. 1st ed. boca raton, fl: crc press; 2018:2-46. figure 1. (a) clinical examination shows hyperkeratotic brownish papules on the legs (better seen in the inset). (b) dermoscopically characterized by central brown globules surrounded by a pigmented halo (magnification in the inset). (c) histology (h&e; 100x) reveals compact orthohyperkeratosis, irregular acanthosis, and amorphous eosinophilic material in the upper dermis which is typified by a green fluorescence under polarized microscopy (inset). (d-f) dermoscopic features of the main clinical mimickers of lichen amyloidosus, namely, pretibial pruritic papular dermatitis (dotted vessels over a pinkish-white background – magnification in the upper right inset) (d), lichen myxedematous (white structureless areas) (e), and lichen planus (wickham striae) (f). 2. errichetti e, stinco g. dermoscopy for improving the diagnosis of pretibial pruritic papular dermatitis. australas j dermatol. 2018;59(1):e74-e75. doi: 10.1111/ajd.12610. pmid: 28636138. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022081 1 should mammography be a prerequisite prior to initiation of biological agents in patients with psoriasis? funda tamer1, ayla gulekon1 1 gazi university school of medicine department of dermatology, ankara, turkey key words: biological agents, breast cancer, mammography, psoriasis citation: tamer f, gulekon a. should mammography be a prerequisite prior to initiation of biological agents in patients with psoriasis? dermatol pract concept. 2022;12(2):e2022081. doi: https://doi.org/10.5826/dpc.1202a81 accepted: september 21, 2021; published: april 2022 copyright: ©2022 tamer et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: funda tamer, assoc. prof. md, gazi university school of medicine department of dermatology, ankara, turkey. e-mail: fundatmr@yahoo.com introduction: psoriasis patients may be susceptible to malignancy due to chronic inflammation. moreover, biological agents which are used in the treatment of psoriasis might increase the risk of malignancy due to their immunosuppressive effect. objectives: we evaluated the mammography results of female patients with psoriasis aged over 40 years before the initiation of biological agent treatment. we aimed to determine whether breast cancer screening with mammography should be a prerequisite before the initiation of biological agent treatment for psoriasis. methods: between april 2019 and march 2021, medical records of female psoriasis patients aged over 40 years were reviewed retrospectively. results: this study included 42 female psoriasis patients (mean age: 53.52 ± 7.09). bi-rads score was 2 in 18 (42.9%) patients, 1 in 13 (31%) patients, 3 in 9 (21.4%) patients and 4a in 1 (2.4%) patient. isodense masses were detected in 10 (23.8%) patients, while 6 (14.3%) patients had intramammary lymph nodes. mammography revealed microcalcifications in 6 (14.3%) patients, macrocalcifications in 1 (2.4%) patient and a hamartoma in 1 (2.4%) patient. isodense masses, calcifications and intramammary lymph nodes were associated with long disease duration (> 10 years). intramammary lymph nodes were more common in patients treated with biological agents previously compared to biologic-naive patients. conclusions: we suggest that female patients over 40 years, especially those who had a long disease duration, family history of breast cancer and previous history of treatment with biological agents should undergo mammography before the initiation of biological agents for the treatment of psoriasis. abstract 2 original article | dermatol pract concept. 2022;12(2):e2022081 introduction psoriasis is a chronic inflammatory skin disorder accompanied by various comorbidities such as psoriatic arthiritis, metabolic syndrome and cardiovascular disease [1]. since chronic inflammation has been implicated in the etiopathogenesis of both psoriasis and malignancy, it has been suggested that psoriasis might be associated with increased risk of malignancy. development of cancer was reported 1.18 times more common in patients with psoriasis compared to individuals without psoriasis [2]. furthermore, mortality rates were elevated in accordance with the severity of psoriasis. malignancies such as squamous cell carcinoma, lymphoma, colorectal, pancreatic, kidney, liver, esophageal and laryngeal cancer have been related to psoriasis [2]. high prevalence of breast cancer has also been reported in patients with psoriasis [3]. however, relationship between psoriasis and the risk for the development of malignancy remains controversial [4]. on the other hand, increased use of biological agents in the treatment of psoriasis leads to concerns about whether biological agents increase the risk of malignancy or not [5]. it has been suggested that tumor necrosis factor-α (tnf-α) inhibitors, anti-interleukin (il)12/il-23 and anti-il-17a antibodies might increase the risk of malignancies due to their immunosuppressive effects [6]. for instance, use of tnf-α inhibitors such as etanercept, adalimumab and infliximab longer than 12 months has been implicated in increased risk for malignancy [5]. development of breast cancer was reported in a patient following systemic psoriasis treatment with conventional therapy, adalimumab and ustekinumab [6]. it has been suggested that breast cancer was one of the most commonly detected malignancy in patients who received ustekinumab [7]. biological agent treatment is not recommended in patients who had an active malignancy within the last five years [8]. evaluation of patients with psoriasis before and throughout the biological agent treatment according to their medical history of cancer and risk for the development of cancer is crucial [9]. therefore, patients with psoriasis receiving biological agents should be encouraged to participate in national cancer screening programmes [9,10]. however, it has been reported that patients with psoriasis who were treated with biological agents did not undergo recommended tests for breast cancer screening adequately despite increased risk for malignancy [11]. objectives within this study, we evaluated the mammography results of female patients with psoriasis aged over 40 years before the initiation of biological agent treatment in order to detect premalignant and malignant breast lesions. we aimed to reveal whether breast cancer screening with mammography should be a prerequisite prior to biological agent treatment for psoriasis or not. methods between april 2019 and march 2021, medical records of the female psoriasis patients aged over 40 years who underwent mammography before the initiation of biological agent treatment were reviewed retrospectively. gazi university ethics committee approval was obtained for this study (approval number: 2021-412). patients who had an increased risk for the development of breast cancer such as previous breast cancer, radiation exposure to the chest, high hereditary risk for breast cancer, patients with ovarian and endometrial malignancies and immunocompromised patients were excluded from the study. mammography was routinely performed in female psoriasis patients over the age of 40 years before treatment with biological agents for screening premalignant or malignant lesions of the breast. breast imaging-reporting and data system (bi-rads) [12], breast density categories, masses, lymph nodes, calcifications and localization of the lesions were evaluated. statistical analysis was performed using spss version 20.0. data were represented as mean ± standard deviation (sd) or median for quantitative variables, counts and percentage for categorical variables. differences between two groups were evaluated by chi-square test. p < 0.05 was considered as statistically significant. results this study included 42 female patients with a mean age of 53.52 ± 7.09 (range: 41-65 years). thity-two (76.2%) patients had psoriasis vulgaris, 5 (11.9%) patients had palmoplantar psoriasis and 5 (11.9%) patients had generalized pustular psoriasis (table 1). the mean disease duration was 17.07 ± 10.99 years (range: 1-47). twenty-eight (66.7%) patients did not complain of joint pain, whereas 14 (33.3%) patients had psoriatic arthritis. past medical history of 16 (38.1%) patients was unremarkable. ten (23.8%) patients had hypertension, 7 (16.7%) patients had both hypertension and type 2 diabetes, 5 (11.9%) patients had type 2 diabetes, 2 (4.8%) had hypothyroidism, 1 (2.4%) had coronary artery disease and 1 (2.4%) had granulomatous mastitis. only 1 (2.4%) patient had a family history of breast cancer. forty-one (97.6%) patients were treated with conventional systemic treatments such as methotrexate, cyclosporine and acitretin, 7 (16.6%) patients were treated with phototherapy and 19 (45.2%) patients were treated with biological agents, previously. twenty-three (54.8%) patients original article | dermatol pract concept. 2022;12(2):e2022081 3 isodense breast masses ranged between 5 to 14 mm. furthermore, mammography revealed microcalcifications in 6 (14.3%) patients, macrocalcifications in 1 (2.4%) patient, both microcalcifications and macrocalcifications in 1 (2.4%) patient and a hamartoma in 1 (2.4%) patient. intramammary lymph nodes were observed in 6 (14.3%) patients, whereas mamography did not reveal an intramammary lymph node in 36 (85.7%) patients. four (9.5%) patients had 1 intramammary lymph node, 1 (2.4%) patient had 2 and 1 (2.4%) patient had multiple intramammary lymph nodes, respectively. intramammary lymph nodes were localized on the left breast in 4 (9.5%) patients and on the right breast in 1 (2.4%) patient. intramammary lymph nodes were detected bilaterally in 1 (2.4%) patient. moreover, in 1 (2.4%) patient mammography recommended further evaluation of an intramammary lymph node on the right breast, which was revealed to be reactive lymph node without an atypical cell. the disease duration was less than 10 years in 4 (9.5%) patients with an isodense mass of the breast and more than 10 years in 6 (14.3%) patients with an isodense mass (p = 0.47). the disease duration was less than 10 years in 1 (2.4%) patient with calcifications of the breast and more than 10 years in 7 (16.7%) patients with calcifications (p = 0.21). the disease duration was less than 10 years in 1 (2.4%) patient with an intramammary lymph node and more than 10 years in 5 (11.9%) patients with intramammary lymph nodes (p = 0.41). were biologicnaïve. among the patients who were treated with biological agents previously, 13 (31%) patients received anti-tnf-α agents such as infliximab, adalimumab, etanercept and certolizumab pegol, 5 (11.9%) patients received both anti-tnf-α agents and ustekinumab, and 1 (2.4%) patient received ustekinumab. mammographic breast density was type b in 24 (57.1%) patients, type c in 13 (31%) patients, type a in 4 (9.5%) patients and type d in 1 (2.4%) patient. bi-rads score was 2 in 18 (42.9%) patients, 1 in 13 (31%) patients, 3 in 9 (21.4%) patients and bi-rads score was 4a in 1 (2.4%) patient. no statistically significant association was observed between bi-rads score and disease duration or previous biological agent treatment (p = 0.51 and p = 0.65, respectively). the patient with bi-rads 4a had microcalcifications with loose clusters in some areas, and mild pleomorphism in the upper outer quadrant of the left breast which was revealed to be nodular adenosis with columnar cell change. isodense masses of the breast were observed in 10 (23.8%) patients whereas mammography of 32 (76.2%) patients did not reveal a breast mass. isodense masses were localized on the left breast in 5 (11.9%) patients and on the right breast in 2 (4.8%) patients. moreover, in 3 (7.1%) patients, isodense masses were localized on the breasts bilaterally. seven (16.7%) patients had 1 isodense mass, 3 (7.1%) patients had multiple isodense masses. largest size of the table 1. characteristics and mammography results of female psoriasis patients who underwent mammography before the initiation of biological agent treatment patients with psoriasis (n = 42) mean age (years, ± sd) 53.52 ± 7.09 (range: 41-65) mean disease duration (years, ± sd) 17.07±10.99 (range:1-47) psoriatic arthritis patients with arthritis 14 (33.3) patients without joint pain 28 (66.7) comorbidities, n (%) patients with comorbidities 26 (61.9) patients without comorbidities 16 (38.1) psoriasis type, n (%) pv 32 (76.2) ppp 5 (11.9) gpp 5 (11.9) previous treatment, n (%) conventional treatment 41 (97.6) phototherapy 7 (16.6) biological treatment 19 (45.2) breast density type, n (%) a 4 (9.5) b 24 (57.1) c 13 (31) d 1 (2.4) bi-rads score, n (%) 1 13 (31) 2 18 (42.9) 3 9 (21.4) 4a 1 (2.4) isodense mass, n (%) patients with im 10 (23.8) patients without im 32 (76.2) localization of im, n (%) left breast 5 (11.9) right breast 2 (4.8) bilateral 3 (7.1%) intramammary lymph node patients with iln 6 (14.3) patients without iln 36 (85.7) localization of iln, n (%) left breast 4 (9.5) right breast 1 (2.4) bilateral 1 (2.4) other lesions, n (%) microcalcifications 6 (14.3) macrocalcifications 1 (2.4) both micro and macrocalcifications 1 (2.4) hamartoma 1 (2.4) bi-rads = breast imaging-reporting and data system; gpp = generalized pustular psoriasis; iln = intramammary lymph node; im = isodense mass; ppp = palmoplantar psoriasis; pv = psoriasis vulgaris; sd = standard deviation. 4 original article | dermatol pract concept. 2022;12(2):e2022081 it may also be stopped in accordance with the agreement of both the physician and the patient [15]. however, us preventive services task force recommends biennial mammography screening between the ages of 50 to 74 years [16,17]. moreover, national comprehensive cancer network recommends to start mammography at the age of 40 years and to repeat it every year [15]. breast cancer has been associated with psoriasis [18]. it has been suggested that the risk of cancer might increase in patients with psoriasis due to chronic inflammation [19]. elevated incidence of psoriasis has also been reported among patients with breast cancer [20]. in addition, there are concerns that biological agents may be associated with cancer development based on their effect on immune system [21]. since biological treatment has been associated with malignancy, it is mandatory to exclude malignancies before the initiation of biological agents and to monitor patients for cancer development during treatment [22]. within this study, mammography results of patients with psoriasis over the age of 40 years were evaluated before the initiation of biological agent treatment. most of the patients (42.9%) had bi-rads score 2, which indicated benign findings [12]. however, bi-rads score 3, which indicated probably benign lesions requiring close follow-up was detected in 21.4% of the patients [12]. furthermore, 1 patient had bi-rads score 4a, which indicated 2% to 10% of risk of malignancy [12]. isodense masses were detected in 23.8%, microcalcifications or macrocalcifications in 19.1% and intramammary lymph nodes in 14.3% patients. isodense masses, calcifications and intramammary lymph nodes were more common in patients with history of psoriasis longer than 10 years. however, no statistically significant difference was observed between disease duration and the frequency of isodense masses, calcifications or intramammary lymph nodes (p = 0.47, p = 0.21, p = 0.41, respectively). on the other hand, intramammary lymph nodes were more common in patients who were previously treated with biological agents compared to biologicnaïve patients (p = 0.04). in addition, a patient with family history of both psoriasis and breast cancer who had already been diagnosed with breast cancer while receiving adalimumab was detected. therefore, we suggest that female patients over 40 years, especially those who had a long disease duration, family history of breast cancer and previous history of treatment with biological agents, should undergo mammography screening before the initiation of biological agents for the treatment of psoriasis. the limitations of this study were small sample size and lack of a control group. british association of dermatologists recommends the evaluation of psoriasis patients before the treatment with biological agents according to existing cancer or future malignancy risk and thus it directs patients to attend the national five (11.9%) patients with an isodense mass of the breast were treated with biological agents, previously and 5 (11.9%) patients with an isodense mass were biologic naïve (p = 0.72). three (7.1%) patients with calcifications were treated with biological agents previously, however, 5 (11.9%) patients with calcifications were biologicnaïve (p = 0.62). five (11.9%) patients with an intramammary lymph node were treated with biological agents previously and 1 (2.4%) patient with an intramammary lymph node was biologicnaïve (p = 0.04). in addition, a 58-year-old female patient with a 30-year history of psoriasis vulgaris and psoriatic arthritis who had already been diagnosed with breast cancer was determined. family history of the patient was remarkable for both psoriasis and breast cancer. the patient was treated with methotrexate, cyclosporine, acitretin, puva and adalimumab, previously. after 10 months of adalimumab treatment, the patient was diagnosed with grade 1 invasive ductal carcinoma, therefore adalimumab treatment was stopped. conclusions breast cancer is the most frequently detected malignancy and the second most frequent reason of malignancy related mortality in women globally. breast cancer is an insidious disease and it is usually detected by routine screening procedures [13]. however, recommendations of major guidelines for breast cancer screening in the united states differ about the initiation age of breast cancer screening with mammography, screening intervals and when to discontinue mammography [14-17]. according to the american cancer society, individuals without medical history of breast cancer, brca1/brca2 gene mutation and former radiation treatment to the chest at the age of 10 to 30 years are at average risk for breast cancer. the american cancer society recommends to start breast cancer screening with mammography for women with average breast cancer risk at 45 years of age [14]. however, women aged 40 to 44 years may also undergo mammography if they request it. the american cancer society recommends to repeat mammography between the ages of 45 to 54 years annually and over the age of 55 years biennially. however, women aged 55 years and over may undergo mammography annually if they request. breast cancer screening should also proceed in healthy individuals with life expectancy longer than 10 years [14]. nevertheless, the american college of obstetricians and gynecologists recommends to start mammography at the age of 40 years, however, screening may be initiated between the ages of 40 to 49 years based on shared decision of the physician and the patient. individuals should repeat mammography every year or biennially. mammography is not required in women older than 75 years, however, original article | dermatol pract concept. 2022;12(2):e2022081 5 dermatol. 2019;155(12):1390-1403. doi: 10.1001/jamadermatol.2019.3056. pmid: 31617868;.pmcid: pmc6802036. 3. kimball ab, sundaram m, cloutier m, et al. increased prevalence of cancer in adult patients with psoriasis in the united states: a claims based analysis. j drugs dermatol. 2018;17(2):180-186. pmid: 29462226. 4. pouplard c, brenaut e, horreau c, et al. risk of cancer in psoriasis: a systematic review and meta-analysis of epidemiological studies. j eur acad dermatol venereol. 2013;27(suppl 3):36-46. doi: 10.1111/jdv.12165. pmid: 23845151. 5. fiorentino d, ho v, lebwohl mg, et al. risk of malignancy with systemic psoriasis treatment in the psoriasis longitudinal assessment registry. j am acad dermatol. 2017;77(5):845-854. doi: 10.1016/j.jaad.2017.07.013. pmid: 28893407. 6. morizane s, sugimoto s, motoki t, katayama n, omori m, iwatsuki k. a case of psoriasis complicated by breast cancer after systemic treatments including biologics. acta med okayama. 2018;72(2):185-187. doi: 10.18926/amo/55860. pmid: 29674768. s 7. subhadarshani s, yusuf n, elmets ca. il-23 and the tumor microenvironment. adv exp med biol. 2021;1290:89-98. doi: 10.1007/978-3-030-55617-4_6. pmid: 33559857. 8. poelman sm, keeling cp, metelitsa ai. practical guidelines for managing patients with psoriasis on biologics: an update. j cutan med surg. 2019;23(suppl 1):3-12. doi: 10.1177/1203475418811347. pmid: 30789012. 9. smith ch, yiu zzn, bale t, et al. british association of dermatologists guidelines for biologic therapy for psoriasis 2020: a rapid update. br j dermatol. 2020;183(4):628-637. doi: 10.1111/bjd.19039. pmid: 32189327. 10. menter a, strober be, kaplan dh, et al. joint aad-npf guidelines of care for the management and treatment of psoriasis with biologics. j am acad dermatol. 2019;80(4):1029-1072. doi: 10.1016/j.jaad.2018.11.057. pmid: 30772098. 11. barbieri js, wang s, ogdie ar, shin db, takeshita j. age-appropriate cancer screening: a cohort study of adults with psoriasis prescribed biologics, adults in the general population, and adults with hypertension. j am acad dermatol. 2021;84(6):16021609. doi: 10.1016/j.jaad.2020.10.045. pmid: 33470207. 12. magny sj, shikhman r, keppke al. breast imaging reporting and data system. 2021 aug 31. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2022. pmid: 29083600. 13. alkabban fm, ferguson t. breast cancer. 2021 aug 7. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2022. pmid: 29493913. 14. oeffinger kc, fontham et, etzioni r, et al. breast cancer screening for women at average risk: 2015 guideline update from the american cancer society. jama. 2015;314(15):1599-1614. doi: 10.1001/jama.2015.12783. pmid: 26501536. pmcid: pmc4831582. 15. practice bulletin number 179: breast cancer risk assessment and screening in average-risk women. obstet gynecol. 2017;130(1):116. doi: 10.1097/aog.0000000000002158. pmid: 28644335. 16. us preventive services task force. screening for breast cancer: u.s. preventive services task force recommendation statement. ann intern med. 2009;151(10):716-726, w-236. doi: 10.7326/00034819-151-10-200911170-00008. pmid: 19920272. 17. siu al. screening for breast cancer: u.s. preventive services task force recommendation statement. ann intern med. 2016;164(4): 279-296. doi: 10.7326/m15-2886. pmid: 26757170. cancer screening programmes [9]. concerning with cancer and biological agents, joint american academy of dermatology-national psoriasis foundation (aad-npf) guideline recommends patients to attend current and age-appropriate cancer screening [10,23]. european s3-guideline suggests to perform clinical examination during the treatment of psoriasis with adalimumab, etanercept, infliximab and secukinumab [24,25]. moreover, japanese guidance for use of biologics for psoriasis recommends to collect medical history of malignancy from patients with psoriasis before the initiation of biological agent treatment [26]. guidelines for the treatment of psoriasis with biological agents recommend to assess patients with medical history and physical examination to exclude malignancy [9,10,2426]. however, british association of dermatologists guidelines for biologic therapy for psoriasis and joint aad-npf point out the importance of the attendance of psoriasis patients to the national cancer screening programmes [9,10]. in the light of this information, there is no consensus on breast cancer screening guidelines regarding the necessity of clinical breast examination, initiation or cessation age of mammography and screening intervals [14-17]. interestingly, the american cancer society does not recommend clinical breast examination. however, american college of obstetricians and gynecologists and national comprehensive cancer network recommend clinical breast examination every 1 to 3 years in women aged 25-39 years and every year in women aged over 40 years [14,15]. moreover, the american cancer society and american college of obstetricians and gynecologists stated that initiation or cessation age and screening intervals of mammography might be determined based on the preference of patients who had an average risk for breast cancer [14,15]. since breast cancer is the most common malignancy in women, mammography should be considered as a prerequisite prior to initiation of biological agents in female patients with psoriasis. discrepancies between breast cancer screening guidelines may lead psoriasis patients to non-adherence with cancer screening recommendations. therefore, patients with psoriasis who undergo treatment with biological agents should be informed in detail about mamography screening intervals, which should also be included within psoriasis treatment guidelines. references 1. kovitwanichkanont t, chong ah, foley p. beyond skin deep: addressing comorbidities in psoriasis. med j aust. 2020;212(11):528-534. doi: 10.5694/mja2.50591. 10. pmid: 32388913. 2. trafford am, parisi r, kontopantelis e, griffiths cem, ashcroft dm. association of psoriasis with the risk of developing or dying of cancer: a systematic review and meta-analysis. jama 6 original article | dermatol pract concept. 2022;12(2):e2022081 18. rademaker m, rubel dm, agnew k, et al. psoriasis and cancer. an australian/new zealand narrative. australas j dermatol. 2019;60(1):12-18. doi: 10.1111/ajd.12889. pmid: 29992535. 19. chiesa fuxench zc, shin db, ogdie beatty a, gelfand jm. the risk of cancer in patients with psoriasis: a population-based cohort study in the health improvement network. jama dermatol. 2016;152(3):282-920. doi: 10.1001/jamadermatol.2015.4847. pmid: 26676102. pmcid: pmc5273859.20. 20. yang h, brand js, li j, et al. risk and predictors of psoriasis in patients with breast cancer: a swedish population-based cohort study. bmc med. 2017;15(1):154. doi: 10.1186/s12916-0170915-4. pmid: 28797265. pmcid: pmc5553678. 21. peleva e, exton ls, kelley k, kleyn ce, mason kj, smith ch. risk of cancer in patients with psoriasis on biological therapies: a systematic review. br j dermatol. 2018;178(1):103-113. doi: 10.1111/bjd.15830. pmid: 28722163. 22. wolinsky c, lebwohl m. biologic therapy and the risk of malignancy in psoriasis. psoriasis forum. 2011;17(4):238-253. doi: 10.1177/247553031117a00401. 23. menter a, gelfand jm, connor c, et al. joint american academy of dermatology-national psoriasis foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. j am acad dermatol. 2020;82(6):1445-1486. doi: 10.1016/j.jaad.2020.02.044. pmid: 32119894. 24. nast a, spuls pi, van der kraaij g, et al. european s3-guideline on the systemic treatment of psoriasis vulgaris update apremilast and secukinumab edf in cooperation with eadv and ipc. j eur acad dermatol venereol. 2017;31(12):1951-1963. doi: 10.1111/jdv.14454. pmid: 28895202. 25. pathirana d, ormerod ad, saiag p, et al. european s3-guidelines on the systemic treatment of psoriasis vulgaris. j eur acad dermatol venereol. 2009(suppl 2);23:1-70. doi: 10.1111/j.14683083.2009.03389.x. pmid: 19712190. 26. saeki h, terui t, morita a, et al. japanese guidance for use of biologics for psoriasis (the 2019 version). j dermatol. 2020;47(3):201-222. doi: 10.1111/1346-8138.15196. pmid: 31916326. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2022;12(03):e2022100 1 dermoscopy for cutaneous melanoma: under the eye of both the dermatologist and the legal doctor vittorio bolcato1, andrea michelerio2,3 1 department of public health, experimental and forensic medicine, forensic medicine unit, university of pavia, pavia, italy 2 dermatology clinic, fondazione irccs policlinico san matteo, piazzale golgi, pavia, italy 3 department of clinical-surgical, diagnostic and pediatric sciences, university of pavia, pavia, italy citation: bolcato v, michelerio a. dermoscopy for cutaneous melanoma: under the eye of both the dermatologist and the legal doctor. dermatol pract concept. 2022;12(03):e2022100. doi: https://doi.org/10.5826/dpc.1203a100 accepted: october 31, 2021; published: july 2022 copyright: ©2022 bolcato et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrea michelerio, md, dermatology clinic, fondazione irccs policlinico san matteo, piazzale golgi, 19, and department of clinical-surgical, diagnostic and pediatric sciences, university of pavia, 27100, pavia, italy. e-mail: andrea.michelerio01@ universitadipavia.it worldwide, melanoma is the 20th most common cancer, with 287,723 estimated new cases (1.6% of all cancers) and 60,712 related deaths (0.6% of all cancer deaths) in 2018, and a five-year prevalence of 965,623 cases [1]. cutaneous melanoma (cm) is by far the most common melanoma subtype and a potentially fatal disease. early recognition is of utmost importance to improve the prognosis, since if melanoma is diagnosed at noninvasive stage, the patient will be treated by excision of the primary tumor, but if melanoma becomes invasive, the chance of recovery decreases as invasion thickness increases [2]. given its dramatic rise in incidence, its predilection for middle-aged patients, and its ability to masquerade as a benign lesion, melanoma is easily misdiagnosed, providing a basis for malpractice claims [3,4]. dermatoscopy, commonly referred as dermoscopy, is a noninvasive technique allowing microscopic visualization of subsurface skin structure not visible to the naked eye [5]. a trained user, through a hand-held microscope, equipped with a magnification lens and a light source (the dermatoscope), can appreciate the deeper primary morphology of cutaneous lesions beyond the gross morphologic features, such as size, shape, colors, contours, and topography. this approach improves the diagnostic accuracy for melanoma [6] and the observers confidence in their clinical diagnosis [7]. unfortunately, even with dermoscopy, some melanomas remain clinically and dermoscopically indistinguishable from other lesions, such as seborrheic keratoses, whose suggestive features might be displayed in up to 18% of melanomas, vascular lesions and pyogenic granulomas, lichen planus-like keratoses, warts, dermatofibromas, ulcers and, finally, from melanocytic nevi, hence difficult to diagnose [8-16]. this is particularly true in patients with atypical mole syndrome, whose nevi share clinically some, or all, the features of cm (the abcds: asymmetry, border, irregularity, color variability, and diameter > 6 mm). a strategy involves the dermoscopic follow‐up of atypical lesions, through sequential digital dermatoscopy imaging, and excision only of those lesions that change over time [17]. 2 review | dermatol pract concept. 2022;12(03):e2022100 the introduction of digital dermatoscopes or so-called videodermatoscopes (vds), the sequential digital dermatoscopy imaging (ssdi) and total body photography (tbp) are further options in the general digital progress within medicine and dermatology. these systems are equipped with high-resolution color video cameras that reveal monitor images obtained using non-polarized or polarized light. they achieve higher magnifications than most common hand-held dermatoscopes and simplify image acquisition, storage, organization, analysis, and retrieval. these techniques are appreciated and requested by the patients who, however, might do not fully understand the rational of the methods , often believing their nevi are being monitored because at risk of malignant evolution, especially the atypical ones [18]. indeed, the actual risk of any given nevus of transforming into a melanoma has been estimated to be low, whereas the majority of melanomas appear to arise de novo [19], and “atypical” nevi are at no higher risk of developing into a melanoma; rather, the “atypical” nevus is more likely to actually be a melanoma whose dermoscopic features may not differ significantly at baseline from nevi [15]. a discrepancy between patients and physician’ expectations towards vds and tbp might be even at the base of the doctor-patient relationship, and this is not without danger. the availability of monitoring during follow-up changes the clinician threshold for biopsy suspicious pigmented lesions, resulting in a fall in the sensitivity for melanoma at the first examination, to increase the specificity and the accuracy for melanoma detection at the next evaluation. there are 2 main approaches: short-term follow-up (3 months) is used to make a clinical decision about single, flat or slightly raised suspicious melanocytic lesion, lacking dermoscopic features of melanoma; while medium or long-term monitoring, generally restricted to patients with multiple nevi, mainly aims at comparison of multiple inconspicuous lesions over standard surveillance periods (usually 6 or 12 months) [20]. to work properly, this method of follow-up needs patients’ compliance with follow-up timing. unfortunately, it has been proven that patients compliance strongly decreases with long-term control visits, with the risk of melanoma un-treatment [21–23], and we cannot exclude this is due to a misunderstanding and miscommunication between patient and physician about how the method works. moreover, the depth of invasion is the most critical prognostic factor of malignant melanoma, but dermoscopic findings do not allow a reliable evaluation of the tumor thickness, nor a sure distinction between an in situ and an early invasive phase [24-26] and, consequently, diagnosis remains only histopathological. the question is of more than academic interest because melanoma is a completely curable disease if diagnosed early, while still in situ. once it becomes invasive, the diagnosis becomes easier but the best chance for recovery has been lost. it has been widely proven that sequential dermoscopy imaging detects mostly thin incipient melanomas [15,27,28] and patients with these lesions are generally considered to be at low risk for metastasis and melanoma-related death, but it is well known that a portion of this group will eventually experience disease recurrence and risk death from melanoma [29–32]. one can wonder if, comprehensively informed, a patient would rather opt for immediate surgical removal, sacrificing specificity over sensitivity. on the other hand, removal of all unusual-appearing nevi, especially in patients with multiple atypical nevi, is usually impractical. the use of tbp might further facilitate the detection of new lesions, as well as visual changes in pre-existing lesions, by providing a comparative reference point of areas of skin for subsequent examinations [33]. during a dermoscopic and clinical visit, we might be tempted to feel that our conversation with a patient sufficiently ensures that the patient has freely and knowingly accepted the procedure. however, while dialogue is necessary, it is not sufficient for legally documenting informed consent, given that in some countries, italy and spain for example, the law stipulates that consent must be given by traceable means, such as in writing [34,35]. the informed consent doctrine has, in fact, three goals: (1) to include patients in the decision-making process; (2) to involve the patient in the choices that affect the psycho-physical aspect; and (3) to ensure the patient is aware of the potential benefits and hazards of the treatment [36]. in dermoscopy context, compared with the issue of patient’s follow-up in medicine as a whole, for the several aforementioned issues and regarding especially the third point, proper documentation of the care planning, with information about prognosis, follow-up, and therapeutic approaches, to which the patient consents, is fundamental in the reduction of litigation related to melanoma misdiagnosis, usually seen as diagnostic delay and illicit reduction of survival and/or quality of life. in medicolegal cases, a physician note may provide additional evidence that the physician met the applicable standard of care, while inadequate documentation may reduce the likelihood of a successful defense [3]. of great interest, a recent pronunciation of the ii civil section of the genua tribunal (n. 939/2017) discusses two of the main issue on diagnostic delay for melanoma: at first, the importance of written health records, to identify the followed diagnostic procedure and the proper information; secondly, the need of standard formation of dermatologist about dermoscopy, to avoid, in cases of doubtful lesions, “that there was not even observation with a dermatoscope” [37]. in addition to documentation, photography becomes more widespread in both general dermatological setting, and in dermoscopy, because specific part of the method; review | dermatol pract concept. 2022;12(03):e2022100 3 photography, in fact, may directly impact patient care by allowing the clinician to detect changes in pigmented lesions. a proper patient’s disclosure over picture management must also be added in the medical records [38,39]. hence, video-dermoscopy and sequential dermoscopy imaging, with their particular characteristics, might need a deep information and appropriate signed written consent [36]. at least in italy, in litigations and trials regarding diagnostic delays of melanomas, the study of lin et al is used to estimate the impact on the prognosis: in our opinion the article has to be considered with extreme caution, because only the rate of growth of the lesion, from a histopathological point of view, is investigated, so it is improper to directly convert this data into patients’ prognosis [40]. consequently, dermatologists and hospitals might face medicolegal concerns for some months delay, even in case of small and likely in situ melanomas, if not properly diagnosed and followed [41]. thus, implementing enough instruments and specialists is mandatory to guarantee optimal follow-up and to meet the patients’ needs and expectations. it is important to remember that the specificity for melanoma diagnosis at the second visit, however, increases only for those with experience with the method, hence the need for trained specialists [17,42]. nowadays, tbp with standard vd is the best standard of care: to identify the best diagnostic tool for cm diagnosis means to define the parameter of the dermatologist diligence, namely, to exclude professional liability. beyond this information, it is critical to understand several key elements, clinical and medicolegal. melanoma diagnosis remains difficult, with frequent misdiagnosis, so the definition of the dermoscopy “standard of care” and the identification of shared diagnostic guidelines is fundamental. to grant this “standard of care”, it is important to be wary of quick and “magical” solutions, in the era of online diagnoses, and to refer to renowned centers and specialists on melanoma, enhancing clinician professionality. to avoid clinical and judicial delays, patients need to be informed about the aim of dermoscopy for cm diagnosis, and about the relevance of follow-up compliance. moreover, lesion pictures and their storage are part of the diagnostic procedure: the patient must be properly informed, and he/she must properly disclose it. in conclusion, the medicolegal gaze could be useful to the dermoscopist, providing him with a different and better confidence in the method, assuring a greater patient safety and peace of mind of both patient and physician. references 1. ferlay j, colombet m, soerjomataram i, et al. estimating the global cancer incidence and mortality in 2018: globocan sources and methods. int j cancer. 2019;144(8):1941-1953. doi: 10.1002/ijc.31937. pmid: 30350310. 2. naik pp. cutaneous malignant melanoma: a review of early diagnosis and management. world j oncol. 2021;12(1): 7-19. doi: 10.14740/wjon1349. pmid: 33738001. pmcid: pmc7935621. 3. marghoob aa, changchien l, defazio j, et al. the most common challenges in melanoma diagnosis and how to avoid them. australas j dermatol. 2009;50(1):1-13; quiz 14-15. doi: 10.1111/j.1440-0960.2008.00496_1.x. pmid: 19178485. 4. cirfera v, toma g, labrini g. introduzione allo studio della dermatologia di interesse legale. prat medica aspetti leg. 2008;2(2):59-60. doi:10.7175/pmeal.v2i2.385. 5. sonthalia s, pasquali p, agrawal m, et al. dermoscopy update: review of its 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haberle s, delong aspey l, grant-kels jm, stoff b. informed consent, use, and storage of digital photography among mohs surgeons in the united states. dermatol surg. 2016;42(3):305-309. doi: 10.1097/dss.0000000000000634. pmid: 26863597. 40. lin mj, mar v, mclean c, kelly jw. an objective measure of growth rate using partial biopsy specimens of melanomas that were initially misdiagnosed. j am acad dermatol. 2014;71(4):691-697. doi: 10.1016/j.jaad.2014.04.068. pmid: 24976443. 41. megaris a, lallas a, bagolini lp, et al. dermoscopy features of melanomas with a diameter up to 5 mm (micromelanomas): a retrospective study. j am acad dermatol. 2020;83(4):11601161. doi: 10.1016/j.jaad.2020.04.006. pmid: 32289392. 42. kittler h, binder m. risks and benefits of sequential imaging of melanocytic skin lesions in patients with multiple atypical nevi. arch dermatol. 2001;137(12):1590-1595. doi: 10.1001/archderm.137.12.1590. pmid: 11735709. dermatology: practical and conceptual 126 observation | dermatol pract concept 2018;8(2)11 dermatology practical & conceptual www.derm101.com case presentation a 32-year-old woman with multiple clark’s nevi, a negative family history for melanoma, and skin phototype iii presented for the first time in october 2016 for a routine mole assessment. an asymmetric, asymptomatic flat, 20 x 8 mm large pigmented lesion on her back was noted. upon dermoscopy an atypical pigmented network with eccentric pigmentation and a small blue veil area were present (figure 1). the patient could not report a precise medical history. at a 6-month digital dermoscopic follow-up, the lesion was not enlarged but had changed and presented a more pronounced atypical network with accentuation of the blue dermoscopy of a spark’s nevus giovanni biondo1,2, matteo gnone3, simona sola4, carlotta pastorino2, cesare massone2 1 dermatology and sexual transmitted disease unit, “p. giaccone” hospital, university of palermo, italy 2 dermatology unit, galliera hospital, genoa, italy 3 dermatology private practice, genoa, italy 4 surgical pathology, galliera hospital, genoa, italy key words: spark’s nevus, dermoscopy, pathology citation: biondo g, gnone m, sola s, pastorino c, massone c. dermoscopy of a spark’s nevus. dermatol pract concept. 2018;8(2):126128. doi: https://doi.org/10.5826/dpc.0802a11 received: october 13, 2017; accepted: december 7, 2017; published: april 30, 2018 copyright: ©2018 biondo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cesare massone, md, dermatology unit, ospedali galliera. via volta 6, 16128, genova, italy. tel. ++ 0039 010 5632 4270; fax. ++0039 010 5632 4272. email: cesare.massone@galliera.it spark’s nevus is a particular type of melanocytic nevus that on histology shows features of both spitz’s and clark’s nevus. clinically, it is an asymmetric, irregular, multicolored, pigmented lesion that is not clearly distinguishable from melanoma or dysplastic (clark’s) nevus. dermoscopic features have not been described yet, and one could speculate that they are similar to those of clark’s nevi because the histopathologic architecture of spark’s nevus is similar to that of a clark’s nevus, resembling spitz’s nevi in the epithelioid morphology of melanocytes. we present a 32-year-old woman with a spark’s nevus, who upon dermoscopy showed a pronounced atypical network with accentuation of the blue veil and mostly peripheral dots. abstract figure 1. dermoscopy at baseline: atypical pigmented network with eccentric pigmentation and a small blue veil area are present. [copyright: ©2018 biondo et al.] observation | dermatol pract concept 2018;8(2):11 127 pigmented lesion, not clearly distinguishable from melanoma or dysplastic (clark’s) nevus. the first description has been attributed “verbally” to ackermann, but the eponym and morphological description of spark’s nevus (spitz’s and clark’s) was coined by glusac in 2009 [1]. in 1991, barnhill et al reported a series of  95  pigmented melanocytic spindle cell nevi (pscn), 8 of which exhibited some overlap with dysplastic nevus called pigmented spindle cell nevus (pscn) with dysplastic changes [2]. toussaint and kamino found 67 out of 2,164 dysplastic nevi showing features of spitz’s nevus [3]. spark’s nevus was reported more frequently on the trunk and lower extremities and in women with a mean age of 33 [1]. according to glusac, histological features of spark’s nevus are: small size (<1 cm), flat/horizontal orientation, symmetric outline, uniform spitzoid cytology across the entire lesion, nest of similar size and shape when not bridged, and sharp circumscription [1]. the differential diagnosis includes clark’s (atypical, dysplastic) nevus, spitz’s nevus, and melanoma. clark’s nevi are melanocytic nevi characterized clinically by variable size, borders, and colors that are difficult to distinguish from melanoma [4–6]. upon dermoscopy clark’s nevi show a variety veil and most peripheral dots had appeared. because the modifications were recorded at digital follow-up, the lesion was excised (figure 2). histopathology showed a junctional and dermal melanocytic proliferation composed of nests predominating over single melanocytes, absence of pagetoid spread in the epidermis, and elongation of the rete ridges with lamellar fibrosis in the papillary dermis together with melanophages and inflammatory infiltrates (figure 3). the nests were regular. in the epidermis, they were exclusively located at the dermoepidermal junction, and there were monomorphous round-to-oval epithelioid pigmented melanocytes reminiscent of spitz nevus (figure 4). as a whole, on histopathology this lesion showed the architecture of a clark’s nevus, but the morphology of melanocytes are more typical of spitz’s nevus and the features are characteristic of a spark’s nevus, compound type. conclusions spark’s nevus is a particular type of melanocytic nevus with histology that shows features of both spitz’s and clark’s nevus. clinically, it is an asymmetric, irregular, multicolored, figure 2. dermoscopy at 6-month follow-up. the lesion was not enlarged but changed, presenting a more pronounced atypical network with accentuation of the blue veil and peripheral dots appeared. [copyright: ©2018 biondo et al.] figure 3. junctional and dermal melanocytic proliferation composed of nests predominating over single melanocytes, absence of pagetoid spread in the epidermis, and elongation of the rete ridges with lamellar fibrosis in the papillary dermis together with melanophages and inflammatory infiltrates (hematoxylin and eosin [h&e], 40x). [copyright: ©2018 biondo et al.] figure 4. the nests are regular, exclusively located at the dermoepidermal junction and present monomorphous round-to-oval epithelioid, pigmented melanocytes reminiscent of those of spitz’s nevus (h&e, 200x). [copyright: ©2018 biondo et al.] 128 observation | dermatol pract concept 2018;8(2)11 globules that are typical features of pigmented spit’s nevi on dermoscopy, but it showed a prominent pigmented network, a blue veil, and dots. the collection and examination of a large series of cases is needed to define prevalent clinical and dermoscopic features of spark’s nevus. references 1. ko cj, mcniff jm, glusac ej. melanocytic nevi with features of spitz nevi and clark’s/dysplastic nevi (“spark’s” nevi). j cutan pathol. 2009;36(10):1063-1068. 2. barnhill rl, barnhill ma, berwick m, mihm mc jr. the histologic spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. hum pathol. 1991;22(1):5258. 3. toussaint s, kamino h. dysplastic changes in different types of melanocytic nevi. a unifying concept. j cutan pathol. 1999; 26(2):84-90. 4. rosendahl co, grant-kels jm, que sk. dysplastic nevus: fact and fiction. j am acad dermatol. 2015;73(3):507-512. 5. kittler h, tschandl p. dysplastic nevus: why this term should be abandoned in dermatoscopy. dermatol clin. 2013;31(4):579-588. 6. farber mj, heilman er, friedman rj. dysplastic nevi. dermatol clin. 2012;30(3):389-404. 7. cheung wl, smoller br. dermatopathology updates on melanocytic lesions. dermatol clin. 2012;30(4):617-622. 8. pizzichetta ma, argenziano g, grandi g, de giacomi c, trevisan g, soyer hp. morphologic changes of a pigmented spitz nevus assessed by dermoscopy. j am acad dermatol. 2002;47(1):137139. 9. lallas a, moscarella e, longo c, et al. likelihood of finding melanoma when removing a spitzoid-looking lesion in patients aged 12 years or older. j am acad dermatol. 2015;72(1):47-53. 10. ferrara g, cavicchini s, corradin mt. hypopigmented atypical spitzoid neoplasms (atypical spitz nevi, atypical spitz tumors, spitzoid melanoma): a clinicopathological update. dermatol pract concept. 2015;5(1):45-52. 11. lallas a, apalla z, ioannides d, et al. international dermoscopy society. update on dermoscopy of spitz/reed naevi and management guidelines by the international dermoscopy society. br j dermatol. 2017;177:645-655. 12. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. 13. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877-1882. 14. argenziano g, catricalà c, ardigo m, et al. seven-point checklist of dermoscopy revisited. br j dermatol. 2011;164(4):785-90. 15. moscarella e, tion i, zalaudek i, et al. both short-term and longterm dermoscopy monitoring is useful in detecting melanoma in patients with multiple atypical nevi. j eur acad dermatol venereol. 2017;31(2):247-251. of reticular, globular and structureless patterns or mixed patterns with different areas of hyperand hypopigmentation. histologically clark’s nevus exhibits an increased number of single melanocytes and nests along the basal layer with elongation of rete ridges [4–7]. nests are cohesive and may vary in size, or may fuse with adjacent rete ridges to produce bridging [4–7]. nests predominate over single melanocytes. morphologically, melanocytes may show a variable cytologic atypia with enlarged, hyperchromatic nuclei without involvement of the upper layers of the epidermis [4–7]. clark’s nevi can be junctional or compound, and in this case shows maturation of melanocytes in the dermis. in the papillary dermis the presence of fibroplasia may be observed—a variable lymphocytic infiltrate with or without melanophages. the spitz’s and reed’s nevi are flat or papular/nodular pigmented or amelanotic melanocytic lesions. different dermoscopic patterns have been recognized for pigmented (starburst: peripheral lines, peripheral globules, black-brown globules) or amelanotic (dotted vessels) spitz’s nevi [8]. on histopathology spitz’s nevi show a well-circumscribed, symmetric architecture with vertically oriented cohesive nests of melanocytes surrounded by clefts, epidermal hyperplasia with hypergranulosis, and kamino bodies in the epidermis. melanocytes are larger than those of clark’s nevi and show an epithelioid (spitz’s nevus) or pigmented spindled morphology (reed’s nevus) [9–11]. melanoma is diagnosed with dermoscopy on the basis of specific criteria according to different algorithms [12–14]. a major risk factor for developing melanoma is a high number of atypical (clark’s, dysplastic) nevi. the aim for these patients is to detect early melanoma thereby reducing the number of unnecessary excisions. two approaches are usually taken: the comparative approach and the digital follow-up. the former aims to recognize the signature nevus pattern, and the latter an asymmetric growth of suspicious lesions at digital follow-up, the typical behavior of melanoma [15]. spark’s nevus is a term mainly defining a histopathological more than a clinical entity that is underdiagnosed—or not always reported by most dermatopathologists though probably quite frequently present. the clinical appearance of spark’s nevi is similar to those of clark’s nevi. dermoscopic features have not been described yet, and one could speculate that they are similar to those of clark’s nevi because the histopathological architecture of spark’s nevus is similar to that of a clark’s nevus, resembling spitz nevi in the epithelioid morphology of melanocytes. in our case, the lesion did not show peripheral lines, peripheral globules or black-brown dermatology: practical and conceptual research | dermatol pract concept 2017;7(3):4 21 dermatology practical & conceptual www.derm101.com successful treatment of plantar warts with intralesional bleomycin and electroporation: pilot prospective study paola pasquali1, azael freites-martinez1, salvador gonzalez2,3, enrico p. spugnini4, alfonso baldi4,5 1 dermatology service, pius hospital de valls, tarragona, spain 2 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 3 medicine department, alcalá university, madrid, spain 4 biopulse srl, naples, italy 5 department of environmental, biological and pharmaceutical sciences and technologies, university of campania “luigi vanvitelli”, caserta, italy key words: warts, electroporation, bleomycin citation: pasquali p, freites-martinez a, gonzales s, spugnini ep, baldi a. successful treatment of plantar warts with intralesional bleomycin and electroporation: pilot prospective study. dermatol pract concept 2017;7(3):4. doi: https://doi.org/10.5826/dpc.0703a04 received: february 22, 2017; accepted: may 27, 2017; published: july 31, 2017 copyright: ©2017 pasquali et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: e.p. spugnini and a. baldi are stockholders in biopulse s.r.l. all authors have contributed significantly to this publication. p.p., a.f.m., s.g. performed the clinical trial; e.p.s. and a.b. performed the statistical analysis; p.p., e.p.s. and a.b. wrote the manuscript. corresponding author: prof. alfonso baldi, department of environmental, biological and pharmaceutical sciences and technologies, university of campania “luigi vanvitelli”, via vivaldi, 43 81100 caserta, italy. email: alfonsobaldi@tiscali.it background: numerous studies have been performed to evaluate the efficacy of intralesional bleomycin for the treatment of warts with inconsistent result. nevertheless, it is well known that the cytotoxicity of bleomycin can be enhanced in vivo by 300 to 700-fold by electroporation. objective and methods: in this article, we present an interventional, one-center, prospective case series, clinical trial of the effectiveness of intralesional bleomycin combined with electroporation for the treatment of plantar warts, in comparison to the use of intralesional bleomycin alone. results: the study’s cohort included 12 men and 10 women, with a mean age of 53.8 years. a total of 22 warts were treated. in dividing the patients in two groups (complete remission against all the others) and analyzing the different outcomes in the two arms of patients, a statistical significant difference was found (p=0.0015), proving a greater efficacy of the treatment with bleomycin combined with ect as opposed to bleomycin alone. electroporation was always well tolerated by the patients with no discomfort. conclusions: this study serves as a basis for the application of novel protocols in the treatment of different benign and locally malignant skin lesion by means of electroporation. abstract 22 research | dermatol pract concept 2017;7(3):4 in comparison to the use of intralesional bleomycin alone (eudract n° 2014-003339-21). patients twenty-two patients with shave biopsy proven warts were recruited to participate in this study. participation was on a volunteer basis, according to the principles of the declaration of helsinki. after detailed clinical assessment of the patient, information of the patient on all available alternative treatment options for her/his disease, information on ect (application and expected results in comparison to other modalities, expected side effects and their management), and the aim of the present study, written informed consent was obtained and a structured follow-up program was discussed. patients were evaluated for eligibility to participate in this study according to the criteria listed in table 1. there were no demographic restrictions for the inclusion. all the patients were recruited from the dermatology service, pius hospital de valls, tarragona, spain. patients were randomly assigned to one of the two arms of the study (bleomycin alone and bleomycin combined with ect). of note, we did not test and stratify for hpv subtype the patients. therapeutic protocol each patient signed a consent form. clinical and dermoscopic images of lesions were taken using a canon powershot g11 (canon, inc, tokyo, japan) camera followed by shave biopsy. affected areas were anesthetized with subcutaneous lidocaine; block anesthesia was not performed. overlying calluses were trimmed with a number 15 blade. bleomycin in a concentration of 1 mg/cm3 was injected into verrucous foci at a depth of about 1.5 mm with a final volume of 0.1 cc. patients enrolled in the arm including the ect treatment, were subjected to trains of 8 biphasic pulses with an interpulse of 10 microseconds and a 50+50 microseconds duration, generated by an electroporator (onkodisruptor®, biopulse s.r.l., naples, italy). the pulses were delivered at a voltage of 700 v/cm, with 1 hz frequency (total treatment introduction cutaneous warts are very common among dermatological diseases and are of benign nature. however, they can be extremely difficult to treat and can significantly impact quality of life [1,2]. human papillomavirus, a double-stranded dna virus, is the etiologic agent of warts. the most common sites of infection are the hands, feet, face, and the anogenital area [3]. several different therapeutic approaches are possible, depending on lesion size, number and location, patient age and comorbidities, as well as adverse reactions associated with therapy [4]. numerous studies have been performed to evaluate the efficacy of intralesional bleomycin for the treatment of warts with inconsistent result [5]. the uptake of this drug by the cells is slow and limited, because bleomycin can pass the cell membrane only through protein receptors due to its lipophobic nature [6]. in vitro studies, indeed, show evidence that less than 0.1% of bleomycin added to a culture medium becomes associated with the cell. therefore, the high toxicity of bleomycin is weakened by its incapacity to freely diffuse through the cytoplasmic membrane [6]. several studies have proved that the cytotoxicity of bleomycin can be enhanced in vivo by 300to 700-fold by electroporation [7]. electrochemotherapy (ect) is a loco-regional therapy that is based on the application of permeabilizing electric pulses on tumors or tumor beds after the administration (either systemic or intralesional) of a chemotherapy agent [6]. in veterinary medicine, ect is currently adopted as first-line therapy, generally in an adjuvant fashion, to improve the chemotherapeutic agent uptake by the neoplastic cells, thus resulting in better local control of the neoplastic disease [7]. in humans, its use is actually focused on palliation of cutaneous metastases of melanoma [8], but it is going to prove to be a valuable skin-directed therapy for a range of malignancies [9]. among the numerous electroporation protocols implemented, our research group recently proposed a novel protocol involving the adoption of bursts of rectangular and biphasic pulses with a selected period of repetition [10]. this schedule enabled decreased morbidity of the treated animals and human beings as well as improving the clinical outcome [10]. in this study, we investigate the potential benefits of combining intralesional bleomycin with ect for the treatment of plantar warts of big dimensions, with respect to the treatment with bleomycin alone. material and methods study description this study is an interventional, one-center, prospective case series, clinical trial on the effectiveness of intralesional bleomycin combined with ect for the treatment of plantar warts, table 1. selection criteria for the patients with warts inclusion criteria exclusion criteria histologically confirmed previous reynaud phenomenon minimal size of the wart 0.5 cm heart patients plantar warts another wart less than 3 cm ability of patients to follow the instructions previous bleomycin use patients older than 18 patients younger than 18 research | dermatol pract concept 2017;7(3):4 23 statistical analysis fisher exact test was used to assess any difference in terms of response rate at the two time points between the control arm and the experimental arm. spss software (version 17.00, spss, chicago) was used for statistical analysis. a p-value of less than 0.05 was considered to indicate statistical significance. results patient demographics characteristics of the patients enrolled in the protocol are depicted in table 2. briefly, the study’s cohort included 12 men and 10 women with ages ranging from 27 to 85 years, with a mean of 53.8 years. a total of 22 warts were treated, exclusively located on the feet. all patients were non-responders of other treatment modalities and had had a treatment history of more than 6 months. efficacy table 2 summarizes the data obtained at 1 month and 3 months follow-up. indeed, focusing on the 3-month followup, 78% (7/9) of patients treated with bleomycin coupled time: 1 ms per cm2 of treated area). the pulses have been delivered by using caliper electrodes. in figure 1, panel a, an example of calipers application on a plantar wart is depicted. a pain scale (0, no pain; 10, maximum pain) was passed on each patient to evaluate pain during the procedure. data collection follow-up of the progress of the treatment process was scheduled at day 30 and day 90 after the treatment. the documentation plan during follow up, including photo-documentation of the treated area, consisted of evaluation of local treatment outcome, de novo appearance of skin warts, development of any disorders from any other organic system, as well as longtime outcome of the scarring process at the site of ect treatment (“cosmetic result”). treatment outcome was evaluated according to endpoint results, at the first or second follow-up appointment, 1 or 3 months after the end of treatment. the endpoints were defined as follows: (1) “cured” (= complete remission, cr): no wart is detectable (2) “partial response” as 50% wart reduction (pr) (3) “non-responding” (4) “progressive disease”: larger final wart table 2. main clinical characteristics of the patients and outcome after one and three months patient age sex treatment outcome after 30 days outcome after 90 days 70 male bl pr pr 59 female bl pr pr 59 female bl pr pr 52 female bl+e pr cr 51 female bl pr pr 54 male bl nr nr 45 male bl cr pr 60 female bl+e pr pr 62 male bl pr pr 62 male bl pr pr 39 male bl+e nr nr 63 female bl pr cr 45 male bl+e cr cr 47 female bl+e cr cr 61 male bl pr pr 48 male bl pr cr 85 male bl+e cr cr 33 female bl+e cr cr 68 female bl pr pr 59 male bl nr pr 27 male bl+e pr cr 21 male bl+e pr cr 24 research | dermatol pract concept 2017;7(3):4 pain is the most commonly described, while no systemic reactions have been linked with the use of bleomycin for warts [12]. interestingly, a recent cochrane meta-analysis has shown with ect had complete remission and only 2 patients displayed partial remission or no response. on the other hand, at 3-month follow-up 16% (2/13) of patients treated with bleomycin had complete remission, while 76% (10/13) of patients displayed partial remission and 8% (1/13) had no response. dividing the two groups of patients (complete remission against all the others) and analyzing the different outcomes in the two arms of treatment, a statistical significant difference was found (p=0.0015), proving a greater efficacy of the treatment with bleomycin combined with ect with respect to bleomycin alone. in figure 1 (panels from b to i) two cases with partial or complete resolution of the wart after one month of treatment are depicted. side effects not one of the patients had adverse systemic effects. the most notable local side effect was he pain during the injection of local anesthetic. none complained of pain during intralesional bleomycin injection or during ect. other side effects were relatively infrequent, occasionally including redness and tenderness, and skin discoloration at the site of injection. one patient of arm a of the study reported pain on the third day after bleomycin injection. concerning ect treatment, it was always well tolerated by the patients without any discomfort. discussion bleomycin has been successfully used for the treatment of recalcitrant warts [11]. the most likely mechanism of action of this drug is the creation of unstable free radicals causing single-strand breaks and apoptosis [12]. multiple bleomycin administration techniques have been studied with various success rates [11,13]. however, several intralesional bleomycin injections are generally necessary to obtain clearance of the warts [14]. concerning side effects, injection that the treatment of choice for warts remains ambiguous, despite the proved efficacy of intralesional bleomycin [15]. several studies have demonstrated that the efficacy of bleomycin can be greatly improved by coupling its injection with f g (continued next page) research | dermatol pract concept 2017;7(3):4 25 references 1. ciconte a, campbell j, tabrizi s, garland s, marks r. warts are not merely blemishes on the skin: a study on the morbidity associated with having viral cutaneous warts. australas j dermatol. 2003;44:169-173. 2. gibbs s, harvey i, sterling j, stark r. local treatments for cutaneous warts: systematic review. bmj. 2002;325:461. 3. cardoso jc, calonje e. cutaneous manifestations of human papillomaviruses: a review. acta dermatovenereol alp pannonica adriat. 2011; 20:145-154. 4. rivera a, tyirng sk. therapy of cutaneous human papillomavirus infections. dermatol ther. 2004;17:4411-4418. 5. buchanan j, nieland-fisher n. document responses from patients regarding warts and current therapy. arch dermatol. 2004;140:487-488. 6. spugnini ep, azzarito t, fais s, fanciulli m, baldi a. electrochemotherapy as first line cancer treatment: experiences from veterinary medicine in developing novel protocols. curr cancer drug targets. 2016;16:43-52. 7. spugnini ep, baldi a. electrochemotherapy in veterinary oncology: from rescue to first line therapy. methods mol biol. 2014;1121:247-256. 8. spugnini ep, melillo a, quagliuolo l, et al. definition of novel electrochemotherapy parameters and validation of their in vitro and in vivo effectiveness. j cell physiol. 2014;229:1177-1181. 9. campana lg, testori a, curatolo p, et al. treatment efficacy with electrochemotherapy: a multi-institutional prospective observational study on 376 patients with superficial tumors. eur j surg oncol. 2016; 42:1914-1923. 10. spugnini ep, fais s, azzarito t, baldi a. novel instruments for the implementation of electrochemotherapy protocols: from bench side to veterinary clinic. j cell physiol. 2017;232:490-495. 11. kruter l, saggar v, akhavan a, , et al. intralesional bleomycin for warts: patient satisfaction and treatment outcomes. j cutan med surg. 2015;19:470-476. electrical pulses enabling the cells to be more prone to incorporate bleomycin [7]. indeed, bleomycin is one of the most used drugs in ect protocols for the treatment of tumors [8]. a major goal of this project was to demonstrate an increased efficacy in the treatment of plantar warts with intralesional bleomycin coupled with electroporation. indeed, the results of our study show that electroporation coupled with bleomycin significantly improve the outcome of patients with respect to the patients treated with bleomycin alone. nevertheless, in our experimental protocol, only one intralesional injection of bleomycin was performed and, when coupled with electroporation, was sufficient to get complete remission in the majority of the patients with disappearance of the wart. this further supports the idea that electroporation is able to amplify the effect of bleomycin, since its efficacy in the treatment of warts is generally linked to multiple injections on the site of the wart [15]. the second goal of the project was to demonstrate that the application of electric voltage to the warts had no adverse side effects. indeed, none of the patients suffered systemic side effects, and the only local adverse effects were the pain at the site of the injection and occasionally redness and tenderness of the skin. electroporation was well tolerated by the patients without any discomfort. the main limitation of our study was the small number of patients enrolled in the protocol. therefore, additional studies are necessary to confirm the efficacy of electroporation coupled with bleomycin in treating plantar warts. nevertheless, the promising results obtained, together with the fact that the treatment was well tolerated by all the patients, represent the basis for the application of novel protocols for the treatment of different benign and locally malignant diseases of the skin by means of electroporation. figure 1. two cases of plantar wart with partial or complete resolution after one month from the treatment with bleomycin and electroporation. (a) the application of the electrodes on the plantar wart; (b) a plantar wart at presentation; (c) partial resolution after one month form the treatment; (d) dermoscopic appearance of the wart at presentation; (e) dermosocopic appearance of the wart after partial remission; (f) a plantar wart at presentation; (g) complete resolution after one month form the treatment; (h) dermoscopic appearance of the wart at presentation; i) dermosocopic appearance of the wart after complete remission. [copyright: ©2017 pasquali et al.] h i 26 research | dermatol pract concept 2017;7(3):4 in both external auditory canals using bleomycin injections. clin exp otorhinolaryngol. 2015;8:295-297. 14. dhar sb, rashid mm, islam a, bhuiyan m. intralesional bleomycin in the treatment of cutaneous warts: a randomized clinical trial comparing it with cryother12. kollipara r, ekhlassi e, downing c, guidry j, lee m, tyring sk. advancements in pharmacotherapy for noncancerous manifestations of hpv. j clin med. 2015;4:832-846. 13. lee jh, burm js, yang wy, kang sy, byun sw. treatment of verruca vulgaris apy. indian j dermatol venereol leprol. 2009;75:262-267. 15. kwok cs, gibbs s, bennett c, holland r, abbott r. topical treatments for cutaneous warts. cochrane database syst rev. 2012;9:cd001781. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023023 1 localized vitiligo and post-inflammatory hypopigmentation at the injection site of a covid-19 mrna vaccine dora mancha1, joana antunes1,2, luís soares-de-almeida1,2,3, joão borges-costa1,2,3,4, paulo filipe1,2,3 1 dermatology department, hospital de santa maria, centro hospitalar universitário de lisboa norte, lisbon, portugal 2 dermatology universitary clinic, faculdade de medicina da universidade de lisboa, lisbon, portugal 3 dermatology research unit, instituto de medicina molecular, universidade de lisboa, lisbon, portugal 4 instituto de higiene e medicina tropical, universidade nova de lisboa, lisbon, portugal key words: vitiligo, covid-19, sars-cov2, mrna, vaccine, bnt162b2 citation: mancha d, antunes j, soares-de-almeida l, borges-costa j, filipe p. localized vitiligo and post-inflammatory hypopigmentation at the injection site of a covid-19 mrna vaccine. dermatol pract concept. 2023;13(1):e2023023. doi: https://doi.org/10.5826/ dpc.1301a23 accepted: may 2, 2022; published: january 2023 copyright: ©2023 mancha et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dora mancha, dermatology department, hospital de santa maria, centro hospitalar universitário de lisboa norte, av. prof. egas moniz mb, 1649-028 lisboa, portugal. phone: +351 21 780 5243; e-mail: dora.mancha@gmail.com introduction the covid-19 pandemic has been a global emergency since january 2020. one of the most commonly used covid-19 mrna vaccines is pfizerbiontech vaccine bnt162b2 [1]. in a registry-based study of 414 cutaneous reactions to mrna covid-19 vaccines, delayed and immediate injection site reactions were the most common [2]. herein, we discuss two similar cutaneous reactions following covid mrna vaccination in order to further characterize dermatologic reactions. case presentation case 1. a 38-year-old woman, fitzpatrick type iii, presented to our consultation after the second dose of pfizer vaccine bnt162b2. after vaccine administration, the patient described an immediate local reaction on the injection site characterized by an erythematous and edematous plaque. this reaction evolved to a hypopigmented patch with irregular borders measuring 20 mm (figure 1a). wood lamp examination of the lesion (figure 1b) revealed neither fluorescence nor accentuation, which is consistent with post-inflammatory hypopigmentation. this cutaneous lesion fainted after 2 months without treatment. case 2. a 30-year-old woman, fitzpatrick type v, presented to our consultation after the first dose of pfizer vaccine. few hours after the vaccine, the patient noted an immediate local reaction characterized by an erythematous and edematous plaque with a central blister. over two weeks, this reaction evolved to a hypopigmented patch with 25 mm of diameter and irregular borders, surrounded by 2 research letter | dermatol pract concept. 2023;13(1):e2023023 another patch with two shades of brown (figure 1, c-e). wood lamp examination demonstrated a sharply demarcated bright blue-white fluorescence (figure 1f), consistent with vitiligo. skin biopsy was also compatible with vitiligo (figure 2) revealing a decrease or absence of melanin pigment in lesional skin with h&e and masson-fontana stains, respectively. autoimmunity laboratory study (anas, ana screening, anti-dsdna, anti-thyroid antibodies) was negative and sars-cov2 anti-spike antibody titers were positive of (50.8 au/ml). she was treated with topical tacrolimus twice daily with poor response. after the second dose of the vaccine, two months later, she had no skin reaction. at four months of follow-up only the vitiligo lesion remains, the brown patch is fading away. conclusions post-inflammatory hypopigmentation is an acquired partial or total loss of skin pigmentation occurring after cutaneous inflammation. there is limited information about the mechanism and pathogenesis. melanogenesis is a complex process. it is controlled by multiple mediators (eg, growth factors, cytokines) acting on melanocytes, keratinocytes and fibroblasts. through the release of these mediators, cutaneous figure 1. skin hypopigmentation. case 1. (a) hypopigmented patch with irregular borders on the left arm at three weeks following the second dose of pfizer vaccine. (b) wood lamp examination revealed neither fluorescence nor accentuation. case 2. (c-e) site injection reaction on the left arm evolved from an erythematous and edematous plaque with a central blister to a hypopigmented patch over a period of hours to two weeks following the first dose of pfizer vaccine. (f) under wood lamp examination the hypopigmented patch showed sharply demarcated bright blue-white fluorescence. research letter | dermatol pract concept. 2023;13(1):e2023023 3 inflammation may cause aberration of melanogenesis leading to loss of melanocytes [3]. in case 1, inflammation resulted in hypopigmented patches at the injection site. the hypopigmentation improved overtime after the inflammation ceased. vitiligo is an autoimmune disease. cytotoxic cd8+ t cells are responsible for the destruction of melanocytes. the potential for vaccines to act as triggers of autoimmune reactions is well known [4,5]. the pathophysiology underlying the relationship between sarscov-2 vaccination and vitiligo remains unclear. mrna vaccines encoding the sars-cov-2 spike protein encapsulated in lipid nanoparticles gain entry into dendritic cells (dcs) at the injection site. in addition, innate sensors are triggered resulting in production of type i interferon and multiple pro-inflammatory cytokines and chemokines. in particular, vaccine-driven production of type i interferon (ifn-1) promotes differentiation of cd4+ and cd8+ effector t cells producing inflammatory and cytotoxic mediators, and cd4+ t follicular helper cells, which promote b cell differentiation into antibody-secreting plasma cells [6]. in the pathogenesis of vitiligo, both ifn-1 and dcs were demonstrated to play a significant role. the activation of dcs and the release of ifn-1 seem to be key events in vitiligo following covid-19 vaccination. additionally, nonspecific activation of autoreactive cd8+/cd4+ t and b cells could stimulate the immune system to produce antibodies against sarscov2 spike protein and incidentally against melanocytes [7-9]. on the other hand, studies with anti-melanoma vaccines demonstrated that vitiligo observed around the injection site does not occur unless autoreactive t cells are recruited into the skin by inflammatory stimuli, suggesting that vitiligo can be initiated by some form of trauma to the skin [10]. to date, there are only five reported cases of new-onset vitiligo following covid-19 mrna vaccine (table 1). in case 1, the hypopigmented patch was a result of an inflammatory response that can occur in any patient and should be differentiated from vitiligo. case 2 is the first report of site injection site vitiligo after an mrna vaccine. vaccines generate an immune response which can be a trigger to develop figure 2. vitiligo, case 2. skin biopsy performed on the edge of the hypopigmented patch. (a) basal epidermal hyperpigmentation explained by the patient phototype. scarce inflammatory infiltrate in the superficial dermis (h&e stain, magnification x100). (b) slight decrease in melanin pigment in lesional skin (h&e stain, magnification x400). (c,d) masson-fontana stain highlights loss of melanin on the left side of the biopsy (fontana-masson stain, magnification x100 and x400). 4 research letter | dermatol pract concept. 2023;13(1):e2023023 5. militello m, ambur ab, steffes w. vitiligo possibly triggered by covid-19 vaccination. cureus. 2022;14(1):e20902. doi: 10.7759/cureus.20902. pmid: 35145806. pmcid: pmc8809499. 6. teijaro jr, farber dl. covid-19 vaccines: modes of immune activation and future challenges. nat rev immunol. 2021;21(4):195-197. doi: 10.1038/s41577-021-00526-x. pmid: 33674759. pmcid: pmc7934118. 7. kaminetsky j, rudikoff d. new-onset vitiligo following mrna-1273 (moderna) covid-19 vaccination. clin case rep. 2021;9(9):e04865.. doi: 10.1002/ccr3.4865. pmid: 34603727. pmcid: pmc8465924. 8. uğurer e, sivaz o, kıvanç altunay i̇. newly-developed vitiligo following covid-19 mrna vaccine. j cosmet dermatol. 2022;21(4):1350-1351. doii:10.1111/jocd.14843. pmid: 35152540. pmcid: pmc9115282. 9. ciccarese g, drago f, boldrin s, pattaro m, parodi a. sudden onset of vitiligo after covid-19 vaccine.  dermatol ther. 2022;35(1):e15196. doi:10.1111/dth.15196. pmid: 34751491. pmcid: pmc8646249. 10. lane lane c, leitch j, tan x, hadjati j, bramson jl, wan y. vaccination-induced autoimmune vitiligo is a consequence of secondary trauma to the skin. cancer res. 2004;64(4):15091514. doi: 10.1158/0008-5472.can-03-3227. pmid: 14973051. vitiligo. we can hypothesize that in case 2, autoreactive t cells responses triggered by a local injection site inflammation along with activation of dcs and the release of ifn-1 might be responsible for the development of vaccine-induced vitiligo at injection site. references 1. rijkers gt, weterings n, obregon-henao a, et al. antigen presentation of mrna-based and virus-vectored sars-cov2 vaccines. vaccines (basel). 2021;9(8):848. doi: 10.3390/vaccines9080848. pmid: 34451973. pmcid: pmc8402319. 2. mcmahon de, amerson e, rosenbach m, et al. cutaneous reactions reported after moderna and pfizer covid-19 vaccination: a registry-based study of 414 cases. j am acad dermatol. 2021;85(1):46-55. doi: 10.1016/j.jaad.2021.03.092. pmid: 33838206. pmcid: pmc8024548. 3. vachiramon v, thadanipon k. postinflammatory hypopigmentation. clin exp dermatol. 2011;36(7):708-714. doi:10.1111/ j.1365-2230.2011.04088.x. pmid: 21671990. 4. aktas h, ertuğrul g. vitiligo in a covid-19-vaccinated patient with ulcerative colitis: coincidence?. clin exp dermatol. 2022;47(1):143-144. doi:10.1111/ced.14842. pmid: 34236714. pmcid: pmc8444736. table 1. literature review: reported cases of new-onset vitiligo following covid-19 mrna vaccine. authors/year age (years) sex vaccine local timing aktas h, ertuğrul g [4] 2021 58 male pfizer-biontech bnt162b2 face 1 week after 1st dose kaminetsky j, rudikoff d [7] 2021 61 female mrna-1273 (moderna) face, neck, chest, abdomen several days after 1st dose ciccarese g [9] 2022 33 female pfizer-biontech bnt162b2 trunk, neck, back 1 week after 1st dose militello et al. [5] 2022 67 female mrna-1273 (moderna) hands 2 weeks after the vaccine uğurer e et al. [8] 2022 47 male pfizer-biontech bnt162b2 axilla, forearms 1 week after 1st dose dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023116 1 the relationship of serum trimethylamine n-oxide levels with carotid intima-media thickness and disease activity in psoriasis patients emre zekey1, fatma tunçez akyürek2, abdullah tunçez3, fikret akyürek4, merve ezgi doğan5 1 department of dermatology, sivas numune hospital, sivas, turkey 2 department of dermatology, selcuk university medical faculty, konya, turkey 3 department of cardiology, selcuk university medical faculty, konya, turkey 4 department of biochemistry, selcuk university medical faculty, konya, turkey 5 department of public health, selcuk university medical faculty, konya, turkey key words: psoriasis, trimethylamine n-oxide , gut microbiota, atherosclerosis, carotid intima-media thickness citation: zekey e, tunçez akyürek f, tunçez a, akyürek f, doğan me. the relationship of serum trimethylamine n-oxide levels with carotid intima-media thickness and disease activity in psoriasis patients. dermatol pract concept. 2023;13(2):e2023116. doi: https://doi.org/10.5826/dpc.1302a116 accepted: november 16, 2022; published: april 2023 copyright: ©2023 zekey et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: emre zekey, department of dermatology, sivas numune hospital, sivas, turkey. e-mail: emre.zekey@gmail.com introduction: psoriasis is an inflammatory disease that can cause cardiovascular comorbidities. some recent studies have indicated that impaired gut microbiota and metabolites may be associated with inflammatory diseases. objectives: in this study, the relationship between serum trimethylamine n-oxide (tmao, a gut bacterial metabolite) level and carotid intima-media thickness (cimt) and disease severity in psoriasis patients was investigated. methods: ageand gender-matched 73 patients and 72 healthy controls were included in the study. in both groups serum trimethylamine n-oxide(tmao), oxidized lowdensity lipoprotein (ox-ldl), high-density lipoprotein cholesterol (hdl-c), low-density lipoprotein cholesterol (ldl-c), triglyceride, total cholesterol, high-sensitivity c-reactive protein (hs-crp), creatinine, aspartate aminotransferase (ast) and alanine aminotransferase(alt) levels were recorded and the carotid intima-media thickness (cimt) was measured by b-mode ultrasonography by a cardiologist. results: tmao, hs-crp, oxidized-ldl, triglyceride and cimt levels were statistically higher in the patient group. hdl levels were statistically higher in the control group. there was no significant abstract 2 original article | dermatol pract concept. 2023;13(2):e2023116 introduction psoriasis is a chronic inflammatory disease managed by the immune system. systemic inflammation that psoriasis causes can affect many organs and systems [1]. effector t lymphocytes such as th1 and th17 are involved in the pathogenesis of psoriasis and atherosclerosis. although the mechanisms underlying the relationship between these two diseases are still poorly understood, the inflammatory cytokine profile that plays a fundamental role in both diseases seems to provide a common pathogenic basis [2]. tmao (oxidized product of trimethylamine) is an intestinal microbial metabolite. most of the trimethylamine produced from the metabolism of choline and l-carnitine by intestinal bacteria is absorbed into the bloodstream and oxidized to tmao by the flavin-containing monooxygenase-3 (fmo-3) enzyme in the liver [3]. increased serum tmao concentration is associated with intestinal dysbiosis [4]. remarkably, a dysbiotic microbiome similar to the dysbiosis detected in individuals with elevated serum tmao levels has also been demonstrated in psoriasis patients [5,6]. cross-sectional and prospective studies show a positive association between elevated plasma tmao levels and increased risk for major cardiovascular events. these studies demonstrated a positive correlation between circulating tmao levels and carotid intima-media thickness after controlling for strong predictors of cardiovascular disease including age, sex and visceral fat mass [7,8]. due to similar laminar flow properties, imaging of the carotid arterial system can provide information about coronary atherosclerosis. carotid intima-media thickness (cimt) measured by b-mode ultrasonography can reliably demonstrate changes in the arterial wall [9,10]. objectives in this study, we aimed to compare serum tmao levels in psoriasis patients and healthy participants and to determine the relationship between tmao levels and cimt and other atherosclerotic risk factors in atherosclerotic disease risk prediction. methods patients and controls seventy-three patients diagnosed with plaque psoriasis (clinically and histopathologically) and 72 healthy participants as the control group were included in the study. an informed consent form was obtained from all participants and they were informed about the study. the study was conducted between 01.06.2020 and 01.06.2021. the exclusion criteria were determined as follows: special dietary practices, continuous use of prebiotics and probiotics consumption of >2 eggs per day, meat and fish >3 times per week use of any medication that may adversely affect the microbiota in the last 1 month those diagnosed with diseases that may affect the microbiome such as inflammatory bowel diseases, irritable bowel disease those diagnosed with diabetes mellitus, hypertension, hypercholesterolemia and/or taking antidiabetic drugs, antihypertensive drugs, antihyperlipidemic drugs thyroid disease, cardiovascular and cerebrovascular diseases, peripheral vascular disease and systemic vasculitis, chronic kidney/liver disease, systemic infectious disease, collagen tissue disease and/or antiaggregant/ anticoagulant drug users use of methotrexate, cyclosporine, biologic agents, systemic steroid and hormonal therapy in the last 3 months malignancy, pregnancy, breastfeeding patients under 18 years of age obesity, smokers, drinkers difference between the two groups in terms of total cholesterol and ldl-c levels. in partial correlation analyzes in the patient group, positive correlations were observed between tmao and cimt, ldl-c and total cholesterol levels. linear regression analysis showed that tmao levels positively predicted cimt levels. conclusions: this study confirmed that psoriasis is a risk factor for the development of cardiovascular disease and that elevated serum tmao levels in these patients indicate the presence of intestinal dysbiosis. furthermore, tmao levels were found to be a predictor of the risk of developing cardiovascular disease in psoriasis patients. original article | dermatol pract concept. 2023;13(2):e2023116 3 demographic information of all participants was recorded and systolic/diastolic blood pressure was measured from the brachial artery after 5 minutes of rest. body-mass index (bmi) of all participants and psoriasis area severity index (pasi) of patients were calculated and recorded. tmao, oxidized-ldl, hs-crp, cholesterol panel, alt-ast, creatinine, alt-ast, creatinine levels were determined in serum samples obtained after 12 hours of fasting. right and left carotid intima-media thicknesses were measured and recorded in all participants. measurement of biochemical markers blood samples were collected from the antecubital regions of the participants into gel propylene tubes using a vacutainer. blood samples were allowed to clot for 20  minutes, centrifuged at 3000 rpm for 10 minutes and stored at -80°c until the study day. frozen serum samples were kept at room temperature on the study day and the samples were thawed. mybiosource brand oxidized ldl (catalog no: mbs265658) commercial kit for oxidized-ldl analysis and mybiosource brand tmao (catalog no: mbs7254766) commercial kits for tmao analysis were used. analyzes were performed using rayto rt-2600microplate washer and bmg labtech enzyme-linked immunosorbent assay (elisa) reader. the quantitation limits for the oxidized ldl kit are 31.2-2000 pg/ml, and the quantitation limits for tmao are 0-100 ng/ml. samples were diluted 1/10 before the study. alt, ast, creatinine, total cholesterol, triglyceride, hdl-cholesterol, total cholesterol, triglyceride, hdl-cholesterol levels were analyzed by spectrophotometric method on beckman coulter au5800 series using beckman coulter commercial kits. hs-crp levels were analyzed by immunoturbidimetric method using beckman coulter brand commercial kits in beckman coulter au5800 series device. measurement of carotid intima-media thickness carotid artery ultrasound to measure carotid intima-media thickness was performed by a cardiologist using a commercially available ultrasound system (vivid e9, ge vingmed) and a linear transducer probe (11l-d, 5-12 mhz). participants were examined in the supine position after resting for at least 5 minutes. imaging of both arteria carotids communis was performed with the participants' head in a slightly extended and slightly retracted position with the carotid bifurcation as the reference point. two-dimensional, real-time, grayscale images in the longitudinal plane were acquired at frame rates of 20-50 fps with focus and gain settings adjusted to maximize visibility of the near and far wall of the artery. statistical method all data were analyzed in computer environment using spss 22.0 package program. categorical data were evaluated with the chi-square exact test. the kolmogorow-smirnow test was performed to determine whether the continuous data showed a normal distribution. continuous data that did not show normal distribution were tested for their conformity to the normal distribution by data transformation. in the comparison of continuous data of two independent groups, student-t test was used when parametric test conditions were met, mann whitney u test was used when parametric test conditions were not met. in order to determine the relationship between continuous variables, pearson correlation test was used when normality conditions were met and spearman correlation test was used when normality conditions were not met. in order to determine the true relationship between the data, the partial correlation test was used by controlling the related variables. simple and multiple linear regression analysis was applied to determine the risk of cardiovascular disease. regression analysis data were reported as r square, adjusted r square, standardized coefficiency β coefficients. in the analysis of all hypothesis tests, the level of significance (p value) was accepted as 0.05. results the patient and control groups were similar in terms of gender. there was no significant difference between the patient and control groups in terms of mean age, bmi, systolic/ diastolic blood pressure(p > 0.05). tmao (323.34 ± 240.36 ng/ml versus 220.96 ± 85.36 ng/ml), hs-crp (2.318 ± 2.00 mg/l versus 1.306 ± 0.74 mg/l), oxidized-ldl(82.50 ± 42.03 pg/ml versus 61.34 ± 31.34 pg/ml) and triglyceride (150.87 ± 87.85 mg/dl versus 119.83 ± 70.02 mg/dl) levels were higher in the patient group compared to the control group (figure 1). there was no significant difference in total cholesterol and ldl-cholesterol levels in the patient and control groups(p > 0.05). hdl-cholesterol levels were higher in the control group compared to the patient group (47.75 ± 10.12 mg/dl versus 39.09 ± 9.38 mg/dl). left-anterior (0.598 ± 0.129 nm versus 0.534 ± 0.068 nm), left-posterior (0.602 ± 0.172 nm versus 0.528 ± 0.093 nm) and right-anterior (0.623 ± 0.177 nm versus 0.537 ± 0.086 nm), right-posterior (0.605 ± 0.164 nm versus 0.520 ± 0.075 nm) 4 original article | dermatol pract concept. 2023;13(2):e2023116 carotid intima-media wall thicknesses were significantly higher in the patient group compared to the control group (figures 2 and 3). the clinical and laboratory data of the patient and control groups are given in table 1. in the partial correlation analysis performed after controlling for age, disease duration and bmi parameters, positive correlations were observed at various levels between tmao levels and total cholesterol, ldl cholesterol, left anterior and right posterior cimt (table 2). when parameters that may affect cimt (age, bmi, disease duration, pasi score, blood cholesterol, hs-crp and oxidized-ldl) were controlled, positive correlations were found between tmao levels and left anterior and right posterior cimt at various levels (table 3). simple linear regression analysis was performed to predict the left cimt variable by using tmao levels. a significant regression model was found in which 10% (r square adjusted = .10) of the variance in the left cimt was explained by the independent variable (f [1, 71]:8.084, p = 0.006). accordingly, tmao predicted left cimt positively and significantly, ß= .32, t(71) = 2.843, p = :0.006 (table.4). multivariate linear regression analysis was performed to predict the left cimt variable by using tmao, pasi, disease duration, age, ox-ldl, total cholesterole, triglyceride, bmi variables. a significant regression model was found in which 41% (r square adjusted= .41) of the variance in the left cimt was explained by the independent variables (f [9, 63]:6,644, p < 0.001). accordingly, tmao predicted left cimt positively and significantly (ß= .371, t(63)=3.801, control patient 0 50 100 150 200 250 300 350 tmao (ng/ml) figure 1. trimethylamine n-oxide levels in patient and control groups. p < 0.001). in addition, age predicted left cimt positively and significantly (ß= .618, t(63)=5.428, p < 0.001). oxidized-ldl, hs-crp, triglyceride, total cholesterol, pasi, disease duration and bmi did not significantly predict left cimt in this model (p > 0.05). the regression model confirmed that tmao was a positive predictor for left anterior cimt and may be a predictor for cardiovascular disease secondary to these outcomes (table 5). conclusions psoriasis is not only a skin and joint disease, but also a systemic inflammatory disease that can be associated with various comorbidities. it is associated with an increased risk of developing serious vascular events, particularly myocardial infarction and stroke. psoriasis and atherosclerotic cardiovascular disease share common genetic and pathophysiological pathways, including genetic factors, inflammatory pathways, secretion of adipokines, insulin resistance, lipoprotein composition and function, angiogenesis, oxidative stress and hypercoagulation [11]. the development of atherosclerosis is a major pathological process that can lead to myocardial infarction and stroke. in the literature, there are studies showing that arterial wall thickness is increased in patients with psoriasis compared to healthy controls and this increase is correlated with disease severity. positron emission tomography/computed tomography studies have found that aortic wall inflammation is higher in patients with psoriasis than in the healthy population and that there is a positive correlation between disease original article | dermatol pract concept. 2023;13(2):e2023116 5 left posterior cimt left anterior cimt 0.48 0.5 0.52 0.54 0.56 0.58 0.6 0.62 control(mm) patient(mm) figure 2. left carotid intima-media thickness levels in patient and control groups. right posterior cimt right anterior cimt 0.46 0.48 0.5 0.52 0.54 0.56 0.58 0.6 0.62 0.64 control(mm) patient(mm) figure 3. right carotid intima-media thickness levels in patient and control groups. severity and inflammation severity. furthermore, aortic inflammation decreases with healing of skin lesions [12,13]. the finding of higher cimt levels in psoriasis patients compared to healthy controls in carotid artery ultrasonography studies clearly demonstrates an increased risk of cardiovascular disease in psoriasis patients [14-16]. our study showed that cimt levels were significantly higher in psoriasis patients compared to the control group. there were also positive correlations between cimt values and patient age, disease duration, tmao, hs-crp, triglyceride, total cholesterol, body mass index and blood pressures. in the light of these data, cimt measurement can be used 6 original article | dermatol pract concept. 2023;13(2):e2023116 to detect the risk of early atherosclerotic disease in patients with psoriasis, which is consistent with previous studies. microbiota related immunomodulation has shown that the gut microbiome plays a role in influencing distant organs, mucosal and hematopoietic immune function. disruption in the composition and function of the intestinal microbiota is associated with a variety of chronic diseases, from gastrointestinal inflammatory and metabolic diseases to neurological, cardiovascular and respiratory system diseases. the changes observed in the composition of the gut microbiome in studies with psoriasis patients have prompted researchers to investigate the molecular mechanisms associated with the microbiome and its possible impact on the disease [17-19]. in recent years, the tmao molecule formed by the oxidation in the liver of tma produced from choline and l-carnitine by the gut microbiome is thought to be associated with increased cardiovascular risk and atherosclerosis, but there are also conflicting results. the dysbiotic gut microbiome observed in psoriasis patients is similar to the composition of the dysbiotic microbiome, which is involved in tmao production [5,6,17]. tmao table 1. data for patients and healthy controls. patient (n = 73) mean ± sd control (n = 72) mean ± sd pa disease type type-1(%86.30) type-2(%13.70) age (year) 41.57 ± 12.98 41.22 ± 9.25 0.851 bmi (kg/m2) 26.14 ± 4.20 25.63 ± 3.35 0.420 systolic blood pressure (mmhg) 121.34 ± 10.05 122,06 ± 10.50 0.676 diastolic blood pressure (mmhg) 79.74 ± 7.27 81.26 ± 7.62 0.187 tmao (ng/ml) 323.34 ± 240.36 220.96 ± 85.36 0.028 hscrp (mg/l) 2.318 ± 2.00 1.306 ± 0.74 0.013 oxidized-ldl (pg/ml) 82.50 ± 42.03 61.34 ± 31.34 0.010 total cholesterol (mg/dl) 189.77 ± 41.12 194.29 ± 34.71 0.475 hdl cholesterol (mg/dl) 39.09 ± 9.38 47.75 ± 10.12 0.001 ldl cholesterol (mg/dl) 120.74 ± 36.71 121.99 ± 29.68 0.323 triglyceride (mg/dl) 150.87 ± 87.85 119.83 ± 70.02 0.025 ast (iu/l) 20.50 ± 5.53 20.93 ± 4.27 0.291 alt (iu/l) 17.13 ± 8.18 17.82 ± 7.95 0.523 creatinine (mg/dl) 0.75 ± 0.14 0.75 ± 0.20 0.948 left anterior cimt (mm) 0.598 ± 0.129 0.534 ± 0.068 0.010 left posterior cimt (mm) 0.602 ± 0.172 0.528 ± 0.093 0.030 right anterior cimt (mm) 0.623 ± 0.177 0.537 ± 0.086 <0.001 right posterior cimt (mm) 0.605 ± 0.164 0.520 ± 0.075 0.020 alt = alanine aminotransferase; ast = aspartate aminotransferase; bmi = body mass index; cimt = carotid intima-media thickness; hscrp = high sensitivity c-reactive protein; hdl = high density lipoprotein; ldl = low density lipoprotein; sd = standard deviation; tmao = trimethylamine n-oxide. athe level of significance (p value) was accepted as 0.05. plays an important role in oxidized-ldl accumulation and foam cell formation within macrophages by increasing the expression of cd36 and macrophage scavenger receptors (sr-a1). it enhances macrophage chemotaxis, expression of inflammatory cytokines including tnf-alpha and il-6, and may exacerbate inflammation via mapk and nf-κb. it also decreases the expression of the anti-inflammatory cytokine il-10 [20-23]. studies investigating serum tmao levels and their relationship with comorbidities in patients with psoriasis are still very limited. sikora et al. found that tmao levels were significantly higher in psoriasis patients than in controls and this elevation was in parallel with the increased cardiovascular risk [24]. in this study, we found that serum tmao levels were significantly higher in psoriasis patients compared to the control group. in the patient group, there were positive correlations between serum tmao concentrations and cimt values when other cardiovascular risk markers were controlled. the results support the presence of gut dysbiosis in psoriasis patients, and these data support the idea that original article | dermatol pract concept. 2023;13(2):e2023116 7 ta b le 2 . c o rr el at io n s w h en c o n tr o ll in g fo r ag e, b m i, a n d d is ea se d u ra ti o n i n t h e p at ie n t gr o u p . t m a o o x id iz e d -l d l h sc r p tr ig ly ce ri d e to ta lc h d lc ld lc pa s i le ft a n t c im t le ft p o st c im t r ig h t a n t c im t r ig h t p o st c im t t m a o p 1 .0 0 0 r 0 .0 0 0 o x id iz ed -l d l p 0 .6 6 7 1 .0 0 0 r 0 .0 5 2 0 .0 0 0 h sc r p p 0 .5 1 0 0 .8 4 7 1 .0 0 0 r -0 .0 8 0 0 .0 2 3 0 .0 0 0 t ri gl yc er id e p 0 .8 2 1 0 .0 2 2 0 .2 6 5 1 .0 0 0 r -0 .0 2 7 0 .2 7 4 0 .1 3 5 0 .0 0 0 t o ta lc p 0 .0 0 6 0 .4 6 5 0 .7 4 8 0 .0 0 3 1 .0 0 0 r 0 .3 2 5 0 .0 8 9 -0 .0 3 9 0 .3 4 5 0 .0 0 0 h d l -c p 0 .6 5 5 0 .5 7 3 0 .0 1 4 0 .0 0 1 0 .9 0 3 1 .0 0 0 r 0 .0 5 4 -0 .0 6 9 -0 .2 9 3 -0 .3 8 7 0 .0 1 5 0 .0 0 0 l d l -c p 0 .0 0 3 0 .9 6 0 0 .8 0 4 0 .8 3 7 < 0 .0 0 1 0 .5 5 9 1 .0 0 0 r 0 .3 4 9 -0 .0 0 6 -0 .0 3 0 0 .0 2 5 0 .9 1 8 -0 .0 7 1 0 .0 0 0 pa si p 0 .5 8 0 0 .2 8 8 0 .6 1 3 0 .3 8 0 0 .1 1 4 0 .5 1 1 0 .1 2 9 1 .0 0 0 r -0 .0 6 7 -0 .1 2 9 0 .0 6 2 -0 .1 0 6 -0 .1 9 1 0 .0 8 0 -0 .1 8 3 0 .0 0 0 l ef t an t c im t p < 0 .0 0 1 0 .3 4 0 0 .5 4 7 0 .4 7 1 0 .1 4 1 0 .0 7 0 0 .1 0 0 0 .2 1 0 1 .0 0 0 r 0 .4 5 3 0 .1 1 6 -0 .0 7 3 0 .0 8 8 0 .1 7 8 -0 .2 1 8 0 .1 9 8 -0 .1 5 2 0 .0 0 0 l ef t p o st c im t p 0 .7 7 3 0 .3 6 2 0 .2 3 8 0 .1 8 9 0 .6 6 1 0 .0 9 5 0 .7 5 8 0 .5 8 3 0 .0 1 9 1 .0 0 0 r 0 .0 3 5 0 .1 1 1 0 .0 4 7 0 .1 5 9 0 .0 5 3 -0 .2 0 1 0 .0 3 8 -0 .0 6 7 0 .2 8 1 0 .0 0 0 r ig h t an t c im t p 0 .9 4 3 0 .0 6 8 0 .4 8 2 0 .6 1 9 0 .7 4 0 0 .0 8 6 0 .4 6 2 0 .4 2 3 0 .0 0 6 0 .0 3 2 1 .0 0 0 r 0 .0 0 9 0 .2 1 9 0 .0 8 5 0 .0 6 1 0 .0 4 0 -0 .2 0 7 0 .0 8 9 -0 .0 9 7 0 .3 2 7 0 .2 5 6 0 .0 0 0 r ig h t p o st c im t p 0 .0 3 4 0 .1 5 0 0 .0 8 4 0 .2 0 8 0 .2 2 6 0 .0 9 4 0 .2 7 2 0 .9 5 1 < 0 .0 0 1 0 .0 0 4 0 .6 1 3 1 .0 0 0 r 0 .2 5 3 0 .1 7 4 0 .2 0 8 0 .1 5 2 0 .1 4 7 -0 .2 0 2 0 .1 3 3 -0 .0 0 8 0 .4 6 1 0 .3 4 3 0 .0 6 1 0 .0 0 0 a lt = a la n in e am in o tr an sf er as e; a st = a sp ar ta te a m in o tr an sf er as e; b m i = b o d y m as s in d ex ; c im t = c ar o ti d i n ti m am ed ia t h ic k n es s; h sc r p = h ig h s en si ti vi ty c -r ea ct iv e p ro te in ; h d l = h ig h d en si ty l ip o p ro te in ; l d l = l o w d en si ty l ip o p ro te in ; pa si = p so ri as is a re a an d s ev er it y in d ex ; sd = s ta n d ar d d ev ia ti o n ; t m a o = t ri m et h yl am in e  n -o x id e. 8 original article | dermatol pract concept. 2023;13(2):e2023116 table 5. multiple linear regression model adjusted for trimethylamine n-oxide, psoriasis area and severity index, disease duration, age, oxlow density lipoprotein, total cholesterol, triglyceride, body mass index (dependent variable: left anterior carotid intima-media thickness). standardized coefficients beta t p variance inflation factor (vif) tmao 0.371 3,801 <0.001 1.169 age 0.618 5.428 <0.001 1.590 oxidized-ldl 0.047 0.499 0.620 1.108 hscrp -0.040 -0.399 0.691 1.248 triglyceride 0.078 0.705 0.483 1.503 total cholesterol -0.023 -0.209 0.835 1.543 pasi -0.088 -0.943 0.350 1.068 disease duration -0.005 -0.047 0.963 1.420 bmi -0.079 -0.794 0.430 1.201 bmi = body mass index; hscrp = high sensitivity c-reactive protein; ldl = low density lipoprotein; pasi = psoriasis area and severity index table 3. correlations between trimethylamine n-oxide and carotid intima-media thickness levels when age, body mass index, disease duration, psoriasis area and severity index score, blood cholesterol, high sensitivity c-reactive protein and oxidizedlow density lipoprotein were controlled. tmao left ant cimt left post cimt right ant cimt right post cimt tmao p 1.000 r 0.000 left ant cimt p <0.001 1.000 r 0.447 0.000 left post cimt p 0.711 0.028 1.000 r 0.048 0.277 0.000 right ant cimt p 0.905 0.004 0.077 1.000 r -0.015 0.358 0.225 0.000 right post cimt p 0.047 <0.001 0.025 0.870 1.000 r 0.251 0.439 0.282 0.021 0.000 cimt = carotid intima-media thickness; tmao = trimethylamine n-oxide. table 4. simple linear regression model, predictor: trimethylamine n-oxide, dependent: left anterior and right posterior carotid intima-media thickness. r2 standardized coefficients beta t p f predictor: tmao dependent: left ant cimt 0.102 0.320 2.843 0.006 8.084 predictor: tmao dependent: right post cimt 0.020 0.141 1.199 0.235 1.199 cimt = carotid intima-media thickness; tmao = trimethylamine n-oxide. tmao is a metabolite originating from the gut microbiota that increases the risk of cardiometabolic disease. in regression models, tmao levels were found to be a positive predictor of cardiovascular disease risk (figure 4). crp is a circulating acute phase reactant that reflects active systemic inflammation. increased hs-crp levels are associated with a higher risk of cardiovascular disease, even in individuals without clinical manifestations of atherosclerotic disease [25]. in psoriasis patients, hs-crp levels are higher than in the healthy population and correlated with the risk of atherosclerotic disease [26,27]. in this study, hs-crp levels were found to be higher in the patient group compared to healthy controls. in addition, positive correlation between hs-crp and triglyceride levels original article | dermatol pract concept. 2023;13(2):e2023116 9 references 1. hu sc-s, lan c-ce. psoriasis and cardiovascular comorbidities: focusing on 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plaque psoriasis: association or causal link? atherosclerosis. 2014;232(1):72-78. doi: 10.1016/j.atherosclerosis. 2013.10.023. pmid: 24401219. 17. masallat d, moemen d, ahmed f. gut bacterial microbiota in psoriasis: a case control study. afr j microbiol res. 2016;10:1337-1343. doi: 10.5897/ajmr2016.8046 18. durack j, lynch sv. the gut microbiome: relationships with disease and opportunities for therapy. j exp med. 2019;216(1):20-40. doi: 10.1084/jem.20180448. pmid: 30322864; pmcid: pmc6314516. 19. ellis sr, nguyen m, vaughn ar, et al. the skin and gut microbiome and its role in common dermatologic conditions. microorganisms. 2019;7(11):550. doi: 10.3390/microorganisms7110550. pmid: 31717915. pmcid: pmc6920876. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022157 1 adiponectin contributes to the inflammatory milieu in hidradenitis suppurativa ersilia nigro1,2, rita polito2, graziella babino3, edi mattera4, elisabetta fulgione3, giovanni ragozzino4, vittoria d’esposito5, serena cabaro5, giuseppe signoriello6, pietro formisano5, giuseppe argenziano4, aurora daniele2,7 1 dipartimento di scienze e tecnologie ambientali, biologiche e farmaceutiche, università degli studi della campania “luigi vanvitelli”, caserta, italy 2 ceinge-biotecnologie avanzate, naples, italy 3 dermatology unit, università degli studi della campania “luigi vanvitelli”, naples, italy 4 department of internal and experimental medicine and surgery unit of internal medicine, università degli studi della campania “luigi vanvitelli”, naples, italy 5 department of translational medicine, university of naples federico ii, naples, italy 6 department of public, clinical and preventive medicine, medical statistics unit, università degli studi della campania “luigi vanvitelli”, naples, italy 7 dipartimento di medicina molecolare e biotecnologie mediche, università degli studi di napoli «federico ii», naples, italy key words: adiponectin, hidradenitis suppurativa, cytokines, inflammation, immune system citation: nigro e, polito r, babino g, et al. adiponectin contributes to the inflammatory milieu in hidradenitis suppurativa. dermatol pract concept. 2022;12(4):e2022157. doi: https://doi.org/10.5826/dpc.1204a157 accepted: march 8, 2022; published: october 2022 copyright: ©2022 nigro et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: por campania fesr 2014/2020. projectcup: b21c17000030007 competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: aurora daniele, phd, dipartimento di medicina molecolare e biotecnologie mediche; università degli studi di napoli «federico ii»; ceinge-biotecnologie avanzate, via gaetano salvatore, 486, 80145 napoli, italy. tel.: +39 081 3737856, fax: +39 081 3737808 e-mail: aurora.daniele@unina.it introduction: hidradenitis suppurativa (hs) is a severe chronic skin disease. although the pathogenesis remains unclear, at the basis of hs there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. cytokine dysregulation is crucial in hs severity and progression. objectives: the aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomers in hs patients compared to both obese and healthy subjects. methods: the concentrations of adiponectin and cytokines were measured using enzyme-linked immunosorbent assay (elisa); the oligomeric distribution of adiponectin (low molecular weight (lmw), medium molecular weight (mmw) and high molecular weight (hmw) oligomers)was evaluated through western blotting analysis. abstract 2 original article | dermatol pract concept. 2022;12(4):e2022157 introduction hidradenitis suppurativa (hs) is a complex, chronic inflammatory skin disease characterized primarily by a dysregulation of the innate immune system and by a chronic inflammation that is not only restricted to skin but, especially in severe cases, affects different tissues and organs [2,3]. in particular, the over-activated immune cell infiltration, that is at the basis of hs disease, enhances the inflammatory response through the secretion of a considerable quantity of pro-inflammatory (il-1β, tnfα, il-17, inf γ) as well as anti-inflammatory cytokines (il-10) and chemokines [4-6]. on the other hand, an immunological “priming” in hs comes also from environmental factors such as, smoking-related inflammatory mediators and obesity related pro-inflammatory signals [7]. in particular, in obesity, the increased adipose tissue determines a pro-inflammatory environment due to the imbalance in production of adipokines that contributes to severity and progression of hs disease [8,9]. recently, it was described a functional interplay among adipose tissue and other organs and tissues whom dysregulation has a key role in inflammation. indeed, adipose tissue is an endocrine organ that produces several adipocytokines among which adiponectin exerts multivalent beneficial functions; it is abundantly secreted in serum where it circulates as oligomers of different molecular weight: low molecular weight (lmw), medium molecular weight (mmw) and high molecular weight (hmw) [10]. the hmw are the most biologically active oligomers [11]. adiponectin is involved in the regulation of energy homeostasis, insulin sensitivity and inflammation [12]; interestingly, adiponectin expression is up-regulated in different inflammatory diseases and in some auto-immune diseases, while is down-regulated in metabolic diseases [13]. regarding hidradenitis, serum adiponectin concentrations were found to be significantly lower, while the levels of the other adipocytokines have been found significantly higher than in controls [14,23]. the aim of this study was to analyze the serum concentrations of 27 cytokines and the most abundant adipocytokine, the adiponectin, in patients affected by hs to investigate the potential relationships with metabolic parameters, disease severity and the risk of hs. we examined cytokines, adiponectin as potential biomarkers of inflammation in hs. objectives to better understand the nature of inflammation in hs and the potential cross link with adipose tissue (at), the aim of our study was to analyze the expression of different cytokines focusing on adiponectin concentrations and its oligomeric distribution in serum of hs patients respect to both obese and healthy subjects. methods participants fifty-three patients (31 females, 22 males), aged 30.0 ± 13.0 years, were recruited from the dermatology unit of the università degli studi della campania “luigi vanvitelli”. subjects were excluded from our study if they met any of the following criteria: age < 18 years, body mass index (bmi) < 17 or > 35, major metabolic disorders (type 2 diabetes, cardiovascular disorders, metabolic syndrome), the presence of concomitant inflammatory cutaneous or systemic disorders and the presence of cancer; were excluded also the patients receiving any systemic treatment which could interfere with the studied parameters. disease staging was based on the three-degree scale proposed by hurley. the mean bmi of 29.67 ± 6.1 kg/m2 qualified our patients as overweight. the smoker rate amounted to 62.3%. forty-two healthy volunteers were recruited from the ceinge staff, they aged 33 ± 12.0 years old and constituted the control group (bmi  = 23.3 ± 3.0); 53 obese subjects, aged 33±12 years old (bmi = 48.4 ± 9.4), were recruited from the foundation “salvatore maugeri” telese, italy [15]. all hs patients fulfilled the established hs diagnostic criteria. all subjects signed an informed consent form. the study was approved results: total adiponectin is statistically higher in hs patients compared to matched controls and obese subjects. interestingly, adiponectin oligomerization state is altered in hs, with an increase of hmw oligomers. serum levels of pdgf-bb, il-1β, il-5, il-6, il12, il13, il15, il-17, gmcsf, infγ, vegf and mcp-1 are statistically higher while il-1ra and rantes levels are statistically lower in hs patients compared to healthy controls. interestingly, adiponectin positively correlates with pdgfbb, and il-13. conclusions: our data confirmed that the complex network that links metabolism to immune homeostasis is dysregulated in hs and that adiponectin and its hmw oligomers are actively involved in this disease. in addition, the correlation between adiponectin and pdgf-bb, and il-13 extends the role of this adipokine in modulation of the immune response, in particular regulating the innate immune system rather that the adaptive one. further researches are needed to clarify the complex inflammatory milieu that characterizes hs syndrome. original article | dermatol pract concept. 2022;12(4):e2022157 3 by the ethic committee of the università degli studi della campania “luigi vanvitelli” (prot. 12478/20). anthropometric and biochemical measurements blood samples from 53 hs patients, 42 healthy subjects and 53 obese subjects were collected after a 12-hours overnight fasting period and centrifuged to collect serum. serum aliquots were immediately frozen in liquid nitrogen and stored at -80°c. for all participants total cholesterol, triglycerides, glycemia, c-reactive protein were measured (table 1). the concentration of total adiponectin was measured in triplicate by an enzyme-linked immunosorbent assay (elisa) as previously described [16]. the levels of 27 cytokine species (pdgf-bb, il1β, il1ra, il2, il4, il5, il6, il7, il8, il9, il10, il12, il13, il15, il17, eotaxin, fgf, gcsf, gmcsf, infγ, ip10, mcp-1, ip1α ip1β, rantes, tnfa , vegf) were measured in 30 hs patients and in 39 healthy controls using a commercially available kit (bio-plex pro™ human cytokine 8-plex assay). the assay was performed according to the manufacturer’s instructions and the concentrations of cytokines were calculated by comparing reads with a 5-parameter logistic standard curve using a bioplex-200 instrument (bio-rad). western blotting analysis of serum adiponectin five micrograms of total serum proteins were treated and subjects to electrophoresis as previously described [17]. the blots were developed by ecl (amersham biosciences) with the use of kodak biomax light film and digitalized with a scanner (1.200 dpi) and analyzed by densitometry with the imagej software. each serum sample was tested 2 times in duplicate. statistical analysis data is expressed as average ± standard deviation (sd) and median. the meanings of the differences in biochemical parameters between the groups were determined using the mann-whitney test and the chi-square test. to evaluate the relationship with median adiponectin levels, multiple logistic regression was performed. a p value <0.05 was considered to indicate statistically significant results. results baseline features and serum levels of adiponectin in hs patients the anthropometric and biochemical characteristics of hs patients, sex and age-matched obese and healthy subjects are shown in table 1. we found statistically significant difference in bmi between hs patients and controls (29.67 ± 6.12 versus 23.3 ± 3.04, p < 0.00) as well as for total adiponectin serum levels (28.25 μg/ml ± 4.49 versus 24.67 μg/ml ± 3.35, p < 0.01); both parameters result significantly higher in hs patients compared to controls. the statistical analysis indicated that the increase of adiponectin levels in hs is independent from bmi and sex, 2 potential confounding factors. statistical analysis did not reveal significant difference in adiponectin concentrations among the hs groups based on the three hurley degrees of disease severity. hs hurley degree of hs patients are reported in table 1: 30.2% of the patients have a hurley i, 52.8% hurley ii and 17.0% hurley iii degree of disease severity. as in literature was reported an opposite trend and to further validate the findings on concentration of adiponectin, we measured the levels of this adipokine in a cohort of 53 obese patients; as shown in table 1, the comparison of table 1. clinical, biochemical and anthropometrical characteristics of hs, obese patients and healthy subjects. hs patients (n 53) obese subjects (n. 53) controls (n 42) p sex (f), n (%) 31 (53.8) 33 (62.3) 20 (47.6) 0.38 age mean (±sd), years 30±13 33±12 33±12 0.37 bmi mean (±sd) 29.67 ± 6.12 48.4 ± 9.4 23.3 ± 3.04 0.00 cholesterol mean (±sd) (mg/dl) 203.54 ± 44.16 169.94 ± 37.21 191.48 ± 35.22 0.00 triglycerides mean (±sd) (mg/dl) 103.62 ± 36.97 146.81 ± 102.54 82.86 ± 50.31 0.00 glycemia mean (±sd) (mg/dl) 94 ± 19 87 ± 28 86 ± 17 0.17 c-reactive protein mean (±sd) (mg/l) 6.87 ± 8.36 8.23 ± 8.48 0.41 hurley in (%) 16 (30.2) hurley ii n (%) 28 (52.8) hurley iii n (%) 9 (17.0) adiponectin mean (±sd) (γg/ml) 28.54 ± 4.49 20.06 ± 4.71 24.67 ± 3.35 0.00 bmi = body mass index; hs = hidradenitis suppurativa; sd = standard deviation. 4 original article | dermatol pract concept. 2022;12(4):e2022157 il12, il13, il15, il-17, gmcsf, infγ, vegf and mcp-1 levels were statistically higher while il-1ra and rantes levels were statistically lower in the serum of hs patients compared to healthy controls (table 2). next, to investigate whether adiponectin is functionally related with any tested cytokines, we divided the hs patients in two subgroups using the median value of adiponectin concentration (27.8 μg/ml) as an arbitrary cut-off. according to adiponectin concentrations, patients with higher adiponectin concentrations (ie with values above the median) represented subgroup 1 and patients with lower adiponectin concentrations (ie with values under the median) represented subgroup 2. statistical analysis performed using the univariate model showed that the patients with higher levels of adiponectin (subgroup 1) have also significantly higher pdgf-bb and a similar trend versus il-13 (table 3). conclusions hidradenitis (hs) is a severe chronic inflammatory skin disease primarily due to the alteration of immunity and to chronic inflammation [2,18]. a functional interconnection between immune system and adipose tissue, link observed in patients affected by metabolic disorders in which the dysregulation of energy metabolism negatively affects the immune biochemical parameters between hs patients and obese subjects showed a statistically differences in bmi (29.67 ± 6.12 versus 48.4 ± 9.4, p < 0.00) as well as in adiponectin levels; these latter are higher in hs than in obese patients (28.25 μg/ ml ± 4.49 versus 20.06 μg/ml ± 4.71, p < 0.00). oligomeric distribution of adiponectin in hs patients to better investigate the involvement of adiponectin in hs patients, we examined the oligomeric profile of this adipokine through the visualization of hmw; mmw and lmw oligomers. western blot evidenced that the hmw and mmw adiponectin oligomers are increased in serum of hs patients if compared to obese and healthy subjects (figure 1, p < 0.05). cytokine concentration in hs patients and healthy controls to better explore the inflammatory milieu in serum from hs patients, we analyzed a panel of 27 different cytokines (pdgf-bb, il1β, il1ra, il2, il4, il5, il6, il7, il8, il9, il10, il12, il13, il15, il17, eotaxin, fgf, gcsf, gmcsf, infγ, ip10, mcp-1, ip1α, ip1β, rantes, tnfα, vegf). we tested 30 hs patients and 39 controls. the results demonstrated that, among the others, pdgf-bb, il-1β, il-5, il-6, hs patients obeses controls hs 4 b a a c b a c b a a b lmwmmwhmw 3,5 3 2,5 o p ti ca l d en si ty 2 1,5 1 0,5 0 obeses controls figure 1. western blotting analysis shows that adiponectin hmw and mmw oligomers are statistically higher in serum from hs patients compared to obese and healthy subjects. (a) representative wb image of adiponectin different oligomers (hmw, mmw, lmw) from four hs patients, four obese subjects and four controls. (b) graphical representation of pixel quantization of adiponectin oligomers analysed in 53 hs patients, 53 obese subjects and 42 controls. for other details see materials and methods. p < 0.05. original article | dermatol pract concept. 2022;12(4):e2022157 5 component of the body protective systemic response to the chronic inflammatory processes and immune system alterations [17,18,21]. in this study, to investigate the nature of the inflammatory milieu in hs and the potential contribute of adipose tissue, we analyzed several cytokines focusing on the most abundant adipokine, ie adiponectin and its oligomeric profile. interestingly, system and viceversa. indeed, in obese or overweight people there is a greater frequency of autoimmune diseases such as rheumatoid arthritis, type i diabetes and hs [24]. this functional interconnection is guaranteed by the hormonal activity of the adipose tissue through the secretion of adipokines such as adiponectin. in literature, numerous studies support the hypothesis that high levels of adiponectin represent a key table 2. cytokine levels (pg/ml) in hs patients and healthy subjects. parameters controls (n 39) hs patients (n 30) p sex n (%) f 17 (44%) 19 (63%) 0.10 m 22 (56%) 11 (37%) age, mean (±sd) 33.8 (6.8) 29.6 (13.5) 0.096 bmi, mean (±sd) 25.5 (3.7) 26.6 (3.8) 0.23 il-1β, mean (±sd) 2.0 (0.5) 2.3 (0.5) 0.014 il-12, mean (±sd) 11.3 (1.3) 13.5 (3.9) 0.002 il-13, mean (±sd) 5.5 (1.1) 8.4 (4.1) <0.001 il-15, mean (±sd) 347.2 (25.0) 390.3 (38.4) <0.001 il-17, mean (±sd) 25.0 (3.9) 27.2 (5.2) 0.048 gm-csf, mean (±sd)) 12.8 (0.7) 14.5 (1.5) <0.001 ifnγ, mean (±sd) 13.3 (3.1) 18.6 (4.7) <0.001 mcp-1 (mcaf), mean (±sd) 36.9 (15.0) 56.1 (31.7) 0.001 rantes, median (iqr) 6833.4 (5469.2, 8214.1) 45145.1 (20829.6, 93670.0) <0.001 pdgf-bb, median (iqr) 1638.5 (1180.5, 1991.2) 2306.6 (1701.6, 3208.0) <0.001 il-1ra, median (iqr) 371.5 (333.0, 446.4) 333.0 (257.0, 400.0) 0.036 il-5, median (iqr) 52.3 (49.0, 55.5) 58.5 (52.3, 67.1) 0.002 il-6, median (iqr) 7.6 (7.0, 8.1) 9.0 (7.8, 10.2) <0.001 vegf, mean (sd) 417.6 (40.2) 452.3 (52.7) 0.003 bmi = body mass index; hs = hidradenitis suppurativa; sd = standard deviation. acronym list: il (interleukin); granulocytemacrophage colony-stimulating (gm-csf); interferon (inf); monocytes chemoattractant protein(mcp); platelet-derived growth factor-bb (pdgf-bb); vascular endothelial growth factor (vegf). table 3. univariate analysis of anthropometric, clinical parameters and cytokines levels (pg/ml) on the basis of adiponectin levels: median value of adiponectin (27.8 μg/ml) was used as an arbitrary cut-off. parameters adiponectin ≤ 27.8 adiponectin > 27.8 p n = 14 n = 16 sex m, n (%) 7 (50%) 4 (25%) 0.16 f, n (%) 7 (50%) 12 (75%) age, mean (±sd) 30.1 (12.1) 29.3 (15.1) 0.87 bmi, mean (±sd) 27.3 (3.7) 26.0 (4.0) 0.36 pdgf-bb, (median) (iqr) 2984.9 (2226.8, 3463.2) 1823.9 (1306.3, 2507.5) 0.020 il-5, median (iqr) 61.5 (55.5, 65.7) 55.5 (48.1, 68.1) 0.18 il-13, median (iqr) 8.8 (7.3, 9.7) 5.8 (4.9, 9.6) 0.05 gm-csf, median (iqr) 14.7 (13.9, 15.5) 13.5 (12.7, 15.8) 0.15 hurley i 5 (36%) 6 (38%) 0.98 ii 5 (36%) 6 (38%) iii 4 (29%) 4 (25%) 6 original article | dermatol pract concept. 2022;12(4):e2022157 reported in one study [30]; in two other studies no statistical difference was found [31,32]. finally, for the first time, we correlated cytokines expression level to adiponectin concentration. we found that adiponectin correlates with pdgf-bb, and il-13 but not with il-17, il-1β, and infγ suggesting that adiponectin function might be related to the innate immune system activation rather that the adaptive one, exerting anti-inflammatory actions. previously, adiponectin has been demonstrated to directly and specifically bind pdgf-bb in smooth muscle cells suppressing their proliferation and migration [33] suppressing the development of atherosclerosis, promoting inflammation. arita et al. demonstrated that the inhibitory effects of adiponectin towards pdgf-bb result in suppression of vasculogenesis and inflammation [33]. the association between adiponectin and pdgf-bb in hs patients suggests that the adipokine probably counteracts the inflammatory process triggered by the disease. as il-13 has been described as anti-inflammatory factor in the adipose tissue, the direct correlation with adiponectin further confirms that adiponectin is acting as anti-inflammatory molecule [34]. in addition, il-13 has been involved in the maintenance of macrophages in an anti-inflammatory state as m2 phenotype supporting the hypothesis that adiponectin might participate in the regulation of the innate immune response [35]. there are two main limitations in the present study, one is the relatively small number of patients and the other is the absence of a large cohort of severe patients. in addition, the great heterogeneity in age, gender, environmental factors and potential comorbidities among the hs analyzed patients in different studies may be at the basis of the variability found in the expression of cytokines. in conclusion, our data confirmed that the complex network that links together metabolism to immune homeostasis is dysregulated in hs and that adiponectin and its hmw oligomers are not only actively involved in the hs but that interacts with the complex inflammatory systemic milieu made by pro-inflammatory cytokines. in addition, the correlation between adiponectin and pdgf-bb, and il-13 extends the role of this adipokine in modulation of the immune response suggesting that adiponectin might act regulating the innate immune system rather that the adaptive one. further researches are needed to clarify the complex inflammatory milieu that characterizes hs syndrome. references 1. vossen a.r.j.v, van der zee h.h., prens e.p. hidradenitis suppurativa: a systematic review integrating inflammatory pathways into a cohesive pathogenic model. front immunol. 2018;9:2965. doi: 10.3389/fimmu.2018.02965. pmid: 30619323. pmcid: pmc6302105. we found increased levels of adiponectin and hmw oligomers in hs patients compared to both healthy and obese subjects independently from bmi. to our knowledge, there are two studies describing adiponectin concentration in hs that found decreased serum level of adiponectin in the patients [22,23]. the discrepancy with our results may be traced back to clinical and biochemical differences of the considered patients: the study by malara et al. analyzed patients with a very high bmi (33 versus 29.6 of our cohort), while gonzalez-lopez considered a cohort of patients with a more severe clinical phenotype of hs [22,23]. it is to notice, however, that we excluded that bmi might represent a confounding factor for adiponectin expression in hs patients; indeed, hs patients are more likely to have obesity and metabolic syndrome and overweight people have a greater incidence of hs [24]. in addition, although the significance of the molecular distribution of adiponectin is still largely unknown, it has been shown that the hmw oligomers have a stronger biological meaning and is the most important contributor to adiponectin functions [10]. our findings that hs is associated with high circulating adiponectin levels, combined with a shift towards the hmw forms reinforce the hypothesis that adiponectin has a strong functional role in regulating inflammation in hs. the specificity of adiponectin role in hs is confirmed also by the significant difference of its concentrations that we found in the two populations, hs and obese subjects. next, in this study, we analyzed different cytokine expression previously reported to spill-over from the skin lesions into the systemic circulation resulting in heightening risk for systemic inflammation in hs patients [1]. among the others, we found that pdgf-bb, il-1β, il-5, il-6, il12, il13, il15, il-17, gmcsf, infγ, vegf and mcp-1 levels are statistically higher in hs patients while il-1ra and rantes levels are statistically lower in the serum of hs patients compared to healthy controls. serum cytokine levels are very often altered in hs patients [25,23]. in accordance with our data, the levels of the pro-inflammatory il-17 cytokine, whose production is made by neutrophils and th17 cells, is increased in hs patients [26,27]. il-17 is crucial in determining the inflammatory process of hs, inducing the expression of other pro-inflammatory cytokines, such as il1β and tnfα and stimulating the activation of adaptive immune cells [1,28]. on the other hand, one study found no differences in il-17 levels between patients and controls [29]. regarding ifn-γ, no statistically decrease was found in the serum of hs patients while a significant difference was found in another study [7]. although not significant, our data also evidenced that il-10 is higher in hs patients than in controls suggesting that the immune system is compensating the dysregulation in th/treg ratio typical of hs compatible with the mild phenotype of most of our patients. 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10.3390/ijms21041219. pmid: 32059381: pmcid: pmc7072842. 14. jiang sw, whitley mj, mariottoni p, jaleel t, macleod as. hidradenitis suppurativa: host-microbe and immune pathogenesis underlie important future directions. jid innovations. 2021;1(1):100001. doi: 10.1016/j.xjidi.2021.100001. pmid: 34909706. pmcid: pmc8659377 15. corbi g, polito r, monaco ml, et al. adiponectin expression and genotypes in italian people with severe obesity undergone a hypocaloric diet and physical exercise program. nutrients. 2019;11(9):2195. doi: 10.3390/nu11092195. pmid: 31547312. pmcid: pmc6769478. 16. nigro e, scudiero o, ludovica monaco m, polito r, schettino p, grandone a, perrone l, miraglia del giudice e, daniele a. adiponectin profile and irisin expression in italian obese children: 8 original article | dermatol pract concept. 2022;12(4):e2022157 31. jiménez-gallo d, de la varga-martínez r, ossorio-garcía l, albarrán-planelles c, rodríguez c, linares-barrios m. the clinical significance of increased serum proinflammatory cytokines, c-reactive protein, and erythrocyte sedimentation rate in patients with hidradenitis suppurativa. mediators inflamm. 2017;2017:2450401. doi: 10.1155/2017/2450401. pmid: 28769536. pmcid: pmc5523401. 32. wolk k, wenzel j, tsaousi a, et al. lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa. br j dermatol. 2017;177(5):1385-1393. doi: 10.1111/bjd.15424. pmid: 28256718. 33. arita y, kihara s, ouchi n, et al. adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-bb-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. circulation. 2002;105(24):2893-8. doi: 10.1161/01.cir.0000018622.84402. ff. pmid: 12070119. 34. kwon h, laurent s, tang y, zong h, vemulapalli p, pessin je. adipocyte-specific ikkβ signaling suppresses adipose tissue inflammation through an il-13-dependent paracrine feedback pathway. cell rep. 2014;9(5):1574-1583. doi: 10.1016/j.celrep.2014.10.068. pmid: 25466256. pmcid: pmc4268106. 35. pirola l, ferraz jc. role of proand anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. world j biol chem. 2017;8(2):120-128. doi: 10.4331/wjbc.v8.i2.120. pmid: 28588755. pmcid: pmc5439163. 36. hattori y, nakano y, hattori s, tomizawa a, inukai k, kasai k. high molecular weight adiponectin activates ampk and suppresses cytokine-induced nf-kappab activation in vascular endothelial cells. febs lett. 2008;582(12):1719-1724. doi: 10.1016/j.febslet.2008.04.037. pmid: 18455514. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e202307 1 diagnosis and differential diagnosis of poikiloderma of civatte: a dermoscopy cohort study alexandros c. katoulis1, dimitrios sgouros1, evangelia bozi1, georgia pappa1, sofia theotokoglou1, marie pauline konstantinou1, alexandra voudouri1, maria voudouri1, melpomeni theofili1, korina tzima1, rainer hofmann-wellenhof2 1 2nd department of dermatology and venereology, national and kapodistrian university of athens, medical school, “attikon” general university hospital, athens, greece 2 department of dermatology, medical university of graz, graz, austria key words: poikiloderma, dermoscopy, epidemiology, diagnosis, differential diagnosis citation: katoulis ac, sgouros d, bozi e, et al. diagnosis and differential diagnosis of poikiloderma of civatte: a dermoscopy cohort study. dermatol pract concept. 2023;13(1):e202307. doi: https://doi.org/10.5826/dpc.1301a7 accepted: july 15, 2022; published: january 2023 copyright: ©2023 katoulis et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: alexandros katoulis, 2nd dept. of dermatology-venereology, “attikon” general university hospital, 1 rimini str., athens 12462, greece. tel: 0030 210 5832396 e-mail: alexanderkatoulis@yahoo.co.uk introduction: poikiloderma of civatte (pc) is a common, acquired, chronic, benign poikiloderma of the neck and face, most commonly affecting peri-menopausal females. at the time of writing, few studies have been published regarding the dermoscopy of pc. objective: to describe the dermoscopic picture of pc, so as to provide a clinico dermoscopic diagnosis and differential diagnosis for pc. methods: twenty-eight patients with pc, aged 26-73 years, of whom 19 females (67.86%) were evaluated by detailed history, clinical examination, and dermoscopic examination with hand-held dermoscope. results: the reticular pattern was observed in 15 cases (53.6%); the white dot in 10 (35.7%); the non-specific in 9 (32.1%); and the combination of linear and dotted vessels in 8 (28.6%). regarding local dermoscopic features, converging curved vessels were observed in 18 cases (64.3%); linear irregular vessels in 17 (60.7%); rhomboidal/polygonal vessels in 15 (53.6%); dotted/globular vessels in 10 (35.7%); white macules in 23 (82.1%); brown macules in 11 (39.3%); and whitish follicular plugs in 6 (21.4%). conclusions: the dermoscopic picture of pc is highly characteristic and corresponds well to both clinical and histological findings. dermoscopy may assist clinical diagnosis, as well as the differentiation from other dermatoses of the neck and face, especially poikilodermas with guarded prognosis. abstract 2 original article | dermatol pract concept. 2023;13(1):e202307 introduction poikiloderma of civatte (pc) is a rather common benign dermatosis of the neck and face, mainly affecting fair-skinned individuals, especially postmenopausal females. it is characterized by a combination of a reticular pattern of linear telangiectasia, mottled hyperpigmentation and superficial atrophy [1,2]. clinically, it involves symmetrically sun-exposed areas of the face, the neck, and the v-shaped area of the chest, invariably sparing the anatomically shaded areas [1,2]. depending on the prevalent clinical feature, pc can be classified into erythemato-telangiectatic, pigmented, and mixed clinical types [2]. the etiopathogenesis of pc is incompletely understood. exposure to ultraviolet radiation, hormonal changes of menopause, contact sensitization to perfumes and cosmetics, and normal ageing have been incriminated. the diagnosis is usually clinical and can be confirmed by histology, which is characteristic, but not pathognomonic [3]. the course is slowly progressive and irreversible, often causing significant cosmetic disfigurement. dermoscopy is an in vivo diagnostic technique that has considerably increased our diagnostic skills. its use has been extended, apart from dermato-oncology, in almost every disease in the context of general dermatology [4-6]. at the time of writing, very few studies have been published regarding the dermoscopy of pc. objectives the aim of the present study was to describe the dermoscopic picture of pc. furthermore, we sought to assist the differentiation of pc from other dermatoses of the face and neck and most importantly from acquired poikilodermas with poor or guarded prognosis (poikiloderma vasculare atrophicans and poikiloderma associated with collagen vascular disease), thus reducing the need for biopsy and histologic verification [1,2]. material and methods the study was conducted at the 2nd department of dermatology and venereology of the national and kapodistrian university of athens at “attikon” general university hospital in athens, greece during a period of 18 months (january 2018 – june 2019). patients with a clinical diagnosis of pc, visiting the outpatient clinic of our department, were recruited after they had given their informed consent. the study was approved by the ethics committee of the hospital. in all patients, a detailed history was obtained which included: demographic characteristics; family history with an emphasis on the presence of a similar condition in other family members; medical history, including drug history; in females, gynecological history and menstrual status; skin phototype according to fitzpatrick’s classification; sun exposure habits: occupational or recreational, and the level of exposure; use of sunscreens; use of fragrances or fragranced cosmetics, applied on the sides of the neck or the décolleté area of the chest; and history of pc. during clinical examination, the following clinical parameters were recorded: location; distribution; clinical type; and presence of clinical manifestations of rosacea. the dermoscopic examination was performed by an experienced evaluator (a.c.k.). for the dermoscopic examination, a dermlite dl200hybrid (3gen, san juan capistrano ca, usa) hand-held dermoscope was used. examination employed polarized light and a 10-fold magnification either without contact of the glass slide with the skin or with contact but without applying pressure on the skin (for better visualization of the vascular component). photographic documentation was made using an iphone 8 camera. photographs were taken from seven preselected sites, the same for all patients, on the upper chest, the sides of the neck, and the peripheral face in a symmetrical manner. firstly, we attempted to describe the local features, pigmented or vascular, that predominated on dermoscopic examination among our patients. the following structures were assessed: (i) rhomboidal/polygonal vessels, (ii) linear irregular vessels, (iii) dotted/globular vessels, (iv) brown macules, (v) white macules, (vi) follicular plugs. secondly, we analyzed and described the global pattern. statistical methods for continuous variables, the mean, standard deviation and range, or the median, 25th and 75th percentiles and range, were used after testing for normal distribution. for categorical variables, the frequencies and percentages were used. the shapiro-wilk test for normality was applied. chi-squared and fischer's exact tests were used for the comparison of categorical variables while unpaired t-tests and mann-whitney u tests were applied depending on the distributions of the continuous variables. all statistical analyses were performed using stata/ic version 15. results the demographics, etiologic factors and clinical characteristics of our patients are summarized in table 1. in total, 28 patients with pc were recruited. the median age was 55 years (range 26-73 years). there were 19 females (67.86%) aged 46-73 years (median age 54 years), and 9 males aged 26-65 years (median age 59 years). on clinical examination, the mixed type was the most prominent (71.43%), followed by the erythemato-telangiectatic type (21.43%) and the pigmented type (7.14%). the original article | dermatol pract concept. 2023;13(1):e202307 3 most common localization was the v-shaped area of the chest. less than one-third of the patients complained of accompanying symptoms (burning, flushing and pruritus). the most commonly reported comorbid skin condition was rosacea (mainly of the erythemato-telangiectatic type), observed in approximately half of the patients. moreover, disorders of the thyroid gland were also common, involving 28.57% of the patients. it is of interest that 4/28 cases (14.28%) had a history of systemic lupus erythematosus. on dermoscopic examination, the local dermoscopic features were assessed. we observed linear irregular vessels in 17 cases (60.7%); rhomboidal/polygonal vessels in 15 cases (53.6%); dotted/globular vessels in 15 cases (53.6%); white macules in 23 cases (82.1%); brown macules in 11 cases (39.3%); and whitish follicular plugs in 6 cases (21.4%). in 18 cases (64.3%), we identified a distinctive type of vessels, the converging curved vessels, presenting as two curved red lines that meet at their neighboring end, giving the impression of a flock of seagulls flying with their wings wide open (“flying-seagull-like” vessels). examples of the local dermoscopic features observed among patients with pc are shown in figure 1. based on the presence of the aforementioned vessel types and their architectural distribution, we described four patterns: • reticular (fishnet-like) pattern: areas with linear telangiectasias that are interconnected forming an irregular red network that is reminiscent of a fishnet. this network consists of thin red lines and quadrilateral or polygonal, irregular openings. • white dot (red-white polka dot) pattern: white roundish macules, regularly distributed in areas of bright red erythema produced by a network of linear telangiectasias. it is reminiscent of a red-white polka dot print. • combination of linear and dotted vessels pattern: a combination of linear irregular vessels and dotted/globular vessels. this pattern was initially described in patients with pc by errichetti and stingo as “spaghetti and meatballs” pattern.7 • non-specific pattern: areas of irregular linear telangiectasias that are irregularly distributed and do not correspond to any specific pattern. the dermoscopic global patterns are summarized in table 2. the reticular pattern was observed in more than table 1. demographics, etiologic factors and clinical characteristics of the patients with pc (n=28). demographics gender females 19 (67.86) males 9 (32.14) age 55 years 59 years etiologic factors phototype (fitzpatrick’s classification) i ii iii iv 3 (10.71) 7 (25) 14 (50) 4 (14.29) occupational sun exposure 3 (10.71) recreational sun exposure 22 (78.57) sunburn in childhood 2 (7.14) use of perfumes 16 (57.14) menopause 13 (68.42) positive family history 9 (32.14) clinical characteristics duration 1-5 years 6-10 years 11-15 years 16-20 years 5 (17.86) 11 (39.29) 9 (32.14) 3 (10.71) location of the lesions v-shaped area of chest: sides of the neck: peripheral face: 27 (96.43) 11 (39.29) 8 (28.57) clinical type erythemato-telangiectatic: pigmented: mixed: 6 (21.43) 2 (7.14) 20 (71.43) symptoms burning: flushing: pruritus: 8 (28.57) 6 (21.42) 5 (17.86) comorbidities rosacea thyroid diseases arterial hypertension: systemic lupus erythematosus: 12 (42.8) 8 (28.57) 5 (17.85) 4 (14.28) numbers in parenthesis represent percentages 4 original article | dermatol pract concept. 2023;13(1):e202307 figure 1. “local structures of poikiloderma of civatte”. a) the rhomboidal/polygonal vessels, b) the converging curved vessels, c) the dotted/globular vessels, d) the linear irregular vessels, e) the white macules, f) the brown macules, and g) the follicular plugs. table 2. dermoscopic features in patients with pc (n=28). dermoscopic patterns/structures description number of patients n (%) global pattern reticular (fishnet-like) areas with linear telangiectasias that are interconnected forming an irregular red network that is reminiscent of a fishnet. this network consists of thin red lines and quadrilateral or polygonal, irregular openings. 15 (53.57) white dot (red-white polka dot) areas of bright red erythema produced by a network of linear telangiectasias, surrounding regularly distributed white roundish macules. it is reminiscent of a red-white polka dot print. 10 (35.71) combination of linear and dotted vessels (spaghetti and meatballs-like7) a combination of linear irregular vessels and dotted/ globular vessels. 4 (14.28) non-specific areas of linear telangiectasias that are irregularly distributed and do not correspond to any specific pattern. 9 (32.14) vascular structures rhomboidal/polygonal bright red, non-branching, linear telangiectatic vessels; tend to connect with surrounding vessels forming interconnected rhomboidal or polygonal vascular structures, thus resembling parts of fishnet with irregular holes. 15 (53.57) linear irregular bright red, non-branching, linear telangiectasias with irregular form and distribution. 17 (60.71) dotted/globular bright red, irregularly distributed dots or globules. 10 (35.71) original article | dermatol pract concept. 2023;13(1):e202307 5 in our statistical analysis, we investigated possible correlations of the dermoscopic features and patterns with epidemiologic parameters, etiologic factors and clinical characteristics of our pc patients (table 4). the following statistical correlations were documented: white macules were correlated with the mixed clinical type (p=0.015); converging curved vessels were correlated with the erythemato-telangiectatic type (p=0.028); brown macules were associated with skin phototype iv (p=0.016) and with disease duration half of the patients, followed by the white dot pattern, and the non-specific pattern, while the combination of linear and dotted vessels pattern was the least frequently identified. in 78.57% of the cases, the coexistence of more than one pattern at different sites was noted. when the global pattern was assessed by anatomic region, i.e. face, neck, and upper chest, no significant differences were observed. examples of the dermoscopic global patterns observed among our patients are shown in figure 2. dermoscopic patterns/structures description number of patients n (%) converging curved vessels (flying seagull-like) double curved short red lines that meet at their neighboring end; usually appear in small clusters. 18 (64.29) pigmented structures brown macules light brown structureless macules, 2-3 mm in diameter, with rather distinct but slightly irregular borders. 11 (39.29) depigmented structures white macules whitish or skin-colored spots, suggesting that they correspond to the holes of the vascular network which is formed by the linear telangiectasias, representing areas of sparing. 23 (82.14) white keratotic follicular plugs follicular hyperkeratosis 6 (21.42) table 3. dermoscopic differential diagnosis of poikiloderma of civatte.11-23 dermoscopic findings riehl’s melanosis • gray dots/granules and pigmented pseudo-network, combined with telangiectatic vessels; • less often flour-like scales, follicular keratotic plugs and perifollicular whitish halo. erythromelanosis follicularis faciei et colli • round whitish areas with follicular plugs, occasionally centered by a hair; • surrounding blue-gray dots or peppering in a reddish-brown background poikiloderma in dermatomyositis • enlarged linear irregular vessels; • mixed features of hyperpigmentation and depigmentation. poikilodermatous mycosis fungoides • multiple polygonal structures consisting of lobules of white storiform streaks, studded with fine red dots or hairpin vessels; • unevenly and intermittently distributed septa of pigmented dots, between the lobules; • red and yellowish smudges. poikiloderma atrophicans et vasculare • blurred branched vessels on a reddish or orangish-brown background; • sparse whitish scales. chronic graft-versushost disease • whitish scales; • vessels of mixed morphology, mostly dotted and linear melasma • light-to-dark brown background; • brown granules/ globules with perifollicular sparing; • global reticular or pseudo-reticular pattern. 6 original article | dermatol pract concept. 2023;13(1):e202307 table 4. distribution of local dermoscopic features by clinical type among patients (n=28) with poikiloderma of civatte. no of patients (%) type of pc dermoscopic features erythemato-telangiectatic type (n=6) pigmented type (n=2) mixed type (n=20) rhomboidal/polygonal vessels 2 (33.33) 0 13 (65) dotted/globular vessels 4 (66.66) 1 (50) 11 (55) linear irregular vessels 3 (50) 2 (100) 13 (65) converging curved vessels 6 (100) 1 (50) 12 (60) white macules 3 (50) 1 (50) 19 (95) brown macules 1 (16.67) 2 (100) 9 (45) figure 2. “global patterns of poikiloderma of civatte”. a) the fishnet-like pattern, b) the red-white polka dot pattern, c) the combination of linear & dotted vessels pattern, and d) the non-specific pattern. original article | dermatol pract concept. 2023;13(1):e202307 7 (converging curved vessels, rhomboidal/polygonal vessels, linear irregular vessels, dotted/globular vessels) that we identified are the dermoscopic correlates of linear telangiectasia of poikiloderma and represent the dilated hyperemic vessels of the papillary dermis that have been described in the histopathology of pc.3 when the course of the vessels is parallel to the skin surface, they appear on dermoscopy as rhomboidal/ polygonal or linear irregular vessels, while when their course is perpendicular they appear as dotted/globular vessels. the mottled hyperpigmentation of poikiloderma is dermoscopically appreciated as brown macules, and results from the increased presence of melanin irregularly distributed in the basal layer of the epidermis, as well as the presence of melanophages laden with melanin in the dermis [3]. in our series, brown macules correlated with the mixed type of pc (p=0.015). white macules correspond to the superficial atrophy that integrates the clinical triad of poikiloderma. white macules correlate histologically to a flattened and atrophic epidermis, overlying an elastotic papillary dermis at sites in between the reticulate telangiectasia [3]. pc presents with a distinctive dermoscopic picture. by dermoscopy, pc can be easily differentiated from other skin conditions characterized also by telangiectasia and reticular pigmentation, such as rosacea, erythromelanosis follicularis faciei et colli and melasma, or true poikiloderma. rosacea which often coexists with pc most commonly involves the central face. in rosacea, linear telangiectatic vessels arranged in horizontal and vertical lines form polygons (polygonal vessels) [5, 8, 9]. vascular polygons are a characteristic dermoscopical feature of erythemato-telangiectatic rosacea [6]. the vascular polygons are similar to the polygonal vessels observed in half of our patients with pc, providing further support to the theory that rosacea and pc are related and, possibly, belong to the same nosological spectrum [10]. in rosacea, additional features such as rosettes, white/yellowish scales, orange-yellowish areas, pigmentation structures, dilated follicles and follicular pustules (in the papulopustular form), have been described that were not present in our cohort allowing differentiation between these entities [5, 8, 9]. the dermoscopic differential diagnosis of pc is depicted in table 3. our study has several limitations. due to the small number of patients, our results need further confirmation in larger prospective cohorts. additionally, due to the lack of a control group, the sensitivity and specificity of the proposed criteria were not calculated. to our knowledge, this is the first study to systematically investigate the dermoscopic characteristics of pc. although not pathognomonic, the dermoscopic picture is highly characteristic, leading to the clinical diagnosis with great confidence. we were able to describe patterns and features that are unique for pc, permitting the differentiation from other >5 years (p=0.009). nevertheless, the number of cases in our study was relatively small to allow the extrapolation of solid conclusions. conclusions as our results indicate, pc exhibits a rather characteristic dermoscopic picture. the dermoscopic findings in pc consist of vascular and pigmented local features, forming a reddish-to-brownish network. we were able to describe four distinct global patterns (reticular, white dot, combination of linear and dotted vessels, and non-specific). the reticular pattern was the most frequently identified (53.57%). in the majority of patients, the coexistence of more than one pattern was noted. we were able to describe four types of telangiectatic vessels (converging curved, rhomboidal/polygonal, dotted/globular, and linear irregular). converging curved vessels have not been described previously in any skin condition and could be considered highly characteristic of the erythemato-telangiectatic type of pc (p=0.028). white macules were seen in the vast majority of our patients and in all clinical types, either regularly (white dot pattern) or irregularly (reticular or non-specific pattern) distributed and in a follicular or pseudo-follicular distribution. brown macules were observed much less often, mostly associated with the pigmented and the mixed clinical type. in the literature, there is little published experience on the dermoscopy of pc. errichetti and stinco studied 8 consecutive cases (6 women and 2 men, aged 42–73 years, mean 51 years) of clinically diagnosed pc.7 the authors described, in all patients, a combination of dotted/globular vessels and linear irregular vessels, giving the impression of “spaghetti and meatballs”, along with perifollicular whitish (spared) areas. in addition, they noted the presence of follicular keratotic plugs and delicate reticular or structureless brownish areas in 25% and 12.5% of the cases, respectively.7 our findings are in line with the findings of errichetti and stinco. however, the combination of linear and dotted vessels pattern was not recognized by us as the predominant global pattern, but it was seen in as much as 28.6% of our patients. the presence of dotted/globular vessels was less common in our cohort as well. accordingly, for the white macules, we noticed that they often have a pseudo-follicular distribution, i.e. they are not strictly related to the follicular openings. in our cohort, brown macules were mainly associated with skin phototype iv (p=0.016) and with a disease duration >5 years (p=0.009). brown macules were mostly identified in the pigmented and mixed clinical types of pc. the dermoscopic findings correlate well with both the clinical and histologic features of pc, supporting the view that dermoscopy represents a bridge between clinical presentation and histology. the vascular dermoscopic structures 8 original article | dermatol pract concept. 2023;13(1):e202307 dermatoses of the face and neck, as well as from other forms of poikiloderma with guarded or serious prognosis. dermoscopic findings correlate well with the clinical and histological features of pc. on this basis, biopsy and histologic examination are rarely necessary. future research will, hopefully, better clarify the pathogenetic mechanisms of this disease and will provide insights for more effective preventive and therapeutic approaches for pc. references 1. katoulis ac, rigopoulos d, tzima k, stavrianeas ng. poikiloderma of civatte: a review. exp rev dermatol 2012; 7:377-382. 2. katoulis ac, stavrianeas ng. poikiloderma of civatte. in: hyperpigmentation, rigopoulos d, katoulis ac (eds.). crc press, boca raton florida, 2018, p.p. 62-65. 3. katoulis ac, stavrianeas ng, panayiotides jg et al. poikiloderma of civatte: a histopathological and ultrastructural study. dermatology 2007; 214:177-182. 4. kittler h, marghoob aa, argenziano g, et al. standardization in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy. j am acad dermatol 2016; 74:1093-1106. 5. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb) 2016; 6:471-507. 6. sgouros d, apalla z, ioannides d, et al. dermoscopy of common inflammatory disorders. dermatol clin 2018; 36:359-368. 7. errichetti e, stinco g. dermoscopy in facilitating the recognition of poikiloderma of civatte. dermatol surg 2018; 44:446-447. 8. lallas a, argenziano g, apalla z, et al. dermoscopic patterns of common facial inflammatory skin diseases. j eur acad dermatol 2014; 28:60-614. 9. lallas a, argenziano g, longo c, et al. polygonal vessels of rosacea are highlighted by dermoscopy. int j dermatol 2014; 53:e325-327. 10. katoulis ac, georgala s, stavrianeas ng. poikiloderma of civatte and rosacea: variants in the same nosological spectrum. dermatology 2005; 211:386-387. 11. wang l, xu ae. four views of riehl’s melanosis: clinical appearance, dermoscopy, confocal microscopy and histopathology. j eur acad dermatol 2014; 28:1199-1206. 12. maouni s, el anzi o, sqalli a, et al. erythromelanosis follicularis faciei et colli: dermoscopy and dermatopathology correlates. jaad case rep 2019; 5:535-536. 13. sonthalia s, jha ak, langar s. dermoscopy of melasma. indian dermatol online j 2017; 8:525-526. 14. yalamanchili r, shastry v, betkerur j. clinico-epidemiologic study of quality of life assessment in melasma. indian j dermatol 2015; 60:519. 15. sarkar r, arora p, garg vk, et al. indian dermatol online j 2014; 5:426-435. 16. barcaui cb, pereira fbc, tamler c, fonseca rmr. classification of melasma by dermoscopy: comparative study with wood’s lamp. surg cosm dermatol 2009; 1:115-119. 17. hasegawa m. use of dermoscopy in the evaluation of connective tissue diseases. dermatol clin res (dcr) 2015; 1(3): 41-48 18. kaminska-winciorek g, czerw t, kruzel t, giebel s. dermoscopic follow-up of the skin towards acute graft-versus-hostdisease in patients after allogeneic hematopoietic stem cell transplantation. biomed res int 2016; 4535717. 19. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol 2013; 27:617–621. 20. mahajan vk, chauhan ps, mehta ks, sharma al. poikiloderma vasculare atrophicans: a distinct clinical entity? indian j dermatol 2015; 60: 216. 21. errichetti e, stinco g. usefuleness of dermoscopy in poikiloderma atrophicans et vasculare/ parakeratosis variegata. eur j dermatol 2016: 26:300-302. 22. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol 2015; 150: 533-546. 23. xu p, cheng t. dermoscopy of poikilodermatous mycosis fungoides (mf). j am acad dearmatol 2016; 74:e45-47. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022118 1 dermatology practical & conceptual elevated serum levels of interleukin-15 in pemphigus vulgaris patients: a potential therapeutic target maedeh kheirodin1, zohreh tehranchinia2,yasaman ketabi2, soheil tavakolpour2, sahar dadkhahfar2, masoomeh faghankhani3, hassan vahidnezhad3, nikoo mozafari2,4 1 school of medicine, shahid beheshti university of medical sciences, tehran, iran 2 skin research center, shahid beheshti university of medical sciences, tehran, iran 3 department of dermatology and cutaneous biology, sidney kimmel medical college, thomas jefferson university, philadelphia, pa, united states 4 department of dermatology, loghman hakim hospital, shahid beheshti university of medical sciences, tehran, iran key words: pemphigus vulgaris, interleukin-15, anti-desmoglein, il-15, absis citation: kheirodin m, tehranchinia z, ketabi y, et al. elevated serum levels of interleukin-15 in pemphigus vulgaris patients: a potential therapeutic target. dermatol pract concept. 2022;12(3):e2022118. doi: https://doi.org/10.5826/dpc.1203a118 accepted: november 13, 2021; published: july 2022 copyright: ©2022 kheirodin et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: the present study was founded by skin research center, shahid beheshti university of medical sciences. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: nikoo mozafari, md, shahrdari st , tajrish sq ,skin research center, shohada-e-tajrish, hospital,tehran, iran tel number: (98) 21-22741507, fax: (98) 21-22741508 e-mail: nikoo_md@yahoo.com introduction: pemphigus vulgaris (pv) is a rare autoimmune disease that causes painful blistering. interleukin-15 (il-15) as a member of the immunoregulatory cytokines family is associated with the development of the chronic inflammatory or autoimmune disease. there is not much information available in the literature on the exact role il-15 plays in pv. objectives: the goal of this study was to evaluate the serum levels of il-15 in patients with pv and assess the association of il-15 with anti-desmoglein antibodies and the severity of the disease. methods: fifty-three individuals affected with active pv and 38 ageand gender-matched healthy controls were participated in this study. disease severity was assessed using autoimmune bullous skin disorder intensity score (absis). serum levels of il-15 (pg/ml) and anti-desmoglein antibodies (dsg1, 3) were determined. results: in the patient group, il-15 serum levels were statistically higher than those in the control group (3.71 ± 1.5 vs. 0.79 ± 1.03, p < 0.001). a positive correlation was found between serum levels of il-15 and absis (r = 0.5, p = 0.04). we found no significant correlation between serum concentrations of il-15 and antidesmoglein antibodies (dsg1 or dsg3). conclusions: an increase in serum level of il-15 in patients with pv and its relationship with disease severity suggest that this cytokine possibly contributes to the pathogenesis of the disease and targeting il-15 will likely provide a new insight into the treatment of this disease. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022118 introduction pemphigus vulgaris (pv) is a rare autoimmune disorder that causes painful blisters and erosions on the skin and mucosa [1]. pv is caused by environmental and genetic factors that lead to immunological impairments. auto-antibodies against the desmosomal adhesion proteins of epidermal keratinocytes, desmoglein3 and/or desmoglein 1, lead to the loss of epidermal cell adhesion and development of erosive lesions [1,2]. to date, different cytokines, such as osteopontin, interleukin (il)-4 and il-21 have been suggested to be associated with disease pathogenesis and severity [3-5]. these cytokines contribute to rising proinflammatory responses and production of autoantibodies through differentiation of naïve t-cells into effector t -ells, increased b-cell responses, and favors a class switch to igg4. interfering with the function of them using monoclonal antibodies, such as dupilumab for il-4/ il-4 receptor could be probably effective in treating some pv patients [6,7]. in contrast, regulatory cytokines, such as tgf-β and il-35-dependent mechanisms could mediate restoration of self-tolerance, which had been broken in patients with autoimmune diseases [8,9]. however, the role of some less studied cytokines, such as il-15 has remained controversial. to our best knowledge, 3 studies have assessed the serum levels of il-15 in pv patients. two have reported increased serum levels of il-15 and one suggested suppressed production of il-15 as compared to the healthy controls [10-12]. il-15 is a glycoprotein cytokine produced by multiple cell types including monocytes, macrophages, dendritic cells, fibroblasts, and epithelial cells. it is well known that il-15 contributes to the survival and proliferation of t-cell [13]. it also increases the proliferation of b lymphocytes and promotes their differentiation into the plasma cells [13,14]. recent studies have indicated that inhibiting il-15 with various methods may be the goal of appropriate treatment to reduce inflammation [14]. objectives il-15 is involved in the pathogenesis of a variety of autoimmune diseases such as sjogren disease, behcet disease, systemic lupus erythematous (sle) and rheumatoid arthritis (ra) [3,15]_enref_14. there has been little information about the exact role of il-15 in pemphigus pathogenesis or how il-15 production relates to the severity of pemphigus. in this regard, the goal of this study was to assess the serum levels of il-15 in patients with pv and to find out whether il-15 levels were associated with severity of their disease. methods patients to evaluate the serum levels of il-15, 53 individuals with active pv and 38 healthy individuals were enrolled in this study. among 53 patients, 37 cases were newly diagnosed while 16 cases were presented with relapse during minimal therapy (5-10 mg prednisolone per day). pv was diagnosed based on clinical evidence, histopathologic findings, direct immune-fluorescence examination and the detection of serum autoantibodies by elisa. participants with any history of inflammatory/autoimmune diseases, hematologic and solid malignancies, viral hepatitis, and hiv were excluded. this study was approved by the ethical committee of our skin research center (ethical code: ir.sbmu.src.rec.1395.41). prior to enrollment in the study, all participants provided written informed consent. clinical and laboratory data all the patients enrolled in the study had an active disease, defined as the development of at least 3 de novo blisters/ erosions, which do not heal spontaneously within one week. the autoimmune bullous skin disorder intensity score (absis) was used to assess the severity of the disease. the absis provides a maximum score of 206 (150 points for skin involvement, 11 points for oral involvement, and 45 points for subjective oral discomfort) [16]. the score is determined by calculating the percentage of blisters involvement and erosions on the skin, along with weighting factors at the stage of the blistering and erosions, respectively. discomfort during eating and drinking is also considered [16]._enref_16 cytokine measurements for evaluating the level of il-15 and anti-desmogleins (dsg), 10 ccs venous blood of each participant was collected. the blood samples were centrifuged to gather the serums. then, the serums were frozen at –80°c. after gathering all the samples, levels of il-15 were measured by an elisa kit (diaclone,france), according to the manufacturer’s instructions. using the elisa method (euroimmun ag) anti-dsg 1 and 3 antibodies were measured in patients. values ≥ 20 of relative units per milliliter (ru/ml) were considered positive. statistical analysis findings were respectively expressed as mean ± standard deviation or as number (percentage) for continuous variables and categorical data, respectively. independent samples t test and non-parametric mann–whitney u test were applied to compare the means of continuous variables and chi squared test was used for categorical variables. analysis of variance (anova test) was used for comparing means between variables. to determine if there was a linear relationship between variables, pearson correlation testing was performed. we used the statistical package of spss version 16.0.0. (spss inc.) to analyze the data. the level of significance was considered as p values less than 0.05. original article | dermatol pract concept. 2022;12(3):e2022118 3 results patient characteristics fifty-three patients with pv (35 females and 18 males) and 38 healthy individuals (24 women and 14 men) were enrolled in the study. the control group was frequency-matched to cases by gender and age. the mean ages of patients and control subjects were equal to 45.62 ± 12.27 and 44.21 ± 13.15, respectively. the baseline demographics and clinical characteristics of the participants have been presented in table 1. the two groups were comparable in age, gender, and comorbidities (table 1). serum levels of il-15 pv patients had significantly higher levels of il-15 than controls. the mean serum levels of il-15 ± sd in pv patients were 3.71 ± 1.5 pg/ml, while for healthy controls were 0.79 ± 1.03 pg/ml, which was statistically different (p < 0.001). figure 1 demonstrates the il-15 levels in these two groups. in patients with pv, no significant correlations were detected between il-15 levels and anti-dsg1 (r = 0.06, p = 0.6) or anti-dsg3 (r = 0.006, p = 0.9) antibodies. serum levels of il-15 were positively correlated with pv severity according to total absis (r = 0.5, p = 0.04). in the patients group, there was no significant difference in the mean levels of serum il-15 between men and women or between patients with cutaneous, mucosal, or mucocutaneous forms of the disease (p = 0.9 and 0.09, respectively). there was a significant correlation between pemphigus severity (absis score) and anti dsg3 (r = 0.3, p = 0.01) and anti-dsg1 levels (r = 0.6, p < 0.001)._enref_15 conclusions in this study, we have evaluated plasma levels of il-15 in patients with pv in the active phase of the disease and searched for a potential relationship between levels of il-15 and the severity of the disease. we have found that levels of il-15 are significantly higher in patients compared to healthy controls. our study group results were comparable to those previously reported [10,11]. 8.00 6.00 4.00 il 1 5 2.00 0.00 patient control * * * participant figure 1. serum il-15 concentrations (pg/ml) in patients with pemphigus in comparison to healthy controls. overall, il-15 levels in the pemphigus group were higher than that of the control group (p < 0.001). il-15 = interleukin-15. 4 original article | dermatol pract concept. 2022;12(3):e2022118 approximately two decades ago, d’auria et al assessed the levels of il-15 in the serum sample of patients affected with three different bullous dermatoses ( 5 with bullous pemphigoid, 15 with pv and 15 with pemphigus erythematosus) [10]. they showed a higher level of il-15 serum in all the dermatosis as compared with healthy subjects. they also showed a significant correlation between the number of lesions and il-15 serum levels [10]._enref_16 additionally, ameglio et al showed increased levels of interleukin 15 in the serum of 15 pv patients with active disease [11]. in contrast, in a recently conducted study, timoteo et al with the evaluation of 20 pv patients and 20 healthy controls revealed a significantly lower serum level of il-15 in patients with pv than in control group patients [12]. in their study the study population consisted of non-active patients under pharmacologic therapy, then their results can be confounded by potential suppressive effects of immunosuppressants on il-15 secretions. il-15 is assumed to be a member of the immunoregulatory cytokines family which is primarily produced by monocytes, macrophage, dendritic cells, fibroblast, and epithelial cells. it is believed that il-15 overexpression is associated with the development of chronic inflammatory disease or autoimmune disorders. when il-15 is overexpressed, autoreactive t-cells are survived for longer periods of time , that results in abnormal lymphocyte activation [14]. furthermore il-15 is also involved in the activation and proliferation of natural killer cells (nks) [17]. stern et al have suggested a possible role for nks in the pathobiology of pv and d’auria et al have shown that the number of circulating natural killer cells is significantly correlated with the concentration of il15 in patients with pemphigus [10,18]. according to the mentioned role of il-15 in the differentiation and development of involved cells in immune responses, the role of this cytokine has been studied in a number of autoimmune diseases. there are some reports showing that the mean levels of il-15 serum are significantly higher in behcet disease, sle and rheumatoid arthritis [19]. active sle patients had significantly higher levels of il-15 serum compared to healthy controls, while it was not directly associated with disease activity [20]. the levels of il-15 in the serum and synovial fluid of patients with rheumatoid arthritis, were much higher compared to the controls [21]. interestingly, the levels of il-15 were related to the disease severity and serum levels of il-15 were strongly correlated with the levels of rheumatoid factor and anti-ccp [21]. collectively these findings indicated that il-15 is a key cytokine in several autoimmune diseases, and raises the possibility that targeting il15 with various anti-il15 approaches table 1. baseline demographics and clinical characteristics of patients with pemphigus and healthy controls. characteristic pv patients (n = 53) healthy controls (n = 38) p gender female male 35 (66.0% ) 18 (34.0% ) 24 (63.2%) 14 (36.8% ) 0.70 age, years mean ± sd median (range) 45.62 ± 12.27 46 (21 – 72 ) 44.21 ± 13.15 45.50 (25 – 73) 0.60 time until diagnosis or exacerbation, month mean ± sd 2.6 ±2.3 — type of pemphigus involvement mucosal cutaneous mucocutaneous 18 (34%) 7 (13.2%) 28 (52.8%) — absis, mean ± sd; total score a 36.88 ± 24.92 — anti-dsg1 antibody (ru/ml) mean ±sd 238.68 ± 47.70 — anti-dsg3 antibody (ru/ml) mean ±sd 729.63 ± 99.05 — il-15 (pg/ml) mean ± sd 3.71 ± 1.5 0.79 ± 1.03 < 0.001 absis = autoimmune bullous skin disorder intensity score; dsg = desmoglein; il-15 = interleukin-15; ; sd = standard deviation. values are reported as numbers (%) unless otherwise specified. atotal score is sum of objective and subjective scores. original article | dermatol pract concept. 2022;12(3):e2022118 5 may provide a new insight for the treatment of such disorders [19]. for instance, in an animal model of human psoriasis (xenograft mouse), the il-15 blockade led to the psoriasis resolution [22]. in rat models of induced arthritis, weekly administration of small interfering rna targeting il-15 reduces the expression of proinflammatory mediators in the inflamed joints, alleviates disease progression and significantly inhibits the clinical, radiologic and histologic features of rheumatoid arthritis [19]. in the case of pemphigus, corticosteroid medications that usually used to suppress auto-antibodies, include delayed and serious side effects [23]. targeting b-cell by the anti-cd20 molecule (rituximab) is currently the best available agent for the treatment of pemphigus patients not responding to conventional treatments [24]. this drug eliminates peripheral b-cells. b-cell depletion, may not be desirable because b-cells are essential for antibody production, activation of t-cells and complements. therefore, interrupting the homing of b-cells by blocking the il-15 pathway might be a suitable alternative to reduce excessive inflammation [14]. torn et al showed that in patients with ra, the treatment with rituximab significantly decreased il-15 serum levels as well as il-15 cellular levels. they concluded that sustained clinical improvement following rituximab treatment was related to il-15 and the mechanisms by which il-15 exerts influence on t-cells [25]. based on our findings, the elevated levels of il-15 in sera of patients with pemphigus suggest that this cytokine may actually be involved in pathogenesis of pemphigus. the generalizability of these results is subject to certain limitations. for instance, in our study, we did not analyze the serum level of il-15 after treatment of patients with steroid pulse or rituximab, and we intend to address it in future work. in our study, although we showed there is a positive correlation between serum il15 levels and disease severity we did not find a direct association between il-15 serum levels and anti-dsg levels. it might be due to different mechanisms regarding pemphigus pathogenesis and autoantibody production. it could be speculated that il‐15 might rather be involved in tuning the immune system towards autoimmunity not to directly exert its influence on antibody production. taken together our findings suggest that levels of il‐15 in the sera of patients with pemphigus are high,which suggests that this cytokine may have a role in the pathogenesis of pemphigus. whether the higher level of il-15 is the cause or result of autoimmune diseases remains to be determined in future studies. 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21. pavkova goldbergova m, pavek n, lipkova j, et al. circulating cytokine pattern and factors describing rheumatoid arthritis: il-15 as one of the biomarkers for ra? biomarkers. 2012;17(7):655-662. doi: 10.3109/1354750x.2012.719036. pmid: 22998011. 22. villadsen ls, schuurman j, beurskens f, et al. resolution of psoriasis upon blockade of il-15 biological activity in a xenograft mouse model. the journal of clinical investigation. 2003;112(10):1571-1580. doi: 10.1172/jci18986. pmid: 14617758. pmcid: pmc259129. 23. gheisari m, faraji z, dadras ms, et al. methylprednisolone pulse therapy plus adjuvant therapy for pemphigus vulgaris; an analysis of ten years’ experience on 312 patients. dermatol ther. 2019;32(5):e13057. doi: 10.1111/dth.13057. pmid: 31400243. 24. wang h-h, liu c-w, li y-c, huang y-c. efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. acta derm venereol. 2015;95(8):928-932. doi: 10.2340/00015555-2116. pmid: 25881672. 25. díaz‐torné c, ortiz de juana ma, geli c, et al. rituximab‐induced interleukin‐15 reduction associated with clinical improvement in rheumatoid arthritis. immunology. 2014;142(3):354-362. doi: 10.1111/imm.12212. pmid: 24219764. pmcid: pmc4080951. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023121 1 skeletal side effects of systemic isotretinoin treatment: do they depend on age, gender, treatment duration, daily dose and isotretinoin-naiveness? defne özkoca1, nazlı caf2, nazan nur alacagöz yılmaz3, tuğba kevser uzunçakmak4, ayşenur özdil5, ayşe nilhan atsü6 1 zonguldak atatürk state hospital, dermatology and venerology clinic, zonguldak, turkey 2 diyarbakır dağkapı military hospital, dermatology and venerology clinic, diyarbakır, turkey 3 zonguldak atatürk state hospital, physical therapy and rehabilitation clinic, zonguldak, turkey 4 şişli memorial hospital, dermatology and venerology clinic, i̇stanbul, turkey 5 i̇stanbul university-cerrahpaşa, cerrahpaşa medical faculty, department of public health, i̇stanbul, turkey 6 i̇stanbul kent university, department of dermatology and venerology, i̇stanbul, turkey key words: acne vulgaris, fatigue, low back pain, isotretinoin, myalgia citation: özkoca d, caf n, alacagöz yılmaz nn, uzunçakmak tk, özdil a, atsü an. skeletal side effects of systemic isotretinoin treatment: do they depend on age, gender, treatment duration, daily dose and isotretinoin-naiveness? dermatol pract concept. 2023;13(2):e2023121. doi: https://doi.org/10.5826/dpc.1302a121 accepted: november 14, 2022; published: april 2023 copyright: ©2023 özkoca et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: defne özkoca, md, zonguldak atatürk devlet hastanesi, site ek binası, bahçelievler, zonguldak, turkey. phone: 00905366561000 e-mail: defneozkoca@yahoo.com introduction: systemic isotretinoin is the most effective treatment modality in acne vulgaris; however, both patients and physicians hesitate to use it due its side effects. objectives: the aim of this study is to determine the prevalence of fatigue, myalgia and low back pain during systemic isotretinoin treatment; and to determine their relationship with age, gender, treatment duration, daily isotretinoin dose and isotretinoin-naiveness of the patient. methods: this is a cross sectional study including the acne vulgaris patients, aged between 13 to 40 years, who have at least received one month of oral isotretinoin treatment. patients were questioned for side effects during their follow-up visits; a physical therapy and rehabilitation specialist further evaluated patients complaining of low back pain. results: fatigue was reported by 4.4% of the patients, myalgia by 2.8% and low back pain by 25% of the patients; 2.2% had inflammatory and 22.8% had mechanical low back pain. none of the patients abstract 2 original article | dermatol pract concept. 2023;13(2):e2023121 introduction systemic isotretinoin (13-cis retinoic acid) is the most effective treatment modality for acne vulgaris given that it is the only treatment method that targets all four of the major etiological factors of acne vulgaris. the us food and drug administration have approved its use for the treatment of severe acne vulgaris in 1982 [1]. the common side effects of systemic isotretinoin treatment are cheilitis, xerosis, xerophthalmia, and myalgias. its tendency for causing depression, and suicidal ideation still remains controversial [2]. arthralgia may also be experienced by the patients during systemic isotretinoin therapy; 20% of the patients complain of either myalgia or arthralgia [3]. inflammatory low back pain is a very common side effect of systemic isotretinoin therapy; sacroiliitis and tendinitis may also occur although much rare. the low back pain ceases with dose reduction [4,5]. objectives the aim of this study is to determine the incidence of fatigue, myalgia and low back pain (inflammatory or mechanical) in acne vulgaris patients receiving oral isotretinoin therapy; and to determine the relationship of these side-effects to the age and the gender of the patient, the isotretinoin dosing regimen, the duration of isotretinoin therapy and the isotretinoin-naiveness of the patient. methods patient selection acne vulgaris patients, aged between 13 to 40 years, who have at least received one month of oral isotretinoin treatment in the dermatology outpatient clinic of zonguldak atatürk state hospital and who were willing to participate in this study were included in this cross-sectional study. patients with already diagnosed rheumatic diseases, musculoskeletal diseases, inflammatory bowel disease, hormonal disturbances, psychiatric comorbidities and who were using non-steroidal anti-inflammatory drugs regularly were excluded from this study. data acquisition the blood chemistry including lipids and beta-human chorionic globulin (for female patients only) of the patients receiving oral isotretinoin were evaluated during monthly consultations. the age, gender, isotretinoin dosage (mg/kg/ day), treatment duration (weeks) and whether the patient is using isotretinoin the first or the second time for acne vulgaris were noted during the monthly consultations. the patients were questioned for the presence of fatigue, myalgia or low back pain; and the patients with low back pain were referred to the physical therapy and rehabilitation outpatient clinic for further evaluation. the physical therapy and rehabilitation specialist has evaluated the patients to determine the character of low back pain (inflammatory or mechanical) along with performing physical examination of the range of motion, muscle power and lordosis. magnetic resonance imaging of the lumber vertebrae was performed on the patients who had inflammatory low back pain in order to evaluate sacroiliitis. statistical analysis spss version 21 was used for the statistical analyses. mann-whitney u test was used to determine the relationship of age, isotretinoin dosage and treatment duration to all of the side effects studied (fatigue, myalgia and low back pain). pearson chi-square test was used to determine the relationship of gender to fatigue and low back pain; and of isotretinoin-naiveness to low back pain. fisher exact test was used to determine the relationship of gender to myalgia; and of isotretinoin-naiveness to fatigue and myalgia. ethics the approval of i̇stanbul kent university ethics committee was obtained before the initiation of the study (27.05.2022). informed consent was taken from all of the patients who were willing to participate in this study; and the study was conducted in accordance with the helsinki declaration. results patient characteristics and side effects a total of 180 patients were included in this study. the mean age of the patients was 20.3 years with a standard deviation of 5 years. of all the patients, 57 (31.7%) were male and 123 (68.3%) were female. fatigue was reported by 8 (4.4%) of the patients, myalgia by 5 (2.8%) and low back pain by 45 (25%) of the patients. four (2.2%) of the patients were diagnosed with inflammatory low back pain by the physical therapy and rehabilitation specialist; and 41 (22.8%) were had sacroiliitis. all the side effects that were examined were found to be independent of age, gender, isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness. conclusions: the side effects are not as common as feared; thus, patients and physicians should not hesitate to use systemic isotretinoin in indicated cases. original article | dermatol pract concept. 2023;13(2):e2023121 3 diagnosed with mechanical low back pain. the mean isotretinoin treatment duration was 9.6 weeks with a standard deviation of 6.7 weeks; the mean isotretinoin dosage was 0.582 mg/kg/day with a standard deviation of 0.18 mg/kg/day; and 144 (80%) of the patients were isotretinoin-naïve, whereas 36 (20%) were using isotretinoin for the second time. patient characteristics and side effects are summarized in table 1. relationship of side effects to patient characteristics fatigue, myalgia and low back pain were the side effects that were examined in this study. all of the side effects that were examined were found to be independent of age, gender, isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness. the relationships of side effects to the patient characteristics are summarized in table 2. character of the low back pain the patients with low back pain were further examined for the character of low back pain by the physical therapy and rehabilitation specialist. within the patients with low back pain, only 4 (8.9%) had inflammatory low back pain. there was no statistically significant relationship between the age of the patient, gender of the patient, isotretinoin dosage (mg/kg/day), treatment duration (weeks) and isotretinoin naiveness of the patient; and the character of low back pain. table 3 summarizes the relationship of the character of low back pain to the patient characteristics. table 1. patient characteristics and side effects. patient characteristics n=180 age mean ± sd median (iqr) 20.3 ± 5 20 (17 – 22) gender, n (%) male female 57 (31.7) 123 (68.3) side effects, n (%) fatigue myalgia low back pain 8 (4.4) 5 (2.8) 45 (25) character of low back pain, n (%) inflammatory mechanical 4 (2.2) 41 (22.8) treatment duration (weeks) mean ± sd median (iqr) 9.6 ± 6,7 8 (4 – 12) isotretinoin naiveness, n (%) naive not naive 144 (80) 36 (20) isotretinoin dosage (mg/kg/day) mean ± sd median (iqr) 0.582 ± 0.18 0.565 (0.5 – 0.695) iqr = interquartile range; sd = standard deviation. table 2. relationship of side effects to patient characteristics. fatigue myalgia low back pain present absent present absent present absent mean age ±,sd median (range) in years 19.8 ± 2 20 (18 -21) 20.3 ± 5.1 20 (17 – 22) 21.6 ± 2 21 (20 – 23,5) 20.3 ± 5.1 20 (17 – 22) 19.3 ± 4.2 19 (16 – 21) 20.6 ± 5.3 20 (17 – 22) p 0.906a 0.162 a 0.1 a gender male female 2 (25) 6 (75) 55 (32) 117 (68) 0 (0) 5 (100) 57 (32.6) 118 (67.4) 14 (31.1) 31 (68.9) 43 (31.9) 92 (68.1) p 0.678 b 0.181 c 0.926 b isotretinoin dosage (mg/ kg/day) 0.625 ± 0.2 0.58 (0.46 – 0.73) 0.58 ± 0.2 0.57 (0.5 – 0.68) 0.582 ± 0.2 0.6 (0.4 – 0.76) 0.582 ± 0.2 0.56 (0.5 – 0.68) 0.599 ± 0.2 0.6 (0.5 – 0.69) 0.576 ± 0.2 0.5 (0.44 – 0.7) p 0.608 a 0.951 a 0.23 a treatment duration (weeks) 9.9 ±8.7 4 (4 – 19) 9.6 ± 6.7 8 (4 – 12) 13.6 ± 9.2 16 (4 – 22) 9.5 ± 6.7 8 (4 – 12) 8.9 ± 6.7 8 (4 – 12) 9.8 ± 6.8 8 (4 – 12) p 0.583 a 0.324 a 0.391 a isotretinoin-naiveness naive not naive 7 (87.5) 1 (12.5) 137 (79.7) 35 (20.3) 5 (100) 0 (0) 139 (79.4) 36 (20.6) 38 (84.4) 7 (15.6) 106 (78.5) 29 (21.5) p 1 c 0,585 c 0,389 b a mann whitney u test; 2pearson chi-squared test; c fisher exact test. conclusions systemic isotretinoin therapy is known to have side effects in many organ systems, including the musculoskeletal system 4 original article | dermatol pract concept. 2023;13(2):e2023121 average doses prescribed in the literature: 0.6 mg/kg/day, 0.55 mg/kg/day and 0.53 mg/kg/day[4,11,12]. there was no relationship between the daily dose of systemic isotretinoin treatment and the prevalence of the side effects. in alignment with this result, karaosmanoğlu and mülkoğlu also concluded that there is no correlation between the cumulative dosage of isotretinoin and the severity of low back pain [8]. previously in the literature, acar et al reported that low back pain was more common in male patients and pain severity increased with increasing age [4]. in contrast, this study revealed that the side effects of systemic isotretinoin treatment are independent of age and gender. our study also revealed that side effects of systemic isotretinoin are independent of the treatment duration and isotretinoin naiveness of the patient. although systemic isotretinoin treatment is the most effective treatment modality for acne vulgaris, both patients and prescribing physicians express fear about the side effects [13]. compared to the previous literature, we report a lower prevalence of fatigue and musculoskeletal side effects (namely myalgia and low back pain) and no case of sacroiliitis in our patient population, which supports the use of systemic isotretinoin in indicated cases of acne vulgaris. furthermore, we also report that side effects of isotretinoin treatment are independent of age, gender, daily isotretinoin dose, treatment duration and isotretinoin naiveness of the patient. fatigue, myalgia and low back pain can be observed during systemic isotretinoin treatment. these side effects are independent of the patient age, gender, daily systemic isotretinoin dosage, treatment duration and isotretinoin-naiveness of the patient. the side effects are not that common; thus, patients and physicians should not hesitate to use systemic isotretinoin in indicated cases. [6,7]. low back pain has been reported to be a common side effect of systemic isotretinoin therapy in the literature [5,8]. low back pain can be categorized into two groups: inflammatory, and mechanical low back pain [9]. approximately 16 percent of the patients receiving systemic isotretinoin therapy develop musculoskeletal side effects including myalgia, arthralgia and low back pain. although rare, sacroiliitis can also be observed in patients receiving systemic isotretinoin therapy, which can be classified as a cause of inflammatory low back pain [10]. in this study, 45 patients (25%) have reported low back pain; of which 4 (2.2%) have been diagnosed with inflammatory low back pain and 41 (22.8%) have been diagnosed with mechanical low back pain by the physical therapy and rehabilitation specialist. none of the patients were diagnosed with sacroiliitis. previous studies on this subject have reported a prevalence of low back pain, among patients receiving systemic isotretinoin treatment, of 78.7%, 46.9%, 49.3% and 10.4% [4,5,11,12]. among the patients with low back pain, 60.3%, 54.7% and 44%1 had inflammatory low back pain [4,11,12]. we report a lower prevalence of low back pain and inflammatory low back pain due to systemic isotretinoin use compared to most of the studies in the literature. in our patient population, the prevalence of fatigue was 4.4% and of myalgia was 2.8%. in the literature, fatigue has been reported to have a prevalence of 54% and of 50.7% [11,12]; myalgia has been reported to have a prevalence of 46.9% and 42.5% [11,12] again, we report a lower prevalence of fatigue and myalgia due to systemic isotretinoin therapy compared to the literature. the average daily dose of systemic isotretinoin prescribed in our study (0.582 mg/kg/day) is similar to the table 3. relationship of the character of low back pain to patient characteristics. character of low back pain pinflammatory (n = 4) mechanical (n = 41) age 22.8 ± 9.7 19 (16.3 – 33) 19 ± 3.4 19 (16 – 21) 0.631a gender male female 3 (21.4) 1 (3.2) 11 (78.6) 30 (96.8) 0.082 b isotretinoin dose (mg/kg/day) 0.593 ± 0.1 0.585 (0.5 – 0.693) 0.599 ± 0.2 0.6 (0.5 – 0.695) 0.967 a treatment duration (weeks) 6.3 ± 6.7 4 (1.75 – 13) 9.2 ± 6.7 8 (4 – 12) 0.234 a isotretinoin naiveness naive not naive 3 (7.9) 1 (14.3) 35 (92.1) 6 (85.7) 0.505 b a mann whitney u test; b fisher exact test. original article | dermatol pract concept. 2023;13(2):e2023121 5 references 1. layton a. the use of isotretinoin in acne. dermatoendocrinol. 2009;1(3):162-169. doi: 10.4161/derm.1.3.9364. pmid: 20436884. pmcid: pmc2835909. 2. leyden jj, del rosso jq, baum ew. the use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. j clin aesthet dermatol. 2014;7(2):s3-s21. pmid: 24688620. pmcid: pmc3970835. 3. kaplan g, haettich b. rheumatological symptoms due to retinoids. baillieres clin rheumatol. 1991;5(1):77–97. doi: 10.1016/s0950-3579(05)80297-3. pmid: 2070429. 4. acar em, şaş s, aybala koçak f. evaluation of musculoskeletal adverse effects in patients on systemic isotretinoin treatment: a cross-sectional study. arch rheumatol. 2022;37(2):223-229. doi: 10.46497/archrheumatol.2022.8645. pmid: 36017204. pmcid: pmc9377170. 5. civelek u, baykal l, aksu arica d, capkin e, yayli s. isotretinoin-induced inflammatory back pain and sacroiliitis in patients with moderate to severe acne vulgaris. j cosmet dermatol. 2022;21(10):4846-4851. doi: 10.1111/jocd.14807. pmid: 35092165. 6. agarwal us, besarwal rk, bhola k. oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial. indian j dermatol venereol leprol. 2011;77(6):688-694. doi: 10.4103/0378-6323.86482. pmid: 22016276. 7. kapała j, lewandowska j, placek w, owczarczyk-saczonek a. adverse events in isotretinoin therapy: a single-arm meta-analysis. int j environ res public health. 2022;19(11):6463. doi: 10.3390/ijerph19116463. pmid: 35682048. pmcid: pmc9180136. 8. karaosmanoğlu n, mülkoğlu c. analysis of musculoskeletal side effects of oral isotretinoin treatment: a cross-sectional study. bmc musculoskelet disord. 2020;21(1):631. doi: 10.1186/s12891-020-03656-w. pmid: 32977793. pmcid: pmc7519514. 9. ledford c. spine conditions: mechanical and inflammatory low back pain. fp essent. 2017;461:15-20. pmid: 29019640. 10. aydog e, ozturk g, comert a, tasdelen n, akin o, kulcu dg. sacroiliitis during isotretinoin treatment: causal association or coincidence? north clin istanb. 2018;6(1):75-80. doi: 10.14744/nci.2018.93798. pmid: 31180372. pmcid: pmc6526982. 11. taheri a, sabouhi s, farazmand f. incidence of low back pain and sacroiliitis in military families with acne vulgaris under isotretinoin therapy.  am j clin exp immunol. 2020;9(2):6-9. pmid: 32419981. pmcid: pmc7218680. 12. baykal selçuk l, aksu arıca d, baykal şahin h, yaylı, bahadır s. the prevalence of sacroiliitis in patients with acne vulgaris using isotretinoin.. cutan ocul toxicol. 2017;36(2):176-179. doi: 10.1080/15569527.2016.1237521. pmid: 27764978. 13. bauer l, ornelas j, elston d, alikhan  a.  isotretinoin: controversies, facts, and recommendations. expert rev clin pharmacol. 2016;9(11):1435-1442. doi: 10.1080/17512433.2016.1213629. pmid: 27414637. dermatology: practical and conceptual review | dermatol pract concept 2017;7(2):3 17 dermatology practical & conceptual www.derm101.com introduction from its bulky long-handle origins, to its current handheld portability, the dermatoscope has developed tremendously, becoming to some dermatologists, what the stethoscope is to the medical physician [1]. while the dermatoscope is most commonly used to assess melanoma and pigmented lesions, other indications for its use include the diagnosis of the need for improved dermoscopy training in residency: a survey of us dermatology residents and program directors parth patel1, sarika khanna1, beth mclellan1, karthik krishnamurthy1,2 1 department of medicine, division of dermatology, albert einstein college of medicine, bronx, ny, usa 2 department of dermatology, nova southeastern university, fort lauderdale, fl, usa key words: dermoscopy; residency training programs; program directors; residents; survey citation: patel p, khanna s, mclellan b, krishnamurthy k. the need for improved dermoscopy training in residency: a survey of us dermatology residents and program directors. dermatol pract concept. 2017;7(2):3. doi: https://doi.org/10.5826/dpc.0702a03 received: december 21, 2016; accepted: february 24, 2017; published: april 30, 2017 copyright: ©2017 patel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. this research was approved on january 14, 2015, by the albert einstein college of medicine/montefiore medical center institutional review board (irb# 2014-4066). funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: karthik krishnamurthy, do, nova southeastern university/park avenue dermatology, 906 park avenue, orange park, fl, 32073, usa. tel. (904) 541-0315; fax. (904) 541-0316. email: kkderm@gmail.com background: inadequate dermoscopy training represents a major barrier to proper dermoscopy use. objective: to better understand the status of dermoscopy training in us residency programs. methods: a survey was sent to 417 dermatology residents and 118 program directors of dermatology residency programs. results: comparing different training times for the same training type, residents with 1-10 hours of dedicated training had similar confidence using dermoscopy in general (p = 1.000) and satisfaction with training (p = .3224) than residents with >10 hours of dedicated training. comparing similar training times for different training types, residents with 1-10 hours of dedicated training had significantly increased confidence using dermoscopy in general (p = .0105) and satisfaction with training (p = .0066) than residents with 1-10 hours of only bedside training. lastly, residents with 1-10 hours of dedicated training and >10 hours of dedicated training had significantly increased confidence using dermoscopy in general (p = .0002, p = .2471) and satisfaction with training (p <.0001, p < .0001) than residents with no dermoscopy training at all. conclusions: dermoscopy training in residency should include formal dermoscopy training that is overseen by the program director and is possibly supplemented by outside dermoscopy training. abstract mailto:kkderm@gmail.com 18 review | dermatol pract concept 2017;7(2):3 were initially sent in august 2015. four hundred seventeen residents were emailed (79 directly, and 338 indirectly, forwarded by pds or program coordinators), and 118 pds were emailed (78 directly, and 40 indirectly, forwarded by program coordinators). non-responding residents, pds, and program coordinators were sent a reminder email after two weeks and four weeks, up to a total of three emails. this study conformed to the ethical guidelines of the 1975 declaration of helsinki as reflected in its approval by the albert einstein college of medicine/montefiore medical center institutional review board. data entry and statistical analysis survey responses were entered on microsoft excel (microsoft co, redmond, wa) and analyzed using graphpad prism 6 (graphpad software inc., la jolla, ca). a two-tailed student’s t-test was used to analyze continuous variables (5-point likert scale questions) with significant levels set at p < .05 and confidence intervals set at 95%. residents with <1 hour of total dermoscopy training were treated no differently than residents with 0 hours of total dermoscopy training. results respondents one hundred twenty-two of the 417 emailed residents, responded to the survey (29% response rate), and 22 of the 118 emailed pds, responded to the survey (19% response rate). data on the breakdown by gender, by region of the us, and by training level for residents and pds is outlined in table 1. dermoscopy use: residents and program directors ninety-one percent of residents (111/122) reported that their attendings advocate the use of dermoscopy, but only 84% (103/122) of residents reported using dermoscopy regularly. in contrast, 100% (22/22) of pds reported using dermoscopy regularly. of those residents who reported that they do not use dermoscopy, the reasons include: inadequate training (79%, 15/19), lack of attending use (26%, 5/19), not owning or having access to a dermatoscope (21%, 4/19), too much time to use a dermatoscope (11%, 2/19), minimal impact on biopsy decision (16%, 3/19), increased user anxiety/liability (5%, 1/19), and dermatoscopes cost too much (11%, 2/19). irrespective of current dermoscopy use, 98% (119/122) of residents planned on using dermoscopy after residency. dermoscopy training types in residency and outside of residency thirty-five percent (43/122) of residents had dedicated dermoscopy training in residency, 27% (33/122) had only bednon-pigmented lesions and other dermatological conditions (e.g., inflammatory diseases, infectious diseases, and hair/nail diseases) [2-6]. in general, studies have shown that proper dermoscopy use improves diagnostic accuracy, reduces unnecessary biopsies, and can even be used to monitor the outcomes and adverse effects of various treatments [3,4,6-8]. despite a reported increase in the rate of dermoscopy use in the united states over the past decade, inadequate dermoscopy training in residency still represents one of the most important barriers to the use of dermoscopy [9-11]. to better understand the status of dermoscopy training in us residency programs, we surveyed dermatology residents and program directors (pds) regarding education practices at their institutions and utilized residents’ confidence with dermoscopy and satisfaction with training as surrogate markers to gauge the quality of dermoscopy training. with the first ever input from pds on this topic, we aim to close the knowledge gap between teacher and student, bringing the perceptions of both groups together for a consensus. methods one hundred eighteen acgme (accreditation council for graduate medical education) dermatology programs were identified on freida online® (fellowship and residency electronic interactive database access). dermatology residents and pds of accredited dermatology programs were contacted via email directly or through forwarded messages, inviting them to participate in a self-report survey. email addresses were obtained from freida online® or from direct correspondence with the contact person listed on freida online®. participation was voluntary and participants did not receive financial compensation. the survey was designed with questions pertaining to demographics, dermoscopy use, and training, using previous dermoscopy survey studies as guidelines [2,9,10,12,13]. pds were additionally asked about their role in teaching dermoscopy and their beliefs regarding resident performance in relation to dermoscopy use. similarly, residents were additionally asked if they planned on using dermoscopy after residency, as well as if their attendings advocated the use of dermoscopy. residents’ confidence using dermoscopy in general and satisfaction with training in residency were scored on a 5-point likert scale, with 1 being not confident/not satisfied and 5 being very confident/very satisfied. the original survey was piloted by academic dermatologists and dermatology residents from the albert einstein college of medicine/montefiore medical center, and revisions were made accordingly before finalization. a link to the appropriate 27-question survey (resident or pd version) (using surveymonkey®) along with a cover letter describing the study goals was emailed to residents, pds, and program coordinators. the surveys http://www.surveymonkey.com review | dermatol pract concept 2017;7(2):3 19 cated training in residency and 55% (18/33) of residents with only bedside training in residency supplemented their training with outside dermoscopy training (table 2). of the various outside training modalities, 60% (31/52) reported training at a national or local conference, 58% (30/52) reported training side dermoscopy training in residency, and 38% (46/122) had no dermoscopy training in residency, which includes residents who had only outside dermoscopy training (12%, 14/122) and residents who had no dermoscopy training at all (26%, 32/122). forty-seven percent (20/43) of residents with deditable 1. characteristics of respondents. [copyright: ©2017 patel et al.] gender residents program directors male 39% (n = 47/122) 41% (n = 9/22) female 61% (n = 75/122) 59% (n = 13/22) region of the united states residents program directors northeast (ct, me, ma, nh, ri, vt, nj, ny, pa) 41% (n = 50/122) 36% (n = 8/22) midwest (il, in, mi, oh, wi, ia, ks, mn, mo, ne, nd, sd) 15% (n = 18/122) 23% (n = 5/22) south (de, fl, ga, md, nc, sc, va, dc, wv, al, ky, ms, tn, ak, la, ok, tx) 32% (n = 39/122) 32% (n = 7/22) west (az, co, id, mt, nv, nm, ut, wy, ak, ca, hi, or, and wa) 12% (n = 15/122) 9% (n = 2/22) residency year residents years post-residency program directors pgy-2 39% (n = 48/122) 0-5 years 5% (n = 1/22) pgy-3 35% (n = 43/122) 6-10 years 32% (n = 7/22) pgy-4 25% (n = 30/122) 7-15 years 27% (n = 6/22) other 1% (n = 1/122, pgy-5) 16-20 years 18% (n = 4/22) 21+ years 18% (n = 4/22) table 2. dermoscopy training type and total hours of training. [copyright: ©2017 patel et al.] dermoscopy training type 1-10 hours of training >10 hours of training dedicated training in residency dedicated training in residency without outside training 14% (n = 17/122) 5% (n = 6/122) dedicated training in residency + 1 outside training modality 7% (n = 8/122) 5% (n = 6/122) dedicated training in residency + 2 or more outside training modalities 2% (n = 3/122) 2% (n = 3/122) total 23% (n = 28/122) 12% (n = 15/122) bedside training in residency only bedside training in residency without outside training 12% (n = 14/122) 1% (n = 1/122) only bedside training in residency + 1 outside training modality 10% (n = 12/122) 1% (n = 1/122) only bedside training in residency + 2 or more outside training modalities 2% (n = 2/122) 2% (n = 3/122) total 23% (n = 28/122) 4% (n = 5/122) no dermoscopy training in residency 1 outside training modality only 7% (n = 9/122) 2 or more outside training modalities only 3% (n = 4/122) 1% (n = 1/122) no dermoscopy training at all total 11% (n = 13/122) 1% (n = 1/122) 20 review | dermatol pract concept 2017;7(2):3 of 5 (95% ci 1.811-2.618) (n = 14), and that for residents with no dermoscopy training at all was 1.875 of 5 (95% ci 1.523-2.22) (n = 32) (table 4). the mean satisfaction with training for residents with 1-10 hours of dedicated training in residency was 3.294 of 5 (95% 2.698-3.891) (n = 17), that for residents with >10 hours of dedicated training in residency was 3.833 of 5 (95% 2.802-4.865) (n = 6), that for residents with 1-10 hours of only bedside training in residency was 2.286 of 5 (95% ci 1.933-2.639) (n = 14), and that for residents with no dermoscopy training at all was 1.781 of 5 (95% ci 1.481-2.081) (n = 32) (table 4). since there was just one resident with >10 hours of only bedside training in residency, his/her response was excluded from our analysis. when comparing the two training times for dedicated training in residency, residents with 1-10 hours of dedicated training had no significant difference in confidence using dermoscopy in general (p = 1.000) or satisfaction with training (p = .3224) than residents with >10 hours of dedicated training. when comparing the two types of dermoscopy trainings in residency, considering similar training times, residents with 1-10 hours of dedicated training had significantly increased confidence using dermoscopy in general (p = .0105) and satisfaction with training (p = .0066) than residents with 1-10 hours of only bedside training. similarly, when comparing dedicating training in residency to no training at all, residents with 1-10 hours of dedicated training and residents with >10 hours of dedicated training both had significantly increased confidence using dermoscopy in general (p = .0002, p = .2471, respectively) and satisfaction with training (p < .0001, p < .0001, respectively) than residents with no dermoscopy training at all. lastly, when comparing only bedside training through an outside course, 19% (10/52) reported training through a web-based course, and 6% (3/52) reported training through a fellowship or research year (table 3). irrespective of current dermoscopy training, 91% (111/122) of residents desired more dermoscopy training in their residency programs; 5% (6/122) did not desire more training; and 4% (5/122) were unsure. confidence using dermoscopy in general and satisfaction with training to assess residents’ confidence using dermoscopy and satisfaction with training as a result of only dermoscopy training in residency, residents with outside training were excluded from our analysis. the mean confidence using dermoscopy in general for residents with 1-10 hours of dedicated training in residency was 3 of 5 (95% 2.555-3.445) (n = 17), that for residents with >10 hours of dedicated training in residency was 3 of 5 (95% 1.850-4.150) (n = 6), that for residents with 1-10 hours of only bedside training in residency was 2.214 table 3. popularity of outside dermoscopy training modalities. [copyright: ©2017 patel et al.] outside dermoscopy training type residents* national or local conference 60% (n = 31/52) outside course 58% (n = 30/52) web-based course 19% (n = 10/52) any fellowship or research year 6% (n = 3/52) *some residents may have participated in more than one outside training modality table 4. residents’ confidence using dermoscopy in general and satisfaction with training. [copyright: ©2017 patel et al.] dermoscopy training type* mean confidence with dermoscopy in general 5-point likert scale (1, not confident; 5, very confident) mean satisfaction with dermoscopy training in residency 5-point likert scale (1, not satisfied; 5, very satisfied) 1-10 hours of dedicated training in residency without outside training (14%, n = 17/122;) 3.000 (95% ci 2.555-3.445) 3.294 (95% ci 2.698-3.891) >10 hours of dedicated training in residency without outside training (5%, n = 6/122) 3.000 (95% ci 1.850-4.150) 3.833 (95% ci 2.802-4.865) 1-10 hours of only bedside training in residency without outside training (12%, n = 14/122;) 2.214 (95% ci 1.811-2.618) 2.286 (95% ci 1.933-2.639) no dermoscopy training at all (26%, n = 32/122) 1.875 (95% ci 1.523-2.227) 1.781 (95% ci 1.481-2.081) *since there was only one resident with >10 hours of bedside training in residency without outside training, his/her response was excluded from our analysis. review | dermatol pract concept 2017;7(2):3 21 in residency is not ideal because the mean confidence using dermoscopy and mean satisfaction with training are only 3.000 (95% 2.555-3.445) and 3.294 (95% 2.698-3.891), respectively, for residents with 1-10 hours of dedicated training, and only 3.000 (95% 1.850-4.150) and 3.833 (95% 2.802-4.865), respectively for residents with >10 hours of dedicated training. with 91% (111/122) of our responding residents desiring more dermoscopy training in their residency programs, one solution may be to supplement dedicated training in residency with outside training, as is done in australian dermatology residency programs, where dedicated dermoscopy training is supplemented with web-based dermoscopy training [2]. unfortunately, given the wide variability of outside training programs, it was not possible for us to evaluate the effect of outside training modalities on our responding residents’ confidence using dermoscopy and satisfaction with training. indeed, trainingspecific prospective studies are needed to evaluate outside training programs as potential supplements to dedicated training in residency. one recent prospective study by boespflug et al [17] reported that residents who trained with spaced education, web-based dermoscopy training combined with formal dermoscopy training had high training satisfaction and had significantly increased dermoscopy skills when compared to residents with just formal dermoscopy training alone. lastly, a majority of pds reported that they play little to no role in teaching dermoscopy (77% play a minor role, and 9% do not teach dermoscopy at all). while it is not necessary that pds themselves teach dermoscopy to residents, pd involvement in creating and/or maintaining a formal dedicated dermoscopy curriculum is important to improving residents’ dermoscopy training. limitations there are some limitations to our study. first, we had a small sample size and a possible selection bias, as only 29% (122/417) of our emailed residents and 19% (22/118) of our in residency to no dermoscopy training at all, residents with 1-10 hours of only bedside training had no significant difference in confidence using dermoscopy in general (p = .2471) than residents with no dermoscopy training at all, but they did have significantly increased satisfaction with training than residents with no dermoscopy training at all (p = .0479). the program director’s role and beliefs surrounding dermoscopy fourteen percent (3/22) of pds reported that they play a large role in teaching dermoscopy to residents; 77% (17/22) reported that they play a minor role; and 9% (2/22) reported that they do not teach dermoscopy at all. nevertheless, 73% (16/22) of pds still believed that those residents who use dermoscopy perform better in identifying suspicious skin lesions than those residents who do not; the remaining 27% (6/22) of pds were unsure whether those residents who use dermoscopy perform any better in identifying suspicious skin lesions than those who do not. discussion this is the first study surveying us dermatology residents across all years concurrently with pds to assess the status of dermoscopy training in residency. we included residents from all years to obtain a comprehensive view of dermoscopy training, and included pds to get a teacher’s view on training. our analysis utilizes residents’ confidence with dermoscopy and satisfaction with training as surrogate markers to gauge dermoscopy training in residency. based on our results, we have made recommendations for improving training as shown in table 5. similar to findings from recent years, 84% (103/112) of residents and 100% (22/22) of pds reported using dermoscopy regularly, and inadequate dermoscopy training was the number one reason for not using dermoscopy by residents (79%, 15/19) [9-11]. in terms of dermoscopy training in residency, 35% (43/122) of residents had dedicated training in residency, 27% (33/122) had only bedside training in residency, and 38% (46/122) had no dermoscopy training in residency. while there was no significant difference in confidence using dermoscopy in general or satisfaction with training between residents with 1-10 hours of dedicated training and >10 hours dedicated training, there was a significant increase in confidence using dermoscopy in general and satisfaction with training between residents with dedicated training and residents with similar hours of only bedside training or no training at all. our results are in accordance with previous studies that suggest that short formal dermoscopy training sessions could increase the dermoscopy naïve dermatologist’s diagnostic capabilities and confidence using dermoscopy [14-16]. nevertheless, in its current form, dedicated training table 5. improving dermoscopy training in residency: dermoscopy training recommendations. [copyright: ©2017 patel et al.] • implement a formal dedicated dermoscopy training curriculum that is overseen by the program director. • avoid solely relying on informal bedside training in residency. • consider supplementing training in residency with one or more outside teaching modalities. • continuously implement resident feedback into improving dermoscopy training through ongoing surveys. 22 review | dermatol pract concept 2017;7(2):3 4. russo t, piccolo v, lallas a, argenziano g. recent advances in dermoscopy. f1000research. 2016;5:184. 5. park jh, kim cw, kim ss. the diagnostic accuracy of dermoscopy for scabies. ann dermatol. 2012;24(2):194-199. 6. micali g, lacarrubba f, massimino d, schwartz ra. dermatoscopy: alternative uses in daily clinical practice. j am acad dermatol. 2011;64(6):1135-1146. 7. van der rhee ji, bergman w, kukutsch na. the impact of dermoscopy on the management of pigmented lesions in everyday clinical practice of general dermatologists: a prospective study. br j dermatol. 2010;162(3):563-567. 8. rudnicka l, olszewska m, rakowska a, slowinska m. trichoscopy update 2011. j dermatol case rep. 2011;5(4):82-88. 9. wu tp, newlove t, smith l, vuong ch, stein ja, polsky d. the importance of dedicated dermoscopy training during residency: a survey of us dermatology chief residents. j am acad dermatol. 2013;68(6):1000-1005. 10. freeman sr, greene re, kimball ab, et al. us dermatology residents’ satisfaction with training and mentoring: survey results from the 2005 and 2006 las vegas dermatology seminars. arch dermatol. 2008;144(7):896-900. 11. terushkin v, oliveria sa, marghoob aa, halpern ac. use of and beliefs about total body photography and dermatoscopy among us dermatology training programs: an update. j am acad dermatol. 2010;62(5):794-803. 12. nehal ks, oliveria sa, marghoob aa, et al. use of and beliefs about dermoscopy in the management of patients with pigmented lesions: a survey of dermatology residency programmes in the united states. melanoma res. 2002;12(6):601-605. 13. engasser hc, warshaw em. dermatoscopy use by us dermatologists: a cross-sectional survey. j am acad dermatol. 2010;63(3):412–419. 14. benvenuto-andrade c, dusza sw, hay jl, et al. level of confidence in diagnosis: clinical examination versus dermoscopy examination. dermatol surg. 2006;32(5):738-744. 15. binder m, puespoeck-schwarz m, steiner a, et al. epiluminescence microscopy of small pigmented skin lesions: short-term formal training improves the diagnostic performance of dermatologists. j am acad dermatol. 1997;36(2 pt 1):197-202. 16. chevolet i, hoorens i, janssens a, et al. a short dermoscopy training increases diagnostic performance in both inexperienced and experienced dermatologists. australas j dermatol. 2015;56(1):5255. 17. boespflug a, guerra j, dalle s, thomas l. enhancement of customary dermoscopy education with spaced education e-learning: a prospective controlled trial. jama dermatol. 2015;151(8):847-853. emailed pds participated in our study, despite our attempts to send multiple emails through various email addresses, including those of program coordinators. it is possible that residents and pds not interested in dermoscopy may have been less likely to complete our survey. additionally, since confidence using dermoscopy and satisfaction with training do not always translate into diagnostic competence, our ability to consider them surrogate markers to gauge dermoscopy training is limited. with no practical way to gauge dermoscopy training, with the exception of implementing an examination, we had to rely on subjective user feedback to quantify and analyze our results. conclusion with 98% (119/122) of residents planning on using dermoscopy after residency, we believe it is our duty to provide quality dermoscopy training during residency. to improve current dermoscopy training in residency, we recommend implementing a formal dedicated dermoscopy training curriculum that is overseen by the program director and is possibly supplemented by outside dermoscopy training (e.g., national/local conference, outside course, web-based training, and/or fellowship year/research year). in the future, testing dermoscopy knowledge on national board examinations may serve as an incentive to implement quality dermoscopy training across all residency programs. acknowledgements we would like to express our gratitude to the residents and program directors who completed our survey. references 1. tasli l, kacar n, argenziano g. a scientometric analysis of dermoscopy literature over the past 25 years. j eur acad dermatol venereol. 2012;26(9):1142-1148. 2. piliouras p, buettner p, soyer hp. dermoscopy use in the next generation: a survey of australian dermatology trainees. australas j dermatol. 2014;55(1):49-52. 3. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol. 2014;170(3):514-526. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022077 1 introduction erythema elevatum diutinum (eed) is a rare, chronic dermatosis characterized by red–violet to red–brown papules, plaques, and nodules that favor extensor surfaces. vesiculobullous variant is a rare form of eed [1]. herein, we present a case of vesiculobullous eed with epidermolysis bullosa acquisita (eba)-like with direct immunofluorescence (dif) findings. case presentation a 65-year-old man presented with progressively increasing nodules on feet for 5 years, pruritic papules on knees and elbows for 1 year (figure1, a–e) and blisters on hands for 1 month. dermatological examination revealed violaceous nodules on feet, erythematous flat-topped papules on elbows and knees with multiple tense blisters on palmar and dorsal region of hands. hematoxylin and eosin staining from 2 punch biopsies of the foot and knee showed nodular and diffuse inflammation rich in neutrophils under uninvolved epidermis (figure 2a). small vessels are damaged by neutrophil rich inflammation and leukocytoclastic debri, resulting in leukocytoclastic vasculitis (lcv) (figure 2b) and storiform fibrosis at the dermis are consistent with eed. the biopsy of the hand dorsum demonstrated subepidermal separation with perivascular and interstitial inflammation rich in eosinophils with fibrin accumulation in the dermis (figure 2, c and d). dif from perilesional skin of the hand revealed linear deposition of immunoglobulins (igg, iga, igm) and complement (c3) along the basal membrane zone (bmz). location of deposits were on the floor of the blister in saltsplit skin test with igg (figure 2e). full blood count showed iron deficiency anemia. serology tests for hiv and hepatitis-b and c were negative. dapsone was initiated 50 mg twice daily. at 5 weeks follow-up, a significant improvement vesiculobullous erythema elevatum diutinum: a rare variant with epidermolysis bullosa acquisita-like immunofluorescence findings basak yalici-armagan1, deniz ates-ozdemir2, gökçe yeter2, nilgun atakan3 1 department of dermatology and venereology, hacettepe university, faculty of medicine, ankara, turkey 2 department of pathology, hacettepe university, faculty of medicine, ankara, turkey 3 dermatology and venereology, private clinic, ankara, turkey key words: direct immunofluorescence, epidermolysis bullosa acquisita, erythema elevatum diutinum, salt-split skin test citation: yalici-armagan b, ates-ozdemir d, yeter g, atakan n. vesiculobullous erythema elevatum diutinum: a rare variant with epidermolysis bullosa acquisita-like immunofluorescence findings. dermatol pract concept. 2022;12(2):e2022077. doi: https://doi. org/10.5826/dpc.1202a77 accepted: october 4, 2021; published: april 2022 copyright: ©2022 yalici-armagan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: basak yalici-armagan, md, department of dermatology and venereology, hacettepe university, faculty of medicine, ankara, turkey. e-mail: basakarmagan@gmail.com 2 research letter | dermatol pract concept. 2022;12(2):e2022077 figure 2. (a-e) diffuse dense inflammation composed of predominantly neutrophils and dermal fibrosis are observed under uninvolved epidermis. (a) fibrin deposition is present around dermal vessels (h&e, 40x magnification). (b) endothelial swelling, leukocytoclastic debri and fibrin deposition are visible in dermal vessels (h&e, 200x magnification). (c) subepidermal separation is seen with fibrin deposition and mild to moderate perivascular and interstitial dermal inflammation (h&e, 40x magnification). (d) subepidermal separation and mild to moderate inflammation are present with eosinophils (h&e, 200x magnification). (e) linear igg deposition is observed at the base of the split cavity (direct immunofluorescence with ig g in salt split skin, 200x magnification). figure 1. (a-e) multiple tense blisters on palmar and dorsal region of hands (a,b); erythematous flat-topped papules on elbows and knees (c,d) and violaceous nodules on feet (e), improving of the vesiculobullous and papular lesions located on the hands (f,g) and knees (h). research letter | dermatol pract concept. 2022;12(2):e2022077 3 was observed in hands, knees and elbows (figure 1, f-h), whereas there was a partial improvement in feet. discussion eed is a rare skin disorder that is associated with a variety of systemic diseases. histopathologically, it is characterized by early changes of lcv with an infiltrate of polymorphonuclear cells, occasionally eosinophils and deposition of fibrin which resolves with fibrosis. the association of eed and autoimmune bullous diseases, such as dermatitis herpetiformis (dh) has been described previously [2]. recently, it is argued that these cases may be more compatible with vesiculobullous eed than with dh. although, perivascular deposition of igg, iga, igm, complement, and fibrin has been demonstrated in dif examination of eed; granular iga deposits with a pseudolinear pattern at bmz was reported in a single case of vesiculobullous eed [1]. to our knowledge, this is the first case of vesiculobullous eed with linear iga, igg, igm and c3 deposition in bmz. the presence of the deposits in the base of the bulla in salt-split skin test was also a remarkable finding in the current case which could be a pitfall for eba in the differential diagnosis. histopathological findings of eba include subepidermal blister formation with none or little inflammation depending on the clinical subtype. while dapsone is an effective treatment option for eed, eba is usually refractory to many systemic agents including dapsone. conclusions dermal inflammation with eosinophils and fibrin deposition in histopathologic examination and dramatic response to dapsone therapy suggested the diagnosis of vesiculobullous eed rather than eba in the current case. the present novel dif and salt-split skin test findings expand the clinicopathological spectrum of vesiculobullous eed. references 1. ossorio-garcía l, jiménez-gallo d, arjona-aguilera c, salamanca-sánchez m, linares-barrios m. vesiculobullous variant of erythema elevatum diutinum. clin exp dermatol. 2017;42(7):777-780. doi: 10.1111/ced.13166.. pmid: 28639709. 2. aftab mn, dee a, helm tn. erythema elevatum diutinum arising in the setting of dermatitis herpetiformis. cutis. 2006;78(2):129132. pmid: 16983903. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022134 1 an updated algorithm integrated with patient data for the differentiation of atypical nevi from early melanomas: the idscore 2021 linda tognetti1, alessandra cartocci1,2, martina bertello1, mafalda giordani1, elisa cinotti1, gabriele cevenini3, pietro rubegni1 1 dermatology unit, department of medical, surgical and neurosciences, university of siena, siena, italy 2 department of medical biotechnologies, university of siena, siena, italy 3 bioengineering & biomedical data science lab university of siena, siena, italy key words: melanoma, atypical nevi, dermoscopy, risk factors citation: tognetti l, cartocci a, bertello m, et al. an updated algorithm integrated with patient data for the differentiation of atypical nevi from early melanomas: the idscore 2021. dermatol pract concept. 2022;12(3):e2022134. doi: https://doi.org/10.5826/dpc.1203a134 accepted: november 27, 2021; published: july 2022 copyright: ©2022 tognetti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: linda tognetti, md, phd, hospital s. maria alle scotte, viale bracci 16, 53100 siena, italy, e-mail: linda.tognetti@ dbm.unisi.it introduction: it is well known that multiple patient-related risk factors contribute to the development of cutaneous melanoma, including demographic, phenotypic and anamnestic factors. objectives: we aimed to investigate which mm risk factors were relevant to be incorporated in a risk scoring-classifier based clinico-dermoscopic algorithm. methods: this retrospective study was performed on a monocentric dataset of 374 atypical melanocytic skin lesions sharing equivocal dermoscopic features, excised in the suspicion of malignancy. dermoscopic standardized images of 258 atypical nevi (an) and 116 early melanomas (emm) were collected along with objective lesional data (i.e., maximum diameter, specific body site and body area) and 7 dermoscopic data. all cases were combined with a series of 10 mm risk factors, including demographic (2), phenotypic (5) and anamnestic (3) ones. results: the proposed idscore 2021 algorithm is composed by 9 variables (age, skin phototype i/ii, personal/familiar history of mm, maximum diameter, location on the lower extremities (thighs/legs/ ankles/back of the feet) and 4 dermoscopic features (irregular dots and globules, irregular streaks, blue gray peppering, blue white veil). the algorithm assigned to each lesion a score from 0 to 18, reached an area under the roc curve of 92% and, with a score threshold ≥ 6, a sensitivity (se) of 98.2% and a specificity (sp) of 50.4%, surpassing the experts in se (+13%) and sp (+9%). abstract 2 original article | dermatol pract concept. 2022;12(3):e2022134 conclusions: an integrated checklist combining multiple anamnestic data with selected relevant dermoscopic features can be useful in the differential diagnosis and management of emm and an exhibiting with equivocal features. introduction an adequate dermoscopic differentiation between atypical melanocytic skin lesions (amsls), ie, atypical nevi (an) and early melanomas (emm) can represent a challenge in daily practice, especially for less experienced dermatoscopists. dermoscopy alone cannot be accurate enough to adequately recognize an exhibiting equivocal dermosocpic feature or, of converse, can fail to identify those emm that do not exhibit clear-cut dermoscopic features suggestive for malignancy [1-6]. in addition, we also debate whether a certain degree of overdiagnosis of in situ mm might have took place in the last decade worldwide [7-10]. in this context, a reasonable way out seems to be to follow a global approach to the patient integrating dermoscopic imaging with multiple risk assessment tools and personal plus lesional data [7,11-18]. objectives we previously demonstrated the efficacy of integrating 3 relevant clinical parameters (ie, age, maximum diameter and body location) into a dermoscopic algorithm (the idscore 2018) [1], which reached high diagnostic accuracy on both a monocentric dataset of 435 amsls and on a multicentric dataset of 980 amsls. we then aimed to extend the list of clinical parameters to the most relevant potential melanoma risk factors and to investigate which were the most significant independent association with a mm histologic diagnosis. secondly, we aimed to select through stepwise logistic regression analysis a series of interdependently significant data, useful to develop a new idscore 2021 checklist, able to provide a differential score to distinguish emm from an with equivocal features. methods this retrospective study was realized in accordance with the declaration of helsinki and approved by the local ethical committee (id16801); all data were de-identified before use. data collection a total of 410 amsls were consecutively excised from january 2018  to  may 2021 in siena university hospital in the suspicion of malignancy. all amsls localized on the face, palms, and soles were excluded a priori due to their specific dermoscopic pattern. histological diagnoses were retrospectively collected, including dermoscopic standardized polarized images (om 20x) have been prospectively collected along with lesional data (maximum diameter and body location based on a sun-exposure classification), as previously described [14]. in addition, patients personal data concerning 8 mm risk factors were collected, ie: personal/familiar history of mm; sunburns before 14 years, phototype, pheomelanin, blond hairs, blue/green eyes, >11 nevi on the right arm (table 1). the presence of pheomelanin phenotype was assessed when the patient had red/carroty/straw red/ brown-reddish hair, pale skin, freckles and high tendency to sunburn and/or inability to tan. dermoscopic-reader study dermoscopic evaluations were independently performed by 4 experts in dermoscopy, blinded for histopathological diagnosis (ec, mb, al, pr). they were asked to recognize a dermoscopic feature among a series of 7, previously selected for the idscore 2018 checklist (tables 1 and 4), including: atypical network (an), irregular streaks (is), blue white veil (bwv), blue gray peppering (bgp), white scar-like areas (wsa), shiny white streaks (sws) and irregular dots globules (idg) (figures 1 and 2). then, they were asked to express an intuitive diagnosis of emm/an. the presence of one or more dermoscopic features inside each lesion and the final diagnosis was assessed based on the agreement of 3 out of 4. integrated dataset after selection (mg, lt, ac) for image quality, availability of patient data and agreement of 2 out of 3 pathologists on histopathological diagnosis, the final database consisted of 374 standardized dermoscopic pictures, 258 and 116 emm. each lesion was paired with 19 objective parameters, including: 8 mm risk factors, 2 patient demographic data, 2 amsl objective data and 7 dermoscopic features (table 1). statistical analysis descriptive analysis was carried out using absolute frequencies and percentages for qualitative variables, mean and standard deviation for age and diameter, median and minimum-maximum range for the idscore. age and diameter were then categorized for the score model purpose, merging classes with same risk. the association of gender, risk original article | dermatol pract concept. 2022;12(3):e2022134 3 p < 0.05 was considered statistically significant. the analyses were carried out with r version 4.10. results case study in table 1 is reported the distribution of all patienst demographic data (2), the melanoma risk factors (8) and the amsls morphologic data (2). concerning the emm, they affected males in 53% versus females in 46% of cases, mean age was 58.9 years, the predominant body area was the upper trunk (49% of cases) and the average diameter was 9.5mm. histologic stages included: tis (50), ia (37), ib (20) and iia (9 cases) [19]. factor and clinical features with histology were evaluated by chi-squared test. the difference of age and diameter between an and emm by t test, instead, the idscore by mann-whitney test. kolmogorov-smirnov test was used to evaluate the normality distribution of quantitative variables. bivariate analysis was performed by logistic regression, the odds ratios (or) and their 95% confidence interval (ci) were estimated, too. in particular, eight bivariate logistic regression were carried out, each one with idscore plus one risk factor. after that, an integer score model was developed based on logistic regression. leave-one-out procedure was used for testing the model. roc curves and their areas (auroc) were also estimated to compare the model performances. a table 1. distribution of patient demographic data, melanoma risk factors and lesional data in the case study idscore database 2018-2020 of 374 atypical melanocytic skin lesions. the results of univariate analysis for significant association with mm histologic diagnosis are also reported with corresponding p-values. atypical nevi (an) n=258 early melanomas (emm) n=116 p demographic data 1. age (years) 48.0±14.2 58.9±15.0 < 0.001 2. gender female 106 (41.1%) 54 (46.6%) 0.366 male 152 (58.9%) 62 (53.4%) anamnestic risk factors 1. history of melanoma (personal / 1st relative) 72 (28.2%) 50 (43.1%) 0.007 2. sunburns before 14 (yes/no) 173 (68.7%) 82 (71.9%) 0.542 3. smoke (>5 cigarettes/day) (yes/no) 66 (26.3%) 19 (22.1%) 0.475 phenotypic risk factors 4. skin phototype i+ii 66 (25.8%) 60 (51.7%) 0.005 iii+iv 190 (74.2%) 56 48.3%) 5. pheomelanin phenotype (yes/no) 23 (9.0%) 21 (18%) 0.005 6. blonde hair (yes/no) 42 (16.4%) 28 (24.3%) 0.05 7. green/light-blue/blue eyes (yes/no) 86 (33.7%) 43 (37.4%) 0.556 8. >11 nevi/right arm (yes/no) 128 (50.4%) 66 (57.4%) 0.005 amsls data 1. maximum diameter (mm) 6.4±2.5 9.5±3.2 <0.001 2. body area / anatomical site upper extremities chronically photoexposed [head/neck/arms/hands] 18 (7.0%) 14 (12.1%) 0.113 upper trunk seldom photoexposed [shoulders/back/chest/breast] 146 (56.6%) 57 (49.1%) 0.217 lower extremities frequently photoexposed [thighs/legs/ankles/back of the feet] 26 (10.1%) 18 (15.5%) 0.164 lower trunk rarely photoexposed [side/bottom/abdomen] 68 (26.4%) 27 (23.3%) 0.608 table1 continues 4 original article | dermatol pract concept. 2022;12(3):e2022134 bivariate analysis each one of the 8 variables assumed as possible mm risk factors was tested in combination with the idscore 2018 checklist for the association with mm histologic diagnosis: according to the bivariate analysis results (table 2), it appeared that only 2 variables added a significant increase in accuracy when incorporated into the previous checklist idscore 2018, namely the “skin phototype i/ii” and the “history of mm” (personal or regarding the 1st degree relative). logistic regression according to the stepwise analysis of the logistic regression (table 3), the new idscore 2021 checklist would be composed by only 9 parameters, including the “age ranges 31-60 years” and ≥ 61 years, the “skin phototype i/ii”, the “history of mm”, the “maximum diameter” ranges 6-10mm dermoscopic-reader study the presence of 7 dermosocpic variables in the 2 groups of an and emm according to experts consensus (ie, number of positive observation, %) is also reported in table 1. the 4 experts in dermoscopy obtained, on average, a sensitivity (se) and specificity (sp) of 85.2% and 41.5%, respectively, on the present dataset of difficult amsls. univariate analysis a total of 12 variables resulted more frequently associated with a emm diagnosis rather than with an diagnosis, and to significantly discriminate (p < 0.05) the 2entities, namely: “age”, “history of mm (personal / 1st relative)”, “skin phototype i/ii”, “pheomelanin phenotype”, “>11 nevi/right arm”, “maximum diameter” and the presence of is, bwv, bgp, wsa, sws and idg (table 1). atypical nevi (an) n=258 early melanomas (emm) n=116 p amsls dermoscopic features 1. atypical network (yes/no) 230 (89.1%) 104 (89.7%) 1.000 2. irregular streaks (yes/no) 29 (11.2%) 49 (39.7%) <0.001 3. blue white veil (yes/no) 18 (7.0%) 29 (25.0%) <0.001 4. blue gray peppering (yes/no) 21 (8.1%) 28 (24.1%) <0.001 5. white scar-like areas (yes/no) 6 (2.3%) 18 (15.5%) <0.001 6. shiny white streaks (yes/no) 1 (0.4%) 4 (3.4%) 0.034 7. irregular dots globules (yes/no) 71 (27.5%) 60 (51.7%) <0.001 idscore 2018 6 [2-11] 9 [4-14] <0.001 table 1. distribution of patient demographic data, melanoma risk factors and lesional data in the case study idscore database 2018-2020 of 374 atypical melanocytic skin lesions. the results of univariate analysis for significant association with mm histologic diagnosis are also reported with corresponding p-values. (continued) table 2. bivariate analysis of the 8 variables/melanoma risk factors combined with the idscore 2018 checklist and association with mm histologic diagnosis. 8 variables/melanoma risk factors idscore 2018 checklist + new variable or (95% ci) p >11 nevi/right arm 1.1 (0.6-2.3) 0.801 history of mm (personal/1st relative) 2.8 (1.4-5.4) < 0.001 sunburns 1.0 (0.5-2.0) 0.928 skin phototype (i+ii vs iii+iv) 2.9 (1.5-5.6) < 0.001 pheomelanin phenotype 1.5 (0.7-3.6) 0.333 green/light-blue/blue eyes 1.0 (0.6-2.0) 0.913 blonde hair 1.3 (0.6-2.7) 0.546 smoke (>5 cigarettes/day) 1.1 (0.5-2.4) 0.803 ci = confidence interval; or odds ratio. original article | dermatol pract concept. 2022;12(3):e2022134 5 addition, the preferred score threshold (st) for both model is reported, along with the corresponding se and sp values, while the global performance is expressed as area under the roc curve with 95% confidence interval. in detail, the idscore 2021 showed: with st ≥ 6, se = 98.2%, sp = 50.4 (+0.6% se and +2.3% sp compared with 2018 model); with st ≥ 5, se = 100%, sp = 30%; with st ≥ 7, se = 96.4% and sp=31.7. in figures 1 and 2 are reported 6 exemplificative cases, namely 3 amsl of the back (figure 1) and 3 amsls of the and ≥11mm, the “body location on the lower extremities (including thighs/legs/ankles/back of the feet), and presence of 4 dermoscopic variables such as idg, is, bwv and bgp. performance analysis of the integrated model table 4 illustrates the composition of the idscore 2018 and the new idscore 2021 model, the partial scores (coefficients) assigned to each variable and the total score (s range) which could be assigned to a given amsl (from s = 0 to s = 18). in table 3. results of the stepwise multivariate logistic regression analysis performed over all variables (2 patient anagraphic data + 8 melanomas risk factors + 2 lesion data + 7 dermoscopic data) for the association with a histologic diagnosis. 9 selected variables (idscore 2021) or (95% ci) p age 31-60 years 16.9 (3.0-54.4) 0.004 age ≥ 61 years 89.5 (14.4-889.4)) < 0.001 maximum diameter 6-10mm 7.4 (3.1-20.2) < 0.001 maximum diameter ≥11mm 36.7 (12.1-126.3) < 0.001 lower extremities 3.1 (1.1-8.7) 0.027 idg 2.6 (1.4-5.1) 0.004 is 5.1 (2.4-11.3) < 0.001 bwv 6.7 (2.5-19.1) < 0.001 bgp 3.7 (1.5-9.3) 0.005 phototype (i+ii vs iii+iv) 3.2 (1.7-6.2) < 0.001 history of melanoma (personal /1st relative) 3.2 (1.6-6.5) < 0.001 bgp = blue gray peppering; bwv = blue white veil; ci = confidence interval; idg = irregular dots globules; is = irregular streaks; or odds ratio. table 4. comparison of the two models of 2 models of integrated idscore checklist: composition and performances obtained over 324 atypical melanocytic skin lesions of the body. idscore 2018 idscore 2021 composition coefficient composition coefficient 1. atypical network 1 1. blue white veil 2 2.irregular streaks 1 2.irregular streaks 2 3.blue white veil 1 3.irregular dots and globules  1 4.blue gray peppering 1 4. blue gray peppering 1 5.white scar-like areas 1 5. maximum diameter 6.shiny white streaks 1 6–10 mm 2 7.irregular dots globules 1 ≥ 11mm 4 8.maximum diameter 1 6. age 6–10 mm 3 31-60 years 3 ≥11 mm 4 ≥ 61 years 5 9.age 7. lower extremities frequently photo-exposed [thighs / legs / ankles / back of the feet] 1 30-40 years 1 41-60 years 2 ≥61 years 3 table4 continues 6 original article | dermatol pract concept. 2022;12(3):e2022134 idscore 2018 idscore 2021 composition coefficient composition coefficient 10.body area 8. fair phototype (i/ii) 1 upper extremities chronically photo-exposed 2 9. history of melanoma (personal/ 1st degree relative) 1 lower extremities frequently photo-exposed 2 upper trunk seldom photo-exposed 1 roc area (ci 95%) 0.904 (0.872-0.935) roc area (ci 95%) 0.917 (0.887-0.944) score range 0-16 score range 0-18 score threshold st ≥6 (se = 97.4%; sp = 48.1%) score threshold st≥ 6 (se = 98.2%; sp = 50.4%) ci = confidence interval; se = sensitivity; sp = specificity; st = core threshold table 4. comparison of the two models of 2 models of integrated idscore checklist: composition and performances obtained over 324 atypical melanocytic skin lesions of the body. (continued) figure 1. examples of atypical melanocytic skin lesions (amsls) on the upper back from the case study. a 71 years-old male, phototype ii, personal history of melanoma, with a 11 mm amsl, idscore 2021 = 15 (idscore 2018 = 9): histological examination revealed an early melanoma (mm t1an0m0, thickness 0.7mm) (aa and b). a 61 years-old male, phototype ii, with 7mm amsl: the idscore 2021 was 9 (idscore 2018 = 7) and the histological examination revealed a nevus with moderate atypia (c and d). a 50 years-old male, 11 mm, phototype ii, > 11 nevi/right arm, 1st relative history of mm, sunburns before the age of 14, with a 10mm amsl: the idscore 2021 was 10 (idscore 2018 = 8) and the histological examination revealed a nevus with severe atypia (e and f). original article | dermatol pract concept. 2022;12(3):e2022134 7 when taking into account the patient demographic data, age confirmed to be a significant independent risk factors for discriminating an from emm, with a flexing point of the s-shaped curve for malignancy incidence at 50 years [2325]. the statistical analyses here conducted on a large dataset of amsls were restricted to two crucial cut-offs at 31 and 60years and allowed to identify three range groups with increasing risk for malignancy (table 4). concerning sex, we here observed that sex variable is not a variable to be considered for an algorithm, because an and emm are similarly distributed among males and females, in line with recent studies confirming no significancy, but only in association with the uv-exposure habits and/or hormonal changes (ie female sex) [26-28]. among the patient anamnestic data, the positive history for mm-personal or in a 1st degree relative is still a considered a nonmodifiable risk for the incidence of a new mm [20-23,27,28]. here in this dataset, this variable chest (figure 2) with the corresponding total scores obtained idscore 2021; for comparison, the idscore 2018 total scores are also reported in brackets. finally, according to the roc curve analysis comparison (figure 3) the new algorithm demonstrates to surpass the previous one by +1.3%. conclusions the debate about the relative impact of modifiable and nonmodifiable risk factors on melanoma development is still ongoing [20-22]. however, some demographic data related to the patient and some characteristics of the lesion itself have currently acquired a considerable body of evidence and deserve to be investigated as possible additional risk score coefficients along with the dermoscopic parameters [1,2,11,13,14]. figure 2. examples of atypical melanocytic skin lesions (amsls) of the chest from the case study. a 80 years-old male, phototype iii, familiar history of melanoma, with a 7 mm amsl: idscore 2021 was 12 (idscore 2018 = 8) and the histological analysis revealed an in situ melanoma (a and b). a 66 years-old male, phototype ii, familiar history of mm, with a 10mm amsl: the idscore 2021 was 10 (idscore 2018 = 8); the histological analysis revealed a nevus with moderate atypia (c and d). a 47 years-old female, phototype iii, with a 7.7 mm amsl, the idscore 2021 was 6 (idscore 2018 = 5) and the histological examination revealed a compound nevus (e and f). 8 original article | dermatol pract concept. 2022;12(3):e2022134 appeared to have a significant discrimination power in the univariate (table1) and bivariate (table 2) analysis and was one of the predictive variable of the score model classifier (tables 3 and 4), in line with previous studies on data from a multivariate analysis of predictors of emm diagnosis [29-31]. the parameter “positive history of sunburns in childhood” is well known to be primary inciting event in the development of acquired melanocytic nevi in adults [30-32]. on the other hand, recent ecological and case-control studies highlighted that is the total cumulative ambient sun exposure during childhood to correlate with melanoma risk development, more than the parameter “positive history of sunburns in childhood” [33-35]. in line with these literature data, here in this study we found similar distribution of the infancy sunburn parameter when comparing the population of patient with dysplastic nevus syndrome/multiple atypical nevi (69%) and emm (70%), which resulted not significant in discriminating among the two entities (tables 2 and 3). renown as a risk factor for several types of human cancer, cigarette smoke was correlated with premature skin aging, squamous cell carcinoma of the skin, psoriasis and impaired wound healing [36]. many studies have been carried out in the last decades for testing the association with mm too, but results were not univocal or clear-cut due to residual statistical confounders or inadequate sample size [36-38]. in a recent case-control study carried out over 1,157 patients diagnosed with mm and 5,595 controls in the netherlands, cigarette smoking was found not to increase the risk of mm development, as well as in a large cohort study on us white women [39,40]. similarly, here in this study we find the smoke habit to involve 26% of patients from the an group and 21% of patients from the emm group (table 1) and not to impact significantly on the differential diagnosis among these two entities (tables 2 and 3). in the last decade, the parameter “total nevi number” was investigated in adult european and american population as possible mm risk factor, both independently or in association with other parameters (mm body site distribution, patient height, etc.) [37,39-43]: the high nevus count > 50 of the whole body appeared to be independently associated with mm incidence, and high nevus count on the extremities (ie photo-exposed areas) appeared to bring more risk than high nevus count on the trunk [37,40,42,44]. then, several investigations were carried out to find a valid esteem of the total body count taking into account the nevi count on the 4 extremities, on the upper extremities (> 20), on the lower extremities (> 10) or on the right arm (> 11) [37,40-42,44]. to facilitate the risk factors collection in clinical practice, we decided to adopt the cut-off of > 11 nevi on the right arm as predictor of the total nevi count, based on current literature knowledge. when investigating this parameter in our adult population of patients with amsls, similar rates of high nevus count in both the em (53%) and the an (50%) group (table 1), and it was not selected by multiple regression analysis. indeed, our an group population hosts a considerable quote of patients with multiple clark nevus phenotype, as occur in many second level referring ambulatories for screening and follow-up. there are however data suggesting that the mm incidence is higher in patients with multiple an/clark nevi in addition to a family history of melanoma among relatives with the same phenotype, but low among people with sporadic phenotype of multiple clark nevi [45,46]. consequently, the nevus count is not a discriminant variable for distinguishing an form ems, but should be evaluated along with the nevi characteristics, such as the stability/change during follow-up and additional patient data (eg the “clark phenotype”). finally, we took into account the impact of all physical characteristics related to melanin type, including the skin phototype of the patient, its hair color, the eye color and the presence/absence of a pheomelanin phenotype. the presence of blond hair and of blue/light-blue or green color were traditionally investigated as risk factor for skin cancer [46-48]. first studies in northern europe population-based studies, the light eye color emerged as independently associated risk factor for mm development (~1.6-fold higher risk for mm compared with dark eyes), while the blond hair color had moderate risk [45-48]; more recently, spanish population-based study revealed that hair and eye color did 1 roc curve 0,9 0,8 0,7 0,6 0,5 se n si ti v it y 0,4 0,3 0,2 0,1 0 0 0,1 0,2 0,3 0,4 0,5 1-specificity idscore idscore 2021 0,6 0,7 0,8 0,9 1 figure 3. receiver operating characteristic (roc) of the 3 integrated algorithms: idscore 2018 (black) and idscore 2021  (blue) obtained on the idscore database 2018-2020 of 324 atypical melanocytic skin lesions. the segments of the curves represent cases obtaining the same score. original article | dermatol pract concept. 2022;12(3):e2022134 9 not show any significant effects even after adjustments for confounders [44]. here in this study based on a southern european population, the univariate analysis (table 1) demonstrated that the discriminant independent power of the variables “fair phenotype”, “blonde hair” and “green/light-blue/blue eyes” is similar. moreover, a significant discrimination is obtained when comparing phenotypes i+ii versus phenotypes iii+iv, in line with literature data that assigned a 3-fold higher risk for mm as compared with phenotypes v+vi [45]. however, the multivariate logistic regression analysis selected the variable fair skin phenotype (i-ii) (table 4) instead of the two variables “blonde hair” and “light-colored eyes”: these two were likely to be statistically “absorbed” by the fair phototype variable, which is nevertheless considered an including category. of converse, the “pheomelanin phototype” is assessed in a patient exhibiting when red/carroty/reddish hair, pale skin and freckles in combination with the high tendency to sunburn and/or inability to tan [45-50]. recent molecular studies in vitro and in vivo on mouse models (including inactivated mutation of the mc1r gene and brafv600e mutation) suggest that the pheomelanin phenotype may facilitate skin carcinogenesis through either an uv-dependent (ie accumulation of dna damage through oxidative stress) and an uv-independent pathway [49-50]. it is understood that this parameter should be regarded as a body-site and sun-exposure independent risk factor for mm, with reported with rates between 1.4 and 3 [45-48]. we indeed observed a discriminant power for this parameter in the dd between an and ems (p = 0.005) according to univariate analysis (table 1). when comparing the new idscore 2021 checklist with its precursor idscore 2018 (table 4), some differences can be highlighted. first, the training phase was based on a total of 19 parameters (3 anamnestic risk factors + 5 phenotypic risk factors + 2 anagraphic data + 2 amsl data + 7 amsls dermoscopic features) instead of the 10 parameters (2 anagraphic data + 2 amsl data + 7 amsls dermoscopic features) of the idscore 2018. second, some modifications were applied in order to simplify the checklist final use: estimation of 3 age groups with different coefficient instead of using 4 age groups; selection of one body area with the high discriminant power, instead of using 3 body areas; reduction of dermoscopic variables from 7 to 4. concerning this final selection of 4 inter-dependently significant dermoscopic variables, the 3 left out were: white scar-like areas, shiny white streaks and atypical network. white scar-like areas and shiny white streaks were significant in the univariate analysis, but not in the multivariate analysis, as they did not reached significant numerosity in the whole dataset. importantly, the atypical network was similarly observed in both the an and the emm groups (89.1% and 89.7% of cases, respectively) (table 1) thus cannot be considered a discriminant factor. thus, the differential diagnosis of an and emm equivocal images, concerning this monocentric dataset, relies essentially on the combination of 4 dermoscopic variables: “blue white veil”, “irregular streaks, irregular dots and globules” and “blue gray peppering” (table 4). third, for the final checklist composition, the selection based on multivariate analysis was restricted to the most relevant interdependent 9 integrated variables, to respect the feasibility requirement for using the checklist in daily practice without reducing the accuracy [1,13]. fourth, the total score range of idscore 2021 is wider, from 0 to 18, while for idscore 2018 was 0-16 (table 4, figures 1 and 2). concerning the performance comparison of the two models, when tested on the same monocentric dataset of 324 amsl, the new idscore 2021 appeared to be more accurate (roc area=92%, se=98%, sp=50%) then the idscore 2018 (roc area = 90%, se = 97%, sp = 48%) (table 4, figure 3), and to surpass the experts in terms of se (+13%) and sp (+9%). the present study has some limitations. first, although the number of emm lesions selected was enough to obtain an adequate discriminant power, the whole sample size was limited. secondly, the evaluators were forced to use a series of selected dermoscopic parameters (ie idscore checklist 2018) in the dermoscopic pattern analysis: this selection of 7 dermoscopic criteria has a practical value but could also be regarded as a bias in the sense that some recent additional terminology/dermoscopic features of an and emm is preventively excluded. taken together, the present findings suggest the following consideration. first, the investigation approach of developing a scoring checklist based on an integrated dataset of patients demographic, phenotypic and anamnestic risk factors integrated with objective clinical and dermoscopic data could help dermatologists in early identification of the patient with high risk of mm in routinary medical consultations. second, using an integrated risk score algorithm such as the new 2021 idscore checklist with 9 parameters, each one associated with a peculiar partial score, could be proposed as a rapid and easy tool to screen patients with multiple amsls and assign them a progressive predictive score ranging from an an to an emm diagnosis based on statistical probability. third, managing these patients according to the peculiar amsl risk score could help not only in reducing the rate of inappropriate excision for benign lesions but also in organizing the proper follow-up timing (3/6/9/12 months) during daily practice. 10 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(eds). cutaneous melanoma. springer, cham 2020. doi: 10.1007/978-3-030-05070-2_8. 47. fortes c, mastroeni s, bakos l, et al. identifying individuals at high risk of melanoma: a simple tool. eur j cancer prev. 2010;19(5):393-400. doi:  10.1097/cej.0b013e32833b492f. pmid: 20520559. 48. psaty el, scope a, halpern ac, marghoob aa. defining the patient at high risk for melanoma. int j dermatol. 2010;49(4):362-376. doi: 10.1111/j.1365-4632.2010.04381.x. pmid: 20465687. 49. mitra d, xi luo,  ann morgan, et al. an ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. nature. 2012;491(7424):449453. doi: 10.1038/nature11624. pmid: 23123854. pmcid: pmc3521494. (2 50. potrony m, badenas c, aguilera p, et al. update in genetic susceptibility in melanoma. ann transl med. 2015;3(15):210. doi:  10.3978/j.issn.2305-5839.2015.08.11. pmid:  26488006. pmcid: pmc4583600. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):13 59 dermatology practical & conceptual www.derm101.com introduction melanoma is the malignant tumor of melanocytes which may present in a wide morphological spectrum including highly pigmented to amelanotic appearance. clinically there are four main subtypes of cutaneous melanoma: superficial spreading melanoma, lentiginous melanoma, nodular melanoma and acral lentiginous melanoma. any of these subtypes may present with pink amelanotic features. the diagnosis of amelanotic variants of melanoma may especially be challenging both clinically and histologically. in addition to clinical variants of melanoma, in the literature various atypical histological variants of melanoma have been reported, such as fibroblastic, desmoplastic, chondroid, osteoid, and myxoid melanoma, which were classified according to stromal changes [1-3]. myxoid melanoma is an unusual variant of malignant melanoma, which is characterized by atypical spindle cells and dense mucin deposition in dermis. the prevalence of this melanoma variant is not well known and may develop on cutaneous or extracutaneous sites, including the sino-nasal passages [4]. this tumor may be confused with other mucinprimary myxoid melanoma with dermoscopic findings tugba k. uzuncakmak1, ilkin zindanci1, ebru i. zemheri2, ayse s. karadag1, burce c. kuru1, necmettin akdeniz1 1 department of dermatology, istanbul medeniyet university, goztepe research and training hospital, istanbul, turkey 2 department of pathology, istanbul medeniyet university, goztepe research and training hospital, istanbul, turkey key words: dermoscopy, interpheron, myxoid melanoma citation: uzuncakmak tk, zindanci i, zemheri ei, karadag as, kuru bc, akdeniz n. primary myxoid melanoma with dermoscopic findings. dermatol pract concept. 2017;7(2):13. doi: https://doi.org/10.5826/dpc.0702a13 received: november 25, 2016; accepted: january 29, 2017; published: april 30, 2017 copyright: ©2017 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: tugba kevser uzuncakmak, md, istanbul medeniyet university, goztepe training and research hospital, dermatology, istanbul, turkey. tel. +90(530) 6640226. email: drtugbakevser@gmail.com myxoid melanoma is a rare variant of melanoma, which is characterized by atypical spindle cells and dense mucin deposition in dermis. this tumor is usually seen in elderly people with a similar progress in other variants of melanoma. a 28-year-old male presented to our outpatient clinic with a 6-month history of a slowly growing asymptomatic pink lesion on his arm. dermoscopic examination revealed pink-white cristalline structures and blue-grayish ovoid globules. the lesion was totally excised with initial diagnosis of basosquamous carcinoma, amelanotic melanoma and basal cell carcinoma. histopathological examination was consistent with myxoid melanoma. we present this case due to the rarity of myxoid melanoma and occurrence at such a young age. abstract mailto:drtugbakevser@gmail.com 60 observation | dermatol pract concept 2017;7(2):13 blood count, routine biochemistry, lactate dehydrogenase and beta-2 microglobulin and imaging test for metastasis, including pet-ct and sentinel lymph node biopsy, were all clear. systemic adjuvant interpheron therapy was administered. the patient is currently well and clinically free of recurrence 18 months after the diagnosis. discussion the presence of myxoid stroma in malignant melanoma was first published by bhuta et al in 1986 in four metastatic malignant melanomas [1,2]. clinically these tumors were reported to be amelanotic, but in some cases melanogenesis was also shown with fontana masson preparations [2]. histologically, this rare variant of melanoma is characterized by large malignant melanocytes and a basophilic mucinous matrix. in all cases, the myxoid stroma is comprised of mesenchymal acidic mucopolysaccharides, as opposed to neutral epithelial mucins. mucinous material is usually located around the tumor cells, as in our case, but not within the tumor cells as in cytoplasmic localization, confirming that the myxoid matrix is produced as a response to the stromal cells in the tumor rather than being a product of the tumor cells. myxcontaining neoplasms, histologically benign or malignant, and clinically is usually reported in elderly people with a similar progress to other variants of melanoma. case report a 28-year-old male presented to our outpatient clinic with a history of an asymptomatic pink nodule which had been growing slowly for last 6 months. dermatological examination revealed a 2.5 x 2 cm diameter pink, mildly infiltrated tumoral lesion with two pigmented papular lesions on left arm (figure 1). dermoscopic examination revealed pinkwhite cristalline structures and blue-grayish ovoid globules (figure 2). the lesion was totally excised with 3 mm margins with the initial diagnosis of basosquamous carcinoma, amelanotic melanoma and basal cell carcinoma. histopathological examination was consistent with myxoid melanoma with breslow thickness 11.6 mm, clark level v (figure 3a,b). there was no vascular, lymphatic or perineural invasion histologically, and mitoses 2/1 per mm. strong positivity was detected with s100 and hmb45 staining, and widespread positive staining was detected with pas-alcian blue for mucin deposition (figure 4a,b). laboratory tests, including complete figure 1. a 2.5 x 2 cm diameter pink, mildly infiltrated tumoral lesion with two pigmented papular lesions on the left arm. [copyright: ©2017 uzuncakmak et al.] figure 2. pink-white cristalline structures and blue-grayish ovoid globules, nonpolarized dermoscopy. [copyright: ©2017 uzuncakmak et al.] figure 3. (a) nests of atypical melanocytes surrounded by myxoid stroma. h&e x40 (b) higher magnification, h&e x200. [copyright: ©2017 uzuncakmak et al.] a b observation | dermatol pract concept 2017;7(2):13 61 mucin contributing to the tumor’s invasive potential; however, in the absence of compelling contrary data, the current series of cases suggests that myxoid stroma is more significant in diagnosis rather than prognosis of myxoid melanoma [5,6]. although the real importance of myxoid changes in tumors is not well known, awareness of this stromal pattern in malignant melanomas may prevent misdiagnosis and therapeutic errors. references 1. hitchcock mg, white wl. malicious masquerade: myxoid melanoma. semin diagn pathol. 1998;15:195-202. 2. inoue t, misago n, narisawa y. metastatic myxoid melanoma with partial regression of the primary lesion. j cutan pathol. 2007;34:508-512. 3. harmse d, saunders s, evans a.nonpigmented intradermal malignant melanoma with cribiform, myxoid, and spindle cell growth patterns. am j dermatopathol. 2010;32:829-831. 4. magro cm, crowson an, mihm mc. unusual variants of malignant melanoma. mod pathol. 2006;19:s41-70. 5. ulamec m, soldo-belić a, vucić m, buljan m, kruslin b, tomas d. melanoma with second myxoid stromal changes after personally applied prolonged phototherapy. am j dermatopathol. 2008; 30:185-187. 6. nummela p, lammi j, soikkeli j, saksela o, laakkonen p, hölttä e. transforming growth factor beta-induced (tgfbi) is an antiadhesive protein regulating the invasive growth of melanoma cells. am j pathol. 2012;180(4):1663-1674. oid changes are more often reported in metastatic tumors than in primary malignant tumors, but in our patient due to the completely intradermal location of tumor cells with no junctional component, ith a nodular architecture, features of malignancy, no ulceration, the absence of peripheral nerves, and an absence of preexisting melanocytic nevus, he was diagnosed as primary dermal melanoma. additionally, based on the histopathologically myxoid stromal changes, he was diagnosed as primary myxoid melanoma. also no other metastatic or primary malignant lesion was detected with pet-ct scanning. typically, s100 staining is strongly positive, but immunostaining with hmb-45 is less uniform and both positive and negative results were reported in the literature. in our patient both s100 and hmb45 staining were strongly positive. the differential diagnosis of myxoid melanoma is broad, including several other benign and malignant myxoid neoplasms of soft tissue as well as epithelial cancers such as myxoid liposarcoma, myxoid malignant fibrous histiocytoma, low-grade fibromyxoid sarcoma, myxoid chondrosarcoma, myxoid peripheral nerve sheath tumors, dermatofibrosarcoma protuberans and metastatic adenocarcinomas [4]. the clinical and the prognostic significance of mucin deposition in melanomas is challenging due to presence of myxoid material both in primary benign or malignant tumors [5]. some authors claimed that mast cells and secretion of transforming growth factor beta stimulates fibroblast secretion of figure 4. (a) pas-alcian blue staining x100 and (b) pas staining x200. [copyright: ©2017 uzuncakmak et al.] a b dermatology: practical and conceptual review | dermatol pract concept. 2023;13(1):e2023066 1 a review of the impact of sun safety interventions in children imran t. baig1, allison petronzio1, brandy maphet2, susan chon3 1 uthealth mcgovern medical school at houston, houston, united states 2 department of dermatology, uthealth mcgovern medical school at houston, houston, united states 3 department of dermatology, university of texas md anderson cancer center, houston, united states key words: behavioral change, skin cancer, sunscreen, sun protection, uv radiation citation: baig it, petronzio a, maphet b, chon s. a review of the impact of sun safety interventions in children. dermatol pract concept. 2023;13(1):e2023066. doi: https://doi.org/10.5826/dpc.1301a66 accepted: november 3, 2022; published: january 2023 copyright: ©2023 baig et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: imran t. baig, b.s.a. uthealth mcgovern medical school at houston, houston, united states, 1711 old spanish trail apt 422, houston, tx 77054 e-mail: imran.t.baig@uth.tmc.edu introduction: in the united states, melanoma and non-melanoma skin cancers comprise the largest proportion of new cancer diagnoses every year. the prevalence of skin cancer can be largely reduced if proper preventative behaviors are adopted at an early age. objectives: we assessed the impact of various informational, economic, and environmental interventions on sun-protective behaviors, knowledge, attitudes, and sun exposure in the pediatric population reported in previous studies. methods: a systematic search for relevant articles was conducted using three databases. studies were included if they met the following three criteria: study subjects less than 18 years old, clear, measurable interventions and outcomes, and publication in the english language. results: a total of 66 studies were included, of which 48 resulted in positive behavioral changes (i.e. increases in sunscreen application, use of hats and sun-protective clothing, shade-seeking, and avoidance of outdoor activities during peak uv radiation), 28 resulted in increased knowledge, 2 resulted in changes in attitudes towards tanning, and 10 resulted in decreased sun exposure effects (i.e. new sunburns, number of new nevi, and change in pigmentation of the skin). conclusions: it is crucial that children be educated on the importance and benefits of sun protection. although a variety of interventions showed promise in achieving this goal, the challenges associated with adopting change were evident. this review provides direction for future interventions aimed at improving sun safety in children and illustrates the potential impact that early intervention can have on the incidence of skin cancer in future generations. abstract 2 review | dermatol pract concept. 2023;13(1):e2023066 introduction in the united states, skin cancer is the most common malignancy and is estimated to affect one in five individuals in their lifetime [1]. the overall incidence of melanoma and non-melanoma skin cancers (nsmc), including basal cell carcinoma (bcc) and squamous cell carcinoma (scc), has been increasing rapidly in recent decades. melanoma is the most lethal type of skin cancer, and it is predicted that over 7,500 americans will die from melanoma in 2022 [2]. although nmscs typically carry a more favorable prognosis, they place a large burden on the united states healthcare system, with an estimated annual cost of $4.8 billion [3]. the largest preventable risk factor for both melanoma and nmsc is ultraviolet radiation (uvr) exposure [4]. uvr is a risk factor for skin cancer at any age; however, children are at an increased risk of excessive uvr exposure [5]. children spend a significant portion of their time outdoors at school when the uv index is highest, where activities such as recess and sporting events can result in extended periods of uvr exposure. in fact, sun damage is cumulative, and about 23 percent of a person’s lifetime sun exposure happens by the age of 18 [6]. there is a strong relationship between total sun exposure and non-melanoma skin cancers, and there is a clear relationship between sunburns and the development of melanoma [7]. interventions aimed at preventing excessive exposure to harmful uvr can decrease the incidence of skin cancer. the american cancer society provides several recommendations aimed at primary prevention of skin cancer: 1) seek shade when uv radiation is strongest (10:00 a.m. 4:00 p.m.); 2) wear sun-protective clothing (i.e. long sleeved shirts and pants); 3) wear wide-brimmed hats; 4) apply sunscreen with a minimal spf of 30; and 5) avoid tanning beds [8]. in addition to primary prevention methods, secondary prevention methods include regular skin self-examinations and professional skin examinations. applying both prevention techniques has illustrated a decrease in the incidence, morbidity, and mortality of skin cancer [4]. since childhood sun exposure increases the risk of skin cancer, it is essential to educate children about primary prevention measures as well as take action to promote sun-protective behaviors. in this review, we evaluated studies that aimed to either educate or change the behavior of children regarding sun safety. by doing this, we aimed to identify the techniques used and summarize them as an example for much-needed future educational efforts. methods the following criteria were used to identify eligible studies: 1) study subjects must be less than 18 years old; 2) study must have clear interventions and outcomes (e.g. behavior or knowledge); and 3) study must be published in the english language. the search for relevant articles utilized ovid medline, ovid embase, and scopus to identify literature published through september 2020: the following mesh terms were used: “adolescent”, “child”, “infant”, “pediatric(s)”, “students”, “teen”, “parent(s)”, “mother”, “father”, “sunscreening agents”, “sun protection factor”, “sunburn”, “skin neoplasms”, “sunlight”, “sun”, “skin”, “health education”, “health promotion”, “education”. results the initial literature search of ovid medline, ovid embase, and scopus yielded 143 articles. after the articles were reviewed and duplicates excluded, 66 articles met the inclusion criteria [9-74]. types of interventions: most studies had an intervention that delivered sun-protective educational information to the study population (figure 1). of the 62 studies that focused on providing information, some of the most popular methods included giving a presentation, handing out newsletters or flyers, and implementing sun safety lessons in the school curriculum. in addition, 17 studies relied on economic intervention. from these studies, distribution of free sunscreen to children was the most popular provision. other economic interventions included providing protective clothing, hats, and sunglasses. lastly, 3 studies changed the physical environment by adding resources such as shaded structures for children to use during peak uv light hours (figure 2). knowledge as an outcome: there were 32 studies that measured change in knowledge as an outcome after implementation of the intervention. of those 32 studies, 27 assessed only for the child’s knowledge, 4 assessed only for the parents’ knowledge, and 1 assessed for both the child and parents’ knowledge. of the studies that focused only on measuring the change in the children’s knowledge after intervention, twenty-six studies noted a significant increase in baseline knowledge and only one study revealed nonsignificant changes. winnett et al. illustrated that even after intervention, the children still had minimal knowledge of appropriate sunscreen use and frequency [67]. even though hingle et al. showed a statistically significant overall increase in knowledge, it was primarily driven by knowledge about skin cancer types [27]. the rest of the knowledge-based questions related to uv radiation, precautions to take to avoid sunburn, and suntanning showed no significant changes. of the four studies directed at only review | dermatol pract concept. 2023;13(1):e2023066 3 types of intervention enviromental, 3, 4% economic, 17, 21% educational, 62, 75% educational economic enviromental figure 1. a pie chart illustrating the various methods of intervention used from all 62 studies. successful studies by type of outcome measured n u m b er o f st u d ie s type of outcome behavior knowledge successful 0 10 20 30 40 50 60 70 unsuccessful sun exposure attitudes figure 2. a bar chart comparing studies that were successful in improving the measured outcome to studies that were not successful in improving the measured outcome. 4 review | dermatol pract concept. 2023;13(1):e2023066 adopting sun safety into their lessons, uv index announcements on the speaker, and guest presenters on uv and sun safety [62]. although elementary students and middle school students had improved perceptions, high school students maintained a positive attitude towards tanned skin. buller et al. utilized an educational computer program on sun safety based on the “sunny days, healthy ways” sun safety curriculum [33]. this cd-rom program did not improve attitudes toward sun-protective behavior. barankin et al. enhanced an existing “sun and the skin” program by educating the parents about the program, providing supplemental information, and distributing sunscreen [28]. the students in the enhanced group illustrated improvement over the control and standard groups in their attitude towards tanning. david et al. included an educational presentation and interactive activities delivered by university students, who underwent rigorous training and volunteering as part of their undergraduate and graduate-level courses [32]. after the intervention, participants reported less appeal for tanned skin than before the intervention (p<0.001). behaviors as an outcome: there were 60 studies that measured change in sun-protective behaviors as an outcome after implementation of the intervention. of those 60 studies, 48 had interventions that were successful at impacting at least one behavior relating to sun protection in either the children or their parents (figure 3). measuring the change in parents’ knowledge, two of them did not result in an increase in the parents’ knowledge. glanz et al. used questions to create a knowledge index that was measured for the parents [14]. the knowledge index was relatively high at baseline and remained virtually unchanged in both intervention groups. glanz et al. assessed the knowledge of parents and staff [53]. although their knowledge scores were relatively high to begin with, they improved slightly; however, neither of the changes was statistically significant. in the study that tested both the children’s and parents’ knowledge, parents were reported to have decreased in knowledge, while elementary and middle schoolers had increased and high schoolers had no change [62]. attitudes toward tanning as an outcome: five studies assessed children’s attitudes and perceptions of tanning before and after intervention. three of the five interventions were considered failures. kristjánsson et al. developed an educational tool kit about skin cancer prevention [74]. this tool kit included a manual for teachers, animated comic figures, a 7-minute video, and recommendations on how to behave in the sun. the students’ attitude to refrain from tanning was not significantly changed. regarding mid-day sun avoidance, most students only progressed from a pre-contemplation stage to a contemplation stage. kouzes et al. utilized a sun safety curriculum which included teachers percent failure by intervention type for behavioral outcomes ty p e o f i n te rv en ti o n percent 12% 0 18% enviromental 0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% economic educational figure 3. a bar chart illustrating what percentage of studies were unsuccessful in changing behavior based on the type of intervention. review | dermatol pract concept. 2023;13(1):e2023066 5 studies directed at the pediatric population can alter their interventions to be better suited to have a significant impact on these outcomes. children’s knowledge about skin cancer and the importance of sun protection was improved in all but two studies [62, 67]. kouzes et al. implemented a sun safety curriculum which included teachers incorporating sun safety into their lessons, uv index announcements on the speaker, and guest presenters on uv and sun safety [62]. the curriculums used differed based on grade level (preschool through first grade used catch global foundation’s ray and the sunbeatables, grades kindergarten through eighth grade used the environmental protection agency sunwise, and grades six through twelve used sunsmart u developed by the skin cancer foundation). knowledge was improved in elementary and middle schoolers; however, high schoolers did not have any change in knowledge of sun protection strategies. knowledge deficits in older age groups could be attributed to inadequate use of the curriculum and could suggest that additional support may be needed from a statewide nonprofit organization dedicated to cancer control. skonieczna et al. demonstrated the significance of partnerships within schools to create long-lasting sun safety programs, so such support could encourage increased participation [75]. winnett et al. studied the effects of an intervention that included informational posters in prominent locations, a poster providing feedback about how many people are practicing the safesun program, a weekly lottery ticket for people wearing sun-protective clothing, and lifeguards modeling the safesun logo on their clothing [67]. knowledge about skin cancer, its causes, and how to appropriately use sunscreen remained low. this intervention did not include formal information lessons, which could explain the lack of knowledge related to skin protection. several studies demonstrated positive attitudes towards tanned skin even after an intervention was implemented [33, 62, 74]. in the previously mentioned study by kouzes et al., in addition to not showing improvements in knowledge, high schoolers also continued to value the appearance of tanned skin [62]. despite acknowledging the risks associated with tanned skin, high school students still maintained a positive attitude towards tanned skin. this illustrates that because older children perceive tanned skin as desirable, they are willing to risk their health to fit into societal norms [76]. another study provided a manual for teachers, animated comic figures, a 7-minute video, and recommendations on how to behave in the sun to adolescents [74]. the students’ attitudes to refrain from tanning were not significantly changed. previous studies have shown that when children reach adolescence, their appreciation of suntans increases [7, 77]. therefore, it might be beneficial to start motivating attitude changes to sunbathing before adolescence. lastly, a few commonly studied behaviors include frequency of sunscreen application, use of hats and sun-protective clothing, shade-seeking, and avoidance of outdoor activities during peak uv radiation. for example, crane et al. is a randomized controlled trial that found changes in many behavioral outcomes after sending newsletters on sun protection and skin cancer to parents and their children over the course of three years [38]. specifically, the post-intervention group demonstrated increased use of sunscreen, protective clothing, hats, shade-seeking, and midday sun avoidance compared to baseline; however, a statistically significant difference compared to the control group was only present for a few select behaviors and in certain years. conversely, bauer et al. is a randomized controlled trial in which parents were randomized to receive either educational material on sun protection, free sunscreen, or neither, and the results demonstrated no significant differences between the groups in sun-protective behaviors or the development of melanocytic nevi in the children [36]. sun exposure as an outcome: there were 15 studies that measured sun exposure via physical skin changes as an outcome after implementation of the intervention. a few commonly studied metrics include incidence of new sunburns, number of new nevi, and change in pigmentation of the skin. of the 10 studies that measured incidence of sunburn as an outcome, 8 studies showed fewer sunburns as a result of the intervention, whereas one study showed no effect on sunburns and another study showed an increase in the number of sunburns despite the intervention [61]. of the 6 studies that looked at increased pigmentation (i.e. tanning, melanin) as an outcome, only 2 studies demonstrated that their intervention decreased the level of skin pigmentation. of the 3 studies that looked at development of new melanocytic nevi as an outcome, none of them showed a statistically significant difference in the development of new nevi post-intervention. discussion the goal of this review was to evaluate the impact of various informational, economic, and environmental interventions on sun-protective behaviors, knowledge, attitudes, and sun exposure in the pediatric population. targeting children is important because, theoretically, the earlier that sun-protective habits are formed, the earlier primary prevention methods from dangerous uv rays can be implemented and lower the burden of future skin cancer. as many of the techniques reviewed were successful in instilling knowledge and sun safety practices, this discussion highlights the interventions that failed to alter children’s behaviors, knowledge, attitudes, and sun exposure. using this information, future 6 review | dermatol pract concept. 2023;13(1):e2023066 measured and impacted outcome compared to the others. in response to sun exposure, sunburns develop rather quickly and can develop after only one outdoor exposure, whereas skin pigmentation and nevi formation are processes that take time and require more chronic exposure to sunlight. many of the studies that assessed skin pigmentation and nevi formation failed to demonstrate any significant change in these metrics, likely due to a lack of significant behavioral change and/or insufficient length of study. in the case of bauer et al., educational and/or economic interventions were administered, and the number of incident melanocytic nevi was measured after a three-year period with no significant difference between groups [36]. in this particular study, the intervention failed to impact sun-protective behaviors, which likely directly affected the success of the intervention in impacting nevi formation. of the studies that had a positive impact on sun-protective behaviors; a common theme was that changes in behavior were often transient or resulted in minimal change in the development of physical skin findings related to sun exposure. in this discussion of sun protection in children, our primary concern is whether early interventions can reasonably decrease a child’s risk of developing skin cancer later in life. it is encouraging to see that children and their parents are able to adopt sun-protective behaviors with the right intervention; however, it is unclear if these behavioral changes will translate to physical changes in the skin and decreased incidence of skin cancer in the future. conclusion it is crucial that children be educated on the importance of sun protection. although a variety of interventions showed promise in achieving this goal, the challenges associated with adopting behavioral change were evident. this review provides direction for future interventions aimed at improving sun safety in children and illustrates the potential impact that early intervention can have on the incidence of skin cancer in future generations. references 1. prevalence of a history of skin cancer in 2007: results of an incidence-based model | dermatology | jama dermatology | jama network. accessed june 4, 2022. https://jamanetwork. com/journals/jamadermatology/fullarticle/209761 2. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2022. ca cancer j clin. 2022;72(1):7-33. doi:10.3322/caac.21708 3. rogers hw, weinstock ma, feldman sr, coldiron bm. incidence estimate of nonmelanoma skin cancer ( keratinocyte carcinomas) in the u.s. population, 2012. jama dermatol. 2015;151(10):1081-1086. doi:10.1001/ jamadermatol.2015.1187 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states: a systematic review of the literature. j adolesc health off publ soc adolesc med. 2013;52(5 0):s52-s59. doi:10.1016/j.jadohealth.2012.09.021 untitled research | dermatol pract concept 2015;5(2):4 29 dermatology practical & conceptual www.derm101.com trends in dermoscopy use in the uk: results from surveys in 2003 and 2012 thomas d. butler1, rubeta n. matin1, andrew g. affleck2, colin j. fleming2, jonathan c. bowling1 1 department of dermatology, churchill hospital, headington, oxford, united kingdom 2 department of dermatology, ninewells hospital & medical school, dundee, united kingdom key words: dermoscopy, uk dermatologists, survey, attitudes citation: butler td, matin rn, affleck ag, fleming cj, bowling jc. trends in dermoscopy use in the uk: results from surveys in 2003 and 2012. dermatol pract concept 2015;5(2):4. doi: 10.5826/dpc.0502a04 received: may 17, 2014; accepted: january 8, 2015; published: april 30, 2015 copyright: ©2015 butler et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: jb, cf and aa have received payments for teaching dermoscopy. jb is author of a dermoscopy textbook and has a medical education company specializing in dermoscopy education. all authors have contributed significantly to this publication. corresponding author: dr. rubeta n. matin, dermatology department, churchill hospital, old road, headington, oxford, ox3 7le, united kingdom. tel. +44 1865 228264; fax. +44 1865 228260. email: rnhmatin@doctors.org.uk background: dermoscopy is a useful tool to aid diagnosis of pigmented and non-pigmented skin lesions, as well as many other dermatological conditions. use of dermoscopy is increasing worldwide, but to date, there are no reported data on attitudes of dermatologists in the united kingdom (uk) towards dermoscopy. objective: to determine current attitudes of uk dermatologists towards dermoscopy and assess how these attitudes have changed over the last decade. methods: in october 2012, an online survey was sent to members of british association of dermatologists over a 12-week period. data were subsequently compared with data from a similar uk nationwide paper questionnaire distributed to members in 2003. results: the 2003 survey collected 292 responses (uptake 42%), and in 2012 there were 209 responses (22%), predominantly from consultants and registrars. in 2012, 86% respondents reported increased use of dermoscopy over the previous decade with 98.5% of respondents reporting regular clinical use of dermoscopy, compared with 54% in 2003. overall, 81% respondents in 2012 had received dermoscopy training, mainly from uk-based courses (62% of respondents) but increasingly via internet-based resources (30% vs. 7% in 2003). however, 39% respondents lacked confidence when making a diagnosis based on their interpretation of dermoscopy findings. conclusions: over the last decade, use of dermoscopy has increased amongst uk dermatologists and the majority of respondents now employ dermoscopy in daily clinical practice. however, the use of dermoscopy in the dermatology community overall is not known and for those individuals there is a continued need for education. abstract 30 research | dermatol pract concept 2015;5(2):4 amongst dermatologists reported as 95% in france [4], 98% in australia [10,11] and 48% in america [12]. to date, no study has formally reported use and attitudes of uk dermatologists. a nationwide uk survey of attitudes towards dermoscopy was undertaken in 2003. we aimed to determine extent of change of prevalence and uptake of dermoscopy amongst uk dermatologists over the last decade. here we present the combined results of this survey and a follow-up survey, performed ten years apart, collecting uk dermatologists’ opinions of dermoscopy. methods the first questionnaire was distributed in paper form to uk dermatologists via the british association of dermatologists (bad) during 2003 (appendix 1). in total, 700 questionnaires were sent and 292 responses were received (survey uptake 42%) (table 1). the second questionnaire was created using survey monkey (www.surveymonkey.com), a professional online survey tool (appendix 2). access to the questionnaire was distributed as a link via email to all members of the british association of dermatologists (which includes all doctors in the uk who spend a significant amount of their time working in dermatology). the questionnaire was live introduction dermoscopy, also known as epiluminescence microscopy, dermatoscopy and incident light microscopy, is a well-recognized technique for interpreting skin lesions and rashes with more detail than the naked eye [1]. it is quick, cheap, noninvasive and in vivo. it provides further visual information that requires training and expertise to interpret [2]. attempts have been made to improve diagnostic accuracy of pigmented skin lesions through the use of objective diagnostic criteria including the abcde rule [3] but in practice these are not regularly used; 98% of respondents in a french survey did not formally use algorithms but rather used pattern recognition [4]. dermoscopy can increase the diagnostic accuracy for melanoma when used by experienced clinicians but its benefits are less conclusive in the hands of untrained practitioners [5]. the role of dermoscopy has been extended to include diagnosis of a variety of dermatological conditions including infections e.g., scabies [6], inflammatory lesions, hair and nail-fold changes [7,8]. in addition, dermoscopy can be used to help monitor lesions over time or response to topical treatments such as 5-fluorouracil or imiquimod [9]. increasingly, dermoscopy is becoming accepted as standard practice worldwide with reported regular clinical use table 1. demographics of respondents to surveys in 2003 and 2012 [copyright: ©2015 butler et al.] 2003 survey (n=292) number (percentage) 2012 survey (n=209) number (percentage) gender male n/a 97 (46%) female n/a 106 (51%) unknown 292 6 (3%) age < 40-years-old n/a 101 (48%) 40-50-years-old n/a 59 (28%) > 50-years-old n/a 43 (21%) unknown 292 6 (3%) job role consultant (specialist) 207 (74%) 113 (54%) registrar (resident) 59 (21%) 72 (34%) sas/career grade (non-training grade) 10 (4%) 12 (6%) general practitioner 5 (2%) 5 (2%) junior medical trainee 0 (0%) 1 (1%) unknown 0 (0%) 6 (3%) n/a—data not collected research | dermatol pract concept 2015;5(2):4 31 increased use of dermoscopy over the previous ten years and no respondents reported decrease use. in 2012, 81% respondents reported receiving dermoscopy training, which is an increase from 40% in 2003. the main source of training in 2012 was a uk-based dermoscopy course (62%) (table 2). use of textbooks and handbooks were also used frequently (49%); however, there was a relative decrease compared with 2003 (64% of respondents). the use of internet training has increased from 7% in 2003 to 30% in 2012. overall, 61% of respondents in 2012 were “confident” or “very confident” when using dermoscopy to make a diagnosis (figure 2). however, 5% of respondents rated “little confidence” in their dermoscopic diagnostic skills. increased confidence in diagnostic skills increased with seniority of training grade for 12 weeks from october 2012 and sent to 728 consultant (specialist) members and 230 trainee (resident) members. the questionnaire was also sent as a reminder email to all bad registrar trainees (residents). in total, 209 members accessed the link, of which 203 (table 1) completed the survey (survey uptake 22%). respondents were not able to access the link more than once ensuring that there were no duplicates. all responses (including partially completed forms) from both surveys were entered into microsoft excel® and analyzed. results demographics of respondents are detailed in table 1. 50% of respondents were aged less than 40 years old and 52% were female (1:1.1 ratio) in the 2012 survey. consultants (specialists) were the highest responders in both surveys, with 74% in 2003 and 56% of responses in 2012. in 2012, the number of registrar (resident) responses increased from 21% to 35% and general practitioner (primary care physicians with a special interest in dermatology who are members of the bad) responses also increased. comparing regular use of dermoscopy in clinical practice, 98.5% respondents reported regular use in 2012, a 45% increase from 2003 (figure 1). furthermore in 2012, 72% of respondents reported “always” using dermoscopy, 24% reported “sometimes” using dermoscopy, but 4% reported using dermoscopy only if there was clinical uncertainty. of those who did not use a dermatoscope regularly in 2012, one person did not find dermoscopy useful, two people reported limited access to a dermatoscope and one person had not received any training. more people have their own personal dermatoscope and twice as many respondents reported receiving training in dermoscopy in 2012 compared with 2003 (figure 1). when asked about a change in dermoscopy use over the previous decade, 86% of respondents in 2012 reported figure 1. responses from 2003 and 2012 questionnaires. [copyright: ©2015 butler et al.] table 2. data from 2003 and 2012 surveys: which sources of dermoscopy training are used? [copyright: ©2015 butler et al.] source of training  2003 (%) 2012 (%) uk dermoscopy course 21 62 handbook 64 49 tuition by expert 33 internet training 7 30 aad session 46* 22 other (please specify)§ 14 eadv session 46* 13 dermoscopy world congress 4 dermoscopy diploma 3 *aad/eadv sessions were combined on 2003 questionnaire. § other sources of training included graz msc in dermoscopy, euroderm excellence session, on the job training and lectures figure 2. degree of confidence reported by dermatologists (percentage responders) when using dermoscopy to make a diagnosis [2012 survey]. [copyright: ©2015 butler et al.] 32 research | dermatol pract concept 2015;5(2):4 “sometimes” changed their management. degree of confidence in using dermoscopy positively correlates with frequency that respondents changed their management (figure 5). figure 6 demonstrates the breakdown of frequency of dermoscopy use, which changes clinician management according to lesion type. dermoscopy frequently changed management across all lesions but in particular for inflammatory lesions, hair disorders and scabies identification. in addition, 46% of respondents have used dermoscopy photographs to aid in follow-up appointments. discussion this is the first study detailing attitudes toward the use of dermoscopy in the uk. it is clear that dermoscopy is now a standard tool used in the assessment of skin disease for pigmented and non-pigmented lesions on all body sites, but it is increasingly being used for other applications including inflammatory/infectious skin disease. the majority of respondents in the most recent survey reported using dermoscopy “always.” we would extrapolate from this that uk dermatologists employ dermoscopy for the extra diagnostic information it provides, not just when making difficult clinical decisions. although dermoscopy is frequently used in clinical practice, a significant proportion of respondents lack confidence in diagnosing lesions. as the majority of respondents were consultants and specialist trainees in dermatology, this lack of confidence is an important issue to address. in addition, those lacking confidence had often received no training. although training in dermoscopy is now an integral part of the uk dermatology specialty training for registrars, in practice this may not be happening across all regions in the uk. a recent survey reported only 36% uk trainees receive dermoscopy training for pigmented lesions “on-the-job” in a dermatology clinic [13]. curriculum uk-based training courses were (figure 3). a subset of 19% of respondents used a dermatoscope regularly without reporting having received training; 70% of these had only little or some confidence in their diagnostic skills. figure 4 demonstrates that overall personal reported confidence in dermoscopy is a reflection of both greater confidence in assessment of structures and greater confidence in making a diagnosis. eighty-three percent of respondents felt there was an adequate evidence base to support the role of dermoscopy in clinical practice; however, a significant 17% of responders were less convinced, reporting that they thought evidence was equivocal (12%) or lacking (5%). in 2012, dermatoscopes were not solely used for diagnosis of pigmented and non-pigmented skin lesions, although these appear to be the most common indications for use (98.5% and 88% respectively). other clinical scenarios where dermoscopy was used include scabies (66% of respondents), hair and nail disorders (57% and 53% respectively) and inflammatory lesions (27%). dermoscopy changed patient management for one-fifth (21%) of respondents. the majority (67%) felt dermoscopy figure 3. degree of confidence in dermoscopy skills when making diagnoses [2012 survey]. [copyright: ©2015 butler et al.] figure 4. comparison of confidence in dermoscopy when assessing structures or when making a diagnosis [2012 survey]. [copyright: ©2015 butler et al.] figure 5. degree of confidence in using dermoscopy to make a diagnosis related to how often clinician’s management is changed [2012 survey]. [copyright: ©2015 butler et al.] research | dermatol pract concept 2015;5(2):4 33 those reporting a lack of interest in the technique [12]. it is the responsibility of the international dermatology community to address these negative attitudes. our study has a number of limitations. similar questions were not identically phrased in both 2003 and 2012 surveys, leading to possible misinterpretation. the surveys were subject to selection bias towards dermatologists who use dermoscopy regularly, and advocates of the technique may be more likely to complete the survey. this is likely to be further compounded by low response rates to our surveys. nevertheless, a comparison between the two time-points demonstrated there was a significant difference in responses over the 10-year decade. in conclusion, dermoscopy is now widely used in the uk, and the consensus would appear to be that this is a useful clinical tool. there are gaps in training and teaching which need to be bridged to ensure full potential is made of this technique. this study adds to the mounting body of evidence in support of dermoscopy practice worldwide. in a resourceprecious uk national health service, the use of dermoscopy has the potential to increase clinical effectiveness through improving the confidence of dermatologists in making optimal management decisions. references 1. pehamberger h, steiner a, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol 1987;17(4):571-83. 2. binder m, schwarz m, winkler a, et al. epiluminescence microscopy. a useful tool for the diagnosis of pigmented skin lesions for formally trained dermatologists. arch dermatol 1995;131(3):286-91. 3. nachbar f, stolz w, merkle t, et al. the abcd rule of dermatoscopy. high prospective value in the diagnosis of doubtful melanocytic skin lesions. j am acad dermatol 1994;30(4):551-9. popular with respondents (62% had attended these in 2012). training does not need to be complex or arduous in order to improve diagnostic accuracy [14]. one study demonstrated 25% improvement in the sensitivity of primary care referrals of pigmented lesions following a one-day training course in dermoscopy, without a reduction in specificity, meaning the overall workload and referral rate was not increased [15]. unsurprisingly, the use of the internet as a training tool for uk dermatologists has significantly increased over the last ten years. delivery of training in dermoscopy should probably exploit the internet as an adjunctive tool to face-to-face training. the best way to improve survival from melanoma is early detection and dermoscopy is an invaluable aid; the evidence supporting this has been summarized [14]. the chance of diagnosing melanoma with dermoscopy is 9-16 times greater than with naked eye examination alone [16]. in the uk guidelines for the management of cutaneous melanoma, it is recommended that dermoscopy should be employed by experienced clinicians to screen and monitor pigmented lesions [17]. dermoscopy can improve the melanoma excision rate, i.e., ratio of benign to malignant lesions excised. in one retrospective study, the ratio improved from 18:1 to 4:1 over a period of four years in users of dermoscopy, compared with no improvement in those who did not use dermoscopy [18]. a recent study also reported training in dermoscopy as one of the factors that significantly improved the efficiency of a uk dermatology skin cancer service by increasing accuracy of clinical diagnosis [19]. nevertheless, use and adoption of dermoscopy is not universal. there are still respondents in our survey who do not believe dermoscopy is a useful technique and feel that the evidence is lacking. this is not unique to the uk; in the most recent american survey published in 2010, 52% of respondents did not regularly use dermoscopy, with 32% of figure 6. frequency of use of dermoscopy, which changes management according to skin lesion type [2012 survey]. [copyright: ©2015 butler et al.] 34 research | dermatol pract concept 2015;5(2):4 13. champagne cah, collins j, sommerlad m, warburton k, esdaile b. experience in diagnosing melanoma among uk dermatology trainees: a nationwide survey. br j dermatol 2014:171(suppl 1):ds30, page 78. 14. argenziano g, ferrara g, francione s, et al. dermoscopy—the ultimate tool for melanoma diagnosis. sem cutan med surg 2009;28(3):142-8. 15. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol2006;24(12):1877-82. 16. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol 2008;159(3):669-76. 17. marsden jr, newton-bishop ja, burrows l, et al. revised u.k. guidelines for the management of cutaneous melanoma 2010. br j dermatol 2010;163(2):238-56. 18. carli p, de giorgi v, crocetti e, et al. improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol 2004;150(4):687-92. 19. esdaile b, mahmud i, palmer a, bowling j. diagnosing melanoma: how do we assess how good we are? clin exp dermatol 2014;39(2):129-34. 4. moulin c, poulalhon n, duru g, et al. dermoscopy use by french private practice dermatologists: a nationwide survey. br j dermatol 2013;168(1):74-9. 5. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol 2002;3(3):159-65. 6. argenziano g, fabbrocini g, delfino m. epiluminescence microscopy. a new approach to in vivo detection of sarcoptes scabiei. arch dermatol 1997;133(6):751-3. 7. zalaudek i, lallas a, moscarella e, et al. the dermatologist’s stethoscope-traditional and new applications of dermoscopy. dermatol pract concept 2013;3(2):67-71. 8. zalaudek i, argenziano g, di stefani a,, et al. dermoscopy in general dermatology. dermatology 2006;212(1):7-18. 9. kacar n, sanli b, zalaudek i, yildiz n, ergin s. dermatoscopy for monitoring treatment of actinic keratosis with imiquimod. clin exp dermatol 2012;37(5):567-9. 10. piliouras p, buettner p, soyer hp. dermoscopy use in the next generation: a survey of australian dermatology trainees. australas j dermatol 2014;55(1):49-52. 11. venugopal ss, soyer hp, menzies sw. results of a nationwide dermoscopy survey investigating the prevalence, advantages and disadvantages of dermoscopy use among australian dermatologists. australas j dermatol 2011;52(1):14-8. 12. engasser hc, warshaw em. dermatoscopy use by us dermatologists: a cross-sectional survey. j am acad dermatol 2010;63(3):412-9. research | dermatol pract concept 2015;5(2):4 35 appendix 1. dermoscopy survey 2003 (paper survey). [copyright: ©2015 butler et al.] 36 research | dermatol pract concept 2015;5(2):4 appendix 2, page 1. dermoscopy survey 2012 (online survey, surveymonkey.com). [copyright: ©2015 butler et al.] research | dermatol pract concept 2015;5(2):4 37 appendix 2, page 2. dermoscopy survey 2012 (online survey, surveymonkey.com). [copyright: ©2015 butler et al.] 38 research | dermatol pract concept 2015;5(2):4 appendix 2, page 3. dermoscopy survey 2012 (online survey, surveymonkey.com). [copyright: ©2015 butler et al.] dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023211 1 a non-interventional study on vismodegib for basal cell carcinoma in swedish patients niels bendsöe1, john paoli2,3, karin söderkvist4, bertil persson1, christina halldin2,3, linda ihrlund5, maria wolodarski6,7 1 skåne university hospital, department of dermatology and venereology, lund, sweden 2 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 3 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 4 department of radiation sciences, umeå university, umeå, sweden 5 roche ab, sweden 6 department of oncology and pathology, karolinska institute, stockholm, sweden 7 theme cancer, patient area head and neck, lung, and skin, karolinska university hospital solna, stockholm, sweden key words: non-interventional, prospective, cohort-study, effectiveness, safety citation: bendsöe n, paoli j, söderkvist k, persson b, halldin c, ihrlund l, wolodarski. a non-interventional study on vismodegib for basal cell carcinoma in swedish patients. dermatol pract concept. 2023;13(2):e2023211. doi: https://doi.org/10.5826/dpc.1302a211 accepted: april 9, 2023; published: april 2023 copyright: ©2023 bendsöe et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: roche ab sponsored this study. we would like to thank all research nurses who assisted with patient inclusion and follow-up. medical writing support was provided by eva karlsson (scientific consulting ab) in the preparation of this paper. responsibility for opinions, conclusions and interpretation of data lies with the authors. competing interests: linda ihrlund is employed at roche ab. the other authors have nothing to declare. authorship: all authors have contributed significantly to this publication. corresponding author: john paoli, m.d., professor; department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden; tel: +46730404044 e-mail: john.paoli@gu.se introduction: real-life data on vismodegib in advanced basal cell carcinoma (abcc) are limited. optimal treatment duration is left to the discretion of the physician. objectives: to assess the effectiveness, safety and treatment pattern for vismodegib in abcc in clinical practice. methods: in this multicenter, non-interventional, prospective study, 49 swedish patients planned for vismodegib treatment were included. the treatment pattern observed was treatment until remission, allowing unlimited discontinuations/pauses. results: the majority of patients (93.8%), discontinued at least once during the study. compared to earlier studies there was a decrease of more than 2 months with actual drug intake, reducing the patients burden and costs, at the same time as a high number of responses were seen (87.8%). median progression-free-survival was 16.7 months, and 90% of the patients were alive at 13.3 months. ten patients were re-challenged with vismodegib at recurrence or progression, resulting in five partial remissions and three complete remissions. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023211 introduction basal cell carcinoma (bcc) is the most common human cancer. in sweden, the number of histopathologically verified bcc cases have increased 10-fold during the last 30 years. in 2019, the number of patients reported to the swedish cancer registry were >61 000, compared to 36 500 in 2008 [1]. the most common reason for bcc is chronic or intermittent exposure of uv-radiation, where the disease development is driven by an abnormal activation of the hedgehog signaling pathway [2-6]. the majority of bccs occur sporadically, but a rare autosomal dominant inherited condition, gorlin syndrome, also exists [7-9]. vismodegib (erivedge®, hoffmann-la roche ltd, basel, switzerland) is a first-in-class, oral small molecule inhibitor of the hedgehog signaling pathway, developed to treat hedgehog mutated tumors. the european approval of vismodegib was based on the pivotal study erivance, an international, phase-2, open-label, non-comparative clinical trial that showed high efficacy and acceptable tolerability in patients with metastatic or locally advanced bcc with or without gorlin syndrome [10, 11]. the results were confirmed in a larger multicenter safety study, stevie [12]. both trials included continuous treatment with vismodegib 150 mg once daily, until disease progression or intolerable toxicity. thirty-one percent of the patients discontinued treatment due to toxicity, although treatment interruptions/pauses up to 4-8 weeks were allowed. to overcome the toxicity with maintained efficacy, the dosing regimen has been further evaluated in several trials, as intermittent dosing, or reduced dosing [1316]. however, there is no established guideline for optimal treatment duration with vismodegib. at the time of initiation of this non-interventional study (nis), data on treatment in a real-life setting was lacking in sweden as well as world-wide. implementing a systematic data collection was encouraged by the necessity to increase knowledge of current treatment patterns, effectiveness and safety. since then, three similar european studies with data collected both retrospectively and prospectively have been published: one from greece with 67 patients and two from germany with 66 and 53 patients, respectively, have been published [17-19]. the current study intends to add more data to the growing collection of evidence on real-life treatment with vismodegib. methods study population, cohorts and data collection this study was a non-interventional, prospective cohort study in adult patients with abcc. all patients were planned for vismodegib treatment within normal routine practice according to the current product label. following non interventional study guidelines, study assessments and timing of visits were not mandatory, but performed according to routine care at each participating clinic (www.encepp. eu 2011). guidelines for good pharmaco-epidemiological practice (gpp) were followed and approval by the swedish ethical review authority was obtained prior to study start in december 2014 (www.pharmacoepi.org). an overview of the study details is published on www.clinicaltrials.gov, nct 02371967. the study enrolled 50 patients at four university hospitals in sweden between april 2015 and september 2017, with a follow-up period of 3 years. the trial sites were two dermatology clinics (skåne university hospital and sahlgrenska university hospital) and two oncology clinics (karolinska university hospital and norrland university hospital). patients included were ≥18 years old, with a diagnosed abcc, defined as metastatic or locally advanced (where other therapy such as surgery or radiotherapy were not an option), or gorlin syndrome requiring systemic treatment and planned for treatment with vismodegib. a signed informed consent for collection of data was obtained from all patients before enrolment. all patients were divided into three cohorts: cohort 1 included patients with abcc without gorlin syndrome and not previously exposed to a hedgehog pathway inhibitor (hpi), cohort 2 included patients with abcc without gorlin syndrome that previously had been exposed to an hpi and cohort 3 included patients with gorlin syndrome independent of previous exposure to an hpi. patients previously included in other clinical trials within 90 days were excluded, with exceptions for patients in cohort 2. the aim of the study was to assess effectiveness, safety and treatment patterns of vismodegib treatment in a real-life setting. clinical outcomes included: clinical response, time to response, duration of response, recurrence rate, progression-free survival and overall survival. safety objectives included: incidence, severity, and relationship of adverse and serious adverse events (saes) including pregnancies, and adverse events leading to treatment interruption or conclusions: clinical response rates with vismodegib for abcc were comparable to those of similar trials despite a shorter and more intermittent treatment duration. the majority of re-challenges lead to partial or complete remissions. original article | dermatol pract concept. 2023;13(2):e2023211 3 discontinuation. toxicity was graded using national cancer institute common terminology criteria for adverse events (nci ctcae) version 4. adverse events of special interest (aesi) included: muscle spasms, alopecia, dysgeusia/ageusia, weight loss, fatigue of grade ≥2, amenorrhea, gastrointestinal events grade ≥2, cardiovascular events and secondary malignancies. patient data were collected from the patient’s medical records into an electronic case report form (crf) (viedoc™, viedoc technologies, uppsala, sweden) and data quality was checked by on-site and remote monitoring. analysis of data was done after a clean file report and database lock. statistical analysis the statistical analysis was done according to the ich e9 guideline for statistical principles of clinical trials using sas® (version 9.4 or higher). the intention-to-treat (itt) population used for the effectiveness analysis was defined as all patients enrolled in the study. the safety population was defined as all patients who received at least one dose of vismodegib during the study. meddra terminology was used for adverse events and nci ctcae version 4 was used for toxicity grading. tumor assessments were done by radiological assessment using recist v 1.1. and/or by clinical assessment. the analysis of the study was exploratory and descriptive methods were used, presenting data by cohort and in total. no pre-specified hypotheses were defined, the sample size of 50 patients was regarded as sufficient to characterize the treatment pattern considering the rare indication of abcc. continuous data were summarized as the number of subjects with evaluable observations and missing observations, arithmetic mean and standard deviation, median with first and third quartiles, minimum and maximum. categorical data were presented using frequency and percentage. confidence intervals were 2-sided with a 95% confidence interval. drug exposure was summarized with number and percentage of patients for the total exposure, maximum treatment duration, including breakdowns for treatment pauses and dose modifications. more than one treatment discontinuation or dose modification could be reported for each patient. results in total, 50 patients were enrolled. one patient was found non-eligible prior to drug intake and excluded from the study. the remaining 49 patients comprised the itt population. one of these patients withdrew consent prior to first administration of vismodegib. thus, the remaining 48  patients constituted the safety population. in total, 40 patients were diagnosed with abcc without gorlin syndrome. the majority of these, 37 patients, were not previously exposed to an hpi and allocated to cohort 1. thus, three patients were allocated to cohort 2. nine patients with gorlin syndrome were allocated to cohort 3 independent of previous exposure to an hpi. baseline patient characteristics can be found in table 1. one patient of childbearing potential was included and followed with monthly pregnancy tests up to 1 year after treatment completion. all tests were negative. all patients had an ongoing locally advanced or metastatic bcc or gorlin syndrome at enrollment, and two patients had recurrent disease following previous treatment. six patients (12.2%) had other prior cancer history (fibrosarcoma, lymphoma, melanoma, nasopharyngeal cancer, prostate cancer and squamous cell carcinoma). the most frequent non-cancer condition was hypertension. six patients (12.2%) were reported to have received vismodegib previously, all patients in cohort 2 and three patients in cohort 3. at baseline, the extent of the disease was clinically assessed in 34 patients whereas 14 patients also required radiological assessment. more than half of the study population, 28 patients (57.1%) completed the study with a 3-year follow-up period. the remaining study population (21 patients, 42.9%) withdrew prematurely from the study. the most common reasons were death (not related to treatment) or progressive disease. treatment discontinuations and pauses were frequent and reported at least once by 45 patients (93.8%) during the study. the most common reasons were complete remissions (22 patients) and adverse events (14 patients). median duration of exposure (including days off treatment) was 5.7 months (range 1-35.9 months) and 5.2 months (range 1-35.5 months) excluding days off treatment (table 2). the overall treatment pattern with number of days of treatment and pauses from treatment per patient showed high variability (table 3). of the 49 included patients, 43 (87.8%) achieved a clinical response (95% ci; 75.2-95.4%). clinical response was observed in 34 patients (91.9%) in cohort 1, two patients (66.7%) in cohort 2 and seven patients (77.8%) in cohort 3. approximately half of the responses were complete remissions as best response. at 2 months of treatment (60 days), approximately half of the study population had achieved a clinical response, and at 3.3 months (100 days), 80% of the patients had achieved a clinical response. median duration of response was approximately 14.3 months (430 days). recurrence during the study occurred in 14 patients (28.6%), 11 of these patients were in cohort 1 and three patients were in cohort 3. the median time to recurrence was 4 original article | dermatol pract concept. 2023;13(2):e2023211 events (77.3%) were regarded to be at least possibly related to vismodegib treatment. most adverse events were mild or moderate and commonly reported as muscle spasms, dysgeusia and alopecia. severe adverse events were reported on 17 occasions, where three events (ageusia, dysgeusia and fatigue) were deemed as related to vismodegib treatment. the frequencies of predefined aesis can be found in table 4. a total of 19 saes were reported during the entire study period by 16 patients (33.3%). of these, 11 saes had a fatal outcome. causes of death included natural causes (3 patients), cardiac failure (2 patients), stroke, complications after brain surgery, gastrointestinal bleeding, metastatic disease and in two patients the cause was unknown. one patient died while on treatment due to natural causes and 10 approximately 20 months (600 days) and there was a 20% probability of an early recurrence at 6.7 months (200 days). ten patients were re-challenged due to progression after an initially achieved response. eight reached new remissions, five with partial remissions and three with complete remissions. both complete and partial responses were achieved. two patients were even re-challenged twice with repeated partial remissions as response. the median progression-free survival (pfs) was estimated to be 16.6 months (500 days). the 80% overall survival rate was 2.7 years and the 90% overall survival rate (os) was 13 months. a median overall survival was not reached within the study period (figure i). there were 45 patients (93.8%) that experienced at least one adverse event, with a total of 194 events. of these, 150 table 1. baseline characteristics. cohort 1 (n=37) cohort 2 (n=3) cohort 3 (n=9) total (n=49) age, years, mean (sd) 78 (11) 66 (20) 56 (11) 73 (14) age, years, min-max 50-97 46-85 43-74 43-97 female, n (%) 16 (43) 0 2 (22) 18 (37) male, n (%) 21 (57) 3 (100) 7 (78) 31 (63) height, mean (sd), cm 171 (11) 179 (8) 184 (9) 173 (11) weight, mean (sd), kg 76 (19) 91 (11) 96 (25) 80 (21) ecog performance status, n (%) ecog 0-1 31 (84) 3 (100) 8 (89) 42 (86) ecog 2 1 (3) 0 1 (11) 2 (4) ecog 3 4 (11) 0 0 4 (8) ecog 4 1 (3) 0 0 1 (2) bcc assessment at time of diagnose, n (%) clinical, histopathology 0 0 2 (22) 2 (4) clinical 2 (5) 0 2 (22) 4 (8) histopathology 23 (62) 1 (33) 0 24 (49) unknown 10 (27) 2 (67) 5 (56) 17 (35) missing data 2 (5) 0 0 2 (4) previous medical treatments, n (%)a imiquimod 1 (3) 0 0 1 (2) vismodegib 0 3 (100) 3 (33) 4 previous surgical procedures, n (%)b surgery 14 (37.8) 0 1 (11.1) 15 (30.6) cryotherapy 2 (5.4) 0 0 2 (4.1) cryosurgery 1 (2.7) 0 0 1 (2.0) cardiac pacemaker insertion 0 1 (33.3) 0 1 (2.0) previous radiotherapy and photodynamic therapy n (%)b radiotherapy 5 (13.5) 0 0 5 (10.2) photodynamic therapy 1 (2.7) 0 0 1 (2.0) areflect at least 14 days prior to study start blast 10 years prior to study start original article | dermatol pract concept. 2023;13(2):e2023211 5 dysgeusia, upper limb fracture, loss of effect and weight loss (table 4). conclusions the aim of the current study was to systematically collect data on effect, safety and treatment patterns of vismodegib in a real-world setting. the resulting study population correlates well in general to other studies on the use of patients died during the follow-up period. none of the fatal events were assessed as related to vismodegib. ten patients (20.8%) withdrew treatment due to an adverse event (table 4). the reasons were ageusia/dysgeusia, weight loss, asthenia, fatigue, muscle spasms/weakness, nausea, pruritus and back pain. there were 12 adverse events reported by seven patients (14.6%) that resulted in an interruption or discontinuation of vismodegib. the reasons were gastrointestinal disorders, nausea, vomiting, diarrhoea, fatigue, table 2. disposition of patients, exposure of drug and efficacy. cohort 1 cohort 2 cohort 3 total patients enrolled n=37 n=3 n=9 n=49 completed the study, n (%) 20 (54.1) 2 (66.7) 6 (66.7) 28 (57.1) prematurely withdrawn from the study, n (%) 17 (45.9) 1 (33.3) 3 (33.3) 21 (42.9) patients treated n=37 n=3 n=8 n=48 discontinued treatment at least once during the study, n (%) 35 (94.6) 3 (100.0) 7 (87.5) 45 (93.8) reason of discontinuation from treatment, n (%) complete remission 15 (42.9) 1 (33.3) 6 (85.7) 22 (48.9) adverse event / serious adverse event 10 (28.6) 1 (33.3) 3 (42.9) 14 (31.1) death 1 (2.9) 0 0 1 (2.2) progressive disease 3 (8.6) 0 0 3 (6.7) lack of efficacy 4 (11.4) 0 1 (14.3) 5 (11.1) physician decision 5 (14.3) 1 (33.3) 0 6 (13.3) other 4 (11.4) 0 5 (71.4) 9 (20) exposure of drug treatment duration, (incl days off treatment), months mean (sd) 11.7 (11.5) 12.5 (19.2) 16.2 (13.3) 12.4 (12.0) median (range) 5.8 (1-35.9) 1.4 (1.4-34.8) 15.2 (2.8-35.7) 5.7 (1-35.9) treatment duration (excl days off treatment), months mean (sd) 8.1 (7.0) 11.1 (16.8) 8.8 (8.2) 8.4 (7.8) median (range) 5.6 (1-35.5) 1.4 (1.4-30.6) 4.1 (2.8-23.9) 5.2 (1-35.5) effectiveness n=37 n=3 n=9 n=49 clinical response (complete or partial remission), n (%) 34 (91.9) 2 (66.7) 7 (77.8) 43 (87.8) 95% ci (78.1-98.3) (9.4-99.2) (40.0-97.2) (75.2-95.4) recurrence during the study, n (%) 11 (29.7) 0 3 (33.3) 14 (28.6) 95% ci (15.9-47.0) (0.0-70.8) (7.5-70.1) (16.6-43.3) median time to response, all patients, months 2 median duration of response, all patients, months 14.3 median time to recurrence, all patients, months 20 median progression-free survival, all patients, months 16.6 median overall survival, all patients, months not reached n, number of patients; sd, standard deviation. since this was an observational study, patients were taking treatment according to normal routine practice. because of this, each patient could report more than one treatment discontinuation (i.e. a patient can discontinue and then restart treatment several times). the table summarizes the number of patients who discontinued at least once including each unique reason for discontinuation. 6 original article | dermatol pract concept. 2023;13(2):e2023211 in the pivotal study [11] and comparable or slightly shorter than the median time to response of 2.7 months in the german real-world study [18]. again, the differences between a controlled and a real-world setting is probably the main reason for the shorter time to response reported in the non-interventional studies. the results illustrate the relatively short time to a clinically relevant effect when used in everyday healthcare. interestingly, ten patients were re-challenged with vismodegib resulting in five partial remissions and three complete remissions. two patients were even re-challenged twice with repeated remissions. these data are in line with the greek study that reported responses after re-challenging in 8 patients [17]. of the predefined aesis, the frequencies of alopecia, fatigue, nausea and weight-loss were lower or much lower compared to those reported in the erivance and stevie studies. other adverse events were as expected in frequency and most events were mild to moderate [11, 12]. ten patients (20.8%) discontinued treatment due to adverse events, while seven patients (14.6%) interrupted or discontinued treatment but could remain on treatment regimen. compared to previously reported trials, this is a low frequency. there were more saes reported in this study (33.3%) compared to the german studies that reported 22.7% and 17.0%, respectively. nevertheless, the majority of the saes were not related to vismodegib in any of the studies [18, 19]. of the vismodegib for abcc, including the pivotal study erivance [10, 11], the safety study stevie [12, 20] and the more recently published non-interventional studies from germany [18, 19] and greece [17]. in the current study, the group with gorlin syndrome were markedly younger than the overall populations, as could be expected with the greater severity and earlier onset of disease for these patients [7, 8]. the predominance of men compared to women in the current study is similar to most studies [11-13, 17-19, 21] and the baseline comorbidity and concomitant treatments as could be expected with respect to the ages and the disease indication. the obtained study data support previous knowledge of vismodegib as highly effective; the pfs and os levels are in line with the pivotal erivance and stevie trials [18, 12] whereas the clinical response of 95.4% in this trial is high compared to other studies, where 50-77% clinical responders were observed [11, 13, 18, 19] and similar to the greek study that reported 95.6% responders [17]. the variability in clinical response rate between studies is most likely due to differences in response evaluation methods. the current study pragmatically allowed for physician assessment to determine clinical response in order to reflect the real-world practice and thus a resulting higher response rate than when using strict radiologic criteria is to be expected. approximately half of the patients had reached a clinical response after 2 months (60 days), and 80% after 3.3 months (100 days) of treatment. this is a shorter time to response, compared to the median time of 5.5-6.7 months table 3. extent of exposure including duration of treatment and pauses from treatment. cohort 1 n=37 cohort 2 n=3 cohort 3 n=8 total n=48 total duration of exposure in days n/nmiss 37/0 3/0 7/1 47/1 mean (sd) 350.1 (344.0) 376.3 (577.4) 485.0 (399.8) 371.8 (361.0) median 173.0 43.0 456.0 173.0 q1, q3 85.0, 441,0 43.0, 1043.0 104.0, 840.0 85.0, 717.0 min, max 30, 1076 43, 1043 85, 1070 30, 1076 total number of days on treatment mean (sd) 241.9 (210.8) 334.3 (504.6) 262.6 (245.8) 250.9 (232.9) median 167 43 124 156 q1, q3 85.0, 361.0 43.0, 917.0 104.0, 497.0 85.0, 374.0 min, max 0, 716 43, 917 85, 717 30, 1066 total number of days on pause from treatment mean (sd) 108.1 (230.2) 42.0 (72.7) 222.4 (293.6) 120.9 (234.6) median 0.0 0.0 0.0 0.0 q1, q3 0.0, 0.0 0.0, 126.0 0.0, 573.0 0.0, 0.0 min, max 0, 716 0, 126 0, 652 0, 716 n/nmiss, number of subjects with evaluable/missing data; q1, first quartile; q3, third quartile; sd, standard deviation. the same patient could report more than one treatment discontinuation. original article | dermatol pract concept. 2023;13(2):e2023211 7 1.0 a 0.9 0.8 0.7 0.6 0.5 p ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 250 time (days) cohort 1 cohort 2 cohort 3 total 300 350 400 450 500 censored time to clinical response 1.0 b 0.9 0.8 0.7 0.6 0.5 p ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 100 200 300 400 500 600 time (days) cohort 1 cohort 2 cohort 3 total 700 800 900 1000 1100 1200 1300 censored duration of response figure 1. kaplan-meier plots of (a) time to clinical response, (b) duration of response and (c) time to recurrence on cohorts 1, 2, 3 and in total. 8 original article | dermatol pract concept. 2023;13(2):e2023211 table 4. adverse events, safety population. cohort 1 (n=37) cohort 2 (n=3) cohort 3 (n=8) total (n=48) any adverse event, n (%) 35 (94.6) 3 (100.0) 7 (87.5) 45 (93.8) any adverse event of special interest, n (%) 28 (75.7) 1 (33.3) 7 (87.5) 36 (75.0) any serious adverse event, n (%) 13 (35.1) 1 (33.3) 2 (25.0) 16 (33.3) saes with fatal outcome, n (%) 11 (29.7) 0 0 11 (22.9) adverse event leading to withdrawal of study treatmentb, n (%) 8 (21.6) 0 2 (25.0) 10 (20.8) number of events 14 0 2 16 ageusia/dysgeusia 4 (21.6) 0 2 (25) abnormal weight loss 2 (5.4) 0 0 asthenia 1 (2.7) 0 0 fatigue 2 (5.4) 0 0 muscular weakness 1 (2.7) 0 0 muscular spasm 3 ( 8.1) 0 0 nausea 1 (2.7) 0 0 pruritus 0 0 1 (12.5) back pain 0 0 1 (12.5) adverse events leading to interruption of study treatment, n 5 (13.5) 1 (33.3) 1 (12.5) 7 (14.6) number of adverse events leading to interruption of study treatment 9 2 1 12 nausea 1 (2.7) 1 (33.3) 0 2 (4.2) 1.0 c 0.9 0.8 0.7 0.6 0.5 p ro p o rt io n o f s u b je ct s 0.4 0.3 0.2 0.1 0.0 0 100 200 300 400 500 600 time (days) cohort 1 cohort 2 cohort 3 total 700 800 900 1000 1100 1200 1300 censored time to recurrence all applicable patients figure 1. kaplan-meier plots of (a) time to clinical response, (b) duration of response and (c) time to recurrence on cohorts 1, 2, 3 and in total. (continued) original article | dermatol pract concept. 2023;13(2):e2023211 9 the journal of investigative dermatology symposium proceedings, 1999; 4: 41-45. doi:10.1038/sj.jidsp.5640179 3. epstein eh. basal cell carcinomas: attack of the hedgehog. nature reviews cancer, 2008; 8: 743-754. doi:10.1038/nrc2503 4. von hoff dd, lorusso pm, rudin cm, et al. inhibition of the hedgehog pathway in advanced basal-cell carcinoma. the new england journal of medicine, 2009; 361: 1164-1172. doi:10.1056 /nejmoa0905360 5. caro i, low ja. the role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. clinical cancer research : an official journal of the american association for cancer research, 2010; 16: 3335-3339. doi:10.1158/1078-0432.ccr-09-2570 6. lindelöf b, lapins j, dal h. shift in occupational risk for basal cell carcinoma from outdoor to indoor workers: a large population-based case-control register study from sweden. acta dermato-venereologica, 2017; 97: 830-833. doi:10.2340 /00015555-2660 7. gorlin rj. nevoid basal-cell carcinoma syndrome. medicine, 1987; 66: 98-113. doi:10.1097/00005792-198703000-00002 8. tang jy, mackay-wiggan jm, aszterbaum m, et al. inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. the new england journal of medicine, 2012; 366: 2180-2188. doi:10.1056/nejmoa1113538 9. spiker am, troxell t, ramsey ml. gorlin syndrome. statpearls. treasure island (fl): statpearls publishing copyright © 2021, statpearls publishing llc., 2021. 10. sekulic a, migden mr, oro ae, et al. efficacy and safety of vismodegib in advanced basal-cell carcinoma. the new england journal of medicine, 2012; 366: 2171-2179. doi:10.1056 /nejmoa1113713 11. sekulic a, migden mr, basset-seguin n, et al. long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal erivance bcc study. bmc cancer, 2017; 17: 332. doi:10.1186/s12885-017 -3286-5 12. basset-séguin n, hauschild a, kunstfeld r, et al. vismodegib in patients with advanced basal cell carcinoma: primary analysis of stevie, an international, open-label trial. european life-threatening or fatal events, none were judged to be related to vismodegib treatment. in all, a non-interventional study design cannot be compared to the strength of a controlled clinical trial. the data collection follows the standard care at each study site and obviously varies between clinics. treatment durations were not standardized but adjusted to each patient and frequent treatment pauses were allowed; all which might influence the response outcome. the patient demographics show some imbalances between the cohorts, but with exception of the younger age in cohort 3, these differences do not appear relevant. comparison of the cohorts must be done with great caution, due to the big differences in number of patients between them. however, in general the collected data mirror the standard of care of the patient population at each clinic and reflect the real-life treatment of patients with abcc, which was the purpose of the study. to conclude, this study is the largest study performed in sweden with abcc patients treated with vismodegib and mirrors the routine clinical care of abcc. vismodegib treatment resulted in a high number of patients with a clinical response and pfs and os in the same range as in other trials despite a shorter and more intermittent treatment duration. the close monitoring of patient safety, tolerability and adaptation of treatment, including re-challenge of treatment in some cases, may be a step towards optimizing the treatment schedule of abcc patients. references 1. stegmayer b. basal cell carcinoma in sweden 2004-2008. socialstyrelsen; 2009 2009-12-12. 2. aszterbaum m, beech j, epstein eh, jr. ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. cohort 1 (n=37) cohort 2 (n=3) cohort 3 (n=8) total (n=48) diarrhoea 1 (2.7) 0 0 1 (2.1) gastrointestinal disorder 1 (2.7) 0 0 1 (2.1) vomiting 1 (2.7) 0 0 1 (2.1) drug ineffective 2 (5.4) 0 0 2 (4.2) fatigue 0 1 (33.3) 0 1 (2.1) dysgeusia 2 (5.4) 0 0 2 (4.2) upper limb fracture 0 0 1 (12.5) 1 (2.1) abnormal loss of weight 1 (2.7) 0 0 1 (2.1) table 4. adverse events, safety population. (continued) n = number of subjects a 10 of the fatal saes occurred during the follow-up period and 1 during the treatment phase. 3 fatal saes occurred during the follow-up study phase but were found after database lock and are included here. b the same patient can report more than one event. 10 original article | dermatol pract concept. 2023;13(2):e2023211 18. gutzmer r, schulze hj, hauschild a, et al. effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in germany the non interventional study niels. journal of the european academy of dermatology and venereology : jeadv, 2021; 35: 1678-1685. doi:10.1111/jdv.17332 19. kaatz m, mohr p, livingstone e, et al. effectiveness, safety and utilization of vismodegib for locally advanced basal cell carcinoma under real-world conditions: non-interventional cohort study jonas. acta dermato-venereologica, 2022; 102: adv00695. doi:10.2340/actadv.v102.293 20. dummer r, basset-seguin n, hansson j, et al. impact of treatment breaks on vismodegib patient outcomes: exploratory analysis of the stevie study. journal of clinical oncology, 2015; 33: 9024-9024. doi:10.1200/jco.2015.33.15_suppl.9024 21. frampton je, basset-séguin n. vismodegib: a review in advanced basal cell carcinoma. drugs, 2018; 78: 1145-1156. doi:10.1007 /s40265-018-0948-9 22. lacouture me, dréno b, ascierto pa, et al. characterization and management of hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. the oncologist, 2016; 21: 1218-1229. doi:10.1634/theoncologist .2016-0186 23. peris k, fargnoli mc, garbe c, et al. diagnosis and treatment of basal cell carcinoma: european consensus-based interdisciplinary guidelines. european journal of cancer (oxford, england: 1990), 2019; 118: 10-34. doi:10.1016/j.ejca.2019 .06.003 journal of cancer (oxford, england : 1990), 2017; 86: 334-348. doi:10.1016/j.ejca.2017.08.022 13. dréno b, kunstfeld r, hauschild a, et al. two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (mikie): a randomised, regimen-controlled, double-blind, phase 2 trial. the lancet oncology, 2017; 18: 404-412. doi:10.1016/s1470-2045(17)30072-4 14. woltsche n, pichler n, wolf i, di meo n, zalaudek i. managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single centre experience. journal of the european academy of dermatology and venereology : jeadv, 2019; 33: e144-e145. doi:10.1111/jdv.15367 15. routt e, ratner d. outcomes for basal cell carcinoma treated with vismodegib extended alternate day dosing. dermatologic surgery : official publication for american society for dermatologic surgery [et al], 2020; 46: 1109-1112. doi:10.1097/dss .0000000000001985 16. wong c, poblete-lopez c, vidimos a. comparison of daily dosing versus monday through friday dosing of vismodegib for locally advanced basal cell carcinoma and basal cell nevus syndrome: a retrospective case series. journal of the american academy of dermatology, 2020; 82: 1539-1542. doi:10.1016/j.jaad.2020.02.050 17. apalla z, spyridis i, kyrgidis a, et al. vismodegib in real-life clinical settings: a multicenter, longitudinal cohort providing long-term data on efficacy and safety. journal of the american academy of dermatology, 2021; 85: 1589-1592. doi:10.1016 /j.jaad.2020.11.036 dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022149 1 aneurysmal dermatofibroma after varicose vein surgery pablo villagrasa-boli1, juan monte-serrano1, sara martínez-cisneros1, alejandro martínez-garcía2 1 dermatology service, lozano blesa university hospital, zaragoza, spain 2 pathology service, lozano blesa university hospital, zaragoza, spain citation: villagrasa-boli p, monte-serrano j, martínez-cisneros s, martínez-garcía a. aneurysmal dermatofibroma after varicose vein surgery. dermatol pract concept. 2022;12(4):e2022149. doi: https://doi.org/10.5826/dpc.1204a149 accepted: january 15, 2022; published: october 2022 copyright: ©2022 villagrasa-boli et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: pablo villagrasa boli, dermatology service, lozano blesa university hospital. san juan bosco avenue, 15, 50009, zaragoza, spain. e-mail: pablovillaboli@gmail.com case presentation a 45-year-old man was referred to dermatology consultations for evaluation of a pigmented lesion on the left leg. the lesion appeared at the incision site of a varicose vein surgery performed one year prior. clinical examination revealed an indurated 12 mm brown plaque (figure 1a). dermoscopy showed at the center white network surrounded by bluish areas and a rainbow pattern, and at the periphery a homogeneous brown color (figure 1b). histopathological examination revealed blood-filled spaces with peripheral hemosiderin deposits, and a dense collagenous stroma containing spindle cells (figure 1c). immunohistochemical tinctions for factor xiiia (figure 1d) and for cd68 were positive, while human herpesvirus 8 was not detected. teaching point aneurysmatic dermatofibroma represents approximately 1.7% of all types of dermatofibromas [1]. like any dermatofibroma, this subtype may appear after local trauma. its clinical diagnosis can be difficult due to its resemblance to malignant tumors, such as kaposi sarcoma, angiomatoid malignant fibrous histiocytoma and melanoma [2]. 2 image letter | dermatol pract concept. 2022;12(4):e2022149 references 1. güngör ş, erdemir at, öztürk sarı ş, büyükbabani n, kocatürk e, gürel ms. aneurysmatic dermatofibroma with dermoscopic and reflectance confocal microscopic features. j eur acad dermatol venereol. 2016;30(5):880-883. doi: 10.1111/jdv.13046. pmid: 25690844. 2. zaballos p, llambrich a, ara m, olazarán z, malvehy j, puig s. dermoscopic findings of haemosiderotic and aneurysmal dermatofibroma: report of six patients. br j dermatol. 2006;154(2):244-250. doi: 10.1111/j.1365-2133.2005.06844.x. pmid: 16433792. figure 1. (a) clinical examination of the lower limbs. the hematoma on the right leg is unrelated to the reason for consultation. (b) multi-component dermoscopic pattern composed of central white stripes with rainbow areas, and a peripheral brown network. (c) dense tumoral stroma with congested blood vessels; the epidermis shows basal layer hyperpigmentation, acanthosis and hyperkeratosis. (d) diffuse positivity for factor xiiia throughout the tumor. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022175 1 lichenoid keratosis simulating melanoma: a case report leire barrutia1,2, nelson lobos1, josep malvehy1, sebastian podlipnik1 1 melanoma unit, dermatology department, hospital clínic de barcelona, idibaps, universitat de barcelona, barcelona, spain. 2 dermatology department, clinical university hospital of valladolid, valladolid, spain. citation: barrutia l, lobos n, malvehy j, podlipnik s. lichenoid keratosis simulating melanoma: a case report. dermatol pract concept. 2022;12(4):e2022175. doi: https://doi.org/10.5826/dpc.1204a175 accepted: january 5, 2022; published: october 2022 copyright: ©2022 barrutia et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: leire barrutia, md, dermatology department, clinical university hospital of valladolid – edificio rondilla. calle rondilla sta teresa s/n, 47010, valladolid, spain. e-mail: leirebarrutia4@gmail.com case presentation an 80-year-old male was referred to the dermatology department for a pigmented lesion on his right arm that had been present for over twenty years but had rapidly grown and become more pigmented in the last three months. physical examination showed a 10 mm dark, bluish-brown plaque and dermoscopy revealed a multicomponent pattern with multiple colors and pseudopods (figure 1b). reflectance confocal microscopy was performed, and the most prominent findings were a regular epidermal architecture, remnants of cord-like pattern in the dermoepidermal junction, and abundant aggregates of plump-bright cells in the papillary dermis, corresponding to melanophages (figure 1c). an excisional biopsy was performed, and histopathological analysis showed epidermal hyperplasia with hyperkeratosis, vacuolar-interface dermatitis, and a dense dermal infiltrate of melanophages and lymphocytes. sox10 stain highlighted dermal melanophage-aggregates (figure 1, d and e). therefore, both confocal microscopy and histopathology were compatible with lichen planus-like keratosis (lplk). teaching point the diagnosis of seborrheic keratosis is typically straightforward. however, in cases of regression, also known as lplk, these lesions may mimic melanoma or other malignancies [1]. dermoscopic findings of lichenoid keratosis change as regression progresses, and several patterns have been described, such as light-brown or gray pseudo-networks, annular-granular structures and blue-gray globules [2]. we present a case in which some of those features were present, but were accompanied by other structures than have not been described yet in lplk and that can be very misleading, such as pseudopods and blue-gray veil. confocal microscopy was particularly useful in this challenging case, and diagnosis was confirmed by histopathology. 2 image letter | dermatol pract concept. 2022;12(4):e2022175 references 1. ramirez-fort mk, al jalbout s, kittler h, pellacani g. lichenoid keratosis: non-invasive imaging in the setting of diagnostic uncertainty. dermatol pract concept. 2013;3(2):63-65. doi: 10.5826/ dpc.0302a10. pmid: 23785648. pmcid: pmc3663400. 2. watanabe s, sawada m, dekio i, ishizaki s, fujibayashi m, tanaka m. chronology of lichen planus-like keratosis features by dermoscopy: a summary of 17 cases. dermatol pract concept. 2016;6(2):29-35. doi: 10.5826/dpc.0602a06. pmid: 27222769. pmcid: pmc4866624. figure 1. (a) physical examination showed a 10 mm bluish-brown plaque. (b) dermoscopy revealed a multicomponent pattern with multiple colors, and asymmetrically distributed blue-gray globules. moreover, diffuse peripheral projections coalescing into pseudopods were observed on the left bottom side, and blue-gray veil and annular-granular structures in the center. (c) reflectance confocal microscopy showed remnants of cord-like pattern, and aggregates of small-bright particles in the papillary dermis, corresponding to melanophages. (d) histopathology, h&e 200x. epidermal hyperplasia with hyperkeratosis, vacuolar-interface dermatitis and a dense dermal infiltrate of melanophages and lymphocytes. (e) sox10 (sry-related hmg-box gene 10), 400x. absence of melanocytic hyperplasia, and dermal melanophage-aggregates can be observed. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023154 1 cyclophosphamide in a recalcitrant case of nekam’s disease aishwarya muddebihal1, ananta khurana1, kabir sardana1 1 department of dermatology venereology and leprosy, atal bihari vajpayee institute of medical sciences and dr ram manohar lohia hospital, new delhi, india key words: nekam’s disease, recalcitrant, cyclophosphamide citation: muddebihal a, khurana a, sardana k. cyclophosphamide in a recalcitrant case of nekam’s disease. dermatol pract concept. 2023;13(3):e2023154. doi: https://doi.org/10.5826/dpc.1303a154 accepted: january 2, 2023; published: july 2023 copyright: ©2023 muddebihal et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. ananta khurana, professor, department of dermatology, venereology and leprosy, atal bihari vajpayee institute of medical sciences and dr ram manohar lohia hospital, new delhi, -110001. phone no: +91-9212370467 e-mail: drananta2014@gmail.com ethics statement: the patient in this manuscript has given written informed consent for publication of case details and clinical photographs. introduction keratosis lichenoides chronica, also called as nekam’s disease, is a rare acquired muco-cutaneous inflammatory disorder affecting adults and rarely children. it is characterized clinically by asymptomatic violaceous papules and plaques arranged in linear and reticular fashion and histologically by interface dermatitis [1]. it may be associated with features like rosacea, seborrheic dermatitis like rash (75%), recurrent oral aphthous ulcer (50%), palmoplantar keratoderma (40%) and nail dystrophy (30%) [2]. we report a rare condition in its classical form and a sustained remission with cyclophosphamide. case presentation a 25-year-old female, presented with 5-years history of mild itchy lesions which had started during pregnancy, and had gradually progressed. she also complained of burning sensation on eating. cutaneous examination revealed multiple, linear, hyperkeratotic violaceous plaques over flexor aspect of upper limbs, dorsum of hands, trunk, abdomen, buttocks, and lower limbs. (figure 1a) she also had rosacea-like lesions on the face (figure 1b) and multiple aphthous ulcers over bilateral buccal mucosa (figure 1c), the combination of features suggesting nekam’s disease. histopathology revealed parakeratotic hyperkeratosis covering acanthotic and focally flattened epidermis and band-like lymphocytic infiltrate admixed with plasma cells abutting the basal layer which showed vacuolization confirming the clinical diagnosis. her routine blood investigations were normal. the patient had received methotrexate (7.5-15 mg for 3 months) and acitretin (25 mg once daily for 1 month) previously with no clinical improvement. she was subsequently administered pulse intravenous methylprednisolone 500 mg for 3  days 2 research letter | dermatol pract concept. 2023;13(3):e2023154 which was deferred later due to ecg changes. she was then treated with cyclophosphamide 100mg once daily (od) which was tapered to 50 mg od after a month, followed by subsequent tapering to 50 mg alternate days. progressive improvement occurred during this with resolution of mucosal lesions and all cutaneous lesions with post inflammatory hyperpigmentation (figure 1d) at the end of five months, at which point cyclophosphamide was stopped. the patient’s blood counts and urine analysis were closely monitored throughout the course of treatment and demonstrated no abnormalities. four months later she had a mild recurrence which responded to cyclophosphamide 50mg given 3 days a week for a month. the patient has since been off systemic treatment with occasional minor localized recurrences manageable with topical agents alone. conclusions nekam’s disease and other lichenoid disorders are characterized by an interface inflammatory cell infiltrate largely consisting of lymphocytes and plasma cells. at a molecular level cd4+ th1 cells and cd8+ t lymphocytes, and natural killer cells mediate the damage to basal cells in this group of disorders [3]. phototherapy, retinoids, methotrexate, dapsone, steroids, antimalarials, ciclosporin, efalizumab, have all been tried with variable efficacy in nekam’s disease [4]. cyclophosphamide is a potent immunosuppressive agent which has demonstrated efficacy in treating resistant dermatoses including recalcitrant lichen planus and cutaneous lupus, dermatomyositis, pleva, refractory graft versus host disease, etc; all characterized by an interface infiltrate rich in figure 1. (a) erythematous to violaceous papules and plaques in reticular fashion over both upper limbs. (b) rosacea like lesions on face. (c) aphthous ulcer over right buccal mucosa. (d) resolution of cutaneous lesions with post inflammatory hyperpigmentation after five months of cyclophosphamide. research letter | dermatol pract concept. 2023;13(3):e2023154 3 lymphocytes. this is as lymphocytes are exquisitely sensitive to the drug owing to lack of detoxifying enzyme aldehyde dehydrogenase [5,6]. the reported case thus exemplifies the drug use in yet another typically difficult to treat dermatologic condition, and adds to the armamentarium to deal with this recalcitrant disorder. references 1. aruna c, ramamurthy dv, neelima t, bandaru h. nekam’s disease. indian dermatol online j. 2016;7(6):520-522. doi: 10.4103/2229-5178.193923. pmid: 27990390. pmcid: pmc5134169. 2. taberner r, puig l, fernández-figueras t, alomar a. keratosis lichenoides chronica.  j eur acad dermatol venereol. 2001;15(1):84-85. doi: 10.1046/j.1468-3083.2001.00178-7.x. pmid: 11451338. 3. tziotzios c, lee jyw, brier t, et al. lichen planus and lichenoid dermatoses: clinical overview and molecular basis. j am acad dermatol. 2018;79(5):789-804. doi: 10.1016/j.jaad .2018.02.010. pmid: 30318136. 4. nomura t, toichi e, miyachi y, kabashima k. a mild case of adult-onset keratosis lichenoides chronica successfully treated with narrow-band uvb monotherapy. case rep dermatol. 2012;4(3):238-241. doi: 10.1159/000345277. pmid: 23185159. pmcid: pmc3506084. 5. deakin ct, campanilho-marques r, simou s, et al. efficacy and safety of cyclophosphamide treatment in severe juvenile dermatomyositis shown by marginal structural modeling. arthritis rheumatol. 2018;70(5):785-793. doi: 10.1002/art.40418. pmid: 29342499. pmcid: pmc5947636. 6. mayer j, krejcí m, doubek m, et al. pulse cyclophosphamide for corticosteroid-refractory graft-versus-host disease. bone marrow transplant. 2005;35(7):699-705. doi: 10.1038/sj.bmt.1704829. pmid: 15696180. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023103 1 biologics for the treatment of severe acrodermatitis continua of hallopeau: report of two cases successfully treated with ixekizumab and ustekinumab luigi gargiulo1,2, francesco toso1,2, luciano ibba1,2, mario valenti1,2, antonio costanzo1,2, alessandra narcisi1,2 1 dermatology unit, irccs humanitas research hospital, rozzano, milano, italy 2 department of biomedical sciences, humanitas university, pieve emanuele, milano, italy key words: psoriasis, acrodermatitis continua of hallopeau, ixekizumab, ustekinumab, biologics citation: gargiulo l, toso f, ibba l, valenti m, costanzo a, narcisi a. biologics for the treatment of severe acrodermatitis continua of hallopeau: report of two cases successfully treated with ixekizumab and ustekinumab. dermatol pract concept. 2023;13(2):e2023103. doi: https://doi.org/10.5826/dpc.1302a103 accepted: september 26, 2023; published: april 2023 copyright: ©2023 gargiulo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: antonio costanzo has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, galderma, boehringer, novartis, pfizer, sandoz, and ucb. alessandra narcisi has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, boehringer, novartis, pfizer and ucb. mario valenti has been a consultant and/or speaker for, leo pharma, eli lilly, boehringer and sanofi. luigi gargiulo, francesco toso and luciano ibba have nothing to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. francesco toso, md, dermatology unit, department of biomedical sciences irccs humanitas research hospital, humanitas university, rozzano (mi), italy. tel: +39 0282244050 email: francesco.toso@humanitas.it introduction acrodermatitis continua of hallopeau (ach) is a rare form of pustular psoriasis, which involves the distal portion of the digits of hands and feet [1]. the exact pathogenesis of this disease is still not completely understood, and a role of interleukin (il)-36 and il-17 related cytokines (il-17a/f, il23receptor) has been proposed [1]. ach has a chronic-relapsing course, and it can lead to severe nail dystrophies [1]. given the rarity of this condition, no data are available from clinical trials regarding the use of biological drugs in these patients [1,2]. we present two cases of severe ach successfully treated with biologics: one patient received ixekizumab, a humanized monoclonal antibody targeting il-17a, and the second was given ustekinumab, an inhibitor of il-12/23. case presentation a 56-year-old patient presented to our dermatology department with a history of psoriasis and psoriatic arthritis (psa), with a dermatology life quality index (dlqi) score of 28. in the past, she was treated with oral acitretin 10 mg, one capsule daily for 3 months, ineffectively. on clinical examination, we observed intense red erythema on the distal surface of the five fingers of the right foot, along with intense pustulation and severe onychopathy (figure 1a), 2 research letter | dermatol pract concept. 2023;13(2):e2023103 and moderate erythema and onychopathy on the left foot (figure 1b). a skin biopsy was not performed as the clinical picture was strongly suggestive for ach. given the severity of the clinical picture, as screening exams were all in the normal ranges, we prescribed therapy with ixekizumab 80 mg, two injections at baseline followed by one injection every two weeks until week 12, and then every four weeks. at week 36, the patient came back to our department showing complete skin clearance, with the persistence of only slight onychopathy (figure 2, a and b) and a dlqi of 1. the second patient is a 32-year-old female, who presented to our institute in 2016 with a history of flares of ach (with fever and elevated neutrophils count), previously ineffectively treated with oral cyclosporine. on physical examination, several pustules on erythematous skin were observed on the distal surface of the fingers of both hands. subsequently, after screening exams returned all in the normal ranges, we prescribed ustekinumab 45 mg, 1 injection at weeks 0, 4, and then every 12 weeks. at week 40, the patient showed complete skin clearance. she is still on treatment to date, without any relapse of the disease. conclusions the treatment of ach is challenging, due to the lack of randomized clinical trials on biological drugs, given the rarity of this condition [2]. there are only a few case reports on the efficacy of ixekizumab in the treatment of pustular variants of psoriasis [3]. in our first case, we prescribed ixekizumab for several reason: the rapid onset of action, the efficacy on psa and our favorable experience on this drug on difficult-to-treat areas [4,5]. on the other hand, more data are available on ustekinumab in patients affected by ach [6]. in a multicenter retrospective study, ustekinumab showed improvement in 75.0% of patients [6]. in our case, we decided to prescribe ustekinumab because at the time it was the most recent and most effective biological drug approved for psoriasis. further studies, with longitudinal design and larger cohorts of patients, are needed to establish the exact role of biologics, including ustekinumab and ixekizumab, in the management of ach. ba figure 1. (a) severe acrodermatitis continua of hallopeau affecting the digits of the right foot of a 56-year-old patient, with intense pustulation on erythematous skin along with severe psoriatic onychopathy. (b) clinical appearance of the left foot. research letter | dermatol pract concept. 2023;13(2):e2023103 3 references 1. navarini aa, burden ad, capon f, et al. european consensus statement on phenotypes of pustular psoriasis. j eur acad dermatol venereol. 2017;31(11):1792-1799. doi:10.1111/jdv .14386. pmid: 28585342. 2. maliyar k, crowley el, rodriguez-bolanos f, o’toole a, gooderham mj. the use of biologic therapy in the treatment of acrodermatitis continua of hallopeau: a review. j cutan med surg. 2019;23(4):428-435. doi:10.1177/1203475419836435. pmid: 30938189. 3. miller ac, holland te, cohen dj. treatment of acrodermatitis continua of hallopeau with ixekizumab. j dermatolog treat. 2021;32(1):117-119. doi:10.1080/09546634.2019.1628170. pmid: 31184530. 4. narcisi a, valenti m, cortese a, et al. anti-il17 and anti-il23 biologic drugs for scalp psoriasis: a single-center retrospective comparative study. dermatol ther. 2022;35(2):e15228. doi:10.1111/dth.15228 pmid: 34820969. 5. husson b, barbe c, hegazy s, et al. efficacy and safety of tnf blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of hallopeau. j eur acad dermatol venereol. 2020;34(10):2330-2338. doi:10.1111/jdv.16265 pmid: 32030802. 6. gargiulo l, pavia g, ibba l, et al. generalized pustular psoriasis and plaque psoriasis successfully treated with ixekizumab. clin exp dermatol ther. 2022;7:183. doi: 10.29011/2575 -8268.100183. figure 2. (a,b) clinical picture at week 36, showing resolution of the cutaneous lesions. only slight onychopathy is observed. dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(3):e2023138 1 supporting healing inside and out: dermatologist-led skin and hair care empowerment for survivors of gender-based violence rachel sally1, nikita lakdawala1, nayoung lee1, kristen lo sicco1, miriam k. pomeranz1 1 the ronald o. perelman department of dermatology, new york university grossman school of medicine, new york, ny, usa citation: sally r, lakdawala n, lee n, lo sicco k, pomeranz mk. supporting healing inside and out: dermatologist-led skin and hair care empowerment for survivors of gender-based violence. dermatol pract concept. 2023;13(3):e2023138. doi: https://doi.org/10.5826/dpc.1303a138 accepted: january 4, 2023; published: july 2023 copyright: ©2023 sally et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: rachel sally, the ronald o. perelman department of dermatology new york university grossman school of medicine 240 east 38th street, 12th floor new york, ny 10016 email: rachel.sally@nyulangone.org the global burden of gender-based violence (gbv) is a significant public health concern, with one in three women estimated to experience some form of gbv throughout their lifetime regardless of racial, socio-economic, or religious background [1]. it has been well-established that experiencing gbv can have devastating consequences on mental and physical health as well as overall quality of life [2]. compounded with this, many women with a history of trauma experience homelessness as they navigate escape and recovery and encounter numerous barriers to accessing medical attention crucial for dermatologic health [2]. furthermore, low self-esteem and persistent stress may decrease adoption of self-care routines [3]. one core theme that emerges when studying healing from gbv is improvement of self-image and empowerment of health and self-care [2]. there is a pressing need for interventions that support such healing for survivors across all fields of medicine, including dermatology. our group developed the skincare empowerment and education with dermatologists (seeds) initiative in the hopes of promoting female dermatologic knowledge in a vulnerable population, thus boosting their self-esteem and aiding in their recovery. there exists precedent for this type of dermatological education effort, including a program at the boston health care for the homeless program (bhchp) [3]. our partner in this initiative was womankind, which is a new york city-based community organization and shelter serving survivors of gender-based violence with a focus on communities of color. the seeds meeting was held in a private, safe, nonclinical setting and hosted by people who identify as women to bolster feelings of emotional and physical safety. twenty-four women from womankind community attended. fundraising efforts allowed participants to take free private car transportation to further enhance feelings of security. educational topics focused on photoprotection in skin of color, vulvar dermatology, skin changes in pregnancy, acne, and alopecia and were presented by board-certified dermatologists. over an hour was set aside for question-and-answer sessions. 2 commentary | dermatol pract concept. 2023;13(3):e2023138 product donations organized during the month prior allowed all participants to take home high-quality skin care kits. the aim of seeds was to promote wellness and self-care through skin and hair care understanding, and feedback from our attendees suggests outcomes in line with this goal. twenty of the participants informally expressed that they would like to attend more events of this type and felt the event was overall a positive experience. three participants said it allowed them to pose questions they “had never been able to ask an actual doctor before.” we believe that encouraging an open forum has an additional benefit of promoting medical engagement and trust in dermatologists. however, our presentations were given in english, which may have limited participation and understanding, and we did not administer formal survey instruments, which limits definitive conclusions on the impact of the event. we hope to establish a sustainable platform for dermatologists to serve our community through recurring educational events. further, we hope to encourage other dermatologists to pursue creative and culturally competent ways of connecting with their communities and working with underserved populations, in particular, women of color and survivors of gbv. references 1. sardinha l, maheu-giroux m, stöckl h, meyer sr, garcíamoreno c. global, regional, and national prevalence estimates of physical or sexual, or both, intimate partner violence against women in 2018. the lancet. 2022;399(10327):803-813. doi:10.1016/s0140-6736(21)02664-7. pmid: 35182472. pmcid: pmc8885817. 2. reid n, kron a, rajakulendran t, kahan d, noble a, stergiopoulos v. promoting wellness and recovery of young women experiencing gender-based violence and homelessness: the role of trauma-informed health promotion interventions. violence against women. 2021;27(9):1297-1316. doi:10.1177 /1077801220923748. pmid: 32573362. 3. raef hs, bartenstein dw, golbari nm, burns z, tan jk. healthy skin from within: a novel intervention for women experiencing homelessness. j am acad dermatol. 2022;87(1):223-225. doi: 10.1016/j.jaad.2021.07.055. pmid: 34364933. dp0303a02_r1 dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2013;3(3):2 3 saline for the sake of style the tokyo-based photojournalist ryoichi “keroppy” maeda, who documents the underground extreme body modification community of japan, introduced the “bagel head” cosmetic modification to japan after learning about the procedure from jerome abramovitch (figures 1 and 2) [1]. in 1999, maeda attended a convention dedicated to extreme body modifications, modcon, that was held in japan that year [2]. at modcon, maeda met abramovitch, a montreal-based photographer and artist involved with extreme body modifications [3]. abramovitch had pioneered saline infusions, and in 2007 maeda established a team in tokyo to administer saline infusions [2]. the procedure takes two hours [2], but the desired welt may take one hour to form [1]. as the saline is infused, the client may experience a stinging sensation and the feeling of liquid trickling along the head and face [4] or headache [1]. as the saline infusion nears completion, the client may become somnolent [4]. four hundred milliliters of saline are the “bagel head” cosmetic modification: myths and medical complications for dermatologists to consider anand n. bosmia1, christoph j. griessenauer2, r. shane tubbs1 1 pediatric neurosurgery, children’s hospital, birmingham, alabama, usa 2 division of neurosurgery, department of surgery, university of alabama at birmingham, birmingham, alabama, usa key words: bagel head, cosmetic modification citation: bosmia an, griessenauer cj, tubbs rs. the “bagel head” cosmetic modification: myths and medical complications for dermatologists to consider. dermatol pract conc. 2013;3(3):2. http://dx.doi.org/10.5826/dpc.0303a02. received: 2013; accepted: 2013; published: july 31, 2013 copyright: ©2013 bosmia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: christoph j. griessenauer, m.d., 1530 3rd ave s, birmingham, al 35209 usa. tel. +205 934 3411. email: cgriessenauer@uabmc.edu. on september 23, 2012, the television program taboo on the national geographic channel featured individuals in tokyo undergoing the “bagel head” cosmetic modification. dermatologists may encounter patients who undergo the bagel head procedure and subsequently present with a cutaneous infection. the purpose of this article is to delineate the bagel head procedure, note responses to sensationalist claims made by the media about this procedure, and discuss potential medical complications from this procedure. specialists and primary care physicians who encounter reports of a specific extreme body modification for the first time should review discussions of the modification by its critics and advocates in order to assess potential medical complications from the procedure more accurately. abstract 4 review | dermatol pract concept 2013;3(3):2 ultimately infused into the person’s forehead to create the welt into which the certified “piercer” overseeing the procedure presses his thumb to create an indent and thereby cause the welt to look like a bagel (figures 3 and 4) [5]. dispelling myths the episode of taboo that featured the bagel head procedure has sparked more discussion about the procedure among various media outlets. the sensationalism of this media coverage has misinformed individuals about the procedure. the company of la carmina, who is a television host and blogger on fashion, was involved in the production of the aforementioned episode and has expertise with the bagel head procedure [6]. la carmina [1] makes three arguments to counter erroneous reports about the bagel head procedure. first, the procedure is rarely performed and not a trend among the japanese. maeda is cited as saying that he has performed about 10 forehead saline infusions per year since 2007. however, there are likely other persons who provide this service. second, the procedure is not permanent, as the saline is absorbed or urinated out in 6 to 24 hours. to note, abraham [4] writes that the welt is present for at least 16 hours. third, precautions are taken so that the procedure is not dangerous. this protocol involves the performance of figure 1 (above). bagel head. image courtesy of la carmina (http://www.lacarmina.com). figure 2 (right). bagel head. image courtesy of la carmina (http://www.lacarmina.com). figure 3. bagel head procedure. image courtesy of la carmina (http://www.lacarmina.com). figure 4. bagel head procedure. image courtesy of la carmina (http://www.lacarmina.com). review | dermatol pract concept 2013;3(3):2 5 the procedure by a certified piercer only when the clients are well rested and sober, and with the use of a sterile saline drip, gloves, and face masks. anticipating medical complications omar ibrahimi, a dermatologist at the connecticut skin institute and visiting assistant professor at harvard medical school, anticipates three complications from the bagel head procedure [5]. first, dehydration secondary to salt overload can occur if an inexperienced piercer uses a hypertonic saline solution instead of normal saline. individuals who undergo the procedure should avoid crowded indoor spaces, such as nightclubs, as diaphoresis secondary to environmental heat in conjunction with the diuretic effect of the saline solution can increase the risk for dehydration. second, failure to use sterile saline solution can increase the risk for bacterial or fungal infections. la carmina [1] acknowledges the possibility of infection, but argues that the use of hospital-grade saline and equipment and the performance of the procedure by a certified piercer minimize this risk. nevertheless, clients should ask from where the saline has been obtained and whether the proper steps have been taken to maintain the saline’s sterility. furthermore, the piercer must sterilize the skin of the forehead with alcohol or another antiseptic prior to the procedure to reduce the risk of a subcutaneous infection by normal skin flora. third, repetition of the procedure could stretch the skin beyond its normal elasticity and thereby cause permanent laxity of the skin. ibrahimi’s concern for this cosmetic complication runs counter to the insistence of the procedure’s advocates that no skin is damaged or stretched. in a 2011 interview with the online magazine vice, maeda stated: “everyone i know who has done it, no matter how many times, their skin has gone back to exactly how it was before” [7]. la carmina endorses maeda’s view: “nothing’s damaged or stretched.” [1] neurovascular injury is another potential complication of the bagel head procedure. piercers should appreciate the vascular supply and innervation of the forehead. the trigeminal nerve provides sensory innervation to the forehead and scalp through the supratrochlear and supraorbital branches of the frontal branch of its ophthalmic division [8]. the supraorbital nerve goes around the superior orbital margin and ascends over the forehead to innervate the skin of the forehead and scalp as far back as the vertex, and the supratrochlear nerve goes around the upper margin of the orbit medial to the supraorbital nerve to innervate the skin of the lower part of the forehead that is close to the median plane [8]. the facial nerve provides motor innervation to the four muscles that move the forehead and eyebrows: frontalis, procerus, corrugator supercilii, and orbital portion of the orbicularis oculi muscles [9]. the blood supply of the forehead consists of the supratrochlear and ipsilateral supraorbital branches of the ophthalmic artery, which is derived from the internal carotid artery [10]. collateral circulation exists between these two branches, and the supratrochlear branch also anastomoses with the angular branch of the facial artery, which is derived from the external carotid artery [10]. the supratrochlear and supraorbital arteries ascend over the forehead with the supratrochlear and supraorbital nerves [8]. piercers must make more medial injections at acute angles relative to the plane of the forehead, as deeper and more lateral punctures increase the risk for neurovascular injury. such injury can result in a hematoma, paresthesias of the skin of the forehead, and paralysis of one or more of the aforementioned muscles. a possible sign for injury secondary to the procedure is failure of the client to elevate the eyebrows, which requires the contraction of the frontalis, the only muscle that functions as a brow elevator [10]. images of individuals who have undergone the bagel head procedure prove that there are variations of the procedure that increase the risk for dehydration, infection, skin laxity, and neurovascular injury. these variations involve using more than one syringe to create a single welt and creating two separate welts. separate welts with an appreciable distance between them require more lateral injections, which increase the risk for neurovascular injury. multiple injections can introduce a larger bolus of saline, thereby increasing the risk for dehydration and skin laxity and for subcutaneous infection injury through repeated penetration of the skin. conclusion the bagel head procedure has received attention from various media outlets in the past year, and media sensationalism may have misinformed individuals about the procedure. medical professionals who encounter reports of a specific extreme body modification for the first time should review discussions of the modification by its critics and advocates in order to assess potential medical complications from the procedure more accurately. dermatologists may encounter patients who undergo the bagel head procedure and who subsequently develop a cutaneous infection. identifying myths promoted by media sensationalism can help the skin specialist evaluate more accurately the risks that this procedure poses for these patients, and also anticipate other potential complications that the patient risks developing if he or she continues to undergo the bagel head procedure, such as dehydration and neurovascular injury. acknowledgements we would like to acknowledge la carmina for her contribution to this article (http://www.lacarmina.com). la carmina 6 review | dermatol pract concept 2013;3(3):2 is a tv host and journalist who has written profusely about extreme body modifications, including the bagel head procedure, and has conducted interviews worldwide with individuals who participate in body modification. her tv company has arranged four shows to date about the bagel head procedure. clips from these shows can be found at the following website: http://www.lacarmina.com/bagelheads.php references 1. carmina l. japanese bagel heads: dangerous? trendy? not. http://www.huffingtonpost.com/la-carmina/bagel-headmyths_b_2080111.html?utm_hp_ref=tw. accessed january 2013. 2. clifton j. japanese bagelheads. http://www.vice.com/en_uk/read/ japanese-bagelheads-wtf. accessed january 2013. 3. abramovitch j. jerome abramovitch is montreal-based photographer and world-renowned artist. http://www.chapter9photography.com/. accessed january 2013. 4. abraham t. could the bizarre “bagel head” look be japan’s most extreme body trend yet? http://www.dailymail.co.uk/femail/article-2208051/bagel-head-trend-are-saline-injections-japans-extreme-beauty-look-yet.html?ito=1490. accessed january 2013. 5. wolchover n. being a “bagel head” is all the rage in tokyo. http://www.businessinsider.com/is-the-bagel-head-trend-dangerous-2012-9. accessed january 2013. 6. carmina l. la carmina and the pirates. 2013; http://www.lacarmina.com/pirates/bagelheads.php. accessed april 2013. 7. maeda r. japanese bagelheads | vice united kingdom. 2011; http://www.vice.com/en_uk/read/japanese-bagelheads-wtf. accessed july 2013. 8. snell rs. clinical anatomy by regions. 9th ed. china: lippincott williams & wilkins; 2012. 9. graham hd, quatela vc, sabini p. endoscopic approach to the brow and midface. in: papel id (ed). facial plastic and reconstructive surgery. 3rd ed. china: thieme medical publishers; 2009. 10. thomas jr. advanced therapy in facial plastic and reconstructive surgery. china: pmph-usa; 2010. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023145 1 long-term omalizumab therapy in patients with chronic spontaneous urticaria: does it increase the risk of covid-19? özge kaya1, zeynep keskinkaya1, selda işık mermutlu1 ,sevilay oğuz kılıç1, sevgi öztürk1 1 department of dermatology and venereology, çanakkale onsekiz mart university faculty of medicine, çanakkale, turkey key words: angiotensin-converting enzyme 2, chronic spontaneous urticaria, covid-19, omalizumab, activation citation: kaya ö, keskinkaya z, işık mermutlu s, oğuz kılıç s, öztürk s. long-term omalizumab therapy in patients with chronic spontaneous urticaria: does it increase the risk of covid-19?. dermatol pract concept. 2023;13(3):e2023145. doi: https://doi.org/10.5826/dpc.1303a145 accepted: december 2, 2022; published: july 2023 copyright: ©2023 kaya et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: özge kaya, md , çanakkale onsekiz mart üniversitesi tıp fakültesi deri ve zührevi hastalıklar anabilim dalı, 17110, çanakkale, türkiye tel: +0902862635950 fax: +0902862635956 e-mail: ozgetrkz@hotmail.com introduction: based on the existing literature, omalizumab (omz) is considered a safe treatment modality in chronic spontaneous urticaria (csu) during the coronavirus disease 19 (covid-19) era. objectives:  the aim of this study is to evaluate the effects of omz on csu patients regarding covid-19 infection. methods: in this retrospective study, files of csu patients using omz during the covid-19 pandemic were reviewed in terms of demographic features, medical history including covid-19 vaccination status, clinical characteristics, pretreatment laboratory parameters, duration, and dosing regimen of omz treatment. patients with a history of covid-19 infection while on omz therapy and patients without covid-19 history were compared with respect to these parameters. the urticaria activations following covid-19 infection or vaccination were also recorded. results: sixty-eight patients with csu (female:male ratio = 1.8:1; mean age = 47.2 ± 15.1 years) continued to receive omz treatment. the median duration of omz treatment was 12 months (range: 6-60). twelve patients (17.6%) were diagnosed with covid-19 showing no exacerbation in urticaria. the duration of omz treatment was significantly higher in the group with covid-19 infection history compared to patients with no history of covid-19 (p = 0.01). among 51 patients (75%) vaccinated against covid-19, urticaria activation occurred in 4 patients without any recurrence following booster vaccinations. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023145 introduction chronic spontaneous urticaria (csu) is a disease lasting more than six weeks and characterized by recurrent erythematous, indurated lesions. infections, drugs, and vaccines are possible triggers that may cause csu exacerbations. the current csu management guideline recommends non-sedative antihistamines in standard or up to 4-fold higher dosages as the first-line treatment. in refractory cases, the anti-immunoglobulin e (anti-ige) antibody omalizumab (omz) is the therapy of choice [1,2]. coronavirus disease 2019 (covid-19) had significant impacts on general health practices. several cases of urticaria triggered by covid-19 or the vaccines developed against the virus have recently been reported [3-5]. csu adversely affects the quality of life of the patients [1,2]. moreover, patients with treatment-resistant csu may be concerned about the reactivation of their disease. for this reason, they may refrain from the newly developed therapeutic options. at the beginning of the covid-19 pandemic, many patients even considered discontinuing their regular medications due to possible immunosuppression. a similar situation was observed for omz treatment, which has no immunosuppressive effect. objectives in this study, we aimed to investigate the effect of omz treatment on csu patients regarding covid-19 incidence and prognosis. methods in this retrospective cohort study, csu patients who were followed up in a tertiary referral center and used at least six months omz therapy between april 2020 and april 2022 were assessed. patients under the age of 18 and those receiving omz treatment for less than six months were excluded. the medical files of the patients were evaluated regarding demographic characteristics (gender, age), medical history (comorbidities, concomitant treatments including antihistamines, covid-19 vaccination status), clinical features (presence of urticaria, angioedema or both, disease activity), laboratory findings (including pre-treatment ig-e levels and blood eosinophil counts), omz treatment duration and dosing frequency. the disease activity was evaluated with urticaria activity score 7 (uas7) [1,2]. the rate of covid-19 infection in patients during omz therapy was recorded. patients with a history of covid-19 infection while on omz therapy and patients without covid-19 history were compared with respect to the parameters mentioned above. moreover, urticaria exacerbations following covid-19 and covid-19 vaccines were noted. the kolmogorov-smirnov test was used to verify the normality of the distribution of continuous variables which were expressed as mean ± standard deviation (sd) or median (min-max) in the presence of abnormal distribution, and categorical variables were expressed as percentages. comparisons between the groups were made by using chi-square or fisher exact test for categorical variables, independent samples t-test for normally distributed continuous variables, and mann-whitney u test when the distribution was skewed. a p -value less than 0.05 was considered statistically significant. all statistical procedures were performed using spss software version 14.0 (spss inc.). the ethics committes of 18 mart university approved the study with the decision number 2022/14-09. results a total of 68 patients with csu continued to receive omz treatment during the study period. the demographic and clinical characteristics of patients are summarized in table 1. the female: male ratio was 1.8:1, while the mean age of the patients was 47.2 ± 15.1 years. urticaria was accompanied by angioedema in 25 patients (36.8%). the median ige level measured prior to omz treatment was 281 ku/l (range: 2-2730). pre-treatment eosinophilia was detected in six patients (9%). the median duration of omz treatment was 12 months (range: 6-60). a standard dose regimen (300 mg every four weeks subcutaneously) was initiated for all patients, while two patients required a reduction in dosing intervals (300 mg every two weeks). an oral h1-antihistamine was required in addition to omz in 24 patients (35.3%) to maintain the disease control. the most commonly used h1-antihistamine was levocetirizine (n = 17, 70.8%). conclusions: considering the likelihood of increased covid-19 infection risk in the setting of longterm omz in csu patients, the duration of omz therapy might be kept at a minimum, or a temporary interruption of the treatment period might be preferred, particularly in high-risk patients regarding covid-19. original article | dermatol pract concept. 2023;13(3):e2023145 3 twelve of the 68 csu patients (17.6%) receiving omz were diagnosed with covid-19 during omz treatment. all twelve patients (17.6%) were diagnosed with covid-19, confirmed by polymerase chain reaction (pcr) test. none of the other 56 patients had a history of covid-19 before or during omz treatment. all patients had mild symptoms during the course of the disease and did not require hospitalization. furthermore, no urticaria activation was observed in any patients following covid-19. the uas7 score was noted to be zero before and after covid-19. when the patients with confirmed covid-19 were compared with those who did not acquire the infection, no difference was detected regarding gender, age, comorbidities, covid-19 vaccination status, pre-treatment ig e levels, pre-treatment eosinophilia, and treatment regimens utilized for csu. in four of 12 patients, the total ige level prior to omz treatment was below 110  ku/l. on the other hand, the duration of omz treatment was significantly higher in the group with covid-19 infection history (p = 0.01) (table 2). fifty-one (75%) patients had been vaccinated against covid-19 while using omz. urticaria activation following vaccination occurred in four patients: one patient who had received inactivated vaccine (sinovac®) and three patients who had received the mrna vaccine (biontech®). activation developed in all patients after the first dose of vaccination and within an average of two days. the urticaria symptoms subsided rapidly in all patients with the administration of oral antihistamine treatment (levocetirizine bid). no recurrence was observed following booster vaccinations in any of the patients. conclusions severe acute respiratory syndrome coronavirus 2 (sarscov-2) has direct and indirect impacts on the immune system. table 1. demographic and clinical characteristics of the chronic spontaneous urticaria patients using omalizumab treatment. characteristics number of patients, n (%) 68 (100%) gender, n (%) female 44 (64.7) age (years), mean ±sd 47.2±15.1 comorbidities hypothyroidism hypertension depression 4 (5.8) 2 (2.9) 1 (1.5) 1 (1.5) oral h1 antihistamine therapy, n (%) levocetirizine ebastine hydroxyzine bilastine rupatadine fexofenadine 24 (35.3) 17 (25) 2 (2.9) 2 (2.9) 1 (1.59 1 (1.5) 1 (1.5) vaccination status, n (%) no vaccination inactivated vaccinea mrna vaccineb inactivated vaccinea+mrnavaccineb 10 (14.7) 27 (39.7) 19 (27.9) 12 (17.6) presence of angioedema, n (%) 25 (36.8) total ige prior to omz treatment(ku/l), median (range) 281 (2-2730) presence of eosinophilia prior to omz treatment, n (%) 6 (9) omz treatment duration (month), median (range) 12 (6-60) dosing regimen of omz, n (%) 300 mg every 4 weeks 300 mg every 2 weeks 66 (97.1) 2 (2.9) omz = omalizumab; sd = standard deviation. ainactivated vaccine produced by sinovacbiotech®. bmrna vaccine produced by pfizer/biontech®. 4 original article | dermatol pract concept. 2023;13(3):e2023145 the level of ige and fcεris [8-10]. moreover, omz has been demonstrated to improve nasal sinus function, which has a significant role in the first line of defense against sarscov-2 [11,12]. hence, patients using omz might benefit from the treatment during the initial phase of covid-19, and some studies highlighted that omz might be a preferable treatment option for covid-19 [12,13]. omz also lessens the disease severity by reducing fcεris on the surface of mast cells, which play a key role in the inflammatory response during the second and third phases of covid-19 and the prolonged covid-19 symptoms referred to as “long-covid” [12-14]. in our study, among 68 patients using omz during the covid-19 pandemic, twelve contracted the sars-cov-2 infection. all patients recovered without progressing to the second pulmonary phase. apart from these twelve patients whose diagnoses were established with a positive pcr test, there might be asymptomatic and underdiagnosed patients. the duration of omz treatment was significantly longer in the patient group with a history of covid-19 compared to patients who did not acquire the infection in our series, although there was no difference between the two groups in terms of covid-19 vaccination status. this might the virus is considered to cause a three-phase disease. the initial phase begins with the entry of the virus into the host and lasts about 5-7 days. the second phase, namely the pulmonary phase, is characterized by pulmonary involvement and occurs within 7-15 days following the disease onset. in the third phase, the inflammatory phase, overactivation of the immune system leads to cytokine storm and consequent development of acute respiratory distress syndrome (ards) [6]. an adequate immune response during the initial phase is desirable, while the primary goal of the treatment is the prevention of the over-activation encountered during the following two phases resulting in cytokine storm [7]. omz is a recombinant human ige antibody that exerts its effect by preventing the binding of ige with high-affinity ige receptors (fcεri). it is utilized in disorders in which ige plays a major role in pathogenesis, such as csu and asthma. furthermore, the antiviral effect of omz has been reported in various studies. this antiviral effect occurs in several different ways. there is a considerable number of fcεris on the surface of plasmacytoid dendritic cells (pdcs) responsible for ifnα production. in several studies, it has been suggested that elevated serum ige levels and increased pdc fcεri expression might reduce ifnα secretion from pdcs. thus, omz contributes to the release of ifn-α by reducing table 2. comparison of demographic and clinical characteristics of patients according to covid-19 infection history. covid-19 (+) n=12 (17.6%) covid-19 (-) n=56 (82.4%) p gender, n (%) female 10 (83.3) 34 (60.7) 0.190 age (years), mean ±sd 39.6±12.8 48.8±15.1 0.056 ccomorbidity, n (%) 1 (8.3) 3(5.4) 0.549 oral h1-antihistamine therapy, n (%) 4 (33.3) 20 (35.7) 1 vaccination status, n (%) no vaccination inactivated vaccinea mrna vaccineb inactivated vaccinea+mrna vaccineb 2 (16.7) 3 (25) 4 (33.3) 3 (25) 8 (14.3) 24 (42.9) 15 (26.8) 9 (16.1) 0.699 presence of angioedema, n (%) 6 (50) 19 (33.9) 0.335 total ige prior to omz treatment (ku/l), median (range) 312.5 (31-740) 280 (2-2730) 0.876 presence of eosinophilia prior to omz treatment, n (%) 2 (16.7) 4 (7.7) 0.291 omz treatment duration (months), median (range) 22.5 (10-60) 12 (6-60) 0.01 dosing regimen of omz, n (%) 300 mg every 4 weeks 300 mg every 2 weeks 12 (100) 0 (0) 54 (96.4) 2 (3.6) 1 omz = omalizumab; sd = standard deviation. ainactivated vaccine produced by sinovacbiotech®. bmrna vaccine produced by pfizer/biontech®. cin the covid-19 + group, one patient had hypertension, while in the covid-19 -group, two patients had hypothyroidism and one patient had depression. original article | dermatol pract concept. 2023;13(3):e2023145 5 of omz therapy following control of csu symptoms to allow et-1 and eosinophil levels to return to levels before omz administration. references 1. zuberbier t, aberer w, asero r, et al. the eaaci/ga²len /edf/wao guideline for the definition, classification, diagnosis and management of urticaria. allergy. 2018;73(7):1393-1414. doi:10.1111/all.13397. pmid: 29336054. 2. zuberbier t, abdul latiff ah, abuzakouk m, et al. the international eaaci/ga²len/euroguiderm/apaaaci guideline for the definition, classification, diagnosis, and management of urticaria. allergy. 2022;77(3):734-766. doi: 10.1111/all.15090. pmid: 34536239. 3. muntean ia, pintea i, bocsan ic, dobrican ct, deleanu d. covid-19 disease leading to chronic spontaneous urticaria exacerbation: a romanian retrospective study.  healthcare (basel). 2021;9(9):1144. doi: 10.3390/healthcare9091144. pmid: 34574918. 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treatment in covid-19. immunopharmacol immunotoxicol. 2021;43(3):259-264. doi: 10 be attributed to a paucity in immune response in the initial covid-19 phase in patients on long-term omz therapy. sars-cov-2 enters the host cells through binding the angiotensin-converting enzyme 2 (ace2) via s-protein [15]. ace2 receptor possesses a significant role in the initiation of covid-19 since sars-cov-2 can only enter cells with ace2 receptors. zietkowski et al demonstrated lowered endothelin-1 (et-1) levels in patients receiving omz. the authors reported that the reduction was more pronounced in patients with more extended treatment duration [16]. in another study, a negative correlation was revealed between et-1 and ace2 receptor, ie, the number of ace2 receptors was elevated as the et-1 level declined [17]. in addition, patients with higher ace2 receptor levels were shown to have a better covid-19 prognosis [18]. it might be a possible explanation for the higher incidence of covid-19 in our patients with a longer duration of omz therapy and the low disease activity that did not necessitate hospitalization in any of these patients. in the aforementioned study, zietkowski et al observed a reduction in the eosinophilic cationic protein (ecp) levels and the blood eosinophil counts in subjects on omz therapy in proportion to the treatment duration [16]. studies investigating the relation between covid-19 and eosinophil levels indicated eosinopenia, particularly in the initial disease phase [19,20]. on the other hand, covid-19 incidence was relatively low in patients with asthma, a disease associated with elevated eosinophil count, suggesting eosinophilia might be a protective factor against covid-19 [21-22]. in the light of these findings, it might be speculated that the extended use of omz facilitated the entry of sars-cov-2 in the host cell by increasing the ace2 receptors and reducing eosinophil counts, while hindering the progression of the disease into more severe forms with its antiviral and anti-inflammatory effects. various case reports and studies confirmed urticaria activation triggered either with covid-19 or covid-19 vaccines [23-25]. in contrast, none of the patients in our series who had covid-19 showed activation of urticaria. similarly, some studies observed no urticaria activation in patients on omz in the setting of covid-19 [13,25]. on the other hand, the urticaria flares following vaccination were not uncommon and were mainly detected following mrna vaccines as in our patients [24]. in conclusion, our study highlights the positive relationship between the duration of omz treatment and the risk of acquiring sars-cov-2. older age (≥65 years old), male gender, hypertension, cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, and malignancies were associated with a higher risk of death from covid-19 infection [26]. in this regard, in patients with aforementioned risk factors, the physicians might consider a temporary 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and the skin: the landscape of cutaneous vaccine reactions worldwide. dermatol clin. 2021;39(4):653-673. doi: 10.1016/j.det.2021.05.016. pmid: 34556254. pmcid: pmc8165093. 25. ayhan e, öztürk m, an i̇, bekçibaşi m. covid-19 infection under omalizumab therapy for chronic spontaneous urticaria: three cases. int j dermatol. 2021;60(2):253254. doi: 10.1111 /ijd.15379. pmid: 33332576. 26. parohan m, yaghoubi s, seraji a, javanbakht mh, sarraf p, djalali m. risk factors for mortality in patients with coronavirus disease 2019 (covid-19) infection: a systematic review and meta-analysis of observational studies. aging male. 2020;23(5):1416-1424. doi: 10.1080/13685538.2020.1774748. pmid: 32508193. .1080/08923973.2021.1925906. pmid: 34018464. pmcid: pmc8146297. 13. passante m, napolitano m, dastoli s, et al. safety of omalizumab treatment in patients with chronic spontaneous urticaria and covid-19. dermatol ther. 2021;34(6):e15111. doi: 10.1111 /dth.15111. pmid: 34427028. pmcid: pmc8646731. 14. lam hy, tergaonkar v, kumar ap, ahn ks. mast cells: therapeutic targets for covid-19 and beyond. iubmb life. 2021;73(11):1278-1292. doi: 10.1002/iub.2552. pmid: 34467628. pmcid: pmc8652840. 15. walls ac, park yj, tortorici ma, wall a, mcguire at, veesler d. structure, function, and antigenicity of the sarscov-2 spike glycoprotein cell. 2020;181(2):281-292.e6. doi:10.1016/j.cell.2020.02.058. pmid: 32155444. pmcid: pmc7102599. 16. zietkowski z, skiepko r, tomasiak-lozowska mm, bodzenta-lukaszyk a. anti-ige therapy with omalizumab decreases endothelin-1 in exhaled breath condensate of patients with severe persistent allergic asthma. respiration. 2010;80(6):534542. doi: 10.1159/000317137. pmid: 20588001. 17. zhang h, li y, zeng y, wu r, ou j. endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells. pharmacology. 2013;91(5-6):297-304. doi: 10.1159/000350395. pmid: 23751363. 18. chen j, jiang q, xia x, et al. individual variation of the sarscov-2 receptor ace2 gene expression and regulation. aging cell. 2020;19(7):e13168. doi:10.1111/acel.13168. pmid: 32558150. pmcid: pmc7323071. 19. lindsley aw, schwartz jt, rothenberg me. eosinophil responses during covid-19 infections and coronavirus vaccination. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023150 1 brownish-yellow dots as a dermoscopic sign of follicular mucinosis javier de la iglesia martin1, jaime piquero-casals2, angels quera3, daniel morgado-carrasco1,3 1 dermatology department, hospital clínic de barcelona, universitat de barcelona, barcelona, spain 2 dermik, clínica dermatológica multidisciplinar, barcelona, spain 3 dermatology department, hospital de figueres, fundació salut empordà, girona, spain citation: de la iglesia martin j, piquero-casals j, quera a, morgado-carrasco d. brownish-yellow dots as a dermoscopic sign of follicular mucinosis dermatol pract concept. 2023;13(3):e2023150. doi: https://doi.org/10.5826/dpc.1303a150 accepted: january 14, 2023; published: july 2023 copyright: ©2023 de la iglesia martin et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, hospital clínic de barcelona, villarroel 170, barcelona (08036), tel. (+34) 935 464 710 fax (+34) 935 464 729 email: morgadodniel8@gmail.com case presentation a 40-year-old man presented with a 2-year history of well defined, erythematous and alopecic plaques, together with alopecic patches on both shins. dermoscopy showed medium-size brownish-yellow dots, arboriform vessels and patchy homogenous ivory-white areas (figure 1). laboratory tests including blood count, antinuclear antibodies, ro/la antibodies, thyroid function and serum protein electrophoresis, together with serologies for syphilis, lyme disease, hepatitis b and c virus, and hiv, and chest x-ray were normal or negative. a punch biopsy revealed a follicular and perifollicular lymphocytic infiltrate with no cellular atypia, and deposition of an amorphic substance around follicles in the dermis. alcian blue at ph 2.5 confirmed the presence of mucin (figure 2). based on clinicopathological characteristics a diagnosis of follicular mucinosis was made. topical corticosteroids and hydroxychloroquine 400 mg/day were started, and long-term follow-up was recommended. teaching point follicular mucinosis is a rare inflammatory dermatosis characterized by abnormal deposition of mucin on hair follicles [1]. there are two subtypes: idiopathic and associated with cutaneous lymphomas or hematological malignancies. the diagnosis of follicular mucinosis can be challenging. dermoscopic features of follicular mucinosis have scarcely been described. dermoscopy may reveal white homogenous patches surrounded by a yellow border, interfollicular red dots and the tooth paste sign1 (white gelatinous material along hair shafts). yamagishi et al haga clic o pulse aquí para escribir texto. reported perifollicular medium-size brownish-yellow dots, which were also seen in 2 image letter | dermatol pract concept. 2023;13(3):e2023150 our patient [2]. these structures can also be observed in discoid lupus erythematosus, among other dermatoses. dermoscopy may be helpful in the diagnosis of follicular mucinosis, and medium-size brownish-yellow dots can be a novel dermoscopic sign. references 1. mumford bp, ryan a, chong ah, lasocki a. follicular mucinosis with novel dermoscopic finding: the toothpaste sign. clin exp dermatol. 2022;47(5):969-970. doi: 10.1111/ced.15083. pmid: 34978345. 2. yamagishi h, ota m, nobeyama y, asahina a. case of follicular mucinosis showing brownish yellow and red dots via dermoscopy. clin case rep. 2022;10(5). doi: 10.1002/ccr3.5815. pmid: 35600022. pmcid: pmc9109645. a b figure 1. (a) follicular mucinosis. well-defined, erythematous alopecic plaques, and alopecic patches on both shins. (b)  dermoscopy reveals multiple medium-size brownish-yellow dots, and arboriform vessels. scattered homogenous white areas can also be seen. aa b figure 2. (a) histopathologic picture. lymphocytic infiltrate and amorphic substance around hair follicles. no cellular atypia was seen. (b) alcian blue at ph 2.5 confirmed the presence of mucin. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022145 1 dermatology practical & conceptual retrospective analysis of dermatological diseases in geriatric patients during dermatology outpatient department visits gulhan aksoy sarac1, mehmet ali can emeksiz1, onur acar2, ersin nazlican3, efsun tanacan1, tufan nayir4 1 department of dermatology and venereology, ufuk university hospital, ankara, turkey 2 ağrı provincial health directorate, republic of turkey ministry of health, ağrı, turkey 3 department of public health, faculty of medicine, çukurova university, adana, turkey 4 republic of turkey ministry of health, ankara, turkey key words: geriatrics, elderly, skin diseases, dermatology, epidemiology citation: aksoy sarac g, emeksiz mac, acar o, nazlican e, tanacan e, nayir t. retrospective analysis of dermatological diseases in geriatric patients during dermatology outpatient department visits. dermatol pract concept. 2022;12(3):e2022145. doi: https://doi.org/10.5826/dpc.1203a145 accepted: december 23, 2021; published: july 2022 copyright: ©2022 akoy sarac et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: onur acar, md, ağrı provincial health directorate, republic of turkey ministry of health, ağrı, turkey, e-mail: dronuracar@yandex.com introduction: the elderly population is vulnerable to experience a great number of dermatological diseases thanks to the intrinsic and extrinsic process of aging. objectives: the aim of this study is to retrospectively investigate the prevalence of dermatological diseases in geriatric patients, their distribution by age and gender, and to provide a reference for studies on aging and skin problems. methods: in the present study, patients who reported to the dermatology outpatient clinic between january 1 2019, and january 1 2021, were evaluated retrospectively. as a result of examining the records of patients, 887 patients over the age of 65 who met the study protocol were included. results: the three most common diseases in all geriatric patients were fungal infections, eczematous dermatitis, and pruritus. fungal infections were frequent in males and the 65-74 age group. in the males, the more frequent were precancerous lesions and malignant neoplasms, whereas in the females it was urticaria and adverse drug reactions. in the logistic regression model, the risk of fungal infection in geriatric patients was increased by being male (odds ratio 1.55, p = 0.006) and being in the range of 65-74 years old (odds ratio 1.46, p = 0.025). male patients were at significantly higher risk for precancerous and malignant lesions (or:2.81 p < 0.001) and actinic keratosis (odds ratio 3.26, p < 0.001) in this disease group. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022145 introduction due to technological advancements and improved living conditions/standards, life expectancy in turkey as in other parts of the world is increasing on a daily basis. according to the turkish statistical institute, life expectancy at birth increased from 78.0 for the 2013-2015 period to 78.6 for the 2017-2019 period. similarly, life expectancy at age 65 for both sexes was 17.8 years in the 2013-2015 period, while it was 18 years in the 2017-2019 period [1]. in the last five years, the proportion of the elderly population, which includes individuals aged 65 and over, increased from 8.2% to 9.5%. it is estimated that the proportion of the elderly population will increase to 11% in 2025, 12.9% in 2030, and 16.3% in 2040[(2]. the geriatric population consists of individuals aged 65 and over. aging is a continuous biological process. during the aging process, many functions such as regeneration capacity, chemical cleaning capacity, dna repair capacity, sensory perception, mechanical protection and immune response of cells forming organs, and tissues decline. due to the effect of these changing cellular functions, the skin structure is adversely affected as in all other organs and systems. the effects of aging on the skin are evaluated under two different pathways as intrinsic and extrinsic pathways. intrinsic aging is considered the unavoidable and unstoppable physiological regression of the functions of cells and tissues. extrinsic aging on the other hand, is both preventable and avoidable. it occurs as a result of exposure to environmental influences such as sunlight and ultraviolet radiation. the effects of extrinsic aging on the skin include not only physiological but also morphological changes. as a result of these aging mechanisms, there is dryness, wrinkles, flabbiness, and loss of flexibility of the skin and many benign neoplasms also occur in the skin due to aging [3]. objectives due to the physiological and morphological effects of aging on the skin and the increase in the number of the elderly in the population over time, dermatological diseases associated with aging have become an important field of study. the aim of this study is to retrospectively investigate the prevalence of dermatological diseases in geriatric patients, their distribution by age and gender, and to provide a reference for studies on aging and skin problems. methods in this study, patients who reported to the dermatology outpatient clinic between january 1 2019, and january 1 2021, were evaluated retrospectively. the records of 887 patients over the age of 65 were examined; 485 (54.7%) of them were females and 402 (45.3%) of them were males. the participants were grouped by gender and by age groups of 65-74 years and 75 years or older. according to the diagnoses, skin diseases and disorders were categorized into 12 groups viral infections, bacterial infections, fungal infections, eczematous dermatitis, papulosquamous diseases, vesiculobullous diseases, precancerous lesions and malignant neoplasms, benign neoplasms, xerosis cutis, pruritus, urticaria and adverse drug reactions and other diseases (cutaneous lymphomas, pigmentation disorders, connective tissue diseases, vascular diseases, metabolic skin diseases, acne and related diseases, hair disorders, nail disorders, skin ulcers). data analysis was performed using spss 23.0 statistical program. descriptive statistical parameters were used for the prevalence of skin diseases. chi-square analysis was used to determine whether there was a significant difference in the prevalence of skin diseases according to gender and age group. a logistic regression model was established for each of the diseases that were significant in the chi-square analysis. a value of p < 0.05 was accepted as significant in the entire analysis. ethics committee approval was obtained from the university ethics committee. results all the 887 patients whose records were examined were geriatric patients aged 65 and over. of these patients, 485 (54.7%) were females and 402 (45.3%) were males. the mean age was 73.34 ± 7.24 (65-101) for women, 73.75 ± 7.08 (65-94) for men, and 73.53 ± 7.16 (65-101) years for all participants. five hundred and thirty-nine (60.8%) of the participants were in the age group of 65-74 years and 348 (39.2%) were in the age group of 75 years and over. of the individuals in the 65-74 age group, 304 (56.4%) were females and 235 (43.6%) were males. one hundred and eighty-one (52.0%) of the individuals in the 75 years and over age group were females and 167 (48%) were males. diseases seen during the entire study period are recorded as; fungal infections (23.0%), eczematous dermatitis (17.1%), pruritus (10.8%), papulosquamous diseases conclusions: men are more vulnerable to life-threatening skin diseases. it is important to determine risk factors for individuals who are more sensitive to environmental factors in terms of increasing the quality of life and protection from diseases. original article | dermatol pract concept. 2022;12(3):e2022145 3 (8.1%), viral infections (7.8%), precancerous lesions and malignant neoplasms (7.2%), benign neoplasms (5.3%), xerosis cutis (4.7%), urticaria and adverse drug reactions (3.2%), bacterial infections (2.5%), vesiculobullous diseases (0.9%) and other diseases (9.1%) (tables 1 and 2). fungal infections were most common in men and women between the ages of 65 and 74, and the incidence in this age range was between 72.6% and 62.4%. fungal infections in both sexes; tinea ungium (63.7%), tinea pedis (23.5%), tinea cruris (5.9%), tinea corporis (5.4%) and candida stomatitis (1.5%). eczematous dermatitis, which is the second most common dermatologic disease in the geriatric population, was most common in men and women between the ages of 65 and 74, with a prevalence of 64.4% and 54.8% in this age table 1. distribution of diagnosed skin diseases by gender and results of chi-square analysis dermatologic diseases females n = 495 (%) males n = 402 (%) total n = 887 (%) p value x2 fungal infections 95 (19.6) 109 (27.1) 204 (23.0) 0.008 7.032 eczematous dermatitis 90 (18.6) 62 (15.4) 152 (17.1) 0.218 1.520 pruritus 52 (10.7) 44 (10.9) 96 (10.8) 0.915 0.011 papulosquamous diseases 38 (7.8) 34 (8.5) 72 (8.1) 0.735 0.114 viral infections 40 (8.2) 29 (7.2) 69 (7.8) 0.567 0.327 precancerous lesions and malignant neoplasms 20 (4.1) 44 (10.9) 64 (7.2) < 0.001 15.278 benign neoplasms 26 (5.4) 21 (5.2) 47 (5.3) 0.928 0.008 xerosis cutis 28 (5.8) 14 (3.5) 42 (4.7) 0.110 2.557 urticaria and adverse drug reactions 24 (4.9) 4 (1.0) 28 (3.2) 0.001 11.238 bacterial infections 11 (2.3) 11 (2.7) 22 (2.5) 0.655 0.199 vesiculobullous diseases 5 (1.0) 3 (0.7) 8 (0.9) 0.655 0.199 table 2. distribution of diagnosed skin diseases by age groups and results of chi-square analysis dermatologic diseases 65-74 years n = 539 (%) 75 years and over n = 348 (%) total n = 887 (%) p value x2 fungal infections 137 (25.4) 67 (19.3) 204 (23.0) 0.033 4.538 eczematous dermatitis 92 (17.1) 60 (17.2) 152 (17.1) 0.947 0.004 pruritus 53 (9.8) 43 (12.4) 96 (10.8) 0.238 1.395 papulosquamous diseases 41 (7.6) 31 (8.9) 72 (8.1) 0.488 0.480 viral infections 39 (7.2) 30 (8.6) 69 (7.8) 0.452 0.565 precancerous lesions and malignant neoplasms 33 (6.1) 31 (8.9) 64 (7.2) 0.117 2.451 benign neoplasms 34 (6.3) 13 (3.7) 47 (5.3) 0.095 2.789 xerosis cutis 20 (3.7) 22 (6.3) 42 (4.7) 0.074 3.197 urticaria and adverse drug reactions 20 (3.7) 8 (2.3) 28 (3.2) 0.240 1.379 bacterial infections 11 (2.0) 11 (3.2) 22 (2.5) 0.295 1.097 vesiculobullous diseases 4 (0.7) 4 (1.1) 8 (0.9) 0.531 0.393 range. eczematous dermatitis was seen in both sexes; allergic contact dermatitis (27.0%), irritant contact dermatitis (9.9%), nummular dermatitis (6.6%), lichen simplex chronicus (6.6%), and erythema intertrigo (3.9%). papulosquamous diseases were most common in women (60.5%) and men (52.9%) in the 65-74 years group. papulosquamous diseases seen in both sexes; psoriasis vulgaris (44.4%), seborrheic dermatitis (37.5%), lichen planus (11.1%), prurigo nodularis (2.8%), lichen sclerosis et atrophicus (2.8%), and parapsoriasis (1.4%). viral infections were more common in women (52.5%) aged 75 and over, and in men (69.0%) in the 65-74 years age group. viral infections seen in both sexes; zona zoster (94.3%), molluscum contagiosum (4.3%) and anogenital warts caused by human papilloma virus (1.4%). 4 original article | dermatol pract concept. 2022;12(3):e2022145 precancerous and malignant lesions were most common in women (55%) aged 75 years and above, while in men (54.5%) they were most common in the group of 65-74 years. precancerous and malignant neoplasms seen in both sexes; actinous keratosis (78.1%), squamous cell carcinoma (10.9%), mycosis fungoides (6.3%), basal cell carcinoma (3.1%), and lentigo maligna (1.6%). benign neoplasms were most common in women (69.2%) and men (76.2%) in the 65-74 years age group. benign neoplasms were seen in both sexes; seborrheic keratosis (27.7%), skin tag (23.4%), epidermal cyst (14.9%), melanocytic nevus (14.9%) and keloid scar (4.3%). when the prevalence of skin diseases was analyzed by gender; fungal infections (p=0.008) and precancerous and malignant neoplasms (p < 0.001) were more common in males than females. among the precancerous and malignant neoplasms, actinic keratosis (p < 0.001) was more common in males than females. when skin diseases were considered according to the distribution among age groups; fungal infections were seen more frequently in the 65-74 age group (p = 0.033, significant) compared to the other age group. tinea corporis (p = 0.039, significant) among fungal infections and allergic contact dermatitis among eczematous dermatitis (p = 0.046, is significant) were seen more frequently in the 65-74 age group compared to the other age group (tables 1 and 2). a logistic regression model was established to analyze the extent to which the parameters with significant differences in the chi-square test increased the risk of developing skin diseases. according to the established logistic regression model, the risk of fungal infection in geriatric patients was increased by being male (odds ratio [or] 1.55, p = 0.006) and being in the range of 65-74 years old (or 1.46, p = 0.025). male patients were at significantly higher risk for precancerous and malignant lesions (or 2.81, p < 0.001) and actinic keratosis in this disease group (or 3.26, p < 0.001) (table 3). conclusions while the average life expectancy in the world increases on one hand, on the other hand, efforts to take preventive measures on the health problems of geriatric patients, provide early diagnosis and necessary medical treatment not only improve their living conditions, but also reduce costs for countries [4,5]. according to 2020 data, 9.5% of turkey’s population consists of individuals aged 65 and over [6]. in our study, 15% of the total number of patients who reported to the outpatient clinic were over 65 years old. in this study, fungal infections, eczematous dermatitis, pruritus, papulosquamous diseases, and viral infections in order of the most prevalent to the least, constitute the first five most common dermatological diseases groups in the geriatric population. bilgili et al. in a study conducted in an eastern city in turkey where winter conditions are severe, it is stated that in order of prevalence, the most common dermatological diseases are eczematous dermatitis, fungal infections, pruritus, urticaria-angioedema and bacterial infections. it is stated that viral infections and papulosquamous diseases are seen less frequently [7]. in another study conducted in turkey, eczematous dermatitis, pruritus, fungal infections, precancerous and malignant lesions, and bacterial infections are listed as the most common dermatological diseases [8]. when we look at the studies conducted in turkey related to the subject of the study, it is seen that the order of the most common dermatological disease groups changes according to geographical and climatic differences, but it is seen that eczematous dermatitis, fungal infections, pruritus disease group generally ranks high in the studies and maintains its significance. in this study, fungal infections constitute the most common disease group in the geriatric population. in addition, fungal infections were 1.55 times more common in men and 1.46 times more common in the 65-74 age group. similarly, in a study conducted by yalçın et al in turkey, fungal infections were reported to be more common in males (18%) and in the 65-74 years age group (16.7%) [9]. age, gender, personal care, epidermal turn-over and decreased immunological functions may be responsible in the frequent occurrence of fungal infections in the geriatric population [10]. it is widely accepted that the fact that men are exposed to physical causal factors more than women and that they do not consider skin care as important as women, results in fungal infections being more common in men. this may be the reason why the prevalence of this disease was higher in males in our study too [9]. in this study, eczematous dermatitis constituted the second most common disease group in the geriatric population. table 3. logistic regression model established for the estimation of risk factors leading to skin diseases dermatologic diseases risk factor b p value odds ratio 95% confidence interval fungal infection male 0.442 0.006 1.555 1.134 2.132 65-74 years 0.380 0.025 1.462 1.0502.036 precancerous and malignant lesion male 1.036 < 0.001 2.819 1.631 4.871 actinic keratosis male 1.184 < 0.001 3.267 1.735 -6.152 original article | dermatol pract concept. 2022;12(3):e2022145 5 eczematous dermatitis is more common in the 65-74 years age group in both men and women. in addition, among eczematous dermatitis, contact dermatitis is the most common disorder. similarly, in the study conducted by yaldız et al, it is stated that allergic contact dermatitis (44.5%) and irritant contact dermatitis (33.2%) are the most common diseases among eczematous dermatitis [4]. the fact that eczematous dermatitis is more common in early geriatric ages and contact dermatitis is more common than others can be explained by the increased exposure to many environmental and physical extrinsic factors in the development of eczematous dermatitis. it is thought that it will continue to be seen more frequently in the coming years due to the changing climatic conditions, increasing exposure to sunlight and increasing chemical exposure. in this study, pruritus was the third most common dermatological disease. although it is seen at the same rate in women and men, it is of significance that it is seen at a higher rate in the 75 and over age group. similarly, in a study conducted in turkey, pruritus (12.8%) was the third most common disease and it was seen to increase from a rate of 12.2% in the 65-74 age group, to 14.3% in the 75-84 age group, and 16.9% in the 85 and over age group [11]. in a study conducted with 46 people staying in a nursing home in denmark, the pruritus rate was reported as 28.9% [12]. it is acknowledged that the incidence of pruritus increases with age. dry skin, nervous degeneration and weakening of immunity due to aging predispose the aged to pruritus [13]. among the causes of diseases such as pruritus, it is important to have preventable or intervening measures in order to reduce this very common disease in later ages. for this reason, it can be said that patient information activities to be carried out in dermatology outpatient clinics and the study of preventive medicine by health professionals will be beneficial in reducing these diseases. in this study, papulosquamous diseases was the fourth most common dermatological disease group. in this group of diseases, psoriasis vulgaris, seborrheic dermatitis and lichen planus, in order of prevalence, are the three most common diseases. in a study by darjani et al in iran, it was reported that papulosquamosis patients were seen in 31.6% of geriatric patients, and seborrheic dermatitis (15.4%) and psoriasis (7.3%) were the first two in this group [14]. in a study by kandwal et al in india, it was reported that papulosquamous diseases (40%) and psoriasis (9.4%) as a constituent of this group were most common in individuals over 60 years of age [15]. in this study, precancerous and malignant lesions were seen in 7.2% of the geriatric population. similar to our study, the prevalence of precancerous and malignant lesions was reported as 5.2% by yalçın et al, 9.6% by polat et al, and 9.7% by yaldız et al [4,8,9]. among these lesions, actinic keratosis, squamous cell carcinoma and mycosis fungoides in decreasing order of prevalence constitute the three most common lesions. when evaluated as a group, these lesions are 2.81 times more frequent in male subjects compared to female subjects. in this study, the prevalence of actinic keratosis was 5.6%. in addition, the risk of developing actinic keratosis, which is a common premalignant lesion, is 3.26 times higher in men. prevalence of actinic keratosis has been reported as 29.3% by kılıç et al, 22.3% by cvitanovic et al, and 21.1% by akdeniz et al [16-18]. likewise, in the study of akdeniz et al., it was emphasized that actinic keratosis was significantly more common in men [18]. actinic keratosis usually presents as red or brown papules 3-6 mm in diameter on sun-exposed body parts in fair-skinned individuals [19]. the fact that men are exposed to sunlight more frequently in working and social life is acknowledged as one of the important factors that cause it to be more common in men. the average life expectancy in most of the world is getting to continues to increase due to preventive approaches and improving treatment options. as depend on this condition, geriatric patients take part in the focus of given medical services higher. an important part of the skin problems seen in geriatric patients are diseases that can be prevented by protecting individuals against adverse environmental conditions. these diseases cause life-threatening conditions albeit at a low rate. it is very important to determine the risk levels of individuals in the geriatric population for dermatological diseases that adversely affect the quality of life. it can supply to improve the medical services given by dermatologists to geriatrics. we believe that this epidemiological study will contribute to the dermatologists and clinicians in assessment and improving preventive approaches to the most seen skin diseases in geriatric. references 1. turkish statistical institute (turkstat). life tables, 2017-2019. 2020. available from: https://data.tuik.gov.tr/bulten/index?p=hayat-tablolari-2017-2019-33711. accessed june 25, 2021 2. turkish statistical institute (turkstat). elderly population statistics, 2020. 2021. available from https://data.tuik.gov.tr/bulten/index?p=istatistiklerle-yaslilar-2020-37227. accessed june 25, 2021 3. yaar m, gilchrest ba. chapter 109: aging of skin. in: goldsmith, la et al (eds), fitzpatrick’s dermatology in general medicine (8th ed.). mcgraw-hill companies, inc; 2012. pp:1213-1226. 4. yaldiz m. dermatological diseases in the geriatric age group: retrospective analysis of 7092 patients.  geriatr gerontol int. 2019;19(7):582-585. doi: 10.1111/ggi.13665. pmid: 30950155. 5. berglund al, ericsson k. different meanings of quality of life: a comparison between what elderly persons and geriatric staff believe is of importance. int j nurs pract. 2003;9(2):112-119. doi: 10.1046/j.1322-7114.2003.00414.x. pmid: 12694480. 6. turkish statistical institute (turkstat). the results of address based population registration system, 2020. 2021. available 6 original article | dermatol pract concept. 2022;12(3):e2022145 from: https://data.tuik.gov.tr/bulten/index?p=adrese-dayali-nufus-kayit-sistemi-sonuclari-2020-37210. accessed june 25, 2021 7. bilgili sg, karadag as, ozkol hu, calka o, akdeniz n. the prevalence of skin diseases among the geriatric patients in eastern turkey. j pak med assoc. 2012;62(6):535-539. pmid: 22755334.  8. polat m, i̇lhan mn. dermatological complaints of the elderly attending a dermatology outpatient clinic in turkey: a prospective study over a one-year period.  acta dermatovenerol croat. 2015;23(4):277-281. pmid: 26724880. 9. yalçin b, tamer e, toy gg, oztaş p, hayran m, alli n. the prevalence of skin diseases in the elderly: analysis of 4099 geriatric patients.  int j dermatol. 2006;45(6):672-676. doi: 10.1111/j.1365-4632.2005.02607.x. pmid: 16796625. 10. özyurt k, avci a, çinar sl, silay e. dermatological disorders in geriatric patients.  turk j dermatol 2014;4:206-209. doi: 10.4274/tdd.2333. 11. bas y, kalkan g, seçkin hy, takci z, sahin s, demir ak. analysis of dermatologic problems in geriatric patients: turkish journal of dermatology. turk j dermatol. 2014;8(2):95-100. 12. 12. dyhre-petersen n, gazerani p. presence and characteristics of senile pruritus among danish elderly living in nursing homes. future sci oa. 2019;5(6):fso399. doi: 10.2144/fsoa-20190036. pmid: 31285844. pmcid: pmc6609920.  13. valdes-rodriguez r, stull c, yosipovitch g. chronic pruritus in the elderly: pathophysiology, diagnosis and management. drugs aging. 2015;32(3):201-215. doi: 10.1007/s40266-015-0246-0. pmid: 25693757. 14. darjani a, alizadeh n, rafiei e, et al. skin diseases among the old age residents in a nursing home: a neglected problem.  dermatol res pract. 2020;2020:8849355. doi: 10.1155/2020/8849355. pmid: 33204253. pmcid: pmc7661112. 15. kandwal m, jindal r, chauhan p, roy s. skin diseases in geriatrics and their effect on the quality of life: a hospital-based observational study.  j family med prim care. 2020;9(3):14531458. doi: 10.4103/jfmpc.jfmpc_1188_19. pmid: 32509632. pmcid: pmc7266226. 16. kiliç a, gül u, aslan e, soylu s. dermatological findings in the senior population of nursing homes in turkey.  arch gerontol geriatr. 2008;47(1):93-98. doi: 10.1016/j.archger.2007.07.007. pmid: 17826853. 17. cvitanović h, knezević e, kuljanac i, jancić e. skin disease in a geriatric patients group in outpatient dermatologic clinic karlovac, croatia.  coll antropol. 2010;34 suppl 2:247-251. pmid: 21305740. 18. akdeniz m, hahnel e, ulrich c, blume-peytavi u, kottner j. prevalence and associated factors of skin cancer in aged nursing home residents: a multicenter prevalence study. plos one. 2019;14(4):e0215379. doi: 10.1371/journal.pone.0215379. pmid: 31009466: pmcid: pmc6476496. 19. kartal sp, altunel ct. premalignant skin tumors. akgül a (eds). gerontological/65+ skin and disorders. first edition. ankara: turkish clinics; 2019. pp 108-10. available from: https:// www.turkiyeklinikleri.com/article/en-premalign-deri-tumorleri-85386.html. accessed june 28, 2021 dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):9 49 dermatology practical & conceptual www.derm101.com case presentation after repeated previous consultations, a 73-year-old woman suffering for several months from itchy plaques and nodules on the face and neck presented for her follow-up visit (figures 1, 2). a biopsy had been performed during previous consultations and the histopathologic diagnosis lay between lymphoma and pseudo-lymphoma. the subsequent immunohistochemical assay did not solve the diagnostic problem. dermoscopy of the lesions revealed a perfectly demarcated burrow and, at its end, a scabies mite (figure 3). the diagnosis of scabies was straightforward and confirmed microscopically after scraping test. the eruption remitted completely after appropriate treatment for scabies. discussion the accuracy of dermoscopy for the diagnosis of scabies has been assessed as at least equal to microscopic examination after skin scraping [1,2]. in fact, dermoscopy has the advantage of rapidly screening several lesions of the patient, in contrast to the microscopic examination which is performed by scraping only one or two lesions. given that in otherwise healthy individuals, no more that 4-5 mites exist on the skin at on time point, scanning all the lesions of the patient minimizes the possibility of a false negative result. in our patient, the atypical clinical manifestation and, especially, the distribution of the eruption on the face, misled the clinicians on repeated visits, whereas dermoscopy was not scabies escaping detection until dermoscopy was applied aimilios lallas1, zoe apalla1, elizabeth lazaridou1, elena sotiriou1, efstratios vakirlis1, dimitrios ioannides1 1 first department of dermatology, aristotle university, thessaloniki, greece citation: lallas a, apalla z, lazaridou e, sotiriou e, vakirlis e, ioannides d. scabies escaping detection until dermoscopy was applied. dermatol pract concept. 2017;7(1):9. doi: https://doi.org/10.5826/dpc.0701a09 received: november 13, 2016; accepted: november 26, 2016; published: january 31, 2017 copyright: ©2017 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aimilios lallas, md, msc, phd, first department of dermatology, aristotle university, thessaloniki, greece,124 delfon str, 54643, thessaloniki, greece. tel. 00302313308882; fax. 00302310277979. email: emlallas@gmail.com dermoscopy is already considered a fairly established method for diagnosing scabies. this is because dermoscopy enables the visualization both of the burrow and the mite itself, forming the so-called “jet with a contrail” structure. in the present report we present an extraordinary case of a patient with scabies lesions on the face and neck, which was misdiagnosed during sequential visits and underwent unnecessary surgical diagnostic procedures. finally, the diagnostic problem was solved when dermoscopy was applied. abstract mailto:emlallas@gmail.com 50 observation | dermatol pract concept 2017;7(1):9 2. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol. 2014;170:514–526. performed during the initial visits, because scabies was not even included in the differential diagnosis. this resulted in unnecessary surgical procedures and histopathologic exams, which might have been continued if dermoscopy was not eventually performed. this case highlights a basic principle of dermoscopy application, namely, that dermoscopy should be applied on every skin lesion and not only in clinically preselected cases [2]. references 1. walter b, heukelbach j, fengler g, et al. comparison of dermoscopy, skin scraping, and the adhesive tape test for the diagnosis of scabies in a resource-poor setting. arch dermatol. 2011;147:468– 473. figure 1. a 6-month-old standing pruritic eruption on the face and neck of a 73-year-old woman. [copyright: ©2017 lallas et al.] figure 2. a close-up clinical photo of one of the lesions, highlighting that the eruption consisted of slightly excoriated papules. the clinical differential diagnosis was broad, including discoid lupus erythematosus, sarcoidosis, lymphoma and pseudolymphoma. [copyright: ©2017 lallas et al.] figure 3. dermoscopy revealed the typical pattern for scabies (jet with a contrail), consisting of an evident burrow ending with a triangular brownish projection, corresponding to the mite. the eruption remitted completely after appropriate treatment. [copyright: ©2017 lallas et al.] dermatology: practical and conceptual observation | dermatol pract concept 2017;7(3):7 35 dermatology practical & conceptual www.derm101.com case report a 65-year-old male presented with a pigmented lesion on his left hip, that he had noticed for some months. on examination a 10 x 15-mm asymmetrically shaped dark brown macule was seen (figure 1). dermatoscopically the lesion show asymmetry of patterns and colours. variegated light and dark brown reticular lines are seen in the periphery and white reticular lines in the centre. a structureless white area was extending to the periphery. an asymmetrical lesion with pigmented reticular lines in the periphery and white reticular lines in the centre, together with an eccentric white structureless zone strongly favours a diagnosis of melanoma with regression and dermal fibrosis. another clue to melanoma is the occurrence of gray structures (figure 2) [3]. the lesion was both clinically and dermatoscopically highly suggestive of melanoma and a diagnostic excision was performed. the histological sections showed broad and superficial zone of acanthosis with a reticulated pattern and clusters of mature sebocytes attached to the bases of the anastomosing rete ridges. focal coalescence of sebaceous lobules and papillary dermis fibrosis are also seen (figure 3). based on this constellation of findings the diagnosis of rasd was rendered. immunohistochemistry revealed intact dna mismatch repair proteins (mlh1, msh2, msh6, and pms2). reticulated acanthoma with sebaceous differentiation mimicking melanoma felipe ribeiro1, elizabeth leocadia1, ricardo s. macarenco2, jan lapins3, pascale huet4, bengu nisa akay5, denise steiner1 1 department of dermatology, mogi das cruzes university, mogi das cruzes, brazil 2 department of pathology, hospital israelita albert einstein, são paulo, brazil 3 department of dermatology, karolinska university hospital, stockholm, sweden 4 dermatology, montferrier-sur-lez, france 5 department of dermatology, ankara university, ankara, turkey key words: reticulated acanthoma with sebaceous differentiation, rasd, melanoma, mimicker, dermatoscopy, dermoscopy, histopathology citation: ribeiro f, leocadia e, macarenco rs, lapins j, huet p, akay bn, steiner d. reticulated acanthoma with sebaceous differentiation mimicking melanoma. dermatol pract concept 2017;7(3):7. doi: https://doi.org/10.5826/dpc.0703a07 received: january 11, 2017; accepted: may 27, 2017; published: july 31, 2017 copyright: ©2017 ribeiro et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: felipe ribeiro, md, department of dermatology, mogi das cruzes university, 201 ottavio giannotti street, 71 08773510 mogi das cruzes, são paulo, brazil. tel. + 55 11 981971166 email: rsfeliperibeiro@gmail.com reticulated acanthoma with sebaceous differentiation (rasd) is a rare, benign cutaneous tumor with peculiar histopathologic characteristics [1]. rasd had been described under various synonyms such as superficial epithelioma with sebaceous differentiation, sebocrine adenoma, poroma with sebaceous differentiation, and seborrheic keratosis with sebaceous differentiation [2]. clinical differential diagnosis of rasd includes cutaneous superficial epithelial neoplasia such as bowen’s disease, superficial basal cell carcinoma (bcc) and intraepidermal eccrine poroma [1]. we report the first case of rasd mimicking both clinically and dermoscopically a melanoma. abstract mailto:rsfeliperibeiro@gmail.com 36 observation | dermatol pract concept 2017;7(3):7 to our case, most significantly the occurrence of yellow structures, implicating sebaceous differentiation, something that discussion to our knowledge, this is the first case of rasd mimicking melanoma. there is only one previous report on dermatoscopic features of rasd, that shows some important differences compared figure 1. a 10 x 15 mm asymmetric brown macule on the hip of a 65-year-old male. [copyright: ©2017 ribeiro et al.] were not present in our case [1]. rasd may be rare; however, another possibility is that rasd has been misinterpreted as seborrheic keratosis, and not excised or not regarded as worth reporting [4]. the histology of the present case has all the features characteristic of rasd. muir-torre syndrome (mts) is characterized by the presence of cutaneous sebaceous neoplasia, such as sebaceous adenoma, sebaceous carcinoma, and sebaceoma. patients with mts develop carcinoma of internal organs very frequently, mostly in the gastrointestinal system, and occasionally in the genitourinary system, and a single skin tumor with sebaceous differentiation can be a sign of mts [5,6]. immunohistochemistry has emerged as a practical screening tool for mts. mismatch repair proteins mlh1, msh2, msh6, and pms2 are currently tested for this purpose [7]. most sebaceous neoplasms in mts lack expression of at least one of the abovefigure 3. dermatoscopic findings in an rasd mimicking melanoma. pigmented reticular lines in the periphery. white reticular lines in the center extending into an eccentric white structureless zone. gray structures. no yellow structures indicating sebaceous differentiation can be seen. [copyright: ©2017 ribeiro et al.] figure 2. dermatoscopic findings in an rasd mimicking melanoma. pigmented reticular lines in the periphery. white reticular lines in the center extending into an eccentric white structureless zone. gray structures. no yellow structures indicating sebaceous differentiation can be seen. [copyright: ©2017 ribeiro et al.] observation | dermatol pract concept 2017;7(3):7 37 5. shon w, wolz mm, newman cc, bridges ag. reticulated acanthoma with sebaceous differentiation: another sebaceous neoplasm associated with muir-torre syndrome? australas j dermatol. 2014;55 (4):e71-73. 6. rothenberg j, lambert wc, vail jt jr, nemlick as, schwartz ra. the muirtorre (torre’s) syndrome: the significance of a solitary sebaceous tumor. j am acad dermatol. 1990;23:638–640. 7. jessup cj, redston m, tilton e, reimann jd. importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for muir-torre syndrome. hum pathol. 2016;49:1-9. 8. roberts me, riegert-johnson dl, thomas bc, et al. a clinical scoring system to identify patients with sebaceous neoplasms at risk for the muir-torre variant of lynch syndrome. genet med. 2014;16(9):711-716. icking melanoma both clinically and dermoscopically. references 1. ito t, yoshida y, furue m, yamamoto o. dermoscopic features of reticulated acanthoma (superficial epithelioma) with sebaceous differentiation. eur j dermatol. 2012;22(5):704-706. 2. haake dl, minni jp, nowak m, abenoza p, nousari ch. reticulated acanthoma with sebaceous differentiation. lack of association with muir-torre syndrome. am j dermatopathol. 2009;31(4):391-392. 3. kittler h, rosendahl c, cameron a, tschandl p. dermatoscopy. an algorithmic method based on pattern analysis. vienna: facultas verlags, 2011. 4. fukai k, sowa j, ishii m. reticulated acanthoma with sebaceous differentiation. am j dermatopathol. 2006;28:158. mentioned proteins, while sporadic sebaceous neoplasms are expected to present all four proteins intact (positive) in the neoplastic cells’ nuclei. although the present case was clinically unlikely to be associated with mts [8], a case of rasd has been recently documented in association with mts [5]. thus, immunohistochemistry was performed in order to rule out such association, and it revealed intact (positive) nuclear proteins, yielding a negative screening result for mts. this immunoprofile is in agreement with most previous reports on rasd that studied mismatch repair proteins by immunohistochemistry. in conclusion, we have presented the dermatoscopic findings in an unusual case of rasd and to our knowledge, we describe the first case of rasd mimhttps://www.ncbi.nlm.nih.gov/pubmed/?term=ito%20t%5bauthor%5d&cauthor=true&cauthor_uid=22858895 https://www.ncbi.nlm.nih.gov/pubmed/?term=yoshida%20y%5bauthor%5d&cauthor=true&cauthor_uid=22858895 https://www.ncbi.nlm.nih.gov/pubmed/?term=furue%20m%5bauthor%5d&cauthor=true&cauthor_uid=22858895 https://www.ncbi.nlm.nih.gov/pubmed/?term=yamamoto%20o%5bauthor%5d&cauthor=true&cauthor_uid=22858895 https://www.ncbi.nlm.nih.gov/pubmed/?term=yamamoto%20o%5bauthor%5d&cauthor=true&cauthor_uid=22858895 https://www.ncbi.nlm.nih.gov/pubmed/22858895 https://www.ncbi.nlm.nih.gov/pubmed/22858895 dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023107 1 inflammatory linear verrucous epidermal nevus assessment with in vivo reflectance confocal microscopy: an easy option to consider giulio gualdi1, cesare ariasi2, paolo amerio1, giovanna galdo3, piergiacomo calzavara-pinton2, gaetano licata2 1 dermatologic clinic, department of medicine and aging science, university g d’annunzio chieti-pescara, chieti, italy 2 department of dermatology, university of brescia, asst spedali civili brescia, brescia, italy 3 department of dermatology, aorn san giuseppe moscati, avellino, italy key words: inflammatory linear verrucous epidermal nevus, confocal microcopy, child, non-invasive technology citation: gualdi g, ariasi c, amerio p, galdo g, calzavara-pinton p, licata g. inflammatory linear verrucous epidermal nevus assessment with in vivo reflectance confocal microscopy: an easy option to consider. dermatol pract concept. 2023;13(2):e2023107. doi: https://doi.org/10.5826/dpc.1302a107 accepted: october 21, 2023; published: april 2023 copyright: ©2023 gualdi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gaetano licata, md, department of dermatology, university of brescia, asst spedali civili di brescia, p.le spedali civili 1, 25123, brescia, italy. phone: +393276215976 e-mail gaetano.licata89@gmail.com introduction inflammatory linear verrucous epidermal nevus (ilven) is a rare disorder characterized by an early age onset [1]. it consists of pruritic linear, or whorled array of inflammatory, following blaschko lines [2], papules and/or plaques and histologic features resembling psoriasis or lichenoid dermatitis [3]. the disease is a distinct variety of keratinocytic epidermal nevus that is clinically inflammatory and reflects a phenomenon of mosaicism caused by somatic mutations. we report the case of a 6-year-old boy in which in vivo reflectance confocal microscopy (rcm) allowed  the diagnosis of ilven avoiding an invasive skin biopsy. case presentation a 6-year-old boy was seen for a linear, mild itchy lesion involving the left part of the nose. diagnosed one year earlier as impetigo, after multiple ineffective topical and systemic antibiotic treatments, referred to our clinic for redness and worsening of the lesion. clinical examination showed a linear dyskeratotic erythematous plaque with a slightly pigmented halo and fine superficial desquamation located on the nose (figure 1a). because of the anatomic site and age of the patient, to avoid biopsy he was subjected assessment with hand-held rcm (vivascope 3000). it proved minimal hyperkeratosis, spongiosis (figure 2a, white circle) with a pattern closer to the honeycombed one with thickened, 2 research letter | dermatol pract concept. 2023;13(2):e2023107 figure 1. (a) linear dyskeratotic erythematous plaque with a slightly pigmented halo and fine superficial desquamation involving the columella, tip and bridge of the left part of the nose. (b) clinical picture one months after treatment with hydrocortisone butyrate ointment 0.1% twice a day; almost complete resolution of lesion. figure 2. (a-d) summary of the main features imaged by in vivo reflectance confocal microscopy (rcm) (vivascope 3000) in rcm in inflammatory linear verrucous epidermal nevus. (a) spongiosis (withe circle) with a pattern closer to the honeycombed one with thickened, highly refractive intercellular space between keratinocytes. (b) presence of a single roundish refractive demodex folliculorum (arrow) within the hair follicles and a pattern closer to the honeycombed. (c) at level of the epithelial-connective tissue junction, non-rimed connective tissue papillae were observed. (d) below the basal layer, connective tissue papillae appeared disrupted and confluent in large dark areas (white circle), peculiar signs of the interface dermatitis. research letter | dermatol pract concept. 2023;13(2):e2023107 3 highly refractive intercellular space between keratinocytes (figure 2b). non-rimed connective tissue papillae were observed at the level of the epithelial-connective tissue junction (figure 2c). below the basal layer, connective tissue papillae appeared disrupted and confluent in large dark areas (figure 2d, white circle), peculiar signs of interface dermatitis. based on these and on the clinical features patient was diagnosed with ilven and treatment started at first with hydrocortisone butyrate ointment 0.1% twice a day for one month with good improvement (figure 1b). then was prescribed tacrolimus ointment 0.03% twice a day for another month leading to complete resolution of the lesion. conclusions ilven is a relatively rare disease and remains a clinical-pathological diagnosis. there are numerous differential diagnoses to be taken into consideration such as: other epidermal nevi, darier disease, linear porokeratosis, linear lichen planus, linear psoriasis and lichen striatus. our diagnosis of ilven was based on pathognomonic clinical signs and rcm-assessed pictures of inflammatory lichenoid dermatitis thus excluding both psoriasiform dermatitis and spongiotic dermatitis [4]. in vivo rcm is a non-invasive imaging and appears interesting for assessment of lesion in special areas and in pediatric patients [5,6]. the main limitation of rcm is its penetration in dermis, reaching nowadays 350–400 μm. this prevents imaging of structures located in the deep dermis, especially in cases of hyperpigmented or hyperkeratotic lesions, as, in these cases, there is strong contrast attenuation because of absorption and scattering of light going through those structures. however, the ilven histological characteristics and the thinner skin of the pediatric patient make the use of this non-invasive technology particularly suitable in this case. finally, it is important to underline how the current contact devices can be best used even on a nonflat surface; fast and handy device make it much more practical also for pediatric patients. references 1. wollina u, t chernev g. ilven complete remission after administration o topical corticosteroid (case review). georgian med news. 2017;(263):10-13. pmid: 28452721. 2. barney e, prose ns, ramirez m. inflammatory linear verrucous epidermal nevus treated successfully with crisaborole ointment in a 5-year-old boy. pediatr dermatol. 2019;36(3):404-405. doi: 10.1111/pde.13793. pmid: 30838675. 3. tanita k, fujimura t, sato y, lyu c, aiba s. widely spread unilateral inflammatory linear verrucous epidermal nevus (ilven). case rep dermatol. 2018;10(2):170-175. doi: 10.1159/000489876. pmid: 30022937. pmcid: pmc6047550. 4. csuka ea, ward sc, ekelem c, csuka da, ardigò m, mesinkovska  na. reflectance confocal microscopy, optical coherence tomography, and multiphoton microscopy in inflammatory skin disease diagnosis. lasers surg med. 2021;53(6): 776-797. doi: 10.1002/lsm.23386. pmid: 33527483. 5. scharf c, argenziano g, brancaccio g, licata g, ronchi a, moscarella e. melanocytic or not? dermoscopy and reflectance confocal microscopy for lesions difficult to diagnose: a cross-sectional diagnostic accuracy study. dermatol pract concept. 2021;11(4):e2021127. doi:  10.5826/dpc.1104a127. pmid: 34631270. pmcid: pmc8480465. 6. ko rf, smidt ac, durkin jr. reflectance confocal microscopy in pediatric dermatology: a state-of-the-art review. pediatr dermatol. 2021;38(6):1488-1499. doi: 10.1111/pde.14837. pmid: 34651341. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022108 1 dermatology practical & conceptual clinical, dermoscopic and radiological features of heel stick calcinosis cutis keshavmurthy a. adya1, arun c. inamadar1 1 department of dermatology, venereology and leprosy, shri b m patil medical college hospital and research centre, blde (deemed to be university), karnataka, india key words: calcinosis cutis, dystrophic calcification, dermoscopy, heel-stick injury citation: adya ka, inamadar ac. clinical, dermoscopic and radiological features of heel stick calcinosis cutis. dermatol pract concept. 2022;12(3):e2022108. doi: https://doi.org/10.5826/dpc.1203a108 accepted: november 8, 2021; published: july 2022 copyright: ©2022 adya et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: arun c. inamadar md, department of dermatology, venereology and leprosy, shri b m patil medical college hospital and research centre, blde (deemed to be university), vijayapur 586101, karnataka, india, e-mail: aruninamadar@gmail.com introduction heel-stick calcinosis is a common disorder of infants due to heel prick injury. although the condition is benign and self-resolving, it may cause anxiety and concern to the parents. dermoscopy allows non-invasive confirmation of the diagnosis and differentiates other disorders with similar morphology thus helping in reassuring the parents. case report an 8-month-old male was brought to us with multiple whitish lesions on the soles of both the feet since the past 4 months. on enquiry, parents revealed multiple heel pricks done for blood tests in the past. examination revealed multiple discrete porcelain-white papules and carateriform keratotic papules (figure 1a). polarized dermoscopy using handyscope (fotofinder® systems gmbh) revealed 2 types of lesions homogenous circumscribed white clods and keratotic lesions showing central amorphous yellow and white clods surrounded by thick concentric scales (figure 1b). a diagnosis of calcinosis cutis secondary to heel stick injury was made. plain x-ray revealed multiple white opacities within the soft tissues of the heels (figure 1c). one of the lesions was punctured and chalky white material was expressed out which was dissolved by hydrochloric acid suggesting that it was calcium hydroxyapatite (figure 2, a-c). laboratory tests for calcium, phosphorous and vitamin d were all normal. a final diagnosis of dystrophic calcinosis cutis following heel-stick injury was hence established. as the condition is self-limiting, the parents were reassured about the same. conclusions heel-stick calcinosis is a form of dystrophic calcification following heel pricks. multiple pricks account for majority of the cases although cases following single prick have also been described. release of alkaline phosphate by injured tissue elevates the local ph favoring calcium deposition. the lesions can be solitary, or multiple discrete yellow-white papules or nodules and keratotic lesions which may be seen extruding through the epidermis. the lesions usually regress within about 2-3 years of age [1]. 2 research letter | dermatol pract concept. 2022;12(3):e2022108 dermoscopy of calcinosis cutis exhibits homogenous white areas as described above. the dermoscopy of keratotic lesions as described above highlights the process of trans-epidermal elimination of calcium deposits. warts, callosities and corns can present as keratotic papules on the soles. dermoscopically they show compact keratin, and the warts in addition show red or black dots surrounded by white halo. these lesions are rare in infants and do not show white homogenous material. porokeratotic eccrine ostial and dermal duct nevus (peoddn) presents with keratotic papules with collarette typically involving palms and soles and presenting at birth or in early childhood. the lesions are grouped and frequently along the blaschko lines. dermoscopy of peoddn on palmar skin showing keratin filled pits has been described [2]. hence, discrete lesions and presence of amorphous white substance centrally differentiates heel-stick calcinosis from peoddn. finally, milia-like calcinosis cutis exhibits similar dermoscopic features as described above. it is mostly associated with down syndrome characterized by discrete white papules involving hands and feet. although a fairly well-known entity and the diagnosis essentially clinical, application of dermoscopy in the diagnosis of heel stick calcinosis provides further support and refutes the need for biopsy and/or radiological imaging. references 1. braham sj, gilliam ae. picture of the month: calcified nodule secondary to heel sticks. arch pediatr adolesc med. 2006;160(6):645. doi: 10.1001/archpedi.160.6.645-a. pmid: 16754828. 2. gupta ak, agrawal a, rambhiya k, makhecha m. generalized unilateral porokeratotic eccrine ostial and dermal duct nevus along the lines of blaschko: a rare entit. indian j dermatopathol diagn dermatol. 2019; 6:51-52. doi: 10.4103/ijdpdd. ijdpdd_47_18. figure 2. (a) chalky-white material expressed out of a papule. (b) material as observed under light microscope. (c) complete dissolution of the material was seen on treatment with hydrochloric acid. figure 1. dermoscopy: polarized, x20. (a) multiple discrete white and keratotic papules on the heels. (b) dermoscopy shows well defined homogenous white dots (black arrows) and keratotic lesions with central yellow and white amorphous clods surrounded by concentric thick scales (blue arrows). (c) plain x-ray shows circumscribed opaque densities along the margins of the heel dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022111 1 dermatology practical & conceptual dermoscopy performs an important role to diagnose radiation-induced angiosarcoma on the breast gabriel tagata seleri1, marina riedi guilherme1, ana lúcia de oliveira prestes1, cássio rafael moreira1 1 department of dermatology, municipal health authority of apucarana, paraná, brazil keywords: angiosarcoma, radiotherapy, oncology, dermoscopy citation: seleri gt, guilherme mr, prestes aldo, moreira cr. dermoscopy performs an important role to diagnose radiation-induced angiosarcoma on the breast. dermatol pract concept. 2022;12(3):e2022111. doi: https://doi.org/10.5826/dpc.1203a111 accepted: november 8, 2021; published: july 2022 copyright: ©2022 seleri et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: cássio rafael moreira, miguel simião, 69, apucarana, paraná, brazil e-mail: cassiorafamoreira@gmail.com introduction radiation-induced angiosarcoma (rias) is a rare subtype of angiosarcoma that originates from endothelial cells exposed to radiation. the breast is the most common location of this condition, and the incidence of rias on women treated with breast-conserving surgery and radiotherapy vary from 0.14% to 0.5%, depending upon the study. prognosis is poor, recurrences are common, distant metastasis may occur, 5-year survival rates are between 28%-54% [1]. on early stages it usually presents itself as painless bluered patches on a previously irradiated skin area, that progresses to red or violaceus plaques and eventually irregular borders with a nodular appearance. differential diagnosis includes hematomas, hemangiomas, cellulitis, radiodermitis or atypical vessel lesions. biopsy is the most accurate method for the diagnosis. this is a case report of rias on the breast, with relevant clinical and dermoscopic features. case presentation a 68-year-old caucasian woman presented with a 3 cm, asymptomatic violaceus plaque on the areola of her right breast (figure 1a), 8 years after radiotherapy for the treatment of an invasive ductal carcinoma on the same location. dermoscopy showed a central hemorrhagic crust, surrounded by a purple background, with blue-red globules and shiny-white structures (figure 1b). histopathological examination with the presence of spindle cells proliferation, forming bundles and compact nodules in the dermis, alongside positive immunohistochemistry for ki-67 and cd34 markers, confirmed well-differentiated angiosarcoma (figure 2). conclusions diagnostic of incipient radiation-induced angiosarcoma is difficult due to the ample differential diagnosis and non-specific characteristics of this neoplasm. although none 2 research letter | dermatol pract concept. 2022;12(3):e2022111 figure 1. (a) clinical photo showing a violaceous plaque, with irregular borders on the areola. (b) dermoscopy (dermlite dl4, x10) with purple background, red globules, hemorrhagic crust and shiny white structures. figure 2. (a) histopathological features showing proliferation of spindle cells, arranged in a lobular pattern on the dermis and extravasated red blood cells (h&e, x10). (b) spindle cells pleomorphism and cellular atypia (h&e, x40). immunohistochemical staining with positive cd34 marker (c) and ki-67 marker (d) on the tumor cells, confirming its endothelial origin and high proliferation activity, respectively. research letter | dermatol pract concept. 2022;12(3):e2022111 3 are pathognomonic of rias, dermoscopic patterns are important to establish the vascular origin of the lesion, and can help in the differential diagnosis with other vascular tumors that already have dermoscopic features known as angiokeratoma and kaposi sarcoma [2]. in the present case, dermoscopic findings corroborate those of past reviews, such as variable red, blue or purple structureless areas, white lines and globules most visible on the periphery, reaffirming these as important characteristics in the diagnostic of rias [3]. in conclusion, the clinical history of previous radiation therapy associated with dermoscopic findings provides a high suspicion of rias, which means that incisional biopsy should be performed early for the correct diagnosis and rapid treatment. references 1. bonito fj, de almeida cerejeira d, dahlstedt-ferreira c, oliveira coelho h, rosas r. radiation-induced angiosarcoma of the breast: a review. breast j. 2020;26(3):458–63. doi: 10.1111/ tbj.13504. pmid: 31448482. 2. jaimes n, chen l, dusza sw, et al. clinical and dermoscopic characteristics of desmoplastic melanomas. jama dermatol. 2013;149(8):973–974. doi: 10.1001/jamadermatol.2013.2248 pmid: 23325288 3. figueroa-silva o, argenziano g, lallas a, longo c, piana s, moscarella e. dermoscopic pattern of radiation-induced angiosarcoma (ria). j am acad dermatol. 2015;73(2):e51-e55. doi: 10.1016/j.jaad.2015.04.054. pmid: 26183996. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023080 1 identification of novel dermoscopic patterns for “featureless melanoma”: clinical-pathological correlation salvatore lampitelli1, carmen cantisani1, federica rega1, camilla chello1,2, francesca farnetani2, giovanni pellacani1,2 1 uoc of dermatology, umberto i hospital, sapienza medical school of rome, rome, italy 2 department of dermatology, university of modena and reggio emilia, modena, italy key words: difficult featureless melanoma, 7-point checklist, dermoscopy citation: lampitelli s, cantisani c, rega f, chello c, farnetani f, pellacani g. identification of novel dermoscopic patterns for “featureless melanoma”: clinical-pathological correlation. dermatol pract concept. 2023;13(2):e2023080. doi: https://doi.org/10.5826/ dpc.1302a80 accepted: september 15, 2022; published: april 2023 copyright: ©2023 lampitelli et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: carmen cantisani, uoc of dermatology, umberto i hospital, sapienza medical school of rome viale del policlinico 155, 00161 rome italy. tel: +39-0649976993 email: c.cantisani@policlinicoumberto1.it; carmencantisanister@gmail.com introduction: diagnosis of melanoma can be very difficult because of its phenotypic and histological heterogeneity. difficult-to-diagnose melanoma can be represented by mucosal melanoma, pink lesions, amelanotic melanoma (amelanotic lentigo maligna, amelanotic acral melanoma, desmoplastic melanoma), melanoma arising on sun-damaged facial skin, and “featureless melanoma”. objectives: the aim of the study was to improve the identification of featureless melanoma (scoring  0-2 according to the 7-point-checklist) describing the variegated dermoscopic features and their histopathological correlation. methods: study samples included all melanomas excised based on clinical and/or dermoscopic findings in the period between january 2017 and april 2021. before excisional biopsy, all lesions were recorded by means of digital dermoscopy at the department of dermatology. only lesions with a diagnosis of melanoma and a high quality of dermoscopic images were included in this study. after clinical and dermoscopic evaluation of 7-point checklist score, single dermoscopic and histological features were considered for lesions with a score of 2 or lower and a diagnosis of melanoma (corresponding to dermoscopic featureless melanoma). results: a total of 691 melanomas fulfilled inclusion criteria and were retrieved from the database. the 7-point checklist evaluation identified 19 “negative-featureless” melanoma. the 100% of the lesions with score 1 showed a globular pattern. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023080 introduction melanoma melanoma is one of the most aggressive forms of malignant skin cancer deriving from altered and atypical neural crest-derived melanocytes principally localized in the hair follicles and in the basal layer of the epidermidis, and along the meninges, choroid, and mucosal surfaces too. it accounts about 3% of the overall skin cancers diagnosed each year and can develop from benign nevomelanocytic lesions, or, more frequently, from normal-appearing skin, as result of a complex interplay of genetic, environmental, and constitutional elements [1-3]. the worldwide incidence of cutaneous melanoma has been growing annually with a very rapid rate placing itself as the 15th most common tumor globally [2]. the most important predictive prognostic factor is the type of growth. the radial growth phase (rgp), typical of melanoma in situ, defines a disease which is still localized and restricted to the epidermidis, above the dermal-epidermal junction showing a pagetoid spread within the skin. the vertical growth phase (vgp), further classified into an early and a late stage, is characterized by the presence of dermal tumoral nests, extending, sometimes, into subcutaneous fat. difficult melanomas one of the hardest challenges is the amelanotic melanoma occurring in about 2% of all malignant melanomas. it is more frequent in red hair patients with skin type i, freckles, a sun-sensitive phenotype, a previous history of amelanotic melanoma or lack of naevi on the back [4,5]. in 1999 koch et al defined the amelanotic melanoma as “the great masquerader” referring to the lack of the clinical hallmark of cutaneous melanoma, that is the presence of several amounts of melanic pigment within the tumor, determining misdiagnoses [6]. amelanotic melanoma may be confused with different benign (intradermal naevus, seborrheic keratosis, eczema, actinic keratosis, granuloma annulare, pyogenic granuloma, verruca vulgaris, naevus depigmentosus, scar, dermatofibroma, lymphocytoma cutis) and malignant (basal cell carcinoma, merkel cell carcinoma, bowen disease, keratoacanthoma, atypical fibroxanthoma, extramammary paget disease, malignant fibrous histiocytoma, malignant schwannoma, squamous cell carcinoma) clinical conditions  [5,6]. the most stringent authors define a melanoma truly amelanotic when there is a clinically and dermoscopically lack of pigmentation with melanin in less than 5% of tumor cells on histological examination [5]. any clinical subtypes of cutaneous melanoma may be amelanotic, considering the desmoplastic melanoma as the most frequent type and the subungual site the most common localization. desmoplastic melanoma is a rare subtype with a nodular or a scar-like appearance. a primarily dermal component of spindle cells represents the main histological finding. most frequent in caucasian people aged sixty to seventy years and in sun-exposed areas of head and neck region. desmoplastic melanoma is more likely a sarcoma, considering the local aggressive biological behavior and the predisposition for local and visceral growth [3]. pink lesions often represent a challenging diagnosis for the absence of the identifiable peculiar characteristics using conventional methods, for example, epiluminescence microscopy. they constitute a very wide and heterogeneous group of skin lesions of inflammatory and/or benign/malignant neoplastic origin [7]. dermoscopy is still far from an accurate diagnosis about pink lesions, considering a rapid identification crucial in the case of amelanotic melanoma or, even worse, nodular amelanotic malignant melanoma. in these cases, particular dermoscopy findings include an irregular shaped vascularization (linear, dotted, or globular vessels having an irregular distribution), whitish/depigmented areas, and ulceration [7]. primary mucosal melanoma was first described in 1856 by weber et al [8]. nowadays, despite its rarity, mucosal melanoma is of great interest because of its worse prognosis compared to cutaneous subtype. overall, only 0.8%-3.7% are mucosal melanomas and, contrary to the recent growing incidence of cutaneous melanoma, its incidence tends to stay stable [9]. no association to any viral infections (human herpes viruses, human papilloma viruses, and polyomavirus), ultraviolet (uv) radiation exposure or racial differences. its etio-pathogenesis remains unclear. contrary to cutaneous melanoma, c-kit is overexpressed in about 80% of mucosal melanomas [9]. mucosal melanoma can be localized within the mucosal membranes of the gastrointestinal, respiratory, and genitourinary tract. head and neck are the most common anatomic sites, in which the prognosis is believed to be better [9]. facial pigmented lesions are often equivocal for the particular skin anatomic architecture of the face as a result of conclusions: dermoscopy is still the best diagnostic method for melanoma. the 7-point checklist provides a simplification of standard pattern analysis because of the algorithm based on a scoring system and the lower number of features to recognize. in the daily practice it is more comfortable for many clinicians to keep in mind a list of principles that may help in the decision. original article | dermatol pract concept. 2023;13(2):e2023080 3 the absence of the rete ridges, the importance of adnexal structures and the varying degrees of sun-damaged epidermidis and solar elastosis in the dermis [10]. they commonly show a pseudo-network pattern bordering the unpigmented hair follicle openings [10]. acral lentiginous melanoma is another type of melanoma whose diagnosis is still challenging. its predilection for acral sites determinates a delayed diagnosis at later stages associated to a worse prognosis. an association between mechanical stress and acral melanoma has been proposed, but further investigations are necessary about it [11]. featureless melanoma abcde rule (asymmetry, border, color, diameter, evolving) only provides 64% accuracy, indicating a necessity to have alternative diagnostic tools. the 7-point checklist score provides a useful algorithm for dermoscopy. in 1998 argenziano et al introduced a new elm 7-point checklist [12]. they identified seven standard elm criteria, selected by their prevalence in melanoma cases and their histopathological correlates. according to odds ratios calculated, a score of 2 was given to 3 criteria (odd ratio more than 5) defined as “major” criteria, and a score of 1 was allowed to the remaining 4 criteria (odd ratio lower than 5) called “minor” criteria. a minimum total score of 3 was necessary for diagnosis of melanoma [12,13]. this new diagnostic algorithm revealed a sensitivity of 97% (percentage of dermoscopic images of melanoma scored as melanomas), a specificity of 71% (percentage of dermoscopic images of naevi scored as benign naevi) with a diagnostic accuracy for melanoma of 68%, greater parameters compared to the abcde rule [12]. to increase sensitivity, a 7-point checklist revisited with a lower threshold for surgical excision has been proposed in 2011 by argenziano et al [14]. one point was attributed to each dermoscopic feature (without differentiation between major criteria and minor ones) and the presence of only one finding was sufficient to propose removal. the necessity to introduce an additional diagnostic tool arises from new knowledges about dermoscopy [14]. objectives the aim of the study was to improve the identification of featureless melanoma (scoring 0-2 according to the 7-point checklist) describing the variegated dermoscopic features and their histopathological correlation. methods study samples included all melanomas excised based on clinical and/or dermoscopic findings in the period between january 2017 and april 2021. before excisional biopsy, all lesions were recorded by means of digital dermoscopy at the department of dermatology, university of modena and reggio emilia. only lesions with a diagnosis of melanoma and a high quality of dermoscopic images were included in this study. after clinical and dermoscopic evaluation of 7-point checklist score, single dermoscopic and histological features were considered for lesions with a score of 2 or lower and a diagnosis of melanoma (corresponding to dermoscopic featureless melanoma). the study was conducted according to the criteria set by the declaration of helsinki. instruments for each lesion a complete set of clinical and dermoscopic images, including the whole lesion, along with histopathology were available. dermoscopic images were carried out by means of dermlite photo (3gen®) equipped with a canon g12 camera. dermoscopic criteria the 7-point checklist score was calculated for each lesion as well as the frequencies of each different dermoscopic finding accounting for the score. subsequently, melanomas with a total score of 2 or lower, according the 7-point checklist score, were classified as “featureless melanoma”. histopathological analysis the histopathological analysis was performed by a board-certified pathologist (amc). statistics frequencies for each dermoscopic parameters were calculated in melanomas for each 7-point checklist score. results a total of 691 melanomas fulfilled inclusion criteria and were retrieved from the database. the 7-point checklist evaluation identified 19 “negative-featureless” melanomas scored between 0 and 2, 194 lesions scored between 3 and 4 and 478 lesions scored between 5 and 10 (table 1). in the population with score ranging from 0 to 2, 8t melanomas were not showing any positive dermoscopic clue (figure 1 and 2), 3 presented a score 1, and 8 with total score 2 (6 presented one major feature positive and 2 having a positivity in two minor ones). concerning the subgroup with a score of 3-4, 25 were associated with score 3 (23 presented 1 major feature with a minor one, and in only 2 cases we found a positivity in 3 minor criteria), while 169 had a score of 4. 4 original article | dermatol pract concept. 2023;13(2):e2023080 the atypical network (75%), followed by irregular dots and globules (25%). concerning the population with 7-point checklist score 3, the most representative features were irregular dots and globules (84%) and atypical network (72%), followed by irregular diffuse pigmentation (16%), regression pattern (12%) and blue-whitish veil (12%). in this work we present 19 difficult-to-diagnosemelanomas in which the only dermoscopic evaluation could not play a diagnostic role. invaluable aids to improve sensibility and specificity for melanoma are represented by anamnesis, the ugly duckling sign, the signature naevus concept and clinical-dermoscopic follow-up. in this context, the aim of this study was to identify the most frequent dermoscopic and histopathological features of “featureless melanoma” trying to establish additional findings, too. all tumors, except for a case with score 0 (superficial spreading melanoma with a 0.34 mm breslow thickness), were in situ melanomas. in the population scoring 1, the 100% of the lesions showed a globular pattern. in a published previous work, as in our study, this pattern was found to be the rarest dermoscopic subtype of in situ melanoma (0.04% in the current case series versus 2.6% in the previous one) and never arising on a naevus [15]. frequencies of the dermoscopic features in lesions with the 7-point checklist ranging 0-2 and score 3 are reported in table 2 and table 3, respectively. in the population with a score of 1, the only positive criterion was irregular dots and globules (100%). concerning the population scoring 2, the most frequent feature was table 1. distribution of the study population according to the 7-point checklist score. 7-point checklist score mm % of mm 0 8 1.2% 1 3 0.04% 2 8 1.2% 3 25 3.8% 4 169 24.3% 5 119 17.2% 6 193 28% 7 76 11% 8 39 5.6% 9 33 4.8% 10 18 2.6% tot 691 100% mm = malignant melanoma. figure 1. facial featureless melanoma scoring 0 of a patient sun-damaged skin affecting by rosacea. any melanoma findings are recognizable by dermoscopy. the hmb-45 staining, in the lower part of the right side, identify dermal and hypodermal tumoral nests. figure 2. featureless melanoma with score of 0 showing a regular pigmented pattern. in the right side of the picture, it is possible to see the histopathological image with irregular melanocytic nests along the rete ridges. original article | dermatol pract concept. 2023;13(2):e2023080 5 as peculiar dermoscopic characteristic, crystalline or chrysalis structures. the presence of these findings is highly indicative of invasive melanoma (ticker than those without them) and cutaneous melanoma metastases [18]. conclusions despite most research about dermoscopy has been managed in white skinned populations and few evidence about an equal ability to work well in non-white populations, dermoscopy is still the best diagnostic method for melanoma. the 7-point checklist provides a simplification of standard pattern analysis because of the algorithm based on a scoring system and the lower number of features to recognize. compared with the latter, the specificity of the 7-point checklist method is worse (75% versus 90%) for its propensity to overclassify atypical melanocytic lesions as melanoma. on the other hand, its sensibility is greater (95%), particularly for the early forms of cutaneous melanomas. this algorithm can be learned more easily by nonexpert dermatologists. in the daily practice it is more comfortable for many clinicians to keep in mind a list of principles that trigger excision. in 2012, lallas et al, edited several management rules to recognize some difficult melanomas using an integrating approach between clinical, dermoscopic, and histological examinations [21]). they summarized in seven simple and practical rules: 1) look basically at all lesions, 2) undress high-risk patients (patients with a personal or family history of melanoma or other skin cancers, people under 50 years presenting more than twenty naevi on the arms, patients over the age of 50 years with a chronic solar damage), 3) use the “10 second rule” in single lesions (an approximated period to reach a conclusion in doubtful lesions), 4) compare and monitor multiple moles (considering that each patient has a naevi’s individual phenotype, this principle results very useful in cases of atypical mole syndrome where the previous rule could be ineffective), 5) excise doubtful nodular lesions (especially for nodules positive to blue-black rule, milky-red areas and/or polymorphous vascular pattern), 6) combine clinical and dermoscopic criteria, 7) combine clinical and about melanomas with score 2, three-quarters of the cases presented a reticular pattern, in the remaining two lesions we noticed a globular patterns with additional regression areas and irregular blotches, respectively. this last was an in situ melanoma arising on a compound nevocytic naevus, showing, as additional feature, an inverse network. prominent skin marks (linear hypopigmented furrows with an intersecting pattern) were found in other two cases. according to several authors, the last dermoscopic finding is a helpful indicator to differentiate an early or an in situ melanoma, especially on sun-damages skin, from a benign naevus [16]. supplementary features were considered. in one lesion we noticed angulated lines (gray-brown not intersecting lines that meet at angles larger than 90 degrees and can form polygonal shapes, rhomboids and zigzag pattern [17]. in the subgroup with 0 points, one lesion, not presenting neither classic nor additional features, was arose on a benign melanocytic naevus. two melanomas showed as unique finding the inverse network, one of which having the prominence skin marks, too. borderline positive melanomas scoring 3 manifested mostly irregular dots and globules, followed by atypical network. supplementary features were considered. in two of twenty-five lesions the prominent skin marks were noticed, angulated lines in one case, and another one presenting both findings. in this group we have a case of melanoma, arisen on a compound benign naevus and with a breslow thickness 0.3mm, exhibiting, table 2. frequencies of dermoscopic features in lesions with 7-point checklist score 0-2. dermoscopic features score 0 score 1 score 2 atypical network 6 (75%) blue-whitish veil atypical vessels irregular diffuse pigmentation (blotches) 1 (12.5%) peripheral streaks and/or pseudopods irregular dots and globules 3 (100%) 2 (25%) regression pattern 1 (12.5%) tot 8 3 8 table 3. frequencies of dermoscopic features in lesions with 7-point checklist score 3. dermoscopic features score 3 atypical network 18 (72%) blue-whitish veil 3 (12%) atypical vessels 2 (8%) irregular diffuse pigmentation (blotches) 4 (16%) peripheral streaks and/or pseudopods 1 (4%) irregular dots and globules 21 (84%) regression pattern 3 (12%) tot 25 6 original article | dermatol pract concept. 2023;13(2):e2023080 9. yde ss, sjoegren p, heje m, stolle lb. mucosal melanoma: a literature review. curr oncol rep. 2018;20(3):28. doi: 10.1007/ s11912-018-0675-0. pmid: 29569184. 10. wurm emt, curchin c e s, lambie d, longo c, pellacani, soyer hp. confocal features of equivocal facial lesions on severely sun-damaged skin: four case studies with dermatoscopic, confocal, and histopathologic correlation. j am acad dermatol. 2012;66(3):463-473. doi: 10.1016/j.jaad.2011.02.040. pmid: 21978574. 11. darmawan cc, jo g, montenegro se, et al. early detection of acral melanoma: a review of clinical, dermoscopic, histopathologic, and molecular characteristics. j am acad dermatol. 2019;81(3):805-812. doi: 10.1016/j.jaad.2019.01.081. pmid: 30731177. 12. argenziano g, fabbrocini g, carli p, de giorgi v, sammarco e, delfino m. epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions comparison of the abcd rule of dermatoscopy and a new 7-point checklist based on pattern analysis. arch dermatol. 1998;134(12):1563-1570. doi: 10.1001/archderm.134.12.1563. pmid: 9875194. 13. haenssle ha, korpas b, hansen-hagge c, et al. seven-point checklist for dermatoscopy: performance during 10 years of prospective surveillance of patients at increased melanoma risk. j am acad dermatol. 2010;62(5):785-793. doi: 10.1016/j. jaad.2009.08.049. pmid: 20226567. 14. argenziano g, catricalà c, ardigo m, et al. seven-point checklist of dermoscopy revisited. br j dermatol. 2011;164(4):785-790. doi: 10.1111/j.1365-2133.2010.10194.x. pmid: 21175563. 15. seidenari s, bassoli s, borsari s, et al. variegated dermoscopy of in situ melanoma. dermatology. 2012;224(3):262-270. doi: 10.1159/000338696. pmid: 22653091. 16. lallas a, longo c, manfredini m, et al. accuracy of dermoscopic criteria for the diagnosis of melanoma in situ. jama dermatol. 2018;154(4):414-419. doi: 10.1001/jamadermatol.2017.6447. pmid: 29466542. pmcid: pmc5876885. 17. vanden da, ferreira i, marot l, tromme i. a digital dermoscopy follow-up illustration and a histopathologic correlation for angulated lines in extrafacial lentigo maligna. jama dermatol. 2016;152(2):200-203. doi: 10.1001/jamadermatol.2015.4132. pmid: 26651094. 18. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67(2):194. e1-194.e8. doi: 10.1016/j.jaad.2011.04.039. pmid: 22030020. 19. lallas a, zalaudek i, apalla z, et al. management rules to detect melanoma. dermatology. 2013;226(1):52-60. doi: 10.1159 /000346645. pmid: 23485555. 20. argenziano g, zalaudek i, ferrara g, et al. dermoscopy features of melanoma incognito: indications for biopsy. j am acad dermatol. 2007;56(3):508-513. doi: 10.1016/j.jaad.2006.10.029. pmid: 17113189. histopathological criteria (for example, in cases of spitzoid tumors, or, similarly, in cases of naevus-associated melanoma or lesions showing a high degree of regression) [19]. in our experience, additional four rules can be memorize with the previous seven, that is: 8) biopsy lesions with unspecific pigment pattern (desmoplastic melanoma can be the classic example), 9) biopsy lesions with spitzoid features (especially in adults), 10) biopsy lesions with extensive regression features (it has been demonstrated that in a contest of no melanoma-specific criteria, the probability for a lesion being melanoma growths consistently with the extent of regression seen with dermoscopy), 11) biopsy pink lesions with an atypical vascular pattern [20]. reduction in thickness increases the complexity of melanoma diagnosis. several dermoscopy subgroups of in situ melanoma have been described, assuming a different origin or biological behavior of the tumor [15,20]. further study will be needed to increase sensibility. references 1. slominski a, wortsman j, carlson aj, et al. special article malignant melanoma an update. arch pathol lab med. 2001;125(10):1295-1306. doi: 10.5858/2001-125-1295-mm. pmid: 11570904. 2. leonardi gc, falzone l, salemi r, et al. cutaneous melanoma: from pathogenesis to therapy (review). int j oncol. 2018; 52(4):1071-1080. doi: 10.3892/ijo.2018.4287. pmid: 2953 2857. pmcid: pmc5843392. 3. pavri sn, clune j, ariyan s, narayan d. malignant melanoma: beyond the basics. plast reconstr surg. 2016;138(2):330e-340e. doi: 10.1097/prs.0000000000002367. pmid: 27465194. 4. roseeuw d. the invisible melanoma. j eur acad dermatol venereol. 2001;15(6):506-507. doi: 10.1046/j.1468-3083. 2001.00323.x. pmid: 11843206. 5. gong hz, zheng, hy, li j. amelanotic melanoma. melanoma res. 2019;29(3):221-230. doi: 10.1097/cmr.0000000000000571. pmid: 30672881. 6. koch se, lange jr. amelanotic melanoma: the great masquerader. j am acad dermatol. 2000;42(5 pt 1):731-734. doi: 10.1067/mjd.2000.103981. pmid: 10775846. 7. gill m, gonzález s. enlightening the pink: use of confocal microscopy in pink lesions. dermatol clin. 2016;34(4):443-458. doi: 10.1016/j.det.2016.05.007. pmid: 27692450. 8. mihajlovic m, vlajkovic s, jovanovic p, stefanovic v. primary mucosal melanomas: a comprehensive review. int j clin exp pathol. 2012;5(8):739-753. pmid: 23071856. pmcid: pmc3466987. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022189 1 instructional strategies to enhance dermoscopic image interpretation education: a review of the literature tiffaney tran1, niels k ternov2, jochen weber3, catarina barata4, elizabeth g berry5, hung q doan1, ashfaq a marghoob3, elizabeth v seiverling6, shelly sinclair7, jennifer a stein8, elizabeth r stoos5, martin g tolsgaard9, maya wolfensperger10, ralph p braun10, kelly c nelson1 1 department of dermatology, the university of texas md anderson cancer center, houston, tx, usa 2 department of plastic surgery, herlev hospital, herlev, denmark 3 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 4 institute for systems and robotics; instituto superior técnico, university of lisbon, lisbon, portugal 5 department of dermatology, oregon health & science university, portland, or, usa 6 division of dermatology, maine medical center, portland, me, usa; department of dermatology, tufts university school of medicine, boston, ma, usa 7 department of biology, davidson college, davidson, nc, usa 8 the ronald o. perelman department of dermatology, new york university school of medicine, new york, ny, usa 9 copenhagen academy for medical education and simulation; department of obstetrics, copenhagen university hospital rigshospitalet, copenhagen, denmark 10 department of dermatology, university hospital of zürich, university of zürich, zürich, switzerland key words: dermoscopy education, image interpretation education, instructional strategies, educational methods, gamification citation: tran t, ternov nk, weber j, et al. instructional strategies to enhance dermoscopic image interpretation education: a review of the literature. dermatol pract concept. 2022;12(4):e2022189. doi: https://doi.org/10.5826/dpc.1204a189 accepted: february 13, 2022; published: october 2022 copyright: ©2022 tran et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: kelly c. nelson, md, department of dermatology, the university of texas md anderson cancer center, 1400 pressler street, unit 1452, houston, tx 77030, usa, telephone: 713-745-1113, fax: 713-745-3597, e-mail: kcnelson1@mdanderson.org introduction: in image interpretation education, many educators have shifted away from traditional methods that involve passive instruction and fragmented learning to interactive ones that promote active engagement and integrated knowledge. by training pattern recognition skills in an effective manner, these interactive approaches provide a promising direction for dermoscopy education. objectives: a narrative review of the literature was performed to probe emerging directions in medical image interpretation education that may support dermoscopy education. this article represents the second of a two-part review series. abstract 2 review | dermatol pract concept. 2022;12(4):e2022189 introduction curricular requirements for medical education emphasize the importance of teaching students how to apply acquired knowledge in solving problems and exercising critical judgment [1].1 the ability to manipulate knowledge in this manner is difficult if declarative concepts (e.g., key terms and definitions) are rigid and decontextualized. in the preclinical phase of medical education, learning often entailed attending organized lectures and memorizing isolated facts specific to the organ systems under study [2]. in light of the evolving educational environment, this traditional structure is being supplanted as educators incorporate classroom technology tools and experiment with different approaches (eg group discussions, case presentations, patient contact experiences) [2]. these emerging approaches aim to integrate knowledge across different specialties while improving long-term retention and preparing learners for real-world practice. in medical education, an instructional approach that promotes integrated knowledge is the illness script theory, derived from schema theory. in psychology, “schemas” are bundles of pre-existing knowledge structures in long-term memory, where information is stored indefinitely, and “scripts” refer to those knowledge structures representing generic event sequences that can be retrieved from long-term memory and activated in the appropriate real-world context. for instance, conceptual knowledge pertaining to a specific illness can be quickly retrieved upon recognition of associated triggers, such as a set of symptoms [3]. in contrast with the container model introduced in the first part of this series, the illness script theory promotes integration of declarative knowledge and pattern recognition and reinforces the development of clinical reasoning skills [3]. in image interpretation education, recent shifts away from the container model as the dominant instructional approach have occurred in radiology education [4]. radiograph interpretation represents a complex skill since learners must apply their knowledge of anatomy and pathology and their problem-solving skills to assess each image and reach a diagnosis or conclusion [5]. in addition to absorbing relevant declarative knowledge, learners must restructure and adapt their knowledge for each new image [4]. in radiology education, traditional teaching methods have been gradually replaced by more interactive approaches, such as case-based instruction [6]. here learners are engaged as problem solvers, actively processing and integrating information [6]. as with radiology education, pathology education has also demonstrated similar shifts away from conventional approaches in favor of more interactive ones [4,5]. through an integrated pathology curriculum, learners become more active in their own learning, and pathology more integrated with other medical subjects [7]. as a result, acquired knowledge is more flexible and primed for application across multiple different contexts. similar educational methods that confer conceptual understanding and train pattern recognition through real-life cases represent a promising new direction for dermoscopy education. combined with developments in technology, these reflect contemporary trends in teaching strategies in medical education. this review seeks to explore an array of emerging instructional strategies in image interpretation education that could meaningfully support dermoscopy training programs. objectives this article represents the second part of a two-part review series on instructional approaches in image interpretation education that may translate to dermoscopy education. the first part of this series discussed limitations of traditional approaches based on the container model and considered contemporary learning theories including whole-task learning, methods: to promote innovation in dermoscopy education, the international skin imaging collaborative (isic) assembled an education working group that comprises international dermoscopy experts and educational scientists. based on a preliminary literature review and their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. for each approach, literature searches were performed for relevant articles. results: through a consensus-based approach, the group identified a number of theory-based approaches, as discussed in the first part of this series. the group also acknowledged the role of motivation, metacognition, and early failures in optimizing the learning process. other promising teaching tools included gamification, social media, and perceptual and adaptive learning modules (palms). conclusions: over the years, many dermoscopy educators may have intuitively adopted these instructional strategies in response to learner feedback, personal observations, and changes in the learning environment. for dermoscopy training, palms may be especially valuable in that they provide immediate feedback and adapt the training schedule to the individual’s performance. review | dermatol pract concept. 2022;12(4):e2022189 3 representations of the player progress, and badges are emblems of achievements that can be earned and collected. for instance, a player may earn a badge for reaching a specified number of points or completing activities. both points and badges provide immediate feedback and function as rewards. finally, performance graphs display a player performance over time, focusing on improvements. each of the above elements are highly personalized aspects of the player experience that serve to sustain learner motivation [13]. by providing clear feedback, many of the elements may also enhance self-regulated learning in which learners control their own learning process and monitor their own performance. the performance data generated by player activity enables educators to analyze learner performance in order to optimize the educational program. applications in dermoscopy education in dermoscopy education, educational applications (or “apps”) such as youdermoscopy (developed by meeter congressi in italy), dermachallenge (developed by a team from the medical university of vienna in austria), and diagnosus (developed by centaur labs in the u.s.) have all embraced a gamified approach [14-16]. the youdermoscopy app divides dermoscopic cases into different levels that can be unlocked and provides feedback on learner performance, such as through point rewards [14]. targeted towards dermatologists, dermachallenge features quizzes containing dermosopic images, and for each image, players select the corresponding diagnosis from choices representing common dermoscopic diagnoses [15]. if incorrect, players receive immediate feedback and review the correct answer. quizzes are similarly organized into multiple levels that players may unlock. more broadly, the diagnosus app allows players to practice image interpretation for dermoscopy in addition to other specialties, such as radiology, ophthalmology (retinography), and obstetrics/gynecology (ultrasonography) [16]. while the app contains other noteworthy features such as crowdbased labeling, its educational component is mainly geared towards medical learners, and the dermoscopy section primarily covers melanoma detection training [16]. quizzes, called “missions,” may contain dermoscopic images of nevi that players classify as benign or malignant. once players submit their answer, they can review the correct answer, see the number of users who answered correctly or incorrectly, and participate in the discussion forum for that case [16]. social media overview with the pervasiveness of social media in daily life, educators are also seeking to leverage social media platforms to enhance curriculum design, promoting classroom interaction microlearning, perceptual learning, and adaptive learning. in this second part, we will explore instructional strategies and methods—such as gamification, social media, perceptual and adaptive learning (palms), metacognition, and productive failure—that may also support dermoscopy education. while these strategies and methods could apply to general dermatology education, the scope of this series is limited to dermoscopy education. methods the methods employed for our literature review are described in detail in the first part of this series [8]. this article presents additional instructional strategies identified during the group consensus and literature search processes of this study. the instructional strategies presented in this second part include: gamification, social media, perceptual and adaptive learning modules (palms), metacognition, and productive failure. results gamification overview in gamification, principles of game design are strategically applied to the learning environment to enhance motivation and engagement. this strategy is derived from motivation theory, which emphasizes the importance of individual motivation in the learning process [9]. motivation is defined as the process by which goal-directed activities are initiated and sustained [10]. in games, factors shown to enhance player motivation include challenge, curiosity, autonomy, fantasy, competition, collaboration, and recognition [10]. conveniently, many of these factors may be incorporated into educational games to make the learning process more engaging. by taking advantage of familiar game mechanics and dynamics, games in the educational setting induce goal-directed activity in an artificial social context, producing quantifiable outcomes [11]. the pursuit of clearly defined goals in games has been associated with increased affective measures and decreased cognitive load [12]. in other words, students have more fun when learning in a gamified environment, where they also benefit from the ability to control their own learning process. game design elements to invoke a sense of challenge and novelty among learners, educators may incorporate the following classical elements of game design: avatars, points, badges, performance graphs, and leaderboards [11]. avatars are digital representations of the player within the game and may be as simple as a customizable icon chosen by the player. points are numerical 4 review | dermatol pract concept. 2022;12(4):e2022189 opinions for cases (eg dermoscopic features, dermoscopic diagnoses, treatment plans) and provide their rationale, sometimes supported by references. by facilitating academic discussion, the forum allows users to learn from each other and enables new ideas to emerge. similarly, the ids facebook group offers another virtual space for users to network and discuss interesting cases [23]. on instagram, a popular photoand video-sharing app, the handle for the most popular dermoscopy account is “@dermoscopy_.”24 managed by a team of dermatologists in brazil, the account boasts over 40,000 followers. the content producers frequently post short educational videos and dermoscopic images with the diagnoses or answers in the captions. many dermatology residency programs also employ group text messaging apps such as whatsapp and groupme. in these virtual spaces, trainees may share interesting de-identified dermoscopic cases from their training experiences and solicit ideas from attending physicians and other trainees. many educational apps that incorporate elements of game design also benefit from social media features. these apps may present cases in a game-like format and then incorporate a forum for users to discuss the cases. for example, the “play live” function on the youdermoscopy app allows players to provide an opinion or request assistance from others in real time [14]. the diagnosus app also has a discussion forum for each case that players may use to ask clarifying questions and share their findings [16]. while the advantages of social media include increased learner engagement through opportunities for collaboration, its incorporation into the learning environment may require administrative training and technical support [17,25]. to ensure a high-quality learning experience, administrative staff may need to routinely monitor online activity to ensure accuracy of information and provide further guidance as needed. perceptual and adaptive learning modules (palms) overview perceptual and adaptive learning modules (palms) represent a novel teaching tool in medical education that combines the strengths of both perceptual learning and adaptive learning in order to accelerate expertise [26]. as discussed in the first part of this series, the perceptual learning technique is an interactive approach that introduces a specific visual feature and then exposes learners to numerous examples so that learners can quickly and accurately identify that feature in new cases [27]. the adaptive learning technique optimizes learning outcomes through continuous performance tracking and personalized modifications [28]. this method equates low response times and high accuracy rates with content mastery [28]. and facilitating peer-to-peer learning [17]. educators may use these platforms to either deliver or complement curriculum delivery. as active participants, learners may contribute discussion points and comments and collaborate with peers via group chats. these interactions may occur in either a synchronous fashion with real-time responses or an asynchronous fashion with delayed responses. applications in medical education in a study in china, investigators evaluated the feasibility of a social networking platform called microblog among pharmacotherapy students [18]. learners completed pharmacotherapy case studies through microblog, and the endof-course survey results indicated that a majority of learners agreed that the platform enhanced their learning experience by increasing their active engagement in the course. some shared that compared to meeting face-to-face, meeting online was more convenient, allowing team members to collaborate from any location “with a simple click”[18] however, some still expressed a preference for face-to-face communication, citing issues such as delayed responses and online chatter. instructors needed to balance between maintaining a discreet online presence to promote student participation and monitoring discussion threads for potential issues (eg wrong/misleading information, repetitive comments). ideally, social media platforms in the educational setting create opportunities for students to share ideas and learn from peers [19]. an example in radiology education is a de novo social media platform called collective minds radiology (developed by a team in sweden) [20]. available to download as a smartphone app, this platform enables users to share their expertise and collaborate on challenging radiology cases [20]. while the development of these platforms de novo may be time-consuming and labor-intensive, the incorporation of existing platforms into the learning environment represents an alternative route. for example, an online research methodology course implemented a collaborative space on the twitter platform to enhance student engagement [21]. in this course, students discussed topics of interest on twitter through tweets (text-based posts constrained by 140-280 characters) and course-specific hashtags (indexed keywords or phrases preceded by the “#” symbol). a significant majority of learners in this study agreed that the collaborative groupwork via the social media platform positively contributed to their learning. applications in dermoscopy education as an online platform for dermatologists to discuss interesting dermoscopic cases, the international dermoscopy society (ids) forum represents an example of social media in dermoscopy education [22]. here users can share their review | dermatol pract concept. 2022;12(4):e2022189 5 images in terms of learning outcomes [33]. while an extensive number of unique example images may thus not be necessary for palms, components that seem essential include opportunities for immediate feedback and repetitive practice. metacognition overview metacognition, a term originally coined in the 1970s, refers to the awareness of one’s own cognitive processes, or cognition about cognition [34]. in medical education, learners who apply metacognition reflect on their study strategies and learning outcomes and correct errors in order to improve performance [35]. in becoming more aware of their learning processes, students may strategically allocate their learning efforts and simultaneously reduce their cognitive load. as medical knowledge and healthcare systems continue to evolve, providers must be able to continually assess their own knowledge, performance, and possible biases to maintain good clinical practice in a rapidly changing world [36]. applications in medical education while metacognitive processes may be difficult to measure given their complexities, researchers have developed various instruments to evaluate metacognition and self-regulation, the latter referring to the ability to control one own learning through planning, monitoring, and evaluation [36]. in the literature, the following methods have been adopted for medical education: 1. the metacognitive awareness inventory (mai) measures two broad categories of metacognition, knowledge of cognition and regulation of cognition [37]. 2. the inventory of learning styles (ils) measures aspects of self-regulation, external regulation, and lack of regulation [38]. the self-regulation scale measures the degree to which students reflect on their learning processes, identify the cause of their learning problems, and manage their efforts in achieving their own learning objectives. the external regulation scale measures the degree to which students rely on didactic aids, such as formal learning objectives, and external support, such as feedback and assignments from instructors. the lack of regulation scale concerns the inability of students to regulate learning and the perceived lack of external support. 3. the self-regulated learning perception scale (srlps) measures motivation and action to learning; planning and goal setting; strategies for learning and assessment; and lack of self-directedness [39]. the above instruments may be employed on a routine basis to gain further insight into metacognitive processes and learning experiences. for example, a study on metacognition across four medical schools employed both the mai the combination of these two approaches in palms has the potential to transform education in medical fields that rely on pattern recognition skills. learners using palms may be asked to classify a number of images from a training library after being introduced to a specific visual feature. adaptive algorithms analyze their individual performance — as assessed in terms of response time and accuracy — and make personalized modifications to their future training [29]. learners continue training until they achieve content mastery, demonstrated by their fulfillment of the objective learning criteria. through this training method, learners develop expert-level pattern recognition skills in an efficient manner while learning how to perform relevant clinical tasks. while the perceptual learning and adaptive learning approaches can be applied individually, learning outcomes seem to be optimized when they are strategically combined. applications in medical education in transesophageal echocardiography (tee) and electrocardiography (ekg) interpretation education, palms have enabled learners to develop pattern recognition skills comparable to those of experts. in a non-randomized controlled study on tee interpretation, anesthesiology residents completed palms that showed about 180 video clips, provided feedback, and measured response time and accuracy [30]. compared to both their baseline and the control group, learners in the palm group performed significantly better in terms of accuracy and fluency after six months. in another before-and-after study on ekg interpretation, learners used palms containing over 400 unique ekg tracings and similarly retained accuracy and fluency gains after one year compared to their baseline [31]. in dermatology education, palms have also been successful in training pattern recognition, as demonstrated in a before-and-after study among medical students [32]. for different visual features, the palms presented example images in a flashcard style and measured response time and accuracy. as learner performance improved, images from that category were spaced further apart to assess long-term retention. applications in dermoscopy education palms may be developed for dermoscopy education in which educators teach key dermoscopic features for common dermatologic diagnoses and then expose learners to numerous example images for each feature. learners practice identifying features on new images and receive feedback, while adaptive algorithms measure response times and accuracy rates and retire specific learning concepts based on objective mastery criteria. to promote optimal learning, the number of example images required for these modules remains to be explored. a study on radiograph interpretation found that reusing images was similarly effective to only using unique 6 review | dermatol pract concept. 2022;12(4):e2022189 productive failure overview productive failure is a relatively novel concept in education that uses early failures to activate retrieval of prior knowledge and promote problem-solving skills [43]. it plays on the proverbial wisdom of failing before succeeding and encourages creative risk-taking [44]. this method is conceptualized as a two-phase process [43]. in the first phase, learners are given a challenging problem to solve on their own or in groups prior to any, or minimal, didactic training (generation and exploration). after struggling to generate their own solutions to the challenging problem, learners are provided formal training (consolidation and knowledge assembly). the learner initial struggle with the challenging problem may facilitate conceptual understanding and meaningful future learning [45]. learners who are prepared for future learning demonstrate the ability to apply key learning concepts in solving new problems [45]. by inducing early failures within a safe learning environment, productive failure may create conditions in which learners become more motivated to obtain and retain a solution to the problem given the effort already invested into solving it [46]. this phenomenon is known as the endowment effect: once learners endow a problem with resources, such as time and effort, it may become more emotionally valuable to know and learn the solution [46]. in a testing-oriented learning environment, instructional design that incorporates productive failure may also benefit from the testing effect, which refers to the positive effects of test taking on long-term memory and knowledge retention [47]. while the challenging problem is not necessarily presented as a test, students may perceive it as a form of assessment as they practice retrieving their prior knowledge. though these difficult exercises may hamper learning performance in the short run, they may improve learning outcomes in the long run [48]. applications in medical education in implementing the productive failure approach, it is important that students actively generate mistakes themselves rather than observe the mistakes of others [49]. yet, the productive failure approach may be uncomfortable for learners with strong aversion to failure. to minimize negative psychological consequences of failure, instructors may apply a classroom strategy called error management training in which errors are framed as “positive” occurrences and natural byproducts of the learning process [50]. in a randomized study, medical students assigned to error management training were encouraged to probe freely, make errors during ultrasound practice, and reflect on their errors [50]. in a simulation-based test conducted a week later with real patients, students in the error management arm performed better than those in the error avoidance arm. and srlps and found that students in the clinical phase of their training demonstrated higher levels of metacognition, especially in terms of planning and goal setting, compared to those in the preclinical phase [39]. students enrolled at schools that applied learner-centered teaching methods, such as problem-based learning, also displayed higher levels of metacognition compared those learning via conventional methods [39]. similar scales may be employed in dermoscopy education to assess changes in metacognitive awareness over the course of a training program. applications in dermoscopy education a proposed strategy to prime metacognitive awareness in dermoscopy learners involves prospective judgments of learning (jols) in which learners rate how likely they would remember an item on a test [40]. the act of making jols has been shown to enhance long-term memory and improve learning performance on cued recall tests [41]. in dermoscopy education, this strategy may be applied by prompting learners to rate their level of confidence in answering a question, such as whether a dermoscopic image contains a specific feature. learners may track changes in their performance as well as changes in their confidence throughout the training program in order to better understand their strengths and weaknesses. metacognition allows learners to more actively engage in their own learning as they consider their knowledge, personal abilities, and learning strategies [42]. to better understand their strengths and weaknesses for metacognitive processes, learners require some form of feedback on their performance. digital solutions, such as mobile apps, may facilitate metacognitive awareness through autogenerated displays of performance data, encouraging proactive adjustments of learning strategies. in incorporating elements of game design, the process of reflecting on learning progress may become more engaging for both learners and educators. beyond the classroom setting, learners may also contemplate instances of cognitive error in real-life clinical practice. cognitive errors specific to skin cancer diagnosis include inattentional blindness (overlooking a melanoma) and diagnostic error (evaluating a melanoma but incorrectly diagnosing it as a benign skin growth). when presented with feedback and performance data, learners may reflect upon errors in their learning strategies and adjust accordingly. in real-life clinical practice, most expert dermoscopists describe systematically capturing dermoscopic images of all biopsied lesions and then reviewing those images when their clinical diagnosis is discordant with the histopathologic diagnosis. in reviewing the images, overlooked clues may be identified, improving the provider proficiency. metacognitive awareness thus has the potential to improve performance and long-term learning outcomes in the clinical setting. review | dermatol pract concept. 2022;12(4):e2022189 7 conclusions a summary of the instructional strategies and methods explored in the second part of this review series is included in tables 1 and 2. over the years, many dermoscopy educators may have intuitively adopted these approaches in response to learner feedback, personal observations, and changes in the learning environment. in dermoscopy education, the strategic integration of these emerging approaches may support the development of pattern recognition skills, such as global interpretation and holistic processing. in light of our review, we envision a hypothetical dermoscopy training program with active learning strategies informed by contemporary learning theories. in this program, learning concepts, such as a specific diagnosis, could be organized as their own unit, and each unit could be prefaced by a challenging problem that simulates productive failure and activates problem-solving processes. for each diagnosis, learners could learn and review educational content using palms that teach key diagnostic features and expose technology tools may also ease learners aversion to failure by creating a low-stakes learning environment, allowing students to explore new problems in a safe and non-threatening setting. the use of technology enables small failures to be “contained and managed” within an external system [44]. applications in dermoscopy education productive failure recognizes the inherent value of mistakes and the educational utility of errors. by inducing early failures within a safe learning environment and activating the problem-solving process, productive failure can be an effective teaching tool. in dermoscopy education, productive failure can be implemented by providing challenging cases before each module, followed by feedback and guidance. this will help activate a shift towards planning and goal-setting and probe metacognitive awareness of potential weaknesses. incorporation of technology tools may also help establish a safe learning environment that permits learners to make mistakes and understand their mistakes, spurring them towards later success in their learning journey. table 1. summary of the instructional methods presented in the second part of this review series plus examples of existing or potential applications in dermoscopy education. educational method description application(s) in dermoscopy education gamification • factors that contribute to learner motivation include challenge, curiosity, autonomy, fantasy, competition, collaboration, and recognition. • in gamification, principles of motivation theory and elements of game design are applied to the educational context to enhance learner engagement and promote goal-directed learning. existing applications • youdermoscopy, created and developed by meeter congressi srl • dermachallenge (dermonaut), created by h. kittler, p. tschandl, and c. rinner • diagnosus, created and developed by centaur labs palms • palms combine both perceptual learning techniques and adaptive learning algorithms to efficiently train pattern recognition skills. • learners classify unique images and receive immediate visual feedback, and adaptive algorithms determine whether to re-sequence or retire specific learning concepts. potential application • dermoscopy palms: • educators teach key diagnostic features and expose learners to numerous example images • learners identify features on new images and receive feedback • adaptive algorithms retire specific learning concepts based on objective mastery criteria social media • social media platforms are leveraged by educators to increase learner engagement and foster peer-to-peer interaction. • learners benefit from opportunities for collaboration on cases plus the convenience of a web-based platform. • disadvantages may include delayed responses, poor quality of interaction, and wrong or misleading information from peers. existing applications • ids forum • facebook pages (e.g., ids page) • instagram accounts (e.g., @dermoscopy_) • whatsapp groups (e.g., dermatology trainee groups) ids = international dermoscopy society; palms = perceptual and adaptive learning modules. 8 review | dermatol pract concept. 2022;12(4):e2022189 schedule to the individual’s performance. the development of technology tools that enable the integration of these different approaches in dermoscopy education will greatly facilitate endeavors to optimize knowledge acquisition and skills development. references 1. liason committee on medical education (lcme). functions and structure of a medical school: standards for accreditation of medical education programs leading to the md degree. 2017:40. available from https://medicine.vtc.vt.edu/content/ dam/medicine_vtc_vt_edu/about/accreditation/2018-19_ functions-and-structure.pdf 2. sadofsky m, knollmann-ritschel b, conran rm, prystowsky mb. national standards in pathology education: developing competencies for integrated medical school curricula. arch pathol lab med. 2014;138(3):328-332. doi:10.5858/arpa .2013-0404-ra. pmid: 24576027. 3. lubarsky s, dory v, audétat mc, custers e, charlin b. using script theory to cultivate illness script formation and clinical reasoning in health professions education. can med educ j. 2015;6(2):e61-e70. pmid: 27004079. pmcid: pmc4795084. 4. linaker kl. pedagogical approaches to diagnostic imaging education: a narrative review of the literature. j chiropr humanit. 2015;22(1):9-16. doi:10.1016/j.echu.2015.09.005. pmid: 26770173. pmcid: pmc4685235. 5. murdoch eaton d, cottrell d. structured teaching methods enhance skill acquisition but not problemsolving abilities: an evaluation of the ‘silent run through’. med educ. jan 1999;33(1):19-23. doi:10.1046/j.1365-2923.1999.00265.x. pmid: 10211272. 6. erinjeri jp, bhalla s. redefining radiology education for first-year medical students: shifting from a passive to an active case-based learners to numerous example images. learners identify features on new images and receive feedback, and adaptive algorithms retire specific learning concepts based on objective mastery criteria. the palms may involve elements of game design such as points and badges that enhance learner engagement. the program could also be supplemented by group forums, hosted either in-person or on social media platforms, where learners collaborate with their peers on challenging cases. using real-time feedback and performance data from multiple components of the course, learners may apply metacognitive processes to identify strengths and weaknesses and modify their learning strategies. this hypothetical program represents just one way to apply active learning strategies in dermoscopic image interpretation education. for a complex multi-component program, technical challenges are to be expected, but existing technology tools, such as virtual delivery formats and smartphone apps, may represent smart solutions to these challenges. as medical educators seek to apply innovative methods to dermoscopy education, the development of appropriate technology will support the seamless integration of multiple methods. collectively, these emerging approaches in image interpretation education illuminate an exciting direction for the future of dermoscopy education. compared to traditional approaches, these strategies may enable the dermoscopy learner to develop expert-level pattern recognition skills more effectively. palms may be especially valuable in that they provide immediate feedback and adapt the training table 2. summary of the educational concepts presented in the second part of this review series plus examples of existing or potential applications in dermoscopy education. educational concept description application(s) in dermoscopy education metacognition • learners who apply metacognition (awareness of one own cognitive processes) reflect on their learning processes and learning outcomes. • when presented with visual feedback and performance data, learners may identify potential errors in their learning strategies and adjust accordingly. potential application • jols: learners “bet” on whether they will remember a given item or rate their level of confidence in answering a question (e.g., whether 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dermatology, shiraz university of medical sciences, shiraz, iran 2 shiraz paramedical school, shiraz university of medical sciences, shiraz, iran 3 student research committee, shiraz university of medical sciences, shiraz, iran 4 school of medicine, shiraz university of medical sciences, shiraz, iran 5 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran key words: platelet-rich fibrin matrix, skin, cosmetics citation: ahmadi mahmoodabadi r, golafshan ah, pezeshkian f, shahriarirad r, namazi m. evaluation of the effect of platelet rich fibrin matrix in the correction of periorbital wrinkles: an experimental clinical trial. dermatol pract concept. 2023;13(1):e2023050. doi: https://doi.org/10.5826/dpc.1301a50 accepted: august 23, 2022; published: january 2023 copyright: ©2023 ahmadi mahmoodabadi et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: mohammadreza namazi; molecular dermatology research center, shiraz university of medical sciences, shiraz, iran; e-mail: namazi_mr@yahoo.com introduction: skin rejuvenation techniques have gained substantial popularity due to increased life expectancy over recent years. platelet-rich fibrin matrix (prfm) is the new generation of platelet aggregate products that have surfaced in recent years to treat skin aging. objectives: we intend to use prf to correct periorbital wrinkles in 15 volunteers and evaluate its effectiveness in this study. methods: to evaluate the efficacy of prfm intervention, eight men and women over the age of thirty entered our study. blood samples were taken and were immediately centrifuged at 700rpm for 5 minutes. prfm was extracted from the plasma and injected at the sub-dermis site in periorbital areas. the initial severity of periorbital wrinkles was determined by visioface 1000d, and obtained data were delivered to the statistical unit for statistical analysis. scoring and evaluation were based on tissue volume and depth and were measured before and twelve weeks after injection. adverse effects were also taken into consideration. results: the results demonstrated noticeable improvement in deep, fine, and small wrinkles, periocular hyperpigmentation, and overall skin freshness of the injection site. the subjects had swelling in the injection site for up to one day after the injection, which resolved without complications. conclusions: prfm was observed to have potential in skin rejuvenation, demonstrating promising outcomes in terms of safety and long-term effects in improving skin condition. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023050 introduction throughout the years, concerns regarding skin aging have increased substantially, even affecting the young generations due to increased life expectancy [1]. the dermis, the inner layer of skin, which mainly consists of collagen and elastin, has the role of forming skin structure. the aging process destructs the elasticity of these fibers and reduces the production of hyaluronic acid; thus, skin aging results from a lack of elasticity, collagen bundle fragility, and fragmentation [2, 3]. alongside intrinsic factors, environmental factors such as chemical exposure, ultraviolet radiation, smoking, and psychological changes also play a noticeable part in the aging process [3, 4]. some studies have discussed the possible role of reactive oxygen species (ros) in leading the skin aging process; however, despite the endeavors to discover the underlying mechanism, its pathogenesis is yet to be fully comprehended [5]. skin aging is categorized into two subgroups, which are intrinsic and extrinsic aging. intrinsic aging progresses with age and can be described by epidermal thinning and fine wrinkles. however, deep wrinkles, hyperpigmentation, and skin laxity can be observed in extrinsic skin aging, which is greatly impacted by chronic sun exposure. all in all, skin wrinkles are the hallmark of skin aging [4, 6]. in recent years, many exogenous filler materials have been put to the test in the hope of improving skin wrinkles by volume augmentation. the mainstay of filler disadvantages is its absorbable nature, which reduces its effect over time. among these methods, platelet-rich plasma (prp) injection has recently attracted significant attention. prp consists of concentrated platelet and growth factors obtained via venous blood centrifuge [7]. platelet-rich fibrin matrix (prfm) is the new prp generation that is richer in growth factor concentration, enabling it to have a significantly better outcome in stimulating angiogenesis, tissue regeneration, and wound healing. moreover, prfm induces mesenchymal stem cell (msc) migration to the site of injection, which bears imperative regenerative function [2]. currently, various exogenous fillers are utilized globally, including in iran. high cost, owing to the exogenous nature of the filler and transient side effects such as edema, erythema, encapsulation, granuloma formation, and even chronic or delayed infection, minimizes its popularity [8]. conclusively, prf as a natural autologous filler has the potential to be a safe candidate with long-lasting effects. objectives several studies have concluded that prf is an effective route in reducing skin wrinkles with minimal side effects. its side effects are mainly limited to transient erythema at the injection site [9]. this study intends to use prf to correct periorbital wrinkles in 15 volunteers and evaluate its effectiveness. methods study design and participants in this prospective clinical trial, sixteen adult women and men over the 30-year-old with facial wrinkles who volunteered to participate were included in the study. participants were excluded in cases younger than 30 years old, significant past medical history, such as connective tissue disorder, myocardial infarction, hypertension, pregnancy, and use of immunomodulatory or anticoagulation (e.g., aspirin, warfarin) medication. the purpose of the study and all side effects of the intervention were clearly explained to all participants. they were assured their information would remain confidential, and they were permitted to withdraw from the study if they requested. subsequently, written informed consent was obtained from all patients. the sample size was estimated based on a study by sclafani et al [10], based on the mean wrinkles assessment score before and after the intervention, taking into account the first type error of 5%, 80% power, and an effect size of 0.8, calculating to a total of 15 participants. intervention for intervention, after evaluating the patient’s medication and drug history, the total depth of wrinkles before injection was measured with the visophysis device. decosept and a tourniquet were applied, and a 15cc blood sample was taken with a syringe at a 15-degree angle from the brachial vein, transferred to three 5cc tubes, and immediately centrifuged at 700 rpm for 5 minutes. then, using a canola, except for 1 cm above the tubes, the rest of the plasma, which had a gel-like consistency, was transferred to a 5-cc sterile syringe. after this, prf was transferred to 1 cc syringes by sterile connection. simultaneously with the beginning of the blood collection process, local anesthesia (xyla p cream, tehran chemie) was used at the injection site. the duration of local anesthesia was at least 30 to 50 minutes, based on the patients’ anesthesia capacity. after sterilizing the injection site with betadine, a 3cc prf solution was injected into the wrinkles around the eyes with a canola number 27 on both sides. the injection was performed at the sub-dermis site and in one session. the patients were advised to visit our clinic in case of delayed alleviation of swelling or adverse effects, such as infection. also, since the effectiveness of prf was to be evaluated in our study, the use of creams or other products was not recommended. participants were also informed that they could also be present at work on the same day of the procedure without any problems. original article | dermatol pract concept. 2023;13(1):e2023050 3 outcome assessment the initial severity of periorbital wrinkles was determined by visioface 1000d (ck electronic, manufactured in germany), and obtained data were delivered to the statistical unit for statistical analysis. scoring and evaluation were based on tissue volume and depth and were measured before and twelve weeks after injection. patients were also advised to visit in case of developing any complications. data analysis data were entered into spss version 21 and subsequently analyzed. an independent sample t-test was used to evaluate the difference in tissue volume among the groups. a p-value of less than 0.05 was considered statistically significant. ethical considerations the study was approved by the research ethics committee of the shiraz university of medical sciences and was conducted in compliance with the relevant guidelines and regulations and the declaration of helsinki. written informed consent was obtained from the patients in our study. the purpose of this research was completely explained to the patients, and they were assured that their information would be kept confidential by the researcher. the present study was approved by the medical ethics committee of the academy (ethical code: ir.sums.med.rec.1400.480) and registered in the clinical trials database (code: irct20220218054054n1). results sixteen patients, consisting of eight males and eight females, were included in our study. each participant was evaluated based on changes in the left and right side periorbital wrinkles after prf injection. the subjects had swelling in the injection site for up to one day after the injection, which resolved without complications. we measured tissue depth with a visophysis device before and twelve weeks after injection. during this period, none of the people had any complications and all were completely satisfied. the tissue volume score of the participants included in our study is demonstrated in figure 1. also, figure 2 demonstrates the cosmetic appearance of the results of our study. there was no significant difference among the male and female groups regarding tissue volume before injection at both sides. (p=0.964 and 0.240 for right and left, respectively). furthermore, as demonstrated in table 1, the tissue volume size on both sides significantly decreased, both in males and females, after prf injection (table 1). however, there was no significant difference among males and females regarding tissue volume after injection (p=0.784 and 0.427, for right and left, respectively) or amount of tissue volume change (p=0.828 and 0.0339, for right and left, respectively) it should be noted that following prf injection, in addition to improving deep wrinkles, noticeable improvement was observed in fine and small wrinkles, periocular hyperpigmentation, and overall skin freshness of the injection site. all subjective reports among our participants reported satisfaction and were eager to repeat and recommend this procedure. discussion in recent years, platelet concentrates injection has gained global popularity, which, combined with the increased demand for skin rejuvenation techniques, calls for further clinical assessment of the safety and function of these products. prf is the new evolutionary face of platelet-rich aggregates [11]. this study puts the effect of prf under conduction and observed significant improvement in periorbital skin rejuvenation accompanied by significant patient satisfaction. pa ti en t 1 r pa ti en t 1 l pa ti en t 2 r pa ti en t 2 l pa ti en t 3 r pa ti en t 3 l pa ti en t 4 r pa ti en t 4 l pa ti en t 5 r pa ti en t 5 l pa ti en t 6 r pa ti en t 6 l pa ti en t 7 r pa ti en t 7 l pa ti en t 8 r pa ti en t 8 l pa ti en t 9 r pa ti en t 9 l pa ti en t 1 0r pa ti en t 1 0l pa ti en t 1 1r pa ti en t 1 1l pa ti en t 1 2r pa ti en t 1 2l pa ti en t 1 3r pa ti en t 1 3l pa ti en t 1 4r pa ti en t 1 4l pa ti en t 1 5r pa ti en t 1 5l pa ti en t 1 6r pa ti en t 1 7l 0 5 10 15 20 25 30 14 12 22 26 10 10 10 10 10 10 10 10 11 11 11 11 11 11 17 15 15 15 15 14 14 14 14 18 18 21 23 25 21 14 14 14 14 14 13 13 13 13 12 12 12 12 18 18 16 8 8 8 8 8 9 9 9 before after 9 9 9 9 9 7 7 figure 1. changes in tissue volume before and after platelet-rich fibrin injection among females (patients 1 to 8) and males (patients 9 to 16). 4 original article | dermatol pract concept. 2023;13(1):e2023050 device. the results revealed significant improvement in deep wrinkles in all candidates. furthermore, noticeable improvements were also noted in fine and small periorbital wrinkles. this result is also in line with previous studies on the benefits of prf [11]. along with the diminishing wrinkles, improvement in skin hyperpigmentation and overall freshness were also of significance. maisel-campbell et al. conducted a systematic review of the benefits of prp injection and observed significant improvement in skin texture through different studies  [14]. a chinese study conducted on the effect of prp injection also concluded that skin quality was significantly enhanced in participants with a substantial decline in wrinkles, pores, and texture. furthermore, prp treatment was detected to inhibit uv-b-induced tyrosinase and metalloproteinase-1 (mmp-1) upregulation, which along with tropoelastin and fibrillin induction, results in photoaging enhancement [15]. the benefits of platelet aggregate products take root from not only its high concentration of growth factors, but also its gelatin constituents. the gelatin part has the potential to bring elasticity and a good support system for wrinkles, cavities, and skin relaxation[16]. in addition, these platelet aggregate products contain cell adhesion proteins prf, the second generation of platelet concentrates, is superior to prp in numerous aspects. first of all, prf preparation consists of only one centrifugation step, making it simpler than prp preparation [12]. as a result of declined centrifuge speed, prf has been observed to contain higher volumes of growth factors, leukocytes, fibrin, and platelets than prp, resulting in a more boosted growth factor-mediated functional aftermath [11]. secondly, prf is completely autologous and does not contain any exogenous additives, which supports the natural physiologic polymerization of fibrin. growth factor binding and platelet capture are facilitated via the three-dimensional fibrin structure of prf that results in the enhancement of the gradual and long-term release of cytokines and growth factors. moreover, this fibrin mesh is also responsible for cell proliferation and differentiation and the formation of new blood vessels [11, 12]. finally, prf prompts cell proliferation, migration, differentiation, and adhesion accompanied by anti-inflammatory properties that further support its therapeutic aptitude in bone regeneration, wound healing, improving scar appearance, and stimulating hair growth [2, 13]. this study utilized a prf solution for periorbital wrinkles, and the depth of the wrinkles was assessed via a visophysis figure 2. results of platelet-rich fibrin matrix in the correction of periorbital wrinkles. table 1. tissue volume score and changes based on gender and laterality. gender right left before after change p-value* before after change p-value* female; n= 15 14.88 ± 6.13 11.00 ± 3.59 3.88 ± 3.94 0.027 13.13 ± 3.23 10.50 ± 2.88 2.63 ± 2.67 0.027 male; n=15 15.00 ± 4.75 11.50 ± 3.59 3.50 ± 2.73 0.008 15.75 ± 5.12 11.63 ± 2.62 4.13 ± 3.36 0.010 p-value* 0.964 0.784 0.828 0.240 0.427 0.339 * independent sample t-test original article | dermatol pract concept. 2023;13(1):e2023050 5 higher sample sizes are warranted to understand the extent of improvement and also possible side effects. references 1. de miranda rb, weimer p, rossi rc. effects of hydrolyzed collagen supplementation on skin aging: a systematic review and meta-analysis. int j dermatol. dec 2021;60(12):1449-1461. doi:10.1111/ijd.15518 2. karimi k, rockwell h. the benefits of platelet-rich fibrin. facial plastic surgery clinics of north america. aug 2019;27(3):331-340. doi:10.1016/j.fsc.2019.03.005 3. evans m, lewis ed, zakaria n, pelipyagina t, guthrie n. a randomized, triple-blind, placebo-controlled, parallel study to evaluate the efficacy of a freshwater marine collagen on skin wrinkles and elasticity. journal of cosmetic dermatology. mar 2021;20(3):825-834. doi:10.1111/jocd.13676 4. liang zj, lu x, li dq, et al. precise intradermal injection of nanofat-derived stromal cells combined with platelet-rich fibrin improves the efficacy of facial skin rejuvenation. cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018;47(1):316-329. doi:10.1159/000489809 5. gu y, han j, jiang c, zhang y. biomarkers, oxidative stress and autophagy in skin aging. ageing res rev. may 2020;59:101036. doi:10.1016/j.arr.2020.101036 6. shin jw, kwon sh, choi jy, et al. molecular mechanisms of dermal aging and antiaging approaches. international journal of molecular sciences. apr 29 2019;20(9)doi:10.3390/ ijms20092126 7. gentile p, garcovich s. systematic review-the potential implications of different platelet-rich plasma (prp) concentrations in regenerative medicine for tissue repair. international journal of molecular sciences. aug 9 2020;21(16):5702. doi:10.3390/ ijms21165702 8. davies c, miron rj. prf in facial esthetics. quintessence publishing company, incorporated; 2020. 9. marliana a, setyopranoto i, setyaningsih i, rhatomy s. the effect of pulsed radiofrequency on radicular pain in lumbal herniated nucleus pulposus: a systematic review and meta-analysis. anesth pain med. apr 2021;11(2):e111420. doi:10.5812/aapm.111420 10. sclafani ap. platelet-rich fibrin matrix for improvement of deep nasolabial folds. journal of cosmetic dermatology. mar 2010;9(1):66-71. doi:10.1111/j.1473-2165.2010.00486.x 11. hassan h, quinlan dj, ghanem a. injectable platelet-rich fibrin for facial rejuvenation: a prospective, single-center study. journal of cosmetic dermatology. dec 2020;19(12):3213-3221. doi:10.1111/jocd.13692 12. vesala a-m, nacopoulos c, gkouskou k, amenta f, ruga e. microneedling with injectable platelet-rich fibrin for facial rejuvenation. 2021;doi:https://doi.org/10.20517/2347-9264.2021.57 13. strauss fj, nasirzade j, kargarpoor z, stahli a, gruber r. effect of platelet-rich fibrin on cell proliferation, migration, differentiation, inflammation, and osteoclastogenesis: a systematic review of in vitro studies. clinical oral investigations. feb 2020;24(2):569-584. doi:10.1007/s00784-019-03156-9 14. maisel-campbell al, ismail a, reynolds ka, et al. a systematic review of the safety and effectiveness of platelet-rich plasma (prp) which could help keep the skin tight and smooth [15]. the decline in hyperpigmentation that was observed in our study is consistent with previous studies and is due to the fact that platelet aggregate products increase skin thickness and ameliorate collagen content which results in reduced pigmentation [11, 14, 15]. the patients in the present study had a 12-week follow-up session to evaluate their skin quality post-prf injection. the periorbital wrinkles, skin hyperpigmentation, and overall freshness were held down, therefore, adding support to the long-term effect of the prf procedure. liang et al. did a 6,12,24-month follow-up after nano fat-prf injection and observed that patient satisfaction was of significant worth even after the 12-month mark [4]. all in all, these findings shed light on the prf’s potential as a long-term and safe skin rejuvenating technique. skin aging can substantially impact each individual's quality of life. youth, health, and activity are three major ideals that are starting to grow in the community’s lives. therefore, skin wrinkles can have psychosocial outcomes in people's lives. a study conducted in germany concluded that those who underwent cosmetic procedures had higher quality of life [17]. conclusively, prf as a potent procedure for skin rejuvenation may, in turn, advance the quality of life in the population. throughout our study, adverse effects of prf were taken into consideration, and the reports were promising as no adverse effects were seen other than the first-day injection site edema. this finding was in line with previous studies [11]. over the literature, no major adverse reactions were reported, and the side effects are observed to be only limited to slight bruising in the injection site [4, 11, 18]. some limitations should be addressed. due to the covid-19 pandemic, patients were only evaluated after 12 weeks, and frequent visits were not applied, limiting our statistical power for the clinical outcomes assessment, while no objective documentation of their satisfaction was carried out. however, all patients reported satisfaction and were eager to repeat and recommend this procedure. additional limitations include the relatively limited number of participants and the treated areas. conclusion in summary, this study demonstrated that intradermal prf injection could be considered as a safe, long-term technique accompanied by favorable objective facial skin rejuvenation and improving patient satisfaction. along with diminishing wrinkles, improvements in skin hyperpigmentation and overall freshness were also of significance. however, further longitudinal studies need to be carried out to assess the long-term outcomes of prf injection. also, studies with 6 original article | dermatol pract concept. 2023;13(1):e2023050 for skin aging. arch dermatol res. jul 2020;312(5):301-315. doi:10.1007/s00403-019-01999-6 15. du r, lei t. effects of autologous platelet-rich plasma injections on facial skin rejuvenation. exp ther med. apr 2020;19(4):30243030. doi:10.3892/etm.2020.8531 16. del fabbro m, panda s, taschieri s. adjunctive use of plasma rich in growth factors for improving alveolar socket healing: a systematic review. j evid based dent pract. jun 2019;19(2):166-176. doi:10.1016/j.jebdp.2018.11.003 17. scharschmidt d, mirastschijski u, preiss s, brahler e, fischer t, borkenhagen a. body image, personality traits, and quality of life in botulinum toxin a and dermal filler patients. aesthetic plast surg. aug 2018;42(4):1119-1125. doi:10.1007/ s00266-018-1165-3 18. nacopoulos c, vesala am. lower facial regeneration with a combination of platelet-rich fibrin liquid matrices based on the low speed centrifugation concept-cleopatra technique. journal of cosmetic dermatology. jan 2020;19(1):185-189. doi:10.1111/jocd.13196 dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023084 1 dermoscopic features of granular cell tumor lluís corbella-bagot1, jaime piquero-casals2, daniel morgado-carrasco1 1 department of dermatology, hospital clínic de barcelona, university of barcelona, barcelona, spain 2 dermik, clínica dermatológica multidisciplinar, barcelona, spain citation: corbella-bagot l, piquero-casals j, morgado-carrasco d. dermoscopic features of granular cell tumor. dermatol pract concept. 2023;13(2):e2023084. doi: https://doi.org/10.5826/dpc.1302a84 accepted: august 22, 2022; published: april 2023 copyright: ©2023 corbella-bagot et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, dermatology department, hospital clínic de barcelona, c/ villarroel, 170, 08036, barcelona, spain. tel: (+34) 93 227 54 00; fax: (+34) 932275438 e-mail: morgadodaniel8@gmail.com case presentation an otherwise healthy 35-year-old male presented with a tender and fast-growing nodule on the flank, of one year of evolution. clinical examination showed a 2 cm firm and shiny pigmented nodule. dermoscopy revealed brown radial lines and perifollicular scaling, together with coiled and twisted hairs. structureless pale areas were also observed (figure 1). histologic evaluation confirmed the diagnosis of a benign form of a granular cell tumor (gct). teaching point gct is an infrequent tumor usually presenting as a firm, sometimes pigmented nodule on mucosae or on the skin of the head or neck. gct seems to originate from schwann cells, which is supported by the expression of s-100 and myelin proteins upon immunohistochemical staining. dermal figure 1. dermoscopic image showing a pigmented tumor with large, radial brown lines. perifollicular scaling, together with coiled and twisted hairs is also observed, as well as structureless pale areas. 2 image letter | dermatol pract concept. 2023;13(2):e2023084 collagen, small nerves and adnexal structures are commonly infiltrated by tumoral cells, even though only 1%-2% of gct are malignant. surgical excision is the recommended treatment. very few dermoscopic reports are found in the literature. dermoscopy of gct can show a yellowish center (with or without hypopigmented lines), surrounded by thin brown reticular lines. small pale circles have also been described [1,2]. differential diagnosis of tumors presenting with brown reticular lines is broad and includes melanocytic and non-melanocytic lesions such as dermatofibroma, seborrheic keratosis, solar lentigo, cutaneous mastocytosis, supernumerary accessory nipple and syringoma [1]. we present new dermoscopic features of gct: large, radial brown lines, and the presence of follicular involvement. differential diagnosis of pigmented lesions can be challenging. dermoscopy may help to confirm suspected gct. a written consent form signed by the patient has been obtained. references 1. popadić m. dermoscopy of cutaneous abrikossoff tumor (granular  cell tumor) in a pediatric patient.   j am acad dermatol. 2015;73(4):e137-e138. doi: 10.1016/j.jaad.2015.06.056. pmid: 26369852. 2. alaoui a, douhi z, elloudi s, baybay h, mernissi f. abrikossoff’s tumor: clinical and dermoscopic features.  j dermatol cosmetol. 2019;3(5):130 doi: 10.15406/jdc.2019.03.00129 dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(1):e2022035 1 extrafacial lentigo maligna: a clinical and dermoscopic analysis according to localization gabriel salerni1, emilia cohen-sabban2, horacio cabo3 1 dermatology department, hospital provincial del centenario de rosario, universidad nacional de rosario, diagnóstico médico oroño, rosario, argentina 2 dermatology service, instituto de investigaciones médicas alfredo lanari, universidad de buenos aires, argentina 3 dermatology department, universidad de buenos aires, argentina key words: skin cancer, melanoma, lentigo maligna, dermoscopy citation: salerni g, cohen-sabban e, cabo h. extrafacial lentigo maligna: a clinical and dermoscopic analysis according to localization. dermatol pract concept. 2022;12(1):e2022035. doi: https://doi.org/10.5826/dpc.1201a35 accepted: august 30, 2021; published: january 2022 copyright: ©2022 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: gabriel salerni, md, dermatology department, hospital provincial del centenario de rosario universidad nacional de rosario diagnóstico médico oroño, rosario, argentina. email: gabrielsalerni@hotmail.com introduction: whether extrafacial lentigo maligna (eflm) differs clinically and/or dermoscopically according to location has not been analyzed in depth. objectives: to evaluate clinical and dermoscopic characteristics regarding different localization in a series of eflm. methods: we conducted a retrospective analysis of clinical and dermoscopic characteristics of 69 histologically proven eflm retrieved from the database of two private institutions. results: of the 69 eflm included in the study, 25 (36.2%) were located in posterior trunk (pt), 16 (23.2%) in anterior trunk (at), 15 (21%) in upper extremities (ue), and 13 (18.8%) in lower extremities (le). mean diameter among localization were as follows: 14.3 mm in pt, 11.8 mm in at, 14 mm in ue, and 10 mm in le (p 0.44). the most frequent dermoscopic criteria were angulated lines and tan structureless areas (70%), followed by atypical pigment network (60%), both with similar distribution among groups. angulated lines pattern was the most frequent global pattern, observed in 55% of cases. tan structureless/granularity pattern and patchy peripheral pigmented islands pattern were seen in 15.6% and 11.6% cases, respectively. no statistically significant differences were observed in the distribution of global dermoscopic pattern in the different localizations. conclusions: from the clinical point of view, eflm did not differ in terms of patient’s age and diameter regarding localization. upon dermoscopy, we found no significant differences in the overall dermoscopic pattern in the different localizations. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022035 introduction lentigo maligna (lm) is a variant of in situ melanoma that develops mainly in chronic sun exposure areas in middle-aged and elderly patients. if left untreated, it can evolve to its invasive form, lm melanoma [1]. hence, early recognition and proper management is crucial to reduce morbidity and mortality associated to melanoma. dermoscopy has shown to increase the sensitivity and specificity in the clinical diagnosis of melanoma by allowing the visualization of diagnostic criteria not visible to naked eye. moreover, its routine use for the evaluation of melanocytic and non-melanocytic skin lesions is recommended in most of the clinical guidelines worldwide [2,3]. dermoscopic criteria such as granularity, angulated lines, or vessels as well as overall dermoscopic patterns have been described to improve recognition of lentigo maligna in nonfacial chronically sun-damaged skin [4]. objectives we sought to evaluate clinical and dermoscopic characteristics regarding different localization in a series of extrafacial lentigo maligna (eflm) confirmed by histopathology. methods we conducted a retrospective analysis of clinical and dermoscopic characteristics of 69 histologically proven eflm diagnosed between 2016 and 2020 in two private clinics. the study included primary lm with clinical and dermoscopic pictures of acceptable quality to allow reliable evaluation. dermoscopic images were captured with polarized light using hand-held dermatoscope (dermlite ii pro hybrid, 3gen llc) attached to a digital camera and digital dermoscopy devices (fotofinder systems gmbh). the study was conducted according to the declaration of helsinki; patient’s written consent was obtained for all invasive procedures. epidemiological data such as age and gender of the patients and clinical data the localization and diameter of the lesions were incorporated along with the clinical and dermoscopic images in a powerpoint presentation (microsoft corp). this collection was presented to 2 dermatologists with experience in dermoscopy (g.s. and h.c.) who performed both clinical and dermoscopic evaluation. dermoscopic images were assessed for the presence or absence of criteria for melanoma previously described in nonfacial skin [4-6]. statistical analysis the χ2 test was used to compare qualitative variables, and the t test was used to compare means. differences were set as statistically significant at p ≤ 0.05. results of the 69 eflm included in the study, 25 (36.2%) were located in posterior trunk (pt), 16 (23.2%) in anterior trunk (at), 15 (21%) in upper extremities (ue), and 13 (18.8%) in lower extremities (le). population the study population consisted of 24 females (34.8%) and 45 males (65.2%), with a mean age of 68.5 years (range 38-86). no statistically significant differences were observed in age according to localization (figure 1). distribution according to gender was homogeneous among the 4 groups. clinical evaluation mean diameter among localization were as follows: 14.3 mm (5-24 mm) in pt, 11.8 mm (6-23 mm) in at, 14 mm (2-30 mm) in ue, and 10 mm (range 4-24 mm) in le (figure 2). no statistically significant differences were observed regarding diameter and localization (p = 0.44). eflm in individuals older than 70 years showed a significantly greater diameter than in those younger than 70 years (p = 0.002). in clinical examination (table 1), 60 out of the 69 eflm included (87%) were considered striking from the clinical point of view. concerning localization, all lesions located in ue were considered clinically striking, 92% of the lesions in pt, 80% in at, and 70% in le, respectively. light brown and dark brown were the most frequent colors, observed in about the 90% of the cases. white, blue-grey and pink were the less frequent colors observed clinically. lesions located in at displayed only 90 80 70 a g e 60 50 40 le ue localization at pt figure 1. age distribution is similar among localization categories (kruskal-wallis test, p = 0.343). le = lower extremities; ue = upper extremities; at = anterior trunk; pt = posterior trunk original article | dermatol pract concept. 2022;12(1):e2022035 3 30 d ia m et er in m m 20 10 uele localization at pt figure 2. diameter distribution is similar among localization categories (kruskal-wallis test, p = 0.44). le=lower extremities; ue=upper extremities; at=anterior trunk; pt=posterior trunk table 1. clinical characteristics. lower extremities n (%) upper extremities n (%) anterior trunk n (%) posterior trunk n (%) total n (%) cases 13 (18.8) 15 (21.7) 16 (23.2) 25 (36.2) 69 (100) colors light brown 11 (84.6) 14 (93.3) 15 (93.7) 23 (92) 63 (91.3) dark brown 12 (92.3) 13 (86.6) 13 (81.2) 24 (96) 62 (89.9) pink 3 (23) 3 (20) 0 (0) 2 (8) 8 (11.6) blue-gray 1 (7.7) 2 (13.3) 2 (12.5) 0 (0) 5 (7.2) white 0 (0) 1 (6.6) 0 (0) 2 (8) 3 (4.3) black 5 (38.4) 5 (33.3) 0 (0) 7 (28) 17 (24.6) borders ill defined 6 (46.1) 6 (40) 8 (50) 20 (80) 41 (59.4) well defined, irregular 5 (38.4) 9 (60) 7 (43.5) 5 (20) 26 (37.7) well defined, regular 2 (15.4) 0 (0) 0 (0) 0 (0) 2 (2.9) striking lesion 9 (69.2) 15 (100) 13 (81.2) 23 (92) 60 (87) 3 colors: light brown, dark brown and blue-grey, while in the other localizations at least 5 colors were observed. dermoscopic evaluation the dermoscopy evaluation findings are shown in table 2. the most frequent dermoscopic criteria were angulated lines and tan structureless areas, observed in more than three quarters of all the eflm analyzed, with quite similar distribution among the different localizations. atypical pigment network was observed in 60% of all the eflm, also with similar observation among groups. hyperpigmented follicular pigmentation was observed in almost one third of the cases, being less frequent in pt. aggregated dots were seen in less than 20% of the eflm, being more frequent in at. bluewhite veil and negative pigment network were observed in 6% of the cases; none of the eflm displayed circle within circle criteria. only 1 lesion located in tp showed radial projections. almost half of the eflm showed regression structures: 36.2% granularity and 23.2% scar-like areas; regression structures were less frequent in le. dotted and polymorphous vessels were the most frequent vascular pattern observed (15.9% and 11.6%, respectively). serpentine vessels and milky-red areas were observed in 7% of all eflm, with similar distribution among different localizations, but milky-red areas criterion was not observed in le. none of the melanomas included showed red globules. near half of the eflm displayed dermoscopic criteria for seborrheic keratosis, being more frequent in pt and ue, but no statistically significant differences were observed regarding localization. the 6 colors were observed in all localizations upon dermoscopy. light brown was observed in all cases, and dark brown in 66 out of 69 lesions. blue-grey color was present in more than half of the lesions, with similar distribution regarding localization. pink, white, and black colors were seen in near 40% of all eflm. pink and white colors were more frequent in pt and ue. black color was more frequent in le. global dermoscopic pattern analysis is shown in table 3. angulated lines pattern was the most frequent pattern, observed in 55% of cases. tan structureless/granularity pat4 original article | dermatol pract concept. 2022;12(1):e2022035 table 2. dermoscopic characteristics. lower extremities n (%) upper extremities n (%) anterior trunk n (%) posterior trunk n (%) total n (%) cases 13 (18.8) 15 (21.7) 16 (23.2) 25 (36.2) 69 (100) angulated lines 13 (100) 11 (73.3) 12 (75) 17 (68) 53 (76.8) aggregated dots 2 (15.4) 1 (6.6) 5 (31.2) 4 (16) 12 (17.4) atypical pigment network 8 (61.5) 8 (53.3) 10 (62.5) 15 (60) 41 (59.4) asymmetric perifollicular hyperpigmentation 5 (38.4) 7 (46.6) 7 (43.5) 2 (8) 21 (30.4) peripheral tan structureless areas 10 (76.9) 12 (80) 14 (87.5) 18 (72) 54 (78.3) negative network 0 (0) 2 (13.3) 0 (0) 2 (8) 4 (5.8) circle within circle 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) blue-white veil 1 (7.7) 1 (6.6) 1 (6.2) 1 (4) 4 (5.8) streaks pseudopods 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) radial projections 0 (0) 0 (0) 0 (0) 1 (4) 1 (1.4) vascular structures dotted vessels 3 (23) 5 (33.3) 0 (0) 3 (12) 11 (15.9) serpentine vessels 1 (7.7) 3 (20) 1 (6.2) 1 (4) 6 (8.7) polymorphous vessels 2 (15.4) 3 (20) 1 (6.2) 2 (8) 8 (11.6) milky-red areas 0 (0) 2 (13.3) 1 (6.2) 2 (8) 5 (7.2) red globules 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) white shiny structures shiny white lines 2 (15.4) 2 (13.3) 1 (6.2) 2 (8) 7 (10.1) white shiny areas 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) rosettes 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) regression structures absence 11 (84.6) 8 (53.3) 8 (50) 10 (40) 37 (53.6) granularity or peppering 2 (15.4) 5 (33.3) 7 (43.5) 11 (44) 25 (36.2) scar-like areas 0 (0) 4 (26.6) 3 (18.7) 9 (36) 16 (23.2) prominent skin markings criteria for seborrheic keratosis 4 (30.7) 8 (53.3) 6 (37.5) 15 (60) 33 (47.8) colors light brown 13 (100) 15 (100) 16 (100) 25 (100) 69 (100) dark brown 13 (100) 15 (100) 16 (100) 24 (96) 66 (98.6) pink 3 (23) 8 (53.3) 5 (31.2) 14 (56) 30 (43.5) blue-gray 7 (53.8) 9 (60) 9 (56.2) 12 (48) 37 (53.6) white 3 (23) 7 (46.6) 5 (31.2) 12 (48) 27 (39.1) black 6 (46.1) 6 (40) 5 (31.2) 8 (32) 25 (36.2) table 3. dermoscopic patterns lower extremities n (%) upper extremities n (%) anterior trunk n (%) posterior trunk n (%) total n (%) p cases per localization 13 (18.8) 15 (21.7) 16 (23.2) 25 (36.2) 69 (100) global dermoscopic pattern patchy peripheral pigmented islands 0 (0) 2 (13.3) 3 (18.7) 3 (12) 8 (11.6) 0.62 angulated lines 8 (61.5) 7 (46.7) 7 (43.7) 16 (64) 38 (55.1) 0.64 tan structureless and granularity 2 (15.4) 1 (6.7) 4 (25) 4 (16) 11 (15.9) 0.59 none 3 (23.1) 5 (33.3) 2 (12.5) 2 (8) 12 (17.4) 0.19 original article | dermatol pract concept. 2022;12(1):e2022035 5 figure 3. global dermoscopic pattern. (a-c) angulated lines, (d-f) granularity (middle row), (g-i) and patchy peripheral pigmented islands. table 4. number of colors in the clinical and dermoscopic examination number of colors in clinical examination n (%) number of colors in dermoscopic examination n (%) 1 7 (10) 64 (92.7) 0 (0) 32 (46.3)2 42 (60.9) 9 (13) 3 15 (21.7) 23 (33.3) 4 2 (2.9) 5 (7.3) 21 (30.4) 37 (53.6)5 3 (4.3) 12 (17.4) 6 0 (0) 4 (5.8) p < 0.001 tern and patchy peripheral pigmented islands pattern were seen in the 15.6% and 11.6% of cases, respectively (figure 3). twelve of 69 lesions (17.3%) showed none of these global patterns. no statistically significant differences were observed in the distribution of global dermoscopic pattern in the different localizations. colors upon clinical versus. dermoscopic evaluation table 4 shows number of colors observed upon clinical and dermoscopic examination. with the use of dermoscopy, the percentage of melanomas displaying at least 4 colors raised from 7.3% to 53.6% (p < 0.001) conclusions lm is a distinct form of melanoma in situ, which is characterized by an increased number of histologically atypical melanocytes situated along the dermo-epidermal junction. it mainly develops in middle-age and elderly individuals on chronically sun exposed areas. although lm can precede by many years the dermal invasion, rapid progression has been 6 original article | dermatol pract concept. 2022;12(1):e2022035 described [7,8]. therefore, early diagnosis and appropriate treatment are essential to improve prognosis. whether eflm differs clinically and/or dermoscopically according to location has not been analyzed in depth. the clinical diagnosis of eflm can be challenging since it can simulate other conditions especially solar lentigo or pigmented actinic keratosis. in our study, 90% of the eflm were striking from the clinical point of view; the lesions were clinically polychromatic (at least 3 colors) and with a similar diameter regardless of location. lesions tend to have a greater diameter in upper extremities and posterior trunk, but differences were not statistically significant. dermoscopy has become a key diagnostic tool to enhance both sensitivity and specificity in the clinical diagnosis of melanoma [2,3]. the dermoscopic criteria of lm and its invasive form, lm melanoma, were first described in facial location. furthermore, a progression model for facial lm has been well established and has been widely accepted [9]. more recently, dermoscopic features of lm in extrafacial location were described [4-6]. in 2013, keir reported that the global criterion of lentigo-like pigment pattern lacking a lentigo-like border, combined with the criteria of asymmetrically pigmented follicular openings and large polygons detected the great majority of melanoma in his series of 20 cases (18 in situ) [5]. jaimes et al described and analyzed the clinical and dermoscopic characteristics of both in situ and invasive melanomas on nonfacial chronically sun-damaged skin; they concluded that outlier lesions manifesting dermoscopic structures, such as granularity, angulated lines, or vessels and any of the 3 described dermoscopic patterns: patchy peripheral pigmented islands, angulated lines pattern and tan structureless and granularity pattern should raise suspicion for melanoma. in our series, peripheral tan structureless areas, angulated lines and atypical pigment network were the most frequent dermoscopic criteria observed. angulated lines were more frequent in le, where they were observed in all cases; conversely, tan structureless areas and atypical pigment network had similar distribution among different localizations. asymmetric perifollicular hyperpigmentation was much less frequent in pt. aggregated dots was more frequent in at. regression structures were less frequently observed in le: granularity was observed in only 2 cases, and none showed scar-like areas. in pt regression structures were more prevalent. all vascular structures evaluated were more frequent in ue than in other locations. shiny white lines, the only white shiny structure observed, were more frequent in extremities than in the trunk. almost half of the eflm in the series showed dermoscopic criteria for seborrheic keratosis, this was more frequently reported in ue and pt. no statistically significant differences were observed in the overall dermoscopic pattern distribution according to localization. our study does not lack of limitations due to its retrospective design, the lack of control groups and the fact that evaluators were not blinded to the diagnoses. additionally, selection and verification bias may lead to an overestimation of specificity of dermoscopic criteria in the diagnosis of eflm. we believe that this study provides useful and valuable information to learn more about the dermoscopic aspects of eflm and to improve early detection, especially by providing relevant information for the identification of the most prevalent dermoscopic criteria in different locations. in this study we evaluated clinical and dermoscopic aspect in a series of 69 eflm according to localization. from the clinical point of view, eflm did not differ in terms of patient age and diameter regarding localization. upon dermoscopy, angulated lines were more frequent in le, aggregated dots were more frequent in at, regression structures were more prevalent in pt, asymmetric perifollicular hyperpigmentation was much less frequent in pt, vascular structures were more frequent in ue, white shiny lines were more frequently observed in extremities than in the trunk. we found no significant differences in the overall dermoscopic pattern in the different localizations. references 1. clark wh, mihm mc. lentigo maligna and lentigo-maligna melanoma. am j pathol. 1969;55(1):39–67. pmid: 5776171. pmcid: pmc2013384. 2. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137:1343-1350. doi: 10.1001/archderm.137.10.1343. pmid: 11594860. 3. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159-165. doi: 10.1016/ s1470-2045(02)00679-4. pmid: 11902502. 4. jaimes n, marghoob aa, rabinovitz h, et al. clinical and dermoscopic characteristics of melanomas on nonfacial chronically sun-damaged skin. j am acad dermatol. 2015 jun;72(6):1027-1035. doi: 10.1016/j.jaad.2015.02.1117. pmid: 25824275. 5. keir j. dermatoscopic features of cutaneous non-facial non-acral lentiginous growth pattern melanomas. dermatol pract concept. 2014;4(1):77-82. doi: 10.5826/dpc.0401a13. pmid: 24520520. pmcid: pmc3919846. 6. lau yn, affleck ag, fleming cj. dermatoscopic features of extrafacial lentigo maligna. clin exp dermatol. 2013;38(6):612616. doi: 10.1111/ced.12063. pmid: 23837933. 7. michalik ee, fitzpatrick tb, sober aj. rapid progression of lentigo maligna to deeply invasive lentigo maligna melanoma. report of two cases. arch dermatol. 1983119(10):831-835. pmid: 6614952. original article | dermatol pract concept. 2022;12(1):e2022035 7 8. kilinc-karaarslan i, akalin t, ozdemir f. lentigo maligna melanoma with folliculotropism: dermoscopic features during rapid progression. arch dermatol. 2009;145(6):725-726. doi: 10.1001/archdermatol.2009.101. pmid: 19528438. 9. stolz w, schiffner r, burgdorf wh. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002;20(3):276-278. doi: 10.1016/s0738-081x(02)00221-3. pmid: 12074867. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022085 1 dermatology practical & conceptual introduction: eccrine porocarcinoma (epc) is a rare subtype of non-melanoma skin cancer developing in the intraepithelial portion of eccrine sweat glands. it is branded with a highly metastatic potential and increased rate of local recurrence after treatment. epc showcased a trend of developing on the extremities, with presentation on the face sparse. objectives: aim of the study was to evaluate the frequency, clinical features, and course of this malignancy presented on the face. methods: a retrospective review of the skin cancers excised between january 2010 and june 2021 was conducted in the plastic surgery department of a tertiary hospital. patients were included in the study if epc on the face was histologically confirmed. a prospectively maintained clinic database and the pathological reports were used to collect data. results: 4 epc cases on the face out of 3984 confirmed skin cancers were identified. none of the cases was suspected clinically, but the diagnosis was established following the histopathologic examination. an aggressive postoperative behavior was confirmed in 2 cases. conclusions: the variance in the clinical presentation and the non-specific characteristics are perplexing clinical diagnosis, with the histopathologic examination representing the current standard for confirmation. early diagnosis and adequate surgical resection are recommended as treatment cornerstones. clinical awareness ought to be raised and a definitive treatment protocol be established for optimized results. eccrine porocarcinoma of the face is a great imitator with aggressive behavior konstantinos seretis1, nikolaos bounas1, evangeli lampri2, efstathios g. lykoudis1 1 department of plastic surgery, medical school, university of ioannina, ioannina, greece. 2 pathology department, medical school, university of ioannina, ioannina, greece. key words: eccrine porocarcinoma, face, skin cancer, sweat gland citation: seretis k, bounas n, lampri e, lykoudis eg. eccrine porocarcinoma of the face is a great imitator with aggressive behavior. dermatol pract concept. 2022;12(2):e2022085. doi: https://doi.org/10.5826/dpc.1202a85 accepted: september 14, 2021; published: april 2022 copyright: ©2022 seretis k et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: konstantinos seretis, department of plastic surgery, ioannina university school of medicine leoforos st. niarchou, 45500, ioannina, greece. e-mail: drseretis@uoi.gr abstract 2 original article | dermatol pract concept. 2022;12(2):e2022085 introduction skin cancer is the most common type of cancer encountered worldwide. however, skin malignancies originating from the sweat glands account only for 1% of these lesions [1]. eccrine porocarcinoma (epc) is a very rare subtype, representing only 0.005% of cutaneous tumors [2]. most often witnessed in people aged over 60 years, it is characterized by a highly metastatic potential and increased rate of local recurrence, even after excision. epc showcased a trend of developing on the extremities, with presentation on the face sparse [2]. objectives aim of the current study was to evaluate the frequency, clinical features, and course of epc presented on the face, shedding light on this rare malignancy. methods an observational cohort study was conducted in the plastic surgery department of a tertiary hospital, using a predetermined protocol, which conformed to the ethical guidelines of the 1975 declaration of helsinki, approved by the local ethical committee and adhered to the strobe statement for cohort studies. all patients who underwent excision of a skin cancer in the department between january 2010 and june 2021 were identified. patients were included in the study if epc on the face was histologically confirmed. a prospectively maintained clinic database and the pathological reports were used to collect data. outcomes of interest were the epc incidence, the clinical and pathological characteristics and the postoperative course of the sample. results four cases of epc out of 3984 confirmed skin tumors (frequency: 0.1%) were revealed. none of the cases was suspected clinically, but they were resected as non-melanoma skin tumors with 5-mm surgical margins (figure 1) [3]. the diagnosis was established following the histopathologic examination, based on the presence of irregular dermis-infiltrating malignant cell clusters that showed an invasive architectural pattern (figure 2). tumor cells were demonstrating marked nuclear pleomorphism and prominent nucleoli, they were large polyhedral to cuboid with moderate to abundant eosinophilic and more rarely clear cytoplasm, as well as many mitotic figures (up to 6-7/hpf). other observed features included squamous differentiation, without keratinization, ductal differentiation and focally desmoplasia. no tumor displayed granular cells or decapitated lumens, ruling out the possibility of apocrine differentiation. ducts were revealed with periodic acid–schiff stain and immunohistochemically with ck19, cea and ema. the characteristics and clinical course are depicted in table 1. an aggressive behavior with local recurrence was revealed in 2 cases, despite the excision with clear margins in both cases and the radiotherapy course, which followed (figure 3). conclusions epc is considered one of the rarest skin tumors a surgeon can encounter. although it develops often on the extremities, the face in particular the auricle is considered an extremely rare location. salih et al reviewed 453 epc cases, with 40% of these located on the head and neck, but 7 cases only on the ear [4]. the cases we encountered concerned male patients exclusively, thus confirming the predilection of facial epc towards the male gender [5]. misdiagnosis of epc due to its atypical presentation is highly probable. it could also be attributed to the diversity of total number of sweat glands on different parts of the body. however, current data annul this idea, as epc occurrence is not correlated with the figure 1. eccrine porocarcinoma macroscopic appearance of patient 4. original article | dermatol pract concept. 2022;12(2):e2022085 3 highest concentration of sweat glands (palmoplantar region) [5]. underreporting of this entity remains also a possibility. it is proposed that epc emerges either de-novo or from a pre-existing benign poroma [2]. the ratio of malignant transformation was estimated around 18% [2]. immunosuppression may be a contributing factor in epc pathogenesis, as well as sun exposure [4]. genetic predisposition may be also implicated, as p53 oncogene expression is witnessed in 88% of cases, while loss of retinoblastoma protein and overexpression of p16 gene, though not consistent, have been also reported [6,7]. none of these implicating factors could be associated with a predilection for epc manifestation on specific areas. from a clinical standpoint, epc usually presents itself as an asymptomatic solitary nodule or mass which can progress to ulceration and cause pain [2]. the lesion is typically noticed over a long period of time (up to several years), although cases of rapid growth in a few months were also noted. considering its rarity, epc needs to be differentiated from a plethora of skin conditions such as seborrheic keratosis, pyogenic granuloma, amelanotic melanoma, squamous cell carcinoma and verruca vulgaris [2]. this task becomes even harder for the dermatologist, as most of the aforementioned table 1. characteristics of the epc cases identified case month/ year age (years) gender location diameter (mm) surgical treatment adjuvant treatment recurrence #1 5/2012 69 m cheek 13 excision -primary repair in 6 months #2 11/2018 80 m lower lid 30 excision eye exenteration-temporalis flap radiotherapy in 4 months #3 12/2019 84 m temple 10 excision -ftsg no #4 3/2021 61 m ear 22 excision -postauricular flap radiotherapy no (5 months postoperatively) ftsg = full thickness skin grafting; m = male. figure 2. eccrine porocarcinoma – histology. (a) diffuse infiltrative pattern. (b) duct formation, nuclear pleomorphism and prominent nucleoli. (c) immunohistochemical expression of cea in ducts. figure 3. eccrine porocarcinoma – locoregional metastasis of patient #2, 2 years following surgery and radiotherapy. 4 original article | dermatol pract concept. 2022;12(2):e2022085 of the patients with confirmed epc of the face enabled the analysis of such a rare malignancy, mitigating the potential effect of the study limitations to the outcomes of interest. overall, epc is very rarely encountered. based on this cohort and the pertinent literature review, the evidence regarding the pathophysiology, surgical and adjuvant treatment is inconclusive and call for further reporting and analysis. currently, awareness should be raised by the clinician to properly recognize epc and treat promptly, and vigilance is needed, due to its high malignant nature and mortality rates. learning points • eccrine porocarcinoma (epc) is an extremely rare subtype of non-melanoma skin cancer, mostly presenting in the extremities of the elderly population. • underreporting and misdiagnosis of epc occurring on the face are distinct possibilities accounting for its rarity. • histologic examination confirms the diagnosis and identifies the histologic subtype, essential for guiding further treatment. • epc is regarded as a very aggressive malignancy exhibiting high rates of local recurrence and metastasis. • wide local excision remains the optimal treatment option, without a clear treatment protocol established up to date. • vigilance is mandatory for prompt recognition and treatment to avoid the high mortality rates reported. acknowledgments the authors acknowledge the pathologist dr. aikaterini zioga for her valuable assistance with the pathological data evaluation. references 1. goldman p, pinkus h, rogin j. eccrine poroma; tumors exhibiting features of the epidermal sweat duct unit. ama arch derm. 1956;74(5):511-521. pmid: 13361538. 2. robson a, greene j, ansari n, kim b, seed pt, mckee ph, calonje e. eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases. am j surg pathol. 2001;25(6):710-20. doi: 10.1097/00000478-200106000-00002. pmid: 11395548. 3. seretis k, thomaidis v, karpouzis a, tamiolakis d, tsamis i. epidemiology of surgical treatment of nonmelanoma skin cancer of the head and neck in greece. dermatol surg. 2010;36(1):15-22. doi:10.1111/j.1524-4725.2009.01379.x. pmid: 19912277. 4. salih am, kakamad f, baba ho, et al. porocarcinoma; presentation and management, a meta-analysis of 453 cases. ann med. 2017;20:74-79. doi: 10.1016/j.amsu.2017.06.027. pmid: 28721214. pmcid: pmc5499034. 5. snow sn, reizner gt. eccrine porocarcinoma of the face. j am acad dermatol. aug 1992;27(2 pt 2):306-311. doi:10.1016/0190-9622(92)70187-k. pmid: 1325487. skin lesions are encountered predominantly in older people, while no clear clinical characteristics for epc have been reported and thus clinical diagnosis often fails. the clinical characteristics of epc act as an insurmountable impediment to the clinical diagnosis and shifted focus on the histological examination. the presence of cytologic atypia with advancing margin and poromatous basaloid cells displaying ductal differentiation confirmσ the diagnosis [2]. robson et al has described 3 histological variants. “infiltrative” is characterized by ill-defined lower limits with malignant clusters infiltrating the dermis and hypodermis, “pushing” by well-defined lower dermal border, and “pagetoid” by intraepidermal clusters of tumoral cells, mimicking paget disease [2]. immunohistochemistry can be a significant diagnostic aid, including various stains for cea, ema, ck-7 and s-100 protein [8]. epc is regarded as a very aggressive malignancy exhibiting high metastatic potential [2]. a 31% of regional or distant metastasis was revealed, with the most common sites being the regional lymph nodes (57.7%), and the lungs (12.8%) [4]. mortality increases drastically in case of metastatic disease, with overall survival ranging between 5 and 24 months [5]. local recurrence after excision is also high, reaching 25%, with the “infiltrative” and “pagetoid” subtypes being implicated most often [2,9]. indeed, 2 of our 4 patients manifested local recurrence few months following tumor excision. multi-nodularity and ulceration are among the signs of aggressiveness, while pedunculated tumors are less aggressive [4]. lympho-vascular invasion, positive tumor margins, high mitotic count (> 14/hpf) and tumor depth (> 7 mm) have been proposed as predictors of worse clinical outcomes [2]. currently, no established treatment guidelines exist. wide local resection with confirmation of clear margins remains the optimal treatment option, achieving therapeutic outcome in 70%-80% of cases [5]. belin et al proposed a surgical algorithm, based on the histological type [2,9]. in particular, all lesions should be excised with 3-mm clear margins and a further 5-mm margin must be achieved using a modified mohs technique, should the “infiltrative” or the “pagetoid” subtypes be confirmed [9]. having high suspicion for an aggressive skin tumor but no access to mohs surgery, we performed an excision with a 5-mm margin. involvement of lymph nodes requires surgical clearance, but little data exists to support routine lymph node dissection [10]. adjuvant treatments have been administered in metastatic disease, with both chemotherapy and radiotherapy provoking mixed responses, which is also supported by our data [5]. limitations of the study include the small sample size and its retrospective nature. however, the data covering a long period, the dedicated to skin cancer plastic surgery department of a tertiary hospital and the long-term follow-up original article | dermatol pract concept. 2022;12(2):e2022085 5 9. belin e, ezzedine k, stanislas s, et al. factors in the surgical management of primary eccrine porocarcinoma: prognostic histological factors can guide the surgical procedure. br j dermatol. 2011;165(5):985-989. doi:10.1111/j.13652133.2011.10486.x. pmid: 21711331. 10. huet p, dandurand m, pignodel c, guillot b. metastasizing eccrine porocarcinoma: report of a case and review of the literature. j am acad dermatol. 1996;35(5):860-864. doi:10.1016/ s0190-9622(96)90105-x. pmid: 8912607. 6. akalin t, sen s, yücetürk a, kandiloğlu g. p53 protein expression in eccrine poroma and porocarcinoma. am j dermatopathol. 2001;23(5):402-406. doi: 10.1097/00000372-20011000000003. pmid: 11801771. 7. gu lh, ichiki y, kitajima y. aberrant expression of p16 and rb protein in eccrine porocarcinoma. j cutan pathol. 2002;29(8):473-479. doi:10.1034/j.1600-0560.2002.290805.x. pmid: 12207741. 8. obaidat na, alsaad ko, ghazarian d. skin adnexal neoplasms—part 2: an approach to tumours of cutaneous sweat glands. j clin pathol. 2007;60(2):145-159. doi:10.1136/ jcp.2006.041608. pmid: 16882695; pmcid: pmc1860616. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023027 1 infections in hospitalized patients with psoriasis in a skin referral hospital nafise zaredar1, hamidreza mahmoudi1,2, tahereh soori1,3, amir teimourpour1, kamran balighi1,2, ali salehi farid1,2, maryam daneshpazhooh1,2 1 department of dermatology, tehran university of medical sciences, tehran, iran 2 autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran 3 department of infectious diseases, tehran university of medical sciences, tehran, iran key words: psoriasis, infection, biologic treatment, anti-tnfa, methotrexate citation: zaredar n, mhamoudi h, soori t, et al. infections in hospitalized patients with psoriasis in a skin referral hospital. dermatol pract concept. 2023;13(1):e2023027. doi: https://doi.org/10.5826/dpc.1301a27 accepted: july 15, 2022; published: january 2023 copyright: ©2023 zaredar et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maryam daneshpazhooh, razi hospital, vahdate-eslami sq, tehran 11996 iran; orcid 0000-0003-1020-8895 phone number and fax: +98-21-55618989; email: maryamdanesh.pj@gmail.com introduction: psoriasis and its treatments may predispose patients to various infections. this is considered one of the most significant complications in patients with psoriasis. objectives: in the present study, we aimed to determine the prevalence of infection in hospitalized psoriasis patients and its relationship with systemic and biologic treatments. methods: all hospitalized patients with psoriasis from 2018 to 2020 in razi hospital in tehran, iran, were studied and cases of infection were recorded. results: overall, 516 patients were studied and 25 types of infection in 111 patients were found. the most common types of infection were pharyngitis and cellulitis, followed by oral candida, urinary tract infections, common cold, fever of unknown origin, and pneumonia. female sex and pustular psoriasis were significantly associated with infection in psoriatic patients. those patients who received prednisolone had a higher risk of infection, and those under treatment with methotrexate or infliximab had a lower risk of infection. conclusion: overall, 21.5% of psoriasis patients in our study had at least one episode of infection. this demonstrates that the prevalence of infection in these patients is not low. using systemic steroids was associated with a higher risk of infection, while using methotrexate or infliximab was concomitant with a lower risk of infection. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023027 introduction psoriasis is a common, chronic, inflammatory cutaneous disease, causing morbidity and mortality in severe cases. the approximate prevalence rate is 0.14-5.32% of the general population. [1, 2] the characteristic of psoriasis is sustained inflammation which causes uncontrolled proliferation of keratinocytes and dysfunctional differentiation that activates through tnf-α, il-17, and ifn-γ. the psoriatic plaque’s histology shows acanthosis, which covers inflammatory infiltrates consisting of dermal dendritic cells, macrophages, t cells, and neutrophils as well as neovascularization [3]. infections are among the most concerning complications of psoriasis per se and its treatments. two types of conventional and biological treatments are used to treat this disease. biologic treatments are mostly used in more severe psoriasis patients; however, infections are the most crucial side effect of these drugs. recent studies have found conflicting results regarding the prevalence of infection in this disease and its relationship with various systemic treatments. this study evaluated the prevalence of infection in psoriasis hospitalized patients in a skin referral hospital and its relationship with variables such as biologic treatments in hospitalized patients with psoriasis. methods in this retrospective cross-sectional study, all hospitalized psoriasis patients from 2018 to 2020 in razi hospital in tehran, iran were examined for any documented infection. demographic data, psoriasis subtypes, the existence of arthropathy, and present treatments (methotrexate, prednisolone, cyclosporine, acitretin, phototherapy, topical treatment, and biological treatment) were extracted. furthermore, the wound, blood, and urine culture results were recorded. all hospital records over the course of the study were reviewed and cases of diagnosed psoriasis were included in the study. cases of comorbid psoriasis with other skin disease were excluded. these data were analyzed with spss software (ibm corp. released 2017. ibm spss statistics for windows, version 25.0. armonk, ny: ibm corp). associations between infections and other variables were examined using the chisquare test. the frequency has been calculated for quantitative data, mean and standard deviation, for qualitative data. the significance level was considered a p-value < 0.05. confidence interval (ci) is the range of values between which you expect your estimate to be if you repeat your test, at a certain level of confidence. an odds ratio (or) is a measure of how an exposure relates to a result. the or represents the probability that a result will occur as a result of a particular exposure compared to the probability that the result will occur in the absence of that exposure. results among 516 patients, 172 (33%) women and 344 (67%) men, with a mean age of 43.85 +/15.95 (range: 8 to 89). the mean age of men was greater than women (44.97 +/ 15.40 vs 41.62 +/16.83) (pvalue: 0.024). 380 (73.6%), 106 (20.5%), 25 (4.8%), 4 (0.8%) and 1(0.2%) were plaque-type, pustular, erythrodermic, inverse and guttate, respectively. furthermore, from 248 available data, 144 (58.06%) patients had arthropathy. meanwhile, 111 (21.5%) patients had at least one episode of infection; overall, 166 cases were detected. considering the low number of patients with inverse and guttate psoriasis, only plaque-type, pustular and erythrodermic psoriasis were analyzed. the most common types of infection were pharyngitis, cellulitis followed by oral candidiasis, urinary tract infections (uti), common cold, fever of unknown origin (fuo), and pneumonia (table 1). there was a significant correlation between age and oral candidiasis, uti, and herpes simplex virus (hsv) infection (p-values: 0.023, 0.012, 0.001, respectively), while no significant relationship was found between age and other types of infections (p-value<0.05 for all). infections were 2 times more frequent in women (30.2%) than men (17.2%) (or: 2.09, 95%ci: 1.36-3.21, p-value: 0.001). additionally, oral candidiasis, flexural candidiasis, and erythrasma were significantly more common in women (p-values: 0.011, 0.044, 0.001, respectively). regarding psoriasis subtypes, there was a significant relation between plaque-type and pustular psoriasis with infection (p-values: <0.001, or: 0.282; p-value <0.001, or: 3.845, respectively). in other words, patients with pustular and plaque-type psoriasis had a 3.8 and 2.8 times higher risk of infection in comparison with other subtypes, respectively. furthermore, cellulitis, pharyngitis, fuo, oral candidiasis, uti, vaginal candidiasis, and bacterial blepharitis were significantly more common in the pustular subtype (table 2). concerning the relationship between medications and infection, patients treated with prednisolone (or: 2.93, 95%ci: 1.82-4.73, p-value< 0.001) had a higher risk of infection. from a total of 99 cases on prednisolone, 38 (38.4%) had at least one episode of infection, while the infection was seen in 73 (17.5%) out of 417 cases who were not receiving prednisolone (p-value: <0.001, or: 2.93). on the other hand, those under treatment of methotrexate (or: 2.1, 95%ci: 0.29-0.76, p-value: 0.002) or infliximab (or: 5.12, 95%ci: 0.10-0.35, p-value< 0.001) had a lower risk of infection (table 3). original article | dermatol pract concept. 2023;13(1):e2023027 3 in patients on prednisolone, the risk of cellulitis, pharyngitis, common cold, fuo, uti, and blepharitis was higher. additionally, cyclosporine was associated with a higher risk of fuo and patients receiving methotrexate had a lower chance of pharyngitis (table 4). regarding the anti-tnfα group, infliximab was associated with a lower risk of cellulitis (or:0.04, p-value: 0.001) (table 4), while adalimumab and etanercept were not linked to any type of infection (all p-values>0.05). it is worth noting that although no case of active tuberculosis was recognized, table 1. types of infections and frequency of each occurrence in psoriatic patients. type of infection number of infections total/person total/infection1 2 3 cellulitis 20 1 21 22 (13.25%) pharyngitis 26 1 27 29 (17.47%) common cold 11 11 11 (6.62%) pneumonia 7 7 7 (4.21%) paronychia 3 3 3 (1.8%) fuo 5 1 6 8 (4.82%) oral candida 17 1 18 19 (11.44%) conjunctivitis 5 1 6 7 (4.21%) uti 12 1 1 14 17 (10.24%) hbv 3 3 3 (1.8%) hcv 4 4 4 (2.41%) hiv 3 3 3 (1.8%) hsv 3 3 3 (1.8%) erythrasma 6 6 6 (3.61%) gastroenteritis 4 4 4 (2.41%) otitis externa 2 2 2 (1.2%) tuberculosis 1 1 1 (0.6%) epididymitis 1 1 1 (0.6%) axillary abscess 1 1 1 (0.6%) septic arthritis 2 2 2 (1.2%) impetigo 1 1 1 (0.6%) flexural candidiasis 7 7 7 (4.21%) folliculitis 1 1 1 (0.6%) vaginal candidiasis 2 2 2 (1.2%) blepharitis 2 2 2 (1.2%) total 166 fuo: fever of unknown origin, uti: urinary tract infection, hbv: hepatitis b virus, hcv: hepatitis c virus, hiv: human immunodeficiency virus, hsv: herpes simplex virus table 2. the relationship between psoriasis subtypes and the most prevalent infection types. plaque type nonplaque type p-value pustular type nonpustular type p-value cellulitis 8 (2.1%) 13 (9.6%) 0.000 11 (10.4%) 10 (2.4%) 0.001 pharyngitis 15 (3.9%) 12 (8.8%) 0.028 11 (10.4%) 16 (3.9%) 0.008 fuo 1 (0.3%) 5 (3.7%) 0.006 4 (3.8%) 2 (0.5%) 0.018 oral candidiasis 7 (1.8%) 11 (8.1%) 0.002 9 (8.5%) 9 (2.2%) 0.004 uti 7 (1.8%) 7 (5.1%) 0.061 6 (5.7%) 8 (2%) 0.047 hsv 0 (0%) 3 (2.2%) 0.018 2 (1.9%) 1 (0.2%) 0.109 vaginal candidiasis 0 (0%) 2 (1.5%) 0.069 2 (1.9%) 0 (0%) 0.042 blepharitis 0 (0%) 2 (1.5%) 0.069 2 (1.9%) 0 (0%) 0.042 4 original article | dermatol pract concept. 2023;13(1):e2023027 detected micro-organisms in blood cultures. in urine cultures, e-coli (18.51%) followed by pseudomonas (11.11%), and in wound cultures, staph epidermidis (29.76%) followed by staphylococcus aureus (28.57%) were the most common pathogens. 63 (12.2%) patients received isoniazid due to positive ppd and use of immunosuppressive therapy. culture results were available in 82 cases; 45 (54.8%) were negative. staphylococcus epidermidis (36.36%) followed by enterobacter (9.09%) were the most commonly table 3. the relationship between infections and current treatments. infection total p-value or 95%cino yes methotrexate no count 237 83 320 0.002 0.47 0.29-0.76 % 74.10% 25.90% 100.00% yes count 168 28 196 % 85.70% 14.30% 100.00% prednisolone no count 344 73 417 0.000 2.93 1.82-4.73 % 82.50% 17.50% 100.00% yes count 61 38 99 % 61.60% 38.40% 100.00% cyclosporine no count 386 103 489 0.29 1.57 0.67-3.7 % 78.90% 21.10% 100.00% yes count 19 8 27 % 70.40% 29.60% 100.00% acitretin no count 249 54 303 0.075 1.68 0.81-1.57 % 82.20% 17.80% 100.00% yes count 186 27 213 % 87.32% 12.68% 100.00% phototherapy no count 375 100 475 0.38 1.37 0.66-2.84 % 78.90% 21.10% 100.00% yes count 30 11 41 % 73.20% 26.80% 100.00% topical no count 92 22 114 0.51 1.18 0.7-2 % 80.70% 19.30% 100.00% yes count 313 89 402 % 77.90% 22.10% 100.00% infliximab no count 241 98 339 0.000 0.19 0.10-0.35 % 71.10% 28.90% 100.00% yes count 164 13 177 % 92.70% 7.30% 100.00% adalimumab no count 401 110 511 1 0.91 0.1-8.23 % 78.50% 21.50% 100.00% yes count 4 1 5 % 80.00% 20.00% 100.00% etanercept no count 401 110 511 1 0.91 0.1-8.23 % 78.50% 21.50% 100.00% yes count 4 1 5 % 80.00% 20.00% 100.00% total count 405 111 516 % 78.50% 21.50% 100.00% original article | dermatol pract concept. 2023;13(1):e2023027 5 disease-based registry (psolar) reported that the most common types of serious infections were pneumonia and cellulitis. [9] likewise, in the present study, the most common infections were respiratory tract infections followed by skin infections and utis. in terms of the psoriasis subtypes, 50% of inverse, 42.5% of pustular, 24% of erythrodermic, and 15.3% of plaque-type psoriasis had a history of infection. in the present study, the chance of infection in patients with pustular psoriasis was 3.8 times higher than with other types; however, because of the low frequency of inverse psoriasis, the high frequency of infections in this group cannot be inferred. patients with psoriasis may be more susceptible to infections due to both the disease per se and the immunosuppressive medications. previous studies have shown conflicting results about the correlation between different treatments and the risk of infection. the essential difference between the biologic and conventional treatments, using combination therapies, could be considered possible reasons for this discrepancy. in our study, cyclosporine was significantly associated with fuo, although the overall risk of infection was not higher in contrast to sejio et al., who reported a higher risk of overall and serious infections. [10] likewise, prednisolone was associated with 2.93 times more frequent infections. furthermore, we did not find any relationship between acitretin and infections, while seijo et al. reported a lower risk of infection with acitretin. [10] these controversial results could be due to the predominant use of acitretin as a combination therapy with other drugs in the present study. another controversial finding of our study was the lower risk of infection among patients treated with methotrexate, which is not in concordance with its immunosuppressive nature. these controversies also exist in the prevalence of infections in psoriasis patients using biologic drugs. hsu et al. stated that biologic treatments might increase the risk of discussion in the present study, we found that 21.5% of hospitalized psoriasis patients had at least one episode of infection; a total of 25 types were recorded in 111 patients. men outnumbered women in this study, which may reflect more severe disease needing hospitalization in men. however, psoriatic women were more prone to infections. in our study, the most common types of infection were pharyngitis (n=29), cellulitis (n=22), oral candidiasis (n=19), uti (n=17), common cold (n=11), fuo (n=8) and pneumonia (n=7). there was a significant correlation between age and oral candidiasis, uti, and hsv. previous studies have shown a higher prevalence of oral and cutaneous candida colonization and infection in psoriasis. [4, 5] similarly, in the present study, oral candidiasis was the third most common infection, especially seen in the elderly; this may be partly attributed to dentures. meanwhile, the older age of prevalence of uti could be due to more common genitourinary problems in the elderly and lack of personal hygiene in this group. we did not have precise details regarding the reason for the patients’ hospitalization, although it was primarily due to the psoriasis flare-up and not the infections per se. the most serious infections that led to hospitalization in this study were probably cellulitis followed by uti. in a prospective cohort study from the british association of dermatologists biologic and immunomodulators register, the most common types of infection in psoriatic patients were lower respiratory tract infections, followed by skin and soft tissue infections, and urinary tract infections. [6] while in a cohort study in the united kingdom, upper and lower respiratory tract infections were the most prevalent. [7] in addition, a population-based cohort in the netherlands showed that respiratory tract, abdominal, and skin infections occurred most frequently in patients with psoriasis. [8] another study in a multicenter, longitudinal, table 4. the relationship between treatments and the most prevalent infection types. methotrexate prednisolone cyclosporine infliximab p-value or p-value or p-value or p-value or cellulitis 0.172 0.497 0.042 2.73 0.302 1.97 0.001* 0.04 pharyngitis 0.032* 0.355 0.016 2.64 0.645 1.48 0.346 0.65 common cold 0.755 1.37 0.009 5.31 1 0.75 0.108 0.18 fuo 0.088 0.12 0.001 22.12 0.035 9.7 0.669 0.38 uti 0.703 1.23 0.034 3.29 0.533 1.408 0.154 0.31 blepharitis 0.528 0.32 0.037 21.41 0.102 18.77 1 1.92 *negative correlation 6 original article | dermatol pract concept. 2023;13(1):e2023027 references 1. al salman m, ghiasi m, farid as, taraz m, azizpour a, mahmoudi h. oral simvastatin combined with narrowband uvb for the treatment of psoriasis: a randomized controlled trial. dermatol ther. 2021;34(5):e15075. 2. parisi r, iskandar iyk, kontopantelis e, augustin m, griffiths cem, ashcroft dm. national, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. bmj. 2020;369:m1590. 3. rendon a, schäkel k. psoriasis pathogenesis and treatment. int j mol sci. 2019;20(6). 4. lesan s, toosi r, aliakbarzadeh r, daneshpazhooh m, mahmoudi l, tavakolpour s, et al. oral candida colonization and plaque type psoriasis: is there any relationship? j investig clin dent. 2018;9(3):e12335. 5. pietrzak a, grywalska e, socha m, rolinski j, franciszkiewicz pietrzak k, rudnicka l, et al. prevalence and possible role of candida species in patients with psoriasis: a systematic review and meta-analysis. mediators of inflammation. 2018;2018:9602362. 6. yiu zz, smith ch, ashcroft dm, lunt m, walton s, murphy r, et al. risk of serious infection in patients with psoriasis receiving biologic therapies: a prospective cohort study from the british association of dermatologists biologic interventions register (badbir). 2018;138(3):534-41. 7. takeshita j, shin db, ogdie a, gelfand jm. risk of serious infection, opportunistic infection, and herpes zoster among patients with psoriasis in the united kingdom. the journal of investigative dermatology. 2018;138(8):1726-35. 8. wakkee m, de vries e, van den haak p, nijsten tjjotaaod. increased risk of infectious disease requiring hospitalization among patients with psoriasis: a population-based cohort. 2011;65(6):1135-44. 9. kalb re, fiorentino df, lebwohl mg, toole j, poulin y, cohen ad, et al. risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and registry (psolar). jama dermatology. 2015;151(9):961-9. 10. davila-seijo p, dauden e, descalzo ma, carretero g, carrascosa jm, vanaclocha f, et al. infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: findings from the biobadaderm registry. the journal of investigative dermatology. 2017;137(2):313-21. 11. hsu dy gk, silverberg ji. serious infections in hospitalized patients with psoriasis in the united states. journal of the american academy of dermatology. 2016;75(2):287-96. 12. carneiro c, bloom r, ibler e, majewski s, sable ka, guido nj, et al. rate of serious infection in patients who are prescribed systemic biologic or nonbiologic agents for psoriasis: a large, single center, retrospective, observational cohort study. 2017;30(5):e12529. 13. yiu zz, exton ls, jabbar-lopez z, mustapa mfm, samarasekera ej, burden ad, et al. risk of serious infections in patients with psoriasis on biologic therapies: a systematic review and meta-analysis. 2016;136(8):1584-91. 14. garcia-doval i, cohen ad, cazzaniga s, feldhamer i, addis a, carretero g, et al. risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti–tumor necrosis factor agents versus infection by controlling the inflammatory process and decreasing the disease severity or increasing this risk by suppressing the immune system. [11] in the present study, patients being treated with tnf-a inhibitors did not have any increase in infection risk, and even a lower risk of cellulitis was detected among patients using infliximab. carneiro et al. [12] and wakkee et al. [8] did not report any increase in infection risk in patients using biologic treatments compared with conventional drugs. likewise, according to the yiu et al. [13] and garcia-doval [14] studies, no increased risk of serious infections was found in patients on anti-tnf treatments. on the other hand, yiu et al. have shown that infliximab was associated with a two-fold increased risk of serious infections compared with non-biologic treatments and a 3-fold increased risk compared with methotrexate. [15] additionally, in a cohort study, kalb et al. showed that serious infections were more likely to occur with adalimumab and infliximab than with non-biologic and non-methotrexate treatments. [9] likewise, in three other studies, the authors found a higher risk of infection in biologic treatment compared with conventional treatments. in recent studies, systemic-immune inflammation index (sii) (neutrophil x platelet/lymphocyte) as a new complete blood cell index has been used in the prediction of disease progression and was associated with psoriasis activation and severity. significantly higher sii values were present in higher pasi scores and indicated increased inflammatory response and poor prognosis. sii can also be an additional indicator of disease activation in autoimmune diseases such as behçet’s disease. [16, 17] limitation this retrospective survey was restricted solely to inpatient psoriatic cases admitted in the dermatology ward of a skin referral hospital. therefore, information about patients treated in outpatient clinics and those hospitalized in general hospitals was unavailable. this study was conducted before the covid-19 outbreak; therefore, it lacks data regarding the relationship between the risk of covid-19 infection and the variables mentioned above. conclusion overall, 21.5% of psoriasis patients in the present study had at least one episode of infection. we observed an increased risk of infection in patients receiving prednisolone, while there was no increase in infection risk in patients treated with biologic drugs and even a relatively reduced risk in mtx-treated patients. original article | dermatol pract concept. 2023;13(1):e2023027 7 16. dincer rota d, tanacan e. the utility of systemic-immune inflammation index for predicting the disease activation in patients with psoriasis. international journal of clinical practice. 2021;75(6):e14101. 17. tanacan e, dincer d, erdogan fg, gurler a. a cutoff value for the systemic immune-inflammation index in determining activity of behçet disease. clinical and experimental dermatology. 2021;46(2):286-91. classic therapies: prospective meta-analysis of psonet registries. 2017;76(2):299-308. e16. 15. yiu zzn, ashcroft dm, evans i, mcelhone k, lunt m, smith ch, et al. infliximab is associated with an increased risk of serious infection in patients with psoriasis in the u.k. and republic of ireland: results from the british association of dermatologists biologic interventions register (badbir). the british journal of dermatology. 2019;180(2):329-37. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023137 1 visualizing touton giant cells under reflectance confocal microscopy in two cases of juvenile xanthogranuloma dominga peirano1, francisca donoso1, sebastián vargas1, leonel hidalgo1, teo feuerhake2, alon scope3,4, caterina longo5,6, cristian navarrete-dechent1,7 1 department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 2 department of pathology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 3 the kittner skin cancer screening & research institute, sheba medical center, ramat gan, israel 4 sackler faculty of medicine, tel aviv university, tel aviv, israel 5 department of dermatology, university of modena and reggio emilia, modena, italy 6 centro oncologico ad alta tecnologia diagnostica-dermatologia, arcispedale santa maria nuova, azienda unità sanitaria locale irccs reggio emilia, reggio emilia, italy 7 melanoma and skin cancer unit, escuela de medicina, pontificia universidad catolica de chile, santiago, chile key words: confocal microscopy, touton cells, diagnosis, juvenile xanthogranuloma citation: peirano d, donoso f, vargas s, et al. visualizing touton giant cells under reflectance confocal microscopy in two cases of juvenile xanthogranuloma. dermatol pract concept. 2023;13(2):e2023137. doi: https://doi.org/10.5826/dpc.1302a137 accepted: november 28, 2022; published: april 2023 copyright: ©2023 peirano et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: cristian navarrete-dechent, md, ifaad, department of dermatology, escuela de medicina, pontificia universidad católica de chile diagonal paraguay 362, 6th floor santiago, chile. 8330077 phone: +56-2-2435 3574 e-mail: ctnavarr@gmail.com introduction juvenile xanthogranuloma (jxg) is a benign nonlangerhans -cell histiocytosis occurring most frequently in childhood [1]. as jxg is rare in adults, it may clinically simulate malignant skin tumors, such as basal cell carcinoma (bcc) or amelanotic melanoma [2]. histopathologically, jxg is characterized by a granulomatous inflammation pattern, whereby the dermal infiltrate consists of histiocytes with abundant cytoplasm and of touton giant cells with a ring-like arrangement of multiple nuclei, separating a central eosinophilic area from the peripheral foamy and pale cytoplasm [3]. reflectance confocal microscopy (rcm) is a non-invasive optical imaging tool that allows for in vivo visualization of skin at cellular-level resolution [4]. herein, we report that an infiltrate of touton giant cells, a key criterion for diagnosis of jxg, can be readily identified via rcm. case presentation case 1. a 63-year-old female was referred for evaluation of a long-standing lesion on the back. on physical examination, a 4-mm orange-pink papule was seen (figure 1a). on dermoscopy, the lesion showed a red-yellow center and discrete 2 research letter | dermatol pract concept. 2023;13(2):e2023137 erythematous halo (“setting-sun appearance”) (figure 1b). on rcm, at the superficial dermis level, an infiltrate of roundish large cells was seen. these were characterized by a hyper-refractile peripheral rim and a hypo-reflective center, measuring 40-50 microns in diameter, suggestive of touton cells (figure 1c). a punch excision of the lesion showed a dense dermal infiltrate of histiocytes. at higher magnification, multinucleated giant cells with nuclei surrounding a central homogeneous cytoplasm measuring 30-50 microns corresponding with touton giant cells, were seen. foamy histiocytes were also visualized (figure 1d). these findings pointed to the diagnosis of jxg. when performing a side-by-side rcm to histopathological correlation, it became clear that the roundish large cells under rcm corresponded to the touton giant cells seen on histopathology. case 2. a 13-year-old healthy boy was referred for evaluation of a solitary pink-yellow lesion on the left arm (figure 2a). dermoscopy revealed homogeneous yellow color (figure 2b). on rcm, a dense infiltrate of roundish, large cells with dark center, surrounded by a hyper-refractile peripheral ring, were visualized (figure 2c). the lesion was excised and diagnosed histopathologically as xgj (figure 2d). figure 1. juvenile xanthogranuloma. a. 4-mm orange-pink papule b. dermoscopy showed a red-yellow center and discrete erythematous halo (‘setting-sun appearance’) (polarized light dermoscopy, original magnification 10x). c. on reflectance confocal microscopy (rcm), a disarranged dermal-epidermal junction was seen, filled with clusters of roundish, large, cells. these were large cells (40-50 microns largest diameter) with a hyperrefractile cytoplasm forming a peripheral rim and a large hypo-reflective nucleus, suggestive of touton cells (yellow arrow). horizontal blood vessels were also seen (red arrows) (0.5 x 0.5 mm, 30x) d. large cells seen on rcm corresponded to the touton cells seen on histopathology (yellow arrows), blood vessels (red arrow) and foamy histiocytes (blue arrows) (h&e, 40x). research letter | dermatol pract concept. 2023;13(2):e2023137 3 conclusions jxg is a benign disease, mostly presenting as a solitary papule or nodule in childhood. we present two cases of jxg, in an adult and in a child, whereby rcm revealed large roundish cells with hypo-reflective center and surrounding hyper-refractile rim appearing as bright halo, corresponding to touton giant cells upon comparison with histopathology. in contrast to touton cells, the foamy cytoplasm of foamy histiocytes does not provide reflectance and are not readily visible under rcm, despite being seen under histopathology in both cases. as the identification of touton giant cells is a key diagnostic finding in jxg, these cases highlight the potential for the bedside diagnosis of jxg with the aid rcm [4,5]. references 1. lacarrubba f, verzì ae, puglisi df, broggi g, caltabiano r, micali g. line-field confocal optical coherence tomography of xanthogranuloma: correlation with vertical and horizontal histopathology. j cutan pathol. 2021;48(9):1208-1211. doi: 10.1111/cup.14067. pmid: 34028070. pmcid: pmc8453847. figure 2. juvenile xanthogranuloma. a. a solitary pink-yellow lesion on the left arm b. on dermoscopy, a homogeneous yellow color was seen (polarized light dermoscopy, original magnification 10x) c. reflectance confocal microscopy shows dilated dermal papillae at dermal-epidermal junction filled with clusters of roundish, large, multinucleated and hyper-refractile atypical cells corresponding to touton cells (yellow arrows) (0.5 x 0.5 mm, 30x). d. histopathology showed a dense histiocytic infiltrate with touton cells (yellow arrows) and foamy histiocytes (blue arrows) (h&e, 40x). 4 research letter | dermatol pract concept. 2023;13(2):e2023137 4. lovato l, salerni g, puig s, carrera c, palou j, malvehy j. adult xanthogranuloma mimicking basal cell carcinoma: dermoscopy, reflectance confocal microscopy and pathological correlation. dermatology. 2010;220(1):66-70. doi: 10.1159/000264670. pmid: 19996569. 5. pimenta r, leal-filipe p, oliveira a. reflectance confocal microscopy for the noninvasive diagnosis of cutaneous juvenile xanthogranuloma. skin res technol. 2019;25(1):106-107. doi: 10.1111/srt.12616. pmid: 30019531. 2. reilly c, chuchvara n, rao b. diagnosing juvenile xanthogranuloma with reflectance confocal microscopy. jaad case rep. 2020;6(10):975-976. doi: 10.1016/j.jdcr.2020.07.034. pmid: 32995422. pmcid: pmc7508718. 3. janssen d, harms d. juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry. am j surg pathol. 2005;29(1): 21-28. doi: 10.1097/01.pas.0000147395.01229.06. pmid: 15613853. research letter | dermatol pract concept. 2023;13(2):e2023137 5 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022109 1 dermatology practical & conceptual a pink nodule with white halo: dermoscopy of halo melanoma francesco borgia1, luca di bartolomeo1, marialorena coppola1, maria lentini2, elvira moscarella3, mario vaccaro1 1 section of dermatology, department of clinical and experimental medicine, university of messina, messina, italy. 2 department of human pathology in adult and developmental age “gaetano barresi”, university of messina, messina, italy. 3 dermatology unit, university of campania “l. vanvitelli”, naples, italy. keywords: melanoma, dermoscopy, halo nevus, amelanotic melanoma citation: borgia f, di bartolomeo l, coppola m, lentini m, moscarella e, vaccaro m. a pink nodule with white halo: dermoscopy of halo melanoma. dermatol pract concept. 2022;12(3):e2022109. doi: https://doi.org/10.5826/dpc.1203a109 accepted: november 8, 2021; published: july 2022 copyright: ©2022 borgia et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: luca di bartolomeo, md. department of clinical and experimental medicine, university hospital g. martino, via consolare valeria, 98125 messina, italy. e-mail: lucadibartolomeo@live.it introduction halo phenomenon consists in an area of depigmentation around a skin lesion. it represents a benign regression phenomenon most associated with acquired nevi [1]. very rarely, a hypopigmented halo can also occur around melanomas (halo melanoma, hm). dermoscopy may help to distinguish them from common halo nevi (hn). case presentation we report the case of a 63-year-old man with a nodular, amelanotic lesion on the back surrounded by an achromic halo. the patient reported that the lesion occurred 1 year before, with a progressive increase in size during the last 5 months. the lesion had become itchy, developing a vitiligo-like halo. physical examination showed a symmetrical, reddish nodule, 8 mm in diameter, surrounded by a whitish area of about 2.5 cm x 2 cm. no other areas of depigmentation were detected on total body examination (figure 1, a and b). dermoscopy revealed central whitish and blue areas on a homogeneous pink-red background and polymorphous vascular pattern characterized by arborizing, hairpin and linear irregular vessels, mainly arranged at the periphery. no pigment network was detected (figure 1, c and d). histology showed achromic atypical melanocytes aggregated in the dermis, without epidermotropism (figure 2a). a perilesional lymphocytic infiltration with fibrosis at the periphery of the nodule was observed. immunohistochemical analysis was positive for melanocytic markers but did not show basal melanocytes in the area of epidermidis surrounding the nodule (figure 2b). total-body positron emission tomography scan results were unremarkable. the diagnosis of dermal melanoma was finally made (breslow thickness 2.4 mm, non-ulcerated). wider local excision and sentinel node biopsies were negative. the patient was disease free at 12 months follow-up. 2 research letter | dermatol pract concept. 2022;12(3):e2022109 figure 1. (a) clinical overview of the patient. (b) naked-eye appearance of amelanotic halo melanoma as a reddish papule surrounded by an achromic halo. (c) dermoscopy showed central whitish and blue areas on a homogeneous pink-red background and polymorphous vascular pattern. (d) close-up of dermoscopic view. figure 2. (a) dermal proliferation of atypical achromic melanocytes with nodular dermal expansion and collarette formation at the periphery (h&e, 4x). (b) immunohistochemistry supports the melanocytic phenotype and emphasizes the lack of junctional melanocytes in the epidermis straddling the collarette (hmb45 immunostaining with hematoxylin counterstain, 4x). conclusions hn occurs in about 1% of the general population while hm is rarer, with only few cases reported in literature [1]. both hn and hm appear as a melanocytic lesion surrounded by a rim of white halo. the main distinguishing clinical feature is that the shape of the achromic halo tends to be more asymmetric in hm compared to hn [1]. hm also research letter | dermatol pract concept. 2022;12(3):e2022109 3 seems to occur at older age. there are only a few reports dealing with dermoscopy of hm, characterized by melanoma-specific multicomponent patterns with atypical pigmented network, irregular dots/globules, streaks, blotches, blue-white veil and atypical vascular structures [2]. in our patient the absence of the pigmentary network and the polymorphous vessels in asymmetric arrangement did not allow to rule out cutaneous melanoma metastasis, even if hypopigmented peripheral halo has been very rarely reported in such cases [1]. histology did not highlight primary melanoma criteria, as ulceration, intraepidermal component, presence of associated nevus or regression. however, the absence of primitive melanoma in another site, as revealed by instrumental exams, led us to conclude for the diagnosis of primary dermal melanoma with peritumoral achromic halo. hm is the most worrisome differential diagnosis of hn. in most cases, dermoscopy may provide useful additional information to clinical assessment, especially about the vascular pattern. however surgical excision and histopathological examination are mandatory especially in case of achromic nodular lesion like in our patient. references 1. nedelcu ri, zurac sa, brînzea a, et al. morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results. rom j morphol embryol. 2015;56 (2 suppl):659-663. pmid: 26429156. 2. conforti c, zelin e, dri a, et al. hypomelanotic halo melanoma: dermoscopic findings. ital j dermatol venerol. 2021;156(3):408409. doi: 10.23736/s0392-0488.20.06727-9. pmid: 33084271. dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(1):e2023003 1 association between lipoid proteinosis and coeliac disease layla bendaoud1, ihssane bigjoine1, ouafa hocar1, said amal1 1 department of dermatology, faculty of medicine and pharmacy, mohammed vi university hospital, cadi ayad university, marrakech, morocco citation: bendaoud l, bigjoine i, hocar o, amal s. association between lipoid proteinosis and coeliac disease. dermatol pract concept. 2023;13(1):e2023003. doi: https://doi.org/10.5826/dpc.1301a3 accepted: july 9, 2022; published: january 2023 copyright: ©2023 bendaoud et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: layla bendaoud, resident in the department of dermatology, rouidate, marrakech, telephone: +212678817589, email: laylabendaoud@gmail.com lipoid proteinosis, also known as urbach-wiethe disease, is a rare autosomal recessive condition, characterized by a mutation of extracellular matrix protein 1(ecm1), leading to deposition of collagenous material in the skin and tissues [1]. this disease may be associated with diabetes and other abnormalities. we report a case of lipoid proteinosis associated with celiac disease in a 23-year-old man. a 23-year-old patient was admitted to our department for facial edema evolving for 1 year, with no other associated signs. the dermatological examination revealed an infiltrated edema of the face, predominantly on the forehead, associated with discrete 3 mm yellow papules in the ear pavilion (figure 1), without mucosal involvement. the histological study of the papule showed a homogeneous, eosinophilic, pas-stained dermal deposit of hyaline substance, in favor of lipoid proteinosis. laboratory tests revealed hypochromic microcytic anemia (hemoglobin of 9 g/dl), ferritin 7ng/ml, hypocholesterolemia 0.7 mmol/l with normal albumin and protein. the patient was further evaluated with an upper endoscopy. the histological examination of the duodenal biopsy revealed atrophic pangastritis with villous atrophy. test iga anti-transglutaminases were highly positive at low titer. the diagnosis of coeliac disease was established. the workup for other disease locations of lipoid proteinosis was negative. the therapeutic approach was to put the patient on a gluten-free diet and acitretin for his skin lesions. after 3 months of treatment with acitretin, the dermatological examination noted a minor improvement of the edema. the cutaneous lesions were still present, without new lesions. then, he was lost to follow-up. lipoid proteinosis, also called hyalinosis cutis mucosae, is a rare, non-life-threatening condition and was first described in 1929 by a dermatologist and an otorhinolaryngologist, e. urbach and c. weithe [2]. around 300 cases have been reported in the literature with higher prevalence in south africa and sweden. hoarseness of the voice is usually the first sign of this disease that appears in childhood. the dermatological manifestations include vesiculobullous lesions, hyperkeratotic plaques on the extensor surfaces of elbows, knees, and hands, yellow papules, and multiple acneiform and pox-like scars that are seen on the face [3]. moniliform blepharitis is the 2 commentary | dermatol pract concept. 2023;13(1):e2023003 characteristic ocular involvement, affecting the eyelid margins. this disease may affect all organ systems of the body. histologic features consist of thick homogeneous, eosinophilic hyaline material, periodic acidschiff positive, in the basement membrane and the dermis [4]. some cases in the literature have mentioned the association of lipoid proteinosis with diabetes [5], and with epilepsy [6]. this is the first report describing an association with coeliac disease. currently, there is no effective treatment. several molecules have been used with different results, such as d-penicillamine, dimethyl-sulfoxide, and retinoids for their inhibitory effect on collagen. also, co2 laser, dermabrasion, and chemical peeling represent other therapeutic means for the management of cutaneous lesions [3]. knowledge of this rare disease will aid health professionals in diagnosing it early, and in providing the appropriate treatment to improve the quality of life. references 1. parida jr, misra dp, agarwal v. urbach-wiethe syndrome. bmj case reports. published online september 2, 2015:bcr2015 212443. doi:10.1136/bcr-2015-212443 2. naha k. lipoid proteinosis mimicking congenital immunodeficiency: a case report. amj. 2011;4(3):155-159. doi:10.4066 /amj.2011.635 3. natarajan b, prathap p, asokan n, balakrishnan s. lipoidproteinosis – an erratic disease with an archetypal presentation. jsstd. 2020;2:56-58. doi:10.25259/jsstd_9_2020 4. giandomenico sd, masi r, cassandrini d, et al. lipoidproteinosis: case report and review of the literature. :6. 5. baykal c, topkarci z, yazganoglu kd, azizlerli g, baykan b. lipoidproteinosis: a case seriesfrom istanbul. international journal of dermatology. 2007;46(10):1011-1016. doi:10.1111/j.13 654632.2007.03115.x 6. tecellioglu m, kamisli o, acar c, et al. lipoidproteinosis and epilepsy: molecular analysis. ann med res. 2019;(0):1. doi:10.5455/annalsmedres.2019.02.100 figure 1. yellowish-white papules of the ear. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023104 1 cutaneous cytomegalovirus infection in a case of myasthenia gravis sree yazhini ramar1, logamoorthy ramamoorthy1, bheemanathi hanuman srinivas2, laxmisha chandrashekar1 1 department of dermatology & std, jipmer, puducherry, india 2 department of pathology, jipmer, puducherry, india citation: ramar sy, ramamoorthy l, srinivas bh, chandrashekar l. cutaneous cytomegalovirus infection in a case of myasthenia gravis. dermatol pract concept. 2023;13(2):e2023104. doi: https://doi.org/10.5826/dpc.1302a104 accepted: september 26, 2022; published: april 2023 copyright: ©2023 ramar et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: laxmisha chandrashekar, m.d, professor, department of dermatology & std, jipmer, puducherry, pin-605006. e-mail: laxmishac@gmail.com case presentation a 66-year-old man with a known case of myasthenia gravis presented with multiple painful ulcers over the buttock, lower abdomen, and trunk for one month. cutaneous examination showed multiple ecthymatous to ulcerative lesions with slough over the buttocks, perianal area, and over the lower abdomen and upper back, largest measuring 3 x 3 cm to smallest measuring 1x1 cm (figure 1). wedge biopsy from the perianal ulcer showed ulceration of the epidermis with lymphocytic infiltrate with epithelioid histiocytes and foreign body type of giant cells in the superficial dermis. the endothelial cells exhibited nucleomegaly with basophilic smudgy chromatin with occasional basophilic prominent intra-nuclear inclusions. immunohistochemistry showed nuclear positivity of the endothelial cells for cytomegalovirus. teaching point human cytomegalovirus (cmv) infection usually occurs in immunocompetent individuals causing the infectious mononucleosis-like syndrome. although systemic symptoms are more common in immunosuppressed individuals with cmv infection, some can present with cutaneous manifestations that are difficult to diagnose based on their clinical appearance. the cutaneous manifestations of the cmv virus are maculopapular rash, blisters, bulla, erosions, plaques, and nodules. the most common presentation is cutaneous ulcers, which may be tender or non-tender and usually located over the genitalia, perianal, gluteal regions, and oral mucosa [1]. since the virus remains latent in the gastrointestinal tract and sheds during reactivation, leading to the preferential location of the 2 image letter | dermatol pract concept. 2023;13(2):e2023104 ulcers over the perianal and gluteal area [2]. cmv-induced skin ulcers should be considered in immunosuppressed patients who are not responding to antibiotic therapy, similar to our case. the diagnosis of cmv ulcers can be made by histology with immunohistochemistry and by serum polymerase chain reaction. histopathological examination shows owl eye inclusions with cytopathic changes predominantly over the vascular endothelial cells and macrophages [2]. figure 1. multiple ulcers over the perianal and gluteal region with minimal slough size ranging from 3 x 3 cm to 1 x 1 cm. references 1. drozd b, andriescu e, suárez a, de la garza bravo mm. cutaneous cytomegalovirus manifestations, diagnosis, and treatment: a review. dermatol online j. 2019; 25(1):13030 /qt84f936cp. pmid: 30710895. 2. lei dk, saul kd, jackson jd, ishaq ny, brodell rt. perianal ulceration in a young woman. am j dermatopathol. 2016; 38(9): 683-684. doi: 10.1097/dad.0000000000000294. pmid: 27541168. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023155 1 erdheim chester disease: a rare entity from north india bhavya swarnkar1, gouri renuka pushpanandan anand1, somesh gupta1, shipra agarwal2 1 department of dermatology, venereology and leprosy, all india institute of medical sciences, new delhi, india 2 department of pathology, all india institute of medical sciences, new delhi, india key words: erdheim chester disease, non-langerhans cell histiocytosis, setting sun, braf citation: swarnkar b, anand grp, gupta s, agarwal s. erdheim chester disease: a rare entity from north india. dermatol pract concept. 2023;13(3):e2023155. doi: https://doi.org/10.5826/dpc.1303a155 accepted: january 6, 2023; published: july 2023 copyright: ©2023 swarnkar et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr somesh gupta, department of dermatology, all india institute of medical sciences, ansari nagar east, new delhi-110029 phone: 9868899120 e-mail: someshgupta@hotmail.com patient consent was taken before sending the report for publication case presentation a man in his 40s presented with yellowish brown papuloplaques over bilateral eyelids for the past 3.5 years (figure 1a). he complained of a mildly tender, skin-colored, cystic swelling over the left shin, diffuse pain over bilateral legs, polydipsia, and polyuria for the past 2 years. dermoscopy showed a ‘setting sun’ sign consisting of yellowish background with subtle erythema at the periphery. increased pigment network and whitish areas were present. branching linear vessels of variable thickness were also seen throughout the lesion (figure 1b). x-rays of the skull and extremities showed lytic lesions with sclerotic margin in bilateral femurs, tibia, (figure 1c) fibula, radius, ulna, and skull (figure 1d). skin biopsy showed features of xanthogranulomatous tissue response. cells were immune-positive for cd68 but negative for s100 and cd1a. v600ebraf mutation was positive. whole body pet scan showed increased fdg uptake over bilateral lower eyelids, hypermetabolic thickening involving the left renal pelvis extending to a calyceal system with left moderate and right mild hydronephrosis. serum osmolality was 292 mosm/kg while urine osmolality was 93 mosm/kg suggestive of diabetes insipidus. based on history, examination, and investigations, we made the diagnosis of erdheim chester disease (ecd). 2 image letter | dermatol pract concept. 2023;13(3):e2023155 figure 1. (a) yellowish brown papuloplaques over bilateral eyelids. (b) ‘setting sun’ sign, increased pigment network, whitish areas, and branching linear vessels (using hand held polarized dermatoscope ids1100, illuco, korea). (c) lytic lesions with sclerotic margin in metaphyseal and diaphyseal region of femur and tibia. (d) lytic lesions with sclerotic margin in skull. teaching point ecd should be ruled out in patients with periocular xanthelasma-like plaques with associated systemic symptoms like bone pain, and diabetes insipidus. bony lytic lesions, as seen in our patient, have been reported uncommonly in around 5-30% of the cases of ecd [1,2]. we also described dermoscopy features. references 1. oweity t, scheithauer bw, ching hs, lei c, wong kp. multiple system erdheim-chester disease with massive hypothalamic-sellar involvement and hypopituitarism. j neurosurg. 2002;96(2): 344–351. doi: 10.3171/jns.2002.96.2.0344. pmid: 11838810. 2. veyssier-belot c, cacoub p, caparros-lefebvre d, et al. erdheim-chester disease. clinical and radiologic characteristics of 59 cases. medicine (baltimore). 1996;75(3):157–169. doi: 10.1097/00005792-199605000-00005. pmid: 8965684. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023031 1 limited access to dermatology specialty care: barriers and teledermatology darlla d. duniphin1,2 1 university of oklahoma health sciences center, oklahoma city, oklahoma, united states 2 a.t. still university, mesa, arizona, united states key words: barriers, teledermatology, melanoma, non-melanoma, skin cancer citation: duniphin dd. limited access to dermatology specialty care: barriers and teledermatology. dermatol pract concept. 2023;13(1):e2023031. doi: https://doi.org/10.5826/dpc.1301a31 accepted: april 17, 2022; published: january 2023 copyright: ©2023 duniphin. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: darlla d. duniphin, university of oklahoma health sciences center, oklahoma city, oklahoma, united states, e-mail: darlla-duniphin@ouhsc.edu introduction: access to dermatology specialty care is limited in the underserved population. barrier identification and exploring the potential role of teledermatology are the first steps to address this problem. objectives: identify the barriers to dermatologist care for the diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. additionally explored was the potential role of teledermatology to provide dermatology care access in the underserved population. methods: a quantitative descriptive study was conducted via an online survey instrument. the survey’s barriers portion was adapted from the 1998 ohio family health survey (ofhs). the survey’s teledermatology portion was adapted from the mcfarland teledermatology provider and imaging technician satisfaction survey. the participants were practicing dermatologists and members of georgia, missouri, oklahoma, and wisconsin dermatology associations. thirty-eight responded to demographic questions, of which twenty-two responded to the survey items. results: the top three barriers ranked as the most concerning were “continually uninsured” (n = 8; 36.40%), “resides in a medically underserved county” (n = 5; 22.70%), and “family under federal poverty level” (n = 7; 33.30%). teledermatology as a potential role for access to care was supported by convenient delivery of healthcare (n = 6; 72.70%), an addition to regular patient care (n = 20; 90.90%), and increase to patient care access (n = 18; 81.80%). conclusion: barrier identification and teledermatology access to provide care to the underserved population is supported. further teledermatology research is necessary to address the logistics regarding how to initiate and deliver teledermatology to the underserved. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023031 introduction access to dermatology specialty care is limited in the underserved population and is related to patient socioeconomic status, rural residence status, and provider location distribution  [1]. melanoma and non-melanoma skin cancer in the underserved population have public health repercussions that include poor patient outcomes directly associated with late-stage diagnoses [2]. barrier identification and dermatology access are the first steps to address the dermatological needs of the underserved population. it is estimated that a 16% increase will occur between 2013 and 2025 for dermatology visits [3]. there are approximately 3.4 dermatologists per 100,000 population, which is lower than what is needed to provide adequate dermatology care in communities [4]. this overall dermatology access shortage includes 67.10% in dedicated medical dermatology patient care time [5].the combination of the rise in skin cancer rates, extended wait times, increased need for dermatology visits, and the shortage of practicing dermatologists prompts a valid public health concern. this concern is exacerbated by barriers to care for the underserved. innovative methods are necessary for patients to have sufficient access to dermatologist care [5]. teledermatology allows providers to diagnose and recommend treatment and address the limited dermatology specialty care access in the underserved population. one of the main teledermatology applications is to triage dermatology patients with higher morbidity and mortality risks to facilitate earlier in-person visits [6]. this access accommodates early detection of potentially lethal dermatological diseases such as melanoma and non-melanoma skin cancers. the barrier-focused framework included patient income, lack of insurance, and where the underserved population seeks health care. the poor, those who live in rural areas, and high minority locations lack access to dermatologists [1]. there is a need for additional research-tested programs for dermatologic treatment for underserved communities [2]. to address and explore potential treatment intervention programs, barrier identification for dermatologist care of skin cancers in the underserved population is necessary in closing the gap of dermatologic specialty care of melanoma and nonmelanoma skin cancers to the underserved population. current research also includes the use of teledermatology for general dermatology care; however, there is a scarcity of teledermatology to provide access for diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. early detection that leads to earlier diagnosis and treatment of melanoma and non-melanoma skin cancers improves patient care outcomes and reduces morbidity and mortality [7]. barrier identification is the first step to find and improve interventions to address and resolve these obstacles. objectives the purpose of this quantitative descriptive research study was to identify the barriers to dermatologist care for diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. additionally explored was the potential role of teledermatology to provide access to this care in this population. methods the research design was a quantitative descriptive study via a survey instrument. the study participants were practicing dermatologists who were members of either georgia, missouri, oklahoma, or wisconsin dermatology associations. the respective state dermatology associations sent the surveys to the memberships. the accessible population included 700 dermatologists. the estimate of this population size with a confidence level of 95%, a margin of error at 5%, and the estimated 10% response rate indicates 248 participant responses was the optimal sample size [8]. a total of 38 responded to demographic questions, of which 22 responded to the survey items. the cover letter served as the survey participation invitation with the inserted surveymonkey link. survey responses were anonymous with computer password protection. the survey data collection range was february 2019 – april 2019. the inclusion criteria were (a) a practicing dermatologist who is a member of his or her respective state dermatology association in the states of georgia, missouri, oklahoma or wisconsin; and (b) between the ages of 25 through 64. the exclusion criteria were (a) a non-practicing dermatologist in any state and (b) below the age of 25 or above the age of 64. the sampling methodology was quantitative. the sampling methodology was non-probability consecutive sampling. the barriers portion of the survey was adapted from the 1998 ohio family health survey (ofhs), which was developed through the ohio department of health [9]. ten rank-order barriers were adapted regarding access to dermatological specialty care. permission to use and adapt the data collection tool, “mcfarland teledermatology provider and imaging technician satisfaction survey” was requested, approved, and received by the author dr. lynne mcfarland. nineteen items on a 5-point likert scale were adapted for the teledermatology items. the demographic portion of the survey included dichotomous, classificatory, and rank-order responses. the demographics included age, sex, degrees, income, and race. also included in the demographics were practice setting, practice-setting location, and if the participant had received training in teledermatology. the validity and reliability of the “mcfarland teledermatology provider and imaging technician satisfaction original article | dermatol pract concept. 2023;13(1):e2023031 3 survey” was based on the validated psq originally developed by ware et al. that classifies similar items [10]. the questions were from a standardized, validated, and reliable instrument (cronbach’s alpha = 0.72-0.92 over the domains for internal consistency) and construct validity regarding multiple patient settings. according to mcfarland, this instrument was for telemedicine in general, but not specifically teledermatology. mcfarland’s questions were dermatologist and medical provider vetted for concerns and satisfaction areas [10]. the satisfaction domains were recommended by a review of kraai et al. telemedicine satisfaction surveys [10]. two dermatologist subject-matter experts were enlisted to establish face and content validity for this study’s survey. the feedback included the addition of the practice setting to specify academic, private, or hospital, and the practice setting location to specify urban, rural, or suburban. feedback also included if the participant had teledermatology training. descriptive statistical analysis was conducted using ibm spss statistics version 25. frequencies and percentages were reported for nominal demographic variables. frequencies, percentages, median, and iqr were reported for ordinal demographic variables. ratio level data were tested for normality using the shapiro-wilk test (α <.05) and the median and iqr were reported. the barriers were rank-ordered with frequencies and percentages noted. a 5-point likert scale was used to rate the responses of the teledermatology items. because the statements were adapted from a standardized data collection instrument and not all of the original questions were included, an item-by-item analysis was conducted. frequencies and percentages were reported for the teledermatology items as well. findings for rank-ordered barriers and teledermatology items were included both in text and in a tabular format. results an estimated 700 potential participants received the survey via the four dermatologist societies. thirty-eight participants responded to demographic questions. of the 38 respondents, 22 responded to the survey items. the remaining 16 surveys were excluded due to not meeting inclusion criteria or not answering the barrier or teledermatology item sets. the approximate number of participants that received surveys was 700, which represents a 5.43% overall response rate. the complete survey response rate was 3.14%. testing for normality for the age demographic was completed by using the shapiro-wilk test (p = .005). the median age was 54 (iqr  =  17) years (see table s1). the majority of the respondents were male (n = 13; 54.20%), and most held md degrees (n = 25; 65.80%). annual income was tested for normality using the shapiro-wilk test. the median income was $200,000 or more (iqr = 0). most practice settings were private (n = 24; 96.00%), and the location setting majority was suburban practice (n = 15; 60.00%). most dermatologists did not have teledermatology training (n = 14; 56.00%) (see table s1). research question 1. the first research question addressed the rank-ordering of the barriers to dermatologist care for the diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. ten barriers were rank-ordered by the respondents in order of greatest to least concerning barrier (see table s2). the top three barriers ranked as the most concerning were “continually uninsured” (n = 8; 36.40%), “resides in a medically underserved county” (n = 5; 22.70%), and “family under federal poverty level” (n = 7; 33.30%), respectively (see table s3). research question 2. the second research question addressed the potential role of teledermatology in providing access to dermatologist care for the diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. the respondents rated each statement on a 5-point likert scale ranging from strongly disagree = 1 to strongly agree = 5. the scale ratings were collapsed to produce a dichotomous response for each statement item. strongly disagree and disagree were combined as well as strongly agree and agree were combined. no opinion was removed from the analysis results to maintain dichotomous results (see table s4). this study found that the major barriers to the diagnosis and treatment of melanoma and non-melanoma in the underserved population were related to insurance status, medically underserved county residence, and income level. the greatest barrier was “continually uninsured patients”, followed by “resides in a medically underserved county”, and “family under federal poverty level”. the results regarding the barriers of “resides in a medically underserved county”, and “family under federal poverty level” support the research by vaidya1 that the poor access to dermatology specialty care in the underserved population is related to patient socioeconomic status, rural residence, and provider location distribution. research results by campagna et al. [11] additionally support that limited access to dermatology specialists is due to rural residence and socioeconomic barriers in the underserved population. the highest-ranked barrier of continually uninsured identified in this study supports the research of nelson et al. [12] that uninsured, medicaid, and rural patients have increased wait times for dermatology office visits. the appointment waiting time for this population to see a dermatologist delays diagnosis and subsequent treatment. this result is also supported by the research of pasquali et al. [13] that a benefit of teledermatology provided dermatology specialty care access to patients in remote areas and patients on long waiting lists. 4 original article | dermatol pract concept. 2023;13(1):e2023031 work. the findings in this study showed that the preference was face-to-face patient visits over teledermatology, and the lack of physical contact for the physical exam was a concern. these results did not support mcfarland, which reports a slight preference for teledermatology over face-to-face visits, as well as the lack of physical contact, which was sufficient. the results of this study included the recognition of the need for access and care for the underserved population, which supported jacobsen et al. [2] showing there is a need for additional research-tested programs for the treatment of the underserved population. the sample size of this study was relatively small compared to the number of u.s. dermatologists. the small sample size limits the generalizability of this study, and the results are suggestive to the population. the findings of this study identified and rank-ordered the barriers to the diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population. these identified findings can be addressed by healthcare providers and administrators to begin to overcome these barriers for patients. the results also indicate that there is a potential role for teledermatology to provide access to dermatology specialty care. these findings can also be used by healthcare providers and administrators to not only address the barriers but to begin the logistical and financial process to provide teledermatology services. by opening the dialogue of barrier identification and teledermatology potential, dermatology diagnosis and treatment of melanoma and non-melanoma skin cancers can result in better patient care and outcome. a limitation of this study was the small sample size, which reduced the generalizability of the study results. the sampling method was also a limitation, as it did not reach a large enough number of practicing dermatologists. due to the time allotted for this study, a limitation was also addressing two different research questions as opposed to one. even though they are related to each other, separate studies would allow greater focus and more in-depth research for each question. recommendations for future research include attempting to resolve the limitations discussed for this study, such as obtaining a larger sample size by additional participant requests and devoting more research time. a recommendation for research includes exploring the logistics and costs associated with providing teledermatology to the underserved as well as patient transportation for follow up faceto-face visits. the cost and payment of treatment, how to initially launch teledermatology, and operational requirements also need to be researched to address the need for care of the underserved. this research process has shown that each item identified opens up new avenues to be explored and studied. the conceptual barrier-focused framework included the lack of insurance, where the underserved population seeks healthcare access, and patient income, which was supported by this study’s findings. the status of the patients’ health, insurance, and income was among barriers associated with the lack of a regular healthcare source [9]. barrier identification is the first step to resolve access and care. innovative methods are necessary for patients to have sufficient access to dermatologist care [5]. this study also found that the role of teledermatology in providing access to dermatological specialty care for diagnosis and treatment of melanoma and non-melanoma is a viable option in the underserved population. this finding supports levitt et al. [6] that using teledermatology in the underserved population increases access to care for this population. the results of this study found that dermatologists agreed regarding the ability to describe and assess dermatology diagnoses and treatment needed as well as monitor the patients’ conditions via teledermatology. these findings agree with leavitt et al. [6] that teledermatology contributes to accurate diagnoses with consistency. teledermatology could increase access to dermatology care, which would ease the ability for patients to contact a dermatologist. the increase in access is supportive of earlier patient care, which could benefit earlier skin cancer detection. these results also support the premise of apalla et al. [7] that early detection leads to early diagnosis and treatment of melanoma and non-melanoma skin cancers and improves patient care outcomes, reducing morbidity and mortality. research by fludiona et al. [14] provides additional support regarding early detection, reporting that suspicious neoplasms were the top diagnosis that recommended accelerated face-to-face consultation for teledermatology patients. teledermatology is the clinical diagnostic technology of choice for patients who have concerning lesions with access barriers to care per skudalski et al. [15]. teledermatology was found to be a convenient form of healthcare delivery and a standard form of healthcare delivery for the future. these results support nelson et al. [12] that teledermatology complements outpatient dermatology healthcare delivery. this study found that dermatologists were willing to add teledermatology to the regular patient care received and agreed there was no threat to patient confidentiality and privacy. these results support mcfarland et al. [10] also showing majority agreement in the same areas. the results of this study indicated that the logistics of using the camera and computer in teledermatology were not difficult; however, trusting the equipment to work was a concern. these results were in agreement with mcfarland regarding whether the equipment was easy to use; however, it was in opposition regarding whether the equipment was trusted to original article | dermatol pract concept. 2023;13(1):e2023031 5 4. glazer am, rigel ds. analysis of trends in geographic distribution of us dermatology workforce density.  jama dermatology. 2017;  153(5): 472. https://doi.org/10.1001 /jamadermatol.2016.6032. 5. buster kj, stevens ei, elmets ca. dermatologic health disparities.  dermatologic clinics. 2012;30(1):53-59. https://doi .org/10.1016/j.det.2011.08.002. 6. leavitt er, kessler s, pun s, et al. teledermatology as a tool to improve access to care for medically underserved populations: a retrospective descriptive study. journal of the american academy of dermatology. 2016;75(6):1259-1261. https://doi .org/10.1016/j.jaad.2016.07.043. 7. apalla z, lallas a, sotiriou e, et al. epidemiological trends in skin cancer. dermatology practical & conceptual. 2017;7(2). 8. sample size table. (n.d.). retrieved from http://researchadvisors .com/tools/samplesize.htm. 9. litaker d, koroukian sm, love te. context and healthcare access: looking beyond the individual.  medical care4. 2005;3(6):531-540. https://doi.org/10.1097/01.mlr.0000163642. 88413.58. 10. mcfarland lv, raugi gj, reiber ge. primary care provider and imaging technician satisfaction with a teledermatology project in rural veterans health administration clinics.  telemedicine and e-health. 2013;19(11):815-825. https://doi.org/10.1089 /tmj.2012.0327. 11. campagna m, naka f, lu j. teledermatology: an updated overview of clinical applications and reimbursement policies. international journal of women’s dermatology. september 2017;3(3):176-179. https://doi.org/10.1016/j.ijwd.2017.04.002 12. nelson ca, takeshita j, wanat ka, et al. impact of store-and-forward (saf) teledermatology on outpatient dermatologic care: a prospective study in an underserved urban primary care setting. journal of the american academy of dermatology. 2016;74(3):484-490.e1. https://doi.org/10.1016/j .jaad.2015.09.058. 13. pasquali p, sonthalia s, moreno-ramirez d, et al. teledermatology and its current perspective. indian dermatology online journal. 2020;jan-feb;11(1):12-20. https://doi.org/10.4103/idoj .idoj_241_9 14. fludiona n, jun l, porto a, et al. impact of dermatology econsults on access to care and skin cancer screening in underserved populations: a model for teledermatology services in community health centers. journal of the american academy of dermatology. 2018;78(2):293-302. https://doi.org/10.1016/j .jaad.2017.09.017 15. skudalski l, waldman r, kerr p, et al. melanoma: how and when to consider clinical diagnostic technologies. journal of the american academy of dermatology. 2022;86(3):503-512. https://doi.org/10.1016/j.jaad.2021.06.90 conclusion the purpose of this study was to identify the barriers to the diagnosis and treatment of melanoma and non-melanoma skin cancers in the underserved population, as well as the potential role of teledermatology to provide access to dermatologist care. the most concerning barriers, namely “continually uninsured”, “resides in a medically underserved county”, and “family under federal poverty level”, prompt the need for additional research to address and overcome these barriers. these barriers raise public issues of affordable health care, healthcare provider incentive to practice in underserved locations, and the effect of poverty regarding healthcare. there is support for the potential role of teledermatology to provide dermatology care for the underserved. even though dermatologists did prefer face-to-face visits over teledermatology as well as a concern for lack of physical contact, the remaining results support teledermatology use. access barriers are also concerning in other countries including india, madagascar, and senegal due to a low dermatologist-to-population ratio. [13]. in addition to identifying barriers to specialty dermatology access for the underserved population, teledermatology includes training to cover basic dermatological conditions on a global scale [13]. within the scope of this study, the accessto-care barriers regarding general skin care versus specialty dermatological care are the same, as the focus is in regards to the underserved population. further research is needed to address the logistics to initiate and deliver teledermatology to the underserved, as well as the costs to provide access, treatment cost, and patient transportation. in summary, identifying the barriers as the first step to providing dermatology care for the underserved raises the need for more research to address and find resolutions. the role of teledermatology to provide access is supported, but there is also a need for further research to explore the logistics and costs to provide this service to the underserved. acknowledgment: helen salisbury, phd, a.t. still university, mesa, arizona, united states references 1. vaidya t, zubritsky l, alikhan a, et al. socioeconomic and geographic barriers to dermatology care in urban and rural us populations. journal of the american academy of dermatology. 2017;78(2):406-408. https://doi.org/10.1016/j.jaad.201707.050. 2. jacobsen aa, galvan a, lachapelle cc, et al. defining the need for skin cancer prevention education in uninsured, minority, and immigrant communities. jama dermatology. 2016;152(12):1342. https://doi.org/10.1001/jamadermatol.2016.3156. 3. yadav g, goldberg hr, barense md, et al. a cross sectional survey of population-wide wait times for patients seeking medical vs. cosmetic dermatologic care.  plos one. 2016;11(9): e0162767. https://doi.org/10.1371/journal.pone.0162767. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023171 1 strawberry gingivitis a diagnostic clue in a male with epistaxis and hemoptysis adhyatm bhandari1, sheetanshu kumar1, anuradha bishnoi1, rajsmita bhattacharjee1, aman sharma2, rahul mahajan1 1 department of dermatology, venereology, and leprology, postgraduate institute of medical education and research, chandigarh, india 2 department of rheumatology, postgraduate institute of medical education and research, chandigarh, india citation: bhandari a, kumar s, bishnoi a, bhattacharjee r, sharma a, mahajan r. strawberry gingivitis a diagnostic clue in a male with epistaxis and hemoptysis. dermatol pract concept. 2023;13(3):e2023171. doi: https://doi.org/10.5826/dpc.1303a171 accepted: february 2, 2023; published: july 2023 copyright: ©2023 bhandari et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr rahul mahajan, associate professor, department of dermatology, venereology, and leprology, postgraduate institute of medical education and research, chandigarh, india. phone no: 91-172-2756564 e-mail: drrahulpgi@yahoo.com case presentation a young male presented with the complaint of gingival swelling which started 15 days before and increased rapidly in size. he gave a history of productive cough with bouts of streaky hemoptysis for the past 9 months along with episodes of rhinitis, nasal crusting and nasal bleeding for the past 1 month. on mucocutaneous examination, enlargement of maxillary gingiva and lower labial mucosa was observed with granular surface and overlying petechial spots giving an appearance of a “ripe strawberry”. investigations revealed ground glass opacities in the lungs on contrast-enhanced computed tomography (cect) chest, maxillary sinusitis on non-contrast computed tomography scan of the paranasal sinuses (ncct pns) and positive cytoplasmic antineutrophil cytoplasmic autoantibody (c-anca) serology. on the basis of above findings, a diagnosis of wegener granulomatosis (wg) was established and the patient was started on oral corticosteroids and immunosuppressants. teaching point wg is characterized by necrotizing and granulomatous vasculitis predominantly affecting the respiratory tract and kidneys but may also involve other tissues [1]. oral involvement in wg is observed in 6%-13% of patients and oral cavity may be the first site of involvement in 5%–6% of cases [1]. strawberry gingivitis is considered to be a characteristic sign of wg and presents as red to purple enlarged gingiva with petechiae and granular surface resembling an over-ripe strawberry. other differentials for similar gingival enlargement include drug-induced gingival hypertrophy, hemangiomas, pyogenic granulomas, crohn’s disease , sarcoidosis, peripheral giant cell granuloma and kaposi sarcoma [2]. presence of characteristic strawberry gingivitis is a vital clue 2 image letter | dermatol pract concept. 2023;13(3):e2023171 in the patients of wg who otherwise lack several other typical features. references 1. almouhawis ha, leao jc, fedele s, porter sr. wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment. j oral pathol med. 2013;42(7):507-516. doi: 10.1111/jop.12030. pmid: 23301777. 2. siar ch, yeo kb, nakano k, et al. strawberry gingivitis as the first presenting sign of wegener's granulomatosis: report of a case. eur j med res. 2011;16(7):331-334. doi: 10.1186/2047783x-16-7-331. pmid: 21813375. pmcid: pmc3352006. figure 1. diffuse edematous and erythematous gingival hyperplasia with petechial spots giving an appearance of a ripe strawberry. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022161 1 subungual eccrine angiomatous hamartoma: description of a novel dermoscopic feature takahiro mizuta1, nobuo isono2, miyuki kato1 1 department of dermatology, tokyo metropolitan tama medical center, fuchu‐shi, tokyo, japan 2 department of plastic and surgery, tokyo metropolitan tama medical center, fuchu‐shi, tokyo, japan citation: mizuta t, isono n, kato m. subungual eccrine angiomatous hamartoma: description of a novel dermoscopic feature. dermatol pract concept. 2022;12(4):e2022161. doi: https://doi.org/10.5826/dpc.1204a161 accepted: january 31, 2022; published: october 2022 copyright: ©2022 mizuta al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: takahiro mizuta, md, tokyo metropolitan tama medical center, 2‐8‐29 musashidai, fuchu‐shi, tokyo 183‐8524, japan. phone: +81-42-323-5111, fax: +81-42-312-9156 e-mail: t.miz.cof.lif2120@gmail.com case presentation a 45-year-old woman presented with a 2-month history of progressive tenderness at the tip of the left first toenail. clinical examination showed no gross abnormalities within and beneath the nail plate. nail plate dermoscopy revealed longitudinal yellowish-brown to yellowish-red areas with no remarkable changes in the nail plate, lunula, or proximal nail fold (figure 1a). histologic examination showed increased number of eccrine glands with irregular, dilated blood vessels (figures 1, b and c), consistent with the diagnosis of eccrine angiomatous hamartoma (eah). teaching point eah is a rare, benign combined eccrine and vascular malformation located mainly on the limbs, rarely in subungual areas. to our knowledge, this is the first report on nail plate dermoscopic descriptions of eah. the presence of yellowish-brown to yellowish-red areas may reflect the 2 image letter | dermatol pract concept. 2022;12(4):e2022161 figure 1. (a) nail plate dermoscopy revealed yellowish-brown to yellowish-red areas, which are arrayed longitudinally under the nail plate. (b, c) histopathology showed the hamartomatous presentation of the lobules of the eccrine glands accompanied by abnormally dilated vessels. (h&e stain; original magnification: b, ×4; c, ×20.) numerous dilated eccrine glands and clusters of dilated capillaries among and around the eccrine glands, which could be helpful in its diagnosis [1,2]. acknowledgments: we thank editage (www.editage.com) for english language editing. references 1. garcía garcía sc, saeb lima m, villarreal martínez a, et al. dermoscopy of eccrine angiomatous hamartoma: the popcorn pattern. jaad case rep. 2018;4(2):165–167. doi: 10.1016/j. jdcr.2017.08.014. pmid: 29387774. 2. kelati a, chiaverini c, giacchero d, ilie m, lacour jp, bahadoran p. dermoscopy of eccrine angiomatous hamartoma: the spitzoid pattern. jaad case rep. 2018;4(8):835–836. doi: 10.1016/j.jdcr.2018.06.026. pmid: 30238051. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023130 1 sorafenib-induced acute generalized exanthematous pustulosis andrea cortese1,2, saverio pancetti3, tiziana pressiani4, francesco toso1,2, giovanni fiorillo1,2, antonio costanzo1,2, riccardo giovanni borroni1,2 1 dermatology, humanitas research hospital – irccs, rozzano (mi), italy 2 department of biomedical sciences, humanitas university, pieve emanuele (mi), italy 3 pathology, humanitas research hospital irccs, rozzano (mi), italy 4 oncology, humanitas research hospital irccs, rozzano (mi), italy key words: sorafenib, acute generalized exanthematous pustulosis, severe cutaneous adverse reaction; tyrosin-kinase inhibitors citation: cortese a, pancetti s, pressiani t, et al. sorafenib-induced acute generalized exanthematous pustulosis. dermatol pract concept. 2023;13(2):e2023130. doi: https://doi.org/10.5826/dpc.1302a130 accepted: november 17, 2022; published: april 2023 copyright: ©2023 cortese et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrea cortese, md, dermatology, humanitas research hospital – irccs, via a. manzoni 56, 20089 rozzano (mi), italy. e-mail: andreacortese08@gmail.com introduction acute generalized exanthematous pustulosis (agep) is a severe cutaneous adverse reaction (scar), with an incidence rate between 1 and 5 cases per million per year. clinically, agep is characterized by the abrupt onset of edematous erythema and widespread small sterile pustules. fever with leukocytosis generally accompany cutaneous findings and mucous membrane may also be affected; the mortality rate of agep is up to 5%. the main differential diagnosis of agep with generalized pustular psoriasis is often challenging [1]. case presentation a 62-year-old man with hbv-related chronic hepatitis was referred to our dermatology unit for the acute onset of skin and mucosal lesions associated with fever, 7 days since the start of oral sorafenib 400 mg twice daily. for radiation therapy-refractory stage iv hepatocellular carcinoma. past medical history was negative for psoriasis. on physical examination, numerous disseminated tiny non-follicular pustules were observed overlying confluent erythematous macules on his trunk and limbs, involving about 75% of the body surface area (figure 1). furred tongue and desquamation of the lips were also present. body temperature was 38.5 °c. no enlarged lymph nodes or hepatosplenomegaly were noticed. complete blood count showed leukocytosis with relative neutrophilia (80%, normal range 50%-75%); serum bilirubin level was increased (3.0 mg/dl, normal range 0.3-1.2 mg/dl). blood and skin cultures resulted negative. histological examination of a skin biopsy showed multifocal spongiosis in the epidermis, with intraepidermal pustules containing fibrin and neutrophils. in the superficial dermis, a mixed inflammatory infiltrate composed of scattered neutrophils and lymphocytes was present (figure 2). according to the validation score of the euroscar study group [2], a diagnosis of acute generalized exanthematous pustulosis (agep) was made; using the naranjo scale [3] the 2 research letter | dermatol pract concept. 2023;13(2):e2023130 skin reaction collected six points and was considered probably relate” to sorafenib (figure 3), so the drug was discontinued with steady improvement in the following days. conclusions sorafenib is an oral multi-kinase inhibitor that mainly targets c-raf, b-raf, vascular endothelial growth factor (vegf) receptors, and platelet-derived growth factor receptor (pdgfr). the drug is approved for the treatment of both unresectable hepatocellular carcinoma and advanced renal cell carcinoma. up to 60% patients treated with sorafenib experience cutaneous adverse events, including hand-foot skin reactions, maculo-papular exanthem, pruritus, alopecia, subungual splinter hemorrhages, seborrheic dermatitis-like eruption and erythema multiforme [4]. agep has been most commonly associated with aminopenicillins, quinolones, chloroquine and sulphonamides, and to our knowledge only three cases of sorafenib-induced pustular reactions were figure 1. confluent erythematous macules on his trunk and limbs, involving about 75% of the body surface area, d with overlying disseminated tiny non-follicular pustules. figure 2. intraepidermal pustule containing fibrin and neutrophils; in the superficial dermis, a mixed inflammatory infiltrate composed scattered neutrophils and lymphocytes was present. research letter | dermatol pract concept. 2023;13(2):e2023130 3 published: one of them defined as acute localized exanthematous pustulosis (alep) [5], while two reported as agep [6,7]. these evidence may suggest an increasing incidence of sorafenib-induced agep due to the relatively recent introduction use of this kinase-inhibitor. we therefore underline the importance of early diagnosis of agep during sorafenib therapy, in order to promptly withdraw the causative drug and at the same time to consider other therapeutic options for metastatic cancer. references 1. sidoroff a, halevy s, bavinck jn, vaillant l, roujeau jc. acute generalized exanthematous pustulosis (agep): a clinical reaction pattern. j cutan pathol. 2001;28(3):113-119. doi: 10.1034/j.1600-0560.2001.028003113.x. pmid: 11168761. 2. sidoroff a, dunant a, viboud c, et al. risk factors for acute generalized exanthematous pustulosis (agep)-results of a multinational case-control study (euroscar). br j dermatol. 2007;157(5):989996. doi: 10.1111/j.1365-2133.2007.08156.x. pmid: 17854366. 3. naranjo ca, busto u, sellers em, et al. a method for estimating the probability of adverse drug reactions. clin pharmacol ther. 1981;30(2):239-245. doi: 10.1038/clpt.1981.154. pmid: 7249508. 4. bracarda s, ruggeri em, monti m, et al. early detection, prevention and management of cutaneous adverse events due to sorafenib: recommendations from the sorafenib working group. crit rev oncol hematol. 2012;82(3):378-386. doi: 10.1016/j. critrevonc.2011.08.005. pmid: 21944842. 5. liang cp, yang cs, shen jl, chen yj. sorafenib-induced acute localized exanthematous pustulosis in a patient with hepatocellular carcinoma. br j dermatol. 2011;165(2):443-445. doi: 10.1111/j.1365-2133.2011.10377.x. pmid: 21495998. 6. pretel m, iñarrairaegui m, lera jm, aguado l, idoate ma. acute generalized exanthematous pustulosis induced by sorafenib. jama dermatol. 2014;150(6):664-666. doi: 10.1001/jamadermatol.2013.6924. pmid: 24671701. 7. alegre-sánchez a, de perosanz-lobo d, pinilla-pagnon i, muñozzato e. sorafenib-induced acute generalized exanthematous pustulosis: an increasing association? actas dermosifiliogr. 2017;108(6):599-601. doi: 10.1016/j.ad.2016.11.018. pmid: 28262110. figure 3. naranjo adverse drug reaction probability scale. # naranjo questions yes no do not know 1. are there previous conclusive reports on this reaction? 1 0 0 2. did the adverse event occur after the suspected drug was administered? 2 -1 0 3. did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 1 0 0 4. did the adverse reaction reappear when the drug was readministered? 2 -1 0 5. are there alternative causes (other than the drug) that could have on their own cause the reaction? -1 2 0 6. did the reaction reappear when a placebo was given? -1 1 0 7. was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 1 0 0 8. was the reaction more severe when the does was increased or less severe when the dose was decreased? 1 0 0 9. did the patient have a similar reaction to the same or similar drugs in any previous exposure? 1 0 0 10. was the adverse event confirmed by any objective evidence? 1 0 0 dermatology: practical and conceptual review | dermatol pract concept. 2023;13(1):e2023016 1 management of infections in psoriatic patients treated with systemic therapies: a lesson from the immunopathogenesis of psoriasis anna balato1, emanuele scala2,3, kilian eyerich2,3,4, nicolò costantino brembilla5, andrea chiricozzi6, robert sabat7,8, kamran ghoreschi9 1 dermatology unit, university of campania, naples, italy 2 division of dermatology and venereology, department of medicine solna, and center for molecular medicine, karolinska institutet, stockholm, sweden 3 department of dermatology and venereology, medical center – university of freiburg, faculty of medicine, university of freiburg, freiburg, germany 4 department of dermatology and venereology, unit of dermatology, karolinska university hospital, stockholm, sweden 5 department of pathology and immunology, university of geneva, geneva, switzerland 6 institute of dermatology, catholic university, rome, italy 7 interdisciplinary group of molecular immunopathology, dermatology/medical immunology, charité–universitätsmedizin, berlin, germany 8 psoriasis research and treatment center, department of dermatology and allergy and institute of medical immunology, charité–universitätsmedizin, berlin, germany 9 department of dermatology, venereology and allergology, charité – universitätsmedizin, berlin, germany key words: psoriasis, infection, prevention, management, covid-19 citation: balato a, scala e, eyerich k, et al. management of infections in psoriatic patients treated with systemic therapies: a lesson from the immunopathogenesis of psoriasis. dermatol pract concept. 2023;13(1):e2023016. doi: https://doi .org/10.5826/dpc.1301a16 accepted: may 30, 2022; published: january 2023 copyright: ©2023 balato et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: emanuele scala, phd, division of dermatology and venereology, department of medicine solna, and center for molecular medicine, karolinska institutet, 17176 stockholm, sweden. email: emanuele.scala@ki.se modern treatments continue to be developed based on identifying targets within the innate and adaptive immune pathways associated with psoriasis. whilst there is a sound biologic rationale for increased risk of infection following treatment with immunomodulators, the clinical evidence is confounded by these agents being used in patients affected with several comorbidities. in an era characterized by an ever greater and growing risk of infections, it is necessary to always be updated on this risk. in this mini-review, we will discuss recent updates in psoriasis immunopathogenesis as a rationale for systemic therapy, outline the risk of infections linked to the disease itself and systemic therapy as well, and provide an overview of the prevention and management of infections. abstract 2 review | dermatol pract concept. 2023;13(1):e2023016 introduction in the last decade, our understanding of psoriasis pathogenesis made significant steps forwards leading to the development of multiple game-changer therapies [1]. although we can confidently say that the horizon is now a little brighter, we cannot argue that “the whole job” has been done. the advent of therapies targeting specific components of the immune response has highlighted the possible association of infections with psoriasis. whilst there is a sound biologic rationale for increased risk of infection following treatment with immunomodulators, the clinical evidence is confounded by these agents being used in moderate-to-severe psoriasis in association with several comorbidities. in this article, we summarize the available information on the risk of infections, including the respiratory ones, linked to psoriasis and immunomodulators as well. lastly, we provide an overview of the prevention and management of infections in psoriatic patients on immunomodulatory therapies. immunopathogenesis of psoriasis: an update psoriasis has been primarily defined as an autoimmune, t-cell-mediated disease with dysregulated inflammatory response that is composed of both innate and adaptive immunity [1-4]. other factors such as environmental ones and genetic susceptibility are also involved [4,5]. several gene loci are associated with psoriasis, such as hla-cw6 and psors1-9, providing initial evidence of a possibly (auto) immune component [6,7]. however, ~ 60 loci identified contain genes involved in the immune system at large and the interleukin (il)-23/t helper (th)17 pathway in particular [8,9]. il-17a is the most studied cytokine of the psoriatic il-23/th17 cell pathogenic axis and is claimed to be directly responsible for the development of the psoriatic lesion [10,11]. it does not act as a single cytokine but exerts its function in a complex cytokine network which includes il-19, il-22, il-23, tumor necrosis factor (tnf)-α and several il-1 family members [12-15]. il-17a is not exclusively produced by th17 cells in the lesion, but possibly also by several other cells: such as γδ t cells, type 3 innate lymphoid cells (ilc3s) and invariant natural killer (ink)t cells, and other thymus-independent cells, including mast cells and neutrophils [16-19]. besides il-17a, the immune-derived il17f, the epithelial-derived il-17c and il-17e, have all been shown to independently participate in psoriasiform inflammation in murine models [20-22]. interestingly, the inhibition of the il-17a/il-23 axis might potentially lead to the enhancement of other il-17 cytokine members, particularly the epithelial-derived cytokines. a better assessment of the different sources and the possible il-17 substitute cytokines is critical to better understand the mechanism of action of the current il-23/il-17-targeted therapies, possibly helping to explain unwanted effects or secondary loss of efficacy. psoriasis and skin infection psoriatic lesions show a disturbed skin barrier function, similar to the affected skin of patients with atopic dermatitis (ad) [23-24]. this altered epidermal barrier facilitates the penetration of bacteria and viruses into the skin and should lead to an increased incidence of cutaneous infections. however, the frequency of skin infections is impressively underrepresented in patients with psoriasis [25, 26]. the main reason for this clinical observation is the specific increase in the levels of antimicrobial peptides (amps) and antiviral peptides (avps) within the epidermis of psoriatic lesions [14, 27-29]. correspondingly, the enhancement of amps and avps in the affected skin of ad patients is only minimal and these patients often suffer from bacterial and viral skin infections. the mostly up-regulated amps in psoriatic skin are human β-defensin (hbd)-2, s100a7 (psoriasin) and to a lesser extent hbd-3, s100a8 (calgranulin a), s100a9 (calgranulin b), and lipocalin (lcn)-2 [27, 30-32]. the spectrum of affected microbes differs among the diverse amps. for example, s100a7 is primarily an e. coli-killing antimicrobial peptide, whereas hbd-3 exhibits a broad spectrum of antimicrobial activity against various gram‐negative and gram‐positive bacteria as well as fungi [33]. amps inhibit propagation and kill microbes through various mechanisms such as destabilization of their membrane or sequestrating metal ions [33, 34]. most of the amps are constitutively expressed at low levels in keratinocytes and might be strongly up-regulated by cytokines under inflammatory conditions. the powerful inducers of amps in epithelial cells are il-17 and il-22 [31, 35]. however, the synergistic action of both cytokines is essential for the strong induction of amps in keratinocytes [36, 37]. in psoriatic lesions, this effect might be amplified by tnf-α, interferon (ifn)-γ, il-19, and il-36s [15, 37-39]. interestingly, the joint action of il-22 and tnf-α seems to be relevant for the maintenance of epidermal integrity during infection with candida albicans [38]. the up-regulated avps in psoriatic lesions comprise oas2, bst2 (tetherin), mx1, and isg15 [29]. the main driver for this increase is il-29, a member of the il-10-ifn family of cytokines [40]. in psoriatic lesions, il-29 is produced by th17 cells [29]. it directly acts on keratinocytes via the transmembrane receptor complex composed of il-28r1 and il-10r2 and activates intracellular jak-stat signaling. interestingly, il-10r2 is also a part of the il-22 receptor complex [41]. the avp-inducing effect of il-29 can be only minimally amplified by ifn-γ in keratinocytes [40]. an overview of the main psoriasis signature cytokines and their effects on infections is shown in table 1. review | dermatol pract concept. 2023;13(1):e2023016 3 psoriasis and respiratory infections lower respiratory tract infections including pneumonia are the most frequent types of serious infections among psoriasis patients as documented by numerous registries [42, 43]. the incidence of pneumonia seems to be even increased among psoriasis patients compared to those without psoriasis [44,45]. however, it is not definitely clear to what extent this increase is related, either to psoriasis itself, its concomitant disorders, or its treatment [44]. in fact, psoriasis patients frequently suffer from diabetes mellitus, hyperlipidemia, and hypertension, are smokers, and have elevated body mass index (bmi), which can make them vulnerable to infectious diseases [25,46]. systemic therapies and infection risk, including sars-cov-2 the conventional systemic therapies for plaque psoriasis include cyclosporine, methotrexate, and oral retinoids [47]. cyclosporine is a calcineurin inhibitor broadly suppressing t cells; methotrexate, and retinoids have multiple effects on several immune cells. more recently, 2 small-molecule drugs table 1. psoriasis signature cytokines and their effects on infections. cytokines cellular sources findings il-12 dcs, monocytes, macrophages, neutrophils, b cells and kcs enhances hbd-2 production in kcs, and the antimicrobial activity of macrophages il-17a th17 cells, ilc3s, mast cells, neutrophils, cd8+ t cells, γδ t cells, nk cells, inkt cells, and lti cells induces the production of amps (hbd-2, ll-37, lcn-2, and s100a7-9) in kcs, neutrophil recruitment, and immunity to extracellular pathogens il-17c prostate and fetal kidney cells, kcs, colonic epithelial cells, and lung epithelial cells enhances epithelial host defense (hbd-2/-3, and s100a7-9) in an autocrine/paracrine manner il-17e intraepithelial lymphocytes, lung epithelial cells, alveolar macrophages, eosinophils, basophils, nkt cells, th2 cells, mast cells, and cells of the gastrointestinal tract and uterus promotes innate cell recruitment and activation. provides immunity to extracellular pathogens il-17f th17 cells, mast cells, neutrophils, cd8+ t cells, γδ t cells, nk cells, nkt cells, and lti cells synergistically cooperates with il-17a and il-22 for the induction of amps in kcs. provides immunity to extracellular pathogens and is involved in neutrophil recruitment il-19 monocytes, dcs and kcs increases the production of amps (s100a7-9) in kcs and amplifies il-17a activity. il-21 th17 cells, th1* cells, th2 cells, cd8+ t cells, and nkt cells enhances the antimicrobial activity of macrophages, and maintains the cd8+ t cell effector activity during the infection il-22 th22 cells, th17 cells, th1 cells, cd8+ t cells, γδ t cells, ilc3s, nkt cells, lti cells, alveolar macrophages*, and neutrophils* increases the expression of hbd-2/-3, and s100a7-9 in kcs, and reinforces tnf-α activity il-23 dcs, macrophages, and psoriatic kcs induces hbd-2 expression in kcs, and optimizes the antimicrobial activity of macrophages il-26 th17 cells, th1 cells, epithelial cells, nk cells, alveolar macrophages, and macrophage-like synoviocytes exerts antiviral and antimicrobial actions, as well as regulates the expression of hbd-2/-3 il-29 (alternative name infλ) th17 cells, dcs, macrophages, mast cells, and alveolar cells induces the production of antiviral proteins (mx1, bst2, isg15, and oas2) in kcs il-36s kcs, macrophages, monocytes, dcs, and lymphocytes promote viral resistance, and the production of amps in kcs tnf-α macrophages, monocytes, dcs, nk cells, t cells, b cells, and kcs induces the production of s100a7 and hbd-2/-3, as well as antimicrobial chemokines cxcl-9/-10/11 in kcs *controversial among researchers. amps antimicrobial peptides, dcs dendritic cells, ilc3s type 3 innate lymphoid cells, kcs keratinocytes, lti lymphoid tissue inducer, inkt invariant natural killer t cells, th t helper. data from multiple sources [12-15, 20-22, 29, 31, 35-41, 81-98] 4 review | dermatol pract concept. 2023;13(1):e2023016 such as il-1β and il-6, which may play a pathogenic role in the severe/fatal course of covid-19 infection are only moderately expressed in psoriatic lesions and do not play an important role in psoriasis pathogenesis compared to other inflammatory skin diseases [57,58]. importantly, the incidence of covid-19 infection, covid-19-related hospitalization, and covid-19-related death do not seem to be elevated among psoriasis patients treated with biologics [60,61]. the disease course in most patients with biological treatment was even milder, indicating that the anti-cytokine therapy may be beneficial in preventing a severe cytokine storm [59,62]. a schematization of the risks and benefits of cytokine-blocking therapies in psoriasis is displayed in figure 1. prevention and management of infections in psoriatic patients treated with systemic therapies as any patient with moderate to severe psoriasis may progress to immunomodulatory therapies, it is important that their immunizations are up to date. two general strategies have been suggested: screening for infection prior to therapy initiation as well as providing protection through vaccination. as for the first strategy, guidelines suggest tuberculosis screening before starting all biological therapies [63,64]. however, data from clinical trials and post-marketing surveillance with il-23 and il-17 inhibitors suggest that they are not crucial to tuberculosis reactivation [65]. furthermore, screening for candida infections, hepatitis, human immunodeficiency virus (hiv), and other chronic infections is generally recommended. as for the latter, vaccination is a proven strategy to reduce infections. in view of this, dermatologists can play an important role in educating patients about immunizations. to prevent severe infections, it is suggested that psoriatic patients receive their complete recommended vaccinations (especially live vaccines) before initiating biological therapy [66]. in short, the medical board of the national psoriasis foundation recommends that all patients with moderate-to-severe psoriasis have an assessment of their immunization status, including immunization or disease history for varicella zoster, haemophilus influenzae, tetanus, pertussis, hepatitis a and b, human papillomavirus (hpv), influenza, neisseria meningitides, and streptococcus pneumoniae during initial workup [67]. notably, vaccines such as mycobacterium vaccae, live attenuated varicella zoster virus and leishmania amastigotes have been reported to be effective during psoriasis treatment [68-70] even though these data need to be confirmed in larger and controlled clinical trials. lastly, vaccination against sars-cov-2 is recommended in patients with psoriasis, even in those under biological therapy [71]. hence, it is clear now that immune pathways involved in psoriasis pathogenesis contribute to host defense against certain pathogens, thus a possible consequence is represented have been approved for the treatment of plaque psoriasis: apremilast, an oral phosphodiesterase (pde)-4 inhibitor, and dimethyl fumarate [48,49]. both molecules impact the nf-kb complex and have broad functions on the immune system. modern biological therapies, such as anti-tnf-α, anti-il-12/23, anti-il-17, and anti-il-23 antibodies, are designed to block specific molecular steps important in the pathogenesis of psoriasis. namely, anti-tnf-α agents neutralize tnf-α which has a dual role as an upstream mediator of t cell differentiation into th1, th17 and th22 cells, as well as a pro-inflammatory mediator synergistic with il-17a, il-17f, and il-22 [50]. the anti-il-12/23 agent targets the p40 subunit shared by il-12 and il-23 preventing their interaction with the receptor and thereby blocking th1/ th17 immunity [1,50]. this was further developed into biologics neutralizing only il-23 via the p19 subunit, thereby only blocking th17 immunity [1]. finally, direct interaction with il-17a and/or other members of the il-17 family is a successful strategy realized through il-17a, il-7ra, or bispecific il-17a/f targeting. however, analysis of the population-based electronic medical record database from the uk on approximately 200,000 patients with psoriasis indicates that patients with moderate-to-severe disease that receive immunosuppressive therapies do have an increased risk for opportunistic infections and reactivation of varicella-zoster virus [51]. furthermore, analyzing data from psoriasis patients treated with biologic (n=2258) or non-biologic systemic agents (n=3631) demonstrated that systemic therapies with biologics significantly increase the overall risk for serious infection [52]. the extent of impairment and the type of infection are related to the mode of action of individual drugs or drug groups [1]. for instance, tnf-α antagonists can lead to the reactivation of latent tuberculosis and il-17 neutralization may result in mucocutaneous candidiasis [1]. however, it should be noted, there is no signal for increased risk of invasive fungal disease due to anti-il-17 therapy [53]. cases of opportunistic infections like atypical histoplasmosis or toxoplasmosis have been mainly reported in connection with blocking tnf-α or il-12/il-23 p40 [53,54]. accordingly, the evaluation of registry data primarily notes the association of the use of infliximab, a chimeric monoclonal anti-tnf-α antibody, with increased incidence of pneumonia [44,45]. furthermore, while neutralizing tnf-α or il-17 has been associated with such a risk, there is no evidence that blocking il-23 increases the risk of respiratory tract infections [55]. despite the relevant concomitant disorders such as obesity, hypertension, and diabetes, recent data accumulated during the covid-19 pandemic indicate that patients with psoriasis with or without systemic treatment are neither at higher risk for infection with sars-cov-2 nor show more severe symptoms [56]. this might be caused by the fact that cytokines, review | dermatol pract concept. 2023;13(1):e2023016 5 antibiotic, antiviral, or antifungal therapy.  evaluating the risk-benefit ratio for recurrent serious infections, therapy can be restarted once infection has been fully resolved, empirically after 2-4 weeks from the resolution of the infectious event [73]. analogous therapeutic management during the sars-cov-2 pandemic has been suggested [74,75]. in the event of sars-cov-2 infection, psoriasis treatments should be suspended and resumed after complete resolution of covid-19 symptoms and sars-cov-2 negativization. on the contrary, in those asymptomatic sars-cov-2+ patients with high-need-to-treat psoriasis, as well as in psoriasis patients who have had a severe hospital course or the persistence of 1 or more symptoms of covid-19, beyond the acute phase of the illness, the decision to restart treatment by the fact that a selective inhibition might predispose to specific infections. nevertheless, some biologic agents and novel small molecule drugs (i.e., apremilast) appeared to be safer or at least not associated with significant increases in the risk of serious infections, compared to conventional nonbiologic systemic compounds [72]. mild to moderate infections (i.e., upper respiratory tract infections) or minor surgery (i.e., skin surgery, dental procedures) do not usually cause treatment discontinuation where it would otherwise be continued. delayed starting or interruption of immunomodulatory therapies is recommended in case of clinically meaningful active infection (severe signs and symptoms requiring systemic oral or intramuscular antibiotic, antiviral, or antifungal therapy) or serious infection requiring hospitalization or intravenous tnf�� il -2 3 �� key psoriatic inflammatory mediators � upper and lower respiratory infections � varicella zoster infections � reactivation of latent tuberculosis � mucocutaneous candidiasis th17 �� neutrophil and t-cell immune response no higher risk of covid-19 infection ��-tnf�� ��-il-12/23 ��-il-23 ��-il-17a ��-il17ra ri sk s an d b en efi ts o f cyto kine blocking therapies in psoriasis il-1 7a , il -17 f d k k figure 1. schematization of risks and benefits of cytokine blocking therapies in psoriasis. d dendritic cell, il interleukin, k keratinocyte, th t helper, tnf tumor necrosis factor. 6 review | dermatol pract concept. 2023;13(1):e2023016 2. boehncke wh, schön mp. psoriasis. lancet. 2015;386(9997):983994. doi:10.1016/s0140-6736(14)61909-7 3. nickoloff bj, qin jz, nestle fo. immunopathogenesis of psoriasis. clin rev allergy immunol. 2007;33(1-2):45-56. doi:10.1007/ s12016-007-0039-2 4. cai y, fleming c, yan j. new insights of t cells in the pathogenesis of psoriasis.  cell mol immunol. 2012;9(4):302-309. doi:10.1038/cmi.2012.15 5. harden jl, krueger jg, bowcock am. the immunogenetics of psoriasis: a comprehensive review. j autoimmun. 2015;64:66-73. doi:10.1016/j.jaut.2015.07.008 6. elder jt. genome-wide association scan yields new insights into the immunopathogenesis of psoriasis.  genes immun. 2009;10(3):201-209. doi:10.1038/gene.2009.11 7. capon f. the genetic basis of psoriasis.  int j mol sci. 2017;18(12):2526. published 2017 nov 25. doi:10.3390/ijms 18122526 8. bianchi e, rogge l. the il-23/il-17 pathway in human chronic inflammatory diseases-new insight from genetics and targeted therapies.  genes immun. 2019;20(5):415-425. doi:10.1038 /s41435-019-0067-y 9. ray-jones h, eyre s, barton a, warren rb. one snp at a time: moving beyond gwas in psoriasis.  j invest dermatol. 2016;136(3):567-573. doi:10.1016/j.jid.2015.11.025 10. li b, huang l, lv p, et al. the role of th17 cells in psoriasis. immunol res. 2020;68(5):296-309. doi:10.1007/s12026-020-09149-1 11. martin da, towne je, kricorian g, et al. the emerging role of il-17 in the pathogenesis of psoriasis: preclinical and clinical findings.  j invest dermatol. 2013;133(1):17-26. doi:10.1038/ jid.2012.194 12. chiricozzi a, guttman-yassky e, suárez-fariñas m, et al. integrative responses to il-17 and tnf-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. j invest dermatol. 2011;131(3):677-687. doi:10.1038/jid .2010.340 13. carrier y, ma hl, ramon he, et al. inter-regulation of th17 cytokines and the il-36 cytokines in vitro and in vivo: implications should be taken on a case-by-case basis [76,77]. similar to active serious infections, in case of major surgery (i.e., under general anesthesia with exposure of large body areas, internal organ surgery), guidelines recommend treatment interruption, evaluating case-by-case patient characteristics, the risk of infection, the risk of psoriasis worsening and consultation with the surgeon [78]. therapy restart can be considered after full recovery. nevertheless, real-life data on perioperative management are limited and do not provide strong evidence of perior post-operative complications due to continuous treatment with biologic agents or apremilast [78-80]. infectious diseases to consider for selecting biological and new small-molecule therapies are listed in table 2. conclusion in an era characterized by an ever greater and growing risk of infections, but at the same time by increasingly specific and advanced immune-mediated therapies, it is necessary to always be updated on the risk of such infections and on the ability to manage them. currently, we are witnessing a revolution in the treatment of psoriasis where the starting point is the translational approach, and we firmly believe that by following this path we can reach a wider knowledge that will help us in preventing and treating properly infections associated with psoriasis. references 1. ghoreschi k, balato a, enerbäck c, sabat r. therapeutics targeting the il-23 and il-17 pathway in psoriasis.  lancet. 2021;397(10275):754-766. doi:10.1016/s0140-6736(21)00184-7 table 2. infectious diseases to consider for selecting biological and new small-molecule therapies. class of agents drug hcv hbv hiv latent tb cmcc anti-tnf-α etanercept adalimumab infliximab certolizumab golimumab preferred not preferred preferred not preferred preferred anti-il-12/23 ustekinumab preferred preferred preferred preferred preferred anti-il-17a secukinumab ixekizumab preferred likely safe/not enough data likely safe/not enough data preferred not preferred anti-il-17ra brodalumab preferred likely safe/not enough data likely safe/not enough data preferred not preferred anti-il-23 guselkumab tildrakizumab risankizumab preferred not enough data not enough data preferred preferred oral novel small molecule apremilast preferred not enough data not enough data preferred preferred cmcc chronic mucocutaneous candidiasis, hbv hepatitis b virus, hcv hepatitis c virus, hiv human immunodeficiency virus, il interleukin, ra receptor a, tb tuberculosis, tnf tumor necrosis factor. data from several sources [99-101]. review | dermatol pract concept. 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nermin karaosmanoglu1 1 department of dermatology, ministry of health, ankara training and research hospital, ankara, turkey key words: covid, consultation, emergency, dermatology citation: temel b, orenay om, karaosmanoglu n. comparative evaluation of dermatological emergency consultations in the coronavirus pandemic era: tertiary clinic experience. dermatol pract concept. 2023;13(1):e20230112. doi: https://doi.org/10.5826/dpc.1301a112 accepted: june 16, 2022; published: january 2023 copyright: ©2023 temel et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: berkay temel, md, adress: department of dermatology, ministry of health, ankara training and research, hospital. sakarya mahallesi, 89, ulucanlar caddesi, 06230, altındağ/ ankara, turkey. phone number: +905058190789 e-mail: berkaytemel42@gmail.com introduction: due to the increase in covid-19 patients during the pandemic, the workload of emergency departments has increased. the profile of patients seeking non-covid medical care has changed significantly because of the pandemic; this includes dermatological emergencies. objective: the aim was to evaluate and compare adult dermatological emergency consultations during the covid-19 period with the pre-pandemic period. methods: consulted patients from ed to dermatology between march 11, 2019, and march 11, 2021 were included (pre-pandemic and pandemic). age, gender, zone of triage, consultation hour, consultation date, consultation response time, icd-10 codes were recorded. results: the total number of consultations was 639. the mean age of the patients was 44.4 in the pre-pandemic period and 46.1 in the pandemic period. the mean consultation response time was 44.4  minutes in the pre-pandemic period and 60.3 minutes in the pandemic. in the pre-pandemic period, the most common consulted diseases were herpes zoster, urticaria, and allergic contact dermatitis. during the pandemic, the most common consulted diseases were herpes zoster, other dermatitis, and urticaria. there was a statistically significant difference in the incidence of other dermatitis, impetigo/folliculitis, cutaneous vasculitis, and pruritus (p<0.05) conclusions: emergency departments are the busiest and fastest areas of the hospital. pandemics such as covid-19 may also occur in the coming years. informing society about dermatological emergencies and adding adequate dermatology training to the training of emergency physicians will facilitate appropriate patient management in emergency departments. abstract 2 original article | dermatol pract concept. 2023;13(1):e20230112 introduction on march 11, 2020, the world health organization declared the coronavirus disease 19 (covid-19) outbreak as a pandemic, reporting more than 118,000 cases and 4,291 deaths in 114 countries [1]. the rapid spread of covid-19 all over the world hit health systems hard and prompted many countries to take various measures that aimed to limit the spread of the virus and reduce the number of patients and deaths [2]. the health system, which was rebuilt under the influence of the pandemic, affected every medical department including the dermatology and emergency departments (ed). almost most of the dermatology inpatient services were reserved for covid-19 patients, and the number of patients in dermatology outpatient clinics was restricted by health authorities to reduce the spread of the virus [3]. therefore, the number of dermatologic patients who applied to clinics during the pandemic period decreased, and in addition to this decrease, fear of contracting covid-19 and skin conditions related to covid-19 (vesicular eruptions, petechial/purpuric rashes, acral lesions, livedoid lesions, urticarial rash, and maculopapular-erythematous rash) changed the profile of faced dermatological diseases [3-5]. during the pandemic, many covid-19 patients were first evaluated in hospital eds. because of this, the workload in ed increased significantly. there have been many studies investigating the impact of the pandemic on the ed. these studies showed that the number of non-covid-19 patients admitted to the ed decreased and their disease profiles changed [6,7]. despite these studies, studies on dermatological diseases consulted from emergency services were limited [8,9]. this study aimed to evaluate adult dermatological emergency consultations during the covid-19 period and to compare them with the pre-pandemic period. material and methods study design, patient selection and variables patients who were consulted to the dermatology clinic by the adult emergency department between march 11, 2020, and march 11, 2021 (pandemic period) and the same dates of the previous year (pre-pandemic period) were included in this study. the dividing point for the pre-pandemic and pandemic period was chosen on march 11, 2020, the day when covid-19 was declared as a pandemic all over the world. this study was conducted in the dermatology clinic of ankara training and research hospital, which is a tertiary clinic in turkey. local ethical approval was obtained for this study. age, gender, zone of triage, consultation hour, consultation date, consultation response time, and international classification of diseases, tenth revision (icd-10) codes were recorded from hospital electronic medical records. zone of triage was determined as green (simple health conditions that present as an outpatient, are stable in general condition and can be treated on an outpatient basis), yellow (conditions with potentially life-threatening, risk of limb loss and significant morbidity) red (conditions that are life-threatening and require a rapid aggressive approach and urgent simultaneous evaluation and treatment). in our center, consultations requested from the adult emergency between 08:00 and 16:00 are evaluated in outpatient clinics. between 16.00-08.00, a doctor is assigned to the inpatient clinic for consultation. consultation time was divided into three time periods 08.00-16.00, 16.00-00.00, and 00.00-08.00. the consulted diseases were classified according to icd-10 codes. these were dermatitis, infection diseases, hypersensitivity diseases, inflammatory diseases, autoimmune bullous disease, and others. the subgroup disease profile was also determined under these headings one by one. bullous disorders with extensive involvement, angioedema, erythroderma, toxic epidermal necrolysis, steven johnson’s syndrome, pustular psoriasis with metabolic complications were accepted as true dermatological emergencies [10]. these data were evaluated and compared according to pre-pandemic and pandemic periods retrospectively. statistical analysis research data was evaluated via statistical package for the social sciences (spss.22, ibm spss statistics for windows, version 22.0. armonk, new york: ibm corp.). descriptive statistics were recorded as mean (±) standard deviation, frequency distribution, and percentage. normality analyses of the data were carried out with the shapiro-wilk test. for categorical variables, whether there is a difference in frequency between groups was compared using pearson chi-square. the t-test was used to evaluate normally distributed means. mann-whitney u test was used to evaluate not normally distributed means. the statistical significance value of this study was accepted as p<0.05. results main characteristics of pre-pandemic and pandemic period consultations the total number of consultations during the pre-pandemic and pandemic period was 639. it was determined that 467 consultations were requested in the pre-pandemic 1-year period, while 172 consultations were requested in the pandemic 1-year period. it was found that consultations decreased by 63.1% during the pandemic period. the mean age of the patients in the pre-pandemic period was calculated as 44.4±18.6. in the pandemic period, the mean age was calculated as 46.1±18.2. there was no statistically significant difference between the periods in terms of mean age (p=0.31) original article | dermatol pract concept. 2023;13(1):e20230112 3 (table 1). 47.3% (n=221) of the patients evaluated in the pre-pandemic period were male and 52.7% (n=246) were female. during the pandemic period, 51.2% (n=88) were men and 48.8% (n=84) were women. there was no statistically significant difference in terms of gender (p=0.38) (table 1). in the pre-pandemic period, 40.3% (n=18) of the consultations were requested from the green zone, 50.7% (n=237) from the yellow zone and 9% (n=42) from the red zone. in the pandemic period, 25% (n=43) were requested from the green zone, 64.5% (n=111) from the yellow zone and 10.5% (n=18) from the red zone. there was a statistically significant difference between the periods in terms of green and yellow triage zones (p=0.01) (table 1). in the pre-pandemic period, 40% (n=187) of the consultations were requested between 08.0016.00, 51.2% (n=239) between 16.00-00.00 and 8.8% (n=41) between 00.00-08.00. in the pandemic period, 45.9% (n=79) of the consultations were requested between 08.00-16.00, 41.3% (n=71) between 16.00-00.00 and 12.8% (n=22) between 00.00-08.00. there was a statistically significant difference between the periods in terms of 16.00-00.00 consultation time (p=0.04) (table 1). the mean consultation response time in the pre-pandemic period was 44.4 minutes. it was 60.3 minutes during the pandemic period. there was no statistically significant difference between the periods in terms of consultation response time (p=0.52) (table 1). 6 (1.3%) of the patients in the pre-pandemic period and 1 (0.6%) of the patients in the pandemic period were hospitalized. there was no statistically significant difference between the periods in terms of hospitalization rates (p=0.34) (table 1). in the pre-pandemic period, consultation was most requested in august 2019 (n=55) and least in september 2019 (n=25). during the pandemic period, consultation was most requested in july 2020 (n=35) and least in january 2021 (n=2) (figure 1). comparison of pre-pandemic and pandemic period disease profiles in the pre-pandemic period, the three most commonly consulted diseases were herpes zoster, urticaria, and allergic contact dermatitis. in the pandemic period, the three most consulted diseases were herpes zoster, other dermatitis, and urticaria. there was a statistically significant difference between the periods in terms of the incidence of other dermatitis, impetigo/folliculitis, cutaneous vasculitis, and pruritus (p=0.01, 0.02, 0.03, 0.01) (table 2). true dermatological emergencies were detected in 37 (7.9%) patients in the pre-pandemic period and 13 (7.6%) patients in the pandemic period. there was no statistically significant difference between the periods in terms of dermatological emergencies (p=0.86) (table 1). discussion the covid-19 pandemic has deeply affected the health system of every country. during the pandemic period, emergency departments became the first points of contact for covid-19 patients. therefore, the number and profile of non-covid-19 patients admitted to the emergency department changed. in this study, the dermatology consultations requested from the adult emergency department during the pandemic period were examined and compared with the pre-pandemic period. table 1. characteristics of study. pre-pandemic (n=467) pandemic (n=172) pvalue age, mean ±std 44.4±18.6 46.1±18.2 0.31* gender, n (%) male female 221 (47.3) 246 (52.7) 88 (51.2) 84 (48.8) 0.38** triage zones, n (%) green yellow red 118 (40.3)a 237 (50.7)a 42 (9)a 43 (25)b 111 (64.5)b 18 (10.5)a 0.01** <0.05 <0.05 >0.05 consultation time 08.00-16.00 16.00-00.00 00.00-08.00 187 (40)a 239 (51.2)a 41 (8.8)a 79 (45.9)a 71 (41.3)b 22 (12.8)a 0.04** >0.05 <0.05 >0.05 consultation response time, min 44.4 60.3 0.52*** hospitalization, n(%) 6 (1.3) 1 (0.6) 0.34* true dermatological emergency,n (%) 37 (7.9) 13 (7.6) 0.86* std: standart deviation, min: minute, *: t-test, **: chi-square test, ***: mann whitney utesta,b: each subscript letter denotes a subset of pandemic status categories whose column proportions do not differ significantly from each other at the 0.5 levels. 4 original article | dermatol pract concept. 2023;13(1):e20230112 0 10 20 30 40 50 60 m ar ch 2 01 9 a p ri l 2 01 9 m ay .2 01 9 ju n e 20 19 ju ly 2 01 9 a u g u st 2 01 9 se p te m b er 2 01 9 o ct o b er 2 01 9 n o ve m b er 2 01 9 d ec em b er 2 01 9 ja n u ar y 20 20 fe b ru ar y 20 20 m ar ch 2 02 0 a p ri l 2 02 0 m ay .2 02 0 ju n e 20 20 ju ly 2 02 0 a u g u st 2 02 0 se p te m b er 2 02 0 o ct o b er 2 02 0 n o ve m b er 2 02 0 d ec em b er 2 02 0 ja n u ar y 20 21 fe b ru ar y 20 21 m ar ch 2 02 1 number of patients figure 1. distribution of the number of patients by month. table 2. comparison of diseases profile. diseases, n (%) pre-pandemic pandemic p-value* dermatitis irrıtant contact dermatitis allergic contact dermatitis dermatitis, others 73 (15.6) 13 (2.8) 39 (8.4) 21 (4.5) 35 (20.3) 4 (2.3) 8 (4.7) 23 (13.4) 0.3 0.96 0.11 0.01 infection diseases impetigo/folliculitis cellulitis dermatophytosis herpes simplex herpes zoster leishmaniasis scabies syphilis 223 (47.7) 28 (6) 25 (5.4) 12 (2.6) 8 (1.7) 125 (20.8) 1 (0.2) 22 (4.7) 2 (0.4) 84 (48.8) 3 (1.7) 13 (7.6) 5 (2.9) 0 (0) 50 (29.1) 1 (0.6) 12 (7) 0 (0) 0.96 0.02 0.29 0.81 0.08 0.56 0.46 0.25 0.39 hypersensitivity diseases urticaria angioedema insect bite maculopapular drug eruption erythema multiforme 115 (24.6) 53 (11.3) 29 (6.2) 11 (2.4) 14 (3) 8 (1.7) 42 (24.4) 16 (9.3) 13 (7.6) 7 (4.1) 6 (3.5) 0 (0) 0.9 0.46 0.54 0.24 0.5 0.08 inflammatory diseases psoriasis pityriasis rosea cutaneous vasculitis behcet disease 25 (5.3) 8 (1.7) 10 (2.1) 5 (1.1) 2 (0.4) 8 (4.6) 1 (0.6) 1 (0.6) 6 (3.5) 0 (0) 0.87 0.28 0.17 0.03 0.54 autoimmune bullous disease 8 (1.7) 0 (0) 0.08 others leg ulcer alopecia areata acne vulgaris pruritus 23 (4.9) 1 (0.2) 2 (0.4) 3 (0.6) 17 (3.6) 2 (1.2) 2 (1.2) 0 (0) 0 (0) 0 (0) 0.32 0.12 0.39 0.290.01 total 467 (100) 172 (100) *: chi-squaretest original article | dermatol pract concept. 2023;13(1):e20230112 5 compared to the pre-pandemic period. similar results were obtained by neslihan ogut et al. [8]. during the covid-19 pandemic, countries started to take measures quickly, the most important of which was the curfew. the curfew was imposed on all weekends and weekdays between 21.00-05.00 in our country. we thought that this situation caused a change in consultation hours. emergency departments are one of the most crowded places in hospitals that work 7 days and 24 hours. turkey has the world’s highest number of emergency department visits annually: some 100 million. the high number of patients, especially in our country, is one of the risk factors for transmission during the covid-19 pandemic. in our study, it was found that consultation response time increased during the pandemic period compared to the pre-pandemic period (44.4 minutes vs 60.3 minutes). both the working of dermatology physicians in the covid departments and the increase of covid patient load on emergency departments should have increased the consultation response time. the prolongation of the consultation response time increased the length of stay of the patients in emergency departments and this situation could have increased the non-covid patient burden on emergency departments. along with the pandemic, the distribution of the number of patients by month also changed. demirel ogut et al. [8] reported that the number of patients decreased in march 2020, april 2020, and may 2020 compared to 2019, and the number of patients started to increase as of june 2020. a similar trend was obtained in our study. interestingly, in our study, the number of patients decreased as of july 2020, and the number of patients in 2019 could never be reached. in our country, full or partial curfews were implemented to coincide with the periods when the number of patients decreased. we thought that this result was caused by the curfews and travel bans during the pandemic period pandemic period studies showed that the profile of the disease consulted from emergency departments has changed  [8,9]. in isoletta et al.’s study, although urticaria, atopic eczema and acute onset infections were reported to be the most frequently consulted diseases during the pandemic period, urticaria, vasculopathic lesions and scabies were found to be statistically significantly higher compared to the pre-pandemic period [9]. in demirel ogut et al’s study, although contact dermatitis, scabies and urticaria were reported to be the most frequently consulted diseases during the pandemic period, scabies and pityriasis rosea were found to be statistically significantly higher and herpes zoster was found statistically significantly lower compared to the pre-pandemic period [8]. in addition to obtaining similar results, the rate of pruritus and impetigo/folliculitis was statistically significantly lower in our study. these results showed that non-urgent situations decreased during the pandemic there were numerous published studies evaluating dermatologic emergency consultations in the pre-pandemic period. the mean age of the patients included in these studies was between 43-51. the rate of male patients was between 47-62% [11-15]. as expected, similar findings were found in the pre-pandemic period of our study. in pre-pandemic period studies, the most frequently consulted diseases were non-specific dermatitis, scabies, contact dermatitis, herpes zoster, superficial fungal infections, maculopapular drug eruptions, urticaria, erysipelas/cellulitis and cutaneous vasculitis [11-15]. however, the incidence of the aforementioned diseases varied in these studies. similar diseases were also consulted in the pre-pandemic period of our study. bullous disorders with extensive involvement, angioedema, erythroderma, toxic epidermal necrolysis, steven johnson’s syndrome, pustular psoriasis with metabolic complications were defined as a true dermatological emergency in gupta et al’s study [10]. on the other hand, murr et al. defined diseases that started or flared up for 5 days as dermatological emergencies [16]. in pre-pandemic period studies, similar to our results, true dermatological emergencies were between 6-24.7% of the consulted diseases [11,12,15]. it was clearly seen that the rate of real dermatological emergencies among the diseases consulted from the emergency department to dermatology was quite low. we thought that this situation was caused by the fact that public and emergency physicians did not know which dermatological disease was a true emergency. there were few studies investigating the impact of the covid-19 pandemic on dermatology consultations requested from emergency departments [8,9]. these studies showed that the number and mean age of consulted patients decreased and the rate of male patients increased during the pandemic period [8,9]. however, our study showed that the mean age of the patients during the pandemic period was higher. on the other hand, demirel ogut et al. [8] reported that the rate of hospitalizations and true dermatological emergencies decreased during the pandemic period. similar results were obtained in our study. emergency department triage systems facilitate the categorization of emergency patients according to their disease severity and determine both treatment priority and treatment location [17]. in our study, while the rate of patients consulted from the yellow zone increased during the pandemic period, the rate of patients consulted from the green zone decreased. this showed that the number of unnecessary consultations decreased during the pandemic period. we thought that these situations were caused by the fear of infection and the curfews. in this study, consultations requested between 08.00-16.00 increased and the consultations requested between 16.00-00.00 decreased during the pandemic period 6 original article | dermatol pract concept. 2023;13(1):e20230112 period. in our study, as in other studies [8, 9], diseases previously associated with covid-19 disease and vaccines such as herpes zoster, cutaneous vasculitis and urticaria were listed. emergency department physicians should be careful about these diseases and covid-19 should be investigated. limitations this study had some limitations. the study was retrospectively planned from a single care center. the diagnoses of the patients were made according to icd-10 codes. there may have been person-based errors in adding the diagnostic codes to the system. more than one doctor was evaluating the consultations. in this case, there may be conflicts about the accuracy of the diagnoses. however, to correct this situation, the diagnosis is confirmed by a second doctor. conclusion this study showed that the prolongation of the consultation response time increased during the covid-19 pandemic period. the distribution of the number of patients by month changed, and the number of patients decreased as of july 2020. the profile of dermatological diseases consulted from the emergency department also has changed. during the pandemic period, non-urgent conditions such as impetigo/folliculitis and pruritus decreased. emergency departments are the busiest and fastest areas of the hospital. pandemics such as covid-19 may also occur in the coming years. informing the public about dermatological emergencies and adding adequate dermatology training to the training of emergency physicians will facilitate appropriate patient management in emergency departments. references 1. puspitasari im, yusuf l, sinuraya rk, abdulah r, koyama h. knowledge, attitude, and practice during the covid-19 pandemic: a review. j multidiscip healthc. 2020;13:727-733. 2. benke c, autenrieth lk, asselmann e, pané-farré ca. lockdown, quarantine measures, and social distancing: associations with depression, anxiety and distress at the beginning of the covid-19 pandemic among adults from germany. psychiatry res. 2020 nov;293:113462. 3. kutlu ö, günes¸ r, coerdt k, metin a, khachemoune a. the effect of the “stay-at-home” policy on requests for dermatology outpatient clinic visits after the covid-19 outbreak. dermatol ther. 2020;33: e13581. 4. sun q, mcmahon de, ugwu-dike po, sun q, tang k, zhang h, suchonwanit p, et.al. how coronavirus disease 2019 changed dermatology practice in 1 year around the world: perspectives from 11 countries. dermatol clin. 2021;39(4):639-651. 5. çaytemel c, erdem o, ağırgöl ş, türkoğlu z. dermatology outpatient clinic outcomes after covid-19 outbreak: what is new normal? dermatol ther. 2021 may;34(3):e14950. 6. hartnett kp, kite-powell a, devies j, et al. impact of the covid-19 pandemic on emergency department visits united states, january 1, 2019-may 30, 2020. mmwr morb mortal wkly rep. 2020;69(23):699-704. 7. santi l, golinelli d, tampieri a, et al. non-covid-19 patients in times of pandemic: emergency department visits, hospitalizations and cause-specific mortality in northern italy. plos one. 2021;16(3):e0248995. 8. demirel öğüt n, tabak gh, gülseren d, yalıcı-armağan b, akdoğan n, doğan s, elçin g, karaduman a, ersoy evans s. the effect of the covid-19 pandemic on dermatology consultation requests from adult and paediatric emergency departments. int j clin pract. 2021;75(12):e14906. 9. isoletta e, vassallo c, brazzelli v, giorgini c, tomasini cf, sabena a, perlini s, de silvestri a, barruscotti s. emergency accesses in dermatology department during the covid-19 pandemic in a referral third level center in the north of italy. dermatol ther. 2020;33(6):e14027. 10. gupta s, sandhu k, kumar b. evaluation of emergency dermatological consultations in a tertiary care centre in north india. j eur acad dermatol venereol. 2003;17:303–5. 11. jack ar, spence aa, nichols bj, et al. cutaneous conditions leading to dermatology consultations in the emergency department. west j emerg med. 2011;12(4):551-555. 12. ozkur e, altunay i, sekerlisoy g, erdem y. evaluation of dermatology consultations in a tertiary care centre emergency service. sisli etfal hastan tip bul. 2020;54(2):197200. 13. drago f, gasparini g, signori a, campisi c, cozzani e, parodi a. dermatological consultations in an observation unit of an emergency department in italy. j eur acad dermatol venereol. 2015;29:973–80. 14. rubegni p, cevenini g, lamberti a, bruni f, tiezzi r, verzuri a, barbini p, manzi p, fimiani m. dermatological conditions presenting at the emergency department in siena university hospital from 2006 to 2011. j eur acad dermatol venereol. 2015;29(1):16 15. demirel öğüt n, gülseren d, yalıcı-armağan b, akdoğan n, günaydın sd, elçin g, karaduman a, ersoy-evans s. dermatology consultation requests from a university hospital’s pediatric and adult emergency departments: a 5-year retrospective analysis. am j emerg med. 2022(4);53:112-117. 16. murr d, bocquet h, bachot n, bagot m, revuz j, roujeau jc. intérêt d’une consultation hospitalière d’urgences dermatologiques [medical activity in a emergency outpatient department dermatology]. ann dermatol venereol. 2003;130:167-70. 17. weyrich p, christ m, celebi n, riessen r. triagesysteme in der notaufnahme [triage systems in the emergency department]. med klin intensivmed notfmed. 2012;107(1):6778. 18. smith m. rise in violence against doctors in turkey, elsewhere. cmaj. 2015;187(9):643. 48. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022164 1 uv irradiation of nevi: impact on performance of electrical impedance spectroscopy and a convolution neural network julia katharina winkler1, holger andreas haenssle1, lorenz uhlmann2, anissa schweizer-rick1, christine fink1 1 department of dermatology, university of heidelberg, heidelberg, germany 2 novartis pharma gmbh, basel, switzerland key words: electrical impedance spectroscopy, dermoscopy, convolution neural network, uv irradiation citation: winkler jk, haenssle ha, uhlmann l, schweizer-rick a, fink c. uv irradiation of nevi: impact on performance of electrical impedance spectroscopy and a convolution neural network. dermatol pract concept. 2022;12(4):e2022164. doi: https://doi. org/10.5826/dpc.1204a164 accepted: february 8, 2022; published: october 2022 copyright: ©2022 winkler et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: christine fink, department of dermatology, university of heidelberg, im neuenheimer feld 440, 69120 heidelberg, germany, tel: +49-6221-56-39554, fax: +49-6221-56-8510 e.mail: christine.fink@med.uni-heidelberg.de introduction: uv irradiation of nevi induces transient melanocytic activation with dermoscopic and histological changes. objectives: we investigated whether uv irradiation of nevi may influence electrical impedance spectroscopy (eis) or convolution neural networks (cnn). methods: prospective, controlled trial in 50 patients undergoing phototherapy (selective uv phototherapy (sup), uva1, sup/uva1, or puva). eis (nevisense, scibase ab) and cnn scores (moleanalyzer-pro, fotofinder systems) of nevi were assessed before (v1) and after uv irradiation (v2). one nevus (nevusirr) was exposed to uv light, another uv-shielded (nevusnon-irr). results: there were no significant differences in eis scores of nevusirr before (2.99 [2.51-3.47]) and after irradiation (3.32 [2.86-3.78]; p = 0.163), which was on average 13.28 (range 4-47) days later. similarly, uv-shielded nevusnon-irr did not show significant changes of eis scores (v1: 2.65 [2.19-3.11]), v2: 2.92 [2.50-3.34]; p = 0.094). subgroup analysis by irradiation revealed a significant increase of eis scores of nevusirr (v1: 2.69 [2.21-3.16], v2: 3.23 [2.72-3.73]; p = 0.044) and nevusnon-irr (v1: 2.57 [2.07-3.07], v2: 3.03 [2.48-3.57]; p = 0.033) for patients receiving sup. in contrast, cnn scores of nevusirr (p = 0.995) and nevusnon-irr (p = 0.352) showed no significant differences before and after phototherapy. conclusions: for the tested eis system increased eis scores were found in nevi exposed to sup. in contrast, cnn results were more robust against uv exposure. abstract 2 original article | dermatol pract concept. 2022;12(4):e2022164 introduction malignant melanoma accounts for the majority of skin cancer deaths and incidence remains at high levels in many countries of the world [1]. thin melanomas are cured by surgical excision with a favorable prognosis. hence, early diagnosis of melanoma is of utmost importance [1]. although biopsy and histopathology remain the diagnostic standard, noninvasive diagnostic techniques are gaining importance [2]. electrical impedance spectroscopy (eis) has been evaluated as an adjunct tool for melanoma detection [3-6]. eis applies alternating electric current and detects differences in the impedance between benign (well-organized) and malignant (more chaotic) tissues. market approved eis devices were shown to reach a sensitivity of more than 95% in melanocytic lesions [6]. another promising non-invasive diagnostic technique is the assessment of dermoscopic images by artificial intelligence algorithms. to this end, deep learning convolutional neural networks (cnn) have been designed that work independently from predefined criteria and were shown to perform on, or even above, the level of trained dermatologists with regard to the classification of benign and malignant skin lesions [7-9]. until today, skin cancer screenings that are assisted by the aforementioned diagnostic techniques have been offered throughout the entire year. however, even intermittent uv exposure was shown to induce transient melanocytic activation with morphological and histological changes [10,  11]. dermoscopic features developing in uv exposed nevi include an increase in pigmentation and the appearance of black-brown globules [12, 13]. histopathologic changes after uv exposition involve an increase in suprabasal melanocytes and an enhanced hmb45 expression [14]. in some cases uv-induced changes in benign nevi may be suggestive of malignant melanoma [15]. thus, for clinicians it is an important question whether the diagnostic performance of eis or cnn-based systems may be influenced by uv irradiation (eg during the summer months). objectives the primary objective of this study was to assess the influence of uv irradiation on the diagnostic scores of an eis system (nevisense, scibase ab) and of a cnn (moleanalyzer-pro, fotofinder systems) when using these systems for examination of nevi. a secondary objective of this study was to address the reproducibility of eis scores by performing 2 consecutive measurements for each lesion at each study visit. methods this clinical study was performed in a prospective controlled setting at the department of dermatology, university of heidelberg in 50 patients with 100 common nevi and a medical indication for phototherapy. the study was conducted in accordance with the declaration of helsinki principles (2013) and applicable local government regulations and independent ethics committee policies and procedures (ethics approval number s-279/2017). inclusion/exclusion criteria fifty patients scheduled for elective phototherapy with a minimum of 4 consecutive treatment sessions at our institution were included in this study. participants had to be at least 18  years old and nevi needed to show the following characteristics: diameter between 2 mm and 20  mm; localized on intact skin without scarring, fibrosis, or other (inflammatory) skin conditions; not localized in hair covered areas or special anatomic sites (i.e. acral skin, mucosa). we only included common nevi without any signs of malignancy. study procedure a total of 100 nevi in 50 patients were assessed by eis. dermoscopic images were acquired at each study visit. for each participant, 1 nevus (nevusirr) was exposed to uv irradiation, whereas a second nevus (nevusnon-irr) was covered with an uv-shielding sticker. eis scores were evaluated at 3 study visits: before the start of phototherapy (v1), during phototherapy (v2), after termination of phototherapy not earlier than 4 weeks following the last irradiation (v3). nevusnon-irr was located in the same body area with similar size and shape as nevusirr and was used as an intraindividual control to account for changes not attributable to direct uv irradiation. moreover, at each study visit eis scores of nevi were measured twice to assess the reproducibility. since all studied nevi were not intended for histological assessment by protocol, the diagnosis of a benign nevus (ground truth) was based on expert consent (jkw, hah, cf). only clearly benign looking nevi were included; hence follow-up of nevi included the study visits performed and a common skin cancer screening thereafter. uv irradiation phototherapy was administered as part of clinical routine when indicated for treatment of diverse (inflammatory) skin diseases. thus, the type of phototherapy was determined by the underlying skin condition and patient characteristics. several treatments per week with increasing uv doses were administered. uva1 phototherapy was performed with an uv-a1 lighting tube (herbert waldmann, spectral range 340–400 nm). sup was administered with original article | dermatol pract concept. 2022;12(4):e2022164 3 a combination of uv-a and uv-b lighting tubes showing a spectral range of 280–400 nm (herbert waldmann). psoralen-uv-a therapy (puva) was either performed as bathor cream-puva-therapy (herbert waldmann, spectral range 315-400 nm). eis measurement eis scores were measured with the market approved nevisense device (scibase ab). according to the manufacturer instructions the skin was moistened with physiological saline for 30 seconds and a reference measurement of healthy skin close to the lesion was obtained. the system computed a score (0-10) reflecting the degree of atypia identified and the validated cut-off of < 4 versus ≥ 4 was used to differentiate eis-negative (benign) from eis-positive (malignant) lesions. cnn assessment dermoscopic images were assessed by a marked approved deep learning cnn (moleanalyzer-pro®, fotofinder systems) based on a modified version of a pretrained googlenet inception v4 architecture [8]. the cnn computed malignancy scores (0-1) with a predefined threshold for malignancy at more than 0.5. statistical analysis descriptive analyses were performed (frequency, mean, confidence intervals, range). for each nevus changes of eis and cnn scores from visit 1 to 2 were assessed (intralesional differences). additionally, for those nevi with measurements from all 3 visits changes of eis and cnn scores from all timepoints were compared. moreover, differences of scores between irradiated and non-irradiated lesions (nevusirr versus nevusnon-irr) were studied per visit (interlesional differences). non-parametric tests were applied to assess for statistical significance (wilcoxon signed rank, friedmann and mcnemar). according to the predefined cut-offs for malignancy, diagnostic specificities were calculated. a linear mixed effects model with a compound symmetry structure was applied to assess whether uv irradiation had an effect on the difference in eis scores at v1 and v2. baseline eis scores, age, gender, and irradiation (yes/no) were used as fixed factors. the patient id was included as a random factor. to evaluate reproducibility of eis measurements an intra-class correlation coefficient was calculated. p < 0.05 was considered statistically significant. spss version 25 (ibm, spss) and r (r core team, 2021) together with the package nlme (pinheiro, 2021) were used [16,17]. results patient characteristics patients (n = 50) were recruited between june 2017 and august 2018 (table 1). mean age was 54.4 years (range  22-75), 24 male and 26 female patients were included. most patients received uv therapy for eczema (42%) or nodular prurigo (26%), some for granuloma annulare (12%), morphea (8%), lichen planus (4%), mycosis fungoides (4%) or others (4%). forty-one patients showed skin type ii, 1 patient skin type ii-iii and 8 patients skin type iii. common nevi with a network pattern and located on trunk or extremities were included. a total of 35 patients received sup, 11 patients uva1, 3 patients puva and 1 patient sup and uva1 in a sequence (table 2). most patients (70%) received sup and a median dosage of 0.26 j/cm2 uvb and 13 j/cm2 uva was administered. considering the skin types of patients, these doses corresponded to about 3-4 minimal erythema doses (med) of uvb and less than 1 med-uva administered over 7.7 sessions. [18]. figure 1 depicts representative images of a patient nevi 1 and 2 from all 3 study visits with accompanying eis and cnn scores. assessment of eis scores mean eis score of the irradiated nevusirr slightly increased from 2.99 (2.51-3.47) at v1 to 3.32 (2.86-3.78) at v2 (figure  2a). for patients attending v3 (n = 24) mean eis score of nevusirr remained almost unchanged at table 1. patient characteristics are depicted. patients (n = 50) age in years (mean; range) 54.4 (22-75) gender (male/female) 24/ 26 skin condition, n (%) eczema 21 (42%) nodular prurigo 13 (26%) granuloma annulare 6 (12%) morphea 4 (8%) lichen planus 2 (4%) mycosis fungoides 2 (4%) others 2 (4%) skin type, n (%) ii 41 (82%) ii-iii 1 (2%) iii 8 (16%) localization nevus1/nevus2, n/n trunk 36/36 upper extremities 5/5 lower extremities 9/9 4 original article | dermatol pract concept. 2022;12(4):e2022164 nor at v2 (p = 0.103, interlesional difference). applying the predefined cut-off indicating malignancy (score ≥ 4), nevusirr was labeled “malignant” in 16  patients at v1 and in 20 patients at v2 (figure 3). in contrast, nevusnon-irr was labeled “malignant” in only 12  patients at v1 and in 13 patients at v2. paired assessment revealed no significant difference in the number of nevi labeled “malignant” at v1 versus v2, neither for nevusirr (p = 0.424) nor for nevusnon-irr (p = 1.0). for patients with measurements available from all 3 visits, eis scores did not significantly vary between timepoints neither for nevusirr (p = 0.428) nor for nevusnon-irr (p = 0.719). finally, when including all eis measurements performed, the device achieved an overall specificity (true-negative rate) of 49.3%. regression analysis including eis scores a linear mixed effects model was used to assess the impact of irradiation on the absolute and relative differences in eis scores at v1 and v2 by comparing uv-irradiated versus shielded nevi. here, irradiation was not a significant predictor (table 3). reproducibility of eis measurements we performed 2 consecutive eis measurements for each nevus and visit to investigate reproducibility. overall, 232 pairs of scores were recorded and the mean difference between consecutive scores was 0.06 (-0.27-0.4). the intraclass correlation coefficient was 0.653 (0.551-0.732). according to the definition of cicchetti this corresponds to a good reliability, according to koo/li to a moderate reliability [19,20]. for 3.25 (2.64-3.86) (figure 2). the mean eis score of nevusnon-irr was 2.65 (2.19-3.11) at v1, 2.92 (2.50-3.34) at v2 and 2.94 (2.29-3.59) for patients attending v3 ( figure 2). first, we statistically compared eis scores attained at v1 versus v2. there were no significant differences of eis scores at v1 versus v2 neither for nevusirr (p = 0.163, intralesional difference) nor for nevusnon-irr (p = 0.094, intralesional difference). additionally, we neither found significant differences in eis scores of nevusirr versus nevusnon-irr at v1 (p = 0.393, interlesional difference) table 2. details on uv irradiation administered. patients n = 50 uv irradiation, n sup 35 uva1 11 sup/uva1 1 puva 3 sup treatments, n (mean; range) 7.7 (3-16) dosage (j/cm2) uva (mean; sd) 13.0; 7.8 dosage (j/cm2) uvb (mean; sd) 0.26; 0.16 uva1 treatments, n (mean; range) 9.9 (3-15) dosage (j/cm2) uva1 (mean; sd) 270; 140 puva bath/cream, n/n 2/ 1 treatments, n (mean; range) 12 (6-20) dosage (j/cm2) uva (mean; sd) 6.6; 5.5 figure 1. nevus1 and nevus2 of a participating patient at all 3 study visits (v1-3) are depicted. from v1 to v2 nevusirr was irradiated with sup during 10 appointments (cumulative dosage uva 14.54 j/cm2, uvb 0.29 j/cm2), whereas nevusnon-irr was uv-shielded. corresponding electrical impedance spectroscopy (eis) scores (0-10, top row) and convolution neural networks malignancy scores (0-1, bottom row) are depicted, scores marked in red illustrate a change in the diagnostic class, ie scores increased above the threshold for a malignant classification. original article | dermatol pract concept. 2022;12(4):e2022164 5 classified “malignant” in none of the patients at v1, but in 2 patients at v2. similarly, nevusnon-irr was classified “malignant” in none of the patients at v1 but in 1 patient at v2. paired assessments revealed no significant difference in the number of nevi classified “malignant” at v1 versus v2 neither for nevusirr (p = 0.5) nor for nevusnon-irr (p = 1.0). when including patients with measurements available from all 3 visits, cnn scores were not significantly different between timepoints neither for nevusirr (p = 0.449) nor for nevusnon-irr (p = 0.420). finally, including all visits the rate of correct “benign” diagnoses was 94.7%. assessment by type of irradiation due to varying irradiation protocols a subgroup analysis was performed for the largest group of patients receiving sup (n = 35). in this analysis mean eis scores of nevusirr significantly increased from 2.69 (2.21-3.16) at v1 to 3.23 (2.72-3.73) at v2 (p = 0.044) and was 3.13 (2.40-3.84) for the 16 patients attending v3 (figure 5). in parallel, mean 70 of the 232 (30.2%) pairs of scores a class change from < 4 to ≥ 4 or vice versa was found. assessment of cnn scores for 42 patients dermoscopic images were available from v1 and v2. mean cnn scores of nevusirr were 0.06 (0.03-0.1) at v1, 0.06 (0.02-0.11) at v2, and 0.11 (-0.02-0.23) for the 15 patients with images available from v3 (figure 4). mean cnn scores of nevusnon-irr were 0.05 (0.02-0.08) at v1, 0.04 (0.01-0.07) at v2, and 0.15 (0.05-0.25) at v3 (figure 4). first, we statistically compared cnn scores before and after irradiation (v1 versus v2). there were no significant differences in cnn scores at v1 versus v2 neither for nevusirr (p = 0.995, intralesional difference) nor for nevusnon-irr (p = 0.352, intralesional difference). additionally, we found no significant differences in cnn scores of nevusirr versus nevusnon-irr at v1 (p = 0.703, interlesional difference) and v2 (p = 0.675, interlesional difference). according to the predefined cnn threshold for malignancy, nevusirr was figure 2. boxplots show electrical impedance spectroscopy (eis) scores of irradiated nevusirr and uvshielded nevusnon-irr at all 3 study visits (v1-before uv irradiation; v2-after uv irradiation; v3-not earlier than 4 weeks following the last irradiation). the upper and lower bounds of boxes represent the 25th and 75th percentiles while the median is given by the line intersecting both boxes. whiskers present the full range of malignancy scores. the a priori cut-off for a malignant classification is indicated by dotted lines (eis score ≥ 4). 6 original article | dermatol pract concept. 2022;12(4):e2022164 scores at v1versus v2, neither for nevusirr (p = 0.344) nor for nevusnon-irr (p = 0.388). for 30 patients cnn scores were available, there was neither a significant difference in cnn scores between v1 and v2 for nevusirr (p = 0.797) nor nevusnon-irr (p = 0.894). eis scores of nevusnon-irr increased to a slightly lesser but still significant extent from 2.57 (2.07-3.07) at v1 to 3.03 (2.48-3.57) at v2 (p = 0.033) and was 3.09 (2.28-3.91) at v3 (figure 5). paired assessments showed no significant differences in the number of nevi labeled “malignant” by eis table 3. a linear mixed-effects model was used to assess the impact of irradiation on the absolute in electrical impedance spectroscopy scores at v1 and v2 (before and after irradiation) by comparing uv-irradiated versus shielded nevi. estimates 95% ci p (intercept) 1.43 0.12; 2.74 0.037 age 0.01 -0.01; 0.03 0.479 gender (male) 0.30 -0.31; 0.91 0.347 eis score at v1 -0.57 -0.73; -0.41 < 0.001 irradiation (no) -0.25 -0.69; 0.18 0.254 ci = confidence interval; eis = electrical impedance spectroscopy. figure 3. figure shows dermoscopic images of two neviirr from v1 and v2 with corresponding electrical impedance spectroscopy (eis) scores. for both lesions and timepoints measurements were repeated and mean values used to define a negative/benign or positive/malignant result. for both lesions mean eis scores increased from v1 to v2 and lesions were assessed negative/benign at v1 versus positive/malignant at v2. table 4. a linear mixed-effects model was used to assess the impact of irradiation on the relative differences in electrical impedance spectroscopy scores at v1 and v2 (before and after irradiation) by comparing uv-irradiated versus shielded nevi. estimates 95% ci p (intercept) 0.88 0.02; 1.74 0.050 age 0.01 -0.01; 0.02 0.502 gender (male) 0.41 0.01; 0.81 0.053 eis score at v1 -0.32 -0.43; -0.21 < 0.001 irradiation (no) -0.18 -0.46; 0.10 0.221 ci = confidence interval; eis = electrical impedance spectroscopy. original article | dermatol pract concept. 2022;12(4):e2022164 7 and after phototherapy with different irradiation protocols performed. we found that for the overall group of patients and across all phototherapy regimen eis scores of both uv irradiated and uv-shielded nevi were not significantly different before and after uv exposure. there may be several explanations for this observation, which are not mutually exclusive. in agreement with others we found a limited reproducibility of eis measurement [21]. this might have probably interfered with the statistical comparison of eis scores before and after uv exposure (background analytical noise covering relevant signals). second, cumulative uv doses until the second visit (v2) might not have been sufficient to induce significant alteration of eis scores. yet, morphological changes in nevi have been reported as early as after 2 med [12]. after two uvb minimal erythema doses marked melanocytic activation was reported, avoided by physical and sunscreen protection [22]. another study found that even after a single dose of uvb clinical and dermoscopic changes in nevi occurred, partially prevented by physical barriers or sunscreens [23]. moreover, a positive correlation of the extent of morphological changes with increasing total conclusions dermoscopic and histopathologic changes of nevi following uv irradiation have previously been described [12, 14]. such changes may be of clinical relevance when patients attend skin cancer screenings following sun exposure. particularly for patients under follow-up by sequential digital dermoscopy subtle changes related to sun exposure, eg increase in the number of dark dots and globules, may result in an increased number of unnecessary excisions. hence, another short time follow-up examination before biopsy of melanotic lesions has previously been recommended after intense uv exposure [12]. according to our literature search, there is no data available on the performance of assistant devices such as eis or cnn when used to assess melanocytic lesions after sun exposure. our study provides first data on eis and cnn scores of common nevi before and after phototherapy. overall, 50patients were included to assess eis scores of 2 nevi per patient (uv irradiated and uv shielded) before figure 4. boxplots show convolution neural networks (cnn) scores of irradiated nevusirr and uv-shielded nevusnon-irr at all 3 study visits (v1-before uv irradiation; v2-after uv irradiation; v3-not earlier than 4 weeks following the last irradiation). the upper and lower bounds of boxes represent the 25th and 75th percentiles while the median is given by the line intersecting both boxes. whiskers present the full range of malignancy scores. the a priori cut-off for a malignant classification is indicated by dotted lines (cnn score > 0.5). 8 original article | dermatol pract concept. 2022;12(4):e2022164 eis scores at v2 for both uv irradiated and shielded nevi. in our study the increase in eis scores was quite similar for directly versus indirectly (because uv-shielded) irradiated nevi, which is in line with previous studies reporting melanocyte activation and proliferation after irradiation in both uv exposed and shielded human skin [25,27]. it has been postulated that mediators from irradiated skin might spread to neighboring uv protected skin through a paracrine pathway [25,27,29]. in confirmation, our linear effects model assessing eis scores before and after irradiation did not reveal an impact of direct uv irradiation. from our results we assessed the rate of nevi correctly labeled as benign by means of eis scores (true negative rate, specificity). eis attained a true negative rate of roughly 50%, which appears low in nevi lacking any dermoscopic signs of malignancy. this finding is in line with previous studies on eis reporting a limited specificity of 34.4% at a high sensitivity of 96.6% [5,6]. due to the study setting malignant lesions were not included, and thus we could not calculate sensitivity (true positive rate). the specificity of 49.3% obtained in the study is still superior to the 34.4% reported in the pivotal study with the method. this difference might be cumulative uv dose has also been shown  [24]. finally, it seems well conceivable, that “moderately” uv exposed nevi have been included in the training data of the device [6], which might have attenuated effects on eis scores, and particularly on class changes (changes from benign to malignant after uv exposure). in contrast, effects of acute sun exposure were not further assessed in pivotal studies since exclusion criteria of the pivotal study included “lesions and/ or reference located on acute sunburn”. in the future, training sets of devices for the evaluation of melanocytic lesions should consider the influence of uv irradiation. the information that sun-exposed lesions were excluded from studies has to be included in clinical tutorials for users and in the webpage of the device. in the literature changes of melanocytic lesions have been reported following exposure to uv light of various wavelengths [12,13,25-27]. although natural sunlight differs from therapeutic irradiation [28], sup includes both the uvb and uva component and thus a subgroup analysis was performed for this largest group of patients. sup patients received a dose of 3-4 med-uvb over a mean number of 7.7 sessions. in these cases, we found a significantly elevated figure 5. boxplots show electrical impedance spectroscopy (eis) scores of nevisirr and nevisnon-irr at all 3 study visits (v1-3) for the subgroup of patients receiving sup. the upper and lower bounds of boxes represent the 25th and 75th percentiles while the median is given by the line intersecting both boxes. the a priori cut-off for a diagnosis of malignancy is indicated by a dotted line (eis score ≥ 4). original article | dermatol pract concept. 2022;12(4):e2022164 9 tested cnn was more robust to the effect of uv exposure with almost unchanged scores. references 1. arnold m, holterhues c, hollestein lm, et al. trends in incidence and predictions of cutaneous melanoma across europe up to 2015. j eur acad dermatol venereol. 2014;28(9):1170-8117. doi: 10.1111/jdv.12236. 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nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety. br j dermatol. 2014;171(5):1099-1107. doi: 10.1111/bjd.13121. pmid: 24841846. pmcid: pmc4257502. 7. esteva a, kuprel b, novoa ra, et al. dermatologist-level classification of skin cancer with deep neural networks. nature. 2017;542(7639):115-118. doi: 10.1038/nature21056. pmid: 28117445. pmcid: pmc8382232. 8. haenssle ha, fink c, schneiderbauer r, et al. man against machine: diagnostic performance of a deep learning convolutional neural network for dermoscopic melanoma recognition in comparison to 58 dermatologists. ann oncol. 2018;29(8): 1836-1842. doi: 10.1093/annonc/mdy166. pmid: 29846502. 9. haenssle ha, fink c, toberer f, et al. man against machine reloaded: performance of a market-approved convolutional neural network in classifying a broad spectrum of skin lesions in comparison with 96 dermatologists working under less artificial conditions. ann oncol. 2020;31(1):137-143. doi: 10.1016/j. annonc.2019.10.013. pmid: 31912788. 10. de gruijl fr. skin cancer and solar uv radiation. eur j cancer. 1999;35(14):2003-2009. doi: 10.1016/s0959-8049(99) 00283-x. pmid: 10711242. 11. tronnier m, smolle j, wolff hh. ultraviolet irradiation induces acute changes in melanocytic nevi. j invest dermatol. 1995;104(4):475-478. doi: 10.1111/1523-1747.ep12605910. pmid: 7706761. 12. hofmann-wellenhof r, soyer hp, wolf ih, et al. ultraviolet radiation of melanocytic nevi: a dermoscopic study. arch dermatol. 1998;134(7):845-580. doi: 10.1001/archderm.134.7.845. pmid: 9681348. 13. hofmann-wellenhof r, wolf p, smolle j, reimann-weber a, soyer hp, kerl h. influence of uvb therapy on dermoscopic features of acquired melanocytic nevi. j am acad dermatol. explained by the different populations of patients and lesions included within the two studies, since the accuracy of eis was shown to be correlated with lesion atypia. for a comparison, the abcd rule of dermoscopy achieves a specificity of 91.2% and a true negative predictive value of 95.8% [30], hence surpassing eis by far. we used this prospective clinical study to additionally assess the reproducibility of eis scores (2 consecutive measurements of the same lesions). one previous publication raised concerns regarding reproducibility, because the authors found that for 45% of benign lesions the difference in eis scores was ≥2 points and differences up to ± 4 points were observed. moreover, for one melanoma included in their study a decrease in eis scores by 2 points was found after repeated measures [4]. according to the correlation coefficient in our study, reproducibility was “good” to “moderate”, depending on the thresholds applied [19,20]. yet, for approximately 30% of repeated measurements a change in the diagnostic category (from benign to malignant or vice versa) was observed, which in our view is an important limitation regarding clinical application of eis. there are various factors which determine electrical impedance during the eis procedure, amongst others the amount of saline solution applied to the skin. the intralesional variability of eis scores may be explained by the intrinsic variability of the method, but possibly also by a modification of the lesion by repeated application of the liquid and electrodes on the skin surface in a short period. besides eis measurements, we assessed dermoscopic images by a deep learning cnn for a second approach based on lesion morphology. here, we found no relevant changes of cnn scores following uv irradiation, which implies a favorable robustness of the applied cnn. the rate of correctly classified benign lesion was 94.7%, which is in line with its previously published high specificity [8,9]. the cnn was trained with > 150.000 labeled dermoscopic images from around the globe comprising a real-life sample of nevi with or without previous sun exposure. in our study cnn scores of included nevi were quite low, reflecting our study setting with inclusion of clinically clear-cut benign nevi. since only common nevi were included, we may not draw any conclusions with regard to atypical nevi or melanomas. altogether, our study reveals several further limitations. the number of included patients was low and only artificial sources of uv irradiation were assessed [31]. furthermore, the applied phototherapy protocols varied with regard to uv spectrum, applied dosage and number of sessions. in conclusion, our study shows that uv exposure may increase eis scores of nevi. uv shielded nevi surrounded by uv exposed skin showed similar changes as directly irradiated nevi. physicians should be aware of these interrelations when applying eis as an assistance system. in contrast, the 10 original article | dermatol pract concept. 2022;12(4):e2022164 comparing protection using a physical barrier vs sunscreen. jama dermatol. 2013;149(7):803-813. doi: 10.1001/jamadermatol.2013.398. pmid: 23699984. 24. 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(eds) environment and skin. springer, cham. 2018. doi: 10.1007/978-3-319-43102-4_2 29. slominski at, zmijewski ma, plonka pm, szaflarski jp, paus r. how uv light touches the brain and endocrine system through skin, and why. endocrinology. 2018;159(5): 1992-2007. doi: 10.1210/en.2017-03230. pmid: 29546369. pmcid: pmc5905393. 30. nachbar f, stolz w, merkle t, et al. the abcd rule of dermatoscopy. high prospective value in the diagnosis of doubtful melanocytic skin lesions. j am acad dermatol. 1994;30(4):551-559. doi: 10.1016/s0190-9622(94)70061-3. pmid: 8157780. 31. oikarinen a, karvonen j, uitto j, hannuksela m. connective tissue alterations in skin exposed to natural and therapeutic uv-radiation. photodermatol. 1985;2(1):15-26. pmid: 3885186. 1997;37(4):559-563. doi: 10.1016/s0190-9622(97)70171-3. pmid: 9344193. 14. tronnier m, smolle j, wolff hh. ultraviolet irradiation induces acute changes in melanocytic nevi. j invest dermatol. 1995;104(4):475-478. doi: 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dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022199 1 patch testing in patients with alopecia areata: a case-series study eirini kyrmanidou1, eleni sotiriou2, demetrios ioannides2, zoi apalla1, a emvalomati1, elisavet lazaridou1 1 second department of dermatology and venereology, aristotle university of thessaloniki, thessaloniki, greece. 2 first department of dermatology and venereology, aristotle university of thessaloniki, thessaloniki, greece. key words: alopecia areata, allergic contact dermatitis, patch test, ifn-γ citation: kyrmanidou e, sotiriou e, ioannides d, apalla z, emvalomati a, lazaridou e. patch testing in patients with alopecia areata: a case-series study. dermatol pract concept. 2022;12(4):e2022199. doi: https://doi.org/10.5826/dpc.1204a199 accepted: january 29, 2022; published: october 2022 copyright: ©2022 kyrmanidou et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: eirini kyrmanidou, md, msc, second department of dermatology and venereology, aristotle university of thessaloniki, i.pasalidi 77, 55132 thessaloniki, greece. tel: +302314047229 email: ekyrmanidou@gmail.com introduction alopecia areata (aa) is a non-scarring disorder of the hair follicle and currently pathogenesis research is focused on determining the role, contribution, and interactions between each of the immune components involved. it has been previously reported that fungal infection, seasonal airborne allergens, and other allergens may contribute to the complex autoimmune pathways of aa [1,2]. recently, allergy to dust mite was associated with time of onset and severity of aa [3]. thus, and in order to examine a possible contributing role of allergic contact dermatitis (acd) in patients with aa, we performed patch testing in patients diagnosed with aa in our clinic. case presentation thirty-one patients, 12 males and 19 females, aged 18 to 83 years, firstly diagnosed with active aa lesions (positive hair pull test) were eligible for inclusion. patients with personal history of atopic dermatitis (ad ) and/or acd were excluded from the study, to diminish possible bias effect. according to the international contact dermatitis research group guidelines, the european baseline series s-100 patch tests consisting of 32 allergens were performed as per protocol, after receiving informed consent from the participants. the interpretation of results was conducted in two consecutive visits, after 48 and 96 hours, to determine late allergic reactions. two patients (6.4%, 2/31) were found positive towards nickel, 1 patient (3.2%, 1/31) had a positive reaction against methylisothiazolinone and 1 patient (3.2%, 1/31) was positive against the fragrance mix. since there was no control group, we can only report frequency of acd in patients with aa. conclusions the hair follicle is characterized by immune privilege, which protects it from being exposed to immune recognition, especially 2 research letter | dermatol pract concept. 2022;12(4):e2022199 during anagen phase of hair growth. immune privilege collapse is considered as the starting point of an immunologic cascade resulting in aa. however, it remains unclear which is the triggering event leading to excessive release of inf-γ in the microenvironment around the hair follicle in patients with aa. acd is a disease with genetic predisposition that is phenotypically expressed after the patient’s exposure to certain environmental factors. inf-γ, among other cytokines, is secreted not only during the sensitization but also during the elicitation phase of acd [4]. furthermore, attia et al. reported that in patients with alopecia universalis tige serum levels were higher than in patients with other types of aa [5]. the rate of acd among aa patients in our series roughly conforms with the rate reported in the general population [4]. patients with a history of ad were excluded, since those patients have shown to have higher rates of positive patch tests compared to the general population [6]. in conclusion, we could not detect a difference in the incidence of acd in our group of patients. we acknowledge the fact that the sample size is limited, and clearly state that larger studies are needed to clarify the precise ratio and investigate a potential role of acd in the susceptibility and/or onset of the immunologic phenomena involved in aa. references 1. rudnicka l, lukomska m. alternaria scalp infection in a patient with alopecia areata. coexistence or causative relationship? j dermatol case rep. 2012;6(4):120-124. doi: 10.3315 /jdcr.2012.1120. pmid: 23329992. pmcid: pmc3543859. 2. zhao y, zhang b, caulloo s, chen x, li y, zhang x. diffuse alopecia areata is associated with intense inflammatory infiltration and cd8+ t cells in hair loss regions and an increase in serum ige level. indian j dermatol venereol leprol. 2012;78(6):709-714. doi: 10.4103/0378-6323.102361. pmid: 23075639.. 3. li sf, zhang xt, qi sl, et al. allergy to dust mites may contribute to early onset and severity of alopecia areata. clin exp dermatol. 2015;40(2):171-176. doi: 10.1111/ced.12471. pmid: 25252126. 4. brites gs, ferreira i, sebastião ai, et al. allergic contact dermatitis: from pathophysiology to development of new preventive strategies. pharmacol res. 2020;162:105282. doi: 10.1016/j. phrs.2020.105282. pmid: 33161140. 5. attia ea, el shennawy d, sefin a. serum interleukin-4 and total immunoglobulin e in nonatopic alopecia areata patients and hla-drb1 typing. dermatol res pract. 2010;2010:503587. doi: 10.1155/2010/503587. pmid: 20671941. pmcid: pmc2910459. 6. milam ec, jacob se, cohen de. contact dermatitis in the patient with atopic dermatitis. j allergy clin immunol pract. 2019;7(1): 18-26. doi: 10.1016/j.jaip.2018.11.003. pmid: 30598176. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023108 1 a midline maxillary tusk-shaped incisor in an infant mario cutrone1, vincenzo piccolo2, alejandro ontiveros-holguín3, ramon grimalt4 1 department of pediatric dermatology, ospedale dell’angelo, venice, italy 2 dermatology unit, university of campania vanvitelli, naples, italy 3 school of medicine, universidad autónoma de durango campus chihuahua, chihuahua, mexico 4 department of dermatology, universitat internacional de catalunya, barcelona, spain citation: cutrone m, piccolo v, ontiveros-holguín a, grimalt r. a midline maxillary tusk-shaped incisor in an infant. dermatol pract concept. 2023;13(2):e2023108. doi: https://doi.org/10.5826/dpc.1302a108 accepted: september 21, 2022; published: april 2023 copyright: ©2023 cutrone et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, md, c/o ii policlinico, edificio 9, primo piano, via pansini 5 80131 napoli, italy. tel: +39-0815666834 fax: +39-0815468759 e-mail: piccolo.vincenzo@gmail.com case presentation a 4-month-old boy, who previously presented for a sizable gingival hemangioma on the lower gingiva two months earlier and was being treated with propranolol and monthly follow-up, now presented with a sudden onset of a white lesion in the upper gingiva that caused great discomfort during breastfeeding to his mother one morning. examination of the oral cavity revealed in the midline of the upper gingiva, a primary dental eruption reminiscent of a tusk or a fang due to its incurved crown and sharp vertex (figure 1a). while waiting dental and maxillofacial surgery consultations, the lesion abruptly disappeared. a small central mucosal swelling with a slightly hemorrhagic pedicle at the site of detachment remained visible. teaching point strictly speaking, this is not a neonatal tooth nor is it a natal tooth. that said, its early decay suggests a somewhat premature dentition with different structural characteristics than the transitional teeth that persist until the time of definitive dentition. solitary median maxillary central incisor syndrome is a mild manifestation of the holoprosencephaly spectrum, typically exhibiting an eruption of normal morphology in the midline of the maxillary alveolus at age of 8 months; present in both primary and permanent dentition [1,2]. an initial head ultrasonography was performed with no anomaly being found. considering the absence of other malformative elements, genetic evaluation was postponed to a later period of life. at age of 6 months, the boy developed an eruption of the upper left canine and lower central incisor teeth of normal morphology (figure 1b). acknowledgement: patient parents in this manuscript has given written informed consent to the publication of her case details. 2 image letter | dermatol pract concept. 2023;13(2):e2023108 references 1. hall rk. solitary median maxillary central incisor (smmci) syndrome. orphanet j rare dis. 2006;1:12. doi: 10.1186/1750 -1172-1-12. pmid: 16722608. pmcid: pmc1464380. 2. garcia rodriguez r, garcia cruz l, novoa medina y, et al. the solitary median maxillary central incisor (smmci) syndrome: associations, prenatal diagnosis, and outcomes. prenat diagn. 2019;39(6):415-419. doi: 10.1002/pd.5451. pmid: 30900264. figure 1. (a) tusk-shaped primary dental eruption in the midline of the upper gingiva at age 4 months. (b) primary eruption of the upper left canine and lower central incisor teeth at age of 6 months. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022128 1 dermatology practical & conceptual an exuberant case of retentional acne: chloracne philippe visintainer melo1, gabriela fortes escobar1 1 department of dermatology, hospital de clínicas de porto alegre, rio grande do sul, brazil citation: visintainer melo p, fortes escobar g. an exuberant case of retentional acne: chloracne. dermatol pract concept. 2022;12(3):e2022128. doi: https://doi.org/10.5826/dpc.1203a128 accepted: november 15, 2021; published: july 2022 copyright: ©2022 melo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication corresponding author: philippe visintainer melo, md, ramiro barcelos street, number 2350, 1st floor, dermatology department – porto alegre, rio grande do sul, brazil90035-903. e-mail: phvisintainer@gmail.com case presentation a 39-year-old woman presented with an 11-year history of facial lesions. she had worked on tobacco, corn and bean plantings for 23 years, having contact with multiple pesticides. physical examination showed open comedones and cysts, predominating on the malar region, over a grayish background (figure 1, a and b). her family history revealed 2sisters with similar lesions, who had also worked in agriculture, while four other sisters without contact with pesticides, had no skin lesions. laboratory exams were normal and skin biopsy showed diffuse hyperkeratosis and infundibular dilatation, with sebaceous gland disappearance (figure 1c). at the moment, the patient is using isotretion 40 mg/day with a partial response, mostly on the open comedones. furthermore, manual extraction of the larger retentional lesions was associated and she remains under follow-up. teaching point chloracne is an acneiform eruption caused by the ingestion, inhalation or transcutaneous penetration of halogenated aromatic hydrocarbons [1]. these compounds induce hyperkeratinization of keratinocytes, transformation of sebocytes to a keratinocytic phenotype and increase melanogenesis [2]. most importantly, the sudden onset of a large number of acneiform lesions in the same household should lead the physician to consider chloracne. 2 image letter | dermatol pract concept. 2022;12(3):e2022128 figure 1. (a and b) numerous open comedones and cysts over a light grayish background, predominating on the malar region. (c) histopathology showing infundibular dilatation, diffuse hyperkeratosis and absence of sebaceous gland (h&e, x40). references 1. chessa ma, la placa m, patrizi a, et al. six cases of chloracne in italy: the success of combined therapy. j eur acad dermatol venereol. 2021;35(2):e108-e111. doi: 10.1111/jdv.16835. pmid: 32706914. 2. furue m, tsuji g. chloracne and hyperpigmentation caused by exposure to hazardous aryl hydrocarbon receptor ligands. int j environ res public health. 2019;16(23):4864. doi: 10.3390/ ijerph16234864. pmid: 31816860. pmcid: pmc6926551. a b c dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023056 1 characterization of chronic urticaria and associated conditions a web-based survey weronika zysk1, magdalena trzeciak2 1 dermatological students scientific association, department of dermatology, venereology and allergology, faculty of medicine, medical university of gdansk, poland 2 department of dermatology, venereology and allergology, faculty of medicine, medical university of gdansk, poland key words: chronic urticaria, autoimmune urticaria, comorbidity, angioedema citation: zysk w, trzeciak m. characterization of chronic urticaria and associated conditions a web-based survey. dermatol pract concept. 2023;13(1):e2023056. doi: https://doi.org/10.5826/dpc.1301a56 accepted: may 28, 2022; published: january 2023 copyright: ©2023 zysk et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: weronika zysk, dermatological students scientific association, department of dermatology, venerology and allergology, faculty of medicine, medical university of gdansk, 17 smoluchowskiego st, 80-214 gdansk, poland. e-mail: weronikazysk@gumed.edu.pl introduction: chronic urticaria is a common disease, characterized by the development of wheals, angioedema, or both, which can be associated with several comorbidities. most of the available studies have focused on specific common comorbidities and their association with cu, but have seldom reported the overall burden of comorbidities. objectives: this study aimed to investigate and analyze self-reported comorbidities in polish patients with cu. methods: an anonymous online survey consisting of 20 questions was conducted on members of an urticaria group on the social media platform facebook. a total of 102 people took part in this survey. the results were analyzed in microsoft excel 2016. results: in the group, 95.1% were females and 4.9% males, with a mean age of 33.8 years. the most common diagnosed type of urticaria was spontaneous (52.9%). angioedema accompanied urticaria in 68.6% of the respondents, mainly those with delayed pressure urticaria (86.4%). 85.3% of respondents reported comorbidities, most often atopic diseases and allergies (49%), chronic inflammation and infections (36.3%), thyroid (36.3%) and psychiatric disorders (25.5%). moreover, in 30.4% of patients, at least one autoimmune disease was noted. as compared to the patients without autoimmune urticaria, many more with autoimmune urticaria had a coexisting autoimmune disease (50% vs. 23.7%). family history of autoimmune diseases was positive in 42.2%, and the familial history of urticaria and atopy was positive in 7.8% and 25.5%, respectively. conclusions: the knowledge of comorbidities of chronic urticaria may support clinicians to manage and treat patients with this common condition. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023056 introduction chronic urticaria (cu), affecting 0.5%–1% of the general population, is defined by the repeated occurrence of itchy hives, angioedema, or both, for 6 weeks or more. according to current guidelines, cu can be divided into chronic spontaneous urticaria (csu) and chronic inducible urticaria (cindu) with several subgroups. both cu types can occur concomitantly in the same patient [1]. cu develops more frequently in adults, in the third to fifth decade of life, and females are affected at least twice as often as males [2]. several studies reported that patients with cu frequently exhibit comorbidities. the association of cu with psychiatric disorders, including depression, anxiety and behavioral problems, atopic disorders, autoimmune disorders, hypertension, osteoporosis, and infections, has been reported previously [3-7]. most of these studies have focused on specific common comorbidities and their association with cu, but have seldom reported the overall burden of comorbidities. objectives this study aimed to investigate and analyze self-reported comorbidities in polish patients with cu. material and methods the study was based on an anonymously filled online survey prepared by the authors. individuals with cu and parents of children with cu were recruited for participation in the study through closed membership cu support groups found on social media platforms (facebook). individuals interested in participating in the survey were directed through an introduction and implicit consent into google forms. the questionnaire consisted of 20 questions: 7 single-choice and 13 multiple-choice. single-choice questions concerned basic demographic information, presence of angioedema, age of the first episode of cu, and frequency of cu symptoms. multiple-choice questions concerned information about diagnosed types of cu, localization of angioedema, family history of urticaria and atopy, family history of autoimmune diseases, the coexistence of connective tissue, thyroid gland, digestive system, inflammatory diseases, metabolic and cardiovascular diseases, skin diseases, allergic diseases, mental disorders, neoplasm diseases, and others that individuals could add in a designated place. data about family history of atopy was defined as the presence of asthma, eczema, allergic rhinitis, or rhino conjunctivitis, whereas autoimmune diseases were defined as hashimoto’s thyroiditis, systemic lupus erythematosus, pernicious anemia, vitiligo, graves’ disease, rheumatoid arthritis, celiac disease, alopecia areata, sclerosis multiplex, scleroderma, diabetes mellitus type 1, crohn’ disease and ulcerative colitis. a total of 102 people (97 women and 5 men) took part in this survey. the average age of patients was 33.8 years (range, 9-57 years). the results were analyzed in microsoft excel 2016 and presented on a percentage scale. the study was approved by the independent bioethics committee for scientific research at the medical university of gdansk (nkbbn/833/2021). results the majority of cu patients were 19–39 years old (59.8%), followed by patients aged ≥40 years old (33.3%), while a small proportion, 6.9% of patients were ≤18 years old. the vast majority of the respondents (80.4%) lived in cities, the remaining 19.6% lived in villages. more than half of the respondents (63.7%) reported higher education, 17.6% secondary, and 3.9% vocational. nearly 16% of respondents were studying. the mean age at disease onset was 27.5 years (range, 3–55 years). among all patients, the most frequent type of cu was csu, diagnosed in 78.4%. autoimmune urticaria, which is a subtype of csu, was diagnosed in 25.5%. among all patients with cu, 59.8% were diagnosed with csu only, 21.6% were diagnosed with isolated cindu only and the remaining 18.6% had a combination of both types. the most common subtypes of cindu were delayed pressure urticaria (21.6%), symptomatic dermographism (14.7%), and cholinergic urticaria (8.8%; fig 1). angioedema symptoms were reported by 70 patients (68.6%) and occurred mainly in patients with delayed pressure urticaria (86.4%; fig 2). of the 70 patients who experienced symptoms of angioedema, the most frequently reported locations for angioedema were non-facial body areas (82.9%), most commonly the hands (68.6%), feet (57.1%), over joints (35.7%), and trunk (5.7%). 17.1% of patients reported experiencing swelling symptoms over the whole body. on the face, angioedema occurred in 68.6% of patients: the areas around the eyes were affected in 67.1% of cases, the lips in 65.7%, the oral mucosa in 12.9%, and the tongue in 11.4%. in more than half of the cases (59.8%), hives appear every day, in 16.7% several times a week, in 8.8% several times a month, in 10.8% several times a year, and in 3.9% less frequently. we examined the prevalence of reported comorbid diseases by cu patients, grouping them into 10 disease categories. the data presented in table 1 summarize the comorbidity profile of cu patients. of 102 cu patients, 85.3% had one or more concomitant diseases. almost 50% of patients had at least one atopic disease or allergy and it was the most original article | dermatol pract concept. 2023;13(1):e2023056 3 commonly reported group of comorbidities, followed by chronic inflammation and infections (36.3%),  thyroid disorders (36.3%), psychiatric disorders (36.3%), skin diseases (18.6%), gastrointestinal diseases (18.6%), cardiometabolic diseases (10.8%), rheumatic diseases (6.9%), malignancies (2.0%), and others included migraine, endometriosis, pernicious anemia and epilepsy. among all comorbidities reported by patients, we determined autoimmune diseases. of 102 cu patients, 31 (30.4%) had one or more comorbid autoimmune diseases (table 2). the most prevalent were autoimmune thyroid diseases (24.5%, mostly ht in 22.5%). other common autoimmune comorbidities included systemic lupus erythematosus (2.9%) and rheumatoid arthritis (2.9%). of the 31 cu patients with a comorbid autoimmune disease, 74.2% had one, most often ht, 22.6% had 2, and 3.2% had 3 (table 2). as compared to the patients without autoimmune urticaria, many more with autoimmune urticaria had a coexisting autoimmune disease (50% vs. 23.7%). interestingly, in 43 patients (42.2%) with cu there was a familial history of autoimmune disease, in 26 patients (25.5%) familial history of atopy, and in 8 patients (7.8%) familial history of chronic urticaria. discussion in line with the findings of previous studies, csu occurs with a higher frequency than cindu, with comorbid cindu likely in a fifth of the cases, despite heterogeneity in the regional distribution of cu and its phenotypes [8]. symptomatic dermographism has previously been reported to be the most common of the physical urticarias [9]. we observed that delayed pressure urticaria was the most commonly diagnosed cindu subtype. figure 1. percentage of patients with chronic urticaria (cu), divided by subtype (n=102). figure 2. percentage of patients with concomitant angioedema, divided by subtype of chronic urticaria (cu). 4 original article | dermatol pract concept. 2023;13(1):e2023056 table 1. the comorbidity profile of chronic urticaria patients. diseases prevalence in all cu patients (n=102) atopy and allergies drug allergy 21,6% 49,0% allergic rhinitis 20,6% food allergy 17,6% asthma 15,7% inhaled allergy 12,7% atopic dermatitis 10,8% rhino-conjunctivitis 6,9% insect venom allergy 6,9% chronic inflammation and infectious sinusitis 17,6% 36,3% gastritis 10,8% urinary tract infection 7,8% helicobacter pylori 6,9% periodontitis 5,9% otitis media 2,0% hepatitis b 1,0% autoimmune hepatitis 1,0% thyroid disorders hashimoto’s disease 22,5% 36,3% hypothyroidism 17,6% hyperthyroidism 2,9% graves’ disease 2,0% goiter 1,0% psychiatric disorders depression 16,7% 25,5% anxiety disorders 14,7% skin diseases allergic contact dermatitis 9,8% 18,6% psoriasis 4,9% vitiligo 2,0% seborrheic dermatitis 1,0% alopecia areata 1,0% gastrointestinal diseases gerd 10,8% 18,6% ibs 8,8% peptic ulcer 2,9% celiac disease 1,0% cardiometabolic diseases arterial hypertension 8,8% 10,8%ischemic stroke 2,0% diabetes mellitus type 2 1,0% connective tissue diseases sle 2,9% 6,9% ra 2,9% mctd 1,0% polymyositis 1,0% neoplasm melanoma 1,0% 2,0% carcinoid tumor 1,0% others migraine 12,7% 19,6% endometriosis 5,9% pernicious anemia 2,0% epilepsy 1,0% cu = chronic urticaria; gerd = gastroesophageal reflux disease; ibs = irritable bowel syndrome; mctd = mixed connective tissue disorder; ra = rheumatoid arthritis; sle = systemic lupus erythematosus. original article | dermatol pract concept. 2023;13(1):e2023056 5 table 2. the number and combination of autoimmune diseases in chronic urticaria patients. aid, no. prevalence in all cu patients with aid (n=31) prevalence in all cu patients (n=102) hashimoto’s disease, 23 74,2% 22,5% sle, 3 9,7% 2,9% ra, 3 9,7% 2,9% vitiligo, 2 6,5% 2,0% graves’ disease, 2 6,5% 2,0% pernicious anemia, 2 6,5% 2,0% autoimmune hepatitis, 1 3,2% 1,0% celiac disease, 1 3,2% 1,0% alopecia areata, 1 3,2% 1,0% mctd, 1 3,2% 1,0% polymyositis, 1 3,2% 1,0% number of aid in cu one, 23 74,2% 22,5% two, 7 22,6% 6,9% three, 1 3,2% 1,0% combination of cu of two or more autoimmune diseases ht + pernicious anemia, 2 6,5% 2,0% ht + celiac disease, 1 3,2% 1,0% ht + vitiligo, 1 3,2% 1,0% ht + ra, 1 3,2% 1,0% ht + sle, 1 3,2% 1,0% ht + sle + ra, 1 3,2% 1,0% alopecia areata + sle, 1 3,2% 1,0% aid = autoimmune diseases; cu = chronic urticaria; ht = hashimoto’s disease; ra = rheumatoid arthritis; sle = systemic lupus erythematosus. the available data suggest that 33–67% of all patients with cu have concomitant angioedema [10]. we obtained very similar results. angioedema usually affects the skin on the face, mainly the lips and eyelids [11]. in contrast, our results showed that non-facial body areas were the most frequent locations for angioedema, which may be related to the relatively high percentage of patients with delayed pressure urticaria in our study, which is characterized by erythematous swelling of the skin 4 to 6 hours after the application of pressure. the swelling of the hands and feet provoked by pressure may be difficult to tell apart from swelling caused by angioedema [12]. most publications do not provide information on the frequency of episodes of cu. the data mainly relate to the duration of the disease, which is estimated at generally 1-5 years [10]. the frequency of urticaria symptoms in this study was estimated as: 59.8% daily, 16.7% several times a week, 8.8% several times a month, and 14.7% irregularly. many researchers analyzed mainly allergic diseases accompanying urticaria. shalom et al. [13] reported that the most common were allergic rhinitis (19.9%) and asthma (10.8%). zuberbier et al. [14] also concluded that atopy, mainly allergic rhinitis (41.9%), and atopic dermatitis (18.9%) were the most common. a korean study also highlighted the high burden of allergic rhinitis, drug allergies, and asthma [15]. in the scandinavian aware study, a follow up-study of patients with cu refractory to antihistamine treatment, the most common comorbidities were atopic diseases including asthma, allergic rhinitis, food allergies, and atopic dermatitis. [16]. our results are similar to these past findings. type-i auto-allergic csu is quite common and possibly more likely associated with atopic comorbidities than typeiib auto-immune driven csu, which seemingly be the reason for the high frequency of atopic comorbidities observed in the overall cu population [17]. on the other hand, the large registry study from germany demonstrated hypertensive diseases (43.5%), lipoprotein metabolism disorders (32.1%), and affective disorders (26.0%) as the most frequently reported comorbidities of 6 original article | dermatol pract concept. 2023;13(1):e2023056 patients. we found the prevalence of thyroid diseases among cu patients was about 36.3%. hashimoto’s thyroiditis was the most prevalent thyroid disease (22.5%), followed by hypothyroidism (17.6%), hyperthyroidism (2.9%), and graves’ disease (2.0%). the relationship of cu with autoimmune thyroid diseases has been underlined for many years and a large number of studies have been conducted worldwide [27]. it is worth noting that most of the studies have analyzed the relationship between csu and thyroid autoimmunity. little is known about whether cindu is also linked to thyroid autoimmunity. our data showed that 26,3% of patients with isolated csu had autoimmune thyroid disease, while with isolated cindu only 13,6%. the guidelines of the eaaci/ga2len/edf/wao recommend that physicians assess cu patients for family history of urticaria and atopy [1]. in our study, family history of urticaria and atopy was negative in the majority of patients, 92.2 % in urticaria and 74.5% in atopy. on the other hand, autoimmune disorders were common in family members. our study has some limitations. first, respondents were recruited through facebook groups and there is a potential sample selection bias. our study population cannot be representative of all chronic urticaria patients as the participation of men has been unrepresentative. we did not use any instrument for assessing urticaria severity therefore we do not know the severity of the disease in the respondents. however, patients participating in urticaria groups typically have more severe and uncontrolled symptoms of the disease. in addition, women participate more actively in social networks and are looking for more information about the diseases they suffer from. another limitation is the fact that middle-aged patients are more likely to participate actively in social networks and online survey studies thus the obtained data may not be representative of all age groups. most of our study population were patients between the ages of 19 and 39. taking into account all of this, our data have over-represented young women and those who have more severe chronic urticaria. as mentioned above, young women and patients with severe diseases seek more information about the disease they suffer from and are more active on social media. such a profile of patients participating in our study may affect the percentage of comorbidities which is relatively high compared to other reported publications. finally, the high registration percentage of delayed pressure urticaria in our study may be a result of the percentage of angioedema. regarding the fact that it can be difficult for patients to distinguish between swelling caused by pressure from swelling caused by angioedema they often confuse the two entities or report them in the same way. special interest [18]. this is in contrast to our findings where coexisting hypertension was reported by only 8.8% of patients. a retrospective danish cohort study that examined the prevalence of cardiovascular diseases did not find any increased risk of these in cu patients compared to the general population [19]. however, an extended duration of csu is more likely in patients with arterial hypertension [5]. in the taiwan study, among the four categories of comorbidities that were examined, inflammatory diseases (9.78%) were the most prevalent, followed by psychiatric disorders (8.53%), rheumatic diseases (2.48%), and thyroid disorders (1.78%) [20]. other studies have found that psychiatric comorbidities were the most commonly recognized in cu patients, ranging up to 60%. anxiety, depression, and somatoform disorders have been reported to be the most prevalent mental disorders in cu patients [21]. in our study, almost 26% of patients reported psychiatric disorders, most often depression. many authors emphasize the possible role of parasitic infestations and inflammation in chronic urticaria [22]. in our analysis, none of the respondents reported parasitic infestations. whereas among inflammatory diseases, the most common were sinusitis (17.6%), gastritis (10.8%), and urinary tract infection (7.8%). authors from taiwan found peptic ulcer was the most prevalent inflammatory disease (4.83%), followed by hepatitis b/hepatitis c (1.64%) and periodontitis (2.82%) [20]. the association between cu and neoplasm diseases is still controversial. one population-based study reported no association between cu and cancer [23]. a study from taiwan demonstrated an increased risk of hematological malignant tumors, especially non-hodgkin lymphoma, in patients with cu [24]. a korean study showed an increased risk of nonhematological tumors, especially stomach, thyroid, and liver cancers in the case of cu, and thyroid, liver, and prostate cancers in the case of csu [15]. in our study, two patients reported the presence of melanoma and carcinoid tumor. a systematic review of the literature on autoimmune comorbidities in patients with cu showed that the most common autoimmune comorbidities were autoimmune thyroid diseases and vitiligo [25]. our results are similar, except that the next most common diseases after autoimmune thyroid diseases (24.5%) were rheumatoid arthritis (2.9%) and systemic lupus erythematosus (2.9%). thyroid dysfunctions, especially autoimmunity, have been most commonly found among cu patients, with the reported prevalence ranging up to more than 50% depending on the inclusion criteria. association studies using the presence of anti-thyroid antibodies as the criteria usually obtained higher frequencies [26]. in this study, we defined the presence of thyroid disorders based on self-reports by original article | dermatol pract concept. 2023;13(1):e2023056 7 allergy organ j. 2018;11(1):32. published 2018 nov 16. doi:10.1186/s40413-018-0216-1 9. sánchez j, amaya e, acevedo a, celis a, caraballo d, cardona r. prevalence of inducible urticaria in patients with chronic spontaneous urticaria: associated risk factors. j allergy clin immunol pract. 2017;5(2):464-470. doi:10.1016/j.jaip.2016.09.029 10. maurer m, weller k, bindslev-jensen c, et al. unmet clinical needs in chronic spontaneous urticaria. a ga²len task force report.  allergy. 2011;66(3):317-330. doi:10.1111/j.1398-9995 .2010.02496.x 11. nowicki rj, grubska-suchanek e, porêbski g, et al. angioedema. interdisciplinary diagnostic and therapeutic recommendations of the polish dermatological society (ptd) and polish society of allergology (pta).  postepy dermatol alergol. 2020;37(4):445-451. doi:10.5114/ada.2020.98226 12. lawlor f, black ak. delayed pressure urticaria.  immunol allergy clin north am. 2004;24(2):247-vii. doi:10.1016/j. iac.2004.01.006 13. shalom g, magen e, dreiher j, et al. chronic urticaria and atopic disorders: a cross-sectional study of 11 271 patients. br j dermatol. 2017;177(4):e96-e97. doi:10.1111/bjd.15347 14. zuberbier t, balke m, worm m, edenharter g, maurer m. epidemiology of urticaria: a representative cross-sectional population survey.  clin exp dermatol. 2010;35(8):869-873. doi:10.1111/j.1365-2230.2010.03840.x 15. kim br, yang s, choi jw, choi cw, youn sw. epidemiology and comorbidities of patients with chronic urticaria in korea: a nationwide population-based study. j dermatol. 2018;45(1):10-16. doi:10.1111/1346-8138.14075 16. thomsen sf, pritzier ec, anderson cd, et al. chronic urticaria in the real-life clinical practice setting in sweden, norway, and denmark: baseline results from the non-interventional multicentre aware study.  j eur acad dermatol venereol. 2017;31(6): 1048-1055. doi:10.1111/jdv.14210 17. maurer m, eyerich k, eyerich s, et al. urticaria: collegium internationale allergologicum (cia) update 2020.  int arch allergy immunol. 2020;181(5):321-333. doi:10.1159/000507218 18. weller k, maurer m, bauer a, et al. epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in germany. j eur acad dermatol venereol. 2022;36(1):91-99. doi:10.1111/jdv.17724 19. egeberg a, kofoed k, gislason gh, vestergaard c, thyssen jp. cardiovascular risk is not increased in patients with chronic urticaria: a retrospective population-based cohort study.  acta derm venereol. 2017;97(2):261-262. doi:10.2340/00015555-2516 20. chu cy, cho yt, jiang jh, lin ei, tang ch. epidemiology and comorbidities of patients with chronic urticaria in taiwan: a nationwide population-based study.  j dermatol sci. 2017;88(2):192-198. doi:10.1016/j.jdermsci.2017.07.006 21. konstantinou gn, konstantinou gn. psychiatric comorbidity in chronic urticaria patients: a systematic review and meta-analysis.  clin transl allergy. 2019;9:42. published 2019 aug 23. doi:10.1186/s13601-019-0278-3 22. bansal cj, bansal as. stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria.  allergy asthma clin immunol. 2019;15:56. published 2019 sep 11. doi:10.1186/s13223-019-0372-z 23. lindelöf b, sigurgeirsson b, wahlgren cf, eklund g. chronic urticaria and cancer: an epidemiological study of 1155 patients. br conclusions in conclusion, cu significantly influences the quality of patients’ lives, which may be negatively affected by the association with a wide range of comorbidities. our study found that the most common comorbidities in cu include atopic and allergic diseases, chronic inflammations, thyroid, and psychiatric disorders. this pattern of comorbidities seems to be specific to cu. our data suggest that patients with autoimmune urticaria are more likely to have autoimmune comorbidities than patients without this subtype of csu. this may be explained by the known co-occurrence of multiple autoimmune phenomena and autoimmune diseases. therefore, autoimmune comorbidities in patients with chronic urticaria may suggest the presence of an autoimmunological subtype of csu, which is usually more severe and has a significantly worse response to omalizumab treatment [28]. knowledge of the comorbidities of cu may support clinicians in appropriately managing and treating this condition. acknowledgments we would like to express our gratitude to the patients who complete our survey. references 1. zuberbier t, aberer w, asero r, et al. the eaaci/ga²len/ edf/wao guideline for the definition, classification, diagnosis, and management of urticaria.  allergy. 2018;73(7):1393-1414. doi:10.1111/all.13397 2. saini ss. chronic 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doi:10.1111/j.1365-2133 .1990.tb01449.x 24. chen yj, wu cy, shen jl, chen tt, chang yt. cancer risk in patients  with chronic urticaria: a population-based cohort study.  arch dermatol. 2012;148(1):103-108. doi:10.1001/ archdermatol.2011.682 25. kolkhir p, borzova e, grattan c, asero r, pogorelov d, maurer m. autoimmune comorbidity in chronic spontaneous urticaria: a systematic review. autoimmun rev. 2017;16(12):1196-1208. doi:10.1016/j.autrev.2017.10.003 26. kolkhir p, metz m, altrichter s, maurer m. comorbidity of chronic spontaneous urticaria and autoimmune thyroid dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023011 1 follow-up of favipiravir-induced nail fluorescence: implications for nail and drugs hüsna güder1, zeynep güneş özünal2 1 department of dermatology, medical faculty, maltepe university, istanbul, turkey 2 department of pharmacology, medical faculty, maltepe university, istanbul, turkey key words: favipiravir, nail, fluorescence, drug citation: güder h, güneş özünal z. follow-up of favipiravir-induced nail fluorescence: implications for nail and drugs. dermatol pract concept. 2023;13(1):e2023011. doi: https://doi.org/10.5826/dpc.1301a11 accepted: july 31, 2022; published: january 2023 copyright: ©2023 güder et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: hüsna güder, department of dermatology, medical faculty, maltepe university, feyzullah caddesi no:39, maltepe/istanbul, turkey. tel: +905056916918 email: husnaguder@gmail.com introduction: favipiravir creates fluorescence on nails, which can be seen with wood’s light. objectives: the objectives of this study are to examine the properties of fluorescence in the nail due to favipiravir and to observe whether other drugs also produce fluorescence in the nail. methods: the research is descriptive, prospective, and quantitative. this study recruited 30 healthcare workers who received favipiravir treatment and 30 volunteers who took or did not take any medication except favipiravir from march 2021 to december 2021. fingernails of the patients and control groups were examined under wood’s light in the darkroom. if fluorescence was observed in the fingernails, we followed up once a month until the fluorescence disappeared. we calculated the nail growth rate by dividing the distance of nail fluorescence from the proximal nail fold by the number of days since favipiravir was started. results: we found nail fluorescence in all patients receiving a loading dose of favipiravir. the fluorescence in the nail decreased and disappeared in the 3rd month. the average nail growth rate at the first visit was 0.14 mm/day. the nail growth rate at the second visit was 0.10 mm/day. a statistically significant difference was found between the first and second visit nail growth rates (z: -2.576; p=0.010<0.05). we found that other drugs did not produce any fluorescence in the nail. conclusions: nail fluorescence induced by favipiravir is dose-dependent and decreases in intensity over time. nail fluorescence due to favipiravir is likely due to the active ingredient of the drug. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023011 introduction the human eye can only process visible light (400−720 nm), which is a narrow segment of the electromagnetic spectrum (ems). our retina is not capable of sensing light in the uv spectrum (10-400 nm) but can detect longer wavelength fluorescence caused by the interaction of uv light with skin chromophores. wood’s light is frequently used in dermatology to detect fluorescence produced by exogenous or endogenous chromophores [1]. favipiravir, a pyrazine carboxamide derivative (6fluoro 3-hydroxy-2-pyrazine carboxamide), is a broad-spectrum antiviral drug with inhibitory effects on a variety of rna viruses [2]. favipiravir is widely used in turkey to treat coronavirus disease 2019 (covid-19) based on the covid-19 treatment guide of the ministry of health, republic of turkey. a loading dose of 2x1600 mg (first day) of favipiravir followed by 2x600 mg/day (4 days) for a total of 4 days is recommended. wood’s lamp is a high-pressure mercury arc lamp filtered with barium silicate and nickel oxide, emitting ultraviolet in the 320-400 nm spectrum with a peak at 365 nm. when examining a wood’s lamp in a dark room, fluorescence is seen if there are fluorophores[3]. so far, the following fluorescence has been reported in the nail due to drug use: yellow for tetracycline, yellow/green for quinacrine, and yellow/ green/blue fluorescence for favipiravir [4-9]. we wanted to follow up on whether nail fluorescence in all patients using favipiravir persisted or not and how long nail fluorescence persists. data on the fluorescence of drugs in nails are limited to a few drugs. we wanted to collect information about whether other drugs create fluorescence in the nails by including people who use drugs as a control group in our study. we thought that the data we obtained could provide information about drug transfer to the nail and the relation between drugs and nails. material and methods patients who received favipiravir treatment due to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polymerase chain reaction (pcr) positivity diagnosis among healthcare workers at our hospital were included in the study as the study group. only an observational study was planned, without any interference with patients’ drug doses or treatment duration. the reason for choosing healthcare professionals is to facilitate follow-up and eliminate the risks that may occur due to patients coming to the hospital. in the control group, individuals who did not receive favipiravir treatment and were or were not using another systemic drug were included in the study. the research is descriptive, prospective, and quantitative. volunteer adults between the ages of 18-65 were included in the study. an informed consent form was obtained from all participants. those who were pregnant or breastfeeding were not included in the study. we recorded the age, gender, drug use, vitamin and supplement use of the study and control groups. the drugs taken as a criterion for systemic drug use were taken at least 15 days before and drugs taken for more than 5 days were recorded. approval from the ministry of health of the republic of turkey with the number 2021-01-13t13_41_11 and permission from the ethics committee of maltepe university with the number 2021/900/19 were obtained. we conducted this study among 30 healthcare workers who received favipiravir treatment and 30 volunteers who took or did not take any medication between 04/03/2021 and 25/12/2021. the fingernails of the patients and control groups were examined under wood’s light (lumio®uv, 3gen dermlite™, 40 uv leds, 75 mm 2x lens, u.s.a.) in the darkroom. if fluorescence was observed in the fingernails, we followed up once a month until the fluorescence disappeared. the length of the third fingernails of the left hand of all patients was measured. the left hand was chosen as it is usually the non-dominant hand and the middle finger because it is easy to position. the cuticle (eponychium) was not included when measuring nail length or fluorescence. we measured the size of the fluorescence in the nail. in addition, the distance of the fluorescence from the distal tip of the nail and the proximal nail fold was also measured. measurements were made from the midpoint of the nail using a digital caliper (figure 1). it was not possible to see all of the patients in the 1st month and the 2nd month. 1st month was accepted as 31±3 days, 2nd month was 61±3 days. the first visit nail growth rate was calculated as mm/ day by dividing the distance between the proximal nail fold and the first distal fluorescence by the measurement day. the 2nd visit nail growth rate was obtained by subtracting the distance of the distal fluorescent from the proximal nail fold measured at the 2nd visit from the first measured at the 1st visit and dividing by the number of days in between (figure 2). statistics power analysis in the research was carried out with the g power 3.1.9.7 program. assuming that the difference between 2 observations will be examined, the t-test family was taken as reference, and the effect size was accepted as 0.8 using the wide cohen reference since there was no similar prior study. in addition, it was concluded that it would be sufficient to have 15 people in the analysis of the main hypothesis at 80% power and 5% significance levels. since there were 20 people who could be followed up in the study, the sample size obtained was considered sufficient. the spss 22.0 (ibm corporation, armonk, new york, united states) program analyzed the variables. we used the original article | dermatol pract concept. 2023;13(1):e2023011 3 pearson chi-square test to examine whether there was a gender difference between the control group and the study group. we examined the distribution of age by skewness and kurtosis (-1 +1). accordingly, we examined the ages of the study/control groups with the t-test. when comparing the elongation rates of the nail fluorescence, the gaussian distribution was examined and it was found that it was not normal. accordingly, the wilcoxon signed-rank test was used. hypothesis tests were performed with the help of the spss 22.0 program at a 95% confidence level. quantitative variables were expressed as mean (± standard deviation), and median (minimum-maximum), while categorical variables were shown as n (%). the variables were analyzed at a 95% confidence level, and a p-value less than 0.05 was considered significant. results 24 (80.0%) of the participants included in the study group were women; 6 of them (20.0%) were male. their mean age is 36.10±9.03 years. the average length of the left-hand third figure 1. measurement methods (a: measurement method for the midpoint of the nail fluorescence b: the measurement of the third fingernails of the left hand). figure 2. the first (a) and second (b) visit measurement of the nail fluorescence size (black lines indicate the size of the fluorescence. the red line shows the distance between the distal end of the fluorescence and the proximal nail fold). 4 original article | dermatol pract concept. 2023;13(1):e2023011 the proximal nail in the other (figure 4). furthermore, in a patient who received favipiravir twice, examined on the 62nd day of the 1st dose and the 48th day of the 2nd dose, fluorescence was observed in the entire nail (figure 5). in the measurements made from the 3rd nail of the left hand, the nail fluorescence of 10 patients could be measured in the 1st month. the mean nail fluorescence length was 3.95±0.67 mm (min-max 3-5) in the first month. the nail fluorescence of 20 patients could be measured in the second month and the mean nail fluorescence length was 4.3±0.77 mm (min-max 2.9-5.9). the last visits of the patients were between 62-122 days (92.07±11.28). nail fluorescence intensity gradually decreased in all patients with fluorescence and disappeared completely in the third month. the first visit nail growth rate could be calculated in 25 patients, and the mean was 0.14 mm/day min-max 0.06-0.22. the second visit nail growth rate could be calculated in 20 patients whose fluorescence measurement could be made in the 2nd-month follow-up, and it was 0.10 mm/day min-max 0.07-0.19. in the analysis comparing the differences between the first and second nail growth rates, a statistical difference was found (z: -2.576; p=0.010<0.05) (table 3). some patients in the study group took additional medications such as valproic acid, lithium carbonate, levothyroxine, olanzapine, mirtazapine, methylphenidate, paroxetine, vitamin d3, zinc, vitamin b1/b2/b6/b12, vitamin c, nicotinamide, biotin, folic acid, paracetamol, enoxaparin, nebivolol, n-acetyl cysteine, magnesium, colchicine, prednisolone, metformin, pantoprazole, pheniramine maleate, amoxicillin/ clavulanic acid, ketoprofen, levocetirizine/montelukast, acetylsalicylic acid, omega 3 and blackberry extract. the fingernails is 11.28±0.188. in the control group, 20 (66.7%) of the 30 participants were female, and 10 (33.3%) were male. their mean age is 37.37±13.12. the average length of the left-hand third fingernails is 11.86±1.85. in total, 44 of 60 participants were women; 16 of them were male. their mean age is 36.73±11.19 years. the average length of the left-hand third fingernails is 11.57±1.88 (table 1). when the study and control groups were compared according to the length of the left-hand third fingernail, no statistically significant difference was found (p>0.05) (table 2). in the study group, fluorescence was observed in 27 of 30 patients (90%) using favipiravir. the three patients without fluorescence did not use the total dose of favipiravir. one of these patients vomited after taking eight tablets on the first day, one took only five tablets of favipiravir, and one did not take the loading dose on the first day (figure 3). blue fluorescence was observed in the fingernails of all patients who used 2x1600 mg (day 1) of favipiravir, followed by 2x600 mg/day for a total of 4 days. the earliest evaluation after starting favipiravir was on the 5th day of treatment, and we did not see fluorescence in her nail. 2 patients were evaluated on day eight, and we found fluorescence of 1 mm in one patient and 3.3 mm in table 1. demographic data of study and control groups. study group n % female 24 80 male 6 20 total 30 100 min max mean sd age 21 51 36.1000 9.03003 left-hand 3rd nail length 7.80 15.30 11.2833 1.88334 control group n % female 20 66.7 male 10 33.3 total 30 100 min max mean sd age 19 64 37.37 13.12 left-hand 3rd nail length 8.60 15.70 11.8633 1.85370 table 2. comparison of study and control groups according to left-hand 3rd nail length. n mean sd t p study 30 11,2833 1,88334 -1,202 0,234 control 30 11,8633 1,85370 t: independent samples t-test value original article | dermatol pract concept. 2023;13(1):e2023011 5 figure 3. patients without nail fluorescence. (a: the patient vomited after taking eight tablets, b: the patient took only five tablets, c: the patient did not take the loading dose of favipiravir. figure 4. the earliest evaluation of the nail fluorescence for three patients after starting favipiravir. a: 5th day of treatment, and no fluorescence is visible. b: 8th day of treatment, and 1 mm fluorescence is seen. c: 8th day of treatment and 3.3 mm of fluorescence is observed). 6 original article | dermatol pract concept. 2023;13(1):e2023011 nail bed. the elongation of fingernails is about 0.1 mm/day and differs between individuals [10]. while aging, acute infections, systemic illness, and malnutrition slow down nail growth, nail growth is faster in those with pregnancy, warmer temperatures, and minor trauma [11]. in the study group, the 1st visit nail growth rate, which represents approximately the 1st month, was found to be significantly higher than the 2nd visit nail growth rate, which approximately represents the 2nd month. the increase in nail growth rate may be related to covid-19 infection, use of favipiravir, taking vitamins due to illness, or trying to eat better. since we could not evaluate the nail growth rate in the control group, we cannot comment. since we could only make the nail growth rate comparison in 20 patients, it is impossible to say this with certainty. in addition, since what we are measuring is fluorescent, the intensity of the light decreases over time, which may have caused inaccuracies in the measurements. fluorescence seen in the nail was consistent with the intake of favipiravir, we did not observe that the above-mentioned drugs affected this fluorescence. in the control group, the drugs taken by the patients include metformin, nebivolol, sertraline, levothyroxine, drospirenone/ ethinylestradiol, desloratadine/montelukast, fluoxetine, budesonide/formoterol, isotretinoin, ibuprofen, ramipril/ hydrochlorothiazide, iron/folic acid, terbinafine, perindopril/ indapamide, alfuzosin, diltiazem, pregabalin, duloxetine, carvedilol, escitalopram, telmisartan, amlodipine, candesartan, enalapril, ofloxacin, zinc, biotin, and melatonin. nail fluorescence was not observed in any of the control group patients. discussion the nail plate is composed of layers of keratinized cells produced by the nail matrix and extends distally over the figure 5. the patient received favipiravir twice. (a: upon examination on the 62nd day of the 1st dose and the 48th day of the 2nd dose, nail fluorescence was observed in the entire nail. b: upon examination on the 103rd day of the 1st dose and the 89th day of the 2nd dose, nail fluorescence disappeared. table 3. comparison of 1st visit and 2nd visit nail growth rate (n=20). mean±sd median (q1-q3) z p 1st visit nail growth rate 0.14±0.044 0.14 (0.10-0.19) -2.576 0.010* 2nd visit nail growth rate 0.10±0.034 0.09 (0.08-0.11) z: wilcoxon signed-rank test statistics value; q1: 25. percentile; q3: 75. percentile; *: p<0.05 original article | dermatol pract concept. 2023;13(1):e2023011 7 the patient and control groups, and fluorescence was not observed in the nails due to these drugs in these patients. based on this information, we think that favipiravir-induced nail fluorescence is mainly caused by the drug rather than the favipiravir tablet additives. however, since these drugs were one-per-day tablets, it would not be correct to compare the dose with 16 tablets a day, as in favipiravir. since the nail is in a structure that can indicate long-term exposure to a substance, it is used to evaluate environmental exposure, in the detection of abused drugs and poisoning [20]. it should be taken into account that the substance accumulated in the nail may decrease over time when drug measurement is made in the samples obtained by nail clipping. and although the time the nail is cut varies from person to person, it gives information about 3-4 months prior in the average fingernail. conclusion favipiravir-induced nail fluorescence is dose-dependent, and its intensity decreases over time. we think that the concentration of the drugs in the nails decreases over time. nail fluorescence due to favipiravir is probably due to the active ingredient in the drug. we think that the information we have obtained may be useful in the treatment of conditions such as onychomycosis where drug transfer to the nail is important and in determining the concentration of nail exposure substances. references 1. mojeski ja, almashali m, jowdy p, et al. ultraviolet imaging in dermatology. photodiagnosis photodyn ther. 2020;30:101743. doi:10.1016/j.pdpdt.2020.101743 2. du yx, chen xp. favipiravir: pharmacokinetics and concerns about clinical trials for 2019-ncov infection. clin pharmacol ther. 2020;108(2):242-247. doi:10.1002/cpt.1844 3. klatte jl, van der beek n, kemperman pm. 100 years of wood’s lamp revised.  j eur acad dermatol venereol. 2015;29(5): 842-847. doi:10.1111/jdv.12860 4. hendricks aa. yellow lunulae with fluorescence after tetracycline therapy. arch dermatol. 1980;116(4):438-440. 5. kierland rr, sheard c. fluorescence of nails from quinacrine hydrochloride.  j am med assoc. 1946;131:809. doi:10.1001 /jama.1946.02870270009004 6. aslan kayıran m, cebeci f, erdemir va, aksoy h, akdeniz n, gürel ms. fluorescence of nails and hair on wood’s lamp examination in covid pandemic; undefined effect of favipiravir in humans.  dermatol ther. 2021;34(1):e14740. doi:10.1111 /dth.14740 7. guder h, ozunal zg. nail fluorescence in covid-19 patients. joj dermatology & cosmetics, 2021, 3.4: 79-82. doi:10.19080 /jojdc.2021.03.555619 8. gülseren d, yalıcı-armagan b. yellow-white fluorescence on the nails: a novel finding of favipiravir used for the treatment the incidence of fluorescence in nails due to the use of favipiravir was previously reported as 81.9% and 84% [9, 12]. similar to the findings in these studies, we observed fluorescence in the nail in 90% of our patients using favipiravir, and we observed that there was fluorescence in the nail in 100% of the patients who received the full loading dose. nail manifestations associated with covid-19 included a red half-moon sign, transverse orange nail lesions, mees’ lines, and beau’s lines [13]. no nail disorder was observed in any of our patients who had covid-19. nail fluorescence due to favipiravir was seen in all patients who received the total dose of favipiravir. it was observed that the density decreased in the 2nd month and disappeared in all patients in the 3rd month. nail fluorescence was not observed in patients who did not receive the loading dose. the fluorescence produced by favipiravir in the nails is dose-dependent and decreases over time. these findings showed that the drug dose is important in drug transfer to the nail. drug delivery to the nail is most important in the treatment of onychomycosis. continuous therapy and intermittent pulse regimens for terbinafine and itraconazole can be used to treat onychomycosis. similar efficacy and side-effect rates have been reported in a meta-analysis [14]. we evaluated the fluorescence in the nails due to the use of high-dose favipiravir for 5 days in our patients as an opportunity to monitor the transfer of the drug to the nails and how long it took to disappear. and the decrease of this fluorescence over time showed that the drug concentration in the nail did not remain the same, and we did not see any fluorescence in the distal 1/3 of the nail, except in one patient who took favipiravir twice. in onychomycosis, the distal lateral subungual type, in which the distal and lateral parts of the nail are affected, is the most common [15]. we think that insufficient access of antifungal drugs to the micelles located in the distal nail may be an important factor in treatment failure in onychomycosis. the maximum plasma concentration of favipiravir occurs 2 hours after oral administration and then decreases rapidly with a short half-life of 2-5.5 hours [2]. itraconazole has plasma half-lives of 42 hours and terbinafine of up to 100 hours [16]. it can be thought that it can affect a much larger area of the nail than favipiravir. it is not known in what way the use of favipiravir creates fluorescence in the nails. in one study, it was claimed that it could be caused by excipients such as titanium dioxide and yellow ferric oxide added to the favipiravir tablet for photo stabilization due to the “fluoro” in the favipiravir formulation [17, 18]. pure favipiravir has been shown to exhibit blue fluorescence in microscopic fluorescence examination [19]. in addition, titanium dioxide and yellow ferric oxide were among the additives of the drugs taken by some patients in 8 original article | dermatol pract concept. 2023;13(1):e2023011 dermatophyte toenail onychomycosis.  j eur acad dermatol venereol. 2020;34(3):580-588. doi:10.1111/jdv.16101 15. lipner sr, scher rk. onychomycosis: clinical overview and diagnosis. j am acad dermatol. 2019;80(4):835-851. doi:10.1016 /j.jaad.2018.03.062 16. debruyne d, coquerel a. pharmacokinetics of antifungal agents in onychomycoses.  clin pharmacokinet. 2001;40(6):441-472. doi:10.2165/00003088-200140060-00005 17. demir b, cicek d, turkoglu s, bozdemir ny, sarikurt f, banoglu e. wood’s lamp examination of hair and nails related to covid-19 treatment.  dermatol ther. 2021;34(6):e15174. doi:10.1111/dth.15174 18. kutlu ö, yılmaz ş. fingernail lunula luminescence in covid-19 patients: is it a favipiravir-related reaction or a novel manifestation of coronavirus infection.  photodermatol photoimmunol photomed. 2021;37(4):343-344. doi:10.1111/phpp.12660 19. zhang t, wang x, zhou h, he yjmc, crystals l. screening and fluorescence investigation on favipiravir cocrystal.  molecular crystals and liquid crystals, 2021, 1-16. doi:10.1080/15421 406.2021.1989653 20. palmeri a, pichini s, pacifici r, zuccaro p, lopez a. drugs in nails: physiology, pharmacokinetics and forensic toxicology. clin pharmacokinet. 2000;38(2):95-110. doi:10.2165/0000 3088-200038020-00001 of covid-19.  j cosmet dermatol. 2021;20(8):2392-2393. doi:10.1111/jocd.14214 9. turan ç, metin n, utlu z, yıldız tt, caferoğlu sakat s. evaluation of the frequency and intensity of favipiravir associated yellow-green fluorescence in lunulae, hair, and face [published online ahead of print, 2021 apr 29]. j cosmet dermatol. 2021;10.1111/jocd.14189. doi:10.1111/jocd.14189 10. baswan s, kasting gb, li sk, et al. understanding the formidable nail barrier: a review of the nail microstructure, composition and diseases. mycoses. 2017;60(5):284-295. doi:10.1111 /myc.12592 11. geyer as, onumah n, uyttendaele h, scher rk. modulation of linear nail growth to treat diseases of the nail.  j am acad dermatol. 2004;50(2):229-234. doi:10.1016/j.jaad.2003.07.011 12. yanatma i, cenk h. evaluation of nail findings in patients with covid-19 history and wood’s lamp examination.  skin appendage disord. 2021;38:1-6. published 2021 oct 12. doi:10.1159/000518983 13. preda-naumescu a, penney k, pearlman rl, brodell rt, daniel cr, nahar vk. nail manifestations in covid-19: insight into a systemic viral disease. skin appendage disord. 2021;183(6):1-6. published 2021 aug 17. doi:10.1159/000518087 14. gupta ak, stec n, bamimore ma, foley ka, shear nh, piguet v. the efficacy and safety of pulse vs. continuous therapy for untitled research | dermatol pract concept 2015;5(2):5 39 dermatology practical & conceptual www.derm101.com dermoscopic patterns in patients with a clinical diagnosis of onychomycosis—results of a prospective study including data of potassium hydroxide (koh) and culture examination miriam américa jesús-silva1, ramón fernández-martínez2, rodrigo roldán-marín3, roberto arenas 1, 2 1 dermatology department, hospital general dr. manuel gea gonzález, mexico city, mexico 2 mycology department, hospital general dr. manuel gea gonzález, mexico city, mexico 3 dermatologist, associate professor, faculty of medicine, universidad nacional autónoma de méxico, mexico city, mexico key words: dermoscopy, onychomycosis, nails, patterns, clinical, koh citation: jesús-silva ma, fernández martínez r, roldán-marín r, arenas r. dermoscopic patterns in patients with a clinical diagnosis of onychomycosis—results of a prospective study including data of potassium hydroxide (koh) and culture examination. dermatol pract concept 2015;5(2):5. doi: 10.5826/dpc.0502a05 received: january 14, 2015; accepted: february 23, 2015; published: april 30, 2015 copyright: ©2015 jesús-silva et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: roberto arenas, m.d., tlalpan 4800 méxico d.f. 14000. tel. +525.5665.7791. email: rarenas98@hotmail.com background: onychomycosis is the most common nail disease, representing 50% of cases affecting the nail apparatus. the diagnosis is made by clinical examination along with the koh exam of the nail and culture of the sample. however, not all dermatologists have access to a mycology lab. objective: to determine the correlation between koh examination and dermoscopic patterns in patients with clinical diagnosis of onychomycosis. patients/methods: a descriptive, open, observational, prospective, cross-sectional study of 178 patients with clinical suspicion of onychomycosis was conducted. all patients underwent clinical examination, dermoscopy with a dermlite photo dermatoscope (3gen, san juan capistrano, ca, usa), koh assessment and culture analysis. the most frequent dermoscopic patterns were identified and their correlation with the clinical subtype of onychomycosis was analyzed. results: the study included 178 patients with clinical suspicion of onychomycosis. of these, 155 (87.1%) had positive direct koh examination for onychomycosis. eighty-seven patients (56.13%) presented with clinical onychomycosis pattern of total dystrophic onychomycosis (tdo), 67 (43.23%) with distal lateral subungual onychomycosis (dlso), 1 (0.65%) with trachyonychia). dermoscopic patterns of onychomycosis showed the following frequencies: the spiked pattern was present in 22 patients (14.19%), longitudinal striae pattern in 51 patients (32.9%) and linear edge pattern in 21 patients (13.55%). we identified a pattern described as “distal irregular termination” in 41 patients with tdo and 26 with dlso. conclusions: this is the fist study conducted in a mexican population that uses dermoscopy as a diagnostic tool along with the koh examination for the diagnosis of onychomycosis. dermoscopy may be used as an important diagnostic tool when evaluating nail disease. however, it should not be used as the only diagnostic criteria for onychomycosis. abstract 40 research | dermatol pract concept 2015;5(2):5 recently, nakamura et al [1], performed the dermoscopic study of 500 cases of nail disorders (onychomycosis, psoriasis, lichen planus and nail brittleness), identifying the most frequent dermoscopic characteristics of each one. in the case of onychomycosis they identified four patterns (chromonychia, onycholysis, opacity and longitudinal stripes), similar to those previously described by piraccini [9]. the objective of our study was to determine the correlation between the koh examination and dermoscopic patterns in patients with clinical diagnosis of onychomycosis. materials and methods we included in our study patients with clinical and mycological diagnosis of onychomycosis that were studied in the dermatology and mycology departments of the general hospital “dr. manuel gea gonzález” in mexico city. patients with previous treatment for onychomycosis were excluded. diagnosis of onychomycosis was made with koh examination and the presence of fungal elements (hyphae, spores or yeasts) was considered positive for the diagnosis. part of the sample was also cultured in all patients. macroscopic images of the affected nails were obtained with canon powershot g1x® camera and digital dermoscopic images were obtained with dermlite photo dermatoscope, with 20x and 40x magnifications. a single observer analyzed each of dermoscopy images in order to identify the most common patterns and compare them with the patterns described by piraccini [10], describing the subtype of onychomycosis and the dermoscopic pattern. data were analyzed with the spss statistics desktop (v21.0.0) program, x2 test was applied. percentages, measures of central tendency and dispersion were performed. the correlation between positive koh examination and culture, koh examination and dermoscopic pattern, and clinical subtype of onychomycosis and dermoscopic pattern were determined. the study was approved by the research and ethics committee of the general hospital “dr. manuel gea gonzález” in mexico city, mexico. results a total of 178 patients with clinical suspicion of onychomycosis were initially included in the study (table 1). of these, 155 (87.07%) had a positive koh examination for onychomycosis and were finally included. ninety-nine (55.6%) were women and the mean age was 50-59 years of age, with a median time of onychomycosis evolution of 24 months. eighty-seven patients (56.13%) were clinically classified as total dystrophic onychomycosis (tdo), 67 (43.23%) as introduction onychomycosis is one of the most common nail disorders, accounting for nearly 50% of them. within skin diseases it has a prevalence of 0.44% with a worldwide prevalence ranging from 2 to 50% [1]. it mainly affects adults between 30 and 60 years of age. the vast majority of cases are caused by dermatophytes as t. rubrum (71-87%) or t. mentagrophytes var interdigitale (9-22%). candida species are isolated from cultures much less frequently (10-20%) [1]. the differential diagnosis of onychomycosis includes inflammatory diseases like psoriasis, lupus erythematosus, lichen planus, lichen striatum, alopecia areata, pityriasis rubra pilaris and also systemic diseases (amyloidosis, diabetes, porphyria, dysthyroidism) [2]. infectious diseases that may mimic onychomycosis include viral warts and chronic paronychia. other important differential diagnoses are cosmetic trauma (manicure or pedicure), secondary trauma (tight shoes or friction) and nail apparatus tumors (squamous cell carcinoma, melanoma or digital fibromas) [2]. accurate diagnosis is important since the treatment of onychomycosis can be long-standing, expensive and may be accompanied by severe adverse effects [2]. currently, the diagnosis is made by clinical suspicion along with koh examination followed by culture of the samples [3,4]. however, the sensitivity and specificity of the potassium hydroxide examination and culture depend on the center where the study is conducted and can be as low as 15% [3,5]. when clinical suspicion of onychomycosis is high despite having a negative koh examination and a negative culture, a punch biopsy or shaving the distal portion of the nail can be performed [3], followed by microscopic observation using stains such as pas (periodic acid schiff) or gomori-grocott. the procedure is simple and easy to perform, but invasive and expensive compared to direct examination. dermoscopy is a noninvasive tool that is widely used for the diagnosis of melanocytic, non melanocytic lesions, inflammatory and infectious diseases [6,7]. currently there are specific algorithms for the analysis of patterns of melanocytic and non-melanocytic lesions, yet, there is no algorithm described and validated for the assessment onychomycosis [1,8]. piraccini et al identified and described specific dermoscopic signs for onychomycosis to distinguish it from traumatic onycholysis [9]. a retrospective analysis of 57 digital dermoscopic images with clinical diagnosis of onycholysis diagnosis was performed. dermoscopic findings were compared with mycological findings and 3 dermoscopic patterns were described, 2 for onychomycosis (jagged proximal edge with spikes of the onycholytic area and longitudinal striae) were identified and 1 for traumatic onycholysis (linear edges without peaks in the area of onycholysis). thus, these authors proposed a new diagnostic algorithm based on the presence of spiked edges [9]. research | dermatol pract concept 2015;5(2):5 41 distal lateral subungual onychomycosis (dlso), 1 (0.65%) with trachyonychia and none had white superficial onychomycosis (wso). the culture was negative in 76.13% (118 samples). in 16 samples t. rubrum was identified as the causative agent (10.33%), trichosporon sp. was identified in 4 samples (2.59%) and candida sp. was isolated in 5 patients (3.23%). the spiked pattern was present in 39 patients (25.16%) (figure 1), the longitudinal striae in 94 (60.65%) (figure 2), linear edge in 34 (21.94%) (figure 3) and distal irregular termination in 67 patients (43.22%) (figure 4). the presence of onychomycosis in the koh examination was correlated with each dermoscopic pattern. chi square test was applied to this correlation, which was not significant in any case (tables 1 and 2). table 1. general characteristics of 178 patients initially included in the study [copyright: ©2015 jesús-silva et al.]   tdo* dlso** trachyonychia wso*** p # % # % # % # % total number of cases 94 52.81 81 45.51 1 0.56 2 1.12 gender female 66 37.08 48 26.97 1 0.56 1 0.56 0.386 evolution 0.66 <25 months 40 22.47 39 21.91 1 0.56 2 1.12 25-48 months 14 7.87 11 6.18 0 0.00 0 0.00 > 49 months 40 22.47 31 17.42 0 0.00 0 0.00 positive direct koh examination 87 48.88 67 37.64 1 0.56 0 0.00 0.001 findings in direct koh examination 0.034 fungal hyphae 84 47.19 73 41.01 0 0.00 2 1.12 yeasts 10 5.62 8 4.49 1 0.56 0 0.00 dermoscopic pattern spiked pattern 24 13.48 24 13.48 0 0.00 0 0.00 0.683 longitudinal striae 56 31.46 50 28.09 1 0.56 1 0.56 0.843 linear edge 23 12.92 17 9.55 0 0.00 1 0.56 0.701 distal irregular termination 42 23.60 29 16.29 0 0.00 0 0.00 0.327 culture positive 75 42.13 58 32.58 0 0.00 1 0.56 0.937 tricophyton rubrum 10 5.62 10 5.62 0 0.00 0 0.00 trichosporon sp. 3 1.69 1 0.56 0 0.00 0 0.00 candida sp. 3 1.69 2 1.12 0 0.00 0 0.00 bacteria 8 4.49 7 3.93 0 0.00 1 0.56 negative 70 39.33 61 34.27 1 0.56 1 0.56 *total dystrophic onychomycosis (tdo) **distal lateral subungual onychomycosis (dlso) *** white superficial onychomycosis (wso) figure 1. spiked pattern, indentations at the proximal edge of the área with onycholysis. [copyright: ©2015 jesús-silva et al.] 42 research | dermatol pract concept 2015;5(2):5 discussion onychomycosis is a disease the dermatologist is faced with great frequency, representing approximately 50% of nail affections. the clinical picture is a critical element for establishing the diagnosis, although it may be insufficient. the mycological diagnosis is performed in our hospital with koh examination and chlorazol black, accompanied by culture of the sample. potassium hydroxide examination is a technique that is observer dependent, but has acceptable sensitivity ranging from 75% up to 80% [10-15]. culture is a method with a low sensitivity for dermatophytes; up to 60% false negatives may occur [7,11] and not all dermatology centers have a mycology laboratory. in our study the culture was not an inclusion parameter, but it was performed in all patients, being positive in only 25 patients. this is consistent with what has been reported in the literature and shows that the culture cannot be used as a gold standard for diagnosis. to the best of our knowledge, this is the third study in which the dermoscopic findings are discussed in onychomycosis. the “longitudinal striae pattern” was more frequently observed in patients with tdo or dlso. our finding is in accordance to what was previously described by piracinni [9]. something similar happened with the spiked pattern, which was also frequently identified in patients with clinical diagnosis of tdo (22) and dlso (17). the presence of “spikes” is important, it is characterized as indentations at the proximal edge of the area with onycholysis compared to the “linear edge” which is manifested as a smooth linear demarcation we next correlated the dermoscopic patterns to the clinical pattern of onychomycosis. the skipped pattern was present in 39 patients and 22 (56.41%) of these showed a clinical pattern of tdo, while 17 (43.59%) showed a clinical pattern of dlso. the longitudinal striae pattern was present in 94 patients, of these 51 (54.25%) showed a clinical pattern of tdo, 42 (44.68%) were clinically compatible with dlso and 1 (1.06%) with trachyonychia (table 3). the linear edged pattern was evident in 34 patients, 21 clinically compatible with tdo (58.8%) and 13 with dlso (38.2%) (table 3). dermoscopically, a pattern described as “distal irregular termination” was present in 67 patients, 41 (61.76%) clinically compatible with tdo and 26 (38.8%) with dlso (table 3). figure 2. longitudinal striae of different colors in the onycholytic nail plate. [copyright: ©2015 jesús-silva et al.] figure 3. linear edge, a smooth linear demarcation without indentations. [copyright: ©2015 jesús-silva et al.] figure 4. distal irregular termination,  distal pulverization characteristic of the thickening of the nail plate. [copyright: ©2015 jesússilva et al.] research | dermatol pract concept 2015;5(2):5 43 table 2. characteristics of 155 patients with positive direct koh examination and finally included on the study tdo* dlso** trachyonychia p # % # % # % positive koh examination 87 56.13 67 43.23 1 0.65   gender—female 59 38.06 39 25.16 1 0.65 0.353 evolution  0.309 <25 months 33 21.29 31 20.00 1 0.65 25-48 months 14 9.03 11 7.10 0 0.00 > 49 months 40 25.81 25 16.13 0 0.00 findings in direct koh examination 0.027 fungal hyphae 77 49.68 59 38.06 0 0.00 yeasts 10 6.45 8 5.16 1 0.65 dermoscopic pattern spiked pattern 22 14.19 17 10.97 0 0.00 0.844 longitudinal striae 51 32.90 42 27.10 1 0.65 0.633 linear edge 21 13.55 13 8.39 0 0.00 0.678 distal irregular termination 41 26.45 26 16.77 0 0.00 0.4 culture  positive 23 14.84 14 9.03 0 0.00 0.992 tricophyton rubrum 9 5.81 7 4.52 0 0.00 trichosporon sp. 3 1.94 1 0.65 0 0.00 candida sp. 3 1.94 2 1.29 0 0.00 bacteria 8 5.16 4 2.58 0 0.00 negative 64 41.29 53 34.19 1 0.65 *total dystrophic onychomycosis (tdo) **distal lateral subungual onychomycosis (dlso) note: white superficial onychomycosis (wso) was not included in this analysis because no patient had a positive direct koh examination. table 3. dermoscopic patterns and their correlation with the different clinical types of onychomycosis spiked pattern longitudinal striae linear edge distal irregular termination total 39 94 34 67 # % # % # % # % tdo * 22 56.41 51 54.26 21 61.76 41 61.19 dlso ** 17 43.59 42 44.68 13 38.24 26 38.81 trachyonychia 0 0.00 1 1.06 0 0.00 0 0.00 p 0.844 0.633 0.68 0.4 *total dystrophic onychomycosis (tdo) **distal lateral subungual onychomycosis (dlso) 44 research | dermatol pract concept 2015;5(2):5 2. allevato ma. diseases mimicking onychomycosis. clin dermatol 2010;28(2):164-77. 3. richert b, lateur n, theunis a, et al. new tools in nail disorders. semin cutan med surg 2009;28(1):44–8. 4. harvey ck, richardson a. techniques for obtaining specimens for culture to confirm onychomycosis. j am podiatr med assoc 2000;90(8):394-6. 5. lilly kk, koshnick rl, grill jp, et al. cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests. j am acad dermatol 2006;55:620-6. 6. campos-do-carmo g, ramos-e-silva m. dermoscopy: basic concepts. int j dermatol 2008;47(7):712–19. 7. gilje o, o’leary pa, baldes ej. capillary microscopic examination in skin disease. ama arch dermatol syphilol 1953;68(2):136–47. 8. micali g, lacarrubba f, massimino d, et al. dermatoscopy: alternative uses in daily clinical practice. j am acad dermatol 2011;64(6):1135-46. 9. piraccini bm, balestri r, starance m, rech g. nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. j eur acad dermatol venereol 2013;27(4):509-13. 10. manzano-gayosso p, mendez-tovar l, arenas r. levaduras causantes de onicomicosis en cuatro centros dermatológicos mexicanos y su sensibilidad antifúngica a compuestos azólicos. rev iberoam micol 2011;28(1):32–5. 11. pehamberger h, steiner a, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol 1987;17(4):571–83. 12. goldman l. some investigative studies of pigmented nevi with cutaneous microscopy. j invest dermatol 1951;16(6):407–27. 13. bahmer fa, fritsch p, kreusch j, et al. terminology in surface microscopy consensus meeting of the committee on analytical morphology of the arbeitsgemeinschaft dermatologische forschung, hamburg, federal republic of germany, nov 17, 1989. j am acad dermatol 1990;23(6 pt1):1159–62. 14. kreusch j, rassner g. structural analysis of melanocytic pigment nevi using epiluminescence microscopy. review and personal experiences. hautarzt 1990;41(1):27–33. 15. scher r, tavakkol a, bact d, et al. onychomycosis: diagnosis and definition of cure. j am acad dermatol 2007;56(6):939-44. without indentations. according to the data of piraccini et al, the presence of the “linear edge” is significantly associated with traumatic onycholysis [9]. therefore, this simple dermoscopic finding may be useful when making the diagnosis of onychomycosis vs. traumatic onycholysis. the “longitudinal striae” have been studied and identified as the manifestation of the progression of dermatophytes along the nail plate, showing changes in coloration secondary colony formation, flakes or subungual debris. another pattern was described, the “distal irregular termination” which corresponds to the distal pulverization characteristic of the thickening of the nail plate in total dystrophic onychomycosis. this pattern was not significantly associated with a specific clinical pattern of onychomycosis, however, it occurred more frequently in patients with the clinical diagnosis of tdo. this is the first study conducted in the mexican population that shows the usefulness of dermoscopy as a diagnostic tool coupled with mycological examination for the diagnosis of onychomycosis. we recommend future studies with homogeneous groups of different clinical subtypes of onychomycosis and including patients with suspected traumatic onycholysis or other nail diseases. the patterns that were studied have not been validated and are not universally recognized, generating a field of opportunity for the study of onychomycosis by use of dermosocopy. the results of our study show that the diagnosis of onychomycosis cannot be performed relying on clinical grounds alone and emphasize the need to rely on tools such as koh examination, culture and dermoscopy. dermoscopy has proven to become an important adjunctive tool in the evaluation of nail diseases. references 1. nakamura rc, costa m. dermatoscopic findings in the most frequent onychopathies: descriptive analysis of 500 cases. int j dermatol 2012;51(4):483–96. dermatology: practical and conceptual 32 observation | dermatol pract concept 2017;7(3):6 dermatology practical & conceptual www.derm101.com case report a 15-year-old boy presented with a single asymptomatic, mildly erythematous plaque on the palmar aspect of his right little finger of 2 years’ duration. there was no history of bleeding or discharge. the patient denied any history of trauma. the plaque had multiple dark red papules in the center with surrounding erythema (figure 1). a differential diagnosis of verruca, pyogenic granuloma, foreign body granuloma, and angiokeratoma was considered. dermoscopy (dermlite, 3gen, san juan capistrano, ca, 10x) of the lesion showed multiple sharply circumscribed red lacunae and dark lacunae covered with whitish veil in the center and scaling at the periphery of these lacunae (figure 2a & b). the histopathological examination showed hyperkeratosis, acanthosis, elongation and broadening of rete ridges with dilated thin-walled capillaries congested with red blood cells in the upper dermis (figure 3). a diagnosis of angiokeratoma was made. the whitish veil corresponds to the hyperkeratosis and acanthosis, the red lacunae to dilated vascular spaces in the upper dermis, and dark lacunae to dilated vessels with thrombosis. the dark lacunae are the diagnostic sign for angiokeratoma. dermoscopy of a single plaque on the finger yasmeen j. bhat1, abid keen1 1 postgraduate department of dermatology, std & leprosy, government medical college, srinagar, university of kashmir, jammu & kashmir, india citation: bhat yj, keen a. dermoscopy of a single plaque on the finger. dermatol pract concept 2017;7(3):6. doi: https://doi. org/10.5826/dpc.0703a06 copyright: ©2017 bhat et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: yasmeen jabeen bhat, md, facp, assistant professor, postgraduate department of dermatology, std & leprosy, government medical college, srinagar, university of kashmir, jammu & kashmir, 190010, india. tel. +91.9419040771. email: yasmeenasif76@gmail.com figure 1. single erythematous plaque with dark red papules in the center. [copyright: ©2017 bhat et al.] mailto:yasmeenasif76@gmail.com observation | dermatol pract concept 2017;7(3):6 33 multiple (papular type), angiokeratoma circumscriptum, and angiokeratoma corporis diffusum [1]. individual lesions are bright red-purple to black, round to oval hyperkeratotic papules [1]. these are usually asymptomatic but can occasionally cause bleeding with slight trauma, pruritus and pain [2]. solitary angiokeratomas are the most common form of angiokeratomas, and the reported frequency varies from 70% clinical features and types angiokeratomas are benign vascular lesions, characterized by ectasia of blood vessels in the upper third of the dermis, often associated with an epidermal reaction such as acanthosis and hyperkeratosis. several clinical variants of angiokeratomas exist: the mibelli type, the fordyce type, the solitary and figure 2. (a) dermoscopy showing whitish veil with scales (yellow arrows), red lacunae (red arrows) and black lacunae (green arrows) [dermlite , 3gen, san juan capistrano, ca 10x polarized mode]. (b) similar findings in non-polarized mode. [copyright: ©2017 bhat et al.] a b figure 3. photomicrograph showing hyperkeratosis, acanthosis, elongated rete ridges, dilated thin walled capillaries congested with red blood cells. (h&e,400x). [copyright: ©2017 bhat et al.] to 83% of all angiokeratomas [3]. solitary angiokeratomas are seen clinically as bright, soft, non-keratotic papules that grow larger and change to firm, blue-violaceous to black, keratotic papules with a diameter of 2 to 10 mm. the etiopathogenesis of angiokeratomas remains unknown, but several factors have been involved like increased venous blood pressure or primary degeneration of vascular elastic tissue. the etiopathogenesis of angiokeratomas remains unknown, but several factors have been involved like increased venous blood pressure or primary degeneration of vascular elastic tissue. pathology angiokeratomas are histologically characterized by dilated subepidermal vessels congested with erythrocytes from large lacunae only in the papillary dermis, acanthosis, papillomatosis and hyperkeratosis. histologically, differential diagnosis of angiokeratomas includes verrucous hemangiomas, lymphangiomas, angiomas and malignant melanomas [4]. differential diagnosis the most common differential diagnosis involves melanocytic nevi, spitz-reed nevi, malignant melanomas, pigmented basal cell carcinomas, seborrheic keratoses, dermatofibromas, and other vascular lesions such as hemangiomas or pyogenic granulomas [5]. etiology the etiopathogenesis of angiokeratomas remains unknown, but several factors have been implicated, such as increased venous blood pressure or primary de generation of vascular elastic tissue. dermoscopy recently, dermoscopy has become a very useful method for the preoperative diagnosis of vascular lesions including 34 observation | dermatol pract concept 2017;7(3):6 although several treatment options for the management of angiokeratomas have been reported, there is no established protocol for the management of angiokeratomas. furthermore, treatment is not always necessary because angiokeratomas are often asymptomatic. treatment options include cryotherapy, curettage, electrodesiccation, carbon dioxide laser, nd-yag laser, and pulsed dye laser [7]. conclusion dermoscopy is helpful in improving the diagnostic accuracy of solitary angiokeratomas and allows the observer to differentiate them from other cutaneous tumors, such as malignant melanomas and pigmented basal cell carcinomas. references 1. keen ma, hassan i. eruptive angiokeratomas on the glans penis. indian j dermatol. 2014;59(4):424. 2. taniguchi s, inoue a, hamada t. angiokeratoma of fordyce: a cause of scrotal bleeding. br j urol. 1994;73(5):589-590. 3. schiller pi, itin ph. angiokeratomas: an update. dermatology. 1996;193(4):275-282. 4. naranjo sintes r, pereda hernandez j, delgado florencio v, linares solano j. angiokeratoma. apropos of 93 cases. med cutan ibero lat am. 1988;16(3):255–261. 5. goldman l, gibson sh, richfield df. thrombotic angiokeratoma circumscriptum simulating melanoma. arch dermatol. 1981;117(3):138-139. 6. zaballos p, daufí c, puig s, et al. dermoscopy of solitary angiokeratomas: a morphological study. arch dermatol. 2007;143(3):318– 325. 7. saha m, barlow r, bunker cb. angiokeratoma circumscriptum of the penis. br j dermatol. 2006;154(4):775-776. angiokeratomas. in the dermoscopic view, zaballos et al. [6] in their multicentric study revealed six dermoscopic patterns in at least 50% of the solitary angiokeratomas and included dark lacunae, whitish veil, erythema, peripheral erythema, red lacunae, and hemorrhagic crusts. red lacunae were defined as sharply ovoid or round red or red-blue structures that corresponded histopathologically to wide and dilated vascular spaces located in the upper or middle dermis [6]. dark lacunae represent dilated vascular spaces in the upper dermis, and their dark violaceous, dark blue, or black colors correspond to vascular spaces that are partially or completely thrombosed [6]. whitish veil refers to an ill-defined structureless area with an overlying whitish “ground glass” film that corresponds to hyperkeratosis and acanthosis [6]. hemorrhagic crusts correspond to bleeding that can occur in some of these lesions [6]. finally, erythema and peripheral erythema are pinkish homogeneous areas that probably represent inflammation of the lesion and erythrocyte extravasation in the papillary dermis [6]. dermoscopy is helpful in improving the diagnostic accuracy of solitary angiokeratomas and allows the observer to differentiate them from other cutaneous tumors such as malignant melanomas and pigmented basal cell carcinomas [6]. with dermoscopy, however, it is difficult to discriminate between verrucous hemangioma and angiokeratomas because of its difficulty in estimating the depth of lesions. treatment treatment of angiokeratomas depends on the site and size of the lesion and the availability of the surgical equipment like electrocautery, radiofrequency, cryotherapy or ablative lasers. dermatology: practical and conceptual 70 quiz | dermatol pract concept 2017;7(3):16 dermatology practical & conceptual www.derm101.com the patient a 39-year-old otherwise healthy woman presented to our dermatology clinic with a two-week history of a swelling and pain on her neck. she noted a low-grade fever and malaise for ten days. the patient reported no history of tick bite, new medication or consuming raw meat. physical examination revealed fever (38.3°c), an enlarged, painful 4.5 x 4.8 cm sized lymphadenopathy in the right submandibular area (figure 1), multiple targetoid erythema multiforme lesions on the palms (figure 2), and multiple erythema nodosum lesions on the shins (figure 3). we performed whole blood count, chest x-ray, serological tests (microagglutination test), fine needle biopsy, and neck ultrasonography. histopathologic examination of the lymph node disclosed epithelioid histiocytes with multinuclear giant cells and a suppurative inflammation (figure 4a and 4b). what is your diagnosis? erythema multiforme and erythema nodosum lesions with cervical lymphadenopathy ümran muslu1, engin şenel 2,3, yasemin y. karabulut4 1 hitit university faculty of medicine, department of plastic aesthetic and reconstructive surgery, çorum, turkey 2 hitit university faculty of medicine, department of dermatology, çorum, turkey 3 hitit university, beekeeping and bee products application and research center, çorum, turkey 4 university faculty of medicine, department of pathology, mersin, turkey citation: muslu ü, şenel e, karabulut yy. erhythema multiforme and erythema nodosum lesions with cervical lymphadenopathy. dermatol pract concept 2017;7(3):16. doi: https://doi.org/10.5826/dpc.0703a16 received: january 13, 2017; accepted: april 12, 2017; published: july 31, 2017 copyright: ©2017 muslu er al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ümran muslu, md, assistant professor of plastic, aesthetic and reconstructive surgery, hitit university faculty of medicine, 19200 çorum, turkey. tel. +90 364 2230300; fax +90 364 2230323. email: umrandr@hotmail.com figure 1. right submandibular lymphadenopathy. [copyright: ©2017 muslu et al.] quiz | dermatol pract concept 2017;7(3):16 71 potentially fatal disease in the northern hemisphere [3]. clinical findings of tularemia vary according to the bacteria’s entry place into the host, virulence, the dose of inoculation and the immunological status of the host. according to these factors, the disease is classified into six major clinical forms, namely oropharyngeal, ulceroglandular, glandular, oculoglandular, typhoid and pneumonic tularemia. oropharyngeal tularemia is caused by bacterial infiltration from the oral mucosa due to ingestion of contaminant foods and waters. fever, sore throat, and inflammation of the oropharyngeal area occurs. unilateral or bilateral lymphadenopathy develops in the neck. the patients are diagnosed wrongly with acute streptococcal tonsillopharyngitis and treated unsuccessfully with beta-lactam antibiotics. the most common complication in this form is lymph node suppuration. skin lesions and lymphadenopathy following contact with an infected animal or tick bite should suggest an ulceroglandular form of tularemia. in glandular form, the entry site of the bacteria into the host is not known and the patient has tender lymphadenopathy and fever. oculoglandular tularemia develops after conjunctival inoculation or contamination with water. this form is accompanied by answer tularemia serum sample of the patient was obtained and microagglutination test was performed for tularemia serology. the diagnosis of oropharyngeal tularemia was confirmed by an antibody titer of 1:320. discussion tularemia, also known as “rabbit fever” and “deer fly fever,” is a bacterial zoonosis caused by a gram-negative, aerobic and intracellular cocobacillus, francisella tularensis. four subspecies of the bacterium were recognized: tularensis, holarctica, novicida and mediasiatica. the most virulent subspecies is tularensis (jellison type a) and has the highest human mortality rate [1]. subspecies holarctica (jellison type b) that causes a less severe form of the disease is responsible for the infections in europe and asia. tularemia was first described in 1911 in tulare county in the u.s. state of california. the incubation period of the disease is 3-5 days (range: 1-21 days) [2]. tularemia is a figure 2. targetoid erythema multiforme lesions. [copyright: ©2017 muslu et al.] figure 3. multiple erythematous subcutaneous nodules on anterior tibias. [copyright: ©2017 muslu et al.] figure 4a, b. epithelioid histiocytes with multinuclear giant cell and a suppurative inflammation (h&e x40 and h&e x100). [copyright: ©2017 muslu et al.] a b 72 quiz | dermatol pract concept 2017;7(3):16 or group agglutination tests is the easiest diagnosis method. microagglutination test (mat) is the most frequently used method. for serological diagnosis of f. tularensis, world health organization (who) and centers for disease control and prevention (cdc) defines four-fold titer increase in agglutination tests as a sign of acute disease [8,9]. in seroprevalence studies, titers equal to or above 1:20 is considered significant [10]. diagnosis is possible if the tube agglutination test shows a positivity at ≥ 160 titer in one sample, presence of symptoms and lack of vaccination history [10]. tularemia is endemic in our country and in this region. based on the fact that tularemia is epidemic in this region and on our experience with similar cases, tularemia was suspected in our patient. we reached the diagnosis with physical examination findings and microagglutination test positivity. the main treatment of tularemia is streptomycin. we used streptomycin in our patient., but ciprofloxacin was added to treatment due to lymph node suppuration. the patient responded to medical treatment favorably. in conclusion, dermatologists, plastic surgeons should be aware that erythema multiforme and nodosum may be seen as the skin manifestations of tularemia and consider tularemia among differential diagnosis in endemic areas of the northern hemisphere. references 1. hansen cm, vogler aj, keim p, wagner dm , hueffer k. tularemia in alaska, 1938-2010. acta vet scan. 2011;53:61. 2. kaya a, deveci k, uysal io, et al. tularemia in children: evaluation of clinical, laboratory and therapeutic features of 27 tularemia cases. turk j pediatr. 2012;54(2):105-112. 3. komitova r, nenova r, padeshki p, ivanov i, popov v, petrov p. tularemia in bulgaria 2003-2004. j infect dev ctries. 2010;4(11): 689-694. 4. eryılmaz a. boyun kitlelerinin ayırıcı tanısı, in: koç c (çeviri ed.) cummings cw, flint pw, harker la, et al. (eds). cummings otolaringoloji başve boyun cerrahisi. 4th ed. güneş tıp kitabevleri, ankara; 2007:2540-2553. 5. aydın ö, boyun k, koç c, ed. kulak burun boğaz hastalıkları ve baş-boyun cerrahisi. güneş kitabevi, ankara; 2004:887-900. 6. gosche jr, vick l. acute, subacute, and chronic cervical lymphadenitis in children. semin pediatr surg. 2006; 15(2):99-106. 7. syrjala h, karvonen j , salminen a. skin manifestations of tularemia: a study of 88 cases in northern finland during 16 years (1967-1983). acta derm venereol. 1984;64(6):513-516. 8. world health organization. who guidelines on tularaemia. switzerland: who press, switzerland, 2007. http://www.who. int/csr/resources/publications/who_cds_epr_2007_7.pdf. last accessed on march 23, 2017. 9. centers for disease control and prevention. case definitions for infectious conditions under public health surveillance. centers for disease control and prevention. mmwr recomm rep. 1997;46(rr-10):1-55. 10. ellis j, oyston pc, green m, titball rw. tularemia. clin microbiol rev. 2002;15(4):631-646. unilateral, rather painful, purulent conjunctivitis and tender lymphadenopathy. the pneumatic form develops primarily due to inhalation of infectious aerosols (primary pleuropulmonary disease) or hematogenous spread of bacteria during other forms of tularemia. in typhoid tularemia, the entry site of the bacteria could not been found and there is no lymphadenopathy. it is a systemic disease frequently causing pneumonia, meningitis, hepatitis, carditis (relative bradycardia), and nephropathy. our case was identified as oropharyngeal tularemia, which is the most common form in our country. the differential diagnoses of masses in the neck include infections causing unilateral lymphadenopathy, lymphoma, metastasis of malignancies of head and heck region. primary malign lesions can be identified in 65% of the cases with a detailed and sufficient anamnesis and a through pharyngeal examination. if the mass does not seem to be related to malignity, laboratory tests for lymphoma should be ordered to avoid time loss [4,5]. acute viral lymphadenopathies (ebv, rubella, cmv), acute bacterial lymphadenopathies (streptococcus pyogenes, staphylococcus aureus, group b streptococci, anaerobic bacteria, yersinia pestis, francisella tularensis, pasteurella multocida, haemophilus influenzae type b, etc.), subacute and chronic lymphadenopathies (cat scratch disease, mycobacterium tuberculosis, parasitic infections [toxoplasma gondii], fungal infections [blastomyces dermatitidis, histoplasma capsulatum, coccidioides immitis], and opportunistic infections] and non-infectious diseases (kawasaki disease, sarcoidosis disease, etc.) are among differential diagnoses [4-6]. primary and secondary skin lesions are seen in almost 35-43% of patients with tularemia. although papules and vesicopapular lesions are the most common form of skin lesions, other skin lesions such as maculopapular or vesiculopapular rash, erythema nodosum, erythema multiforme, pustules, acneiform lesions, and urticaria also develop. syrjala et al. reported that erythema nodosum was seen in 28% and erythema multiforme in 9% of the patients [7]. skin lesions manifest in the second week and continue for about six weeks. tularemia diagnosis is based on characteristic disease history, physical examination and laboratory findings. since oropharyngeal tularemia does not have specific clinical or laboratory findings, it is frequently recognized in endemic areas. identification of bacteria with culture is the gold standard diagnostic test in tularemia diagnosis. f. tularensis can be isolated in the early period. therefore, getting samples in suspected cases is very important. since microbiological culture of f. tularensis requires a biosecurity level 3 laboratory and experienced personnel, demonstration of bacteria-specific gene sequences with polymerase chain reaction can be used instead. however, serological tests have been the most frequently used method in the diagnosis of tularemia for around a century. looking for antibodies against f. tularensis in tube http://www.who.int/csr/resources/publications/who_cds_epr_2007_7.pdf http://www.who.int/csr/resources/publications/who_cds_epr_2007_7.pdf dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(1):e2023063 1 treatment of diabetes in bullous pemphigoid patients: where do we stand? maria inês alexandre1, pedro miguel garrido2, paulo filipe2,3,4 1 endocrinology department, hospital de santa maria, centro hospitalar universitário de lisboa norte, lisbon, portugal 2 dermatology department, hospital de santa maria, centro hospitalar universitário de lisboa norte, lisbon, portugal 3 university dermatology clinic, faculty of medicine, university of lisbon, lisbon, portugal 4 dermatology research unit, instituto de medicina molecular, university of lisbon, lisbon, portugal citation: alexandre mi, garrido pm, filipe p. treatment of diabetes in bullous pemphigoid patients: where do we stand? dermatol pract concept. 2023;13(1):e2023063. doi: https://doi.org/10.5826/dpc.1301a63 accepted: april 13, 2022; published: january 2023 copyright: ©2023 alexandre et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maria inês alexandre, serviço de endocrinologia, hospital de santa maria, centro hospitalar universitário de lisboa norte, 1649-028 lisboa, portugal. phone: 00351 21 780 5000; e-mail: mariaines.f.alexandre@gmail.com bullous pemphigoid (bp) affects predominantly elderly patients, and the disease incidence rises exponentially with age. a high prevalence of diabetes mellitus (dm) in patients with bp has been noticed, ranging from 20 to 30% [1]. the treatment of bp patients is challenging and should be carefully assessed bearing in mind their multiple comorbidities. corticosteroids are the mainstay of treatment for bp. however, their systemic use is limited in diabetic patients by the risk of acute hyperglycemic complications. this is particularly concerning given the age group of bp patients and the chronicity of treatment. adjunctive therapy with immunosuppressants such as azathioprine, mycophenolate mofetil or methotrexate may also be needed [2]. also, novel targeted therapeutic approaches such as omalizumab and dupilumab have been reported as effective alternatives, but their use in bp is still off-label [3]. several population-based studies supported an increased risk of developing bp in diabetic patients treated with dipeptidyl peptidase-4 inhibitors (dpp4i). a recent meta-analysis showed that the odds ratio (or) for bp among patients receiving any dpp4i ranged from 1.27 to 3.45 [4]. the exact pathogenesis of how dpp4i might induce bp remains largely unclear and it is not known if the suspension of dpp4i can revert this immunological process. however, the clinical outcome appears to be better if dpp4i is discontinued. a presumed association between bp and glucagon-like peptide-1 (glp-1) receptor agonists has also been reported [5]. the underlying mechanism is unclear, however since dpp4i and glp-1 receptor agonists both rely on enhancing the activity of the incretin hormone glp-1, a common effect between these two classes of antidiabetic drugs should be sought. although more robust studies are required, we suggest that this association is taken into account when selecting the most appropriate medication for bp patients. other widely used antidiabetic drugs like second-generation sulfonylureas and metformin seem safer options, but their use can be limited by the patient’s comorbidities [6]. the sodium–glucose cotransporter (sglt)2 inhibitors also seem like good alternatives. these drugs do not increase the risk of hypoglycemia, have low rates of adverse effects and may be continued in patients with moderate renal impairment. overall, they can be used in selected bp patients. 2 commentary | dermatol pract concept. 2023;13(1):e2023063 in many cases, insulin is the most suitable choice, particularly for inpatients on corticosteroids. morning basal insulin may closely fit the glucose excursion induced by a single dose of morning corticosteroid. the initial dose and titration should take into account the patient’s weight and dose of corticosteroid. dairy adjustments are frequently necessary and often difficult to predict. based on the previous data, a treatment algorithm for bp patients with type 2 dm is proposed in fig. 1. in conclusion, it is decisive that we view bp patients beyond a single-disease framework and treat them in the context of multi-morbidities. diabetes management in these patients can be particularly troublesome and, to date, there are no orienting guidelines on this matter. endocrinologists should be aware of bp as a challenging problem in patients with dm and collaboration with dermatologists is essential for good outcomes. references 1. chai zt, tan c, meiqi liau m, et al. diabetes mellitus and hyperglycemic complications in bullous pemphigoid. j am acad dermatol. 2020 may;82(5):1234-1237. 2. di lernia v, casanova dm, goldust m, ricci c. pemphigus vulgaris and bullous pemphigoid: update on diagnosis and treatment. dermatol pract concept. 2020 jun 29;10(3):e2020050. 3. garrido pm, alexandre mi, travassos ar, filipe p. dipeptidyl-peptidase iv inhibitor-associated bullous pemphigoid type 2 dm with bp consider discontinuation of dpp4i, if present if patient is treated with systemic corticosteroids consider referral to an endocrinologist if glycemia is persistently above 200 mg/dl insulintreated patients non-insulintreated patients morning basal insulin 0,2 u/kg/day (ex: glargin/nph) increase basal insulin 2u every 2-3 days if glycemia before dinner is above 180 mg/dl after discharge, return to oral antidiabetic drugs if possible (see outpatient care scheme); evaluate need to maintain basal insulin pre-prandial rapid/short action insulin according to glycemia (ex: <140 mg/dl: ou; 140-200mg/dl: 2u; 201-250mg/dl: 4u; 251-300mg/dl: 6u; 301-350mg/dl: 8u; 351-400mg/dl: 10u; 401-450mg/dl: 12u; ≥451mg/dl: 14u) switch to basal morning administration and consider increase dose in 10-20%. if ambulatory dose is not known start at 0,3-0,4 u/kg/day increase basal insulin 2u every 2-3 days if glycemia before dinner is above 180 mg/dl check glycemia at admission and every 4 hours inpatient care outpatient care advise to check glycemia before every meal optimize metformin dose if tolerated and patient’s egfr>30 ml/min/1.72m2 consider adding sglt2i (adjustments may be needed for renal impairment; see drug information) sulfonylureas (later generation) also an option; higher risk of hypoglycemia avoid dpp4i combination/mono therapy caution with glp1a morning basal insulin may be needed if glycemia is above 180 mg/dl before dinner figure 1. proposed treatment algorithm for bullous pemphigoid patients with type 2 diabetes mellitus treated with corticosteroids. bp, bullous pemphigoid; dm, diabetes mellitus; dpp4i, dipeptidyl peptidase-4 inhibitor; egfr, estimated glomerular filtration rate; glp1a, glucagon-like peptide 1 receptor agonist; sglt2i, sodium–glucose cotransporter 2 inhibitor. commentary | dermatol pract concept. 2023;13(1):e2023063 3 efficiently treated with omalizumab. dermatol ther. 2020 nov;33(6):e14160. 4. kridin k, cohen ad. dipeptidyl-peptidase iv inhibitor-associated bullous pemphigoid: a systematic review and meta-analysis. j am acad dermatol. 2021 aug;85(2):501-503. 5. burruss cp, jones jm, burruss jb. semaglutide-associated bullous pemphigoid. jaad case rep. 2021 aug 5;15:107-109. 6. lee h, chung hj, pawar a, patorno e, kim dh. evaluation of risk of bullous pemphigoid with initiation of dipeptidyl peptidase-4 inhibitor vs second-generation sulfonylurea. jama dermatol. 2020 oct 1;156(10):1107-1114. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022086 1 milium of the nipple li-wen zhang1, juan wu2, ling-yi zhao1, tao chen1 1 department of dermatovenereology, chengdu second people’s hospital, chengdu, sichuan, china 2 sexually transmitted disease institute, shanghai skin disease hospital, school of medicine, tongji university, shanghai, china citation: zhang l, wu j, zhao l, chen t. milium of the nipple. dermatol pract concept. 2022;12(2):e2022086. doi: https://doi .org/10.5826/dpc.1202a86 accepted: october 7, 2021; published: april 2022 copyright: ©2022 zhang et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: tao chen, department of dermatovenereology, chengdu second people’s hospital, 165 caoshi street, chengdu 610017, sichuan, china. e-mail: 13980427003@163.com case presentation a 4-year-old boy presented with a 1-year history of a single pearly white papule on the right nipple (figure 1a). no previous skin inflammation or trauma was observed at the same location. the left nipple was normal. his growth and psychomotor development were normal. the dermoscopy showed a pearly white rounded structure with branching vessels (figure 1b). histopathology showed an epidermoid cyst containing keratinous material (figure 1c). the diagnosis of milium was made. teaching point milium is a common benign keratinous cyst characterized by pearly white dome-shaped lesion of 1 mm to 4 mm in diameter, but the involvement of the nipple seems to be rare and bigger. milium may occur as either primary or secondary lesions. four cases of milium involving the nipple were found by searching pubmed databases [1,2]. among them, the male-to-female ratio was 1:3; the age range was from 6 to 16 months. they presented a unilateral single pearly white dome-shaped papule with a diameter of 3 mm to 8 mm. three cases underwent surgical excision, and 1 spontaneously disappeared. the dermoscopic manifestation shows a white or yellowish-white rounded structure with linear or branching vessels. the differential diagnosis includes molluscum contagiosum, calcinosis cutis, juvenile xanthogranuloma, and syringoma. references 1. ferreira mg, salgado mb. congenital milium of the nipple. pediatr dermatol. 2017;34(1):e28–e29. doi: 10.1111/pde.13010. pmid: 27778385. 2. jain s, sarkar r, garg vk, khurana n. epidermal inclusion cyst or giant milium of the nipple. indian j dermatol venereol leprol. 2012;78(1):103–105. 2011/12/27. doi: 10.4103/03786323.90960. pmid: 22199072. 2 image letter | dermatol pract concept. 2022;12(2):e2022086 figure 1. (a) a single pearly white papule on the right nipple. (b) the dermoscopy showed a pearly white rounded structure with branching vessels. (c) histopathology showed an epidermoid cyst containing keratinous material (h&e; ×100 magnification) dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(02):e2022094 1 prevalence and clinical-pathological features of nevus-associated versus de novo melanoma: a retrospective cross-sectional study of 2806 cases michela lai1,2, simonetta piana3, giovanni pellacani4, caterina longo1,2, riccardo pampena1,2 1 centro oncologico ad alta tecnologia diagnostica, azienda unità sanitaria locale irccs di reggio emilia, reggio emilia, italy 2 department of dermatology, university of modena and reggio emilia, modena, italy 3 pathology unit, azienda unità sanitaria locale irccs di reggio emilia, reggio emilia, italy 4 dermatology clinic, department of clinical internal, anesthesiological and cardiovascular sciences, la sapienza university of rome, rome, italy key words: melanoma, nevus-associated melanoma, de novo melanoma citation: lai m, piana s, pellacani g, longo c, pampena r. prevalence and clinical-pathological features of nevus-associated versus de novo melanoma: a retrospective cross-sectional study of 2806 cases. dermatol pract concept. 2022;12(02):e2022094. doi: https://doi.org/10.5826/dpc.1202a94 accepted: october 19, 2021; published: april 2022 copyright: ©2022 el-azhary et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: caterina longo, md, phd, department of dermatology, university of modena and reggio emilia, italy, azienda unità sanitaria locale – irccs di reggio emilia, centro oncologico ad alta tecnologia diagnostica-dermatologia, viale risorgimento, 80, 42123, reggio emilia, italy. e-mail: longo.caterina@gmail.com  introduction: nevus-associated melanoma (nam) accounts for almost one third of all cutaneous melanomas; it is often associated with younger age, trunk location and lower breslow’s thickness compared to de novo melanoma (dnm). objectives: to define the prevalence of nam in a tertiary referral center in italy and to analyze its distribution according to demographics, clinical and histopathological variables methods: data were retrospectively retrieved from the archive of the pathology unit from june 2011 to august 2020. nams were compared with dnms according to demographic, clinical and histopathological variables. results: a total of 2806 consecutive cases of melanoma were excised in 2537 patients. of these, 431 (15.4%) were nam. nam patients were significantly younger than dnm patients (55.1±14.1 vs. 62.0±15.0 years, p<0.001); they were predominantly located on the trunk (64.0% vs. 47.9% of dnms). melanoma located on the head and neck, trunk and upper limbs respectively had 2.3 (95%ci:1.2-4.5, p:0.014), 3.2 (95%ci:2.1-5.1, p<0.001) and 3.5 (95%ci:2.0-6.1, p<0.001) more odds to be nam than those on the lower limbs. abstract 2 original article | dermatol pract concept. 2022;12(02):e2022094 introduction nevus-associated melanoma (nam) accounts for almost one third of all cutaneous melanomas [1]. a growing body of literature demonstrated that nam is associated with younger age, trunk location and lower breslow’s thickness compared to de novo melanoma (dnm) [2-9]. objectives in this retrospective cross-sectional study, we reviewed our 10-year real-life experience at a tertial referral center for skin cancers with the aim to analyze the prevalence of nam and its distribution according to demographics, clinical and histopathological variables. methods from the archive of the pathology unit, we retrieved 2806 consecutive cases of skin melanoma excised in 2537 patients from june 2011 to august 2020: 431 (15.4%) melanomas were nam. nams were compared with dnms according to demographic, clinical and histopathological variables using the student’s t and chi square tests; statistical significance was set at p<0.05 and age was categorized according to quartiles. statistical analysis was performed using the ibm spss 27.0 package (statistical package for social sciences, ibm spss inc., chicago, ill.). the study was approved by local ethical committee (protocol number: 1249/ce). results our study revealed that nam patients were significantly younger than dnm patients (55.1 ± 14.1[standard deviation, sd] versus 62.0 ± 15.0 sd years, p < 0.001), with 67.7% nams having ≤61 years and 52.5% of dnms being older than 61 years. moreover, the nam ratio decreased with increasing age. interestingly, when considering body site distribution, a significant higher proportion of nams were on the trunk (64.0% vs. 47.9% of dnms, nam ratio: 19.5%) whereas dnms were predominantly located on the lower limbs (23.9% vs. 14.7% of nam, nam ratio: 8.1%) (figure 1). no significant differences were found according to sex and breslow’s thickness, while ulceration was significantly more observed among dnms (table 1). conclusions: our results confirm the association of nam with younger age and trunk location. we also demonstrated that body site differences of nam distribution are enhanced before the sixth decade of life. figure 1. ratio of nevus-associated versus de-novo melanoma according to body site and age-groups. dnm = de novo melanoma; nam = nevus-associated melanoma. original article | dermatol pract concept. 2022;12(02):e2022094 3 table 1. demographic, clinical and histopathological features of nevus-associated vs. de-novo melanoma (nam vs. dnm). variables nevus-association nam ratio total p valuenam dnm age at excision (y) ≤50 176 (40.8%) 576 (24.3%) 23.4% 752 (26.8%) <0.001 51 61 116 (26.9%) 551 (23.2%) 17.4% 667 (23.8%) 62 73 88 (20.4%) 651 (27.4%) 11.9% 739 (26.3%) ≥74 51 (11.8%) 597 (25.1%) 7.9% 648 (23.1%) sex m 237 (55.0%) 1269 (53.4%) 15.7% 1506 (53.7%) 0.551 f 194 (45.0%) 1106 (46.6%) 14.9% 1300 (46.3%) location hn 39 (9.0%) 350 (14.7%) 10.0% 389 (13.9%) <0.001 trunk 276 (64.0%) 1138 (47.9%) 19.5% 1414 (50.4%) upper limbs 66 (15.3%) 320 (13.5%) 17.1% 386 (13.8%) lower limbs 50 (11.6%) 567 (23.9%) 8.1% 617 (22.0%) stage in situ 203 (47.1%) 1183 (49.8%) 14.6% 1386 (49.4%) 0.3 invasive 228 (52.9%) 1192 (50.2%) 16.1% 1420 (50.6%) breslow (mm) ≤1 181 (79.4%) 881 (73.9%) 17.0% 1062 (74.8%) 0.107 >1 & ≤2 27 (11.8%) 134 (11.2%) 16.8% 161 (11.3%) >2 & ≤4 11 (4.8%) 87 (7.3%) 11.2% 98 (6.9%) >4 9 (3.9%) 90 (7.6%) 9.1% 99 (7.0%) ulceration superficial 11 (4.8%) 106 (8.9%) 9.4% 117 (8.2%) 0.041 total 431 2375 15.4% 2806 nam, nevus-associated melanoma; dnm, de-novo melanoma; y, years; m, male; f, female, hn, head and neck; mm, millimeters. to identify major independent factors associated with nam status we constructed a multivariable logistic regression model with backward variables selection including sex, location, ulceration, breslow and age categories. we demonstrated that melanoma located on the head and neck, trunk and upper limbs, respectively had 2.3 (95% confidence interval [ci]1.2 -4.5, p = 0.014), 3.2 (95% ci 2.1-5.1, p <0.001) and 3.5 (95% ci 2.0-6.1, p < 0.001) more odds to be nam than those on the lower limbs. also, melanomas in patients aged ≤61 years were more likely to be nam than those in patients ≥74 years (≤50 years: or: 3.3; 95% ci 2.0-5.3, p<0.001; 51-61 years: or: 2.7; 95%ci:1.6-4.5, p<0.001). furthermore, we reported the prevalence of nam and dnm according to the body site in two age groups: ≤61 years and ≥74 years (nam ratio: 20.6% and 7.9%, respectively). we found significant differences between nam and dnm only in the ≤61 years group, with higher prevalence of nam on the trunk (69.2%, nam ratio 26.1%) and dnm on the lower limbs (29.1%, nam ratio: 9.4%) (figure 1). conclusions in conclusion, although we found a lower nam prevalence than expected from literature data, our results confirm the association of nam with younger age and trunk location [1]. we also demonstrated that body site differences of nam distribution are enhanced before the sixth decade of life. together with previous studies, our findings further support the existence of 2 divergent pathways of melanoma development [8,10]. references 1. pampena r, kyrgidis a, lallas a, moscarella e, argenziano g, longo c. a meta-analysis of nevus-associated melanoma: prevalence and practical implications. j am acad dermatol. 2017;77(5). doi: 10.1016/j.jaad.2017.06.149. pmid: 28864306 2. pandeya n, kvaskoff m, olsen cm, et al. factors related to nevus-associated cutaneous melanoma: a case-case study. j invest dermatol. 2018;138(8). doi: 10.1016/j.jid.2017.12.036. pmid: 29524457 3. longo c, rito c, beretti f, et al. de novo melanoma and melanoma arising from pre-existing nevus: in vivo morphologic differences as evaluated by confocal microscopy. j am acad dermatol. 2011;65(3). doi: 10.1016/j.jaad.2010.10.035. pmid: 21715047 4. haenssle ha, mograby n, ngassa a, et al. association of patient risk factors and frequency of nevus-associated cutaneous melanomas. jama dermatol. 2016;152(3). doi: 10.1001/ jamadermatol.2015.3775. pmid: 26536613 5. pampena r, pellacani g, longo c. nevus-associated melanoma: patient phenotype and potential biological implications. 4 original article | dermatol pract concept. 2022;12(02):e2022094 j invest dermatol. 2018;138(8). doi: 10.1016/j.jid.2018.01.025. pmid: 30032788 6. cymerman rm, shao y, wang k, et al. de novo vs nevus-associated melanomas: differences in associations with prognostic indicators and survival. j natl cancer inst. 2016;108(10). doi: 10.1093/jnci/djw121. pmid: 27235387 7. massi d, carli p, franchi a, santucci m. naevus-associated melanomas. melanoma res. 1999;9(1). doi: 10.1097/00008390199902000-00011. pmid: 10338338 8. pampena r, lai m, piana s, lallas a, pellacani g, longo c. nevus-associated melanoma: facts and controversies. g ital dermatol venereol. 2020;155(1). doi: 10.23736/s03920488.19.06534-9. pmid: 32100974 9. kaddu s, smolle j, zenahlik p, hofmann-wellenhof r, kerl h. melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis. melanoma res. 2002;12(3). doi: 10.1097/00008390-200206000-00011. pmid: 12140384 10. whiteman dc, pavan wj, bastian bc. the melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. pigment cell melanoma res. 2011;24(5). doi: 10.1111/j.1755-148x.2011.00880.x. pmid: 21707960 dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023068 1 hypomelanotyc basomelanocytic tumor cesare massone1, sanja javor1, stefano chiodi2, simona sola3 1 dermatology unit, e.o. “ospedali galliera”, genoa, italy 2 plastic surgery, e.o. “ospedali galliera”, genoa, italy 3 surgical pathology, e.o. “ospedali galliera”, genoa, italy key words: basal cell carcinoma, melanoma, collision tumor, basomelanocytic tumor citation: massone c, javor s, chiodi s, sola s. hypomelanotyc basomelanocytic tumor. dermatol pract concept. 2023;13(2):e2023068. doi: https://doi.org/10.5826/dpc.1302a68 accepted: july 14, 2023; published: april 2023 copyright: ©2023 massone et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: cesare massone, md, dermatology unit ospedali galliera. via volta 6, 16128, genova (it). phone: 0039 010 5632 4271. e-mail: cesare.massone@galliera.it introduction dermoscopic diagnosis of collision tumor (ct) is a challenge. zaballos et al recently found that the most frequent cts are: basal cell carcinoma (bcc)-seborrheic keratosis (37.9%), bcc-melanocytic nevus (19.9%), and melanoma-seborrheic keratosis (6.8%).1 the collision bcc-melanoma is very rare (reported under the terms “basomelanocytic tumor (bmt)”) and its dermoscopic features have been described in only few cases [1,3-6]. case presentation a 58-year-old woman presented with an enlarging ulcerated erythematous-brown plaque of 16 x 8 mm on her left leg appeared almost six months before. the clinical diagnosis was ulcerated bcc. dermoscopy showed an asymmetric polychromatic multicomponent pattern with shiny white structures, structureless blue-grey areas, grayish peppering, milky red areas, atypical vessels, ulceration and crusts (figure 1, a and b). she denied previous history of skin cancer. histopathological examination showed an irregular hyperplastic epidermis and, in the dermis, berep4-positive large nests (figure 1f) composed by basaloid keratinocytes with palisading of cells at the periphery and clefts with the surrounding stroma (figure 1, c-e and i). inside some nests and in the dermis was present a second cell population of spindle cells and also dentritic cells that stained positive for melan-a, s100 and hmb-45 (figure 1, g and h). an increased number of single atypical melanocytes at the dermoepidermal junction was also observed. a bmt (bcc and pt2b melanoma of 1mm breslow thickness; braf wt) was diagnosed. wide surgical excision and lymph node biopsy were performed with no evidence of metastatic cells, also at staging investigations (pt2b n0 m0). after 24-months follow-up the patient is still without evidence of secondary disease. 2 research letter | dermatol pract concept. 2023;13(2):e2023068 figure 1. (a) erythematous violaceous plaque of 16 x 8 mm with erosive surface on the lower limb of atypical morphology and multicolor appearance. (b) asymmetric polychromatic multicomponent pattern with shiny white structures, structureless blue-gray areas, milky red areas, atypical vessels, ulceration and crusts without clearly pigment network at the periphery. (c) irregular hyperplastic epidermis and, in the dermis, large nests composed by basaloid keratinocytes with palisading of cells at the periphery, clefts with the surrounding stroma and inflammatory infiltrate of the perilesional area (h&e; original magnification 5x). (d) irregular hyperplastic epidermis and, in the dermis, large nests of basaloid cells with a second cell population of spindle cells and dentritic cells. heavy inflammatory infiltrate of the perilesional area (h&e; original magnification 5x). (e). higher magnification of the basaloid cells, atypical spindle and dentritic cells with mitotic figures (h&e; original magnification 20x). (f) strong immunoreactivity for berep4 evidenced the basal cell carcinoma component (original magnification 5x). (g) melan-a stained the atypical melanocytes of the melanoma component. an increased number of single atypical melanocytes at the dermoepidermal junction and in the dermis was also observed (original magnification 5x). (h) hmb-45 stained the atypical melanocytes of the melanoma component. an increased number of single atypical melanocytes at the dermoepidermal junction and in the dermis was also observed (original magnification 5x).(i) large nest of basaloid cells with palisading at the periphery (original magnification 5x). conclusions histologically, bmt may result by a variety of modality of “collisions” like colonization, combined, biphasic, biphenotypic, or intermingled neoplasms [2]. pathogenetic explanations are different and refer to: the field cancerization theory (proliferation of two distinct clones resulting in the development of two intermingled neoplasms); the tumor divergent theory (biphasic neoplasm with two neoplastic populations); tumor convergent theory (two phenotypically different cell populations derive from a common progenitor stem cell). bmt has also been considered a low-grade malignancy with a dual phenotype; in fact, the histologic merging between two malignant cell types argues against a simple collision [2,3]. to our knowledge, about 50 cases of bmt have been reported in the literature [1,3-6]; dermoscopy has been described in details in only 9 cases (table 1). one of the two tumors is usually recognized upon dermoscopy when one of the two component is prevalent, but usually the exact diagnosis of bmt is difficult. reflectance confocal microscope (rcm) can be highly useful in the diagnosis [4]. moreover, bmt can occur in patient with basal cell nevus syndrome or xeroderma pigmentosum, therefore an accurate examination of the patients is needed [6]. our patient presented an ulcerated hypomelanotic bmt, representing a further pitfall. the biologic behavior of bmt is still not clearly understood. according to amin et al distant metastases are uncommon and combined cutaneous tumors may have a better prognosis when compared to similarly staged conventional melanomas [2]. in contrast, erickson et al, reported a 56-year-old man with bmt of the scalp who developed a subsequent metastasis [2]. in conclusion, bmt represent a clinical diagnostic challenge and suspicious lesions should be observed accurately with dermoscopy and also with rcm, when available. research letter | dermatol pract concept. 2023;13(2):e2023068 3 references 1. zaballos p, álvarez salafranca m, medina c, et al. the usefulness of dermoscopy for the recognition of malignant collision tumors. dermatology. 2022;238(1):132-139. doi: 10.1159/000514583. pmid: 33789291. 2. cota c, saggini a, lora v, et al. uncommon histopathological variants of malignant melanoma: part 1. am j dermatopathol. 2019;41(4):243-263. doi: 10.1097/dad.0000000000001218. pmid: 30024414. 3. busam kj, halpern a, marghoob aa. malignant melanoma metastatic to a basal cell carcinoma simulating the pattern of a basomelanocytic tumor. am j surg pathol. 2006;30(1):133-136. doi: 10.1097/01.pas.0000179118.76904.02. pmid: 16330954. 4. moscarella e, rabinovitz h, oliviero mc, et al. the role of reflectance confocal microscopy as an aid in the diagnosis of collision tumors. dermatology. 2013;227(2):109-117. doi: 10.1159/000351771. pmid: 24080548. 5. blum a, siggs g, marghoob aa, et al. collision skin lesions results of a multicenter study of the international dermoscopy society (ids). dermatol pract concept. 2017;7(4):51-62. doi: 10.5826/dpc.0704a12. pmid: 29230351. pmcid: pmc5720595. 6. bostanci s, akay bn, kirmizi a, okcu heper a, farabi b. basosquamous carcinoma and melanoma collision tumor in a child with xeroderma pigmentosum. pediatr dermatol. 2020;37(2):390-392. doi: 10.1111/pde.14097. pmid: 31957124. table 1. dermoscopic features of the basomelanocytic tumors reported in the literature [1,3-6]. age/sex location clinical diagnosis collision dermoscopy 70-year-old man face lentigo maligna melanoma bcc – lentigo maligna melanoma annular granular pattern with rhomboid structures and a dark blotch; large blue-gray ovoid nests with leaf-like structures 69-year-old man postauricular region bcc metastatic melanoma colliding with bcc multilobulated bluish nodule with a shiny surface, fine blood vessels and large gray-blue ovoid structures. 70-year-old man frontoparietal region lentigo maligna bcclentigo maligna a flat brownish asymmetric lesion with an irregular pigmented network, whitish areas, vessels with linear or arciform shapes and a well-defined, darker area showing four colors (blue, black, white ⁄ grey, red) and black, bluish rounded structures; scales and an erosive site, as well as numerous vessels with arboriform shape; projections of bulbous shape reminiscent of leaf-like structures. 74-year-old man head/neck bcclentigo malignaa bcclentigo maligna pink-white area with arborizing vessels and a pseudo network with asymmetrically pigmented follicular openings. na na lentigo maligna bcc – lentigo maligna pigmented follicles and destroyed follicle with patchy pigmentation; arborizing vessels and pigmented bluegrayish globules 60-year-old man frontal region melanoma bcc – lentigo maligna melanoma multi-component pattern with multiple blue-gray spots, hypochromic area, shiny white streaks and amorphous areas, in addition to an atypical vascular pattern 60-year-old man left lumbar region melanoma and bcca bcc – melanoma in situ asymmetric lesion with multicomponent pattern, atypical pigment network irregular globules in the periphery, multiple colors, particularly a blue coloration in the centerright of the lesion 13-year-old boy with a history of xp-c right jawline melanoma bcc – nodular melanoma ulcerated lesion showed chaos of colors including pink, white, black, gray, and blue structureless areas, gray dots, linear, looped, and serpentine vessels, ulceration, hemorrhage, keratin, scale, and fiber sign 48-year-old man with with basal cell nevus syndrome back bcc? melanoma? bcc – melanoma in situ pink structureless area in the center with short, fine telangiectasias and an atypical network at the periphery bcc = basal cell carcinoma; na = not available; xp = xeroderma pigmentosum. adiagnosed with the aid of reflectance confocal microscopy. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022115 1 efficacy of a topical formulation of henna (lawsonia inermis linnaeus) on the itch and wound healing in patients with epidermolysis bullosa: a pilot single-arm clinical trial mehdi niazi1, mohammad mahdi parvizi2,3,4, nasrin saki5, zahra parvizi6, mehrzad mehrbani1,7, mojtaba heydari3,,4 1 department of traditional medicine, faculty of traditional medicine, kerman university of medical sciences, kerman, iran. 2 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran. 3 research center for traditional medicine and history of medicine, department of persian medicine, school of medicine, shiraz university of medical sciences, shiraz, iran. 4 persian medicine network (pmn), universal scientific education and research network (usern), tehran, iran 5 molecular dermatology research center, department of dermatology, school of medicine, shiraz university of medical sciences, shiraz, iran 6 health system research, vice chancellor of treatment, shiraz university of medical sciences, shiraz, iran. 7 herbal and traditional medicines research center, kerman university of medical sciences, kerman, iran. key words: epidermolysis bullosa, lawsonia plant, wound healing, pruritus, complementary therapies citation: niazi m, parvizi mm, saki n, parvizi z, mehrbani m, heydari m. efficacy of a topical formulation of henna (lawsonia inermis l.) on the itch and wound healing in patients with epidermolysis bullosa: a pilot single-arm clinical trial. dermatol pract concept. 2022;12(3):e2022115. doi: https://doi.org/10.5826/dpc.1203a115 accepted: november 22, 2021; published: july 2022 copyright: ©2022 niazi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this study was supported by vice chancellor of research, shiraz university of medical sciences, shiraz, iran (grant no: 98-01-65-19435). competing interests: the authors declare that there is conflict of interest, in the way that two individuals listed in authors’ list, mmp and zp, suffer from deb and they participated in this clinical trial, but they did not have any role in response evaluation of the drug. authorship: conception and design of the work: mn, mmp, mh, ns, mm, zp; data collection: mn, ns, mm; analysis and interpretation of the data: mn, mh, mm, ns; statistical analysis: mmp, mm; drafting the manuscript: mn, mmp, ns, mm, zp; critical revision of the manuscript: mmp, mm, ns, mh, final approval: mn, mmp, mh, ns, mm, zp corresponding author: mohammad mahdi parvizi, md, mph, phd, assistant professor of persian medicine, molecular dermatology research center, shiraz university of medical sciences, shiraz, iran; zand avenue, shahid faghihi hospital, shiraz, iran, 7134844119. telephone: 00989173237031. e-mail: mmparvizi@gmail.com introduction: epidermolysis bullosa (eb) is a rare inherited genetic skin disorder with severe skin itching and recurrent blisters and erosion. there is no effective and specific therapy for all types of eb. objectives: the aim of this study was to evaluate a topical formulation of henna (lawsonia inermis linnaeus) in the management of wounds and the itching sensation in patients with eb. methods: this is a pilot single-arm clinical trial. nine patients with recessive dystrophic eb, with the age range of 5 to 32 years were enrolled in the study. the patients were instructed to apply the topical abstract 2 original article | dermatol pract concept. 2022;12(3):e2022115 objectives to the best of our knowledge, there are no studies on the efficacy of henna in the management of wounds and itch in patients with rdeb. the aim of this study was to evaluate the efficacy of henna in the wound healing process and itching complaints in patients with rdeb. methods study design this study was designed as a single-arm, uncontrolled clinical trial. this study was in compliance with the declaration of helsinki (1989 revision) [17], and also approved and monitored by the ethics committee of shiraz university of medical sciences (license number: ir.sums.rec.1398.761). moreover, the enrolled patients were informed completely about the protocol of the study and signed the written informed consent. the patients were permitted to withdraw from the study at any time of the study. this clinical trial was registered at the iranian registry of clinical trials (irct) by irct20150825023753n14 code (http://www.irct.ir/trial/41647). sample size and study population patients with rdeb were recruited from faghihi dermatology clinic, shiraz university of medical sciences, shiraz, iran. given the rarity of rdeb, the researchers decided to enroll at least seven patients in this pilot study. inclusion criteria were patients with rdeb, who signed the written informed consent (themselves or their parents if less than 15 years old) to participate in the study. the exclusion criteria were a positive history of allergic reaction to henna, or glucose-6-phosphate dehydrogenase (g6pd) deficiency, and any other systemic diseases. drug preparation henna (lawsonia inermis linnaeus) leaves were gathered from shahdad fields (kerman, iran) and dried. a botanist introduction inherited epidermolysis bullosa (eb) is a rare genetic skin disorder that can affect many extracutaneous organs including the gastrointestinal and genitourinary system, eye and etc [1,2]. there are four major types of inherited epidermolysis bullosa; epidermolytic (eb simplex [ebs]), lucidolytic (junctional eb [jeb]), dermolytic (dystrophic eb [deb]), and kindler syndrome [3]. the common characteristics of all subtypes of eb are recurrent blistering and erosions (after even minor trauma or traction) of skin and the organs covered by mucous membrane [4]. the pathogenesis of eb is the mutation of the genes which is caused due to dysfunction of collagen type vii that is the main component of the anchoring fibrils located below the lamina densa layer of the epidermal basement membrane zone [2]. eb patients, especially patients with recessive dystrophic eb (rdeb), suffer from severe skin itching and also recurrent blisters and erosion [2,5]. there is no specific therapy for all types of eb, therefore supportive care including wound care, control of infection and itching are very important [6]. using topical and systemic antibiotics, analgesics, antihistamines are very popular in these patients. henna (lawsonia inermis linnaeus) is one of the most commonly used medicinal plants in traditional persian medicine as a treatment for dermatological conditions and improving wound healing [7,8]. there are several studies demonstrating the efficacy of henna on skin disorders such as dermatitis including diaper dermatitis, bedsore, itch, and et. [9-12]. it has been shown that henna can improve the wound healing process and also has antipruritic effects [13,14]. in addition, some investigations revealed the antimicrobial and antifungal properties of henna. these effects are considered to be due to high concentrations of some components in this plant including carbohydrates, anthraquinones, naphthoquinone derivatives, flavonoid, and phenolic components. [15,16]. 1% henna ointment once daily on two erosions and on also two sites with moderate to a severe itching sensation. the total duration of the intervention was 4 weeks with weekly follow-up visits. patient global impression of improvement, visual analog scale, and clinical global impression of improvement were used for assessing the wound healing process and itching discomfort. results: there was a significant improvement in the skin symptoms of epidermolysis bullosa including skin redness, itching, burning, and local warmness (p < 0.05). local pain decreased during the study period, but this was not statistically significant (p < 0.19). one patient reported moderate xerosis of skin after continuous usage. conclusions: it seems that the topical formulation of henna may be effective in the management of itching, burning, stringing, and cutaneous warmness sensation in patients with eb. further controlled studies with larger sample sizes are recommended to better evaluate this formulation. original article | dermatol pract concept. 2022;12(3):e2022115 3 at a specified interval, 1 ml volume of pbs solution was sampled and replaced with the same volume of pbs. the samples were analyzed by uv spectrophotometer and repeated three times and the amount of active ingredient release was calculated according to the standard curve. microbial control the microbial and fungal control tests of the product were performed by barij essence® pharmaceutical company ( serial number:1521m98; batch number: 9805101) for aerobic microorganisms, pseudomonas aeruginosa, staphylococcus aureus, modals, and yeasts enumeration. intervention and follow-up of the patients the patients were instructed to use a fingertip of henna ointment once a day on two erosions and also on two sites with moderate to severe itching for 4 weeks with first, second, and fourth week follow-up visits. patient global impression of improvement (pgi-i), visual analog scale (vas), and clinical global impression of improvement (cgi-i) were used to assess the wound healing process and itching discomfort. furthermore, photographs were taken of all of the patients. furthermore, wound improvement response was defined as excellent (90% improvement), good (50%-90% improvement), mild (20%-50% improvement), and fair (less than 20% or worse) according to general appearance. at the end of the study, patients or their parents (for children participants) were asked to express their opinions about the efficacy of henna ointment in comparison to other used medications. statistical analysis statistical package for social sciences, spss version 18 (spss inc.), was used for data analysis. according to the low sample size, freedman test was used for assessment of the effects of henna ointment on the variables of the study. p value equal to or less than 0.05 was considered significant. results pharmaceutical characterization the measured ph of ointment was 6.4 ± 0.3. this ointment displayed rheological thixotropic behavior. the results of the spreadability test showed that the mean diameter for henna ointment was 9 ± 0.8 cm. folin-ciocalteu method was used to determine total phenolic contents in terms of gallic acid equivalent (gae) in mg/g of the extract. based on the equation of the calibration curve (y = 0.007x+0.006, r2 = 0.999), the total phenolic content of the extract and ointment were 129.6 ± 1.1 and 0.98 ± 0.18 mg/g of extract, respectively. at kerman university of medical sciences authenticated the plant and recorded it with a specified voucher number (no: kf-1408). the maceration method five times was conducted to prepare the hydro-ethanolic extraction (30:70). the gathered extract was purified through filtration and concentrated by a vacuum rotary evaporator and dried in an oven 40°c. the ointment containing 1% henna was prepared by dissolving a one-gram fine powder of dried henna extract in the minimum volume of ethanol 40%, then it was dispersed in 99 grams of eucerin through geometric dilution. the prepared ointment was packed in 50-gram containers for delivery to the patients. pharmaceutical properties of the ointment the quality control of the prepared ointment was performed according to who guideline [18]. pharmaceutical characterizations of henna ointment were evaluated as follows [19-23]: determination of ph some ointment was heated up to the melting point and diluted with a 1:9 dilution ratio (1 unit of drug and 9 units of water) and measured with a ph meter. this procedure was repeated three times and its mean and standard deviation were recorded. homogeneity homogeneity of the herbal ointment was evaluated for any aggregation by the skin test. in this study, 12 healthy volunteers tested some of the product on the back of their hands and were asked to express their satisfaction with the particle being present in the ointment. total polyphenolic content the total phenolic content of the extract and ointment were measured based on the folin-ciocalteu method. rheological behavior cone and plate brookfield rheometer (brookfield engineering laboratories) at 25°c was performed to evaluate the rheological behavior of ointment for triplicate. spreadability test two horizontal glass plates (10 cm × 10 cm) were conducted to assess the spreadability of the prepared ointment. the spreading diameter of one gram of sample between plates was measured under 25 grams standard weight shear application three times. in vitro drug release two grams of henna ointment were poured into a 10-kda semi-permeable dialysis membrane bag. after dispersing, it was immersed in 50 ml of 25 mm phosphate buffer solution (pbs) at 37 ± 0.5 ° c and rotated at 100 rpm. for 24 hours, 4 original article | dermatol pract concept. 2022;12(3):e2022115 on pgi-i, 6 patients reported “very much better” and 1 reported “much better” in itching discomfort after using henna ointment. according to cgi-i, the physician concluded that all the patients were “much better” and “very much better” after using henna ointment. there was a significant improvement in the skin symptoms of epidermolysis bullosa including skin redness, itching, burning, and local warmness sensation (p < 0.05). local pain decreased during the study period, but this was not statistically significant (p < 0.19) (table 2). moreover, figure 3 shows the photos of 3 patients with rdeb before the treatment and after four weeks of receiving topical 1% henna ointment. qualitative evaluation of patients opinion about topical henna ointment five out of 7 patients who participated in the study reported henna as the most effective ointment for their pruritus in comparison to other medications, including corticosteroids, vaseline, and repair creams. in addition, most patients had a good experience in wound healing effect while using henna ointment, at least as well as conventional medicine such as mupirocin, mebo® and biafine® topical emulsion. side effects evaluation no serious adverse effect was observed. one patient reported moderate xerosis of skin after continuous application of henna after 4 weeks so that he needed to apply larger amounts of emollient medicines. conclusions this study showed that the 1% henna ointment could improve skin redness, itching, burning, and local warmness. but it should be considered that it was a pilot study and further studies with a higher number of cases are necessary to approve these results. although eb patients suffer from several severe complications related to their disease, the rate of drug substance release is presented in table 1. as shown in figure 1, the release of active ingredients of henna ointment follows the weibull equation (q=1-exp -t k a ) with r2=0.97 so that k (time constant) is equal to 6.92 and a (shape parameter) is equal to 1.03. the prepared product releases half of its active ingredient content up to 4 hours and about 90% of its active ingredient content releases up to 12 hours after application. this release kinetic is consistent with topical products containing ointment-based hydroalcoholic extracts. participants enrollment and basic characteristics a detailed description of the patients enrolment and analysis is given in figure 2. nine patients were enrolled in the study. two patients were lost to follow-up. finally, 7 out of 9 patients including 3 boys and 4 girls completed the study. the age range of the patients was 5-32 years. efficacy outcomes the average drug satisfaction rate was reported 74% (min = 50%, and max = 90%) by the patients. for more details, based table 1. mean percentage of release of henna ointment time (hours) cumulative % qa standard deviation 0.5 8.3 2.1 1 11.4 1.2 2 17.9 2.1 4 50.1 2.5 6 70.5 3.1 12 89.3 2.4 24 95.2 5.3 a. cumulative amount released figure 1. in vitro release of total phenolic compounds from henna ointment performed according to the folin-ciocalteau method (mean ± standard deviation, n=3). 100 80 60 40 20 0 0 4 8 12 time (hr) c u m u la ti v e % q 16 20 24 original article | dermatol pract concept. 2022;12(3):e2022115 5 enrollment assessed for eligibility (n=12) excluded (3) not meeting inclusion criteria (n=3) not randomized (n=9) allocated to intervention (n=9) lost to follow-up (2 leaving city)(n=2) discontinued intervention (n=0) analysed (n=7) excluded from analysis (n=0) received allocated intervention (n=9) allocation follow-up analysis figure 2. trend flow chart of efficacy of a topical formulation of henna (lawsonia inermis linnaeus) on the itch and wound healing in patients with epidermolysis bullosa. table 2. mean of dermatological complaints scores from baseline to weeks 1, 2 and 4 in patients with epidermolysis bullosa who treated with local henna ointment outcome measures weeks paweek 0 week 1 week 2 week 4 skin redness (mean ± sdb) 6.28 ± 1.26 6.14 ± 1.10 3.57 ± 0.68 2.42 ± 0.48 0.003 itching sensation (mean ± sd) 8.57 ± 0.71 4.71 ± 0.47 3.42 ± 0.86 2.00 ± 0.43 0.001 skin burning (mean ± sd) 3.57 ± 1.21 2.28 ± 0.77 1.57 ± 0.61 1.00 ± 0.436 0.003 local warmness sensation (mean ± sd) 5.14 ± 0.98 4.00 ± 0.92 3.14 ± 0.93 2.00 ± 0.75 0.001 local pain (mean ± sd) 4.71 ± 1.45 4.14 ±1.29 3.57 ± 1.19 2.71 ± 0.74 0.197 a. p-value; b. sd = standard deviation there are not enough randomized clinical trials for novel drugs that can manage their complications. eb is a non-curable hereditary condition with several cutaneous and extracutaneous manifestations. skin redness (dermatitis), pruritus, burning sensation in the skin, local warmness sensation, repeated ulceration, and pain are the most common cutaneous manifestations and complaints of patients with eb [24]. these manifestations could affect the quality of life in patients with eb and their families [25,26]. therefore, most of the time patients, their parents, and health care providers try to administer multiple topical medications including natural and herbal remedies to manage or relieve these symptoms [27]. henna is one of the herbal medications that is used commonly in both traditional and folk medicine for the treatment of skin, hair, and nail diseases, as well as cosmetic problems [7,28,29]. niazi et al demonstrated that henna ointment could improve the symptoms of contact dermatitis including skin edema, itching, sweating, skin thinning and pain which is consistent with our study [12]. however, unlike our study, 6 original article | dermatol pract concept. 2022;12(3):e2022115 the mechanisms of wound healing of topical henna are unclear till now, but one recent study suggests that these mechanisms may include reduction of tissue inflammation and increasing cellular glucose uptake, which was mediated by up-regulating the expression of glucose transporter-1 and insulin-like growth factor i. furthermore, this study showed that topical henna could shorten the inflammatory phase of the wound healing process, accelerate cellular proliferation, raise wound contraction ratio, and caused improvement of revascularization, collagen deposition, and re-epithelialization rate, and promotion of intracytoplasmic carbohydrate storage [34]. according to the knowledge of tpm, “ ghabz”, with nearly meaning of “contraction” in conventional medicine, is the common feature of drugs that are effective in wound healing [35,36], as well as henna [29,37], that is in line with the finding of conventional medicine. the findings of our study showed that topical henna ointment did not relieve pain sensation of the patients with eb. this result may be referred to stimulate pain receptors of the selected sites by pain signals coming from contiguous wounds. this finding was not in line with the other studies. the study of nesa et al showed remarkable analgesic, anti-inflammatory, and central nervous system (cns) depressant effects of henna [38]. hasan imam et al suggested that the analgesic effect of henna was resulted from alpha skin redness increased due to the use of henna ointment, which may be due to the method of measuring erythema [30]. keshavarz et al showed that henna had a significant effect in comparison to hydrocortisone ointment in the improvement of diaper rash [10]. ansari et al revealed that topical alpha® ointment (containing natural henna) had a significant therapeutic effect on the healing of radiation-induced dermatitis in breast cancer patients [31]. another study conducted by yucel et al. showed that topical henna had significant effects in the treatment of capecitabine-induced hand-foot syndrome. the authors of this study suggested that these therapeutic effects could be related to anti-inflammatory, antipyretic and analgesic effects of henna [32]. the present study showed that 1% of henna ointment had an acceptable effect on skin characteristics in patients with eb. in fact, all the selected wounds of these patients were improved clinically during to first two weeks of the study. mourad et al demonstrated that the henna gel had a significant effect on wound healing in in-vivo model. the results of this study were confirmed by histological stain assessments [13]. the study of shiravi et al revealed that henna had anti-inflammatory and anti-bacterial effects in wistar rats. according to this study, reduction of inflammation, edema, bleeding, and increased collagen formation resulted in acceleration of wound healing, angiogenesis, and vasodilatation in these rats [33]. figure 3. this image shows the patients with recessive dystrophic epidermolysis bullosa(rdeb) who were enrolled in the study before the treatment (a-c) and after four weeks of receiving topical 1% henna ointment (d-f). (a and d) the right knee of a 6-year-old boy with rdeb. (b and e) the left forearm of a 32-year-old girl with rdeb. (c and f) the back of a 10-year-old boy with rdeb. original article | dermatol pract concept. 2022;12(3):e2022115 7 references 1. murrell df. life with epidermolysis bullosa (eb): etiology, diagnosis, multidisciplinary care and therapy. j am acad dermatol. 2009;61(6):1092–1093. doi:10.1016/j.jaad.2009.06.011 2. fine jd. epidemiology of inherited epidermolysis bullosa based on incidence and prevalence estimates from the national epidermolysis bullosa registry. jama dermatol.2016;152(11):1231–1238. doi:10.1001/jamadermatol.2016 .2473. pmid: 27463098. 3. fine jd, bruckner-tuderman l, eady ra, et al. inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. j am acad dermatol. 2014;70(6):1103–1126. doi: 10.1016/j.jaad.2014.01.903. pmid: 24690439. 4. fine jd. inherited epidermolysis bullosa. orphanet j rare dis. 2010;5(1):12. doi: 10.1186/1750-1172-5-12. pmid: 20507631. pmcid: pmc2892432. 5. rizzo c, anandasabapathy n, walters rf, et al. pretibial epidermolysis bullosa. dermatology online journal. oct 15 2008;14(10):26. 6. el hachem m, zambruno g, bourdon-lanoy e, et al. multicentre consensus recommendations for skin care in inherited epidermolysis bullosa. orphanet j rare dis.2014;9:76. doi:10.1186/1750-1172-9-76. pmid: 24884811. pmcid: pmc4110526. 7. aghili khorasani mh. makhzan al-advieh. tehran: tehran university of medical sciences. 2009:341. 8. arzani ma. teb-e-akbari. qom, iran: jalaledin publication. 2008; 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therefore, the results of this study had not been compared with placebo or other medications. we did not administer a second arm for this trial because there is not any standard and defined treatment for eb ulcers and patients usually apply different or multiple medications for controlling the itching sensation and wound healing with different responses. second, we used a researcher-made checklist for evaluating the patients. although the face validity and content validity of this questionnaire were acceptable, we could not evaluate the internal validity of the questioner because of a low sample size of the study. next, because of the rarity of the disease, the sample size of the study was low. finally, the age range of the patients was wide (5-32 years); therefore, the parents evaluated the efficacy of the drug for children and this can be a probable confounding factor. according to the results of this pilot study, the topical formulation of henna may be effective in the management of wound, itching, burning, stringing, and cutaneous warmness sensation in patients with eb. in this regard, we suggest further controlled clinical trials with larger sample sizes and longer duration of follow-up to evaluate the efficacy of this herbal medication. 8 original article | dermatol pract concept. 2022;12(3):e2022115 (containing natural henna) compared to topical hydrocortisone (1%) in the healing of radiation-induced dermatitis in patients with breast cancer: a randomized controlled clinical trial. iran j med sci. 2013;38(4):293–300. pmid: 24293782. pmcid: pmc3838980. 32. yucel i, guzin g. topical henna for capecitabine induced hand– foot syndrome. i nvest new drugs.. 2008;26(2):189–192. doi: 10.1007/s10637-007-9082-3. pmid: 17885735. 33. shiravi ah, alebooyeh m, hojati v, akbari h. the effect of extract of henna leaves (lawsonia inermis) on skin wound healing in wistar rats. journal of animal biology. 2011;3(4):45–51. 34. daemi a, farahpour mr, oryan a, karimzadeh s, tajer e. topical administration of hydroethanolic extract of lawsonia inermis (henna) accelerates excisional wound healing process by reducing tissue inflammation and amplifying glucose uptake. kaohsiung j med sci. 2019;35(1):24–32. doi: 10.1002/kjm2.12005. pmid: 30844141. 35. parvizi mm, handjani f, moein m, et al. efficacy of cryotherapy plus topical juniperus excelsa m. bieb cream versus cryotherapy plus placebo in the treatment of old world cutaneous leishmaniasis: a triple-blind randomized controlled clinical trial. plos negl trop dis. 2017;11(10):e0005957. doi: 10.1371/journal. pntd.0005957. pmid: 28981503. pmcid: pmc5655399. 36. jowkar f, godarzi h, parvizi mm. can we consider silymarin as a treatment option for vitiligo? a double-blind controlled randomized clinical trial of phototherapy plus oral silybum marianum product versus phototherapy alone. j dermatolog treat. 2019:1–5. doi: 10.1080/09546634.2019.1595506. pmid: 30935260. 37. qarshi in. al-mujaz fi al-tibb. islamic heritage revival committee, supreme council for islamic affairs, ministry of endowments; 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[therapeutic effect of impatiens balsamina, lawsonia inermis l. and henna on androgenetic alopecia in mice]. nan fang yi ke da xue xue bao. 2019;39(11):1376–1380. doi: 10.12122/j.issn.1673– 4254.2019.11.17. pmid: 31852654. pmcid: pmc6926075. 45. poursadra e, anvari-tafti m, dehghani a, eghbali-babadi m, rafiei z. comparing the effect of henna oil and olive oil on pressure ulcer grade one in intensive care units patients. adv biomed res. 2019;8:68. doi: 10.4103/abr.abr_207_19. pmid: 31897406. pmcid: pmc6909547. 46. vahabi s, hakemi-vala m, gholami s. in vitro antibacterial effect of hydroalcoholic extract of lawsonia inermis, malva sylvestris, and boswellia serrata on aggregatibacter dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023030 1 identifying pitfalls for diagnosing pigmented bowen disease on reflectance confocal microscopy: misleading dendritic cells banu farabi1,2,3, babar k. rao4, manu jain4,5 1 department of dermatology, new york medical college, valhalla, new york, ny, usa 2 department of dermatology, nyc health + hospitals/metropolitan, new york, ny, usa 3 department of dermatology, nyc health + hospitals/coney island, brooklyn, ny, usa 4 department of dermatology, weil cornell medical school, ny, usa 5 dermatology department, memorial sloan kettering cancer center, ny, usa key words: bowen’s disease, squamous cell carcinoma in situ, reflectance confocal microscopy, dermatoscopy, dermoscopy, dendritic cells citation: farabi b, rao bk, jain m. identifying pitfalls for diagnosing pigmented bowen’s disease on reflectance confocal microscopy: misleading dendritic cells. dermatol pract concept. 2023;13(1):e2023030. doi: https://doi.org/10.5826/dpc.1301a30 accepted: june 13, 2022; published: january 2023 copyright: ©2023 farabi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: banu farabi, 1901 first avenue, new york, ny, 10029. telephone: +1 (212) 423 7467, fax: +1 (212) 423 8464, email: banufarabi91@gmail.com introduction pigmented bowen disease (pbd) is a rare variant of squamous cell carcinoma in situ of the skin. precise diagnosis of pbd can be difficult based only on clinical and dermatoscopic findings. reflectance confocal microscopy (rcm) plays an important role by showing atypical keratinocytes and full thickness atypia in vivo. previous studies showed confounding presence of hyper-refractile elongated dendritic cells in pigmented actinic keratosis (ak)/pbd on rcm [1]. we present a case of pbd located on the facial skin misdiagnosed as lentigo maligna with rcm due to the presence of abundant hyper-refractile, atypical dendritic cells in the interfollicular spaces. case presentation a 73-year-old female with skin type ii was seen for a 5 mm pigmented lesion on the right cheek (figure 1a). dermatoscopic examination showed an asymmetrical pigmented lesion with multiple colors, pigmented circles, and dotted and fine linear vessels on an erythematous background (figure 1b). rcm images at the spinous and supra-papillary/ basal layer showed an atypical honeycomb (figure 1, c and d) pattern and numerous bright edged papillae (figure 1e) and dispersed bright fusiform and stellate shaped cells with thin dendrites (figure 1f). a complete surgical excision of the lesion was performed with 2 mm of tumor-free margins. histopathology revealed a pbd including full thickness keratinocytic atypia, prominent basal layer pigmentation, 2 research letter | dermatol pract concept. 2023;13(1):e2023030 and dermal melanophages (figure 2). the patient continues routine care via skin cancer surveillance. conclusions the diagnosis of pbd can be challenging clinically due to relative rarity and various clinical presentations. dermatoscopy can be a helpful tool in diagnosing these lesions [2]. however, in equivocal cases, rcm plays an important role in differentiating pbd from lentigo maligna (lm). typical rcm features of bd are full thickness keratinocytic atypia and architectural disorganization of the epidermis which presents as atypical or disarranged honeycomb pattern. recent studies highlighted that intraepidermal dendritic cells can be found in pigmented ak/pbd which creates a potential diagnostic pitfall. moscarella et al reported dendritic cells in 12/17 cases of ak/bd [3]. persechino et al found bright interfollicular dendritic cells in 53% of ak cases [4]. rcm features of lm includes atypical melanocytes and nests surrounding adnexal openings, sheets of cells composed of mainly dendritic cells giving a ‘medusa head’ appearance at dermo-epidermal junction (dej). folliculotropism is a typical feature of lm and is visualized as dendritic, atypical cells infiltrate the follicles [4]. thus, it is important to visualize figure 1. (a) clinical examination of the lesion on the right preauricular area shows a 5 mm diameter asymmetrical pigmented. (b) dermatoscopy reveals an asymmetrical pigmented lesion with multiple colors, pigmented circles, dotted and fine linear vessels on an erythematous background. (c) rcm images at the spinous and suprapapillary/basal layer shows an atypical honeycomb pattern and numerous bright edged papillae. (d) higher magnification of atypical honeycomb pattern adjacent to the lesion which is highlighted with red bracket in (c). (e) higher magnification of bright ringed-edged papillae at the level of dermo-epidermal junction shown with yellow arrow in (c). (f) higher magnification of dendritic cells between ringed edged papillae (this image is obtained with vivastack mode). figure 2. histologic examination shows full thickness keratinocyte atypia, disorganization of the keratinocyte and prominent basal layer pigmentation with dermal melanophages. research letter | dermatol pract concept. 2023;13(1):e2023030 3 dej in detail and follicular structures for signs of dendritic cell infiltration to rule out lm. other clues for pbd are numerous marked small bright rings at dej [5,6]. since dej is infiltrated by malignant melanocytes in lm, presence of regularly shaped bright rims can signify pigmented ak/pbd. intraepithelial hyper-reflective dendritic cells are found quite high in pbd. the exact nature of these cells is unknown, and density of dendritic cells can correlate with clinical pigmentation of the lesion. thus, it is imperative to be aware of the presence of dendritic cells. in the presence of dendritic cells in a pigmented lesion should not prompt extensive surgical excision without the evidence of melanocytic neoplasm. in doubt, incisional biopsy of the lesion should be considered to avoid extensive surgical treatment. thus, rcm plays a critical role for the management of facial pigmented lesions in aesthetically sensitive sites. references 1. debarbieux s, perrot jl, cinotti e , et al. reflectance confocal microscopy of pigmented bowen’s disease: misleading dendritic cells. skin res technol. 2017;23(1):126-128. doi: 10.1111 /srt.12304. pmid: 27430726. 2. inskip m, cameron a, akay bn, et al. dermatoscopic features of pigmented intraepidermal carcinoma on the head and neck. j dtsch dermatol ges. 2020;18(9):969-976. doi: 10.1111/ddg.14220. pmid: 32841518. 3. moscarella e, rabinovitz h, zalaudek i, et al. dermoscopy and reflectance confocal microscopy of pigmented actinic keratoses: a morphological study. j eur acad dermatol venereol. 2015;29(2):307-314. doi: 10.1111/jdv.12532. pmid: 24754497. 4. persechino f, de carvalho n, ciardo s, et al. folliculotropism in pigmented facial macules: differential diagnosis with reflectance confocal microscopy. exp dermatol. 2018;27(3):227-232. doi: 10.1111/exd.13487. pmid: 29274094. 5. mazzilli s, gamo-villegas r, pampin-franco a, et al. reflectance confocal microscopy of pigmented bowen’s disease: a case series of difficult to diagnose lesions. case rep dermatol. 2020;12(2):98-106. doi: 10.1159/000507916. pmid: 32518541. pmcid: pmc7265740. 6. karaarslan i, tepret s, yildiz s, yaman b, ozdemir f. the role of reflectance confocal microscopy in a case of bowen’s disease difficult to diagnose. dermatol pract concept. 2018;8(1): 63-65. doi: 10.5826/dpc.0801a15. pmid: 29445580. pmcid: pmc5808377. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022093 1 dermatology practical & conceptual square-shaped alopecia after embolization of intracranial aneurysm: a case report and review jorge román-sainz1, nicolás silvestre-torner1, fernando gruber-velasco1, belen romero-jiménez1, alejandro lobato-berezo2, adrián imbernón-moya1 1 department of dermatology, hospital universitario severo ochoa, leganés, madrid, spain 2 department of dermatology, hospital del mar-parc de salut mar, barcelona, spain key words: alopecia, radiation, trichoscopy, intracranial aneurysm citation: román-sainz j, silvestretorner n, grubervelasco f, romerojiménez b. square-shaped alopecia after embolization of intracranial aneurysm: case report and review. dermatol pract concept. 2022;12(3):e2022093. doi: https://doi.org/10.5826/dpc.1203a93 accepted: october 15, 2021; published: july 2022 copyright: ©2022 román-sainz et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecomm ons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: jorge román sainz, md, travesía de téllez 8, 7º r. cp: 28007, madrid, phone: 680653019, e-mail: jorgesheldon@gmail.com introduction endovascular interventional procedures are widely used for intracranial arterial pathologies treatment. they require realization of fluoroscopy, a technique that relies on x-rays to obtain real-time images [1]. many cases of transient alopecia after this procedure have been reported. case presentation a 45-year-old male was admitted with an intracranial hemorrhage after a rupture of an aneurysm in the anterior communicating artery. two embolization procedures were required. after 2 weeks, he experienced a partial hair loss, comprising the left temporoparietal scalp region. a 7,5-cm sized alopecia plaque with angular edges and rectangular morphology was observed (figure 1). pull test was positive. trichoscopy showed black dots and short vellus hairs (figure 2). lack of peladic hairs ruled out alopecia areata. skin biopsy revealed multiple pilosebaceous units with obliterated follicles without signs of fibrosis. after 2 months the patient showed complete hair regrowth without treatment. conclusions transient radiation alopecia (tra) is an adverse effect, which usually appears with accumulated doses between 3-6 gy. greater doses than 6 gy may cause scarring alopecia [1,2]. this is caused by the simultaneous entry of multiple follicular cells in catagen phase. the dose of radiation produced by a fluoroscopy unit is usually between 0.02-0.05 gy/min. fifty-eight cases of tra have been reported after intracranial arterial embolization, being more frequent in women, with a ratio of 1.41:1. the age varies from 13 years to 70 years, but most of the patients were between 30-50 years. patients report sudden hair loss, producing plaques of alopecia whose size and shape vary depending on the model of the device used. the characteristic angular edges and the medical history are essential for the differential diagnosis with alopecia areata [1,2]. 2 research letter | dermatol pract concept. 2022;12(3):e2022093 figure 1. alopecia area in the patient left temporoparietal region. note the angular edges which give it a perfectly square contour. figure 2. trichoscopy performed on the edge of the alopecia area. black dots can be observed, as well as short vellus hair. research letter | dermatol pract concept. 2022;12(3):e2022093 3 the cumulative radiation dose was in most cases greater than 3 gy, with 92% of cases ranging between 3-6 gy [1]. only one case of scarring tra has been reported [2]. in the case of our patient, we do not know the exact dose of radiation received, but a total dose greater than 3 gy was estimated. in trichoscopy, the most common findings include black dots and yellow dots, followed by short, vellus hairs. broken hairs and white dots are less common [2]. these findings can be observed in alopecia areata. however, exclamation hairs are often seen in the latter, a finding that is not present in tra. histological findings show anagen or catagen follicles lacking inflammatory infiltrate or scar tissue [2]. differential diagnosis should be made mainly with alopecia areata, in which a perior intra-bulbar lymphocytic infiltrate with a “honey-comb” image is usually observed. time from the embolization procedure to the onset of alopecia ranges from 1-8 weeks. most cases spontaneously resolve between 2-6 months, with complete regrowth. in some cases, cryotherapy, topical corticosteroids, topical minoxidil and/or intralesional triamcinolone were applied, without significant differences compared to untreated patients [2]. tra is a transient condition that resolves without the need of treatment. given the increase of such interventional procedures in recent years, it is important to know this entity and differentiate it mainly from alopecia areata. it should also be considered adding this side effect to the informed consent of such interventions. references 1. freysz m, mertz l, lipsker d. temporary localized alopecia following neuroradiological procedures: 18 cases. ann dermatol venereol. 2014;141;15-22. doi: 10.1016/j.annder.2013.09.655. pmid: 24461089. 2. cho s, choi mj, lee js, zheng z, kim dy. dermoscopic findings in radiation-induced alopecia after angioembolization.  dermatology.  2014;229:141–145. doi: 10.1159/000362810. pmid: 25171463. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):5 27 dermatology practical & conceptual www.derm101.com introduction laugier-hunziker syndrome (lhs) is a benign pigmentary condition characterized by hyperpigmented mucocutaneous macules progressively arising during adulthood. the asymptomatic melanotic macules most commonly involve the lips, oral mucosa, and acral surfaces, with occasional nail involvement. while lhs is a rare disorder of unknown etiology, it is important to differentiate it from conditions with similar pigmentary changes with somatic abnormalities that necessitate further investigation and treatment. in this case, we present the history, clinical findings, and histopathology of a patient exhibiting the pigmentary features consistent with lhs in order to highlight the critical differential diagnosis of asymptomatic mucosal and acral hyperpigmentation and to explore the potential pathogenesis of lhs. case presentation a man in his 50s presented with multiple pigmented macules of the lips, palate, and fingers. over the course of one year, the patient noted the gradual onset and progression in the number of lesions and degree of pigmentation. the lesions were asymptomatic and the patient felt otherwise well. the laugier-hunziker syndrome: a case of asymptomatic mucosal and acral hyperpigmentation elizabeth h. cusick1, ashfaq a. marghoob2, ralph p. braun3 1 stony brook university school of medicine, stony brook, ny, usa 2 memorial sloan kettering skin cancer center, new york, ny, usa 3 department of dermatology, university hospital zurich, zurich switzerland key words: laugier-hunziker, mucosal and acral hyperpigmentation, mucocutaneous hyperpigmentation citation: cusick eh, marghoob aa, braun rp. laugier-hunziker syndrome: a case of asymptomatic mucosal and acral hyperpigmentation. dermatol pract concept. 2017;7(2):5. doi: https://doi.org/10.5826/dpc.0702a05 received: january 3, 2017; accepted: january 14, 2017; published: april 30, 2017 copyright: ©2017 cusick et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elizabeth h. cusick, bs, stony brook university school of medicine, 101 nicolls road, stony brook, ny 11794, usa. tel. 718-354-5936. email: elizabeth.cusick@stonybrookmedicine.edu laugier-hunziker syndrome (lhs) is a rare condition characterized by acquired hyperpigmentation involving the lips, oral mucosa, acral surfaces, nails and perineum. while patients with lhs may manifest pigmentation in all of the aforementioned areas, most present with pigmentation localized to only a few of these anatomical sites. we herein report a patient exhibiting the characteristic pigment distribution pattern associated with lhs. since lhs is a diagnosis based on exclusion, we discuss the differential diagnosis of mucocutaneous hyperpigmentation. due to the benign nature of the disease, it is critical to differentiate this disorder from conditions with similar mucocutaneous pigmentary changes with somatic abnormalities that require medical management. we also explore potential mechanisms that may explain the pathogenesis of lhs. abstract 28 observation | dermatol pract concept 2017;7(2):5 given the morphology and distribution of the pigmented macules on the palate, lower lip, and fingers, and based on the fact that the patient had no exposure to heavy metals, no signs of addison’s disease, or peutz-jeghers syndrome, leads one to conclude that the patient has lhs. patient’s history was significant for melanoma in situ which was treated five years prior to the onset of the pigmentation of his lips and fingers. the patient was a non-smoker and he had no other relevant medication history. the patient denied a history of trauma or exposures to heavy metals. there was no familial history of pigmentary disorders and digestive polyposis or tumors. physical examination revealed multiple 2 to 5 mm brown to grayish macules on the lower lip (figure 1a) and two grayish macules on the hard palate (figure 2). on dermoscopy the macules on the lip revealed a fish scale-like dermoscopy pattern (figure 1b). there were several brown to grayish-brown macules on the lateral aspect of his right index, thumb, and middle fingers (figure 3), accompanied by similar appearing macules on his left thumb. dermoscopy revealed pigmented macules with a brown to grayish homogeneous pattern (figure 4a, b). there were no pigmented lesions noted on the palms, soles, nails, perineum, or conjunctiva. no axillary or inguinal lymphadenopathy was found. a biopsy of a representative lesion on the lower lip was performed. histopathologic examination revealed hyperpigmentation of the stratum basalis. there was hyperparakeratosis and acanthosis of the epithelium, with elongated rete ridges, as well as a few melanophages in the dermis. figure 2. clinical manifestations of the pigmented macules located on the hard palate. [copyright: ©2017 cusick et al.] figure 1. (a) clinical manifestations of the pigmented macules of the lower lips, (b) dermoscopic examination of the pigmented lesions reveals a fish scale-like pattern. [copyright: ©2017 cusick et al.] a b figure 3. clinical manifestations of the pigmented macules of the lateral aspects of the second and third right finger. [copyright: ©2017 cusick et al. figure 4. (a, b) dermoscopic examination of the pigmented lesions reveal homogeneous brownish to grayish pattern. [copyright: ©2017 cusick et al.] a b observation | dermatol pract concept 2017;7(2):5 29 cytic hyperplasia involved in formation of mucosal and acral macules of lhs. it has been shown that at the site of the ligand stem cell factor (scf) injection (used for promoting hematopoiesis), there is an increased number of melanocytes, melanocytic dendrite extension and melanin [11]. with the xenografts of normal human skin, scf stimulation resulted in hyperplasia of melanocytes, causing the increased size and number of melanocytes and expression of melanocyte differentiation antigen, while inhibition of kit resulted in decreased antigen expression, and size and number of melanocytes [11]. several differential diagnoses must be considered in an adult patient presenting with multiple mucocutaneous pigmented macules. due to the benign nature of the disease, it is critical to differentiate this disorder from conditions with similar mucocutaneous pigmentary changes with somatic abnormalities that require medical attention [12]. the differential diagnosis considered for this adult patient with hyperpigmentation of fingers and lips included medicationinduced, exposures to heavy metals, addison’s disease, and rare genetic syndromes such as peutz-jeghers syndrome (pjs). drug-induced pigmentation, most commonly associated with phenytoin, anti-malarial, and hiv medications, will usually occur after months or years of chronic use of drugs and resolves once the drug is discontinued [3]. anti-malarial drug administration may cause asymptomatic hyperpigmented macules on the oral mucosa and pretibial shin [2]. exogenous brown to black pigmentation may also result from exposure to tar, dirt, tobacco, and potassium permanganate [3]. for example, cigarette smoking may result in oral mucosal pigmentation in the anterior gingiva [13]. addison’s disease, an endocrine disease caused by insufficient cortisol and aldosterone production, is characterized by hyperpigmentation of the skin and mucosal membranes, with increased level of circulating adrenocorticotropic hormone (acth). in addison’s disease, longitudinal pigmented bands may appear on the nails and diffuse pigmentation may appear on mucosal surfaces, especially the buccal mucosa, gums, and tongue [3]. the well-circumscribed macules of lhs are distinctive from the more diffuse pigmentation of addison’s disease. negative systemic symptoms, such as fatigue and weight loss, and normal plasma levels of cortisol and acth rule out this possibility [14]. peutz–jeghers syndrome (pjs), an autosomal dominant genodermatosis due to mutations in the gene encoding serine/ threonine kinase 11 (stk11), is notable for mucocutaneous lentigines and intestinal polyposis [2]. patients with pjs present with hyperpigmented macules of oral and acral skin arising in the first few years of life. a histologic examination of these lesions shows increased melanin in the stratum basalis, and melanin is concentrated at the tips of the rete ridges [2]. overlapping clinical features in both lhs and pjs may cause diagnostic confusion. in pjs, hyperpigmented macules of the discussion laugier and hunziker first reported an uncommon condition characterized by acquired melanotic hyperpigmented macules of the oral mucosa, lips, fingers, with occasional nail involvement, in otherwise asymptomatic patients [1]. lhs typically arises during adulthood and follows a chronic course without remission. the lesions are most commonly located on the lips and oral cavity, including the buccal mucosa, soft palate, hard palate, and gingiva [2]. longitudinal melanonychia is evident in about half the cases. pigmentation may spread from the proximal nail fold into the surrounding skin [3]. histopathologic features of the pigmented macules described by laugier and hunziker demonstrated intraepidermal melanosis without melanocytosis [1]. the majority of subsequent reports of melanotic macules from lhs demonstrate normal numbers and normal morphologic appearance of melanocytes with increased basal pigmentation due to melanin deposition without hyperplasia of melanocytes [3]. however, there have been some publications reporting increased numbers of intraepidermal melanocytes distributed in a lentiginous pattern [4,5]. due to the rarity of this condition, there are no long-term studies to determine risk for malignant degeneration. with that said, there is one reported case of mucosal melanoma of the upper lip in a patient affected by the long-standing melanocytic hyperplasia of lhs [6]. although the etiology of lhs is unknown, the pathogenesis is thought to be due to an alteration of melanocytes, resulting in an increased synthesis of melanosomes and their transport to the basal cell layers, resulting in the accumulation of melanin in the basal keratinocytes of the epidermis [4]. to our knowledge, no prior studies have examined the significance of the distribution of the lesions in lhs. localization of this condition primarily to mucosal and acral surfaces may provide a clue into the mechanism of action of this disease. advancements in our understanding of mucosal and acral melanoma have revealed the type iii tyrosine kinase receptor c-kit (cd117) as a key player in the oncogenic alterations involved in some acral and mucosal melanomas [7]. this is supported by evidence of successful use of c-kit inhibitors, such as imatinib, in achieving remission for patients with metastatic melanomas from acral and mucosal sites with c-kit aberrations [8,9]. gain-of-function mutations in the kit oncogene, encoding c-kit, are associated with chronic myeloid leukemia and gastrointestinal stromal tumor (gist) development [10]. interestingly, there are reported cases of germline mutation of c-kit demonstrated in a patient with numerous lentigines and gists [10]. it is possible that the gain-of-function mutation of c-kit pathway may activate the downstream pathways and promote proliferation of melanocytes, leading to the melano30 observation | dermatol pract concept 2017;7(2):5 3. rangwala s, doherty cb, katta r. laugier-hunziker syndrome: a case report and review of the literature. dermatol online j. 2010 dec 1;16(12). 4. moore rt, chae km, rhodes ar. laugier and hunziker pigmentation: a lentiginous proliferation of melanocytes. j am acad dermatol. 2004;50(5):70-74. 5. koch se, leboit pe, odom rb. laugier-hunziker syndrome. j am acad dermatol. 1987;16(2):431-434. 6. simionescu o, dumitrescu d, costache m, blum a. dermatoscopy of an invasive melanoma on the upper lip shows possible association with laugier–hunziker syndrome. j am acad dermatol. 2008;59(5):s105-s108. 7. tacastacas jd, bray j, cohen yk, et al. update on primary mucosal melanoma. j am acad dermatol. 2014;71(2):366-375. 8. posch c, moslehi h, sanlorenzo m, et al. pharmacological inhibitors of c-kit block mutant c-kit mediated migration of melanocytes and melanoma cells in vitro and in vivo. oncotarget. 2016;7(29):45916-45925. 9. alexis jb, martinez ae, lutzky j. an immunohistochemical evaluation of c-kit (cd-117) expression in malignant melanoma, and results of imatinib mesylate (gleevec) therapy in three patients. melanoma res. 2005;15(4):283-5. 10. shibusawa y, tamura a, mochiki e, kamisaka k, kimura h, ishikawa o. c-kit mutation in generalized lentigines associated with gastrointestinal stromal tumor. dermatology. 2004; 208(3):217-220. 11. costa jj, demetri gd, harrist t, et al. recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. j exper med. 1996;183(6):2681-2686. 12. vachiramon v, mcmichael aj. approaches to the evaluation of lip hyperpigmentation. int j dermatol. 2012;51(7):761-770. 13. wang wm, wang x, duan n, jiang hl, huang xf. laugier–hunziker syndrome: a report of three cases and literature review. int j oral sci. 2013;4(4):226-230. 14. lema b, najarian dj, lee m, miller c. numerous hyperpigmented macules of the oral mucosa. j am acad dermatol. 2010;62 (1):171-173. oral mucosa and acral skin may be present at birth or appear in early life, in contrast to the lesions in lhs, which usually occur in adulthood. unlike lhs, lesions of pjs typically do not involve the tongue, palate, or fingernails. lastly, pjs is associated with hamartomatous polyps of the gastrointestinal tract, whereas lhs is not [3]. although rare, bandler syndrome presents as hyperpigmented macules on the hands, nails, and oral mucosa and is associated with intestinal vascular malformation developing in infancy [3]. lamb syndrome is characterized by pigmentation of the skin mucosa, atrial and mucocutaneous melanomas, and multiple blue nevi [2]. leopard syndrome is manifested by numerous lentigines, electrocardiographic abnormalities, occasional hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness [2]. given that our patient’s pigmented macules of the lips and oral mucosa appeared late in life, in the absence of other somatic abnormalities and without a relevant family history of findings typical of pjs, our diagnosis was most consistent with lhs. in conclusion, lhs is an important consideration with a patient presenting with otherwise asymptomatic mucosal and acral hyperpigmentation. despite the low prevalence of the lhs, the prompt clinical recognition avoids the need for excessive and invasive procedures and workup. references 1. laugier p, hunziker n. pigmentation melanique lenticulaire, essentielle de la muqueuse jugale et des levres. arch belges dermatol syphiligr. 1970;26(3):391-399. 2. nikitakis ng, koumaki d. laugier–hunziker syndrome: case report and review of the literature. oral surg oral med oral pathol oral. 2013;116(1):e52-8. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023074 1 optical super-high magnification dermoscopy: a complementary means in the diagnosis of trombiculosis corinne orsini1, giulio cortonesi1, arianna lamberti1, marco campoli1, pietro rubegni1, elisa cinotti1 1 department of medical, surgical and neurological science, dermatology section, university of siena, s. maria alle scotte hospital, siena, italy citation: orsini c, cortonesi g, lamberti a, campoli m, rubegni p, cinotti e. optical super-high magnification dermoscopy: a complementary means in the diagnosis of trombiculosis. dermatol pract concept. 2023;13(2):e2023074. doi: https://doi.org/10.5826 /dpc.1302a74 accepted: august 3, 2022; published: april 2023 copyright: ©2023 orsini et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: corinne orsini, dermatology section, university of siena, s. maria alle scotte hospital, 53100 siena, italy. tel: 0039-0577 585481. fax: 0039 0577 585488, email: corinne.orsini@student.unisi.it case presentation in october 2021, a 27-year-old man working in the countryside of tuscany (italy) presented with a 3-day history of diffuse intense pruritus. dermatological examination revealed multiple, erythematous macules localized on his right side of the trunk, the genitals, and the right popliteal fossa (figure  1, a and b). a 10x dermoscopy examination revealed in the center of each macula the presence of a tiny bright yellow mite, hard to recognize due to its small size (figure 1c). videodermoscopy at 40x (figure 1d) and 400x (figure 1e) magnification (medicam 1000, fotofinder system(r)) allowed to observe six-legged golden colored parasites, strongly attached to the skin, and thus to identify an infestation of the larval stage of neotrombicula autumnalis, a mite involved in the underestimated and misdiagnosed trombiculosis. teaching point trombiculosis is a common but underreported ectoparasitosis caused in europe by the larval stage of neotrombicula autumnalis. diagnosis of trombiculosis can be difficult: clinical presentation is extremely vague, mainly asymptomatic, occasionally consists of multiple pruritic papules due to parasite biting. 2 image letter | dermatol pract concept. 2023;13(2):e2023074 figure 1. (a, b) multiple, erythematous macules scattered on the right side of the trunk and right popliteal fossa. (c) conventional dermoscopy 10x showed a tiny golden mite in the center of each macula. (d, e) videodermoscopy at 40x (d) and 400x (e) magnification of neotrombicula autumnalis (medicam 1000, fotofinder system(r)). futhermore, larvae show tiny dimensions (200-400 µm) and can easily be missed at conventional 10 x dermoscopy, so high-magnification dermoscopy could represent an useful means in the diagnosis of trombiculosis. only one case of neotrombicula autumnalis described by using high-magnification videodermoscopy was found in literature [1, 2]. in particular, under optical 400 x magnification, the color, the entire contour of the body and the details of the legs of the parasite are better visible, allowing a precise diagnosis. references 1. di meo n, fadel m, trevisan g. pushing the edge of dermoscopy in new directions: entomodermoscopy of trombicula autumnalis. acta dermatovenerol alp pannonica adriat. 2017;26(2):45–46. doi: 10.15570/actaapa.2017.14. pmid: 28632887 2. nasca mr, lacarrubba f, micali g. diagnosis of trombiculosis by videodermatoscopy. emerg infect dis. 2014;20(6): 1059–1060. doi:10.3201/eid2006.130767. pmid: 24856873. pmcid: pmc4036784. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022053 1 childhood flexural comedones li-wen zhang1, md, juan wu2, lu zheng1, tao chen1 1 department of dermatovenereology, chengdu second people’s hospital, chengdu, sichuan, china 2 sexually transmitted disease institute, shanghai skin disease hospital, school of medicine, tongji university, shanghai, china citation: zhang l, wu j, zheng l, chen t. childhood flexural comedones. dermatol pract concept. 2022;12(2):e2022053. doi: https://doi.org/10.5826/dpc.1202a53 accepted: august 14, 2021; published: april 2022 copyright: ©2022 zhang et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: tao chen, department of dermatovenereology, chengdu second people’s hospital, 165 caoshi street, chengdu 610017, sichuan, china. e-mail: 13980427003@163.com case presentation a 20-year-old female complained of an asymptomatic papule on the left postauricular skin that occurred shortly after birth. the lesion presented a single papule with double orifice comedones (figure 1a). at the same site, previous skin lesion or inflammation were not observed. the dermoscopy manifested double-ended pseudo-comedones (figure  1b). childhood flexural comedones (cfc) with late diagnosis in adulthood was established. teaching point cfc usually occur in the skin folds including axilla, neck, cubital fossa, and perineum, and present as double opening comedones connected by a thin layer of the epidermis. figure 1. (a) a single papule with double-orifice comedones on the left postauricular skin. (b) the dermoscopy manifested double-ended pseudo-comedon. 2 image letter | dermatol pract concept. 2022;12(2):e2022053 the etiology hypotheses included potential precursors of hidradenitis suppurativa, friction, genetic background, and hamartomatous origin [1]. histopathology showed typical open comedo with follicular plugging and infundibular dilatation [2]. three different dermoscopic patterns of cfc have been described including cuneiform comedo, multiorifice comedo, and double-ended pseudo-comedones [1]. the differential diagnosis includes other diseases associated with comedones, such as nevus comedonicus, acne neonatorum, familial dyskeratotic comedones, and idiopathic disseminated comedones. references 1. piccolo v, russo t, silva pereira c, darlington md, argenziano g. dermoscopy of childhood flexural comedones: description of 4 cases. int j dermatol. 2018; 57(3):e21–e23. doi: 10.1111/ ijd.13894. pmid: 29318614. 2. larralde m, abad me, munoz as, luna p. childhood flexural comedones: a new entity. arch dermatol. 2007;143(7): 909–911. doi: 10.1001/archderm.143.7.909. pmid: 17638736. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023095 1 eosinophilic annular erythema due to certolizumab pegol therapy for rheumatoid arthritis post-covid-19 vaccine andrea bassi1, vincenzo piccolo2, alessandro ginori3, grazia galippi3, carlo mazzatenta1 1 division of dermatology, azienda usl toscana nord ovest, lucca, italy 2 dermatology unit, university of campania luigi vanvitelli, naples, italy 3 pathology unit, “monterosso polyspecialistic center”, azienda usl toscana nord ovest, lucca, italy key words: eosinophilic annular erythema, certolizumab pegol, adverse drug reaction, covid-19 citation: bassi a, piccolo v, ginori a, galippi g, mazzatenta c. eosinophilic annular erythema due to certolizumab pegol therapy for rheumatoid arthritis post-covid-19 vaccine. dermatol pract concept. 2023;13(2):e2023095. doi: https://doi.org/10.5826/dpc.1302a95 accepted: october 7, 2022; published: april 2023 copyright: ©2023 bassi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrea bassi, md, division of dermatology, azienda toscana nord ovest, lucca, italy. tel: +393389340371 email: bassiderma@gmail.com introduction certolizumab pegol (cp) is a pegylated, humanized antibody which binds to and neutralizes tnf-α, a key pro-inflammatory cytokine that plays a central role in inflammatory processes in immune-mediated inflammatory diseases. it is usually well-tolerated and rarely reported as a cause of skin reactions, except for the paradoxical worsening of psoriasis during treatment [1,2]; here we report a unique case of possible drug-induced diffuse eosinophilic annular erythema. case presentation a 22-year-old girl presented to our dermatologic department with a diffuse itchy dermatitis involving the trunk, arms and legs. medical history revealed that after the first dose of bnt162b2 mrna covid-19 vaccine in january 2021 she developed persistent joint pain on the hands and knees for which she had a diagnosis of vaccine induced reactive arthritis and started therapy with courses of nsaids. in april, due to worsening of the arthritis, hydroxychloroquine and prednisone were added. in july, on the basis of the clinical features and serologic tests, she received a conclusive diagnosis of rheumatoid arthritis. hence treatment with cp 200 mg/eow was added to therapy. three weeks after, ie after the second dose of cp, the patient noticed the appearance of isolated, mildly itchy annular lesions on the upper arms and on the back, which were initially diagnosed as annular granuloma (figure 1a) and treated with topical steroids. at the end of october, the patient was referred to our department for the rapid worsening of the cutaneous lesions which spread on the trunk, arms and legs in association with increasing itch. on clinical examination we observed diffuse erythematous lesions with annular conformation, most of them with a polycyclic figurate aspect. the edge of 2 research letter | dermatol pract concept. 2023;13(2):e2023095 the lesions appeared slightly infiltrated with sparse vesicles and crusts (figure 1b). the histologic skin sections showed spongiosis of the epidermis and intraepidermal vesicles. in the superficial and deep dermis, mostly in perivascular areas, there was a dense inflammatory infiltrate constituted by lymphocytes and eosinophils, with intraepidermal eosinophilic exocytosis. there were no mucin deposits in the dermis and the pas stain to detect fungi was negative. a diagnosis of acute spongiotic dermatitis was made, suggesting a possible drugs etiology due to the clinical findings (figure 2). direct immunofluorescence was negative. blood tests including indirect immunofluorescence and antitransglutaminase were negative. based on clinical pathological correlations, according to naranjo algorithm [3] we posed a diagnosis of a “possible” drug-induced eosinophilic annular erythema (eae). our diagnosis was supported by the improvement of the cutaneous rash and itchy sensation about three weeks after the discontinuation of certolizumab pegol while continuing therapy with hydroxychloroquine and prednisone. eae is a chronic, recurrent skin disease of an unknown etiology. it presents as erythematous, usually asymptomatic or mildly pruritic, annular papules and plaques on the trunk and extremities. annular papules often coalesce into palpable erythematous arches or rings. during resolution, transient pigment changes may be observed, but no atrophy or scarring occurs. it has a variable response to systemic steroids, antimalarial agents, or, as recently reported, to dupilumab [4]. clinical differential diagnosis is with other figurate erythema such as: wells syndrome, erythema chronicum migrans, erythema annulare centrifugum, erythema gyratum repens, annular granuloma, subacute cutaneous lupus erythematosus and dermatosis of the pemphigoid group [5,6]. histologically, eae is characterized by superficial and deep perivascular lymphocytic infiltrate with a prominent eosinophilic component. conclusions in our case the strict temporal association between drug administration and appearance/disappearance of eae indicate that this reaction should be added to the list of rare adverse events related to certolizumab pegol. figure 1. clinical evolution of the skin lesions from september (a) to the end of october (b). research letter | dermatol pract concept. 2023;13(2):e2023095 3 references 1. capogrosso sansone a, mantarro s, tuccori m, et al. safety profile of certolizumab pegol in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis. drug saf. 2015;38(10):869-888.  doi: 10.1007/s40264-015 -0336-2. pmid: 26316054. 2. klein rq, spivack j, choate ka. psoriatic skin lesions induced by certolizumab pegol. arch dermatol. 2010;146(9):1055-1056. doi: 10.1001/archdermatol.2010.225. pmid: 20855720. 3. naranjo ca, busto u, sellers em, et al. a method for estimating the probability of adverse drug reactions. clin pharacol ther. 1981;30:239–245. doi: 10.1038/clpt.1981.154. pmid: 7249508. 4. maione v, caravello s, cozzi c, et al. refractory eosinophilic annular erythema treated successfully with dupilumab. j dtsch dermatol ges. 2020;18(9):1031-1032.  doi: 10.1111 /ddg.14254. pmid: 32909389. 5. heras mo, muñoz np, sancho mi, et al. eosinophilic annular erythema in adults: report of two cases and review of the literature. an bras dermatol. 2017;92(5 suppl 1):65-68. doi: 10.1590/abd1806-4841.20176373. pmid: 29267450. pmcid: pmc5726681. 6. bassi a, scarfi f, galeone m, et al. generalized granuloma annulare and non-hodgkin’s lymphoma. acta derm venereol. 2013;93(4):484-485. doi: 10.2340/00015555-1510. pmid: 23250047. figure 2. cutaneous histology showed an inflammatory infiltrate in the superficial and deep dermis, mostly in perivascular areas (a), (40x, h&e stain); there was also spongiosis of the epidermis and the infiltrate was constituted by lymphocytes and eosinophils with eosinophilic exocytosis (b, 200x, h&e stain; c, 400x, h&e stain). dermatology: practical and conceptual 44 observation | dermatol pract concept 2017;7(3):9 dermatology practical & conceptual www.derm101.com introduction malignant fibrous histiocytoma (mfh), currently classified as undifferentiated pleomorphic sarcoma, is the most frequent soft tissue sarcoma in adulthood, but it is not as common as a primary skin tumor [1]. the age of presentation ranges between 50 and 70 years, two-thirds occur among men, and the caucasian population is more commonly affected. mfh affects mostly the thighs and trunk. infrequently, it presents in the head and neck in adults [2,3]. the lesions are usually diagnosed in advanced stages, and despite currently proposed therapies such as radiotherapy or chemotherapy, the patient’s prognosis is usually poor with a tendency to local recurrence and systemic metastasis [1]. early recognition is crucial to improve clinical outcome. dermoscopy has shown to be useful in the assessment of both melanoma and non-melanoma skin tumors [4]. case report a 75-year-old male with history of multiple basal cell carcinomas and actinic keratosis presented for a biannual routine skin examination. in the left cheek a hypopigmented lesion was detected. it was discretely erythematous, with poorly defined limit, and increased consistency on palpation (figure 1). the lesion was not present at the time of his previous visit and the patient was not aware of the lesion and did not know the evolution. no previous history of radiotherapy dermoscopic findings in an early malignant fibrous histiocytoma on the face gabriel salerni1,2, carlos alonso1,2, german sanchez-granel2, mario gorosito1,3 1 dermatology department, hospital provincial del centenario de rosario, argentina 2 diagnóstico medico oroño, rosario, argentina 3 dermatopathology department, hospital provincial del centenario de rosario-universidad nacional de rosario, argentina key words: dermoscopy, skin cancer citation: salerni g, alonso c, sanchez-granel g, gorosito m. dermoscopic findings in an early malignant fibrous histiocytoma on the face. dermatol pract concept 2017;7(3):9. doi: https://doi.org/10.5826/dpc.0703a09 received: february 14, 2017; accepted: april 11, 2017; published: july 31, 2017 copyright: ©2017 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, v oroño 1515, rosario, argentina. tel. +54.341.5222222. email: gabrielsalerni@hotmail.com malignant fibrous histiocytoma (mfh), currently classified as undifferentiated pleomorphic sarcoma, is the most frequent soft tissue sarcoma in adulthood, but it is not as common as a primary skin tumor. mfh affects mostly the thighs and trunk, head and neck is an infrequent presentation in adults. mfh is often diagnosed in advanced stages, with a tendency to local recurrence and systemic metastasis. since tumor thickness and size are identified as major prognostic factors, early recognition becomes crucial to improve prognosis. we present a case of a cutaneous malignant fibrous histiocytoma located on the face in which dermoscopy was useful in clinical management and definition. abstract observation | dermatol pract concept 2017;7(3):9 45 irregular cells, some giant, with large and hyperchromatic nuclei and high mitotic index, which adopted a storiform arrangement, intermixed with thick collagen bundles (figure 3a and b). in the immunohistochemical study, the cytokeratins and the hmb45 were negative, whereas the cd68 was marked strongly positive (figure 3c, d and e). discussion malignant fibrohistiocytic tumors include various soft tissue sarcomas that show a spectrum of peculiar clinical-pathoor other procedure was reported. there were no regional lymphadenopathies. dermoscopy showed a shiny white-red structureless area with crystalline structures such as short white streaks and rosettes, the latter term used to designate four closely aggregated white, small dots in correspondence to a follicular opening arranged in a rhombus [5]. focal superficial linear telangiectasias were also noted. no specific criteria for melanocytic lesion were observed (figure 2). excisional biopsy was performed. histopathology reported acanthosis, hyperkeratosis and marked cellular vacuolization. the dermis was totally invaded by a neoformation formed by a large number of intensely pleomorphic, figure 1. clinical image. hypopigmented lesion with discrete erythema and poorly defined limits. [copyright: ©2017 salerni et al.] figure 2. dermoscopy image. a white-red structureless area with crystalline structures (short white streaks and rosettes) was observed. focal superficial linear telangiectasias were also noted. [copyright: ©2017 salerni et al.] figure 3. non-ulcerated, mitotically active dermal fibrohistiocytic proliferation with infiltrative pattern; cd 68 positive, cytokeratin and hmb45 negative. [copyright: ©2017 salerni et al.] 46 observation | dermatol pract concept 2017;7(3):9 the dermoscopic findings were not conclusive: the presence of erythema and a shiny white-red structureless area along with short white streaks and rosettes primarily suggested a squamous tumor and less likely a basal cell carcinoma. the findings were not specific for melanocytic lesion or non-melanocytic lesion, so according to the two-step algorithm, the diagnosis of melanoma cannot be ruled out and biopsy is mandatory. tumor size and depth have been identified as the main prognostic factors [8]. therefore, establishing an accurate and early diagnosis is of crucial in improving the tumor prognosis. to our knowledge, this is the first description of the dermoscopic aspect of mfh. dermoscopy was helpful in defining clinical management allowing for the early recognition of this tumor in an unusual presentation. mfh should be included in the differential diagnosis when assessing nonpigmented lesions with dermoscopy. references 1. weiss sw, enzinger fm. malignant fibrous histiocytoma: an analysis of 200 cases. cancer. 1978;41:2250-2266. 2. gibbs j, huang p, lee r, mcgrath b, et al. malignant fibrous histiocytoma: an institutional review. cancer invest. 2001;19:23-27. 3. sureda n, bosch m, valente e, kurpis m, ruiz a. malignant fibrohistiocytoma: cephalic location as infrequent presentation. arch argent dermatol. 2008;58:55-59. 4. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377-386. 5. cuellar f, vilalta a, puig s, palou j, salerni g, malvehy j. new dermoscopic pattern in actinic keratosis and related conditions. arch dermatol. 2009;145(6):732. 6. o’brien je, stout ap. malignant fibrous xanthomas. cancer. 1964; 17: 1445-55. 7. weiss sw, goldblum jr. malignant fibrohistiocytic tumors. in: gibson le, ed. enzinger and weiss’s soft tissue tumors. 4th ed. st. louis: cv mosby; 2001:535–569. 8. pezzi cm, rawlings ms, esgro jj, pollock re, romsdahl mm. prognostic factors in 227 patients with malignant fibrous histiocytoma. cancer. 1992;69:2098-2103. logical findings with distinctive biological behavior. these tumors are grouped into three subtypes: atypical fibroxanthoma, dermatofibrosarcoma protuberans and malignant fibrohistiocytoma. malignant fibrous histiocytoma (mfh) is a high-grade sarcoma that was first described by o’brien and stout in 1964 [6] and is currently classified as undifferentiated pleomorphic sarcoma. the term mfh is used in the medical literature to describe a high-grade pleomorphic sarcoma that affects adults. it is the sarcoma most frequently present in this age group [1]. mfh originates from pluripotent mesenchymal cells with the ability to differentiate into histiocytes, fibroblasts and myofibroblasts of the muscle or muscle fascia. the etiology of these tumors is unknown, although, as in all sarcomas, previous radiotherapy in the area may induce its occurrence. there are five histological subtypes: storiform-pleomorphic, myxoid, giant cell, inflammatory and angiomatoid. the pleomorphic storiform pattern is the most common, found in two-thirds of cases. in this variety, a large pleomorphic cell population with high nuclear atypia and mitosis is observed together with cells with fusiform morphology that adopt a “spoke wheel” or storiform pattern [7]. mfh usually affects the proximal limbs, although it has been described in the cephalic location. it can present as a cutaneous lesion in the form of a primary tumor or as metastasis from mfh at other sites. the pathogenesis is undefined, although mfh has been associated with physical, chemical and viral factors. approximately two-thirds of the tumors are located within the skeletal muscle, with fewer than 10% confined to the subcutis [7]. it usually presents as a slow-growing tumorous lesion, though there is no clinically characteristic presentation that allows for differentiation from other sarcomas. the definitive diagnosis of mfh relies on histological studies, while immunohistochemistry helps establish the differential diagnosis with other entities with similar morphological patterns, such as pleomorphic varieties of rhabdomyosarcoma, leiomyosarcoma, liposarcoma, dermatofibrosarcoma protuberans, melanoma and atypical fibroxanthoma. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023144 1 scabies affects quality of life in correlation with depression and anxiety sema koç yıldırım1, neslihan demirel öğüt1, ece erbağcı1, çağrı öğüt2 1 department of dermatology and venereology, uşak university training and research hospital, uşak, turkey 2 department of psychiatry, uşak university training and research hospital, uşak, turkey key words: scabies, quality of life, dermatology life quality index, depression, anxiety citation: koç yıldırım s, demirel öğüt n, erbağcı e, öğüt ç. scabies affects quality of life in correlation with depression and anxiety. dermatol pract concept. 2023;13(2):e2023144. doi: https://doi.org/10.5826/dpc.1302a144 accepted: november 3, 2022; published: april 2023 copyright: ©2023 koç yıldırım et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. sema koç yıldırım; uşak university training and research hospital, department of dermatology and venereology, uşak, turkey; tel: +90 536 7371594; e-mail: semakocyildirim@gmail.com introduction: scabies is a highly contagious disease affects many people worldwide each year and a major public health problem. a small number of studies have shown that scabies causes impairment in the quality of life in adult patients. objectives: the aims of this study are to assess the impact of scabies on adult patients quality of life (qol) and evaluate the relationship between depression and anxiety levels and impairment in life quality. methods: this cross-sectional study included adult patients diagnosed with scabies in our dermatology outpatient clinic. the effect of scabies on qol was evaluated by dermatology life quality index (dlqi), and the levels of depression and anxiety were evaluated by beck depression scale (bds) and beck anxiety scale (bas). results: totally, 85 patients included to the study. qol of 72.2% of the patients was moderate to extremely large affected. there was a positive correlation between the duration of the disease, the total dlqi score and the severity of the disease impact on qol (rs= 0.287, p = 0.01 and rs=0.280, p = 0.008, respectively). a positive correlation was found between the number of treatments received and the total dlqi (rs= 0.223, p = 0.042). there was a positive correlation between bds and bas, and total dlqi score (rs=0.448 and p = 0.000; rs=0.456 and p = 0.000, respectively). conclusions: scabies has a moderate to severe effect on qol. there was a positive correlation between impairment qol and anxiety and depression scores. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023144 introduction scabies is a contagious skin infestation caused by the mite sarcoptes scabiei variant hominis. it affects approximately 455 million people worldwide each year and is still a major public health problem in many resource poor-urban and rural regions of developing world [1]. recently, scabies outbreaks have been reported in many countries. it was also announced as the most common neglected tropical diseases (ntds) with skin manifestation according to the world health organization list of ntds [2,3]. in a study from turkey, it was found nearly 30-fold increase in the number of patients with the diagnoses of scabies comparing 2017 and 2019 and it was also detected that, approximately 13% of patients were resistant to repetitive topical treatments [4]. scabies often causes severe itching and patients suffered from social stigma, sleep disruption, difficulties in concentration and productivity [2,5]. it was reported that scabies was responsible for 0.21% of disability adjusted life years from all conditions studied by global burden of disease 2015 worldwide [6]. therefore, the morbidity of scabies may be related to both the degree of clinical pathology and emotional aspects of the disease. further, scabies may reduce the quality of life (qol) of patients with the increasing incidence and treatment resistance. there are few reports in the literature evaluating qol of adult patients with scabies [5,7-9]. to the best of our knowledge, there is no study evaluating the relationship between scabies and depression and anxiety. objectives in our study, we aimed to investigate 1) the effects of the disease on qol by dermatology life quality index (dlqi) and to evaluate the depression and anxiety scores through beck depression scale (bds) and beck anxiety scale (bas) in adult patients diagnosed with scabies 2) the relationship between the social and demographic characteristics of the patients and these measures, and 3) the relationship between dlqi and anxiety and depression scores. methods study design this cross-sectional study included patients with scabies aged 18 years or older during the period between june 2021 and december 2021 in our dermatology outpatient clinics. informed consent was obtained from all patients. the approval of the institutional review board was received (irb approval status [approval date and number: 20.05.2021/602.03.99]). patients demographic data of patients including age, gender, education status, marital status, time between onset of disease and diagnosis, previous treatment history for scabies, personal and familial psychiatric disease history were recorded. according to the age, patients were classified as young adults (18-44 years), middle-aged persons (45-65 years) and aged persons (> 65 years). educational levels of patients were classified according to the turkish national education system such as literate, primary school graduate, secondary school graduate, high school graduate and university graduate. the diagnosis of scabies depended on the 2020 international alliance for control of scabies (iacs) consensus criteria for the diagnosis of scabies [10]. patients diagnosed with scabies according to level b (clinical scabies) and level c ( suspected scabies) by the dermatology specialist were included to the study. patients who used 5% permethrin cream or lotion with an interval of 7-14 days or 12.5% sulfur ointment for 3 consecutive days were considered to have received appropriate treatment [11]. each cycle of these treatments was considered a single time treatment. individuals younger than 18 years of age, being pregnant, having crusted scabies and having personal psychiatric disease history were not included in the study. all patients were asked to complete the questionnaires, including dlqi, bds and bas. questionnaires dlqi is comprised of 10 items focuses on 6 domains including symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. the dlqi were scored on a 4-point likert scale (0, “not at all”; 1, “a little”; 2, “a lot”; 3, “very much”), with the total score ranging from 0 to 30. the higher scores mean the more qol impaired. during the analysis, scores were banded into five categories according to the severity of the disease impact on patient life as follows: 0-1, no effect; 2-5 small effect; 6-10, moderate effect; 11-20, very large effect and 21-30, extremely large effect. also, a score of 1 or more for each domain was accepted as impairment in that domain. turkish validity study of dlqi was conducted [12]. bds is a 21-item self-report inventory. for each symptom category, there are four sentences; the subject endorses one of them according to his/her experience during the previous week. this form provides a four-point likert-type measurement. each item gets progressively increasing points between 0-3. a high total score indicates a high level of depression severity. the bdi was developed by beck et al was adapted to the turkish population by hisli [13,14]. bai is a 21-item self-report inventory. the items involve symptoms of anxiety. subjects are asked how much they original article | dermatol pract concept. 2023;13(2):e2023144 3 experienced each symptom during the previous week on a four-point likert-type scale of 0–3. higher total scores indicate higher levels of anxiety. bai was developed by beck et al and adapted to the turkish population by ulusoy et al. [15,16]. statistical analysis the statistical analysis was carried out using ibm spss statistics 28.0. continuous data were given as mean ± standard deviation (sd) and median ± interquartile range [iqr]. categorical data were given as percentage. pearson chi-square and pearson exact chi-square analyzes were performed in the analysis of the cross tables. mann-whitney or independent samples t tests were used for quantitative variables. the correlation analyses were performed using spearman rank correlation coefficient (rs). for statistical significance, p < 0.05 was accepted as the criterion. results demographics a total of 85 patients with scabies were included in the study. forty-one (48.2%) of the cases were female and 44 (51.8%) were male. the mean age ± sd of the study population was 34.07 ± 12.33 (17-66) years. according to the age categories, most of the patients were young adults (76.5%), while 22.1% of the patients were middle-aged and 1.2% were aged. the median disease duration was 8 weeks (iqr 9). the median duration between the onset of disease symptoms and the time of diagnose was 6 weeks (iqr 4). thirty of patients (35.3%) had received at least one of the appropriate treatment options including 5% permethrin cream or lotion and 12.5% sulfur ointment. fourteen percent of patients had received one of the treatment options at least two or more times. the medications were prescribed by a dermatologist to 43.3% of the treated patients and the close contacts of 70% of the treated patients were also offered treatment. only two patients had a familial history of psychiatric illness. the demographic and social characteristics of patients shown in table 1. dlqi eighty-three of the patients had completed dlqi. the overall mean dlqi score ± sd was 10.54 ± 6.17 (median 9.00). according to the severity of the scabies impact on qol of 72.2% of the patients was moderate to extremely large affected. banding of dlqi with the scores of the patients was shown in table 2. the mean score ranged from 0.98 to 3.55 and the median score ranged from 1 to 3 in the individual domains (figure 1). the domain with the highest impact on patients that ‘symptoms and feelings’ was impaired in all table 1. demographic and social features of patients. number of patients, n (%) 85 (100) gender, n (%) female male 41 (48.2) 44 (51.8) age (year), mean ± sd 34.07 ± 12.33 disease duration (weeks), median (iqr) 8 (9) education, n (%) • literate • primary school graduate • secondary school graduate • high school graduate • university graduate 2 (2.4) 21 (24.7) 21 (24.7) 24 (28.2) 17 (20) number of patients received appropriate treatment 5% permetrin cream/lotion n (%) 12.5 % sulfur ointment n (%) 30 28 (93.3) 10 (33.3) number of treatments, n (%) • single time • two times • three times • four times 18 (21.25 (5.9) 3 (3.5) 4 (4.7) iq = interquartile range; sd =standard deviation. ‡. patients. the other domains that had the most impact on patients were ‘work and school’, ‘personal relationships’ and ‘daily activities’, respectively. the impairment of each domain was demonstrated in table 3. there was no statistically significant relationship between total dlqi and gender, education status, marital status, having appropriate treatment and having any comorbid disease. the total dlqi score was higher in young adults and the difference was statistically significant (p = 0.06). a positive correlation was found between the duration of the disease, the total dlqi score and the effect severity (rs= 0.287, p = 0.01 and rs=0.280, p = 0.008, respectively). there was also a positive correlation between the number of treatments received and the total dlqi (rs= 0.223, p = 0.042). the time between the onset of complaints and table 2. banding of the dermatology life quality index with the scores. number of patients, n (%) score effect severity 1 (1.2) 0-1 no effect 22 (26.5) 2-5 small effect 25 (30.1) 6-10 moderate effect 28 (33.7) 11-20 very large effect 7 (8.4) 21-30 extremely large effect 4 original article | dermatol pract concept. 2023;13(2):e2023144 disease duration and the number of treatments were higher in those who were with impairment in the ‘treatment’ domain (question 10) than those who were not (p = 0.042 and p = 0.015, respectively). for other domains, there was no significant difference in disease duration, time to diagnose and the number of treatments between those with impairment and those who were not. bds and bas seventy-five of patients completed bds and bas. the mean bds score ± sd was 12.11 ± 9.52 and the mean bas score ± sd was 8.81 ± 9.45. there was no statistically significant relationship between bds and bas with age, gender, education status, having appropriate treatment and having any comorbid disease. no correlation was found between the duration of the disease, time to diagnose, number of treatment, and bds and bas (table 4). there was a positive correlation between bds and bas with total dlqi score (rs=0.448 and p = 0.000; rs=0.456 and p = 0.000, respectively). also, we have compared the bds and bas scores of affected patients and non-affected patients for each dlqi domain. those who have impairment in the domain 2 (daily activities) and domain 4 (work and school) had significantly higher bds and bas scores than those without. the bds scores of those with impairment in the domain 5 (personal the diagnosis was not effective on total dlqi score and the severity of the impact on qol. the correlations related to total dlqi scores and the severity of the disease impact on life quality were shown in table 4. there was no difference between the patients with impairment and without impairment for each domain in terms of gender, age, educational status, presence of any comorbid disease and having appropriate treatment. when we compare those with and without impairment in individual domains, the disease duration and the time to diagnosis was longer in those with impairment in ‘daily activities’ (question 3 and 4) than those without, and this difference was statistically significant (p = 0.016 and p = 0.019, respectively). also, the figure 1. mean scores of the patients for each domain. table 3. impairment of each dlqi domain in patients with scabies. domain dlqi questions number of patients, n (%) 1. symptoms and feelings 1,2 83 (100) 2. daily activities 3,4 55 (66.2) 3. leisure 5,6 49 (59.0) 4. work and school 7 57 (68.6) 5. personal relationships 8,9 55 (66.2) 6. treatment 10 46 (55.4) original article | dermatol pract concept. 2023;13(2):e2023144 5 ‘leisure’, ‘work and school’ and ‘daily activities’ was greater in males [9]. on the other hand, in a different study, the authors were not found any relationship between the gender and education similar to our study [5]. these differences may be related to the fact that the studies were conducted in different geographical regions of the world and sociocultural differences. in studies, the effect of symptom duration on qol was not generally mentioned, and only one study reported that those with a symptom duration of 8 weeks or longer tended to have more severe impairment on qol [8]. in our study, the median disease duration was 8 weeks and we found a positive correlation between the duration of the disease, the total dlqi score and the effect severity. recently, scabies outbreaks have been reported in many countries [17-20. in a study conducted in distinct geographic regions of turkey, a 7-fold increase was found comparing 2017 and 2018, and a 30-fold increase was found and 2017 and 2019 [4]. moreover, in recent years, treatment resistance of scabies has been remarkable, and this may be a cause of the prolonged disease duration [4,19–23]. in our study, 14% of patients had received one of the treatment options at least two or more times and we found a positive correlation between the number of treatments received and the total dlqi. it is possible to say that treatment unresponsiveness negatively affects qol. relationships between some dermatological diseases such as psoriasis, vitiligo, atopic dermatitis, acne vulgaris, seborrheic dermatitis, hidradenitis suppurativa and chronic pruritus and depression and anxiety were evaluated in different studies [24-28]. however, to the best of our knowledge, no study has been conducted to evaluate the relationship between scabies and depression and anxiety. in a study evaluated the depressiveness and anxiety of psoriasis patients, the mean bds score was calculated as 9.36 ± 1.88 and the mean bas score was found as 11.36 ± 1.79 [29]. in another study including the chronic urticaria patients, while the mean bds score was 10.56 ± 7.90, the mean bas was 14.28 ± 11.58 [30]. in our study the mean bds score was 12.11 ± 9.52 and the mean bas score was 8.81 ± 9.45. while bds scores were comparable to these studies, the bas scores in relationship) and domain 6 (treatment) had higher than those without. also, the bas scores of the patients with impairment in the domain 3 (leisure) were higher than without impairment. these findings were shown in table 5. conclusions to the best of our knowledge, this is the first study to evaluate the life quality of turkish patients diagnosed with scabies and also the depression and anxiety scores and their relationship between dlqi scores in the literature. in the previous studies that investigated health-related quality of life, it was found that scabies had a small to moderate effect on life quality [3,5,7-9]. in our study, it was clearly found that scabies had considerable effect on quality of life of patients. according to the dlqi scores, the qol of 72.2% of the patients was affected moderate to extremely large. the mean dlqi ± sd score of patients in our study was 10.54 ± 6.17. in a study from china it was reported 10.09 ± 5.96 similar to our study [5] . in another study, the mean score was reported as 3.1 but it was stated there was a positive correlation between the severity of the disease and the scores and, the mean score of adults with severe scabies was 7.8 [9]. in our study, the domains with the most impact on patients were ‘symptoms and feelings’, ‘work and school’, ‘personal relationships’ and ‘daily activities’, respectively. all of patients had impairment in the domain of ‘symptoms and feelings’ and the impairment percent of other domains were close to each other. in a study, it was reported that ‘symptoms and feelings’, ‘work and school’ and ‘personal relationships’ had the most impact on patients [5]. in another study, the major domains affected in adults were ‘work’ and ‘feelings’ [7]. our findings were comparable to these results in the literature. in our study, there was no difference between the gender and educational status, and the dlqi score but the total dlqi scores were higher in young adults (p = 0.06) also, most of the patients of our study population was the young adults (76.5%). in a study, it was reported that ‘feeling of shame’ significantly more often reported by female adults as compared with males[8]. in another study, the impact on table 4. the spearman rank correlation coefficients (rs) for the total dlqi scores, dlqi effect severity, bds and bas. total dlqi dlqi severity bds bas rs p rs p rs p rs p disease duration 0.280 0.010 0.287 0.008 0.201 0.084 0.05 0.963 time to diagnosis 0.098 0.378 0.159 0.150 0.122 0.297 0.026 0.824 number of treatments 0.223 0.042 0.203 0.066 0.095 0.417 0.07 0.551 bas = beck anxiety scale; bds = beck depression scale; dlqi = dermatology life quality index. 6 original article | dermatol pract concept. 2023;13(2):e2023144 ta b le 5 . t h e co m p ar is o n o f th e b d s an d b a s sc o re s o f p at ie n ts w it h a n d w it h o u t im p ai rm en t fo r ea ch d l q i d o m ai n . d o m a in 2 d o m a in 3 d o m a in 4 d o m a in 5 d o m a in 6 a ff e ct e d n o n a ff e ct e d p a ff e ct e d n o n a ff e ct e d p a ff e ct e d n o n a ff e ct e d p a ff e ct e d n o n a ff e ct e d p a ff e ct e d n o n a ff e ct e d p b d s sc o re , m ea n ± s d 1 4 .1 2 ± 9 .2 2 8 .3 1 ± 9 .0 6 0 .0 3 1 3 .4 4 ± 9 .3 2 1 0 .3 3 ± 9 .4 9 0 .0 5 1 1 4 .1 0 ± 9 .5 6 7 .9 6 ± 8 .5 6 0 .0 0 2 1 3 .7 7 ± 9 .6 0 9 .0 8 ± 9 .1 0 0 .0 1 7 1 3 .9 5 ± 9 .5 2 1 0 .0 0 ± 9 .4 6 0 .0 3 3 b a s sc o re , m ea n ± s d 1 0 .9 8 ± 9 .8 8 4 .4 8 ± 6 .8 5 0 .0 0 0 1 0 .1 9 ± 9 .3 1 5 .6 ± 7 .0 9 0 .0 0 1 9 .8 6 ± 9 .3 5 4 .9 1 ± 6 .0 5 0 .0 1 9 .5 2 ± 9 .4 1 5 .9 6 ± 6 .7 7 0 .0 8 2 9 .6 5 ± 9 .6 1 6 .6 7 ± 7 .3 1 0 .0 6 b a s = b ec k a n x ie ty s ca le ; b d s = b ec k d ep re ss io n s ca le ; d l q i = d er m at o lo gy l if e q u al it y in d ex ; sd = s ta n d ar d d ev ia ti o n . original article | dermatol pract concept. 2023;13(2):e2023144 7 6. karimkhani c, colombara d v., drucker am, et al. the global burden of scabies: a cross-sectional analysis from the global burden of disease study 2015. lancet infect dis. 2017;17(12): 1247-1254. doi:10.1016/s1473-3099(17)30483-8 7. ashok nair pa, vora rv, jivani nb, gandhi ss. a study of clinical profile and quality of life in patients with scabies at a rural tertiary care centre. j clin diagn res. 2016;10(10):wc01-wc05. doi:10.7860/jcdr/2016/20938.8703 8. worth c, heukelbach j, fengler g, walter b, liesenfeld o, feldmeier h. impaired quality of life in adults and children with scabies from an impoverished community in brazil. int j dermatol. 2012;51(3):275-282. doi:10.1111/j.1365-4632.2011.05017.x 9. lake sj, engelman d, sokana o, et al. health-related quality of life impact of scabies in the solomon islands. trans r soc trop med hyg. 2022;116(2):148-156. doi:10.1093/trstmh /trab096 10. engelman d, yoshizumi j, hay rj, et al. the 2020 international alliance for the control of scabies consensus criteria for the diagnosis of scabies. br j dermatol. 2020;183(5):808-820. doi:10.1111/bjd.18943 11. salavastru cm, chosidow o, boffa mj, janier m, tiplica gs. european guideline for the management of scabies. j eur acad dermatol venereol. 2017;31(8):1248-1253. doi:10.1111/jdv.14351 12. öztürkcan s, ermertcan at, eser e, turhan şahin m. cross validation of the turkish version of dermatology life quality index. int j dermatol. 2006;45(11):1300-1307. doi:10.1111 /j.1365-4632.2006.02881.x 13. beck at, ward ch, mendelson m, mock j, erbaugh j. an inventory for measuring depression. arch gen psychiatry. 1961;4(6):561-571. doi:10.1001/archpsyc.1961.01710120031004 14. hisli n. a study on the validity of beck depression inventory. j psychol (psikoloji dergisi) . 1988;6:118-122. 15. beck at, epstein n, brown g, steer ra. an inventory for measuring clinical anxiety: psychometric properties. j consult clin psychol. 1988;56(6):893-897. doi:10.1037//0022-006x.56.6.893 16. ulusoy m, hisli-sahin n, erkmen h. turkish version of the beck anxiety inventory: psychometric properties. journal of cognitive psychotherapy . 1998;12(2):163-undefined. 17. redondo-bravo l, fernandez-martinez b, gómezbarroso  d, et al. scabies in spain? a comprehensive epidemiological picture. plos one. 2021;16(11). doi:10.1371/journal. pone.0258780 18. lugović-mihić l. the increase in croatia’s scabies incidence: how did refugees and traveling contribute? travel med infect dis. 2019;29:74. doi:10.1016/j.tmaid.2019.02.002 19. sunderkötter c, aebischer a, neufeld m, et al. increase of scabies in germany and development of resistant mites? evidence and consequences. j dtsch dermatol ges. 2019;17(1):15-23. doi:10.1111/ddg.13706 20. turan ç, metin n, utlu z. epidemiological evaluation of scabies cases encountered in the last three years as a tertiary health center. turkiye parazitol derg. 2020;44(2):77-82. doi:10.4274 /tpd.galenos.2020.6796 21. khalil s, abbas o, kibbi ag, kurban m. scabies in the age of increasing drug resistance. plos negl trop dis. 2017;11(11). doi:10.1371/journal.pntd.0005920 22. de sainte marie b, mallet s, gaudy-marqueste c, et al. [therapeutic failure in scabies: an observational study]. ann dermatol venereol. 2016;143(1):9-15. doi:10.1016/j .annder.2015.10.588 our study were lower. we did not find any correlation between the duration of the disease and the number of treatment with bds and bas but we found a positive correlation between bds and bas with total dlqi. nearly, all of patients with impairment in each dlqi domain had higher scores of bas and bds except for bds in domain 3 and for bas in domain 5 and 6. these findings may be due to the chronicity of the pruritus, given the mean disease duration of patients in our study. it was demonstrated that chronic pruritus were associated with depression and anxiety [26,31]. these findings made us think that scabies, which affects qol negatively like other chronic dermatologic diseases, may also have negative effects on depressiveness and anxiety, and may have effects beyond being a contagious skin disease. the limitations of our study are the relatively small number of patients, lack of a control group, being not grouped the patients according to the clinical severity of scabies. also, we did not follow up the patients after the treatment response and could not compared the dlqi, bds and bas before and after treatment. as a conclusion, scabies is a common dermatological problem in our daily routines and the factors such as the disease duration, the necessity of repeating treatment protocols, itching severity and contagiousness may complicate the management of the disease. scabies has a moderate to severe impact on patients qol, and as with chronic skin diseases, depression and anxiety scores increase as quality of life impairment. in this setting, scabies is an important health problem and it should be kept in mind that patients diagnosed with scabies are affected not only clinically but also emotionally, and they can be consulted to psychiatry departments when necessary. references 1. vos t, abajobir aa, abbafati c, et al. global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study 2016. lancet. 2017;390(10100):1211-1259. doi:10.1016/ s0140-6736(17)32154-2 2. cox v, fuller lc, engelman d, steer a, hay rj. estimating the global burden of scabies: what else do we need? br j dermatol. 2021;184(2):237-242. doi:10.1111/bjd.19170 3. collinson s, timothy j, zayzay sk, et al. the prevalence of scabies in monrovia, liberia: a population-based survey. plos negl trop dis. 2020;14(12):e0008943. doi:10.1371/journal. pntd.0008943 4. özden mg, ertürk k, kartal sp, et al. an extraordinary outbreak of scabies in turkey. j eur acad dermatol venereol. 2020;34(12):e818-e820. doi:10.1111/jdv.16699 5. jin-gang a, sheng-xiang x, sheng-bin x, et al. quality of life of patients with scabies. j eur acad dermatol venereol. 2010;24(10): 1187-1191. doi:10.1111/j.1468-3083.2010.03618.x 8 original article | dermatol pract concept. 2023;13(2):e2023144 28. misery l, touboul s, vinçot c, et al. [stress and seborrheic dermatitis]. ann dermatol venereol. 2007;134(11):833-837. doi:10.1016/s0151-9638(07)92826-4 29. taner e, coşar b, burhanoǧlu s, çalikoǧlu e, önder m, arikan z. depression and anxiety in patients with behçet’s disease compared with that in patients with psoriasis. int j dermatol. 2007;46(11):11181124. doi:10.1111/j.1365-4632.2007.03247.x 30. engin b, uguz f, yilmaz e, özdemir m, mevlitoglu i. the levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria. journal of the european academy of dermatology and venereology. 2008;22(1):36-40. doi:10.1111/j.1468-3083.2007.02324.x 31. cole ef, ojeaga a, chen s, swerlick ra. symptoms of depression and anxiety are associated with poorer functional outcomes in chronic pruritus. j am acad dermatol. 2021;85(3):730-731. doi:10.1016/j.jaad.2019.06.031 23. mazzatenta c, piccolo v, argenziano g, bassi a. is scabies becoming less sensitive to permethrin therapy? j eur acad dermatol venereol. 2021;35(9):e607-e609. doi:10.1111/jdv.17339 24. akoglu g, yildiz i, karaismailoğlu e, esme p. disease severity and poor mental health are the main predictors of stigmatization in patients with hidradenitis suppurativa. dermatol ther. 2021;34(3). doi:10.1111/dth.14910 25. talamonti m, galluzzo m, silvaggio d, lombardo p, tartaglia c, bianchi l. quality of life and psychological impact in patients with atopic dermatitis. j clin med. 2021;10(6):1-9. doi:10.3390/jcm10061298 26. lee j, suh h, jung h, park m, ahn j. association between chronic pruritus, depression, and insomnia: a cross-sectional study. jaad int. 2021;3:54-60. doi:10.1016/j.jdin.2021.02.004 27. pietrzak d, pietrzak a, krasowska d, et al. depressiveness, measured with beck depression inventory, in patients with psoriasis. j affect disord. 2017;209:229-234. doi:10.1016/j .jad.2016.11.045 dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):10 51 dermatology practical & conceptual www.derm101.com cases two women in their fifties presented with a bleeding lesion on their nose. at clinical examination, they presented as small pink papules; one was soft and one was firm on palpation. polarized dermoscopy revealed a structureless whitish-pink background in both lesions, and an erosion was present in one case (figure 1a). due to the curvature of the face, a handheld reflectance confocal microscope (vivascope 3000, caliber i.d., rochester, ny) was used. an adhesive paper ring was placed surrounding the lesion to guide rcm navigation [1]. the indication for rcm was to exclude bcc due to occasional bleeding. other differential diagnoses included irritated angiofibroma, intradermal nevus, and adnexal neoplasm. reflectance confocal microscopy (rcm) showed a regular epidermal honeycombed pattern with bcc-like structures identified at the dermal-epidermal junction and papillary dermis (figure 1c). these structures varied in size and shape and had increased cellular density compared to hair follicles. many had clefting (dark signal-void region) around them. in the papillary dermis, abundant thick collagen bundles were identified mainly around hair follicles (figure 1c). additionreflectance confocal microscopy features of facial angiofibromas josé-francisco millán-cayetano1, oriol yélamos2,3, anthony m. rossi2, michael a. marchetti2, manu jain2 1 dermatology department, hospital costa del sol, marbella, spain 2 dermatology service, department of medicine, memorial sloan kettering cancer center, new york, usa 3 dermatology department, hospital clinic, universitat de barcelona, barcelona, spain key words: reflectance confocal microscopy, angiofibroma, fibrous papule, basal cell carcinoma citation: millán-cayetano j-f, yélamos o, rossi am, marchetti ma, jain m. reflectance confocal microscopy features of facial angiofibromas. dermatol pract concept. 2017;7(1):10. doi: https://doi.org/10.5826/dpc.0701a10 received: november 16, 2016; accepted: november 26, 2016; published: january 31, 2017 copyright: ©2017 millán-cayetano et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part through the nih/nci cancer center support grant p 30 ca008748 and the beca excelencia fundación piel sana. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: manu jain, md, dermatology service, department of medicine, memorial sloan-kettering cancer center, 16 east 60th street, new york, ny, usa. tel. +1 646 888 6109. email: jainm@mskcc.org facial angiofibromas are benign tumors presenting as firm, dome-shaped, flesh-colored to pink papules, typically on the nose and adjoining central face. clinically and dermoscopically they can mimic melanocytic nevi or basal cell carcinomas (bcc). reflectance confocal microscopy (rcm) is a noninvasive imaging tool that is useful in diagnosing melanocytic and non-melanocytic facial lesions. to date no studies have described the rcm features of facial angiofibromas. herein, we present two cases of facial angiofibromas that were imaged with rcm and revealed tumor island-like structures that mimicked bcc, leading to skin biopsy. abstract 52 observation | dermatol pract concept 2017;7(1):10 figure 1. clinical image of an irritated angiofibroma located on the nose (panel a) showing a superficial erosion and a whitish-reddish background on dermoscopy (arrow, inset). corresponding hematoxylin and eosin stained histology (panel b; 20x) of angiofibroma showing dilated vessels (arrows), and abundant thick collagen bundles surrounding hair follicles (asterisks) and inflammatory cells (histiocytes and lymphocytes) in the stroma. the area encircled in panel b shows the superficial portion of external root sheath of hair follicle surrounded by thickened collagen (asterisks), which could have been the source of bcc-like nodular structures. rcm images of angiofibroma (panels c and d; ~0.75 mm x 0.75 mm) taken at dermoepidermal junction (corresponding to the level of black dashed line on panel b) shows bcc-like nodular structures with clefting but no palisading (yellow arrowheads, panel c), thick collagen bundles surrounding hair follicles (asterisks, panel c), horizontal linear vessels (arrow, panel c), numerous vertical round vessels (circles, panels c and d), and numerous small bright cells and angulated cells corresponding to lymphocytes and histiocytes, respectively (yellow rectangle, panel d). conversely, rcm images of basal cell carcinoma (panels e and f; ~0.75 mm x 0.75 mm; taken from a separate case) show tumor nodules with clefting and palisading (red arrowheads, panel e), horizontal canalicular vessels (red arrows, panel e), and an inflammatory stroma with numerous small bright cells (red rectangle, panel f) and plump bright cells (red ellipse, panel f). [copyright: ©2017 millán-cayetano et al.] a b c d e f observation | dermatol pract concept 2017;7(1):10 53 bromas that are diagnostically challenging. favia et al have previously described the ex vivo confocal findings of a gingival angiofibroma in a patient with tuberous sclerosis [5]. they reported the presence of variably sized vessels with dilated lumina and collagen fibers with random orientation [5]. in our cases, we found structures mimicking bcc due to increased cellular density and clefting. however, unlike bcc, peripheral palisading (figure 1e) was absent. using vertical stacks (going from the dermis to the epidermis) we identified continuation between some bcc-like structures and hair follicles. further, the stroma of angiofibromas lacked typical bcc features such as gossamer collagen, numerous horizontal vessels with leukocyte trafficking, and melanophages (figure 1f). ally, numerous small round (vertical) to linear and canalicular (horizontal) dilated blood vessels were seen (figure 1c and d), as well as small bright round cells (inflammatory cells) and angulated bright cells (figure 1d). large plump cells (melanophages) and palisading were not identified. these findings were correlated with histopathology (table 1). conclusions facial angiofibromas can sometimes mimic melanocytic nevi or basal cell carcinomas (bcc) under clinical and dermoscopic evaluation [2]. reflectance confocal microscopy is useful in diagnosing melanocytic and non-melanocytic facial lesions [3,4] and can be helpful in diagnosing facial angiofitable 1. reflectance confocal microscopy features observed in angiofibromas, comparing to those observed in bcc and histopathological correlation. reflectance confocal microscopy angiofibroma basal cell carcinoma reflectance confocal microscopy histopathology reflectance confocal microscopy histopathology epidermis • normal epidermis with regular honeycomb pattern • normal epidermis • epidermal streaming • variable epidermal disarray • keratinocytes focally elongated along the same axis • variable epidermal pleomorphism dej and superficial dermis aggregates • nodules with increased cellular density and occasional clefting (bcclike structures) • epidermal invagination in the papillary dermis or superficial portion of external root sheath of hair follicle • tumor islands • cordlike structures with palisading • clefting • dark silhouettes • tumor nodules comprised of atypical basaloid cells with peripheral palisading • cords of atypical basaloid cells • peritumoral mucin/clefting • aggregates of tumor cells vascularization • small round to linear and canalicular vessels • increased vascularization with variablysized dilated blood vessels • horizontal “enface” canalicular vessels with leukocyte rolling/trafficking • prominent, dilated and enlarged blood vessels collagen • thickened collagen bundles surrounding hair follicles and bcclike structures • thickened collagen bundles arranged around hair follicles • gossamer like stroma wrapping around tumor islands • myxoid stroma wrapping around tumor nodules stroma • small bright round cells • lymphocytes • numerous large plump cells • dendritic cells • small bright round cells • melanophages • langerhans cells • melanocytes • lymphocytes abbreviations: dej, dermal-epidermal junction; bcc, basal cell carcinoma 54 observation | dermatol pract concept 2017;7(1):10 with handheld reflectance confocal microscope. skin res technol. 2016;22:519-520. 2. de cambourg g, cribier b. [fibrous papules of the face: a retrospective anatomoclinical study of 283 cases]. ann dermatol venereol. 2013;140(12):763-770. 3. longo c, moscarella e, argenziano g, et al. reflectance confocal microscopy in the diagnosis of solitary pink skin tumours: review of diagnostic clues. br j dermatol. 2015;173(1):31-41. 4. fraga-braghiroli na, stephens a, grossman d, rabinovitz h, castro rp, scope a. use of handheld reflectance confocal microscopy for in vivo diagnosis of solitary facial papules: a case series. j eur acad dermatol venereol. 2014;28(7):933-942. 5. favia g, tempesta a, limongelli l, maiorano e. tuberous sclerosis: histological analysis with confocal laser scanning microscope of gingival angiofibromatosis. pathologica. 2015;107(3-4):197-200. 6. kraft s, granter s. fibrous and fibrohistiocytic tumors. in: barnhill r, crowson a, magro c, piepkorn m, eds. dermatopathology. 3rd ed. new york: mcgraw-hill; 2010:766-801. 7. misago n, kimura t, narisawa y. fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and immunohistochemical features. j cutan pathol. 2009;36(9):943-951. histologically, angiofibromas are dermal proliferations containing dilated vessels, fibrosis surrounding hair follicles, stellate fibrocytes and distorted hair follicles (figure 1b) [6,7]. we speculate that the bcc-like structures on rcm represent the base of a rete ridge, a portion of a hair follicle or another adnexal structure that due to the intense perifollicular collagen proliferation could show clefting. we also identified angulated large bright cells, which appeared smaller than melanophages and could correspond to stellate/ spindled fibrocytes [7]. the density of inflammatory cells (bright small round cells) could have been a result of irritation. a comparison between the rcm and histologic features present in our angiofibroma cases and the bcc features are summarized in table 1. references 1. marino ml, rogers t, sierra gil h, rajadhyaksha m, cordova ma, marghoob aa. improving lesion localization when imaging dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023092 1 the histopathologic evaluation of diagnostic procedures in nail melanoma emi dika1,2, michela starace1,2, aurora alessandrini1,2, annalisa patrizi1,2, carlotta baraldi1,2, cosimo misciali1,2, pier alessandro fanti1,2, anna waśkiel-burnat2,3, lidia rudnicka2, bianca maria piraccini1,2 1 dermatology unit, irccs azienda ospedaliero-universitaria di bologna 2 department of medical and surgical sciences, alma mater studiorum university of bologna, bologna, italy 3 department of dermatology, medical university of warsaw, warsaw, poland key words: nail melanoma, subungual melanoma, pathology, surgical excision, biopsy citation: dika e, starace m, alessandrini a, et al. the histopathologic evaluation of diagnostic procedures in nail melanoma. dermatol pract concept. 2023;13(2):e2023092. doi: https://doi.org/10.5826/dpc.1302a92 accepted: september 25, 2022; published: april 2023 copyright: ©2023 dika et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: michela starace, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138, bologna, italy. tel +39051-6364867; fax +39-0516364867; e-mail:michela.starace2@unibo.it introduction: the diagnostic delay in nail melanoma (nm) has been repeatedly emphasized. it may be related to both clinical misinterpretations and to errors in the bioptic procedure. objectives: to assess the efficacy of histopathologic examination in different diagnostic biopsies in nm. methods: we retrospectively investigated the diagnostic procedures and histopathologic specimens referred to the laboratory of dermatopathology for the clinical suspicion of nm from january 2006 to january 2016. results: eighty-six nail histopathologic specimens were analyzed consisting in 60 longitudinal, 23 punch and 3 tangential biopsies. a diagnosis of nm was performed in 20 cases, benign melanocytic activation in 51 cases and melanocytic nevi in 15 patients. longitudinal and tangential biopsy were diagnostic in all cases, regardless of the clinical suspicion. nail matrix punch biopsy instead was not diagnostic in most of the cases (13/23 specimens). conclusions: in the presence of an nm clinical suspicion, longitudinal biopsy is recommended (lateral or median) because it provides exhaustive information on the characteristics of melanocytes morphology and distribution in all the components of the nail unit. tangential biopsy, recently encouraged by expert authors due to the optimal surgical outcome, in our experience gives incomplete information on tumor extension. punch matrix biopsy gives limited evidence in the diagnosis of nm. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023092 introduction nail melanoma (nm) prevalence in caucasians is estimated to range from 0.3 to 2.8 % of all melanomas. nm clinical presentation may be heterogeneous, and misdiagnoses are frequent [1-8]. the most frequent clinical misdiagnoses of nm are benign inflammatory diseases or benign neoplasms that cause nail plate pigmentation. non-pigmented nm, also called amelanotic nm could be difficult to differentiate from squamous cell carcinoma of the nail (nscc) or other conditions. misdiagnoses in nm may be also due to inappropriate surgical sampling and subsequent difficulties in the interpretation of histopathologic specimens. because of the particular anatomic location and the scarce number of cases in caucasians, in the clinical suspicion of nm, no absolute consensus exists regarding the optimal diagnostic procedures. bioptic techniques have been adequately described by nail experts [9-23], but the two main problems in the correct choice and performance of the biopsy are probably related to the difficulty in performing surgery in the nail unit (insufficient familiarity with nail apparatus anatomy among dermatologic surgeons) and the risk of permanent nail dystrophy when an excessive amount of nail matrix is excised. objectives the aim of the study was to assess the efficacy of histopathologic examination in different diagnostic biopsies in nm. methods we retrospectively investigated the diagnostic procedures administered in patients referring for a clinical suspicion of nm. histopathologic data were obtained from the archive of dermatopathology, university of bologna, from january 2006 to january 2016. since our laboratory is a referral center for nail pathology, specimens are prevenient from our institution, but also from other centers or private practices. the key words for the database search were: “melanocytic activation”, “melanocytic hyperplasia”, “melanoma” and “nevi”. the histopathologic charts containing the selected key words were reviewed for the following: 1) clinical query 2) the type of biopsy, and 3) histopathologic diagnosis. the type of bioptic procedures assessed were: 1) punch biopsy (pb) 2) longitudinal biopsy (lb) considering both types lateral and median, and 3) tangential biopsy (tb). transverse matrix biopsy was not considered among the evaluated procedures since it is not widely used in the surgical practice in our institution and no cases were referred in our laboratory (9). finally, the appropriateness of the bioptic procedures was evaluated in correlation to the final histopathologic responses. all nm histopathologic specimens were assessed by two dermatopathologists (paf and cm) respecting the american joint committee on cancer (ajcc) guidelines [24]. results eight-six cases were selected (54 females/32 males). demographic data are presented in table 1. the most frequent queries from clinicians (first endpoint) were nm in 55 patients (64%); followed by nm versus melanocytic nevus in 9 cases (10%) and nm versus friction/ post-traumatic melanonychia in 22 patients (26%). the second endpoint of the study was the evaluation of the bioptic procedures: a. lb was performed in 60 patients; b. a 3 or 4 mm pb was performed in 23 cases; c. a tb was performed in 3 cases. table 1. patients, clinical presentation and diagnostic procedures of the nail unit. diagnosis (cases) gender (female/ male) age in years (median) site (hands/ feet) clinical presentation bioptic procedure total (86) 54/32 46 56/27 81 melanonychia/ 5 nodular neoplasms 60 longitudinal biopsy/ 23 punch biopsy/ 3 tangential biopsy nail melanoma (20) 14/6 61 14/3 16 longitudinal melanonychia/ 4 nodular neoplasms 12 longitudinal biopsy/ 5 punch biopsy/ 3 tangential biopsy benign melanocytic activation (51) 33/18 52 32/19 50 nail pigmentation/ 1 nodular mass of the nail bed 34 longitudinal biopsy/ 17 punch biopsy nevus (15) 8 / 7 25 10 / 3 15 nail pigmentations 14 longitudinal biopsy/ 1 punch biopsy original article | dermatol pract concept. 2023;13(2):e2023092 3 on histopathologic evaluation a diagnosis of nm was performed in 20 cases, benign melanocytic activation in 51 patients and melanocytic nevi in 15 cases, respectively. regarding the final endpoint of the study, on the appropriateness of the bioptic procedure: a. 12/20 patients affected by nm had undergone a lb; 5/20 a pb and 3/20 a tb. lb was diagnostic in all cases. pb was diagnostic only in 2/5 of melanoma cases. in both diagnosed cases of nm, pb was performed at the level of nail matrix. in the remaining 3 cases (in all them, pb was performed at the nail bad), dermatopathologists had requested clinical patient re-evaluation and a second lb was performed in 2 cases and en-block tumor excision in 1 case (the clinical features were strongly suggestive of nm). the histopathologic interpretation of tb was consistent with the diagnosis of melanoma in all the 3 cases. b. a lb was diagnostic in 34/51 cases that were finally diagnosed with benign melanocytic activation and in the remaining 17 cases a pb was performed. pb was not diagnostic in 10/17 cases, all performed at the nail bed level. a second biopsy was requested in all cases together with a clinical re-evaluation. the remaining 7  cases of pb were diagnostic and were performed at the nail matrix level. c. a lb was performed in 14/15 cases that were diagnosed as melanocytic nevi and a pb at the nail matrix level was performed in 1/15 cases. all cases were correctly diagnosed. all nm patients underwent therapeutic surgery (conservative approach or phalanx disarticulation) and are still undergoing regular clinical and instrumental controls. patients with a different diagnosis (nevi or benign melanocytic activation) are undergoing clinical follow up where necessary. conclusions misdiagnoses of nm are continuously reported in the scientific literature [25,26]. the most common clinical presentation of nm is longitudinal melanonychia, which is a brown to black band of the nail plate, starting from the proximal nail fold and extending to the distal margin of the nail. nail plate pigmentation is due to melanin granules incorporated in the nail plate during the process of nail matrix keratinization. in nm, both melanin granules and atypical (pagetoid) melanocytes (figure 1, a and b) can be observed (authors experience). the process of keratinization in the nail unit is an evolving process. it initiates at the nail matrix level and is deduced clinically with the expansion of the plate. melanocytes are present among matrix keratinocytes, but they are usually quiescent and not produce pigment. melanin synthesis may occur in benign and malignant conditions, and it is characterized by incorporation of melanin in nail matrix keratinocytes during nail plate production. the pigmentation therefore initially starts in the proximal nail plate and occupies the whole length of it during growth. this process is estimated to last from 4-6 to 10-12 months (hands and feet). when we observe a pigmented band, we therefore only see the degree and distribution of melanin within the nail plate and not the site of origin of it, as the matrix lies below the proximal nail folds and only its distal part, the lunula, is visible from the outside. both technicians and dermatopathologists should be familiar with the nail anatomy to achieve an optimal processing of the specimens and to avoid diagnostic misinterpretations. but, most important, the surgeon should know that a biopsy of melanonychia should excise the nail matrix, which is the source of the pigmentation. in the present study, two main issues were considered on the suspicion of nm: 1) where to biopsy and 2) which type of biopsy offers the best diagnostic approach. figure 1. (a, b) nail melanoma: histopathologic aspects of a nail matrix biopsy (h&e original magnification 10x; 25x) showing proliferation of atypical melanocytes in the basal and supra-basal layers of the nail matrix. 4 original article | dermatol pract concept. 2023;13(2):e2023092 information on the characteristics of melanocytes morphology and distribution in all the components of the nail unit. references 1. quinn mj, thompson je, crotty k, mccarthy wh, coates as. subungual melanoma of the hand. j hand surg am. 1996;21(3):506–511. doi: 10.1016/s0363-5023(96)80371-6. pmid: 8724488. 2. banfield cc, redburn jc, dawber rp. the incidence and prognosis of nail apparatus melanoma. a retrospective study of 105 patients in four english regions. br j dermatol. 1998;139(2):276– 279. doi:10.1046/j.1365-2133.1998.02365.x. pmid: 9767242. 3. blessing k, kernohan nm, park kg. subungual malignant melanoma: clinicopathological features of 100 cases. histopathology. 1991;19(5):425–429. doi: 10.1111/j.1365-2559.1991. tb00232.x. pmid: 1757081. 4. dika e, patrizi a, fanti pa, et al. the prognosis of nail apparatus melanoma: 20 years of experience from a single institute. dermatology. 2016;232(2):177-184. doi: 10.1159/000441293. pmid: 26771575. 5. dika e, piraccini bm, fanti pa. a gray pigmented band of the third fingernail with distal splitting. jama dermatol. 2014;150(2):199-200. doi: 10.1001/jamadermatol.2013.5731. pmid: 24337039. 6. boyer a. fungus hematode de petit doights. gaz med par. 1834;2:212. 7. hutchinson j. melanosis often not black: melanotic whitlow. br med j. 1886;1:491. 8. piraccini bm, dika e, fanti pa. tips for diagnosis and treatment of nail pigmentation with practical algorithm. dermatol clin. 2015;33(2):185-195. doi: 10.1016/j.det.2014.12.002. pmid: 25828711. 9. braun pr, baran r, le gal af, et al. diagnosis and management of nail pigmentations. j am acad dermatol. 2007;56(5):835-847. doi: 10.1016/j.jaad.2006.12.021. pmid: 17320240. 10. haneke e, baran r. longitudinal melanonychia. dermatol surg. 2001;27(6):580-584. pmid: 11442597. 11. baran r, haneke e. diagnose und behandlung von longitudinalen nagel pigmentierungen. hautarzt. 1984;35:359-365. 12. baran r, kechijian p. longitudinal melanonychia (melanonychia striata): diagnosis and management. j am acad dermatol. 1989;21(6):1165-1175. doi: 10.1016/s0190-9622(89)70324-8. pmid: 2685057. in the nail unit, biopsies can be performed on four main locations: the nail folds, bed, plate and matrix. in physiologic conditions, most melanocytes are located at the nail matrix level, while very few or no melanocytes can be observed at the nail bed [27]. benign conditions that correlate to melanocytic activation (51 cases herein analyzed), show that the pigmentation of the nail plate is mainly due to distal matrix activated melanocytes, whereas melanocytes at the nail bed are almost absent (figure 2, a and b). regarding the correct choice and execution of the bioptic procedure and its correlation to the definitive diagnosis, we can state, that in our experience, in the presence of a nm clinical suspicion, a longitudinal biopsy is recommended in all cases of nail pigmentation (lateral or median). in our survey, lb offered the correct diagnosis in 60/ 60 cases while pb was diagnostic in 10/23 patients. on lb, correct information is obtained regarding melanocytes morphology and distribution through the nail matrix, nail bed and hyponychium. a pb of the nail matrix is correctly performed for pigmented bands, in the clinical suspicion of a benign melanocytic activation (patients history of drug assumption, ethnicity). nail bed biopsy should be avoided since it can often lead to misdiagnoses of nm. in our experience, a tb, recently encouraged by expert authors due to the optimal surgical outcome (less dystrophy of the nail plate), gives incomplete information on tumor extension [23]. in the present study, the final determination of breslow thickness after en bloc excision of the nail unit was evaluated as difficult and imprecise by histopathologists (during the first tb a major portion of the distal matrix was excised in all three cases). breslow thickness evaluation could be an issue of concern since it represents one of the most important predictive factors when dealing with nm. we believe tb could be proposed to highly collaborative and compliant patients after adequate explanations. a limitation of this study was the retrospective evaluation of cases. in conclusion, in the presence of an nm clinical suspicion, lb is recommended because it provides exhaustive figure 2. (a, b) benign melanocytic activation: histopathologic aspects of a longitudinal nail biopsy (h&e original magnification 20x; 25x) showing proliferation of melanocytes in the nail matrix and nail bed. original article | dermatol pract concept. 2023;13(2):e2023092 5 13. rich p. nail biopsy. indications and methods. j dermatol surg oncol. 1992;18(8):673-682. doi: 10.1111/j.1524-4725.1992. tb02000.x. pmid: 1307222. 14. jellinek n. nail biopsy. indications and methods. j am acad dermatol. 2007;56(5):803-810. doi: 10.1111/j.1524-4725.1992. tb02000.x. pmid: 1307222. 15. banfield cc, dawber rp. nail melanoma: a review of the literature with recommendations to improve patient management. br j dermatol. 1999;141(4):628-632. doi: 10.1046/j.13652133.1999.03099.x. pmid: 10583108. 16. glat pm, shapiro rl, roses df, harris mn, grossman ja. management considerations for melanonychia striata and melanoma of the hand. hand clin. 1995;11:183-189. 17. ruben bs. pigmented lesions of the nail unit. semin cutan med surg. 2015 jun;34(2):101-108. doi: 10.12788/j.sder.2015.0146. pmid: 26176288. 18. jellinek nj, vélez nf. dermatologic manifestations of the lower extremity: nail surgery. clin podiatr med surg. 2016;33(3):319-336. doi: 10.1016/j.cpm.2016.02.002. pmid: 27215154. 19. vélez nf, jellinek nj. nailing it: promoting nail procedural training in residency and beyond. dermatol surg. 2015;41(3):424-426. doi: 10.1097/dss.0000000000000295. pmid: 25705945. 20. jellinek nj, rubin ai. lateral longitudinal excision of the nail unit. dermatol surg. 2011;37(12):1781-1785. doi: 10.1111/j.1524-4725.2011.02167.x. pmid: 22093115. 21. jellinek n. nail matrix biopsy of longitudinal melanonychia: diagnostic algorithm including the matrix shave biopsy. j am acad dermatol. 2007;56(5):803-810. doi: 10.1016/j. jaad.2006.12.001. pmid: 17437887 22. cogrel o, haneke e. tangential excision for a longitudinal melanonychia. ann dermatol venereol. 2015;142(6-7):450-451. doi: 10.1016/j.annder.2015.04.012. pmid: 25979755. 23. di chiacchio n, loureiro wr, michalany ns, kezam gabriel fv. tangential biopsy thickness versus lesion depth in longitudinal melanonychia: a pilot study. dermatol res pract. 2012;2012:353864. doi: 10.1155/2012/353864. pmid: 22496683. pmcid: pmc3312251 24. balch cm, gershenwald je, soong sj, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199-6206. doi: 10.1200/jco.2009.23.4799. pmid: 19917835. pmcid: pmc2793035. 25. levit ek, kagen mh, scher rk, grossman m, altman e. the abc rule for clinical detection of subungual melanoma. j am acad dermatol. 2000;42(2): 269–274. doi: 10.1016/s01909622(00)90137-3. pmid: 10642684. 26. metzger s, ellwanger u, stroebel w, et al. extent and consequences of physician delay in the diagnosis of acral melanoma. melanoma res. 1998;8(2):181–186. doi: 10.1097/00008390199804000-00014. pmid: 9610874. 27. kazi r, moghaddam s, chu p, marghoob a. a histologic evidence of melanocytes isolated to the nail matrix. jama dermatol. 2016;152(5):573–575. doi:10.1001/jamadermatol.2015.5869. pmid: 26865087. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023069 1 dermoscopic features of schwannoma dong hyo kim1, je-ho mun1 1 department of dermatology, seoul national university college of medicine, seoul, korea key words: dermoscopy, dermatoscopy, diagnosis, schwannoma, skin neoplasms citation: kim dh, mun jh. dermoscopic features of schwannoma. dermatol pract concept. 2023;13(2):e2023069. doi: https://doi. org/10.5826/dpc.1302a69 accepted: july 11, 2022; published: april 2023 copyright: ©2023 kim et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: je-ho mun, md, phd, department of dermatology, seoul national university college of medicine, 101, daehak-ro, jongno-gu, seoul 03080, korea. telephone: +82-2-2072-3274, fax: +82-2-742-7344, e-mail: jehomun@gmail.com introduction schwannomas present as ill-defined soft tissue masses that are painful in one-third of cases [1]. clinical diagnosis based on morphologic patterns alone is often difficult. it requires differentiation from other dermal or subcutaneous tumors, including neurofibroma, intradermal nevus, epidermal cyst, lipoma, and basal cell carcinoma [2]. dermoscopy is a useful non-invasive diagnostic tool in differentiating various benign and malignant skin tumors. however, the dermoscopic features of schwannomas remain largely unknown. case presentation cases of histopathologically confirmed schwannoma with available clinical and dermoscopic photographs from the department of dermatology, seoul national university hospital from 2016 to 2021 were analyzed. a total of 4 patients (2 males, median age 38.5 [range 30-47] years) were included. all patients presented with palpable dermal or subcutaneous nodules. fifty percent were accompanied with pain or tenderness. two were located on the head and neck, and 2 were located on the upper limb. the primary clinical diagnoses of the patients included ganglion cyst, epidermal cyst, and lipoma. in all 4 patients, tumors were surgically removed. histopathological examination revealed encapsulated spindle cell tumor with characteristic hypercellular and hypocellular areas, which is consistent with schwannoma. polarized dermoscopy in half of the cases revealed a dermoscopic pattern of arborizing vessels with whitish translucent surfaces (table 1 and figure 1). written informed consent for publication of clinical details and clinical images was obtained from the patients. conclusions as schwannomas are usually located in the dermis and subcutaneous layer, dermoscopic findings may not be prominent. nevertheless, in our case series, schwannomas demonstrated arborizing vessels and translucent surfaces on dermoscopy in half of the cases. dermoscopic features of schwannoma have been reported previously in the literature [1,3]. one case report described multiple arborizing vessels and speckled pigmentation on a translucent yellowish surface [1]. these findings are similar to our cases. therefore, we suggest that dermoscopy may help differentiate schwannoma 2 research letter | dermatol pract concept. 2023;13(2):e2023069 from other dermal or subcutaneous tumors in select cases by narrowing down the differential diagnosis. dermoscopic patterns of neurofibromas include peripheral pigmented networks and pink-red structureless areas [4]. epidermal cysts present a distinctive central punctum [5]. dermoscopic patterns of intradermal nevus include pigmented structures such as dots, globules, and comma-like vessels [6]. although basal cell carcinoma presents arborizing vessels, additional features include blue-gray ovoid nests, leaf-like structures, ulceration, multiple small erosions, and spoke-wheel pigmentations [6]. the limitations of our study include its small sample size. in addition, as we excised the tumors with linear incision and extirpation methods, we could not investigate table 1. clinical and dermoscopic findings of four patients with schwannoma. no sex age at first visit duration of disease location clinical features symptoms primary diagnosis dermoscopic features size of excised tissue (cm) 1 m 30 6 months dorsum of right 1st finger 0.5 cm sized palpable dermal or subcutaneous nodule (-) ganglion cyst whitish translucent surface with arborizing vessels 0.8 x 0.6 x 0.4 2 m 32 18 months right shoulder dermal or subcutaneous nodule tenderness epidermal cyst, lipoma whitish translucent surface with arborizing vessels 1.6 x 1.3 x 0.9 3 f 45 unknown left anterior neck palpable dermal or subcutaneous nodule (-) epidermal cyst none 0.5 x 0.5 x 0.4 4 f 47 35 years left occipital scalp 3cm sized dermal or subcutaneous nodule pain lipoma, epidermal cyst none 7.0 x 3.0 x 1.3 m = male; f = female. figure 1. clinical photographs (a,e). dermoscopic image showing a whitish translucent structure with arborizing vessels (b,f). photographs of surgically excised tumors (c,g). a histopathologic study revealed an encapsulated spindle cell tumor with a characteristic hypercellular antoni a area and hypocellular antoni b area. (d,h; h&e; original magnifications: x100). research letter | dermatol pract concept. 2023;13(2):e2023069 3 the association between the location or depth of the tumors and the presence of dermoscopic findings in schwannomas. further studies are warranted to elucidate the dermoscopic patterns of schwannomas. references 1. daulatabad d, pandhi d, tanveer n, sharma s, kaur i. solitary dome-shaped erythematous lump of long duration on the palm. indian j dermatol venereol leprol. 2018;84(4):437-439. doi: 10.4103/ijdvl.ijdvl_845_16. pmid: 29380752. 2. park js, moon j, cho si, mun jh. schwannoma presenting as a scalp mass: a case report with magnetic resonance imaging findings. ann dermatol. 2020;32(1):64-68. doi: 10.5021/ad.2020 .32.1.64. pmid: 33911711. pmcid: pmc7992636. 3. miyamoto k, yanagi t, maeda t, et al. dermoscopic features of haemorrhagic schwannoma. australas j dermatol. 2021;62(2) :e322-e323. doi: 10.1111/ajd.13477. pmid: 33094832. 4. duman n, elmas m. dermoscopy of cutaneous neurofibromas associated with neurofibromatosis type 1. j am acad dermatol. 2015;73(3):529-531. doi: 10.1016/j.jaad.2015.05.021. pmid: 26282805. 5. suh ks, kang dy, park jb, et al. usefulness of dermoscopy in the differential diagnosis of ruptured and unruptured epidermal cysts. ann dermatol. 2017;29(1):33-38. doi: 10.5021 /ad.2017.29.1.33. pmid: 28223744. pmcid: pmc5318524. 6. williams nm, navarrete-dechent c, marghoob aa, abarzua-araya á, salerni g, jaimes n. differentiating basal cell carcinoma from intradermal nevi along the eyelid margin with dermoscopy: a case series. j am acad dermatol. 2021;84(1):173-175. doi: 10.1016/j.jaad.2020.04.059. pmid: 32330634. pmcid: pmc8442835. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023082 1 brooke-spiegler syndrome: age-related progression in a family group andrea michelerio1,2, eloisa arbustini3, camilla vassallo2 1 department of clinical-surgical, diagnostic and pediatric science, university of pavia, pavia, italy 2 dermatology clinic, fondazione irccs policlinico san matteo, pavia, italy 3 centre for inherited diseases, fondazione irccs policlinico san matteo, pavia, italy citation: michelerio a, arbustini e, vassallo c. brooke-spiegler syndrome: age-related progression in a family group. dermatol pract concept. 2023;13(2):e2023082. doi: https://doi.org/10.5826/dpc.1302a82 accepted: july 15, 2022; published: april 2023 copyright: ©2023 michelerio et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrea michelerio, m.d., department of clinical-surgical, diagnostic and pediatric sciences, university of pavia, and dermatology clinic, fondazione irccs policlinico san matteo, pavia, italy. e-mail: andrea.michelerio01@universitadipavia.it case presentation a 56-year-old woman complained about numerous skin-colored papules localized on the face, mostly on the periorbital area, the nasolabial folds and the forehead ( figure 1, a and b). the first lesions had appeared during early adulthood and had slowly grown in number and size during the following years. some had been removed and the histopathological examinations had revealed trichoepitheliomas, cylindromas and an eccrine spiradenomas. the 81-year-old mother of the proband presented numerous nontender, skin-colored nodules and papules, varying in size, especially on her forehead, nasolabial folds, preauricular and occipital areas (figure 1, c and d). the 24-years-old daughter of the proband presented few barely detectable papules on the nasolabial folds (figure 1, e and f). a heterozygous pathogenetic variant (c.2552dup p.his851glnfs*39) in exon 19 of the cyld gene was found in the three women, confirming the diagnosis of brooke-spiegler syndrome (bss). teaching point bss is a rare autosomal dominant inherited syndrome due to germline mutations in the cylindromatosis (cyld) gene, a tumor suppressor gene located on chromosome 16q12–q13. the disease is characterized by multiple adnexal cutaneous neoplasms such as cylindromas, trichoepitheliomas, and spiradenomas [1,2]. these appear as multiple papules or nodules on the head and neck but can also arise on the trunk, genitals and armpits. the neoplasms typically develop at puberty and progressively accumulate through adulthood [1]. they are usually benign but may undergo malignant transformation in about 5%–10% of the patients [1]. rarely salivary gland tumors can be found [1]. the treatment is limited to repeated surgical excisions. 2 image letter | dermatol pract concept. 2023;13(2):e2023082 figure 1. brooke-spiegler syndrome. (a,b) the 56-year-old proband with multiple confluent skin-colored papules located on the face, especially in the periorbital area, in the nasolabial folds and forehead. (c,d) the 81-year-old mother of the proband with multiple discrete and confluent skin-colored papules and nodules. (e,f) the 24-years-old daughter of the proband, few barely detectable papules on the nasolabial folds (arrow). image letter | dermatol pract concept. 2023;13(2):e2023082 3 references 1. kazakov dv. brooke-spiegler syndrome and phenotypic variants: an update. head neck pathol. 2016;10(2):125-130. doi: 10.1007/s12105-016-0705-x. pmid: 26971504. pmcid: pmc4838966. 2. andersson mk, kölby l, nilsson ja, stenman g. clinical, genetic and experimental studies of the brooke-spiegler (cyld) skin tumor syndrome. j plast surg hand surg. 2019;53(2):71-75. doi: 10.1080/2000656x.2018.1547736. pmid: 30676842. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023177 1 development of a patient-reported outcome measure (prom) for dysgeusia during treatment with smoothened (smo) inhibitors for basal cell carcinomas: the smo-id questionnaire elisa camela1, alessia villani1, sonia sofia ocampo garza2, claudia costa1, gabriella fabbrocini1, matteo megna1, luca potestio1, angelo ruggiero1, massimiliano scalvenzi1 1 dermatology unit, department of clinical medicine and surgery, university of naples federico ii, naples, italy 2 universidad autónoma de nuevo león, university hospital ̈ dr. josé eleuterio gonzález ̈, dermatology department, monterrey, nuevo león, méxico key words: patient-reported outcome measure, dysgeusia, sonic hedgehog inhibitors, prom, basal cell carcinoma citation: camela e, villani a, ocampo garza ss, et al. development of a patient-reported outcome measure (prom) for dysgeusia during treatment with smoothened (smo) inhibitors for basal cell carcinomas: the smo-id questionnaire. dermatol pract concept. 2023;13(3):e2023177. doi: https://doi.org/10.5826/dpc.1303a177 accepted: february 16, 2023; published: july 2023 copyright: ©2023 camela et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: elisa camela, dermatology unit, department of clinical medicine and surgery, university of naples, federico ii, naples, italy. tel: +39 081 -7462457 fax: +39 081 – 7462442 orcid: 0000-0001-7201-9163 email: elisacamela@gmail.com acknowledgement: the patients in this manuscript have given written informed consent to publication of their case details introduction: dysgeusia may occur during conventional or target-therapies and affect patients adherence-to-treatment. therefore, it should be monitored to improve clinical outcome. to date, available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to target-therapies as the pathogenetic mechanism and clinical expression differ. objectives: to develop a patient-reported outcome measure (prom) to screen for and monitor the occurrence and severity of dysgeusia in patients under smoothened (smo) inhibitors: the smo-id questionnaire. methods: patients with locally advanced basal cell carcinomas referring dysgeusia under smo inhibitors at the university hospital of naples federico ii, were enrolled between january-december 2020. the prom was elaborated based on chemotherapy-induced dysgeusia (citas) scale (development phase) and then validated by measuring internal consistency and reliability (validation phase). abstract 2 original article | dermatol pract concept. 2023;13(3):e2023177 introduction dysgeusia is a prominently subjective gustatory disturb that may occur during chemotherapies and affect patients adherence to treatment and quality of life with severe implications on clinical outcome [1,2]. therefore, physicians should thoroughly monitor the occurrence of any taste alteration in order to undertake strategies to address it and at the same time not compromise the therapeutic goal. to date, there are several questionnaires that investigate dysgeusia and related symptoms following traditional chemotherapies and radiotherapy [2,3]; however, the advent of new target therapies has led to the occurrence of selective side effects, including taste impairment, that are different under both the qualitative and quantitative aspects and brought out the need of new reporting tools. objectives in detail, dysgeusia occurring during treatment with smoothened (smo) inhibitors results from the blockade of the sonic hedgehog (shh) pathway, that has been proven to be a fundamental regulator of the gustatory functioning without impacting the olfactory one [4,5]. for this reason, we developed a new and specific patient-reported outcome measure (prom) to characterize it: the smo inhibitors-induced dysgeusia (smo-id) questionnaire. methods the cosmin (consensus-based standards for the selection of health measurement instruments) ‘study design for proms’ checklist was followed during the process of questionnaire creation [6]. a prospective study was conducted on patients affected by locally advanced basal cell carcinomas (labccs) treated with smoothened inhibitors (sonidegib and vismodegib) referring dysgeusia, that were admitted to the university hospital federico ii of naples, italy, between january 2020 and december 2020. informed consent was required before participation. inclusion criteria were labccs treated with smo inhibitors and age ≥ 18 years old. by contrast, exclusion criteria included any pre-existing gustatory and/or olfactory disturbs, gastrointestinal and/or mental diseases that could interfere with the analysis. the study was drawn according to the ethical standards laid down in the world medical association declaration of helsinki (june 1964) and its later amendments and was approved by the local ethical committee. the questionnaire creation was structured in two phases: development and validation. the development phase (january 2020june 2020) an extensive literature research concerning questionnaires on dysgeusia was performed. above all, the chemotherapy-induced taste alterations (citas) scale developed by kano and kanda in 2013 was selected and employed as theorical model from which developing the questionnaire in issue, given its high consistency in literature [3,7,8]. such questionnaire consists of 18 items exploring taste alterations, nausea/discomfort, food temperature intolerability and olfactory disturbs [7]. the citas scale was administered by 5 investigators (ec, av, ms, ss og, mm) to enrolled patients together with broader and open questions to better define the quality and severity of dysgeusia and any potential impact on eating habits. interviews were conducted in-person every 8 weeks from study start and patients answers were recorded and transcribed verbatim. the validation phase (july 2020-december 2020) all enrolled patients took part in the second phase of prom development. they were administered the smo-id questionnaire by the same investigators with the same schedule and procedure of the previous one (the citas), ie, every 8 weeks, and answers recorded. the validation process of prom went through qualitative and quantitative analysis as follows. results preliminary results of the development phase thirty-nine patients meeting the inclusion and exclusion criteria were enrolled in the study. overall, 160 interviews were made and recorded. from the answers analysis, some results: thirty-nine patients were enrolled and interviewed every 8 weeks. in the first phase, 160 citas questionnaires were collected, and the smo-id questionnaire was developed. in the second phase, 195 smo-id questionnaires were recorded, and reliability and validity assessed. cronbach alpha was 0.89. conclusions: the smo-id questionnaire is a validated questionnaire that shows high face and content validity as well as high internal consistency and reliability. hence, it may be introduced in daily clinical setting to monitor dysgeusia in patients under smo-inhibitors. original article | dermatol pract concept. 2023;13(3):e2023177 3 questions of the citas scale resulted redundant and inappropriate: indeed, they explored aspects not reported by the study population nor in literature concerning smo inhibitors side effects, such as olfactory impairment and food temperature intolerance [9,10]. moreover, from the open questions, patients referred variable impact of dysgeusia on social life and eating habits (appetite, nausea and weight) and better detailed the quality and severity of their taste alteration. on this basis, a new and specific questionnaire consisting of 4 domains and 14 items was developed as illustrated in table  1: the smo-id questionnaire. the herein provided version was translated from italian into english according to the cosmin-principles. no scoring was provided since the questionnaire is intended to give physicians a toll to screen for and monitor the occurrence of dysgeusia and related symptoms in patients under smo inhibitors. moreover, as displayed in the last domain, patients’ self-assessment of dysgeusia severity may guide physicians in changing drug posology or eating behaviors during treatment to improve their quality of life and increase compliance. preliminary results of the validation phase the qualitative validation of the prom in issue derived from investigators interviews recording participants’ opinion about accuracy of questions and standardized answers as well as overall approval of the questionnaire. a total of 195 smo-id questionnaires were collected and analyzed. in general, the questionnaire was appreciated by patients and defined as more focused to describe their taste alterations compared to the previous one. moreover, it was depicted as easily understandable, repeatable, and fast. also, the quantitative validation was performed employing the cronbach alpha (ca), a test that measures the internal consistency of a survey, since it makes inferences about the health status of individuals (ie, dysgeusia), which is an unobservable variable for the practitioner, using available evidence (questions), which instead is observable. the test gave an alpha coefficient of 0.89 which indicates high internal consistency (note that a reliability coefficient of .70 or higher is considered “acceptable” in most social science research situations). also, the 95% confidence intervals were computed based on 1000 bootstrapped samples which resulted in [0.83, 0.950]. the narrow bands, small standard errors, also supported the accuracy of the survey. in addition to computing the alpha coefficient of reliability, the dimensionality of the scale was investigated, since the unobservable variable was assumed unidimensional. factor analysis is one method of checking dimensionality (table 2). looking at the table labeled “total variance explained”, the eigenvalue for the first factor is significantly larger than the eigenvalue for the next factor assessing taste perception do you perceive the salty taste? do you perceive the sweet taste? do you perceive the bitter taste? do you perceive the sour taste? do you perceive the umami taste? □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot assessing taste distortion do you have a metallic taste in your mouth? do you have a bitter taste in your mouth? do you have a foul taste in your mouth? do you have a salty taste in your mouth? do you have a sickly-sweet taste in your mouth? □ yes □no □ yes □no □ yes □no □ yes □no □ yes □no assessing impact on food habits do you have nausea? have you lost appetite? have you lost weight? □ yes □no □ yes □no □ yes □no assessing severity of dysgeusia how would you grade your dysgeusia? □ mild □moderate □severe table 1. smoothened inhibitors-induced dysgeusia (smo-id) questionnaire: it is composed by 4 domains that investigate the quality of taste perception and distortion, the impact on food habits and an overall patient self-assessment of dysgeusia severity. 4 original article | dermatol pract concept. 2023;13(3):e2023177 and frame [3,7,8]. on the basis of the answers given by interviewed patients, the citas questionnaire was restructured and modified, reducing the number and topic of items as to make it more focused and specific. moreover, such new version, the smo-id, gives the possibility to have a direct esteem of patients self-assessment of dysgeusia, that may guide the development of tailored treatment strategies. hence, the smo-id questionnaire was developed and subsequently validated, showing high face and content validity as well as high internal consistency and reliability. such results suggest its potential important applicability in daily clinical practice to collect, monitor and screen for such side effect with a specific tool. hence, further and real-life studies are needed to support our findings. the smo-id questionnaire has been proven to be characterized by high face and content validity as well as high internal consistency e reliability. hence, it may be promisingly introduced in daily clinical settings to help physicians screen for and monitor the occurrence and the social impact of dysgeusia in patients under smo-inhibitors. references 1. jafari a, alaee a, ghods k. the etiologies and considerations of dysgeusia: a review of literature. j oral biosci. 2021;63(4):319326. doi: 10.1016/j.job.2021.08.006. pmid: 34487857. 2. malta cen, de lima martins jo, carlos acam, et al. risk factors for dysgeusia during chemotherapy for solid tumors: a retrospective cross-sectional study. support care cancer. 2022; 30(1):313-325. doi: 10.1007/s00520-021-06219-4. pmid: 34283319. 3. sözeri e, kutlutürkan s. taste alteration in patients receiving chemotherapy. breast health. 2015;11(2):81-87.doi: 10.5152 /tjbh.2015.2489. pmid: 28331697. pmcid: pmc5351492. 4. kumari a, ermilov an, allen bl, et al. hedgehog pathway blockade with the cancer drug lde225 disrupts taste organs and taste sensation. j neurophysiol. 2015;113(3):1034-1040. doi: 10.1152/jn.00822.2014. pmid: 25392175. pmcid: pmc4312875. 5. hall jmh, bell ml, finger te. disruption of sonic hedgehog signaling alters growth and patterning of lingual taste papillae. dev biol. 2003;255(2):263-277. doi: 10.1016/s0012 -1606(02)00048-9. pmid: 12648489. (3.10 versus 0.52). additionally, the first factor accounts for 76.23% of the overall variance. this suggests that the scale domains are unidimensional, that is, the questions in the survey are inherent to one single common factor, ie, the presence of dysgeusia. conclusions the rationale of creating a new questionnaire to investigate chemotherapy-induced dysgeusia derives from development of the so called “target therapies”ie, agents that selectively target a specific pathogenetic mechanism that sustains an oncological disease [11]. hence, the concept of chemotherapy -induced side effects has changed dramatically as they are not the result of a generalized antimitotic effect common to the category of traditional antineoplastics but appears to be class-specific [11]. moreover, the development of target therapy implies a complete knowledge of the role of certain molecules in the pathogenesis of the disease and in some way may foresee its side effects [11]. concerning the smo inhibitors, the shh pathway has been proven to be crucial for taste functioning maintenance, and its tackle predictably leads to gustatory impairment [5,12]. in fact, an alteration of the morphology of fungiform papilla, a reduction in the number of taste buds and an impairment in the chorda tympani response to all taste quality has been described in patients with labccs treated with such agents [4]. by contrast, shh pathway is not involved in olfactory functioning, that is not affected [4,5]. in those patients, taste alterations have been proven to affect quality of life as well as therapeutic compliance and efficacy [13,14]. in literature, no proms or questionnaire on target-chemotherapy induced dysgeusia exist, as the available questionnaires relate to conventional chemotherapies or radiotherapy, and do not perfectly apply to the condition in issue, with the risk of not completely understanding patients’ discomfort. for this reason, we decided to create a target-therapy specific questionnaire to investigate the peculiarity of dysgeusia under smo inhibitors, that manifests with different characteristics compared to conventional antineoplastic agents. a validated and certified questionnaire, the citas, has been used as theoretical model table 2. principal component analysis: the table shows the results of principal component analysis applied to domains survey. components eigenvalues percentage variance % cumulative percentage% 1 3.10 76.23 76.23 2 0.52 11.22 87.45 3 0.20 9.40 96.85 4 0.18 3.15 100.00 original article | dermatol pract concept. 2023;13(3):e2023177 5 6. mokkink lb, patrick dl, alonso j, et al. cosmin study design checklist for patient-reported outcome measurement instruments. 2019. available at: https://www.cosmin.nl/wp-content /uploads/cosmin-study-designing-checklist_final.pdf. accessed january 2022). 7. kano t, kanda k. development and validation of a chemotherapy-induced taste alteration scale. oncol nurs forum. 2013;40 (2):e79-85. doi: 10.1188/13.onf.e79-e85. pmid: 23448748. 8. simeone s, esposito mr, gargiulo g, et al. the citas scale for evaluating taste alteration induced by chemotherapy: state of the art on its clinical use. acta biomed. 2019;90:17–25. doi: 10.23750 /abm.v90i6-s.8278. pmid: 31292411; pmcid: pmc6776177. 9. erivedge, inn-vismodegib european medicines agency: summary of product characteristics [internet]. available from: https://www.ema.europa.eu/en/documents/product-information /erivedge-epar-product-information_en.pdf. jan 2022. 10. odomzo, inn-sonidegib european medicines agency: summary of product characteristics [internet]. available from: https://www.ema.europa.eu/en/documents/product-information /odomzo-epar-product-information_en.pdf. jan 2022. 11. alam a, farooq u, singh r, et al. chemotherapy treatment and strategy schemes : a review chemotherapy treatment and strategy schemes : a review. open acc j of toxicol. 2018;2(5): 555600. doi: 10.19080/oajt.2018.02.555600. 12. gutzmer r, solomon ja. hedgehog pathway inhibition for the treatment of basal cell carcinoma. target oncol. 2019;14(3):253-267. doi: 10.1007/s11523-019-00648-2. pmid: 31243642. target oncol [internet]. 2019;14:253–267. doi:10.1007/s11523-019-00648-2. 13. villani a, costa c, fabbrocini g, et al. dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor sonidegib to manage adverse effects: a retrospective case series. j am acad dermatol. 2021;84(4):e211-e212. doi: 10.1016/j.jaad.2020.12.006. pmid: 33301802. 14. villani a, megna m, fabbrocini g, et al. long-term efficacy of vismodegib after its withdrawal and patients’ health-related quality of life using the dermatology life quality index (dlqi). dermatol ther (heidelb). 2019;9(4):719-724. doi: 10.1007/s13555 -019-00323-4. pmid: 31506916. pmcid: pmc6828856.9 :719–724. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022102 1 dermoscopy of atrofic dermatofibroma as a rare variant tugba kevser ustunbas uzuncakmak1, bengu cobanoglu simsek2 1 sisli memorial hospital, department of dermatology, istanbul, turkey 2 istanbul medeniyet university medical faculty, department of pathology, istanbul, turkey citation: uzuncakmak tku, cobanoglu simsek b. dermoscopy of atrofic dermatofibroma as a rare variant. dermatol pract concept. 2022;12(3):e2022102. doi: https://doi.org/10.5826/dpc.1203a102 accepted: october 25, 2021; published: july 2022 copyright: ©2022 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: dr tugba kevser ustunbas uzuncakmak, md, sisli memorial hospital, department of dermatology, istanbul, turkey, telephone: 0 +90(530) 6640226 e-mail: drtugbakevser@gmail.com case presentation  a 12-year-old boy presented with a 1-year history of slowly growing, 1,5 cm x 2 cm, livedoid, hard and depressed livedoid lesion on his back (figure 1, a and b). dermoscopic evaluation showed homogenous gray-whitish and livedoid large clods and crystalline structures (figure 1c). the patient was referred for total excision. histologically, fibro-histiocytic benign tumoral lesion located in a dense collagenized stroma separated from the epidermis by a cell-poor zone was observed. a few scattered lymphocytes were observed in between (figure 1, d and e). teaching point atrophic dermatofibroma is a rare variant of dermatofibroma which was first described by page and assaad in 1987 [1]. it is commonly seen on the upper back of middle-aged women, and the mean age of the patients affected is 49.7 years, according to literature [1]. we present this uncommon entity, which is in the differential diagnosis with many benign and malignant lesions including atrophic scars, anetodermas, morphea, atrophic dermatofibrosarcoma protuberans and sclerosing basal cell carcinomas, as it is rare in the pediatric age group [2]. 2 image letter | dermatol pract concept. 2022;12(3):e2022102 references 1. ohnishi t, sasaki m, nakai k, watanabe s. atrophic dermatofibroma. j eur acad dermatol venereol. 2004;18(5):580-583. doi: 10.1111/j.1468-3083.2004.00975.x. pmid: 15324399. 2. mota an, tortelly vd, obadia dl, silva rs. atrophic dermatofibroma. an bras dermatol. 2013;88(5):793-795. doi: 10.1590/abd1806-4841.20132234. pmid: 24173186. pmcid: pmc3798357. figure 1. (a and b) clinical presentation of a 1,5 cm x 2 cm, hard and depressed livedoid lesion on the back. (c) gray-whitish and livedoid large clods with a homogenous distribution seen at dermoscopy. (d and e) correlated histological images: fibro-histiocytic benign tumoral lesion located in a dense collagenized stroma separated from the epidermis by a cell-poor zone (h&e, x100, x200). dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022112 1 dermatology practical & conceptual perinevoid alopecia: an unusual presentation of alopecia areata josé leonardo rodrigues machado1, rita fernanda cortez de almeida2, simone carolina frattini3, daniel fernandes melo2 1 dermatology department, faculdade ipemed de ciências médicas (afya), rio de janeiro, brazil 2 dermatology department, universidade do estado do rio de janeiro, rio de janeiro, brazil 3 mental health department, guelph general hospital, guelph, ontario, canada citation: machado jlr, cortez de almeida rf, frattini sc, melo df. perinevoid alopecia: an unusual presentation of alopecia areata. dermatol pract concept. 2022;12(3):e2022112. doi: https://doi.org/10.5826/dpc.1203a112 accepted: november 12, 2021; published: july 2022 copyright: ©2022 machado et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: daniel fernandes melo, msc md, address: estrada dos tres rios 1200 – office 810 – zip code 22745-052 email address: danielfernandesmelo@yahoo.com.br case presentation a 19-year-old healthy male complained of sudden onset of asymptomatic single patch alopecia on the occiput for three months. the round patch of non-scarring alopecia surrounded a pre-existent pigmented dome-shaped compound nevus, which did not change over time (figure 1). trichoscopic features were compatible with alopecia areata (aa), and the patient decided on conservative management. teaching point perinevoid alopecia (pa) is an extremely rare variant of aa associated with a central generally pigmented nevus [1]. although the pathogenesis is still unclear, it is thought that pa is secondary to an inflammatory response against nevus cells or melanocytic structures [1,2]. immune cells around the nevus attack the hair follicle, similarly to the destruction of melanocytes in a halo nevus, other nevocentric phenomena [2]. surgical removal of the nevus may lead to hair regrowth a figure 1. a 1-cm diameter round patch of non-scarring alopecia surrounding a pre-existent pigmented dome-shaped compound subtype nevus on the right side of the occiput. 2 image letter | dermatol pract concept. 2022;12(3):e2022112 few weeks after excision [1,2]. recognizing pa is essential to properly manage this unique variant of aa. references 1. kimura h, nagase k, narisawa y. perinevoid alopecia: a case report and literature review. br j dermatol. 2018;179(4):969-970. doii:10.1111/bjd.16709. mid: 29704462. 2. ruiz-arriaga lf, lópez-garcía l, vega-memije me. perinevoid alopecia: a case report. skin appendage disord. 2019;5(2): 94-96. doi:10.1159/000490469. pmid: 30815441. pmcid: pmc6388562.\ dermatology: practical and conceptual research | dermatol pract concept 2017;7(4):7 25 dermatology practical & conceptual www.derm101.com introduction atopic dermatitis (ad) is an inflammatory skin disease with an onset in infancy or early childhood and is characterized by severe pruritus, chronic and relapsing course, and typical clinical morphology including xerosis and eczematous lesions [1,2]. the incidence of ad has increased in the past 30 years, whereas its current prevalence is estimated to be 12%. atopic dermatitis is often associated with remarkable morbidity, which results in patient hospitalization, absence from work or school, and loss of several working days [3,4]. in children, sleep disorders leading to behavioral disturbances are known to be one of the most hazardous effects of ad [5,6]. furthermore, this disease may cause growth retardation in children [7]. unpredictable course, chronic and relapsing nature of the disease, and disturbing pruritus can impose extensive psychological and emotional burden on patients with ad and their families [8-11]. basal serum cortisol and adrenocorticotropic hormone levels in patients with atopic dermatitis zohreh tehranchinia1, hoda rahimi1, sara lotfi1 1 department of dermatology, skin research center, shahid behehshti university of medical sciences, tehran, iran key words: adrenocorticotropic hormone, atopic dermatitis, cortisol, ige citation: tehranchinia z, rahimi h, lotfi s. basal serum cortisol and adrenocorticotropic hormone levels in patients with atopic dermatitis. dermatol pract concept 2017;7(4):25-29. doi: https://doi.org/10.5826/dpc.0704a07 received: december 11, 2016; accepted: june 21, 2017; published: october 31, 2017 copyright: ©2017 tehranchinia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: zohreh tehranchinia, md, associate professor of dermatology, skin research center, shohada-e tajrish hospital, shabid behehshti university of medical sciences, tehran, iran, 1989934148. email: zohreh_tehranchi@yahoo.com background: certain studies suggest that percutaneous absorption of topical steroids may cause suppression of hypothalamic–pituitary–adrenal axis (hpaa) in atopic dermatitis (ad) patients. this study aimed to investigate the basal serum cortisol, adrenocorticotropic hormone (acth), and ige levels in patients with ad and their correlation with the disease severity. methods: levels of basal serum cortisol, acth, and ige were assessed by elisa in 31 patients with ad and 31 controls. clinical severity of ad was evaluated by the scoring of atopic dermatitis (scorad) index. results: no statistical difference was observed between the two groups for basal serum cortisol and acth levels. the serum ige level was significantly higher in the ad group. the scorad index was correlated with serum ige level. conclusions: basal serum cortisol and acth levels are normal in ad patients. serum ige level is significantly higher in ad patients and is correlated with the disease severity. abstract 26 research | dermatol pract concept 2017;7(4):7 informed consent was obtained from all participants or their parents (if age <16 years), before participation. investigations morning basal serum cortisol levels at 8 am (expected value: male 5–22 mg/dl; female 5.2–21.7 mg/dl; sensitivity 0.25 mg/dl, serum acth levels (expected value: 17–58.2 pg/ ml; sensitivity 0.22 pg/ml), and serum ige levels (positive expected value>190 iu/ml; sensitivity 25 iu/ml) were measured using the enzyme link immunosorbent assay (elisa; biomerica, ca, usain the case and control groups. disease severity clinical severity of the disease was evaluated by the scoring of atopic dermatitis (scorad) index and was graded as mild (scorad<25), moderate (scorad: 25–50), and severe (scorad >50) [18]. statistical analysis all statistical analyses were performed using spss 16.0 (spss inc, chicago, il, usa). to assess the quantitative variables, student’s t-test and mann–whitney u test were used for independent groups and categorical variable, as appropriated. spearman correlation test was used to assess the correlation between variables. p<0.05 was considered as statistically significant. results this study included 31 patients with vitiligo and 31 healthy controls. demographics and clinical data of patients and controls are summarized in table 1. basal serum cortisol level was found to be higher than the reference range in one patient from the ad group (3.2%); however, none of the topical corticosteroids are the most widely used and the mainstay of treatment for ad [12], but there is increasing concern about their systemic side effects, especially adrenal suppression. there is some evidence that the percutaneous systemic absorption of topical steroids may occur after the prolonged use of these drugs and may lead to the suppression of hypothalamic–pituitary–adrenal axis (hpaa) [13,14]; however, in the majority of these studies, “basic” hpaa function (before application of topical steroids) remained unevaluated. in other words, in most of these studies, the hpaa function was compared with controls only “after” the application of topical steroids. few studies have evaluated the basic hpaa function, especially in children; however, the results are conflicting [15-17]. this study aimed to evaluate the basal serum cortisol, adrenocorticotropic hormone (acth), and ige levels in patients with ad (without any age limitation) and their correlation with the disease severity. patients and methods patients this study included 31 patients (22 females and 9 males) with mean age of 34.1±19.2 years (range 0.5–78 years) who were visited by dermatologists and were diagnosed as ad, according to the criteria of hanifin and rajka [1], and 31 ageand sex-matched control subjects. the control subjects had neither self-reported allergies or allergic symptoms, nor any inflammatory skin disease. subjects with history of treatment with any systemic steroids during the previous year or topical steroids during the previous month, history of adrenal insufficiency, cushing’s syndrome, active inflammation, alcoholism, and depression were excluded from the study. the study was carried out in accordance with the ethical standards established in the declaration of helsinki, and table 1. demographics and clinical data of patients and controls patients (n=31) controls (n=31) p value age, years mean ±sd 34.1±19.2 35.6±17.3 0.75 range 0.5-78 1-80 median 28 30 gender female 22 23 0.86 male 9 8 disease duration, years mean 7.1 range 0.5-21 research | dermatol pract concept 2017;7(4):7 27 5–932) in the control group. as expected, the serum ige level was significantly higher in the ad group (p=0.02; figure 1). most of our patients displayed moderate ad according to the scorad index. table 2 summarizes scorad grading in our patients. the scorad index was correlated with serum ige level (p<0.05; rs=0.41), but not with the basal serum cortisol level (p=0.87; rs=0.03) and acth level (p=0.53; rs=0.12; figure 2). scorad index was not correlated with age, sex, and clinical features of ad. discussion in this case–control study, no significant difference was observed in the basal serum cortisol and acth levels in patients with ad and the control group. interestingly, we found that the severity of ad (scorad index) correlated with serum ige level, but not with the serum cortisol level. the literature review reveals various studies with distinct research designs and methodologies and conflicting results (table 3). a study by matsuda et al., reported significantly lower basal cortisol levels and lower response to acth in ad subjects from the control group displayed high basal serum cortisol level. this difference was not significant (p=0.63). the mean of basal serum cortisol level was 10.09±5.24 mg/ dl (range 5.1–29.4) in the ad group and 9.32±3.59 mg/dl (range 5–17.5) in the control group. the mean of basal serum cortisol level between the two groups showed no statistical significant difference (p=0.67). the mean of acth level in the ad group was 26.76±17.57 pg/ml (range 6.8–66.8), whereas it was 26.42±14.92 in the control subjects. the mean of acth level between two groups showed no statistical significant difference (p=0.74) the mean of serum ige level was 328.48±362.77 iu/ml (range 8–1033) in the ad group and 121.55±185.47 (range figure 2. correlation between scorad index and serum levels of acth, cortisol, and total ige. there was no correlation between serum acth (a) or basal cortisol levels (b) and scorad index. total serum ige level was positively correlated with scorad index. [copyright: ©2017 tehranchinia et al.] figure 1. comparison of serum levels of (a) acth (p>0.05), (b) cortisol (p>0.05), and (c) total ige (p<0.05) in patients with atopic dermatitis and healthy controls. data shown as median (horizontal line), 25th to 75th percentiles (box), and range (capped lines). [copyright: ©2017 tehranchinia et al.] table 2. disease severity evaluated by scorad index in patients with atopic dermatitis disease severity n (%) mild (scorad<25) 6 (19.86) moderate (scorad: 25-50) 19 (61.28) severe (scorad>50) 6 (19.36) 28 research | dermatol pract concept 2017;7(4):7 the pediatric ad group [22]. the results of this study were compatible with our findings, although it was performed only on pediatric patients. we found a positive correlation between the total serum ige values and disease severity, and our study is in correlation with the results of choen et al. [23]. in conclusion, in the present study no difference was observed in both basal cortisol levels and acth values between the ad and control groups. the basal cortisol levels were not correlated with the disease severity, whereas the serum ige level was significantly higher in ad patients and correlated with the disease severity. to the best of our knowledge, this was the first case–control study that evaluated hpaa in ad patients without any age limitation. the limitation of our study was its sample size; thus, further studies with larger sample size are necessary to investigate the complex interaction of the neuroendocrine, metabolic, and immune systems and to explain the available conflicting results. references 1. hanifin jm, rajka g. diagnostic features of atopic dermatitis. acta derm venreol. 1980;92:44-47. 2. williams hc. epidemiology of human atopic dermatitis—seven areas of notable progress and seven areas of notable ignorance. vet dermatol. 2013;24:3-9.e1-2. 3. madhok v, futamura m, thomas ks, barbarot s. what’s new in atopic eczema? an analysis of systematic reviews published in children than the control group, providing an evidence of impaired hpaa function in patients with ad [17]; however, the main pitfall of this study was that their control group consisted of asthmatic patients. as asthma itself lies in the spectrum of atopia and forms one of the three parts of allergic triad (ad, allergic rhinitis, and asthma), selecting controls from asthmatic patients may result in an inappropriate and biased comparison. a study which has been the mainstay and reference of most of recent investigations is the report of haeck et al., which demonstrated lower basal cortisol level in patients with severe, active ad (group 1) than the patients with moderate, controlled ad (group 2). furthermore, this study found no significant correlation between the amount of prescribed topical corticosteroid and serum cortisol levels, and concluded that disease activity, rather than the use of topical corticosteroids, is responsible for the low basal cortisol values in patients with severe ad [16]. nevertheless, two years later, the authors of this article confessed that they had made a fatal flaw in the execution of their study, which led to wrong interpretation and incorrect conclusion [20]. surprisingly, none of the recent studies has referred to this corrigendum. afsar et al. reported that none of the pediatric patients with ad had basal serum cortisol levels below the lower limit of the reference range, and no difference was observed in the basal cortisol values when they were compared with those of the control group. they also reported that the severity of ad did not correlate with the serum cortisol values in table 3. different studies evaluating serum cortisol levels in patients with atopic dermatitis authors study population result comments matsuda et al. [17] children with ad ↓response to acth control group was selected from asthmatic children patel et al. [19] children with moderate to severe ad who were under regular treatment with corticosteroid normal basal cortisol levels haeck et al. [16] patients with moderate or severe ad ad activity is responsible for low basal cortisol levels two years later, the authors confessed that their results were incorrect [20] natan et al. [21] children with ad ↓basal cortisol level in 50% of patients, which was in correlation with disease severity ↓acth response. recovery of the hpaa after application of topical steroid afsar et al. [22] children with ad normal basal cortisol level with no correlation with disease severity ad: atopic dermatitis; acth: adrenocorticotropic hormone; hpaa: hypothalamic-pituitary-adrenal axis. http://www.ncbi.nlm.nih.gov/pubmed/?term=williams%20hc%5bauthor%5d&cauthor=true&cauthor_uid=23331673 http://www.ncbi.nlm.nih.gov/pubmed/23331673 http://www.ncbi.nlm.nih.gov/pubmed/?term=madhok%20v%5bauthor%5d&cauthor=true&cauthor_uid=25622689 http://www.ncbi.nlm.nih.gov/pubmed/?term=futamura%20m%5bauthor%5d&cauthor=true&cauthor_uid=25622689 http://www.ncbi.nlm.nih.gov/pubmed/?term=thomas%20ks%5bauthor%5d&cauthor=true&cauthor_uid=25622689 http://www.ncbi.nlm.nih.gov/pubmed/?term=barbarot%20s%5bauthor%5d&cauthor=true&cauthor_uid=25622689 research | dermatol pract concept 2017;7(4):7 29 and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. bmc pediatr. 2016 16:75. 15. buske-kirschbaum a, von auer k, krieger s, weis s, rauh w, hellhammer d. blunted cortisol responses to psychosocial stress in asthmatic children: a general feature of atopic disease? psychosom med. 2003;65:806-810. 16. haeck im,timmer-de mik l, lentjes egwm, et al. low basal serum cortisol in patients with severe atopic dermatitis: potent topical corticosteroids wrongfully accused. br j dermatol. 2007;156:979-985. 17. matsuda k, katsunuma t, iikura y, kato h, saito h, akasawa a. adrenocortical function in patients with severe atopic dermatitis. ann allergy asthma immunol. 2000;85:35-39. 18. gelmetti c, colonna c. the value of scorad and beyond. towards a standardized evaluation of severity? allergy. 2004;59:6165. 19. patel l, clayton pe, addison gm, price da, david tj. adernal function following topical steroid treatment in children with atopic dermatitis. br j dermatol. 1995;132:950-955. 20. haeck im,timmer-de mik l, lentjes egwm, et al. erratum to low basal serum cortisol in patients with severe atopic dermatitis: potent topical corticosteroids wrongfully accused. br j dermatol. 2009;161:218. 21. nutan, kanwar aj, bhansali a, parsad d. evaluation of hypothalamic-pituitary-adrenal axis in patients with atopic dermatitis. indian j dermatol venereol leprol. 2011;77:288-293. 22. afsar fs, isleten f, sonmez n. children with atopic dermatitis do not have more anxiety or different cortisol levels compared with normal children. j cutan med surg. 2010;14:13-18. 23. cheon br, shin je, kim yj, et al. relationship between serum 25-hydroxyvitamin d and interleukin-31 levels, and the severity of atopic dermatitis in children. korean j pediatr. 2015;58:96-101. 2012 and 2013. part 1. epidemiology, mechanisms of disease and methodological issues. clin exp dermatol. 2015;40:238-242. 4. van moerbeke d. european allergy white paper. allergic disease as a public health problem in europe. brussels: ucb institute of allergy. 1997. 5. yaghmaie p, koudelka cw, simpson el. mental health comorbidity in patients with atopic dermatitis. j allergy clin immunol. 2013 ;131:428-33. 6. kong ts, han ty, lee jh, son sj. correlation between severity of atopic dermatitis and sleep quality in children and adults. ann dermatol. 2016;28:321-326. 7. palit a, handa s, bhalla ak, kumar b. a mixed longitudinal study of physical growth in children with atopic dermatitis. indian j dermatol venereol leprol. 2007;73:171-175. 8. whiteley j, emir b, seitzman r, makinson g. the burden of atopic dermatitis in us adults: results from the 2013 national health and wellness survey. curr med res opin. 2016; 21:1-7. 9. al shobaili ha. the impact of childhood atopic dermatitis on the patient’s family. pediatr dermatol. 2010;27:618-623. 10. mckenna sp, doward lc. quality of life of children with atopic dermatitis and their families. curr opin allergy clin immunol. 2008;8:228-231. 11. lewis-jones s. quality of life and childhood atopic dermatitis: the misery of living with childhood eczema. int j clin pract. 2006;60:984-992. 12. eichenfield lf, tom wl, berger tg, et al. guidelines of care for the management of atopic dermatitis: section 2. management and treatment of atopic dermatitis with topical therapies. j am acad dermatol. 2014;71:116-132. 13. silverberg ji, nelson db, yosipovitch g. addressing treatment challenges in atopic dermatitis with novel topical therapies. j dermatol treat. 2016;11:1-9. 14. siegfried ec, jaworski jc, kaiser jd, hebert aa. systematic review of published trials: long-term safety of topical corticosteroids http://www.ncbi.nlm.nih.gov/pubmed/27267134 http://www.ncbi.nlm.nih.gov/pubmed/?term=buske-kirschbaum%20a%5bauthor%5d&cauthor=true&cauthor_uid=14508024 http://www.ncbi.nlm.nih.gov/pubmed/?term=von%20auer%20k%5bauthor%5d&cauthor=true&cauthor_uid=14508024 http://www.ncbi.nlm.nih.gov/pubmed/?term=krieger%20s%5bauthor%5d&cauthor=true&cauthor_uid=14508024 https://www.ncbi.nlm.nih.gov/pubmed/?term=weis%20s%5bauthor%5d&cauthor=true&cauthor_uid=14508024 https://www.ncbi.nlm.nih.gov/pubmed/?term=rauh%20w%5bauthor%5d&cauthor=true&cauthor_uid=14508024 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http://www.ncbi.nlm.nih.gov/pubmed/?term=jaworski%20jc%5bauthor%5d&cauthor=true&cauthor_uid=27267134 http://www.ncbi.nlm.nih.gov/pubmed/?term=kaiser%20jd%5bauthor%5d&cauthor=true&cauthor_uid=27267134 http://www.ncbi.nlm.nih.gov/pubmed/?term=hebert%20aa%5bauthor%5d&cauthor=true&cauthor_uid=27267134 dermatology: practical and conceptual commentary | dermatol pract concept 2017;7(3):5 27 dermatology practical & conceptual www.derm101.com commentary conceptually and practically all epithelial neoplasms can and should be classified as one of the following three categories, namely, benign lesion, carcinoma in situ and invasive carcinoma. when the term carcinoma used unmodified, such as squamous cell carcinoma, sebaceous carcinoma, adenocarcinoma, generally means invasive carcinoma. non-invasive carcinoma is synonymous to carcinoma in situ. the concept of carcinoma in situ was first introduced by broders in 1932 [1] and has been accepted as a well-established term and diagnostic category in many organ systems such as breast and skin (e.g., ductal carcinoma in situ of the breast and squamous cell carcinoma in situ of the skin). however, for unknown reasons, sebaceous carcinoma in situ (scis) has not yet to be recognized by many as a concept and diagnostic entity. from the first classification of neoplasms with sebaceous differentiation proposed by warren and warvi in 1943 [2], to the one by rulon and helwig in 1974 [3], lever in 1949 and 1989 [4, 5], elder et al in 1997 and 2005 [6, 7], prioleau and santa cruz in 1984 [8], troy and ackerman in 1984 [9] and steffen and ackerman 1994 [10], mehregan and hashimoto in 1991 and 1995 [11,12] and burgdorf in 1990 [13], mckee in 1996 and 2012 [14,15], barnhill in 1998 [16], maize in 1998 [17], farmer and hood in 2000 [18], and weedon in editions from 2002 to 2017 [19-22], scis was not even mentioned in any of their classifications of sebaceous neoplasms. beside the flat scis (see below for detail), which has been called by some as scis and considered as an exceedingly rare phenomenon, chen was the first one who pointed out the existence of other histologic types of scis and proposed to establish scis as a concept and diagnostic entity [23-24]. like the definition for any other type of carcinoma in situ, the definition of scis would be a sebaceous neoplasm with these microscopic features: (1) architectural findings of confinement, namely, no invasive growth, indicating neoplastic cells still confined in epithelium (within surface epithelium, infundibular epithelium, sebaceous carcinoma in situ as a concept and diagnostic entity miglena k. komforti1, masoud asgari2, sheng chen3 1 department of pathology, hofstra northwell school of medicine, hempstead, ny, usa 2 department of pathology, wake forest baptist medical center, winston-salem, nc, usa 3 departments of pathology and dermatology, hofstra northwell school of medicine, hempstead, ny, usa citation: komforti mk, asgari m, chen s. sebaceous carcinoma in situ as a concept and diagnostic entity. dermatol pract concept 2017;7(3):5. doi: https://doi.org/10.5826/dpc.0703a05 copyright: ©2017 komforti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: sheng chen, md, phd, departments of pathology and dermatology, hofstra northwell school of medicine, 1991 marcus ave, suite 300 lake success, ny 11042, usa. tel. 844.719.7284. email: schen@northwell.edu. although carcinoma in situ has been accepted as a well-established concept and diagnostic category, for reasons unknown sebaceous carcinoma in situ has not been recognized yet in general pathology or dermatopathology. such lesions have always been misinterpreted as either benign neoplasm or sebaceous carcinoma. in the present essay, we provide a convincing account supporting sebaceous carcinoma in situ as a valid concept and diagnostic entity via critical literature review and histopathological assessment and illustration. recognizing sebaceous carcinoma in situ as a valid concept and diagnostic entity will certainly help to avoid misinterpretation and subsequently under or over treatment of such lesions. abstract zenaidavega sticky note delete period here 28 commentary | dermatol pract concept 2017;7(3):5 tiva) with no evidence of underlying sebaceous carcinoma or nodular/cystic scis (figure 2). flat scis can only be diagnosed after excluding pagetoid involvement of surface epithelium by either underlying sebaceous carcinoma or nodular/ cystic scis. flat scis is a rare lesion and often reported in the literature under the term of intraepithelial or epidermotropic sebaceous carcinoma [25-27]. some authors call this variant as superficial type of sebaceous carcinoma [15]. the nodular type of scis is the most common type of scis. nodular scis is located in the dermis and/or subcutis with or without surface epithelial involvement, has a multilobulated (figure 3a-c) or solid nodular configuration (figure 4a-c). the lesion is well circumscribed with smooth border. there is no desmoplastic stromal response or any features of infiltrative growth. the cystic type of scis is located in the dermis and usually extends into subcutis. it consists of an encapsulated or welldefined cystic sebaceous lesion with smooth outer border lined by multiple layers of neoplastic sebocytes (figure 5a & b). sebaceous gland, sebaceous duct, and/or follicular epithelium); and (2) cytological attributes of malignancy, i.e. presence of nuclear atypia, enlarged nuclei, hyperchromasia, increase of nucleus to cytoplasm ratio, decrease of differentiation, increase of mitotic activity and necrosis in the form of individual cells or necrosis en masse. of note, carcinoma in situ can certainly grow very large and render the original epithelial structure unrecognizable. that is often the case for ductal carcinoma in situ of the breast, which can form a palpable mass (figure 1a & b). thus, the histopathologic diagnosis of carcinoma in situ can still be made even the original epithelial structure is distorted or unrecognizable. regarding the origin of sebaceous neoplasm, kazakov et al. stated that “whereas in periorbital sebaceous lesions, it is accepted that sebaceous lesions arise from meibomian glands and glands of zeis, sebaceous glands elsewhere in the skin practically never appear to give rise to a sebaceous carcinoma” [25]. it is true no one knows for sure the exact origin of sebaceous neoplasm. but one can be certain that it must originate from epithelium, namely, epidermis, follicular epithelium or sebaceous gland. among these elements, it is reasonable to believe sebaceous neoplasm originates from sebaceous gland. if one accepts that ocular sebaceous neoplasm arises from sebaceous gland (meibomian as well as zeis glands), there is no reason to reject the notion that extraocular or cutaneous sebaceous neoplasm arises from cutaneous sebaceous gland, which is actually identical to zeis sebaceous gland in the eyelid. scis has a number of different histopathologic expressions. in our opinion, there are three histopathologic types, namely, flat, nodular and cystic types. the flat type of scis refers to proliferation of malignant sebocytes within surface epithelium (epidermis or conjuncfigure 1. (a) normal breast tissue showing terminal duct lobules (h&e stain). (b) ductal carcinoma in situ of breast, solid type, with central necrosis and calcifications. note that the ductal carcinoma in situ forms expansile nodules completely distorting and effacing the original breast epithelial structure (h&e stain). [copyright: ©2017 komforti et al.] a b figure 2. sebaceous carcinoma in situ, flat type, showing proliferation of atypical neopastic sebocytes within epidermis (h&e stain). [copyright: ©2017 komforti et al.] commentary | dermatol pract concept 2017;7(3):5 29 sebaceous differentiation published in 2009 [26]. although this view has been accepted by some, it is not shared by many others in the field of dermatopathology. in an essay published in 2010, chen proposed a different view and asserted that the so-called sebaceous adenoma is really scis based on the above-mentioned definition of scis [23]. on the other hand, poorly differentiated or high nuclear grade nodular/cystic scis is often misinterpreted as sebaceous carcinoma or so-called unclassifiable sebaceous neoplasm. welland moderately-differentiated nodular/cystic scis was called sebaceous adenoma initially by early authors [3, 28] and subsequently has been called this way by many up to this day. however, in an article published in 1998, nussen and ackerman revised this concept and stated that the so-called sebaceous adenoma is not a benign neoplasm but sebaceous carcinoma [29]. this notion was upheld by them in another article published in 1999 [30] and subsequently in the second edition of a book devoted to neoplasms with figure 3. (a) low power view of sebaceous carcinoma in situ, multilobulated nodular type (h&e stain). (b) intermediate power view of sebaceous carcinoma in situ, multilobulated nodular type (h&e stain). (c) high power view of sebaceous carcinoma in situ, multilobulated nodular type (h&e stain). [copyright: ©2017 komforti et al.] a b c figure 4. (a) low power view of sebaceous carcinoma in situ, solid nodular type (h&e stain). (b) intermediate power view of sebaceous carcinoma in situ, solid nodular type (h&e stain). (c) high power view of sebaceous carcinoma in situ, solid nodular type (h&e stain). [copyright: ©2017 komforti et al.] a b c 30 commentary | dermatol pract concept 2017;7(3):5 3. rulon db, helwig eb. cutaneous sebaceous neoplasms. cancer. 1974;33(1):82-102. 4. lever wf. histopathology of the skin. philadelphia, pa: lippincott; 1949. 5. lever wf, schaumburg-lever g. histopathology of the skin. 7th ed. philadelphia, pa: lippincott; 1989. 6. elder d, elenitsas r, jaworsky c, johnson jr b. lever’s histopathology of the skin. 8th ed. philadelphia, pa: lippincott-raven; 1997. 7. elder d, elenitsas r, johnson jr b, murphy gf. lever’s histopathology of the skin. 9th ed. philadelphia, pa: lippincott-raven; 2005. 8. prioleau pg, santa cruz dj. sebaceous gland neoplasia. j cutan pathol. 1984 oct; 11(5):396-414. 9. troy jl, ackerman ab. sebaceoma. a distinctive benign neoplasm of adnexal epithelium differentiating toward sebaceous cells. am j dermatopathol. 1984 feb; 6(1):7-13. 10. steffen c, ackerman ab. neoplasms with sebaceous differentiation: a method by pattern analysis ackerman’s histologic diagnosis of neoplastic skin diseases. philadelphia, pa: lea & febiger; 1994. 11. mehregan ah, hashimoto k. epidermal precancer, squamous cell carcinoma, and pseudocarcinoma. in: pinkus guide to dermatohistopathology. 5th ed. east norwalk, ct: appleton & lange; 1991:501-521. 12. mehregan ah, hashimoto k, mehregan da, mehregan dr. intradermal epithelioma. in: pinkus’ guide to dermatopathology. 6th ed. norwalk, ct: appleton & lange; 1995:643-644. 13. burgdorf whc. tumor of sebaceous gland differentiation. in: farmer er, hood af, eds. pathology of the skin. norwalk, ct: appleton & lange; 1990:615. 14. mckee ph, marsden ra. pathology of the skin: with clinical correlations. 2nd ed. london, uk: mosby-wolfe; 1996. 15. calonje e, brenn t, mckee p, lazar a. mckee’s pathology of the skin, (expert consult). 4th ed. philadelphia, pa: elsevier saunders; 2011. 16. barnhill rl. textbook of dermatopathology. new york, ny: mcgraw-hill; 1998. 17. maize jc, ed. cutaneous pathology. philadelphia, pa: churchill livingstone; 1998. 18. steffen c. neoplasms with sebaceous differentiation. in: farmer er, hood af, eds. pathology of the skin. 2nd ed. new york, ny: mcgraw-hill; 2000:1035-1058. for example, one of the sebaceous lesions interpreted as low-grade sebaceous carcinoma in a recent article by kacerovska et al. is clearly scis based on the photomicrographs the authors presented (well-defined lobulated lesion with no evidence of invasion; figure 4 in that article) [31]. other examples include five cases of sebaceous neoplasms with architectural features of benignancy and cytologic features of malignancy reported by kazakov et al., who stated that “the classification of such lesions as sebaceoma (with atypia) or sebaceous carcinoma remains unresolved” [32]. this opinion was in contrast to that of resnik, who reviewed the manuscript as well as glass slides of the five neoplasms under discussion and did not agree with the authors’ assessment that these lesions cannot be classified as either sebaceoma or sebaceous carcinoma [33]. in resnik’s opinion, four out of the five cases represented sebaceous carcinoma and one sebaceoma. kramer and chen had yet another view. based on the architectural features of benignancy (well-circumscription with smooth border of lobules with no invasive growth) and cytological features of malignancy (presence of nuclear atypia, increased mitotic figures including atypical ones, and necrosis), kramer and chen thought most if not all of the five sebaceous neoplasms presented by kazakov et al. are actually examples of scis [24]. in summary, as one can see from above scis is a valid concept and diagnostic entity. the histopathological criteria for diagnosing such lesion are clear, precise and understandable. recognizing scis as a diagnostic entity can certainly prevent misinterpreting this kind of lesions as others, thus avoiding under or over treatment. references 1. broders ac. carcinoma in situ contrasted with benign penetrating epithelium. jama. 1932; 99(20):1670-1674. doi:10.1001/ jama.1932.02740720024007 2. warren s, warvi wn. tumors of sebaceous glands. am j pathol. 1943;19(3):441-459. figure 5. (a) low power view of sebaceous carcinoma in situ, cystic type (h&e stain). (b) intermediate view of sebaceous carcinoma in situ, cystic type (h&e stain). [copyright: ©2017 komforti et al.] a b commentary | dermatol pract concept 2017;7(3):5 31 29. nussen-lee s, ackerman ab. sebaceous “adenoma” is sebaceous carcinoma. dermatopathology: practical & conceptual. 1998; 4(1):5–14. https://www.derm101.com/dpc-archive/jan-mar-1998volume-4-no-1/dpc0401a02-sebaceous-adenoma-is-sebaceouscarcinoma/. accessed february 1, 2017. 30. ackerman ab, nussen-lee s. neoplasms in all organs of muir-torre syndrome are carcinomas: sebaceous carcinomas and squamouscell carcinomas (keratoacanthomas) in skin and adenocarcinomas, squamous-cell carcinomas, and transitional-cell carcinomas in internal organs. dermatopatholology: practical & conceptual. 1999; 5(4):312-318. https://www.derm101.com/dpc-archive/ october-december-1999-volume-5-no-4/dpc0504a03-neoplasmsin-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceouscarcinomas-and-squamous-cell-carcinomas-keratoacanthomasin-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/. accessed february 1, 2017. 31. kacerovska d, drlik l, slezakova l, et al. cutaneous sebaceous lesions in a patient with mutyh-associated polyposis mimicking muir-torre syndrome. am j dermatopathol. 2016;38(12):915923. 32. kazakov dv, kutner h, spagnolo dv et al. discordant architectural and cytologic features in cutaneous sebaceous neoplasms a classification dilemma: report of 5 cases. am j dermatopathol. 2009; 31(1):31-36. 33. resnik ks. the concepts of carcinoma in situ and carcinoma. am j dermatopathol. 2010; 32(8):855-856. 19. weedon d. weedon’s skin pathology. 2nd ed. new york, ny: churchill livingstone; 2002. 20. weedon d. weedon’s skin pathology. 3rd ed. new york, ny: churchill livingstone; 2009. 21. patterson jw. weedon’s skin pathology. 4th ed. philadelphia, pa: elsevier; 2016. 22. johnston rb. weedon’s skin pathology essentials. 2nd ed. edinburgh: elsevier; 2017. 23. chen s. a different view: sebaceous adenoma is sebaceous carcinoma in situ. dermatopathology: practical & conceptual. 2010;16(2):16. https://www.derm101.com/dpc-archive/ april-june-2010-volume-16-no.2/dpc1602a16-a-different-viewsebaceous-adenoma-is-sebaceous-carcinoma-in-situ/. accessed february 1, 2017. 24. kramer jm, chen s. sebaceous carcinoma in situ. am j dermatopathol. 2010; 32(8):854-855. 25. kazakov dv, kutzner h, spagnolo dv, et al. what is extraocular cutaneous sebaceous carcinoma in situ? am j dermatopathol. 2010; 32(8):857-858. 26. ackerman ab, nussen-lee s, tan ma. histopathologic diagnosis of neoplasms with sebaceous differentiation. atlas and text. 2nd ed. new york, ny: ardor scribendi; 2009. 27. currie gp, plaza ja, harris gj. intraepithelial sebaceous carcinoma: a case report of an unusual occurrence. am j dermatopathol. 2014;36(8):673-676. 28. lever wf. sebaceous adenoma; review of the literature and report of a case. arch derm syphilol. 1948; 57(1):102-111. https://www.derm101.com/dpc-archive/october-december-1999-volume-5-no-4/dpc0504a03-neoplasms-in-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceous-carcinomas-and-squamous-cell-carcinomas-keratoacanthomas-in-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/ https://www.derm101.com/dpc-archive/october-december-1999-volume-5-no-4/dpc0504a03-neoplasms-in-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceous-carcinomas-and-squamous-cell-carcinomas-keratoacanthomas-in-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/ https://www.derm101.com/dpc-archive/october-december-1999-volume-5-no-4/dpc0504a03-neoplasms-in-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceous-carcinomas-and-squamous-cell-carcinomas-keratoacanthomas-in-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/ https://www.derm101.com/dpc-archive/october-december-1999-volume-5-no-4/dpc0504a03-neoplasms-in-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceous-carcinomas-and-squamous-cell-carcinomas-keratoacanthomas-in-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/ https://www.derm101.com/dpc-archive/october-december-1999-volume-5-no-4/dpc0504a03-neoplasms-in-all-organs-of-muir-torre-syndrome-are-carcinomas-sebaceous-carcinomas-and-squamous-cell-carcinomas-keratoacanthomas-in-skin-and-adenocarcinomas-squamous-cell-carcinomas-an/ dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(2):e2023090 1 nail dermatologist and patient educational content lacks adequate skin of color representation: implications for care julianne m. falotico1, shari r. lipner2 1 renaissance school of medicine at stony brook university, stony brook, ny, usa 2 weill cornell medicine, department of dermatology, new york, ny, usa citation: falotico jm, lipner sr. nail dermatologist and patient educational content lacks adequate skin of color representation: implications for care. dermatol pract concept. 2023;13(2):e2023090. doi: https://doi.org/10.5826/dpc.1302a90 accepted: september 22, 2022; published: april 2023 copyright: ©2023 falotico et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: ms. falotico has no conflicts of interest. dr. lipner has served as a consultant for ortho dermatologics, verrica, hoth therapeutics, belletorus corporation, and hexima. authorship: all authors have contributed significantly to this publication. corresponding author: shari r. lipner md, phd 1305 york avenue, ny, ny 10021. phone: 646-962-3376 fax: 646-962-0033 email: shl9032@med.cornell.edu skin of color (soc) representation in dermatology educational content is lacking, which has been recognized only recently [1]. poor inclusion of soc images in training materials may contribute to delays and missed diagnoses in soc patients [2], which can have significant implications for care. in an analysis of trends of soc representation in dermatology textbooks over time [3], on average, there were only 11.5% of fitzpatrick skin type v-vi images across 26 dermatology textbooks, with an overall 1.3% average increase in representation with later textbook editions. in this commentary, we corroborate these findings of limited soc representation specifically for nail diseases in dermatology textbooks, review other learning modalities, and highlight resources for soc images. in an analysis of 1288 nail images of 34 nail conditions across nine dermatology and nail-specialty textbooks [4], only 4% of images overall represented skin types v-vi, with no v-vi representation for 47.1% (16/34) of nail conditions. the mean proportion of v–vi nail images per textbook was 6.6% (range 0.9%–23.5%). compared to all dermatology images [3], nail-specific images had less v-vi representation in 80% (4/5) of textbooks (table 1). therefore, nail conditions lack adequate soc representation in dermatology textbooks. in a google image analysis of the same 34 nail conditions [5], categorizing the first 50 images per condition by fitzpatrick skin type, only 8% of 1700 images demonstrated v-vi skin types. the highest proportion of v-vi images were found for anonychia (36%) and longitudinal melanonychia (22%), with no v-vi images for onychomycosis, despite it being the most common nail disease encountered in clinical practice [6]. therefore, public education images of nail pathology in soc patients are lacking. in addition, in a systematic review of 182 onychomycosis clinical trials (1988– 2020) [7], only 5.4% (8/149) of 2 commentary | dermatol pract concept. 2023;13(2):e2023090 participant images depicted skin types v-vi. there was a decrease in the proportion of v-vi onychomycosis images from 15.7% to 2.1% between 1996 and 2020. therefore, there is a need to recruit diverse patient populations in nail clinical trials and depict images of participants with darker fitzpatrick skin types in publications. taken together, these findings highlight inadequate demonstration of nail pathology in soc for both dermatologist and patient education. there is limited nail training during dermatology residency [8], and the lack of adequate representation of nail pathology across all skin types in different educational platforms further compounds this problem. therefore, we encourage dermatology residents and attendings to supplement their learning with resources that prioritize soc education and/or have sections specific to soc, such as websites for visualdx, skin deep, and the skin of color society [9]. while the need to diversify physician and patient dermatological content has been recognized, there is a lag in implementing change, particularly for nail content. failure to sufficiently portray educational soc nail images may result in worse outcomes for this patient population. therefore, dermatology residency programs should use dedicated soc resources to demonstrate nail pathology during didactic lectures, and dermatologists who review online medical websites should advocate for increased diversity specifically for nail content. references 1. adelekun a, onyekaba g, lipoff jb. skin color in dermatology textbooks: an updated evaluation and analysis. j am acad dermatol. 2021;84(1):194-196. doi: 10.1016/j.jaad.2020.04.084. pmid: 32335181. 2. lester j, taylor s, chren m. under-representation of skin of colour in dermatology images: not just an educational issue. br j dermatol. 2019;180(6):1521-1522. doi: 10.1111 /bjd.17608. pmid: 31157429. 3. abduelmula a, akuffo-addo e, joseph m. the progression of skin color diversity and representation in dermatology textbooks. j cutan med surg. 2022;26(5):523-525. doi: 10.1177 /12034754221099668. pmid: 35544370. 4. falotico jm, lipner sr. lack of skin of color images of nail conditions in dermatology textbooks. int j dermatol. 2023;62(1):e48-e50. doi: 10.1111/ijd.16028. pmid: 34865217. 5. falotico jm, lipner sr. few skin of color images in google image searches of nail conditions. int j dermatol. 2023;62(3):e153-e155. doi: 10.1111/ijd.16121. pmid: 35119690. 6. lipner sr, scher rk. onychomycosis: clinical overview and diagnosis. j j am acad dermatol. 2019;80(4):835-851. doi: 10.1016/j.jaad.2018.03.062. pmid: 29959961. 7. chang mj, qiu y, lipner sr. race reporting and representation in onychomycosis clinical trials: a systematic review. mycoses. 2021; 64(8):954-966. doi: 10.1111/myc.13262. pmid: 33655595. 8. hare aq, rich p. clinical and educational gaps in diagnosis of nail disorders. dermatol clin. 2016;34(3):269-273. doi: 10.1016/j.det.2016.02.002. pmid: 27363883. 9. chang mj, lipner sr. resources for skin of color images. j am acad dermatol. 2021;84(6):e275-e277. doi: 10.1016/j .jaad.2021.01.040. pmid: 33484764. table 1. proportion of fitzpatrick skin type v-vi images for all dermatology images and nail-specific images in five dermatology textbooks. textbook all dermatology images [3] nail images [4] jean bolognia et al., eds. dermatology. 4th ed. elsevier; 2018. 13.53 5.9 klaus wolff et al., eds. fitzpatrick’s color atlas and synopsis of clinical dermatology. 8th ed. mcgraw-hill education; 2017. 7.64 6.7 thomas p. habif. clinical dermatology: a color guide to diagnosis and therapy. 6th ed. saunders; 2015. 4.88 1.4 christopher e. m. griffiths et al., eds. rook’s textbook of dermatology. 8th ed. john wiley & sons, ltd; 2010 9.56 5.9 brian j. hall, john c. hall, eds. sauer’s manual of skin diseases. 11th ed. wolters kluwer; 2017. 15.99 23.5 dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023078 1 eosinophilic pustular folliculitis in the setting of solid organ transplant immunosuppression jeffrey chen1, colleen j beatty2, lauryn m falcone3, joseph c english iii3, viktoryia kazlouskaya2 1 university of pittsburgh school of medicine, pittsburgh, pennsylvania, united states 2 university of pittsburgh department of dermatology/dermatopathology, pittsburgh, pennsylvania, united states 3 university of pittsburgh department of dermatology, pittsburgh, pennsylvania, united states key words: eosinophilic pustular folliculitis, ofuji disease, hematopoietic stem cell transplantation, immunosuppression, immune reconstitution inflammatory syndrome citation: chen j, beatty cj, falcone lm, english jc, kazlouskaya v. eosinophilic pustular folliculitis in the setting of solid organ transplant immunosuppression. dermatol pract concept. 2023;13(2):e2023078. doi: https://doi.org/10.5826/dpc.1302a78 accepted: june 20, 2023; published: april 2023 copyright: ©2023 chen et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: viktoryia kazlouskaya, md, phd, university of pittsburgh, department of dermatology and dermatopathology, medical arts building, 3708 5th avenue, suite 500.68, pittsburgh, pennsylvania 15213 e-mail: viktoriakozlovskaya@yahoo.com introduction eosinophilic pustular folliculitis (epf) is an inflammatory dermatosis that presents as follicular papulopustules with pronounced eosinophils. subtypes include classic epf, infancy-associated epf, and immunosuppression-associated epf (is-epf). is-epf can be sub-divided into hiv-associated (is/hiv) and non-hiv-associated (is/non-hiv), with the latter associated with hematologic malignancy, particularly after hematopoietic stem cell transplantation (hsct) [1]. herein, we describe a case of is-epf in the setting of chronic immunosuppression due to cardiac transplantation. this is the second reported case of is-epf associated with solid organ transplant, with the first reported case in 2014 by kim et al [2]. case presentation a 69-year-old male on long-term immunosuppression for cardiac transplantation secondary to non-ischemic cardiomyopathy was evaluated for a diffuse pruritic rash that began several weeks after switching medications from tacrolimus to sirolimus. skin examination revealed multiple erythematous to purpuric papules involving the torso, upper back, and upper extremities (figure 1). exanthematous drug eruption was favored as the initial diagnosis due to temporal correlation, but graft-versus-host disease, neutrophilic dermatitis, and infectious process were also considered. histopathological examination revealed mid-dermal perifollicular collections of lymphocytes, histiocytes, and 2 research letter | dermatol pract concept. 2023;13(2):e2023078 prominent eosinophils (figure 2). gms, gram, afb, and pas stains were negative. biopsy findings were consistent with epf, likely associated with the patient’s immunosuppression. the patient was treated with triamcinolone acetonide cream and showed gradual resolution. conclusions while the pathophysiology of epf is unknown, prostaglandin d2 (pgd2) and the il-36 cytokine family are speculated to be involved in the folliculotropic infiltration of eosinophils [3,4]. increases in pgd2 production in epf have been demonstrated to increase mrna expression of eotaxin-3, which is an eosinophilic chemotactic factor produced by sebocytes [3]. il36α, il-36β, il-36γ, and il36ra are known modulators of the cutaneous inflammatory response involved in eosinophil recruitment. previous studies showed that il-36β, il-36γ, and il36ra are upregulated in epf. interestingly, the expression of il36ra was negatively correlated with il-36β and il-36γ in normal skin, suggesting figure 1. erythematous swollen papulopustules on the back. that the expression patterns of il-36β, il-36γ, and il36ra contribute partially to the eosinophil migration in epf [4]. unlike classic epf, the lesions observed in is-epf are less strongly associated with the formation of pustules and do not show the same predilection for the face, as they tend to affect the upper body and extremities [1]. moreover, is-epf responds more favorably to topical or systemic steroids compared to classic epf suggesting different pathogenesis [5]. the clinicopathological features of this case are similar to those observed in is/non-hiv patients, specifically, cases of is-epf that developed after hsct. a study by sasaki et al likened the lesions of is-epf following hsct to the development of is-epf in hiv patients caused by immune reconstitution inflammatory syndrome (iris) [6]. in our case, the patient developed epf after his tacrolimus was switched to sirolimus, which is a decrease in immunosuppression and a step closer to immune reconstitution. accordingly, this case provides preliminary evidence to suggest a relationship between iris and is-epf in the setting of solid organ transplant immunosuppression, however, further accumulation of cases is needed to investigate this potential association. research letter | dermatol pract concept. 2023;13(2):e2023078 3 figure 2. (a) perifollicular granulomatous inflammation (h&e, x200). (b) high power demonstrating numerous eosinophils in the infiltrate (h&e stain, x400). (c) another focus with keratin remnants surrounded by granulomatous inflammation (h&e stain, x200). (d) high power demonstrating numerous eosinophils in the infiltrate (h&e stain, x400). references 1. katoh m, nomura t, miyachi y, kabashima k. eosinophilic pustular folliculitis: a review of the japanese published works. j dermatol. 2013;40(1):15-20. doi: 10.1111/1346-8138.12008. pmid: 23083212. 2. kim bw, lee jh, won ch, et al. eosinophilic pustular folliculitis: association with long-term immunosuppressant use in a solid organ transplant recipient. ann dermatol. 2014;26(4):520-521. doi: 10.5021/ad.2014.26.4.520. pmid: 25143686. pmcid: pmc4135112. 3. nakahigashi k, doi h, otsuka a, et al. pgd2 induces eotaxin-3 via pparγ from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis. j allergy clin immunol. 2012;129(2):536-543. doi: 10.1016/j.jaci.2011.11.034. pmid: 22206772. 4. sato s, chiba t, nakahara t, furue m. upregulation of il-36 cytokines in folliculitis and eosinophilic pustular folliculitis. australas j dermatol. 2020;61(1):e39-e45. doi: 10.1111 /ajd.13143. pmid: 31424098. 5. nomura t, katoh m, yamamoto y, miyachi y, kabashima k. eosinophilic pustular folliculitis: a published work-based comprehensive analysis of therapeutic responsiveness. j dermatol. 2016;43(8):919-927. doi: 10.1111/1346-8138.13287. pmid: 26875627. 6. sasaki y, kishi a, takagi s, uchida n, hayashi n. eosinophilic pustular folliculitis after hematopoietic stem cell transplantation: a study of 11 cases. j dermatol. 2021;48(5):e231-e233. doi: 10.1111/1346-8138.15846. pmid: 33715192. pmcid: pmc8251622. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(3):e2023166 1 trichodysplasia spinulosa in a 71-year-old heart transplant recipient maulik m dhandha1, debjit ghosh2, james dekay3 1 woodland clinic dignity health, woodland, ca 2 mgl group, rajkot, india 3 maine general medical center, augusta, me citation: dhandha mm, ghosh d, dekay j. trichodysplasia spinulosa in a 71-year-old heart transplant recipient. dermatol pract concept. 2023;13(3):e2023166. doi: https://doi.org/10.5826/dpc.1303a166 accepted: january 25, 2023; published: july 2023 copyright: ©2023 dhandha et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maulik m dhandha, md, woodland clinic, 632 w gibson road, woodland, ca. e-mail: maulikdhandha@gmail.com case presentation a 71-year-old caucasian male with a past medical history of heart transplant approximately 18 months ago, on tacrolimus and prednisone presented with chief complaints of redness on the face and hair loss on the eyebrows and mustaches. on examination, he had small spicules overlying scaly erythematous plaques on scalp, eyebrows, chin, upper cutaneous lip and nose (figure 1). skin biopsy showed dilated and distorted follicles with absent hair shaft and expansion of the matrix from the inner root sheath and outer root sheath with dense keratohyalin granules (figure 2), which are concerning for trichodysplasia spinulosa (ts). figure 1. small spicules overlying thin erythematous plaque on the right ala. figure 2. histopathology showing dilated and distorted follicles with absent hair shaft and expansion of the matrix from the inner root sheath and outer root sheath with dense keratohyalin granules. 2 image letter | dermatol pract concept. 2023;13(3):e2023166 the patient was given an oral valganciclovir low dose of 450 mg daily. at follow up in 4 weeks, the erythema and spicules were significantly decreased. he continued the regimen for another 4 weeks and only had minimal erythema and spicules remaining. given his history of chronic kidney disease, valganciclovir was stopped with caveat to restart it for short duration as needed. teaching point ts is a rare dermatological condition which was first reported in the year 1995, and named later in the year 1999. ts is often known as an emerging infectious disease. however, the cases of ts may rise due to the increase in the number of patients on immunosuppressive drug regimens [1]. differential diagnosis for ts includes trichostasis spinulosa, follicular hyperkeratotic spicules associated with multiple myeloma, lichen spinulosus, spiky follicular mycosis fungoides, disseminated spiked hyperkeratosis, ulerythema ophryogenes, follicular-based graft versus host disease. trichodysplasia spinulosa polyomavirus (tspyv) infects the skin, but in asymptomatic cases the viral dna is rarely found even if the individuals possess antibodies to the virus. as it is a rare disease, there is no gold standard treatment available till date, but ts has to be timely diagnosed otherwise it may develop into leonine facies [2]. references 1. curman p, nasman a, brauner h. trichodysplasia spinulosa: a comprehensive review of the disease and its treatment. j eur acad dermatol venereol. 2021;35(5):1067-1076. doi: 10.1111/ jdv.17081. pmid: 33559344. pmcid: pmc8247895. 2. haycox cl, kim s, fleckman p, et al. trichodysplasia spinulosa--a newly described folliculocentric viral infection in an immunocompromised host. j investig dermatol symp proc. 1999;4(3): 268-271. doi: 10.1038/sj.jidsp.5640227. pmid: 10674379. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022192 1 impact of covid-19 pandemic on hidradenitis suppurativa patients: a cross-sectional study from tertiary referral hospital ecem bostan1, adam jarbou1, aysen karaduman1, duygu gulseren1, basak yalici-armagan1, neslihan akdogan1 1 department of dermatology and venereology, hacettepe university, faculty of medicine, ankara, turkey key words: covid-19, hidradenitis suppurativa, impact, treatment citation: bostan e, jarbou a, karaduman a, gulseren d, yalici-armagan b, akdogan n. impact of covid-19 pandemic on hidradenitis suppurativa patients: a cross-sectional study from tertiary referral hospital. dermatol pract concept. 2022;12(4):e2022192. doi: https://doi.org/10.5826/dpc.1204a192 accepted: march 21, 2022; published: october 2022 copyright: ©2022 bostan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ecem bostan, md, hacettepe university, faculty of medicine, department of dermatology and venereology, ankara, turkey, phone: 03123051704, fax: 0 3123054127, e-mail: bostanecem@gmail.com introduction: hidradenitis suppurativa (hs) is a chronic, disabling skin disorder which is characterized by recurrent attacks of nodule, abscess, sinus tract formation and scarring. oral/topical antibiotics, oral retinoids and tnf-alpha inhibitors are used for the treatment of hs. objectives: in the present study, we aimed to determine the prevalence of coronavirus disease 2019 (covid-19) real-time polymerase chain reaction (real-time pcr) positivity and the presence of covid-19 related symptoms in relation to the age, gender, body mass index, disease duration, treatment used for hs, treatment duration and smoking. methods: we conducted a comparative, cross-sectional study of 178 patients diagnosed with hs in a referral hospital. age, gender, smoking status, body mass index, treatment modalities used for hs, the presence of covid-19 related symptoms, history of close contact to a person with covid-19 and covid-19 real time-pcr results were determined by a telephone questionnaire. results: sixty-three patients were female, whereas 115 patients were male. during covid-19 pandemic, 94 out of 178 patients had covid-19 related symptoms; covid-19 real time-pcr test was performed in 109 (61.2%) patients. thirty (27.5%) cases tested positive for covid-19 whereas 79 (72.5%) tested negative. abstract 2 original article | dermatol pract concept. 2022;12(4):e2022192 introduction hidradenitis suppurativa (hs) is a chronic, inflammatory, debilitating skin disorder characterized by painful, deep-seated nodules and abscesses, draining sinus tracts and cicatrisation [1]. the disease is more likely to be seen in the intertriginous areas of the body including groin, gluteal area, axillae and inframammary region [1]. hs is staged according to the type, extent and severity of the skin lesions [2]. single or multiple nodules or abscesses without sinus tracts and cicatrix formation refer to hurley stage 1; recurrent nodules or abscesses with limited sinus tract formation and scarring refers to hurley stage 2; whereas stage 3 disease is characterized by diffuse involvement of the affected area by nodules/abscesses, multiple interconnected sinus tracts and cicatrisation [2]. genetic, environmental, endocrinologic, bacterial and host defense related immunologic factors as well as obesity, smoking have all been implicated in the etiology of hs [3]. depression, inflammatory bowel disease, spondyloarthropathy, diabetes mellitus, hyperlipidemia and metabolic syndrome are among the common associated comorbidities in hs patients [4]. low self-confidence, sexual dysfunction, impairment of daily functioning, chronic anxiety and depression all lead to poor life quality for hs patients [5,6]. in the early stages of the disease characterized by only a few nodules or abscess, only systemic antibiotics in combination with topical antibiotics or intralesional corticosteroids, are usually enough to control disease activity [7,8]. however, advanced stages require both surgical intervention and systemic treatment modalities. tumor necrosis factor-alpha (tnf-α) inhibitors (especially adalimumab and infliximab) are the much-preferred agents used in the treatment of advanced stage hs, in combination with topical and systemic antibiotics [9]. during coronavirus disease 2019 (covid-19) pandemic, the safety of biologic agents is one of the most frequently investigated issues in dermatology practice. the use of antibiotics and tnf-α inhibitors in the patients with hs does not seem to increase the risk for covid-19 [10]. objectives in our study, we aimed to investigate the prevalence of covid-19 real-time polymerase chain reaction (real time-pcr) positivity and the presence of covid-19 related symptoms in relation to the age, gender, body mass index (bmi), smoking status, accompanying systemic diseases, disease duration and different treatment modalities used for hs. methods we conducted a cross-sectional, descriptive study of 178 hs patients who were followed up in our dermatology outpatient clinic. all 178 participants were clinically diagnosed with hs and further receiving various treatment modalities according to disease stage in our center’s chronic dermatologic illnesses outpatient clinic between january 2018 and september 2021. only patients who were under active-continuous treatment for hs during covid-19 pandemic, were included. local ethics committee approval was obtained for the present study (the date, project number, decision number: september 7, 2021, go 21/934, 2021/14-66). an oral questionnaire composed of 15 questions related to the demographical data, hs disease and covid-19, was formed (supplementary file  1). the answers were obtained via a telephone survey and an oral informed consent was taken from all the patients before the start of the survey. the accuracy of questions related to covid-19 status of the participants, characteristics of treatment given for hs and treatment duration, was also verified from the medical data records. ibm spss for windows version 20.0 was used for the statistical analysis. numerical variables were shown as mean ± standard deviation (range: minimum-maximum), whereas categorical variables were given as percentages and frequencies. shapiro-wilk test was used to determine if the numerical variables are distributed normally. fisher’s exact test or chi-square test was used to compare the differences between patients receiving various different modalities for hs (divided into 4 groups as oral antibiotics± topical antibiotics, oral retinoids± topical antibiotics, tnf-α inhibitors ± oral/topical antibiotics and only topical antibiotics).logistic regression analyses (in which age, gender, bmi, the presence of any other systemic disease and smoking were included as independent variables) were also performed taking the presence of covid-19 symptoms and covid-19 real time-pcr results (positive or negative) as the dependent variables. p  values less than 0.05 were considered statistically significant. conclusions: patients having covid-19 related symptoms were shown to have statistically significantly higher mean age compared to the ones who did not have any symptoms (p = 0.031). no statistically significant relationship was found covid-19 real time-pcr positivity and the type of treatment administered for hs when categorized as tumor necrosis factor-alpha inhibitor, oral retinoid, topical antibiotic and oral antibiotic group (p > 0.05). original article | dermatol pract concept. 2022;12(4):e2022192 3 results a total number of 178 patients were included in the study. the mean age was 35.69 ± 11.21 years (range:16-61). sixty-three (35.4%) patients were female, whereas 115 (64.6%) patients were male. fifty-two (29.2%) patients had hurley stage 1 disease, 52 (29.2%) patients had hurley stage 2 disease whereas 74 (41.6%) had stage 3 disease. the mean bmi was 27.55 ±3 .30 kg/ m2 (range:17.09-43.25); one (0.6%) patient had a bmi of <18.5 kg/m2 (underweight); 31 (17.4%) patients had a bmi in 18.5 to 24.9 kg/m2 range (optimal). one hundred ten (61.8%) out of 178 cases were determined to fall within the overweight category (a bmi of 25-29.9 kg/m2) whereas 36 (20.2%) patients were within the obese category (a bmi of >30 kg/m2). one hundred nine out of 178 patients were current smokers, the mean pack-years of smoking was 21.06 ± 14.12 pack-years (range: 3-80). the mean duration of treatment for hs was 18.37 ± 18.90 months (1-108) whereas the average duration of the disease was 119.38 ± 91.97 months (2-552). forty-eight (27%) cases were on oral antibiotics (doxycycline, clindamycin and rifampicin, only clindamycin, tetracycline) treatment either alone or combination with topical treatment modalities. thirty (16.9%) patients were on oral retinoid (isotretinoin or acitretin) treatment whereas 85 (47.8%) were using tnf-α inhibitors either alone or with oral/topical antibiotics. out of 85 patients from anti-tnf-α group, 9 (10.58 %) patients were under infliximab treatment, whereas 76 (89.41%) were under adalimumab treatment. patients with stage 2 and 3 hs were additionally using colchicine. out of 178 cases, 75 (42.1%) patients had at least one systemic disease. nineteen (10.7%) patients had rheumatologic illnesses (most common ones being familial mediterranean fever, behçet disease and ankylosing spondylitis); 22 (12.4%) patients had cardiovascular diseases most frequently being hypertension, coronary artery disease and heart failure. five (2.8%) case presented with nephrologic diseases whereas five other (2.8%) patients had prior history of malignancy. endocrinologic disorders such as diabetes mellitus, hypothyroidism and hyperlipidemia were seen in 33 (18.5%) cases, whereas respiratory diseases (most commonly asthma, allergic rhinitis) were present in 11 (6.2%) patients. during covid-19 pandemic, 94 (52.8%) out of 178 patients had covid-19 related symptoms such as fever, anosmia, ageusia, malaise, sore throat, dry cough, diarrhea and myalgia. covid-19 real time-pcr test was performed in one hundred nine (61.2%) out of 178 patients. thirty (27.5%) cases tested positive for covid-19 whereas 79 (72.5%) tested negative. forty-seven (26.4%) cases had a history of close contact to someone with a confirmed diagnosis of covid-19. of 109 patients with covid-19 real-time pcr test, 30 (27.5%) had positive test result whereas 79 (72.5%) were tested negative. the average age of patients with positive real-time pcr was statistically significantly higher compared to the patients with negative result (p=0.007) (table  1). there was no statistically significant relationship between gender versus covid-19 real-time pcr positivity (p = 0.275) and bmi vs covid-19 real-time pcr positivity (p = 0.873) (table 1). there was no statistically significant difference in covid-19 real-time pcr positivity between smokers and non-smokers (p = 0.111) (table 2). there was no statistically significant relationship between the mean pack-years of smoking of patients who tested positive and negative for covid-19 (p = 0.222) (table 2). we found a statistically significant relationship between covid-19 real-time pcr results and the mean disease duration for hs (p = 0.031) (table 3). the patients with positive real-time pcr results have a higher mean disease duration compared to the ones with negative covid-19 real-time pcr results. however, no statistically significant relationship was found between the positive results of covid-19 real-time pcr and the mean duration of treatment for hs (p = 0.716) (table 3). table 1: covid-19 real time-pcr results in relation to the age, gender and body-mass index. covid-19 real time-pcr results number of patients (n) age (years) gender body-mass index mean sd minimum maximum female n (%) male n (%) mean sd minimum maximum negative 79 35.65 9.94 17 60 27 (79.4) 52 (69.3) 27.38 3.17 17.09 38.74 positive 30 42.07 11.75 20 61 7 (20.6) 23 (30.7) 27.72 3.62 20.2 37.72 total 109 37.41 10.80 17 61 34 (100) 75 (100) 27.48 3.29 17.09 38.74 sd = standard deviation. the average age of patients with positive covid real time-pcr was statistically significantly higher compared to the patients with negative result (p < 0.007). there was no statistically significant relationship between the gender vs covid-19 real time-pcr results (p = 0.275). additionally, there was also no statistically significant relationship between the body-mass index versus covid-19 real time-pcr results (p = 0.873). 4 original article | dermatol pract concept. 2022;12(4):e2022192 categories as tnfα inhibitors ± oral/topical antibiotics and others (p = 0.248). in all patients, with a confirmed diagnosis of covid-19; anti-tnf-α treatment was immediately suspended until full recovery from the disease. lastly, there was no statistically significant relationship between covid-19 real time-pcr results and the presence of previous malignancy history; respiratory, cardiovascular, no statistically significant relationship was found between covid-19 real-time pcr positivity and the type of treatment administered for hs when the treatment modalities are divided into four categories as oral antibiotics± topical antibiotics, oral retinoids ± topical antibiotics, tnf-α inhibitors ± oral/topical antibiotics and only topical antibiotics (p = 0.657) (table 4 and figure 1) or divided into two table 2. covid-19 real time-pcr results in relation to smoking status and pack-years of smoking. covid-19 real time-pcr results number of patients smoking status pack-years of smoking (among smokers) non-smoker n (%) smoker n (%) number of patients mean sd minimum maximum negative 79 24 (63.2) 55 (77.5) 55 21.73 15.11 4 80 positive 30 14 (36.8) 16 (22.5) 16 25.75 14.85 10 54 total 109 38 (100) 71 (100) 71 22.63 15.04 4 80 there was no statistically significant difference in covid-19 real time-pcr positivity between smokers and non-smokers (p = 0.111). among smokers, no statistically significant relationship was found between the mean pack-years of smoking of patients who tested positive and negative for covid-19 (p = 0.222). table 3. covid-19 real time-pcr results in relation to disease duration and treatment duration. covid-19 real time-pcr results negative positive total disease duration (months) number of patients 79 30 109 mean 109.29 155.40 121.98 standard deviation 82.15 112.99 93.43 minimum 2 4 2 maximum 432 552 552 treatment duration (months) mean 19.37 16.77 18.65 standard deviation 19.15 13.80 17.81 minimum 1 1 1 maximum 84 48 84 statistically significant relationship was present between covid-19 real time-pcr results and the mean disease duration for hs (p = 0.031). the patients with positive real time-pcr results have a higher mean disease duration compared to the ones with negative covid-pcr results. however, no statistically significant relationship was found between the positive results of covid-19 real time-pcr and the mean duration of treatment for hs (p = 0.716). table 4. covid-19 real time-pcr results with respect to the treatment groups. covid-19 real time-pcr results treatment groups oral antibiotics ± topical antibiotics n (%) oral retinoids ± topical antibiotics n (%) tnf-alpha inhibitors ± oral/topical antibiotics n (%) only topical antibiotics n (%) negative 20 (74.1) 15 (78.9) 35 (67) 9 (81.8%) positive 7 (25.9) 4 (21.1) 17 (33) 2 (18.2) total 27 (100) 19 (100) 52 (100) 11 (100) no statistically significant relationship was found between covid-19 real time-pcr positivity and the type of treatment administered for hs when the treatment modalities are divided into four categories as oral antibiotics± topical antibiotics, oral retinoids± topical antibiotics, tnf-alpha inhibitors ± oral/topical antibiotics and only topical antibiotics (p = 0.657) original article | dermatol pract concept. 2022;12(4):e2022192 5 significantly higher pack-years of smoking compared to the ones with no symptoms (p = 0.024) (figure 4). as expected, there seems to be a statistically significant relationship between the presence of covid-19 symptoms and covid-19 rt-pcr positivity (p < 0.001) (table 5). of 109 patients who were tested for covid-19, 75 (68.8 %) had covid-19 related symptoms; 30 (40%) cases out of 75 cases with covid-19 related symptoms, were tested positive for covid. thirty-four patients who did not demonstrate any symptoms still gave covid-19 pcr test, were all tested negative. of 109 patients who were tested for covid-19, 43 (39.45 %) had close contact to someone with a confirmed diagnosis of covid-19; whereas 66 (60.55%) did not have any close contact. twenty-seven (62.8%) cases out of 43 with close contact to a person diagnosed with covid-19 had positive rt-pcr result. we found a statistically significant relationship between the history of close contact to someone with a confirmed covid-19 diagnosis and covid-19 rt-pcr positivity (p < 0.001) (table 5). no patient was hospitalized for severe covid-19 infection. binary logistic regression analyses (in which age, gender, bmi, the presence of any other systemic disease and smoking were included as independent variables) were performed nephrological diseases, endocrinologic and rheumatologic disorders (p > 0.05). patients having covid-19 related symptoms were shown to have statistically significantly higher mean age compared to the ones who did not have any symptoms (p = 0.031). the percentage of patients with covid-19 related symptoms according to the treatment type was shown in figure 2. we found no statistically significant relationship between the presence of covid-19 symptoms and the gender (p = 0.241), bmi (p = 0.472), cigarette smoking (p  =  0.272), treatment duration (p = 0.353), disease duration (p = 0.850) and given treatment type when grouped as oral antibiotics± topical antibiotics, oral retinoids, tnf-α inhibitors ± oral/topical antibiotics, colchicine and topical antibiotics (p = 0.124). patients with cardiovascular disease were shown to present with covid-19 related symptoms compared to the ones with no accompanying cardiovascular disease (p = 0.035). additionally, patients who had at least one systemic disease (classified as respiratory, nephrologic, cardiovascular, rheumatologic, gastroenterologic, endocrinologic disorders) had higher probability to exhibit covid-19 symptoms (figure 3). lastly, patients who reported to have covid-19 related symptoms were shown to present with p e r c e n t a g e o f p a t ie n t s w it h p o s it iv e c o v id -1 9 r t -p c r percentage of patients with positive covid-19 rt-pcr vs treatment type treatment type 50.0% 45.0% 25.9% 21.1% 33.0% 18.2% 40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% oral antibiotics (n=27) topical antibiotics (n=11) oral retinoids (n=19) tnf-alfa inhibitors (n=52) figure 1. the percentage of the patients with a positive covid-19 real-time polymerase chain reaction (rt-pcr) result according to the treatment type. 6 original article | dermatol pract concept. 2022;12(4):e2022192 the presence of any other systemic disease were considered as independent variables) were also carried out by taking covid-19 rt-pcr result (positive or negative) as the dependent variable. as a result, it was found that age, gender, bmi and the presence of at least one systemic illness did not contribute significantly to the outcome of covid-19 test result. taking the presence of covid-19 symptoms as the dependent variable. smoking (odds ratio [or] 2.595; 95% confidence interval: 1.009-6.674; p = 0.048) and the presence of any other systemic illness (or 6.968; 95% interval: 2.754-17.631; p < 0.001) were associated with an increased risk of developing covid-19 related symptoms. in addition, logistic regression analyses (in which age, gender, bmi and p e r c e n t a g e o f p a t ie n t s w it h c o v id -1 9 r e la t e d s y m p t o m s treatment type oral antibiotics (n=27) topical antibiotics (n=11) oral retinoids (n=19) 100.0% 35.4% 40.0% 55.0% 53.3% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% tnf-alfa inhibitors (n=52) percentage of patients with covid-19 related symptoms vs treatment type figure 2. the percentage of the patients with covid-19 related symptoms according to the treatment type. 60% 40% 62% a bpatients without any systematic disease (n=103) patients with at least one systemic disease (n=75) 38% absent covid-19 symptomsabsent covid-19 symptoms present covid-19 symptomspresent covid-19 symptoms figure 3. the distribution of the percentages of the patients with absent and present covid-19 related symptoms among the participants without any systematic disease (a) and among the participants with at least one systematic disease (b) original article | dermatol pract concept. 2022;12(4):e2022192 7 females compared to males with a ratio of 3:1 [6,14]. since patients with hs suffer from acute (bacterial superinfections, lymphadenopathy) and chronic complications of the disease (amyloidosis, chronic disease anemia, lymphedema, lymphatic obstruction, significant scarring, chronic pain, malodor and fistula formation) [15] ; early diagnosis and adequate treatment of this debilitating disease are quite essential. topical and systemic antibiotics, anti-inflammatory agents, anti-androgens, oral retinoids, immunosuppressive treatments, tnf-α inhibitors (especially adalimumab and infliximab), apremilast, surgical intervention and laser excision repair are among the miscellaneous therapeutic interventions used for hs [16]. generally, hurley stage 1 hs is treated conclusions hs is one of the most challenging diseases of dermatology, which has a great impact on patients quality of life and presents with various associated comorbidities. the disease is characterized by deep-seated, tender, inflamed, draining nodules and abscesses subsequently leading to sinus tract and scar formation mainly in the flexural areas of the body [11]. hs is most commonly seen in the third and fourth decades of life [12]. since different clinical entities including furunculosis, nodulocystic acne, epidermoid cyst, cutaneous crohn disease may be considered in the differential diagnoses of hs, a mean diagnostic delay of 7.2 years has been reported in a study [13]. the disease is more commonly observed in 70 60 50 40 30 32 33 3 present absent 21 15 10 60 20 20 10 10 0 5 pack-years of smoking vs. covid-19 symptoms p=0.024 covid-19 symptoms p a c k -y e a r s o f s m o k in g figure 4. the pack-years of smoking according to the absence and presence of covid-19 symptoms: boxplot representing median values, 25-75% range (box) and minimum-maximum range (bars) of the pack-years of smoking with respect to the patients with covid-19-related symptoms and patients without any covid-19-related symptoms. table 5. covid-19 real-time pcr results with respect to the presence of covid-19-related symptoms and close contact to someone with a diagnosis of covid-19. covid-19 real time-pcr results covid-19 related symptoms n (%) close contact to someone with a diagnosis of covid-19 n (%) not present present not present present total negative 34 (100) 45 (60) 63 (95.5) 16 (37.2) 79 (72.5) positive 0 (0) 30 (40) 3 (4.5) 27 (62.8) 30 (27.5) total 34 (100) 75 (100) 66 (100) 43 (100) 109 (100) p < 0.001 p < 0.001 statistically significant relationships were found between covid-19 real time-pcr positivity versus history of close contact to someone with a confirmed covid-19 diagnosis (p < 0.001) and between covid-19 real time-pcr positivity versus the presence of covid-19 related symptoms (p < 0.001). 8 original article | dermatol pract concept. 2022;12(4):e2022192 patients with hs have multiple associated comorbidities including metabolic syndrome, obesity, diabetes mellitus, dyslipidemia, polycystic ovarian syndrome, thyroidal dysfunction, axial spondyloarthropathy and cardiovascular associated adverse events [22]. a recent meta-analysis revealed that cardiovascular diseases, obesity, hypertension, history of smoking, old age are also risk factors for critical and mortal cases of covid-19 infection [23]. being male, smoking and being at an age greater than 65 years were shown to be associated with covid-19 disease progression [23]. critical covid-19 cases had higher rates of having underlying diseases such as hypertension, cardiovascular disease and diabetes mellitus compared to the non-critical covid-19 patients [23]. even though, in our cohort no patient was needed to be hospitalized for severe covid-19, we found that the mean age of the patients with positive results of covid rt-pcr was statistically significantly higher compared to the ones with negative results (p < 0.007). additionally, patients who demonstrated covid-19 related symptoms were shown to have statistically significantly higher average age compared to the ones who did not demonstrate any symptoms (p = 0.031). in line with the data in the literature, patients who had any cardiovascular disease (most common one being hypertension) were shown to have covid-19 related symptoms at a higher rate compared to the ones with no accompanying cardiovascular disease (p = 0.035). wang et al [24] showed that hypertension prevalence was higher in covid-19 patients admitted to intensive care unit compared to ones who did not. in our study, we have also showed that patients who had at least one systemic disease had higher proportions of demonstrating covid-19 symptoms compared to the ones who did not have any known systemic comorbidity. a recent study by lowe et al [25] revealed that patients with > 30 pack-years of smoking were 2.25 times more likely to be hospitalized. even though, we did not have any patient who was hospitalized for covid-19, our study disclosed that patients with covid-19 symptoms were shown to have statistically significantly higher pack-years of smoking compared to the ones without any symptoms (p = 0.024). lastly, we found no statistically significant relationship between the presence of covid-19 symptoms/covid-19 rt-pcr positivity and gender, bmi, smoking status (current smoker vs non-smoker) and treatment duration (p > 0.05). in contrast, a study which investigated the relationship between covid-19 and metabolic associated fatty liver disease, showed that obesity significantly increases the risk of having severe covid-19 disease [26]. since in our cohort population, not all the patients with covid-19 related symptoms and with a history of close contact to someone with a confirmed diagnosis of covid-19, were tested for covid-19 we might have missed some real positive covid-19 cases which might have limited our findings. with topical and systemic antibiotics, surgical procedures; systemic antibiotics, oral retinoids, anti-tnfα agents, surgical deroofing or laser excision are used for stage 2 and 3 disease [16]. from the start of covid-19 outbreak in december 2019, the effect of immunosuppressive agents on the clinical course of covid-19 is gradually being questioned by both physicians and patients [17]. covid-19 infection is a multiphasic viral disease which commences with an antiviral response phase followed by an hyperinflammatory state [17,18]. the main cytokines that dominate the first (antiviral) phase differ from the cytokines which prevail the hyperinflammatory phase [18]. interleukin (il)-15, interferon-α, interferon-β and interferon-γ are the major cytokines responsible for viral clearance whereas tnf-α, il-17, il-6 and granulocyte-monocyte colony stimulating factor preponderate during the hyperinflammatory phase [17,18]. therefore, it seems reasonable to use anti-tnfα and anti-il-17 agents during the hyperinflammatory state of covid-19 since these agents do not seem to affect the course of the antiviral phase [18]. in phase 3 trials of adalimumab for hs, it was shown that there is a slightly escalated risk for total infections and nasopharyngitis by 2.5% but there was no significant difference between adalimumab and placebo group in terms of upper respiratory tract infections [19]. in line with this observation, in our study we found that no statistically significant relationship exists between covid-19 real-time pcr positivity and the therapeutic interventions used for hs when the treatment modalities are divided into four categories as oral antibiotics ± topical antibiotics, oral retinoids ± topical antibiotics, tnf-α inhibitors ± oral/topical antibiotics and only topical antibiotics (p = 0.657). also, similar to our study, marasca et al [20] reported their experience with 93 hs patients during covid-19 pandemic. in this study, 75 patients were on adalimumab treatment, 15  patients were using oral antibiotics and 3 patients were not on any treatment [20]. only one patient reported covid-19 related symptoms which subsided immediately and three patients (one under rifampicin+clindamycin treatment, the two others under adalimumab treatment) had been isolated due to a close contact to someone with a suspected diagnosis of covid-19, without having positive real-time pcr test result [20]. furthermore, molinelli et al [21] declared that none of the 35 patients treated with adalimumab for hs in their cohort group had any symptoms related to covid-19 and the ongoing biologic treatment was not discontinued in any patient. supporting the findings of this study, we also did not find any statistically significant difference between the presence of covid-19 symptoms and the given treatment modalities when categorized as oral antibiotics± topical antibiotics, oral retinoid, tnf-α inhibitors ± oral/topical antibiotics and topical antibiotics (p = 0.124). original article | dermatol pract concept. 2022;12(4):e2022192 9 10. giamarellos-bourboulis ej, bettoli v, jemec gbe, et al. anti-covid-19 measurements for hidradenitis suppurativa patients. exp dermatol. 2021;30 suppl 1(suppl 1):18-22. doi: 10.1111/exd.14339. pmid: 34085330. pmcid: pmc8207032. 11. wolk k, join-lambert o, sabat r. aetiology and pathogenesis of hidradenitis suppurativa. br j dermatol. 2020;183(6):999-1010. doi: 10.1111/bjd.19556. pmid: 33048349. 12. vazquez bg, alikhan a, weaver al, wetter da, davis md. incidence of hidradenitis suppurativa and associated factors: a population-based study of olmsted county, minnesota. j invest dermatol. 2013;133(1):97-103. doi: 10.1038/jid.2012.255. pmid: 22931916. pmcid: pmc3541436. 13. saunte dm, boer j, stratigos a, et al. diagnostic delay in hidradenitis suppurativa is a global problem. br j dermatol. 2015;173(6):1546-1549. doi: 10.1111/bjd.14038. pmid: 26 198191. 14. miller im, mcandrew rj, hamzavi i. prevalence, risk factors, and comorbidities of hidradenitis suppurativa. dermatol clin. 2016;34(1):7-16. doi: 10.1016/j.det.2015.08.002. pmid: 26617352. 15. yuan jt, naik hb. complications of hidradenitis suppurativa. semin cutan med surg. 2017;36(2):79-85. doi: 10.12788/j. sder.2017.022. pmid: 28538749. 16. agrawal a, sharma yk. errata: review article: hidradenitis suppurativa: a systematic review and meta-analysis of therapeutic interventions. indian j dermatol venereol leprol. 2019;85(6):617. doi: 10.4103/ijdvl.ijdvl_453_19. pmid: 31512583. 17. jones me, kohn ah, pourali sp, et al. the use of biologics during the covid-19 pandemic. dermatol clin. 2021;39(4):545-553. doi: 10.1016/j.det.2021.05.010. pmid: 34556244. pmcid: pmc8166518. 18. schett g, sticherling m, neurath mf. covid-19: risk for cytokine targeting in chronic inflammatory diseases? nat rev immunol. 2020;20(5):271-272. doi: 10.1038/s41577-020-0312-7. pmid: 32296135. pmcid: pmc7186927. 19. kimball ab, okun mm, williams da, et al. two phase 3 trials of adalimumab for hidradenitis suppurativa. n engl j med. 2016;375(5):422-434. doi: 10.1056/nejmoa1504370. pmid: 27518661. 20. marasca c, ruggiero a, megna m, annunziata mc, fabbrocini g. biologics for patients affected by hidradenitis suppurativa in the covid-19 era: data from a referral center of southern italy. j dermatolog treat. 2022;33(1):592. doi: 10.1080/09546634.2020.1769828. pmid: 32403954. 21. molinelli e, diotallevi f, simonetti o, et al. management of patients with hidradenitis suppurativa during the covid-19 pandemic: risk and benefit of immunomodulatory therapy. dermatol ther. 2020;33(6):e14256. doi: 10.1111/dth.14256. pmid: 32860474. 22. cartron a, driscoll ms. comorbidities of hidradenitis suppurativa: a review of the literature. int j womens dermatol. 2019;5(5):330-334. doi: 10.1016/j.ijwd.2019.06.026. pmid: 31909152. pmcid: pmc6938918. 23. zheng z, peng f, xu b, et al. risk factors of critical & mortal covid-19 cases: a systematic literature review and meta-analysis. j infect. 2020;81(2):e16-e25. doi: 10.1016/j. jinf.2020.04.021. pmid: 32335169. pmcid: pmc7177098. 24. wang d, hu b, hu c, et al. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china. jama. 2020;323(11):1061-1069. all in all, we would like underline once again that hs patients have multiple associated comorbidities some of which are also risk factors for critical/mortal covid-19 disease. in our study, older age, higher pack-years of smoking, having at least one systemic disease, having a cardiovascular disease, were associated with increased risks of having covid-19 related symptoms whereas higher disease duration of hs and older age were correlated with significantly higher levels of covid-19 rt-pcr positivity. treatment type did not seem to contribute significantly to the outcome of covid-19 rt-pcr test and the incidence of covid-19 associated symptoms. we suggest the ongoing tnf-α inhibitor treatment should be continued in patients with hs, unless a definitive diagnosis of covid-19 is established. our study has some limitations since it was a single center study and no control group was present. further multicenter, prospective studies with large number of patients are required to support our findings. references 1. lee ey, alhusayen r, lansang p, shear n, yeung j. what is hidradenitis suppurativa? can fam physician. 2017;63(2):114-120. pmid: 28209676. pmcid: pmc5395382. 2. ovadja zn, schuit mm, van der horst cmam, lapid o. inter and intrarater reliability of hurley staging for hidradenitis suppurativa. br j dermatol. 2019;181(2):344-349. doi: 10.1111/ bjd.17588. pmid: 30585304; pmcid: pmc6850108. 3. alikhan a, lynch pj, eisen db. hidradenitis suppurativa: a comprehensive review. j am acad dermatol. 2009;60(4):539-361. doi: 10.1016/j.jaad.2008.11.911. pmid: 19293006. 4. pescitelli l, ricceri f, prignano f. hidradenitis suppurativa and associated diseases. g ital dermatol venereol. 2018;153(3 suppl 2): 8-17. doi: 10.23736/s0392-0488.17.05772-8. pmid: 30468375. 5. kirby js, butt m, esmann s, jemec gbe. association of resilience with depression and health-related quality of life for patients with hidradenitis suppurativa. jama dermatol. 2017;153(12):1263-1269. doi: 10.1001/jamadermatol.2017 .3596. pmid: 29117300. pmcid: pmc5817438. 6. nguyen tv, damiani g, orenstein lav, hamzavi i, jemec gb. hidradenitis suppurativa: an update on epidemiology, phenotypes, diagnosis, pathogenesis, comorbidities and quality of life. j eur acad dermatol venereol. 2021;35(1):50-61. doi: 10.1111/ jdv.16677. pmid: 32460374. 7. tchero h, herlin c, bekara f, fluieraru s, teot l. hidradenitis suppurativa: a systematic review and meta-analysis of therapeutic interventions. indian j dermatol venereol leprol. 2019;85(3):248-257. doi: 10.4103/ijdvl.ijdvl_69_18. pmid: 30924446. 8. zouboulis cc, desai n, emtestam l, et al. european s1 guideline for the treatment of hidradenitis suppurativa/acne inversa. j eur acad dermatol venereol. 2015;29(4):619-644. doi: 10.1111/ jdv.12966. pmid: 25640693. 9. lowe mm, naik hb, clancy s, et al. immunopathogenesis of hidradenitis suppurativa and response to anti-tnf-α therapy. jci insight. 2020;5(19):e139932. doi: 10.1172/jci.insight.139932. pmid: 32841223. pmcid: pmc7566733. 10 original article | dermatol pract concept. 2022;12(4):e2022192 intern med. 2021;181(5):709-711. doi: 10.1001/jamainternmed.2020.8360. epmid: 33492361. pmcid: pmc7835916. 26. kwok s, adam s, ho jh, et al. obesity: a critical risk factor in the covid-19 pandemic. clin obes. 2020;10(6):e12403. doi: 10.1111/cob.12403. pmid: 32857454. pmcid: pmc7460880. doi: 10.1001/jama.2020.1585. pmid: 32031570. pmcid: pmc7042881. 25. lowe ke, zein j, hatipoglu u, attaway a. association of smoking and cumulative pack-year exposure with covid-19 outcomes in the cleveland clinic covid-19 registry. jama dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023119 1 clinicopathological study of 307 patients with lichen planus actinicus and pigmentosus referred to razi skin hospital from 2016 to 2021 kambiz kamyab1, zahra gholi1, maryam ghiasi2, marzieh pirzadeh1, maryam nasimi2 1 department of dermatopathology, razi hospital, tehran university of medical sciences, tehran, iran 2 babol university of medical sciences, babol, iran key words: lichen planus actinicus, lichen planus pigmentosus, clinicopathology, vacuolar degeneration citation: kamyab k, gholi z, ghiasi m, pirzadeh m, nasimi m. clinicopathological study of 307 patients with lichen planus actinicus and pigmentosus referred to razi skin hospital from 2016 to 202. dermatol pract concept. 2023;13(2):e2023119. doi: https://doi. org/10.5826/dpc.1302a119 accepted: november 30, 2022; published: april 2023 copyright: ©2023 kamyab et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maryam nasimi, department of dermatology, razi hospital, tehran university of medical sciences, vahdate eslami street, tehran, iran. zip code: 1199663911 tel: 00982155618989, nsm.maryam@gmail.com introduction: the two less-known subtypes of lichen planus (lp) are lichen planus actinicus (lpa) and lichen planus pigmentosus (lpp), with the highest prevalence in the middle east. objectives: we aimed to evaluate the clinicopathological profile of these patients. methods: three hundred and seven cases including 184 lpa and 123 lpp patients were recruited from the registered pathology reports of razi skin hospital of tehran from april 2016 to march 2021. the clinical features and pathological reports were extracted and analyzed. results: among 307 patients, 117 (63.9%) in the lpa group and 88 (71.5%) in the lpp group were women. duration of disease ranged from 1 month to 20 years and 1 month to 12 years in the lpa and lpp groups, respectively. face (159 patients), limbs (68), and neck (23) were the most frequent sites of involvement in lpa patients, whereas face (60 patients), limbs (47), and trunk (42) were more commonly involved in the lpp patients. pruritus and oral mucosal lesions were found with similar frequency in both groups. pathological evaluation showed vacuolar degeneration of basal layer (100%), lymphocytes infiltration (97.3%), and melanin incontinence (58.2%) as the most frequent findings in lpa and vacuolar degeneration of basal layer (100%), lymphocytes infiltration (100%), and melanin incontinence (52/8%) as the most frequent findings in lpp cases. conclusions: lpa and lpp were both more prevalent among women. face was the most common site of involvement in both lpa and lpp. vacuolar degeneration, lymphocyte infiltration, melanin incontinence, and hyperkeratosis were more common histological findings in this study. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023119 introduction lichen planus (lp) is a chronic, inflammatory, mucocutaneous, and autoimmune disease that involves the skin and mucous membrane of the mouth and genitalia, scalp, and nails [1,2]. lp prevalence is unknown, but it is estimated that less than 1% of the population are affected by lp [2,3]. so far, about 13 subtypes of this disease have been reported including: classic, annular, hypertrophic, atrophic, ulcerative, bullous, pemphigoides, erythrodermic, inverse, linear, follicular, pigmentosus, and actinic [4]. lp actinic (lpa) is a photo-distributed type of lp which is often reported in darker-skinned people in the middle east region and india. lesions of lpa usually occur in the forehead, face, neck, and extensor surfaces of the forearm and hands. the lesions usually flare up in warm seasons (spring and summer) and disappear in the winter. however, in rare cases, areas such as the trunk, legs, genitals, and feet that are not usually exposed to sunlight may also be involved. contrary to the classic lp, the actinic type usually starts at younger age with a longer duration and more tendency for involvement of women with darker skin. pigmentosus lp (lpp), which is more common in india and the middle east, usually begins in the third and fourth decades of life and is slightly more common in women. lesions usually involve the face, neck, and, less commonly, flexor areas such as the axilla, groin, and infra-mammary folds. similar to lpa, this type of lp is also more common in areas exposed to the sun [5,6]. lesions of both lpp and lpa often occur in sun-exposed areas such as the face and neck, as well as presenting in the third to fifth decades of life [5-8]. thus, these lesions can cause discomfort and anxiety for patients and significantly affect their professional, social, and family relationships. therefore, prompt and timely diagnosis and treatment of the disease can improve the quality of life of patients. iran is located in the middle east region; therefore, the prevalence of lpp and lpa is higher than in countries outside the middle east. however, no extensive study has been conducted in iran to investigate the clinical features of these two types of diseases and to search for their indigenous differences compared to other countries. discovering the common clinical signs and pathological features of lpa and lpp can help to accelerate the process of diagnosis, treatment, and improvement of the disease outcome, saving time and money. objectives in this regard, we aimed to evaluate the clinicopathological features of patients with lpp and lpa who referred to razi hospital, tehran, iran, between april 2016 and march 2021. methods this study is a cross-sectional descriptive retro-respective study including patients who referred to the outpatient clinic of razi hospital, and their pathology samples had been recorded in the pathology department of razi hospital in tehran, iran, from april 2016 to march 2021. among all patients, the cases whom lpa and lpp were reported as the differential diagnosis were evaluated and cases with final diagnosis of these two entities were selected for final evaluation. cases that their diagnoses were postponed to clinical follow-up and needed further evaluation were excluded from the study. age, sex, clinical features, duration of symptoms, presence of pruritus, location of lesions, and pathology registered data were extracted and recorded from the records of patients. pathology registered data were also extracted. finally, 184 patients with lpa and 123 patients with lp were included in the study. results actinic lichen planus among 184 lpa patients, 117 (63.9%) were women, and 67 (36.4%) were men and the female to male ratio was 1.74. the mean age of patients was 48.02±14.83, range of 8-102 years. the highest prevalence of lpp was among the age group of 50-59 years (29.35%). the interval between the onset of symptoms and diagnosis varied from one month to 20 years, and the average interval was 23 months. in 44.25% of patients, it was less than one year, in 22.12% one to two years, and in 8% of patients more than 5 years (table 1). considering the site of involvement, 159 (86.4%) of patients had facial lesions and face was the most common site of involvement in lpa. among 159 patients with facial lesions, the forehead, cheeks, nose were the most common sites of facial lesions, respectively. after the face, the limbs were the second most common site of involvement (68 out of 184 patients), most commonly on the dorsum of the hands, arms, forearms, and lower limbs. followed by the face and limbs, the neck, trunk, ears, axilla, and groin were commonly involved, and in one patient, generalized lesions were recorded (table 1 and figure 1). out of 184 patients, 7 had oral mucosal involvement and 25% of patients experienced pruritus (table 1). regarding the pathological features found in the skin biopsies of patients with lpa, we demonstrated that the most prevalent pathological features were vacuolar degeneration (100%), lymphocyte infiltration (97.3%), melanin incontinence (58.2%), hyperkeratosis (55.4%), and melanophage (42.9%), respectively. among 179 skin biopsy slides that had lymphocytic infiltration, 4 types of infiltration were observed original article | dermatol pract concept. 2023;13(2):e2023119 3 table 1. clinicopathological features of lichen planus. lpa (n = 184) lpp (n = 123) gender female 117 (63.59%) 88 (71.54%) male 67 (36.41%) 35 (28.46%) age mean ± sd 48.02 ± 14.83 41.55 ± 14.23 range 0-9 year 1 (0.5%) 2 (1.6%) 10-19 8 (4.3%) 5 (4.1%) 20-29 9 (4.9%) 15 (12.2%) 30-39 30 (16.3%) 35 (28.5%) 40-49 46 (25%) 31 (25.5%) 50-59 54 (29.3%) 20 (16.3%) 60-69 24 (13%) 13 (10.6%) 70-79 9 (4.9%) 2 (1.6%) 80-89 2 (1.1%) 0 90-99 0 0 100-110 1 (0.5%) 0 duration mean ± sd 23±36.47 21±31.66 range <1year 50 (44.2%) 42 (50.6%) 1-2 25 (22.1%) 22(26.51%) 2-3 13 (11.5%) 3 (3.61%) 3-4 6 (5.3%) 4 (4.81%) 4-5 10 (8.8%) 2 (2.4%) 5< 9 (8%) 10 (12.05%) pruritus 46 (25%) 30 (24.39%) location face 159 (86.4%) 60 (48.8%) limbs 68 (37%) 47 (38.2%) neck 23 (12.5%) 21 (17.1%) trunk 11 (6%) 42 (34.1%) scalp 4 (2.2%) 1 (0.8%) ears and around 3 (1.6%) 3 (2.4%) groin 1 (0.5%) 8 (2.4%) axilla 2 (1.1%) 20 (16.3%) generalized 1 (0.5%) 4 (3.3%) mucosal involvement 7 (3.8%) 4 (3.3%) histopathology vacuolar degeneration 184(100%) 123(100%) hyperkeratosis 102 (55.4%) 54 (43.9%) lymphocyte infiltration 179 (97.3%) 123 (100%) melanin incontinence 107 (58.2%) 65 (52.8%) acanthosis 52 (28.3%) 38 (30.9%) hypergranulosis 36 (19.6%) 14 (11.4%) parakeratosis 22 (12%) 4 (3.3%) infiltration of melanophages 79 (42.9%) 74 (60.2%) civatte body 56 (30%) 40 (32.5%) thinning or atrophy of the epidermis 54 (29.3 43 (35.5%) infiltration type band like 128 (71.5%) 95 (77.2%) deep 33 (18.4%) 12 (9.8%) perifollicular 46 (25.7%) 19 (15.4%) perivascular 85 (47.5%) 72 (58.5%) lpa = lichen planus actinicus; lpp = lichen planus pigmentosus; sd = standard deviation. 4 original article | dermatol pract concept. 2023;13(2):e2023119 of involvement and forehead was the most common site on the face. following the face, limbs were the second common site, that 47 out of 123 (38.2%) patients were presented with limb lesions, mainly on the dorsum of the hands, arms, forearms, and lower limb. out of 42 patients (34.1%) who had trunk lesions, distribution of lesions were back lesions (15), intermammary (4), inframammary (3) chest (5), abdominal (5), lumbar (2), and 1 case of flank and buttock lesions. in addition, only 7 patients with trunk involvement were male, and 35 were female (table 1 and figure 1). regarding pathological findings, vacuolar degeneration (100%), lymphocyte infiltration (100%), melanophage infiltration (60.2%), melanin incontinence (52.8%), hyperkeratosis (43.9%), thinning or atrophy of the epidermis (35.5%), civatte body (32.5%), acanthosis (30.9%), and hypergranulosis (11.4%) were the most common findings, respectively (table 1). of the 123 skin biopsy slides that had lymphocytic infiltration, four types of infiltration were found, including band-like or superficial (77.2%), deep (9.8%), perifollicular (15.4%), and perivascular (58.5%) (table 1). as follow: superficial or band-like (71.5%), deep (18.4%), perifollicular (25.7%), and perivascular (47.5%) (table 1). pigmented lichen planus evaluating the clinical features of 123 patients with lpp, similar to lpa, lpp was more frequent in the female sex, 88  were women (71.5%) and 35 were men (28.4%). the mean age of patients with lpp was 41.55±14.23 years (range 6-77 years). the 53.66% of patients were aged 30-49 years. the interval between the onset of symptoms and diagnosis was ranging from one month to 12 years with the average interval of 21 months. in 50.6% of patients, this interval was less than one year, in 26.51% one to two years, and in 12.05% of patients more than 5 years. among 123 patients, 30 of them experienced itching at the time of referral or in the past. mucosal involvement was seen in 4 of 123 patients (table 1). generally, the most common sites of lesions in lpp were: face, limbs, trunk, neck, axilla, and groin, respectively. furthermore, 4 patients had generalized lesions. sixty patients (48.8%) had facial lesions as the most common site figure 1. clinical and histopathological features of lichen planus actinicus (lpa). (a,c) clinical picture of lpa. (b,d) photomicrograph of lichen planus actinicus showing hyperkeratosis, atrophy of epidermis, wedged shaped hypergranulosis, vacuolar degeneration, melanin incontinence, civatte bodies and perivascular lymphocyte infiltration. original article | dermatol pract concept. 2023;13(2):e2023119 5 interval of 23 months. in 44.25% of patients, the period was less than one year. however, 8% of patients have had a course of more than 5 years, which is a significant number compared to previous studies. dilaimy et al reported that minimal itching could accompany lpa lesions only in the summer [11]. similarly, m. salman et al. demonstrated that itching was almost always absent in lpa patients [12]. in our study, we found that out of 184 patients, 46 patients (25%) had pruritus. therefore, the presence of pruritus cannot rule out the diagnosis of lpa. in salman et al study, out of 16 patients with lpa, 15 had facial lesions, 12 had involvement of the dorsum of the hands or the outer surface of the forearm, and 3 had involvement of the v area of the chest. non-exposed areas and mucus membranes were not involved in these patients [12]. similarly, our results demonstrated that the involvement of sun-exposed areas was predominant. besides among patients with limb involvement, the dorsum of the hands, forearms and arms were the most affected sites, respectively. oral mucosal involvement was also observed in 7 patients. an important finding of our results that is worth to be mentioned was the involvement of axillary and groin regions which are not exposed to the sun. conclusions to the best of our knowledge, our study described the clinicopathological features of lpa and lpp patients in a large population for the first time. it has been investigated that women suffering from lpa outnumbered men suffering from lpa based on previous reports similar to our results [9-12]. dostrovsky et al have shown that lpa was most common in 21 to 31 years (39%) [9]. in the contrary, our results showed that although 90.2% of patients were over 30 years old, but the highest prevalence of lpa was in the age group of 50-59 years (29.35%). studies reported the majority of lpa cases in young adults from second to forth decade of their lives from middle eastern descent [13]. this difference could be attributed to the ethnic population and geographic difference [14]. according to salman et al study, the interval between the onset of symptoms and lpa diagnosis in 81% of patients was one year or less [12]. the duration of lpa was reported one year in 74% of patients, two years in 11%, and more than two years in 13% of patients in dostrovsky et al study [9]. in our study, this interval varied from one month to 20 years with an average figure 2. clinical and histopathological features of lichen planus pigmentosus (lpp). (a,c) clinical picture of lpp. (b,d) photomicrograph of lichen planus pigmentosus showing epidermal thinning, hyperkeratosis, vacuolar degeneration of basal cell layer, basal cell layer pigmentation, and perivascular lymphocyte infiltration. 6 original article | dermatol pract concept. 2023;13(2):e2023119 and 3.2% of patients, respectively [5]. mendiratta et al. found that the most common sites of involvement were the head and neck, followed by the involvement of the upper back. the disease did not affect the mucous membranes, palmar and plantar surfaces [17]. in al-mutairi et al study, mucosal lesions were present in only one patient, and the nails, palmar and plantar surfaces were all intact [15]. in our study, face was the most common site of involvement (48.8%). facial involvement was mainly on the forehead, cheeks, and eyelids. followed by the face, the limbs (38.2%), trunk (34.2%), neck (17%), axilla (16.3%), and groin (6.5%) were the most frequent involved parts, respectively. 4 patients (3.3%) had mucosal involvement. similar to other studies, palmar and plantar surfaces were not affected in patients. the back was the most common site of lesions among trunk lesions. regarding pathological findings, al-mutairi et al reported that band-like infiltration of lymphocytes was the most common form of lymphocyte infiltration pattern in biopsy samples of lpp patients (63%) [15]. in our study, vacuolar degeneration and lymphocyte infiltration were found in all samples. the most common lymphocyte infiltration pattern was superficial. other pathological findings were macrophage infiltration, melanin incontinence, hyperkeratosis, thinning or atrophy of the epidermis, hypergranulosis, and parakeratosis. our lpa cases had higher mean age. prevalence of pruritus was 25% in lpa patients with 7 patients with oral mucosal involvement which were considered absent or rare in some studies. in contrast to prior studies, lymphocyte infiltration was not all band-like and confined to the upper dermis, in many cases, they were patchy and involved reticular dermis. hypergranulosis, which was considered a constant finding in some studies, was present in 19.6% of cases. among lpp cases, a higher rate of trunk lesions was recorded compared to previous studies. vacuolar degeneration, lymphocyte infiltration, epidermal atrophy, and hyperkeratosis were also more prevalent in this study among lpp patients. availability of data and materials: the datasets used and/ or analyzed during the current study are available from the corresponding author on reasonable request. references 1. le cleach l, chosidow o. clinical practice. lichen planus. n engl j med. 2012;366(8):723-732. doi: 10.1056/nejmcp1103641. pmid: 22356325. 2. [usatine rp, tinitigan m. diagnosis and treatment of lichen planus. am fam physician. 2011;84(1):53-60. pmid: 21766756. 3. parihar a, sharma s, bhattacharya sn, singh ur. a clinicopathological study of cutaneous lichen planus. j dermatology regarding pathological findings, in our study, vacuolar degeneration was observed in all samples, which is the main finding of diseases involving dermo-epidermal junction. the next finding was lymphocytic infiltration in 97.3% of cases. the most common pattern for lymphocyte infiltration was superficial, perivascular, perifollicular, and deep, respectively. unlike previous studies, in many cases, superficial infiltration was not band-like and continuous; instead, it was in the form of patchy and scattered areas. contrary to expectations, infiltration was not limited to the papillary dermis, and in 18.4% of cases, infiltration was also found in the deeper layers of the dermis. unlike the salman and dostrovsky et al studies, in which hypergranulosis was seen in most or all cases, in this study, hypergranulosis was only observed in 19.6% of pathology samples [12]. unlike the salman study, which showed hyperkeratosis in all samples and parakeratosis in 62.5% samples, in our study, hyperkeratosis was found in 58.2% and parakeratosis in 12% of the slides. therefore, their absence will not rule out the diagnosis of lpa [12]. the difference in histopathological patterns may be attributed to different factors including the duration of the lesions and biopsy location [7,15,16]. in our study, among 123 patients with lpp, 88 were women (71.54%) and 35 men (28.46%). however, in al-mutairi et al study of 33 patients with lpp, men outnumbered female [15]. the mean age of the onset of the disease was 46 years (ranging from 9 to 68 years) in vega et al study. our results showed that patients age ranged from 6 to 77 years with a mean age of 41.5 that 54% of our patients were in the range of 30-49 years [15]. in kanwar et al study, the duration of the disease was reported to range from 2 months to 21 years [5]. in the almutairi study, the length of the disease period varied from 3 months to 6 years [15]. in our study, 43.4% of patients were diagnosed for 6  months or less, and 50.6% less than one year. it is noteworthy that 12 patients (9.8%) in our study have had symptoms for more than 3 years. longer lpp duration has been associated with positive anti-hcv antibodies [15]. according to kanwar study, 31.5% of patients experienced itching with their lesions [5]. in al-mutairi et al study, 9 patients (27%) complained of itching, and others were completely asymptomatic [15]. in our study, 24.3% of patients also presented with itching lesions in the past or when they referred to our hospital. in kanwar et al study, the most common site of lesions were head and neck (88.7%), followed by the trunk (4%) and limbs (1.6%). the preauricular area and temples were the primary sites of lesions in patients with facial involvement. involvement of flexural areas, including axilla, inframammary folds, and groin, were observed in 8.9%, 6.5%, original article | dermatol pract concept. 2023;13(2):e2023119 7 dermatologic surg. 2015;19(1):21–26. doi: 10.1016/j. jssdds.2013.12.003. 4. wagner g, rose c, sachse mm. clinical variants of lichen planus. j dtsch dermatol ges. 2013;11(4):309-319. doi: 10.1111/ ddg.12031. pmid: 23320493. 5. kanwar aj, dogra s, handa s, parsad d, radotra bd. a study of 124 indian patients with lichen planus pigmentosus. clin exp dermatol. 2003;28(5):481-485. doi: 10.1046/j.13652230.2003.01367.x. pmid: 12950331. 6. bourra h, leila b. lichen planus pigmentosus. pan afr med j. 2013;15:55. doi: 10.11604/pamj.2013.15.55.2976. pmid: 24147181. pmcid: pmc3801232. 7. weston g, payette m. update on lichen planus and its clinical variants. int j womens dermatol. 2015;1(3):140-149. doi: 10.1016/j.ijwd.2015.04.001. pmid: 28491978. pmcid: pmc5418875. 8. meads sb, kunishige j, ramos-caro fa, hassanein am. lichen planus actinicus. cutis. 2003;72(5):377-381. pmid: 14655778. 9. dostrovsky a, sagher f. lichen planus in subtropical countries; study of an annular type with inverse localization (uncovered surfaces of the skin). arch derm syphilol. 1949;59(3): 308-328. doi: 10.1001/archderm.1949.01520280060007. pmid: 18115015. 10. bouassida s, boudaya s, turki h, gueriani h, zahaf a. lichen plan actinique: 32 cas [actinic lichen planus: 32 cases]. ann dermatol venereol. 1998;125(6-7):408-413. pmid: 9747296. 11. kilaimy m. lichen planus subtropicus. arch dermatol. 1976;112(9):1251-1253. doi: 10.1001/archderm.112.9.1251. pmid: 999301. 12. salman sm, kibbi ag, zaynoun s. actinic lichen planus. a clinicopathologic study of 16 patients. j am acad dermatol. 1989;20(2 pt 1):226-231. pmid: 2915056. 13. kim t, borok j, wright kt. oral prednisone: a unique and effective treatment for actinic lichen planus. jaad case rep. 2018;4(10):976-978. doi: 10.1016/j.jdcr.2018.07.001. pmid: 30406171. pmcid: pmc6214885. 14. durgaraju s, katakam n. a clinico-histopathological study of lichen planus.  journal of pharmaceutical research international. 2020;3(2):165–168. doi: 10.9734/jpri/2021/v33i731197. 15. al-mutairi n, el-khalawany m. clinicopathological characteristics of lichen planus pigmentosus and its response to tacrolimus ointment: an open label, non-randomized, prospective study. j eur acad dermatol venereol. 2010;24(5):535-540. doi: 10.1111/j.1468-3083.2009.03460.x. pmid: 19840200. 16. boch k, langan ea, kridin k, zillikens d, ludwig rj, bieber k. lichen planus. front med (lausanne). 2021;8:737813. doi: 10.3389/fmed.2021.737813. pmid: 34790675. pmcid: pmc8591129. 17. mendiratta v, sanke s, chander r. lichen planus pigmentosus: a clinico-etiological study. indian dermatol online j. 2019;10(3):288-292. doi: 10.4103/idoj.idoj_253_18. pmid: 31149573. pmcid: pmc6536068. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023017 1 the role of ischemia-modified albumin and ischemia-modified albumin to albumin ratios in patients with alopecia areata efsun tanacan1, aynure oztekin2, unsal savcı3, engin senel2, coskun oztekin4, salim neselioglu5, ozcan erel5 1 department of dermatology and venerology, ufuk university hospital, ankara, turkey 2 department of dermatology and venerology, hitit university faculty of medicine çorum, turkey 3 department of microbiology, hitit university faculty of medicine, çorum, turkey 4 department of family medicine, hitit university faculty of medicine, çorum, turkey 5 department of clinical biochemistry, faculty of medicine, yildirim beyazit university, ankara, turkey key words: alopecia areata, ischemia-modified albumin, ima/albumin, disease severity citation: tanacan e, oztekin a, savci u, et al. the role of ischemia-modified albumin and ischemia-modified albumin to albumin ratios in patients with alopecia areata. dermatol pract concept. 2023;13(1):e2023017. doi: https://doi.org/10.5826/dpc.1301a17 accepted: september 7, 2022; published: january 2023 copyright: ©2023 tanacan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: efsun tanacan, department of dermatology and venerology, ufuk university hospital, ankara, turkey. tel: +903122044151 e-mail: efsunkln@yahoo.com introduction: objective: to investigate the role of ischemia-modified albumin (ima) and ima/albumin levels in patients with aa. methods: the present prospective crossectional study includes patients ≥18 who were admitted to the dermatology and venerology department of hitit university hospital between april 1, 2021, and september 30, 2021. 70 patients participated in the study (n=34 for the study group and n=36 for the control group). demographic features, clinical characteristics, ima, and ima/albumin levels were compared between the groups. the study group was divided into subgroups based on the number of patches, disease duration, and the number of disease attacks. ima and ima/albumin levels were compared between each subgroup. results: the study and control groups were similar with regard to demographic features and clinical characteristics. significant differences were observed between the mean ima and ima/albumin ratio (p=0.004 and 0.012, respectively). the study subgroups were comparable in the number of patches, disease duration, and number of disease attacks. conclusion: although oxidative stress is an important component in the etiology of aa, ima and ima/albumin may not be useful in the prediction of disease severity in patients with aa. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023017 introduction alopecia areata (aa) is a chronic, immune-mediated disease resulting in non-scarring hair loss with an approximate prevalence of 1/1000 [1]. hair follicles in the anagen phase prematurely transform into catagen and telogen phases by autoimmune and inflammatory mechanisms resulting in a sudden hair loss in patients with aa [2]. although the pathophysiological mechanisms behind aa have not been clearly revealed yet, immune dysregulation, genetic predisposition, and excessive oxidative stress seem to be the main predisposing factors behind the development of aa [3]. oxidative stress and free radical damage alter the chemical structure of albumin, leading to the production of ischemia-modified albumin (ima) [4]. hence, the utility of ima and ima/albumin were investigated in various studies for revealing the oxidative stress-related events behind the etiology of autoimmune and inflammatory diseases [5, 6]. the role of ima was also investigated in several dermatologic diseases like psoriasis, behçet’s disease, and alopecia areata [7-9]. however, no consensus has been reached on the utility of ima in daily dermatology practice. for this reason, more data is necessary to reach more precise results. the aim of the present study is to investigate the role of ima and ima/albumin levels in patients with aa. material and methods the present prospective crossectional study consisted of patients ≥18 who were admitted to the dermatology and venerology department of hitit university hospital between april 1, 2021, and september 30, 2021. seventy patients participated in the study (n=34 for the study group and n=36 for the control group). patients with alopecia areata served as the study group. thirty-six gender and age-matched patients with dermatologic complaints other than inflammatory skin diseases were used as the control group. cases with pregnancy, lactation, history of malignancy, and active or chronic infection were excluded from the study. written informed consent was signed by all participants. the institutional ethics committee approved the study protocol with reference number 449. firstly, the clinical characteristics of aa patients were evaluated. gender, pattern of alopecia area, duration of disease, family history with aa, involved area (scalp, beard, eyebrow) and the number of disease attacks were evaluated for each aa patient. both study and control groups were evaluated for gender, age, height (m), weight (kg), body mass index (bmi), smoking and alcohol consumption, ima, and albumin levels. the ima/albumin ratio of all participants was calculated. afterwards, the study group was divided into subgroups based on number of patches, disease duration, and number of disease attacks. ima and ima/albumin levels were compared between each subgroup. all the blood samples (peripheral venous blood) from all participants were collected after overnight fast. statistical analyses were performed by statistical package for the social sciences (spss.22, ibm spss statistics for windows, version 22.0 armonk, ny: ibm corp.). student t-test was used for comparing the mean values between the groups as the data was normally distributed. chi-square test was conducted to compare the categorical variables. pearson correlation test was performed for correlation analyses. a two-tailed p value < 0.05 was regarded as statistically significant. results the clinical characteristics of the patients with alopecia areata were shown in table 1. in the alopecia areata group, most of the participants were male. approximately 60% of the patients had a single patch. disease duration was less than one year in 19 patients. only three patients had a family history of alopecia areata. table 1. demographic features and disease characteristics of the patients with alopecia areata. n % gender female 12 35.3% male 22 64.7% patern of aa single patch 20 58.8% multiple patch 14 41.2% duration of illnes < 1 year 19 55.9% 1-4 years 9 26.5% ≥5 years 6 17.6% family history of aa yes 3 8.8% no 31 91.2% involvement area scalp 22 64.7% beard 8 23.5% eyebrow 2 5.9% ≥2 2 5.9% number of attacks 1 20 58.8% 2 10 29.4% 3 4 11.8% original article | dermatol pract concept. 2023;13(1):e2023017 3 the patients’ most common areas of disease involvement were scalp, beard, and eyebrows, respectively. in addition, 58.8% of the patients had an alopecia attack for the first time, while the other 4 in 10 patients had an alopecia attack for the third time. comparison of the gender distribution, mean age, height, weight, bmi, smoking, alcohol consumption, ima, and albümin levels between the study and control groups are shown in table 2. significant differences were observed between the mean ima and ima/albumin ratio (p=0.004 and 0.012, respectively). the study subgroups were comparable for the number of patches, disease duration, and number of disease attacks, as shown in table 3. discussion the pathogenetic mechanisms of aa have still not been clarified. impaired immune system activation and genetic predisposition seem to be the main events behind aa. destruction of hair follicles by immune-mediated cells and inflammatory products results in reversible hair loss in a specific pattern [1]. excessive oxidative stress is considered to be another triggering event in the development of aa. there are many studies showing the effect of oxidative stress on aa and many other dermatological diseases [10-17]. degradation products resulting from oxidative stress may damage hair follicles and they may alter the balance between the anagen, telogen and catagen phases. furthermore, some of these products may be used as biological markers of oxidative stress [18-20]. ima (ischemic modified albumin) is produced by the modification of albumin due to the reactive oxygen species (ros). a higher level of ima was observed in various diseases like ischemic heart disease, pulmonary embolism, cancer, and stroke [21-24]. the role of ima was also evaluated in dermatological diseases. elevated levels of ima were shown in psoriasis, hair diseases, and vitiligo. in recent years, some studies have addressed the risk of thrombosis, acute myocardial infarction, and stroke in aa with various results [25-28]. shakoei et al. found elevated ddimer levels and increased risk of thromboembolism in aa. kang et al. defined that patients with aa were associated with a higher risk of stroke in the 3-year follow-up period. however, some data do not support the risk of heart attack and stroke in alopecia table 2. comparison of the gender distribution, mean age, height, weight, bmi, smoking, alcohol consumption, ima, and albümin levels between the study and control groups. patients (n=34) controls (n=36) p value gender female 12 13 0.57 male 22 23 mean age 31.56±8.5 31±8.5 0.78 height 170.8±9.5 169.7±9.9 0.72 weight 72.6±12.8 72.2±10.04 0.86 bmi 24.79±3.3 25.05±2.8 0.72 smoking 0 0 n/a alcohol consumption 0 0 n/a family history of aa 3 0 n/a ima 0.71±0.17 0.50±0.14 0.04 albumin 4.09±0.10 4.08±0.11 0.62 ima/albumin 0.17±0.04 0.12±0.03 0.012 table 3. comparison of ima, albumin, and ima/albumin according to number of patches, disease duration, and number of disease attacks. single patch (n=20) multiple patch (n=14) p value <6 months (n=19) >6 months (n=15) p value number of attack 1 (n=20) number of attack ≥2 (n=14) p value ima 0.70±0.20 0.72±0.10 0.76 0.75±0.21 0.66±0.09 0.13 0.73±0.21 0.68±0.08 0.39 albumin 4.09±0.11 4.10±0.09 0.65 4.05±0.10 4.13±0.09 0.04 4.08±0.13 4.11±0.05 0.38 ima/albumin 0.17±0.05 0.17±0.02 0.81 0.18±0.05 0.16±0.02 0.11 0.18±0.05 0.16±0.02 0.35 4 original article | dermatol pract concept. 2023;13(1):e2023017 6. türedi, s., et al., ischemia-modified albumin and the ima/ albumin ratio in the diagnosis and staging of hemorrhagic shock: a randomized controlled experimental study. turkish journal of trauma and emergency surgery, 2020. 26(2): p. 153-162. 7. işik, s., et al., the correlation between the psoriasis area severity index and ischemia-modified albumin, mean platelet volume levels in patients with psoriasis. advances in dermatology and allergology /postȩpy dermatologii i alergologii, 2016. 33(4): p. 290. 8. kılıç, s., et al., the ischemia modified albumin and mean platelet volume levels in patients with behçet’s disease. advances in dermatology and allergology/postȩpy dermatologii i alergologii, 2016. 33(5): p. 345. 9. incel-uysal, p., et al., assessment of metabolic profile and ischemia-modified albumin level in patients with alopecia areata: a case–control study. indian journal of dermatology, 2019. 64(1): p. 12. 10. sachdeva, s., et al., does oxidative stress correlate with disease activity and severity in alopecia areata? an analytical study. j cosmet dermatol, 2021. 11. mustafa, a.i., et al., cross talk between oxidative stress and inflammation in alopecia areata. j cosmet dermatol, 2021. 20(7): p. 2305-2310. 12. peluso, i., a. cavaliere, and m. palmery, plasma total antioxidant capacity and peroxidation biomarkers in psoriasis. j biomed sci, 2016. 23(1): p. 52. 13. qiu, l., z. song, and v. setaluri, oxidative stress and vitiligo: the nrf2-are signaling connection. j invest dermatol, 2014. 134(8): p. 2074-2076. 14. shah, a.a., et al., increased oxidative stress in pemphigus vulgaris is related to disease activity and hla-association. autoimmunity, 2016. 49(4): p. 248-57. 15. emre, s., et al., the association of oxidative stress and disease activity in seborrheic dermatitis. arch dermatol res, 2012. 304(9): p. 683-7. 16. narendhirakannan, r.t. and m.a. hannah, oxidative stress and skin cancer: an overview. indian j clin biochem, 2013. 28(2): p. 110-5. 17. okayama, y., oxidative stress in allergic and inflammatory skin diseases. curr drug targets inflamm allergy, 2005. 4(4): p. 517-9. 18. akar, a., et al., antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata. journal of dermatological science, 2002. 29(2): p. 85-90. 19. naziroglu, m. and i. kokcam, antioxidants and lipid peroxidation status in the blood of patients with alopecia. cell biochemistry and function: cellular biochemistry and its modulation by active agents or disease, 2000. 18(3): p. 169-173. 20. abdel fattah, n., a. ebrahim, and e. el okda, lipid peroxidation /antioxidant activity in patients with alopecia areata. journal of the european academy of dermatology and venereology, 2011. 25(4): p. 403-408. 21. zhong, y., et al., ischemia-modified albumin in stable coronary atherosclerotic heart disease: clinical diagnosis and risk stratification. coronary artery disease, 2012. 23(8): p. 538-541. 22. ellidag, h.y., et al., ischemia modified albumin levels and oxidative stress in patients with bladder cancer. asian pacific journal of cancer prevention, 2013. 14(5): p. 2759-2763. 23. ahn, j.h., et al., the usefulness of albumin-adjusted ischemia modified albumin index as early detecting marker for ischemic stroke. neurological sciences, 2011. 32(1): p. 133-138. areata [27, 28]. on the other hand, recently, in alopecia areata, literature data show a tendency to thrombosis and an increased risk of heart attack and stroke. in addition, studies have found elevated levels of cardiac biomarker troponin i and congestive heart disease biomarker bnp in patients with alopecia areata [29, 30]. there are publications in the literature indicating the association of ima with the severity and deterioration of aa [9, 31]. these reports focused on the pathophysiological pathways related to increased oxidative stress in patients with aa. as excessive oxidative stress was reported to be an important triggering event in the development of aa, markers associated with oxidative stress might increase with disease severity [32]. moreover, although the utility of ima/albumin was investigated in various conditions like chronic liver disease and hemorrhagic shock, to the best of our knowledge, it has not been studied in cases with aa [6, 33]. however, similar to other autoimmune and inflammatory diseases, the etiology of aa is complex, and using a single oxidative biomarker may be insufficient to predict the severe course of the disease [34]. in the present study, no significant differences were observed for ima and ima/albumin between the cases with regard to patch characteristics, duration of the disease and number of attacks per year. in our opinion, more studies, including a larger number of cases and many more study parameters, are necessary to reach more reliable results for the role of ima in the prognosis of aa. the main strengths of the present study were its prospective design and investigation of ima/albumin levels in patients with aa. on the other hand, the relatively low number of cases and single-center experience were the main limitations. in conclusion, although oxidative stress seems to play an important role in the etiology of aa, ima and ima/albumin may not be useful in the prediction of disease severity in patients with aa. references 1. strazzulla, l.c., et al., alopecia areata: disease characteristics, clinical evaluation, and new perspectives on pathogenesis. journal of the american academy of dermatology, 2018. 78(1): p. 1-12. 2. rajabi, f., et al., alopecia areata: a review of disease pathogenesis. br j dermatol, 2018. 179(5): p. 1033-1048. 3. simakou, t., et al., alopecia areata: a multifactorial autoimmune condition. journal of autoimmunity, 2019. 98: p. 74-85. 4. sbarouni, e., p. georgiadou, and v. voudris, ischemia modified albumin changes–review and clinical implications. clinical chemistry and laboratory medicine, 2011. 49(2): p. 177-184. 5. dominguez-rodriguez, a. and p. abreu-gonzalez, current role of ischemia-modified albumin in routine clinical practice. biomarkers, 2010. 15(8): p. 655-662. original article | dermatol pract concept. 2023;13(1):e2023017 5 30. el‐sayed mahmoud marie, r., et al., evaluation of serum cardiac troponin i and n‐terminal pro‐b‐type natriuretic peptide levels in patients with alopecia areata. clinical and experimental dermatology, 2021. 46(1): p. 153-156. 31. ataş, h., et al., ischemic modified albumin as a new biomarker in predicting oxidative stress in alopecia areata. turkish journal of medical sciences, 2019. 49(1): p. 129-138. 32. acharya, p. and m.c. mathur, oxidative stress in alopecia areata: a systematic review and meta‐analysis. international journal of dermatology, 2020. 59(4): p. 434-440. 33. yavuz, f., et al., serum ischemic modified albumin (ima) concentration and ima/albumin ratio in patients with hepatitis b-related chronic liver diseases. turkish journal of medical sciences, 2017. 47(3): p. 947-953. 34. amin, s.s. and s. sachdeva, alopecia areata: a review. journal of the saudi society of dermatology & dermatologic surgery, 2013. 17(2): p. 37-45. 24. hogg, k., et al., is ischaemia-modified albumin a test for venous thromboembolism? emergency medicine journal, 2012. 29(6): p. 455-459. 25. shakoei, s., m. ghiasi, and k. ziaee, coagulation status in patients with alopecia areata: a cross-sectional study. giornale italiano di dermatologia e venereologia : organo ufficiale, societa italiana di dermatologia e sifilografia, 2020. 26. kang, j.-h., et al., alopecia areata increases the risk of stroke: a 3-year follow-up study. scientific reports, 2015. 5(1): p. 1-6. 27. lee, h., y.c. kim, and j.w. choi, alopecia areata is not a risk factor for heart diseases: a 10-year retrospective cohort study. plos one, 2021. 16(5): p. e0250216. 28. huang, k.p., et al., cardiovascular risk in patients with alopecia areata (aa): a propensity-matched retrospective analysis. journal of the american academy of dermatology, 2016. 75(1): p. 151-154. 29. shoeib, m.a., et al., troponin i in alopecia areata and female pattern hair loss. menoufia medical journal, 2021. 34(2): p. 498. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):8 37 dermatology practical & conceptual www.derm101.com introduction an 18-year-old male presented with a plaque consisting of vesicles containing serum and serohematic fluid on the upper back (figure 1). the plaque appeared seven years earlier and gradually acquired its current size. the overal clinical aspect was suggestive of a lymphatic or venous tumor or malformation. dermoscopy (polarized, 10x) revealed multiple white-yellowish well circumscrimbed roundish areas (lacunae), which were surrounded by pale septa (figure 2). several lacunae included variable amounts of blood. in some of them, the blood was characteristically accumulated in the lowest part of the lacuna, resulting in an appearance similar to the so-called “hypopyon” of the eye or the “half-and-half” blister seen in sneddon-wilkinson disease. histopathology confirmed the diagnosis of cutaneous lymphangioma circumscriptum (clc). discussion lymphangiomas are hamartomatous, congenital malformations of the lymphatic system derived embryologically from five primitive buds developing from the venous system [1]. histologically, there are mainly three types of lymphangioma, depending on the size of the lymphatic channels: cystic dermoscopy of cutaneous lymphangioma circumscriptum abhijeet k. jha1, aimilios lallas2, sidharth sonthalia3 1 department of skin and vd, patna medical college & hospital, patna, bihar, india 2 first department of dermatology, aristotle university, thessaloniki, greece 3 skinnocence: the skin clinic, gurgaon, india key words: dermoscopy, lymphangioma, cutaneous lymphangioma circumscriptum citation: jha ak, lallas a, sonthalia s. dermoscopy of cutaneous lymphangioma circumscriptum. dermatol pract concept. 2017;7(2):8. doi: https://doi.org/10.5826/dpc.0702a08 received: december 30, 2016; accepted: february 24, 2017; published: april 30, 2017 copyright: ©2017 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & vd, patna medical college & hospital, patna, bihar, india. email: drabhijeetjha@gmail.com lymphangiomas are congenital lymphatic malformations. they are clinically characterized by clusters of translucent vesicles, and on dermoscopy, yellow lacunae surrounded by pale septa as well as reddish to bluish lacunae have been described. a young male presented with a seven-year history of a vesicular lesion. dermoscopy revealed multiple white-yellowish well-circumscribed roundish areas (lacunae) surrounded by pale septa. a few lacunae contained blood, which was characteristically accumulated in the lowest part of the lacuna, resulting in an appearance similar to the so-called “hypopyon” of the eye. we suggest a new “dermatologic” metaphoric term to desrcibe this peculiar feature (half-and-half lacuna). abstract 38 observation | dermatol pract concept 2017;7(2):8 logic similarity of this feature to the characteristic blisters of sneddon-wilkinson disease, which is better known among dermatologists and, therefore, easier to remember. references 1. singh s, baboo ml, pathak lc. cystic lymphangioma in children: report of 32 cases including lesions at rare sites. surgery. 1971;69: 947–951. 2.  arpaia n, cassano n, vena ga. dermoscopic features of cutaneous lymphangioma circumscriptum. dermatol surg. 2006;32:852–854. 3.  amini s, kim nh, zell ds, oliviero mc, rabinovitz hs. dermoscopic-histopathologic correlation of cutaneous lymphangioma circumscriptum. arch dermatol. 2008;144:1671–1672. 4. gencoglan g, inanir i, ermertcan at. hypopyon-like features: new dermoscopic criteria in the differential diagnosis of cutaneous lymphangioma circumscriptum and haemangiomas. j eur acad venereol. 2012;26:1023–1025. (macrocystic), capillary (super-microcystic), and cavernous (microcystic). it has been suggested that dermoscopically clc displays two distinct patterns: yellow lacunae surrounded by pale septa without inclusion of blood and yellow to pink lacunae alternating with dark-red or bluish lacunae, due to the inclusion of blood. clc displaying the latter pattern might occasionaly be difficult to discriminate from haemangiomas [2,3]. an additional dermoscopic clue has recently been described as the “hypopyon-like feature.” as sedimentation of blood occurs, its corpuscles aggregate according to their density, with cellular components lying at the bottom and serum at the upper part, resulting in a color transition from dark to light in some lacunae, creating a similar effect to that seen on the eye—the hypopyon [4]. our case confirms that the latter feature might be typical of clc. in addition, we suggest a new “dermatologic” metaphoric term to desribe this peculiar feature (half-and-half lacuna). this is based on the morphofigure 1. plaque consisting of vesicles on the upper back. [copyright: ©2017 jha et al.] figure 2. dermoscopy [polarized, 10x] revealed multiple whiteyellowish well-circumscribed roundish areas (lacunae) surrounded by pale septa. few lacunae contained blood, which was characteristically accumulated in the lowest part of the lacuna. [copyright: ©2017 jha et al. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022146 1 introduction: it has been reported that the use of oral isotretinoin may have positive and negative effects on the course of covid-19 and the risk of transmission. objectives: the purpose of our study is to evaluate how our patients that took oral isotretinoin during the pandemic were affected by covid-19. methods: the clinical processes of moderate-to-severe acne vulgaris patients between march 2020 and february 2021 were evaluated. results: of 102 moderate-to-severe acne patients, 67 were using oral isotretinoin and 35 were using a topical treatment. of 27 patients who tested positive for covid-19, 16 (59.3%) were using oral isotretinoin and 11 (40.7%) were using topical treatment, there was no statistical difference in the rates of covid-19 positivity between the two groups (p = 0.412). the rates of positive tests for covid-19 were similar between contacted patients of two groups (p = 0.391). loss of smell/taste was lower in patients using oral isotretinoin compared to patients receiving topical treatment (46.7% and 72.7%, respectively.). headache symptoms were less common in patients using oral isotretinoin (p = 0.047). conclusions: the use of oral isotretinoin did not cause an increase or decrease in the risk of covid-19 transmission. the patients using oral isotretinoin had a lower incidence of taste/smell loss and headache. how are acne vulgaris patients using oral isotretinoin affected by covid-19? mine müjde kuş1, perihan öztürk1, tutku bulut1, celal kuş2, mehmet enes güner1, hülya nazik1, mehmet kamil mülayim1 1 kahramanmaraş sütçü i̇mam university, faculty of medicine, department of dermatology, kahramanmaraş, turkey 2 kahramanmaraş sütçü i̇mam university, faculty of medicine, department of family medicine, kahramanmaraş, turkey key words: covid-19, isotretinoin, smell, taste, headache citation: kuş mm, öztürk p, bulut t, et al. how are acne vulgaris patients using oral isotretinoin affected by covid-19? dermatol pract concept. 2022;12(3):e2022146. doi: https://doi.org/10.5826/dpc.1203a146 accepted: december 26, 2021; published: july 2022 copyright: ©2022 kuş et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: concept: m.m.k., p.ö., design: m.m.k., p.ö., c.k., data collection or processing: t.b.,m.e.g., h.n., m.k.m., analysis or interpretation: m.m.k., t.b., c.k., literature search: m.m.k., t.b., m.e.g., c.k., h.n., m.k.m., writing: m.m.k., p.ö.,m.e.g., h.n., m.k.m. corresponding author: mine müjde kuş md, kahramanmaraş sütçü i̇mam university, department of dermatology, kahramanmaraş, turkey– 0 (507) 204 55 36 e-mail: mmujde_ozdemir@hotmail.com abstract 2 original article | dermatol pract concept. 2022;12(3):e2022146 introduction the coronavirus disease 19 (covid-19) pandemic was declared by the world health organization in march 2020, and covid-19 was the leading cause of death in many countries in 2020 [1]. no specific treatment has yet been found for covid-19. in addition, as in other branches of medicine, the positive and/or negative effects of the drugs we frequently use in dermatology on the course of covid-19 remain unclear. oral isotretinoin (13-cis-retinoic acid), a synthetic analog of vitamin a, is a first-generation retinoid used for the treatment of acne vulgaris [2]. nasal mucosal dryness is observed in two-thirds of patients during oral isotretinoin treatment [3]. the covid-19 agent sars-cov-2 enters the human body through angiotensin-converting enzyme-2 (ace2) receptors. ace-2 receptor expression was found in the basal layer of nonkeratinized squamous epithelium in the nasal mucosa. isotretinoin has the effect of revealing ace-2 receptors by causing nasal mucosa dryness and down-regulating ace-2 receptors at the same time [4-6]. biological processes showing the pharmacological functions of vitamin a for the treatment of covid-19 have been defined and its therapeutic mechanisms have been proven by signaling pathways and it is thought that it can be used in the treatment of covid-19  [7]. however, some authors suggested that covid-19 is a hypervitaminosis of vitamin a and that all drugs metabolized in the liver should be discontinued [8]. objectives according to these data in the literature, the effects of oral isotretinoin, a vitamin a derivative, on the transmission and course of covid-19 are not clear. the aim of our study is to evaluate whether the use of oral isotretinoin affects the findings and symptoms of covid-19 and the risk of transmission. methods our study was a retrospective, descriptive and cross-sectional study. the clinical processes of moderate-to-severe acne vulgaris patients aged 16 years and older who were followed up in our clinic between march 2020 and february 2021 and using oral isotretinoin at a dose of 0.5-1mg/kg or topical treatment (patients who do not accept systemic treatment), were evaluated. the data form was filled via file scanning, during control examination, or by teleconference interview method. in the data, form followings were questioned: patients age, gender, body mass index, treatment received, disease severity, smoking, additional disease, additional treatments, pneumococcal and influenza vaccines, history of contact with someone with covid-19, whether patients had covid-19, if they had, symptoms, treatment of choice (without treatment, with medication at home, inpatient, in intensive care), whether there were any sequelae. the obtained data were transferred to the computer. spss version 20.0 statistical package program was used in the analysis of the data. in the representation of the descriptive statistics of the study, mean ± standard deviation (sd), minimum-maximum values for continuous numerical variables, number (n), and percentage (%) were used for categorical variables. pearson chi-square and fisher tests were used to compare categorical variables. according to the normality evaluation made by kolmogorov-smirnov and shapiro-wilk tests; parametric tests (paired sample t-test and t-test in independent groups) were used where continuous variables fit the normal distribution, and nonparametric tests (mann-whitney u test, kruskal wallis test) were used where they did not fit the normal distribution. statistical significance level was accepted as p < 0.05. results the study included 102 moderate-to-severe acne patients aged 16 years and older who were followed up and treated in our clinic, using oral isotretinoin at a dose of 0.5-1mg/kg or topical treatment (topical retinoid or topical benzoylperoxide plus clindamycin) for at least two months. the clinical processes between march 2020 and february 2021 were evaluated. of the 67 patients who took oral isotretinoin during the pandemic, 52 (77.6%) were female and 15 (61%) were male, mean age was 22.64 ± 6.62. of 35 patients who used topical treatment, 19 (54.3%) were female and 16 (61%) were male, the mean age was 25.74 ± 8.16. twenty (74.1%) of the women and 7 (25.9%) of the men had a history of 27 covid-19 positivity confirmed by polymerase chain reaction (pcr) in the nasal swab sample. the mean age of those who were positive for covid-19 was 24.88 ± 8.65, and there was no statistical difference in age and gender between those who were positive for covid-19 and those who were negative for covid-19 (p = 0.773 and p = 0.556, respectively). there was no statistical difference between covid-19 positive and covid-19 negatives in terms of body mass index (bmi) average, smoking, additional disease status, acne severity, pneumococcal and influenza vaccination status (table 1). of the 27 patients who were positive for covid-19, 16 (59.3) were using oral isotretinoin and 11 (40.7%) were using a topical treatment. there was no statistical difference in covid-19 positivity rates between patients using oral isotretinoin and patients using topical treatment (p = 0.412). original article | dermatol pract concept. 2022;12(3):e2022146 3 considering the rates of covid-19 transmission after contact with a covid-19 positive person, covid-19 positivity in 14 of 29 patients, who were using oral isotretinoin and came into contact with someone that tested positive for covid-19 was confirmed by pcr test; covid-19 positivity in 11 of 18 patients who were using the topical treatment and came into contact with someone that tested positive for covid-19 was confirmed by pcr test. there was no statistical difference in the rates of being positive for covid-19 between contacted patients using oral isotretinoin and contacted patients using topical treatment (p = 0.391). of the 27 patients who were positive for covid-19, 26 had symptoms, only one patient using oral isotretinoin was asymptomatic, and there was no statistical difference in the rates of asymptomatic covid-19 positivity between patients using oral isotretinoin and patients using topical treatment (p = 0.593). in order of frequency, the symptoms associated with covid-19 were: taste\smell loss (15), headache (13), fever (12), malaise (12), arthralgia\myalgia (11), cough (8), sore throat (6), shortness of breath (4). there was no statistical difference between patients using oral isotretinoin and patients using topical treatment in terms of the incidence of symptoms other than headache. headache was seen at a lower rate in patients using oral isotretinoin compared to those using topical treatment (33.3%, 72.7%, respectively), and there was a statistically significant difference (p = 0.047). taste\smell loss developed in 7 (46.7%) of 16 covid-19-positive patients using oral isotretinoin and 8 (72.7%) of 11 covid-19-positive patients using topical treatment, but there was no statistical difference (p = 0.246) (table 2). among the gastrointestinal (nausea, vomiting, abdominal pain) and respiratory symptoms (dyspnea, chest pain) associated with severe covid-19, only shortness of breath was seen in 4 of our patients, other severe symptoms were not encountered. dyspnea was observed in one patient (6.7%) using oral isotretinoin and 3 (27.3%) patients receiving topical treatment. there was no statistically significant difference between the two groups (p = 0.279). no patient with covid-19 needed hospitalization or intensive care. of the 16 covid-19-positive patients who took oral isotretinoin, 10 recovered with medical treatment at home and 6 without treatment. all 11 covid-19-positive patients who received topical treatment recovered with medical treatment at home. there was no statistical difference between the two groups in terms of the need for medical treatment (p = 0.054). six of the patients with covid-19 had partial taste\ smell loss that continued 1 month after they had the disease, table 1. sociodemographic and clinical characteristics of the acne vulgaris patients (comparison between covid-19-positive and negativepatients) covid (+) mean é sd / n (%) covid (-) mean é sd / n (%) p age 24.88 ± 8.65 23.28 ± 6.76 0.773 a bmi 23.25 ± 2.88 22,64 ± 3.01 0.201 a gender male 7 (25.9) 24 (32.0) 0.556b female 20 (74.1) 51 (68.0) smoking yes 4 (14.8) 15 (20.0) 0.553b no 23 (85.2) 60 (80.0) additional disease yes 1 (3.7) 7 (9.3) 0.678b no 26 (96.3) 68 (90.7) pneumococcal vaccine yes 0 (0.0) 4 (5.3) 0.571b no 27 (100) 71 (94.7) influenza vaccine yes 1 (3.7) 2 (2.7) 0.607b no 26 (96.3) 73 (97.3) bmi = body mass index; sd = standard deviation. amann-whitney u test; bchi-squared or fisher test for the comparison between the groups. 4 original article | dermatol pract concept. 2022;12(3):e2022146 thanks to their antioxidant and surfactant-mediated properties [9]. we did not see ards symptoms in any of our patients. we could not associate this with the protective use of oral isotretinoin, because our patients had a low mean age and a very low rate of possible risk factors for ards. gastrointestinal (nausea, vomiting, abdominal pain) and respiratory symptoms (shortness of breath, chest pain) have been associated with severe covid-19 [10]. severe covid-19-associated dyspnea was seen at a lower rate in patients using oral isotretinoin compared to patients receiving topical treatment 6.7%, and27.3%, respectively), we thought that this might be related to the protection of oral isotretinoin against severe covid-19, but we did not detect a statistically significant difference (p = 0.279). ace2 has been shown to be a functional receptor for sars-cov to enter host target cells [11]. ace2 receptor expression has been found in the basal layer of the squamous epithelium in the nasal mucosa. the use of oral isotretinoin, which causes dryness in the nasal mucosa, causes mucosal fragmentation, and may facilitate the adhesion of the coronavirus to the nasal mucosa by exposing the basal layer [4,5]. on the other hand, since isotretinoin is one of the strongest down-regulators of ace-2 receptors, it was thought that the use of isotretinoin may be protective against the transmission of covid-19 in that it reduces the possibility of cellular entry of the virus [6]. to evaluate these hypotheses, we looked at the rates of being positive for covid-19 after contact with a covid-19(+) person, and we did not find any difference in the rates of being covid-19-positive between contact patients using oral isotretinoin and contact patients using topical treatment (p = 0.391). öğüt et al also found that oral isotretinoin treatment was not associated with an increased risk of contracting covid-19 [12]. these results suggest that oral isotretinoin use increases the risk of transmission by exposing ace2 receptors, while reducing the risk of transmission by down-regulating ace2 receptors, leading to a similar risk of transmission with people who do not use isotretinoin. 2 (12.5%) were receiving oral isotretinoin and 4 (36%) were receiving topical treatment. there was no statistical difference between the patients using oral isotretinoin and the patients using topical treatment in terms of taste/smell loss sequela (p = 0.350). discussion it has been reported that the use of oral isotretinoin may have positive and negative effects on the course of covid-19 and the risk of transmission (table 3). mawson et al. found that covid-19 disease is very similar to an endogenous form of a hypervitaminosis of vitamin a, that liver damage caused by the sars-cov-2 virus causes toxic concentrations of retinoic acid and stored retinyl esters to be released into the circulation, including the lungs, heart, blood vessels, and skin, without binding to protein. they claimed it caused damage to organs. they recommended that treatment strategies focus on reducing circulating retinoid concentrations. they argued that all nonessential drugs that are metabolized in the liver should be discontinued, and also that all drugs that damage the liver should be avoided during the acute phase of treatment [8]. however, the patients using oral isotretinoin included in our study did not need hospitalization or intensive care even though they continued their medication when they became covid-19-positive. retinoic acid and carotenoids exert many physiological effects, along with the enhancement of t-cell function, which develops an inducible immune response against pathogens such as viruses [9]. bioinformatics computational findings showed that vitamin a has anti-viral, anti-inflammatory, and immunomodulatory effects through different biological processes and cell signaling pathways. as a result of these findings, the therapeutic mechanisms of vitamin a for the clinical treatment of covid-19 have been defined [7]. therefore, contrary to mawson et al, it is thought that vitamin a derivatives may have a protective role in the pathogenesis of ards, which is a complication of severe covid-19 cases, table 2. symptoms of covid-19-positive patients (comparison between oral retinoid users and topical treatment users) symptom oral retinoid users n (%) topical treatment users n (%) p taste\smell loss 7 (46.7) 8 (72.7) 0.246 headache 5 (33.3) 8 (72.7) 0.047 fever 7 (46.7) 5 (45.5) 0.951 malaise 7 (46.7) 5 (45.5) 0.951 artralgia/myalgia 4 (26.7) 7 (63.9) 0.109 cough 6 (40.0) 2 (18.2) 0.395 sore throat 4 (26.7) 2 (18.2) 0.999 shortness of breath 1 (6.7) 3 (27.3) 0.279 original article | dermatol pract concept. 2022;12(3):e2022146 5 loss of taste/smell, which persisted 1 month after recovery, was lower in patients using oral isotretinoin compared to patients receiving topical treatment (12.5% and 36%, respectively), which may be related to the faster recovery of olfactory function by isotretinoin, but again, no statistical difference was observed (p = 0.350). the main weakness of this study is that the small number of patients. smell/taste loss levels could not be evaluated objectively because it is a retrospective study. in conclusion, the use of oral isotretinoin did not cause an increase or decrease in the risk of covid-19 transmission. headache symptom was seen less frequently in oral isotretinoin users. in patients using oral isotretinoin, the rates of taste/smell loss were lower, although not statistically significant. the rates of complete recovery of taste/smell loss were higher in oral isotretinoin users, although it was not statistically significant. references 1. who announces covid‐19 outbreak a pandemic. available from: https://www.who.int/director-general/speeches/detail/who -director-general-s-opening-remarks-at-the-media-briefing-on -covid-19—11-march-2020. accessed may 23, 2020. 2. abdelmaksoud a, lotti t, anadolu r, et al. low dose of isotretinoin: a comprehensive review. dermatol ther. 2020;33(2):e13251. doi: 10.1111/dth.13251. pmid: 32022958. 3. skroza n, tolino e, mambrin a, et al. adult acne versus adolescent acne: a retrospective study of 1,167 patients. j clin aesthet dermatol. 2018;11(1):21-25. pmid: 29410726. pmcid: pmc5788264. 4. hamming i, timens w, bulthuis ml, lely at, navis g, van goor h. tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis. j pathol. 2004;203(2):631-637. doi:10.1002/path.1570. pmid: 15141377;.pmcid: pmc7167720. 5. abdelmaksoud a, vestita m, el-amawy hs, ayhan e, an i̇, öztürk m, goldust m. systemic isotretinoin therapy in the era of covid-19. dermatol ther. 2020;33(4):e13482. doi: 10.1111 /dth.13482. pmid: 32358858. pmcid: pmc7261989. during the course of covid-19, the most common clinical symptoms were reported as fever, cough, headache, and sore throat, in decreasing order of frequency [13]. in our patients, this order was taste\smell loss, headache, fever, malaise, arthralgia\myalgia, cough, sore throat, and shortness of breath. we found that the headache symptom decreased with the use of oral isotretinoin (p = 0.047). various mechanisms have been described for headaches due to covid-19. the first of these mechanisms has been reported to be the invasion of the trigeminal nerve endings of the virus that is bound to ace2 receptors in the nasal cavity. we thought that the use of oral isotretinoin may cause a less frequent occurrence of headache due to covid-19, with the down-regulating effect of isotretinoin on ace2 receptors [6,11,14]. although taste\smell loss is one of the most commonly known symptoms of covid-19 in the non-medical community, its incidence varies between 0% and 98% [15]. we found the rate of taste\smell loss to be 55%, this rate was higher in patients using a topical treatment (72.7%). it has been reported that the loss of taste/smell is resolved in most cases within an average of 14 days from the full recovery of covid-19. however, in some of the patients, it was observed that the loss of taste/smell partially improved after months or did not improve at all [15]. it was found that retinoic acid treatment in mice increased the number of macrophages expressing retinoic acid receptors, and this increase was associated with a faster recovery of olfactory function [16,17]. oral isotretinoin has been shown to improve the sense of smell in humans according to the olfactory function test evaluated before starting oral isotretinoin treatment and at the third month of treatment [18]. according to the data of our study, loss of smell/ taste was lower in patients using oral isotretinoin compared to patients receiving topical treatment (46.7% and 72.7%, respectively.), this may be related to the improvement of the sense of smell by oral isotretinoin use, but we found no statistically significant difference (p = 0.246). partial table 3. possible associations between oral isotretinoin and covid-19 covid-19 transmission risk and oral isotretinoin use oral isotretinoin may increase the risk of transmission by exposing ace-2 receptors in the nasal mucosa. oral isotretinoin can reduce the risk of transmission by down-regulating ace-2 receptors. severe covid-19 and use of oral isotretinoin because covid-19 disease resembles an endogenous form of hypervitaminosis of vitamin a, the use of oral isotretinoin may worsen the disease severity. thanks to its antioxidant and surfactant-mediated properties, oral isotretinoin may be protective in the pathogenesis of ards, which is a complication of severe covid-19 cases. covid-19 treatment and oral isotretinoin use oral isotretinoin can be used in the treatment of covid-19 as it has anti-viral, anti-inflammatory, and immunomodulatory effects. symptoms due to covid-19 and use of oral isotretinoin oral isotretinoin can alleviate covid-19-related headache with its down-regulating effect on ace-2 receptors and anti-inflammatory-immunomodulatory effects. since oral isotretinoin increases the sense of smell and improves the lost sense of smell, it can reduce the level of taste-smell loss due to covid-19 and accelerate its recovery. 6 original article | dermatol pract concept. 2022;12(3):e2022146 12. demirel öğüt n, kutlu ö, rbağcı e. oral isotretinoin treatment in patients with acne vulgaris during the covid-19 pandemic: a retrospective cohort study in a tertiary care hospital. j cosmet dermatol. 2021;20(7):1969-1974. doi: 10.1111/jocd.14168. pmid: 33884755. pmcid: pmc8251193. 13. lavezzo e. suppression of a sars-cov-2 outbreak in the italian municipality of vo’. nature. 2020;584(7821):425–429.doi: 10.1038/s41586-020-2488-1. pmid: 32604404. 14. bolay h, gül a, baykan b. covid-19 is a real headache!. headache. 2020;60(7):1415-1421. doi:10.1111/head.13856. pmid: 32412101. pmcid: pmc7272895. 15. boscutti a, delvecchio g, pigoni a, et al. olfactory and gustatory dysfunctions in sars-cov-2 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202003.0446.v1. 7. li r, wu k, li y, et al. revealing the targets and mechanisms of vitamin a in the treatment of covid-19.  aging (albany ny). 2020;12(15):15784-15796. doi:10.18632/aging.103888. pmid: 32805728. pmcid: pmc7467385. 8. mawson ar, croft am, gonzalez-fernandez f. liver damage and exposure to toxic concentrations of endogenous retinoids in the pathogenesis of covid-19 disease: hypothesis.  viral immunol. 2021;34(6):376-379. doi: 10.1089/vim.2020.0330. pmid: 33983857. pmcid: pmc8392079. 9. jovic th, ali sr, ibrahim n, et al. could vitamins help in the fight against covid-19?  nutrients. 2020;12(9):2550. published 2020;12(9):2550. doi:10.3390/nu12092550. pmid: 32842513. pmcid: pmc7551685. 10. li j, huang dq, zou b, et al. epidemiology of covid-19: a systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.  j med virol. 2021;93(3):14491458. doi:10.1002/jmv.26424. pmid: 32790106. pmcid: pmc7436673. 11. li w, moore mj, vasilieva n, et al. angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus.  nature. 2003;426(6965):450-454. doi:10.1038/nature02145. pmid: 14647384. pmcid: pmc7095016. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023096 1 frontal fibrosing alopecia associated with oral erosive lichen planus: two locations, one disease francesco toso1,2, andrea cortese1,2, giovanni fiorillo1, 2, antonio costanzo1,2, riccardo g. borroni1,2 1 dermatology unit, humanitas research hospital irccs, rozzano, milano, italy 2 department of biomedical sciences, humanitas university, pieve emanuele, milano, italy key words: alopecia, lichen, dermopathology, dermoscopy citation: toso f, cortese a, fiorillo g, costanzo a, borroni rg. frontal fibrosing alopecia associated with oral erosive lichen planus: two locations, one disease. dermatol pract concept. 2023;13(2):e2023096. doi: https://doi.org/10.5826/dpc.1302a96 accepted: july 27, 2023; published: april 2023 copyright: ©2023 toso et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: francesco toso, md, department of biomedical sciences, humanitas university, dermatology unit, humanitas research hospital – irccs, via rita levi montalcini, 4 20090 pieve emanuele, milano, italy. e-mail: francesco.toso@humanitas.it introduction frontal fibrosing alopecia (ffa) is a primary scarring alopecia that mainly affects postmenopausal women and is clinically characterized by recession of the fronto-temporal line with loss of the eyebrows [1]. case presentation an 89-year-old woman presented to our dermatology unit for a localized burning sensation in the oral cavity for 3 months, that was treated with oral acyclovir without noticeable improvement. family history included cutaneous lichen planus in her son. personal history included arterial hypertension, osteoporosis, and rectal resection surgery for t2n0 rectal adenocarcinoma. physical examination revealed a few erosions, partially covered by whitish pseudo-membranes, over an erythematous base on the oral vestibule and buccal mucosa bilaterally, where whitish striae referable to wickham striae were also observed (figure 1a). at the same time, a symmetrical eyebrow alopecia accompanied by a bilateral fronto-temporal hairline recession with loss of visible follicular ostia was noted (figure 1b). trichoscopic examination showed rarefaction of follicular ostia, in the absence of active inflammatory lesions, yellow dots, or vellus hair (figure 1c). a clinical diagnosis of frontal fibrosing alopecia was then established. general examination excluded the presence of other lesions on the skin or concomitant lichen planopilaris. the patient laboratory tests were all within reference range except for mildly increased ferritin and mild neutrophilia. a comprehensive serological autoimmunity panel gave negative results, while microscopic and culture examination of an oral cavity swab excluded the presence of bacteria or yeasts. histopathologic examination of a biopsy specimen of the edge of an oral erosion showed a band-like lymphocytic infiltrate in the superficial chorion and at the junction with the overlying mucosa (figure 1d), consistent with the diagnosis of oral erosive lichen planus. 2 research letter | dermatol pract concept. 2023;13(2):e2023096 conclusions frontal fibrosing alopecia belongs to the group of interface (lichenoid) dermatitis, being characterized histopathologically by a perifollicular lymphohistiocytic infiltrate, resulting in fibrosis and scarring [1]. these features make ffa indistinguishable histologically from lichen planopilaris, of which it is therefore considered a clinical variant [1,2]. to date, only rare cases of ffa associated with oral lichen planus (olp) have been described [2]. oral lichen planus is a chronic inflammatory disease also characterized by interface dermatitis on histopathology. clinically, it can be distinguished into three main subtypes: reticular, atrophic, and erosive [3]. it has been reported a small but consistent increased risk of oral squamous cell carcinoma development among olp patients [4]. in olp, stimulation of cell-mediated immunity leads to activation of cytotoxic cd8+ t lymphocytes directed against cells in the basal layer of the epithelium, with an early increase in th1-type cytokines [3]. similarly, in ffa the interaction of genetic, hormonal, and environmental factors would cause the loss of the immune privilege of hair follicles induced by th1-type inflammation, with upregulation of the jak/stat signaling pathway and pro-fibrotic markers, increased production of ifn-γ, and subsequent activation of cd8+ lymphocytes directed against the hair follicle [1,2]. immune dysregulation seems to be limited to the lesional skin [5]. the coexistence of olp and ffa in our patient suggests that, although rarely associated, these two disorders could represent two manifestations of the same immune-mediated process. the presence of olp should therefore be looked for in all patients with ffa by careful clinical inspection of the oral cavity, also taking into consideration the risk of malignant progression of oral mucosal lesions. figure 1. (a) erosions over an erythematous base, partially covered by whitish pseudomembranes, located at the level of the vestibule of the mouth and buccal mucosa. (b) symmetrical eyebrow alopecia accompanied by bilateral fronto-temporal hairline recession. (c) trichoscopy; loss of visible follicular ostia in the absence of active inflammatory lesions, yellow dots or vellus hair. (d) histology; band-like lymphocytic infiltrate in the superficial chorion and at the junction with the overlying mucosa. research letter | dermatol pract concept. 2023;13(2):e2023096 3 references 1. mcsweeney sm, christou eaa, dand n, et al. frontal fibrosing alopecia: a descriptive cross-sectional study of 711 cases in female patients from the uk. br j dermatol. 2020;183(6):11361138. doi:10.1111/bjd.19399. pmid: 32652611. 2. porriño-bustamante ml, fernández-pugnaire ma, arias-santiago s. frontal fibrosing alopecia: a review. j clin med. 2021;10(9):1805. doi: 10.3390/jcm10091805. pmid: 33919069. pmcid: pmc8122646. 3. alrashdan ms, cirillo n, mccullough m. oral lichen planus: a literature review and update. arch dermatol res. 2016;308(8):539-551. doi: 10.1007/s00403-016-1667-2. pmid: 27349424. 4. aghbari smh, abushouk ai, attia a, et al. malignant transformation of oral lichen planus and oral lichenoid lesions: a meta-analysis of 20095 patient data. oral oncol. 2017;68:92102. doi: 10.1016/j.oraloncology.2017.03.012. pmid: 28438300. 5. dubin c, glickman jw, del duca e, et al. scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement. j  am acad dermatol. 2022;86(3):551-562. doi: 10.1016/j. jaad.2021.05.016. pmid: 34044102. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):14 63 dermatology practical & conceptual www.derm101.com introduction dermoscopy reveals structures and features invisible to the naked eye, providing additional morphologic information during clinical examination of skin lesions. this diagnostic technique was utilized in the detection of melanoma and other tumors [1]. more recently, utility of dermoscopy has expanded to inflammatory and infective conditions where vascular alterations, color variegations and follicular disturbances are observed [2] dermoscopic patterns are described in many granulomatous conditions such as lupus vulgaris, sarcoidosis and granuloma annulare [3]. however, dermoscopy of leprosy, is a chronic granulomatous disease, is not described in the literature. here, we describe dermoscopic patterns in a patient with histoid leprosy (hl). case report a 54-year-old male presented with a history of asymptomatic skin lesions over the back and trunk for four months. they were progressive in nature. detailed examination revealed multiple slightly erythematous to skin-colored infiltrated, non-tender papules and nodules situated on the back, trunk and arms (figure 1). peripheral nerve examination was nordermoscopy of histoid leprosy: a case report balachandra s. ankad1, punit s. sakhare1 1 department of dermatology, s. nijalingappa medical college, karnataka, india key words: dermoscopy, histoid leprosy, granuloma citation: ankad bs, sakhare ps. dermoscopy of histoid leprosy: a case report. dermatol pract concept. 2017;7(2):14. doi: https://doi. org/10.5826/dpc.0702a14 received: december 3, 2016; accepted: december 23, 2016; published: april 30, 2017 copyright: ©2017 ankad et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: balachandra s. ankad, md, professor, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587103, karnataka, india. email: drbsankad@gmail.com figure 1. clinical image showing coppery red papules and nodules on the back. mailto:drbsankad@gmail.com 64 observation | dermatol pract concept 2017;7(2):14 and whitish color is probably due to whorled arrangement of spindle-shaped histiocytes in the granuloma in hl. a peripheral rim of brownish pigmentation was observed, which might be because of color of the skin type. however, pigmentation is not mentioned in literature [3,5]. vessels were in linear branching patterns, similar to the patterns described in granulomatous conditions, especially in lupus vulgaris and sarcoidosis [3]. different vascular patterns are described in various granulomatous conditions. in cutaneous leishmaniasis, vessels are in comma-like, dotted, hairpin and linear patterns, whereas in necrobiosis lipoidica, a prominent vascular network is noted. in granuloma annulare, vessels are in dotted or linear [3]. conclusion to conclude, dermoscopy of hl shows characteristic patterns of a granulomatous skin condition. a whitish-yellow structureless area and peripheral brownish pigmentation were new dermoscopic observations in hl. to the best of our knowledge, this is first report of dermoscopy of leprosy in general and of hl in particular. further studies are recommended involving a large sample size. references 1. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24:1877–1882. 2. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63:377–386. mal. differential diagnosis of hl, sarcoidosis, neurofibromatosis and deep fungal infection was considered. dermoscopy was performed using handheld manual dermlite 3 (3gen, inc, san juan capistrano, ca, usa) with polarized mode and it demonstrated a whitish-yellow structureless area over entire lesion surrounded by a rim of brownish pigmentation. vessels, in a linear branching pattern, were noted running towards the center (figure 2). slit skin smear from the lesions revealed bacteriological index of 4+. skin biopsy showed features suggestive of hl (figure 3). discussion hl is known for unusual presentations that challenge clinicians in the diagnosis. hl presents as asymptomatic nontender nodules. there are many reports of unusual manifestations of hl. this necessitates the need for histopathological examination for confirmation [4]. dermoscopy, being a non-invasive technique, can expand the armamentarium of diagnostic methods in hl. since all types of leprosy are endemic to the indian subcontinent, dermoscopy can be a better screening method considering the time, cost and experience as compared to histopathological diagnosis. although dermoscopic patterns in granulomatous conditions such as granuloma annulare, sarcoidosis and lupus vulgaris have been studied, there are no descriptions of dermoscopy of hl in the literature [3,5]. generally, yellow-orange structures in combination with linear vessels in branching pattern under dermoscopy suggest granulomatous skin condition [3]. in this case, dermoscopy demonstrated a whitish-yellow structureless area, which was in contrast to previous observations in granulomatous conditions wherein yellow-orange globules were noted. a whitish-yellow structureless area corresponds to granuloma figure 2. dermoscopy demonstrating whitish-yellow structureless area (black star), peripheral rim of brownish pigmentation (black arrows) and linear branching vessels (yellow arrow). figure 3. histopathology showing epidermal atrophy, grenz zone. dermis is replaced by spindle shaped histiocytes in an interlacing pattern. (h & e, 10x) http://www.ncbi.nlm.nih.gov/pubmed/?term=ferrara%20g%5bauthor%5d&cauthor=true&cauthor_uid=20708470 http://www.ncbi.nlm.nih.gov/pubmed/?term=catrical%c3%a0%20c%5bauthor%5d&cauthor=true&cauthor_uid=20708470 http://www.ncbi.nlm.nih.gov/pubmed/?term=argenziano%20g%5bauthor%5d&cauthor=true&cauthor_uid=20708470 http://www.ncbi.nlm.nih.gov/pubmed/?term=argenziano%20g%5bauthor%5d&cauthor=true&cauthor_uid=20708470 observation | dermatol pract concept 2017;7(2):14 65 5. pellicano r, tiodorovic-zivkovic d, gourhant jy, et al. dermoscopy of cutaneous sarcoidosis. dermatology. 2010;221:51–54. 3. lallas a, zalaudek i, argenziano g, et al. dermoscopy in general dermatology. dermatol clin 2013; 13: 679–694. 4. jindal r, shirazi n. uncommon clinical presentations of leprosy: apropos of three cases. lepr rev. 2016;87:246–251. dermatology: practical and conceptual letter to editor | dermatol pract concept. 2023;13(1):e2023042 1 eyelid lentigo maligna treated with imiquimod 5%: should we fear of ocular side effects? claudio conforti1, carmen dell’aquila2, daniele tognetto2, iris zalaudek1, nicola di meo1 1 dermatology clinic, maggiore hospital of trieste, trieste, italy 2 eye clinic, department of medicine, surgery and health sciences, university of trieste, trieste, italy citation: conforti c, dell’aquila c, tognetto d, zalaudek i, di meo n. eyelid lentigo maligna treated with imiquimod 5%: should we fear of ocular side effects? dermatol pract concept. 2023;13(1):e2023042. doi: https://doi.org/10.5826/dpc.1301a42 accepted: july 25, 2022; published: january 2023 copyright: ©2023 conforti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: cc and cd wrote the article; dt and iz reviewed the literature; ndm provided images of the patients. corresponding author: claudio conforti, md, dermatology clinic, maggiore hospital of trieste, trieste, italy. phone +390403992056 e-mail: claudioconforti@yahoo.com to the editor, lentigo maligna (lm) represents the most common subtype of melanoma in the elderly, affecting predominantly the head and neck region in photodamaged patients. surgery with 5 mm margins is the treatment of choice but patient comorbidities, impact of surgery intervention and the reduction of quality of life resulting from surgery can limit its application. in situations for which surgery would have a major impact on the functionality of the anatomic region or would results in cosmetically devasting outcome, radiotherapy or imiquimod (imq) represent valid alternatives. imq could cause significant skin reactions and little is currently known on its impact of the eye if applied in the periorbital region. herein, we report the case of a 74-year-old woman, referred to our skin cancer department for a brownish macule located on left lower eyelid. previous history revealed the excision with 5 mm margins of a lm 4-years before. a first recurrence appeared two years later and was surgically treated. at current visit, a brownish macule of about 6-mm located on the lower eyelid was observed (figure 1a). dermoscopic evaluation showed a brown pseudo-network with intense pigmentation and obliterations of follicles (figure 1b). a 4mm punch biopsy was performed, confirming the dermoscopic diagnosis of lentigo melanoma. the patient was discussed in our multidisciplinary tumor board because surgery would have an impact on the functionality of the eye and also because the patient refused further surgery. based on the data suggesting a good response of lm to topical treatment with imq 5%, it was started five days per week. considering the tumor closeness to conjunctiva and cornea and the risk of occasional applications of the drug in the eye during the treatment, a close dermatological and ophthalmological evaluations were performed every two weeks. after 4 weeks a partial response was observed ( figure 1, c  and d) and after 6 weeks a complete response was achieved (figure 1, e and f). at the ophthalmologic evaluation after 2  weeks of treatment, redness, burning and foreign body sensation of the conjunctivae was noted, without any decreased visual acuity. however, to limit discomfort, a combination of topical steroid and hyaluronic acid eyedrops were prescribed every day for ten days with a rapid improvement of the symptoms. then, to prevent redness and burning sensation, hyaluronic acid eyedrops were prescribed for the entire 2 letter to editor | dermatol pract concept. 2023;13(1):e2023042 treatment period. at 6 months follow up visit, no clinical and dermoscopic signs of recurrence were observed and the conjunctiva did not show inflammation or impairment. the optimal response of lm to imq and its dermoscopic evaluation has been already proved (1,2); moreover, clinicians may be reluctant to prescribe imq on the eyelid because of risk of ocular adverse effects. however, o’neill et al (3) described the case of a 52-year-old woman affected by lm, successfully treated with imq and, despite the patient giving a history of having applied treatment into the eye on occasion (in error) there were no adverse effects. other reports show that the most common side effects during treatment of lm of the eyelids with imq are redness and burning, improved without permanent ocular damages after its discontinuation (4,5). to prevent ocular redness and burning, the first advice to be given to patients is undoubtedly to use daily hyaluronic acid tears associated with good eyelid hygiene. in more severe scenarios, non-steroid tears should be prescribed to reduce discomfort and to increase therapeutic compliance. therefore, considering the benefits of imq and the absence of permanent ocular side effects, the use of imq in the periocular area should not be avoided for fear of conjunctival inflammation which, if it occurs, can be treated, and prevented with topical therapy. references 1. lallas a, moscarella e, kittler h, et al. real-world experience of off-label use of imiquimod 5% as an adjuvant therapy after surgery or as a monotherapy for lentigo maligna. br j dermatol. 2021;185(3):675-677. doi: 10.1111/bjd.20407. pmid: 33894006. 2. hamilko de barros m, conforti c, giuffrida r, seabra resende fs, di meo n, zalaudek i. clinical usefulness of dermoscopy in the management of lentigo maligna melanoma treated with topical imiquimod: a case report. dermatol ther. 2019;32(5):e13048. doi: 10.1111/dth.13048. pmid: 31365164. 3. o’neill j, ayers d, kenealy j. periocular lentigo maligna treated with imiquimod. j dermatolog treat. 2011;22(2):109-112. doi: 10.3109/09546630903559798. pmid: 20666668. 4. elia md, lally se, hanlon am, et al. periocular melanoma in situ treated with imiquimod. ophthalmic plast reconstr surg. 2016 sep-oct;32(5):371-373. doi: 10.1097/ iop.0000000000000554. pmid: 26325381. 5. murchison ap, washington cv, soloman ar, bernardino cr. ocular effects of imiquimod with treatment of eyelid melanoma in situ. dermatol surg. 2007;33:1136–1138. doi: 10.1111/j.1524-4725.2007.33232.x. pmid: 17760609. figure 1. a brownish macule of about 6-mm located on the lower eyelid was observed. [fig.1a] dermoscopic evaluation showed a brown pseudo-network with intense pigmentation and obliterations of follicles. [fig1b]. after 4 weeks of treatment with imiquimod 5%, a partial response was observed [fig1c, fig1d] and after 6 weeks a complete response was achieved. [fig1e, fig1f] dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023070 1 an enigmatic case of focal sweating: naevus sudoriferous deepak vashisht1, preema sinha1, parul kamboj1, manoj g madakshira2, kumar alok1, juhi sharma1 1 department of dermatology, central command hospital, lucknow, india 2 department of pathology, central command hospital, lucknow, india key words: eccrine, sudoriferous, dermoscopy, vaporimeter, histopathology citation: vashisht d, sinha p, kamboj p, madakshira mg, alok k, sharma j. an enigmatic case of focal sweating: naevus sudoriferous. dermatol pract concept. 2023;13(2):e2023070. doi: https://doi.org/10.5826/dpc.1302a70 accepted: june 20, 2022; published: april 2023 copyright: ©2023 vashisht et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: juhi sharma, department of dermatology, command hospital, lucknow, india 226002, email: drjuhisharma.sharma17@gmail.com introduction nevus sudoriferous is a rare entity with only a few reports in literature [1]. these nevi usually present during childhood or adolescence as excessive sweating in a well-defined area on forehead, trunk or extremities. it is of two types ie pure eccrine nevus and eccrine angiomatous hamartoma. we report a rare case of pure eccrine nevus and discuss its histopathology, immunohistochemistry, vaporimeter, and dermoscopic findings. case presentation a 12-year-old girl presented with excessive focal sweating on distal forearm (right) of one month duration (figure 1a). she experienced more than three episodes of hyperhidrosis per week. sweating was not associated with rise of environmental temperature, emotional stress, or exercise. there was no history of trauma. examination revealed focal hyperhidrosis in a well-defined area measuring 10 × 0.5 cm on the anterolateral aspect of the distal forearm (right), it lacked hypertrichosis, comedones, nodules, plaque, or papules. axillary, palmoplantar and forehead sweating was normal. general, physical and neurological examination was normal. thyroid function test and vertebral column radiograph were also normal. objective assessment of hyperhidrosis by vaporimeter (delfin technologies ltd) in standard room conditions at a temperature of 26˚c showed sweat loss at the rate of 44 g/m2h. dermoscopy revealed larger and clearly visible sweat pores compared to normal adjacent skin (figure 1b). skin biopsy showed lobular pattern of hyperplastic eccrine sweat glands (figure 2a), immunohistochemistry with epithelial membrane antigen stain, highlighted the outer cells of the eccrine duct and luminal surface of the sweat glands suggesting naevus sudoriferous (figure 1b). the patient was treated with intralesional injections of botulinum, which significantly improved her symptoms. 2 research letter | dermatol pract concept. 2023;13(2):e2023070 conclusions hyperhidrosis is characterized by excessive sweating, and it not only adversely affects patient quality of life but also has a tremendous emotional and psychological bearing. it can either be generalized or focal. diagnostic criteria of primary focal hyperhidrosis include either of the two: age less than 25 years, positive family history, cessation of sweating during sleep, frequency of at least one episode per week, impairment of daily activities, bilateral and relatively symmetrical sweating [2]. the vapometer is an effective non-invasive device which assist in measuring trans-epidermal water loss [3], similarly dermoscopy is also assists in assessing hyperhidrosis by ascertaining the number and activity of sweat glands. assessment of eccrine gland density variability not only aids in the diagnosis of sweat gland abnormality but also helps in therapeutic evaluation and monitoring [4]. nevus sudoriferous has increased eccrine secretory and ductal elements and lacks enlargement of vascular channels seen in eccrine angiomatous hamartoma [5]. depending on the severity, nevus sudoriferous can be managed with topical application of aluminum chloride, iontophoresis, or intralesional injections of botulinum toxin. however, the definitive treatment is surgical excision. this case is being reported for the rarity of pure eccrine naevus, as only a few cases have been reported till date. it also highlights the role of different investigation modalities such as histopathology, immunohistochemistry, vaporimeter and dermoscopy in arriving at the correct diagnosis. figure 1. (a) area over anterolateral aspect of right forearm shows excessive sweating. (b) larger and clearly visible sweat pores (black arrows) on dermoscopy. figure 2. (a) h&e stain 100x magnification. the glands show increased number of coils indicating hyperplasia. (b) immunohistochemistry 400x magnification with ema highlights the luminal cells of the glands by the membranous staining pattern in the luminal aspect. research letter | dermatol pract concept. 2023;13(2):e2023070 3 references 1. vázquez mr, gómez de la fuente e, fernández jg, martin fj, estebaranz jl, moraleda fp. eccrine naevus: case report and literature review. acta derm venereol. 2002;82(2):154-156. doi: 10.1080/00015550252948310. pmid: 12125955. 2. hornberger j, grimes k, naumann m, et al. recognition, diagnosis, and treatment of primary focal hyperhidrosis. j am acad dermatol. 2004;51(2):274-286. doi: 10.1016/j. jaad.2003.12.029. pmid: 15280848. 3. de paepe k, houben e, adam r, wiesemann f, rogiers v. validation of the vapometer, a closed unventilated chamber system to assess transepidermal water loss vs. the open chamber tewameter. skin res technol. 2005;11(1):61-69. doi: 10.1111/j.1600-0846.2005.00101.x. pmid: 15691261. 4. sonthalia s, errichetti e, sehgal vn. “hidroscopy”suggesting dermoscopy for expendable indications. skin res technol. 2019;25(6):909-911. doi: 10.1111/srt.12724. pmid: 31120561. 5. kawaoka jc, gray j, schappell d, robinson-bostom l. eccrine nevus. j am acad dermatol. 2004;51(2):301-304. doi: 10.1016/j.jaad.2003.12.030. pmid: 15280853. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022091 1 dermatology practical & conceptual association of flame-retardant clothing with mycosis fungoides: a retrospective analysis katherine e. park1, vignesh ramachandran2, jessica tran3, tejas p. joshi4, naveen garg5, madeleine duvic3 1 department of dermatology, university of new mexico school of medicine, albuquerque, new mexico, usa 2 department of dermatology, new york university grossman school of medicine, new york, new york, usa 3 department of dermatology, university of texas, md anderson cancer center, houston, texas, usa 4 school of medicine, baylor college of medicine, houston, texas, usa 5 department of radiology, university of texas, md anderson cancer center, houston, texas, usa key words: mycosis fungoides, cutaneous t-cell lymphoma, flame-retardant clothing, flame-retardant chemicals, occupational-related exposure citation: park ke, ramachandran v, tran j, joshi tp, garg n. association of flame-retardant clothing with mycosis fungoides: a retrospective analysis. dermatol pract concept. 2022;12(2):e2022091. doi: https://doi.org/10.5826/dpc.1202a91 accepted: october 21, 2021; published: april 2022 copyright: ©2022 park ke et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: tejas p. joshi, bs school of medicine baylor college of medicine, one baylor plaza, houston, tx, usa. e-mail: tejas.joshi@bcm.edu introduction: mycosis fungoides (mf), the most prevalent form of cutaneous t-cell lymphoma (ctcl), has been associated with a variety of environmental and occupational exposures. flame-retardant clothing (frc), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard. objectives: to report an association between frc and mf. methods: after encountering several young male patients whose onset of mf coincided with the occupational use of frc and occupation as fire fighters, we did a retrospective search. additional biopsy proven mf patients with use of frc were identified by the epic electronic medical record using the search terms “ctcl, mycosis fungoides, flame, and flame-retardant.” results: eight mf patients, all males, ranging in age from 31 years to 64 years (median age, 35 years) with exposure to frc were identified. mf remission was noted in three patients who discontinued frc use and in one patient who used a cotton undershirt barrier, while disease persistence was noted in one patient who continued to use frc. conclusions: frc appears to be associated with development of mf through chronic antigen stimulation. use of frc is an occupational hazard for fire fighters. any patient whose mf coincides with use of frc should avoid further exposure through avoidance or switching to clothing made from inherently flame-resistant fibers. abstract 2 original article | dermatol pract concept. 2022;12(2):e2022091 introduction mycosis fungoides (mf), the most common form of cutaneous t-cell lymphoma (ctcl), is characterized initially by eczematous skin lesions containing clonal epidermotropic memory cd4+ t-cells [1]. tan et al first suggested that mf is a disease of “chronic antigen stimulation” but the “antigen” is unknown [2]. our finding of significant hla-dr5 and dq-301 associations with mf also supports the possibility of antigen restriction [3] (mf. as in other non-hodgkin lymphomas, increased rates of mf have also been reported in association with occupational exposures to agent orange, aromatic hydrocarbons, and pesticides [4,5]. there have also been several reports of non-random clustering of mf, which further implicate possible environmental or occupational exposure as triggers for mf [6–8]. moreover, we have demonstrated the presence of geographic hot spots in texas, a finding consistent with the hypothesis that mf is triggered by particular exposures [9,10]. if occupation-related exposure is associated with increased mf risk, then it may result from chronic antigenic exposure to skin and inherent immune system-altering properties of the compounds [11]. occupations previously reported to be associated with mf include painters, fire fighters, the military, and oil and chemical plant workers, which require specific workplace attire such as flame-retardant clothing (frc). unlike flame-resistant clothing which is made of inherently flame-resistant fibers, frc is chemically treated and may be worn against the skin. while the specific chemicals used vary by manufacturers, historically these have included compounds such as brominated and chlorinated flame-retardants, as well as formaldehyde-based flame-retardants [12]. many flame-retardant chemicals have been banned or voluntarily withdrawn from the market; however, they have been replaced with other brominated flame retardants. previous studies have shown brominated and chlorinated flame retardants to be associated with adverse health effects, including reproductive toxicity, neurologic impairment, hormonal disturbances, and cancer [13–15]. the epilymph study, a multicenter case-control study, demonstrated a significantly increased risk of mature b-cell lymphomas in patients exposed to brominated flame retardants [16]. objectives after encountering 3 young males who presented with early mf lesions in areas where their skin was chronically exposed to frc, we performed a retrospective search. we report a case series of 8 patients who used frc prior to developing mf and whose mf improved when frc was no longer worn. methods a retrospective chart review approved by the md anderson institutional review board was performed by dr. naveen garg at the university of texas md anderson cancer center (mdacc) to identify and investigate mf patients with a history of exposure to frc. all patients were seen by a ctcl expert dermatologist (dr. duvic) between may 1, 2009 and may 31, 2019. inclusion criteria for this study were a patient age of 18 years or older, biopsy-proven mf confirmed by expert ctcl dermatopathologists at mdacc, and current/ prior exposure to frc. patients with use of frc were identified by searching the epic electronic medical record using the garg lab search method to create the study population [17]. search terms included “ctcl, mycosis fungoides, flame, and flame-retardant.” eight patients met the inclusion criteria. descriptive and demographic data were collected for each patient including demographics (age and sex), stage at presentation, location of skin involvement, treatment history, response to treatment, and length of follow-up. results we identified 8 patients with mf who had worn frc (table 1). all patients were men and ranged in age from 31 to 64 years (median, 35 years). we were unable to determine the exact brand of frc used in 7 patients, although 1 patient (case #2) recalled having used “bulwark” brand frc. three patients were diagnosed with stage ia mf, 3 with stage ib mf, 1 with stage iib mf, and 1 with stage iiib mf (erythroderma with blood involvement). body surface area involvement ranged from 0.25% to 97% (median, 18.95%). in 4 patients, we were able to ascertain the period of frc use preceding lesion appearance: 2 patients (cases #2 and #8) had worn frc for 2 years prior to development of mf; the other 2 patients had worn frc for 3(case #1) and 4 (case #4) years before developing mf. the sequential nature of mf onset after a median of 2.5 years of starting frc use is suggestive of a causal link between mf and cutaneous exposure to frc. unfortunately, we were unable to assess the exact duration of frc use prior to mf development in any of the remaining four patients. three patients (cases #1, 2 and 4) who discontinued use of frc achieved near complete remission of mf with only minimal adjunctive treatment (natural uvb and topical triamcinolone); 1 patient witnessed partial mf resolution after discontinuing frc and complete regression following radiation therapy. one patient (case #5), who continued to wear frc required by his job, had complete remission of his mf by using a cotton undershirt barrier. one patient (case #3) continued to wear frc without any barrier and has persistent disease. the remission of disease in patients who discontinued frc, and the persistence of malignancy in the 1 original article | dermatol pract concept. 2022;12(2):e2022091 3 table 1. mycosis fungoides patients with a history of exposure to flame-retardant chemicals case no. age, sex hpi rash location initial stage/ bsa topical steroid other interventions cessation of frc follow-up 1 31, m 3 yr history of pink to light brown patches beginning after starting work at an oil refinery where he used frc popliteal fossa, hips, flanks, and groin ib/18.95% y ns y 6 mo 2 48, m 2 yr history of hypopigmented patches starting 2 yrs after beginning to wear bulwark frc arms, lower abdomen, thighs ia/4.5% y nb-uvb y 1 yr 3 35, m hyperand hypopigmented patches with atrophy and telangiectasias of unknown duration recently diagnosed as mf; current frc use axilla, hips, thighs, buttocks ib/15% y ns n 1.5 yrs 4 31, m 4 yr history of erythematous scaly patch located where flame-retardant harness rubbed  thigh ia/0.25% y uv-b y 2 yr 5 47, m 10 yr history of “psoriasis,” 4 yr history of exposure to flame retardant clothing; wears cotton undershirt after previous urticarial reaction to frc scalp, arms, trunk, legs ib/54% y puva, topical nitrogen mustard cotton undershirt barrier 13 yrs 6 35, m history of flameretardant exposure since age 18 with erythematous patches diagnosed as mf at osh; presented with unrelated rash dorsal feet ia/% unknown unknown puva unknown 6 mos at osh 7 64, m 4 yr history of erythematous patches with desquamation initially on lower legs with previous exposure to frc  generalized iiib/97% y ecp, bexarotene 225 mg unknown 5 mo 8 35, m 10 yr history of erythematous patches, plaques, and tumors that began 2 yrs after starting job with exposure to frc and gamma-radiation head, trunk, and extremities iib/48% y tseb; bexarotene 300 mg y 3 mo bsa = body surface area; frc = flame-retardant clothing; m = male; n = no; no = number; ns = natural sunlight; ecp = extracorporeal photopheresis; tseb = total skin electron beam; puva = psoralen + ultraviolet a; nb-uvb = narrow band ultraviolet b; osh = outside hospital; y = yes; yr = year. 4 original article | dermatol pract concept. 2022;12(2):e2022091 patient who continued frc use, further implicate frc as the trigger for mf induction. while we are unable to exclude the possibility that other factors (eg environmental and occupational exposures independent of frc use) could have also initiated mf in our patients, the distribution of lesions in sun shielded areas in most of our patients is also consistent with frc use (although it should be noted that presentation of mf lesions in sun shielded areas is also common in mf not associated with frc). seven of the 8 patients (cases #1-5, 7-8) we report had mf lesions in skin regions that directly contacted frc, suggesting that frc exposure to the skin may have induced malignancy of skin resident t-cells. notably, patient #4 reported a history of an erythematous scaly patch on the thigh at the exact location where the frc harness rubbed, further strengthening the association between frc and mf. altogether, considering the temporal and spatial nature of the association between mf and frc, we suggest that frc could be the offending agent in the development of mf in our patients. of note, treatment with topical steroids and uvb therapy was successful in producing remissions in early-stage ia or ib patients; mf did not recur following removal of the clothing and topical therapy. conclusions although the precise mechanism(s) through which frc could have induced mf in our patients is unclear, we speculate that chemicals in frc may have been absorbed in exposed skin causing mutations in t-cells or acting as antigens driving t-cell proliferation. indeed, dermal absorption of flame retardants has been demonstrated in both in vitro and human studies [18,19]. additionally, there have been other reports of undefined skin rashes associated with frc which could have been undiagnosed mf [13,14,20]. moreover, our proposed explanation of mf induction is consistent with the paradigm of mf pathogenesis first suggested by tan et al, who first hypothesized that mf results from persistent antigen stimulation [2]. although we did not have the means to conduct a patch test for frc components, we note that a positive patch test would have lent further support to our hypothesis of antigen stimulation. patch testing for evaluation of future mf patients with history of exposure to frc may be suggested to further elucidate the mechanism of mf induction by frc. frc use appears to be associated with mf and may be an unrecognized occupational hazard for firefighters or other chronically exposed individuals. patients who develop suspicious rashes in areas of contact with frc should have skin biopsies for diagnosis. patients with mf coinciding with frc use should limit further exposure through avoidance or switching to clothing made from inherently flame-resistant fibers. newer inherently flame-resistant clothing alternatives use next-generation polymers and fibers rather than chemical flame-retardants. additionally, unlike frc, clothing from inherently flame-resistant fibers does not lose efficacy with repeated washes [21], and therefore represents both a safer and more economical option compared to frc. references 1. beyer m, möbs m, humme d, sterry w. pathogenesis of mycosis fungoides. j dtsch dermatol ges. 2011;9:594–598. doi: 10.1111/j.1610-0387.2011.07635.x. pmid: 21371258. 2. tan rs, butterworth cm, mclaughlin h, malka s, samman pd. mycosis fungoides--a disease of antigen persistence. br j dermatol. 1974;91:607–616. doi: 10.1111/j.1365-2133.1974. tb12449.x. pmid: 4281316. 3. jackow cm, mcham jb, friss a, alvear j, reveille jr, duvic m. hla-dr5 and dqb1*03 class ii alleles are associated with cutaneous t-cell lymphoma. j invest dermatol. 1996;107:373– 376. doi: 10.1111/1523-1747.ep12363352. pmid: 8751973. 4. wohl y, tur e. environmental risk factors for mycosis fungoides. curr probl dermatol. 2007;35:52–64. doi: 10.1159/000106410. pmid: 17641490. 5. slodownik d, moshe s, sprecher e, goldberg i. occupational mycosis fungoides a case series. int j dermatol. 2017;56: 733–737. doi: 10.1111/ijd.13589. pmid: 28255994. 6. ghazawi fm, netchiporouk e, rahme e, et al. comprehensive analysis of cutaneous t-cell lymphoma (ctcl) incidence and mortality in canada reveals changing trends and geographic clustering for this malignancy. cancer. 2017;123:3550–3567. doi: 10.1002/cncr.30758. pmid: 28493286. 7. ghazawi fm, alghazawi n, le m, et al. environmental and other extrinsic risk factors contributing to the pathogenesis of cutaneous t cell lymphoma (ctcl). front oncol. 2019;9:300. doi: 10.3389/fonc.2019.00300. pmid: 31106143. pmcid: pmc6499168. 8. moreau jf, buchanich jm, geskin jz, akilov oe, geskin lj. non-random geographic distribution of patients with cutaneous t-cell lymphoma in the greater pittsburgh area. dermatol online j. 2014;20:13030/qt4nw7592w. pmid: 25046454. 9. litvinov iv, tetzlaff mt, rahme e, et al. identification of geographic clustering and regions spared by cutaneous t-cell lymphoma in texas using 2 distinct cancer registries. cancer. 2015;121:1993–2003. doi: 10.1002/cncr.29301. pmid: 25728286. pmcid: pmc4457714. 10. litvinov iv, tetzlaff mt, rahme e, et al. demographic patterns of cutaneous t-cell lymphoma incidence in texas based on two different cancer registries. cancer med. 2015;4:1440–1447. doi: 10.1002/cam4.472. pmid: 26136403; pmcid: pmc4567029. 11. aschebrook-kilfoy b, cocco p, la vecchia c, et al. medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and sézary syndrome: the interlymph non-hodgkin lymphoma subtypes project. j natl cancer inst monogr. 2014;2014:98–105. doi: 10.1093/jncimonographs/ lgu008. pmid: 25174030. pmcid: pmc4155463. 12. shaw sd, blum a, weber r, et al. halogenated flame retardants: do the fire safety benefits justify the risks? rev environ health. 2010;25:261–305. doi: 10.1515/reveh.2010.25.4.261. pmid: 21268442. original article | dermatol pract concept. 2022;12(2):e2022091 5 13. andersen ke. sensitivity to a flame retardant, tris(2,3-dibromopropyl)phosphate (firemaster lvt 23 p). contact dermatitis. 1977;3:297–300. doi: 10.1111/j.1600-0536.1977.tb03690.x. pmid: 606484. 14. parlew r, king cm, evans s. primary sensitization to a single accidental exposure to a flame retardant and subsequent allergic contact dermatitis. contact dermatitis. 1995;33:286. doi: 10.1111/j.1600-0536.1995.tb00499.x. pmid: 8654099. 15. flame retardants [internet]. [cited 2021 aug 26]. available from: https://www.niehs.nih.gov/health/materials/flame_retardants_508.pdf accessed on 26 august 2021. 16. costas l, infante-rivard c, zock j-p, et al. occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric european study. br j cancer. 2015;112:1251–1256. doi: 10.1038/bjc.2015.83. pmid: 25742473. pmcid: pmc4385964. 17. garg n, rayan j, adams m, et al. newsearch: an architecture for fast analytic search of electronic medical records. available from: http://garglab.com/projects/ehr-search. accessed on 26 august 2021. 18. hughes mf, edwards bc, mitchell ct, bhooshan b. in vitro dermal absorption of flame retardant chemicals. food chem toxicol. 2001;39:1263–1270. doi: 10.1016/s0278-6915(01)00074-6. pmid: 11696400. 19. liu x, li w, yuan h, gu w, chen d. surgical treatment of rare giant malignant tumors of the scalp: a report of 3 cases with different tumor types. oncol lett. 2016;12:3411–3416. doi: 10.3892/ol.2016.5113. pmid: 27900013. pmcid: pmc5103960. 20. mcconnell dc, harris tj, tucker sb. fire-retardant clothing-related dermatitis. dermatitis. 2012;23:27–31.doi: 10.1097/ der.0b013e31823d18ef. pmid: 22653066. 21. effects of laundering | duponttm nomex® ta newsletter volume 1 [internet]. [cited 2021 aug 26]. available from: https:// safety.dupont.com/lp=6862. accessed on 26 august 2021. dermatology: practical and conceptual cutaneous squamous cell carcinoma: an update on diagnosis and treatment table of contents risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio, giulia briatico, cristina pellegrini, tea rocco, elvira moscarella, maria concetta fargnoli surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez, francisca silva-clavería, almudena fernández-orland, noemí eiris, andrés ruiz de casas, lara ferrándiz radiotherapy in the adjuvant and advanced setting of cscc paolo muto and francesco pastore immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh, daniel morse, jigar patel, michael r. migden treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi, luigi lorini mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples, italy guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s2): e2021166s 1 risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio1, giulia briatico1, cristina pellegrini2, tea rocco2, elvira moscarella1, maria concetta fargnoli2 1 dermatology unit, university of campania “luigi vanvitelli”, naples, italy 2 dermatology, department of biotechnological and clinical sciences, university of l’aquila, l’aquila, italy. key words: advanced cutaneous squamous cell carcinoma, risk factors, prognostic factors, recurrence, metastasis citation: brancaccio g, briatico g, pellegrini c, rocco t, moscarella e, fargnoli mc. risk factors and diagnosis of advanced cutaneous squamous cell carcinoma. dermatol pract concept. 2021;11(s2): e2021166s. doi: https://doi.org/10.5826/dpc.11s2a166s accepted: july 13, 2021; published: september 2021 copyright: ©2021 brancaccio et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: maria concetta fargnoli, md, dermatology, department of biotechnological and applied clinical sciences, university of l’aquila, via vetoio, coppito 2, l’aquila, italy. email: mariaconcetta.fargnoli@univaq.it cutaneous squamous cell carcinoma (cscc) is the second most common cancer affecting humans. the combination of the increasing incidence and high mortality in advanced stages of the disease, defines cscc as an emerging public health problem. advanced disease includes metastatic and locally advanced cscc. metastatic disease refers to the presence of locoregional metastasis (in transit or to regional lymph nodes) or distant metastasis. locally advanced disease has been defined as non-metastatic cscc that is unlikely to be cured with surgery, radiotherapy, or combination treatment. while metastatic cscc is easily diagnosed, locally advanced disease lacks consensus definition and diagnosis is made after multidisciplinary board consultation. identifying patients with aggressive cscc at highest risk for relapse may prevent the occurrence of advanced disease. prognostic factors suggested by most guidelines include tumor diameter (>2 cm), localization on temple/ear/lip/area, thickness (>6 mm), or invasion beyond subcutaneous fat, poor grade of differentiation, desmoplasia, perineural invasion, bone erosion, immunosuppression, undefined borders, recurrence, growth rate, site of prior abstract this article is part of the dpc journal special issue cutaneous squamous cell carcinoma: an update on diagnosis and treatment guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. 2 review | dermatol pract concept. 2021; 11(s2): e2021166s introduction cutaneous squamous cell carcinoma (cscc) is considered the second most common non melanoma skin cancer after basal cell carcinoma (bcc). evidence indicates however that the incidence is still underestimated. contrary to the reported bcc:scc ratio of 4:1, a ratio of 1:1 was observed in the us medicare fee-for-service population from 2006 to 2012 [1], and an overall 263% increase in the incidence rate of scc was observed from 1976 to 2010 in a population cohort from minnesota [2]. cscc is also regarded as the second most frequent cause of death due to skin cancer after melanoma, although, on a population-based scale, the absolute number of deaths from cscc equals that of melanoma [3]. despite the overall favorable clinical outcome of low risk cscc, there is a subset of csccs that tends to recur and metastasize exhibiting a more aggressive course. the rate of recurrence varies from 2.7% [4] to 4.6% [5], as reported in 2 large studies including 653 and 985 patients with cscc followed for approximately 10 years, respectively. the rate of metastases ranges from 1.2% to 4%, with 2.1% disease-specific death [5]. because of the increasing incidence related to the aging population and the high mortality in advanced disease, cscc is increasingly emerging as a public health problem. the term “advanced cutaneous squamous cell carcinoma” defines csccs that are no longer amenable to surgery and/ or radiotherapy (rt) and are eligible to anti pd-1 treatment [6]. the introduction of this class of drugs has raised awareness on advanced cscc that was previously under-recognized and under-treated because of its poor prognosis. this draw attention towards the need for a clear and shared definition of advanced cscc. however, the difficult management of advanced csccs requires that clinical and scientific efforts should be directed to prevent the occurrence of advanced disease. risk assessment is therefore particularly important to identify the few csccs with a high risk of local recurrence or metastasis among all other low-risk tumors. high-risk cscc should not turn into the advanced or metastatic form if properly managed with adequate surgery, follow-up, and adjuvant therapy. a thorough clarification of cscc characteristics associated with poor prognosis is urgently needed, as it is crucial factor in guiding multidisciplinary discussions on an adequate management strategy. classification and staging of cscc the who classification of skin tumors identifies several histologic variants of cscc which have important implication for management and prognosis [7]. among invasive cscc, keratoacanthoma and verrucous scc are considered low-grade variants as they have little, if any, metastatic potential, while acantholytic, spindle cell, adenosquamous, and clear cell scc are characterized by a more aggressive behavior and worse prognosis [7]. the 8th edition of the tnm classification of malignant tumor (tnm8) was published in 2017, with a version from both the american joint committee on cancer (ajcc) [8] and the union for international cancer control (uicc) [9]. uicc and ajcc work closely together and, in most instances, the tnm version of each organization is the same or very similar. unexpectedly, ajcc limited its tnm8 edition to the staging system for cscc of the head and neck and did not provide a staging system for cscc of the trunk and limbs. in comparison, uicc tnm8 provides 2 chapters for skin carcinoma: one covering the primary sites on the head and neck and one covering the trunk and limbs. overall, the 2 chapters in uicc 8th and ajcc 8th ed. for cscc tnm of head and neck are essentially identical except for the definition of perineural involvement (tables 1-4) [9,10]. the t subcategory is defined by the clinical diameter and deep invasion of the primary tumor (with thresholds of 2 and 4 cm for clinical diameter and 6 mm as limit for deep invasion) and by perineural invasion or bone erosion as parameters of upgrade to t3 or t4a/b. however, the t2 subcategory comprises a wide range of tumors, some of them associated with poor prognosis [6]. the brigham and women’s hospital (bwh) classification system for the t stage was developed to better correlate higher tumor stages with poor outcomes, radiotherapy, and lymphatic or vascular involvement. although risk factors associated with worse outcomes are well known, there is still a gap of knowledge on the precise risk of each factor taken individually. the aim of this review is to summarize cscc prognostic factors and encompass the various staging systems to guide management and follow-up in cscc patients at higher risk for local recurrence and metastasis. finally, we describe the hallmarks of the advanced disease. advanced cscc diagnosis should be made by a multidisciplinary board considering patients’ performance status and disease characteristics. review | dermatol pract concept. 2021; 11(s2): e2021166s 3 as an effort to more accurately separate high-risk from lowrisk tumors [11]. in detail, this classification system identifies poor differentiation, perineural invasion, invasion beyond subcutaneous tissue and diameter ≥2 cm as risk factors associated with worse prognosis and provides a quantifiable risk value according to the number of identified risk factors. thus, t2 tumors are stratified into a low-risk t2a stage (with one of the above risk factors) with 16% of these patients accounting for all scc-related events (recurrence, nodal metastasis and/or death) and a high-risk t2b with tumors combining 2-3 risk factors and accounting for 64% of all scc-related events. t3 stage includes tumors combining all 4 risk factors, as well as those with bone invasion. the n subcategory is differently addressed in the 2 chapters of the uicc classification system (skin carcinoma of the head/neck and carcinoma of trunk/limbs) [9]. unlike cscc of trunk and limbs, cscc of the head and neck incorporates extranodal extension and laterality into its staging criteria. the combination of t, n, and m categories defines the stage of the tumor, with uicc and ajcc as the most widetable 1. tnm clinical classification for skin carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) according to uicc 8th edition t – primary tumor tx primary tumor cannot be identified t0 no evidence of primary tumor tis carcinoma in situ t1 tumor 2 cm or less in greatest dimension t2 tumor > 2 cm and ≤4 cm in greatest dimension t3 tumor > 4 cm in greatest dimension or minor bone erosion or perineural invasion (clinical or radiographic involvement of named nerves without foramen or skull base invasion or transgression*) or deep invasion (invasion beyond the subcutaneous fat or > 6 mm measured from the granular layer of adjacent normal epidermis to the base of the tumor) t4a tumor with gross cortical bone/marrow invasion t4b tumor with axial skeleton invasion including foraminal involvement and/or vertebral foramen involvement to the epidural space nb. in the case of multiple simultaneous tumors, the tumor with the highest t category is classified and the number of separate tumors is indicated in parentheses, eg t2(5). *in ajcc staging, perineural invasion is defined, above this definition, also as “tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber” n – regional lymph nodes nx regional lymph nodes cannot be assessed n0 no regional lymph node metastasis n1 metastasis in a single lymph node 3 cm or less in greatest dimension n2 metastasis in a single ipsilateral lymph node, more than 3 cm but no more than 6 cm in greatest dimension or in multiple ipsilateral lymph nodes none more than 6 cm in greatest dimension n3 metastasis in a lymph node more than 6 cm in greatest dimension m – distant metastasis m0 no distant metastasis m1 distant metastasis (comprising contralateral nodes) table 2. ptnm pathological classification for skin carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) according to uicc 8th edition the pt and pn categories correspond to the clinical t and n categories pn0 histological examination of a regional lymphadenectomy specimen will ordinarily include 6 or more lymph nodes. if the lymph nodes are negative, but the number of ordinarily is not met, classify as pn0. pm1 distant metastasis microscopically confirmed. 4 review | dermatol pract concept. 2021; 11(s2): e2021166s spread and used staging systems (table 5). noteworthy, stage iii in both uicc and ajcc staging systems includes cscc, with or without nodal involvement, and stage iv includes cases with or without distant metastasis. these classifications seem to equate patients with advanced disease but with different characteristics. likewise, both uicc and ajcc staging systems do not encompass all the potential risk factors for a worse prognosis of cscc (eg location and differentiation) whereas a combination of prognostic factors should better guide management of cscc in the multidisciplinary board. prognostic factors in cscc among the most authoritative guidelines for diagnosis and management of cscc, eado [12] and nccn [13] guidelines, address the differentiation of high-risk from low-risk tumors (table 6) (figure 1). prognostic high-risk factors proposed by eado include tumor diameter (>2 cm), location on temple/ear/lip/area, thickness (>6 mm), or invasion beyond subcutaneous fat, poor grade of differentiation, desmoplasia, microscopic, symptomatic, or radiological perineural invasion, bone erosion, and immunosuppression. nccn guidelines add as prognostic factors positive borders, table 3. tnm clinical classification for skin carcinoma of the head and neck according to ajcc/ uicc 8th edition t – primary tumor tx primary tumor cannot be identified t0 no evidence of primary tumor tis carcinoma in situ t1 tumor 2 cm or less in greatest dimension t2 tumor > 2 cm and ≤4 cm in greatest dimension t3 tumor > 4 cm in greatest dimension or minor bone erosion or perineural invasion (clinical or radiographic involvement of named nerves without foramen or skull base invasion or transgression*) or deep invasion (invasion beyond the subcutaneous fat or > 6 mm measured from the granular layer of adjacent normal epidermis to the base of the tumor) t4a tumor with gross cortical bone/marrow invasion t4b tumor with skull base or axial skeleton invasion including foraminal involvement and/or vertebral foramen involvement to the epidural space nb. in the case of multiple simultaneous tumors, the tumor with the highest t category is classified and the number of separate tumors is indicated in parentheses, eg t2(5). * in ajcc staging, perineural invasion is defined, above this definition, also as “tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber” n – regional lymph nodes n0 no regional lymph node metastasis n1 metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension n2a metastasis in a single ipsilateral lymph node, more than 3 cm but no more than 6 cm in greatest dimension without extranodal extension n2b metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension without extranodal extension n2c metastasis in bilateral or controlateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal extension n3a metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension n3b metastasis in a single or multiple lymph nodes with clinical extranodal extension (defined as the presence of skin involvement or soft tissue invasion with deep fixation/tethering to underlying muscle or adjacent structures or clinical signs of nerve involvement) m – distant metastasis m0 no distant metastasis m1 distant metastasis (comprising contralateral nodes) review | dermatol pract concept. 2021; 11(s2): e2021166s 5 primary vs recurrent, growth rate, site of prior radiotherapy, lymphatic, or vascular involvement and, very recently, subclassified cscc into high-risk and very high-risk. any highrisk factor places the patient in the high-risk category. risk factors associated with poor prognosis in cscc can be classified as intrinsic (tumor-related) and extrinsic (patient and physician-related) [6]. tumor-related prognostic factors size. tumor diameter > 2 cm is the risk factor most associated with disease-specific death, with a 3-fold greater risk of recurrence and a 6-fold greater risk of metastasis [8]. a meta-analysis that included 36 studies and 17,248 patients set at 4 cm the most specific cutoff for determining the risk associated with tumor size [14]. other studies have confirmed worse outcomes in t2 than in t1 tumors, but revealed that beyond the 2 cm cut-off, the effect on disease free survival (dfs) becomes smaller [15][16]. location. cscc of the ear, temples and lips are associated with higher risk of recurrence and metastasis compared to other body regions. the risk of nodal metastasis is 5-fold greater for csccs on the vermilion lip compared with those on the cutaneous lip. the absence of subcutaneous fat in the vermilion lip might allow quicker tumor access to the rich lymphovascular space of muscle leading to a greater metastatic potential [17]. also, hands, feet, pretibial and anogenital area are considered location at risk independent of the size. depth of invasion. concerning thickness, the cut-off to differentiate low-risk versus high-risk cscc has been set at 6 mm, and it is unanimously reported by all the available staging systems, guidelines and meta-analyses [13,14,18] when the depth of cscc is reported as tumor invasion level, referring to the deepest tissue plan involved, the considered cut-off is the invasion beyond subcutaneous fat. bone invasion is mentioned in many guidelines as an independent prognostic factor, as its presence upgrades to t3 (minor erosion) or t4 (gross invasion) according to the ajcc 8th ed. staging system. however, it is comprised, by definition, in the tumor invasion level. table 4. ptnm pathological classification for skin carcinoma of the head and neck according to uicc 8th edition the pt categories correspond to the clinical t categories pn – regional lymph nodes histological examination of a selective neck dissection specimen will ordinarily include 10 or more lymph nodes. histological examination of a radical or modified radical dissection specimen will ordinarily include 15 or more lymph nodes. pnx regional lymph nodes cannot be assessed pn0 no regional lymph node metastasis pn1 metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension without extranodal extension pn2a metastasis in a single ipsilateral lymph node, less than 3 cm in greatest dimension with extranodal extension, or more than 3 cm but not more than 6 cm in greatest dimension without extranodal extension pn2b metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal extension pn2c metastasis in bilateral or controlateral lymph nodes, none more than 6 cm in greatest dimension, without extranodal extension pn3a metastasis in a lymph node more than 6 cm in greatest dimension without extranodal extension pn3b metastasis in a lymph node more than 3 cm in greatest dimension with extranodal extension or multiple ipsilateral, or any contralateral or bilateral node(s) with extranodal extension pm – distant metastasis pm1 distant metastasis microscopically confirmed table 5. staging system for both skin carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) and skin carcinoma of the head and neck according to ajcc/ uicc 8th edition stage 0 tis n0 m0 stage i t1 n0 m0 stage ii t2 n0 m0 stage iii t3 n0 m0 t1, t2, t3 n1 m0 stage iva t1, t2, t3 n2, n3 m0 t4 any n m0 stage ivb any t any n m1 6 review | dermatol pract concept. 2021; 11(s2): e2021166s perineural invasion. the impact of perineural invasion as risk factor for negative outcomes is the most well characterized. many single institution reviews report a strong association with disease recurrence [15,17,19,20] and the meta-analysis by thompson et al [14] confirmed a statistically significant association with disease-specific death and disease recurrence, with a risk ratio of 4.3 for disease recurrence. thus, the ajcc 8th ed. upstages thin csccs to t3 if a nerve greater than 0.1 mm in caliber is involved [18]. poor differentiation. the histologic grading system proposed by broder in 1921 identifies 4 grades of differentiation according to the percentage of well-differentiated cells in the tumor tissue (grade 1: 75% of well-differentiated cells; grade 2: 50% of well-differentiated cells; grade 3: 25% to 50% of well-differentiated cells; grade 4: <25% of well-differentiated cells) [21]. tumors are also classified into well-differentiated, moderately-differentiated, and poorlydifferentiated according to the presence of clear keratinization, horn pearls, and other classic histologic features of cscc, or the difficulty to determine a keratinocyte lineage [22]. the grade of histologic differentiation is not taken into account by the 8th edition of uicc and ajcc staging systems but remains a high-risk factor in the bwt system, nccn, and eado guidelines [6,11,13]. desmoplasia. desmoplastic cscc is an aggressive histologic variant of cscc characterized by narrow cords of cells and large amounts of extracellular stroma and often by perineural and perivascular invasion. recurrence rate and metastatic potential are 10-fold and 6-fold higher than other cscc variants, respectively [23]. growth rate. it has been observed that a growth rate > 4 mm/month in the long axis of the tumor is associated with poor prognosis and a greater risk of lymph node metastasis [24]. however, only nccn guidelines identify rapidly growing tumor among risk groups for local recurrence, metastases, or death from disease [13]. extrinsic prognostic factors (patientand physicianrelated) the role of extrinsic risk factors is more difficult to analyze, as features such as patient’s request to limit the extent of surgery or physician’s expertise in the treatment are impossible to standardize and systematically compare. however, in clinical practice, extrinsic factors have the greatest impact on the natural history of the tumor, as they may turn an early tumor with clinical and histological low-risk features into a cscc with a high-risk of recurrence and worse outcome, namely an advanced cscc. positive margins and recurrent disease. eado guidelines do not include recurrence in the list of high-risk cscc prognostic factors as it can be considered as the result of positive margins. positive margins correspond to a residual tumor, table 6. prognostic factors in cscc according to the eado and nccn guidelines. definition of high-risk patients (and very high-risk patients in the nccn classification) eado nccn intrinsic factors size > 2 cm high-risk: > 2 and < 4 cm very high-risk: > 4 cm location temple, ear, lip head, neck, hands, feet, pretibial, anogenital area depth of invasion > 6 mm or beyond fat tissue > 6 mm or beyond fat tissue perineural invasion microscopic, symptomatic or radiological high-risk: + very high-risk: tumor cell within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥ 0.1 mm degree of differentiation poor differentiation poor differentiation desmoplasia + very high-risk: + other subtypes for high-risk: acantholytic, adenosquamous, metaplastic growth rate + rapidly growing tumor bone erosion + borders + poorly defined lymphatic or vascular involvement high-risk: very high-risk: + extrinsic factors primary vs recurrent recurrent prior radiotherapy + immunosuppression + + review | dermatol pract concept. 2021; 11(s2): e2021166s 7 which has potential for recurrence a priori. when initial removal is incomplete, cscc is more likely to recur, mostly locally and less frequently in regional lymph nodes [6]. in order to obtain optimal tumor clearance in cscc < 2 cm in size, eado suggests 5 mm clinically tumor-free margins, while in cscc >2 cm in size suggested margins are 6-10 mm [6]. however, involved borders after the initial excision often derive from subclinical infiltration in sun-damaged skin [25]. recurrent cscc are twice as likely to recur after excisional surgery when compared with primary tumors [25]. site of prior radiotherapy or chronic inflammatory process. csccs arising from a leg ulcer, burn scar, radiation dermatitis, discoid lupus, and other chronic wounds have a reported metastatic risk of 26% [26]. this risk factor is only listed by the nccn guidelines. immunosuppression. the incidence of cscc in immunosuppressed individuals has been estimated to be 64 to 250 times higher than in the general population. the cumulative incidence of cscc increases progressively with duration of immunosuppression and tumors developed in this setting show a more aggressive behavior [27,28]. comorbidities and patient’ preferences. comorbidities represent one of the major obstacles to surgery, which is the first-line therapy of cscc. furthermore, in the case of high-risk tumors located on the head and neck area, primary excision can be often destructive, leading the patient to refuse the treatment. patient’s request to limit extent of surgery is indeed an additional, substantial risk factor. managing prognostic factors practical implications although numerous risk factors associated with worse outcomes have been identified, there is still a gap of knowledge on the precise risk of each factor individually. combination of 2 or more factors is considered to significantly increase the risk of poor outcome. eado guidelines recommend considering the variations of patientand tumor-related characteristics when assessing the level of overall prognostic risk [6]. however, the decision still relies on the physician’ expertise and opinion, as neither a nomogram nor a scoring system are available yet to define which cscc would deserve adjuvant rt or a closer follow-up program. figure 1. high-risk cutaneous squamous cell carcinoma (cscc). (a) cscc on the lower lip of a male aged 49, with high-risk features as location, thickness (4 mm), poor differentiation, and perineural invasion. despite the small size, the patient developed nodal metastasis after 6 months from primary excision and adjuvant radiotherapy. (b) cscc on the cheek of a female aged 77, defined as very high-risk according to nccn guidelines: thickness 11.0 mm, > 4 cm in diameter, poor differentiation. (c) cscc on the forehead of a patient aged 58, at high-risk because of poor differentiation, presence of perineural invasion, diameter > 2 cm. (d) cscc on the nose of a patient aged 83 characterized by poor differentiation and perineural invasion. 8 review | dermatol pract concept. 2021; 11(s2): e2021166s adjuvant rt is offered as part of clinical practice in many medical centers for patients with high-risk cscc, particularly for tumors with perineural invasion. however, there is still a lack of significant evidence, including randomized controlled trial data, showing a clear benefit of adjuvant rt in this setting [12]. there is no standardized follow-up schedule for patients with cscc due to the lack of randomized controlled trials. patients with high-risk cscc should be followed up every 3-6 months for the first 2 years, and every 6-12 months for years 3-5, and annually thereafter [13]. lymph node ultrasound should be performed every 3-6 months in the first 2 years depending on risk stratification. again, as the independent prognostic effect of high-risk factors has not been consistently defined, eado guidelines advice individual risk assessment to guide follow-up decisions [12]. diagnosis of advanced cutaneous squamous cell carcinoma advanced cscc is classified as metastatic cscc or locally advanced cscc. metastatic disease includes locoregional metastasis (in transit or to regional lymph nodes) or distant metastasis which are easily diagnosed by imaging (stage iii and iv according to ajcc /uicc 8th ed.]. noteworthy, the 8th ed. of ajcc/uicc staging system does not include the presence of in-transit metastases. the prognostic role of satellite and in transit metastasis in cscc has been recently investigated by xu et al [29] who found a significant association with worse overall survival. locally advanced cscc has been defined as non-metastatic cscc that is unlikely to be cured with surgery, radiotherapy, or combination treatment (surgery and radiotherapy) (figure 2). however, locally advanced disease lacks consensus definition and diagnosis is made after multidisciplinary board consultation. thus, the diagnosis of locally advanced cscc is influenced by the expertise of each center. the need for standardized definition criteria of locally advanced cscc is high in the clinical trial setting. in phase 2 trial of cemiplimab for advanced cscc, locally advanced cscc patients were included if they experienced recurrence after 2 or more surgical procedures with subsequent unlikely curative resection, if the tumor already reached substantial local invasion precluding complete resection, or if surgical treatment would lead to substantial complications or deformity. acceptable reasons for rt to be considered inapfigure 2. locally advanced cutaneous squamous cell carcinoma (cscc). (a) cscc in a 83-year-old male patient, located on the right parietal region, no previous treatment, late diagnosis. (b) cscc in a 77-year-old male patient on the left shoulder, recurrent to surgery. (c) cscc on the leg of a 61-year-old immunosuppressed male, no previous treatment. (d) cscc on the scalp of a 89-year-old male patient, recurrent after radiotherapy. review | dermatol pract concept. 2021; 11(s2): e2021166s 9 propriate were: previous rt with further rt exceeding the threshold of an acceptable cumulative dose, judgment of the radiation oncologist that the tumor was unlikely to respond to rt, or a risk–benefit assessment that rt was contraindicated for the patient [30]. clinical progression of cscc into the advanced form seems to be associated not only to the intrinsic aggressiveness of cscc, but also to patient characteristics that may impact on clinician decision and incomplete tumor initial management. regarding real-life profile of advanced cscc patients, a retrospective study by hillen et al [3], analyzed 190 patients with advanced cscc. patients presented a median age of 78 years, an ecog status 0-1, and location of the primary tumor most frequently on the head and neck, including highrisk locations such as ears or lips. despite nonmalignant comorbidities influenced the decision for cscc-specific therapy in only 21% of patients, the authors highlighted the fact that many clinicians might be unaware that locally advanced cscc can lead to death. eigentler et al [31], showed that in a cohort of 1,434 patients who excised a cscc between 2005 and 2015 and were followed-up for a median period of 36.5 months, a higher number of patients died due to local infiltration in the head region or regional infiltration into neck lymph nodes, compared to death due to visceral metastases. concerning pitfalls of initial management of cscc, a retrospective study by deilhes et al [32], in a cohort of 109 patients with advanced cscc, showed that 63% of patients had a delay of more than 3 months between the lesion’s first observation and biopsy, 62% of patients had incomplete histological examinations, and only 35% of patients completed all the procedures required for optimal management of the disease. moreover, the authors highlighted that 75% of their patients’ cohort were living in rural areas and the decreased availability of dermatologists might have impacted mismanagement of the disease. conclusion the clinician’s goal should be the recognition and appropriate treatment of cscc at higher risk for recurrence and/or for progressing into advanced disease. however, it should be acknowledged that diagnosis, management, and follow-up of high-risk cscc are still not straightforward. more studies are needed to standardize the relevance of each risk/prognostic factor, to explore the risk estimation of outcomes, and to prove the utility of disease-staging modalities. the adjuvant setting should be further explored to prevent progression of the disease. currently, diagnosis and management of highrisk and advanced cscc rely on a multidisciplinary approach that favors the most suitable therapeutic option based on the characteristics of the patient and of the disease. references 1. rogers hw, weinstock ma, feldman sr, coldiron bm. 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groups with alopecia areata farzaneh shirazi1, safoura shakoei2, maryam nasimi3, zahra saffarian2, robabeh abedini3 1 school of medicine, tehran university of medical sciences (tums), tehran, iran 2 department of dermatology, imam khomeini hospital, tehran university of medical sciences (tums), tehran, iran 3 department of dermatology, razi hospital, tehran university of medical sciences (tums), tehran, iran key words: alopecia areata, blood group, abo, rh citation: shirazi f, shakoei s, nasimi m, abedini r. the relationship between abo and rh blood groups with alopecia areata. dermatol pract concept. 2023;13(1):e2023060. doi: https://doi.org/10.5826/dpc.1301a60 accepted: april 28, 2022; published: january 2023 copyright: ©2023 shirazi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: it is financially supported by the vice-chancellor of research affairs of the tehran university of medical sciences. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: safoura shakoei md, department of dermatology, imam khomeini hospital, tehran university of medical sciences (tums), tehran, iran. tel: 00982161192655 fax: 00982188046767 email: dr.shakoei@gmail.com introduction: alopecia areata (aa) is a common non-scaring hair loss disease. genetic susceptibility and environmental factors can develop the disease. objectives: we investigated the association between aa and abo and rh blood groups. methods:  this cross-sectional study was done on 200 patients with aa and 200 healthy controls (hcs) between march 2021 and september 2021. results: the prevalence of blood groups o, a, b, and ab in patients with aa was 30%, 30.5%, 10.5%, and 29%, respectively. a significant difference was detected between the two groups in the frequency of the abo and abo*rh blood groups (p-value < 0.05). compared to the hcs, the prevalence of the ab and ab+ blood group was higher in aa patients. no significant relationship was detected between sex, bmi, duration of disease, age at onset, severity of alopecia tool (salt) score, hair loss pattern, and nail involvement with abo and rh blood groups (p-value > 0.05). conclusion: in conclusion, the highest difference was related to the ab+ blood group, so compared to hcs, the ab+ blood group frequency was higher in patients with aa. however, more studies with larger sample sizes on different ethnicities should be performed to verify the results of this study. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023060 introduction alopecia areata (aa) is a common non-scaring hair loss disorder. the prevalence of the disease is 1 in 1000 cases and has a lifetime incidence of 2% [1]. the prevalence of the disorders indicated above is expected to be roughly 0.2 percent in the overall population. moreover, genetic susceptibility and environmental factors can also induce the disease to develop [2]. however, the specific cause of the disease is unidentified. there are several lines of evidence linking aa to autoimmune diseases, like type 1 diabetes mellitus (dm), rheumatoid arthritis (ra), systemic lupus erythematosus (sle), vitiligo, and pemphigus vulgaris [3-6]. human gene variation, such as hla systems, is defined by red cell isoenzymes, blood groups, hemoglobin variations, and serum proteins [7]. the abo blood group system includes four o, a, b, and ab common blood groups. the presence of specific carbohydrate sugars on the surface of red blood cells distinguishes these different blood groups. a is identified by n-acetylgalactosamine, and b is identified as d-galactose for the b antigen. these sugars can be built on the h antigen, and in cases of the unmodified h antigen, the blood group will be o since the a and b antigens are unable to adhere to the surface of red blood cells [7]. the rhesus blood group system is composed of rhesus monkey erythrocyte antigens like the d antigen that can be found on the red cells of most rh+ humans. this system is highly complicated, and some rh alloantigens have yet to be biochemically described [8]. because blood types are unaffected by environmental factors, they are a useful and essential resource in the pathogenesis of diseases. in this regard, many investigations have been conducted to study the relationship between cancer types, blood types, and other disorders [9]. objectives also, some case series demonstrated substantial connections between blood groups and autoimmune disorders like multiple sclerosis, psoriasis, and pemphigus [10-12]. however, the exact nature of the linkage between blood groups and aa is not identified. thus, we investigated the association between aa and abo, and rh systems. methods the current cross-sectional study investigated the association between aa and abo/rh blood groups. the study was conducted on 200 cases with aa and 200 healthy controls (hcs) that attended our dermatology clinic in hospitals between march 2021 and september 2021. participants with other autoimmune and systemic disorders were excluded. the patients referred to the aa clinic were enrolled in the study and our healthy control objects were selected among people who did not have known systemic and skin disorders and were often referred for cosmetic problems. we matched age and sex between the two groups. we followed the principles of the helsinki declaration. the institutional review board of our university approved the protocol of this study. informed consent was attained from all participants. statistical analysis spss version 20 (ibm company, usa) was applied to analyze the variables. continuous variables are displayed as mean (standard deviation), and categorical variables are reported as frequency (percentage). student t-test (two-tailed) was applied for the comparison of continuous variables. the chi-square or fisher’s exact test was employed for the comparison of the categorical variables between the two study groups. a p-value <0.05 was regarded as significant. results baseline characteristics of participants two hundred patients with aa and 200 hcs were included. the baseline characteristics of the subjects in the aa and hc groups are detailed in table 1. the two study groups were comparable in terms of age, sex, and bmi. of 200 aa patients, 81 patients had patchy hair loss, 80 had universalis hair loss, 35 had totalis hair loss, and 3 had ophiasis hair loss. nail involvement was seen in 51 patients to some degree and in 19 patients as dystrophy (table 1). comparison of blood groups between aa patients and hcs table 2 indicates the frequency of different types of blood groups in aa patients and hcs. abo blood groups were significantly different between study groups (p=0.001). in this regard, the aa group showed a higher prevalence of the ab blood group, while the prevalence of the o, a, and b blood groups was higher in hcs (p=0.001). nonetheless, no significant between-group differences were found based on o/non-o (p=0.391) and rh (p=0.605) blood groups. finally, abo*rh blood groups were significantly different between study groups (p=0.017). the most difference was related to the ab+ blood group, whose frequency was markedly higher in patients with aa compared to hcs (table 2). association between blood groups and clinical characteristics in patients with aa according to table 3, no significant association was detected between sex, bmi, disease duration, age of onset, salt original article | dermatol pract concept. 2023;13(1):e2023060 3 table 1. baseline characteristics of the patients in aa and hc groups. aa group (n=200) hc group (n=200) p-value age [years; mean (sd)] 33.26 (14.33) 33.73 (12.05) 0.726a sex [n (%)] 0.468b • male 77 (38.5%) 70 (35%) • female 123 (61.5%) 130 (65%) bmi [kg/m2; mean (sd)] 25.87 (17.86) 26.06 (23.11) 0.926a disease duration [years; mean (sd)] 8.56 (8.04) age of onset [years; mean (sd)] 23.15 (12.94) current episode [months; mean (sd)] 8.25 (7.71) salt score [mean (sd)] 75.68 (29.93) the pattern of hair loss • patchy 81 (40.6) • universalis 80 (40%) • totalis 35 (17.6%) • ophiasis 3 (1.6%) nail involvement • none 129 (64.6%) • some 51 (25.6%) • dystrophy 19 (9.6%) a p-value of < 0.05 was considered statistically significant. sd: standard deviation a student t-test b chi-square test table 2. comparison of different types of blood groups between aa and healthy control group groups. aa group (n=200) hc group (n=200) p-value abo [n (%)] 0.001a • o 60 (30%) 68 (34%) • a 61 (30.5%) 79 (39.5%) • b 21 (10.5%) 28 (14%) • ab 58 (29%) 25 (12.5%) rh [n (%)] 0.605a • negative 17 (8.5%) 20 (10%) • positive 183 (91.5%) 180 (90%) abo*rh [n (%)] 0.017b • o9 (4.5%) 10 (5%) • a3 (1.5%) 5 (2.5%) • b3 (1.5%) 4 (3%) • ab2 (1%) 1 (0.5%) • o+ 51 (25.5%) 58 (29%) • a+ 58 (29%) 74 (37%) • b+ 18 (9%) 24 (12%) • ab+ 56 (28%) 24 (12%) hc: healthy control. a p-value of < 0.05 was considered statistically significant. a chi-square test b fisher exact test 4 original article | dermatol pract concept. 2023;13(1):e2023060 ta b le 3 . a ss o ci at io n b et w ee n b lo o d g ro u p s an d c li n ic al c h ar ac te ri st ic s o f p at ie n ts w it h a a . o a b a b p -v a lu e r h r h + p -v a lu e se x [ n ( % )] 0 .2 0 1 a 0 .2 0 1 a • m al e 2 2 ( 3 6 .7 % ) 3 0 ( 4 9 .2 % ) 7 ( 3 3 .3 % ) 1 8 ( 3 1 % ) 9 ( 5 2 .9 % ) 1 1 5 ( 6 2 .8 % ) • f em al e 3 8 ( 6 3 .3 % ) 3 1 ( 5 0 .8 % ) 1 4 ( 6 6 .7 % ) 4 0 ( 6 9 % ) 8 ( 4 7 % ) 6 8 ( 3 7 .2 % ) b m i [k g/ m 2 ; m ea n ( sd )] 2 4 .3 7 ( 4 .0 0 ) 2 4 .3 9 ( 4 .6 2 ) 3 0 .1 6 ( 3 5 .. 4 7 ) 2 8 .6 1 ( 3 5 .3 1 ) 0 .6 8 7 a 2 5 .8 7 ( 1 7 .8 6 ) 2 6 .0 6 ( 2 3 .1 1 ) 0 .9 2 6 a d is ea se d u ra ti o n [ ye ar s; m ea n ( sd )] 8 .9 0 ( 8 .6 8 ) 7 .8 1 ( 7 .5 5 ) 7 .4 8 ( 8 .0 2 ) 9 .7 1 ( 7 .9 3 ) 0 .2 9 0 a 8 .8 3 ( 8 .1 7 ) 6 .7 5 ( 6 .4 4 ) 0 .3 1 0 a a ge o f o n se t [y ea rs ; m ea n ( sd )] 2 3 .8 1 ( 1 1 .6 1 ) 2 0 .6 7 ( 1 1 .3 0 ) 1 9 .7 6 ( 9 .4 3 ) 2 6 .3 1 ( 1 6 .0 6 ) 0 .1 7 5 a 2 3 .0 3 ( 1 3 .1 1 ) 2 4 .4 1 ( 1 1 .1 4 ) 0 .6 6 7 a sa lt s co re [ m ea n ( sd )] 7 1 .8 0 ( 3 1 .4 0 ) 7 7 .4 4 ( 2 9 .6 4 ) 8 2 .6 6 ( 2 5 .9 2 ) 7 5 .3 1 ( 3 0 .1 5 ) 0 .5 0 8 a 7 5 .5 1 ( 3 0 .7 1 ) 7 7 .4 1 ( 2 8 .0 6 ) 0 .8 0 4 a h ai r lo ss [ n ( % )] 0 .5 4 4 a 0 .0 6 0 a • p at ch y 2 8 ( 4 6 .7 % ) 2 0 ( 3 3 .3 % ) 8 ( 3 8 .1 % ) 2 5 ( 4 3 .1 % ) 7 ( 4 1 .2 % ) 7 4 ( 4 0 .7 % ) • u n iv er sa li s 2 2 ( 3 6 .7 % ) 2 9 ( 4 8 .3 % ) 1 0 ( 4 7 .6 % ) 1 9 ( 3 2 .8 % ) 9 ( 5 2 .9 % ) 7 1 ( 3 9 % ) • t o ta li s 9 ( 1 5 % ) 9 ( 1 5 % ) 3 ( 1 4 .3 % ) 1 4 ( 2 4 .1 % ) 0 ( 0 % ) 3 5 ( 1 9 .2 % ) • o p h ia si s 1 ( 1 .7 % ) 2 ( 3 .3 % ) 0 ( 0 % ) 0 ( 0 % ) 1 ( 5 .9 % ) 2 ( 1 .1 % ) n ai l in vo lv em en t [n ( % )] 0 .0 9 0 a 0 .4 5 7 a • n o n e 3 9 ( 6 6 .1 % ) 4 3 ( 7 0 .5 % ) 1 6 ( 7 6 .2 % ) 3 1 ( 5 3 .4 % ) 1 3 ( 7 6 .5 % ) 1 1 6 ( 6 3 .7 % ) • so m e 1 5 ( 2 5 .4 % ) 1 5 ( 2 4 .6 % ) 5 ( 2 3 .8 % ) 1 6 ( 2 7 .6 % ) 4 ( 2 3 .5 % ) 4 7 ( 2 5 .8 % ) • d ys tr o p h y 5 ( 8 .5 % ) 3 ( 4 .9 % ) 0 ( 0 % ) 1 1 ( 1 9 % ) 0 ( 0 % ) 1 9 ( 1 0 .4 % ) p -v al u e o f < 0 .0 5 w as c o n si d er ed s ta ti st ic al ly s ig n if ic an t. an i n d ep en d en t tte st original article | dermatol pract concept. 2023;13(1):e2023060 5 the association between alopecia areata and abo and rh blood groups. they indicated a similar distribution of the abo blood group in the patient and healthy groups. however, the rh+ blood group was markedly higher in the healthy group than the patient group. also, rather et al. [24] conducted a case-control study in kashmir to examine the relationship between abo blood groups and different skin diseases (psoriasis, vitiligo, aa, pemphigus vulgaris). also, 37.1% of patients with psoriasis showed o blood group, followed by type b (30%) and a (25.7%), with no significant differences between study groups. in cases with vitiligo, 47.4% showed the b blood group, followed by blood groups o (36.8%) and a (10.5%). the frequency of a and b blood groups was significantly different between vitiligo patients and controls. in aa patients, blood group b was detected in 45.2% of patients, and groups o (28.6%) and a (19%) ranked second and third, with no significant differences between study groups. in patients with pemphigus vulgaris, 40% of patients showed o and b blood groups, followed by blood group a (20%), with no significant differences between the groups. contrary to the results of these studies, a significant difference was found between the two groups in our study. the highest difference was related to the ab+ blood group, so compared to the control group, patients with aa belonged to the ab blood group with higher frequency. we also examined the relationship between the characteristics of aa and the frequency of abo and rh blood groups; no significant association was detected between abo or rh blood groups and sex, bmi, disease duration, age of onset, salt score, hair loss pattern, and nail involvement in patients with aa. conclusion a significant difference was found between the two groups regarding the frequency of the abo*rh blood group. the frequency of the ab+ blood group was higher in patients with aa. further studies could verify the results of this study. references 1. villasante fricke ac, miteva m. epidemiology and burden of alopecia areata: a systematic review. clinical, cosmetic and investigational dermatology. 2015;8:397-403. doi:10.2147/ccid. s53985 2. sterkens a, lambert j, bervoets a. alopecia areata: a review on diagnosis, immunological etiopathogenesis and treatment options. clinical and experimental medicine. may 2021;21(2):215-230. doi:10.1007/s10238-020-00673-w 3. chang y-j, lee y-h, leong p-y, wang y-h, wei jc-c. impact of rheumatoid arthritis on alopecia: a nationwide population-based cohort study in taiwan. original research. 2020-april-28 2020;7(150)doi:10.3389/fmed.2020.00150 score, patterns of hair loss, nail involvement, and abo/rh blood groups in patients with aa (p>0.05). discussion we assessed the relationship between aa and abo and rh blood groups. the prevalence of blood groups o, a, b, and ab in patients with aa was 30%, 30.5%, 10.5%, and 29%, respectively. a significant difference was detected between the two study groups regarding the frequency of the abo blood group. the highest difference was related to the ab blood group, so compared to hcs, patients with aa showed a higher frequency of the ab blood group. the highest difference was related to the ab+ blood group, so compared to hcs, patients with aa showed a higher frequency of the ab+ blood group. aa is a recurrent inflammatory disorder that affects people of all ages and genders. despite the disease’s importance, the specific etiology has yet to be fully understood. the abo blood group family antigens have long been identified. blood group alloantigens can be found on the membrane of epithelial cells and red blood cells. there is a link between blood types and various dermatologic conditions [9, 13, 14], leading to the elucidation of disease pathogenesis. for instance, malignant melanoma was found to have a statistically significant higher risk in patients with the o blood group [9]. several previous reports have linked certain infections to specific abo blood groups [15]. tuberculoid leprosy is linked to the o blood group, while lepromatous leprosy is linked to the a and b blood groups, gonorrhea to the b blood group, smallpox to the a and b blood groups, and escherichia coli o 157 infection to the o blood type [16]. many studies have investigated the association between blood groups and autoimmune disorders like pemphigus vulgaris, dm, ra, spondyloarthropathy, vasculitis,  behcet’s disease, sle, systemic sclerosis, and sjogren’s syndrome [10,17, 18]. among these, no link was found between the abo blood types and pemphigus vulgaris, which is a well-known autoimmune skin disorder [18, 19]. in the etiopathogenesis of aa, autoimmunity is more prominent.   different researchers have established the relevance of t cells in the disease [20]. however, genetic variables play a role in illness susceptibility and severity as well. in single-twin investigations, the frequency of concurrent disease was found to be 55 percent, indicating that genetic and environmental variables play a role in the disease’s development [20, 21]. the genes that code for blood group antigens are found on chromosome 9q34.2 (for the abo blood group) and chromosome 1p36.11 (for the rh blood group) [22]. up to now, only two investigations have examined the relationship between blood type and aa. in 2018, i̇slamoğlu et al. [23] conducted a clinical study in turkey to investigate 6 original article | dermatol pract concept. 2023;13(1):e2023060 14. eiermann th, vejbaesya s, prestel h, roepke a, müller-myhsok b, schmitt-egenolf m. association and linkage of human leukocyte antigens with psoriasis – revisited. transfusion medicine and hemotherapy. 2002;29(6):326-330. doi:10.1159/000068267 15. garratty g. blood groups and disease: a historical perspective. transfusion medicine reviews. oct 2000;14(4):291-301. doi:10.1053/tmrv.2000.16228 16. g. g. relationship of blood groups to disease: do blood group antigens have a biological role? rev med inst mex seguro soc. 2005;(43(suppl: 1):113-121.) 17. çildağ s, kara y, şentürk t. abo blood groups and rheumatic diseases. european journal of rheumatology. dec 2017;4(4): 250-253. doi:10.5152/eurjrheum.2017.17044 18. tirado-sánchez a, ponce-olivera rm. abo and rhesus blood groups and their non-existent relationship with pemphigus vulgaris. acta dermatovenerologica alpina, pannonica, et adriatica. oct 2010;19(3):47-8. 19. shahkar h, fallahzadeh mk, namazi mr. abo blood groups and pemphigus vulgaris: no relationship. acta dermatovenerologica alpina, pannonica, et adriatica. 2010;19(1):49-51. 20. norris d. alopecia areata: current state of knowledge. journal of the american academy of dermatology. jul 2004;51(1  suppl): s16-7. doi:10.1016/j.jaad.2004.01.013 21. martinez-mir a, zlotogorski a, ott j, gordon d, christiano am. genetic linkage studies in alopecia areata. the journal of investigative dermatology symposium proceedings. oct 2003;8(2):199-203. doi:10.1046/j.1087-0024.2003.00809.x 22. mouhari-toure a, saka b, kombaté k, et al. is there an association between keloids and blood groups? isrn dermatology. 2012/12/06 2012;2012:750908. doi:10.5402/2012/750908 23. i̇slamoğlu zgk, unal m. is there an association of abo blood groups and rhesus factor with alopecia areata? 2018;17(6):12711274. doi:https://doi.org/10.1111/jocd.12491 24. rather pa, hassan i, naaz s, rasool f, reshi r. evaluation of abo blood types in various dermatoses in kashmiri population: a casecontrol study. journal of pakistan association of dermatologists. 01/01 2014;24:224-230. 4. forouzan p, cohen pr. systemic lupus erythematosus presenting as alopecia areata. cureus. 2020;12(6):e8724-e8724. doi:10.7759/cureus.8724 5. inamadar ac. association of alopecia areata, vitiligo and pemphigus vulgaris. indian journal of dermatology, venereology and leprology. may-jun 1995;61(3):157-8. 6. makino s, uchihashi t, kataoka y, fujiwara m. recovery from alopecia areata in a patient with autoimmune polyglandular syndrome type 3. endocrinology, diabetes & metabolism case reports. 01 feb. 2015 2015;2015:14-0084. doi:10.1530/edm-14-0084 7. storry jr, olsson ml. the abo blood group system revisited: a review and update. immunohematology. 2009;25(2):48-59. 8. westhoff cm. the rh blood group system in review: a new face for the next decade. transfusion. nov 2004;44(11):1663-73. doi:10.1111/j.0041-1132.2004.04237.x 9. de giorgi v, grazzini m, gori a, et al. abo blood group and risk of cutaneous malignant melanoma. european journal of cancer prevention : the official journal of the european cancer prevention organisation (ecp). mar 2011;20(2):121-2. doi:10.1097/ cej.0b013e3283429e1d 10. bakhtiari s, toosi p, azimi s, esmaili n, montazami a, rafieian n. is there a relation between abo blood groups and clinical outcome in patients with pemphigoid? a case-control study. dermatol res pract. 2016;2016:3916750-3916750. doi:10.1155/2016/3916750 11. lopetegi i, muñoz-lopetegi a, arruti m, et al. abo blood group distributions in multiple sclerosis patients from basque country; o(-) as a protective factor. mult scler j exp transl clin. 2019;5(4):2055217319888957-2055217319888957. doi:10.1177 /2055217319888957 12. tirant m, scala j, jafferany m, goldust m, sadoughifar r, lotti t. therapeutic and etiologic considerations related to blood group and triggers in psoriasis-a retrospective study. dermatologic therapy. may 2020;33(3):e13401. doi:10.1111/dth.13401 13. valikhani m ks, toosi s, kavand g, ghiasi m. . abo blood groups, rhesus factor and pemphigus. indian j dermatol. 2007;52:176-8 dermatology: practical and conceptual cutaneous squamous cell carcinoma: an update on diagnosis and treatment table of contents risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio, giulia briatico, cristina pellegrini, tea rocco, elvira moscarella, maria concetta fargnoli surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez, francisca silva-clavería, almudena fernández-orland, noemí eiris, andrés ruiz de casas, lara ferrándiz radiotherapy in the adjuvant and advanced setting of cscc paolo muto and francesco pastore immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh, daniel morse, jigar patel, michael r. migden treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi, luigi lorini mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples, italy guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. dermatology practical & conceptual review | dermatol pract concept. 2021:11(s2):e2021170s 1 treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi1, luigi lorini1 1 medical oncology unit, department of medical and surgical specialties, radiological sciences and public health, asst spedali civili of brescia, university of brescia, brescia, italy. key words: cutaneous squamous cell carcinoma, special population, auto-immune disease, immunosuppression, immunodepression citation: bossi p, lorini l. treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations. dermatol pract concept. 2021:11(s2):e2021170s. doi: https://doi.org/10.5826/dpc.11s2a170s accepted: september 25, 2021; published: november, 2021 copyright: ©2021 bossi and lorini. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: pb participated in advisory boards or received conference honoraria from merck, sanofi-regeneron, merck sharp & dohme, sun pharma, angelini, molteni, bristol-myers squibb, gsk. authorship: both authors have contributed significantly to this publication. corresponding author: paolo bossi, md. medical oncology unit, department of medical and surgical specialties, radiological sciences and public health, asst spedali civili of brescia, university of brescia, brescia, italy. email: paolo.bossi@unibs.it this article is part of the dpc journal special issue cutaneous squamous cell carcinoma: an update on diagnosis and treatment guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy cutaneous squamous cell carcinoma (cscc) may develop in patients with dysregulated immune activation (pre-existing autoimmune diseases or immunosuppression due to hematopoietic/solid organ transplant recipients), patients with a compromised immune function (long-term immunosuppression), and patients carrying chronic viral infections, or those affected by lymphoproliferative diseases. it should be also considered that patients presenting with immunosuppression have a high incidence of cscc (65–250-times higher than general population), highlighting the central role played by the immune system in the development of cscc. all these cases must be considered as “special populations” abstract 2 review | dermatol pract concept. 2021:11(s2):e2021170s introduction cutaneous squamous cell carcinoma (cscc) is the second most common non-melanoma skin cancer, accounting for 20% of skin cancers [1]. incidence rates change according to skin phenotype, gender (highest risk for men compared with women), and geographic areas: in north america, the incidence changes between canada (60/100,000 inhabitants) and arizona (usa) (290/100,000 inhabitants); in europe, age-standardized incidence is 9–96/100,000 inhabitants for males and 5–68/100,000 inhabitants for females; and in australia, the incidence reported is 387/100,000 inhabitants [2]. mortality rates for cscc are not always well documented; however, 5-year survival rate is estimated to be ranging from 88% for localized disease, to 50% for metastatic disease [3,4]. most csccs are diagnosed in the early stage and are eligible for curative treatment (more than 90% of cases), however, up to 5% of cases may present with a non-resectable disease [5] and other cases may not be eligible for surgery due to comorbidities. immune checkpoint inhibitors (icis) offer new therapeutic perspectives to cscc not amenable to locoregional treatments, achieving response rates in up to 50% of cases and providing benefits to a subgroup with durable disease control [6]. despite general good tolerability, immunotherapy could be rarely associated with severe immune-related adverse events (iraes), due to uncontrolled activation of the immune system. in this regard, immunotherapy safety profile should also be studied in “special populations”, ie, the patients whose comorbidities or frailties excluded them from clinical trials that led to the approval of icis. special populations include patients with dysregulated immune activation (pre-existing autoimmune diseases or immunosuppression due to hematopoietic/solid organ transplant recipients), patients with a compromised immune function (long-term immunosuppression), patients with chronic viral infections, or those affected by lymphoproliferative diseases in which the safety of icis is not well studied. “special population” in immunotherapy treatment patients receiving solid organ transplantation (sot) or hematopoietic stem cell transplant (hsct) require modulation of the immune system to maintain allograft tolerance and avoid rejection, and graft versus host disease (gvhd). preclinical data showed that the pd-1/pd-l1 axis has an important role in maintaining tolerance, even if not well understood. pd-1/pd-l1 axis is required for the maintenance of t-cell tolerance to prevent alloimmunity following hsct, and reduces the risk of gvhd [7]. as the intervention with icis migh induce alteration in the mechanism of t-cell exhaustion, thus reinvigorating immune response, icis could be also responsible for organ rejection [8,9]; as a consequence sot recipients were usually excluded from main ici clinical trials. data in literature regarding the use of icis in this population are related to case series and case reports. rejection rates in patients receiving icis are reported in 36% and 54% of liver and kidney transplantation, respectively [10]. recently, 19 patients receiving liver transplant and 29 patients receiving kidney transplant were treated with icis, showing a disease control rate of 35% and an organ rejection rate of 37% and 45% for liver and kidney transplantation, respectively [11]. a literature search and review of 27 articles reported a 40% rate of allograft rejection in renal transplant recipients treated with icis for advanced solid cancers (mainly melanoma); 17% of these patients achieved a partial response to immunotherapy [12]. a large systematic review on sot recipients undergoing icis due to advanced solid cancer confirmed the rejection rate of approximately 40%, similar across the type of icis and primary tumor histology [13]. an important issue is how to reduce risk of organ rejection without affecting immunotherapy efficacy: lowering or withdrawing immunosuppressive regimens is possible, however this needs to be discussed in multidisciplinary tumor board [14,15]. intriguingly, immune-suppressive agents used in combination with corticosteroids could modulate the risk of organ rejection. it seems that the use of mtor inhibitors, instead of calcineurin inhibitors, could be an option for sot recipients with cancer for treatment with immune checkpoint inhibitors (icis), as the safety and activity of these drugs have not been studied on these specific cases, since these patients were excluded from clinical trials leading to approval of icis. it is therefore important to gain as much information as possible from the analysis of real-life data, to derive an indication to be adopted in everyday clinical setting. moreover, therapeutic alternatives other than icis are scarce, mainly consisting in chemotherapy and anti-egfr agents, whose activity is lower than immunotherapy and whose toxicity (particularly with chemotherapy) are not sustainable by this frail population. here, we describe the current evidence of treatment with icis in special populations and conclude that it is necessary to find a balance between treatment risks (toxicities) and benefits (efficacy), as well as engaging a multidisciplinary team of experts to thoroughly manage and treat these patients. review | dermatol pract concept. 2021:11(s2):e2021170s 3 requiring ici treatment, due to the reduction of the risk to develop organ rejection, combined with the known antitumor activity [16,17]. icis are currently used in hematological diseases as salvage therapies in patients affected by hodgkin lymphoma, while there is limited evidence of their use in other types of lymphoma and lymphoproliferative disease [18]. patients who need icis treatment for solid cancer with a history of hematological disease could have previously received an immunotherapy treatment or could have also received an autogenic/allogenic transplant. if treatment with icis was well tolerated by hematological patients, further retreatment with icis is not contraindicated [8]. on the other hand, patients who previously received an allogeneic transplant due to hematological diseases need to be carefully evaluated: icis treatment increases the risk of gvhd; intriguingly antictla-4 ipilimumab appears to have higher safety in this setting [19–21]. well-known risk factors that increase the risk of gvhd during icis treatment are: a previous gvhd, the status of chronic gvhd, and previous toxicities [8]. another group of patients at higher risk of toxicities by immunotherapy are those suffering from autoimmune diseases. in these cases, further immune stimulation could lead to a possible flare in immune activation, with clinical consequences. therefore, patients affected by autoimmune diseases, even if silent, are usually excluded from clinical trials with icis, for fear of new, potentially life-threatening, symptoms’ appearance. preclinical data showed that mice deficient for ctla-4 or pd-1/pd-l1 may develop serious immune-mediated symptoms, including one death due to fulminant autoimmune disease [22]. however, cancer patients suffering from previous autoimmune disease do not represent a small portion of cancer patients: for instance, it is estimated that 13% of lung cancer patients had a positive anamnesis for autoimmune disease [23]. a series of 30 patients affected by melanoma, treated with icis and with concurrent diagnosis of autoimmune disease showed that 27% of patients had exacerbations of their autoimmune disease, 33% developed immune-related adverse events (iraes) requiring treatment, and one patient with psoriasis died of autoimmune colitis; the response rate was comparable with other ipilimumab clinical trials [24]. safety and efficacy of anti-pd-1/anti-pd-l1 therapy in cancer patients affected by autoimmune disorders have been shown in various series: rates of iraes and autoimmune flare were consistent, ranging from 23% to 44%, and efficacy did not differ from clinical trials in patients without autoimmune disorders. to note, iraes and autoimmune flares responded well to a classic therapeutic algorithm [25–28]. is important to consider cancer patients with specific circulating autoimmune markers or antibodies without evidence of autoimmune disease: this population experienced greater efficacy and greater toxicities from icis treatment [29]. recently, an italian series showed no difference in grade 3–4 iraes among 751 cancer patients treated with anti-pd-1 agents comparing patients with or without autoimmune disorders [30]. chronic immune suppression due to treatment of the aforementioned conditions may hind the effects of immunotherapy by blocking t-cell activity. patients receiving chronic immunosuppressant agents or high-dose steroids are usually excluded from trials with icis, consequently, data in literature is limited. experiences from ipilimumab trials, given the frequency of primary or secondary adrenal insufficiency, showed that a physiologic (replacement) dose of corticosteroids did not influence icis activity [31,32]. on the other hand, patients with prior autoimmunity receiving high-dose steroids showed less activity of icis if compared with patients who did not need high-dose corticosteroids (response rate: 15% vs 40%, respectively) [25]. a study of ipilimumab in patients affected by metastatic melanoma with brain metastasis, confirmed a lower response rate in patients receiving high-dose steroids [33]. recently, a single-institution study showed that the early start of steroids during immunotherapy could be linked to a lower probability of response and lower survival [34]. importance of considering “special populations” with cscc the immune suppressed population has an incidence of cscc that is 65–250-times higher compared with the general population. this draws attention to the central role played by the immune system in the development of cscc [35]. immunosuppression could be iatrogenic, usually due to therapies used for allogenic organ transplants, hematological or autoimmune diseases, related to hiv, or primary immunodeficiency. the immune-suppressed population represents a challenging target in the treatment of advanced or metastatic cscc not amenable to locoregional treatment, as they present with a more aggressive disease and with a higher risk of developing immune related toxicities due to icis. cscc grows more rapidly in immunosuppressed patients and has a higher tendency to develop local and distance recurrences [36]. moreover, mortality rates are higher for cscc patients with a history of sot [37]. immunotherapy with icis anti-pd-1 (cemiplimab and pembrolizumab), are now recommended as first-line treatment for patients with advanced cscc who are not eligible for surgery or radiotherapy based on results of phase ii clinical trials [6,38,39]. however, patients affected by autoimmune disease requiring immunosuppressive agents, anamnesis of prior solid organ transplant, active viral infection requiring specific therapy, such as hiv or hepatitis b virus or hepatitis c virus, and affected by chronic lymphocytic leukemia were 4 review | dermatol pract concept. 2021:11(s2):e2021170s excluded by registration drug clinical trials. in addition, international guidelines do not give specific guidance to treat these patiens. therapeutic alternatives for those populations who are excluded by clinical trials with icis are scarce, possibly limited by less activity and more toxicity, mainly based on platinum-based chemotherapy and antiegfr-targeted treatment. platinum-based chemotherapy for advanced cscc showed an objective response rate of 44%, median progression free survival (mpfs) and median overall survival (mos) was 5.5 months and 10.9 months, respectively, and the 3-year survival was 22% [40]. cetuximab (anti-egfr-targeted treatment), when employed as monotherapy, showed 27.7% of response rate with 2 complete responses out of 36 patients, responses were rapid, and 61% of patients had serious adverse events (grade 3–4) [41]. within this scenario it becomes strikingly important to balance risks (toxicities) and benefits (efficacy) of icis, when managing treatment for the “special population” excluded from icis in previous clinical trials. immunotherapy in cscc and special patient populations there is a lack of prospective data in the literature regarding immunotherapy in cscc “special populations”. data are mostly derived from case reports, case series, or retrospective data. an immune-suppressed patient with hiv and metastatic cscc has been reported to experience stabilization of disease and no side effects with pembrolizumab as third-line systemic treatment [42]. a patient with a kidney transplant showed complete pathological response to the combination of nivolumab + ipilimumab, but experienced allograft rejection [43]. two other cases were affected by advanced scalp squamous cell carcinoma and kidney transplant recipients have been successfully treated with cemiplimab [44,45]. real-world retrospective series on patients affected by cscc [46] showed a response rate of 42% and duration of response of 2 years (range: 1–32 months) with cemiplimab in immunosuppressed patients, described as patients who needs chronic immune suppression due to hiv, hematologic malignancies, sot recipients, and autoimmune disorders. out of 5 sot recipients, the duration of response was 20 months and just 1 patient experienced acute allograft rejection. a low rate of rejection was probably due to the fact that 3 out 5 sot recipients were receiving immunosuppression with prednisone + mtor inhibitors. intriguingly, the rate of grade 3 or 4 adverse events (21%) was not statistically different between the immunosuppressed population and the immunocompetent population. all patients with rheumatologic disease experienced lower-grade immune exacerbation. a french case series on patients receiving icis for advanced cscc [47] showed 3 serious adverse events out of 8 immune-compromised patients (due to hematological disease and hiv infection). the cemiplimab-rwlc survivorship and epidemiology (c.a.s.e.) study, is a prospective study aimed at evaluating safety and effectiveness of cemiplimab in a real-life setting. among the 138 patients enrolled up to now, 30 were immunocompromised or immunosuppressed; 1 patient experienced an acute renal failure, and no treatment-related deaths were reported, while the overall response rate (45.5%) was superimposable of that obtained in other clinical trials with no “special populations” [48]. conclusion what to do before starting icis in a cscc special patient population? management of patients with advanced cscc changed with the introduction of icis; however, treatment for the “special population” remains an important unmet medical need. it is important to carefully detail immunotherapy’s pros and cons to patients, considering the impact on prognosis and the possible toxicities that could develop and could potentially be life-threatening. to reduce the risk of possible immune complications, in the case of sot recipients, the change of the immunosuppressive regimens from the inhibitor of calcineurin to mtor inhibitors is indicated. steroids are often employed as preventative measures in high-risk cases, even if there are no clear dose and time indications. we suggest adjusting the dose of steroids according to the foreseen risk and the developed toxicities, to balance the need of limiting adverse effects of exaggerated immune activation with the possibility to achieve clinical response and not to compromise therapeutic effectiveness. each case of cscc patient belonging to the “special population” needs to be discussed and treated within a multidisciplinary team of experts, aiming to offer the best possible therapeutic armamentarium built ad hoc depending on the required needs. lastly, considering constraints of enrolling these patients in randomized clinical trials, the enrollment of “special patient populations” treated with immunotherapy in observational studies may contribute to increase the understanding of their treatment opportunities. references 1. rogers hw, weinstock ma, harris ar, et al. incidence estimate of nonmelanoma skin cancer in the united states, 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squamous cell carcinoma (cscc): data from prospective cemiplimab-rwlc survivorship and epidemiology (c.a.s.e.) study. jco. 2021;39(15_suppl):9547–9547. doi: 10.1200/jco.2021.39.15_suppl.9547. dermatology: practical and conceptual observation | dermatol pract concept 2018;8(1):9 43 dermatology practical & conceptual www.derm101.com introduction verrucous hemangioma is an uncommon congenital vascular malformation described by imperial and helwig as a separate entity in 1967 [1]. it usually presents at birth or in early childhood, with the commonest site being the lower extremities. the initial lesion presents as a reddish macular area resembling a vascular stain. gradually with the growth of child, the lesions increase in size, spread locally and become verrucous. the lesions are usually scattered but linear, serpiginous and reticular patterns can be seen rarely [2]. the linear arrangement of these lesions usually reflects genetic mosaicism or dermatomal distribution [3]. verrucous hemangioma does not involute spontaneously, rather, incomplete excision can result in regrowth [3]. clinically, vh is a close mimicker of other vascular lesions like angiokeratoma, infantile hemangioma and venous or lymphatic malformations. thus, dermoscopic and microscopic evaluation aids in confirming the clinical diagnosis. case report a 13-year-old female presented with purplish, warty skin lesions over the inner surface of the left foot. her mother stated that these lesions were noticed in early infancy, and with age they enlarged, increased in number, and became irregular on the surface. there was no history of any trauma or bleeding from these lesions. cutaneous inspection revealed well-defined erythematous to violaceous plaques and nodules with verrucous surfaces arranged in a linear array over the medial aspect of the left foot that were tender on palpation (figure 1a, b). no limb length discrepancy was noted. systemic examination did not reveal any abnormalities, nor did laboratory investigations. linear verrucous hemangioma—a rare case and dermoscopic clues to diagnosis aditi dhanta1, payal chauhan1, dilip meena1, neirita hazarika1 1 department of dermatology, venereology & leprology, all india institute of medical sciences, rishikesh, india key words: verrucous hemangioma, vascular malformation, dermoscopy citation: dhanta a, chauhan p, meena d, hazarika n. linear verrucous hemangioma—a rare case and dermoscopic clues to diagnosis. dermatol pract concept. 2018;8(1):43-47. doi: https://doi.org/10.5826/dpc.0801a09 received: june 26, 2017; accepted: november 21; published: january 31, 2018 copyright: ©2018 dhanta et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: payal chauhan, md, department of dermatology, venereology & leprology, all india institute of medical sciences, rishikesh, india. email: chauhanpayal89@gmail.com verrucous hemangioma (vh) is a rare, congenital and localized vascular malformation, which usually presents as warty, bluish, vascular papules, plaques, or nodules, mainly on the lower extremities. linear presentation of the disease is rare. a deep biopsy is necessary to confirm the clinical diagnosis by histopathological examination, with dermoscopy acting as a useful tool for evaluating the precise vascular structure. here, we report on a 13-year-old female child with linear vh presenting over her foot since infancy and dermoscopic findings of vh along with the clinical-pathologic features. abstract 44 observation | dermatol pract concept 2018;8(1):9 a parakeratotic epidermis. small and thin-walled capillaries lined by flattened endothelial cells were seen predominantly in the dermis (papillary and deep dermis) reaching up to the dermosubcutaneous junction. a few capillaries were dilated and filled with fresh fibrin thrombi (figure 2a-c). these features, thus, confirmed the diagnosis of verrucous hemangioma. the patient was referred to plastic surgery, where serial excisions were planned to remove the whole lesion. discussion in 1937, halter introduced the term “verrucous haemangioma” which is an uncommon vascular malformation. it was first described as a separate entity and distinguished the dermoscopic features were different depending on the type and site of the lesions. the most striking feature was a prominent bluish background. hyperkeratosis and bluish lacunae were observed in most of the lesions but they were most prominent in verrucous plaques (figure 1c). the periphery of the plaque showed well-defined dark blue lacunae characteristic of vascular lesions(figure 1d). doppler sonography of the lower limb (arterial system) showed diffuse irregular echogenicity in the subcutaneous plane of the affected area of the left foot. at some places, minimum vascularity was observed and these sonographic features were suggestive of hemangioma. a 4 mm punch biopsy was taken for histopathological evaluation. microscopy revealed elongation of rete ridges, thick parakeratosis and dense infiltration of eosinophils in a b c d figure 1. (a) erythematous to violaceous plaques with verrucous surface (black circle) arranged in a linear array over the medial aspect of the left foot. (b) satellite plaques (black arrow) arranged linearly over the dorsum of foot. (c) dermoscopy of verrucous lesions showing the prominent hyperkeratosis over bluish background (black circle) along with the reddish blue lacunae (black arrow) indicating the underlying dilated vascular channels. (d) peripheral areas of the lesion showing the bluish lacunae (black arrow) characteristic of vascular lesions correlating with the vascular channels seen in histopathology. [copyright: ©2018 dhanta et al.] observation | dermatol pract concept 2018;8(1):9 45 hyperkeratosis seen in the verrucous lesions over a bluish background, which again favored a vascular etiology. vh in its pre-verrucous state may be indistinguishable from infantile hemangioma, venous or lymphatic malformation and angiokeratoma. dermoscopy of infantile hemangioma has been reported to exhibit a polymorphous pattern of vascular structures with or without red linear and red dilated vessels [14]. the absence of a bluish component in hemangioma can help distinguish it from vh in early stages. as mentioned by osio et al. [14], the color of the hemangioma can help classify infantile hemangioma with the superficial type showing a bright reddish color, and the superficial and deep type depicting a dark red color. we would like to believe that a prominent bluish component in vh is seen due to the depth of the vascular involvement. angiokeratoma has been described as having three patterns in dermoscopy with dark lacunae and whitish veil in all three, peripheral erythema as a second pattern and hemorrhagic crust as a third [15]. although it is difficult to distinguish between angiokeratoma and vh on the basis of dermoscopy the presence of reddishblue lacunae without whitish veil, as seen in our case points more towards vh. more studies are needed to differentiate angiokeratoma from vh concretely. in its mature phase, the clinical and dermoscopic differential diagnoses of vh include pigmented lesions like pigmented basal cell carcinoma, verrucous epidermal nevus and seborroheic keratosis in smaller lesions. blue or dark lacunae are rarely seen with dermoscopic examination of non-vascular lesions. complete absence of a pigment network which is a highly specific dermoscopic feature of melanocytic lesions, helps in differentiating the two. the absence of leaf-like and spoke-wheel pigmentation, arborizing vessels, and erosions separates pigmented basal cell carcinoma from vh. verrucous epidermal nevus (ven) shows a large brown circle represented by oval or round structures with a hyperchromic brown edge surrounding a hypochromic area. in ven dermoscopic pattern is brown in color given its superficial nature and never blue, which helps in differentiating it from vh [16]. seborrheic keratosis shows milia-like cysts, comedo-like openings, and fissuring from angiokeratoma and its other variants by imperial and helwig in 1967 [1]. vh usually presents at birth or in early childhood and then gradually progresses in size with age. the initial presentation is a reddish macular area of a vascular anomaly resembling a ‘‘port-wine’’ stain. recurrent episodes of bleeding and infection result in the characteristic bluish-black color along with the development of a verrucous, hyperkeratotic surface [4]. localized or scattered lesions on the unilateral lower extremity are the most common presentation. however linear, serpiginous, or reticular pattern can also be seen, though uncommonly [2]. in our literature search, we could find only eight reported cases of linear verrucous hemangioma, making our patient the ninth [1,2,5-10]. apart from the clinical picture, confirmation of diagnosis is made with histopathology. characteristic microscopic features of vh are irregular acanthosis and hyperkeratosis in the epidermis. the abnormal proliferating vascular channels are located in the dermis and hypodermis, which differentiates it from angiokeratomas, where the lesion is limited to the papillary dermis. currently, no specific immunohistochemical marker exists to diagnose vh. in one study, positivity for glucose transporter protein 1 (glut1), a determinant expressed by infantile hemangioma, was seen in 7 of 11 vh lesions [11]. the dermoscopic features reported in the literature include an alveolar appearance with numerous small, oval to polygonal elements surrounded by slightly darker pigmentation. different shades of blue, including light blue, indigo blue, dark bluish black and a bluish white veil have been described [12,13]. well-defined dark lacunae were seen in the periphery in our case, which is characteristic of vascular lesions and further correlated well with the vascular channels seen on histopathology. dermoscopy of the late lesions showed more prominent hyperkeratosis along with the bluish lacunae indicating the underlying dilated vascular channels (dermlite ii hybrid m [3gen, san juan capistrano, ca, usa]; 10 × magnification). in our case we could not find a significant alveolar pattern, but all the other features were seen. the highlight of our case was the expected dominant a b c figure 2. (a) scanning view showing hyperkeratosis, elongation of rete ridges, and vascular dilatations in the papillary dermis extending to subcutaneous tissue (h&e, 4x). (b) hyperkeratosis, papillomatosis, acanthosis, and dilated blood vessels in the dermis (h&e, x10). (c) small and thin-walled dilated capillaries seen in dermis lined by flattened endothelial cells (black arrow) with fibrin thrombi present in some of the vessels (h&e, x40). [copyright: ©2018 dhanta et al.] 46 observation | dermatol pract concept 2018;8(1):9 2. hayashi h, shimizu t, nakamura h, shimizu h. linear verrucous haemangioma on the abdomen. acta dermatol venereol. 2004;84(1):79-80. 3. calduch l, ortega c, navarro v, martinez e, molina i, jorda e. verrucous haemangioma: report of two cases and review of the literature. pediatr dermatol. 2000;17(3):213-217. 4. wang g, li c, gao t. verrucous haemangioma. int j dermatol. 2004;43(10):745-746. 5. klein ja, barr rj. verrucous hemangioma. pediatr dermatol. 1985;2:191-193. 6. jain vk, aggarwal k, jain s. linear verrucous hemangioma on the leg. indian j dermatol venereol leprol. 2008;749(6):656–658. 7. nupur p, savant ss, kumar p, hassan s. linear verrucous hemangioma. indian dermatol online j. 2014;5(suppl 2):s136–s137. 8. kaliyadan f, dharmaratnam ad, jayasree mg, sreekanth g. linear verrucous hemangioma. dermatol online j. 2009;15(11):7. 9. srinivas sm, mukherjee ss. linear verrucous hemangioma in a child a rare case report. indian j paediatr dermatol. 2015;16:227-229. 10. naveen kn, pai vv, athanikar sb, athanikar vs, rai v. bluish red verrucous lesions on the leg. cutis. 2015;95(3):e12-4. 11. tennant lb, mulliken jb, perez-atayde ar, kozakewich hp. verrucous haemangioma revisited. pediatr dermatol. 2006; 23(3):208-215. 12. popadić m. dermoscopic diagnosis of a rare, congenital vascular tumor: verrucous haemangioma. j dermatol. 2012; 39(12):10491050. 13. prabhakar v, kaliyadan f. a case of verrucous haemangioma and its dermoscopic features. indian dermatol online j. 2015; 6, suppl s1:56-58. 14. oiso n, kawada a. the dermoscopic features in infantile hemangioma. pediatr dermatol. 2011; 28(5):591-593. 15. jh, kim mr, lee sh, lee se, lee sh. dermoscopy: a useful tool for diagnosis of angiokeratoma. ann dermatol. 2012;24(4): 468-471. 16. carbotti m, coppola r, graziano a, et al. dermoscopy of verrucous epidermal nevus: large brown circles as a novel features for diagnosis. int j dermatol. 2016;55(6):653-656. without any vascular lacunae, which helps in distinguishing it form vh [17]. the dermoscopic findings of the differential diagnosis of verrucous hemangioma is summarized in table 1. dermoscopy can help play an important role in clinching the diagnosis and aiding in management when clinical findings alone or an inadequate (superficial) biopsy specimen is misleading. the importance of reaching an accurate diagnosis cannot be overemphasized when planning treatment, given that the treatment of choice for vh is complete surgical excision. incomplete excision leads to persistence, recurrence and continued enlargement of the lesion. due to the deeper vascular infiltration, the recurrence rate of vh is 33%, especially when the lesions are larger than 2 cm in diameter [3]. various other options that have been tried with limited results include ultrasound, cryosurgery and electrocautery, especially for smaller lesions [4,18,19]. recently, a combination of co2 and dual pulsed dye laser nd:yag has been reported to provide satisfactory response in some cases [20]. conclusion in this report, we describe clinical, dermoscopic and histopathological features of vh in a 13-year-old girl. we emphasize that vh has distinct dermoscopic features and suggests that dermoscopy can contribute significantly to diagnosing such a rare congenital vascular malformation. the interesting fact about this case is rarity of disease more so than the linear presentation along with the presence of both verrucous and pre-verrucous stages. further, the dermoscopic pattern in both the types of lesions is another highlight of this case. references 1. wentscher u, happle r. linear verrucous hemangioma. j am acad dermatol. 2000;42(3):516-518. table 1. dermoscopic findings of verrucous hemangioma and its differential diagnosis 1. verrucous hemangioma alveolar appearance with various shadows of bluish small, oval to polygonal elements surrounded by slightly darker pigmentation with well-defined dark lacunae in the periphery. dominant hyperkeratosis seen in the verrucous lesions [12,13] 2. infantile hemangioma polymorphous pattern of vascular structures with or without red linear and red dilated vessels [14] 3. angiokeratoma dark lacunae and whitish veil, peripheral erythema, and hemorrhagic crust in third pattern [15] 4. pigmented basal cell carcinoma leaf-like and spoke-wheel pigmentation, arborizing vessels, erosions, blurred lacunae that may look like blue-gray ovoid nests [12] 5. verrucous epidermal nevus large brown circle seen as oval or round structures with a hyperchromic brown edge surrounding a hypochromic area [16] 6. seborrheic keratosis milia-like cysts, comedo-like openings, fissures and ridges and sharply demarcated border [17] https://www.ncbi.nlm.nih.gov/pubmed/?term=kaliyadan%252520f%25255bauthor%25255d&cauthor=true&cauthor_uid=19624993 https://www.ncbi.nlm.nih.gov/pubmed/?term=dharmaratnam%252520ad%25255bauthor%25255d&cauthor=true&cauthor_uid=19624993 https://www.ncbi.nlm.nih.gov/pubmed/?term=jayasree%252520mg%25255bauthor%25255d&cauthor=true&cauthor_uid=19624993 https://www.ncbi.nlm.nih.gov/pubmed/?term=sreekanth%252520g%25255bauthor%25255d&cauthor=true&cauthor_uid=19624993 https://www.ncbi.nlm.nih.gov/pubmed/19624993 https://www.ncbi.nlm.nih.gov/pubmed/?term=oiso%252520n%25255bauthor%25255d&cauthor=true&cauthor_uid=21854412 https://www.ncbi.nlm.nih.gov/pubmed/?term=kawada%252520a%25255bauthor%25255d&cauthor=true&cauthor_uid=21854412 https://www.ncbi.nlm.nih.gov/pubmed/?term=kim%252520mr%25255bauthor%25255d&cauthor=true&cauthor_uid=23197916 https://www.ncbi.nlm.nih.gov/pubmed/?term=lee%252520sh%25255bauthor%25255d&cauthor=true&cauthor_uid=23197916 https://www.ncbi.nlm.nih.gov/pubmed/?term=lee%252520se%25255bauthor%25255d&cauthor=true&cauthor_uid=23197916 observation | dermatol pract concept 2018;8(1):9 47 19. fatani m, al otaibi h, mohammed m, hegazy o. verrucous hemangioma treated with electrocautery. case rep dermatol. 2016;8(2):112-117. 20. segura palacios jm, boixeda p, rocha j, alcántara gonzález j, alonso castro l, de daniel rodríguez c. laser treatment for verrucous hemangioma. lasers med sci. 2012;27(3):681-684. 17. braun rp, rabinovitz hs, krischer j, et al. dermoscopy of pigmented seborrheic keratosis a morphological study. arch dermtol. 2002;138(12):1556-1560. 18. maejima h, katsuoka k, sakai n, uchinuma e. verrucous hemangioma successfully treated using 13-mhz ultrasonography. eur j dermatol. 2008;18(5):597. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023149 1 dermoscopic features of herpes zoster: case series and review of the literature giulia bazzacco1, claudio conforti1, ludovica toffoli1, enrico zelin1, iris zalaudek1, nicola di meo1 1 dermatology clinic of trieste, maggiore hospital, university of trieste, trieste, italy key words: herpes, zoster, dermoscopy, clue, halo citation: bazzacco g, conforti c, toffoli l, zelin e, zalaudek i, di meo n. dermoscopic features of herpes zoster: case series and review of the literature. dermatol pract concept. 2023;13(3):e2023149. doi: https://doi.org/10.5826/dpc.1303a149 accepted: january 14, 2023; published: july 2023 copyright: ©2023 bazzacco et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: giulia bazzacco, md, dermatology clinic of trieste, maggiore hospital, university of trieste, trieste, italy phone: +39 0403992056 e-mail: giuliabazzacco@gmail.com ethics statement: the patients in this manuscript have given written informed consent to publication of their case details. introduction herpes zoster (hz) is a major health burden that affects individuals of any age. the typical skin manifestation is a painful and unilateral vesicular exanthema, limited to a single or contiguous dermatomes [1]. diagnosis is usually easy and occurs with just clinical evaluation, however recognition of atypical hz can be a challenge for clinicians. when clinical presentation is ambiguous, laboratory tests such as polymerase chain reaction (pcr), tzanck preparation and histopathology are the gold standard for diagnosis. however, laboratory test usually takes at least one day to perform it and histopathology is an invasive procedure [1]. thus, dermoscopy, a non-invasive rapid diagnostic tool, can be helpful for early diagnosis of hz, but there are limited descriptions on dermoscopic patterns in the literature. the aim of this study was to compare a case series of hz with the relevant literature, evaluating the role of dermoscopy as a useful tool able to provide an early diagnosis. reviewing and comparing the available data, we observed a new dermoscopic pattern only partially described in literature. case presentation a group of patients with atypical hz diagnosed within the last 6 months were retrospectively retrieved from our secondary referral centers. dermoscopic evaluation was performed by a polarized handheld dermoscope with x10 magnification. the study included 14 patients (8 males, 6  females) aged between 29 and 84 (mean 54 years), skin phototype (fitzpatrick) ranged from i/ii (71%) to v/vi (29%). clinical diagnosis of the atypical eruption was difficult for three main reasons: early stage of rash with only few and small lesions, in most cases (50%) (figure 1); in 28,5% of cases hz arose on skin of color and the erythema was less clear (figure 2); in 21,5% there was a diffuse non-dermatomal eruption in immunocompromised hosts. dermoscopically, according to the existing literature [2-4], 2 research letter | dermatol pract concept. 2023;13(3):e2023149 white polyglobular structures were the most common features (100%), followed by meliceric crusts (100%), and erythematous background (71%). conclusions in literature a total of 75 patients, irrespective of age and gender, with a clinical presentation suggestive of hz were evaluated for dermoscopic features [2-4]. erythematous background (increased vascularity) was the most common finding (100%), followed by round cloudy white polyglobular structures (grouped vesicles) 53%-80%, and central brown dots 50%-80% (table 1). comparing the available data, one interesting finding arising from our study: the “halo sign”. it was an annular white/yellowish structure, that was present in the total of the retrospectively cases analyzed. “halo sign” was due to the contrast between the yellowish/brownish crusted center of vesicular lesions and the red color of the erythematous background which create an annular pattern around every element of the skin rash. it has been previously only partially described by narkhede et al and it could be a significant and easy method to recognize dermoscopic clue [2]. the role of dermoscopy for the early diagnosis of hz has previously been reported, it facilitated an earlier diagnosis by 1.62 days [2]. form our data analysis there were three clinical situations in which dermoscopy demonstrated its utility: (1) early-stage lesions (2) skin of color (phototypes v/vi) and (3) immunocompromised host [5,6]. limited data are available but dermoscopy is a useful tool to allow an early diagnosis and antiviral treatment when clinical presentation is uncommon. due to the lack of literature, these observations need further confirmation on larger series of patients. references 1. patil a, goldust m, wollina u. herpes zoster: a review of clinical manifestations and management. viruses. 2022;14(2):192. doi: 10.3390/v14020192. pmid: 35215786. pmcid: pmc8876683. 2. narkhede nd, nikham b, jamale v, hussain a, kale m. evaluation of dermoscopic patterns of vesiculobullous disorders. indian j dermatol. 2021;66(4):445. doi: 10.4103/ijd .ijd_294_20. pmid: 34759418. pmcid: pmc8530039. 3. rao kms, gaikwad s , dermoscopy in viral infections: an observational study. ip indian j clin exp dermatol. 2020;6(3): 261-267. doi: 10.18231/j.ijced.2020.053. 4. nayak ss, mehta hh, gajjar pc, nimbark vn. dermoscopy of general dermatological conditions in indian population: a descriptive study. clin dermatol rev. 2017;1:41-51. 5. dayan rr, peleg r. herpes zoster typical and atypical presentations. postgrad med. 2017;129(6):567-571. doi: 10.1080 /00325481.2017.1335574. pmid: 28540752. 6. lewis dj, schlichte mj, dao h jr. atypical disseminated herpes zoster: management guidelines in immunocompromised patients. cutis. 2017;100(5):321;324;330. pmid: 29232422. table 1. dermoscopic features of herpes zoster in literature references. the relevant literature was found by searching different databases: pubmed, google scholar. the following keywords alone or in combination were used: “herpes”, “zoster”, “dermoscopy”, “viral”, and “infection”. a wide review of the bibliography of each of the selected article was performed. references patients (n) dermoscopic features, percentage (%) dermoscope employed erythematous background cloudy white polyglobular structures central brown dots white halos grey to black dots erosions grayish structureless areas white globules narkhede et al [2] 50 100% +++ 50% +++ 50% nr 20% 20–80% dermlite dl 4 dermatoscope rao et al [3] 10 100% 80% 80% nr 30% 20% nr nr handheld contact dermoscope, derm lite 4 nayak et al [4] 15 +++ 53% 53% nr nr nr nr nr handheld pocket dermoscope dermlite ii pro nr = not reported; +++ = well represented. research letter | dermatol pract concept. 2023;13(3):e2023149 3 figure 1. (a) clinical image of herpes zoster involving left mandibular branch of trigeminal nerve. (b) dermoscopy shows millimetric brownish crusts on white polyglobular structures and an erythematous background (halo sign). figure 2. (a) clinical image of herpes zoster involving right axilla. (b,c) dermoscopy shows brownish crusts that cover white polyglobular structures on skin of color (halo sign). dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023012 1 lip mesotherapy with dexpanthenol as a novel approach to prevent isotretinoin-associated cheilitis çağrı turan1, ümran öner2 1 department of dermatology and venereology, medical park ankara hospital, ankara, turkey 2 department of dermatology and venereology, kastamonu university school of medicine, kastamonu, turkey key words: cheilitis, dexpanthenol, isotretinoin, mesotherapy, mucocutaneous side effect citation: turan ç, öner ü. lip mesotherapy with dexpanthenol as a novel approach to prevent isotretinoin-associated cheilitis. dermatol pract concept. 2023;13(1):e2023012. doi: https://doi.org/10.5826/dpc.1301a12 accepted: september 22, 2022; published: january 2023 copyright: ©2023 turan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: ümran öner, md, kuzeykent mah. cankat sok. no: 4 kastamonu, turkey. tel: +905422357700 email: umran.yildiz9@gmail.com introduction: isotretinoin (iso)-associated cheilitis is the most common side effect and the most common reason for discontinuation of ongoing therapy. so, various lip balms are also routinely recommended for all patients. objectives: we aimed to investigate the effectiveness of local intradermal injections (mesotherapy) of dexpanthenol into the lips to prevent iso-associated cheilitis. methods:  this pilot study was conducted on patients over the age of 18 using iso (about 0.5 mg/kg/ day). all patients were prescribed only hamamelis virginiana distillate in ointment form as a lip balm. in the mesotherapy group (n=28), 0.1 ml of dexpanthenol was injected into each lip tubercle (4 points total) to the submucosal level. the patients in the control group (n=26) used only the ointment. “iso cheilitis grading scale (icgs)” was used in the evaluation of iso-associated cheilitis. the patients were followed for 2 months. results:  although there was an increase in icgs scores in the mesotherapy group compared to the baseline, no statistically significant change was observed after treatment (p=0.545). however, in the control group, there was a statistically significant increase in icgs scores in the 1st and 2nd months compared to the baseline (p<0.001). lip balms were needed significantly less frequently in the mesotherapy group compared to the control, both in the 1st and 2nd months (p=0.006, p=0.045; respectively). conclusions: lip mesotherapy with dexpanthenol will be a useful option for preventing iso-associated cheilitis because of its easy application, cost-effectiveness, low complication risk, and high patient satisfaction. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023012 introduction acne vulgaris is the most common disease in dermatology practice, which can occur at any age, especially in adolescents. systemic isotretinoin (iso, 13-cis-retinoic acid) is frequently prescribed for approximately 6-12 months in patients with moderate to severe acne vulgaris, based on a total cumulative dose of 120-150 mg/kg. [1,2] despite its high efficacy, it has mucocutaneous side effects such as xerosis and cheilitis, which significantly affect the comfort of the patients’ life, as well as systemic side effects such as muscle-bone pain, headache, teratogenicity, lipid metabolism, and liver function impairment [1]. side effects other than teratogenicity are thought to be dose-dependent [2]. although long treatment duration and side effects are challenging for patients, it is a safe treatment [3]. severe side effects may lead to dose reduction or termination of treatment. therefore, it is crucial to control side effects in successful patient management. iso-associated cheilitis is the most common side effect caused by treatment-related reduction in sebum production, thinning of the stratum corneum, and changes in the skin barrier [2-4]. the frequency of cheilitis was found to be 77.5% at low doses (0.26-0.50 mg/kg/day) and 96.4% at high doses (0.76-1 mg/kg/day) [2]. it has been reported that the most common cause of patients’ ongoing-treatment refusal is cheilitis [2]. so, various lip balms/moisturizers are also routinely recommended for all patients prescribed iso. the disadvantages of lip moisturizers are their cost, frequent use, and unsatisfactory results. although vitamin e and omega-3 supplements have been reported to reduce iso-associated mucocutaneous side effects, they have not been exactly adopted in practice yet [5,6]. dexpanthenol (d-pantothenyl alcohol, provitamin b5) is frequently used as a topical and localized intradermal microinjection (mesotherapy) in dermato-cosmetology and various diseases. dexpanthenol moisturizes the skin thanks to its hygroscopic properties and repairs the skin barrier by hydrating the stratum corneum and reducing transepidermal water loss [7]. it has been commonly used as an over-the-counter topical drug for more than 70 years in diseases such as nappy rash, contact dermatitis, seborrheic dermatitis, cracked nipples, especially atopic dermatitis, and dry skin [7]. it supports skin regeneration and wound healing by increasing epidermal differentiation [8]. also, it reduces inflammation after irritation with its anti-inflammatory properties [9,10]. allergic reaction due to dexpanthenol is rare, and it is a safe agent [11]. dexpanthenol may be useful in the prevention and treatment of iso-associated cheilitis due to these properties. objectives we aimed to investigate the effect of the combination of conventional topical lip balm and lip mesotherapy (dexpanthenol) in the prevention of iso-associated cheilitis on patient satisfaction, need for moisturizer, and clinical outcomes. methods this study was approved by the local ethics committee (decision no: 2021/12-186). the study was performed as per the latest version of the helsinki declaration and the guidelines for good clinical practice. in the study protocol, the aim was not to investigate the superiority of mesotherapy over lip balm, but to evaluate the benefits of combining it with conventional topical care. this pilot study was conducted on patients who received iso for the first time in dermatology outpatient clinics between january 2021 and march 2021. only patients over 18 years using about 0.5 mg/kg/day iso were enrolled in the study. written informed consent was obtained from all participants. exclusion criteria from the study were the following: the presence of atopy, change of dose during follow-up, presence of any rheumatological disease, additional drug use, lip-licking/biting habit, acne excorie, immunodeficiency, local infection, using any steroid cream on the lips and dexpanthenol allergy. in our practice, we recommend dexpanthenol mesotherapy to the lips in addition to lip balm to all eligible patients using iso with a proactive approach to reduce the risk of cheilitis or dry lips. we have got quite positive feedback from this procedure, which has a low side effect profile. in this study, we retrospectively evaluated patients with and without dexpanthenol mesotherapy to the lips. we conventionally recommend a lip balm to every patient using iso, even if lip mesotherapy has been applied. all patients included in the study were prescribed only hamamelis virginiana distillate in ointment form (hametan® 25% ointment) as a lip balm. none of the patients used any additional product to moisturize their lips. firstly, 5% lidocaine pomade was applied to the lips of patients who approved the procedure. after waiting approximately 10-15 minutes, 0.1 ml of dexpanthenol (bepanthen® 500 mg/2 ml ampoule with the solution for injection) was injected into each lip tubercle (4 points in total) to the submucosal level (approximately 3-4 mm depth) using a 30  gauge-13 mm needle. during the follow-up with the p atients, data such as the pain level of the procedure (visual analog scale (vas, 0-10 points)), possible side effects such as edema and ecchymosis, subjective satisfaction levels, and effect duration of the treatment were recorded. “iso cheilitis grading scale (icgs)” developed by ornelas et al. was used in the evaluation of iso-associated cheilitis [5] (table 1). all procedures were conducted using statistical package for social sciences software (spss inc., chicago, il, usa, v21.0). after checking the normality distribution of scale original article | dermatol pract concept. 2023;13(1):e2023012 3 variables by shapiro wilks, wilcoxon and friedman’s tests were used to compare two and more than two dependent groups, respectively. bonferroni adjustment was applied as post-hoc (wilcoxon signed-rank tests) after friedman’s test (bonferroni-adjusted two-sided significance level<0.05). mann-whitney u test was used for independent groups. pearson’s chi-square test was used to compare independent categorical variables. results the study involved 28 patients receiving dexpanthenol mesotherapy (mesotherapy group) and 26 patients without the procedure (control group, ointment only). the groups were identical in terms of age and sex distribution (p=0.917, p=0.627; respectively). the groups were identical for baseline icgs (p=0.728). all patients were using iso at a dose of approximately 0.5 mg/kg, and there was no statistical difference between the groups in terms of dosage (p=0.141) (table 2). the groups were compared with themselves and each other for the icgs scores and frequencies of daily use of lip balm during the 2-month follow-up period (table 3). in the mesotherapy group, despite the iso treatment, although there was an increase in icgs scores compared to the baseline, no statistically significant change was observed (p=0.545). however, there was a statistically significant increase in icgs scores at the 1st and 2nd months of iso treatment in the control group compared to the baseline (p<0.001). while there was no difference between the groups in terms of icgs scores at baseline, there was a statistically significant difference at both 1 and 2 months (both, p<0.001) (figure 1). the daily need for lip balm increased significantly in both groups compared to the baseline (both, p<0.001). however, in the mesotherapy group, lip balms were needed significantly less frequently compared to the control group both in the 1st and 2nd months of iso treatment (p=0.006, p=0.045; respectively). as seen in table 3, the patients had high satisfaction rates from dexpanthenol mesotherapy, and a statistically significant increase was observed in the satisfaction rates after the 2nd session (p=0.005). according to 96.4% (n=27) of the patients, the effect of mesotherapy appeared in only 1-2 days. after two mesotherapy sessions, it was observed that the patients’ opinions about the effect duration of the treatment had altered. the effect duration was more than four weeks according to 26.1% of the patients, and 2-4 weeks according to 34.8%-65.2% of them. in the follow-up with the patients, mild angular cheilitis was observed in 3 (10.7%) patients in the mesotherapy group. the mean score of the procedure-related pain after topical anesthesia was 4.1±1.1. no additional complications were observed. table 1. isotretinoin cheilitis grading scale. erythema scale/crust fissure commissures 0 no involvement no involvement no fissures no involvement 1 mild erythema mild scale/crust one fissure mild involvement: erythematous or scaly 2 moderate erythema moderate scale/ crust two to four fissures moderate involvement: erythematous and scaly, lichenified, mild fissuring 3 severe erythema severe scale/crust greater than four fissures severe involvement: more extensive erythema, scale, and lichenification or any of those with severe fissuring total score: ranges from 0 to 12 table 2. comparison of patient characteristics and iso dose between groups. mesotherapy group (n=28) control group (n=26) p-value age, years 23.8 ± 3.2 24.0 ± 3.6 0.917 sex man 9 (32.1%) 10 (38.5%) 0.627* woman 19 (67.9%) 16 (61.5%) baseline icgs (ranging 0-12 points) 0.6 ± 0.7 0.6 ± 0.7 0.728 body-mass index (kg/m2) 22.3 ± 3.4 22.4 ± 2.9 0.890 daily iso-dose (mg/day) 29.6 ± 6.4 31.9 ± 4.0 0.142 daily iso-dose/kg (mg/kg/day) 0.50 ± 0.06 0.51 ± 0.05 0.141 icgs: isotretinoin cheilitis grading scale, iso: isotretinoin mann whitney u and pearson’s chi-square* tests were used. 4 original article | dermatol pract concept. 2023;13(1):e2023012 table 3. comparison of several parameters with dependent and independent groups. baseline 1st month 2nd month p-value * grade score of iso-associated cheilitis (ranging 0-12 points) mesotherapy group (n=27) 0.6 ± 0.7 1.1 ± 1.3 0.8 ± 0.7 0.545 control group (n=26) 0.6 ± 0.7 2.8 ± 0.7 3.4 ± 1.5 <0.001a,b p-value ** 0.728 <0.001 <0.001 frequency of daily use of lip balm (hamamelis ointment) mesotherapy group (n=27) 0.9 ± 0.5 4.7 ± 2.3 4.3 ± 2.4 <0.001a,b control group (n=26) 0.8 ± 0.7 6.0 ± 2.5 6.9 ± 4.6 <0.001a,b p-value ** 0.597 0.006 0.045 the patients’ opinions in the mesotherapy group regarding the treatment satisfaction level (n=23) very satisfied 7 (30.4%) 13 (56.5%) 0.005 satisfied 14 (60.9%) 10 (43.5%) slightly satisfied 2 (8.7%) 0 (0.0%) unsatisfied 0 (0.0%) 0 (0.0%) effect duration (n=23) ≥4 weeks 6 (26.1%) 6 (26.1%) 0.106 2-4 weeks 8 (34.8%) 15 (65.2%) ≤2 weeks 9 (39.1%) 2 (8.7%) data are expressed as mean ± standard deviation. * wilcoxon and friedman’s tests were used for comparisons of two and more than two dependent groups, respectively. bonferroni adjustment was applied as post-hoc (wilcoxon signed-rank tests) after friedman’s test (bonferroni-adjusted significance level<0.05). ** mann whitney u test was used for independent groups. a: p<0.05 for the difference between baseline and 1st month; b: p<0.05 for the difference between baseline and 2nd month; c: p<0.05 for the difference between 1st month and 2nd month in 2-month patient follow-up control group (hametan® ointment) mesotherapy group (bepathen® ampoule) 5 4 3 ic g s (9 5% c i) 2 1 0 baseline 1st month 2nd month figure 1. iso-associated mucositis was significantly lower in the mesotherapy group than in the control group both at 1st month and 2nd months when compared by icgs scores. icgs: isotretinoin cheilitis grading scale, ci: confidence interval. original article | dermatol pract concept. 2023;13(1):e2023012 5 minerals, and various bioactive substances into the skin layers to stimulate fibroblast activity and collagen genesis and reverse elastin degeneration and transepidermal water loss [15,16]. patients may experience injection-related side effects such as pain, erythema, edema, and ecchymosis. only one of the patients in the study hesitated to continue treatment because of pain. the patients stated that they had no experience of any bruising or ongoing pain after the procedure and that the edema on the lips usually regressed within 1-2 hours. mild-moderate pain was noted despite topical anesthesia. we think that this may be reduced further by adding lidocaine solution to dexpanthenol. since we observed angular cheilitis in some patients, although the vermilion was normal, we concluded that 0.05-0.1 ml dexpanthenol mesotherapy to the lip commissures, in addition to 4-point injection, would yield better clinical results. the satisfaction rates of the patients were high, and the significant increase conclusions cheilitis is characterized by erythema, dryness, crusting, fissures, and inflammation of the commissures on the lips. it greatly affects the quality of life of patients due to burning, itching, and edema [5]. various sub-clinical types of cheilitis can be encountered secondary to different etiological factors such as actinic damage, systemic diseases, immunosuppression, nutritional deficiencies, local irritants and allergens, infections, and drugs [9,10]. the main cause of drug-associated cheilitis is systemic retinoids [10]. iso is an indispensable and safe agent of dermatology practice with high cure rates for acne vulgaris [1]. however, it should not be overlooked that iso-associated cheilitis is the leading cause of early termination of treatment, with a rate of 1.4% [2]. effectively reducing the risk of cheilitis will increase patient comfort and treatment sustainability. although various supplements such as vitamin e, omega 3, and primrose oil have been recommended in some studies for mucocutaneous side effects, there is no established treatment method other than moisturizers [6,11,12]. in randomized controlled studies, it was reported that vitamin e supplementation did not significantly reduce the xerosis associated with iso [13,14]. patients may not be willing to use another systemic therapy while also undergoing long-term iso therapy. therefore, we consider it to be challenging to use oral supplements in practice. we introduce lip mesotherapy with dexpanthenol as a novel approach. we have experienced highly satisfactory results with lip mesotherapy with dexpanthenol, which has a high safety profile and which we frequently prefer in indications such as hair loss, wound healing, and rejuvenation. to the best of our knowledge, the effectiveness of dexpanthenol in lip mesotherapy has not been reported so far. in this study, we found that dexpanthenol mesotherapy combined with topical therapy has excellent efficacy in preventing iso-associated cheilitis. while there was no difference between the groups in terms of the severity of baseline cheilitis and the frequency of lip balm use before treatment, both parameters were lower in the mesotherapy group compared to the control group in both 1st and 2nd-month examinations. however, even if mesotherapy is performed in patients using iso, topical care should be offered to every patient due to the significant increase in the need to use lip balm. the clinical results recorded in the follow-up of the patients in the mesotherapy and control groups after iso were presented in figure 2 and figure 3, respectively. it is assumed that mesotherapy allows slower diffusion, higher levels, and longer-lasting effects of drugs in the tissues around the injection site compared to intramuscular injection or topical applications [15]. this method is a safe transdermal drug delivery tool applied by injecting vitamins, figure 2. patients administered with dexpanthenol mesotherapy to the lips. 6 original article | dermatol pract concept. 2023;13(1):e2023012 and gene regulation effects of dexpanthenol on dermal fibroblasts [8,19,20]. we think dexpanthenol injected into the submucosa reduces the severity of cheilitis and the need for moisturizer by increasing hydration and regeneration in iso-damaged skin, reducing irritation. there are limited studies comparing the efficacy of mesotherapy compared to topical applications of the same agent. while there is no research on the efficacy of dexpanthenol, submucosal injection of vitamin c in gingival hyperpigmentation has been found to be superior to the use of its topical form [21]. although the main limitation is a small sample size, statistically significant high efficacy rates were achieved. transepidermal water loss measurement was not included in the protocol due to technical impossibility. the shortcoming of the study was that we could not compare dexpanthenol mesotherapy with the topical form of dexpanthenol and placebo. the non-reimbursement of dexpanthenol ointment and the excessive diversity of similar products on the market necessitated the use of hamamelis virginiana as a control group in our retrospective study. because hamamelis virginiana (hametan® ointment), an alternative to dexpanthenol, is one of the most frequently preferred reimbursed medical products in our country. indeed, wolff and kieser investigated the clinical effects of ointment forms of hamamelis and dexpanthenol in the treatment of skin/mucous membrane inflammation in children [22]. accordingly, physicians’ and parents’ efficacy assessments revealed similar or better treatment ratings of hamamelis ointment than dexpanthenol. while it is plausible that water intake reduces the mucocutaneous side effects of iso, there is no evidence to our knowledge. therefore, water intake is lacking in the study protocol. in conclusion, the effectiveness of lip mesotherapy with dexpanthenol in the prevention of iso-associated cheilitis was remarkable. we believe that this method will be a useful adjuvant option for both the prevention and treatment of iso-associated cheilitis because of its easy application, low cost, low complication risk, and high patient satisfaction. however, patients’ opinions and approvals on whether they want such a needle application should be evaluated. further placebo-controlled, randomized studies with larger sample sizes are needed. references 1. brelsford m, beute tc. preventing and managing the side effects of isotretinoin. semin cutan med surg. 2008; 27: 197-206. doi: 10.1016/j.sder.2008.07.002. 2. rademaker m. adverse effects of isotretinoin: a retrospective review of 1743 patients started on isotretinoin. australas j dermatol. 2010;5 1: 248-253. doi: 10.1111/j.1440-0960.2010.00657.x. 3. brito mf, sant’anna i, galindo j, rosendo l, santos j. evaluation of clinical adverse effects and laboratory alterations in the satisfaction rates after the second session was remarkable. it has been claimed that the most disturbing period in iso-associated cheilitis is the first month of treatment, after which patients adapt to xerotic changes [11]. the increase in the satisfaction levels of the patients after the second session may be related to this adaptation process. dexpanthenol is an important molecule for the physiological function of the epithelium. after absorption through the skin, it quickly turns into pantothenic acid, a component of coenzyme-a.11,17 coenzyme-a is an essential cofactor in the metabolism of carbohydrates, fatty acids, sphingolipids, proteins, sterols, and steroid hormones [12]. dexpanthenol interacts with the relevant lipid and protein molecular segments in the corneocytes, thus increasing the hydration of the skin by contributing to molecular fluidity [17,18]. studies have demonstrated the migration, proliferation, figure 3. control patients applying hamamelis ointment to the lip. original article | dermatol pract concept. 2023;13(1):e2023012 7 as used in acne vulgaris: a randomized trial. j am acad dermatol. 2000; 43: 777-784. doi: 10.1067/mjd.2000.110391. 14. kus s, gün d, demirçay z, sur h. vitamin e does not reduce the side effects of isotretinoin in the treatment of acne vulgaris. int j dermatol. 2005; 44: 248-251. doi: 10.1111/j.1365-4632. 2004.02072.x. 15. markiewicz a, zasada m, erkiert-polguj a, wieckowska-szakiel m, budzisz e. an evaluation of the antiaging properties of strawberry hydrolysate treatment enriched with l-ascorbic acid applied with microneedle mesotherapy. j cosmet dermatol. 2019; 18: 129-135. doi: 10.1111/jocd.12545. 16. lee jc, daniels ma, roth mz. mesotherapy, microneedling, and chemical peels. clin plast surg. 2016;43:583-595. doi: 10.1016/j.cps.2016.03.004. 17. bergler-czop b and brzezińska-wcisło l. the new therapy schema of the various kinds of acne based on the mucosa-skin side effects of the retinoids. cutan ocul toxicol. 2012;31:188-194. doi: 10.3109/15569527.2011.633949. 18. björklund s, pham qd, jensen lb, et al. the effects of polar excipients transcutol and dexpanthenol on molecular mobility, permeability, and electrical impedance of the skin barrier. j colloid interface sci. 2016; 479: 207-220. doi: 10.1016/j. jcis.2016.06.054. 19. heise r, skazik c, marquardt y, et al. dexpanthenol modulates gene expression in skin wound healing in vivo. skin pharmacol physiol. 2012; 25: 241-248. doi: 10.1159/000341144. 20. wiederholt t, heise r, skazik c, et al. calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. exp dermatol. 2009;18:969-978. doi: 10.1111/j. 1600-0625.2009.00884.x. 21. el-mofty m, elkot s, ghoneim a, yossri d, ezzatt om. vitamin c mesotherapy versus topical application for gingival hyperpigmentation: a clinical and histopathological study. clin oral investig. 2021; 25(12): 6881-6889. doi: 10.1007/s00784021-03978-6. 22. wolf h, kieser m. hamamelis in children with skin disorders and skin injuries: results of an observational study. eur j pediatr. 2007; 166: 943-948. doi: 10.1007/s00431-006-0363-1. in patients with acne vulgaris treated with oral isotretinoin. an bras dermatol. 2010; 85: 331-337. doi: 10.1590/s0365-05962 010000300006. 4. mclane j. analysis of common side effects of isotretinoin. j am acad dermatol. 2001; 45: s188-194. doi: 10.1067/mjd.2001 .113719. 5. ornelas j, rosamilia l, larsen l, et al. objective assessment of isotretinoin-associated cheilitis: isotretinoin cheilitis grading scale. j dermatolog treat. 2016; 27: 153-155. doi: 10.3109/09546634.2015.1086477 6. goforoushan f, azimi h, goldust m. efficacy of vitamin e to prevent dermal complications of isotretinoin. pak j biol sci. 2013; 16: 548-550. doi: 10.3923/pjbs.2013.548.550. 7. proksch e, de bony r, trapp s, boudon s. topical use of dexpanthenol: a 70th anniversary article. j dermatolog treat. 2017; 28: 766-773. doi: 10.1080/09546634.2017.1325310. 8. gorski j, proksch e, baron jm, schmid d, zhang l. dexpanthenol in wound healing after medical and cosmetic interventions (postprocedure wound healing). pharmaceuticals (basel). 2020; 13: 138. doi: 10.3390/ph13070138. 9. proksch e and nissen h. dexapanthenol enhances skin barrier repair and reduces inflammation after sodium lauryl sulphate-induced irritation. j dermatolog treat. 2002; 13: 173-178. doi: 10.1080 /09546630212345674. 10. ebner f, heller a, rippke f, tausch i. topical use of dexpanthenol in skin disorders. am j clin dermatol. 2002; 3: 427-433. doi: 10.2165/00128071-200203060-00005. 11. park ky, ko ej, kim is, et al. the effect of evening primrose oil for the prevention of xerotic cheilitis in acne patients being treated with isotretinoin: a pilot study. ann dermatol. 2014;26:706-712. doi: 10.5021/ad.2014.26.6.706 12. mirnezami m, rahimi h. is oral omega-3 effective in reducing mucocutaneous side effects of isotretinoin in patients with acne vulgaris? dermatol res pract. 2018; 2018: 6974045. doi: 10.1155/2018/6974045. 13. strauss js, gottlieb ab, jones t, et al. concomitant administration of vitamin e does not change the side effects of isotretinoin dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023079 1 crusted scabies of hands: constraints of teledermatology sümeyre seda ertekin1, ayşenur botsalı2, senem danacı3, seçil vural1 1 department of dermatology and venereology, koç university school of medicine, i̇stanbul, turkey 2 university of health sciences, gulhane school of medicine, ankara, turkey 3 koç university school of medicine, i̇stanbul, turkey key words: crusted scabies, teledermatology, contact dermatitis, corticosteroids, covid19 citation: ertekin ss, botsalı a, danacı s, vural s. crusted scabies of hands: constraints of teledermatology. dermatol pract concept. 2023;13(2):e2023079. doi: https://doi.org/10.5826/dpc.1302a79 accepted: june 20, 2022; published: april 2023 copyright: ©2023 ertekin et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: secil vural, md, department of dermatology, koç university school of medicine. telephone: +905054324682 e-mail: sevural@ku.edu.tr introduction during the covid-19 pandemic, teledermatology has emerged as an accurate and cost-effective alternative for conventional face-to-face dermatological consultations [1]. during the pandemic period, we observed 2 cases of crusted scabies induced by prolonged topical potent corticosteroid use. case report two healthy male (aged 18 and 19 years, respectively) patients were diagnosed with hand irritant contact dermatitis caused by frequent hand-washing and sanitizer use with teledermatology. they received topical betamethasone cream treatment initially. the physicians escalated the treatment to clobetasol cream occlusion therapy via another teledermatology appointment as the symptoms did not improve. the patients used this therapy continuously without any follow-up appointments for one and two months and presented to our clinic with worsening of pruritus on hands. face-to-face physical examination revealed hyperkeratotic and fissured plaques on the dorsum of hands, prominently around the proximal phalanges, whereas the palmar sides of the hands were relatively spared. dermoscopic examination revealed numerous furrows and delta-wing jet signs corresponding to the mites (figure 1). the patients were diagnosed with crusted scabies and treated with oral ivermectin and topical 5% sulfur ointment. the consent is taken from each patient to publish their photos and treatment. conclusions physicians and patients report high satisfaction using teledermatology, and it has a promising future in daily clinical practice [2]. however, there are some concerns regarding the diagnostic accuracy of teledermatology services. poor image quality and the inability of evaluating textural characteristics of lesions may confuse a dermatologist. here, the lack of dermoscopic examination and the inability to perform 2 research letter | dermatol pract concept. 2023;13(2):e2023079 a detailed full-body examination may have mislead the clinicians. in teledermatology, if the patient is not improving with the prescribed treatment, he/she should be invited for the in-person visits to avoid any delay in the diagnosis. references 1. elsner p. teledermatology in the times of covid-19 a systematic review. j dtsch dermatol ges. 2020;18(8):841-845. doi: 10.1111/ddg.14180. pmid: 33448667. 2. yeroushalmi s, millan sh, nelson k, sparks a, friedman aj. patient perceptions and satisfaction with teledermatology during the covid-19 pandemic: a survey-based study. j drugs dermatol. 2021;20(2):178-183. doi: 10.36849/jdd.5714. pmid: 33538563. figure 1. clinical and dermatoscopic findings. (a-b) hyperkeratotic and fissured plaques on the dorsum of the hands in case 1, with relatively spared palmar side, (c) thick, hyperkeratotic plaques, erythematous papules on the dorsum of hands of case 2, (d-e) numerous furrows filled with dark-brown triangular structures (delta-wing jet sign with contrail) corresponding to the mites on the dermatoscopic examination of case 1. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2014;4(2):3 17 papulonecrotic tuberculid—clinicopathologic and molecular features of 12 indian patients rajalakshmi tirumalae1, inchara k. yeliur1, meryl antony1, geojith george2, john kenneth2 1 departments of pathology & dermatology, st. john’s medical college & hospital, bangalore, india 2 division of infectious diseases, st. john’s research institute; john nagar, bangalore, india keywords: cutaneous tuberculosis, papulonecrotic tuberculid citation: tirumalae r, inchara yk, antony m, george g, kenneth j. papulonecrotic tuberculid—clinicopathologic and molecular features of 12 indian patients. dermatol pract concept. 2014;4(2):3. http://dx.doi.org/10.5826/dpc.0402a03 received: september 9, 2013; accepted: december 19, 2013; published: april 30, 2014 copyright: ©2014 tirumalae. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: research society, sjmc. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author:rajalakshmi tirumalae, m.d.,dnb, department of pathology, st. john’s medical college, bangalore 560034, india. email: rajnav@gmail.com introduction india has the highest burden of tuberculosis (tb) in the world and cutaneous tb accounts for about 1.5% of extrapulmonary disease [1,2]. it is seen in greater frequency with hiv infection, which is also rampant there [1,3]. skin lesions could be either “true” cutaneous tb (lupus vulgaris, tb verrucosa cutis, scrofuloderma, orificial tb, military tb) or tuberculids [4]. the latter are believed to represent an arthus-type hypersensitivity reaction to a focus of infection elsewhere and by definition are culture negative [4]. tuberculids include lichen scrofulosorum (the commonest), erythema induratum of background: papulonecrotic tuberculid (pnt) is said to be a hypersensitivity reaction to m. tuberculosis. some reports indicate that organisms are demonstrable by polymerase chain reaction (pcr). methods: we describe 12 patients with pnt over 6 years. we reviewed the histopathologic features, clinical data and follow-up. pcr for m. tuberculosis dna was done in all cases. results: there were 7 men and 5 women. the ages ranged from 3-58 years. upper limbs were commonly involved (8 cases). all patients had multiple papulonodular lesions, 5 showed ulceration and scarring. mantoux test was strongly positive in all. seven patients had systemic tuberculosis. on microscopy, necrosis was seen in 11 cases, varying from minimal to extensive. epithelioid granulomas were common, except for 1 case with palisading and interstitial patterns. the infiltrate showed mostly lymphocytes, while 3 cases showed eosinophils. vasculitis was seen in 8 cases. two cases had dermal mucin, one also with interface dermatitis. this patient had concurrent le. mycobacterial dna was detectable by pcr in 3 cases. seven patients showed improvement/resolution of lesions on treatment. conclusions: pnt is a rare disease. a positive pcr reiterates the question whether these are “tuberculids”. pnt may be better classified as true cutaneous tuberculosis and patients screened for systemic disease. abstract 18 research | dermatol pract concept 2014;4(2):3 bazin and papulonecrotic tuberculid. pnt is a rare tuberculidwith very few case series in literature [5,6,7]. indian data is limited mainly to case reports or to broader studies on cutaneous tb in general [8,9,10]. there are reports which state that mycobacteria are detected by polymerase chain reaction (pcr) in these lesions [11,12]. we seek to describe the clinicopathologic features of pnt and to study the role of pcr in identifying m. tuberculosis dna in these lesions. material and methods there were 12 cases diagnosed as papulonecrotic tuberculid between 2006 and 2011 based on clinical and histopathologic criteria. two cases signed out as papulonecrotic tuberculid on histopathology were excluded. one of these was culture positive for m. tuberculosis and the other one did not fit the clinical picture. we reviewed hematoxylin and eosin stained sections, special stains for acid-fast bacilli (ziehl-nielsen) and fungi (periodic acid-schiff, gomori methenamine silver). the slides were assessed in particular for epidermal changes, type and location of granulomas, necrosis, nature of inflammatory cell infiltrate and presence of vasculitis and dermal mucin (confirmed by alcian blue stain, ph 2.5). clinical data was retrieved from patient records. we particularly noted the age, gender, nature and distribution of lesions, associated systemic features, mantoux test, treatment and follow-up data. figure 1b. lesion on the arm showing ulceration and scarring at the periphery. [copyright: ©2014 tirumalae.] figure 1a. papulonodular lesions over buttocks and lower limbs in a child. [copyright: ©2014 tirumalae.] sections were recut from the paraffin blocks and stained with h&e to ensure adequacy and representativeness of the samples for pcr. after this, 20μ sections were cut from each block and placed in sterile microcentrifuge tubes. dna was extracted using the “dna extraction kit” (qiagen india pvt ltd)after deparaffinization with xylene. the samples were subjected to nested pcr using primers specific to heat shock protein hsp65gene (eurofins mwg operon, india) with appropriate positive and negative controls [13].the positive controls comprised of skin, lung and lymph nodes, two of which were also culture positive. the reaction products were visualized after agarose gel electrophoresis. results there were 12 patients, 7 men and 5 women. there were 4 children and 8 adults. the age ranged from 3 to 58 years (mean age: 28.1 years); 8 cases were in the first three decades. all patients had multiple papulonodular lesions in a somewhat symmetric distribution (figure 1a). ulceration and scarring were seen in 5 cases. upper limbs were most commonly involved (8 cases) (figure 1b), followed by the lower limbs, trunk and face (6, 5 and 3 cases respectively). all patients showed strong mantoux positivity. evidence of systemic tb was found in 7 cases. of these, 3 had tb lymphadenitis, 2 patients had osteomyelitis, and 1 patient had hepatic and pulmonary tb. one case had associated hiv infection and one had concurrent systemic lupus erythematosus (le) with joint involvement. the histopathologic findings are detailed in table 1. most cases had tuberculoid granulomas (figure 2a), with research | dermatol pract concept 2014;4(2):3 19 minimal to extensive necrosis (figures 2b & c). the necrosis was focal in 3 cases. the remainder showed extensive caseous necrosis. in 1 case, the necrosis was wedge-shaped, reminiscent of an infarct. one case showed interstitial and palisading granulomatous patterns (figures 3a & b). leucocytoclastic vasculitis was present in 8 cases (figures 3c & d). most cases had a preponderance of lymphocytes, while table 1. histopathologic findings in 12 cases of pnt psoriasiform acanthosis 12 interface dermatitis 1 type of granulomas tuberculoid 10 palisading 1 interstitial 1 dermal necrosis 10 minimal 3 extensive 7 perifollicular location of granulomas 8 superficial and deep infiltrates 8 neutrophils 6 eosinophils 3 leucocytoclastic vasculitis 8 extravasated rbcs 6 dermal mucin 2 acid-fast bacilli & fungi 0 3 of them showed an admixture of eosinophils. abundant dermal mucin was seen in 1 case, together with extensive interface dermatitis and cellular infiltrate consistent with sle (figures 4a & b). this patient tested positive for antinuclear antibodies, anti-ss-a and anti-ro. special stains for figure 2a. tuberculoid granulomas with lymphocytes and overlying psoriasiform acanthosis (h&e, x40). [copyright: ©2014 tirumalae.] figure 2b. interstitial granulomatous pattern with epithelioid cells and histiocytes (h&e, x200). [copyright: ©2014 tirumalae.] figure 2c. palisading granuloma with central necrosis (h&e, x200). [copyright: ©2014 tirumalae.] figure 3a. epithelioid granulomas with minimal necrosis (h&e, x200). [copyright: ©2014 tirumalae.] 20 research | dermatol pract concept 2014;4(2):3 fungi and mycobacteria were negative in all cases. culture was done in 2 cases, both being negative. mycobacterial dna was detected by rt-pcr in 3/12 cases. treatment and follow-up of the 12 patients, 1 refused treatment. eleven patients were started on first-line tuberculostatic chemotherapy as per the guidelines on rntcp (revised national tuberculosis figure 3b. extensive dermal necrosis (h&e, x40). [copyright: ©2014 tirumalae.] figure 3c. blood vessels showing fibrinoid necrosis, microthrombi and leucocytoclasis (h&e, x400). [copyright: ©2014 tirumalae.] figure 3d. dilated blood vessels and extravasated red cells (h&e, x400). [copyright: ©2014 tirumalae.] figure 4a. extensive interface dermatitis, melanophages and underlying granuloma (h&e, x200). [copyright: ©2014 tirumalae.] figure 4b. abundant alcian blue positive dermal mucin (alcian blue, x40). [copyright: ©2014 tirumalae.] research | dermatol pract concept 2014;4(2):3 21 control programme). this consisted of isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months (intensive phase) followed by isoniazid and rifampicin for 4 months (continuation phase). three patients were lost for follow-up. the remaining 8 patients showed significant improvement/ resolution of lesions by 6 weeks, including the 3 pcr positive cases. two patients developed drug-induced hepatitis. one patient developed neurotuberculosis. discussion papulonecrotic tuberculid seems to be the least common form of cutaneous tb, even in countries with a high prevalence of tb [9,10]. it is deemed to be a type iii hypersensitivity reaction to the presence of a focus of infection elsewhere in the body. by definition, tuberculids do not show bacilli on special stains and are negative by culture [4]. there has been conjecture about the association of papulonecrotic tuberculid with tb, but a positive tuberculin skin test and resolution of lesions following anti-tubercular therapy are strong proofs in its favor. similar lesions have also been documented following bcg immunization, but a temporal link is difficult to establish [14]. it is generally seen in young adults, as in the present study [5,6]. only one patient had concurrent hiv infection. only sporadic occurrences of papulonecrotic tuberculid with hiv have been reported [15]. in a recent study from india, there were 5 cases of papulonecrotic tuberculid out of 131 cutaneous tb and none of them were retroviral positive [3]. it is mostly seen in immunocompetent hosts. clinically, papulonecrotic tuberculid is characterized by papulonodular, pustular or necrotic lesions with crusting in a more or less symmetric fashion, with a predilection for extremities [4,5,6]. this was also the case in the present study with upper limbs being the commonest involved site. the lesions heal over several weeks with residual scarring. genital involvement is rare [8]. none of our cases had mucosal/genital lesions. association with other tuberculids, particularly erythema induratum of bazin, have been recorded, but we did not observe this [5]. it is noteworthy that almost half of our cases showed evidence of systemic tb in the past or simultaneously, particularly the extrapulmonary forms. papulonecrotic tuberculid may be regarded as a “sentinel” lesion, and these patients should be thoroughly investigated for systemic involvement. previous studies report that between 38 and 75% cases have evidence of tb elsewhere, most commonly in lymph nodes [16,17]. we concur with these findings. some cases have been associated with takayasu’s arteritis and gangrene of extremities [18]. all our patients showed strong mantoux positivity, which is essential for diagnosis [4]. histopathology of the lesions showed psoriasiform epidermal hyperplasia in all our cases. most cases showed epithelioid granulomas with lymphocytes and langhans giant cells with variable amounts of necrosis. they were mostly seen in the upper and mid-dermis with a perifollicular distribution in most instances. this is reminiscent of lichen scrofulosorum [4]. some reports of follicular destruction by the infiltrate are found in literature but none in the present study [5]. ls does not show follicular involvement. the grenz zone was never clear and we noted granulomas impinging on the epidermis insome cases. this feature is likely to precede transepidermal elimination of granulomas and subsequent healing. one case showed interstitial granulomas with chiefly histiocytes while another showed a palisading granuloma with central necrosis, mimicking granuloma annulare. this has been reported in one previous study [5]. however, there was no dermal mucin or altered collagen. it is important to be aware of these variations, as granuloma annulare is also a clinical mimic, especially the perforating form. in some cases, necrosis was very focal. leucocytoclastic vasculitis (lcv) was found in threequarters of our cases. this is an important finding to support the diagnosis. the pathogenesis of pnt has been explained by an arthus-like phenomenon where mycobacterial products cause initial vascular endothelial damage [17]. in patients with a potent immune system, this later transforms into a delayed hypersensitivity-like picture with the occurrence of granulomas. some authors opine that established lesions of papulonecrotic tuberculid do not show lcv, as the neutrophils are replaced by lymphocytes or macrophages [16]. our findings differ. in addition, we also saw microthrombi within some vessels, endothelial swelling and extravasated red cells. the finding of lcv in a majority of our cases underscores the importance of an immune-complex mediated mechanism. the infiltrate around the necrotic areas consisted of lymphocytes, neutrophils and in some, eosinophils. if considerable numbers of eosinophils are present, other parasitic infections or arthropod bite reactions need to be excluded. an unsual finding in the present series is the abundant dermal mucin in two cases. one of them also had extensive interface dermatitis, thickened basement membranes and clinical features consistent with associated sle. it is known that tb is more common in patients with sle and usually lupus vulgaris is the common form [19]. our case represents a rare occurrence of papulonecrotic tuberculid in sle. acid-fast bacilli were not seen in any of our cases. sporadic reports of papulonecrotic tuberculid lesions showing positive mycobacterial cultures exist, but on review, these were better classified as lupus vulgaris [16]. pcr is a very sensitive tool to demonstrate organisms and the first instance of pnt yielding m. tuberculosis dna was reported by victor et al. in 11/22 cases [11]. following this, 22 research | dermatol pract concept 2014;4(2):3 there have been other series reporting positive rates varying from 0 to 80% [12,20]. twenty-five percent of our cases showed amplification by pcr, and this is the first study from india exploring this link. the rate may actually be higher, depending on the fixation and age of the blocks. other mycobacteria have also been identified, such as m. bovis and atypical mycobacteria [21]. our findings further support a strong link between pnt and tb. to summarize, papulonecrotic tuberculid is a distinct clinicopathologic form of tb. these patients require a detailed workup to look for systemic disease and should receive a complete course of multi-drug therapy. based on identification of mycobacteria from the lesions and bolstered by the resolution of lesions after anti-tubercular therapy, it is perhaps better to classify pnt as a morphologic form of “true” cutaneous tb rather than a “tuberculid.” references 1. tb india 2011; rntcp annual status report. new delhi: central tb division, directorate general of health services, ministry of health and family welfare. new delhi, 2011:6. 2. sethuraman g, ramesh v, ramam m, sharma vk. skin tuberculosis in children: learning from india. dermatol clin. 2008;26(2):285-94. 3. varshney a, goyal t. incidence of various clinico-morphological variants of cutaneous tuberculosis and hiv concurrence: a study from the indian subcontinent. ann saudi med 2011; 31(2):134-9. 4. fitzpatrick tb, eisen az, wolff k, freedberg im, austen kf. tuberculosis and other mycobacterial infections. in: dermatology in general medicine. 5th ed. new york: mcgraw-hill, 1999:2370-95. 5. jordaan hf, van niekerk djt, louw m. papulonectrotic tuberculid. a clinical, histopathological and immunohistochemical study of 15 patients. am j dermatopathol 1994;16(5):474-85. 6. jordaan hf, schneider jw, schaaf hs, et al. papulonecrotic tuberculid in children. a report of eight patients. am j dermatopathol. 1996;18(2):172-85. 7. ena p, retanda g, masala ge, manunta v. papulonecrotic tuberculide. presentation of 4 cases. g ital dermatol venereol. 1989; 124(11-12): 499-504. 8. jeyakumar w, ganesh r, mohanram ms, shanmugasundararaj a. papulonecrotic tuberculids of the glans penis: case report. genitourin med. 1988;64(2):130-2. 9. vashisht p, sahoo b, khurana n, reddy bs. cutaneous tuberculosis in children and adolescents: a clinicohistological study. j eur acad dermatol venereol. 2007;21(1):40-7. 10. kumar b, rai r, kaur i, et al. childhood cutaneous tuberculosis: a study over 25 years from northern india. int j dermatol. 2001; 40(1):26-32. 11. victor t, jordaan hf, van niekerk djt, louw m. papulonecrotic tuberculid. identification of mycobacterium tuberculosis dna by polymerase chain reaction. am j dermatopathol 1192; 14(6):491-5. 12. quirós e., bettinardi a, quirós a, piédrola g, maroto mc. detection of mycobacterial dna in papulonecrotic tuberculid lesions by polymerase chain reaction. j clin lab anal. 2000;14:133-5. 13. mohl d, giordano tj. detection and speciation of mycobacteria in formalin-fixed, paraffin-embedded tissue sections. methods mol med. 2001;49:379-87. 14. figueiredo a, poiares-baptista a, branco m, carmona da mota h. papular tuberculids post bcg vaccination. int j dermatol. 1987;26:291-4. 15. akhras v, mccarthy g. papulonecrotic tuberculid in an hivpositive patient. int j std aids. 2007;18(9):643-4. 16. morrison jgl, fourie ed. the papulonecrotic tuberculide: from arthus reaction to lupus vulgaris. br j dermatol. 1974;91:263-70. 17. wilson-jones e, winkelmann rk. papulonecrotic tuberculid: a neglected disease in western countries. j am acad dermatol. 1986:14:815-26. 18. rose ag, sinclair smith cc. takayasu’s arteritis. a study of 16 autopsy cases. arch pathol lab med. 1980:104:231-7. 19. navarra sv, leynes ms. infections in systemic lupus erythematosus. lupus. 2010; 19(12):1419-24. 20. tan sh, tan hh, sun yj, goh cl. clinical utility of polymerase chain reaction in the detection of mycobacterium tuberculosis in different types of cutaneous tuberculosis and tuberculids. ann acad med singapore. 2001;30(1):3-10. 21. iden dl, rogers rs, schroeter al. papulonecrotic tuberculid secondary to mycobacterium bovis. arch dermatol. 1978;114: 564-6. dermatology: practical and conceptual letter | dermatol pract concept 2018;8(2):10 123 dermatology practical & conceptual www.derm101.com mycosis fungoides (mf), the most frequent primary cutaneous lymphoma, belongs to the group of extranodal nonhodgkin lymphomas with a mean age at onset of >40 years [1]. the manifestation of mf in children is rare and has only been studied by a number of case series [2]. we report on a 15-year-old female adolescent presenting with pruritic eczematous lesions of the neck and trunk that had persisted for one year (figure 1a). clinical examination revealed erythematous, oval-shaped to polycyclic, eczematous macules and plaques with a cigarette paper-like cutaneous atrophy and moderate scaling (figure 1a-d). the histopathological as well as immunohistochemical investigations included stains for hematoxylin-eosin, cd3, cd4, cd5, cd8, cd20, and cd30, which showed a dense infiltrate of mainly cd3 and cd4 positive atypical lymphocytes with epidermal exocytosis forming pautrier’s microabscesses (figure 1e-g). expression of cd5 as a marker of potential loss of differentiation was retained. expectedly, flow cytometry analysis of peripheral blood cells showed results within normal limits (36% cd3-positive lymphocytes, cd4:cd8 ratio of 1.5). at the molecular level, a t-cell-receptor (tcr) gene rearrangement analysis from lesional skin showed two monoclonal gene rearrangements, agreeing well with the clinical and histopathological diagnosis of stage ia mf. a topical treatment with 0.1% mometasone furoate cream was initiated and achieved a partial response at the time of the first follow-up examination (6-week interval). mf is the most common primary cutaneous t-cell lymphoma. however, in children and adolescents mf is very rare with an incidence of 0.05 new cases per year per 100,000 [3]. while in adults the female to male ratio was reported to be 1:2, nanda et al described a 1:1 ratio in children and adolescents [4]. the difficulties in diagnosing early stage mf in children arise from the multitude of differential diagnoses with similar clinical morphology but much higher incidences in this specific age group. in mf three stages may be differentiated clinically. the patch stage presents with eczematous skin lesions, moderate desquamation, cutaneous atrophy, and predilection for non-sun-exposed skin areas [5]. in children such lesions are often erroneously diagnosed as (atopic) eczema, dermatophyte infection, or early onset psoriasis vulgaris [2]. therefore, diagnosis is often delayed until the patches evolve into infiltrative plaques (plaque stage) or tumors (tumor stage), with all three types of skin patholomycosis fungoides in a 15-year-old adolescent sarah estelmann1, anna neuberger1, ferdinand toberer1, christine fink1, alexander enk1, holger a. haenssle1 1 department of dermatology, venereology, and allergology; university medical center, ruprecht-karls university, heidelberg, germany key words: mycosis fungoides, childhood, adolescent citation: estelmann s, neuberger a, toberer f, fink c, enk a, haenssle ha. mycosis fungoides in a 15-year-old adolescent. dermatol pract concept. 2018;8(2):123-125. doi: https://doi.org/10.5826/dpc.0802a10 received: november 12, 2017; accepted: december 12, 2017; published: april 30, 2018 copyright: ©2018 estelmann et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: holger a. haenssle, md, department of dermatology, venereology and allergology, university medical center, ruprecht-karls university, im neuenheimer feld 440, 69120 heidelberg, germany. tel. +49-6221-56-39555; fax. +49-6221-56-7771. email: holger.haenssle@med.uni-heidelberg.de 124 letter | dermatol pract concept 2018;8(2):10 figure 1. clinical images and histopathological examination of patches and plaques in a 15-year-old girl with mycosis fungoides. the overview image shows disseminated, bizarrely shaped, erythematous lesions on the back (a). close-up images reveal more infiltrated erythematous plaques with scaling (b) and patches with epidermal atrophy, sharply demarcated borders and moderate scaling (c, d). hematoxylin and eosin staining (e) reveals psoriasiform epidermal hyperplasia and a superficial band-like lymphocytic infiltrate. some of the atypical lymphocytes are present within the epidermis (original magnification x 100). at higher magnification typical pautrier microabscesses show atypical lymphocytes with hyperchromatic and irregular nuclei (f, original magnification x 630). immunostaining shows positivity for cd3 marker in epidermotropic, intraepidermal t lymphocytes (g, original magnification x 200). [copyright: ©2018 estelmann et al.] letter | dermatol pract concept 2018;8(2):10 125 ally add up to a relevant increase of the risk of uv-induced skin cancers [3]. references 1. trautinger f, eder j, assaf c, et al. european organisation for research and treatment of cancer consensus recommendations for the treatment of mycosis fungoides/sézary syndrome—update 2017. eur j cancer. 2017;77:57-74. 2. boulos s, vaid r, aladily tn, ivan ds, talpur r, duvic m. clinical presentation, immunopathology, and treatment of juvenileonset mycosis fungoides: a case series of 34 patients. j am acad dermatol. 2014;71(6):1117-1126. 3. ai wz, keegan th, press dj, et al. outcomes after diagnosis of mycosis fungoides and sézary syndrome before 30 years of age: a population-based study. jama dermatol. 2014;150(7):709-715. 4. nanda a, al-ajmi h. mycosis fungoides in children and adolescents. expert rev dermatol. 2013;8(3):309-320. 5. girardi m, heald pw, wilson ld. the pathogenesis of mycosis fungoides. n engl j med. 2004;350(19):1978-1988. 6. jawed si, myskowski pl, horwitz s, moskowitz a, querfeld c. primary cutaneous t-cell lymphoma (mycosis fungoides and sézary syndrome): part i. diagnosis: clinical and histopathologic features and new molecular and biologic markers. j am acad dermatol. 2014;70(2):205-216. 7. stadler r, assaf c, klemke cd, et al. brief s2k guidelines—cutaneous lymphomas. j dtsch dermatol ges. 2013;11 suppl 3:1930. 8. wain em, orchard ge, whittaker sj, spittle mf, russell-jones r.. outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study. cancer. 2003;98(10):2282-2290. 9. ceppi f, pope e, ngan b, et  al. primary cutaneous lymphomas in children and adolescents. pediatr blood cancer. 2016;63(11):1886-1894. 10. laws pm, shear nh, pope e. childhood mycosis fungoides: experience of 28 patients and response to phototherapy. pediatr dermatol. 2014;31(4):459-464. gies possibly existing simultaneously [6]. in contrast to most adult cases of mf that show a predominance of cd4-positive pathologic t-cells, many pediatric cases (approximately 50%) are characterized by cd8-positive epidermotropic infiltrates [2]. while a number of relevant molecular mechanisms for the manifestation of mf were reported [5] the exact pathogenesis of mf remains unknown. many of the affected children are diagnosed at early stages of the disease (stage ia: 50%, stage ib: 47%) [7,8]; however, a mean time interval from first symptoms until a final diagnosis of five years was reported [8]. the prognosis of mf in children and adolescents is more favorable than in adults, with 5-year and 10-year survival rates of 95% and 93%, respectively [3,8]. skin lesions of the patient presented as erythematous macules and plaques. in contrast, other authors described a high frequency of hypopigmented mf lesions in children often associated with a predominance of cd8-positive atypical t-cells [8] and a non-caucasian skin phenotype [4]. the literature is somewhat discordant in terms of tcr clonality when assessed in skin biopsies. while wain et al [8] described monoclonality of tcr genes in 26 of 34 cases (76.5%), ceppi et al [9] reported of only 3 out of 14 cases (21.4%). there are no specific guidelines for the therapy of juvenile mf. recommendations for first-line treatment of mf stages ia, ib, and iia are either emollients plus observation only or, as used in our case, topical corticosteroids. in refractory cases, topical corticosteroids may be combined with phototherapy (broadband/narrowband ultraviolet b [uvb], psoralen and ultraviolet a [puva])[1]. most authors prefer narrowband uvb to broadband uvb or puva because of its decreased carcinogenic potential and less side effects [1,10]. as for any phototherapy in children, it should be kept in mind that mf is a chronic disease with slow progression. repeated phototherapies along the course of the disease may eventudermatology: practical and conceptual 48 quiz | dermatol pract concept 2018;8(1):10 dermatology practical & conceptual www.derm101.com a 49-year-old caucasian man was referred to our unit for the recent occurrence of a nodular lesion on a long-standing nevus. a smooth, dome-shaped, reddish lesion, 1 cm in diameter, on a flesh-colored plaque with a velvety and verrucous surface was observed (figure 1). dermoscopy of the nodule showed yellow to pink-colored lobules of different sizes, interposed by whitish pale septae. glomerular and hairpin vessels were detected (figure. 2). the underlying plaque revealed yellowish/orange structures sometimes gathered in clusters. the entire lesion was excised. microscopic examination revealed cystic invaginations: the upper parts were lined by epithelial cells that resembled those present on the surface epidermis, and the lower parts were characterized by irregular papillary projections of various size and aspect. the epithelium was made up of two layers of cells that were cylindrical at the luminal side and cuboidal at the base. dilated capillaries, decapitation secretion, and plasmocyte-rich inflammatory infiltrate within papillary projections were observed (figure 3). a red nodule of the scalp martina lambertini1, emi dika1, annalisa patrizi1, pier alessandro fanti1, carlotta baraldi1, ambra di altobrando1 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy citation: lambertini m, dika e, patrizi a, fanti pa, baraldi c, di altobrando a. a red nodule of the scalp. dermatol pract concept. 2018;8(1):48-50. doi: https://doi.org/10.5826/dpc.0801a10 received: july 26, 2017; accepted: november 29, 2017; published: january 31, 2018 copyright: ©2018 lambertini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. ml and ed contributed equally to this work. corresponding author: emi dika, md, v. massarenti 1, 40138 bologna, italy. tel. +39051-6364849. email: emi.dika3@unibo.it figure 1. clinical presentation of a red nodule of the scalp arising on a flesh-colored plaque with a velvety and verrucous surface. [copyright: ©2018 lambertini et al.] what is your diagnosis? quiz | dermatol pract concept 2018;8(1):10 49 other regions, such as the trunk, eyelids and genitalia [2-4]. clinically it appears as a hairless, smooth, or verrucous single papule or plaque, but multiple elements may occur, especially on sn [2-4]. scap may also be associated with different types of lesions, both benign (viral warts, sn, apocrine poroma, hidradenoma papilliferum) and malignant (basal cell carcinoma, sebaceous carcinoma) [2,3]. scap is most frequently related to sn (1/3 of cases) [2,4,6]. the differential diagnosis could include a wide spectrum of lesions presenting clinically as red nodules. in our patient, the occurrence of scap on an underlying sn was helpful in orienting the clinician, since amelanotic melanoma, hemangiomas, and angiokeratomas are rarely described on this background. furthermore, dermoscopic examination was a final diagnosis of syringocystadenoma papilliferum (scap) on sebaceous nevus (sn) was made. discussion scap is a rare, benign adnexal neoplasm with hamartomatous features. the histopathogenesis is still to be determined, but the origin from apocrine glands seems to be the most accepted. a possible derivation from eccrine or undifferentiated pluripotential cells has also been reported [1-4]. scap affects males and females equally [2], developing at birth (50% of cases) or in childhood/adolescence [3,5]. at puberty a dimensional growth may be displayed [2,3]. scap usually arises on the scalp, face and neck, and less commonly on figure 2. (a, b) dermoscopy of the nodular lesion showing yellowto pink-colored lobules of different sizes, interposed by whitish pale septae with few glomerular and hairpin vessels on an erythematous background. [copyright: ©2018 lambertini et al.] figure 3. (a, b) a histopathologic image revealing cystic invaginations with the upper parts lined by epithelial cells similar to the adjacent epidermis and the lower parts characterized by irregular papillary projections. the two-layered epithelium was made up of cylindrical cells at the luminal side and cuboidal cells at the base. dilated capillaries, decapitation secretion, and plasmocyte-rich inflammatory infiltrate within papillary projections were observed (original magnification, h&e, 2x; 10x ). [copyright: ©2018 lambertini et al.] 50 quiz | dermatol pract concept 2018;8(1):10 2. agrawal r, kumar p, varshney r. syringocystadenoma papilliferum: an unusual presentation. j clin diagn res. 2014 may; 8(5): qd03–qd04. 3. nascimento ba, carneiro cm, carvalho ah, et al. syringocystadenoma papilliferum in an unusual location. an bras dermatol. 2015 nov-dec;90(6):900-902. 4. behera m, chatterjee s. a case of syringocystadenoma papilliferum of eyelid with literature review. indian j ophthalmol. 2015 jun;63(6):550-551. 5. kaehler kc, lange-asschenfeldt b, proksch e, hauschild a. giant naevoid syringocystadenoma papilliferum. acta derm venereol. 2005;85(5):453-454. 6. kamyab-hesari k, seirafi h, jahan s, et al. nevus sebaceus: a clinicopathological study of 168 cases and review of the literature. int j dermatol. 2016 feb;55(2):193-200. 7. lombardi m, piana s, longo c, et al. dermoscopy of syringocystadenoma papilliferum. australas j dermatol. 2017 jul 11. 8. zaballos p, serrano p, flores g, et al. dermoscopy of tumours arising in naevus sebaceous: a morphological study of 58 cases. j eur acad dermatol venereol. 2015 nov;29(11):2231-2237. useful in excluding other tumors displaying specific criteria, such as arborizing telangiectasias, large blue-gray ovoid nests, and multiple blue-gray globules, characteristic of basal cell carcinoma [7,8]. the detection of homogeneous areas or yellowish lobules observed in hidrocystomas, hidradenomas and pilomatricomas was suggestive for the diagnosis of an adnexal tumor. despite the uncommon malignant transformation into basal cell carcinoma (10%), squamous cell carcinoma, or syrigocystadenocarcinoma, surgical excision is considered the treatment of choice in order to arrive at a final histological diagnosis [3,4]. after histopathologic confirmation, carbon dioxide laser treatment may be considered an option [2,3]. references 1. bruno cb, cordeiro fn, soares fdo e, takano gh, mendes ls. dermoscopic aspects of syringocystadenoma papilliferum associated with nevus sebaceus. an bras dermatol. 2011 novdec;86(6):1213-1216. untitled research | dermatol pract concept 2015;5(2):6 45 dermatology practical & conceptual www.derm101.com introduction dermoscopy is a non-invasive tool that is widely recognized and used in the diagnosis of pigmented and non-pigmented skin tumors [1,2]. in recent years, dermoscopy has been used for other dermatologic diseases including psoriasis, lichen planus, alopecia, and skin infestations [1,2]. lichen planus (lp) is an acute or chronic inflammatory skin disorder characterized by discrete, violaceous, polygonal papules [2,3]. though the diagnosis of lp can be made clinically, it can sometimes be challenging and histopathological examination is needed. dermoscopic examination may be helpful in these settings to aid the diagnosis. in this study, we aimed to categorize the dermoscopic images of lp patients before and after treatment. materials and methods we analyzed and categorized the dermoscopic images of 255 lp lesions from 60 patients who had been diagnosed with lp or lp variants clinically and confirmed by histopathological examination. the mean age of the patient group was 38.0 years old (range 19-60 years old). out of 60 patients, 38 had classical lp (clp), eight had acute generalized lp (aglp), three had lp pigmentosus inversus (lppi) and clp coexistence, three had lichen planopilaris (lpp), one had a solitary lpp (slpp) on the abdomen, one had a solitary annular lp on the glans penis (galp), three had generalized annular atrophic lp (aalp), two had lp actinicus, and one had zosteriform lpp (zlpp). we reanalyzed and categorized the dermoscopic images of 50 lesions from fifteen patients after treatment. the same dermatologist investigated each patient using a foto-finder handyscope® that magnifies lesions tenfold. results among the 255 active lp lesions, 170 were clp, 30 were aglp, 15 were lpp, 15 were lppi, three were zlpp, ten were aalp, ten were ac lp, one was slpp, and one was galp (table 1). among 170 clp lesions, ws was observed in 152 lesions at a rate of 89.4%. these were morphologically sub-grouped as reticular ws in 110 lesions (64.7%), circular ws in two lesions (1.1%), linear ws in 13 lesions (7.6%), globular ws in dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study şule güngör1, ilteriş o. topal1, emek k. göncü1 1 okmeydanı training and research hospital, dermatology department, istanbul, turkey key words: dermoscopy, lichen planus, annular lichen planus, wickham striae, pigment pattern citation: güngör s, topal io, göncü ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept 2015;5(2):6. doi: 10.5826/dpc.0502a06 received: december 3, 2014; accepted: january 9, 2015; published: april 30, 2015 copyright: ©2015 güngör et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sule güngör, okmeydani hospital, dermatology department, sisli, istanbul, turkey 34000. tel. ++505 438 2883; email: drsulegungor@yahoo.com 46 research | dermatol pract concept 2015;5(2):6 table 1. dermoscopic patterns in active or regressive lp and lp variants. clp 170 lesions n (%) aglp 30 lesions n (%) lpp 15 lesions n (%) lppi 15 lesions n (%) slpp 1 lesion n (%) zlpp 3 lesions n (%) galp 1 lesion n (%) aalp 10 lesions n(%) ac lp 10 lesions n(%) rlp 50 lesions n (%) ws morphology reticular circular linear globular radial streaming perpendicular veil like combined color white yellow blue-white ws (–) invisible ws 152(89,4) 110(64,7) 2(1,1) 13(7,6) 15(8,8) 9(5,2) – – 3(1,7) 112(65,8) 13(7,6) 27(15,8) 18(10,5) – 18(60) 10(33,3) 4(13,3) 4(13,3) 4(13,3) 10(33,3) 4(13,3) 4(13,3) 10(33,3) 2(6,6) 6(40) 1(6,6) 1(6,6) 1(6,6) 3(20) 1(6,6) 5(33,3) 9(60) – – 15(100) – – 1(100) – – 3(100) – 1(100) 1(100) 1(100) – – 7(70) 7(70) 7(70) 3(30) – – 10(100) – – 50(100) – pigment pattern dots/globules –peripheral –diffuse peppering –peripheral –diffuse perifollicular/ annular linear reticular circular cobblestone homogen cloud like –peripheral –diffuse pigment pattern (–) 20(11,7) 8(4,7) 2(1,1) 10(5,8) 150(88,2) – 30(100) 13(86,6) 8≠(53,3) 5(33,3) 2(13,3) 15(100) 5(33,3) 3(20) 8*(53,3) 8*(53,3) 3*(20) – 1(100) 1+(100) 1+ (100) – 3(100) 3(100) – 1(100) 1(100) – 10(100) 2(20) 2(20) 8(80) – 10(100) 10(100) – – 30 (60) 6(12) 6(12) 3(6) 3(6) 2*–2≠ 2*(4) 1+ (2) 1(2) 2* (4) 1(2) 1(2) 20(40) vascular pattern red dots –perifollicular –peripheral –diffuse red globules radial linear peripheral homogen vascular pattern (–) 46(27) 4(2,3) 15(8,8) 8(4,7) 19(11,1) 124(72,9) 24(80) 6(20) 5(16,6) 9(30) 4(13,3) – – 6(20) 3(20) 3(30) 12(80) – 15(100) – 1(100) – 3(100) 1(100) 1(100) – 3(30) 3(30) 7(70) – 10(100) – 50(100) background color pink violet red brown yellow 64(37,6) 66(38,8) – 30(17,6) 10(5,8) 5(16,6) 10(33,3) 15(50) – – 2(13,3) 5(33,3) 8(53,3) 15(100) 1(100) 3(100) 1(100) 10(100) 40(80) 10(20) white dots yellow dots 2(1,1) 10(5,8) – – 4(26,6) 3(20) 10(66,6) – 1(100) – – – – – – – – – 3(6) – *+≠: same lesions clp: classical lichen planus aglp: acute generalized lichen planus lpp:lichen planopilaris slpp: soliter lichen planus pigmentosus lppi: lichen planus pigmentosus inversus lpp: lichen planus pigmentosus aalp: annular atrophic lichen planus ac lp: lp actinicus zlpp: zosteriform lichen planus pigmentosus galp: genital annular lichen planus rlp: regressive lichen planus ws: wickham striae research | dermatol pract concept 2015;5(2):6 47 a b c d e f g h i figure 1. (a) radial streaming ws pattern surrounded by red dots. (b) white broad reticular ws on a pink background. (c) yellow fine reticular ws surrounded by red dots. (d). white-blue veil-like ws surrounded by red globules and diffuse yellow dots. (e) yellow globular ws surrounded by red dots. (f) yellow reticular veil-like ws and peripheral red dots. (g) linear yellow ws with peripheral diffuse pigmentation. (h) yellow reticular ws and radial linear vessels perpendicular to ws. (i) reticular-circular ws and yellow dots. [copyright: ©2015 güngör et al.] 48 research | dermatol pract concept 2015;5(2):6 figure 2. clinical and dermoscopic images of a clp patient. (a) multiple discrete, violaceous, polygonal papules on the leg. (b) dermoscopic examination without gel. (c) dermoscopic examination with gel; yellow dots corresponds to hyperkeratosis. (d) the same patient lp lesion in axilla; different from the leg lesions, diffuse brown dots without ws are seen. [copyright: ©2015 güngör et al.] figure 3. (a) white reticular-circular ws surrounded by red dots of a clp patient. (b) peripheral brown dots in circular arrangement of the same lesion after treatment. [copyright: ©2015 güngör et al.] 15 lesions (8.8%), radial streaming ws in nine lesions (5.2%), and combined ws patterns in three lesions (1.7%). the ws color was white in 112 lesions (65.8%), yellow in 13 lesions (7.6%), and blue-white in 27 lesions (15.8%). among 170 clp lesions, pigment patterns were observed in 20 lesions (11.7%). they were sub-grouped as peripheral dots/globules in eight lesions (4.7%), peripheral homogeneous cloudlike pigment pattern in ten lesions (5.8%), and reticular pigment pattern in two lesions (1.1%). among 170 clp lesions, vascular patterns were observed in 46 lesions (27%). these were subgrouped as peripheral red dots in four lesions (2.3%), diffuse red dots in 15 lesions (8.8%), red globules in eight lesions (4.7%), and radial linear vessels in 19 lesions (11.1%). violet, pink, brown, and yellow background colors were observed (listed in order of decreasing frequency). yellow dots were observed in ten lesions and white dots were observed in two lesions among clp lesions. dermoscopic images of clp lesions are shown in figures 1-4. among 30 aglp lesions, ws was observed in 18 lesions (60%). these were morphologically sub-grouped as reticular ws in ten lesions (33.3%), cirfigure 4. (a) circular white ws and reticular blue-white ws and diffuse homogeneous pigmentation. (b) circular pigmentation without ws of the same lesion after four weeks of treatment. [copyright: ©2015 güngör et al.] a b a b c d a b research | dermatol pract concept 2015;5(2):6 49 cular ws in four lesions (13.3%), perpendicular ws in four lesions (13.3%), and veil-like ws in four lesions (13.3%) (some lesions showed more than one pattern). in two aglp lesions, a circular space between diffuse red dots were observed; as it is consistent with the same patients’ other lesions’ ws configuration, we defined this lesion as “invisible ws.” the ws color was white in ten lesions (33.3%), yellow in four lesions (13.3%), and blue-white in four lesions (13.3%). pigment patterns were not observed in any of the aglp lesion. vascular patterns were observed in 24 of 30 aglp lesions (80%). these were sub-grouped as perifollicular red dots in six lesions (20%), peripheral red dots in five lesions (16.6%), diffuse red dots in nine lesions (30%), and red globules in four lesions (13.3%). red, violet, and pink background colors were noticed (listed in order of decreasing frequency). dermoscopic images of aglp are shown in figures 5-7. among 15 lpp lesions, ws was observed in six lesions (40%). these were morphologically sub-grouped as reticular ws in one lesion (6.6%), radial streaming ws in one lesion (6.6%), perpendicular ws in one lesion (6.6%), and veil-like ws in three lesions (20%). the ws color was blue-white in five lesions (33.3%) and white in one lesion (6.6%). pigment patterns were observed figure 5. (a) white reticular ws on the center, on a red background, and peripheral homogeneous yellow-white ws in an aglp patient. (b) perpendicular white ws in an aglp patient. [copyright: ©2015 güngör et al.] figure 6. (a) perifollicular red dots, on a yellow-pink background without ws in an aglp patient. (b) diffuse brown dots and reticulated pigmentation on a brown background after three months of treatment of the same patient. [copyright: ©2015 güngör et al.] a b a b figure 7. the clinical and dermoscopic images of the same aglp patient. (a) multiple erythematous purple macules and papules on the back of the patient. (b) white circular ws surrounded with red dots. (c) diffuse red dots without ws; we interpreted white circular area as a ws, defined as “invisible ws.” [copyright: ©2015 güngör et al.] a b c 50 research | dermatol pract concept 2015;5(2):6 ing in three lesions (20%), perifollicular/ annular pigmentation in eight lesions (53.3%), linear pigmentation in eight lesions (53.3%), and cobblestone pigmentation in three lesions (20%). some lppi lesions demonstrated more than one pigment pattern. the background color was brown in all lppi lesions and white dots were observed in ten lesions (66.6%). dermoscopic images of lppi are shown in figures 10-11. the sole slpp lesion demonstrated a pigment pattern of diffuse peppering combined with perifollicular/annular pigmentation on a brown background with white dots, while ws and vascular pattern were absent (figure 12). in 13 of 15 lpp lesions (86.6%), further sub-grouped as perifollicular/annular in eight lesions (53.3%) and diffuse in five lesions (33.3%). vascular patterns were observed in three of 15 lpp lesions (20%) as diffuse red dots. brown, violet, and pink background colors were observed (listed in order of decreasing frequency). white dots were noticed in four lesions (26.6%) and yellow dots in three lesions (20%). dermoscopic images of lpp are shown in figures 8-9. among fifteen lppi lesions, ws and vascular patterns were not observed. pigment patterns were observed in all lppi lesions (100%) as diffuse dots/globules in five lesions (33.3%), diffuse pepperamong three zlpp lesions, diffuse dots/globules were detected on a pink background in all lesions while ws and vascular patterns were absent (figure 13). the sole galp lesion showed circular white ws with diffuse homogeneous cloud-like pigment pattern and peripheral red dots on a pink background (figure 14). among ten aalp lesions, circular white ws was observed in seven lesions (70%), pigment patterns were observed in all aalp lesions, perifollicular-annular pigmentation was observed in two lesions (20%), diffuse homogeneous cloud-like pigmentation was observed in eight lesions (80%), diffuse reticular pigmentation was observed in two lesions (20%), and a peripheral homogeneous vascular pattern was detected in three lesions (30%) (some lesions showed more than one pigment pattern) (figures 15-16). in all ten aclp lesions, diffuse peppering pigment pattern on a brown background was observed, while ws and vascular patterns were completely absent (figure 17). among 50 rlp lesions, we observed no ws or vascular patterns in any of the lesions. pigment pattern was observed in 30 of 50 rlp lesions (60%), subfigure 8. dermoscopic images of a patient diagnosed with lichen planopilaris (lpp) with a history of four weeks. (a) blue-white veil-like ws. (b) white veil-like ws on a pink background. [copyright: ©2015 güngör et al.] figure 9. dermoscopic image of a patient diagnosed with lichen planopilaris (lpp) with a history of six months, perifollicular pigmentation on a pink-brown background is seen. [copyright: ©2015 güngör et al.] a b figure 10. (a) reticular peripheral pigmentation and white dots on a brown-yellow background without ws in an lpp patient on the trunk. (b) perifollicular-annular pigmentation and white dots in an lppi patient. [copyright: ©2015 güngör et al.] a b research | dermatol pract concept 2015;5(2):6 51 figure 11. (a) one of three different lesions of the same patient with lppi: perifollicular (red arrow) and reticular pigmentation. (b) one of three different lesions of the same patient with lppi: perifollicular and cobblestone (black arrow) pigmentation. (c) one of three different lesions of the same patient with lppi: perifollicular and linear pigmentation. perifollicular pigmentation progress to reticular, cobblestone pigmentation or linear pigmentation. white dots are also seen in all lesions. [copyright: ©2015 güngör et al.] a b c figure 12. (a) a purple macule on abdomen. (b) diffuse peppering, perifollicular pigmentation and white dots are seen in a lesion of an slpp patient in the first visit. (c) the dermoscopic image of the same lesion after four weeks, the pigmentation pattern was changed to reticular pigmentation sparing epidermal furrows. [copyright: ©2015 güngör et al.] figure 13. the clinical and dermoscopic image of a zlpp patient with a two-week history. (a) purple macular lesions in zosteriform arrangement on the trunk. (b) diffuse brown globules and perifollicular pigmentation on a yellow-pink background, sparing epidermal furrows. [copyright: ©2015 güngör et al.] figure 14. (a) a solitary annular lesion on glans penis. (b) circular white ws, diffuse homogeneous pigmentation and peripheral red dots on dermoscopic evaluation in a genital annular lp patient. [copyright: ©2015 güngör et al.] a b c a b 52 research | dermatol pract concept 2015;5(2):6 lesions (4%), peripheral homogeneous cloud-like pigmentation in one lesion (2%), and diffuse homogeneous cloudlike pigmentation in one lesion (2%). brown and yellow background colors were observed, with brown seen more frequently. dermoscopic images of rlp are shown in figures 3b, 4b, 6b, 15c. discussion the results show that different ws, pigment, and vascular patterns can be seen grouped as peripheral dots in six lesions (12%), diffuse dots in six lesions (12%), peripheral peppering in three lesions (6%), diffuse peppering in three lesions (6%), perifollicular-annular pigmentation in four lesions (8%), linear pigmentation in two lesions (4%), reticular pigmentation in one lesion (2%), circular pigmentation in one lesion (2%), cobblestone pigmentation in two according to the lp variant, lesion localization, and disease duration. but there are certain patterns that can be categorized for particular lp variants. even in the active and early phase, wickham striae (ws) patterns and vascular patterns are not observed in lpp (including lppi, zlpp, and slpp) and lp actinicus lesions, but pigment patterns are seen in all lpp and lp actinicus lesions. different pigment patterns can be seen in the different lesions of the same lpp patient at the same time; moreover different pigment patterns can be seen in the same lesions at different visits. the variable dermoscopic patterns show the dynamic course of lp disease. but in lpp lesions, perifollicular/annular, linear, and cobblestone pigment patterns are seen both at the first visit and after steroid treatment. as we demonstrated before, pigment patterns on dermoscopic examination correspond to dermal melanophages and pigment incontinence, which can be resistant to anti-inflammatory therapy because of the absence of the inflammatory cells [4]. the pigment pattern of the slpp lesion changed from ‘diffuse peppering’ pattern to “reticular” pattern in four weeks, suggesting that the ‘peppering’ pigment pattern is seen in the early phase of the disease and profigure 15. clinical and dermoscopic images of an annular atrophic lp patient with a two-week history. (a) numerous 0.5-1.5 cm annular plaques on the trunk. (b) central diffuse homogeneous cloud-like pigmentation, peripheral homogeneous vascular patterns and peripheral red dots are seen at the first visit before treatment. (c) the dermoscopic image of the same lesion after four weeks of topical steroid treatment. the vascular pattern has disappeared, but central homogeneous cloud-like pigmentation persists. [copyright: ©2015 güngör et al.] figure 16. clinical and dermoscopic image of an annular atrophic lp patient with a two-month history. (a) an annular plaque with central pigmentation on the patient’s back. (b) linear white annular ws, perifollicular-annular pigmentation on a brown background is seen upon dermoscopic examination. [copyright: ©2015 güngör et al.] figure 17. (a) brown macular lesions on the forehand of an lp actinicus patient with a four-week history. (b) diffuse peppering without ws upon dermoscopic examination. [copyright: ©2015 güngör et al.] a b a b a b c research | dermatol pract concept 2015;5(2):6 53 after treatment, vascular patterns disappeared but pigment patterns persisted upon dermoscopic examination (figure 15). seven lesions from two untreated, latestage aalp patients showed circular, peripheral, white ws, and homogeneous pigmentation (figure 16). these findings show that vascular structures in early phases can disappear via treatment, but they transform to ws without treatment. in lpp of the scalp, dermoscopic patterns differ according to disease duration. ws patterns are prominent in early lesions, but pigment patterns are prominent in long-duration disease. veil-like structureless ws pattern is the main ws pattern in lpp lesions, unlike in clp lesions. we also observed co-existence of different lp types in three patients. three patients had clp lesions on the extremities and trunk, plus lppi lesions on flexural regions. as we reported one of these patients previously [4], we believe that lppi is a variant of clp, but the course of the lesions differs due to friction, resulting in histopathological-clinicaldermoscopic differences from clp lesions. as seen in figure 2, though all lesions appear at the same time, dermoscopic patterns differ according to localization. in histological examination, hyperkeratosis and hypergranulosis are absent, but pigment incontinence is prominent in inverse lp lesions, resulting in pigment pattern prominence and ws absence in dermoscopic examination. in conclusion, we described the dermoscopic images of lp, lp variants, and regressive lp lesions. we believe that dermoscopic evaluation can be useful both in the diagnosis and follow up of lp. references 1. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol 2012;166(6):1198-205. 2. zalaudek i, argenziano g. dermoscopy subpatterns of inflammatory skin disorders. arch dermatol 2006;142(6):808. 3. vazquez-lopez f, palacios-garcia l, gomez-diez s, argenziano g. dermoscopy for discriminating between lichenoid sarcoidosis and lichen planus. arch dermatol 2011;147(9):1130. 4. gungor s, topal io, erdogan s, ozcan d. classical lichen planus and lichen planus pigmentosus inversus overlap with dermoscopıc features. our dermatol online 2014; 5(1):42-44. 5. vázquez-lópez f, gómez-díez s, sánchez j, pérez-oliva n. dermoscopy of active lichen planus. arch dermatol 2007;143(8):1092. 6. vázquez-lópez f, vidal am, zalaudek i. dermoscopic subpatterns of ashy dermatosis related to lichen planus. arch dermatol 2010;146(1):110. 7. tan c, min zs, xue y, zhu wy. spectrum of dermoscopic patterns in lichen planus: a case series from china. j cutan med surg 2014;18(1):28-32. gresses to the ‘reticular’ pattern over the course of time. we assume that the “reticular” pigment pattern is an incomplete and moderate form of the “perifollicular/annular” pattern that manifests as half circular fine pigmentation instead of annular dark pigmentation and the combination of these half-circular fine pigmentations gives the image of “reticular” pigmentation. in some lpp lesions, the pigment pattern was absent in skin furrows, which has not been mentioned before in the literature. we suggest that the skin furrows are not exposed to friction, which could be the reason for the absence of pigmentation. ws is commonly seen on dermoscopic examination in clp lesions and it corresponds to hypergranulosis histologically [3-6]. ws disappears after treatment, suggesting that we can use it as an activation marker in lp lesions. in aglp lesions, ws is seen at a lower rate compared to clp lesions. interestingly, “invisible ws” is also seen in aglp patients. the lower rate of ws and invisible ws may be due to the acute attack of the inflammatory cells in aglp and inadequate time to progress to hypergranulosis. conversely, vascular patterns are seen at a higher rate in aglp compared to clp, which may also be due to the rapid onset of the lesions. ws is classically seen as white crossing lines on dermoscopic evaluation and defined as “reticular pattern ws” [3,5]. in our study, we detected nine additional ws patterns beyond the “classical reticular” pattern. leaf venation, circular, and radial streaming patterns were previously defined by tan et al [7]. in the current study, leaf venation ws pattern was not detected, but circular and radial streaming ws patterns were detected similar to the tan et al. study. we defined additional ws patterns as linear, globular, perpendicular, veil-like structureless, and a combination of these patterns. reticular ws pattern is commonly seen in clp but not that often in aglp and lpp lesions. this can be due to distinct histopathological features in lp variants. we found white dots in lpp, lpp, rlp, and clp with decreasing frequency. we interpret white dots as follicular openings surrounded by dermal melanophages. the absent of white dots in aglp may be due to the absence of pigment patterns in aglp. we observed yellow dots in clp lesions, which corresponds to hyperkeratosis and acanthosis histopathologically. in rlp lesions, ws was totally absent while pigment patterns were frequently seen. this shows that ws is seen in active lesions and disappears with treatment, but pigment patterns resist treatment. they can even appear during late stages in spite of treatment. figures 3 and 4 show that ws disappears but pigment patterns appear after treatment. in early aalp lesions, peripheral homogeneous vascular patterns and central homogeneous pigmentation were seen; dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023091 1 congenital multiple nevoid hypertrichosis nicola lippolis1, alex curti2, caterina longo1,2, vito di lernia3 1 centro oncologico ad alta tecnologia diagnostica-dermatologia, azienda unità sanitaria locale irccs di reggio emilia, reggio emilia, italy 2 dermatology department, university of modena & reggio emilia, modena, italy 3 dermatology unit, arcispedale santa maria nuova, azienda usl-irccs di reggio emilia, reggio emilia, italy citation: lippolis n, curti a, longo a, di lernia v. congenital multiple nevoid hypertrichosis. dermatol pract concept. 2023;13(2):e2023091. doi: https://doi.org/10.5826/dpc.1302a91 accepted: august 17, 2022; published: april 2023 copyright: ©2023 lippolis et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vito di lernia, dermatology unit, arcispedale santa maria nuova, azienda usl-irccs di reggio emilia, reggio emilia, italy. e-mail: vito.dilernia@ausl.re.it case presentation a 3-month-old male infant of georgian origin was brought for evaluation of three congenital, well-demarcated patches characterized by dark, terminal hairs on the sacral-lumbar region and right lower limb (figure 1, a and b). on physical examination, the patches had coarse hair of abnormal length. no changes in the underlying skin were found. dermoscopy did not show brown pigmentation or pigment network. the pseudo-darier sign was not detected on palpation. there was no relevant family history. the child had followed normal developmental milestones. a multidisciplinary pediatric consultation did not disclose abnormalities. histology performed on the patient’s back showed only terminal hair without additional relevant epidermal and dermal changes. a diagnosis of nevoid hypertrichosis was made. a magnetic resonance imaging was considered but postponed in absence of clinical issues. at eighteen-month follow-up no additional clinical problems were discovered. teaching point nevoid hypertrichosis is a rare disorder consisting of a solitary, circumscribed area characterized by terminal hair growth on otherwise appearing skin [1]. multiple patches may be rarely observed. it is predominant in females and arises at birth or shortly after. hypopigmentation of the underlying skin has rarely been reported. histopathologically, hair follicles are increased in number, but structurally normal, without characteristic or diagnostic features. nevoid hypertrichosis, in particular when it occurs with multiple patches, may be associated with a series of ocular, cerebral, mental, musculoskeletal, neurological, gastrointestinal, pulmonary, cardiac abnormalities and with facial dysmorphia [1,2]. due to heterogeneity in extracutaneous manifestations, specific diagnostic procedures should follow a clinical suspicion. the differential diagnosis includes hypertrichosis cubiti [1]. patches of unusually long pigmented hair or focal 2 image letter | dermatol pract concept. 2023;13(2):e2023091 hypertrichosis may be observed in individuals with gorlin syndrome and aicardi syndrome, suggesting a role of the ptch protein, a negative regulator of pathways involved in hair follicle formation and growth cycle and subjects with proteus syndrome, due to a possible role of the akt1 kinase in the hair follicle development [1]. smooth muscle hamartoma, becker nevus, and melanocytic nevi may present an overlying focal hypertrichosis, but epidermal changes are helpful for the diagnosis. references 1. sotiriadis d, patsatsi a, lazaridou e, sotiriou e, devliotou-panagiotidou d. multiple nevoid hypertrichosis as an isolated developmental defect. pediatr dermatol. 2009;26(4):436-438. doi: 10.1111/j.1525-1470.2009.00948.x. pmid: 19689520. 2. gupta l, gautam rk, bharadwaj m. nevoid hypertrichosis: case report with review of the literature. int j trichology. 2011;3(2): 115-117. doi: 10.4103/0974-7753.90829.pmid: 22223975. pmcid:pmc3250008. figure 1. coarse, black hair on the lumbosacral region (a) and right lower limb (b) (lateral aspect of the right thigh and right ankle). dermatology: practical and conceptual observation | dermatol pract concept 2017;7(2):10 47 dermatology practical & conceptual www.derm101.com case presentation a 57-year-old woman developed multiple (>20) melanoma in-transit metastatic nodules on her right thigh (figure 1a), as confirmed by histological examination, after removal, six months earlier, of a primary 2.2 mm thick ulcerated nodular melanoma on her right leg for which the initial sentinel lymph node biopsy was negative. after completion of fdg pet-ct to exclude distant metastasis and assessment of the extent of limb metastasis, the patient was referred to a specialized center to receive, isolated limb perfusion (ilp) of melphalan under hyperthermia, tnf-α and interferon γ. superficial and deep pelvic (ilioinguinal) lymphadenectomy was simultaneously performed and revealed two additional deep pelvic in vivo reflectance confocal microscopy: a useful non-invasive tool to assess the response to isolated limb perfusion for superficial pigmented melanoma in-transit metastatic disease. report of a case rastine merat1, wolf-henning boehncke1, gürkan kaya1 1 division of dermatology, university hospital of geneva, switzerland key words: reflectance confocal microscopy, isolated limb perfusion, metastatic melanoma citation: merat r, boehncke w-h, kaya g. in vivo reflectance confocal microscopy: a useful non-invasive tool to assess the response to isolated limb perfusion for superficial pigmented melanoma in-transit metastatic disease. report of a case. dermatol pract concept. 2017;7(2):10. doi: https://doi.org/10.5826/dpc.0702a10 received: september 10, 2016; accepted: january 14, 2017; published: april 30, 2017 copyright: ©2017 merat et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rastine merat, md, phd, division of dermatology, university hospital of geneva, rue gabrielle-perret-gentil 4, ch-1205 geneva, switzerland. tel. +41.22.37.22.94.37; fax. +41.22.372.94.77. email: rastine.merat@hcuge.ch. complete response can be difficult to assess after isolated limb perfusion (ilp) for metastatic in-transit melanoma, especially when numerous and unresectable post-necrotic persisting pigmented lesions occur. these residual lesions are mainly seen in the more superficial and pigmented types of metastatic disease and correspond to the residual melanophage granuloma that persists after tumor tissues undergo complete necrosis. reflectance confocal microscopy (rcm) is a non-invasive technique that allows the exploration of the superficial dermis. here, we present the case of a patient in whom numerous post-ilp limb residual pigmented lesions were explored using combined rcm and histological examination of sample lesions and could be characterized as non-active. this approach allowed us to avoid additional excisions. abstract figure 1. (a) in-transit metastatic nodules before ilp. (b) persisting non-changing pigmented macules after ilp. the designated lesions (a, b) are the ones for which dermoscopy follow-up is shown in figure 4. [copyright: ©2017 merat et al.] a b 48 observation | dermatol pract concept 2017;7(2):10 pigmented lesions (figure 1b) in which a similar characteristic image was consistently seen. this approach allowed us to avoid additional excision. the patient has now been followed for more than a year without any clinical or radiological sign of relapse and most lesions have slowly resolved (figure 4). discussion around 5-10% of patients with malignant melanoma develop lymphatic dissemination and in-transit metastasis. even in the era of effective systemic therapies, isolated limb perfusion (ilp) with hyperthermia performed using various agents (melphalan, with addition of chemokines, i.e., tnf-α and/or other chemokines) is still a valuable therapeutic approach and is being used for patients who develop numerous limb lesions simultaneously and are therefore considered inoperable [1]. according to the literature, a 50% complete response rate can be obtained with ilp [2]. nevertheless complete response can be difficult to assess if post-necrotic persisting pigmented lymph node metastases. one month after the end of this procedure, most in-transit lesions had undergone necrosis. four months later, all lesions had healed and persisted as non-changing pigmented macules (figure 1b) with no clinical or radiological (including fdg pet-ct) signs of relapse. in order to confirm that none of the residual pigmented macules was an active lesion, two of them were excised after being previously examined by rcm. histological examination showed a persisting melanophage granuloma (nodular melanosis) within areas of fibrosis in the upper dermis with no sign of tumor infiltration (figure 2a and 2b). rcm imaging, performed using the vivascope 1500 (vivascope systems, munich, germany) showed ill-defined aggregates of dermal bright cells, typical of melanophages with almost no visible nuclei. sometimes a characteristic ring-shaped deposit was seen within the network of bright collagen fibers and bundles (figure 3). such deposits could be seen in many areas of the excised lesions and correlated with the histological images. we then performed rcm imaging on 12 other main persisting figure 3. rcm mosaic from the upper dermis: ill-defined aggregates of dermal bright cells typical of melanophages and characteristic ringshaped deposits within the network of collagen fibers. [copyright: ©2017 merat et al.] figure 2. histology (a) persisting melanophage granuloma within areas of fibrosis in the upper dermis, original magnification x10. (b) original magnification x20. note the ring-shaped deposits as seen in rcm. [copyright: ©2017 merat et al.] a b observation | dermatol pract concept 2017;7(2):10 49 [3-6] where, in the case of superficial intransit metastasis, post-necrotic residual melanophage granuloma (nodular melanosis) might be localized. morphologic features of melanophages under in vivo rcm have been well characterized, allowing their distinction from melanocytes [7,8]. here, using combined rcm and histological examination of two sample lesions, numerous unresectable post-ilp limb residual pigmented lesions were considered by rcm to be non-active as confirmed by the subsequent dermoscopy follow-up. although in the case presented here there was not any doubt at follow-up regarding the absence of residual disease, considering that the deeper reticular dermis cannot lesions occur, especially if numerous and unresectable. these residual lesions occur mainly in the more superficial and pigmented types of metastatic disease. as it was the case with our patient, these lesions can often correspond to the residual melanophage granuloma (nodular melanosis) that persists after tumor tissues undergo complete necrosis and can be difficult to distinguish from partial response and persisting in-transit metastasis. rcm is a non-invasive technique that allows the exploration of the superficial dermis. confocalhistopathological correlation has been shown to be possible for the visualization of some histologic features in the superficial dermis up to 300um deep figure 4. examples of dermoscopy follow-up of pigmented macules after ilp (a1, b1) and one year later (a2, b2). note the gradual pigment resorption. [copyright: ©2017 merat et al.] be explored with rcm, biopsy remains mandatory in case of doubt during the subsequent needed close follow-up. references 1. nieweg oe, kroon bb. isolated limb perfusion with melphalan for melanoma. j surg oncol. 2014;109: 332-337. 2. olofsson r, mattsson j, lindnér p. longterm follow-up of 163 consecutive patients treated with isolated limb perfusion for intransit metastases of malignant melanoma. int j hyperthermia. 2016;29:551-557. 3. hofmann-wellenhof r, pellacani g, malvehy j, soyer hp. reflectance confocal microscopy for skin diseases. berlin heidelberg: springer; 2012. 4. rajadhyaksha m, gonzález s, zavislan jm, anderson rr, webb rh. in vivo confocal scanning laser microscopy of human skin ii: advances in instrumentation and comparison with histology. j invest dermatol. 1999;113:293-303. 5. pellacani g, guitera p, longo c, avramidis m, seidenari s, menzies s. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127:2759-2765. 6. scope a, benvenuto-andrade c, agero al, halpern ac, gonzalez s, marghoob aa. correlation of dermoscopic structures of melanocytic lesions to reflectance confocal microscopy. arch dermatol. 2007; 143:176-185. 7. busam kj, charles c, lee g, halpern ac. morphologic features of melanocytes, pigmented keratinocytes, and melanophages by in vivo confocal scanning laser microscopy. mod pathol. 2001;14:862-868. 8. guitera p, li lx, scolyer ra, menzies sw. morphologic features of melanophages under in vivo reflectance confocal microscopy. arch dermatol. 2010;146:492-498. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022179 1 apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature aikaterini tsentemeidou1, elena sotiriou1, nikolaos sideris1, katerina bakirtzi1, ilias papadimitriou1, aimilios lallas1, dimitrios ioannides1, efstratios vakirlis1 1 first department of dermatology and venereology, school of medicine, aristotle university, thessaloniki, greece key words: apremilast, comorbidities, medical dermatology, psoriasis, biologics citation: tsentemeidou a, sotiriou e, sideris n, et al. apremilast in psoriasis patients with serious comorbidities: a case series and systematic review of literature. dermatol pract concept. 2022;12(4):e2022179. doi: https://doi.org/10.5826/dpc.1204a179 accepted: march 18, 2022; published: october 2022 copyright: ©2022 tsentemeidou et al. this is an open-access article distributed under the terms of the creative commons attribution-non commercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: elena sotiriou, phd, first department of dermatology and venereology, school of medicine, aristotle university, 124 delfon str, 54645, thessaloniki, greece, +302313308822, email: elenasotiriou@yahoo.gr introduction: patients with serious comorbidities are traditionally excluded from clinical trials. apremilast is not contraindicated in active infections, malignancy and serious hepatic or renal impairment, but real-life data is needed to support this recommendation. objectives: the aim of this paper is to present our personal as well as literature-sourced real-world evidenced on apremilast use in psoriasis patients with serious baseline comorbidities. methods: a case-series and systematic literature review were performed. the psoriasis archives of a tertiary-care hospital, four electronic databases (medline, sciencedirect, cochrane library, google scholar) and other sources were searched (january 2014 – july 2021). identified records were considered eligible, if they reported on the use of apremilast monotherapy in psoriasis patients with chronic infections, history of malignancy, serious liver, renal, psychiatric, or other disease(s). results: at least 841 psoriasis patients with serious baseline diseases received apremilast. only 3 cases of cancer progression and no infection reactivations or worsening of other diseases were documented. no increased frequency/severity of adverse events or reduced drug efficacy were noted. main limitations of this study are the exclusion of a few reports due to inappropriately documented data and the fact that at least some patients might have been counted more than once. conclusions: apremilast is a safe and adequately efficacious option for psoriasis that cannot be treated/is challenging to treat with classic systemic agents and/or biologics. abstract 2 review | dermatol pract concept. 2022;12(4):e2022179 introduction psoriasis is a chronic cutaneous disease of inflammatory nature, with a worldwide prevalence ranging between 1-3%; it has a substantial negative effect on patient physical wellbeing and quality-of-life, as well as on national health expenditure [1–3]. apremilast (otezla®, amgen), a small molecular inhibitor of phosphodiesterase 4 (pde4), has been used for the treatment of psoriatic arthritis and psoriasis since 2014 (first us food and drug administration [fda] approval). contrary to biologics, it does not target any one specific component of the inflammatory process involved in the pathophysiology of psoriasis, but rather achieves some sort of equilibrium of pro-inflammatory and anti-inflammatory agents [4,5]. apremilast comes with a set of favorable attributes, among which are the oral distribution, lower cost comparing to biologics and good safety profile [3,6]. it is not contraindicated in patients with active infections or serious liver impairment, nor is routine lab monitoring necessary. similarly, it can be administered to patients with past or current malignancy [8]. patients with severe renal impairment can still receive a reduced dose of apremilast [9]. a pooled analysis (≥ 156 weeks) from the 2 apremilast-approving (esteem) trials showed that serious infection rate was low among patients receiving apremilast, while no serious opportunistic infections or cases of tuberculosis reactivation were noted [10]. however, as patients with chronic infections, cancers and serious co-existing diseases are traditionally excluded from clinical trials testing new drugs, conclusions regarding the use of said drugs in these occasions cannot always be safely drawn [7,11]. objectives the purpose of this study is to present our five-year experience in administering apremilast to psoriasis patients with serious comorbidities in the setting of a tertiary-care center in terms of drug safety and efficacy, as well as to concisely portray relevant real-life evidence sourced through a systematic literature search. methods case series the march 2016 (apremilast approval in greece) to june 30th, 2021 archives of both the psoriasis outpatient clinic and afternoon private clinics of the first dermatology department, aristotle university, thessaloniki, greece were consecutively searched for all psoriasis patients having received at least one dose of apremilast. patients with an appropriately documented chronic/latent infection, recent (past 10 years) malignancy excluding basal cell carcinoma, serious kidney (stage iv and v) or liver (child-pugh c) disease, severe psychiatric disorder or other serious illness as was defined by kelley [12] were included in the study. the following data were retrieved by two collaborating authors (at and ns): age, gender, comorbidity(-ies), year of comorbidity diagnosis, apremilast dose, baseline psoriasis area and severity index (pasi), treatment outcome in terms of efficacy, duration of apremilast treatment (weeks) and adverse events (aes) including adverse outcomes related to comorbidity(-ies) in question. written informed consent was obtained by all participants. this project was designed and conducted based on the declaration of helsinki and was approved by the ethics committee of the hospital of venereal and cutaneous diseases, thessaloniki, greece. systematic review eligibility criteria we conducted this systematic review as stated by meta-analyses of observational studies in epidemiology (moose) statement. published and unpublished prospective or retrospective observational studies reporting on the use of apremilast for the treatment of psoriasis patients with serious baseline comorbidities (chronic/latent infections such as tuberculosis, hepatitis and hiv, cancer diagnosis within past ten years excluding basal cell carcinoma, stage iv and v chronic kidney disease hemodialysis, child-pugh class c liver disease, serious psychiatric disorders or other serious illness as was defined by kelley [12]) were considered eligible for inclusion in our study. clinical trials or studies not presenting real-life data, as well as studies reporting on combination therapy of apremilast and other systemic agents aside from phototherapy, systemic corticosteroids or other medication administered systemically for existing comorbidities were excluded from our review. only studies performed after 2014 (apremilast first fda approval) were considered. no language restrictions were placed. information sources three electronic databases were searched (medline, sciencedirect, and the cochrane library electronic databases). google scholar (https://scholar.google.com/) was also browsed. abstract compendia of the world congresses of dermatology, world psoriasis and psoriatic arthritis congresses, american academy of dermatology annual meetings and european academy of dermatology and venereology annual congresses of the last five years were examined (online browsing). last search date for all above mentioned platforms was july 4th, 2021. amgen® was review | dermatol pract concept. 2022;12(4):e2022179 3 contacted and kindly asked to supply our team with any published or unpublished data abiding by our search criteria. the “reference” section of studies included in our review was hand searched for additional eligible work. search strategy the following search strategy was used for medline database and modified accordingly for the rest of searched platforms: (apremilast[title]) and (psoriasis[title/abstract]) filtered by year of publication (2014 to 2021). the search was performed independently by two authors (at and ns). study endpoints the primary endpoint of this study was the documentation of any safety-related outcomes in patients with serious comorbidities having received apremilast (for example comorbidity progression, aes commonly related to apremilast use or other events). secondary endpoint was treatment efficacy, without any limitations imposed on efficacy measures used. selection process and data collection duplicate records were independently manually removed by two reviewers (ns and at). subsequently, two reviewers (at and ns) independently screened titles and abstracts for relevance to the study objective. the full text of remaining records was read, and eligible studies were included in the review. at and ns separately extracted the following data from included studies according to a pre-formulated sheet: first author, year of publication / research completion, comorbidity(-ies), age and gender of patient(-s), apremilast dose, baseline pasi, aes including comorbidity-related events. any disagreements were resolved in consultation with a third author (es). quality assessment two authors (at and es) independently assessed included reports based on two different tools, namely the joanna briggs institute (jbi) critical appraisal tool for case reports/case series and the jbi critical appraisal tool for analytical crosssectional studies, each comprising eight questions (supplement). each study was assigned an overall rating of poor, good or fair, if 0-5, 6-7 or 8 criteria were met respectively. results the psoriasis-archives search returned 16 eligible cases, one of which was not included in the analysis due to incompletely documented patient data (table 1). no progression of malignancy, reactivation of chronic / latent infection or deterioration of already deficient renal or hepatic function were noted. apremilast was generally well-tolerated and only mild transient aes were reported in 6 patients. patient compliance to treatment was high (three cases of temporary drug discontinuation, < 14 days, due to covid-19-related restrictions and consequent difficulties in drug prescription). desired response (pasi50) was not achieved in 1 case and apremilast was therefore discontinued (primary drug failure). the systematic literature search yielded 52 studies eligible for inclusion (figure 1). one additional study was identified after the last search date (published july 8th 2021) and does not appear in the flow diagram (figure 1) [13]. a total of at least 826 psoriasis patients with serious comorbidities (various malignancies – at least 456 patients –, latent / past tuberculosis – 49 patients –, hepatitis b, c and hiv infections – at least 83 patients –, serious renal – 7 patients – or liver impairment – at least 110 patients –, serious psychiatric disorders – 49 patients – or other serious illness as was defined by kelley [12]) were prescribed apremilast twice or once daily (table 2). the exact number of patients with serious comorbidities prescribed apremilast was not reported in a few studies, therefore, the numbers mentioned above are a conservative underestimation of the studied population. included patients manifested all types of psoriasis and/or nail psoriasis. overall, apremilast was hardly ever associated with negative comorbidity-related outcomes and reported aes were apparently not more severe or frequent than those experienced by the average psoriasis patient. sufficient response of psoriasis to apremilast was recorded in most cases. overall, the quality of included studies was good (table 3). conclusions this case series and systematic review reports on the use of apremilast in 841 psoriasis patients with serious baseline comorbidities, which would have made the use of classic systemic agents and/or biologics inappropriate or challenging. according to our study, the use of apremilast in this group of patients apparently neither leads to deterioration / exacerbation of severe pre-existing comorbidity(-ies) nor is it associated with an increased risk of adverse events. what is more, drug efficacy does not seem to be affected by the underlying comorbidity, with cases of remarkable response even in erythrodermic patients with very serious underlying diseases. a drug safety profile, especially in the context of pre-existing comorbidities, is one of its major attributes to be taken into consideration, when deciding on a treatment regimen [14]. psoriasis patients receiving apremilast, as opposed to other systemic agents, seem to have a lower infection risk [15]. rates of herpes zoster infection were lowest for users of apremilast among a cohort of psoriasis patients treated with biologics and/or small molecules (5.4, 95% ci  1.7-12.6) [16]. comparing to methotrexate (mtx), as investigated in a cohort of 2845 psoriasis patients treated 4 review | dermatol pract concept. 2022;12(4):e2022179 viral load, discussion with an infectious-disease specialist is warranted, with apremilast and acitretin being the preferred options [19]. based on the same recommendations, the preferred options for short-term systemic treatment of psoriasis patients with chronic hepatitis c infection are adalimumab and etanercept, as there is not enough evidence to support the use of other biologics and apremilast [19]. as far as chronic hepatitis b infection is concerned, ustekinumab, apremilast, cyclosporine and acitretin are preferred [19]. apremilast has shown potential in the treatment of psoriasis patients with a history of malignancy. it may even help treat lung cancer, as pde4 is expressed in lung cancer cells [20]. in the current pandemic era, it is important to examine a drug safety with regards to the covid-19 infection. according to the world health organization, psoriasis patients on with nine systemic agents in spain, apremilast had a lower infection (incidence rate 0.3 [95% ci 0.1-0.9]) and malignant neoplasm risk (incidence rate 0.1 [95% ci 0-0.7]) [14]. psoriasis may be more severe or difficult to treat in patients with hiv infection [17,18]. what is more, hiv-positive patients are immuno-compromised and prone to reactivation of latent infections [17]. according to the 2020 belgian practical recommendations for the treatment of psoriasis in hiv-positive patients, apremilast and acitretin are considered first-line choices ]. furthermore, many biologics (adalimumab, certolizumab pegol, etanercept, infliximab, ustekinumab, guselkumab, risankizumab, brodalumab, secukinumab, ixekizumab) can be used in patients receiving highly active antiretroviral therapy (haart) and having undetectable viral load [19]. in case of detectable table 1. cases of psoriasis patients with serious baseline comorbidities treated with apremilast. case sex age comorbidity (diagnosis) apr dose bas pasi tx outcome apr duration aes 1 m 69 prostate cancer (2013) 30 mg bid 10.3 pasi50 week 16 53 (looe) none 2 m 76 lung tuberculosis (1968) 30 mg bid 9 pasi50 week 16 52 (lost to f/u) none 3 m 73 latent tuberculosis 30 mg bid 13.4 pasi75 week 16 72 (looe) none 4 m 79a lung cancer (2015) 30 mg bid 15.9 pasi50 not achieved 21 (laoe) abdominal pain 5 f 65 breast cancer (2016), hepatitis b 30 mg bid 5.3 pasi100 24 weeks 35 (clear skin) dyspepsia 6 m 63 hepatitis c and liver fibrosis 30 mg bid 6.7 pasi50 week 16 37 (looe) none 7 m 44 hemodialysis (stage 5 chronic kidney disease – iga nephropathy) 30 mg od 13.2 pasi50 week 24 40 (looe) none 8 f 66 lung tuberculosis (1980) 30 mg bid 11.1 pasi50 week 16 4 (aes) headache 9 m 33 hiv positive (2011) (cd4+ 602 cells/mm3) 30 mg bid 15.8 pasi75 week 16 149 (sod) none 10 m 65 urinary bladder cancer (2015), stage 2 chronic kidney disease 30 mg bid 9.1 pasi50 week 16 31 (looe) none 11 f 56 cervical cancer (2013) 30 mg bid 10.8 pasi75 week 24 154 (sod) none 12 m 37 hiv positive (2009) (cd4+ 590 cells/mm3) 30 mg bid 24.5 pasi50 week 24 56 (sod) transient nausea 13 m 44 hiv positive (2002) (cd4+ 550 cells/mm3) 30 mg bid 33.6 pasi90q week 52 104 (sod) transient diarrhea 14 m 32 hiv positive (2009) (cd4+ 702 cells/mm3) 30 mg bid 19.3 pasi90 week 24 34 (sod) transient diarrhea 15 m 88 hepatitis b 30 mg bid 28.6 pasi90 week 8 16 (sod) none aes = adverse events; apr = apremilast; bas = baseline; f = female; f/u = follow-up; hiv = human immunodeficiency; laoe = lack of efficacy; looe = loss of efficacy; m = male; o.d. = once daily; pasi = psoriasis area and severity index;; bid = twice daily (bis in die); pasi50  = 50% reduction of baseline pasi; pasi75 = 75% reduction of baseline pasi; virus; pasi90 = 90% reduction of baseline pasi; sod = still on drug; tx = treatment. adeceased. review | dermatol pract concept. 2022;12(4):e2022179 5 identification of studies via databases and other sources records identified from: medline (n=263) sciencedirect (n = 161) cochrane library (n = 207) google scholar (n = 471) congresses (n = 129) amgen (n = 21) records screened (n = 846) reports sought for retrieval (n = 215) reports not retrieved (n = 12) reports excluded due to not meeting inclusion criteria and/or meeting exclusion criteria: (n =151) reports assessed for eligibility (n = 203) reports sourced through reference search of eligible records (n= 0) reports included in review (n = 52) records excluded (n = 631) records removed before screening: duplicate records removed (n = 405) records removed for other reasons (n = 1) id en ti fi c a ti o n sc r ee n in g in c lu d ed figure 1. prisma (preferred reporting items for systematic reviews and meta-analyses) flow diagram detailing the number and origin of records identified, included in and excluded from this systematic review, as well as the reasons for exclusion. 6 review | dermatol pract concept. 2022;12(4):e2022179 ta b le 2 . l it er at u re c as es o f ap re m il as t ad m in is te re d t o p so ri as is p at ie n ts w it h s er io u s b as el in e co m o rb id it ie s. r e p o rt c o m o rb id it y a g e /s e x a p r d o se b a s pa s i t x o u tc o m e a e s m u gh ed d u 2 0 2 0 [ 2 2 ] r ec u rr en t b ra in o li go d en d ro gl io m a u n d er te m o zo lo m id e an d p re d n is o n e 4 5 /m 3 0 m g b id 4 5 im p ro ve m en t n /r c o v id -1 9 p n eu m o n ia , f u ll r ec o ve ry m an fr ed a 2 0 1 9 [ 1 5 ] h iv p o si ti ve ( c d 4 + 6 2 8 c el ls /m m 3 ), h ep at it is b , d ru g ad d ic ti o n h is to ry 4 1 /m 3 0 m g b id 1 2 pa si 9 0 w 2 4 n o n e, s ta b le c d 4 + c o u n t z ar b afi an 2 0 1 9 [ 5 ] h iv p o si ti ve ( c d 4 + > 1 0 0 0 c el ls /m m 3 ) 5 4 /m 3 0 m g b id 1 0 .2 7 3 % p a si re d u ct io n m 7 t ra n si en t d ia rr h ea , f re q u en t u r t is , st ab le c d 4 + c o u n t r ed d y 2 0 1 7 [ 4 ] h iv p o si ti ve , h ep at it is c 4 6 /m 3 0 m g b id b sa 8 % b sa 1 .5 % m 5 n o n e sh ah 2 0 1 9 [ 1 8 ] h iv p o si ti ve ( c d 4 + 7 4 2 /μ l) 3 5 /m 3 0 m g b id , th en o d 1 4 .7 pa si 1 0 0 w 6 n o n e, s ta b le c d 4 + c o u n t sa cc h el li 2 0 1 8 [ 3 2 ] h iv p o si ti ve ( 2 0 0 2 ) (c d 4 + 5 6 6 /m c) , p as t h ep at it is b a n d c 5 5 /m 3 0 m g b id 8 n a p si q 2 1 pa si 7 5 m 6 n a p si 7 m 6 n o n e a p al la 2 0 1 9 [ 1 1 ] m et as ta ti c lu n g ad en o ca rc in o m a, s ta ge i ii b ( 2 0 1 3 ) 6 7 /f 3 0 m g b id 1 8 pa si 7 5 w 1 6 n o n e, c an ce r co u rs e n o t af fe ct ed b y a p r r ed d y 2 0 1 9 [ 1 7 ] h iv p o si ti ve ( c d 4 + 4 6 0 c el ls /m m 3 ) 5 0 /m 3 0 m g b id an d t h en o d b sa 1 0 % b sa 0 % m 3 n /r f o ti ad o u 2 0 1 8 [ 3 3 ] c h ro n ic h ep at it is b , u n d et ec ta b le v ir al l o ad 5 2 /f 3 0 m g b .i .d . 1 3 .2 pa si 9 0 w 2 4 n o n e, n o rm al h b lo ad a n d l f t s je o n 2 0 1 7 [ 3 4 ] a ct iv e h ep at it is c , d ec o m p en sa te d c ir rh o si s, m et as ta ti c h c c 5 5 /m 3 0 m g b id n /r pa si 1 0 0 w 6 in it ia l n au se a g o n zá le zc an te ro 2 0 1 8 [3 5 ] m al ig n an cy : 3 , l iv er d is ea se : 1 , a lc o h o li sm : 1 , in fe ct io u s d is ea se : 1 , r en al i n su ffi ci en cy : 1 , d em ye li n at in g d is ea se : 1 n /r n /r n /r n /r n o c h an ge s in t h e co u rs e o f co m o rb id it ie s g o tt li eb 2 0 2 1 [ 3 6 ] m al ig n an cy : 9 2 , s er io u s in fe ct io n : 5 3 n /r n /r n /r n /r n /r k ah n 2 0 1 9 [ 3 7 ] 1 . r en al c el l ca rc in o m a 2 . m el an o m a 6 3 , n /r 6 4 , n /r n /r b sa 1 0 % b sa 5 % n /r n o c li n ic al /r ad io gr ap h ic al s ig n s o f ca n ce r re cu rr en ce n ag at a 2 0 1 9 [ 3 8 ] h em o d ia ly si s 6 0 , m 3 0 m g o d p ss i 3 6 p ss i 1 0 w 1 2 n au se a (t ra n si en t) u va is 2 0 2 0 [ 3 9 ] b ip o la r af fe ct iv e d is o rd er 3 0 , f 3 0 m g/ d ay n /r n /r n /r v ic o -a lo n so 2 0 2 0 [ 4 0 ] c h ro n ic m ye lo id l eu k em ia u n d er i m at in ib , l at en t tu b er cu lo si s, a lc o h o li sm , s te at o h ep at it is 5 8 , m 3 0 m g b id 2 2 .4 pa si 9 0 w 2 4 n o n e, s ta b le t u m o ra l st at e, n o rm al la b t es ts m el is 2 0 2 0 [ 4 1 ] m al ig n an cy ( ex cl . n m sc ): 1 3 ( b re as t, b la d d er , co lo re ct al ), s ev er e in fe ct io n : 7 ( h iv , h b v , h c v ), p sy ch ia tr ic d is o rd er : 6 , l iv er d is ea se : 3 , l at en t tu b er cu lo si s: 2 n /r 3 0 m g b id n /r n /r n /r p er ro n e 2 0 1 7 [ 4 2 ] c h ro n ic a n em ia a n d t h ro m b o cy to p en ia 7 1 , m n /r n /r n /r f an co n i sy n d ro m e review | dermatol pract concept. 2022;12(4):e2022179 7 r e p o rt c o m o rb id it y a g e /s e x a p r d o se b a s pa s i t x o u tc o m e a e s c ar p en ti er i 2 0 2 0 [ 4 3 ] m al ig n an cy ( ex cl . n m sc ): 1 0 n /r n /r n /r m o st p at ie n ts sh o w ed im p ro ve m en t n o c li n ic al o r ra d io gr ap h ic re cu rr en ce o r p ro gr es si o n o f th ei r ca n ce r p ei ts ch 2 0 1 9 [ 4 4 ] m an te l ce ll l ym p h o m a u n d er r it u x im ab , h ep at ic an d p u lm o n ar y as p er gi ll o si s 6 0 , m 3 0 m g b id 1 7 .2 pa si 9 0 m 5 n o n e, l ym p h o m a in r em is si o n t ak am a 2 0 2 0 [ 4 5 ] u ri n ar y b la d d er c an ce r u n d er p em b ro li zu m ab 7 4 , m 3 0 m g b id , th en o d 2 .9 pa si 5 0 w 2 , pa si 9 0 m 2 n au se a f o ti 2 0 2 1 [ 4 6 ] m el an o m a w it h l ym p h n o d e m et as ta si s u n d er n iv o lu m ab 6 2 , m 3 0 m g b id 4 4 pa si 5 0 m 6 , pa si 9 0 m 1 2 n o n e, n o w o rs en in g o f m el an o m a d i l er n ia 2 0 2 1 [ 4 7 ] m al ig n an cy : 3 c o lo re ct al , 2 g i st ro m al , 1 l eu k em ia , 1 l ym p h o m a, 1 k id n ey , 1 u te ru s an d t h yr o id , 2  m el an o m a, 1 u ri n ar y b la d d er ,1 m et as ta ti c sc c , 1  p ro st at e 5 f , 9 m (a ge n /r ) 3 0 m g b id n /r n /r d ia rr h ea , h ea d ac h e (3 p at ie n ts , d is c. a p r ), u ri n ar y b la d d er c an ce r an d m et as ta ti c sc c r ec u rr en ce a ft er a p r d is c. a ra go n -m ig u el 2 0 1 9 [4 8 ] m al ig n an cy h x : 6 , l at en t tu b er cu lo si s: 1 6 , h ep at it is c o r b ( ch ro n ic o r p as t) : 7 n /r n /r n /r n /r n /r n o i n fe ct io n r ea ct iv at io n s t am p o u ra tz i 2 0 1 9 [ 4 9 ] c h ro n ic h ep at it is b , u n d er e n te ca vi r 6 4 , m n /r n /r e x ce ll en t re sp o n se n o n e p ap ad av id 2 0 1 8 [ 5 0 ] m al ig n an cy h x : 1 , l at en t tu b er cu lo si s: 1 , c h ro n ic la te n t h ep at it is b : 1 n /r n /r n /r n /r n /r sa h u q u il lo -t o rr al b a 2 0 2 0 [ 5 1 ] l at en t tu b er cu lo si s: 1 , a ct iv e h ep at it is b : 1 , sp o n ta n eo u s b ac te ri al p er it o n it is : 1 , i m m u n e h ep at it is : 1 n /r n /r n /r n /r n /r si ci li an o 2 0 2 0 [ 5 2 ] m et as ta ti c m el an o m a (2 0 1 8 ) 7 5 , m 3 0 m g b id n /r im p ro ve m en t n o n e, m el an o m a re m is si o n l an n a 2 0 2 0 [ 5 3 ] t u m o rs : 5 n /r n /r n /r n /r n /r l an n a 2 0 1 9 [ 5 4 ] h ep at it is e 5 5 , m 3 0 m g b id 1 8 pa si 9 0 m 6 n o n e b al at o 2 0 2 0 [ 5 5 ] m al ig n an cy : 4 0 n /r n /r n /r n /r l o w er p a si 5 0 a n d p a si 7 5 r es p o n se ra te s q u ei ro s il va 2 0 2 0 [ 2 1 ] h ai ry c el l le u k em ia 5 5 , m n /r n /r n /r se ve re c o v id -1 9 i n fe ct io n ig h an i 2 0 1 8 ( 1 ) [5 6 ] m al ig n an cy h x : 1 5 , l iv er d is ea se : 8 , p sy ch ia tr ic d is o rd er : 9 n /r n /r n /r n /r n /r ig h an i 2 0 1 8 ( 2 ) [5 7 ] m al ig n an cy h x : 3 1 , l iv er d is ea se : 2 7 , p sy ch ia tr ic d is o rd er : 2 9 n /r n /r n /r n /r n /r t ab le 2 c o n ti n u es 8 review | dermatol pract concept. 2022;12(4):e2022179 r e p o rt c o m o rb id it y a g e /s e x a p r d o se b a s pa s i t x o u tc o m e a e s ig h an i 2 0 1 8 ( 3 ) [5 8 ] m al ig n an cy h x : 5 , l iv er d is ea se : 4 , p sy ch ia tr ic d is o rd er : 4 n /r n /r n /r n /r n /r p h an 2 0 2 0 [ 5 9 ] m al ig n an cy : 4 0 > 6 5 y n /r n /r n /r n /r ig h an i 2 0 1 8 ( 4 ) [6 0 ] h ep at it is c : 2 , b re as t ca n ce r: 2 , r en al d is ea se (u n sp ec ifi ed ): 2 n /r n /r n /r n /r n /r m eg n a 2 0 2 0 [ 6 1 ] m al ig n an cy : 9 , h ep at it is c : 4 , l at en t tu b er cu lo si s: 3 n /r n /r n /r n /r n /r d el a lc áz ar 2 0 2 0 [ 6 2 ] l u n g ca n ce r: 2 0 , l at en t tu b er cu lo si s: 2 0 , h ep at it is c : 1 7 , h ep at it is b : 1 3 , h ep at it is b a n d c : 2 , m al ig n an cy h x : 9 2 , l iv er d is ea se : 3 3 n /r n /r n /r n /r n o c as es o f in fe ct io n r ea ct iv at io n o r ca n ce r re cu rr en ce f re m li n 2 0 1 7 [ 6 3 ] c as es o f al co h o l ex ce ss , a lc o h o li c li ve r d is ea se , p re vi o u s m al ig n an cy ( u n sp ec ifi ed n u m b er ) n /r n /r n /r n /r n /r f o u lk es 2 0 1 7 [ 6 4 ] c as es o f m al ig n an t m el an o m a an d h iv ( u n sp ec ifi ed n u m b er ) n /r n /r n /r n /r n /r m al ar a 2 0 1 8 [ 6 5 ] l at en t tu b er cu la r sk in i n fe ct io n : 2 , p re vi o u s h ep at it is : 1 , e n d o ca rd it is -r el at ed c ar d ia c va lv e fa il u re : 1 , m al ig n an cy : 4 n /r n /r n /r n /r n o n e d au d én 2 0 2 0 [ 1 4 ] m al ig n an cy h x : 1 4 ( 6 i n l as t 5 y ea rs ), h ep at it is b :1 2 , h ep at it is c : 5 , c h ro n ic l iv er d is ea se : 2 0 , r en al in su ffi ci en cy : 3 n /r n /r n /r n /r n /r k u n gu ro v 2 0 1 9 [ 6 6 ] h ep at it is b : 1 , c h ro n ic p an cr ea ti ti s, c h o le cy st it is an d c o li ti s: 1 , h ep at it is c : 1 4 7 , f 3 8 , f 3 1 , m n /r 2 7 .3 2 9 .9 3 3 pa si 7 5 w 2 4 pa si 7 5 w 6 pa si 7 5 w 2 8 n o n e a ra go n -m ig u el 2 0 1 9 [6 7 ] b re as t ca n ce r: 1 , g al lb la d d er c an ce r: 1 , t re at ed la te n t tu b er cu lo si s: 3 n /r n /r n /r n /r n /r b u li c 2 0 1 9 [ 6 8 ] 1 . l ar yn ge al s c c ( 2 0 1 3 ) 2 . p ap il la ry t h yr o id c an ce r (2 0 1 4 ) 3 . l iv er c ir rh o si s (c h il d -p u gh b )/ p o rt al h yp er te n si o n / h ep at o ce ll u la r ca n ce r (p t 2 p n x p m x )/ li ve r tr an sp la n t (2 0 1 7 ) 4 . m el an o m a (p t 1 a, b re sl o w 0 .8 1 m m ) (2 0 1 3 ) 5 1 , m 5 0 , m 5 1 , m 5 8 , f n /r n /r n /r n o r ec u rr en cy o f m al ig n an cy o ve r a tw o -y ea r fo ll o w -u p f at to re 2 0 1 9 [ 6 9 ] n o n -m et as ta ti c n o n -s m al lce ll l u n g ca n ce r u n d er n iv o lu m ab 7 4 , f 3 0 m g b id n /r pa si 1 0 0 w 6 t ra n si en t n au se a m ag d al en o 2 0 1 9 [ 7 0 ] c h ro n ic l iv er d is ea se : 1 3 , s ev er e in fe ct io n : 1 1 , p re vi o u s m al ig n an cy : 8 n /r n /r n /r n /r n /r ta b le 2 . l it er at u re c as es o f ap re m il as t ad m in is te re d t o p so ri as is p at ie n ts w it h s er io u s b as el in e co m o rb id it ie s. ( co n ti n u ed ) review | dermatol pract concept. 2022;12(4):e2022179 9 r e p o rt c o m o rb id it y a g e /s e x a p r d o se b a s pa s i t x o u tc o m e a e s m ag d al en o -t ap ia l 2 0 1 9 [7 1 ] c h ro n ic a ct iv e al co h o li sm a n d h yp er -t ra n sa m in as em ia 6 1 , m n /r n /r n a p si 3 2 pa si < 5 m 6 n o s er io u s a e s g io e 2 0 2 1 [ 7 2 ] c h ro n ic h ep at it is b , b ip o la r d is o rd er , a cu te m r sa ee b ac te re m ia , p u lm o n ar y em b o lu s 3 4 , f n /r n /r ( > 9 5 % b sa ) b sa < 1 5 % m 1 n /r ib ar gu re n 2 0 2 1 [ 7 3 ] 1 . s ta ge i v u ve al m el an o m a 2 . s ta ge i v l ar yn ge al c ar ci n o m a 3 . s ta ge i v s q u am o u s ce ll l u n g ca rc in o m a al l 3 u n d er n iv o lu m ab 5 0 , m 7 0 , m 6 0 , m 3 0 m g b id 1 2 1 3 .8 6 .4 pa si 5 0 m 1 2 pa si 7 5 ( ti m e n /r ) pa si 5 0 n o t ac h ie ve d 1 . d ia rr h ea 2 . h ea d ac h e, c an ce r p ro gr es si o n a ft er 1 0 m o n th s 3 . c an ce r p ro gr es si o n a ft er 1 0 m o n th s k u ra ta 2 0 2 1 [ 7 4 ] c o lo re ct al c an ce r w it h in p as t ye ar 8 2 , f n /r 5 .5 n a p si 7 7 pa si 9 0 a n d n a p si 5 0 w 8 γg t i n cr ea se a ft er 8 w ee k s & d ru g d is c. c o h en -s o rs 2 0 2 1 [ 1 3 ] h em at o lo gi c m al ig n an cy : 1 0 n /r n /r n /r n /r e vo lu ti o n o f p re vi o u sl y st ab le c l l (1 c as e) a e s = a d ve rs e ev en ts ; a p r = a p re m il as t; b as = b as el in e; b id = t w ic e d ai ly ; b sa = b o d y su rf ac e ar ea ; f = f em al e; c l l = c h ro n ic l ym p h o cy ti c le u k em ia ; d is c. = d is co n ti n u at io n ; h b v = h ep at it is b v ir u s; h c c  =   h ep at o ce ll u la r ca rc in o m a; h c v = h ep at it is c v ir u s; h iv = h u m an i m m u n o d ef ic ie n cy v ir u s; h x = h is to ry ; l f t s = l iv er f u n ct io n t es ts ; m = m al e; m = m o n th ; m r sa = m et h ic il li n r es is ta n t st ap h yl o co cc u s au re u s; n a p si = n ai l p so ri as is s ev er it y in d ex ; n m sc = n o n -m el an o m a sk in c an ce r; n /r = n o t re p o rt ed ; o d = o n ce d ai ly ; p a si = p so ri as is a re a an d s ev er it y in d ex ; p a si 5 0 = 5 0 % r ed u ct io n o f b as el in e pa si ; p a si 7 5 = 7 5 % r ed u ct io n o f b as el in e pa si ; pa si 9 0 = 9 0 % r ed u ct io n o f b as el in e pa si ; pa si 1 0 0 = 1 0 0 % r ed u ct io n o f b as el in e pa si ; p ss i = p so ri as is s ca lp s ev er it y in d ex ; sc c = s q u am o u s ce ll c ar ci n o m a; t x  =  t re at m en t; y = y ea rs o ld ; u r t is = u p p er r es p ir at o ry t ra ct i n fe ct io n s; w = w ee k . 10 review | dermatol pract concept. 2022;12(4):e2022179 ta b le 3 . m et h o d o lo gi ca l q u al it y as se ss m en t o f in cl u d ed r ep o rt s. r e p o rt m u g h e d d u 2 0 2 0 [2 2 ] m a n fr e d a 2 0 1 9 [ 1 5 ] z a rb a fi a n 2 0 1 9 [ 5 ] r e d d y 2 0 1 7 [4 ] s h a h 2 0 1 9 [1 8 ] s a cc h e ll i 2 0 1 8 [ 3 2 ] a p a ll a 2 0 1 9 [1 1 ] r e d d y 2 0 1 9 [1 7 ] fo ti a d o u 2 0 1 8 [ 3 3 ] je o n 2 0 1 7 [3 4 ] q u al it y f ai r f ai r f ai r f ai r f ai r f ai r f ai r f ai r f ai r f ai r r ep o rt g o n za le zc an te ro 2 0 1 8 [ 3 5 ] g o tt li eb 2 0 2 1 [3 6 ] k ah n 2 0 1 9 [3 7 ] n ag at a 2 0 1 9 [3 8 ] u va is 2 0 2 0 [3 9 ] v ic o -a lo n so 2 0 2 0 [ 4 0 ] m el is 2 0 2 0 [4 1 ] p er ro n e 2 0 1 7 [4 2 ] c ar p en ti er i 2 0 2 0 [ 4 3 ] p ei ts ch 2 0 1 9 [4 4 ] q u al it y g o o d g o o d g o o d g o o d g o o d f ai r g o o d f ai r g o o d f ai r r ep o rt t ak am a 2 0 2 0 [ 4 5 ] f o ti 2 0 2 1 [ 4 6 ] d i l er n ia 2 0 2 1 [ 4 7 ] a ra go n m ig u el 2 0 1 9 [4 8 ] t am p o u ra tz i 2 0 1 9 [ 4 9 ] p ap ad av id 2 0 1 8 [ 5 0 ] sa h u q u il lo t o rr al b a 2 0 2 0 [5 1 ] si ci li an o 2 0 2 0 [5 2 ] l an n a 2 0 2 0 [5 3 ] l an n a 2 0 1 9 [5 4 ] q u al it y f ai r f ai r g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d r ep o rt b al at o 2 0 2 0 [ 5 5 ] q u ei ro s il va 2 0 2 0 [ 2 1 ] ig h an i 2 0 1 8 (1 ) [5 6 ] ig h an i 2 0 1 8 (2 ) [5 7 ] ig h an i 2 0 1 8 (3 ) [5 8 ] p h an 2 0 2 0 [5 9 ] ig h an i 2 0 1 8 (4 ) [6 0 ] m eg n a 2 0 2 0 [6 1 ] d el a lc az ar 2 0 2 0 [ 6 2 ] f re m li n 2 0 1 7 [6 3 ] q u al it y g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d r ep o rt f o u lk es 2 0 1 7 [ 6 4 ] m al ar a 2 0 1 8 [6 5 ] d au d én 2 0 2 0 [1 4 ] k u n gu ro v 2 0 1 9 [ 6 6 ] a ra go n m ig u el 2 0 1 9 [6 7 ] b u li c 2 0 1 9 [6 8 ] f at to re 2 0 1 9 [6 9 ] m ag d al en o 2 0 1 9 [ 7 0 ] m ag d al en o t ap ia l 2 0 1 9 [7 1 ] g io e 2 0 2 1 [7 2 ] q u al it y g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d g o o d r ep o rt ib ar gu re n 2 0 2 1 [7 3 ] k u ra ta 2 0 2 1 [7 4 ] c o h en -s o rs 2 0 2 1 [ 1 3 ] q u al it y g o o d g o o d g o o d c as e re p o rt s h av e b ee n a ss es se d t h ro u gh t h e jb i cr it ic al a p p ra is al c h ec k li st f o r ca se r ep o rt s. c ro ss -s ec ti o n al s tu d ie s h av e b ee n a ss es se d t h ro u gh t h e n ih q u al it y as se ss m en t to o l fo r o b se rv at io n al c o h o rt a n d cr o ss -s ec ti o n al s tu d ie s. e ac h r ep o rt h as b ee n a ss ig n ed a n o ve ra ll q u al it y m ar k in g o f p o o r, go o d o r fa ir . review | dermatol pract concept. 2022;12(4):e2022179 11 small molecules like apremilast are thought to be immunosuppressed [6]. there have been reports of asymptomatic, as well as of fast and uneventful resolution of covid-19 infections in psoriasis patients under apremilast, even in the case of serious comorbidities [21-23 ]. what is more, it seems that apremilast use does not hinder the formation of antibodies against sars-cov-2 [6]. it is important to remember that common apremilast aes like taste alteration and gastrointestinal symptoms can mimic covid-19 manifestations [6]. a relatively new, special population of psoriatic patients are those receiving therapy with immune checkpoint inhibitors (icpis) for various types of cancer. icpis have revolutionized cancer treatment and their use expands constantly. they include monoclonal antibodies that target cytotoxic t lymphocyte–associated antigen-4 (ctla-4), programmed cell death protein 1 (pd-1), or programmed death ligand 1  (pd-l1) [24]. due to the unique nature of icpis, a new category of aes emerged concurrently with their clinical use  [24]. they are known as ‘‘immune-related adverse events’’ (iraes) and although they can affect any organ, skin is the one most frequently involved [24]. morbilliform exanthems, pruritus, vitiligo and lichenoid eruptions are by far the most common cutaneous iraes [25,26]. numerous others have been reported, among which newly occurring or exacerbating previous psoriasis. in the majority of cases, cutaneous iraes are mild-to moderate (grade 1-2) and anti-cancer treatment is not interrupted, although severity may vary, up to life-threatening stevens-johnson syndrome/toxic epidermal necrolysis [27,28]. similarly, psoriasis is usually managed with topical treatment [24,29]. in moderate/severe cases, treatment is more complicated since immunosuppression by anti-psoriatic drugs can theoretically lead to tumor escape. in those patients, apremilast seems to be a relatively safe and effective choice, however its use is supported only by case reports/ small case series. finally, an algorithm published recently by the encado (european network for cutaneous adverse event to oncologic drugs) also suggests apremilast if the patient does not respond to phototherapy and/or acitretin [30]. our study is not without its limitations. a few large studies like armstrong and levi were excluded from this review and potentially significant data was missed, because results were not reported separately for patients receiving apremilast monotherapy and those receiving combination treatment or other systemic agents [31]. on the other hand, it is fairly possible that some patients included in this review have been counted more than once, as they might have been sourced from the same databases or research centers (eg  multiple publications by the same authors, table 2). what is more, in studies reporting on multiple patients, efficacy and safety outcome measures were usually presented indistinguishably for all included patients and not individually, based on the comorbidity status, therefore the relevant fields of table 2 could not be filled in. last but not least, baseline comorbidity cases such as chronic infections were sometimes presented as a total number, without distinguishing among different types of eg infections. all in all, according to this case series and systematic review, real-life use of apremilast so far suggests that the latter is indeed a safe and adequately efficacious option for moderate-to-severe psoriasis that cannot be treated/ is challenging to treat with classic systemic agents and/or biologics. what is more, there seems to be no increased risk of covid-19 infection in patients receiving apremilast, with evidence suggesting a smoother course of the disease. references 1. gottlieb ab, strober b, krueger jg, et al. an open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. curr med res opin. 2008;24(5):1529–1538. doi:10.1185/030079908x301866. pmid: 18419879. 2. shutty b, west c, pellerin m, feldman s. apremilast as a treatment for psoriasis. expert opin pharmacother. 2012;3(12): 1761-1770. doi: 10.1517/14656566.2012.699959. pmid: 22712800. 3. palfreeman ac, mcnamee ke, mccann fe. new developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast. drug des devel ther. 2013;7:201-210. doi: 10.2147/ dddt.s32713. pmid: 23569359. pmcid: pmc3615921. 4. reddy sp, shah v v., wu jj. apremilast for a psoriasis patient with hiv and hepatitis c. j eur acad dermatol venereol. 2017;31(11):e481–e482. doi:10.1111/jdv.14301. pmid: 28449227. 5. zarbafian m, cote b, richer v. treatment of moderate to severe psoriasis with apremilast over 2 years in the context of long-term treated hiv infection: a case report. sage open med case rep. 2019;7:2050313x1984519. doi:10.1177/2050313x19845193. pmid: 31105941. pmcid: pmc6503584. 6. pacifico a, d’arino a, pigatto pdm, malagoli p, young d, damiani g. covid-19 vaccines do not trigger psoriasis flares in patients with psoriasis treated with apremilast. clin exp dermatol. 2021;46(7):1344–1346. doi:10.1111/ced.14723. pmid: 33969530. pmcid: pmc8239919. 7. piaserico s, messina f, russo fp. managing psoriasis in patients with hbv or hcv infection: practical considerations. am j clin dermatol. 2019;20(6):829–845. doi:10.1007/s40257-01900457-3. pmid: 31222626. 8. paul c, cather j, gooderham m, et al. efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase iii, randomized controlled trial (esteem 2). br j dermatol. 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half-dose of apremilast. eur j dermatol. 2019;29(3):341-342. doi: 10.1684/ ejd.2019.3588. pmid: 31389793. 39. uvais na, rakhesh s v., afra tp, hafi nab, razmi t m. comorbid psoriasis-bipolar disorder successfully treated with apremilast: much more than a mere coincidence? gen psychiatr. 2020;33(3):e100181. doi: 10.1136/gpsych-2019-100181. pmid: 32524074. pmcid: pmc7245448. 40. vico-alonso c, sánchez-velázquez a, pinilla-martin b, et al. psoriasis and chronic myeloid leukemia: treatment with apremilast. int j dermatol. 2020;59(4):e102-e103. doi: 10.1111/ ijd.14598. pmid: 31347142. 41. melis d, mugheddu c, sanna s, atzori l, rongioletti f. clinical efficacy, speed of improvement and safety of apremilast for the treatment of adult psoriasis during covid-19 pandemic. dermatol ther. 2020;33(4):e13722. doi: 10.1111/dth.13722. pmid: 32475036. pmcid: pmc7300475. 42. perrone d, afridi f, king-morris k, komarla a, kar p. proximal renal tubular acidosis (fanconi syndrome) induced by apremilast: a 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(2017), bristol cup posters. br j dermatol, 177: 25-77. doi: 10.1111/bjd.15426 65. malara g, micelli gf, arceri f. is apremilast a promising treatment for psoriasis and psoriatic arthritis? j am acad dermatol. 2018;79:ab171. doi:10.1016/j.jaad.2018.05.699. 66. kungurov nv, zilberberg nv, kokhan mm, keniksfest jv, grishaeva ev. experience in the treatment of psoriasis patients using apremilast, a selective signalling pathway inhibitor. vestn dermatol venerol. 2019;94:67–76. 67. aragon-miguel r, calleja‐algarra a, andres-lencina j, et al. generalized and palmoplantar pustular psoriasis and acrodermatitis continua of hallopeau: a case series of 8 patients treated with apremilast. in: 28th eadv congress. 2019.p1758. 68. bulic s, dediol i. apremilast in psoriasis patients with a history of malignancy case series. in: 28th eadv congress. 2019.p1682. 69. fattore d, annunziata mc, panariello l, marasca c, fabbrocini g. successful treatment of psoriasis induced by dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022225 1 yellow urticaria teresa kränke1, birger kränke1 1 department of dermatology, medical university of graz, graz, austria citation: kränke t, kränke b. yellow urticaria. dermatol pract concept. 2022;12(4):e2022225. doi: https://doi.org/10.5826/ dpc.1204a225 accepted: march 29, 2022; published: october 2022 copyright: ©2022 kränke et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: prof. birger kränke, md, department of dermatology, medical university of graz, auenbruggerplatz 8, 8036 graz, austria. phone: +43 31638512204 e-mail: birger.kraenke@medunigraz.at case presentation a 51-year-old patient with metastatic colorectal cancer, treated with dabrafenib, trametinib and cetuximab, presented with the acute onset of yellowish skin lesions. on clinical examination, multiple itching, intense yellowish skin swellings on the trunk and extremities were observed. the unaffected skin, however, was not icteric, contrary to the sclerae (figure 1 a-c). besides marked leukocytosis and elevated liver function parameters (ggt 708 u/l, got 80 u/l, gpt 52 u/l) laboratory investigations revealed a markedly increased serum bilirubin level (9.55  mg/dl; 0.1-1.2). our patient suffered from acute urticaria with wheals appearing yellowish due to marked elevated serum bilirubin. an association with the aforementioned drugs in our case is likely, but urticaria may also be induced by an inflammatory process in a patient suffering from cancer. the lesions resolved within a few days under antihistamine treatment, and the skin color of the previous prominent yellowish lesions adapted to that of the surrounding skin. due to his underlying disease, the patient died a few weeks later. teaching point novel therapies like checkpoint-inhibitors or immuno oncological agents revolutionized treatment in several advanced malignancies. consequently, a broad spectrum of adverse events in different degrees of severity can occur at any time of therapy, even after cessation of treatment. urticaria is a very common skin disease; yellow urticaria, however, is a seldom and unusual variant and to date no more than ten cases are reported since the first report in 1969 and all hitherto reported cases have a hyperbilirubinemia as definitive cause in common [1,2]. references 1. pollack mh, betof a, dearden h, et al. safety of resuming anti-pd-1 in patients with immuni-related adverse events (iraes) during combined anti-ctla-4 and anti-pd1 in metastatic melanoma. ann oncol. 2018;29(1):250-255. doi: 10.1093/annonc/ mdx642. pmid: 29045547. pmcid: pmc5834131. 2. combalia a, fustá x, guilabert a, mascaró jm jr, estrach t. hyperbilirubinaemia: the common denominator of yellow urticaria. j eur acad dermatol venereol. 2017;31(12):e533. doi: 10.1111/jdv.14397. pmid: 28609589. 2 image letter | dermatol pract concept. 2022;12(4):e2022225 figure 1. (a) clinical image showing the left arm with multiple yellowish skin swellings. (b) close up. (c)yellow-colored sclerae. dermatology: practical and conceptual 60 title | dermatol pract concept 2017;7(3):# dermatology practical & conceptual www.derm101.com case presentations a 31-year-old hiv positive male presented with a two-year history of a slowly growing, 2 cm, asymptomatic, solitary blue-gray nodular lesion on dorsum of right foot (figure 1a). dermoscopic examination revealed a well-circumscribed lesion with homogenous blue-grayish globular pattern, scaly surface and striking color changes of yellow, green, purple and pink resembling the colors of a rainbow centrally in polarized dermoscopy (figure 2a [dermlite 4, 3gen, san juan capistrano, ca]). the lesion was completely excised with 3 mm clear margins, and histopathological examination was consistent with blue nevus (figures 3, 4). a 59-year-old male presented with a five-year history of a 2 cm, black nevus on his right foot, which was disturbing while walking with no history of changing (figure 1b). he was healthy and had no complaint from this lesion. dermoscopic examination revealed a wellcircumscribed blue-gray lesion and striking color changes of yellow, green, purple and pink resembling the colors of a rainbow centrally in polarized dermoscopy (figure 2b). his lesion was completely excised, and histopathological examination revealed heavily pigmented melanocytes in dermis. dermoscopic rainbow pattern in blue nevus tuğba k. uzunçakmak1, seyma ozkanli2, ayşe serap karadağ1 1 department of dermatology, istanbul medeniyet university, goztepe research and training hospital, istanbul, turkey 2 department of pathology, istanbul medeniyet university, goztepe research and training hospital, istanbul, turkey key words: blue nevus, dermoscopy, rainbow pattern citation: uzunçakmak t, ozkanli s, karadağ as. dermoscopic rainbow pattern in blue nevus. dermatol pract concept 2017;7(3):13. doi: https://doi.org/10.5826/dpc.0703a13 received: april 14, 2017; accepted: may 27, 2017; published: july 31, 2017 copyright: ©2017 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: tugba kevser uzuncakmak, md, specialist, department of dermatology, istanbul medeniyet university, goztepe research and training hospital, istanbul, turkey. tel. +90(530) 6640226. e-mail: drtugbakevser@gmail.com figure 1. (a) a 2 cm, asymptomatic, solitary blue-grayish nodule on dorsum of right foot. (b) a 2 cm, solitary blue-gray nodule on dorsum of left foot. [copyright: ©2017 uzuncakmak et al.] mailto:drtugbakevser@gmail.com observation | dermatol pract concept 2017;7(3):13 61 rainbow pattern is a metaphoric term, which was first described by hu et al as a multicolored dermoscopic feature in which all or part of a lesion contains areas of various colors simulating colors of the rainbow that correspond to polychromatic lines dermoscopically and does not have a distinct histological correlation [2,3]. varying absorption and reflection of light seems to result in polychromatic appearance. early on this pattern was thought be a specific diagnostic pattern for kaposi sarcoma; however, it was reported in non-kaposi sarcoma lesions such as melanoma, basal cell carcinoma, atypical fibroxanthoma, angiokeratoma, scar tissue, stasis dermatitis and lichen planus [4-6]. discussion blue nevi are benign, congenital or acquired, dermal dendritic melanocytic proliferations that present as solitary or multiple, firm blue, blue-gray, or blue brown colored papules, nodules, or plaques [1]. dermoscopic appearance is commonly characterized by global patterns such as homogeneous bluish or steel-blue grayish pigmentation without any other dermoscopic pattern being reported [1]. vascular structures are not commonly seen in blue nevi, but in some case series vascular structures such as polymorphic, dotted, comma, linear irregular, and arborizing vessels have been reported with significant association with the multichromatic global pattern [1]. in our patient we did not observe any vascular structures in dermoscopic examination. figure 2. (a) dermoscopically homogenous blue-grayish globular pattern, scaly surface and striking color changes of yellow, green, purple and pink resembling the colors of a rainbow centrally. (b) homogenous blue-grayish pattern without any vascular structures and yellow, green, purple and pink circles all over the lesion. [copyright: ©2017 uzuncakmak et al.] figure 3. complete excision of tumoral lesion. [copyright: ©2017 uzuncakmak et al.] figure 4. heavily pigmented melanocytes with dendritic processes the reticular dermis between collagen bundles (h&e x4). [copyright: ©2017 uzuncakmak et al.] the rainbow pattern was previously reported to be associated with the vascular structure of a lesion, due to presence of this pattern in different types of skin lesions with increased vascularization, such as kaposi sarcoma with a specificity of 100%, pyogenic granuloma and scars [2,6]. indeed, the rainbow pattern is accepted as a more complex physical phenomenon in which polarized light interacts with various elements in different skin structures as it passes through tissue not only vascular structures in the skin. while cheng et al claimed that the light beam is diffracted as it penetrates the dermis, vázquez-lópez et al highlighted the term of dichroism in which light in different states of polarization 62 observation | dermatol pract concept 2017;7(3):13 2. hu sc, ke cl, lee ch, wu cs, chen gs, cheng st. dermoscopy of kaposi’s sarcoma: areas exhibiting the multicoloured ‘rainbow pattern’. j eur acad dermatol venereol. 2009;23:1128-1132. 3. cheng st, ke cl, lee ch, wu cs, chen gs, hu sc. rainbow pattern in kaposi’s sarcoma under polarized dermoscopy: a dermoscopic pathological study. br j dermatol. 2009;160:801-809. 4. vázquez-lópez f, garcía-garcía b, rajadhyaksha m, marghoob aa. dermoscopic rainbow pattern in non-kaposi sarcoma lesions. br j dermatol. 2009;161:474-475. 5. pinos león vh, granizo rubio jd. acral pseudolymphomatous angiokeratoma of children with rainbow pattern: a mimicker of kaposi sarcoma. j am acad dermatol. 2017;76:s25-s27. 6. pérez-pérez l, garcía-gavín j, allegue f, zulaica a. the rainbow pattern and rosettes in cutaneous scars. actas dermosifiliogr. 2014;105:96-97. reaches variable degrees of absorbance and retardance and it interacts with the components of the tissue leading to different colors, as seen in our patient [3,4,6]. dermoscopic rainbow pattern in blue nevus is another sample of the interaction of light with different structures in the skin except for vascular lesions. with the common use of polarized dermoscopy, dermoscopic rainbow pattern will be observed in various skin lesions. references 1. di cesare a, sera f, gulia a, et al. the spectrum of dermatoscopic patterns in blue nevi. j am acad dermatol. 2012;67:199-205. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual & educational notes | dermatol pract concept 2013;3(4):9 37 clinical findings a 57-year-old man presented with a solitary flat pigmented lesion on his face, which had appeared two years previously and was slowly enlarging over time. physical examination revealed a flat pigmented lesion, 8 mm in size, on the patient’s right cheek. the clinical diagnosis was suggestive of a solar lentigo (sl) because of the symmetric shape, the regular border, and the homogenous brown color (figure 1). pigmented actinic keratosis (pak) and lentigo maligna (lm) were also included in the differential diagnosis. dermoscopically, the lesion exhibited a brown pseudonetwork and a striking gray color, especially in the center (figure 2). there were large gray circles that resembled rhomboidal structures, though unconvincingly, in the absence of the well-known clues for the diagnosis of lm. however, the presence of gray color, asymmetrically distribthe importance of gray color as a dermoscopic clue in facial pigmented lesion evaluation: a case report danica tiodorovic-zivkovic1, iris zalaudek2,3, aimilios lallas2, alexander j. stratigos4, simonetta piana5 giuseppe argenziano2 1 clinic of dermatovenerology, clinical center of nis, medical faculty, university of nis, serbia 2 skin cancer unit, arcispedale santa maria nuova, irccs, reggio emilia, italy 3 department of dermatology, medical university of graz, graz, austria 4 dermato-oncology unit, department of dermatology, university of athens medical school, andreas sygros hospital, athens, greece 5 unit of anatomic pathology, arcispedale santa maria nuova irccs, reggio emilia, italy key words: melanoma, lentigo maligna, solar lentigo, dermoscopy citation: tiodorovic-zivkovic d, zalaudek i, lallas a, stratigos aj, piana s, argenziano g. the importance of gray color as a dermoscopic clue in facial pigmented lesion evaluation: a case report. dermatol pract conc. 2013;3(4):9. http://dx.doi.org/10.5826/dpc.0304a09. received: may 20, 2013; accepted: july 17, 2013; published: october 31, 2013 copyright: ©2013 tiodorovic-zivkovic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: study supported in part by the italian ministry of health (rf-2010-2316524). competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: giuseppe argenziano, m.d., skin cancer unit, arcispedale santa maria nuova irccs, viale risorgimento 80—42100 reggio emilia, italy. tel. +39 335 415093; fax. e-mail: g.argenziano@gmail.com figure 1. clinical image of solitary flat pigmented lesion on the face. [copyright: ©2013 tiodorovic-zivkovic et al.] 38 practical, conceptual & educational notes | dermatol pract concept 2013;3(4):9 includes sl or early seborrheic keratosis (sk), pak, lm and lichen planus-like keratosis (lplk) [1]. especially in the context of early lesions, clinical characteristics can be insufficient to allow differentiation among these entities, since they all present as flat pigmented lesions typically developing on sundamaged skin of elderly individuals. in contrast to their clinical similarity, these entities significantly differ in their physical course, prognosis and management strategies. accordingly, accurate discrimination among them is mandatory. dermoscopy improves the diagnostic accuracy when evaluating pigmented skin lesions and is nowadays considered an irreplaceable part of clinical examination of skin tumors [2]. however, evaluation of pigmented facial lesions remains challenging, even with the addition of dermoscopic information [3,4]. the traditional dermoscopic criteria of lm include asymmetrically pigmented follicles, circle within the circle, annulargranular pattern, rhomboidal structures, obliteration of the hair follicles and gray pseudo-network [5,6]. darkening at dermoscopic examination, target-like pattern, red rhomboidal structures and increased density of the vascular network are recently described additional features [7]. dermoscopy of a large-size lm typically reveals several of the above criteria, allowing a straightforward diagnosis. however, at earlier stages, such as the lm presented herein, dermoscopic criteria of lm have not yet fully developed. in such cases, clinical differentiation from benign pigmented lesions remains troublesome even when coupled with dermoscopy. this is because each of the classic lm criteria may also be present in sl/early sk and pak, and only the simultaneous presence of four or more criteria has been shown to predict accurately the diagnosis of melanoma. interestingly, all the classic lm criteria have a common denominator, namely, the gray color. the example of the patient presented here highlights that grey color can be detected even before the formation of the characteristic lm structures, such as circles or rhomboids. in our estimation, this is the single most sensitive feature for the dermoscopic recognition of early facial melanoma and its presence should always prompt the clinician to perform a biopsy. learning points • clinical differentiation of early lm from solar lentigo/ early seborrheic keratosis and pigmented actinic keratosis is challenging. dermoscopy may enhance the clinical diagnosis, but in small sized lm the typical diagnostic criteria could be not yet fully developed. • in our estimation, gray color is the single most sensitive feature for the dermoscopic recognition of facial melanoma and its presence should always prompt the clinician to perform a biopsy. uted, prompted us to perform a punch biopsy and a histopathologic examination. histopathological findings histopathologically, the lesion was characterized by a junctional proliferation of atypical melanocytes with pleomorphic nuclei, as solitary units that displayed crowding and uneven distribution, along with presence of junctional nests of melanocytes. in addition, melanocytes were seen in pagetoid spread. marked solar elastosis was present within the underlying dermis (figure 3). diagnosis melanoma in situ (lentigo maligna type) on chronically sun damaged skin. discussion the differential diagnosis of flat pigmented macules on chronically sun-damaged facial skin is challenging and figure 2. dermoscopic examination of the lesion showed striking gray color. [copyright: ©2013 tiodorovic-zivkovic et al.] figure 3. histopathologic examination revealed an early lentigo maligna. [copyright: ©2013 tiodorovic-zivkovic et al.] practical, conceptual & educational notes | dermatol pract concept 2013;3(4):9 39 4. schiffner r, perusquia am, stolz w. one-year follow-up of a lentigo maligna: first dermoscopic signs of growth. br j dermatol. 2004;151(5):1087-9. 5. stolz w, schiffner r, burgdorf wh. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002;20(3):276-8. 6. tanaka m, sawada m, kobayashi k. key points in dermoscopic differentiation between lentigo maligna and solar lentigo. j dermatol. 2011;38(1):53-8. 7. pralong p, bathelier e, dalle s, et al. dermoscopy of lentigo maligna melanoma: report of 125 cases. br j dermatol. 2012;167(2):280-7. references 1. akay bn, kocyigit p, heper ao, erdem c. dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. br j dermatol. 2010;163(6):1212-7. 2. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068-73. 3. stante m, giorgi v, stanganelli i, alfaioli b, carli p. dermoscopy for early detection of facial lentigo maligna. br j dermatol. 2005;152(2):361-4. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):14 71 dermatology practical & conceptual www.derm101.com case presentation a 71-year-old caucasian man with neurofibromatosis type 1 (nf1) attended our skin cancer clinic for routine dermatooncologic follow up of primary multiple minimal invasive melanomas (melanoma stage ia) diagnosed during the past eight years. physical examination revealed the presence of numerous neurofibromas and café au lait spots on his trunk and limbs, as well as axillary freckles. in addition, a light brown nodule with a pinkish halo of 8 mm in diameter was noticed at the left lumbar region (figures 1, 2). although this lesion was clinically unremarkable, it differed somehow from the surrounding other nodules (i.e., revealing the so-called “little red riding hood sign”) [1]. upon dermoscopy, the central nodular part revealed brown-gray rhomboidal lines and white lines, whereas the pink halo exhibited small diameter, polymorphic microvessels and white crossing lines (figure 3). based on the dermoscopic appearance, as well as on the history of multiple primary melanomas, a clinical diagnosis of melanoma was suspected. the lesion was subsequently excised. histopathological evaluation confirmed the clinical suspect of a focally hypomelanotic melanoma detected by the “little red riding hood sign” in a patient with neurofibromatosis type 1 roberta giuffrida1, maximilian uranitsch2, karin schmid3, teresa deinlein2, fabrizio favero2, iris zalaudek2 1 department of clinical and experimental medicine, section of dermatology, university of messina, messina, italy 2 department of dermatology and venereology, university of trieste, ospedale maggiore, trieste, italy 3 department of physiology, medical university of graz, graz, austria key words: neurofibromatosis type 1, melanoma, dermoscopy citation: giuffrida r, uranitsch m, schmid k, deinlein t, favero f, zalaudek i. hypomelanotic melanoma detected by the “little red riding hood sign” in a patient with neurofibromatosis type 1. dermatol pract concept 2017;7(4):71-73. doi: https://doi.org/10.5826/ dpc.0704a14 received: july 15, 2017; accepted: august 28, 2017; published: october 31, 2017 copyright: ©2017 giuffrida et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: iris zalaudek, md, department of dermatology and venereology, university of trieste, ospedale maggiore, trieste, 34129, italy. tel. +43.676.33 282 69. email: iris.zalaudek@gmail.com neurofibromatosis type 1 (nf1) is a genetic disorder commonly associated with an increased risk for development of malignancy, including skin cancers. herein we describe a case of invasive melanoma occurring in a patient with nf1 and discuss the association between these two diseases, highlighting the importance of comparative clinical and dermoscopic approaches in this category of patients in which the detection of melanoma can be difficult because of the presence of multiple skin tumors. abstract 72 observation | dermatol pract concept 2017;7(4):14 phic vessels. until future research reveals new insights into a potential common pathogenesis of nf1 and melanoma, we propose close follow-up dermatological visits of patients affected by nf1. references 1. mascaro jm jr, mascaro jm. the dermatologist’s position concerning nevi: a vision ranging from “the ugly duckling” to “little red riding hood.” arch dermatol. 1998 nov;134(11):1484-1485. 2. kiuru m, busam kj. the nf1 gene in tumor syndromes and melanoma. lab invest. 2017 feb;97(2):146-157. regressive invasive melanoma (breslow thickness 1.05 mm, pt2a). imaging staging examinations revealed no evidence for metastases. the patient is currently scheduled for wide local excision and sentinel node biopsy. conclusion neurofibromatosis type 1 (nf1) is an autosomal dominant genetic disorder resulting from a mutation in or a deletion of the nf1 tumor suppressor gene on the long (q) arm of chromosome 17 that encodes a protein named neurofibromin 1 [2]. a mutated form of the latter leads to a predisposition for malignant neoplasms, most commonly derived from the neural crest [3]. melanocytes are derived from embryologic neural crest, so these patients can develop malignant melanocytic proliferations [2,3]. although several sporadic cases of patients with nf1 associated with melanoma have been reported in literature, the relationship between nf1 and melanoma is still a matter of debate [4]. our case supports such an association, given that our patient suffered from seven multiple primary melanomas. moreover, our case highlights the benefit of the comparative approach in patients with multiple skin tumors, as the melanoma in our patient, albeit not evident, differed from the surrounding neurofibromas [5]. finally, dermoscopy pointed towards the correct diagnosis of hypoand amelanotic melanoma by allowing the visualization of melanoma-specific features such as brown-gray lines, white lines and polymorfigure 1. numerous neurofibromas and one café au lait spot on the trunk. the black arrow indicates a light brown nodule with a pinkish halo. [copyright: ©2017 giuffrida et al.] figure 2. close up of the lesion indicated by the black arrow in figure 1. [copyright: ©2017 giuffrida et al.] figure 3. dermoscopy displays brown-gray rhomboidal lines and white lines in the central part of the nodule and small diameter, polymorphic microvessels and white crossing lines in the pink halo; at the borders at 6 and 10 o’clock, two neurofibromas with structureless white to skin-colored areas are seen. [copyright: ©2017 giuffrida et al.] observation | dermatol pract concept 2017;7(4):14 73 other skin manifestations characteristic of nf1. nf1 and cancer. actas dermosifiliogr. 2016 jul-aug;107(6):465-473. 5. gaudy-marqueste c, wazaefi y, bruneu y et al. ugly duckling sign as a major factor of efficiency in melanoma detection. jama dermatol. 2017 apr 1;153(4):279-284. 3. guillot b, dalac s, delaunay m, et al. cutaneous malignant melanoma and neurofibromatosis type 1. melanoma res. 2004 apr;14(2):159-163. 4. hernández-martín a, duat-rodríguez a. an update on neurofibromatosis type 1: not just café-au-lait spots and freckling. part ii. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023085 1 the role of ereg, ptpn1, and serpinb7 genes in the pathogenesis of psoriasis: may serpinb7 be protective and a marker of severity for psoriasis? havva hilal ayvaz1, kuyaş hekimler öztürk2, mehmet ali seyirci1, emrah atay3, selma korkmaz1, i̇jlal erturan1, mehmet yıldırım1 1 department of dermatology, faculty of medicine, suleyman demirel university, isparta, turkey 2 department of medical genetics, faculty of medicine, suleyman demirel university, isparta, turkey 3 public health expertise, eskişehir directorate of health, eskişehir, turkey key words: psoriasis, epiregulin, tyrosine-protein phosphatase non-receptor type 1, serine proteinase inhibitors citation: ayvaz hh, öztürk kh, seyirci ma, et al. the role of ereg, ptpn1, and serpinb7 genes in the pathogenesis of psoriasis: may serpinb7 be protective and a marker of severity for psoriasis? dermatol pract concept. 2023;13(2):e2023085. doi: https://doi .org/10.5826/dpc.1302a85 accepted: september 26, 2022; published: april 2023 copyright: ©2023 ayvaz et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: havva hilal ayvaz, çünür mah sdü dermatology department, 32260, isparta, turkey. e-mail: drhhilalayvaz@gmail.com, phone number: +905309505907 introduction: psoriasis is a chronic inflammatory dermatological disease with complex pathogenesis in which many immune system cells, including keratinocytes, play a role. many genes regulate the proliferation of keratinocytes and other immune cells that have essential roles in the pathogenesis of psoriasis. the expressions of ereg, ptpn1, and serpinb7 genes were shown as upregulated in psoriatic skins in a few studies previously. objectives: we aimed to evaluate the expressions of these genes in psoriatic lesional skin and compared them with non-lesional adjacent skin of the same patients and normal skin of healthy controls. results: our results revealed that the expressions of ereg and ptpn1 genes were upregulated, whereas the serpinb7 gene expression was down regulated in the psoriatic skin of the patients than normal skin of controls. moreover, the expression level of the serpinb7 gene was also negatively correlated with the severity of the disease among patients. conclusions: according to our results, overexpression of ereg and ptpn1 genes, and decreased expression of serpinb7 gene may lead to the development of psoriasis. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023085 introduction psoriasis is an auto-inflammatory dermatological disease with complex pathogenesis, including immunological, biochemical, vascular, and neurological changes [1]. the main pathological findings of psoriasis are the hyperproliferation of epidermis, altered keratinocytes, dermal angiogenesis, a dense epidermal and dermal infiltrate consisting of macrophages, lymphocytes, and neutrophils [2]. keratinocytes are one of the principal cells playing essential roles in the pathogenesis of psoriasis and, many cytokines and chemokines regulate the proliferation of them. the most important signal for proliferation of keratinocytes comes from the epidermal growth factor (egf) receptor, and epiregulin (ereg) is a member of the egf family [3]. serpin family b member 7 (serpinb7) is a cytoplasmic member of the serine protease inhibitor family that can alter the epithelium of the skin, and also protects keratinocytes from oxidative stress-mediated cellular damage [4]. protein tyrosine phosphatase non-receptor type 1 (ptpn1) is a member of the ptp family that has regulatory effects on munc18c protein, which interacts with snare in adipocytes, insulin signaling pathways, and also immunological processes which may also be related to its role in the pathogenesis of psoriasis [5,6]. objectives in the literature, the expression of ereg, ptpn1, and serpinb7 genes have been evaluated in a few studies, and these genes are claimed to be novel susceptible genes for psoriasis especially related to keratinocytes, adipocytes, other immunological cells [2,7-10]. unlike these studies, we investigated all these genes together, at the tissue level, and in more samples. we also compared the genes expressions between lesional skin and non-lesional adjacent skin of patients with psoriasis, and normal skin of healthy controls. methods the present prospective case-control study was performed according to the declaration of helsinki guidelines and approved by the ethics committee of suleyman demirel medical faculty (decision 11 on 16.01.2020). all participants in the study were provided informed consent. study population twenty-five patients diagnosed with psoriasis clinically and histopathologically, aged over 18 and under 65 years, presenting to the dermatology outpatient clinic of suleyman demirel medical faculty between february 2020 and january 2021, were considered for this study. detailed anamnesis was taken, skin examination was performed, and the presence of arthritis or nail involvement was also examined and noted by the same physician. psoriasis area and severity index (pasi) scores were calculated, and according to the pasi scores, patients were divided into two subgroups: a mild disease with pasi score ≤ 10, moderate-severe disease with pasi score > 10 [11]. all participants were selected from patients not treated with systemic therapy, including phototherapy, for at least eight weeks before the study entry. ageand sex-matched 11 healthy volunteers without any systemic inflammatory diseases, including cardiovascular and/or neurovascular diseases, inflammatory skin disorders, and regular drug intake for any reason, were also enrolled as the control group. patients with a history of cardiovascular or cerebrovascular events, active infection, and inflammatory systemic (including diabetes mellitus [dm]) or skin diseases, other autoimmune diseases, and/ or malignancy in the last 5 years were excluded. skin samples, 3 mm in size, were collected from 25 patients with psoriasis and 11 healthy controls. the lesional and non-lesional psoriatic skin (each 3 mm in size) were taken from each patient with psoriasis and one skin sample in similar size from healthy controls. these skin tissues were taken into dnase rnase-free 1.5 ml eppendorf tubes and stored in the refrigerator at -80˚c. mrna extraction and cdna synthesis mrna isolation from tissue samples belonging to the study group was performed with hybrid-rtm mrna isolation kit (geneall biotechnology) according to the manufacturer instructions. the concentration and purity of isolated total mrnas were measured with a thermo fisher nanodroptm spectrophotometer. wizscript™ cdna synthesis kit (wizbio) was used to obtain cdna from the obtained mrna. reverse transcription was performed using the simpliamp thermal cycler (thermo fisher scientific) according to the manufacturer instructions. obtained cdna samples were stored at -80ºc until real-time (rt)-pcr analysis. primary sequences and quantitation of genes the sequence used for ereg (accession no: nm_001432) includes primers as follows. f: ggacagtgcatctatctggtgg, r: ttggtggacggttaaaaagaagt, for ptpn1 (accession no: nm_002827) f: gcagatcgacaagtccggg, r: gccactctacatgggaagtcac, for serpinb7 (accession no: nm_001040147) f: taagctcatctgctgtaatggtg, r: ggcaatttatggtttcgctcttg, for actb (accession no: nm_001101) f: catgtacgttgctatccaggc r: ctccttaatgtcacgcacgat. quantitation of the obtained mrnas was performed with rotor-gene q (qiagen, hiden) according to the manufacturer instructions. mrnas were analyzed by sybr green original article | dermatol pract concept. 2023;13(2):e2023085 3 method using β-actin (actb as an internal control, housekeeping gene). cycle threshold (ct) values of mrnas were determined, and the obtained ct values were normalized to actb. the fold change of each mrna expression was calculated using the 2−δδct equation. statistical analysis data were analyzed using ibm spss statistics 27.0. the descriptive values of participants were presented as mean ± standard deviation (sd) (also minimum and maximum values). the categorical variables were presented as frequency and percentage. chi-square analysis was used for categorical variables. the distribution characteristics were first examined with the shapiro wilk test to analyze continuous variables across groups. mann whitney u or kruskal wallis test was used for non-parametric distributions according to the number of groups. for analysis of 2 scale/continuous type variables, spearman correlation analysis was used. p value < 0.05 was accepted as statistically significant for all analyses. results twenty-five patients (13 females and 12 males) with a mean age of 39.8 ± 13.72 years and 11 control (6 females and 5 males) subjects with a mean age of 40.6 ± 14.07 years were included in the study. no significant difference was found between the groups regarding mean age and sex (p = 0.866, p = 0.999 respectively). the mean duration of the disease in the patient group was 9.8 years, and the mean pasi score was 13.3 ± 6.1. according to the pasi scores, 12 (48%) patients had mild, and 13 (52%) patients had moderate-severe psoriasis. furthermore, 13 patients (52%) had nail involvement, 10 (40%) had psoriatic arthritis, and 14 (56%) had a positive family history. patients and controls had approximately similar body mass index (26.06 kg/m2 versus 26.76 kg/m2) (p  = 0.946). descriptive features of the participants were given in table 1. gene expression levels in tissue samples in the real time (rt)-pcr analysis, we observed that the ereg gene expression level was significantly upregulated in the lesional psoriatic skin tissue compared to the non-lesional psoriatic tissue (fc=1.60, p = 0.010). in addition, a significant down-regulation was demonstrated in the expression levels of the ereg gene in the adjacent non-lesional skin tissue of patients compared to the healthy skin tissue of controls (fc = -1.82, p = 0.001) (table 2). it was observed that ptpn1 gene expression level was significantly increased in the lesional tissue compared to healthy control tissue (fc = 2.44, p < 0.001). in addition, no difference was found in the expression levels of the ptpn1 gene in the adjacent non-lesional skin tissue of psoriasis patients compared to the healthy skin tissue of controls (fc = -1.35, p > 0.05) (table 2). it was observed that the expression level of the serpinb7 gene was significantly decreased in psoriatic tissue compared to the healthy control tissue (fc = -2.33, p < 0.001). moreover, no significant difference was seen in the expression levels of the serpinb7 gene in the adjacent non-lesional skin tissue of psoriasis patients compared to the healthy skin tissue of controls (fc = -9.1, p > 0.05) (table 2). according to these results, the expression levels of all genes were significantly different between psoriatic skin and healthy control skin (for all p < 0.05) (figure 1). table 1. baseline characteristics of the study groups. patient group (n = 25) control group (n = 11) pa age, years, mean ± sd 39.8 ± 13.72 40.6 ± 14.07 .866 sex female, n (%) male, n (%) 13 (52%) 12 (48%) 6 (45.5%) 5 (54.5%) .999 bmi, mean ± sd 26.06 ± 4.8 26.19± 3.18 .946 duration of disease, years, mean ± sd 9.8 ± 9.2 (1-35)b pasi scores, mean ± sd 13.3 ± 6.1 arthritis, n (%) 10 (40%) nail involvement, n (%) 13 (52%) positive family history, n (%) 14 (56%) severity of the disease mild disease, n (%) moderate-severe disease, n (%) 12 (48%) 13 (52%) bmi = body mass index; pasi = psoriasis area and severity index; sd = standard deviation. a p value is significant at the 0.05 level b minimum and maximum values 4 original article | dermatol pract concept. 2023;13(2):e2023085 table 2. comparison of the expression of ereg, ptpn1, and serpinb7 genes between the lesional and non-lesional skins of the psoriatic patients and normal skins of healthy controls. lesional skin of psoriatic patients non-lesional skin of psoriatic patients controls pa pb ereg, mean ± sd (min-max) 1.82 ± 0.95 (0.6-4.11) 0.57 ± 0.2 (0.34-1.06) 1.03 ± 0.3 (0.7-1.68) 0.012 ab:<0.001 ac:0.345 bc:0.004 ptpn1, mean ± sd (min-max) 3.76 ± 1.89 (1.26-10.6) 1.18 ± 0.57 (0.24-2.19) 1 ± 0.13 (0.86-1.24) <0.001 ab:<0.001 ac:<0.001 bc:0.999 serpinb7, mean ± sd (min-max) 2.54 ± 0.61 (1.5-4.14) 4.49 ± 0.42 (3.95-5.31) 4.29 ± 0.32 (3.79-4.72) <0.001 ab:<0.001 ac:<0.001 bc:0.999 a = lesional skin of patients; b = non-lesional skin of patients; c = normal skin of controls; ereg = epiregulin; ptpn1 = tyrosine-protein phosphatase non-receptor type 1; sd = standard deviation; serpinb7 = serpin family b member 7. a triple comparison of the groups (with kruskal-wallis, p < 0.05 is accepted as statistically significant) b pairwise comparison of the groups (bonferroni correction was used, and p < 0.05 is accepted as statistically significant) non-lesional adjacent skin normal skin ereg ptpn1 5,00 4,50 4,00 3,50 3,00 2,50 2,00 1,50 1,00 0,50 0,00 -0,50 serpinb7 lesional skin m r n a f o ld c h a n g e figure 1. comparison of the expression levels of ereg, ptpn1, serpinb7 genes between the lesional and non lesional skins of the psoriatic patients and the normal skin of healthy controls. rt-pcr analysis of the indicated genes in indicated skin tissues was performed. * p < 0.05; ** p < 0.001 ereg = epiregulin; ptpn1 = tyrosine-protein phosphatase non-receptor type 1; serpinb7 = serpin family b member 7. furthermore, the decrease of the expression of the serpinb7 gene was correlated with pasi scores in the patient group (p = 0.038, r = 0.417) (figure 2). there was no correlation between other genes’ expression levels and pasi scores (figures 3 and 4). in addition, there were no correlations between the expression levels of the genes and nail involvement, positive family history, and presence of arthritis, either. conclusions over the years, as our knowledge of the pathogenesis of psoriasis has increased considerably, we know that it includes complex, multiple factors covering the genetic factors that only explain about 70% of disease susceptibility [12]. up to now, many single nucleotide polymorphism microarray and genome-wide association studies have been performed original article | dermatol pract concept. 2023;13(2):e2023085 5 p*=0.038 r=0.417 1.00 2.00 3.00 4.00 .0 10.0 20.0 pasi 30.0 40.0 se r p in b 7 figure 2. the correlation graph between serpinb7 gene expression levels and pasi scores *p < 0.05. pasi = psoriasis area and severity index; serpinb7 = serpin family b member 7. pasi p=0.639 r=0.098 ,0 10,0 20,0 30,0 40,0 p tp n 1 ,00 12,00 10,00 8,00 6,00 4,00 2,00 figure 3. the correlation graph between ptpn1 gene expression levels and pasi scores (spearman correlation). pasi = psoriasis area and severity index; ptpn1 = tyrosine-protein phosphatase non-receptor type 1. [13-15]. however, there is still a gap between genetic basis and environmental triggers in pathogenesis. there have been many identified potential susceptibility genes for psoriasis, and this discovery has been continued [8,13-15]. shirakata et al compared ereg gene expressions of 12 psoriatic skin samples and 10 healthy skin samples [2]. they observed that ereg mrna was expressed very faintly in the basal layer of the epidermis of normal control skin, whereas it was overexpressed in the spinous layer of the epidermis of the psoriatic skin. thus, they reported ereg might lead hyperproliferation of epidermis via possible intracellular signaling systems such as stat3 and may have essential for the development of psoriasis-like phenotype. in the same way, iwata et al reported that the expression of ereg in dermal fibroblasts was significantly upregulated approximately 50 times fold by co-stimulation with il-17a and tnf-α, and 6 original article | dermatol pract concept. 2023;13(2):e2023085 which is an inhibitor of insulin signaling pathway in many studies [6,21-23]. in chronic inflammatory situations such as psoriasis, it was demonstrated that high levels of proinflammatory cytokines activate p38mapk, which induces insulin receptors, and leads to blockade of differentiation and hyperproliferation of basal keratinocytes. in addition, as a result of the insulin receptor induction, much more insulin was produced than normal. this condition, called hyperinsulinemia, accelerates lipogenesis with increased production of free fatty acids, though [24]. we know that psoriatic patients have a higher risk of having type 2 dm compared to controls [25]. in addition, as mentioned before, the regulatory effect of ptpn1 on munc18c protein affects adipocytes which are also attendant cells to the psoriasis pathogenesis [24]. in our study we excluded the psoriatic patients who also have systemic inflammatory diseases or conditions such as dm and hyperlipidemia, thus we did not evaluate the association of psoriasis and them at all. however, since the expression of the ptpn1 gene was observed significantly upregulated in the lesional skin of patients compared to normal skin of controls, there could be an underlying undiagnosed insulin resistance or glucose intolerance conditions or altered lipid metabolism pathways in our patient group enrolled in the study. besides these, yin et al evaluated the common genetic factors shared between psoriasis and schizophrenia. even though they reported that any common variant was not found between two diseases, they claimed that ptpn1 gene may be a novel-susceptible gene for psoriasis which interacts with well-known susceptible genes for psoriasis such as nfkba, stat3, and tyk2 genes [7]. similarly, we showed this upregulation of ereg leads to keratinocyte proliferation in vitro [16]. thus, both study showed that ereg is a vital stimulator of keratinocyte proliferation which is crucial feature of immunopathogenesis of psoriasis as well. although we could not show expression levels of the ereg gene according to the layers of the skin, since it is known histopathologically that the spinous layer is hyperproliferated in psoriasis [17], it might be thought that overexpression of ereg gene seems to be related to this change. our study supports these notions about ereg gene with the result of overexpressed ereg gene in the lesional skin of psoriatic patients. furthermore, the non-lesional skin of patients with psoriasis has significantly down-regulated expression of the ereg gene than the healthy skin of controls, which may be caused by the migration of immune cells including fibroblasts to the inflammation regions in the psoriatic patients. in 2004, shirasawa et al showed that ereg is expressed not only in keratinocytes but also in tissue-resident macrophages which are important cells for the immune balance in the skin. they claimed that ereg is physiologically a critical molecule for tight regulation of il-18 in keratinocytes and proper production of proinflammatory cytokines by macrophages [18]. il-18 belongs to il-1 cytokine family that plays a pathogenetically important role in chronic inflammatory conditions of skin such as psoriasis [19,20]. therefore, we assume that upregulation of ereg gene causes hyperproliferation of keratinocytes and chronic inflammation in psoriasis via intracellular signaling pathways. up to now, ptpn1 was shown as associated with dyslipidemia, insulin resistance, type 2 dm, and obesity via ptp1b pasi p=0.103 r=0.333 ,0 10,0 20,0 30,0 40,0 er eg ,00 1,00 -1,00 2,00 figure 4. the correlation graph between ereg gene expression levels and pasi scores (spearman correlation). ereg = epiregulin; pasi = psoriasis area and severity index. original article | dermatol pract concept. 2023;13(2):e2023085 7 with future studies. even though our study is the only study evaluating serpinb7 gene in a high number of real patients lesional, non-lesional skins and normal skins of healthy controls, these findings need to be proven in further studies. with this study, we demonstrated that balanced function of the ereg gene, decreased function of the ptpn1 gene, and normal function of the serpinb7 gene play a critical role in preventing the development of psoriasis. we believe that in the future, gene therapies that can even cure diseases will be more important than inhibiting the underlying inflammatory mechanism in chronic inflammatory diseases. acknowledgement: this work was supported by scholarship from turkish dermatology association. references 1. gudjonsson je, ding j, johnston a, et al. assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models. j invest dermatol. 2010;130(7):1829-1840. doi: 10.1038/jid.2010.36. pmid: 20220767. pmcid: pmc3128718. 2. shirakata y, kishimoto j, tokumaru s, et al. epiregulin, a member of the egf family, is over-expressed in psoriatic epidermis. j dermatol sci. 2007;45(1):69-72. doi: 10.1016/j. jdermsci.2006.08.010. pmid: 16996251. 3. hashimoto k. regulation of keratinocyte function by growth factors. j dermatol sci. 2000;24 suppl 1:46-50. doi: 10.1016/ s0923-1811(00)00141-9. pmid: 11137396. 4. kubo a, shiohama a, sasaki t, et al. mutations in serpinb7, encoding a member of the serine protease inhibitor superfamily, cause nagashima-type palmoplantar keratosis. am j hum genet. 2013;93(5):945-956. doi: 10.1016/j.ajhg.2013.09.015. pmid: 24207119; pmcid: pmc3824127. 5. alfadhli s, al-zufairi aam, nizam r, alsaffar ha, al-mutairi n. de-regulation of diabetic regulatory genes in psoriasis: deciphering the unsolved riddle. gene. 2016;593(1):110-116. doi: 10.1016/j.gene.2016.08.024. pmid: 27530212. 6. cheyssac c, lecoeur c, dechaume a, et al. analysis of common ptpn1 gene variants in type 2 diabetes, obesity and associated phenotypes in the french population. bmc med genet. 2006;7:44. doi: 10.1186/1471-2350-7-44. pmid: 16677372. pmcid: pmc1525165. 7. yin x, lin y, shen c, et al. integration of expression quantitative trait loci and pleiotropy identifies a novel psoriasis susceptibility gene, ptpn1. j gene med. 2017;19(1-2):10.1002/jgm.2939. doi: 10.1002/jgm.2939. pmid: 27976820. 8. wang z, zheng h, zhou h, et al. systematic screening and identification of novel psoriasis-specific genes from the transcriptome of psoriasis-like keratinocytes. mol med rep. 2019;19(3):15291542. doi: 10.3892/mmr.2018.9782. pmid: 30592269. pmcid: pmc6390042. 9. benezeder t, painsi c, patra v, et al. dithranol targets keratinocytes, their crosstalk with neutrophils and inhibits the il-36 inflammatory loop in psoriasis. elife. 2020;9:e56991. doi: 10.7554/elife.56991. pmid: 32484435. pmcid: pmc7266641. significantly upregulated ptpn1 gene expression in the lesional psoriatic skin than the non-lesional skin of the same patients, and also healthy skin of controls. moreover, to the best of our knowledge, the present study is the only study evaluating ptpn1 gene expression at the tissue layer. in addition, even though we have yet to learn very little about how the ptpn1 gene causes psoriasis development, upregulation of ptpn1 might lead to hyperproliferation of epidermis via stat3 like ereg gene, and therefore, upregulated expression of ptpn1 gene has crucial roles in the psoriasis pathogenesis as well. a type of hereditary palmoplantar keratoderma (ppk) with serpinb7 gene mutations was identified by kubo et al and, they reported that mutations in the serpinb7 gene cause alteration in the epithelium of the skin [4]. they also claimed that the normal functioned serpinb7 gene protects keratinocytes from oxidative stress-mediated cellular damage. therefore, the most critical roles of serpinb7 in the pathogenesis of psoriasis are mainly epidermis development, epithelial cell differentiation, and keratinization [10]. wang et al showed upregulated expressions of serpinb7, ereg, nipal4, and wfdc12 in the keratinocytes of psoriatic skin, and they claimed that serpinb7 and the other 3 genes lead to hyperproliferation and abnormal differentiation of keratinocytes in psoriatic epidermis, and also migration of a large number of inflammatory cells into the dermal lesions [8]. similar to this study, benezeder et al reported after dithranol application serpinb7 expressions and other immunological mechanisms including t-cell infiltration were decreased in the psoriatic skin [9]. contrary to these studies, zheng reported that serpinb7 deficiency leads to excessive proliferation and impaired differentiation of keratinocytes, and also excessive production of chemokines and antimicrobial peptides via calcium mediated pathways and, as a result psoriasis develops [10]. similar to this report, our findings regarding significantly down-regulated expression levels of serpinb7 in the lesional skin of psoriatic patients makes us think that serpinb7 has protective roles for many cells including keratinocytes. shiba et al reported significant down-regulation of serpinb7 gene expression in oral squamous cell carcinoma samples than in normal tissue samples which also supports our findings about protective role of serpinb7 gene [26]. furthermore, we also found a negative correlation between the severity of the disease and serpinb7 gene expression levels. nevertheless, the contradictory results about serpinb7 in the literature may be related to low number of tissue sample or different methods of the studies such as cell culture, mice tissues in vitro. besides the protective roles of serpinb7, it also seems to be a marker of disease severity. we also think that serpinb7 might be showed as a determinant of prognosis and response to treatment in patients with psoriasis 8 original article | dermatol pract concept. 2023;13(2):e2023085 10. zheng h. serpinb7 deficiency contributes to development of psoriasis via calcium-mediated keratinocyte differentiation dysfunction. cell death dis. 2022 21;13(7):635. doi: 10.1038/s41419-022-05045-8. pmid: 35864103. pmcid: pmc9304369. 11. langley rg, ellis cn. evaluating psoriasis with psoriasis area and severity index, psoriasis global assessment, and lattice system physician’s global assessment. j am acad dermatol. 2004;51(4):563-569. doi: 10.1016/j.jaad.2004.04.012. pmid: 15389191 12. ogawa k, okada y. the current landscape of psoriasis genetics in 2020. j dermatol sci. 2020;99(1):2-8. doi: 10.1016/j.jdermsci.2020.05.008. pmid: 32536600. 13. griffiths ce, barker jn. pathogenesis and clinical features of psoriasis. lancet. 2007;370(9583):263-271. doi: 10.1016/ s0140-6736(07)61128-3. pmid: 17658397. 14. sagoo gs, tazi-ahnini r, barker jw, et al. meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in caucasian and chinese hans population. j invest dermatol. 2004;122(6):1401-1405. doi: 10.1111/j.0022-202x.2004.22607.x. pmid: 15175030. 15. pastore s, mascia f, mariani v, girolomoni g. the epidermal growth factor receptor system in skin repair and inflammation. j invest dermatol. 2008;128(6):1365-1374. doi: 10.1038/sj. jid.5701184. pmid: 18049451. 16. iwata h, haga n, ujiie h. possible role of epiregulin from dermal fibroblasts in the keratinocyte hyperproliferation of psoriasis. j dermatol. 2021;48(9):1433-1438. doi: 10.1111/1346-8138.16003. pmid: 34128258. 17. lu q, jiang g. progress in the application of reflectance confocal microscopy in dermatology. postepy dermatol alergol. 2021;38(5):709-715. doi: 10.5114/ada.2021.110077. pmid: 34849113; pmcid: pmc8610039. 18. shirasawa s, sugiyama s, baba i, et al. dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage. proc natl acad sci usa. 2004;101(38):13921-13926. doi: 10.1073/ pnas.0404217101 pmid: 15365177. pmcid: pmc518854. 19. wittmann m, macdonald a, renne j. il-18 and skin inflammation. autoimmun rev. 2009;9(1):45-48. doi: 10.1016/j.autrev.2009.03.003. pmid: 19285156. 20. sedimbi sk, hagglof t, karlsson mc. il-18 in inflammatory and autoimmune disease. cell mol life sci. 2013; 70:4795–4808. doi: 10.1007/s00018-013-1425-y. pmid: 23892891. 21. combs ap. recent advances in the discovery of competitive protein tyrosine phosphatase 1b inhibitors for the treatment of diabetes, obesity, and cancer. j med chem. 2010;53(6):2333-2344. doi. 10.1021/jm901090b. pmid: 20000419. 22. kipfer-coudreau s, eberlé d, sahbatou m, et al. single nucleotide polymorphisms of protein tyrosine phosphatase 1b gene are associated with obesity in morbidly obese french subjects. diabetologia. 2004;47(7):1278-1284. doi: 10.1007/s00125004-1432-5. pmid: 15235769. 23. bento jl, palmer nd, mychaleckyj jc, et al. association of protein tyrosine phosphatase 1b gene polymorphisms with type 2 diabetes. diabetes. 2004;53(11):3007-3012. doi: 10.2337/diabetes.53.11.3007. pmid: 15504984. 24. buerger c, richter b, woth k, et al. interleukin-1β interferes with epidermal homeostasis through induction of insulin resistance: implications for psoriasis pathogenesis. j invest dermatol. 2012;132(9):2206-2214. doi: 10.1038/jid.2012.123. pmid: 22513786. 25. holm jg, thomsen sf. type 2 diabetes and psoriasis: links and risks. psoriasis (auckl). 2019;9:1-6. doi: 10.2147/ptt. s159163. pmid: 30697518. pmcid: pmc6340647. 26. shiiba m, nomura h, shinozuka k, et al. down-regulated expression of serpin genes located on chromosome 18q21 in oral squamous cell carcinomas. oncol rep. 2010;24(1):241-249. doi: 10.3892/or_00000852. pmid: 20514468. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022092 1 solitary nodular lesion on the face in a 9-year-old boy mohamed ben rejeb1, haifa mkhinini1, badreddine sriha1, mohamed denguezli1 1 dermatology department, anatomopathology department, hached university hospital of sousse, sousse-tunisa citation: rejeb mb, mkhinini h, sriha b, denguezli m. solitary nodular lesion on the face in a 9-year-old boy. dermatol pract concept. 2022;12(2):e2022092. doi: https://doi.org/10.5826/dpc.1202a92 accepted: october 3, 2021; published: april 2022 copyright: ©2022 rejeb et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ben rejeb mohamed, dermatology department, hached university hospital of sousse-tunisia. e-mail: med.benrejeb@gmail.com case presentation  a 9-year-old boy presented with a 4-month history of chronic nodular lesion on the cheek resistant to antibiotics. dermatological examination showed a 15-mm, solitary, firm erythematous nodule on his right cheek (figure 1a). a punch biopsy specimen revealed a dermal chronic inflammatory, granulomatous perifollicularinfiltrate consisting of histiocytes, neutrophils, and giant cells without necrosis (figure 1: b, c). based on these findings,we diagnosed the case as idiopathic facial aseptic granuloma (ifag). teaching point ifag is a rare, benignpediatric entity characterized by chronic, painless erythematous-violaceous nodular lesions frequently located on cheeks and eyelids with no predisposing factor [1]. although pathogenesis remains unclear, the disease is thought to be associated with granulomatous rosacea in childhood [1]. histologically, ifag lesion is characterized by a dermal chronic inflammation of histiocytic granuloma with giant cells, and abscesses without necrosis. in general, ifag tends to resolve spontaneously in less than a year. antibiotics, such as doxycycline and metronidazole, could be used to accelerate the involution of ifag [2]. 2 research letter | dermatol pract concept. 2022;12(2):e2022092 references 1. satta r, montesu ma, biondi g, lissia a. idiopathic facial aseptic granuloma: case report and literature review. int j dermatol.2016;55(12):1381-1387. doi: 10.1111/ijd.13161. pmid: 27259697. 2. hasbún z c, ogueta c i, dossi c t, wortsman x. idiopathic facial aseptic granuloma: updated review of diagnostic and therapeutic difficulties. actasdermosifiliogr (engl ed). 2019;110(8):637-641. doi: 10.1016/j.ad.2019.01.005. pmid: 30819406. figure 1. (a): solitary, firm, nodular, erythematous lesion on the right cheek, chronic granulomatous inflammatory infiltrate in the dermis (b, he*40) composed of histiocytes, lymphocytes, neutrophils and giant cells without necrosis (c, he*200). dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023097 1 risankizumab for the treatment of palmoplantar pustular psoriasis: a report of two cases luigi gargiulo1,2, carlo alberto vignoli1,2, giulia pavia1,2, alessandra narcisi1,2, antonio costanzo1,2, chiara perugini1 1 dermatology unit, irccs humanitas research hospital, rozzano, milano, italy 2 department of biomedical sciences, humanitas university, pieve emanuele, milano, italy key words: psoriasis, palmoplantar pustular psoriasis, risankizumab, biologics, anti-il-23 citation: gargiulo l, vignoli ca, pavia g, narcisi a, costanzo a, perugini c. risankizumab for the treatment of palmoplantar pustular psoriasis: a report of two cases. dermatol pract concept. 2023;13(2):e2023097. doi: https://doi.org/10.5826/dpc.1302a97 accepted: july 27, 2023; published: april 2023 copyright: ©2023 gargiulo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: antonio costanzo has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, galderma, boehringer, novartis, pfizer, sandoz, and ucb. alessandra narcisi has been a consultant and/or speaker for abb-vie, almirall, amgen, janssen, leo pharma, eli lilly, boehringer, novartis, pfizer and ucb. luigi gargiulo, carlo alberto vignoli, giulia pavia and chiara perugini have nothing to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. carlo alberto vignoli, md, dermatology unit, department of biomedical sciences, irccs humanitas research hospital, humanitas university, rozzano (mi), itlay. tel: +39 0282244050 email: c.alberto.vignoli@gmail.com introduction palmoplantar pustular psoriasis (pppp), according to the eraspen (european rare and severe psoriasis expert network) guidelines, is defined as primary, persistent (>3 months), sterile, macroscopically visible pustular eruption on palms and/or soles [1,2]. it can present with or without concomitant plaque psoriasis [2]. the pathophysiology of this condition is not fully understood, both the innate and adaptive immune systems are involved [2]. a primary role is played by the increased expression of interleukin-8 (il-8) and by il-17 related cytokines (including l-17a/f, il-23a, il-23 receptor). a role has been proposed also for the antimicrobial peptide ll-37, which may contribute to neutrophil recruitment by upregulating il-8, il-23, il-17c, il-1 [2]. only limited data are available regarding the treatment of pppp with biologics and no standardized guidelines have been published yet [3]. case presentation we present 2 patients with pppp who were successfully treated with risankizumab, an anti-il-23 monoclonal antibody. the first patient is a 32-year-old woman, affected by pppp and plaque psoriasis since 2020. on clinical examination, we observed pustular lesions on the palms and soles (figure 1) along with erythematous and scaly plaques on the scalp. palmoplantar investigator global assessment (ppiga) score was 3 on a 5-point scale. psoriasis area severity index (pasi) was 5.2. as topical corticosteroids had previously been ineffective, given the age of the patient, acitretin was not recommended. because of the impact of the disease on her quality of life (dermatology life quality index [dlqi] was 12), we prescribed risankizumab 75mg, two subcutaneous injections at weeks 0, 4, and then every 12 weeks. after 16 weeks the patient returned showing only a slight improvement, but at week 28 we observed complete skin 2 research letter | dermatol pract concept. 2023;13(2):e2023097 clearance, with a ppiga of 0 (figure 2). the patient to date has completed a year of therapy and she has maintained the remission. the second patient is a 47-year-old woman, affected from pppp since 2018, previously unsuccessfully treated with acitretin. she had a history of hepatitis b with positive anti-hbc and anti-hbs. on physical examination we observed erythematous, scaly patches on the palms and palmoplantar pustules (ppiga=3, pasi=11.3). given her comorbidities and the concomitant presence of plaque psoriasis, with the consensus of the hepatologist, we started risankizumab. at week 16 she achieved complete skin clearance and she has maintained the remission after two years (ppiga=3). both patients had provided written consent for retrospective study of data collected during routine clinical practice (demographics, clinical scores). conclusions in scientific literature there is paucity of data regarding the efficacy of biologics in pustular psoriasis, especially for palmoplantar subtype. a few data from real-life experiences and case reports are available for guselkumab, secukinumab and apremilast, which have demonstrated a moderate efficacy [4]. we decided to prescribe risankizumab for multiple reasons: our favorable experience with this drug, including a patient with a flare of generalized pustular psoriasis [5]; the high safety profile, even in patients with serological evidence of viral hepatitis [6]; the high effectiveness on difficult-to-treat areas [5]. in the first patient, we observed a slower response compared to our experience with risankizumab in psoriasis vulgaris, however this is expectable given the resistance of these areas to treatment [5]. to our knowledge, the experience on the effectiveness of risankizumab in pppp is limited. further data, corroborated by longitudinal studies with higher numbers of patients, are needed to assess the role of risankizumab and other biologic drugs for the treatment of pppp. references 1. navarini aa, burden ad, capon f, et al. european consensus statement on phenotypes of pustular psoriasis. j eur acad dermatol venereol. 2017;31(11):1792-1799. doi:10.1111/jdv .14386. pmid: 28585342. figure 1. (a,b) sterile pustules on erythematous skin with moderate scaling on the left foot (a) and on the right palm (b) of a 32-year-old woman, before the start of the therapy. figure 2. (a,b) clinical appearance of the patient soles (a) and palms (b) after 28 weeks of therapy with risankizumab. complete resolution of the pustules is observed, with the persistence of only slight erythema and scaling. research letter | dermatol pract concept. 2023;13(2):e2023097 3 2. uppala r, tsoi lc, harms pw, et al. “autoinflammatory psoriasis”-genetics and biology of pustular psoriasis. cell mol immunol. 2021;18(2):307-317. doi:10.1038/s41423-020-0519-3. pmid: 32814870. pmcid: pmc8027616. 3. wang wm, jin hz. biologics in the treatment of pustular psoriasis. expert opin drug saf. 2020;19(8):969-980. doi:10.1080 /14740338.2020.1785427. pmid: 32615817. 4. mrowietz u, bachelez h, burden ad, et al. secukinumab for moderate-to-severe palmoplantar pustular psoriasis: results of the 2precise study. j am acad dermatol. 2019;80(5): 1344-1352. doi:10.1016/j.jaad.2019.01.066. pmid: 30716404. 5. borroni rg, malagoli p, gargiulo l, et al. real-life effectiveness and safety of risankizumab in moderate-to-severe plaque psoriasis: a 40-week multicentric retrospective study. acta derm venereol. 2021;101(11):adv00605. doi:10.2340/actadv .v101.283. pmid: 34596230. pmcid: pmc9455321. 6. gargiulo l, pavia g, valenti m, et al. safety of biologic therapies in patients with moderate-to-severe plaque psoriasis and concomitant viral hepatitis: a monocentric retrospective study. dermatol ther (heidelb). 2022;12(5):1263-1270. doi:10.1007/s13555-022-00726-w. pmid: 35460018. pmcid: pmc9110615. dermatology: practical and conceptual research | dermatol pract concept 2017;7(4):2 3 dermatology practical & conceptual www.derm101.com cell junction protein armadillo repeat gene deleted in velo-cardio-facial syndrome is expressed in the skin and colocalizes with autoantibodies of patients affected by a new variant of endemic pemphigus foliaceus in colombia ana maria abreu-velez1, hong yi2, michael s. howard1 1 georgia dermatopathology associates, atlanta, ga, usa 2 robert p. apkarian integrated electron microscopy core, emory university medical center, atlanta, ga, usa key words: endemic pemphigus foliaceus, autoimmunity, cell junctions, arcvf, skin citation: abreu-velez am, yi h, howard ms. cell junction protein armadillo repeat gene deleted in velo-cardio-facial syndrome is expressed in the skin and colocalizes with autoantibodies of patients affected by a new variant of endemic pemphigus foliaceus in colombia. dermatol pract concept 2017;7(4):3-8. doi: https://doi.org/10.5826/dpc.0704a02 received: june 7, 2017; accepted: july 31, 2017; published: october 31, 2017 copyright: ©2017 abreu-velez et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. declaration of sources of funding: our work was performed with funding from georgia dermatopathology associates and mineros sa, el bagre, the hospital nuestra señora del carmen, el bagre; and el bagre municipal office, colombia, south america. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ana maria abreu-velez, md, phd, georgia dermatopathology associates, 1534 north decatur rd ne, suite 206, atlanta, ga 30307-1000, usa. tel. (404) 371-0027; fax: (404) 371-1900. email: abreuvelez@yahoo.com. background: we previously described a new variant of endemic pemphigus foliaceus in el bagre, colombia, south america (el bagre-epf, or pemphigus abreu-manu). el bagre-epf differs from other types of epf clinically, epidemiologically, immunologically and in its target antigens. we reported the presence of patient autoantibodies colocalizing with armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf), a catenin cell junction protein colocalizing with el bagre-epf autoantibodies in the heart and within pilosebaceous units along their neurovascular supply routes. here we investigate the presence of arvcf in skin and its possibility as a cutaneous el bagre-epf antigen. methods: we used a case-control study, testing sera of 45 patients and 45 controls via direct and indirect immunofluorescence (dif/iif), confocal microscopy, immunoelectron microscopy and immunoblotting for the presence of arvcf and its relationship with el bagre-epf autoantibodies in the skin. we also immunoadsorbed samples with desmoglein 1 (dsg1) ectodomain (el bagre-epf antigen) by incubating with the positive arvcf samples from dif and iif. results: arvcf was expressed in all the samples from the cases and controls. immunoadsorption with dsg1 on positive arvcf immunofluorescence dif/iif cases showed that the immune response was present against non-desmoglein 1 antigen(s). overall, 40/45 patients showed colocalization of their autoantibodies with arvcf in the epidermis; no controls from the endemic area displayed colocalization. conclusions: we demonstrate that arvcf is expressed in many areas of human skin, and colocalizes with the majority of el bagre-epf autoantibodies as a putative antigen. abstract 4 research | dermatol pract concept 2017;7(4):2 tures, and whether we could further confirm colocalization of el bagre-epf autoantibodies with arvcf in the skin. materials and methods a human quality assurance review board approved the studies at the hospital nuestra señora del carmen in el bagre, and all participants provided signed consent. we tested 45 patients affected by el bagre-epf, and 45 controls from the endemic area matched by age, sex, demographics, comorbidities, and work activities. all of the tests were performed in both cases and controls. the patients and controls were evaluated by hematoxylin and eosin (h&e) histology, dif, iif, confocal microscopy (cfm), indirect immunoelectron microscopy (iem) immunoblotting (ib), by immunoprecipitation (ip) and by elisa. only patients meeting diagnostic criteria for el bagre-epf were included; specifically, they had to display clinical and epidemiologic features described for this disease; live in the endemic area; and have serum displaying intercellular staining (ics) between epidermal keratinocytes and to the basement membrane zone (bmz) of the skin via either dif or iif using fluorescein isothiocyanate (fitc) conjugated monoclonal antibodies to human total igg or igg4, as described elsewhere [5-9]. further, each patient had to be positive by ib for reactivity against dsg1 [6], as well as for plakin molecules; each patient’s serum immunoprecipitated a concanavalin a (con a) affinity-purified bovine tryptic 45 kda fragment of dsg1 [14]; and each patient’s serum had to yield a positive result using an elisa test when screening for autoantibodies to pemphigus foliaceus (pf) antigens [15]. dif and iif: we performed our dif and iif as previously described [8,9]. dif: in brief, we incubated a 4 μm thickness frozen skin section using pbs with 0.1% triton x-100 and 1% normal goat serum for five minutes for partial permeabilization, to detect cytoplasmic, nuclear, and membrane binding putative antigens, and for blocking non-specific staining. the slides were then washed with pbs [8,9]. the nuclei of the cells were counterstained with 4,6-diamidino-2-phenylindole (dapi, pierce; rockford, il, usa). we used antibodies to arvcf, source guinea pig, cat. no. gp155; progen biotechnik (heidelberg, germany). for its secondary, we used alexa fluor®555 goat-anti-guinea pig (molecular probes life technologies/thermofisher scientific; waltham, ma, usa). all samples were run with positive and negative controls. we classified our findings as negative (-), weakly positive (+), moderately positive (++) and strongly positive (+++). for iif, our substrate tissue included human, bovine, rat and mouse skin. written consents were obtained from all patients, and institutional review board permission was obtained from the hospital nuestra señora de el carmen, in el bagre, colombia. introduction endemic pemphigus foliaceus (epf) is an autoimmune blistering disease characterized by the presence of autoantibodies (primarily to desmoglein 1 [dsg1]). on direct immunofluorescence (dif) and indirect immunofluorescence (iif), the epf autoantibodies display intercellular staining (ics) between epidermal keratinocytes [1-3]. in brazil, epf is titled fogo selvagem (fs) and principally affects children and young adults. epf has also been documented in rural areas of south and central america (argentina, bolivia, el salvador, paraguay, peru and venezuela) [1-3]. one additional variant has been described in tunisia, africa [4]. we previously described a new variant of epf in el bagre, colombia, south america (el bagre-epf, or pemphigus abreu-manu). el bagre-epf differs from other types of epf because it affects predominantly 30to70-year-old or older males, and a few peri/postmenopausal females [5-7]. the patients are primarily miners, who also work in agricultural activities. the patients have autoantibodies to dermal eccrine, sebaceous and meibomian glands, and their neurovascular bundles; to cardiac molecules; to pacinian receptors and other cutaneous neural receptors; and to tarsal muscles and to other structures [8-10]. for over two decades, we have followed the el bagre-epf patients [5-7,8-10]. the disease was originally thought to be a new focus of brazilian epf with some differences [19]; however, we later documented it as a new and unique disease, resembling senear-usher syndrome. we documented el bagre epf to have a unique autoimmune response due to environmental and genetic factors [10-14]. we also previously reported that one-third of the el bagreepf patients present with a systemic form, as observed in systemic lupus erythematosus [10-15]. we previously reported the colocalization of el bagre-epf patient autoantibodies with armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf) in cardiac tissue, as well as within pilosebaceous units along their neurovascular supply routes [9,11]. arvcf is an adhesion molecule of the catenin-like protein family that is one of the mutated molecules in the disease called velo-cardio-facial syndrome (vcfs). vcfs, along with digeorge syndrome (dgs), and conotruncal anomaly face syndrome are part of the disease complex termed chromosomal microdeletions dissecting (cmd): del22q11 syndrome [11-13]. cmd is known to be associated with multiple autoimmune diseases, as well as some alterations in the immune system [11-13]. arvcf also is related to the protein p120 subfamily of armadillo-related proteins, which includes p0071 and delta-catenin/nprap; these are distantly related plakophilins, and are involved in cell-cell adhesion [11-13]. in our current study, we investigated whether arvcf was expressed in the skin, including the sebaceous glands and their neurovascular supply strucresearch | dermatol pract concept 2017;7(4):2 5 iif: performed as the dif, but utilizing skin from plastic surgeries as an antigen source. colocalization of the patient’s autoantibodies with commercial antibodies utilizing confocal microscopy (cfm): our cfm studies were performed as previously described [8,9]. in brief, we utilized standard 20x and 40x objective lenses; each photoframe included an area of approximately 440 x 330 μm. images were obtained using ez-1 image analysis software (nikon, tokyo, japan). for colocalization experiments with serum autoantibodies, we used the previously described antibodies to arvcf. indirect immunoelectron microscopy (iem): our technique was performed as described [8,9]. in brief, postembedding immunogold labeling was performed on samples on the subjects of the study. mouse skin was used as an antigen; the tissue was fixed in 4% glutaraldehyde with 0.2% paraformaldehyde, and embedded in lowicryl® resin [8,9]. the tissue was then sectioned at a 70 nm thickness. the samples were blocked with a solution from aurion™ (electron microcopy sciences/ems; hatfield, pa, usa). grids were then washed with pbs-bsac (aurion™, ems). the primary antibodies were incubated, washed, and a secondary antibody solution, specifically 10 nm gold-conjugated protein a pbs-bsac (aurion, ems™) was applied [8,9]. the samples were then double-stained with uranyl acetate and lead citrate. the samples were observed under a hitachi h7500 transmission electron microscope. immunogold particle images displaying any pattern of positivity were then converted to tif format. immunoadsorption of skin dsg1 1 autoantibodies: patients with el bagre-epf have circulating autoantibodies directed against dsg1 [5,6]. based on the fact that the purified tryptic fraction of dsg1 induces loss of adhesion in organ culture and in a neonatal mouse model, it has been proposed that these anti-dsg1 antibodies play a pathogenic role in blister formation. to investigate if the arvcf putative autoantibodies reactivity was the same as shown by dsg1, we performed immunoadsorption experiments as previously described by incubating the tryptic ectodomain of dsg1 with samples that tested positive for dif and iif [14]. we used affinity tryptic-purified antigen, obtained as described using the con a column [14]. in brief, protein samples were released from bovine snout epidermis by means of trypsin digestion, and purified with the use of a con a column. the eluted dsg1 antigen was then incubated with el bagre-epf dif and iif slides that were positive previously in colocalization of arvcf with the el bagre-epf serum. statistical analysis: we used fisher exact test to compare two nominal variables (e.g., positive and negative) of antibody response. p < 0.05 with a 95% of confidence or more was considered statistically significant. we used the software graphpad quickcalcs (graphpad sofware inc., la jolla, ca, usa). results a clinical picture of an exfoliative lesion of el bagre-epf is shown in figure 1a. in figure 1b, we show the corresponding histologic pattern. our testing demonstrated positive staining for arvcf in all layers of the epidermis, on the basement membrane zone and in upper areas of the subjacent dermis (including cell junctions and neurovascular bundles) by dif, iif, cfm, ib, and iem. see figure 1c, demonstrating one example of dif staining with colocalization of the el bagreepf autoantibodies and arvcf. overall, 40/45 patients affected by el bagre-epf demonstrated autoantibodies that colocalized perfectly with the arvcf antibody via dif. in the remaining five patients affected by el bagre-epf we observed the expression of arvcf, but the autoantibodies did not colocalize with the arvcf antibody. in table 1 are shown the results of the polyclonal immune response using dif and iif, the strength of the stains and the colocalization with the el bagre-epf autoantibodies and the arvcf reactivity. the cfm studies also demonstrated 100% colocalization of the patient autoantibodies and the commercial antibody to arvcf (p < 0.01) (figure 1c, d). none of the controls from the endemic area showed autoantibodies colocalizing to arvcf via dif, iif, cmf, or iem. however, the arvcf molecule is ubiquitous in the skin. after the immunoadsorption with the pre-incubated dsg1 antigen with the patient samples testing positive for colocalization with arvcf, the immunoreactivity to arcvf persisted. our iem data (figure 1e, f) demonstrated positive staining for patient autoantibodies in skin cell junctions. the ib studies confirmed multiple antigens detected by patient sera, that also perfectly colocalized with the progen antibody to arvcf (data not shown). discussion to our knowledge, we present evidence for the first time in the medical literature that arvcf is expressed in the skin via diverse methods. we also demonstrated that el bagre-epf autoantibodies colocalized with the commercial antibody to arvcf from progen in the skin of 40/45 patients. we further demonstrated that after immunoadsorption with an ectodomain of dsg1 the reactivity remained, demonstrating that the el bagre-epf patient’s autoantibodies are directed to a non-dsg1 antigen. we noted that 5/45 el bagre-epf patients did not display autoantibodies against arvcf. el bagre epf patients present a diverse spectrum of clinical lesions (hyperpigmented, prurigoid, generalized, blistering, etc.) [1,3,5]. the patients may also present in an acute, relapsing or chronic stage of https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0ahukewjkxrseloxsahufscykhypmdsmqfgg4mae&url=http%3a%2f%2fgraphpad.com%2fquickcalcs%2fcontingency1%2f&usg=afqjcnfmcqtfuoz8qklz92jezpj4wqbviq https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&sqi=2&ved=0ahukewjzw4oc6uxsahxlryykhuj3acgqfggjmae&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fimmunoadsorption&usg=afqjcneu_h_tlpiro8yfpaaxwntlqah4oq&bvm=bv.150120842,d.ewe 6 research | dermatol pract concept 2017;7(4):2 metals and other metalloids [5] that can compete with calcium. el bagre soils are extremely acidic, contain very scarce organic matter and are thus scarce in calcium, phosphates, magnesium (mg++), and potassium. phosphates are constituents of atp, dna, rna, and the phospholipids, which form all cell membranes where the cells junctions are situated. the existence or absence of a given metal/metalloid is crucial to the conformation or activity of most proteins. thus, the metal/metalloid ions in the environment could compete with physiologic ions (e.g., ca++), altering the conformation of relevant molecules and generating antigenicity. arvcf (a.k.a. catenin delta 1) binds sulfate (s04) as well as magnesium (mg++ are their ligands. dp also has an s04 ligand and to phosphoserine is classified as uniprotkb/ disease. thus, each case may present a range of autoantigens and immune responses, depending of the clinical phase of the disease. we also showed that the immune response is polyclonal in patients affected by el bagre-epf, as previously described [8,9]. we speculate that disruption of epidermal cells in el bagre-epf could induce epitope spreading, or expose new molecules that could then become antigenic since like dsg1, arvcf represents a cell junction protein. arvcf is a protein with three cellular locations: in the plasma membrane, the cytoplasm and the nucleus [13-16]. we also hypothesize that arvc becomes antigenic because this molecule is calcium (ca++) dependent (similar to dsg1); further, that the el bagre soils are polluted by mercury, figure 1. (a) an el bagre epf clinical blister (black arrow). (b) h&e staining of one of multiple patterns seen in el bagre epf. in this case, note the loss of the upper layers of the epidermis (black arrow), and a dilated dermal blood vessel (blue arrow) with dermal edema and inflammation. (c) dif of the skin from a patient affected by el bagre-epf, showing positive double staining in the epidermis (in orange stain, as result of the patient’s autoantibodies in green and the arvcf in red) (+++) (black arrow), basement membrane zone (greenish stain) (+++) (white arrow) and a dermal neurovascular bundle (yellowish stain) (+++) (blue arrow) using fitc conjugated anti-human igg (green staining) and alexa 555 conjugated arvcf (red staining). the staining observed represents overlap staining of different strength from yellowish-orange to green (400x). (d) confocal microscopy, with multiple channels of fluorescence utilized. in the presented case we used a fitc channel (green peaks) (excitation/emission (nm):495/519), a dapi channel (blue peaks) (excitation/emission (nm):360⁄460), and an alexa fluor®555 channel (red peaks) (excitation /emission (nm):555/568). the graphic shows the colocalization of the peaks of the immunofluorescence of the patient’s antibodies (green peaks; white arrow) with the arvcf antibody (red peaks; white arrow). both green and red are aligned, demonstrating colocalization. the blue peaks represent dapi (nuclear counterstaining). (e) and (f) iem photographs of patient skin, showing arvcf antibodies labelled with 10 nm gold-conjugated protein a antibodies (tiny black dots). in (e), the antibodies are located in the epidermal cells junctions (black arrow), at the cutaneous basement membrane zone (black dots; red arrow) and in the upper papillary dermis (tiny black dots; blue arrow) (100kv). (f) positive iem staining in the upper epidermal keratinocytes cells junction showing arvcf antibody gold labeled grouped in some areas (tiny black dots; red arrows) (100kv). [copyright: ©2017 abreu velez et al.] research | dermatol pract concept 2017;7(4):2 7 respective sequence is available to researchers to investigate if arvcf may be a putative antigen in other autoimmune blistering diseases. more than 9% of the protein sequences provided by uniprotkb are derived from translation of the coding sequences. acknowledgement we wish to thank jonathan s. jones, ht (ascp) at georgia dermatopathology associates for excellent technical assistance. references 1. diaz la, sampaio sa, rivitti ea, et al. endemic pemphigus foliaceus (fogo selvagem). i. clinical features and immunopathology. j am acad dermatol. 1989;20(4):657-659. 2. ortega-loayza ag, ramos w, gutierrez el, et al. endemic pemphigus foliaceus in the peruvian amazon. clin exp dermatol. 2013;38(6):594-600. 3. castro rm, proença ng. similarities and differences between brazilian wild fire and pemphigus foliaceus cazenave. hautarzt. 1982;33(11):574-577. 4. morini jp, jomaa b, gorgi y, et al. pemphigus foliaceus in young women. an endemic focus in the sousse area of tunisia. arch dermatol. 1993;129(1):69-73. 5. abreu-velez am, hashimoto t, bollag w, et al. a unique form of endemic pemphigus in northern colombia. j am acad dermatol. 2003(4);49:599-608. 6. abreu-velez am, beutner eh, montoya f, hashimoto t. analyses of autoantigens in a new form of endemic pemphigus foliaceus in colombia. j am acad dermatol 2003;49(4):609-614. 7. hisamatsu y, abreu-velez am, amagai m, ogawa mm, kanzaki t, hashimoto t. comparative study of autoantigen profile between colombian and brazilian types of endemic pemphigus foliaceus by various biochemical and molecular biological techniques. j dermatol sci. 2003.32(1):33-41. 8. howard ms, abreu-velez am. broad histopathologic patterns of non-glabrous skin and glabrous skin from patients with a new variant of endemic pemphigus foliaceus (part 1). j cutan pathol. 2010;37(2):222-230. swiss-prot (o00192), and is a member of the catenin family, which contain an armadillo/beta-catenin-like repeat sequence [11-13]. arvcf is a ca++ dependent cell-cell adhesion molecule, acting via plasma membranes. the catenin family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inner and outer environments of cells [11-13]. the data suggest that arvcf is a putative el bagre-epf antigen. our data indicates that arvcf is a putative non-dsg1 antigen in el bagre-epf patients. the p120 protein family includes p120-catenin, δ-catenin, p0071, and arvcf [10]. arvcf associates with p68, hnrnp h2, sff1, zonula occludens zo-1 and zo-2 (in the last two, binding to pdz-domain proteins) [11-13]. all three diseases belonging to the cmd syndrome are associated with impaired function of t cells due to abnormal development of the thymus gland, abnormalities of t-cell clonality, and/or in b lymphocytic function [11-13,16]. we believe there is an abnormality in the immune response in el bagre-epf patients, which we are currently investigating. pemphigus abreu-manu differs from previously described forms of epf. indeed, el bagre-epf is a chronic inflammatory disease that has protean manifestations, including a form fruste (localized to the skin and resembling senear-usher syndrome, and with a unique autoimmune response due to environmental and genetic factors) with photosensitivity; and a systemic form [8,9]. patients affected by this disease may present with relapsing episodes; the systemic form affects multiple organs with a less favorable prognosis [5,6,12]. in conclusion, we demonstrate the expression of the protein arcvf in multiple areas of the skin. we prove colocalizing or this protein with the majority of the el-bagre-epf autoantibodies, and that the reactivity is directed against a non-dsg1 antigen. we aim in our future research to establish the precise pathologic role of arvcf in el bagre-epf patients and in the skin. the arvcf uniprotkb/swiss-prot (000192) table 1. dif and iif autoantibody staining in the skin and colocalization with arvcf dif iif el bagre-epf autoantibodies number of positive cases strength of staining colocalization with arvcf number of positive cases strength of staining colocalization with arvcf igg 40/45 (+++) 100% 39/45 (+++) 100% fibrinogen 39/45 (+++) 100% 38/45 (++) 100% igm 38/45 (+++) 100% 38/45 (+++) 100% albumin 38/45 (+++) 100% 38/45 (++) 100% complement/c3c 35/45 (+++) 100% 35/45 (++) 100% complement/c1q 35/45 (++) 100% 35/45 (++) 100% iga 15/45 (++) 100% 15/45 (++) 100% igd 16/45 (++) 100% 16/45 (++) 100% ige 7/45 (++) 100% 7/45 (++) 100% 8 research | dermatol pract concept 2017;7(4):2 proteins and cell-cell adhesion regulate plasma membrane and nuclear localization of arvcf. mol biol cell. 2004;15(12):55035515. 14. abreu-velez am, javier patiño p, montoya f, bollag wb. the tryptic cleavage product of the mature form of the bovine desmoglein 1 ectodomain is one of the antigen moieties immunoprecipitated by all sera from symptomatic patients affected by a new variant of endemic pemphigus. eur j dermatol. 2003;13(4):359-366. 15. abréu-vélez am, yepes mm, patiño pj, bollag wb, montoya f sr. a cost-effective, sensitive and specific enzyme linked immunosorbent assay useful for detecting a heterogeneous antibody population in sera from people suffering a new variant of endemic pemphigus. arch dermatol res. 2004; 295(10):434-441. 16. mclean-tooke a, spickett gp, gennery ar. immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. scand j immunol. 2007;66(1):1-7. 9. abreu-velez am, zhe j, howard ms, dudley sc. cardiac autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in colombia, south america. j clin immunol. 2011;31(6):985-997. 10. abreu-velez am, howard ms, hashimoto t, grossniklaus he. human eyelid meibomian glands and tarsal muscle are recognized by autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in el-bagre, colombia, south america. j am acad dermatol. 2010;62(3):437-447. 11. hatzfeld m. the p120 family of cell adhesion molecules. eur j cell biol. 2005;84(2-3):205-214. 12. mariner dj, sirotkin h, daniel jm, et al. production and characterization of monoclonal antibodies to arvcf. hybridoma. 1999;18(4): 349-399. 13. kausalya pj, phua dc, hunziker w. association of arvcf with zonula occludens (zo)-1 and zo-2: binding to pdz-domain dermatology: practical and conceptual 16 research | dermatol pract concept 2017;7(3):3 dermatology practical & conceptual www.derm101.com introduction surgical site infections (ssi) account for up to 20% of healthcare associated infections, [1] which amounts to approximately 35,000-40,000 infections in australia each year [2]. as australia has the highest rate of skin cancer in the world, and as the majority of skin cancer is managed in general practice [3], gp minor surgery and optimal postoperative management is a particular issue for australian gps. it is projected that close to a million surgical procedures for both squamous cell carcinoma (scc) and basal cell carcinoma (bcc) will be performed in 2016 [4], the majority of these by general practitioners (gps). the acceptable rate of ssi following clean minor surgery (class 1) is less than 5% [5], however, the infection rate may topical antibiotics to prevent surgical site infection after minor surgery in primary care clare heal1, phoebe lepper1, jennifer banks1 1 james cook university, mackay base hospital, mackay, australia key words: surgical site infection, skin cancer, topical antibiotics citation: heal c, lepper p, banks j. topical antibiotics to prevent surgical site infection after minor surgery in primary care. dermatol pract concept 2017;7(3):3. doi: https://doi.org/10.5826/dpc.0703a03 received: december 12, 2016; accepted: april 28, 2017; published: july 31, 2017 copyright: ©2017 heal et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: prof clare heal, phd, james cook university rural clinical school, mackay base hospital mackay qld 4740, australia. tel. 0457506701. email: clare.heal@jcu.edu.au background: surgical site infection (ssi) after minor surgery in primary care can compromise cosmetic outcomes, delay wound healing and increase costs. in addition to efficacy, adverse effects must be considered when considering antibiotic prophylaxis. there is no prior published literature regarding the proportion of general practitioners (gps) who use topical antibiotics as ssi prophylaxis following minor surgery. objectives: to identify the proportion of gps in a regional center in queensland, australia who apply topical antibiotics to wounds prevent ssis after minor surgery. method: a database of 90 gps was established, and they were invited to complete a questionnaire. results: the response rate was 62% (56/90). topical antibiotics prophylaxis was reported as being used always or sometimes in routine practice by 18% (10/56) of participants after both skin lesion excision and repair of lacerations. in the context of high-risk situations, on the other hand, use was higher. they were more likely to be used in high-risk situations, most frequently in diabetic patients (41.0% [23/56]) and immunocompromised patients (46.5% [26/56]). conclusions: evidence-based prescribing of antibiotics is vital. topical antibiotic prophylaxis is often prescribed excessively after clean dermatological surgery, however, in our sample of gps, only 18% used topical antibiotics always or sometimes in their practice. abstract research | dermatol pract concept 2017;7(3):3 17 tionnaire was pilot tested in may 2014 and based on feedback was further refined before distribution. the questionnaire aimed to investigate topical antibiotic prescribing both in routine practice and in the context of high-risk situations. the categories of “always and sometimes” were further combined for the purposes of interpretation to indicate that topical antibiotics were used “ever,” as opposed to “seldom or never.” data collection the questionnaire, information sheet, and consent form were individually posted to all gps in the database. each practice was initially sent an email to inform them of the survey and to request the return of the completed questionnaires and consent forms. after a period of three months, a second copy of the survey was sent to eligible participants with a follow-up email. data from completed questionnaires were de-identified and stored securely. data analysis data collected from the survey was analyzed using statistical package for social sciences (spss, inc. version 22). participant characteristics and outcomes were presented using frequencies and descriptive statistics. comparisons of outcomes were analyzed with a chi-squared test or fisher’s exact test where appropriate, with a p value less than 0.05 considered significant. ethical considerations ethical approval for the study was obtained from the james cook university human research ethics committee (h5616). results completed surveys were returned by 56/90 participants (62% response rate). the characteristics of those gps who responded are presented in table 1. of the participants who responded, 53.6% were male, 60% (34/56) were aged 46-55, and 34% had a length of practice between 21 and 30 years. this is representative of the demographics of gps in mackay. use of topical antibiotics after excisions and lacerations in the context of routine practice in the context of routine practice, topical antibiotics were reported to be used always or sometimes (as opposed to seldom and never) to prevent wound infections after minor skin excisions by 18% (10/56) of participants. after lacerations, 18% (10/56) of participants also reported using topical antibiotics always or sometimes (table 2). there was no association between the gp characteristics of age, gender, and length of time in practice and the use of topical antibiotics in excisions and lacerations. be higher because of body site, [6,7] the pathology of the lesion removed [6-8] or environmental conditions [8,9]. limited guidelines exist regarding antibiotic prophylaxis of dermatological procedures [10-12,13], and those available guidelines do not recommend any type of antibiotic to prevent ssi in clean (class 1) minor surgery [11]. the national institute for health and care excellence (nice) guidelines also state “do not use topical antibiotics in wounds healing by primary intention to reduce the risk of surgical site infection.” [12] in practice, antibiotic prophylaxis is prescribed excessively or inappropriately for dermatological surgery, in general, and it is recommended it be reserved for high-risk situations [13-15]. a recent cochrane review found moderate quality evidence that topical antibiotics probably prevent ssi compared to no treatment (rr 0.61, 95% ci 0.42 to 0.87), but did not recommend use in clean (class 1) surgery, where the baseline infection rate is already low. there was insufficient evidence in the review to make judgments about adverse events such as allergic contact dermatitis and antibiotic resistance [16] that limits the ability to make an overall evaluation of the use of topical antibiotics. currently, there is no data available to assess the proportion of australian gps who use topical antibiotics as ssi prophylaxis in wounds healing by primary intention. the aim of this study was to identify the proportion of gps in mackay, queensland who use topical antibiotics to prevent ssi in excisions and lacerations healing by primary intention as well as identifying the class of topical antibiotics used and clinical and patient factors that may influence this use. methods study design and setting all gps, including gp registrars working within the 4740 postcode, were initially identified by a search of the townsville-mackay medicare local service finder. each gp clinic was contacted by a study author (pl) to confirm the gps working at that service. those gps who were on leave at the time of the survey were excluded as were gps working in settings that did not involve minor surgery (women’s health, occupational health). a database of 90 gps was established. sample size based on an estimated incidence of 50% for our primary outcome (incidence of prescribing topical antibiotics), the sample size was calculated to be 47 for 95% confidence and 10% precision. questionnaire the two-page questionnaire was designed by one author (pl) with assistance from other authors (ch and jb), using current guidelines and literature to ensure content validity. the ques18 research | dermatol pract concept 2017;7(3):3 one other study of topical antibiotic use was identified in the literature. this was a survey of uk plastic surgeons regarding topical chloramphenicol use, which was initially conducted in 1999 and then repeated in 2010. in the initial survey, 66% of uk plastic surgeons reported using topical chloramphenicol ointment in their practice, and in 2010 a slightly higher proportion of 72% was reported [17,18]. this is higher than the reported rate of 18% in our gp survey and may in part be due to a difference in types of surgery or patient expectations. it was interesting that, in the context of routine practice, topical antibiotics were reported to be used always or sometimes by the same number of gps (18%) after excisions as lacerations. excisions are classified as class 1 wounds with an acceptable postoperative infection rate of less than 5% [5], while lacerations are classified class 3 wounds, with an acceptable infection rate of 10-17% [19]. assuming that the relative risk reduction in both clinical situations is the same, topical antibiotics would be of more clinical value after lacerations than skin excisions, where the likely absolute risk reduction in infection would be higher. in our previous studies of risk factors for infection, we established excision from the lower limb as being the most significant independent risk factor for ssi, with infection rates as high as 30% [6,7,20] and, therefore, in the context of highrisk practice, the reported high frequency of use of topical antibiotics by gps in excisions from the lower limb (39%) is probably justified. the evidence for diabetes as a risk factor class of topical antibiotics used the different subtypes of topical antibiotics used by gps in any area of their practice are reported in table 3. the two most commonly used antibiotics were chloramphenicol, which was reported to be used by 56.6% (30/53) of gps, and mupirocin, which was reported to be used by 43.4% (23/53) of gps. there was no significant association between gp characteristics and the class of topical antibiotic used. use of topical antibiotics in the context of highrisk situations the reported use of topical antibiotics was higher in the context of clinical situations that are considered to be at higher risk for infection (table 4). a total of 41.0% (23/56) of gps reported ever (always or sometimes) using topical antibiotics in diabetic patients, 46.5% (26/56) of gps reported the same for immunocompromised patients, 46.5% (26/56) for patients with previous surgical site infection, 39.3% (22/56) for lower limb sites, 17.9% (10/56) for upper limb sites and 33.4% (19/56) for facial wounds. gps who had been in practice for less than ten years reported they were significantly more likely to use antibiotics always or sometimes for immunocompromised patients (p= 0.01), and patients with previous surgical site infections (p= 0.02) compared with gps who had been in practice for a longer period. discussion the judicious use of antibiotics is critical. in addition to efficacy, health system costs, side effects, and the rise in antibiotic resistance must be taken into account when considering antibiotic use prophylactically. while there is much discussion about gp oral antibiotic use, we believe that this is the first study to establish the frequency of topical antibiotic use in the context of minor surgery by gps. table 1. characteristics of respondents characteristics n (%) n=56 gender male female 30 (53.6) 26 (46.4) age in years ** < 30 30-44 45-59 60 and older 2 (3.6) 13 (23.2) 34 (60.7) 5 (8.9) length of practice in gp (y) 10 years or less 11-20 21-30 more than 30 years 15 (26.8) 16 (28.6) 19 (33.9) 6 (10.7) ** 2 participants did not report age table 2. frequency of topical antibiotic use in the context of routine practice frequency excisions % lacerations % never 29 (51.8) 36 (64.3) seldom 17 (30.4) 10 (17.9) sometimes 8 (14.3) 9 (16.1) always 2 (3.6) 1 (1.8) table 3. types of topical antibiotics used** antibiotic used frequency n (%)* mupirocin 23 (43.4) chloramphenicol 30 (56.6) polymixin b sufate 1 (1.9) bacitracin zinc, neomycin sulfate, polymyxin b sulfate combination ointment (tao) 1(1.9) neomycin 2 (3.8) not used 10 (18.8) * there was missing data from 3 gps, denominator=53 gps ** this question referred to topical antibiotics used in any clinical situation by gps https://www.drugs.com/mtm/bacitracin-neomycin-and-polymyxin-b-topical.html https://www.drugs.com/mtm/bacitracin-neomycin-and-polymyxin-b-topical.html research | dermatol pract concept 2017;7(3):3 19 implications for general practice evidence-based prescribing of antibiotics is vital. in practice, antibiotic prophylaxis is often prescribed excessively or inappropriately for dermatological surgery [13-15]; however, in our sample of gps only 18% used topical antibiotics always or sometimes in their practice. it is evident that topical antibiotics are used too frequently for prophylaxis against infection after clean surgery and that they should be reserved for high-risk situations. acknowledgements professor jill thistlethwaite. references 1. magill ss, edwards jr, bamberg w, et al. multistate pointprevalence survey of health care–associated infections. n engl j med. 2014;370(13):1198-1208. 2. brannigan e, holmes a. healthcare associated infections—the size of the problem. in: gould im, van der meer jwm, eds. antibiotic policies. springer: new york; 2012:1-14. 3. askew da, wilkinson d, schluter pj, eckert k. skin cancer surgery in australia 2001-2005: the changing role of the general practitioner. med j aust. 2007;187(4):210-214. 4. fransen m, karahalios a, sharma n, english dr, giles gg, sinclair rd. non-melanoma skin cancer in australia. med j aust. 2012;197(10):565-568. 5. mangram aj, horan tc, pearson ml, silver lc, jarvis wr. guideline for prevention of surgical site infection, 1999. centers for disease control and prevention (cdc) hospital infection control practices advisory committee. am j infect control. 1999;27(2):97-132; quiz 133-134; discussion 196. 6. heal c, buettner p, browning s. risk factors for wound infection after minor surgery in general practice. med j aust. 2006;185(5):255-258. 7. heal cf, buettner pg, drobetz h. risk factors for surgical site infection after dermatological surgery. int j dermatol. 2012;51(7):796-803. 8. heal c, buettner p, raasch b, et al. can sutures get wet? prospective randomised controlled trial of wound management in general practice. bmj. 2006;332(7549):1053-1056. for surgical site infection after minor surgery has been conflicting [6,7], and the frequency of use of topical antibiotics in diabetic patients (41%) is not justified, based on our previous research. excisions from the facial regions have a lower than average rate of wound infection [21], however, gps reported that they were more likely to use topical antibiotics in this situation (33.4%) compared with routine skin excisions. this may be a reflection of concern about cosmetic appearance, but again, considering the low infection rate in this clinical situation, it is not likely justified. chloramphenicol has been shown to result in a statistically significant decrease in wound infection after minor skin excisions, and this is reflected by topical chloramphenicol being the most commonly reported topical antibiotic used [22]. however, mupirocin was not shown to be effective compared with a placebo in preventing surgical site infection, even though it is the second highest reported topical antibiotic used in our survey [23]. secondary to contamination, there has been a recent shortage in australia, and worldwide, of mupirocin and fucidin ointment (leo laboratories, berkshire, uk) [24], and therefore chloramphenicol ointment is one of the few options available in australia. however, despite proven efficacy, chloramphenicol ointment is not approved for use on wounds, and therefore must be prescribed off-label for this purpose. chloramphenicol is also now available over the counter in australia, which may increase inappropriate use. with all topical antibiotics, there is a risk of allergic contact dermatitis as well as antibiotic resistance [25]. there were some limitations associated with our study. the sample was a small number of gps in one regional area. some practices involved have participated in skin cancer research in the past and therefore may be more knowledgeable of current guidelines than the general practice population. our infection rate has been shown to be higher than other similar gp cohorts, likely due to our tropical environment; therefore, our prescribing may not be the same as other parts of australia with lower infection rates. the power of the study was restricted due to the small sample size. some outcomes showed a tendency to statistical significance, but there was not enough power to establish statistical significance. table 4. antibiotic use in high-risk situations frequency n (%) diabetes mellitus immunocompromised previous ssi lower limb sites upper limb sites facial sites never 14 (25) 11 (19.6) 13 (23.2) 16 (28.6) 25 (44.6) 22 (39.3) seldom 19 (33.9) 18 (32.1) 17 (30.4) 18 (32.1) 21 (37.5) 18 (32.1) sometimes 19 (33.9) 16 (28.6) 21 (37.5) 19 (33.9) 10 (17.8) 18 (26.8) always 4 (7.1) 10 (17.9) 5 (8.9) 3 (5.3) 0 (0) 1 (1.8) 20 research | dermatol pract concept 2017;7(3):3 18. erel e, goodyear s, misra a. a survey of chloramphenicol use in plastic surgery: a follow-up. j plast reconstr aesthet surg. 2010;63(1):e102-e103. 19. ortega g, rhee ds, papandria dj, et al. an evaluation of surgical site infections by wound classification system using the acsnsqip. j surg res. 2012;174(1):33-38. 20. smith sc, heal cf, buttner pg. prevention of surgical site infection in lower limb skin lesion excisions with single dose oral antibiotic prophylaxis: a prospective randomised placebo-controlled double-blind trial. bmj open. 2014;4(7):e005270. 21. sylaidis p, wood s, murray ds. postoperative infection following clean facial surgery. ann plast surg. 1997;39(4):342-346. 22. heal cf, buettner pg, cruickshank r, et al. does single application of topical chloramphenicol to high risk sutured wounds reduce incidence of wound infection after minor surgery? prospective randomised placebo controlled double blind trial. bmj. 2009;338:a2812. 23. dixon aj, dixon mp, dixon jb. randomized clinical trial of the effect of applying ointment to surgical wounds before occlusive dressing. br j surg. 2006;93(8):937-943. 24. pharmacy news. http://www.pharmacynews.com.au/news/latestnews/bactroban-contamination-causes-australia-wide-shor. 2nd may 2016. accessed june 2016. 25. blondeel a, oleffe j, achten g. contact allergy in 330 dermatological patients. contact dermatitis. 1978;4(5):270-276. 9. heal c, sriharan s, buttner pg, kimber d. comparing non-sterile to sterile gloves for minor surgery: a prospective randomised controlled non-inferiority trial. med j aust. 2015;202(1):27-31. 10. bratzler dw, dellinger ep, olsen km, et al. clinical practice guidelines for antimicrobial prophylaxis in surgery. am j health syst pharm. 2013;70(3):195-283. 11. scottish intercollegiate guidelines n. antibiotic prophylaxis in surgery. http://www.sign.ac.uk/pdf/sign104.pdf. edinburgh2014. 12. national institute for health and care excellence. surgical site infection (clinical guideline 74). www.nice.org.uk. accessed on december 12, 2016. 13. wright ti, baddour lm, berbari ef, et al. antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. j am acad dermatol. 2008;59(3):464-473. 14. messingham mj, arpey cj. update on the use of antibiotics in cutaneous surgery. dermatol surg. 2005;31(8 pt 2):1068-1078. 15. rosengren h, dixon a. antibacterial prophylaxis in dermatologic surgery: an evidence-based review. am j clin dermatol. 2010;11(1):35-44. 16. heal cf, banks jl, lepper pd, kontopantelis e, van driel ml. topical antibiotics for preventing surgical site infection in wounds healing by primary intention. cochrane database syst rev. 2016;11:cd011426. 17. erel e, platt aj, ramakrishnan v. chloramphenicol use in plastic surgery. br j plast surg. 1999;52(4): 326-327. http://www.pharmacynews.com.au/news/latest-news/bactroban-contamination-causes-australia-wide-shor http://www.pharmacynews.com.au/news/latest-news/bactroban-contamination-causes-australia-wide-shor http://www.sign.ac.uk/pdf/sign104.pdf http://www.nice.org.uk dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(2):e2023073 1 importance of board-certified dermatologist online reviews: small steps to improve patient experiences and perspectives julianne m. falotico1, shari r. lipner2 1 renaissance school of medicine at stony brook university, stony brook, ny, usa 2 weill cornell medicine, department of dermatology, new york, ny, usa citation: falotico jm, lipner sr. importance of board-certified dermatologist online reviews: small steps to improve patient experiences and perspectives. dermatol pract concept. 2023;13(2):e2023073. doi: https://doi.org/10.5826/dpc.1302a73 accepted: september 13, 2022; published: april 2023 copyright: ©2023 falotico et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: ms. falotico has no conflicts of interest. dr. lipner has served as a consultant for ortho dermatologics, verrica, hoth therapeutics, belletorus corporation, and hexima. authorship: all authors have contributed significantly to this publication. corresponding author: shari r. lipner md, phd 1305 york avenue, ny, ny 10021. phone: 646-962-3376 fax: 646-962-0033 email: shl9032@med.cornell.edu online physician reviews and ratings are becoming increasingly popular, potentially influencing prospective patients and their decisions regarding where to seek dermatologic care [1]. cosmetic dermatologists, in particular, may rely heavily on online profiles to attract patients [2]. previous work found significantly higher proportions of negative online reviews of dermatology (20.4%-32.7%) versus non-dermatology (4.7%-8.5%) practices performing botulinum toxin injections (p < 0.0001) [3]. in this commentary, we review digital review trends and make recommendations to improve online reviews of board-certified dermatologists. waqas et al [4] analyzed online ratings of 167 dermatologists and found that the lowest average ratings in the most and least dermatologist-dense areas were on yelp (3.61) and google (3.45), respectively. ratings on healthcare versus general consumer websites were closer to the overall average (4.06) and had a higher degree of correlation across sites. therefore, healthcare versus general consumer websites may more accurately reflect authentic patient experiences. waqas et al [5] also analyzed dermatologist reviews across five websites and found no differences in achieving higher ratings for males versus females [odds ratio (or):1.56; p = 0.226]. there was a greater likelihood of higher ratings in dermatologist-dense areas (or: 2.61; p = 0.48) and lower ratings with increased years of experience (or: 0.96; p = 0.006). therefore, patients reported greater satisfaction with younger dermatologists in urban areas, which may be due to their spending more time with patients and using newer technologies. we postulate that younger patients, who are more comfortable using the internet, may be more likely to utilize online reviews. older patients may need encouragement and guidance to write online reviews. trager et al [6] analyzed 12,272 online ratings of 187 mohs micrographic surgeons and found that of 5,255 2 commentary | dermatol pract concept. 2023;13(2):e2023073 written comments, the majority (87%) were positive and most discussed perceived experiences [50.2%; 95% confidence interval (ci): 49%-52%] and bedside manner (33.2%; 95% ci: 32%-34%). therefore, the content of written reviews may give insight into the things that matter most to patients. riemer et al [7] analyzed online ratings of 100 dermatologists, reporting that the mean ratings across all five websites were high (3.60-4.58). zocdoc.com had significantly fewer negative comments than other websites (χ2 = 12.02; p = 0.007) and had the highest overall total (1231) and mean ratings per dermatologist (102.6), with notifications built in to solicit patient reviews. therefore, encouraging patients to share their experiences may help negate the impact of outlier reviews when the overall volume is low. first impressions from online reviews may impact where patients choose dermatological care and current reviews may not be entirely indicative of true patient experiences. we suggest analyzing ratings and content on healthcare-specific versus consumer websites to better gauge patient experiences and overall satisfaction. since patients emphasize bedside manner in their reviews, delivering exceptional patient care as well as clear communication and relatability will likely improve patient satisfaction and translate to improved online ratings. since the overwhelming majority of patients probably have positive visits with dermatologists, it is helpful to encourage patients to write reviews and share their experiences. future studies should analyze reviews in the context of patient demographics, as differing priorities and expectations may contribute to perceived experiences and dermatologist ratings. references 1. smith rj, lipoff jb. evaluation of dermatology practice online reviews: lessons from qualitative analysis. jama dermatol. 2016;152(2):153-157. doi: 10.1001/jamadermatol.2015.3950. pmid: 26606326. 2. wang jv, heitmiller k, boen m, saedi n. fake online physician reviews in aesthetic dermatology: bioethical and professional obligations. dermatol surg. 2021;47(5):748-749. doi: 10.1097/dss.0000000000002516. pmid: 33905402. 3. avila c, pootrakul l, shipp d, massick s, kaffenberger b. dermatologist online ratings for botulinum toxin injections are nuanced and may be misleading. j am acad dermatol. 2021;85(5): 1313-1315. doi: 10.1016/j.jaad.2020.09.045. pmid: 32956739. 4. waqas b, cooley v, lipner sr. comparison of dermatologist ratings on health care-specific and general consumer websites. cutis. 2021;107(4):182-184. doi: 10.12788/cutis.0220. pmid: 34096845. 5. waqas b, cooley v, lipner sr. association of sex, location, and experience with online patient ratings of dermatologists. j am acad dermatol. 2020;83(3):954-955. doi: 10.1016/j .jaad.2020.01.055. pmid: 32006602. 6. trager mh, ensslin ce, fan w, samie fh. factors impacting patient ratings of mohs micrographic surgeons: lessons gleaned from analysis of 17,527 online reviews. j am acad dermatol. 2020;83(6):1825-1827. doi: 10.1016/j.jaad.2020.05.082. pmid: 32450101. 7. riemer c, doctor m, dellavalle rp. analysis of online ratings of dermatologists. jama dermatol. 2016;152(2):218-219. doi: 10.1001/jamadermatol.2015.4991. pmid: 26677133. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022168 1 mycoplasma pneumoniae-associated subcorneal pustular dermatosis: not as rare as we think? gloria baeza-hernández1, alberto guerrero-torija1, ricardo francisco rubio-aguilera1, radia khedaoui2, cristina martínez-morán1, jesús borbujo1 1 department of dermatology, hospital universitario de fuenlabrada, madrid, spain 2 department of pathology, hospital universitario de fuenlabrada, madrid, spain key words: mycoplasma pneumoniae, subcorneal pustular dermatosis, sneddon-wilkinson disease, pustular eruption citation: baeza-hernández g, guerrerotorija a, rubioaguilera rf, khedaoui r, martínez-morán c, borbujo j. mycoplasma pneumoniae-associated subcorneal pustular dermatosis: not as rare as we think? dermatol pract concept. 2022;12(4):e2022168. doi: https://doi.org/10.5826/dpc.1204a168 accepted: march 8, 2022; published: october 2022 copyright: ©2022 baeza-hernández et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gloria baeza-hernández, servicio de dermatología, hospital de fuenlabrada, camino del molino 2, 28942 fuenlabrada, madrid. e-mail: gloria.baeza@salud.madrid.org introduction subcorneal pustular dermatosis (spd) or sneddonwilkinson disease is a rare condition included in the spectrum of neutrophilic dermatoses. seldom it can be triggered by infections caused by mycoplasma pneumoniae (mp) [1]. herein we present the case of a young woman with spd associated with an otherwise asymptomatic mp infection. topical corticosteroids resolved lesions with no relapses after one-year follow-up. case presentation a 40-year-old woman presented with a two-week history of asymptomatic skin lesions located on the cervical, axillar, inframammary and inguinal folds, with no improvement despite treatment with topical clotrimazole and oral fluconazole. she felt otherwise well and reported no other symptoms. she was diagnosed with irritative eczema and treated with 0.5 mg/kg daily oral prednisone with clinical worsening a few days later. clinical examination revealed well-demarcated non-infiltrated erythematous plaques with multiple fragile pustules measuring less than 1 mm over them, located on the aforementioned folds (figure 1), some of them with annular and polycyclic borders. physical examination was otherwise unremarkable. oral prednisone was immediately switched to mometasone furoate 0.1% cream twice a day. skin samples were culture-negative for bacterial and fungal pathogens and blood tests showed positive mp igm and negative igg. skin biopsy (figure 2) showed a subcorneal pustule filled with neutrophils, neutrophilic exocytosis below the pustule without other prominent epidermal changes, and dermal perivascular and interstitial infiltrate composed by neutrophils and lymphocytes. direct immunofluorescence was negative, and no fungal structures were observed with pas stain. these histological features were consistent with that of subcorneal pustular dermatosis. a few weeks later, blood tests demonstrated mp igg seroconversion. after 15 days with topical mometasone the skin lesions had completely healed. with a diagnosis of mp-associated spd, the patient was followed up for 1 year, with no recurrence. 2 research letter | dermatol pract concept. 2022;12(4):e2022168 conclusions mp-associated spd has been previously reported by winnock et al in a 43-year-old male, papini et al in an 8-year-old male, bohelay et al in a 19-year-old male and lombart et al in a 36-year-old woman [2-5]. all the patients were young like our case, and mp infection clinical manifestations varied: some patients had a mild cough while others suffered pneumonia that required inpatient treatment. a few days later, the patients developed the skin manifestations figure 1. clinical examination: large well-demarcated erythematous plaques with annular and polycyclic borders involving axillar and inframammary folds, with pustules measuring less than 1 mm. figure 2. h&e ×20. skin biopsy suggestive of subcorneal pustular dermatosis. a subcorneal pustule with neutrophilic exocytosis in the epidermis below it is observed, with no other remarkable epidermal changes; neutrophilic and lymphocytic dermal perivascular and interstitial infiltrate. research letter | dermatol pract concept. 2022;12(4):e2022168 3 compatible with spd. winnock and papini patients´ were treated with oral dapsone with resolution of the skin lesions in 1-3 months, and bohelay and lombart patients´ were treated with topical corticosteroids with improvement in 5-15 days, similarly to our case [2-5]. none of the patients suffered a relapse during follow-up [2-5]. these findings suggest that mp-spd may require a different approach than “classical” spd, for these patients have self-limiting and non-relapsing disease. thus, we propose topical corticosteroids as a first-line therapy; oral dapsone could be reserved for unresponsive or serious cases. a scheduled follow-up visit may be unnecessary. as stated by bohelay and lombart mp is probably an underestimated trigger for spd, given the asymptomatic course of the infection in many cases like our patient [4,5]. even without symptoms of infection, laboratory testing for mp should be performed in young patients with spd, as it may change the clinical approach to the patient, thus avoiding unnecessary systemic treatment and follow-up. references 1. watts pj, khachemoune a. subcorneal pustular dermatosis: a review of 30 years of progress. am j clin dermatol. 2016;17(6): 653-671. doi:10.1007/s40257-016-0202-8. pmid: 27349653. 2. winnock t, wang j, suys e, de coninck a, roseeuw d. vesiculopustular eruption associated with mycoplasma pneumoniae pneumopathy. dermatology. 1996;192(1):73-74. doi:10.1159/000246322. pmid: 8832960. 3. papini m, cicoletti m, landucci p. subcorneal pustular dermatosis and mycoplasma pneumoniae respiratory infection. acta derm venereol. 2003;83(5):387-388. doi:10.1080/00015550310010630. pmid: 14609116. 4. bohelay g, duong ta, ortonne n, chosidow o, valeyrie-allanore l. subcorneal pustular dermatosis triggered by mycoplasma pneumoniae infection: a rare clinical association. j eur acad dermatol venereol. 2015;29(5):1022-1025. doi:10.1111/ jdv.12446. pmid: 24650287. 5. lombart f, dhaille f, lok c, dadban a. subcorneal pustular dermatosis associated with mycoplasma pneumoniae infection. j am acad dermatol. 2014;71(3):e85-e86. doi:10.1016/j. jaad.2014.02.038. pmid: 25128138. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023152 1 persistent chemotherapy-induced alopecia treated with low dose oral minoxidil: a multicenter retrospective case series of 15 patients matilde iorizzo1, anna waśkiel-burnat2, jasmine anedda3, bianca maria piraccini4, zoe apalla5, lidia rudnicka2, michela starace4 1 private dermatology practice, bellinzona/lugano, switzerland 2 department of dermatology, medical university of warsaw, warsaw, poland 3 dermatology clinic, department of medical sciences and public health, university of cagliari, cagliari, italy 4 dermatology unit irccs policlinico sant’orsola department of specialized, experimental and diagnostic medicine, university of bologna, bologna, italy 5 second dermatology department, aristotle university of thessaloniki, papageorgiou general hospital, thessaloniki, greece key words: persistent chemotherapy induced alopecia, permanent chemotherapy induced alopecia, cancer survivors, cancer patients, oral minoxidil citation: iorizzo m, waśkiel-burnat a, anedda j, et al. persistent chemotherapy-induced alopecia treated with oral minoxidil: a multicenter retrospective case series of 15 patients. dermatol pract concept. 2023;13(3):e2023152. doi: https://doi.org/10.5826/dpc.1303a152 accepted: february 3, 2023; published: july 2023 copyright: ©2023 iorizzo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: michela starace, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, v. massarenti 1, 40138, bologna, italy. tel +39051-6364867; fax +39-0516364867; e-mail: michela.starace2@unibo.it introduction persistent chemotherapy-induced alopecia (pcia) is defined as the absence of hair regrowth after more than 6 months of treatment discontinuation [1]. topical minoxidil has been considered as the drug of choice in prevention or treatment of cia. in a case of pcia the efficacy of topical minoxidil may be limited [2,3]. moreover, it may cause scalp irritation with itching, dryness and scaling. the use of low-dose oral minoxidil (ldom) for the treatment of various forms of hair loss has demonstrated great efficacy [4]. to date, data considering efficacy of ldom in pcia are limited [2,5]. case presentation a retrospective analysis of case series of 15 patients treated with ldom for pcia (table 1) was performed. all patients with biopsy-proven pcia with no efficacy from topical minoxidil used for at least one year were included. patients with diagnosis of other form of hair loss or using other, than oral minoxidil, drug for alopecia were excluded. all patients presented with thinned and sparse hair, with more or less pronounced areas of bare scalp. trichoscopy showed a reduction of follicular units with an increase in vellus hair formation in the absence of inflammation and scarring. ldom was used at a daily dose of 1.5 mg in less 2 research letter | dermatol pract concept. 2023;13(3):e2023152 severe cases (seven cases with grade 1 alopecia according to ctcaev5.0) and 2.5 mg in more severe ones (eight cases with grade 2 alopecia). efficacy of ldom was assessed based on clinical and trichoscopic pictures. after six to 12 months, clinical improvement was observed in seven (100%) patients with grade 1 and in six (75%) patients with grade 2 alopecia. trichoscopy revealed an increased hair thickness and growth of new hair (figure 1). two out of eight patients affected by grade 2 alopecia were not able to abandon the wig, but partial hair regrowth and increased thickness made them feel more confident. dose reduction from 2.5 mg to 1.5 mg was necessary, at the three months follow up, in three females due to non-acceptable facial hypertrichosis. no other, including cardiological, side effects were reported. no cardiological tests were needed during and after the therapy. all patients refused a post-treatment scalp biopsy. the results of the present study is consistent with the study conducted by kang et al. (5) who observed efficacy of combination of ldom and topical minoxidil in patients with pcia. in our study, ldom used in monotherapy was effective. the limitation of the study is a small group of the patients included into analysis and the lack of post-treatment histology which would allow to define improvement on pathology grounds. further studies are needed to better clarify the mechanism of action of ldom in patients affected by pcia and to draw conclusions concerning optimal drug dosages. conclusions to conclude, we believe that ldom is a promising therapeutic option for patients with pcia who do not benefit from the topical solution or report disadvantages related to friction on a delicate scalp with thin hair. references 1. freites-martinez a, shapiro j, van den hurk c, et al. hair disorders in cancer survivors. j am acad dermatol. 2019;80(5): 1199-1213. doi: 10.1016/j.jaad.2018.03.056. pmid: 29660423. pmcid: pmc6186205. 2. yang x, thai ke. treatment of permanent chemotherapy induced alopecia with low dose oral minoxidil. australas j dermatol. 2016;57(4):e130-e132. doi: 10.1111/ajd.12350. pmid: 25966934 3. bhoyrul b, asfour l, lutz g, et al. clinicopathologic characteristics and response to treatment of persistent chemotherapy-induced alopecia in breast cancer survivors. jama dermatol. 2021;157(11):1335-1342. doi: 10.1001 /jamadermatol.2021.3676. pmid: 34586345. pmcid: pmc8482302. 4. vañó-galván s, pirmez r, hermosa-gelbard a, et al. safety of low-dose oral minoxidil for hair loss: a multicenter study of 1404 patients. j am acad dermatol. 2021;84(6):1644-1651. doi: 10.1016/j.jaad.2021.02.054. pmid: 33639244. 5. kang j, lee jw, kwon o. efficacy of low-dose oral minoxidil in the management of anticancer therapy-induced alopecia in patients with breast cancer: a retrospective cohort study. j am acad dermatol. 2023;88(5):1170-1173. doi: 10.1016/j .jaad.2022.12.005. pmid: 36526083. table 1. characteristics of patients with persistent chemotherapy-induced alopecia treated with low dose oral minoxidil. patients numbers females males 15 13 2 age (years), mean (range) 49 (35-71) disease breast adenocarcinoma lung adenocarcinoma myelodysplasia hodgkin lymphoma 12 1 1 1 taxane-based therapy docetaxel paclitaxel 3 7 non-taxane based therapy carboplatin cisplatin cyclophosphamide dacarbazine doxorubicin epirubicin etoposide 5-fluorouracil vincristine vinorelbine 3 1 10 1 2 3 3 1 1 1 targeted therapy pertuzumab trastuzumab 3 4 alopecia grade grade 1 grade 2 7 8 trichoscopy circle hairs / yellow dots hair thinning / empty follicules 3 15 research letter | dermatol pract concept. 2023;13(3):e2023152 3 figure 1. clinical and trichoscopy images of a patient with persistent chemotherapy-induced alopecia (a,b) before treatment. (c,d) after 6 months of treatment with oral minoxidil 1.5 mg/day. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022222 1 clinicopathological and demographic characteristics of paget’s disease: a 4-year study showing a male predominance in extra-mammary paget kamran balighi1,2, yasamin kalantari1,2, kambiz kamyab hesari3, vahide lajevardi2, hamidreza kheiri2, zeinab aryanian1,4 1 autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran 2 department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 3 department of dermatopathology, school of medicine, razi hospital, tehran university of medical sciences, tehran, iran 4 department of dermatology, babol university of medical sciences, babol, iran key words: paget, extramammary paget, mammary paget, paget cells citation: balighi k, kalantari y, kamyab hesari k, lajevardi v, kheiri h, aryanian z. clinicopathological and demographic characteristics of paget’s disease: a 4-year study showing a male predominance in extra-mammary paget. dermatol pract concept. 2022;12(4):e2022222. doi: https://doi.org/10.5826/dpc.1204a222 accepted: march 31, 2022; published: october 2022 copyright: ©2022 balighi et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: zeinab aryanian, assistant professor of dermatology, autoimmune bullous diseases research center, tehran university of medical sciences, tehran; department of dermatology, babol university of medical sciences, babol, iran, 1445613131, iran. tel. 021-55630223. e-mail: z_aryanian@yahoo.com introduction paget disease is a rare skin neoplasm and is categorized into mammary (mpd) and extra-mammary (empd) [1,2]. to date, its detailed histopathological features along with patients demographic characteristics have not been investigated in iran. in this study, we performed a clinic-pathological analysis of paget cases in a single tertiary center between 2016 and 2020. cases presentation a total of 32 cases including 26 (81.25%) females and 6 (18.75%) males with the mean age of 53 ±9 .96 years (range 34-78) were included in our study. all patients gave informed consent for participating in our study. the majority of our patients 26/32 (81.25%) had mpd, and 6/32 (8.75%) had empd. all cases had a history of scaly and erythematous prolonged lesions. out of the 26 mpd cases, 25/26 (96.1%) were female and 1/26 (3.9%) were male. the mean age of the mpd cases was 51.03 ± 8.80 (range 34-78). out of the 6 empd cases, 5/6 (83.3%) were male and 1/6 (16.7%) were female. the mean age of the empd cases was 61.5 ± 10.98 (range 42-74). of note, all empd patients had ano-genital involvement. 2/6 (33.33%) cases had scrotum empd, 1/6 (16.66%) patient had penis and scrotum empd, 2/6 (33.3%) had peri-anal involvements, and 2 research letter | dermatol pract concept. 2022;12(4):e2022222 1/6 (16.66%) patient had labia major empd. histopathological examination revealed the presence of cells with pale cytoplasm in addition to prominent nuclei along with a high nuclei cytoplasm ratio (n/c) in all 32 cases. moreover, 10/32 (31.25%) had lymphocyte infiltration. ihc was performed for 6 empd patients and all of them were positive for ck7 and (ck ae3/ae1) (table 1). conclusions it is believed that paget disease is more prevalent among older female patients [1-5]. the peak incidence of mpd is reported after the age of 60, while the mean age of the mpd patients in our study was 51 years [1]. asian studies have shown a significant empd predominance in males and likewise, in our study, we found that the majority of empd patients were men, although, other studies have reported a higher prevalence of empd in female patients [1]. the most common location for empd is the vulva in 65% of cases, perianal area, scrotum, penis, and axilla [1]. in this regard, the only female empd patient in our study had labia major involvement. based on the ghazawi et al study, the most common sites for empd in males are the scrotum and penis, which is consistent with the findings of our study [4]. the histologic hallmark of paget disease is the presence of paget’s cells [1]. in our study, the pathologic examination revealed the presence of paget cells in all cases along with lymphocytic infiltrations in one-third of patients. in a study done by elbendary et al the histopathologic evaluation showed no significant differences between mpd and empd which is consistent with our study [5]. our study confirms that mpd is more prevalent than empd. based on our study, there is a female predominance in mpd cases at younger ages in comparison to other reports, and penis and scrotal involvements of empd are highly probable locations. acknowledgment: the authors would like to thank the autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran for its technical and editorial assists references 1. lopes filho ll, lopes im, lopes lr, enokihara mm, michalany ao, matsunaga n. mammary and extramammary paget’s disease. an bras dermatol. 2015;90(2):225-231. doi:10.1590/ abd1806-4841.20153189. pmid: 25830993. pmcid: pmc4371672. 2. yasir m, khan m, lotfollahzadeh s. mammary paget disease. 2021 jun 2. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2021 jan–. pmid: 33085375. 3. shu b, shen xx, chen p, fang xz, guo yl, kong yy. primary invasive extramammary paget disease on penoscrotum: a clinicopathological analysis of 41 cases. hum pathol. 2016;47(1):70-77. doi: 10.1016/j.humpath.2015.09.005.. pmid: 26508372. 4. ghazawi fm, iga n, tanaka r, et al. demographic and clinical characteristics of extramammary paget’s disease patients in japan from 2000 to 2019. j. eur. acad. dermatol. venereol. 2021;35(2):e133-e135. doi: 10.1111/jdv.16868. pmid: 32780877. 5. elbendary a, xue r, valdebran m, et al. diagnostic criteria in intraepithelial pagetoid neoplasms: a histopathologic study and evaluation of select features in paget disease, bowen disease, and melanoma in situ. am j dermatopathol. 2017;39(6):419-427. doi: 10.1097/dad.0000000000000704. pmid: 28525420. table 1. the results of immunohistochemistry staining. number of patients that were assessed for the presence of this antigen number of patients that were positive n (%) ck7 6 6 (100%) ck ae1/ae3 6 6 (100%) s100 3 2 (66.66%) cea 6 5 (83.4%) melan a 4 3 (75%) ki-67 2 2 (100%) hmb-45 2 1 (50%) dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023081 1 antinuclear antibody positivity in patients with hair loss after covid-19 infection vildan manav1,2, duygu erdil1, ayşe esra koku aksu1 1 department of dermatology, university of health sciences, i̇stanbul training and research hospital, i̇stanbul, turkey 2 cosmetology, i̇stanbul university graduate school of medicine, i̇stanbul, turkey key words: sars-cov-19, hair loss, antinuclear antibody positivity, trichodynia citation: manav v, erdil d, koku aksu a. antinuclear antibody positivity in patients with hair loss after covid-19 infection. dermatol pract concept. 2023;13(2):e2023081. doi: https://doi.org/10.5826/dpc.1302a81 accepted: august 29, 2022; published: april 2023 copyright: ©2023 manav et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vildan manav, md, istanbul training and research hospital, department of dermatology, kasap i̇lyas mah. org. abdurrahman nafiz gürman cd. pk: 34098, istanbul, turkey. phone: +905334323524. fax: +9002126320060, e-mail: drvildanmanav@gmail.com introduction: hair loss is one of the most common disorders after coronavirus disease 2019 (covid-19) infection. this study aimed to investigate the relationship between covid-19-related hair loss and antinuclear antibody (ana) positivity and patterns. methods: ana positivity and patterns were analyzed in 30 female covid-19 patients with hair loss complaints and compared in terms of the presence of autoimmunity between patients with and without covid-19 exhibiting hair loss. results: ana positivity and cytoplasmic patterns were detected in 40% of the patients with covid-19 infection and hair loss. trichodynia and diffuse hair loss were observed in 63.3% and 53.3%, respectively. conclusions: in patients with covid-19-related hair loss, diffuse hair loss and ana positivity may be related to the high antibody levels triggered by covid-19 infection. abstract introduction more than 175 million people were infected with coronavirus disease 2019 (covid-19) within one year of the first covid-19 infection reported in china in early december 2019 [1]. it has been reported that 80% of patients with covid-19 infection develop one or more long-term symptoms. the most common symptoms are fatigue (58%), headache (44%), attention deficit (24%), and hair loss (25%) [2]. skin findings have received increasing attention for the early 2 original article | dermatol pract concept. 2023;13(2):e2023081 diagnosis of covid-19. covid-19-related skin findings include vascular eruptions, maculopapular eruptions (atypical forms of pityriasis rosea) [3], urticarial rash, vesicular, petechiae/purpuric eruptions, erythema multiforme–like rash, palmar erythema, perifollicular eruption, pruritus, mucosal rash, and androgenetic alopecia [4]. autoimmune diseases that develop or worsen after covid-19 infection have also been increasingly reported. these include connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus vasculitis, myositis, systemic sclerosis, and psoriatic arthritis) [5], multiple sclerosis, and autoimmune hepatitis [6] in adults, as well as rheumatic diseases [7,8] and type 1 diabetes in children [9]. antinuclear antibody (ana) tests were mainly developed for systemic lupus erythematosus screening. however, ana positivity has also been detected in many rheumatic diseases and is an indicator of autoimmunity [10]. ana positivity is not expected in non-scarring hair loss. in only one study, the rate of ana positivity was reported in patients with pattern hair loss (30.4%) [11]. objectives since covid-19 can trigger autoimmunity, and as hair loss is one of the most common symptoms after covid-19 infection, this study aimed to evaluate the relationship between the two and investigate the differences between autoimmunity and non-autoimmunity-related hair loss. methods this cross-sectional case-control study was performed between june and september 2021. the case group consisted of 30 patients who had contracted covid-19 up to 12 weeks previously and had hair loss complaints. the control group consisted of 60 patients who complained about hair loss but did not have covid-19. for the control group, each patient consisted of 2 consecutive patients who came to the dermatology outpatient clinic immediately after the patient selected for covid-19related hair loss. patients under the age of 18 years, patients with autoimmune or inflammatory diseases or acute or chronic infections, patients receiving any medications (corticosteroids, biological agents, antibiotics, or vitamin or mineral supplements), and pregnant or lactating women were excluded from the study. covid-19 infection was confirmed using nasopharyngeal swabs and polymerase chain reaction tests. demographic characteristics (age and gender) and clinical findings (date of covid-19 infection, duration of hair loss after covid-19 infection (time from hair loss onset to presentation to the clinic), severity of hair loss, and presence of trichodynia, oily scalp, dandruff, and diffuse hair loss) were collected. hair loss was recorded using the hair-shedding visual scale [12] as follows: < 50, 50–100, 100–150, and > 150 hairs/day. additionally, a pull test was performed at four locations on the scalp. the pull test was considered positive when more than 10% of the hair at each location was removed after applying steady traction. chemiluminescence enzyme immunoassays were performed to measure vitamin b12 and ferritin levels using an immunity 2000 device (diagnostic products corporation). tsh (thyroid stimulating hormone) and anti-tpo (anti-thyroid peroxidase) levels were measured using an architect ci16200 integrated system (abbot diagnostics). antinuclear antibody titers and patterns were studied using enzyme-linked immunosorbent assays and immunofluorescence, with human epithelioma type 2 (hep-2) cells used as the substrate. the ana tests were first run at titers of 1:100 with both kits, and positive samples were reanalyzed with further serial dilutions (1:160, 1:320, 1:640, 1:1280, 1:2560, and 1:5120). c3 and c4 levels were measured using a behring nephelometer and beckman reagent kits. this study was approved by the tertiary hospital ethics committee (no. 2939; october 8, 2021). written informed consent was obtained from all participants. statistical analysis statistical analyses were performed using spss version 25.0 (ibm). histograms and the kolmogorov–smirnov test were used to assess data normality. in descriptive analyses, means ± standard deviations and medians were used. categorical variables were compared using pearson chi-squared test. the mann–whitney u test was used to evaluate non-normally distributed (nonparametric) variables between the case and control groups, and the kruskal–wallis test was used for comparisons between more than two variables. spearman correlation coefficient was used to investigate correlations between variables. the ability of c3 and c4 values to predict ana positivity was investigated using receiver operating characteristic (roc) curves. values of p < 0.05 were considered statistically significant. results the mean ages of the patients in the case and control groups were 30.0 ± 11.2 and 29.2 ± 8.3 years, respectively. the difference was not statistically significant (p = 0.952). all patients were female. there were no statistically significant differences in standard laboratory test values between the two groups (table  1). conversely, the duration of hair loss was significantly longer in the control group than in the case group (p < 0.001). in the case group, hair loss started 5.2 ± 3.4 weeks after covid-19 infection. original article | dermatol pract concept. 2023;13(2):e2023081 3 the rate of patients in the case group losing more than 100 hairs per day was 86%, whereas the corresponding rate in the control group was only 26% (p < 0.001). trichodynia, oily scalp, and diffuse hair loss were significantly more common in the case group than in the control group (table 2). moreover, the case group had a significantly higher number of ana-positive patients (40.0%) than the control group (11.6%) (p = 0.002). the rate of cytoplasmic ana patterns in the case group was 83%, which was significantly higher than that in the control group (p = 0.001). in the control group, granular ana patterns represented 71.4% of the patients. there was no significant relationship between ana patterns and the severity of hair loss in the case group (table 3). the relationships between ana positivity and clinical findings are shown in table 4. in the covid-related hair loss group, the relationship between ana positivity and trichodynia, duration of hair loss (week), oilyscalp, dandruff, diffuse loss of hair volume, pull test was investigated. accordingly, in the covid-related hair loss group, all ana positive patients had diffuse hair loss (12/12) whereas only %22 of ana negative patients (4/18) had diffuse hair loss and pull test positivity were statistically significantly higher in patients with ana positivity.in the case group, there were no significant relationships between ana positivity and pattern or trichodynia (p = 0.279 and p = 0.670, respectively). likewise, there was no significant correlation between hair loss duration and ana positivity (r = −0.012, p = 0.949). no significant relationships were observed between ana positivity and c3 or c4 levels in the case group (p = 0.735 and p = 0.566, respectively). furthermore, the roc analysis indicated no significant cut-off values. conclusions ana positivity is detected in many viral and autoimmune diseases. however, studies on antibody responses after covid-19 infection have not produced definitive results [13,14]. it remains unclear whether hair loss after covid-19 infection is caused by the infection itself, the autoimmune response to the infection, or stress triggered by the covid-19 pandemic. to our knowledge, the relationship between covid-19-related ana positivity and hair loss developing after the infection has not been previously investigated. in this study, we detected ana positivity in 40% of patients exhibiting hair loss after covid-19 infection. this is consistent with previous studies reporting rates ranging from 21% to 64% [15-20]. nevertheless, it is important to note that all covid-19 patients in those studies had severe or moderate covid-19, whereas the patients included in our study had mild covid-19 and did not require hospitalization. the rate of ana positivity observed in this study is also in line with studies on hair diseases triggering stronger autoimmunity. such studies have reported rates of 21.2% in telogen effluvium [21], 30.4% in pattern hair loss [11], and 46% in lichen planopilaris [22]. surprisingly, in this study, cytoplasmic ana patterns were observed in 83.3% of the patients with hair loss after covid-19 infection. trachtenberg et al., who reported 64% ana positivity, found a highly dense and fine-speckled cytoplasmic pattern associated with covid-19 worsening clinical severity scores [20]. however, as previously noted, all patients with hair loss in our study had mild covid-19. chang et al detected cytoplasmic patterns at titers higher than 1:160 [23], whereas in this study, we observed table 1. comparison of standard laboratory test values of patients with covid-related hair loss and without covid-related hair loss. covid-related hair loss group control total pamean sd medin mean sd median mean sd median age (years) 30.03 ±11.22 27.00 29.15 ±8.32 27.00 29.44 ±9.33 27.00 0.952 duration of hair loss (weeks) 13.87 ±7.54 12.00 20.50 ±6.47 20.00 18.29 ±7.49 20.00 <0.001 vitamin b12(ng/l) 295.83 ±125.18 280.50 300.13 ±117.86 279.00 298.70 ±119.66 279.50 0.911 ferritin (μgr/l) 36.35 ±28.63 32.60 33.33 ±32.62 25.47 34.34 ±31.22 26.38 0.419 c3(g/l) 1.27 ±0.27 1.26 1.23 ±0.30 1.26 1.24 ±0.29 1.26 0.945 c4(g/l) 0.64 ±2,20 0.25 0.29 ±0.19 0.26 0.41 ±1.28 0.25 0.566 tsh (mu/l) 2.65 ±2.36 1.98 2.12 ±0.97 2.04 2.30 ±1.58 2.04 0.939 sd = standard deviation. amann whitney u test 4 original article | dermatol pract concept. 2023;13(2):e2023081 table 2. comparison of clinical examination and laboratory findings of patients with covid-related hair loss and without covid-related hair loss. covid-related hair loss group control total pan (%) n (%) n (%) pre-exisiting te no 20 (66.67) 41 (68.33) 61 (67.78) 0.873 yes 10 (33.33) 19 (31.67) 29 (32.22) amount of hair loss 50hairs/day 0 (0.00) 5 (8.33) 5 (5.56) <0.001 50-100hairs/day 4 (13.33) 39 (65.00) 43 (47.78) 100-150hairs/day 24 (80.00) 16 (26.67) 40 (44.44) >150hairs/day 2 (6.67) 0 (0.00) 2 (2.22) trichodynia no 11 (36.67) 42 (70.00) 53 (58.89) 0.002 yes 19 (63.33) 18 (30.00) 37 (41.11) oilyscalp no 15 (50.00) 44 (73.33) 59 (65.56) 0.028 yes 15 (50.00) 16 (26.67) 31 (34.44) dandruff no 11 (36.67) 35 (58.33) 46 (51.11) 0.053 yes 19 (63.33) 25 (41.67) 44 (48.89) diffuse loss of hair volume no 14 (46.67) 45 (75.00) 59 (65.56) 0.008 yes 16 (53.33) 15 (25.00) 31 (34.44) pull test negative 9 (30.00) 15 (25.00) 24 (26.67) 0.613 positive 21 (70.00) 45 (75.00) 66 (73.33) ana positivity negative 18 (60.00) 53 (88.33) 71 (78.89) 0.002 positive 12 (40.00) 7 (11.67) 19 (21.11) ana pattern cytoplasmic 10 (83.33) 0 (0.00) 10 (52.63) 0.001 granular 0 (0.00) 5 (71.43) 5 (26.32) nucleolar 1 (8.33) 0 (0.00) 1 (5.26) nuclear/granular 1 (8.33) 2 (28.57) 3 (15.79) antitpo μl <9 29 (96.67) 57 (95.00) 86 (95.56) 0.718 >9 1 (3.33) 3 (5.00) 4 (4.44) ana = antinuclear antibody; anti-tpo = anti-thyroid peroxidase; te = telogen effluvium achi-square test table 3. the relationship between the antinuclear antibody pattern and the amount of hair loss in patients in the covid-related hair loss group. covidrelated hair loss group amount of hair loss p 50 hairs/day 50-100 hairs/day 100-150 hairs/day > 150 hairs/day n (%) n (%) n (%) n (%) ana positivity negative 0(.00) 3(75.00) 14(58.33) 1(50.00) 0.784 positive 0(00) 1(25.00) 10(41.67) 1(50.00) ana pattern cytoplasmic 0(00) 1(10.00) 9(90.00) 0(.00) 0.016 granular 0(00) 0(.00) 0(.00) 0(.00) nucleolar 0(00) 0(.00) 1(10.00) 0(.00) nuclear/granular 0(00) 0(.00) 0(.00) 1(100.00) ana = antinuclear antibody original article | dermatol pract concept. 2023;13(2):e2023081 5 ana positivity and trichodynia or between trichodynia and autoimmunity. since no financial support is received, ena (extractable nuclear antigen) (anti-rnp, anti-scl70, anti-sm, anti-ss-a/ro52, anti-ss-a/ro60, or anti-ss-b/la), p-anca (perinuclear anti-neutrophil cytoplasmic antibodies), anticardiolipin igm, and igg, which are frequently measured in covid-19 antibody studies, were not measured and were performed. scalp biopsies. moreover, we did not evaluate patients stress levels using an anxiety scale to investigate the relationship between hair loss and stress. in conclusion, hair loss after covid-19 infection may be triggered by the release of autoantibodies in response to the infection. cytoplasmic ana patterns may be essential clinical markers for elucidating the pathogenesis of hair loss after covid-19 infection. references 1. harapan h, itoh n, yufika a, et al. coronavirus disease 2019 (covid-19): a literature review. j infect public health. 2020;13(5):667-673. doi: 10.1016/j.jiph.2020.03.019. pmid: 32340833. pmcid: pmc7142680. 2. galeotti c, bayry j. autoimmune and inflammatory diseases following covid-19. nat rev rheumatol. 2020;16(8):413-414. doi: 10.1038/s41584-020-0448-7. pmid: 32499548. pmcid: pmc7271827. 3. martora f, picone v, fornaro l, fabbrocini g, marasca c. can covid-19 cause atypical forms of pityriasis rosea refractory to conventional therapies? j med virol. 2022;94(4):1292-1293. doi: 10.1002/jmv.27535. pmid: 34931329. 4. wollina u, karadağ as, rowland-payne c, chiriac a, lotti t. cutaneous signs in covid-19 patients: a review. dermatol cytoplasmic patterns even at a titer of 1:100. furthermore, nucleolar patterns have been shown to be dominant in covid-19 [15,17,18,23]. thus, our results differ from those of previous studies in this respect. massabki et al [24] and eystathioy et al [25] suggested that cytoplasmic patterns at low and moderate titers had low clinical relevance. conversely, pazini et al reported that they were associated with autoimmune diseases even at low titers [26]. in our study, the cytoplasmic pattern of ana was positive even at low titer, but it was also clinically significant. trichodynia is a symptom of local paresthesia often associated with telogen effluvium, androgenetic alopecia, and alopecia areata [27,28]. it is a crucial dermatological marker of the severity of hair disease and the response to treatment [29]. the pathophysiology of trichodynia is unclear, although substance p, a stress-related neuronal peptide, has been suggested to elicit the sensation [28]. according to previous studies, the rates of coexistence between telogen effluvium and trichodynia range from 34% to 73.6%, while the rates of coexistence between aga (androgenetic alopecia) and trichodynia range from 26.4% to 36% [30-32]. starace et al reported that telogen effluvium coexisted with trichodynia in 58.4% of covid-19 patients [33], which is comparable to our findings. di landro et al. suggested that severity of trichodynia might be directly related to the severity and intensity of hair loss [34]. in this study, diffuse hair loss after covid infection was observed in 53.3% of the patients. the significant relationship between trichodynia and diffuse hair loss supports di landro et al.’s hypothesis. however, our results did not show a significant relationship between table 4. the relationship between antinuclear antibody positivity and clinical findings in patients in the covid-related hair loss group. ana pa negative positive n (%) n (%) trichodynia no 8 (44.44) 3 (25.00) 0.279 yes 10 (55.56) 9 (75.00) duration of hair loss (weeks), mean ± sd 12.89±6.48 15.33±9.00 0.520b oilyscalp no 9 (50.00) 6 (50.00) 1.000 yes 9 (50.00) 6 (50.00) dandruff no 5 (27.78) 6 (50.00) 0.216 yes 13 (72.22) 6 (50.00) diffuse loss of hair volume no 14 (77.78) 0 (0.00) <0.001 yes 4 (22.22) 12 (100.00) pull test negative 8 (44.44) 1 (8.33) 0.034 positive 10 (55.56) 11 (91.67) a chi-square test; bmann whitney u test ana = antinuclear antibody. 6 original article | dermatol pract concept. 2023;13(2):e2023081 2020;3:100073. doi: 10.1016/j.jtauto.2020.100073. pmid: 33263103. pmcid: pmc7691817. 18. pascolini s, vannini a, deleonardi g, et al. covid-19 and immunological dysregulation: can autoantibodies be useful? clin transl sci. 2021;14(2):502-508. doi: 10.1111/cts.12908. pmid: 32989903. pmcid: pmc7536986. 19. sacchi mc, tamiazzo s, stobbione p, et al. sars-cov-2 infection as a trigger of autoimmune response. clin transl sci. 2021;14(3):898-907. doi: 10.1111/cts.12953. pmid: 33306235. pmcid: pmc8212749. 20. trahtemberg u, fritzler mj; on behalf of the covid-19 chapter of the “longitudinal biomarkers in lung injury” study group. covid-19-associated autoimmunity as a feature of acute respiratory failure. intensive care med. 2021;47(7):801-804. doi: 10.1007/s00134-021-06408-z. pmid: 33928414. pmcid: pmc8084710. 21. yorulmaz a, hayran y, ozdemir ak, et al. telogen effluvium in daily practice: patient characteristics, laboratory parameters, and treatment modalities of 3028 patients with telogen effluvium. j cosmet dermatol. 2022;21(6):2610-2617. doi: 10.1111 /jocd.14413. pmid: 34449961. 22. kłosowicz a, englert k, pełka k, pastuszczak m, pastuszczak a. autoimmunity in lichen planopilaris patients. pol merkur lekarski. 2019;46(271):32-35. pmid: 30810113. 23. chang se, feng a, meng w, et al. new-onset igg autoantibodies in hospitalized patients with covid-19. nat commun. 2021;12(1):5417. doi: 10.1038/s41467-021-25509-3. pmid: 34521836. pmcid: pmc8440763. 24. massabki ps, accetturi c, nishie ia, da silva np, sato ei, andrade le. clinical implications of autoantibodies in hiv infection. aids. 1997;11(15):1845-1850. doi: 10.1097/00002030-199715000 -00009. pmid: 9412703. 25. eystathioy t, chan ek, tenenbaum sa, keene jd, griffith k, fritzler mj. a phosphorylated cytoplasmic autoantigen, gw182, associates with a unique population of human mrnas within novel cytoplasmic speckles. mol biol cell. 2002;13(4): 1338-1351. doi: 10.1091/mbc.01-11-0544. pmid: 11950943. pmcid: pmc102273. 26. pazini am, fleck j, dos santos rs, beck st. clinical relevance and frequency of cytoplasmic and nuclear dense fine speckled patterns observed in ana-hep-2. rev bras reumatol. 2010;50(6):655-660. pmid: 21243306. 27. xerfan ems, andersen ml, facina as, tufik s, tomimori j. the role of sleep in telogen effluvium and trichodynia: a commentary in the context of the current pandemic. j cosmet dermatol. 2021;20(4):1088-1090. doi: 10.1111/jocd.13929. pmid: 33387387. 28. rebora a. trichodynia: a review of the literature. int j dermatol. 2016;55(4):382-384. doi: 10.1111/ijd.13204. pmid: 26696219. 29. mubki t, rudnicka l, olszewska m, shapiro j. evaluation and diagnosis of the hair loss patient: part i. history and clinical examination. j am acad dermatol. 2014;71(3):415.e1-415.e15. doi: 10.1016/j.jaad.2014.04.070. pmid: 25128118. 30. baldari m, montinari m, guarrera m, rebora a. trichodynia is a distinguishing symptom of telogen effluvium. j eur acad dermatol venereol. 2009;23(6):733-734. doi: 10.1111/j. 1468-3083.2009.03201.x. pmid: 19281607. ther. 2020;33(5):e13549. doi: 10.1111/dth.13549. pmid: 32390279. pmcid: pmc7273098. 5. wollina u, karadağ as, rowland-payne c, chiriac a, lotti t. cutaneous signs in covid-19 patients: a review. dermatol ther. 2020;33(5):e13549. doi: 10.1111/dth.13549. pmid: 32390279. pmcid: pmc7273098. 6. hong jk, chopra s, kahn ja, kim b, khemichian s. autoimmune hepatitis triggered by covid-19. intern med j. 2021;51(7): 1182-1183. doi: 10.1111/imj.15420. pmid: 34278694. pmcid: pmc8447478. 7. nikiphorou e, alpizar-rodriguez d, gastelum-strozzi a, buch m, peláez-ballestas i. syndemics & syndemogenesis in covid-19 and rheumatic and musculoskeletal diseases: old challenges, new era. rheumatology (oxford). 2021;60(5): 20402045. doi: 10.1093/rheumatology/keaa840. pmid: 33496334. pmcid: pmc7928641. 8. walters hm, mian z, thomas l, et al. seroprevalence and clinical outcomes of sars-cov-2 in paediatric patients with rheumatic disease. rheumatology (oxford). 2022;61(si2):si112-si119. doi: 10.1093/rheumatology/keab730. pmid: 34599820. 9. vlad a, serban v, timar r, et al. increased incidence of type 1 diabetes during the covid-19 pandemic in romanian children. medicina (kaunas). 2021;57(9):973. doi: 10.3390/ medicina57090973. pmid: 34577896. pmcid: pmc8470921. 10. aringer m, johnson sr. systemic lupus erythematosus classification and diagnosis. rheum dis clin north am. 2021;47(3): 501-511. doi: 10.1016/j.rdc.2021.04.011. pmid: 34215376. 11. choi wj, kim je, kang h. frequency of antinuclear antibody positivity in patients with pattern hair loss. ann dermatol. 2015;27(2):210-212. doi: 10.5021/ad.2015.27.2.210. pmid: 25834364. pmcid: pmc4377414. 12. martínez-velasco ma, vázquez-herrera ne, maddy aj, asz-sigall d, tosti a. the hair shedding visual scale: a quick tool to assess hair loss in women. dermatol ther (heidelb). 2017;7(1):155-165. doi: 10.1007/s13555-017-0171-8. pmid: 28220468. pmcid: pmc5336434. 13. peker bo, şener ag, kaptan aydoğmuş f. antinuclear antibodies (anas) detected by indirect immunofluorescence (iif) method in acute covid-19 infection; future roadmap for laboratory diagnosis. j immunol methods. 2021;499:113174. doi: 10.1016/j .jim.2021.113174. pmid: 34737165. pmcid: pmc8556075. 14. ruggiero a, martora f, picone v, et al. the impact of covid-19 infection on patients with psoriasis treated with biologics: an italian experience. clin exp dermatol. 2022;47(12): 2280-2282. doi: 10.1111/ced.15336. pmid: 35867020. pmcid: pmc9349949. 15. chang sh, minn d, kim yk. autoantibodies in moderate and critical cases of covid-19. clin transl sci. 2021;14(5): 1625-1626. doi: 10.1111/cts.13036. pmid: 33934534. pmcid: pmc8239866. 16. gazzaruso c, carlo stella n, mariani g, et al. high prevalence of antinuclear antibodies and lupus anticoagulant in patients hospitalized for sars-cov2 pneumonia. clin rheumatol. 2020;39(7):2095-2097. doi: 10.1007/s10067-020-05180-7. pmid: 32462425. pmcid: pmc7251560. 17. lerma la, chaudhary a, bryan a, morishima c, wener mh, fink sl. prevalence of autoantibody responses in acute coronavirus disease 2019 (covid-19). j transl autoimmun. original article | dermatol pract concept. 2023;13(2):e2023081 7 33. starace m, iorizzo m, sechi a, et al. trichodynia and telogen effluvium in covid-19 patients: results of an international expert opinion survey on diagnosis and management. jaad int. 2021;5:11-18. doi: 10.1016/j.jdin.2021.07.006. pmid: 34368790. pmcid: pmc8328568. 34. di landro a, naldi l, glaser e, paus r, tosti a. pathobiology questions raised by telogen effluvium and trichodynia in covid-19 patients. exp dermatol. 2021;30(7):999-1000. doi: 10.1111/exd.14352. pmid: 33838048. pmcid: pmc8250761. 31. kivanç-altunay i, savaş c, gökdemir g, köşlü a, ayaydin eb. the presence of trichodynia in patients with telogen effluvium and androgenetic alopecia. int j dermatol. 2003;42(9):691-693. doi: 10.1046/j.1365-4362.2003.01847.x. pmid: 12956679. 32. durusoy c, ozenli y, adiguzel a, et al. the role of psychological factors and serum zinc, folate and vitamin b12 levels in the aetiology of trichodynia: a case-control study. clin exp dermatol. 2009;34(7):789-792. doi: 10.1111/j.1365-2230.2008.03165.x. pmid: 19508569. dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(1):2 3 dermatology practical & conceptual www.derm101.com the patient a 44-year-old caucasian woman presented with asymptomatic skin lesions on the trunk, arms and legs. these lesions had suddenly appeared 4 months before and have been unchanged ever since. medical history included arterial hypertension and hypertriglyceridemia. the patient recalled an acute episode of painful subcutaneous nodules on the lower legs some years ago that disappeared with nsaid and leg rest. on physical examination, we observed a bilateral and symmetric dermatosis composed of multiple well-defined erythematous papules and plaques involving the trunk, arms and legs, and sparing the face, acral sites and mucosae. some of the papules appeared to be pseudovesicular with a yellowish hue (figure 1). further dermoscopic examination disclosed multiple orange and yellowish globules and structureless areas in combination with linear vessels (figure 2). a 4 mm punch biopsy was performed. histopathological examination revealed an unchanged epidermis and organized collections of epithelioid histiocytes on the superficial and deep dermis (figures 3 and 4). underneath the “apple-jelly” pedro mendes-bastos1, andré oliveira1, cândida fernandes1 1department of dermatology and venereology, centro hospitalar de lisboa central, lisboa, portugal citation: mendes-bastos p, oliveira a, fernandes c. underneath the “apple-jelly.” dermatol pract concept 2016;6(1):2. doi: 10.5826/ dpc.0601a02 received: september 4, 2015; accepted: october 16, 2015; published: january 31, 2016 copyright: ©2016 mendes-bastos et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: pedro mendes-bastos, md, department of dermatology and venereology, alameda de santo antónio dos capuchos, 1169-050 lisboa, portugal. tel. +351213136380; fax. +351213136380. email: pmendesbastos@gmail.com figure 1. disseminated papules and plaques on the trunk, arms and legs. [copyright: ©2016 mendes-bastos et al.] figure 2. multiple orange-yellowish structureless areas (surrounded by asterisks) and linear vessels in a yellow-tone background. [copyright: ©2016 mendes-bastos et al.] 4 quiz | dermatol pract concept 2016;6(1):2 included secondary syphilis, eruptive xanthomas and cutaneous lymphoma. the term inflammoscopy has been introduced to describe the use of dermoscopy in the diagnosis of inflammatory skin diseases [2]. the combination of orange and yellow translucent globules and linear vessels is commonly seen under dermoscopy in granulomatous diseases. these structures correlate well with the underlying dermal granulomas. thus, they are frequently found in cutaneous sarcoidosis and lupus vulgaris, probably mirroring the classically described “apple-jelly” sign observed upon diascopy. therefore, under appropriate clinical correlation, dermoscopy can be a valuable non-invasive tool for the diagnosis of cutaneous sarcoidosis [3]. references 1. tchernev g. cutaneous sarcoidosis: the “great imitator”: etiopathogenesis, morphology, differential diagnosis and clinical management. am j clin dermatol. 2006;7:375-82. 2. zalaudek i, lallas a, moscarella e, et al. the dermatologist’s stethoscope—traditional and new applications of dermoscopy. dermatol pract concept. 2013;3(2):11. doi: 10.5826/dpc.0302a11 3. lallas a, zalaudek i, argenziano g, et al. dermoscopy in general dermatology. dermatol clin. 2013;31:679-94. no necrosis or other inflammatory infiltrate were observed. periodic acid-schiff (pas), grocott and ziehl-neelsen stains were unremarkable. what is your diagnosis? diagnosis cutaneous sarcoidosis clinical course chest ct revealed bilateral hilar lymphadenopathy. the patient was referred to pulmonology, and stage i sarcoidosis was diagnosed. answer and explanation sarcoidosis is an idiopathic multisystemic granulomatous disease that mostly involves the lung, lymph nodes, eyes and skin. cutaneous involvement is seen in 25% of patients. specific skin lesions of sarcoidosis are highly polymorphous and establishing a correct diagnosis is frequently a challenge [1]. in this particular case, the clinical differential diagnoses figure 3. unchanged epidermis and a dermal granulomatous dermatitis. [copyright: ©2016 mendes-bastos et al.] figure 4. organized collections of epithelioid histiocytes on the superficial and deep dermis, with scattered multinucleated giant cells. [copyright: ©2016 mendes-bastos et al.] quiz | dermatol pract concept 2016;6(1):2 5 dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020012 1 dermatology practical & conceptual pseudoepitheliomatous, keratotic, and micaceous balanitis sweta subhadarshani,1 vishal gupta,1 jayati sarangi,2 shipra agarwal,1 kaushal k. verma1 1 department of dermatology and venereology, all india institute of medical sciences, new delhi, india 2 department of pathology, all india institute of medical sciences, new delhi, india key words: balanitis, pseudoepitheliomatous, keratotic, squamous cell carcinoma, glans citation: subhadarshani s, gupta v, sarangi j, agarwal s, verma kk. pseudoepitheliomatous, keratotic, and micaceous balanitis. dermatol pract concept. 2020;10(1):e2020012. doi: https://doi.org/10.5826/dpc.1001a12 accepted: september 9, 2019; published: december 31, 2019 copyright: ©2019 subhadarshani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: kaushal k. verma, md, department of dermatology and venereology, all india institute of medical sciences, ansari nagar, new delhi 110049, india. email: prokverma@hotmail.com introduction pseudoepitheliomatous, keratotic, and micaceous balanitis (pekmb) is a genital disease of uncertain malignant potential that warrants close clinical observation, as it can rarely evolve into squamous cell carcinoma or verrucous carcinoma. case presentation a 46-year-old man presented with complaints of scaling and erosion over the glans for the preceding 5 years. he had undergone circumcision 12 years earlier, when he noticed depigmentation over the glans; a few years later, thick, scaly crust developed over the glans. he had no history of high-risk sexual behavior. the patient had previously been treated with topical steroids, emollients, and calcineurin inhibitors without much improvement. on examination, there was hypopigmentation and sclerosis of the glans with localized, thick, yellowish, nail-like keratotic scaling along with underlying induration and superficial erythematous erosions (figure 1). there was no associated lymphadenopathy, and systemic examination was within normal limits. a skin biopsy from scaly indurated plaque showed hyperkeratosis, parakeratosis, and acanthosis with dysplastic changes limited to lower layers of epidermis along with a few mitotic figures and an essentially normal dermis (figure 2). a diagnosis of pekmb was made. the patient was treated with topical 5-fluorouracil, once daily application over scaly and indurated areas, and he was followed up monthly. however, after 4 months of treatment there was a residual area of persistent induration, a biopsy of which showed moderately differentiated squamous cell carcinoma with areas of necrosis. there was no lymphovascular invasion or distant metastases. a final diagnosis of figure 1. clinical photograph showing scaling and erosion on the glans. mailto:prokverma@hotmail.com 2 letter | dermatol pract concept 2020;10(1):e2020012 references 1. krunic al, djerdj k, starcevic-bozovic a, et al. pseudoepitheliomatous, keratotic and micaceous balanitis: case report and review of the literature. urol int. 1996;56(2):125-128. 2. perry d, lynch pj, fazel n. pseudoepitheliomatous, keratotic, and micaceous balanitis: case report and review of the literature. dermatol nurs. 2008;20(2):117-120. pekmb evolving to squamous cell carcinoma was made and the lesion was excised with wide margins. conclusions pekmb is a rare, nonvenereal, premalignant genital dermatosis. it was first described by lortat-jacob and civatte in 1961, and until now approximately 20 cases have been reported in the literature. it occurs in older men, most of whom were circumcised late in life. it presents as a keratotic plaque with thick, white, mica-like silvery scales and keratotic horny masses on the glans. ulcerations and fissuring may develop. the etiology of pekmb is unknown and it progresses through 4 different stages: plaque, tumor, verrucous carcinoma, and later squamous cell carcinoma [1]. although pekmb has uncertain malignant potential, it can sometimes progress to verrucous carcinoma and squamous cell carcinoma and therefore an early biopsy and close follow-up are warranted [2]. histological examination of these lesions reveals acanthosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia with no cytological atypia. treatment depends on severity and may range from topical treatment with 5-flurouracil cream, cryotherapy, shaving biopsy plus electrocoagulation, or triamcinolone acetonide cream (0.1%) to excision with wide margins. however, treatment is not always satisfactory and relapses are frequent. figure 2. histopathology (h&e, ×4) showing hyperkeratosis, parakeratosis, and acanthosis with dysplastic changes limited to lower layers of epidermis along with a few mitotic figures and an essentially normal dermis. dermatology: practical and conceptual letter | dermatol pract concept 2018;8(4):11 303 dermatology practical & conceptual www.derm101.com introduction reactive perforating collagenosis (rpc) is a rare disorder in which abnormal collagen fibers extrude through the epidermis. in the acquired form, erythematous keratotic papules and plaques with firmly adherent central crust and ulceration develop, commonly on the trunk and extremity extensor surfaces, and often at sites of superficial trauma [1]. intense itch is common. acquired rpc is often associated with longstanding diabetes and chronic renal failure, particularly in patients undergoing dialysis [2,3]. however, because rpc is uncommon, the clinical presentation can vary between patients, and it can be difficult to differentiate clinically from other conditions, the true diagnosis is often missed or delayed. differential diagnosis includes ecthyma, prurigo nodularis, perforating granuloma annulare, dermatitis artefacta, and other perforating diseases [4]. clinical diagnosis of rpc is supported or confirmed by characteristic histopathological features in most cases, although repeated biopsies may be required. histological features vary according to stage of disease; in the early stages degenerate collagen fibers accumulate in dermal papillae and epidermal hyperplasia may be seen. in more established lesions a cupshaped depression of the epidermis develops with an overlying keratin plug containing inflammatory cells, keratinous debris, and collagen fibers [4,5]. vertically oriented collagen fibers, stained red by elastic van gieson staining or blue by masson’s trichrome stain, are extruded through the epidermis and there may be a mild perivascular lymphohistiocytic infiltrate. dermoscopy is a noninvasive technique which is now a standard tool used in the preoperative clinical diagnosis of skin tumors [6]. it is also increasingly used to aid in the diagnosis in other dermatological conditions including inflammatory dermatoses [7,8]. to our knowledge, the dermoscopic features of rpc have been described in 2 previous case reports [9,10]. here we report the dermoscopic findings in a series of 5 patients with rpc. case presentations we identified 5 patients with a diagnosis of acquired rpc in our department over the past 2 years. case notes, pathology dermoscopy features of acquired reactive perforating collagenosis: a case series emma ormerod1, ausama atwan2, laszlo intzedy3, natalie stone2 1 dermatology department, bristol royal infirmary, bristol, uk 2 dermatology department, royal gwent hospital, newport, wales, uk 3 pathology department, royal gwent hospital, newport, wales, uk key words: dermoscopy, perforating collagenosis, acquired, diagnostics citation: ormerod e, atwan a, intzedy l, stone n. dermoscopy features of acquired reactive perforating collagenosis: a case series. dermatol pract concept. 2018;8(4):303-305. doi: https://doi.org/10.5826/dpc.0804a11 received: december 4, 2017; accepted: april 20, 2018; published: october 31, 2018 copyright: ©2018 ormerod et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: emma ormerod, ma, mrcp, bristol dermatology unit, bristol royal infirmary, marlborough street, bristol bs2 8hw. email: emma.ormerod@uhbristol.nhs.uk 304 letter | dermatol pract concept 2018;8(4):11 onset of his skin problems; he subsequently started a regimen of low molecular weight heparin. routine blood values, including renal function, were normal. skin biopsy showed ulceration of epidermis, acute and chronic inflammation at the ulcer base with leukocytoclasis, and a perivascular chronic inflammatory infiltrate in the mid-dermis. patient 3. a 58-year-old man with a previous diagnosis of sarcoidosis was taking no regular medications. routine blood values at the time of presentation were normal. skin biopsy from an ulcer showed florid reactive changes and vertically oriented collagen fibers at the ulcer base consistent with rpc. renal function was normal. patient 4. an 83-year-old woman was housebound and unable to attend the dermatology clinic. she was referred via teledermatology for review of her images and clinical history. she had a history of an aortic aneurysm, hypertension, atrial fibrillation, and transient ischemic attack. blood tests revealed microcytic anemia but normal renal function. biopsy was not felt to be appropriate for this patient; the diagnosis was made from classic clinical and dermoscopy features. patient 5. an 80-year-old woman had a history of longstanding type 2 diabetes mellitus, ischemic heart disease, and hypertension. medications included lercanidipine, furosemide, reports, and dermoscopy pictures were analyzed. dermoscopic images were taken using a digital dermoscopy system (nikon d33s camera [nikon, tokyo, japan]; heine delta® 20t dermatoscope [heine optotechnik, herrsching, germany]). minimal pressure was applied and ultrasound gel was used during the process to help preserve vessel morphology as much as possible. there were 3 female and 2 male patients, with age ranging from 53 to 83 years. all of them gave a history of a very itchy rash, affecting the trunk and/or lower limbs. the rash had a similar appearance in all patients, with erythematous nodules of varying sizes and central keratin plug (figure 1). the diagnosis of rpc was suspected clinically in all patients and confirmed histologically in 4 of the 5 cases (in 1 patient, biopsy was felt to be inappropriate). patient 1. a 53-year-old woman had a 20-year history of type 2 diabetes mellitus, peripheral vascular disease, and ischemic heart disease. her medications included metformin, clopidogrel, bisoprolol, and lisinopril. routine blood values, including renal function, were normal, and skin biopsy was consistent with rpc, showing vertical collagen orientation. patient 2. a 67-year-old man was diagnosed with bilateral pulmonary embolism at approximately the same time as the figure 2. dermoscopic images of a typical lesion from the rash in each of the 5 patients (patients 1-5, labeled a-e). [copyright: ©2018 ormerod et al.] figure 1. macroscopic images of the rash in each of the 5 patients (patients 1-5, labeled a-e). [copyright: ©2018 ormerod et al.] letter | dermatol pract concept 2018;8(4):11 305 references 1. millard pr, young e, harrison de, wojnarowska f. reactive perforating collagenosis: light, ultrastructural and immunohistological studies. histopathology. 1986;10:1047-1056. 2. morton ca, henderson is, jones mc, lowe jg. acquired perforating dermatosis in a british dialysis population. br j dermatol. 1996;135:671-677. 3. poliak sc, lebwohl mg, parris a, prioleau pg. reactive perforating collagenosis associated with diabetes mellitus. n engl j med. 1982;306:81-84. 4. kim sw, kim ms, lee jh, et al. a clinicopathologic study of thirty cases of acquired perforating dermatosis in korea. ann dermatol. 2014;26:162-171. 5. cerio r, calnan cd, wilson-jones e. a clinic-pathological study of reactive perforating collagenosis: report of 10 cases. br j dermatol. 1987;117:16-17. 6. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48:679–693. 7. goncharova y, attia ea, souid k, protzenko o, koktishev i. dermoscopic features of clinically inflammatory dermatoses and their correlation with histopathologic reaction patterns. arch dermatol res. 2015;307:23-30. 8. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166:1198-1205. 9. kittisak p, tanaka m. dermoscopic findings in a case of reactive perforating collagenosis. dermatol pract concept. 2015;5:75-77. 10. ramirez-fort mk, khan f, rosendahl co, mercer se, shin-chang h, levitt jo. acquired perforating dermatosis: a clinical and dermatoscopic correlation. dermatol online j. 2013;19:18958. nicorandil, candesartan, and atenolol. blood values were normal apart from an elevated hba1c in keeping with her known diabetes. histology showed focal necrosis, ulceration and epidermal inflammation, with perivascular chronic inflammatory cell infiltrate in the dermis. dermoscopic images showed almost identical features in all 5 patients (figure 2). the 3 clear, consistent features were (1) a yellow-brown structureless area in the center of the lesion in keeping with surface crust; (2) a white rim surrounding the crust which can vary in thickness between patients and in a single lesion, possibly correlating to epidermal invagination or keratinous debris; and (3) an outer pink circle of inflammation with visible vessels, commonly short looped vessels centrally and dotted vessels peripherally. these features are similar to those previously described in 2 separate reports of single cases with rpc [9,10]. conclusions rpc is an unusual condition that can mimic other conditions and is often initially misdiagnosed. the dermoscopic findings in our cases reinforce the features described in previous reports [9,10] and indicate that dermoscopy in rpc gives a very characteristic, consistent appearance and can therefore be a useful and quick aid to make the diagnosis. dermoscopy of rpc is particularly helpful in cases in which biopsy is not possible or is nondiagnostic. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023139 1 female pattern hair loss and negative psychological impact: possible role of brain-derived neurotrophic factor (bdnf) noha e mohamed1, mohamed r soltan2, sara a galal3, hassan salem el sayed4, hadir m hassan1, basma hm khatery1 1 department of dermatology, stds, and andrology, faculty of medicine fayoum university, faiyum, egypt 2 psychiatry department, fayoum university, faiyum, egypt 3 dermatology and venereology department, faculty of medicine for girls, al-azhar university, cairo, egypt 4 medical biochemistry and molecular biology, faculty of medicine fayoum university, egypt the research was conducted in the outpatient clinic of the department of dermatology, stds, and andrology, faculty of medicine, fayoum university key words: androgenetic alopecia, bdnf, psychological impact, dlqi citation: mohamed ne, soltan mr, galal sa, el sayed hs, hassan hm, khatery bhm. female pattern hair loss and negative psychological impact: possible role of brain-derived neurotrophic factor (bdnf). dermatol pract concept. 2023;13(3):e2023139. doi: https://doi.org/10.5826/dpc.1303a139 accepted: january 2, 2023; published: july 2023 copyright: ©2023 mohamed et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sara ahmed galal, dermatology and venereology department, faculty of medicine for girls, al-azhar university, 53, new cairo, 3rd zone fifth, settlement, cairo, egypt telephone number: 01008876877 email address: drsaragalal@azhar.edu.eg introduction: female pattern hair loss (fphl) is considered the most common type of hair loss in females. women with fphl may suffer from psychological distress and defective social functioning. patients with psychiatric and neurodegenerative disorders almost have a deficient brain and blood brain-derived neurotrophic factor levels (bdnf). this serum bdnf level may act as a diagnostic marker for negative psychological impact in fphl patients. objectives: evaluate the levels of serum bdnf in patients with fphl and correlate its level to the severity of alopecia and the degree of psychological impact. methods: forty-six female patients with fphl and 41 healthy age-matched female volunteers as a control were included in the study. patients filled out a dermatology life quality index questionnaire. both patients and controls filled beck depression inventory, beck anxiety inventory, and perceived stress scale (pss) questionnaires. serum levels of bdnf were measured for all the participants using the elisa technique. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023139 introduction female pattern hair loss (fphl) is a common cause of non-scarring alopecia in females manifested as, successive loss of terminal hairs in the vertex and frontal areas of the scalp. aga is distinguished by follicular miniaturization which is characterized by a short anagen phase and increased vellus hairs [1]. in general, alopecia is known to be associated with many psychiatric comorbidities such as depression, anxiety, personality disorders, and drug abuse. moreover, patients with alopecia have noticeably higher suicidal rates and get hospitalized for mental health diseases. regarding specific types of hair loss, fphl may be linked to many psychiatric comorbidities, especially in patients with extensive scalp affection [2]. fphl may lead to depression and decreased life quality, poor self-esteem, and negative body image [3]. brain-derived neurotrophic factor (bdnf) is a member of the neurotrophins family which is known for its action on the growth of central and peripheral nerves. neurotrophins show a variety of immunomodulatory impacts on non-neuronal cells especially mast cells, keratinocytes, and eosinophils [4]. bdnf controls human hair growth via tropomyosin receptors (trkb). bdnf markedly decreases hair shaft elongation, promotes premature catagen, and decreases keratinocyte proliferation [5]. panchaprateep et al postulated that bdnf may be essential in exerting the androgens impacts on hair follicles acting as a negative regulatory factor. this study showed that balding scalp follicles produced 12-fold more bdnf than the nonbalding scalp [6]. objectives this study evaluates serum bdnf levels in patients with fphl. we suggest that there may association between serum bdnf levels and fphl. therefore, we aimed to evaluate the levels of serum bdnf in patients with fphl and correlate its level to both the degree of psychological impact and the severity of alopecia. methods the present case-control study included 46 female patients with fphl and 41 age-matched healthy female volunteers. the patients were recruited from the dermatology, stds, and andrology department clinic, during the period between may 2021 to august 2021. all included individuals, or their families provided an informed written agreement to be included in the study. this study was conducted according to the declaration of helsinki and the protocol approved by the ethics committee of würzburg university and by the institutional review board of the faculty of medicine, fayoum university (irb number irb00003613) in january 2018. an informed written arabic consent form was signed by every participant in the presence of one of the authors. patients female patients 15-50 years old complaining of aga were included in this study. patients were diagnosed and classified according to female pattern hair loss severity index [7]. we exclude patients suffering from any systemic or cutaneous diseases other than fphl. we also exclude patients with a past or present history of psychiatric illness or receiving any regular psychotropic medication, antidepressants were also excluded. pregnant and lactating women were excluded from the study. control forty-one healthy female volunteers 15-50 years old were included in the study as a control. study design all subjects were subjected to a full history taking and clinical examination. results: patients with fphl had significantly lower levels of bdnf and significantly higher beck depression inventory score and pss questionnaire scores. there is a significant negative correlation between serum levels of bdnf and beck depression inventory, beck anxiety inventory, and pss questionnaire scores. conclusions: patients with fphl are at a high risk to develop chronic stress and depression. the serum level of bdnf is a good predictor for the assessment of chronic stress and depression in fphl patients. original article | dermatol pract concept. 2023;13(3):e2023139 3 the patients were diagnosed and classified according to fphl severity index [7]. questionnaires to access the psychological state for all participants were done including beck depression inventory, beck anxiety inventory and perceived stress (pss) scale [8-10]. dlqi was done for the patient group only [11]. the serum level of bdnf was measured for all subjects using elisa kits which were provided by biodiagnostic kits (sun red biological technology company). five ml of blood were collected from the antecubital vein by venipuncture and left for 30 minutes at room temperature to allow clotting and then centrifuged for 15 minutes at 3000 rpm. serum was separated, stored in an eppendorf tube and kept at −20°c until used for measurement of bdnf level. each female was subjected to full history, measurement of serum level of bdnf using elisa technique. statistical analysis chi-square test was used for categorical variables, to compare between different groups. fisher exact test or monte carlo correction were used for correction for chi-square when more than 20% of the cells have expected count less than 5. student t-test was used for normally distributed quantitative variables, to compare between two studied groups. mann whitney test was used for not normally distributed quantitative variables, to compare two studied groups. spearman coefficient was used to correlate between two distributed not normally quantitative variables. kruskal wallis test was used for not normally distributed quantitative variables, to compare between more than two studied groups. receiver operating characteristic curve (roc) is generated by plotting sensitivity (tp) on y axis versus 1-specificity (fp) on x axis at different cut off values. the area under the roc curve denotes the diagnostic performance of the test. area more than 50% gives acceptable performance and area about 100% is the best performance for the test. the roc curve allows also a comparison of performance between two tests. logistic regression analysis was used to detect the most independent/ affecting factor for affecting cases. linear regression analysis was used to detect the most independent/ affecting factor for affecting serum bdnf. results this case-control study included 87 females, 46 female patients suffering from fphl, and 41 age-matched healthy female subjects as a control. the participants were recruited from the dermatology, stds, and andrology department clinic. the patients were diagnosed and classified according to fphl severity index. patient group included 46 female patients, their ages ranged from 15 to 50 years old with a mean ± sd (29.85 ± 9.73) with a median (iqr) of 29.50 (22.0 38.0). control group included 41 healthy females, their ages ranged from 20 – 51 years with a mean ± sd (26.44 ± 7.38) with median (iqr) 26.0 (19.0 – 32.0). there was no statistically significant difference (p value ≤ 0.05) between both groups. in the patient group 34 patients (73.9%) had positive family history of fphl, while in the control group only 6 patients (14.9%) had positive family history. diet changes was reported in one patient (2.2%) in the patient group, while 4 individuals (9.8%) in the control group have diet change (table 1). clinical parameters of the studied groups in the patient group acne was reported in 11 patient (23.9%), while only 1 individual (2.4%) in the control group have acne. there was a high statistically significant difference regarding presence of acne between the case and the control groups (p value ≤ 0.05). table 1. clinical parameters of the studied group. cases (n = 46) control (n = 41) χ2 p family history of fphl n % n % negative 12 26.1 35 85.4 30.669 <0.001 positive 34 73.9 6 14.9 diet changes 1 2.2 4 9.8 2.301 0.183 acne 11 23.9 1 2.4 8.407 <0.05 hirsutism 8 17.4 4 9.8 1.063 >0.05 signs of virilization 0 0.0 0 0.0 – – menstrual irregularity 11 23.9 5 12.2 1.983 >0.05 4 original article | dermatol pract concept. 2023;13(3):e2023139 (p <0.001) between serum bdnf and beck anxiety score, beck depression score and a high statistically significant negative correlation (p < 0.001) regarding pss (table 6). correlation between fphl severity index score and different parameters in patient group there were high statistically significant positive correlations between fphl severity index score and age of patients, age of onset, duration of the fphl and sinclair hair density scale (p value ≤ 0.001) (table 7). the univariate logistic regression analysis for the parameters affecting cases showed that there were statistically significant relations (p value ≤ 0.05) regarding presence of hormonal acne, presence of scaling, presence of hair pull test, increasing in the perceived stress scale, increasing in the beck depression score and increasing in the beck depression scale. there was high statistically significant relation (p value ≤ 0.001) regarding presence of family history of fphl. the multivariate logistic regression analysis showed that there was a high statistically significant relation (p value ≤ 0.001) regarding presence of family history of fphl. there was a statistically significant relation (p value ≤ 0.05) regarding hair pull test (table 8). the univariate logistic regression analysis for the parameters affecting serum level of bdnf in the case group (n = 46 vs. 41) showed that there were statistically significant relations (p value ≤ 0.05) regarding duration of fphl, increasing in perceived stress scale, increasing in beck anxiety score, increasing in beck anxiety scale, increasing in beck depression score and increasing in beck depression scale. the multivariate logistic regression analysis showed that there was a statistically significant relation (p value ≤ 0.05) regarding increasing in beck depression score (table 9). conclusions neurotrophins including bdnf and their receptors have role in skin hemostasias and hair growth [12]. botchkarev et al reviewed that stress may induced hair loss, psoriasis, and other skin diseases. bdnf is a member of a family of neurotrophins [13]. this study aimed to evaluate the levels of serum bdnf in patients with fphl and correlate its level to the severity of alopecia and the degree of psychological impact. our study included (87) female subjects that were divided into two groups; group a (case group): included 46 female patients with fphl while group b (control group): included 41 age matched healthy female volunteers as control group. regarding hirsutism of the studied patients 8 patient (17.4%) had hirsutism, while in the control group hirsutism was reported in 4 patient (9.8%). signs of virilization was not reported in patients and controls. there was no statistically significant difference regarding hirsutism, the signs of virilization and menstrual irregularity (table 1). local examination of the scalp of the studied groups scalp itching and soreness were reported in 34.8%, and 10.9% of the patients while in 22% and 0% in the control group respectively with no statistically significant difference. scalp scaling was significantly statistically higher than the control group (p ≤ 0.05). there was a high statistically significant difference (p = 0.001) regarding hair pull test, sinclair hair shedding scale, sinclair hair density scale, fphl severity index scale and fphl severity index score between the case group and the control group (table 2). comparison between the two studied groups as regards to the psychological state in the patient group pss and beck depression was statistically significantly higher than the control group (p ≤ 0.05), while the score beck depression scale showed no statistically significant difference. regarding beck anxiety score and scale showed no statistically significant difference between both groups (p value > 0.05) (table 3). analysis of the dermatology life quality index in the patient group only 2 cases (4.3%) had no effect on patient life, 9 cases (19.6%) with minor effect on patient’s life, 20 cases (43.5%) with moderate effect on patients life, 10 cases with very great impact on patient life and 5 cases (10.9%) with extreme impact on patient life respectively. serum bdnf in the studied groups in the patient group serum level of bdnf was statistically significantly lower than the control group (p value < 0.05). in patients mean ± sd was 0.85 ± 1.07, while in the controls was 1.07 ± 1.26 (table 4). the cut off point for serum bdnf to discriminate patients from control was ≤ 0.714. the sensitivity was 76.09 and the specificity was 56.10 (table 5 and figure 1). correlation between serum bdnf and different parameters in patients group there were statistically significant positive correlations (p ≤ 0.05) between serum bdnf and fphl duration, while there was a statistically significant negative correlation original article | dermatol pract concept. 2023;13(3):e2023139 5 table 2. local examination of the studied groups. cases (n = 46) control (n = 41) scalp n % n % χ2 p itching 16 34.8 9 22.0 1.743 >0.05 scaling 28 60.9 15 36.6 5.114 <0.05 erythema 0 0.0 0 0.0 – – soreness 5 10.9 0 0.0 4.728 p =0.057 hair pull test no. % no. % χ2 p negative 29 63.0 38 92.7 10.757 0.001 positive 17 37.0 3 7.3 sinclair hair shedding scale no. % no. % χ2 p bundle with 10 hairs 27 58.7 41 100 24.494 <0.001 bundle with 50 hairs 17 37.0 0 0.0 bundle with 100 hairs 2 4.3 0 0.0 sinclair hair density scale no. % no. % χ2 p 1 6 13.0 41 100.0 77.196* <0.001 2 32 69.6 0 0.0 3 8 17.4 0 0.0 min.– max. 1.0– 3.0 1.0– 1.0 min-max. 1.0 – 3.0 123.0* <0.001 mean ± sd. 2.04±0.56 1.0±0.0 mean±sd 2.04±0.56 median (iqr) 2.(2.0-2.0) 1.0 (-) median (iqr) 2 (2-2) fphl severity index no. % no. % χ2 p fphl unlikely 0 0.0 41 100.0 87.0 <0.001 early fphl 13 28.3 0 0.0 established fphl 33 71.7 0 0.0 fphl severity index score no. % no. % χ2 p min. – max. 6.0-14.0 0.0-4.0 min.-max. 6.0 – 14.0 t= 25.839 <0.001 mean ± sd. 11.09±2.53 0.78±0.91 mean±sd 11.09±2.53 median (iqr) 11(9.0-13) 1(0-1) median (iqr) 11(9-13) fphl = female pattern hair loss; iqr = interquartile range; sd = standard deviation. all female was subjected to full history, measurement of serum level of bdnf and questionnaires to access the psychological state. quality of life was accessed in the patient group only. the patients were diagnosed and classified according to fphl severity index [7]. the cases age ranged from 15 to 50 years with a mean of 29.85 ± 9.73, while the control age ranged from 15 to 41 years with a mean of 26.44 ± 7.38. we selected this age group as androgen effects in addition to cosmetic concerns are marked during this age group. there was no statistically significant difference regarding age between the case and control groups as they were age matched. there was a high statistically significant difference regarding presence of acne between the case and the control groups (p value ≤ 0.05). this is due to that female pattern hair loss and hormonal acne can be due to androgen receptors hypersensitivity to circulating dihydrotestosterone or coexisted hyperandrogenic status such as virializing tumor, polycystic ovarian syndrome, or those on oral contraceptive pills that 6 original article | dermatol pract concept. 2023;13(3):e2023139 table 5. validity for serum brain-derived neurotrophic factor to discriminate patients (n = 46) from control (n = 41). auc p 95% ci cut off sensitivity specificity ppv npv serum bdnf 0.635 0.030 0.517 – 0.753 ≤0.714 76.09 56.10 66.0 67.6 auc = area under the curve; bdnf = brain-derived neurotrophic factor; ci: confidence intervals; npv = negative predictive value; ppv = positive predictive value. table 3. comparison between the two studied groups according to stress, anxiety, and depression scales. cases (n = 46) control (n = 41) test p perceived stress scale min. – max. 13.0 – 39.0 10.0 – 35.0 2.939 <0.05 mean ± sd. 25.17 ± 5.96 21.27 ± 6.44 median (iqr) 25.0 (22.0 – 29.0) 21.0 (16.0 – 27.0) beck anxiety score min. – max. 12.0 – 49.0 13.0 – 53.0 0.028 >0.05 mean ± sd. 28.83 ± 8.09 28.88 ± 9.18 median (iqr) 27.50 (24.0 – 35.0) 26.0 (23.0 – 36.0) beck anxiety scale low anxiety 6 (13%) 5 (12.2%) 0.654 >0.05 moderate anxiety 30 (65.2%) 24 (58.5%) potentially concerning level of anxiety 10 (21.7%) 12 (29.3%) beck depression score min. – max. 1.0 – 36.0 6.0 – 33.0 2.347 <0.05 mean ± sd. 20.39 ± 8.02 16.73 ± 6.29 median (iqr) 19.0 (15.0 – 26.0) 16.0 (11.0 – 20.0) beck depression scale ups and downs are normal 3 (6.5%) 6 (14.6%) 5.402 0.349 mild depression 11 (23.9%) 15 (36.6%) border line depression 13 (28.3%) 11 (26.8%) moderate depression 13 (28.3%) 7 (17.1%) severe depression 5 (10.9%) 2 (4.9%) extreme depression 1 (2.2%) 0 (0.0%) iqr = interquartile range; sd = standard deviation. table 4. comparison between the two studied groups regarding serum brain-derived neurotrophic factor. serum bdnf cases (n = 46) control (n = 41) umann whitney p min. – max. 0.31 – 7.68 0.47 – 7.18 688.50* <0.05*mean ± sd. 0.85 ± 1.07 1.07 ± 1.26 median (iqr) 0.65 (0.58 – 0.71) 0.73 (63.0 – 81.0) bdnf = brain-derived neurotrophic factor; iqr = inter quartile range; sd: standard deviation. original article | dermatol pract concept. 2023;13(3):e2023139 7 figure 1. receiver operating characteristic curve for serum brain-derived neurotrophic factor to discriminate patients (n = 46) from control (n = 41). table 6. correlation between serum bdnf and different parameters in cases group (n = 46). serum bdnf vs. rs p age (years) 0.038 >0.05 age of onset of fphl -0.072 >0.05 duration in years 0.293 <0.05 sinclair hair density scale 0.036 >0.05 fphl score -0.050 >0.05 perceived stress scale -0.336 0.001 beck anxiety score -0.336 <0.05 beck depression score -0.328 <0.05 dlqi score 0.228 >0.05 bdnf = brain-derived neurotrophic factor; dlqi = dermatology life quality index; fphl = female pattern hair loss. table 7. correlation between female pattern hair loss severity index score and different parameters in cases group (n = 46). fphl score r p age (years) 0.630 <0.001 age of onset of fphl 0.501 <0.001 duration in years 0.535 <0.001 sinclair hair density scale 0.661 <0.001 perceived stress scale 0.006 >0.05 beck anxiety score -0.034 >0.05 beck depression score 0.117 >0.05 dlqi score -0.008 >0.05 dlqi = dermatology life quality index; fphl = female pattern hair loss. contains progesterone with a high androgenic potential such as norethindrone [14]. bienenfeld and his colleagues stated that androgens are important in the incidence of fphl and acne. they had essential but inadequate role in the development of, acne, and fphl in women [15]. regarding hirsutism, the signs of virilization and menstrual irregularity in our study there was no statistically significant difference regarding between the patient group and the control. carmina and his colleagues suggest that fphl may be evident in the absence of other signs of hyperandrogenism, as it may be related to many factors, including genetic influences, androgen sensitivity and levels, and perhaps inflammation in the scalp [3]. scalp scaling was significantly statistically higher than the control group (p-value ≤ 0.05). this can be interpreted by that the hair follicle miniaturization and apoptosis occurring in fphl are often associated with micro-inflammation. this micro-inflammation causes destruction of the erector pili muscle and sebaceous gland hyperplasia. this led to an oily surface and scalp inflammation in form of seborrheic dermatitis. hence, fphl usually coexists with seborrheic dermatitis [16,17]. in our study there was a statistically significantly higher family history in the patient group (p value ≤ 0.001). family history is an important risk factor for an early onset fphl [18]. our findings were in accordance with lukasik and his colleagues who revealed that a positive history on the mother side is of great importance for fphl incidence. hair loss in more than one family member and in one grandparents may also indicate a higher risk of disease development [19]. in the current study the hair pull test, sinclair hair shedding scale, sinclair hair density scale, fphl severity index scale and fphl severity index score were statistically significant a higher in the patient group (p value ≤ 0.001). fphl has a negative psychological effect on the patients. it includes stress, depression and anxiety which are also important causes of telogen effluvium. brenner and oldoni in their study reported that telogen effluvium may be the initial symptom in patients with fphl [20]. in the patient group the perceived stress scale and beck depression was a statistically significantly higher than the control group (p value ≤ 0.05). this may be due to that the low self-steam and negative body image caused by fphl lead to deep psychological impact such as anxiety, stress and depression [3]. our findings agree with camacho and garcía-hernández who found that aga patients have personality changes in general and that depression was higher in female 55% with aga [21]. 8 original article | dermatol pract concept. 2023;13(3):e2023139 fphl acts as a source of depression and chronic stress which leads to decrease in circulating bdnf concentration in case group [2]. on the contrary, pancrateep and his colleagues found that in late male androgenic alopecia, mesenchymal dermal papillae cells of the balding scalp follicles produced about 12-fold more bdnf than those from the nonbalding scalp. they stated that the bdnf may be essential in mediating the impact of androgens on the hair follicles, acting as a negative regulatory factor [6]. this may be due to local production of bdnf by fibroblasts in the skin and t-lymphocytes may also produce neurotrophies in the skin [12]. in our study, there was statistically significant negative correlation regarding serum bdnf with perceived stress scale, beck anxiety score and beck depression score respectively (p value ≤ 0.05). various studies have studied the link between bdnf levels and psychological disorders like major depression, regarding to quality of life most patient had impaired dermatology life quality index. this may be caused by psychosocial problems in patients with fphl, due to low self-esteem, altered self-image leading to depression, and less frequent positive social engagements. patients with aga usually do alter their behavior peculiarly due to hair loss. some patients use diverse haircuts or wash their hair more frequent in order to gain more volume [22]. our study agrees with shilpashree and his colleagues who found that most patients of fphl suffer from moderate to severe psychosocial impact [23]. in our study the patient group serum level of bdnf was statistically significantly lower than the control group (p value < 0.05). this can be interpreted by the relation between bdnf levels and major depressive disorders, anxiety related disorders, response to stressful events, and neurodevelopmental disorders. most of these studies showed decreased bdnf levels with these psychiatric disorders.12 table 8. univariate and multivariate logistic regression analysis for the parameters affecting cases (n = 46 versus. 41). univariate #multivariate p or (95%ci) p or (95%ci) age (years) 0.075 1.047 (0.995 – 1.101) presence of diet changes 0.165 0.206 (0.022 – 1.919) presence of hirsutism 0.309 1.947 (0.540 – 7.023) presence of hormonal acne 0.018 12.571 (1.544 –102.33) 0.165 8.642 (0.412 – 181.091) presence of menstrual irregularity 0.166 2.263 (0.713 – 7.182) scalp presence of itching 0.190 1.896 (0.729 – 4.936) presence of scaling 0.025 2.696 (1.131 – 6.427) 0.898 0.879 (0.121 – 6.377) presence of family history of fphl <0.001 16.528 (5.570 –49.046) <0.001 27.072(5.532 –132.498) presence of hair pull test 0.003 7.425 (1.985 – 27.771) 0.023 7.677 (1.319 – 44.696) increasing in sinclair hair shedding scale 0.189 0.664 (0.360 – 1.223) increasing in sinclair hair density scale 0.999 – increasing in fphl score 0.990 – increasing in perceived stress scale 0.006 1.108 (1.029 – 1.192) 0.197 1.082 (0.960 – 1.221) increasing in beck anxiety score 0.977 0.999 (0.951 – 1.050) increasing in beck anxiety scale 0.518 0.793 (0.393 – 1.602) increasing in beck depression score 0.026 1.074 (1.009 – 1.144) 0.270 0.915 (0.781 – 1.071) increasing in beck depression scale 0.023 1.577 (1.066 – 2.332) 0.103 2.229 (0.851 – 5.838) increasing in serum bdnf 0.625 0.911 (0.627 – 1.324) bdnf = brain-derived neurotrophic factor; ci = confidence interval; fphl = female pattern hair loss; ll = lower limit; or = odds ratio; ul = upper limit. original article | dermatol pract concept. 2023;13(3):e2023139 9 a significant association between decreased serum bdnf levels and fphl. bdnf may be an etiologic factor in its progression. limitations of this study was the lack of estimation of the tissue bdnf level in the balding scalp. further studies are needed to investigate bdnf in both serum and skin. references 1. tamashunas nl, bergfeld wf. male and female pattern hair loss: treatable and worth treating. cleve clin j med. 2021;88(3): 173-182. doi: 10.3949/ccjm.88a.20014. pmid: 33648970. 2. davis ds, callender vd. review of quality of life studies in women with alopecia. int j womens dermatol. 2018;4(1):18-22. doi: 10.1016/j.ijwd.2017.11.007. pmid: 29872671. pmcid: pmc5986111. anxiety-related disorders, chronic stress, and neurodevelopmental disorders. the vast majority have reported that the development of the psychiatric diseases is associated with deficient bdnf levels. furthermore, other studies have demonstrated that sufficient effective treatment improves the bdnf level of such patients [24]. in this study there were high statistically significant correlations between fphl score and age of patients, age of onset of fphl, fphl duration and 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-0.119 (-0.794 – 0.555) presence of scaling 0.108 -0.521 (-1.161 – 0.119) age of onset of fphl 0.968 -0.001 (-0.040 – 0.038) duration of fphl in years 0.009 0.117 (0.031 – 0.204) 0.362 0.030 (-0.036 – 0.096) presence of family history of fphl 0.643 0.169 (-0.562 – 0.900) presence of hair pull test 0.275 -0.361 (-1.018 – 0.297) increasing in sinclair hair shedding scale 0.252 -0.315 (-0.863 – 0.232) increasing in sinclair hair density scale 0.957 0.016 (-0.569 – 0.601) increasing in fphl score 0.983 0.001 (-0.127 – 0.130) increasing in perceived stress scale 0.010 -0.068 (-0.118 – -0.017) 0.872 0.003 (-0.038 – 0.044) increasing in beck anxiety score 0.005 -.059 (-0.099 – -0.019) 0.080 -0.039 (-0.082 – 0.005) increasing in beck anxiety scale 0.011 -0.675 (-1.187 – -0.163) 0.948 -0.017 (-0.554 – 0.519) increasing in beck depression score 0.009 -.080 (-0.140 – -0.021) 0.011 -0.044 (-0.078 – -0.011) increasing in dlqi 0.561 -0.019 (-0.084 – 0.046) increasing in beck depression scale 0.024 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camacho fm, garcía-hernández m. psychological features of androgenetic alopecia. j eur acad dermatol venereol. 2002;16(5):476-480. doi: 10.1046/j.1468-3083.2002.00475.x. pmid: 12428841. 22. chan l, cook dk. female pattern hair loss. aust j gen pract. 2018;47(7):459-464. doi: 10.31128/ajgp-02-18-4498. pmid: 30114864. 23. shilpashree p, syrti clarify, ak jaiswal, shashidhar t. impact of female pattern hair loss on the quality of life of patients j pak assoc dermatol. 2016;26(4):347-352. 24. autry ae, monteggia lm. brain-derived neurotrophic factor and neuropsychiatric disorders. pharmacol rev. 2012;64(2):238528. doi: 10.1124/pr.111.005108. pmid: 22407616. pmcid: pmc3310485. 25. redler s, messenger ag, betz rc. genetics and other factors in the aetiology of female pattern hair loss. exp dermatol. 2017;26(6):510-517. doi: 10.1111/exd.13373. pmid: 28453904. 3. carmina e, azziz r, bergfeld w, et al. female pattern hair loss and androgen excess: a report from the multidisciplinary androgen excess and pcos committee. j clin endocrinol metab. 2019;104(7):2875-2891. doi: 10.1210/jc.2018-02548. pmid: 30785992. 4. kashyap mp, roberts c, waseem m, tyagi p. drug targets in neurotrophin signaling in the central and peripheral nervous system. mol neurobiol. 2018;55(8):6939-6955. doi: 10.1007 /s12035-018-0885-3. pmid: 29372544. pmcid: pmc7444275. 5. peters em, hansen mg, overall rw, et al. control of human hair growth by neurotrophins: brain-derived neurotrophic factor inhibits hair shaft elongation, induces catagen, and stimulates follicular transforming growth factor beta2 expression. j invest dermatol. 2005;124(4):675-685. doi: 10.1111/j.0022202x.2005.23648.x. pmid: 15816823. 6. panchaprateep r, korkij w, asawanonda p. brain-derived nerve factor and neurotrophins in androgenetic alopecia. br j dermatol. 2011;165(5):997-1002. doi: 10.1111/j.1365 -2133.2011.10514.x. pmid: 21729031. 7. harries m, tosti a, bergfeld w, et al. towards a consensus on how to diagnose and quantify female pattern hair loss the ‘female pattern hair loss severity index (fphl-si)’. j eur acad dermatol venereol. 2016;30(4):667-676. doi: 10.1111 /jdv.13455. pmid: 26676524. 8. garcía-batista ze, guerra-peña k, cano-vindel a, herrera-martínez sx, medrano la. validity and reliability of the beck depression inventory (bdi-ii) in general and hospital population of dominican republic. plos one. 2018;13(6):e0199750. doi: 10.1371/journal.pone.0199750. pmid: 29958268. pmcid: pmc6025862. 9. kaviani h, mousavi as. psychometric properties of the persian version of beck anxiety inventory (bai). tehran university medical journal. 2008;66(2),136-140. 10. cohen s, kamarck t, mermelstein r. perceived stress scale. j health soc behav. 1983;24(4):385-396. pmid: 6668417. 11. shikiar r, harding g, leahy m, lennox rd. minimal important difference (mid) of the dermatology life quality index (dlqi): results from patients with chronic idiopathic urticaria. health qual life outcomes. 2005;3:36. doi: 10.1186/1477-7525-336. pmid: 1590721.; pmcid: pmc1180464. 12. yanik me, erfan g, albayrak y, aydin m, kulac m, kuloglu m. reduced serum brain-derived neurotrophic factor in patients with first onset vitiligo. neuropsychiatr dis treat. 2014;10:23612367. doi: 10.2147/ndt.s74826. pmid: 25540586. pmcid: pmc4270357. 13. botchkarev va, yaar m, peters em, et al. neurotrophins in skin biology and pathology. j invest dermatol. 2006;126(8):17191727. doi: 10.1038/sj.jid.5700270. pmid: 16845411. 14. fabbrocini g, cantelli m, masarà a, annunziata mc, marasca c, cacciapuoti s. female pattern hair loss: a clinical, dermatology: practical and conceptual review | dermatol pract concept. 2022;12(2):e2022099 1 introduction: pain is experienced by most patients with hidradenitis suppurativa (hs) and has a severe impact on their quality of life. its management still presents a challenge. adalimumab, a tnf-a antagonist, has shown promising results in hs-related pain reduction. objectives: to aggregate and synthesize all existing evidence regarding the effect of adalimumab on hs-associated pain. methods: we identified original controlled and uncontrolled studies with participants receiving adalimumab, which included change in pain score post-treatment compared to baseline as an endpoint. we searched medline, sciencedirect, the cochrane library, clinicaltrials.gov and international clinical trials registry platform. the primary endpoint of our study was the mean change (continuous variable) of pain scores at week 12 compared to baseline. results: we performed a meta-analysis of 4 randomized controlled trials (282 patients in the intervention group and 266 patients in the control group). adalimumab brought about a 0.418 reduction in mean pain score at its worst with 95%ci [–0.588, –0.248] and p = 0.000 at 12 weeks after treatment commencement. four more studies were included in a qualitative synthesis, 2 of which reported statistically significant reduction in pain scores at week 12. conclusions: adalimumab could be prescribed more readily in cases of hs associated with significant pain. adalimumab effect on pain in hidradenitis suppurativa patients: systematic review and meta-analysis aikaterini tsentemeidou1, elena sotiriou1, nikolaos sideris1, alexandra kourouklidou1, aimilios lallas1, dimitrios ioannides1, efstratios vakirlis1 1 first department of dermatology and venereology, school of medicine, aristotle university, thessaloniki, greece keywords: hidradenitis suppurativa, adalimumab, pain, vas, nrs30 citation: tsentemeidou a, sotiriou e, sideris n, et al. adalimumab effect on pain in hidradenitis suppurativa patients: systematic review and meta-analysis. dermatol pract concept. 2022;12(2):e2022099. doi: https://doi.org/10.5826/dpc.1202a99 accepted: october 30, 2021; published: april 2022 copyright: ©2022 tsentemeidou et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: elena sotiriou, phd, first department of dermatology and venereology, school of medicine, aristotle university, thessaloniki, greece. email: elenasotiriou@yahoo.gr abstract 2 review | dermatol pract concept. 2022;12(2):e2022099 introduction hidradenitis suppurativa (hs) is a chronic, inflammatory, recurrent, debilitating skin disease (of the terminal hair follicle) that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly in the axillary, inguinal, and anogenital regions [1]. pain is experienced by the majority of hs patients [2–4]. hs-related pain is greater than the one associated with other skin diseases, such as eczema, psoriasis, skin tumors and acne, and constitutes one of the major reasons for the seriously impaired patient quality of life [4,5]. among other things, pain is responsible for the poor sleep quality, impaired general activity, negatively affected inter-personal relationships and reduced life enjoyment of this population [2,6]. perception of hs pain is influenced by depression and anxiety, which are frequent comorbidities, as well as by gender and age [3]. hs-related pain derives from deep-seated skin lesions and is of two types: acute/episodic, attributed to disease flares (newly formed and/or old recurring nodules and abscesses), and chronic, which is the result of longstanding inflamed lesions such as sinuses, dermal nodules and contracted scars [7–9]. acute-pain relief is usually facilitated through abscess rupture or acute surgical interventions [7,9]. hs pain is most commonly described as “shooting” (83%), “itchy” (79%) and “blinding” (75%) and is more intense when more anatomic areas are involved or when disease is more severe (hurley stage iii) [3]. the 3 most common self-reported pain aggravators are friction from tight clothing (47%), heat (40%) and stress (13%) [10]. according to ring et al hs patients tend to desperately seek for ways to alleviate their pain [10]. the majority of them make use of analgesics (77%) [11]. common pain relief strategies include non-steroidal anti-inflammatory drugs (nsaids) and paracetamol received either topically or systemically, as well as cold baths and wraps [9,10,12]. it is worth noting that this data has originated from european studies. when pain is very severe, careful administration of opioids in collaboration with a pain specialist should be considered [9,13]. selfreported use of tramadol was 37% in a 2016 study and opioids were reported the most efficient in offering relief [11]. other options may include antidepressants, anticonvulsants, specialist psychological support and patient support groups [9,12]. only a small number of studies have looked into the prevalence and impact of pain or strategies for its alleviation in hs populations [5,14]. what is more, it seems that the analgesics most commonly used by hs patients are inadequate [10]. adalimumab, a tumor necrosis factor antagonist, has been approved for the treatment of moderate-to-severe hs, based on the results of 2 clinical trials (pioneer i and ii) [15,16]. a number of studies have reported that adalimumab can effectively reduce pain. this is the first systematic review and meta-analysis to aggregate and synthesize all existing data concerning adalimumab efficacy in alleviating hs-related pain. methods study design this systematic review aimed at examining the effect of adalimumab on hs-related pain. it was conducted in accordance with the preferred reporting items for systematic reviews and meta‐analysis (prisma) statement and was registered with prospero (id: crd42021229190). eligibility criteria to answer the research question, we identified original studies with participants receiving adalimumab, which included change in pain scores compared to baseline as an endpoint. we imposed no restrictions on adalimumab dose, language and year of publication and publication status. we included both clinical trials and controlled and uncontrolled observational studies in our review. literature search a comprehensive electronic search of 5 databases was conducted, namely medline, sciencedirect, the cochrane library, clinicaltrials.gov and international clinical trials registry platform, from november 5–20, 2020, to source studies pertaining to the research question. we also searched google scholar and the archives of the major recent dermatology conferences to identify gray literature. finally, we contacted abbvie, the major sponsor of adalimumab trial projects, requesting unpublished material. the “reference” section of manuscripts relevant to the research question was hand-searched, to maximize the sensitivity of our search. as this study was a review of existing research projects, neither informed consent nor ethics approval was required. the comprehensive database search was performed independently by 2 authors (a.t. and e.s.). we used the following free-text terms for the medline database search: (hidradenitis suppurativa) or (acne inversa) and (adalimumab) or (biologic) or (humira®) or (anti-tnf) or (monoclonal antibody) and (pain) or (skin pain) or (ache). appropriate modifications were applied to the above search strategy, so that it would comply with the search rules of the rest of used databases. study selection after removing duplicates, a.t. and e.s. initially, independently, read titles and abstracts to eliminate records out of the scope of this review. they subsequently went through the full details of each record and settled disputes through consensus, having a set of predetermined inclusion and review | dermatol pract concept. 2022;12(2):e2022099 3 exclusion criteria as a guide. studies adhering to the following criteria were considered for inclusion: 1) trial or observational study, controlled or not, 2) recruited patients with a clinical diagnosis of hs, 3) patients (all of them or intervention arm) received adalimumab subcutaneously, 4) pain intensity was assessed with a validated pain measuring scale at baseline and 12 weeks after commencing treatment, 5) change in pain scores and/or proportion of patients achieving a certain reduction in such scores was documented, 6) included patients were adults of any age, gender and background population. a study was excluded if it included: 1) non-human subjects, 2) pregnant or lactating females. all selected studies were included in the qualitative synthesis, but only controlled ones were included in the quantitative synthesis. data extraction eligible studies were subjected to data extraction using a pre-formulated extraction sheet. this process was performed independently by two researchers (a.t. and e.s) and any discrepancies were settled through discussion and agreement. the following data was retrieved from each one of the selected studies: general characteristics (study identifier, clinicaltrials. gov identifier, study design, phase, number of study sites, countries included, study period, funding, inclusion criteria, exclusion criteria, intervention, comparator, follow-up duration, primary endpoint(s), secondary endpoints) and outcome data. data items pain intensity is measured with scales assigning increasing value to increasing pain intensity. in dermatology, both generic visual analogue scales (vas) and specific tools, such as the patient's global assessment of skin pain numeric rating scale (nrs), are commonly used [17]. the former represents a 100 mm-long scale, with 0 corresponding to “no pain” and 100 to “worst possible pain” [17]. nrs consists of successive numbers (the actual length of the scale is not important), usually presented on a horizontal linear configuration, from 0 (no pain) to 5 or 10 (worst possible pain) [17]. the patient is asked to mark the point/length that best corresponds to his/her pain intensity and this value is documented [17]. mean change and the proportion of patients achieving a certain score reduction are common efficacy endpoints. nrs30 is a 30% and at least 1 unit reduction in the pga skin pain nrs score compared to baseline. we imposed no restrictions to our search regarding the pain measuring tools used, on the basis that vas data can be turned into nrs data through dividing by ten. the primary endpoint of our study was mean change (continuous variable) of pain scores at week 12 compared to baseline. in the absence of published statistical measures needed, we contacted authors and requested said data. secondary endpoint was the percentage of patients achieving nrs30 (dichotomous variable) at week 12. the 12-week timeframe was chosen, as it is a sensible and widely used milestone regarding assessment of biologics’ efficacy both in research and clinical practice. risk of bias assessment two researchers (a.t. and e.s) independently used the cochrane risk-of-bias tool [18] to assess the risk of bias for included randomized controlled clinical trials. any disagreements were resolved through consensus. seven items were rated as “high risk,” “low risk,” or “unclear risk” of bias: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective outcome reporting; and (7) other sources of bias. non-randomized and/or uncontrolled studies were assessed through the methodological index for non-randomized studies (minors) [19]. studies were considered low risk if all items were reported and adequate. observational studies were evaluated through the national institutes of health (nih) quality assessment tool for observational cohort and cross-sectional studies. fourteen individual points were thus examined and an overall quality rating of good, fair, or poor was allocated to each study [20]. statistical analysis we performed all statistical analyses with comprehensive meta analysis software (comprehensive meta-analysis version 3, borenstein m, hedges l, higgins j, rothstein h. biostat). confidence intervals, p values, standard deviations (sd) and other statistical measures were mentioned, if available. in the opposite case, authors were contacted and if they did not respond, results were described only narratively. the primary goal of this systematic review was to culminate in a meta-analysis – quantitative synthesis – of the main outcome measure. the principal summary measure used for the analysis of the primary endpoint was the mean difference in pain scores between baseline and week 12. a decrease in the mean of pain scores meant that adalimumab had a positive effect on pain. associated 95% confidence intervals (ci) were estimated and differences were considered significant when p ≤ 0.05 (two-tailed). the secondary endpoint was analyzed through descriptive statistics (frequencies). the presence of heterogeneity across studies was examined through the i2 statistic (0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity). in case heterogeneity was substantial or considerable (≥50%), the random effects model was used. in the opposite case, the fixed effects model was used. a funnel plot was created to check for publication bias. 4 review | dermatol pract concept. 2022;12(2):e2022099 dosing of adalimumab was not consistent across all 8 studies or all study arms. three studies [14,24,25] examined the efficacy of 40 mg of adalimumab administered every other week and 4 studies [14, 23, 26–28] evaluated the efficacy of 40 mg of adalimumab administered weekly. alternate weekly dosing was also investigated in the second period of the 2 main phase iii rcts (pioneer i and ii), on which drug approval was based [23]. in the second period of a recent phase iii study, alternate weekly administration of 80 mg of adalimumab was also assessed [26]. in most studies [14, 23,26–28] an introductory dosage of 160 mg at week 0, 80 mg at week 2, and 40 mg at week 4 was administered prior to maintenance treatment. a different introductory regimen was employed in 2 studies [24,25] (160 mg at week 0, 80 mg at week 1, 40 mg at week 4, and 80 mg at week 0 respectively). baseline characteristics of participants are presented in table 2. results study selection and characteristics our search and screening process (figure 1) culminated in 8 studies eligible for inclusion. basic study characteristics are presented in table 1. all studies were published in english. more than 1 publication was identified for 3 studies [14,21– 23], in which case, one of those was chosen as the study identifier based on its relevance to this review’s primary endpoint. four of the included studies were randomized controlled trials (rcts)[14,23,24], 2 were prospective open-label uncontrolled trials [25,26], 1 was a retrospective cross-sectional study [27] and one was a post-marketing observational study [28,29]. a total of 863 participants with a mean age of 36.51 (sd = 11.59) years received either adalimumab subcutaneous injection (489 participants) or placebo (374 participants). the figure 1. flow diagram of study selection based on the 2009 prisma statement format. review | dermatol pract concept. 2022;12(2):e2022099 5 ta b le 1 . st u dy c h ar ac te ri st ic s s tu d y i d e n ti fi e r s ch e in fe ld e t a l 2 0 1 6 [ 1 4 ,2 1 ] a m a n o e t a l 2 0 1 0 [ 2 5 ] p io n e e r i 2 0 1 6 [ 2 2 , 2 3 ] p io n e e r i i 2 0 1 6 [ 2 2 , 2 3 ] c li n ic al t ri al s. go v n c t 0 0 9 1 8 2 5 5 n c t 0 0 8 2 7 9 9 6 n c t 0 1 4 6 8 2 0 7 n c t 0 1 4 6 8 2 3 3 st u dy d es ig n c li n ic al t ri al c li n ic al t ri al c li n ic al t ri al c li n ic al t ri al p h as e ii ii ii i ii i st u dy s it es 2 6 1 4 8 1 0 1 i n p io n e e r i & i i c o u n tr ie s in cl u d ed d en m ar k , g er m an y, n et h er la n d s, u n it ed s ta te s u n it ed s ta te s a u st ra li a, c an ad a, c ze ch r ep u b li c, g er m an y, h u n ga ry , u n it ed s ta te s a u st ra li a, c an ad a, d en m ar k , f ra n ce , g re ec e, n et h er la n d s, p u er to r ic o , s w ed en , s w it ze rl an d , t u rk ey , u n it ed s ta te s st u dy p er io d a p ri l 2 0 0 9 – n o ve m b er 2 0 1 0 f eb ru ar y 2 0 0 7 – a u gu st 2 0 0 8 n o ve m b er 2 0 1 1 – j an u ar y 2 0 1 4 n o ve m b er 2 0 1 1 – a p ri l 2 0 1 4 f u n d in g a b b o tt f lo ri d a a ca d em ic d er m at o lo gy c en te rs , a b b o tt a b b v ie ( p ri o r sp o n so r, a b b o tt ) a b b v ie ( p ri o r sp o n so r, a b b o tt ) in cl u si o n c ri te ri a h ea lt h y ad u lt s, a b le t o a d m in is te r su b cu ta n eo u s in je ct io n s, n eg at iv e ch es t x -r ay a n d p p d t es t o r co m p le te d a n ti -t u b er cu lo si s th er ap y ≥1 8 y ea rs , m o d er at e to s ev er e h s an d ≥ 1 o f: ≥ 1 ye ar d u ra ti o n , m u lti p le e r o r d o ct o r vi si ts , > 5 /y ea r tr ia m ci n o lo n e in je ct io n s, f ai le d re ti n o id s an d a n ti b io ti cs , r ec o n st ru ct iv e su rg er y, n o rm al l ab o ra to ry va lu es 1 8 -9 9 y ea rs , h s fo r at l ea st 1 y ea r an d st ab le f o r at l ea st 2 m o n th s, a t le as t 2 a n at o m ic a re as , o n e at l ea st h u rl ey st ag e ii o r ii i, a n c o u n t ≥3 , i n ad eq u at e re sp o n se t o a t le as t 9 0 d ay s o f an ti b io tic s fo r h s 1 8 -9 9 y ea rs , h s fo r at l ea st 1 y ea r an d st ab le f o r at l ea st 2 m o n th s, a t le as t 2 a n at o m ic a re as , o n e at l ea st h u rl ey st ag e ii o r ii i, a n c o u n t ≥3 , i n ad eq u at e re sp o n se t o a t le as t 9 0 d ay s o f an ti b io tic s fo r h s e x cl u si o n c ri te ri a p ri o r an ti -t n f t re at m en t, u n st ab le an ti b io ti c th er ap y fo r h s, r eq u ir ed m ed ic at io n w as h o u ts f o r o th er h s tr ea tm en ts , p ri o r ex p o su re t o t ys ab ri ® (n at al iz u m ab ), r ec en t in fe ct io n r eq u ir in g tr ea tm en t, s ig n ifi ca n t m ed ic al e ve n ts o r co n d it io n s, p re gn an cy o r b re as tfe ed in g o r co n si d er in g b ec o m in g p re gn an t d u ri n g th e st u d y, h is to ry o f ca n ce r, ex ce p t su cc es sf u ll y tr ea te d s k in c an ce r, re ce n t h is to ry o f d ru g o r al co h o l ab u se p re gn an cy , l ac ta ti o n , p la n n in g p re gn an cy , a d al im u m ab a ll er gy , sy st em ic a n ti -i n fl am m at o ry m ed ica ti o n e x ce p t n sa id a n d l o w -d o se sy st em ic s te ro id s, h iv , h b v o r h c v s er o p o si ti ve , s er io u s in fe cti o n s in p re vi o u s 3 m o n th s, m yc o b ac te ri al o r o p p o rt u n is ti c in fe ct io n w it h in p ri o r 6 m o n th s, l ym p h o p ro li fe ra ti ve d is ea se , l ym p h ad en o p at h y o r sp le n o m eg al y, m al ig n an cy w it h in 5 y ea rs e x ce p t fu ll y ex ci se d b c c , se ve re o rg an f ai lu re , s o li d o rg an tr an sp la n t, g ra n u lo m at o u s in fe ct io n p ri o r ad al im u m ab o r o th er a n ti -t n f tr ea tm en t, a n ti b io ti cs f o r h s w it h in p re vi o u s 2 8 d ay s, o ra l an al ge si cs f o r h s w it h in p as t 1 4 d ay s, o ra l o p io id o r n o n -s ta b le d o se o f n o n -o p io id a n al ge si cs f o r re as o n u n re la te d w it h h s w it h in p as t 1 4 d ay s p ri o r ad al im u m ab o r o th er a n ti -t n f tr ea tm en t, n o n -s ta b le d o se o f p er m it te d a n ti b io ti cs f o r h s w it h in p re vi o u s 2 8  d ay s, o ra l an al ge si cs f o r h s w it h in p as t 1 4 d ay s, o ra l o p io id o r n o n -s ta b le d o se o f n o n -o p io id a n al ge si cs f o r re aso n u n re la te d w it h h s w it h in p as t 1 4 d ay s (c o n ti n u ed ) 6 review | dermatol pract concept. 2022;12(2):e2022099 s tu d y i d e n ti fi e r s ch e in fe ld e t a l 2 0 1 6 [ 1 4 ,2 1 ] a m a n o e t a l 2 0 1 0 [ 2 5 ] p io n e e r i 2 0 1 6 [ 2 2 , 2 3 ] p io n e e r i i 2 0 1 6 [ 2 2 , 2 3 ] in te rv en ti o n p er io d 1 : a d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at w ee k 0 , 8 0 m g at w ee k 2 , a n d 4 0 m g w ee k ly s ta rt in g at w ee k 4 t h ro u gh w ee k 1 5 . o r 8 0 m g at w ee k 0 a n d 4 0 m g ev er y o th er w ee k s ta rt in g at w ee k 1 t h ro u gh w ee k 1 5 p er io d 2 : 3 6 w ee k s, o p en l ab el , a d al im u m ab 4 0 m g ev er y o th er w ee k a d al im u m ab s u b cu ta n eο u s in je cti o n , 1 6 0 m g at w ee k 0 , f o ll o w ed b y 8 0 m g at w ee k 1 , a n d 4 0 m g at al te rn at e w ee k s u n ti l w ee k 1 2 p er io d 1 : a d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at w ee k 0 , 8 0 m g at w ee k 2 , 4 0 m g ev er y w ee k f ro m w ee k 4 to w ee k 1 2 p er io d 2 : p ri o r p la ce b o > a d al im u m ab 4 0 m g ev er y w ee k u n ti l w ee k 3 5 , p ri o r ad al im u m ab > p la ce b o e ve ry w ee k , ad al im u m ab 4 0 m g ev er y w ee k o r ad al im u m ab 4 0 m g ev er y o th er w ee k p er io d 1 : a d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at w ee k 0 , 8 0 m g at w ee k 2 , 4 0 m g ev er y w ee k f ro m w ee k 4 t o w ee k 1 2 p er io d 2 : p ri o r p la ce b o > a d al im u m ab 4 0 m g ev er y w ee k u n ti l w ee k 3 5 , p ri o r ad al im u m ab > p la ce b o e ve ry w ee k , ad al im u m ab 4 0 m g ev er y w ee k o r ad al im u m ab 4 0 m g ev er y o th er w ee k c o m p ar at o r p la ce b o w ee k ly s ta rt in g at w ee k 0 th ro u gh w ee k 1 5 n o t ap p li ca b le p la ce b o p la ce b o fo ll ow -u p d u ra ti o n 1 6 w ee k s 1 2 w ee k s 3 6 w ee k s 3 6 w ee k s p ri m ar y en d p o in t( s) p ro p o rt io n o f p at ie n ts a ch ie vi n g an h sp g a s co re o f cl ea r, m in im al , o r m il d w it h a t le as t a 2 -g ra d e im p ro ve m en t re la ti ve t o b as el in e at w ee k 1 6 p ro p o rt io n o f p at ie n ts a ch ie vi n g d ec re as e o f 5 0 % f ro m b as el in e in th e h ss i s co re a ft er 1 2 w ee k s o f tr ea tm en t p er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g h is c r a t w ee k 1 2 p er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g h is c r a t w ee k 1 2 se co n d ar y en d p o in ts p ro p o rt io n o f p at ie n ts a ch ie vi n g cl in ic al re sp o n se a t w ee k s 2 , 4 , 8 , a n d 1 2 a n d al l vi si ts ( p er io d 2 ), h sp g a s co re o f cl ea r, m in im al , o r m il d , m ea n c h an ge in m ss , m ea n p er ce n ta ge o f im p ro ve m en t in a b sc es se s, d ra in in g fi st u la s, o r in fl am m at o ry n o d u le s, m ea n c h an ge i n c -r ea ct iv e p ro te in l ev el s, m ea n c h an ge in d l q il sc o re , t o ta l w o rk p ro d u ct iv it y im p ai rm en t at w ee k 1 6 . p o st h o c an al ys is : p ro p o rt io n o f p at ie n ts a ch ie vi n g 3 0 % o r gr ea te r re d u ct io n a n d a 1 0 -m m o r gr ea te r ab so lu te r ed u ct io n i n p ai n v is u al a n al o gu e sc al e sc o re d if fe re n ce f ro m b as el in e at 1 2  w ee k s in p ai n m ea su re d b y a v isu al a n al o g sc al e, d l q i, a n d p g a o f d is ea se s ev er it y, n u m b er o f p ati en ts w it h a > 3 0 a n d > 5 0 % d is ea se ac ti vi ty a t 1 2 w ee k s, a d ve rs e ev en ts p er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g a n co u n t 0 , 1 o r 2 , n r s3 0 – a t w o rs t at w ee k 1 2 , c h an ge o f m ss a t w ee k 1 2 p er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g a n co u n t 0 , 1 o r 2 , n r s3 0 – a t w o rs t at w ee k 1 2 , c h an ge o f m ss a t w ee k 1 2 h s = h id ra d en it is s u p p u ra ti va ; e r = e m er ge n cy r o o m ; a n c o u n t = a b sc es s an d in fl am m at o ry n o d u le c o u n t; n sa id = n o n -s te ro id al a n ti -i n fl am m at o ry d ru g; h iv = h u m an im m u n o d ef ic ie n cy v ir u s; h b v  =   h ep at it is b v ir u s; h c v = h ep at it is c v ir u s; h sp g a = h id ra d en it is s u p p u ra ti va – p h ys ic ia n ’s g lo b al a ss es sm en t; h ss i = h id ra d en it is s u p p u ra ti va s ev er it y in d ex ; h is c r = h id ra d en it is s u p p u ra ti va c li n ic al r es p o n se ; m ss : m o d if ie d s ar to ri u s sc o re ; d l q i = d er m at o lo gy l if e q u al it y in d ex ; n r s3 0 = a t le as t 3 0 % a n d 1 u n it r ed u ct io n i n p ai n n u m er ic r at in g sc al e sc o re . ta b le 1 . st u dy c h ar ac te ri st ic s (c o n ti n u ed ) review | dermatol pract concept. 2022;12(2):e2022099 7 ta b le 1 . st u dy c h ar ac te ri st ic s (c o n ti n u ed ) s tu d y t it le m o ri ta e t a l. 2 0 1 9 [ 2 6 ] h o p e 2 0 1 9 [ 2 8 ] m il le r e t a l. 2 0 1 1 [ 2 4 ] c a p o si e n a c a ro e t a l. 2 0 2 0 [ 2 7 ] c li n ic al t ri al s. go v n c t 0 2 9 0 4 9 0 2 n c t 0 2 7 3 9 8 2 8 n o t ap p li ca b le n o t ap p li ca b le st u dy d es ig n c li n ic al t ri al o b se rv at io n al c li n ic al t ri al c ro ss -s ec ti o n al p h as e ii i n o t ap p li ca b le n o t re p o rt ed n o t ap p li ca b le st u dy s it es 8 1 1 2 n o t re p o rt ed c o u n tr ie s in cl u d ed ja p an sw ed en d en m ar k n o t re p o rt ed st u dy p er io d se p te m b er 2 0 1 6 – m ay 2 0 1 9 a p ri l 2 0 1 6 – m ar ch 2 0 1 8 2 0 0 7 – j u ly 2 0 1 0 n o t re p o rt ed f u n d in g a b b v ie a b b v ie a b b o tt n o t re p o rt ed in cl u si o n c ri te ri a 1 8 –9 9 y ea rs , h s fo r at l ea st 6 m o n th s & s ta b le f o r at l ea st 2 m o n th s, ≥ 2 a n at o m ic a re as , o n e at l ea st h u rl ey s ta ge i i o r ii i, a n co u n t ≥3 1 8 –9 9 y ea rs , h s d ia gn o si s, r ec ei vi n g a d al im u m ab a cc o rd in g to t h e su m m ar y o f p ro d u ct c h ar ac te ri st ic s, w il li n gn es s to s ig n in fo rm ed c o n se n t ≥1 8 y ea rs , h u rl ey s ta ge i i o r ii i h s fo r at l ea st 6 m o n th s, a t le as t 4 w ee k s o f w as h -o u t fo r p re vi o u s tr ea tm en ts , f em al es i n st ru ct ed t o u se c o n tr ac ep ti o n ≥ 1 8 y ea rs , d ia gn o si s o f h s, a n co u n t ≥ 3 a t b as el in e, ≥ 1 y ea r o f tr ea tm en t w it h a d al im u m ab e x cl u si o n c ri te ri a p ri o r ad al im u m ab o r o th er a n ti -t n f t re at m en t, o th er s k in c o n d it io n i m p ed in g h s as se ss m en t, an ti b io ti cs f o r h s o th er t h an a st ab le d o se o f d o x yc yc li n e o r m in o cy cl in e fo r p as t 2 8 d ay s, t o p ic al tr ea tm en ts o r o ra l an al ge si cs f o r h s w it h in p as t 1 4 d ay s, s ys te m ic tr ea tm en t fo r h s w it h in p as t 2 8 d ay s p ri o r b io lo gi c tr ea tm en t d is co n ti n u ed < 6 m o n th s b ef o re t h e b as el in e vi si t p at ie n t n o t ab le t o u n d er st an d t h e la n gu ag e o f p ro vi d ed p at ie n t q u es ti o n n ai re s, h is to ry o f n o n -c o m p li an ce w it h m ed ic at io n o r a m ed ic al h is to ry t h at c o u ld e n h an ce n o n -c o m p li an ce w it h m ed ic at io n p ri o r b io lo gi c tr ea tm en t, c o n ve n ti o n al h s tr ea tm en t w it h in p as t 4 w ee k s, c h ro n ic o r re cu rr en t in fe cti o n s, a ll er gy t o s tu d y d ru g, s er io u s h ea lt h p ro b le m s, p re gn an cy a n d b re as tf ee d in g, u n tr ea te d o r la te n t tu b er cu lo si s, c an ce r h is to ry , d ru g o r al co h o l ab u se n o t re p o rt ed in te rv en ti o n a d al im u m ab 1 6 0 m g su b cu ta n eo u s in je ct io n w ee k 0 , 8 0 m g w ee k 2 , a n d 4 0 m g ev er y w ee k s ta rt in g w ee k 4 . a ft er w ee k 5 2 s w it ch to 8 0 m g ev er y o th er w ee k a ft er co n se n t a d al im u m ab a cc o rd in g to s u m m ar y o f p ro d u ct c h ar ac te ri st ic s a d al im u m ab , 8 0 m g su b cu ta n eo u sl y at w ee k 0 f o ll o w ed b y 4 0 m g ev er y o th er w ee k f o r 1 2 w ee k s a d al im u m ab 4 0 m g ev er y w ee k c o m p ar at o r n o t ap p li ca b le n o t ap p li ca b le p la ce b o e ve ry o th er w ee k f o r 1 2 w ee k s n o t ap p li ca b le fo ll ow -u p d u ra ti o n u p t o 1 2 w ee k s u p t o 2 4 w ee k s 2 4 w ee k s 1 0 8 w ee k s (c o n ti n u ed ) 8 review | dermatol pract concept. 2022;12(2):e2022099 s tu d y t it le m o ri ta e t a l. 2 0 1 9 [ 2 6 ] h o p e 2 0 1 9 [ 2 8 ] m il le r e t a l. 2 0 1 1 [ 2 4 ] c a p o si e n a c a ro e t a l. 2 0 2 0 [ 2 7 ] p ri m ar y en d p o in t( s) p er ce n ta ge o f p ar ti ci p an ts a ch ie vin g h is c r a t w ee k 1 2 c h an ge i n d l q i sc o re f ro m b as el in e at w ee k 1 2 c h an ge i n s ar to ri u s an d h u rl ey sc o re s at w ee k s 1 2 a n d 2 4 n o o u tc o m e d efi n ed a s p ri m ar y se co n d ar y en d p o in ts p er ce n ta ge o f p ar ti ci p an ts a ch ie vin g a n c o u n t 0 , 1 o r 2 a t w ee k 1 2 , n r s3 0 – a t w o rs t at w ee k 2 , c h an ge o f m ss f a t w ee k s 2 ,4 ,8 & 1 2 c h an ge f ro m b as el in e: o f p ai n n u m er ic r ar in g sc al e – at w o rs t an d o n a ve ra ge a t w ee k s 4 , 1 2 a n d 2 4 , o f d l q i at w ee k s 4 a n d 2 4 , o f e q -5 d g q u es ti o n n ai re r esp o n se s, e q -5 d v a s sc o re , h si a o ve ra ll sc o re , w pa ish p s co re a t w ee k s 4 , 1 2 & 2 4 , a ch ie ve m en t o f h is c r a t w ee k s 4 , 1 2 & 2 4 c h an ge i n v a s p ai n s co re a t w ee k s 1 2 a n d 2 4 , s el fre p o rt ed d ay s w it h le si o n s b et w ee n v is it s, d l q i an d ev al u at io n o f sc ar ri n g [m an ch es te r p o st -i n fl am m at o ry s ca r sc o ri n g an d p h ys ic ia n g lo b al a ss es sm en t sc ar s co ri n g] , d o cu m en ta ti o n o f ad ve rs e ev en ts e ve ry 1 2 w ee k s: n u m b er o f p ati en ts a ch ie vi n g h is c r o f ≥ 5 0 % re d u ct io n i n i n fl am m at o ry l es io n co u n t, n u m b er o f fl ar es , m ea n t im e b et w ee n fl ar es , h id ra d en it is s u p p u ra ti va i h s4 # # , p ai n v a s an d l es io n co u n t. a d d it io n al ly , d l q i w as as se ss ed t o m ea su re q u al it y o f li fe (q o l ) ev er y 2 4 w ee k s. h s = h id ra d en it is s u p p u ra ti va ; a n c o u n t = a b sc es s an d i n fl am m at o ry n o d u le c o u n t; h is c r = h id ra d en it is s u p p u ra ti va c li n ic al r es p o n se ; d l q i = d er m at o lo gy l if e q u al it y in d ex ; n r s3 0 = a t le as t 3 0 % a n d 1 u n it r ed u ct io n i n p ai n n u m er ic r at in g sc al e sc o re ; m ss = m o d if ie d s ar to ri u s sc o re ; e q -5 d = i n st ru m en t fo r ev al u at io n o f m o b il it y, s el fca re , u su al a ct iv it ie s, p ai n /d is co m fo rt , a n d a n x ie ty /d ep re ss io n ; v a s = v is u al a n al o gu e sc al e; h si a = h id ra d en it is s u p p u ra ti va i m p ac t a ss es sm en t; w pa ish p = w o rk p ro d u ct iv it y an d a ct iv it y im p ai rm en t – sp ec if ic h ea lt h p ro b le m ; h is c r : h id ra d en it is s u p p u ra ti va c li n ic al r es p o n se ; ih s4 = i n te rn at io n al h id ra d en it is s u p p u ra ti va s ev er it y sc o re s ys te m . ta b le 1 . st u dy c h ar ac te ri st ic s (c o n ti n u ed ) review | dermatol pract concept. 2022;12(2):e2022099 9 ta b le 2 . b as el in e c h ar ac te ri st ic s o f pa rt ic ip an ts s tu d y i d e n ti fi e r s ch e in fe ld e t a l 2 0 1 6 a m a n o e t a l 2 0 1 0 p io n e e r i 2 0 1 6 p io n e e r i i 2 0 1 6 m o ri ta e t a l 2 0 1 9 h o p e 2 0 1 9 m il le r e t a l. 2 0 1 1 c a p o si e n a -c a ro e t a l. 2 0 2 0 n u m b er o f p ar ti ci p an ts 1 5 4 1 0 3 0 7 3 2 6 1 5 1 0 2 1 2 0 a d al im u m ab ( a d a) (n , % ) 1 0 3 ( 6 6 .8 8 ) 1 0 ( 1 0 0 ) 1 5 3 ( 4 9 .8 4 ) 1 6 3 ( 5 0 ) 1 5 ( 1 0 0 ) 1 0 ( 1 0 0 ) 1 5 ( 7 1 .4 3 ) 2 0 ( 1 0 0 ) p la ce b o ( p b o ) (n , % ) 5 1 ( 3 3 .1 2 ) 0 1 5 4 ( 5 0 .1 6 ) 1 6 3 ( 5 0 ) 0 0 6 ( 2 8 .5 7 ) 0 g en d er ( % ) a d al im u m ab f: 7 4 ( 4 8 .0 5 ) f: 7 ( 7 0 .0 ) f: 9 1 ( 2 9 .6 4 ) f: 1 0 8 ( 3 3 .1 3 ) f: 2 ( 1 3 .3 ) f: 7 ( 7 0 ) f: 1 2 ( 5 7 .1 4 ) f: 1 4 ( 7 0 ) m : 2 9 ( 1 8 .8 3 ) m : 3 ( 3 0 .0 ) m : 6 2 ( 2 0 .2 0 ) m : 5 5 ( 1 6 .8 7 ) m : 1 3 ( 8 6 .7 ) m : 3 ( 3 0 ) m : 3 ( 1 4 .2 9 ) m : 6 ( 3 0 ) p la ce b o f: 3 6 ( 2 3 .3 8 ) 0 f: 1 0 5 ( 3 4 .2 0 ) f: 1 1 3 ( 3 4 .6 7 ) 0 0 f: 5 ( 2 3 .8 1 ) 0 m : 1 5 ( 9 .7 4 ) m : 4 9 ( 1 5 .9 6 ) m : 5 0 ( 1 5 .3 4 ) m : 1 ( 4 .7 6 ) a ge ( ye ar s, m ea n , sd /9 5 % c i) a d a: 3 5 .6 (1 1 .6 ) 3 2 .6 ( 1 1 .1 4 ) a d a: 3 6 .2 ( 1 0 .8 3 ) a d a: 3 4 .9 ( 9 .9 6 ) 4 2 .1 ( 6 .9 4 ) 4 2 .7 ( 1 1 .4 7 ) a d a: 3 8 .7 (3 0 .9 –4 6 .4 ) 3 5 .1 ( 1 2 ) p b o : 3 7 .8 (1 2 .1 ) p b o : 3 7 .8 ( 1 1 .3 3 ) p b o : 3 6 .1 ( 1 2 .1 8 ) p b o : 4 0 .2 (2 5 .8 –5 4 .5 ) r ac e/ et h n ic it y (n , % ) w h it e a d a: 7 3 ( 4 7 .4 ) 5 ( 5 0 ) a d a: 1 1 6 ( 3 7 .7 9 ) a d a: 1 4 3 ( 4 3 .8 7 ) 0 n r n r n r p b o : 3 7 ( 2 4 .0 3 ) p b o : 1 1 8 ( 3 8 .4 4 ) p b o : 1 3 0 ( 3 9 .8 8 ) b la ck a d a: 2 1 ( 1 3 .6 4 ) 3 ( 3 0 ) a d a: 3 3 ( 1 0 .7 5 ) a d a: 9 ( 2 .7 6 ) 0 n r n r n r p b o : 8 ( 5 .1 9 ) p b o : 2 9 ( 9 .4 5 ) p b o : 2 0 ( 6 .1 3 ) o th er n r 2 ( 2 0 ) a d a: 4 ( 1 .3 ) a d a: 1 1 ( 3 .3 7 ) 1 5 ( 1 0 0 ) n r n r n r p b o : 7 ( 2 .2 8 ) p b o : 1 3 ( 3 .9 8 ) w ei gh t (k g, m ea n , sd ) a d a: 9 7 .6 2 (2 4 .9 2 ) n r a d a: 9 7 .1 ( 2 4 .9 0 ) a d a: 9 0 .2 ( 2 1 .7 4 ) n r n r n r n r p b o : 9 6 .5 (2 4 .8 ) p b o : 9 9 .3 ( 2 5 .1 3 ) p b o : 9 5 .7 ( 2 5 .8 7 ) b m i (k g/ m 2 , n ) m ea n ( 9 5 % c i) m ea n ( sd ) < 2 5 a d a: 1 5 ( 9 .7 4 ) a d a: 2 4 ( 7 .8 2 ) a d a: 3 6 ( 1 1 .0 4 ) 7 ( 4 6 .7 ) 0 a d a: 3 2 ( 2 5 .7 – 3 8 .4 ) 2 8 .4 ( 6 ) p b o : 9 ( 5 .8 4 ) p b o : 1 3 ( 4 .2 3 ) p b o : 2 6 ( 7 .9 8 ) (c o n ti n u ed ) 10 review | dermatol pract concept. 2022;12(2):e2022099 s tu d y i d e n ti fi e r s ch e in fe ld e t a l 2 0 1 6 a m a n o e t a l 2 0 1 0 p io n e e r i 2 0 1 6 p io n e e r i i 2 0 1 6 m o ri ta e t a l 2 0 1 9 h o p e 2 0 1 9 m il le r e t a l. 2 0 1 1 c a p o si e n a -c a ro e t a l. 2 0 2 0 2 5 t o < 3 0 a d a: 2 3 ( 1 4 .9 4 ) n r a d a: 3 1 ( 1 0 .1 0 ) a d a: 4 2 ( 1 2 .8 8 ) 4 ( 2 6 .7 ) 2 ( 2 0 ) p b o : 3 2 .4 ( 2 4 .7 – 4 0 .2 ) p b o : 6 ( 3 .9 0 ) p b o : 3 8 ( 1 2 .3 8 ) p b o : 3 6 ( 1 1 .0 4 ) > 3 0 a d a: 6 5 ( 4 2 .2 1 ) a d a: 9 7 ( 3 1 .6 0 ) a d a: 8 5 ( 2 6 .0 7 ) 4 ( 2 6 .7 ) 8 ( 8 0 ) p b o : 3 6 ( 2 3 .3 8 ) p b o : 1 0 3 ( 3 3 .5 5 ) p b o : 1 1 7 ( 3 5 .8 9 ) d is ea se d u ra ti o n (y ea rs , m ea n /m ed ia n , sd /r an ge ) a d a: 1 1 .1 ( 9 .0 ) n r a d a: 8 .8 [ 1 .1 , 4 0 .4 ] a d a: 9 .0 [ 1 .0 ,4 3 .5 ] 1 4 .1 ( 1 0 .5 8 ) n r n r 1 5 .8 ( 1 0 ) p b o : 1 3 .4 (1 0 .4 ) p b o : 9 .4 [ 1 .0 , 4 3 .0 ] p b o : 9 .9 [ 1 .2 ,6 8 .5 ] sm o k in g a d a: 5 6 ( 3 6 .3 6 ) n r a d a: 8 1 ( 5 2 .6 0 ) a d a: 1 0 5 ( 3 2 .2 0 ) 1 2 ( 8 0 ) 4 ( 4 0 ) a d a: 1 0 ( 4 7 .6 2 ) 1 2 ( 7 0 ) p b o : 2 9 ( 1 8 .8 3 ) p b o : 9 2 ( 5 9 .7 4 ) p b o : 1 0 9 ( 3 3 .4 4 ) p b o : 5 ( 2 3 .8 1 ) h u rl ey s ta ge i o r ii a d a: 7 3 ( 4 7 .4 0 ) n r a d a: 8 0 ( 5 1 .9 5 ) a d a: 8 6 ( 2 6 .3 8 ) 9 ( 6 0 ) 2 ( 2 0 ) n r 1 1 ( 5 5 ) p b o : 3 6 ( 2 3 .3 8 ) p b o : 8 1 ( 5 2 .6 ) p b o : 8 9 ( 2 7 .3 0 ) ii i a d a: 3 0 ( 1 9 .4 8 ) n r a d a: 7 3 ( 4 7 .4 0 ) a d a: 7 7 ( 2 3 .6 2 ) 6 ( 4 0 ) 8 ( 8 0 ) n r 9 ( 4 5 ) p b o : 1 5 ( 9 .7 4 ) p b o : 7 3 ( 4 7 .4 0 ) p b o : 7 4 ( 2 2 .7 0 ) b as el in e p ai n s co re (v a s o r n r s, m ea n , sd /9 5 % c i) a d a: 5 2 .5 (2 5 .3 6 ) a d a: 5 .1 ( 2 .5 1 ) a d a: 4 .3 ( 2 .6 2 ) 4 .6 ( 0 .6 0 ) 5 .9 ( 2 .5 9 ) a d a: 5 8 (4 0 .6 3 –7 5 .3 7 ) 4 .8 ( n r ) p b o : 5 7 .8 (2 8 .5 ) p b o : 4 .8 ( 2 .6 8 ) p b o : 4 .8 ( 2 .7 3 ) p b o : 3 6 .1 7 (5 .9 7 –6 6 .3 7 ) n = n u m b er o f p ar ti ci p an ts ; f = f em al e; m = m al e; s d = s ta n d ar d d ev ia ti o n ; 9 5 % c i = 9 5 % c o n fi d en ce i n te rv al ; n r = n o t re p o rt ed ; v a s = v is u al a n al o gu e sc al e; n r s = p ai n n u m er ic al r at in g sc al e; b m i = b o d y m as s in d ex . ta b le 2 . b as el in e c h ar ac te ri st ic s o f pa rt ic ip an ts ( co n ti n u ed ) review | dermatol pract concept. 2022;12(2):e2022099 11 methodological quality assessment the methodological quality of the 4 included rcts [14,23,24] was assessed through the cochrane risk of bias tool (figure 2). the overall risk for these studies was found to be low. the 2 open-label uncontrolled studies were assessed through the minors tool (table 3) and were found to be high risk. the observational studies were assessed through the quality assessment tool for observational cohort and cross-sectional studies and their methodological quality was deemed fair (table 4). according to the funnel plot no publication bias was detected (figure 3). outcomes quantitative synthesis of the 4 controlled studies was possible for the primary outcome (data available for a total of 282 patients in the intervention group and 266 patients in the control group) (figure 4). vas values [14,24] were converted to pga-nrs values through dividing by 10. the figure 2. a overall risk of bias of randomized controlled trials, calculated with the cochrane risk of bias tool. b risk of bias of individual randomized controlled trials, calculated with the cochrane risk of bias tool. random sequence generation (selection bias) allocation concealment (selection bias) blinding of participants and personnel (performance bias) blinding of outcome assessment (detection bias) incomplete outcome data (attrition bias) selective reporting (reporting bias) other bias high risk of biasunclear risk of biaslow risk of bias 0% 25% 50% 75% 100% a b 12 review | dermatol pract concept. 2022;12(2):e2022099 table 4. quality assessment tool for observational cohort and cross-sectional studies assessed items hope 2019 caposiena caro et al 2020 1. was the research question or objective in this paper clearly stated? yes yes 2. was the study population clearly specified and defined? yes yes 3. was the participation rate of eligible persons at least 50%? yes not reported 4. were all the subjects selected or recruited from the same or similar populations (including the same time period)? were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? yes yes 5. was a sample size justification, power description, or variance and effect estimates provided? no no 6. for the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? yes yes 7. was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? yes yes 8. for exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (eg, categories of exposure, or exposure measured as continuous variable)? not applicable not applicable 9. were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? yes yes 10. was the exposure(s) assessed more than once over time? yes yes 11. were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? yes yes 12. were the outcome assessors blinded to the exposure status of participants? no no 13. was loss to follow-up after baseline 20% or less? no yes 14. were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? no no overall rating (good, fair, poor) fair fair table 3. methodological index for non-randomized studies (minors) assessed items amano et al 2010 morita et al 2019 1. a clearly stated aim 2 2 2. inclusion of consecutive patients 0 0 3. prospective collection of data 2 2 4. endpoints appropriate to the aim of the study 2 2 5. unbiased assessment of the study endpoint 0 0 6. follow-up period appropriate to the aim of the study 2 2 7. loss to follow up less than 5% 1 1 8. prospective calculation of the study size 0 2 9. an adequate control group n/a n/a 10. contemporary groups n/a n/a 11. baseline equivalence of groups n/a n/a 12. adequate statistical analyses n/a n/a total score 9 11 judgement high risk high risk methodological index for non-randomized studies (minors) scale contains 8 assessment points for non-comparative studies and 4 extra points for comparative studies[19]. each item receives 0, 1 or 2 points, if it is not reported, reported but inadequate or reported and adequate respectively, with an ideal overall score of 16 for non-comparative and 24 for comparative studies. n/a = not applicable or not available?please explain review | dermatol pract concept. 2022;12(2):e2022099 13 miller 2011 + ? ? ? + + – – –+ + + + +++ + + + ++ + + + + +++ r a n d o m s eq u en c e g en er a ti o n (s el ec ti o n b ia s) a ll o c a ti o n c o n c ea lm en t (s el ec ti o n b ia s) b li n d in g o f pa r it c ip a n ts a n d p er so n n el (p er fo r m a n c e b ia s) b li n d in g o f o u tc o m e a ss es sm en t (d et ec ti o n b ia s) in c o m p le te o u tc o m e d a ta (a t tr it io n b ia s) se le c ti v e r ep o r ti v e (r ep o r ti n g b ia s) o th er b ia s pioneer i pioneer ii scheinfeld 2016 0.0 funnel plot of standard error by std diff in means 0.1 0.2 st a n d a r d e r r o r 0.3 0.4 0.5 -2.0 -1.5 -1.0 -0.5 0.0 std diff in means 0.5 1.0 1.5 2.0 figure 3. funnel plot for the assessment of publication bias, designed with comprehensive meta analysis software. meta-analysis performed showed that adalimumab administered for 12 weeks significantly decreased pain compared to placebo (-0.418 reduction in mean pain score [95% ci –0.588, –0.248] and p = 0.000). there was very little heterogeneity across studies based on the i2 statistic (2.985). only the “adalimumab every week” arm of scheinfeld et al [14] was included in the meta-analysis, as statistical data regarding the “adalimumab every other week” arm was missing. we contacted authors via email in an effort to acquire this data, but they did not respond. no quantitative synthesis of controlled studies was possible for the secondary outcome, due to missing data (email communication with authors was fruitless). according to scheinfeld et al [14], 63% (p < 0.001) and 43% of patients 14 review | dermatol pract concept. 2022;12(2):e2022099 patients’ quality of life and the established under-treatment or difficult treatment of hs-related pain, the key finding of this study suggests that dermatologists should consider adalimumab when pain is a primary concern of a hs patient (in terms of severity, frequency and or perception). the limitations of our study are the small number of studies included in the quantitative synthesis, which, however, reflects the actual paucity of evidence regarding the effect of adalimumab on hs-associated pain. what is more, the main body of evidence included in this review and analysis came from pre-drug-approval rcts, which, though solid methodologically, may not accurately simulate real-life conditions eg strict inclusion and exclusion criteria, higher treatment compliance, more frequent doctor visits, etc. another limitation of our study is th that we did not check for confounding factors such as the impact of mood improvement on pain perception. pain is the principal determinant of life quality in hs patients [31]. a recent (2020) cross-sectional study included 1,795 hs patients, 83.6% of whom experienced pain [32]. pain intensity correlated positively with female gender, smoking, multiple affected areas and more severe disease [32]. commonly employed hs treatments offer inadequate pain relief and, on top of this, dermatologists tend to be insufficiently trained in clinical pain management [31]. as a result, patients frequently self-medicate and may expose themselves to the dangers of opioid or other substance misuse [31]. on another note, 82% of 110 hs patients tried to alleviate their pain through manually draining pus from their own lesions [33]. according to the european guidelines for the treatment of hs [34] a holistic approach is mandatory, when deciding how to manage hs patients. aside from the principal pharmaceutical therapy, a plan should be made, among other things, for handling pain. there is, however, receiving adalimumab every week and every other week respectively achieved minimum clinically important difference in pain at week 12 (defined as half of standard deviation of baseline pain score) comparing to 26% of patients receiving placebo [30]. the same study revealed that 52.1% (p  <  0.001) and 27.7% of patients receiving adalimumab every week and every other week, respectively, achieved ≥50% reduction in baseline vas score at week 12, contrary to 18.8% of patients receiving placebo [14]. according to pioneer i, 27.9% of patients receiving adalimumab and 24.8% of patients receiving placebo achieved nrs30 at week 12 (p = 0.628) [23]. according to pioneer ii, 45.7% of patients receiving adalimumab and 20.7% of patients receiving placebo achieved nrs30 at week 12 (p < 0.001). amano et al found that the median vas pain score decreased from 60.0 to 57.5 at week 12 (p = 0.55) [25]. morita et al found that 66.7% (95%ci 29.9, 92.5) of participants achieved nrs30 at week 12. according to the swedish post-marketing study, pain score decreased by 3.5 (95% ci 1.04, 5.96) after 12 weeks of adalimumab (p = 0.0147) (data available for 6 patients) [28]. caposiena caro et al measured a 1.3 reduction in vas score after 12 weeks of adalimumab (no variance or significance data reported) [27]. conclusions we performed a meta-analysis of 4 good-quality rcts assessing the efficacy of adalimumab in reducing hs-related pain. adalimumab was found significantly superior to placebo regarding pain score reduction after 3 months of treatment. our systematic review yielded 4 more open-label uncontrolled studies, 2 of which [26,28] showed that mean pain scores reduced significantly after 12 weeks of adalimumab treatment. in light of the severe impact of pain on hs figure 4. forest plot of comparison between adalimumab and placebo regarding skin pain reduction: adalimumab significantly reduced mean pain score at week 12 comparing to placebo. standard mean difference = –0.418 (95% confidence interval –0.588, –0.248), p = 0.000 review | dermatol pract concept. 2022;12(2):e2022099 15 in hidradenitis suppurativa. curr pain headache rep. 2017;21(12):49. doi:10.1007/s11916-017-0647-3. pmid: 29094219. pmcid: pmc5784845. 6. chernyshov pv, zouboulis cc, tomas-aragones l, et al. quality of life measurement in hidradenitis suppurativa: position statement of the european academy of dermatology and venereology task forces on quality of life and patient-oriented outcomes and acne, rosacea and hidradenitis suppurativa. j eur acad dermatology venereol. 2019;33(9):1633–1643. doi: 10.1111/jdv.15519. pmid: 31037773. 7. zouboulis cc, desai n, emtestam l, et al. european s1 guideline for the treatment of hidradenitis suppurativa/acne inversa. j eur acad dermatol venereol. 2015;29(4):619–644. doi: 10.1111/jdv.12966. pmid: 25640693. 8. puza cj, wolfe sa, jaleel t. pain management in patients with hidradenitis suppurativa requiring surgery. dermatologic surg. 2019;45(10):1327–1330. doi: 10.1097/ dss.0000000000001693. mid: 30570515. 9. horváth b, janse ic, sibbald gr. pain management in patients with hidradenitis suppurativa. j am acad dermatol. 2015; 73(5 suppl 1): s47–s51. doi: 10.1016/j.jaad.2015.07.046. pmid: 26470616. 10. ring hc, theut riis p, miller im, saunte dm, jemec gb. self-reported pain management in hidradenitis suppurativa. br j dermatol. 2016;174(4):909–911. doi: 10.1111/bjd.14266. epub 2016 jan 6. pmid: 26521975. 11. ring hc, sørensen h, miller im, list ek, saunte dm, jemec gb. pain in hidradenitis suppurativa: a pilot study. acta derm venereol. 2016;96(4):554–556. doi 10.2340/00015555–2308. pmid: 26631388. 12. jemec g. quality of life considerations and pain management in hidradenitis suppurativa. semin cutan med surg. 2017;36(2):75–78. doi: 10.12788/j.sder.2017.016. pmid: 28538748 13. enamandram m, rathmell jp, kimball ab. chronic pain management in dermatology. pharmacotherapy and therapeutic monitoring with opioid analgesia. j am acad dermatol. 2015;3(4):575–582;quiz 583–584. doi: 10.1016/j. aad.2014.11.038. pmid: 26369841. 14. scheinfeld n, sundaram m, teixeira h, gu y, okun m. reduction in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. dermatol online j. 2016;22(3):13030/qt38x5922j. pmid: 27136622. 15. kimball ab, sundaram m, shields al, et al. adalimumab alleviates skin pain in patients with moderate-to-severe hidradenitis suppurativa: secondary efficacy results from the pioneer i and pioneer ii randomized controlled trials. j am acad dermatol. 2018; 79(6):1141-1143. doi: 10.1016/j.jaad.2018.05.015. pmid: 29787843. 16. gupta ak, studholme c. adalimumab (humira) for the treatment of hidradenitis suppurativa. skin therapy lett. 2016; 21(4):1–4. pmid: 27388530. 17. haefeli m, elfering a. pain assessment. eur spine j. 2006; 15 suppl 1(suppl 1):s17–s24. doi: 10.1007/s00586-005-1044-x. pmid: 16320034. pmcid: pmc3454549. 18. higgins jpt, altman dg, gøtzsche pc, et al. the cochrane collaboration’s tool for assessing risk of bias in randomised trials. bmj. 2011;343:d5928. doi:10.1136/bmj.d5928. pmid: 22008217. pmcid: pmc3196245. only low-strength evidence (d) for the administration of common mild (nonsteroidal anti-inflammatory drugs) and strong (opioids) analgesics [34]. therefore, well-studied drugs against hs with an established pain-reducing action, like adalimumab, are most precious weapons in the dermatologist’s arsenal. increased tnf-a levels in hs patients, and improvement of hs in patients with crohn disease receiving adalimumab, led to adalimumab being tried as a primary treatment for moderate-to-severe hs [35]. trials showed that the drug is both efficacious and easily tolerated, while positively affecting important secondary endpoints, like quality of life and pain [35]. secukinumab reduced vas pain score in a reported case of recalcitrant hs and its efficacy against hs is currently being examined in clinical trials [36]. ustekinumab brought about significant reduction in vas pain score in a phase ii open-label trial of patients with moderate-to-severe hs [37]. apremilast was also found to significantly reduce vas pain score in a case-series of 9 patients (p = 0.026) [38]. it has been undoubtedly established, that pain should be brought into focus as far as hs-related research is concerned. existing and potential new anti-hs drugs should be studied more rigorously in terms of their ability to mitigate acute and chronic hs pain, while standardized pain outcome measures, such as the newly introduced pain index, should be consistently used across such studies [39]. on the other hand, high-quality large-scale studies testing the efficacy and safety of various analgesics in hs patients should be designed and conducted soon. this evidence will act as the basis for the issuing of pain-specific treatment guidelines that will support dermatologists in their difficult role and improve the life-quality of hs patients. references 1. kurzen h, kurokawa i, jemec gbe, et al. what causes hidradenitis suppurativa? exp dermatol. 2008;17:455–456; discussion 457–472. doi: 10.1111/j.1600-0625.2008.00712_1.x. pmid: 18400064. 2. kaaz k, szepietowski jc, matusiak ł. influence of itch and pain on sleep quality in patients with hidradenitis suppurativa. acta derm venereol. 2018;98(8):757–761. doi: 10.2340/000155552967. pmid: 29756157. 3. nielsen rm, lindsø andersen p, sigsgaard v, theut riis p, jemec gb. pain perception in patients with 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the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. ann intern med. 2012;157(12):846-855. doi: 10.7326/0003-4819-157-12-201212180-00004. pmid: 23247938. 22. ryan c, sobell jm, leonardi cl, et al. safety of adalimumab dosed every week and every other week: focus on patients with hidradenitis suppurativa or psoriasis. am j clin dermatol. 2018;19(3):437–447. doi: 10.1007/s40257-017-0341-6. pmid: 29380251. pmcid: pmc5945711. 23. kimball ab, okun mm, williams da, et al. two phase 3 trials of adalimumab for hidradenitis suppurativa. n engl j med. 2016;375(5):422–434. doi: 10.1056/nejmoa1504370. pmid: 27518661. 24. miller i, lynggaard cd, lophaven s, zachariae c, dufour dn, jemec gb. a double-blind placebo-controlled randomized trial of adalimumab in the treatment of hidradenitis suppurativa. br j dermatol. 2011;165(2):391–398. doi: 10.1111/j.1365– 2133.2011.10339.x. pmid: 21457202. 25. amano m, grant a, kerdel fa. a prospective open-label clinical trial 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popovich-silwerfeldt k, weyler l. post marketing observational study to assess quality of life changes in swedish patients with moderate or severe hidradenitis suppurativa on adalimumab treatment (hope study), interim analysis. exp dermatol. 2018; 27:16–17. doi: 10.1111/exd.13538. 30. kimball ab, chen k, okun m, sundaram m. adalimumab reduces pain in patients with hidradenitis suppurativa: results from a placebo-controlled phase ii trial. j am acad dermatol. 2012;66(4):suppl 1:ab42. doi: 10.1016/j.jaad.2011.11.185. 31. savage kt, singh v, patel zs, et al. pain management in hidradenitis suppurativa and a proposed treatment algorithm. j am acad dermatol. 2021;85(1):187–199. doi:10.1016/j. jaad.2020.09.039. pmid: 32950543. pmcid: pmc8176324. 32. krajewski p, matusiakn ł, von stebut e, et al. pain in hidradenitis suppurativa: a cross-sectional study of 1,795 patients. acta derm venereol. 2021;101(1):adv00364. doi: 10.2340/000155553724. pmid: 33320274. 33. ravn jørgensen ah, yao y, thomsen sf, christian ring h. self-reported pain alleviating methods in patients with hidradenitis suppurativa. actas dermosifiliogr. 2021;112(2):153–158. doi:10.1016/j.ad.2020.08.011. pmid: 33232705. 34. gulliver w, zouboulis cc, prens e, jemec gb, tzellos t. evidence-based approach to the treatment of hidradenitis suppurativa/acne inversa, based on the european guidelines for hidradenitis suppurativa. rev endocr metab disord. 2016;17(3):343–351. doi: 10.1007/s11154-016-9328-5. pmid: 26831295. pmcid: pmc5156664. 35. fotiadou c, vakirlis e, ioannides d. spotlight on adalimumab in the treatment of active moderate-to-severe hidradenitis suppurativa. clin cosmet investig dermatol. 2016;9:367–372. doi: 10.2147/ccid.s93619. pmid: 27799806. pmcid: pmc5076543 36. thorlacius l, theut riis p, jemec gbe. severe hidradenitis suppurativa responding to treatment with secukinumab: a case report. br j dermatol. 2018;179(1):182–185. doi: 10.1111/ bjd.15769. pmid: 28654150. 37. blok jl, li k, brodmerkel c, horvátovich p, jonkman mf, horváth b. ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum. br j dermatol. 2016;174(4):839–846. doi: 10.1111/bjd.14338. pmid: 26641739. 38. weber p, seyed jafari sm, yawalkar n, hunger re. apremilast in the treatment of moderate to severe hidradenitis suppurativa: a case series of 9 patients. j am acad dermatol. 2017;76(6):1189– 1191. doi: 10.1016/j.jaad.2017.02.026. pmid: 28522043. 39. zouboulis cc. pain index: a new prospective hidradenitis suppurativa patient-reported outcome measure instrument. br j dermatol. 202;184(6):1203–1204. doi:10.1111/bjd.19798. pmid: 33492666. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4):e2021144 1 the new era of biologics in atopic dermatitis: a review simon schneider1, linda li1, alexander zink1,2 1 technical university of munich, school of medicine, department of dermatology and allergy, munich, germany 2 division of dermatology and venereology, department of medicine solna, karolinska institute, stockholm, sweden key words: atopic dermatitis, therapy, biological, dupilumab citation: schneider s, li l, zink a. the new era of biologics in atopic dermatitis: a review. dermatol pract concept. 2021;11(4):e2021144. doi: https://doi.org/10.5826/dpc.1104a144 accepted: october 19, 2021; published: october, 2021 copyright: ©2021 schneider et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: ss and ll have equally contributed to this publication. corresponding author: simon schneider, technical university of munich, school of medicine department of dermatology and allergy, munich, germany. email: simon.a.schneider@tum.de atopic dermatitis (ad) is a prevalent inflammatory skin disorder affecting all age and ethnic groups. the age-dependent varying appearance and extent of pruritic lesions are accompanied by distinct individual suffering, highlighting the importance of effective treatment options. over the past years systemic drugs have considerably extended therapeutic approaches of patients with moderate to severe ad, in particular new biologics, most notably dupilumab has appeared as major breakthrough. in addition to monoclonal blockade of il-4 and il-13 pathway, more cytokines have been found to play a substantial role in ad pathogenesis, presenting potential targets for new therapy options. abstract this article is part of a series of reviews dedicated to atopic dermatitis, guest edited by prof anna balato. guest editor prof. anna balato, md, phd associate professor of dermatology, dermatology unit, university of campania, naples, italy 2 review | dermatol pract concept. 2021;11(4):e2021144 introduction atopic dermatitis (ad), one of the most common inflammatory skin disorders affecting people of all ages and ethnicities, is characterized by typical age-dependent clinical features and substantial individual suffering as well as extensive economic impact [1, 2]. whereas infants often present acute eczematous pruritic lesions involving the face, cheeks, and trunk, children, adolescents, and adults develop rather diffuse lesions affecting the flexures, alternating between acute and chronic areas [3]. with numerous new emerging drugs expanding the clinical practice of ad healthcare in recent years, the approval of dupilumab, represented a major breakthrough in the therapy of patients with moderate to severe ad. this review aims to describe currently available biological treatment options and potential future developments. dupilumab the pathophysiology of ad is multifactorial, involving a genetic predisposition, epidermal barrier dysfunction, the skin microbiome, and type-2-t-helper-cells (th2)-predominant inflammation [4-6]. the latter is mediated by various type-2 cytokines, among others interleukin-4 (il-4), and il-13. moreover, il-4 induces differentiation of th-cells into th2-cells, thus promoting further production of il-4 and il-13 [7]. both using the same il-4 receptor subunit alpha (il-4rα), these cytokines are responsible for ige class switching in b-cells [8]. given its key role in the pathway of type-2 mediated immune response, il-4rα blockade was anticipated to represent a therapeutic approach to treating allergic diseases. indeed, dupilumab, a human monoclonal antibody blocking il-4rα, was first shown to be effective in the treatment of ad in an early-phase randomized, double-blind, placebo-controlled trial in adults in 2014 [9]. monotherapy of dupilumab at 4 weeks compared to placebo showed a rapid and dose-dependent 50% improvement in the eczema area and severity index score (easi-50) and decline in the pruritus numerical-rating scale. this effect was further intensified at 12 weeks [9]. dupilumab was previously shown to be efficient in treating persistent, moderate-to-severe asthma with elevated eosinophil levels [10]. simpson et al reported in 2016 an improvement of 75% in the easi, a reduction of pruritus and improvement in quality of life in two phase-3 trials of dupilumab versus placebo in ad, comprising almost 1,400 patients aged 18 years and older in north america, europe, and asia. adverse effects were mild to moderate and comprised nasopharyngitis, upper respiratory tract infections, conjunctivitis, injection-site reactions, and exacerbation of ad [11]. in 2017, dupilumab was authorized for the treatment of ad in the european union by the european medicines agency (ema). shortly after, phase-3 trials for adolescents [12] and children aged 6 years and older [13] were conducted, which showed an improvement in easi, investigator’s global assessment (iga) score, and quality of life compared to placebo with similar adverse effects in these age groups as well. currently, the treatment of ad with dupilumab is authorized by ema for patients aged 6 years and older. recently, a promising phase-2, two-age cohort, two-dose level, multicenter study of dupilumab in the treatment of severe uncontrolled ad in children aged 6 months to < 6 years has showed efficacy and a similar safety-profile as seen in older age groups [14]. these data could support a phase-3 trial of dupilumab in this patient population to further offer therapeutic approaches for topical corticosteroid-refractory ad in this age group. further biologics in atopic dermatitis’ treatment in addition to il-4 and il-13, other cytokines have been identified to play an important role in the pathophysiology of chronic inflammatory skin disease. these are il-31, thymic stromal lymphopoietin (tslp), il-17, and il-22 cytokines, which can also negatively affect the expression of barrier proteins. il-13 a th-2 mediated exuberant immune response is stated to be the key mechanism in the pathogenesis of ad. zheng et al induced pruritic dermatitis and skin remodeling in an il-13 overexpressing mouse model. they showed that il-13 was mainly produced in the skin and caused xerosis, itching lesions, chronic inflammation of the skin, and dermal infiltration of cd4+-cells, mast cells, and eosinophils. mice models’ skin also showed increased fibrosis and vascularization [15]. another study was able to show a relative upregulation of il-13 mrna compared to il-4 mrna in lesional skin of ad patients, thus providing first evidence that il-13 may be the crucial cytokine in the il-4/il-13 axis [16]. il-13 as a potent stimulator of dermal inflammation and remodeling is another hypothesis for the pathogenesis of ad [17, 18]. both lebrikizumab and tralokinumab, monoclonal antibodies that target il-13, have been recently investigated for ad treatment. the effectiveness of a therapy with tralokinumab was analyzed in two 52-week, randomized, double-blind, multicenter, placebo-controlled phase-3-trials among more than 1,500 participants. tralokinumab showed significant reduction in easi and iga scores in a dose-dependent manner compared to placebo. participants receiving tralokinumab had a response rate of up to 70% for easi-50 and up to 40% for easi-75. in addition, early improvements were observed in pruritus, sleep disturbances, dermatology life quality index (dlqi), and the severity scoring of atopic dermatitis (scorad). those effects were demonstrated in most participants at week 16, and after extended use, at week review | dermatol pract concept. 2021;11(4):e2021144 3 52. the most common adverse reactions due to tralokinumab use were upper respiratory tract infections, conjunctivitis, and injection site reactions [19]. based on these study results, the ema recommended tralokinumab approval for the treatment of moderate to severe ad, in june 2021. like tralokinumab, lebrikizumab is an il-13 antibody. guttman-yasky et al examined the effects of the biological lebrikizumab in a double-blind, placebo-controlled, 16-week, phase-2b study among 280 individuals who were randomly assigned to a placebo group or to groups receiving lebrikizumab in different doses. a rapid dose-dependent effect of lebrikizumab was described in clinical scores and symptoms when compared to placebo. for instance, after 16 weeks, an easi improvement of up to 72.1% was shown in the group receiving 250 mg lebrikizumab every 2 weeks compared to placebo (p < 0.001). adverse events were mainly injection site reactions, herpes virus infections, and conjunctivitis. no adverse events led to premature patient discontinuation. if the positive effect of this biological can be reproduced in currently underway phase-3 studies, lebrikizumab can be considered a highly effective therapy modality in the treatment of moderate to severe ad [20]. il-31 intense itching is one of the greatest burdens of ad patients. il-31, a cytokine primarily produced by cd4+ t-cells, has been found to be increased in skin samples of ad patients compared to healthy subjects [21]. takamori et al studied il-31-deficient mice models. interestingly these showed decreased scratch frequency and duration, during induced contact dermatitis [22]. treatment with il-31-antibodies also showed reduced scratching behavior in ad-induced nc/nga mice [17, 18, 23, 24]. in a randomized, double-blind, placebo-controlled study, ruzicka et al investigated the safety and efficacy of nemolizumab, a humanized antihuman il-31a receptor antibody, in combination with topical steroids in patients with ad. the results showed that subcutaneous administration of nemolizumab was well tolerated by all subjects. nemolizumab significantly decreased pruritus compared to placebo (p < 0.01), but no significant reduction in easi was observed. accordingly, nemolizumab appears to be another therapeutic option, especially for ad patients suffering from pruritus [24, 25]. currently, there are 3 ongoing clinical phase-3 studies to prove nemolizumab safety and efficacy among a larger number of patients suffering from ad (nct03989349, nct03989206, nct03985943, clinicaltrials.gov). thymic stromal lymphopoietin and ox40 the tslp is a cytokine that is upregulated by il-13 and directly leads epidermic dendritic cells (dc) to a th-2-response. tslp is mainly produced in keratinocytes and appears to play a key role in the activation of dc. due to allergen damage, keratinocytes express tslp, which in turn activates dc, thus increasing their expression of ox40l. ox40l leads to the differentiation of naive cd4+-cells into inflammatory th-2-memory cells. ox40l is expressed by dc and activates t-cells and memory cells. the interaction between ox40 and ox40l appears to be critical for the long-term survival of cd4+ t-cells, which are responsible for inflammation in ad [17, 18]. there is evidence that mice overexpressing tslp develop ad and that their lesional skin contains increased numbers of th-2 cells. current studies are investigating whether this pathway can be used for new therapeutic options for the treatment of ad. guttman-yassky et al investigated the efficacy and safety of gbr830, a humanized antibody against ox40, in an explorative phase-2a, placebo-controlled study among patients with moderate to severe ad. first results showed that gbr380 was well tolerated and showed a significant reduction in th1-, th2, and th17/22 expression in lesional skin compared to placebo (p < 0.01). furthermore, a significant reduction in the epidermal thickness could be observed (p < 0.001)[26]. the phase-2b trial is completed, but results have not yet been published (nct03568162). a phase-2a study from japan, which also showed promising results, investigated khk4083, a monoclonal antibody against ox40. a continuous reduction of easi and iga scores was achieved in this study. furthermore, khk4083 showed an acceptable safety profile [27]. tepezelumab, a monoclonal antibody, is another medication targeting tslp. in a phase-2 study, 113 patients were 1:1 randomized and treated either with placebo or subcutaneous tepezelumab every 2 weeks. results of this trial showed that a higher percentage of patients treated with tepezelumab reached an easi50 after 12 weeks compared to the placebo group; however, the effect was not significant (p = 0.91) [28]. to show possible beneficial effects of this treatment option, larger studies need to be conducted. il-33 il-33 is another key cytokine involved in ad pathogenesis. increased amounts of il-33 have been detected in ad patients’ lesional skin as well as in mice models. furthermore, il-33 has been shown to induce th-2 immune response and significantly promote the release of il-4, il-5, and il-13 as well as increase the activity of ox40l. blocking il-33 and subsequently suppressing the mentioned cytokines could also be leveraged in the therapy of ad [29-31]. the first effects of an il-33 inhibition were showed in a mouse model [32]. in a phase-2a study, chen et al examined the in-vivo effect of etokimab, (anb020), a monoclonal igg-antibody, in 12 patients with moderate to severe ad. after a single systemic administration of etokimab, 83% of patients achieved easi50 and 33% easi-75 at day 29. a significant reduction in 4 review | dermatol pract concept. 2021;11(4):e2021144 neutrophile infiltration of the skin was also observed compared to placebo. these results suggested that il-31 suppression can positively affect inflammatory responses and may represent another component of ad therapy [33]. a phase-2 trial has been initiated and is currently in the recruiting phase (nct03533751). th-22/il-22 ad is traditionally considered a th-2-mediated disease. however, it has previously been shown that th-22 cells also play an important role in pathogenesis. th-22 cells express il-22, which in turn activates a receptor responsible for epidermal hyperplasia, migration of keratinocytes, downregulation of keratinocytic differentiation, and elevation of proinflammatory cytokines. in vitro analyses of skin biopsies of patients showed a correlation between the severity of ad with the presence of cd8+-il-22-cells [17, 34, 35]. guttmann-yasky et al performed a randomized, double-blind, placebo-controlled trial testing the efficacy and safety of fezakinumab, a monoclonal igg-antibody against il-22. a significant reduction in the scorad (≥ 50) was found in the subgroup of patients with severe ad compared to placebo (p < 0.029), but this effect was not found for the entire study population. at week 12, a significant reduction of the body surface area involvement was observed in all patients receiving fezakinumab compared to placebo. in addition, fezakinumab demonstrated a beneficial safety profile, with upper respiratory tract infections being the most reported adverse event, which will require further investigation in a larger study population [36]. conclusion new findings on the pathogenesis of ad introduce new therapeutic approaches almost daily as summarized in table 1 and figure 1. for example, the th-17/il-23 axis, which was long considered pathognomonic for psoriasis, could now also be proven to play a role in the pathogenesis of ad [37]. already proven agents for the therapy of psoriasis are available and may be used for therapeutic approaches for patients suffering table 1. overview of biologicals approved or tested for atopic dermatitis treatment. biological target current phase of clinical trials main findings in clinical trials dupilumab il-4/il-13 approved for clinical use by ema easi-75 improvement after 16-weeks of trial (phase iii) [11] tralokinumab il-13 approved for clinical use by ema easi-75 improvement & iga 0 or 1 after 16-weeks of trial compared to placebo (phase iii) [19] lebrikizumab il-13 3, still recruiting up to 72.1% improvement easi (250mg dose) after 16-weeks of trial compared to placebo (phase iib) [20] nemolizumab il-31 3, still recruiting up to 63.1% change in the pruritus vas score after 12-weeks compared to placebo (phase iib) [24] gbr830/ibs830 ox40 2b, finished, results not published easi-50 improvement after 71 days compared to placebo (phase iia) [26] khk4083 ox40 2a, completed, results not published continued improvement in easi and iga (phase i) [27] tepezelumab tslp 2b, still recruiting numerical easi50 improvement after 12-weeks of trial compared to placebo (phase iia) [28] etokimab il-31 2b, still recruiting 83% improvement of easi50 and 33% easi75 after 29-days of a single dose (phase iia) [33] fezakinumab il-22 2a, completed scorad improvement greater compared to placebo at 12-weeks of trial (phase iia) [36] * data from clinicaltrials.gov, worm et al [18], & li et al [17]. allergens epidermis: barrier defects tslp tezepelumab gbr830/ibs830 khk4083 dupilumab ox40 il-4 il-13 il-31 il-33 il-22 th22 th2 th1 dc th17 b-cellil-12 il-23 il-17 ige tralokinumab nemolizumab etokimab lebrikizumab fezakinumab uste kinu mab om al izu ma b secukinumab figure 1. pathogenesis and therapeutic targets in atopic dermatitis (ad). modified according to worm et al [35] and li et al [14]. increased skin penetration of allergens due to epidermal barrier defects results in type-2-t-helper-cells (th2)-predominant inflammation with and without activation of dendritic cells (dc). various cytokines contribute in the pathogenesis of ad, representing effective and future possible therapeutic targets for biologics in combating ad. cells that activate dc or those that are activated by them, such as tslp or ox40, represent potential targets. review | dermatol pract concept. 2021;11(4):e2021144 5 from ad. described findings and clinical results illustrate the viability of biologicals and support the endeavor of targeted, patient-specific medication for the treatment of ad. references 1. ring j, zink a, arents bwm, et al. atopic eczema: burden of disease and individual suffering results from a large eu 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gdańsk, gdańsk, poland key words: dermoscopy, videodermoscopy, demodicosis, eye citation: sławińska m, jaworska k, wyszomirski a, rychlik k, nowicki rj, sobjanek m. videodermoscopy in the assessment of patients with ocular demodicosis. dermatol pract concept. 2023;13(2):e2023109. doi: https://doi.org/10.5826/dpc.1302a109 accepted: october 24, 2022; published: april 2023 copyright: ©2023 sławińska et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: martyna sławińska, md, phd, mariana smoluchowskiego 17, 80-214 gdańsk. phone number: +48 58 584 40 14; fax number: +48 58 584 40 10 e-mail address: mslawinska@gumed.edu.pl introduction: there is growing evidence of the potential uses of dermoscopy in diagnostics of demodicosis. no previous studies have analyzed dermoscopic features in patients with ocular demodicosis. objectives: to evaluate the potential usefulness of videodermoscopy in diagnostics of ocular demodicosis. methods: it was a single-center prospective observational study in which results of videodermoscopic examination of the eyelids were compared to the results of classic microscopic examination in patients with suspected ocular demodicosis and healthy volunteers. results: study group included 16 women and 15 men. in fifteen (48.4%) patients, microbiological examination of epilated eyelashes was positive. the results of forms filled by the patients concerning known subjective clinical symptoms of ocular demodicosis revealed no significant differences between the group with positive and negative results of microscopic examination. the presence of demodex tails and madarosis observed during dermoscopic assessment correlated positively with positive results of microscopic examination. at least one demodex tail was found in 86.7% (13/15) cases with positive results of microscopic examination. in the two remaining cases microscopic evaluation showed the presence of demodex brevis. in 37.5% (6/16) of patients with negative results of microscopic examination, videodermoscopy showed the presence of demodex tails. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023109 introduction there is growing evidence on the potential role of dermoscopy in diagnosis of demodicosis [1-6]. dermoscopy proved to be an effective diagnostic tool and to correlate with standard skin surface biopsy results in cases of facial, scalp and truncal disease [4,7,8]. demodex tails and demodex follicular openings visualized in dermoscopy have been found to be highly specific diagnostic features. some reports also showed the utility of dermoscopy in the treatment monitoring [9]. although ocular demodicosis may affect patients with facial demodicosis, no previous studies have analyzed dermoscopic features in this group of patients. standardized skin surface biopsy, which is currently a gold diagnostic standard of facial demodicosis, cannot be used to examine the eyelid margin and currently there is no diagnostic standard for ocular demodicosis [2,10]. objectives the aim of the study was to evaluate clinical and dermoscopic features of patients with ocular demodicosis and compare these findings with results of classical microscopic evaluation. methods this was a single-center, prospective study performed in the department of dermatology and dermatology outpatient clinic, medical university of gdańsk (poland) which concerned patients referred to a dermatology outpatient clinic with suspected ocular demodicosis. before classical microscopic assessment, videodermoscopic examination was performed. the same assessment was performed in generally healthy volunteers who presented to the dermatology outpatient clinic for dermoscopic evaluation of nevi, with no previous history/clinical signs of demodicosis. all study participants filled in a previously prepared form concerning clinical symptoms and were assessed clinically and dermoscopically by the same dermatologist. in the second step classical microscopic evaluation of the eyelashes was performed by the same laboratory assistant. only patients who did not wash their face and eyelid area for the previous 12 hours and did not wear make-up at the time of examination were included. current or previous (within 6 months) history of demodicosis/rosacea treatment and age under 18 were exclusion criteria. clinical and dermoscopic pictures were made using fotofinder videodermoscope (non-polarized dermoscopy; video camera medicam 800hd) with no immersion fluid (x20 magnification; open front cap). two dermoscopic pictures of the upper eyelid margin were performed with a closed eye to include the whole eyelid margin; in each studied person, both eyelids were evaluated. classical microscopic examination was performed with an mb-100 microscope equipped with a camera. six upper eyelid eyelashes and six lower eyelid eyelashes were collected from each patient (after clinical assessment from the areas with visible erythema/scaling or randomly when no such symptoms were observed). eyelashes were placed on a coverslip with a mixture of dimethyl sulfoxide and 20% potassium hydroxide. a criterion for positive result was at least one demodex mite visible under the microscope (x100 magnification). clinical and dermoscopic pictures were evaluated by consensus of two experienced dermoscopists, blinded to the results of the classical microscopic evaluation, for predefined criteria (table 1). in case of discrepancy, the final score for a particular case and structure was obtained based on the decision of the third evaluator. the mann–whitney u test for comparison of the age distribution between unpaired two groups was applied, and the chi-square test was applied to compare categorical data. the two-tailed tests were carried out at a significance level of p ≤ 0.05. all statistical analyses were performed using the r statistical package (version  3.6.3; https://www.r-project.org/). the study was approved by the ethics committee, medical university of gdańsk (nkbbn/606/2018; nkbbn/606-675/2020) and all study participants gave informed consent before participation in the study. results study group included 16 women and 15 men. in fifteen patients (48.4%), microscopic examination of epilated eyelashes was positive (10 male, 5 female). mean age was conclusions: videodermoscopy may facilitate the diagnostics of ocular demodicosis. patients reporting clinical symptoms suggesting ocular demodicosis but negative results of videodermoscopic examination should be referred to classical microscopic examination to exclude the presence of demodex brevis. in patients with negative microscopic examination results and symptoms suggesting ocular demodicosis, dermoscopy-guided microscopic re-evaluation could be considered. original article | dermatol pract concept. 2023;13(2):e2023109 3 significantly higher in the group with positive microscopic examination results (64.5 versus 49.5 years, p = 0.009). the results of forms filled in by the patients concerning known subjective clinical symptoms of ocular demodicosis, revealed no significant differences between the group with positive and negative results of microscopic evaluation. previously diagnosed eye disease, skin disease and diabetes also did not correspond with microscopic diagnosis of ocular demodicosis. table 1 presents details of the evaluated variables in patients with positive and negative results of microscopic evaluation and figure 1 depicts details of videodermoscopic assessment. the presence of demodex tails and madarosis observed during dermoscopic assessment correlated positively with positive results of microscopic examination (p = 0.042 and p = 0.025), respectively). at least one demodex tail was found in 86.7% (13/15) of cases with positive results from the microscopic examination. in the two remaining cases, microscopic evaluation showed the presence of demodex brevis (d. brevis). these two patients reported symptoms such as burning/itching within the eyes as well as a feeling of dry eyes/gritty sensation. in 37.5% (6/16) of patients with negative results of microscopic examination, videodermoscopy showed the presence of demodex tails. in these patients, the most common clinical symptom was epiphora (present in 3/6 patients), followed by burning/itching within the eyes (1 patient) as well as a feeling of dry eyes/gritty sensation (1 patient). no significant correlation was found for other analyzed dermoscopic features (demodex follicular openings, table 1. clinical and dermoscopic features in patients with positive and negative result of microscopic evaluation. patients with a positive result of microscopic evaluation patients with a negative result of microscopic evaluation p data obtained from patients history gender, n (%) female versus males 5 (33.3%) versus 10 (66.7%) female versus males 11 (68.8%) versus 5 (31.2%) 0.049 age (mean/median), years 64.5/68.0 49.5/53.5 0.009 feeling of dry eyes/gritty sensation, n (%) 7 (50.0%) 6 (37.5%) 0.491 burning/itching within the eyes, n (%) 9 (60.0%) 5 (31.2%) 0.108 epiphora, n (%) 4 (26.7%) 6 (37.5%) 0.519 conjunctivitis treatment in the previous 6 months, n (%) 14 (93.3%) 16 (100.0%) 0.294 eye disease, n (%) 6 (40.0%) a 3 (18.8%) b 0.193 history of skin disease, n (%) 6 (40.0%) c 9 (56.2%) d 0.366 tendency to blush easily, especially after eating, under the influence of temperature, or drinking alcohol, n (%) 2 (13.3%) 3 (18.8%) 0.682 diabetes, n (%) 4 (26.7%) 1 (6.2%) 0.122 dermoscopic features demodex tails (at least 1), n (%) 13 (86.7%) 6 (37.5%) 0.005 demodex tails (median/mean) 6/12.8 0/2.750 0.002 demodex follicular openings (gray dots), n (%) 3 (20.0%) 1 (6.2%) 0.254 follicular hypertrophy, n (%) 11 (73.3%) 7 (43.8%) 0.095 follicular annular pigmentation, n (%) 0 0 yellow dots, n (%) 0 0 red dots, n (%) 0 0 scale, n (%) 13 (86.7%) 9 (56.2%) 0.062 pustules, n (%) 1 (6.7%) 0 (0.0%) 0.294 madarosis, n (%) 6 (40.0%) 1 (6.2%) 0.025 poliosis, n (%) 0 0 a [cataract, epiretinal membrane, floaters suspected, macular degeneration, myopia, retinal cyst]; b [glaucoma] c [acne, atopic dermatitis, chronic eczema, previous history of bcc, previous history of melanoma]; d [acne, atopic dermatitis, psoriasis, previous history of bcc, previous history of melanoma]. 4 original article | dermatol pract concept. 2023;13(2):e2023109 assessment with an open front cap provides precise and non-contact evaluation of the eyelid region [13]. we have found two dermoscopic features that have been observed significantly more often in patients with positive microscopy, namely demodex tails and madarosis. demodex tail is defined as a gelatinous, whitish, creamy thread, 1–3 mm in length, indicating a mite protruding from the follicular orifice [14]. it has been previously identified as a feature typical of demodicosis on the face, scalp and trunk and found in 20-100% of patients with a positive result of microscopic examination [2,4,6,9,14,15]. as mentioned previously, in two patients from our study in whom dermoscopic assessment did not show the presence of demodex tails, d. brevis could be found in microscopic evaluation. according to the literature, this species is smaller in size (about 190 micrometers), compared to d. folliculorum (about 290 micrometers) [16]. therefore, when present in deep parts of the sebaceous glands, can potentially be invisible on the body surface and therefore beyond the scope of videodermoscopic assessment. both species can be present in the same patient. none of the previous studies assessed the correlation between dermoscopic presentation and d. brevis. in microscopic studies, d. brevis was found to be the only species in 0.7%–31.7% of patients [17,18]. follicular hypertrophy, follicular annular pigmentation, scales, pustules, poliosis). conclusions patients with suspected/confirmed facial demodicosis should be assessed for ocular demodicosis. clinical symptoms that may indicate involvement of the ocular region include eyelid erythema, eyelid itching, eyelid burning sensation, ocular foreign body sensation, conjunctival injection, epiphora, dry eye sensation, increased sensitivity to light, smoke and dust, mucus discharge and contact lens intolerance [1,11]. most patients in the studied group reported at least one symptom and the frequency of the reported symptoms did not differ between groups of patients with positive and negative results of microscopic examination. therefore, the decision to refer to microscopic examination based only on clinical symptoms may be difficult. the authors hypothesized that videodermoscopy could be helpful in initial evaluation of patients and in some cases could be an alternative method used to confirm the diagnosis of ocular demodicosis. evaluation of the eyelid margin with a classical dermoscope is possible, unless the front cap is too wide. videodermoscopic figure 1. dermoscopic assessment of the upper eyelid region may facilitate the assessment of a patient with clinical suspicion of ocular demodicosis. (a) dermoscopic presentation in a healthy person – no signs of the presence of demodex spp. (b) dermoscopy shows two demodex tails (black arrows) and mild madarosis. (c) dermoscopy shows areas of madarosis (white arrow) as well as the presence of demodex tails. (d) dermoscopy shows the presence of multiple demodex tails (black arrows), mild madarosis and follicular hypertrophy (white circles) (all pictures made with fotofinder, medicam 800hd, x20 magnification, no immersion fluid). original article | dermatol pract concept. 2023;13(2):e2023109 5 2. karadağ köse ö, borlu m. definition of videodermoscopic features of demodicosis. int j dermatol. 2019;58(10):1153-1159. doi:10.1111/ijd.14547. pmid: 31198996. 3. gonzález hp, santas md, domper lf, agud de dios m, boixeda p. ex vivo dermoscopy in demodicosis j am acad dermatol. 2023;88(3):e127-e128. doi: 10.1016/j.jaad.2021.07.031. pmid: 34329644. 4. serarslan g, makbule kaya ö, dirican e. scale and pustule on dermoscopy of rosacea: a diagnostic clue for demodex species. dermatol pract concept. 2021;11(1):e2021139. doi:10.5826 /dpc.1101a139. pmid: 33614217. pmcid: pmc7875658. 5. sonthalia s, agrawal m, bhatia j, et al. entodermoscopy update: a contemporary review on dermoscopy of cutaneous infections and infestations. indian dermatol online j. 2021;12(2):220-236. doi:10.4103/idoj.idoj_559_20. pmid: 33959518. pmcid: pmc8088165. 6. trave i, micalizzi c, gasparini g, cozzani e, parodi a. dermoscopy of papulopustular rosacea and comparison of dermoscopic features in patients with or without concomitant demodex folliculorum. clin exp dermatol. 2021;46(8):1434-1440. doi:10.1111/ced.14731. pmid: 33987859. 7. durdu m, errichetti e, eskiocak ah, ilkit m. high accuracy of recognition of common forms of folliculitis by dermoscopy: an observational study. j am acad dermatol. 2019;81(2):463-471. doi:10.1016/j.jaad.2019.03.054. pmid: 30914342. 8. tatu al, cristea vc. pityriasis folliculorum of the back thoracic area: pityrosporum, keratin plugs, or demodex involved?. j cutan med surg. 2017;21(5):441. doi:10.1177/12034754177 11114.  pmid: 28920478. 9. friedman p, sabban ec, cabo h. usefulness of dermoscopy in the diagnosis and monitoring treatment of demodicidosis. dermatol pract concept. 2017;7(1):35-38. doi:10.5826/dpc.0701a06. pmid: 28243492. pmcid: pmc5315038. 10. zhang ac, muntz a, wang mtm, craig jp, downie le. ocular demodex: a systematic review of the clinical literature. ophthalmic physiol opt. 2020;40(4):389-432. doi:10.1111 /opo.12691. pmid: 32691894. 11. bitton e, aumond s. demodex and eye disease: a review. clin exp optom. 2021;104(3):285-294. doi:10.1111/cxo.13123. pmid: 32885484. 12. jaworska k, sławińska m, sobjanek m, lipowski p. ophthalmic manifestations of demodex spp. infection – what should a dermatologist know? dermatology review/przegląd dermatologiczny 2021;108(6):485-503. 13. kozubowska k, sławińska m, sobjanek m. the role of dermoscopy in diagnostics of dermatological conditions of the eyelid, eyelashes, and conjunctiva a literature review. int j dermatol. 2021;60(8):915-924. doi:10.1111/ijd.15315. pmid: 33226125. 14. segal r, mimouni d, feuerman h, pagovitz o, david m. dermoscopy as a diagnostic tool in demodicidosis. int j dermatol. 2010;49(9):1018-1023. doi:10.1111/j.1365-4632.2010.04495 .x. pmid: 20931672. 15. sławińska m, rogowska p, nowicki rj, sobjanek m. an unexpected cause of an itchy tattoo revealed in videodermoscopic examination. clin exp dermatol. 2021;46(2):355-356. doi:10.1111/ced.14375. 16. kosik-bogacka di, łanocha n, łanocha a, et al. demodex folliculorum and demodex brevis in healthy and immunocompromised patients. ophthalmic epidemiol. 2013;20(3):159-163. doi:10.3109/09286586.2013.789532. pmid: 23713917. based on that, it can be concluded that the patients reporting clinical symptoms suggesting ocular demodicosis with negative result of videodermoscopic examination should be referred to classical microscopic examination to exclude the presence of d. brevis. importantly, a relatively high percentage of patients with negative results of microscopic examination upon videodermoscopic examination showed the presence of demodex tails. this could be explained by the fact that classical microscopic examination allows for the assessment of a limited number of eyelashes only. in these patients, videodermoscopy-guided microscopic re-evaluation could be considered, especially in case of persisting clinical symptoms. an ideal scenario would be videodermoscopy-assisted microscopic examination, that could potentially help to detect these patients, especially in cases clinically symptomatic but with negative results of classical microscopic examination. madarosis is defined as a loss of eyelashes and/or eyebrow hair. it was also significantly more common in patients with ocular demodicosis, however it is a non-specific symptom that may be also a result of numerous skin diseases, infectious diseases, endocrine disorders, drugs, trauma, tumors, congenital diseases (eg lamellar ichthyosis, monilethrix, ehlers-danlos syndrome), contact allergy, alopecia areata or trichotillomania [19,20]. a limitation of the study is the lack of evaluation of the lower eyelid margin. nevertheless, the aim was to develop a quick, non-invasive and non-contact evaluation of the eyelid area. another limitation is lack of evaluation with polarized light, which could allow for vessel morphology assessment. finally, a relatively low number of patients were studied. to sum up, based on our experience, videodermoscopy may facilitate the diagnosis of ocular demodicosis. patients reporting symptoms suggesting ocular demodicosis with negative results of videodermoscopic examination should be referred to classical microscopic examination to exclude the presence of d. brevis. in patients with negative microscopic examination and symptoms suggesting ocular demodicosis, videodermoscopy-guided microscopic re-evaluation could be considered. acknowledgements the patients in this manuscript have given written informed consent to the publication of their case details. references 1. kara ya, özden hk. dermoscopic findings of rosacea and demodicosis. indian j dermatol. 2021;66(2):165-168. doi:10.4103/ ijd.ijd_290_18. pmid: 34188272. pmcid: pmc8208267. 6 original article | dermatol pract concept. 2023;13(2):e2023109 19. khong jj, casson rj, huilgol sc, selva d. madarosis. surv ophthalmol. 2006;51(6):550-560. doi:10.1016/j. survophthal .2006.08.004. pmid: 17134645. 20. sachdeva s, prasher p. madarosis: a dermatological marker. indian j dermatol venereol leprol. 2008;74(1):74-76. doi:10.4103 /0378-6323.38426. pmid: 18187839. 17. zeytun e, karakurt y. prevalence and load of demodex folliculorum and demodex brevis (acari: demodicidae) in patients with chronic blepharitis in the province of erzincan, turkey. j med entomol. 2019;56(1):2-9. doi:10.1093/jme/tjy143. pmid: 30137440. 18. zhong j, tan y, li s, et al. the prevalence of demodex folliculorum and demodex brevis in cylindrical dandruff patients. j  ophthalmol. 2019;2019:8949683. doi:10.1155/2019/8949683. pmid: 31073414. pmcid: pmc6470415. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023019 1 digital ulcers: multidisciplinary approach and dermatological management michela starace1,2, gionathan orioni1,2, aurora alessandrini1,2, francesca bruni1,2, carlotta baraldi1,2, cosimo misciali1,2, bianca maria piraccini1,2 1 dermatology unitirccs azienda ospedaliero-universitaria di bologna 2 department of experimental, diagnostic and specialty medicine alma mater studiorum university of bologna, italy key words: digital ulcer, multidisciplinary approach, dermatology, diabetes, ischaemic wound citation: starace m, orioni g, alessandrini a, et al. digital ulcers: multidisciplinary approach and dermatological management. dermatol pract concept. 2023;13(1):e2023019. doi: https://doi.org/10.5826/dpc.1301a19 accepted: june 9, 2022; published: january 2023 copyright: ©2023 starace et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: gionathan orioni, irccs azienda ospedaliero-universitaria di bologna; dipartimento di medicina specialistica, diagnostica e sperimentale (dimes) alma mater studiorum – università di bologna, via massarenti 1, 40138 bologna, italy. telephone number +390512144838 e-mail: gionathan.orioni@studio.unibo.it introduction: digital ulcers represent a current public health issue, due to the relevant difficulties in their management and their tendency to become chronic, non-healing lesions. objectives: our case series represents an opportunity to discuss the main comorbidities of digital ulcers and to present an evidence-based treatment protocol that has proved highly effective in our clinical practice. methods: we collected the clinical data about clinical features, associated diseases and diagnostic therapeutical procedures of 28 patients with digital ulcers referred to our wound care service at s. orsola-malpighi hospital. results: digital ulcers were divided into 5 categories, based on the causative agent: peripheral artery disease: 5/16 females and 4/12 males, diabetes-associated wounds: 2/16 females and 1/12 males, mixed wounds: 4/12 males, pressure wounds: 3/16 females and 2/12 males, and immune-mediated diseases associated with wounds: 6/16 females and 1/12 males. each group received specific management, based on the characteristics of the ulcer and the underlying comorbidities. conclusions: the clinical evaluation of digital wounds requires a thorough knowledge of their aetiopathogenesis. a multidisciplinary approach is necessary to achieve a precise diagnosis and correct treatment. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023019 introduction with the increase in life expectancy, more and more patients are suffering from chronic diseases and an increasingly innovative and personal approach, which includes the collaboration between specialists from various branches of medicine and surgery, is now part of a comprehensive care plan [1]. limb chronic ulcers have an increasing incidence, due to the higher prevalence of chronic vascular and metabolic diseases, such as peripheral artery disease (pad) and diabetes mellitus, which play the main role in their aetiology. within the category of limb chronic ulcers, digital ulcers (du) represent a small but peculiar group, due to their difficult management and their scarce tendency to heal. we present an observational study of 28 patients with du referred to our wound care service, focusing on multidisciplinary and dermatological management. methods we collected the clinical data of patients with du referred to the wound care service (a tertiary referral center) of the dermatology unit of the s.orsola-malpighi hospital over a period of 18 months, from january 2020 to june 2021. only patients presenting with non-healing digital ulcers of the limbs, present for at least 6 weeks, were enrolled. demographic and clinical data were collected, including associated comorbidities and their therapy and previous ulcerative episodes in other cutaneous areas. diagnosis of the disease that caused the du was based on clinical history, laboratory evaluation and histopathological study, when necessary. management of these conditions was based on the main international guidelines for the management of peripheral artery disease in patients with foot ulcers and diabetes [2-4] and on the evidence-based protocol for diabetic foot ulcers [5]. all the digital wounds were assessed for excluding any signs of local or surrounding infection. in particular, the presence of at least 3 or more stonees criteria (size is bigger, temperature elevated, os, new breakdown, exudate, erythema, smell) lead to a systemic antibiotic treatment. the presence of at least three nerds criteria (nonhealing, exudate increase, red friable granulation, debris) was followed by a topical antimicrobial therapy [3]. the evaluation of pain associated with the du was performed using the vas (visual analogue scale). all patients with pain equal or superior to 5 on the vas scale, despite adequate medication and non-responder to paracetamol, were managed by our pain therapy service. despite the cause of the du, mechanical debridement of the necrotic tissues was performed in all cases. in three cases, the use of local medications was preceded by a total surgical debridement of necrotic tissue. in the other patients, an ambulatorial mechanical debridement was performed. gauze soaked in iodine was used as the main antiseptic medication. results from january 2020 to june 2021, we treated 28 patients with du, 12 males and 16 females (table 1). median age was 72.6 years (range 38-97 years): average age of males was 68.3 years, that of females 75.9 years. the toes were the most common site of du (24 patients), with 16 patients having ulcers of several digits (ranging from 2 digits to 4); finger ulcers were present in 4 patients, one of them having du in 3 fingers, the other 3 in one finger. the diseases detected as causes of du were as follows: peripheral artery disease (pad): 9 cases, all with du of the toes; type 2 diabetes mellitus with poor glycaemic control: 3 patients, all with du of the toes; association of pad with type 2 diabetes mellitus: 4 patients, 3 with du of the toes and 1 of a finger; pressure ulcers with toe involvement: 5 patients; vasculitis: 3 patients with du of the toes; systemic sclerosis (ssc) in 4 patients, 3 with du of the fingers and 1 of a toe. pad-associated du the 9 patients with pad were evaluated by specific imaging investigation (color duplex ultrasound, computed tomographic angiography, magnetic resonance angiography) and then referred to a vascular surgeon for possible revascularization. only 4 cases were revascularized, while in the other 5 the procedure was not possible due to the poor general conditions and the high anaesthetic risk. the topical medication of the du after debridement in all these patients was an iodine-based antiseptic dressing or a soft silicon foam dressing, in order to diminish the risk of bacterial superinfection of necrotic tissue (figure 1a). all the cases that underwent revascularization showed a better outcome compared to the other cases, with a significant reduction in healing times. no correlations with any lymphatic drainage impairment were found in this group of patients after specific imaging investigation. diabetes-associated du seven patients presented type 2 diabetes mellitus in poor glycaemic control, associated with the presence of du. in 3 cases diabetes was identified as the primary cause of the ulcerative lesions, as laboratory and technical evaluations excluded other comorbidities: these patients were referred to the diabetology service for a review of their metabolic status and chronic hypoglycaemic therapy and underwent local medications with gauze soaked in iodine to accelerate wound healing. a better clinical outcome was achieved only after the diminishment of these patients’ plasma glucose values. original article | dermatol pract concept. 2023;13(1):e2023019 3 in 4 patients, type 2 diabetes was associated with arteriopathy of the large vessels of the lower limbs that required prompt revascularization (figure 1b). surgery increased the chances of wound healing in these patients. obesity and metabolic syndrome are often present in patients with diabetes ii and pad, as they recognize a sedentary lifestyle as a common denominator, associated with unbalanced nutrition. however, no direct correlations were found between these factors and the development of digital ulcerative lesions. pressure du five patients with pressure ulcers of the feet developed toe lesions as an effect of continuous forces directed to the distal pulp, causing progressive skin ischemia above bone prominences4. these patients were bedbound due to progressive neurological diseases, such as multiple sclerosis with spinal involvement (4 cases) or a severe form of motor-sensitive polyneuropathy of the lower limbs (1 case). in these cases, mechanical debridement of the eschar followed by topical therapy with iodine gauzes was associated with a physiatrist consultation that lead to the prescription of plantar orthosis and anti-decubitus mattresses. all the procedures allowed wound healing with restoration of the physical integrity of the toe skin (figure 1c). immune-mediated disease-associated du four patients, 3 with du of the fingers and 1 of a toe suffered from ssc (figure 1d). a skin biopsy of the du showed in all cases skin calcinosis. these patients were managed through the close collaboration of rheumatologists. one patient with du of the toe was affected by rheumatoid arthritis and 2 by systemic lupus erythematous. a biopsy of the perilesional skin showed leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls and prominent polymorphonuclear cell infiltration. table 1. clinical characteristics of the patients with digital ulcers. patient age sex number of wounds localization aetiology 1 50 f 2 toe diabetes ii 2 70 m 2 toe diabetes ii and pad 3 95 f 4 toe pad 4 80 m 3 finger ssc 5 64 m 2 toe pad 6 81 f 1 toe pad 7 50 m 1 finger diabetes ii and pad 8 82 f 1 toe pressure ulcer 9 82 f 4 toe vasculitis 10 83 m 2 toe diabetes ii 11 58 m 1 toe pad 12 81 m 1 toe diabetes ii and pad 13 83 f 1 toe vasculitis 14 46 m 3 toe pressure ulcer 15 69 m 1 toe diabetes ii and pad 16 97 f 5 toe pad 17 89 f 2 toe diabetes ii 18 92 f 4 toe pad 19 84 f 2 toe pressure ulcer 20 56 f 1 toe ssc 21 64 f 3 toe vasculitis 22 80 f 2 toe pad 23 80 m 3 toe pressure ulcer 24 83 f 2 toe pressure ulcer 25 58 m 1 toe pad 26 58 f 1 finger ssc 27 38 f 1 finger ssc 28 80 m 2 toe pad m: male; f: female; pad: peripheral artery disease; ssc: systemic sclerosis. 4 original article | dermatol pract concept. 2023;13(1):e2023019 and on the respective aetiologies. the multidisciplinary management of the different cases represents the standard model to get better the outcome of patients suffering from multiple comorbidities. pad-associated du the term peripheral arterial disease defines the lower extremity artery disease, including obstruction at the aortoiliac, femoropopliteal and infrapopliteal arterial segments [5]. studies have shown an increased risk of cardiovascular mortality, as well as of morbidity from myocardial infarction the clinical suspicion of autoimmune disease in this group of patients derived from suggestive anamnestic data collection and from the execution of skin biopsies of the ulcerative lesions. a subsequent rheumatological evaluation confirmed the clinical suspicion. discussion our literature search could not identify any studies that collected such a large number of cases regarding du of both fingers and toes, making a subdivision based on clinical aspects figure 1. clinical images of patients with digital ulcers of different aetiology. a 92-year-old female patient with two recently occurring ischemic ulcers at her right first toe, in the context of peripheral artery disease (a); a 50-year-old female patient with extensive necrosis at her distal phalanx of the right first toe, in the context of poorly controlled diabetes mellitus (b); an 82-year-old female patient with a well-demarcated pressure ulcer at the fourth finger of her left foot (c); an 80-year-old male patient with a necrotic ulcer at the distal phalanx of the fourth finger of his left hand, in the context of systemic sclerosis (d). original article | dermatol pract concept. 2023;13(1):e2023019 5 must be carried out [19]. it is important to assess the pedal pulses, and unless a pulse is clearly palpable, all patients with foot ulcers should undergo non-invasive vascular testing, to determine if the patient would benefit from revascularization. in an observational study, shorter time to revascularization (<8 weeks) was associated with a higher possibility of healing of ischaemic foot ulcers [20]. in addition, it is mandatory that every patient be evaluated for proper orthotics, and appropriate footwear should be prescribed that adequately protects the foot from trauma induced by shoes and alleviates pressure, considering the fact that pressure and pain sensation are often impaired in these patients [21]. pressure du prolonged bed rest caused by paraplegia and various central nervous system diseases plays an important role in the formation of pressure acral lesions, which follow prolonged skin ischemia and are especially located above bony prominences. the first signs of ischemia are the formation of calluses at the level of the toepads. if not recognized and treated, they lead to the formation of painless and difficult-to-treat chronic ulcers. the application of physical means such as intermittent pneumatic compression devices and the evaluation from expert physiotherapists is necessary in these patients, in order to prevent the extension of the wound and the arising of other similar lesions in other toes [22]. in people suffering from advanced neurological conditions, spasticity is significantly associated with the development of pressure ulcers in typical and even atypical locations  [23]. severe spastic conditions might facilitate wound onset in various ways: increased tonus of the limbs leads to immobility and to a reduced capacity to reposition the body, with an abnormal pressure redistribution. this prolonged rigidity causes severe soft tissue injury [4, 24]. a comprehensive assessment is warranted with a focus on identifying the source of pressure, contributing factors, underlying comorbidities, and elements affecting wound healing. pressure redistribution targeting the duration and/or magnitude of loading is critical [25, 26]. evidence exists that advanced support surfaces are superior to standard hospital beds in preventing and managing pressure injuries. however, no clear advantage has been identified for one specific advanced support surface over another [27]. there is strong evidence that a moist wound environment accelerates healing in this type of du: occlusive dressings seem to be superior to more-traditional simple gauze, especially in terms of maintaining a moist wound environment [28]. ultimately the dressing selection may be guided by the characteristics of the wound, balance of moisture and exudate, bacterial control, debridement balance, ease of use, cost, and patient preference [29]. and stroke in patients with asymptomatic or symptomatic arterial disease [2]. the distal localization of the vascular obstruction leads to the formation of chronic ulcerative lesions of the acral extremities, mainly of the lower limbs, with the appearance of necrotic eschars of the distal phalanges of the toes. these ulcers are at high risk of bacterial superinfection. the association with both uncontrolled type ii diabetes mellitus is common, therefore in these patients, the evaluation of the arterial function with imaging techniques should always be associated with laboratory monitoring of the glycaemic state, as type ii diabetes comorbidity greatly impairs local wound management [6]. the symptoms and signs of pad are variable and range from the classic symptom of claudication to other non– joint-related limb symptoms (atypical leg symptoms) or are absent [7-10]. in these cases, the du may be the first sign that leads to the diagnosis. the vascular examination for pad includes pulse palpation, auscultation for femoral bruits, and inspection of the legs and feet [8]. to confirm the diagnosis of pad, abnormal physical examination findings must be confirmed with diagnostic testing [5]. studies for anatomic imaging assessment (duplex ultrasound, computed tomography angiography [cta], or magnetic resonance angiography [mra], invasive angiography) are generally reserved for highly symptomatic patients in whom revascularization is being considered [9]. patients with pad associated with skin ulcers fall into a high-risk cardiovascular group, due to the signs of advanced disease10: for this category, a careful multidisciplinary evaluation is important in order to select patients eligible for surgical revascularization and to increase the chance of wound healing, as well as of reducing a progression of disease [11]. adequate pharmacological therapy associated with a healthy lifestyle is mandatory for the chronic management of this disease and to reduce the global cardiovascular risk [12, 13]. diabetes-associated du as for diabetic foot ulcers, they occur in between 12 and 25% of patients with type 2 diabetes mellitus [14] and precede 84% of all non-trauma limb amputations in this growing slice of the population [15]. a diabetic foot ulcer is defined as any skin breakdown on the foot of a diabetic person [16]. early recognition of the skin defect and treatment prevents its progression to a chronic wound that is often recalcitrant to therapy [17-18]. when a patient with a diabetic foot ulcer is first seen, a comprehensive history and treatment plan must be put into place. then, a laboratory evaluation based on their metabolic status, and the monitoring for any complications (e.g. heart disease, renal failure, retinopathy, neuropathy) 6 original article | dermatol pract concept. 2023;13(1):e2023019 the autoimmune disease is imperative. adalimumab with methotrexate (mtx) has shown promise in ra-associated ulcers [39]. improving wound bed preparation by the application of moisture-retentive dressings has been shown to be beneficial [40]. systemic lupus erythematosus (sle) is a systemic autoimmune connective tissue disease that can affect most organ systems. ulcerations are not infrequent and, like other connective tissue diseases, they are multifactorial [41]. vasculitis, noninflammatory thrombosis of small or large vessels, venous insufficiency, lupus profundus, lichen planus overlap, and drug-induced lupus syndrome has been associated with leg ulcerations. the ulcers are usually painful, sharply margined, or punched out. adjacent skin can appear erythematous, purpuric, or rolled and violaceous. histological examination of vasculitis ulcers in sle shows a leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls and prominent polymorphonuclear cell infiltration. thrombocclusive histologic findings can be associated with the presence of antiphospholipid antibodies (lupus anticoagulant) [42]. sle-associated leg ulcers are a therapeutic challenge, as local wound care is not always sufficient. the underlying cause of the ulceration needs to be established and treated. if vasculitis is present, systemic corticosteroids with cytotoxic agents should be utilized [37]. conclusion the clinical evaluation of dus requires a thorough knowledge of their possible causes. a careful clinical evaluation is necessary together with laboratory and imaging technique investigations. a multidisciplinary approach in the management of these wounds is the only effective way to achieve a precise diagnosis and a correct treatment, as described in  figure 2. immune-mediated disease-associated du inflammatory and autoimmune systemic diseases may first become clinically evident with the appearance of an ischemic digital wound. ssc is the best described among these types of conditions [30]. cutaneous and/or systemic vasculitis can also present with the formation of necrotic lesions involving the fingers of the limbs, both the upper and lower ones. ssc is an immune-mediated disease that represents a major clinical challenge for physicians and patients. for the patient, ssc is associated with great uncertainty of outcome and development of manifestations that are potentially lethal or can reduce quality of life [31]. the problem of digital ulcers is increasingly recognised [32]. du occur in around half of ssc cases during their disease history, and about one in five patients might have this complication at any one time [33, 34]. there is now a better appreciation of the effects of digital ulcers, which include impaired function, pain, and loss of employment, as well as the more obvious medical complications of cellulitis, osteomyelitis, digital infarction, and severe pain. treatment of digital ulcers with drugs or systemic therapies needs to be combined with appropriate expert local care and dressings, and this treatment usually benefits from specialist nurse input. evidence-based treatments include phosphodiesterase-5 inhibitors and endothelin receptor antagonists, although some studies have not shown a clear treatment benefit [35, 36]. rheumatoid arthritis (ra) is a chronic, inflammatory autoimmune disorder expressed most commonly as a symmetrical, deforming arthropathy [37]. a well-known cause of ulceration in rheumatoid arthritis is vasculitis. vessels of different sizes may be affected. these patients will require systemic therapy because mortality can be high [38]. workup for the patients should include a complete history and thorough physical exam, screening laboratory studies and biopsies. treatment is a challenge, but stabilizing clinical assessment of the wound assess the lower extremity pulses make a doppler ultrasound exam if they are not present start with antiseptics and/or antimicrobials topics if clinical signs of local infection are present refer to a physiotherapist if the patient is bedbound or if a rehabilitation program is required refer to a pain management specialist if not adeguately controlled start systemic antibiotics and refer to an infectious disease specialist if clinical and laboratory signs of deep and progressive infection are present exclude a concomitant involvement of large vessels with an ecd ultrasound refer to a diabetologist for the correct metabolic management refer to a rheumatologist for an evaluation an oncological evaluation is requiredrefer to an angiologic examination if perfusion signs are not present exclude a bacterial superinfection using the nerds/stonees criteria evaluate the degree of mobilization evaluate the pain with the vas scale presence of a history of diabetes mellitus with a scarce glycemic control make a skin biopsy if an ad and/or a secondary vasculitis history is present exclude a paraneoplastic syndrome if an acute onset with multiple lesions are associated with a neoplastic history figure 2. clinical evaluation in the management of digital wounds. nerds: nonhealing, exudate increase, red friable granulation, debris; stonees: size is bigger, temperature elevated, os, new breakdown, exudate, erythema, smell; vas: visual analogue scale; ecd: echo colour doppler; ad: autoimmune disease. original article | dermatol pract concept. 2023;13(1):e2023019 7 16. brem h, sheehan p, rosenberg hj, schneider js, boulton 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the global burden of diabetic foot disease. the lancet. 2005;366(9498):1719-1724. doi:10.1016/s0140-6736 (05)67698-2 15. morris ad, mcalpine r, steinke d, et al. diabetes and lower-limb amputations in the community: a retrospective cohort study. diabetes care. 1998;21(5):738-743. doi:10.2337/ diacare.21.5.738 8 original article | dermatol pract concept. 2023;13(1):e2023019 digital ulcers in the digital ulcer outcome registry: a prospective, observational cohort. ann rheum dis. 2016;75(9):17361740. doi:10.1136/annrheumdis-2016-209481 34. mihai c, landewé r, van der heijde d, et al. digital ulcers predict a worse disease course in patients with systemic sclerosis. ann rheum dis. 2016;75(4):681-686. doi:10.1136/ annrheumdis-2014-205897 35. khanna d, denton cp, merkel pa, et al. effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: dual-1 and dual-2 randomized clinical trials. jama. 2016;315(18):1975. doi:10.1001/jama.2016.5258 36. domsic rt, nihtyanova si, wisniewski sr, et al. derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis: a validated two-year mortality model for early diffuse scleroderma. arthritis & rheumatology. 2014;66(6):1616-1624. doi:10.1002/art.38381 37. dabiri g, falanga v. connective tissue ulcers. journal of tissue viability. 2013;22(4):92-102. doi:10.1016/j.jtv.2013.04.003 38. danning cl, lllei gg, boumpas dt. vasculitis associated with primary rheumatologic diseases: current opinion in rheumatology. 1998;10(1):58-65. doi:10.1097/00002281-199801000-00009 39. hirche d, rubbert a, lunau l, krieg t, eming sa. successful treatment of refractory rheumatoid arthritis-associated leg ulcerations with adalimumab. br j dermatol. 2005;152(5):10621064. doi:10.1111/j.1365-2133.2005.06520.x 40. öien rf, håkansson a, hansen bu. leg ulcers in patients with rheumatoid arthritis—a prospective study of aetiology, wound healing and pain reduction after pinch grafting. rheumatology. 2001;40(7):816-820. doi:10.1093/rheumatology/40.7.816 41. goslen jb. autoimmune ulceration of the leg. clinics in dermatology. 1990;8(3-4):92-117. doi:10.1016/0738-081x(90)90050-b 42. fink am, kottas-heldenberg a, mayer w, et al. lupus anticoagulant and venous leg ulceration. br j dermatol. 2002;146(2):308-310. doi:10.1046/j.0007-0963.2001.04546.x dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(4):e2022136 1 recurrent microinvasive subungueal squamous cell carcinoma in a hiv patient: a case of good response to photodynamic therapy aurora alessandrini1,2, valeria evangelista1,2, alessia barisani1,2, sabina vaccari1,2, emi dika1,2, bianca maria piraccini1,2, michela starace1,2 1 dermatology irccs azienda ospedaliero-universitaria di bologna, bologna, italy 2 department of experimental, diagnostic and specialty medicine (dimes) alma mater studiorum university of bologna, italy key words: subungueal squamous cell carcinoma, squamous cell carcinoma, hiv infection, photodynamic therapy, 5-aminolaevulinic acid citation: alessandrini a, evangelista v, barisani a, et al. recurrent microinvasive subungueal squamous cell carcinoma in a hiv patient: a case of good response to photodynamic therapy. dermatol pract concept. 2022;12(4):e2022136. doi: https://doi.org/10.5826/ dpc.1204a136 accepted: february 21, 2022; published: october 2022 copyright: ©2022 alessandrini et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: bianca maria piraccini, dermatology irccs policlinico di sant’orsola department of experimental, diagnostic and specialty medicine (dimes) alma mater studiorum university of bologna, italy. via g. massarenti 1, 40138 bologna, italy. e-mail: biancamaria.piraccini@unibo.it introduction a 37-year-old male patient with a verrucous lesion affecting the second finger of the left hand, present for about 3 months. medical history revealed hiv infection, kaposi sarcoma, anal squamous cell carcinoma (scc) and muco-cutaneous leishmaniasis. the diagnosis of microinvasive subungual scc was made with a punch biopsy. the patient denied radical surgery and a conservative shaving was performed. eight months later, the lesion relapsed (figure1, a and b). the diagnosis of recurrent subungual scc was made by pathology. an x-ray of the finger excluded a bone involvement. due to the patient decision of denying surgery, we decided to perform a cycle of 4 sessions of conventional photodynamic therapy (c-pdt), using methyl aminolevulinate (mal) (metvix® cream, galderma medical solutions) under occlusion for three hours. the lesion was irradiated by a red light-emitting diode lamp (aktilite cl128®, galderma, wavelength 630 nm), at 80 mw/cm2 for 12 minutes. the procedure was repeated 4 times at one-week intervals. after the first step we observed a partial improvement (figure 1, c and d) after the fourth c-pdt step, the lesion had almost completely disappeared (figure 1, e and f). the patient did not relapse 6 months after last c-pdt session. 2 image letter | dermatol pract concept. 2022;12(4):e2022136 figure 1. (a) clinical presentation of recurrent subungual squamous cell carcinoma (scc) on the second finger of the left hand. (b) dermoscopy of the verrucous lesion, with hyperkeratosis and dotted vessels. (c) recurrent subungual scc after the first step of conventional photodynamic therapy (c-pdt). (d) dermoscopy of the lesion after the first step of c-pdt. (e) recurrent subungual scc after the fourth step of c-pdt. (f) dermoscopy of the lesion after the fourth step of c-pdt. image letter | dermatol pract concept. 2022;12(4):e2022136 3 teaching point pdt is a safe, non-invasive therapy, with good cosmetic results, for several dermatologic conditions, such as actinic keratosis and superficial non-melanoma skin cancer [1-2]. we hypothesize that c-pdt may be a promising therapy for high-risk recurrence scc, especially in acral sites, leading to a rapid healing process and being at the same time a well-tolerated, less painful procedure. references 1. tan b, sinclair r, foley p. photodynamic therapy for subungual bowen's disease. australas j dermatol. 2004;45(3):172-174. doi: 10.1111/j.1440-0960.2004.00082.x. pmid: 15250896. 2. wu l, chen w, su j, et al. efficacy of the combination of superficial shaving with photodynamic therapy for recalcitrant periungual warts. photodiagnosis photodyn ther. 2019;27:340344. doi: 10.1016/j.pdpdt.2019.06.021. pmid: 31252143. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023047 1 dermoscopic evolution of mycosis fungoides after allogeneic hematopoietic stem cell transplantation: a case series grażyna kamińska-winciorek1, anastazja szlauer-stefańska1, włodzimierz mendrek1, sebastian giebel1 1 the department of bone marrow transplantation and onco-hematology, maria sklodowska-curie national research institute of oncology (mscnrio), gliwice branch, poland key words: dermoscopy, cutaneous t-cell lymphomas, allogeneic hematopoietic stem cell transplantation, lymphoma, hematologic neoplasms citation: kamińska-winciorek g, szlauer-stefańska a, mendrek w, giebel s. dermoscopic evolution of mycosis fungoides after allogeneic hematopoietic stem cell transplantation: a case series. dermatol pract concept. 2023;13(1):e2023047. doi: https://doi. org/10.5826/dpc.1301a47 accepted: september 22, 2022; published: january 2023 copyright: ©2023 kamińska-winciorek et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: grażyna kamińska-winciorek, department of bone marrow transplantation and onco-hematology, maria sklodowska-curie national research institute of oncology (mscnrio), gliwice branch, poland; wybrzeże armii krajowej 15, 44-101 gliwice, poland. telephone: +48604070208 e-mail: dermatolog.pl@gmail.com introduction allogeneic hematopoietic stem cell transplantation (allohsct) is a potentially curative treatment in patients with mycosis fungoides (mf) and may be used in selected patients with advanced disease [1]. the differentiation of mf relapse from other skin diseases that occur after transplantation is challenging. in this case series we present the dermoscopic observation of mf lesions after allohsct. case presentation we have performed a dermoscopic follow-up of mf skin lesions in 3 patients before and after allohsct. dermoscopic images were captured using the dermlite cam with polarized light and independently analyzed by two certified dermoscopists (g.k-w, a.sz-s), blinded to the clinical status of the disease. the progression was determined as new mf lesions were confirmed in the histopathologic examination. the details of the disease, allohsct procedure and dermoscopic assessment are presented in table 1. treatment was tolerated well, and there was no case of transplant related mortality. in active mf, red and orange color of the background was found with the presence of numerous dotted and/or linear vessels, distributed unspecifically, uniformly, or in clusters. in one case increased white and yellow scaling was noted in patchy distribution. in cases of disease regression, a visible change in background color was noted (from red to skin-colored or light brown) (2/3), with the disappearance of the previously described vessels. 2 research letter | dermatol pract concept. 2023;13(1):e2023047 ta b le 1 . d er m o sc o p ic a ss es sm en t o f sk in l es io n s in t h e co u rs e o f al lo ge n ei c h em at o p o ie ti c st em c el l tr an sp la n ta ti o n f o r m yc o si s fu n go id es . pa ti en t ca se n u m b er ; g en d er 1 ; m 2 ; f 3 ; f c o n d it io n in g re gi m en ; d o n o r; i m m u n o su p p re ss io n f lu d ar ab in e+ m el p h al an ; m u d ; c sa + m tx t si + t l i+ a t g ; m u d ; c sa + m m f f lu d ar ab in e+ t b i; m u d ; c sa o ve ra ll r es p o n se ( ti m e af te r al lo h sc t ) p r , t h en p d ( tr ea te d w it h d l i) , t h en p r ( 5 ,5 y ea rs ) c r ( 3 y ea rs ) p d ( 1 0 0 d ay s) d ay ( al lo h sc t i s d ay 0 ) 1 + 1 4 + 4 1 + 6 9 6 -1 + 1 4 + 2 7 + 8 7 -1 + 1 4 + 5 6 + 1 0 0 sc al e (c o lo r an d d is tr ib u ti o n ) w h it e an d ye ll ow p at ch y o th er s tr u ct u re s (c o lo r an d m o rp h o lo gy ) b ro w n p ar al le l li n es b ro w n p ar al le l li n es gr ey d o ts a n d gl o b u le s; w h it e an gu la te d li n es gr ey d o ts a n d gl o b u le s; w h it e an gu la te d li n es w h it e d if fu se st ru ct u re le ss ar ea s; g re y d o ts a n d gl o b u le s w h it e d if fu se st ru ct u re le ss ar ea s; b ro w n d o ts an d g lo b u le s w h it e fo ca l st ru ct u re le ss ar ea s; b ro w n gl o b u le s w h it ef o ca l st ru ct u re le ss ar ea s; b ro w n li n es w h it e fo ca l st ru ct u re le ss ar ea s; b ro w n f o ca l gl o b u le s w h it e fo ca l st ru ct u re le ss ar ea s v es se ls d is tr ib u ti o n a n d m o rp h o lo gy u n sp ec ifi c d o tt ed cl u st er ed d o tt ed u n if o rm d o tt ed u n if o rm d o tt ed p er ip h er al d o tt ed u n sp ec ifi c li n ea r u n sp ec ifi c li n ea r u n sp ec ifi c li n ea r u n sp ec ifi c d o tt ed a n d li n ea r c o lo r o f th e b ac k gr o u n d re d , o ra n ge (s al m o n ) o ra n ge (s al m o n ) sk in -c o lo re d sk in -c o lo re d re d a n d p u rp le o ra n ge (s al m o n ) o ra n ge (s al m o n ) li gh t b ro w n sk in -c o lo re d sk in -c o lo re d sk in -c o lo re d sk in -c o lo re d a b b re vi at io n s: a ll o h sc t al lo ge n ei c h em at o p o ie ti c st em c el l tr an sp la n ta ti o n ; a t g an ti th ym o gl o b u li n ; c sa cy cl o sp o ri n e a ; c r co m p le te r em is si o n ; d l i d o n o r ly m p h o cy te i n fu si o n ; f fe m al e; m m al e; m m f m yc o p h en o la te m o fe ti l; m tx m et h o tr ex at e; n o n u m b er ; m u d m at ch ed u n re la te d d o n o r; p d p ro gr es si ve d is ea se ; p r p ar ti al r em is si o n t b i t o ta l b o d y ir ra d ia ti o n ; t l i t o ta l ly m p h at ic i rr ad ia ti o n ; t si -t o ta l sk in i rr ad ia ti o n . research letter | dermatol pract concept. 2023;13(1):e2023047 3 dermoscopy in the setting of allohsct may help to differentiate between a variety of skin conditions after the procedure, including relapse of the primary disease, cutaneous graft versus host disease, drug-induced rashes, infectious skin disorders, and secondary cutaneous neoplasms. dermoscopy is an auxiliary tool in the differentiation of inflammatory disorders and mf based on the vessels’ morphology and their distribution, color of the background, color and distribution of the scales [2]. dermoscopic features of mf described in the literature include short linear and dotted vessels [3,4,5,6] and spermatozoa-like vascular structures [3,4,5]. in our cohort, both dotted and linear vessels were noted, and they were indicative of an active disease process. background color in mf is red, yellow-orange [5] or a mix of the two colors [2]. the primary red or orange background color, changing to skin-colored or light brown in the case of healing of the lesions was also noted in our patients. the presence of scale seems to be not specific in the dermoscopy of mycosis fungoides. the large variation in descriptions of its presence and distribution [2,4,6] may be due to the use of a dermoscope with non-polarized light requiring immersion vs. polarized light, where scale is more easily visualized [2]. in our group, scaling was reported in active lesions. other noted structures such as white diffuse structureless areas, brown lines and globules were present irrespective of disease status. figure 1. patient 1, the skin of the left hand in the course of mycosis fungoides before allogeneic stem cell transplantation (allohsct). (a) clinical image of skin lesions: numerous juicy red indurated areas covering >80% of the body surface with a tendency to create crusts can be seen. (b) dermoscopy: yellow and white scale on juicy red and salmon background is evident. what is more, numerous dotted vessels in unspecific distribution can be seen. figure 2. day +696 after allohsct. (a) clinical image: full healing of lesions in the course of mf. (b) dermoscopy: on skin-colored background multiple light brown lines are distributed in unspecific arrangement, creating light brown discolorations, no scale. 4 research letter | dermatol pract concept. 2023;13(1):e2023047 2. bilgic s.a., cicek d., demir b. dermoscopy in differential diagnosis of inflammatory dermatoses and mycosis fungoides. int j dermatol. 2020, 59(7), 843-850. doi: 10.1111/ijd .14925.3. 3. bosseila m., sayed sayed k., el-din sayed s.s., abd el monaem n.a. evaluation of angiogenesis in early mycosis fungoides patients: dermoscopic and immunohistochemical study.  dermatology. 2015, 231(1), 82-86. doi:10.1159/0003 82124 4. lallas a., apalla z., lefaki i., et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatology venereol. 2013, 27(5), 617-621. doi:10.1111/j.1468-3083.2012.04499.x 5. bombonato c., pampena r., lallas a., giovanni p., longo c. dermoscopy of lymphomas and pseudolymphomas. dermatol clin. 2018, 36(4), 377-388. doi:10.1016/j.det.2018.05.005 6. errichetti e., apalla z., lallas a, et al. dermoscopic spectrum of mycosis fungoides: a retrospective observational study by the international dermoscopy society. j eur acad dermatol venereol. 2022, 36(7), 1045-1053. doi: 10.111/jdv.18078 conclusion our report adds to the information about the dermoscopic characteristics of mf lesions and their evolution. observations in the case of disease remission included a change of the background color from initial red-orange to skin-colored or light brown and the disappearance of numerous dotted and linear vessels, while the persistence of vessels was indicative of progressive disease. references 1. trautinger f., eder j., assaf c., et al. european organisation for research and treatment of cancer consensus recommendations for the treatment of mycosis fungoides/sézary syndrome – update 2017. eur j cancer. 2017, 77, 57-74. doi:10.1016/j .ejca.2017.02.027 dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023086 1 unicentric castleman disease in the temporal region of a pediatric patient jeffrey dickman1, samantha haraszti1, karen warschaw1,2, weimin hu1,3 1 kansas city university (kcu-gmec) phoenix dermatology, phoenix, arizona, united states 2 sonic healthcare usa, arizona dermatopathology, scottsdale, arizona, united states 3 specialists in dermatology, tucson, arizona, united states key words: castleman disease, pediatric, temple, lymphoproliferative disorders citation: dickman j, haraszti s, warschaw k, hu w. unicentric castleman disease in the temporal region of a pediatric patient. dermatol pract concept. 2023;13(2):e2023086. doi: https://doi.org/10.5826/dpc.1302a86 accepted: september 13, 2023; published: april 2023 copyright: ©2023 dickman et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: jeffrey dickman, do, 4801 e mcdowell rd, ste 150, phoenix, arizona 85008, united states. 602-954-3919 e-mail: jstdickman@gmail.com introduction castleman disease (cd) encompasses a group of rare lymphoproliferative disorders with common histopathologic features. the most common subtype is unicentric cd (ucd) which involves a single region of enlarged lymph nodes. cd can occur in any lymph node; however, cd has a predilection for the mediastinum, and rarely presents on the face [1]. here we report a case of ucd presenting in the temporal region of a pediatric patient. case presentation an 11-year-old female presented for excisional biopsy of an enlarging mass on the right temple which had been present for 17 months and was occasionally tender. an mri revealed a well-circumscribed 3.4 cm x 1.4 cm x 3 cm soft tissue mass lateral to the temporalis muscle. histological analysis of the specimen revealed lymphoid tissue with atretic and hyalinized germinal centers, concentric laminations resulting in an “onion-skin appearance,” and penetrating hyalinized arterioles (figure 1). immunohistochemistry demonstrated cd20 and pax-5 positive b cells figure 1. lymphoid tissue with atretic and hyalinized germinal centers, concentric laminations resulting in an “onion-skin appearance,” and penetrating hyalinized arterioles (h&e, 40x). 2 research letter | dermatol pract concept. 2023;13(2):e2023086 within the germinal centers, as well as cd21 positive follicular dendritic cells forming a laminated meshwork and occasionally merging with neighboring germinal centers. these findings in a single region, along with the absence of prominent plasmacytosis, atypical lymphocytes, and large or transformed lymphoid populations are consistent with the features of ucd. conclusions cd is categorized into two groups: unicentric and multicentric. ucd involves a single region of enlarged lymph nodes and is more common than multicentric cd (mcd). mcd affects multiple lymph node regions and usually presents with systemic symptoms or laboratory abnormalities demonstrating chronic inflammation such as elevated c-reactive protein [2]. there are three major histological subtypes of cd: hyaline-vascular cd (hv-cd), plasma cell cd (pc-cd) and a mixed histopathologic subtype. over half of ucd cases demonstrate the hyaline-vascular cd morphology, whereas mcd more often demonstrates the plasma cell variant [3]. ucd is typically asymptomatic and often discovered as an incidental finding on imaging or physical examination; however, it can also present with mass effect on neighboring structures [3,4]. ucd in the pediatric population is most commonly found within the mediastinum [4]. a complete resection of the lymphoid tissue is almost always curative for ucd. it is unknown if ucd in the temporal region carries a distinct prognosis from other locations, however, the prognosis following complete resection of ucd affecting a peripheral lymph node is significantly better than ucd in the chest or abdominal cavities. in a systematic review of 278 ucd cases, 249 had surgical resection alone, and 13 had combination surgical and immunosuppressive treatments with a 5-year disease free recurrence rate of approximately 81% and a 10-year survival rate of approximately 95%. continued follow-up is essential to monitor for recurrences. treatment of mcd is more complex and the prognosis is generally worse with a 10-year survival rate of approximately 67% [5]. there have been two other case reports of cd presenting in the temporal region [1,3]. this case is unique given the presentation of temporal ucd in a pediatric patient. dermatologists should be aware that cd may develop in this region in both children and adults. references 1. kang n, chung j, jung s. rare location of castleman disease in the temporal region. j craniofac surg. 2009;20(3)830-2. doi: 10.1097/scs.0b013e3181a14c19. pmid: 19349907. 2. dispenzieri a, fajgenbaum dc. overview of castleman disease. blood. 2020;135(16):1353-1364. doi: 10.1182/ blood.2019000931. pmid: 32106302. 3. ryu w, park mh, kim h, koh ic, kim kn. rare location of castleman’s disease in the temporal region: a case report involving a young korean woman and review of the literature. arch craciofac surg. 2017;18(2)122-127. doi: 10.7181/ acfs.2017.18.2.122. pmid: 28913319. pmcid: pmc5556893. 4. wala s, fallon e, forlenza c, shukla n, laquaglia m. unicentric castleman disease in the mediastinum. j pediatric surg case reports. 2018;34:51-53. 5. talat n, belgaumkar ap, schulte km. surgery in castleman's disease: a systematic review of 404 published cases. ann surg. 2012 apr;255(4):677-84. doi: 10.1097/sla.0b013e318249dcdc. pmid: 22367441. dermatology: practical and conceptual case report | dermatol pract concept 2016;6(2):2 5 dermatology practical & conceptual www.derm101.com introduction bowen’s disease (bd) is an in situ variant of cutaneous squamous cell carcinoma (scc). etiological factors for bd include ultraviolet radiation (solar, iatrogenic and sunbeds) [1,2], radiotherapy, carcinogens (arsenic), immunosuppression [3,4], and infection with human papillomavirus [5-7]. histopathologically it is characterized by abnormal and pleomorphic keratinocytes that in the precursor stages involve only the lower part of the epidermis and, in time, with progression to bd, the full thickness of it. dermatoscopic criteria have been described for pigmented and non-pigmented bd, actinic keratosis (ak) and superficial forms of scc [8-10]. a recent study has focused on a progression model of actinic keratosis and intraepidermal carcinomas to invasive carcinoma but was limited to facial cases [10]. case report a 44-year-old male presented with a 10-year history of a 35x25 cm erythematous hyperkeratotic, crusted, and ulcerdevelopment of poorly differentiated invasive squamous cell carcinoma in giant bowen’s disease: a case report with dermatoscopy bengu nisa akay1, aysenur maden1, oguzhan kocak2, seher bostanci1, ayşe boyvat1, pelin kocyigit1, aylin okcu heper3 1 ankara university faculty of medicine, department of dermatology, ankara, turkey 2 kutahya evliya celebi state hospital, department of dermatology, kutahya, turkey 3 ankara university faculty of medicine, department of pathology, ankara, turkey key words: bowen’s disease squamous cell carcinoma, dermatoscopy, dermoscopy citation: akay bn, maden a, kocak o, bostanci s, boyvat a, kocyigit p, okcu heper a. development of poorly differentiated invasive squamous cell carcinoma in giant bowen’s disease: a case report with dermatoscopy. dermatol pract concept 2016;6(2):2. doi: 10.5826/ dpc.0602a02 received: august 24, 2015; accepted: january 12, 2016; published: april 30, 2016 copyright: ©2016 akay et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aysenur maden, md, ankara university faculty of medicine, department of dermatology, ankara, turkey. tel. +90 (312) 5082231; fax. +90 (312) 3108636. e-mail: abotsali@hotmail.com bowen’s disease (bd) is an in situ form of squamous cell carcinoma (scc), often occurring in the chronically uv-damaged skin of elderly people. the risk of progression of bd to invasive scc varies between 3% and 5%, and one-third of invasive tumors may metastasize. herein we discuss the dermatoscopic findings of a case of giant bowen’s disease, which progressed to poorly differentiated invasive scc. abstract mailto:abotsali@hotmail.com 6 case report | dermatol pract concept 2016;6(2):2 whole lesion. multiple skin biopsies from the peripheral and central parts were taken. central parts were histopathologically consistent with poorly differentiated invasive scc, while peripheral parts were compatible with bd (figure 4). there were no cytopathic changes compatible with human papillomavirus infection. the patient’s arsenic level was found to be elevated on blood analysis. thoracic-abdominal-pelvic computed tomography did not show any metastasis. the lesion was totally excised with safe surgical margins and split-thickness skin grafting was performed in the plastic surgery department. discussion bowen’s disease (bd) can be considered a low-grade form of scc, with the majority of studies reporting the risk of progression to scc at 3-5% [12,13]. despite the low incidence of malignant progression, bd has significant consequences since ated plaque on his abdominal region (figure 1). the patient did not report previous history of trauma, immunosuppression or radiotherapy to the lesion site. dermatoscopic examination of the central part of the lesion with dermlite pro hr (3gen, llc, san juan capistrano, ca, usa) mounted on an iphone 5s®, revealed white circles and a vascular pattern, observed as large coiled vessels in linear arrangement intermingled with ulcerations and adherent fibrin crusts (figure 2). the peripheral parts showed a linear arrangement of gray dots and coiled vessels without prominent white circles and ulceration (figure 3). the diameter of the coiled vessels on the central part was larger in size than seen in the periphery. in addition, red and white structureless areas were distributed throughout the figure 1. clinical image of the patient showed a 35x25 cm erythematous hyperkeratotic, crusted, and ulcerated plaque on the abdominal region. [copyright: ©2016 akay et al.] figure 2. dermatoscopy of the central region. (a) linear arrangement of coiled vessels becoming convoluted and larger in size (blue arrows) intermingled with ulceration and adherent fibrin crusts. (b) white circles (blue arrows). [copyright: ©2016 akay et al.] figure 3. dermatoscopy the peripheral region. (a, b) white and pink structureless areas, white lines (green circle) and a linear arrangement of gray dots and coiled vessels (blue arrows). no ulceration or white circles are seen. [copyright: ©2016 akay et al.] figure 4. (a) histopathology of the peripheral part which is consistent with bd: an acanthotic epidermis shows full-thickness epidermal replacement by crowded keratinocytes that demonstrate disordered dyspolarity, lack of maturation, atypical mitotic figures and nuclear pleomorphism with hyperchromasia. a band-like lymphocytic infiltrate is apparent in the papillary dermis. (b) histopathology of the central region shows invasive part of tumor which extends as invasive broad tongues into the dermis. this part of the tumor composed of pleomorphic atypical epithelioid cells with high nucleocytoplasmic ratio and frequent mitosis. squamous differentiation features, such as squamous pearls or single cell keratinization, are not obvious. foci of necrosis can be noted at the right part of the figure. [copyright: ©2016 akay et al.] case report | dermatol pract concept 2016;6(2):2 7 in the infundibular epidermis, which in effect is invasion of adnexa and can be a feature of well-differentiated scc. the white circles observed in our case were poorly formed and sparse which may be associated with the poor differentiation status. in the present case, the periphery of the lesion corresponding to bd showed gray to brownish dots and coiled vessels arranged in lines, while the central part corresponding to invasive scc revealed white circles, large coiled vessels arranged in lines and ulceration. the diameter of the coiled vessels on the central part was larger in size than seen on the periphery, similar to the progression model of zalaudek et al [10]. in addition, white circles and ulceration were not observed on the parts where there was bd. rosendahl et al., found the positive predictive value of white circles as 92% in scc when compared with bd [14]. in conclusion, we have presented the first description of dermatoscopic findings of poorly differentiated invasive scc developing on a huge bd. dermatoscopy may help to differentiate intraepidermal carcinoma from invasive scc, especially when confronted with white circles and coiled vessels with large diameter. this in turn may help clinicians not only to diagnose in situ or invasive lesions but also to improve the selection of lesions requiring biopsy or excision for definitive histopathologic diagnosis. references 1. kossard s, rosen r. cutaneous bowen’s disease. an analysis of 1001 cases according to age, sex, and site. j am acad dermatol 1992; 27:406–10. pmid: 1401276. 2. reizner gt, chuang ty, elpern dj, stone jl, farmer er. bowen’s disease (squamous cell carcinoma in situ) in kauai, hawaii. a population-based incidence report. j am acad dermatol 1994; 31:596–600. pmid: 8089285 3. drake al, walling hw. variations in presentation of squamous cell carcinoma in situ (bowen’s disease) in immunocompromised patients. j am acad dermatol 2008; 59:68–71. pmid: 18440666. doi: 10.1016/j.jaad.2008.03.028 4. moloney fj, comber h, o’lorcain p, et al. a population-based study of skin cancer incidence and prevalence in renal transplant recipients. br j dermatol 2006; 154:498–504. pmid: 16445782. doi: 10.1111/j.1365-2133.2005.07021.x 5. kettler ah, rutledge m, tschen ja, buffone g. detection of human papillomavirus in nongenital bowen’s disease by in situ dna hybridization. arch dermatol 1990; 126:777–81. pmid: 2161202. doi: 10.1001/archderm.1990.01670300077011 6. collina g, rossi e, bettelli s et al. detection of human papillomavirus in extragenital bowen’s disease using in situ hybridization and polymerase chain reaction. am j dermatopathol 1995; 17:236–41. pmid: 8599431. 7. hama n, ohtsuka t, yamazaki s. detection of mucosal human papilloma virus dna in bowenoid papulosis, bowen’s disease and squamous cell carcinoma of the skin. j dermatol 2006; 33:331–7. pmid: 16700665. doi: 10.1111/j.1346-8138.2006.00078.x 8. zalaudek i, argenziano g, leinweber b, et al. dermoscopy of bowen’s disease. br j dermatol 2004; 150:1112–6. pmid: 15214896. doi: 10.1111/j.1365-2133.2004.05924.x approximately 20% of the tumors that develop into scc will eventually become metastatic [12]. therefore, patients with bd should be diagnosed and treated as early as possible. dermatoscopy is considered a helpful and non-invasive tool for increasing the diagnostic accuracy of bd. in 2004, zalaudek et al., described dermatoscopic features of bd in 21 cases [8]. they observed a particular type of vascular pattern in bd, named glomerular vessels, a variant form of dotted vessels that are large in size and often grouped and regularly arranged in clusters, mimicking the glomerular apparatus of the kidney. they emphasized that the “glomerular” vessels together with a scaly surface and, in cases of pigmented bd, the additional presence of pigmented small globules and/or homogeneous pigmentation, represent specific dermatoscopic criteria for the diagnosis of bd. in their study glomerular vessels were observed in 100% of the non-pigmented and 80% of the pigmented bd. this special type of tortuous capillary was histopathologically correlated to a convolution of grouped, frequently dilated capillaries in the dermal papillae and papillary dermis [8]. in 2010, cameron et al., described dermatoscopic findings of pigmented bd, and they found that the linear arrangement of brown and/or gray dots and/or coiled vessels were specific clues to pigmented bd [9]. pink, white or skin-colored structureless areas were found to be the most common finding in their study. histopathologically, the brown to gray dots in bd may correspond to the presence of melanophages arranged in clusters and diffusely situated in the superficial dermis, and/or to a slightly increased number of pigmented keratinocytes in the basal layer and less frequently in suprabasal locations. dermatoscopy of scc has been the subject of very recent studies. zalaudek et al., proposed a progression model of facial ak developing into bd and invasive scc based on dermatoscopic findings [10]. in this model, those ak that progress to increasing atypia tend to display vessels around follicles that become dotted (or coiled on higher magnification), then as the lesion develops into scc in situ the dotted/coiled vessels appear to enlarge, become more convoluted and clustered, and the follicles in that area appear to miniaturize and disappear eventually forming the discrete whitish, opaque scaly areas. with progression of bd to invasive scc, looped and/ or linear irregular vessels will appear, and a central mass of keratin forms and ulceration may occur [10]. white circles, keratin, and blood spots were the strongest features associated with the diagnosis of scc in a recent study by rosendahl et al [14]. especially, white circles were useful clues to differentiate scc and keratoacanthoma from other raised nonpigmented skin lesions by dermatoscopy. white circle is a new dermatoscopic criterion, represented by white circles centered around a dilated infundibulum filled with a keratin plug that is visible as a yellow or an orange clod on dermatoscopy. white circles correspond to acanthosis and hypergranulosis 8 case report | dermatol pract concept 2016;6(2):2 12. peterka es, lynch fw, goltz rw. an association between bowen’s disease and internal cancer. arch dermatol 1961; 84:623–9. pmid: 14485715. doi: 10.1001/archderm.1961.01580160087015 13. kao gf. carcinoma arising in bowen’s disease. arch dermatol 1986; 122:1124-26. pmid: 3767398. doi: 10.1001/archderm.1986.01660220042010 14. rosendahl c, cameron a, argenziano g, et al. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol 2012; 148:1386-92. pmid: 22986634. doi: 10.1001/archdermatol.2012.2974 9. cameron a, rosendahl c, tschandl p, et al. dermatoscopy of pigmented bowen’s disease. j am acad dermatol 2010; 62:597604. pmid: 20079953. doi: 10.1016/j.jaad.2009.06.008 10. zalaudek i, giacomel j, schhmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma and invasive squamous cell carcinoma: a progression model. j am acad dermatol 2012; 66:589-97. pmid: 21839538. doi: 10.1016/j. jaad.2011.02.011 11. cox nh, eedy dj, morton ca. guidelines for management of bowen’s disease: 2006 update. br j dermatol 2007; 156:11-21. pmid: 17199561. doi: 10.1111/j.1365-2133.2006.07610.x dermatology: practical and conceptual observation | dermatol pract concept 2016;6(1):7 23 dermatology practical & conceptual www.derm101.com a 23-year-old man presented with multiple lip pigmentations. longitudinal hyperpigmented streaks on his nails, as well as an ill-defined 2x3 mm pigmented spot on his right eye were noted (figure 1). the family history was unremarkable. he was not taking any medication. colonoscopy and barium radiography of intestine were unremarkable. complete blood count, complete metabolic panel, and urinalysis were within normal limits. the patient was diagnosed with laugier-hunziker syndrome (lhs). dermoscopic features of conjunctival, mucosal, and nail pigmentations in a case of laugier-hunziker syndrome nida kaçar1, ceren c. yildiz1, nese demirkan2 1 department of dermatology, pamukkale university, denizli, turkey 2 department of pathology, pamukkale university, denizli, turkey key words: dermoscopy, laugier-hunziker syndrome citation: kaçar n, yildiz cc, demirkan n. dermoscopic features of conjunctival, mucosal, and nail pigmentations in a case of laugierhunziker syndrome. dermatol pract concept 2016;6(1):7. doi: 10.5826/dpc.0601a07 received: july 29, 2015; accepted: october 6, 2015; published: january 31, 2016 copyright: ©2016 kaçar et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nida kaçar, md, pamukkale universitesi tip fakultesi, dermatoloji anabilim dali, e-409, kinikli, 20070 denizli, turkey. tel. 905326977935; fax. +902582424010. email: n_gelincik@yahoo.com figure 1. clinical view of labial (a), ungual (b) and conjunctival (h) pigmentations are shown. dermoscopic findings included reticular lines (b), globules (c), and parallel lines (d) in the labial pigmentation; brown to gray longitudinal regular lines (f, g) in the ungual pigmentationand light brown colored homogeneous pattern (i) in the conjunctival pigmentation (10x). [copyright: ©2016 kaçar et al.] 24 observation | dermatol pract concept 2016;6(1):7 ground, micro-hutchinson’s sign have also been reported in benign nail pigmentations of some lhs cases [2,5,8]. parallel furrow pattern, brown and blue-gray granular pigmentation along with linear and dotted vessels on whitish pink areas are the dermoscopic findings reported in labial pigmentations of lhs cases [5]. the only lhs case with labial melanoma in the literature exhibited blue-whitish veil on dermoscopic examination [1]. dermoscopic findings in the present case were consistent with benign nature. the dermoscopic finding of a conjunctival pigmentation in lhs is being reported for the first time by the present study. the identification of dermoscopic features of this syndrome may simplify the management of lhs. further reports are necessary to arrive at a conclusion. this case was presented in a poster presentation at the 11th european academy of dermatology and venereology spring symposium 2014, belgrade, serbia. references 1. simionescu o, dumitrescu d, costache m, et al. dermatoscopy of an invasive melanoma on the upper lip shows possible association with laugier-hunziker syndrome. j am acad dermatol. 2008;59:s105-8. 2. thomas l, phan a, pralong p, et al. special locations dermoscopy: facial, acral, and nail. dermatol clin. 2013;31:615-24. 3. blum a, simionescu o, argenziano g, et al. dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the international dermoscopy society (ids). arch dermatol. 2011;147:1181-7. 4. li k, xin l. palpebral conjunctiva melanoma with dermoscopic and clinicopathological characteristics. j am acad dermatol. 2014;71: e35-7. 5. tamiya h, kamo r, sowa j, et al. dermoscopic features of pigmentation in laugier-hunziker-baran syndrome. dermatol surg. 2010;36:152-4. 6. ko jh, shih yc, chiu cs, et al. dermoscopic features in laugierhunziker syndrome. j dermatol. 2011;38:87-90. 7. sendagorta e, feito m, ramírez p, et al. dermoscopic findings and histological correlation of the acral volar pigmented maculae in laugier-hunziker syndrome. j dermatol. 2010;37:980-4. 8. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138:1327-33. dermoscopic examination of the lip pigmentations disclosed parallel lines, reticular lines and globules. the only recognized color was brown, which had a grayish hue in some parts of the lesion. a light brown colored homogeneous pattern was observed in the conjunctival pigmentation. the pigmented nail streaks showed brown-to-gray longitudinal regular lines (figure 1). histopathological examination of the labial pigmentation revealed basal keratinocyte pigmentation. no increase in the melanocyte count was identified with s100 and hmb45 immunohistochemical staining. iron accumulation was not seen with specific perls’ stain. the histopathological findings were compatible with the diagnosis of melanotic macule. impression cytology examination of the conjunctival pigmentation revealed melanocytes with only a mild atypia suggesting a benign nature. the patient was processed to follow-up. lhs is a rare, acquired disease characterized by hyperpigmented macules of the lips and oral mucosa along with longitudinal melanonychia. pigmentations in other mucosal surfaces may also exist. although this syndrome is being regarded as benign, invasive mucosal melanoma has been reported in a case of lhs [1]. parallel ridge pattern and irregular diffuse pigmentation in acral lesions; irregular lines on a brown background and micro-hutchinson’s sign in nail apparatus lesions [2]; and the combination of blue, gray, or white color with structureless zones in mucosal lesions are the dermoscopic findings suggestive of melanoma [3]. little data exists regarding the dermoscopic features of conjunctival pigmentations in the literature. atypical pigment network, irregular dots and globules, regression structures, and a blue-white veil are the dermoscopic findings reported in a case of palpebral conjunctival melanoma [4]. dermoscopic findings may differ from usual in some pigmentation syndromes including lhs. parallel ridge pattern has been determined in benign acral pigmentations of several lhs cases [5-7]. although nail pigmentations in lhs have been found to demonstrate similar dermoscopic findings with that seen in ethnic type and drug induced pigmentation, which are regular linear pigmentation lines on a grayish backdermatology: practical and conceptual observation | dermatol pract concept 2018;8(1):2 7 dermatology practical & conceptual www.derm101.com introduction microvenular hemangioma (mvh) is an acquired benign type of hemangioma with distinctive histological findings, first named in 1991 [1]. it is a rare lesion, and less than 70 cases of mvh have been published to date [2]. it usually presents with an asymptomatic, slowly growing reddish-blue papule, plaque, or nodule, less than 30 mm in diameter [1,2]. herein, we describe an adult male with mvh, presenting unique and atypical clinical features. case report a 62-year-old man presented with a nontender, bluish-red area on his nose, present for two years. the lesion had gradually enlarged and deepened in color during the previous year. an unusual lesion on the nose: microvenular hemangioma a. tulin mansur1, gulsen tukenmez demirci2, eltaf a. ozbal koc3, semsi yildiz4 1 dermatology department, istanbul hospital, baskent university, istanbul, turkey 2 dermatology department, acibadem altunizade hospital, acibadem university, istanbul, turkey 3 ear, nose and throat diseases department, istanbul hospital, baskent university, istanbul, turkey 4 pathology department, istanbul hospital, baskent university, istanbul, turkey key words: vascular anomaly, hemangioma citation: mansur at, tukenmez demirci g, ozbal koc ea, yildiz s. an unusual lesion on the nose: microvenular hemangioma. dermatol pract concept. 2018;8(1):7-11. doi: https://doi.org/10.5826/dpc.0801a02 received: april 25, 2017; accepted: october 6, 2017; published: january 31, 2018 copyright: ©2018 mansur et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gulsen tukenmez demirci, associate professor, dermatology department, acibadem altunizade hospital, üsküdar 34662, i̇stanbul, turkey. email: gulsentukenmez@yahoo.com microvenular hemangioma (mvh) is an acquired, benign type of hemangioma that usually manifests itself as a solitary, slowly growing, red to violaceous, asymptomatic papule, plaque or nodule. it is typically located on the trunk or extremities of young adults. it can be difficult to differentiate mvh from other types of hemangioma and kaposi sarcoma. herein we report a case of mvh unusual for its location, age of onset, and morphologic features. a 62-year-old man complained of an asymptomatic, bluish-red discoloration on the tip of his nose that had been present for two years. dermatologic examination showed a violaceous patch 2 x 2 cm in diameter with indistinct borders. incisional biopsy revealed irregularly branched small or mediumsized vascular spaces lined with benign endothelial cells, positive for cd34 and negative for hhv-8. mvh is a rare lesion, and less than 70 cases have been published to date. a review of 40 reported cases revealed that 15% of mvh patients were over 40 years of age and only 3% of the cases showed macules or patches. a literature survey showed only two cases of mvh located on the facial region, one on the chin and the other on the cheek. our case was unique for its location and interesting for other rarely encountered features. mvh should be considered in the differential diagnoses of vascular lesions on nasal skin. abstract 8 observation | dermatol pract concept 2018;8(1):2 histologically, hyperkeratosis, irregular acanthosis, and minimal papillomatosis were observed in the epidermis. small and medium-caliber, irregularly branched vessels, lined by a single layer of benign endothelial cells were distributed in the upper dermis. between the blood vessels, increased fibrous tissue and sparse lymphoplasmacytic inflammatory infiltration were noticed (figure 2 a, b). immunohistochemically, the cells lining the lumina were positive for cd34 (figure 3 a,b). hhv-8 immunostaining was negative for vascular lesions. based on these findings, mvh was diagnosed. discussion a review of 40 cases of mvh revealed that mvh mostly manifested itself with nodules, and less frequently with papules or plaques. only a minority (3%) of the cases showed macules or patches [3]. mvh is typically located on the extremities and trunk and rarely the neck and face can be involved. the review menthe patient had several comorbidities including hypertension, nodular goiter, erosive gastritis, renal calculi, cervical discopathy, gonarthrosis, and patellofemoral arthrosis. his medications included esomeprazole, isosorbide dinitrate, nifedipine, betahistine dihydrochloride, acemetacin, and chlorzoxazone. he had quit smoking two years prior and denied drinking alcohol. he had blue eyes, and skin type ii. cuperosis in the nasal lesion was considered by previous physicians, and sunscreen lotions were prescribed with no beneficial effect. physical examination revealed facial erythema and prominent telangiectasia on both cheeks. a bluish-red, partially blanchable patch with indistinct borders, measuring 2 cm in diameter, was seen on the tip of the nose and columella. superficial and thin blood vessels were noticed throughout the patch (figure 1a, b). anterior rhinoscopy of the nose and otolaryngological examination was normal. an incisional biopsy was performed with a clinical prediagnosis of kaposi sarcoma, hemangioma, pseudolymphoma, and angiolupoid type of cutaneous sarcoidosis. figure 2. (a, b) histopathologic features consisted of a proliferation of irregular vascular channels involving the dermis (hematoxylin-eosin stain; original magnification ×200). [copyright: ©2018 mansur et al.] a b figure 1. the lesion is a poorly circumscribed, bluish-red patch involving the tip of the nose (a), and columella (b). [copyright: ©2018 mansur et al.] a b observation | dermatol pract concept 2018;8(1):2 9 similarities between these entities have been reported [2,6-8]. hhv8 is an important clue that helps to distinguish mvh from early stages of ks, since ks expresses the marker, while mhv does not [9]. ks and some other vascular lesions were taken into account for the differential diagnosis of mvh and are listed in table 1. our patient’s histologic and immunohistochemical findings were diagnostic of mvh, while his clinical manifestation was unique in its localization. in addition, our case was interesting in that the onset of mvh was in advanced age and it presented with a patch type lesion. our report adds mvh to the broad list of the lesions that could be located on the nose. mvh should be considered in the differential diagnoses of vascular lesions in this area. references 1. requena l, sangueza op. cutaneous vascular proliferation. part ii. hyperplasias and benign neoplasms. j am acad dermatol. 1997 dec;37(6):887-919. 2. koch ps, goerdt s, peitsch wk. solitary red-purple plaque on the chest of a 7-year-old boy: a quiz. microvenular haemangioma. acta derm venereol. 2015 mar;95(3):378-82. 3. linos k, csaposs j, carlson ja. microvenular hemangioma presenting with numerous bilateral macules, patches, and plaques: a case report and review of the literature. am j dermatopathol. 2013 feb;35(1):98-101. 4. miyashita h, yokoyama a, tanaka k. a case of microvenular hemangioma with presentation resembling inflammatory skin tumor. j plast reconstr aesthet surg. 2009 jun;62(6):e166-167. 5. xu xl, xu cr, chen h, cao yh, zeng xs, sun jf, guo y. eruptive microvenular hemangiomas in 4 chinese patients: clinicopathologic correlation and review of the literature. am j dermatopathol. 2010 dec;32(8):837-840. 6. napekoski km, fernandez ap, billings sd. microvenular hemangioma: a clinicopathologic review of 13 cases. j cutan pathol. 2014 nov;41(11):816-822. tioned above showed that 59% of the lesions were located on the trunk, 56% on the extremities, and only 10% on the head and neck region [3]. in cases where mvh was located on the head, lesions appeared on the chin and cheek [3-5]. to date, there is no report of mvh involving the nose. in most cases, lesions occur in young to middle-aged adults, with equal incidence in males and females. only 15% of mvh cases occur in patients older than 40 years. in the beginning, mvh shows a rapid growth in three months, then the lesion becomes stable or continues growing only slowly. the factors that predispose, trigger, or facilitate the development of mvh are not known yet [1-6]. histologically the tumor is composed of irregularly branched, thin-walled small blood vessels of uniform diameter, infiltrating the superficial and deep dermis, surrounded by a collagenous or desmoplastic stroma. the endothelial cells are normal to plump and display no atypia, mitotic figures, or pleomorphism. the vascular lumina are narrow but recognizable with a few red blood cells inside, without any extravasation. there may be a mild lymphoplasmacytic infiltrate [5,6]. mvh expresses several vascular markers, such as cd34, cd31, wt1, viii-related antigen, vwf, or uea-1, confirming the endothelial origin of the tumor [7]. clinically mvh can mimic other benign and malignant vascular lesions. even some nonvascular tumors and inflammatory lesions, including leiomyoma, dermatofibroma, leukemia and lymphoma with cutaneous involvement, lymphomatoid papulosis, papulonecrotic tuberculoid, and bacillary angiomatosis may be listed in the differential diagnosis [2,6]. the correct diagnosis of mvh cannot be made based on clinical features in most patients, but it can be established with routine histology and immunohistochemistry. the most important vascular lesions that must be considered are kaposi sarcoma (ks) and angiosarcoma, since some morphological figure 3. (a) here, vascular spaces are clearly visible with endothelial cells positive for cd 34. (b) vascular spaces are visible with endothelial cells positive for cd31. [copyright: ©2018 mansur et al.] a b http://www.ncbi.nlm.nih.gov/pubmed/?term=requena%20l%5bauthor%5d&cauthor=true&cauthor_uid=9418757 http://www.ncbi.nlm.nih.gov/pubmed/?term=sangueza%20op%5bauthor%5d&cauthor=true&cauthor_uid=9418757 http://www.ncbi.nlm.nih.gov/pubmed/9418757 http://www.ncbi.nlm.nih.gov/pubmed/25138781 http://www.ncbi.nlm.nih.gov/pubmed/25138781 http://www.ncbi.nlm.nih.gov/pubmed/22722465 http://www.ncbi.nlm.nih.gov/pubmed/22722465 http://www.ncbi.nlm.nih.gov/pubmed/22722465 http://www.ncbi.nlm.nih.gov/pubmed/19059016 http://www.ncbi.nlm.nih.gov/pubmed/19059016 http://www.ncbi.nlm.nih.gov/pubmed/20881833 http://www.ncbi.nlm.nih.gov/pubmed/20881833 http://www.ncbi.nlm.nih.gov/pubmed/25263662 http://www.ncbi.nlm.nih.gov/pubmed/25263662 10 observation | dermatol pract concept 2018;8(1):2 table 1. clinical differentiation of mvh from cutaneous vascular tumors clinical features / course / prognosis histopathological features mvh differential points cutaneous angiosarcoma • purplish-red, ill-defined bruise-like patch • bluish-violaceous nodule or plaque that may bleed or ulcerate • mostly on the head and neck in elderly people • rapidly growing • high rate of recurrence and metastasis • involve dermis extensively, sometimes with subcutis and fascia • irregular, dissecting, anastomosing vascular channels • tumor cells pile up along vessel lumina • absence of a pericyte layer • a more disordered architecture • prominent cytologic atypia with large cells, hyperchromatic and pleomorphic nuclei • high mitotic activity “kaposi sarcoma • brown-red macules/papules bluish-purple nodules or plaques • any location but typically on legs/feet, head and neck • variable extention and course due to immune status • may involve oral mucosa, lymph nodes, viscerae • proliferation of spindle cells • prominent slit-like vascular spaces extravasated red blood cells • perivascular lymphocytes and plasma cells • eosinophilic hyaline globules • more architectural complexity • absence of conspicuous pericyte layer • anastomosing vascular spaces • ectatic vascular channels surrounding the normal blood vessels (promontory sign) • ihc: hhv-8 (+) hobnail hemangioma (targetoid hemosiderotic hemangioma) • violaceous central papule surrounded with palor and brown ring • trunk and limbs • in young and middle aged people • not a true neoplasm, instead reactive process • dilated superficial dermal vessels • plump, ‘’hobnail’’ endothelial cells that protrude to lumina • inflammation and fibrosis • extravasated red blood cells hemosiderin deposition lymphangiectases • ihc: lymphatic markers (+); (d2-40) tufted angioma • firm, dark-red, brownish or violet plaques/nodules • mostly on trunk, neck and extremities • more frequent in infants and children • benign, slow and progressive growth • tightly packed “tufted” capillaries in discrete lobules (cannonball appearance) • distinctive nodular growth pattern • semilunar clefts at periphery of the lobules • ihc: lymphatic markers (+); (d2-40) pyogenic granuloma • red-brown polypoid or pedunculated papule/nodule • friable, prone to bleed • gingiva, lips, finger, face • usually in children and young adults • evolves over weeks • benign, may recur after treatment • multiple lobules of closely packed capillaries • loose, edematous stroma • mixed inflammatory infiltrate • well-developed collarette from elongated rete ridges • fibrous connective tissue septae reactive angioendotheliomatosis • red patches/plaques tumors/ ulcerated lesions • any site on body • coexistent systemic disease • intravascular proliferation of endothelial cells • dilated vessels • mild atypia • minimal inflammation • fibrin thrombi • reactive (fasciitis-like) dermal alterations observation | dermatol pract concept 2018;8(1):2 11 9. cheuk w, wong ko, wong cs, dinkel je, ben-dor d, chan jk. immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish kaposi sarcoma from its mimickers. am j clin pathol. 2004 mar;121(3):335-342. 7. trindade f, kutzner h, requena l, tellechea ó, colmenero i. microvenular hemangioma-an immunohistochemical study of 9 cases. am j dermatopathol. 2012 dec;34(8):810-812 8. berk dr, abramova l, crone kg, bayliss sj. microvenular haemangioma: report of a paediatric case. clin exp dermatol. 2009 oct;34(7):e304-306. http://www.ncbi.nlm.nih.gov/pubmed/15023037 http://www.ncbi.nlm.nih.gov/pubmed/15023037 http://www.ncbi.nlm.nih.gov/pubmed/23169416 http://www.ncbi.nlm.nih.gov/pubmed/23169416 http://www.ncbi.nlm.nih.gov/pubmed/19456787 http://www.ncbi.nlm.nih.gov/pubmed/19456787 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):4 23 introduction in general, epithelial neoplasm can be classified into three categories, namely, benign neoplasm, carcinoma in situ (noninvasive carcinoma) and invasive carcinoma. when the term carcinoma used unmodified, it generally refers to invasive carcinoma. however, since the introduction of the concept of carcinoma in situ by broder in 1932 [1], there have been only occasional case reports of adenocarcinoma in situ of skin in the literature [2-6]. adenocarcinoma in situ of skin as a concept and as a diagnostic category has not been established in the field of dermatopathology [7-9]. in this essay, four cases of papillary adenocarcinoma in situ (pacis) of skin are reported. furthermore, the notion that lesions previously reported in the medical literature under the term of papillary eccrine adenoma are actually pacis is discussed. materials and methods case history case 1 the patient was a 82-year-old female with a 1.2 cm painful mass in her right second toe. the lesion was excised and diagnosed by a dermatopathologist as sweat duct carcinoma, involving the specimen margins. subsequently, amputation of the right second toe was performed. upon review of the amputation specimen along with the prior excision specimen, another dermatopathologist in a different institution interpreted the lesion as papillary eccrine adenoma. case 2 the patient was a 47-year-old female with a 1.5 cm skin nodule on her right leg. the lesion was excised and was reported to be adenocarcinoma with negative margins. papillary adenocarcinoma in situ of the skin: report of four cases sheng chen1, masoud asgari2 1 department of pathology and laboratory medicine and department of dermatology, hofstra north shore-lij school of medicine, ny, usa 2 department of pathology and laboratory medicine, staten island university hospital, ny, usa keywords: papillary eccrine adenoma; adenocarcinoma in situ; aggressive digital papillary adenocarcinoma; eccrine gland; apocrine gland citation: chen s, asgari m. papillary adenocarcinoma in situ of the skin: report of four cases. dermatol pract concept. 2014;4(2):4. http:// dx.doi.org/10.5826/dpc.0402a04 received: september 26, 2013; accepted: january 7, 2013; published: april 30, 2014 copyright: ©2014 chen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sheng chen, m.d., ph.d., department of pathology and laboratory medicine, hofstra north shore-lij school of medicine, 6 ohio drive, suite 202, lake success, ny 11042, usa. tel. 516.304.7284; fax. 516.304.7270. email. schen@nshs.edu although rare isolated cases of adenocarcinoma in situ of skin have been reported in the literature, adenocarcinoma in situ of skin as a concept and as a diagnostic category has not been established in the field of dermatopathology. in this work, four cases of papillary adenocarcinoma in situ of the skin are presented. in addition, the notion that lesions previously reported in the medical literature under the term of “papillary eccrine adenoma” are actually adenocarcinoma in situ is discussed. abstract mailto:schen@nshs.edu 24 observation | dermatol pract concept 2014;4(2):4 the clinical summaries of the four cases are listed in table 1. results histopathologic and immunocytochemical features: by light microscopy, the tumors in all our cases consisted of circumscribed but not encapsulated intradermal proliferations of variously-sized tubules and ducts embedded in a sclerotic stroma (figures 1 and 2). many of them were lined by a double layer of cells. the outer layer composed of flattened myoepithelial cells. the inner cells were cuboidal to columnar and formed in most lumens papillary projections. squamous metaplasia was also noted in one case. cytologically, the cells showed mild to moderate nuclear atypia. mitotic figures and single cell necrosis were noted. an intact myoepithelial layer was evident on h&e-stained sections of all four cases and this was further confirmed by immunohistochemistry for p63, which was performed on two cases (cases 2 and 3), and revealed strong positive reaction in outer layer (figure 3a). ki-67 staining was performed on one case (case 3) and was positive in at least 30% of neoplastic cells (figure 3b). various diagnoses ranging from papillary eccrine adenoma, carcinoma in situ, and carcinoma were rendered by different pathologists or dermatopathologists (table 2). discussion since the introduction of the concept of carcinoma in situ in 1932 [1], although rare cases of adenocarcinoma in situ of the skin have been reported [2-6], adenocarcinoma in situ of the skin as a concept and as a diagnostic category has not been case 3 the patient was a 43-year-old male, who presented with a 1.4 cm lesion on his right index finger. the lesion was excised and reported as papillary eccrine carcinoma in situ. subsequently the patient requested a second opinion from two dermatopathologists from two separate institutions, who both interpreted the lesion as aggressive digital papillary adenocarcinoma. case 4 the patient was a 68-year-old female with 1.8 cm nodule in her right leg. the nodule was excised and interpreted as eccrine carcinoma in situ extending to surgical margin. reexcision was performed and showed focal residual tumor with negative surgical margin. one month earlier, the patient had right breast mastectomy with sentinel lymph node biopsy, which showed the presence of a 3.0 cm low-grade invasive ductal carcinoma with mucinous features in the breast. four sentinel lymph nodes were negative for tumor. two years later, the patient had radical right hemicolectomy for a 10.5 cm moderately to poorly differentiated adenocarcinoma of the cecum with 5/17 positive lymph nodes and liver metastasis. table 1. clinical summary of the four cases case age sex lesion location lesion size 1 82 female right 2nd toe 1.2 cm 2 47 female right leg 1.5 cm 3 43 male right index finger 1.4 cm 4 68 female right leg 1.8 cm figure 1. case 2, papillary adenocarcinoma in situ. (a) low power view showing a circumscribed lesion located in a fibrotic dermis (h&e, x20); (b) medium power view showing dilated ducts with prominent papillary projections (h&e, x100); (c) high power view showing clearly the presence of intact myoepithelial cell layer (h&e, x400). [copyright: ©2014 chen et al.] observation | dermatol pract concept 2014;4(2):4 25 malignancy (nuclear atypia, single cell necrosis and mitotic figures) with intact myoepithelial cell layer (no evidence of invasion), fulfilling the criteria for carcinoma in situ set forth by broder in 1932 [1]. if one employs the diagnostic criteria of breast pathology, these lesions are morphologically identical to the micropapillary type of ductal carcinoma in situ in the breast [10]. although these cases were variably interpreted as invasive adenocarcinoma, they are obviously not invasive adenocarcinoma because of the presence of an intact myoepithelial cell layer. the main reason they were interpreted as invasive adenocarcinoma is that cutaneous adenocarcinoma in situ has not been established as a diagnostic category or entity. when pathologists encounter these kinds of lesions, they would classify them either as adenoma or invasive adenocarcinoma. in 1973, panet-raymond and johnson described a very similar lesion under the term of adenocarcinoma of the eccrine sweat gland [11]. they reported a case of a 49-year-old man who had a slow growing tumor on his left forearm since childhood. the tumor rapidly began to grow and for this reason it was excised. the histopathologic features were deemed by the authors to be adenocarcinoma of the sweat gland. however, based on what the authors described and illustrated microscopically in their article, the lesion is identical to the cases presented here. they called it carcinoma “on the basis of nonencapsulation, areas of intracystic papillary projections, and the presence of hyperchromatic nuclei, a moderate number of mitoses and some atypical cells in these latter areas.” we believe that lesions reported under the term papillary eccrine adenoma are not adenoma but pacis. in 1977, rulon and helwig described an identical lesion but named it for the first time “papillary eccrine adenoma” [12]. they reported on 14 cases of distinctive cutaneous glandular established [7-9]. conceptually cases of adenocarcinoma in situ of skin must exist. the four cases presented here, in our opinion, are such examples. these lesions show cytological figure 2. case 3, papillary adenocarcinoma in situ. (a) low power view showing a lesion in a fibrotic dermis (h&e, x40); (b) medium power view showing prominent papillary structure formation (h&e, x 200); (c) high power view showing the presence of necrosis and peripheral myoepithelial cell layer (h&e, x400). [copyright: ©2014 chen et al.] figure 3. case 3, papillary adenocarcinoma in situ. immunocytochemical stain for p63 (a, x400) and ki67 (b, x400). p63 stain highlights the intact layer of myoepithelial cells. at least 30% of neoplastic cells are positive for ki67. [copyright: ©2014 chen et al.] 26 observation | dermatol pract concept 2014;4(2):4 in all the above examples, we think the confusion was due to unawareness of adenocarcinoma in situ as a concept and as one diagnostic category in the skin. in 2003, denianke and ackerman published an article and claimed that the so-called papillary eccrine adenoma is really apocrine papillary carcinoma [33]. although we agree with denianke and ackerman that the so-called papillary eccrine adenoma is not adenoma, namely, a benign glandular neoplasm, we believe for the reasons stated above that the lesion under discussion is best categorized as pacis, not carcinoma, which when used unmodified generally means invasive carcinoma. of note, our case 3 was interpreted as aggressive digital papillary adenocarcinoma by two dermatopathologists from two independent institutions. this is not surprising, since to our knowledge at least two similar cases, which were reported as aggressive digital papillary adenocarcinoma in the literature, are actually adenocarcinoma in situ in our opinion. one case appeared in an article published in 2006 by crowson et al [34]. the authors illustrated a case (figures 15 and 16 in the article) under the term digital papillary adenocarcinoma and commented that histopathologically the lesion was “cognate to that of ductal carcinoma in situ of the breast.” from the photomicrographs illustrated there, it appears that an intact peripheral myoepithelial cell layer was present, so we believe the case is actually adenocarcinoma in situ rather than digital papillary adenocarcinoma. the other case was presented in an article in 2010 by hsu et al [35]. the authors described an 8 mm nodule on the finger of a 28-year-old woman diagnosed as aggressive digital papillary adenocarcinoma. according to the authors, the lesion was excised with a positive margin, and there was no evidence of disease progression at the six-year follow-up. the photomicrographs of h&e and p63 stain provided by the authors for their case (figures 2 and 3 in the article) showed clearly the presence of an intact myoepithelial cell layer. this led us (m.a. and s.c.) to conclude that the lesion actually represented so-called papillary eccrine adenoma (pacis in neoplasm, which they stated, “were difficult to interpret and had been believed to occupy the gray zone separating benign and malignant neoplasms of the sweat glands. since none was found to have metastasized, this lesion is provisionally considered benign. the diagnostic term of papillary eccrine adenoma is suggested.” the lesions varied in size from 0.5 to 2.0 cm and could be found in any part of the skin including fingers and toes. histologically the lesions they described are very similar, if not identical, to the four cases described here in the present study. regarding treatment and nature of the lesions, rulon and helwig stated “surgical excision with assurance of complete removal by histologic examination of the surgical margins is considered the treatment of choice. the lesion is considered benign on the basis of available follow-up information.” as one can see, rulon and helwig considered the lesions benign, namely, papillary eccrine adenoma, based on no recurrence or metastases following complete surgical excision or digital amputation. however, this does not argue against the notion that the lesions were actually adenocarcinoma in situ, since carcinoma in situ would behave exactly the same way, namely, no recurrence or metastases following complete surgical excision. subsequent studies using the term papillary eccrine adenoma have been published by different authors, but the majority of them are single case reports or a small series of cases [13-30]. very few authors questioned the true nature of the lesion under discussion and most simply followed rulon and helwig and considered their own cases as adenomas. in 1987, urmacher and lieberman reported four cases using the term of papillary eccrine adenoma [31]. they did mention that three patients were seen prior to 1977 and diagnosed with sweat gland carcinoma. because the histology in all four cases was similar to what rulon and helwig described as papillary eccrine adenoma in 1977, they reassessed the diagnosis and described them with the term papillary eccrine adenoma. aloi and pich admitted difficulty in differentiating between papillary eccrine adenoma and low-grade sweat gland carcinoma [32]. table 2. diagnoses offered by different pathology/dermatopathology consultants case 1st opinion 2nd opinion 3rd opinion 1 sweat duct carcinoma (by dermatopathologist) papillary eccrine adenoma (by dermatopathologist) not applicable 2 adenocarcinoma (by pathologist) not applicable not applicable 3 papillary eccrine carcinoma in situ (by dermatopathologist) aggressive digital papillary adenocarcnioma (by dermatopathologist) aggressive digital papillary adenocarcnioma (by dermatopathologist) 4 eccrine carcinoma in situ (by dermatopathologist) not applicable not applicable observation | dermatol pract concept 2014;4(2):4 27 9. elder d, elenitsas r, johnson jr bl, et al. lever’s histopathology of the skin. 9th ed. philadelphia: lippincott williams & wilkins, 2005. 10. rosen pp. rosen’s breast pathology. 3rd ed. philadelphia: lippincott williams & wilkins, 2009. 11. panet-raymond g, johnson wc. adenocarcinoma of the eccrine sweat gland. arch dermatol. 1973;107:94-6. 12. rulon db, helwig eb. papillary eccrine adenoma. arch dermatol. 1977;113:596-8. 13. elpern dj, farmer er. papillary eccrine adenoma. arch dermatol. 1978;114:1241. 14. sina b, dilaimy m, kallayee d. papillary eccrine adenoma. arch dermatol. 1980;116:719-20. 15. white sw, rodman og. papillary eccrine adenoma. natl med assoc. 1982;74:573-6. 16. cooper ph, frierson hf. papillary eccrine adenoma. arch pathol lab med. 1984;108:55-7. 17. falck vg, jordaan hf. papillary eccrine adenoma. a tubulopapillary hidradenoma with eccrine differentiation. am j dermatopathol. 1986;8:64-72. 18. kanitakis j, hermier c, thivolet j. papillary eccrine adenoma. am j dermatopathol. 1988;10:180-2. 19. sexton m, maize jc. papillary eccrine adenoma. a light microscopic and immunohistochemical study. j am acad dermatol. 1988;18:1114-20. 20. tellechea o, truchetet f, grosshans e. papillary eccrine adenoma [portuguese]. med cutan ibero lat am. 1989;17:85-91. 21. jerasutus s, suvanprakorn p, wongchinchai m. papillary eccrine adenoma: an electron microscopic study. j am acad dermatol. 1989;20:1111-4. 22. hashimoto k, kato i, taniguchi y, et al. papillary eccrine adenoma. immunohistochemical and ultrastructural analyses. j dermatol sci. 1990;1:65-71. 23. requena l, peña m, sánchez m, sánchez yus e. papillary eccrine adenoma—a light-microscopic and immunohistochemical study. clin exp dermatol. 1990;15:425-8. 24. megahed m, hölzle e. papillary eccrine adenoma. a case report with immunohistochemical examination. am j dermatopathol. 1993;15:150-5. 25. biernat w, kordek r, woźniak l. papillary eccrine adenoma—a case of cutaneous sweat gland tumor with secretory and ductular differentiation. pol j pathol. 1994;45:319-22. 26. mizuoka h, senzaki h, shikata n, uemura y, tsubura a. papillary eccrine adenoma: immunohistochemical study and literature review. j cutan pathol. 1998;25:59-64. 27. guccion jg, patterson rh, nayar r, saini nb. papillary eccrine adenoma: an ultrastructural and immunohistochemical study. ultrastruct pathol. 1998;22:263-9. 28. kurtz dh, finnell ja, mehler as. papillary eccrine adenoma of the heel: a case report. j foot ankle surg. 2000;39:249-52. 29. blasini w, hu s, gugic d, vincek v. papillary eccrine adenoma in association with cutaneous horn. am j clin dermatol. 2007;8:179-82. 30. laxmisha c, thappa dm, jayanthi s. papillary eccrine adenoma. indian j dermatol venereol leprol. 2004;70:370-2. 31. urmacher c, lieberman ph. papillary eccrine adenoma. lightmicroscopic, histochemical, and immunohistochemical studies. am j dermatopathol. 1987;9:243-9. 32. aloi f, pich a. papillary eccrine adenoma. a histopathological and immunohistochemical study. dermatologica. 1991;182:47-51. our current opinion, see above) misinterpreted as aggressive digital papillary adenocarcinoma [36]. of interest, in a recent book published in 2012 titled cutaneous adnexal tumors by kazakov et al., in the pages regarding digital papillary adenocarcinoma the existence of adenocarcinoma in situ is mentioned briefly in these words: “in several cases, the authors have noticed that a constant feature is the presence of a recognizable myoepithelial cell layer around the glands and sometimes at the peripheral of the cystic-papillary areas. invasion into the stroma is sometimes seen and no myoepithelial cells are present in the invasive foci. on the contrary, the authors have encountered a case in which the whole lesion was endowed with a peripheral myoepithelial cell layer consistent with the concept of carcinoma in situ” [37]. in our opinion, this is probably the first time adenocarcinoma in situ was ever mentioned in the acral location. is pacis eccrine or apocrine origin? rulon and helwig thought it of eccrine origin [12], while denianke and ackerman of apocrine origin [33]. other authors pointed out a bimodal differentiation, to wit, originating from both apocrine and eccrine (apoeccrine) origin [38]. we believe that pacis can derive from eccrine as well as apocrine glands. currently there are no reliable histological or immunocytochemical features that can distinguish it for sure. for practical purposes, there is really no need to distinguish them. it does not matter clinically whether it is of eccrine or apocrine origin. it should be treated the same way, namely, simple complete but conservative excision. thus, we would suggest using the term pacis without using either of the modifiers eccrine or apocrine. references 1. broders ac. carcinoma in situ contrasted with benign penetrating epithelium. jama. 1932;99(20):1670-4. 2. castro cy, deavers m. ductal carcinoma in-situ arising in mammary-like glands of the vulva. int j pathol. 2001;20:277-83. 3. castelli e, wollina u, anzarone a, et al. extramammary paget disease of the axilla associated with comedo-like apocrine carcinoma in situ. am j dermatopathol. 2002;24:351-7. 4. obaidat na, awamleh aa, ghazarian dm. adenocarcinoma in situ arising in a tubulopapillary apocrine hidradenoma of the peri-anal region. eur j dermatol. 2006;16:576-8. 5. shah ss, adelson m, mazur mt. adenocarcinoma in situ arising in vulvar papillary hidradenoma: report of 2 cases. int j gynecol pathol. 2008;27:453-6. 6. weinreb i, bergfeld wf, patel rm, ghazarian dm. apocrine carcinoma in situ of sweat duct origin. am j surg pathol. 2009;33:155-7. 7. leboit pe, burg g, weedon d, et al. pathology and genetics of skin tumours (iarc who classification of tumours). lyon: iarcpress, 2006. 8. weedon d. skin pathology. 8th ed. new york: elsevier, 2010. http://www.ncbi.nlm.nih.gov/pubmed/677931 28 observation | dermatol pract concept 2014;4(2):4 37. kazakov dv, michal m, kacerovska d, et al. cutaneous adnexal tumors. philadelphia: lippincott williams & wilkins, 2012: 95-99. 38. fox sb, cotton dw. tubular apocrine adenoma and papillary eccrine adenoma. entities or unity? am j dermatopathol. 1992;14:149-54. 33. denianke k, ackerman ab, the issue of eccrine versus apocrine differentiation of cutaneous neoplasms affiliated with tubules, dermatopatholology: practical & conceptual. 2003;9(4). 34. crowson an, magro cm, mihm mc. malignant adnexal neoplasms. mod pathol. 2006; suppl 2:s93-126. 35. hsu hc, ho cy, chen ch, et al. aggressive digital papillary adenocarcinoma: a review. clin exp dermatol. 2010;35:113–9. 36. asgari m, chen s. papillary eccrine adenoma should not be mistaken for aggressive digital papillary adenocarcinoma. clin exp dermatol. 2014;39:223-4. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023105 1 effect of histopathological explanations for dermoscopic criteria on learning curves in skin cancer training: a randomized controlled trial niels kvorning ternov1, martin tolsgaard2,3, lars konge2,3, anders nymark christensen4, sigrid isabella pilgaard kristensen1, lisbet rosenkrantz hölmich1,2, jonathan stretch5,6, richard anthony scolyer5,6,7,8, tine vestergaard9, pascale guitera5,6,10, annette hougaard chakera1,2 1 department of plastic surgery, copenhagen university hospital, herlev and gentofte, copenhagen, denmark 2 department of clinical medicine, university of copenhagen, copenhagen, denmark 3 copenhagen academy for medical education and simulation, rigshospitalet, copenhagen, denmark 4 department of applied mathematics and computer science, technical university of denmark, kongens lyngby, denmark 5 melanoma institute australia, the university of sydney, sydney, new south wales, australia 6 faculty of medicine and health, the university of sydney, sydney, new south wales, australia 7 tissue pathology and diagnostic oncology, royal prince alfred hospital and new south wales health pathology, sydney, new south wales, australia 8 charles perkins centre, the university of sydney, sydney, new south wales, australia 9 department of dermatology and allergy center, odense university hospital, denmark 10 the sydney melanoma diagnosis centre, royal prince alfred hospital, sidney, australia key words: education, melanoma, pigmented lesions, dermatopathology, carcinoma citation: kvorning ternov n, tolsgaard m, konge l, et al. effect of histopathological explanations for dermoscopic criteria on learning curves in skin cancer training: a randomized controlled trial. dermatol pract concept. 2023;13(2):e2023105. doi: https://doi .org/10.5826/dpc.1302a105 accepted: october 20, 2022; published: april 2023 copyright: ©2023 kvorning ternov et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: nkt is ceo and co-founder of the start-up melatech aps that developed the educational mobile application used in this trial. ras has received fees for professional services from f. hoffmann-la roche lt d, evaxion, provectus biopharmaceuticals australia, qbiotics, novartis, merck sharp & dohme, neracare, amgen inc., bristol-myers squibb, myriad genetics, glaxosmithkline. authorship: all authors have contributed significantly to this publication. corresponding author: niels kvorning ternov, dep. of plastic surgery, herlev and gentofte university hospital, borgmester ib juuls vej 1, 2370 herlev, denmark. e-mail: niels.kvorning.ternov@regionh.dk introduction: case-based training improves novices pattern recognition and diagnostic accuracy in skin cancer diagnostics. however, it is unclear how pattern recognition is best taught in conjunction with the knowledge needed to justify a diagnosis. objectives: the aim of this study was to examine whether an explanation of the underlying histopathological reason for dermoscopic criteria improves skill acquisition and retention during case-based training in skin cancer diagnostics. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023105 introduction skin cancer is the most common malignancy among fair-skinned people worldwide [1,2]. early detection and treatment of skin cancers reduce patient mortality and the associated socioeconomic costs [3]. in most countries, skin cancer triage is performed by personnel without standardized training in the domain [4,5]. courses that teach structured checklists for skin cancer diagnostics such as the abcd (asymmetry, borders, colour, and diameter) algorithm improve novices short-term accuracy, but frequent refresher courses are needed to maintain the skill [6,7]. it is unclear if the training effect is caused by the structured checklists or the simultaneous exposure to many skin lesion images. a cochrane review recently stated that structured checklists do not improve clinicians accuracy in skin cancer diagnostics [8]. case-based training improves novices accuracies in skin cancer diagnostics significantly more than structured checklist practice [9-11]. exposure to annotated skin lesion images improves novices pattern recognition, which is the primary diagnostic strategy of experts [12-14]. it is unclear how pattern recognition and the declarative knowledge needed to justify a diagnosis, are best taught in conjunction. related work from odontology suggests that teaching the underlying biomedical reason for visual criteria improves the students ability to recognize and remember the criteria [15,16]. objectives this study investigated a novel approach towards teaching skin cancer diagnostics through a mobile educational application. our primary objective was to examine whether an explanation of the underlying histopathological reason for the dermoscopic criteria used in skin cancer diagnostics affects medical students’ learning curves and skill retention. we hypothesized that a deeper biomedical understanding of the dermoscopic criteria would improve the students’ ability to recognize and remember them. methods in this double-blinded randomized controlled trial (allocation ratio 1:1), we enrolled medical students with no prior experience in skin cancer diagnostics that had previously passed an exam in general histology. the students were invited to participate through a facebook group for danish medical students. participants were enrolled through virtual meetings between the 8th and 27th of july 2021. during inclusion, we helped participants download and get started in the educational application (onboarding process). participants were automatically and randomly (simple randomization) assigned to the intervention or control group during the onboarding process. the principal investigator (n.k.t.), a student assistant (s.k.), and participants were all blinded towards trial group allocation. following the onboarding process, all participants underwent a pre-test and were instructed to diagnose 500 skin lesion cases (including the pre-test cases) over 8 days (training phase), pause for 14 days (washout phase 1), diagnose another 100 cases in 2 days (retention phase), pause for another 7 days (washout phase 2), and finally, complete a retention test (figure 1). all participants received daily reminders during the training and retention phases, and those that completed the entire study received a certificate of completion. during the training and retention phase, participants had access to written learning modules that described the most common skin lesion diagnoses. the learning modules included a dermoscopy subsection that differed between the trial groups. participants in the control group saw a brief description of the dermoscopic criteria, while the intervention group saw the same description supplemented with a histopathological explanation (figure 2). neither group were informed about the group-dependent learning module differences. we planned and conducted the study per the principles of the declaration of helsinki. participants were informed about the study before participation and gave informed consent. the study was voluntary, held no consequences for the participants, and received a waiver from the regional ethics committee methods: in this double-blinded randomized controlled trial, medical students underwent eight days of case-based training in skin cancer diagnostics, which included access to written diagnosis modules. the modules dermoscopic subsections differed between the study groups. all participants received a general description of the criteria, but the intervention group additionally received a histopathological explanation. results: most participants (78%) passed a reliable test in skin cancer diagnostics, following a mean training time of 217 minutes. access to histopathological explanations did not affect participants’ learning curves or skill retention. conclusions: the histopathological explanation did not affect the students, but the overall educational approach was efficient and scalable. original article | dermatol pract concept. 2023;13(2):e2023105 3 figure 1. trial flow. participants performed a pre-test (12 cases) at the beginning and a retention test (25 cases) at the end of the trial. during the training and retention phases, each participant practiced skin lesion diagnostics on 500 (including the pre-test cases) and 100 training cases, respectively, while accessing the learning modules of their own accord. we instructed participants to abstain from any training during both washout phases. figure 2. educational intervention (mobile application). the educational intervention consisted of an educational mobile application that included quizzes and written learning modules. the red circles within the figure indicate where users “press” the mobile screen to proceed towards the next screen, indicated by the red arrow. the “quiz feature” presents skin lesions for diagnostics. the small images representing the clinical image (a) and the avatar (b) are buttons that open the clinical image and 3d avatar. when users press “benign” (c) or “malignant”, an array of new buttons representing the various benign or malignant differential diagnoses appear. when users press one of the diagnosis buttons (d), they receive immediate feedback. the feedback consists of the chosen diagnosis, the correct diagnosis, and access to learning modules on both the chosen and correct diagnoses (e). each learning module consists of the following sections: introduction, pathology, clinical presentation, dermoscopy, differential diagnoses, and references. the dermoscopy sections included an overview and subsections describing the primary dermoscopic criteria. each subsection included a detailed description of the dermoscopic criterium (f). users from both trial groups received descriptions and annotated images representing the dermoscopic criteria. however, the subsections presented to the intervention group participants also explained the underlying histopathological correlation for the dermoscopic criteria. when the learning modules in the application are closed (g), users return to the previous training case feedback page. 4 original article | dermatol pract concept. 2023;13(2):e2023105 participants received immediate feedback on their quiz diagnoses, including the correct diagnosis and access to the aforementioned learning modules. time spent reading the learning modules and diagnosing the quiz cases were automatically registered throughout the study. preand retention test the preand retention tests consisted of skin lesion cases from a test item library with validity evidence previously described by our group [4]. the pre-test consisted of 12 randomly sampled test items (generalizability coefficient of 0.7), while the retention test included all 25 test items (cronbach α of 0.83). a former pass-fail test revealed a pass-fail limit of twelve, ie a score above 12/25 is enough to pass the test [4]. statistics data was divided into a training (0-500 cases) and a retention phase (501-600 cases). a mixed-effects logistic regression model with correct or false case-answers as an outcome and a random intercept and slope for each individual was applied to estimate the learning curves on the log-odds scale. we sought the most straightforward description of the participants learning curves by comparing (likelihood-ratio tests) cubic and linear spline models with four, one, or zero knots. the retention phase data were described using a simple line. once we had located the optimal statistical equation for describing the training phase, we compared the control and intervention groups training and retention learning curves using likelihood-ratio tests. the control group retention test results were compared to those of the intervention group using the welch t-test. for exploratory post hoc analyses, we used the participants test scores on the retention test to divided them into three equally big performance groups; low (1st tertile), intermediate(2nd tertile) and high(3rd tertile) performance. we compared the learning curves, time spent reading, and time spent diagnosing training cases between the 1st and 3rd tertile using likelihood ratio tests and welch t-tests. all statistical analyses were performed in r version 4.1.0 (r foundation for statistical computing). results eighty-seven medical students were enrolled, and 76 completed the entire trial, see the consort diagram in figure 3. retention test results on the retention test were equal (t= 0.13, degrees of freedom (df) = 71.3, p = 0.90) for the intervention (mean: 13.8, sd: 3.06) and control (mean: 13.9, sd: 3.35) groups. fifty-nine (78%) out of the 76 participants passed the retention test (>12/25 correct answers). the 76 participants of region hovedstaden, denmark (jr nr. h-20066667). the danish health data authorities and data protection agency approved access, anonymization, handling, and storage of the skin lesion cases (jr. nr. 21/5103 and 18/53664). we submitted a study protocol on clinicaltrial.gov prior to initiating the study (identifier: nct05087485). skin lesions library we developed a case library consisting of 2,376 anonymous skin lesions for this study. each lesion belonged to one of the following seven diagnostic groups: nevus, seborrheic keratosis/solar lentigo, dermatofibroma, hemangioma, melanoma, basal cell carcinoma, and squamous cell carcinoma. each case included a clinical and dermoscopic image of the lesion, the lesion location on a human 3d avatar, a diagnosis, and the patient age and gender. the lesions diagnoses were based on either a histopathological assessment (n = 1,293) or a clinical consensus (n = 1,083), consisting of a joint judgment by 2-3 clinicians. all images were captured by nurses and doctors at the department of dermatology and allergy centre, odense university hospital, in denmark, from the 1st of september 2010 until the 8th of may 2021. dermoscopic images were photographed using digital dermoscopes ( medicam 800 and 1000, fotofinder systems gmbh). written learning modules the mobile application’s written content consisted of 38 diagnosis (eg melanoma) and sub-diagnosis learning modules (eg superficial spreading melanoma). each sub-diagnosis module included the following subsections: introduction, pathology, clinical presentation, dermoscopy, differential diagnoses, and references (figure 2). we created two versions of each dermoscopic sub-section; one described the dermoscopic criteria with annotated images (control group), and another version that additionally explained the histopathological correlation for each dermoscopic criterion (intervention group) (figure  2). all diagnosis and sub-diagnosis modules were written by the first author (n.t.) and reviewed by content experts in pathology, dermatology, and skin cancer surgery (co-authors: a.c., p.g., t.v., r.s., l.h., and j.s.). mobile application in this study, we employed a mobile application for training skin lesion diagnostics, called dermloop learn (melatech aps), developed in cooperation with our group (figure 2). a continuously updated version of the application can be accessed online (https://training.dermloop.io/) or through the app store (“dermloop learn”). the application included three functionalities: skin lesion quizzes, written learning modules, and user tracking. each quiz consisted of ten randomly sampled skin lesion cases from the case library. original article | dermatol pract concept. 2023;13(2):e2023105 5 intervention and control groups (training phase: χ2= 0.35, df = 2, p = 0.83, retention phase: χ2=0.94, df = 1, p = 0.33). the learning curves of the intervention and control group participants were also equal within the lowand high-performance groups (training phase: χ2= 0.80, df = 2, p = 0.67, retention phase: χ2=0.15, df = 1, p = 0.70). however, there was a significant difference between the overall (intervention + control) learning curves of the lowversus high-performance groups, (training phase: χ2= 25.71, df = 1, p = <0.01, retention phase: χ2=15.29, df = 1, p < 0.01). the mean time spent training was 217 minutes, 117  minutes diagnosing training cases, and 100 minutes reading the learning modules. there was no difference in time spent diagnosing cases (t= -0.03, df = 51.9, p = 0.98) or reading (t= -0.02, df = 73.9, p = 0.98) between the intervention and control participants. the high-performance who completed the retention test were split into low-, intermediate-, and high-performance groups (n = 25, 25, and 26) based on their test results. intervention and control participants were equally distributed across the low (n = 14/11) and high-performance (n = 14/12) groups. learning curves and time spent training an almost straight line with a single knot, ie breaking point, at 100 cases provided a significantly better data-fit for the training phase than a straight line without knots (χ2= 125.0, df = 2, p = <0.01). there was no added benefit from adding three additional knots at 200, 300, and 400 training cases (χ2= 7.5, df = 6, p = 0.28), or performing a cubic transformation (χ2= 4.3, df = 4, p = 0.37) (figure 4). there were no significant learning curve differences in the training or retention phase, when comparing the assessed for eligibility (n=87) excluded (n= 0) randomized (n= 87) fallout (n=2) fallout (n=3) training phase (n=42) fallout (n= 1) retention phase (n=41) fallout (n= 1) retention test (n= 40) part of the intended program (n=42) participants with data for analysis of: -learning curves (n=42) -t-test retention test (n=40) -time used reading and practicing (n= 40) part of the intended program (n= 40) participants with data for analysis of: -learning curves (n=40) -t-test retention test (n= 36) -time used reading and practicing (n= 36) retention test (n= 36) fallout (n= 0) retention phase (n= 36) fallout (n=4) training phase (n= 40) intervention group (n=44) (description of criteria + histopathological explanations) -male (n=9) -female (n= 35) control group (n= 43) (description of criteria) -male (n= 8) -female (n= 35) figure 3. consort diagram. 6 original article | dermatol pract concept. 2023;13(2):e2023105 (78%), irrespective of trial groups, passed a reliable test in skin cancer diagnostics, following a mean training time of 217 minutes. access to explanations of the histopathological correlation for dermoscopic criteria did not affect participants learning curves or skill retention. the rapid diagnostic improvement observed in this study resonates with former studies on case-based pattern recognition training for skin cancer diagnostics [9,10]. this proposed model for teaching complex visual diagnostics could potentially democratize skin cancer diagnostics. primary care providers, nurses, and medical students can be educated in mass, improving access to high-quality skin cancer triage group spent the same amount of time reading (t= 0.13, df = 30.5, p = 0.90) and significantly more time diagnosing the training cases (t=-3.8, df = 43.8, p = <0.001) compared to the low-performance group (table 1). participants spent 40% of their training time on the first 100 cases (mean: 93.8 min) and the remaining time on the last 500 cases (mean: 146.8 min). conclusions this study explored a novel approach towards digital training in skin cancer diagnostics. the vast majority of participants simple line es ti m a te d p r o b a b il it y o f c o r r ec t a n sw er number of completed cases 0 0. 2 0. 3 0. 4 0. 5 0. 6 a 100 200 300 400 500 control intervention spline with 4 knots knots 1 c knots 2 knots 3 knots 4 control intervention 0 0. 2 0. 3 0. 4 0. 5 0. 6 100 200 300 400 500 es ti m a te d p r o b a b il it y o f c o r r ec t a n sw er number of completed cases spline with 1 knot knot 1 0 0. 2 0. 3 0. 4 0. 5 0. 6 b 100 200 300 400 500 control intervention es ti m a te d p r o b a b il it y o f c o r r ec t a n sw er number of completed cases cubic spline es ti m a te d p r o b a b il it y o f c o r r ec t a n sw er number of completed cases 0 0. 2 0. 3 0. 4 0. 5 0. 6 d 100 200 300 400 500 control intervention figure 4. learning curve models for the training phase. the figure depicts the various statistical equations applied to the data. red dashed, and solid black lines represent the intervention and control groups, respectively. (b) an almost straight line with one knot provided a simple yet reliable fit for the data. (c,d) increasing the complexity of the model by introducing additional knots (c) or a cubic function (d) did not provide any additional value compared to model b. table 1. time spent training within the mobile application. activity time spent reading (min) time spent diagnosing training cases (min) group intervention control 1st tertile 3rd tertile intervention control 1st tertile 3rd tertile mean 100.7 100.1 94.7 90.4 117.1 116.6 80.9 124.5 sd 121.9 105.7 150.1 56.6 49.2 93 32.2 48.4 min = minutes; sd = standard deviation. time spent reading learning modules and diagnosing training cases among the participants within both study groups (intervention, control) and performance groups (1st and 3rd tertile). the 1st and 3rd tertile groups consist of the 33% participants with the lowest and highest performance on the retention test. original article | dermatol pract concept. 2023;13(2):e2023105 7 postpone the deceleration of learning curves, further discussed below. during post hoc analyses, we found that high-performers were more accurate than the low-performers throughout the study. high-performers were more accurate than low-performers already at the beginning of the trial, despite all participants being supposedly equally inexperienced. these findings suggest that some participants were dishonest about their expertise during inclusion or possessed a superior innate diagnostic accuracy. regardless of the difference in diagnostic accuracy, both groups maintained parallel learning curves throughout the trial. in theory, the accuracy of low-performers should have increased faster than it did for the high-performers. it is significantly more challenging to increase one’s diagnostic accuracy when it is high compared to low [21]. high-performers likely had a more efficient and intentional learning strategy throughout the trial. this hypothesis is supported by the fact that high-performers spent 35% more time diagnosing training and reducing some of the current inequality in melanoma mortality [17,18]. improved competencies could also pave the way for clinical implementation diagnostic artificial intelligence, providing a human safeguard against the algorithms erroneous predictions and inherent biases [19]. according to the “deliberate practice framework” for teaching diagnostics, novice learners need assistance from a domain expert, as they lack the competencies needed to identify and address their knowledge gaps [20]. a synthetic algorithm-driven domain expert could, in theory, be developed and integrated as a digital mentor within learning interventions such as the one used in this study. a digital mentor could be taught how to identify a students learning pattern, weaknesses, and strengths based on prior students training data. the identified patterns could then be used to select and present the instructional material (cases, modules) most likely to increase the student competencies at any given time. such individualized approaches could potentially reduce the observed difference between lowand high-performers and learning curves training phase washout period (14 days) number of completed cases es ti m a te d p r o b a b il iy o f c o r r ec t a n sw er s 0 0,2 0,3 0,4 0,5 0,6 0,25 0,35 0,45 0,55 100 200 300 400 500 600 total intervention total control low intervention low control high intervention high control retention phase figure 5. learning curves during the training and retention phases. the diagram depicts the learning curves for the entire group (intervention: dark blue, control: red), the high-performance group (intervention: light blue, control: orange), and the low-performance group (intervention: green, control: purple). 8 original article | dermatol pract concept. 2023;13(2):e2023105 explanations for dermoscopic criteria did not affect the students knowledge acquisition and retention. acknowledgments: we wish to extend a special thanks to assistant professor morten hannemose and statistician søren grimstrup for their statistical assistance. references 1. lomas a, leonardi-bee j, bath-hextall f. a systematic review of worldwide incidence of nonmelanoma skin cancer. br j dermatol. 2012;166(5):1069-1080. doi: 10.1111/j.13652133.2012.10830.x. pmid: 22251204. 2. whiteman dc, green ac, olsen cm. the growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. j invest dermatol. 2016;136(6):1161-1171. doi: 10.1016/j. jid.2016.01.035. pmid: 26902923. 3. petrie t, samatham r, witkowski am, esteva a, leachman sa. melanoma early detection: big data, bigger picture. j invest dermatol. 2019;139(1):25-30. doi: 10.1016/j.jid.2018.06.187. pmid: 30482597. pmcid: pmc6685706. 4. ternov nk, vestergaard t, hölmich lr, et al. reliable test of clinicians’ mastery in skin cancer diagnostics. arch dermatol res. 2021;313(4):235-243. doi: 10.1007/s00403-020-02097-8. pmid: 32596742. 5. tschandl p, codella n, akay bn, et al. comparison of the accuracy of human readers versus machine-learning algorithms for pigmented skin lesion classification: an open, web-based, international, diagnostic study. lancet oncol. 2019;20(7):938-947. doi: 10.1016/s1470-2045(19)30333-x. pmid: 31201137. pmcid: pmc8237239. 6. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin. 1985;35(3):130151. doi: 10.3322/canjclin.35.3.130. pmid: 3921200. 7. hharkemanne e, baeck m, tromme i. training general practitioners in melanoma diagnosis: a scoping review of the literature. bmj open. 2021;11(3):e043926. doi: 10.1136/bmjopen-2020-043926. pmid: 33757946. pmcid: pmc7993310. 8. dinnes j, deeks jj, chuchu n, et al. dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. cochrane database syst rev. 2018;12(12):cd011902. doi: 10.1002/14651858.cd011902.pub2. pmid: 30521682. pmcid: pmc6517096. 9. speelman c, martin k, flower s, simpson t. skill acquisition in skin cancer detection. percept mot skills. 2010;110(1):277-297. doi: 10.2466/pms.110.1.277-297. pmid: 20391892. 10. lacy fa, coman gc, holliday ac, kolodney ms. assessment of smartphone application for teaching intuitive visual diagnosis of melanoma. jama dermatol. 2018;154(6):730-731. doi: 10.1001/jamadermatol.2018.1525. pmid: 29799954. pmcid: pmc6145647. 11. monteiro sm, norman g. diagnostic reasoning: where we’ve been, where we’re going. teach learn med. 2013;25 suppl 1:s26-s32. doi: 10.1080/10401334.2013.842911. pmid: 24246103. 12. norman gr, rosenthal d, brooks lr, allen sw, muzzin lj. the development of expertise in dermatology. arch dermatol. 1989;125(8):1063-1068. pmid: 2757402. cases than low-performers. learning curves decelerated following the first 100 training cases, possibly due to a faltering engagement, poor clinical contextualization, or a plateau in the trainees ability to recognize and mitigate their diagnostic errors. on average, each participant spent almost the same amount of time (40% of total time) diagnosing and reviewing the first 100 training cases as they did on the remaining 500 cases. this indicates that they shifted from a slow but actively engaged learning strategy towards a faster trial-and-error strategy that yielded a significantly worse outcome [22,23]. educational engagement is strongly associated with internal and external motivation [24]. the academic curiosity, which was the sole motivation of the trial participants, may have faltered following 100 training cases, resulting in the learning curve deceleration. adopting new clinical skills and knowledge becomes easier if the trainee has former clinical experience within the given domain, possibly because it is easier to conceptualize the clinical relevance of the skills being taught [22,25]. participants in this trial had no former clinical experience, potentially impeding their ability to contextualize and acquire complex skills in visual diagnostics. finally, the deceleration may have been caused by a plateau in the participants ability to analyze and address their knowledge gaps, ie failure of metacognition [26]. additional studies, such as think-aloud verbal protocol studies, are needed to further our understanding of the low versus high-performers learning strategies [27,28]. during think-aloud verbal protocol studies, participants are asked to perform a task and “think aloud” while being recorded. the thought processes are later deconstructed by a trained observer and converted into standardized code blocks prior to statistical analyses. our study has several limitations. first, we did not collect data on which subsections of the learning modules participants had read during the trial, limiting our ability to perform sub-analyses on the effect of the histopathological explanations. secondly, the retention test is a proxy rather than an accurate measure of clinical skills. finally, it is unclear whether our results can be reproduced among clinicians. thirdly, domain experience generally increases a student ability to contextualize knowledge, and we theorize that our results would have been more pronounced among clinicians compared to medical students. finally, several factors such as the participants general interest, motivation, and social or cultural status may have introduced biases in our results. this study describes an efficient and scalable approach towards teaching pattern recognition in skin cancer diagnostics. we investigated the learning curves of medical students and found a deceleration following approximately 100 training cases and a continuous and stable superiority among the upper compared to lower tertile. access to histopathological original article | dermatol pract concept. 2023;13(2):e2023105 9 13. norman gr, coblentz cl, brooks lr, babcook cj. expertise in visual diagnosis: a review of the literature. acad med. 1992;67(10 suppl):s78-s83. doi: 10.1097/00001888-199210000-00045. pmid: 1388563. 14. yoon js, boutis k, pecaric mr, fefferman nr, ericsson ka, pusic mv. a think-aloud study to inform the design of radiograph interpretation practice. adv health sci educ theory pract. 2020;25(4):877-903. doi: 10.1007/s10459-020-09963-0. pmid: 32140874. pmcid: pmc7471179. 15. baghdady mt, pharoah mj, regehr g, lam ew, woods nn. the role of basic sciences in diagnostic oral radiology. j dent educ. 2009;73(10):1187-1193. pmid: 19805783. 16. baghdady mt, carnahan h, lam ew, woods nn. integration of basic sciences and clinical sciences in oral radiology education for dental students. j dent educ. 2013;77(6):757-763. pmid: 23740912. 17. harvey vm, patel h, sandhu s, wallington sf, hinds g. social determinants of racial and ethnic disparities in cutaneous melanoma outcomes. cancer control. 2014;21(4):343-349. doi: 10.1177/107327481402100411. pmid: 25310216. pmcid: pmc4505912. 18. ibfelt eh, steding-jessen m, dalton so, lundstrøm sl, osler m, hölmich lr. influence of socioeconomic factors and region of residence on cancer stage of malignant melanoma: a danish nationwide population-based study. clin epidemiol. 2018;10:799-807. doi: 10.2147/clep.s160357. pmid: 30022857. pmcid: pmc6044336. 19. tschandl p, rinner c, apalla z, et al. human-computer collaboration for skin cancer recognition. nat med. 2020;26(8):12291234. doi: 10.1038/s41591-020-0942-0. pmid: 32572267. 20. ericsson ka. acquisition and maintenance of medical expertise: a perspective from the expert-performance approach with deliberate practice. acad med. 2015;90(11):1471-1486. doi: 10.1097/acm.0000000000000939. pmid: 26375267. 21. loerch ag. learning curves. in: gass, s.i., fu, m.c. (eds) encyclopedia of operations research and management science. springer, boston, ma. 2013 doi: 10.1007/978-1-4419-1153-7_526 22. schwartz d, bransford j, sears d. efficiency and innovation in transfer. in j. mestre (ed.), transfer of learning from a modern multidisciplinary perspective. greenwich, ct: information age publishing. 2005:1-51. 23. davis jm, leelawong k, belynne k, ret al. intelligent user interface design for teachable agent systems. international conference on intelligent user interfaces. miami, florida, the association for computing machinery. 2003:26-33. 24. cook da, artino ar jr. motivation to learn: an overview of contemporary theories. med educ. 2016;50(10):997-1014. doi: 10.1111/medu.13074. pmid: 27628718. pmcid: pmc5113774. 25. andreasen la, tabor a, nørgaard ln, ret al. multicenter randomized trial exploring effects of simulation-based ultrasound training on obstetricians’ diagnostic accuracy: value for experienced operators. ultrasound obstet gynecol. 2020;55(4):523-529. doi: 10.1002/uog.20362. pmid: 31152560. 26. flavell jh (1979). metacognition and cognitive monitoring: a new area of cognitive–developmental inquiry. american psychologist. 1979;34(10): 906–911. doi: 10.1037/0003-066x.34.10.906 27. ericsson ka, simon ha. protocol analysis: verbal reports as data. 1993. doi:10.7551/mitpress/5657.001.0001. 28. fox mc, ericsson ka, best r. do procedures for verbal reporting of thinking have to be reactive? a meta-analysis and recommendations for best reporting methods. psychol bull. 10 original article | dermatol pract concept. 2023;13(2):e2023105 2011;137(2):316-344. doi: 10.1037/a0021663. pmid: 21090887. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022150 1 objectives: to evaluate clinical chart of patients with ih who had cardiologic evaluation before propranolol therapy and to compare our findings with literature data. introduction: some studies have assessed the incidence of heart defects in children suffering from infantile hemangioma (ih) treated with propranolol, showing a possible higher prevalence of cardiac abnormalities in this group of patients. methods: we retrospectively reviewed clinical charts of children with infantile hemangiomas referred to our dermatologic division from 2016 to 2021, who underwent our pediatric cardiology protocol screening before starting propranolol therapy. results: a total of 60 infants were enrolled. electrocardiograms were available for all the patients and echocardiography for 50/60 (83.3%) children. electrocardiogram didn’t reveal any alterations in most cases (pathologic in 2/60 ones, 3.3%) while echocardiograms revealed findings in 31/50 (51.7%) patients. of these, persistent foramenovale, which was found in 14/50 patients (28%), was considered as non-pathologic. interatrial septal defects were the main pathological finding in 15/50 patients (30%), as single defect or in association with other abnormalities. conclusions:  our study confirms the presence of a higher rate of cardiologic findings in patients with infantile hemangioma evaluated before starting oral propranolol, compared to the known rate of those defects in healthy newborns. we also confirm that interatrial septal defects are the most frequent pathologic finding with a higher prevalence compared to published studies. large prospective studies are needed to clarify a possible association of pathological cardiac findings in all patients with infantile hemangiomas and thereafter to evaluate the possible effect of propranolol therapy on these defects during time. infantile hemangioma and cardiac defects: a puzzling association. a single-center experience andrea bassi1, andrea azzarelli2, angelina vaccaro3, carlo mazzatenta1 1. dermatology unit , azienda toscana nord ovest, lucca, italy 2. pediatric cardiology, azienda toscana nord ovest, lucca, italy 3. pediatric and neonatology unit, azienda toscana nord ovest, lucca, italy key words: infantile haemangiomas, hearth, septal defects, propranolol citation: bassi a, azzarelli a, vaccaro a, mazzatenta c. infantile hemangioma and cardiac defects: a puzzling association. a single center experience. dermatol pract concept. 2022;12(3):e2022150. doi: https://doi.org/10.5826/dpc.1203a150 accepted: december 28, 2021; published: july 2022 copyright: ©2022 bassi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrea bassi, md, dermatology unit, azienda toscana nord ovest, lucca, italy, telephone number: +39-3389340371, e-mail address: andrea.bassi@uslnordovest.toscana.it abstract dermatology practical & conceptual 2 original article | dermatol pract concept. 2022;12(3):e2022150 introduction infantile hemangiomas (ih) are the most common benign tumor in infancy with an incidence between 5% and 10% in different population [1]. usually, they undergo a natural regression and do not require any treatment, therefore a “wait and see” approach is considered the best option for most affected newborns. however, in a subset of patients, ih can be worrisome for the risk of functional or aesthetic consequences. in 2008, following a serendipitous clinical observation, oral propranolol has been shown to be highly effective in the treatment of ih since then this drug has been widely used as galenic formulation. in 2014 an oral formulation has been licensed in europe and oral propranolol is now considered the gold standard for the therapy of complicated hemangioma. in our hospital patients starts treatment with oral propranolol at 1 mg/kg in 2 divided doses under pediatric observation for 2 hours. the dose is then gradually increased over the subsequent weeks following the standard protocol of stepping the dose up to 2 mg/kg daily the second week of treatment and up to 3 mg/kg daily the third week. another possibility is to follow an “at home” dose escalation strategy with telemedicine follow-up [2]. we developed and applied this protocol during the lock-down phase related to the sars-cov-2 pandemic, but we now offer this possibility to all families aiming to reduce the number of hospital visits. the therapy is usually continued until the 12th month of life with rare exceptions, such as rapid improvement of the lesion or extensive/recurrent ih in which therapy length could be respectively reduced or prolonged. potential side effects of propranolol include bradycardia, hypotension, hypoglycemia, bronchospasm and sleep disturbances. all these are rare and usually not lead to discontinue the treatment [3]. nevertheless in order to exclude congenital hidden heart disease which would contraindicate propranolol administration and to identify children in whom the drug may potentially induce side effects before starting therapy a general evaluation it is usually performed by a pediatrician. however, in our hospital, while not specifically requested in routine practice patients with ih who need propranolol therapy are also evaluated by a pediatric cardiologist [4]. our cardiology unit offers a care package in which next to cardiologic examination also an electrocardiogram (ecg) and echocardiography (echo) are performed in all children. objectives few published studies have shown a raised incidence of cardiac defects in patients with ih [5,6]. we then decided to retrospectively evaluate clinical chart of patients with ih who had cardiologic evaluation before propranolol therapy and to compare our findings with literature data. methods study population we retrospectively evaluated clinical charts of all children with ih requiring propranolol therapy at our countryside hospital between january 2016 and january 2021. according to our protocol patients referred to our outpatient service for ih undergo a complete pediatric and cardiology evaluation including ecg and echocardiogram before starting therapy. children with segmental ih are also investigated with magnetic resonance imaging (mri) to exclude the association with other congenital vascular malformations. two-dimensional, m-mode, continuous doppler and color doppler echocardiography is performed using ie33 philips medical ultrasound system equipped with a high-frequency phased-array sector scan probe (s8) and second-harmonic technology. all the evaluations are performed by the same senior cardiologist (aa) and comprise a complete sequential segmental analysis for each child. atrial septal defect is diagnosed when a shunt through the interatrial septum can be documented by color flow mapping in subcostal four-chambers and sagittals views. we do not record as atrial septal defect (asd) the interatrial communications less than 4 mm in length detected in infants less than 3 months of age. according to the local ethical board, informed consent was not required, since it was retrospective study with anonymous data. statistical analysis data were analyzed by spss statistics, 24.0 statistics software. categorical variables and frequencies were compared by means of the χ2 test or fisher test, as appropriate. quantitative variables were reported as median and interquartile range (iqr) and compared by means of nonparametric tests (mann–whitney u). a p value of 0.05 was considered to indicate statistical significance. results during this study period 950 children with ih presented in our clinic. of these, 60 (6.3%) patients with ih were treated with oral propranolol in the study frame time and all clinical charts were reviewed to retrieve relevant data. the median corrected age at first evaluation was 3 months (iqr: 2-5). seventy percent of cases were female (42/60), and the median gestational age at delivery was of 40 weeks (iqr: 36-40). in our population, 18/60 (30%) infants were born preterm. regarding the localization of ih, in 40/60 (66.7%) children was on the head and among these in 7/40 (17.5%) were “cyrano” ih. 12/40 (30%) were on the scalp, 5/40 (12.5%) on the cheek (2 of these were diagnosed as original article | dermatol pract concept. 2022;12(3):e2022150 3 phace syndrome after mri imaging), 4/40 (10%) on the ears and 12/40 (30%) on the forehead. in 9/60 (15%) ih were localized on the lower and upper arms including shoulder, 7/60 (11.7%) on the trunk, 1/60 (1.7%) on the diaper area and 3/60 (5%) presented with multiple ih. all data are summarized in table 1. data about cardiologic screening in particular for ecg examination were available for all the patients and almost all (58/60, 96.7%) presented a regular ecg for age. only 2 patients presented a right ventricular overload. ultrasound examination was available for 83.3% (50/60) of the patients. among these, 19/50 (38%) didn’t reveal any alterations and 14/50 (28%) had a persistent foramen ovale, a common finding considered to be non-pathological. pooling together these two groups 33/50 patients (66%) had a normal ultrasound, while the remaining 17/50 (34%) showed significant cardiac alterations. the most frequent cardiac defect was an isolated interatrial septal defect observed in 13/17 (26% of all patients). moreover, one patient had an interatrial septal defect associated with persistent left superior vena cava and another one associated with pulmonary stenosis. finally, one patient had a patent ductus arteriosus and in another one a flow acceleration in the aortic arch was seen. the median age (corrected for gestational age) at which the interatrial septal defect was observed was 3 months (iqr: 2-4); 9 out of these were observed at ≥ 3 months of age (18% of all patients) and 6 at < 3month (12% of all patients). of the 9 patients observed at ≥ 3months, 8 presented an interatrial defect > 3mm. the median defects diameter was 4 mm (iqr: 3-6) with an ostium secundum type and left to right shunt in all patients. the 2 patients with abnormal ecg didn’t present any ultrasound alterations. a possible association of abnormal cardiac findings with demographic or clinical variables was evaluated. however, no statistically significant association was found with age (p = 0.354), sex (p = 0.757), gestational age (p = 0.480), prematurity (p = 0.329) or hemangioma localization (p = 0.494). none of the ecg and echo findings were considered contraindications for systemic propranolol treatment. conclusions since systemic propranolol therapy was introduced for the treatment of ih several protocols of administration and monitoring have been proposed in order to reduce the potential risks related to the therapy [1,6]. pretreatment evaluation is warranted both to exclude congenital hidden heart disease which would contraindicate propranolol administration and table 1. clinical and cardiological screening results of the study population characteristics patients (n = 60) age starting propranolol and cardiac screening 3 months (iqr: 2-5) sex (female) 42 preterm 18 gestational age 40 weeks (iqr: 36-40) ih localization • face 40 • trunk 7 • arms 9 • diaper 1 • multiple ih 3 cardiological findings electrocardiogram (60/60available) 58/60 no pathologic findings echocardiogram (50/60available) • no findings 19/50 • persistent foramen ovale 14/50 • interatrial septal defect 13/50 • interatrial septal defect+ patent doctus arteriosus 1/50 • interatrial septal defect + pulmunary stenosis 1/50 • flow acceleration in aortic arch 1/50 • persistent left superior vena cava 1/50 ih = infantile hemangiomas; iqr = interquartile range. 4 original article | dermatol pract concept. 2022;12(3):e2022150 children older than 3 months (thus excluding children less than 3 months), the prevalence of asd is anyway clearly greater than data reported in literature for general population (18% versus 0.8%-1%) [12-13]. the limited number of patients and the intrinsic limitations of retrospective studies does not allow us to draw a definitive conclusion however our study along with literature data seems to confirm that patients with ih have a substantially higher prevalence of congenital heart disease in respect to general population. indeed, these data needs confirmation in larger prospective, multicenter, studies which should include all patients with ih to be evaluated at specific time points irrespectively of therapy with propranolol. such a study will also be of interest to reveal a possible effect of propranolol therapy on the closure of asd and also the significance and the possible value of ih as a clue to suspect the presence of a cardiac defect. in particular it would be of great importance to understand whether along with well-known syndromes such as phace a particular combination of characteristics such as dimension, number and or localization could indicate a raised risk of cardiac disease [19]. references 1. drolet ba, frommelt pc, chamlin sl, et al. initiation and use of propranolol for infantile hemangiomas: report of a consensus conference. pediatrics. 2013;131(1):128-140. doi: 10.1542/ peds.2012-1691. pmid: 23266923. pmcid: pmc3529954. 2. bassi a, azzarelli a, vaccaro a, mazzatenta c. at-home dose escalation of propranolol for infantile hemangiomas during the covid-19 pandemic. dermatol ther. 2020;33(6):e13977. doi: 10.1111/dth.13977. pmid: 32633450. pmcid: pmc7361163. 3. drolet ba, frommelt pc, chamlin sl, et al. initiation and use of propranolol for infantile hemangioma: report of a consensus conference. pediatrics. 2013;131(1):128-140. doi: 10.1542/ peds.2012-1691. pmid: 23266923. pmcid: pmc3529954. 4. hemangiol summary of product characteristics. available from: https://www.ema.europa.eu/en/documents/product-information/ hemangiol-epar-product-information_en.pdf 5. blei f, mcelhinney db, guarini a, presti s. cardiac screening in infants with infantile hemangiomas before propranolol treatment. pediatr dermatol. 2014;31(4):465-470. doi: 10.1111/ pde.12344. pmid: 24889812. 6. frongia g, byeon jo, arnold r, mehrabi a, günther p. cardiac diagnostics before oral propranolol therapy in infantile hemangioma: retrospective evaluation of 234 infants. world j pediatr. 2018;14(3):254-258. doi: 10.1007/s12519-018-0137-7. pmid: 29796952.et al. 7. olsen gm, hansen lm, stefanko ns, et al. evaluating the safety of oral propranolol therapy in patients with phace syndrome. jama dermatol. 2020;156(2):186-190. doi: 10.1001/jamadermatol.2019.3839. pmid: 31825455. pmcid: pmc6990697. 8. raphael mf, breugem cc, vlasveld fa, et al. is cardiovascular evaluation necessary prior to and during beta-blocker therapy to identify children in whom the drug may potentially induce side effects including bradycardia, hypotension, bronchospasm or hypoglycemia. whether to perform ultrasound, ecg or simply a clinical examination is however controversial. the most recent literature underlines the lack of additional value of performing instrumental evaluations such as ecg as a pretreatment screening tool [7-11]. in our hospital a clinical protocol in which a complete pediatric and cardiologic screening, including ecg and ultrasound, is usually performed in all patients as part of a specific care package. in line with previous studies, in our population we didn’t find any cardiac contraindications to start propranolol treatment. in particular ecg was performed in all the patients, but no significant findings were found thus confirming the low informative value of this exam. on the contrary some interesting data were derived from ultrasound heart examination. echo was available for 83.3% patients and in 38% of patients was normal. a persistent foramen ovale was found in 28% of patients and considered as a normal variant. the most frequent pathological abnormality was an interatrial septal defect that was present in 15/50 of patients (30%) either as an isolated finding (13/50 26%) with a presentation as ostium secundum type with left to right shunt or associated with a persistent left superior vena cava or pulmonary stenosis. few other studies have addressed this topic. in particular, blei et al analyzed 239 patients and found 16% of interatrial septal defects, while frongia et al analyzed 234 patients with only 8.1% of prevalence of this defect [5,6]. in any case, these studies clearly showed that in patients with ih there is a higher frequency of cardiac abnormalities compared with the reported incidence of congenital heart disease in the general population, which has been shown to range from 0.8% to 1.0% and going up to 7.5% only with the inclusion of other alteration such as patent foramen ovale [12-16]. our study confirms the higher prevalence of cardiac abnormalities among patients with ih in particular of interatrial septal defect. the clinical significance of our findings is supported by the median age at observation and the median diameter of the defect which are in line with the criteria of inclusion to define congenital heart disease, ie the observation after 3 months of life and the dimension more or equal 4 mm (our median diameter was 4 mm) [17]. the 3 months age as a cut-off to consider an ultrasound finding to be relevant is because before this age the interatrial communications are common and account for 78% of the heart disease compared to 25% in older infants and children [18]. at the same time, it has been demonstrated that the incidence of spontaneous closure of interatrial communications before 3 months of age is about 60% and, in addition, interatrial defects of less than 3 mm undergo spontaneous closure in almost 100% of cases [17,18]. our data shows that even considering only original article | dermatol pract concept. 2022;12(3):e2022150 5 14. hoffman ji. incidence of congenital heart disease: i. postnatal incidence. pediatr cardiol.1995;16(3):103-113. doi: 10.1007/ bf00801907. pmid: 7617503. 15. hoffman ji, kaplan s. the incidence of congenital heart disease. j am coll cardiol. 2002;39(12):1890-1900. doi: 10.1016/ s0735-1097(02)01886-7. pmid: 12084585. 16. zhao qm, ma x-j, jia b, huang gy. prevalence of congenital heart disease at live birth: an accurate assessment by echocardiographic screening. acta paediatr. 2013;102(4):397-402. doi: 10.1111/apa.12170. pmid: 23350618. 17. hansen lk, oxhoj h. high prevalence of interatrial communications  during the first three months of life. pediatr cardiol. 1997;18(2):83-85. doi: 10.1007/s002469900120. pmid: 9049116. 18. bostan om, cil e, ercan i. the prospective follow-up of the natural course of interatrial communications diagnosed in 847 newborns. eur heart j. 2007;28(16):2001-2005. doi: 10.1093/ eurheartj/ehm268. pmid: 17623678. 19. winter pr, itinteang t, leadbitter p, tan st. phace syndrome--clinical features, aetiology and management. acta paediatr. 2016;105(2):145-153. doi: 10.1111/apa.13242. pmid: 26469095. for infantile hemangiomas? a cohort study. j am acad dermatol. 2015;72(3):465-472. doi: 10.1016/j.jaad.2014.12.019. pmid: 25592625. 9. yarbrough kb, tollefson mm, krol al, et al. is routine electrocardiography necessary before initiation of propranolol for treatment of infantile haemangiomas? pediatr dermatol. 2016;33(6):615-620. doi: 10.1111/pde.12972. pmid: 27599450. 10. streicher jl, riley eb, castelo-soccio la. reevaluating the need for electrocardiograms prior to initiation of treatment with propranolol for infantile hemangiomas. jama pediatr. 2016;170(9):906-907. doi: 10.1001/jamapediatrics.2016.0824. pmid: 27454424. 11. lund eb, chamlin sl, mancini aj. utility of routine electrocardiographic screening before initiation of propranolol for infantile hemangiomas. pediatr dermatol. 2018;35(4):e233-e234. doi: 10.1111/pde.13508. pmid: 29683225. 12. botto ld, correa a, erickson jd. racial and temporal variations in the prevalence of hearth defect. pediatrics. 2001;107(3):e32. doi: 10.1542/peds.107.3.e32. pmid: 11230613. 13. shuler co, black gb, jerrel jm. population-based treated prevalence of congenital heart disease in a pediatric cohort. pediatr cardiol. 2013;34(3):606-611. doi: 10.1007/s00246-012-05053. pmid: 22976198. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023032 1 facial bier spots unresponsive to botulinum toxin: a case series pelin esme1, burcu beksac1, gulsen akoglu1, ercan caliskan1 1 department of dermatology and venereology, university of health sciences, gulhane training and research hospital, ankara, turkey key words: bier spots, angiospastic macules, face, botulinum toxin citation: esme p, beksac b, akoglu g, caliskan e. facial bier spots unresponsive to botulinum toxin: a case series. dermatol pract concept. 2023;13(1):e2023032. doi: https://doi.org/10.5826/dpc.1301a32 accepted: june 9, 2022; published: january 2023 copyright: ©2023 esme et al. this is an open-access article distributed under the terms of the creative commons attribution-non commercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: pelin eşme, md, department of dermatology and venereology, university of health sciences, gulhane training and research hospital, 06010, kecioren, ankara, turkey, +9 0 312 304 44 67 fax number: +9 0 312 304 27 00, pelinnesme@gmail.com introduction bier spots are asymptomatic, irregular anemic macules in a blanchable erythematous background. however, the pathogenesis is not clear yet; abnormal vasoconstriction of vessels has been suggested as the primary mechanism [1]. lesions often involve extremities and the trunk; only one case with facial involvement has been reported previously [2]. lesions do not require specific treatment, but patients may experience cosmetic problems [3]. herein, we described 3 cases with bier spots on the face with accompanying tension-type headaches in all patients and tested the hypothesis that botulinum toxin might improve facial bier spots. case presentation a 45-year-old male patient (patient 1) was admitted to our outpatient dermatology clinic with a complaint of pale, whitish macules on the forehead. the complaints had started six months ago after trauma and become more visible with emotional stress and bending down. he also suffered from headaches and forehead wrinkles. a diagnosis of bier spots was made upon clinical examination. laboratory evaluations and imaging methods revealed no abnormalities. a total of 150 speywood units (reconstituted with 2.5 ml normal saline) of botulinum toxin (abobotulinumtoxina, dysport®, ipsen, 500 units) were injected to forehead lines considering the localization of bier spots (figure 1). in addition to cosmetic improvement of the frontal wrinkles within one week, headache severity regressed from 10 to 5 points according to the visual analog scale (vas) for pain. unfortunately, there was no response in bier spots six weeks after botulinum toxin injection. the symptoms of a 48-year-old male patient (patient 2) started one year ago on the trunk and face without any triggering (figure 2). a 32-year-old female patient ( patient 3) had experienced similar complaints on the forehead six months after her first vaginal delivery. strikingly, both were accompanied by tension-type headaches. laboratory evaluations and imaging methods of both patients did not reveal any abnormality. 2 research letter | dermatol pract concept. 2023;13(1):e2023032 figure 1. case 1. (a) pretreatment. bier spots were marked with black color to orient the injector. the hypopigmented macule highlighted with a red arrow was selected as a control area, and no injection was performed. (b) post-treatment. significant improvement was recorded in forehead lines at week 1, while there was no improvement in bier spots. figure 2. case 2. the patient provoked these lesions by holding his breath for about a half minute and bending down just before the photographs. research letter | dermatol pract concept. 2023;13(1):e2023032 3 botulinum toxin injections were performed to bier spots on the forehead of the patient 2, similar to patient 1. while no improvement was observed in bier spots at the end of the 6th week, the headache severity regressed from 10 to 2 points after one week according to the vas score. patient three recommended no treatment due to breastfeeding. conclusions recently, botulinum toxin in non-cosmetic medical conditions, including tension-type headaches, is becoming increasingly popular. considering its effects on the cutaneous vasculature [4-6], we aimed to test the hypothesis that botulinum toxin might relax the muscles around the small arterioles and increase transcutaneous blood flow, thereby reducing hypoxia and improving bier spots. possible common pathogenesis for the coexistence of both diseases appears to be genetic and triggering factors for an exaggerated vasoconstrictive response [1,6]. however, while tension-type headaches in both patients improved, bier spots did not. therefore, failure to botulinum toxin may be related to insufficient dosage or other unknown factors that play a role more critical than the exaggerated vasoconstrictive response. references 1. fan y-m, yang y-p, li w, li s-f. bier spots: six case reports. j  am acad dermatol. 2009;61(3):e11-e12. doi: 10.1016/j. jaad.2009.03.009. pmid: 19700009. 2. yildiz h, saman h. bier spots on the face: the first case report. trichol cosmetol open j. 2016;1(1):8-10. doi: 10.17140/ tcoj-1-102. 3. shen t, gao k, li h, hu z. bier spots treated with intense pulsed light. australas j dermatol. 2018;59(4):338-339. doi: 10.1111/ ajd.12792. pmid: 29460279. 4. esme p, botsali a, erbil h, aksoy oa, caliskan e. bioactivity of abobotulinum toxin is preserved till 2  weeks upon storage at room temperature: half body comparative study on rabbit model. j cosmet dermatol. 2021;20(5):1367-1373. doi: 10.1111/jocd.13836. pmid: 33170993. 5. botsali a, erbil h. management of nail psoriasis with a single injection of abobotulinum toxin. j cosmet dermatol. 2021;20(5):1418-1420. doi: 10.1111/jocd.13633. pmid: 32783318. 6. grando s, zachary c. the non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond. br j dermatol. 2018;178(5):1011-1019. doi: 10.1111/bjd.16080. pmid: 29086923. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(1):e2023001 1 validation of the turkish version of the skin cancer quality of life impact tool (scqolit): a health-related quality of life questionnaire for non-metastatic melanoma and non-melanoma skin cancer hilayda karakok1, seher bostanci2, bengu nisa akay2, deniz calıskan3, can ateş4, kenan köse5 1 sifa okulu, private practice office of dermatology and venereology, ataturk bulvarı, tasbası mahallesi, altınordu ordu, turkey 2 department of dermatology and venereology, ankara university school of medicine, turkey 3 department of public health, ankara university school of medicine, turkey 4 department of biostatistics, van yüzüncü yıl university, school of medicine 5 department of biostatistics, ankara university school of medicine, turkey key words: skin cancer, skin cancer related quality of life, melanoma, non-melanoma skin cancer citation: karakok h, bostanci s, akay bn, calıskan d, ateş c, köse k. validation of the turkish version of the skin cancer quality of life impact tool (scqolit): a health related quality of life questionnaire for non-metastatic melanoma and non-melanoma skin cancer. dermatol pract concept. 2023;13(1):e2023001. doi: https://doi.org/10.5826/dpc.1301a1 accepted: april 24, 2022; published: january 2023 copyright: ©2023 karakok et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: hilayda karakok, sifa okulu, private practice office of dermatology and venereology by dr. hilayda karakok, kosk apt, no:84/a, ataturk bulvarı, tasbası mahallesi, altınordu ordu, turkey. telephone number: 0090 0452 225 00 25 e-mail address: hk@hilaydakarakok.com introduction quality of life instruments (qol) have been developed to measure the efficacy of treatments in chronic illnesses and cancers [1]. skin cancers, including melanoma and non-melanoma (nmsc), are the third most common type of cancer worldwide and have been increasing in incidence [2]. there have been plenty of investigations on the qol of patients with skin cancers and several instruments were developed [3-8]. there is only one instrument which was validated for non-metastatic skin cancers, the skin cancer quality of life impact tool (scqolit) [9]. numerous tools have been developed to measure qol. important characteristics of the tools are validity, reliability, interpretability, structure (using factor analysis or item response theory), responsiveness, interpretability, brief response burden and an acceptable administrative burden [10]. while both generic and specific tools are used to measure qol in various types of chronic diseases, specific tools give more accurate information and may detect aspects not identified with generic tools [11]. 2 research letter | dermatol pract concept. 2023;13(1):e2023001 there are two validated disease-specific qol instruments for melanoma. the eortc-mm was developed for metastatic melanoma. fact-mm can assess all the stages of melanoma. patients diagnosed with melanoma had lower emotional well-being on fact-mm scale than normal population [12]. there are several instruments developed for the assessment of qol of patients with nmsc. the questionnaire developed by esser et al, was made to assess the health status of patients with basal cell carcinoma (bcc) before a surgical procedure. it is not clear whether this tool may be used to evaluate qol and the reliability of the tool has not been investigated [13]. scqol was developed from a questionnaire originally developed to evaluate the qol in patients with actinic keratosis. only the term ‘sun damage’ has been changed as ‘skin cancer’ for this tool. it is not clear if this tool is able to measure all the aspects affected by skin cancer [14]. facial skin cancer index was developed for nmsc located on the head and neck region. the validity and reliability are well established, the instrument is designed to measure the dimensions affected by nmsc. on the other hand, it cannot be used for nmsc located anywhere but the head and neck region [5]. a specific qol tool basqol was developed by waalboer-spuijr et al. face, content and construct validation, reliability and internal consistency of basqol was proven. the validation of the english version of basqol is currently being searched. the tool is designed for bcc and squamous-cell carcinoma (scc) [15]. the only validated tool which is used in non-metastatic skin cancer types is the scqolit. the scqolit was shown to have construct and external validation, reliability, internal consistency and responsiveness [9]. wali et al also showed feasibility of this tool in dermatology skin cancer clinics for patients with nmsc [16]. objectives the objective of this study is to validate the turkish version of the skin cancer quality of life impact tool (scqolit) [9]). the translation and validation of the turkish version of the scqolit provides a tool that can be used to measure qol of nmsc in turkish populations. the current study aims to investigate internal validation, construct validation, external validation and convergent validity, reliability and internal consistency of the turkish version of the tool. methods the study was carried out at ankara university school of medicine, department of dermatology and venereology between december 2015 and september 2016. the scqolit was originally developed by burdon-jones et al to measure the qol of patients with non-metastatic skin cancers. the permission for the translation and validation of the tool was granted by burdon-jones. the tool was translated into turkish by 2 specialists in the department of dermatology and by a scientist of foreign languages department in accordance with international translation guidelines. three documents were created. one by the 2 specialists of dermatology. the other two by independent translators who translated it back to english. the text was evaluated by a scientific team including a foreign linguist and a specialists of dermatology. a total of 141 patients who had been diagnosed and treated for skin cancer within the previous 3 months were included in this study. patients younger than 18 years and patients with impaired cognitive functions and illiterate patients were excluded from the study. confirmatory factor analysis was used for the internal validation of the scoqlit. comparative compliance statistics (comparative fit index [cfi], tucker-lewis index [tli], root mean square error of approximation [rmsoa]) were used to evaluate the efficacy of the model which was produced as a result of the confirmatory factor analysis. the dermatology quality of life index (dlqi) was translated into turkish and has been used in various studies since. the dlqi was used for external validation of the scqolit. the hypothesis to be tested was whether dlqi and scqolit had same directional correlations. the scqolit was tested to discriminate melanoma and nmsc to evaluate the convergent validity. the internal consistency was assessed by using cronbach alpha and intraclass correlation coefficient (icc) in terms of reliability (defined by test-retest method). demographic characteristics of the patients and tumor characteristics were recorded to investigate their impact on qol. mplus trial version and spss 20.0 programs were used for statistical analyses. for bcc, size and location of the tumor, primary or recurrent origin, histopathological subtype, presence or lack of perineural invasion, history of radiotherapy at the site of the tumor and immunological status of the patient were recorded to assess risk analysis. for scc, size and location of the tumor, primary or recurrent origin, histopathological features (differentiation, tumor thickness, presence of perineural, lymphatic or vessel invasion), immunological status of the patient, history of radiotherapy and the presence of a chronic inflammation or a scar at the site of the tumor were recorded to assess the risk analysis. high risk tumor features were classified in accordance with nccn guidelines [17]. melanoma risk analysis was conducted in accordance with the nccn guidelines [18]. breslow thickness, clark level, ulceration, presence of regression, and mitosis rate were recorded to define the stage of the melanoma. research letter | dermatol pract concept. 2023;13(1):e2023001 3 the ethics committee approval was granted (10-439-16) all the participants gave written informed consent. results the mean ages were 63.75 ± 12.07, 66.53 ± 13.55, 49.24 ± 16.67 in patients with bcc (n = 65), scc (n = 30) and melanoma (n = 46), respectively. twenty-nine of the patients with bcc, 11 of the patients with scc and 24 of the patients with melanoma were females (table 1). patients data, number of nevi, personal and family history of skin cancer, fitzpatrick skin type and treatment modality are shown in table 2. thirty-eight bcc (n = 65) and 10 scc (n = 30) had high risk features. forty melanoma patients were found to be at the first stage and 6 of them were at the second stage (table 1). table 1. age, gender, risk classification of non-melanoma skin cancer and stage of melanoma mean age gender risk classification of non-melanoma skin cancer: female male high risk low risk bcc (n=65) 63.75 ±12.07 29 36 38 27 scc (n=30) 66.53±13.55 11 19 10 20 melanoma stage: stage 1 stage 2 m (n=46) 49.24 ±16.67 24 22 40 6 table 2. sociodemographic features of the patients number of patients median score of the scoqlit (min-max) mean score of the scoqlit ± sd age ≤65 83 11 (0-28) 12.25 ± 7.038 > 65 53 6 (0-28) 7.81 ± 6.864 gender female 64 11 (0-28) 11.59 ± 7.648 ss male 77 9 (0-28) 9.65 ± 7.045 number of nevi <100 125 9 (0-28) 10.41 ± 7.42 >100 16 10 (3-28) 11.50 ± 7.04 history of skin cancer positive 108 12 (0-27) 12.36 ± 7.61 negative 33 9 (0-28) 9.97 ± 7.22 family history of skin cancer positive 23 12.5 (0-27) 11.81 ± 8.07 negative 119 9 (0-28) 10.52 ±7.59 fitzpatrick skin type type 1 1 17 17 type 2 53 9 (0 28) 10.51 ± 7.1 type 3 74 9 (0 28) 10.04 ± 7.49 type 4 13 10 (5-28) 12.92 ± 7.79 treatment modality i̇miquimod 1 1 1 cryotherapy 1 28 28 i̇miquimod + excision 1 7 7 primary excision 89 9 (0-27) 10.44 ± 7.49 table 2 continues 4 research letter | dermatol pract concept. 2023;13(1):e2023001 the relationship between age and qol was found to have a statistically significant negative correlation (r = -0.333, p < 0.001). patients under the age of 65 had poorer qol (table 4). there was no statistically significant relation with gender and qol (p = 0.101). personal and family history of skin cancer had no effect on qol (p = 0.099, p = 0.132 respectively). there was neither statistically significant relation between fitzpatrick skin type, the number of nevus and qol (p = 0.589, p = 0.536). furthermore, high-risk tumor characteristics in non melanoma skin cancer and stage of melanoma had no impact on qol (p = 0.235 for bcc, p = 1.00 for scc, p = 0.635 for melanoma). conclusions in the current study, the turkish version of the tool was shown to have internal validation, construct validation, external validation and convergent validity, reliability and internal consistency. the factor load of question 3 was lower than 0.4 indicating the inadequacy of this term in predicting qol. this was not investigated in the original study. scqolit is a well-established tool in terms of internal validation, construct validation, external validation and convergent validity, reliability, internal consistency and feasibility [9,16]. the scqolit was shown to have one dimensional structure in the original study. in the current study, the question items of the turkish version of the scqolit were assessed with confirmatory factor analysis to demonstrate tools one-dimensional structure. the compliance to the model was found to be efficient (cfi:0.952, tli:0.938, rmseoa:0.102). most of the question items had a factor load greater than 0.4 except for question 3 with a factor load of 0.372, indicating the inadequacy of this question in predicting qol, a point that the original study did not mention. internal validity of the turkish version of the scqolit was excellent (cronbach alpha = 0.863). test-re-test correlation coefficient was found as high as 0.824 (%95 confidence interval 0.644 – 0.918). the scores for scqolit and dqli were both statistically significant with same directional correlations, confirming external validity of the tool. to test the convergent validity of the scqolit, the total score of the patients with melanoma and non-melanoma skin cancer was compared. total score of the scqolit in patients with melanoma was statistically significantly higher than nmscs indicating the tool ability to discriminate these 2skin cancer types (p = 0.024) (table 3). the administrative and response burden of the tool was found to be quite low as it took 2.5 to 4 minutes to respond to all the questions and the recording process of the data was easy. table 3. mean and median total score of the scqolit in patients with melanoma and nmsc median score of the scoqlit (min-max) mean score of the scoqlit ± sd melanoma 11 (2-28) 11.96 ± 5.94 nmsc 9 (0-28 9.84 ± 7.885 table 4. total score of the scqolit of patients under and above the age of 65 age number of patients median score of the scoqlit (min-max) mean score of the scoqlit ± sd ≤65 83 11 (0-28) 12.25 ± 7.038 ≥65 53 6 (0-28) 7.81 ± 6.864 number of patients median score of the scoqlit (min-max) mean score of the scoqlit ± sd excision+ sentinell ymph node dissection 16 12 (0-28) 12.56 ± 6.59 excision+ flap or graft procedure 27 9 (0-28) 9.26 ± 6.74 amputation 1 7 7 radiotherapy 2 16 (15-17) 16 ± 1.41 vismodegib 3 9 (0-21) 10 ± 10.53 table 2. sociodemographic features of the patients. (continued) research letter | dermatol pract concept. 2023;13(1):e2023001 5 can be used to measure qol of non-metastatic skin cancers in turkishspeaking populations. this tool can be used to investigate qol and many parameters mentioned above in further studies. references 1. karimi m, brazier j. health, health-related quality of life, and quality of life: what is the difference? pharmacoeconomics. 2016;34(7):645-649. doi: 10.1007/s40273-016-0389-9. pmid: 26892973. 2. leiter u, garbe c. epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight. adv exp med biol. 2008;624:89-103. doi: 10.1007/978-0-387-77574-6_8. pmid: 18348450. 3. burdon-jones d, thomas p, baker r. quality of life issues in nonmetastatic skin cancer. br j dermatol. 2010;162(1):147-151. doi: 10.1111/j.1365-2133.2009.09469.x. pmid: 19796177. 4. hawkins dm, jacobsen g, johnson cc, lim hw, eide mj. self-reported quality of life after skin cancer in young adults. j dermatolog treat. 2015;26(4):357-360. doi: 10.3109/ 0954 6634.2014.991671. pmid: 25490454. 5. rhee js, matthews ba, neuburg m, logan br, burzynski m, nattinger ab. validation of a quality-of-life instrument for patients with nonmelanoma skin cancer. arch facial plast surg. 2006; 8(5):314-318. doi: 10.1001/archfaci.8.5.314. pmid: 1698 2987. pmcid: pmc2556600. 6. schlesinger-raab a, schubert-fritschle g, hein r, stolz w, v olkenandt m, holzel d, et al. quality of life in localised malignant melanoma. ann oncol. 2010;21(12):2428-2435. doi: 10.1093/annonc/mdq255. pmid: 20494965. 7. waalboer-spuij r, nijsten te. a review on quality of life in keratinocyte carcinoma patients. g ital dermatol venereol. 2013; 148(3):249-254. pmid: 23670061. 8. winstanley jb, young te, boyle fm, et al. cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an eortc melanoma module. melanoma res. 2015;25(1):47-58. doi: 10.1097/cmr.0000000000000122. pmid: 25325247. 9. burdon-jones d, gibbons k. the skin cancer quality of life impact tool (scqolit): a validated health-related quality of life questionnaire for non-metastatic skin cancers. j eur acad dermatol venereol. 2013;27(9):1109-1113. doi: 10.1111/j.14683083.2012.04669.x. pmid: 22909179. 10. chen sc. dermatology quality of life instruments: sorting out the quagmire. j invest dermatol. 2007;127(12):2695-2696. doi: 10.1038/sj.jid.5701176. pmid: 18007683. 11. both h, essink-bot ml, busschbach j, nijsten t. critical review of generic and dermatology-specific health-related quality of life instruments. j invest dermatol. 2007;127(12):2726-2739. doi: 10.1038/sj.jid.5701142. pmid: 17989733. 12. cornish d, holterhues c, van de poll-franse lv, coebergh jw, nijsten t. a systematic review of health-related quality of life in cutaneous melanoma. ann oncol. 2009;20 suppl 6:vi51-vi58. doi: 10.1093/annonc/mdp255. pmid: 19617298. pmcid: pmc2712593. 13. essers ba, nieman fh, prins mh, krekels ga, smeets nw, neumann ha. determinants of satisfaction with the health state of the facial skin in patients undergoing surgery for facial basal the mean scores of scqolit of the patients with melanoma were similar in both the current and the original study. on the other hand, the mean scores (mean = 9, range 0-28) of the scqolit of patients with nmsc in the current study was higher than those in the original study (mean = 4, range 0-19)]. the percentage of patients with scc in the present study was 31.6% whereas it was 10% in the original study. additionally, 58.4% of all bccs had high risk features in the current study. the original study did not mention the risk classification and the percentage of the high-risk tumors in their population [9]. these findings might be related with the differences between populations. in terms of factors that might impact scqolit scores in current study was age. age was shown to be the only factor having a statistically significant impact on scqolit. there was a negative correlation between age and the scores. patients under the age of 65 had poorer qol. the lower median age of the study population in the current study compared with the original study might be the explanation of this result. el abbadi et al also found a negative correlation between skin cancer and patients age, gender and location of the tumor [19]. while similar results were also observed in the literature, some investigators found no relation between age and qol [20-25]. there was no statistically significant relation between previous skin cancer history and qol in the present study. rhee et al found that in patients with nmsc the history of previous skin cancer had a negative impact on qol in contrast to steinbauer et al who observed no relation [24,25]. current study has a very limited number of patients with melanoma, and findings showed no relation between qol and a positive family history of melanoma. barbato et al found that patients with melanoma who had a positive family history of melanoma had better qol scores [26]. both the current study and the original study found no relationship between melanoma breslow thickness and qol while holterhouse et al observed that the stage of the tumor (stage 0-2) had a negative impact on qol [9,27]. we found no relation between fitzpatrick skin type or high-risk tumor features and qol in the current study. as the current study aimed to validate the turkish version of the scqolit, the sample size was too small (not  large enough) to investigate and demonstrate the relation between qol and age, fitzpatrick skin type, personal or family history of skin cancer, stage or high-risk tumor features. this was the main limitation of the study. further studies with larger patient groups and repeated scqolit in defined timeframes could be planned to investigate the relation between age and qol. in conclusion, the translation and validation of the turkish version of the scqolit provides a valid tool that 6 research letter | dermatol pract concept. 2023;13(1):e2023001 a register-based cohort study. plos one. 2015;10(1):e0116440. doi: 10.1371/journal.pone.0116440. pmid: 25615573. pmcid: pmc4304781. 21. bourdon m, blanchin m, tessier p, changes in quality of life after a diagnosis of cancer: a 2-year study comparing breast cancer and melanoma patients. qual life res. 2016;25(8):1969-1979. doi: 10.1007/s11136-016-1244-3. pmid: 26886927. 22. engel j, schlesinger-raab a, emeny r, holzel d, schubert-fritschle  g. quality of life in women with localised breast cancer or malignant melanoma 2 years after initial treatment: a comparison. int j behav med. 2014;21(3):478-486. doi: 10.1007/s12529-013-9334-x. pmid: 23897272. 23. schubert-fritschle g, schlesinger-raab a, hein r, et al. quality of life and comorbidity in localized malignant melanoma: results of a german population-based cohort study. int j dermatol. 2013;52(6):693-704. doi: 10.1111/j.1365-4632.2011.05401.x. epub 2013 feb 22. pmid: 23432215. 24. steinbauer j, koller m, kohl e, karrer s, landthaler m, szeimies rm. quality of life in health care of non-melanoma skin cancer results of a pilot study. j dtsch dermatol ges. 2011;9(2):129-135. sdoii: 10.1111/j.1610-0387.2010.07547.x. pmid: 21029377. 25. rhee js, matthews ba, neuburg m, smith tl, burzynski m, nattinger ab. quality of life and sun-protective behavior in patients with skin cancer. arch otolaryngol head neck surg. 2004;130(2):141-146. doi: 10.1001/archotol.130.2.141. pmid: 14967741. 26. barbato mt, bakos l, bakos rm, prieb r, andrade cd. predictors of quality of life in patients with skin melanoma at the dermatology department of the porto alegre teaching hospital. an bras dermatol. 2011;86(2):249-256. doi: 10.1590/s036505962011000200007. pmid: 21603807. 27. holterhues c, cornish d, van de poll-franse lv, et al. impact of melanoma on patients’ lives among 562 survivors: a dutch population-based study. arch dermatol. 2011;147(2):177-185. doi: 10.1001/archdermatol.2010.433. pmid: 21339445. cell carcinoma. patient educ couns. 2006;60(2):179-186. doi: 10.1016/j.pec.2005.01.002. pmid: 16442459. 14. vinding gr, christensen kb, esmann s, olesen ab, jemec gb. quality of life in non-melanoma skin cancer--the skin cancer quality of life (scqol) questionnaire. dermatol surg. 2013;39(12):17841793. doi: 10.1111/dsu.12353. pmid: 24237851. 15. waalboer-spuij r, hollestein lm, timman r, van de poll-franse lv, nijsten te. development and validation of the basal and squamous cell carcinoma quality of life (basqol) questionnaire. acta derm venereol. 2018;98(2):234-239. doi: 10.2340/00015555-2806. pmid: 28952653. 16. wali gn, gibbons e, kelly l, reed jr, matin rn. use of the skin cancer quality of life impact tool (scqolit) a feasibility study in non-melanoma skin cancer. j eur acad dermatol venereol. 2020;34(3):491-501. doi: 10.1111/jdv.15887. pmid: 31419362. 17. danesh mj, menge td, helliwell l, mahalingam m, waldman a. adherence to the national comprehensive cancer network criteria of complete circumferential peripheral and deep margin assessment in treatment of high-risk basal and squamous cell carcinoma. dermatol surg. 2020;46(12):1473-1480. doi: 10.1097/dss.0000000000002354. pmid: 32149872. 18. swetter sm, thompson ja, albertini mr, et al. nccn guidelines® insights: melanoma: cutaneous, version 2.2021. j  natl compr canc netw. 2021;19(4):364-376. doi: 10.6004/jnccn.2021.0018. pmid: 33845460. 19. el abbadi s, susok l, stockfleth e, comparison of the skin cancer quality of life impact tool and the skin cancer index questionnaire in measurement of health-related quality of life and the effect of patient education brochures in patients with actinic keratosis, non-melanoma skin cancer, and cutaneous melanoma. dermatol ther (heidelb). 2021;11(3):929-940. doi: 10.1007/s13555-021-00522-y. pmid: 33847880. pmcid: pmc8163937. 20. beutel me, fischbeck s, binder h, et al. depression, anxiety and quality of life in long-term survivors of malignant melanoma: dermatology: practical and conceptual 140 research | dermatol pract concept 2018;8(2):14 dermatology practical & conceptual www.derm101.com acral lentiginous melanoma in the turkish population and a new dermoscopic clue for the diagnosis fezal ozdemir1, micol a. errico2, banu yaman3, isil karaarslan 1 1 ege university, medical faculty, dermato-oncology unit, department of dermatology, izmir, turkey 2 department of medical sciences, university of turin, turin, italy 3 ege university, medical faculty, department of pathology, izmir, turkey key words: acral lentiginous melanoma, amelanotic melanoma, nail unit melanoma, parallel-ridge pattern, dermoscopy citation: ozdemir f, errico ma, yaman b, karaarslan i. acral lentiginous melanoma in the turkish population and a new dermoscopic clue for the diagnosis. dermatol pract concept. 2018;8(2)140-148. doi: https://doi.org/10.5826/dpc.0802a14 received: july 31, 2017; accepted: february 7, 2018; published: april 30, 2018 copyright: ©2018 ozdemir et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: micol alessandra errico, md, dermatology unit, department of medical sciences, university of turin, turin, italy. tel. +390165545426; fax. +390165545583. email: micolerr@libero.it background: the incidence of acral lentiginous melanoma (alm) in the white population is low. dermoscopy enhances diagnosis of alm; however, diagnostic accuracy may sometimes be poor due to the considerable proportion of amelanotic alm variants. objectives: to calculate the proportion of alm among all melanoma subtypes and to determine the frequency of dermoscopic features of alm in the turkish population. methods: out of 612 melanomas, there were 70 cases of alm, of which 46 showed sufficient image quality for retrospective study of dermoscopic features. data from patients and their lesions was classified according to clinical features and histopathologic parameters. the dermoscopic variables evaluated were based on pertinent literature on dermoscopy of acral melanocytic neoplasms. results: the prevalence of alm among all melanoma subtypes was  11.4%. parallel-ridge pattern (prp) was detected in 60.8% of cases and irregular diffuse pigmentation (idp) in 28.3%. the alms were amelanotic in 24%, showing an atypical vascular pattern in all cases; a new dermoscopic pattern, named “vascularized parallel-ridge pattern” (vprp), was detected in  13% of alms. irregular lines were observed in 81.8% of subungual melanomas and were often associated with a multicolored background. conclusions: alm has site-specific dermoscopic patterns, with prp being the most prevalent pattern. the newly described vprp pattern may be an additional clue for alm diagnosis, especially in thin amelanotic melanomas. abstract research | dermatol pract concept 2018;8(2):14 141 dermoscopic pictures were taken prior to biopsy or excision using a polarized light immersion dermoscopic camera (dermlite foto system, 3gen, san juan capistrano, ca, usa) with oil immersion. in selected cases, we obtained additional images of normal appearing skin around the lesions or at the contralateral acral site. the clinical and dermoscopic images of all included alm cases in were analyzed independently by two authors (fo and ik). clinical data included age, gender, and anatomic distribution. histopathologic parameters included breslow tumor thickness and clark’s level of invasion. the dermoscopic variables evaluated were based on pertinent literature on dermoscopy of acral melanocytic neoplasms [22,23,2528,30,31]. in nail apparatus melanomas, we also analyzed the pattern of involved periungual skin. results there were 612 cases of melanoma in our database. of these, 70 (11.4%) were diagnosed as alm. the patients’ mean age was 61.2 (range 16-88), and 38 (54.3%) were females. eighty percent (n=56) of melanomas were located on the feet (50 on plantar surfaces and 6 in toenails) and 20% on hands (5 on palmar surfaces and 9 in fingernails). the mean breslow thickness was 3.84 mm; 14.3% (n=10) were classified as in situ melanomas, 11.4% (n=8) were <1 mm, while 74.3% were thick melanomas (breslow thickness 1-2 mm in 7 patients; >2-4 mm in 23 patients; >4 mm in 22 patients). the majority of melanomas (47.1%; n=33) exhibited clark’s level iv. of acral melanomas, we analyzed the dermoscopic features in 46 melanomas with sufficient image quality (table 1). among global features, prp was seen in 60.8%, idp was seen in 28.3%, and multicomponent pattern in 47.8%. among focal dermoscopic patterns, most frequent were the irregular fibrillar pattern (ifp) in 34.8% and pfp in 30.4%. among dermoscopic findings described in melanoma on nonglabrous skin, an abrupt edge was seen in 34.8%, irregular streaks in 32.6%, and blue-whitish veil (bwv) in 30.4%. most lesions (76.1%) showed multiple colors, 52.2% exhibited atypical vessels, and 39.1% showed ulceration. we observed a new dermoscopic feature in 13.0% (n=6) of the melanomas, termed henceforth as “vascularized parallel-ridge pattern” (vprp). this new dermoscopic finding is defined as “erythema and dotted vessels filling the ridges and sparing the sulci” (figures 1-5). of alms, 24% were amelanotic melanomas, including 4 non-pigmented melanomas and 7 hypopigmented with some remnants of pigmentation under dermoscopy. atypical vessels were observed in all lesions, with dotted vessels being most common (72.7%, figure 6). of amelanotic melanomas, 4/11 (36.4%) showed the vprp pattern (figures 1-3). background acral lentiginous melanoma (alm) accounts for 2-8% of all melanomas in caucasians [1-3], 15% to 35% in darkskinned [4-7], and up to 60% in asians [8]. the nail unit or subungual melanoma, an anatomical variant of alm, is even less frequent, accounting for 1-2% of all melanomas in white population [9-12] and 10-20% in asians [13,14]. “lentiginous” relates to a histopathologic pattern of proliferation of melanocytes along the dermoepidermal junction (dej) as single cells and small nests with areas of confluent growth, although not all acral melanomas display this specific pattern [15]. of acral melanomas, alm is the most prevalent histopathologic subtype (40%-80%) [16-18]. due to the low incidence of alm, clinical experience is limited to specialized centers. moreover, the atypical clinical presentation and relatively high frequency of amelanotic variants are seen among alms. as a result, delayed diagnosis or misdiagnosis may lead to detection of alm at a more advanced stage with poor prognosis [15]. dermoscopy increases the diagnostic accuracy for early alm diagnosis, helping to differentiate it from acral nevi [19-23]. alm is typified by pigmentation along the skin ridges, termed “parallel-ridge pattern” (prp), while acral nevi display mostly the “parallel-furrow pattern” (pfp) [2428]. among alms, other dermoscopic patterns include the irregular diffuse pigmentation (idp), defined as structureless, diffuse pigmentation with variable shades of brown to black color and without parallel disposition of pigment [22-24,28]; the multicomponent pattern, defined as exhibiting more than one predominant dermoscopic criteria [29] or a combination of pigmentation patterns [30]; and the polymorphic vascular pattern that is especially seen among amelanotic acral melanomas. the aim of the present study was to calculate the proportion of alm among all melanoma subtypes and to determine the frequency of dermoscopic features of alm in the turkish population. methods all melanoma cases between 2005 and 2014 were identified retrospectively from the archive of the dermato-oncology unit, department of dermatology of ege university, izmir, turkey. our institution did not require an ethics committee approval for this retrospective study of dermoscopic images. for all cases included in the study, the diagnosis of alm was based on the histopathologic report. images of all cases of alm were reviewed; we excluded cases that lacked a dermoscopic image of the primary lesion or when image quality was insufficient for evaluation of pattern. 142 research | dermatol pract concept 2018;8(2):14 discussion in our series, the prevalence of alm among the melanomas was 11.4%, in contrast to the reported prevalence among caucasians of 2-8% [1-3]; this slightly higher prevalence may be related to turkish ethnicity. the most prevalent dermoscopic pattern in our series was the prp, seen in 60.8% of alms, and in line with previous studies. saida et al, who first described prp [25], found this pattern in 86% of cases, with sensitivity and specificity of prp for alm diagnosis being 86.4% and 99%, respectively [23]. likewise, thomas et al [31] and argenziano et al [29] have reported that prp was detectable in 53% and 65.3% of their cases. idp has been reported as the second most common dermoscopic pattern of alm; it is more suggestive of invasive melanoma [19,21,23,31]. in our study, idp was found in 28.3%. the prevalence of idp reported in the literature is variable: argenziano et al reported 13.6% [29], braun et al reported 20.5% [30], thomas et al 60% [31] and saida et al 85% [23]. we speculate that idp is seen in lower frequency in thicker melanomas, as notably 60% of alms in our series reached clark’s level iv and v. with regard to other acral patterns, a benign pattern such as pfp can be observed at times [30] but only focally and always together with melanomaspecific criteria. multicomponent pattern (47.8%) and ifp (34.8%) were the other most prevalent patterns, as expected, in the literature [19]. additional melanoma-specific criteria, seen in melanomas on non-glabrous skin [32,33]—including abrupt edge, irregular dots and globules (d/g), streaks, and blue-whitish veil (bwv)— were observed in one-third of our series; in addition, the high frequency of ulceration (40%), atypical vessels (>50%), and notably multiple colors (76%) are again attributable to the high proportion of thick melanomas in our series [19]. about one-fifth of cases were nail unit melanomas mainly exhibiting an irregular msl pattern, with variability in lines, color, thickness, spacing and parallelism, in addition to hutchinson’s sign seen in all cases. notably, the usual finding of brown background, as previously reported by thomas et al [31], was replaced by a multicolored background in most of our cases (73%); we find this to be a useful diagnostic clue. about one-quarter were amelanotic melanomas, in line with the previous reported frequencies by thomas et al (28%34%) [31], and kato and coworkers (19.6%) in the japanese population [34]. furthermore, all melanomas exhibited atypical vessels, and in fact, the lack or scarcity of pigmentation allowed a clear visualization of the dermoscopic vascular pattern. argenziano et al found that dotted vessels were detectable in 22.7% of melanomas, while erythema (defined as pinkish color within areas of regression or at the border of the lesion) was combined with different types of vessels in 43/159 melanomas [35]. erythema was also slightly more prevalent among in situ melanomas, compared with invasive of nail unit melanomas, 11  of  15  cases (73.3%) showed adequate dermoscopic image quality for evaluation. hutchinson’s sign (i.e., pigmentation of the periungual skin) was detected in all cases. the mean breslow thickness was 1.73 mm and 2 cases were in situ (18.2%). melanonychia striata longitudinalis (msl), i.e. a pigmented band of the nail plate, was observed in 9 cases (81.8%); however, the bands were comprised of irregular lines with respect to their color, thickness, spacing and parallelism (figures 7-8). nail plate dystrophy was seen in 7 cases (64%, figure 9). the most prevalent dermoscopic feature corresponded to irregular lines (81.8%) and multicolored background (72.7%) (table 2). table 1. dermoscopic patterns found in our 46 cases of acral lentiginous melanomas (alm), including involvement of periungual skin in nail apparatus melanoma. dermoscopic patterns number of alm (n, total= 46) percentage of alm (%) parallel-ridge pattern (prp) 28 60.8 irregular diffuse pigmentation (idp) 13 28.3 other patterns: multicomponent 22 47.8 polymorphic vascular 5 10.9 starburst 1 2.2 parallel-furrow (focal) 14 30.4 irregular fibrillar (focal) 16 34.8 lattice-like (focal) 1 2.2 reticular (focal) 2 4.3 homogeneous (focal) 1 2.2 non-typical 0 0 negative fibrillar 5 10.9 abrupt edge 16 34.8 irregular dots and globules 13 28.3 irregular streaks 15 32.6 homogenous area 11 23.9 irregular blotch 6 13 blue-white veil 14 30.4 scar-like depigmentation 11 23.9 peppering or grey dots 3 6.5 ulceration 18 39.1 atypical vessels 24 52.2 multiple colors 35 76.1 vascularized prp 6 13 research | dermatol pract concept 2018;8(2):14 143 figure 1. vascularized parallel-ridge pattern (vprp). acral lentiginous melanoma, breslow 3.3 mm, clark iii. at dermoscopic evaluation, presence of erythema and some dotted vessels on the ridges, sparing the sulci (right). no erythema is detectable on the other healthy sole (left). [copyright: ©2018 ozdemir et al.] figure 2. vascularized parallel-ridge pattern (vprp). acral lentiginous melanoma, breslow  0.8  mm, clark ii. evidence of erythema and few dotted vessels on the ridges, together with negative fibrillary pattern; white lines corresponding to eccrine ducts in the horny layer are seen throughout the lesion (arrows). [copyright: ©2018  ozdemir et al.] figure 3. parallel-ridge pattern (prp) and vascularized prp (vprp). recurrent, in situ, acral lentiginous melanoma (original lesion was alm, breslow 2.5 mm, clark iv). both patterns are detectable sideby-side (prp in circle, vprp in rectangles). [copyright: ©2018 ozdemir et al.] 144 research | dermatol pract concept 2018;8(2):14 figure 4. vascularized prp (vprp). acral lentiginous melanoma, breslow 4.39 mm, clark iv. vprp (in circles) is detectable along with remnants of pigmentation and gray dots. [copyright: ©2018 ozdemir et al.] figure 5. parallel-ridge pattern (prp) and vascularized prp (vprp). acral lentiginous melanoma, breslow 2.26 mm, clark iv. both patterns are seen side-by-side (top left) and intermingled with each other (bottom left and right). [copyright: ©2018 ozdemir et al.] research | dermatol pract concept 2018;8(2):14 145 figure  7. nail unit melanoma dermoscopic features. breslow  0.9  mm, clark iii. the longitudinal bands show irregular colors and lack of parallelism. hutchinson’s sign is detectable at clinical inspection. [copyright: ©2018 ozdemir et al.] figure  6. examples of amelanotic melanomas showing remnants of pigmentation and atypical vessels on dermoscopy. [copyright: ©2018 ozdemir et al.] 146 research | dermatol pract concept 2018;8(2):14 figure 9. nail unit melanoma dermoscopic features. (on the left) breslow 2.7 mm, clark iii. (on the right) breslow 3.2 mm, clark iv. both show nail plate dystrophy. triangular shape of the band and microhemorrhage are detectable on the right. [copyright: ©2018 ozdemir et al.] figure 8. nail unit melanoma dermoscopic features. two in situ melanomas. the lines are irregular in thickness and spacing. [copyright: ©2018 ozdemir et al.] research | dermatol pract concept 2018;8(2):14 147 lations, with prp being the most frequent. a lower incidence of idp pattern may be related to the higher mean thickness of melanomas in our series. a newly described dermoscopic pattern, vprp, may be important for the diagnosis of thin amelanotic alms. however, the significance of this dermoscopic feature needs to be validated in larger series. references 1. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-127. 2. de giorgi v, sestini s, massi d, maio v, giannotti b. dermoscopy for “true” amelanotic melanoma: a clinical dermoscopy-pathologic case study. j am acad dermatol. 2006;54(2):341-344. melanomas [35]. steglich et al stated that melanoma initially shows dotted vessels and that with greater thickness, vascular polymorphism increases, with hairpin and linear-irregular vessels associated with milky-red areas. dotted vessels may be the only clue to suspect non-pigmented melanoma [36]. similar to thin amelanotic melanomas on non-glabrous skin showing only dotted vessels under dermoscopy, vprp may be an important alerting sign for early diagnosis of alm. melanoma cells, mostly among in situ melanomas, tend to cluster around the crista intermedia, leading to pigmentation on the ridges, seen as prp on dermoscopy [22]. this may be due to the tendency, shown by melanocytic stem cells generating melanoma, to reside, at the beginning, near the crista intermedia or the eccrine ducts. on the other hand, in deeply invasive melanomas, tumor cells tend to diffusely proliferate with a similar intensity in both crista intermedia and crista limitans [22]. since vascularization and inflammation is likely to be greater where the neoplastic melanocytes proliferate, we reason that in amelanotic cases, the increased vasculature will be most prominent along the same region, namely, the crista intermedia (figure 10). this will manifest under dermoscopy as erythema and dotted vessels on the ridges, along the crista intermedia areas, accounting for the dermoscopic feature described herein as vprp (figure 11). in pigmented alm, melanin obscures the increased vascularization leading to the prp pattern. this is best seen in hypopigmented melanomas, whereby prp in the lightly pigmented and vprp in the amelanotic areas can both be seen. conclusion in conclusion, we found that alms in turkish patients display similar dermoscopic patterns as reported in other poputable 2. dermoscopic patterns of nail unit melanomas. dermoscopic patterns number of subungual melanomas (n, total = 11) percentage of subungual melanomas (%) multicolored background 8 72.7 brown background 3 27.3 irregular lines 9 81.8 blood spots 6 54.5 linear microhemorrhages 2 18.2 triangular shape of the band 1 9 micro-hutchinson’s sign 0 0 figure 10. histopathologic section of periphery of acral melanoma shown in figure 2. breslow 0.8 mm, clark ii. proliferation of nonpigmented cells may be identified around crista intermedia (arrows). hematoxylin and eosin (h&e) staining (original magnification x100). [copyright: ©2018 ozdemir et al.] figure  11. histopathological section of periphery of acral melanoma shown in figure 5. breslow  2.26  mm, clark iv. prominent vascular proliferation (asterisk) is detectable around crista intermedia/eccrine ducts, compared to other parts. h&e staining (original magnification x100). 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volar skin using video macroscope. arch dermatol. 1995;131(3):298-304. 26. malvehy j, puig s. dermoscopic patterns of benign volar melanocytic lesions in patients with atypical mole syndrome. arch dermatol. 2004;140(5):538-544. 27. ozdemir f, karaarslan ik, akalin t. variations in the dermoscopic features of acquired acral melanocytic nevi. arch dermatol. 2007;143(11):1378–1384. 28. saida t, koga h. dermoscopic patterns of acral melanocytic nevi: their variations, changes, and significance. arch dermatol. 2007;143(11):1423-1426. 29. lallas a, sgouros d, zalaudek i, et al. palmar and plantar melanomas differ for sex prevalence and tumor thickness but not for dermoscopic patterns. melanoma res. 2014;24(1):83-87. 30. braun rp, thomas l, dusza sw, et al. dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society. dermatology. 2013;227(4):373-380. 31. phan a, dalle s, touzet s, ronger-savlé s, balme b, thomas l. dermoscopic features of acral 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prognostic significance. j dermatol surg oncol. 1994;20(12):817–822. 17. kuchelmeister c, schaumburg-lever g, garbe c. acral cutaneous melanoma in caucasians: clinical features, histopathology and prognosis in 112 patients. br j dermatol. 2000;143(2):275–280. 18. slingluff cl jr, vollmer r, seigler hf. acral melanoma: a review of 185 patients with identification of prognostic variables. j surg oncol. 1990;45(2):91–98. 19. saida t, koga h, uhara h. key points in dermoscopic differentiation between early acral melanoma and acral nevus. j dermatol. 2011;38(1):25–34. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):17 71 dermatology practical & conceptual introduction in 2013, ex vivo derm dotting was published as a technique to mark a dermoscopically interesting area by dotting it with nail polish after fixation of the specimen [1]. although interesting, this technique may have its disadvantages. first, the pathologist needs to know dermoscopy. second, we already have shown that ex vivo and in vivo dermoscopic images display different features: some structures and colors are less clear or even lost, while others become more prominent [2]. this may lead to different areas of interest in vivo and ex vivo. moreover, pathologists have been using the technique for only a few years, and they are still developing criteria for it. case presentation dermatologists are trained dermoscopists and know the areas of highest interest (eg, ulceration in melanoma, changed area in existing nevus, blood vessel alterations, and collisional lesions). hence we tried to perform derm dotting in vivo by placing the nail polish dot before excision and processing. the dot survived transportation in formalin and the different processing stages in the laboratory (formalin 10% fixation for 48 hours, paraffin embedding, cutting, and hematoxylin and eosin staining or immunohistochemical staining). the dot remained in place, which enabled us to make a pathology slide through it. the marked area remained easily detectable and visible under the microscope (figure 1). to fine-tune the practical aspects, we applied different types, sizes, and colors of nail polish to pig skin. applying the nail polish drop with a toothpick or a nail art brush was most rewarding. the thicker drops created using the commercial brush covered bigger areas than intended and detached easily during processing. smaller drops were easily discernable by the laboratory technician and under the microscope. their quicker drying times also allowed us to check dermoscopically in vivo to determine whether the dot was accurately placed. red, orange, blue, and black yielded the best visibility. multiple colors in one specimen are possible for collisional lesions or multiple areas of interest (figure 2). in vivo derm dotting: an easy and inexpensive way for clinicopathological correlation sven lanssens1, katrien vossaert1, sofie de schepper2 1 dermatologie maldegem, maldegem, belgium 2 university hospital ghent, department of dermatology, ghent, belgium key words: clinicopathological correlation, derm dotting, dermoscopy, nail polish citation: lanssens s, vossaert k, de schepper s. in vivo derm dotting: an easy and inexpensive way for clinicopathological correlation. dermatol pract concept. 2019;9(1):71-72. doi: https://doi.org/10.5826/dpc.0901a17 published: january 31, 2019 copyright: ©2019 lanssens et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sven lanssens, md, dermatologie maldegem, stationsstraat 92 9990 maldegem, belgium. email: sven.lanssens@ gmail.com 72 letter | dermatol pract concept 2019;9(1):17 conclusions we conclude in vivo derm dotting is an easy and inexpensive method for clinicopathological correlation, and we believe it should be incorporated in routine dermatological practice. all tested commercially available nail polishes worked perfectly, but small drops of red, orange, blue, and black yielded the best results. references 1. haspeslagh m, degryse n, de wispelaere i. routine use of ex vivo dermoscopy with “derm dotting” in dermatopathology. am j dermatopathol. 2013;35(8):867-869. 2. haspeslagh m, vossaert k, lanssens s, et al. comparison of ex vivo and in vivo dermoscopy in dermatopathologic evaluation of skin tumors. jama dermatol. 2016;152(3):312-317. figure 1. pig skin with different nail polish drops (a). preparing for routine processing (b, c). view under the microscope after routine processing, with a clearly visible dot on top, without damaging the underlying skin (d). [copyright: ©2019 lanssens et al.] figure 2. clinical view of lesion on the nose (a). dermoscopic view of the same lesion, composed of potential collision of 4 different lesions (b). dotting of the 4 different areas in 4 different colors (c). clinical view after dotting the lesion and before excision (d). [copyright: ©2019 lanssens et al.] a b c d d a b c dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022098 1 butterfly sign in scabies: towards an evolutionary process? teresa oranges1, fausto andrea pedaci2, cesare filippeschi1 1 dermatology unit, department of pediatrics, meyer children's hospital, florence, italy. 2 department of health sciences, meyer children’s hospital, florence, italy. key words: scabies, sarcoptes scabiei hominis, dermoscopy, dermatoscopy, resistance citation: oranges t, pedaci fa, filippeschi c. butterfly sign in scabies: towards an evolutionary process? dermatol pract concept. 2022;12(3):e2022098. doi: https://doi.org/10.5826/dpc.1203a98 accepted: october 25, 2021; published: july 2022 copyright: ©2022 oranges et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: teresa oranges, md, phd, department of pediatrics, dermatology unit, meyer children's hospital, viale gaetano pieraccini 24, 50139, florence, italy tel +39 0555662944 e-mail: teresa.oranges@gmail.com dermatology practical & conceptual introduction human scabies is a worldwide skin infestation caused by the mite sarcoptes scabiei  hominis and remains a significant public health concern. the detection of the mite is essential for diagnosis and entodermoscopy strongly improves diagnostic reliability. the mite is visible on dermoscopy at the head of the burrow, due to its refractile area located between the buccal apparatus and the second pair of legs. this sign is called “triangle” sign or “delta glider” sign, or “hang glider” sign (figure 1a, asterisk) [1]. the “triangle” sign is usually accompanied by reflecting bubbles along the tunnel called “jet trail” sign on wet dermoscopy (figure 1a, arrow) [1]. other less frequently observed dermoscopic signs have been described and one of the most recently described feature is the “gray-edge line” sign, that it’s due to the presence of mite feces containing melanin (figure 1a, arrowhead) [1]. we present a new dermoscopic sign observed in 2 cases, in the era of progressive resistance of sarcoptes scabiei hominis to standard treatments. figure 1. (a) dermoscopy of a scabies burrow showing the “delta glider” sign (asterisk), reflective bubbles within the burrow referred to as “jet trail” sign (arrow) and blackish-gray lines at some points of the burrow walls consistent to the “gray-edge line” sign (arrowhead). (b) microscopic examination of a sarcoptes scabiei hominis with classical features: the gut area appears poorly demarcated and of the same color of the adjacent structures (arrow). 2 research letter | dermatol pract concept. 2022;12(3):e2022098 figure 2. dermoscopic evaluation of a scabies burrow of the 5-years old patient (a) and of the 10-years old patient (c) with the corresponding microscopic appearance of the scraped mites (b and d). (a-c) both dermoscopic images show the “delta glider” sign (asterisks) and the presence, just below, of a reddish structure corresponding to the “butterfly” sign (arrows). (b-d) microscopic features of the anterior part of the mite body (asterisks) and of the underlying gut area which appear well demarcated and reddish in color (arrows). case presentation we observed 2 cases of young patients (a 10-year-old male and a 5-year-old male) referred to the dermatologic unit for scabies present for several months, treated with multiple cycles of permethrin 5% cream. physical examination revealed persistent multiple mite burrows with classic dermoscopic image of “delta glider” sign (figure 2, a-c, asterisk), corresponding to the anterior part of the mite (figure 2, b-d, asterisk), associated with a new dermoscopic sign, which we called the “butterfly” sign, characterized by a butterfly-shaped reddish area just below the “delta glider” sign (figure 2, a-c, arrow). the microscopic examination of the scraped skin in correspondence to the burrow showed in both patients the presence of the mite with a well-defined butterfly-shaped gut area, with a reddish coloration resembling blood (figure 2, b-d, arrow). of note, the gut area of the sarcoptes scabiei hominis mite is usually not so clearly visible under the microscope (figure 1b, arrow). conclusions recently, several authors described the emerging phenomenon of resistance of mites to standard treatments, in particular research letter | dermatol pract concept. 2022;12(3):e2022098 3 to permethrin, as in our cases [2]. considering these recent evidences, this report suggests a new dermoscopic sign as a possible marker of sarcoptes scabiei hominis evolution. references 1. ueda t, katsura y, sasaki a, minagawa d, amoh y, shirai k. gray-edged line sign of scabies burrow. j dermatol. 2021;48(2): 190-198. doi: https://doi.org/10.1111/1346-8138.15650. pmid: 33063894. 2. mazzatenta c, piccolo v, argenziano g, bassi a. is scabies becoming less sensitive to permethrin therapy? j eur acad dermatol venereol. 2021;35(9):e607-e609. doi: 10.1111/jdv.17339. pmid: 33974300. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(2):8 41 spitz nevus on the sole of the foot presenting with transepidermal elimination hiromi kobayashi1, kyosuke oishi1, miho miyake1, chihiro nishijima1, atsuhiro kawashima2, hiroto kobayashi3, makoto inaoki1 1 department of dermatology, national hospital organization kanazawa medical center, kanazawa, japan 2 department of laboratory medicine, national hospital organization kanazawa medical center, kanazawa, japan 3 kobayashi dermatological clinic, kanazawa, japan keywords: dermoscopy, histopathology, spitz nevus, transepidermal elimination citation: kobayashi h, oishi k, miyake m, nishijima c, kawashima a, kobayashi h, inaoki m. spitz nevus on the sole of the foot presenting with transepidermal elimination. dermatol pract concept. 2014;4(2)8. http://dx.doi.org/10.5826/dpc.0402a08 received: november 11, 2013; accepted: march 1, 2014; published: april 30, 2014 copyright: ©2014 kobayashi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: makoto inaoki, m.d., department of dermatology, national hospital organization kanazawa medical center, 1-1 shimoishibiki-machi, kanazawa, ishikawa 920-8650, japan. tel. 81.76.262.4161; fax. 81.76.222.2758. e-mail: inaoki-m@kinbyou. hosp.go.jp case presentation a 10-year-old japanese girl presented with an 8-month history of pigmented lesion on the sole of the right foot. examination showed a rhomboid-shaped brown macule with keratotic scale, 4x3 mm in size, on the lateral center side of the sole (figure 1). dermoscopic examination revealed that a number of black dots and globules were evenly distributed on the ridges of the skin, marking an area of symmetrical brown pigmentation (figure 2). on the periphery, a streak-like arrangement of black dots/globules on the brown pigmentation was observed along the ridges, simulating a “starburst” pattern. the lesion was excised under the diagnosis of atypical melanocytic nevus. histological examination showed epidera 10-year-old japanese girl presented with a rhomboid-shaped brown macule, 4x3 mm in size, on the sole of the right foot. dermoscopic examination revealed a number of black dots and globules on the ridges of the skin, marking an area of symmetrical brown pigmentation. on the periphery, a streaklike arrangement of black dots/globules on the brown pigmentation was observed along the ridges, simulating a “starburst” pattern. the lesion was excised and histological examination showed a symmetrical wedge-shaped compound melanocytic lesion that consisted of junctional and intradermal nests of a mixture of large spindle and epithelioid cells. none of the cells were atypical, and maturation of the cells with increasing depth was observed. from these findings, a diagnosis of spitz nevus was made. transepidermal elimination of nevus cell nests was observed and there were small groups of degenerated melanin-laden cells in the cornified layer. masson fontana stain revealed fine melanin deposits in the nevus cells of the junctional and intradermal nests, as well as heavy melanin deposits in the small groups of degenerated cells in the cornified layer. the distribution of melanin may contribute to a unique dermoscopic finding in this case. abstract mailto:inaoki-m@kinbyou.hosp.go.jp mailto:inaoki-m@kinbyou.hosp.go.jp 42 observation | dermatol pract concept 2014;4(2):8 finding of brown pigmentation, and heavy melanin deposits in the groups of degenerated cells in the cornified layer may correspond to the black dots on dermoscopy. these two components of melanin deposits constitute the dermoscopic pattern found in the present case. the small groups of degenerated melanin-laden cells in the cornified layer may come from the junctional nevus cell nests through transepidermal elimination. transepidermal elimination is infrequently observed in spitz nevus [3,4], but this phenomenon may provide a unique pattern on dermoscopy, as seen in the present case. involution as the natural evolution of spitz nevi on the face, extremities, and trunk has been reported [5]. in the regression of pigmented skin lesions such as melanoma, fibrosis, melanosis, and numerous telangiectasis are histopathologically observed [6], but the combination of these features is not found in spitz nevi. the mechanism of involution of spitz nevi remains unclear. however, the transepidermal elimination observed in the present case may be related to this mechanism. dermoscopy is a useful tool for differentiating early melanomas from benign melanocytic nevi on acral volar skin. parallel ridge pattern is a highly specific dermoscopic pattern of malignant melanoma, including melanoma in situ on acral volar skin [7]. an irregular diffuse pigmentation pattern is also highly specific to malignant melanoma on acral volar skin [7]. in contrast, a parallel furrow pattern is the most prevalent pattern in melanocytic nevi on acral volar skin [7]. in the present case as well as in the case of hatta et al. [2], dermoscopic examination showed dominant pigmentation on the ridges. thus, pigmented spitz nevus on the sole of the foot may be a differential diagnosis of malignant melanocytic lesion. however, dermoscopic patterns of the present case, including the equal and symmetrical distribution of black dots and globules in the area of the brown pigmentation, are mal hyperplasia and a symmetrical, wedge-shaped compound melanocytic lesion (figure 3a). junctional and intradermal nests were well circumscribed, and consisted of a mixture of large spindle and epithelioid cells. none of the nevus cells were atypical, and maturation of the cells with increasing depth was observed (figure 3b). upward epidermal spread of a single nevus cell or small groups of cells was absent. from these findings a diagnosis of spitz nevus was made. transepidermal elimination of nevus cell nests was seen and there were small groups of degenerated melanin-laden cells in the cornified layer (figure 3c). the nevus cells, including the degenerated cells in the cornified layer, were s-100 protein positive. masson fontana stain revealed fine melanin deposits in the nevus cells of the junctional and intradermal nests, as well as heavy melanin deposits in the small groups of degenerated cells in the cornified layer (figure 3d). conclusion spitz nevus, also known as spindle and epithelioid cell nevus, is found primarily on the lower extremities, followed by the trunk and upper extremities. a report on japanese patients demonstrated that spitz nevus on glabrous skin represents 2% of all spitz nevi [1]. thus, little is known about the dermoscopic findings of spitz nevus on the plantar aspect due to its rarity. dermoscopic examination of a pigmented spitz nevus on the sole of the foot by hatta et al. [2] revealed a central black astructural area, large peripheral blue-black globules, and streaks along the ridges of the skin marking simulating starburst pattern [2]. the dermoscopic finding in the present case of black dots and globules on the ridges in the peripheral area is similar to the finding of that previous published case [2]. however, the number of black dots and globules in the area of diffuse brown pigmentation in the present case are very different from the dermoscopic finding of that previous case [2]. in the present case, fine melanin deposits in the junctional and intradermal nests may correspond to the dermoscopic figure 1. clinical image. there is a brown macule on the lateral side of the sole of the right foot. [copyright: ©2014 kobayashi et al.] figure 2. dermoscopy shows a number of black dots and globules on the ridges of the skin, marking an area of symmetrical brown pigmentation. on the periphery, a streak-like arrangement of black dots/globules on the brown pigmentation simulate a starburst pattern. [copyright: ©2014 kobayashi et al.] observation | dermatol pract concept 2014;4(2):8 43 3. rupec m, kint a, horn w. [juvenile melanoma; a clinical and histological study]. hautarzt. 1979;30(11): 581-5. 4. merot y, frenk e. spitz nevus (large spindle cell and/or epithelioid cell nevus). age-related involvement of the suprabasal epidermis. virchows arch a pathol anat histopathol. 1989;415(2): 97-101. 5. argenziano g, agozzino m, bonifazi e, et al. natural evolution of spitz nevi. dermatology. 2011;222(3):256-60. 6. kaya g, braun rp. histopathological correlation in dermoscopy. in: marghoob aa, braun rp, kopf aw, eds. atlas of dermoscopy. 1st ed. abingdon: taylor & francis, 2005:23-7. 7. saida t, miyazaki a, oguchi s, et al. significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in japan. arch dermatol. 2004;140(10):1233-8. different from the patterns of malignant melanoma on acral volar skin. the dermoscopic pattern of the present case may be novel, and this report may help in the diagnosis of melanocytic lesions on acral volar skin. references 1. banba k, fujioka a, takasu h, ishibashi a, ohta m. spitz nevus on the palmar surface. j dermatol. 2000;27(5):333-6. 2. hatta n, arai m, makino s. dermoscopic findings of pigmented spitz nevus of the sole. j dermatol. 2012;39(12): 1048-9. figure 3. histopathological features: (a) epidermal hyperplasia and a symmetrical, wedge-shaped compound melanocytic lesion are seen (hematoxylin & eosin, 2x). (b) the junctional and intradermal nests by an eccrine duct consist of a mixture of large spindle and epithelioid cells, but none of them was atypical. maturation of the cells with increasing depth is observed (hematoxylin & eosin, 100x). (c) a transepidermal elimination of nevus cell nests and a small group of degenerated melanin-laden cells over the elimination in the cornified layer are seen (hematoxylin & eosin, 150x). (d) fine melanin deposits in the nevus cells of the junctional and intradermal nests, as well as heavy melanin deposits in the small groups of degenerated nevus cells in the cornified layer, are seen (masson fontana, 4x). [copyright: ©2014 kobayashi et al.] dermatology: practical and conceptual 160 letter | dermatol pract concept 2019;9(2):17 dermatology practical & conceptual introduction a wide spectrum of skin tumors may mimic basal cell carcinoma (bcc) on both clinical and dermoscopic appearance. among these, adnexal skin neoplasms and in particular benign follicular tumors are commonly indistinguishable from bcc [1]. benign follicular tumors are uncommon skin neoplasms, mainly represented by trichoblastoma and trichoepithelioma; however, other rarer subtypes may be also encountered, such as trichoadenoma, trichofolliculoma, and panfolliculoma. to the best of our knowledge, no reports have previously described the dermoscopic appearance of trichoadenoma. herein we report a case of a man in his 40s who had a long-standing 5-mm papule located on his left eyebrow; the lesion was flesh-colored, firm, and painless (figure1a). case presentation dermoscopic evaluation was performed with a contact polarized dermatoscope (dermlite foto, 3gen llc, dana point, ca, usa) and showed a general bcc-like appearance. in particular, crystalline structures could be identified through the lesion, together with an ovoid blue-gray area at the periphery of the tumor and diffuse on-focus linear vessels, visible only when gentle pressure was applied. in addition, another dermoscopic feature could also be observed that is not typically seen in bcc, consisting of small whitish circles with a diffuse distribution (figure 1, b and c). the lesion was excised with the suspicion of bcc. the histopathological diagnosis was trichoadenoma (figure 1d). trichoadenoma is an uncommon benign tumor originating from the infundibular part of the pilosebaceous unit, broadening the list of basal cell carcinoma mimickers: dermoscopic features of trichoadenoma riccardo pampena1, stefania borsari1, simonetta piana2, caterina longo1,3 1 centro oncologico ad alta tecnologia diagnostica, azienda unità sanitaria locale irccs di reggio emilia, italy 2 pathology unit, azienda unità sanitaria locale irccs di reggio emilia, italy 3 department of dermatology, university of modena and reggio emilia, modena, italy key words: trichoadenoma, basal cell carcinoma, adnexal tumors, dermoscopy citation: pampena r, borsari s, piana s, longo c. broadening the list of basal cell carcinoma mimickers: dermoscopic features of trichoadenoma. dermatol pract concept. 2019;9(2):160-161. doi: https://doi.org/10.5826/dpc.0902a17 accepted: january 10, 2019; published: april 30, 2019 copyright: ©2019 pampena et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was supported by italian ministry of health (project code: net-2011-02347213). competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: riccardo pampena, md, centro oncologico ad alta tecnologia diagnostica, azienda unità sanitaria locale – irccs, viale risorgimento 80, 42123, reggio emilia, italy. email: riccardopampena@gmail.com letter | dermatol pract concept 2019;9(2):17 161 of bcc mimickers. in particular, we found a prevalence of crystalline structures, arranged as shiny white lines and white circles. the former were previously described as characterizing both bccs and skin adnexal tumors [1]; the latter were also previously reported in adnexal tumors, but are commonly absent in bccs. white circles are probably histopathologically correlated with the infundibulocystic structures characterizing trichoadenoma, although further studies are needed to support this preliminary hypothesis. references 1. lallas a, moscarella e, argenziano g, et al. dermoscopy of uncommon skin tumors. australas j dermatol. 2014;55(1):53-62. 2. shimanovich i, krahl d, rose c. trichoadenoma of nikolowski is a distinct neoplasm within the spectrum of follicular tumors. j am acad dermatol. 2010;62(2):277-283. which was first described in 1958 by nikolowski as “organoid follicular hamartoma.” generally, it involves adults without sex predilection and appears as a solitary skin-colored papule. more than half of cases have been described on the face and almost one quarter on the buttock [2]. occasionally, trichoadenoma was also reported in association with a nevus sebaceous. histopathologically, it shows a level of organization intermediate between trichofolliculoma and trichoepithelioma, with distinctive features from both of these neoplasms. in particular, trichoadenoma commonly appears as a well-circumscribed, dermal nodule, characterized by multiple infundibulocystic structures lined with stratified squamous epithelium, with a granular layer, showing epidermoid differentiation and resembling multiple cross-sections of the infundibular portion of hair follicles. however, hair shafts are generally absent. the main differential diagnosis of trichoadenoma is represented by desmoplastic trichoepithelioma, and some authors have suggested that trichoadenoma could even be a variant of the latter. however, clinical, histopathological, and immunohistochemical differences suggest that these tumors should be considered distinct entities [2]. conclusions in this report we first described the dermoscopic features of trichoadenoma, showing that this tumor should also be considered in the broad spectrum figure 1. (a) clinical picture revealing a 5-mm flesh-colored papule over the left eyebrow of a 45-year-old man. (b,c) dermoscopic pictures with polarized light, without (b) and with (c) compression. on-focus linear vessels may be seen when compression was not applied; in addition, an ovoid blue-gray area was visible at the periphery of the tumor. when compression was not applied, white structures were more visible: in particular, shiny white lines (black arrows) and small whitish circles (red arrows). (d) at histological examination, the dermis showed irregularly shaped keratinous cysts, many filled with keratotic material and lined with stratified squamous epithelium with epidermoid differentiation. some cysts were superficial and opened into the epidermis (hematoxylin and eosin, ×40). [copyright: ©2019 pampena et al.] a c b d dermatology: practical and conceptual 28 research | dermatol pract concept 2018;8(1):6 dermatology practical & conceptual www.derm101.com immunoreactivity of wilms tumor 1 (wt1) as an additional evidence supporting hemangiomatous rather than inflammatory origin in the etiopathogenesis of angiolymphoid hyperplasia with eosinophilia fatma tokat1, julia s. lehman2, engin sezer3, emel dikicioglu cetin1, umit ince1, emel ozturk durmaz3 1 department of pathology acibadem university school of medicine, istanbul, turkey 2 department of dermatopathology mayo clinic, rochester, mn, usa 3 department of dermatology acibadem university school of medicine, istanbul, turkey key words: angiolymphoid hyperplasia with eosinophilia, wilms tumor 1, glut1, hemangioma citation: tokat f, lehman js, sezer e, dikicioglu cetin e, ince u, ozturk durmaz e. immunoreactivity of wilms tumor 1 (wt1) as an additional evidence supporting hemangiomatous rather than inflammatory origin in the etiopathogenesis of angiolymphoid hyperplasia with eosinophilia. dermatol pract concept. 2018;8(1):28-32. doi: https://doi.org/10.5826/dpc.0801a06 received: july 18, 2017; accepted: november 14, 2017; published: january 31, 2018 copyright: ©2018 tokat et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: engin sezer, md, acibadem university school of medicine, department of dermatology, buyukdere caddesi no: 40, istanbul, 34457, turkey. tel. 902123044626; fax. 902123044440. email: eseze@yahoo.com background: angiolymphoid hyperplasia with eosinophilia (alhe) is a rare vascular proliferative disorder mainly located in the periauricular region. the etiopathogenesis of alhe is unknown, and it is still controversial as to whether the entity represents a benign vascular neoplasm or an inflammatory process. aim: recently, the intracytoplasmic staining pattern of wilms tumor 1 (wt1) on immunohistochemistry has highlighted true vascular neoplasms, such as microvenular hemangioma, tufted angioma, and spindle cell hemangioma, which has made it helpful to distinguish alhe from vascular malformations, as there is a negative staining pattern in the other entities. we aimed to investigate the immunoreactivity of alhe specimens for wt1 as well as glucose transporter protein 1 (glut1) immunohistochemistry, an important and sensitive marker for the diagnosis of infantile hemangioma, which recently has been described to label other hemangiomas, such as verrucous hemangioma. material and methods: clinical data and histopathological specimens from patients diagnosed with alhe were reviewed, and immunohistochemical staining and microscopic analysis for wt-1 and glut1 were performed. results: intracytoplasmic endothelial staining of wt1 was detected in 19 of 20 alhe specimens. glut1 was not detected in any alhe specimen. conclusions: we conclude that alhe may represent a true hemangioma (i.e., benign vascular neoplasia) characterized by an eosinophiland lymphocyte-rich inflammatory component as opposed to the reactive inflammatory dermatosis with a positive intracytoplasmic staining pattern for wt1. as far as we are aware, wt1 staining for alhe has not been described to date. abstract mailto:eseze@yahoo.com research | dermatol pract concept 2018;8(1):6 29 distilled water and tap water. the tissue was counterstained with mayer’s hematoxylin. all slides were covered with a cover slip. the staining intensity was evaluated as negative (-), weak (+), moderate (++), and strong staining (+++) with a primary intensity score of tumor cell staining as a positive control for the immune markers. results clinical findings clinical data for 20 patients with histopathologically confirmed alhe were evaluated. the age of the patients ranged from 9 and 93 years of age at the time of biopsy procedure with a median age of 48. a slightly increased male (n = 12) to female (n = 8) ratio was identified. most of the lesions were located on the head and neck (n = 15), followed by upper extremities (n = 4) and in a lower extremity (n = 1). immunohistochemical findings nineteen of 20 specimens were positive for wt1 intracytoplasmic staining (figure 1). moderate staining intensity (n = 10) was more frequent than weak (n = 5), and strong (n = 4) introduction angiolymphoid hyperplasia with eosinophilia (alhe) is an uncommon, idiopathic vascular proliferative disorder characterized by dermal or subcutaneous red to brown papules or nodules, commonly located in the head and neck regions. alhe is mainly a disorder of young adulthood to middle age, although children and elderly patients with the disorder have also been described. the precise etiopathogenesis of alhe is unknown and it is controversial whether it is a true vascular neoplasm (i.e., a hemangioma variant with overlying eosinophilic and lymphocytic infiltration related to cytokine expression) or a vascular proliferative disorder (secondary to an inflammatory tissue response). in this investigation, we assessed the immunoreactivity for wilms tumor 1 (wt1) in alhe specimens, which shows a cytoplasmic staining pattern in benign neoplasms such as microvenular hemangioma, tufted angioma, and spindle cell hemangioma, to highlight the pathogenesis of this rare entity [1,2]. in these tissues, we also assessed glucose transporter protein 1 (glut1) immunohistochemistry, an important and sensitive marker for the diagnosis of infantile hemangioma, which recently has been described to label some other hemangiomas such as verrucous hemangioma [3]. material and methods clinical data and histopathological specimens from patients (n = 20) diagnosed with alhe (between 2006 and 2016) were obtained from the acibadem university school of medicine pathology department and the mayo clinic dermatopathology department. approval was obtained from the institutional review board (irb) of the mayo clinic regarding the ethical concerns for the study. the diagnosis of alhe was histopathologically confirmed with the characteristic features of epithelioid endothelial cells with cytoplasmic vacuoles and a perivascular inflammatory cell infiltrate composed of numerous eosinophils, lymphocytes, and histiocytes. immunohistochemical staining and microscopic analysis for wt1 and glut1 were performed for all alhe specimens. the method used for immunostaining was the streptavidin-biotin-amplified system. the slides were submitted for subsequent steps of deparaffinization and rehydration. sections were sliced (6 µm thick) and air-dried for 30 minutes. then the sections were fixed in cold acetone for 10 minutes. after blocking endogenous peroxidase using 0.2% sodium azide for 5 minutes, they were washed with phosphate buffered saline for 15 minutes. subsequently, the sections were incubated with primary antibodies for 1 hour. the primary antibodies were wt-1 (cell marque, california, usa) and glut1 (cell marque, california, usa) with a dilution of 1:100. after incubation, the sections were rinsed with figure 1. histopathologic panoramic view of alhe (hematoxylin and eosin stain) (a) and positive staining pattern for wt1 (b) on low power magnification. 30 research | dermatol pract concept 2018;8(1):6 this rare condition has also been termed epithelioid hemangioma, histiocytoid hemangioma, inflammatory angiomatous nodule, and pseudoor atypical pyogenic granuloma [5]. the lesions commonly arise in the third and third decade of life with a slight predilection in females. histopathologically, alhe presents as an ill-defined, dermal, lobulated mass composed of numerous vascular spaces of varying luminal diameter lined by large rounded endothelial cells with conspicuous eosinophilic cytoplasm and cytoplasmic vacuoles representing primitive lumina. a prominent inflammatory infiltrate composed largely of lymphocytes, numerous eosinophils, and histiocytes surrounding the vessels are identified [6]. the etiology of alhe is unclear, and it is still controversial whether the disorder represents a benign vascular neoplasm or an inflammatory process. association with arteriovenous shunts in 43% of cases of alhe strengthens the conclusion that the entity may represent a vascular neoplastic proliferation [7]. alhe has also been reported to develop within a port wine stain in a patient, and the authors highlighted the role of increased serum renin levels in the pathogenesis of this case in which the histopathology specimen revealed expression of angiotensin converting enzyme and angiotensin ii receptors [8]. in a retrospective study of 116 alhe patients, 10 cases (9%) were found to be associated with antecedent trauma patterns. the staining pattern for wt1 was intracytoplasmic in endothelial cells, similar to that reported previously for various benign vascular neoplasms such as microvenular hemangioma and verrucous hemangioma, which revealed an intracytoplasmic staining pattern as well [1,2] (figure 2). glut1 immunohistochemistry was negative for all alhe specimens despite positive controls (figure 3). table 1 summarizes the results of the immunohistochemical stains for wt1 and glut1 in 20 histopathologically proven alhe specimens. discussion alhe was first described by wells and whimster in 1969 and was originally considered to represent late-stage kimura’s disease, but it is now widely accepted as a separate entity [4]. alhe is a benign vascular proliferation characterized by dull, single or multiple nodules mainly located in the head and neck region. involvement of the oral mucosa, arm, hand, shoulder, genital region, breast, parotid gland, orbit, colon, bone, and parapharyngeal spaces has also been described. figure 2. details of the same specimen with epithelioid endothelial cells showing characteristic cytoplasmic vacuoles and associated eosinophilic and lymphocytic inflammation (a) intracytoplasmic staining pattern for wt1 is identified on high power magnification revealing a strong staining intensity (b). figure 3. the lack of staining with glut1 in endothelial cells (arrows). erythrocytes in blood vessels serve as the positive control. table 1. immunohistochemical results of wt1 and glut1 immunoreactivity. staining intensity wt1 (n) glut1 (n) strong staining (+++) 4 0 moderate staining (++) 10 0 weak staining (+) 5 0 negative staining (-) 1 20 research | dermatol pract concept 2018;8(1):6 31 suggesting that it is a vascular neoplasm rather than a vascular malformation [3]. in another study, wt1 was found to be focally positive in 14/74 cases of verrucous hemangioma [14]. in this study, a positive control for wt1 is omitted and a high false-negative rate may explain the discrepancy, which may also result from differences in immunohistochemical techniques and reagents. in our study, cytoplasmic staining of wt1 was detected in the vascular endothelial cells of 19/20 specimens. this result is in keeping with the context that the entity may represent a true vascular neoplasm rather than a vascular proliferative response to inflammation. this concept is supported by the fact that various anti-inflammatory medications are not effective in most cases of alhe, but that the best therapeutic response would be excision/destructive treatment modalities [15-17]. a case report of a congenital alhe with a blaschkoid segmental distribution in the anogenital region also suggests that the vascular proliferation may be unlikely to represent a secondary phenomenon of reactive inflammatory process, which is not expected to develop during intrauterine period, but rather a true vascular neoplasm such as congenital involuting/noninvoluting hemangioma [18]. this phenomenon also supports our point of view regarding these study results. rapid remission of severe pruritus related to alhe with pulsed dye laser in a patient, who was persistent to topical, intralesional, and oral corticosteroid medications suggests that the inflammatory component of this entity would be secondary to vascular neoplastic proliferation. the proliferating endothelial cells of alhe express adhesion molecules icam-1, elam-1, and vla-1, -3, -5, which is considered to result in an inflammatory response [19]. in a systemic review of alhe including 416 studies representing 908 patients, treatment failure was found to be lowest for excision and pulsed dye laser compared with anti-inflammatory treatment strategies [20]. we suggest that this phenomenon supports the conclusion that eosinophil and lymphocytic inflammatory component would be related to vascular endothelial cells expressing proinflammatory cytokines such as icam-1. the efficacy of imiquimod, an immune response modifier that induces interferon-alpha, in alhe, as well as other vascular neoplasms such as retiform hemangioendothelioma, infantile hemangioma and proliferating hemangioma of infancy also supports this point of view [21,22]. glut1 is an erythrocyte-type glucose transporter protein expressed in juvenile hemangiomas. it is a member of the facilitative cell-surface glucose transporter family, which includes five other isoforms originally identified in human erythrocyte membranes. glut1 is also expressed in brain capillary endothelium, where it plays a critical role in the transport of glucose across the blood-brain barrier. glut1 staining has been identified in a variety of normal cell types (frostbite, surgery, laceration, frictional trauma, and other unspecified) with a time course between injury and the onset of lesions ranging from 7 months to 20 years (median, 30 months) [8]. this phenomenon has also been described in pyogenic granulomas, another vascular proliferative disorder, which developed after thermal burn, lightning, or mine injury [9]. in one patient, multiple alhe lesions on the volar surfaces on both wrists and antecubital fossae, situated over a superficial vein and corresponding to a site of recent venipuncture, also supports the role of trauma in the etiopathogenesis of this entity [10]. alhe that arises during pregnancy suggests that hormonal changes may also take place in the etiopathogenesis of this condition, a phenomenon also described in other vascular neoplasms such as hobnail hemangioma, pyogenic granuloma, liver, pancreatic, and spinal epidural hemangiomas [11]. immunohistochemistry for wt1 antigen permits differentiation of vascular neoplasms and malformations; the former show cytoplasmic staining pattern, as in our study, whereas the latter is negative for this marker. in a large study (n = 167), cytoplasmic wt1 was detected in 117 various vascular neoplasms, and was not detected in 50 cases of capillary, venous and lymphatic malformations [1]. in a true vascular neoplasm such as microvenular hemangioma, immunoreactivity for wt1 was found in 9/10 tumors, which is similar to the results described herein [12]. despite the detailed dermatopathological evaluation of the wt1 negative case, the diagnosis was consistent with alhe in our study. we suggest that wt1 expression could be lost in a subset of hemangiomas such as alhe, microvenular hemangioma and verrucous hemangioma reminding the phenomenon that mart-1 (melanoma antigen recognized by t cells 1) antibody, which is a highly sensitive marker, is lost in some melanoma specimens. in another study, wt1 was detected in 9/9 cases of microvenular hemangioma [2]. in a comparative study of wt1 expression in 23 vascular tumors and 20 vascular malformations, cytoplasmic staining of wt1 was detected in cases of infantile hemangiomas (8/9), angiosarcomas (9/9), pyogenic granulomas (2/2), and epithelioid hemangioendothelioma (1/1), whereas complete vascular malformations consisting of port wine stains, venous, and lymphatic malformations were negative for wt1. cytoplasmic wt1 staining pattern has been described in complete cases with tufted angioma (n = 8) and a single case of spindle cell hemangioma [1]. wt1 reactivity was also shown in extracutaneous hemangiomas such as anastomosing hemangioma of the kidney, histopathologically characterized by irregular fenestrated vascular spaces and reminiscent of the splenic red pulp with tightly packed, capillary-sized vessels with small lumen [13]. in a recent study, cytoplasmic immunoreactivity of wt1 was detected in complete cases with verrucous hemangioma 32 research | dermatol pract concept 2018;8(1):6 8. manton rn, itinteang t, de jong s, brasch hd, tan st. angiolymphoid hyperplasia with eosinophilia developing within a port wine stain. j cutan pathol. 2016;43(1):53-56. 9. bakan v, aliagaoglu c, yildiz a, emsen a. multiple pyogenic granulomas on the face after landmine injury. pediatr dermatol. 2008;25(3):397-398. 10. stewart n, zagarella s, mann s. angiolymphoid hyperplasia with eosinophilia occurring after venipuncture trauma. j dermatol. 2013;40(5):393-395. 11. hollo p, marschalko m, sikos g, harsing j, horwart a. angiolymphoid hyperplasia with eosinophilia in pregnancy. j eur acad dermatol venereol. 2005;19(5):645-646. 12. napekoski km, fernandez ap, billings sd. microvenular hemangioma: a clinicopathological review of 13 cases. j cutan pathol. 2014;41(11):816-822. 13. chou s, subramanian v, lau hm, achan a. renal anastomosing hemangiomas with a diverse spectrum: report of two cases and review of the literature. int j surgi pathol. 2014; 22(4):369-373. 14. wang l, gao t, wang g. verrucous hemangioma: a clinicopathological and immunohistochemical analysis of 74 cases. j cutan pathol. 2014;41(11):823-830. 15. ali fr, madan v. facial angiolymphoid hyperplasia with eosinophilia: sustained remission following treatment with carbondioxide laser. clin exp dermatol. 2016;41(1):96-98. 16. garrido-rios aa, sanz-munoz c, torrero-anton mv, martinezgarcia miranda-romero a. angiolymphoid hyperplasia with eosinophilia on the tongue. clin exp dermatol. 2009;34: (8):729731. 17. sotiriou e, apalla z, patsatsi a, panagiotidou dd, ioannides d. angiolymphoid hyperplasia with eosinophilia: good response to photodynamic therapy. clin exp dermatol. 2009;34(8):629-631. 18. su hh, shan sj, elston dm, guo y, men jl. congenital blaschkoid angiolymphoid hyperplasia with eosinophilia of the anogenital region. am j dermatopathol. 2016;38(4):305-306. 19. sebok b, batai i, anga b, schneider i. angiolymphoid hyperplasia with eosinophilia. orv hetil. 1998;139(12):1-15. 20. adler bl, krausz ae, minuti a, silverberg ji, lew-tov h. epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (alhe): a systemic review. j am acad dermatol. 2016;74(3):506-512. 21. isohisa t, masuda k, nakai n, takenaka h, katoh n. angiolymphoid hyperplasia with eosinophilia treated successfully with imiquimod. int j dermatol. 2014;53(1):43-44. 22. nobeyama y, ishiuji y, nakagawa h. retiform hemangioendothelioma treated with conservative therapy: report of a case and review of the literature. int j dermatol. 2016;55(2): 238-243. 23. ahrens wa, ridenour rv, caron bl, caron bl, miller dv, folpe al. glut1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms. human pathol. 2008;39(10):1519-1526. 24. wang l, liu l, gao t. congenital disseminated tufted angioma. j cutan pathol. 2013; 40(4):40-48. 25. van vugt lj, van der vleuten cjm, flucke u, blokx wam. the utility of glut1 as a diagnostic marker in cutaneous anomalies: a review of literature and recommendations for daily practice. pathol res pract. 2017;213(6):591-597. 26. johann ac, salla jt, gomez rs, et al. glut-1 in oral benign vascular lesions. oral dis. 2007;13:51-55. including placental trophoblasts and perineural cells as well as in a subset of mesenchymal neoplasms such as epithelioid sarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma [23]. glut1 is a useful marker for differentiation of infantile hemangiomas and other vascular neoplasms such as congenital hemangioma, tufted angioma and kaposiform hemangioendothelioma, being positive in the infantile hemangiomas and negative in the other entities [24]. a recent research highlighted that complete cases of microvenular hemangioma (n = 9) and congenital hemangiomas (n = 16) were found to be devoid of glut1 expression [25]. in a study, the positivity of glut1 was described in complete specimens with verrucous hemangioma, which was negative in our study [3]. as far as we are aware, staining findings regarding this marker for alhe have not been described to date. glut1 was not detected in various benign oral vascular lesions including; 19 hemangiomas, 9 varices, 48 pyogenic granulomas, and 17 vascular malformations, which suggests that most of benign vascular proliferations (other than infantile hemangiomas, such as alhe) are negative for this marker [26]. the limitation of our study is the small patient numbers related to rarity of alhe. in conclusion, alhe may represent a true hemangioma (i.e., benign vascular neoplasia) that shows an eosinophiland lymphocyte-rich inflammatory component instead of a reactive inflammatory dermatosis with positive intracytoplasmic staining pattern for wt1. references 1. trindade f, tellechea o, torrelo a, requena l, colmenero i. wilms tumor 1 expression in vascular neoplasms and vascular malformations. am j dermatopathol. 2011;33(6):569-672. 2. trindade f, kutzner h, requena l, tellechea o, colmenero i. microvenular hemangioma: an immunohistochemical study of 9 cases. am j dermatopathol. 2012;34(8):810-812. 3. trindade f, torrelo a, requena l et al. an immunohistochemical study of verrucous hemangiomas. j cutan pathol. 2013;40(5):472476. 4. sezer e, erbil h, koseoglu d, filiz n, kurumlu z. angiolymphoid hyperplasia with eosinophilia mimicking bowenoid papulosis. clin exp dermatol. 2007;32(1):281-283. 5. busquets a, sanchez jl. angiolymphoid hyperplasia with eosinophilia induced by trauma. int j dermatol. 2006;45(10):12111214. 6. calonje e, brenn t, lazar a, mckee ph. tumors of vascular origin. in: calonje e, ed. mckee’s pathology of the skin. 4th ed. london: elsevier saunders; 2010:1720-1722. 7. onishi y, ohara k. angiolymphoid hyperplasia with eosinophilia associated with arteriovenous malformations: a clinicopathological correlation with angiography and serial estimation of serum levels renin, eosinophil cationic protein and interleukin 5. br j dermatol. 1999;140(6):1153-1156. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023141 1 extragenital lichen sclerosus et atrophicusmorphea overlap masquerading as lupus vulgaris: histopathology to the rescue swati prasanna1, nishigandha s haridas1, vidya kharkar1, pandharinath khade1 1 department of dermatology, leprosy and venereology, seth g.s. medical college and k.e.m. hospital, mumbai, maharashtra, india key words: lichen sclerosus, cutaneous tuberculosis, lupus vulgaris, inflammoscopy citation: prasanna s, haridas ns, kharkar v, khade p. extragenital lichen sclerosus et atrophicus-morphea overlap masquerading as lupus vulgaris: histopathology to the rescue. dermatol pract concept. 2023;13(3):e2023141. doi: https://doi.org/10.5826/dpc.1303a141 accepted: december 19, 2022; published: july 2023 copyright: ©2023 prasanna et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr nishigandha s haridas, department of dermatology, seth g.s. medical college and k.e.m. hospital, parel, mumbai, 400012, maharashtra, india email: drnishigandhaharidas@gmail.com introduction lichen sclerosus et atrophicus (lsa) presents as atrophic plaques in genital region usually but can present at extragenital locations such as neck, shoulder, trunk and proximal extremities [1,2]. morphea is characterized by skin thickening and increased collagen within the indurated lesion [3]. although both these pathologies have been described as distinct clinical and histopathological entities, there are cases and retrospective studies which suggest that both the diseases could be a part of the spectrum of localized sclerosing disorders [1,2]. case presentation a 56-year-old male presented with an asymptomatic reddish plaque over neck, gradually increasing in size for 8 months. he gave history of taking anti-tuberculous drugs for inguinal tuberculous lymphadenitis twenty years ago. physical examination revealed an erythematous plaque with central atrophy and purpuric borders, approximately 4 x 3 cm in size, with an advancing elevated edge and an atrophic regressing edge (figure 1a) with no regional lymphadenopathy. mantoux skin test was positive (15 mm). however, interferon gamma release assay (igra) and chest x-ray were normal. dermoscopy revealed follicular plugging, white structureless areas, yellowish to orange globules, network of linear vessels within white streaks along with few unfocussed violaceus vessels (figure 1, b and c)]. a provisional diagnosis of plaque type lupus vulgaris (lv) was given and a skin biopsy was done for histopathology and cbnaat (cartridge based nucleic acid amplification test). histopathology from the advancing edge of the plaque revealed follicular plugging, pan dermal sclerosis with thickening and homogenization of dermal collagen with replacement of subcutaneous fat below eccrine apparatus by thickened collagen. there was sparse interstitial lymphocytic infiltrate between the collagen fibres (figure 1, d-f). ziehl neelson staining of 2 research letter | dermatol pract concept. 2023;13(3):e2023141 figure 1. cutaneous examination and dermoscopic and histopathological findings (h&e stain). (a) erythematous plaque with central orange yellow hue, advancing edge at one border and regressing atrophic edge at the other end. (b) dermoscopy showing follicular plugs (black arrow) with yellowish brown crust, 100x without polarization. (c) yellowish orange globules (black star) with few unfocused vessels (black arrow) at 100x magnification with polarization. (d) pandermal sclerosis with thickened collagen (black star) and scarce appendages pulled up in the mid dermis (arrow), 2x magnification, h&e stain. (e) subcutaneous fat below eccrine apparatus replaced by thickened collagen (black star) with lymphocytic interstitial infiltrate (black arrow) 40x magnification, h&e stain. (f) pulled-up eccrine ducts, 100x magnification, h&e stain. figure 2. results after topical calcitriol 0.0003% ointment application. (a) pretreatment. (b) after 2 weeks of treatment. (c) after 4 weeks of treatment. histopathological section was negative for acid fast bacilli. skin biopsy cbnaat was negative for mycobacterium tuberculosis. a final diagnosis extragenital lsa-morphea overlap was given and the patient was started on calcitriol 0.0003% ointment. there was decrease in the size of plaque within 4 weeks of commencing treatment (figure 2, a-c). research letter | dermatol pract concept. 2023;13(3):e2023141 3 conclusions lsa presents with white atrophic plaques and papules, most commonly on the vulvar and perianal area but may be seen anywhere, with trunk and extremities being the most common extragenital sites. dermoscopy of lsa shows porcelain white structureless areas, comedo like openings and a network of dotted blood vessels [1] .on histopathology, lsa presents with follicular plugging, lichenoid papillary dermal infiltrate and homogenization of papillary dermis whereas morphea presents with increased basal layer melanization, reticular dermal sclerosis, thickened collagen bundles, interstitial lymphocytic infiltrate and decreased appendages [1]. lv on dermoscopy presents with follicular plugging, hemorrhagic crusts, yellowish orange background suggestive of granuloma, linear vessels arranged along the white streaks, and white structureless areas. on histopathology, tuberculoid granulomas in reticular dermis with absent or scanty caseation are seen along with hyperkeratosis, atrophy and fibrosis. findings in support of lv included past history of tb lymphadenitis with positive mantoux test, classical morphology of the lesion with an advancing edge, patulous follicles, orange red background with white streaks and structureless areas however, the presence of pan dermal sclerosis, diminished appendages, replacement of subcutaneous fat beneath eccrine glands by thickened dermal collagen were against lv. this case posed a diagnostic challenge due to its disguise as cutaneous tuberculosis which emphasizes on the importance of clinico-dermoscopic-histopathological correlation. acknowledgement: we would like to thank dr rajiv joshi for his valuable inputs in histopathology. references 1. rose ae, boyd kp, meehan sa, latkowski ja. lichen sclerosus et atrophicus. dermatol online j. 2013;19(12):20714. pmid: 24365005. 2. almuqati rr, hariri j, abduljabbar m. histopathological coexistence of extragenital lichen sclerosus and morphea in a single lesion. cureus. 2020;12(12):e12215. doi: 10.7759 /cureus.12215. pmid: 33489622. pmcid: pmc7815259. 3. careta mf, romiti r. localized scleroderma: clinical spectrum and therapeutic update. an bras dermatol. 2015;90(1):62-73. doi: 10.1590/abd1806-4841.20152890. pmid: 25672301. pmcid: pmc4323700. dermatology: practical and conceptual research | dermatol pract concept 2018;8(4):10 299 dermatology practical & conceptual www.derm101.com differentiation of pityriasis rubra pilaris from plaque psoriasis by dermoscopy abhijeet kumar jha1, aimilios lallas2, sidharth sonthalia3, deepak jhakar4, uday k. udayan1, r. k. p. chaudhary1 1 department of skin & vd, patna medical college and hospital, patna, bihar, india 2 first department of dermatology, aristotle university, thessaloniki, greece 3 skinnocence: the skin clinic, gurgaon, india 4. department of dermatology, deen dayal upadhyay hospital, new delhi, india key words: pityriasis rubra pilaris, plaque psoriasis, lichen spinulosus, lichen nitidus, dermoscopy citation: jha ak, lallas a, sonthalia s, jhakar d, kumar udayan uk, chaudhary rkp. differentiation of pityriasis rubra pilaris from plaque psoriasis by dermoscopy. dermatol pract concept. 2018;8(4):299-302. doi: https://doi.org/10.5826/dpc.0804a10 received: february 8, 2018; accepted: july 3, 2018; published: october 31, 2018 copyright: ©2018 jha ak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, assistant professor, department of skin and vd, patna medical college, ashok rajpath, patna-800004, bihar, india. email: drabhijeetjha@gmail.com background: diagnosing and differentiating pityriasis rubra pilaris (prp) from other disorders can be a challenging task. although histopathology remains the gold standard, it may not be feasible at times, especially in children. being noninvasive, dermoscopy can be of great diagnostic importance in such a scenario. dermoscopy overcomes the refractive properties of stratum corneum by interface medium or cross-polarization enabling easier visualization of lesions. objective: to study the dermoscopic features of prp and compare them with dermoscopic features of psoriasis. patients and methods: retrospective observational analysis of dermoscopic characteristics of 28 patients with prp (16) and psoriasis (12). polarized dermoscopy at 10× magnification was performed and photographs were captured by apple iphone 7. the selection of dermoscopic variables was based on preexisting literature on the dermoscopic patterns of the 2 entities. results: the most frequent dermoscopic criteria of prp were the presence of a central hair (16/16; 100%), follicular plugs (11/16; 68.7%), and perifollicular yellow/orange halos (9/16; 56.2%). no vascular structures were seen in our cases of prp. psoriasis was characterized by regularly distributed dotted vessels (12/12; 100%) and white scales (8/12; 66.6%). conclusions: round-to-oval yellowish areas surrounding a central hair with or without follicular plugs represents the most frequent dermoscopic pattern of prp. abstract 300 research | dermatol pract concept 2018;8(4):10 included dotted and linear vessels, white scales, follicular plugs, perifollicular yellow/orange halos, and central hair (table 1). histological diagnosis of prp and pp was based on the identification of the characteristic features of each disease under microscopic examination. analytically, alternating orthokeratosis and parakeratosis in both directions, hypergranulosis, irregular acanthosis, thick suprapapillary plates, and sparse-to-moderate lymphocytic perivascular infiltrate in the dermis, and dilated hair follicles filled with a dense, horny plug were criteria for prp. in contrast, psoriasiform epidermal hyperplasia accompanied by tortuous, dilated capillaries in the superficial papillary dermis and a perivascular mononuclear cell infiltrate were the criteria for the histopathological diagnosis of pp. any disagreement in the assessment of morphological criteria and diagnosis between the 2 dermoscopists or pathologists were resolved by consensus. all evaluators were unaware of patients’ clinical details. results overall, 28 lesions from 28 patients were included in the study. the histopathological diagnosis was prp in 16 patients and pp in 12 patients. the male-to-female ratio was 3.5:1 and the mean age was 18.2 years. as shown in table 1, the most frequent dermoscopic criteria of prp were the presence of a central hair (16/16; 100%), follicular plugs (11/16; 68.7%), and perifollicular yellow/orange halos (9/16; 56.2%) (figures 1 and 2). no vascular structures were seen in our cases of prp. psoriasis was characterized by regularly distributed dotted vessels (12/12; 100%) and white scales (8/12; 66.6%) (figure 3, table 1). discussion our results suggest that the dermoscopic pattern of prp consists of yellow/orange halos surrounding follicles with a introduction pityriasis rubra pilaris (prp) is a relatively uncommon skin disease, clinically characterized by follicular keratotic plugs, red to orange plaques, and palmoplantar hyperkeratosis. however, in cases with atypical clinical presentation, prp is sometimes confused with psoriasis, both clinically and histopathologically. in such cases, repeated biopsies may be needed to confirm the diagnosis. the main differential diagnosis of adult-onset prp is psoriasis.  dermoscopy has been shown to represent a useful clinical tool for the clinical evaluation of several inflammatory skin diseases and the differential diagnosis among entities with similar clinical manifestations. available data of the dermoscopic morphology of prp are scant, whereas evidence on the value of dermoscopy for discriminating prp from psoriasis is even poorer. the aim of the present study was to investigate the dermoscopic findings in a series of patients with prp as compared with those in a control group of patients with psoriasis. patients and methods in this retrospective observational study we evaluated the dermoscopic criteria of prp and psoriasis. ethics committee approval was obtained. the database of our center was screened for eligible patients. inclusion criteria included a histopathological diagnosis of prp or plaque psoriasis (pp) affecting the trunk and/or upper or lower extremities and the availability of a clinical and dermoscopic image of a recently appeared lesion. patient demographics were recorded and the most recently evolved lesion was examined dermoscopically and histopathologically. dermoscopy preceded histology, and no treatment was allowed between these examinations. patients with previous history of treatment were excluded. dermoscopic examination was performed with a handheld dermatoscope (dermlite dl 4, 3gen, san juan capistrano, ca) and the images were captured with apple iphone 7. dermoscopic evaluation was retrospectively performed by 2 independent dermoscopists (with more than 10 and 5 years of experience, respectively) who were unaware of the clinical and histopathological diagnosis. the sequence of the dermoscopic images was randomized, using a computer-generated program, and the  2  evaluators were blinded with respect to clinical information and diagnosis. selection of the dermoscopic variables included in the evaluation process was based on the available published data and personal experience and expertise of the examiners. the selection of dermoscopic variables was based on previous evidence on the dermoscopic morphology of prp and psoriasis, as well as our personal observations, and table 1. dermoscopic variables dermoscopic criteria (polarized, 10×) prp (n = 16) psoriasis (n = 12) dotted vessels 0 12 (100%) linear vessels 0 0 perifollicular yellow/ orange halos 9 (56.2%) 0 follicular plugs 11 (68.7%) 0 central hair 16 (100%) 0 white scales 8 (66%) research | dermatol pract concept 2018;8(4):10 301 to remain identical. it seems that the vascular structures of psoriasis are too prominent to be hidden by the increased pigment of patients with dark skin type. overall, our results suggest that dermoscopy might be particularly useful to discriminate between prp and psoriasis, at least in an indian population, since the dermoscopic patterns of the 2 entities are clearly different. of note, yellow color, which was in our study and previous studies central hair and with or without follicular plugs. in contrast, psoriasis is typified by the presence of dotted vessels in a regular distribution and white scales. previous reports on dermoscopy of prp suggested that the disease is dermoscopically characterized by round-to-oval yellowish areas surrounded by vessels of mixed morphology, namely, linear and dotted [1–3]. in addition, central keratin plugs were also described [1]. our results are partially consistent with previous reports, since we also identified yellowish areas and follicular plugs. our results suggest that the yellowish areas of prp are almost always perifollicular. this information was not provided in previous reports. in addition, in our series vessels were not observed. this discrepancy with previous studies might be related to the different skin types of populations, since the increased pigment in the skin of our patients might have impeded the visualization of vascular structures. our findings on the features of psoriasis were in perfect agreement with previous reports, suggesting that the disease is dermoscopically typified by regularly distributed dotted vessels and white scales. it is remarkable that although our study and previous studies were conducted in populations of different skin types, the dermoscopic pattern of psoriasis appears figure 1. multiple round-to-oval yellowish areas with keratotic follicular plugs surrounded by erythema and the presence of a central hair (dermoscopy, polarized, 10×). [copyright: ©2018 jha et al.] figure  2. multiple round-to-oval whitish areas with keratotic follicular plugs surrounded by erythema and the presence of a central hair (dermoscopy, polarized, 10×). [copyright: ©2018 jha et al.] figure 3. regular dotted vessels with white scales on a reddish background (dermoscopy, polarized, 10×). [copyright: ©2018 jha et al.] 302 research | dermatol pract concept 2018;8(4):10 limitations the number of patients recruited in the study was small and larger scale studies are required. all patients were indian and interethnic variability could not be evaluated. conclusions round-to-oval yellowish areas surrounding a central hair with or without follicular plugs represents the most frequent dermoscopic pattern of prp. in contrast, psoriasis is typified by numerous and regularly distributed dotted vessels and white scales. this information might aid clinicians to differentiate atypical cases of prp from psoriasis. references 1. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol. 2015;150(5):533-546. 2. lallas a, apalla z, karteridou a, lefaki i. photoletter to the editor: dermoscopy for discriminating between pityriasis rubra pilaris and psoriasis. j dermatol case rep. 2013;7(1):20-22. 3. errichetti e, stinco g. dermoscopy as a supportive instrument in the differentiation of the main types of acquired keratoderma due to dermatological disorders. j eur acad dermatol venereol. 2016;30(12):e229-e231. 4. errichetti e, piccirillo a, stinco g. dermoscopy as an auxiliary tool in the differentiation of the main types of erythroderma due to dermatological disorders. int j dermatol. 2016;55(12):e616-e618.  5. lópez-gómez a, vera-casaño á, gómez-moyano e, et al. dermoscopy of circumscribed juvenile pityriasis rubra pilaris. j am acad dermatol. 2015;72(1 suppl):s58-s59. 6. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. 7. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012; 66(6):1198-1205. one of the consistent findings of prp, has been suggested as a potent negative predictive factor for the diagnosis of psoriasis. a previous study investigated the accuracy of dermoscopic criteria for the differentiation of psoriasis from other inflammatory diseases. according to the latter study, the presence of regularly distributed dotted vessels is very highly suggestive of psoriasis over any other diagnosis. although the latter study did not include prp in the control group, our results and previous results on dermoscopy of prp suggest that the same conclusion is very likely to be valid for the differential diagnosis between psoriasis and prp. in addition, the latter study suggested yellow color as a potent negative predictive factor for the diagnosis of psoriasis. in the present and previous studies, yellow color was one of the most consistent findings of prp, supporting further that dermoscopy is useful for the differential diagnosis between prp and psoriasis. previous reports investigated also the dermoscopic findings in peculiar subtypes of prp. specifically, erythrodermic prp was suggested to dermoscopically display orange blotches and islands of nonerythematous (spared) skin displaying reticular vessels [4,5]. in contrast, erythrodermic psoriasis is typified by diffusely distributed whitish scales and regularly arranged dotted/glomerular vessels [6]. keratoderma resulting from prp has been suggested to display structureless orange areas of different sizes in a patchy distribution along with white scales [4]. dermoscopy of juvenile prp also shows multiple whitish keratotic follicular plugs and a yellowish peripheral keratotic ring surrounded by erythema with some linear vessels [7]. our sample did not include patients with these peculiar forms of prp, so the latter evidence cannot be assessed by the present study. dermatology: practical and conceptual 322 letter | dermatol pract concept 2018;8(4):15 dermatology practical & conceptual www.derm101.com introduction early diagnosis of lentigo maligna (lm) represents one of the most challenging tasks in dermato-oncology. this is because pigmented actinic keratosis (pak), solar lentigo (sl), seborrheic keratosis (sk), and lichen planus-like keratosis (lplk) share several phenotypic features with melanoma in situ both macroscopically and on dermoscopic examination [1]. dermoscopy remains the primary diagnostic method for differentiating among these tumors; however, currently used algorithms demonstrate a low accuracy for lm [2]. for instance, gray structures in a flat pigmented facial lesion can be a sign of lm but can be found also in pak and lplk [1,2]. rhomboidal structures can be seen in both lm and pak whereas a pseudonetwork can be additionally present in many sl and sk [1]. total excision provides a definite diagnosis but is associated with the risk of undesirable cosmetic result. recently, a new algorithm was introduced with high specificity and nearly 70% sensitivity for lm. rather than aiming to the recognition of melanoma-specific criteria, it focuses on the dermoscopic presence or absence of 7 features of nonmelanoma tumors: scales, white follicles, erythema, reticular or curved lines, structureless brown color, sharp demarcation, and classic criteria of sk such as milia-like cysts [2]. if any of these 7 features is clearly recognized and widely distributed on the surface of the lesion, the diagnosis of lm is excluded and biopsy is not necessary. in the absence of these features, the lesion is considered suspicious even without displaying any melanoma-specific criterion. case presentation we report a case of a 50-year-old woman who visited our department with a 0.8 × 0.8 cm pigmented macule on the right side of her nose (figure 1). she reported that she had the lesion for the past 10 months and did not notice any change in size, shape, or color. she reported intermittent sun exposure in the past and admitted not to use sun protection a tiny facial pigmented macule: overcoming the diagnostic challenge athanasios j. stefanis1, zoe apalla2, chryssoula papageorgiou2, dimitrios ioannides2, christina nikolaidou3, aimilios lallas2 1 department of dermatology, third faculty of medicine, charles university, prague, czech republic 2 first department of dermatology, aristotle university, thessaloniki, greece 3 department of histopathology, hippokration general hospital, thessaloniki, greece key words: dermoscopy, lentigo maligna, melanoma, pigmented actinic keratosis, solar lentigo citation: stefanis aj, apalla z, papageorgiou c, ioannides d, nikolaidou c, lallas a. a tiny facial pigmented macule: overcoming the diagnostic challenge. dermatol pract concept 2018;8(4):322-323. doi: https://doi.org/10.5826/dpc.0804a15 received: february 11, 2018; accepted: june 7, 2018; published: october 31, 2018 copyright: ©2018 stefanis et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: none. all authors have contributed significantly to this publication. corresponding author: dr. aimilios lallas, first department of dermatology, aristotle university, 124 delfon street, 54643, thessaloniki, greece. email: emlallas@gmail.com letter | dermatol pract concept 2018;8(4):15 323 references 1. lallas a, argenziano g, moscarella e, longo c, simonetti v, zalaudek i. diagnosis and management of facial pigmented macules. clin dermatol. 2014;32(1):94-100. 2. tschandl p, gambardella a, boespflug a, et al. seven non-melanoma features to rule out facial melanoma. acta derm venereol. 2017;97(10):1219-1224. 3. cengiz fp, cengiz ab, emiroglu n, comert e, wellenhof rh. dermoscopic and clinical features of head and neck melanoma. an bras dermatol. 2015;90(4):488-493. 4. lallas a, tschandl p, kyrgidis a, et al. dermoscopic clues to differentiate facial lentigo maligna from pigmented actinic keratosis. br j dermatol. 2016;174(5):1079-1085. 5. ellis lz, cohen jl, high w, stewart l. melanoma in situ treated successfully using imiquimod after nonclearance with surgery: review of the literature. dermatol surg. 2012;38(6):937-946. frequently. she had a negative personal and family history of melanoma or other skin cancer. dermoscopic examination revealed a light-brown discoloration among follicular openings (pseudo network). no feature suggestive of melanoma could be recognized (figure 2). in more detail, rhomboidal structures or circles were not clearly evident, follicular openings were not pigmented, gray globules could be hardly detected, and vascular network or scar-like depigmentation was not present [3,4]. however, neither the diagnosis of pak nor that of sk/sl could be established, since the only detectable feature was pigmentation among the follicles (pseudonetwork). overall, the establishment of a definite diagnosis based on clinical and dermoscopic examination was not possible. following the aforementioned novel algorithm, since none of the 7 nonmelanoma features was clearly present, we could not exclude the diagnosis of facial melanoma and performed an excisional biopsy. indeed, the histopathological examination revealed melanoma in situ and the patient underwent wide excision of the scar with safety margins (figure 3). in addition, the patient received adjuvant treatment with imiquimod 5% cream, consisting of 5 daily applications per week for 6 weeks [5]. conclusions the recognition of such a small and dermoscopically inconspicuous melanoma would be impossible by any strategy focusing on melanoma-specific structures. early dermoscopic diagnosis of facial melanoma should rather be a diagnosis of exclusion, based on the absence of nonmelanoma features. figure  1. a flat brown macule  0.8 × 0.8  cm on the right side of the nose of a 50-year-old woman. [copyright: ©2018 stefanis et al.] figure 2. dermoscopic examination revealed light-brown discoloration among follicular openings, which are variably sized and retain their white color (right). [copyright: ©2018 stefanis et al.] figure 3. photomicrograph of histology. findings include the presence of proliferation of single atypical melanocytes along the basal cell layer and the follicular epithelium. mild elastosis is also present. [copyright: ©2018 stefanis et al.] dermatology: practical and conceptual research | dermatol pract concept 2018;8(2):15 149 dermatology practical & conceptual www.derm101.com introduction merkel cell carcinoma (mcc) is an aggressive tumor of the skin and mucous membranes first described by toker in 1972 [1]. mcc classically presents as a rapidly growing, firm, violaceous nodule and is thought to be due to extensive radiation exposure and/or polyomavirus. like melanoma, mcc has a strong propensity to recur locally, spread regionally, and disseminate widely, leading to a fatal outcome [1]. however, unlike melanoma, mcc is highly radiosensitive, with in vitro mcc cell lines demonstrating substantially lower surviving fractions (mean: 0.30) than melanoma cell lines (mean: 0.57) when exposed to 2 gy of radiation [2]. although there have been few prospective studies to guide management of the disease, it is generally agreed that for the primary tumor, surgery with or without adjuradiotherapy for inoperable merkel cell carcinoma: a systematic review and pooled analysis parth patel1, chirag modi2, beth mclellan1, nitin ohri2 1 department of medicine, division of dermatology, montefiore medical center, albert einstein college of medicine, bronx, new york 2 department of radiation oncology, montefiore medical center, albert einstein college of medicine, bronx, new york key words: merkel cell carcinoma, radiotherapy, inoperable, relapse, survival citation: patel p, modi c, mclellan b, ohri n. radiotherapy for inoperable merkel cell carcinoma: a systematic review and pooled analysis. dermatol pract concept. 2018;8(2):149-157. doi: https://doi.org/10.5826/dpc.0802a15 received: november 12, 2017; accepted: march 2, 2018; published: april 30, 2018 copyright: ©2018 patel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nitin ohri, md, department of radiation oncology, montefiore medical center albert einstein college of medicine, bronx, ny 10467, usa. tel. (718) 430-3682; fax. (718) 430-8618. email: ohri.nitin@gmail.com background: cumulative data on radiation monotherapy for merkel cell carcinoma (mcc) is lacking. objective: we sought to synthesize all available data on treatment outcomes for radiation monotherapy for inoperable stage i-iii mcc. methods: we performed a systematic review of the current literature. articles published in english in the pubmed database up to july 29, 2016, were evaluated. results: eight case reports, 4  case series, and  6  retrospective studies, yielding  68  patients, were included in our analysis. of the 24 stage i/ii patients treated with local irradiation, 6 (25%) relapsed and 1 (4%) died from mcc. of the 24 stage i/ii patients treated with local and regional nodal irradiation, 5 (21%) relapsed and 2 (8%) died from mcc. of the 20 stage iii patients treated with local and regional nodal irradiation, 12 (60%) relapsed and 7 (35%) died from mcc. conclusions: radiation monotherapy appears to be a reasonable treatment modality for patients with inoperable stage i-iii mcc. further investigation with prospective studies is needed to draw definitive conclusions. abstract 150 research | dermatol pract concept 2018;8(2):15 preferred reporting items for systematic reviews and metaanalyses (prisma) selection process (figure 1). from the selected articles, the following data was extracted: language, author, date of publication, study design, sample size, age of patients at diagnosis, sex of patients, location and size of primary tumor, stage of cancer at diagnosis, total radiation dose, immunocompromised status, recurrence/metastasis, and survival. discrepancies in opinion about article eligibility, the quality of studies, and/or data extraction, were reviewed jointly by pp and cm to achieve consensus. quality assessment the quality of the selected studies was evaluated according to the grading of recommendations assessment, development, and evaluation (grade) guidelines (table 1) [5]. the level of evidence supporting each article was determined using criteria from the oxford center for evidence-based medicine (table 1) [6]. data analysis survivorship estimates were generated using descriptive statistics and the kaplan-meier method in graphpad prism 6 (graphpad software inc., la jolla, ca). for the analysis of relapse-free survival, the endpoint was any recurrence or metastasis; for the analysis of overall survival, the endpoint was death from any cause; and for the analysis of causespecific survival the endpoint was death from mcc. aggregate and individual patient data were combined using the two-stage method, with a fixedor random-effects approach, in comprehensive meta analysis 2.0 (biostat inc., englewood, nj) [7,8]. based on cochran’s q test for heterogeneity, the fixed-effects model was only used if the p value > 0.1 [9]. when aggregate data was reported as a median, the mean and variance were estimated using distribution-free formulas [10]. tumor staging was standardized using the 2010 tnm staging system for mcc [11]. a tumor was considered stage i if it was <2 cm with no metastases; stage ii if it was 2-5 cm with no metastases; stage iii if there was lymph node metastasis; and stage iv if distant metastasis occurred. local recurrence was defined as recurrence within or adjacent to the primary site; regional recurrence was defined as recurrence in the regional nodal basin or in-transit metastasis (cutaneous/ intradermal metastasis en-route to the regional nodal basin), and distant metastasis was defined as tumor spreading distant to the regional nodal basin. results description of studies a n i n i t i a l s e a r c h o f t h e p u b m e d d a t a b a s e i d e n t ified 586 records. a title-abstract screen resulted in 83 artivant radiation therapy is the preferred treatment modality; for nodal involvement, node dissection and/or radiation therapy is the preferred treatment modality; and for distant metastasis, chemotherapy, radiation therapy and/or surgery should be considered [3]. when surgery is not possible due to tumor location and size, patient comorbidities, and/or patient refusal, radiation monotherapy is typically the preferred treatment modality, regardless of whether the intent is palliative or curative. due to the rarity of mcc, with an incidence of only 0.79 per 100,000 [4], the efficacy of radiotherapy for inoperable mcc is not well defined. here we present a systematic review of the literature to evaluate radiation monotherapy for mcc patients, focusing on the effects of local and regional radiation therapy on relapse and survival. we hope the results of this article help raise awareness that radiation monotherapy, as opposed to other local-regional nonsurgical treatment modalities, is a reasonably effective option for patients with inoperable mcc. methods and materials data search we searched the pubmed database for articles published in english up to july, 29 2016. the search terms included a combination of “merkel cell carcinoma” or “merkel-cell carcinoma” and “radiation therapy” or “radiotherapy.” the references of articles selected for full-text evaluation were also considered for additional studies. inclusion/exclusion criteria all study types (case reports/series, retrospective studies and prospective studies) were considered in our analysis. studies with the following criteria were included: 1) published in english, 2) published as a full article, 3) reported known primary mccs without distant metastasis (m+) or prior treatment, 4) the primary treatment modality was radiation therapy without surgery and/or chemotherapy, and 5) reported tumor staging data, total radiation dose data, and at least one of the following primary outcomes data: recurrence, metastasis, or survival. for studies with aggregate data, if part of the patients in the aggregate data were treated with combination therapy (surgery and/or chemotherapy) the cohort was excluded because we could not determine what part of the data represented those patients who received radiation monotherapy. study selection, quality assessment and data extraction authors pp and cm independently searched the pubmed database and reviewed all the selected articles using the research | dermatol pract concept 2018;8(2):15 151 figure 1. preferred reporting items for systematic reviews and meta-analyses (prisma) selection process. table 1. study characteristics and quality assessment study characteristics and quality assessment author(s) year published study design comparative/ non-comparative† sample size‡ (n = 68) level of evidence grade quality ashby et al [40] 1989 case series non-comparative 1 4 very low chatzinasiou et al [41] 2015 case report non-comparative 1 4 very low elliot [42] 1981 case report non-comparative 1 4 very low handa et al [43] 2000 case report non-comparative 1 4 very low hasle et al [44] 1991 case report non-comparative 1 4 very low kitamura et al [45] 2015 case report non-comparative 1 4 very low lawenda et al [46] 2008 retrospective non-comparative 2 3 low luaces rey et al [47] 2008 case series non-comparative 1 4 very low magrini et al [48] 1992 case series non-comparative 1 4 very low makino et al [49] 2005 case report non-comparative 1 4 very low pacella et al [50] 1988 retrospective non-comparative 1 3 low pape et al [12] 2011 retrospective comparative 25 3 low seki et al [51] 2003 case series non-comparative 2 4 very low suntharalingam et al [52] 1995 retrospective comparative 2 3 low tuskada et al [53] 2016 case report non-comparative 1 4 very low veness et al [*54, 55] 2009/2015 retrospective non-comparative 25 3 low yamakawa et al [56] 2008 case report non-comparative 1 4 very low grade, grading of recommendations assessment, development and evaluation * includes two articles that represent one cohort of patients † comparative refers to studies that had multiple treatment groups; non-comparative refers to studies that had only 1 treatment group ‡ only represents those relevant patients included in our study 152 research | dermatol pract concept 2018;8(2):15 increase to 5 (21%) in the local radiation group and 5 (21%) in the localregional radiation group (table 3). stage iii disease of the 68 patients treated with radiation monotherapy, 20 (29%) presented with stage iii mcc. all of these patients were treated with local-regional radiation. the mean duration of follow-up for these patients was 18.9 months (range: 4-53). the mean total radiation dose to the primary tumor was 52.2 gy (range: 20-70) and that to the regional nodal basin was 51.5 gy (range: 20-70). the relapse rate was 60% (n = 12/20) (2 regional recurrences, 4 distant metastasis, and 6 unspecified recurrences/ metastases). there were  7  reported deaths (35%) in the local-regional radiation group, all of which were from mcc. if we assumed that those patients who were alive with disease at the last follow-up eventually died from mcc and all other patients did not die from mcc, the number of deaths from mcc would increase to 10 (50%) (table 3). surgery plus radiation vs. radiation monotherapy a retrospective study by pape et al [12]. compared  25  stage i mcc patients treated with radiation monotherapy to  25  stage i mcc patients treated with surgery + radiation. in the radiation monotherapy group, the total dose of radiation was 70 gy to the primary tumor for all patients and ~50-55 gy cles. after applying inclusion/exclusion criteria and removing duplicate data, 18 articles were included in our analysis. of these articles, 8 were case reports, 4 were case series, and 6 were retrospective studies, yielding a total of 68 patients (table 1 and table 2). stage i/ii disease of the 68 patients treated with radiation monotherapy, 48 (71%) presented with stage i/ii mcc. of these, 24 (50%) underwent local tumor irradiation, and 24 (50%) underwent local tumor and regional nodal irradiation. the mean duration of follow-up for patients in the local radiation group was 13.4 months (range: 3-42) and that for patients in the local-regional radiation group was 15.1 months (range: 4-35). the duration of follow-up was only available for 7 patients in the local radiation group and 9 patients in the local-regional radiation group. the mean total radiation dose to the primary tumor was 55.2 gy (range: 20-70) in the local radiation group and 64.5 gy (range: 38.5-70) in the local-regional radiation group. patients in the localregional radiation group also received a mean total radiation dose of 50.8 gy (range: 40-55) to the regional nodal basin (prophylactically). the relapse rate in the local radiation group was 25% (n = 6/24) (1 local recurrence, 3  regional recurrences, and  2  distant metastasis) and that in the local-regional radiation group was 21% (n = 5/24) (1 local recurrence, 1 regional recurrence, 2 distant metastasis, and  1  unspecified recurrence/ metastasis). there were  5  reported deaths (21%) in the local radiation group, of which 1 (4%) was from mcc. there were 9 reported deaths (38%) in the local-regional radiation group, of which 2 (8%) were from mcc. if we assumed that all patients who were alive with disease at the last follow-up eventually died from mcc and all other patients did not die from mcc, the total number of deaths from mcc would table 2. patient characteristics patient characteristics stage i/ii (n = 48 ) stage iii (n = 20 ) all stages (n = 68 ) sex male 9 (19%) 13 (65%) 22 (32%) female 37 (77%) 7 (35%) 44 (65%) unknown 2 (4%) 0 (0%) 2 (3%) age at diagnosis <60 y 3 (6%) 2 (10%) 5 (7%) 60-69 y 7 (15%) 1 (5%) 8 (12%) 70-79 y 11 (23%) 7 (35%) 18 (26%) ≥ 80 y 25 (52%) 10 (50%) 35 (52%) unknown 2 (4%) 2 (3%) mean age y (range) 77.8 (45-98) 78.1 (54-96) 77.9 (45-98) location of primary tumor head and neck 35 (73%) 12 (60%) 47 (69%) trunk 3 (15%) 3 (4%) upper extremities 2 (4%) 1 (5%) 3 (4%) lower extremities 10 (21%) 4 (20%) 14 (21%) unspecified extremity 1 (2%) 1 (2%) lesion size ≤ 2 cm 21 (44%) 6 (30%) 27 (40%) > 2 cm 22 (46%) 13 (65%) 35 (51%) unknown 5 (10%) 1 (5%) 6 (9%) mean size cm (range) 3.0 (0.4-18) 4.0 (0.5-10) 3.3 (0.4-18) immunosuppression yes 2 (4%) 2 (10%) 4 (6%) no 46 (96%) 18 (90%) 64 (94%) research | dermatol pract concept 2018;8(2):15 153 ity for patients with inoperable stage i-iii mcc. compared to radiation monotherapy, isolated case reports of other nonsurgical treatment modalities using cryotherapy [13,14], topical immunotherapy (dinitrochlorbenzol [15], imiquimod [14,16,17]), intralesional immunotherapy (interluekin-12 [18], tumor necrosis factor-alpha [19], interferon-alfa [16], interferon-beta [20], glucopyranosyl lipid-a [18]) and/or isolated limb perfusion with chemotherapy (melphalan, tumor necrosis factor-alpha +/ interferon-gamma) [21,22], have shown variable efficacy, often with only transient response or adjuvant radiation therapy required for maintenance. despite the fact that patients treated with radiation monotherapy often have adverse prognostic features such as large lesion size and head and neck tumor location [23,24], the incidences of relapse and death from mcc in the studied patients were similar, if not lower, than the to the regional nodal basin for patients in the local-regional group. in the surgery + radiation group, the total dose of radiation was ~50-55 gy to the surgical bed for all patients and ~50-55 gy to the regional nodal basin for patients in the local-regional group. there were 2 regional recurrences at 6 and 15 months in the radiation monotherapy group and 4 regional recurrences at 5, 16, 17 and 109 months in the surgery + radiation group. in this study, there was no significant difference in relapse-free survival (log-rank, p = .18) or cause-specific survival (log-rank, p = .32) between the radiation monotherapy group and surgery + radiation group [12]. discussion in this review, we have demonstrated that radiation monotherapy appears to be a reasonable treatment modaltable 3. treatment characteristics and outcomes treatment local recurrence regional recurrence distant metastasis unspecified recurrence/ metastasis death from mcc stage i/ii (n = 48 ) local radiation monotherapy (n = 24) mean duration of follow-up: 13.4 months (range: 3-42) (n = 7)* primary tumor mean total radiation dose: 55.2 gy (range: 20-70)† event 1 (4%) 3 (13%) 2 (8%) 1 (4%) time-to-event (months) 3 6, 7* 18, 31 23 local-regional radiation monotherapy (n = 24) mean duration of follow-up: 15.1 months (range: 4-35) (n = 9)* primary tumor mean total radiation dose: 64.5 gy (range: 38.5-70) nodal basin mean total radiation dose: 50.8 gy (range: 40-55) event 1 (4%) 1 (4%) 2 (8%) 1 (4%) 2 (8%) time-to-event (months) 4 15 4, 15 10 7, 12 stage iii‡ (n = 20) local-regional radiation monotherapy (n = 20) mean duration of follow-up: 18.9 months (range: 4-53) (n = 20) primary tumor mean total radiation dose: 52.2 gy (range: 20-70) nodal basin mean total radiation dose: 51.5 gy (range: 20-70) event 2 (10%) 4 (20%) 6 (30%) 7 (35%) time-to-event (months) 1 (in-transit), 2 1, 3, 6, 9 2, 3, 5, 6, 8, 36 5, 5, 5, 7, 10, 10, 14 * duration of follow-up (time from date of diagnosis to either outcome of interest or date of last follow-up) was not available for all patients † fixed-effects model was used (heterogeneity q = .221, i2 < .001, p = .638) ‡ all stage iii patients were treated with local-regional radiation therapy 154 research | dermatol pract concept 2018;8(2):15 while the response of mcc to radiation therapy is impressive, radiation therapy is not without toxicity; cumulative experience from the treatment of non-melanoma skin cancer indicates that nearly all patients treated with potentially curative radiotherapy doses will develop at least mild-tomoderate acute side effects such as atrophy, pigment change, incidences in similarly staged patients treated with surgery +/radiation (figure 2) [1,25-27]. we additionally found that in the absence of nodal disease (stage i/ii) in patients with inoperable mcc, prophylactic radiation to the nodal basin resulted in a similar incidence of relapse and death as no prophylactic radiation to the nodal basin. interestingly, in the only randomized trial evaluating prophylactic radiation to the nodal basin in mcc patients, nodal irradiation with a dose of 50 gy was associated with a significant decrease in regional recurrences (log-rank, p = .007) but no difference in overall survival (log-rank, p = .989) or progression-free survival (log-rank, p = .400) [28]. when considering nodal disease (stage iii), however, radiation is typically provided to the nodal basin in patients with inoperable mcc, as was the case for all stage iii patients included in this review. in fact, in a study where all the patients underwent surgery +/radiation to the primary tumor, it was suggested that radiation to nodal disease is comparable to nodal dissection +/radiation, with no difference in 2-year regional recurrence-free survival (log-rank, p = 1, p = .8) or disease-specific survival (log-rank, p = .7, p = .9) [29]. currently, for inoperable stage i-iii mcc, the 2016 nccn (national comprehensive cancer network) guidelines recommend a total radiation dose of 60-66 gy to the primary tumor. radiation monotherapy to the nodal basin is only recommended if there is clinical or microscopic nodal involvement, or if the patient is at risk for subclinical nodal disease. unfortunately, the nccn guidelines do not define who is at risk for subclinical nodal disease, leaving it to the treating physician’s discretion. for clinical lymphadenopathy, 60-65 gy is given; for microscopic nodal involvement, 50-56 gy is given; and for patients at risk for subclinical nodal disease, 46-50 gy is given. typically, radiation of intransit lymphatics is not feasible unless the primary site is in close proximity to the nodal basin. in most settings, conventional radiotherapy fraction sizes of approximately 2 gy/day are utilized (figure 3). at this time, the nccn guidelines do not recommend chemotherapy for inoperable stage i-iii mcc. chemotherapy is generally reserved for stage iv mcc (metastatic disease), although there is no high-level evidence demonstrating that chemotherapy prolongs overall survival in this setting [30]. while adding chemotherapy to radiation monotherapy has the theoretical advantage of radiosensitizing mcc, there is limited data justifying this approach for local or regional radiation, and it could possibly even worsen prognosis due to immunosuppression [26,31]. systemic immunotherapy with recently developed checkpoint inhibitors is a promising approach for the treatment of advanced mcc [32]. anecdotal data [33] and results from early phase trials [34] for other malignancies suggest that the combination of systemic immunotherapy and radiotherapy should be explored in mcc. a b c figure  2. kaplan-meier survival curves. (a) relapse-free survival curve; (b) overall survival curve; (c) cause-specific survival curve. [copyright: ©2018 patel et al.] research | dermatol pract concept 2018;8(2):15 155 conclusions to our knowledge, this is the first review to collectively present the outcomes of mcc patients treated with radiation monotherapy. available data suggest that radiation monotherapy may be able to provide reasonable outcomes for mcc patients unable to undergo surgery. prospective studies are sorely needed to guide the management of this rare and potentially fatal disease. references 1. lewis kg, weinstock ma, weaver al, otley cc. adjuvant local irradiation for merkel cell carcinoma. arch dermatol. 2006;142(6):693-700. telangiectasia, or fibrosis [35,36]. fortunately, serious or severe complications occur in only ~1% of patients [37-39]. there are several limitations to our review. there was a dearth of available prospective studies, requiring us to rely on observational studies. this introduces a high risk of bias to our data and confounding factors that may obscure the overall results. our search also yielded a small sample of patients treated with radiation monotherapy, and many studies lacked detailed information regarding follow-up time and radiation techniques used. this limited the power of the conclusions that could be drawn from our results. pooled analysis of individual patient data from several large institutions and/or analysis of registry data should be pursued to further describe the use and efficacy of radiotherapy in the management of mcc. figure 3. radiation monotherapy recommendations for inoperable stage i-iii merkel cell carcinoma. modeled after the national comprehensive cancer network’s (nccn) guidelines for merkel cell carcinoma (version 1.2016). gy, gray; ln, lymph node; sln, sentinel lymph node; slnb, sentinel lymph node biopsy. all doses are at 2 gy/day standard fractionation. a less protracted fraction schedule may be used in the palliative setting such as 30 gy in 10 fractions. wide margins (5 cm) should be used, if possible, around the primary site. radiation of in-transit lymphatics is often not feasible unless the primary site is in close proximity to the nodal basin. *nccn guidelines based on category  2a recommendations: based upon lower-level evidence, there is uniform nccn consensus that the intervention is appropriate. 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carcinoma: the role of primary treatment with radiotherapy. clin oncol (r coll radiol). 1991;3(2):114116. 45. kitamura n, tomita r, yamamoto m, yoshizawa y, sasabe e, yamada t. complete remission of merkel cell carcinoma on the upper lip treated with radiation monotherapy and a literature review of japanese cases. world j surg oncol. 2015;13:152. 46. lawenda bd, arnold mg, tokarz va, silverstein jr, busse pm, mcintyre jf. analysis of radiation therapy for the control of merkel cell carcinoma of the head and neck based on 36 cases and a literature review. ear nose throat j. 2008;87(11):634-643. 47. luaces rey r, fernandez alba j, martin r, garcia rozado a, paradela s, robles o. merkel cell carcinoma of the head and dermatology: practical and conceptual research | dermatol pract concept 2016;6(3):4 11 dermatology practical & conceptual www.derm101.com introduction seborrheic dermatitis (sd), a common skin disorder that typically presents as erythematous plaques or patches and can vary from mild dandruff to dense, diffuse, adherent scale affecting the areas where sebaceous glands are prominent, including the scalp, face and chest. its precise etiology remains unknown, though it is associated with genetic, environmental, and general health factors. other important pathogenic factor seems to be malassezia colonization. its role could be effect of itraconazole on the quality of life in patients with moderate to severe seborrheic dermatitis: a randomized, placebo-controlled trial zaheer abbas1, seyedeh z. ghodsi1, robabeh abedeni1 1 department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran key words: itraconazole, seborrheic dermatitis, quality of life, malassezia citation: abbas z, ghodsi sz, abedeni r. effect of itraconazole on the quality of life in patients with moderate to severe seborrheic dermatitis: a randomized, placebo-controlled trial. dermatol pract concept 2016;6(3):4. doi: 10.5826/dpc.0603a04 received: november 3, 2015; accepted: april 22, 2016; published: july 31, 2016 copyright: ©2016 abbas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: zaheer abbas, md, department of dermatology, razi hospital, tehran university of medical sciences and health services, vahdate eslami sq. vahdate eslami ave., tehran, iran. tel. 00989128432179. e-mail: drzaheerabbas@yahoo.com background: few studies have examined the effect of seborrheic dermatitis (sd) and/or its consequent therapy on a patient’s quality of life. itraconazole has been suggested as an effective therapy for severe sd but its impact on quality of life (qol) in these patients has never been studied before. objective: the study aimed to verify the efficacy of the itraconazole on the quality of life in patients with moderate to severe sd. methods: a randomized, double-blind, placebo controlled trial was planned to describe the effect of sd per se on qol and to determine the impact of oral itraconazole or placebo on qol of sd patients. sixty-eight patients with moderate to severe sd participated in the study to receive either itraconazole or placebo. dermatology life quality index was used to evaluate their quality of life before and after treatment. itraconazole 200 mg/daily or placebo was prescribed for one week and then the first two days of every month for the following three months. fifty-seven patients completed the study. results: significant improvement was observed in qol of both itraconazole and placebo groups, but itraconazole group showed significantly higher improvement as compared to placebo (p=0.001). qol was impaired significantly with high disease severity (p=0.002) and facial involvement (p=0.017). conclusions: itraconazole significantly improves the qol in patients with moderate to severe sd. abstract mailto:drzaheerabbas@yahoo.com 12 research | dermatol pract concept 2016;6(3):4 methods this was a randomized placebo controlled, double-blind trial carried out with patients attending the outpatient ward of the dermatology department at the razi hospital tehran, between june 2012 and march 2014. patients were informed clearly and understandably about the possible risks or benefits of the trial and informed consent was provided by each patient included in the study. the approval of the study was obtained by the local and university ethics committees and performed in accordance with the helsinki declaration of 1964, as revised in 2013. the study design is summarized in figure 1. inclusion criteria were clinical diagnosis of sd made by a dermatologist, moderate to severe sd (seborrheic dermatitis area severity index [sdasi] =4 plus: ≥3 anatomical sites involved and/or recurrent sd and/or disease unresponsive to conventional topical therapy) and age ≥18 years. exclusion criteria included the following: any concomitant skin disease (e.g. acne, rosacea, contact dermatitis) or hiv+/aids, recent use of antiseborrheic treatment (2 weeks for topical and 4 weeks for systemic therapy), history of allergy to azoles, renal, liver or cardiac disease, patients using drugs interacting with itraconazole (e.g., cyclosporine, isoniazide, omeprazole, warfarin, statins), and pregnant/lactating women. both itraconazole supported by the positive correlation between yeast density on the skin and the severity of sd and a high efficacy of antifungal agents in the treatment of this disorder [1,2,3]. while sd rarely causes serious complications, it almost always leads to marked aesthetic deterioration and psychological distress due to its chronic and relapsing nature. despite high frequency of sd, surprisingly, only few studies have examined the effect of sd on quality of life (qol) [4-6]. although the topical treatment of sd with corticosteroids or antifungals is effective, there is a high risk of relapse and poor patient compliance [7], and therefore in some cases it is necessary to resort to systemic antifungals, especially in severe disease. various oral antifungals have been used to control sd with variable success rates. among them, itraconazole was the most frequently reported oral treatment particularly for severe sd [8], but therapeutic efficacy was evaluated only by clinical signs and symptoms in previous studies [7,9-11]. assessing qol can help in providing patients better service, by acknowledging their real needs and interfering with treatment decisions. because qol is a very important aspect in health and no study exists in the literature which assess the effect of treatment on qol in sd patients, this randomized controlled trial was set up to determine the impact of oral itraconazole on qol in patients with moderate to severe sd. figure 1. flow diagram of the study. [copyright: ©2016 abbas et al.] research | dermatol pract concept 2016;6(3):4 13 sone ointment once daily and 2% ketoconazole cream twice daily plus either oral itraconazole 200 mg/day or oral placebo was prescribed for one week. patients were advised to apply topical therapy on the areas involved. topical treatment was included in the study for ethical issues. in the second phase (one month after initial treatment), which was maintenance period, oral itraconazole 200 mg/day or oral placebo was given on the first two days of every month (400 mg/month) for three months. no other topical treatment, including therapeutic shampoos (except moisturizers) or oral medications, was allowed during this study period. during the second phase, in cases of relapse or flare of disease, patients of either group were allowed to use topical treatment (1% hydrocortisone ointment once daily and 2% ketoconazole cream twice daily) for a maximum of three days as a rescue regimen after informing the study investigator. statistical analysis was performed using ibm spss software. the difference in sdasi, symptom severity and dlqi scores before and after therapy was compared by using paired t-test. comparisons of mean age, disease duration, number of relapses and bmi between itraconazole and placebo groups and placebo were in capsule form and identical in appearance and were delivered to patients by a third person recruited for this purpose. the study investigator and patients were blind to intervention, and that was maintained until patients completed their last follow up visit. the qol was assessed at the start and end of the study by a standard dermatological life quality index (dlqi) questionnaire (persian version) filled by patients, which consisted of 10 questions each referring to the previous week. each question was scored from 3 (very much) to 0 (not relevant or not at all). the maximum possible score was 30. a questionnaire including the patient’s basic profile was filled in the first visit for assessing other secondary outcomes like effect of age, sex, education level, disease duration, number of relapses and body mass index (bmi) on qol. sdasi was used to determine the disease severity. this scoring system was modified from psoriasis area severity index (pasi) and the comert et al study [12] that had already been used in a previous study by ghodsi et al [13]. the treatment was administered in two different phases. in the first phase (initial treatment), topical 1% hydrocortitable 1. main characteristics of patients at baseline and at the end of study [copyright: ©2016 abbas et al.] itraconazole placebo p value patients enrolled sex, n (%) male female education level, n (%) intermediate bachelor master/phd n=35 23 (65.7%) 12 (34.3%) 19 (54.3%) 14 (40.0%) 2 (5.71%) n=33 24 (72.7%) 9 (27.3%) 20 (60.6%) 13 (39.4%) 0 0.532 0.652 age (years), mean ±sd duration of disease (years), mean ±sd number of relapses before treatment, mean ±sd bmi(kg/m2), mean ±sd quality of life (dlqi), mean ±sd 28.17 ±7.32 4.19±3.93 5.17±5.12 23.03±3.67 6.66±4.64 26.45±8.09 4.76±4.56 6.45±7.83 23.38±3.11 4.88±3.78 0.362 0.581 0.424 0.670 0.089 patients who completed the study quality of life (dlqi), mean ±sd before aftera severity of sd (sadsi), mean ±sd baseline at the end of studya itching, mean ±sd baseline at the end of studya burning sensation, mean ±sd baseline at the end of studya side effectsb, n (%) n=29 6.72±4.67 1.79±1.63 9.78±4.41 1.82±1.66 2.00±0.84 0.52±0.63 1.17±1.07 0.17±0.46 3 (10.3%) n=28 5.04±3.87 3.57±3.27 10.47±3.71 5.47±2.19 1.68±0.67 1.07±0.53 0.71±0.65 0.43±0.50 5 (17.9%) 0.001 0.023 0.002 0.003 0.470 sdasi seborrheic dermatitis area severity index, dlqi dermatology life quality index, bmi body mass index, sd seborrheic dermatitis a at the end of study=at the end of 16 weeks, b nausea, abdominal pain, diarrhea 14 research | dermatol pract concept 2016;6(3):4 significantly in both groups (table 1), patients taking itraconazole had greater reduction compared to placebo (p =0.001) (figure 2). the most compromised elements of qol were clinical symptoms, feelings (question 1, 2 of dlqi) and daily activities (question 3, 4) (figure 3). qol was not affected by age, sex, educational level, bmi, disease duration and number of relapses (p >0.05) but was impaired significantly with high disease severity (sdasi) (p =0.002) and presence of symptoms (itching and burning sensation) (p =0.001 each). furthermore, dlqi was not significantly different between the two groups of itraconazole and placebo (p =0.089). the most common site involved in our study was the scalp, but the location with significant effect on quality of life was the face (including forehead, eyebrows, nasolabial folds and cheeks collectively compared with scalp and trunk) (p =0.017). one patient in the itraconazole group as opposed to four patients in the placebo group required rescue medication in the second phase of the study. side effects like nausea, mild abdominal pain and diarrhea were reported by only three patients in itraconazole group. discussion in our study, we showed that quality of life is significantly improved by systemic itraconazole in moderate to severe sd patients. one of the important findings of our study was that patients in the itraconazole group had experienced a 73.36% reduction in dlqi after four months’ treatment, compared with 29.16% in the placebo group, and this effect of itraconazole on severe sd (mean dlqi before 6.72 and after 1.79) is comparable to systemic isotretinoin in acne patients (mean dlqi before=6.7, after=2.8) [14]. were performed using unpaired t-test. the pearson correlation was used to assess the link between dlqi and other secondary parameters. p-value<0.05 was considered significant. results sixty-eight patients who met study criteria were randomly assigned to itraconazole and placebo groups. eleven patients were lost to follow up. consequently, 57 patients completed the study and were included in the analysis (figure 1). the main characteristics of patients at baseline and at the end of study are summarized in table 1. the mean dlqi score in our study was 5.88±4.30. although dlqi scores decreased figure 2. comparison of dlqi before and after treatment in both groups. [copyright: ©2016 abbas et al.] figure 3. categories of dlqi and comparison of mean score in both groups (left itraconazole, right placebo). [copyright: ©2016 abbas et al.] research | dermatol pract concept 2016;6(3):4 15 dramatically improve quality of life and disease severity. due to the complex interactions among diseases, the patients’ qol and therapeutics, physicians must couple subjective assessment of qol with objective measurements for the proper management of severe sd. trial registration: irct2012091510842n1 (www.irct.ir) acknowledgements this study was sponsored and funded by tehran university of medical sciences. references 1. gupta ak, bluhm r. seborrheic dermatitis. j eur acad dermatol venereol 2004;18:13-26. pmid: 14678527. 2. johnson ba, nunley jr. treatment of seborrheic dermatitis. am fam physician 2000;61:2703-2710, 2713-2714. pmid: 10821151. 3. schwartz ra, janusz ca, janniger ck. seborrheic dermatitis: an overview. am fam phys 2006;74:125-30. pmid: 16848386. 4. szepietowski jc, reich a, wesołowska szepietowska e, baran e. national quality of life in dermatology group. quality of life in patients suffering from seborrheic dermatitis: influence of age, gender and education level. mycoses 2009;52(4):357-63. pmid: 18793259 doi: 10.1111/j.1439-0507.2008.01624.x. 5. peyri j, lleonart m, grupo español del studio sebderm. clinical and therapeutic profile and quality of life of patients with seborrheic dermatitis. actas dermosifiliogr 2007;98(7):476-82. pmid: 17669302. 6. oztas p, calikoglu e, cetin i. psychiatric tests in seborrhoeic dermatitis. acta derm venereol 2005;85(1):68-9. pmid: 15848997 doi: 10.1080/00015550410021574. 7. baysal v, yildirim m, ozcanli c, ceyhan am. itraconazole in the treatment of seborrheic dermatitis: a new treatment modality. int j dermatol 2004;43(1):63-6. pmid: 14693026. 10.1111/j.13654632.2004.02123.x. 8. gupta ak, richardson m, paquet m. systemic review of oral treatments for seborrheic dermatitis. j eur acad dermatol venereol 2014;28(1):16-26. pmid: 23802806 doi: 10.1111/jdv.12197. 9. kose o, erbil h, gur ar. oral itraconazole for the treatment of seborrhoeic dermatitis: an open, noncomparative trial. j eur acad dermatol venereol 2005; 19(2):172-5. pmid: 15752285. doi: 10.1111/j.1468-3083.2005.01090.x. 10. shemer a, kaplan b, nathansohn n et al. treatment of moderate to severe facial seborrheic dermatitis with itraconazole: an open non-comparative study. isr med assoc j 2008; 10(6):417-8. pmid: 18669136. 11. das j, majumdar m, chakraborty yu, et al. oral itraconazole for the treatment of severe seborrhoeic dermatitis. indian j dermatol 2011;56:515–6. pmid: 22121267. doi: 10.4103/00195154.87137. 12. comert a, bekiroglu n, gurbuz o, ergun t. efficacy of oral fluconazole in the treatment of seborrheic dermatitis: a placebocontrolled study. am j clin dermatol 2007;8(4):235-8. pmid: 17645378. 13. ghodsi sz, abbas z, abedeni r. efficacy of oral itraconazole in the treatment and relapse prevention of moderate to severe seborrheic dermatitis: a randomized, placebo-controlled trial. am j clin the mean dlqi score in our study was similar to harlow et al (mean dlqi: 5.9, n=20) [15] but lower than szepietowski et al (mean 6.92±5.34) [4]. the difference could be explained by the different regional and social backgrounds and disease severity level in these studies. there is marked impairment of qol in patients with more severe disease, with a greater effect observed in women and in young patients (age subgroup: 26-35 years) with higher educational level (master and phd level), and this is almost parallel to previous studies [4-5]. interestingly, in our study, disease duration and number of relapses had no effect on qol. here, adaptations of the patients to the nature of their disease and coping more efficiently with the disease and therapies over a certain period of time may have had effect. the most common site involved in our study was the scalp, but qol impairment was higher significantly in facial disease. as the appearance plays important role in the society, a patient with a red and flaky face may feel more embarrassed. the assessment of the impact on quality of life in patients with skin diseases is important for clinical management. it is essential to detect patients at a higher risk of experiencing a worse quality of life in order to treat him/her in a more integrated way. to our knowledge, this trial was the first using a randomized, placebo-controlled design that investigated the effect of itraconazole on the quality of life in moderate to severe sd patients. therapeutic efficacy of itraconazole has already been studied in many previous clinical trials [7, 9-11, 13]. although study designs and measurement scales were different, the results regarding effect of itraconazole were almost similar in these studies, and this fact shows the marked efficacy of itraconazole in the treatment of severe sd. our study met with several limitations. first, no fungal culture was performed and therefore clinical outcome could not be correlated directly to malassezia colonization. second, the power of the study is limited by the monocentric design and small sample size of our study, therefore, a larger, multicentric study is warranted to evaluate the therapeutic effect of itraconazole or other newer therapies for sd patients. third, the short period of follow up; a longer study period would have been beneficial. fourth, it is well known that sd may worsen or improve due to many factors such as seasonal variation, host immunity, and host mood status; these factors might have changed the clinical condition in some patients. fifth, although the effect of topical therapy declined mainly after two weeks, it might have affected partly over the final result of clinical picture and dlqi. conclusions sd can significantly reduce qol particularly in severe disease and facial involvement. pulse therapy with itraconazole can http://www.irct.ir/searchresult.php?id=10842&number=1 http://www.irct.ir 16 research | dermatol pract concept 2016;6(3):4 15. harlow d, poyner t, finlay ay, dykes pj. impaired quality of life of adults with skin disease in primary care. br j dermatol. 2000;143(5):979-82.pmid: 11069506. 10.1046/j.13652133.2000.03830.x. dermatol 2015;16(5):431-7. pmid: 26016699. doi: 10.1007/ s40257-015-0133-9. 14. lewis v, finlay ay. 10 years experience of the dermatology life quality index (dlqi). j invest dermatol symp proc 2004;9:169– 80. pmid: 15083785 doi: 10.1111/j.1087-0024.2004.09113.x. dermatology: practical and conceptual review | dermatol pract concept 2019;9(4):1 249 dermatology practical & conceptual introduction sunlight is composed of a spectrum of radiations that span from infrared to visible and uv light; uv radiation itself is further subdivided into uva, uvb, and uvc. uvc radiation is blocked by stratosphere gases, and therefore only uva and uvb rays reach the earth’s surface [1]. excessive solar exposure presents well-recognized risks and side effects, solar radiation being the most important environmental risk factor for skin cancer, the main cause of photoaging, and also an exacerbating factor for several photo-aggravated dermatoses [2,3]. however, in the last few years a variety of connections between solar exposure and prevention and/or treatment of several diseases have been discussed, with studies suggesting that regular solar exposure may have more benefits than previously thought [4]. the big question is, therefore, to which point actual practices of sun avoidance bring effective benefits to our health. mechanisms of action of ultraviolet radiation in the past, benefits of sun exposure were attributed only to vitamin d. effectively, the most well-known advantage of sun exposure is the synthesis of vitamin d, which is important for several physiological functions, uvb radiation being the most responsible for vitamin d levels in the vast majority of the population [5]. vitamin d production starts with the sun exposure: beyond the risks catarina soares queirós1, joão pedro freitas, md1 1 serviço de dermatologia do hospital de santa maria, centro hospitalar e universitário de lisboa norte, lisbon, portugal key words: sun, vitamin d, skin neoplasms, nitric oxide citation: queirós cs, freitas jp. sun exposure: beyond the risks. dermatol pract concept. 2019;9(4):249-252. doi: https://doi. org/10.5826/dpc.0904a01 accepted: july 23, 2019; published: october 31, 2019 copyright: ©2019 soares queirós et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: catarina soares queirós, md, serviço de dermatologia do hospital de santa maria, centro hospitalar e universitário de lisboa norte, avenida prof. egas moniz, 1649-035, lisboa, portugal. email: catarina.squeiros@gmail.com excessive solar exposure presents well-recognized risks and side effects, solar radiation being the most important environmental factor concerning skin cancer. in the last few years, several connections between solar exposure and prevention and/or treatment of several diseases have been discussed, with studies suggesting that regular solar exposure may be beneficial for conditions such as colorectal, breast, prostate, and pancreatic cancer; non-hodgkin lymphoma; arterial hypertension; obesity; type 2 diabetes mellitus and metabolic syndrome; nonalcoholic hepatic steatosis; multiple sclerosis; alzheimer disease; and several psychiatric disturbances. in most cases, uv radiation’s beneficial effects are mediated through vitamin d; however, studies show that in other instances other mediators are responsible for these associations, specifically nitric oxide. moderation is therefore essential, as a strict strategy of total sun avoidance may be inadequate. abstract 250 review | dermatol pract concept 2019;9(4):1 nevertheless, in recent years, several previously unrecognized connections between solar exposure and a decreased risk of some diseases have been proposed. some studies have even demonstrated a reduction in all-cause mortality or cardiovascular mortality in patients with regular and moderate sun exposure [10]. cancer cancer prevention is one of the areas of greatest interest concerning the benefits of vitamin d and, therefore, of sun exposure. indeed, in the past decade numerous studies supported a strong association between uv exposure and a decreased risk of several cancers, namely breast, colon, ovary, and prostate cancer and non-hodgkin lymphoma [5]. recently, in a systematic review from van der rhee et al on this topic, it was concluded that chronic regular solar exposure (as opposed to intermittent exposure) seems to have a protective effect against the incidence of colorectal, breast, and prostate cancer and non-hodgkin lymphoma [11]. focusing on breast cancer, in the following year a meta-analysis from mohr et al demonstrated a significant mortality reduction in patients with normal levels of vitamin d, when compared with patients with insufficient levels of this vitamin [12], thus confirming the previously described inverse link between solar exposure and breast cancer. although vitamin d has a strong influence on the effect of solar exposure on cancer prevention, it is not the only explanation for this association, which is not entirely reproduced by nutritional supplementation [1]. therefore, other proposed mechanisms include immunomodulation induced by sun exposure and the effect of melatonin on the regulation of circadian rhythms, whose disruption is associated with carcinogenesis [2]. cardiovascular diseases arterial hypertension several recent studies have evaluated the effects of uv exposure on blood pressure, and a protector effect seems to exist [13]. this effect does not seem to be dependent on its influence on vitamin d levels, but on the release of nitric oxide from skin storages upon solar exposure, with consequent vasodilation, as previously explained [9]. type 2 diabetes mellitus and obesity in 2017, a study from gorman et al on the effect of solar exposure in the development of obesity and type 2 diabetes mellitus concluded that continuous or regular sun exposure may control the appearance of both conditions [1]. in fact, in the last few years several studies have demonstrated the existence of an inverse correlation between body mass index and serum levels of vitamin d, although in these observareaction of 7-deoxycholesterol, produced in abundant quantity in the skin, with uvb radiation. this reaction leads to the production of cholecalciferol, which is transported to the liver, where it is hydroxylated at position 25 (a step catalyzed by the microsomal enzyme 25hydroxylase), thus producing calcifediol. calcifediol is then released into the circulation, reaching the kidneys, where it is again hydroxylated at position 1-α (a step catalyzed by the enzyme hydroxyvitamin d 3 1-α-hydroxylase), leading to the formation of calcitriol, the most active form of vitamin d and the one responsible for most of its effects [5]. vitamin d is important when it comes to the absorption of calcium originated in the diet, therefore being essential to the maintenance of an adequate bone mineral density, its deficiency being associated with an increased risk of osteoporosis and rickets [6]. apart from these effects, recent studies also suggest that vitamin d deficit possibly correlates with disease activity in rheumatoid arthritis [7] and that an increase in vitamin d levels in osteoarthritis may be associated with an improvement in life quality and muscular strength in these patients [8]. recently, other mechanisms have been proposed to explain the beneficial association between solar exposure and certain diseases [4]; these include the action of nitric oxide, immunomodulation, the production of melatonin and serotonin, and the effect of light in circadian rhythms [2]. the role of nitric oxide is one of the most studied mechanisms; uva radiation induces the release of this molecule from its storages in the skin, as well as its translocation to the blood. here, nitric oxide is responsible for a variety of effects such as vasodilation and decrease of peripheral vascular resistance with a consequent decrease of blood pressure and suppression of glucose intolerance and insulin resistance [9]. as far as immunomodulation is concerned, it is known that both uva and uvb have a direct immunosuppressor effect, by induction of cytokines such as tumor necrosis factor-α (tnf-α) and interleukin-10 (il-10) and stimulation of t regulatory cells. this mechanism may explain the benefit of sun exposure in the protection from certain autoimmune disorders such as multiple sclerosis or rheumatoid arthritis [10]. other less well-studied mechanisms include the synthesis of endorphins and photodegradation of folic acid [2]. benefits of sun exposure the most-recognized benefits of sun exposure include the prevention and treatment of several dermatoses (such as psoriasis and eczema), vitamin d synthesis (important to normal bone and muscle physiology), and prevention and treatment of seasonal affective disorder. all these links are well established and supported, uv radiation being used in the treatment of some of these conditions, such as psoriasis. review | dermatol pract concept 2019;9(4):1 251 effect of solar exposure on the prevention and treatment of seasonal affective disorder, a benefit that seems to extend to other depressive states [2,17]. in this area, vitamin d seems to be one of the major mediators of the benefits of uv radiation [17]. hepatic disease in the last few years, evidence has emerged in favor of a protective role of uv exposure on the development of nonalcoholic hepatic steatosis. this protective effect seems to be partially dependent on vitamin d, but other factors are probably implicated [13]. conclusions in the last decade, several studies have proposed a strong connection between sun exposure and a decrease in the risk of developing certain diseases, including colorectal, breast, prostate, and pancreatic cancer; non-hodgkin lymphoma; arterial hypertension; obesity; type 2 diabetes mellitus and metabolic syndrome; nonalcoholic hepatic steatosis; multiple sclerosis; alzheimer disease; and several psychiatric disturbances. these potential relations are even more important if we consider that many of these conditions have a mortality rate that is higher than that of skin cancer. frequently, beneficial effects of uv radiation are mediated through vitamin d; however, in other circumstances, other mediators are responsible for these associations, more precisely nitric oxide. therefore, it is easy to acknowledge that vitamin d supplementation does not replace adequate sun exposure. obviously, the other side of sun exposure must not be forgotten, as it is the major risk factor for skin cancer. therefore, combinations of sun protection practices including the use of beach umbrellas, sunscreens with high sun protection factors, and protective clothing remain important and should be emphasized by dermatologists [18]. a strict strategy of total sun avoidance seems to be inadequate, so as with everything, moderation is essential. references 1. gorman s, lucas rm, allen-hall a, fleurya n, feelischc m. ultraviolet radiation, vitamin d and the development of obesity, metabolic syndrome and type-2 diabetes. photochem photobiol sci. 2017;16(3):362-373. 2. van der rhee hj, de vries e, coebergh jw. regular sun exposure benefits health. med hypotheses. 2016;97:34-37. 3. weller rb. the health benefits of uv radiation exposure through vitamin d production or non-vitamin d pathways: blood pressure and cardiovascular disease. photochem photobiol sci. 2017;16(3):374-380. 4. van der rhee hj, de vries e, coomans c, van de velde p, coebergh jw. sunlight: for better or for worse? a review of positive and negative effects of sun exposure. cancer research frontiers. tional studies it is difficult to establish a cause-effect relation between these 2 variables [14]. on the other hand, the benefits of sun exposure in these settings may result through other mediators, namely through the release of nitric oxide from the skin after sun exposure or via secretion of α-melanocyte-stimulating hormone (α-msh) [1]. after regular and moderate sun exposure, patients with type 2 diabetes mellitus show an increase in insulin secretion and a decrease in high-sensitivity c reactive protein (an inflammatory marker). regarding the high prevalence and mortality of this condition, this is an area where further studies are crucial to clarify these potential associations [1]. metabolic syndrome taking into account the proposed benefits of uv radiation exposure on arterial hypertension, obesity, and type 2 diabetes mellitus, it is easy to recognize that solar exposure may also bring benefits to patients with metabolic syndrome. indeed, a study from vitezova et al showed that higher levels of vitamin d are associated with a lower prevalence of metabolic syndrome in middle-aged and older people, even after adjusting for body mass index [15]. neurological diseases multiple sclerosis as far as multiple sclerosis is concerned, several studies demonstrated an increased risk of developing this disease in individuals with insufficient solar exposure, probably due to mechanisms unrelated to vitamin d [11,13]. in addition, prospective and case-control studies in caucasian patients suffering from multiple sclerosis revealed a decrease in mortality risk as sun exposure hours increased [4]. dementia recent studies have pointed toward the existence of a close relationship between low levels of vitamin d and the development of cognitive deficit and dementia. in particular, a prospective study from littlejohns et al revealed that patients with vitamin d deficit have a 2-fold increased risk of developing alzheimer disease compared with individuals with normal levels of this same vitamin [16]. although more evidence is needed, these findings may well be important in the future, as we are dealing with an increasingly elderly population, who therefore have a greater predisposition toward this type of pathology. other diseases psychiatric disease one of the first recognized associations between solar exposure and development or treatment of certain diseases was in the field of psychiatry. here, emphasis is given to the 252 review | dermatol pract concept 2019;9(4):1 a systematic review of epidemiological studies. eur j cancer. 2013;49(6):1422-1436. 12. mohr sb, gorham ed, kim j, hofflich h, garland cf. meta-analysis of vitamin d sufficiency for improving survival of patients with breast cancer. anticancer res. 2014;34(3):1163-1166. 13. hoel dg, berwick m, de gruijl fr, holick mf. the risks and benefits of sun exposure 2016. dermatoendocrinol. 2016;8(1):e1248325. 14. earthman cp, beckman lm, masodkar k, sibley sd. the link between obesity and low circulating 25-hydroxyvitamin d concentrations: considerations and implications. int j obes (lond). 2012;36(3):387-396. 15. vitezova a, zillikens mc, van herpt tt, et al. vitamin d status and metabolic syndrome in the elderly: the rotterdam study. eur j endocrinol. 2015;172(3):327-335. 16. littlejohns tj, henley we, lang ia, et al. vitamin d and the risk of dementia and alzheimer disease. neurology. 2014;83(10):920928. 17. melrose s. seasonal affective disorder: an overview of assessment and treatment approaches. depress res treat. 2015;2015:178564. 18. ou-yang h, jiang li, meyer k, et al. sun protection by beach umbrella vs sunscreen with a high sun protection factor: a randomized clinical trial. jama dermatol. 2017;153(3):304-308. 2016;2(2):156-183. available at: http://cancer-research-frontiers. org/wp-content/uploads/2016/04/crf-2016-2-156.pdf. 5. grant wb. health benefits of solar uv-b radiation through the production of vitamin d: comment and response. photochem photobiol sci. 2003;2(12):1307-1308; discussion 1308-1310. 6. lips p, van schoor nm. the effect of vitamin d on bone and osteoporosis. best pract res clin endocrinol metab. 2011;25(4):585591. 7. caraba a, crisan v, romosan i, mozos i, murariu m. vitamin d status, disease activity, and endothelial dysfunction in early rheumatoid arthritis patients. dis markers. 2017;2017:5241012. 8. manoy p, yuktanandana p, tanavalee a, et al. vitamin d supplementation improves quality of life and physical performance in osteoarthritis patients. nutrients. 2017;9(8):799. 9. liu d, fernandez bo, hamilton a, et al. uva irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. j invest dermatol. 2014;134(7):1839-1846. 10. wright f, weller rb. risks and benefits of uv radiation in older people: more of a friend than a foe? maturitas. 2015;81(4):425431. 11. van der rhee hj, coebergh jw, de vries e. is prevention of cancer by sun exposure more than just the effect of vitamin d? dermatology: practical and conceptual 230 letter | dermatol pract concept 2019;9(3):16 dermatology practical & conceptual introduction verrucous epidermal nevus (ven) is a benign, noninflammatory malformation usually present at birth or occurring within the first years of life. it is composed of keratinocytes that arise from pluripotential germ cells in the basal layer of the embryonic ectoderm and results from mosaic postzygotic mutations. ven clinically appears as skin-colored to brown, sharply demarcated, papillomatous papules coalescing into plaques. the diagnosis is usually based on clinical presentation and, in selected cases, on histopathology examination that reveals epidermal hyperplasia, papillomatosis with elongation of rete ridges, and pigmented keratinocytes surrounding the dermal papillae. dermoscopy and reflectance confocal microscopy (rcm) are valuable, noninvasive techniques that support the diagnosis in clinical practice in several fields of dermatology including cutaneous tumors as well as inflammatory and infectious dermatoses [1]. dermoscopy has shown in 8 cases of ven the characteristic presence of large brown circles, consisting of hyperchromic brown edge surrounding a hypochromic area. the aim of this study was to evaluate and correlate dermoscopy (dermlite; 3gen, san juan capistrano, ca, usa), rcm (vivascope3000; caliber i.d., rochester, ny, usa) and histopathological findings in a series of 9 patients with a clinical and/or histopathologically proven diagnosis of ven. in all cases ven had been present since early infancy. all participants provided informed consent. case presentation all examined lesions—3 located on the head, 4 on the neck, and 2 on the trunk—clinically appeared as velvety plaques with linear distribution and variable degree of pigmentation, ranging from light to dark brown (figure 1a). at dermoscopy, all lesions showed the presence of large brown circles on a brownish background. no pigment network, globules, comedo-like openings, or milia-like cysts were observed (figure 1b). rcm revealed, in all cases, a normal epidermal honeycomb pattern (bright polygonal cellular outlines and dark nuclei), papillomatosis, and the constant presence of a well-defined, strongly bright rim of verrucous epidermal nevus: dermoscopy, reflectance confocal microscopy, and histopathological correlation anna elisa verzì1, francesco lacarrubba1, enrica quattrocchi1, giuseppe micali1 1 dermatology clinic, university of catania, italy key words: dermatoscope, dermoscopy, reflectance confocal microscopy, verrucous epidermal nevus, histopathology citation: verzì ae, lacarrubba f, quattrocchi e, micali g. verrucous epidermal nevus: dermoscopy, reflectance confocal microscopy, and histopathological correlation. dermatol pract concept. 2019;9(3):230-231. doi: https://doi.org/10.5826/dpc.0903a16 accepted: december 3, 2019; published: july 31, 2019 copyright: ©2019 verzì et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: giuseppe micali, md, dermatology clinic, university of catania, via s. sofia 78, 95123 catania, italy. email: cldermct@gmail.com letter | dermatol pract concept 2019;9(3):16 231 pattern at rcm may also be observed in solar lentigo, lentigo simplex, and ink spot lentigo; in the first case, the bright ring is due to hyperpigmentation of the basal keratinocytes, and in the remaining 2 to hyperproliferation of melanocytes. however, these disorders are clinically different from ven presenting with flat, nonpalpable, pigmented lesions. in conclusion, our study suggests that the combined use of dermoscopy and rcm may assist in the enhanced diagnosis of ven, especially in those cases with unusual clinical presentation. references 1. lacarrubba f, ardigò m, di stefani a, verzì ae, micali g. dermatoscopy and reflectance confocal microscopy correlations in nonmelanocytic disorders. dermatol clin. 2018;36(4):487-501. 2. carbotti m, coppola r, graziano a, et al. dermoscopy of verrucous epidermal nevus: large brown circles as a novel feature for diagnosis. int j dermatol. 2016;55(6):653-656. monomorphous cells demarcating each dark dermal papilla throughout the lesion (figure 1c). conclusions to the best of our knowledge, this is the first study describing the rcm features of ven. in our series, ven showed peculiar dermoscopic and rcm findings. in particular, the typical presence at dermoscopy of large brown circles, as previously reported [2], correlated with dermal papillae demarcated by a rim of monomorphous and strongly bright cells seen at rcm and corresponds to the histological arrangement of pigmented keratinocytes surrounding the dermal papillae (figure 1d). the dermoscopic brown circles have been observed, along with other findings, in seborrheic keratosis and pigmented squamous cell carcinoma, 2 disorders that, however, show different age at onset and clinical features. a similar ringed figure 1.  ven of the neck.  (a)  clinical aspect.  (b) dermoscopy showing large brown circles (insert: a detail) on a brownish background.  (c)  rcm showing a well-defined, strongly bright rim of monomorphous keratinocytes demarcating each dark dermal papilla. (d) histopathology showing arrangement of pigmented keratinocytes surrounding the dermal papillae (arrow). [copyright: ©2019 verzì et al.] a c b d dermatology: practical and conceptual 320 letter | dermatol pract concept 2018;8(4):14 dermatology practical & conceptual www.derm101.com introduction a 78-year-old man presented with 2 asymptomatic lesions on the back (discovered by a family member a few days earlier) of unknown time of appearance. case presentation examination revealed 2 pink macules approximately 2 cm in diameter with sharp edges, located in the right dorsal and central lumbar areas (figure 1). polarized light dermoscopy of the upper macule revealed red-milky areas, punctiform vessels, irregular linear vessels, and a small area with negative pigment network with graybrown spots (figure 2). similar examination of the lumbar lesion revealed shiny, whitish blotches over a whitish-pink background, shiny white streaks or chrysalis, and a number of fine, short, and isolated telangiectasias (figure 3). both lesions were excised. a histological diagnosis of superficial melanoma with a 0.3 mm breslow thickness was reached for the upper lesion, and a diagnosis of superficial basal cell carcinoma (bcc) was made for the lumbar lesion. clinically, both lesions appeared to be very similar and required dermoscopy for diagnoses to be reached. in such nonpigmented lesions, the morphology and distribution of the vasculature can offer diagnostic clues [1]. punctiform or pinhead vessels are characteristic of melanoma challenging clinical diagnosis of 2 lesions on the back: dermoscopy gives the clue lucia campos-muñoz1, alberto conde-taboada1, alejandro fueyo-casado1, eduardo lopez-bran1 1 department of dermatology, hospital clínico san carlos, madrid, spain key words: hypopigmented lesions, dermoscopy, melanoma, spitz-reed nevus citation: campos-muñoz l, conde-taboada a, fueyo-casado a, lopez-bran e. challenging clinical diagnosis of 2 lesions on the back: dermoscopy gives the clue. dermatol pract concept. 2018;8(4):320-321. doi: https://doi.org/10.5826/dpc.0804a14 received: january 3, 2018; accepted: june 7, 2018; published: october 31, 2018 copyright: ©2018 campos-muñoz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: lucia muñoz-campos, md. email: luciacampos78@hotmail.com figure  1. two pink macular lesions on the patient’s back. [copyright: ©2018 campos-muñoz et al.] letter | dermatol pract concept 2018;8(4):14 321 [2], and for this reason is proposed as a diagnostic criterion (specificity 91%, sensitivity 30%). in the present patient’s upper lesion, a minimum amount of pigment appearing as brown spots suggested it to be melanocytic. the negative pigment network appeared as dark areas surrounded by clear, reticulate, and serpiginous lines. histologically, it appeared to correspond to elongated fine crests. this finding is characteristic of melanoma and spitz-reed nevus. conclusion in conclusion, this report highlights the need to assess the vasculature and brilliant white structures of nonpigmented skin lesions. references 1. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy, part ii: nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377-386. 2. navarrete-dechent c, bajaj s, marchetti ma, rabinovitz h, dusza sw, marghoob aa. association of shiny white blotches and strands with nonpigmented basal cell carcinoma: evaluation of an additional dermoscopic diagnostic criterion. jama dermatol. 2016;152(5):546-552. and spitz nevus, as well as of psoriasis and bowen disease. irregular linear vessels can be seen in different malignant cutaneous tumors, and when present it is advisable to take a biopsy. red-milky areas are thought to represent neoangiogenesis and are a characteristic sign of hypomelanotic and amelanotic melanoma, but have also been described in nodular and sclerodermiform bcc [1]. arboriform telangiectasias are very specific of bcc, but superficial lesions such as that of the present patient may only show very fine linear or serpiginous vessels with few ramifications. recently the importance of shiny white structures (blotches, long lines, rosettes, and chrysalis) in the diagnosis of nonpigmented bcc has been highlighted [2]. these signs are visible only under polarized light. the blotches are destructured areas and can be large or small and are brilliant white. the long lines may be thick or thin; they are never oriented orthogonally. the rosettes are groups of 4 white spots in a 4-leaf-clover arrangement. the chrysalis are short, shiny features oriented orthogonally with respect to one another and are present in bcc, melanoma, spitz nevus, dermatofibromas, and benign melanocytic lesions. the lower lesion of the present patient showed brilliant white blotches, features seen more commonly in bcc (38%) than melanoma (9%). the simultaneous presence of blotches and long lines has been reported in some 48% of nonpigmented bcc lesions figure 2. upper lesion. note the irregularly distributed punctiform vessels (black triangle and red triangle), gray-brown spots (black circle), and asymmetrically distributed negative pigment network (black arrow). [copyright: ©2018 campos-muñoz et al.] figure  3. lower lesion. note the brilliant white blotches (green triangles), chrysalis (red triangle), and fine, ramified vessels over the whitish-pink background (black triangles). [copyright: ©2018 campos-muñoz et al.] 104 research | dermatol pract concept 2018;8(2):7 dermatology practical & conceptual www.derm101.com morphologic characteristics of nevi associated with melanoma: a clinical, dermatoscopic and histopathologic analysis temeida alendar1, harald kittler1 1  department of dermatology, medical university vienna, vienna, austria key words: nevus, melanoma, dermatopathology, dermatoscopy citation: alendar t, kittler h. morphologic characteristics of nevi associated with melanoma: a clinical, dermatoscopic and histopathologic analysis. dermatol pract concept. 2018;8(2):104-108. doi: https://doi.org/10.5826/dpc.0802a07 received: january 8, 2018; accepted: february 1, 2018; published: april 30, 2018 copyright: ©2018 alendar et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: harald kittler, md, department of dermatology, medical university vienna, waehringer gürtel 18-20, 1090, vienna, austria. tel: ++44.1.40400.77110. email: harald.kittler@meduniwien.ac.at background: the aim of this retrospective study was to determine the frequency of nevus-associated melanomas and to better characterize the preexisting nevus from a histopathologic, clinical and dermatoscopic point of view. methods: we reviewed the histopathologic slides of a consecutive series of 357 melanomas and corresponding clinical and dermatoscopic images, if available. results: we found that 31 (8.7%) melanomas were associated with a preexisting nevus, 284 (79.5%) melanomas developed de novo, and in 42 (11.8%) a preexisting nevus could not be excluded, although the alternative explanation that the entire lesion represented a melanoma was also possible. the preexisting nevus was a “superficial” or “superficial and deep” congenital nevus in 27 cases (87%) and a clark nevus in 4 cases (13%). clinical or dermatoscopic images were available in 149 (41.7%) cases. the preexisting nevus, if visible, looked inconspicuous clinically or dermatoscopically. the median invasion thickness of nevus-associated melanoma was not significantly different from “de novo” melanomas but the frequency of in situ melanomas was higher in the “de novo“ group (40.1% versus 16.1%). patients with melanoma in association with a nevus were significantly younger (mean age=55 years, sd: 16 years) than patients with “de novo” melanomas (mean age=68 years sd: 15 years, p<0.001). when controlled for age and invasion thickness overall, survival did not differ significantly between patients with nevus-associated melanomas and patients with de novo melanomas. conclusions: from a histomorphologic point of view, the majority of melanomas arise de novo. if melanomas develop in a preexisting nevus, they usually occur in association with a “superficial” or “superficial and deep” congenital nevus. abstract research | dermatol pract concept 2018;8(2):7 105 toscopic images on a computer screen without knowledge of the histopathologic diagnosis. statistical analysis continuous data are given as mean and standard deviations (sd) or as median and range, as appropriate. t-tests or mann-whitney u tests were used to compare groups and the chi-square test for the comparison of proportions. the kaplan-meier method and a cox proportional hazards analysis were used to analyze differences in overall survival. all given p-values are two-tailed. a p-value <.05 was considered statistically significant. results general data we included  357  melanomas of  194  males (54.3%) and 163 females (45.7%). the mean age was 66.4 years (sd: 15.4). the majority of melanomas were located on the trunk (n=118, 33%), 137 (38.4%) melanomas were in situ and 220 (61.6%) were invasive. the median invasion thickness of all lesions was 0.94 mm (range 0.18 -10 mm). the general characteristics of the melanomas are given in table 1. after reviewing the histopathologic slides, we found that 284 melanomas (79.5%) developed de novo and 31 (8.7%) in association with a preexisting nevus. in 42 (11.8%) cases a preexisting nevus could not be excluded, although the alternative explanation that the entire lesion represented a melanoma was also possible. introduction it is generally agreed that the majority of melanomas arise de novo [1-5]. tsao et al stated that the risk of malignant transformation of any specific melanocytic nevus is low [5]. some authors, however, believe that melanomas frequently develop in so called “dysplastic nevi” [6-8]. kaddu et al, on the other hand, proposed that small, superficial congenital nevi might play an important role as precursor lesions of melanomas [3]. the classification of the type of associated nevus is difficult because of the lack of a generally accepted classification of nevi. it has also been reported that patients with a melanoma in association with a preexisting nevus are significantly younger than patients with de novo melanomas [1,3]. the purpose of this study was to determine the frequency of melanoma in association with a preexisting nevus and to characterize the clinical, histopathologic and dermatoscopic appearance of nevi that are associated with melanoma. materials and methods general characteristics we analyzed a series of 357 consecutive cases of histologically verified melanomas excised between january 1, 2005, and december 31, 2007, at the department of dermatology, university of vienna medical school. clinical images were taken with a nikon d300 12.3mp dslr camera (nikon corp, tokyo, japan). dermatoscopic images were acquired either with dermlite fotosystem (dermlite foto model combined with canong12 digital camera; 3gen, san juan capistrano, ca, usa) or with a digital dermatoscopic imaging system molemax iitm (derma medical systems, vienna, austria). histopathologic assessment and review of images all cases were subjected to standard histopathologic processing. histopathologic slides were reviewed by the study authors and classified into the following subgroups: (1) de novo melanomas, (2) melanomas arising in a preexisting nevus, and (3) non-decidable cases. histopathologic review of the case was performed without knowledge of the respective clinical or dermatoscopic images. we used standard histopathologic criteria to differentiate between melanomas and nevi. for the classification of associated nevi, we used the nevus classification according to ackerman and differentiated between clark nevi, superficial congenital nevi (ackerman nevi), and “superficial and deep” congenital nevi (zitelli nevi) [9]. a schematic presentation of the histopathologic characteristics of these nevi is given in figure 1. the two study authors reviewed all available clinical and dermafigure 1. schematic drawings of histomorphologic patterns of nevi. (a) clark nevus; (b) superficial congenital nevus; (c) superficial or deep congenital nevus. 106 research | dermatol pract concept 2018;8(2):7 the nevus was of the congenital type. dermatoscopic images were available in 5 nevus-associated melanomas. the clinical, dermatoscopic and histopathologic images of nevus-associated melanomas are shown in figures 3 and 4. figure 5 shows clinical and dermatoscopic images of 2 melanomas arising in a superficial and deep congenital nevus; differences between de novo and nevus-associated melanomas the mean age of patients diagnosed with de novo melanomas was 68.2 years (sd: 14.8 years). patients with a melanoma in association with a preexisting nevus were significantly younger with a mean age of  54.9  years (sd: 16.3 years, p<0.001). the frequency of in situ melanomas was significantly higher in the group of de novo melanomas (40.1%, n=114) than in the group of melanomas in association with a preexisting nevus (16.1%, n=5, p<0.001). the median tumor thickness of invasive melanomas in association with a preexisting nevus was 0.85 mm (range:0.3– 7.0 mm) and not significantly different from de novo melanomas 0.80 mm (range: 0.2–10.0 mm, p=0.99). histomorphologically the associated nevus was a “superficial” or “superficial and deep” congenital nevus in  27  cases (87%) and a clark nevus in 4 cases (13%). nevus associated melanomas more frequently occurred on the trunk than de novo melanomas (58.1% versus 27.4%, p=0.004). the mean survival was 8.9 years (95% ci: 8.6–9.4 years) in the group of nevus-associated melanomas and 7.7 years 95% ci: 7.3– 8.0 years) in the group of de novo melanomas. age (hazard ratio: 1.06, 95% ci: 1.03–1.08, p<0.001) and invasion thickness (hazard ratio: 1.37, 95% ci: 1.19–1.58, p<0.001) were independent predictors of survival but not of whether the melanoma was nevus-associated or de novo (hazard ratio: 4.99, 95% ci: 0.67–37.23, p=0.12) clinical and dermatoscopic morphology clinical or dermatoscopic images were available in 17 cases of nevus-associated melanomas, and the preexisting nevus was visible clinically or dermatoscopically in 11 cases. the clinical images of 4 nevus-associated melanomas in figure 2 show nevus remnants, mostly at the periphery of the lesion. in all 4 cases table 1. general characteristics of cases de novo melanomas nevus associated melanomas undecided n (%) 284 (79.5%) 31 (8.7%) 42 (11.8%) mean age (years) 68.3 54.9 62.7 gender male 141 (49.6%) 20 (64.5%) 33 (78.6%) female 143 (50.4%) 11 (35.5%) 9 (21.4%) anatomic site head and neck 92 (32.4%) 4 (12.9%) 3 (7.1%) trunk 78 (27.5%) 18 (58.1%) 22 (52.4%) upper extremities 51 (17.9%) 5 (16.1%) 9 (21.4%) lower extremities 63 (22.2%) 4 (12.9%) 8 (19.1%) histopathologic criteria median invasion thickness (mm) 0.80 0.85 0.60 in situ melanomas (n, %) 114 (40.1%) 5 (16.1%) 19 (45.2%) ulceration (n,%) 29 (10.2%) 2 (6.5%) 3 (7.1%) figure 2. clinical images of nevus-associated melanomas. [copyright: ©2018 alendar et al.] one nevus has a pattern of clods and the other a reticular pattern. discussion the results of our study support the view that most melanomas arise de novo. the proportion of nevus-associated melanomas in our study was smaller than 10% research | dermatol pract concept 2018;8(2):7 107 and thus lower than in most other studies on this topic [2]. the reason for this might be that we were very strict with regard to the applied histopathologic criteria to differentiate between melanocytes of a nevus and a melanoma. this resulted in a considerable proportion of cases in which we could not decide if there was an associated nevus or not. if these cases were to be added to the obvious nevus-associated melanomas, the proportion of nevus-associated melanomas in our study would be in the range of 20%, which is similar to most other studies. the concept of stepwise tumor progression from a common nevus over a “dysplastic nevus” to melanoma, as set forth by clark and others, is not supported by our data [10]. we found that if melanomas develop in an associated nevus, it is most often a “superficial” or a “superficial and deep” congenital nevus. a clark nevus is less often associated with a melanoma. our findings do not support the concept that “melanocytic dysplasia,” if it exists, has any predictive value with regard to the chance that a melanoma may arise in a specific nevus. given the original description by clark and coworkers, it has been proposed that the “dysplastic nevus” is a risk marker and a precursor of melanoma[11]. recently the latter view has been questioned because clinical data have shown that it lacks legitimacy. the subject of the “dysplastic nevus” and its role as a precursor of melanoma is difficult to comprehend because what is usually termed “dysplastic nevus” is a heterogeneous group of melanocytic proliferations. according to ackerman, what is termed “dysplastic nevi” consist of three figure 3. clinical-dermatoscopic-pathologic correlation of a melanoma-associated nevus. [copyright: ©2018 alendar et al.] figure 4. clinical-dermatoscopic-pathologic correlation of a melanoma-associated nevus. [copyright: ©2018 alendar et al.] 108 research | dermatol pract concept 2018;8(2):7 tal nevi are most commonly associated with melanoma, we do not think that this supports the view that they should be excised prophylactically to prevent melanoma. the risk of malignant transformation of a single nevus is so low that a general recommendation for prophylactic excision cannot be given. it is important to note, however, that we used the term “congenital” in a histopathologic sense. it does not mean that those nevi are present at birth. “superficial” and “superficial and deep” congenital nevi usually appear in childhood or adolescence but share histomorphologic features (architecture, adnexocentricity) with large congenital nevi. to answer the question as to whether prophylactic excisions of small congenital nevi are worthwhile, we would need a prospective interventional study, but the low incidence of melanoma in comparison to the high number of nevi make it highly unlikely that such a prospective interventional trial will ever be conducted. different types of nevi: (1) clark nevi, (2) “superficial”congenital nevi, and (3) “superficial and deep” congenital nevi. clark nevi are clinically flat and mainly junctional, although a few nests of melanocytes may be present in the papillary dermis. dermatoscopically they usually show a reticular pattern. “superficial” and “superficial and deep” congenital nevi usually have a junctional part but a more prominent dermal part. while melanocytes in a “superficial” congenital nevus are confined to the papillary dermis and the upper part of the reticular dermis they extend to the deep reticular dermis in a “superficial and deep” congenital nevus. both nevi are usually raised clinically. dermatoscopically they may show a pattern of clods, a reticular pattern, or a combination of both. if clinical and dermatoscopic images of these nevi were available in our series, they looked rather inconspicuous and not atypical or “dysplastic.” although our study shows that small congenifigure 5. clinical and dermatoscopic images of two nevus-associated melanomas. [copyright: ©2018 alendar et al.] references 1. bevona c, goggins w, quinn t, et al. cutaneous melanomas associated with nevi. arch dermatol. 2003;139:1620-1624. 2. p a m p e n a r , k y r g i d i s a , l a l l a s a , moscarella e, argenziano g, longo c. a meta-analysis of nevus-associated melanoma: prevalence and practical implications. j am acad dermatol. 2017 nov;77(5):938-945.e4. 3. kaddu s, smolle j, zenahlik p, et  al. melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis. melanoma res. 2002;12:271-278. 4. banky j, kelly jw, english dr, et al. incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma. arch dermatol. 2005;141:998-1006. 5. tsao h, bevona c, goggins w, et al. the transformation rate of moles (melanocytic nevi) into cutaneous melanoma. arch dermatol. 2003;139:282-288. 6. crowson an, magro cm, sanchez-carpintero i, mihm mc jr. the precursors of malignant melanoma. recent results cancer res. 2002;160:75-84. 7. gruber sb, barnhill rl, stenn ks, et al. nevomelanocytic proliferations in association with cutaneous malignant melanoma: a multivariate analysis. j am acad dermatol. 1989;21:773. 8. kanzler mh, mraz-gernhard s. primary cutaneous malignant melanoma and its precursor lesions: diagnostic and therapeutic overview. j am acad dermatol. 2001 aug;45(2):260-276. 9. ackerman ab, milde p. naming acquired melanocytic nevi. common and dysplastic, normal and atypical, or unna, miescher, spitz, and clark? am j dermatopathol. 1992 oct;14(5):447-453. 10. miller aj, mihm mc jr. melanoma. n engl j med. 2006 jul 6;355(1):51-65. 11. clark wh jr, reimer rr, greene m, ainsworth am, mastrangelo mj. origin of familial malignant melanomas from heritable melanocytic lesions. ‘the b-k molesyndrome’. arch dermatol. 1978 may;114(5):732-738. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):16 69 dermatology practical & conceptual introduction early recognition is the most effective intervention to improve the prognosis of patients with melanoma. dermoscopy is a noninvasive clinical examination technique that has been shown to increase both sensitivity and specificity in the clinical diagnosis of melanoma. nevertheless, melanoma may be clinically but also dermoscopically indistinguishable from melanocytic nevi, making recognition a diagnostic challenge, especially in early stages. the comparison of sequential dermoscopic images of melanocytic lesions in search of subtle changes over time has been helpful in the diagnosis of early melanomas, which might lack specific criteria for malignancy [1]. in addition, the use of baseline regional photographs might facilitate the detection of new lesions, and visual changes in preexisting lesions, by providing a comparative reference for subsequent examinations [2]. case presentation we present a case of a 47-year-old woman diagnosed with multiple primary invasive small-diameter melanomas. melanoma 1 (figure 1a), located on the right leg, was detected at the first visit in march 2015. it was a light-brown macule with a diameter of 3.1 mm. dermoscopy revealed atypical pigment network with irregular streaks and negative pigment network. histology reported breslow 0.2 mm thickness. melanoma 2 (figure 1b) was identified as a new lesion by body-mapping comparison at the first follow-up visit (figure 2a) in october 2017. melanoma 2 was 2.6 mm in diameter with atypical pigment network and grayish coloration on dermoscopy. histology informed 0.4 mm breslow thickness. melanomas 3 and 4 (figure 1, c and d), located on the back and the abdomen, respectively, were diagnosed in march 2018 after changes were observed during digital monitoring (figure 2, b and c). both lesions were less than 5 mm in diameter, and dermoscopy revealed typical reticular pattern in melanoma 3 and a quite regular globular pattern in melanoma 4. the decision to excise resulted only from the subtle dermoscopic changes observed. histology informed breslow thickness of 0.3 and 0.6 mm, respectively. conclusions early recognition is the most effective intervention to improve melanoma prognosis. several strategies such as the abcd(e) multiple primary invasive small-diameter melanomas: importance of dermoscopy and digital follow-up gabriel salerni1,2, carlos alonso1,2, ramón fernández-bussy1 1 hospital provincial del centenario de rosario, argentina, & faculty of medicine, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina key words: melanoma, dermoscopy, skin cancer, imaging techniques citation: salerni g, alonso c, fernández-bussy r. multiple primary invasive small-diameter melanomas: importance of dermoscopy and digital follow-up. dermatol pract concept. 2019;9(1):69-70. doi: https://doi.org/10.5826/dpc.0901a16 published: january 31, 2019 copyright: ©2019 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, bv. oroño 1515, cp 2000, rosario, argentina. email: gabrielsalerni@hotmail.com 70 letter | dermatol pract concept 2019;9(1):16 in the context of high-risk patients, the combined use of total-body photography and sequential digital dermoscopy enables the detection of incipient melanomas that might have been overlooked if assessed solely by the naked eye. references 1. salerni g, carrera c, lovatto l, et al. benefits of total body photography and digital dermoscopy (“two-step method of acronym, the “ugly duckling sign,” or the efg for the recognition of nodular melanoma (e for elevation, f for firm, and g for growth), just to mention a few, have been proposed to enhance clinical recognition of atypical lesions that should undergo excision or close monitoring, but their usefulness in the detection of melanoma at early stages is questionable. the routine use of dermoscopy allows the detection of melanomas of which patients are unaware. figure 1. clinical aspect of the 4 melanomas diagnosed, all with a diameter of less than 5 mm. (a) melanoma breslow 0.2 mm located on the right leg, diagnosed at baseline. (b) melanoma breslow 0.4 mm located on the right arm detected during the first follow-up control. (c, d) melanomas located on the back and abdomen, 0.3 and 0.6 mm breslow thickness, respectively. [copyright: ©2019 salerni et al.]  digital follow-up”) in the early diagnosis of melanoma in high-risk patients. j am acad dermatol. 2012;67(1):e17-e27. 2. salerni g, terán t, alonso c, fernándezbussy r. the role of dermoscopy and digital dermoscopy follow-up in the clinical diagnosis of melanoma: clinical and dermoscopic features of 99 consecutive primary melanomas. dermatol pract concept. 2014;4(4):39-46. a b c d figure 2. (a) body-mapping comparison that allowed for the detection of melanoma 2 as a new lesion. (b, c) dermoscopic changes leada b c ing to excision in melanomas 3 and 4. [copyright: ©2019 salerni et al.] dermatology: practical and conceptual 66 observation | dermatol pract concept 2017;7(3):15 dermatology practical & conceptual www.derm101.com introduction diffuse neonatal hemangiomatosis (dnh) is a rare condition with a very high mortality rate (50-90%) if left untreated [1]. hemangiomas otherwise are the most common vascular tumours of infancy with excellent prognosis. however, the presence of multiple hemangiomas is associated with a strong possibility of visceral organ involvement, which is termed diffuse neonatal hemangiomatosis [2]. visceral lesions are most commonly found in the liver followed by nervous system, intestine, lungs, rarely skeletal system and proliferate till infancy. the common causes of mortality are high-output cardiac failure as a result of arteriovenous shunting in liver or haemorrhage in intestine or brain [3]. prompt treatment with corticosteroids or beta blockers like propranolol inhibits the proliferation, promotes early regression of hemangiomas and is life saving [4]. case report a 20-day-old, full term male baby with birth weight of 2.5 kg was referred to the out-born nursery of our tertiary care hospital with a history of insidious onset respiratory distress, difficulty in feeding since day 5 of life and multiple cutaneous hemangiomas since birth. the baby was delivered by caesarean section at a private hospital with an uneventful antenatal diffuse neonatal hemangiomatosis presenting as congestive heart failure sheetal agarwal1, anu sharma1, arti maria2 1 department of pediatrics, pgimer and dr rml hospital, delhi, india 2 department of neonatology, pgimer and dr rml hospital, delhi india key words: hemangiomas, vascular tumors, neonatal, congestive heart failure citation: agarwal s, sharma a, maria a. diffuse neonatal hemangiomatosis presenting as congestive heart failure. dermatol pract concept 2017;7(3):15. doi: https://doi.org/10.5826/dpc.0703a15 received: march 2, 2017; accepted: april 11, 2017; published: july 31, 2017 copyright: ©2017 agarwal et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: arti maria, md, dm, professor and head, department of neonatology, 2nd floor, opd block, dr rml hospital, delhi, india. tel. +91.9310034300. email: artimaria@gmail.com diffuse neonatal hemangiomatosis is a rare condition with a very high mortality rate if left untreated. we report a neonate having around 490 cutaneous and multiple diffuse liver hemangiomas presenting as congestive heart failure. prompt treatment was instituted with decongestive drugs and prednisolone for anticipated life threatening complications due to hepatic hemangiomas. propranolol was added later as it is known to precipitate congestive failure and also to avoid long-term complications of steroids. the child responded well. however, there is no consensus regarding the initial line of management, which needs to be individualized keeping in mind the efficacy, long-term side effects of the drug and the clinical presentation. abstract observation | dermatol pract concept 2017;7(3):15 67 6 cm below the costal margin. the possibility of congenital heart disease with congestive heart failure was made, and the baby was managed accordingly with fluid restriction and diuretics. sepsis screen was negative, and x-ray chest showed cardiomegaly with pulmonary plethora. echocardiography revealed severe pulmonary hypertension (systolic gradient 88 mm hg) with patent ductus arteriosus and right to left shunt. usg abdomen revealed multiple diffuse hemangiomas in liver, with the maximum size being 14 mm x 13 mm (figure 3). a whole body mri confirmed the ultrasound and echo findings and ruled out cns, renal, intestinal and skeletal involvement. thyroid functions were normal. prompt treatment was instituted with prednisolone (2 mg/kg/day) for anticipated life threatening complications due to hepatic hemangiomas. congestive heart failure responded in three to five days with the continuing anti-congestive therapy. after five days, propranolol (2 mg/kg/day) was added with a plan to and perinatal course. at birth there were multiple cutaneous hemangiomas widely spread all over the body. baby was discharged on fourth day of life on exclusive breastfeeding. on day 5, he developed tachypnea and diaphoresis over the forehead during feeding that gradually progressed over the next 15 days. on admission to our institute, the baby was euthermic with tachycardia (heart rate -170/min), tachypnea (respiratory rate70/min), hypoxia (spo2 at room air80%) and mild cyanosis. blood pressure was 86/53 mm of hg and was similar in all four limbs. all central and peripheral pulses were well palpable and there was no preor postductal difference in oxygen saturation. there were multiple maculopapular cutaneous hemangiomas (around 490) ranging from pin head size to 1.5 cm x 1.5 cm spread all over the body (figure 1 and 2). cardiac examination revealed grade 3/6 systolic murmur in left sternal border with fine crepitations in chest. on abdominal exam there was huge firm liver, figure 1. multiple maculopapular cutaneous hemangiomas. [copyright: ©2017 agarwal et al.] figure 2. multiple maculopapular cutaneous hemangiomas. [copyright: ©2017 agarwal et al.] figure 3. echocardiography revealed severe pulmonary hypertension. [copyright: ©2017 agarwal et al.] figure 4. after treatment, some cutaneous lesions regressed while some changed from bright red to wine color. [copyright: ©2017 agarwal et al.] 68 observation | dermatol pract concept 2017;7(3):15 considered second-line treatment in cases of non-resolution of infantile hemangiomas or of failure of other treatments, but recently, it has been used successfully as a first-line agent in dnh with vital organ involvement (10-13). however, complete failure of treatment and rebound growth following cessation of treatment with this drug has also been documented [14,15]. also, beta adrenergic blockers have to be used cautiously in the presence of severe heart failure as they may further decrease the cardiac function and induce cardiac failure. hence, we instituted immediate treatment with corticosteroids, and propranolol was started after resolution of chf with a plan to taper steroids in four weeks. the response to this treatment was satisfactory. a multimodal and individualized treatment approach may be necessary in life threatening and complicated cases of dnh as there is no specific drug of choice. randomized trials with corticosteroids and beta blockers would be ideal, but considering the rarity of this disease, it seems less feasible. hence, reporting of such cases and sharing the personal experiences would help to establish the most effective medical treatment. key message although a consensus regarding the exact number of hemangiomas defining dnh has not been reached, it should be suspected in all cases of multiple infantile hemangiomas with or without systemic manifestations. number of cutaneous lesions as less as three have also been reported to have hepatic hemangiomas on routine ultrasound. [8]. early diagnosis and prompt medical treatment is lifesaving, as it is a potentially fatal condition. the first-line management needs to be individualized, keeping in mind the efficacy, long-term side effects of the drug, and the clinical presentation. references 1. becker jm, heitler ms. hepatic hemangioendotheliomas in infancy. surg gynecol obstet. 1989; 168:189–200. 2. lister wa. the natural history of strawberry naevi. lancet. 1938;1:1429-1434 3. gottschling s, schneider g, meyer s, reinhard h, dill-mueller d, graf n. two infants with life-threatening diffuse neonatal hemangiomatosis treated with cyclophosphamide. pediatr blood cancer. 2006; 46:239-242. 4. sommers smith sk, smith dm. beta blockade induces apoptosis in cultured capillary endothelial cells. in vitro cell dev biol anim. 2002; 38: 298–304. 5. takahashi k, mulliken jb, kozakewich hp, rogers ra, folkman j, ezekowitz ra. cellular markers that distinguish the phases of hemangioma during infancy and childhood. j clin invest. 1994 jun. 93(6):2357-64. 6. wananukul s, voramethkul w, nuchprayoon i, seksarn p. diffuse neonatal hemangiomatosis: report of 5 cases. j med assoc thai. 2006;89:1297-1303. taper steroids in four weeks to avoid long-term complications of steroids. however, they had to be tapered at three weeks due to intercurrent systemic bacterial infection. after eight weeks, an ultrasound of the abdomen demonstrated decrease in size of hepatic lesions. echocardiography showed resolving pulmonary hypertension (pg-32mm of hg), and decrease in right ventricular hypertrophy. some cutaneous lesions regressed while some changed from bright red to wine color (figure 4). the baby was continued on the same treatment with careful monitoring of adverse effects of propranolol like hypoglycemia, bradycardia, hypotension, and airway hyperreactivity. the baby is now thriving well without any side effects of propranolol or increase in size of lesions. discussion dnh is potentially a fatal condition owing to the involvement of vital organs resulting in hemodynamic alterations and haemorrhages. dnh occurs most commonly in caucasian infants, with females being affected more often than males (3:1) [5]. our patient was a male baby with multiple cutaneous hemangiomas involving the whole body and diffuse hemangiomas in the liver and clinical presentation of congestive heart failure (chf). chf is an unusual presentation of dnh in neonates and can be mistaken for a variety of congenital heart diseases. the other likely differentials like kasabach-merrit syndrome and phaces were ruled out with absence of thrombocytopenia, bleeding manifestations or brain tumor. the vascular lesions are made up of proliferating endothelial cells, which in the early stage form vascular channels filled with blood cells. the proliferative capacity of these immature endothelial cells is maintained for a limited period during postnatal life due to various angiogenic peptides and vascular endothelial growth factor (vegf) [6]. hence, these hemangiomas tend to increase initially for 8-12 months (proliferative phase), followed by regression over the next 1-5 years (involuting phase), with continuous improvement until 6-12 years (involuted phase). an early diagnosis and prompt treatment inhibits the progression and induces regression of the vascular lesions, thus reducing the mortality to 27% [7]. although a variety of medical and surgical treatment options are available, drug therapy is the primary mode of treatment, and most cases of infantile hemangiomas with visceral involvement have been successfully treated by corticosteroids as the first-line agents [8,9]. however, keeping in mind their adverse effects in the long run, we reviewed the literature for other medical options. propranolol, due its vasoconstrictor and inhibitory effects on endothelial and fibroblast growth factor, has shown promising results in early induction of cell apoptosis, involution of hemangiomas and arteriovenous formations (avms) [8,14]. previously, it was observation | dermatol pract concept 2017;7(3):15 69 12. dotan m, lorber a. congestive heart failure with diffuse neonatal hemangiomatosis—case report with literature review. acta paediatr. 2013;102(5):e232-238. 13. nip sy, hon kl, leung wk, leung ak, choi pc. neonatal abdominal hemangiomatosis: propranolol beyond infantile hemangioma, case rep pediatr. 2016;2016:803975. 14. blanchet c, nicollas r, bigorre m, amedro p, mondain m. management of infantile subglottic hemangioma: acebutolol or propranolol? int j pediatr otorhinolaryngol. 2010;74:959-961. 15. chai q, chen wl, huang zq, zhang dm, fan s, wang l. preliminary experiences in treating infantile hemangioma with propranolol. ann plast surg. 2014;72(2):169-172. 7. poirier vc, ablin ds, frank eh. diffuse neonatal hemangiomatosis: a case report. ajnr am j neuroradiol. 1990;11(6):10971099. 8. u p t o n a . d i f f u s e n e o n a t a l h e m a n g i o m a t o s i s . j d m s . 2005;21:350-353. http://journals.sagepub.com/doi/pdf/10. 1177/8756479305278971. accessed september 13, 2016. 9. d’angelo g, lee h, weiner ri. camp-dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking raf activation. j cell biochem. 1997;67:353–366. 10. gunturi n, ramgopal s, balagopal s, scott jx. propranolol therapy for infantile hemangioma. indian pediatr. 2013;50:307-313. 11. zhou h, li qf, cao gl, ling hz, dai hr, chen xh. successful treatment of diffuse neonatal hemangiomatosis with propranolol: a case report. j dtsch dermatol ges. 2014 jul;12(7):625-628. dermatology: practical and conceptual commentary | dermatol pract concept. 2023;13(3):e2023167 1 kaposi's sarcoma, a gateway to understanding healthcare disparities present in the racial minority communities of america michelle anthony1, christopher farkouh2, parsa abdi3 1 university of arizona college of medicine, tucson, az, usa 2 rush medical college, chicago, il, usa 3 memorial university faculty of medicine, st. john’s, newfoundland, canada citation: anthony mr, farkouh c, abdi p. kaposi's sarcoma, a gateway to understanding healthcare disparities present in the racial minority communities of america. dermatol pract concept. 2023;13(3):e2023167. doi: https://doi.org/10.5826/dpc.1303a167 accepted: january 30, 2023; published: july 2023 copyright: ©2023 anthony et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: michelle anthony 2069 east cedar place, chandler, az 85249 phone: 4803530913 e-mail: michelleanthony@ arizona.edu kaposi sarcoma (ks) is a spindle cell malignancy derived from endothelium cells and is caused by human herpesvirus-8 (hhv-8) [1]. clinically, it often presents as a patch that progresses into purple to reddish-brown nodules. ks is commonly subdivided into four known variants, namely, aids-associated, classic, african, and iatrogenic [2]. ks has increased incidence in individuals with human immunodeficiency virus (hiv) due to immune dysfunction allowing for the proliferation of oncogenic hhv-8 [3]. in the united states, highly active antiretroviral treatment (haart) for hiv has decreased the incidence of ks by improving immune function. still, the current trends of ks in america illustrate the racial disparity prevalent in the u.s. healthcare system [4]. hsieh et al. evaluated racial/ethnic differences in soft tissue sarcoma trends and incidence. they found that from 1995–2008 there was a higher incidence of ks in black and hispanic males compared to white males [5]. similarly, royse et al. analyzed the surveillance, epidemiology, and end results (seer) database to determine the incidence of ks by race and geographic location from 2000 to 2013. their finds suggest ks significantly decreased in white males but increased in black males, especially from the us southern states (figure 1). compared to other races, black males in the south developed ks six times more frequently and were more likely to pass away (figure 1). the increased rates of ks in southern states may be due to decreased hiv testing and treatment prevalent in these states [6,7]. furthermore, haart compliance and use are lower in black males, leading to an increased risk of hhv-8 activation and subsequent ks [7]. higher rates of poverty and lower education rates adversely affect access to healthcare needed to prevent and treat hiv. in 2016, black americans comprised 54% of hiv diagnoses in southern individuals, of which 59% were men who had sex with men [8]. hiv is a stigmatized illness, especially in racial and minority communities, and decreased acceptance of homosexuality in the south can hinder homosexual males from obtaining needed health care. in addition, stigma adversely reduces social support, resulting in increased psychological 2 commentary | dermatol pract concept. 2023;13(3):e2023167 distress and decreased efforts to prevent transmission through harm reduction [9]. the studies indicate an increasing need to tackle racial disparities in accessing diagnostic tools, physicians, and treatment for hiv to prevent unnecessary comorbidities like ks. working with federal agencies to address socioeconomic factors like decreased education and increased incarceration rates that exacerbated hiv-related disparities is essential. to improve hiv testing in racial communities, it is crucial to implement clinical and non-clinical settings that promote feasible accessibility to hiv testing. many black american men distrust the medical system, which can lead to decreased access and adherence to haart [10]. this needs to be addressed by training culturally competent physicians focused on providing a therapeutic patient-provider relationship. further studies need to be performed to understand healthcare disparities and effective methods to address the transmission of hiv and the comorbid development of ks in racial minority communities [9]. references 1. lebbe c, garbe c, stratigos aj, et al. diagnosis and treatment of kaposi's sarcoma: european consensus-based interdisciplinary guideline (edf/eado/eortc). eur j cancer. 2019;114:117127. doi:10.1016/j.ejca.2018.12.036. pmid: 31096150. 2. radu o, pantanowitz l. kaposi sarcoma. arch pathol lab med. 2013;137(2):289-294. doi:10.5858/arpa.2012-0101-rs. pmid: 23368874. 3. godbole s, ghate m, mehendale s. understanding racial diversities in kaposi's sarcoma. indian j med res. 2019;149(3):319-321. doi:10.4103/ijmr.ijmr_2164_18. pmid: 31249194. pmcid: pmc6607822. 4. kumar v, soni p, garg m, hashmi at, chandra ab. racial disparities in incidence & survival of kaposi's sarcoma in the united states. indian j med res. 2019;149(3):354-363. doi:10.4103 /ijmr.ijmr_1436_17. pmid: 31249200. pmcid: pmc6607828. 5. hsieh mc, wu xc, andrews pa, chen vw. racial and ethnic disparities in the incidence and trends of soft tissue sarcoma among adolescents and young adults in the united states, 1995-2008. j adolesc young adult oncol. 2013;2(3):89-94. doi:10.1089/ jayao.2012.0031. pmid: 24066270. pmcid: pmc3778995. 6. royse ke, el chaer f, amirian es, hartman c, krown se, et al. (2017) disparities in kaposi sarcoma incidence and survival in the united states: 2000-2013. plos one. 2017;12(8):e0182750. doi: 10.1371/journal.pone.0182750. pmid: 28829790. pmcid: pmc5567503. 7. ragi sd, moseley i, ouellette s, rao b. epidemiology and survival of kaposi's sarcoma by race in the united states: a surveillance, epidemiology, and end results database analysis. clin cosmet investig dermatol. 2022;15:1681-1685. doi:10.2147 /ccid.s380167. pmid: 36003526. pmcid: pmc9394645. 8. nunn a, jeffries wl 4th, foster p, et al. reducing the african american hiv disease burden in the deep south: addressing the role of faith and spirituality. aids behav. 2019;23 (suppl 3):319-330. doi:10.1007/s10461-019-02631-4. pmid: 31444712. pmcid: pmc6800644. 9. kenya s, okoro i, wallace k, carrasquillo o, prado g. strategies to improve hiv testing in african americans. j assoc nurses aids care. 2015;26(4):357-367. doi:10.1016/j .jana.2015.04.001. pmid: 26066691. pmcid: pmc4489406. 10. dale sk, bogart lm, wagner gj, galvan fh, klein dj. medical mistrust is related to lower longitudinal medication adherence among african-american males with hiv. j health psychol. 2016;21(7):1311-1321. doi: 10.1177/1359105314551950. pmid: 25293970. pmcid: pmc4388759. figure 1. kaposi sarcoma incidence in the us by race, 2000–2013. copyright © 2017 royse et al [6]. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023098 1 dermoscopy of abortive hemangioma: morphological study of 11 cases leopoldo fernández-domper1, esmeralda silva diaz1, manuel ballesteros redondo1, jose maria martin hernández1, angeles revert fernández1 1 department of dermatology, hospital clínico universitario, university of valencia, valencia, spain key words: abortive hemangiomas, dermoscopy, infantile hemangiomas, vascular anomalies citation: fernández-domper l, silva diaz e, ballesteros redondo m, martín hernández jm, revert fernandez a. dermoscopy of abortive hemangioma: morphological study of 11 cases. dermatol pract concept. 2023;13(2):e2023098. doi: https://doi.org/10.5826/ dpc.1302a98 accepted: august 31, 2023; published: april 2023 copyright: ©2023 fernández-domper et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this research was supported by the dermatology department of the clinical universitary hospital of valencia. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: leopoldo fernández-domper, md, department of dermatology hospital clínico universitario de valencia, blasco ibañez avenue, 17, valencia, comunidad valenciana, 46010, spain tel: +34636683965 e-mail: lfernandezdomper@gmail.com introduction abortive hemangiomas (ah) or minimal or arrested growth hemangiomas constitute a distinct subgroup of infantile hemangioma (ih) with a characteristic clinical presentation and natural history that are often clinically confused with other vascular anomalies (va) [1,2]. dermoscopy can be a useful tool for distinguishing vas that may be clinically similar such as ih precursor lesions, port wine stains (pws) and, probably, ah [3]. however, dermoscopy pattern of ah has only been previously described by toledo-alberola et al in 2 cases [4]. case presentation the aim of this study was to evaluate the dermoscopy findings of an ah single-center case series, comparing these findings with those described in other clinically similar vas such as ih precursor lesions and pws. we evaluated the dermoscopy patterns and structures of 11 consecutives clinically diagnosed ah cases in our pediatric dermatology department, assessed during 2021, and we compared these findings with those described for ih precursor lesions and pws. clinical and demographic findings are summarized in table 1. serpinginous or tortuous vessels, punctate vessels and vascular lacunae were observed in 100% of the cases clinically diagnosed as ah (figures 1 and 2). conclusions ah is a distinctive variant of ih present from birth in most cases, and, with little ability to proliferate. although they could be clinically similar to other vas they have different morphologic and immunostaining patterns. on histology, they show dilated thin-walled vessels within the superficial dermis, with a glut-1 positivity immunostaining demonstrating a clear distinction between ah and pws or congenital hemangiomas [1,2]. dermoscopic examination may facilitate the identification of ah for early diagnosis and treatment. in our case series, serpiginous or tortuous 2 research letter | dermatol pract concept. 2023;13(2):e2023098 ta b le 1 . c li n ic al a n d d em o gr ap h ic fi n d in gs . p a ti e n t d e m o g ra p h ic c h a ra ct e ri st ic s d e rm o sc o p y fi n d in g s a g e a t d ia g n o si s (y e a rs ) a g e o cc u rr e n ce s e x lo ca ti o n tr e a tm e n t a ss o ci a te l e si o n s a d d it io n a l te st s s e rp in g in o u s/ to rt u o u s v e ss e ls p u n ti fo rm v e ss e ls v a sc u la r la cu n a e 1 6 f ir st d ay s m r ig h t le g t im o lo l y es y es y es 2 1 u n k n o w n m l ef t b u tt o ck t im o lo l in fa n ti le h em an gi o m a y es y es y es 3 2 b ir th f l ef t k n ee t im o lo l e ch o gr ap h y an d d o p p le r y es y es y es 4 2 b ir th m l ef t th ig h t im o lo l y es y es y es 5 0 b ir th f sa cr al f o ss a sp in al e ch o gr ap h y y es y es y es 6 1 b ir th f r ig h t ex te rn al m al le o lu s t im o lo l y es y es y es 7 1 b ir th f l ef t h an d t im o lo l so ft t is su e e ch o gr ap h y y es y es y es 8 1 4 u n k n o w n m a b d o m en y es y es y es 9 6 f ir st d ay s f r ig h t lu m b ar t im o lo l + p ro p an o lo l y es y es y es 1 0 2 b ir th m n ec k y es y es y es 1 1 1 b ir th f r ig h t th ig h t im o lo l y es y es y es research letter | dermatol pract concept. 2023;13(2):e2023098 3 figure 1. (a) clinically macule with telangiectasias erythematous background. (b,c) dermoscopy image showing serpiginous or tortuous vessels, punctate vessels and vascular lacunae. figure 2. (a,b) telangiectasias on an erythematous or reticulated background. (c) dermoscopy image showing serpiginous or tortuous vessels, punctate vessels and vascular lacunae. 4 research letter | dermatol pract concept. 2023;13(2):e2023098 vessels, punctate vessels and vascular lacunae was observed in 100% of the cases clinically diagnosed as ah. ih precursor lesions dermoscopy features have been described as large linear vessel and branching vessels with erythematous background [5]. on the other hand, linear vessels, reticular vessels, sausage-like vessels, dots or globules vessels and mixed vessels, as well as white circles and whitish veil have been described in pws [6]. when comparing our findings in ah, with those described ih precursor lesions and pws, we found these to be differential and characteristic of ah. as limitations, no control group was included, therefore, no definitive conclusions could be made. dermoscopy might improve the clinical diagnosis of ah. it might help distinguish ah from ih precursor or pws. more studies including other lesions are needed to confirm our findings. references 1. martin jm, sanchez s, gonzález v, cordero p, ramon d. infantile hemangiomas with minimal or arrested growth: a retrospective case series. pediatr dermatol. 2019;36(1):125–131. doi: 10.1111/pde.13695. pmid: 30318787. 2. rodríguez bandera ai, sebaratnam df, wargon o, wong l-cf. infantile hemangioma. part 1: epidemiology, pathogenesis, clinical presentation and assessment. j am acad dermatol. 2021;1379–1392. doi: 10.1016/j.jaad.2021.08.019. pmid: 34419524. 3. piccolo v, russo t, moscarella e, brancaccio g, alfano r, argenziano g. dermatoscopy of vascular lesions. dermatol clin. 2018;36(4):389–395. doi: 10.1016/j.det.2018.05.006. pmid: 30201148. 4. toledo-alberola f, betlloch-mas i, cuesta-montero l, et al. abortive hemangiomas. description of clinical and pathological findings with special emphasis on dermoscopy. eur j dermatol. 2010;20(4):497-500. doi: 10.1684/ejd.2010.0959. pmid: 20400393. 5. sun y, hu scs. dermoscopy as a diagnostic aid in the precursor stage of infantile hemangioma. int j dermatol. 2022;61(2):e54– e55. doi: 10.1111/ijd.15841. pmid: 34363688. 6. huang y, yang j, li z, zhang l, sun l, bi m, wang l. dermoscopic features of port-wine stains: a study of 264 cases. australas j dermatol. 2021;62(2):e201-e206. doi: 10.1111/ ajd.13470. pmid: 32955124. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):20 239 dermatology practical & conceptual introduction basal cell carcinoma (bcc) is the most frequent nonmelanoma skin neoplasm in caucasians. bcc is mostly located in photo-exposed areas; however, it can be observed in nonexposed areas such as armpits, genital and perianal regions, palms and soles, and in oral mucosa. vulvar bcc is infrequent, being about 1% of all bccs and 2%-4% of vulvar neoplasms. the dermoscopic aspect of bcc in this location has been described in very few cases. case presentation a 73-year-old woman presented with a 5-month history of a gradually enlarging tumor with gray-black coloration in the right upper labia majora, 0.5 × 0.5 mm, rounded, with raised edges and central ulceration (figure 1a). the lesion was indurated on palpation; inguinal adenopathies were not identified. dermoscopy showed the presence of irregularly shaped blue-black clods and structureless blueish areas. structureless red-pink areas were also observed. the lesion was surrounded by a whitish halo; no specific vascular pattern was identified (figure 1b). full excisional biopsy was performed and histology evaluation reported the diagnosis of bcc (figure 2). conclusions although it is believed that ultraviolet radiation is the main risk factor for the development of bcc, physiopathogenesis behind the occurrence in sun-protected areas is not yet defined. it has been suggested that advanced age, local trauma, chronic inflammation, and radiotherapy can contribute to the appearance in this area, as well as risk factors commonly associated with bcc including artificial ultraviolet radiation, exposure to arsenic, immunodeficiency, and genetic mutations. vulvar bcc occurs more frequently in postmenopausal women, aged between 50 and 70 years. labia majora mucosa is the usual location in most cases. clinical findings are diverse and do not always suggest bcc. vulvar bcc usually presents as a single lesion, superficial, exophytic, ulcerated, infiltrating or nodular; only 3% of the lesions are pigmented. dermoscopy of pigmented vulvar basal cell carcinoma carolina bertaina1, gabriel salerni1,2, melisa celoria1, silvina lombardo1, mario gorosito3, ana molteni1, ramón fernández-bussy1 1 hospital provincial del centenario de rosario, argentina; faculty of medicine, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina 3 pathology department, universidad nacional de rosario, argentina key words: basal cell carcinoma, dermoscopy, skin cancer, imaging techniques citation: bertaina c, salerni g, celoria m, lombardo s, gorosito m, molteni a, fernández-bussy r. dermoscopy of pigmented vulvar basal cell carcinoma. dermatol pract concept. 2019;9(3):239-240. doi: https://doi.org/10.5826/dpc.0903a20 accepted: january 22, 2019; published: july 31, 2019 copyright: ©2019 bertaina et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, bv. oroño 1441, cp 2000, rosario, argentina. email: gabrielsalerni@hotmail.com 240 letter | dermatol pract concept 2019;9(3):20 they are usually diagnosed in advanced stages, since most are asymptomatic and slow-growing; eventually the presence of itching, burning, or bleeding may raise concern. the dermoscopic characteristics are usually the same as those observed in cutaneous bcc [1]; blue-gray ovoid nests and arborizing vessels have been reported in pigmented vulvar bcc [2]. vulvar bcc is usually locally aggressive, so it requires complete excision with 4-mm margins to minimize recurrences; mohs surgery is recommended. prognosis is usually favorable, since it rarely metastasizes, but the risk of recurrence demands strict periodic monitoring. in this case, dermoscopy was shown to be a helpful tool for the identification of vulvar pigmented bcc, improving diagnostic accuracy and allowing a correct therapeutic approach. references 1. de giorgi v, massi d, mannone f, et al. dermoscopy in vulvar basal cell carcinoma. arch dermatol. 2007;143(3):426427. 2. dobrosavljevic vukojevic d, djurisic i, lukic s, kastratovic-kotlica b, vukicevic j. dermatoscopy in vulvar basal cell carcinoma. j eur acad dermatol venereol. 2017;31(4):e180-e181. figure 1. (a) clinical aspect of the lesion. (b) dermoscopy image: irregularly shaped blueblack clods and structureless bluish and red-pink areas were observed. the lesion was surrounded by a whitish halo. [copyright: ©2019 bertaina et al.] a b figure 2. neoplastic proliferation with basaloid pattern, with neoplastic nodules in the dermis and in contact with the surface epithelium. (a) the stroma exhibits leukocytic infiltrate and numerous melanophages (h&e, ×20). (b) ulceration and presence of basaloid nodules and infiltrating cords were observed (h&e, ×40). h&e = hematoxylin and eosin. [copyright: ©2019 bertaina et al.] a b dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022167 1 evaluation of sleep quality in patients with genital and non-genital cutaneous warts: a prospective controlled study müge göre karaali1, vildan manav2 1 department of dermatology, erzincan binali yildirim university, mengücek gazi training and research hospital, erzincan, turkey 2 department of dermatology, university of health sciences, i̇stanbul training and research hospital, i̇stanbul, turkey key words: warts, sleep quality, pittsburgh sleep quality index, genital warts citation: göre karaali m, manav v. evaluation of sleep quality in patients with genital and nongenital cutaneous warts: a prospective controlled study. dermatol pract concept. 2022;12(4):e2022167. doi: https://doi.org/10.5826/dpc.1204a167 accepted: march 23, 2022; published: october 2022 copyright: ©2022 göre karaali et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: muge gore karaali, md, erzincan binali yıldırım university, mengücek gazi training and research hospital, department of dermatology, erzincan, turkey. phone number: +9005303093328, e-mail: mugegore@hotmail.com introduction: diseases affect sleep quality, and sleep quality may also affect diseases by affecting the immune system. depending on the immune status of patients with cutaneous warts, the extent of the disease and the response to treatment may vary. objectives: this study aimed to characterize the association between cutaneous warts and sleep quality. methods: a prospective controlled study was conducted. patients over 18 years with cutaneous warts were enrolled. the control subjects were healthy, ageand sexmatched people. demographic and clinical data on the participants were gathered. the sleep quality of participants was evaluated with the pittsburgh sleep quality index (psqi). results: a total of 138 patients with genital or non-genital cutaneous warts (n  =  59, n  =  79, respectively) and 83 controls were interviewed. the average global psqi score of the group with cutaneous warts was significantly higher than that of the control group (1.292 95% confidence interval 1.174-1.422). the rate of poor sleep quality in the patient group was higher than in the control group (odds ratio 3.835). patients with genital warts had a significantly higher average global psqi score than patients with non-genital warts (8.61 ± 3.63 versus. 6.98 ± 3.32). female patients with genital warts had a significantly higher average global psqi score than male patients with genital warts. conclusions: evaluation of sleep quality in patients with warts, especially in patients with genital warts, may be suggested. the management of sleep disturbances associated with cutaneous warts may help increase the quality of life of patients and may affect disease control. abstract 2 original article | dermatol pract concept. 2022;12(4):e2022167 introduction sleep is an active, restorative, physiological, and neurobiological state that occupies approximately one third of our lives. it is mainly regulated by the homeostatic sleep drive and the circadian system, often called the “central clock,” controlled particularly by the cortisol and melatonin hormones [1,2]. sleep disruption associated with skin diseases may impair quality of life. poor sleep quality also has a significant effect on the nervous and immune systems. moreover, poor sleep quality may induce and/or aggravate skin disease by affecting the regional immune function [3]. skin also plays a major role in convenient sleep activity by regulating body temperature, peripheral circadian oscillators, ultraviolet (uv)-induced fluctuations in melatonin levels, and cortisol [1]. it has been reported that only one night of sleep deprivation may hinder the recovery of the skin barrier. natural killer cells and some proinflammatory cytokines (interleukin-1beta/tumor necrosis factor-alfa), which play an important role in the regulation of non-rapid eye movement (nrem) sleep, may increase after sleep disruption [4]. especially chronic inflammatory skin conditions (eg atopic dermatitis, psoriasis vulgaris, and chronic urticaria) may affect sleep quality [5–7]. recently, rosacea, lichen planus, hidradenitis suppurativa, acne vulgaris, and behçet disease have been shown to negatively affect sleep quality [8–12]. cutaneous warts are a common infectious skin disease caused by human papillomavirus (hpv). depending on a patient immune status, common warts may appear anywhere on the skin; moreover, spontaneous remission and treatment-resistant lesions may be seen, and it is thought that the immune system is effective in the response to treatment [13]. although diseases themselves affect the quality of sleep, sleep quality can also affect diseases by affecting the immune system. objectives: the aim of this study was to better characterize the association between cutaneous warts and sleep quality. methods study participants a prospective, controlled study was conducted between january and july 2021. the study included patients over 18 years old who were enrolled from tertiary referral dermatology outpatient clinics and diagnosed with cutaneous warts. the control subjects were healthy, ageand sexmatched people. exclusion criteria for patient group patients aged < 18 years, patients known to have sleep disorders, patients with other chronic and/or any inflammatory systemic and/or dermatologic disorders that may affect sleep quality, and pregnant and lactating women were excluded from the patient group. exclusion criteria for control group patients aged < 18 years, patients with other chronic and/ or any inflammatory systemic and/or dermatologic disorders that may affect sleep quality, and pregnant and lactating women were excluded from the control group. ethical considerations all participants signed the written consent form before the questionnaire, provided information, and gave permission to use that information in the study regarding the survey. ethics committee approval was received from the university scientific research and publication ethics board. survey in the first section, the demographic and clinical data of the participants were queried. the questions included age, sex, and presence of systemic, autoimmune, and dermatological diseases. the type of warts (genital/non-genital), number of warts (single, 1–5 warts, >5 warts), localization of warts (if non-genital), and duration of the disease were recorded. the sleep quality of participants was evaluated with the pittsburgh sleep quality index (psqi). it is a self-rated questionnaire evaluating sleep quality and sleep disturbances over an interval of the previous month. the questionnaire included 11 questions about subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction. each domain was scored with 0–3 points. psqi scores range from 0–21 points. a global psqi score of 5 or higher reflects poor sleep quality. statistical analysis spss 22.0 package program was used to evaluate the data. the descriptive statistics were the number and percentage for categorical variables and numerical variables as mean, standard deviation, minimum, maximum, and median. the rates in groups were compared using the chi-squared test, mann– whitney u test, and kruskal–wallis test. the distribution of variables was measured by the kolmogorov–smirnov test. since the numerical variable did not meet the normal distribution condition, the mann–whitney u and kruskal–wallis tests were used for comparison. statistical alpha significance level was accepted as p < 0.05. original article | dermatol pract concept. 2022;12(4):e2022167 3 results demographic and clinical characteristics a total of 138 patients with genital and non-genital cutaneous warts (n = 59, n = 79, respectively) and 83 healthy, sexand age-matched controls were interviewed. general characteristics of the participants are shown in table 1. the majority of patients with genital warts were male (89.8%). the sex distribution in patients with nongenital warts was similar. the most frequent localizations of non-genital warts were plantar and palmar (40.5% and 39.2%, respectively). comparison of sleep quality between patient and control groups patients with cutaneous warts had a significantly higher average global psqi score than the control group with an odds ratio [or] of 1.292, 95% confidence interval (ci) 1.1741.422, with a significantly higher score in all components of the psqi excluding use of sleeping medication. poor sleep quality was observed in 79.7% of the patient group and in 50.6% of the control group (p < 0.05). it was determined that the rate of poor sleep quality in the patient group was higher than in the control group (or: 3.835; 95% ci: 2.110-6.972) (table 2). table 1. general characteristics of participants and association between sleep quality and demographic characteristics. nongenital (n = 79) mean ± sd genital (n = 59) mean ± sd control (n = 83) mean ± sd age (years) 27.94±10.23 31.54±10.01 30.20±9.57 disease duration (years) 1.08±1.55 1.20±1.39 n (%) n (%) n (%) sex male female 39(49.4) 40(50.6) 53(89.8) 6(10.2) 47(56.6) 36(43.4) number of warts 1 1-5 >5 36(45.6) 28(35.4) 15(19.0) 1(1.7) 16(27.1) 42(71.2) localization – hand – plantar – facial – palmoplantar – others 31(39.2) 32(40.5) 9(11.4) 4(5.1) 3(3.8) non-genital (n = 79) genital (n = 59) z/p n mean ± sd n mean ± sd age ≤ 30 years >30 years 56 23 6.76±3.09 7.52±3.83 33 26 8.33±3.72 8.96±3.56 -1.898/0.058 -1.327/0.184 z/p -0.786/0.432 -0,797/0.425 sex male female 39 40 6.87±3.18 7.10±3.48 53 6 8.30±3.65 11.33±2.06 -1.737/0.082 -2.621/0.009* z/p -0.015/0.988 -2.102/0.036* disease duration ≤ 1 year >1 year 65 14 6.87±3.40 7,.0±2.95 42 17 8.66±3.88 8.47±3.04 -2.278/0.023* -0.979/0.327 z/p -0.574/0.566 -0.109/0.913 sd = standard deviation; z = mann whitney u test. * p < 0.05. 4 original article | dermatol pract concept. 2022;12(4):e2022167 warts (11.33 ± 2.06 versus 8.30 ± 3.65). there was no significant difference in sleep quality regarding age, number of warts, or disease duration (table 1). conclusions although the reason cannot be fully clarified, chronic inflammatory skin diseases (eg atopic dermatitis, psoriasis vulgaris, chronic urticaria) and rosacea, lichen planus, hidradenitis suppurativa, acne vulgaris and behçet disease are shown to have a negative effect on sleep quality [5–12]. apart from symptoms such as pain and itching caused by diseases, the comparison of sleep quality between patients with genital and non-genital warts patients with genital warts had a significantly higher average global psqi score than patients with non-genital warts (8.61 ± 3.63 versus 6.98 ± 3.32), with a significantly higher score in 2 components of the psqi, ie sleep disturbance and daytime dysfunction (table 3; figure 1). association between sleep quality and demographic characteristics female patients with genital warts had a significantly higher average global psqi score than male patients with genital table 2. comparison of sleep quality between patient and control group. pittsburgh sleep quality index (psqi) and psqi domains patients (n = 138) mean ± sd control (n = 83) mean ± sd z/p odds ratio a (95% confidence interval) global psqi 7.68±3.53 4.92±2.91 -5.549/0.000* 1.292 (1.174-1.422) subjective sleep quality 1.42±0.64 1.18±0.68 -2.498/0.012* 1.764 (1.152-2.701) sleep latency 1.55±0.88 1.03±0.86 -4.127/0.000* 1.955 (1.405-2.720) sleep duration 1.18±1.06 0.77±0.83 -2.738/0.006* 1.541 (1.153-2.060) habitual sleep efficiency 0.55±0.74 0.12±0.32 -4.813/0.000* 4.587 (2.299-9.154) sleep disturbance 1.23±0.63 0.74±0.55 -5.460/0.000* 3.936 (2.316-6.690) use of sleeping medication 0.47±0.91 0.27±0.70 -1.648/0.099 1.363 (0.952-1.950) daytime dysfunction 1.25±1.01 0.79±0.77 -3.210/0.001* 1.704 (1.251-2.321) sleep quality n (%) n (%) x2/p poor sleep quality 110 (79.7) 42 (50.6) 20.449/0.000* 3.835 (2.110-6.972) good sleep quality 28 (20.3) 41 (49.4) sd = standard deviation; z = mann whitney u test; x2 = xi square test. * p < 0.05; , a logistic regression analysis. table 3. comparison of sleep quality between patients with genital and non-genital warts. pittsburgh sleep quality index (psqi) and psqi domains non-genital (a) (n = 79) mean ± sd genital (b) (n = 59) mean ± sd control (c) (n = 83) mean ± sd kw/p global psqi 6.98±3.32 8.61±3.63 4.92±2.91 36.79/0.000* b>a>c a subjective sleep quality 1.39±0.70 1.47±0,56 1.18±0.68 6.904/0.032* b>a=c a sleep latency 1.46±0.85 1.66±0.90 1.03±0.86 18.222/0.000* a=b>c a sleep duration 1.06±1.01 1.33±1.10 0.77±0.83 9.666/0.008* b>a=c a habitual sleep efficiency 0.54±0.81 0.55±0.65 0.12±0.32 23.997/0.000* a=b>c a sleep disturbance 1.13±0,61 1.37±0.64 0.74±0.55 33.497/0.000* a=b>c a use of sleeping medication 0.36±0.78 0.62±1.04 0.27±0.70 4.411/0.110 daytime dysfunction 1.01±0.98 1.57±0.98 0.79±0.77 21.785/0.000* b>a>c a kw = kruskal wallis test. * p < 0.05; a bonferroni’s correction: p < 0.0167. original article | dermatol pract concept. 2022;12(4):e2022167 5 figure 1. comparison of sleep quality among patients with genital and non-genital warts and controls. *p < 0.05. non-genital: a. genital: b. control: c. global psqi b>a>c** subjective sleep quality b>a=c** sleep latency a=b>c** sleep duration b>a=c** habitual sleep efficiency a=b>c** sleep disturbance a=b>c** use of sleeping medication daytime dysfunction b>a>c** **bonferroni correction: p < 0.0167. psychosocial effects of dermatological diseases cannot be denied. sleep quality is also one of the most important of these psychosocial effects. for this reason, the effects of dermatological diseases on sleep quality have been frequently investigated in recent studies. in fact, although diseases themselves affect sleep quality, sleep quality may also affect diseases by affecting the immune system. sleep disorders may result in some changes in immune system functions. in accordance with the association between cytokines, host immune function, and the sleepwake cycle, sleep disturbance may play a role in the inflammatory cascade that can result in a chronic inflammatory state [1]. cutaneous warts are a common disease, and depending on the immune status of the person, the extent of the disease and the response to treatment may vary [14]. in the literature, only one study has mentioned the effect of cutaneous warts on sleep quality [15]. in the study of liu et al, 6 original article | dermatol pract concept. 2022;12(4):e2022167 the shortcoming of the study is that concurrent quality of life was not evaluated. in addition, since the treatment options were not standard in all patients, it was not evaluated whether the sleep quality of the patients had an effect on the response to treatment. our study reveals the association between poor sleep and cutaneous warts. cutaneous warts seem to have an effect on sleep, but perhaps the reverse direction is also true. evaluation of sleep quality in patients with warts, especially in patients with genital warts, may be suggested. the management of sleep disturbances in cutaneous warts may help increase the quality of life of patients and may affect disease control. references 1. gupta ma, gupta ak. sleep-wake disorders and dermatology. clin dermatol. 2013;31(1):118-126. doi: 10.1016/j.clindermatol.2011.11.016. pmid: 23245983. 2. lavery mj, stull c, kinney mo, yosipovitch g. nocturnal pruritus: the battle for a peaceful night’s sleep. int j mol sci. 2016;17(3):425. doi: 10.3390/ijms17030425. pmid: 27011178. pmcid: pmc4813276. 3. pedroni mn, hirotsu c, porro am, tufik s, andersen ml. the role of sleep in pemphigus: a review of mechanisms and perspectives. arch dermatol res. 2017;309(8):659-664. doi: 10.1007/ s00403-017-1765-9. pmid: 28726005. 4. altemus m, rao b, dhabhar fs, ding w, granstein rd. stress-induced changes in skin barrier function in healthy women. j invest dermatol. 2001;117(2):309-317. doi: 10.1046/j.15231747.2001.01373.x. pmid: 11511309. 5. kaaz k, szepietowski jc, matusiak ł. influence of itch and pain on sleep quality in atopic dermatitis and psoriasis. acta derm venereol. 2019;99(2):175-180. doi: 10.2340/00015555-3065. pmid: 30307027. 6. kaaz k, szepietowski jc, matusiak ł. sleep quality among adult patients with chronic dermatoses. postepy dermatol alergol. 2019;36(6):659-666. doi: 10.5114/ada.2019.84007. pmid: 31997991. pmcid: pmc6986286. 7. thorburn pt, riha rl. skin disorders and sleep in adults: where is the evidence? sleep med rev. 2010;14(6):351-358. doi: 10.1016/j.smrv.2009.12.001. pmid: 20188609. 8. wang z, xie h, gong y et al. relationship between rosacea and sleep. j dermatol. 2020;47(6):592-600. doi: 10.1111/13468138.15339. pmid: 32291809. 9. adamo d, ruoppo e, leuci s, aria m, amato m, mignogna md. sleep disturbances, anxiety and depression in patients with oral lichen planus: a case-control study. j eur acad dermatol venereol. 2015;29(2):291-297. doi: 10.1111/jdv.12525. pmid: 24754427. 10. kaaz k, szepietowski jc, matusiak ł. influence of itch and pain on sleep quality in patients with hidradenitis suppurativa. acta derm venereol. 2018;98(8):757-761.  doi: 10.2340/000155552967. pmid: 29756157. 11. schrom kp, ahsanuddin s, baechtold m, tripathi r, ramser a, baron e. acne severity and sleep quality in adults. clocks sleep. 2019;1(4):510-16. in which 215 patients with palmoplantar warts were evaluated, 11.0% of the patients reported poor sleep quality; however, this study was conducted without questionnaires or a control group. although the reason is not mentioned, it was observed that the treatment response was low in those with poor sleep quality [15]. our study is significant in that it is the first controlled study in this respect and that patients with genital warts (ie as opposed to only non-genital warts) were also evaluated. in our study, patients with cutaneous warts had a significantly higher average global psqi score than that of the control group. here, the disease itself, treatment processes, and response or non-response to treatment may affect sleep quality. however, the sleep quality of the patients may also affect their immune status, thus affecting the elimination of the virus or the extent of the virus and the response to treatment. sleep is actually an immunological activity. human sleep consists of two phases: rem (rapid eye movement) and nrem (non-rem) sleep. natural killer cells and some proinflammatory cytokines (interleukin-1beta/tumor necrosis factor-alfa), which play an important role in the regulation of nrem sleep, may increase after sleep disruption [4]. however, slow-wave sleep (deep sleep) plays a role in reducing immune system activation, while sleep deprivation can activate the immune system, leading to an increase in il-1, il-6, tnf a, leukocytes, nk, and monocyte cells. hypothalamic-pituitary-adrenal (hpa) activation reduces the sleep-enhancing effects of cytokines, decreases non-rem sleep, and increases wakefulness in the advanced stages of inflammation [16]. patients with genital warts had a significantly higher average global psqi score than patients with non-genital warts and controls in this study. the transmission of genital warts by sexual contact and the feeling of guilt and shame caused by it, relapses during treatment, and the risk of malignancy are the most important causes of psychological damage in patients. in addition, the sexual life of patients may be affected [17]. the degree of this impact on quality of life may also affect sleep quality. female patients with genital warts showed a significantly higher average global psqi score than male patients with genital warts in this study. evaluating the literature, it has been shown that the quality of life of female patients with genital warts is more affected than that of male patients [17,18]. this suggests that the anxiety and stress caused by the disease in women are more intense and that women are more sensitive to changes in their quality of life. however, genital warts remind women of cervical cancer, and thanks to preventive medicine, women’s awareness of cervical cancer has increased in recent times. for all these reasons, it was thought that the sleep quality of women might be more affected. original article | dermatol pract concept. 2022;12(4):e2022167 7 doi: 10.1038/s41598-018-33511-x. pmid: 30337549. pmcid: pmc6194033. 16. ranjbaran z, keefer l, stepanski e, farhadi a, keshavarzian a. the relevance of sleep abnormalities to chronic inflammatory conditions. inflamm res. 2007;56(2):51-57. doi: 10.1007/ s00011-006-6067-1. pmid: 17431741. 17. erdem y, özarmağan g. evaluation of the quality of life in patients with genital warts. turkderm-turk arch dermatol venereol. 2016;50(1):21-24. doi: 10.4274/turkderm.78477. 18. qi sz, wang sm, shi jf, et al. human papillomavirus related psychosocial impact of patients with genital warts in china: a hospital-based cross-sectional study. bmc public health. 2014;14:739. doi: 10.1186/1471-2458-14-739. pmid: 25048000. pmcid: pmc4223584. 12. yazmalar l, batmaz i̇, sarıyıldız ma, et al. sleep quality in patients with behçet’s disease. int j rheum dis. 2017; 20(12):2062-2069. doi: 10.1111/1756-185x.12459. pmid: 25195840. 13. ockenfels hm. therapeutic management of cutaneous and genital warts. j dtsch dermatol ges. 2016;14(9):892-899. doi: 10.1111/ddg.12838. pmid: 27607030. 14. chen sl, tsao yp, lee jw, sheu wc, liu yt. characterization and analysis of human papillomaviruses of skin warts. arch dermatol res. 1993;285(8):460-465. doi: 10.1007/bf00376818. pmid: 8274034. 15. liu j, li h, yang f, et al. epidemiology and clinical profile of cutaneous warts in chinese college students: a cross sectional and follow-up study. sci rep. 2018;8(1):15450. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):16 81 dermatology practical & conceptual www.derm101.com the patient a 66-year-old female presented to our clinic with a 12-month history of a new, growing, asymptomatic nodule on her right leg. the physical examination revealed a firm, slightly depressible, pink nodule with light brown peripheral pigmentation and superficial visible vessels, measuring 10 mm in maximum diameter (figure 1). dermoscopy disclosed a central white structureless area, surrounded by an erythematous halo with areas of light brown atypical network. additionally, fine linear-irregular and medium caliber, well-focused comma-like vessels were seen (figure 2). complete surgical excision of the lesion was performed. histopathological examination revealed an intradermic nodular lesion with few small fusiform cells, abundant eosinophilic collagen bundles and capillary vessels (figure 3). immunohistochemistry was negative to cd34 and s100 protein. diagnosis atrophic dermatofibroma. clinical course as it is considered a benign non-melanocytic lesion, a conservative management was proposed. no further unnecessary therapeutic procedures were performed. discussion dermatofibroma (df) is one of the most common skin neoplasms seen by dermatologists. out of the various histopathological subtypes of df, the atrophic variant is considered rare. clinical and dermoscopic diagnosis of df is straightforward in most cases. however, deeply atypical clinical and nodular lesion with polymorphous vascular pattern virgínia coelho de sousa1, andré oliveira2 1 department of dermatology, hospital de santo antónio dos capuchos, centro hospitalar de lisboa central, lisbon, portugal 2 centro académico de medicina, university of lisbon, lisbon, portugal key words: dermatofibroma, dermoscopy, comma-like vessels, dermatopathology citation: coelho de sousa v, oliveira a. nodular lesion with polymorphous vascular pattern. dermatol pract concept 2017;7(4):81-83. doi: https://doi.org/10.5826/dpc.0704a16 received: july 31, 2017; accepted: september 8, 2017; published: october 31, 2017 copyright: ©2017 coelho de sousa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. virgínia coelho de sousa, department of dermatology and venereology, hospital de santo antónio dos capuchos, alameda de santo antónio dos capuchos, 1169-050 lisbon, portugal. tel. +351 213136300. e-mail: virginiacoelhodesousa@ gmail.com dermatofibroma (df) is one of the most common skin neoplasms seen by dermatologists. out of the various histopathological subtypes of df, the atrophic variant is considered rare. clinical and dermoscopic diagnosis of df is straightforward in most cases. however, deeply atypical clinical and dermoscopic presentations can simulate other benign and malignant tumors. we present a case of atrophic df, describing its dermoscopic features and the correlation with histopathology. abstract https://doi.org/10.5826/dpc.0704a 82 observation | dermatol pract concept 2017;7(4):16 white scar-like patches; peripheral homogeneous area with a central white scar-like patch; or peripheral homogeneous area with a central white network; and atypical pattern [3]. vascular structures can be present in 49.5% of df. the most common vascular structure is erythema, followed by dotted vessels [3]. vascular structures are one of the criteria used for the dermoscopic diagnosis of melanoma and other pigmented and vascular tumoral lesions that may simulate melanoma [4]. we present a case of a new, growing, nodular lesion presenting in an elderly patient. dermoscopy showed polymordermoscopic presentations can simulate other benign and malignant tumors [1]. dermoscopy is a fast, noninvasive technique that increases diagnostic accuracy for both melanocytic and non-melanocytic skin tumors, allowing for better differentiation of clinical simulators of melanoma [2]. common dermoscopic features of df include pigment network, white scar-like patch and white network. ten dermoscopic patterns were described, according to the presence or absence of peripheral pigment network. df with peripheral pigment network are divided in four patterns: total delicate pigment network; peripheral delicate pigment network with central white scar-like patch; peripheral delicate pigment network with a central white network; and peripheral delicate pigment network with a central homogeneous area. df without peripheral pigment network can present as total white network; total homogeneous area; total or multiple figure 1. clinical presentation of a nodular lesion located on the leg. [copyright: ©2017 coelho de sousa et al.] figure 2. dermoscopic presentation with a central white structureless area, surrounded by areas of light brown atypical network (arrows). fine linear-irregular (circles) and medium caliber, wellfocused comma-like vessels (arrows) were seen (polarized contact dermoscopy, x10). [copyright: ©2017 coelho de sousa et al.] figure 3. histopathology showing an intradermic nodular lesion with few small fusiform cells, abundant eosinophilic collagen bundles and capillary vessels (hematoxylin-eosin, x40). [copyright: ©2017 coelho de sousa et al.] observation | dermatol pract concept 2017;7(4):16 83 ous tumors. histopathological examination should always be performed in such confounding lesions. references 1. ferrari a, argenziano g, buccini p, et al. typical and atypical dermoscopic presentations of dermatofibroma. j eur acad dermatol venereol. 2013;27:1375-1380. 2. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: result of a consensus meeting via internet. j am acad dermatol. 2003;48:679-693. 3. zaballos p, puig s, llambrich a, malvehy j. dermoscopy of dermatofibromas: a prospective morphological study of 412 cases. arch dermatol. 2008;144:75-83. 4. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermatol. 2004;140(12):1485-1489. 5. kilinc karaarslan i, gencoglan g, akalin t, ozdemir f. different dermoscopic faces of dermatofibromas. j am acad dermatol. 2007;57(3):401-406. 6. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-1127. 7. alves jv, matos dm, barreiros hf, bártolo ea. variants of dermatofibroma – a histopathological study. an bras dermatol. 2014;89(3):472-427. phous vascular structures including erythema, linear-irregular and comma-like vessels. comma-like vessels are the dermoscopic hallmark of dermal nevi, being rarely described in df [5]. the presence of comma-like vessels in a regular distribution or as the dominant vascular type is considered a negative predictor for amelanotic melanoma [6]. however, considering the atypical clinical and dermoscopic presentation of polymorphous vascular structures described as a feature of amelanotic melanoma, excision was mandatory to rule out this entity. histopathology later confirmed the presence of a benign tumor. to our knowledge, this is the first dermoscopic description of the rare atrophic variant of df. atrophic df is identified by dermal atrophy with prominent sclerotic collagen, as well as low cellularity. it has been proposed that dense elastic fibers around the vessels interfere with blood circulation, causing dermal atrophy, and thus low cellularity [7]. the white strutureless area seen on dermoscopy correlates with the dense collagen fibers found on dermis. well-focused, medium caliber comma-like vessels represent superficial vessels running above the dermal collagen bundles. df can thus present with a wide range of dermoscopic patterns, sometimes mimicking melanoma and other cutanedermatology: practical and conceptual 324 research | dermatol pract concept 2018;8(4):16 dermatology practical & conceptual www.derm101.com impact of clinical and personal data in the dermoscopic differentiation between early melanoma and atypical nevi linda tognetti1,2, elisa cinotti1, elvira moscarella3,4, francesca farnetani5, josep malvehy6, aimilios lallas7, giovanni pellacani5, giuseppe argenziano3,4, gabriele cevenini2, pietro rubegni1 1 dermatology division, department of medical, surgical and neurosciences, university of siena, siena, italy 2 department of medical biotechnologies, university of siena, siena, italy 3 skin cancer unit, arcispedale santa maria nuova, irccs, reggio emilia, italy 4 dermatology unit, university of campania, naples, italy 5 department of dermatology, university of modena and reggio emilia, modena italy 6 melanoma unit, department of dermatology, university of barcelona, barcelona, spain 7 first department of dermatology, aristotele university, thessaloniki, greece key words: melanoma, atypical nevi, dermoscopy, clinical and personal data citation: tognetti l, cinotti e, moscarella e, farnetani f, malvehy j, lallas a, pellacani g, argenziano g, cevenini g, rubegni p. impact of clinical and personal data in the dermoscopic differentiation between early melanoma and atypical nevi. dermatol pract concept. 2018;8(4):324-327. doi: https://doi.org/10.5826/dpc.0804a16 received: march 26, 2018; accepted: may 23, 2018; published: october 31, 2018 copyright: ©2018 tognetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. lt and pr contributed equally to this study. corresponding author: linda tognetti, md, hospital s. maria alle scotte, viale bracci 16, 53100 siena, italy. email: l.tognetti@ studentunisi.it background: differential diagnosis of clinically atypical nevi (an) and early melanomas (emm) still represents a challenge even for experienced dermoscopists, as dermoscopy alone is not sufficient to adequately differentiate these equivocal melanocytic skin lesions (msls). objectives: the objectives of this study were to investigate what were the most relevant parameters for noninvasive differential diagnosis between emm and an among clinical, personal, and dermoscopic data and to evaluate their impact as risk factors for malignancy. methods: this was a retrospective study performed on 450 msls excised from 2014 to 2016 with a suspicion of malignancy. dermoscopic standardized images of the 450 msls (300 an and 150 emm) were collected and evaluated. patients’ personal data (ie, age, gender, body site, maximum diameter) were also recorded. dermoscopic evaluations were performed by 5 different experts in dermoscopy blinded to histopathological diagnosis. fleiss’ κ was calculated to measure concordance level between experts in the description of dermoscopic parameters for each msl. the power of the studied variables in discriminating malignant from benign lesions was also investigated through f-statistics. abstract research | dermatol pract concept 2018;8(4):16 325 liar dermoscopic pattern. after selection for image quality, availability of patient data, and agreement of 3/3 experts on histopathological diagnosis, the final database consisted of 450 standardized dermoscopic micrographs—300  an and 150 emm—acquired at 17× magnification. dermoscopic evaluations were independently performed by 5 experts in dermoscopy. they were asked to assess the presence/absence of a series introduction dermoscopy is a useful noninvasive diagnostic method for differentiating benign from malignant melanocytic skin lesions (msls) [1]. in clinical practice, equivocal msls, including early melanomas (emm), that do not yet exhibit clear-cut atypical features and atypical nevi (an) showing clinical and dermoscopic features usually associated with malignancy are seen frequently. early diagnosis of these equivocal msls can be challenging even for experienced dermoscopists [2-5]. in daily practice, dermatologists consider a patient’s risk factors that together form a basis for the decision “to leave or to excise” that include lesion dimension, localization, evolution in time, number of nevi, personal/familial history of melanoma, and skin phototype [6-8]. however, only 4 criteria—body site, maximum diameter, age, and sex—represent objective and standardized variables to assess for malignancy. the objective of this study was to define which clinical and personal data are the most relevant risk factors for malignancy and to investigate their impact in the dermoscopic differential diagnosis between emm and an. methods a total of  493  atypical msls were excised from 2014 to 2016 with suspected malignancy (figure 1). msls localized on the face, palms, and soles were excluded a priori due to their pecuresults: the variables age and maximum diameter supplied the highest discriminant power (f  = 253 and 227, respectively). atypical network, blue white veil and white shiny streaks were the most significant dermoscopic patterns suggestive of malignancy (f = 110, 104 and 99.5, respectively). shiny white streaks was the only dermoscopic parameter to obtain satisfactory concordance value. gender was not a discriminant factor. the specific statistical weight of clinical and personal data (ie, “patient’s age” and “lesion diameter”) surpassed those of atypical dermoscopic features. conclusions: the objective clinical and personal data collected here could supply a fundamental contribution in the correct diagnosis of equivocal msls and should be included in diagnostic algorithms along with significant dermoscopic features (ie, atypical network, blue-white veil, and shiny white streaks). abstract of 18 dermoscopic structures designed to include only the features most commonly associated with atypical msls according to the current in literature. to ensure a thorough, blinded pattern recognition analysis, all experts were unaware of the histopathological diagnosis, clinical and personal data. then, each one of the 18 selected dermoscopic structures was defined as absent/present within a lesion when 5/5 experts agreed. figure 1. examples of dermoscopically and clinically equivocal msls from the case study (polarized dermoscopy, 20×) diagnosed histologically. atypical nevi exhibiting atypical network (a, b), blue-white veil and shiny white streaks (b). early melanomas (c, d) showing only irregular dots and globules (c) and irregular pigmented blothes (d). nevi were excised from the abdomen of a 43-year-old woman (a) and the arm of a 51-year-old man (b). melanomas were excised from the upper back of an 83-year-old man (c) and a 79-year-old woman (d). a b c d 326 research | dermatol pract concept 2018;8(4):16 tomical criteria and further grouped into  4  body areas according to uv exposure, ie, group a, chronically photoexposed body sites (head, neck, arms/ hands); group b, frequently photoexposed body sites (thighs, legs, ankle, back of the feet); group c, seldom photoexposed body sites (shoulders, chest/breast, back); and group d, rarely photoexposed body sites (abdomen, bottom, side). results univariate discriminant analysis of all 47 integrated variables, shown in table 1, was performed taking the histopathological diagnosis as outcome. univariate power to discriminate between overall interobserver agreement was estimated by fleiss’ κ and its 95% confidence interval (ci). in a second phase, we retrospectively collected  2  clinical data (diameter and body site) and 2 personal data (age and sex) sets for each of the 450 msls, obtaining an integrated database of 450 images associated with 18 subjective (ie, dermoscopic data) and 4 objective variables (ie, clinical-personal data). in order to be tested for risk factors for malignancy, they were evaluated both in their original form as 5 whole variables and in their binary-coded form as 42 simple variables. age and maximum diameter were dichotomized to account for some interesting cut-off values. the lesion site was described according to anatable 1. discriminant analysis showing f-statistics (f) and p-value (p) of all dermoscopic, clinical, and personal variables (47) coded into 38 simple variables, 5 whole variables (bold), and 4 grouped variables (italics) integrated variables f p integrated variables f p age (years) 253 .000 atypical vascular pattern (avp) 21.2 .000 maximum diameter (mm) 227 .000 shoulders 13.7 .000 age cut-off ≥40 years 197 .000 group c: seldom exposed sites 13.5 .000 age cut-off ≥60 years 167 .000 hypopigmented areas 13.4 .000 maximum diameter cut-off ≥8 152 .000 blue-gray globules 13.3 .000 age cut-off ≥50 years 146 .000 arms + hands 12.6 .000 maximum diameter cut-off ≥5 133 .000 group a: chronically exposed sites 12.1 .001 maximum diameter cut-off ≥7 mm 129 .000 group d: rarely exposed sites 9.73 .002 maximum diameter cut-off >10 mm 124 .000 back 7.21 .007 atypical network 110 .000 anatomical site 6.82 .009 age cut-off ≥30 years 108 .000 neck 6.78 .009 blue-white veil 104 .000 chest/breast 5.68 .017 shiny white streaks 99.5 .000 ankle + back of the feet 5.47 .019 irregular pigmented blotches 67.6 .000 side 4.35 .037 irregular streaks 55.6 .000 head 2.69 .102 pink areas 52.3 .000 multicolor pattern 2.68 .06 blue-white veil >30% 47.6 .000 broad network 2.57 .08 white scar-like areas 41.1 .000 bottom 2.55 .110 blue-gray peppering 39.2 .000 abdomen 2.30 .130 uv-exposed body areas 39.2 .000 radial streaming 2.6 .10 group b: frequently exposed sites 27.9 .000 multiple brown dots 2.3 .12 legs 23.5 .000 light brown areas 2.1 .13 irregular dots and globules (idg) 22.6 .000 gender 2.1 .28 emm and an was quantified by means of f-statistics. statistical significance (p<0.05) was obtained by 37/47 variables. taken together, the results of this analysis showed that: 1) age and diameter exhibited the highest discriminant power for emm when considered as whole or simple variables; 2) the classification of anatomical sites into 4 body area groups according to uv exposure resulted in association with malignancy (eg, body site “head” obtained p>0.05 and f<2.69 as simple variable, but p<0.05 and f=12.1 when as part of group a, chronically exposed body areas); 3) none of the dermoscopic features reached f>110, demonstrating moderate impact; and 4) as reported in table 2, agreement between experts research | dermatol pract concept 2018;8(4):16 327 that develop due to uv exposure [5-7]. in conclusion, despite the contemporary presence of an atypical network, blue-white veil, and shiny white streaks within an equivocal msls, which may indicate malignancy, the objective clinical and personal data collected could supply a fundamental contribution in the correct diagnosis of equivocal msls and should be included in diagnostic algorithms. references 1. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10-year multicenter survey. j am acad dermatol. 2012;67(1):54-59. 2. carrera c, marchetti ma, dusza sw, et al. validity and reliability of dermoscopic criteria used to differentiate nevi from melanoma: a web-based international dermoscopy society study. jama dermatol. 2016;152(7):798-806. 3. abbasi nr, yancovitz m, gutkowiczkrusin d, et al. utility of lesion diameter in the clinical diagnosis of cutaneous melawas generally poor, with the exception of white shiny streaks (κ =0.418, 95% ci 0.403-0.432) albeit of intermediate level, which was probably due to the clear-cut appearance of this pattern. conclusions the method of combining clinical and personal data with dermoscopic variables proved to be highly useful diagnostically in differentiating regressing mm from regressing nevi [8]. here in this dataset of emm and an, the relative impact of dermoscopic structures was moderate and their recognition was confirmed to be a rather subjective and equivocal method with unsatisfactory agreement [1,2]. our findings are in line with recent epidemiological data in that emm shows a trend to be increasing in prevalence in the elderly with no gender predominance [5,6], a strong correlation with lesion maximum diameter [7,8], and a moderate correlation with uv exposure (f=39.4). this probably reflects only a fraction of emm table 2. concordance levels of experts (d 1 -d 5 ) in recognition of dermoscopic structures (only variables that obtained p > 0.05 are shown) dermoscopic variable fleiss’ κ [95% ci] strength of agreement shiny white streaks 0.418 [0.403-0.432] intermediate irregular dots and globules 0.375 [0.360-0.389] poor blue-white veil 0.334 [0.320-0.349] poor blue-gray globules 0.302 [0.287-0.316] poor hypopigmented areas 0.297 [0.283-0.312] poor irregular streaks 0.254 [0.239-0.268] poor atypical network 0.238 [0.224-0.253] poor white scar-like areas 0.214 [0.200-0.229] poor pigmented areas 0.163 [0.148-0.177] poor blue-white veil >30 0.151 [0.137-0.166] poor atypical vascular pattern 0.100 [0.085-0.114] poor blue-gray peppering 0.098 [0.084-0.113] poor irregular pigmented blotches 0.077 [0.063-0.091] poor noma. arch dermatol. 2008;144(4):469474. 4. moreno-ramírez d, ojeda-vila t, ríosmartín jj, et  al. association between tumor size and breslow’s thickness in malignant  melanoma: a cross-sectional, multicenter study. melanoma  res. 2015;25(5): 450-452. 5. haenssle ha,  mograby n,  ngassa a, et  al. association of patient risk factors and frequency of nevus-associated cutaneous melanomas. jama dermatol. 2016;152(3):291-298. 6. whiteman dc, green ac, olsen cm. the growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. j invest dermatol. 2016;136(6):1161-1171. 7. liu f, bessonova l, taylor th, et al. a unique gender difference in early onset melanoma implies that in addition to ultraviolet light exposure other causative factors are important. pigment cell melanoma res. 2013; 26(1):128–135. 8. rubegni p, tognetti l, argenziano g, et al. a risk scoring system for the differentiation between melanoma with regression and regressing nevi. j dermatol sci. 2016; 83(2):138-144. dermatology: practical and conceptual review | dermatol pract concept. 2022;12(4):e2022193 1 eruptive non-melanoma skin cancers/squamous atypia following skin surgery. report of two new cases, concise review of the literature with special emphasis on treatment options marco adriano chessa1,2, valentino marino picciola3, federica filippi1,2, annalisa patrizi1,2, cosimo misciali1,2, bianca maria piraccini1,2, ignazio stanganelli4, francesco savoia4 1 irccs azienda ospedaliero-universitaria di bologna, bologna, italy 2 dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy 3 university of bologna, school of medicine and surgery, bologna, italy 4 skin cancer unit, istituto scientifico romagnolo per lo studio e la cura dei tumori (irst) irccs, meldola, italy key words: eruptive non-melanoma skin cancers, keratoacanthomas after cutaneous surgery, keratoacanthomas and split-thickness skin graft, cutaneous squamous cell carcinomas and split-thickness skin graft citation: chessa ma, marino picciola v, filippi f, et al. eruptive non-melanoma skin cancers/squamous atypia following skin surgery. report of two new cases, concise review of the literature with special emphasis on treatment options. dermatol pract concept. 2022;12(4):e2022193. doi: https://doi.org/10.5826/dpc.1204a193 accepted: march 7, 2022; published: october 2022 copyright: ©2022 chessa et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: federica filippi, md, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti, 1 – 40138 bologna, italy tel: +39051-2144849; fax +39-0512144867; e-mail: federicafilippi8@gmail.com introduction: eruptive cutaneous squamous cell carcinomas (escc), eruptive squamous atypia (esa) and eruptive keratoacanthomas (eka) are different terms used to describe the occurrence of multiple cutaneous squamous neoplasms after skin surgery, laser treatment, traumas, such as tattoos, and local or systemic medical treatments. escc have been reported to arise at the sites of skin surgery, including the area affected by the primary tumor and split thickness skin graft (stsg) donor and recipient sites. objectives: the aim of this study is to report 2 additional cases of escc after skin surgery and make a critical revision of the literature, analyzing the clinical, histological features and outcomes of escc after cutaneous surgery. methods: up to august 2021, according to our systematic review of the literature, we have collected 19 published articles and a total of 34 patients, including our 2 cases. results: the results of this review highlight five red flags that clinicians should consider: (i) lower and upper limbs represent the cutaneous site with the highest risk, representing 83,78% of the cases in the abstract 2 review | dermatol pract concept. 2022;12(4):e2022193 introduction eruptive cutaneous squamous cell carcinomas (escc), eruptive squamous atypia (esa) and eruptive keratoacanthomas (eka) are different terms used to describe the occurrence of multiple cutaneous squamous neoplasms occurring after skin surgery, laser treatment, traumas, such as tattoos, local or systemic medical therapies. in this paper, we decided to use only the term escc. escc have been reported to arise at the sites of skin surgery, including the area affected by the primary tumor and split thickness skin graft (stsg) donor and recipient sites [1-19]. the best therapeutic option for escc after surgery in our opinion is still a challenge. objectives the aim of our study is to report 2 additional cases of escc after skin surgery and make a critical revision of the literature, analyzing the clinical, histological features and outcomes of escc after cutaneous surgery [18]. an overview of this rarely reported condition is provided, in order to raise awareness of this clinical entity and of the treatment options. methods we identified studies indexed in pubmed from its inception to june 31, 2021. all papers reported in the present study involved human clinical studies, including case reports, case series and reviews. search parameters included the terms ‘‘keratoacanthomas after cutaneous surgery”, “keratoacanthomas and stsg”, ‘‘cutaneous squamous cell carcinomas and stsg”, “cutaneous squamous cell carcinomas after cutaneous surgery’’, “squamous cell carcinoma after mohs micrographic surgery (mms)”, “eruptive squamous cell carcinoma and surgery”, “eruptive squamous atypia and surgery”, “eruptive keratoacanthomas and surgery”, “koebnerized cutaneous squamous cell carcinoma”. a subsequent review of the relative bibliographies aimed to identify any undetected reports. we collected sex, age, involved cutaneous area, surgical procedure, medical treatment and histopathology findings of primary cutaneous skin cancer of all the patients included in this review. furthermore, we reported the time lapse from the primary surgery to the onset of escc, clinical and histological features, management, recurrences and outcome. in addition, we describe here our personal experience with two patients visited at the skin cancer unit of bologna between january 2012 and august 2021, who developed escc after cutaneous squamous cell carcinoma (cscc) excision and reconstruction with stsg. results up to august 2021, according to our systematic review of the literature, we found only 19 published articles (table 1). a total of 34 ascertained patients, including our two cases, were included in this study, with a sex ratio f/m = 0.88, a mean age = 68.94 years (standard deviation [sd] = 13.6). the main clinical features of the 34 patients diagnosed with escc after surgery are reported in table 2. the extremities (upper and lower limbs) were the sites most frequently involved by primary tumors, representing 83.78% of cases in our sample. the second most involved site was the head, with 13.51% of cases. regarding our two patients, the first had a cscc of the head and the second a cutaneous scc of the right leg. histological examination of the primary skin cancer was consistent with a cssc in 30/37 cases (81.08%), while basal cell carcinoma, actinic keratosis, malignant melanoma and lentigo maligna were detected in 7 cases (18.92%). different surgical techniques were used for the excision of the primary skin tumors, although classic fusiform excision, excision plus stsg, mms and subsequent reconstruction with or without stsg were the most commonly performed procedures, in 32/37 cases (86.49%). the main clinical features of the escc after skin surgery are reported in table 3. the median time to the onset is approximately 6 weeks, and in 28/34 of the patients (82.35%) it occurred within 16 weeks from the primary surgery. surprisingly, escc occurred in the area of the skin affected by the primary tumor in 26/37 of the cases literature; (ii) the median time to onset of escc is approximately 6 weeks; (iii) primary cutaneous squamous cell carcinomas were completely excised with free margins on histologic examination in the totality of the cases of the literature, and therefore escc should not be considered recurrences; (iv) any surgical technique involves a risk to promote escc; (v) treatment of escc includes medical treatment, surgery or combined surgical and medical treatment. conclusions: this review highlights 5 red flags which could support clinicians in the diagnosis and management of escc after skin surgery. review | dermatol pract concept. 2022;12(4):e2022193 3 ta b le 1 . e ru p ti ve n o n -m el an o m a sk in c an ce rs f o ll ow in g sk in s u rg er y: l it er at u re r ev ie w a n d o u r ca se s. s tu d y a n d y e a r p a ti e n ts fi rs t s k in l e si o n e ru p ti v e n m s c n . c a se a g e , s e x a re a in v o lv e d s u rg e ry p ro ce d u re p e rf o rm e d m e d ic a l tr e a tm e n t h is to p a th o lo g y fi n d in g s t im e o n se t a ft e r s u r g e ry (w e e k s) a re a in v o lv e d h is to p a th o lo g y fi n d in g s s u rg ic a l tr e a tm e n t m e d ic a l tr e a tm e n t r e cu rr e n ce n ei ls o n et a l, 1 9 8 8 [1 ] 1 5 9 , m d o rs u m o f h is r ig h t ri n g fi n ge r (u p p er li m b s) e x + s t sg n o n e sc c s 1 2 g d s sc c e x n o n e n o c la rk e t al ., 2 0 1 5 1 7 3 , f b l eg s (l o w er l im b ) e x + s t sg n o n e sc c s 4 e x s + g d s k a sp e x + s t sg a ci tr et in 2 5 m g/ d y es ju h ás z an d m ar m u r, 2 0 1 4 1 8 2 , f r s h in (l o w er l im b ) m m s + st sg 3 m o n th s o f to p ic al m u p ir o ci n + w ar m 2 % m il k c o m p re ss es fo r lo ss o f th e gr af t, w o u n d d eh is ce n ce , an d p er si st en t u lc er at io n k a 2 0 m m s si te k a m m s n o n e n o b an ga sh et a l, 2 0 0 9 5 1 8 1 , f l w ri st a n d h an d ( u p p er li m b ) m m s n o n e sc c 4 m m s si te sc c m m s n o n e n o 2 6 3 , m l h an d (u p p er l im b ) m m s n o n e sc c 8 m m s si te sc c m m s n o n e n o 3 5 4 , m l o cc ip it al r id ge ( h ea d ) e x n o n e sc c 7 e x s sc c w it h fe at u re s o f k a m m s n o n e n o 4 5 8 , m l ef t le g an d r e lb o w (u p p er a n d lo w er l im b ) m m s n o n e sc c ; sc c 6 m m s si te ; m m s si te sc c ; sc c m m s n o n e y es , y es 5 5 5 , f l h an d (u p p er l im b ) m m s + st sg n o n e sc c 7 2 m m s si te sc c m m s + st sg a ci tr et in 1 0 m g/ d ie y es t ab le 1 c o n ti n u es 4 review | dermatol pract concept. 2022;12(4):e2022193 s tu d y a n d y e a r p a ti e n ts fi rs t s k in l e si o n e ru p ti v e n m s c n . c a se a g e , s e x a re a in v o lv e d s u rg e ry p ro ce d u re p e rf o rm e d m e d ic a l tr e a tm e n t h is to p a th o lo g y fi n d in g s t im e o n se t a ft e r s u r g e ry (w e e k s) a re a in v o lv e d h is to p a th o lo g y fi n d in g s s u rg ic a l tr e a tm e n t m e d ic a l tr e a tm e n t r e cu rr e n ce h ad le y et a l, 2 0 0 9 3 1 6 7 , m f o re ar m (u p p er l im b ) m m s n o n e sc c 1 6 m m s si te k a e x n o n e y es 2 7 0 , f f o re ar m (u p p er l im b ) e x n o n e sc c 1 2 e x s k a m m s n o n e y es 3 8 8 , f b l eg s (l o w er l im b ) s + c o + e d n o n e k a 2 t re at m en t si te k a c o + e d n o n e y es h ai k e t al , 2 0 0 8 1 6 4 , m l ef t b ig t o e (l o w er l im b ) a + s t sg n o n e m m 6 g d s sc c e x n o n e n o g o ld b er g et a l, 2 0 0 4 6 1 7 2 , m l l eg a n d f in ge r (l o w er l im b ) m m s n o n e ss c s 6 m m s si te k a m m s n o n e y es 2 6 9 , m l f o re ar m . (u p p er l im b ) m m s n o n e sc c 4 m m s si te k a m m s n o n e n o 3 7 4 , f r l eg (l o w er l im b ) m m s is o tr et in o in 4 0 m g/ d f o r 3 0 d ay s sc c 3 m m s si te k a c o + e d is o tr et in o in 4 0 m g/ d y es 4 7 9 , m r f o re ar m (u p p er l im b ) m m s n o n e l m 4 m m s si te k a e x n o n e n o 5 7 1 , m r t h ig h (l o w er l im b ) m m s n o n e sb c c 2 m m s si te k a n o n e is o tr et in o in (4 0 m g/ d ) fo r 1 m o n th . n o 6 7 5 , m r f o re h ea d (h ea d ) c o + e d n o n e sc c 4 t re at m en t si te k a m m s is o tr et in o in (4 0 m g/ d ) fo r 1 m o n th . n o h u ss ai n et a l, 2 0 1 0 1 5 2 , m r h an d (u p p er l im b ) e x + s t sg n o n e sc c 8 g d s sc c e x + re co n st ru ct ed w it h a n is la n d ed v ey ad va n ce m en t fl ap n o n e n o p o n n u ve lu et a l, 2 0 1 1 2 1 5 8 , m l ef t p ar ie ta l sc al p ( h ea d ) e x + s t sg n o n e n o d u lo cy st ic b c c 2 g d s sc c e x n o n e n /a 2 8 8 , f le ft s h in (l o w er l im b ) e x + s t sg n o n e k a 5 g d s sc c e x + fl ap n o n e n o l ee e t al , 2 0 1 7 1 9 5 , f r s h in (l o w er l im b ) e x + s t sg n o n e k a 2 0 e x s + g d s k a c o + e d im iq u im o d 5 % c re am ap p li ca ti o n y es sa lt iv ig a n d m at ze n , 2 0 1 8 1 7 8 , f l k n ee (l o w er l im b ) e x + s t sg n o n e m m 9 6 0 st sg p ri m ar y ex ci si o n si te m ar jo li n u lc er e x n /a n /a k im ya ia sa d i et a l, 2 0 0 4 1 7 6 , m r h an d (u p p er l im b ) e x n o n e sc c 8 e x s k a e x n o n e n o n eg as e et a l, 2 0 1 6 1 7 8 , f n o se ( h ea d ) f t sg n o n e a k 3 st sg p ri m ar y ex ci si o n si te k a e x n o n e n /a m ar cu s an d b ra d y, 2 0 2 1 1 3 9 , f l t h ig h (l o w er l im b ) m m s + st sg n o n e sc c 1 2 g d s sc c m m s n o n e n /a v er ga ra et a l, 2 0 0 7 1 8 0 , f r l eg (l o w er l im b ) e x + s t sg n o n e k a 9 6 g d s k a e x n o n e y es l . k ea rn ey et a l, 2 0 1 5 1 4 8 , m r c h es t e x + s t sg n o n e m m 6 g d s sc c e x n o n e n /a m o rr it t an d k h an d w al a, 2 0 1 2 1 8 2 , f l l eg ( lo w er li m b ) e x + s t sg n o n e sc c s 1 1 7 e x s + g d s sc c s e x n o n e y es g am b ic h le r 2 0 2 1 2 1 4 9 f l eg ( lo w er li m b ) m m s + st sg n o n e sc c 3 m m s sc c e x n o n e y es 2 6 0 m b ac k o f th e h an d ( u p p er li m b ) m m s + st sg n o n e sc c 3 m m s sc c e x n o n e y es ta b le 1 . e ru p ti ve n o n -m el an o m a sk in c an ce rs f o ll ow in g sk in s u rg er y: l it er at u re r ev ie w a n d o u r ca se s. ( co n ti n u ed ) review | dermatol pract concept. 2022;12(4):e2022193 5 s tu d y a n d y e a r p a ti e n ts fi rs t s k in l e si o n e ru p ti v e n m s c n . c a se a g e , s e x a re a in v o lv e d s u rg e ry p ro ce d u re p e rf o rm e d m e d ic a l tr e a tm e n t h is to p a th o lo g y fi n d in g s t im e o n se t a ft e r s u r g e ry (w e e k s) a re a in v o lv e d h is to p a th o lo g y fi n d in g s s u rg ic a l tr e a tm e n t m e d ic a l tr e a tm e n t r e cu rr e n ce h ad le y et a l, 2 0 0 9 3 1 6 7 , m f o re ar m (u p p er l im b ) m m s n o n e sc c 1 6 m m s si te k a e x n o n e y es 2 7 0 , f f o re ar m (u p p er l im b ) e x n o n e sc c 1 2 e x s k a m m s n o n e y es 3 8 8 , f b l eg s (l o w er l im b ) s + c o + e d n o n e k a 2 t re at m en t si te k a c o + e d n o n e y es h ai k e t al , 2 0 0 8 1 6 4 , m l ef t b ig t o e (l o w er l im b ) a + s t sg n o n e m m 6 g d s sc c e x n o n e n o g o ld b er g et a l, 2 0 0 4 6 1 7 2 , m l l eg a n d f in ge r (l o w er l im b ) m m s n o n e ss c s 6 m m s si te k a m m s n o n e y es 2 6 9 , m l f o re ar m . (u p p er l im b ) m m s n o n e sc c 4 m m s si te k a m m s n o n e n o 3 7 4 , f r l eg (l o w er l im b ) m m s is o tr et in o in 4 0 m g/ d f o r 3 0 d ay s sc c 3 m m s si te k a c o + e d is o tr et in o in 4 0 m g/ d y es 4 7 9 , m r f o re ar m (u p p er l im b ) m m s n o n e l m 4 m m s si te k a e x n o n e n o 5 7 1 , m r t h ig h (l o w er l im b ) m m s n o n e sb c c 2 m m s si te k a n o n e is o tr et in o in (4 0 m g/ d ) fo r 1 m o n th . n o 6 7 5 , m r f o re h ea d (h ea d ) c o + e d n o n e sc c 4 t re at m en t si te k a m m s is o tr et in o in (4 0 m g/ d ) fo r 1 m o n th . n o h u ss ai n et a l, 2 0 1 0 1 5 2 , m r h an d (u p p er l im b ) e x + s t sg n o n e sc c 8 g d s sc c e x + re co n st ru ct ed w it h a n is la n d ed v ey ad va n ce m en t fl ap n o n e n o p o n n u ve lu et a l, 2 0 1 1 2 1 5 8 , m l ef t p ar ie ta l sc al p ( h ea d ) e x + s t sg n o n e n o d u lo cy st ic b c c 2 g d s sc c e x n o n e n /a 2 8 8 , f le ft s h in (l o w er l im b ) e x + s t sg n o n e k a 5 g d s sc c e x + fl ap n o n e n o l ee e t al , 2 0 1 7 1 9 5 , f r s h in (l o w er l im b ) e x + s t sg n o n e k a 2 0 e x s + g d s k a c o + e d im iq u im o d 5 % c re am ap p li ca ti o n y es sa lt iv ig a n d m at ze n , 2 0 1 8 1 7 8 , f l k n ee (l o w er l im b ) e x + s t sg n o n e m m 9 6 0 st sg p ri m ar y ex ci si o n si te m ar jo li n u lc er e x n /a n /a k im ya ia sa d i et a l, 2 0 0 4 1 7 6 , m r h an d (u p p er l im b ) e x n o n e sc c 8 e x s k a e x n o n e n o n eg as e et a l, 2 0 1 6 1 7 8 , f n o se ( h ea d ) f t sg n o n e a k 3 st sg p ri m ar y ex ci si o n si te k a e x n o n e n /a m ar cu s an d b ra d y, 2 0 2 1 1 3 9 , f l t h ig h (l o w er l im b ) m m s + st sg n o n e sc c 1 2 g d s sc c m m s n o n e n /a v er ga ra et a l, 2 0 0 7 1 8 0 , f r l eg (l o w er l im b ) e x + s t sg n o n e k a 9 6 g d s k a e x n o n e y es l . k ea rn ey et a l, 2 0 1 5 1 4 8 , m r c h es t e x + s t sg n o n e m m 6 g d s sc c e x n o n e n /a m o rr it t an d k h an d w al a, 2 0 1 2 1 8 2 , f l l eg ( lo w er li m b ) e x + s t sg n o n e sc c s 1 1 7 e x s + g d s sc c s e x n o n e y es g am b ic h le r 2 0 2 1 2 1 4 9 f l eg ( lo w er li m b ) m m s + st sg n o n e sc c 3 m m s sc c e x n o n e y es 2 6 0 m b ac k o f th e h an d ( u p p er li m b ) m m s + st sg n o n e sc c 3 m m s sc c e x n o n e y es t ab le 1 c o n ti n u es 6 review | dermatol pract concept. 2022;12(4):e2022193 s tu d y a n d y e a r p a ti e n ts fi rs t s k in l e si o n e ru p ti v e n m s c n . c a se a g e , s e x a re a in v o lv e d s u rg e ry p ro ce d u re p e rf o rm e d m e d ic a l tr e a tm e n t h is to p a th o lo g y fi n d in g s t im e o n se t a ft e r s u r g e ry (w e e k s) a re a in v o lv e d h is to p a th o lo g y fi n d in g s s u rg ic a l tr e a tm e n t m e d ic a l tr e a tm e n t r e cu rr e n ce q u e et a l 2 0 1 9 1 6 2 m r a n d l le gs ( l o w er li m b s) e x n o n e 3 s c c n o t sp ec ifi ed e x s si te s su sp ec te d er u p ti ve sq u am o u s at yp ia n o n e in tr al es io n al 5 -fl u o ro u ra ci l p lu s ac it re ti n n o c h es sa e t al , 2 0 2 1 2 1 6 5 ,m r o cc ip it al ar ea o f th e sc al p ( h ea d ) e x + s t sg n o n e sc c 4 st sg p ri m ar y ex ci si o n si te sc c e x a ci tr et in 2 5 m g/ d ie y es 2 8 0 ,f r l eg (l o w er l im b ) e x + s t sg n o n e sc c 6 st sg p ri m ar y ex ci si o n si te sc c e x ac it re ti n 2 5 m g/ d ai ly a n d in tr al es io n al m et h o tr ex at e 1 0 m g/ w ee k ly n o a k = a ct in ic k er at o si s; a = a m p u ta ti o n ; b = b il at er al ; c e m p = c u ta n eo u s ex tr am ed u ll ar y p la sm ac yt o m as ; c o = c o u re tt ag e; e d = e le ct ro d es ic ca ti o n ; e x = e x ci si o n ; e x s = e x ci si o n s it e; f = f em al e; f t sg = f u ll -t h ic k n es s sk in g ra ft ; g d s = g ra ft d o n o r si te ; ; k a = k er at o ac an th o m a; k a sp = k er at o ac an th o m at o u s at yp ic al s q u am o u s p ro li fe ra ti o n ; l = l ef t; n /a = d at a n o t av ai la b le l m = l en ti go m al ig n a; m = m al e; m m = m al ig n an t m el an o m a; m m s = m o h s m ic ro gr ap h ic s u rg er y; m u = m ar jo li n u lc er ; n = n u m b er o f p at ie n ts i n vo lv ed ; sc c = s q u am o u s c el l c ar ci n o m a; s g = s k in g ra ft ; sg s = s k in g ra ft s it e; s h = s h av e; s t sg = s p li tt h ic k n es s sk in g ra ft . r = r ig h t; s b c c = s u p er fi ci al b as al c el l ca rc in o m a; ta b le 1 . e ru p ti ve n o n -m el an o m a sk in c an ce rs f o ll ow in g sk in s u rg er y: l it er at u re r ev ie w a n d o u r ca se s. ( co n ti n u ed ) review | dermatol pract concept. 2022;12(4):e2022193 7 table 2. clinical findings of primary tumor in 34 patients diagnosed with eruptive squamous cell carcinomas/squamous atypia following skin surgery. findings number of primary skin cancers excised 37 patients with one primary skin cancer 32 (94.12%) patients with two primary skin cancer 2 (5.88%) sex male 18 (52.94%) female 16 (47.06%) mean age ± sd 68.94± 13.06 (39-95) cutaneous site involved head and neck 5 (13.51%) upper limbs 12 (32.43%) lower limbs 19 (51.35%) chest 1 (2.70%) histopathology squamous cell carcinoma 25 (67.56%) keratoacanthoma 5 (13.51%) melanoma 3 (8.12%) basal cell carcinoma 2 (5.41%) actinic keratosis 1 (2.70%) lentigo maligna 1 (2.70%) treatment performed excision 6 (16.22%) excision plus split-thickness skin graft 12 (32.43%) mohs micrographic surgery 10 (27.03%) mohs micrographic surgery plus split-thickness skin graft 5 (13.51%) courettage plus electrodesiccation 2 (5.41%) amputation plus split-thickness skin graft 1 (2.70%) excision plus full-thickness skin graft 1 (2.70%) table 3. main features of eruptive squamous cell carcinomas/squamous atypia following skin surgery. features number of primary skin cancers excised 37 patients with one primary skin cancer 32 (94.12%) patients with two primary skin cancers 2 (5.88%) time onset after surgery median weeks 6 (2-960) cutaneous site involved by eruptive squamous cell carcinomas/squamous atypia cutaneous site affected by primary tumor treated with mohs micrographic surgery 14 (37.84%) cutaneous site affected by primary tumor treated with simple excision. 6 (16.22%) cutaneous site affected by primary tumor treated with split-thickness skin graft 4 (10.81%) cutaneous site affected by primary tumor treated with courettage plus electrodesiccation 2 (5.41%) graft donor site 8 (21.61%) cutaneous site affected by primary tumor treated with excision and graft donor site 3 (8.11%) cutaneous site affected by eruptive squamous cell carcinomas/squamous atypia head and neck 3 (8.11%) upper limbs 10 (27,03%) table 3 continues 8 review | dermatol pract concept. 2022;12(4):e2022193 (70.27%), the graft donor site (gds) or both. all primary tumors in our series were completely excised, with free margins on histological examination. in our sample, cutaneous stsg was harvested from the lateral thigh in almost all patients and was therefore considered the only cutaneous donor site affected. escc were histologically represented by cscc and keratoacanthomas (ka) in 91.9% of cases while in 3 patients was not performed histopathological examination. the same histological diagnosis between the primary skin cancer and the escc was found in 50% of cases and eruptive kas or csccs also appeared after excision of lentigo maligna or melanoma. the surgical treatment of escc is extremely varied ( table 3). however, simple fusiform excision and mms were the most used surgical techniques, comprising 62.16% of cases. medical therapy was associated with surgery in 7/34 cases while two patients were treated with isotretinoin 40 mg/die without surgery and 1 patient was treated with intralesional 5-fluorouracil plus acitretin 20 mg daily (table 3). features lower limbs 11 (37.84%) donor site affected by eruptive squamous cell carcinomas/squamous atypia lower limbs 13 (35.14%) histopathology of eruptive squamous cell carcinomas/squamous atypia squamous cell carcinoma 18 (48.65%) keratoacanthoma 14 (37.84%) marjolin ulcer 1 (2.70%) keratoacanthomatous atypical squamous proliferation 1 (2.70%) not performed histopathological examination 3 (8.11%) concordance between histological diagnosis of primary tumor and and eruptive squamous cell carcinomas/squamous atypia yes 17 (50.00%) no 17 (50.00%) treatment performed surgery without medical treatment excision 13 (38.24%) excision plus flap 2 (5.88%) mohs micrographic surgery 10 (29.42%) courettage plus electrodesiccation 1 (2.94%) surgery associated with medical treatment excision plus acitretin 25 mg/die 1 (2.94%) excision plus acitretin 25 mg/daily and intralesional methotrexate 10 mg/weekly 1 (2.94%) excision plus split-thickness skin sraft and acitretin 25 mg/die 1 (2.94%) mohs micrographic surgery plus split-thickness skin graft and acitretin 25 mg/die 1 (2.94%) mohs micrographic surgery plus isotretinoin 40 mg/die 1 (2.94%) courettage plus electrodesiccation plus imiquimod cream application 1 (2.94%) courettage plus electrodesiccation isotretinoin 40 mg/die 1 (2.94%) medical treatment without surgery isotretinoin 40 mg/die without surgery 1 (2.94%) intralesional 5-fluorouracil plus acitretin 1 (2.94%) recurrences yes 15 (40.54%) no 17 (45.95%) not available 5 (13.51%) table 3. main features of eruptive squamous cell carcinomas/squamous atypia following skin surgery. (continued) review | dermatol pract concept. 2022;12(4):e2022193 9 of note, the paper from que et al describe 30 cases of escc, but only one case is clearly and without doubts associated to a previous skin surgery and was added to our review [19]. the treatment was effective without recurrences in 17/37 cases; these patients were treated with surgery alone in 13 cases, combined surgical and medical treatment in 2 cases and with medical therapy in two cases. isotretinoin 40 mg/ die resulted effective alone and in combination with mohs surgery [7]. surgery combined with acitretin (25 mg/daily) plus intralesional methotrexate 10 mg/weekly was administered to the first our patient, favoring a complete resolution without recurrences (figure 1). recurrences of escc were reported in 15/37 cases (10 treated with surgery alone and 5 treated with combined medical and surgical therapy). all 15 cases with recurrences were treated with a combination of surgery and medical therapy. patients showed a complete resolution of escc recurrences at follow-up in 6/15 cases (40%). the following therapies proved effective on recurrences: 1 to 2 ml in intralesional administration of 50 mg/ml 5-fluorouracil (fu)  [5,19]; acitretin (25 mg/day); combined intralesional 5-fu and methotrexate to reduce the toxicity of any single agent [5]; isotretinoin 40mg/die [7]; oral acitretin (20 to 25 mg/day) [10,15]; lastly our second patient was treated with surgery plus 25 mg/daily acitretin (figure 2). in 5/34 cases data on recurrences were not available in the papers (table 1). finally, 2/34 patients died, due to lung cancer in one case and cssc metastases in 1 of our patients, who was also affected by chronic lymphatic leukemia [5]. conclusions the pathogenesis of escc is not clarified and is currently a matter of debate [18-23]. local appearance of escc could be referred to residual cancer tissue following the excision of the primary tumor [21,22]. however, eruptive nmsc in skin graft donor sites have no local relation to the original tumor site, even if tumor cells could theoretically spread by direct contact (if the same needle was used to infiltrate the tumor and donor site) or systemically (via the blood or lymphatic vessels). moreover, escc different from primary tumor excised, such as kas after lentigo maligna or melanoma, have been reported [6,7,11,16]. the patient immune system must also be taken into account. immunodeficiency induced by drugs or other diseases, such as hematologic disorders, may explain the propensity for the development of cancer, inducing a generalized ‘field of cancerization’ that can induce a koebner phenomenon and the development of new cutaneous cancers in the site of surgery [17,21-23]. the presence of a chronic lymphatic leukemia may have been a predisposing factor in one of our patients for the figure 1. (a) six weeks after local excision and repair with an stsg, 6 x 4.5 cm in diameter, of large squamous cell carcinomas of the right leg, three keratotic nodules appeared, two closes to the surgical wound and one a few centimeters far from it. (b) histopathological examination eruptive keratotic nodules: proliferation of atypical keratinocytes extends into the reticular dermis. the nuclei are large, hyperchromatic, and pleomorphic, and the cytoplasm is eosinophilic (10 x h&e). (c) complete healing after surgery and medical therapy with oral acitretin 25 mg/daily and intralesional methotrexate 10 mg/ weekly after 8 months of treatment. no recurrences were observed at 2-year follow-up and regional lymph nodes were free from metastases. development of escc soon after surgery, as well as a negative prognostic factor for the development of distant metastases, leading to exitus. interestingly, the only patient that developed distant metastases after the development of escc had the primary cssc located on the scalp, while none of the cases of escc reported in the literature localized both on upper or lower extremities had a poor prognosis. this distinction can be important and to confirm this statement in the paper of que et al reporting 30 cases of eruptive squamous atypia, without the specification if the onset was spontaneous, after surgery or other treatments o traumas, all the 10 review | dermatol pract concept. 2022;12(4):e2022193 escc after skin surgery. first of all, the extremities (lower and upper limbs) represent the cutaneous site with the highest risk, representing 82.35% of the cases in the literature. the second point concerns the time of onset of escc, which is wide, ranging from 2 to 960 weeks. the median time to onset of escc is approximately 6 weeks, and in 28/34 (82.35%) of cases reported in the literature they appeared within 16 weeks from the primary cutaneous surgery. the third point is that primary cscc were completely excised with free margins on histologic examination in all cases of the literature, and therefore the escc reported were not considered recurrences. this concept has important legal implications. the fourth point is that any surgical technique, including classic fusiform excision, excision plus stsg, mms and subsequent reconstruction with or without stsg, involves a risk to promote escc, which can surprisingly affect both the area affected by the primary tumor and the graft donor site. patients had a localization on upper or lower extremities or both and none developed metastases [19]. according to nwabudike lc et al, escc could also be a perfect example of locus minoris resistentae as described by ruocco [20,24]. an immunocompromised district can be defined as a regional destabilization of the neuro-immuno-cutaneous system, and surgical procedures, as well as the scars resulting from them, impair both lymph circulation and neuro-immune crosstalk in the traumatized area [24,25]. gambichler and colleagues demonstrated in two patients affected by “koebnerized” cscc that the wound healing processes can induce a proliferative stimulus and growth factors release, which could be able to promote the growth of pre-neoplastic keratinocytes and cancer formation, on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation [18]. the results of this review highlight five red flags that clinicians should consider in the diagnosis and management of figure 2. (a) split thickness skin graft (stsg) on the scalp, 5 x 3.5 cm in diameter, after simple excision of ulcerated cutaneous squamous cell carcinomas (scc) of the right occipital area of the scalp. (b) thirty days after the removal of the stitches, on the site of the stsg, an erythematous firm papule appeared. (c) the papule quickly enlarged to form a nodule and then multiple keratoacanthoma-like lesions appeared. (d) initial good response to surgery and acitretin 25 mg/die therapy, with only 1 residual nodule in the occipital area, which was surgically removed. three months after the last surgery treatment, scc metastases to the latero-cervical lymph nodes were detected both clinically and with ultrasound examination. the patient died 6 months later. review | dermatol pract concept. 2022;12(4):e2022193 11 skin cancer excision. j am acad dermatol. 2004;50(5):753-758. doi: 10.1016/j.jaad.2003.11.065. pmid: 15097960. 8. hussain a, ekwobi c, watson s. metastatic implantation squamous cell carcinoma in a split-thickness skin graft donor site. j plast reconstr aesthet surg. 2011;64(5):690-692. doi: 10.1016/j.bjps.2010.06.004. pmid: 20584636. 9. ponnuvelu g, ng mf, connolly cm, hogg fj, naasan a. inflammation to skin malignancy, time to rethink the link: scc in skin graft donor sites. surgeon. 2011;9(3):168-169. doi: 10.1016/j. surge.2010.08.006. 10. lee s, coutts i, ryan a, stavrakoglou a. keratoacanthoma formation after skin grafting: a brief report and pathophysiological hypothesis. australas j dermatol. 2017;58(3):e117-e119. doi: 10.1111/ajd.12501. pmid: 27273800. 11. saltvig i, matzen sh. marjolin’s ulcer in a 20 years old split thickness skin graft on the knee-a case report. int j surg case rep. 2018;42:102-103. doi: 10.1016/j.ijscr.2017.11.059. pmid: 29241101. pmcid: pmc5730427. 12. kimyai-asadi a, shaffer c, levine vj, jih mh. keratoacanthoma arising from an excisional surgery scar. j drugs dermatol. 2004;3(2):193-194. pmid: 15098978. 13. nagase k, suzuki y, misago n, narisawa y. acute development of keratoacanthoma at a full-thickness skin graft donor site shortly after surgery. j dermatol. 2016;43(10):1232-1233. doi: 10.1111/1346-8138.13368. pmid: 27027399. 14. marous m, brady k. cutaneous squamous cell carcinoma arising in a split thickness skin graft donor site in a patient with systemic lupus erythematosus. dermatol surg. 2021;47(8):1106-1107. doi: 10.1097/dss.0000000000002955. pmid: 33731573. 15. vergara a, isarría mj, domínguez jd, gamo r, rodríguez peralto jl, guerra a. multiple and relapsing keratoacanthomas developing at the edge of the skin grafts site after surgery and after radiotherapy. dermatol surg. 2007;33(8):994-996. doi: 10.1111/j.1524-4725.2007.33207.x. 16. l. kearney, r.t. dolan, n.a. parfrey, e.j. kelly. squamous cell carcinoma arising in a skin graft donor site following melanoma extirpation at a distant site: a case report and review of the literature. jpras open. 2015;3:35-38. doi: 10.1016/j. jpra.2015.02.002 17. morritt, d.g., khandwala, a.r. the development of squamous cell carcinomas in split-thickness skin graft donor sites.  eur j plast surg. 32013;6:377–380. doi:10.1007/s00238-012-0786-z. 18. gambichler t, rüddel i, hessam s, bechara fg, stockfleth e, schmitz l. altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery. j eur acad dermatol venereol. 2018;32(9):1485-1491. doi: 10.1111/ jdv.14887. pmid: 29478287. 19. que skt, compton la, schmults cd. eruptive squamous atypia (also known as eruptive keratoacanthoma): definition of the disease entity and successful management via intralesional 5-fluorouracil. j am acad dermatol. 2019;81:111-122. doi: 10.1016/j.jaad.2018.10.014. pmid: 31103317. 20. nwabudike lc, tatu al. reply to gambichler t et al.: altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery. j eur acad dermatol venereol. 2019;33(1):e3-e4. doi: 10.1111/jdv.15084. pmid: 29797668. 21. slaughter dp, southwick hw, smejkal w. “field cancerisation” in oral stratified epithelium. clinical implications large longitudinal surgery studies are necessary to evaluate the risk assessment of surgical technique and escc. the fifth point is that the treatment of escc includes medical treatments, surgery or combined surgical and medical treatments. que et al reported a 67% resolution rate using intralesional 5-fluorouracil for eruptive squamous atypia of the upper and lower limbs. however, 5-fluorouracil is chemotherapeutic agent that can be used only in hospital, it is off-label and much more difficult to obtain in italy than intralesional methotrexate or oral acitretin. moreover, que et al have specified that it can be used only for lesions smaller than 15 mm, while over 15 mm of diameter, surgery is still considered the best choice. according to our review, escc recurrences are a medical challenge and have been treated combining surgical and medical treatment, with complete resolution in about one third of patients [5,7,10,15]. when using a nonsurgical treatment modality for escc, the concern of missing an aggressive cssc is an important issue, that must be kept in mind, especially in sites different from the upper and lower extremities. in conclusion, even though the pathogenesis remains unclear, this review highlights 5 red flags which could help support clinicians in the diagnosis and management of escc after skin surgery. references 1. neilson d, emerson dj, dunn l. squamous cell carcinoma of skin developing in a skin graft donor site. br j plast surg. 1988;41(4):417-419. doi: 10.1016/0007-1226(88)90086-0. pmid: 3293679. 2. clark ma, guitart j, gerami p, marks br, amin s, yoo ss. eruptive keratoacanthomatous atypical squamous proliferations (kasps) arising in skin graft sites. jaad case rep. 2015;1(5):274-276. doi: 10.1016/j.jdcr.2015.06.009. pmid: 27051751. pmcid: pmc4809229. 3. juhász mlw, marmur es. a multiple recurrent keratoacanthoma of the lower leg after repeated wide-excision and mohs micrographic surgery. dermatol surg. 2018;44(7):1028-1030. doi: 10.1097/dss.0000000000001422. pmid: 29953419. 4. bangash sj, green wh, dolson dj, cognetta ab jr. eruptive postoperative squamous cell carcinomas exhibiting a pathergy-like reaction around surgical wound sites. j am acad dermatol. 2009;61(5):892-897. doi: 10.1016/j.jaad.2009.01.037. pmid: 19766351. 5. hadley jc, tristani-firouzi p, florell sf, bowen gm, hadley ml. case series of multiple recurrent reactive keratoacanthomas developing at surgical margins. dermatol surg. 2009;35(12): 2019-2024. doi: 10.1111/j.1524-4725.2009.01327.x. pmid: 19758354. 6. haik j, georgiou i, farber n, volkov a, winkler e. squamous cell carcinoma arising in a split-thickness skin graft donor site. burns. 2008;34(6):891-893. doi:10.1016/j.burns.2007.06.006. pmid: 17869430. 7. goldberg lh, silapunt s, beyrau kk, peterson sr, friedman pm, alam m. keratoacanthoma as a postoperative complication of 12 review | dermatol pract concept. 2022;12(4):e2022193 of multicentric origin. cancer. 1953;6(5):963–968. doi: 10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q. pmid: 13094644. 22. höckel m, dornhöfer n. the hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection. cancer res. 2005;65(8):2997-3002. doi: 10.1158/0008-5472. can-04-3868. pmid: 15833823. 23. vakharia pp, nardone b, schlosser bj, lee d, serrano l, west dp. chronic exposure to tetracyclines and subsequent diagnosis for non-melanoma skin cancer in a large midwestern u.s. patient population. j eur acad dermatol venereol. 2017;31(12):e534-e536. doi: 10.1111/jdv.14399. pmid: 28609551. 24. ruocco v, brunetti g, puca rv, ruocco e. the immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. j eur acad dermatol venereol. 2009;23(12):1364-1373. doi: 10.1111/j.14683083.2009.03345.x. pmid: 19548975. 25. baroni a, buommino e, piccolo v, et al. alterations of skin innate immunity in lymphedematous limbs: correlations with opportunistic diseases. clin dermatol. 2014;32(5):592-598. doi: 10.1016/j.clindermatol.2014.04.006. pmid: 25160100. dermatology: practical and conceptual review | dermatol pract concept 2017;7(4):8 31 dermatology practical & conceptual www.derm101.com introduction dermatologists frequently recommend dietary modification to patients with rosacea, with recommendations to avoid “trigger” foods and beverages. anecdotally, many patients describe rosacea flares with spicy foods or with hot drinks. in this review, we present the possible mechanisms linking these foods and others to rosacea exacerbations. we also highlight the gut-skin connection as it pertains to rosacea, which presents an intriguing avenue for further research. background rosacea is a chronic inflammatory skin condition that is estimated to affect up to 15% of certain populations, with an increased prevalence in fair-skinned individuals of european descent [1]. it is characterized by recurrent episodes of flushing, along with other skin findings, concentrated to the skin of the central face. in the earlier stages of rosacea, patients may only experience intermittent flushing. in later stages, they may develop persistent erythema and telangiectasias, and/or recurrent papules and pustules. rosacea is divided into four main subtypes based on these clinical characteristics. these subtypes include erythematotelangiectatic, papulopustular, phymatous, and ocular [2]. patients may present with symptoms from multiple subtypes concurrently, or with isolated findings that do not fit a specific subtype. these symptoms often fluctuate between intervals of exacerbation and disease-free remission. for patients not responsive to topical medications, oral anti-inflammatory antibiotics, specifically tetracyclines, are diet and rosacea: the role of dietary change in the management of rosacea emma weiss1, rajani katta1 1 baylor college of medicine, houston, tx, usa key words: rosacea, diet, gut-skin connection citation: weiss e, katta r. diet and rosacea: the role of dietary change in the management of rosacea. dermatol pract concept 2017;7(4):31-37. doi: https://doi.org/10.5826/dpc.0704a08 received: june 7, 2017; accepted: august 21, 2017; published: october 31, 2017 copyright: ©2017 weiss et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajani katta, md, katta dermatology, 6800 west loop south, suite 180, bellaire, tx, 77401, usa. email: info@ kattamd.com dietary change may play a role in the therapy of rosacea. certain foods and beverages may act as “triggers” for rosacea exacerbations. these may be divided into heat-related, alcohol-related, capsaicinrelated, and cinnamaldehyde-related. one potential pathogenic mechanism may be via the activation of transient receptor potential cation channels, which result in neurogenic vasodilatation. further research is needed on the role of the gut skin connection in rosacea. epidemiologic studies suggest that patients with rosacea have a higher prevalence of gastrointestinal disease, and one study reported improvement in rosacea following successful treatment of small intestinal bacterial overgrowth. while further research is required in this area, patients may be advised on measures to support a healthy gut microbiome, including the consumption of a fiber-rich (prebiotic) diet. abstract 32 review | dermatol pract concept 2017;7(4):8 increases klk5 expression and activity [6]. however, this is not considered the only likely pathogen, as one study found that when d. folliculorum colonization was decreased using topical antibiotics, there was no corresponding improvement in symptoms [7]. as antibiotics have been used in the treatment of rosacea, researchers have theorized that bacteria may be a causative factor. bacillus oleronius, a nonmotile, gram-negative bacterium isolated from demodex mites, has been shown to induce antigenic proteins in patients with specific rosacea subtypes [8,9]. when exposed to b. oleronius, neutrophils have increased production of matrix metalloproteinase (mmp)-9, tumor necrosis factor, and il-8, stimulating a robust inflammatory response even in people unaffected by rosacea [2,8,10]. other studies have looked at the role of staphylococcus epidermidis, a commensal bacterium. in normal skin, s. epidermidis produces amps that help prevent disease caused by pathogenic bacteria. when placed on skin with rosacea, however, studies have demonstrated that s. epidermidis generates specific virulence factors resulting in tlr2 activation and the cathelicidin-klk5 inflammatory cascade [6]. triggers anecdotally, there are many triggers that may exacerbate rosacea symptoms. these include hot temperatures, sun exposure, spicy foods, alcohol consumption, exercise, and feelings of anger or embarrassment. some of these triggers, such as hot temperatures, act directly to trigger vasodilatation. other factors act via different mechanisms, with an ultimate increase in skin inflammation. sun exposure is one of the most commonly cited triggers for flushing and worsening of rosacea symptoms. exacerbations from ultraviolet (uv) radiation are thought to be the result of three processes. first, vitamin d induces keratinocyte cathelicidin overexpression, which then initiates a pro-inflammatory cascade. secondly, uvb light increases skin vasculature proliferation via fibroblast growth factor 2 (fgf2) and vascular endothelial growth factor 2 (vegf2) [11]. lastly, skin exposed to excess uv radiation has more reactive oxygen species (ros), further propagating the klk5cathelicidin inflammatory cascade [10]. these proposed mechanisms may help guide dietary recommendations to ameliorate these changes. dietary triggers are also frequently cited by patients, although there is a lack of research in this area. in one survey by the national rosacea society of over 400 patients, 78% had altered their diet due to rosacea. of this group, 95% reported a subsequent reduction in flares [12]. the triggers reported in this group may be broken down into heat-related, alcohol-related, capsaicin-related, and cinnamaldehyde-related. specifically, hot beverages acted as the mainstay of treatment. however, long-term oral antibiotic therapy is not ideal due to potential side effects as well as the potential for bacterial resistance. therefore, the role of modifiable lifestyle factors, including diet, has received renewed interest. it is well known anecdotally that certain foods may act as rosacea triggers. research has even suggested certain mechanisms whereby other foods may be helpful. as the understanding of the pathogenesis of rosacea continues to evolve, dietary modifications may become an essential component of rosacea therapy. pathogenesis the exact pathogenesis of rosacea is unknown. given the higher incidence in persons of north european descent, an underlying genetic etiology is hypothesized, although a specific causative gene has not yet been found. at this time, rosacea is thought to result from a combination of immune system dysregulation, abnormal neurological and vascular signaling, and dysbiosis of microorganisms ultimately leading to skin sensitivity and inflammation. the innate immune system is disrupted in patients with rosacea. this leads to an abnormal inflammatory cytokine release and an anti-microbial peptide (amp) response. when compared to normal skin, skin affected with rosacea has significantly more cathelicidin expression [3]. cathelicidin, an amp expressed by leukocytes and epithelial cells, is an important bacterial defense molecule. cathelicidin is cleaved into its active form, ll-37, by the serine protease kallikrein 5 (klk5) [4]. in patients with rosacea, both the ll-37 and klk5 molecules are different from those in normal skin. these differences cause aberrant downstream effects, including leukocyte chemotaxis, vasodilatation, angiogenesis, and extracellular matrix deposition. abnormal neurological signaling also plays a role in rosacea pathogenesis. heat and other factors, including dietary factors, stimulate transient receptor potential cation channels [5]. the stimulation of these channels acts to initiate pro-inflammatory cascades. trp receptors are expressed by sensory nerves as well as by keratinocytes. they play a role in vasoregulation, pain perception, and inflammation, and are upregulated in patients with rosacea [2]. in addition, microorganisms are thought to be etiopathogens in rosacea, although their role has yet to be clearly defined. a number of studies have documented differences in the skin microbial composition of rosacea patients as compared to those without. specifically, rosacea patients have higher concentrations of demodex folliculorum, a saprophytic mite that is normally found in sebaceous glands. it is hypothesized that the cell-membrane components of demodex mites activate toll-like receptor 2 (tlr2), which review | dermatol pract concept 2017;7(4):8 33 the association between inflammatory bowel disease (ibd) and rosacea is another topic of interest. a taiwanese nationwide cohort study of over 89,000 patients with rosacea found an independent association with ibd incidence, as compared to matched controls [31]. this association has been replicated by egeberg et al.’s danish study and li et al.’s prospective study in american women [30,32]. moreover, both ibd and rosacea share possible genetic overlap on the histocompatibility complex class ii gene hla drb1*03:01 [33,34]. from a clinical standpoint, rosacea patients reporting gastrointestinal (gi) symptoms warrant referral to a specialist for further evaluation. both h. pylori and sibo can be diagnosed with non-invasive laboratory tests including urine, fecal and breath tests. specifically, sibo can be detected using a lactulose and glucose h2/ch4 breath test [27,35,36], although reports indicate a wide range of sensitivity and specificity [37]. similarly, h. pylori can be diagnosed with noninvasive urea breath tests, stool antigen test, and serum/urine antibody tests [38]. the urea breath test, in particular, has a high reported sensitivity and specificity [39]. while studies on gi interventions as therapies for rosacea are limited, given the evidence for a gut-skin connection, such interventions provide a promising avenue for further research. these findings also suggest that dietary measures to decrease the risk of gi comorbidities may become standard recommendations in the future. the gi system as a therapeutic target the association between gi disease and rosacea is intriguing, as it suggests avenues for therapeutic intervention. in one study, researchers found that patients with rosacea were 13 times more likely to have sibo. they theorized that circulating cytokines, particularly tnf-α, may have played a role in the increased prevalence of rosacea. treatment of the sibo with antibiotics in 40 patients led to remission of rosacea in all cases. even more remarkable was the finding that the remission persisted in the majority at the three-year follow-up [40]. in addition, sibo has been linked to decreased gut motility. in one case report, a reduction of gut transit time via a high-fiber intervention resulted in improvement of rosacea [41], suggesting another promising area of investigation. prebiotics, probiotics, and the role of the microbiome given the evidence for an increased risk of gi disease in rosacea, further research into the role of the microbiome in rosacea is warranted. the role of the gut microbiome is an area of research of multiple inflammatory skin diseases. synbiotics are a combination of prebiotics and probiotics, substances a trigger, including hot coffee (33% described it as a trigger) and hot tea (30%). alcohol was another frequent trigger, including wine (52%) and hard liquor (42%). capsaicin is found in certain spices and peppers. respondents frequently reported spices as a trigger (75%), as well as hot sauce (54%), cayenne pepper (47%), and red pepper (37%). finally, cinnamaldehyde is found in several seemingly unrelated foods, including tomatoes, citrus, cinnamon, and chocolate [13]. in this survey, cinnamaldehyde-containing foods were also described as frequent triggers, including tomatoes (30%), chocolate (23%), and citrus (22%). as discussed in the preceding section, transient receptor potential (trp) channels are one possible pathogenic mechanism in rosacea. various stimuli can activate trp channels and cause increased skin blood flow via neurogenic vasodilatation leading to symptoms of flushing and burning [14]. sulk et al. found that several of the vanilloid channels (trpv1-6) are active in patients with rosacea [5]. located in keratinocytes, neuronal, endothelial, and immune cells [15], vanilloid receptors are activated by increased temperatures and capsaicin [16], which results in vasodilation and inflammationinduced hyperalgesia [14,17]. similarly, trpa1 is an ankyrin receptor located primarily in sensory neurons. activated by mustard oil and cinnamaldehyde, trpa1 regulates vasodilation and may be responsible for flushing episodes [18,19]. the gut-skin connection increased risk of gi disease in rosacea patients research indicates the possible role of a gut-skin connection in rosacea. in a population-based cohort study of close to 50,000 danish patients with rosacea, the prevalence of celiac disease, crohn’s disease, ulcerative colitis, helicobacter pylori infection (hpi), small intestinal bacterial overgrowth (sibo), and irritable bowel syndrome were all higher among patients with rosacea as compared with control subjects [20]. others have looked at this connection as well, with conflicting results noted in different populations and for different conditions. in the case of hpi, several studies have reported a higher frequency in patients with rosacea [21-25]. h. pylori are gram-negative bacteria that may cause chronic gastritis, gastric and duodenal ulcers, and gastric adenocarcinoma. numerous studies have indicated improvement of rosacea symptoms following h. pylori eradication [2,23,26-29]. however, the pathogenic link is difficult to establish, as antibiotics are helpful in the treatment of each disease [2,29]. in the case of sibo, two separate studies found an increased association of sibo in patients with rosacea, although a prospective study by gravina et al. did not confirm these results [23,27-30]. 34 review | dermatol pract concept 2017;7(4):8 dietary measures to promote a healthy gut microbiome prebiotics and dietary fiber recommendations to promote a healthy gut microbiome include the consumption of a fiber-rich diet. many dietary plant fibers act as prebiotics. prebiotics have been defined as non-digestible food ingredients that selectively stimulate the growth and/or activity of beneficial gi microbes [50]. research indicates that consuming a wide variety of dietary fibers, in sufficient quantity, will encourage the growth of a diverse and a healthy gut microbiome [46,51]. studies indicate that dietary effects on the microbiome may occur rapidly [43]. a lack of dietary fiber has been linked to deleterious effects on the gut flora and the gut itself. in one study, mice fed a diet lacking in fiber experienced a proliferation of pathogenic bacteria. these bacteria then began to digest the protective gut mucus layer [52]. in contrast, a diet rich in plant fibers supports the growth of beneficial microbes. these beneficial microbes have been shown to support gut health and skin health in multiple ways. probiotics the growth of beneficial microbes in the gi tract may be encouraged by diet. such microbes may also be consumed in the form of probiotics. the food and agriculture organization of the united nations (fao) and world health organization (who) define probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [53]. probiotic foods and supplements are worth further study, although at this time clinical trials in rosacea are lacking. probiotic foods include fermented foods in which live active microbial communities are a key component. this includes such foods as yogurt, kefir, miso, kimchi, and sauerkraut. a number of retail probiotic food products have been developed in which live microbes are added to food products, although studies suggest that many contain a lower number and diversity of microbes [54]. a number of probiotic supplements are sold as well, with marked differences in variety and type of microbes, as well as dosages. further research is necessary to determine optimal dosages and strains of microbes, as well as to determine viability of ingested microbes. despite some promising results in other inflammatory skin diseases, clinical trials in rosacea are lacking. however, research has suggested potential mechanisms whereby probiotics may be helpful in rosacea therapy. first, they shift the composition of gut bacteria and help to counter pathogenic bacteria. an imbalance of gut microbiota has been linked to ibd, as well as other chronic diseases [55]. studies have demonstrated anti-inflammatory effects, as in the alleviation of t-cell mediated skin inflammation in mice that support a healthy gut microbiome. in a meta-analysis of published randomized controlled trials (rcts ) in atopic dermatitis (ad), it was found that the use of synbiotics for at least eight weeks had a significant effect on a measure of ad severity [42]. research is underway into the use of synbiotics in other inflammatory skin diseases. the microbiome there has been much research into the gut microbial community, known as the microbiota, along with its component genes, known as the microbiome [43]. the human microbiome shows marked variation among individuals, and can be impacted by multiple factors, including diet. research is underway to explore the role of the microbiome as an important regulator in human immunity and as an instigator of disease. the human microbiome is comprised of multifaceted microbial communities that colonize the human body. the implication of the microbiome in human disease has been an increasing topic of research. the human microbiome project, established in 2008, seeks to characterize the human microbiome and its role in human health and disease [44,45]. in the gi tract, the microbiome is made up of trillions of microbes including bacteria and other microbes such as fungi and archaea [46]. the skin is also colonized by an equally complex microbiome that varies with host genetic and environmental influences. emerging research suggests that the collection of microbial communities that populate the skin and gi tract, rather than single microorganisms alone, is responsible for disease [47]. the gut microbiome plays an important role in training both the innate and adaptive immune systems. in a mouse model, it was found that specific strains of gut microbiota regulated the expression of genes that impacted intestinal barrier function and immunity, among other effects [48]. given these effects, the gut microbiome has the potential to affect many organ systems, including the skin. the composition of intestinal bacteria has been postulated to play a role in the pathogenesis of rosacea. in one theory, dysbiosis of intestinal bacteria results in activation of plasma kallikrein-kinin pathways, leading to downstream neurogenic inflammation [41]. some authors have suggested that this may, in part, explain the effectiveness of antibiotics in rosacea therapy [31]. while the microbiome represents an important therapeutic target, it is important to recognize the marked variation of human intestinal microbiome among individuals. factors that may account for these differences include genetics, diet, environmental exposures, hygiene, and other variables. notable geographical variations have been seen in gut microbiome composition, warranting further research of gut composition in global communities [49]. review | dermatol pract concept 2017;7(4):8 35 rosacea found no increased risk of adverse cardiovascular events [64]. given these findings, more research is required into the risk of cvd in rosacea patients. if confirmed, then dietary modifications to reduce this risk would be warranted. conclusion dietary triggers are frequently cited by patients as playing a role in rosacea exacerbations. at this time, patient-reported triggers fall into four categories: heat-related, alcohol-related, capsaicin-related, and cinnamaldehyde-related. one suggested mechanism of action is via activation of trp channels, which result in neurogenic vasodilation. diet may also impact rosacea via a gut-skin connection. while epidemiologic research supports this connection, research is underway to determine the pathophysiologic mechanisms. at this time, patients may be advised on measures to promote a healthy gut microbiome, including the importance of a fiber-rich (prebiotic) diet. references 1. rainer bm, fischer ah, luz felipe da silva d, kang s, chien al. rosacea is associated with chronic systemic diseases in a skin severity-dependent manner: results of a case-control study. j am acad dermatol. 2015;73(4):604-608. 2. two am, wu w, gallo rl, hata tr. rosacea: part i. introduction, categorization, histology, pathogenesis, and risk factors. j am acad dermatol. 2015;72(5):749-758. 3. duman n, ersoy evans s, atakan n. rosacea and cardiovascular risk factors: a case control study. j eur acad dermatol venereol. 2014:28(9):1165-1169. 4. yamasaki k, di nardo a, bardan a, et al. increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. nat med. 2007;13(8):975-980. 5. sulk m, seeliger s, aubert j, et al. distribution and expression of non-neuronal transient receptor potential (trpv) 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[63]. other comorbidities while the association of cardiovascular disease (cvd) and chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis, is well established, the risk of cvd in rosacea is not clear. in psoriasis, dietary modification to decrease the risk of comorbidities is now considered an important aspect of therapy, given the increased risk of cvd as well as metabolic diseases such as diabetes and hypertension [1,3]. a number of studies have examined this risk in rosacea patients. in one case-control study, patients with rosacea had an increased risk of cvd [3]. the authors hypothesized that cathelicidin peptides and serine proteases acted as common etiopathogens for both rosacea and atherosclerosis. however, a danish case-control study of close to 5,000 patients with 36 review | dermatol pract concept 2017;7(4):8 ease in women. clin gastroenterol hepatol. 2016;14(2):220-225. e3. 33. chang als, raber i, xu j, et al. assessment of the genetic basis of rosacea 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dermatology practical & conceptual www.derm101.com introduction   basal cell carcinoma (bcc) presents with a range of subtypes. presentation may be as either a single subtype bcc or combination of subtypes. these subtypes are based on architectural and cytological features [1]. certain subtypes are more common in certain locations [2]. along with the differing histopathological features, the rates of recurrence and positive margins are more common in certain subtypes as well as locations [3]. these differences are likely secondary to the growth pattern and depth of invasion. little is currently known on the variation in invasion depth of bcc subtypes by anatomic location. a recent study [4] limited to 100 cases showed that sex and site did not correlate with the depth of invasion in bccs. micronodular and infiltrating bccs were found to have the basal cell carcinoma: variation in invasion depth by subtype, sex, and anatomic site in 4,565 cases john h. pyne1, esther myint1, elizabeth m. barr1, simon p. clark1, ruihang hou1 1 faculty of medicine, university of new south wales, sydney, australia key words: basal cell carcinoma, superficial, nodular, infiltrating, micronodular, depth, anatomic site citation: pyne jh, myint e, barr em, clark sp, hou r. basal cell carcinoma: variation in invasion depth by subtype, sex, and anatomic site in 4,565 cases. dermatol pract concept. 2018;8(4)314-319. doi: https://doi.org/10.5826/dpc.0804a13 received: november 21, 2017; accepted: march 26, 2018; published: october 30, 2018 copyright: ©2018 pyne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: john pyne, m.med, phd, 131 ellesmere road, gymea bay nsw 2227 australia. email: j.pyne@uq.edu.au background: the depth of invasion by basal cell carcinoma (bcc) subtypes varies. objective: to investigate bcc invasion depth variation by subtype and anatomic site. method: a prospective consecutive case series of excised bcc from 2009 to 2014 in a single australian clinic. results: descending mean depths for a total of 4,565 bcc cases by subtype were as follows: nodulocystic, 1.9 mm (n = 84, 95% ci: 1.70–2.03, p = 0.66); nodular, 1.6 mm (n = 947, 95% ci: 1.53–1.63, p < 0.0001); aggressive, 1.5 mm (n = 925, 95% ci: 1.44–1.59, p < 0.0001); superficial combined with nodular, 0.9 mm (n = 1,081, 95% ci: 0.83-0.90, p < 0.0001); and superficial, 0.3 mm (n = 1,528, 95% ci: 0.32-0.36, p < 0.0001). deeper invasion was associated with increased chronic sunlight exposed sites. the deepest aggressive bccs occurred on the neck with a mean depth of 1.8 mm (n = 46, 95% ci: 1.47–2.21). conclusion: we found significant differences in the depth of invasion for bccs by sex, subtype, and anatomic site. for bcc with characteristics matching this study, overall adequate microscopic excision depths are proposed: superficial, 1.0 mm; superficial combined with nodular, 2.0 mm; nodular, 3.0 mm; and aggressive, 3.0 mm. abstract research | dermatol pract concept 2018;8(4):13 315 in each patient’s notes. all following excisions were checked against this body map to identify and thus exclude residual or recurrent cases. no cases were excluded based on age or anatomic site. after histopathological assessment, each bcc case was classified into one of the following categories: superficial (only subtype present), superficial combined with nodular (no other subtypes), nodular, nodulocystic, or aggressive. the aggressive bcc category included all cases with any of the following subtypes: infiltrating, morpheaform, micronodular, and bccs displaying squamous differentiation. these bcc subtypes were collectively allocated to the aggressive category as they commonly have histology with infiltrative architecture compared with the other bcc subtypes. the aggressive category included cases of aggressive bcc combined with superficial and/or nodular bcc subtypes. microscopic tumor diameters were measured in the laboratory prior to further processing. invasion depth was measured from the granular layer of the epidermis to the deepest tumor tissue in increments of 0.1 mm. examples of depth measurements for respective bcc subtypes are shown in figure 1 (a –d): (a) superficial bcc, (b) nodular bcc, (c) nodulocystic bcc, and (d) infiltrative bcc. initial excisions with deep margin involvement were re-excised. if no residual bcc was reported in the second excision, the depth was recorded as the depth stated in the first excision. however, if a second excision revealed further residual bcc, the recorded residual tumor depth from the second excision was added to the depth of the first excision to provide an approximate overall depth. it is conceded that combining the 2 separate depths for a single case from 2 separate excisions provides only an approximation of the true depth. however, these combined depth data were included, as excluding the second residual depth measurements, or all 2-stage excisions, would have resulted in the collective depth data being underestimated. results the patients’ tumor characteristics are presented in table 1. of the bcc subtypes examined, nodulocystic bccs recorded the oldest mean ages for both men aged 76 years (95% ci: 73–79, p = 0.013) and women aged 77 years (95% ci: 73–91, p > 0.1). conversely, superficial bccs recorded the youngest mean ages: 67 years in men (95% ci: 66-68, p < 0.0001) and 66 years in women (95% ci: 65-68, p < 0.0004). the mean maximum microscopic tumor surface diameter for all bcc subtypes ranged from 7.6 mm for nodular bcc (95% ci: 7.3–7.8, p < 0.0001) up to 9.1 mm for aggressive subtypes (95% ci: 8.1–10.0, p < 0.0001); see table 1. table 2 shows the bcc subtypes as recorded in relation to separate anatomic sites. deepest invasion followed by nodular and superficial bccs. increased tumor recurrence following excision has been recorded for bccs that invade beyond the reticular dermis and/or display perineural invasion [5]. furthermore, complete response rates following photodynamic therapy were found to be more strongly related to depth of invasion by facial bcc rather than subtype [6]. recent studies have improved the understanding of the correlation between the clinical features, dermoscopy appearance, and histopathology of different bcc subtypes [7-9]. improved identification of bcc subtypes combined with a better understanding of the depth of invasion of bcc subtype by anatomic location will lead to better clinical management. the goal of this study was to quantify bcc invasion depth by subtype and anatomic site. materials and methods this prospective study was conducted at a single mixed primary care and referral clinic in sydney, australia. the university of queensland granted ethics approval for this study. all patients gave informed consent prior to each case being included in the study. demographic data were collected from retrospective chart review. all consecutive histopathological proven cases of initial presentation bcc were collected from 2009 until the end of 2014. the intention of each surgical procedure was full excision of each bcc case. gross excision margins were initially estimated by clinical assessment. all cases were then examined using dermoscopy to identify the visible bcc edge and mark the final surgical margin some millimeters from this visible tumor edge. a heine delta 20 nonpolarized dermatoscope was used to examine each bcc to identify the lesion edge. for bccs with clinical diameters less than 5 mm, the surgical margin was typically marked 2 mm from the dermoscopy image of the tumor edge. those bccs with diameters greater than 5 mm had a minimum 3 mm surgical margin. excisions were routinely performed as an ellipse down to fat. however, for the nasal ala and on selected locations on the ear (i.e., on the thin skin directly overlaying the cartilage), excisions were performed down to the perichondrium. all excised tissue was submitted in formalin for histopathological assessments in which transverse “bread-loafing” sections were examined following hematoxylin and eosin staining. each ellipse of tissue was fully sectioned at 3-mm intervals. based on the histopathological assessments, cases of diagnoses other than bcc were excluded. in addition, bcc cases were also excluded if there was any historical, clinical, dermatoscopic, or histopathological evidence at the initial presentation that the case was a residual or recurrent case from a previous excision. during the study, the location of each bcc excision was recorded on an individual body map 316 research | dermatol pract concept 2018;8(4):13 within each specified subtype: superficial, 0.3 mm; superficial and nodular, 0.8 mm; nodular, 1.5 mm; nodulocystic, 1.8 mm; and aggressive, 1.2 mm. table 3 lists mean tumor depths by anatomic site and bcc subtype. owing to the small number of cases (n = 84), nodulocystic bccs were not assessed by anatomic site. table 4 provides a convenient comparison of the mean depths of bcc subtypes by sex (a comparison was made between head and neck sites combined and trunk and limb combined). superficial bcc mean depths ranged from 0.17 mm on the cheek to 0.40 mm on the foot. combined superficial and nodular bcc subtype depths ranged from 0.63 mm on the thigh to 1.50 mm on the lip. nodular bcc depths ranged from 1.36 mm on the eyelid to 1.98 mm on the hand. finally, aggressive bcc subtype depths ranged from 0.94 mm on the shoulder to 1.80 mm on the neck. mean tumor depths ranged from 0.3 mm for superficial bcc (95% ci: 0.32–0.36, p < 0.0001) up to 1.86 mm for nodulocystic bcc (95% ci: 1.7–2.03, p < 0.0001); see table 1. across all cases, 4.1% (n = 185) were reported with deep margin involvement at the initial excision. the most common site of deep margin involvement was the nose (n = 44, 13.5% of nose cases) followed by the ear (n = 20, 11.8% of ear cases). when first excisions with an involved deep margin (n = 185) were excised a second time, 131 (71%) of these re-excision cases reported no residual tumor. from of a full total of 4,565 bcc cases, only 54 cases (1.2%) required an approximation additive depth from the 2 consecutive excisions on the same case. for all cases combined, the following depths (to the nearest 0.1 mm) represent the 95th percentile for invasion depth a b c d figure  1a. superficial basal cell carcinoma: maximum invasion depth indicated by a vertical line from the granular layer in the epidermis down to the deepest tumor cells. [copyright: ©2018  pyne et al.] figure  1c. nodulocystic basal cell carcinoma: maximum invasion depth indicated by the same method as in figure  1a. [copyright: ©2018 pyne et al.] figure  1b. nodular basal cell carcinoma: maximum invasion depth indicated by the same method as in figure  1a. [copyright: ©2018 pyne et al.] figure  1d. infiltrating basal cell carcinoma: maximum invasion depth indicated by the same method as in figure  1a. [copyright: ©2018 pyne et al.] research | dermatol pract concept 2018;8(4):13 317 table 1. characteristics of basal cell carcinoma: sex, age, maximum microscopic diameter, and depth for all sites combined total cases (n = 4,565) superficial only (n = 1,528) superficial + nodular (n = 1,081) nodular (n = 947) nodulocystic (n = 84) aggressive (n = 925) sex male 935 (61.2) 712 (65.9) 686 (72.4) 61 (72.6) 608 (65.7) female 593 (38.8) 369 (34.1) 261 (27.6) 23 (27.4) 317 (34.3) age of patients male mean 67 71 70 76 73 range 20–97 25–101 26–101 48–98 34–103 95% ci 66–68 70–72 69–71 73–79 72–74 p value <0.0001 <0.0005 <0.0001 0.013 0.0002 female mean 66 73 70 77 72 range 25–97 36–100 35–99 36–98 37–102 95% ci 65–68 72–74 68–71 73–81 71–74 p value 0.0004 <0.0001 0.0667 >0.1 <0.0001 bcc maximum histological diameter, all sites, mm (95% ci) 8.5 (8.3–8.7) 8.3 (8.1–8.5) 7.6 (7.3-7.8) 9.0 (8.1–10.0) 9.1 (8.8-9.4) p value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 bcc depth, all sites, mm 0.30 (0.32–0.36) 0.86 (0.83–0.90) 1.58 (1.53-1.63) 1.86 (1.70–2.03) 1.51 (1.44-1.59) p value <0.0001 <0.0001 <0.0001 0.66 (ns) <0.0001 table 2. basal cell carcinoma: subtypes by anatomic site (nodulocystic cases not shown) total cases (n = 4,481) superficial only (n = 1,528) superficial + nodular (n = 1,081) nodular (n = 947) aggressive (n = 925) scalp 17 (16.4) 21 (6.9) 21 (4.5) 21 (0.43) ear 8 (7.7) 34 (11.1) 46 (9.8) 81 (16.5) eyelid 2 (2.0) 18 (5.9) 31 (6.6) 11 (2.3) nose 13 (12.5) 67 (21.9) 127 (27.0) 120 (24.4) forehead 14 (13.5) 62 (20.3) 110 (23.4) 119 (24.2) lip 0 6 (2.0) 20 (4.3) 12 (2.4) cheek 13 (12.5) 42 (13.7) 63 (13.4) 82 (16.7) neck 37 (35.6) 56 (18.3) 53 (11.3) 46 (9.4) shoulder 201 (14.1) 127 (16.4) 96 (20.0) 78 (18.1) chest 109 (7.7) 75 (9.7) 69 (14.4) 57 (13.2) back 480 (33.7) 219 (28.3) 129 (26.8) 134 (31.0) upper arm 243 (17.1) 109 (14.1) 43 (8.9) 38 (8.8) forearm 54 (3.8) 52 (6.7) 31 (6.4) 24 (5.6) hand 10 (0.7) 8 (1.0) 9 (1.9) 2 (0.5) thigh 89 (6.25) 47 (6.1) 38 (7.9) 24 (5.6) leg 227 (15.9) 135 (17.4) 60 (12.5) 72 (16.7) foot 11 (0.8) 3 (4.0) 6 (1.3) 3 (0.7) 318 research | dermatol pract concept 2018;8(4):13 where more than one subtype of bcc presented with a tumor, the percentage of the total mass occupied by each subtype was not recorded. many of the aggressive bcc subtype cases in this study were combined with the nodular bcc subtype cases. thus, the single maximum depth of invasion measurement for cases of aggressive combined with nodular subtype could relate to either subtype. superficial bcc is a straightforward histopathological diagnosis. interobserver concordance analyses for the histological diagnoses of the different bcc subtypes were not undertaken. limitations this study was conducted at a single community center with ambulant patients. the findings of this study should not be extrapolated to more advanced disease such as those cases typically managed in tertiary facilities. case inclusion was based on histopathologically proven bcc. a selection bias is present as a bcc without any bcc-associated clinical or dermoscopy features may not have been excised and thus would not have been entered into the study. table 3. basal cell carcinoma: tumor depth by anatomic site and subtype anatomic site superficial only mean depth, mm (95% ci) superficial + nodular, mm (95% ci) nodular only mean depth, mm (95% ci) aggressive mean depth, mm (95% ci) scalp 0.33 (0.14–0.53) 0.93 (0.69–1.17) 1.80 (1.47–2.12) 1.48 (1.01–1.94) ear 0.35 (n/a) 1.47 (0.87–2.06) 1.81(1.66–1.97) 1.66 (1.44–1.88) eyelid n/a 0.87 (0.69–1.04) 1.36 (1.17–1.54) 1.30 (0.70–1.90) nose 0.35 (n/a) 1.03 (0.90–1.16) 1.71(1.58-1.83) 1.49 (1.29–1.69) forehead n/a 1.06 (0.90–1.22) 1.51 (1.40–1.62) 1.50 (1.40–1.66) lip n/a 1.50 (1.16–1.84) 1.91 (1.10–2.25) 1.00 (0.57–1.43) cheek 0.17 (0.02–0.31) 1.12(0.94–1.29) 1.89 (1.72–2.06) 1.44 (1.26–1.62) neck 0.39 (0.22–0.55) 1.14 (0.93–1.35) 1.82 (1.58–2.05) 1.84 (1.47–2.21) shoulder 0.38 (0.30–0.45) 0.74 (0.67–0.81) 1.50 (1.31–1.70) 0.94 (0.76–1.13) chest 0.36 (0.31–0.41) 0.79 (0.70–0.88) 1.53 (1.33–1.74) 1.05 (0.75–1.35) back 0.36 (0.34–0.39) 0.76 (0.70–0.82) 1.39 (1.26–1.53) 1.06 (0.91–1.21) upper arm 0.27 (0.24–0.30) 0.74 (0.68–0.80) 1.44 (1.24–1.63) 1.01 (0.72–1.29) forearm 0.24 (0.18–0.30) 0.93 (0.80–1.06) 1.64 (1.36–1.92) 1.23 (1.01–1.46) hand 0.35 (0.07–0.63) 0.87 (0.49–1.25) 1.98 (1.28–2.67) n/a thigh 0.28 (0.22–0.34) 0.63 (0.54–0.71) 1.53 (1.16–1.89) 1.01 (0.57–1.46) leg 0.33 (0.29–0.37) 0.69 (0.63–0.76) 1.34 (1.20–1.49) 1.10 (0.94–1.27) foot 0.40 (0.15–0.65) 0.83 (0.50–1.50) 1.48 (0.81–2.16) n/a n/a (n = 3 or fewer cases). table 4. basal cell carcinoma: depth comparison by sex and subtype male female superficial + nodular nodular aggressive superficial + nodular nodular aggressive head + neck mean depth, mm 1.1 1.8 1.7 1.1 1.6 1.6 95% ci 1.0–1.2 1.7–1.8 1.6–1.8 0.9–1.3 1.5–1.7 1.5–1.7 p value <0.0001 <0.0001 <0.0001 <0.0001 <0.01 <0.0001 case numbers (n) 201 (26.2%) 296 (38.6%) 269 (35.1%) 93 (25.6%) 137 (37.6%) 134 (36.8%) trunk + limbs mean depth, mm 0.76 1.5 1.5 0.76 1.3 1.0 95% ci 0.73–0.80 1.4–1.6 1.3–1.7 0.71–0.81 1.2–1.4 0.92–1.2 p value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 case numbers (n) 476 (45.6%) 336 (32.2%) 233 (22.3%) 266 (53.4%) 101 (20.3%) 131 (26.3%) research | dermatol pract concept 2018;8(4):13 319 conclusions knowledge of potential tumor depth should be used to guide biopsy techniques and depth selection during excisions. our study found that bcc subtypes vary in mean depth across both sex and anatomic site. nodulocystic and nodular bcc subtypes presented as the deepest tumors. head and neck bccs were found to have an increased mean depth compared with those on trunk and limb sites. another trend identified by this study was an increase in mean tumor depth on both the upper and lower limbs for distal sites compared with proximal limb sites. references 1. lang pg, maize jc sr. basal cell carcinoma. in: rigel ds, friedman rj, dzubow lm, reintgen ds, bystryn j-c, marks r, eds. cancer of the skin. philadelphia: elsevier; 2005:101-132. 2. sexton m, jones db, maloney me. histologic pattern analysis of basal cell carcinoma: study of series of 1039 consecutive neoplasms. j am acad dermatol. 1990;23:1118-1126. 3. armstrong ltd, magnusson mr, guppy mpb. risk factors for recurrence of facial basal cell carcinoma after surgical excision: a follow-up analysis. j plast reconstr aesthet surg. 2017;70:17381745. 4. welsch mj, troiani bm, hale l, et al. basal cell carcinoma characteristics as predictors of depth of invasion. j am acad dermatol. 2012;67:47-53. 5. codazzi d, van der velden j, carminati m, et al. positive compared with negative margins in a single-centre retrospective study on 3,957 consecutive excisions of basal cell carcinomas: associated risk factors and preferred surgical management. j plast surg hand surg. 2014;48:38-43. 6. li q, gao t, jiao b, et al. tumor thickness predicts long-term complete response of facial basal cell carcinomas in asian skin types iv/v treated with methyl aminolaevulinate photodynamic therapy. photomed laser surg. 2011;29:501-507. 7. ahnlide i, zalaudek i, nilsson f, bjellerup m, nielsen k. preoperative prediction of histopathological outcome in basal cell carcinoma: flat surface and multiple small erosions predict superficial basal cell carcinoma in lighter skin types. br j dermatol. 2016;175:751-761. 8. lallas a, argenziano g, ioannides d. dermoscopy for basal cell carcinoma subtype prediction. br j dermatol. 2016;175:674-675. 9. pyne jh, fishburn p, dicker a, david m. infiltrating basal cell carcinoma: a stellate peri-tumor dermatoscopy pattern as a clue to diagnosis. dermatol pract concept. 2015;5:21-26. 10. scrivener y, grosshaans e, cribier b. variations of basal cell carcinomas according to gender, age, location and histopathological subtype. br j dermatol. 2002;147:41-47. 11. gualdi g, monari p, crotti s, et al. matter of margins. j eur acad dermatol venereol. 2015;29:255-261. discussion a previous french study on bcc examined 13,457 cases. of these 13,457 cases, 15.1% were superficial bcc subtype and  6.2% were morpheaform bcc subtype [10]. conversely, our study recorded 33.5% superficial bcc subtype cases and 20.3% aggressive bcc subtype cases. this french study also reported that 94.8% of morpheaform bccs were located on the head while 30.6% of morpheaform bccs were located on the nose. similarly, our study found that the nose had the highest proportion of aggressive bccs (24.4%, n = 120). our study showed that tumor invasion for bccs was deeper among male than among female patients, as previously recorded [3]. our study also compared the invasion depths of (1) superficial combined with nodular subtypes; (2) nodular alone; and (3) aggressive bcc subtypes across men and women. invasion was significantly deeper in men than in women across all 3 categories of bcc subtype. this trend (i.e., that all 3 bcc subtypes were deeper in men than women) applied to the head and neck as well as the trunk and limb sites. increased invasion depth was associated with sites exposed to higher chronic sunlight. a distal shift from the upper arm to the hand and from the thigh to the foot showed an increasing depth of invasion across all bcc subtypes except nodular bccs on leg sites. data from our study indicate elliptical excisions with a microscopic depth of 1 mm appear to be quite adequate for deep margin clearance on superficial bccs at all anatomic sites. for bcc with dimensions within the range of the study cases recorded, excisions with a microscopic 2-mm depth appear adequate for the majority of superficial combined with nodular bccs. nodular bccs may require deeper excisions of up to a microscopic depth of 3 mm on the hand, neck, and scalp. finally, aggressive bccs may require 3 mm deep elliptical excisions on the neck. because of cosmetic considerations, mohs surgery may be preferred on aggressive subtype bccs located on central facial sites and the ear rather than performing elliptical excisions. nodulocystic bccs recorded the largest mean maximum microscopic tumor diameter and deepest mean depth compared with all other bcc subtypes. another previous study reported that nodulocystic bccs on nose and eyelid sites tend to have deeper margin involvement following excisions [11]. in our study, none of the nodulocystic cases were combined with aggressive subtype bcc. dermatology: practical and conceptual review | dermatol pract concept. 2023;13(3):e2023065 1 impact of uv modifying factors on the incidence of keratinocyte carcinomas in solid organ transplant recipients: a systematic review syed minhaj rahman1, fahad ahmed2, amir amanullah3, adel haque4 1 department of dermatology, university of rochester school of medicine and dentistry, rochester, new york 2 department of dermatology, perelman school of medicine, university of pennsylvania, philadelphia, pennsylvania 3 department of dermatology, lewis katz school of medicine, temple university, philadelphia, pennsylvania 4 department of medicine, jefferson health northeast, philadelphia, pennsylvania key words: keratinocyte, organ transplant recipient, ultraviolet radiation, fitzpatrick skin type, sun exposure citation: rahman sm, ahmed f, amanullah a, haque a. impact of uv modifying factors on the incidence of keratinocyte carcinomas in solid organ transplant recipients: a systematic review. dermatol pract concept. 2023;13(3):e2023065. doi: https://doi.org/10.5826/dpc.1303a65 accepted: january 11, 2023; published: july 2023 copyright: ©2023 rahman et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: syed minhaj rahman, ba, department of dermatology, university of rochester school of medicine and dentistry, 1188 mount hope ave, apt 503 rochester, ny 14620 telephone: (718)-598-4637 e-mail: minhaj_rahman@urmc.rochester.edu introduction: solid organ transplant recipients (sotr) are at an increased risk for developing keratinocyte carcinomas (kc). four ultraviolet (uv) modifying factors have been identified that impact the incidence of kc: fitzpatrick skin type (fst), race, sun exposure, and sun-protective factors. objectives: we conducted a systematic review to summarize the association between uv modifying factors and the incidence of kc in sotr. methods: we systematically searched pubmed, scopus, and web of science databases, and after screening for inclusion and exclusion criteria, we included 13 studies with 6,910 solid organ transplant recipients in our analysis. results: our review found that lower fst (i-ii), white and latinx populations, lack of regulated sunscreen application, and occupational and residential sun exposure are individual risk factors among solid organ transplant recipients for kc incidence. although previous studies showed an increased scc:bcc ratio, some studies found a contradictory increased bcc:scc ratio. limitations include few research studies that analyze these uv modifying factors and a lack of incorporating both varying immunosuppressant factors and transplantation follow-up times. conclusions: these findings support the need for dermatological advice in increased risk patient demographic populations, lower fst and white and latinx populations, and subsequently moderating sun exposure and protective factors. abstract 2 review | dermatol pract concept. 2023;13(3):e2023065 introduction keratinocyte carcinomas (kc) are non-melanoma skin cancers (nmsc) consisting of basal cell carcinomas (bcc) and squamous cell carcinomas (scc) [1]. kcs are the most prevalent cancer worldwide with 20-25% of kcs being scc [2,3]. solid organ transplant recipients (sotr) have an increased risk of developing kc and these patients are at a 65-250 increased risk for cutaneous scc than the general population [4-6]. specifically, a recent delphi consensus survey found that male thoracic organ recipients aged 50 or older at the time of transplant are at the highest risk for developing skin cancer [7]. there are several uv modifying factors that can impact kc incidence in sotr, however, the 4 major variables are: fitzpatrick skin type (fst), race, sunscreen use, and sun exposure. the fst classifies 6 skin complexions and reactions to sun exposure ranging from very light skin, burns easily, and never tans (fst i) to very dark skin, never burns, and tans profusely (fst vi) [8]. although there are overlapping factors in fst and race, several other factors should be accounted for such as: environmental, geographic, and socioeconomic factors. all of these factors impact the association between race and kc incidence. aside from fst, sun exposure and sun protective actions are major contributors to skin cancer incidence [9]. sun exposure and sunburn can be used indirectly as tools to assess skin cancer risk as it accounts for uv exposure amount and skin sensitivity [10]. although some studies show that continuously high sun exposure is more closely associated with an increase in scc incidence, other studies have also reported a positive association between sunburn history and kc incidence [11-15]. sunscreen is a primary photoprotective factor against uv radiation that absorbs environmental uv rays to protect the skin [16]. a trial conducted in queensland, australia found that daily morning use of broad-spectrum sun protection factor (spf)-16 sunscreen on the head, neck, arms, and hands of healthy individuals decreased both the number of individuals with sccs and the incidence of scc tumors up to 8 years post-cessation of intervention [17]. however, this same protective factor for regular use of sunscreen was not significant in reducing bcc incidence. objectives to the author best knowledge, there is a lack of systematic reviews that assess the impact of uv modifying factors on skin cancer incidence in the adult sotr population. although there is substantial evidence suggesting immunosuppression increases the risk of sotr developing kc, this systematic review will synthesize the evidence from retrospective cohort, prospective cohort, case-control, and observational studies to summarize the association between uv modifying factors and the incidence of kc in sotr. the results of this study will help clinicians better assess what pertinent, significant risk factors to be aware of when treating adult sotr and monitoring for the development of kc. results of this study will allow us to lead a discussion regarding skin phenotype, race, and uv protection/exposure and better guide physicians treating sotr adults. methods study identification a systematic literature search using pubmed and scopus databases was performed. this search included all years through april 2022 and consisted of the search terms: “ organ transplantation” or “organ graft” or “organ transplant recipients” and “skin cancer” or “squamous cell carcinomas” or “basal cell carcinomas” or “cutaneous squamous cell carcinoma” or “nonmelanoma skin cancer” or “keratinocyte carcinoma” and “skin tone” or “skin color” or “fitzpatrick skin type” or “sunscreen” or “sun protective factors”. additionally, we searched the reference lists of selected studies. the search was conducted adhering to the updated 2020 standards of the preferred reporting items for systematic reviews and meta-analysis (prisma) statement [18]. eligibility criteria two reviewers (sr and fa) selected studies that met the following inclusion criteria: i) the population of interest adult solid organ transplant recipients, including fst or skin tone identification, race, sunscreen behaviors, or sun exposure; ii) the outcomes of interest cutaneous squamous cell carcinomas, basal cell carcinomas, or non-melanoma skin cancers; and iii) observational or interventional study designs (cross-sectional studies, cohort studies, case studies, cases series, or randomized controlled trials). studies were excluded if there was no record of uv modifying risk factors. any disagreement was resolved by a third reviewer (aa). data extraction a total of 480 studies were screened and 13 were included. information was collected on study design, data source, number of participants, selection criteria, and outcomes of interest including scc, bcc, kc, and overall nmsc incidence based on our 4 uv modifying risk factors. fst and race data collected and analyzed is presented in table 1. sun exposure and sunscreen data collected and analyzed is presented in table 2. review | dermatol pract concept. 2023;13(3):e2023065 3 ta b le 1 . st u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, f it zp at ri ck s k in t yp e, a n d r ac e in s o li d o rg an t ra n sp la n t re ci p ie n ts . k c r is k v a ri a b le s tu d ie d s tu d y a u th o r( s ) a n d y e a r p u b li sh e d s tu d y d e si g n d a ta c o ll e ct io n lo ca ti o n ( y e a r r a n g e s) n u m b e r o f s u b je ct s in s tu d y k c r e p o rt e d ty p e o f tr a n sp la n t( s ) u v m o d if y in g r is k v a ri a b le s r e p o rt e d r is k t y p e /d a ta f st g o gi a et a l 2 0 1 3 r et ro sp ec ti ve c o h o rt u sa c a 2 0 0 4 -2 0 0 8 5 5 6 3 1 7 c sc c k id n ey , h ea rt , lu n g, p an cr ea s, an d l iv er f st i ii ii i iv v sc c h r ( 9 5 % c i) 3 .4 7 ( 1 .4 6 -8 .2 8 ) 2 .6 3 ( 1 .1 6 -5 .9 2 ) 2 .7 9 ( 1 .2 4 -6 .3 0 ) 2 .0 7 ( 0 .9 1 -4 .7 0 ) 1 .5 8 ( 0 .6 6 -3 .8 1 ) m o lo n ey e t  al 2 0 0 5 o b se rv at io n al co h o rt ir el an d (2 0 0 0 -2 0 0 1 ) 2 7 0 4 4 s c c a n d 2 2  b c c k id n ey f st % i ii ii i iv sc c 5 2 .3 % 2 5 .0 % 1 8 .2 % 4 .5 % b c c 5 4 .5 % 2 7 .3 % 1 8 .2 % 0 % d e r o sa e t  al 2 0 1 9 r et ro sp ec ti ve c o h o rt a u st ra li a 9 4 h ea rt a n d l u n g f st ii iv i iii c ar ci n o m a ty p e h r ( 9 5 % c i) n m sc 0 .6 0 ( 0 .3 5 -1 .0 2 ) sc c 0 .5 7 ( 0 .3 3 -1 .0 0 ) b c c 0 .5 5 ( 0 .2 9 -1 .0 2 ) n m sc 1 * sc c 1 * b c c 1 * n g et  a l  2 0 1 4 p ro sp ec ti ve co h o rt a u st ra li a (2 0 0 4 -2 0 0 9 ) 1 4 2 2 5 3 c sc c an d 8 8 b c k id n ey f st i ii ii i iv c ar ci n o m a ty p e ac cr u al ( sd ) n m sc 2 .3 7 ( ± 3 .2 5 ) sc c 1 .7 6 ( ± 2 .7 0 ) b c c 0 .6 1 ( ± 1 .6 6 ) n m sc 3 .0 5 ( ± 8 .8 8 ) sc c 2 .4 1 ( ± 7 .4 8 ) b c c 0 .6 4 ( ± 1 .6 0 ) n m sc 0 .8 0 ( ± 1 .5 7 ) sc c 0 .6 0 ( ± 1 .4 0 ) b c c 0 .2 0 ( ± 0 .4 9 ) n m sc 0 .4 5 ( ± 2 .8 5 ) sc c 0 .4 0 ( ± 1 .7 5 ) b c c 0 .0 5 ( ± 0 .1 6 ) t ab le 1 c o n ti n u es 4 review | dermatol pract concept. 2023;13(3):e2023065 k c r is k v a ri a b le s tu d ie d s tu d y a u th o r( s ) a n d y e a r p u b li sh e d s tu d y d e si g n d a ta c o ll e ct io n lo ca ti o n ( y e a r r a n g e s) n u m b e r o f s u b je ct s in s tu d y k c r e p o rt e d ty p e o f tr a n sp la n t( s ) u v m o d if y in g r is k v a ri a b le s r e p o rt e d r is k t y p e /d a ta g ar ci a et a l 2 0 1 3 p ro sp ec ti ve + r et ro sp ec ti ve co h o rt m ed it er ra n ea n r eg io n (1 9 9 6 -2 0 1 0 ) 2 8 9 4 1 c sc c a n d 9 1 b c c k id n ey f st iii ≥ ii i r el at iv e n m sc h r ( 9 5 % c i) 1 * 0 .5 ( 0 .2 7 -0 .9 2 ) d u cr o u x e t  al 2 0 1 4 r et ro sp ec ti ve co h o rt 1 9 9 6 -2 0 0 8 (f ra n ce ) 3 7 1 5 0 k c ( cs c c an d /o r b c c ) l u n g f st iii i iv -v i n m sc o r ( 9 5 % c i) 1 0 .9 1 ( 1 .4 5 -8 1 .7 7 ) 1 * c af o ri o e t  al 2 0 0 0 p ro sp ec ti ve c o h o rt it al y 3 0 0 5 3 s c c a n d 3 7 b c c h ea rt f st ii ii iiv n m sc h r ( 9 5 % c i) 2 .6 ( ± 1 -7 ) 1 * r ac e d u se n d an g et  a l 2 0 2 2 c as eco n tr o l u sa c a (2 0 0 9 -1 9 ) 3 3 0 8 o t r v s 6 5 ,8 8 3 n o o t r h ea rt , k id n ey , li ve r, lu n g, a n d p an cr ea s r ac e w h it e a a a si an a m er ic an l at in x o th er cs c c h r ( 9 5 % c i) 1 .0 0 * 0 .0 4 ( 0 .0 2 -0 .0 7 ) 0 .0 7 ( 0 .0 5 -0 .0 9 ) 0 .2 3 ( 0 .1 8 -0 .2 9 ) 0 .5 2 ( 0 .4 1 -0 .6 5 ) a a = a fr ic an a m er ic an ; b c c = b as al c el l ca rc in o m a; c i = c o n fi d en ce i n te rv al ; cs c c = c u ta n eo u s sq u am o u s ce ll c ar ci n o m a; f st = f it zp at ri ck s k in t yp e; h r = h az ar d r at io ; k c = k er at in o cy te c ar ci n o m a; n m sc = n o n -m el an o m a sk in c an ce r; o r = o d d s r at io ; sc c = s q u am o u s ce ll c ar ci n o m a; s d = s ta n d ar d d ev ia ti o n ; * = h az ar d o r o d d s ra ti o i n r ef er en ce t o t h is v al u e. ta b le 1 . st u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, f it zp at ri ck s k in t yp e, a n d r ac e in s o li d o rg an t ra n sp la n t re ci p ie n ts . ( co n ti n u ed ) review | dermatol pract concept. 2023;13(3):e2023065 5 ta b le 2 . st u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, s u n sc re en , a n d s u n e x p o su re i n s o li d o rg an t ra n sp la n t re ci p ie n ts . k c r is k v a ri a b le s tu d ie d s tu d y a u th o r( s ) a n d y e a r p u b li sh e d s tu d y d e si g n d a ta c o ll e ct io n lo ca ti o n ( y e a r r a n g e s ) n u m b e r o f s u b je ct s in s tu d y k c r e p o rt e d ty p e o f tr a n sp la n t( s ) u v m o d if y in g r is k v a ri a b le s r e p o rt e d r is k t y p e /d a ta su n sc re en sa vo ia e t al 2 0 1 1 r et ro sp ec ti ve co h o rt it al y (1 9 9 7 -2 0 1 0 ) 2 8 2 9 9 s k in c an ce rs 7 0 n m sc (4 7  b c c a n d 2 3  s c c ) k id n ey ss u se y es n o r is k f ac to rs si gn ifi ca n t li n k n eo p la sm h r ( 9 5 % ) 1 .0 0 * 1 .2 5 ( 0 .5 6 -2 .7 9 ) n o s u n sc re en u se ( p = 0 .0 2 5 2 ) o u td o o r jo b ( p = 0 .0 4 1 3 ) u lr ic h e t al 2 0 0 9 c as eco n tr o l b er li n , g er m an y 1 2 0 1 9 n m sc ( b c c an d s c c ) (8 sc c , 1 1 b c c ) h ea rt , k id n ey , an d l iv er t x ( 2 0 ea ch ) ss u se cs c c b c c p p < 0 .0 1 n o t si gn ifi ca n t su n e x p o su re v ad n er k ar e t al 2 0 1 0 r et ro sp ec ti ve c o h o rt u sa p it ts b u rg h , pa (2 0 0 3 -2 0 0 8 ) 5 4 3 1 7 s c c l u n g r is k f ac to r: r es id en ce i n re gi o n w it h h ig h su n e x p o su re sc c p v al u e p = 0 .0 0 0 1 c af o ri o e t al 2 0 0 0 p ro sp ec ti ve c o h o rt it al y 3 0 0 5 3 s c c a n d 3 7 b c c h ea rt r is k f ac to r: h ig h s u n li gh t ex p o su re sc c h r ( 9 5 % c i) 7 .6 ( 2 .5 -2 2 .8 ) p p = 0 .0 0 0 3 r o d ri gu ez -a co st a et a l 2 0 1 5 c as eco n tr o l m ex ic o (2 0 1 1 -2 0 1 2 ) 1 4 0 5 9 s c c a n d 1 9 b c c k id n ey a n d li ve r r is k f ac to r: to ta l su n b u rd en (r ec re at io n al + o cc u p at io n al ) n m sc o r ( 9 5 % c i) ( p ) 1 9 ( 3 -1 2 0 ) (p < 0 .0 0 1 ) ia n n ac o n e et a l 2 0 1 6 p ro sp ec ti ve c o h o rt q u ee n sl an d , a u st ra li a (2 0 1 2 -2 0 1 4 ) 4 9 5 1 3 5 n m sc ( 4 1 cs c c , 5 0 b c c , 7 7 b o w en ) k id n ey a n d li ve r r is k f ac to r: b o rn i n a u st ra li a n m sc p r ( 9 5 % c i) 2 .3 8 ( 1 .2 8 -4 .4 2 ) h r = h az ar d r at io ; k c = k er at in o cy te c ar ci n o m a; n m sc = n o n -m el an o m a sk in c an ce r; o r = o d d s r at io ; p r = p re va le n ce r at io ; ss = s u n sc re en . 6 review | dermatol pract concept. 2023;13(3):e2023065 patients older than age 18 and collected one of the four uv modifying factors. these studies included solid organ transplants of the: kidney, heart, lung, liver, and pancreas. dates for incorporated studies ranged from 2000 to 2022 (figure 1). results thirteen studies were selected for review after assessing a total of 480 full-text studies. overall, the 13 studies included 6910 patients with solid organ transplantations in figure 1. flowchart of the identification of eligible studies. review | dermatol pract concept. 2023;13(3):e2023065 7 nmsc incidence and found that higher tumor accrual rates in both fst i (1.76 scc/patient per year, 0.61 bcc/patient per year) and fst ii (2.41 scc/patient per year, 0.64 bcc/ patient per year) compared to fsts iii, iv, and v [22]. a similar association was reported in an italian cohort study where fst ii was found to be a significant risk factor (hr=2.60) in nmsc incidence in heart sotr compared to fsts iii, iv, and v [23]. although the australian study noted both scc and bcc, it is vital to point out the increased scc:bcc ratio (2.86:1), an association comparable with previous studies [24,25]. additionally, fst i patients specifically had a much higher scc:bcc ratio compared to other fsts. it is imperative for clinicians to keep this increased scc:bcc ratio in mind when treating sotr patients as this impacts the regularity of skin screenings and requires more patient-centered treatment plans. a retrospective and prospective follow-up study examined the risk factors for nmsc in renal transplant patients. lighter fsts (i and ii) were associated with a significantly greater risk of nmsc compared to fst ≥iii (hr 0.50 +/ 0.27-0.92, p = 0.026) [26]. interestingly, garcia et al found an increased bcc:scc ratio (2.21:1) which conflicts with the studies previously mentioned. this inverse relationship between lower fst and higher risk of nmsc in renal transplant patients was also supported by savoia et al (bcc:scc ratio 2.1:1) [27]. lower fst has been shown in numerous studies to be a significant risk factor for incidence of nmsc, and more specifically, kc, in sotr. although previous studies have shown an overall increased scc:bcc ratio, some studies have found a surprisingly increased bcc:scc ratio. there is a need for additional well-designed prospective studies to be included in the literature to further distinguish the factors which affect varying scc and bcc ratios. the impact of race on kc in sotr although race is associated with fst, many environmental, socioeconomic, genetic, and patient outcome factors contribute to race as a distinct identifier. along with fst, race also contributes to scc incidence in sotr. a retrospective cohort study examining the incidence of scc in sotr from 2009 to 2019 found that the annual incidence rate of scc in white sotr was 4.70% compared to 0.38% in non-white sotr (african american, asian american, latinx, multiple/ other, or unknown) [28]. additionally, white sotr were more likely to have a history of skin cancers than non-white sotr. this trend was consistent with kang et al and could be the result of earlier diagnoses or a greater chance to get a diagnosis [28,29]. latinx sotr also had an increased scc incidence compared to other non-white groups [28]. our search was limited to one study that examined race association with kc incidence in sotr. all 13 studies provide adequate data supporting increased risk for kc associated with one of the four uv modifying risk factors. seven studies explored fst impact and found that sotr with lower fst (fst i and ii) have an increased incidence of kc. one study identified the impact race has on kc incidence; the results indicated that white sotr patients had a higher kc incidence than non-white sotr. within the non-white population, latinx sotr had the highest kc incidence. two studies examined the impact of sunscreen application and suggested that controlled application of sunscreen can significantly reduce kc incidence in sotr. lastly, four studies explored sun exposure as a uv modifying factor and found that both occupational sun exposure and residence sun exposure are major contributors to kc incidence in sotr. the impact of fst on kc in sotrs this systematic review explores the incidence of kc in adult solid organ transplant recipients of uv modifying risk factors, including fst. seven studies supported an increased risk in kc for lighter skin fsts (fst i-ii). a major cohort study by gogia et. al examined 556 organ transplant recipients with skin cancer history between 2004 and 2008 and recorded patient demographics, transplant type, and fst [19]. scc incidence and fst displayed an inverse relationship ie the risk of scc increased with each incremental decrease in fst. fst i patients had a 1.67fold increased risk in developing scc compared to fst iv patients, but a fst i patients had an even higher, 3.47-fold risk increase when compared to fst vi patients [19]. this trend continued over a 15-year period where scc incidence of fst i participants was 68% compared to 27% in fst vi participants. however, the 15-year scc incidence rates for fst ii and fst iii participants were 66% and 63%, respectively, indicating that fair skin types were more likely to have to develop scc than the overall population. this trend was observed in an earlier study examining skin cancer development in renal transplant recipients. out of the 44 subjects that developed squamous cell carcinomas, 52.3% were of fst i while 25.0% were of fst ii [20]. the remaining 22.7% were of fst iii and fst iv. the results of this study were also suggestive that scc were more probable to develop in lighter skin type individuals. furthermore, an australian retrospective cohort study that traced 94 heart and/or lung transplant patients reported results that also supported this trend. compared to fsts i-ii, fsts iii-vi had a 0.57-fold decreased risk of developing scc [21]. although these studies reiterated similar trends, some of the variability in scc incidence can likely be attributed to the variability in worldwide sun exposure levels and various uv modifying factors. fst also impacts bcc incidence in sotr. a 60-month prospective australian study examined fst impact on 8 review | dermatol pract concept. 2023;13(3):e2023065 the impact of sun exposure on kc in sotr in addition to sun protective factors, sun exposure has been shown to be a major contributor to scc in sotr. for example, queensland, australia is known for its excessive sunlight exposure [33]. one study of sotrs found that australia sotrs had a 10-year nmsc incidence of 70%, compared to sotrs in italy (10%) and northern europe (20%) [34]. additionally, this study also found that cumulative amounts of sun exposure strongly predicted the risk of nmsc in both the italian and australian cohorts [34]. moreover, the geographic impact of australia sun exposure on nmsc was supported by iannacone et al. the authors reported that patients born in australia had a 2.38 prevalence ratio for nmsc compared to those born outside of australia [35]. a separate retrospective case-cohort study (1:3 case-tocontrol ratio) in pittsburgh examined the impact of highlevel sun exposure on scc incidence in single and double lung otr (n = 543). high-level sun exposure was defined as residence south of 35° latitude with high to very high uv indexes. the authors found that residing in high-level sun exposure areas was an independent risk factor for scc in lung otr (p = 0.0001) [36]. additionally, 94% of the patients who developed scc presented on sun-exposed parts of the body and this finding may be explained by the impact sun exposure has on the increased risk for scc. in addition to residential sun exposure, savoia et al retrospective study reported that outdoor occupation was one of two exogenous risk factors significantly associated with skin cancer incidence [27]. additional studies have also reported similar conclusions regarding the association between increased outdoor labor and increased risk of skin cancer. a case-control study in mexico displayed that greater than 20 hours per week of occupational sun exposure was a significant risk factor associated with increased nmsc incidence (p < 0.01) [37]. another study examined the risk factors for skin cancers in heart transplant recipients and found that cumulative increased sun exposure during work was independently associated with an increased risk of scc (p = 0.0003) [23]. limitations this systematic review has several limitations. the first limitation is the high disparity in quantifiable variables to validly measure the effect of uv modifying factors reported in studies. seven studies supported fst as a risk factor for skin cancer, but only one study supported race as a risk factor for cancer, even though both race and fst are factors determined by skin phenotype. therefore, we require more standardized protocols for sotr studies that monitor kc to collect demographics such as race to further support its impact on increased kc incidence. additionally, we were unable to account for the effect of time from sotr status to kc presentation, and how this would be related to various uv modification habits in sotr patients. overall, white sotr had a significantly higher incidence rate of scc than non-white sotr while the latinx population had an increased scc incidence when compared to the remaining non-white group. the impact of sun protective factors on kc in sotr sun protective factors, such as sunscreen, are major contributors to scc incidence in sotr. in a 24-month prospective case-control study of 120 patients, treatment groups were divided into a sunscreen group and a control group to explore the impact of regular application of >60 spf sunscreen on scc incidence in sotr. the study included heart, kidney, and liver organ transplant recipients (otr). after the 24-month phase, no new invasive scc occurred in the sunscreen group while control patients developed 8 new invasive scc (p < 0.01) (5 heart otr, 3 kidney otr, and 0 liver otr) [30]. this trend was also supported by an australian study of 1383 immunocompromised non-sotr patients, demonstrating a similar trend found in both sotr and non-sotr populations [30,31]. although the initial sotr case-control study supported the potential protective benefits of sunscreen in decreasing the incidence of scc, it is imperative to note that a 24-month period is too narrow to determine the full development of nmsc. lastly, in a single-center retrospective study in italy, savoia et al examined risk factors for skin cancers in kidney otr. they found that the two exogenous risk factors that were significantly associated with skin cancers were the lack of sunscreen use (p = 0.0252) and outdoor occupation (p = 0.0413) [27]. although this controlled trial suggested that sunscreen is a protective factor against scc in sotr, a retrospective study examining nmsc incidence in kidney otr found that self-reported sunscreen was not a significant protective factor in nmsc incidence [32]. this comparison highlights the importance of educating sotr patients on daily appropriate usage of sunscreen and emphasizing the use of higher sunscreen strength to best achieve the potential reduced risks of the development of scc. overall, sunscreen may be an effective protective factor to reduce the incidence of nmsc in sotr. however, due to the limited number of supporting studies, we cannot draw conclusions regarding sunscreen potential protective benefits. further studies are required to understand the association between sunscreen and nmsc development. additionally, although spf was not a controlled variable, further research is required to determine the effect of varying spf intensities in reducing nmsc incidence in sotr. future, prospective studies interested in this relationship should also explore determining an adequate cut-off point for spf strength that is associated with a significantly decreased risk for nmsc. review | dermatol pract concept. 2023;13(3):e2023065 9 sotr in comparison to kidney sotr [39]. gjersvik et al further confirmed this finding by displaying a 2.8-fold higher risk [40]. the increased risk can be explained by the elevated immunosuppressive dosage by heart sotr compared to kidney sotr [39]. additionally, numerous studies have concluded that nmsc incidence increases in proportion to immunosuppressive duration [26,33,41,42]. we presented immunosuppressive drugs, percent distribution of drug types, and median time of immunosuppression for all included patients in table 3. lastly, although we analyzed the influence of exogenous factors on the development of nmsc, our review did not account for the impact of immunosuppression. pharmacological immunosuppression is necessary for post-operative sotr and is deemed the biggest risk factor contributing to nmsc incidence in sotr [38]. nmsc incidence rates are proportional to the type of organ transplant, immunosuppressant type, dosage, and duration of the drug [39]. a single-center norwegian study found a 3-fold higher risk of developing scc in heart table 3. immunosuppressive drugs, percent distribution of drug types, and median time of immunosuppression from studies included in retrospective analysis. study type of immunosuppressant % of sotr median time gogia et al 2013 nr nr nr moloney et al 2005 cyclosporine, azathioprine, and prednisolone nr nr de rosa et al 2019 nr nr 8.4 years (range: 0.4-27 years) dusendang et al 2022 mycophenolate mofetil and tacrolimus 93% 15 months other mycophenolate 53% 4 months other tacrolimus 44% 4 months savoia et al 2011 tacrolimus 58.9% 7.2 years cyclosporine 36.2% azathioprine, mycophenolate, and sodium mofetil nr ng et al 2014 calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil, and prednisolone 53% 11.6 years (+/8.2 years) azathioprine, mycophenolate mofetil, and prednisolone 27% garcia et al 2013 mycophenolate, mtor-sirolimus, and/or everolimus inhibitors 6.2% nr tacrolimus and mycophenolate 66.4% cyclosporine and mycophenolate 25.6% older regimens and azathioprine 1.7% ducroux et al 2014 cyclosporine 19.5% 8.2 years tacrolimus 95.7% sirolimus 20.8% caforio et al 2000 cyclosporin a and azathioprine 79.3% nr cyclosporin a, azathioprine, and prednisone 20.7% ulrich et al 2009 cyclosporine, prednisolone, and mycophenolate or azathioprine 33.3% 24 months tacrolimus, mycophenolate, and prednisolone 33.3% tacrolimus 33.3% vadnerkar et al 2010 calcineurin inhibitor, mycophenolate, and prednisolone 88.2% nr voriconazole 23.5% 6 months voriconazole 76.5% > 6 months rodriguez-acosta et al 2015 cyclosporine, azathioprine, and prednisolone nr nr iannacone et al 2016 calcineurin inhibitor, antiproliferative agent, and corticosteroid 53.5% 8.9 years calcineurin inhibitor with or without corticosteroid 35.5% nr = not reported ; sotr = solid organ transplant recipients. 10 review | dermatol pract concept. 2023;13(3):e2023065 9. brenner m, hearing vj. the protective role of melanin against uv damage in human skin†. photochem photobiol. 2008;84(3):539-549. doi: 10.1111/j.1751-1097.2007.00226.x. pmid: 18435612. pmcid: pmc2671032. 10. watson m, holman dm, maguire-eisen m. ultraviolet radiation exposure and its impact on skin cancer risk. semin oncol nurs. 2016;32(3):241-254. doi: 10.1016/j.soncn.2016.05.005. pmid: 27539279. pmcid: pmc5036351. 11. wu s, han j, vleugels ra, et al. cumulative ultraviolet radiation flux in adulthood and risk of incident skin cancers in women. br j cancer. 2014;110(7):1855-1861. doi:10.1038/bjc.2014.43. pmid: 24595003. pmcid: pmc3974077. 12. xiang f, lucas r, hales s, neale r. incidence of nonmelanoma skin cancer in relation to ambient uv radiation in white populations, 1978-2012: empirical relationships. jama dermatol. 2014; 150(10):1063-1071. doi:10.1001/jamadermatol.2014.762. pmid: 25103031. 13. english dr, armstrong bk, kricker a, winter mg, heenan pj, randell pl. case-control study of sun exposure and squamous cell carcinoma of the skin. int j cancer. 1998;77(3):347-353. doi:10.1002/(sici)1097-0215(19980729) 77:3<347::aid-ijc7>3.0.co;2-o. pmid: 9663594. 14. iannacone mr, wang w, stockwell hg, et al. patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin--a case-control study. bmc cancer. 2012;12:417. doi:10.1186/1471-2407-12-417. pmid: 22994655. pmcid: pmc3517361. 15. zanetti r, rosso s, martinez c, et al. the multicentre south european study “helios”. i: skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin. br j cancer. 1996;73(11):1440-1446. doi:10.1038/bjc.1996.274. pmid: 8645595. pmcid: pmc2074488. 16. gabros s, nessel t, zito p. sunscreens and photoprotection. statpearls. published online november 15, 2021. available from https://www.ncbi.nlm.nih.gov/books/nbk537164/accessed april 2, 2022. 17. van der pols jc, williams gm, pandeya n, logan v, green ac. prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. cancer epidemiol biomarkers prev. 2006;15(12):2546-2548. doi:10.1158/1055-9965.epi-06-0352. pmid: 17132769. 18. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021;372:n71. doi:10.1136/bmj.n71. pmid: 33782057. pmcid: pmc8005924. 19. gogia r, binstock m, hirose r, boscardin wj, chren mm, arron st. fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation. j am acad dermatol. 2013;68(4):585-591. doi:10.1016/j .jaad.2012.09.030. pmid: 23107311. pmcid: pmc3562416. 20. moloney fj, almarzouqi e, o’kelly p, conlon p, murphy gm. sunscreen use before and after transplantation and assessment of risk factors associated with skin cancer development in renal transplant recipients. arch dermatol. 2005;141(8):978-982. doi:10.1001/archderm.141.8.978. pmid: 16103326. 21. de rosa n, paddon vl, liu z, glanville ar, parsi k. nonmelanoma skin cancer frequency and risk factors in australian heart and lung transplant recipients. jama dermatol. 2019;155(6):716. doi:10.1001/jamadermatol.2018.4789. pmid: 30865218. pmcid: pmc6563540. conclusions overall, our systematic review of 13 retrospective cohort, prospective cohort, case-control, and observational studies suggests a significant association between uv modifying factors and the risk of kc among individuals who have undergone solid organ transplantation. the four uv modifying factors were fst, race, sunscreen use, and sun exposure. this study identifies sotr patient cohorts at increased risk for the development of kc by fst and race and identifies moderating factors that can contribute to the development of kc that providers can utilize in counseling patients. geographic and occupational sun exposure are 2 noted uv modifying risk factors that increase the incidence of kc in sotr. to the author’s knowledge, there is a dearth of data in the literature which can adequately assess the relationship between sotr patient status and the development of kc. therefore, there is a need for more high-quality, well-powered, prospective studies to give clinicians a better understanding of optimal risk-reducing, patient-centered treatment plans when caring for sotr patients. references 1. sánchez g, nova j, rodriguez-hernandez ae, et al. sun protection for preventing basal cell and squamous cell skin cancers. cochrane database syst rev. 2016;7(7):cd011161. doi:10.1002/14651858.cd011161.pub2. pmid: 27455163. pmcid: pmc6457780. 2. alam m, ratner d. cutaneous squamous-cell carcinoma. n engl j med. 2001;344(13):975-983. doi:10.1056 /nejm200103293441306 pmid: 11274625. 3. madan v, lear jt, szeimies rm. non-melanoma skin cancer. lancet. 2010;375(9715):673-685. doi:10.1016/s0140 -6736(09)61196-x. pmid: 20171403. 4. zamoiski rd, yanik e, gibson tm, et al. risk of second malignancies in solid organ transplant recipients who develop keratinocyte cancers. cancer res. 2017;77(15):4196-4203. doi:10.1158/0008-5472.can-16-3291. pmid: 28615224. pmcid: pmc5540772. 5. greenberg jn, zwald fo. management of skin cancer in solid-organ transplant recipients: a multidisciplinary approach. dermatol clin. 2011;29(2):231-241, ix. doi:10.1016/j .det.2011.02.004. pmid: 21421148. 6. grulich ae, van leeuwen mt, falster mo, vajdic cm. incidence of cancers in people with hiv/aids compared with immunosuppressed transplant recipients: a meta-analysis. lancet. 2007;370(9581):59-67. doi:10.1016/s0140-6736(07)61050-2. pmid: 17617273. 7. crow ld, jambusaria‐pahlajani a, chung cl, et al. initial skin cancer screening for solid organ transplant recipients in the united states: delphi method development of expert consensus guidelines. transpl int. 2019;32(12):1268-1276. doi:10.1111 /tri.13520. pmid: 31502728. 8. sachdeva s. fitzpatrick skin typing: applications in dermatology. indian j dermatol venereol leprol. 2009;75(1):93-96. doi:10.4103/0378-6323.45238. pmid: 19172048. review | dermatol pract concept. 2023;13(3):e2023065 11 transplant recipients. medicina (kaunas). 2019;55(6):e279. doi:10.3390/medicina55060279. pmid: 31208110. pmcid: pmc6631054. 33. bouwes bavinck jn, hardie dr, green a, et al. the risk of skin cancer in renal transplant recipients in queensland, australia. a follow-up study. transplantation. 1996;61(5):715-721. doi:10.1097/00007890-199603150-00008. pmid: 8607173. 34. tessari g, girolomoni g. nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and management. dermatol surg. 2012;38(10):1622-1630. doi:10.1111/j.1524-4725.2012.02520.x. pmid: 22805312. 35. iannacone mr, sinnya s, pandeya n, et al. prevalence of skin cancer and related skin tumors in high-risk kidney and liver transplant recipients in queensland, australia. j invest dermatol. 2016;136(7):1382-1386. doi: 10.1016/j.jid.2016 .02.804. pmid: 26968258. 36. vadnerkar a, nguyen mh, mitsani d, et al. voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. j heart lung transplant. 2010;29(11):1240-1244. doi: 10.1016/j.healun.2010.05.022. pmid: 20591690. 37. rodríguez-acosta ed, calva-mercado jj, alberú-gómez j, vilatoba-chapa m, domínguez-cherit j. [patients with solid organ transplantation and skin cancer: determination of risk factors with emphasis in photoexposure and immunosuppressive regimen. experience in a third level hospital]. gac med mex. 2015;151(1):19-24. 38. penn i, starzl te. malignant tumors arising de novo in immunosuppressed organ transplant recipients. transplantation. 1972;14(4):407-417. doi:10.1097/00007890-197210000 -00001. pmid: 4345337. pmcid: pmc3006181. 39. jensen p, hansen s, møller b, et al. skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. j am acad dermatol. 1999;40(2):177-186. doi:10.1016/s0190-9622(99)70185-4. pmid: 10025742. 40. gjersvik p, hansen s, møller b, et al. are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients? transpl int. 2000;13(7):s380-s381. doi:10.1007 /s001470050366. pmid: 11112037. 41. otley c, pittelkow m. skin cancer in liver transplant recipients. liver transpl. 2000;6(3):253-262. doi:10.1016/s1527 -6465(05)80001-2. pmid: 10827224. 42. ulrich c, kanitakis j, stockfleth e, euvrard s. skin cancer in organ transplant recipients-where do we stand today? am j transplant. 2008;8(11):2192-2198. doi: 10.1111/j.1600 -6143.2008.02386.x. pmid: 18782290. 22. ng jc, cumming s, leung v, chong ah. accrual of non-melanoma skin cancer in renal-transplant recipients: experience of a victorian tertiary referral institution: nmsc accrual in otr. australas j dermatol. 2014;55(1):43-48. doi: 10.1111 /ajd.12072. pmid: 23808627. 23. caforio alp, fortina ab, piaserico s, et al. skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. circulation. 2000;102(suppl_3). doi:10.1161/circ.102.suppl_3.iii-222. pmid: 11082391. 24. ramsay hm, fryer aa, hawley cm, smith ag, harden pn. non-melanoma skin cancer risk in the queensland renal transplant population. br j dermatol. 2002;147(5):950-956. doi:10.1046/j.1365-2133.2002.04976.x. pmid: 12410706. 25. carroll rp, ramsay hm, fryer aa, hawley cm, nicol dl, harden pn. incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in queensland, australia. am j kidney dis. 2003;41(3):676-683. doi:10.1053/ajkd.2003.50130. pmid: 12612993. 26. garcía j, suárez-varela m, vilata j, marquina a, pallardó l, crespo j. risk factors for non-melanoma skin cancer in kidney transplant patients in a spanish population in the mediterranean region. acta derm venerol. 2013;93(4):422-427. doi:10.2340/00015555-1525. pmid: 23303600. 27. savoia p, stroppiana e, cavaliere g, et al. skin cancers and other cutaneous diseases in renal transplant recipients: a single italian center observational study. eur j dermatol. 2011;21(2): 242-247. doi: 10.1684/ejd.2011.1272. pmid: 21382788. 28. dusendang jr, carlson e, lee ds, et al. cohort and nested case-control study of cutaneous squamous cell carcinoma in solid organ transplant recipients, by medication. j am acad dermatol. 2022;86(3):598-606. doi: 10.1016/j.jaad.2021.07.065. pmid: 34384835. 29. kang w, sampaio ms, huang e, bunnapradist s. association of pretransplant skin cancer with posttransplant malignancy, graft failure and death in kidney transplant recipients. transplantation. 2017;101(6):1303-1309. doi:10.1097 /tp.0000000000001286. pmid: 27336396. 30. ulrich c, jürgensen js, degen a, et al. prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. br j dermatol. 2009;161 suppl 3:78-84. doi:10.1111/j .1365-2133.2009.09453.x. pmid: 19775361. 31. green a, williams g, neale r, et al. daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. lancet. 1999;354(9180):723-729. doi:10.1016 /s0140-6736(98)12168-2. pmid: 10475183. 32. zavattaro e, fava p, veronese f, et al. identification of risk factors for multiple non-melanoma skin cancers in italian kidney dermatology: practical and conceptual 162 letter | dermatol pract concept 2019;9(2):18 dermatology practical & conceptual introduction we report the case of a 34-year-old white man with an 8-month history of erythematoviolaceous papulonodules distributed from the left hand to the arm in a sporotrichoid pattern. case presentation a papulonodule was initially noted on the tip of the patient’s fourth left finger. more lesions progressed over the next months along his left arm, with associated tenosynovitis of the same finger. physical examination revealed several nonconfluent, mildly scaling papulonodules on the dorsal aspect of the left hand, forearm, and arm, with a discrete nonpurulent discharge (figure 1a). dermoscopy revealed orange structureless areas associated with white scaling, erosions, serohematic crusts, and dotted/glomerular vessels (figure 1b). the remaining physical examination was unremarkable. the patient worked as a waiter and had some fish tanks and a dog with leishmaniasis. a biopsy specimen disclosed mild acanthosis, orthokeratosis, and occasional epidermal erosions (figure 2a). a diffuse, noncaseating, granulomatous inflammatory infiltrate, composed of lymphocytes, histiocytes, and multinucleated giant cells, was present in the papillary and reticular dermis (figure 2b). gram, ziehl-neelsen, and pas stains failed to detect microorganisms. polymerase chain reactions for both leishmania spp and mycobacterium spp were negative. mycobacterial cultures from a skin biopsy isolated several strains of mycobacterium marinum. our patient started treatment with doxycycline 100 mg once daily for 4 weeks plus clarithromycin 500 mg twice daily for 12 weeks. the lesions disappeared, leaving a mild residual hyperpigmentation. discussion in dermoscopy, orange color is highly suggestive of dermal granulomas, although it has also been described in nonred and orange colors as dermoscopic clues for fish-tank granuloma alejandro lobato-berezo1,2, gemma martín-ezquerra1, ainhoa vidal-navarro1, ramón m. pujol1 1 department of dermatology, hospital del mar-parc de salut mar, barcelona, spain 2 department of dermatology, hospital universitari general de catalunya, sant cugat del vàlles, barcelona, spain key words: orange, red, nodule, arm, fish-tank granuloma citation: lobato-berezo a, martín-ezquerra g, vidal-navarro a, pujol rm. red and orange colors as dermoscopic clues for fish-tank granuloma. dermatol pract concept. 2019;9(2):162-164. doi: https://doi.org/10.5826/dpc.0902a18 accepted: november 19, 2018; published: april 30, 2019 copyright: ©2019 lobato-berezo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alejandro lobato-berezo, md, department of dermatology, hospital del mar, barcelona, passeig marítim, 25-29, 08003 barcelona, spain. e-mail: allobe@hotmail.es letter | dermatol pract concept 2019;9(2):18 163 within the dermis. dotted and glomerular vessels are secondary to the increased inflammatory granulomatous infiltrate. on the other hand, histological and even molecular diagnosis of fish-tank granuloma can be challenging. ziehlneelsen staining is able to detect acid-fast bacilli in a low number of cases, between 13% and 50%, depending both on the stage and the presence of tuberculoid granulomas. culture in löwenstein-jensen agar can detect mycobacterium marinum in 93.3% of the cases and is still considered one of the most specific diagnostic tools [3-5]. conclusions we present the first description of fish-tank granuloma dermoscopy. we would like to highlight the association of orange structureless areas with dotted/glomerular vessels in the dermoscopy as an additional clue to the clinical lesions and the unilateral location to distinguish it from other granulomatous granulomatous diseases [1]. yellowish to orange color has been the main clue for the description of different patterns in granulomatous diseases. in addition, other dermoscopic features could help in the diagnosis, for example, long and very branched telangiectasias in necrobiosis lipoidica, short telangiectasias and white lines and dots between the translucent orange globules in cutaneous sarcoidosis, unfocused vessels in granuloma annulare, pinkish homogeneous background with no or dull orangish areas in rheumatoid nodules, reddish or purple vascular polygons in granulomatous rosacea, yellow tear drops or white starburst pattern in cutaneous leishmaniasis, follicular openings filled with whitish or yellowish keratotic plugs in acne agminata, white areas with areas of alopecia in borderline tuberculoid leprosy, well-focused linear-branching vessels in lupus vulgaris, or granuloma foreign body reaction. these areas may show focal or diffuse distribution [2]. however, lack of this color does not exclude the diagnosis of cutaneous granulomatous disease, mainly at early stages of the disease or when deep granulomas are present in the reticular dermis. in this case, white scales could correspond to epidermal orthokeratosis and orange structureless areas to granulomas figure 1. (a) crusted nodule on the left forearm. (b) small orange structureless areas associated with white scaling, erosions, serohematic crusts, and dotted/glomerular vessels. [copyright: ©2019 lobato-berezo et al.] a b figure 2. (a) mild acanthosis, orthokeratosis, and occasional epidermal erosions (h&e, ×10). (b) diffuse, noncaseating, granulomatous inflammatory infiltrate, composed of lymphocytes, histiocytes, and multinucleated giant cells (h&e, ×40). h&e = hematoxylin and eosin. [copyright: ©2019 lobato-berezo et al.] a b 164 letter | dermatol pract concept 2019;9(2):18 3. belz d, tantcheva-poor i, rasokat h, fabri m, schlaak m. mycobacterium marinum infection initially diagnosed as metastatic crohn’s disease. j eur acad dermatol venereol. 2016;30(3):514515. 4. bonamonte d, de vito d, vestita m, et al. aquarium-borne mycobacterium marinum skin infection: report of 15 cases and review of the literature. eur j dermatol. 2013;23(4):510-516. 5. collina g, morandi l, lanzoni a, reggiani m. atypical cutaneous mycobacteriosis diagnosed by polymerase chain reaction. br j dermatol. 2002;147(4):781-784. diseases. these dermoscopic findings have been found in a single case and need to be validated in future case series. references 1. bañuls j, arribas p, berbegal l, deleón fj, francés l, zaballos p. yellow and orange in cutaneous lesions: clinical and dermoscopic data. j eur acad dermatol venereol. 2015;29(12):2317-2325. 2. errichetti e, stinco g. dermatoscopy of granulomatous disorders. dermatol clin. 2018;36(4):369-375. dermatology: practical and conceptual cutaneous squamous cell carcinoma: an update on diagnosis and treatment table of contents risk factors and diagnosis of advanced cutaneous squamous cell carcinoma gabriella brancaccio, giulia briatico, cristina pellegrini, tea rocco, elvira moscarella, maria concetta fargnoli surgery for cutaneous squamous cell carcinoma and its limits in advanced disease david moreno-ramírez, francisca silva-clavería, almudena fernández-orland, noemí eiris, andrés ruiz de casas, lara ferrándiz radiotherapy in the adjuvant and advanced setting of cscc paolo muto and francesco pastore immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh, daniel morse, jigar patel, michael r. migden treatment of cutaneous squamous cell carcinoma with immune checkpoint inhibitors in special populations paolo bossi, luigi lorini mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples, italy guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s2): e2021169s 1 immunotherapy and systemic treatment of cutaneous squamous cell carcinoma nader aboul-fettouh1, daniel morse1, jigar patel2, michael r. migden3 1 department of dermatology, the university of texas mcgovern medical school at houston, houston, tx, usa 2 department of dermatology, the university of texas md anderson cancer center, houston, tx, usa 3 departments of dermatology and head and neck surgery, the university of texas md anderson cancer center, houston, tx, usa citation: aboul-fettouh n, morse d, patel j, migden mr. immunotherapy and systemic treatment of cutaneous squamous cell carcinoma. dermatol pract concept. 2021; 11(s2): e2021169s. doi: https://doi.org/10.5826/dpc.11s2a169s accepted: may 17, 2021; published: october 2021 copyright: ©2021 aboul-fettouh et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding. none. competing interests: none. this report has not been presented or published previously. authorship: all authors have contributed significantly to this publication. corresponding author: michael r. migden, md, professor, departments of dermatology and head and neck surgery, the university of texas md anderson cancer center, houston, tx, usa. email: mrmigden@mdanderson.org this article is part of the dpc journal special issue cutaneous squamous cell carcinoma: an update on diagnosis and treatment guest editors prof. luc thomas, md, phd full professor and vice-chair, department of dermatology, lyon cancer research center, lyon 1 university, centre hospitalier lyon sud, france. prof. ketty peris, md full professor of dermatology, chief of the complex operative unit of dermatology director of the dermatology and venereology postgraduate school catholic university of rome fondazione policlinico universitario agostino gemelli irccs rome, italy. cutaneous squamous cell carcinomas (cscc) represent one of the most diagnosed non-melanoma skin cancers and its incidence is increasing globally. whereas early stage and low risk cscc is typically treated with surgery, and in some cases other localized therapeutic modalities, locally advanced or metastatic cscc is a cause of significant morbidity and mortality that requires a different approach to therapy. therapeutic attempts at treating advanced cscc include a multi-disciplinary approach with considerations for surgery, radiation, and systemic therapies. in this review, we will discuss the various systemic therapies that have been trialed for advanced cscc, beginning with the early cytotoxic and platinum-based agents as well as their corresponding limitations. we will then review the targeted approaches using egfr inhibitors prior to discussing the more recent immunotherapeutics that have shown good tumor responses in this often-lethal disease. abstract 2 review | dermatol pract concept. 2021; 11(s2): e2021169s introduction the increasing global incidence of cutaneous squamous cell carcinoma (cscc) is an emerging health crisis [1, 2]. studies in the united kingdom, sweden, and germany suggest an incidence of cscc between 9-96 per 100,000 males and 5-68 per 100,000 females [3-5], where australian data reveals an even higher incidence of 499 per 100,000 males and 291 per 100,000 females [6]. variations in cscc incidence may be due to differing nosologic classifications of cscc between regions, which may include actinic keratoses or be limited to only invasive disease. a population-based study by the mayo clinic revealed that between 1976-1984 and 2000-2010 the incidence of cscc increased by 263% [7]. in addition, recent reports show an increasing incidence of scc relative to bcc in the aging population [8]. the majority of early stage cscc cases are successfully treated by surgery. in some cases, other localized therapeutic modalities may be used [9,10]. these include topical cytostatic therapy (5-fluorouracil), topical immunotherapy (imiquimod), or intralesional injection (methotrexate, bleomycin). destructive methods with cryosurgery, lasers, photodynamic therapy, radiotherapy, or curettage and electrodessication may also be used in the appropriate clinical context. approximately 5% of cscc progress into advanced cscc [11]. advanced cscc is comprised of locally advanced contiguous disease that is a poor candidate for surgery, single-modality radiation, or a combination of the two; and metastatic cscc. in cases of larger, more aggressive cscc where surgery can feasibly remove all of the tumor burden, it may come with the cost of significant morbidity and/or disfigurement from damage to nearby anatomical structures and thus is not a reasonable option. treatment of metastatic cscc also presents major challenges. surgery, radiotherapy, and systemic therapy may be used in an attempt to control disease. surgery can be used for tumor debulking as well as excision of isolated metastatic lesions or involved lymph nodes. radiotherapy may be beneficial in treating bone metastases and locally advanced symptomatic tumors. in certain circumstances, these modalities can be used with a palliative intent in order to improve a patient’s quality of life. combining surgery and radiotherapy with systemic therapy can be helpful, as complete remission of disease with purely systemic therapy is not guaranteed. until recently, systemic treatment for cscc was not highly effective and often difficult to tolerate, thus negatively impacting patient’s quality of life. in this article, we will review the various systemic agents that have been used to treat advanced cscc. our discussion will range from the older, more antiquated, therapies, to modern small molecule targeted therapies and immunotherapies, of which pd-1 inhibitors have shown adequate tumor responses for locally advanced or metastatic cscc. we will re-examine the systemic agents that have been trialed for advanced cscc, discuss the limitations of each agent, and highlight future considerations and investigations needed to optimize systemic treatment for advanced cscc. cytotoxic chemotherapy for cscc prior to the development of more modern systemic agents used today, cytotoxic chemotherapy and platinum-based agents were the mainstay of therapy for advanced cscc. numerous agents, including cisplatin, bleomycin, interferon, 5-fluorouracil and doxorubicin had been trialed; many were published as case reports or case series. these articles reported widely varying response rates from 17%-84% [1214]. very few adequately powered randomized controlled trials were available to guide treatment regimens and there were no formal treatment recommendations. in many cases, these agents were combined with other therapy modalities such as radiotherapy or surgery which further confounded long term data evaluation of these treatment regimens [15]. results showed short progression free survival (pfs) and/or overall survival (os). in several cases reporting long-term tumor remission, patients had received subsequent surgical or radiation therapy. table 1 summarizes several studies investigating cytotoxic agents for treatment of advanced cscc and their limitations. these therapies are frequent causes of nausea and emesis, and at times severe hematological toxicities including neutropenia, thrombocytopenia, and anemia [16]. the use of cisplatin in combination with 5-fu and bleomycin showed an objective response rate (orr) of 84% [13] but these types of regimens are not commonly used due to the significant toxicity that is not tolerable in the elderly population which makes up a large portion of the cscc population. in this small combination study, the median age of the 14 patients enrolled was 59, patients had only locally developed tumors (none with metastasis), and 10 patients received adjuvant surgery or radiotherapy. it is worthwhile to note that these therapies continue to be under investigation in combination with more modern small molecule targeted therapies and immunotherapies that are the mainstay of our discussion in this article [17]. targeted therapy for advanced cscc epidermal growth factor receptor (egfr) is a member of the erbb family of tyrosine kinase (rtks) receptors and transmits a growth-inducing signal to cells when stimulated by an egfr ligand [18]. egfr is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation of cells in both physiology and tumor development [19]. the activation of egfr affects numerous biochemical pathways including ras-raf-mek-mapk, plc-gamma/pkc review | dermatol pract concept. 2021; 11(s2): e2021169s 3 and pi3k/akt/mtor, stat and nfkb [20]. these pathways, frequently altered in cscc, allow for increased tumor cell proliferation, migration, survival, altered differentiation, and resistance to apoptosis [21]. differences in expression of egfr between primary and metastatic lesions of cscc have been reported, although egfr expression is not always a requirement for cscc carcinogenesis [22]. egfr inhibitors were one of the earliest systemic targeted therapies for the treatment of advanced cscc. both monoclonal antibodies against the ligand binding domain of egfr, as well as small tyrosine kinase inhibitors (tki)molecules, have been trialed. cetuximab, a human/mouse chimeric monoclonal antibody, competitively binds and inhibits the ligand binding domain of egfr thus limiting its interaction with the egfr-ligand. a phase ii study of cetuximab as first-line single-drug therapy in patients with advanced cscc, conducted by maubec and colleagues [23], included 36 patients that received cetuximab at an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 for at least 6 weeks with a 48 week follow up. orr was 28%, with 2 complete remissions (6%) and 8 partial responses (22%), and a short mean os of 8.1 months. notably, the safety profile of the study was acceptable and similar to that of other studies. a larger retrospective clinical trial by montaudié and colleagues, showed an orr of 42% and 70% disease control rate (dcr) at 12 weeks in chemotherapy-naïve patients treated with cetuximab for advanced cscc. median os was 17.5 months, and the majority of adverse events were grade 1 to 2. notably, this trial included a large proportion of immunocompromised patients (~33% of the 58-patient cohort) which are typically excluded from clinical trials. the authors did note that their trial included a significantly higher table 1. cytotoxic chemotherapy for the treatment of cscc study regimen line of therapy pts (n) response rate duration of response notes/limitations guthrie t et al. 1985(75) cisplatin + doxorubicin mixed first/ second+ 4 cr 25% pr 50% orr 75% 3–24 months one patient had subsequent st guthrie t et al. 1990(14) cisplatin + doxorubicin mixed first/ second+ 12 cr 33% pr 25% orr 58% sole therapy (7) or neoadjuvant (5) receiving rt or st sadek h et al. 1990(13) cisplatin + 5-fluorouracil† + bleomycin second+ 13 cr 30% pr 54% orr 84% almost all pts received subsequent st/rt khansur t et al. 1991(76) cisplatin + 5-fluorouracil first line 7 cr 43% pr 43% orr 86% one patient received subsequent st. several patients lost to follow up merimsky o et al. 1992(77) adriamycin + cisplatin second+ line 2 cr 50% pr 50% orr 100% both patients had only locally advanced disease. cartei g et al. 2000(78) oral 5-fluorouracil second+ line 14 cr 0% pr 14% orr 14% median 30 weeks none had distant metastasis. some received oral + topical 5-fu shin dm et al. 2002(79) ifn-alpha and 13-cis-retinoic acid and cisplatin mixed first/ second+ 39 cr 17% pr 17% orr 34% median 9 months none had distant metastasis. median survival 14.6 months. fujisawa y et al. 2006(80) cisplatin + 5-fluorouracil + rt first line 2 cr100% pr 0% orr 100% both patients had only locally advanced disease. nottage mk et al. 2017(15) (cisplatin or carboplatin) + rt first line 19 cr 53% pr 47% orr 100% median survival just over 24 months note this table is just a limited sampling of published reports including cytotoxic chemotherapy for advanced cutaneous scc. cr= complete response; pr = partial response; orr = overall response rate; st = surgical therapy; rt = radiation therapy; pts = patients; ifn-alpha = interferon alpha 4 review | dermatol pract concept. 2021; 11(s2): e2021169s portion of patients with only local disease (~66%) compared to that of the maubec study (39%). this same group had also reported an orr of 48% and dcr of 68% at six weeks in a separate retrospective cohort of 31 patients treated with cetuximab, with 47% of patients having local disease rather than metastatic [24]. panitumumab, a fully humanized monoclonal antibody targeted at the egfr, reported a 31% orr in a phase ii clinical trial by foote and colleagues [25]. this cohort of patients only included 16 patients, with 14 patients receiving previous radiotherapy and 7 patients having received prior cytotoxic chemotherapy. progression-free survival (pfs) was 8 months and median os was 11 months. in a translational sub-study, total egfr expression levels were not found to be associated with treatment efficacy. gefitinib and erlotinib are small tkis molecules targeting the egfr that have been studied in advanced cscc. gefitinib showed an orr of 16% and dcr of 51% as monotherapy for advanced cscc [26] but had a notably improved 45.5% orr when used as neoadjuvant therapy where treatment included standard surgery or radiotherapy [27]. erlotinib has also failed to show great efficacy as monotherapy, with a single-arm phase ii trial reporting an orr of 10% (all partial responses) although there was a notable dcr of 72% [28]. erolitinib combined with surgery and postoperative adjuvant radiation therapy in a phase i trial showed a recurrence rate of 26.7% with mean time to recurrence in 10.5 months, again highlighting the use of these agents in combination with other systemic agents or therapeutic modalities [29]. lapatinib, a tki that blocks the her2 receptor, has been found to be anecdotally effective in treatment of advanced cscc [30], prompting larger trials to investigate its efficacy in larger cohorts [31]. egfr-targeted therapies are typically more tolerable with adverse effects being less severe when compared to cytotoxic agents. cutaneous adverse events are incredibly frequent, occurring from 50-100% of the time in reported clinical trials using these agents, and can be a cause of poor drug compliance and/or drug cessation [32]. acneiform eruptions in seborrheic areas are common, but patients may also develop xerosis, paronychia, and other cutaneous toxicities. there is a positive correlation between the occurrence and severity of cutaneous adverse effects and tumor response, which can be a supporting detail to discuss with patients when helping manage these skin toxicities [33]. due to significant egfr expression in epithelial cells of the gastrointestinal tract, diarrhea is a common adverse event of egfr targeted agents, with incidence varying from 27% to 87% in various phase iii clinical trials for various malignancies [34]. nevertheless, these adverse events are more manageable in comparison to the severe side effects that can occur with cytotoxic therapies. intrinsic and acquired resistance to egfr inhibitors is well recognized [35]. several mechanisms of resistance in advanced malignancies have been described and many include genomic alterations in downstream effectors of the egfr signaling pathway [36]. these may arise either as new genetic alterations in the tumor after start of therapy, or through positive selection pressure of anti-egfr therapies on an already-present group of egfr-resistant cells present at time of treatment initiation [37]. strategies to combat anti-egfr resistance include the use of combination therapy with other therapeutic modalities such as radiotherapies, or combination therapies with other systemic agents including traditional cytotoxic chemotherapy [38]. table 2 summarizes a small sample of studies investigating targeted therapies for treatment of advanced cscc. treatment with these agents may be limited due to short durations of response and progression free survival. table 2. targeted therapies for the treatment of advanced cutaneous scc study regimen line of therapy pts (n) response rate duration of response notes/limitations maubec e et al. 2011(23) cetuximab first line (42%) second+ line (58%) 36 cr 6% pr 22% orr 28% mean 6.8 months mean os 8.1 months median pfs 4.1 months dcr of 69% some patients received subsequent surgical excision montauedié h et al. 2020(24) cetuximab first line (36%) second+ line (64%) 58 cr 2% pr 40% orr 42% retrospective study dcr at 12 weeks 70% median pfs 9.7 months median os 17.5 months hillen u. et al. 2018(81) cetuximab majority second+ line 15 cr 6% pr 13% orr 20% mean 7 months retrospective study table 2 continues review | dermatol pract concept. 2021; 11(s2): e2021169s 5 systemic immunotherapy for advanced cscc immunogenicity of cutaneous squamous cell carcinoma a discussion of the immune system’s role in development of cscc and tumor progression is essential to understanding how immunotherapy acts and mediates destruction of target tumor cells. it is known that immunosuppression significantly increases the incidence of non-melanoma skin cancer including cscc which occurs 65-250 times more frequently in patients after organ transplantation compared to the general population [39]. in addition, cscc in the organ transplant population tend to be more aggressive with an increased risk of local recurrence, regional and distant metastasis, and mortality [40]. chronic immunosuppression impairs normal immune surveillance and eradication of carcinogenic changes within tumor cells. ultraviolet (uv) radiation, a primary pathogenic factor for development of squamous cell carcinoma, directly causes uv-specific mutations in keratinocytes as well as a functional and quantitative reduction in the cutaneous immune response, which in turn suppresses the cutaneous antigen presentation and recognition in the cutaneous environment [41]. cutaneous scc has one of the highest mutational burden (tmb) of all tumors including melanoma and other squamous tumor types [42]. tmb has shown to have predictive value of tumor response using immune checkpoint inhibitors in advanced malignancies [43], making cscc an ideal candidate for immunotherapy treatment. tumor cells attempt to evade the immune system through a variety of mechanisms, and those cells that succeed show a loss of expression of immunogenic tumor-specific antigens [44]. these cells are admixed with a variety of infiltrating leukocytes of both innate and adaptive origin in what is called a tumor microenvironment (tme). this microenvironment includes many complex and dynamic interactions between tumor cells and the immune cells, including t-cells which constitute a major cell type found in this microenvistudy regimen line of therapy pts (n) response rate duration of response notes/limitations preneau s et al. 2014(82) cetuximab (6), cetuximab + rt (5), cetuximab + carboplatin (9) first line (10%) second+ line (90%) 20 orr 47% os 11.1 months pfs 5.7 months orr: cetuximab monotherapy (33%), cetuximab + carboplatin (38%), cetuximab + rt (80%) reigneau m et al. 2015(83) neoadjuvant cetuximab +/(platinum based agent + 5-fluorouracil) prior to st mixed first line and second+ line 34 locally advanced scc only 9 pts received cetuximab monotherapy tumors became resectable in 28 of 34 patients (82%) some patients received adjuvant rt galbiati d et al. 2019(17) cetuximab + (cisplatin or carboplatin) second+ line 12 cr 8% pr 42% orr 50% median 4.8 months median pfs 6.6 months median os 14.6 months some patients subsequently received st or rt foote mc et al. 2014(25) panitumumab first line (6%) second+ line (92%) 16 cr 12 % pr 19% orr 31% median 5 months median pfs 8 months median os 11 months william wn et al. 2017(26) gefitinib second+ line 37 cr 0% pr 16% orr 16% median 31.4 months dcr 51% median os 12.9 months median pfs 3.8 months lewis et al. 2012(27) neoadjuvant gefinitib prior to st and/or rt first line (43%) second+ line (57%) 22 cr 18% pr 27% orr 45% 2-year os 72.1% 2-year pfs 63.6% gold et al. 2018(28) erlotinib second+ line 29 cr 0% pr 10% orr 10% dcr 72% median os 13 months median pfs 4.7 months note this table is just a limited sampling of published reports including targeted therapies for advanced cutaneous scc. cr= complete response; pr = partial response; orr = overall response rate; st = surgical therapy; rt = radiation therapy; pts = patients; dcr = disease control rate; scc = squamous cell carcinoma. 6 review | dermatol pract concept. 2021; 11(s2): e2021169s ronment [45]. tumor cells can evade the immune system in the tme by t-cell co-stimulation through tumor cell upregulation of immune-checkpoint co-signaling proteins such as cytotoxic t-lymphocyte-associated antigen 4 (ctla-4) and programmed death-1 (pd-1) protein. these act as brakes on the anti-tumor immune response, and have become immunotherapeutic targets in treatment of cscc. exploring the vast and intricate interactions between the immune response and cscc is beyond the scope of this review. nevertheless, a strong emphasis should be placed on recognizing that these interactions form the backbone from which modern immunotherapeutics have been designed and developed. pd-1 inhibitors pd-1 inhibitors have become a mainstream approach for the treatment of a variety of cancers including, but not limited to, non-small cell lung cancer, metastatic melanoma, colorectal cancer, as well as advanced cscc [46]. the pd-1 receptor protein on t-cells interacts with its corresponding ligand, pd-l1 or pd-l2, which may be expressed on tumor cells or tumor infiltrating lymphocytes that may be in the tme. this interaction transmits downstream signals that inhibit t-cell proliferation, cytokine production, and cytolytic function, thus inhibiting the immunogenic antitumor response [47-49]. pd-1 inhibitors are one type of immune checkpoint inhibitor that blocks the pd-1/pd-l1 interaction and allows for enhanced immune surveillance and destruction of tumor cells. pembrolizumab, nivolumab, and most recently cemiplimab are anti-pd1 monoclonal antibodies used in the treatment of advanced malignancies. in 2018, registration trials by migden and colleagues showed orrs of 41.1-50% in the phase i and ii studies that included patients with locally advanced or metastatic cscc treated with weight-based dosing of cemiplimab (3mg/kg q2weeks) or a fixed dose (350 mg q3weeks). disease control rates ranged from 62-71.2% [5052]. it is worthwhile to note that there were patients included in these trials where partial response was not obtained until after 6-10 months of treatment and thus only a few cycles of therapy seem insufficient to determine response. some patients who initially appeared as non-responders later showed impressive tumor regression and at times a complete response. the keynote-629 trial by grob and colleagues, a single arm phase ii trial that treated 105 patients with 200 mg pembrolizumab q3 weeks (q3w), observed a 34.4% orr with a 52.4% dcr [53]. it should be noted that in 86.7% of patients in the keynote-629 trial, pembrolizumab was at least second line therapy. maubec and colleagues reported a slightly higher orr of 41% and dcr of 54% in a phase ii study of pembrolizumab as first-line monotherapy [54]. although nivolumab lacks completed large scale phase i and ii trials for advanced cscc as seen with cemiplimab and pembrolizumab, it has been used as therapy for advanced cscc. table 3 summarizes several studies investigating anti-pd1 therapies for advanced cscc. table 3. anti-pd1 therapies for advanced cscc study regimen line of therapy pts (n) response rate duration of response notes/limitations migden mr et al. 2018 (50) cemiplimab first line (31%) second+ line (69%) 26 cr 0% pr 50% orr 50% median nr expansion cohorts of phase i study including locally advanced or metastatic cscc migden mr et al. 2020(52) cemiplimab first and second+ line 78 cr 13% pr 31% orr 44% median nr km dor 89% phase ii locally advanced cscc cohort km 1 year os 81% km 1 year pfs 53% richscin d et al. 2020(51) cemiplimab first and second+ line 71 cr 11% pr 34% orr 45% median nr km dor 90% dcr 68% km 1 year os 81% km 1 year pfs 51.2% in gk et al. 2020(84) cemiplimab (13) pembrolizumab (7) nivolumab (6) first and second+ line 26 cr 23% pr 19% orr 42% median 7.6 months retrospective study median pfs 5.4 months maubec e et al. 2020(54) pembrolizumab first line (31%) second+ line (69%) 57 cr 8% pr 33% orr 41% median nr dcr 60% salzmann m et al. 2020(85) cemiplimab (8) pembrolizumab (28) nivolumab (10) first line (67%) second+ line (33%) 46 cr 15% pr 44% orr 59% retrospective study dcr 80% km 1 year pfs 59% table 3 continues review | dermatol pract concept. 2021; 11(s2): e2021169s 7 immunotherapy brings with it a wide variety of possible immune related adverse events (iraes) involving various organ systems that may be monitored, managed symptomatically, or treated with systemic steroids if grade 3 or higher. in the large-scale trials of cemiplimab mentioned above, the most reported side effects in the study were diarrhea and fatigue, experienced by 25% of enrolled patients, of which the majority were low grade [50]. patients should be very closely monitored and informed to report even the mildest of symptoms, as life-threatening irae such as colitis, pneumonitis, and hepatitis represent a possible downside of immunotherapy. most clinical trials involving immunotherapy have excluded patients with a prior history of autoimmune disease. those that included patients with a history of autoimmune disease showed that anti-pd1 agents may cause disease flares. although some patients did experience significant anti-tumor activity, the degree of flares did not correlate with degree of response [55]. pd-1 inhibitors are not excluded from the shortfalls of intrinsic or acquired tumor resistance. in the open-label, multicohort phase 1b clinical trial for patients with metastatic melanoma, 25% of patients treated with pd-1 inhibitors who demonstrated an objective response later developed disease progression [56]. mechanisms of resistance are believed to include loss of cell function, disruption of antigen presentation, as well as several other immune-associated factors [57]. acquired resistance of pd-1 inhibitors in non-melanoma skin cancer has not been frequently reported or characterized at this time, but may be revealed as additional larger trials with these agents are completed. intralesional therapy of immune checkpoint inhibitors are an appealing approach to treatment. this may allow for higher local tissue concentrations of the agent within the tumor site, with limited systemic exposure and possibly lower systemic toxicity. a study investigating intralesional pd-1 inhibitor therapy for recurrent cscc is currently underway [58]. pd1/pd-l1 expression and tumor response identification of tumors that are most likely to respond to anti-pd1 agents has been difficult. studies on pd1 inhibitors for the treatment of various advanced malignancies have shown that pretreatment tumor pd-l1 expression has a potential association with response to the pd-1 pathway blockade [59]. however, in other cases, pd-l1 negative patients showed excellent response to treatment whereas pd-l1 positive patients showed no response to therapy [6062]. there are no established guidelines, understandably, when considering how and when to biopsy a tumor sample. small needle biopsies versus punch biopsies of cutaneous tumors may provide differing results. in addition, gene expression is not uniform throughout a tumor [63] and 1 biopsy alone may be far from sufficient to provide adequate sampling. in some instances, pd-l1 expression is limited or may even be absent in tumor cells while significant expression of this marker was noted in the tumor infiltrating lymphocytes. variations between methods used including immunohistochemistry and staining techniques, as well as definitions of pd-l1 ‘positivity’ (cell surface expression, cytoplasmic expression, by tumor cells only, by immune related cells, threshold of positivity) make for less conclusive predictive value of these markers. there is much more work needed to determine the validity and reliability of pd-l1 expression as a predictor of tumor response. anti-pdl1 agents complementing the anti-pd1 agents discussed above, antipdl1 agents have been developed in hopes of adding yet another agent in our fight against advanced malignancies. atezolizumab, avelumab, and durvalumab are igg1 antibodies targeting against the pd-l1 ligand. these agents have been used for treatment of various malignancies including urothelial carcinoma, non-small cell lung cancer, and metastatic merkel-cell carcinoma. in 2017, there were 117 ongoing clinical trials that involved atezolizumab [64]. although there study regimen line of therapy pts (n) response rate duration of response notes/limitations grob jj et al. 2020(53) pembrolizumab first line (13%) second+ line (87%) 105 cr 4% pr 31% orr 34% median nr dcr 52.4% median pfs 6.9 months median os nr eton o et al. 2020(86) pembrolizumab + panitumumab (1) nivolumab + panitumumab (1) second+ line 2 cr 100% orr 100% case series note this table is just a limited sampling of published reports including pd-1 inhibitor therapies for advanced cutaneous scc. cr= complete response; pr = partial response; orr = overall response rate; st = surgical therapy; rt = radiation therapy; pts = patients; dcr = disease control rate; dor= duration of response; cscc = cutaneous squamous cell carcinoma; nr= not reached; kr = kaplan-meier estimate 12-month estimate 8 review | dermatol pract concept. 2021; 11(s2): e2021169s are studies using anti-pdl1 agents for advanced cscc, there is no data published at this time. the second pd-1 ligand, pd-l2, is selectively expressed on monocytes and dendritic cells and could similarly be another molecular target [65]. rp1 monotherapy and in combination with pd-1 inhibitors oncolytic virotherapy (ov) is the use of a replication-competent virus for the treatment of cancer. ov must be non-pathogenic to normal cells and can work in a variety of mechanisms to selectively kill tumor cells. in the last few decades, commercially available ovs have been used in a variety of cancers including metastatic melanoma [66]. ov has the ability to stimulate an anti-cancer immune response, increasing the immune activity within the tme. by enhancing this immune response, targeting tumor cells, and exposing tumor neoantigens, ov could provide a logistical complement to immune checkpoint inhibition. unfortunately, a detailed discussion of ovs and their effects on the tme is beyond the scope of this review. an open-label, single-arm phase ii clinical trial of the oncolytic hsv rp1 in combination with nivolumab has shown early promising results, with 5 of 6 metastatic cscc patients enrolled showing disease response and 3 complete responses [67]. larger ongoing studies will evaluate the efficacy and durability of responses in patients with advanced cscc. ctla-4 inhibitors ipilimumab is a ctla-4 blocking antibody that became the first checkpoint inhibitor to be tested and shown to be effective for the treatment of cancer patients, specifically metastatic melanoma [68]. in 2015, ipilimumab showed durable complete responses in patients with metastatic melanoma and became a standard-of-care adjuvant treatment of resected stage iii melanoma [69]. day and colleagues reported a durable response in metastatic cscc using ipilimumab, although larger trials are needed to fully characterize ipilimumab’s safety and efficacy for this cancer [70]. the combination of ipilimumab and nivolumab has reported increased efficacy over that of single agent checkpoint blockade. these effects were more durable and significantly prolonged survival of responsive patients for various malignancies [71]. this combination therapy is currently under investigation for the treatment of advanced cscc [72]. summary of systemic therapy for advanced cscc advanced cscc manifests with highly variable presentation having many patient-specific features and considerations. although some early use of cytotoxic chemotherapy agents for advanced cscc showed impressive response rates, many of these trials included a combination of agents, as well as subsequent surgery or radiation therapy. the limitations of cytotoxic chemotherapy include their significant and at times lethal side effect profiles which is poorly tolerated in the elderly population that characterizes advanced cscc. egfr targeted therapies such as cetuximab showed reasonable responses, with less toxic side effect profiles that included cutaneous eruptions and gastrointestinal adverse events. however, the durability of response was suboptimal with a high percentage of tumor recurrence and low overall survival at the 2-year mark. immunotherapy with pd-1 inhibitors demonstrate good response rates and generally good tolerability. although severe iraes have occurred, lower grade adverse events are more common. as monotherapy, large scale trials of pd1 inhibitors showed orrs close to 50%. while biomarkers are conceptually well suited for deciding which systemic agents would provide the most clinical benefit, assessment of these to date has yielded mostly inconsistent results. patients with advanced cscc treated with cetuximab showed efficacy in a cohort of patients that did not reveal significant egfr mutations, although this is specific to the investigated loci in the study by picard and colleagues [73]. as noted above, similar findings have been noted with pd-1 inhibitors where complete responses occurred in tumors that lacked tumor and til pd-l1 expression, or the lack of response was seen in tumors that strongly expressed pd-l1[60-62]. in addition, differences in the methods used for biomarker testing or other assays further confound the interpretation of these results [74]. standardization of biomarker testing in large-scale trials may lead to more conclusive findings of any correlations identified. conclusions significant advances have been made in the quest to achieve durable tumor responses with limited systemic toxicity in the fight against advanced cscc. although we have reviewed numerous agents and trials including cytotoxic chemotherapies, targeted agents, and immunotherapies, head-to-head comparisons are not appropriate due to the differences in study design. there are substantial differences of the demographics enrolled in these studies, and many trials did not involve first line therapy. although different drugs within the same class may work in a similar fashion, we cannot assume that they are equivalent in efficacy or safety. nevertheless, the rise of immunotherapy, specifically pd-1 inhibitors, have shown adequate tumor responses with less frequent severe systemic toxicities. cytotoxic agents and targeted based therapies should not be altogether forgotten, and can continue to be considered in specific cases where immune checkpoint inhibition is contraindicated. the large number of trials in progress today include adjuvant, neoadjuvant monotherapy and combinations of the agents discussed in this review. even so, much work is needed to improve outcomes while review | dermatol pract concept. 2021; 11(s2): e2021169s 9 decreasing risks from adverse events in the fight against advanced cscc. references 1. lomas a, leonardi-bee j, bath-hextall f. a systematic review of worldwide incidence of nonmelanoma skin cancer. br j dermatol. 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thrombocytopenia (27,000x109/l) and elevated d-dimer level (84,369 mcg/l) were observed, all of which supported the diagnosis of kasabach-merritt phenomenon (kmp). a doppler ultrasound study and magnetic resonance imaging (mri) revealed the importance of early diagnosis and treatment of kaposiform hemangioendothelioma complicated by kasabach-merritt phenomenon grecia v. vivas-colmenares 1, gema l. ramirez-villar2, jose bernabeu-wittel3, jose a. matute de cardenas1, israel fernandez-pineda1 1 department of pediatric surgery, virgen del rocio children’s hospital, sevilla, spain 2 department of pediatric oncology, virgen del rocio children’s hospital, sevilla, spain 3 department of pediatric dermatology, virgen del rocio children’s hospital, sevilla, spain key words: kaposiform hemangioendothelioma, kasabach-merritt phenomenon, vincristine, ticlopidine, aspirin citation: vivas-colmenares gv, ramirez-villar gl, bernabeu-wittel j, matute de cardenas ja, fernandez-pineda i. the importance of early diagnosis and treatment of kaposiform hemangioendothelioma complicated by kasabach-merritt phenomenon. dermatol pract concept 2015;5(1):18. doi: 10.5826/dpc.050118 received: august 19, 2014; accepted: september 22, 2014; published: january 30, 2015 copyright: ©2015 vivas-colmenares et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: israel fernandez-pineda, md, department of pediatric surgery, virgen del rocio children’s hospital, av. manuel siurot s/n, seville, spain. tel. 34 955012924. email: israel.fernandez.pineda@gmail.com kaposiform hemangioendothelioma (khe) is a locally aggressive vascular tumor that may be complicated by kasabach-merritt phenomenon (kmp), a profound thrombocytopenia resulting from platelet trapping within a vascular tumor, either khe or tufted angioma (ta). typical features also include low fibrinogen and elevated d-dimers. it is well known that kmp is not caused by infantile hemangiomas. management of vascular tumors complicated by kmp is challenging, and it is common for referral centers to receive patients in critical medical condition after multimodality treatment failure of vascular anomalies. our aim is to communicate the importance of early diagnosis and treatment of khe associated with kmp. a full-term male newborn with khe complicated by kmp is reported. treatment with vincristine, aspirin and ticlopidine normalized the coagulation parameters within one week, requiring a total of six doses of vincristine, seven months of ticlopidine and 17 months of aspirin. early diagnosis and treatment of khe complicated by kmp may allow the administration of fewer doses of vincristine and avoid the use of corticosteroids. abstract mailto:israel.fernandez.pineda@gmail.com 92 observation | dermatol pract concept 2015;5(1):18 ing kmp [1-5]. in an extensive review of khe, croteau et al [6] reported that superficial tumors, tumors isolated to bone, or presentation at an older age are each a characteristic that is associated with decreased frequency of kmp. patients with khe with fascial involvement but not deeper invasion of muscle or bone seem to present with few complications of kmp. the consensus-derived practice standards plan for complicated khe was published in 2013 and reported that 64% of experts’ centers did not think that a tissue biopsy was necessary to confirm diagnosis of kmp [7]. as in our case, most of the patients present are diagnosed based on clinical, imaging and laboratory findings (profound thrombocytopenia and elevated serum d-dimer). diagnosis of khe associated with kmp is usually delayed, and several factors may be implicated such as lack of experience in clinical diagnosis of vascular anomalies, deep tumor location (mediastinum, retroperitoneum) and/or the coagulation abnormalities that makes the biopsy challenging. differential diagnosis with other tumors that may cause coagulopathy should be performed. baselga et al [8] described that rapidly involuting congenital hemangioma (rich) may present with thrombocytopenia and coagulopathy similar to mild kmp early in the neoa multichanneled fast-flowing vascular tumor. clinical appearance of the tumor, radiological findings, and the coexisting kmp supported the diagnosis of kaposiform hemangioendothelioma (khe). treatment was according to seop (spanish society of pediatric oncology) guidelines for vascular tumors complicated by kmp and included vincristine, aspirin and ticlopidine (vat therapy). the patient received vat therapy with vincristine: 0.05 mg/kg weekly; aspirin: 10 mg/kg/day; and ticlopidine: 10 mg/ kg/day. treatment response was based on platelet count and classified as good response (increase of >50% of platelet count) observed in obtained blood tests no longer than three weeks since the treatment was started and repeated every two weeks. coagulation parameters normalized within one week, along with the decrease in size of the tumor. the patient required a total of six doses of vincristine, seven months of ticlopidine and 17 months of aspirin. twelve months after discontinuation of aspirin, the patient remains asymptomatic with no tumor regrowth and normal platelet count. discussion khe involves a spectrum of lesions from small, superficial tumors without kmp to large, infiltrative lesions with life-threatening complications includfigure 1. right latero-cervical kaposiform hemangioendothelioma at birth (a) and 17 months later, after completion of therapy (b). (copyright: ©2015 vivas-colmenares et al.) natal period. however, in contrast to true kmp, these abnormal laboratory findings are self-limited and are usually not complicated by bleeding problems. rich is fully formed at birth and it does not enlarge within the first weeks of life. clinical appearance of rich is characterized by superficial prominent veins and is encircled by a pale halo, while khe is a plaque-like lesion with ecchymosis. a biopsy would have been useful to obtain a histological diagnosis in our case, but the patient presented a profound thrombocytopenia and severe abnormalities in coagulation parameters, which made the biopsy a high-risk bleeding procedure. on imaging studies (mri, doppler-us), both tumors are highly vascularized lesions with highflow, but khe has a more infiltrative pattern compared to rich. evaluation of treatment outcomes is difficult and based on personal opinions, isolated case reports and small series. most of the patients receive multimodality therapy, and some delays of initiation of therapy may cause significant morbidity and mortality. the literature describes a variable response to corticosteroid therapy (20–70%), and depending on the dosage can cause several adverse side effects such as severe hypertension, growth restriction, and osteoporosis [9,10]. although case reports have described the efficacy of propranolol for the treatment of khe, chiu et al [11] found that propranolol was ineffective in seven of their eleven patients and recommend clinicians to proceed cautiously before treating these life-threatening conditions with propranolol. recently, sirolimus has been described to be effective and safe in patients with life-threatening khe and may represent a promising tool in treating refractory khe [12]. vincristine is usually used in combination with other therapies for severe, life-threatening cases because of its good tolerance and response. several studies used vincristine monotherapy for kmp with good response rates of 86-100% [13,14]. in observation | dermatol pract concept 2015;5(1):18 93 is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. plast reconstr surg 1997;100:1377–86. 5. enjolras o, wassef m, mazoyer e, et al. infants with kasabachmerritt syndrome do not have “true” hemangiomas. j pediatr 1997;130:631–40. 6. croteau se, liang mg, kozakewich hp, et al. kaposiform hemangioendothelioma: atypical features and risks of kasabachmerritt phenomenon in 107 referrals. j pediatr 2013;162:142-47. 7. drolet ba, trenor cc, brandão lr, et al. consensusderived practice standards plan for complicated kaposiform hemangioendothelioma. j pediatr 2013;163(1):285-91. 8. baselga e, cordisco mr, garzon m, et al. rapidly involuting congenital haemangioma associated with transient thrombocytopenia and coagulopathy: a case series. br j dermatol 2008;158:1363. 9. fahrtash f, mccahon e, arbuckle s. successful treatment of kaposiform hemangioendothelioma and tufted angioma with vincristine. j pediatr hematol oncol 2010;32(6):506-10. 10. hall gw. kasabach-merritt syndrome: pathogenesis and management. br j haematol 2001 mar;112(4):851-62. 11. chiu ye, drolet ba, blei f, et al. variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and kasabach-merritt phenomenon. pediatr blood cancer 2012;59(5):934-8. 12. kai l, wang z, yao w, dong k, xiao x. sirolimus, a promising treatment for refractory kaposiform hemangioendothelioma. j cancer res clin oncol 2014;140(3):471-76. 13. hermans dj, van beynum im, van der vijver rj, et al. kaposiform hemangioendothelioma with kasabach-merritt syndrome: a new indication for propranolol treatment. j pediatr hematol oncol 2011;33(4):171-73. 14. haisley-royster c, enjolras o, et al. kasabach-merritt phenomenon: a retrospective study of treatment with vincristine. j pediatr hematol oncol 2002;24(6):459-62. 15. monagle p, chalmers e, chan a, et al. antithrombotic therapy in neonates and children: american college of chest physicians evidence-based clinical practice guidelines (8th edition). chest 2008;133(6suppl):887s–968s. our protocol, antiaggregant therapy (aspirin and ticlopidine) in combination with vincristine is used as primary treatment for kmp associated with khe (vat therapy). this therapy is continued until normal platelet count is obtained; then, vincristine is generally discontinued and antiaggregant agents are continued, although the optimal duration of treatment has not been defined. the interest of the case lies in the benefit of the early management of khe complicated by kmp, avoiding the use of corticosteroids and allowing the administration of fewer doses of vincristine. however, some discussion should be highlighted; early referral of patients with khe to centers with expertise in vascular anomalies is uncommon and diagnosis is delayed in most of the cases. also, there are potential side effects associated with early treatment in younger patients. vincristine may cause neuropathy and antiaggregant agents may cause bleeding. chronic use of aspirin has been associated with the development of reye syndrome, but the current recommendation is to discontinue the use of aspirin only during suspected influenza or varicella infections [15]. references 1. zukerberg lr, nickoloff bj, weiss sw. kaposiform hemangioendothelioma of infancy and childhood. an aggressive neoplasm associated with kasabach-merritt syndrome and lymphangiomatosis. am j surg pathol 1993;17:321-28. 2. sarkar m, mulliken jb, kozakewich hp, robertson rl, burrows pe. thrombocytopenic coagulopathy (kasabach-merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. plast reconstr surg 1997;100:1377-86. 3. kelly m. kasabach-merritt phenomenon. pediatr clin north am 2010;57:1085–89. 4. sarkar m, mulliken jb, kozakewich hpw, et al. thrombocytopenic coagulopathy (kasabach-merritt 129 phenomenon) dermatology: practical and conceptual 166 letter | dermatol pract concept 2018;8(3):2 dermatology practical & conceptual www.derm101.com the role of dermoscopy in a topical steroid-damaged face sidharth sonthalia1, abhijeet k. jha2, reena sharma3 1 skinnocence: the skin clinic, guragaon, india 2 patna medical college and hospital, patna, bihar, india 3 department of dermatology, derma essence clinic, noida, india key words: dermoscopy, steroid abuse, topical steroid-damaged face citation: sonthalia s, jha ak, sharma r. the role of dermoscopy in a topical steroid-damaged face. dermatol pract concept. 2018;8(3):166167. doi: https://doi.org/10.5826/dpc.0803a02 received: february 8, 2018; accepted: april 21, 2018; published: july 31, 2018 copyright: ©2018 sonthalia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sidharth sonthalia, skinnocence: the skin clinic, c-2246, sushant lok-1, block c, gurgaon, 122009, india. email: sidharth.sonthalia@gmail.com a 29-year old male presented with pinkish-red erythema over the cheeks with patchy brown discoloration and grossly visible telangiectasias of 6 months’ duration (figure 1). he also complained about his facial skin being very sensitive, especially to sun exposure. the patient was aware that he had melasma and gave a history of occasional use of sunscreen in the past. despite repeated and persuasive questioning, he staunchly denied applying any topical steroid-containing formulations or depigmenting creams. polarized dermoscopic examination (escope; nakoda, ×20) of the cheeks revealed a reddish-brown background, brown dots, globules and clods, multiple tortuous and branching linear vessels and telangiectasias, and ivory white-to-strawberry ice cream colored patches in addition to conspicuous hypertrichosis (figure 2a-2b). suspecting topical steroid abuse, he was shown the dermoscopic features on the computer screen and cautioned about the complications of “topical steroid-damaged face.” he finally admitted to having used a mometasonecontaining triple combination cream over the cheeks twice a day for the previous 4 months, at the suggestion of a friend. since his last examination, the patient has been using a broadspectrum sunscreen on a daily basis, topical vitamin 20% serum and has been scheduled for intense pulsed light therapy for facial rejuvenation. prominent telangiectasias, ivory white-to-strawberrycolored patches (suggestive of skin atrophy) and lesional hypertrichosis constitute dermoscopic features which are figure  1. clinical picture of the patient showing pinkish-red erythema over the cheeks with patchy brown discoloration and grossly visible telangiectasias. [copyright: ©2018 sonthalia et al.] letter | dermatol pract concept 2018;8(3):2 167 indicative of “topical steroid-damaged face,” while the brown pigmented structures suggest a background of melasma. the abuse of topical steroid-containing formulations over the face has now been well established as a dermatological nuisance in india [1]. conclusions through this report, we wish to highlight that many of these patients are in a denial about their steroid abuse. importantly, dermoscopy not only noninvasively confirms the suspicion, but also aids in the patient’s understanding of the seriousness figure 2. (a, b) dermoscopy of the cheek revealing reddish-brown background, brown dots, globules and clods (black arrows) suggestive of a background of melasma, multiple tortuous and branching linear vessels (white arrows), telangiectasias and ivory white-to-strawberrycolored patches (blue arrow) suggestive of skin atrophy, in addition to conspicuous hypertrichosis (escope, videodermoscope, polarizing mode, 20×). [copyright: ©2018 sonthalia et al.] of topical steroid abuse through the demonstration of pictures explained in patient-friendly language. in the majority of cases it also ensures further steroid abuse and improves treatment compliance [2]. references 1. coondoo a, phiske m, verma s, lahiri k. side-effects of topical steroids: a long overdue revisit. indian dermatol online j. 2014;5(4):416-425. 2. sonthalia s, errichetti e. dermoscopy—not just for diagnosis and not just for dermatologists! kathmandu univ med j (kumj). 2017;15(57):1-2. dermatology: practical and conceptual 328 letter | dermatol pract concept 2018;8(4):17 dermatology practical & conceptual www.derm101.com introduction primary cutaneous lymphomas are a diverse group of neoplasms with different clinical presentation, histopathology, and prognosis [1,2]. dermoscopy is a noninvasive, low-cost method that allows assessment of colors, patterns, and vascular structures, and today we know very well that dermoscopy corresponds well with histopathology. the importance of dermoscopy for the differential diagnosis of pink nodules has already been established and in case of the presence of the pink-yellow structureless areas and polymorphous vessels, the possibility of lymphoma should be taken into consideration [3]. discussion the dermoscopic pattern for early patch stage mycosis fungoides (mf) lesions characteristically consists of fine, short, linear vessels; orange-yellow patchy areas; and spermatozoalike vascular structures [1]. in a recently published report of a pilot study of primary cutaneous lymphomas, comedo-like openings were observed in folliculotropic mf, likely reflecting follicular plugging and loss of normal hair follicle architecture. the authors describe the dermoscopic perifollicular accentuation presumably reflecting the atypical lymphoid infiltrate within/adjacent to the hair follicle [2]. patients with the classic clinical and dermoscopic picture of mf do not exhibit follicular changes, and follicles are not usually dermoscopically observed in mf lesions. in dermoscopy, follicles are usually seen if there are some changes in arrangement of melanocytic cells (as in lentigo maligna) or in some diseases in which the follicle is affected (such as discoid lupus, actinic keratosis). in our patients with patch stage mf (figure 1a), dermoscopy revealed perifollicular accentuation described as a white halo around the follicles (figure 2). folliculotropism early dermoscopic sign of folliculotropism in patients with mycosis fungoides ruzica jurakic toncic1, daniela ledic drvar1, mirna bradamante1, jaka rados1, sandra jerkovic-gulin2, stefano caccavale3, giuseppe argenziano4 1 department of dermatology and venereology, university hospital centre zagreb, university of zagreb school of medicine, zagreb, croatia 2 department of dermatology and venereology, general hospital sibenik, sibenik, croatia 3 dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, naples, italy 4 dermatology unit, university of campania, nuovo policlinico, naples, italy key words: dermoscopy, primary cutaneous lymphoma, mycosis fungoides, folliculotropism, folliculotropic mycosis fungoides citation: jurakic toncic r, ledic drvar d, bradamante m, rados j, jerkovic-gulin s, caccavale s, argenziano g. early dermoscopic sign of folliculotropism in patients with mycosis fungoides. dermatol pract concept. 2018;8(4):328-329. doi: https://doi.org/10.5826/ dpc.0804a17 received: february 20, 2018; accepted: may 22, 2018; published: october 31, 2018 copyright: ©2018 jurakic toncic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, university department of dermatology and venerology, university hospital centre zagreb, university of zagreb, school of medicine, salata 4, zagreb 10000, croatia. email: rjtoncic@gmail.com letter | dermatol pract concept 2018;8(4):17 329 ers to standard puva and re-puva treatment, and this group can benefit from additional therapy, such as radiotherapy. conclusions accentuation of the follicle is an easily recognized dermoscopic sign that can be found in patients who do not exhibit clinical signs of folliculotropic mf. it represents a very early sign that allows us to choose a proper biopsy site, predict histology even at an early stage of mf, select more complex treatment and, finally, to predict the group of mf patients who will have a poor response to the standard treatment references 1. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol venereol. 2013;27(5):617-621. 2. ghahramani gk,  goetz ke,  liu v. dermoscopic characterization of cutaneous lymphomas: a pilot survey. int j dermatol. 2018;57(3):339-343. 3. uzuncakmak tk, akdeniz n, karadag, et al. primary cutaneous cd 30 (+) alk (−) anaplastic large cell lymphoma with dermoscopic findings: a case report. dermatol pract concept. 2017;7(1): 59-61. was confirmed by histopathology (figure 1b). perifollicular accentuation made follicles visible (figure 2). this accentuation depends on the amount of lymphoid infiltrate; therefore, white halos present with different sizes. perifollicular accentuation can be seen using handheld dermoscopy, but in lesions that do not clinically exhibit criteria for folliculotropism these changes of follicles can be discrete, and we observed that using greater enlargement on the digital dermoscopy device and a nonpolarized camera allows better visualization of the effect on the follicle. of note, we did not observe accentuation of the follicle in patients with mf without folliculotropism in histopathology. therefore, we believe this is a very early sign of folliculotropism. this finding is clinically useful and can be used as a marker for choosing the adequate site of biopsy. therefore, we suggest using dermoscopy to examine all mf lesions, and especially, if possible, we recommend using greater enlargement of the digital dermoscopic device (30×), as it allows for visualization of more discrete changes in the follicle. this is even more important in light of the clinical observation that patients with folliculotropism may not respond as well as othfigure 1. (a) clinical findings: erythematous patch on the right side of a forehead, with site of biopsy. (b) histopathological findings: irregular psoriasiform hyperplasia of the epidermis with parakeratosis, heavy lymphocytic infiltrate in the dermis with signs of folliculotropism with some mucin deposits (hematoxylin and eosin, ×4). [copyright: ©2018 jurakic toncic et al.] figure  2. (a,b) dermoscopic view: perifollicular accentuation seen as a white halo around the follicles. [copyright: ©2018 jurakic toncic et al.] dermatology: practical and conceptual research | dermatol pract concept 2018;8(1):8 39 dermatology practical & conceptual www.derm101.com introduction the ability to identify common benign and malignant skin lesions is augmented by the use of dermoscopy and is relevant to medical students pursuing careers in medicine, surgery, and subspecialties [1]. medical students who received dermoscopy instruction as an adjunct to their skin examination education were more likely to examine a patient’s skin during physical examination when evaluated one year after skin examination education [2]. standard dermatoscopes, utilized in the aforementioned studies, permit a single user to view skin lesions in greater detail by incorporating 10-fold magnification. as with standard dermoscopy, videodermoscopy allows examination of microstructures within the epidermis and dermis. videodermoscopy further enhances viewing by increasing the magnification potential to 50-fold or greater and by enabling multiple users to visualize skin lesions concurrently (figure 1). in this study, we aim to assess whether the use of videodermoscopy improves the ability of medical students to identify benign and malignant skin lesions. methods ninety second-year medical students were invited to participate in this study during a dermatologic education session. all students received a 45-minute lecture on general dermatologic topics. the study consisted of a pre-test with 6 demographic questions and 13 knowledge-based analytic and image identification questions, followed by a 7-minute training session with a live patient where the dermatology resident used either a standard dermatoscope (dermlite dl3; 3gen, san juan capistrano, ca, usa) or a videodermatoscope (dino-lite am4115zt; dunwell tech, inc, torrance, ca). participants subsequently completed a post-test including the same 13 knowledge-based questions. in total, 54 students completed the study: 24 and 30 students received instruction using standard dermoscopy and videodermoscopy, respectively. dermoscopic features of seborrheic keratoses, melanocytic nevi, and angiomata were demonstrated, and those of melanoma and blue nevi were discussed during training. final analysis omitted 4 knowledge-based questions on lesions not standard dermoscopy and videodermoscopy as tools for medical student dermatologic education hyunje g. cho1, sarah l. sheu1, audris chiang1,2, kristin m. nord3 1 department of dermatology, stanford university school of medicine, stanford, ca, usa 2 university of california, irvine school of medicine, irvine, ca, usa 3 dermatology service, va palo alto health care system, palo alto, ca, usa key words: dermoscopy, videodermoscopy, education citation: cho hg, sheu sl, chiang a, nord km. standard dermoscopy and videodermoscopy as tools for medical student dermatologic education. dermatol pract concept. 2018;8(1):39-42. doi: https://doi.org/10.5826/dpc.0801a08 received: august 20, 2017; accepted: december 6, 2017; published: january 31, 2018 copyright: ©2018 cho et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: stanford medicine teaching and mentoring academy innovation grant. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: kristin m. nord, md, department of dermatology, stanford university school of medicine, 450 broadway, pavilion c-233, mc 5334, redwood city, ca 94063, usa. tel. 650.721.7193. email: knord@stanford.edu https://doi.org/10.5826/dpc.0801a08 mailto:ksarin@stanford.edu 40 research | dermatol pract concept 2018;8(1):8 with a dermatologist or dermoscopy (table 1). both intervention groups reported openness to incorporating dermoscopy into future practice before and after instruction. in the combined cohort, self-reported confidence in the ability to identify benign and malignant lesions increased from disagree to agree in all lesion types, except wart, including melanocytic nevi (p=0.004) and melanoma (p<0.001) (table 2). this self-reported increase in confidence was observed in both demonstrated or discussed. the study was approved by the stanford institutional review board (irb 40202) and the dean’s office of the school of medicine. results the majority of subjects were interested in medicine and related subspecialties and had no prior experience working table 1. study cohort demographics videodermoscopy (n=30) standard dermoscopy (n=24) p-value1 male gender, n (%)1 15 (50) 8 (33.3) 0.274 career interest1 0.367 medicine or related, n (%) 15 (50) 13 (54.2) surgery or related, n (%) 9 (30) 3 (12.5) dermatology, n (%) 3 (10) 1 (4.2) other, n (%) 3 (10) 5 (20.8) undecided, n (%) 5 (16.7) 7 (29.2) no prior dermatologist exposure, n (%)1 26 (86.7) 21 (87.5) 1.000 no prior dermoscopy exposure, n (%)1 27 (90) 20 (83.3) 0.687 willingness to use dermoscopy in future practice2 0.231 pre-intervention, n (%) 26 (86.7) 18 (75) post-intervention, n (%) 28 (93.3) 21 (87.5) 1p-value from two-sided fisher’s exact test 2p-value from two proportion difference z-test a d b e c figure 1. dermoscopic images of melanocytic nevus and melanoma. (a) standard dermoscopy of a melanocytic nevus (magnification 10x). (b) videodermoscopy of the same nevus (magnification 85x). (c) standard dermoscopy of a melanoma (magnification 10x). (d) videodermoscopy of the same melanoma (magnification 85x). (e) videodermoscopy of the same melanoma (magnification 140x). [copyright: ©2018 cho et al.] research | dermatol pract concept 2018;8(1):8 41 ta b le 2 . e ff ec t o f d er m o sc o p ic t ra in in g o n s el fre p o rt ed c o n fi d en ce a n d a cc u ra cy i n s k in l es io n i d en ti fi ca ti o n to ta l st u d y c o h o rt (n = 5 4 ) v id e o d e rm o sc o p y (n = 3 0 ) s ta n d a rd d e rm o sc o p y (n = 2 4 ) p -v a lu e o f p re v s p o st f o r to ta l co h o rt 1 p -v a lu e o f v id e o d e rm o sc o p y v s st a n d a rd d e rm o sc o p y 2 p re p o st p re p o st p re p o st se lf -r ep o rt ed c o n fi d en ce i n l es io n i d en ti fi ca ti o n , s ca le d 1 ( st ro n gl y d is ag re e) t o 5 ( st ro n gl y ag re e) se b o rr h ei c k er at o si s, m ea n ( sd ) 2 .5 ( 1 .2 ) 3 .5 ( 1 .0 ) 2 .4 ( 1 .1 ) 3 .6 ( 1 .1 ) 2 .7 ( 1 .2 ) 3 .5 ( 1 .0 ) < 0 .0 0 1 0 .2 2 7 d er m at o fi b ro m a, m ea n ( sd ) 2 .1 ( 1 .0 ) 2 .4 ( 0 .9 ) 2 .1 ( 1 .0 ) 2 .4 ( 0 .9 ) 2 .0 ( 1 .0 ) 2 .5 ( 0 .9 ) 0 .0 2 4 0 .1 1 6 m el an o cy ti c n ev u s, m ea n ( sd ) 2 .8 ( 1 .0 ) 3 .3 ( 0 .9 ) 2 .7 ( 1 .0 ) 3 .5 ( 0 .7 ) 2 .9 ( 1 .1 ) 3 .2 ( 1 .1 ) 0 .0 0 4 0 .0 5 3 w ar t, m ea n ( sd ) 2 .9 ( 1 .1 ) 3 .0 ( 1 .0 ) 2 .9 ( 1 .1 ) 3 .0 ( 1 .0 ) 3 .0 ( 1 .2 ) 3 .0 ( 1 .0 ) 0 .3 9 5 0 .5 0 0 a n gi o m a, m ea n ( sd ) 2 .3 ( 1 .0 ) 3 .7 ( 1 .0 ) 2 .3 ( 0 .9 ) 3 .6 ( 0 .9 ) 2 .3 ( 1 .0 ) 3 ,8 ( 1 .0 ) < 0 .0 0 1 0 .1 1 5 a n gi o fi b ro m a, m ea n ( sd ) 2 .0 ( 0 .8 ) 2 .5 ( 0 .9 ) 2 ( 0 .7 ) 2 .5 ( 0 .9 ) 1 .9 ( 0 .9 ) 2 .4 ( 1 .0 ) 0 .0 0 2 0 .2 3 2 m el an o m a, m ea n ( sd ) 2 .5 ( 1 .0 ) 3 .1 ( 1 .0 ) 2 .5 ( 1 .0 ) 3 .2 ( 0 .9 ) 2 .5 ( 1 .1 ) 3 .0 ( 1 .0 ) < 0 .0 0 1 0 .3 5 3 l es io n i d en ti fi ca ti o n t es t sc o re 3 sc o re , m ea n ( sd ) 3 .4 ( 1 .4 ) 6 .0 ( 1 .6 ) 3 .5 ( 1 .6 ) 6 .0 ( 1 .8 ) 3 .4 ( 1 .2 ) 5 .9 ( 1 .4 ) < 0 .0 0 1 0 .4 9 4 n , n um be r; s d , s ta nd ar d de vi at io n 1 p -v al ue fr om o ne -s id ed p ai re d st ud en t t -t es t c om pa ri ng s co re s po st -t es t v er su s pr ete st in th e to ta l s tu dy c oh or t 2 p -v al ue fr om o ne -s id ed s tu de nt t -t es t c om pa ri ng s co re d iff er en ce (p os tte st s co re – p re -t es t s co re ) o f v id eo de rm os co py v er su s st an da rd d er m os co py g ro up s 3 f ou r ou t o f 1 3 qu es tio ns n ot c ov er ed d ur in g de rm os co pi c in st ru ct io n w er e om itt ed . th e re m ai ni ng 9 q ue st io ns in vo lv ed m at ch in g of c ha ra ct er is tic d er m os co pi c fe at ur es to le si on s an d re vi ew o f d er m osc op ic p ho to gr ap hs fo r id en tifi ca tio n of le si on s an d be ni gn v er su s m al ig na nt d is cr im in at io n. 42 research | dermatol pract concept 2018;8(1):8 improve accuracy in identifying benign non-melanocytic lesions, prior work suggests limited accuracy in melanoma identification [3]. an increase in confidence not matched by adequate training can be dangerous particularly for melanoma detection. given the utility of dermoscopy in fields like primary care where dermoscopy use can decrease dermatology referrals and biopsies performed, adequate student training is an important consideration [4]. a limitation of the study includes the small sample sizes of the intervention groups. further studies are needed to determine effective ways to improve medical student dermatologic education, including further examination of the potential educational benefits of videodermatoscopy given the subjective benefits noted during this study. references 1. liebman tn, goulart jm, soriano r, et al. effect of dermoscopy education on the ability of medical students to detect skin cancer. arch dermatol. 2012;148:1016-1022. 2. chen ll, liebman tn, soriano rp, et al. one-year follow-up of dermoscopy education on the ability of medical students to detect skin cancer. dermatology. 2013;226:267-273. 3. secker lj, buis pa, bergman w, kukutsch na. effect of a dermoscopy training course on the accuracy of primary care physicians in diagnosing pigmented lesions. acta derm venereol. 2017;97:263265. 4. chappuis p, duru g, marchal o, et al. dermoscopy, a useful tool for general practitioners in melanoma screening: a nationwide survey. br j dermatol. 2016;175:744-750. the standard dermoscopy and videodermoscopy groups, but did not differ between the groups. confidence in identifying melanocytic nevi approached statistical significance, with a greater increase in the videodermoscopy group (p=0.053). the combined cohort demonstrated improvement in the ability to identify dermoscopic features of benign and malignant skin lesions with a mean (sd) pre-test score of 3.4 (1.4) and a post-test score of 6.0 (1.6) out of 9 knowledge-based questions (p<0.001). the change in performance was not significantly different between groups (table 2). discussion brief instruction with either a standard dermatoscope or a videodermatoscope can increase medical students’ confidence and accuracy in identifying benign and malignant skin lesions. compared to prior studies, our study included lesion identification in addition to benign versus malignant distinction [1,2]. while there was no statistically significant difference between the use of standard dermatoscopy and videodermatoscopy in this small cohort, the subjective experience of students and the instructor included better engagement of attention and ease of instruction with videodermoscopy training compared with standard dermoscopy training. increase in self-reported confidence, particularly in identification of benign nevi and melanoma, highlights the need to emphasize adequate training to achieve competence in dermoscopy. while a short dermoscopic training session can dermatology: practical and conceptual 232 letter | dermatol pract concept 2019;9(3):17 dermatology practical & conceptual introduction we present a case of a patient with fitzpatrick skin type v presenting with primary cutaneous amyloidosis, in whom polarized dermoscopy mainly showed irregular white central areas, surrounded completely or partially by thick hyperpigmented blotches. case presentation a 57-year-old woman with fitzpatrick skin type v presented with hyperpigmented skin lesions over her body of more than 6 years’ duration. the lesions were located mainly over the upper trunk and limbs and were moderately itchy (figure 1). there was a history of previous treatment with topical corticosteroids and antihistamines. prior to the lesions, she was regularly using loofahs and scrubs, which were stopped as per the advice of the dermatologist. on examination, areas of reticulate macular hyperpigmentation and hyperpigmented papules were seen. a clinical diagnosis of primary amyloidosis was considered (a possibility of a biphasic amyloidosis was thought of because the lesions showed features suggestive of both macular and lichen amyloidosis dermoscopy of primary cutaneous amyloidosis in skin of color feroze kaliyadan1, abdulaziz alkhateeb1, joel kuruvilla1, krishna swaroop2, abdulrahim a. alabdulsalam2 1 department of dermatology, college of medicine, king faisal university, al ahsa, saudi arabia 2 department of pathology (biomedical sciences), college of medicine, king faisal university, al ahsa, saudi arabia key words: dermoscopy, primary cutaneous amyloidosis, high dynamic range conversion citation: kaliyadan f, alkhateeb a, kuruvilla j, swaroop k, alabdulsalam aa. dermoscopy of primary cutaneous amyloidosis in skin of color. dermatol pract concept. 2019;9(3):232-234. doi: https://doi.org/10.5826/dpc.0903a17 accepted: december 23, 2018; published: july 31, 2019 copyright: ©2019 kaliyadan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: feroze kaliyadan, md, dnb, mnams, fimsa, sce-rcp, faculty of dermatology, college of medicine, king faisal university, al ahsa, saudi arabia-31982. email: ferozkal@hotmail.com figure 1. hyperpigmented macules and papules over the forearm. [copyright: ©2019 kaliyadan et al.] letter | dermatol pract concept 2019;9(3):17 233 patterns seen included a central hub, either white or brown, surrounded by various configurations of hyperpigmentation and for cases with prominent hyperkeratosis such as in lichen amyloidosis, the central hub was replaced by a scar-like white area [1,2]. atypical patterns such as yellow, teardrop-like areas and orange-yellow homogeneous backgrounds with serpentine vessels have been described in cases of nodular amyloidosis [3,4]. arnold and bowling have reported “shiny white streaks” on polarized dermoscopy in 2 patients with lichen amyloidosis. one of the patients mentioned in this report is of “indian ethnicity,” but the patient’s exact skin type was not mentioned. the author hypothesized that under polarizing dermoscopy birefringent amyloid fibrils are detected as shiny white streaks [5]. we could not find something similar in our case. we suggest that hdr conversion is a useful tool in accentuating pigmentary patterns on dermoscopy. hdr has been described to improve visualization of dermoscopy patterns in the context of skin tumors [6]. we have done some work in the use of hdr in vitiligo (in print) and believe that it is a useful tool to enhance visualization of patterns in the context of pigmentary disorders in with combination of flat and raised lesions). a skin biopsy showed deposits of amorphous eosinophilic material in the superficial dermis associated with numerous pigment-laden macrophages (figure 2). immunohistochemistry showed strongly positive staining with ck 34be12 (figure 3). based on the clinical and histopathology findings, a diagnosis of primary cutaneous amyloidosis was confirmed. dermoscopy (polarized ×10, dermlite foto ii pro) showed a combination of patterns. the papular lesions showed a central white area encircled by thick brown to black pigmentation. some of the flat lesions showed irregular white central areas, surrounded completely or partially by thick hyperpigmented blotches, while other flat lesions just showed irregular hyperpigmented blotches. streaks were not visualized (figure 4). the patterns were further highlighted using high dynamic range (hdr) conversion (figure 5; topaz filter in adobe photoshop cc 2015). conclusions there are very few reports related to the dermoscopy of primary cutaneous amyloidosis. chuang et al reported a study of 35 cases in which the primary figure 2. histopathology shows deposits of amorphous eosinophilic material in the superficial dermis associated with numerous pigment-laden macrophages. there is minimal perivascular inflammatory infiltrate (hematoxylin and eosin, ×400). [copyright: ©2019 kaliyadan et al.] figure 3. multiple deposits of amorphous material in the superficial dermis, strong positive staining with cytokeratin staining (ck 34be12, ×200). [copyright: ©2019 kaliyadan et al.] figure 4. the papular lesions show a central white area encircled by thick brown to black pigmentation (blue arrow). some of the flat lesions show irregular white central areas, surrounded completely or partially by thick hyperpigmented blotches (black arrow), while other flat lesions just show irregular hyperpigmented blotches (red arrow). [copyright: ©2019 kaliyadan et al.] figure 5. hdr conversion of figure 4 showing accentuation of the pigmentary patterns. [copyright: ©2019 kaliyadan et al.] 234 letter | dermatol pract concept 2019;9(3):17 general. while in this report we use single-image conversion using a specific software, most digital cameras nowadays, including mobile phones, have in-built hdr conversion mechanisms, which can be used to improve the quality of dermoscopy images in general. although we realize that significant conclusions cannot be made from a single case, we propose that the dermoscopy patterns for primary cutaneous amyloidosis are likely to be different in patients with skin of color. while we did see areas corresponding to the pattern described by chuang et  al in the form of white hubs surrounded by different patterns of hyperpigmentation, the specific morphology and amount of pigmentation was different. we did not see specific patterns like venation or streaks. in addition, the pigmentation appeared to be thicker and darker in our case, which we believe could correlate with the darker skin type. references 1. chuang yy, lee dd, lin cs, et al. characteristic dermoscopic features of primary cutaneous amyloidosis: a study of 35 cases. br j dermatol. 2012;167(3):548-554. 2. moscarella e, ronchi a, agozzino m, franco r, argenziano g. image gallery: dermoscopy of lichen amyloidosis. br j dermatol. 2018;179(6):e231. 3. rongioletti f, atzori l, ferreli c, pinna a, aste n, pau m. a unique dermoscopy pattern of primary cutaneous nodular amyloidosis mimicking a granulomatous disease. j am acad dermatol. 2016;74(1):e9-e10. 4. di meo n, noal c, fadel m, trevisan g. yellow teardrop-like structures in primary nodular skin amyloidosis. g ital dermatol venereol. 2018;153(1):118-119. 5. arnold sj, bowling jc. “shiny white streaks” in lichen amyloidosis: a clue to diagnosis. australas j dermatol. 2012;53(4):272-273. 6. braun rp, marghoob a. high-dynamic-range dermoscopy imaging and diagnosis of hypopigmented skin cancers. jama dermatol. 2015;151(4):456-457. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(1):e2023020 1 what do patients want to see on social media? evidence from a two-year experiment leire barrutia1,2, jesús vega-gutiérrez1,3, alba santamarina-albertos1,2 1 dermatology, medicine and toxicology department, university of valladolid, valladolid, spain 2 dermatology department, clinical university hospital of valladolid, valladolid, spain 3 dermatology department, río hortega university hospital, valladolid, spain key words: social media, internet, acne, health promotion, education citation: barrutia l, vega-gutiérrez j, santamarina-albertos a. what do patients want to see on social media? evidence from a two-year experiment. dermatol pract concept. 2023;13(1):e2023020. doi: https://doi.org/10.5826/dpc.1301a20 accepted: april 11, 2022; published: january 2023 copyright: ©2023 barrutia et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: leire barrutia, md, dermatology department, clinical university hospital of valladolid, calle rondilla sta teresa s/n, 47010 valladolid, spain. e-mail: leirebarrutia4@gmail.com introduction: dermatological information on social media is dominated by misleading and potentially harmful content from nonexperts. literature suggests that, to address this issue, dermatologists should develop an online presence. however, the successful presence of dermatologists on social media has been criticized for focusing on cosmetic dermatology and not representing the broad spectrum of the specialty. objectives: the aim of this study was to systematically analyze which dermatological topics interest the public most, and to find out whether it is feasible for a dermatologist to become influential on social media while presenting all dermatological topics equally. methods: the study was performed on an educational dermatology youtube channel. the 101 videos published in a two-year period were divided into cosmetic (51 videos) and medical dermatology (50 videos). student’s t-test was conducted to determine whether there were significant differences in views. medical dermatology videos were then classified into three categories: acne, facial dermatoses (excluding acne) and other dermatological diseases. a kruskal-wallis test was used to compare these three categories and cosmetic dermatology. results: when comparing cosmetic and medical dermatology, no significant differences were found. when comparing the four categories, cosmetic dermatology and acne were found to generate significantly more views that other dermatological diseases. conclusions: the public seems to be particularly interested in cosmetic dermatology and acne. this might make it challenging to become successful on social media while presenting a balanced portrayal of dermatology. however, focusing on popular topics can provide a real chance to be influential and protect vulnerable people from misinformation. abstract 2 original article | dermatol pract concept. 2023;13(1):e2023020 introduction dermatological information on social media is dominated by misleading and potentially harmful content from nonexperts [1,2]. an analysis of instagram hashtags [3] found that most top dermatology-related posts are made by individuals without formal dermatology training. a study [4] on the quality of youtube videos about psoriasis classified 63% of videos as misleading or dangerous. many other studies [5-8] have noted a vast amount of inaccurate or low-quality dermatological information on different social media platforms. this problem primarily affects vulnerable people, such as adolescents and young adults, who are the most active users of these platforms [2,9,10]. it has been suggested that in order to address this issue, dermatologists should develop an online presence [5,11-13]. however, dermatologists’ participation in social media is a new phenomenon, and the extant literature offers little insight into how dermatologists can develop a successful social media presence. one exception is a study by sierro et al. [11], which identified the top 10 dermatology influencers on social media and found that 83% of the content they produced focused on cosmetic dermatology. according to sun et al. [12], this finding might lead to the public perception that dermatologists spend the majority of their time treating conditions with modest morbidity, which is inconsistent with reality. they highlighted the need to dispel this misconception and create content on a wide variety of dermatological diseases from both clinical and histological perspectives [12]. guzman and barbieri [1] shared this concern and noted that the presence of dermatologists on social media is limited in comparison with non-dermatologist sources, which are prone to bias and misinformation. similarly, green and britten [14] argued that dermatologists should create content showcasing, in a balanced manner, the broad spectrum of dermatology by presenting interesting medical cases, dermoscopic and histologic images, or commentaries on medical literature. therefore, the successful presence of dermatologists on social media remains limited and has been criticized for focusing on cosmetic dermatology as opposed to accurately representing the role of dermatologists [1,12,13]. in this context, this study examined a research question that has not been systematically addressed in the literature: is it feasible for a dermatologist to develop a relevant presence on social media while equally representing all dermatological topics? objectives the emergence and prevalence of social media is a relatively new and unknown phenomenon. probably the best way to understand new phenomena is to explore them as an insider [14]. consequently, there is a need for insider research exploring how the public reacts to the presentation of various dermatological topics by dermatologists. accordingly, the aim of this research is to determine from the inside which dermatological topics social media users find most interesting. this analysis will allow us to deduce whether it is feasible for a dermatologist to become influential on social media while presenting all dermatological topics with equal prominence, as suggested from a conceptual perspective [1,12,14]. methods study design most previous contributions on dermatology in social media have relied on conceptual developments and secondary sources. this is distinct from the tradition of dermatologic research, which has mostly relied on primary sources (i.e., everyday practice). the present study is based on the direct experience of a dermatologist on social media over a two-year period. in october 2019, one of the authors launched an educational dermatology youtube channel. the channel was designed to avoid the risks and ethical challenges that social media involves for dermatologists [15]. the channel did not include sponsored or personal content, and videos followed the discern quality criteria [9]. references to relevant scientific literature were provided, individual consultations were not answered, and viewers were encouraged to consult a dermatologist. while commercial products were shown because of strong demand from subscribers, product assessments relied on effectiveness. no commercial agreements were established. a new video was launched weekly, and following a two-year period, the channel had over 134,000 subscribers and 5.5  million views. in total, 101 videos were posted about a wide variety of dermatological topics including acne and acne scars, rosacea, melasma, hidradenitis suppurativa, psoriasis, vitiligo, hair loss, atopic dermatitis, seborrheic dermatitis, nevi, sun protection, melanoma, basal cell carcinoma, squamous cell carcinoma, polymorphous light eruption, hyperhidrosis, folliculitis, laser hair removal, keratosis pilaris, post-inflammatory hyperpigmentation, dermatological treatments such as benzoyl peroxide and isotretinoin, skin type, medical peelings, botulinum toxin, and active ingredients in cosmetics. all videos were presented by the same dermatologist in the same setting and followed a similar approach. they were also similar in terms of duration and aesthetic design. we can assume, therefore, that the differences in the average daily video views were mostly due to varying public interest in the topics covered. data collection and overview of channel analytics data were collected from youtube studio, a platform provided by youtube to help content creators manage their original article | dermatol pract concept. 2023;13(1):e2023020 3 channels. youtube studio provides key channel analytics to better understand video and channel performance. this research focuses on a specific metric: average daily views (i.e., views/days since upload). other metrics provided by youtube studio include subscribers, watch time (hours), likes, dislikes, and shares. all videos posted from 25 october 2019 to 25 october 2021 were included in the study. statistical analysis statistical analysis was performed using stata 16 (statacorp llc). we categorized the videos according to the topic covered and analyzed whether there were significant differences in average daily views depending on the video category. to categorize the videos under study, we followed a two-step approach. in the first step, we grouped the videos into two broad categories: cosmetic dermatology (51 videos) and medical dermatology (50 videos). we conducted a student’s t-test to determine whether there were significant differences between the views counted for both types of videos. despite the absence of normality in our data, the relatively large number of observations in both categories (n = 50 and n = 51, respectively) led us to use the parametric student’s t-test [16]. in the second step, we created several subgroups among the medical videos. subcategorization was performed because it was apparent that there was great variance in the views within this category. specifically, we divided the medical videos into three subgroups: acne; facial dermatoses, excluding acne; and other dermatological diseases. this arrangement was based on our empirical observations. overall, we observed that acne and, to a lesser extent, other facial dermatoses, such as rosacea and melasma, generated more views than other dermatological diseases. this may be because self-care is erroneously considered feasible for these conditions. additionally, facial dermatoses are highly visible, with substantial social repercussions [17-19]. we established an individual category for acne because of its particularly high prevalence and because it markedly affects adolescents and young adults, who comprise youtube’s largest user base [2,9,10]. we then performed a non-parametric kruskal-wallis rank test to compare the three medical categories and cosmetic videos. this non-parametric test was chosen due to the absence of normality in our data and the relatively scarce number of videos in some categories [16]. the videos had been published on different dates, which implies that they had had different opportunities to be viewed. therefore, the videos were not compared in terms of total views but in terms of average daily views [20]. results videos on acne had the highest average daily views (268.66), followed by those on cosmetic dermatology (255.49) and other facial dermatoses (160.18). videos on other dermatological diseases had the lowest average daily views (91.61). student’s t-test determined that there were no significant differences between views of cosmetic dermatology and medical dermatology videos, even though the cosmetic videos had more views on average (p = .1511). the kruskal-wallis rank test, which compared the three medical categories and cosmetic videos, showed that videos on acne and cosmetic dermatology received significantly more views than those on other dermatological diseases (p = .0028 and p = .0005, respectively). there was a marginally significant difference (p = .0533) between views of videos on other facial dermatoses and those on other dermatological diseases. no significant differences were found between cosmetic dermatology and acne (p = .2392), cosmetic dermatology and other facial dermatoses (p = .5493), and acne and other facial dermatoses (p = .1266) (see table 1). while this research focused on comparing average daily video views, other engagement analytics may add information about the qualitative perceptions of the public on a youtube channel conducted by a dermatologist. the two-year period under study led to 221,993 likes, 47,162 shares, and 17,815 comments (see table 2). to evaluate the degree of goodness of these channel analytics, we used a study on 104,899 youtube accounts and classified them as poor, average, or good [21]. metrics scoring at the 60th percentile or higher were considered good. specifically, the study considered the following engagement analytics: 1. like-to-dislike rate (i.e., percentage of number of likes over the sum of likes and dislikes); 2. views-to-subscriber ratio (i.e., number of views over number of subscribers); 3. comments-to-views rate (i.e., percentage of users who have watched the video and commented on it); and 4. likes-to-view rate (i.e., percentage of users who have watched the video and explicitly stated that they liked it). when these metrics were applied to the channel, we observed that in all cases, the channel was above the threshold level required to be considered good. first, the like-to-dislike rate was 98.6% (> 97.4%). second,  the views-to-subscriber ratio was 41.01 (> 33.1). third, the comments-to-views rate was .32% (> .04%). lastly, the  like-to-view rate was 4.03 (> 3.72). most comments were highly positive. many users recognized the value of the knowledge conveyed through the channel and were highly appreciative that a dermatologist had offered evidence-based knowledge on social media. 4 original article | dermatol pract concept. 2023;13(1):e2023020 [22-24]. therefore, it is essential that dermatologists share evidence-based information on appropriate sun safety attitudes to educate the population and fight misinformation [25-27]. several studies [26,28,29] have shown that social media can be a cost-effective way to disseminate awareness on this topic, and dermatological associations, such as the national academy of sciences’ interdisciplinary perspectives on skin cancer, have concluded that there is a need to promote sun protection in children and young adults on these platforms [30]. other examples of non-popular dermatological diseases that could be addressed on social media include chronic inflammatory skin conditions, such as psoriasis or hidradenitis suppurativa. several studies [24,31,32] have shown that discussion and conclusions our findings show that public concerns focus on acne and cosmetic dermatology and that viewers are not equally interested in all dermatological topics. therefore, it might be difficult to become successful on social media and ensure visibility while presenting a balanced portrayal of our specialty. this represents an important challenge for dermatologists because some topics, despite being less popular, need to be addressed due to their importance, such as skin cancer and its prevention. the literature shows that most videos about tanning on youtube portray it positively, and that there are more advertisements for tanning salons than the total number of videos portraying the dangers of tanning table 1. types of videos: testing for significant differences. videos (101) views per video since uploaded average daily views per video since uploaded type of video mean sd mean sd cosmetic dermatology 51 61,639.94 71,612.31 255.49 32.54 medical dermatology 50 46,627.06 44,008.43 181.06 173.69 acne 21 70,828.95 50,304.45 268.66 201.94 other facial dermatoses (excluding acne) 11 49,641.82 30,999.87 160.18 115.60 other dermatological diseases 18 16,549.17 18,779.03 91.61 113.51 testing for significant differences t-test t d.f. p-value cosmetic dermatology vs. medical dermatology -1.4467 77.355 .1511 kruskal-wallis rank test chi-sq. d.f. p-value four groups (cosmetic dermatology, acne, other facial dermatoses excluding acne, other dermatological diseases) 13.884 3 .0031** cosmetic vs. acne 1.385 1 .2392 cosmetic vs. other facial dermatoses .359 1 .5493 cosmetic vs. other dermatological diseases 8.956 1 .0028** acne vs. other facial dermatoses 2.333 1 .1266 acne vs. other dermatological diseases 12.007 1 .0005** other facial dermatoses vs. other dermatological diseases 37.375 1 .0533 notes: period: 25 october 2019–25 october 202. sd: standard deviation; t-test: two-sample t-test with unequal variances; d.f.: degrees of freedom. table 2. overview of channel analytics. variable total mean sd min. max. views 5,504,165 54,207.82 59,750.06 939 399,436 subscribers 134,208 1167.54 1800.94 4 13,111 watch time (hours) 463,840 4,573.17 5,539.08 56 34,079 likes 221,993 2,182.53 2,126.77 50 12,439 dislikes 3,043 29.93 40.50 0 324 shares 47,162 465.30 521.58 6 3182 comments 17,815 175 141.47 3 771 notes: observations (videos) = 101. period: 25 october 2019–25 october 2021. sd: standard deviation. min: minimum. max: maximum. original article | dermatol pract concept. 2023;13(1):e2023020 5 would otherwise, thereby increasing the likelihood that the youtube algorithm will promote them to other users. consequently, focusing on popular topics can, in the end, facilitate the dissemination of accurate knowledge about the broad spectrum of dermatology. our results show an overall preference for topics related to facial dermatological issues. the commonality among acne, cosmetic dermatology, and other facial dermatoses is that they affect the face. views on videos about these topics are significantly higher than those on videos about dermatological diseases that do not normally affect this body area, such as psoriasis, hyperhidrosis, or hidradenitis suppurativa. because the face is the most visible body part, previous studies have found that skin diseases in this area can have a remarkable effect on patients’ self-esteem and a profoundly negative impact on quality of life [17-19]. as a consequence, it seems logical that users search for these topics more than for less noticeable dermatological diseases. previous research suggests that social media allows dermatologists to do social work of great significance, disseminating an evidence-based dermatological culture and influencing the habits of the most vulnerable people [10,25,26,29,33,36,37]. for this reason, many authors have encouraged dermatologists into more active participation on these platforms [5,11-13]. previous literature on the topics that dermatologists should present on social media is very scarce, but it has been suggested in the context of other aspects of social media content that dermatologists should adapt their content to the population. for instance, güder and güder [5] focused on the language used and highlighted that in order to increase visibility, dermatologists should use words that are familiar to patients instead of technical terms. we consider that focusing on popular topics can be a successful strategy that follows a similar approach. while dermatologists must share information on important topics, such as skin cancer, even at the expense of losing visibility, our findings indicate that prioritizing the goal of a balanced portrayal of dermatology is difficult to achieve in the real context of social media. this is so because meeting this goal implies trying to lead social media users to focus their attention on topics in which they have no or little interest. disregarding this balance in favor of popular content, without completely neglecting other relevant dermatological topics, might be worthy for dermatologists in terms of accomplishing a very relevant social mission. references 1. guzman ak, barbieri js. comment on “dermatologists in social media: a study on top influencers, posts, and user engagement”. j am acad dermatol. 2022;86(2):e49-e50. doi:10.1016/j. jaad.2020.03.118 patient education through social media improves the quality of life of patients with these diseases. consequently, dermatologists face the difficult challenge of finding a balance between prioritizing popular topics and not disregarding others that may have an important impact on people’s well-being. while keeping this balance in mind, we believe that prioritizing the topics that people want to see (i.e., acne and cosmetic dermatology) can have the next three benefits for dermatologists and society as a whole: (1) ensuring visibility, (2) having a positive, evidence-based influence on dermatological culture and health-related decisions, and (3) having a real option to convey a complete portrayal of dermatological topics (albeit with unequal prominence). first, to ensure visibility, youtube videos must be promoted by the youtube algorithm. while the operation of the algorithm is a black box, it seems to favor content that is viewed more frequently by users (i.e., what users, through their behavior, have revealed they want to see) [21]. this mechanism makes it extremely difficult to garner public influence while presenting topics that the public does not usually search for on youtube. second, focusing on what people want to see provides dermatologists with a real opportunity to have a positive, evidence-based influence on people’s culture and behavior. comments on videos about popular topics illustrate that they can help foster important dermatological culture that extends beyond the focal topic: “since watching your videos, i use sunscreen regularly.” in particular, focusing on acne can lead to increased visibility among adolescents [9,10]. this can facilitate the dissemination of important dermatological habits, such as sun protection, from a young age, aiding in skin cancer prevention [26,29,33,34]. therefore, focusing on popular topics can be a way to convey important messages about other important dermatological issues. schneiderbanger et al. [35] presented an interesting example of how dermatologists’ concerns about a disease (skin cancer) can be associated with the main interests of young females (skin aging). since the prevention of skin aging seems to be an important concern among young females, a dermatologist could broadcast a video emphasizing the association between tanning and premature skin aging, thus helping discourage this behavior and, therefore, contributing to reducing the prevalence of skin cancer [35]. consequently, dermatologists can create content about topics that concern users and use it to convey additional skin health advice in a compelling way. third, focusing on people’s interests serves to gain subscribers and build loyalty [2]. loyal subscribers tend to watch more channel videos, including those on less frequently searched dermatological content. some video comments are illustrative of this: “i watch all your videos,” “i do not have vitiligo, but the video is interesting.” therefore, videos on 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insight into the patient perspective. j dermatolog treat. 2021;32:188-192. doi:10.1080/09546634.2 019.1631432. 37. buntinx-krieg t, caravaglio j, domozych r, et al. dermatology on reddit: elucidating trends in dermatologic communications on the world wide web. dermatol online j 2017;23:2. 13030/ qt9dr1f7x6. published 2017 jul 15. dermatology: practical and conceptual 54 research | dermatol pract concept 2019;9(1):13 dermatology practical & conceptual braf mutation status in primary, recurrent, and metastatic malignant melanoma and its relation to histopathological parameters aris spathis1, alexander c. katoulis2, vasileia damaskou1, aikaterini i. liakou2, christine kottaridi1, danai leventakou1, dimitrios sgouros2, andreas mamantopoulos3, dimitrios rigopoulos2, petros karakitsos4, ioannis g. panayiotides1 1 second department of pathology, national and kapodistrian university of athens, school of medicine, attikon university hospital, athens, greece 2 second department of dermatology and venereology, national and kapodistrian university of athens, school of medicine, attikon university hospital, athens, greece 3 department of surgery, ierapetra general hospital, ierapetra (crete), greece 4 department of cytopathology, national and kapodistrian university of athens, school of medicine, attikon university hospital, athens, greece key words: malignant melanoma, histopathological features, braf mutations citation: spathis a, katoulis ac, damaskou v, liakou ai, kottaridi c, leventakou d, sgouros d, mamantopoulos a, rigopoulos d, karakitsos p, panayiotides ig. braf mutation status in primary, recurrent, and metastatic malignant melanoma and its relation to histopathological parameters. dermatol pract concept. 2019;9(1):54-62. doi: https://doi.org/10.5826/dpc.0901a13 published: january 31, 2019 copyright: ©2019 spathis et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: the first 3 authors contributed equally to this work. all authors have contributed significantly to this publication. corresponding author: a. spathis, phd, scym(ascp)cm, second department of pathology, national and kapodistrian university of athens, attikon university hospital, 1, rimini str., gr-12462 chaidari, athens, greece. email: aspathis@med.uoa.gr background: braf mutations are a common finding in malignant melanoma (mm). nevertheless, apart from their significance as a therapeutic target in advanced melanoma, their prognostic value is still debated. objective: to assess braf mutation status in primary, recurrent, or metastatic mm and its correlations with histopathological findings. methods: we analyzed 203 samples from 178 consecutive patients: 129 primary cutaneous mm, 49 metastatic and recurrent mm of unknown primary site, and 25 cases of recurrences or metastases of primary mm. braf mutations in exon 15 were identified with real-time polymerase chain reaction and/or direct sequencing or pyrosequencing. histopathological examination was performed according to standard procedures. results: we observed a 42.1% prevalence of braf mutations at codon 600 among our patients, 84% of whom harbored the v600e mutation. mutations showed a statistically significant increase in abstract research | dermatol pract concept 2019;9(1):13 55 topathological parameters associated with prognosis and survival of mms being tumor thickness, ulceration, and, more recently, mitotic score at primary site [10]. we assessed the braf mutation status among 178 patients with primary, recurrent, or metastatic mm. our aim was to study the correlations between histopathological findings in primary mm and the presence of mutated braf in a greek population. methods specimens a total of 203 consecutive specimens from 178 patients referred for histopathological examination during a 12-year period (2003-2015) were analyzed (table 1). these included 129 primary cutaneous mms (a primary site recurrence was also included in 13 cases and a metastasis in 12 cases), 44 cases of metastatic mm of unknown primary site, and 5 cases of cutaneous recurrence without an initial tumor. the institutional review board of the hospital approved the study, while analysis was performed on anonymized data. all specimens were fixed in a buffered 10% formalin solution, processed according to standard protocols, and initially diagnosed by the same experienced pathologist. another, equally experienced pathologist performed a second, blind evaluation of histopathological diagnosis for the purpose of this study. in case of disagreement, slides were conjointly rereviewed. braf mutation analysis five 5-µm-thick sections were obtained from a paraffin block containing a representative tumor area, as assessed in a hematoxylin and eosin–stained section. dna was extracted with purelink dna mini kit (invitrogen, darmstadt, germany) according to the manufacturer’s instructions. detection of braf p.v600e mutation was performed with the use of 2 molecular beacons in a real-time polymerase chain reaction as previously described [11]. all wild-type and selected mutated samples were sent for verification with direct sequencing of exon 15 of braf using previously published primers or were introduction malignant melanoma (mm) is one of the most common types of cancer in humans, being the fifth most common in men and the sixth in women in the united states [1]. although mm represents less than 2% of skin cancer, it accounts for the vast majority of deaths, with increasing incidence worldwide [1]. the underlying etiopathogenetic mechanisms remain so far largely unknown. following discovery of braf oncogenic mutations in various types of malignancies, a significant pathogenetic role for mutated braf has been proposed for mm [2]. to date, more than 30 different mutations in the braf gene have been identified. the most frequent, accounting for almost 90%, concerns substitution of thymine by adenine at nucleotide c.1799, leading to valine (v) being substituted by glutamate (e) at codon 600 (p.v600e) in the activation segment of the gene promoting cell survival via the erk or mek signaling cascade [3]. frequency of braf mutations varies widely, from more than 80% in melanomas and nevi, to 1%-3% in lung and 5% in colorectal carcinoma [2]. of note, braf mutations are not exclusive to mm, having also been found in up to 80% of benign melanocytic lesions, albeit in limited study populations [4]. oncogenic mutations of braf are mimicking a constantly activated state, resulting in uncontrolled cell growth and proliferation. more recently, oncogenic braf mutations have been connected to up-regulated cell proliferation and invasion ability [5]. it has been suggested that braf mutations may constitute a tumor progression event rather than an initiating event in mm tumorigenesis, and that other genetic or epigenetic factors are also involved [6, 7]. the presence of a braf mutation in primary mm of stage iii has been associated with worse prognosis and also seems to be related to progression-free interval and overall survival [8]. mutated braf constitutes a therapeutic target for patients with advanced mms. different braf inhibitors have been tested, with significant benefits in terms of increased response rate, progression-free survival, and overall survival [9]. nevertheless, the prognostic value of braf mutations has not been fully assessed, with the only established hisyounger patients (p = 0.011), in ulcerated tumors (p = 0.020), and in tumors lacking solar elastosis in adjacent dermis (p = 0.008). mutations were also more common in male patients, as well as in primary mms of the torso, and in nonvisceral metastases, however without reaching statistical significance. logistic regression analysis identified type and ulceration as the only significant predictors of braf mutation. the highest frequencies of mutated braf were identified in superficial spreading and nodular types, and the lowest in acral lentiginous and lentigo maligna types. in situ mm and primary dermal melanoma displayed intermediate frequencies. conclusion: frequency of mutated braf is type-related and correlated with ulceration, a known adverse prognostic factor. abstract 56 research | dermatol pract concept 2019;9(1):13 an average of 70 months (range 1-162 months). recurrent samples were received within 1 to 32 months (mean 8.5 months), while reported metastases were collected within 0 to 49 months (mean 11.9 months). metastases were identified in lymph nodes (31/56), gastrointestinal tract (6/56), bone marrow (1/56), lung (1/56), ovaries (2/56), liver (7/56), and skin sites distant from the initial tumor area (8/56). all 18 recurrent specimens concerned cutaneous tumors. braf mutation distribution braf mutations were identified in a total of 92/203 samples (45.3%). analyzing only unique samples, braf mutations were identified in 75/178 samples (42.1%). of these 75 samples, 63 (84%) carried the v600e mutation (c.1799t>a), 10 samples (13.3%) the v600k mutation (c.1799_1800tg>aa), 1 sample (1.3%) carried the v600r mutation (c.1798_1799gt>ag), and 1 sample (1.3%) the v600a (c.1799t>c) mutation. the v600k, v600r, and v600a mutations were identified by sequencing only, since the molecular beacons, as expected, could not identify them (figures 1 and 2). in 12 patients, samples from both primary site and metastasis were available: in 10/12 (83.3%) cases both sites had the same genotype, whereas one primary carried a v600e mutation not identified in nodal metastasis, and another was wt in the primary with a v600e mutation in the visceral metastasis. correlation of braf status to epidemiological and clinical parameters correlation of braf mutation status with epidemiological and clinical parameters is shown in table 1. results for sequenced in-house using a commercially available kit (therascreen braf pyro kit, qiagen, düsseldorf, germany) [11]. primers and beacons braf primers and molecular beacons were designed with beacon designer 7 (premier biosoft, palo alto, ca). oligos were synthesized by jena bioscience gmbh (jena, germany). quality assurance both the department of cytopathology and the second department of pathology have successfully participated in the european quality assurance schemes of the european society of pathology for molecular identification of mutations in kras, nras, and braf since 2013 and through 2016. statistical analysis statistical analysis was performed using ibm statistics spss 24 (ibm corporation, new york, ny) and involved the fisher exact test for 2 × 2 tables, χ2 for trend for 2 × y tables, mannwhitney test for differences of mean of categories, and spearman correlation analysis for scale correlations. binary logistic regression was used for validation of observed differences of braf status with all mutations grouped in a single category. results demographic and clinical data one hundred seventy-eight melanoma patients aged 21-95 years (mean 62.1 years) were included in the study. there were 105 men with a mean age of 62.4 years and 73 women with a mean age of 61.4 years. received samples were monitored to identify repeated samples from the same patients for table 1. sample types and braf status braf status total mutated (%) p wt mutated patients 103 75 178 42.1 sample type 111 92 203 45.3 primary melanoma 77 52 129 40.3 0.300 metastasis of primary 6 6 12 50.0 metastasis w/o primary 23 21 44 47.7 recurrence of primary 2 11 13 84.6 recurrence w/o primary 3 2 5 40.0 age, mean (95% ci) (n = 178) 64.6 (61.5-67.6) 58.9 (55.6-62.2) 62.1 (59.9-64.4) 0.011 sex (n = 178) male 55 50 105 47.6 0.090 female 48 25 73 34.2 ci = confidence interval; wt = wild type. research | dermatol pract concept 2019;9(1):13 57 figure 1. (continues) 58 research | dermatol pract concept 2019;9(1):13 figure 1. real-time polymerase chain reaction plots of serial dilutions depicting that even rare mutation-harboring populations be identified using molecular beacons (red-colored line = mutant; green-colored line = wild type). [copyright: ©2019 spathis et al.] [copyright: ©2019 spathis et al.] figure 1, continued research | dermatol pract concept 2019;9(1):13 59 test), although limited samples were available. patients with melanoma metastasis showed a slightly increased frequency of braf mutations (37% vs 30.7%, p = 0.413, fisher exact test), without reaching statistical significance. these results are only indicative because we analyzed reported metastases and recurrences that had been referred to our laboratory. association of braf status to histopathological parameters in primary mms (table 4), mutated braf was significantly more common in ulcerated tumors (51.7% vs 31%, p = 0.002, fisher exact test) or when the adjacent dermis lacked solar elastosis (44.3% vs 7.1%, p = 0.008, fisher exact test). in contrast, the number of mitoses, presence of tumor-infiltrating lymphocytes (tils), clark level, or breslow thickness were not significantly related to braf mutation status, apart primary and metastatic mms are shown in tables 2 and 3, respectively. briefly, braf mutations were more common among younger patients (p = 0.011, mann-whitney u test), while the same trend was present for primary and metastatic samples, however without reaching statistical significance. primary mms of the torso showed a slightly increased mutation frequency, compared with those located at the extremities or head and neck area (40.3% vs 36.3%, p = 0.269, fisher exact test). cutaneous and lymph node metastases also displayed higher mutation frequency, again without reaching statistical significance (53.8% vs 35.2, p = 0.143, fisher exact test). mutations were more common in men, although this was statistically significant only in metastatic samples (p = 0.029, fisher exact test). patients with a recurrent melanoma had higher mutation frequency (13/18 vs 41/116, p = 0.004, fisher exact figure 2. sequencing chromatographs of a wild-type sample and samples carrying a v600e mutation, a v600k mutation, and a v600r mutation. [copyright: ©2019 spathis et al.] table 2. patient characteristics of primary melanomas and braf status braf status total mutated (%) p wt mutated age, mean (95% ci) (n = 129) 65.3 (61.8-68.7) 60.2 (56.1-64.3) 63.2 (60.5-65.8) 0.086 sex (n = 129) male 43 35 78 44.9 0.205 female 34 17 51 33.3 primary site (n = 129) head and neck 17 9 26 34.6 0.254 extremities 34 20 54 37.0 torso 26 23 49 40.3 ci = confidence interval; wt = wild type. 60 research | dermatol pract concept 2019;9(1):13 significance, as some of them did in previous studies [12, 13]. almost all pairs of primary and metastatic sites had the same genotype, except 2 patients, in whom a discordance of braf status between primary site and metastasis was found [7, 14]. in a recent meta-analysis, braf and nras mutations were associated with histological subtype and tumor site, but not with patient age or sex [15]. braf mutations were frequently detected in patients with ssm and in mms arising in non–chronically sun-damaged skin. in contrast, nras mutations were more frequent in patients with nm and in mms arising in chronically sun-damaged skin [15]. another meta-analysis of braf mutations and their associations with the clinicopathological characteristics of primary mm showed an association of braf mutations with younger age, location at the torso, non–chronically sun-damaged skin, ssm type, and advanced melanoma stage [16]. similar results were identified in our sample set, but after using a logistic regression model, only ulceration and melanoma type were significant predictors. in agreement with previous studies, braf mutations were more commonly found in ssm, and with decreasing frequency in nm, alm, and lmm [12, 13, 16, 17]. as expected, intraepidermal (in situ) mms had an intermediate braf mutation frequency. upon further analysis, we identified that ulcerated nms had a braf mutation frequency similar to ssms (56.4%), whereas non-ulcerated nms had a percentage more akin to that of the alm/lmm group (14.3%). this could be explained if one considers ulcerated nms as rapidly growing ex-ssms, whose adjacent intraepidermal component was phased out [18]. another histopathological parameter significantly related to braf mutations was ulceration. some studies have also reported increased braf mutation percentage in ulcerated samples [12, 17, 19-21], while others, including a meta-analysis, did not [13, 16]. the 2 studies that included only 1 type from a slight increase in braf mutations among cases with tils (42.9% vs 37.5%, fisher exact test) or mms with breslow thickness >1 mm (43.9% vs 38.1%, fisher exact test). concerning the type of mm, mutations were more common in superficial spreading mm (ssm) and nodular mm (nm) and less common in acral lentiginous mm (alm) and lentigo maligna melanomas (lmm). primary dermal mm and intraepidermal (in situ) melanomas displayed an intermediate frequency. the trend was significant when analyzing the different types, whether primary dermal and in situ melanomas were included in the analysis or not. cross-tabulation of melanoma types with braf status divided by presence of ulceration showed similar mutated samples with or without ulceration for alm (1/4 vs 0/4), lmm (1/5 vs 1/7), and smm (10/16 vs 13/27), but not for nm (2/14 vs 18/32, 14.3% vs 56.2%, p = 0.010, fisher exact test). we then used a backward step-wise wald binary logistic regression analysis including all borderline and statistically significant parameters. topology and age were removed during model creation, while ulceration (p = 0.008, odds ratio = 3.509) and type (p = 0.024), specifically ssm type (p = 0.020, odds ratio = 7.626), were the only predictors. discussion per our results, a 42.1% prevalence of braf mutations at codon 600 among our patients with mm was observed. these mutations were statistically more common in younger patients, in ulcerated mms, and in mms lacking solar elastosis in adjacent papillary dermis. these findings are consistent with previous experience [7, 12]. a trend for increased percentage of braf mutations was documented in men with mms of the torso, in mms more than 1 mm breslow thickness, higher mitotic rate, reported metastasis, and earlier reported recurrences. however, these findings did not reach statistical table 3. patient characteristics of metastatic melanomas and braf status braf status total mutated (%) p wt mutated age, mean (95% ci) (n = 56) 61.5 (55.3-67.7) 57.7 (51.9-63.5) 59.7 (55.5-63.8) 0.251 sex (n = 56) male 14 21 35 60.0 0.029 female 15 6 21 28.6 metastasis site (n = 56) distant skin or ln 18 21 39 53.8 0.149 lung 0 1 1 100 other visceral 11 5 16 31.3 ci = confidence interval; ln = lymph node; wt = wild type research | dermatol pract concept 2019;9(1):13 61 ulceration has been correlated with braf mutations [12, 17, 19] and increased mitotic rate [20, 22]. upon further analysis, lower mitotic rates were found in mutated tumors compared with wild-type ones (2.2 vs 6.83) in alm, lmm, and nonulcerated nm, whereas the contrary was true concerning ulcerated nm and ssm (6.80 vs 4.82). of melanoma (nm) identified a clear correlation [20, 21]. furthermore, we identified increased mitotic rate in ulcerated melanomas (8.71 vs 2.21, p < 0.001, mann-whitney test), yet no correlation between an increased mitotic rate and braf mutation percentage was identified (4.8 vs 5.6, p = 0.307, mann-whitney test). this seems contradictory, since table 4. histopathological findings and braf status of primary mm braf status total mutated (%) p wt mutated type (n = 126) alm 7 1 8 12.5 0.004 lmm 10 2 12 16.7 primary dermal 2 1 3 33.3 in situ 9 5 14 35.7 nm 26 20 46 43.5 ssm 20 23 43 53.5 clark level (n = 121) 2.68 (2.4-3.0) 2.54 (2.3-2.8) 2.62 (2.4-2.8) 0.741 1 9 5 14 35.7 0.386 2 31 23 54 42.6 3 12 13 25 52.0 4 12 8 20 40.0 5 7 1 8 12.5 breslow thickness in mm, (n = 113), mean (95% ci) 3.63 (2.8-4.5) 3.87 (2.6-5.1) 3.73 (4.9-7.8) 0.585 breslow thickness ≤1mm 26 16 42 38.1 0.569 breslow thickness >1mm 46 36 82 43.9 tis 10 6 16 37.5 0.828 t1 16 10 25 38.5 t2 9 8 17 47.1 t3 9 10 19 52.6 t4 28 18 46 39.1 tils (n = 109) absent 20 12 32 37.5 0.875 nonbrisk 32 24 56 42.9 brisk 12 9 21 42.9 mitoses (n = 129), mean (95% ci) 5.8 (3.8-7.8) 6.74 (4.6-8.8) 6.3 (4.9-7.8) 0.307 mitoses <1/mm2 16 9 25 36.0 0.658 mitoses ≥1/mm2 61 43 104 41.3 ulceration (n = 129) no 49 22 71 31.0 0.020 yes 28 30 58 51.7 solar elastosis (n = 129) no 64 51 115 44.3 0.008 yes 13 1 14 7.1 ci = confidence interval; tis = tumor in situ; wt = wild type. 62 research | dermatol pract concept 2019;9(1):13 iiic melanoma: implications for melanoma staging and adjuvant therapy. eur j cancer. 2014;50(15):2668-2676. 9. flaherty kt, puzanov i, kim kb, et al. inhibition of mutated, activated braf in metastatic melanoma. n engl j med. 2010;363(9):809–819. 10. balch cm, soong s-j, gershenwald je, et al. prognostic factors analysis of 17,600 melanoma patients: validation of the american joint committee on cancer melanoma staging system. j clin oncol. 2001;19(16):3622-3634. 11. spathis a, georgoulakis j, foukas p, et al. kras and braf mutation analysis from liquid-based cytology brushings of colorectal carcinoma in comparison with formalin-fixed, paraffin-embedded tissue. anticancer res. 2010;30(6):1969-1975. 12. ellerhorst ja, greene vr, ekmekcioglu s, et al. clinical correlates of nras and braf mutations in primary human melanoma. clin cancer res. 2011;17(2):229–235. 13. jakob ja, bassett rl jr, ng cs, et al., nras mutation status is an independent prognostic factor in metastatic melanoma. cancer. 2012;118(16):4014-4023. 14. colombino m, capone m, lissia a, et al. braf/nras mutation frequencies among primary tumors and metastases in patients with melanoma. j clin oncol. 2012;30(20):2522-2529. 15. lee jh, choi jw, kim ys. frequencies of braf and nras mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. br j dermatol. 2011;164(4):776-784. 16. kim sy, kim sn, hahn hj, lee yw, choe yb, ahn kj. metaanalysis of braf mutations and clinicopathologic characteristics in primary melanoma. j am acad dermatol. 2015;72(6):10361046.e2. 17. yamazaki n, tanaka r, tsutsumida a, et al. braf v600 mutations and pathological features in japanese melanoma patients. melanoma res. 2015;25(1):9-14. 18. mooi wj, krausz t. melanoma: subtypes and variants. in: hodder a, ed. pathology of melanocytic disorders. london: taylor & francis ltd. 2007:285-342. 19. safaee ardekani g, jafarnejad sm, khosravi s, martinka m, ho v, li g. disease progression and patient survival are significantly influenced by braf protein expression in primary melanoma. br j dermatol. 2013;169(2):320-328. 20. akslen la, angelini s, straume o, et al. braf and nras mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. j invest dermatol. 2005;125(2):312-317. 21. hugdahl e, kalvenes mb, puntervoll he, ladstein rg, akslen la. braf-v600e expression in primary nodular melanoma is associated with aggressive tumour features and reduced survival. br j cancer. 2016;114(7):801-808. 22. shen s, wolfe r, mclean ca, haskett m, kelly jw. characteristics and associations of high-mitotic-rate melanoma. jama dermatol. 2014;150(10):1048-1055. 23. greene vr, johnson mm, grimm ea, ellerhorst ja. frequencies of nras and braf mutations increase from the radial to the vertical growth phase in cutaneous melanoma. j invest dermatol. 2009;129(6):1483–1488. 24. mar vj, liu w, devitt b, et al. the role of braf mutations in primary melanoma growth rate and survival. br j dermatol. 2015;173(1):76-82. 25. akbani r, akdemir kc, aksoy aa, et al; cancer genome atlas network. genomic classification of cutaneous melanoma. cell. 2015;161(7):1681-1696. braf mutations have been previously linked to transition from radial to vertical growth phase [6, 23]; to shorter recurrence-free, disease-specific survival [8]; and to overall survival with a more protracted growth rate [24]. however, the exact role and the pathways mirrored in specific morphological features such as ulceration and pathology types is elusive. conclusions our results suggest that braf mutations are more frequent in ssm, ulcerated mms independent of histological type, and mms arising in non–chronically sun-damaged skin, ie, lacking solar elastosis. a significantly higher number of cases is required to clarify whether these correlations identified by many studies, as well as ours, are influenced by the variance of different populations, ages, and melanoma types included in each study. braf-mutated melanoma patients already have the advantage of being more effectively treated with drugs that specifically target braf-mutated cells, a fact that may mask the potential contribution of mutation presence to metastasis development. furthermore, as both new immunerelated therapies and driver mutations for development and metastasis of mm are further identified, molecular profile of mms may contribute to distinguishing melanoma types and estimating prognosis more accurately [25]. acknowledgment in loving memory of professor petros karakitsos, a dedicated doctor, an outstanding scientist and a pythagorean teacher, who passed away on june 26, 2017. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2017. ca cancer j clin. 2017;67(1):7-30. 2. davies h, bignell gr, cox c, et al. mutations of the braf gene in human cancer. nature. 2002;417(6892):949-954. 3. buscà r, abbe p, mantoux f, et al. ras mediates the campdependent activation of extracellular signal-regulated kinases (erks) in melanocytes. embo j. 2000;19(12):2900-2910. 4. poynter jn, elder jt, fullen dr, et al. braf and nras mutations in melanoma and melanocytic nevi. melanoma res. 2006;16(4):267-273. 5. arozarena i, sanchez-laorden b, packer l, et al. oncogenic braf induces melanoma cell invasion by downregulating the cgmpspecific phosphodiesterase pde5a. cancer cell. 2011;19(1):4557. 6. dong j, phelps rg, qiao r, et al. braf oncogenic mutations correlate with progression rather than initiation of human melanoma. cancer res. 2003;63(14): 3883-3885. 7. shinozaki m, fujimoto a, morton dl, hoon dsb. incidence of braf oncogene mutation and clinical relevance for primary cutaneous melanomas. clin cancer res. 2004;10(5):1753-1757. 8. barbour ap, tang yh, armour n, et al. braf mutation status is an independent prognostic factor for resected stage iiib and dermatology: practical and conceptual research | dermatol pract concept 2019;9(3):2 181 dermatology practical & conceptual involvement of the areae compositae of the heart in endemic pemphigus foliaceus ana maria abreu-velez1, yulieth a. upegui-zapata2, carlos a. valencia-yepes3, eduardo upegui-quiceno4, alejandra m. jiménez-echavarría4, césar d. niño-pulido5, bruce r. smoller6, michael s. howard1 1 georgia dermatopathology associates, atlanta, ga, usa 2 pecet group, pharmaceutical sciences, medical research institute, school of medicine, university of antioquia, medellín, colombia 3 department of education, university of antioquia, medellín, colombia 4 pecet group, university of antioquia, medellín, colombia 5 ces university, medellín, colombia 6 departments of pathology and laboratory medicine & dermatology, university of rochester medical center, school of medicine and dentistry, rochester, ny, usa key words: areae compositae of the heart, endemic pemphigus foliaceus, myzap, left cardiac hypertrophy, p0071, arvcf, desmoplakins i and ii citation: abreu-velez am, upegui-zapata ya, valencia-yepes ca, upegui-quiceno e, jiménez-echavarría am, niño-pulido cd, smoller br, howard ms. involvement of the areae compositae of the heart in endemic pemphigus foliaceus. dermatol pract concept. 2019;9(3):181-186. doi: https://doi.org/10.5826/dpc.0903a02 accepted: march 14, 2019; published: july 31, 2019 copyright: ©2019 abreu-velez et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this work was funded by georgia dermatopathology associates; mineros sa, medellín, colombia; hospital nuestra señora del carmen, el bagre, colombia; the embassy of japan in colombia; and the el bagre mayoral office. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ana maria abreu-velez, md, phd, drsc, georgia dermatopathology associates, 1534 north decatur road, ne, suite 206, atlanta, ga 30307-1000, usa. email: abreuvelez@yahoo.com background: a new variant of endemic pemphigus foliaceus in el bagre (el bagre-epf), colombia, south america, shares features with senear-usher syndrome and occurs in an endemic fashion. patients affected by el bagre-epf have heterogeneous antigenic reactivity not only to the skin but to other organs, including the heart. here we test for autoantibodies to the areae compositae of the heart (structure consisting of typical desmosomal amalgamated fascia adherens molecules) and evaluate any possible clinical correlation. methods: a case-control study comparing 45 patients and 45 controls from the endemic area, matched by demographics including age, gender, weight, work activities, and comorbidities, was performed. direct and indirect immunofluorescence, immunohistochemistry, confocal microscopic studies, and echocardiogram studies were completed. results: the main clinical abnormally seen in the el bagre-epf patients was left ventricular hypertrophy in 15/45 patients, compared with no such findings in the control population (p < 0.1). seventy abstract 182 research | dermatol pract concept 2019;9(3):2 antigen bovine tryptic 45-48 kda fragment of dsg1 [7]; and (6) each patient’s serum yielded a positive result using an enzyme-linked immunosorbent assay test when screening for autoantibodies to pemphigus foliaceus antigens [8]. in addition, blood pressure was taken in the patients and controls. direct and indirect immunofluorescence in brief, for dif from skin biopsies and iif we incubated 4-micron-thickness sections on slides with secondary antibodies as previously described (4-10). rat and cow were used for the iif and were partially permeabilized using 1× phosphatebuffered saline with 0.1% triton and blocked with 1% normal goat serum [4-10]. fitc-conjugated rabbit anti-total igg, iga, igm, complement/c1q, and complement/c3 were used. these antibodies were used at 1:25 dilution. we also used fibrinogen and albumin at 1:50 dilution. all of the preceding antibodies were obtained from dako (carpinteria, ca, usa). in addition, anti-human ige antiserum (epsilon chain) was obtained from kent laboratories (bellingham, wa, usa) and anti-human igd antibodies from southern biotechnology (birmingham, al, usa). these latter antibodies were used at 1:25 dilution. the dif slides were counterstained with 4',6-diamidino-2-phenylindole (dapi) (pierce, rockford, il, usa). commercial antibodies to known components of the areae compositae of the heart were used to study possible colocalization markers with the patients’ autoantibodies. these include mouse monoclonal multiepitope cocktail to anti-desmoplakin i and ii (dspi-ii) (catalog no. 65146), to armadillo repeat gene deleted in velocardiofacial syndrome (arvcf) polyclonal antibody (catalog no. gp155) (secondarily used alexa fluor 555 goat-antiguinea pig igg [h&l], molecular probes life technologies incorporated by thermofisher scientific, waltham, ma, usa) [9]. we also used mouse monoclonal multiepitope cocktail to anti-p0071 (catalog no. 651166), mouse monoclonal antibody to myozap (also known as mizap) (catalog no. 651169) as the secondary antibodies to the dspi-ii, to p007, and to myozap goat anti-mouse texas red-conjugated igg (h&l) (thermofisher). the antibodies to myozap, dspi-ii, p0071, and arcvf were all from progen biotechnik (heidelberg, germany). the samples were consistently run with positive and negative controls. we classified our findings as negative introduction a new variant of endemic pemphigus foliaceus in el bagre (el bagre-epf) (also known as pemphigus abreu-manu) occurs in a well-defined geographic area of colombia, south america. this disease provides an outstanding natural model for studying the interactions among genetics, the immune system, and possible environmental risk factors in the development of autoimmunity [1-8]. continuous exogenous antigenic stimulation and a genetic predisposition may be required in the pathogenesis of this disease [4-8]. patients affected by el bagre-epf have autoantibodies to multiple cell junctions in the skin and one-third of them also demonstrate autoantibodies against other organs’ cell junctions. we tested for autoreactivity to a more complex cell junction in the heart, the areae compositae, and evaluated for any possible clinical associations. materials and methods a case-control study on 45 patients affected by el bagreepf and 45 controls from the endemic area matched by age, gender, and work activities was performed. a human quality assurance review board at the nuestra señora del carmen hospital in el bagre approved the studies. the study participants signed consent forms, and no patient identifiers were retained. to make the diagnosis of el bagre-epf, we took skin biopsies from the chest and they were evaluated by hematoxylin and eosin histology, direct and indirect immunofluorescence (dif, iif), and immunoblotting [4-8]. only patients meeting diagnostic criteria for el bagre-epf were included, specifically: (1) patients displayed clinical and epidemiological features described for this disease; (2) patients lived in the endemic area; and (3) patient serum displayed intercellular staining between epidermal keratinocytes and the basement membrane zone of the skin, via either dif or iif using fluorescein isothiocyanate (fitc)-conjugated monoclonal antibodies to human total immunoglobulin (ig) g or igg4, as described elsewhere [4-8]. furthermore, (4) each patient’s serum tested positive by immunoblotting for reactivity against desmoglein-1 (dsg1), as well as for plakin molecules as previously described [4-8]; (5) each patient’s serum immunoprecipitated a concanavalin a affinity-purified percent of el bagre-epf patients and none of the controls displayed polyclonal autoreactivity using different immunoglobulins and complement to the areae compositae of the heart using different methods and antibodies (p < 0.1). conclusions: patients affected by el bagre-epf demonstrated autoantibodies to the areae compositae of the heart. this finding was associated with left ventricular hypertrophic cardiomyopathy. the areae compositae may play a role in cell junction tension and the el bagre-epf patients’ autoantibodies possibly disrupting these junctions and thereby contributing to the left ventricular hypertrophy. abstract research | dermatol pract concept 2019;9(3):2 183 (–), weakly positive (+), moderate positive (++), positive (+++) and strongly positive (++++). b-mode 2-dimensional ultrasound imaging we tested for any cardiovascular pathology. visualsonics ultrasound (fujifilm, toronto, ontario, canada) was used, and the testing was performed as described [11]. m-mode echocardiograms were done and recorded at 50 mm/second paper speed using black and white photographic paper. the following m-mode parameters were analyzed: left ventricular fractional shortening (lvfs), left ventricular end-diastolic diameter (lvedd), left ventricular end-systolic diameter (lvesd), posterior wall thickness (pwth), left ventricular end-diastolic radius/posterior wall thickness (r/th), interventricular septum thickness (ivsth), percentage of ivs systolic thickening (ivs%th), percentage of pw systolic thickening (pw%th), and left atrium dimensions (la). statistical analysis we used fisher exact test to compare 2 nominal variables (eg, positive and negative) of antibody response. we also compared the differences between patient cases and controls when evaluating positivity of the el bagre-epf autoantibodies. p < 0.1 with a 98% confidence interval (or better) was considered statistically significant. for all statistical analyses, the software graphpad quickcalcs (graphpad software inc., la jolla, ca, usa) was used. results seventy percent of el bagre-epf cases and none of the controls displayed polyclonal autoreactivity with different immunoglobulins and complement components to the areae compositae of the heart using different methods and antibodies (p < 0.1). the iif showed colocalization with the commercial antibodies to mizap, arvcf, dspi-ii, and p0071 in the tested species (rat and cow). the positive antibodies were anti-human igg, igm, c3c, c1q, fibrinogen, and albumin (figures 1 and 2). in table 1, we present the data of the presence of autoantibodies against the areae compositae of the heart using iif comparing serum el bagre-epf autoantibodies in cases vs controls. the patients’ daily dosage of prednisone is also presented in this table. figure 1. (a) confocal microscopy showing colocalization of the el bagre-epf patients with the commercial antibody to mizap (white arrow, red stain). (b) the area composita has nuclei as shown in the positive stain with dapi (white arrow, blue stain). (c) el bagre-epf autoantibodies stained using anti-human igg-fitc-conjugated antibodies against the area composita of the heart (white arrow, green stain). (d, e) using pseudo color, the shape of the area composita is positive (red arrows). (a-f) ×630. (g) the overlapping of the peaks of the fluorochromes to el bagre-epf in fitc and mizap with texas red at the area composita of the heart (white arrows). (h) an overlapping of dapi, el bagre-epf autoantibodies, and mizap (×1,000) (white arrow). [copyright: ©2019 abreu-velez et al.] a d b e g c f h 184 research | dermatol pract concept 2019;9(3):2 the main echocardiogram abnormalities seen in the el bagre-epf patients include a left ventricular hypertrophy (lvh) in 15/45 patients, and this was not identified in any of the control patients (p < 0.1). the echocardiogram findings revealed the following parameters in all 15 patients: lvh and normalization of left ventricular dimensions and function were done. the average measurement of the 15 patients was 11 cm; lvfs changed from 15.0 ± 5.2% to 39.7 ± 5.4% (p < 0.1), lvedd from 6.6 ± 0.6 to 4.6 cm (p < 0.01), lvesd from 5.6 ± 0.8 to 2.8 ± 0.6 cm (p < 0.01), pwth from 1.1 ± 0.1 to 1.2 ± 0.1 cm (not significant), r/th from 3.1 ± 0.5 to 2.0 ± 0.4 cm (p < 0.01), ivsth from 1.2 ± 0.3 to 1.5 ± 0.3 cm (p < 0.01), ivs%th from 14.2 ± 4.1% to 28.5 ± 7.8% (p < 0.01), pw%th from 31.0 ± 14.4 to 54.3 ± 19.6% (p < 0.01), and la from 4.6 ± 0.6 to 3.5 ± 0.9 cm (p < 0.01). blood pressure levels were similar in the cases and controls. using iif, 23/45 patients affected by el bagre-epf had anti-human igg-fitc-conjugated autoantibodies and comtable 1. presence of autoantibodies (ab) against the areae compositae of the heart using iif and cow as antigen source and comparison with the respective titers of seric autoantibodies in cases vs controls and their daily dosage of prednisone iif autoantibodies and markers el bagre-epf titers of ab in serum daily dosage of oral prednisone controls titers of ab p values igg 15/45 (320) 10 mg 0/45 (0) <0.01 fibrinogen 15/45 (320) 15 mg 0/45 (0) <0.01 igm 13/45 (160) 20 mg 0/45 (20) <0.01 albumin 11/45 (160) 25 mg 0/45 (20) <0.01 c3c 13/45 (160) 30 mg 0/45 (20) <0.01 c1q 12/45 (80) 30 mg 0/45 (20) <0.01 iga 15/45 (40) 30 mg 0/45 (0) <0.01 igd 15/45 (40) 15 mg 0/45 (0) <0.01 ige 7/45 (40) 20 mg 0/45 (0) <0.01 kappa 15/45 (160) 15 mg 0/45 (0) <0.01 lambda 15/45 (160) 15 mg 0/45 (0) <0.01 figure 2. (a) confocal microscopic image shows positive staining with el bagreepf autoantibodies labeled with fitc-conjugated antihuman igg (green staining) colocalizing with the antibody to arvcf (texas redconjugated) at multiple areae compositae of the heart (yellow arrow) (×1,000). (b) a zoom of the areae compositae of the heart (white arrow shows the complexity of the multiple dotted molecules inside it) (×140). (c) diagram of the areae compositae. [copyright: ©2019 abreu-velez et al.] a b c research | dermatol pract concept 2019;9(3):2 185 plement directed to the areae compositae of the heart (p < 0.1) (figures 1 and 2). no controls were positive. discussion the areae compositae of the heart is composed of an amalgamation of mixed-type cell-cell adhering junctions with desmosomes, adhering junctions, and some vessel junctions [9,12-19]. in recent years it has become clear that numerous other junction types exist that are different from the classically recognized junctions such gap, desmosome, hemidesmosome, tight junctions, and adherens junctions, and some of them are located where 3 or more cell junctions converge [20]. the biological constitution of the area composita and its clinical importance has recently gained attention. only a few studies on the areae compositae have shown that mutations in the areae compositae protein αt-catenin are associated with arrhythmogenic right ventricular cardiomyopathy [20,21]. our study provides new information about the possible role of the areae compositae, especially at the left ventricle, where stronger junctions are needed to handle the higher intraventricular pressure. further investigations are needed [22]. hypertrophic cardiomyopathy is clinically defined by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading condition [23]. the most common cause of lvh is high blood pressure (hypertension). the patients in this study who demonstrated lvh had no evidence of high blood pressure [24]. other causes of lvh include athletic hypertrophy (a condition related to exercise). the patients in this study, although they work outside as farmers and or miners, are not athletes. valve disease is also a cause of lvh (some of the patients have valve disease due to the presence of autoantibodies) (manuscript in preparation). this presents an alternative explanation for the increased incidence of lvh in our patient population. other conditions such hypertrophic cardiomyopathy, and congenital heart disease, such as autosomal dominant trait caused by cardiac sarcomere protein gene mutation, can also give rise to lvh. (so far these 2 conditions have been undetected in any of our patients, although we suspect they carry several genetic anomalies.) other conditions, such as myocardial infarction and dilated cardiomyopathy, can cause cardiomegaly. experimentally mutated mizap in mice results in lvh [25]. el bagre-epf autoantibodies colocalize with mizap and other molecules at the areae compositae of the heart. the areae compositae is part of the contractile tissue of the heart making specific cell-cell contacts necessary to ensure strong mechanical and electrochemical coupling during beating. these contact sites, termed the intercalated discs, have gained increased attention recently because of their potential involvement in cardiac disease. conclusions we conclude that el bagre-epf patients have autoantibodies to the areae compositae of the heart colocalizing with mizap, arvcf, dspi-ii, and p0071. clinically, these patients often present with lvh. as shown in this study, the localization and nature of 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αt-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia. j cell sci. 2012;125(pt 4):1058-1067. 22. perriard jc, hirschy a, ehler e. dilated cardiomyopathy: a disease of the intercalated disc? trends cardiovasc med. 2003;13(1):3038. 23. stewart mh, lavie cj, shah s, et al. prognostic implications of left ventricular hypertrophy. prog cardiovasc dis. 2018;61(56):446-455. 24. loncaric f, bijnens b, sitges m. added value of cardiac deformation imaging in differential diagnosis of left ventricular hypertrophy. glob cardiol sci pract. 2018;2018(3):21. 25. rangrez ay,  eden m,  poyanmehr r,  et  al. myozap  deficiency promotes adverse cardiac remodeling via differential regulation of mitogen-activated protein kinase/serum-response factor and β-catenin/gsk-3β protein signaling. j biol chem. 2016;291(8):4128-4143. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020013 1 dermatology practical & conceptual introduction keratoacanthoma is a relatively common, low-grade cutaneous tumor that most commonly exhibits a self-limiting behavior. the lesions present as firm, sharply defined nodules with a central ulceration or prominent keratin plug. pertinent physical findings are usually limited to the skin, with the majority of the lesions favoring the sun-exposed areas [1]. histopathological characteristics highly resemble those of squamous cell carcinoma. observation strategy is questionable and rarely practiced as a therapeutic means. surgical excision of the entire lesion is a gold standard regimen [1,2]. case presentation a 65-year-old caucasian man with an unremarkable medical history presented with a 1-month history of 2 painless nodules in a linear arrangement on his right leg (figure 1, a and b). the patient reported that both lesions appeared 1 week after he sustained a penetrating plant thorn injury while fishing in fresh water. prior to clinical admission he had received amoxicillin/clavulanic acid by mouth along with topical fusidic acid cream for 2 weeks without noticeable clinical improvement. cutaneous examination revealed 2 dome-shaped, well-demarcated, flesh-colored, nontender nodules with peripheral scaling and central crust, arranged in a sporotrichoid fashion over the pretibial area of the right leg. the proximal and the distal lesions were located inferior to the patient’s knee and on the lower part of his right shin, respectively. enlarged lymph nodes were palpated in the right inguinal area. he was afebrile and the overall physical examination was normal. differential diagnosis included keratoacanthomas, cutaneous sporotrichosis, nocardiosis, mycobacterium marinum infection, and merkel cell carcinomas. routine hematological, biochemical, and immunological investigations were either negative or within normal range. mantoux test was negative and chest x-ray revealed no pathological findings. direct gram stain, periodic acid-schiff stain, ziehl neelsen and giemsa stains as well as tissue cultures were found negative for mycobacteria, protozoa, fungi, and yeasts, including nocardia brasiliensis, sporothrix schenckii, mycobacterium marinum, actinomyces, and leishmania, and positive for serratia marcescens and escherichia coli, which were considered bacterial contamination. two 6-mm punch biopsies were obtained for histopathological examination. polymerase chain reaction for detection of cutaneous nodules arranged in a sporotrichoid distribution over the lower extremity georgia kyriakou,1 eleftheria vryzaki,1 efthymia gialeli,1 sophia georgiou1 1 department of dermatology, university general hospital of patras, greece key words: keratoacanthoma, skin neoplasms, squamous cell carcinoma citation: kyriakou g, vryzaki e, gialeli e, georgiou s. cutaneous nodules arranged in a sporotrichoid distribution over the lower extremity. dermatol pract concept. 2020;10(1):e2020013. doi: https://doi.org/10.5826/dpc.1001a13 accepted: september 16, 2019; published: december 31, 2019 copyright: ©2019 kyriakou et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: georgia kyriakou, md, msc, cphd, university general hospital of patras, rion, patras, p.o. 265 04, greece. email: geo_kyr@yahoo.gr mailto:geo_kyr@yahoo.gr 2 letter | dermatol pract concept 2020;10(1):e2020013 mycobacteria was negative. pending the biopsy results and given the clinical suspicion of lymphocutaneous sporotrichosis, the patient commenced a course of systemic antibiotics and antifungals. since the biopsy results were consistent only with pseudoepitheliomatous hyperplasia, and minimal improvement was noticed during the antibiotic and fungal treatment, we proceeded to complete surgical excision of both lesions. the biopsied tissue specimens were additionally stained with periodic acid-schiff and grocott-gomori stains without identification of an infectious agent. histopathology was consistent with keratoacanthomas in regression stage (figures 2 and 3). there was no evidence of regional lymphadenopathy or relapse at the follow-up visit, conducted 6 months later. conclusions apart from infectious diseases, a number of neoplasms are uncommonly described to present in a sporotrichoid fashion. these include melanoma, squamous cell carcinoma, b-cell and t-cell lymphoma, langerhans cell histiocytosis, peripheral nerve sheath tumor, and epithelioid sarcoma [2]. nevertheless, in the majority of cases the tumors represented recurrent or metastatic disease rather than primary neoplasms. to our knowledge, a similar pattern of keratoacanthomas with each lesion being a primary tumor was first reported by abudu and cohen [2]. our patient is the second case described, thus rendering it a necessity to take keratoacanthomas into consideration when encountering atypical cutaneous lesions arranged in a sporotrichoid pattern. references 1. kwiek b, schwartz ra. keratoacanthoma (ka): an update and review. j am acad dermatol. 2016;74(6):1220-1233. 2. abudu b, cohen pr. sporotrichoid keratoacanthomas: case report and review of neoplasms presenting in a sporotrichoid pattern. cureus. 2018;10(8):e3196. figure 1. (a) keratoacanthomas in sporotrichoid distribution presenting as firm, sharply defined, dome-shaped nodules with a purulent, ulcerated surface. the distal lesion was 2.0 × 2.0 cm and located on the lower part of the patient’s right shin, while the proximal lesion was 2.5 × 2.5 cm and presented an ill-defined broad halo of  surrounding rubor and edema (b). a b figure 2. histopathological examination of the biopsy specimen revealing a central crater filled with keratin (keratin plug), downward cupping of the epidermis, and hyperkeratosis with little or no parakeratosis (h&e, ×40). figure 3. keratin-producing squamous cells demonstrate minimal or absence of nuclear atypia. marked inflammatory cell infiltrate is present around the lesion (h&e, ×200). dermatology: practical and conceptual 38 review | dermatol pract concept 2019;9(1):10 dermatology practical & conceptual introduction the term melanonychia describes a black-brown-gray pigmentation of the nail plate. although nail matrix melanocytes are normally quiescent, these cells can eventually become activated with or without proliferation, thus inducing the pigmentation of the nail plate. melanonychia can present itself in many different ways, but most frequently it appears as a longitudinal band (longitudinal melanonychia) that starts from the proximal margin of the nail and extends to the distal margin, following the growth of the nail. less commonly, the pigment can be transverse (transverse melanonychia) [1] or even involve all of the nail plate (total melanonychia). melanonychia can be observed at any age, affecting one digit or several digits, in both fingernails and toenails. the causes of longitudinal melanonychia can be difficult to differentiate clinically and, first of all, depend on the number of the bands and on their color, edge, and width. biopsy and histopathological examination is recommended when a longitudinal melanonychia occurs in an adult and it is localized in one single digit, even more so in the absence of local or systemic causes that may explain its onset. the real problem of how to distinguish whether the lesion is benign or malignant remains, as an early diagnosis of melanoma can be crucial for the prognosis. use of nail dermoscopy in the management of melanonychia: review michela starace1, aurora alessandrini1, nicolò brandi1, bianca maria piraccini1 1 department of experimental, diagnostic and specialty medicine-division of_dermatology, university of bologna, bologna, italy key words: pigmentation, melanonychia, dermoscopy, nail citation: starace m, alessandrini a, brandi n, piraccini bm. review of the use of nail dermoscopy in the management of melanonychia: review. dermatol pract concept. 2019;9(1):38-43. doi: https://doi.org/10.5826/dpc.0901a10 published: january 31, 2019 copyright: ©2019 starace et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: michela starace md, phd, department of experimental, diagnostic and specialty medicine-division of dermatology, university of bologna, bologna, italy, via massarenti, 1, 40138 bologna, italy. email: michela.starace2@unibo.it the term melanonychia describes a black-brown-gray pigmentation of the nail plate that, in most cases, appears as a longitudinal band. melanonychia can be observed at any age, affecting one digit or several digits, in both fingernails and toenails. its causes can be difficult to differentiate clinically and depend on the number of bands and on their color, edge, and width. for this reason, especially in adults and when the pigmentation is localized in one single digit, biopsy and histopathological examination still represent the gold standard for a definitive diagnosis. dermoscopy should be used routinely in the evaluation of a pigmented nail, as it provides important information for the management of melanonychia and can help avoid unnecessary nail biopsies. in cases of melanonychia it is important to establish whether the pigment is melanin or not and to determine whether the pigmentation of melanin is due to activation or proliferation and whether it is benign or malignant. abstract review | dermatol pract concept 2019;9(1):10 39 in green nails, the pigmentation is due to bacterial colonization by pseudomonas aeruginosa and is characterized by a bright green color that fades to yellow, laying under the nail plate [5] (figure 3). if the pigmentation is due to melanin produced by nail matrix, the second step of melanonychia management is to identify whether the pigmentation is due to an activation or proliferation. the number of digits involved is an important diagnostic clue: if more than one digit is affected, it is likely to be a melanocytic activation. the dermoscopic pattern that suggests a melanocytic activation is a gray background of the band with thin grayish regular and parallel lines (figure 4); moreover, hyperpigmentation of the nail can also be associated with tion, which peripherally fades and lacks the longitudinal lines of true melanonychia (figure 1). fungal melanonychia is a rare variant of onychomycosis caused by trichophyton rubrum variant melanoid, which can present itself with a longitudinal band on the nail plate, thus further complicating differential diagnosis. dermoscopy of fungal melanonychia reveals a usually brown band of melanonychia, with thick subungual hyperkeratosis and yellow and brown scales, wider at the distal ends and focalizing on reddish hue that may be related to traumatic hemorrhages from subungual hyperkeratosis; moreover, there are no visible inclusions of melanin, supporting a nonmelanocytic origin of the pigmentation [4] (figure 2). with this in mind, dermoscopy should be used routinely in the evaluation of a pigmented nail, as it provides important information for the management of melanonychia and can help to avoid unnecessary nail biopsies. in case of melanonychia, it is important to follow 3 steps: (1) to establish whether the pigment is melanin or not, (2) to determine whether the pigmentation of melanin is due to activation or proliferation, and (3) if it is a proliferation, to determine whether it is benign or malignant [2]. discussion when performing dermoscopy on nail pigmentation, it is important to observe all the visible part of the nail unit where it is possible to put the dermatoscope. moreover, it is fundamental to remember that the use of gel is recommended for the examination of any pigmented lesions because it increases the visibility through the nail plate, even if it is more difficult with the gel because of the tendency to slide off the plate. first of all, dermoscopy permits differentiating melanocytic from nonmelanocytic pigmentation, particularly the quite common brown-black nail discolorations due to subungual hematoma or fungal infection [3]. in fact, melanocytic pigmentation is generally brown-black, within the nail plate and with a longitudinal aspect, whereas exogenous pigmentation typically includes the spectrum of color of the substance that adheres to the nail plate and does not always have a longitudinal appearance located near the nail folds or in the center of the nail plate. the most common causes of nonmelanocytic pigmentation include subungual hematoma, fungal melanonychia, and green nails. subungual hematoma is one of the most frequent causes of brown-black nail pigmentation, and blood can be recognized by the presence of the red-purple-brown globule pattern within the nail plate and the homogeneous color of the pigmentafigure 1. dermoscopy of a brown-black nail pigmentation due to subungual hematoma. red-purple globule pattern within the nail plate with homogeneous color of the pigmentation peripherally fading (a). the pigmentation disappears with nail clipping (b). [copyright: ©2019 starace et al.] figure 2. melanonychia due to onychomycosis caused by trichophyton rubrum variant melanoid. [copyright: ©2019 starace et al.] figure 3. dermoscopy of green nails due to pseudomonas aeruginosa colonization of the nail. the convexity of the onycholytic border is linear. [copyright: ©2019 starace et al.] a b 40 review | dermatol pract concept 2019;9(1):10 lar and parallel lines with regular spacing and thickness. a new dermoscopic sign that can indicate a regression of a nevus and not represent a warning sign of a melanoma, especially in children, is the presence of black dots along melanocytic lines [12]. these dots are black, with a regular size and shape (less than 0.1 mm), and are distributed along the pigmented lines; sometimes they form a shallow pit at the periphery while other times it is possible to find them within the pigmented lines, often interrupting them. the authors have explained the presence of these dots as an accumulation of melanin derived from a cluster of nevus cells that migrate upward allow us to differentiate melanonychia due to benign melanocytic proliferation, ie, nail matrix lentigo or nevus, from melanonychia due to malignant melanocytic proliferation [7]. the first cutoff in cases of longitudinal melanonychia due to proliferation is the age of the patient since nail melanoma is rare in children; only 20 cases are described in the literature, frequently in darker skin phototypes [6-10]. dermoscopic patterns that suggest melanoma in children are rapid evolution of brown background with longitudinal brown to black lines with irregular degree of color pigmentation, spacing or varying thickness and ending abruptly or having a parallel distribution. however, these features can also be seen in nail matrix nevi in children and thus their specificity is low. for this reason, dermoscopy could have less value in childhood melanonychia [11]. nonetheless nail matrix nevi may be present at birth; they can also occur with age. nail matrix nevi affect fingernails more frequently than toenails, most often the thumb. usually, the nail has one or more longitudinal heavily pigmented bands whose size can vary from a few millimeters to the whole nail and whose color may not be homogeneous and more or less dark [3]. dermoscopic patterns that suggest a nail matrix nevus are the presence of a brown background with longitudinal brown to black regua hyperpigmentation of the periungual skin [6]. when multiple nails present longitudinal melanonychia, it is important to consider a normal ethnic/racial variant, particularly in darker skin phototypes; the use of drugs; mechanical factors such as frictional melanonychia and onychotillomania; pregnancy; or an inflammatory disease or the manifestation of one of the multiple signs of a syndrome, such as peutz-jeghers syndrome and laugier-hunziker syndrome [5]. frictional melanonychia is a very common form of melanocytic activation and is typically localized only on the fifth and/or fourth toenails, due to the frequently chronic friction of these digits with the shoes. the band is usually grayblack and its background is brown with parallel thin lines (figure 5); in some cases, the friction of the toenails could induce trauma in the capillaries, thus leading to the appearance of red spots or splinter hemorrhages that reinforce the traumatic etiology of the pigmented band. in a similar way, in onychotillomania the mechanical trauma of biting of the proximal nail folds induces an activation of the melanocytes. in these cases, however, it is frequent to observe more digits involved and signs of chewing such as crusts or wounds on the most affected digits. dermoscopy of melanocytic nail pigmentation is difficult to interpret, as there are still not uniform criteria that figure 4. clinical picture of melanocytic activation affecting all fingernails during combined chemotherapy (a); onychoscopy reveals gray background of the bands with thin grayish regular and parallel lines, associated with muehrcke lines, which appear as white parallel transverse bands (b, c). [copyright: ©2019 starace et al.] figure 5. nail dermoscopy of frictional melanonychia of the fifth toenail. nail pigmentation is gray-brown with a brown background with parallel thin lines. [copyright: ©2019 starace et al.] a b c review | dermatol pract concept 2019;9(1):10 41 range from 1 mm to spanning the entire nail plate, the corresponding nail plate can show some changes or be completely normal, and, finally, brown-black periungual pigmentation (hutchinson sign) may or may not be present. the dermoscopic features of benign melanocytic proliferation are characterized by gray or brown homogeneous color of the background and brown bands with multiple thin brown lines; these lines are usually regular and parallel to each other, with regular spacing and thickness and similar shades of brown throughout the whole lesion, as in nevi. on the contrary, dermoscopic features suggestive of nail melanoma include a brown to black background of the band with longitudinal lines irregular in their thickness, spacing, color, or parallelism [17] (figure 7). however, this rule is not always reliable, as it is possible to find lines that are irregular in width or color also in benign lesions [5,18]. a recent study identified 3 important dermoscopic features that could help to distinguish whether the band is benign or malignant. in particular, a band involving more than two-thirds of the nail plate, a color gray to black, and the presence of nail dystrophy increase 3 times the risk of detecting a nail melanoma [19]. the years, first for the use of the abcds rule for nail pigmentation [15] and second for the introduction of nail dermoscopy [16] and its criteria for benign and malignant lesions [17]. in fact, even if the abdef rule is a useful clinical tool to suspect a melanoma, nail dermoscopy offers further help and permits seeing with high magnification the details of the pigmentation aspects not visible to the naked eye, enabling the visualization of different signs of melanoma. however, it is important to remember that dermoscopy is not always reliable in the evaluation and management of the pigmented nail [18], since there are some conditions for which dermoscopy is not performable, such as thickened nails, blurred borders of the lesions, and a nail plate that is totally black [5,18]. because of its rarity, there are only a few studies focused on melanoma dermoscopic features; therefore, dermoscopy should still be assisted by the clinical features and the history of the nail pigmentation. when only one digit is involved by melanonychia, a proliferative process has to be considered and a diagnosis of melanoma suspected. the clinical features of the band can be very different: the color can be more or less pronounced and homogeneous, the borders can be well defined or less sharp, the width can from the dermo-epidermal junction. in most young patients, the disappearance of the dots will occur over time and will accompany the fading of melanonychia. dark bands are associated with pseudo-hutchinson sign, because the dark nail plate pigmentation is visible through the transparent nail fold (illusory phenomenon); the pigmentation may be homogeneously distributed or darker bands may appear over diffuse pale pigmentation (figure 6). periungual pigmentation is typical in congenital nevi and may involve both the nail proximal fold and the hyponychium, thus alarming the clinician. in children, it is not uncommon to notice a gradual darkening and enlargement of the band that may have a proximal part broader than the distal (triangular shape); thinning and fissuring of the pigmented nail plate may also occur. it is also quite common to observe a gradual fading of the band with age [13]. this “regressing nevoid nail melanoma in childhood” is unique to children and not indicative of regression of the nevus but may just indicate decreased melanocytic activity from nevus cells [14]. the diagnostic accuracy of longitudinal melanonychia has improved over figure 6. dermoscopy of a nail matrix nevus in a 5-year-old child. brown background with longitudinal brown to black irregular and not parallel lines with irregular spacing and thickness, with the presence of black dots along melanocytic lines. the pseudo-hutchinson sign is also evident in the proximal nail fold. [copyright: ©2019 starace et al.] figure 7. clinical picture of nail melanoma of the ii digit of right hand (a); a brown-black band of melanonychia characterized by irregular lines in their thickness, spacing, color, and parallelism at dermoscopy (b). [copyright: ©2019 starace et al.] a b 42 review | dermatol pract concept 2019;9(1):10 prominently dotted vessels [20]. distinguishing this tumor from pyogenic granuloma could be difficult sometimes. in summary, dermoscopy is useful for the diagnosis of melanoma in adults especially in 2 cases: when there is the micro-hutchinson sign, ie, when melanoma is present as an ulcerated nodule of the nail bed, and when melanoma is present as a band of longitudinal melanonychia, not associated with periungual pigmentation and/or nail plate changes. a useful algorithm may help us to understand what is the best management in case of suspected nail apparatus melanoma and possibly allow an earlier diagnosis with detection of in situ nail melanoma [21]. false-negative and false-positive dermoscopic results are not rare, especially in cases of benign lesions with irregular lines. nevertheless, a delayed diagnosis of melanoma remains common and a poor prognosis is often attributable to longstanding disease. the misdiagnosis rate has been found to be higher than 20% [22]. intraoperative dermoscopy enables visualization of the origin of the pigmentation, revealing aspects not observed when the nail plate is interposed between the pigmented lesion and the dermatoscope [23]. this type of dermoscopy is more reliable and accurate than plate dermoscopy and has high sensitivity and specificity in differentiating pigmented nail lesions, albeit is a part of an invasive procedure and cannot be performed in all cases of melanonychia. with the intraoperative method, 4 dermoscopic features have been recognized: regular gray pattern, typical of hypermelanosis; regular brown pattern, typical of benign melanocytic hyperplasia; regular brown pattern with globules or blotches, typical of melanocytic nevi; and irregular pattern, typical of melanoma. the use of intraoperative procedure may facilitate selecting the best site to perform biopsy [24]. dermoscopy of the free edge of the distal nail plate can also be very helpful in distinguishing whether the pigment is produced by proximal or distal nail matrix. in fact, if the pigment is in the dorsal part of the free edge its origin comes from the proximal nail matrix, while if the pigment is in the ventral part of the free edge its origin is the distal nail matrix [5]. moreover, dermoscopic features of the nail plate and periungual tissues also offer interesting information for the selection of cases in which pathological examination is indicated, permitting the evaluation of hutchinson sign, one of the most important signs of malignancy. dermoscopically, this sign appears as a brown-black periungual pigmentation, characterized by polychromia and asymmetry. however, the most important role of nail dermoscopy is the ability to detect the micro-hutchinson sign, a periungual pigmentation visible only with a dermatoscope and not with the naked eye, which represents an initial sign of radial growth into adjacent tissue. moreover, the micro-hutchinson sign could be present also in amelanotic melanoma, a malignant lesion characterized by the lack of melanin pigment. the clinical features of this type of melanoma are the absence of the nail plate and a nail dystrophy due to nail bed hyperkeratosis or ulceration; other dermoscopic patterns typical of amelanotic melanoma are eroded nail bed nodule, vascular pattern characterized by a red discoloration with a milky-red veil and variable aspect of vessels, with some appearing as dots and others as irregular lines. the color of amelanotic melanoma is white in the center of the lesion and red in the periphery (figure 8) and can also correlate with the duration of the lesion. in older lesions the predominant color is dark red, probably due to the presence of crusts and vascular disarrangement, with irregular vessels assuming a mix of hairpin, linear, or dotty aspect; on the other hand, younger lesions have a lighter red color and present figure 8. amelanotic melanoma of the toenail. at clinical examination the absence of the nail plate with ulceration is evident (a); dermoscopy magnifies a nail bed nodule with irregular vascular pattern with milky red veil and hutchinson sign at hyponychium (b-e). [copyright: ©2019 starace et al.]  a b c d e review | dermatol pract concept 2019;9(1):10 43 9. uchiyama m, minemura k. two cases of malignant melanoma in young persons. nippon hifuka gakkai zasshi. 1979;89:668. 10. iorizzo m, tosti a, di chiacchio n, et al. nail melanoma in children: differential diagnosis and management. dermatol surg. 2008;34(7):974-978. 11. tosti a, piraccini bm, cagalli a, haneke e. in situ melanoma of the nail unit in children: report of two cases in fair-skinned caucasian children. pediatr dermatol. 2012;29(1):79-83. 12. murata y, kumano k. dots and lines: a dermoscopic sign of regression of longitudinal melanonychia in children. cutis. 2012;90:293-296. 13. tosti a, baran r, morelli r, et al. progressive fading of a longitudinal melanonychia due to a nail matrix melanocytic nevus in a child. arch dermatol. 1994;130(8):1076-1077. 14. kikuchi i, inoue s, sakaguchi e, ono t. regressing nevoid nail melanosis in childhood. dermatology. 1993;186:88-93. 15. levit ek, kagen mh, scher rk, grossman m, altman e. the abc rule for clinical detection of subungual melanoma. j am acad dermatol. 2000;42(2):269-274. 16. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138(10):1327-1333. 17. thomas l, dalle s. dermoscopy provides useful information for the management of melanonychia striata. dermatol ther. 2007;20(1):3-10. 18. di chiacchio n, hirata ah, daniel r, et al. consensus on melanonychia nail plate dermoscopy. an bras dermatol. 2013;88(2):309-313. 19. benati e, riberio s, longo c, et al. clinical and dermoscopic clues to differentiate pigmented nail bands: an international dermoscopy society study. j eur acad dermatol venereol. 2017;31(4):732-736. 20. phan a, dalle s, touzet s, ronger-savlé s. balme b, thomas l. dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population. br j dermatol. 2010;162(4):765-771. 21. starace m, dika e, fanti pa, et al. nail apparatus melanoma: dermoscopic and histopathologic correlations on a series of 23 patients from a single centre. j eur acad dermatol venereol. 2018;32(1):164-173. 22. phan a, touzet s, dalle s, et  al. acral lentiginous melanoma: a clinicoprognostic study of 126 cases. br j dermatol. 2006;155(3):561-569. 23. hirata sh, yamada s, enokihara my, et al. patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy. j am acad dermatol. 2011;65(2):297-303. 24. hirata sh, yamada s, almeida fa, et al. dermoscopic examination of the nail bed and matrix. int j dermatol. 2006;45(1):28-30. 25. sawada m, yokota k, matsumoto t, et al. proposed classification of longitudinal melanonychia based on clinical and dermoscopic criteria. int j dermatol. 2014;53(5):581-585. 26. ackerman ab. malignant melanoma in situ: the flat, curable stage of malignant melanoma. pathology. 1985;17(2):298-300. 27. ruben bs. pigmented lesions of the nail unit: clinical and histopathologic features. semin cutan med surg. 2010;29(3):148-158. there are no evidence-based studies that determine the ideal frequency of dermoscopic follow-up in patients with longitudinal melanonychia nor any that make precise dermoscopic criteria to decide when the pigmented lesions require biopsy [3]. one suggestion is to monitor the patient every 6 months with dermoscopy in cases of benign melanocytic lesions and to have a strict follow-up every 3 months in cases of irregular pigmentation without other signs of malignancy [25]. nevertheless, the gold standard for a definitive diagnosis of nail pigmentation still remains histopathology [26,27]. conclusions dermoscopy of the nail (onychoscopy) is nowadays used routinely, as it provides important information, giving specific criteria for the dermoscopic assessment of nail pigmentation. the causes of melanonychia vary from subungual hematoma, to a fungal and/or bacterial infection, to a melanocytic lesion (nevus melanoma, etc), and the differential diagnosis is not easy for the nonexpert dermatologist. in addition, the management is often a reason for concern. dermoscopy helps to identify the type of pigment and to determine the origin of the pigment. it is an important technique for the evaluation of melanocytic pigmentation; however, it has to be added to clinical data and, in cases of suspected melanoma, to biopsy for pathology. references 1. mirfazaelian h, alaeen a, daneshbod y. transverse melanonychia. br j hosp med (lond). 2014;75(7):413. 2. lencastre a, lamas a, sà d, et al. onychoscopy. clin dermatol. 2013;31(5):587-593. 3. tosti a, piraccini bm, de farias dc. dealing with melanonychia. semin cutan med surg. 2009;28(1):49-54. 4. wang yj, sun pl. fungal melanonychia caused by trichophyton rubrum and the value of dermoscopy. cutis. 2014;94(3):e5-e6. 5. piraccini bm, dika e, fanti pa. tips for diagnosis and treatment of nail pigmentation with practical algorithm. dermatol clin. 2015;33(2):185-195. 6. braun r, baran r, saurat jh, thomas l. surgical pearl: dermoscopy of the free edge of the nail to determine the level of nail plate pigmentation and the location of its probable origin in the proximal or distal nail matrix. j am acad dermatol. 2006;55(3):512513. 7. goettmann-bonvallott s, andré j, belaich s. longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. j am acad dermatol. 1999;41(1):17-22. 8. lyall d. malignant melanoma in infancy. j am med assoc. 1967;202(13):1153. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023099 1 pustular psoriasis triggered by a subcutaneous tissue expander mario alessandri-bonetti1, claudio conforti2, francesco amendola1, riccardo carbonaro1, manuela cirami3, luca vaienti1 1 department of reconstructive and aesthetic plastic surgery, university of milan, i.r.c.c.s. istituto galeazzi, milan, italy 2 dermatology clinic, maggiore hospital of trieste, trieste, italy 3 department of pathology, i.r.c.c.s. policlinico san donato, piazza edmondo malan, san donato milanese, italy citation: alessandri-bonetti m, conforti c, amendola f, carbonaro r, cirami m, vaienti l. pustular psoriasis triggered by a subcutaneous tissue expander. dermatol pract concept. 2023;13(2):e2023099. doi: https://doi.org/10.5826/dpc.1302a99 accepted: september 23, 2022; published: april 2023 copyright: ©2023 alessandri-bonetti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: mario alessandri-bonetti, md, department of reconstructive and aesthetic plastic surgery, university of milan, ircss istituto galeazzi, via riccardo galeazzi 4 20161 milan, italy. telephone number: +393385033483; e-mail: m.alessandribonetti@gmail.com case presentation an african 50-year-old female presented to our department complaining of retracting, painful and dystrophic scarring caused by a previous childhood burn in the right pectoral area. past medical history was unremarkable. we chose a two-step approach to treat her burn sequelae. first, we inserted a 400-cc silicone smooth rectangular tissue expander (mentor, irvine, usa) in the right suprascapular area. the expander was progressively filled during ambulatory visits. secondly, three months later, the dystrophic area was excised and reconstruction was performed using the expanded skin flap. at 12-months follow-up, the patient complained of itch above the advancement flap. we noticed an indurated purple plaque within the distal part of the flap, measuring 15x16 cm and surrounded by erythematous borders (figure 1a). multiple pruritic pustules were noted in the upper arms, abdomen and dorsum (figure 1b). biopsies of the right pectoral plaque and of a left supraclavicular pustule were taken. histology revealed parakeratosis, acanthosis, epidermal spongiotic pustules, perivascular inflammatory infiltrate with neutrophils in the epidermis and psoriasiform hyperplasia. although the negative family history of the patient, our findings were compatible with pustular psoriasis (figure 1, c and d). teaching point pustular psoriasis (pp) is clinically characterized by sterile pustules corresponding to a neutrophilic infiltrate in the dermis. usually, pp affects palms and soles while sometimes it may present in a generalized form associated with systemic symptoms. we hypothesized that the keratinocytes stretching and skin insult provoked by tissue expansion could have triggered the development of cutaneous psoriasis presenting as a plausible koebner phenomenon [1,2]. 2 image letter | dermatol pract concept. 2023;13(2):e2023099 references 1. okamoto t, ogawa y, kinoshita m, et al. mechanical stretch induced atp release from keratinocytes triggers koebner phenomenon in psoriasis. j dermatol sci. 2021;103(1):60-62. doi: 10.1016/j.jdermsci.2021.06.001. pmid: 34187740 2. qiao p, guo w, ke y, et al. mechanical stretch exacerbates psoriasis by stimulating keratinocyte proliferation and cytokine production. j invest dermatol. 2019;139(7):1470-1479. doi: 10.1016/j.jid.2018.12.019. pmid: 30641039 figure 1. (a) hyperchromic psoriatic plaque in the right pectoral area, developed above the expanded skin flap. (b) multiple psoriatic pustules developed above abdominal area and upper arms. (c) psoriasiform acanthosis and thinning of suprapapillary plates. mild inflammatory infiltrate (h&e, x10). (d) subcorneal pustules, parakeratosis and hypogranulosis. mild inflammatory perivascular and interstitial infiltrate composed predominantly of lymphocytes (h&e, x20). dermatology: practical and conceptual 306 letter | dermatol pract concept 2019;9(4):14 dermatology practical & conceptual introduction unilateral nevoid telangiectasia (unt) is a benign cutaneous vascular disorder, first described by blaschko in 1899, characterized by clustered telangiectasias with a reticular appearance, blanching with diascopy, and often following a dermatomal pattern especially in c3 and c4 dermatomes, although there are reported cases without this distribution. the pathogenesis is linked mostly to estrogenic action to release nitric oxide causing capillary relaxation; this theory is supported by the predominance in female teenagers and patients with chronic liver disease presenting with this condition; however, the estrogenic role remains unclear because of the lack of receptors in skin and normal estrogen and progesterone levels in some patients with unt [1]. case presentation a 13-year-old female patient presented with a 16-month history of erythematous reticulated macules (figure 1), sized from 5 mm to 30 mm, affecting the right mammary region and posterior right arm, which was asymptomatic and appeared a few months after her menarche. dermoscopy showed red tortuous capillaries with a reticulated appearance (figure 2). the lesion blanched completely with diascopy. skin biopsy revealed a normal epidermis and dermoscopy as an important tool for differentiating unilateral nevoid telangiectasia and angioma serpiginosum uriel villela-segura1 1 dermatology department, hospital regional licenciado adolfo lópez mateos issste, mexico city, mexico key words: unilateral nevoid telangiectasia, angioma serpiginosum, vascular skin tumors citation: villela-segura u. dermoscopy as an important tool for differentiating unilateral nevoid telangiectasia and angioma serpiginosum. dermatol pract concept. 2019;9(4):306-307. doi: https://doi.org/10.5826/dpc.0904a14 accepted: may 23, 2019; published: october 31, 2019 copyright: ©2019 villela-segura. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: uriel villela-segura, md, hospital regional licenciado adolfo lópez mateos issste, av. universidad 1321, florida, bo 01030, delegación álvaro obregón, mexico city, mexico. email: uvise08@gmail.com figure 1. red-violaceous reticulated macules. [copyright: ©2019 villela-segura.] letter | dermatol pract concept 2019;9(4):14 307 dilated capillaries composed of 1 endothelial layer in the papillary dermis (figure 3). unt was diagnosed and the patient received treatment with nd:yag laser, showing a good response. the main clinical differential diagnosis is the angioma serpiginosum (as), which is more common than unt, appearing mostly in young female patients, and whose origin has been linked to estrogens as well as a mutation in the porcn gene. unlike unt, this entity does not blanch with diascopy and in dermoscopy the presence of multiple red oval lagoons are characteristic. histological findings are the same as in unt [2]. both conditions show excellent response with nd:yag laser. as can be treated with a good outcome also with argon laser, 532 nm potassium titanyl phosphate laser, and intense pulsed light [1]. conclusions dermoscopy is a useful tool to achieve the diagnosis of unt, since red tortuous capillaries in a reticulated pattern are distinctive in this entity. these findings help us to differentiate this condition from the as and to better select the most adequate aesthetic treatment. figure 3. dilated capillaries in dermis (h&e, ×20). [copyright: ©2019 villela-segura.] figure 2. (a) nonmelanocytic lesion with red tortuous capillaries on dermoscopy. (b) reticular appearance. [copyright: ©2019 villela-segura.] a b references 1. wenson sf, jan f, sepehr a. unilateral nevoid telangiectasia syndrome: a case report and review of the literature. dermatol online j. 2011;17(5):2. 2. ghanadan a, kamyab-hesari k, moslehi h, abasi a. dermoscopy of angioma serpiginosum: a case report. int j dermatol. 2014;53(12):1505-1507. dermatology: practical and conceptual 158 observation | dermatol pract concept 2018;8(2):16 dermatology practical & conceptual www.derm101.com introduction vulvar melanoma (vm) is the second most common vulvar malignancy, but represents less than 1% of all melanomas and 1.0% to 2.3% of all melanomas in women [1]. it typically affects postmenopausal women with a peak incidence in the seventh decade of life [1,2]. vm is associated with a poor prognosis. the reported five-year survival rates are less than 60% [3]. it is unclear if the poor prognosis of vm is due to delayed detection or a highly aggressive biological behavior, but early identification and intervention may improve patient outcomes. dermoscopy improved the early diagnosis of melanoma, but little is known about the dermoscopy features of melanoma of the vulva [4]. given the low incidence of vm, most of the information is derived from small retrospective case series and single case reports [1,5]. raised vulvar lesions: be aware! fernanda s. resende1, claudio conforti1, roberta giuffrida2, mayara hamilko de barros3, iris zalaudek1 1 dermatology clinic, university of trieste, hospital maggiore, trieste, italy 2 department of clinical and experimental medicine, section of dermatology, university of messina, messina, italy 3 professor rubem david azulay institute, charity hospital of rio de janeiro, rio de janeiro, brazil key words: vulvar melanoma, vulvar lesions, dermoscopy citation: resende fs, conforti c, giuffrida r, hamilko de barros m, zalaudek i. raised vulvar lesions: be aware! dermatol pract concept. 2018;8(2):158-161. doi: https://doi.org/10.5826/dpc.0802a16 received: october 29, 2017; accepted: november 7, 2017; published: april 30, 2018 copyright: ©2018 resende et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, università campus biomedico (ucbm), via alvaro del portillo 200. 00128 rome, italy. email: claudioconforti@yahoo.com vulvar melanoma is a rare and deadly cancer in women, and the prognosis is often poor. there are limited studies on the dermoscopic features of vulvar melanoma. described criteria include the presence of blue, gray, or white colors. herein we present the clinical and dermoscopic characteristics of a hypopigmented and heavily pigmented nodule in a 92-year-old and an 80-year-old woman. dermoscopy in the former revealed structureless milky-red to white areas, remnants of brown pigmentation at the base and polymorphic vessels, while the latter displayed structureless blue-gray areas with black dots and peripheral lines at the base. in both cases, histopathology revealed a stage iii melanoma. our two cases along with a review of the literature suggest that the dermoscopic features described for diagnosing cutaneous nodular melanoma, apply also for vulvar melanoma. clinicians should always raise the suspicion if observing plaques or nodules with a dermoscopic polymorphic vascular pattern and blue-black color on the genitals of postmenopausal women. abstract observation | dermatol pract concept 2018;8(2):16 159 discussion our findings are consistent with the current literature suggesting that vm typically affects woman after the seventh decade of life, is often detected at late stage and has a poor prognosis and outcome (table 1). among the clinical features of vm, the data consistently report a nodular polypoid shape and lack of pigmentation in up to 27% of cases [6]. this underlines the need for careful evaluation of both pigmented and non-pigmented vulvar lesions, especially if raised. dermoscopy is proven to increase early melanoma detection compared to the naked eye, but its impact on early diagnosis of vm remains to be defined. a review of the literature revealed a dermoscopic description of 22 cases of vm [4,6,7-15]. in the majority of cases, patterns of advanced melanoma such as a multicomponent pattern composed by a blue-white veil, atypical network, irregular streaks, dots and atypical vessels were described (table 2) [6,7-10]. in a study by the international dermoscopy society, the dermoscopic patterns of a large series of mucosal lesions were analyzed. in that study, the presence of blue, gray, or white colors with or without structureless areas yielded a 100% diagnostic sensitivity for mucosal melanoma, only two cases of vm were included [7]. among those two, was one amelanotic and revealed polymorphous vessels [8]. clinically, vm can present as a flat or raised lesion with irregular borders and multiple colors [4,6,7] (table 2). a 2004 review that included 20 cases of vm demonstrated median breslow thickness at diagnosis of 3.1 mm and the clitoris or periclitoris as the common location and reported the superficial spreading and nodular as the most common histological subtypes. herein we report the clinical and dermoscopic characteristics of two cases of vm seen in a routine dermatology service and review of the literature on dermoscopy of this rare but highly aggressive melanoma. case 1 a 92-year-old caucasian woman was referred to our skin cancer unit because of a bleeding nodule on the right periclitoral region. physical examination showed an ill-defined, reddish nodule with a flat, pigmented base measuring 2 cm in diameter (figure 1a). dermoscopy revealed milky-red and white structureless areas and polymorphic vessels. at the base of the nodule, a small brown pigmentation was seen (figure 1b, c). histopathology revealed a nodular melanoma measuring > 5 mm thickness. at time of diagnosis, the patient had lymph node metastases and died shortly thereafter from widespread metastatic disease. case 2 an 80-year-old caucasian woman was referred to our skin cancer unit with a rapidly growing nodule on the right side of the labium majus. clinically an ulcerated, blue-black nodule measuring 3 cm in diameter was seen. dermoscopy revealed structureless blue-gray areas, black and brown dots, and some streaks at the periphery. histopathology revealed a melanoma with a breslow thickness of 1.2 cm. at time of diagnosis, inguinal lymph node metastases were present, and she died few months thereafter from metastatic melanoma. figure 1. vulvar melanoma, clinical and dermoscopic presentation. (a) ill-defined, brownish red colored tumor with smooth surface, 2 cm in diameter. (b) dermoscopy shows milky-red (blue circle) and white structureless areas (black asterisk), unfocused arborizing vessels (red arrows), with a © structureless brown zone around the nodule (white arrows). [copyright: ©2018 resende et al.] 160 observation | dermatol pract concept 2018;8(2):16 conclusion in conclusion, our cases highlight the importance of an inspection of the genital areas especially in postmenopausal woman. the dermoscopic patterns of vm do not differ from melanomas at other body sites. any pigmented or non-pigmented nodule, dermoscopically exhibiting blue and black or blue-white colors or polymorphic vessels should be carefully evaluated with a very low threshold for biopsy [9]. based on this data, it appears that the majority of melanomas were at advanced stage at diagnosis. whether this was caused by delayed self-detection of patients, low frequency of genital inspections during skin examinations or the tumor biology itself, remains unclear. it is noteworthy that we observed in both of our patients a flat, pigmented area at the base of the nodular tumor, which points towards an at least initially, horizontal growth pattern. table 1. patient demographics and tumor characteristics of vulvar melanoma. numbers of reported cases are shown in brackets. references n age location size in mm clinical feature tumor thickness in mm stolz et al. 2002 1 n.a. n.a. n.a. n.a. n.a. virgili et al. 2004 2 **79 lab. min. (2) > 10 mm (1) < 10 mm (1) nodular (1) flat (1) 0.25 mm (1) de giorgi et al. 2005 1 68 lab. min. & maj. 10 mm flat 0.5 mm lin et al. 2009 2 n.a. n.a. n.a. n.a. n.a. blum et al. 2011 2 n.a. n.a. n.a. n.a. n.a. ferrari et al. 2011 5 36 43 53 63 67 lab. min. (3) clitoris (1) multifocal (1) > 10 mm (4) < 10 mm (1) nodular (4) flat (1) 0.6 mm (range 0.5 to 4 mm) * ronger-savle et al. 2011 5 n.a. n.a. < 10 mm (3) < 10 mm (4) papule (1) papule (2) nodular (5) n.a. (1) 0.3 mm (2) 0.15 mm (3) 0.2 mm (4) 0.12 mm (5) rogers et al. 2016 1 50 lab. min. & clitoris > 10 mm flat mis oakley a 2016 3 62 67 62 pubis (1) lab. maj. (2) lab. min. (3) > 10 mm nodular 7.2 mm (1) 4.95 mm (2) 7 mm (3) blum et al. 2016 1 70 lab. min. <10 mm papule n.a.. *mean tumor thickness; ** mean age, mis: melanoma in situ; n.a.: not applicable; lab. min.: labia minora; lab. maj.: labia majorum table 2. dermoscopy of vulvar melanoma reference n dermoscopy patterns stolz et al. 2002 1 polymorphous pattern, large blue-gray areas, irregular dots and globules virgili et al. 2004 2 asymmetric darkening, whitish gray area, irregular globules, linear irregular vessels de giorgi et al. 2005 1 nonhomogeneous lesion, central blue-gray area, whitish veil lin et al. 2009 2 multiple colors, homogeneous regions, irregular network, blue-white veil, irregular vessels blum et al. 2011 2 blue, gray, white color, structureless zones ferrari et al. 2011 5 irregular brown black dots, blue-white veil, atypical vessels, reticular depigmentation ronger-savle et al. 2011 5 irregular-reticular or irregular-polycircular, blue-whitish veil, white veil, regression structures, irregular globules, irregular vessels, milky-red areas rogers et al. 2016 1 asymmetric darkening, structureless areas, central blue and pink colors oakley a 2016 3 asymmetry of color and structure, blue-gray structures, polymorphous vessels blum et al. 2016 1 polymorphous vessels (linear, curved, hairpin-like with different diameter) observation | dermatol pract concept 2018;8(2):16 161 8. blum a, beck-zoul u, held l, haase s. dermoscopic appearance of an amelanotic mucosal melanoma. dermatol pract concept. 2016;6(4):23-25. 9. seifried s, haydu le, quinn mj, scolyer ra, stretch jr, thompson jf. melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases. ann surg oncol. 2015;22(6):1959-1966. 10. lin j, koga h, takata m, saida t. dermoscopy of pigmented lesions on mucocutaneous junction and mucous membrane. br j dermatol. 2009;161(6):1255-1261. 11. stolz w, braun-falco o, bilek p, landthaler m, burgdorf whc, cognetta ab. pigmented lesions on the mucosa. in: stolz w, braun-falco o, bilek p, landthaler m, burgdorf whc, cognetta ab, eds. color atlas of dermoscopy, 2nd ed. berlin: blackwell publishing. 2002:151–154. 12. virgili a, zampino mr, corazza m. primary vulvar melanoma with satellite metastasis: dermoscopic findings. dermatology. 2004;208(2):145-148. 13. de giorgi v, massi d, savino c, mannone f, carli p. pigmented seborrheic keratoses of the vulva clinically mimicking a malignant melanoma: a clinical, dermoscopic‐pathologic case study. clin exp dermatol. 2005;30(1):17-19. 14. ronger-savle s, julien v, duru g, raudrant d, dalle s, thomas l. features of pigmented vulval lesions on dermoscopy. br j dermatol. 2011;164(1):54-61. 15. oakley a. dermatoscopic features of vulval lesions in 97 women. australas j dermatol. 2016;57(1):48-53. references 1. wechter me, gruber sb, haefner hk, et al. vulvar melanoma: a report of 20 cases and review of the literature. j am acad dermatol. 2004;5(4):554-562. 2. sanchez a, rodriguez d, allard cb. primary genitourinary melanoma: epidemiology and disease-specific survival in a large population-based cohort. urol oncol. 2016;34(4):166.e7-14. 3. hou jy, baptiste c, hombalegowda rb, et  al. vulvar and vaginal melanoma: a unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with  2253  cases of nongynecologic melanoma. cancer. 2017;123(8):1333-1344. 4. ferrari a, zalaudek i, argenziano g, et al. dermoscopy of pigmented lesions of the vulva: a retrospective morphological study. dermatology. 2011;222:157–166. 5. vaysse c, pautier p, filleron t, et al. a large retrospective multicenter study of vaginal melanomas: implications for new management. melanoma res. 2013;23:138–146. 6. rogers t, pulitzer m, marino ml, marghoob aa, zivanovic o, marchetti ma. early diagnosis of genital mucosal melanoma: how good are our dermoscopic criteria? dermatol pract concept. 2016; 6(4):43-46. 7. blum a, simionescu o, argenziano g, et al. dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the international dermoscopy society (ids). arch dermatol. 2011;147(10):1181-1187. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):18 73 dermatology practical & conceptual introduction we describe an uncommon case of papillomatous erythematous plaques of the scrotum. case presentation a 28-year-old man presented with a 2-month history of painful growing scrotal lesions and relapsing fever. the patient was otherwise in good health. he was heterosexual and did not report any recent high-risk sexual behavior. physical examination revealed 2 broad-based, elevated papillomatous erythematous plaques 10 and 6 mm in diameter, respectively, located on the front of the scrotum (figure 1a). no other cutaneous or mucosal abnormalities were found. dermoscopy revealed whitish papillomatous structures on a milky-red background; vessels showed a homogeneous punctiform pattern (figure 1b). a skin biopsy and serological tests were performed. histopathology of a 4-mm punch biopsy showed a prominent dermal infiltrate, rich in plasma cells, together with endothelial proliferation and swelling (figure 2). serological tests for syphilis were requested, and the treponema pallidum enzyme immunoassay titer was positive, t pallidum hemagglutination was reactive, and the rapid plasma reagin titer was 1:64. human immunodeficiency virus (hiv), hepatitis c virus, and hepatitis b virus serology results were negative. a diagnosis of secondary syphilis was made, and scrotal lesions were diagnosed as condylomata lata. lesions and symptoms completely resolved with a single dose of 2.4 million units im of penicillin g benzathine. conclusions due to their friable consistency, condylomata lata represent an infectious form of secondary syphilis, a systemic venereal disease caused by t pallidum that can involve most organs and tissues of the human body and have several clinical stages (primary, secondary, early latent, late latent, and tertiary). after a decline in the late 20th century, a new wave of syphilis has been reported over the last 2 decades, especially among men who have sex with men and patients with hiv. primary syphilis is often overlooked because of its quick course and poor symptomatology; therefore, many patients come to clinical consultation when they show mucocutaneous involvement in the secondary stage of the disease, 6-8 weeks after inoculation of t pallidum [1,2]. papillomatous erythematous plaques of the scrotum ambra di altobrando1, carlotta gurioli1, antonietta d’antuono1, valeria gaspari1 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy key words: syphilis, condylomata lata, plaques, treponema pallidum citation: di altobrando a, gurioli c, d’antuono a. gaspari v. papillomatous erythematous plaques of the scrotum. dermatol pract concept. 2019;9(1):73-74. doi: https://doi.org/10.5826/dpc.0901a18 published: january 31, 2019 copyright: ©2019 di altobrando et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ambra di altobrando, md, dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138 bologna, italy. email: ambra.dialtobrando@gmail.com 74 letter | dermatol pract concept 2019;9(1):18 references 1. afra tp, handa s, razmi tm, vinay k. secondary syphilis: lest we forget it. postgrad med j. 2018;94(1113):415. 2. rysgaard c, alexander e, swick bl. nodular secondary syphilis with associated granulomatous inflammation: case report and literature review. j cutan pathol. 2014;41(4):370-379. tigations, including serological tests for syphilis. however, the absence of dermoscopic pathognomonic features and increasing unusual clinical manifestations justify the frequent missed and delayed diagnosis of condylomata lata and of secondary syphilis. in conclusion, a high level of suspicion is necessary to achieve early diagnosis and therapy and prevent further progression. skin lesions of secondary syphilis can take many mucocutaneous forms, including condylomata lata, but also macular, papular, follicular, lichenoid, psoriasiform, pustular, sweet syndrome-like, and annular aspects, thus justifying the label “the great imitator.” besides skin lesions, systemic symptoms such as fever, headache, malaise, and lymphadenopathy are common in secondary syphilis [2]. however, the absence of pathognomonic features and the increasing unusual manifestations often determine a delay in diagnosis and treatment. in our case, the clinical presentation could be suggestive of condylomata lata, even if the patient’s history was quite misleading. aside from the protean clinical manifestations, the histopathological features of condylomata lata are also polymorphic and aspecific, representing a diagnostic challenge for the dermatopathologist. the most frequent histological patterns show hyperkeratotic, psoriasiform, or ulcerated aspects. the dermis generally shows a perivascular and periadnexal infiltrate, rich in plasma cells [1,2]. dermoscopy may turn out to be very useful in order to exclude differential diagnoses, especially neoplastic ones. differential diagnoses include squamous cell carcinoma, basocellular carcinoma, genital warts, eruptive xanthomas, papular granuloma annulare, lymphoma, leukemia, leprosy, sarcoidosis, psoriasis, and cutaneous tuberculosis [2]. moreover, the observation of papillomatous structures and homogenous dotted vessels on dermoscopy can suggest to the clinician an infectious origin and support further invesfigure 2. a prominent dermal infiltrate rich in plasma cells together with endothelial proliferation and swelling. [copyright: ©2019 di altobrando et al.] figure 1. (a) broad-base infiltrated papillomatous, erythematous plaques measuring 10 and 6 mm in diameter, respectively, on the front of the scrotum. (b) whitish papillomatous structures on a milky-red background; dotted vessels represent the main vascular pattern. [copyright: ©2019 di altobrando et al.] a b untitled quiz | dermatol pract concept 2015;5(4):5 17 dermatology practical & conceptual www.derm101.com the patient an otherwise healthy 34-year-old brazilian male presented with an asymptomatic, slow-growing lesion on his left malar region for six months. no previous personal or familial similar findings were known. on examination, there was a well-circumscribed, raised, pink, telangiectatic, smooth nodule of hard consistency, measuring 1.2 x 1.2 cm in its base (figure 1a). an excisional biopsy with clear margins was carried out. additional select histopathologic pictures are depicted (figures 1b, 2a-g, 3). a quiz from manaus, brazil mario f. ribeiro de miranda1, antonio p. mendes schettini2, laís cruz lobato2, renato c. da silva jr2, patricia motta de morais2, maraya de jesus semblano bittencourt1 1 department of dermatology, universidade federal do para, belem, pa, brazil 2 fundação de dermatologia tropical e venereologia alfredo de matta, manaus (am), brazil citation: de miranda mfr, schettini apm, lobato lc, da silva jr rc, de morais pm, bittencourt mjs. a quiz from manaus, brazil. dermatol pract concept 2015;5(4):5. doi: 10.5826/dpc.0504a05 copyright: ©2015 miranda et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: antonio pedro mendes schettini, msc, rua benjamin lima, 16, planalto, manaus (am), 69044-040 brazil. email: apmschettini@gmail.com figure 1a. nodular lesion over a background of acne scars. [copyright: ©2015 miranda et al.] figure 1b. hyper(top) and hypocellular (bottom) areas with clefts. note atrophic epidermis, grenz zone and a dilated entrapped follicle (h&e x40). [copyright: ©2015 miranda et al.] what is your diagnosis? answer and explanation sclerotic fibroma a sharply circumscribed, mostly hypocellular, non-encapsulated, spindle cell proliferation, expanded to the deep dermis, along with hyalinized collagen and clefts, arranged in a storiform/whorled (so-called “plywood”-like) pattern is in concert 18 quiz | dermatol pract concept 2015;5(4):5 figure 2a. stromal clefts and spindle cells in storiform and whorled fashions (h&e x100). [copyright: ©2015 miranda et al.] figure 2b. hypocellular area with fusiform and stellate-shaped neoplastic cells in sclerotic collagen (h&e x400). [copyright: ©2015 miranda et al.] figure 2c. histiocytoid cells with plump nuclei, some showing multinucleation, are seen in the uppermost part of the lesion (h&e x400). [copyright: ©2015 miranda et al.] figure 2d. sharp demarcation of the lesion from the surrounding dermal tissue (h&e x40). [copyright: ©2015 miranda et al.] figure 2e. epidermal collarette (h&e x40). [copyright: ©2015 miranda et al.] quiz | dermatol pract concept 2015;5(4):5 19 basaloid follicular induction and basal hyperpigmentation. in contrast to df, sf affects mainly the face, shows an expansile growth pattern and a sharp circumscription, but no acanthosis or basaloid follicular induction [2]. besides df, an involutional sclerotic stage of other pre-existing inflammatory, hamartomatous or neoplastic lesion such as angiofibroma, neurofibroma, melanocytic nevus, lipoma, tendon sheath fibroma (which is never dermal), giant cell collagenoma, erythema elevatum diutinum, solitary myofibroma and chronic folliculitis had been also considered [6,7]. in addition, although some of the above-mentioned sf attributes may be observed in df, cd34 staining is usually absent in the latter [2,8,9]. multinucleated and stellate-shaped cells, dilated vessels and collagen bundles oriented around hair follicles are seen in fibrous papules/angiofibromas, but hyalinization and cleft formation are not expected features [10]. as fibrosis was not oriented in parallel to the epidermis in this case, a scar has easily been excluded. although the hyalinizing process seen in keloids share striking similarities with sf, these sclerosing lesions lacked the “plywood”-like pattern characteristic of sf [11]. dermatofibrosarcoma protuberans (dfsp) is a malignant mesenchymal neoplasm of low metastatic potential. in contrast to sf, it shows infiltration of the subcutis and poor circumscribed margins. moreover, hyalinized areas are usually absent, and one observes a denser cellularity. expression of cd34 is used as an ancillary help to the differential diagnosis of dfsp with other cutaneous spindle cell neoplasms [8]. giant cell fibroblastoma (gcf) is closely related to dfsp sharing the same cytogenetic abnormality involving genes colia1 on chromosome 17 and pdgfb on chromosome 22 [8]. gcf primarily affects children, presenting as a subcutaneous mass composed of a hypocellular proliferation of spindle-shaped cells and scattered giant cells with multiple with sclerotic fibroma (sf) [1-3]. immunohistochemically the neoplastic cells showed diffuse reactivity to cd34 (figure 3), but negative staining with s-100 protein, desmin, smooth muscle actin and d2-40. taking into account morphologic and immunohistochemical features observed in our case, dermatofibroma, fibrous papule/angiofibroma, scar, keloid, dermatofibrosarcoma protuberans, giant cell fibroblastoma, solitary fibrous tumor, hemangiopericytoma, kaposi’s sarcoma, sclerosing perineurioma, dermal lipoma, end-stage of an inflammatory condition, pleomorphic fibroma and sclerotic fibroma have been considered in the differential diagnosis. dermatofibroma (df) may exhibit hyaline and hypocellular areas. according to some authors, sf could represent an ancient or degenerated stage of df [4,5], but lacks other classical architectural signs of it, as preferential limb location, hyperplastic epidermis, infiltrative growth pattern, sometimes figure 2f. discrete condensation of the surround collagen and presence of a dilated follicular structure included in the neoplastic proliferation, in which vellus hair shafts are seen (gomori’s trichrome stain x100). [copyright: ©2015 miranda et al.] figure 2g. spindle and histiocytoid cell proliferation in a sclerotic stroma along with ectatic vessels (h&e x100). [copyright: ©2015 miranda et al.] figure 3. diffuse cd34 expression by neoplastic cells (immunoperoxidase x100). [copyright: ©2015 miranda et al.] 20 quiz | dermatol pract concept 2015;5(4):5 trum pf/psf/sf. the presence of follicle remnants [18] seen in the histopathologic picture (figures 1b, 2f), a finding in general not referred for sf [6], cannot rule out the role of an eventual previous inflammatory trigger for this case, such as acne or folliculitis. acknowledgments the authors wish to acknowledge consultoria em patologia staff, botucatu, sp, brazil, for their excellent technical assistance in performing immunohistochemical stains. references 1. mahmood mn, salama me, chaffins m, et al. solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for o13 (cd99) and cd34. j cutan pathol. 2003;30:631-6. 2. sánchez mh, fernández rs, heredero mc, et al. sclerotic fibroma. dermatology. 1998;196:429–30. 3. bhambri s, bhambri a, del rosso jo. solitary sclerotic fibroma. j clin aesth dermatol. 2009;2:36-8. 4. cohen pr, tschen ja, abaya-blas r, cochran rj. recurrent sclerotic fibroma of the skin. am j dermatopathol. 1999;21:51-4. 5. sohn ib, hwang sm, lee sh, et al. dermatofibroma with sclerotic areas resembling a sclerotic fibroma of the skin. j cutan pathol. 2002;29:44-7. 6. abbas o, ghosn s, rahhady r, et al. solitary sclerotic fibroma on the scalp of a young girl: reactive sclerosis pattern? (letter). j dermatol 2010;37:575–7. 7. high wa, stewart d, essary lr, et al. sclerotic fibroma-like change in various neoplastic and inflammatory skin lesions: is sclerotic fibroma a distinct entity? j cutan pathol. 2004;31:373–8. 8. tardio jc. cd34-reactive tumors of the skin. an updated review of an ever-growing list of lesions. j cutan pathol. 2009;36:89– 102. 9. alawi f, freedman pd. sporadic sclerotic fibroma of the oral soft tissues. am j dermatopathol. 2004;26:182-7. 10. chen tm, purohit sk, wang ar. pleomorphic sclerotic fibroma: a case report and literature review. am j dermatopathol. 2002;24:54-8. 11. val-bernal jf, gonzález-vela mc, de grado m, et al. sclerotic fibroma (storiform collagenoma)-like stroma in a fibroadenoma of axillary accessory breast tissue. j cutan pathol. 2012;39:798–802. 12. weyers w, menzel t, kasper rc, et al. fibrous, fibrohistiocytic and histiocytic tumours. in: leboit p, burg g, weedon d et al. who pathology & genetics skin tumours. lyon; iarc press. 2006:254-62. 13. hansen t, katenkamp k, katenkamp d. d2-40 staining in sinonasal-type hemangiopericytoma--further evidence of distinction from conventional hemangiopericytoma and solitary fibrous tumor. virchows arch. 2006;448:459-62. 14. kahn hj, bailey d, marks a. monoclonal antibody d2-40, a new marker of lymphatic endothelium, reacts with kaposi’s sarcoma and a subset of angiosarcomas. mod pathol. 2002;15:434-40. 15. kaku y, fukumoto t, louise opada g, et al. a clinicopathological and immunohistochemical study of 7 cases of sclerosing perineurioma. am j dermatopathol. 2015;37:122-8. nuclei conglomerated toward the center or arranged peripherally. the stroma may vary from myxoid to collagenous to sclerotic. angioectoid lymphangioma-like spaces and immunoreactivity with cd34 are also seen [12]. solitary fibrous tumor (sft) of the skin is a very uncommon lesion consisting of alternating hypercellular and hypocellular areas of bland spindle cells, arranged in a combination of fascicular, storiform and hemangiopericytoma-like vascular patterns in thick hyalinized collagen. like sf, sft is diffusely cd34 positive. subsets of hemangiopericytoma (hp) and sft are closely related neoplasms (hp/sft family). hp may present with either positive or negative d2-40 immunostaining [13]. areas of diffuse proliferation of spindle cells intermingled with vessels, as observed in the present case (figure 2g), also recommended the exclusion of kaposi’s sarcoma (ks), in which a typical morphology and d2-40 positivity would be expected to occur [14]. ks is also often positive to anti-hhv8. sclerosing perineurioma (sp), like sf, show hypocellular areas, however, usually occurs on hands and feet, and does not react with cd34 [15]. dermal lipoma with prominent sclerosis may simulate a sf, but mature adipocytes are always demonstrated in the former lesion [16]. focal changes simulating sf may also be seen in inflammatory conditions such as erythema elevatum diutinum and folliculitis [17]. many histological and immunohistochemical features present in a pleomorphic fibroma (pf), as dermal circumscription, epidermal atrophy, expansile growth pattern, and prominent clefted “plywood” appearance, were focally seen in one series [1]. the term “pleomorphic sf” (psf) was further coined for lesions presenting histological features of pf in the superficial portion of the dermal nodule, sf features in the deeper portion, and positive or negative cd34 immunolabeling. based on these findings, it has been proposed that pf, psf and sf are components of one spectrum [1,10]. sf—also known as storiform collagenoma, hypocellular fibroma and “plywood” fibroma—is an uncommon benign neoplasm with fibroblastic/dermal dendrocytic differentiation first described in association with cowden’s disease, an autosomal-dominant familial cancer syndrome (multiple hamartoma and neoplasia syndrome) involving the pten tumor suppressor gene on chromosome 10q; in such cases, sf often occurs as multiple papules or nodules either on the oral mucosa or the skin [4,10,16,17]. clinically sf is an asymptomatic, dome-shaped and well-circumscribed lesion of hard consistency [17]. further sf cases, mostly solitary and on the skin, were observed in patients not affected by cowden’s disease [9]. in conclusion, we believe our patient has fulfilled chief histopathological criteria, including cd34 reactivity (figure 3) [1,8], for a diagnosis of sf to be made. we also speculate our case could be inserted into the mid-portion of the specquiz | dermatol pract concept 2015;5(4):5 21 18. sung-nam c, soo ii c, tae kee m, et al. sclerotic fibroma of the skin: degenerated sclerotic change of inflammatory conditions especially folliculitis. am j dermatopathol. 2000;22:22-5. 16. calonje e, lazer a, brenn t. storiform collagenoma. in: mckee’s pathology of the skin. 4th ed. china; saunders, 2012:1614-5. 17. franco gn, garibay jar, gonzález mg. fibroma esclerótico. comunicación de 16 casos. estudio clínico-patológico y revisón del tema. dermatol ver mex. 2013;57:104-10. dermatology: practical and conceptual research | dermatol pract concept 2017;7(4):13 63 dermatology practical & conceptual www.derm101.com introduction: family physicians (fps) play a critical role in the early detection of skin cancers. dermoscopy can improve diagnostic accuracy but its use by fps in the united states (us) remains understudied. objectives: to examine dermoscopy use, factors associated with ever having used (model 1) and currently using the dermascope (model 2), and barriers. methods: we recruited 705 practicing fps in-person at conferences and on-line to complete an anonymous, 46 item survey measuring: demographic factors, physician and practice characteristics; confidence in differentiating skin lesions; knowledge and use of dermoscopy; intentions to use; and barriers to use. we conducted bivariate analysis for each outcome and entered the significant predictors into two logistic regressions. results: almost 20% had ever used a dermascope and 8.3% were currently using it. ever having used a dermascope was associated with being 39 years of age or younger, practicing in academia or community centers, and having higher confidence differentiating skin lesions. current use was associated with seeing more than 400 patients per month and being 60 years-of-age or older. conclusion: use of dermoscopy by fps is low. this study is an initial step in understanding its use among us fps. abstract introduction as the initial point of contact with the health care system, family physicians (fps) play a critical role in the early detection of preventable diseases such as skin cancers. fps routinely screen for skin cancer through visual inspections, which may not be the most optimum strategy [1]. use of dermoscopy, a relatively inexpensive technology, improves diagnostic accuracy and reduces unnecessary biopsies and referrals to dermatologists [2]. although studies suggest the dermascope maybe a valuable tool [2,3], little is known about its use among fps. we examine fp’s use of dermoscopy in the united states (us), factors associated with use, and barriers. examining the factors associated with past and present dermoscopy use among family physicians jeffrey b. morris1, sarah v. alfonso1, nilda hernandez1, m. isabel fernández1 1 college of osteopathic medicine, nova southeastern university, ft. lauderdale, fl, usa key words: dermoscopy, dermatoscopy, epiluminescence microscopy, family physicians, primary care citation: morris jb, alfonso sv, hernandez n, fernández mi. examining the factors associated with past and present dermoscopy use among family physicians. dermatol pract concept 2017;7(4):63-70. doi: https://doi.org/10.5826/dpc.0704a13 received: may 5, 2017; accepted: july 15, 2017; published: october 31, 2017 copyright: ©2017 morris et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: funding for the nsu research fellowship program was obtained by internal university funds. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: m. isabel fernández, phd, professor and director nsu com research fellowship program, 2000 s. dixie highway suite 108, miami, fl 33133, usa. tel. 305-860-8710; fax. 305-860-8742. email: mariafer@nova.edu mailto:mariafer@nova.edu 64 research | dermatol pract concept 2017;7(4):13 table 1. sample characteristics characteristics % of total sample % that have ever used a dermascope % currently using of those who have ever used age (n*=695) ≤39 (n=177) 25.5 36.7 (n=65) 35.4 (n=23) 40–49 (n=171) 24.6 21.1 (n=36) 36.1 (n=13) 50–59 (n=181) 26.0 11.6 (n=21) 57.1 (n=12) ≥60 (n=166) 23.9 6.6 (n=11) 81.8 (n=9) ethnicity (n*=702) white (n=548) 78.1 19.0 (n=104) 42.3 (n=44) black (n=63) 9.0 22.2 (n=14) 42.9 (n=6) hispanic/latino (n=33) 4.7 12.1 (n=4) 25.0 (n=1) asian/pacific islander (n=45) 6.4 22.2 (n=10) 50.0 (n=5) other (n=13) 1.9 23.1 (n=3) 66.7 (n=2) gender (n=705) male (n=412) 58.4 17.5 (n=72) 48.6 (n=35) female (n=293) 41.6 21.8 (n=64) 35.9 (n=23) degree (n=705) d.o. (n=532) 75.5 19.4 (n=103) 43.7 (n=45) m.d. (n=173) 24.5 19.1 (n=33) 39.4 (n=13) location (n*=702) urban (n=201) 28.6 20.9 (n=42) 52.4 (n=22) suburban (n=306) 43.6 17.0 (n=52) 38.5 (n=20) rural (n=186) 26.5 26.3 (n=49) 30.6 (n=15) other (n=9) 1.3 33.3 (n=3) 33.3 (n=1) type of medical practice (n=705) solo (n=190) 27.0 10.0 (n=19) 63.2 (n=12) group (n=272) 38.6 19.9 (n=54) 42.6 (n=23) hospital-based (n=72) 10.2 16.7 (n=12) 33.3 (n=4) academic medicine (n=68) 9.2 33.8 (n=23) 43.5 (n=10) community health center (n=72) 10.2 30.6 (n=22) 31.8 (n=7) other (n=31) 4.4 19.4 (n=6) 33.3 (n=2) time in direct patient care (n=705) ≤25% (n=28) 4.0 17.9 (n=5) 20.0 (n=1) 26%–50% (n=31) 4.4 25.8 (n=8) 25.0 (n=2) 51%–75% (n=67) 9.5 29.9 (n=20) 40.0 (n=8) ≥76% (n=579) 82.1 17.8 (n=103) 45.6 (n=47) number of patients/month (n*=695) ≤100 (n=115) 16.5 18.3 (n=21) 14.3 (n=3) 101–200 (n=116) 16.7 25.0 (n=29) 37.9 (n=11) 201–300 (n=149) 21.4 22.1 (n=33) 45.5 (n=15) 301–400 (n=161) 23.2 15.5 (n=25) 36.0 (n=9) ≥401 (n=154) 22.2 16.2 (n=25) 68.0 (n=17) number of patients/month with suspicious lesions that might be cancerous (n*=689) ≤1.5 (n=84) 12.2 16.7 (n=14) 21.4 (n=3) 1.51–4.99 (n=135) 19.6 20.0 (n=27) 29.6 (n=8) 5–9.99 (n=132) 19.2 20.5 (n=27) 40.7 (n=11) 10–19.99 (n=159) 23.1 18.2 (n=29) 37.9 (n=11) ≥20 (n=179) 26.0 20.0 (n=35) 65.7 (n=23) research | dermatol pract concept 2017;7(4):13 65 years of age or younger (or=8.9, ci=4.3–18.6), practicing in academic (or=2.8, ci=1.3–5.8) or community centers (or=2.6, ci=1.2–5.5), and having higher confidence differentiating skin lesions (or=1.7, ci=1.4–2.2). currently using the dermascope (model 2) was associated with seeing more than 400 patients per month (or=8.0, ci=1.6–40.8) and being 60 years of age or older (or=6.2, ci=1.1–34.6). both models were highly significant and correctly classified 80.8% (model 1) and 68.8% (model 2) of participants. the main barriers were: cost of the equipment (m=3.9, sd=1.2); time and training requirements (m=3.6, sd=1.2); and insufficient reimbursement (m=3.4, sd=1.4) (table 2). discussion despite the benefits of dermoscopy, only 19.5% of participants had ever used it and 8.3% were currently using it. it is not surprising that younger age was the strongest predictor in model 1, given the increasing availability of dermascopes in current training programs [4]. this could also explain the association with practicing in academia. since they serve lower socioeconomic status communities, fps practicing in community centers may be drawn to dermoscopy to reduce costs and improve outcomes. the relationship between greater confidence differentiating lesions and ever having used a dermascope is perplexing. are fps with higher diagnostic confidence more likely to have used the dermascope per se, or has experience using the dermascope increased their confidence? methods we recruited 705 practicing fps in-person at conferences and online to complete an anonymous, 46-item survey measuring demographic factors; physician and practice characteristics; confidence in differentiating skin lesions; knowledge and use of dermoscopy; intentions to use in the next 12 months; and barriers to use (see survey). we ran descriptive analyses and determined the bivariate associations between key factors and ever having used the dermascope (model 1) and currently using the dermascope among those who had ever used it (model 2). for each dependent variable, we ran a logistic regression on the significant factors (p<0.05). results sample characteristics are described in table 1. ever having used a dermascope (model 1) was associated with being 39 table 2. main barriers to incorporating dermoscopy into clinical practice mean standard deviation cost of the equipment 3.9 1.2 time and training requirements to become proficient in its use 3.6 1.2 insufficient reimbursement 3.4 1.4 characteristics % of total sample % that have ever used a dermascope % currently using of those who have ever used confidence differentiating benign and malignant skin lesions (n*=702) not confident at all (n=15) 2.1 6.7 (n=1) (n=0) a little confident (n=132) 18.8 16.7 (n=22) 18.2 (n=4) neither confident nor unconfident (n=154) 21.9 13.6 (n=21) 33.3 (n=7) confident (n=335) 47.7 20.6 (n=69) 47.8 (n=33) very confident (n=66) 9.4 34.8 (n=23) 60.9 (n=14) heard of a dermascope (n*=702) yes (n=432) 61.5 31.5 (n=136) 42.6 (n=58) read about a dermascope (n*=690) yes (n=210) 30.4 41.0 (n=86) 52.3 (n=45) used a dermascope (n*=698) yes (n=136) 19.5 – – currently use a dermascope (n*=698) yes (n=58) 8.3 – – intentions to incorporate dermoscopy into clinical practice in 12 months (n*=618) yes (n=393) 63.6 22.6 (n=89) – *n varies due to missing data 66 research | dermatol pract concept 2017;7(4):13 tool that may help fps promote the health and well being of their patients. acknowledgments: we thank the dean of nsu com and the nsu research fellowship program for the opportunity to conduct this research. we also thank the professional organizations and conference officials who helped us with data collection. most importantly, we thank all survey participants. references 1. herschorn a. dermoscopy for melanoma detection in family practice. can fam physician. 2012;58(7):740–745. 2. menzies sw, emery j, staples m, et al. impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. br j dermatol. 2009;161(6):1270–1277. 3. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877–1882. 4. terushkin v, oliveria sa, marghoob aa, halpern ac. use and beliefs about total body photography and dermatoscopy among us dermatology training programs: an update. j am acad dermatol. 2010;62(5):794–803. in model 2, seeing an average of more than 400 patients per month was the strongest predictor of current dermascope use. it could be that fps who see more patients recognize the need to find tools that increase diagnostic accuracy such as the dermascope. interestingly, older age, rather than younger age, predicted current use. since two of the top three barriers to using the dermascope involved financial issues, it could be that older fps with well-established practices that generate higher revenues have overcome these financial barriers. although we recruited participants from 47 states, our sample may not be representative of the us population of fps. another limitation was the use of self-report; however, since we were not dealing with sensitive topics, the tendency to provide socially desirable responses was reduced. last, because many participants completed the survey without direct oversight, there were skip pattern errors and missed responses. conclusion our study represents an initial step in understanding dermoscopy use among us fps. dermoscopy is an underutilized research | dermatol pract concept 2017;7(4):13 67 — survey — 68 research | dermatol pract concept 2017;7(4):13 research | dermatol pract concept 2017;7(4):13 69 70 research | dermatol pract concept 2017;7(4):13 untitled observation | dermatol pract concept 2015;5(3):4 17 dermatology practical & conceptual www.derm101.com introduction blue nevus is considered a benign lesion that only in rare cases may progress into melanoma. the term “malignant blue nevus” includes both a melanoma that arose within a common or a cellular blue nevus or a de novo melanoma simulating a blue nevus [1]. a peculiar type of blue nevus is the so-called large plaque type blue nevus with subcutaneous cellular nodules (lptbnsn), a clinical variant characterized by large dimensions, plaque-like features, localization on the trunk, presence since birth or early childhood, and onset of discrete subcutaneous nodules many years later [2]. the long history of a melanoma associated with a congenital large plaque type blue nevus with subcutaneous cellular nodules francesco savoia1, giuseppe gaddoni1, giuseppe re2, emilia crisanti3 1 ausl della romagna, ravenna, unit of dermatology, lugo and faenza, italy 2 ausl della romagna, ravenna, unit of internal medicine, lugo, italy 3 ausl della romagna, ravenna, unit of pathology, ravenna, italy keywords: blue nevus, melanoma, congenital, large plaque type blue nevus with subcutaneous cellular nodules citation: savoia f, gaddoni g, re g, cristanti e. the long history of a melanoma associated with a congenital large plaque type blue nevus with subcutaneous cellular nodules. dermatol pract concept 2015;5(3):4. doi: 10.5826/dpc.0503a04 received: march 9, 2015; accepted: june 8, 2015; published: july 31, 2015 copyright: ©2015 savoia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. francesco savoia, viale dante 10, 48022, lugo (ra), italy. tel. +39 0545 214371; fax. +39 0545 214372. email: francesco.savoia@auslromagna.it the term large plaque type blue nevus with subcutaneous cellular nodules (lptbn-sn) refers to a huge blue nevus, usually located on the trunk, that develops subcutaneous nodules many years after the lesion has appeared. the potential malignancy of an lptbn-sn was only discovered in 2012. we report the case of a 56-year-old caucasian man that developed a cutaneous melanoma on an lptbn-sn of the trunk. the first diagnosis was made more than 10 years before his death due to melanoma metastasis. the case reported here highlights the malignant potential of an lptbn-sn, the very long course even without treatment and the possible coexistence of benign, borderline or malignant subcutaneous nodules in the same lptbn-sn. patients with large congenital blue nevi should be advised on the potential oncologic transformation of these lesions, the importance of follow-ups should be emphasized and, whenever possible, a preventive complete surgical removal should be evaluated before subcutaneous nodules develop. abstract 18 observation | dermatol pract concept 2015;5(3):4 table 1. clinical and histological features of the different variants of blue nevi. variant clinical features histological features possible evolution common blue nevus a patch of blue-grey or blueblack pigmentation usually slightly raised and with a smooth surface; the diameters are usually less than 1 cm. bipolar and dendritic melanocytes are located in the dermis. the melanocytes tend to concentrate in the lower dermis, often around appendages or in the perivascular and perineural areas. deeper tissues may be involved. reported, although very rare. cellular blue nevus a patch of blue-grey or bluebrown pigmentation, raised, palpable and with a smooth surface; diameters are usually between 1 and 3 cm. bipolar and dendritic melanocytes are located in the dermis, but in addition there are islands of larger cells arranged in a neuroid or sarcomatoid fashion. reported, although rare. combined blue and acquired nevus a patch of both blue and brown pigmentation, with atypical appearance. bipolar and dendritic melanocytes are located in the dermis, with additional dendritic cells in the overlying epidermis. not reported; lesions are benign but are usually excised because of the atypical clinical and dermoscopic features. sclerosing (desmoplastic) blue nevus firm, solitary, variably pigmented (usually grey-blue) papule or nodule. histological features are that of a typical blue nevus but in association with an exaggerated dermal fibrosis. not reported; differential diagnosis with melanoma may be difficult. epithelioid blue nevus / pigmented epithelioid melanocytoma the clinical features are the same of a common blue nevus. it can be associated with carney complex. epithelioid blue nevus and pigmented epithelioid melanocytoma are considered the same entity. variably pigmented epithelioid melanocytes with only a few melanophages and a few dendritic melanocytes. not reported. hypomelanotic / amelanotic blue nevus firm, solitary, papule or nodule, usually flesh-coloured. histological features are that of a blue nevus, with dermal proliferation of spindle cells associated with variably desmoplastic stroma. not reported; differential diagnosis includes melanoma. large plaque type blue nevus a huge blue nevus, usually located on the trunk, that develops subcutaneous nodules many years after the lesion has appeared. the nodules are characterized by areas resembling common blue nevi and areas resembling cellular blue nevi, with infiltration of subcutaneous and soft tissues, including the fascia and the mammary tissue. reported, although rare. deep penetrating blue nevus deep blue or black papules or nodules, usually with irregular lateral margins; lesions are usually larger than common blue nevi. characteristic is the extension of nevus cells deep into the dermis, in a wedge shape, the base towards the epidermis. there are clusters of deep nevus cells throughout the dermis, frequently around the skin appendages. cytology is characterized by a spindle cell population and mitotic figures are rare. not reported. observation | dermatol pract concept 2015;5(3):4 19 the patient, no treatment was performed. unexpectedly, no metastases had developed and only a slow increase of the nodules was observed in the following years. case presentation a 56-year-old caucasian man was hospitalized in our hospital in may 2012 because of a hemorrhagic cystitis with fever. the patient was affected by severe cognitive impairment, mild blood hypertension, prostatic hypertrophy and had a permanent catheter. during the hospitalization, a dermatologic visit was required because of a large blue lesion on the trunk. on clinical examination, a large mammillated blue plaque involving more than half of the chest wall was observed (figure 1). the anamnesis revealed that the patient was born with a large congenital blue nevus that had developed subcutaneous nodules in the last 15 years, slowly increasing in number and size. we formulated the diagnosis of lptbn-sn. the relatives of the patient reported on a previous large and deep biopsy, performed almost nine and a half years before in another hospital, which showed the presence of a melanoma on a congenital blue nevus. at that time, due to the dimensions of the lesion and the psychiatric illness of variant clinical features histological features possible evolution common blue nevus with satellite lesions a blue-black papule or nodule with a irregular borders, accompanied by guttate blueblack satellite lesions. histologic features are that of a common blue nevus. not reported. this entity needs to be differentiated from malignant melanoma. agminated blue nevus multiple blue nevi grouped in a circumscribed area. histologic features are that of a common blue nevus. not reported. atypical (cellular) blue nevus a patch of blue-greay or bluebrown pigmentation, usually large (> 5 cm) and sometimes ulcerated. large, asymmetrical and ulcerated lesions, usually with infiltrative margins; cytologic atypia is usually present (nuclear pleomorphism); there are up to 2/mmq mitotic figures but no atypical mitoses; necrosis is absent. atypical histologic features raise the problem of the histologic differential diagnosis with malignant blue nevus/melanoma. there is no consensus among dermatopathologists for the diagnosis of an atypical blue nevus. some authors consider it a variant with histologic intermediate features intermediate between a cellular blue nevus and a malignant blue nevus, with uncertain behaviour. some authors do not accept the existence of this entity. [7] malignant blue nevus / metastasizing blue nevus a blue-black nodule or plaque, that may arise within a cellular blue nevus (most often on the scalp), a nevus of ota, a combined congenital blue nevus or de novo. malignant cells of melanocytic origin are observed in the deeper dermis, while epidermal melanocytes are normal. a sheet-like growth pattern is seen. necrosis, infiltrative borders, nuclear pleomorphism, hyperchromasia and atypical mitotic figures allow a correct diagnosis. there is debate whether the differences with melanoma are only semantic; some authors do not accept the existence of this entity, others consider it a malignant variant of a blue nevus. [7] figure 1. a large mammillated blue plaque involving more than half of the chest wall. note the surgical scar of the first wide and deep biopsy. [copyright: ©2015 savoia et al.] 20 observation | dermatol pract concept 2015;5(3):4 case reported by yeh and colleagues in 2012, an interval of 22 years between the diagnosis of melanoma and death due to metastases occurred [5]. this is in contrast with the usually very quick course occurring when a nodular melanoma arises within a congenital nevus. a possible explanation of this strange behavior is the slow accumulation of chromosomal mutations during the years, with a tumoral progression finally leading to an overt aggressive melanoma. however, the absolute and relative risk for developing a melanoma in an lptbn-sn is still unknown. there are three peculiar clinical entities that may have a biologic behavior similar to lptbn-sn: a variant of a nevus of ota showing a progressive evolution to melanoma with intermediate stages resembling a cellular blue nevus; a giant congenital cellular blue nevus of the scalp; and pigmented neurocristic hamartoma [10-13]. the nodules that develop in the context of such lesions can be regarded as true low-grade melanocytic malignancies that can progress to a higher grade of malignancy over many years. initially, the lesions can have the trend to grow and infiltrate the surrounding tissues and, if untreated, metastasis and death can occur. cutaneous neurocristic hamartoma is the less known entity among the three. it belongs to the group of dermal melanocytic lesions and is characterized by hamartomatous lesions clinically and histologically similar to blue nevi, but with a neural crest-derived schwann cell component [14]. the case reported here highlights the malignant potential of an lptbn-sn, the very long course even without treatment and the possible coexistence of benign, borderline or malignant subcutaneous nodules in the same lptbn-sn. patients with large congenital blue nevi should be advised on the potential oncologic transformation of these lesions, the importance of follow-ups should be emphasized and, whenever possible, a preventive complete surgical removal should be evaluated before subcutaneous nodules develop. we decided to repeat a skin biopsy of a subcutaneous nodule, and the histopathology was consistent with a benign cellular blue nevus, while the revision of the previous biopsy confirmed the diagnosis of melanoma on a congenital blue nevus. a strict follow-up of the patient every four months was undertaken, and after one year we observed the rapid increase of two of the subcutaneous nodules with ulceration (figure 2). a new biopsy was performed, and in this case a histopathologic diagnosis of melanoma was made, confirming the final diagnosis of melanoma arising on an lptbn-sn (figure 3). a total body computer tomography showed lymph node enlargement at the right axilla. mutation of the braf gene was negative. the patient was sent to the palliative care center of our hospital and died three months later. conclusions the term large plaque type blue nevus with subcutaneous cellular nodules was coined in 1999 and refers to a huge blue nevus, usually located on the trunk, that develops subcutaneous nodules many years after the lesion has appeared [8, 9]. histopathologically, the nodules are characterized by areas resembling common blue nevi and areas resembling cellular blue nevi, with infiltration of subcutaneous and soft tissues, including the fascia and mammary tissues. the potential malignancy of an lptbn-sn was discovered only in 2012 [3-6]. melanoma arising on an lptbn-sn has a slow local growth and develops local recurrences after surgery or distant metastasis only after many years. in the figure 2. rapid increase of two of the subcutaneous nodules with ulceration. [copyright: ©2015 savoia et al.] figure 3. extremely atypical tumoral cells in the subcutaneous tissue. [copyright: ©2015 savoia et al.] observation | dermatol pract concept 2015;5(3):4 21 8. zattra e, salmaso r, montesco mc, et al. large plaque type blue nevus with subcutaneous cellular nodules. eur j dermatol 2009;19:287-8. 9. skowron f, balme b. large plaque type blue nevus with subcutaneous cellular nodules. clin exp dermatol 2009;34:e782-4. 10. gerami p, pouryazdanparast p, vemula s, bastian bc. molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus. am j dermatopathol 2010; 32:301-5. 11. micali g, innocenzi d, nasca mr. cellular blue nevus of the scalp infiltrating the underlying bone: case report and review. pediatr dermatol 1997;14:199-203. 12. golden n, maliawan s, mulyadi k. cellular blue nevus of the scalp with brain invasion. j clin neurosci 2000;7:453-4. 13. pathy al, helm tn, elston d, bergfeld wf, tuthill rj. malignant melanoma arising in a blue nevus with features of pilar neurocristic hamartoma. j cutan pathol 1993;20:459-64. 14. garcía-rabasco a, marín-bertolín s, esteve-martinez a, alegre-de-miquel v. dermal melanocytosis of the scalp associated to intracranial melanoma: malignant blue nevus, neurocutaneous melanosis, or neurocristic cutaneous hamartoma? am j dermatopahol 2012;34:177-81. references 1. granter sr, mckee ph, calonje e, mihm mc jr, busam k. melanoma associated with blue nevus and melanoma mimicking cellular blue nevus. a clinicopathologic study of 10 cases on a spectrum of so-called “malignant blue nevus”. am j surg pathol 2001;25:316-23. 2. busam kj, woodfuff jm, erlandson ra, brady ms. large plaquetype blue nevus with subcutaneous cellular nodules. am j surg pathol 2000;24:92-9. 3. north jp, yeh i, mccalmont th, leboit pe. melanoma ex blue nevus: two cases resembling large plaque-type blue nevus with subcutaneous cellular nodules. j cutan pathol 2012;39:1094-9. 4. sanada s, higaki k, torii y, et al. malignant melanoma arising in a plaque-type blue nevus. pathol int 2012;62:749-53. 5. yeh i, fang y, busam kj. melanoma arising in a large plaque-type blue nevus with subcutaneous cellular nodules. am j surg pathol 2012;36:1258-63. 6. held l, metzler g, eigentler tk, et al. recurrent nodules in a periauricular plaque-type blue nevus with fatal outcome. j cutan pathol 2012;39:1088-93. 7. mones jm, ackerman ab. atypical blue nevus, malignant blue nevus, and metastasizing blue nevus: a critique in historical perspective of three concepts flawed fatally. am j dermatopathol 2004;26:407-30. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):11 47 dermatology practical & conceptual www.derm101.com introduction warty dyskeratoma (wd), also known as isolated follicular dyskeratosis, is a relatively uncommon benign epidermal proliferation first reported by szymanski in 1957 [1]. wd presents as a whitish or grayish solitary papule or as a small nodule with a keratotic plug, usually limited to the head and neck of middle-aged patients. lesions are generally solitary, but grouped verrucous papules on the scalp have been reported [2]. oral and genital mucosa involvement has been described [3]. the dermoscopic aspect of wd has been recently reported as a pale homogeneous area with brown to yellow marbled clods [4]. the pathogenesis of wd is unclear. the common histopathologic finding is the presence of focal acantholysis and dyskeratosis [5]. we present a case of a 59-year-old male patient with multiple warty dyskeratomas located on the back, in which dermoscopy was helpful in clinical diagnosis. case report a 59-year-old male patient was referred to our unit for evaluation because of a history of multiple basal cell carcinomas. on clinical examination, multiple grayish-brownish papules with central keratin plugs were observed on the back (figure 1a); similar lesions were not detected on the head and neck, and the oral mucosa was uninvolved. sun damage and lentiginosis was observed in photo-exposed areas. the patient was unaware of these lesions since they were asymptomatic. no familial history of relevant skin conditions was reported. dermoscopy revealed a similar appearance in each of the observed lesions, composed of a round homogeneous grayish area with multiple structureless brown round and irregularly shaped central clods that corresponded to keratotic plugs, separated by white areas or septum. some linear vascular vessels with no specific morphology or arrangement were noted at the periphery of the lesions (figure 1b-e). four lesions were selected for excision. histopathology revealed an endo-exophytic cup-shaped lesion with a wellcircumscribed invagination of epidermis consisting of epithelial proliferation covered by a parakeratotic plug (figure 2a) with prominent dyskeratosis and acantholysis (figure 2b). histopathology of all four lesions was consistent with warty dyskeratomas. dermoscopy of multiple warty dyskeratomas gabriel salerni1, 2, carlos alonso1, 2, maría calligaris1, mario gorosito3, ramón fernández-bussy 1 1 dermatology department, hospital provincial del centenario de rosario, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina 3 dermatopathology department, hospital provincial del centenario de rosario, universidad nacional de rosario, argentina key words: dermoscopy, inflammatory skin diseases, diagnosis dyskeratoma citation: salerni g, alonso c, calligaris m, gorosito m, fernández-bussy r. dermoscopy of multiple warty dyskeratomas. dermatol pract concept 2017;7(4):47-49. doi: https://doi.org/10.5826/dpc.0704a11 received: july 31, 2017; accepted: august 27, 2017; published: october 31, 2017 copyright: ©2017 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript corresponding author: gabriel salerni, md, phd, urquiza 3101. cp: s2002kdr, rosario, argentina. tel. +54 341 4398586; fax. +54 341 5232300. email: gabrielsalerni@hotmail.com mailto:gabrielsalerni@hotmail.com 48 observation | dermatol pract concept 2017;7(4):11 endo-exophytic epithelial proliferation of benign squamous cells (which distinguish it from other acantholytic and dyskeratotic disorders) demonstrating elongated dermal papillae with suprabasilar acantholysis and dyskeratosis. a central keratin-filled invagination may be identified. the lesion can sometimes be seen originating from a hair follicle or sebaceous gland. the dermoscopic findings detected in wd are similar to those of other acantholytic and dyskeratotic disorders, including acantholytic dyskeratotic acanthoma, vemurafenibinduced acantholytic dyskeratosis and grover’s disease; such data is easily explained by their related histopathological discussion the pathogenesis of wd is unclear. it represents a sporadic localized error in epithelial maturation and cohesiveness. even though wd was originally referred to as isolated keratosis follicularis, there is no evidence that patients with a wd carry germline mutations in atp2a2, the gene responsible for darier disease. it has been suggested a range of exogenous factors or an infectious viral agent may be involved, but these assumptions have not been confirmed [6]. the common histopathologic denominator is the presence of focal acantholysis and dyskeratosis [5]. the pathologic process is that of a well-circumscribed endophytic or figure 1. clinical examination revealed multiple grayish-brownish papules with central keratin plugs (a). in the evaluated lesions, dermoscopy showed a pattern composed of a round homogeneous grayish area with multiple structureless brown to yellow round and irregularly shaped central clods (b-e). [copyright: ©2017 salerni et al.] figure 2. endo-exophytic cup-shaped lesion displaying a well-circumscribed invagination of epidermis consisted of epithelial proliferation covered by a parakeratotic plug (figure 2a, he x40). prominent dyskeratosis and acantholysis is observed (figure 2b, he x100). [copyright: ©2017 salerni et al.] observation | dermatol pract concept 2017;7(4):11 49 2. griffiths tw, hashimoto k, sharata hh, ellis cn. multiple warty dyskeratomas of the scalp. clin exp dermatol. 1997 jul;22(4):189-91. 3. laskaris g ,sklavounou a. warty dyskeratoma of the oral mucosa. br j oral maxillofac surg. 1985 oct;23(5):371-375. 4. lencastre a, campos s, cabete j. warty dyskeratoma. j am acad dermatol. 2016 sep;75(3):e97-e98. 5. kaugars ge, lieb rj, abbey lm. focal oral warty dyskeratoma. int j dermatol. 1984;23:123-130. 6. kaddu s, dong h, mayer g, kerl h, cerroni l. warty dyskeratoma--”follicular dyskeratoma”: analysis of clinicopathologic features of a distinctive follicular adnexal neoplasm. j am acad dermatol. 2002 sep;47(3):423-428. 7. specchio f, argenziano g, tiodorovic-zivkovic d, et al. dermoscopic clues to diagnose acantholytic dyskeratosis. dermatol pract concept. 2015 jan 30;5(1):59-60. 8. de abreu l, guimarães cordeiro ng, buçard am, quintella dc, argenziano g. dermoscopy of grover disease. j am acad dermatol. 2017 feb;76(2s1):s60-s63. basis. in the latter group, the papules display a central yellowish to brown star-like pattern overlying a pinkish homogeneous structureless area that is otherwise not detectable at clinical examination [7,8]. in our case, the keratin plug did not show the star-like pattern described, but a pattern composed of multiple brownish round and irregularly shaped central clods, as reported in the original description of the dermoscopy of wd [4]. histopathology remains the gold standard for diagnosis, but dermoscopy can be useful to improve clinical recognition. further studies are needed to confirm our preliminary observations. references 1. szymanski fj. warty dyskeratoma: a benign cutaneous tumor resembling darier’s disease microscopically. arch dermatol. 1957;75:567-72. dermatology: practical and conceptual 340 letter | dermatol pract concept 2018;8(4):20 dermatology practical & conceptual www.derm101.com introduction vandetanib is an oral tyrosine kinase inhibitor used in the treatment of different types of cancer. it acts by inhibiting the vascular and epidermal growth factor receptor and is associated with frequent adverse cutaneous reactions such as acneiform eruption, photosensitivity, pigmentary changes, exanthema, pruritus, and xerosis. we describe an unusual, peculiar form of perifollicular pigmentation associated with the use of the drug and show its dermoscopic findings. case presentation a 26-year-old male patient was diagnosed with metastatic medullary thyroid carcinoma. after combined treatment with surgery, radiotherapy, and chemotherapy, the disease progressed and vandetanib was started. two weeks later, the patient developed an acneiform rash with lesions on the trunk and face and was subsequently treated with doxycycline 200 mg/day for 6 months with improvement. on dermatological follow-up, the patient was still taking vandetanib, with clearance of the acneiform lesions, but many pigmented follicular macules with a comedo-like appearance were noted on the face and chest (figure 1). the pigmentadermoscopic findings of perifollicular pigmentation associated with vandetanib jade cury-martins1, jose antonio sanches1 1 department of dermatology, university of são paulo, são paulo, brazil key words: cutaneous adverse events, tyrosine kinase inhibitor, pigmentation, dermoscopy citation: cury-martins j, sanches ja. dermoscopic findings of perifollicular pigmentation associated with vandetanib. dermatol pract concept. 2018;8(4):340-341. doi: https://doi.org/10.5826/dpc.0804a20 received: march 28, 2018; accepted: may 7, 2018; published: october 31, 2018 copyright: ©2018 cury-martins et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: jade cury-martins, md, phd. email: jadecury@yahoo.com.br figure  1. pigmented follicular macules with comedo-like appearance on the face. [copyright: ©2018 cury-martins et al.] letter | dermatol pract concept 2018;8(4):20 341 the use of photoprotective measures prevented worsening of the condition, [1]. conclusion in conclusion, we report the first description of dermoscopic findings of this rare pattern of perifollicular pigmentation associated with vandetanib use. as oncodermatology is involved in the supportive care of cancer patients, it is important for dermatologists to identify these possible adverse events and use dermoscopy as an additional tool. references 1. kong hh, fine ha, stern jb, turner mlc. cutaneous pigmentation following photosensitivity induced by vandetanib. arch dermatol. 2009;145(8):923-925. 2. giacchero d, ramacciotti c, arnault jp, et al. new spectrum of skin toxic effects associated with the multikinase inhibitor vandetanib. arch dermatol. 2012;148(12):1418-1420. tion was apparently follicular; however, on dermoscopy, the blue-gray pigment was evident only in the perifollicular area with preservation of the center of the hair follicle (figure 2). after orienting the patient on photoprotective measures, only a little improvement was noted. one year later, the patient had complete clearing, despite the continuous use of vandetanib. discussion among the pigmentary changes associated with vandetanib therapy, diffuse pigmentation in the exposed area is the most reported form. the blue-gray perifollicular pigmentation was rarely reported, and there are no similar reports of it with other agents of the same class. this seems to be specifically caused by this medication. the pathogenesis of this peculiar pattern of pigmentation is not well established. previous reports have demonstrated the histopathological alterations in a few similar cases revealing dermal iron and melanin deposition. the presence of pigmented macrophages and inflammatory infiltrate in the dermis was also documented [1]. those findings correlate with the dermoscopy, with the blue-gray pigmentation corresponding to the presence of dermal pigment. the previous use of doxycycline did not seem to factor into the etiology of this condition. giacchero et al [2] showed that less than half of the patients in their series were treated with this medication. prior photosensitivity preceding the pigmentation was described in two cases [1]. definitive treatment of the lesions involves stopping the use of vandetanib followed by improvement after 3–6 months. however, recurrence occurs if the medication is reintroduced [2]. the use of topical depigmentation agents such as the combination of hydroquinone, tretinoin, and corticosteroids did not show benefits [1]. in a few cases, figure 2. on dermoscopy, the blue-gray pigment is evident only on the perifollicular area. [copyright: ©2018 cury-martins et al.] dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022103 1 dermatology practical & conceptual cutaneous spitzoid melanoma in childhood after acute lymphocytic leukemia beatriz ferreira do prado bassetti1, sergio albertini daiuto1, gilles landman2, francisco macedo paschoal3 1 medical student, centro universitário fmabc, santo andré, brazil. 2 department of pathology, escola paulista de medicina, universidade federal de são paulo, são paulo, sp, brazil 3 discipline of dermatology, centro universitário fmabc, santo andré, brazil. keywords: melanoma, acute lymphocytic leukemia, spitz nevus, skin cancer citation: bassetti bfp, daiuto sa, landman g, paschoal fm. cutaneous spitzoid melanoma in childhood after acute lymphocytic leukemia. dermatol pract concept. 2022;12(3):e2022103. doi: https://doi.org/10.5826/dpc.1203a103 accepted: november 4, 2021; published: july 2022 copyright: ©2022 ferreira do prado bassetti et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sergio albertini daiuto, discipline of dermatology at centro universitário fmabc, avenida lauro gomes, 2000 vila sacadura cabral, cep: 09060-870, santo andré são paulo, brazil e-mail: s.daiuto@gmail.com introduction acute lymphocytic leukemia (all) is the most common childhood malignancy. it has a good prognosis but one-third of all childhood all deaths are due to toxicity or secondary malignancies. we report the case of a patient with a personal history of all who had cutaneous spitzoid melanoma at the beginning of puberty. case presentation a 13-year-old female patient from são paulo, brazil, presented, in 2015, a well-defined, erythematous, ulcerated brown nodule in the left temporal region, with a 1-year evolution (figure 1a). she presents a personal history of all diagnosed in 2013, treated with chemotherapy. dermoscopy shows polymorphic vessels, exulceration, hematic crusts, and chrysalis (figure 1b). no specific finding of the melanocytic lesion was present. the initial hypotheses were keratinocytic or vascular neoplasms being performed incisional biopsy for diagnosis. a histopathological analysis showed a neoplasm with cells arranged in nests, ample and eosinophilic cytoplasm, with oval or rounded nuclei and prominent nucleoli, whose diagnosis was infiltration by primary melanoma. excisional biopsy confirmed the diagnosis of nodular, ulcerated, spitzoid, clark v melanoma with tumor thickness (breslow) of 4.7 mm (figures 2). surgical treatment with wide excision was performed, followed by adjuvant treatment with interferon alpha 2b at a dose of 6350,000 iu, subcutaneously, 3 times a week for 2 years, the only adjuvant treatment available at the time of diagnosis. the patient remained in oncological follow-up for 5 years and in remission of both neoplasms. conclusions this case report shows a remarkable clinical similarity with what was reported by goldes et al. in 1984, whose initial 2 research letter | dermatol pract concept. 2022;12(3):e2022103 figure 1. (a) well-delimited, ulcerated brown nodule on the left temporal skin. (b) dermoscopy showing polymorphic vessels, exulceration, hematic crusts and chrysalis streaks. figure 2. melanocytic neoplasm characterized by proliferation of cells that are either epithelioid or fusiform with eosinophilic cytoplasm, whose nuclei have a moderate degree of polymorphism and prominent nucleoli, forming an extensive dermal lesion (h&eeosin, 100x). diagnosis, however, was spitz nevus, but the patient died of metastatic melanoma [1]. the differential diagnosis between spitz nevus in its atypical presentation, such as aggressive spitz tumor of undetermined biological significance, and spitzoid melanoma is a major challenge [2]. both may share findings such as fusiform melanocytes, prominent nucleoli, junctional nests, diameter greater than 10 mm, and high-grade nuclear atypia. the characteristics that favor the diagnosis of melanoma are greater depth of the lesion, involvement of reticular and subcutaneous dermis, mitosis in the deep dermis, nuclear and cellular pleomorphism, asymmetry and ill-defined limits, all of them present in our report. nevertheless, in certain situations only the development of metastasis will define the diagnosis. we can assume that the approach presented in the face of the diagnosis of spitzoid melanoma (wide excision and adjuvant immunotherapy) may have influenced the outcome of the present report. the most common secondary malignant neoplasms after all are lymphoreticular (acute myelocytic leukemia and hodgkin disease), followed by endocrine, keratinocytic, and renal tumors. immunosuppression by chemotherapy and radiotherapy is related to an increased risk of developing a subsequent neoplasm but not necessarily related to their causes. in addition to being rare in childhood, the occurrence of cutaneous melanoma as a secondary neoplasm after all, is even more uncommon, and this case in our knowledge is the second case reported in the literature. however, it should be considered mainly in the presence of a pigmented nodule on the face. references 1. goldes j, holmes s, satz m, cich j, dehner l. melanoma masquerading as spitz nevus following acute lymphoblastic leukemia. pediatr dermatol. 1984;1(4):295-298. doi: 10.1111/ j.1525-1470.1984.tb01132.x. pmid: 6593699.2. harms kl, lowe l, fullen dr, harms pw. atypical spitz tumors: a diagnostic challenge. arch pathol lab med. 2015;139(10):12631270. doi: 10.5858/arpa.2015-0207-ra. pmid: 26414472. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(4):e2022182 1 indications for digital monitoring of patients with multiple nevi: recommendations from the international dermoscopy society teresa russo1, vincenzo piccolo1, elvira moscarella1, philipp tschandl2, harald kittler2, john paoli3, aimilios lallas4, ralph p. braun5, luc thomas6, h. peter soyer7, josep malvehy8, susana puig8, ashfaq marghoob9, alon scope10, andreas blum11, allan c. halpern9, horacio cabo12, scott menzies13, wilhelm stolz14, masaru tanaka15, harold rabinovitz16, rainer hofmann-wellenhof17, renato marchiori bakos18, iris zalaudek19, giovanni pellacani20, ana varela veiga21, laura rosende maceiras21, cristina de las heras-sotos21, giuseppe argenziano1 1 dermatology unit, university of campania “luigi vanvitelli”, naples, italy 2 department of dermatology, medical university of vienna, vienna, austria 3 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 4 first department of dermatology, aristotle university, thessaloniki, greece 5 department of dermatology, university hospital zürich, zürich, switzerland 6 department of dermatology, lyon-1 university, and cancer research center lyon, lyon, france 7 the university of queensland diamantina institute, the university of queensland, dermatology research centre, brisbane, australia 8 melanoma unit, dermatology department, hospital clinic barcelona, universitat de barcelona & idibaps & ciberer, barcelona, spain 9 memorial sloan kettering cancer center, hauppauge, new york, usa 10 the kittner skin cancer screening and research institute, sheba medical center and sackler school of medicine, tel aviv university, tel aviv, israel 11 public, private and teaching practice of dermatology, konstanz, germany 12 dermatology institute of medical research, university of buenos aires, buenos aires, argentina 13 discipline of dermatology, sydney medical school, the university of sydney and sydney melanoma diagnostic centre, royal prince alfred hospital, camperdown, nsw australia 14 department of dermatology, allergology, and environmental medicine clinic thalkirchen, hospital munich, munich, germany 15 department of dermatology, tokyo women’s medical university medical center east, japan 16 department of dermatology medical college of georgia, augusta, united states 17 department of dermatology and venerology, medical university of graz, graz, austria 18 department of dermatology, hospital de clınicas de porto alegre universidade federal do rio grande do sul, porto alegre, brazil 19 department of dermatology, university of trieste, trieste, italy 20 department of dermatology, university of rome la sapienza, rome, italy 21 department of dermatology, university hospital complex of ferrol, a coruña, spain key words: dermoscopy, dermatoscopy, digital monitoring, multiple nevi, total body photography citation: russo t, piccolo v, moscarella e, et al. indications for digital monitoring of patients with multiple nevi: recommendations from the international dermoscopy society. dermatol pract concept. 2022;12(4):e2022182. doi: https://doi.org/10.5826/dpc.1204a182 accepted: january 13, 2022; published: october 2022 copyright: ©2022 russo et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. 2 original article | dermatol pract concept. 2022;12(4):e2022182 competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, dermatology unit, university of campania “luigi vanvitelli”, naples, italy. e-mail: piccolo.vincenzo@gmail.com introduction: in patients with multiple nevi, sequential imaging using total body skin photography (tbsp) coupled with digital dermoscopy (dd) documentation reduces unnecessary excisions and improves the early detection of melanoma. correct patient selection is essential for optimizing the efficacy of this diagnostic approach. objectives: the purpose of the study was to identify, via expert consensus, the best indications for tbsp and dd follow-up. methods: this study was performed on behalf of the international dermoscopy society (ids). we attained consensus by using an e-delphi methodology. the panel of participants included international experts in dermoscopy. in each delphi round, experts were asked to select from a list of indications for tbsp and dd. results: expert consensus was attained after 3 rounds of delphi. participants considered a total nevus count of 60 or more nevi or the presence of a cdkn2a mutation sufficient to refer the patient for digital monitoring. patients with more than 40 nevi were only considered an indication in case of personal history of melanoma or red hair and/or a mc1r mutation or history of organ transplantation. conclusions: our recommendations support clinicians in choosing appropriate follow-up regimens for patients with multiple nevi and in applying the time-consuming procedure of sequential imaging more efficiently. further studies and real-life data are needed to confirm the usefulness of this list of indications in clinical practice. abstract introduction a combined clinical and dermoscopic examination of melanocytic lesions allows for the recognition of most melanomas at a baseline visit [1-3]. in a patient with a single doubtful lesion, although only moderately atypical, the best approach is prompt excision and histopathologic examination. conversely, in patients with multiple nevi, the approach of excising any atypical lesion appears neither reasonable nor cost-effective. in this scenario, sequential monitoring and imaging using total body skin photography (tbsp) coupled with digital dermoscopy (dd) documentation represents the best approach to minimize unnecessary excisions while maximizing early detection of melanoma (figures 1 and 2). while dd is useful to evaluate morphologic changes of the individual monitored lesions, tbsp mostly helps in the recognition of new lesions or significant changes in lesions that were not previously documented dermoscopically [2-7]. it has been calculated that about 10% of melanomas are diagnosed over time in the context of clinically and dermoscopically inconspicuous tumors in patients with multiple and/or atypical nevi [1,2]. in a recent cohort study dealing with high-risk patients in a melanoma dermatology clinic, 60.8% of melanomas were found with the assistance of tbsp (31.6%) or sequential dd imaging (29.2%) [3]. melanomas detected via sequential monitoring with tbsp and dd usually escape baseline detection because they neither display melanoma-specific criteria, nor substantially differ from the patients nevi [9]. this more frequently occurs in individuals with peculiar nevus phenotypes, such as familial melanoma patients [10]. however, tbsp and dd are time-consuming techniques, so appropriate indications are crucial for the method to be effective. recently, a study by haenssle et al on 688 patients concluded that patients with multiple nevi and additional risk factors for melanoma had the highest benefit from sequential dd imaging in terms of early melanoma detection over time [6,7]. several additional studies deal with the relevant additional risk factors to be evaluated when referring a patient for digital monitoring, but there is some heterogeneity among them [11-14]. since a consensus agreement is still lacking, we are trying to provide one. objectives the purpose of this study was, therefore, to set up a list of indications for digital follow-up performed via tbsp coupled with dd through the selection of specific melanoma risk factors that may serve to better recognize patients who will benefit from this approach. original article | dermatol pract concept. 2022;12(4):e2022182 3 figure 2. patient with more than 40 nevi and previous melanoma. lesion c showed remarkable change in the lesion after 3 months of follow-up and was therefore excised and confirmed to be a melanoma in situ, while lesion a and b did not show significant modifications. figure 1. patient with more than 60 nevi. side by side comparison of 3 lesions (a, b, c) during follow-up. note the increased regression structures over time of the first lesion (a) on the left, which was therefore excised and diagnosed as a melanoma in situ. methods this study was performed on behalf of the international dermoscopy society (ids), with consensus obtained through the e-delphi methodology [15]. participants were recruited among the executive board members of the ids who were specifically asked by email invitation for their consent to take part in the study. only those who accepted to join the project received the surveymonkey (https://www.surveymonkey. com/) link and password for taking part in the survey. the study consisted of two steps: (i) identification of major risk factors for melanoma in patients with multiple nevi according to the most relevant meta-analyses and studies; and (ii) selection of indications for tbsp and dd after a threeround questionnaire proposed to a panel of international experts in dermoscopy. during each round, participants were 4 original article | dermatol pract concept. 2022;12(4):e2022182 the oxford 2011 levels of evidence [16]. melanoma risk factors were expressed in terms of relative risk (rr) and odds ratio (or) with the exception of cdkn2a mutation [17-21], for which we considered the ratio between lifetime risk of melanoma in patients with the mutation and lifetime risk in the general population (table 1). variables increasing the melanoma risk at least 3 times were considered as major risk factors; variables increasing the risk between 2 and 3 times were considered as intermediate risk factors; and variables increasing the risk by less than 2 times were considered as minor risk factors [22]. step 2: selection of indications for tbsp and dd after a three-round questionnaire proposed to a panel of international experts in dermoscopy participants were first asked if a given risk factor, in combination with the presence of multiple nevi, is relevant enough to justify inclusion in the list of indications. the questions were uploaded in two different blinded delphi rounds on the surveymonkey platform and were proposed to the experts who were included for the 1st round survey. they were asked to judge their agreement for each sentence using the 5-point given a 4-week period to complete the survey and reminders were sent to non-responders on days 7, 14 and 21. the three rounds were conducted over a 6-month period and the final list of indications was obtained and completed within 8 months. the aforementioned criteria for the enrolment of patients for digital monitoring programs were finally drawn up with the collaboration of expert members of the ids, who contributed to the study with their answers, advice and feedback. step 1: identification of risk factors for melanoma in patients with multiple nevi the questions for the survey were obtained after a literature search of relevant meta-analyses and studies about major melanoma risk factors. the presence of multiple nevi was considered the basic requirement for patient enrolment in a digital monitoring program using tbsp coupled with dd. the number and type of nevi needed to reach the cut-off point were discussed in the second step. the lower size limit to consider the nevus eligible to be counted has been conventionally established at 2 mm. the proposed questions were associated with their background studies and their relative levels of evidence assigned based on table 1. risk factors for cutaneous melanomas and their relative risks (modified from chen et al [4]). characteristic risk factor for cutaneous melanoma summary statistics (rr, or) common nevi (total number) 16-40 1.47 41-60 2.24 61-80 3.26 81-100 4.74 101-120 6.89 atypical nevi (total number) 1 1.45 2 2.10 3 3.03 4 4.39 5 6.36 eye color blue 1.47 green 1.61 hazel 1.52 hair color red 3.64 blond 1.96 light brown 1.62 family history of melanoma positive 1.74 personal history of non-melanoma skin cancer positive 2.74 genetic factors cdkn2a mutation 10a sun exposure strong history of sunburn 2.03 ever use of tanning booth 2.06 organ transplant history positive 2.38 rr = relative risk; or = odds ratio. a for cdkn2a, the risk is based on the ratio between the lifetime risk of melanoma in patients with the mutation and the lifetime risk of melanoma in the general population. original article | dermatol pract concept. 2022;12(4):e2022182 5 for selecting patients suitable for digital monitoring were established. fifteen (65%) experts agreed on the definition of a common nevus being a macular or papular symmetrical lesion, smaller than 6 mm in diameter, uniform in color, with well-defined borders and regular overall architecture in dermoscopy. consequently, an atypical nevus was defined as a flat or slightly raised lesion usually larger than 6 mm, with ill-defined borders, irregular pigmentation, and a mixed pattern dermoscopically. given the rr of 3.26 of developing melanoma in patients with 61-80 common nevi [24], 70% (n = 16) of responders agreed to establish the threshold of at least 60 common nevi to select patients requiring digital monitoring, in the absence of additional risk factors. the experts showed their consensus to reduce the threshold to 40 common nevi (rr 2.24) if the patient had additional melanoma risk factors because of a higher cumulative risk of melanoma. however, the experts did not agree on establishing a cut-off number of atypical nevi as an indication for tbsp and dd if this was the only melanoma risk factor of the patient. for the other melanoma risk factors, we asked whether the anxiety (as suggested by 2 experts) could be an indication for tbsp and dd. only 52% (n = 12) of participants considered it a relevant risk factor in patients with multiple nevi. this criterion was therefore excluded from the final list of indications. nineteen (83%) experts agreed on considering a personal history of melanoma coupled with more than 40 nevi as an indication for tbsp and dd. they also agreed to enlist patients for digital monitoring if they had more than 40 nevi and red hair, with (65%, n = 15) or without a mc1r mutation (74%, n = 17). organ transplant recipients with at least 40 nevi were also judged suitable for digital monitoring (65%, n = 15). finally, almost all members agreed (91.3%, n = 21) on considering digital monitoring to be useful in patients with a cdkn2a mutation (familial melanoma) even in patients with less than 40 nevi. in the open final discussion of this round, with almost total agreement among the experts, it emerged that even if in absence of referring relative risk data, other rarer identified melanoma-predisposing mutations different from cdkn2a and mc1r variants (ie bap-1, cdk-4, and mit-f) should not be ignored independently from the nevus count. there was no agreement on indicating digital monitoring in patients with few atypical nevi or with less than 40 nevi. personal history of non-melanocytic skin cancer, sunbed exposure or sunburns were not considered as valid criteria to select a patient for tbsp and dd even when associated with the presence of more than 40 nevi. likert scale for surveys (1: strongly agree, 2: agree; 3: neither agree nor disagree; 4: disagree; 5: strongly disagree) [23]. each parameter was admitted to the 2nd round questionnaire of the consensus procedure if at least 65% of the experts rated it 1 or 2 according to the likert scale for surveys [23]. the questions of the 2nd round were formulated based on the 1st one and, again, participants were asked to answer using the 5-point scale. finally, in the last round, participants were asked to confirm or refute the list of indications obtained as a result of the first two rounds. results first round of the executive board members of the ids invited by email, all (n = 27) confirmed their participation and received the link to answer the round 1 questionnaire anonymously. of them, 25 completed the questionnaire. more than 90% of experts agreed (32%, n = 8) or strongly agreed (64%, n  =  16) on the necessity to establish selection criteria for patients with multiple nevi who need digital monitoring. for 92% (n = 23) of participants, the total number of nevi was considered relevant to select these patients. table 1 shows the most common risk factors for melanoma and their relative risks. the great majority agreed (88%, n = 22) that significant risk factors for melanoma were those having a rr (relative risk) > 2. moreover, 92% (n = 23) of participants agreed that patients with multiple nevi and at least one additional risk factor for melanoma could have a higher cumulative risk for melanoma than patients with only one risk factor, thus making them more eligible for long-term digital monitoring. participants were asked to propose other factors that should be considered as indication for digital monitoring. two of 25 participants proposed the anxiety of patients with multiple nevi as a criterion for digital monitoring. therefore, this criterion was added for the second round of questions. in the open answers, some participants underlined the necessity to avoid digital monitoring in the following clinical scenarios: (i) in children before puberty, even if multiple nevi were present; (ii) in patients with complex health conditions that can render the examination difficult; (iii) in the context of nodular lesions, especially if rapidly changing. second round the 2nd round questionnaire was sent to the 25 members who completed the first one, with 23 completing the round. at first, this round had the purpose to establish the number and type of nevi needed as cut-off for the definition of a patient with multiple nevi; secondly, the additional criteria 6 original article | dermatol pract concept. 2022;12(4):e2022182 to be 2.24 for a number of common nevi ranging from 41-60 nevi and 3.26 for 61-80 nevi. thus, patients with more than 40 nevi (with a rr between 2 and 3) were considered to deserve this follow-up procedure only if presenting with additional risk factors, namely: a personal history of melanoma, red hair with or without a mc1r variant associated to melanoma risk or a history of organ transplantation [25,26]. in the same meta-analysis by gandini et al, patients with two atypical nevi showed a rr of 2.10 [25,26]. therefore, we asked participants if patients with multiple nevi (more than 40) and at least 2 atypical nevi should be enrolled for digital monitoring. this criterion probably did not reach a consensus because it is very frequent that a patient with more than 60 nevi also exhibits some atypical ones. in 2015, chen et al found a stable 2to 3-fold increased risk depending on the number of previous melanomas, in both patients with familial melanoma and those with sporadic melanoma(s) [27]. for instance, in patients with a single previous melanoma, the risk for a second melanoma was 2.5 for patients with familial melanoma and 2.3 in patients with a sporadic melanoma. in 2019, lallas et al in a prospective study in a cohort of 977 patients showed 8% cumulative risk of second primary melanoma, thus highlighting the value of tbsp and dd in this group of patients [28]. according to these findings, the personal history of melanoma (both in familial melanoma and in sporadic melanoma) was judged as a very effective criterion to better select patients for digital monitoring, as also suggested by haenssle et al [6,7]. in 2010, wheless et al reported a rr of 2.74 for developing melanoma in patients with a history of nmsc, compared to controls with no prior nmsc [29]. this group of patients, even when having multiple nevi, was not considered eligible for digital monitoring. given the high prevalence of nmsc, this criterion could potentially increase the number of patients referred for this special follow-up procedure too much, without a real benefit in finding more melanomas over time. in contrast, almost all participants agreed on including the red hair phenotype in the final list of indications. in a meta-analysis on phenotypic risk factors for cutaneous melanoma, the red hair phenotype was the only phenotypic aspect found to have a rr greater than 3 (3.64) for melanoma development, while all the other clinical features showed a third round the results of the second round allowed us to propose the following five indications for digital monitoring in the third round: 1. patients with more than 60 melanocytic nevi. 2. patients with a cdkn2a mutation or other rarer high-risk melanoma genetic variants. 3. patients with more than 40 melanocytic nevi and a personal history of melanoma. 4. patients with more than 40 melanocytic nevi and red hair and/or a mc1r mutation 5. patients with more than 40 melanocytic nevi and a history of organ transplantation. this final list (table 2) was proposed by mail to the 25 members of the first delphi round, clarifying that the strategy of silent consensus would be used (i.e. no answer would be interpreted as a positive response). ultimately, 17 members (68%) confirmed their consensus to this list of criteria, while the remaining participants expressed their silent consensus. conclusions in the last decade, many studies focused on digital monitoring of patients with multiple nevi, with special emphasis on the duration and scheduling of follow-up visits, the type and number of lesions to be digitally documented, and the type of changes that should lead to a biopsy [3-5]. however, no sufficient and exhaustive data have been reported about the indications for patient enrolment to digital monitoring. being aware of the costs and duration of the tbsp and dd procedure, our aim was to more precisely identify the patient categories that can benefit from this diagnostic approach [24]. a high total number of nevi is clearly the basic condition to include a patient in a digital monitoring program. the participants considered a total nevus count of at least 60 (rr >3) sufficient to refer the patient for digital monitoring. this was based on a meta-analysis published by gandini et al in 2005 that confirmed such patients’ propensity to develop melanoma [25,26]. in detail, the higher the number of common nevi, the higher the rr for melanoma, which was estimated table 2. list of indications for digital monitoring in patient with multiple nevi. indications for digital monitoring in patients with multiple nevi. i. patients with more than 60 melanocytic nevi. ii. patients with a cdkn2a mutation or other rarer high-risk melanoma genetic variants. iii. patients with more than 40 melanocytic nevi and a personal history of melanoma. iv. patients with more than 40 melanocytic nevi and red hair and/or a mc1r mutation v. patients with more than 40 melanocytic nevi and a history of organ transplantation. original article | dermatol pract concept. 2022;12(4):e2022182 7 of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669–676. doi: 10.1111/j.1365-2133.2008.08713.x. pmid: 18616769. 2. brancaccio g, russo t, lallas a, moscarella e, agozzino m, argenziano g. melanoma: clinical and dermoscopic diagnosis. g ital dermatol venereol. 2017;152(3):213-223. doi: 10.23736/s0392-0488.17.05571-7. pmid: 28121084. 3. guitera p, menzies sw, coates e, et al. efficiency of detecting new primary melanoma among individuals treated in a high-risk clinic for skin surveillance. jama dermatol. 2021;157(5):521–530. doi: 10.1001/jamadermatol.2020.5651. pmid: 33729464. pmcid: pmc7970391. 4. moscarella e, tion i, zalaudek i, et al. both short-term and long-term dermoscopy monitoring is useful in detecting melanoma in patients with multiple atypical nevi. j eur acad dermatol venereol. 2017;31(2):247-251. doi: 10.1111/jdv.13840. pmid: 27422807. 5. chen st, geller ac, tsao h. update on the epidemiology of melanoma. curr dermatol rep. 2013;2(1):24-34. doi: 10.1007/ s13671-012-0035-5. pmid: 23580930. pmcid: pmc3619431. 6. haenssle ha, korpas b, hansen-hagge c, et al. selection of patients for long-term surveillance with digital dermoscopy by assessment of melanoma risk factors. arch dermatol. 2010;146(3):257-264. doi: 10.1001/archdermatol.2009.370. pmid: 20231495. 7. haenssle ha, mograby n, ngassa a, et al. association of patient risk factors and frequency of nevus-associated cutaneous melanomas. jama dermatol. 2016;152(3):291-298. doi: 10.1001/jamadermatol.2015.3775. pmid: 26536613. 8. lallas a, longo c, moscarella e, et al. reasons for excision of skin tumors: a one-year prospective study in a tertiary skin cancer unit. dermatology. 2015;230(4):340-346. doi: 10.1159/000371878. pmid: 25675954. 9. tschandl p, hofmann l, fink c, kittler h, haenssle ha. melanomas vs. nevi in high-risk patients under long-term monitoring with digital dermatoscopy: do melanomas and nevi already differ at baseline? j eur acad dermatol venereol. 2017;31(6):972-977. doi: 10.1111/jdv.14065. pmid: 27896853. 10. longo c, barquet v, hernandez e, et al. dermoscopy comparative approach for early diagnosis in familial melanoma: influence of mc1r genotype. j eur acad dermatol venereol. 2021;35(2):403-410. doi: 10.1111/jdv.16679. pmid: 32455486. pmcid: pmc9290446. 11. moloney fj, guitera p, coates e, et al. detection of primary melanoma in individuals at extreme high risk: a prospective five-year follow-up study. jama dermatol. 2014;150(8):819-827. doi: 10.1001/jamadermatol.2014.514. pmid: 24964862. 12. watts cg, cust ae, menzies sw, coates e, mann gj, morton rl. specialized surveillance for individuals at high risk of melanoma: a cost analysis of a high risk clinic. jama dermatol. 2015;151(2):178-186. doi: 10.1001/jamadermatol.2014.1952. pmid: 25389712. 13. watts cg, cust ae, menzies sw, mann gj, morton rl. cost-effectiveness of skin surveillance through a specialised clinic for patients at high risk of melanoma. j clin oncol. 2017;35(1):63-71. doi: 10.1200/jco.2016.68.4308. pmid: 28034073. 14. guitera p, menzies sw, coates e, et al. efficiency of detecting new primary melanoma among individuals treated in a high-risk clinic for skin surveillance: a multi-center prospective rr below 2 [5,25,26]. particularly, different studies, as that of duffy et al confirmed the importance of the association of a mc1r genotype and the presence of multiple nevi in contributing synergically to increase the individual’s melanoma risk [30-32]. a rr for melanoma of 2.03 was found in a meta-analysis by gandini et al in case of strong sunburn history [33]. similarly, a large case-control study from the nurses health study published in 2006 found an or of 2.06 for “ever” versus “never” usage of tanning booths [34]. despite this risk, the ids members did not consider patients with a strong history of sunburn or ever use of tanning booths to be qualified for digital monitoring if they had less than 60 nevi. concerning the potentially increased risk of melanoma after organ transplantation, the standardized incidence ratio for melanoma was reported to be 2.38 in this population, indicating a substantially increased risk [5,35,36]. although other immune deficiencies increase the melanoma risk, their rrs are not well calculated yet. thus, participants reached the consensus to refer patients with a history of organ transplantation to digital monitoring if they have more than 40 nevi. the only exception to the rule of multiple nevi was made for patients with a known cdkn2a variant. cdkn2a variant carriers have at least a 10-fold risk of melanoma compared to people not carrying the mutation. moreover, patients with cdkn2a often have more than 50 melanocytic nevi [17-21]. due to this high risk, participants considered this category of patients deserving digital monitoring independently from the total nevus count. in the final open discussion, with almost total agreement among the experts, an indication emerged to also consider patients with other rarer melanoma-predisposing mutations different from cdkn2a and mc1r variants (ie cdk-4, bap-1, mitf, pot1, acd, terf2ip and tert), even if for them the exact relative risk still remains unknown. these rarer patients have multiple nevi and an increased the risk of melanoma, therefore they were considered an exception independent from the nevus count [37-40]. in conclusion, this study suggests a list of indications for digital monitoring of patients at high risk for melanoma. this list could be a guide to help in selecting patients who could benefit the most from this time-consuming procedure. however, these criteria should always be integrated with the physicians experience in order to include also those exceptions that may escape using them strictly. further studies and real-life data are needed to confirm the usefulness of this list of indications in clinical practice. references 1. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis 8 original article | dermatol pract concept. 2022;12(4):e2022182 cohort study. jama dermatol. 2021;157(5):521-530. doi: 10.1001/jamadermatol.2020.5651. pmid: 33729464. pmcid: pmc7970391. 15. hasson f, keeney s, mckenna h. research guidelines for the delphi survey technique. j adv nurs. 2000;32(4):1008-1015. pmid: 11095242. 16. burns pb, rohrich rj, chung kc. the levels of evidence and their role in evidence-based medicine. plast reconstr surg. 2011;128(1):305-310. doi: 10.1097/prs.0b013e318219c171. pmid: 21701348. pmcid: pmc3124652. 17. american cancer society. key statistics for melanoma skin cancer. last revised: january 12, 2022. available from https://www. cancer.org/cancer/melanoma-skin-cancer/about/key-statistics. html#:~:text=overall%2c%20the%20lifetime%20risk%20 of,factors%20for%20melanoma%20skin%20cancer. 18. bishop dt, demenais f, goldstein am, et al. geographical variation in the penetrance of cdkn2a mutations for melanoma. j natl cancer inst. 2002;94(12):894-903. doi: 10.1093/ jnci/94.12.894. pmid: 12072543 19. mcwilliams rr, wieben ed, rabe kg, et al. prevalence of cdkn2a mutations in pancreatic cancer patients: implications for genetic counseling. european journal of human genetics. eur j hum genet. 201119(4):472-478. doi: 10.1038/ejhg.2010.198. pmid: 21150883. pmcid: pmc3060321. 20. begg cb, orlow i, hummer aj, et al. lifetime risk of melanoma in cdkn2a mutation carriers in a population-based sample. j natl cancer inst. 2005;97(20):1507-1515. doi: 10.1093/jnci/ dji312. pmid: 16234564. 21. bishop ja, wachsmuth rc, harland m, et al. genotype/phenotype and penetrance studies in melanoma families with germline cdkn2a mutations. j invest dermatol. 2000;114(1):28-33. doi: 10.1046/j.1523-1747.2000.00823.x. pmid: 10620111. 22. boffetta p. causation in the presence of weak association. crit rev food sci nutr. 2010;50(s1):13–16. doi: 10.1080 /10408398.2010.526842. pmcid: pmc3024843. 23. jovancic n. “likert scale: how to create your own survey”. leadquizzes. retrieved 9 march 2020 24. watts cg, dieng m, morton rl, mann gj, menzies sw, cust ae. clinical practice guidelines for identification, screening and follow-up of individuals at high risk of primary cutaneous melanoma: a systematic review. br j dermatol. 2015 jan;172(1):33-47. doi: 10.1111/bjd.13403. pmid: 25204572. 25. gandini s, sera f, cattaruzza ms, et al. meta-analysis of risk factors for cutaneous melanoma: i. common and atypical naevi. eur j cancer. 2005;41(1):28–44. doi: 10.1016/j.ejca.2004.10.015. pmid: 15617989. 26. gandini s, sera f, cattaruzza ms, et al. meta-analysis of risk factors for cutaneous melanoma: iii. family history, actinic damage and phenotypic factors. eur j cancer. 2005;41(14):2040– 2059. doi: 10.1016/j.ejca.2005.03.034. pmid: 16125929. 27. chen t, fallah m, försti a, kharazmi e, sundquist k, hemminki k. risk of next melanoma in patients with familial and sporadic melanoma by number of previous melanomas. jama dermatol. 2015;151(6):607-615. doi: 10.1001/jamadermatol.2014.4777. pmid: 25671687. 28. lallas a, apalla z, kyrgidis a, et al. second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring. j am acad dermatol. 2020;82(2):398-406. doi: 10.1016/j.jaad.2019.08.074. pmid: 31499156. 29. wheless l, black j, alberg aj. nonmelanoma skin cancer and the risk of second primary cancers: a systematic review. cancer epidemiol biomarkers prev. 2010;19(7):1686–1695.doi: 10.1158/1055-9965.epi-10-0243. pmid: 20570907. pmcid: pmc2901413. 30. duffy dl, lee kj, jagirdar k, et al. high nevus count and mc1r red hair alleles contribute synergistically to increased melanoma risk. br j dermatol. 2019;181(5):1009-1016. doi: 10.1111/ bjd.17833. pmid: 30820946. 31. raimondi s, sera f, gandini s, et al. mc1r variants, melanoma and red hair color phenotype: a meta-analysis. int j cancer. 2008;122(12):2753–2760. doi: 10.1002/ijc.23396. pmid: 18366057. 32. williams pf, olsen cm, hayward nk, whiteman dc. melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. int j cancer. 2011;129(7):1730–1740. doi: 10.1002/ijc.25804. pmid: 21128237. 33. gandini s, sera f, cattaruzza ms, et al. meta-analysis of risk factors for cutaneous melanoma: ii. sun exposure. eur j cancer. 2005;41(1):45–60. doi: 10.1016/j.ejca.2004.10.016. pmid: 15617990. 34. han j, colditz ga, hunter dj. risk factors for skin cancers: a nested case-control study within the nurses’ health study. int j epidemiol. 2006;35(6):1514–1521. doi: 10.1093/ije/dyl197. pmid: 16943234. 35. brewer jd, christenson lj, weaver al, et al. malignant melanoma in solid transplant recipients: collection of database cases and comparison with surveillance, epidemiology, and end results data for outcome analysis. arch dermatol. 2011;147(7):790– 796. doi: 10.1001/archdermatol.2011.159. pmid: 21768478. 36. engels ea, pfeiffer rm, fraumeni jf jr. et al. spectrum of cancer risk among us solid organ transplant recipients. jama. 2011; 06(17):1891–1901. doi: 10.1001/jama.2011.1592. pmid: 22045767. pmcid: pmc3310893. 37. lang ue, yeh i, mccalmont th. molecular melanoma diagnosis update: gene fusion, genomic hybridization, and massively parallel short-read sequencing. clin lab med. 2017;37(3):473-484. doi: 10.1016/j.cll.2017.06.002. pmid: 28802496. 38. guo l, qi j, wang h, jiang x, liu y. getting under the skin: the role of cdk4/6 in melanomas. eur j med chem. 2020;204:112531. doi: 10.1016/j.ejmech.2020.112531. pmid: 32712436. 39. hartman ml, czyz m. mitf in melanoma: mechanisms behind its expression and activity. cell mol life sci. 2015;72(7):12491260. doi: 10.1007/s00018-014-1791-0. pmid: 25433395. pmcid: pmc4363485. 40. read j, wadt ka, hayward nk. melanoma genetics. j med genet. 2016;53(1):1-14. doi: 10.1136/jmedgenet-2015-103150. pmid: 26337759. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(1):5 15 dermatology practical & conceptual www.derm101.com a rare complication of follicular hair unit extraction: kaposi’s varicelliform eruption a. tulin mansur1, gulsen t. demirci1, m. adnan uzunismail2, semsi yildiz3 1 department of dermatology, baskent i̇stanbul university hospital, i̇stanbul, turkey 2 department of plastic surgery, baskent i̇stanbul university hospital, i̇stanbul, turkey 3 department of pathology, baskent i̇stanbul university hospital, i̇stanbul, turkey key words: kaposi’s varicelliform eruption, hair unit, follicular hair unit extraction citation: mansur at, demirci gt, uzunismail a, yildiz s. a rare complication of follicular hair unit extraction: kaposi’s varicelliform eruption. dermatol pract concept 2016;6(1):5. doi: 10.5826/dpc.0601a05 received: august 21, 2015; accepted: november 5, 2015; published: january 31, 2016 copyright: ©2015 mansur et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gulsen tukenmez demirci, md, başkent üniversitesi i̇stanbul hastanesi 3. poliklinik binası mahiri̇z cad. no:43 p.k. 34662, turkey. tel. +9005334918376; fax. +902166515153. email: gulsentukenmez@yahoo.com follicular hair unit extraction (fue) is becoming a popular type of hair transplantation recently. kaposi’s varicelliform eruption (kve) is an uncommon skin emergency due to cutaneous dissemination of several types of viruses, most notably herpes virus, over the lesions of preexisting skin disorders. a 34-year-old man visited our dermatology outpatient clinic with a blistering, itchy and tender eruption on his head and body. he had undergone follicular fue for androgenic alopecia 12 days previously, and 5 days after the procedure, umbilicated and/or hemorrhagic vesiculopustules appeared firstly on the occipital scalp skin where the hair units were taken. the lesions had rapidly spread over the upper chest and back. after the operation, he had taken oral methylprednisolone, amoxicillin clavulanate and had used fusidic acid ointment without any benefit. bacterial culture of the pustules yielded no microorganism, while tzanck smear from the vesicles revealed multinuclear giant cell groups. based on a diagnosis of kve, we treated the patient with oral valacyclovir hydrochloride 1000 mg 3 times a day for 14 days. symptoms cleared rapidly, pustules and vesicles dried in a few days, and re-epithelialization of the eroded areas started at the end of the first week. the reported complications of fue include necrosis of the donor site, postoperative hyperesthesia, recipient area folliculitis, keloids, bleeding, infection and pyogenic granuloma. up to this date there are only three reports of kve developing just after dermatological surgery, including dermabrasion, laser resurfacing, and skin grafting. according to our knowledge, this is the first case of kve occurring after the fue procedure. we think that the traumatic effects and skin barrier disruption due to operation and immune alteration due to postsurgical steroid treatment might have precipitated the activation and dissemination of latent herpesvirus infection. abstract 16 observation | dermatol pract concept 2016;6(1):5 skin examination revealed numerous dome-shaped vesiculopustules, some umbilicated, hemorrhagic, and crusted. they were mostly seated on the hairy scalp but also scattered over the neck, upper chest and back (figure 1). tender discrete lymph nodes were palpated on cervical areas. there was no sign of ophthalmic or labial herpes. oral mucosa was intact and the rest of his physical examination was unremarkable. routine biochemical and hematologic tests were within normal limits except for increased white blood cell count (12,000/μl), and increased level of c reactive protein (28 mg/l). serum total ige level was not elevated (40.2 u). bacterial culture of the pustules yielded no microorganism, while tzanck smear from the vesicles revealed multinucleate giant cell groups (figure 2). after diagnosis of kve based on clinical and laboratory findings, we treated the patient with oral valacyclovir hydrochloride 1000 mg 3 times a day, and topical mupirocin ointment twice a day for 14 days. symptoms cleared rapidly, pustules and vesicles dried up in a few days, and re-epithelialization of the eroded areas started at the end of the first week. at the fourth week, the lesions had mostly improved with some of them leaving behind atrophic scars (figure 3). introduction follicular hair unit extraction (fue) has become a popular type of hair transplantation in recent years because of many advantages for both patients and the surgeons. fue is performed by extracting follicular units with the aid of 1 mm punches and implanting them to the unhaired scalp skin [1]. although this procedure has been performed on a large number of patients, only a few complications have been reported in the literature [2]. kaposi’s varicelliform eruption (kve) is an uncommon skin emergency due to cutaneous dissemination of certain viral agents, most commonly herpesviruses, on a preexisting dermatosis. there are some reports of kve developing just after some dermatological treatments, such as dermabrasion and skin grafting [3-5]. herein, we report a case of kve that occurred after an fue procedure. case report a 34-year-old man visited our dermatology outpatient clinic with an itchy and tender eruption on his head and body. twelve days before his referral, he had fue for androgenetic alopecia at another clinic. after the operation he had been given methylprednisolone 32 mg per day for 3 days, and 16 mg per day for 2 days. on the sixth postoperative day, vesiculopustular lesions had started to appear on the occipital area where the hair units had been taken, and then they rapidly spread over the whole scalp, neck and upper trunk. he had received amoxacillin clavulanate 625 mg 3 times a day and applied topical fusidic acid ointment twice a day, with a diagnosis of pyoderma. as the lesions did not improve, it was suggested that the eruption was an allergic drug reaction, and the patient was referred to our hospital. he had no preexisting dermatoses including atopic dermatitis and he was immunocompetent. figure 1. (a, b) several vesiculopustules spreading on the hairy scalp. note some of them are intact, dome shaped and/or umbilicated vesicles, some contain hemorrhagic serum with overlying dark-colored scabs. (c, d) there are also similar lesions scattered over the neck and upper trunk. [copyright: ©2015 mansur et al.] figure 2. tzanck smear with giemsa stain show multinucleated giant cells. [copyright: ©2015 mansur et al.] figure 3. at the end of the fourth week almost all lesions were healed with atrophic scars. [copyright: ©2015 mansur et al.] observation | dermatol pract concept 2016;6(1):5 17 tion or immune disorder, kve developed just after fue procedure. we think that the traumatic effect of punch biopsies and multiple minute wounds causing skin barrier dysfunction might have been a triggering factor for kve. psychogenic stress due to the operation and the oral corticosteroid regimen just after the procedure might have suppressed the immune defense of the patient and precipitated the activation and dissemination of latent herpes virus infection. the reported complications of fue include necrosis of the donor site, postoperative hyperesthesia, recipient area folliculitis, keloids, and pyogenic granuloma [2,10]. kve occurring after dermatologic surgery, including skin autografting, laser resurfacing, and dermabrasion, has only been reported three times [3-5]. according to our knowledge, this is the first report of kve occurring after fue procedure. it is important to diagnose the clinical features of this disease because it may progress to a systemic disease if the antiviral treatment is not started promptly. surgeons dealing with hair transplantation should be aware of this rare complication. references 1. rassman wr, bernstein rm, mcclellan r, et al. follicular unit extraction: minimally invasive surgery for hair transplantation. dermatol surg. 2002;28(8):720-8. 2. konior rj. complications in hair-restoration surgery. facial plast surg clin north am. 2013;21(3):505-20. 3. mander sm, chetty bv. eczema herpeticum occurring in autografted skin. j am acad dermatol. 1991;24:509-10. 4. rodriguez-serna m, mercader p, pardo j, fortea-baixauli jm, aliaga a. kaposi’s varicelliform eruption in an hiv-positive patient after laser resurfacing. j eur acad dermatol venereol. 2004;18(6):711-2. 5. bestue m, cordero a. kaposi’s varicelliform eruption in a patient with healing peribucal dermabrasion dermatol surg. 2000;26(10):939-40. 6. olson j, robles dt, kirby p, colven r. kaposi varicelliform eruption (eczema herpeticum). dermatol online j. 2008;14(2):18. 7. kucukyilmaz i, alpsoy e, yazar s. kaposi’s varicelliform eruption in association with rosacea. j am acad dermatol. 2004;51:s16972. 8. santmyire-rosenberger b, nigra tp. psoriasis herpeticum: three cases of kaposi’s varicelliform eruption in psoriasis. j am acad dermatol. 2005;53(1):52-6. 9. bork k, brauninger w. increasing evidence of eczema herpeticum: analysis of seventy-five cases. j am acad dermatol. 1988;19:1024-9. 10. salanitri s, gonçalves aj, helene a jr, lopes fh. surgical complications in hair transplantation: a series of 533 procedures. aesthet surg j. 2009;29(1):72-6. discussion kaposi’s varicelliform eruption (kve) is an uncommon skin disorder resulting from sudden dissemination of herpes simplex virus (hsv) type i and ii, coxsackie virus and vaccinia virus over some skin conditions. the most common etiologic agent is herpes simplex virus, and the lesions are mainly superimposed on atopic dermatitis [6]. kve has also been reported in patients with darier’s disease, pityriasis rubra pilaris, psoriasis, seborrheic dermatitis, rosacea, contact dermatitis, pemphigus foliaceus, hailey-hailey disease, grover’s disease, ichthyosis vulgaris, congenital ichthyosiform erythroderma, mycosis fungoides, sézary syndrome, lupus vulgaris and burns [7,8]. kaposi’s varicelliform eruption is characterized by closely grouped, painful, monomorphic, umbilicated vesicles, accompanied by fever, malaise, and regional lymphadenopathy. the vesicles tend to evolve rapidly to pustules or dry out, forming crusts over punched-out erosions during the course of the disease. the eruption is most frequently located on the head, neck, and the upper part of the body, and spreads caudally in 7 to 10 days [3-9]. the diagnosis of kve is mainly clinical and usually not challenging, when there are umbilicated vesiculopustules that progress to punched-out and crusted erosions in areas of preexisting dermatosis, accompanied by systemic findings. tzanck test is a time-honored and quick test that can provide diagnosis when characteristic acantholysis and multinucleated giant cells appear. viral culture, direct fluorescent antibody staining, and pcr can support the diagnosis if the lesions are atypical and tzanck smear is not fruitful [6]. both histopathologic examination and serology are of little diagnostic value and are not recommended on a routine base [9]. in our patient, the virtually pathognomonic lesions, which started on the donor area and rapidly spread over the head and upper trunk in addition to multinucleated giant cells consistent with the hsv infection, led us to the diagnosis of kve that developed on areas of fue. the etiopathogenesis of kve is not elucidated yet, but the impaired function of skin barrier has been suggested to play the major role for the disease [6,9]. accordingly, kve has been reported on skin disorders in which the skin barrier is disrupted, either by congenital defects, such as atopic dermatitis and ichthyosis, or by acquired disorders, such as pemphigus and burns. immunosuppression due to medication or immune deficiency disorders, also have been an additional risk factor for increased spread of hsv on the skin [4,6,9]. in our patient, who had not had an underlying skin condidermatology: practical and conceptual review | dermatol pract concept. 2022;12(2):e2022116 1 dermatology practical & conceptual introduction the skin is the largest organ of the body, protecting us from the environment, regulating body temperature and permitting the sensation of touch. it is divided into 3 main layers: the outermost epidermis layer, the middle dermis layer and the lower hypodermis layer [1]. the epidermis is mainly made up of keratin producing cells called keratinocytes. the protective barrier, regulation of epidermal temperature and nutrients and other functions of the epidermis are dependent upon the maintenance of stable connections between keratinocytes and other epidermal structures primarily mediated by adhesive desmosomal and hemidesmosomal proteins [2]. desmosomes are specialized tight junctions critical to cellular adhesion (figure 1). they are arranged on adjacent sides of plasma membranes and can be seen in tissues serological biomarkers and their detection in autoimmune bullous skin diseases ilana heckler1, michael hong2,3, animesh amart sinha3, iswariya venkataraman1 1 euroimmun us inc, 1 bloomfield ave, mountain lakes, new jersey, united states 2 college of medicine, florida state university, tallahassee, florida, united states 3 department of dermatology, jacobs school of medicine, university at buffalo, buffalo, new york, united states key words: diagnostics, pemphigoid, pemphigus, antibodies citation: heckler i, hong m, sinha a, venkataraman i. serological biomarkers and their detection in autoimmune bullous skin diseases, dermatol pract concept. 2022;12(2):e2022116. doi: https://doi.org/10.5826/dpc.1202a116 accepted: november 22, 2021; published: april 2022 copyright: ©2022 heckler et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: iswariya venkataraman, ph.d., euroimmun us, 1 bloomfield ave, mountain lakes, new jersey, united states. e-mail: iswariya.venkataraman@euroimmun.us autoimmune bullous diseases (aibds) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. key aibds include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (eba), and dermatitis herpetiformis (dh). each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. pemphigus diseases primarily target desmoglein (dsg) 3 and dsg1 proteins but several non-dsg autoantibodies have also been linked to pemphigus. pemphigoid diseases typically target bullous pemphigoid (bp)180 and bp230; eba is associated with antibodies directed against anti-type vii collagen and dh by iga autoantibodies against tissue transglutaminase and deaminated gliadin. investigation into the serological biomarkers found in aibds have allowed the development of diagnostic assessments (i.e. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group. the methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve. abstract 2 review | dermatol pract concept. 2022;12(2):e2022116 including cardiac muscle, gastrointestinal mucosa, and epithelia, all of which can be subject to significant mechanical stress during normal physiological and disease states [3]. within desmosomes, there is a vast network of cadherin proteins (desmogleins, desmocollins and desmoplakins), linker proteins (eg plakoglobin, plakophilin) and keratin intermediate filaments, that connect as desmosome-intermediate filament complexes (difcs). desmoplakin, which coordinates other cadherin proteins and keratin filaments, is the most prevalent protein within the desmosome [4]. hemidesmosomes resemble tiny stud-shaped structures and are similar in shape to desmosomes. however, there are several differences between these 2 structural components. hemidesmosomes attach keratinocytes to the extracellular matrix and utilize integrins rather than desmogleins and desmocollins. key hemidesmosomal-associated proteins include the cytoplasmic protein bp230, the transmembrane protein bp180, laminin 332 and collagen type vii [5]. another feature of hemidesmosomes is their role in signaling pathways, relevant for the migration of keratinocytes (figure 1) [6]. autoimmunity involves the presence of antibodies (produced by b lymphocytes) and t lymphocytes that have escaped mechanisms of self-tolerance, both centrally and peripherally, that are reactive to one’s own self-antigens. when auto-reactive lymphocytes cause enough target tissue damage, autoimmune disease can occur. there are over 80 human autoimmune diseases in existence, affecting over 20 million americans [7]. indicators of autoimmunity (ie antinuclear antibodies) suggest that the incidence of autoimmune disease has been increasing over the past few decades [8]. collectively, autoimmune diseases present a tremendous, and likely under-estimated burden on healthcare costs: over $100 billion annually in the united states [9]. these costs figure 1. graphical representation of human skin. desmosomes connect adjacent keratinocytes and are critical to cellular adhesion (top circle within desmosomes: there is a vast network of cadherin proteins [desmogleins, desmocollins and desmoplakins]), linker proteins [eg plakoglobin, plakophilin] and keratin intermediate filaments). hemidesmosomes facilitate the adhesion of basal keratinocytes to the underlying basal lamina. key hemidesmosomal-associated proteins include the cytoplasmic protein bp230, the transmembrane protein bp180, laminin 332 and collagen type vii. review | dermatol pract concept. 2022;12(2):e2022116 3 reflect a multitude of factors which are impacted by delays in diagnosis, poor or infrequent monitoring of disease activity leading to less than optimal disease management. systemic autoimmune diseases affect multiple organs, whereas organ-specific diseases target a single organ such as the skin. autoimmune diseases that affect the skin include vitiligo, scleroderma, lupus, psoriasis, vasculitis, and autoimmune bullous dermatoses (aibds). aibds are a collection of autoimmune skin specific disease characterized by the production of autoantibodies against structural components of the skin including desmosomes and hemidesmosomes [10]. such an autoimmune reaction interferes with intercellular connections within the epidermis in addition to the crucial linkage between the epidermis and the dermis. aibds manifest as skin layer separation and blistering and are divided into 4 main groups according to their target antigens and localization of the blisters: pemphigus diseases, pemphigoid diseases, acquired epidermolysis bullosa (eba), and dermatitis herpetiformis (dh) (table 1) [10]. clearly, there is need for a greater understanding of the epidemiology, pathophysiology, and natural history of aibd. the continued evolution of methods for the reliable, accessible, and cost-effective detection of disease relevant autoantibodies is an ongoing endeavor to improve our ability to diagnose and monitor autoimmune activity, with impact in clinical management and decision-making accurately and rapidly. objectives here, we discuss the key autoantigens in aibds and highlight how serological testing can be used in conjunction with clinical symptoms for diagnostic purposes. pemphigus diseases pemphigus diseases are commonly characterized by the production of autoantibodies primarily against the desmosomal proteins desmoglein (dsg)3 and dsg1 which results in the loss of epidermal cell-cell adhesion and subsequent blister formation [11]. some patients experience only mucous membrane erosions with minimal skin blistering, others exhibit lesions on both mucosal as well as non-mucosal surfaces, while others still may only show skin involvement without mucous membrane involvement [11]. the clinical phenotype of pemphigus has been linked to defined dsg3 and dsg1 antibody profiles [12]. additionally, differences in the normal tissue distribution of dsg1 and dsg3 proteins (dsg1 on the epidermal surface and dsg3 in deep epidermal layers/ mucous membranes) may explain the varying clinical manifestations of different pemphigus forms [13]. for example, in pemphigus foliaceus (pf), igg antibodies are only directed against dsg1 and blistering is confined to the skin surface. on the other hand, in pemphigus vulgaris (pv), autoantibodies against both dsg1 and dsg3 can be observed, and table 1. target antigens in autoimmune bullous dermatoses aibd subtype blister location target antigena ig type pemphigus pv (mucosal-dominant type) intraepidermal dsg3 igg pv (mucocutaneous type) intraepidermal dsg3, dsg1, dsc1, dsc2, dsc3 igg iga pemphigus intraepidermal dsg3, dsg1, desmocollins pf intraepidermal dsg1 igg pnp intraepidermal envoplakin, dsg3, dsg1, periplakin, epiplakin, plectin, desmoplakins, dsc(13), bp230, α2-macroglobulin-like 1 igg pemphigoid bp subepidermal bp180, bp230 igg mmp subepidermal bp180, bp230, laminin332, integrin α6/ β4, and collagen vii igg eba subepidermal type vii collagen igg dh subepidermal epidermal/tissue transglutaminase, endomysium, deamidated gliadin iga/igg pemphigoid gestationis subepidermal bp180, bp230 igg linear iga bullous dermatosis subepidermal ectodomain fragment of bp180, bp230 iga amain target antigens are indicated in bold. aibd = autoimmune bullous dermatoses; pv = pemphigus vulgaris; pf = pemphigus foliaceus; dsc = desmocollins; pnp = paraneoplastic pemphigus; bp = bullous pemphigoid; mmp = mucous membrane pemphigoid; eba = epidermolysis bullosa acquisita; dh = dermatitis herpetiformis; dsg = desmoglein. 4 review | dermatol pract concept. 2022;12(2):e2022116 the degree of blistering and mucous membrane involvement varies based on the prevalence of either anti-dsg1 and anti-dsg3 [12]. this framework, correlating the clinical presentation of pemphigus to antibody profile, is known as the dsg compensation hypothesis (dch), featured prominently in dermatology textbooks and previous research studies [14]. as elegant as the hypothesis may be, however, recent studies have identified exceptions to this hypothesis [15,16]. pv accounts for 80% of all pemphigus cases and mainly affects middle-aged and elderly populations [17]. while dsg3 (89% 90% of patients) and dsg1 (50% 60% of patients) are the major autoantigens in pv, additional structural and metabolic autoantigens have been identified including desmocollins (dsc) 1 and 3, muscarinic and nicotinic acetylcholine receptors, mitochondrial antigens, thyroid peroxidase, hspca1, plakophilin 3, plakoglobin, and e-cadherin [18]. studies have shown that autoantibodies against these additional targets may complement the effects of anti-dsg autoantibodies and explain individual variations in pemphigus disease severity [18]. in paraneoplastic pemphigus (pnp), autoantibodies are directed against desmosomes including dsg1 and dsg3, α2-macroglobulin-like 1, and the plakins envoplakin, desmoplakin i and ii, plectin, periplakin and the hemidesmosome bp230. the presence of desmoplakin autoantibodies is also common to pv, pf, and bp. however, autoantibodies for envoplakin and periplakin on immunoblot, as well as autoantibodies for desmoplakin (on indirect immunofluorescence and rat bladder epithelium), appear to be sensitive and specific for pnp diagnosis [19]. this has led to the development of an enzyme-linked immunosorbent assay (elisa) that detects envoplakin in consideration for a diagnostic tool for pnp. pnp is associated in a majority of cases with non-hodgkin lymphoma, chronic lymphocytic leukemia and castleman disease [20]. a common clinical feature is stomatitis which presents with painful erosions and ulcerations of the oropharynx. anti-envoplakin antibodies are highly specific for pnp and are used for the differentiation of pnp from other aibds [21]. in iga pemphigus, a rare form of pemphigus with unclear etiology, serum iga autoantibodies are associated with reactivity against the desmosomal cadherins dsc1, dsc2, dsc3, dsg1, and dsg3 [17]. these circulating iga antibodies lead to formation of pruritic and painful eruptions that present as vesicles and pustules on the skin [22]. as iga pemphigus is so rare, there is currently no reported sex, age, or race distribution of this disease. however, iga pemphigus has been observed in all age demographics [23]. pemphigoid diseases pemphigoid diseases are characterized by subepidermal blister formation in the skin and mucous membranes [24]. pemphigoid diseases occur when the immune system produces autoantibodies against proteins involved in the linkage between the epidermis and dermis. as a result of this autoimmune reaction, the epidermal layer separates from the dermis. several different types of pemphigoid diseases exist including bullous pemphigoid (bp), pemphigoid gestationis, mucous membrane pemphigoid, linear iga dermatosis and p200 pemphigoid [10]. the hemidesmosomal proteins, bp180 and bp230, which tether the 2 skin layers together, are the common autoantibody targets in bp. bp is the most common aibd in the general population, with an annual incidence ranging between 2.3 to 23 cases per million. bp disproportionately affects elderly people, with an incidence of 190-312 cases per million among those 80 years and older [14]. this disease manifests with bulging skin blisters and minimal mucous membrane involvement [25]. unlike pemphigus, bp shows a negative nikolsky sign (ie no splitting of skin upon applying pressure) [26]. autoantibodies against bp180 represent the most significant biomarker in bp due to their high prevalence [27]. additional screening for anti-bp230 antibodies is important as they occur in 40% of patients who are seronegative for anti-bp180 antibodies. the parallel detection of both anti-bp230 antibodies and anti-bp180 antibodies increases the sensitivity of bp detection significantly, to a combined 97.1% [28]. pemphigoid gestationis is the manifestation of bp in pregnant women and is characterized by autoantibodies predominately against epitopes in the immunodominant nc16a domain of bp180 (bp180-nc16a) [29]. in children, linear iga dermatosis occurs from the autoantibody recognition of the ectodomain fragment of bp180 [30]. in addition to bp180, laminin 332 is a major target in mucous membrane pemphigoid (mmp) [31]. additionally, patients with mucous membrane pemphigoid may show antibodies against bp230, integrin α6/β4, and collagen vii [31,32]. the identification of anti-laminin 332 is important for determining a patients prognosis as anti-laminin 332 positive patients seem to be at an increased risk of malignancies [33]. epidermolysis bullosa acquisita eba is a severe blistering dermatosis characterized by autoantibodies against type vii collagen [34]. eba manifests as subepidermal blisters and erosions in response to the minor irritation of skin and affects both the skin and mucous membranes. the level of the cleavage in the basal membrane contributes to the various phenotypes of eba, including the most common inflammatory and mechanobullous (noninflammatory) variants [35]. dermatitis herpetiformis dh is an itchy dermatosis affecting 10% of celiac patients. it manifests as blisters in the subepidermis of areas such as the review | dermatol pract concept. 2022;12(2):e2022116 5 elbows, knees, and buttocks. there is also minimal blistering of the mucous membranes. dh is one of many manifestations of gluten-sensitivity and is characterized by iga autoantibodies against endomysium tissue/epidermal transglutaminase (anti-ttg/-etg) and/or deamidated gliadin (iga/igg) [36]. in contrast to the increase in diagnosis of celiac disease, dh incidence appears to be decreasing (table 1) [37]. diagnostic approach the diagnosis of aibds requires the detection of both circulating and tissue-bound antibodies, and histopathology, in conjunction with clinical symptoms [38]. the pathway to aibd diagnosis can be broken down into 4 pillars. first, the clinical manifestations of the disease must be assessed. second, histopathology can be performed to provide information on the location of skin involvement (subor intraepidermal separation). third, the detection of tissue bound autoantibodies by direct immunofluorescence (dif) is done. dif is the current diagnostic gold standard for aibds but gives limited information on the target antigens. dif has a sensitivity of 82% 91% and a specificity of 98% [17]. the fourth pillar is the identification of autoantibodies by serological testing such as indirect immunofluorescence (iif) microscopy, monospecific elisa or immunoblot techniques.17 serological testing for the detection of circulating antibodies in aibds has the advantage of being minimally invasive and may be suitable for diagnostic purposes in conjunction with the clinical manifestations, and for aiding therapy decisions and disease prognosis [17]. conventional serological detection of aibd-specific antibodies involves an initial iif screen using tissue substrates, followed by an antigen-specific assay such as elisa. in 2016, the international bullous diseases consensus group met to standardize the diagnosis and management of pemphigus [39]. the diagnosis of pemphigus was agreed to be based on the clinical presentation and histopathology consistent with pemphigus and either a positive dif microscopy or serologic detection of autoantibodies against epithelial cell surface antigens [39]. the determination of serum autoantibodies was recommended for therapeutic decision making as serum levels of igg against dsg1 and dsg3 correlate with the clinical activity of pemphigus. aibd autoantibody screening using tissue iif due to their high sensitivity, tissue substrates are ideal for screening for aibds autoantibodies (esophagus, salt-split skin, bladder mucosa) [40]. the esophagus substrate yields characteristic honeycomb-like immunofluorescence patterns which can be differentiated when screening for antibodies in suspected cases of pv or pf. iif using esophagus as a substrate has proven to be useful for the detection of autoantibodies against dsg1 and dsg3, with a sensitivity of 81% 100% and a specificity of 89% 100% [17,41]. for the differentiation of autoantibodies in subepidermal aibds, tissue sections of salt-split skin are used [42]. salt-split skin substrate has a sensitivity of 73% 96% and a specificity of 97% for such subepidermal antibodies. additionally, as antibodies have varying antigenic binding properties on salt-split skin, this allows for the differentiation between the subepidermal aibds bp, pemphigoid gestationis, linear iga dermatosis and other subepidermal aibds such as eba, and anti-laminin-332-type mmp. where bp180 and bp230 are located on the epidermal side of salt-split skin, collagen type vii and laminin 332 remain on the dermal side. urinary bladder is an ideal substrate for distinguishing between pnp and other pemphigus diseases as plakins like envoplakin are highly expressed in the bladder while dsg1 and dgs3 are not [43]. urinary bladder is therefore a highly specific substrate for pnp (99% 100%) and having a sensitivity of 74% [17]. finally, liver tissue is useful for the detection of iga autoantibodies against endomysium in dh [44]. the international bullous diseases consensus group recommends using iif microscopy on monkey esophagus or human skin to detect autoantibodies against surface proteins of epidermal keratinocytes [39]. in cases of atypical presentation or the suspicion of another aibd, the use of iif microscopy on rat bladder and immunoblot/immunoprecipitation is discussed. they also describe the use of recombinantly expressed dsg1, dsg3, or envoplakin substrates (euroimmun) when dsgor envoplakin-specific elisa cannot be used [39]. antigen-specific detection of aibds the detection of antigen-specific autoantibodies in aibds can be achieved using monospecific iif and elisas [17]. monospecific iif can be accomplished using transfected cells as a substrate in which the target antigen has been recombinantly expressed. additionally, designer antigens have been created to enhance diagnostic sensitivity and specificity of iif. such purified recombinant designer antigens are utilized as monospecific iif substrates. biochips, which are coated with an iif substrate and arranged onto microscope slides, allow for autoantibody screening and confirmatory discrimination in a single incubation. in this way, various types of aibds can be screened for in one test. iif biochip mosaics contain combinations of different substrates (esophagus, salt-split skin, bladder mucosa, transfected cells, purified designer antigens). a study which compared the performance of the “dermatology mosaic 7” with a multistep serum analysis using single antibody tests, found a 94% diagnostic agreement between both methods. therefore, multiparametric biochip mosaics offer a cost and time effective iif method. 6 review | dermatol pract concept. 2022;12(2):e2022116 autoantibodies can be mono-specifically identified using elisas which utilize purified recombinant proteins [17]. commercial assays which utilize the recombinant ectodomains of dsg1 and dsg3 have a high sensitivity and specificity for the detection of pemphigus foliaceus and pemphigus vulgaris (96% 100%, 96% 100% and 85% 100%, 96 100%, respectively) [17]. in addition to their use as monospecific substrates in iif, designer antigens have been developed for elisas (for the detection of antibodies against bp180 and bp230, deamidated gliadin peptides) to improve immunoreactivity. elisa techniques provide quantitative measurement which is useful for the application of therapy monitoring. profile elisas containing a combination of antigens enables the simultaneous detection of multiple aibds subtypes in patients with suspected aibds. experts recommend determining anti-dsg1 and/or anti-dsg3 igg antibodies by elisa for the detection of pf, and mucosal/mucocutaneous pv (mannose-binding lectin, euroimmun) [39]. serum concentrations of antibodies against dsg1 and dsg3 are associated with pemphigus disease activity in and high levels of anti-dsg1 by elisa has a positive predictive value for skin relapses. therefore, the determination of serum autoantibodies against skin structural proteins by elisa has a prognostic value for guiding pemphigus treatment. conclusions a definitive diagnosis of aibd is based on a combination of clinical signs and symptoms and the analysis of autoantibodies using iif and elisa. iif, using various tissue substrates, is a useful application for antibody screening while transfected cells and purified antigen substrates are suitable for antigen-specific iif. elisa allows for the quantitative measurement of antibody levels to support the detection of different aibd subtypes. serological antibody testing is important for distinguishing between the various aibd subtypes due to differences in their prognosis and treatment. immunologic testing has also a key role in providing an accurate diagnosis as blistering skin diseases are easily misdiagnosed. oral blisters are often misdiagnosed as an infection such as candidiasis or herpes. without a proper diagnosis, a patient is at risk of being mistreated, potentially with a chronic overexposure to steroids which may reduce some symptoms without fully addressing the underlying problem. additionally, serological testing allows for the monitoring of aibd disease. serum levels of anti-bp180 antibodies correlate with disease activity of bp while anti-bp230 levels correlate with the disease duration [45]. moreover, levels of anti-dsg1 and dsg3 are associated with severity of pemphigus diseases and response to therapy while anti-envoplakin titers correlate with the degree of pnp symptoms as well as differential diagnostic clarification [46]. the detection of anti-collagen type vii antibodies aids in the detection of eba and allows for the differentiation of eba from other aibds [47,48]. in addition to disease monitoring, correlations 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therapy of autoimmune bullous diseases. ther clin risk manag. 2007;3(1):29-40. doi: 10.2147/tcrm.2007.3.1.29. pmid: 18360613. pmcid: pmc1936286. 50. alaeen h, toosi r, mahmoudi h, et al. short-term clinical and serological follow-up with conventional and conformational anti-desmoglein antibodies in treatment-naïve and previously treated patients with pemphigus vulgaris after receiving rituximab. int j womens dermatol. 2019;5(5):372-377. doi: 10.1016/j.ijwd.2019.05.008. pmid: 31909160. pmcid: pmc6938821. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):8 43 dermatology practical & conceptual www.derm101.com introduction targetoid hemosiderotic hemangioma (thh) or hobnail hemangioma (hh) is a benign vascular lesion, which mainly affects young people with a prevalence in men. the classical clinical presentation is a ring-shaped vascular lesion having a targetoid appearance, with a central purple-brown papule surrounded by a thin pale area and an ecchymotic ring on the outside [1,2]. however, hh tends to undergo cyclical changes and, therefore, the clinical presentation can vary. thus, depending on the staging, the differential diagnosis considered should include lesions such as hemangioma, angiokeratoma, kaposi’s sarcoma, dermatofibroma, insect-bite reactions, melanocytic nevus and melanoma. dermoscopy is a non-invasive diagnostic technique useful for diagnosing both melanocytic and non-melanocytic pigmented lesions, as well as vascular skin lesions. dermoscopic features and patterns of hh have been increasingly documented and have proven to be sufficient to make a clinical diagnosis in many cases. here, we present a facial lesion in which both the clinical presentation and dermoscopy were atypical. the presence of arborizing vessels in the dermoarborizing vessels in a targetoid hemosiderotic hemangioma: mistaken dermoscopic diagnosis of basal cell carcinoma maría l. enei1, francisco m. paschoal2, rodrigo valdes3 1 dermatology, brazilian society of dermatology, iquique, chile, 2 dermatology, abc school of medicine, fmabc, são paulo (sp), brazil 3 institute of histopathology, histonor, antofagasta, chile key words: dermoscopy, hobnail hemangioma, targetoid hemosiderotic hemangioma, basocellular carcinoma citation: enei ml, paschoal fm, valdes r. arborizing vessels in a targetoid hemosiderotic hemangioma: mistaken dermoscopic diagnosis of basal cell carcinoma. dermatol pract concept. 2017;7(1):8. doi: https://doi.org/10.5826/dpc.0701a08 received: october 24, 2016; accepted: november 26, 2016; published: january 31, 2017 copyright: ©2017 enei et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: maría leonor enei, md, dermatologist, 2030, santiago polanco street, 2°, office 10, iquique, chile, 1100000. tel. +56 572343804. email: leonorenei@vtr.net targetoid hemosiderotic hemangioma (thh) or hobnail hemangioma (hh) is a benign vascular lesion that presents with the classical clinical presentation of a ring-shaped tumor having a targetoid appearance, with a central purple-brown papule surrounded by a thin pale area and an ecchymotic ring on the outside. dermoscopic features and patterns of hh have been documented and have proven to be sufficient to establish a clinical diagnosis in many cases. we present a facial lesion in which both the clinical presentation and dermoscopy were atypical. the presence of arborizing vessels in the dermoscopic pattern, never before described for this lesion, led us to the diagnosis of basocellular carcinoma (bcc). we also report the changes in this pattern experienced over 12 months of progression and their correlation with the histopathologic findings. abstract mailto:leonorenei@vtr.net 44 observation | dermatol pract concept 2017;7(1):8 discussion the histopathogenesis of hh is not yet clear. it is accepted that a local precipitating factor (trauma or hormonal influence) leads to the development of scopic pattern, never before described for this lesion, led us to the diagnosis of basal cell carcinoma (bcc). we also report the changes in this pattern experienced over 12 months of progression and their correlation with the histopathological findings. clinical case a 68-year-old man presented for consultation for a lesion on the nasal dorsum, which was asymptomatic with a few months of progression. there was no history of trauma or preexisting lesions in the area. on clinical examination a pigmented papule was observed (5 x 5 mm) with a smooth surface and regular edges (figure 1). dermoscopic analysis with a fotofinder video dermoscope (fotofinder systems gmbh, bad birnbach, germany) detected the presence of arborizing vessels throughout the lesion, a bluish-gray ovoid structure, multiple cluster brown points and diffuse brown pigment (figure 1). these findings led us to the diagnosis of bcc and indicated resection. however, the patient returned after 12 months without presenting notable clinical changes. a new dermoscopy showed the presence of a dense bluishbrown pigment following a reticular distribution and the disappearance of most arborizing vessels; the extreme distal vessels remained in some areas and telangiectasia in others (figure 2). an excisional biopsy of the lesion was performed, and the tissue was sent for histopathologic analysis, which reported the presence of irregularly dilated blood vessels mainly in the superficial dermis having a prominent endothelium composed of relatively small cells, with little cytoplasm and hyperchromatic nuclei that projected towards the lumen (hobnail aspect). also the presence of sparse aemosiderin and hemosiderotic histiocytes in the dermis was reported (figure 3). the diagnosis was htt. the patient has been managed for 10 years without further recurrence. figure 1. clinical appearance. pigmented papule, 5 mm diameter, nasal dorsum, brown to black, well delimited. the surrounding skin is of normal appearance. (b) dermoscopic analysis: arborizing vessels (arrows), multiple brown points (circle) and a large blue-gray oval nest structure (triangle). there is little brown pigment dispersed through the lesion (star). [copyright: ©2017 enei et al.] microshunts between the lymphatic and blood vessels in the dermis. the capillary pressure of the latter would cause erythrocytes to pass into the lymphatic spaces forming aneurysmal structures. in older lesions, the emerging lymph figure 2. (a) clinical appearance after one year of evolution. the papule shows no significant changes, including size and color (b) dermoscopic analysis: the centre of the lesion displays a dense blue-brown pigment with reticular distribution (stars). at the periphery are the extreme distal vessels from figure 1 (black arrows) and artifacts (black triangles). two round, yellowish brown structures are in the middle of the pigmented area (segmented arrows). [copyright: ©2017 enei et al.] observation | dermatol pract concept 2017;7(1):8 45 for skin lesions. the first reference to epiluminescence microscopy for hh dates back to 1998 and describes welldemarcated red lagoons in the papular region of the lesion [6]. since then, no more than 12 reports based on this technique have been published, covering a total of 48 lesions studied (table 1; [5-16]). we highlight the series of 35 cases recently published by zaballos et al [7] in which the authors were able to establish that the unequivocal dermoscopic pattern for hht is only present in 52% of lesions and is represented by the presence of lagoons in the center, a yellowish circular intermediate area, and a purple or ecchymotic ring on the periphery. in this series, the most common pattern (71.2%) consisted of central lagoons and a homogeneous area on the periphery, which can also be observed in other vascular tumors and 22.8% of the lesions were fully occupied by a reddish purple or reddish brown homogeneous area. this variety of dermoscopic patterns correlates with the different stages of tumor progression. thus, the proliferation of dilated vessels in the superficial dermis correlates with the lagoon structures; the hemorrhagic phenomena are reflected in the ecchymotic ring, and fibrosis of older lesions gives rise to whitish homogeneous structures. in our case, neither of the two dermoscopic evaluations showed the structures or patterns described to date for hh. thus, vessels become clogged, causing the disappearance of these ectatic vessels in the papillary dermis. additionally, there is increased deposition of hemosiderin and subsequent fibrosis [3]. thus, the histology shows a vascular lesion confined to the dermis, with a biphasic pattern. the upper portion has dilated and irregular vascular spaces with thin walls delineated by endothelial cells display a “hobnail” aspect, i.e., round, with little cytoplasm and a large nucleus that protrudes into the vascular lumen. in the lower portion, thinner vascular spaces appear to cut their way through the collagen bundles. local deposits of hemosiderin or siderophages are common, secondary to a local hemorrhagic processes. although studies based upon immunohistochemistry lead to recognition of the lymphatic origin of hh [4], recent observation of these markers suggests also a biphasic histological behavior for these lesions. takayama, et al [5], found not only positivity for cd31 and d2-40 in the upper portion of the hobnail, confirming the lymphatic nature of the lesion, but also positivity for cd31, cd34-factor viii, and α-sma, suggesting an endothelial origin of the lower portion. as far as diagnosis is concerned, this is often difficult, especially if the lesion lacks the typical targetoid appearance. dermoscopy is a noninvasive imaging technique that allowed us to significantly increase the diagnostic precision we highlight that, as far as we know, this is the first time these arborizing vessels have been mentioned for this lesion. this finding, in conjunction with the blue, round structure, was the pattern that led us to posit the diagnosis of bcc. however, several lesions have been reported to predominantly feature arborizing vascular structures, making it impossible to discard the diagnosis of bcc. some examples are hidradenoma, trichoblastoma, trichoepithelioma, cylindroma, hydrocystoma, and poroma. other vascular structures, such as points or polymorphous irregular vessels, have been described in hh in the central portion of the lesion, which have been linked to deeper vessels in the dermis [7]. on the other hand, we believe that the round, blue structure and brown points, in addition to the diffuse brown pigmentation of the first image (figure 1), corresponded as a set to an ecchymotic point and initial deposition of hemosiderin and siderophages in the middle dermis, respectively; this phenomenon increased until becoming a dense network in the center of the lesion after 12 months of progression, covering the globular structure and brown points. it was interesting to compare the two dermoscopic studies and observe the collapse of the central portion of the vessels with the persistence of extreme fine vessels and telangiectasias. the emergence of two round, yellowish brown figure 3. histopathologic analysis. irregularly dilated blood vessels mainly in the superficial dermis, having a prominent endothelium composed of relatively small cells (a), with little cytoplasm and hyperchromatic nuclei, projected towards the lumen (hobnail aspect)(b). [copyright: ©2017 enei et al.] a b 46 observation | dermatol pract concept 2017;7(1):8 and immunohistochemical analysis of 62 cases. j cutan pathol. 1999;26(6):279-286. 2. trindade f, kutzner h, tellechea ó, requena l, colmenero i. hobnail hemangioma reclassified as superficial lymphatic malformation: a study of 52 cases. j am acad dermatol. 2012;66:112115. 3. guillou l, calonje e, speight p, rosai j, fletcher cd. hobnail hemangioma: a pseudomalignant vascular lesion with a reappraisal of targetoid hemosiderotic hemangioma. am j surg pathol. 1999;23:97-105. 4. franke fe, steger k, marks a, kutzner h, mentzel t. hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. j cutan pathol. 2004;31:362-367. 5. takayama r, ueno t, futagami a, ansai s, fukumoto t, saeki h. hobnail hemangioma: a case report. j nippon med sch. 2015;82(3):151-155. 6. avci o, soyal mc, sagol o, gunes at. targetoid hemosiderotic hemangioma. j eur dermatol venereol. 1998;11:186-187. 7. zaballos p, llambrich a, del pozo lj, et al. dermatology. 2015;231 (4):339-344. 8. yang g, tan c. red-violaceous lacunae with a yellowish ecchymotic halo. j cutan med surg. 2016 may 4. pii: 1203475416649140. [epub ahead of print] structures in the middle of the pigmented area is also reported (figure 2), which could correspond to ectatic vessels in the superficial dermis described in the histopathology report, similar to the structures observed in the lymphangiomas. in neither of the two stages did we observe homogenous areas, lagoons, thin pigmented networks, or whitish structures, such as the ones described in published cases of hh. in conclusion, arborizing vessels and blue clods are not unique to bcc and have been described for other tumors. however, this is the first time that they are described in a lesion of hh. we highlight this case because of its unusual dermoscopic presentation. therefore, we add bcc to the differential diagnosis of hh and highlight the fact that when the clinical presentation is uncharacteristic, histopathology continues to be the gold standard for diagnosing this lesion. references 1. mentzel t, partanen ta, kutzner h. hobnail hemangioma (“targetoid hemosiderotic hemangioma”): clinicopathologic table 1. published dermoscopic descriptions of hobnail hemangioma year published reference number number of cases dc pattern vessels hp dermoscopy monitoring clinical and dc diagnosis 2016 8 1 b no no yes yes 2015 7 35 a (71.4%) b (52%) c (22.8%) dots and polymorphous (40%) yes not described yes (77%) 2015 9 1 d no yes no no 2015 10 1 a no no yes yes 2015 5 1 b no yes yes (4 weeks) yes 2014 11 1 e no yes no no 2010 12 1 a no yes no no 2009 13 1 d no yes no no 2009 14 1 a no no yes (3 months) yes 2007 16 1 a-d no yes no no 2005 16 3 b no yes yes yes 1998 6 1 a no yes yes (34 days) yes a: central red and dark peripheral circular lacunae and reddish-violaceous homogeneous area / violaceous nuclei surrounded by a pale halo / well-defined network of circular blebs. b: red lacunae located at the center, an intermediate yellow circular homogeneous area, and a violaceous or ecchymotic homogeneous ring on the periphery. c: homogeneous area. d: red, roundish lagoon-like areas in the focus of the injury, with a fine pigment network at the periphery. e: slight peripheral pigment network surrounding an extensive reddish, structureless area with chrysalis-like structures. hp: histopathology. dc: dermoscopy. http://www.ncbi.nlm.nih.gov/pubmed/?term=yang%20g%5bauthor%5d&cauthor=true&cauthor_uid=27207353 http://www.ncbi.nlm.nih.gov/pubmed/?term=tan%20c%5bauthor%5d&cauthor=true&cauthor_uid=27207353 http://www.ncbi.nlm.nih.gov/pubmed/?term=mentzel%20t%5bauthor%5d&cauthor=true&cauthor_uid=10472756 http://www.ncbi.nlm.nih.gov/pubmed/?term=partanen%20ta%5bauthor%5d&cauthor=true&cauthor_uid=10472756 http://www.ncbi.nlm.nih.gov/pubmed/?term=kutzner%20h%5bauthor%5d&cauthor=true&cauthor_uid=10472756 observation | dermatol pract concept 2017;7(1):8 47 14. ghibaudo n, lacour jp, argenziano g, ortonne jp, bahadoran p. fully regressive targetoid haemosiderotic haemangioma. j eur acad dermatol venereol. 2009;23(6):722-723. 15. morales-callaghan am, 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junctional nevus and early melanoma on sun-damaged skin of the head/neck: a clinico-pathologic challenge elvira moscarella1, pascale guitera2-4, richard a. scolyer2,3,5,6, lilian rocha5, luc thomas7,8,9, andrea ronchi10, camila scharf1, gabriella brancaccio1, giuseppe argenziano1 1. dermatology unit, university of campania l.vanvitelli, naples, italy 2. melanoma institute australia, the university of sydney, sydney, nsw, australia 3. faculty of medicine and health, the university of sydney, sydney, nsw, australia 4. sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, nsw, australia 5. tissue pathology and diagnostic oncology, royal prince alfred hospital and nsw health pathology, sydney, nsw, australia 6. charles perkins centre, the university of sydney, sydney, nsw, australia 7. centre hospitalier lyon sud, lyons, france 8. lyon 1 university, lyons, france 9. lyons cancer research center, lyons, france 10. pathology unit, university of campania l.vanvitelli, naples, italy key words: melanoma, junctional nevus, dermoscopy, partial biopsy, facial lesions citation: moscarella e, guitera p, scolyer ra, et al. junctional nevus and early melanoma on sun-damaged skin of the head/neck: a clinico-pathologic challenge. dermatol pract concept. 2023;13(2):e2023122. doi: https://doi.org/10.5826/dpc.1302a122 accepted: november 18, 2022; published: april 2023 copyright: ©2023 moscarella et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this work was supported by a national health and medical research council of australia (nhmrc) program grant (app1093017) (to ras). ras is supported by an nhmrc practitioner fellowship (app1141295). support from colleagues at the authors’ respective institutions is also gratefully acknowledged. competing interests: ras has received fees for professional services from f. hoffmann-la roche ltd, evaxion, provectus biopharmaceuticals australia, qbiotics, novartis, merck sharp & dohme, neracare, amgen inc., bristol-myers squibb, myriad genetics, glaxosmithkline.pg received honoria form metaoptima. authorship: all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, dermatology unit, university of campania l. vanvitelli, naples, italy. email: elvira.moscarella@gmail.com introduction: melanoma on the head/neck area can show subtle clinical, dermoscopic and histologic features at early stages, being difficult to differentiate from junctional nevi. objectives: this case series aims to raise awareness on the topic of misdiagnosis of early lentigo maligna as junctional nevi. methods: from the databases of three pigmented lesion clinics in italy, australia, and france, we retrieved all cases of lesions of the head/neck area with an initial histopathologic diagnosis abstract 2 original article | dermatol pract concept. 2023;13(2):e2023122 introduction the clinical and histologic diagnosis of early melanoma on sun-damaged skin of the head/neck area may be challenging. lentigo maligna (lm) is the commonest melanoma subtype occurring on the head and neck region. clinically, lm usually presents as a macule or patch of variable dimension and coloration, ill-defined borders and slowly grows over time [1-3]. dermoscopically, atypical pseudo network with asymmetric perifollicular pigmentation, peppering and/or gray circles are found in classical cases. lm is typically characterized histologically by a lentiginous and sometimes nested proliferation of atypical melanocytes arising in skin typified by sun damaged features of epidermal atrophy and solar elastosis. cases of lm lacking the typical clinical and histologic hallmarks can be challenging to diagnose. from a clinical and dermoscopic point of view, the main differential diagnoses of lm include non-melanocytic benign lesions, such as solar lentigo, pigmented actinic keratoses and lichen planus-like keratoses (lplk). nevi are rarely included in the differential diagnosis of lm, since most nevi on the head/neck of adults and elderly are of the compound and dermal subtype. these nevi clinically present as dome shaped to nodular lesions, skin colored or only slightly pigmented [4]. in recent years, it has become increasingly recognized that lm can include a prominent nested component mimicking a junctional or dysplastic nevus. zalaudek et al first reported one case of a lesion initially diagnosed as junctional nevus on the neck of an adult patient that recurred twice during a 4-year period, after apparent complete surgical excision with clear margins, and was ultimately diagnosed as lm [5]. histopathologically, the diagnosis of lm can be challenging. in its early phases of development, lm may display subtle features, with only mild cellular atypia and a mixed junctional and lentiginous appearance of proliferating melanocytes with occasional nests [6,7]. in this report, we discuss the challenge of diagnosing facial atypical melanocytic tumors with nested and lentiginous components. objectives with the aim of raising awareness on this clinico-pathologic challenge, we present a series of 14 cases all of which were initially diagnosed as atypical/dysplastic junctional nevi but were ultimately considered to represent melanoma. these include two main scenarios, namely the difficulty of diagnosing melanoma on a partial biopsy of suspicious lesions on the head/neck area, and the diagnosis of melanoma only after several recurrences of completely excised flat junctional lesions. methods from the databases of three pigmented lesion clinics in italy, australia, and france, we retrieved all cases of lesions of the head/neck area with an initial histopathologic diagnosis of junctional nevus (jn) or dysplastic junctional nevus (djn) which subsequently recurred and were ultimately diagnosed as melanoma. moreover, we also retrieved those cases with an initial diagnosis of jn/djn made on a partial biopsy that were diagnosed as melanoma after a complete surgical removal. information about patient demographic, lesion location, type of biopsy, and first and subsequent histopathologic diagnoses were recorded. in most cases, the initial biopsies were taken outside, and then the patient was referred to one of our specialized centers only after the lesion recurred. given the difficulty to retrieve the material from the initial biopsies, central histologic review was not performed. all cases had clinical and dermoscopic images taken before the final excision that led to the diagnosis of melanoma. dermoscopic evaluation was conducted by consensus by two experienced dermoscopists (gb, cs). follow up information was recorded when available. ethic committee approval was not required, this was analysis of datasets, where the data are properly anonymized. results we collected 14 cases of pigmented lesions of the head and neck with an initial diagnosis of jn/djn that were ultimately of junctional nevus (jn) or dysplastic junctional nevus (djn) which subsequently recurred and were ultimately diagnosed as melanoma. moreover, we also retrieved those cases with an initial diagnosis of jn/djn made on a partial biopsy that were diagnosed as melanoma after complete surgical removal. results: here we report 14 cases in which the initial histologic diagnosis was junctional nevus or dysplastic junctional nevus. the lesions recurred over time with a final diagnosis of lentigo maligna. conclusions: clinicians should critically question a given histologic diagnosis of junctional or dysplastic junctional nevus on the head/neck area if the clinical or dermoscopic features are discordant. clinico-pathologic correlation is the best way to increase diagnostic accuracy and optimize management for the patient. original article | dermatol pract concept. 2023;13(2):e2023122 3 considered melanoma. we can recognize two main scenarios. eleven cases had an initial diagnosis of jn/djn and the final diagnosis of melanoma was made only after several recurrences (cases 1 to 11 in table 1). the majority of lesions recurred ones after a complete surgical excision (n = 7; 63.6 %), in 3 (27.3%) cases there were 2 recurrences over time, in 1 case the lesion initially diagnosed as jn recurred 4 times after complete surgical excision, with a final diagnosis of lm 12 years after the first biopsy. mean time from first biopsy to the latest recurrence for the 11 cases was 4.5 years (range 1-12 years). the second scenario comprises three other cases in which the diagnosis of djn was made on partial biopsy; however, because of suspicious clinical and dermoscopic features the lesions were excised, and the final diagnosis on the whole specimen was lm (case 12, table 1) and early invasive melanoma (cases 13-14, table 1). clinical and demographic information of the cases are summarized in table 1, as well as data on the type of biopsy and the total number of recurrences. all lesions were flat pigmented macules. dermoscopically most lesions had ill-defined borders (84.6%). structureless brown pigmentation was present in six lesions (42.9%), while a black pigmented blotch was seen in 2 (14.3%) lesions. gray globules were detected in six cases (42.9%). an atypical pseudo network was identified in five cases (35.7%), background erythema was seen in four lesions (28.6%), a regular pseudo-network was seen in three lesions (21.4%). in two lesions, moth-eaten borders were observed (14.3%). gray circles were seen in one lesion (7.1%). none of them showed prevalent non-melanoma features [8]. conclusions the diagnosis of early melanoma involving the head/neck can be very difficult for both clinicians and pathologists. (9) our series highlights this challenge that encompasses two main scenarios, namely, (i) the diagnostic underestimation following a partial (incisional) biopsy, and (ii) the problem of histopathologically inconspicuous features of very early melanomas that were completely excised. flat pigmented lesions of the head and neck are often large in diameter, or even if small in size, given their location, they are frequently biopsied with punch or partial shave biopsies to obtain a histologic diagnosis before performing larger excisions. in three cases in our series (cases 12-14, table 1), the clinician decided to remove the lesion completely after an initial diagnosis of djn was made on table 1. demographic information of patients and history of lesions, including number of recurrences and type of initial biopsy. patient  id age at first excision sex lesion location type of biopsy  (incisional=0; excisional=1) first histologic diagnosis total number of recurrences final histologic diagnosis years from first biopsy 1 45 m scalp 1 djn 1 lm 3 2 71 m right temple 1 djn 1 lm 1 3 48 f chin 1 djn 1 lm 2 4 37  m left cheek 1 jn 4 lm 12 5 60 f right eyelid 1 djn 1 lm 1 6 51 f neck 1 jn 2 lm 3 7 53 f right cheek 1 jn 1 lmm 0.5 mm breslow 9 8 45 m frontal 1 jn 1 lm 1 9 55 f right temple 1 djn 1 lm 3 10 62 f right eyelid 0 djn 2 lm 7 11 71 f left cheek 0 djn 2 lm 7 12 53 m frontal 0 djn lm 1 13 89 f right cheek 0 djn lmm 0.2 mm breslow 14 78 f scalp 0 djn lmm 0.2 mm breslow djn = dysplastic junctional nevus; jn = junctional nevus; lm = lentigo maligna; lmm = lentigo maligna melanoma. 4 original article | dermatol pract concept. 2023;13(2):e2023122 view, junctional nevi are extremely rare in the adult/elderly population, the majority facial naevi in the adult are intradermal naevi of the miescher type, clinically presenting as dome-shaped, hypopigmented or skin-colored nodules [10]. clinicians should be aware of the possibility of diagnostic errors and should promote the best possible clinico-pathologic correlation for these cases. of note, two of the partially biopsied lesions in our series were finally diagnosed as early invasive melanomas, which would have progressed, even if slowly, if left untreated. in the other group (case 1 to 11, table 1), we have a series of lesions with an initial diagnosis of nevus that, despite displaying very subtle features histologically, behaved as melanoma, recurring and growing after apparently complete surgical excision (figure 2). the time to reach a definite diagnosis ranged from 1 to 12 years after the initial biopsy, partial biopsy. the lesions displayed features of melanoma at clinical and dermoscopic examination. in these 3 cases, the final histologic evaluation revealed lm and early invasive melanomas of the lm subtype (lmm) (figure 1). these cases underline the need for clinicians to always critically evaluate a histologic diagnosis performed on partial biopsies in the clinical and dermoscopic context of the lesion. the final decision on patient management is in the hands of the clinician, who should be aware of the possibility of a diagnostic underestimation on a small biopsy sample of the given lesion either due to non-representative sampling or simply insufficient tissue to enable full evaluation of the lesion [5-9]. the histologic similarities between lm, lmm and djn are well-known and can be difficult or impossible to distinguish on small biopsies and represent a recognized pitfall for pathologists [6,7]. moreover, from an epidemiological point of figure 1. (a) a flat pigmented macule on the frontal region of a 53-year-old man. on an initial punch biopsy, the lesion was diagnosed as atypical junctional nevus. the lesion was left untreated for 1 year. the patient sought consultation because the lesion was enlarging in size. (b) in dermoscopy, pseudo-network and asymmetrically pigmented follicular openings are seen. histologic diagnosis after a complete surgical removal revealed a lentigo maligna (case #12 from table 1). figure 2. (a) a flat pigmented lesion on the frontal area in a 45-year-old man. the pigmented lesion was recurring one year after acomplete surgical excision, a scar is visible, the initial diagnosis was jn. (b) on dermoscopy brown pseudo network and gray circles were visible at the time of the recurrence. the lesion was excised with a final diagnosis of lentigo maligna (case #8 from table 1). original article | dermatol pract concept. 2023;13(2):e2023122 5 2. ferrara g, ligrone l, zalaudek i, mordente i, argenziano g. lentigo maligna in a young adult. dermatology. 2008; 17(1):66-68. doi: 10.1159/000125549. pmid: 18401175. 3. stolz w, schiffner r, burgdorf wh. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002; 20(3):276-278. doi: 10.1016/s0738-081x(02)00221-3. pmid: 12074867. 4. witt c, krengel s. clinical and epidemiological aspects of subtypes of melanocytic nevi (flat nevi, miescher nevi, unna nevi). dermatol online j. 2010;16(1):1. pmid: 20137743. 5. zalaudek i, cota c, ferrara g, et al. flat pigmented macules on sun-damaged skin of the head/neck: junctional nevus, atypical lentiginous nevus, or melanoma in situ? clin dermatol. 2014;32(1):88-93. doi: 10.1016/j.clindermatol.2013.05.029. pmid: 24314381. 6. sina n, saeed-kamil z, ghazarian d. pitfalls in the diagnosis of lentigo maligna and lentigo maligna melanoma, facts and an opinion. j clin pathol. 2021;74(1):7-9. doi: 10.1136/ jclinpath -2020-207051. pmid: 33051287. 7. farrahi f, egbert bm, swetter sm. histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopathologic distinction. j cutan pathol. 2005;32(6):405-412. doi: 10.1111/j.0303-6987.2005.00355.x. pmid: 15953373. 8. lallas a, lallas k, tschandl p, et al. the dermoscopic inverse approach significantly improves the accuracy of human readers for lentigo maligna diagnosis. j am acad dermatol. 2021;84(2):381-389. doi: 10.1016/j.jaad.2020.06.085. pmid: 32592885. 9. mccarthy sw,  scolyer ra. melanocytic lesions of the face: diagnostic pitfalls. ann acad med singap. 2004;33(4 suppl):3-14. pmid: 15389301 10. moscarella e, kyrgidis a, sperduti i, et al. age-related prevalence and morphological appearance of facial skin tumours: a prospective, cross-sectional, observational, multicentre study with special emphasis on melanocytic tumours. j eur acad dermatol venereol. 2015;29(7):1331-1338. doi: 10.1111/jdv.12844. pmid: 25399612. 11. kossard s. atypical lentiginous junctional naevi of the elderly and melanoma. australas j dermatol. 2002;43(2):93-101. doi: 10.1046/j.1440-0960.2002.t01-1-00568.x. pmid: 11982564. 12. kossard s, commens c, symons m, doyle j. lentinginous dysplastic naevi in the elderly: a potential precursor for malignant with a mean time of 4.5 years and a number of recurrences after complete excision ranging from 1 to 4. the scenario of completely excised junctional proliferations recurring over time and finally diagnosed as lm can be interpreted into different ways, namely precursor lesions or early phases of a neoplastic process. some authors elaborated the concept of atypical junctional nevi being possibly melanoma precursors, acquiring malignant potential over time [11,12]. however, in our estimation a lesion showing the tendency to multiple recurrences after complete excision is most probably a very early phase of a neoplastic proliferation rather than a precursor lesion. from a clinical point of view, these very initial lesions will probably never affect the patients’ life expectancy. however, it is well known that melanoma prognosis depends mainly on breslow thickness rather than the histologic subtype, and until now we do not have a reliable marker to predict which lesion will evolve to invasive melanoma [13-15]. one limitation of our study is that we did not review the histological slides from the initial biopsies. this was because they were mainly cases from other centers that were referred to us only after recurrence. however, the majority had only slight atypia also at the final histologic evaluation, as highlighted by figure 3. from a clinician perspective this case series aims to raise awareness on the topic of misdiagnosis of early lm. clinicians should revise critically a given histologic diagnosis of jn, djn on the head/neck area. the best possible clinico-pathologic correlation is the only way to increase diagnostic accuracy and assure the best possible management to the patient. references 1. reed ja, shea cr. lentigo maligna: melanoma in situ on chronically sun-damaged skin. arch pathol lab med. 2011;135(7):838-841. doi: 10.5858/2011-0051-rair.1. pmid: 21732771. figure 3. histologic image of the case in figure 2. (a) histology showing a lentiginous intraepidermal proliferation of melanocytes (right, blue arrowheads). a benign intradermal nevus is detectable on the left (yellow star) (h$e, original magnification 40x). (b) the melanocytic proliferation is arranged in a continuous lentiginous pattern (h&e, original magnification 100x). 6 original article | dermatol pract concept. 2023;13(2):e2023122 versus body melanoma: a population-based study. bmc cancer. 2021;21(1):420. doi: 10.1186/s12885-021-08105-y. pmid: 33863315. pmcid: pmc8052690. 15. grossman d, okwundu n, bartlett ek, et al. prognostic gene expression profiling in cutaneous melanoma: identifying the knowledge gaps and assessing the clinical benefit. jama dermatol. 2020;156(9):1004-1011. doi: 10.1001/jamadermatol.2020.1729. pmid: 32725204. pmcid: pmc8275355. melanoma. australas j dermatol. 1991;32(1):27-37. doi: 10.1111/j.1440-0960.1991.tb00679.x. pmid: 1930003. 13. gershenwald je, scolyer ra, hess kr, et al. melanoma staging: evidence-based changes in the american joint committee on cancer eighth edition cancer staging manual. ca cancer j clin. 2017;67(6):472-492. doi: 10.3322/caac.21409. pmid: 29028110. pmcid: pmc5978683. 14. ding y, jiang r, chen y, et al. comparing the characteristics and predicting the survival of patients with head and neck melanoma dermatology: practical and conceptual research | dermatol pract concept 2019;9(2):5 105 dermatology practical & conceptual introduction palmoplantar pustulosis (ppp) is a chronic inflammatory condition characterized by the recurrent appearance of crops of sterile pustules on the palms and soles, in conjunction with erythematous keratotic lesions that tend to crack, causing bleeding and pain [1-4]. since 1930 when barber described the condition under the name of ppp and classified the disease as a local pustular variant of psoriasis, this entity has been in the middle of an endless debate regarding the etiology and the possible association with other diseases [1-4]. several authors have suggested that ppp should be regarded as a separate entity and not a clinical variant of psoriasis despite the presence of certain phenotypes common in both diseases [4-8], palmoplantar pustulosis and allergies: a systematic review alexandra m.g. brunasso vernetti1, matteo puntoni2, cesare massone1 1 department of dermatology, galliera hospital, genoa, italy 2 unit of biostatistics, scientific directorate, galliera hospital, genoa, italy key words: palmoplantar pustulosis, contact allergy, psoriasis, metals, nickel, patch test citation: brunasso vernetti amg, puntoni m, massone c. palmoplantar pustulosis and allergies: a systematic review. dermatol pract concept. 2019;9(2):105-110. doi: https://doi.org/10.5826/dpc.0902a05 accepted: december 12, 2018; published: april 30, 2019 copyright: ©2019 brunasso vernetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alexandra maria giovanna brunasso, md, dermatology unit, galliera hospital, mura delle cappuccine, 14, genoa, italy. email: alexandra.brunasso@galliera.it background: in 2007 the international psoriasis council considered palmoplantar pustulosis (ppp) a condition separate from psoriasis, and several authors maintain that ppp is a reactive process to metal contact allergies independent from psoriasis. objectives: to evaluate the frequency of allergies and psoriasis in patients with ppp and to determine the role of allergens in ppp. methods: a systematic search of the english databases (pubmed and web of science) from january 1964 to august 2018 to identify all patients affected by ppp and allergies and/or psoriasis. results: in total, 16 publications describing a total of 519 patients with ppp were evaluated and 122 cases of concomitant ppp and metal allergy were found. the frequency of allergies among patients with ppp was 22.7%; between the identified allergens, 84.3% of cases correspond to metal allergies. in 65.1% of metal allergies, an improvement in ppp was seen after withdrawal of contact. the concomitant presence of psoriasis was recorded in 18% of the cases. conclusion: there is some evidence to support the association of ppp with metal allergies but also with psoriasis, suggesting the role of metal allergens as a trigger factor in patients with ppp. abstract 106 research | dermatol pract concept 2019;9(2):5 literature search and selection of studies we performed a systematic search of english databases (pubmed and web of science) from january 1964 until august 2018, using the following key words and mesh terms: “palmoplantar pustulosis,” and/or “palmoplantar,” and/or “pustulosis,” and/or “psoriasis,” and/or “palms and soles,” and/or “patch test,” and/or “contact allergy,” and/or “contact dermatitis,” and/or “metals,” and/or “psoriasis,” and/or “acropustulosis,” and/or “pustulosis palmaris et plantaris,” and/or “nickel,” and/or “zinc,” and/or “cobalt,” and/ or “platinum,” and/or “tin,” and/or “iron,” and/or “mercury,” and/or “copper,” and/or “chromium,” and/or “palladium.” no exclusion criteria were applied. data extraction and quality assessment three reviewers (a.b.v., c.p., and c.m.) independently screened all the identified studies and any disagreement was discussed and resolved. because of the quality of the observational studies included (no cohort, nor case-control or cross-sectional studies) it was not possible to perform a meta-analysis. results we identified 506 reports; 50 were assessed for eligibility and only 16 publications fulfilled the requirements for the present systematic review. the overview of the research strategy is illustrated in figure 1 [1-6,8-17]. the majority of the articles retrieved are case series, case reports, and retand in 2007 the international psoriasis council considered ppp as a condition separate from psoriasis [9]. in the last 15 years many authors have considered ppp as a reactive process (a subtype of systemic contact dermatitis) because of the numerous reports available in the literature that link ppp to metal allergies (nickel, iron, cobalt, zinc, and copper), and such association has driven many dermatologists to ignore the possible concomitant presence of psoriasis in patients with ppp [10-12]. in the literature, there are different isolated reports of the association of ppp and allergies, but well-designed studies are missing. motivated by these controversial issues, we performed this systematic review to assess the association between ppp and allergies. in the current article we present a systematic literature review that identifies all cases reported of ppp patients with a concomitant contact allergy (identified by a positive patch test and/or by an aggravation of the ppp related to a contact allergy and/or patients in whom the elimination of dental alloys or devices containing metals brought to complete remission of the ppp). we also evaluated in the identified cases the concomitant presence of psoriasis, if available. methods we followed the meta-analysis of observational studies in epidemiology (moose) guidelines during the present systematic literature review. no ethical approval was requested. figure 1. overview of the research strategy. sapho = synovitis, acne, pustulosis, hyperostosis, andosteitis. [copyright: ©2019 brunasso vernetti et al.] research | dermatol pract concept 2019;9(2):5 107 patch testing was reported; all were patients with metal contact allergies (platinum, tin, copper, nickel, cobalt, iron, and palladium) [9,12,14]. data regarding concomitant psoriasis and ppp were available in 7 publications concerning 428 patients affected by ppp; in 77 of such cases the presence of concomitant psoriasis (mild to moderate plaque psoriasis and/or nail psoriasis and/ or psoriatic arthritis) was reported and in 4 cases family history of psoriasis was recorded [1-3,8,10,17]. the frequency of psoriasis in the available data regarding patients affected by ppp and allergies was 18%, but in 115 cases the concomitant presence of psoriasis in patients with ppp was not recorded. discussion after extensive review we found 519 ppp patients evaluated for contact allergies; 23.5% were affected by both ppp and contact allergies. in 28.7% of the cases, the allergen was not reported and metal allergies were identified in 55% of the patients. considering that in only 86 cases of ppp and contact allergies the allergen was described, 67 of such cases (78%) had metal allergies while in only 19 (22%) contact allergy was associated with other nonmetallic allergens. of interest, 4 other cases of high blood levels of mercury and ppp improved after diet and/or chelation, suggesting a close relation between metal exposure and ppp [10]. considering only the 28 out of 48 cases (58.3%) of metal allergies or high blood mercury levels (excluding 3 cases of nonmetal allergies, see table 1), an improvement in ppp was seen after withdrawal of contact and/or diet change or chelation, suggesting that patients affected by ppp and metal allergies may benefit from allergen contact withdrawal [1-6,8-17]. other supporting evidence for the role of metal allergy in ppp regards the exacerbation of ppp lesions after patch test (effect only described with metals and not with other allergens) [9,12,14]. our data support and confirm the frequency of allergic sensitization in patients with ppp (121/519: 23.3%) previously reported in a study conducted with 248 patients with ppp (allergic sensitization frequency of 15.3%) [1]. on the other hand, in the same cohort of patients it was possible to establish the concomitant presence of psoriasis in 18% of the patients with ppp. it is notable that in the 121 patients found to have concomitant ppp and allergies, the presence of psoriasis elsewhere in the body was evaluated and reported in only 45% of cases [1-4,8,10,15,17]. this psoriasis frequency in ppp is lower than the known prevalence of psoriasis in patients with ppp (approximately 33.5%), but this finding probably represents a collection bias of the studies selected for the present systematic review that can be attributed to the fact that many authors consider ppp a form of contact allergy and ignore the concomitant presence of rospective observational studies. well-designed prospective studies in which patients affected by ppp are concomitantly tested for contact allergies are missing. publication biases and selective reporting within studies were identified; the majority of ppp studies do not report concomitant allergies or patch test results (and were not included) and the studies analyzed in the present systematic review were prone to report a positive correlation between ppp and allergies. one hundred twenty-two cases affected by ppp and contact dermatitis or metal allergy between the years 1964 and 2018 were identified [1-6,8-17]. the patients were evaluated for the following variables: disease, sex, smoking habits, allergy type, patch test result (positivity and allergen), improvement of ppp lesions after allergen avoidance (permanent or partial improvement), exacerbation of ppp lesions after patch test, and concomitant psoriasis (psoriasis vulgaris, nail psoriasis, and/or psoriatic arthritis). the patients identified were 519 in total, 105 males and 395 females, but in 19 cases sex data were not available. for those with available sex data, males comprised 21% (105/500) and females 79% (395/500) of the whole cohort (table 1). data regarding smoking (previous or active) were available in fewer than 50% of the records and are not included in this analysis. positive patch tests were recorded in 121 of 519 (23.3%) patients. metal allergens (chromium, mercury, platinum, tin, copper, nickel, cobalt, zinc, iron, gold, iridium, molybdenum, and palladium) were reported in 67 cases (55%), and another 4 cases presented high blood mercury levels that improved ppp after diet changes and/or chelation [10]. one patient presented with concomitant ppp and irritant dermatitis. in 19 cases contact allergies were due to different allergens (neomycin, formalin, benzyl salicylate, colophony, eucerin, turpentine, p-phenylenediamine, fragrance mix, cinnamic aldehyde, and balsam of peru), and in 35 cases (28.9%) allergic reactions were reported without the specific allergen [1-6,8-17]. in summary, in 67 of the 86 cases the allergens were metals corresponding to 78% (67/86), while in 22% (19/86) other allergens (not metals) were described. in 10 publications regarding 48 patients affected concomitantly by ppp and allergies, data about improvement after allergen withdrawal were available [6,8,9-17]. in 31 of these 48 patients, permanent/definitive improvement of ppp was seen after allergen withdrawal (in 28 of 31 cases metals were identified as the causative allergen and the source was mainly from dental amalgams: chromium, mercury, platinum, tin, copper, nickel, cobalt, and zinc) [9-17]. partial ppp improvement was observed in 7 cases (not related to metal allergies), while in 8 cases no improvement was observed after allergen avoidance [8-16] and in 2 cases an improvement was described but it was not clear whether it was permanent or partial [17]. in 9 cases an exacerbation of ppp lesions after 108 research | dermatol pract concept 2019;9(2):5 still considered a rare disease, in order to understand the role of allergies and/or metal exposure in such cases it would be helpful in the future to report the association of ppp with a number of factors, such as sex, age, smoking habits, patch test results, presence of dental amalgams containing metals, type of metal, outcome of ppp after allergen avoidance, presence of other concomitant comorbidities, presence of psoriasis elsewhere in the body, and presence of psoriatic arthritis. psoriasis. the concomitant presence of psoriasis in patients with ppp is 10 to 25 times higher than in the general population in different cohorts [18-21]. there were several limitations concerning the quality of the data found in the literature. the majority of the articles included were case reports and case series; cohort or casecontrol studies are missing. in addition, significant heterogeneity among reports was found. considering that ppp is table 1. description of contact allergies and/or metal exposure and psoriasis in patients affected by ppp first author, year no. of ppp patients (m/f) no. of patients with eczema (type) no. of patients improved after allergen withdrawal (permanent, partial, or absent) exacerbation of ppp after patch test no. of patients with psoriasis (skin or nails) ashurst, 1964 [1] 43 (5/38) 1 (nickel dermatitis), 1 irritant dermatitis na na 1 (skin) 6 (nails) enfors, 1971 [2] 248 (56/192) 38 (na) na na 34 (14%) thomsen, 1973 [3] 40 (8/32) 2 (co) 1 (ni) 1 (neomycin) 1 (formalin) 1 (benzyl salicylate) na na 12 (skin and/or nails) fransson, 1985 [4] 7 (na) 1 (co chloride, balsam of peru, fragrance mix) na na 60% (nails) pasic, 1989 [5] 8 (na) 20% (1 patient) na na na nakayama, 1990 [6] 11 (2/9) 11 (cr, hg, pt, hg, sn, cu, ni, co, zn) 11 permanent na na yiannias, 1998 [8] 21 (5/16) 9 patients, 7 with multiple positive patch tests 4 (fragrance mix) 2 (cinnamic aldehyde) 2 (balsam of peru) 1 (ni) 7 partial 2 absent (1 ni) na 2 mild psoriasis (skin) 1 family history of psoriasis nakamura, 2000 [7] 7 (3/4) 7 (ni, co, pt, sn, fe, pa) 2 na 7 patients na dantzig, 2003 [10] 4 (na) 4 (hg) 4 permanent na 1 psoriasis yanagi, 2005 [11] 1 (f) 1 (zn) 1 permanent na na wen, 2008 [12] 1 (f) 1 (cu) 1 permanent yes na song, 2011 [13] 1 (m) 1 (co) 1 permanent no na ito, 2014 [14] 1 (f) 1 (ni) 1 permanent yes na liu, 2016 [15] 2 (1/1) 1 (no + co) 1 (ni) 2 permanent no no/na kouno, 2017 [16] 85 (23/62) 29 (10 hg, 8 ni, 8 go, 7 pa, 6 sn, 5 co, 5 zn) 4(3 cr, 2 ir, 2 mo) 3 permanent na na misiak-galazka, 2018 [17] 39 (1/38) 12 (5 ni, 1 cr, 2 co, rest other allergens) 7/9 na na 27% + 5% family history na = not available; co = cobalt; cr = chromium; cu = copper; fe = iron; go = gold; hg = mercury; ir = iridium; mo = molybdenum; ni = nickel; pa = palladium; pt = platinum; sn = tin; zn = zinc. research | dermatol pract concept 2019;9(2):5 109 conclusions we believe that such findings cannot be ignored, making ppp a particular condition with a specific epidemiological presentation and with a precise genetic background but closely related to psoriasis, also in cases in which the role contact allergic reactions, mainly metal exposure, represents a key factor. of interest, the european rare and severe psoriasis expert network (eraspen) in 2017 agreed that there is insufficient evidence-based proof to support the classification of pustular psoriasis in 3 groups: ppp, generalized pustular psoriasis, and acrodermatitis continua of hallopeau. the association of ppp and psoriasis vulgaris remains in debate [28]. references 1. ashurst pj. relapsing pustular eruptions of the hands and feet. br j dermatol. 1964;76:169-180. 2. enfors w, molin l. pustulosis palmaris et plantaris: a follow-up study of a ten-year material. acta derm venereol. 1971;51(4):289294. 3. thomsen k, osterbye p. pustulosis palmaris et plantaris. br j dermatol. 1973;89(3):293-296. 4. fransson j, storgårds k, hammar h. palmoplantar lesions in psoriatic patients and their relation to inverse psoriasis, tinea infection and contact allergy. acta derm venereol. 1985;65(3):218-223. 5. pasić a, lipozencić j, kansky a, ben-ghazeil m. contact allergy in psoriatic patients with palmar and plantar lesions. acta derm venereol suppl (stockh). 1989;146:66-68. 6. nakayama h, nogi n, kasahara n, matsuo s. allergen control: an indispensable treatment for allergic contact dermatitis. dermatol clin. 1990;8(1):197-204. 7. nakamura k, imakado s, takizawa m, et al. exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene b4 in pustules. j am acad dermatol. 2000;42(6):1021-1025. 8. yiannias ja, winkelmann rk, connolly sm. contact sensitivities in palmar plantar pustulosis (acropustulosis). contact dermatitis. 1998;39(3):108-111. 9. griffiths ce, christophers e, barker jn, et al. a classification of psoriasis vulgaris according to phenotype. br j dermatol. 2007;156(2):258-262. 10. dantzig p. the role of mercury in pustulosis palmaris et plantaris. j occup environ med. 2003;45(5):468-469. 11. yanagi t, shimizu t, abe r, shimizu h. zinc dental fillings and palmoplantar pustulosis. lancet. 2005;366(9490):1050. 12. wen l, xu t, yin j. boils? or coils? lancet. 2008;372(9637):506. 13. song h, yin w, ma q. allergic palmoplantar pustulosis caused by cobalt in cast dental crowns: a case report. oral surg oral med oral pathol oral radiol endod. 2011;111(6):e8-e10. 14. ito t, mori t, fujiyama t, tokura y. dramatic exacerbation of palmoplantar pustulosis following strongly positive nickel patch testing. int j dermatol. 2014;53(5):e327-e329. 15. liu f, zhang m, lou y, et al. the spontaneous regression of palmoplantar pustulosis following removal of dental amalgams: a report of two cases. australas j dermatol. 2016;57(3):e93-e96. 16. kouno m, nishiyama a, minabe m, et al. retrospective analysis of the clinical response of palmoplantar pustulosis after after the extensive review we conducted, we can conclude that there is enough evidence to support some sort of association between ppp and metal allergies in a subgroup of patients; data regarding the improvement of ppp after allergen avoidance confirms such a link. unfortunately, the frequency of contact allergy among ppp patients that we were able to calculate needs to be considered with caution because of the presence of publication biases. in fact, several authors reported metal allergies as the cause of ppp or classified ppp as a reactive process or a form of allergy, ignoring the possible coexistence of psoriasis and forgetting the possibility that koebnerization (isomorphic response) that may occur in allergic contact dermatitis might explain the association of ppp with contact eczema [22]. exacerbation of ppp after metal patch test has been reported in 7 patients, with improvement in 2 cases after dental amalgam removal, confirming the trigger role of contact allergens [11]. moreover, the onset of pustular patch reactions has been described for more than 30 years [23]. such reactions have been particularly observed with metal compounds (nickel, chromium, mercury, arsenic) and halogens (iodine, fluoride) [23]. the new onset of pustules seems to directly correlate with concentration and vehicle of contact [21-25]. if we decide to ignore the available data that connect ppp to psoriasis and we consider the condition a reactive process to a contact allergy, the avoidance of the allergen will be our primary matter of contention, although nickel is very hard to avoid completely. several proven facts have brought some colleagues to consider ppp a condition separate from psoriasis: the female predominance in ppp, the strong association of ppp with smoking (much stronger than psoriasis vulgaris), the close relation to metal allergies, some genetic findings as the absence of association between ppp and psor1 locus and a higher expression of several genes involved in neural pathways (gprin and adam23) in ppp compared with psoriasis vulgaris, and the differences in the response to therapy between the 2 conditions [26]. there is a strong association between smoking and ppp, suggesting that smoking has a role in the pathogenesis of this disease. the reported prevalence of current or previous smoking among patients with ppp ranges from 42% to 100%. the mechanism through which smoking could contribute to ppp has not been established. proposed mechanisms have included effects of nicotine on sweat gland function or keratinocyte function (eg, nicotine-induced increase in keratinocyte cornification). in addition, differences in nicotine acetylcholine receptor staining patterns in ppp skin observed in a study of biopsy specimens taken from patients with ppp, healthy smokers, and healthy nonsmokers prompted consideration that an abnormal response to nicotine could contribute to inflammation [27]. 110 research | dermatol pract concept 2019;9(2):5 23. wahlberg je, maibach hi. sterile cutaneous pustules: a manifestation of primary irritancy? identification of contact pustulogens. j invest dermatol. 1981;76(5):381-383. 24. nielsen nh, menné t. allergic contact dermatitis caused by zinc pyrithione associated with pustular psoriasis. am j contact dermat. 1997;8(3):170-171. 25. bangsgaard n, engkilde k, thyssen jp, et al. inverse relationship between contact allergy and psoriasis: results from a patient and a population-based study. br j dermatol. 2009;161(5):1119–1123. 26. bissonnette r, suárez-fariñas m, li x, et al. based on molecular profiling of gene expression, palmoplantar pustulosis and palmoplantar pustular psoriasis are highly related diseases that appear to be distinct from psoriasis vulgaris. plos one. 2016;11(5):e0158190. 27. brunasso amg, massone c. palmoplantar pustulosis: epidemiology, clinical features, and diagnosis. available at: http://www. uptodate.com. accessed november 12, 2018. 28. navarini aa, burden ad, capon f, et al; eraspen network. european consensus statement on phenotypes of pustular psoriasis. j eur acad dermatol venereol. 2017;31(11):1792-1799. dental infection control and dental metal removal. j dermatol. 2017;44(6):695-698. 17. misiak-galazka m, wolska h, galazka a, kwiek b, rudnicka l. general characteristics and comorbidities in patients with palmoplantar pustulosis. acta dermatovenerol croat. 2018;26(2):109118. 18. brunasso am, puntoni m, aberer w, et al. clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study. br j dermatol. 2013;168(6):1243-1251. 19. brunasso am, massone c. can we really separate palmoplantar pustulosis from psoriasis? j eur acad dermatol venereol. 2010;24(5):619-621. 20. misiak-galazka m, wolska h, rudnicka l. what do we know about palmoplantar pustulosis? j eur acad dermatol venereol. 2017;31(1):38-44. 21. kubota k, kamijima y, sato t, et al. epidemiology of psoriasis and palmoplantar pustulosis: a nationwide study using the japanese national claims database. bmj open. 2015;5(1):e006450. 22. quaranta m, eyerich s, knapp b, et al. allergic contact dermatitis in psoriasis patients: typical, delayed, and non-interacting. plos one. 2014;9(7):e101814. dermatology: practical and conceptual research | dermatol pract concept 2019;9(2):6 111 dermatology practical & conceptual dermoscopy in the diagnosis of cutaneous leishmaniasis gamze serarslan1, özlem ekiz2, cahit özer3, gökhan sarıkaya4 1 mustafa kemal university, faculty of medicine, department of dermatology, hatay, turkey 2 medical park hospital, department of dermatology, ordu, turkey 3 mustafa kemal university, faculty of medicine, department of family medicine, hatay, turkey 4 magnet hospital, department of dermatology, kayseri, turkey key words: dermoscopy, leishmaniasis, vascular, cutaneous citation: serarslan g, ekiz ö, özer c, sarıkaya g. dermoscopy in the diagnosis of cutaneous leishmaniasis. dermatol pract concept. 2019;9(2):111-118. doi: https://doi.org/10.5826/dpc.0902a06 accepted: december 7, 2018; published: april 30, 2019 copyright: ©2019 serarslan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gamze serarslan, md, mustafa kemal university, faculty of medicine, department of dermatology, hatay, turkey. email: gserarslan@hotmail.com background: cutaneous leishmaniasis (cl) is a protozoan infectious disease. dermoscopy is a noninvasive diagnostic tool that has been applied to several skin diseases, including infestations. objectives: to determine the dermoscopic patterns of cl lesions and to investigate whether a relationship exists between dermoscopic characteristics and the disease duration, localization, and type of cl lesions. methods: seventy-nine patients (48 male, 31 female) from hatay, turkey, were enrolled in the study and a dermoscopic evaluation was performed on 139 lesions. images of cl lesions were taken via polarized light contact dermoscopy. chi-square and fisher exact tests were used for statistical analyses and p values <0.05 were considered significant. results: generalized erythema was seen in all cl lesions. vascular structures (94.2%), yellow tears (75.5%), and a white starburst-like pattern (58.3%) were the other most common dermoscopic features. hyperkeratosis (p = 0.001) and white starburst-like pattern (p < 0.001) were more prevalent in the extremities than elsewhere. among vascular structures, linear irregular (45.8%), hairpin (43.5%), and comma-shaped (25.9%) patterns were the most common dermoscopic findings. linear irregular (p = 0.023) and arborizing vessels (p = 0.001) were observed in the head-neck region. dotted (p = 0.009), hairpin (p < 0.001), and glomerular-like (p = 0.016) morphological findings were more prevalent in the extremities. statistical significances in disease duration were detected in microarborizing (p = 0.027) and arborizing (p = 0.004) vessels and were most prevalent with a disease duration of >6 months. hairpin vessels were prevalent in the plaque and nodulo-ulcerative type of lesions. dotted vessels were most commonly seen in the plaque type (47.4%) of lesions. conclusions: generalized erythema, yellow tears, and starburst-like patterns, as well as linear irregular, hairpin, comma-shaped, and arborizing vessels, were the most commonly detected dermoscopic features of cl lesions. we suggest that the presence of these features can be helpful when diagnosing cl lesions by dermoscopy. abstract 112 research | dermatol pract concept 2019;9(2):6 (mole max ii, derma instruments, vienna, austria; 20to 40-fold magnification). we applied 70% alcohol or water over the lesions before taking dermoscopic images. when taking the images, we applied minimal downward pressure to visualize the vascular structures. dermoscopic evaluation of vascular structures was based on previous reports in the studies of argenziano et al [7] and zalaudek et al [8]. the background color of lesions was evaluated and performed according to the study presented by lallas et al [3]. we also assessed the distribution of vascular structures in the cl lesions and categorized them into the following patterns: peripheral (observed predominantly at the periphery of the lesion), patchy (arranged in an asymmetrical distribution which could not be classified as clustered), central, regular (vessels distributed uniformly throughout the lesion), and cluster (aggregated in small groups) [3]. data were analyzed using spss for windows (version 13; spss inc., chicago, il, usa). values were given as mean ± standard deviation (sd) or frequency and percent. disease duration was dichotomized as ≤6 months or >6 months. the dermoscopic characteristics of the cl lesions were compared with the duration of the disease, the location, and the type of lesion using the chi-square and fisher exact tests. p values < 0.05 were considered significant. results demographic data one hundred thirty-nine cl lesions from 79 patients (48 male [60.76%], 31 female [39.24%]) were enrolled in the study. the mean age of the patients was 24.05 ± 18.89 (range, 2-85 years; median, 17 years) and the duration of the disease was 8.68 ± 20.63 (range, 1-240 months). the duration of the disease was ≤6 months in 54.4% of patients and >6 months in 45.6% of patients. the most frequent lesion localization was the head, followed by the upper and lower extremities. cl lesions were described as papular, nodular, nodulo-ulcerative, and plaque type. most of the lesions were nodules (42.4%). the details of the clinical and demographic characteristics of the patients and lesions are shown in table 1. dermoscopic findings general pattern the descriptive results of the dermoscopic analysis are shown in table 2. the fitzpatrick skin types of the patients were ii and iii. generalized erythema was seen in all cl lesions. the color of erythema was dusky red (33.8%), light red (43.9%), and yellowish red (22.3%) (figure 1). vascular structures (94.2%), yellow tears (75.5%), and white starburst-like pattern (58.3%) were the other most common dermoscopic features (figures 2 and 3). introduction cutaneous leishmaniasis (cl) is a protozoan infectious disease caused by the leishmania genus of flagellate protozoan, and the disease is widespread in most countries in the mediterranean basin, including turkey [1]. more than 70% of global cl cases occur in 10 countries (afghanistan, algeria, brazil, colombia, costa rica, ethiopia, islamic republic of iran, peru, sudan, and the syrian arab republic) [2]. dermoscopy is a noninvasive diagnostic tool that has been used in melanocytic lesions. dermoscopy has also been also used in several skin diseases, such as inflammatory skin disorders, hair disorders, and infestations [3]. although there have been a few studies about dermoscopic patterns of cl, there are conflicting results about the location, duration, type of lesions, and dermoscopic findings [4-6]. in this study, we aimed at determining the dermoscopic features of cl lesions and at investigating whether a relationship exists between the dermoscopic characteristics of cl lesions and the disease duration, localization, and type of lesion. in addition, the background color and distribution of vascular structures in the cl lesions were evaluated. methods this prospective study was performed at a tertiary care hospital in the region hatay, which is an endemic area for cl and located in the southern part of turkey. the study was conducted in accordance with the declaration of helsinki. the local ethics committee approved the study (approval number 010620122-06), and informed consent was obtained from all participants. a total of 79 patients (48 male, 31 female; age range 2-85 years), who were seen in the dermatology outpatient clinic and were diagnosed with cl, were included in the study. cl was diagnosed clinically, and the diagnosis was confirmed by a laboratory demonstration of the presence of the parasite in the smears obtained from the lesions. if the smear was negative, a histopathological examination was performed. identification of leishmania organisms in the histiocyte cytoplasm with giemsa staining was also considered as leishmania-positive. exclusion criteria were any cl treatment (topical, intralesional, or systemic) before recruitment to the study. full demographic details and history of the disease, including age, gender, duration of the disease, localization, and clinical type of the lesion, were recorded in a predesigned clinical record form for each patient. all cl lesions were evaluated following the diagnosis. the dermoscopic evaluation was performed by 2 clinicians (g.s., ö.e.). clinical and dermoscopic photographs of the lesions were performed with a polarized light contact dermoscopy research | dermatol pract concept 2019;9(2):6 113 with regard to localization of cl (p ≥ 0.05). dermoscopic structures including central erosion/ulceration (ce/u), white scar-like patch, yellowish hue, and salmon-colored ovoid, corkscrew, and crown were not included in the statistical analysis because of low rate of these features. hyperkeratosis was more prevalent in cl lesions with a disease duration of ≤6 months (p = 0.036). there were no statistically significant differences between the disease duration and color of erythema, hk+e/u, yellow tears, white starburst-like pattern, and milia (p ≥0.05). there was also no statistically significant difference between the disease duration and cl type (p = 0.605). the features, including ce/u, yellowish hue, salmon-colored ovoid, and white scar-like patch, were not included in the statistical analysis because of low rate of these features. vascular morphology linear irregular (45.8%), hairpin (43.5%), and commashaped (25.9%) patterns were the most common dermoscopic findings among vascular structures. vascular structures, including linear irregular, dotted, hairpin, arborizing, hyperkeratosis and white starburst-like pattern were more prevalent in the extremities than elsewhere (p = 0.001 and p < 0.001, respectively). however, there was no statistically significant difference in color of erythema, hyperkeratosis + erosion/ulceration (hk+e/u), yellow tears, and milia table 2. dermoscopic features in cl dermoscopic features n (%) general features erythema 139 (100) dusky red 47 (33.8) light red 61 (43.9) yellowish red 31 (22.3) hyperkeratosis 49 (35.3) ce/u 10 (7.2) hk+e/u 23 (16.5) yellow tears 105 (75.5) white starburst-like pattern 81 (58.3) white scar-like patch 7 (5.0) milia-like cyst 12 (8.6) yellowish hue 1 (0.7) salmon-colored ovoid 4 (2.9) vascular features 131 (94.2) comma-shaped 34 (25.9) linear irregular 60 (45.8) dotted 19 (14.5) hairpin 57 (43.5) arborizing 24 (18.3) corkscrew 5 (3.8) glomerular-like 28 (21.4) milky red globules/areas 15 (11.4) microarborizing 21 (16.0) crown 4 (3.0) table 1. clinical and demographic characteristics of the patients and lesions characteristics n (%) sex female 48 (60.7) male 31 (39.2) age (yrs), mean ± sd 24.05 ± 18.89 duration of disease, mean ± sd ≤6 months 43 (54.4) >6 months 36 (45.6) total no. of lesions 139 (100) no. of lesions 1 52 (65.8) 2 12 (15.2) 3 4 (5.1) 4 6 (7.6) 5 3 (3.8) 6 2 (2.5) type of lesion papular 20 (14.4) nodular 59 (42.4) nodulo-ulcerative 33 (23.7) plaque 27 (19.4) location of lesions face forehead 7 (5) periorbital region 3 (2.2) malar region 35 (25.2) ear 1 (0.7) nose 9 (6.5) lip 5 (3.6) chin 5 (3.6) neck 3 (2.2) upper extremities shoulder 3 (2.2) arm 31 (22.3) elbow 7 (5.0) hand 19 (13.7) lower extremities leg 5 (3.6) knee 1 (0.7) foot 5 (3.6) 114 research | dermatol pract concept 2019;9(2):6 linear irregular and arborizing vessels were observed in the head-neck localization in 60.0% and 79.2% of lesions, respectively, with a statistically significant difference (p = 0.023 and p = 0.001, respectively). dotted (78.9%), hairpin (70.2%), and glomerular-like (71.4%) morphology were more prevalent in the extremity localizations (p = 0.009, p < 0.001, and p = 0.016, respectively). there was no statistically glomerular-like, crown, and corkscrew types, were most commonly seen in the peripheral distribution. the distributions of vascular structures are shown in table 3. in 54.7% of lesions, there were 2 or more vascular structures, and most of the lesions were the nodular type (39.5%). hairpinlike vessels were most frequently combined with linear and glomerular-like vessels. table 3. distribution of vascular structures peripheral n (%) patchy n (%) central n (%) regular n (%) cluster n (%) total (n) comma-shaped 10 (29.4) 15(44.1) 4 (11.8) 1 (2.9) 4 (11.8) 34 linear irregular 29 (48.3) 14 (23.3) 4 (6.7) 10 (16.7) 3 (5.0) 60 dotted 10 (52.6) 4 (21.0) — 2 (10.5) 3 (15.8) 19 hairpin 24 (42.1) 17 (29.8) — 7 (12.3) 9 (15.8) 57 arborizing 20 (83.3) — — 4 (16.7) — 24 corkscrew 3 (60.0) 1 (20.0) 1 (20.0) — — 5 glomerular 15 (53.6) 9 (32.1) — 2 (7.1) 2 (7.1) 28 crown 3 (75.0) 1 (25.0) — — — 4 microarborizing 7 (33.3) 2 (9.5) — 12 (57.7) — 21 milky red areas 5 (33.3) 5 (33.3) 4 (26.7) — 1 (6.7) 15 figure 1. examples of background color with polarized light contact dermoscopy (plcd). (a) dusky red (plcd × 20). (b) light red (plcd × 40). (c) yellowish red (plcd × 30). [copyright: ©2019 serarslan et al.] a b c figure 2. (a,c) clinical picture of cl lesion. (b) dermoscopically lesion reveals yellow tears (plcd × 30). (d) yellow tears with central crust (plcd × 30). [copyright: ©2019 serarslan et al.] a b c d figure 3. (a,c) clinical features of leishmaniasis. (b,d) examples of starburst-like pattern (plcd × 20 and × 30). [copyright: ©2019 serarslan et al.] a b c d research | dermatol pract concept 2019;9(2):6 115 burst-like pattern (58.3%) were the most common dermoscopic features in cl lesions. similar to our study, llambrich et al [9], ayhan et al [4], and yücel et al [5] also reported that generalized erythema was present in all lesions. however, in their study, taheri et al [6] reported that generalized erythema was present in 81.9% of lesions and was more common in advanced and ulcerated lesions. we also detailed the color of erythema as dusky red (33.8%), light red (43.9%), and yellowish red (22.3%). we detected no significant differences in our analyses of the color of erythema and disease duration and localization. however, we detected that 45.5% of dusky red lesions were of the nodulo-ulcerative type, 63% of light red lesions were the plaque type, and 50% of yellowish red lesions were the papular type. yellow tear-like structures were the third most common dermoscopic finding in our study. these structures were observed both in the head-neck region (52.4%) and extremities (47.6%). although in several studies these structures have been reported only on the face and neck [4,5], in another study [6] extremities were reported to be the more prevalent localization. similar to other studies, in our study yellow tearlike structures were more common in lesions with a duration significant difference in comma-shaped, microarborizing, and milky red areas with regard to the localization of cl lesions (p ≥ 0.05). a statistically significant difference was detected only in microarborizing vessels with regard to the disease duration among vascular structures, which was more prevalent with the disease duration >6 months (p = 0.027). hairpin vessels were more prevalent in the plaque (n = 19) and nodulo-ulcerative (n = 19) type of lesions. more than half (53.3%) of the milky red areas were seen in the nodulo-ulcerative type of lesions. the majority of the nodular type of cl lesions presented comma-shaped, linear irregular, arborizing, microarborizing, and glomerular type of vessels. dotted vessels were most commonly seen in the plaque type (47.4%) of lesions. dermoscopic features according to the types of cl lesions are shown in table 4. examples of the vascular structures are shown in figure 4. discussion we detected that generalized erythema (100%), vascular structures (94.2%), yellow tears (75.5%), and white startable 4. dermoscopic features according to the types of cl lesions papule (n) plaque (n) nodule (n) nu (n) total (n) general features erythema 20 27 59 33 139 hyperkeratosis 3 19 23 4 49 ce/u 1 — 2 7 10 hk+e/u — 1 2 20 23 yellow tears 13 23 44 25 105 white starburst-like 2 23 27 29 81 white scar-like — 2 4 1 7 milia-like cyst 1 4 3 4 12 yellowish hue — — 1 — 1 salmon-colored ovoid — 1 3 — 4 vascular features comma-shaped 4 7 16 7 34 linear irregular 7 12 30 11 60 dotted — 9 3 7 19 hairpin 2 19 17 19 57 arborizing 2 2 15 5 24 corkscrew — 2 1 2 5 glomerular-like 5 7 9 7 28 milky red globules/areas 1 2 4 8 15 microarborizing 4 2 12 3 21 crown — 2 2 — 4 nu = nodulo-ulcerative. 116 research | dermatol pract concept 2019;9(2):6 of linear irregular vessels [4]. however, in another study, linear irregular vessels were reported to be more common in advanced lesions and not related to the lesion site [6]. comma-shaped vessels were seen mostly in the nodular type (47.1%) of lesions and were not related to the lesion site (head-neck, 52.9%; extremity, 47.1%) or duration of the disease. in our study, the distribution of comma-shaped vessels was mostly in the patchy pattern (44.1%). the prevalence of hairpin vessels has been reported to be between 17% and 43.5% in cl lesions. we found that hairpin vessels were more prevalent in the extremities and that these structures were more common in advanced lesions, but were not related to the lesion site. hairpin vessels were seen mostly in the plaque and nodulo-ulcerative type of lesions. other studies, including ayhan et al [4], llambrich et al [9], and yücel et al [5], also reported that extremities were the most common site and were observed in nodulo-ulcerative lesions. in contrast, taheri et al [6] reported that hairpin vessels were not related to the type of skin lesions. we differentiated arborizing structures as arborizing or microarborizing based on the study of zalaudek et al. microarborizing vessels represented a variation of arborizing vessels and were defined as linear straight/linear serpentine vessels with a small caliber [8]. the arborizing type of vascular morphology was most prevalent in the head-neck region. however, no statistical difference was detected for microarborizing vessels when comparing lesion sites. both structures were more frequent in the nodular type of lesions, and also both of these structures were common when the disease duration was >6 months. conclusions cl presents a variety of dermoscopic patterns that might cause difficulties during dermoscopic diagnosis. when we compared the most frequent first 5 findings for general dermoscopic and vascular features, we found that generalized erythema, yellow tears, and white starburst-like patterns, as well as and linear irregular, hairpin, comma-shaped, and of ≤6 months (58.1%) [5, 9]. these structures were seen mostly in the nodular type (41.9%) of lesions followed by the nodulo-ulcerative (23.8%), plaque (21.9%), and papule (12.4%) type. taheri et al [6] reported that these structures were more prevalent in ulcerated plaques. yücel et al [5] reported that yellow tear-like structures were observed more commonly in nodules. we detected that the white starburst-like pattern was more prevalent in the extremities localization and noduloulcerative type of lesions. in 61.7% of lesions, the disease duration was ≤6 months. yücel et al [5] reported that the white starburst-like pattern was observed more commonly in nodulo-ulcerative lesions and lesions with durations of 0-6 and 7-12 months. also, llambrich et al [9] detected that the white starburst-like pattern was more prevalent in the extremities. however, in another study, in contrast to our findings, these authors reported that this pattern was more prevalent in lesions older than 6 months and was related to nodular lesions [6]. vascular structures, including linear irregular (45.8%), hairpin (43.5%), and comma-shaped (25.9%) morphology, were the most common dermoscopic findings among vascular structures in our study. although previous studies reported conflicting results on these common vascular structures, most of them, including in our study, showed that linear irregular and hairpin vessels were the most common (table 5). we also evaluated the distribution of vascular structures in the lesions. as shown in table 3, most of the vascular structures were present in peripheral distribution. the linear irregular type of vascular morphology was more prevalent in the head-neck region. the linear irregular vascular morphology was seen mostly in the nodular (50.0%) and plaque (20.0%) type of lesions. the distribution of linear irregular vascular structure in the cl lesions represented peripheral (48.3%), followed by patchy (23.3%) and regular (16.7%). duration of the disease was ≤6 months in 34 (56.7%) lesions and >6 months in 26 (43.3%) lesions, and there was no statistical significance. similar to our study, the face has been reported to be the most common localization figure 4. vascular structures of cl lesions (plcd × 40). (a) arborizing vessels with peripheral distribution. (b) regularly distributed hairpin vessels. (c) microarborizing vessels. [copyright: ©2019 serarslan et al.] a b c research | dermatol pract concept 2019;9(2):6 117 2. who. leishmaniasis in high-burden countries: an epidemiological update based on data reported in 2014. wkly epidemiol rec. 2016;91(22):287-296. 3. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198-1205. 4. ayhan e, ucmak d, baykara sn, akkurt zm, arica m. clinical and dermoscopic evaluation of cutaneous leishmaniasis. int j dermatol. 2015;54(2):193-201. 5. yücel a, günasti s, denli y, uzun s. cutaneous leishmaniasis: new dermoscopic findings. int j dermatol. 2013;52(7):831-837. 6. taheri ar, pishgooei n, maleki m, et al. dermoscopic features of cutaneous leishmaniasis. int j dermatol. 2013;52(11):1361-1366. arborizing vessels, were associated with cl lesions in our study, as well as in most previous studies. therefore, we suggest that the presence of these parameters will help during the diagnosis of cl lesions by dermoscopy. we also think that dermoscopy can be used more reliably in the diagnosis of cl by comparing the dermoscopic features of the diseases with similar clinical appearances, such as other granulomatous diseases [10] and cutaneous b-cell lymphoma [11-13]. references 1. uz ok, balcıoğlu ic, taylan özkan a, ozensoy s, ozbel y. leishmaniasis in turkey. acta trop. 2002;84(1):43-48. table 5. dermoscopic features of cl in the 5 performed studies dermoscopic features llambrich et al [9] (n = 26) % taheri et al [6] (n = 144) % yücel et al [5] (n = 145) % ayhan et al [4] (n = 127) % current study (n = 139) % general features generalized erythema 100 81.9 100 100 100 yellow tears 53 41.7 40 42.5 75.5 white starburst-like pattern 38 60.4 19 8.6 58.3 hyperkeratosis 50 33.3 — 15 35.3 hk+e/u 38 — 35 — 16.5 milia-like cyst — 4.9 — 15.7 8.6 salmon-colored ovoid — — 13 15.7 2.9 ce/u 46 59 — 44.1 7.2 yellowish hue — 43.8 — — 0.7 perilesional hypopigmented halo — — 3 — — scar (white scar-like patch) — — — 17.3 5.0 pustules — — — 7.1 — crust — — — 70.1 — vascular features 100 87 90.6 94.2 glomerular-like vessels 7 22.9 17 3.1 21.4 hairpin vessels 19 37.5 17 39.4 43.5 linear irregular vessels 57 30.6 54 26 45.8 arborizing telangiectasia 11 10.4 37 38.6 18.3 crown-like vessels — — — 1.6 3.0 dotted vessels 53 61.1 16 24.4 14.5 comma-shaped vessels 73 29.9 4 19.7 25.9 polymorphous/atypical vessels 26 — 3 40.2 15.2 corkscrew vessels 7 4.2 — 3.1 3.8 strawberry pattern — — — 1.6 — milky red globules/areas — — — — 11.4 microarborizing — — — — 16.0 —not reported or evaluated. 118 research | dermatol pract concept 2019;9(2):6 11. piccolo v, russo t, agozzino m, et al. dermoscopy of cutaneous lymphoproliferative disorders: where are we now? dermatology. 2018;234(3-4):131-136. 12. piccolo v, mascolo m, russo t, staibano s, argenziano g. dermoscopy of primary cutaneous b-cell lymphoma (pcbcl). j am acad dermatol. 2016;75(4):e137-e139. 13. mascolo m, piccolo v, argenziano g, et al. dermoscopy pattern, histopathology and immunophenotype of primary cutaneous bcell lymphoma presenting as a solitary skin nodule. dermatology. 2016;232(2):203-207. 7. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors. arch dermatol. 2004;140(12):1485-1489. 8. zalaudek i, kreusch j, giacomel j, ferrara g, catriacala c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy, part i: melanocytic skin tumors. j am acad dermatol. 2010;63(3):361-374. 9. llambrich a, zaballos p, terrasa f, torne i, puig s, malvehy l. dermoscopy of cutaneous leishmaniasis. br j dermatol. 2009;160(4):756-761. 10. errichetti e, stinco g. dermoscopy of granulomatous disorders. dermatol clin. 2018;36(4):369-375. dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):7 43 dermatology practical & conceptual www.derm101.com introduction microcystic adnexal carcinoma (mac) is a rare malignant cutaneous neoplasm with pilar and eccrine gland differentiation. mac was first described as a separate clinical entity by goldstein et al in 1982 [1]. it is locally aggressive but rarely metastasizes, usually presenting as a slow growing asymptomatic lesion on the head and neck. mac arises from pluripotent keratinocytes that possess the capability for adnexal differentiation. predisposing factors include exposure to uv radiation, immunosuppression, and history of radiotherapy [2]. fewer than 300 cases have been reported worldwide, according to an analysis by yu et al [3]. case presentation a 67-year-old man presented to a primary care skin cancer clinic in melbourne, australia for a routine six-month skin cancer examination. there was a long history of recreational sun exposure. his brother had a history of melanoma of his thigh in his 40s. seven separate basal cell carcinomas had required excision from his forehead, nose, pinna, posterior neck, mid back calf in the last decade. most recently a moderately differentiated squamous cell carcinoma had been excised from his right upper forehead some six months previous. a whole body skin examination was undertaken with the aid of a heine delta 20 non-polarizing dermatoscope (heine optotechnik, herrshing, germany). digital clinical and dermatoscopic images were taken with a medicam 800 fotofinder non-polarizing camera (fotofinder systems gmbh, aichner, birnbach, germany), the dermatoscopy images being at 20x magnification. examination confirmed fitzpatrick skin type 2 with severe actinic damage to the skin of his face, upper trunk and distal limbs with multiple solar lentigines and actinic keratoses. significant actinic damage to the lower lip (actinic cheilitis) was apparent. microcystic adnexal carcinoma of the cheek— a case report with dermatoscopy and dermatopathology mike inskip1, jill magee2 1 sun patrol skin care cancer clinic, berwick, australia 2 dorevitch pathology, heidelberg, australia key words: dermatoscopy, dermoscopy, microcystic adenexal carcinoma citation: inskip m, magee j. microcystic adnexal carcinoma of the cheek—a case report with dermatoscopy and dermatopathology. dermatol pract concept 2015;5(1):7. doi: 10.5826/dpc.0501a07 received: october 5, 2014; accepted: october 15, 2014; published: january 30, 2015 copyright: ©2015 inskip et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. both authors have contributed significantly to this publication. corresponding author: dr mike inskip mbchb (uk) fracgp, sun patrol skin cancer clinic, 48 van der haar avenue, berwick, victoria 3806, australia. tel. (03) 9769 3358; fax. (03) 9769 3357. email. sunpatrol.scc@bigpond.com we present a case report of a microcystic adnexal carcinoma on the cheek of a 67-year-old man. clinical, dermatoscopic and dermatopathologic images are presented. a search of the literature has not discovered any previously published dermatoscopy images of microcystic adenexal carcinoma. abstract mailto:sunpatrol.scc@bigpond.com 44 observation | dermatol pract concept 2015;5(1):7 during the examination the patient pointed out a white, scar-like lesion on his mid left cheek measuring 8 x 4 mm in diameter. it was non-pigmented and was composed of a clearly demarcated flat white plaque (figure 1). dermatoscopically the lesion exhibited a dense white structureless area with fine linear branched blood vessels centrally. a notable feature was the white clods of variable diameter superiorly (figure 2). differential diagnosis included morphoeic or fibrosing basal cell carcinoma and desmoplastic trichoepithelioma [4]. eccrine syringoid carcinoma, a rare malignant cutaneous adnexal tumor, should also be included in the differential diagnosis [5]. an excisional biopsy was performed using an elliptical excision, and the specimen was submitted for assessment by a specialist dermatopathologist. histology examination of the histological sections revealed a deeply invasive dermal neoplasm composed superficially of keratin filled cysts with calcification, and in the underlying reticular dermis, of infiltrative aggregates of basaloid cells in slender strands and syringomatoid aggregates. these extended to the subcutis. there were areas suspicious for small nerve invasion present within the tumor. excision appeared complete. the differential diagnosis was between a microcystic adnexal carcinoma and a fibrosing basal cell carcinoma with follicular differentiation. immunohistochemical stains were performed. the lesion stained positively for ber-ep4. there was also strong ck15 positivity. cea stained some lumina within the lesion. this staining pattern, although not entirely specific, was more in favour of microcystic adnexal carcinoma than fibrosing basal cell carcinoma. ber-ep4 expression has been noted in 38% of microcystic adnexal carcinomas and 100% of basal cell carcinomas. however ck15 is expressed in 92% of microcystic adnexal carcinomas, whereas basal cell carcinomas are negative [6]. hence, in conjunction with the positive cea, the findings favoured a microcystic adnexal carcinoma (figures 3 to 11). figure 1. clinical image of a non-pigmented skin lesion on the left mid cheek of a 67-year-old man. [copyright: ©2014 inskip, magee.) figure 2. dermatoscopy showing a dense white structureless area with fine linear branched blood vessels centrally. note the white clods of variable diameter superiorly. (copyright: ©2014 inskip, magee.) figure 3. low power view demonstrates a poorly circumscribed, deeply invasive, infiltrative neoplasm, with superficial cyst formation and calcification, and a more morphoeiform desmoplastic deep component (copyright: ©2014 inskip, magee.) figure 4. intermediate power image shows superficial follicular differentiation with cysts and calcification, and more infiltrative deep component. (copyright: ©2014 inskip, magee.) observation | dermatol pract concept 2015;5(1):7 45 conclusion a search of the literature has not discovered any previously published dermatoscopy images of a microcystic adenexal carcinoma. the two most notable dermatoscopic features of the lesion we present were the dense white structureless area centrally and the white clods of variable diameter peripherally. white clods of this pattern have also been observed in the more common adnexal skin tumor trichoepithelioma and may represent keratin retention cysts [7]. microcystic adenexal carcinoma is currently considered a rare tumor. however, such rarities will present more often as the world population increases in age and has increased access to modern medicine. dermatoscopy is a relatively new diagnostic tool. the authors feel it is important to publish such dermatoscopic images as ours to as wide an audience as possible to aid clinical diagnosis in future. figure 5. intermediate power of superficial follicular keratin-filled cysts. (copyright: ©2014 inskip, magee.) figure 6. intermediate power of superficial follicular keratin-filled cysts. (copyright: ©2014 inskip, magee.) figure 7. high power of basaloid infiltrative aggregates in deeper portion of tumor .(copyright: ©2014 inskip, magee.) figure 8. focus of perineural invasion in deeper portion of tumor. (copyright: ©2014 inskip, magee.) figure 9. ber-ep4 stain is strongly positive. this finding is not specific as ber-ep4 is positive in basal cell carcinoma. one study showed berep4 positivity in 38% of microcystic adnexal carcinomas, 57% of desmoplastic trichoepitheliomas, 100% of basal cell carcinomas, and 38% of squamous carcinomas [6]. (copyright: ©2014 inskip, magee.) 46 observation | dermatol pract concept 2015;5(1):7 references 1. goldstein dj, barr rj, santa cruz dj. microcystic adnexal carcinoma: a distinct clinicopathologic entity. cancer 1982;50:566-72. 2. mckinley lh, seastrom s, hanly aj, miller ra. microcystic adnexal carcinoma: review of a potential diagnostic pitfall and management. cutis 2014;93(3):162-65. 3. yu jb, blitzblau rc, patel sc, et al. surveillance, epidemiology, and end results (seer) database analysis of microcystic adnexal carcinoma (sclerosing sweat duct carcinoma) of the skin. am j clin oncol 2010;33(2):125-27. 4. sánchez armendáriz k, toussaint caire s, gutiérrez mendoza d, fonte ávalos v. trichoepithelioma: a retrospective study 19932012—dr manuel gea gonzález general hospital. gac med mex 2014;150(1):96-100. [article in spanish.] 5. sidiropoulos m, sade s, al-habeeb a, ghazarian d. syringoid eccrine carcinoma: a clinicopathological and immunohistochemical study of four cases. j clin pathol. 2011;64(9):788-92. 6. hoang mp, dresser ka, kapur p, high wa, mahalingam m. microcystic adnexal carcinoma: an immunohistochemical reappraisal. mod pathol 2008;21(2):178-85. 7. mccoll i, dermoscopy made simple—adnexal tumours. 6 jan 2011. website. youtube.com. http://www.youtube.com/ watch?v=fytxm98nwjg. accessed oct 5, 2014. figure 10. cytokeratin 15 stain is also strongly positive. ck15 is a marker of the stem cells in the hair follicle bulge area. this finding favours microcystic adnexal carcinoma. hoang et al found 92% of mac and 100 % of desmoplastic trichoepitheliomata expressed ck15 whilst morphoeic bcc and squamous cell carcinomata were all negative. thus this is a helpful marker to distinguish mac from morphoeic bcc with adnexal differentiation [6]. (copyright: ©2014 inskip, magee.) figure 11. cea stain marks some of the ductular lumina within the aggregates. this is a marker of eccrine and apocrine ducts, which would favor microcystic adnexal carcinoma. (copyright: ©2014 inskip, magee.) http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed?term=sidiropoulos%20m%5bauthor%5d&cauthor=true&cauthor_uid=21642659 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed?term=sade%20s%5bauthor%5d&cauthor=true&cauthor_uid=21642659 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed?term=al-habeeb%20a%5bauthor%5d&cauthor=true&cauthor_uid=21642659 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed?term=ghazarian%20d%5bauthor%5d&cauthor=true&cauthor_uid=21642659 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/21642659 http://www.youtube.com/watch?v=fytxm98nwjg http://www.youtube.com/watch?v=fytxm98nwjg untitled letter | dermatol pract concept 2015;5(3):5 23 dermatology practical & conceptual www.derm101.com letter to the editor dear editor, giacomel, zalaudek and marghoob analyzed the different approaches of metaphoric and descriptive terminology in dermoscopy based on lessons from the cognitive sciences [1]. in our view, both approaches are used effectively daily and worldwide: • “blink” is the first, more metaphoric-based diagnosis at a glance for most of the lesions in our clinical setting (e.g., “arborizing” vessels or “spoke-wheel” pigmentation are the hint for a basal cell carcinoma, “strawberry” pattern for actinic keratosis). • “think” is the analytic procedure which starts when “blink” fails in describing a lesion and this mostly descriptive analysis then starts the process for a correct dermoscopic diagnosis. there is no doubt that for the metaphoric and descriptive based diagnoses, a simplified and clear, effective and universal dermoscopic language should be the basis in any clinical and scientific setting [1]. for the dermoscopy method, in teaching and in daily use, the question is not that either “blink” (more metaphoric) or “think” (more descriptive) is correct, but both methods could be applied effectively and should be complimentary. reference 1. giacomel j, zalaudek i, marghoob aa. metaphoric and descriptive teminology in dermoscopy: lessons from the cognitive sciences. dermatol pract concept 2015;5(2):11. metaphoric and descriptive terminology in dermoscopy: combine “blink” with “think” andreas blum1, giuseppe argenziano2 1 dermatology, public, private and teaching practice, konstanz, germany 2 dermatology unit, second university of naples, italy citation: blum a, argenziano g. [letter] metaphoric and descriptive terminology in dermoscopy: combine “blink” with “think”. dermatol pract concept 2015;5(3):5. doi: 10.5826/dpc.0503a05 copyright: ©2015 blum et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: andreas blum, md, public, private and teaching practice of dermatology, seestrasse 3a, 78464, konstanz, germany. tel. +49 7531 643 11; fax. +49 7531 600 54. e-mail: a.blum@derma.de mailto:a.blum@derma.de dermatology: practical and conceptual 174 observation | dermatol pract concept 2018;8(3):4 dermatology practical & conceptual www.derm101.com dermoscopy of a single plaque on the face: an uncommon presentation of cutaneous sarcoidosis claudio conforti1, roberta giuffrida2, mayara hamilko de barros3, fernanda simoes seabra resende4, lorenzo cerroni4, iris zalaudek1 1 dermatology clinic, maggiore hospital, university of trieste, trieste, italy 2 university of messina, department of clinical and experimental medicine, section of dermatology, messina, italy 3 charity hospital of rio de janeiro, institute of dermatology, rio de janeiro, brazil 4 department of dermatology, medical university of graz, graz, austria key words: plaque, cutaneous sarcoidosis, dermoscopy, inflammatory disease, face, granulomatous disease citation: conforti c, giuffrida r, hamilko de barros m, resende fss, cerroni l, zalaudek i. dermoscopy of a single plaque on the face: an uncommon presentation of cutaneous sarcoidosis. dermatol pract concept. 2018;8(3):174-176. doi: https://doi.org/10.5826/ dpc.0803a04 received: october 31, 2017; accepted: march 1, 2018; published: july 31, 2018 copyright: ©2018 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, università campus bio-medico (ucbm), via alvaro del portillo 200, 00128 rome, italy. email: claudioconforti@yahoo.com. case presentation a 43-year-old woman was referred to our skin cancer unit with a history of therapy-resistant actinic keratosis (ak), which had been treated by a practice-based dermatologist with topical isotretinoin and 3% diclofenac in 2.5% hyaluronic acid without improvement. clinically, the lesion appeared as a reddish, slightly scaling plaque 6 mm in diameter on the right temple (figures 1 and 2). the patient recalled the presence of the lesion for the past several months but denied any symptoms or history of trauma. the digital epiluminescence microscope system with polarized light (dermlite, 3gen, ×20) with immersion oil revealed whitish-yellow scales and whitish structureless areas on a yellow-orange background, with diffuse linear irregular vessels (figure 2). due to the yellow-to-orange color, which is typically seen in granulomatous diseases, the differential diagnosis included cs, lupus vulgaris (lv), and sarcoidosis is a multisystemic granulomatous disease of unknown causes, and cutaneous sarcoidosis (cs) is an early manifestation of the disease. dermoscopy has gained increasing interest in the past few years as an aid in the clinical diagnosis of inflammatory and infectious skin manifestations. we present a case report about a single, erythematous, and asymptomatic plaque on the face with unexpected dermoscopy characteristics of cs. learning points: • cs on the face of a therapy-resistant actinic keratosis should be considered a differential diagnosis. • dermoscopy can change the diagnosis and lead to the correct management. abstract observation | dermatol pract concept 2018;8(3):4 175 spective dermoscopic evaluation of the 7 cases of histologically confirmed cs. linear vessels overlying the translucent orange ovoid structures were the only vascular structures seen in all cases [4]. in line with this, vázquez-lópez et al evaluated the dermoscopic patterns in a large series of different nontumoral dermatoses; their series included 3 cases of cs, of which 2 lesions exhibited monomorphous linear vessels [5]. we also found linear vessels as the only vascular pattern in our case. histologically, cs shows noncaseating epithelioid granulomas, with minimal or absent lymphocytes or plasma cells (naked granuloma) [6]. inside giant cells, schaumann bodies and asteroid bodies may be found, although they are not specific. many of these features are not exclusively seen in cs and may also occur in infectious diseases, immunologic/ foreign body granulomas, neoplasia, immunodeficiency disorders, and drug eruptions. for this reason, sarcoidosis is one of the “great imitators” clinically and histopathologically, though its diagnosis is facilitated by dermoscopy. cutaneous leishmaniasis. a biopsy was performed. subsequent histopathology confirmed the suspected dermoscopic diagnosis of cs, showing noncaseating epithelioid granulomas (figure 3). blood tests showed a high level of angiotensin converting enzyme (ace) and antinuclear antibody (ana). the patient did not present with pulmonary involvement. discussion sarcoidosis is a multisystemic granulomatous disease of unknown causes. it may involve various tissues and organs, but the lungs, lymph nodes, eyes, and skin are commonly involved. cs is usually an early manifestation of the systemic disease. specific cutaneous manifestations of sarcoidosis are highly polymorphous, including solitary or multiple, red, yellow-brown or purple macules or papules, plaques, infiltrations, annular lesions, and subcutaneous nodules [1-3]. in past years, specific dermoscopic patterns of a variety of inflammatory and infectious skin disorders have been described, including some commonly considered cs in differential diagnosis [4,5]. pellicano et al [4] reported a retrofigure 1. clinical image of a single erythematous plaque on temple area. [copyright: ©2018 conforti et al.] figure 3. histology (×40) shows noncaseating epithelioid granulomas. [copyright: ©2018 conforti et al.] figure  2. dermoscopy (polarized ×20) exhibits whitish-yellow scales and  whitish structureless areas (red arrow) on a yellow orange background (black arrow), with diffuse linear irregular vessels. [copyright: ©2018 conforti et al.] 176 observation | dermatol pract concept 2018;8(3):4 management. am j clin dermatol. 2006;7(6):375-382. doi: 10.2165/00128071-200607060-00006. 2. elgart ml. cutaneous sarcoidosis: definitions and types of lesions. clin dermatol. 1986;4(4):35-45. doi: 10.1016/0738081x(86)90032-5. 3. fernandez-faith e, mcdonnell j. cutaneous sarcoidosis: differential diagnosis. clin dermatol. 2007;25(3):276-287. doi: 10.1016/j. clindermatol.2007.03.004. 4. pellicano r, tiodorovic-zivkovic d, gourhant jy, et al. dermoscopy of cutaneous sarcoidosis. dermatology. 2010;221(1):51-54. doi: 10.1159/000284584. 5. vázquez-lópez f, kreusch j, marghoob aa. dermoscopic semiology: further insights into vascular features by screening a large spectrum of nontumoral skin lesions. br j dermatol. 2004;150(2):226-231. doi: 10.1111/j.1365-2133.2004.05753.x. 6. wilson nj, king cm. cutaneous sarcoidosis. postgrad med j. 1998;74(877):649-652. doi: 10.1136/pgmj.74.877.649. conclusions in our patient, clinical features were indeed consistent with the diagnosis of ak. however, dermoscopy exhibited whitish structureless areas on a yellow-orange background associated with linear vessels, compatible with granulomatous skin disease. the dermoscopy findings changed the diagnosis from tumoral to granulomatous disease and led to the correct management. references 1. tchernev g. cutaneous sarcoidosis: the “great imitator”: etiopathogenesis, morphology, differential diagnosis, and clinical dermatology: practical and conceptual observation | dermatol pract concept 2018;8(1):14 59 dermatology practical & conceptual www.derm101.com introduction leopard syndrome (ls) is also known as gorlin syndrome ii, cardiocutaneous syndrome, lentiginosis profusa syndrome, moynahan syndrome, and more recently noonan syndrome with multiple lentigines (nsml). it is a rare autosomal dominant fully penetrant multisystemic disorder with characteristic features that include multiple lentigines and café au lait spots (l), electrocardiographic conduction defects (e), ocular hypertelorism (o), pulmonary stenosis (p), abnormalities of the genitalia (a), retardation of growth (r), and sensorineural deafness (d). patients usually do not present with all of these classical clinical features. patient with confirmed leopard syndrome developing multiple melanoma caroline colmant1, deborah franck1, liliane marot1, gert matthijs2, yves sznajer1,3, sandrine blomme4, isabelle tromme1,4 1 department of dermatology, cliniques universitaires saint-luc, université catholique de louvain, brussels, belgium 2 centrum menselijke erfelekheid, universitaire ziekenhuizen leuven, leuven, belgium 3 université catholique de louvain, brussels, belgium 4 king albert ii institute, cliniques universitaires saint-luc, université catholique de louvain, louvain-la-neuve, belgium key words: leopard syndrome, melanomas, dermoscopy citation: colmant c, franck d, marot l, matthijs g, sznajer y, blomme s, tromme i. patient with confirmed leopard syndrome developing multiple myeloma. dermatol pract concept. 2018;8(1)59-62: .doi: https://doi.org/10.5826/dpc.0801a14 received: august 29, 2018; accepted: november 13, 2018; published: january 31, 2018 copyright: ©2018 colmant et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr isabelle tromme, service de dermatologie, cliniques universitaires saint-luc, avenue hippocrate, 10, 1200 bruxelles, belgium. tel. 0032 2 764 1472. email: dermato@tromme.eu leopard syndrome, also known as gorlin syndrome ii, cardiocutaneous syndrome, lentiginosis profusa syndrome, moynahan syndrome, was more recently coined as noonan syndrome with multiple lentigines (nsml), inside the rasopathies. historically, the acronym leopard refers to the presence of distinctive clinical features such as: lentigines (l), electrocardiographic/conduction abnormalities (e), ocular hypertelorism (o), pulmonary stenosis (p), genital abnormalities (a), retardation of growth (r), and sensorineural deafness (d). this condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in ptpn11 gene. association of melanoma to nsml seems to be rare: to our knowledge, two patients so far were reported in the literature. we herein present a patient diagnosed with leopard syndrome, in whom molecular investigation confirmed the presence of the c.1403c>t mutation in exon 12 of the ptpn11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. three of the melanomas were achromic or hypochromic, three were in situ, and one had a breslow index under 0.5 mm. dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis. abstract mailto:dermato@tromme.eu 60 observation | dermatol pract concept 2018;8(1):14 allowed a complete excision, with melanoma in situ being still close to the lateral resection margins (< 2 mm). six months later, a new hyperpigmented and hypopigmented lesion appeared about 20 cm away from the last scar in the back (figure 2b). the clinical and dermoscopic features suggested another melanoma. that lesion also displayed some white lines with thickening at their crossings, alongside some more classic negative pigment network. due to the large dimensions of the lesion, several biopsies were performed. histopathology and immunostaining (pan-melanoma cocktail and hmb45) confirmed the diagnosis of lentigo maligna in situ with regression. although recommended treatment for in situ melanoma is excision with a 0.5 cm margin, the previous diffuse melanoma history led us to use the “slow-mohs,” also called the “spaghetti technique” [3], suggested by some teams for the treatment of lentigo maligna melanoma. this allowed us to achieve complete surgical excision of the lesion. six months later, we observed four new lesions suggestive of melanoma at dermoscopic examination (figure 3). on two of them we found white lines again. one of the lesions was a lentigo maligna; the others were atypical lentiginous hyperplasias. three of them were incompletely removed. so many melanomas and atypical lentiginous hyperplasias with infra-clinic extension led us to think about other ways to prevent the relapses of the lesions. we suggested the application of imiquimod 5 days a week for 8 weeks on the concerned lesions [4]. this was successful in preventing relapses as after a follow-up period of three years, no more doubtful lesions could be found. a missense mutation in the protein tyrosine phosphatase non-receptor type 11 (ptpn11) gene is identified in about 85% of the ls patients. ptpn11 encodes for the src homology 2 (shp-2), a cytoplasmic protein tyrosine phosphatase which regulates intracellular signaling of ras pathway downstream of receptors for growth factors, cytokines and hormones responsible for the development of nslm [1,2]. missense change in nslm is responsible for conformational switch that leaves the protein in an active state but with unexpected decreased phosphatase activity. we herein report a ls patient with multiple melanomas. case a 62-year-old man was referred to our clinic for a lesion of the upper foot, which had already been biopsied. pathologic examination showed mild atypical melanocytes. on physical examination, he had a high number of flat, brown to dark brown, small macules symmetrically distributed over a large portion of the skin, including the face. these had irregular borders and ranged in size from 1 mm in diameter to café-au-lait spots of several centimeters in diameter. some lentigines had been present at birth, but most of them occurred after the age of 3. the patient had a history of cryptorchidism surgery. electrocardiographic conduction defect at the age of 49 led to the diagnosis of sick sinus syndrome. there was no cognitive disorder or intellectual disability so far. the family history revealed similar findings: the patient’s mother had lentigines and died of a melanoma and one of the patient’s sisters had similar skin with associated cardiac abnormalities and partial deafness. the upper foot lesion (figure 1) was hypochromic and rough. dermoscopic examination showed numerous white structures and dotted vessels. after removal of the whole lesion, pathologic examination concluded in a superficial spreading melanoma arising on a nevus, clark’s level ii, breslow index 0.42 mm, and regression in the papillary dermis. after obtaining informed consent, direct sequencing of entire coding of ptpn11 gene was completed. the ptpn11 c.1403 c>t (p.t468m) mutation was identified, confirming ls. the same mutation was found in the patient’s sister. no access to parents’ dna was available. one year later, a new lesion appeared on the back. it was hypopigmented, well limited and slightly erythematous. dermoscopy showed a lot of white lines with unusual thickening at their crossings (figure 2a). pathologic examination of the clinically visible lesion revealed a lentigo maligna arising on a nevus with regression phenomenon. a large excision was performed, which was incomplete; however, a second excision with a 2 cm margin figure 1. first melanoma of the foot: clinical aspect and dermoscopical aspect. aspect of eczema. on dermoscopy, shiny white strands, dotted vessels and a structureless pink and brown-gray background (polarized dermoscopy, dermlite foto, [3gen, san juan capistrano, ca, usa]). pathology: superficial spreading melanoma developed on nevus, clark’s level ii, a breslow index of 0.42 mm, and regression phenomenon in the papillary dermis. [copyright: ©2018 colmant et al.] observation | dermatol pract concept 2018;8(1):14 61 figure 2. first and second melanoma of the back: clinical aspect and dermoscopical aspect. (a) first melanoma of the back: on dermoscopy white lines with thickening at their crossings (white arrows) (polarized dermoscopy, dermlite foto). pathology: lentigo maligna in situ arising on a nevus, with regression phenomenon. (b) second melanoma of the back: on dermoscopy, classic negative pigment network (black arrow); negative pigment network with thickening at the crossings of some white lines (white arrows) (polarized dermoscopy, dermlite foto). pathology: lentigo maligna with regression. . [copyright: ©2018 colmant et al.] figure 3. dermoscopy of the four last lesions (a) not well defined white lines, (b) and (c) signature pattern: in the negative pigment network, the white lines show thickening at their crossings (white arrows). (d) shiny white strands and dotted vessels (polarized dermoscopy dermlite foto). pathology: (a,) (b), (d) atypical lentiginous hyperplasia; (c) lentigo maligna. [copyright: ©2018 colmant et al.] 62 observation | dermatol pract concept 2018;8(1):14 in this patient. we could see that pattern both in polarized and non-polarized dermoscopy. this case report enhances the importance of careful skin examination in ls patients. references 1. sarkozy a, digilio mc, dallapiccola b. leopard syndrome, orphanet j rare dis. 2008,3:13. 2. lodish mb, stratakis ca. the differential diagnosis of familial lentiginosis syndromes, fam cancer. 2011;10(3):481-490. 3. gaudy-marqueste c, perchenet as, taséi am, et al. the “spaghetti technique”: an alternative to mohs surgery or staged surgery for problematic lentiginous melanoma (lentigo maligna and acral lentiginous melanoma). j am acad dermatol. 2011;64(1):113-118. 4. swetter sm, chen fw, kim dd, egbert bm. imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type. j am acad dermatol. 2015;72(6):1047-1053. 5. seishima m, mizutani y, shibuya y, et al. malignant melanoma in a woman with leopard syndrome: identification of a germline ptpn11 mutation and a somatic braf mutation. br j dermatol. 2007;157:1297-1299. 6. yu-pin cheng, hsien-yi chiu, tzu-lin hsiao, et al. scalp melanoma in a woman with leopard syndrome possible implication of ptpn11 signaling in melanoma pathogenesis. j am acad dermatol. 2013;69(4):e186-187. 7. lesinski gb. the potential for targeting the stat3 pathway as a novel therapy for melanoma. future oncol. 2013;9(7):925-927. 8. bard-chapeau ea, li s, ding j, et al. ptpn11 shp2 acts as a tumor suppressor. cancer cell. 2011;19(5):629-639. as a result of the multiple melanomas found in this patient and his positive family history, we looked for a mutation of the cdkn2a gene, which was not found. discussion we report the first case of a leopard patient with multiple melanomas. two previous leopard patients with melanoma have been described: a 62-year-old woman, who developed a melanoma with a somatic braf mutation on top of her germline ptpn11 gene mutation [5] and a 24-year-old patient who suffered from a scalp melanoma [6]. ls patients could present a higher risk for melanomas. indeed, it has been suggested that, although shp2, the protein encoded by ptpn11, acts usually as an oncogene, it could also, in specific cell types, act as a tumor suppressor [7]. this has been shown in hepatocellular carcinogenesis: deletion of shp2 promotes malignant transformation through the stat3 pathway [8]. stat3 pathway is also important in melanoma genesis, and deletion of ptpn11/shp2 could therefore promote survival of malignant cells, metastasis, angiogenesis and immune evasion [7]. on most of the melanomas we found a dermoscopic signature pattern: in the negative pigment network, the white lines showed thickening at their crossings. this pattern was very useful for diagnosing the clinically difficult melanomas http://www.ncbi.nlm.nih.gov/pubmed/?term=lesinski%25252525252520gb%2525252525255bauthor%2525252525255d&cauthor=true&cauthor_uid=23837753 http://www.ncbi.nlm.nih.gov/pubmed/23837753 http://www.ncbi.nlm.nih.gov/pubmed/?term=bard-chapeau%25252525252520ea%2525252525255bauthor%2525252525255d&cauthor=true&cauthor_uid=21575863 http://www.ncbi.nlm.nih.gov/pubmed/?term=li%25252525252520s%2525252525255bauthor%2525252525255d&cauthor=true&cauthor_uid=21575863 http://www.ncbi.nlm.nih.gov/pubmed/?term=ding%25252525252520j%2525252525255bauthor%2525252525255d&cauthor=true&cauthor_uid=21575863 http://www.ncbi.nlm.nih.gov/pubmed/21575863 dermatology: practical and conceptual observation | dermatol pract concept 2015;5(4):13 51 dermatology practical & conceptual www.derm101.com introduction dermoscopy is a non-invasive tool that allows us to recognize key structures of lichen planus, which is useful for its diagnosis, follow-up and prognosis. case reports case 1 a 50-year-old female patient with no relevant history was seen in the hospital due to a pruritic erythematous papule with months of evolution on the anterior side of her right lower limb associated with asymptomatic confluent whitish papules on buccal mucosa. two weeks later it had evolved with an eruption of pruritic violaceous plaques in the neck area. dermoscopy of the lesion on the patient’s thigh revealed small pinpoint vessels associated with whitish striations (projections) with a “fern leaf’ aspect on an erythematosus background (figure 1). pathological examination revealed: sawtooth acanthosis, orthokeratotic hyperkeratosis, hypergranulosis, hydropic degeneration of the basal layer, and band-like lymphocytic infiltrate compatible with lichen planus. case 2 a 36-year-old female patient, with no medical history, sought medical attention due to multiple alopecic areas on the scalp of uneven distribution, erythema and follicular plugging. a trichoscopy revealed multiple irregular cicatricial alopecic areas with perifollicular whitish-gray scaling associated dermoscopic findings in different clinical variants of lichen planus. is dermoscopy useful? paula friedman1, emilia cohen sabban2, carolina marcucci3, rosario peralta3, horacio cabo2 1 department of dermatology, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina 2 dermatology, buenos aires, argentina key words: lichen planus, dermoscopy citation: friedman p, cohen sabban e, marcucci c, peralta r, cabo h. dermoscopic findings in different clinical variants of lichen planus. is dermoscopy useful? dermatol pract concept 2015;5(4):13. doi: 10.5826/dpc.0504a13 received: may 21, 2015; accepted: september 17, 2015; published: october 31, 2015 copyright: ©2015 friedman et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: paula friedman, md, 2562 arcos st, 2nd floor, buenos aires, argentina. tel. +0541158406476. email: paufriedman@gmail.com lichen planus (lp) is a papulosquamous dermatosis that involves the skin, scalp, nails and mucous membranes. although its pathogenesis is still unknown, there is evidence that an imbalance of immunologic cellular reactivity plays an important role. histopathologic examination reveals characteristic interface dermatitis. dermoscopy is a non-invasive tool, useful in the assessment of inflammatory dermatoses, such as lichen planus. in this paper we describe the dermoscopic findings of different variants of lp (ungual, cutaneous, planopilaris, pigmentosus). abstract 52 observation | dermatol pract concept 2015;5(4):13 mycological exam, x-ray of both hands, routine laboratory tests and hbv, hcv and hiv serologies were unremarkable. pathological examination of the nail bed and plate (protocol 133239, dr. casas) revealed: hyperkeratosis, parawith erythema, arboriform vessels, absence of follicular openings, and follicular plugging (figures 2, 3). pathological examination (protocol 14-03006, dr. calb) revealed: hair follicles with vacuolar degeneration of follicular wall basal cells and numerous perifollicular lymphocytes; the histological image was compatible with lichen planopilaris. case 3 a 59-year-old male patient with no medical history was seen in the hospital due to an active and progressive onychodystrophy of the first, fourth and fifth fingers of both hands, and the third finger of the left hand, of 1 year’s evolution. within the nail, there was pterygium, thinning, and destruction of the nail plate, longitudinal ridging, fissuring, onycholysis and subungual hyperkeratosis. the rest of the physical examination was unremarkable (figure 4). on dermoscopy, we observed chromonychia, subungual hyperkeratosis, onycholysis, and destruction of the nail plate (figure 5). figure 1. leaf venation pattern. white pearly structures corresponding to ws with arboriform projections of “fern leaf” aspect (arrow), erythematous globules at their edges (circle). [copyright: ©2015 friedman et al.] figure 2. absence of follicular openings (circle), erythema, perifollicular scales (arrow). [copyright: ©2015 friedman et al.] figure 3. absence of follicular openings (circle), whitish-gray scales (arrow), arboriform vessels (star). [copyright: ©2015 friedman et al.] figure 4. (a & c) destruction of nail plate; (b) fissuring, thinning, fragility, longitudinal ridging; (d) chromonychia, trachyonychia. [copyright: ©2015 friedman et al.] figure 5. (a) destruction of nail plate; (b) onycholysis; (c) subungual hyperkeratosis; (d) chromonychia. [copyright: ©2015 friedman et al.] observation | dermatol pract concept 2015;5(4):13 53 discussion cutaneous lichen planus the classic skin lesion consists of a flat-topped polygonal papule that is slightly erythematous to violaceous. a thin and adherent scale can be observed on top of it. on the surface there are reticular or pinpoint whitish structures, known as wickham striae (ws), pathognomonic of this entity [1]. dermoscopy findings consist of polymorphic pearly whitish structures that correspond to ws with arboriform “fern leaf” projections. at the borders linear vessels (radial capillaries) and erythematous globules may be observed (figure 1), ws dermoscopic patterns [2] (table i): • reticular (the most common) • circular • radial streaming • leaf venation: characterized by delicate secondary striae branching from the centered ws venation, linked together at either end, mimicking the crystal structure of snow • starry sky/white dots: clustered, follicular white dots at dermoscopy, the ws is the diagnostic key to differentiate lichen planus from other entities such as the pityriasis rosea and psoriasis [3,4,5]. lichen planopilaris lichen planopilaris (lpp) is characterized by keratotic follicular papules that coalesce, forming plaques. at the final stage, the scalp shows multiple cicatricial alopecic areas with irregular aspect, perifollicular erythema and absence of follicular openings with follicular plugging [6]. trichoscopy reveals multiple irregular cicatricial alopecic areas with perifollicular whitish-gray scaling associated with erythema, arboriform vessels, absence of follicular openings and follicular plugging (figures 2, 3). dermoscopic findings vary according to the stage of evolution and the degree of disease activity. in early stages, perifollicular inflammation leads to the appearance of whitish-gray scales (peripilar casts) associated with perifollicular erythema, characterized by the presence of arboriform veskeratosis, focal hypergranulosis, and inflammatory activity, consisting of band-like lymphocyte infiltration that involved the epithelial connective interface, compatible with lichen planus of the nail bed. case 4 a 59-year-old female patient with no medical history sought medical attention since she had bilateral brownish-violet macules localized to her armpits and groin that had evolved over years. they exhibited a lighter center, had well-defined limits, and were 0.5 to 1 cm in diameter. they were slightly itchy. there was no nail or mucous involvement. the dermoscopy image revealed a mixed pattern, characterized by brownish-gray dots with diffuse brownish areas (figure 6). pathological examination (protocol 14-06238, dr. calb) revealed hyperkeratosis, hypergranulosis, acanthosis, interpapillary ridges of irregular outline, vacuolated basal cell with juxtaposed lymphocytes, colloid bodies in the epidermis. the superficial dermis revealed melanophages and band-like lymphocytic infiltrate compatible with lichen planus. figure 6. mixed pattern: blue, gray, brown dots (arrow). brownish structureless areas (circle). [copyright: ©2015 friedman et al.] 54 observation | dermatol pract concept 2015;5(4):13 nail lichen planus the clinical manifestations of nail lichen planus are thinning, fragility, and destruction of the plate nail, longitudinal ridging, fissuring, onycholysis, trachyonychia, chromonychia and subungual hyperkeratosis [10] (figure 4). dermoscopy findings demonstrate the compromise of the matrix that leads to the thinning and consequent fragility of the nail plate with fissuring, pitting, and its progression to trachyonychia, longitudinal ridging, dorsal pterygium, erythematous patches in the lunula, eritronychia, melanonychia and atrophy. sels. in lpp, the inflammatory phenomenon usually affects the hair follicles in a selective manner with respect to the interfollicular epidermis (this sign helps its differentiation from other causes of cicatricial alopecia, such as chronic discoid lupus) [7,8]. in the fibrotic stage, whitish or milky-red areas are observed, covered by “classic irregular whitish dots” (fibrous tracts as a result of a variable loss of follicular units). additionally, there are blue-violet areas and blue-gray dots reflecting perifollicular incontinentia pigmenti [9] (table ii). the compromise in the nailbed would explain the subungual hyperkeratosis, chromonychia and the onycholysis [11] (figure 5) (table iii). lichen planus pigmentosus inversus lichen planus pigmentosus inversus is an uncommon variant of lichen planus pigmentosus involving predominantly folds, characterized by the presence of well-defined, brownish-purple oval macules, whose size varies from few millimeters to several centimeters and which may adopt a linear configuration. the lesions tend to be bilateral and asymptomatic, although some patients report mild pruritus. they heal belatedly, leaving an area of atrophic and hyperpigmented skin [12]. dermoscopic patterns (table iv): • diffuse: characterized by diffuse, structureless, brownish areas probably associated with epidermal pigmentation • dotted: fine or coarse gray-blue or brown dots or globules related to dermal melanophages • mixed: combining diffuse brownish areas with dotted structures dermoscopic findings are of prognostic value, since those lesions with a dotted pattern tend to be persistent because the pigment is localized deeper [13]. conclusion we describe the key dermoscopic findings of lichen planus and the different clinical variants, highlighting that dermoscopy can improve the diagnosis and follow-up of patients with this dermatosis. references 1. sharma a, bialynicki-birula r, schwartz r. lichen planus: an update and review. cutis. 2012;90:17-23. 2. tan c, min zs, xue y, zhu wy. spectrum of dermoscopic patterns in lichen planus: a case series from china. j cutan med surg. 2014:18(1):28-32. observation | dermatol pract concept 2015;5(4):13 55 9. rudnicka l, olszewska m, rakowska a, slowinska m. trichoscopy update 2011. j dermatol 2011;5(4):82-8. 10. goettmann s, zaraa i, moulonguet i. nail lichen planus: epidemiological, clinical, pathological, therapeutic and prognosis study of 67 cases. j euro acad dermatol venereol. 2012;26:1304-9. 11. nakamura r, broce aa, palencia d, ortiz ni, leverone a. dermatoscopy of nail lichen planus. int j dermatol. 2013;52:684-7. 12. gomez b, huerta salazar cm, lopez s, romano s, lorenz am. liquen plano pigmentado: a proposito de un caso y revisión de literatura. arch argent dermatol. 2012; 62:102-5. 13. vázquez-lópez f, maldonado-seral c, lópez-escobar m, pérezoliva n. dermoscopy of pigmented lichen planus lesions. clin and exp dermatol. 2003;28:554-5. 3. vásquez-lópez f, gómez-diez s, sánchez j. dermoscopy of active lichen planus. arch dermatol. 2007;143(8):1092. 4. zalaudek i, argenziano g. dermoscopy subpatterns of inflammatory skin disorders. arch dermatol. 2006;142(6):808. 5. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br. j dermatol. 2012;166(6):1198-205. 6. tosti, a. lichen planopilaris. in: tosti a (ed.) dermoscopy of hair and scalp disorders with clinical and pathological correlations. london: informa healthcare, 2007:98-104. 7. sánchez dueñas l. dermatoscopía en enfermedades del pelo y la piel cabelluda. dermatol rev mex. 2012;56(3):187-92. 8. tosti a, duque-estrada b. dermoscopy in hair disorders. j egypt women dermatol soc. 2010;7:1-4. dermatology: practical and conceptual review | dermatol pract concept 2019;9(4):2 253 dermatology practical & conceptual dermoscopy update: review of its extradiagnostic and expanding indications and future prospects sidharth sonthalia1, paola pasquali2, mahima agrawal3, poonam sharma4, abhijeet k. jha5, enzo errichetti6, aimilios lallas7, virendra n. sehgal8 1 skinnocence: the skin clinic & research centre, gurugram, india 2 department of dermatology, pius hospital de valls, tarragona, spain 3 department of dermatology & std, lhmc & associated hospitals, new delhi, india 4 skin institute & school of dermatology (sisd), new delhi, india 5 department of dermatology & std, patna medical college & hospital, patna, india 6 institute of dermatology, university hospital santa maria della misericordia, udine, italy 7 first department of dermatology, aristotle university, thessaloniki, greece 8 department of dermatology, sehgal nursing home, new delhi, india key words: dermoscopy, trichoscopy, onychoscopy, clinico-dermoscopic correlation, dermatopathology-dermoscopic correlation, teledermoscopy citation: sonthalia s, pasquali p, agrawal m, sharma p, jha ak, errichetti e, lallas a, sehgal vn. dermoscopy update: review of its extradiagnostic and expanding indications and future prospects. dermatol pract concept. 2019;9(4):253-264. doi: https://doi.org/10.5826/ dpc.0904a02 accepted: july 7, 2019; published: october 31, 2019 copyright: ©2019 sonthalia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sidharth sonthalia, md, dnb, mnams, skinnocence: the skin clinic & research centre, c-2246, sushant lok-1, block-c, gurugram 122009, india. email: sidharth.sonthalia@gmail.com the technique of dermoscopy has come a long way since its inception for characterization of suspicious nevi for early detection of dysplastic changes in predisposed individuals. not only has its scope expanded to aid in quick diagnosis of a majority of nonmelanocytic disorders of the skin, hair, and nails, but it is being rightfully exploited for a plethora of nondiagnostic uses. its use in the diagnosis of various pigmentary, papulosquamous, and infectious disorders and disorders of the scalp and hair, nails, and mucosa bears testimony to the ongoing expansion of its protean indications across skin types. dermoscopy has transformed the conventional approach to dermatological diagnosis from clinicopathological correlation to clinico-dermoscopic-pathological correlation. it aids in convincing an otherwise reluctant patient to agree to biopsy and guides the selection of optimum site for the same. dermoscopic clues suggestive of stability or activity of the lesion and/or disease in various dermatoses are being accrued. early assessment of therapeutic response to treatment is helpful for physicians, patients, and researchers conducting clinical studies. aesthetic uses of dermoscopy are opulent and being explored. dermoscopy has also provided the much-needed balancing act of interaction between practitioners and the new generation of patients. last but not the least, dermoscopy has resulted in patients’ better understanding of their disorders and improved compliance with treatment protocols. abstract 254 review | dermatol pract concept 2019;9(4):2 introduction since the inception of dermoscopy, hitherto envisaged to evaluate suspicious nevi and noninvasively detect changes in melanocytic lesions of white-skinned individuals, the technology and its applications have come a long way. the diagnostic scope has expanded to practically every disorder of the skin and its appendages. the technology is now being rightfully exploited for its additional nondiagnostic uses [1,2]. internet and social media have induced a huge change in patients’ attitude toward health care. dermatologists are confronted with the challenge of treating a wider spectrum of patients, from the presumed highly assertive health-seeking individuals to those still consumed by archaic sociocultural beliefs. for each of these individuals, dermatologists need to deal with a different set of biases and expectations. the versatility of the dermatoscope is indeed fostering the dermatologist’s need to maintain and fine-tune the cardinal balance between the science and art of practicing dermatology. in this review, we shall discuss the plethora of uses of dermoscopy, with special reference to the versatility of the technique including its applications beyond diagnosis. impact of the publication spree p u b l i c a t i o n s i n i n d e x e d j o u r n a l s addressing “dermoscopy”/”dermatoscopy” have shown a constant upward trend as depicted in table 1. although we employed a rather crude method for these statistics (explained in table 1 footnotes), the figures offer a fair hint about the increase in awareness with regard to using and publishing about this technique. diagnostic applications of dermoscopy: advancing and evolving in the past few years, this technique has been successfully explored for diagnosis of various skin, scalp, and nail disorders [3]. subspecialties such as pigmentaroscopy, inflammoscopy (papulosquamous disorders), entodermoscopy (infections and infestations), trichoscopy (scalp and hair), onychoscopy (nails), and mucoscopy are branching out within the broad ambit of dermoscopy. although histopathology remains the current gold standard of cutaneous diagnosis, dermoscopy and other noninvasive techniques have revolutionized the approach to diagnosis of cutaneous disorders. dermoscopy has expanded from its original use (observation–pattern recognition– diagnosis) to other applications listed in table 2. dermoscopy and skin biopsy patient counseling, dermoscopyinduced biopsy, and the psychological realm of the dermatoscope: stethoscope of the dermatologist skin biopsy, despite its exigency in many situations, is sometimes refused by the patient on various premises. facial lesions assume a special significance in this context. despite the appearance of a biopsy-worthy and otherwise distressing lesion/pigmentation on the face, table 1. gross estimate of the trend of publications addressing “dermoscopy” and “dermatoscopy” time period no. of publicationsa jan 2015-dec 2017 1,173 jan 2012-dec 2014 2,029 jan 2009-dec 2011 1,010 jan 2006-dec 2008 574 jan 2003-dec 2005 268 athe figures (number of publications) have been derived from a single portal (www.ncbi.nlm.nih.gov/pubmed/), using the search key words “dermoscopy” and “dermatoscopy” and applying timed filter under “publication dates.” table 2. major extradiagnostic applications of dermoscopy dermoscopy and skin biopsy • patient counseling, dermoscopy-induced biopsy, and the psychological realm of the dermatoscope, akin to the stethoscope of an internist • from clinicopathological correlation to clinico-dermoscopic-pathological correlation • dermoscopy-guided biopsy and the role of ex-vivo dermoscopy in processing of histopathological samples dermoscopy as a diagnostic enhancer and monitoring tool • defining lesional or disease activity/instability • defining adequate margins for surgical excision of tumors • early assessment of therapeutic response and disease stabilization • enhancing accuracy of reading patch test and pathergy test results • therapeutic efficacy evaluation in clinical studies expanding the realm of dermoscopy applications • ”cosmetic wart mapping” • aesthetic applications of dermoscopy • detection of intra/subcutaneous foreign bodies and retained sutures teledermoscopy psychosocial significance • the dermatologist’s tool in the era of social media empowerment of patients • a professional highlight for dermatologists • the dermatologist’s stethoscope review | dermatol pract concept 2019;9(4):2 255 inflammation at the dermoepidermal junction, basal cell degeneration, and colloid bodies (figure 2b). however, a single lesion, atypical morphology, and lack of mucosal involvement were clinical pointers against lp. dermoscopic evaluation revealed light brown pseudonetworks, overlapping pinkish areas, and multiple dark brown to blue-gray dots and globules (figure 2c), with characteristic absence of wickham striae. the dermoscopic features not only ruled out lp, but were characteristic of an early inflammatory lesion of lp-like keratosis [4]. thus, an unconvincing clinicopathological diagnosis of lp was revised and confirmed to be lp-like keratosis on clinico-dermoscopic-pathological correlation. thus, despite histopathology remaining the gold standard for diagnosis of skin disorders, cutaneous diagnosis is trending from clinicopathological correlation to clinico-dermoscopic-pathological correlation [1,2]. cicatricial alopecias, especially discoid lupus erythematosus (dle) and lichen plano pilaris, have a considerable overlap in their histology, especially in the late stage of the disease [5-8]. appendageal loss and replacement with fibrotic tissue, vacuolar degeneration, interface dermatitis, and perifollicular infiltrate are common to both [6,7]. although the inflammatory gitudinal melanonychia being dreaded to suggest subungual melanoma. finally, the dermatoscope is in essence the stethoscope of the dermatologist (vide infra). the majority of skin and hair disorders are chronic and recurring, with many being recalcitrant to treatments. examining a lesion with a dermatoscope and discussing the images with the patient can help in the overall management of the disorder. from clinicopathological correlation to clinicodermoscopic-pathological correlation dermoscopists are sometimes faced with situations in which the clinicopathological diagnosis is revised after dermoscopic inputs are considered. for example, a 60-year-old, otherwise healthy man presented with a single, asymptomatic light brown plaque of 2 years’ duration over the lower abdomen. examination revealed a solitary, ovalshaped, 3× 4-cm, sharply demarcated annular plaque over the lower right side of the anterior abdomen that had a violaceous-to-brown central region and raised erythematous borders (figure 2a). histopathology suggested lichen planus (lp) with mild hyperkeratosis, hypergranulosis with flattening of rete ridges, max-joseph space formation, dense bandlike lymphohistiocytic facial biopsy is often not acceptable by the patient due to concerns of potential scarring. in such commonly encountered situations, dermoscopy helps in multiple ways. used judiciously, dermoscopy can foster doctor-patient communication and improve patient compliance and overall management of the disorder. demonstration of the dermoscopic image to the patient (as per the dermatologist’s discretion) and limited but tactful conversation regarding the visible features can allay the patient’s curiosity to understand the pathogenesis of his or her dermatoses. in addition, patients who warrant a skin biopsy but refuse it owing to procedure-related anxiety are more inclined to consent after having been shown the dermoscopic image with emphasis on disease-specific features. in our own experience, since we started using dermoscopy for every patient, we have observed >90% success in convincing a reluctant patient to consent to a biopsy, a concept we call “dermoscopy-induced skin biopsy” [1]. dermoscopy can also be used to reassure a patient who fears having a condition that requires a biopsy and instead has a benign condition, eg, idiopathic guttate hypomelanosis and/or extragenital lichen sclerosus atophicus perceived as vitiligo (figure 1), or racial benign lonfigure 1. lesions of idiopathic guttate hypomelanosis and extragenital lichen sclerosus atrophicus over the forearm of a 45-year-old woman. (a) clinical picture of multiple discrete “confetti” hypopigmented macules over the forearm that made the patient anxious that she was suffering from vitiligo or leprosy. (b) dermoscopy confirming the diagnosis of idiopathic guttate hypomelanosis with concomitant evolving lesions of extragenital lichen sclerosus atrophicus. ameboid and nebuloid variants of idiopathic guttate hypomelanosis arranged in a “cloudy sky” pattern. additionally, note the scattered white structureless areas with comedo-like plugs typical of lichen sclerosus atrophicus. dermoscopy-guided biopsy of 2 lesions confirmed dermoscopic diagnosis. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; ×20.) [copyright: ©2019 sonthalia et al.] 256 review | dermatol pract concept 2019;9(4):2 is often required in later stages, for which the disease and the lesion should be “stable.” we have encountered several cases of failure of vitiligo surgery, despite the patient’s meeting the clinical criterion of stability of lack of any new lesions and/or worsening of existing lesions for at least 6 months to 2 years. some of us (s.s., a.k.j., a.l.) have recently reported certain dermoscopic features highly suggestive of stability of vitiligo lesions that may serve as valuable adjuvant markers in qualification of the patient as a suitable candidate for surgery [17,18]. in our observation, perifollicular depigmentation, marginal hyperpigmentation, and presence of leukotrichia are suggestive of lesional stability (figure 3a). an altered pigment pattern, perifollicular pigment retention, and certain specific features such as starburst appearance, comet tail sign, and “tapioca sago” appearance (figure 3b) are suggestive of disease activity [17,18]. more recently, in vitiligo lesions treated surgically with micropunch grafting, we have described dermoscopic features that may serve as possibly the earliest prognostic markers of surgical outcome [19]. another example is that of perifollicular erythema on trichoscopy as a well-established marker of active/ enous ochronosis), collection of nail scrapings for mycological testing, and skin tumors, among others [10-15]. dermoscopy has recently been reported to contribute further to the accuracy of histopathological diagnosis. dermoscopy-guided histological sectioning of the biopsy tissue has been shown to optimize the sectioning of melanocytic neoplasms [15]. this principle of adapted sectioning employing ex-vivo dermoscopy may be combined with derm-dotting (marking a dermoscopically suspicious area of the specimen with nail varnish) to allow more accurate and less time-consuming histopathological diagnosis of skin tumors in a dermatopathology setting [16]. dermoscopy as a diagnostic enhancer and tool for monitoring disease activity defining lesional or disease activity/instability in chronic dermatoses with a relapsing-remitting course, the disease and/ or lesional activity assumes importance when a specific intervention is being considered. prototypically, in vitiligo medical treatment remains the primary approach but surgical repigmentation infiltrate is deeper in dle, this feature is often insufficient for a confident diagnosis of dle. furthermore, the interpretation of a scalp biopsy sample is highly dependent on the site from which it is obtained. the cost and logistics of direct immunofluorescence often override the technique’s utility in differentiation of the 2 conditions. trichoscopy dramatically simplifies this issue because classic lichen plano pilaris, scalp dle, and frontal fibrosing alopecia have distinctive trichoscopic features [6,8]. dermoscopy-guided biopsy and the role of ex-vivo dermoscopy in histopathology processing the dermatopathologist’s efficiency in providing a straightforward, confident diagnosis is highly dependent on various factors from the site selection, adequacy of biopsy sample, and details filled in the pathology requisition form [9]. dermoscopy helps in selection of the optimum site for biopsy, which increases the likelihood of a definitive histopathological diagnosis instead of reporting of nonspecific features by the pathologist. this concept of “dermoscopy-guided skin biopsy” has been reported to be advantageous in cicatricial alopecias, vasculitis, facial melanosis (eg, patient with melasma with concomitant exogfigure 2. clinico-dermoscopic-pathological correlation. (a) single, light brown, oval-shaped annular plaque over the lower anterior abdomen. (b) histopathology suggestive of lichen planus, revealing mild hyperkeratosis, hypergranulosis with flattening of rete ridges, max-joseph space formation, dense bandlike lymphohistiocytic inflammation at the dermoepidermal junction, basal cell degeneration, and colloid bodies (h&e, ×400). (c) dermoscopy revealed light brown pseudonetworks, overlapping pinkish areas, and multiple dark brown to blue-gray dots and globules. wickham striae were not seen. final diagnosis of early inflammatory lesion of lichen planus-like keratosis was confirmed. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] review | dermatol pract concept 2019;9(4):2 257 for further sessions of intralesional steroid [27]. this application of dermoscopy has been documented to be useful in disorders of hyperpigmentation with either a relapsing-remitting course such as melasma [28] or a very slowly and poorly responsive course such as lichen planus pigmentosus [29]. in melasma, a recently published study as well as our own experience has shown that the presence of a prominent vascular component on dermoscopy (widened vessels) is a reliable indicator of expected improvement with vascular therapies such as pulsed-dye laser [30] and oral tranexamic acid (figure 6). savior in such challenging situations, as the dermoscopic improvement tends to precede clinical improvement [1]. in alopecia areata (aa) for example, dermoscopy can confidently predict disease activity following treatment. active aa shows black dots, “exclamation mark” or tapering hairs, broken hairs, yellow dots, and short vellus hairs (figure 5a), whereas in a treatment-responsive patch of aa, black dots tend to disappear, pigtail and upright regrowing hairs appear, and yellow dots persist [11,25-27] (figure 5b). thus, trichoscopic review of aa patches being treated with regular intralesional steroid can help the clinician decide on the need progressive disease in frontal fibrosing alopecia [20-22] (figure 4). defining adequate margins for surgical excision of tumors akin to ex-vivo dermoscopy, which is useful for the histopathologist, in-vivo dermoscopy can add to clinical examination for the operating surgeon during surgical excision of tumors such as the basal cell carcinoma (bcc). when surgical ablation is contemplated for a bcc, excision margins between 3 and 10 mm allow for radical excision in up to 95% of cases depending on the tumor site, size, borders, and histology. in a prospective study, 200 consecutive bccs of the head and neck were removed with 2-mm dermoscopically detected excision margins that yielded histologically confirmed complete excisions in all but 3 cases (197/200 = 98.5%) [23]. in another prospective case-control study that comprised 44 patients who underwent mohs micrographic surgery, the group in which surgical margins were guided by dermoscopy demonstrated an outcome that was similar to that of the control group, suggesting that further research is warranted before recommending dermoscopy as an aid in demarcating surgical margins for mohs micrographic surgery [24]. early assessment of therapeutic response and disease stabilization the conventional method of evaluation of response to treatment involves interrogating the patient about symptomatic improvement and examining the skin for the extent and morphology of lesions. it is a hard fact that clinically appreciable improvement in many chronic skin disorders, especially pigmentary dermatoses and alopecias, often requires weeks to months. this often translates into a challenging situation for the treating dermatologist with respect to making a decision on continuing or changing the treatment protocol. this also results in patient dissatisfaction, noncompliance with further therapy, and “doctor hopping.” dermoscopy may serve as a figure 4. application of dermoscopy in suggesting disease activity in frontal fibrosing alopecia. (a) clinical image of suspected frontal fibrosing alopecia in an elderly woman. (b) dermoscopic features of multiple large white dots (fibrosed follicular ostia) with perifollicular scales and casts confirming the diagnosis and prominent perifollicular erythema suggestive of active disease. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] figure 3. application of dermoscopy in suggesting disease activity in vitiligo. (a) a stable lesion of vitiligo fit for surgery displaying perifollicular depigmentation (black circles) and leukotrichia (blue arrow). (b) an unstable lesion displaying altered pigment network, “tapioca sago” appearance with multiple pearly-white dots (larger than eccrine openings), and micro-köbner phenomenon (red arrows). (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] 258 review | dermatol pract concept 2019;9(4):2 constitutes their primary treatment modality, ensuring their dermatological treatment compliance is vital until their psychiatric comorbidity improves. in our experience, the majority of such patients at least acknowledge the objective improvement appreciable on dermoscopy, which reinforces treatment compliance while the psychiatric treatment continues. enhancing accuracy of reading patch test and pathergy test results reading allergy patch test reactions can be challenging in the dark skin, even with a hand lens. in doubtful reactions, we have found dermoscopic imaging to be helpful in confirmation of the reaction being true positive or irritant (figure 7). dermoscopy has also proved useful in the confirmation of pathergy test results in patients with behçet disease [46]. therapeutic efficacy evaluation in clinical studies the satisfaction of many clinicians with dermoscopic images serving as an early, objective, and reliable measure of pre and posttreatment comparison has culminated in the use of dermoscopy as an important ancillary tool for efficacy evaluation of existing as well as novel therapeutic modalities in clinical studies [30-42,47-50]. while the avoidance of or difficulty in repeating skin biopsy (whether due to patient noncompliance or due to the posttreatment unremarkability of the lesional morphology rendering biopsy-site selection difficult) constitutes one of the important reasons for the increasing use of dermoscopy and other noninvasive imaging techniques in therapeutic efficacy evaluation in clinical studies, in studies involving both histological and dermoscopic evaluation, the objective served is the concomitant establishment and validation of dermoscopic criteria for use in future studies that may not warrant histological confirmation. response, certain dermoscopic criteria (eg, pigmented structures, ulceration, and arborizing vessels in superficial bccs treated with nonablative modalities) have been suggested to predict the presence of residual disease (residual disease-associated dermoscopic criteria) [43]. the aforesaid contention deepens due to the high prevalence (3%-53.6%) of dysmorphophobia or body dysmorphic disorder in patients seeking clinical dermatology consultation as well as cosmetic procedures [44,45]. although psychiatric/psychological intervention dermoscopic reevaluation of the baseline lesion(s) on the subsequent visit not only allows the clinician to appreciate posttreatment improvement (or lack thereof), but provides reassurance to the patient about the commencement of improvement, thereby maintaining treatment compliance. this use of dermoscopy is not limited to only some disorders or any particular skin type, as it has been reported from various regions and for various disorders [3042], a few of which are enumerated in table 3. other than the evaluation of disease activity and therapeutic figure 5. dermoscopy in evaluating treatment response with disease activity. (a) alopecia areata patch over the beard before treatment displaying a patch of alopecia with multiple black dots (yellow arrows) and a few yellow dots, short vellus hairs (red arrows), tapering hair (blue arrow), and dystrophic hairs (white arrows). (b) an adjacent patch after 2 sessions of intralesional triamcinolone displaying hair growth, dramatic reduction of black dots, persistent yellow dots, and multiple short up-growing hairs (white arrows) suggestive of good treatment response. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] figure 6. dermoscopy in early demonstration of treatment response in melasma. (a) dermoscopic image from an untreated macule of melasma over the cheek of a woman displaying a diffuse nonspecific pattern of dark brown pigmentation with plentiful scattered dark brown globules and clods with perifollicular sparing and multiple prominent telangiectasias. (b) after 30 days of nightly local application of a 2% hydroquinone cream and daytime sunscreen and oral tranexamic acid (250 mg twice daily), dermoscopy from the same spot showing dramatic lightening of the background hue and erythema and reduction of pigmented structures and the telangiectasias. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] review | dermatol pract concept 2019;9(4):2 259 expanding the realm of dermoscopy “cosmetic wart mapping” akin to “mole-mapping” in the whiteskinned population, video dermoscopic scanning can be useful for mapping of multiple cosmetic pigmented warts (usually verruca plana [vp]) in darkskinned patients, particularly involving the beard area in men and periorbital area in women. cosmetic warts arise from a single or few verrucae over the face due to pseudoköbnerization induced by temporary hair removal methods such as shaving, threading, and waxing [51]. men with multiple vp of the beard region or women with vp involving the threading-treated areas around the eyebrows can be provided with ablation of many more lesions if video dermoscopy is used to scan the affected area compared to the conventional ablation of lesions visible to the unaided eye (figure 8). if left untreated, these tiny lesions invisible to the eye and hand lens might contribute to further dissemination [1,2,28]. aesthetic applications of dermoscopy dermoscopy also finds its utility in certain cosmetic/aesthetic procedures. a dermoscopic photo-aging scale has been recently conceived and found to be a figure 7. dermoscopic aid in confirming patch test results. a grossly faint positive reaction displayed erythema and papulovesicles on dermoscopy confirming grade 2 patch test positivity. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] figure 8. dermoscopy for cosmetic wart mapping in darker skin. (a) linear köbnerized cluster of verruca barbae in an indian man before ablation. (b) dermoscopy done after radiofrequency ablation of the warts (erosions) revealing at least 2 warts (black arrows) missed despite using magnifying surgical loupes during the procedure. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] table 3. list from published literature on the use of dermoscopy for posttreatment improvement evaluation in some skin and appendageal disorders [30-42] condition treatment administered or evaluated remarks melasma 1,064-nm q-switched nd:yag (qsny) laser vs qsny + pulsed-dye laser (pdl) 17 patients (split-face study) actinic keratosis ingenol mebutate 0.015% gel 52 patients seborrheic keratosis novel aqueous solution containing nitric acid, zinc and copper salts, and organic acids 15 patients with 50 seborrheic keratoses male androgenetic alopecia platelet-rich plasma therapy + microneedling 20 patients pigmented basal cell carcinoma imiquimod 5% cream 20 lesions plaque psoriasis biological therapy: any of the 4 agents (adalimumab, etanercept, infliximab, and ustekinumab) 75 patients verrucous epidermal nevus pulsed co2 laser vs erbium:yag laser 20 patients (10 in each group) bowen disease imiquimod 5% cream or photodynamic therapy 23 patients with 29 lesions vulvar lichen sclerosus mometasone furoate 0.1% ointment + tretinoin 0.05% cream in short-contact therapy (group a) vs mometasone furoate 0.1% + emollient (group b) 32 patients vitiligo (localized) combination therapy of tacrolimus ointment + 308-nm excimer laser 147 patients axillary hair removal diode laser vs intense pulsed light (ipl) 21 patients (splithalf protocol) facial/upper limb telangiectasias associated with systemic sclerosis pdl vs ipl 19 patients (splithalf protocol) scabies foam containing 0.165% pyrethrins and 1.65% piperonyl butoxide 20 patients 260 review | dermatol pract concept 2019;9(4):2 skinned individuals (fitzpatrick skin photo types iv-vi). in our own experience, dermoscopic evaluation of the scattering and thickness of hairs before the laser session has proven useful in dark-skinned patients with hirsutism. optimal laser parameters (especially pulse duration that depends on the thickness of the hair being targeted) can thus be correspondingly fine-tuned. moreover, apprehensive patients can be shown the laser-induced scattering and thinning of hirsute hairs to maintain or improve compliance (figure 11). in fact, a recent study has emphasized the utility of trichoscopy in monitoring the response to laser hair reduction in women [56]. trichoscopy is of great value to a hair transplant surgeon. it aids in recording the number of existing follicular units, the number of hairs per follicular unit, the size of hair follicles, as well enlarged facial skin pores is a common cosmetic complaint, especially in individuals with oily skin. dermoscopy can aid in evaluating and defining “enlarged” open facial pores [54]. kim et al have defined and categorized the morphological subtypes of skin pores into 3 different categories: “visible skin pores” (0.1-0.6 mm2), “enlarged skin pores” (0.3-0.6 mm2), and “blackhead embedded skin pores” using the robo skin analyzer cs50 (niic, tokyo, japan), which has a dermatoscope-like attachment mode in addition to other functions [55]. figure 10 provides a gross idea of types of pores on a standard dermoscopic evaluation. selecting the right parameters while using devices for laser hair reduction is not only crucial for optimum outcome and patient satisfaction, it is critical to prevent laser-induced burn and postprocedure hyperpigmentation in darkreliable and valid diagnostic tool for quantitative evaluation of photo-aged facial skin in a white population and to study the effect of preventive and therapeutic approaches to skin aging in the future [52]. dermoscopic evaluation of periocular hyperpigmentation and under-eye bags can provide a clue to the predominant abnormality (skin pigmentation, abnormal vasculature, skin laxity) (figure 9) and aid in development of customized treatment protocols. in a recent study evaluating the impact of normobaric oxygen therapy on periorbital darkening, dermoscopy was used as the main tool to document posttherapy improvement and revealed a substantial reduction in vascularity and pigmentation with more than a quarter of patients showing >50% improvement [53]. figure 9. dermoscopy of the under-eye region for management of periocular pigmentation. (a) predominantly pigmentary component; (b) predominantly vascular component; and (c) combination of pigmentary and vascular component. (dermlite dl4, 3 gen inc., usa; polarized, ×10.) [copyright: ©2019 sonthalia et al.] figure 11. dermoscopy for deciding laser/light device and parameters for permanent hair reduction. (a) dermoscopy of the chin of an obese woman with polycystic ovarian syndrome revealing thick terminal hairs and darkly pigmented skin. (b) image from the same patient after 8 sessions of diode laser (with low energy) showing dramatic scattering and thinning of chin hairs. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] figure 10. dermoscopy of skin pores. well-defined pilosebaceous openings or pores visible on dermoscopy of the cheek of an indian woman with enlarged open pores. note the presence of visible skin pores (black arrows), enlarged skin pores (blue arrows), and blackhead-embedded skin pores (white arrows). (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] review | dermatol pract concept 2019;9(4):2 261 sary referrals, wait times, and the cost of providing and receiving dermatological care [61]. inclusion of dermoscopic images in teledermatology-based consultations is known to improve decisions on triaging and surgical excision of meladeveloping area that will soon change our way of seeing and understanding a new device or medication. teledermoscopy’s greatest strength may be as a triage and monitoring tool, as it can reduce the number of unnecesas the interfollicular distance at both the donor and recipient site. in addition, trichoscopy may be useful for early differential diagnosis of posttransplant surgical complications such as folliculitis and secondary lichen planopilaris. a detailed account of clinco-trichoscopic correlation in the scalp of patients who underwent hair transplantation has been documented by madura et al [57]. detection of intra/subcutaneous foreign bodies and retained sutures the detection and removal of retained sutures in a crusted wound may sometimes become daunting, especially when black threads (typically silk) are used in individuals with darker skin due to the relative lack of color contrast compared with fair skin. in such situations, dermoscopic assessment provides an excellent 3-dimensional view that may facilitate their prompt identification and removal (figure 12) [28]. a blue prolene suture should help in avoiding this issue in all skin types, although dermoscopy may still help in visualizing the ends of the residual suture if stitch removal is done incorrectly. dermoscopy has also been documented for its application in facilitating identification and removal of a foreign body lodged in the skin (figure 13) [28,58]. teledermoscopy teledermatology is a subspecialty of dermatology that uses telecommunication technologies to transfer medical information over varying distances. the format can be audio, visual, and/or data-based. digital dermoscopy refers to the acquisition and storage of digital images from a dermoscopic examination. teledermoscopy is the transferring of a digitalized dermoscopic image (visual data) for diagnosis (figure 14), education, consultation, or follow-up. mobile teledermoscopy uses a smartphone to deliver the same type of service [59]. these images are also used in machine learning [60,61], a rapidly figure 12. dermoscopy for identification and removal of retained sutures in a heavily crusted wound. (a) before removal, the black suture, which was otherwise extremely difficult to delineate from the surrounding brownish black crust, is easily visible on dermoscopy (white circle). (b) after removal. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) [copyright: ©2019 sonthalia et al.] figure 13. dermoscopy for identification and removal of intracutaneous foreign body. (a) clinical image before removal—the tiny foreign body lodged intracutaneously (black arrow) with no visibility of protruding head or tail for removal. (b) low magnification (×20) polarized dermoscopic image. (c) high magnification (×70) polarized dermoscopic image revealing the protruding head-end of the foreign body. (escope video dermatoscope, timpac healthcare pvt. ltd., new delhi, india; polarized, ×20.) (d) clinical image after dermoscopically facilitated removal revealing a tiny linear subcorneal erosion (black arrow). [copyright: ©2019 sonthalia et al.] 262 review | dermatol pract concept 2019;9(4):2 well-being and response to therapy need not be overemphasized. dermoscopic examination and counseling thereof tend to make such patients and family members feel they are being cared for. future perspective innovations in the technique and utilization of dermoscopy for better imaging and expanding its extradiagnostic application are being conceived and published at a fast pace. one such newfangled approach is dermoscopy-guided darkfield multifunctional optical coherence tomography, conceptualized and developed by kwon et al [66]. by combining the 2 imaging techniques, kwon et al achieved simultaneous high-contrast superficial information (dermoscopy) and depth-resolved structural, birefringent, and vascular information of the skin (multifunctional optical coherence tomography) and documented its utility in better overall evaluation of different skin lesions. akin to endoscopic procedures in surgical branches, we believe that the dermatoscope may be amenable to redesigning with creation of multiple portals for diagnostic and therapeutic interventions [67] delivered through the device to allow high-precision diagnostic and dermatosurgical procedures under concomitant dermoscopic visualization. conclusions dermoscopy has far-reaching uses beyond just diagnosis of skin, hair, and nail disorders. some can be highly relevant for both physicians and patients, offering prompt resolution to diagnostic and therapeutic dilemmas encountered routinely. the quest for more uses of this technique continues and mastering this technology becomes imperative for not only dermatologists, but also primary care physicians, pediatricians, and specialists of other branches of medicine. prescribe guidelines for normative behavior to regulate and reduce social media use in dermatology [64]. pending global and regional consensus guidelines on regulating the use of social media in health care, dermoscopy may serve as an efficient tool for counteracting the invalid and illogical interjections of the “google generation” patients in the diagnostic and therapeutic decisions made by dermatologists. dermatoscope: a professional highlight for dermatologists while a hand lens, corneal loupe, and other conventional tools of magnification are present in nearly every dermatologist’s office, a dermatoscope definitely adds to the professional standing. patients tend to place more faith in a dermatologist who is well-versed in dermoscopy and uses it not just for making diagnoses, but also to counsel them on pertinent features appreciable on dermoscopy that are of relevance to their understanding and improved therapeutic compliance. dermatoscope: the dermatologist’s stethoscope cutaneous disorders are often chronic, treatment-recalcitrant, and with an unpredictable/relapsing-remitting course. patients with conditions such as psoriasis, vitiligo, nonremitting aa, and chronic eczemas typically consult different dermatologists over time, hoping for a permanent cure. chronic skin diseases may have a devastating effect on a person’s physical and psychological well-being, affecting his or her education, relationships, career choices, social and leisure activities, and sex life. the adverse physical, psychological, and social consequences of chronic dermatoses affect not only the patient, but also caregivers and family members [65]. demonstration of dermoscopic images (in select cases) to the patient and/or relatives tends to improve the patient’s psychodermatology profile and provides reassurance to caregivers [1,2]. the relation between a patient’s psychological nomas and other skin cancers [59]. the concept of teledermoscopy has futuristic implications for health care systems in the developing world [61], where a large proportion of dermatology patients are still managed by primary care physicians [62]. of course, this goal can be successfully achieved only with proper training into dermoscopy and principles of teledermoscopy of both primary care physicians and dermatologists. psychological realm of dermoscopy dermoscopy: the dermatologist’s tool in the era of social media empowerment of patients in the current era, the practice of medicine and specifically dermatology is facing a new challenge. over and above the chronicity and relapsing nature of the majority of cutaneous disorders, the impact of health-related information available on the internet and exchanged on social media has dramatically altered the approach to practicing dermatology [63]. while a detailed discussion on the impact of social media on the practice of dermatology is beyond the scope of this article, it may suffice to mention that the above concerns make a strong point favoring the concept of “e-professionalism” as a distinct new paradigm requiring particular training, practice, and formulation of new policies that figure 14. dermoscopic image received via teledermatology consultation with a family physician. the patient was referred directly to surgery, and the diagnosis of melanoma was confirmed by pathology. (dermlite dl4, 3 gen inc., usa; polarized, ×10.) 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treatment for benign hand hyperpigmentation treatment. j cosmet dermatol. 2016;15(4):413-419. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023093 1 dermoscopy in selected latin american countries: a preliminary look into current trends and future opportunities among dermatology residency programs mariana perez1, natalie m. williams1, alejandra m. avila2, renato bakos3, flavia bittencourt4, blanca carlos-ortega5, laura garzona6, alejandra larre-borges7, cristian naverrete-dechent8, victor pinos9,10, gabriel salerni11, jackie shum-tien12,13, natalia jaimes1,14 1 dr. phillip frost department of dermatology and cutaneous surgery, university of miami miller school of medicine, miami, florida 2 department of dermatology, universidad pontificia bolivariana, medellin, colombia 3 department of dermatology, universidade federal do rio grande do sul, porto alegre, brazil 4 universidade federal de minas gerais, belo horizonte, brazil 5 consultorio privado, hospital durango, roma norte, ciudad de méxico, méxico 6 hospital clínica bíblica, san josé, costa rica 7 hospital británico, montevideo uruguay. former hospital de clínicas udelar, montevideo, uruguay 8 melanoma and skin cancer unit, department of dermatology, escuela de medicina, pontificia universidad católica de chile, santiago, chile 9 department of dermatology, hospital metropolitano, quito, ecuador 10 universidad central del ecuador, quito, ecuador 11 department of dermatology, hospital provincial del centenario de rosario, universidad nacional de rosario, argentina 12 clínica dermatológica arosemena, ciudad de panamá, panamá 13 clínica mediskin, ciudad de panamá, panamá 14 sylvester comprehensive cancer center, university of miami miller school of medicine, miami, florida key words: dermoscopy, dermatology residency, latin america, medical education citation: perez m, williams nm, avila am, et al. dermoscopy in selected latin american countries: a preliminary look into current trends and future opportunities among dermatology residency programs. dermatol pract concept. 2023;13(2):e2023093. doi: https://doi.org/10.5826/dpc.1302a93 accepted: october 19, 2022; published: april 2023 copyright: ©2023 perez et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: natalia jaimes, md, dr. phillip frost department of dermatology and cutaneous surgery, sylvester comprehensive cancer center, miami, florida. university of miami miller school of medicine, dermatology research clinic 1600 nw 10th ave. rsmb 2023a, miami, fl 33136 phone: 305-243-6735 e-mail: njaimes@med.miami.edu 2 original article | dermatol pract concept. 2023;13(2):e2023093 introduction skin cancer continues to be a public health burden globally. early detection remains the most cost-effective means of improving prognosis and reducing morbidity, mortality, and health-related costs [1-3]. dermoscopy is a non-invasive, in-vivo imaging technique that allows for the visualization of subsurface structures of the skin that are otherwise not visible to the naked eye [4,5]. dermoscopy increases the diagnostic accuracy for skin cancer, including melanoma, by up to 50% compared to the naked eye examination alone; however, this is contingent on adequate training [6,7]. although dermoscopy has demonstrated its value in early detection of skin cancer, it is not uniformly taught to residents worldwide. studies show that dermoscopy use among dermatology residents in europe and australia is on the rise [8-10]. similarly, studies assessing the use of dermoscopy among dermatology residents in the united states (us) demonstrate that the majority of trainees are receiving didactic lectures and clinical training on the use of this tool in differentiating benign (eg nevi, seborrheic keratosis) from malignant lesions (eg melanoma, basal cell carcinoma, squamous cell carcinoma) [11]. nevertheless, dermoscopy training continues to have one of the lowest satisfaction rates among residency programs [12,13]. objectives the use of dermoscopy among dermatology residents in latin america has not been explored. the objective of this study was to better understand current dermoscopy training among dermatology residency programs in latin america (eg types of training modalities, training modalities considered to be most effective by residents, preferred training modalities by residents, and the diseases/pathologies taught) as a first step toward the creation and implementation of educational and training initiatives. methods we performed a cross-sectional study using an electronic anonymous survey. only the chief residents of selected latin american dermatology residency programs from argentina, brazil, colombia, costa rica, chile, ecuador, guatemala, mexico, panama, and uruguay were invited to participate in the study. only chief residents were invited to answer the survey, since they would be familiar with their curriculum and the educational practices of their institution. the survey was distributed via e-mail between march and may of 2021, and participation was voluntary. the survey was available in english, spanish, and portuguese on the online introduction: skin cancer remains a global public health burden. dermoscopy is a useful technique that aids in early detection and increases diagnostic accuracy with adequate training. however, dermoscopy is not uniformly taught to residents worldwide. dermoscopy training in latin american dermatology residency programs has not been explored. objectives: to assess current dermoscopy training among dermatology residency programs in latin america (eg training modalities, preferred/most effective modalities per residents, diseases/pathologies taught). methods: cross-sectional survey distributed via e-mail between march and may 2021. chief residents from argentina, brazil, colombia, costa rica, chile, ecuador, guatemala, mexico, panama, and uruguay were invited to participate. results: 81 chief residents completed the questionnaire (81/126, 64.2%). seventy-two percent of programs had an established dermoscopy curriculum, with dedicated hours of training varying greatly by program. institutions commonly utilized sessions with “unknown” dermoscopy images and direct teaching by experts in the clinical setting as supplements to lectures, also described by residents as most effective. the most commonly taught methods included pattern analysis (74.1%), the two-step algorithm (61.7%), and the abcd rule (59.3%). almost all respondents reported desiring additional training during residency and believe that dermoscopy training should be a requirement to graduate from residency. conclusions: this study highlights a preliminary look into current landscape in dermoscopy training among selected latin american dermatology residency programs, demonstrating room for improvement and standardization in dermoscopic education and training. our results serve as a baseline reference and provide valuable information to guide future educational initiatives incorporating successful teaching strategies (eg. spaced education/repetition, flipped classroom model) used in dermatology and other fields. abstract original article | dermatol pract concept. 2023;13(2):e2023093 3 qualtrics® platform (qualtrics, llc, sap america inc. company). multiple submissions were prevented by use of qualtrics® software. participating countries were selected by convenience sampling, based on availability of representative contacts. based on the number of dermatology residency programs in each country, the estimated sample size was 126. summary statistics and descriptive frequencies were collected using microsoft excel™. the study was approved by the institutional review board at university of miami. results the response rate was 64.2% (81/126). overall, 81 chief residents from dermatology residency programs in brazil, argentina, colombia, mexico, chile, ecuador, guatemala, panama, uruguay, and costa rica completed the questionnaire (table 1). almost all respondents hailed from urban training programs. half of the participants (54%) reported receiving a dermatoscope from their institution (table 2). the hybrid table 1. participant demographics including location and country of residency. demographics n (%) all 81 sex female 64 (79.0) male 16 (19.8) other 1 (1.2) year of dermatology residency 1st 5 (6.2) 2nd 7 (8.6) 3rd 56 (69.1) other 13 (16.0) location urban 78 (96.3) suburban 2 (2.5) rural 1 (1.2) country argentina 17 (21.0) brazil 29 (35.8) chile 4 (4.9) colombia 13 (16.0) costa rica 1 (1.2) ecuador 2 (2.5) guatemala 2 (2.5) mexico 10 (12.4) panama 2 (2.5) uruguay 1 (1.2) table 2. participant-reported current dermoscopy use. current dermoscopy use n (%) all 81 daily dermatoscope use yes 80 (98.8) no 1 (1.2) dermatoscope typea handheld dermatoscope, hybrid (polarized and nonpolarized light) 69 (85.1) handheld dermatoscope adaptable to photo camera or smartphone 30 (37.0) specific device for digital dermoscopy 10 (12.3) handheld dermatoscope, only polarized light 4 (4.9) dermatoscope provided by institution yes 44 (54.3) no 37 (45.7) situations for dermatoscope usea to aid in melanoma detection 81 (100.0) to aid in basal cell carcinoma detection 81 (100.0 to aid in squamous cell carcinoma detection 81 (100.0) to aid in actinic keratosis detection 73 (90.1) to aid in seborrheic keratosis detection 71 (87.7) to aid in vascular neoplasm detection 74 (91.4) to aid in diagnosing infectious skin conditions 56 (69.1) to aid in differentiating cutaneous tumors from inflammatory dermatoses 70 (86.4) to aid in hair diseases 79 (97.5) to aid in nail diseases 68 (84.0) other: mucosal lesions, guided biopsy 5 (6.2) amultiple response (ie “select all that apply”). handheld dermatoscope (ie polarized and non-polarized light) was the most commonly used type of dermatoscope. all participants reported using a dermatoscope to aid in the detection of malignant tumoral pathologies such as melanoma, basal cell carcinoma, and squamous cell carcinoma. 4 original article | dermatol pract concept. 2023;13(2):e2023093 not all of them had a formal training program. specifically, 72% reported an established dermoscopy training curriculum as part of the residency program, and hours of training varied greatly by institution (table 3). dermoscopy lectures frequently covered topics such as differentiation of nevi from melanoma, non-melanoma malignancies, benign lesions including seborrheic keratoses; facial lesions, acral lesions, and hair dermoscopy. less commonly covered topics included mucosal lesions, nail dermoscopy, and inflammatory a large majority of participants also reported using dermatoscopes to assist in the diagnosis of hair diseases (97.5%), actinic keratoses (90.1%), vascular neoplasms (91.4%), seborrheic keratoses (87.7%), inflammatory dermatoses (86.4%), nail diseases (84.0%), and infectious skin conditions (69.1%). other cited uses included guided biopsies and mucosal lesions. although almost all participants (99%) reported using a dermatoscope in their everyday clinical practice (table 2), current dermoscopy training n (%) dermoscopy training is part of residency curriculum yes 58 (71.6) no 23 (28.4) hours of training per academic year 0 9 (11.1) 1-5 9 (11.1) 5-10 10 (12.4) 10-20 15 (18.5) 20-30 9 (11.1) >30 29 (35.8) topics covered in dermoscopy lecturesa differentiation of nevi from melanoma 73 (90.1) non-melanoma malignancies (ie basal cell carcinoma, squamous cell carcinoma) 71 (87.7) benign lesions (ie seborrheic keratoses, angiomas) 64 (79.0) skin infections 30 (37.0) inflammatory condition 32 (39.5) hair dermoscopy 53 (65.4) nail dermoscopy 39 (48.1) mucosae 27 (33.3) facial lesions 54 (66.7) acral lesions 60 (74.0) other 4 (4.9) n/a (do not receive dermoscopy lectures) 8 (9.9) dermoscopy sessions using images (aka “kodachromes” or “unknowns”) provided by institution yes 51 (63.0) no 29 (35.8) no answer 1 (1.2) methods taught by institutiona abcd rule of dermoscopy 48 (59.3) menzies method 28 (34.6) current dermoscopy training n (%) pattern analysis or revised pattern analysis 60 (74.1) 7-point checklist 29 (35.8) cash algorithm (colors, architecture, symmetry, homogeneity) 10 (12.3) two-step algorithm 50 (61.7) tada (triage amalgamated dermoscopy algorithm) 8 (9.9.) none 5 (6.2) other 3 (3.7) no answer available 1 (1.2) use of other dermoscopy training resources no 20 (24.7) no answer available 1 (1.2) yes 60 (74.1) if answer to “use of other dermoscopy training resources” is yes, what are other resources used?a online quizzes 32/60 (53.3) online lectures 41/60 (68.3) textbooks 53/60 (88.3) online text 43/60 (71.7) online forums/discussion groups 27/60 (45.0) other 4/60 (6.7) training by dermoscopy expert no 35 (43.2) no answer available 2 (2.5) yes 44 (54.3) hours per month spent with dermoscopy expert in clinical setting 1-5 15/44 (34.1) 5-10 7/44 (15.9) 10-20 10/44 (22.7) 20-30 2/44 (4.5) >30 8/44 (18.2) no answer available 2/44 (4.5) table 3. participant-reported current dermoscopy training. amultiple response (ie “select all that apply”). original article | dermatol pract concept. 2023;13(2):e2023093 5 conditions. more than half of programs employed case-based sessions with dermoscopy images (63%) and direct teaching by a dermoscopy expert in the clinical setting (54.3%). pattern analysis was the most commonly reported method (74.1%), followed by the two-step algorithm (61.7%) and the abcd rule (59.3%). in addition to institutional lectures, sessions using dermoscopy images and expert training, 74% of respondents reported utilizing other dermoscopy training resources, such as textbooks and online material. almost all chief residents reported desiring additional training during residency (91.3%) and believe that dermoscopy training should be a requirement to graduate from residency (93.8%) (table 4). although the ideal training duration varied greatly among respondents, sessions using table 4. participant preferences for dermoscopy training. dermoscopy training preferences n (%) additional dermoscopy training desired in residency yes 74 (91.3) no 3 (3.7) no answer available 4 (4.9) dermoscopy training should be required to graduate residency yes 76 (93.8) no 1 (1.2) no answer available 4 (4.9) most effective method of traininga sessions with dermoscopy images/cases (aka unknowns /kodachromes) 66 (81.5) didactic lectures 57 (70.3) hands-on training with expert 66 (81.5) independent learning (online, textbook) 32 (39.5) other 3 (3.7) ideal duration of hands-on training hours (mean ± sd) (18.5 ± 40.2) days (mean ± sd) (12.7 ± 21.7) ideal duration of in-person course hours (mean ± sd) (12.3 ± 11.6) days (mean ± sd) (10.5 ± 13.3) ideal duration of online dermoscopy video hours (mean ± sd) (5.7 ± 11.2) sessions (mean ± sd) (11.8 ± 13.3) sd = standard deviation.amultiple response (ie “select all that apply”). dermoscopy images, hands-on training with experts, and didactic lectures were regarded as effective teaching methods, followed by independent learning. conclusions dermoscopy has proved to be a valuable instrument in the early detection of skin cancer, thus reducing morbidity, mortality, and health-related costs, while improving patient care and quality of life. the efficacy and thereby utility of this device, however, depends on adequate training [6,7]. data shows that at least 62%-84% of dermatology residents in the us receive training during residency [13,14]. residents in europe have not been specifically studied, but surveys of practicing dermatologists show that at least 32%-42% received training during residency [15]. in australia, dermoscopy education is a core part of residency training, with all residents receiving formal didactic training and most programs providing dermatoscopes for resident use [16]. in our study, almost all surveyed residents from latin american dermatology programs reported using a dermatoscope in their everyday practice in a variety of clinical contexts, but only half reported receiving a dermatoscope from their training program. dermoscopy was formally included in the didactic curriculum of more than two thirds of programs (72%), with lectures spanning a broad range of topics, including differentiation of nevi from melanoma and non-melanoma malignancies. given the different modalities for teaching dermoscopy and associated learning preferences, in addition to understanding the current landscape of dermoscopy use among trainees in a given region, it is also important to understand the modalities taught, the effectiveness of these strategies, and the trainee learning preferences before embarking on larger dermoscopy education initiatives. among the surveyed residents, pattern-analysis was taught in 74% of programs, followed by the two-step algorithm (61.7%) and the abcd rule (59.3%). institutions employed the use of lectures, sessions with dermoscopy images, and expert training, though 74% of residents reported utilizing supplemental training resources such as textbooks and online content. importantly, almost all residents believed dermoscopy training should be a requirement for graduation and desired additional training than they were currently receiving. there is limited evidence in the literature regarding specific approaches to dermoscopic education and their long-term efficacy. at one us institution, a flipped classroom approach for dermoscopic education (students review preparatory instructional content outside the classroom and participate in faculty-guided active learning within the classroom) was suggested to improve satisfaction and learning by promoting accountability, though data was mostly anecdotal 6 original article | dermatol pract concept. 2023;13(2):e2023093 [17]. in france, a spaced-education internet dermoscopy module (involving question-based educational content with spaced repetition as well as an adaptive rescheduling algorithm) combined with in-class training implemented in dermatologists and senior residents led to improved performance and learning retention compared to in-class training alone [18]. in belgium, a two-stage training course taught by experts (consisting of a 3-hour basic course followed by a 3-hour advanced course six weeks later) improved diagnostic accuracy in residents even more than practicing dermatologists and showed sustained effects in learning [19]. these and other teaching strategies have also been employed with success in various medical specialties, including online spaced-education in urology and cardiology, and mobile app technology with spaced repetition in otolaryngology [20-22]. limitations of the study include a low response rate (64%), which could represent lack of interest in the study or in dermoscopy, but can be expected with anonymous surveys. further, the evaluation of dermoscopic education practices of each institution was based on responses from a single resident (ie chief resident) and therefore may represent only a single opinion. in addition, the length of training programs is not standardized between countries and may impact the amount of dermoscopy training provided. last, the convenience sampling (ie surveying chief residents from countries selected based on available representative contacts) impedes generalization of survey results and may result in biased data due to underrepresentation of the population. of note, the total number of residents of all years represented by the survey amounts to more than 1,300; though specific information regarding the precise number of residents in each program and each country was not available for all countries. therefore, these results can be considered preliminary and may be improved upon with a larger and more representative sample. in summary, our study, though limited by small sample size and potential selection bias, provides initial insight into the current landscape and preferences in dermoscopy training among dermatology residency programs in latin america, demonstrating room for improvement and standardization in dermoscopic education and training. our results serve as a baseline reference and provide valuable information to guide future educational initiatives, which can include successful teaching strategies (eg spaced education/repetition, flipped classroom model) in dermatology and other fields. references 1. elliott tm, whiteman dc, olsen cm, gordon lg. estimated healthcare costs of melanoma in australia over 3  years post-diagnosis. appl health econ health policy. 2017;15(6): 805-816. doi: 10.1007/s40258-017-0341-y. pmid: 28756584. 2. guy gp, jr., thomas cc, thompson t, et al. vital signs: melanoma incidence and mortality trends and projections united states, 1982-2030. mmwr morb mortal wkly rep. 2015;64(21):591-596. pmid: 26042651. pmcid: pmc4584771. 3. hanson jl, kingsley-loso jl, grey kr, et al. incidental melanomas detected in veterans referred to dermatology. j am acad dermatol. 2016;74(3):462-469. doi: 10.1016/j.jaad.2015.09.057. pmid: 26612677. 4. argenziano g, ferrara g, francione s, di nola k, martino a, zalaudek i. dermoscopy--the ultimate tool for melanoma diagnosis. semin cutan med surg. 2009;28(3):142-148. doi: 10.1016 /j.sder.2009.06.001. pmid: 19782937. 5. menzies sw, ingvar c, mccarthy wh. a sensitivity and specificity analysis of the surface microscopy features of invasive melanoma. melanoma res. 1996;6(1):55-62. doi: 10.1097 /00008390-199602000-00008. pmid: 8640071. 6. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. doi: 10.1111 /j.1365-2133.2008.08713.x. pmid: 18616769. 7. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. doi: 10.1016/s1470-2045(02)00679-4. pmid: 11902502. 8. blum a, kreusch j, stolz w, et al. the status of dermoscopy in germany results of the cross-sectional pan-euro-dermoscopy study. j dtsch dermatol ges. 2018;16(2):174-181. doi: 10.1111 /ddg.13431. pmid: 29384261. 9. forsea am, tschandl p, del marmol v, et al. factors driving the use of dermoscopy in europe: a pan-european survey. br j dermatol. 2016;175(6):1329-1337. doi: 10.1111/bjd.14895. epmid: 27469990. 10. piliouras p, buettner p, soyer hp. dermoscopy use in the next generation: a survey of australian dermatology trainees. australas j dermatol. 2014;55(1):49-52. doi: 10.1111/ajd.12061. pmid: 23713814. 11. chen ya, rill j, seiverling ev. analysis of dermoscopy teaching modalities in united states dermatology residency programs. dermatol pract concept. 2017;7(3):38-43. doi: 10.5826 /dpc.070308. pmid: 29085718. pmcid: pmc5661161. 12. freeman sr, greene re, kimball ab, et al. us dermatology residents' satisfaction with training and mentoring: survey results from the 2005 and 2006 las vegas dermatology seminars. arch dermatol. 2008;144(7):896-900. doi: 10.1001 /archderm.144.7.896. pmid: 18645141. 13. patel p, khanna s, mclellan b, krishnamurthy k. the need for improved dermoscopy training in residency: a survey of us dermatology residents and program directors. dermatol pract concept. 2017;7(2):17-22. doi: 10.5826/dpc.0702a03. pmid: 28515987. pmcid: pmc5424656. 14. wu tp, newlove t, smith l, vuong ch, stein ja, polsky d. the importance of dedicated dermoscopy training during residency: a survey of us dermatology chief residents. j am acad dermatol. 2013;68(6):1000-1005. doi: 10.1016/j.jaad.2012.11.032. pmid: 23374231. 15. forsea am, tschandl p, zalaudek i, et al. inequalities in the patterns of dermoscopy use and training across europe: conclusions of the eurodermoscopy pan-european survey. eur j dermatol. 2020;30(5):524-531. doi: 10.1684/ejd.2020.3872. pmid: 33052101. original article | dermatol pract concept. 2023;13(2):e2023093 7 and experienced dermatologists. australas j dermatol. 2015;56(1):52-55. doi: 10.1111/ajd.12203. pmid: 25302740. 20. kerfoot bp. learning benefits of on-line spaced education persist for 2 years. j urol. 2009;181(6):2671-2673. doi: 10.1016 /j.juro.2009.02.024. pmid: 19375095. 21. kerfoot bp, turchin a, breydo e, gagnon d, conlin pr. an online spaced-education game among clinicians improves their patients' time to blood pressure control: a randomized controlled trial. circ cardiovasc qual outcomes. 2014;7(3):468-474. doi: 10.1161 /circoutcomes.113.000814. pmid: 24847084. pmcid: pmc4040124. 22. kuperstock je, horný m, platt mp. mobile app technology is associated with improved otolaryngology resident in-service performance. laryngoscope. 2019;129(1):e15-e20. doi: 10.1002 /lary.27299. pmid: 30151970. 16. piliouras p, buettner p, soyer hp. dermoscopy use in the next generation: a survey of australian dermatology trainees. australas j dermatol. 2014;55(1):49-52. doi: 10.1111/ajd.12061. pmid: 23713814. 17. muzumdar s, waldman ra, grant-kels jm, kerr p. implementing the flipped classroom approach to dermatopathology and dermoscopy resident education: a single-institution experience. j cutan pathol. 2019;46(10):753-755. doi: 10.1111/cup.13515. pmid: 31148219. 18. boespflug a, guerra j, dalle s, thomas l. enhancement of customary dermoscopy education with spaced education e-learning: a prospective controlled trial. jama dermatol. 2015;151(8):847-853. doi: 10.1001/jamadermatol.2015.0214. pmid: 25902339. 19. chevolet i, hoorens i, janssens a, et al. a short dermoscopy training increases diagnostic performance in both inexperienced untitled review | dermatol pract concept 2015;5(3):8 29 dermatology practical & conceptual www.derm101.com introduction terra-firma forme dermatosis is a benign condition with a characteristic clinical appearance of brown or black hyperkeratotic plaques or papules. the application of 70% isopropyl alcohol is both diagnostic and therapeutic for this disorder. we describe ten patients who presented with terrafirma forme dermatosis that usually affected skin creases and that resolved after wiping with 70% isopropyl alcohol pads. case series terra-firma forme dermatosis was diagnosed in ten caucasian patients whose clinical characteristics are summarized terra firma-forme dermatosis: a report of ten individuals with duncan’s dirty dermatosis and literature review tanya greywal1, philip r. cohen2 1 school of medicine, university of california, san diego, ca, usa 2 department of dermatology, university of california, san diego, ca, usa key words: dermatosis, duncan’s dirty dermatosis, isopropyl alcohol, terra firma, terra firma-forme citation: greywal t, cohen pr. terra firma-forme dermatosis: a report of ten individuals with duncan’s dirty dermatosis and literature review. dermatol pract concept 2015;5(3):8. doi: 10.5826/dpc.0503a08 received: march 27, 2015; accepted: april 9, 2015; published: july 31, 2015 copyright: ©2015 greywal et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: terra-firma forme dermatosis, also known as duncan’s dirty dermatosis, is a benign skin condition that presents as dirt-like plaques in patients of all ages. purpose: we describe a series of ten patients that presented with terra-firma forme dermatosis. methods and materials: we reviewed pubmed for the following terms: dermatosis, duncan’s dirty dermatosis, isopropyl alcohol, terra firma, and terra firma-forme dermatosis. we also reviewed papers containing these terms and their references. results: the diagnosis of terra firma-forme dermatosis was confirmed in all patients who had complete resolution of each lesion after the application of 70% isopropyl alcohol. conclusions: terra-firma forme dermatosis is easily diagnosed and treated with 70% isopropyl alcohol. it is important to recognize this benign dermatologic condition since it can be confused with other cutaneous disorders. therefore, in order to avoid unnecessary referrals, biopsies, blood tests, and medications, we suggest a trial of wiping the skin lesion with 70% isopropyl alcohol pads when the diagnosis of terra-firma forme dermatosis is considered. abstract 30 review | dermatol pract concept 2015;5(3):8 with 70% isopropyl alcohol pads. our patients included nine men and one woman. the men’s ages ranged from 54 to 86 years, with a mean age of 70 years. the woman was 59 years of age. most of the patients were unaware of their asympin table 1. the morphology of each lesion was similar and consistent with terra-firma forme dermatosis: brown and/or black plaques or papules or both. final diagnosis was confirmed with the resolution of each lesion after firm rubbing table 1. clinical characteristics of ten patients with terra firma-forme dermatosis [1,2] case age (yrs) race sex location hx of nmsc other medical conditions 1 54 c m right and left inguinal folds right suprapubic region no none 2 58 c m all interspaces between the first through fourth toes on both feet no • addison disease • chronic lymphocytic leukemia • chronic inflammatory demyelinating polyneuropathy • hypothyroidism 3 61 c m skin folds on the anterior neck yes: scc • atrial fibrillation • coronary artery disease • depression • generalized anxiety disorder • hypertension 4 66 c m concha of right ear yes: scc • depression • hyperlipidemia • hypertension • narcolepsy • prostate cancer • urge urinary incontinence • vocal cord palsy 5 66 c m central chest yes: bcc, scc • anxiety • gout • hypercholesterolemia • hypertension • insomnia • macular puckering of retina 6 73 c m occipital scalp no • meningioma 7 82 c m right distal neck fold right and central chest left inguinal fold yes: bcc, scc • benign prostatic hyperplasia • chronic lymphocytic leukemia • hypertension • obstructive sleep apnea 8 82 c m right and left inguinal folds yes: bcc • coronary artery disease • diverticulosis • hypertension • prostate cancer 9 86 c m right and left subclavicular chest yes: bcc • melanoma 10 59 c w right chest, skin fold beneath the right breast no • anxiety • asthma • breast cancer • hypertension • hypothyroidism • insomnia • osteoporosis 1. abbreviations: bcc, basal cell carcinoma; c, caucasian; hx, history; m, man; nmsc, nonmelanoma skin cancer; scc, squamous cell carcinoma; w, woman; yrs, years 2. the morphology of all lesions was similar, consisting of brown or black plaques or papules. all lesions resolved with firm application of 70% isopropyl alcohol review | dermatol pract concept 2015;5(3):8 31 1 and 2) or flexor areas or skin folds (figure 3); less common locations included in-between the toes (case 2) (figure 4), the right ear concha (case 4) (figure 5), and the occipital scalp (case 6). only one patient had involvement of two distant sites, the chest and the groin (case 7). in addition, most of tomatic dermatosis. all patients practiced good hygiene and showered a minimum of every other day or daily. in addition, with the exception of one patient (case 4), all were capable of reaching the affected locations while showering. most of the lesions (except case 6) were located on concave sites (figures a b c d figure 1. terra firma-forme dermatosis in an 82-year-old man (case 7). a brown plaque is present on the concave skin of the right distal neck (a). resolution of the brown plaque after rubbing with several 70% isopropyl alcohol pads (b). the isopropyl alcohol pads before (c) and after (d) use, showing evidence of the brown pigmentation that was removed. [copyright: ©2015 greywal et al.] figure 2. the initial appearance of a brown plaque on the subclavicular chest of an 86-year-old man (case 9) (a). resolution of the brown plaque after rubbing with 70% isopropyl alcohol (b). [copyright: ©2015 greywal et al.] a b 32 review | dermatol pract concept 2015;5(3):8 the patients had other medical conditions that were most likely a reflection of their age and not a predisposing factor to terra-firma forme dermatosis. several patients had a history of non-melanoma skin cancer (cases 3, 4, 5, 7, 8, and 9), while only one patient had a history of melanoma (case 9). discussion terra firma-forme dermatosis is a benign condition of acquired dirt-like plaques. the name, “terra firma,” is derived from the latin words meaning “solid land” [1,2]. it has also been referred to as duncan’s dirty dermatosis since the condition was first described by duncan, tschen, and knox in 1987 [3]. this condition affects people of all ages, with some reports of a higher incidence in children and young adults [1,3-7]. terra firma-forme dermatosis does not figure 3. an 82-year-old man (case 8) with a hyperkeratotic brown plaque in the inguinal fold, as seen on initial presentation (a). clearing of the lesion in the inguinal fold after aggressive wiping with 70% isopropyl alcohol pads (b). [copyright: ©2015 greywal et al.] a b figure 4. clinical presentation of terra firma-forme dermatosis in a 58-year-old man (case 2). brown plaques affecting the interspaces between the first through fourth toes, bilaterally (a). clearing of terra firma-forme dermatosis after wiping with 70% isopropyl alcohol pads (b). [copyright: ©2015 greywal et al.] a b figure 5. terra firma-forme dermatosis in a 66-year-old man (case 4). initial presentation of black and brown papules and plaques on the concha of the right ear (a). resolution of all pigmentation after the application of 70% isopropyl alcohol (b). [copyright: ©2015 greywal et al.] a b review | dermatol pract concept 2015;5(3):8 33 new lesions on his subclavicular chest within three months after the original lesions had been completely removed [2]. in this situation, additional wiping with isopropyl alcohol is recommended [2,8]. some patients may require weekly application of isopropyl alcohol to maintain resolution or for prophylaxis [2,8]. consistent moisturizing to the effected skin is important to prevent xerosis after regular treatments with isopropyl alcohol. conclusion terra firma-forme dermatosis presents as asymptomatic, brown, dirt-like plaques. all of our patients presented with this typical morphology, and their lesions successfully resolved after the application of 70% isopropyl alcohol. while terra firma-forme dermatosis typically presents on the neck, face, trunk, and ankles, our patients’ lesions predominantly involved skin folds. it is important to consider the possibility of this benign dermatologic condition and the many locations in which it can present since it can readily mimic other cutaneous disorders. therefore, in order to avoid unnecessary referrals, biopsies, blood tests, and medications, we suggest a trial of wiping the skin lesion with 70% isopropyl alcohol pads when the diagnosis of terra firma-forme dermatosis is entertained. references 1. akkash l, badran d, al-omari aq. terra firma-forme dermatosi. case series and review of the literature. j dtsch dermatol ges 2009;7:102-7. 2. ozturk f, kocabas e, ertan p, ermertcan at. terra firma-forme dermatosis. cutan ocul toxicol 2010;29:303-5. 3. duncan wc, tschen ja, knox jm. terra firma-forme dermatosis. arch dermatol 1987;123:567-9. 4. guarneri c, guarneri f, cannavo sp. terra firma-forme dermatosis. int j dermatol 2008;47:482-4. 5. pavlovic md, dragos v, potocnik m, adamic m. terra firmaforme dermatosis in a child. acta dermatovenerol alp pannonica adriat 2008;17:41-2. 6. berk dr, bruckner al. terra firma-forme dermatosis in a 4-month-old girl. pediatr dermatol 2011;28:79-81. 7. ratcliffe a, williamson d, hesseling m. terra firma-forme dermatosis: it’s easy when you know it. arch dis child 2013;98:520. 8. erkek e, sahin s, cetin ed, sezer e. terra firma-forme dermatosis. indian j dermatol venereol leprol 2012;78:358-60. 9. berk dr. terra firma-forme dermatosis: a retrospective review of 31 patients. pediatr dermatol 2011;29:297-300. 10. thomas rs, collins j, young rj, bohlke a. atypical presentations of terra firma-forme dermatosis [published online ahead of print january 30 2015]. pediatr dermatol 2015. doi: 10.1111/ pde.12505. 11. tavli yu, mevlitoglu pi, toy h, unal m. terra firma forme disease. j paediatr child health 2012;48:1046-7. 12. berk dr, mutizwa mm. comment regarding the histopathology of terra firma-forme dermatosis. j cutan pathol 2012;39:300-1. have a predilection for any particular gender, although our patients were predominantly men [4,6]. it is also unrelated to any known genetic condition or familial inheritance [8]. terra firma-forme dermatosis usually presents as asymptomatic black or brown, dirt-like plaques [1,4,6,9,10]. it may also have a papillomatous, verrucous, or reticulate appearance [6,11]. lesions are typically located on the neck, face, trunk, and ankles, although they may involve any area of the body [1,2,4,5,7-9]. one study observed that terra firmaforme dermatosis had a predilection for heavier patients and concave skin areas, which is consistent with the majority of our patients’ presentations [12]. the distribution of terra firma-forme dermatosis varies; it can be localized, generalized, bilateral, or unilateral [4,7-9]. lesions appear in patients with normal hygiene, yet are resistant to scrubbing with soap and water [1,3,10,11]. in addition, investigators have suggested that terra firma-forme dermatosis most often presents during the warmer months of the year [3,4]. the diagnosis of terra firma-forme dermatosis is classically based upon clinical presentation and subsequent lesion resolution after the application of 70% isopropyl alcohol [1-4,6,9,11]. aggressive rubbing with 70% isopropyl alcohol pads is sometimes required to achieve the appropriate shearing forces to remove all pigmentation [2]. biopsies are not frequently performed. if tissue is obtained, hematoxylin and eosin staining will show lamellar hyperkeratosis with compact orthokeratotic whorls and an absence of parakeratosis, acanthosis, papillomatosis, keratotic material between the papillae, and melanin deposition not only within the basal layer but also in the hyperkeratotic areas [1-6,8,10,11]. numerous keratin globules can also be visualized throughout the stratum corneum with toluidine blue staining [1,2,5]. the differential diagnosis for terra firma-forme dermatosis includes acanthosis nigricans, confluent and reticulate papillomatosis, dermatosis neglecta, dirty neck syndrome of atopic dermatitis, epidermal nevi, epidermolytic hyperkeratosis, granular parakeratosis, ichthyosis, idiopathic deciduous skin, omphalith, pseudoacanthosis nigricans, seborrheic keratosis, and tinea versicolor [1-6,8-11]. the etiology of terra firma-forme dermatosis is unclear [1-5,11]. many believe this condition is caused by delayed keratinocyte maturation, which leads to the retention of keratinocytes and melanin within the epidermis [3,4,6,8,10]. this disordered keratinocyte buildup and compaction with surrounding sebum and dirt may ultimately explain the hyperkeratosis and hyperpigmentation clinically seen in terra firma-forme dermatosis [3,8,10]. the treatment of terra firma-forme dermatosis consists of the application of 70% isopropyl alcohol; it is both diagnostic and therapeutic [1,3-5,10,11]. occasionally, lesions may recur after the initial complete removal of all hyperpigmentation; indeed, one of our patients (case 7) developed easily treated dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022110 1 agminated nevi of the foot with checkerboard and blaschkoid distribution vito ingordo1, nicola licci2, stefano caccavale3, gerardo ferrara4 1 outpatients’ service of dermatology, district n. 6, local health centre taranto, taranto, italy, centro studi gised, bergamo, italy 2 outpatients’ service of dermatology, district n. 1, local health centre taranto, taranto, italy 3 dermatology unit, university of campania “l. vanvitelli”, napoli, italy 4 anatomic pathology unit, hospital of macerata, macerata, italy key words: agminated nevi, acquired melanocytic nevi, congenital melanocytic nevi, acral nevi, dermoscopy citation: ingordo v, licci n, caccavale s, ferrara g. agminated nevi of the foot with checkerboard and blaschkoid distribution. dermatol pract concept. 2022;12(3):e2022110. doi: https://doi.org/10.5826/dpc.1203a110 accepted: november 8, 2021; published: july 2022 copyright: ©2022 ingordo et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: stefano caccavale, md, dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy; phone: +39 3336365526; fax: +39 0815468759; e-mail: stefano85med@libero.it introduction agminated nevi (an) are an infrequent group of melanocytic nevi (mn), whose name derives from the latin word agmen, meaning “aggregation.” an are indeed a clustered group of lesions confined to a localized area of the body. many pigmented lesions have been described in the literature as agminated, including spitz nevi, blue nevi, lentigines, congenital melanocytic nevi (cmn), acquired melanocytic nevi (amn). we report a case of a woman with an of the foot with a peculiar checkerboard and blaschkoid distribution. case presentation a 34-years-old woman was seen for multiple mn arranged in a checkerboard pattern on her right foot. she reported that some nevi have been present on the sole since infancy, while many other nevi appeared on the lateral, medial and plantar location later on. dermoscopically, the pigmented lesions of the lateral margin of the foot (figure 1a), as well as those located on the fourth and fifth toe and in fourth interdigital space (figure1b) showed a reticular pattern ( figure1d) and a transition pattern (reticular plus parallel furrow or lattice-like) (figure1e). the nevi located on the sole (figure1c) disclosed various dermoscopic patterns: homogeneous, figure 1f), fibrillary (figure1g), lattice-like pattern (figure1h), lattice-like pattern with ovoid structure of the furrows (figure1i). according to the patient medical history and dermoscopic patterns of acral nevi, a diagnosis of uncommon coexistence of acral cmn and amn was done. unfortunately, the patient refused the biopsy and histopathologic examination of some nevi. anyhow, we decided to plan clinical and dermoscopic monitoring of our patient every 3–6 months. 2 research letter | dermatol pract concept. 2022;12(3):e2022110 besides, we know from the literature that common and dysplastic amn can be arranged seldom in a checkerboard pattern, while cmn are commonly arranged along the blaschko lines [1]. briefly, the checkerboard pattern of acral amn has been explained by an early postzygotic mutational event giving rise to loss of heterozygosity, that is the loss of a normal wild-type allele, and which leads to the expression of a mutant or recessive allele [2]. although the diagnosis was not confirmed by a biopsy, this is a case with a peculiar arrangement of an involving the acral area. reference 1. torchia d. melanocytic naevi clustered on normal background skin. clin exp dermatol. 2015;40(3):231-237. doi: 10.1111/ ced.12586. pmid: 25703021.2. happle r. loss of heterozygosity in human skin. j am acad dermatol 1999; 41: 143-61. j am acad dermatol. 1999;41(2 pt 1):143–164. doi: 10.1016/s0190 -9622(99)70042-3. pmid: 10426882. conclusions according to the dual concept of nevogenesis, small cmn are present at birth or in the first years of life (so-called tardive small cmn) and are clinically and dermoscopically indistinguishable from early-onset amn. they are both genetically determined, usually share the same dermoscopic features (ie globular pattern) and evolve in nevi with a cobblestone or homogeneous pattern in adult life. these nevi often exhibit overlapping clinical and histopathological features. on the contrary, the “true” amn develops in adolescence and adult life and could be influenced by environmental factors, such as an intermittent sun exposure. in our patient, the lesions with a homogeneous brown-grayish or a parallel-furrow pattern combining with an ovoid shape of the lines, mainly located on the sole along blaschko lines, and appeared in infancy, could be cmn. on the contrary, the lesions with a reticular and checkerboard pattern, on lateral, medial and interdigital sides of the foot, appeared in late childhood and adolescence, could be amn. figure 1. (a) clinical image of the pigmented lesions of the lateral margin of patient right foot. (b) close-up picture of agminated nevi located on the fourth and fifth toe and in fourth interdigital space. (c) clinical picture of agminated nevi of the right sole. (d and e) dermoscopy of agminated nevi on the lateral margin of patient right foot. (f-i) dermoscopy of agminated nevi of the right sole. dermatology: practical and conceptual research | dermatol pract concept 2019;9(3):4 195 dermatology practical & conceptual effects of a 1-day training course in dermoscopy among general practitioners anna augustsson1, john paoli2,3 1 praktikertjänst ab, centrumpraktiken kungälv, sweden 2 department of dermatology and venereology, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, sweden 3 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden key words: dermoscopy, general medicine, diagnostic accuracy, malignant melanoma, nonmelanoma skin cancer citation: augustsson a, paoli j. effects of a 1-day training course in dermoscopy among general practitioners. dermatol pract concept. 2019;9(3):195-199. doi: https://doi.org/10.5826/dpc.0903a04 accepted: may 20, 2019; published: july 31, 2019 copyright: ©2019 augustsson and paoli. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: anna augustsson, md, resident in general medicine praktikertjänst, centrumpraktiken kungälv, triogatan 5, 442 43 kungälv, sweden. email: anna.augustsson@ptj.se background: general practitioners (gps) are often the first point of contact for swedish patients seeking medical advice for skin lesions of concern, but many lack training in dermoscopy. objective: to examine the effects of a 1-day training course in dermoscopy among swedish gps. methods: the intervention group consisted of gps who underwent a 1-day training course in dermoscopy and a control group that did not undergo any education. before the training course, the intervention group performed a test consisting of 30 dermoscopy cases including 9 different benign and malignant melanocytic and nonmelanocytic diagnoses. the participants then took the same test directly after the course and again after 6 months. the control group took the same test twice with a 6-month interval in between tests in order to avoid recall bias. results: twenty-seven gps in the intervention group took the test before and immediately after the course with an improvement of their median test scores by 8 points (13 vs 20 correct answers, p < 0.01). eighteen participants also took the test a third time after 6 months with similar results compared with the second test (median scores of 20.5 vs 20.0, p = 0.3). in the control group, 16 persons preformed both tests with an improvement of their median score by 2 points (13.5 vs 15.5 correct answers, p = 0.06). conclusions: the results of this study show positive effects on diagnostic accuracy in a test situation among gps receiving a 1-day training course in dermoscopy. abstract 196 research | dermatol pract concept 2019;9(3):4 tions asking to diagnose 30 dermoscopy cases. the participants were then asked to take the same test directly after the course and again after 6 months. the control group completed the same test twice with a 6-month interval between tests in order to avoid recall bias. participants and controls were informed of the number of correct answers after each test occasion, but the correct answers to the cases were not released until after the last test occasion. the 30 multiple-choice questions in the online test contained a clinical and a dermoscopic image of a single lesion followed by 4 different diagnostic alternatives with only 1 diagnosis being correct. the test had a time limit of 20 minutes. the cases consisted of 9 melanomas, 8 nevi, 3 basal cell carcinomas, 2 squamous cell carcinomas, 3 seborrheic keratoses, 2 dermatofibromas, 1 squamous cell carcinoma in situ, 1 solar lentigo, and 1 angioma. the pictures were taken with a smartphone (iphone 4, apple, cupertino, california, usa) and a hand-held dermatoscope compatible with the smartphone (fotofinder handyscope, fotofinder systems gmbh, bad birnbach, germany) at the department of dermatology at sahlgrenska university hospital in gothenburg, sweden. the malignant diagnoses were all confirmed by histopathological examination, whereas most of the benign cases were diagnosed by clinical examination only by an expert in dermoscopy. none of the images in the test were shown during the course. the dermoscopy course used in the study was certified by lipus (the physicians’ institute for the professional development of healthcare), a national organization that certifies courses for physicians in sweden (www.lipus.se). the course comprised 5 separate lectures on the dermoscopic technique and terminology (30 minutes); an introduction to “pattern analysis” and the diagnosis of benign nonmelanocytic lesions (30 minutes), followed by 3 lectures focusing on the dermoscopic diagnosis of melanocytic lesions (60 minutes), basal cell carcinoma (30 minutes) as well as squamous cell carcinoma and precursor lesions (30 minutes). these lectures were interlaced with 2 case-based interactive sessions (45 and 60 minutes, respectively) and the courses concluded with a question-and-answers session (15 minutes). all participants were provided with pdf files of the presentations. the dermoscopy algorithm taught was “pattern analysis” [12]. an online questionnaire about previous experience concerning dermoscopy was also sent to both groups. the questionnaire contained questions regarding previous training in dermoscopy, how many patients seeking care for skin lesions of concern they met every week, whether they had access to a dermatoscope and, if so, how often they used dermoscopy during their clinical examination. the intervention group consisted of resident physicians and specialists in general medicine that participated in the 1-day training course. the control group consisted of a ranintroduction the incidence of malignant melanoma in sweden has increased by 5% every year during the last decade, making it the sixth most common form of cancer in men and the fifth in women [1]. early diagnosis is important for prognosis and survival [2]. furthermore, nonmelanoma skin cancer (excluding basal cell carcinomas) is the second most common type of cancer for both men and women in sweden. the number of cases per 100,000 persons has increased yearly by an average of 6.5% among women and 4.9% among men during the past decade [1]. swedish patients seeking medical advice for skin lesions of concern most often have their first contact with health care at their local primary health care center. it has proven to be challenging for general practitioners (gps) to diagnose skin lesions correctly and to avoid unnecessary excisions or referrals to dermatologists with the associated increase in health care costs [3]. previous studies have shown that dermoscopy in addition to clinical examination can increase the diagnostic accuracy of pigmented skin lesions when performed by trained physicians. results from a meta-analysis showed that physicians who underwent at least minimal training in dermoscopy increased their diagnostic accuracy in identifying melanoma when examining pigmented skin lesions [4]. a study by rosendahl et al showed increased diagnostic accuracy when examining both melanocytic and nonmelanocytic skin lesions using dermoscopy in addition to clinical examination [5]. to increase the diagnostic accuracy, some form of training in dermoscopy seems necessary. binder et al showed improved diagnostic accuracy among dermatologists after 9 hours of dermoscopy training, whereas the diagnostic accuracy without previous training declined [6]. positive effects on diagnostic accuracy for both melanocytic and nonmelanocytic lesions have also been shown among gps after dermoscopy training [7-9]. the amount of training among gps in diagnosing skin tumors may vary between different countries [10]. in sweden, no training in dermoscopy is required for gps during their residency program [11]. the aim of this study was to examine the effects of a 1-day training course in dermoscopy among swedish residents and specialists in general medicine directly after the course and after a 6-month follow-up period. materials and methods the study was designed using an intervention group of gps that underwent a 1-day training course in dermoscopy and a control group that did not undergo any education. approximately 6 weeks before the training course, the intervention group took an online test consisting of multiple-choice quesresearch | dermatol pract concept 2019;9(3):4 197 domly selected mix of resident physicians and specialists in general medicine who were invited via email. the goal was to recruit the same number of participants in both groups. the collection of all data was retrieved by email invitations with links to the online test and questionnaire. statistical analysis stata (statacorp llc, texas, usa) was used for the statistical analysis. since normal distribution could not be assumed owing to the small sample size, wilcoxon signed rank test was used to calculate changes in individual test scores after completion of the training course (cases) and after 6 months (cases and controls). the results of the questionnaire are presented with simple descriptive statistics. results the intervention group initially consisted of 56 physicians of which 41 answered the first test, 32 took the second test, and 26 also replied to the last test. this resulted in 27 cases with paired observations between the first and second test and 18 cases in which the physicians performed all 3 tests. the control group consisted of 121 physicians invited by email. among these, 30 answered the first test and 16 also took the second test with 16 paired observations. table 1 presents descriptive data received from the questionnaires of the 27 participants in the intervention group that had at least 1 paired observation and the 16 participants in the control group with paired observations. among the 27 paired observations in the intervention group, the median number of correct answers on the first test before the course was 13 out of 30 cases (43.3%) (interquartile range [iqr] = 4.0). in the second test immediately after the course, the median was 21 points (70.0%) (iqr = 4.0), which meant an improvement of the median score by 8 points or 26.7% (p < 0.01). table 2 shows the results of the 18 participants who also took the test a third time after 6 months. a significant table 1. previous experience with dermoscopy among physicians with paired observations in both groups intervention group (n = 27) control group (n = 16) clinical experience specialist in general medicine 16 (59.3%) 2 (12.5%) resident physician in general medicine 11 (40.7%) 14 (87.5%) do you have access to dermatoscope at your clinic? yes 26 (96.3%) 14 (87.5%) no 1 (3.7%) 2 (12.5%) how many patients seeking advice for skin lesions of concern do you see every week? 0-3 19 (70.4%) 13 (81.3%) ≥4 8 (29.6%) 3 (18.8%) how often do you use dermoscopy to diagnose skin lesions? once a week or more often 19 (70.4%) 11 (68.8%) a few times per month or never 8 (29.6%) 5 (31.3%) do you have any previous educational experience in dermoscopy? yes 15 (55.6%) 8 (50.0%) no 12 (44.4%) 8 (50.0%) table 2. test results among the course participants before vs after course vs 6 months after course test before course test after course test 6 months after course median (interquartile), n = 18 14.0 (4.0) 20.5 (3.0) 20.0 (5.0) p valuea before vs after course (<0.01) p valuea before vs 6 months after course (<0.01) p valuea after vs 6 months after course (0.3) awilcoxon signed rank test. 198 research | dermatol pract concept 2019;9(3):4 change was observed between the first and second test, but no significant change was demonstrated between the second and third test. among the 16 physicians in the control group with paired observations, the median score for the first test was 13.5 points (iqr = 5.0) compared with 15.5 points (iqr = 4.5) in the second test after 6 months. the improvement of 2.0 points was not significant (p = 0.06). the baseline results (first test) were similar in both groups with 13.5 points (iqr = 5.0) in the intervention group and 13.0 points (iqr = 4.0) in the control group (p = 0.093). discussion after completion of the 1-day training course in dermoscopy, the course participants increased their diagnostic accuracy measured as an increase of their median test scores by 8.0 points. the improvement was statistically significant compared with the control subjects and was also considered to be a relevant improvement. at the follow-up test after 6 months, there was no significant difference in test results among participants, meaning that the newfound knowledge seemed to persist over time. although the control group also showed a small improvement of 2 points in their test scores after 6 months, the change was not significant. the prior educational experience in dermoscopy was similar in both groups as was the number of patients they met and how often they used dermoscopy in their clinical practice. the main difference between the groups was the distribution of specialists and resident physicians, with 59.3% being specialists in the intervention group compared with only 12.5% in the control group. nevertheless, both groups showed similar baseline test results, which indicates that selection bias was not a major problem. our results are in line with those of a dutch study by secker et al in which 309 gps underwent a 1-day course in dermoscopy and took a test with 20 cases before the course and 3 months after. the authors found that the diagnostic accuracy increased for all pigmented skin lesions except nevi [9]. in our study, we have not carried out subgroup analyses on the diagnostic accuracy for different lesion types considering our small sample size. another study by argenziano et al also showed positive effects among gps in spain and italy using dermoscopy when diagnosing skin lesions [7]. in this study, gps underwent a 1-day educational program in skin cancer diagnostics including dermoscopy training using the “3-point checklist” algorithm [13]. physicians were randomized into 2 groups where 1 group was allowed to use dermoscopy in addition to the clinical examination and 1 group was allowed only a clinical examination. the group using dermoscopy had a 25% higher sensitivity in detecting lesions with a suspicion of skin cancer. the number of participants and controls was unfortunately smaller than we had first hoped for despite many reminders to those invited. however, the addition of a control group strengthened our results showing that a 1-day training course improved the test results and that there was no obvious recall bias despite repeating the same online test. the follow-up time of 6 months between the tests was also longer than that of previous studies [9]. conclusions since the overall incidence of skin cancer is increasing in sweden and gps are often the first contact with health care that the patients encounter, good diagnostic accuracy of skin lesions of concern in primary care is essential. in previous studies, it has been shown that dermoscopy in addition to clinical examination increases the diagnostic accuracy among both dermatologists and gps [4,5,7,8]. increased competence among gps can potentially also decrease the number of unnecessary excisions and referrals to dermatologists. the results of this study show the positive effects of a 1-day training course in dermoscopy for gps. hopefully, this can spread the interest in dermoscopy within primary care. references 1. national board of health and welfare. cancer incidence in sweden 2017 [in swedish]. 2018. retrieved from: https://www. socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf. accessed march 5, 2019. 2. confederation of regional cancer centres in sweden. malignant melanoma: national guideline [in swedish]. 2018. retrieved from: https://www.cancercentrum.se/globalassets/cancerdiagnoser/hud/ vardprogram/nationellt-vardprogram-malignt-melanom.pdf. accessed march 5, 2019. 3. lindelöf b, hedblad ma, ringborg u. nevus or malignant melanoma? correct diagnostic competence results in lower costs [in swedish]. läkartidningen. 2008;105(39):2666-2669. 4. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. 5. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068-1073. 6. binder m, puespoeck-schwarz m, steiner a, et al. epiluminescence microscopy of small pigmented skin lesions: short-term formal training improves the diagnostic performance of dermatologists. j am acad dermatol. 1997;36(2):197-202. 7. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877-1882. 8. rosendahl c, williams g, eley d, et al. the impact of subspecialization and dermatoscopy use on accuracy of melanoma diagnosis among primary care doctors in australia. j am acad dermatol. 2012;67(5):846-852. https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf research | dermatol pract concept 2019;9(3):4 199 9. secker lj, buis pa, bergman w, kukutsch na. effect of a dermoscopy training course on the accuracy of primary care physicians in diagnosing pigmented lesions. acta derm venereol. 2017;97(2):263-265. 10. cate ot. medical education in the netherlands. med teach. 2007;29(8):752-757. 11. national board of health and welfare. regulations and general guidelines for doctor´s specialist medical training (sosfs 2015:8) [in swedish]. acting general counsel pär ödman; 2015. retrieved from: http://www.socialstyrelsen.se/lists/artikelkatalog/ attachments/19743/2015-3-1.pdf. accessed april 26, 2017. 12. marghoob aa, braun r. proposal for a revised 2-step algorithm for the classification of lesions of the skin using dermoscopy. arch dermatol. 2010;146(4):426-428. 13. soyer hp, argenziano g, zalaudek i, et al. three-point checklist of dermoscopy: a new screening method for early detection of melanoma. dermatology. 2004;208(1):27-31. dermatology: practical and conceptual 272 research | dermatol pract concept 2019;9(4):5 dermatology practical & conceptual alopecia areata incognita and diffuse alopecia areata: clinical, trichoscopic, histopathological, and therapeutic features of a 5-year study aurora alessandrini1, michela starace1, francesca bruni1, nicolò brandi1, carlotta baraldi1, cosimo misciali1, pier alessandro fanti1, bianca maria piraccini1 1 department of experimental, diagnostic and specialty medicine, division of dermatology, university of bologna, bologna, italy key words: alopecia areata incognita, diffuse alopecia areata, yellow dots, histopathology, therapy citation: alessandrini a, starace m, bruni f, brandi n, baraldi c, misciali c, fanti pa, piraccini bm. alopecia areata incognita and diffuse alopecia areata: clinical, trichoscopic, histopathological, and therapeutic features of a 5-year study. dermatol pract concept. 2019;9(4):272-277. doi: https://doi.org/10.5826/dpc.0904a05 accepted: july 23, 2019; published: october 31, 2019 copyright: ©2019 alessandrini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: aurora alessandrini, md, department of experimental, diagnostic and specialty medicine, division of dermatology, university of bologna, via massarenti 1, 40138 bologna, italy. email: aurora.alessandrini@alice.it background: alopecia areata is a nonscarring hair loss that usually causes round patches of baldness, but alopecia areata incognita (aai) and diffuse alopecia areata (daa) can cause a diffuse and acute pattern of hair loss. objective: to analyze the clinical, trichoscopic, histological, and therapeutic features of aai and daa. methods: the study was designed to include data of patients with histological diagnosis of aai and daa enrolled in our hair disease outpatient consultations. results: daa had a greater involvement of the parietal and anterior-temporal regions, while aai manifested itself mainly in the occipital-parietal regions. the most frequent pattern was empty yellow dots, yellow dots with vellus hairs, and small hair in regrowth, but the presence of pigtail hair was found almost exclusively in those with aai. in cases of dda, the finding of dystrophic hair and black dots was more frequent. the most frequent trichoscopic sign in both diseases was the presence of empty yellow dots, which, however, were described in a higher percentage in cases of daa. the diseases have a benign course and are responsive to topical steroid therapy. conclusions: trichoscopy is very important for the differential diagnosis between the 2 diseases and to select the best site for biopsy. in the presence of diffuse hair thinning, these entities must be considered. abstract research | dermatol pract concept 2019;9(4):5 273 trichoscopy trichoscopy was performed in all patients and showed several patterns, especially in the parietal-occipital region (74.7%) (figure 1). the different trichoscopic patterns were correlated with clinical presentation and degrees of severity: the most frequent pattern—empty yellow dots, yellow dots with vellus hair, small hair in regrowth, and pigtail hair—corresponded to grade iii (49 patients); the pattern empty yellow dots, yellow dots with vellus hair, and small hair in regrowth was correlated with grade ii (33 patients); and the remaining patterns were associated with grade i (25 patients) (table 1). pathology aai is characterized by a preserved number of follicular units but a reduced number of terminal follicles, in particular those in anagen; in addition, a greater number of telogen units and numerous dilated infundibular hosts, rich in keratin and sebum, are evident. in 32 patients with positive pull test (29.9%), a mild inflammatory infiltrate was found around the hair follicle in the upper dermis. the hair follicles in pull test, trichoscopy, and trichoscopy-guided scalp biopsy in a standardized technique using local anesthesia and a 5-mm punch. finally, the prescribed pharmacological treatment and its efficiency were reported. results alopecia areata incognita between april 2012 and april 2017, we diagnosed aai in 107 patients, of whom 105 were female (98.13%) and only 2 were male; most were caucasians (97.19%) and the average age was 40.55 years (range 21-79). clinical features all patients were characterized by increased and diffuse hair thinning without patches, lasting months, and were grouped in 3 degrees of severity as follows: 25 patients (23.3%) with grade i, 33 patients (30.8%) with grade ii, and 49 patients (45.7%) with grade iii. a high percentage of patients were affected also by a concomitant androgenetic alopecia (102/107, 95.3%). pull test was positive in 32 patients (29.9%), showing telogen roots. this clinical classification is based on the ludwig scale [3]. introduction alopecia areata (aa) is a common cause of nonscarring hair loss that generally causes round patches of baldness on the scalp, or the whole scalp, or the entire body. in some patients, however, aa is characterized by a diffuse hair loss, commonly misdiagnosed as telogen effluvium or androgenetic alopecia. the 2 most common variants of nonpatchy aa are alopecia areata incognita (aai) and diffuse alopecia areata (daa). first described by rebora in 1987 [ 1 ] , a a i i s m o r e c o m m o n ( a b o u t 86%) among young women, especially between 20 and 40 years old [2]. clinically, it is characterized by widespread and severe hair loss, which develops rapidly in a few weeks in aai, while daa can appear over a prolonged period. currently there are no studies that describe daa and aai in a standardized way; therefore, these clinical variants of aa are often not recognized. the aim of our study is to analyze the clinical, trichoscopic, histological, and therapeutic features of these 2 entities and to underline main differences between them, especially through the aid of trichoscopy and skin biopsy, essential for diagnosis confirmation. methods the study was designed to include data of patients with a histological diagnosis of aai and daa enrolled in our hair disease outpatient consultation, from april 2012 to april 2017. inclusion criteria were histological diagnosis of aai or daa and a signed informed consent. exclusion criteria were diagnosis of other scalp diseases and/or unavailability of complete data. the study was approved by our university ethics committee. general patient information was collected, including age at onset, clinical history of the disease, and previously prescribed therapies. then each patient was subjected to global photography, figure 1. trichoscopy (magnification ×20) showing the most frequent patterns of alopecia areata incognita (a) with empty yellow dots, yellow dots with vellus hair, small hair in regrowth, and pigtail hair; (b) empty yellow dots, yellow dots with vellus hair, and small hair in regrowth. trichoscopy (magnification ×20) showing the most typical patterns of diffuse alopecia areata (c) with empty yellow dots + yellow dots with vellus hair + dystrophic hair; (d) empty yellow dots + yellow dots with vellus hair + black dots + dystrophic hair. [copyright: ©2019 alessandrini et al.] 274 research | dermatol pract concept 2019;9(4):5 catagen and telogen and the telogenic germ units were instead increased. the main histopathological aspect, described in 100% of cases, was the presence of dilated infundibular ostia (0.02-0.05 mm), empty or full of sebum and keratin, corresponding to yellow dots described by trichoscopy. small follicles in telogen were found in 86 patients (80.3%), mainly located at the bulge level. the number of vellus hair follicles and miniaturized follicles was also increased. the presence of fibrous root sheath remnants or streamers was also observed, as a result of previous damage, localized in the dermis and hypodermis, prevalently in those patients with acute hair loss and positive pull test (figure 2). therapy therapy was prescribed according to the severity of the disease, pull test, and trichoscopy (table 2). in particular, clobetasol propionate 0.05% cream under occlusion was prescribed for 69 patients (64.4%) and clobetasol propitable 1. trichoscopic features of aai and daa in our study. trichoscopic features aai, n (%) aad, n (%) empty yellow dots + yellow dots with vellus hair + small hair in regrowth + pigtail hair 53 (49.53) 3 (12) empty yellow dots + yellow dots with vellus hair + small hair in regrowth 29 (27.10) 12 (48) empty yellow dots + yellow dots with vellus hair 2 (1.86) 1 (4) empty yellow dots + small hair in regrowth 7 (6.54) yellow dots with vellus hair + small hair in regrowth + pigtail hair 4 (3.73) yellow dots with vellus hair + pigtail hair 3 (2.80) yellow dots with vellus hair + small hair in regrowth 3 (2.80) empty yellow dots + yellow dots with vellus hair + pigtail hair 2 (1.86) empty yellow dots + small hair in regrowth + black dots 2 (1.86) empty yellow dots 2 (1.86) empty yellow dots + yellow dots with vellus hair + dystrophic hair 4 (16) empty yellow dots + yellow dots with vellus hair + pigtail hair + dystrophic hair + black dots 2 (8) empty yellow dots + yellow dots with vellus hair + black dots + dystrophic hair 2 (8) dystrophic hair + black dots 1 (4) aai = alopecia areata incognita; daa = diffuse alopecia areata. figure 2. histopathological section of alopecia areata incognita: (a,b) reduced number of terminal anagen follicles, a dilated infundibular ostium with vellus hair and increased number of streamers (hematoxylin). histopathological section of diffuse alopecia areata: (c) normal number of terminal anagen follicles, slight increase in the number of streamers, an infundibular ostium dilated with cadaverized hair (h&e, eosin, ×4). horizontal section: an early anagen follicle (h&e, ×8); (d) deep perifollicular lymphocyte infiltrate (h&e, ×8). [copyright: ©2019 alessan drini et al.] a c b d research | dermatol pract concept 2019;9(4):5 275 pathology the difference in pathology from aai is a smaller number of terminal follicles in anagen, a greater number of telogen units, and numerous dilated infundibular ostia, rich in keratin and sebum. a mild inflammatory infiltrate was found around the hair follicle in the hypodermis. hair follicles in early anagen were in greater number in daa than in aai. the number of miniaturized follicles was lower in daa, according to the lower percentage of patients affected by a concomitant androgenetic alopecia. the presence of fibrous root sheath remnants or streamers was also observed, localized in the dermis and hypodermis, as a result of previous damage, prevalently in those patients with acute hair loss and positive pull test (figure 2). therapy therapy was prescribed according to the severity of the disease, pull test, and trichoscopy. in particular, clobetasol propionate 0.05% cream under occlusion was prescribed for 22 patients (88%) while clobetasol propionate 0.05% foam was prescribed for 3 patients (12%). topical corticosteroids were applied 6 nights/week for 4 months and then reduced in direct proportion to patient’s clinical and trichoscopic improvement, with further checks after 8 months and 1 year. minoxidil 2% solution twice a day clinical features all patients were characterized by diffuse hair thinning that developed quickly and was associated with increased hair loss. only 1 patient had suffered from patchy aa in the past. based on severity of hair thinning, they were grouped in 3 degrees per the ludwig scale, as follows: 7 patients (28%) with grade i, 8 patients (32%) with grade ii, and 10 patients (40%) with grade iii. androgenetic alopecia is present in 24% of patients (6/25). trichoscopy in all patients, typical trichoscopic features were not homogeneously observed in all areas of the scalp but were seen with a higher prevalence in the parietal (48%) and the anterior-temporal regions (32%). the different trichoscopic patterns were correlated with clinical presentation and severity degree: the most frequent pattern—empty yellow dots, yellow dots with vellus hair, and small hair in regrowth—corresponded to grade iii (10 patients); the pattern empty yellow dots, yellow dots with vellus hair, and dystrophic hair was correlated with grade ii (6 patients); and the remaining patterns, observed to a lesser extent, were associated with grade i (9 patients) (figure 1; table 1). onate 0.05% foam was prescribed for 38 patients (35.5%). topical corticosteroids were applied 3 nights/week for 4 months and then reduced in direct proportion to the patient’s clinical and trichoscopic improvement, with further checks after 8 months and 1 year. in only 1 case it was necessary to prescribe intramuscular triamcinolone acetonide 40 mg in association with clobetasol cream due to the severity of the disease. minoxidil 2% solution, applied twice a day, was prescribed for treating androgenetic alopecia in 88 patients (82.2%), while in 10 patients we prescribed finasteride 2.5 mg/day for allergic reaction. response to therapy was assessed based on degree of severity of the disease, pull test, and trichoscopy and was rated as decrease-arrest of hair shedding and decrease-disappearance of trichoscopy signs of aai. data collected showed that topical steroid therapy, although in different formulations, was very effective in aai treatment, even just after 4 months of therapy, with results that were maintained after 8-12 months. diffuse alopecia areata between april 2012 and april 2017, we diagnosed dda in 25 patients, all female (100%) and caucasian (25/25); average age was 38.58 years (range 24-58). table 2. response to topical steroid therapy in patients with aai and daa. therapy n (%) stability improvement remission t4 t8 t12 t4 t8 t12 t4 t8 t12 aai clobetasol 0.05% cream 69 (64.49) 17 (24.64) 6 (8.69) 5 (7.24) 52 (75.36) 34 (49.27) 16 (23.19) 0 (0) 29 (42.03) 48 (69.56) clobetasol 0.05% foam 38 (35.51) 11 (28.95) 5 (13.16) 3 (7.89) 27 (71.05) 13 (34.21) 9 (23.68) 0 (0) 20 (52.63) 26 (68.42) daa clobetasol 0.05% cream 22 (88) 5 (22.72) 2 (9.09) 1 (4.54) 17 (77.27) 5 (22.73) 0 (0) 0 (0) 15 (68.18) 21 (95.45) clobetasol 0.05% cream 3 (12) 1 (33.33) 0 (0) 0 (0) 2 (66.66) 1 (33.33) 1 (33.33) 0 (0) 2 (66.66) 2 (66.66) aai = alopecia areata incognita; daa = diffuse alopecia areata. 276 research | dermatol pract concept 2019;9(4):5 parietal and anterior-temporal regions of the scalp. the main distinguishing histopathological characteristic between daa and aai is the lymphocytic infiltrate, more abundant and profound in daa, where it is located at the level of the hypodermis and therefore represents a sign of more severe acute damage. moreover, aai is characterized by a preserved number of follicular units but a reduced number of terminal follicles, with numerous dilated infundibular hosts, corresponding to yellow dots [7]; an increased number of vellus hairs and miniaturized follicles is also observed, greater than androgenetic alopecia but lower than telogen effluvium [8]. in daa the widespread hair loss is evidenced by a lower number of terminal anagen follicles, a greater number of telogen units, and numerous yellow dots. finally, especially in patients with acute hair loss and positive pull test, there are also fibrous root sheath remnants or streamers located in the dermis and hypodermis. the evolution of aa is unpredictable: many cases, especially those affecting less than 40% of the entire scalp, heal spontaneously but recurrences are frequent and often more severe than the onset episode [8]. in our experience, the prognosis for aai and dda is generally more favorable than for patchy aa and they do not tend to relapse. no scientific papers have been published concerning therapeutic approaches and prognosis of aai, only single-case reports [3,9]. according to our evidence, both aai and daa can be considered benign. in more detail, an improvement was recorded after only 4 months of therapy in 73.8% of patients with aai and after 8 months, 49 patients (52.4%) were already in remission. similarly, improvement was observed in 68% of patients with daa after 4 months of therapy, with remission in 60% of cases after 8 months. high-potency topical steroids are therefore the therapy of choice for these forms of nonpatchy aa. combination of yellow dots and/or short hairs in regrowth has a diagnostic sensitivity for aai of 96%. the characteristic trichoscopic features of daa include instead the presence of black dots and diffuse yellow dots, with an amount proportional to the severity of the disease; in this case, black dots are the result of acute damage to the follicles, not grouped to oval areas but widespread and expanded to the whole scalp. these data have never been standardized and come from our clinical experience. the most frequent pattern seen in aai was empty yellow dots, empty yellow dots with vellus hair, and small hair in regrowth, but the presence of pigtail hair was very frequent and almost exclusively in aai (57.9%), while this sign was found only in 5 patients with dda (20%). in our opinion, this trichoscopic sign is indicative of inflammatory damage, which causes hair to fall out and, once it regrows, prevents it from getting longer and thicker. in daa, the follicular inflammatory insult is greater than in aai; therefore, the trichoscopic and histopathological features are similar to those seen in “classic” patches of acute aa. this observation is reflected by the data collected by our study, which show a greater presence of dystrophic hairs and black dots in patients with aad (9/25, 36%) compared with patients with aai (only 2 cases with trichoscopic evidence of black dots and no case with dystrophic hair) (figures 3 and 4). the most common trichoscopic sign in both diseases was the presence of empty yellow dots; >5 empty yellow dots in a 40× field were described in 23 patients with daa (92%) and in only 9 patients with aai (8.4%), corresponding to the ones with a more severe clinical presentation (grade iii). our study pointed out also a different distribution of trichoscopy patterns in the 2 diseases: aai predominately affects parietal-occipital regions whereas daa manifests itself mainly in was prescribed for treating androgenetic alopecia in 6 patients (24%). response to therapy was assessed based on the degree of severity of the disease, pull test, and trichoscopy. data collected showed that topical steroid therapy was very effective and after 1 year, almost all patients underwent complete remission of daa (21/22) (table 2). discussion aai cases amounted to 107, whereas the patients affected by daa were notably fewer (only 25), pointing out a significant difference in prevalence. both diseases were clearly prevalent in young women, with a slightly lower average age in daa (40.5 aai vs 38.5 daa). second, androgenetic alopecia was reported in 95.23% of cases of aai but in only 24% of cases of daa. these data may be related to rebora’s [1] hypothesis, which affirms aai is more frequent in patients with androgenetic alopecia because they have a high percentage of hair follicles in telogen and a low number of hair follicles in anagen with high mitotic activity. another possible hypothesis [4] claims that not all anagen hair, if affected by an inflammatory process, undergoes mitotic arrest with formation of black dots and dystrophic hair; some follicles, in fact, could pass from anagen to telogen (“escape in telogen”) without falling out immediately, thus avoiding the formation of the bald patches but instead determining a more widespread hair loss. the role of trichoscopy in aai was described for the first time by tosti et al [5], who documented the presence of diffuse yellow dots in 95% of patients. another typical trichoscopic feature of aai is the presence of short regrowing hair (0.2-0.4 mm). finally, in a small percentage of cases we found the presence of exclamation point hair, black dots, and dystrophic hair, confirming aai as a variant of classic aa. according to inui et al [6], the trichoscopic research | dermatol pract concept 2019;9(4):5 277 between the 2 pathologies. moreover, in cases of daa, the finding of dystrophic hair and black dots is more frequent, indicating the acute and deep inflammatory damage present in this disease. another important role of trichoscopy is to select the best site for biopsy, in order to correlate trichoscopy with the histopathological findings. both aai and daa have a benign course and are responsive to topical steroid therapy. in conclusion, in a case of a patient with excessive hair loss in a short time in whom trichoscopy reveals typical signs of aa in a diffuse location, a suspicion of aai or daa must be considered along with histological examination. references 1. rebora a. alopecia areata incognita: a hypothesis. dermatologica. 1987;174(5): 214-218. 2. molina l, donati a, valente ns, et al. alopecia areata incognita. clinics (sao paulo). 2011;66(3):513-515. 3. ludwig e. classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. br j dermatol. 1977;97(3):247-254. 4. park j, song kh, nam kh. circumscribed alopecia areata incognita. australas j dermatol. 2013;54(1):52-54. 5. tosti a, whiting d, iorizzo m, et al. the role of scalp dermoscopy in the diagnosis of alopecia areata incognita. j am acad dermatol. 2008;59(1):64-67. 6. inui s, nakajima t, itami s. significance of dermoscopy in acute diffuse and total alopecia of the female scalp: review of twenty cases. dermatology. 2008;217(4):333336. 7. müller csl, el shabrawi-caelen l. “follicular swiss cheese” pattern—another histopathologic clue to alopecia areata. j cutan pathol. 2011;38(2):185-189. 8. miteva m, misciali c, fanti pa, et al. histopathologic features of alopecia areata incognito: a review of 46 cases. j cutan pathol. 2012;39(6):596-602. 9. strazzulla lc, wang ehc, avila l, et al. alopecia areata: an appraisal of new treatment approaches and overview of current therapies. j am acad dermatol. 2018;78(1):15-24. cient. trichoscopy is a noninvasive diagnostic technique that directly evaluates the scalp and assumes enormous importance in the diagnosis and follow-up of hair diseases. the most frequent pattern seen in our series of patients with aai was empty yellow dots, yellow dots with vellus hair, and small hair in regrowth, but the presence of pigtail hair was very frequent and almost exclusive in aai; thus, this trichoscopic sign can represent a useful clue in the differential diagnosis conclusions in our experience, both aai and daa are typical of young women with associated androgenetic alopecia, and they present with diffuse hair thinning. however, from our analysis, we found that daa had a greater involvement of the parietal and anterior-temporal regions, whereas aai manifests itself mainly in the occipital and parietal regions. the clinical examination alone is insuffifigure 3. clinical and trichoscopic improvement in a patient with alopecia areata incognita: (a) at the first visit; (b) after 1 year of therapy. [copyright: ©2019 alessandrini et al.] a b figure 4. clinical and trichoscopic improvement of a patient with diffuse alopecia areata: (a) at the first visit; (b) after 4 months of therapy. [copyright: ©2019 alessandrini et al.] a b dermatology: practical and conceptual 24 letter | dermatol pract concept 2019;9(1):7 dermatology practical & conceptual introduction osteoma cutis is a benign uncommon tumor characterized by the presence of bone tissue in dermis or hypodermis. it is classified as primary when the bone tissue originates from the skin without a preexisting lesion and secondary when there has been a previous inflammatory, traumatic, cicatricial, or neoplastic process [1]. we report a case of primary plaque osteoma cutis. case presentation a 27-year-old woman presented with a 9-year history of slowly enlarging, hard lesions on her scalp, forehead, and nose, which created 2 irregular plaques that were painful on palpation, both with erythema in their periphery. the plaques measured approximately 1 to 5 mm in diameter (figure 1). dermoscopy showed concentric white and yellowish structures with an erythematous border area (figure 2). at age 18 the patient noted 2 small scalp lesions, hard and painful, that increased in number and size over the years. there was no personal or family history relevant to her condition. her otorhinolaryngologist reported a slight visible central nasal pyramid with slight irregularities. histopathology showed a stratum corneum with basketweave pattern, irregular acanthosis and hyperpigmentation of basal layer, superficial, and middle dermis with dilated blood vessels, atrophic hair follicles, no alteration of sweat glands, and a mild perivascular inflammatory lymphocytic infiltrate. the subcutaneous cellular tissue contained a cluster of mature bone tissue with blood vessels and connective tissue. bone trabeculae had osteocytes (figure 3). the simple lateral skull and contrast inversion radiograph showed punctiform images in the skin and subcutanedermoscopic and histopathological findings in osteoma cutis involving the face and scalp marina romero navarrete1, maría-elisa vega memije2, roberto arenas guzmán3, aureliano castillo solana4, gloria e. reyes lópez5, julieta ruiz esmenjaud6 1 dermatology, hospital general de acapulco, secretaría de salud, guerrero, mexico 2 dermatopathology, hospital general dr. manuel gea gonzález, ciudad de mexico, mexico 3 mycology, hospital general dr. manuel gea gonzález, ciudad de mexico, mexico 4 epidemiology, hospital general de acapulco, secretaría de salud, guerrero, mexico 5 otorhinolaryngology, hospital general de acapulco, secretaría de salud, guerrero, mexico 6 dermatology, private practice, ciudad de méxico, mexico key words: plaque-like osteoma cutis, primary osteoma cutis, secondary osteoma cutis citation: romero navarrete m, vega memije m-e, arenas guzmán r, castillo solana a, reyes lópez ge, ruiz esmenjaud j. dermoscopic and histopathological findings in osteoma cutis involving the face and scalp. dermatol pract concept. 2019;9(1):24-27. doi: https://doi. org/10.5826/dpc.0901a07 published: january 31, 2019 copyright: ©2019 romero navarrete et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship statement: all authors have contributed significantly to this publication. corresponding author: marina romero navarrete, de la nao 1809-501 fraccionamiento la bocana, acapulco, guerrero, méxico, 39670. email: marinaromero@live.com.mx letter | dermatol pract concept 2019;9(1):7 25 ous cellular tissue of the frontal region and nasal pyramid (figure 4a,b). laboratory values such as thyroid and lipid profile, blood chemistry, and serum calcium and phosphorus levels were within normal ranges. discussion osteoma cutis, first described by wilkens in 1858, is a benign tumor of bone in the dermis or hypodermis [1]. it is classified as primary or secondary. the primary forms represent 14%-15% of all cutaneous ossifications and can be present in association with albright hereditary osteodystrophy, progressive ossification, fibrodysplasia, or progressive osseous heteroplasia, as well as isolated, osteoma, generalized or multiple facial miliaria and plaques; and occasionally they present with transepidermal bone elimination. secondary forms have a previous trauma, infection, inflammation, or neoplasia [1,2]. the term osteoma cutis in plaque was given by worret and burgdorf in 1978 [3]. this entity can be congenital or be present in the first year of life. it is associated with neither metabolic calcium nor phosphorus alteration, nor with previous trauma or infections. it is composed of one or more plaques of bone tissue. figure 1. clinical features: plaque-like tumor on the patient’s scalp, forehead, and nose. [copyright: ©2019 romero navarrete et al.] figure 2. dermoscopic image: well-limited, concentric structures in linear arrangement with an erythematous and nacreous pink border. [copyright: ©2019 romero navarrete et al.] figure 3. histopathology: clusters of mature bone and bone trabeculae with osteocytes, blood vessels, and connective tissue (hematoxylin and eosin, 40×). [copyright: ©2019 romero navarrete et al.] figure 4. x-ray: forehead and nasal pyramid with punctiform lesions in the skin and subcutaneous cellular tissue. [copyright: ©2019 romero navarrete et al.] 26 letter | dermatol pract concept 2019;9(1):7 we searched pubmed using the key words osteoma cutis, primary osteoma cutis, plaque-like osteoma cutis, acquired plate-like, plate-like osteoma cutis, and primary osteoma cutis. we found 20 publications concerning primary osteoma cutis [1,2], and with our report there are 21 (table 1). previous reports found 57% of osteoma cutis occurring in males and 43% in females, with an age range from 10 to 77 years, median 37.8. our patient had the most frequently found topography, with clinical features similar to those of previously osteoma cutis is also used to name similar lesions that are acquired after the first year of life [1]. its pathogenesis is unknown, and it has been related to the abnormal migration of osteoblast to the skin or a metaplasia of fibroblast to osteoblasts. the case described in this report corresponds to a primary plaque osteoma cutis in an adult woman, with 9 years of evolution without reported abnormality in calcium, phosphorus, or any previous trauma or infection. histopathology showed mature bone cluster in the subcutaneous cellular tissue. table 1. publications describing plaque-like osteoma cutis: 1985-2017 author year sex age at onset (years) topography histo­ pathology dermo­ scopy evolution (years) transepidermal elimination of bone katz m et al 1985 f 24 thorax yes no 2 no cottoni f et al 1993 m 31 forehead yes no 20 yes henrich de et al 1997 f 69 scalp yes no 15 yes fazeli p et al 1999 f 66 thigh, knee yes no 30 yes boschert mt et al 2000 m 77 hand yes no 5 no grandhe n et al 2004 m 50 scalp yes no 1 yes douri t et al 2006 f 25 scalp yes no n/a no ayavini nam et al 2006 f 20 forehead, parietal region yes no 4 no cohen pr et al 2007 m 48 temporal region yes no childhood no haro r et al 2009 m 35 scalp, forehead, cheek yes no 14 yes aneiros fj et al 2010 m 25 forehead yes no 18 months no salhi a et al 2010 m 22 postauricular yes no 18 months no vashi n et al 2011 m 50 scalp, cheek, thorax, thighs yes no 31 no wu m et al 2011 m 40 scalp, nose, thorax, lower extremities yes no 13 no talsania n et al 2011 m 25 scalp yes no birth no orme cm et al 2014 m 53 scalp yes no childhood no ma hj et al 2014 f 25 parietal region, forehead yes no 5 no coutinho i et al 2014 f 10 parietal region yes no 9 no swaroop mr et al 2016 m 28 scalp yes no 4 no moreira ag et al 2017 f 44 scalp, forehead yes yes 20 no romero navarrete m et ala 2019 f 18 scalp, forehead, nose yes yes 9 no a our case. letter | dermatol pract concept 2019;9(1):7 27 uncommon entity and our case is the second one that includes dermoscopic findings. references 1. haro r, revelles jm, angulo j, et al. plaque-like osteoma cutis with transepidermal elimination. j cutan pathol. 2009;36(5):591-593. 2. moreira ag, mastrangelo mfe, carvalho qd, cuzzi t, canedo de mt, raso bp. primary isolated osteoma cutis on the face. dermatol online j. 2017;23(4):1-4. 3. worret wi, burgdorf w. congenital plaque-like osteoma of the skin in an infant [in german]. hautzart. 1978;29(1):590-596. reported cases; it is the second case described with dermoscopic findings [1,2]. previously reported treatments include surgery in 40% of cases [1,2]. one patient was treated with 0.025% retinoic acid [2]. two cases with follow-up at 6 months and 2 years reported no new lesions or recurrences [1,2]. conclusions we report the first primary plaque-like osteoma cutis case in mexico with histopathological correlation. this is an dermatology: practical and conceptual observation | dermatol pract concept 2017;7(3):11 51 dermatology practical & conceptual www.derm101.com case presentation grover’s disease, also called transient acantholytic dermatosis, is a benign condition of unknown origin characterized by an erythematous papulovesicular eruption mainly affecting the trunk of middle-aged or elderly men. uv radiation, heat and sweating may trigger or exacerbate the disease. although in some patients the disease is self-limited, it may be very persistent [1,2]. histopathologically, it is characterized by acantholysis and intraepidermal clefting. four different histopathological patterns of acantholysis have been described: darier-like, pemphigus-like, spongiotic, and hailey-haileylike [1]. these patterns may occur alone or simultaneously in the same patient. a case of grover’s disease showing a darier-like histopathological pattern and evaluated by polarized light dermoscopy (pld) and reflectance confocal microscopy (rcm) is described. grover’s disease: dermoscopy, reflectance confocal microscopy and histopathological correlation francesco lacarrubba1, simona boscaglia1, maria rita nasca1, rosario caltabiano2, giuseppe micali1 1 dermatology clinic, university of catania, italy 2 department “g.f. ingrassia”, section of anatomic pathology, university of catania, italy key words: confocal microscopy, dermoscopy, grover’s disease, darier’s disease, acantholysis, corp ronds, dyskeratosis, parakeratosis citation: lacarrubba f, boscaglia s, nasca mr, caltabiano r, micali g. grover’s disease: dermoscopy, reflectance confocal microscopy and histopathological correlation. dermatol pract concept 2017;7(3):11. doi: https://doi.org/10.5826/dpc.0703a11 received: may 13, 2017; accepted: june 5, 2017; published: july 31, 2017 copyright: ©2017 lacarrubba et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: giuseppe micali, md, dermatology clinic, university of catania, via s. sofia 78, 95123 catania, italy. tel. + 39 095 321705; fax. + 39 095 3782425. email: cldermct@gmail.com grover’s disease is a benign condition of unknown origin characterized clinically by an erythematous papulovesicular eruption and histopathologically by intraepidermal clefting and four different patterns of acantholysis: darier-like, pemphigus-like, spongiotic, and hailey-hailey-like. a case of a 54-year-old female affected by grover’s disease and showing a darier-like histopathological pattern is described. polarized light dermoscopy (pld) revealed the presence of polygonal, star-like shaped yellowish/brownish areas of various sizes surrounded by a thin whitish halo. handheld reflectance confocal microscopy (rcm) showed the presence of intraepidermal dark spaces histopathologically corresponding to intraepidermal clefts, roundish, bright cells correlating to acantholytic keratinocytes, target-like cells with a dark center and a highly reflectant halo corresponding to dyskeratotic cells, and epidermal, polygonal, structureless areas reflecting hyperparakeratosis. in conclusion, the use of pld and rcm combined with clinical presentation, personal/family history, and genetic evaluation may be useful for the non-invasive diagnosis of darier-like grover’s disease. abstract 52 observation | dermatol pract concept 2017;7(3):11 the presence of intraepidermal dark spaces; several roundish, bright cells were observed at their periphery and floating within them (figure 3a). some of these cells presented a peculiar target-like appearance, with a dark center and a highly reflectant peripheral halo (figure 3b). the polygonal areas observed at dermoscopy appeared as intraepidermal low-reflectant areas containing structureless, high-reflectant material (figure 2b). histopathological examination from a skin biopsy showed the presence of acantholysis, intraepidermal cleft formation, dyskeratosis with corp ronds and grains, and hyperparakeratosis (figure 4). direct immunofluorescence and elisa testing of anti-desmoglein 1 and 3 antibodies were negative. based on anamnestic, clinical, instrumental and laboratory data, the diagnosis of darier-like grover’s disease was made. discussion the clinical differential diagnosis of grover’s disease includes a variety of skin disorders such as pemphigus foliaceus, pemphigus vulgaris, impetigo, dermatitis herpetiformis, hailey-hailey disease and darier’s disease. histopathology examination represents the gold standard for the diagnosis. in the darier-like variety, which represents the most frequent pattern seen in grover’s disease, the histopathological aspect is similar to darier’s disease, consisting of acantholysis mainly involving suprabasal layers, dyskeratosis (with presence of grains and corps ronds), hyperkeratosis, acanthosis, and parakeratosis [1,2]. dermoscopy of grover’s disease has been described [3-5] showing similarities with darier’s disease [6,7], papua 54-year-old female presented with a three-year history of itchy papules on her trunk. as reported by the patient, lesions worsened during summer and improved in wintertime. the use of topical antibiotics and corticosteroids in the past determined transient improvements. familiar history was negative for a similar skin disorder. clinical evaluation revealed the presence of multiple papules, vesicles, excoriations and crusts localized on the back and in the infra-mammary regions (figure 1). pld (dermlite hybrid®, x10; 3 gen, san juan capistrano, ca, usa) revealed the presence of the same features in all lesions, consisting of numerous polygonal, star-like shaped yellowish/brownish areas of various sizes surrounded by a thin whitish halo (figure 2a). handheld rcm (vivascope 3000®, caliber i.d., rochester, ny, usa, distributed in europe by mavig gmbh, munich, germany) performed in different lesions showed figure 1. multiple papules, vesicles, excoriations and crusts of the trunk in a patient with grover’s disease. [copyright: ©2017 lacarrubba et al.] figure 2. polarized light dermoscopy showing polygonal, star-like shaped yellowish/brownish areas surrounded by a thin whitish halo (a). reflectance confocal microscopy of the same field showing a polygonal, intraepidermal low-reflectant area containing structureless, highreflectant material (b). [copyright: ©2017 lacarrubba et al.] observation | dermatol pract concept 2017;7(3):11 53 references 1. quirk cj, heenan pj. grover’s disease: 34 years on. australas j dermatol. 2004;45:83-6; quiz 87-8. 2. griffiths c, barker j, bleiker t, chalmers r, creamer d, eds. rook’s textbook of dermatology. 9th edition. oxford, uk: wiley-blackwell, 2016. 3. giacomel j, zalaudek i, argenziano g. dermatoscopy of grover’s disease and solitary acantholytic dyskeratoma shows a brown, star-like pattern. australas j dermatol. 2012;53:315-316. 4. specchio f, argenziano g, tiodorovic-zivkovic d, et al. dermoscopic clues to diagnose acantholytic dyskeratosis. dermatol pract concept. 2015;5(1):11. 5. errichetti e, de francesco v, pegolo e, stinco g. dermoscopy of grover’s disease: variability according to histological subtype. j dermatol. 2016;43(8):937-9. 6. lacarrubba f, verzì ae, errichetti e, stinco g, micali g. darier disease: dermoscopy, confocal microscopy, and histologic correlations. j am acad dermatol. 2015;73(3):e97-99. lar dowling–degos disease [8], and solitary acantholytic dyskeratoma [3]. common dermoscopy findings consist of polygonal, star-like shaped yellowish/brownish areas that histopathologically correspond to marked hyperparakeratosis and acanthosis, and a peripheral whitish halo that correlates with orthokeratosis and hypergranulosis. the use of rcm has been reported for the diagnosis of some vesicobullous disorders [9-13], not for grover’s disease. in our case, rcm allowed to recognize in vivo the histopathological aspects of the darier-like variety of grover’s disease: intraepidermal dark spaces corresponding to intraepidermal clefts; roundish, bright cells observed at the periphery and within these spaces correlating to acantholytic keratinocytes; epidermal, polygonal, structureless areas reflecting hyperparakeratosis; target-like cells with a dark center and a highly reflectant halo corresponding to dyskeratotic cells. these cells rule out other acantholytic disorders such as pemphigus and hailey-hailey disease, in which dyskeratosis is generally absent. similar rcm features, however, may be seen in darier’s disease [6,14]. in conclusion, the pattern seen with pld may point towards a diagnosis of darier-like grover’s disease but cannot exclude other diseases that may show similar features. rcm imaging can further narrow down the differential diagnosis to darier-like grover’s disease and darier’s disease. differentiating these two entities by histopathology is difficult to achieve, and the combined use of pld with rcm may obtain similar results without requiring skin biopsy. clinical presentation, absence of family history and, in selected cases, genetic evaluation (absence of atpa2 mutations) may address the definitive diagnosis. further pld/rcm studies on other histological variants of grover’s disease are desirable. figure 3. reflectance confocal microscopy (a and b) of another field showing the presence of intraepidermal clefts (asterisks), acantholytic cells (arrows) and dyskeratotic cells (arrowheads). [copyright: ©2017 lacarrubba et al.] figure 4. histopathology showing hyperparakeratosis, intraepidermal clefts, acantholysis and dyskeratotic cells with irregular nucleus surrounded by clear halo enclosed in eosinophilic shell (arrows). [copyright: ©2017 lacarrubba et al.] 54 observation | dermatol pract concept 2017;7(3):11 diagnosing pemphigus vulgaris and pemphigus foliaceus by reflectance confocal microscopy. skin res technol. 2012;18:339-346. 12. levi a, ophir i, lemster n, et al. noninvasive visualization of intraepidermal and subepidermal blisters in vesiculobullous skin disorders by in vivo reflectance confocal microscopy. lasers med sci. 2012;27:261-266. 13. debarbieux s, depaepe l, poulalhon n, dalle s, balme b, thomas l. reflectance confocal microscopy characteristics of eight cases of pustular eruptions and histopathological correlations. skin res technol. 2013;19:e444-452. 14. gonzález s, rubinstein g, mordovtseva v, rajadhyaksha m, anderson rr. in vivo abnormal keratinazation in darier-white’s disease as viewed by real-time confocal imaging. j cutan pathol. 1999;26(10):504-508. 7. errichetti e, stinco g, lacarrubba f, micali g. dermoscopy of darier’s disease. j eur acad dermatol venereol. 2016;30(8):13921394. 8. geissler s, dyall-smith d, coras b, guther s, peters b, stolz w. unique brown star shape on dermatoscopy of generalized dowling–degos disease. australas j dermatol. 2011;52:151-3. 9. lacarrubba f, verzì ae, pippione m, micali g. reflectance confocal microscopy in the diagnosis of vesiculobullous disorders: case series with pathologic and cytologic correlation and literature review. skin res technol. 2016;22(4):479-486. 10. angelova-fischer i, pfeuti t, zillikens d, rose c. in vivo confocal laser scanning microscopy for noninvasive diagnosis of pemphigus foliaceus. skin res technol. 2009;15:40-44. 11. kurzeja m, rakowska a, rudnicka l, olszewska m. criteria for untitled note | dermatol pract concept 2015;5(2):11 69 dermatology practical & conceptual www.derm101.com summary • metaphoric or analogical terminology is common in clinical dermatology, dermoscopy and dermatopathology. • metaphoric language in dermatology has been criticized for a perceived lack of clear definition and specificity, and non-metaphoric (descriptive) terms and diagnostic algorithms have attempted to be constructed. • metaphors are pervasive in human language and appear to be deeply rooted in our conceptual frameworks. • the utility of metaphors in dermoscopy is discussed, with particular reference to research in the cognitive sciences. introduction: metaphoric language in dermatology, dermoscopy and dermatopathology metaphor is a complex subject in language and cognitive science. it is a linguistic and conceptual tool commonly used in science and the arts and has been defined as “understanding and experiencing one kind of thing in terms of another” [1]. metaphors are a special form of analogy or association, and aim to help the learner comprehend and communicate new or unfamiliar (“target”) information based on known or familiar (“source”) knowledge. lakoff and johnson propose that our abstract thoughts are largely metaphoric, and that metaphoric language is secondary to this [1]. in their view “metaphoric thought is unavoidable, ubiquitous, and mostly unconscious,” having developed automatically in childhood as we learn to function in our everyday world [1]. consequently, they regard metaphor as a natural and unavoidable aspect of human language. metaphors are widely used in the dermatology lexicon, developed to aid recognition and description of clinical, dermoscopic, and dermatopathologic criteria. examples include the prefix “lichen” in lichen planus, “bamboo” hair, “guttate” psoriasis, “arborizing” telangiectasias, “saw tooth” pattern, and so on. besides explicit metaphoric terminology, covert metaphoric concepts are also common. the “disease as an enemy” metaphor is one example, wherein the dermatologist uses various diagnostic or therapeutic “armamentaria” to “fight” or “combat” the disorder [2]. however, metaphors have received criticism in the dermatologic literature in recent years. notably, ackerman says [3]: “. . . clichés are ubiquitous in dermatology and pathology in general and in dermatopathology in particular, the realm of inflammatory skin diseases being no exception. . . . images like ‘corps ronds and grains’ . . . , ‘dilapidated brick wall’ . . . , ‘tombstone pattern’ . . . , ‘festooning’ . . . , ‘flame figures’ . . . , ‘ground-glass cytoplasm’ . . . , and ‘saw tooth pattern’ . . . may be picturesque, but none of them lend themselves to definition meaningfully by those who mouth them . . . moreover, not a single one of those whimsical mental pictures has specificity.” metaphoric and descriptive terminology in dermoscopy: lessons from the cognitive sciences jason giacomel1, iris zalaudek2, ashfaq a. marghoob3 1 skin spectrum medical services, como, western australia, australia 2 department of dermatology, medical university of graz, graz, austria 3 memorial sloan kettering cancer center, hauppauge, ny, usa citation: giacomel j, zalaudek i, marghoob aa. metaphoric and descriptive terminology in dermoscopy: lessons from the cognitive sciences. dermatol pract concept 2015;5(2):11. doi: 10.5826/dpc.0502a11 copyright: ©2015 giacomel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: jason giacomel, mbbs, po box 270, south perth, wa, 6951, australia. tel. +61 8 9450 2113; fax. +61 8 9450 2116. email: jasongiacomel@gmail.com 70 note | dermatol pract concept 2015;5(2):11 several metaphoric terms used in traditional dermoscopic nomenclature have been defined clearly and have high specificity [8,9]; for example, “spoke-wheel” pigmentation in pigmented basal cell carcinoma (bcc) [8] (table 1). descriptive terminology is perhaps most useful when it is brief and describes simple dermoscopic features (such as a line, circle or dot), but becomes difficult when dealing with complex criteria (i.e., composed of multiple basic elements); for example, “spoke-wheel” pigmentation, or the “strawberry” pattern of facial actinic keratoses [10] (table 1). metaphors may be able to express succinctly not only basic morphologic elements of a dermoscopic feature or features, but also information relating to an often complex combination or arrangement of these features (e.g., the “strawberry” pattern of erythema surrounding hyperkeratotic follicles). lengthy descriptive text is typically harder to visualize and is less memorable than a striking and suitable metaphor, which can usually be expressed in one or few words and is frequently visual in nature (e.g., “spoke-wheel” pigmentation). however, descriptive terminology might still be useful in defining or explaining such a metaphor. schematic illustration clinical dermatology and dermoscopy are highly visual disciplines. we can infer, therefore, that the use of illustration would be an effective strategy for teaching and communicating features of skin disease. schematic illustration is well known in psychology for facilitating effective learning and communication of technical or scientific concepts. levin and mayer [11] and carney and levin [12] discuss and attempt to explain this by postulating that pictures make text more: i. concentrated: pictures focus the reader’s attention on key points in the text; ii. compact or concise: a picture can highlight essential information that may take many sentences of text to explain (i.e., “a picture is worth a thousand words”); iii. concrete: allows for easy visualization of text content. concrete pictures overcome the barrier of literal language to describe complex or abstract concepts; iv. coherent: provides a framework or clear structure for the text material. for example, sequential diagrams showing a cause-and–effect process; and v. comprehensible: links new, complex, unfamiliar text to a reader’s previous knowledge. that is, aims to help the student understand new, difficult ideas more effectively by connection to past knowledge and experience. learning and communication in dermoscopy appears to be assisted significantly by using illustration. however, effective terminology is required to describe or label these pictures. [3] in sum, ackerman regards these metaphors as lacking clear definition and specificity. similarly, kittler criticizes metaphors in traditional dermoscopy [4]: “the images invoked by metaphoric terms and opaque expressions result inevitably in failure to conjure the very same construct in the brain of any two individuals. examples: ‘leaf-like areas,’ ‘fingerprint-like structures,’ ‘fat fingers,’ ‘radial streaming,’ ‘moth-eaten border,’ ‘blue gray veil,’ and ‘honeycomb-like pattern.’ those images impede repeatable diagnosis by dermatoscopy and prevent rational communication between dermatoscopists.” moreover, alendar et al [5] write, under the heading “no need for metaphoric language,” that “the current language of dermatoscopy consists mainly of metaphoric terms that are badly defined. this language is extremely confusing and discourages students to learn the technique profoundly.” the above viewpoints present metaphors as being nonscientific, lacking clear definition and specificity. metaphor is thus regarded as a hindrance to understanding and communication in dermatology, dermatopathology and dermoscopy. descriptive terminology in dermoscopy following on from their criticism of metaphoric language in dermoscopy, kittler and colleagues have set about constructing a new dermoscopic vocabulary based on descriptive (analytic) language only, exempt from metaphors [4,6]. pigmented structures are described as “lines,” “pseudopods,” “circles,” “clods,” and “dots.” vessel morphologies are broadly described as “dots,” “clods,” and “linear” vessels, with the latter subdivided into “straight,” “looped,” “curved,” “serpentine,” “helical, ” and “coiled” type vessels (table 1). however, some of these terms are actually metaphoric. for example, “clod” is a metaphor, meaning “a lump of earth or clay” [7]. hence, the traditional dermoscopic metaphor (ovoid nest or lacunae/saccule) has been exchanged for a new metaphor (blue/gray or red clods). “pseudopod” is also used, which is employed also in traditional dermoscopy and is metaphoric, meaning ‘false foot’ (in greek). similarly, “branched serpentine” vessels describe “arborizing telangiectasias” [6] (table 1). however, “branched” is fundamentally a metaphor, meaning a natural subdivision of a plant stem or tree trunk [7]. “serpentine” vessel is used as an alternative to the traditional descriptor “linear irregular.” however, “serpentine” is metaphoric, meaning to resemble the shape of a serpent or snake [7]. paradoxically, the traditional term in this case (“linear irregular”) is essentially descriptive rather than metaphoric. although the descriptive terminologies mentioned above have been well defined by kittler and colleagues [4,6], their specificities have yet to be thoroughly assessed. conversely, note | dermatol pract concept 2015;5(2):11 71 table 1. metaphoric and descriptive terminologies listed for various dermoscopic features. definitions are also provided. dermoscopic feature (pictorial) metaphoric term descriptive (analytic) term* definition ‘comma’ vessel curved vessel broad, curved, slightly unfocused vessels. stereotypically present in dermal nevi. ‘hairpin’ vessel looped vessel vascular loops resembling a hairpin in morphology. may also be twisted. surrounded by a whitish halo when occurring in keratinizing tumors, such as ka and invasive scc. ‘glomerular’ vessel coiled vessel tortuous vessels, frequently arranged in clusters and resembling the glomerular apparatus of the kidney. classically seen in bd. ‘arborizing’ vessel branched (serpentine) vessel classical arborizing telangiectasias resemble tree branches in morphology. stem vessels of large diameter branch irregularly into focused, fi ner capillaries. a hallmark of bcc. ‘strawberry pattern’ red structureless pattern interrupted by follicular openings and white circles erythema between hyperkeratotic hair follicles (white-yellow circles), resembling the surface of a strawberry. typical of facial ak. ‘spoke-wheel’ pigmentation central (often darker) clod with radial lines radial lines, usually tan-colored, meeting at an often darker central (circular to ovoid) axis (i.e., ‘hub’ of the spoke wheel). highly specifi c for pigmented bcc. ‘(maple) leaf-like’ pigmentation radial lines connected to a common base discrete, brown to gray-blue, bulbous extensions resembling a (maple) leaf. not connected to a pigment network. highly specifi c for pigmented bcc. *according to kittler h et al [4,6]. abbreviations: ak = actinic keratosis; bcc = basal cell carcinoma; bd = bowen disease (squamous cell carcinoma in situ); ka = keratoacanthoma; scc = squamous cell carcinoma. 72 note | dermatol pract concept 2015;5(2):11 many aspects, involves seeing one kind of thing in terms of another kind of thing—what we have called metaphorical thought. metaphor is thus imaginative rationality.” we already see evidence of experientialism in dermatology by the way art can compliment science through the close personal study of visual artwork (painting). such experience can improve student’s recognition and description of essential visual features in dermatologic conditions [19,20,21]. furthermore, the paintings are basically being used as metaphors for patients, with braverman referring to the paintings as “patient surrogates” [21]. that is, the process of developing visual analytical skills might be considered in a broad sense to be an example of analogical (metaphoric) learning: with the appreciation of the visual details (clues) in the narrative paintings and their possible interpretations being used as a “source” metaphor to extrapolate to a more precise description, diagnosis and interpretation of “target” dermatological features in patients. it is also an example of experiential learning which aims to heighten observational and diagnostic skills (and hence optimized management decisions) in the student, rather than to rely on less effective methods such as mere memorization or rote learning. apt metaphoric concepts and language could therefore have a place in dermatology and dermoscopy. however, to be effective in diagnosis and communication the metaphoric term should be well constructed and used appropriately. we propose that the following four parameters should be considered; that is, the metaphor should be: (1) well defined and clearly pictured. there should be adequate text to clearly explain the (prototypical) metaphor. descriptive terminology may be useful in describing the metaphor. (2) useful. the metaphor should help the student understand a new concept that has a degree of difficulty or complexity (e.g., “strawberry” appearance of facial actinic keratosis). if the new information is relatively simple and nontechnical a metaphor may not be required—a brief descriptive, “kittlerian” type term (e.g., “line,” “circle”) may be more effective. furthermore, if an effective descriptor already exists for a given feature then introducing subsequent, less effective metaphors should be avoided. (3) fairly straightforward and commonplace (i.e., easily and quickly recognized, and easily remembered). the metaphor should be seen commonly in the everyday life of the target audience; and (4) similar in appearance to the dermatologic or dermoscopic feature it is describing. the metaphor (“source”) should resemble the feature (“target”) in form or structure and preferably also in color. too little or too much (visual) detail should be avoided. differences between the metaphor and the dermoscopic feature should be appreciated, in order to avoid over-generalization of the metathis can be provided by metaphor or descriptive text (or a mixture of both). visual metaphors visual metaphors (graphic analogies) are a form of pictorial representation and psychological studies have demonstrated that students perform better when text is accompanied by visual metaphors or analogies [13,14]. performance has been measured by using parameters such as recognition and recall of new knowledge, comprehension and application (i.e., problem solving). furthermore, visual metaphors can assist students in solving complex or highly technical (scientific) problems [15], and tend to make lessons more interesting and enjoyable for students [14]. synthesis: seeking a clear, effective terminology in dermoscopy evidence from psychology contradicts the notion that all metaphors (analogical concepts) are ineffective. contrarily, well-constructed metaphors can assist learning, comprehension, and problem solving in technical subjects. the idea that metaphors should be avoided in science may reflect the general notion that science should seek objectivity, and that “metaphor and other kinds of poetic, fanciful, rhetorical, or figurative language can always be avoided in speaking objectively, and they should be avoided, since their meanings are not clear and precise and do not fit reality in any obvious way.” [1] this is indeed the prevalent idea in the west and may in part be traced back to ancient and enormously influential thinkers like plato, who would banish poetry (and poets) from his utopian republic [16]. however, not all ancient philosophers were opposed to metaphor. aristotle believed that “it is a great thing, indeed, to make proper use of the poetic forms, . . . but the greatest thing by far is to be a master of metaphor” [1,17]; and “ordinary words convey only what we know already; it is from metaphor that we can best get hold of something fresh” [1, 18]. this function of metaphor as a tool of learning or understanding (with new “target” information built on old “source” knowledge) was one of the fundamental purposes of metaphor mentioned in the introduction. rather than rational, empirical, unemotive science being an antithesis to the subjective, emotive, imaginative arts, these two fields might alternatively be seen to compliment each other. in this way, imagination is intertwined with rationality and scientific creativity, rather than being separate to it. as lakoff and johnson [1] state: “ . . . metaphor unites reason and imagination. reason, at the very least, involves categorization, entailment, and inference. imagination, in one of its note | dermatol pract concept 2015;5(2):11 73 “shiny white streaks/lines” [25, 26, 27]. these metaphors also appear to lack specificity, being so far described in malignant as well as benign conditions such as bcc, melanoma, dermatofibroma and spitz nevi [24-27]. (2) “clods”: a clod of earth may have various sizes and shapes, and colors. the metaphor appears therefore to be somewhat vague (not readily visualized) and appears to lack high specificity; for example, “red clods“ may describe both “red lacuna” (seen in hemangioma) and “blood spots” (a feature that may be present in tumors such as invasive scc). “white clods” may refer to keratotic follicles (facial ak), the whitish globules in sebaceous hyperplasia, or the whitish globular structures of balloon cell nevi, to name but a few. the various types of “clods” could be described instead using pre-existing (but perhaps more precisely defined) metaphoric terms, for example “globule,” “ovoid nest,” and “lacunae” [4,6]. metaphors are enmeshed in our everyday language and appear to be deeply rooted in our conceptual frameworks, influencing (often subconsciously or automatically) the way we think, learn, and act [1]. the difficulty of extricating metaphor from human language in general, and dermoscopy in particular, is mentioned above and highlighted in kittler’s work [4,6] which aims to create a novel dermoscopic method without metaphoric language, but which paradoxically contains new metaphoric terms (such as “clod” and “serpentine”). as lakoff and johnson propose: “you don’t have a choice as to whether to think metaphorically. because metaphorical maps are part of our brains, we will think and speak metaphorically whether we want to or not. since the mechanism of metaphor is largely unconscious, we will think and speak metaphorically, whether we know it or not” [1]. with the traditional language of dermoscopy and the newer kittlerian terminology now co-existing side-by-side, the dermoscopy lexicon has ironically become more difficult to learn and communicate. there are now multiple terms to describe the same dermoscopic feature. these difficulties have been potentiated by a proliferation of various algorithms for diagnosing both pigmented and non-pigmented skin lesions. ideally, we should have a consistent, clear, effective, and simplified dermoscopy language (with as few algorithms as possible), which is used universally. this will require critical review of terms used in both traditional and kittlerian systems and an expert consensus reached on the favored term to be used for each feature, whether it be metaphoric or simply descriptive. a project with these objectives is currently being organized by the international skin imaging collaboration [28]. references 1. lakoff g, johnson m. metaphors we live by. 2nd edition. chicago: the university of chicago press, 2003. phor. a metaphor may be particularly useful in describing a feature that has a high specificity (e.g., “spoke wheel” and “leaf-like” pigmentation in pigmented bcc), however it may still have utility if it evokes a relatively short list of differential diagnoses. as williams notes in the cognitive science field [22]: “visual metaphors must be constructed carefully in order to be effective instructional strategies. the metaphor must be familiar to the target learner. it must come from everyday experiences and be appropriate for the developmental/educational level of the learner. the metaphor designer must create visuals with an appropriate degree of accuracy and detail. too much detail and the learner may not be able to interpret the metaphor; too little detail and the learner may not be able to find enough analogies to use the metaphor. a very accurate metaphor may contain so much detail that the learner is overwhelmed and abandons the attempt to interpret it at all. finally, the judicious use of text along with the visual metaphor may assist in the interpretation.” if care is taken to clearly construct, define and illustrate a metaphor then interobserver variability or confusion in interpretation of the dermoscopic feature may be potentially minimized. effectively constructed metaphors would defray many of the general criticisms of metaphor made by ackerman, kittler and alendar in the introduction. dermoscopic metaphors which appear to satisfy the above parameters include (see table 1): (1) “arborizing” telangiectasias: the morphology of these vessels closely resemble tree branches, and are highly specific for bcc [8]; (2) “spoke-wheel” pigmentation: the form and also color of the “source” metaphor can closely resemble the dermoscopic feature it is symbolizing, and has a high specificity (reported as 100%) for pigmented bcc [8]; (3) “strawberry” pattern: a concise, compact description of the complex arrangement of dermoscopic features seen in facial actinic keratoses [10]. an accurate representation of structure and colors. the high sensitivity and specificity of this feature has recently been reported [23]. an effective metaphor allows a dermoscopic feature to be quickly visualized and easily remembered. complex descriptive language is avoided, which may confuse the student and not be readily committed to memory. however, if a metaphor does not fulfill the above-mentioned four parameters it may be ineffective and obstruct learning. furthermore, these opaque metaphors may also lack high specificity. in our view, examples of less effective dermoscopic metaphors include: (1) “chrysalis” or “crystalline” structures [24, 25]: these are relatively complicated metaphors that do not closely resemble the corresponding dermoscopic feature. instead, simple descriptive language may be effective, namely 74 note | dermatol pract concept 2015;5(2):11 15. beveridge m, parkins e. visual representation in analogical problem solving. memory and cognition 1987;15:230-7. 16. plato. the republic (360 bc). translated by benjamin jowett. project gutenberg online ebook. available at: http://www.gutenberg.org/files/150/150.txt. accessed 23rd april 2014. 17. aristotle. poetics (section 1459a). translated by s. h. butcher. the internet classics archive. available at: http://classics.mit.edu// aristotle/poetics.html. accessed 12th september 2014. 18. aristotle’s rhetoric (section 1410b). translated by w. rhys roberts. online version available at: http://rhetoric.eserver.org/ aristotle/rhet3-10.html. accessed 12th september, 2014. 19. dolev jc, friedlaender lk, braverman im. use of fine art to enhance visual diagnostic skills. jama 2001;286(9):1020-1. 20. naghshineh s, hafler jp, miller ar, et al. formal art observation training improves medical students’ visual diagnostic skills. j gen intern med 2008;23(7):991-7. 21. braverman im. to see or not to see: how visual training can improve observational skills. clin dermatol 2011;29(3):343-6. 22. williams vs. creating effective visual metaphors. www.personal. psu.edu/staff/v/q/vqw/portfolio/vislmeta.pdf. accessed 25th june 2012. 23. huerta-brogeras m, olmos o, borbujo j, et al. validation of dermoscopy as a real-time noninvasive diagnostic imaging technique for actinic keratosis. arch dermatol 2012;148(10):1159-64. 24. marghoob aa, cowell l, kopf aw, scope a. observation of chrysalis structures with polarized dermoscopy. arch dermatol 2009;145(5):618. 25. liebman tn, rabinovitz hs, balagula y, jaimes-lopez n, marghoob aa. white shiny structures in melanoma and bcc. arch dermatol 2012;148(1):146. 26. giacomel j, zalaudek i. dermoscopy of superficial basal cell carcinoma. dermatol surg 2005;31(12):1710-3. 27. zalaudek i, ferrara g, broganelli p, et al. dermoscopy patterns of fibroepithelioma of pinkus. arch dermatol 2006;142(10):131822. 28. website. international society for digital imaging of the skin (isdis). http://www.isdis.net/index.php/projects. accessed 3rd october 2014. 2. lebwohl m. combining the new biologic agents with our current psoriasis armamentarium. j am acad dermatol 2003;49(suppl):118-24. 3. ackerman ab, böer a, bennin b, gottlieb gj. histologic diagnosis of inflammatory skin diseases: an algorithmic method based on pattern analysis. 3rd edition. new york: ardor scribendi ltd. 2005:367-8. 4. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual 2007;13(1):3. 5. alendar f, kittler h, helppikangas h, alendar t. clear definitions, simple terminology, no metaphoric terms. expert rev dermatol 2008;3:27-29. 6. kittler h, riedl e, rosendahl c, cameron a. dermatoscopy of unpigmented lesions of the skin: a new classification of vessel morphology based on pattern analysis. dermatopathology: practical & conceptual 2008;14(4):3. 7. merriam-webster dictitionary, online edition—available at: www.merriam-webster.com/dictionary. accessed 5th february 2014. 8. menzies, sw, westerhoff k, rabinovitz h, et al. the surface microscopy of pigmented basal cell carcinoma. arch dermatol 2000;136:1012-16. 9. menzies sw, crotty ka, mccarthy wh. the morphologic criteria of the pseudopod in surface microscopy. arch dermatol 1995;131(4):436–40. 10. zalaudek i, giacomel j, argenziano g, et al. dermoscopy of facial non-pigmented actinic keratosis. br j dermatol 2006;155(5):95156. 11. levin jr, mayer re. understanding illustrations in text. in: britton b, woodward a. (eds.). learning from textbooks: processes and principles hillsdale, nj: erlbaum, 1993: 95-134. 12. carney rn, levin jr. pictorial illustrations still improve students’ learning from text. educational psychology review 2002;14(1):526. 13. royer jm, cable gw. illustrations, analogies, and facilitative transfer in prose learning. journal of educational psychology 1976;68:205-9. 14. rigney jw and lutz ka. effect of graphic analogies on concepts in chemistry on learning and attitude. journal of educational psychology 1976;68:305-11. dermatology: practical and conceptual research | dermatol pract concept 2017;7(4):12 51 dermatology practical & conceptual www.derm101.com collision skin lesions—results of a multicenter study of the international dermoscopy society (ids) andreas blum1, graeme siggs2, ashfaq a. marghoob3, jürgen kreusch4, horacio cabo5, gabriella campos-do-carmo6, ana flávia cavalcanti shiraishi 7, alexander kienitz8, cayetana maldonado-seral9, paola maltagliati-holzner10, zeljko p. mijuskovic11, andrea m. yoshimura12, elvira moscarella13, harold s. rabinovitz14, cristina rodriguez-garcia15, sonia rodríguez saa16, pietro rubegni17, francesco savoia18, olga simionescu19, pedro zaballos diego20, rainer hofmann-wellenhof21 1 public, private and teaching practice of dermatology, konstanz, germany 2 sundoctors skin cancer clinic, glenunga, adelaide, australia 3 department of dermatology, memorial sloan kettering skin cancer center, new york, ny, usa 4 public and private practice of dermatology, lübeck, germany 5 research institut, university of buenos aires, argentina 6 gávea medical center, rio de janeiro, brazil 7 dermatology service, hospital e maternidade celso pierro, pucc, campinas, sao paulo, brazil 8 public and private practice of dermatology, dingolfing, germany 9 department of dermatology, hospital universitario central de asturias, oviedo, spain 10 public and private practice of dermatology, stuttgart, germany 11 department of dermatology and venereology, faculty of medicine, military medical academy, belgrade, serbia 12 university of campinas, campinas, brazil 13 dermatology and skin cancer unit, arcispedale s. maria nuova, irccs, reggio emilia, italy 14 university of miami, miller school of medicine, miami, fl, usa 15 department of dermatology, hospital universitario de canarias, la laguna, tenerife, spain 16 department of dermatology, hospital del carmen, mendoza, argentina 17 department of clinical medicine and immunological science, dermatology section, university of siena, siena, italy 18 unit of dermatology, ausl della romagna, lugo, italy 19 1st clinic of dermatology, carol davila university of medicine and pharmacy, colentina hospital, bucharest, romania 20 dermatology department, hospital de sant pau i santa tecla, tarragona, spain 21 department of dermatology, medical university of graz, graz, austria key words: collision skin lesions, dermoscopy, dermatoscopy citation: blum a, siggs g, marghoob aa, kreusch j, cabo h, campos-do-carmo g, cavalcanti shiraishi af, kienitz a, maldonado-seral c, maltagliati-holzner p, mijuskovic zp, yoshimura am, moscarella e, rabinovitz h, rodriguez-garcia c, rodriguez saa s, rubegni p, savoia f, simionescu o, zaballos diego p, hofmann-wellenhof r. collision skin lesions—results of a multicenter study of the international dermoscopy society (ids). dermatol pract concept 2017;7(4):51-62. doi: https://doi.org/10.5826/dpc.0704a12 received: june 7, 2017; accepted: august 20, 2017; published: july 31, 2017 copyright: ©2017 blum et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: andreas blum, md, msc, dermprevoncol, public and private teaching practice of dermatology, augustinerplatz 7, 78462 konstanz, germany. tel.+49 7531 64311; fax. +49 7531 60054. email: a.blum@derma.de 52 research | dermatol pract concept 2017;7(4):12 methods patient selection and design in this retrospective, observational study, patients’ data and dermoscopic images of histopathologically diagnosed csls were included from 21 pigmented lesion clinics in nine countries: argentina (2 centers), australia, brazil (3), germany (4), italy (4), romania, serbia, spain (3), and united states of america (2). csls were collected from july through december 2012 via an e-mail request sent to all ids members. for each lesion, a patient data intake form, digital dermoscopic polarized and/or non-polarized and in-focus image(s) in jpeg format were requested. the csls had to fit within the field of view of the image to be included in the study. the following data variables were recorded for each lesion: gender, age, anatomic site, and the histopathology report. csls of the nails and mucosa were excluded. anatomic sites were classified into head and neck, upper extremities, trunk, and lower extremities. the micro-anatomical location of the skin was classified as epidermal or dermal. based on this the different subpopulations of cells within the csls were subdivided into epidermal-epidermal, epidermal-dermal and dermal-dermal combination according to the histopathology reports. all data and digital images were assigned unique identifiers, anonymized, and sent via e-mail to the study coordinator (ab). the approval for this study was waived by the ethics committee of the medical council baden-wuerttemberg, stuttgart, germany. introduction human skin consists of several layers with different cell types. any possible intrinsic or extrinsic stimulation can trigger any one of these cells to proliferate, which can lead to the development of various combinations of skin tumors, both benign and malignant (table 1). the challenge for the patient and clinician is to correctly diagnose these lesions with the aim of excising early skin cancer and minimizing the biopsy or excision of benign lesions. derm(at)oscopy is a noninvasive tool that helps improve the clinician’s diagnostic sensitivity and specificity. dermoscopy is widely accepted and used for the diagnosis of primary and recurrent pigmented and non-pigmented lesions of the skin, nail apparatus, hair, acral skin and mucosal areas [1-7] with a high diagnostic accuracy [8-12]. while the dermoscopic features of single lesions have been well described (table 1), the possibilities and causes of collision skin lesions (csls) remain to be characterized. a medline search performed before starting this study revealed a few case reports [13-31], and a few dermoscopic observations of a collection of csls with 17 pigmented actinic keratoses [32] in 3/130 dermatofibromas (2.3%) [33] and in 9/412 basal cell carcinomas (bccs) (2.2%) [34]. in an effort to accrue a larger number of cases of csls, the international dermoscopy society (ids) launched this multicenter retrospective, observational study. the aim of the study was to characterize the dermoscopic features of csls, to determine the most common lesions that occur in csls and to analyze possible reasons. background: collision lesions as two independent and unrelated skin tumors often manifest an atypical morphology. objective: to determine the combinations of collision skin lesions (csls). methods: twenty-one pigmented lesion clinics in nine countries included 77 histopathologically proven csls in this retrospective observational study. results: seventy-seven csls from 75 patients (median age 59.8 years) were analyzed; 24.7% of csls were located on the head and neck area, 5.2% on the upper extremities, 48.1% on the trunk, and 11.7% on the lower extremities; 40.3% revealed a melanocytic component (median age 54.7 years), followed by 45.5% with a basal cell carcinoma (bcc) (median age 62.4 years) and 11.7% with a seborrheic keratosis (median age 64.7 years). csls with a bcc component were more often found on the head and neck area compared to tumors with a melanocytic component (34.3% versus 16.1%). lesions with a melanocytic component were more often detected on the trunk compared to lesions with a bcc (64.5% versus 37.1%). patients with csls with epidermal-epidermal cell combination were older than patients with epidermal-dermal cell combination (63 versus 55.2 years), were more often male than female (63% versus 43.3%), more often had the lesion on the head and neck area (32.6% versus 13.3%), and less often on the upper (2.2 % versus 10%) or lower extremities (8.7% versus 16.6%). conclusions: csls consist of a heterogeneous group of lesions of varying cell types. they are associated with advancing age and cumulative uv-exposure. csls manifest a complex morphology making it challenging to diagnose correctly. abstract research | dermatol pract concept 2017;7(4):12 53 remaining lesions comprised one solar lentigo in combination with an angioma (1.3%) and one clear cell acanthoma with a dermatofibroma (1.3%). patients with csls in which a melanocytic tumor occurred were younger compared to patients with csls with bcc and seborrheic keratoses (54.7 versus 62.4 and 64.7 years). csls with melanocytic or basal cell carcinoma were more often observed in males than in females (64.5% and 65.7%) compared to lesions with seborrheic keratoses (33.3%). csls with bcc were more often found on the head and neck area compared to lesions with melanocytic parts (34.3% versus 16.1%). finally, lesions with melanocytic parts were more often detected on the trunk compared to lesions with bcc (64.5% versus 37.1%) (table 2). regarding the 31 csls with a melanocytic component, 22 were nevi, one was a severe melanocytic dysplasia and eight were melanomas. with these 31 melanocytic lesions, 14 seborrheic keratoses (figure 2), seven angiomas (figure 3), six bccs, three dermatofibromas and one squamous cell carcinoma were found as part of the csls. the case of the severe melanocytic dysplasia was associated with an angioma (figure 4). four melanomas were associated with a seborrheic keratosis (figure 5), three melanomas with a bcc (figure 6) and one melanoma with a squamous cell carcinoma in situ. with regard to the 35 csls with a bcc component, 18 seborrheic keratoses (figure 7), five angiomas (figure 8), classification of dermoscopic images during the process of evaluating and recording the dermoscopic criteria present in each image the researchers were aware of the histopathology diagnosis [35]. results general data the study consisted of 77 csls from 27 females (35.1%) and 43 males (55.8%); for seven patients (9.1%) the gender was not recorded. the mean age of the patients was 59.8 years (range from 24 to 88 years); for 10 patients (12.9%) the age was not provided. regarding the anatomic site, 19 csls were located on the head and neck (24.7%), four on the upper extremities (5.2%), 37 on the trunk (48.1%), and nine on the lower extremities (11.7%); for eight lesions this data was not available (10.3%) (table 2). various combinations of csls the 77 cases were subclassified as follows (figure 1): in the first step the csls were analyzed for the presence of any melanocytic features (benign or malignant) (n= 31; 40.3%); in the second step, lesions were analyzed for any bcc features (n=35; 45.5%); in the third step the lesions were analyzed for features of a seborrheic keratosis (n= 9; 11.7%) and the table 1. skin lesions or tumors with their original cell types of the different skin layers (focused only on skin lesions detectable by dermoscopy) layer of the skin cell type or functional structure associated proliferations/neoplasms epidermis keratinocytes solar lentigo seborrheic keratosis actinic keratosis bowen’s disease keratoacanthoma squamous cell carcinoma basal cell layer (non-differentiated folliculo-sebaceous-apocrine germ) trichoblastoma basal cell carcinoma melanocytes melanocytic nevus melanoma merkel cells merkel cell carcinoma dermis blood capillaries angioma melanocytes melanocytic (dermal or blue) nevus melanoma fibroblasts dermatofibroma dermatofibrosarcoma protuberans non-langerhans cells/histiocytes xanthogranuloma infundibulo-follicular-sebaceous unit sebaceous hyperplasia, milia, cyst, pilomatrixoma, trichoepithelioma, adnexal (benign or malignant) tumor myocytes kaposi sarcoma 54 research | dermatol pract concept 2017;7(4):12 in 30 cases and the dermal-dermal combination in only one case (dermal nevus with an angioma, not listed in table 3). patients with the epidermal-epidermal combination were older than patients with the epidermal-dermal combination (63 versus 55.2 years), were more likely to be male than female (63% versus 43.3%), and more often had the lesions on the head and neck area (32.6% versus 13.3%) and less often on the upper (2.2% versus 10%) and lower extremities (8.7% versus 16.6%). discussion any possible combination of benign and malignant collision skin lesions (csls) comprising melanocytic, epithelial, dermal five dermatofibromas (figure 9), two actinic keratoses, two hyperplasias of sebaceous glands, one clear cell acanthoma (figure 10), one keratoacanthoma and one solar lentigo were found. the nine csls with a seborrheic keratosis component (and without a melanocytic or bcc component), two solar lentigines (figure 11), four angiomas (figure 12), one hyperplasia of sebaceous glands and two squamous cell carcinomas were found. referencing table 1, the data were additionally classified based on the combination of cells within the csls as either epidermal cells only, epidermal and dermal cells, and dermal cells only (table 3). the epidermal-epidermal combination was found in 46 cases, the epidermal-dermal combination table 2. overview of age, gender and anatomic site data for all csls (which include the single lesion of a solar lentigo with an angioma, a clear cell acanthoma with a dermatofibroma and six lesions with additional inflammations), lesions with a melanocytic part (melanocytic), basal cell carcinomas (bcc), and seborrheic keratoses (seb.-ker.). all lesions (n=77) melanocytic (n=31) bcc (n=35) seb.-ker. (n=9) median age in years (range in years) 59.8 (24-88) 54.7 (24-86) 62.4 (24-88) 64.7 (48-81) male (%) 43 (55.8) 20 (64.5) 23 (65.7) 3 (33.3) female (%) 27 (35.1) 8 (25.8) 10 (28.6) 4 (44.4) missing data for gender (%) 7 (9.1) 3 (9.7) 2 (5.7) 2 (22.2) head and neck (%) 19 (24.7) 5 (16.1) 12 (34.3) 2 (22.2) upper extremities (%) 4 (5.2) 1 (3.2) 2 (5.7) trunk (%) 37 (48.1) 20 (64.5) 13 (37.1) 3 (33.3) lower extremities (%) 9 (11.7) 1 (3.2) 6 (17.1) 2 (22.2) missing data for anatomic site (%) 8 (10.3) 4 (12.9) 2 (5.7) 2 (22.2) figure 1. subdivision of the 77 csls according to any detectable melanocytic origin (n= 31, melanocytic) in the first step, followed by any present basal cell carcinoma (n=35, bcc) in the second step, and finally nine seborrheic keratosis (seb.-ker.), one solar lentigo (sl) with an angioma and one clear cell acanthoma (cca) with a dermatofibroma detected. [copyright: ©2017 blum et al.] research | dermatol pract concept 2017;7(4):12 55 figure 2a. csl of a melanocytic nevus and a seborrheic keratosis in a 48-year-old male. [copyright: ©2017 blum et al.] figure 2b. melanocytic nevus with regular brown network (a), and a seborrheic keratosis with comedo-like openings (b) and sulci/ crypts (c). [copyright: ©2017 blum et al.] figure 3a. csl of a dermal nevus and an angioma in a 41-year-old female on her trunk. [copyright: ©2017 blum et al.] figure 3b. dermal nevus with distinct brown globules (a), and an angioma with red lacunas (b). [copyright: ©2017 blum et al.] figure 4a. csl of a severe melanocytic dysplasia and an angioma (unknown age, gender or area of lesion). [copyright: ©2017 blum et al.] figure 4b. severe melanocytic dysplasia with asymmetrical radial streaks (a) and an angioma with red lacunas (b). [copyright: ©2017 blum et al. 56 research | dermatol pract concept 2017;7(4):12 figure 5a. csl of an invasive melanoma and a seborrheic keratosis in a 62-year-old male on his belly. [copyright: ©2017 blum et al.] figure 5b. invasive melanoma with a brown-to-black homogenous symmetric pigmented single blotch (a) with distinct radial asymmetric streaming (b), and a seborrheic keratosis with sulci/crypts in early (c) and advanced stages (d). [copyright: ©2017 blum et al.] figure 6a. csl of a lentigo maligna and a basal cell carcinoma of a male at his face (unknown age). [copyright: ©2017 blum et al.] figure 6b. lentigo maligna with pigmented follicles (a) and destroyed follicle with patchy pigmentation (b), and a basal cell carcinoma with arborizing vessels (c) and pigmented blue-grayish globules (d). [copyright: ©2017 blum et al.] figure 7a. csl of a basal cell carcinoma and a seborrheic keratosis in a 65-year-old male on his arm. [copyright: ©2017 blum et al.] figure 7b. basal cell carcinoma with ovoid blue-gray nests (a) and a seborrheic keratosis with brown fat-fingers (b), pseudo horn cysts (c) and sulci/crypts (d). [copyright: ©2017 blum et al.] research | dermatol pract concept 2017;7(4):12 57 figure 8a. csl of a basal cell carcinoma and an angioma in a 67-year-old male on his back. [copyright: ©2017 blum et al.] figure 8b. basal cell carcinoma with arborizing vessels (a) and one pigmented blue-grayish globule (b) and an angioma with red globules/lacunas (c). [copyright: ©2017 blum et al.] figure 9a. csl of a basal cell carcinoma and a dermatofibroma in a 40-year-old female on her arm [39]. [copyright: ©2017 blum et al.] figure 9b. basal cell carcinoma with arborizing vessels (a) and a dermatofibroma with a central white patch and shiny white lines (b) and post-inflammatory peripheral hyperpigmentation (c) [39]. [copyright: ©2017 blum et al.] figure 10a. csl of a basal cell carcinoma, a clear cell acanthoma and a seborrheic keratosis (unknown age, gender and area of lesion). [copyright: ©2017 blum et al.] figure 10b. basal cell carcinoma with arborizing vessels (a) and pigmented blue-grayish globules (b), a clear cell acanthoma with dotted vessels in a line (c) and a seborrheic keratosis with brown fingerprint-like structures (d). [copyright: ©2017 blum et al.] 58 research | dermatol pract concept 2017;7(4):12 or adnexal cells can occur in human skin [13-34,36-43]. both intrinsic and extrinsic factors contribute to the likelihood of having two unrelated skin lesions occurring adjacent and contiguous with each other [44]. age is an intrinsic factor, and although skin lesions are not found in abundance during youth or adolescence, when present, most of the lesions are melanocytic nevi. during adulthood more skin lesions from different cell types occur from epithelial more than melanocytic cells [45,46]. in this retrospective observational study, csls with a melanocytic component were found more often in patients younger than 60 years of age. this can be explained by the fact that there is a progressive reduction of nevi with advancing age [47]. in contrast, in the groups of csls with bcc and seborrheic keratosis components, the median age was older than 60 years. once again, this can be explained by the fact that bccs and seborrheic keratoses are more prevalent the older we get. interestingly, in our image database we found melanocytic lesions with one squamous cell carcinoma and six with bccs, which contradicts the observation of the literature and our study about the age distribution and the origin of melanocytic and epithelial skin lesions. this confirms again that probabilities are observed, but exceptions are always possible [13-34,36-43]. skin type is also a known intrinsic factor. in fitzpatrick skin types i and ii, more epithelial skin lesions can occur durfigure 11a. csl of a seborrheic keratosis and a solar lentigo in an 81-year-old male on his trunk. [copyright: ©2017 blum et al.] figure 11b. seborrheic keratosis with comedo-like openings (a) and initial sulci/crypts (b) and a solar lentigo with brown homogenous (c) and more prominent network (d). [copyright: ©2017 blum et al.] figure 12a. csl of a seborrheic keratosis, an angioma and a solar lentigo in a 67-year-old female on her belly. [copyright: ©2017 blum et al.] figure 12b. seborrheic keratosis with initial sulci/crypts (a) and comedo-like opening (b), an angioma with red lacunas (c) and a solar lentigo with brown homogenous network (d). [copyright: ©2017 blum et al.] research | dermatol pract concept 2017;7(4):12 59 the observer from placing so much emphasis on dermoscopically prominent features within a csl that the clinician stops searching for potentially subtler features that may be present and would assist in detecting skin cancer [51]. a good rule to follow is to evaluate, especially in benign lesions, all four quadrants of a lesion and to ensure that there are no signs of malignancy in any quadrant [50,52]. in complex dermoscopic images the switch between polarized and non-polarized light may be helpful as well [53,54]. this study has several limitations. (1) csls were only classified dermoscopically according to the histopathology reports given to the study coordinator. a further project with the collected images of csls should be the evaluation of diagnostic accuracy with a higher number of dermoscopists blinded to the histopathological result. (2) the specific diagnosis of the melanocytic nevi was rarely given (e.g., lentiginous or compound or dermal nevus), which could have influenced the analysis of the level of cell layers. in conclusion, csls are found increasingly in the aging population with higher accumulative lifetime uv exposure (figure 13). many of these lesions will manifest a complex clinical morphology, including when the csl consists of two benign lesions, leading, at times, to unnecessary biopsies and excisions. dermoscopy may assist in correctly identifying the benign components of the csls that are composed of two or even more benign entities. however, dermoscopy can also lead to anchoring errors, resulting in the missed opportunity to biopsy a csl that is composed of a benign and malignant entity. awareness of this pitfall should help the observer in avoiding it. reflectance confocal microscopy could be a new additional and helpful diagnostic tool for these csls [26,5557]. however, uncertain or non-classifiable lesions still need a complete excision for the final, correct diagnosis. ing a lifetime compared to skin types iii and iv [46,48]. this observation could not be investigated in this study because the data were not available. the total lifetime dosage of uv radiation is considered an extrinsic reason for having csls [16,21,31,32,48]. uvinduced proliferation of benign or malignant cell types can occur resulting in various combination of csls. our study confirmed this observation: bccs were more often found in sun-exposed areas (head and neck followed by the trunk) compared to melanocytic lesions (trunk followed by head and neck). patients with csls with epidermal-epidermal tumor combinations were older than patients with the epidermaldermal tumoral combinations, more males than females had csls, and the csls were more often on the head and neck area—these three observations suggest that uv exposure is associated with csls and that the lifetime uv-exposure load may be greater in men then in women [45,48]. viral infections in the elderly could also be an extrinsic factor for proliferation of epidermal skin cells, which could lead to bowen’s disease or squamous cell carcinoma—but this hypothesis is still under discussion [49]. any further investigation was not possible in this present study. csls can pose diagnostic challenges. csls composed of two or more benign lesions can manifest a clinically irregular morphology leading to unnecessary biopsies or excisions. however, and more importantly, csls composed of benign and malignant lesions can sometimes be diagnosed as benign lesions due to anchoring bias (also known as confirmation bias) [50]. this occurs when the observer anchors their diagnosis on the benign features within a csl and stops searching for features suggestive of malignancy. such errors in visual perception can lead to the missed opportunity to biopsy or excise a skin cancer. being aware of anchoring bias prevents table 3. overview of age, gender and anatomic site data according to the combination of epidermalepidermal cells and epidermal-dermal cells of the csls epidermal – epidermal cells (n=46) epidermal – dermal cells (n=30) median age in years (range in years) 63.0 (24-88) 55.2 (24-85) male (%) 29 (63.0) 13 (43.3) female (%) 13 (28.3) 13 (43.3) missing data for gender (%) 4 (8.7) 4 (13.4) head and neck (%) 15 (32.6) 4 (13.3) upper extremities (%) 1 (2.2) 3 (10.0) trunk (%) 22 (47.8) 14 (46.7) lower extremities (%) 4 (8.7) 5 (16.6) missing data for anatomic site (%) 4 (8.7) 4 (13.4) 60 research | dermatol pract concept 2017;7(4):12 7. blum a, hofmann-wellenhof r, marghoob aa, et al. recurrent melanocytic nevi and melanomas in dermoscopy: results of a multicenter study of the international dermoscopy society. jama dermatol. 2014;150:138-145. 8. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma—a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159:669-676. 9. lallas a, tzellos t, kyrgidis a, et al. accuracy of dermoscopic criteria for discriminating superficial from other subtypes of basal cell carcinoma. j am acad dermatol. 2014;70:303-311. 10. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10-year multicenter survey. j am acad dermatol. 2012;67:54-59. 11. chevolet i, hoorens i, janssens a, et al. a short dermoscopy training increases diagnostic performance in both inexperienced and experienced dermatologists. australas j dermatol. 2015;56:5255. 12. koelink cj, vermeulen km, kollen bj, et al. diagnostic accuracy and cost-effectiveness of dermoscopy in primary care: a cluster randomized clinical trial. j eur acad dermatol venereol. 2014;28:1442-1449. 13. ferrara g, zalaudek i, cabo h, soyer hp, argenziano g. collision of basal cell carcinoma with seborrhoeic keratosis: a dermoscopic aid to histopathology? clin exp dermatol. 2005;30:586-587. 14. de giorgi v, massi d, sestini s, alfaioli b, carelli g, carli p. cutaneous collision tumour (melanocytic naevus, basal cell carcinoma, acknowledgement: the present study was based on the results for the master thesis in studies in dermoscopy and preventive dermato-oncology at the university of graz, austria. references 1. kittler h, marghoob aa, argenziano g, et al. standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy. j am acad dermatol. 2016 jun;74(6):1093-1106. 2. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159-165. 3. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144:1120-1127. 4. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138:1327-1333. 5. saida t, miyazaki a, oguchi s, et al. significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in japan. arch dermatol. 2004;140:1233-1238. 6. blum a, simionescu o, argenziano g, et al. dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the international dermoscopy society (ids). arch dermatol. 2011;147:1181-1187. figure 13. skin model for collision skin lesions with benign and malignant lesions from the epidermal and dermal origin. 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editor: collision tumor of melanoma and atypical fibroxanthoma of the scalp. j dermatol case rep. 2014;30;8(3):84-85. 39. zaballos-diego p. collision tumors. actas dermosifiliogr. 2014;105(3):310-311. 40. medeiros pm, alves nr, silva cc, et al. collision of malignant neoplasms of the skin: basosquamous cell carcinoma associated with melanoma. an bras dermatol. 2015;90:39-42. 41. oliveira a, arzberger e, zalaudek i, hofmann-wellenhof r. desmoplastic trichoepithelioma and melanocytic nevus: dermoscopic and reflectance confocal microscopy presentation of a rare collision tumor. j am acad dermatol. 2015;72:s13-15. 42. marcucci c, sabban ec, friedman p, et al. dermoscopic findings in a collision tumor composed of a dermatofibroma and a melanocytic nevus mimicking melanoma. dermatol pract concept. 2015;31;5(4):47-9. 43. bernardini mc, moscarella e, borsari s, et al. collision tumors: a diagnostic challenge. j am acad dermatol. 2016;75(6):e215e217. 44. nikolakis g, makrantonaki e, zouboulis cc. skin mirrors human aging. horm mol biol clin investig. 2013;16:13-28. 45. xiang f, lucas r, hales s, neale r. incidence of nonmelanoma skin cancer in relation to ambient uv radiation in white populations, 1978-2012: empirical relationships. jama dermatol. 2014;150:1063-1071. 46. zalaudek i, lallas a, longo c, et al. problematic lesions in the elderly. dermatol clin. 2013;31:549-564. 47. piliouras p, gilmore s, wurm em, soyer hp, zalaudek i. new insights in naevogenesis: number, distribution and dermoscopic patterns of naevi in the elderly. australas j dermatol. 2011;52:254258. 48. leiter u, eigentler t, garbe c. epidemiology of skin cancer. adv exp med biol. 2014;810:120-140. 49. smola s. human papillomaviruses and skin cancer. adv exp med biol. 2014;810:192-207. 50. braga jc, scope a, klaz i, mecca p, spencer p, marghoob aa melanoma mimicking seborrheic keratosis: an error of perception precluding correct dermoscopic diagnosis. j am acad dermatol. 2008:58:875-880. 51. groopman j. how doctors think. boston: houghton mifflin, 2007:65, 169-70. 52. kittler h, marghoob aa, argenziano g, et al. standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy. j am acad dermatol. 2016;74:1093-1106. seborrhoeic keratosis): a clinical, dermoscopic and pathological case report. br j dermatol. 2005;152:787-790. 15. zaballos p, llambrich a, puig s, malvehy j. dermoscopy is useful for the recognition of benign-malignant compound tumours. br j dermatol. 2005;153:653-656. 16. ahlgrimm-siess v, hofmann-wellenhof r, zalaudek i, cerroni l, kerl h. collision of malignant melanoma (lentigo maligna type) with squamous cell carcinoma in solar-damaged skin of the face. dermatol surg. 2007;33:122-124. 17. birnie aj, varma s. a dermatoscopically diagnosed collision tumour: malignant melanoma arising within a seborrhoeic keratosis. clin exp dermatol. 2008;334:512-513. 18. gonzález-vela mc, val-bernal jf, gonzález-lópez ma, novell m, fernández-llaca h. collision of pigmented benign tumours: a possible simulator of melanoma. acta derm venereol. 2008;88:92-93. 19. fernández-canedo i, blázquez n, de troya m, pérez-salguero t. collision tumor detected by dermatoscopy. actas dermosifiliogr. 2009;100:617-619. 20. alves r, ocaña j, vale e, correia s, viana i, bordalo o. basal cell carcinoma and atypical fibroxanthoma: an unusual collision tumor. j am acad dermatol. 2010;63:e74-76. 21. martorell a, botella-estrada r, nagore e, guillen-barona c. dermoscopic features of a collision tumour composed of a pigmented basal cell carcinoma and a melanoma. j eur acad dermatol venereol .2010;24:982-984. 22. tsai tm, wu yh, yang kc, yang cy, tsai th, chan jy. sebaceous carcinoma associated with seborrheic keratosis. j cutan med surg 2010;14:240-244. 23. scruggs jm, rensvold ea, parekh pk, butler df. cutaneous collision cancers: a report of two squamomelanocytic malignancies and review of the literature. dermatol surg. 2011;37:1679-1683. 24. kim j, roh hj, chung ky, roh mr. collision of two rare adnexal tumors with folliculosebaceous differentiation. j am acad dermatol. 2011;64:e84-85. pmid: 21496693. 25. menezes n, rita g, inês l, paulo v, armando b. letter: collision tumor: importance of the new auxiliary tools for diagnosis (an illustrative case report). dermatol online j. 2011;17:12. 26. salerni g, lovatto l, carrera c, et al. correlation among dermoscopy, confocal reflectance microscopy, and histologic features of melanoma and basal cell carcinoma collision tumor. dermatol surg. 2011;37:275-279. 27. hyatt am, mutasim df, spicknall ke. collision of atypical fibroxanthoma and acantholytic squamous cell carcinoma in situ. am j dermatopathol. 2012;34:563-564. 28. lee hc, tan kw, chia mw, sim cs. an unusual collision tumour masquerading as a basal cell carcinoma on the nose. singapore med j. 2012;53:e267-268. 29. smith lj, husain ea. colonisation of basal cell carcinoma and actinic 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hofmann-wellenhof r. desmoplastic trichoepithelioma and melanocytic nevus: dermoscopic and reflectance confocal microscopy presentation of a rare collision tumor. j am acad dermatol. 2015;72(1 suppl):s13-15. 53. wang sq, dusza sw, scope a, braun rp, kopf aw, marghoob aa. differences in dermoscopic images from nonpolarized dermoscope and polarized dermoscope influence the diagnostic accuracy and confidence level: a pilot study. dermatol surg. 2008;34:13891395. 54. pan y, gareau ds, scope a, rajadhyaksha m, mullani na, marghoob aa. polarized and nonpolarized dermoscopy: the explanation for the observed differences. arch dermatol. 2008;144:828829. 55. salerni g, lovatto l, carrera c, et al. correlation among dermoscopy, confocal reflectance microscopy, and histologic features of dermatology: practical and conceptual research | dermatol pract concept 2015;6(2):5 21 dermatology practical & conceptual www.derm101.com introduction research on the link between diet and acne goes back decades. in the 1960s, several research groups studied this subject, and one of the largest studies involved 65 patients. over a fourweek period, subjects were administered either a chocolate bar or a placebo bar, and no difference in acne severity was seen [1]. based on such studies, patients were counseled diet and acne: an exploratory survey study of patient beliefs quynh-giao nguyen1, ramsey markus1, rajani katta1 1 department of dermatology, baylor college of medicine, houston, tx, usa key words: acne, diet, internet, dermatologist, foods citation: nguyen qg, markus r, katta r. diet and acne: an exploratory survey study of patient beliefs. dermatol pract concept 2016;6(2):5. doi: 10.5826/dpc.0602a05 received: november 6, 2015; accepted: january 10, 2016; published: april 30, 2016 copyright: ©2016 nguyen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajani katta, md, professor of dermatology, baylor college of medicine, 1977 butler blvd, 6th floor, suite e6.200, houston, tx 77030, usa. email: info@kattamd.com background: in the past, medical literature reflected that diet was not a proven cause of acne. however, studies in recent years have substantiated a link between certain dietary factors and acne. it is unclear whether patients are aware of recent research findings. objectives: acne patients were surveyed to explore beliefs regarding the link between diet and acne, to determine whether these beliefs translated into behavior change and to identify health information sources. patients/methods:  upon institutional review board (irb) approval, surveys were administered to 50 acne patients at an academic dermatology clinic in 2014, with 49 completed in full and included in this analysis. results: ninety-two percent of respondents believed that diet could affect acne. seventy-one percent attempted to change their diet to improve acne. seventy-one percent believed acne to be caused by fried or greasy foods, although chocolate (53%), dairy (47%), and soda drinks (35%) were highly implicated. patients obtained information from google searches (49%), dermatologists (43%), family members and tv (41% each), and medical websites (31%). conclusions: in this exploratory study, patients reported utilizing a diversity of information sources, a majority from the internet. in those surveyed, there was a persistence of long-held belief that fried/ greasy foods and chocolate may serve as acne triggers, and less belief in trigger foods supported by recent research, including refined carbohydrates and sugar. given the multiplicity of beliefs and utilized sources among acne patients in our survey, there is a need to establish up-to-date and reliable methods to educate patients on diet and acne. abstract 22 research | dermatol pract concept 2016;6(2):5 this study was designed to be an initial, exploratory survey study of current patient perceptions about the link between diet and acne. the aim was to identify common beliefs, misconceptions, and current information sources regarding the connection between diet and acne. as in other exploratory survey studies [13], these findings would help indicate directions for future research and would be of benefit to clinicians when counseling patients. materials and methods this protocol was approved by the baylor college of medicine institutional review board. patients presenting to an academic dermatology clinic for the treatment of acne or acne scarring were asked if they wished to participate in a survey study about the link between diet and acne. if so, they completed a self-administered questionnaire prior to the physician visit. subjects were asked to classify their acne from mild to severe, based on their personal perception of the disease’s impact. demographic data, such as age, gender, weight, height, and education level, was included in the questionnaire. surveys were administered from march to november of 2014. results of the 50 questionnaires administered, 49 were completed in full and were included in the analysis. the mean age of that diet did not impact acne. this belief was reflected in textbooks, patient information brochures, and the medical literature [2]. however, later researchers noted methodological flaws in the original study, including the fact that the placebo bar contained a similar total sugar and fat content as the chocolate bar [3]. further studies have now correlated a number of dietary factors and acne. the strongest studies to date indicate that dietary glycemic load may contribute to acne. a randomized controlled trial of australian males [4] demonstrated significant improvement of acne severity after 12 weeks of adherence to a low-glycemic-load diet, compared to the high-glycemic-load diet control group. follow-up studies [5,6] have noted that switching to a low glycemic diet led to better insulin sensitivity, lower androgen bioavailability, and altered skin sebum production. it is not known, however, what role individual differences, duration of dietary changes, and other factors play in this association. therefore, studies such as di landro et al.’s [7] have documented the opposing view that weekly consumption of cakes, sweets, and chocolate—foods high in glycemic load—was not associated with a higher risk of acne. in addition, researchers examining the link between dairy consumption and acne have noted some association. studies [8,9,10] have demonstrated this link in three separate populations, though in each instance the correlation results were considered relatively weak. closer evaluation of this link revealed that only skim milk showed a statistically significant correlation with acne, perhaps due to its increased processing and/or decreased estrogen content in comparison to whole milk [8]. a number of other dietary factors have been studied for their potential role in improving acne. for example, an inverse relationship has been found between acne severity and consumption of omega-3-rich fish [11,7] with the mechanism of action postulated as omega-3-mediated reduction of inflammatory acne [12]. while some promising results have been noted from in vitro or animal studies, studies in humans are limited, and each of these dietary factors requires further investigation before recommendations may be made to patients. these include foods or supplements containing vitamin a, omega-3 fatty acids, zinc, antioxidants, and fiber. [12]. given that the scientific literature on this topic is rapidly evolving, it would be expected that patients might receive conflicting advice. patients have long held certain beliefs about diet and acne, including the common perception that fried, greasy foods would lead to oily skin and acne. however, it is not known whether patients are aware of the research findings that support a link between specific dietary factors and acne. patients seek out and receive medical information from multiple sources, and current patient beliefs about diet and acne are not known. table ia. sample characteristics, n (%). [copyright: ©2016 nguyen et al.] gender male 11 (22.4) female 38 (77.6) age 16-19 5 (10.2) 20-29 24 (48.9) 30-39 17 (34.7) 40-45 3 (6.1) bmi <18.5 3 (6.1) 18.5-24.9 31 (63.3) 25-29.9 13 (26.5) 30+ 2 (4.1) education <high school 1 (2.0) high school 3 (6.1) college+ 45 (91.8) research | dermatol pract concept 2015;6(2):5 23 a combination of over-the-counter and prescription medications (table iib). the dietary item most frequently implicated to worsen acne was fried, greasy foods (71%). other responses included chocolate (53%), followed by dairy products (47%). this was followed by soda drinks (35%), caffeine (27%), and refined carbohydrates (27%). among the named categories of dietary items believed to aggravate acne, sugar was named by the lowest percentage of respondents (16%). a total of 10% of respondents listed “other” (table iiia). the majority of respondents believed that certain foods or supplements could help acne. a minority (27%) believed that food or supplements did not help acne. the category listed by most respondents as helping acne was that of vitamin a (41%), followed by antioxidants (33%), fish/omega-3s (29%), and zinc (27%) (table iiib). of respondents, a minority reported improvement with dietary changes. twenty percent reported acne improvement with less fried or greasy foods, followed by 14% reporting patients was 28.5 years (range, 16 to 45 years); 38 were female and 11 were male. three respondents had an underweight bmi of less than 18.5; 30 respondents had a normal bmi between 18.5-24.9; 13 respondents were overweight with bmi 25-29.9; and 2 respondents qualified as obese with bmi greater than 30.0. a majority, 45 of 49 respondents, was educated at the college level (table ia). respondents reported the following acne severity distribution: 13 patients had mild acne, 1 patient had mild-moderate, 29 patients had moderate, 1 had moderate-severe, and 5 had severe acne (table ib). among our population, patients overwhelmingly believed that diet could affect acne (table ic). only 3 of 38 (8%) female patients and 1 of 11 (9%) male patients believed that diet had no effect on acne. of female patients, 30 of 38 (81%) patients believed that diet affected acne either somewhat, a lot, or was the complete cause of acne. among male patients, results were similar: 10 of 11 (91%). a majority, 35 of 49 patients (71%), had changed their diets in order to help their acne (table iia). thirteen of the 35 (37%) tried dietary changes before medications, compared to the 14 patients that first attempted medications. of those 14, 9 tried over-the-counter medications first (25%) and 5 tried prescription first (14%). four patients tried a combination of dietary changes with prescription medications (11%); 2 combined dietary changes with over-the-counter medications (6%); and the remaining tried a combination of all three or table ib. self reported acne severity, n (%). [copyright: ©2016 nguyen et al.] mild x x       moderate   x x x   severe       x x total n = 49 13 (26.5) 1 (2.0) 29 (59.2) 1 (2.0) 5 (10.2) table ic. gender and belief that diet can affect acne, n (%). [copyright: ©2016 nguyen et al.]   not at all slightly somewhat a lot completely male 1 (9.1) 0 (0) 6 (54.5) 3 (27.3) 1 (9.1) female 3 (7.9) 5 (13.1) 15 (39.5) 14 (36.8) 1 (2.6) total n = 49 4 (8.2) 5 (10.2) 21 (42.8) 17 (34.7) 2 (4.1) table iia. changed diet to improve acne, n (%). [copyright: ©2016 nguyen et al.] yes 35 (71.4) no 14 (28.6) table iib. acne interventions that patients first attempted, n (%). [copyright: ©2016 nguyen et al.] diet x     x x x   otc meds   x   x   x x rx meds     x   x x x total n = 35 13 (37.1) 9 (25.7) 5 (14.3) 2 (5.7) 4 (11.4) 1 (2.8) 1 (2.8) 24 research | dermatol pract concept 2016;6(2):5 specifically sites such as webmd or that of the american academy of dermatology, were used by 31%, while primary care physician (pcp) was used by 18% (table iva). respondents were split evenly between those satisfied with the information provided on their sources (49%) and those not satisfied (51%) (table ivb). this trend was found in almost all categories of sources listed except for: dermatologist, family members, medical websites, and pcp. improvement with less dairy products and 14% reporting improvement with less refined carbohydrates (table iiic). the most widely utilized source of information was a google search (49%), followed by dermatologist (43%) and then family members and tv (tied at 41%). medical websites, table iiia. dietary items believed by patients to aggravate acne, n (% n/n). [copyright: ©2016 nguyen et al.] fried or greasy foods 35 (71.4) chocolate 26 (53.1) dairy products 23 (46.9) soda drinks 17 (34.7) caffeine 13 (26.5) refined carbohydrates 13 (26.5) spicy foods 10 (20.4) sugar 8 (16.3) other 5 (10.2) n/a diet ø aggravate acne 1 (2.0) table iiib. dietary items believed by patients to help acne, n (% n/n). [copyright: ©2016 nguyen et al.] vitamin a 20 (40.8) antioxidants 16 (32.7) fish or omega-3’s 14 (28.6) zinc 13 (26.5) n/a diet ø help acne 13 (26.5) dietary fiber 10 (20.4) other 3 (6.1) table iiic. reported acne improvement with dietary change, n (% n/n). [copyright: ©2016 nguyen et al.] less fried or greasy foods 10 (20.4) less dairy products 7 (14.3) less refined carbohydrates 7 (14.3) less sugar 6 (12.2) more water 4 (8.2) less soda drinks 3 (6.1) less caffeine 2 (4.1) less chocolate 2 (4.1) less spicy foods 2 (4.1) less red meats 1 (2.0) more basil 1 (2.0) more fruits or vegetables 1 (2.0) table ivc. satisfied with diet and acne information provided from sources, n (% n/n). [copyright: ©2016 nguyen et al.] google search 11 (45.8) 13 (52.0) dermatologist 18 (75.0) 3 (12.0) family members 7 (29.2) 13 (52.0) tv 9 (37.5) 11 (44.0) friends 8 (33.3) 9 (36.0) medical websites 10 (41.7) 5 (20.0) magazines 3 (12.5) 10 (40.0) pcp 6 (25.0) 3 (12.0) other 3 (12.5) 3 (12.0) social media sites 2 (8.3) 2 (8.0) newspaper 1 (4.2) 1 (4.0) significant other 1 (4.2) 0 (0) yes no table iva. sources of information on diet and acne used by patients, n (% n/n). [copyright: ©2016 nguyen et al.] google search 24 (49.0) dermatologist 21 (42.9) family members 20 (40.8) tv 20 (40.8) friends 17 (34.7) medical websites 15 (30.6) magazines 13 (26.5) pcp 9 (18.4) other 6 (12.2) social media sites 4 (8.2) newspaper 2 (4.1) significant other 1 (2.0) table ivb. satisfied with information from sources, n (%). [copyright: ©2016 nguyen et al.] yes 24 (49.0) no 25 (51.0) research | dermatol pract concept 2015;6(2):5 25 sugar, and refined carbohydrates would have similar ratings by patients, as they may all contribute to a high gi index diet. our findings indicate that this is not the case. in fact, while 53% reported chocolate as a possible trigger food, only 16% reported sugar as a potential trigger. this is another area in which dermatologists must counsel patients. while chocolate bars may serve as an acne trigger, sugar and other sugary foods are just as concerning. of note, although some studies have shown a link to dairy [14], less than half (47%) of our respondents believed that dairy products could aggravate acne. patients also believe that certain foods may help acne an interesting finding is that a significant proportion of respondents believed that certain foods or supplements could help acne. vitamin a was reported by the highest proportion (41%). this may be due to reports of high-dose vitamin a therapy used in the past as acne therapy, and the fact that acne medications such as tretinoin and isotretinoin are related to vitamin a. our survey did not distinguish between standard vitamin a supplements and high-dose supplementation, and therefore it is not known whether a belief in vitamin a therapy extends to standard supplement dosing. when vitamin a is removed from the analysis, the highest category becomes antioxidants (33%), followed by fish or omega-3s (29%), zinc (27%), and dietary fiber (20%). for each of these nutrients, while some promising results in the treatment of acne have been noted from in vitro or animal studies, studies in humans are limited. at this point, these cannot be recommended routinely, but their use by patients cannot be dismissed entirely either. in conclusion, while there is limited research performed in the area of foods or supplements that may help in the treatment of acne, many of our respondents believe they may help. in an era of rapid dissemination of information, patients are sometimes made aware of promising findings from small studies. this highlights the need for dermatologists to stay abreast of the latest dietary findings, and in particular not to dismiss these out of hand. in addition, dermatologists must be cognizant of the fact that a significant proportion of patients may believe that certain foods or supplements have the ability to combat acne, and therefore must be able to provide information on the limited evidence that exists to support their use. information sources in order to disseminate accurate, evidence-based information, we must understand what sources patients utilize for medical information. in our survey study, less than half (43%) relied on dermatologists for information. the remaining respondents turned to a variety of sources, including the internet (google search and medical websites), mass media (magaof the 24 out of 49 satisfied respondents, 18 (75%) marked dermatologist as one of their sources of diet and acne information. this is in contrast to the unsatisfied respondents. of the 25 respondents not satisfied with their information, only 3 (12%) had marked dermatologist as a source of information. similarly, 10 of 24 satisfied respondents (42%) marked medical websites as one of their sources, whereas 5 of 25 unsatisfied respondents (20%) reported the use of medical websites. these findings reverse when looking at family members as a source of information. among unsatisfied respondents, 52% had marked family members as a source of diet and acne education, as compared to 29% of satisfied respondents (table ivc). discussion these beliefs are translating to behavior change respondents overwhelmingly believed that diet could affect acne. in fact, only 5% of female patients and only 9% of male patients believed that diet had no effect on acne. these are strongly held beliefs, in that they are translating to behavior change. a majority of respondents, 71%, had changed their diet in order to help their acne. the majority of patients believed that certain foods may worsen acne respondents overwhelmingly believed that foods could aggravate acne. of the foods listed, the highest percentage of respondents (71%) chose a category that patients have historically described as an acne trigger food: that of fried/ greasy foods. this is a popular, long-held belief, as anecdotally, patients sometimes make the connection between greasy foods and increased oil production on the face. the strongest research evidence, however, supports a link between a high glycemic index (gi) diet and acne [14]. while fried or greasy foods may contribute to a high gi diet, so would sugar, soda drinks, and refined carbohydrates. these categories, however, were listed by much lower percentages of respondents (16%, 35%, and 27%, respectively). this is an important point to emphasize to our patients. while fried, greasy foods are a concern, so are a number of other foods. as dermatologists, we should be emphasizing that even innocuous foods, such as white bread, pasta, and other refined carbohydrates, when part of an overall high gi diet, may worsen acne. chocolate was also noted by a majority of respondents (53%). chocolate as a dietary factor triggering acne is also a long-held belief, and studies evaluating its role in acne were performed in the 1960s [15]. at this time, though, there is no evidence that a factor specific to chocolate can trigger acne. rather, research points to its sugar content and contribution to a high gi diet as a possible trigger. ideally, then, chocolate, 26 research | dermatol pract concept 2016;6(2):5 study weaknesses due to the design of this exploratory survey study, patients were recruited from the population of patients seeking treatment for acne at a single academic institution. this resulted in a skewed patient population. most, 45 of 49, were college educated (92%). most, 38 of 49, were female (78%). most, 31 of 49, were of normal weight (63%), with only 15 of 49 (31%) categorized as overweight or obese. this is in contrast to the u.s. population, in which 69% are overweight or obese; 29% are college educated; and 51% are female [17,18,19]. another weakness of the study may be the lack of a quantitative definition of acne severity. in the past, multiple quantitative classification systems have been proposed, though these methods have been inconsistently accurate in the clinical setting [20]. given the variable expressions of acne, as well as its psychosocial factors difficult to quantitate, a more important assessment of severity may be the patient’s perception of its impact [20], which we elicited in the study. conclusion this survey study was designed to explore patient beliefs regarding the link between diet and acne. in this small sample, the overwhelming majority of respondents believed that diet could affect acne. this belief impacted behavior, as the majority had changed their diets in order to improve their acne. due to the study design, the results from this patient sample cannot be applied to the general population. however, even in this highly educated patient population, there was a persistence of long-held beliefs that certain foods may serve as acne triggers (i.e., fried or greasy foods and chocolate) and less recognition of the foods that research has identified as potential triggers (i.e., sugars, refined carbohydrates, and dairy). many respondents also reported a belief that certain foods or supplements could help acne, an area with some promising preliminary results but one that requires further investigation before any conclusions may be drawn. especially given the multiplicity of information sources utilized by patients, as well as the ongoing research in this area and subsequent evolving recommendations, dermatologists must serve as an authoritative information source. dermatologists must be able to provide a balanced overview of this topic to their patients and be able to direct patients to credible, balanced sources for additional dietary change recommendations. these findings indicate a need for further study on the best practices in providing health information, especially as medical recommendations are evolving. our population was highly educated, and the majority was of normal weight. further research in this area must target a more diverse population. even within this skewed population, however, we noted zines, television, and newspaper), and personal relationships (mainly family members and friends). the sources of information utilized by patients have changed markedly. in a survey study from 1999, general information on acne was obtained most frequently from family physicians (71%) [16]. in our survey, only 18% utilized their primary care physician as a source of information. the mass media continues to play a role in providing health information. in the 1999 survey study, magazines and television were utilized by 44% each [16]. in our survey study, magazines were utilized by 27%, and television was utilized by 41% of respondents. the most notable change has been the rise of the internet as a tool for health information. our respondents utilized google most frequently (49%) as a source of information, with medical websites utilized by 31%. in the 1999 study [16], the internet was not listed as a source of information. it is clear that the internet has had a significant impact on health information-seeking behavior. what is less clear is how physicians should respond to this change when educating our patients. in this study, more patients obtained information from the internet than from their primary care physician or their dermatologist. however, a significant number of those satisfied with their diet and acne education had marked pcp (25%) or dermatologist (75%) as one of their sources of information. conversely, the majority of respondents not satisfied with their information source did not mark dermatologist or pcp as a source of information (86%). thus, with so many acne patients making dietary changes, and many of them turning to the internet for information to guide them, it becomes even more imperative that physicians be educated on the topic of acne and diet and be able to serve as an authoritative source. for those patients who seek further information, we also need to be able to refer patients to credible sources of online health information, with specific recommendations for high-quality, up-to-date health information websites. our study suggests that education from physicians and medical websites is correlated with higher satisfaction in patients. physicians must also counsel patients on the drawbacks of utilizing search engines for health information, as opposed to utilizing well-regarded medical websites. if relying on a google search, patients may be directed to commercial sites or sites containing inaccurate information. patients must be made aware of this notable risk when using a google search. finally, we need to ensure, as a profession, that health education materials are easily available on the internet and that such information is accurate, evidence-based, free from commercial bias, and reflective of the most current research findings. research | dermatol pract concept 2015;6(2):5 27 9. adebamowo ca, spiegelman d, berkey cs, et al. milk consumption and acne in adolescent girls. dermatol online j 2006; 12(4):1. pmid: 17083856 10. adebamowo ca, spiegelman d, berkey cs, et al. milk consumption and acne in teenaged boys. j am acad dermatol 2008; 58(5):787-93. pmid: 18194824 doi: 10.1016/j. jaad.2007.08.049 11. jung jy, yoon my, min su, et al. the influence of dietary patterns on acne vulgaris in koreans. eur j dermatol 2010; 20(6):768-72. pmid: 20822969. doi: 10.1684/ejd.2010.1053 12. bowe wp, joshi ss, shalita ar. diet and acne. j am acad dermatol. 2010; 63(1):124-41. pmid: 20338665. doi: 10.1016/j. jaad.2009.07.043 13. borup g, mikkelsen kl, tønnesen p, christrup ll. exploratory survey study of long-term users of nicotine replacement therapy in danish consumers. harm reduc j 2015; 12:2. pmid: 26239277. doi: 10.1186/1477-7517-12-2 14. spencer eh, ferdowsian hr, barnard nd. diet and acne: a review of the evidence. int j dermatol. 2009;48(4):339-47. pmid: 19335417. doi: 10.1111/j.1365-4632.2009.04002.x 15. anderson pc. foods as the cause of acne. american family physician. 1971; 3:102-3. 16. tan jkl, vasey k, fung ky. beliefs and perceptions of patients with acne. j am acad dermatol 2001; 44:439-45. pmid: 11209112 17. “obesity and overweight.” centers for disease control and prevention. june 2, 2015. accessed august 18, 2015. http://www. cdc.gov/nchs/fastats/obesity-overweight.htm. 18. “united states census bureau.” usa quickfacts from the us census bureau. accessed august 18, 2015. http://quickfacts. census.gov/qfd/states/00000.html. 19. howden lm, meyer ja. “age and sex composition.” 2010 census briefs from the us census bureau. may 2011. accessed december 15, 2015. http://www.census.gov/prod/cen2010/briefs/ c2010br-03.pdf 20. pochi pe, shalita ar, strauss js, et al. report of the consensus conference on acne classification. washington, d.c., march 24 and 25, 1990. j am acad dermatol 1991; 24(3):496-500. pmid: 1829466 widely conflicting beliefs among acne patients. there is a clear need for easily available, evidence-based, and up-to-date information on the link between diet and acne. references 1. fulton je, plewig g, kligman am. effect of chocolate on acne vulgaris. jama 1969; 210:2071-4. pmid: 4243053. doi: 10.1001/ jama.1969.03160370055011 2. rosenberg ew, kirk bs. acne diet reconsidered. arch dermatol 1981; 117(4):193-5. pmid: 6452097. doi: 10.1001/archderm.1981.01650040009010 3. goh w, kallianpur kj, chow d, et al. chocolate and acne: how valid was the original study? clin dermatol 2011; 29(4): 459-60. pmid: 21679875. doi: 10.1016/j.clindermatol.2011.05.002 4. smith rn, mann nj, braue a, makelainen h, varigos ga. the effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial. j am acad dermatol 2007; 57:247-56. pmid: 17448569. doi: 10.1016/j.jaad.2007.01.046 5. smith rn, mann nj, makelainen h, roper j, braue a, varigos ga. a pilot study to determine the short-term effects of a low glycemic load diet on hormonal markers of acne: a nonrandomized, parallel, controlled feeding trial. mol nutr food res 2008; 52:718-26. pmid: 18496812. doi: 10.1002/mnfr.200700307 6. smith rn, braue a, varigos ga, mann nj. the effect of a low glycemic load diet on acne vulgaris and the fatty acid composition of skin surface triglycerides. j dermatol sci 2008; 50(1):41-52. pmid: 18178063. doi: 10.1016/j.jdermsci.2007.11.005 7. di landro a, cazzaniga s, parazzini f, et al. family history, body mass index, selected dietary factors, menstrual history, and risk of moderate to severe acne in adolescents and young adults. j am acad dermatol 2012; 67(6):1129-35.pmid: 22386050. doi: 10.1016/j.jaad.2012.02.018 8. adebamowo ca, spiegelman d, danby fw, et al. high school dietary dairy intake and teenage acne. j am acad dermatol 2005; 52(2):207-14. pmid: 15692464. doi: 10.1016/j. jaad.2004.08.007 http://www.cdc.gov/nchs/fastats/obesity-overweight.htm http://www.cdc.gov/nchs/fastats/obesity-overweight.htm http://quickfacts.census.gov/qfd/states/00000.html http://quickfacts.census.gov/qfd/states/00000.html http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023110 1 “rt strikes back”: radiotherapy in ultra elderly with cutaneous basal cell carcinoma valerio nardone1, federico gagliardi1, gabriella brancaccio2, stefania napolitano1, giulia briatico2, alfonso reginelli1 1 department of precision medicine, university of campania “luigi vanvitelli”, naples, italy 2 dermatology unit, university of campania “luigi vanvitelli”, naples, italy key words: skin cancer, basal cell carcinoma, elderly patients, radiotherapy citation: nardone v, gagliardi f, brancaccio g, napolitano s, briatico g, reginelli a. “rt strikes back”: radiotherapy in ultra elderly with cutaneous basal cell carcinoma. dermatol pract concept. 2023;13(2):e2023110. doi: https://doi.org/10.5826/ dpc.1302a110 accepted: october 17, 2023; published: april 2023 copyright: ©2023 nardone et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: valerio nardone, department of precision medicine, university of campania “l. vanvitelli”, naples, via de crecchio 7, 80138 naples, italy; email: valerio.nardone@unicampania.it introduction basal cell carcinoma (bcc) is the most common human cancer and, recently, its clinical management among elderly patients represents an important issue [1]. we present the case of a 99-year-old patient affected by an advanced and heavily pre-treated bcc that was successfully treated with radiotherapy. case presentation the reported patient presented an ulcerated skin lesion in the left subnasal region for several years. the patient underwent in june 2019 a skin punch biopsy that showed solid nested basal cell carcinoma with morphoeic aspects. noted the clinical condition, a surgical approach was excluded and was referred to upfront curettage plus electrode-dissecation. due to disease progression, the patients in the subsequent months also underwent cryotherapy and administration of topical imiquimod, with little efficacy. in october 2021 (figure 1a), the patient was discussed in the multidisciplinary tumor board (mtb) of skin cancers, evaluating the possibility of a radiotherapy approach. the patient came to our hospital in november 2021 (figure 1b) with a locally advanced morphoeic lesion (>5 cm). we proposed hypofractionated radiotherapy (twice weekly, for a total duration of 5 weeks of therapy, total dose of 60gy) [2], using a 6mev electron beam with a treatment field included the lesion with a free margin of 2 cm. after each session the skin lesion was medicated with saline solution, betadine and hyaluronic acid medication. the patient finished radiation treatment in december, reporting no acute toxicities except grade 1 mucositis (ctcae v.5) (figure 1c). the follow-up was postponed due to increase of covid-19 pandemic, following the patient choice. 2 research letter | dermatol pract concept. 2023;13(2):e2023110 we saw the patient only in april 2022 (figure 1d), and the patient presented a clinical and dermoscopical complete response of the skin lesion, with the presence of only residual area of alopecia in the irradiation area. all procedures performed were in accordance with the ethical standards of the institutional and national research committees and with the helsinki declaration. conclusions radiotherapy can be safely used if imaging procedures can define the tumor area and the depth of invasion [3], in patients with a high risk of uncomplete surgical resection or if surgery is contraindicated. rt has been reported as a valid alternative to surgery, with a negligible risk of developing secondary skin cancer [3-5]. a recent systematic review investigating the efficacy of different strategies for bcc reported an estimated recurrence rate of 3.8% for surgery, 3.8% for mohs surgery and 3.5% for radiotherapy [6]. higher doses per fraction lead to higher rates of late toxicity, therefore accelerated fractionation schedules should be reserved for a limited subset of patients. in fact, elderly patients may not be able to attend hospital daily, especially in the pandemic era that we are experiencing, therefore they can benefit from hypofractionation schemes that can still reach an high control rate (92.4% of complete response rate) [2]. our patient responded excellently to hypofractionated rt treatment after the failure of several local treatments. although blind techniques and topical therapies can be easier to perform, “difficult to treat” bcc should be always discussed in mtb, in order to choose and to tailor the most efficacious therapy, especially for elderly patients. references 1. linos e, schroeder sa, chren mm. potential overdiagnosis of basal cell carcinoma in older patients with limited life expectancy. jama. 2014;312(10):997-998. doi: 10.1001/jama.2014.9655. pmid: 25203077. 2. valeriani m, nicosia l, agolli l, et al. monoand bi-weekly hypofractionated radiation therapy for the treatment of epithelial skin cancer in very elderly patients. anticancer res. 2017;37(2):825-830. doi: 10.21873/anticanres.11384. pmid: 28179337. 3. peris k, fargnoli mc, garbe c, et al. diagnosis and treatment of basal cell carcinoma: european consensus-based interdisciplinary guidelines. eur j cancer. 2019;118:10-34. doi: 10.1016/j. ejca.2019.06.003. pmid: 31288208. 4. work group; invited reviewers; kim jys, kozlow jh, mittal b, moyer j, olencki t, rodgers p. guidelines of care for the management of basal cell carcinoma. j am acad dermatol. 2018;78(3):540-559. doi: 10.1016/j.jaad.2017.10.006. pmid: 29331385. 5. nasr i, mcgrath ej, harwood ca, et al. british association of dermatologists guidelines for the management of adults with basal cell carcinoma 2021. br j dermatol. 2021;185(5):899-920. doi: 10.1111/bjd.20524. pmid: 34050920. 6. drucker am, adam gp, rofeberg v, et al. treatments of primary basal cell carcinoma of the skin: a systematic review and network meta-analysis. ann intern med. 2018;169(7):456-466. doi: 10.7326/m18-0678. pmid: 30242379. figure 1. evolution of the reported case. (a) discussion of the patient in the multidisciplinary tumor board. (b) locally advanced morphoeic lesion (>5 cm), that was contiguous to nasal vestibule and upper lip, photo taken at the beginning of rt. (c) photo taken at the end of radiotherapy, the lesion showed an initial response. panel d: (d) at 4-month follow-up visit, complete resolution of the basal cell carcinoma. untitled case report | dermatol pract concept 2015;5(2):20 99 dermatology practical & conceptual www.derm101.com introduction the use of lasers and intense pulsed light (ipl) technology has become an established practice in dermatology and aesthetic medicine. the number of treatments performed with lasers and ipl has increased remarkably in the last two decades. an 810 nm, high-power diode laser system (lightsheer™ diode laser [lumenis ltd, yokneam, israel]) is among one of the newer lasers now available for hair removal [1,2]. we report clinical, dermoscopic and histological features of a complete regressed pigmented melanocytic nevus after hair removal treatment with lightsheer diode laser. case report a 30-year-old woman with multiple acquired melanocytic nevi and fitzpatrick skin type iii, presented for digital dermoscopy. she had a family history of malignant melanoma (in her father) and reported recent changes in a pigmented mole of unknown duration in her right calf. upon examination, this pigmented lesion measured 5 mm in diameter, was dark brown in color (figure 1) and displayed a homogeneous disorganized complete regression of a melanocytic nevus after epilation with diode laser therapy manuela boleira1, laila klotz de almeida balassiano1, thiago jeunon3 1 dermatology, policlínical geral do rio de janeiro (pgrj), brazil 2 dermatopathology, hospital federal de bonsucesso (hfb); id—investigação em dermatologia, rio de janeiro, brazil key words: laser, regression, melanocytic nevus, dermatoscopy, histopathology citation: boleira m, balassiano lk, jeunon t. complete regression of a melanocytic nevus after epilation with diode laser therapy dermatol pract concept 2015;5(2):20. doi: 10.5826/dpc.0502a20 received: december 15, 2014; accepted: january 26, 2015; published: april 30, 2015 copyright: ©2015 boleira et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: manuela boleira, av. nilo peçanha, 38. centro, 20020-100. rio de janeiro—rj. brazil. tel: +55 21 98187-9939; fax: +55 21 3619-1511. email: manubsg@yahoo.com.br the use of lasers and intense pulsed light (ipl) technology has become an established practice in dermatology and aesthetic medicine. the use of laser therapy and ipl in the treatment of pigmented melanocytic lesions is a controversial issue. we report clinical, dermoscopic and histological changes of a completely regressed pigmented melanocytic nevus after hair removal treatment with the lightsheer™ diode laser (lumenis ltd, yokneam, israel). abstract figure 1. melanocytic lesion in the right calf, measured 5 mm and dark-brownish in color. [copyright: ©2015 boleira et al.] 100 case report | dermatol pract concept 2015;5(2):20 presumably a melanocytic nevus, secondary to previous laser therapy was rendered (figure 4). the histopathologic diagnosis prompted an active inquiry for previous laser therapies, and it was discovered that the patient had undergone cosmetic removal of leg hair with an 810 nm, pulsed, high-power diode laser (lightsheer diode laser) 15 days prior to the biopsy. discussion the majority of lasers used for hair removal target melanin as the chromophore, consequently there are limitations and potential side effects mostly pertaining to alterations in pigmentation. in healthy skin, the higher density of melanin within the hair shaft and within the follicular matrix cells as well the presence the larger and more heavily melanized melanosomes relative to the epidermis contributes to the preferential targeting of melanin in the hair follicle over melanin in the epidermis. in a nevus, the increased number of melanocytes and melanin suggests that the photons of the laser for hair removal might be absorbed by the neoplastic melanocytes and pigmented keratinocytes, resulting in aforementioned clinical, dermoscopic and histological changes. in patients with multiple clark’s nevi or with a personal or family history of melanoma, a mole undergoing changes in clinical or dermoscopic features during a period of followup or with a distinct morphology in comparison to the other nevi are concerning findings [3]. these changes or atypical findings often warrant that a biopsy be performed to rule out malignancy [3-6]. pattern on dermoscopy (figure 2), differing from the other nevi located on the abdomen and back region which exhibited a predominantly reticular pattern (figure 3). there were no clinical signs of inflammation. this lesion was considered suspicious and an excisional biopsy was performed to rule out melanoma. histologically, there was scale-crust permeated by melanin situated above a basket-weave stratum corneum and, at the center of the lesion, there was a geometric triangular area of basophilic collagen degeneration with the vertex pointed downwards in the papillary dermis characteristic of laser injury and numerous associated melanophages. there was no evidence of a residual melanocytic neoplasm in the sections of tissue examined. imunohistochemical stains using anti-s100 protein, anti-melan-a and anti-hmb45 primary antibodies were unable to show scattered residual neoplastic melanocytes. the diagnosis of a regressed pigmented lesion, figure 2. homogeneous disorganized pattern on dermoscopy. [copyright: ©2015 boleira et al.] figure 3. digital dermoscopy of others nevi located on the abdomen and back region showed a diffuse regular reticular pattern with a delicate pigment network, ranging from light to dark brown in color. [copyright: ©2015 boleira et al.] case report | dermatol pract concept 2015;5(2):20 101 dermoepidermal junction and in pagetoid distribution within the epidermis, simulating malignant melanomas. however, the distinction is possible because in the former these findings are restricted to the area above the dermal fibrosis, while in the latter they often extend beyond it [13-16]. in cases where an unequivocal distinction between recurrent nevus and melanoma cannot be achieved, review of the previous biopsy (when available) usually resolves the quandary. there are also cases in which a diagnosis of melanoma has been made subsequent to laser treatment of a melanocytic lesion. we believe some of these lesions were actually melanomas from the outset and, therefore, inadequately treated with lasers, while others could have been nevi that displayed changes of recurrent nevus (pseudomelanoma) after laser therapy that were ultimately misconstrued as transformation of a nevus in melanoma [1,5]. an electronic search on the pubmed database yielded a small number of publications regarding changes in melanocytic nevi after hair removal treatment with laser or ipl. this is summarized in table 1, which includes two cases that the patient herein presented experienced complete histological involution presumably of a melanocytic nevus after diode laser therapy. since the lesion was biopsied just 15 days after epilation, it was possible to identify the characteristic geometrical collagen degeneration that prompted the recognition of laser damage, as well the presence of crust permeated by melanin atop the corneum layer [7,8,9]. if the lesion were biopsied substantially later, it would have displayed superficial dermal fibrosis in conjunction with melanophages, similar to previous case reports of completely regressed melanocytic nevi after laser therapy [1,10,11,12]. in some instances, melanocytic nevi have persisted after laser injury. in such cases, the residual neoplasm displayed dermoscopic and histopathological changes similar to those seen in recurrent nevi (so called pseudomelanomas) occurring in surgical scars. with dermoscopy, these lesions may exhibit irregular network, streaks, globules of variable sizes and colors and dark brown blotches over a white scar area. histopathologically, recurrent/persistent nevi may present variably atypical melanocytes irregularly disposed along the a b c d figure 4. (a) scale-crust and melanin granules over a reticular stratum corneum. papillary dermis showed basophilic degeneration of collagen. h&e, x10. (b) papillary dermis showed basophilic degeneration of collagen in a triangular shape with the apex pointing downward and melanophages. h&e, x40. (c) basophilic degeneration of collagen in a triangular shape with the apex pointing downward and peripheral melanophages. h&e, x100. (d) a close-up to the scale-crust permeated by melanin. h&e, 100x. [copyright: ©2015 boleira et al.] 102 case report | dermatol pract concept 2015;5(2):20 therapy for axillary hair removal in a cosmetic center. dermatology 2012;224(3):193-7. 2. souza fhm, ribeiro cf, weigert s, et al. the use of 810 nm diode laser versus intense pulsed light (filter 695 nm) in axillary epilation: a comparative study. surg cosmet dermatol 2010;2(3):185-90. 3. fikrle t, pizinger k, szakos h, et al. digital dermatoscopic followup of 1027 melanocytic lesions in 121 patients at risk of malignant melanoma. j eur acad dermatol venereol 2013;27(2):180-6. 4. soden ce, smith k, skelton h. histologic features seen in changing nevi after therapy with an 810 nm pulsed diode laser for hair removal in patients with dysplastic nevi. int j dermatol 2001;40(8):500-45. 5. sillard l, mantoux f, larrouy jc, hofman v, passeron t, lacour jp, bahadoran p. dermoscopic changes of melanocytic nevi after laser hair removal. eur j dermatol 2013; 23(1):121-3. 6. garridos-ríos a, muñoz-repeto i, huerta-brogeras m, et al. dermoscopic changes in melanocytic nevi after depilation techniques. j cosmet laser ther 2013; 15(2):98-101. 7. drnovsek-olup b, beltram m, pizem j. repetitive er:yag laser irradiation of human skin: a histological evaluation. lasers surg med 2004; 35(2):146-51. 8. hardaway ca, ross ev, barnette dj, paithankar dy. nonablative cutaneous remodeling with a 1.45 microm mid-infrared diode laser: phase i. j cosmet laser ther 2002;4(1):3-8. 9. reda am, taha ir, riad ha. clinical and histological effect of a single treatment of normal mode alexandrite (755 nm) laser on small melanocytic nevi. j cutan laser ther 1999;1(4): 209-15. 10. westerhof w, gamei m. treatment of acquired junctional melanocytic nevi by q-switched and normal mode ruby laser. br j dermatol 2003; 148(1):80-5. 11. baba m, bal n. efficacy and safety of the short-pulse erbium:yag laser in the treatment of acquired melanocytic nevi. dermatol surg 2006; 32(2):256-60. 12. piccolo d. the usefulness of dermoscopy in laser and intense pulsed light treatments. florence: remo sandron editor, 2012. 13. trau h, orenstein a, schewach-millet m, tsur h. pseudomelashowed complete histological regression of a melanocytic nevus under intense pulsed light therapy for axillary hair removal [1,4,5,6,12]. conclusion hair removal with lasers in areas containing melanocytic nevi may result in incidental treatment of nevi and subsequent changes in clinical and dermoscopic features, which, in turn, may raise suspicion for melanoma, especially in patients with multiple risk factors. dermatologists should be aware of this phenomenon and be careful to avoid melanocytic nevi while treating an anatomic area with laser for epilation. despite many publications reporting treatment of melanocytic nevi with lasers, it remains a controversial issue. in our opinion, laser therapy should not be considered a routine indication for melanocytic lesions that have not been biopsied and histopathologically evaluated and in the event of incomplete treatment may induce changes that could simulate malignant melanoma. when presented with a melanocytic nevus that has undergone recent change in an area previously treated with laser epilation, dermatologists should be mindful that it might represent a “recurrent nevus” rather than a melanoma. moreover, it is essential that the pathologist interpreting the biopsy be provided with as much clinical information as possible, minimizing the possibility of erroneously rendering a diagnosis of melanoma and consequently unnecessary surgical procedures, adjuvant treatment and follow-up regimens. references 1. martín j, monteagudo c, bella r, reig i, jordá e. complete regression of a melanocytic nevus under intense pulsed light table 1. reports of melanocytic nevi that changed after hair removal treatment with laser or intense pulsed light. first author clinical evaluation laser type outcome soden, 2001 [3] four melanocytic nevi diode laser clinical changes martin, 2012 [1] one melanocytic nevus intense pulsed light complete regression, histologically confi rmed sillard, 2013 [4] two melanocytic nevi intense pulsed light dermoscopic changes garrido-ríos, 2013 [5] patient 1—two melanocytic nevi patient 2—two melanocytic nevi patient 3—several melanocytic nevi (no specifi c number) diode laser alexandrite laser intense pulsed light dermoscopic and histopathological changes dermoscopic and histopathological changes clinical and dermoscopic changes piccolo 2012 [11] patient 1—melanocytic nevus patient 2—congenital nevus intense pulsed light complete regression, histologically confi rmed dermoscopic changes; no signifi cant changes histologically case report | dermatol pract concept 2015;5(2):20 103 15. hwang k, lee wj, lee si. pseudomelanoma after laser therapy. ann plast surg 2002; 48(5):562–4. 16. lee hw, ahn sj, lee mw, et al. pseudomelanoma following laser therapy. j eur acad dermatol venereol 2006;20(3):342–3. noma following laser therapy for congenital nevus. j dermatol surg oncol 1986;12(9):984–6. 14. dummer r, kempf w, burg g. pseudo-melanoma after laser therapy. dermatology 1998;197(1):71–3. dermatology: practical and conceptual 330 research | dermatol pract concept 2018;8(4):18 dermatology practical & conceptual www.derm101.com degree of differentiation of cutaneous squamous cell carcinoma: a comparison between a swedish cohort of organ transplant recipients and immunocompetent patients caroline stenman1, helena gonzalez1, martin gillstedt1, göran dellgren2,3, bengt hasséus4, erik holmberg5, helena rexius2, jenny öhman4, john paoli1 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 department of cardiothoracic surgery and transplant institute, sahlgrenska university hospital, gothenburg, sweden 3 department of molecular and clinical medicine, institute of medicine, sahlgrenska academy, university of gothenburg, gothenburg, sweden 4 department of oral medicine and pathology, institute of odontology, sahlgrenska academy, university of gothenburg, gothenburg, sweden 5 department of oncology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg sweden key words: cutaneous squamous cell carcinoma, organ transplant recipients, immunosuppression, histopathological differentiation, nonmelanoma skin cancer citation: stenman c, gonzalez h, gillstedt m, dellgren g, hasséus b, holmberg e, rexius h, öhman j, paoli j. degree of differentiation of cutaneous squamous cell carcinoma: a comparison between a swedish cohort of organ transplant recipients and immunocompetent patients. dermatol pract concept. 2018;8(4):330-336. doi: https://doi.org/10.5826/dpc.0804a18 received: february 25, 2018; accepted: may 23, 2018; published: october 31, 2018 copyright: ©2018 stenmen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: the study was financed by grants from the federal government of sweden under the alf agreement. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: john paoli, department of dermatology, sahlgrenska university hospital, gröna stråket 16, 413 45 gothenburg, sweden. email: john.paoli@vgregion.se background: organ transplant recipients (otrs) have a very high risk of developing cutaneous squamous cell carcinoma (cscc). immunosuppressed otrs may have a higher proportion of poorly differentiated cscc than non-otrs. objectives: the aim of this study was to investigate the degree of differentiation of csccs in otrs compared with immunocompetent individuals. patients/methods: data from the swedish cancer registry were crosschecked with data from the transplant registry of the transplant institute at sahlgrenska university hospital in gothenburg, sweden. all otrs with a diagnosis of cscc, basosquamous carcinoma, and/or cscc in situ established at the department of dermatology, sahlgrenska university hospital, during 2002-2015 were included. the control group consisted of non-otrs with the same diagnoses during the same time period. abstract research | dermatol pract concept 2018;8(4):18 331 one may hypothesize that csccs in otrs tend to have a higher proportion of poorly differentiated tumors than csccs in immunocompetent patients, which could also contribute to an increased mortality. to investigate this, we aimed to study the degree of differentiation of csccs in immunosuppressed otrs compared with immunocompetent individuals. materials and methods gothenburg’s regional ethical review board approved the study. study population data pertaining to all diagnosed skin cancers were obtained from the swedish cancer registry of the national board of health and welfare, which contains data on all cancers diagnosed among the swedish population since 1958 [17]. the transplant registry at the transplant institute at sahlgrenska university hospital (suh) contains data regarding all patients who received transplants from january 1965 at suh. this registry was used to acquire data on the otrs who underwent organ transplantation between 1965 and 2010. the international statistical classification of diseases (icd-10) codes c44.0s-c44.9s (cscc), d04.0-d04.9 (cscc in situ), and z08.9b (follow-up visit for cscc) were used to identify patients. patients from the transplant registry were crosschecked with patients from the swedish cancer registry in order to find otrs with an icd code for cscc in situ and/or cscc. tumors occurring prior to the first transplantation were excluded. only patients diagnosed at the department of dermatology, suh from 2002 (the year the electronic chart system was introduced) but prior to may 31, 2015, were included in this group, a total of 82 patients with 515 tumors. the control group consisted of non-otrs diagnosed with cscc and/or cscc in situ at the department of dermatology, suh from 2002 to may 31, 2015. a total of 883 patients with 1,247 tumors were included. the histopathological report for each tumor was collected from the electronic chart system at suh. the tumors were classified into 6 groups: cscc in situ, well-differentiated introduction organ transplant recipients (otrs) have a well-known increased risk of developing cancer due to immunosuppression [1]. nonmelanoma skin cancer, particularly cutaneous squamous cell carcinoma (cscc), is the most common malignancy seen in otrs. compared with the general population, the risk of developing cscc is 60 to 100 times greater in otrs [2-4]. furthermore, csccs in otrs have been shown to be more numerous and more aggressive compared with csccs in immunocompetent individuals [5-7]. in addition, the incidence of cscc is proportional to the level of immunosuppression and is often associated with human papillomavirus (hpv) infection [8]. the pathogenesis of cscc is multifactorial. for both otrs and immunocompetent individuals, the most important risk factor for development of cscc is uv radiation [9]. fair skin is also seen as a risk factor [10]. there is a strong correlation between age and cscc, with the highest incidence rates observed in men and women over 85 years of age [11]. another risk factor for cscc is the presence of oncogenic viruses in the skin [12]. in recent years, hpv has been associated with cscc in otrs. among these patients, 80% of csccs are associated with hpv infection, in contrast to only 40% among immunocompetent individuals [13]. greater age at transplantation as well as higher doses and longer duration of immunosuppressive regimens have also been identified as risk factors [9,14]. histopathologically, cscc originates from epidermal keratinocytes and consists of nests, sheets, and strands of epithelial cells that arise from the epidermis and invade into the dermis for a variable distance. the csccs are commonly divided into 3 categories: well differentiated, moderately differentiated, and poorly differentiated depending on the resemblance of the tissue of origin. there are no clear objective parameters for grading the differentiation of csccs [15], but one classification is that >75% of the cells are differentiated in well-differentiated tumors, 25%-75% in moderately differentiated tumors, and <25% in poorly differentiated tumors [7]. well-differentiated csccs tend to grow at a slower rate and metastasize to a lesser extent than tumors that are poorly differentiated [16]. results: during 2002-2015, 82 otrs diagnosed with 515 tumors and 883 non-otrs with 1,247 tumors were included. otrs developed  0.47  tumors/year vs  0.10  tumors/year for non-otrs, but no significant differences were observed in the degree of tumor differentiation of invasive csccs between otrs and non-otrs (p = 0.4). the distribution of poorly, moderately, and well-differentiated invasive csccs among otrs and non-otrs were 8.5% vs 12.5%, 22.1% vs 29.9%, and 69.4% vs 57.6%, respectively. conclusions: otrs do not develop a higher proportion of poorly differentiated csccs than nonotrs. abstract 332 research | dermatol pract concept 2018;8(4):18 diagnosis were 59 years and 61 years, respectively (range: 31-82 years). the otr cohort comprised 70 kidney, 6 liver, 5 heart, and 1 lung recipient. the mean and median time since transplantation was 15 and 14 years, respectively (range: 0.435 years). the average follow-up time was 13.5 years. in the non-otr group, 883 patients were included, comprising 405 (46%) women and 478 (54%) men. the mean and median ages at diagnosis were 79 and 81 years, respectively (range: 32-101 years). the average follow-up time was 13.5 years. cscc and cscc in situ the tumor characteristics for both groups are presented in table 2. the degrees of differentiation of the invasive csccs in otrs compared with non-otrs are shown in figure 1. in the otr group, a total of 515 tumors were found with an average of 6.3 tumors/patient. the average follow-up time was 13.5 years, which corresponds to 0.47 tumors/year. of the 515 tumors, 198 were cscc in situ and 258 were cscc with a known degree of differentiation. in these cases, 22 (8.5%) were poorly differentiated, 57 (22.1%) were moderately differentiated, and 179 (69.4%) were well differentiated. the number of tumors in the non-otr group was 1,247, an average of 1.4 tumors/patient and 0.10 tumors/year. among these tumors, 86 were cscc in situ and 1,019 were cscc with a known degree of differentiation: 127 (12.5%) were poorly differentiated, 305 (29.9%) were moderately differentiated, and 587 (57.6%) were well differentiated. when comparing the distribution of the level of differentiation of the csccs with available data while also stratifying with respect to age group between the otrs and non-otrs, no significant difference was seen (p value 0.4, mantel-haenszel test). as an incidental finding, an association was seen between the distribution of the level of differentiation of csccs and age groups below and above the median age at diagnosis in both groups. otrs who were above the median age of 62 years had significantly fewer well-differentiated csccs (61%, ci 52-70) than younger otrs (76%, ci 69-83) cscc, moderately differentiated cscc, poorly differentiated cscc, and “cscc, other” (including cases of invasive or microinvasive cscc without a specified degree of differentiation, cscc and basosquamous carcinoma). in some cases, the same tumor had several histopathological reports, eg, the first report was from a punch biopsy and the second report from when the tumor was excised in toto. in such cases, the lowest differentiation level was chosen, and the same tumor is represented only once in the material. statistical analysis all data were analyzed using r version 3.0.3 (the r foundation for statistical computing, vienna, austria) and stata version 13.1 (stata corporation, college station, tx). the fisher exact test was used to compare proportions. the mantel-haenszel test was used to compare proportions across groups stratifying with respect to age group (<55 years, 55-64 years, and ≥65 years). the wilcoxon rank sum test was used for 2-sample tests. all tests are 2-sided. p values <0.05 and 95% confidence intervals (ci) were considered statistically significant. relative survival was computed using the ederer ii method [18]. mortality data for the general population in sweden were used to estimate expected survival rates for the study populations. the mortality data contained the probability of death for single-year age groups and gender in 1-year calendar periods. the strs macro, developed by paul dickman, enzo coviello, and michael hills, in the stata statistical software, version 13.1, was used for the calculation of the relative survival. survival time was calculated from date of diagnosis to date of death or to december 31, 2016. results analysis of study population patient characteristics are shown in table  1. a total of 82 otrs were included, of which 36 (44%) were women and 46 (56%) were men. the mean and median ages at table 1. demographic statistics and number of tumors per patient in the otr and non-otr groups otrs (n = 82) non-otrs (n = 883) mean median sd 95% ci mean median sd 95% ci lower upper lower upper age (years) at first diagnosis (2002-2015) men 61 62 10 57 64 78 80 10 77 79 women 57 59 13 53 61 80 82 12 79 81 all 59 61 12 57 62 79 81 11 78 80 no. of tumors/patient (2002-2015) 6.3 3.0 7.3 4.7 7.9 1.4 1.0 1.6 1.3 1.5 research | dermatol pract concept 2018;8(4):18 333 table 2. descriptive statistics regarding the distribution of the different types of cscc and the anatomic location of the tumors in the otr and non-otr groups tumors in otrs (n = 515) tumors in non-otrs (n = 1,247) n % n % tumor type cscc in situ 198 38% 86 7% well-differentiated cscc 179 35% 587 47% moderately differentiated cscc 57 11% 305 24% poorly differentiated cscc 22 4% 127 10% cscc, other* 59 11% 142 11% anatomic location head or neck 175 34% 738 59% upper extremity 140 27% 121 10% lower extremity 86 17% 187 15% trunk 114 22% 199 16% unknown 0 0% 2 0% anatomic location (only invasive cscc) head or neck 116 38% 689 60% upper extremity 90 29% 107 9% lower extremity 47 15% 167 15% trunk 56 18% 186 16% unknown 0 0% 2 0% anatomic location (only cscc in situ) head or neck 56 28% 42 49% upper extremity 49 25% 14 16% lower extremity 38 19% 18 21% trunk 55 28% 12 14% unknown 0 0% 0 0% * includes 8 basosquamous carcinomas in otrs and 10 basosquamous carcinomas in non-otrs. figure 1. distribution of the degrees of differentiation for the otr and non-otr groups. the vertical lines within the bars denote 95% confidence intervals. [copyright: ©2018 stenmen et al.] 334 research | dermatol pract concept 2018;8(4):18 non-otrs 60%, p < 0.0001) and cscc in situ (otrs 28% and non-otrs 49%, p = 0.001). there was no significant difference in the degree of differentiation for csccs in the head and neck area when comparing otrs and non-otrs. however, csccs in the head and neck area showed significantly poorer tumor differentiation compared with csccs on other body sites, when stratifying with respect to age groups (p < 0.00001). survival analysis the relative survival showed no difference between the  2 groups (figure 2). for non-otrs, the relative survival was  0.84 (ci 0.78-0.89) and for otrs it was 0.78 (ci 0.65-0.88). discussion the correlation between immunosuppression and skin cancer has been extensively studied [1,3,4], but far less is known about the difference in degree of differentiation of csccs in otrs as compared with csccs in immunocompetent patients. to our knowledge, only harwood et al and, more recently, cheng et al have previously compared the degree of differentiation of csccs among otrs and non-otrs, finding no significant differences in smaller series [19,20]. there are several studies that show a more lethal and more aggressive behavior of csccs in otrs [7,21]. however, 69.4% of csccs in otrs in this study were well differentiated, which is consistent with the results from lindelöf et al showing an almost identical proportion of well-differentiated (p value 0.03, fisher exact test). the same phenomenon was seen among the non-otrs when looking at patients above the median age of 81 years with 51% (ci 46-55) of csccs being well differentiated compared with 64% (ci 60-68) in non-otrs below the median age (p value 0.0005, fisher exact test). furthermore, otrs were diagnosed with significantly more cscc in situ (n = 198, 0.18 per person and year) than the non-otrs (n = 86, 0.01 per person and year) (p < 0.0001) despite the 20-year difference in mean age between the groups (59 years for otrs and 79 years for non-otrs). tumor site another incidental finding was the distribution of the anatomic location of the tumors in the 2 groups. the tumor site differed significantly between the otr and the non-otr groups when stratifying for age group (p < 0.0001, mantelhaenszel test). otrs had a significantly larger proportion of tumors on the upper extremities (27% vs 10%, p < 0.0001) and the trunk (22% vs 16%, p = 0.003). in contrast, the non-otrs had a significantly higher proportion of tumors in the head and neck area (59% vs 34%, p < 0.0001). when comparing the anatomic location of the tumors between the otr and non-otr groups for invasive csccs and cscc in situ lesions separately, the significant difference remained (p < 0.0001 for invasive csccs and p = 0.003 for the in situ lesions). when comparing the proportion of lesions on the head and neck between otrs and non-otrs, the significant difference also remained for invasive csccs (otrs 38% and figure 2. relative survival comparing otrs and non-otrs who had ≥1 invasive cscc. [copyright: ©2018 stenmen et al.] research | dermatol pract concept 2018;8(4):18 335 infection, in contrast to only 40% among immunocompetent individuals [13]. with regard to the relative survival, no significant difference was seen between otrs and non-otrs, but the comparison is difficult to make due to the large difference in mean age between the groups. a strength of this study is that the conditions for population studies in sweden are ideal, thanks to a history of extensive record-keeping and the fact that each citizen is assigned a unique social security number at birth, allowing all citizens to be traced through different records over time across the whole country without missing data, except if patients emigrate. there are, however, some limitations as well. among both otrs and non-otrs, 11% of the invasive csccs had an unknown degree of differentiation. we were also confined to the use of the electronic chart system, which was implemented at suh in 2002. since there is no national central medical record, we were not able to follow up with patients who may have been diagnosed with cscc at other clinics. finally, other factors that may also contribute to the aggressiveness of csccs (eg, tumor depth) were not analyzed. conclusions there was no significant difference between the groups with regard to the proportion of poorly differentiated csccs. otrs develop a significantly higher number of csccs and scc in situ than non-otrs. these tumors are more often located on the trunk and upper extremities in otrs, whereas non-otrs develop more tumors on the chronically uvexposed skin of the head and neck area. although csccs in otrs have traditionally been considered more aggressive, the larger number of csccs in otrs might be what increases the risk for recurrences and metastases and not the intrinsic malignant potential of each individual cscc per se. acknowledgments we thank dr. britta krynitz for her valuable input and discussions surrounding the histopathology of cutaneous squamous cell carcinoma. references 1. lindelöf b, sigurgeirsson b, gabel h, stern rs. incidence of skin cancer in 5356 patients following organ transplantation. br j dermatol. 2000;143(3):513-519. 2. moloney fj, comber h, o’lorcain p, o’kelly p, conlon pj, murphy gm. a population-based study of skin cancer incidence and prevalence in renal transplant recipients. br j dermatol. 2006;154(3):498-504. csccs (68.3%) [22]. in comparison with the non-otrs, there was no significant difference in the degree of tumor differentiation. in fact, there was a slightly higher proportion of poorly differentiated csccs among non-otrs (not significant). as an incidental finding, we discovered that there was a higher frequency of poorly differentiated csccs in the patients above the median age, independently of whether the patient was an otr or not. the fact that otrs acquire their tumors at a much younger age (20 years earlier than the nonotrs) may explain the finding that otrs have a relatively small proportion of poorly and moderately differentiated tumors. our findings corroborate a study by harwood et al in which otrs were 15 years younger than the non-otrs [19]. otrs developed on average 6.3 tumors per patient during an average follow-up time of 13.5 years, which gave a number of tumors per patient-year of 0.47. this high number of csccs per patient-year is most probably due to the immunosuppressive medication [1,2,23], but early diagnoses thanks to closer follow-up visits may also play a role among otrs [23]. notably, cscc in situ was significantly more common in otrs. this has also been seen in other studies [2,24]. in a swedish study from 2000, 172 otrs had a total of 325 nonmelanoma skin cancers (nmscs), not including basal cell carcinomas. the average follow-up time was 9.2 years. for these patients with nmscs, the number of nmscs per person-year was 0.20 [1]. in a study from the united kingdom, 257  otrs had 622 nmscs including cscc in situ and basal cell carcinomas. the follow-up time was 8 years and the number of nmscs per person-year was 0.30 [2]. the higher number of tumors per person-year in our study may be explained by the fact that the study period was more recent and the incidence of cscc in sweden has increased during the past decade [25]. the patients in our study had also been immunosuppressed for a longer period of time (13.5 years vs 9.2 years). furthermore, the knowledge about the risk of cscc in otrs has increased and nowadays there is a much more organized system for follow-up visits which might have resulted in more diagnosed cases per patient. surprisingly, non-otrs had a significantly higher proportion of tumors in the head and neck area compared with otrs and the significance remained when comparing the anatomic location of the tumors between the groups for csccs and cscc in situ lesions separately. all patients who undergo transplantation at suh receive information about the risks of sun exposure. a hypothesis may be that otrs therefore use sunscreen on the chronically exposed facial skin more frequently than non-otrs. another explanation could be that uv radiation is not the only risk factor for csccs in otrs. in otrs, 80% of csccs are associated with hpv 336 research | dermatol pract concept 2018;8(4):18 15. weedon d, morgan mb, gross c, nagoro e, yu ll. squamous cell carcinoma. in: leboit pe, ed. pathology and genetics of tumors of the skin. lyon: iarc press; 2006:20-25. 16. kumar v, abbas ak, fausto n, robbins sl, cotran rs. pathologic basis of disease vol 7. robbins sl, cotran rs, eds. philadelphia: elsevier saunders; 2005. 17. swedish national board of health and welfare. cancer incidence in sweden 2011. 2012; available at: https://www.socialstyrelsen. se/lists/artikelkatalog/attachments/18919/2012-12-19.pdf. accessed february 25, 2018. 18. ederer f, axtell lm, cutler sj. the relative survival rate: a statistical methodology. natl cancer inst monogr. 1961 sep;6:101-21. 19. harwood ca, proby cm, mcgregor jm, sheaff mt, leigh im, cerio r. clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series. j am acad dermatol. 2006;54(2):290-300. 20. cheng jy, li fy, ko cj, colegio or. cutaneous squamous cell carcinomas in solid organ transplant recipients compared with immunocompetent patients. jama dermatol. 2018;154(1):60-66. 21. berg d, otley cc. skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. j am acad dermatol. 2002;47(1):1-17; quiz 18-20. 22. lindelöf b, dal h, wolk k, malmborg n. cutaneous squamous cell carcinoma in organ transplant recipients: a study of the swedish cohort with regard to tumor site. arch dermatol. 2005;141(4):447-451. 23. ramsay hm, fryer aa, hawley cm, smith ag, nicol dl, harden pn. factors associated with nonmelanoma skin cancer following renal transplantation in queensland, australia. j am acad dermatol. 2003;49(3):397-406. 24. ramsay hm, fryer aa, reece s, smith ag, harden pn. clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. am j kidney dis. 2000;36(1):167-176. 25. swedish national board of health and welfare. cancer incidence in sweden 2014. 2015; available at: http://www.socialstyrelsen. se/lists/artikelkatalog/attachments/20008/2015-12-26.pdf. accessed february 25, 2018. 3. krynitz b, edgren g, lindelöf b, et al. risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008: a swedish population-based study. int j cancer. 2013;132(6):1429-1438. 4. euvrard s, kanitakis j, claudy a. skin cancers after organ transplantation. n engl j med. 2003;348(17):1681-1691. 5. boyle j, mackie rm, briggs jd, junor bj, aitchison tc. cancer, warts, and sunshine in renal transplant patients: a case-control study. lancet. 1984;1(8379):702-705. 6. gupta ak, cardella cj, haberman hf. cutaneous malignant neoplasms in patients with renal transplants. arch dermatol. 1986;122(11):1288-1293. 7. lindelöf b, jarnvik j, ternesten-bratel a, granath f, hedblad ma. mortality and clinicopathological features of cutaneous squamous cell carcinoma in organ transplant recipients: a study of the swedish cohort. acta derm venereol. 2006;86(3):219-222. 8. buell jf, gross tg, woodle es. malignancy after transplantation. transplantation. 2005;80(2 suppl):s254-s264. 9. vajdic cm, van leeuwen mt. cancer incidence and risk factors after solid organ transplantation. int j cancer. 2009;125(8):17471754. 10. english dr, armstrong bk, kricker a, winter mg, heenan pj, randell pl. demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study. int j cancer. 1998;76(5):628-634. 11. hussain sk, sundquist j, hemminki k. incidence trends of squamous cell and rare skin cancers in the swedish national cancer registry point to calendar year and age-dependent increases. j invest dermatol. 2010;130(5):1323-1328. 12. penn i. cancers in renal transplant recipients. adv ren replace ther. 2000;7(2):147-156. 13. accardi r, gheit t. cutaneous hpv and skin cancer. presse med. 2014;43(12 pt 2):e435-e443. 14. webb mc, compton f, andrews pa, koffman cg. skin tumors posttransplantation: a retrospective analysis of 28 years’ experience at a single centre. transplant proc. 1997;29(1-2):828-830. https://www.socialstyrelsen.se/lists/artikelkatalog/attachments/18919/2012-12-19.pdf https://www.socialstyrelsen.se/lists/artikelkatalog/attachments/18919/2012-12-19.pdf dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com background: the incidence of nodular melanoma (nm) has been consistently described as at least 10-15% of total melanomas for over 15 years despite advances in diagnostic algorithms and medical technology. nms are strongly correlated with faster rates of growth and poorer prognosis and thus provide clinicians with a challenge for early recognition. objective: to evaluate diagnostic clues of consecutive histopathologically proven nms in one general practice with particular emphasis on dermatoscopic characteristics and compare this to the published literature. method: a retrospective observational study was performed of five consecutive histologically proven nm, from a total of 212 consecutive melanomas from a general practice in brisbane, queensland, australia. dermatoscopic images, both polarized and non-polarized, which appears to be a unique resource, and dermatopathologic slides were available for all lesions. results: all of the nms in this series were pigmented although one was hypomelanotic. two of them were symmetrical. the most highly sensitive clues to nm were gray or blue structures and polarizingspecific white lines. limitations: due to the small number of nms in this report no statistical significance can be attributed to the observational findings. conclusion: this small series supports what is already known: that a significant proportion of nms may be dermatoscopically symmetrical but that known clues to melanoma are frequently present. nodular lesions, pigmented or non-pigmented, should be excised to exclude nm if there is any clue to malignancy, regardless of symmetry, unless a confident specific benign diagnosis can be made. abstract observation | dermatol pract concept 2014;4(2):15 69 nodular melanoma: five consecutive cases in a general practice with polarized and non-polarized dermatoscopy and dermatopathology cliff rosendahl1, matthew hishon1, alan cameron1, sarah barksdale2, david weedon2, harald kittler3 1 school of medicine, the university of queensland, australia 2 sullivan nicolaides pathology, brisbane, australia 3 department of dermatology and venereology, medical university of vienna, austria keywords: dermatoscopy, dermoscopy, dermatopathology, nodular, melanoma, nodular melanoma, polarizing-specific white lines, chrysalis structures citation: rosendahl c, hishon m, cameron a, barksdale s, weedon d, kittler h. nodular melanoma: five consecutive cases in a general practice with polarized and non-polarized dermatoscopy and dermatopathology. dermatol pract concept. 2014;4(2):15. http://dx.doi. org/10.5826/dpc.0402a15 received: july 29, 2013; accepted: december 9, 2013; published: april 30, 2014 copyright: ©2014 rosendahl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, phd, po box 734, capalaba, queensland, 4157australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com mailto:cliffrosendahl@bigpond.com 70 observation | dermatol pract concept 2014;4(2):15 introduction nodular melanoma (nm), defined as a melanoma with any junctional component extending no more than three rete ridges beyond the invasive component, is the second largest melanoma subtype, comprising 10-15% of melanomas in caucasians [1]. nms have been shown to have a faster growth rate (gr) (median gr 0.49 mm/month) than lentigo maligna melanomas (median gr 0.13 mm/month) and superficial spreading melanomas (ssm) (median gr 0.12 mm/month) [2]. the gr of malignant melanomas (mm) has also been shown to be an independent prognostic indicator for the prediction of relapse after one year of follow up [3]. studies have been performed in an attempt to determine diagnostic features, both clinical and dermatoscopic, which facilitate earlier diagnosis of nm, when breslow thickness is less and prognosis therefore more favorable [4]. a general practice, with a special interest in skin cancer medicine and dermatoscopic photo-documentation of all treated lesions, provides a unique perspective on the evaluation of this condition. methods a retrospective analysis was performed with respect to all nms diagnosed between january 1, 2008, and june 30, 2013, in a general practice in brisbane, queensland, australia. all lesions treated were prospectively recorded on the skin cancer audit research database (scard) for both tracking and research purposes [5]. during the time interval of this study, five nms were diagnosed from a total of 212 melanomas, 163 (76.8%) in-situ and 49 (23.2%) invasive. the percentage of melanomas which were nodular was therefore 2.4% of total melanomas and 10.2% of invasive melanomas. from january 1, 2008, to june 30, 2013, the ‘number needed to treat’ (nnt) with respect to all melanomas diagnosed in this practice, calculated from the prospectively declared intention to confirm or exclude melanoma, was 5.36 [6]. photo-documentation was routinely performed on all lesions submitted for histopathology, including clinical, macro and dermatoscopic images. dermatopathologic copy-slides were also collected, catalogued and where appropriate, photographed. dermatoscopic images were taken of all cases with a dermlite fluid non-polarizing dermatoscope (3gen, llc) coupled to a canon 50d digital camera (canon usa, inc.) and after october 2010, also with either a dermlite ii hr polarized or dermlite dl3 (polarized and non-polarized) dermatoscope (3gen, llc) coupled to an olympus e-450 digital camera (olympus corporation). both non-polarized and polarized dermatoscopic images were available for each of the five nm. cases the five cases of histologically diagnosed nm are presented in tables 1 and 2 with relevant clinical, dermatoscopic and dermatopathologic information. in estimation of melanoma growth rate (gr) we used the ratio mm thickness/duration of the mm visible growth as defined in a previously described assessment tool [3]. clinical images are displayed in figure 1, close-up images in figure 2 and dermatoscopic and dermatopathologic images of each lesion are displayed in figures 3 to 7. t a b le 1 . pa ti en t d is co ve ry a n d l es io n d et ai ls o f a se ri es o f fi ve c o n se cu ti ve n o d u la r m el an o m as i n a g en er al p ra ct ic e. * c a se s e x a g e s k in t y p e p re v io u s m e la n o m a s e lf d is co v e re d d ia m e te r (m m ) b re sl o w (m m ) m it o ti c ra te (m m /s q u a re ) u lc e ra ti o n g ro w th r a te (m m /m o n th ) 1 m 4 2 3 n o ye s 4 1 .3 5 5 ye s 1 .3 0 2 m 7 5 3 n o ye s 1 1 5 .0 0 9 ye s 3 .3 0 3 m 8 5 1 n o ye s 1 0 3 .8 0 4 ye s 5 .1 0 4 m 5 8 1 ye s ye s 4 0 .8 2 1 ye s 1 .0 9 5 f 6 2 2 n o n o 3 0 .9 0 1 n o n /k * g ro w th r at e (g r ) is c al cu la te d a cc o rd in g to a p re vi o u sl y p u b li sh ed c al cu la ti o n t o o l as m el an o m a th ic k n es s d iv id ed b y th e d u ra ti o n o f vi si b le m el an o m a gr o w th . t h e g r w as c as e 5 w as n o t k n o w n a s th e p at ie n t h ad n o k n o w le d ge o f th e le si o n . [ c o p yr ig h t: © 2 0 1 4 r o se n d ah l et a l. ] observation | dermatol pract concept 2014;4(2):15 71 discussion the incidence of nms in this study was 10.2% (n=5/49) of invasive melanomas comparing to 10-15% in published large studies [4]. table 2. dermatoscopy features of the series of five consecutive nodular melanomas listed in table 1.* case asymmetry blue/black structures gray/blue structures lines white (nonpolarized) lines white polarizing specific polymorphous vessels 1 yes no no yes yes yes 2 no yes yes yes yes yes 3 yes no yes no yes yes 4 yes yes yes no yes no 5 no yes yes no no no *asymmetry is defined as asymmetry of structure or color and is based on pattern, not outline. blue/black structures are defined as blue/black color covering at least 10% of the lesion. gray or blue structures are rated if these colors are seen on any part of the lesion. white lines (non-polarized) are rated if seen with non-polarizing dermatoscopy. polarizing-specific white lines are white lines, perpendicularly orientated to each other, seen only with polarized dermatoscopy and polymorphous vessels are defined as a pattern including more than one vessel type. [copyright: ©2014 rosendahl et al.] figure 1. clinical images of five consecutive nodular melanomas from a general practice. case 1: a small brown nodule on non-sundamaged skin adjacent to the right areola on a 42-year-old man. case 2: a blue nodule on sun-damaged skin on the right upper calf of a 75-year-old man. case 3: a brown nodule on sun-damaged skin on the right lateral leg of an 85-year-old man. case 4: a small blue nodule on sun-damaged skin on the upper calf of a 58-year-old man. case 5: a very small brown nodule on non-sun-damaged skin on the back of a 62-year-old woman. [copyright: ©2014 rosendahl et al.] a dermatoscope footplate. there is macular brown pigment on three sides. case 2: a well demarcated shiny blue nodule with a regular border, with surface scale. case 3: a well demarcated brown nodule with surface scale, more lightly colored centrally, with an eccentric darker area at one part of the slightly irregular border. case 4: a well demarcated black nodule with an irregular border. case 5: a well demarcated irregularly pigmented brown and black nodule with a markedly irregular border. [copyright: ©2014 rosendahl et al.] figure 2. close-up images of the nodular melanomas displayed in figure 1. case 1: a well demarcated brown nodule with a regular border, surmounted by a pool of fresh blood following contact with 72 observation | dermatol pract concept 2014;4(2):15 the doctor without the patient having any prior awareness of it (case 5). this compares to the non-nodular melanomas in the same practice where only 9.6% (n= 20/207) were discovered by the patient (of the remainder 14 were discovered by another doctor, 5 by another person and the remainder by the treating practitioner). we believe that this highlights the importance of patient education and awareness in the recognition of abnormal changes in skin lesions but it also illustrates the value of a clinician proceeding to examine the total skin surface when presented with any lesion of concern. the clinical abcd method is the most widely known algorithmic method for the clinical diagnosis of melanoma and has been promoted both to healthcare professionals and patients [10]. one of the criteria for melanomas to be detected using this method is that they have a minimum diameter of 6 mm. it has been agreed among many authors that a significant proportion of nms do not fulfil the abcd criteria including the criterion of a minimum lesion size of 6mm [8,11]. in one series of eleven thin nms (breslow thickness 2 mm or less), 63.6% (n=7/11) had a diameter of less than 6 mm [4]. similarly, in our series 60% (n=3/5) had a diameter less than 6mm and furthermore, each of these also had a breslow thickness less than 2 mm. one study of 1789 patients with melanoma found that nm was most frequently found in older men and most commonly on the lower limbs or head and neck [7]. in addition, it was shown to be more strongly correlated with actinic keratosis rather than high nevi counts [7]. this suggests that nms have an association with sun-damaged skin. in our series 80% (n= 4/5) were male and 75% (n=3/4) of these males were over 50. with respect to body site, 60% (n=3/5) were on the leg (on sun-damaged skin) and 40% (n=2/5) were on the torso (on non-sun-damaged skin). in a study involving 92 ssms and 33 nms, a higher proportion of nm was discovered by the patient (60.6%) compared to ssm (48.9%) [8], and in a study of 22 patients with nm, 61% were first detected by the patient and another 17% detected by another family member and the patient [9]. in our series 60% (n= 3/5) were reported by the patient and another was known of by the patient, but this information was not volunteered until after the lesion was discovered (case 4). in one case where the lesion was only 3 mm in diameter and on the posterior torso, it was discovered by figure 3. case 1: (a) nonpolarized dermatoscopic image; (b) polarized dermatoscopic image; (c, d and e) dermatopathology images. white lines seen in both dermatoscopy images (perpendicularly orientated in the polarized image) arguably correlate with vertical bands of collagen seen in the dermatopathologic overview (c). a mitotic figure is seen centrally in (e). [copyright: ©2014 rosendahl et al.] figure 4. case 2: (a) nonpolarized dermatoscopic image; (b) polarized dermatoscopic image; (c, d and e) dermatopathology images. the polarizing-specific perpendicular white lines are concentrated peripherally (b) and arguably correlate with vertical bands of collagen seen peripherally in the dermatopathologic images (c and d). [copyright: ©2014 rosendahl et al.] observation | dermatol pract concept 2014;4(2):15 73 10% of the lesion had 78.2% sensitivity for melanoma [14]. the clue of ‘blue-black color’ was present in 60% (n=3/5) of the nms in our series. the clues to malignancy of gray or blue structures and polarizing specific white lines (defined as perpendicularly orientated white lines visible only on polarized dermatoscopy) displayed the highest sensitivity for nm in our small consecutive series; each of them (n=5/5) had either one or the other clue and 60% (n=3/5) had both. polarizing-specific white lines were first named ‘chrysalis structures’ [15] and were attributed to the presence of increased collagen, which has birefringent properties causing rapid randomization of polarized light thus making the collagen more conspicuous. in a study by balagula et al. it was found that in non-biopsied lesions these structures were most commonly found in dermatofibromas and scars, but in 265 biopsied lesions including 20 melanomas they were observed with respect to dermatoscopic examination there were some similarities between the melanomas in our series (see table 2) and those in larger published studies. it has been shown that in nm many of the classic dermatoscopic features of ssm are lacking, however, irregularity of color is usually present in those that do contain pigment [12]. all of the melanomas in our series contained melanin pigment, although in one (case 3) 75% of the lesion was non-pigmented and this would categorize it as an amelanotic/ hypomelanotic melanoma (ahm) [13]. in our series symmetry was present in 40% (n=2/5; cases 2 and 5) and if the accompanying nevus was ignored case 1 was also symmetrical; all were pigmented. the asymmetrical melanomas in our series were asymmetrical in both structure and color. in a published series of 33 nms, 80% were symmetrical and 60.7% were classified as amelanotic [8]. in another published study 64% (n=7/11) of thin nms (breslow 2 mm of less) were symmetrical and 18% (n=2/11) were classified as amelanotic [4]. a study of a series of 283 nodular pigmented lesions found that the presence of blue/black color covering at least figure 5. case 3: (a) nonpolarized dermatoscopic image; (b) polarized dermatoscopic image; (c, d and e) dermatopathology images. polarizing-specific white lines are seen centrally (b) and arguably correlate with dermatopathologic vertical collagen bands, not apparent in the overview (c) but seen in the central part of the lesion in the higher power view (d). [copyright: ©2014 rosendahl et al.] figure 6. case 4: (a) nonpolarized dermatoscopic image; (b) polarized dermatoscopic image; (c, d and e) dermatopathology images. heavily pigmented melanocytes concentrated in the dermis correlate with the structureless blue, caused by the tyndall effect, seen in (a) and pagetoid nests and single cells in the epidermis correlate with black clods and dots respectively seen in both (a) and (b). polarizing-specific blue-white lines seen in (b) arguably correlate with vertical bands of collagen seen in (d). [copyright: ©2014 rosendahl et al.] 74 observation | dermatol pract concept 2014;4(2):15 image (figure 3c). in case 2, polarizing specific white lines are seen peripherally (centrally is structureless white) and vertical collagen bands are seen peripherally in the dermatopathology image (figure 4d). in case 3 no white lines are seen in the non-polarizing image—just a white structureless area—but they are seen centrally in the polarized image. correspondingly, vertical collagen bands, while not conspicuous in the low power view, are seen centrally in the medium-high power view (figure 5d). in case 4 the polarizing-specific lines are actually blue/white and there are no white or blue lines in the non-polarized view, just a very prominent structureless blue area. there is an abundance of collagen evident in the dermatopathology images of this case and significant vertical orientation of this is seen in the medium-high power view (figure 6d). case 5 is the exception in our series and contains no dermatoscopic white lines in either the polarized on non-polarized images. of significance, no vertically oriented bands of collagen are seen in any of the dermatopathological images of this case. we believe this supports the hypothesis that polarizingspecific white lines represent increased collagen production as vertically orientated bands, probably reflecting increased fibroblast activity related to the vertical growth phase of melanoma [16]. conclusion nm is a subtype of melanoma distinct from ssm both dermatopathologically and in its biological behavior. the presentation of five consecutive nms with both polarized and non-polarized dermatoscopy provides a unique perspective on this lesion and supports what is already known: that a significant proportion of nodular melanomas may be dermatoscopically symmetrical but that known clues to melanoma are frequently present. every one of these five nms, whether symmetrical or not, had either gray/blue color or polarizingspecific white lines or both. the hypothesis that perpendicular white lines correlate to vertical bands of collagen related to the growth dynamics of invasive melanoma is supported by the fact that the four nms in our series which displayed dermatoscopic polarizing-specific white lines also displayed dermatopathologic vertical bands of collagen in the dermis, while the one that did not have this feature had no dermatopathologic vertical collagen bands. we would suggest that more nms would be diagnosed earlier if nodular lesions with any known clue to malignancy were considered for biopsy regardless of symmetry. in particular, the clue of polarizing-specific white lines should lead to excision unless a confident specific benign diagnosis, for example, of dermatofibroma, can be made on historic and clinical grounds. in 47.6% of basal cell carcinomas and 84.6% of invasive melanomas [16]. they were found to be more frequently observed in invasive melanomas than in-situ melanomas and their prevalence correlated to increased thickness of melanomas. in our series of 212 melanomas (23.2% n=49 invasive), both polarized and non-polarized dermatoscopy images were available in 142 (19.7% n=28 invasive). while 80% (n=4/5) of the nodular melanomas had polarizing-specific white lines only 7.2% (n=10/137) of the non-nodular melanomas displayed this feature and all but one of those were in-situ. in case 1 of our series the polarizing-specific white lines appear to correlate with white lines also seen with nonpolarized dermatoscopy and we speculate that they correlate with vertical bands of collagen seen in the dermatopathology figure 7. case 5: (a) nonpolarized dermatoscopic image; (b) polarized dermatoscopic image; (c and d) dermatopathology images. there are no dermatoscopic polarizing-specific white lines (b), and consistent with the hypothesis that these structures correlate to vertical collagen bands, none of these are seen in the dermatopathologic images although abundant collagen surrounds nests of melanocytes (c and d). on the extreme left side (c and shown at high power in d) an eccrine duct can be seen attenuated by a large melanocyte nest which appears to be bulging into it. this would correlate with a dermatoscopic peripheral brown clod, as there is no apparent collagen within or superficial to this nest to induce the tyndall effect. [copyright: ©2014 rosendahl et al.] observation | dermatol pract concept 2014;4(2):15 75 9. bergenmar m, hansson j, brandberg y. detection of nodular and superficial spreading melanoma with tumour thickness < or = 2.0 mm—an interview study. eur j cancer prev. 2002 feb;11(1):49–55. 10. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin 1985;35(3):130-51. 11. kelly jw, chamberlain aj, staples mp, mcavoy b. nodular melanoma. no longer as simple as abc. aust fam physician. 2003 sep;32(9):706–9. 12. segura s, pellacani g, puig s, et al. in vivo microscopic features of nodular melanomas: dermoscopy, confocal microscopy, and histopathologic correlates. arch dermatol. 2008 oct;144(10):1311– 20. 13. moloney fj, menzies sw. key points in the dermoscopic diagnosis of hypomelanotic melanoma and nodular melanoma. j dermatol. 2011 jan;38(1):10–5. 14. argenziano g, longo c, cameron a, et al. blue-black rule: a simple dermoscopic clue to recognize pigmented nodular melanoma. br j dermatol. 2011;165(6):1251-5. 15. marghoob aa, cowel l, kopf aw, scope a. observation of chrysalis structures with polarized dermoscopy. arch dermatol. 2009 may 1;145(5):618. 16. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012 aug;67(2):194.e1–8. references 1. porras bh, cockerell cj. cutaneous malignant melanoma: classification and clinical diagnosis. semin cutan med surg. 1997 jun;16(2):88–96. 2. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol. 2006 dec;142(12):1551–8. 3. grob jj, richard ma, gouvernet j, et al. the kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study. int j cancer. 2002 nov 1;102(1):34–8. 4. kalkhoran s, milne o, zalaudek i, et al. historical, clinical, and dermoscopic characteristics of thin nodular melanoma. arch dermatol. 2010 mar;146(3):311–8. 5. rosendahl c, hansen c, cameron a, et al. measuring performance in skin cancer practice: the scard initiative. int j dermatol. 2011 jan;50(1):44–51. 6. rosendahl c, williams g, eley d, et al. the impact of subspecialization and dermatoscopy use on accuracy of melanoma diagnosis among primary care doctors in australia. j am acad dermatol. 2012 nov;67(5):846–52. 7. chamberlain aj, fritschi l, giles gg, dowling jp, kelly jw. nodular type and older age as the most significant associations of thick melanoma in victoria, australia. arch dermatol. 2002 may;138(5):609–14. 8. chamberlain aj, fritschi l, kelly jw. nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection. j am acad dermatol. 2003 may;48(5):694–701. untitled observation | dermatol pract concept 2015;5(4):15 59 dermatology practical & conceptual www.derm101.com pseudocyst of the auricle in patients with movement disorders: report of two patients with ataxia-associated auricular pseudocysts bryce d. beutler1, philip r. cohen2 1 university of nevada school of medicine, reno, nv, usa 2 department of dermatology, university of california san diego, san diego, ca, usa key words: ataxia, auricle, dyskinesia, ear, friedreich’s, neurological, pinna, pseudocyst, spasticity, spinocerebellar, trauma citation: beutler bd, cohen pr. pseudocyst of the auricle in patients with movement disorders: report of two patients with ataxiaassociated auricular pseudocysts. dermatol pract concept 2015;5(4):15. doi: 10.5826/dpc.0504a15 received: february 28, 2015; accepted: march 3, 2015; published: october 31, 2015 copyright: ©2015 beutler et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md, department of dermatology, university of california san diego, san diego, ca, 92093, usa. email: mitehead@gmail.com background: pseudocyst of the auricle is a benign condition of the ear characterized by an asymptomatic, noninflammatory swelling on the lateral or anterior surface of the auricle. it typically presents as a 1 to 5 centimeter cystic lesion located within the scaphoid or triangular fossa. in most patients, the lesion develops spontaneously. however, pseudocyst of the auricle has also been associated with trauma to the ear. purpose: we describe the clinical findings of two men who developed pseudocyst of the auricle associated with ataxia-induced trauma to their ear. we also summarize the differential diagnosis, the postulated pathogenesis, and the treatment options for this condition. materials and methods: the features of two men with pseudocyst of the auricle are presented. using pubmed, the following terms were searched and relevant citations assessed: ataxia, auricle, dyskinesia, ear, friedreich’s, neurological, pinna, pseudocyst, spasticity, spinocerebellar, and trauma. in addition, the literature on pseudocyst of the auricle is reviewed. results: pseudocyst of the auricle was observed in two men with neurological disorders: a 33-yearold asian man with spinocerebellar ataxia and a 47-year-old caucasian man with friedreich’s ataxia. each patient had a history of ataxia-induced head and ear trauma. the clinical features of the lesions were sufficient to establish a diagnosis of pseudocyst of the auricle. neither patient desired treatment. conclusion: pseudocyst of the auricle is a benign cystic lesion that is occasionally precipitated by trauma to the affected ear. patients with neurological disorders, particularly those associated with ataxia and/or dyskinesias, may have an increased risk of developing the traumatic variant of the condition. diagnosis can usually be established by clinical presentation. however, in some patients, a tissue specimen may be secured for microscopic evaluation to exclude infection or during surgical repair. various treatment options exist for pseudocyst of the auricle, including: (1) needle aspiration—with or without subsequent injection of an irritant substance—followed by a pressure dressing and (2) surgical deroofing. alternatively, reassurance of the benign nature of the condition and observation is a reasonable management alternative. abstract 60 observation | dermatol pract concept 2015;5(4):15 lesion was interpreted as an abscess with cellulitis and he had undergone an incision and drainage with adjuvant systemic antibiotic therapy. however, the swelling had recently returned. his past medical history was significant for friedreich’s ataxia. he permanently resides in a skilled nursing facility secondary to his ataxia-associated difficulty in motor movements. he has a history of hitting his head on the rails of his bed. cutaneous examination revealed a 4.0 x 2.0 cm cystic lesion involving primarily the crura of antihelix of his left ear. it was asymptomatic and noninflammatory (figure 2). the lesion was initially soft to the touch; however, it had become firm. based on correlation of the clinical presentation and lesion morphology, a diagnosis of pseudocyst of the auricle was established. since he was at continual risk of repeatedly traumatizing his ear, no intervention was performed to his auricular pseudocyst. discussion pseudocyst of the auricle was first described by the german physician arthur hartmann in 1846 [1]. however, the condition did not appear in the english-language literature until 1966, when engel observed the lesion in chinese men [2]. one year later, hansen reported several caucasian patients who had pseudocyst of the auricle [3]. the initial observations made by hartmann, engel, and hansen remain relevant today. engel and hansen both noted that the condition occurs predominantly in men [2,3]. indeed, in a 1990 world literature review of 114 cases of pseudocyst of the auricle, 93% of auricular pseudocyst patients were men [4]. their findings were later corroborated by lim et al., who reviewed the medical records of 41 patients who were treated for pseudocyst of the auricle in singapore and concluded that 87% were men [5]. the age of onset typically ranges introduction pseudocyst of the auricle is a benign, noninflammatory, asymptomatic cystic lesion of the ear. it most commonly develops progressively over a 4to 12-week period in the scaphoid or triangular fossa. the lesion may, or may not, be associated with trauma to the affected ear. patients with neurological disorders that are associated with motor dysfunction, such as ataxias, may be at a heightened risk for developing trauma-related pseudocyst of the auricle. we describe two men who developed pseudocyst of the auricle after sustaining ataxia-associated head and ear injuries. we also review the differential diagnosis, the postulated pathogenesis, and the treatment options of pseudocyst of the auricle. case reports case 1. a 33-year-old asian man with spinocerebellar ataxia (which clinically became symptomatic 10 years earlier) presented for evaluation of a nontender swelling on his upper right ear that was present for one month. he had poor motor control of his movements and had repeatedly hit his ear against the head support on his motorized wheelchair. cutaneous examination revealed a firm cystic nodule measuring 3.0 x 2.0 cm on the anterior surface of the auricle of his right ear. the lesion was asymptomatic, flesh-colored, and had progressively enlarged over the previous four weeks (figure 1). based on correlation of the clinical presentation and distinct lesion morphology, a diagnosis of pseudocyst of the auricle was established. since he was at continual risk of repeatedly traumatizing his ear, no intervention was performed to his auricular pseudocyst. case 2. a 47-year-old caucasian man presented for evaluation of a cystic lesion on his left ear. six months prior, the a b c figure 1 (a, b, and c). distant (a), intermediate (b), and close (c) views of the right ear show a 3.0 x 2.0 centimeter pseudocyst of the auricle in a 33-year-old asian man with spinocerebellar ataxia. [copyright: ©2015 beutler et al.] observation | dermatol pract concept 2015;5(4):15 61 side of the auricle, usually at the juncture of the crura anthelicis” [2]. indeed, most patients, including our own, present with lesions that involve the crura of antihelix and scaphoid and triangular fossae. however, pseudocysts may also occur at other sites; in a 2001 review of 17 patients, supiyaphun et al. observed that lesions often develop in the concha [8]. between 30 and 39 years [4,5]. however, albeit rarely, lesions may appear in either childhood [6] or old age [7]. there is no ethnic predilection. pseudocyst of the auricle typically presents as a solitary lesion on the anterior aspect of the ear. in his 1966 report, engel observed that the pseudocysts “were localized in the upper half of the anterior regardless of the site of presentation, pseudocysts of the auricle develop progressively over a 4to 12-week period and present as flesh-colored, nontender, noninflammatory cystic lesions. they range in size from 1 to 5 cm in diameter. the lesions are often soft initially and become increasingly firm over time. they are filled with a viscous fluid that is usually straw-yellow in color, resembling olive oil. however, serous and serosanguinous fluid may be present [4,9]. pseudocyst of the auricle typically presents unilaterally—most commonly on the right ear—but bilateral presentations have also been reported [4,10-12]. histologically, pseudocysts are characterized by an intracartilaginous cystic space with surrounding fibrosis. they can be distinguished from cysts by the absence of an epithelial lining on the inner surface of the intracartilaginous cavity. degeneration of cartilage is common; rarely, calcification may be observed. a perivascular mononuclear infiltrate, predominantly of lymphocytes, is often present [13]. the clinical differential diagnosis of pseudocyst of the auricle is listed in table 1 [2,4,9,13]. it includes not only local conditions, but also systemic disorders with skin lesions that may mimic pseudocyst of the auricle. the mechanism of pathogenesis for pseudocyst of the auricle is unknown. in most patients, lesions arise spontaneously. it has been hypothesized that these pseudocysts result from a defect in embryogenesis in which residual planes of tissue are created during the folding of the branchial outgrowths that fuse to form the auricle. the excess tissues could theoretically reopen when subjected to mechanical stress, thus predisposing affected individuals to pseudocyst development [2,14]. it has also been postulated that trauma contributes to pseudocyst formation. indeed, several patients presenting with pseudocyst of the auricle have reported a recent injury to the affected area of their ear [15,16]. other patients a b c d e figure 2 (a-e). posterior (a), oblique (b), and side (c) views of a flesh-colored pseudocyst of the auricle measuring 4.0 x 2.0 centimeters can be seen projecting from the left ear of a 47-year-old caucasian man with friedreich’s ataxia. posterior (d) and side (e) views of the patient’s unaffected right ear show normal auricular structure. [copyright: ©2015 beutler et al. 62 observation | dermatol pract concept 2015;5(4):15 of autosomal dominantly inherited progressive neurological conditions. there are over 30 known types of spinocerebellar ataxias; the age of onset, clinical presentation, and prognosis vary between the different types. however, all spinocerebellar ataxias are characterized by ataxia, dysarthria, and ultimately bulbar dysfunction [21]. friedreich’s ataxia is distinct from most other spinocerebellar ataxias in that it is inherited in an autosomal recessive pattern. it is characterized by gait ataxia, dysarthria, dysphagia, spasticity, and loss of muscle tone [22]. indeed, both of our patients had recent histories of ataxiarelated head and ear trauma. we hypothesize that traumainduced pseudocyst of the auricle may occur more frequently in patients with neurological conditions that have disease-related movement disorders than in the general population. to the best of our knowledge, only one other patient with a movement disorder and pseudocyst of the auricle has been described: a young woman with cerebral palsy who, due to disease-related immobility, developed an auricular pseudocyst after lying in bed with her ear against the pillow for an extended period of time (table 2) [23, current report]. in contrast to our patients’ abnormal motor activity and likely repeated trauma to their affected ear, the auricular pseudocyst in the woman with cerebral palsy was not secondary to trauma. treatment of pseudocyst of the auricle should ideally be initiated promptly in order to preserve the normal architecture of the ear. fortunately, various effective chemical and surgical interventions have been developed in recent years. therapeutic interventions for successful management of patients’ auricular pseudocysts often involves: (1) alteration of the exposed cartilage surfaces and (2) adequate compression of the separated cartilage to enable healing without allowing fluid to accumulate in the prior space between the cartilage [24]. miyamoto et al. reported excellent results with steroid injection therapy. in a review of 8 patients who were treated with intralesional steroid injections, 3 patients had no recurrences and another 4 were treated successfully after 1 to 3 recurrences; only 1 patient failed to respond to treatment and required surgery [23]. however, in a recent prospective study of 28 patients, patigaroo et al. concluded that intralesional steroid injections were no more effective than simple observation [25]. furthermore, corticosteroid injections may result have engaged in practices that would subject their ears to chronic pressure or friction, such as wearing a tight motorcycle helmet [17] and sleeping on a hard pillow [18]. two trauma-related etiologies have been proposed. glamb and kim hypothesized that constant pressure and/or friction reduces blood flow to the perichondrium, inducing ischemia and subsequent cartilaginous degeneration [17]. conversely, choi et al. suggested that repetitive minor traumas lead to the formation of numerous microcysts, which ultimately coalesce to form a large pseudocyst [18]. both hypotheses are supported by recent work from miyamoto et al. and chen et al., who detected elevated lactate dehydrogenase levels within the pseudocyst fluid. two lactate dehydrogenase isozymes, lactate dehydrogenase-4 and lactate dehydrogenase-5, are present in auricular cartilage and could conceivably be released upon degeneration or tearing of the tissue [19,20]. patients who have neurological conditions with movement disorders may have an increased risk of developing trauma-induced pseudocyst of the auricle (table 2) [21, current report]. each of our patients suffered from neurological conditions characterized by ataxia and sudden, involuntary jerking movements. the spinocerebellar ataxias, also known as autosomal dominant cerebellar ataxias, represent a group table 1. clinical differential diagnosis of pseudocyst of the auricle angiosarcoma cauliflower ear cellulitis chondrodermatitis nodularis chronica helices dermal cyst epidermal inclusion cyst fibroma hidrocystoma perichondritis relapsing polychondritis rheumatoid nodule subperichondral hematoma tophus xanthoma table 2. characteristics of patients with movement disorders and pseudocyst of the auricle case age race gender affected ear neurological condition treatment reference 1 16 years asian female not reported cerebral palsy intralesional corticosteroids 23 2 33 years asian male right spinocerebellar ataxia reassurance and observation current report 3 47 years caucasian male left friedreich's ataxia reassurance and observation current report observation | dermatol pract concept 2015;5(4):15 63 be more susceptible to developing trauma-induced auricular pseudocysts. pseudocysts of the auricle are typically flesh-colored and range in size from 1 to 5 cm in diameter. they develop progressively over a 4to 12-week period, becoming increasingly firm over time. incision and drainage usually reveals a viscous, straw-yellow colored fluid that resembles olive oil. histologically, pseudocysts appear similar to cysts but lack an epithelial lining on the inner surface of the intracartilaginous cystic space. successful treatment for pseudocyst of the auricle initially includes either: (1) aspiration or incision and drainage, followed by injection of an agent to cause fibrosis and adherence of the cartilage or (2) surgical deroofing. subsequently, adequate and sustained compression—using a button bolster—is important for the intervention to be effective. however, since the lesions are usually asymptomatic, treatment is not always necessary—especially in patients with trauma-related auricular pseudocysts who are at risk for repeat injury to the affected ear. references 1. hartmann a. uber cystenbildung in der ohrenmuschel. arch ohren nasen kehlkopfheilkd. 1846;15:156-66. 2. engel d. pseudocyst of the auricle in chinese. arch otolaryngol. 1966;83:197-202. 3. hansen je. pseudocyst of the auricle in caucasians. arch otolaryngol. 1967;85(1):13-4. 4. cohen pr, grossman me. pseudocyst of the auricle: case report and world literature review. arch otolaryngol head neck surg. 1990;116(10):1202-4. 5. lim cm, goh yh, chao ss, lynne l. pseudocyst of the auricle. laryngoscope. 2002;112(11):2033-6. 6. ruda jm, piliang m, anne s. pseudocyst of the auricle in a very young child. int j pediatr otorhinolaryngol extra. 2014;9(3): 116-8. 7. foglia fernández m, gonzález compta x, arias cuchí g, et al. an auricular pseudocyst. a report of 4 cases. an otorrinolaringol am. 1998;25(2):121-9. 8. supiyaphun p, decha w, kerekhanjanarong v, hirunwiwatkul p. auricular pseudocysts: a treatment with chulalongkorn university vacuum device. otolaryngol head neck surg. 2001;124(2):213-6. 9. khan na, ul islam m, ur rehman a, ahmad s. pseudocyst of the pinna and its treatment with surgical deroofing: an experience at tertiary hospitals. j surg tech case rep. 2013;5(2):72-7. 10. santos vb, polisar ia, ruffy ml. bilateral pseudocysts of the auricle in a female. ann otol rhinol laryngol. 1974;83(1):9-11. 11. fukamizu h, imaizumi s. bilateral pseudocysts of the auricles. arch dermatol. 1984;120(9):1238-9. 12. cohen pr, grossman me. pseudocyst of the auricle. am j med. 1990;89(2):249-50. 13. lim cm, goh yh, chao ss, lim lh, lim l. pseudocyst of the auricle: a histologic perspective. laryngoscope. 2004;114(7):1281-4. 14. harder mk, zachary cb. pseudocyst of the ear. surgical treatment. j dermatol surg oncol. 1993;19(6):585-8. in permanent deformity of the auricle and therefore may not be appropriate for first-line treatment [4,17]. a conservative surgical approach for the management of pseudocyst of the auricle involves induction of fibrosis and scarring on the intracartilaginous cavity of the pseudocyst. job et al. described a procedure in which incision and drainage of the lesion is followed by curettage of the pseudocyst walls. bilateral contour pressure dressings are then applied in order to prevent fluid accumulation in the underlying tissue [26]. two modifications to the aforementioned surgical procedure may help improve patient outcomes. first, several investigators introduced either a 1% iodine tincture or another sclerosant (such as 50% trichloroacetic acid) into the pseudocyst cavity following drainage to induce fibrosis and to reduce the risk of lesion recurrence [2-4,10,27]. second, button bolsters were used in lieu of pressure dressings [27]; specifically, two sterilized shirt buttons were sutured to the auricle—one to the anterior side and another to the posterior side—following incision and drainage. the buttons not only help maintain localized pressure, but also substantially reduce the risk of recurrence and necrosis of the skin overlying the cartilage [28]. deroofing the cartilage of the pseudocyst may be the most effective, albeit invasive, treatment. indeed, multiple researchers have reported outstanding results with this surgical technique [14,25,29]. deroofing entails curetting and cauterizing the base of the pseudocyst and removing the degenerated cartilage from the roof of the pseudocyst; this procedure eliminates the possibility of any future recurrence. however, it is critically important to excise only the anterior wall of the pseudocyst; accidental removal of the posterior wall can result in deformity of the auricle [18]. surgical deroofing should be followed by button bolstering for optimal results [27]. pseudocyst of the auricle is usually asymptomatic. therefore, observation is a reasonable alternative to management if the patient is unconcerned about the cosmetic appearance of the lesion. in addition, clinical monitoring of the auricular pseudocyst may be appropriate in patients with neurological conditions associated with uncontrolled movements of the head and the potential for repeated trauma to the affected ear. conclusion pseudocyst of the auricle is a rare condition of the ear. it typically presents as an asymptomatic, noninflammatory, unilateral cystic swelling affecting the upper auricle. lesions may develop spontaneously or, less commonly, in response to trauma. pseudocyst of the auricle occurs predominantly in middle-aged men, but may also occasionally be observed in women, children, and the elderly. patients with neurological conditions that are associated with movement disorders may 64 observation | dermatol pract concept 2015;5(4):15 22. koeppen ah, mazurkiewicz je. friedreich ataxia: neuropathology revised. j neuropathol exp neurol. 2013;72(2):78-90. 23. miyamoto h, oida m, onuma s, uchiyama m. steroid injection therapy for pseudocyst of the auricle. acta derm venereol. 1994;74(2):140-2. 24. cohen pr. successful treatment of auricular pseudocyst using a surgical bolster. cutis. 2007;80(4):274. 25. patigaroo sa, mehfooz n, patigaroo fa, et al. clinical characteristics and comparative study of different modalities of treatment of pseudocyst pinna. eur arch otorhinolaryngol. 2012;269(7):1747-54. 26. job a, bhanu ts, mathai r, raghaven r. pseudocyst of the auricle. j laryngol otol. 1988;102(4):344-5. 27. cohen pr, katz be. pseudocyst of the auricle: successful treatment with intracartilaginous trichloroacetic acid and button bolsters. j dermatol surg oncol. 1991;17(3):255-8. 28. kanotra sp, lateef m. pseudocyst of the pinna: a recurrence-free approach. am j otolaryngol. 2009;30(2):73-9. 29. chang ch, kuo wr, lin ch, et al. deroofing surgical treatment for pseudocyst of the auricle. j otolaryngol. 2004;33(3):177-80. 15. kallini jr, cohen pr. rugby injury-associated pseudocyst of the auricle: report and review of sports-associated dermatoses of the ear. dermatol online j. 2013;19(2):11. 16. grabski wj, salasche sj, mccollough ml, angeloni vl. pseudocyst of the auricle associated with trauma. arch dermatol. 1989;125(4):528-30. 17. glamb r, kim r. pseudocyst of the auricle. j am acad dermatol. 1984;11(1):58-63. 18. choi s, lam kh, chan kw, ghadially fn, ng as. endochondral pseudocyst of the auricle in chinese. arch otolaryngol. 1984;110(12):792-6. 19. miyamoto h, okajima m, takahashi i. lactate dehydrogenase isozymes in and intralesional steroid injection therapy for pseudocyst of the auricle. int j dermatol. 2001;40(6):380-4. 20. chen pp, tsai sm, wang hm, et al. lactate dehydrogenase isozyme patterns in auricular pseudocyst fluid. j laryngol otol. 2013;127(5):479-82. 21. rossi m, perez-lloret s, doldan l, et al. autosomal dominant cerebellar ataxias: a systematic review of clinical features. eur j neurol. 2014;21(4):607-15. dermatology: practical and conceptual 146 commentary | dermatol pract concept 2019;9(2):11 dermatology practical & conceptual introduction the first dermoscopic description of caviar tongue with a beautiful image by jha et al published in a recent issue of this journal is indeed commendable [1]. however, i wish to highlight few pertinent issues regarding this report and, more important, regarding the interpretation of mucoscopy, perhaps the latest [2] and one of the trickiest realms of dermoscopy. comments owing to its noninvasive nature, ease, and promptness of suggesting a diagnosis, for experienced dermatologists dermoscopy is rapidly replacing histopathology for diagnosis of many disorders of general dermatology [3]. however, the above assertion is logically practical only for conditions in which the dermoscopic-histological correlation has been well established, that too in a substantial number of cases, eg, psoriasis, lichen planus, ezcemas, alopecias, and certain skin tumors. similarly, if the clinical presentation alone may be sufficient for a correct diagnosis (as in many mucous membrane conditions including caviar tongue), then researchers may of course comment on their dermoscopic appearance but prefer not to label the latter as diagnostic hallmarks. also, when the dermoscopic features of a skin or mucosal condition are being documented for the first time in scientific literature, its validation against the gold standard diagnostic criteria becomes essential. while the diagnosis of caviar tongue is nearly always clinical, differentials including hemangioma, lymphangioma, kaposi sarcoma, and mucosal melanoma are worth consideration. notwithstanding the clinical certainty of the case described by jha et al being caviar tongue, in the absence of confirmatory histopathology, the dermoscopic features described should not be unduly glorified as an “auxiliary tool for its diagnosis” lest there is sufficient evidence (not a single patient’s findings) and correlation with histopathology (the current gold standard of diagnostic confirmation) has been established. i also wish to highlight that the mutual contradiction between the following authors’ statements should be avoided in future such reports: “to the best of our knowledge, this is the first report on dermoscopy of caviar tongue” and “ . . . based on location, age, clinical and dermoscopic appearance, it was diagnosed as lingual varicosities.” if as per the authors’ own assertion this was the first published report on interpreting mucoscopy in lingual varicosities and beyond sidharth sonthalia1 1 skinnocence: the skin clinic & research centre, gurungram, india key words: dermoscopy, mucoscopy, caviar tongue, lingual varicosities, angiokeratoma citation: sonthalia s. interpreting mucoscopy in lingual varicosities and beyond. dermatol pract concept. 2019;9(2):146-147. doi: https://doi.org/10.5826/dpc.0902a11 accepted: january 23, 2019; published: april 30, 2019 copyright: ©2019 sonthalia. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: sidharth sonthalia, md, dnb, mnams, skinnocence: the skin clinic & research centre, c-2246, sushant lok-1, block-c, gurungram, 122009, india. email: sidharth.sonthalia@gmail.com commentary | dermatol pract concept 2019;9(2):11 147 4. ranjan n, mahajan vk. oral angiokeratomas: proposed clinical classification. int j dermatol. 2009;48(7):778-781. 5. sonthalia s, jha ak, bosseila m, errichetti e. dermoscopy—master by analysis and patience, not haste and nonchalance. pigment int. 2018;5:117-119. available from: http://www.pigmentinter national.com/text.asp?2018/5/2/117/247509. accessed on january 23, 2019. dermoscopy of caviar tongue, then how could it simultaneously be taken as one of the criteria for diagnosis, that too in the absence of histological confirmation? authors should be more careful about the use of terminology for dermoscopic characterization. pending the algorithm and scheme of systematic description of mucoscopic findings, i believe and suggest that mucoscopic description should include at least certain minimum parameters (table 1). in my opinion, the complete description of the dermoscopic image of caviar tongue displayed in the concerned report should have been as follows: absence of pigmentation, presence of multiple loosely scattered red lacunae with bluish white (rather than white) veil present over a yellowish crimson background, surrounded and interspersed with fine arborizing vessels and scattered telangiectasias and focal white structureless areas (figure 1). while the authors dwelled upon the dermoscopic differentiation from hemangioma and lymphangioma, it would have been better to mention the lack of melanocytic structures and rainbow pattern for formal differentiation from mucosal melanoma and mucosal kaposi sarcoma, respectively, which constitute closer clinical differentials of caviar tongue than pyogenic granuloma. and although oral angiokeratomas are relatively rare and typically involve the tip or the dorsum of the tongue [4], mentioning them in the discussion may have been better than discussing angiokeratomas of mibelli. conclusions dermoscopy is not a new technology, but its exploration for noninvasive diagnosis in general dermatology, including mucosal disorders, is a relatively recent phenomenon. while acquiring the skills to use this technique is no longer “optional” for dermatologists, great caution must be exercised while capturing the image and interpreting and reporting features according to the best and latest available guidelines. mucoscopy warrants extra care in this regard. thus i request all dermatology colleagues who are practicing and reporting dermoscopic findings of different dermatoses to descry the science by analysis, not nonchalance, and master the art with patience, not haste [5]. references 1. jha ak, zeeshan md, jha amar ak. mucoscopy in lingual varicosities. dermatol pract concept. 2018;8(1):54-55. 2. sonthalia s, varma s, jha ak, jakhar d, kaliyadan f. case report: dermoscopic features of oral lichen planus—the evolution of mucoscopy. version 2. f1000res. 2018 mar 6 [revised 2018 mar 27];7:284. 3. sonthalia s, errichetti e. dermoscopy—not just for diagnosis and not just for dermatologists! kathmandu univ med j (kumj). 2017;15(57):1-2. table 1. suggested minimum parameters for adequate dermoscopic (mucoscopic) characterization of a mucosal lesion parameter/structure characteristics melanocytic criteria absent/present/suspiciousa veil present/absent color: white, bluish white background color homogeneity vascular structures including lacunae absent/present distribution morphology for lacunae (lagoons) variant (red and/or dark) distribution within the lesion additional/specific dermoscopic feature(s) (if present) for example structureless areas ulceration white streaks asince mucous membrane architecture is different from that of the skin and conventional melanocytic criteria such as brown globules or lines are frequent in nonmelanocytic lesions, this terminology of “melanocytic criteria—absent/present/suspicious” may be replaced with a more descriptive approach, eg, presence of a particular pattern of pigmentary network. figure 1. reannotated figure 2 of the original case report [1]. the mucoscopic image shows a yellowish crimson background with multiple loosely scattered red lacunae (black arrows) with bluish white veil (white arrows), interspersed fine arborizing vessels (blue arrows), and scattered telangiectasias and focal white structureless areas (green arrows) (polarized dermoscopic image from the original case, ×10). [copyright: ©2018 jha et al] dermatology: practical and conceptual 22 research | dermatol pract concept 2018;8(1):5 dermatology practical & conceptual www.derm101.com introduction ingrown toenail is a common condition among adolescents and young adults. surgical intervention is usually recommended for stage 2 and stage 3 ingrown toenails as classified under the heifetz and mogensen system [1,2]. we have performed crescent excision of soft tissue, bony shortening of the distal phalanx, as well as nail avulsion for several years [3], but have not defined an objective standard for excision of the soft tissue and distal phalanx. moreover, routine nail avulsion seems obsolete. in recent years, we have found the nail plate itself to be a good landmark for more accurate excision. we were interested in seeing whether our patient could get a good result if the nail plate was not avulsed and used as an objective standard for excision of the soft tissue and distal phalanx. our aim was to evaluate the outcomes following a new perspective on the nail plate for treatment of ingrown toenail jia tian1, jin li1, fabin wang1, zhenbing chen1 1 department of hand surgery, union hospital, tongji medical college, huazhong university of science and technology, wuhan, p.r. china key words: ingrown toenail, soft tissue excision, distal phalanx bone shortening, nail plate citation: tian j, li j, wang f, chen z. a new perspective on the nail plate for treatment of ingrown toenail. dermatol pract concept. 2018;8(1):22-27. doi: https://doi.org/10.5826/dpc.0801a05 received: august 14, 2017; accepted: september 22, 2017; published: january 31, 2018 copyright: ©2018 tian et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: zhenbing chen, md, department of hand surgery, union hospital, tongji medical college, huazhong university of science and technology, 1277 jiefang avenue, 430022 wuhan, hubei, p.r. china. tel.: +8613871103730. email: whunionczb@foxmail. com background: our routine treatment for ingrown toenail was removal of the surrounding soft tissue and shortening the bone of the distal phalanx. we determined the range and volume of excision based on our experience without an objective standard and routinely performed avulsion of the nail plate. objective: to take the nail plate as an objective mark during surgical treatment of ingrown toenail to ensure accurate excision. patients and methods: fifteen patients with ingrown toenails were treated with this technique. we used the lateral borders of the nail plate as a landmark to determine the volume of soft tissue surrounding the nail plate and distal phalanx to be removed. no avulsion of nail plate was performed. results: no recurrence was observed during the follow-up period, which ranged from 24 to 35 months (29.9 months on average). the visual analog scale for pain showed significant pain relief in the patients. the vancouver scar scale showed acceptable cosmetic outcomes. the width of excised skin ranged from 3.5 to 6.2 mm (5.0 mm on average). conclusion: the use of the lateral borders of the nail plate as a landmark for surgical intervention of ingrown toenail offered excellent outcomes and reduced loss of healthy tissues. abstract mailto:3086233557@qq.com mailto:3086233557@qq.com research | dermatol pract concept 2018;8(1):5 23 of the nail plate buried in the bulky tissue, which would be used as a reference to decide how much of the soft tissue to resect. after that, an incision was made 2–3 mm distal to the hyponychium on the toe tip and then extended proximally parallel to both sides of the nail folds to the base of the toenail. the next incisions would be performed along the first incision (figure 1). the incision was made deep enough to the periosteum of the distal phalanx. we performed a distal phalanx shortening to achieve primary wound closure with no tension. we transected the distal phalanx meticulously to avoid damage to the supporting structures of the nail bed, taking care to avoid injuring the neurovascular bundles as well. we retracted the bulky tissue overlapping the nail plate downwards to check whether it was sufficient to expose the lateral borders of the nail plate. we would stop resecting skin around the nail when it was enough to expose the borders of the nail plate after closing the wound (figure 2). if the granulation tissue overlapping the nail plate was too bulky, we trimmed it to expose the lateral borders of the nail plate if necessary (figure 3). the defect was closed using interrupted 4-0 polypropylene sutures. the tourniquet was released and the wound was covered with petrolatum gauze to avoid adhesion of the dressings to the wounds. the dressings were changed every two days for two weeks; the sutures were then removed. the patients were taught to wear proper shoes and trim their nails correctly. results all patients returned to daily activity two weeks after surgery. there was no recurrence of ingrown toenail during the follow-up period. we used the visual analog scale for pain to assess pain relief in our patients about three months ingrown toenail correction in patients who had undergone our surgical approach in terms of healing time, relief of pain, recurrence, and scar formation. patients and methods fifteen patients with ingrown toenail, nine males and six females (aged 12–35 years; 20 years of age on average) at stages 2 and 3, were included in this study. these surgeries were performed in our hospital between december 2013 and may 2015. this study was conducted in compliance with the world medical association declaration of helsinki on medical research ethics. all patients provided informed consent before surgery, and institutional review board approval was obtained. all of them were affected on their great toes. nearly half of the patients came to us after ineffective conservative treatment. patients who had onychomycosis were treated with miconazole and soaking the affected area in warm water with potassium permanganate solution (1:5000) 30 minutes per day for two weeks. patients with acute infection were treated with oral antibiotics, with the addition of topical antibiotics when necessary. their nail plates were not avulsed for drainage. the operation was performed in the operating room approximately one week after resolution of the inflammation. povidone-iodine solution was used to disinfect the affected foot. all patients underwent local anesthesia with 1% lidocaine. the local anesthetic was administered circumferentially at the base of the hallux to block the plantar digital nerves and the ending sensory branches of the deep and superficial peroneal nerves. a tourniquet was fastened at the base of the hallux to occlude circulation. before making incisions, we explored the lateral nail borders to evaluate the width figure 1. the width of excised skin (a, b) and the width of preserved skin (c, d). [copyright: ©2018 tian et al.] 24 research | dermatol pract concept 2018;8(1):5 figure 2. illustration of the technique in the lateral and transverse views. [copyright: ©2018 tian et al.] after surgery and found the outcome to be satisfactory (table 1). the width of excised skin ranged from 3.5 to 6.2 mm (mean 5.0 mm) (table 1). we used the vancouver scar scale to evaluate the scar formation 24–35 months after surgery. the median values of vascularity, scar height, pigmentation, and pliability were either 0 or 1 (table 2). no patients experienced osseous inflammation after surgery. no patient had nail deformity or spicule formation. discussion patients with ingrown toenail experience pain, limitation of daily activities, and topical infections. various surgical interventions have been introduced by surgeons for treatment of ingrown toenail, such as matricectomy [4,5], phenolization [6], winograd technique [7,8], knot technique [9], and soft tissue resection without matricectomy [10,11]. each intervention has certain advantages and disadvantages based on the clinical scenario. figure 3. preoperative and postoperative views of a case with ingrown toenail. (a) the involved toe with bulky granulation tissue overlapping the nail plate. the yellow color on the nail plate was due to iodine solution used by the patient himself. (b) the wound was closed with no tension. almost one-third of the nail plate was removed from the distal edge to trim the bulky granulation tissue completely for a better exposure of the lateral nail borders. (c) one week after surgery. there was no further bleeding, but a little oozing. (d) 25-month postoperative view. the nail plate was normal in appearance with no recurrence. [copyright: ©2018 tian et al.] research | dermatol pract concept 2018;8(1):5 25 soft tissue, which leaves the nail matrix intact [14]. we had also performed soft-tissue resection for several years. we had not hesitated to perform nail plate avulsion, partly because we understood that the removal would aid in drainage of the infection. afterwards, we realized the important role of the nail plate in the surgical intervention and used them to define an objective standard to perform an accurate excision. meanwhile, we were convinced that the drainage enhancement afforded by avulsion was largely unnecessary due to the usual thorough reduction of inflammation through other ingrown toenail is caused by the conflict between the nail plate and the soft tissue. there must be something unbalancing the relationship, whether it is the ingrown toenail or the overgrown toe skin [12]. córdoba-fernández et al. showed that abnormal hallux interphalangeal angle increases the risk of ingrown hallux nail [13], but other potential causes remain unclear. the primary aim of most surgeries is to prevent interference between the nail and the soft tissue. many surgeons have prioritized treatments of the nail, such as nail avulsion. other surgeons instead recommend resection of table 1. patients and follow-up outcomes patient age (years) sex involved digits (hallux) follow-up period (months) vas width of excised skin (mm) recurrence before surgery after surgery 1 13 m left 27 4 0 4.1 no 2 22 m right 33 6 0 5.3 no 3 15 f right 34 5 0 5.6 no 4 33 m left 25 7 0 6.2 no 5 21 f right 34 5 0 5.7 no 6 16 f right 35 6 0 6.1 no 7 12 f both 31 5 0 4.4/4.1 no 8 17 m both 32 4 0 5.6/5.3 no 9 23 m left 30 4 0 3.5 no 10 25 m left 24 7 1 5.8 no 11 14 f left 27 6 0 4.3 no 12 15 m right 35 6 0 5.3 no 13 19 m both 29 4 0 5.2/5.3 no 14 35 f right 26 6 0 4.2 no 15 22 m right 26 5 0 5.6 no abbreviation: vas, visual analog scale for pain. table 2. numerical scale of vss used for assessment of scar formation score (points) pigmentation vascularity pliability height 0 normal normal normal normal to flat 1 hypopigmentation pink supple 0-1 mm 2 mixed pigmentation red yielding 1-2 mm 3 hyperpigmentation purple firm 2-4 mm 4 banding >4 mm 5 contracture median value (range) n=15 1(0-2) 0(0-1) 1(0-3) 0(0-1) abbreviation: vss, vancouver scar scale. 26 research | dermatol pract concept 2018;8(1):5 4. risks of poor vascularity and necrosis for the thin skin strip along the nail plate. no thinner than 2 mm is safe in our experience. this technique is not an appropriate treatment for all kinds of ingrown toenail. patients with congenital nail deformity or diabetes mellitus are not encouraged to be treated with this procedure. patients with nonstandard presentation sometimes required personalized treatment, and avulsion of the nail plate was unavoidable in certain cases [15]. this technique has been considered to be quite invasive with substantial postoperative pain, risk for bone infection and downtime compared to other common treatments such as gutter-splint treatment or phenolization and is therefore only indicated for a relatively small number of patients. usually only those teenagers who were eager to get back to school would accept it unhesitatingly in our practice. some patients did not consider the ingrown toenail to be a serious problem and were intimidated by the details of the procedure. it is easy to understand why simple avulsion of the nail plate was so popular despite its poor effectiveness. although our sample size was small and follow-up period short in our reported series, we believe that soft tissue excision guided by the lateral borders of the nail plate combined with bony shortening of the distal phalanx is an effective treatment for ingrown toenail. given our promising results, further research is warranted, more patients should be treated, and a longer follow-up period tracked to overcome the limitations of our small study. the technique’s several advantages, including the short healing time, excellent aesthetic appearance, and lack of any recurrence, could benefit many more patients with ingrown toenail in the future. references 1. heifetz cj. operative management of ingrown toenail. mo med. 1945;42:213-216. 2. mogensen p. ingrowing toenail: follow-up on 64 patients treated by labiomatricectomy. acta orthop scand. 1971;42(1):94-101. 3. li j, chen j, hong g, chen z, weng y, wang f. clinical study of treatment for recalcitrant ingrown toenail by partial distal phalanx removal. j plast reconstr aesthet surg. 2009;62(10):13271330. 4. cocunubo-blanco ha, gonzález-sixto b, pérez-paredes g, rodríquez-prieto má. partial nail matricectomy with carbon dioxide laser. actas dermosifilioqr. 2014;105(4):418-419. 5. grover c, khurana a, bhattacharya sn, sharma a. controlled trial comparing the efficacy of 88% phenol versus 10% sodium hydroxide for chemical matricectomy in the management of ingrown toenail. indian j dermatol venereol leprol. 2015;81(5):472-477. 6. di chiacchio n, di chiacchio ng. best way to treat an ingrown toenail. dermatol clin. 2015;33(2):277-282. 7. huang j, zhang y, ma x, wang x, zhang c, chen l. comparison of wedge resection (winograd procedure) and wedge resection means. therefore, we considered that the risk of incomplete damage might be outweighed by the benefit of preserving more healthy tissue. the goals of our approach are to offer our patients a great relief of pain with shorter recovering time, an aesthetic appearance, and no recurrence in the future. resection of skin surrounding the nail means removing an adequate amount of soft tissue to eradicate the possible causes of recurrence associated with bilateral and distal nail folds. on the other hand, resection of skin surrounding the nail also plays an important role in keeping the new bilateral and distal nail folds in a symmetric position, which will influence the aesthetic appearance if asymmetric nail folds appear. as we know, primary wound closure with no tension is critical for healing in a short time and for lowering the risks of dehiscence and scarring. resection of skin at the toe tip can make it easier to shorten the distal phalanx, which is necessary to achieve primary wound closure with no tension. as a matter of fact, bone shortening is inconspicuous and most patients do not perceive any change in the toe. generally speaking, our patients can get an acceptable result from this procedure without any severe complications. there are several advantages of this technique, and they are as follows: 1. shorter time period needed to regain daily activities. primary healing can be achieved in almost all patients. it usually takes two weeks for wound healing after surgery. 2. no observed recurrence, indicating that the technique may have eradicated the factors that unbalanced the relationship between the nail plate and soft tissue. 3. no narrowing of the nail plate. the key point of this technique is to reserve the nail plate, rendering it unnecessary for the patient to worry about the narrowing of the nail plate postoperatively. 4. no damage to the nail matrix. we do not perform ablation of the nail matrix to limit the growth of the nail, resulting in a normal-looking toe after recovery. 5. acceptable scarring. scar formation is acceptable due to the wound closure with no tension. the disadvantages of this technique include: 1. necessity of shortening the bone of the distal phalanx, which some patients may not have understood. 2. pain, which is caused by the large and deep defects necessary to treat the toe, and is obvious to most patients in two or three days after surgery and mitigated with analgesics. 3. risk of osseous infection, which might have been transmitted through the transection defect, especially in patients with severe infections. the latter is mitigated with sensitive management of inflammation, which is critical for our patients to avoid severe complications after surgery. research | dermatol pract concept 2018;8(1):5 27 12. chapeskie h. ingrown toenail or overgrown toe skin? alternative treatment for onychocryptosis. can fam physician. 2008;54(11):1561-1562. 13. córdoba-fernández a, montaño-jiménez p, coheña-jménez m. relationship between the presence of abnormal hallux interphalangeal angle and risk of ingrown hallux nail: a case control study. bmc musculoskelet disord. 2015;16:301. 14. debrule mb. operative treatment of ingrown toenail by nail fold resection without matricectomy. j am podiatr med assoc. 2015;105(4):295-301. 15. pandhi d, verma p. nail avulsion: indications and methods (surgical nail avulsion). indian j dermatol venereol leprol. 2012;78(3):299-308. plus complete nail plate avulsion in the treatment of ingrown toenails. j foot ankle surg. 2015;54(3):395-398. 8. acar e. winograd method versus winograd method with electrocoagulation in the treatment of ingrown toenails. j foot ankle surg. 2017;56(3):474-477. 9. ince b, dadaci m, altuntas z. knot technique: a new treatment of ingrown nails. dermatol surg. 2015;41(2):250-254. 10. gualdi g, monari p, crotti s, calzavara-pinton pg. surgical treatment of ingrown toe nail: the monaldi technique, a new simple proposal. dermatol surg. 2014;40(2):208-210. 11. rosa ip, di chiacchio n, di chiacchio ng, caetano l. “super u”−a technique for the treatment of ingrown nail. dermatol surg. 2015;41(5):652-653. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022151 1 dermatology practical & conceptual evaluation of mcv/rdw ratio and correlations with ferritin in telogen effluvium patients saadet i̇biş1, gülhan aksoy saraç2, turan akdağ3 1 karapınar state hospital biochemistry laboratory karapınar, konya, turkey 2 ufuk university faculty of medicine, department of dermatology, ankara, turkey 3 necmettin erbakan university, meram vocational school, konya, turkey key words: telogen effluvium, mcv/rdw, ferritin, correlation, alopecia citation: i̇biş a, aksoy saraç g, akdağ t. evaluation of mcv/rdw ratio and correlations with ferritin in telogen effluvium patients. dermatol pract concept. 2022;12(3):e2022151. doi: https://doi.org/10.5826/dpc.1203a151 accepted: december 22, 2021; published: july 2022 copyright: ©2022 i̇biş et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: concept – gas, ta, sk, design gas, ta, supervision – gas, ta, sk, funding none; materials – gas, sk data collection and/or processing – gas, sk; analysis and/or interpretation – gas, ta, sk, literature search – gas, ta, sk: writing – gas, ta, critical review – gas, ta, sk. corresponding author: gülhan aksoy saraç, ufuk university faculty of medicine, department of dermatology, ankara/turkey, e-mail: gulhan1984@yahoo.com introduction: telogen effluvium is one of the chronic diseases that affect the quality of life (qol) in women. genetic factors, vitamin deficiencies, hormonal and environmental conditions take roles in the etiology of hair loss. objectives: the study aimed to evaluate the rdw(red cell distribution witdh)/mcv(mean corpuscular volume) ratio and its correlation with ferritin in telogen effluvium patients and to reveal their potential role in the etiopathogenesis of telogen effluvium. methods: we retrospectively evaluated the medical data of 250 patients who were admitted to the dermatology outpatient clinic between september 2020 and december 2020 with a diagnosis of telogen effluvium. the control group was created retrospectively from the medical records of 250 healthy individuals. hb(hemoglobin), hct(hematocrit), mpv(mean platelet volume), mcv, rdw, ferritin, and mcv/rdw ratio of both groups were compared and evaluated statistically. results: all telogen effluvium patients were women in terms of gender. the mean age of the patient group was 33.11 ± 9.66 years and the mean age of the control group was 34.98 ± 12.37 years. the ratio of mcv/rdw, mpv, mcv, and ferritin is lower in the group with telogen effluvium compared to the control group and a statistically significant difference was found (p < 0.05). conclusions: iron deficiency anemia is thought of as a factor in female patients with telogen effluvium. although the data shows the correction of iron deficiency is insufficient telogen effluvium, we proposed that laboratory tests should be routinely used in the diagnosis and treatment phase of patients who apply with the complaint of hair loss. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022151 introduction the etiology of hair loss consists of unavoidable genetic factors as well as hormonal reasons, vitamin deficiencies, and environmental reasons. hair loss is seen as an important cosmetic problem that is increasing day by day, and therefore, the number of patients who apply to clinics is increasing [1,2]. studies have shown that the most common cause of hair loss in women is telogen effluvium, and it’s listed that the most common factors causing hair loss as low ferritin, vitamin b12 deficiency, and thyroid dysfunctions [3,4]. iron deficiency is the most common nutritional deficiency in the world [5]. one of the many problems caused by iron deficiency is hair loss [3]. it can even be considered as one of the most accused factors in the etiology of this disease [6,7]. it is thought that hair loss develops due to the lack of iron, which plays a role in oxygen transport to the tissues, and the inability to carry enough oxygen to the hair follicle [8]. iron is stored by ferritin together with apoferritin, and serum ferritin level reflects iron stores in the body [9]. kantor et al found low serum iron levels in patients with diffuse hair loss in their study, while rushton et al found low ferritin levels in 72% of the patients [10,11]. özden et al reported that women with diffuse hair loss had a low ferritin value of 36%, and in another study when 72 mg of iron was given daily to 22 women with chronic hair loss, they have shown that hair loss decreased [5,12]. the red cell distribution range (rdw) is a measure of the heterogeneity of circulating erythrocytes. high rdw can generally occur as a result of increased erythrocyte destruction (hemolysis), nutritional deficiency, or blood transfusion [13]. in addition, rdw elevation is observed as a result of ineffective erythropoiesis due to chronic inflammation and neurohumoral activation [14]. objectives as far as we know, the role of iron, rdw, and mcv(mean corpuscular volume) in hair loss seems unresolved so far. since the laboratory reference intervals were different in the studies, the results were also controversial. the spresent tudy aimed to evaluate the rdw/mcv ratio and its correlation with ferritin in patients with telogen effluvium and to reveal the roles of telogen effluvium in its etiopathogenesis. methods we retrospectively evaluated the medical data of 250 patients who were admitted to the dermatology outpatient clinic between september 2020 and december 2020 with a diagnosis of telogen effluvium. the diagnosis of telogen effluvium was performed as clinical. the control group was created retrospectively from medical records of 250 healthy individuals who applied to family health centers, with no complaints of hair loss or any other inflammatory skin disease, and were similar to the patient group in terms of mean age and gender. patients who were in the period of chronic disease, stress, thyroid disease, pregnancy, lactation, had a history of surgical operation in the last 3 months, and took vitamin supplements were excluded from the study. serum ferritin levels were evaluated by electrochemiluminescence (eclia, roche) method, and hemogram parameters (hgb, hct, mpv, and rdw) were performed with mindray bc-6800 (mindray bio-medical electronics co., ltd) hematology analyzer which analyzes complete blood count based on laser light scattering (forward and light scatter) and side fluorescent light. this retrospective study was approved by the non-invasive clinical research ethics committee of necmettin erbakan university (decision no: 2021/3515). the study has conducted by the principles of the declaration of helsinki. statistical analysis spss version 25.0 program was used for database creation and statistical analysis. pearson correlation test was used to measure the relationship and degree of relationship between variables and p < 0.05 was accepted as significance limit. results all patients consisted of females in the study. the mean age of the patient group was 33.11 ± 9.66 years and the mean age of the control group was 34.98 ± 12.37 years. there was no difference between the two groups in terms of age (p > 0.05). rdw value was elevated in telogen effluvium patients (p = 0.02), mpv and mcv values were decreased in telogen effluvium patients compared with the control group as p = 0.00 and p = 0.04, respectively. mcv/rdw ratio of the telogen effluvium patients was lower than the mcv/rdw ratio of the control group as 6.41 versus 7.41 (p = 0.00) (table 1). the correlation between mcv/rdw ratio and ferritin was evaluated, and no significant correlation was found between the parameters (p > 0.05). when patients with telogen effluvium with positive and negative pull tests were compared, no statistically significant difference was found between the two groups in terms of hb, hct, mpv, mcv, rdw, ferritin, and mcv/rdw ratios (p > 0.05) (table 2). conclusions telogen effluvium is the most common cause of diffuse hair loss. also, it’s a non-cicatricial form of hair loss that develops approximately 3 months after a triggering factor and is characterized by widespread hair loss. telogen effluvium original article | dermatol pract concept. 2022;12(3):e2022151 3 can be observed in both genders. on the other hand, women constitute the majority of patients who apply for treatment, because the frequency of the disease may be higher in women, or that the number of admissions in men is low and the cases remain subclinical [15,16]. several studies were reported that fever, stress, major surgery, increase in androgen or estrogen hormone levels, hyperthyroidism, and many other causes have been associated with telogen effluvium [17]. to define the etiological diagnosis in telogen effluvium, a detailed history, and laboratory tests to exclude endocrine, nutritional, and autoimmune diseases should be performed [18]. while many studies have reported serum iron deficiency in telogen effluvium patients, some of them do not show a relationship between iron deficiency and the incidence of telogen effluvium [19]. sinclair et al declared that low serum ferritin and hair loss were show not a relation between ferritin levels and hair loss [20]. a recent study reported that telogen effluvium patients had significantly lower serum ferritin concentrations compared to those in the control group (17.35 ± 18.54 ng/ml versus 39.27 ± 29.44 ng/ml, p = 0.001) [21]. as similar, patients with telogen effluvium had lower serum ferritin levels which compared to the control group in our study (28.83 µg/l versus 64.89 µg/l, p = 0.00) (table 1). mcv, is known as one of the red blood cell indices and defines the size of the red blood cells. mcv could determine the classification of anemia as microcytic anemia below the normal range, normocytic anemia within the normal range, macrocytic anemia above the normal range [22].  ferritin is a measure of iron stores and the most sensitive biomarker to test for early stages of iron deficiency as well as iron deficiency anemia. obaidat et al reported a significant association between low serum ferritin levels and chronic telogen effluvium [23]. table 1. comparison of some parameters between patient and control group patient group control group p age, years, mean ± sd 33.11±9.66 34.98±12.37 > 0.05 hb, g/dl 13.60 13.47 > 0.05 hct, % 42.13 40.18 > 0.05 mpv, µm3 7.83 10.47 0.00 mcv, fl 84.22 86.65 0.04 rdw, % 14.30 11.68 0.02 ferritin, µg/l 28.83 64.89 0.00 mcv/rdw, fl/% 6.41 7.41 0.00 hb = hemoglobin; hct = hematocrit; mpv = mean platelet volume; mcv = mean corpuscular volume; mcv/rdw m= mean corpuscular volume/red cell distribution width ratio; rdw = red cell distribution width; sd = standard deviation. table 2. comparison of telogen effluvium with positive and negative pull test pull test n mean p hb positive 66 13.50 >0.05 negative 146 13.64 hct positive 66 40.30 >0.05 negative 146 42.95 mpv positive 66 7.78 >0.05 negative 146 7.85 mcv positive 66 85.47 >0.05 negative 146 85.10 rdw positive 66 11.72 >0.05 negative 146 11.66 ferritin positive 66 30.71 >0.05 negative 146 27.97 mcv/rdw positive 66 7.43 >0.05 negative 146 7.41 hb = hemoglobin; hct = hematocrit; mpv = mean platelet volume; mcv = mean corpuscular volume; mcv/rdw m= mean corpuscular volume/red cell distribution width ratio; rdw = red cell distribution width. 4 original article | dermatol pract concept. 2022;12(3):e2022151 as a routine parameter, rdw represents the variation in diameters of red blood cells in the complete blood count [24]. rdw has been investigated in several diseases, such as rheumatoid arthritis, psoriasis, heart failure, and cutaneous vasculitis, and has been considered as a marker of inflammation [25]. the mcv/rdw ratio is used to evaluate for many diseases such as acute pancreatitis, cardiovascular disease [26,27]. while rdw value was elevated in telogen effluvium patients (p = 0.02), mpv and mcv values were decreased in telogen effluvium patients compared with the control group as p = 0.00 and p = 0.04, respectively. mcv/rdw ratio of telogen effluvium patients was lower than the mcv/rdw ratio control group as 6.41 versus 7.41 (p = 0.00). also, the correlation between mcv/rdw ratio and ferritin was evaluated in telogen effluvium patients, and no significant differences were found between the patient and control group (p > 0.05) (table 2). from the literature, controversial findings of related parameters were observed in telogen effluvium. to clarify our study results, more comprehensive and further studies are needed. references 1. özden mg, öztaş mo, gülekon a, gürer ma. kadın olgularda yaygın saç kaybı ve eşlik eden bulgular. j exp clin med 2008;25(2):50-56. 2. obaidat na, rawashdeh bt, wreikat a, awamleh aa. a potential relation between telogen effluvium and iron deficiency in adult females. j res med sci 2005;12(1):26-66. 3. sinclair r. diffuse hair loss. int j dermatol. 1999;38(s1):8-18. doi: 10.1046/j.1365-4362.1999.00003.x. pmid: 10369535. 4. shrivastava sb. diffuse hair loss in an adult female: an approach to diagnosis and management. indian j dermatol venereol leprol. 2009;75(1):20-27. quiz 27-8. doi: 10.4103/03786323.45215. pmid: 19172026. 5. akyurek ft, demirbas gu, demirbas a, akyurek f, kurtipek gs. retrospective evaluation of laboratory data of patients with telogen effluvium. ann med res. 2019;26(12):2754-2757. 6. trost lb, bergfeld wf, calogeras e. the diagnosis and treatment of iron deficiency and its potential relationship to hair loss. j am acad dermatol. 2006;54(5):824-844. doi: 10.1016/j. jaad.2005.11.1104. pmid: 16635664. 7. rushton d, ramsay i, james k, norris m, gilkes j. biochemical and trichological characterization of diffuse alopecia in women. br j dermatol. 1990;123(2):187-197. doi: 10.1111/j.13652133.1990.tb01846.x. pmid: 2400721. 8. trost lb, bergfeld wf, calogeras e. the diagnosis and treatment of iron deficiency and its potential relationship to hair loss. j am acad dermatol. 2006;54(5):824-844. doi: 10.1016/j. jaad.2005.11.1104. pmid: 16635664. 9. cook jd, flowers ch, skikne bs. the quantitative assessment of body iron. blood. 2003;101(9):3359-3364. doi: 10.1182/ blood-2002-10-3071. pmid: 12521995. 10. rushton dh, norris mj, dover r, busuttil n. causes of hair loss and the developments in hair rejuvenation. int j cosmet sci. 2002;24(1):17-23. doi: 10.1046/j.0412-5463.2001.00110.x. pmid: 18498491. 11. kantor j, kessler lj, brooks dg, cotsarelis g. decreased serum ferritin is associated with alopecia in women. j invest dermatol. 2003;121(5):985-958. doi: 10.1046/j.15231747.2003.12540.x. pmid: 14708596. 12. güler özden m, öztaş mo, gülekon a, gürer ma. [diffuse hair loss in females and associating findings]. omü tıp dergisi 2008;25(2):50-6. 13. evans tc, jehle d. the red blood cell distribution width. j emerg med 1991;9 suppl 1:71-74. doi: 10.1016/07364679(91)90592-4. pmid: 1955687. 14. bessman jd, gilmer pr, gardner fh. improved classification of anemias by mcv and rdw. am j clin patho.l 1983;80:322326. doi: 10.1093/ajcp/80.3.322. pmid: 6881096. 15. springer k, brown m, stulberg dl. common hair loss disorders. am fam physician. 2003;68(1):93-102. pmid: 12887115. 16. bergfeld w. diffuse hair loss: its triggers and management. cleve clin j med. 2009;76(6):361-370. doi: 10.3949/ccjm.76a.08080. pmid: 19487557. 17. malkud s. telogen effluvium: a review. j clin diagn res. 2015;9(9):1-3. doi: 10.7860/jcdr/2015/15219.6492. pmid: 26500992. pmcid: pmc4606321. 18. messenger ag, berker da, sinclair rd. disorders of hair. in: burns t, breathnach s, cox n, griffiths c, eds. rook’s textbook of dermatology. 8th ed. oxford: blackwell publishing 2010:66-100. 19. cheung ej, sink jr, english iii jc. vitamin and mineral deficiencies in patients with telogen effluvium: a retrospective cross-sectional study. j drugs dermatol. 2016;15(10):1235-1237. pmid: 27741341. 20. sinclair r. there is no clear association between low serum ferritin and chronic diffuse telogen hair loss. br j dermatol. 2002;147(5):982-984. doi: 10.1046/j.1365-2133.2002.04997.x. pmid: 12410711. 21. ertug ey, yilmaz ra.  reduced ferritin, folate, and vitamin b12 levels in female patients diagnosed with telogen effluvium. int j med biochem. 2018;1(3):111-114. doi: 10.14744/ ijmb.2018.75047. 22. maner bs, moosavi l. mean corpuscular volume. [updated 2021 jul 10]. in: statpearls treasure island (fl): statpearls publishing; 2021. 23. rasheed h, mahgoub d, hegazy r, et al. serum ferritin and vitamin d in female hair loss: do they play a role? skin pharmacol physiol. 2013;26(2):101-107. doi: 10.1159/000346698. pmid: 23428658. 24. seçkin hy, bütün i, baş y, takcı z, kalkan g. effects of colchicine treatment on mean platelet volume and the inflammatory markers in recurrent aphthous stomatitis. j dermatolog treat. 2016;27(4):389-391. doi: 10.3109/09546634.2015.1116680. pmid: 26943669. 25. kim ds, shin d, kim tg, et al. red blood cell distribution width as a useful indicator to predict systemic vasculitis in patients with cutaneous vasculitis. rheumatol int. 2015;35(4):719-725. doi: 10.1007/s00296-014-3144-6. pmid: 25284376. 26. önmez a, bilir e, torun s. akut pankreatit şiddeti ile trombosit lenfosit oranı, nötrofil lenfosit oranı, eritrosit dağılım genişliği ve ortalama platelet volümü arasındaki i̇lişki. konuralp med j. 2019;11(1):24-29. doi: 10.18521/ktd.492274 27. fava c, cattazzo f, hu zd, lippi g, montagnana m. the role of red blood cell distribution width (rdw) in cardiovascular risk assessment: useful or hype? ann transl med. 2019;7(20):581. doi: 10.21037/ atm.2019.09.58. pmid: 31807562. pmcid: pmc6861793. dermatology: practical and conceptual 80 research | dermatol pract concept 2018;8(2):4 dermatology practical & conceptual www.derm101.com staphylococcus aureus is the most common bacterial agent of the skin flora of patients with seborrheic dermatitis funda tamer1, mehmet eren yuksel2, evren sarifakioglu3, yavuz karabag4 1 department of dermatology, ufuk university school of medicine, ankara, turkey 2 department of general surgery, aksaray university school of medicine, aksaray, turkey 3 department of dermatology, evren sarifakioglu clinic, ankara turkey 4 department of cardiology, kafkas university school of medicine, kars, turkey key words: bacterial skin flora, malassezia, seborrheic dermatitis, staphylococcus aureus citation: tamer f, yuksel me, sarifakioglu e, karabag y. staphylococcus aureus is the most common bacterial agent of the skin flora of patients with seborrheic dermatitis. dermatol pract concept. 2018;8(2):80-84. doi: https://doi.org/10.5826/dpc.0802a04 received: september 25, 2017; accepted: january 8, 2018; published: april 30, 2018 copyright: ©2018 tamer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: funda tamer, md, assistant professor, department of dermatology, ufuk university school of medicine, mevlana bulvari (konya yolu), no 86-88, 06510, balgat, ankara, turkey tel: +903122044151. email: fundatmr@yahoo.com background: seborrheic dermatitis is an inflammatory skin disease that affects 1–3% of the general population. the malassezia species has been implicated as the main causative agent; however, the bacterial flora of the skin may also play role in the etiopathogenesis. therefore, we investigated the most common bacterial agent of the skin flora of patients with seborrheic dermatitis. materials and methods: fifty-one patients with seborrheic dermatitis and 50 healthy individuals are included in this study. sterile cotton swabs were rubbed on the scalp of the participants for bacterial culture. colonial morphology was identified with gram stain and catalase test. results: staphylococcus aureus was isolated from  25 (49%) patients with seborrheic dermatitis and 10 (20%) healthy individuals within the control group. coagulase-negative staphylococci were isolated from 24 (47.1%) patients with seborrheic dermatitis and 17 (34%) healthy individuals within the control group. diphtheroids were present in  2 (3.9%) patients and  1 (2%) subject within the control group. gram-negative bacilli were present only in 1 (2%) patient. hemolytic streptococci and bacilli were identified in 1 (2%) subject from each group. colonization of coagulase-negative staphylococci, diphtheroids, gram-negative bacilli, hemolytic streptococci, and bacillus did not differ between patients and healthy controls. however, s. aureus colonization was significantly more common in patients with seborrheic dermatitis than in healthy controls. conclusion: within this study we revealed that s. aureus colonization was significantly higher among the patients. therefore, we propose that, in addition to the malassezia species, s. aureus may play a role in the etiopathogenesis of seborrheic dermatitis. abstract research | dermatol pract concept 2018;8(2):4 81 for 48 hours under aerophilic and capnophilic conditions. the microorganisms were identified by conventional methods. colonial morphology was identified with gram stain and catalase test. catalase positive, coagulase positive, and gram-positive cocci that produced yellow pigmentation on mannitol-salt agar were described as s. aureus. statistical analysis was performed using spss 22.0 (spss inc., chicago, il). continuous variables were defined as the mean (±) standard deviation and medians (minimum-maximum). categorical variables were expressed as percentages. differences between groups were analyzed by independent samples t test for numerical variables and chi-square test for categorical variables. a p-value <0.05 was considered statistically significant. results fifty-one patients with seborrheic dermatitis (28 female, 23 male) and 50 healthy individuals within the control group (30 female, 20 male) were included in the study (p=0.60). the median age of the patients and control group was 27 years (range: 17 to 57 years, 95% confidence interval [ci]: 24-32) and 28 years (range: 17 to 56 years, 95% ci: 26-35), respectively (p=0.35). seven (13.7%) patients with seborrheic dermatitis had a family history of seborrheic dermatitis. the median disease duration was four years (range: 1-40 years, 95% ci: 3-10) (table 1). in addition to scalp involvement, 8 (15.7%) patients had seborrheic dermatitis lesions on the eyebrows, 6 (11.8%) patients had lesions on nasolabial folds, 5 (9.8%) patients had lesions on the retroauricular region, 3 (5.9%) patients had lesions on the chest and 1 (2%) patient had lesions on the glabella. according to the koca scoring index, 24 (47.1%) patients had mild seborrheic dermatitis, 22 (43.1%) patients had moderate seborrheic dermatitis, and 5 (9.8%) patients had severe seborrheic dermatitis. table 2 shows the results of bacterial cultures. s. aureus was isolated from 25 (49%) patients with seborrheic dermatitis and 10 (20%) healthy individuals within the control group. coagulase-negative staphylococci were isolated from 24 (47.1%) patients with seborrheic dermatitis and 17 (34%) healthy individuals within the control group. diphtheroids were present in 2 (3.9%) patients, and 1 (2%) subject within the control group gram-negative bacilli were present only in 1 (2%) patient. hemolytic streptococci and bacillus were identified in 1 (2%) subject from each group. colonization of coagulase-negative staphylococci, diphtheroids, gram-negative bacilli, hemolytic streptococci and bacillus did not differ significantly between patients and healthy controls (p=0.18, 0.57, 0.32, 0.99 and 0.99, respectively). however, s. aureus was significantly more frequent in patients with seborrheic dermatitis compared to the control group (p=0.02). introduction seborrheic dermatitis is a chronic inflammatory skin disease that affects 1–3% of the general population [1]. seborrheic dermatitis is more common in men than in women and usually occurs in adolescents and young adults. seborrheic dermatitis presents with erythematous, yellowish, greasy, scaly plaques. the lesions predominantly occur on sebaceous gland-rich areas like scalp, eyebrows, ears, nasolabial folds, chest, axillae, and groin [1]. the diagnosis of seborrheic dermatitis is usually made on the basis of its clinical features. the etiology remains unknown; however, malassezia yeasts, skin sebum levels, androgens, and immunologic mechanisms have been described as contributing factors [2]. overgrowth of malassezia species has been found to be associated with inflammation in seborrheic dermatitis. however, similar amounts of malassezia species have also been reported in patients with seborrheic dermatitis and control groups [2,3]. nevertheless, bacterial skin microbiota has been implicated in the pathogenic process of seborrheic dermatitis [4]. propionibacterium acnes and micrococci like micrococcus butyricus, micrococcus pyogenes var. aureus have been considered as possible etiologic agents [5]. however, the association of bacteria with seborrheic dermatitis remains controversial [4]. therefore, in this study, we aim to investigate the most common bacterial agent of the skin flora in patients with seborrheic dermatitis. materials and methods this study included 51 patients with seborrheic dermatitis of the scalp and 50 healthy individuals within the control group who were admitted to the dermatology outpatient clinic between february and april 2016. all participants provided written informed consent. the exclusion criteria were having an inflammatory skin disease like psoriasis or lichen planus and receiving any topical or systemic treatment for seborrheic dermatitis. the scoring index that was described by koca et al was used to determine the severity of seborrheic dermatitis [6]. we evaluated the presence of erythema, desquamation, pruritus and irritation as absent (0), mild (1), moderate (2) and severe (3) according to koca scoring index. the sum of these values indicated the severity of seborrheic dermatitis (0-4; mild, 5-8; moderate, 9-12; severe). sterile cotton swabs were moistened with sterile distilled water and rubbed on the frontal aspect of the scalp of each participant for bacterial culture. the test site was uniform for all the patients and the control group. the samples were taken from skin lesions of the patients with seborrheic dermatitis and normal skin of the healthy individuals within the control group. the samples were plated on 5% sheep blood agar and chocolate agar. afterward, they were incubated at 37°c 82 research | dermatol pract concept 2018;8(2):4 was significantly more prevalent in patients with seborrheic dermatitis compared to healthy controls [8]. nevertheless, tehrani et al showed no association between seborrheic dermatitis and demodicosis. tehrani et al investigated the prevalence of seborrheic dermatitis in patients with demodex infestation. included in their study were 123 demodicosis positive patients and 57 demodicosis negative individuals. the prevalence of seborrheic dermatitis in patients with discussion the etiopathogenesis of seborrheic dermatitis is not clearly understood. however, malassezia species has been implicated as the main causative agent in seborrheic dermatitis [7]. in addition, karincaoglu et al indicated that demodex folliculorum might play a role in the etiopathogenesis of seborrheic dermatitis. karincaoglu et al claimed that the demodex mite table 1. demographic features of the subjects and disease severity score in patients with seborrheic dermatitis patients with seborrheic dermatitis (n=51) healthy controls (n=50) p-value age (years) mean ±sd 30.6±11.4 32.7±10.7 0.35 median/range 27/ (17-57) 28/ (17-56) 95% ci 24-32 26-35 gender (n/%) female 28 (54.9%) 30 (60%) 0.60 male 23 (45.1%) 20 (40%) 0.60 disease duration (years) mean ±sd 7.30±8.50 median/range 4 / (1-40) 95% ci 3-10 disease severity (n/%) mild 24 (47.1%) moderate 22 (43.1%) severe 5 (9.8%) sd: standard deviation ci: confidence interval the patients and healthy individuals in the control group were statistically similar in age and gender; 46 patients (90.2%) had mild to moderate seborrheic dermatitis. only 5 patients (9.8%) had severe seborrheic dermatitis according to the seborrheic dermatitis disease severity scoring index that was described by koca et al. table 2. bacterial culture results of the patients with seborrheic dermatitis and control group isolated bacteria patients with seborrheic dermatitis (n/%) healthy controls (n/%) p value staphylococcus aureus 25 (49.0%) 10 (20.0%) 0.02 coagulase-negative staphylococci 24 (47.1%) 17 (34.0%) 0.18 diphtheroids 2 (3.9%) 1 (2.0%) 0.57 gram-negative bacilli 1 (2.0%) 0 (0.0%) 0.32 hemolytic streptococci 1 (2.0%) 1 (2.0%) 0.99 bacillus 1 (2.0%) 1 (2.0%) 0.99 s. aureus colonization was significantly more common in patients with seborrheic dermatitis than in healthy individuals (p=0.02). colonization of coagulase-negative staphylococci, diphtheroids, gram-negative bacilli, hemolytic streptococci and bacillus were statistically similar in patients and healthy controls. research | dermatol pract concept 2018;8(2):4 83 mon in patients (47.1%) than in healthy subjects (34.0%). however, colonization of coagulase-negative staphylococci, diphtheroids, gram-negative bacilli, hemolytic streptococci and bacillus did not show statistically significant difference between the patient and control group. we have revealed that bacterial skin communities of the patients with seborrheic dermatitis are different from the healthy individuals. s. aureus was significantly more common among the patients. our results are consistent with the previous studies reported by mcginley et al in 1975 and by ihrke et al in 1978. mcginley et al isolated s. aureus from 21% of seborrheic dermatitis cases, 4% of normal subjects and 3% of patients with dandruff. ihrke et al demonstrated that skin flora of dogs with seborrheic dermatitis were mainly composed of s. aureus. however, humans and canines are different species, making a direct comparison is not possible. in conclusion, bacterial diversity in the skin lesions of seborrheic dermatitis as interactions between malassezia species and bacterial flora of the skin seem to be associated with the development of seborrheic dermatitis. s. aureus is a pathogenic microorganism commonly found in the skin flora of the patients with seborrheic dermatitis. we propose that, in addition to malassezia species, s. aureus may play a role. therefore, appropriate antibiotic therapy should be considered in the treatment of severe and persistent seborrheic dermatitis cases. references 1. clark gw, pope sm, jaboori ka. diagnosis and treatment of seborrheic dermatitis. am fam physician. 2015;91:185-190. 2. gupta ak, bluhm r. seborrheic dermatitis. j eur acad dermatol venereol. 2004;18:13-26. 3. dessinioti c, katsambas a. seborrheic dermatitis: etiology, risk factors, and treatments: facts and controversies. clin dermatol. 2013;31:343-351. 4. paulino lc. new perspectives on dandruff and seborrheic dermatitis: lessons we learned from bacterial and fungal skin microbiota. eur j dermatol. 2017;27:4-7. 5. pachtman ea, vicher ee, brunner mj. the bacteriologic flora in seborrheic dermatitis. j invest dermatol. 1954;22:389-396. 6. koca r, altinyazar hc, esturk e. is topical metronidazole effective in seborrheic dermatitis? a double-blind study. int j dermatol. 2003;42:632-635. 7. sampaio al, mameri ac, vargas tj, ramos-e-silva m, nunes ap, carneiro sc. seborrheic dermatitis. an bras dermatol. 2011;86:1061-1071. 8. karincaoglu y, tepe b, kalayci b, atambay m, seyhan m. is demodex folliculorum an aetiological factor in seborrhoeic dermatitis? clin exp dermatol. 2009;34:516-520. 9. tehrani s, tizmaghz a, shabestanipour g. the demodex mites and their relation with seborrheic and atopic dermatitis. asian pac j trop med. 2014;7s1:s82-84. 10. mcginley kj, leyden jj, marples rr, kligman am. quantitative microbiology of the scalp in non-dandruff, dandruff, and seborrheic dermatitis. j invest dermatol. 1975;64:401-405. demodicosis was 63.4% and in demodex negative subjects was 57.9%. the results did not show statistically significant differences between the two groups [9]. there have been a few studies investigating the bacterial flora of the patients with seborrheic dermatitis. in 1954, pachtman et al reported no correlation between bacteriologic flora and seborrheic dermatitis. the most frequent bacteria isolated from both seborrheic and normal subjects were micrococci and some corynebacterium species [5]. in 1975, mcginley et al evaluated scalp flora of the patients with dandruff, patients with seborrheic dermatitis, and healthy controls. coagulase-negative cocci were the most common bacteria isolated from all subjects. however, s. aureus was identified in 20% of the patients with seborrheic dermatitis, while it was uncommon in patients with dandruff and healthy controls [10]. in 1978, ihrke et al investigated bacterial flora of normal and seborrheic canine skin. cutaneous flora of seborrheic dogs consisted mostly of s. aureus, while the flora of normal dogs consisted primarily of coagulase-negative cocci [11]. in 1980, höffler et al investigated the bacterial flora of non-affected skin of patients with seborrheic dermatitis and bacterial skin flora of healthy individuals. höffler et al reported that the mean count for propionibacteria in the pilosebaceous ducts of the forehead was reduced in patients compared to the control group. in addition, the mean counts of the coagulase-negative staphylococci were the same on the backs of the patients and healthy individuals [12]. in 2016, tanaka et al examined bacterial microbiota of lesional and non-lesional skin of patients with seborrheic dermatitis. acinetobacter, corynebacterium, staphylococcus, streptococcus, and propionibacterium were found on both lesional and non-lesional sites. however, propionibacterium was predominantly present on non-lesional skin. acinetobacter, staphylococcus and streptococcus were predominantly present on lesional sites. tanaka et al suggested that bacterial microbiota might play a role in the development of seborrheic dermatitis by hydrolyzing sebum and providing nutrients for malassezia [13]. park et al investigated scalp microbiome in patients with dandruff, seborrheic dermatitis and healthy individuals. bacteroides, propionibacterium and chryseobacterium revealed by random forest analysis showed an increase in disease groups. park et al claimed that symptoms such as itching, burning, and pain were caused by bacterial community [14]. in our study, s. aureus and coagulase-negative staphylococcus were the most common bacteria isolated from the patient and control groups, respectively. s. aureus colonization was significantly more frequent in the skin lesions of patients with seborrheic dermatitis (49%) than in healthy subjects within the control group (20%). there was no clinical sign and symptom of any bacterial infection in the lesions of the patients with seborrheic dermatitis. in addition, coagulase-negative staphylococcus was more com84 research | dermatol pract concept 2018;8(2):4 13. tanaka a, cho o, saito c, saito m, tsuboi r, sugita t. comprehensive pyrosequencing analysis of the bacterial microbiota of the skin of patients with seborrheic dermatitis. microbiol immunol. 2016;60:521-526. 14. park t, kim hj, myeong nr. collapse of human scalp microbiome network in dandruff and seborrhoeic dermatitis. exp dermatol. 2017;26:835-838. 11. ihrke pj, schwartzman rm, mcginley k, horwitz ln, marples rr. microbiology of normal and seborrheic canine skin. am j vet res. 1978;39:1487-1489. 12. höffler u, gloor m, peters g, et al. qualitative and quantitative investigations on the resident bacterial skin flora in healthy persons and in the non-affected skin of patients with seborrheic eczema. arch dermatol res. 1980;268:297-312. dermatology: practical and conceptual 90 review | dermatol pract concept 2019;9(2):3 dermatology practical & conceptual introduction in 1660, hafenreffer wrote, “itching is an unpleasant cutaneous sensation which provokes the desire to scratch” [1], a definition that not only has remained unchanged for centuries, but also marks itching and scratching as interdependent symptoms. the complex generation of itch and the automatic scratch response lead to the clinically challenging itch-scratch cycle. in the uk, approximately 80% of skin-related general practice consultations have itch as an underlying symptom [2]. despite being one of the most common presenting dermatological symptoms, itching continues to challenge health care professionals because it is notoriously difficult to control [3]. research continues into fully exposing the origins of this mysterious symptom and is steering its focus toward understanding the mechanisms of chronic itch. this review attempts to answer the 2-part question, “why do we itch and scratch?” by first touching on the history of itchy disease, the neurobiology of itch, and the 4 different clinical origins of itch: pruritogenic, neurological, neuropathic, and psychological. in addition, we explore the reflex of scratching and discuss whether it should be deemed a protective mechanism or rather an uncontrollable human impulse that evolution has rendered obsolete. the itch-scratch cycle: a review of the mechanisms giulia rinaldi1 1 st. george’s university & hospital of london, uk key words: itch, prurigo, scratch, pruritus citation: rinaldi g. the itch-scratch cycle: a review of the mechanisms. dermatol pract concept. 2019;9(2):90-97. doi: https://doi. org/10.5826/dpc.0902a03 accepted: january 28, 2019; published: april 30, 2019 copyright: ©2019 rinaldi. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: giulia rinaldi, st. george’s university & hospital of london, cramer terrance, london, sw17 0re, uk. email: m1401237@sgul.ac.uk background: despite being one of the most common presenting dermatological symptoms, itching continues to perplex health care professionals because it is notoriously difficult to control. objective: this review gathers evidence to answer the 2-part question, “why do we itch and scratch?” by exploring the history of itchy disease, the neurobiology of itch, and the 4 different clinical origins of itch: pruritogenic, neurological, neuropathic, and psychological. results: the automated scratching reflex and its biological and psychological reasons for existence are complicated and poorly understood. currently, there are a myriad of treatments available for individuals suffering from this condition; however, many remain symptomatic. conclusions: the itch-scratch cycle is a complex pain-like sensation with a reflex-like response. in the future, continued exploration into the mechanisms behind itch and scratch may open the doors for new therapeutic interventions. abstract review | dermatol pract concept 2019;9(2):3 91 are other mediators involved [1,19]. indeed, mechanisms of dermatological itch are extensive and known to consist of multiple pruritogens, receptors, and chemical signalers [1]; the most common of these are briefly summarized in table 1. this table uniquely lists pruritogens, their origins, presumed receptors, as well as supportive research, including some potential clinical applicability of this knowledge. neurogenic itch neurogenic itch, sometimes also referred to as systemic itch, is an itch that originates from organs other than the skin, without evidence of peripheral nerve damage or psychiatric roots [3]. conditions frequently causing neurogenic itch are hematological disease, hepatobiliary disease, and chronic kidney disease [47]. hematological itch, seen in polycythemia vera, myeloproliferative disorders, or myelofibrosis, is often aquatogenic, occurring after a warm shower. indeed, this itch is shown to be subdued by selective serotonin reuptake inhibitors; this response is hypothesized to be due to the upregulation of serotonin receptors creating a higher activation threshold; however, a confirmed mechanism is unknown [42,45,48]. cholestatic pruritus, seen in a variety of hepatocellular disorders, is thought to be due to the accumulation of bile salts that trigger histamine and lysophosphatidic acid release [49]. lysophosphatidic acid is a powerful pruritogen as seen by the correlation between high serum levels and pruritus in patients [49-51]. furthermore, cholestatic patients also have higher levels of endogenous opioids, possibly produced by the diseased liver and thought to contribute to systemic itch [52]. indeed, administration of oral or intravenous opioid antagonists has been shown to significantly reduce scores on visual analogue scales of pruritus in patients with hepatobiliary disease [53-55]. similarly, more than 40% of patients with chronic kidney disease present with pruritus thought to originate from endogenous opioid upregulation [56]. therefore, opioid antagonist therapies are trialed; however, higher quality trials are still needed to confirm the efficacy, safety, and addictive risks of these treatments [28,57-59]. neuropathic itch the third etiology of itch is neuropathic, which refers to a neuronal origin of itch, occurring due to damaged central or peripheral afferent nerves. this type of itch is often accompanied by localized neuropathic symptoms, such as pain and paresthesia, or as part of a larger neurological diagnosis, such as multiple sclerosis [3,60]. the mechanisms of this itch are often debated between erroneous stimulation of pruritic signals or damage of itch-inhibiting neurons [3]. overall, neuropathic itch presents in a variety of ways, from a brief history of itch itch has troubled humanity throughout history. dating back to the bc era, ancient greeks and egyptians recorded instances of itchy rashes, akin to today’s infectious pruritus, that coincided with outbreaks of diarrhea, smallpox, and hookworms [4]. in 121 ad, roman historian suetonius also made reference to records of atopic dermatitis. he wrote of emperor augustus’s atopic symptoms consisting of seasonal allergies, chronic itch, and dry, hardened patches of skin [5]. subsequently, in 1726, daniel turner, the alleged first british dermatologist, described itchiness as a symptom that is “impure,” beginning as a contagious process through the skin, which then spreads into the bloodstream [6], possibly reflecting the stark religious influences of 18thcentury medicine. in some of the earliest records of modern dermatological medicine, dr. hazen (1915) described an impressive array of various skin pathologies, which are much the same as those seen today, however, with the depth of knowledge into their etiology being far more primitive [7]. the symptom of itchiness was habitually mentioned by patients, but its purpose was largely diagnostic in nature. in contrast, itchiness today remains a prominent symptom; however, the focus has shifted away from diagnosis and rather toward management [8-11]. in an effort to successfully manage pruritus, current research has focused on understanding the cellular pathways and the neurobiology of itch, with the objective of identifying target mediators that can be inhibited to relieve itch. for this reason, to answer the question, “why do we itch?” the following sections will concisely discuss the 4 different underlying etiologies of itch. etiology of itch the human etiology of itch can be divided into pruritoceptive (dermatological), neurogenic (systemic), neuropathic, and psychogenic mechanisms [12,13]. pruritoceptive itch a pruritoceptive, also known as dermatological, itch refers to the cellular mechanisms originating from layers of the skin to produce the somatic sensation of itch [3]. this pathology of itch remains the most common cause of pruritus in dermatology, and a vast amount of research has been done to understand and target therapies against it. histamine was the first and remains the most explored pruritogen [14-16]; in fact, antihistamines, such as levocetirizine, are often used successfully for the treatment of histamine-induced itch with an observed dose-response pattern [17]. however, antihistamines often give poor relief to chronic itch, for example in atopic dermatitis [18], reinforcing the theory that there 92 review | dermatol pract concept 2019;9(2):3 parasitosis hallucinations, depression, or compulsive scratching syndromes. at other times, it can coincide with lifestyle stress which exacerbates itchy pathologies such as eczema, urticaria, and psoriasis [64,65]. the pathophysiology behind psychogenic itch is uncertain; however, imbalances in serotonin, opioids, and dopamine may play a part. opioids have been shown to mediate responses to social pain and opioid receptor modulators are now being explored as antidepressants; however, their concomitant addictiveness has delayed their clinical use [66-68]. furthermore, patients with depressive disorders have been shown to have elevated levels of the pruritogen substance p in their cerebrospinal fluid [68]. the evidence above suggests that the origin of itch in patients with psychiatric conditions is not purely an illusion of the mind, rather, a true stimulation of their afferent itch fibers due to a possible inherent imbalance of central pruritogens. postherpetic to brachioradial pruritus. as such, neurologists should be involved to confirm the neuropathological diagnosis of itch [60]. this itch is perhaps the most overlooked by researchers and dermatologists as it can be easily labeled as a defective neuropathic stimulus and passed to neurologists for treatment. nevertheless, collaboration between dermatologists and neurologists has optimistically led to the trial of neuropathic medications, such as gabapentin, to treat different etiologies of chronic itch with promising results [61-63]. psychogenic itch psychogenic itch, the fourth etiology of itch, is a diagnosis of exclusion whereby another reason for itch is not found and mental health symptoms are present [3]. psychogenic itch can often present with a psychiatric condition such as table 1. physiology of pruritoceptive itch pruritogens origin receptors & mediators clinical applicability peripheral histamine mast cells h1 & h4, trpv1 h1 & h4 antagonists show benefit in reducing pruritus both in chronic itch and in patients with atopic dermatitis [20-22] tryptase mast cells par2, par4 [3], trpv1, bnp par2 upregulated in atopic dermatitis [23] & causes an itch without wheal [24]; par2 antagonists could combat chronic nonhistaminic itch [25]; removal of trpv1 ion channel and bnp from neurons suppressed itch in mice [26] mucunain cowhage dust mites mites capsaicin chili trpv1 [1] topical capsaicin reduced itch in chronic psoriasis [27], uremic patients [28], and hemodialysis attenders [29]; the capsaicin 8% patch has also shown success in addressing neurogenic itch such as brachioradial pruritus and meralgia paresthetica [30] endothelin 1 endothelium et(a), et(b) [31] upregulated in chronic itch patients [31] cytokines th2 cells il-31, il-31ra, osmr [32] il-31 induces itch in mice [33]; anti-il-31 shown to reduce itch in atopic dermatitis patients [34] kallikrein 5 epithelium par2 [35] increased scratching in mice with increased kallikrein 5 expression [35,36] substance p afferent neurons nk1 [37] substance p levels involved in atopic dermatitis pathophysiology [38,39]; trpv1 agonists shown to deplete substance p levels peripherally [1]; substance p elevated in prurigo nodularis patients [40] central opioids exogenous neurons & keratinocytes µ& κ-receptors morphine induces scratching and µ-opioid antagonist shown to relieve chronic itch [41] 5-ht 5-ht trpv1 involved in polycythemia vera & cholestasis itch [42]; more pruritogenic than histamine in rats [43]; serotonin injection induces pruritus in healthy patients [44]; ssris shown to reduce chronic itch [45]; ondansetron effective in cholestatic itch [46] 5-ht = serotonin; bnp= type b natriuretic polypeptide; et = endothelin; il-31ra = interleukin-31 receptor a; nk1 = neurokinin 1; osmr = oncostatin m receptor; par= protease activated receptors; ssri = selective serotonin reuptake inhibitor; trpv1 = transient receptor potential villanoid 1. review | dermatol pract concept 2019;9(2):3 93 can transmit both pain and itch. if itch fibers in humans are polymodal, pain and itch must be differentiated more proximally; in fact, functional magnetic resonance imaging of the cortex has shown different activation areas [93,94]. owing to the unethical nature of isolating spinothalamic sections in humans, unanswered questions remain about the role central ascending tracts partake in the perception of itch [95]. nonetheless, knowledge that itch is transmitted by polymodal fibers is useful for the discovery of new therapies to combat chronic itch by trialing treatments used to break other hypersensitivities such as chronic pain or chronic cough cycles [61,62,96]. pathways of itch conduction and perception vary between humans and animals, suggesting that evolution may have devolved our separate pathway for itch. this could mean that itching may have been beneficial in animals who needed to “scratch-away” invaders (such as ticks and fleas) from their fur coat, a response that was no longer necessary once we had lost our primate-like hairy coat. this would explain why scratching can often be traumatic to human skin, whereas in furred animals it is required to rid the hairs of invaders and does not often damage their underlying skin. scratching scratching is often presumed to provide mechanical protection and subsequent inflammatory defense against harmful elements on the skin [97,98]. however, scratching is also known to disrupt the epidermal barrier and facilitate infection [11]. another view is that we scratch because we want to relieve the itch by causing localized pain that will suppress the intolerable itch, suggesting we prefer to withstand mild pain rather than be itchy [98]. moreover, relieving an itch via scratching often causes a feeling of pleasure, thought to be due to both the riddance of the intolerable itch and the release of serotonin during scratching [99]. although our body seems to be “rewarded” for scratching an itch, it is well known that repeated scratching prolongs and aggravates the itch in various situations ranging from mosquito bites to atopic dermatitis [100]. indeed, itchy stimuli activate the striatum and limbic region of the cortex, the reward and motivation centers, causing a reward-driven but altogether damaging itch-scratch cycle [101]. in addition, when we advise patients to stop scratching, we are fundamentally implying that the human scratch response is innately flawed. patients aware of this detrimental itchscratch cycle continue to scratch, knowing it will only provide short-term relief. scratching has been reported to increase at night due to itch being exacerbated by higher circadian skin temperatures, increased trans-epidermal water losses, reduced corticosteroid neurobiology of itch as shown above, itch is triggered by 4 distinct mechanisms either centrally or peripherally. to understand how pruritogenic stimulation is transmitted to the brain and interpreted, we must study the different afferent (mechanical, thermal, and polymodal) neurons, how they respond to pruritogens, and which parts of the cortex they activate [69-72]. previously, itch was believed to be a mild form of pain transmitted by the same nociceptive fibers and suppressed by greater painful (mechanical or thermal) stimuli [73]. this “intensivity” theory was later discredited by evidence from both humans and animals. not only did increasing the intensity of an itchy stimulus not convert to a painful stimulus, but also a distinct subpopulation of nerves were shown to be activated by pruritogenic vs painful stimuli [74-76]. similarly, itch triggers a targeted scratch response, while pain generates an unrelated withdrawal reaction, suggesting itch and pain are not transmitted via identical neurological pathways. currently, newer theories exist about how itch is transmitted to the brain, specifically the “selectivity” and “labeledline” theories. the “selectivity” theory states that itch fibers are more selective toward pruritogenic stimuli, but are polymodal, also transmitting pain. in contrast, the “labeled-line” theory supports the existence of afferent fibers exclusively responsive to pruritogenic stimuli [3]. to explore both theories, research has used animal experiments to alter the expression of presumed pruritoceptive mediators and evaluate variations in scratch response [77-83]. cats have been shown to have afferent nerve fibers solely activated by pruritogens both peripherally and in the spinothalamic tract [84]. moreover, mice possess afferent neurons expressing specific pruritogenic modulators such as mas-related-g-protein-coupled receptor (mrgpra3+) and gastrin-related peptide (grp), the latter expressed only in a small subset of dorsal ganglia and in the lamina i tract of the spinothalamic cord [85,86]. the genetic removal of these receptors significantly reduces the scratch response, but not pain response. this evidence essentially supports that in animals itch is probably mediated via the “labeled-line” theory and that their itch and pain neurons are distinct [86,87]. in humans, more than 90% of afferent fibers are polymodal; they respond to 2 or more types of stimuli [75,88]. skin stimulation has shown that different fibers responded to histamine and non-histamine-induced itch, suggesting that humans possess distinctive peripheral pathways for the transmission of different pruritogens [89,90]. these fibers have been shown to go on to activate separate subsets of the spinothalamic tract; however, all these pruritogenic pathways were also activated by painful stimuli [91,92]. this finding suggests that in humans, itch is probably transmitted in line with the “selectivity theory” using polymodal fibers, which 94 review | dermatol pract concept 2019;9(2):3 logical pruritus can often be subdued by the use of tricyclic antidepressants or selective serotonin reuptake inhibitors, both by encouraging sleep and upregulating serotonin receptors, contributing to itch signal transmission [42,45,115]. in severe cases of chronic pruritus, novel systemic therapies can be considered. neurokinin 1 receptor antagonists and anti-interleukin 31 have shown promising results in battling chronic pruritus, with the latter showing significant reduction in pruritus scores and body surface areas affected by atopic dermatitis [115-118]. neurokinin 1 antagonists, mediating the substance p pathway, have recently shown a dose-dependent decrease of baseline pruritic visual analogue scales after a few weeks of use [119,120]. in atopic dermatitis, monoclonal antibodies targeting interleukin 4 and 13 have also shown promise in increasing the quality of life of patients through itch reduction [121]. these innovative therapies to combat itch are being revealed thanks to an increased understanding of its different pathways and transmitters. nevertheless, additional data are required to explore the success rates, cost-effectiveness, and long-term adverse effects of innovative therapies in patients suffering from chronic itch. conclusions an itch can arise from a variety of underlying mechanisms and is transmitted to the cortex via a subset of polymodal fibers that are more selective toward pruritogens. pruritic skin conditions continue to compromise a large psychological and financial burden, with up to 20% of children in britain suffering from eczema [122] and 3% of adults from psoriasis. these conditions have a significant psychological influence, proven akin to that of chronic pain, with 10% of patients with chronic psoriasis, hand eczema, or atopic dermatitis exhibiting signs of clinical depression [8,123]. evolutionally, the benefit of itch is thought to be the accompanying scratch which removes harmful elements from skin or fur; however, in chronic pruritic conditions this often leads to a detrimental cycle of skin changes and further scratching. therefore, could the benefits of itch just be a remnant from our fur-coated ancestors? as we are currently unable to remove this seemingly unnecessary response from our genes, we must focus on providing safe and successful itch relief for people suffering from debilitating chronic itchy conditions. the failure to do so may leave us with an itch that we just must scratch. references 1. ikoma a, steinhoff m, ständer s, yosipovitch g, schmelz m. the neurobiology of itch. nat rev neurosci. 2006;7(7):535-547. 2. von hospenthal t. lessons for the nhs: commissioning a dermatology service. based on case studies from england. british association of dermatologists. 2013. available from: https://www. anti-inflammatory levels, and a disinhibited scratch response [102,103]. times of unawareness, such as sleep, may result in uncontrolled scratching leading to greater dermatological inflammation and individual awakening. the consequences of chronic sleep insufficiency can be debilitating to an individual’s mental function, physical energy, and long-term health; individuals with chronic sleep deficiency have an increased chance of depression, obesity, and smoking, and a reduced life expectancy due to various general medical causes [104,105]. ultimately, pain and itch differ in the responses they provoke; pain causes a withdrawal response, telling our body to rest, hold, or hide the affected area from external stimuli. on the contrary, itch causes the scratch response, an attentiondrawing reflex, which tells us to topically injure that area. would we be healthier in a scratch-free world? management of pruritus the management of pruritus is evolving toward targeted therapies tackling specific etiologies of itch. before initiating treatment, patients with itch of unknown origin should undergo a thorough medical history and examination. the severity of pruritus should be assessed using an official quality-of-life tool such as the visual analogue scales and dermatology life quality index [106,107]. the british association of dermatology recommends initial blood tests including full blood cell count, iron levels, thyroid function tests, urea and electrolyte levels, liver function tests, and an autoimmune screen [108]. this will help diagnose or exclude hematological malignancy, iron deficiency or overload, thyroid disease, uremia, hepatic pruritus, or autoimmune disease among systemic causes of itch [28,56,109-112]. further investigations such as imaging and skin biopsies can be obtained if rarer causes of itch, for example paraneoplastic syndromes, or dermatosis is suspected. pruritoceptive itch, if thought to be triggered by skin barrier flaws or dermatological disease, will most often be controlled via topical treatments targeting the specific skin condition and using intensive skin moisturizing regimens [17]. dermatological itch of urticarial origin, thought to arise from histamine release, is most often controlled with oral high-dose antihistamines, intermittent steroids, or, in refractory cases, the biological anti-ige omalizumab [17,113]. in refractory dermatological pruritus, disease-specific interventions, for example narrow-band phototherapy in psoriasis, can control flares; however, this must be balanced with the long-term risks of skin malignancy [114]. specific subtypes of itch can also be managed using therapies that directly target their transmission pathways. 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strine tw, chapman dp. associations of frequent sleep insufficiency with health-related quality of life and health behaviors. sleep med. 2005;6(1):23-27. 105. nocturnal pruritus: prevalence, characteristics, and impact on itchyqol in a chronic itch population. j am acad dermatol. 2017;76(6):ab179. untitled quiz | dermatol pract concept 2015;5(3):6 25 dermatology practical & conceptual www.derm101.com clinical presentation a 61-year-old white female presented with a 7 x 4 mm nodule that was firm to palpation on her right leg (figure 1) of 5 months’ duration. the lesion was not painful, but bleeding with minimal trauma. dermoscopic appearance the main findings were milky red-white areas, ulceration and atypical vessels on the palpable component and two pigmented areas at the periphery that were asymmetrically distributed (figure 2). dermatoscopy: a nodule on a woman’s leg ramon pigem1, susana puig1, lidia maroñas-jiménez2, josep malvehy1 1 melanoma unit, department of dermatology, hospital clinic, idibaps, universitat de barcelona, barcelona, spain 2 department of dermatology, hospital doce de octubre, madrid, spain citation: pigem r, puig s, maroñas-jiménez l, malvehy j. dermatoscopy: a nodule on a woman’s leg. dermatol pract concept 2015;5(3):6. doi: 10.5826/dpc.0503a06 copyright: ©2015 pigem et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: ramon pigem, md, melanoma unit, department of dermatology, hospital clinic of barcelona, c/villarroel 170, 08036 barcelona, spain. tel. +34 932279867; fax: +34 932275438. e-mail: rpigem@clinic.ub.es figure 1. the lesion is located on the right leg, just below the right knee. it is an asymmetrical erythematous plaque with ill-defined borders. the pigmented area is attached to a palpable and ulcerated nodule. [copyright: ©2015 pigem et al.] figure 2. asymmetry in its structures with a palpable area (right side of the picture) that presents atypical vessels and ulceration is seen. on the other side (left), adjacent to the nodule, a delicate pigmented area may be observed. [copyright: ©2015 pigem et al.] 26 quiz | dermatol pract concept 2015;5(3):6 have been already reported [1]. even though dermoscopy may be useful in the recognition of compound tumors, some cases may be more difficult to recognize. in the present case the main differential diagnosis was melanoma. amelanotic/ hypomelanotic melanoma is characterized clinically by the presence of asymmetry and ulceration, whereas irregular pigmentation and certain vascular patterns (milky-red areas and dotted and linear irregular vessels) are commonly seen in the dermoscopy of these tumors, similar to the present case [2]. references 1. zaballos p, llambrich a, puig s, et al. dermoscopy is useful for the recognition of benign-malignant coumpond tumours. br j dermatol 2005;153:653-6. 2. zalaudek i, kreusch j, giacomenl j, et al. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part i. melanocytic skin tumors. j am acad dermatol 2010;63:361-74. what is your diagnosis? diagnosis the lesion was totally excised to rule out malignancy with a final diagnosis of a compound tumor. the nodule with erosion and atypical vessels corresponded to an infiltrating basal cell carcinoma (figure 3), whereas the firm area with pigmentation to a dermatofibroma (figure 4). discussion a compound (collision) tumor is the result of two different neoplasms occuring in the same lesion. correct diagnosis is important in order to offer proper treatment when benign and malignant lesions coexist. in the literature several compound tumors and their dermoscopic features, including the association between dermatofibroma and basal cell carcinoma, figure 3. compound tumor. the histopathologic analysis revealed an infiltrating basal cell carcinoma. erosion is observed on the tumor surface (epidermis) and a tumoration of small basophilic cells forming micronodules and infiltrating cords with peripheral palisading surrounded by stroma is observed. there is also an inflammatory infiltrate (hematoxilin and eosin stain 10x). [copyright: ©2015 pigem et al.] figure 4. compound tumor. the other tumoral component of this lesion was a dermatofibroma. a not very well defined dermal tumoration of fusocellular cells with epidermal hyperplasia and hyperpigmentation of the basal layer are seen (hematoxilin and eosin stain 10x). [copyright: ©2015 pigem et al.] dermatology: practical and conceptual research | dermatol pract concept 2017;7(2):12 53 dermatology practical & conceptual www.derm101.com introduction dermoscopy is a noninvasive method that allows in vivo evaluation of microstructures of the epidermis, the dermoepidermal junction, and the papillary dermis otherwise not visible to the naked eye. dry dermoscopy, also called trichoscopy, is ideal because it has a blocking filter against light reflection from the skin surface. sometimes differentiating scarring alopecia from non-scarring alopecia is difficult and dermoscopy can be helpful at this stage. characteristic dermoscopic features of aa are yellow dots, black dots, broken hairs, tapering hair (exclamation marks), and short vellus hairs [1-4]. dermoscopy of alopecia areata— a retrospective analysis abhijeet k. jha1, uday k. udayan1, p.k. roy1, amar k.j. amar1, r.k.p. chaudhary1 1 department of skin and vd, patna medical college & hospital, patna, bihar, india key words: dermoscopy; alopecia areata; yellow dots; exclamation mark hair citation: jha ak, udayan uk, roy pk, amar akj, chaudhary rkp. dermoscopy of alopecia areata in restrospective analysis. dermatol pract concept. 2017;7(2):12. doi: https://doi.org/10.5826/dpc.0702a12 received: october 27, 2016; accepted: december 28, 2016; published: april 30, 2017 copyright: ©2017 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & vd, patna medical college & hospital, patna, bihar, india. email: drabhijeetjha@gmail.com background: dermoscopy devices can overcome the refractive properties of stratum corneum by interface medium or cross polarization such that the lesion can be easily seen. aim: to examine the dermoscopic feature in alopecia areata and correlate the severity of disease with dermoscopic features. materials and methods: retrospective analysis of 72 patients suffering from alopecia areata (aa), irrespective of age and sex, who visited the dermatology outpatient department of a tertiary care center in eastern india was carried out. the most recently developed cases of aa were examined dermoscopically. variables included yellow dots (yds), black dots (bds), broken hair (bh), short vellus hair (svh), and exclamation mark hair (emh) on the basis of available literature and expertise. results: yellow dots was the most common finding seen in 57 cases (79.16%), black dots in 51 cases (70.8%). short vellus hair was seen in 32 cases (44.44%), broken hair was seen in 31 cases (43.05%), and exclamation mark hair in 23 cases (31.9%). yds per field of vision was considered as the most common finding with increased severity of aa. conclusion: yds, in increased number per field of vision, is the most consistent finding seen in severe cases of aa, as they are in progressive aa and alopecia universalis. an increased number of svh and terminal hairs were seen in patients who were being treated. abstract 54 research | dermatol pract concept 2017;7(2):12 thyroid autoantibodies (13.88%). coexisting autoimmune disease such as vitiligo was seen in one patient (1.38%) and psoriasis in one patient (1.38%). type of aa: patients with progressive aa numbered 56 (77.77%), whereas 16 patients (22.22%) had non-progressive aa. only scalp involvement was seen in 40 cases (55.55%). in the scalp, common sites involved were occipital (13 patients) and parietal regions (11 patients). other sites involved were temporal (4 patients); frontal (4 patients); vertex (3 cases); whole scalp (5 cases); only beard involvement in 12 cases (16.66%); only eyebrow involvement in 1 case (1.38%); only eyelash involvement in 1 case (1.38%); ophiasis in 5 cases (6.94%); sisiapho in 3 cases (4.1%); alopecia totalis in 9 cases; and alopecia universalis in 5 cases (6.94%). patchy alopecia was the most common type (50/72, 69.4%); single patch aa was discovered in 21 cases (29.16%); and multiple patch aa in 29 cases (40.27%) (table 1). yellow dots were seen in 57 cases (79.16%), black dots in 51 cases (70.8%), short vellus hair was seen in 32 cases (44.44%), broken hair was seen in 31 cases (43.05%), and exclamation mark hair in 23 cases (31.9%). the maximum number of yellow dots per field of vision were seen in all cases of alopecia universalis. the occurrence of yds and bds were seen together in 39 cases of progressive aa, yds and bh in 31 cases, yds, bds and bh together in 23 cases. yds and svh in 19 cases, yds and emh in 19 cases (figures 1-7). treatment: five patients were given intralesional triamcinolone acetonide. one patient with coexistent stable vitiligo was given bimatprost 0.03% ophthalmic solution, as there was presence of leukotrichia with the patch. an increased number of terminal hairs along with growth of svh were seen in 5 out of 7 cases on treatment. white peripilar sign (figure 8) was also seen in 4 out of 7 cases after treatment, with two to three hair units emerging from each follicle—a sign of hair regrowth. discussion a study done by inui et al [2] of 300 patients with aa, in different stages and different subtypes of the disease, identified yellow dots, black dots, broken hairs, coudability hairs, and clustered short vellus hairs (<10 mm) as the most common materials and methods a retrospective analysis of 72 patients suffering from alopecia areata, irrespective of age and sex, who visited the dermatology outpatient department was carried out. institutional ethical committee clearance was obtained. all patients visiting the dermatology outpatient department were screened for aa. all patients with alopecia areata, including those under treatment, were included in the study. the clinical diagnosis of aa was established after a detailed history and clinical examination. relevant investigations like 10% koh preparation and biopsy was carried out in select cases. thyroid profile was performed in all cases. the various patterns of aa were noted as patchy, diffuse, ophiasis, totalis, and universalis. the severity of aa was graded on the basis of the severity of alopecia tool (salt) score. dermoscopy was performed using dermlite ii hybrid m (3gen, san juan capistrano, ca) dermatoscope at 10x magnification in polarized mode and photographs were captured with an iphone 6 (apple, cupertino, ca). dermoscopy image capturing was performed by a single dermoscopist to ensure consistent photographsduring the procedure [5]. dermoscopic variables included yellow dots (yds), black dots, broken hair, exclamation mark hair, short vellus hair and any other new findings. white dots were differentiated from yellow dots by three independent dermoscopists. in accordance with available literature and data, yellow dots and black dots were considered the most common variables for severity. additionally an increased number of yellow dots, broken dots, or broken hairs per field of vision was considered as an increase in severity of aa. results all patients were of the south asian ethnic group and of indoaryan race from northern india with mainly fitzpatrick skin type 4 and 5 (dark brown color). age and gender: there were 41 male (56.94%) and 31 female (43.05%) patients. the male to female ratio was 1.3:1, with a mean age of 24.43 years, median 24, and range from 5-50 years. the most common age group for aa in our study was seen in the 21-40 year age group. history and associated disorders: family history of aa was positive in 5 cases (6.94%). ten patients were positive for table 1. patient demographics. [copyright: ©2017 jha et al.] age group (years) clinical type of vitiligo male female progressive aa non progressive aa on therapy 0-20 21-40 41-60 >60 22 41 9 0 41 31 56 9 7 research | dermatol pract concept 2017;7(2):12 55 seen in 63.7% (191/300) of cases in contrast to ross et al’s study, where 94.8% cases with aa had yds (55/58 cases) [8]. mane et al [3] reported an incidence of 81.8% among 66 patients and hegde et al [9] reported the incidence of yds was 57.3%. yellow dots per field of vision, as described by bapu et al, was seen in all cases of au depicting increased severity of disease [10]. black dots (cadaverized hairs) and broken hairs correspond to the fragmented and destroyed hair shafts and represent a sign of disease activity. black dots are only seen in dark-haired individuals. inui et al [2], demonstrated bds in 44.3% (133/300) cases of aa. mane et al reported 67.7% (44/66) of patients had bds [3] and hegde et al [9] in 84% of cases. in our study bds (figures 3,5) were seen in 51 cases (70.8%) . features [6]. yellow dots and short vellus hairs were the most sensitive markers for the diagnosis, and black dots, tapering hairs, and broken hairs were the most specific markers [2]. yellow dots present as round or polycyclic yellow to yellow-pink dots that may be devoid of hairs or contain miniaturized, cadaverized, or dystrophic hairs. although the yellow dots are sensitive (detected in all of 58 patients with different types of aa [6]), they correspond on pathology to the dilated infundibular ostia filled with sebum and degenerated follicular keratinocytes [1,7]. in our study, yellow dots (figures 1, 2) were the most common finding seen in 57 cases (79.16%). in a study conducted by inui et al [4], yds were figure 1. red arrow showing yellow dots on dermoscopy. [copyright: ©2017 jha et al.] figure 2. red arrow showing yellow dots and blue arrow showing curly hair. [copyright: ©2017 jha et al.] figure 3. red arrow showing black dots, blue arrow showing broken hair and orange arrow showing tapering hair. [copyright: ©2017 jha et al.] figure 4. red arrow shows curly hair. [copyright: ©2017 jha et al.] 56 research | dermatol pract concept 2017;7(2):12 in 45.7% (137/300) of alopecia cases. mane et al observed 55.4% patients with bh [3], and hegde et al [9] reported the incidence of bh in 37.33% of cases. in our study bhs (figure 3) was seen in 31 cases (43.05%). tapering hairs include exclamation mark hairs and coudability hairs and are a marker for disease activity and severity [4,11]. in our study ths were noted in 23 cases (31.9%). inui et al noted ths in 31.7% (95/300) cases of aa [2], mane et al [3] 12.1% (8/66), and hegde et al [9] 14 (18.67%) cases of ths (figure 3). one patient with coexistent stable vitiligo was given bimatprost 0.03% ophthalmic solution, as there was presence of leukotrichia with the patch. in one study, after one short vellus hairs (<10 mm) are a relatively common finding in aa (44.37%) [10]. they may be white and are most prevalent in the remitting stage of aa. short vellus hairs may appear as circle hairs and is a predominant feature in some patients. inui et al [2] observed svhs in 72.7% (218/300) of cases. mane et al [3] demonstrated svhs in 40.9% of patients, hegde et al [9] demonstrated svhs in 68% of cases. in our study svhs and curly hairs (chs) (figures 5, 6) were noted in 32 cases (44.44%). broken hairs are not exclusive to aa, as they are seen also in trichotillomania [1,3]. inui et al [4] demonstrated bhs figure 5. blue dots showing black dot and red arrow showing curly hair. [copyright: ©2017 jha et al.] figure 6. red arrow showing short vellus hair. [copyright: ©2017 jha et al.] figure 7. yellow dots in alopecia universalis. [copyright: ©2017 jha et al.] figure 8. white peripilar sign seen in patients on treatment with two to three hair unit emerging from each follicle a sign of hair regrowth. [copyright: ©2017 jha et al.] research | dermatol pract concept 2017;7(2):12 57 4. inui s, nakajima t, itami s. coudability hairs: a revisited sign of alopecia areata assessed by trichoscopy. clin exp dermatol. 2010;35:361-365. 5. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166:1198-205. 6. tosti a. dermoscopy of hair and scalp disorders: with clinical and pathologic correlations. london: informa healathcare; 2007. 7. ihm cw, hong ss, mun jh, kim hu. histopathological pictures of the initial changes of the hair bulbs in alopecia areata. am j dermatopathol. 2004;26:249-253. 8. ross ek, vincenzi c, tosti a. videodermoscopy in the evaluation of hair and scalp disorders. j am acad dermatol. 2006;55:799806. 9. hegde sp, naveen kn, athanikar sp, reshme p. clinical and dermatoscopic pattern of alopecia areata: a tertiary care centre experience. int j trichol. 2013;5:132-136. 10. bapu ng, chandrashekar l, munisamy m, thappa dm, mohanan s. dermoscopic findings of alopecia areata in dark skinned individuals: an analysis of 116 cases. int j trichol. 2014;6(4):156159. 11. shuster s. ‘‘coudability’’: a new physical sign of alopecia areata. br j dermatol. 1984;111:629. 12. jha ak, sinha r, prasad s, nandan n. bimatoprost in periorbital vitiligo: a ray of hope or dilemma. j eur acad dermatol venereol. 2016;30:1247–1248. 13. jha ak, sinha, r. bimatoprost in vitiligo. clin exp dermatol. 2016;41:821–822. patient was prescribed bimatoprost 0.03% ophthalmic solution for six weeks, there was partial repigmentation of the depigmented area, but the treatment was stopped due to localized hypertrichosis [12]. another study showed partial repigmentation of leukotrichia [13]. white peripilar sign was also seen in 4 out of 7 cases on treatment with two to three hair units emerging from each follicl—a sign of hair regrowth. although white peripilar has been described in other disorders to assess severity of disease, we found this to be a sign denoting hair growth. conclusion: yds in increased number per field of vision is the most consistent finding and are seen with severe cases of aa, as they are in progressive aa and alopecia universalis. an increased number of svh and terminal hairs were seen in patients who were being treated. references 1. tosti a, whiting d, iorizzo m, et al. the role of scalp dermoscopy in the diagnosis of alopecia areata incognita. j am acad dermatol. 2008;59:64-67. 2. inui s, nakajima t, nakagawa k, itami s. clinical significance of dermoscopy in alopecia areata: analysis of 300 cases. int j dermatol. 2008;47:688-693. 3. mane m, nath ak, thappa dm. utility of dermoscopy in alopecia areata. indian j dermatol. 2011;56:407-411. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(2):e2023101 1 super-high magnification dermoscopy can help for the diagnosis of lentigo maligna: a pilot study on 61 cases elisa cinotti1, alessandra cartocci2, flavio giulio liso1, vittoria cioppa1, francesca falcinelli1, linda tognetti1, pietro rubegni1, jean luc perrot3 1 department of medical, surgical and neurological science, dermatology section, university of siena, s. maria alle scotte hospital, siena, italy 2 department of medical biotechnology, university of siena, siena, italy 3 department of dermatology, university hospital of saint-etienne, saint-etienne, france key words: dermoscopy, super-high magnification, melanocyte, lentigo maligna, melanoma citation: cinotti e, cartocci a, liso fg, et al. super-high magnification dermoscopy can help for the diagnosis of lentigo maligna: a pilot study on 61 cases. dermatol pract concept. 2023;13(2):e2023101. doi: https://doi.org/10.5826/dpc.1302a101 accepted: october 21, 2022; published: april 2023 copyright: ©2023 cinotti et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vittoria cioppa, department of medical, surgical and neurological science dermatology section, university of siena, s. maria alle scotte hospital, viale bracci 16, 53100 siena, italy. tel: 0039-0577 585428. fax: 0039 0577 585488, e-mail: v.cioppa@student.unisi.it introduction: facial lentigo maligna/lentigo maligna melanoma (lm/lmm) is a significant diagnostic clinical challenge and dermoscopy can help its diagnosis. objectives: the following study aimed to evaluate if super-high magnification dermoscopy at 400x can add further details for the diagnosis of the lm/lmm. methods: this is a retrospective observational, multicentric study enrolling patients who received a 20x and 400x (d400) magnification dermoscopic examination of facial skin lesions in clinical differential diagnosis with lm/lmm. dermoscopic images were retrospectively evaluated by four observers for the presence/absence of nine 20x and ten 400x dermoscopic features. univariate and multivariate analyses were carried out to find predictors of lm/lmm. results: we enrolled 61 patients with a single atypical skin lesion of the face, including 23 lms and 3 lmms. the presence of roundish and/or dendritic melanocytes (p < 0.001), irregular arrangement of melanocytes (p <0.001), irregular in shape and size melanocytes (p = 0.002), and folliculotropism of melanocytes (p <0.001) at d400 were more frequent in lm/lmm than other facial lesions. according to the multivariate analysis, roundish melanocytes at 400x dermoscopy were more indicative of lm/ lmm (odds ratio-or 49.25, 95% ci 8.75-513.2, p < 0.001), and sharply demarcated borders at 20x dermoscopy were more indicative of not-lm/lmm (or 0.1, 95% ci 0.01-0.79, p = 0.038). conclusions: d400 can identify atypical melanocyte proliferation and folliculotropism that can help to identify lm/lmm together with conventional dermoscopy data. our preliminary observations should be confirmed by larger studies. abstract 2 original article | dermatol pract concept. 2023;13(2):e2023101 introduction although cutaneous melanoma represents 4% of the overall tumor amount in the whole body, it is a public health issue, particularly in fair-skinned populations, due to its high morbidity and mortality [1,2-4]. the head and neck region is of particular interest for melanoma; despite accounting for only 9% of the total body surface, it harbors 20% of melanoma cases, mainly of lentigo maligna/lentigo maligna melanoma (lm/lmm) subtype [5]. lm and lmm appear on sun-damaged skin, most often on the head and neck and in elderly patients [6]. over the last three decades, the global incidence of melanoma has steadily increased, and the current increase in life expectancy of the population could also favor the development of lm/lmm [7,8]. despite recent advances in both diagnosis and treatment, cutaneous melanoma continues to represent a significant clinical challenge [9]. earlier detection of melanoma improves the survival rates but the clinical presentation of lm/lmm can be subtle and varied [10]. the differential diagnosis of lm/lmm includes pigmented actinic keratoses, solar lentigines, seborrheic keratoses, and lichen planus-like keratoses [11]. also, early lm may not exhibit the tell-tale signs of an evolving melanoma (changes in diameter, border, color, and asymmetry), and it is often difficult to distinguish from the surrounding sun-damaged skin [12]. although histological evaluation, remains the gold standard for the confirmation of the diagnosis, several non-invasive imaging procedures such as dermoscopy and reflectance confocal microscopy (rcm) may improve lm/ lmm clinical diagnostic accuracy [13-15]. moreover, they can help in biopsy site selection, margin delineation, and treatment monitoring. recently, our group has shown that dermoscopy at 400x magnification (d400 or super-high magnification dermoscopy) can aid the non-invasive diagnosis of melanoma by observing single pigmented cells [16,17]. objectives the following study aimed to evaluate if d400 can add further details for the clinical diagnosis of the lm/lmm and its differential diagnosis with other facial lesions. methods study design retrospective observational, multicentric study. setting data were collected on patients who came to the dermatology department of the university hospital of siena (italy) or saint-etienne (france) for a dermatological examination between the 1st january 2018 and 31st december 2020. data were analyzed from april 2021 to june 2021. the study was conducted according to the criteria set by the declaration of helsinki. all data were de-identified before use. all patients gave their consent to the processing of their data. participants we enrolled non-consecutive patients with pigmented skin lesions of the face that needed to be removed or followed up for their atypical clinical and/or 20x dermoscopic features according to a skin imaging expert dermatologist (e.c. or j.l.p.). data sources for this study, we selected only patients who received a 20x and 400x (d400) magnification dermoscopic examination of facial lesions in clinical differential diagnosis with lm/ lmm. these lesions were recorded with the videodermoscope fotofinder medicam 1000 (fotofinder system, bad birnbach). to perform d400, we used the same camera as for 20x video-dermoscopy and we changed the terminal lens. specialists in skin imaging (e.c. and j.l.p), acquired at least 5 images for each lesion, for a total of 1138 images of 61 skin lesions, as d400 does not show an entire lesion (d400 field of view of 1 mm x 0.5625 mm). we included cases with histological diagnosis or lesions unmodified at clinical and dermoscopic follow-up of at least 12 months. variables for the clinical variables, we evaluated the patient sex and age. a group of 4 dermatologists (e.c, f.g.l., f.f., and v.c.) belonging to the university departure of dermatology of the hospital-university of siena evaluated the images and defined the dermoscopy variables to be analyzed. the 20x dermoscopy variables included: benign benchmarks (white and wide follicular opening, reticular or parallel brown lines, sharply demarcated borders, mila-like cysts/comedo-like openings, erythema and red pseudo-network) and malignant benchmarks (polygons/rhomboids/zigzag pattern/angulated lines, annular granular pattern / gray circles, asymmetrical pigmented follicular openings, and follicular obliteration). the d400 variables were the presence of the pigmented cells and their features, out of focus blue or gray/brown structureless areas, vessels, and their shape (linear/arborizing, and irregular), hyperkeratotic roundish concentric structures, and folliculotropism of melanocytes. pigmented cells were differentiated into keratinocytes (seen as polygonal brown regular mostly in focus cells, evenly spread and/ or inside a network), roundish melanocytes (seen as large original article | dermatol pract concept. 2023;13(2):e2023101 3 roundish brown-to violet/blue scattered cells; cells were defined as “large” when they were larger than keratinocytes), dendritic melanocytes (large dendritic brown-to-violet/blue scattered cells), and melanophages (large blue-to-violet non in focus cells with a not defined polymorphous shape). considered cell features were cell color (violet and blue colors are difficult to differentiate with d400 and were considered together; light and dark brown were also considered together because brown is often present with multiple shades in the same structure), shape and size irregularity of melanocytes, and irregular arrangement of single melanocytes. statistical analysis descriptive statistics were performed: absolute frequencies and percentages were calculated for qualitative variables and mean and standard deviations for the quantitative ones. the association between qualitative variables and the outcome (ie lm/not lm) and 20x dermoscopy or d400 was evaluated by fisher exact test. t-test was carried out if the variables were normally distributed (normal distribution evaluated by kolmogorov smirnov test) and there was homoscedasticity between variances evaluated by bartlett test, otherwise mann-whitney test was used. logistic regression was later performed to evaluate variables that were statistically significant at the previous univariate analysis (p < 0.05). the best subset of variables was selected by a stepwise procedure based on akaike criterion. odds ratio (or) and 95% confidence intervals (ci) were estimated by logistic regression. the analyses were carried out by r software version 3.6.2. results participants and lesion data in this study 61 patients, 32 (52%) women and 29(48%) men, with a mean age of 72.3 years (range 44 – 91 years) with a single atypical skin lesion of the face, were selected. the 61 skin lesions included 23 lms, 3 lmms, 15 solar lentigines, 12 seborrheic keratoses, 6 lichenoid keratoses, and 2 pigmented actinic keratoses. 20x dermoscopy 20x dermoscopy features are reported in table 1. concerning malignant benchmarks, the annular-granular pattern and gray circles were more frequent in lm/lmm than in the other lesions [figure1, 19 lm/lmms (73.1%) and 14(41.2%) p = 0.019]; asymmetric pigmented follicular openings and follicular obliteration were not present in any of the benign lesions analyzed, while these features were associated to lm/lmms (p < 0.001). regarding benign benchmarks, sharply demarcated borders were present in 17 (50%) not-lm/lmm lesions and only three (11.5%) lm/lmms (p  = 0.002), while the presence of milia-like cysts/comedo-like openings was detected in seven (20.6%) not-lm/lmm lesions and no lm/lmms (p = 0.016). 400x dermoscopy 400x dermoscopy features are reported in table 2. the presence of roundish and/or dendritic melanocytes was mainly observed in skin lesions diagnosed as lm/lmm compared to the other lesions (figure 1, p < 0.001). roundish melanocytes were seen in four not-lm/lmm lesions (11.4%) and 24 lm/lmms (92.3%), while dendritic melanocytes were found in seven not lm/lmm lesions (20.0%) and 25 lm/ lmms (96.2%). pigmented keratinocytes were present in almost all the images analyzed (figure 2). besides, lm/lmm showed more frequently than the other facial lesions melanocytes with irregular arrangement (p < 0.001) and irregularity in shape and size (p = 0.002). cell color, out-of-focus bluish or gray/brown structureless areas and vessel presence were not statistically significant table 1. 20x dermoscopy features of facial lesions. lm/lmm n=26 n(%) othera n=35 n(%) p-value white and wide follicular opening 0 (0.0) 3 (8.8) 0.251 reticular or parallel brown lines 10 (38.5) 8 (23.5) 0.261 sharply demarcated borders 3 (11.5) 17 (50.0) 0.002 milia like cysts /comedo-like openings 0 (0.0) 7 (20.6) 0.016 erythema 4 (15.4) 4 (11.8) 0.717 polygons / rhomboids / zig-zag pattern / angulated lines 3 (11.5) 7 (20.6) 0.491 annular granular pattern / gray circles 19 (73.1) 14 (41.2) 0.019 asymmetrical pigmented follicular openings 20 (76.9) 0 (0.0) <0.001 follicular obliteration 10 (38.5) 0 (0.0) <0.001 a this group included 15 solar lentigines, 12 seborrheic keratoses, six lichenoid keratoses, and two pigmented actinic keratoses. 4 original article | dermatol pract concept. 2023;13(2):e2023101 table 2. 400x dermoscopy features of facial lesions. lm/lmm n=26 n(%) othera n=35 n(%) p-value cell presence: roundish melanocytes 24 (92.3) 4 (11.4) <0.001 dendritic melanocytes 25 (96.2) 7 (20.0) <0.001 roundish or dendritic melanocytes 25 (96.2) 9 (25.7) <0.001 keratinocytes 26 (100.0) 33 (94.3) 0.503 melanophages 15 (57.7) 11 (31.4) 0.066 melanocytes irregular in shape and size 18 (69.2) 10 (28.6) 0.002 melanocyte colour: brown 26 (100.0) 10 (28.6) 0.503 violet/blue 4 (15.4) 8 (22.9) 0.532 black 0 (0.0) 1 (2.9) 1.000 melanocytes distribution: irregular arrangement 20 (76.9) 9 (25.7) <0.001 out of focus bluish structureless areas 13 (50.0) 12 (34.3) 0.294 out of focus grey/brown structureless areas 8 (30.8) 9 (25.7) 0.775 vessels 16 (61.5) 20 (57.1) 0.796 vessels shape: linear + arborizing 7 (43.8) 6 (30.0) 0.493 irregular in shape 8 (50.0) 6 (30.0) 0.307 hyperkeratotic roundish concentric structure 2 (7.7) 10 (28.6) 0.055 folliculotropism 24 (92.3) 0 (0.0) <0.001 a this group included 15 solar lentigines, 12 seborrheic keratoses, six lichenoid keratoses, and two pigmented actinic keratosis. figure 1. 20x dermoscopy (a), clinical (b) and 400x dermoscopy (c-f) images of a lentigo maligna. 400x dermoscopy shows dendritic (red arrow) and roundish (yellow arrow) melanocytes and melanocytic invasion of a hair follicle (asterisk). scale bar 100µm. original article | dermatol pract concept. 2023;13(2):e2023101 5 conclusions conventional dermoscopy at 20x magnification can help the diagnosis of lm/lmm and our series found five criteria (demarcated borders, milia-like cysts/comedo-like openings, annular-granular pattern/gray circles, asymmetric pigmented follicular openings, and follicular obliteration) that could help the differential diagnosis in the monovariate analysis [14,15].our results agreed with a recent study that highlighted how 20x dermoscopic features suggestive of solar lentigo/flat seborrheic keratosis or pigmented actinic keratosis can help to exclude the possibility of an lm/lmm [18]. the presence of sharply demarcated borders, a typical feature of solar lentigo/flat seborrheic keratosis, was the most relevant parameter to exclude lm/lmm in the multivariate analysis (or: 0.1, 95% ci 0.01-0.79, p = 0.038). recently, it has been demonstrated that d400, a new non-invasive skin imaging tool that can reveal pigmented cells in the skin, could also help the clinical diagnosis of cutaneous melanoma, but no data on facial melanoma were available [17]. our study found that d400 could also have a role in the diagnosis of facial melanoma, namely lm/lmm. according to our results shown in table 2, we observed that the presence of roundish and/or dendritic melanocytes in d400 was more frequently associated with lm/lmm than the other pigmented facial lesions (p < 0.001, figure 1). for the differential diagnosis between lm/lmm and benign lesions. folliculotropism of melanocytes was present in 24 lm/lmms (92.3%, figure 1) while it was absent in all benign skin lesions analyzed (p < 0.001). lastly, hyperkeratotic roundish concentric structures were found in 10 benign skin lesions (28.6%) and 2 lm/lmms (7.7%), with a p value just above the threshold of statistical significance (p = 0.055). multivariate analysis the multivariate regression considered the following variables: sharply demarcated borders, milia-like cysts /comedo-like openings, annular granular pattern/ gray circles, roundish melanocytes, melanocyte irregularity in shape and size, irregular arrangement of melanocyte distribution, and follicular obliteration. although asymmetrical pigmented follicular openings, dendritic melanocytes, roundish or dendritic melanocytes, and folliculotropism were statistically significant at univariate analysis, they were excluded from multivariate analysis since their presence/absence almost perfectly explained the presence/absence of lm/lmm. according to the stepwise procedure, roundish melanocytes at 400x dermoscopy were more indicative of lm/lmm (or 49.25, 95% ci 8.75-513.2, p < 0.001), and sharply demarcated borders at 20x dermoscopy were more indicative of not-lm/lmm lesion (or 0.1, 95% ci 0.01-0.79, p = 0.038). figure 2. 20x dermoscopy (a), clinical (b) and 400x dermoscopy (c-e) images of a solar lentigo. 400x dermoscopy shows pigmented keratinocytes (white arrow) in the epidermis around hair follicles (asterisk). scale bar 100µm. 6 original article | dermatol pract concept. 2023;13(2):e2023101 references 1. iannacone mr, youlden dr, baade pd, aitken jf, green ac. melanoma incidence trends and survival in adolescents and young adults in queensland, australia. int j cancer. 2015;136(3):603-609. doi: 10.1002/ijc.28956. pmid: 24806428. pmcid: pmc4277328. 2. sacchetto l, zanetti r, comber h, et al. trends in incidence of thick, thin and in situ melanoma in europe. eur j cancer. 2018;92:108-118. doi: 10.1016/j.ejca.2017.12.024. pmid: 29395684. 3. ferlay jsh, bray f, et al. globocann cancer incidence and mortality worldwide: iarc cancerbase no. 10. lyon, france: international agency for research on cancer. 2010. available from: http://globocan.iarc.fr (last accessed 1 december 2021). 4. rapporto aiom-airt 2017. available from: http://media.aiom.it/ userfiles/files/doc/documenti_scientifici/2017_numeri _del_ cancro. pdf. (last accessed 1 december 2021). 5. dabouz f, barbe c, lesage c, et al. clinical and histological features of head and neck melanoma: a population-based study in france. br j dermatol. 2015;172(3):707-715. doi: 10.1111/ bjd.13489. pmid: 25333719. 6. robinson m, primiero c, guitera p, et al. evidence-based clinical practice guidelines for the management of patients with lentigo maligna. dermatology. 2020;236(2):111-116. doi: 10.1159/000502470. pmid: 31639788. 7. lachiewicz am, berwick m, wiggins cl, thomas ne. survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the surveillance, epidemiology, and end results (seer) program. arch dermatol. 2008;144(4):515-521. doi: 10.1001/archderm.144.4.515. pmid: 18427046. 8. international agency for research on cancer (iarc) w. cancer incidence in five continents ci5plus: iarc cancerbase no 9. 2018. available from: http://ci5.iarc.f r/ci5plus/default.aspx (last accessed 1 december 2021). 9. lee ka, nathan p. cutaneous melanoma a review of systemic therapies. acta derm venereol. 2020;100(11):adv00141. doi: 10.2340/00015555-3496. pmid: 32346745. pmcid: pmc9189748. 10. j jerant af, johnson jt, sheridan cd, caffrey tj. early detection and treatment of skin cancer. am fam physician. 2000;62(2):357-368, 375-6, 381-2. pmid: 10929700. 11. tanaka m, sawada m, kobayashi k. key points in dermoscopic differentiation between lentigo maligna and solar lentigo. j dermatol. 2011;38(1):53-58. doi: 10.1111/j.13468138.2010.01132.x. pmid: 21175756. 12. stante m, giorgi v, stanganelli i, alfaioli b, carli p. dermoscopy for early detection of facial lentigo maligna. br j dermatol. 2005;152(2):361-364. doi: 10.1111/j.13652133.2004.06328.x. pmid: 15727654. 13. kasprzak jm, xu yg. diagnosis and management of lentigo maligna: a review. drugs context. 2015;4:212281. doi: 10.7573/ dic.212281. pmid: 26082796. pmcid: pmc4453766. 14. cinotti e, fiorani d, labeille b, et al the integration of dermoscopy and reflectance confocal microscopy improves the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2019;33(10):e372-e374. doi: 10.1111/jdv.15669. pmid: 31074539. notably, the presence of roundish melanocytes was highly in favor of lm/lmm (or 49.25, 95% ci 8.75-513.2, p < 0.001). moreover, the irregular shape and size (p = 0.002) and distribution of melanocytes (p < 0.001) in d400 were also more frequent in lm/lmm. a distinctive feature of lm/lmm is the invasion of the follicular structures, which can be indirectly appreciated in conventional dermoscopy as pigmentation around hair follicles [19]. as expected, in our series we found annular granular pattern/gray circles (p = 0.019) or asymmetrical pigmented follicular openings (p < 0.001) up to a complete follicular obliteration (p < 0.001) as 20x dermoscopic features associated with lm/lmm. however, as demonstrated by several studies, these dermoscopic features are not specific of lm/lmm [20]. our case series revealed that d400 can directly show single melanocyte invasion of the hair follicles increasing the diagnostic specificity for facial melanoma: almost all lm/lmms and no other pigmented facial lesions had visible folliculotropism (p < 0.001) in our series (figure 1). vessel presence and out-of-focus bluish structureless areas, features considered as predictive of melanoma with d400 in our previous study, were not relevant for the identification of lm/lmm [17]. neovascularization is probably less evident in pigmented superficial melanoma of lm/lmm subtype than in other mm and the presence of bluish structureless areas in non-melanoma lesions of our series could be explained by regression features (aggregates of melanophages) mainly seen in lichenoid keratoses. the main limitation of this study is represented by the small sample and the fact that the acquisition and the evaluation of the images were dependent on the expertise of the investigators. in addition, correlation with histopathological images and images of other new non-invasive imaging techniques such as rcm was lacking. if we compare d400 to rcm, d400 has less concern of false-positive results given by the presence of dendritic langerhans cells in the epidermis possibly mistaken for melanocytes under rcm and has a lower cost. however, d400 can miss atypical melanocytes that are not heavily pigmented or deeper located and can show large cells suggestive of atypical melanocytes when multiple keratinocytes are superposed due to the lack of confocal sections. in conclusion, our study about the use of d400 for the diagnosis of facial lesions found that d400 can identify atypical melanocyte proliferation and folliculotropism that can help the diagnosis of lm/lmm together with conventional dermoscopy data. moreover, we could assume that d400 could help to direct the choice of the more representative site to perform a biopsy. our preliminary observations should be confirmed by larger studies. original article | dermatol pract concept. 2023;13(2):e2023101 7 15. cinotti e, labeille b, debarbieux s, cet al. dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2018;32(8):1284-1291. doi: 10.1111/jdv.14791. pmid: 29341263. 16. cinotti e, rossi r, ferrara g, tognetti l, rubegni p, perrot jl. image gallery: super-high magnification dermoscopy can identify pigmented cells: correlation with reflectance confocal microscopy. br j dermatol. 2019;181(1):e1. doi: 10.1111/ bjd.17781. pmid: 31259403. 17. cinotti e, tognetti l, campoli m, et al. super-high magnification dermoscopy can aid the differential diagnosis between melanoma and atypical naevi. clin exp dermatol. 2021;46(7):1216-1222. doi: 10.1111/ced.14566. pmid: 33486758. 18. lallas a, lallas k, tschandl p, et al. the dermoscopic inverse approach significantly improves the accuracy of human readers for lentigo maligna diagnosis. j am acad dermatol. 2021;84(2):381-389. doi: 10.1016/j.jaad.2020.06.085. pmid: 32592885. 19. dika e, lambertini m, patrizi a, et al. folliculotropism in head and neck lentigo maligna and lentigo maligna melanoma. j dtsch dermatol ges. 2021;19(2):223-229. doi: 10.1111/ddg.14311. pmid: 33166059. 20. akay bn, kocyigit p, heper ao, erdem c. dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. br j dermatol. 2010;163(6):1212-1217. doi: 10.1111/j.13652133.2010.10025.x. pmid: 21083845. dermatology: practical and conceptual originai research | dermatol pract concept 2015;5(1):8 47 dermatology practical & conceptual www.derm101.com introduction merkel cells, which likely derive from the neural crest, are basally located skin cells believed to function in mechanoreception and/or the neuroendocrine system. merkel cell carcinoma (mcc), is a rare cutaneous malignancy first described in 1972 by toker [1]. also known as primary neuroendocrine carcinoma of skin, this aggressive neoplasm has a higher mortality rate than melanoma and an annual incidence of 0.6 per 100,000 in the united states [2]. mcc in combination with other primary epithelial malignancies and clinically presenting as a cutaneous horn is a rarity. herein we report such a case. case report a 93-year-old female presented with a six-month history of an enlarging cutaneous horn over the left angle of the mandible. she underwent local excision and microscopic examination revealed a squamous cell carcinoma in situ (scc-is) with an underlying dermal mcc. a chest x-ray was negative for a primary small-cell lung cancer. the patient was advised of a 50-60% recurrence rate and offered wide local excision with ipsilateral neck dissection and radical radiotherapy. she opted for yearly clinical and radiographic (ct head and neck) surveillance and is currently free of disease 24 months after the local excision. incidental merkel cell carcinoma in a cutaneous horn: a case report brian a. schick1, joshua s. tobe2, mariamma g. joseph1, tyler b. rouse3, manal y. gabril1 1 department of pathology, london health sciences centre and western university, london, ontario, canada 2 schulich school of medicine & dentistry and western university, london, ontario, canada 3 department of pathology, huron perth healthcare alliance, stratford general hospital, stratford, ontario, canada key words: merkel cell carcinoma, squamous cell carcinoma, cutaneous horn citation: schick ba, tobe js, joseph mg, rouse tb, gabril my. incidental merkel cell carcinoma in a cutaneous horn: a case report. dermatol pract concept 2015;5(1):8. doi: 10.5826/dpc.0501a08 received: october 21, 2014; accepted: november 26, 2014; published: january 30, 2015 copyright: ©2015 schick et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. manal y. gabril, md, frcpc, london health sciences centre, department of pathology, university hospital, 339 windermere road, london, ontario, canada n6a5a5. tel. 519 685 8500 x 32956; fax. 519 663 2930. email: manal.gabril@lhsc. on.ca merkel cell carcinoma (mcc) is a rare cutaneous neuroendocrine malignancy, which usually presents as an asymptomatic, rapidly growing, firm nodule on sun-damaged skin. we present a 93-year-old female who presented with a “cutaneous horn” on the face. on excision, histologic examination revealed a combined squamous cell carcinoma in situ with underlying mcc. merkel cell polyomavirus immunohistochemistry was negative in this lesion. this case report highlights the significant association between mcc and squamous cell carcinoma and the uncommon clinical presentation of this combined tumor in the form of a cutaneous horn. abstract 48 original research | dermatol pract concept 2015;5(1):8 pathological findings histologic examination of the cutaneous horn showed a sccis with marked hyperkeratosis, acanthosis and full thickness atypia of the squamous epithelium (figures 1, 2a, 2b). there was an underlying dermal mcc with an infiltrative growth pattern, composed of a monotonous population of malignant small cells with hyperchromatic nuclei, scant cytoplasm, frequent mitoses (14/mm2) and apoptotic bodies (figure 2c). the estimated mcc tumor thickness was 1.6 cm. the closest deep margin was 1.5 mm, the closest peripheral margin was 8.0 mm, and there was no lymphovascular invasion. the immunohistochemical phenotype of the dermally located malignant cells was consistent with a primary cutaneous mcc, with dotlike cytoplasmic positivity for ck20, diffuse positivity for chromogranin a and synaptophysin, and strong nuclear positivity for ki-67 (figure 3a-c). immunohistochemical stains for the merkel cell polyoma virus (mcpv; calbiochem® anti-sv40 t antigen ab2 mouse mab), ttf1, and ck7 were negative. discussion mccs usually present in late adulthood, slightly more commonly in women, as an asymptomatic, rapidly growing, pink-red or violaceous, firm solitary papule or nodule, typically on the head or neck, but also on the extremities or the buttocks. they are aggressive, often with early metastases and a fatal outcome. risk factors include sun damage, age > 60 years, immunodeficiency, arsenic exposure, statin therapy, and psoriasis treatments (100-fold risk with methoxsalen and ultraviolet a). merkel cell polyomavirus (mcpv) was discovered in 2008, and is monoclonally integrated into the host genome of approximately 75% of mccs [3]. the cell of origin is unknown; proposed culprits include primitive pluripotent adnexal or epidermal stem cells, and neural crestderived cells of the amine precursor uptake and decarboxylation (apud) system [4]. an informative literature review performed by walsh tallies the cases of mcc associated with scc (both in-situ and invasive), bowen’s disease (bd), basal cell carcinoma, actinic keratosis and other sweat gland adnexal carcinomas. figure 1. whole mount view of the cutaneous horn, composed predominantly of a hyperkeratotic scc-is, with an underlying lesion. hematoxylin and eosin (h&e). (copyright: ©2015 schick et al.) a figure 2. (a & b) higher magnification shows two lesions: a sccis and underlying mcc located in the dermis. h&e. (copyright: ©2015 schick et al.) b c figure 2c. the mcc is composed of malignant small blue cells with oval nuclei, finely dispersed chromatin, scant cytoplasm, and frequent mitoses. h&e. (copyright: ©2015 schick et al.) originai research | dermatol pract concept 2015;5(1):8 49 [5] in this review, there is a 37% association of mcc with scc; 26% of mccs with overlying bd or ak [5]. in addition, in a detailed evaluation of 29 cases of mcc in her own centre, walsh demonstrated either scc (3) or bd (5) in the tumor [5]. the genesis of combined tumors and the significant morphologic link between scc and mcc is attributed to chronic sun damage explaining the propensity of these tumors to involve the head and neck region of elderly patients [5]. this association also highlights the importance of thorough histological evaluation of lesions suspicious of mcc, although there is no significant difference in outcome in these combined tumors [5]. clinically, the bulk of the documented case reports of these combined tumors highlight an array of presentations: papules, nodules, ulcerations, erythematous plaques and keratotic plaques [5-11]. hyperkeratotic projections of the skin in the form of a cutaneous horn, as described in our case report, has not been previously documented. the etiological role of mcpv in solitary and combined mccs is not fully understood. it has been reported that approximately 75% of pure mccs show immunohistochemical positivity for the mcpv, yet nearly all combined mccs appear to be mcpv negative [12]. in our case, both the sccis and the mcc were non-reactive for mcpv. tumor thickness (measured from the stratum granulosum to the deepest infiltrating tumor cells), tumor growth pattern (nodular or infiltrative), and lymphovascular invasion are independent predictors of survival and disease stage in patients with mcc [13]. there are no guidelines regarding the measurement of tumor thickness in combined tumors. the primary tumor thickness, an important prognostic indicator, was difficult to determine in the presented case. we report a rare case of mcc combined with scc-is, and its unusual presentation as a cutaneous horn. ongoing investigation of the oncogenic role of mcpv in pure and combined mccs may facilitate the development of adjuvant treatment modalities including targeted immunostimulation. this case report demonstrates the rare association of mcc with other primary cutaneous epithelial malignancies, and highlights the importance of thorough histologic evaluation of clinically suspicious merkel cell carcinomas. references 1. toker c. trabecular carcinoma of the skin. arch dermatol 1972;105(1):107-10. 2. albores-saavedra j, batich k, chable-montero f, et al. merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. j cutan pathol 2010; 37(1):20-7. 3. spurgeon me, lambert pf. merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. virology 2013;435(1):118-30. 4. sirikanjanapong s, melamed j, patel rr. intraepidermal and dermal merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature. j cutan pathol 2010; 37(8):881-85. 5. walsh nm. primary neuroendocrine (merkel cell) carcinoma of the skin: morphologic diversity and implications thereof. hum pathol 2001;32(7):680-89. figure 3a. the mcc cells are negative for mcpv. (copyright: ©2015 schick et al.) figure 3b. the mcc cells demonstrate dot-like positivity for ck20. (copyright: ©2015 schick et al.) figure 3c. the mcc cells demonstrate strong positivity for ki-67. (copyright: ©2015 schick et al.) a b c 50 original research | dermatol pract concept 2015;5(1):8 11. al-ahmadie ha, mutasim df, mutema gk. a case of intraepidermal merkel cell carcinoma within squamous cell carcinoma in-situ: merkel cell carcinoma in-situ? am j dermatopathol 2004;26(3):230-33. 12. busam kj, jungbluth aa, rekthman n, et al. merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. am j surg pathol 2009;33(9): 1378-85. 13. andea aa, coit, dg, amin b, busam kj. merkel cell carcinoma: histologic features and prognosis. cancer 2008;113(9):2549-58. 6. park hc, kang hs, park kt, et al. merkel cell carcinoma concurrent with bowen’s disease. ann dermatol 2012;24(1):77-80. 7. hanna gs, ali mh, akosa ab, maher ej. merkel-cell carcinoma of the pinna. j laryngol otol 1988;102(7):608-11. 8. vieites b, suárez-peñaranda jm, delgado v, et al. merkel cell carcinoma associated with in situ and invasive squamous cell carcinoma. acta derm venereol 2009;89(2):184-6. 9. rohaizak m, meah fa, norlia a, et al. merkel cell carcinoma on pre-existing bowen’s disease of the nipple in a patient with chronic arsenic poisoning: is it incidental? asian j surg 2001;24(1):58-60. 10. schenk p, konrad k. merkel cell carcinoma of the head and neck associated with bowen’s disease. eur arch otorhinolaryngol 1991;248(8):436-41. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023094 1 juvenile pityriasis rubra pilaris yihang xie1, lixia xie1, xin shi2, sijia chen3 1 chengdu second people’s hospital, chengdu, china 2 the second affiliated hospital of soochow university, suzhou, china 3 traditional chinese medicine hospital of shangyu, shaoxing, china citation: xie y, xie l, shi x, chen s. juvenile pityriasis rubra pilaris. dermatol pract concept. 2023;13(2):e2023094. doi: https://doi.org/10.5826/dpc.1302a94 accepted: september 27, 2022; published: april 2023 copyright: ©2023 xie et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: xin shi, department of dermatovenereology, the second affiliated hospital of soochow university, 1055 sanxiang street, suzhou 215000, jiangsu, china. e-mail: shx9@163.com case presentation a 4-year-old girl, without a prior history of eczema or psoriasis, presented with a 4-weeks history of extensive erythematous scaly eruption which started on her face and scalp, and spread rapidly to her torso and limbs (figure 1, a, b, e and f). she also had well-circumscribed, red-orange, waxy plaques on the palms and soles (figure 1, c and d). her growth and psychomotor development were normal. histopathology showed basket-like hyperkeratosis, diffuse orthokeratosis and spotted parakeratosis, and a dermal superficial perivascular lymphocytic infiltration (figure 1g). the final diagnosis was pityriasis rubra pilaris. teaching point pityriasis rubra pilaris is a rare inflammatory skin disease that affects men and women of all ages, which presents with hyperkeratotic follicular papules, erythematous-desquamative plaques, palmoplantar keratoderma [1]. its classification into five subgroups is based on age at onset, clinical course, morphologic features, and prognosis [2]. we present a type iii pityriasis rubra pilaris. the differential diagnosis includes psoriasis vulgaris, perifollicular keratosis, lichen spinulosus. 2 image letter | dermatol pract concept. 2023;13(2):e2023094 figure 1. (a,b,e,f) extensive erythematous scaly eruption on the trunk and limbs. (c,d) well-circumscribed, red-orange, waxy plaques on the patient palms and soles. (g) basket-like hyperkeratosis, diffuse orthokeratosis and spotted parakeratosis, and a dermal superficial perivascular lymphocytic infiltration (h&e x400). references 1. wang d, chong vc, chong ws, oon hh. a review on pityriasis rubra pilaris. am j clin dermatol. 2018;19(3):377390. doi:10.1007/s40257-017-0338-1. pmid: 29302927. 2. cohen pr, prystowsky jh. pityriasis rubra pilaris: a review of diagnosis and treatment. j am acad dermatol. 1989;20 (5 pt 1):801-807. doi:10.1016/s0190-9622(89)70093-1. pmid: 2654219. dermatology: practical and conceptual 224 observation | dermatol pract concept 2018;8(3):14 dermatology practical & conceptual www.derm101.com asymptomatic heterogeneously black-pigmented plaque in a 58-year-old man: an unusual presentation of a melanoma mimicker daniela majerson1, paula majluf1, álvaro abarzúa-araya1 , sergio gonzález-bombadiére1 1 dermatology department, pontificia universidad católica de chile, santiago, chile key words: melanoma, dermatofibroma, basal cell carcinoma, seborrheic keratosis, dermoscopy, citation: majerson-grinberg d, majluf p, abarzúa-araya a, gonzález-bombadière. asymptomatic heterogeneously black-pigmented plaque in a 58-year-old man: an unusual presentation of a melanoma mimicker. dermatol pract concept. 2018;8(3):224-226. doi: https:// doi.org/10.5826/dpc.0803a14 received: november 2, 2017; accepted: december 3, 2017; published: july 31, 2018 copyright: ©2018 majerson-grinberg et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: daniela majerson, md, dermatology department, pontificia universidad católica de chile, vicuña mackenna 4686, macul. centro médico san joaquin uc, santiago, chile. email: djamerson@gmail.com. case presentation a 58-year-old man with a history of nodular basal cell carcinoma presented with an asymptomatic black-pigmented lesion on his left shoulder, without variation in size over time, which had been present for years. physical examination revealed an irregular black-bluish-pigmented plaque with a maximum diameter of 8 mm. the dimple sign was negative (figure 1). dermoscopy showed a pseudo-pigmentary network and comedo-like openings at its center, asymmetrical peripheral streak-like structures, areas of brown-bluish pigmentation, fingerprint-like structures, and eccentric milialike cysts (figure 2). the lesion was excised and histological examination was performed (figure 3). diagnosis pigmented dermatofibroma figure  1. physical examination revealed an irregular black-bluishpigmented plaque with a maximum diameter of 8 mm. [copyright: ©2018 majerson-grinberg et al.] observation | dermatol pract concept 2018;8(3):14 225 nonmelanocytic lesions, the black color may correspond to hemosiderin deposits inside the skin (as in the case presented), or be derived from the oxidized plug of keratin masses (as in the pseudocysts in the seborrheic keratosis [sk]), or result from artificial tattoos. other melanoma mimickers with blue pigmentation are vascular lesions, kaposi sarcoma, basal cell carcinomas (bcc), and radiation tattoos [5]. most of the dermatoscopic criteria for mm were described in its superficial spreading variety. however, pigmented nodular melanoma could be recognized by the presence of a combination of blue and black color within the lesion (the “blue-black rule”). the presence of this feature plus one or more of the standard melanoma criteria reach a sensitivity of 84.6% [6]. pigmented bcc may dermatoscopically simulate melanoma: when melanin from the tumor nest, as well as in stroma, is increased, the nests coalesce, forming an unstructured pigmented area. other elements like ulceration, arborizing vessels, or maple-leaf-like or spoke-wheel areas can help identify it [7]. clonal sk are characterized by milia cysts and sharply demarcated borders, but they often show areas of bluish pigmentation composed of multiple, variously sized, and irregularly distributed blue-gray ovoid roundish structures, which resemble the asymmetricalglobular pattern observed melanoma or the ovoid nests commonly described in bbc [8]. on the other hand, ferrari et al described a group of atypical “non-df like” patterns, including a melanoma-like subtype. one of the lesions showing this pattern was, as in this case, characterized by the presence of irregular streaklike structures [1,9] and this group was histopathologically related with hdf [1]. the most frequent dermatoscopic microscopic findings histopathologically, the biopsy showed hyperorthokeratosis with acanthosis and hyperpigmentation of basal keratinocytes; small buds of basaloid cells and sebaceous glands were also visible. the dermis showed a fibrohistiocytic proliferation, with fibrous stroma, denser at the periphery, some blood vessels, and hemosiderophages consistent with hemosiderotic dermatofibroma with epidermal folliculosebaceous induction. discussion dermatofibroma (df) is a common benign dermal lesion composed of fibroblasts, collagen, macrophages, and capillaries that presents with a wide clinicopathological variety. it appears as a firm papule, plaque, or nodule, with a variable degree of pigmentation, more commonly on the lower extremities of young adults [1,2]. there are more than 40 histological variants. the pigmented or hemosiderotic type (hdf) represents 2% and was first described in 1938 as a differential diagnosis of melanoma (mm) [2]. it is composed of small vessels, extravasated erythrocytes, and intraand extracellular hemosiderotic deposits. clinically it presents as a firm, hard, smooth-surface papule or nodule with reddish to bluish coloration, more frequently in middle-aged women, and its recurrence is about 19%. however, because of its rarity, it is not often suspected as a melanoma mimicker [2,3]. dermoscopy improves the diagnostic accuracy in the clinical evaluation of pigmented skin disorders that mimic melanoma. melanoma simulators comprise a heterogeneous group of melanocytic and nonmelanocytic lesions: black or blue color does not always indicate melanoma [4]. in figure 2. dermatoscopy showed a pseudo-pigmentary network and comedo-like openings at its center, asymmetrical peripheral streaklike structures, areas of brown-bluish pigmentation, fingerprint-like structures, eccentric milia-like cysts, and a peripheral milky red area. [copyright: ©2018 majerson-grinberg et al.] figure 3. hematoxylin and eosin (h&e) staining ×100. hemosiderotic dermatofibroma with epidermal folliculosebaceous induction. note the hyperpigmentation of basal keratinocytes, small buds of basaloid cells, and sebaceous glands. the dermis showed a fibrohistiocytic proliferation, with fibrous stroma, denser at the periphery, some blood vessels, and hemosiderophages. [copyright: ©2018 majerson-grinberg et al.] 226 observation | dermatol pract concept 2018;8(3):14 ickers. however, histopathological examination remains mandatory to reach an accurate diagnosis. references 1. ferrari a, argenziano g, buccini p, et al. typical and atypical dermoscopic presentations of dermatofibroma. j eur acad dermatol venereol. 2013;27(11):1375-1380. doi: 10.1111/jdv.12019. 2. zaballos p, llambrich a, ara m, olazarán z, malvehy j, puig s. dermoscopic findings of haemosiderotic and aneurysmal dermatofibroma: report of six patients. br j dermatol. 2006;154(2):244250. doi: 10.1111/j.1365-2133.2005.06844.x. 3. scalvenzi m, balato a, de natale f, francia mg, mignogna c, de rosa g. hemosiderotic dermatofibroma: report of one case. dermatology. 2007;214(1):82-84. doi: 10.1159/000096918. 4. kaminska-winciorek g, wydmanski j. benign simulators of melanoma on dermoscopy – black colour does not always indicate melanoma. j pre clin res. 2013;7(1):6-12. 5. scope a, benvenuto-andrade c, agero al, marghoob aa. nonmelanocytic lesions defying the two-step dermoscopy algorithm. dermatol surg. 2006;32(11):1398-1406. 6. argenziano g, longo c, cameron a, et al. blue-black rule: a simple dermoscopic clue to recognize pigmented nodular melanoma. br j dermatol. 2011;165(6):1251-1255. doi: 10.1111/j.13652133.2011.10621.x. 7. menzies sw. dermoscopy of pigmented basal cell carcinoma. clin dermatol. 2002;20(3):268-269. doi: 10.1016/s0738081x(02)00229-8. 8. squillace l, cappello m, longo c, moscarella e, alfano r, argenziano g. unusual dermoscopic patterns of seborrheic keratosis. dermatology. 2016;232(2):198-202. doi: 10.1159/000442439. 9. cardoso r, massone c, soyer hp, hofmann-wellenhof r. additional dermoscopic presentation of haemosiderotic dermatofibroma. br j dermatol. 2007;156(1):199-200. doi: 10.1111/j.13652133.2006.07611.x. 10. arpaia n, cassano n, vena ga. dermoscopic patterns of dermatofibroma. dermatol surg. 2005;31(10):1336-1339. doi: 10.1097/00042728-200510000-00015. features described of hdf are a homogeneous central bluish or reddish area, with white structures inside, and a delicate pigment network at the periphery with variable vascular structures [2]. thus, melanoma cannot be ruled out, considering the multicomponent dermatoscopic pattern of this entity. various df dermoscopic structures appear to correlate with evolutive stages histopathologically. in our case, the basal keratinocytes accumulating melanin pigment in response to the inflammatory process would correspond dermatoscopically to a pseudo-pigmentary network and irregular streak-like structures [1,10] as brown-bluish pigmentation that represents the blood phagocytosed by the tumor cells. we also propose that fingerprint-like structures are correlated with elongation of the rete ridges, as small buds of basaloid cells and sebaceous glands would reflect comedolike openings and eccentric milia-like cysts. milky red areas would correspond to blood vessels in the peripheral stroma of the tissue. dermatoscopic features of our case were highly indicative for melanoma and shared some features with clonal sk, such as milia-like cysts and areas of brown-bluish pigmentation, and clinically, it can be confused with a superficial pigmented bcc. conclusions the present case of pigmented dermatofibroma is the first reported, to our knowledge, to exhibit simultaneously a milia-like cyst and streak-like and fingerprint-like structures. in conclusion, we report an hdf with different dermoscopic features from previously reported observations, highlighting the importance of understanding that this rare subtype of df presents polymorphic features at dermoscopy, so it should be included in the spectrum of melanoma mimdermatology: practical and conceptual 244 letter | dermatol pract concept 2019;9(3):22 dermatology practical & conceptual introduction we read with interest the article by kaminska-winciorek et al [1] describing neglected nipples with acanthosis nigricans-like appearance. we present another case of this condition and briefly review the differential diagnosis. case presentation the patient was a 43-year-old man with a history of chronic renal disease who had undergone a second kidney transplant 3 months previously and was receiving tacrolimus, mycophenolate mofetil, and prednisone. he was referred to the dermatology department because of a slowly growing pigmented lesion on his left nipple, which appeared after the second transplant. the lesion was asymptomatic, with no history of bleeding. examination revealed a brown, warty, keratotic, 3× 1-cm plaque on the upper portion of the left areola (figure 1a). at dermoscopy, no pigment network, atypical vessels, or any other signs of malignancy were observed. it showed polygonal and angulated clods with a keratotic, shiny blackish surface (figure 1b). a broad differential diagnosis was made, given the presence of a pigmented lesion on an organtransplant recipient with immunosuppressive therapy. however, dermoscopy was an essential and reassuring examination, allowing a presumptive diagnosis of hyperkeratosis of the areola. interestingly, the patient was very concerned and uncomfortable during examination; he experienced extreme sensitivity of the left nipple, referring discomfort and unbearable tickling in reaction to touching and laying the dermatoscope on this area. when asked, he admitted the possibility of poor hygiene in that area due to this condition. after 2 hours of occlusive anesthetic cream, the lesion was smoothed and easily removed using a 4-mm curette (figure 1, c and d, and figure 2), with no pain or bleeding. conclusions hyperkeratosis of the nipple and areola (hna) is an uncommon and benign condition first described in 1923 by tauber. since then, a few attempts to classify this entity have been unsuccessful and it remains controversial whether hna is a hyperkeratosis of the nipple as a neglected dermatosis juan jimenez-cauhe1, ana suarez-valle1, diego fernandez-nieto1, daniel ortega-quijano1 1 dermatology department, ramon y cajal hospital, madrid, spain key words: dermoscopy, nipple hyperkeratosis, neglected dermatosis citation: jimenez-cauhe j, suarez-valle a, fernandez-nieto d, ortega-quijano d. hyperkeratosis of the nipple as a neglected dermatosis. dermatol pract concept. 2019;9(3):244-245. doi: https://doi.org/10.5826/dpc.0903a22 accepted: february 11, 2019; published: july 31, 2019 copyright: ©2019 jimenez-cauhe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: juan jimenez-cauhe, md, dermatology department, ramon y cajal hospital, carretera colmenar, viejo km 9.100, 28034 madrid, spain. email: jjimenezc92@gmail.com letter | dermatol pract concept 2019;9(3):22 245 references 1. kaminska-winciorek g, wydmanski j, scope a, argenziano g, zalaudek i. “neglected nipples”: acanthosis nigricans-like plaques caused by avoidance of nipple cleansing. dermatol pract concept. 2014;4(3):81-84. 2. baykal c, büyükbabani n, kavak a, alper m. nevoid hyperkeratosis of the nipple and areola: a distinct entity. j am acad dermatol. 2002;46(3):414-418. 3. carr es, brown sc, fiala kh. painful nipple hyperkeratosis secondary to vemurafenib. dermatol ther. 2017;30(3). epub 2017 feb 17. distinct entity or a clinical presentation of other dermatoses [2]. in practice, it is a morphological diagnosis that depicts a unilateral or bilateral brown keratotic plaque on the nipple and/or areola. the idiopathic type is usually known as nevoid hyperkeratosis of the nipple and is more common in women after puberty. however, this entity is questioned and most authors point out that hyperkeratosis results from other dermatoses. differential diagnosis includes acanthosis nigricans, seborrheic keratosis, and epidermal nevus and, rarely, malignant tumors such as pigmented squamous cell carcinoma, paget disease, and melanoma may mimic this condition. some cases have been associated with endocrinopathies or estrogen hormonal treatment [2] and, recently, with braf inhibitor therapy [3]. nevertheless, hna resulting from avoidance of cleansing is not reported on previous cases and probably underestimated. only 2 cases of acanthosis nigricans-like plaques on both nipples due to neglecting hygiene have been reported by kaminska-winciorek et al. this hyperkeratotic brownish appearance, similar to other terra firma-forme dermatosis, is caused by retention of keratinocyte debris [1]. in conclusion, increased skin sensitivity in certain body areas might be an important clue in the anamnesis of this kind of lesion. when present, neglected dermatosis should be in the differential diagnosis of hyperkeratosis of the nippleareola complex. figure 1. clinical and dermoscopic overview of the lesion before (a, b) and after (c, d) curette removal. brown, warty, keratotic plaque on upper portion of left areola (a), showing polygonal and angulated clods with a keratotic, shiny blackish surface on dermoscopy (b). [copyright: ©2019 jimenez-cauhe et al.] a c b d figure 2. keratotic material removed using a 4-mm curette. [copyright: ©2019 jimenez-cauhe et al.] dermatology: practical and conceptual 66 observation | dermatol pract concept 2018;8(1):16 dermatology practical & conceptual www.derm101.com introduction an “outbreak of pigmented moles” was first described by hutchinson in 1868, in a 22-year-old healthy woman. although there is no current clear definition of eruptive melanocytic nevi (emn), it generally describes the abrupt development of multiple melanocytic nevi over weeks to month in association with an underlying trigger [1]. case report a 2-year-old child with fitzpatrick skin type ii was referred by her general practitioner because of abrupt development of pigmentation on her left palm. the child had accidentally burned her hand on a hotplate a half year prior to the consultation. the accident was presumably a mixture of firstand superficial second-degree burns. initially the patient developed small reddish macular papules on the left palm, which over the next couple of months became pigmented (figure 1). prior to the accident, a congenital nevus on the palm near the proximal interphalangeal third and fourth digits had been observed. the patient had otherwise only a few nevi on the body. dermatoscopy revealed an abundant number of 1-4 mm melanocytic nevi with light and dark brown colors, symmetrically arranged globules and dots at the periphery, and with a parallel furrow pattern (figure 2). the patient’s nevi are being monitored for further development. discussion there are no clear predisposing factors for the development of emn, though a variety of associations have been proposed. there has been an association in cases of stevens-johnson syndrome/toxic epidermal necrolysis, erythema multiforme, bullous pemphigoid, eczema herpeticum, and exposure to sulfur mustard gas. there has also been an association with eruptive nevi after burn injury ali tareen1, kristine pallesen1, tine vestergaard1 1 department of dermatology and allergy centre, odense university hospital, odense, denmark key words: eruptive nevi, burn injury, traumatic nevi, emn citation: tareen a, pallesen k, vestergaard t. eruptive nevi after burn injury. dermatol pract concept. 2018;8(1):66-67. doi: https://doi. org/10.5826/dpc.0801a16 received: september 11, 2017; accepted: october 24, 2017; published: january 31, 2018 copyright: ©2018 tareen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ali tareen, md, department of dermatology, odense university hospital kløvervænget 15, indgang 142. 5000 odense c, denmark. tel. +45 51270721. email: dr.alitareen@gmail.com eruptive melanocytic nevi (emn) is an unusual phenomenon characterized by the abrupt development of multiple melanocytic nevi over weeks to months in association with an underlying trigger. the underlying mechanisms are not fully understood, however, they have been associated with a variety of conditions. emn is relatively uncommon and might be underreported due to the absence of close monitoring, insufficient recognition, and the presumed benign course of the condition. we describe the first case report of acral emn associated with a burn wound on a 2-year-old child. familiarity is important to differentiate emn from neoplasms. abstract observation | dermatol pract concept 2018;8(1):16 67 which could contribute to the proliferation of melanocytic cells on the palmoplantar skin [11]. the small number of cases suggests that it is a relatively uncommon phenomenon, however, emn might be underreported due to the absence of close dermatologic monitoring, insufficient recognition by practitioners, and the presumed benign course of the condition. this case is unique because this is the first described case of acral eruptive nevi associated with a burn wound. references 1. bovenschen hj, tjioe m, vermaat h, et al. induction of eruptive benign melanocytic naevi by immune suppressive agents, including biological. br j dermatol. 2006 may;154(5):880-884. 2. perry bm, nguyen a, desmond bl, blattner cm, thomas rs, young rj. eruptive nevi associated with medications (enams). j am acad dermatol. 2016;75:1045-1052. 3. navarini aa, kolm i, calvo x, et al. trauma as triggering factor for development of melanocytic nevi. dermatology. 2010;220:291-296. 4. yoshida y, yamada n, adachi k, tanaka m, yamamoto o. traumatized recurrent melanocytic naevus with typical starburst pattern on dermoscopy. acta derm venereol. 2008;88(4):408-409. 5. schulze f, erdmann h, hardkop lh, et al. eruptive naevi and darkening of pre-existing naevi 24 h after a single mono-dose injection of melanotan ii. eur j dermatol. 2014;24(1):107-109. 6. colson f, arrese je, nikkels af. localized eruptive blue nevi after herpes zoster. case rep dermatol. 2016;8(2):118-123. 7. john jk, smalley ks. identification of braf mutations in eruptive melanocytic nevi: new insights into melanomagenesis? expert rev anticancer ther. 2011;11(5):711-714. 8. levy rm, ming me, shapiro m, et al. eruptive disseminated spitz nevi. j am acad dermatol. 2007;57:519-523. 9. dedhia a, someshwar s, jerajani hr. idiopathic eruptive macular pigmentation: what is it actually? int j dermatol. 2015;54(12):1462-1465. 10. rhodes ar, albert ls, weinstock ma. congenital nevomelanocytic nevi: proportionate area expansion during infancy and early childhood. j am acad dermatol. 1996;34(1):51-62. 11. woodhouse j, maytin ev. eruptive nevi of the palms and soles. j am acad dermatol. 2005;52(5 suppl 1):s96-s100. conditions leading to compromised immunity, such as biologic and non-biologic immunosuppressants, biologic and non-biologic chemotherapeutics, malignancy, and aids. emn has also been linked to addison’s disease, cutaneous mastocytosis, melanocyte stimulators, insulin, puva, and koebner phenomenon [1-8]. the relevant differential diagnoses include postinflammatory melanosis and idiopathic eruptive macular pigmentation, which typically presents as non-confluent macules on the face, neck, proximal extremities, and trunk without preceding inflammatory lesions or drug exposure [9]. the dermoscopic presence of globules and dots make these diagnoses less likely. nevus spilus typically has a larger background patch with more pigmented macules within the borders and a stable appearance. there was no pigmented background patch in our case, and the pigmented pattern had an eruptive appearance. it is not known whether the close proximity to a congenital nevus, as in this case, plays a role in the development of emn. this has not been described in the literature, to the best of our knowledge, and we do not believe that there is a causative connection. congenital nevi have a steady growth during early childhood [10]. the abrupt presence of melanocytic nevi with an underlying trigger makes the diagnosis of emn likely. some authors believe that the common denominator is precipitated in genetically predisposed individuals. emn has been linked to mutation in the braf v600e gene, which contributes to the development of malignant melanoma [2,7]. association between emn and malignant melanoma has not been described. familiarity is important to differentiate emn from neoplasms. emn has a strong predilection for the palmoplantar skin, although it has been described in other distributions [2]. this is different from sporadic melanocytic nevi that appear less frequently at acral sites. a hypothesis to support this could be that eccrine glands have a higher amount of melanocortin5-receptors that bind melanocyte-stimulating hormone, figure 1. eruptive nevi on the palm 6 months after burn injury. [copyright: ©2018 tareen et al.] figure 2. dermoscopic view of eruptive nevi on the palm after burn injury. [copyright: ©2018 tareen et al.] dermatology: practical and conceptual 44 research | dermatol pract concept 2019;9(1):11 dermatology practical & conceptual dermoscopic features of psoriasis, lichen planus, and pityriasis rosea in patients with skin type iv and darker attending the regional dermatology training centre in northern tanzania maitseo k. nwako-mohamadi1,2, john e. masenga1,2, david mavura1,2, ola f. jahanpour3, eva mbwilo4, andreas blum5 1 regional dermatology training centre, kilimanjaro christian medical centre, moshi, tanzania 2 kilimanjaro christian medical university college, moshi, tanzania 3 school of public health, department of epidemiology and biostatistics, catholic university of health and allied sciences, mwanza, tanzania 4 safe focus laboratory, arusha, tanzania 5 public, private, and teaching practice of dermatology, konstanz, germany key words: dermoscopy, papulosquamous, dark skin, tanzania, africa citation: nwako-mohamadi mk, masenga je, mavura d, jahanpour of, mbwilo e, blum a. dermoscopic features of psoriasis, lichen planus, and pityriasis rosea in patients with skin type iv and darker attending the regional dermatology training centre in northern tanzania. dermatol pract concept. 2019;9(1):44-51. doi: https://doi.org/10.5826/dpc.0901a11 published: january 31, 2019 copyright: ©2019 nwako-mohamadi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maitseo k. nwako-mohamadi, regional dermatology training centre @kcmc, longuo b, moshi, tanzania. email: madireks@yahoo.com background: papulosquamous skin diseases can be challenging to diagnose, especially in dark skin. dermoscopy is reported to be helpful, but few data are available on its use in skin type iv or darker. objective: to describe dermoscopic features in plaque-type psoriasis (pp), lichen planus (lp), and pityriasis rosea (pr) patients attending the regional dermatology training centre in moshi, northern tanzania, and to compare findings with published data. methods: a descriptive cross-sectional study was conducted at a tertiary hospital from october 2016 to june 2017. fifty-six patients with pp, 25 with lp, and 9 with pr were enrolled consecutively. clinical diagnosis was confirmed with histopathology in 74.4%. dermoscopic vascular and nonvascular features from 225 lesions were analyzed. results: of the 90 patients enrolled, 58.9% were male and the median age was 50 (interquartile range 32.8-60.0) years. in pp lesions, red dots were found in 64.2% and white scale in 45.5%. in lp lesions the background was violet in 45.5% and 58.2% revealed wickham striae. in pr lesions a dull red background was found in 50.0%, white scale in 83.3%, but no vessels were detectable. conclusion: dermoscopy features in pp, lp, and pr in dark skin are mostly similar to those in light skin. abstract research | dermatol pract concept 2019;9(1):11 45 [6,8]. the no treatment group was defined as no topical treatment in the last 4 weeks or none at all; no systemic treatment was defined as no systemic corticosteroids in the last 4 weeks, no methotrexate in the last 3 months, or no systemic treatment at all [6,8]. patients who had mucous membrane or nail lesions only, and those with atypical clinical appearance and refused biopsy, were excluded. patient characteristics included sex, age, diagnosis, treatment status, anatomical site, fitzpatrick skin type [12], and lesion morphology. the skin color was assessed at a non–sunexposed area (right upper medial arm). dermoscopic images of active lesions were taken using polar light mode in a handyscope (fotofinder, bad birnbach, germany) coupled with an iphone 6 (8 megapixels, 1334 × 750 pixel resolution at 326 pixels/inch; apple inc., cupertino, ca, usa). in any particular person, lesions were chosen (if present) from 6 different sites, ie, scalp, face, trunk/limbs, intertriginous areas (axilla, inframammary, or groin), palms/ soles, and knees/elbows [7]. vascular features (background color, vessel morphology, vessel distribution/pattern) and nonvascular features (scale color, scale distribution, wickham striae/pearly whitish structures, follicular disturbances, and pigmentary changes) were assessed [6,8]. two examiners (m.k.n.-m. and r.m.) independently analyzed the dermoscopic images and a third examiner (a.b.) was involved when no consensus was reached. data capture and analysis were through spss version 20 (ibm spss inc., armonk, ny, usa).continuous variables were summarized using medians and interquartile ranges (iqrs), while categorical variables were summarized using frequency and percentages. results ninety patients were enrolled (58.9% men and 41.1% women). the median age was 50 years (iqr 32.8-60). patients with pp (n = 56) and lp (n = 25) were older (51 years [iqr 36.2-59.8] and 55 years [iqr 45.5-69]) than the patients with pr (n = 9) (19 years [iqr 7-30]). the demographic characteristics according to the 3 skin diseases are shown in table 1. in patients with pp, 148 lesions were assessed. the majority of the lesions (64.2%) were from the trunk and limbs, followed by elbows/knees (15.3%), scalp (13.5%), palmoplantar (8.8%), face (7.4%), and intertriginous sites (6.1%). in the patients with lp, 55 lesions were examined and the majority (67.3%) were from the trunk or limbs. in the pr patients, 54.5% of the 22 lesions were located on the trunk and limbs. dermoscopic features in pp the most common features of the 148 pp lesions were light red background (43.9%), red dotted vessels (64.2%), reguintroduction and background plaque-type psoriasis (pp), lichen planus (lp), and pityriasis rosea (pr) are common skin diseases and may have a negative impact on quality of life [1]. the clinical diagnosis can be challenging; sometimes a biopsy is needed, thus delaying the diagnosis and correct treatment [2]. moreover, erythema often observed in these papulosquamous conditions may be masked in a dark-skin population [3,4]. in general, misdiagnosis is reported in up to 32% of papulosquamous diseases but may be even higher in patients with dark skin [5]. dermoscopy as a noninvasive diagnostic tool can help to diagnose without the need of a biopsy [6]. however, few data are available so far about its use and impact in inflammatory skin diseases in patients with skin type iv or darker [6]. published data about dermoscopy on inflammatory lesions, so-called inflammoscopy, is mainly from countries with caucasian or asian patients, but only a few articles describe their patients’ skin type [7,8]. thus, there is little knowledge regarding dermoscopic features in papulosquamous conditions in patients with dark skin (fitzpatrick iv or darker) so far. a higher degree of dyspigmentation and less noticeable erythema has been described in psoriasis lesions in dark skin because of poorly visible dermal vessels [4,6]. in lp, a violaceous color is helpful as a diagnostic feature in lighter skin but it is less visible in darker skin, and therefore it is still not evident whether dermoscopy could be helpful here [9]. the aim of this descriptive study was to describe dermoscopic features in pp, lp, and pr lesions in a clinical setting where most of the patients had fitzpatrick type iv or darker skin and to compare the results with the present literature. methods this hospital (tertiary)-based descriptive cross-sectional study was conducted at the regional dermatology training centre outpatient department, kilimanjaro christian medical centre in moshi, northern tanzania, from october 2016 to june 2017. the study received approval from the kilimanjaro christian medical university college research and ethics committee and was conducted in accordance with the helsinki declaration, and written informed consent was obtained from participants. all patients with clinical diagnoses of pp, lp, and pr were enrolled consecutively. clinical diagnosis was guided by standard descriptions [9–11]. a biopsy was performed wherever possible and in all cases of any atypical presentation. patients who were not receiving any treatment as well as those receiving treatment were enrolled. the on treatment group included topical treatment (eg, steroids, salicylic acid, calcipotriene, or crude coal tar) or oral medication (steroids for at least 1 month or methotrexate for at least 3 months) 46 research | dermatol pract concept 2019;9(1):11 10; 47.6%). among the 12 palmoplantar lesions the 2 most common colors were light and dark red (both at 47.6%). red dots were seen at intertriginous sites (n = 8; 88.9%), scalp (n = 15; 75%), elbows/knees (n = 15; 71.4%), trunk/limbs (n = 46; 62.2%), palmoplantar (n = 7; 53.8%), and face (n = 4; 36.4%). the most common distribution was regular across all sites, seen in intertriginous sites (n = 7; 77.8%), trunk/ limbs (n = 36; 48.6%), palmoplantar (n = 6; 46.2%), scalp (n = 9; 45.0%), elbows/knees (n = 8; 38.1%), and face (n = 3; 27.3%). white scales were seen in face (n = 6; 54.5%), elbows/knees (n = 15; 71.4%), trunk/limbs (n = 58; 78.4%), intertriginous sites (n = 7; 77.8%), palmoplantar (n = 11; 84.6%), and scalp (n = 17; 85%). the scale distribution was mostly patchy across all the body sites, ranging between 55% lar vessels (46.6%), white scales (77.0%), patchy scale distribution (55.4%), and pigmentary changes (56.8%), while pearly white structures (pws) (100%) or follicular changes (79.9%) were not observed. differences between the no and the on treatment group were less than 10% with the exception of more regular vessels in the on compared with the no treatment group (51.8% vs 40.0%), no follicular changes (86.7% vs 70.8%), and no pigmentary changes (48.2% vs 36.9%) (table 2). dermoscopy features were stratified according to various body sites. dull red was the most common background color in face (n = 8; 72.7%), intertriginous areas (n = 5; 55.6%), and scalp (n = 9; 45.0%), while light red was more often found in trunk/limbs (n = 37; 50.0%) and elbows/knees (n = table 1. characteristics of pp, lp, and pr patients (and lesions) at regional dermatology training centre, northern tanzania (n = 90; 225 lesions) variable pp (n = 56); 148 lesions lp (n = 25); 55 lesions pr (n = 9); 22 lesions patients n (%) lesions scoped n (%) patients n (%) lesions scoped n(%) patients n (%) lesions scoped n (%) sex female 20 (35.7) 11 (44.0) 6 (66.7) male 36 (64.3) 14 (56.0) 3 (33.3) age (years) median (iqr) 51.0 (36.2-59.8) 55 (45.5-69.0) 19 (7.0-30.0) <20 4 (7.1) 1 (4.0) 6 (66.7) 20-39 13 (23.2) 4 (16.0) 2 (22.1) 40-59 25 (44.6) 11 (44.0) 1 (11.1) 60-79 12 (21.4) 6 (24.0) ≥80 2 (3.6) 3 (12.0) fitzpatrick skin type type iv 3 (5.4) 10 (6.8) type v 11 (19.6) 42 (28.4) 10 (40.0) 20 (36.4) 4 (44.4) 10 (45.5) type vi 42 (75.0) 96 (64.9) 15 (60.0) 35 (63.6) 5 (55.6) 12 (54.5) treatment status on treatment 37 (66.1) 83 (56.1) 17 (68.0) 36 (65.5) 2 (22.2) 4 (16.7) no treatment 19 (33.9) 65 (43.9) 8 (32.0) 19 (34.5) 7 (77.8) 18 (83.3) body site scalp 20 (13.5) 1 (1.8) face 11 (7.4) 2 (3.6) 3 (13.6) intertriginous 9 (6.1) 3 (5.5) 5 (22.7) trunk/limbs 74 (50.0) 37 (67.3) 12 (54.5) palms/soles 13 (8.8) 0 (0) 1 (4.5) knees/elbows 21 (14.2) 12(21.8) 1(4.5) lesion morphology macule/patch 70 (47.3) 19 (34.5) 19 (86.4) papule 5 (3.4) 14 (25.5) 2 (9.1) plaque 73 (49.3) 22 (40.0) 1 (4.5) research | dermatol pract concept 2019;9(1):11 47 major pigmentary changes in patches (n = 3; 60%) and papules (n = 2; 33.3%). plaques showed brown dots and patches (n = 2; 22.2%), gray dots and patches (n = 2; 22.2%), and a mix of brown and gray dots and patches (n = 2; 22.2%). (n = 5). patchy scale distribution was found of in 60% of patches (n = 3) and in 44.4% of plaques (n = 4). pws were seen in 83.3% of papules (n = 5), 88.9% of plaques (n = 8), and 40% of patches (n = 2). gray dots and patches were the in scalp lesions (n = 11) to 69.2% in palmoplantar lesions (n = 9). pigmentary and follicular changes were similar across different anatomical sites. seventy-four (50.0%) of the pp lesions were located on the trunk and limbs and were stratified according to type of lesions: 34 were patches (45.9%), 1 p a p u l e ( 1 . 4 % ) a n d 3 9 p l a q u e s (52.7%). the main background color was light red in 15 patches (44.1%) and 22 plaques (56.4%), followed by dark red in 9 patches (26.5%) and 14 plaques (35.9%). red dots were seen in 29 plaques (74.4%) and in 16 patches (47.1%) (figure 1a). there was regular distribution of vessels in 22 plaques (56.4%) and 13 patches (38.2%). white scales were seen in 23 patches (67.6%) and in 34 plaques (87.2%). patchy scale distribution was found in 15 patches (44.1%) and in 21 plaques (53.8%). dermoscopic features in lp the most common features of the 55 lp lesions were pigmentary changes (69.1%), pws (58.2%), and a violet background (45.5%), while vessel morphology and pattern (each 80.0%), scales (65.5%), or follicular changes (67.3%) were not observed. more than 10% differences between the no and the on treatment group were observed, being in the violet background color (75.0% vs 28.6%), no scales (50.0% vs 74.3%), pws (75.0% vs 48.6%), and no follicular disturbance (90.0% vs 54.3%) (table 3; figure 1b). in addition, 20 lesions of the no treatment group were stratified according to lesion type (5 patches, 6 papules, and 9 plaques). the most common background color was violet in all lesion types (6 papules [100%], 7 plaques [77.8%], and 2 patches [40%]). yellow color was seen only in patches (n = 2; 40%). linear vessels were observed in 33.3% of papules (n = 2), in 11.1% of plaques (n = 1), and in none of patches. also, none of the papules had scales. white scales were observed in 80.0% of patches (n = 4) and 55.6% of plaques table 2. dermoscopic features in pp lesions at regional dermatology training centre, northern tanzania (n = 148 lesions) variable no treatment (n = 65) n (%) on treatment (n = 83) n (%) total (n = 148) n (%) background color light red 30 (46.2) 35 (45.2) 65 (43.9) dull red 25 (38.5) 34 (41.0) 59 (39.9) others 10 (15.4) 14 (13.8) 24 (16.2) vessel morphology no vessels 26 (40.0) 27 (32.5) 53 (35.8) red dots 39 (60.0) 56 (67.5) 95 (64.2) vessel pattern no vessels 26 (40.0) 27 (32.5) 53 (35.8) regular 26 (40.0) 43 (51.8) 69 (46.6) patchy 13 (20.0) 13 (15.7) 26 (17.6) scale color no scale 10 (15.4) 9 (10.8) 19 (12.8) white 48 (73.8) 66 (79.5) 114 (77.0) others 7 (10.8) 8 (9.5) 15 (10.2) scale distribution no scale 10 (15.4) 9 (10.8) 19 (12.8) diffuse 19 (29.2) 18 (21.7) 37 (25.0) patchy 33 (50.8) 49 (59.0) 82 (55.4) others 3 (4.6) 7 (8.5) 10 (6.8) pws no pws 65 (100) 83(100) 148 (100) pws present 0 (0) 0 (0) 0 (0) follicular changes no changes 46 (70.8) 72 (86.7) 118 (79.7) comedo-like opening 3 (4.6) 4 (4.8) 7 (4.7) perifollicular hyperpigmentation 4 (6.2) 2 (2.4) 6 (4.1) perifollicular hypopigmentation 6 (9.2) 3 (3.6) 9 (6.1) milia-like cysts 2 (3.1) 1 (1.2) 3 (2.0) others 4 (6.2) 1 (1.2) 5 (3.4) pigmentation no pigmentary changes 24 (36.9) 40 (48.2) 64 (43.2) brown dots and patches 14 (21.5) 10 (12.0) 24 (16.2) gray dots and patches 11 (16.9) 19 (22.9) 30 (20.3) mix of gray and brown 16 (24.6) 14 (16.9) 30 (20.3) 48 research | dermatol pract concept 2019;9(1):11 discussion dermoscopic features in pp, lp, and pr were observed to differ between these skin diseases in patients with skin type iv and darker (table 5). compared to the literature, these findings were mostly similar to lighter skin types (i-iii) (figure 1, d-f), but in lower frequencies. among patients with pp, red dots were seen in 64.2% of lesions in contrast to lallas et al [7], who described them in 97.1% (figure 1e). a light red background with regularly distributed dotted vessels and white diffuse scales is reported to help in the diagnosis of psoriasis with 80%-88% specificity and 84.9%-87.8% sensitivity as studied in caucasian patients [6,13]. in this study, the same features were present, although in lower percentages, ie, a light red background in 43.9%. regular vessels were seen in 46.6% compared to 63%-100% [7,13], white scale in 77% vs 64.7%-87.5% [7,8], and diffuse scale in 25% vs 44.6%-60% [7,14]. a possible explanation could be that in darker skin, the red background and vessels are not easily visible compared to patients with a lighter skin type. the majority of psoriasis lesions had white scales, in agreement with the literature, but most had a patchy distribution in contrast to a diffuse distribution reported in most studies [6,8]. in addition, we found white scales in 77.8% of intertriginous lesions compared to 13.2% in another study [7]. with these contrasting results, further research might be of help. the on and no treatment groups showed features in similar proportions except for vessel distribution, follicular changes, and pigmentary changes, suggesting that dermoscopy can be of use in diagnosis of psoriasis even for patients who are receiving treatment. the type of lesion also seems to affect features, with the expected features seen more in plaques compared to patches (eg, red dots [74.5% vs 47.1%]; white scale [87.2% vs 67.6%]). this is between the no and the on treatment group were observed in the dull red background color (55.6% vs 25.0%), white scales color (77.8% vs 100%), patchy scales distribution (27.8% vs 75%), peripheral scales distribution (38.9% vs 25%), and mix of brown and gray pigmentation (each 38.9% vs 25%) (table 4; figure 1c). dermoscopic features in pr the most common features of the 22 pr lesions were pigmentary changes ( 6 3 . 6 % ) , a d u l l r e d b a c k g r o u n d (50.0%), white scale color (81.8%), and patchy/peripheral scale distribution (each 36.4%) no vessels, pws, or follicular changes were seen in the pr lesions. more than 10% differences figure 1. (a) psoriasis plaque dermoscopy image showing dotted vessels and white scales in skin type vi. (b) lichen planus patch dermoscopy image showing a violet background, wickham striae (black arrow), and comedo-like openings (red arrow) in skin type v. (c) pityriasis rosea dermoscopy image showing a dull red background and white scale in skin type vi. (d) psoriasis plaque dermoscopy showing dotted vessels in skin type ii. (e) lichen planus dermoscopy image showing wickham striae and dotted vessels in skin type ii. (f) pityriasis rosea dermoscopy image showing dotted vessels and peripheral scale. [copyright: ©2019 nwakomohamadi et al.] a b c d e f research | dermatol pract concept 2019;9(1):11 49 the white scale observed was similar in proportion to other studies (81.8% in our study and 85% by lallas et al [6]), but in our patients patchy and peripheral distribution were in equal more dull/dark red in dark skin (figure 1c). perhaps due to the dark pigmentation, we observed no vessels, in contrast to lallas et al, who reported red dots in 100% of their patients [6]. not surprising as plaques are expected to be more active. we noted nonvascular features as seen in figure 1b to be more common in lp, in agreement with literature reports. a pearly white background (pws) was the most common finding, in 58.2%, and this is similar to the 60% described by chandravathi and colleagues [8]. pws were also more often detectable in the nontreated lesions [15]. in the nontreated group, pws were seen more in papules and plaques compared to patches, and this is expected as pws correspond to compact orthokeratosis over areas of hypergranulosis and acanthosis [16]. no difference was found in the frequency of violet background in our population compared to the caucasian population of güngör et al [15] (45.5% vs 38%). nonetheless a clear difference could be found in the no vs the on treatment group (75% vs 27.3%). the violet color might correspond to inflammatory infiltrate, necrotic keratinocytes, and pigmentary incontinence over blood vessels [17]. in the no treatment group, the violaceous color was seen more in raised lesions compared to patches, and this is expected as papules and plaques are expected to be more active in lp. follicular changes were some of the less observed findings, with comedolike openings at 16.4% similar to the 20% reported by garg et al [18]. pigmentary changes were seen in 69.1% of lesions, and this could be related to more pigmentation in dark skin [9]. pws are reported to be the most helpful dermoscopic feature in diagnosing lp, especially in untreated patients [6]. our study confirms this observation in skin type iv and darker. in pr lesions the most common background color in our study was dull red (50%) compared to yellow (65%) among caucasian patients, as reported by lallas and colleagues [6]. this observation supports the idea that erythema could have various presentations based on pigmentation, ie, more yellowish in light skin (figure 1f) and table 3. dermoscopic features in lp lesions at regional dermatology training centre, northern tanzania (n = 55 lesions) variable no treatment (n = 20) n (%) on treatment (n = 35) n (%) total (n = 55) n (%) background color light red 1 (5.0) 7 (20.0) 8 (14.5) violet 15 (75.0) 10 (28.6) 25 (45.5) yellow 2 (10.0) 6 (17.1) 8 (14.5) brown 1 (5.0) 9 (25.7) 10 (18.2) others 1 (5.0) 3 (8.6) 4 (7.3) vessel morphology no vessels 16 (80.0) 28 (80.0) 44 (80.0) red dots 0 (0) 3 (8.6) 3 (5.5) lines 3 (15.0) 3 (8.6) 6 (10.9) others 1 (5.0) 1 (2.8) 2 (3.6) vessel pattern no vessels 16 (80.0) 28 (80.0) 44 (80.0) patchy 1 (5.0) 4 (11.4) 5 (9.1) peripheral 2 (10.0) 3 (8.6) 5 (9.1) others 1 (5.0) 0 (0) 1 (1.8) scale color no scale 10 (50.0) 26 (74.3) 36 (65.5) white 9 (45.0) 8 (22.8) 17 (30.9) others 1 (5.0) 1 (2.9) 2 (3.6) scale distribution no scale 10 (50.0) 26 (74.3) 36 (65.5) diffuse 1 (5.0) 0 (0) 1 (1.8) patchy 8 (40.0) 9 (25.7) 17 (30.9) peripheral 1 (5.0) 0 (0) 1 (1.8) pws no pws 5 (25.0) 18 (51.4) 23 (41.8) pws 15 (75.0) 17 (48.6) 32 (58.2) follicular disturbance no disturbance 18 (90.0) 19 (54.3) 37 (67.3) comedo-like opening 1 (5.0) 8 (22.8) 9 (16.4) milia-like cysts 0 (0) 5 (14.3) 5 (9.1) others 1 (5.0) 3 (8.6) 4 (7.2) pigmentation no pigmentary changes 6 (30.0) 11 (31.4) 17 (30.9) brown dots and patches 5 (25.0) 7 (20.0) 12 (21.8) gray dots and patches 7 (35.0) 7 (20.0) 14 (25.5) mix of gray and brown 2 (10.0) 10 (28.6) 12 (21.8) 50 research | dermatol pract concept 2019;9(1):11 recommendations further studies, probably with high-resolution dermoscopy and bigger sample sizes, are needed especially in skin type iv and darker to further elaborate dermoscopic features in inflammatory skin diseases. acknowledgments we thank dr. alex mremi for reading the pathology slides, ms. madeline kudra for helping with data input and specimen preparation, mr. george semango cular features, predominant background colors, and pigmentary changes revealed differences between light and dark skin which could be explained by the different intensity of skin pigmentation. however, the dermoscopic diagnosis of pp, lp, and pr is possible in patients with dark skin and should encourage the use of dermoscopy in daily clinic for an early correct diagnosis and to avoid unnecessary biopsies. further studies, probably with higher-resolution dermatoscopes, are needed to further explore dermoscopic features in dark skin. proportion (36% each) while in the literature peripheral distribution was seen in 70% [6] (figure 1c). strengths this study explored dermoscopy features of pp, lp, and pr with focus on skin type iv and darker, thus adding to scientific data available on dark skin. similar, but less frequent, dermoscopic features were found in skin type iv and darker compared to the caucasian skin type. our results may encourage the use of dermoscopy and further research among dark-skinned patients with papulosquamous and other skin diseases. limitations this study was performed in one center only and participants were recruited consecutively. this may lead to a selection bias. however, the study was at a referral hospital that receives patients from several regions and thus the sample would provide a good representation of the population having skin diseases in this area. consecutive enrollment allowed us to capture a reasonable number of patients. we used a medium price range dermatoscope, and the difference in resolution compared with pricier models might be of significance in dark skin. conclusions among dark-skinned patients (fitzpatrick type iv and darker) in pp, lp, and pr, dermoscopic findings were mostly the same as for skin types i-iii as reported in the literature. the main findings in pp lesions were vascular, while in lp and pr the predominant findings were nonvascular. only the frequencies of vastable 4. dermoscopic features in pr lesions at regional dermatology training centre, northern tanzania (n = 22 lesions) variable no treatment (n = 18) n(%) on treatment (n = 4) n(%) total (n = 22) n(%) background color light red 7 (38.9) 1 (25) 8 (36.4) dull red 10 (55.6) 1 (25) 11 (50.0) yellow 1 (5.5) 1 (25) 2 (9.1) brown 0 (0) 1 (25) 1 (4.5) vessels 0 (0) 0 (0) 0 (0) scale color no scale 4 (22.2) 0 (0) 4 (18.2) white 14 (77.8) 4 (100) 18 (81.8) scale distribution no scale 4 (22.2) 0 (0) 4 (18.1) diffuse 2 (11.1) 0 (0) 2 (9.1) patchy 5 (27.8) 3 (75) 8 (36.4) peripheral 7 (38.9) 1 (25) 8 (36.4) pws 0 (0) 0 (0) 0 (0) follicular disturbance 0 (0) 0 (0) 0 (0) pigmentation no pigmentary changes 7 (38.9) 1 (25) 8 (36.4) brown dots and patches 2 (11.1) 2 (50) 4 (18.1) gray dots and patches 2 (11.1) 0 (0) 2 (9.1) mix of brown and gray 7 (38.9) 1 (25) 8 (36.4) table 5. most common features in pp, lp, and pr in dark skin (skin type iv or darker) plaque-type psoriasis lichen planus pityriasis rosea light red background red dotted vessels regular vessels white scales violet background pearly white structures dull red background white scale color patchy and peripheral scale distribution mix of brown and gray pigmentation research | dermatol pract concept 2019;9(1):11 51 13. pan y, chamberlain aj, bailey m, chong ah, haskett m, kelly jw. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque: features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268– 274. 14. abdel-azim ne, ismail sa, fathy e. differentiation of pityriasis rubra pilaris from plaque psoriasis by dermoscopy. arch dermatol res. 2017;309(4):311– 314. 15. güngör s, topal io, göncü ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept. 2015;5(2):45–53. 16. vásquez-lópez f, manjón-haces ja, maldonado-seral c, raya-aguado c, pérez-oliva n, marghoob aa. dermoscopic features of plaque psoriasis and lichen planus: new observations. dermatology. 2003;207(2):151–156. 17. goncharova y, attia eas, souid k, protzenko o, koktishev i. dermoscopic features of clinically inflammatory dermatoses and their correlation with histopathologic reaction patterns. arch dermatol res. 2015;307(1):23–30. 18. garg p, kaur t. study of the dermoscopic findings and their correlation with histopathological findings in various lichenoid dermatoses. j clin exp dermatol res. 2015;6:308. 6. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198–1205. 7. lallas a, apalla z, argenziano g, et al. dermoscopic pattern of psoriatic lesions on specific body sites. dermatology. 2014;228(3):250–254. 8. chandravathi pl, awake p, kota m. a cross-sectional analysis of dermoscopic patterns distinguishing between psoriasis and lichen planus : a study of 80 patients. j evolution med dent sci. 2015;4(105):17017–17022 9. gorouhi f, davari p, fazel n. cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis. sci world j. 2014; jan 30;2014:742826. 10. who. who: iris global report on psoriasis. who press; 2016:1–48. h t t p : / / a p p s . w h o . i n t / i r i s / b i t s t r e a m / 10665/204417/1/9789241565189_eng. pdf. accessed may 11, 2016. 11. zawar v, chuh a. follicular pityriasis rosea: a case report and a new classification of clinical variants of the disease. j dermatol case rep. 2012;6(2):36–39. 12. treesirichod a, chansakulporn s, wattanapan p. correlation between skin color evaluation by skin color scale chart and narrowband reflectance spectrophotometer. indian j dermatol. 2014;59(4):339– 342. for helping with specimen preparations, dr. wilhellmuss mauka for helping to design the data capture form, and dr. regina mtayangulwa for assisting in reading dermoscopy images. we thank fotofinder for donating the dermatoscope that we used for this study. references 1. armstrong aw, schupp c, wu j, bebo b. quality of life and work productivity impairment among psoriasis patients: findings from the national psoriasis foundation survey data 2003-2011. plos one. 2012;7(12):e52935. 2. korfitis c, gregoriou s, antoniou c, katsambas ad, rigopoulos d. skin biopsy in the context of dermatological diagnosis: a retrospective cohort study. dermatol res pract. 2014;2014:734906. 3. lisi p. differential diagnosis of psoriasis. reumatismo. 2007;59 suppl 1:56–60. 4. alexis af, blackcloud p. psoriasis in skin of color: epidemiology, genetics, clinical presentation, and treatment nuances. j clin aesthet dermatol. 2014;7(11):16– 24. 5. faraz a, dharamshi ha, zahir n, saleem a, ullah s. role of skin biopsy in papulosquamous lesions—a comparative study. comp clin path. 2015;24(5):1205–1209. dermatology: practical and conceptual 28 research | dermatol pract concept 2019;9(1):8 dermatology practical & conceptual introduction the rate of surgical site infection (ssi) for clean dermatological surgery is usually less than 3% [1-3], which is significantly lower than the 5% acceptable ssi rate quoted by many authorities [4,5]. the incidence of ssi is influenced by body site, and certain anatomical sites are at much higher risk than the acceptable rate [6-9], with lower limb surgery most consistently complicated by infection [3,10-16]. in tropical north queensland, the infection rates following excisions from the effect of a single preoperative dose of oral antibiotic to reduce the incidence of surgical site infection following below-knee dermatological flap and graft repair helena rosengren1, clare f. heal2, petra g. buettner3 1 school of medicine, james cook university, townsville, queensland, australia; skin cancer college of australasia, brisbane, queensland, australia; skin repair skin cancer clinic, townsville, queensland, australia 2 school of medicine, james cook university, mackay, queensland, australia 3 centre for chronic disease prevention, james cook university, cairns, queensland, australia key words: antibiotic prophylaxis, surgical site infection, dermatological surgical wound infection, operative surgical procedures, grafts citation: rosengren h, heal cf, buettner pg. effect of a single preoperative dose of oral antibiotic to reduce the incidence of surgical site infection following below-knee dermatological flap and graft repair dermatol pract concept. 2019;9(1):28-35. doi: https://doi.org/10.5826/ dpc.0901a08 published: january 31, 2019 copyright: ©2019 rosengren et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. clare heal, james cook university, mackay, queensland, australia. email: clare.heal@jcu.edu.au background: surgical site infection (ssi) rates for below-knee dermatological surgery are unacceptably high, particularly following complex flap and graft closures. the role of antibiotic prophylaxis for these surgical cases is uncertain. objective: to determine whether ssi following complex dermatological closures on the leg could be reduced by antibiotic prophylaxis administered as a single oral preoperative dose. methods: a total of 115 participants were randomized to 2 g of oral cephalexin or placebo 40-60 minutes prior to surgical incision in a prospective, randomized, double-blind, placebo-controlled trial at a primary care skin cancer clinic in north queensland, australia. results: overall 17/55 (30.9%) controls and 14/55 (25.5%) intervention participants developed infection (p = 0.525). there was no difference between the study groups in adverse symptoms that could be attributed to high-dose antibiotic administration (p = 1). conclusion: a single oral 2-g dose of cephalexin given before complex below-knee dermatological closure did not reduce ssi. abstract research | dermatol pract concept 2019;9(1):8 29 despite the importance of this topic, few randomized controlled trials (rcts) have been published on the use of oral antibiotic prophylaxis in dermatological surgery [17]. the aim of our randomized, double-blind, placebo-controlled trial was to ascertain the effect of a single preoperative oral prophylactic antibiotic dose on ssi following complex below-knee dermatological surgery. methods this randomized, double-blind, placebo-controlled trial recruited consecutive eligible patients booked for flap or graft closure following skin cancer excision below the knee at a primary care skin cancer clinic in townsville, north queensland, australia, between january 2014 and february 2016. each individual patient gave signed informed consent and was allowed to participate in the trial only once. specific exclusion criteria (figure 1) were age under 18, taking any antibiotic within 48 hours of the surgery, suspected ssi at the time of surgery, allergy to the protocol suture, dressing materials, cephalosporins or penicillin, intellectual or mental impairment, and previous participation in this study. if histology confirmed the need for a wider excision or participants received antibiotics for another ssi during the 30-day study period, participants were to be withdrawn from the study. lower limb have ranged from 14.75% to 18.18% [13,16]. below-knee surgery has been shown to have an even higher infection rate [13,16,17]. the reasons for this are unclear, but reduced perfusion pressure in the distal limbs [18], higher tension closures [19], as well as the frequent necessity for complex graft/ flap surgery are postulated reasons. more complex skin closures, such as flap and graft procedures, are known also to be independently associated with significantly higher risk of ssi [20]. large observational prospective studies have shown that flap repair increases the likelihood of infection by 2 to 15 times compared with simple elliptical closure [3,18,20,21]. graft repair has also been linked to much higher infection rates [3,18,20,21]. established ssi may require multiple medical visits, can result in poorer cosmetic outcome and significant bacteremic complications [8,17], and also requires several days of treatment with antibiotics. antibiotic treatment may be associated with unpleasant side effects, allergy, and the development of antibiotic resistance [8]. as a result of indiscriminate antibiotic prescribing, antibiotic resistance is increasing at a dramatic rate, causing significant morbidity and mortality globally [22,23]. a single, high-dose preoperative oral prophylactic antibiotic has been proposed for anatomical sites and dermatological procedures at high risk of ssi [8]. it is suggested that administration of such a single prophylactic dose may be less likely to result in antibiotic resistance than a longer-term course prescribed for established infection, with a resulting reduction in the quantity of antibiotics prescribed overall [17,19,24]. if antibiotic prophylaxis is to be effective, antibiotics should optimally be in the bloodstream and at the operative site at the time of incision [25,26]. the administration of antibiotics within 2 hours prior to incision is associated with the lowest risk of ssi [26]. figure 1. inclusion and exclusion criteria for study. [copyright: ©2019 rosengren et al.] capsules containing either 2 g of cephalexin or placebo were given 30 minutes prior to the excision appointment time, ensuring that skin incision would be within 60 minutes of ingestion of capsules. at the time of surgery baseline demographic data, pertinent medical and drug history, defect size, time from intervention to incision, and closure technique were documented. histology was documented once it had been reported. intraand postoperative protocol if the wound required deep dermal absorbable sutures, monosyn (b. braun, sydney, australia) was used. all defects were closed superficially with nylon sutures (dynek pty ltd., hendon, south australia). following wound closure, melolin (smith and nephew medical ltd, hull, uk) and fixomull (bsn medical, luxenburg) was applied. standardized verbal and written postoperative wound care instructions were given to all participants, stressing the importance of applying no topical creams, ointments, or antiseptics to the wound for the month after surgery. all participants were reviewed 7 days postoperatively for wound inspection and redressing. information related to the use of postoperative oral analgesia (strongest analgesic used) was also recorded at this time. early review at the study practice was encouraged in the event of discomfort, erythema, swelling, or discharge associated with the wound. 30 research | dermatol pract concept 2019;9(1):8 t test, chi-square test, and fisher exact test. intervention and control group differences at baseline as well as treatment modality differences were assessed using unpaired t test, mann-whitney test, chisquare test, and fisher exact test. all data were analyzed using intention-to-treat analysis. incidence of ssi was compared between intervention and control groups using chi-square test. the difference in infection rate was calculated and presented with 95% confidence interval (95% ci). the number needed to treat for benefit was calculated with 95% ci [29]. a sensitivity analysis was conducted including all 115 patients who were originally randomized by assuming various outcome scenarios for the 5 patients who were lost to follow-up. logistic regression models were applied to assess potential confounding effects of all baseline characteristics on difference in incidence of infection between intervention and control groups. chi-square and fisher exact tests were used to compare postoperative analgesia requirements, adverse effects, and treatment of occurring infections between intervention and control groups. analysis was conducted using stataic12 (statacorp lp, lakeway drive, college station, tx, usa). a p value less than 0.05 was considered statistically significant. capsules filled with either antibiotic (intervention) or placebo (control) were transferred to screw-top containers numbered according to the randomization sequence and sent to the recruiting practice in batches. clinic staff and participants remained blind to group allocation during the trial. sample size a small prestudy observational trial at the practice had shown approximately 25% infection rates for flap and graft closures below the knee. our hypothesis was that antibiotic prophylaxis would reduce the infection rate to 5%. fortyfour patients were required in each study group to show this with statistical confidence (power in excess of 80%; significance level 0.05). we planned to recruit a minimum of 110 participants (55 intervention and 55 placebo), allowing for a 25% drop out. statistical analysis and presentation statistical analysis and result preparation followed the consort guidelines [28]. numerical data were described using mean and standard deviation when symmetrically distributed and median and interquartile range when skewed. categorical data were presented using absolute and relative frequencies. eligible nonparticipants were compared with participants using unpaired sutures were removed 14 days after surgery. if at the time of suture removal the wound had not fully healed, it was dressed again and regularly reviewed until it had completely epithelialized. clinical outcome the wound was assessed at the time of suture removal (14 days postoperatively) by 1 of the 6 treating doctors. an adapted version of the 1988 centers of disease control and prevention of national nosocomial infections surveillance system definition for dermatological surgical site infection was used [27]. standardized criteria for surgical site skin infection included occurrence within 30 days of surgery and purulent discharge, erythema more than 1 cm from wound edges, or presence of localized swelling, heat, pain, or tenderness (figure 2). if ssi was suspected, a swab was taken for microscopy, culture, and sensitivity and a 5-day course of cephalexin (500 mg 4 times a day) was prescribed pending swab results. each participant was phoned by the study nurse 1 month after surgery to ensure no ssi was inadvertently missed. randomization and blinding the randomization sequence was generated electronically using ibm spss statistics (v 22.0, ibm corp., armonk, ny, usa) by author and statistician (p.g.b.) and emailed to a compounding pharmacy where batches of generic gel capsules had been filled with either cephalexin or placebo (microcrystalline cellulose and calcium carbonate powder). four identical-looking gel figure 3. consort flow diagram for trial. [copyright: ©2019 rosengren et al.] figure 2. criteria for surgical site infection in dermatological surgery. [copyright: ©2019 rosengren et al.] research | dermatol pract concept 2019;9(1):8 31 during the study follow-up period. three participants (2 controls, 1 intervention) were lost to follow-up despite repeated attempts at phone contact. there were no demonstrable differences between the characteristics of the 5 participants who did not complete the study and the 110 who did. surgical site infection the main analysis based on available cases at follow-up (table 3) showed 17 (30.9%; n = 55) ssis for control and 14 (25.5%; n = 55) for intervention participants (p = 0.525). a sensitivity analysis including all 115 initially randomized patients did not alter this result, regardless of whether the patients who were lost to follow-up were assumed to have had an infection or not to have had an infection (table 3). logistic regression analyses to assess effects of possible confounding variables did not alter the main result of the trial. only 1 (intervention) of 8 split thickness graft closures developed ssi. all other cases of ssi occurred in flap closures. the difference in infection rate between the control and intervention groups was 5.4% (95% ci: 11.4%22.2%). nineteen patients needed to be treated (number needed to benefit) to prevent an infection. the power to detect the 5.4% difference in infection rates between intervention and control groups was 9.6%. a sample size of 1,089 participants in each group would have been needed to reach a power of 80%. secondary outcome measures there was no difference in analgesia requirement between study groups, with the majority of participants (81.8% of controls; 78.2% of intervention group) taking no postoperative analgesia (table 4). one patient in the intervention group reported nausea in the follow-up period. no other symptoms that might have been attributable to the intervention were recorded in either study group. of the 115 participants, 57 were randomized to administration of placebo (control group) and 58 to administration of cephalexin (intervention group). the 2 study groups were comparable at baseline for all variables measured (age, sex, diabetes, smoking status, anticoagulant or immunosuppressive medication, anatomical site and histology of tumor, defect size, and repair technique) (table 2). defect closure was with flap repair for 106 (52 control, 55 intervention) participants and graft repair for 8 (5 control, 3 intervention) participants. the remaining participant had an elliptical closure. graft repair in all cases was with split thickness skin taken from the area surrounding the defect. this method of graft closure is referred to as a halo graft [30]. two participants (both intervention) violated protocol and were withdrawn from the study, one because the treating doctor opted to close the defect with an ellipse and the other because of needing antibiotic treatment for an unrelated ssi results sixteen of 152 consecutive patients requiring flap or graft closures below the knee were ineligible for this study because of penicillin or cephalosporin allergy (n = 9), taking antibiotics for unrelated reasons at the time of surgery (n = 4), and previous participation in this study (n = 3). twenty-one eligible patients declined to participate. the most common reasons given for nonparticipation were not wanting to take unnecessary tablets (n = 12) and fear of possible diarrhea (n = 3). other reasons given (n = 6) were being too old, fear of allergy, and being unwell on the day of the procedure. with the exception of site tumor, there was no difference between eligible nonparticipants and participants (table 1). nonparticipants were more likely to have the neoplasm on the anterior leg whereas participants were more likely to have it on the calf (p = 0.030) (table 1). table 1. comparison of nonparticipants who fulfilled inclusion criteria with those participating in the study characteristic nonparticipants (n = 21) participants (n = 115) p value mean age (sd), years 71.9 (12.4) 69.4 (10.8) 0.336 male (%) 10 (47.6%) 73 (63.5%) 0.171 body site of lesion (%) foot ankle anterior leg calf 1 (4.8%) 1 (4.8%) 15 (71.4%) 4 (19.0%) 8 (7.0%) 6 (5.2%) 44 (38.3%) 57 (49.6%) 0.030 histologya (%) bcc scc keratoacanthoma melanoma 6 (30.0%) 11 (55.0%) 2 (10.0%) 1 (5.0%) 54 (47.0%) 48 (41.7%) 7 (6.1%) 6 (5.2%) 0.059 active smokera (%) 0 2 (1.7%) 1.0 type 2 diabetes mellitusa (%) 1 (5.0%) 13 (11.3%) 0.693 user of anticoagulant medicationa (%) 0 27 (23.5%) 0.065 user of immunosuppressive medicationa (%) 0 1 (0.9%) 1.0 bcc = basal cell carcinoma; scc = squamous cell carcinoma; sd = standard deviation. a missing information for 1 nonparticipant. 32 research | dermatol pract concept 2019;9(1):8 swab results for ssi cases all patients with clinical ssi were treated with antibiotics, the majority (16/17 controls and 12/14 intervention participants) receiving cephalexin (table 4). doctors forgot to take swabs for microscopy, culture, and sensitivity in 5 participants presenting to the study clinic with suspected ssi. a further 5 study participants presented to clinicians elsewhere (hospital in 2 cases, own family doctor in 3 cases) with suspected ssi and were treated with antibiotics without first taking swabs. of the 10 participants (5 control, 5 intervention) with suspected ssi not confirmed on microscopy, 8 were treated with cephalexin and 1 with dicloxacillin. in the final case, we were unable to ascertain what antibiotic had been prescribed. clinical ssi settled in all 10 cases without the need for further intervention. of the 21 swabs taken, 12 (8 control, 4 intervention) grew staphylococcus aureus sensitive to cephalexin, 1 (intervention) produced stenotrophomonas maltophilia sensitive to cephalexin, and a further 4 (2 control, 2 intervention) developed no organism. clinical ssi in all of these 17 swabbed cases responded fully to cephalexin which had been prescribed. table 2. baseline comparison of control group (n = 57) with intervention group (n = 58) characteristic control (n = 57) intervention (n = 58) p value mean age (sd), years 69.4 (11.6) 69.4 (10.1) 0.982 male (%) 34 (59.6%) 39 (67.2%) 0.398 body site of lesion (%) foot ankle anterior leg calf 3 (5.3%) 2 (3.5%) 21 (36.8%) 31 (54.4%) 5 (8.6%) 4 (6.9%) 23 (39.7%) 26 (44.8%) 0.633 histology (%) bcc scc keratoacanthoma melanoma 30 (52.6%) 18 (33.4%) 5 (8.8%) 3 (5.3%) 24 (41.4%) 29 (50%) 2 (3.4%) 3 (5.2%) 0.412 active smoker (%) 1 (1.8%) 1 (1.7%) 1.0 type 2 diabetes mellitus (%) 7 (12.3%) 6 (10.3%) 0.777 user of anticoagulant medication (%) 10 (17.6%) 17 (29.3%) 0.248 repair technique ellipse rom flap keystone flap rotation a-t flap other transposition flap other advancement flap split thickness (halo) graft 0 31 (54.4%) 6 (10.5%) 6 (10.5%) 6 (10.5%) 2 (3.5%) 1 (1.8%) 5 (8.8%) 1 (1.7%)a 28 (48.3%) 7 (12.1%) 7 (12.1%) 8 (13.8%) 3 (5.2%) 1 (1.7%) 3 (5.2%) 0.970 median average diameter defect size 20.0 20.0 0.335 (iqr), mm (16, 22) (16, 24.5)b bcc = basal cell carcinoma; iqr = interquartile range; scc = squamous cell carcinoma; sd = standard deviation; rom = reducing opposed multilobed flap. a patient receiving ellipse repair technique was removed from follow-up. b based on 57 patients. table 3. sensitivity analysis of surgical site infection by intention to treat control group intervention group difference: control minus intervention two-sided 95% ci p value participants who completed follow-up 17/55 (30.9%) 14/55 (25.5%) 5.4% −11.4, 22.2 0.525 sensitivity analysis assuming all lost to followup did not develop ssi 17/57 (29.8%) 14/58 (24.1%) 5.7% −10.5, 21.9 0.492 assuming all lost to followup did develop ssi 19/57 (33.3%) 17/58 (29.3%) 4.0% −12.9, 20.9 0.642 ci = confidence interval; ssi = surgical site infection. research | dermatol pract concept 2019;9(1):8 33 rate of 12.5% in the intervention group, although this study was underpowered to produce statistical significance [17]. our study differed in that we included only below-knee excisions, which are at higher risk than the entire lower limb, and flap and graft surgery, which are at higher infection risk than ellipse excisions. other studies examining antibiotic prophylaxis for surgical sites elsewhere have also demonstrated the effectiveness of antibiotic prophylaxis, in contrast with our study. two rcts—one involving flap and graft repairs in a dermatological surgery setting [31] and the other involving ear and nose only [32]—confirmed that single-dose oral antibiotic prophylaxis prevented ssi. although a further rct involving graft repairs on the nose was underpowered to show a reduction in ssi, graft survival was better for those randomized to antibiotic prophylaxis [33]. a recent meta-analysis of 12 rcts studying antibiotic prophylaxis in dermatological surgery demonstrated that preoperative antibiotic prophylaxis was effective in preventing ssi and furthermore that single antibiotic use is of adequate efficacy and safety for preventing ssi [34]. it should be noted, however, that only 2 of these rcts investigated oral antibiotic prophylaxis, with intravenous antibiotics investigated in the remaining 10 studies [34]. in 4 participants with ssi, the infection did not respond to cephalexin. swabs in 2 cases (1 intervention, 1 control) isolated organisms not sensitive to cephalexin (pseudomonas aeruginosa in one case, enterobacter cloacae in the other). in a further 2 participants (1 control, 1 intervention), 2 organisms were isolated on microscopy and culture: the s aureus found in each case was sensitive to cephalexin but the second organism isolated (p aeruginosa in one case and streptococcus c in the other) was not sensitive to cephalexin. ciprofloxacin was introduced for each ssi not responding to cephalexin, in accordance with swab sensitivity results. discussion the results of this trial did not show any clinically or statistically significant reduction in the rate of ssi from a single dose of cephalexin administered 40-60 minutes before skin incision. there was no increase in adverse outcomes related to antibiotic administration in the intervention group. these results contrast to the only previously identified study examining the effect of antibiotic prophylaxis in lower limb ellipse skin excisions, which showed a reduction in the incidence of ssi from a similar baseline rate of 35.7% to a table 4. comparison of analgesia requirements, adverse symptoms, follow-up treatment, and swab results for intervention and control study participants characteristic control (n = 55) intervention (n = 55) p value surgical site infection 17 (30.9%) 14 (25.5%) 0.525 analgesia requirements (%) none strongest paracetamol strongest panadeinea strongest panadeine fortea strongest endoneb 45 (81.8%) 8 (14.5%) 0 2 (3.6%) 0 43 (78.2%) 11 (20.0%) 0 0 1 (1.8%) 0.329 adverse symptoms (%) nausea following ingestion of study capsules diarrhea following ingestion of study capsules 0 0 1 (1.8%) 0 1.0 1.0 antibiotics started (%) none cephalexin dicloxacillin unknown antibiotic started by nonpractice doctor 38 (69.1%) 16 (29.1%) 0 1 (1.8%) 41 (74.5%) 12 (21.8%) 1 (1.8%) 1 (1.8%) 0.753 swab result (%) (n = 21) s aureus sensitive to cephalexin s aureus sensitive to cephalexin + 2nd organism not sensitive to cephalexin other organism sensitive to cephalexin other organism not sensitive to cephalexin normal skin flora 8 (%) 1 (%) 0 1 (%) 2 (%) 4 (%) 1 (%) 1 (%) 1 (%) 2 (%) 0.879 a paracetamol and codeine. b oxycodone. 34 research | dermatol pract concept 2019;9(1):8 conclusions despite confirmation that the majority of complex belowknee closure ssis responded effectively to oral cephalexin postoperatively, we were unable to demonstrate that a single preoperative 2-g dose of cephalexin could prevent ssi from occurring. infection rates for below-knee surgery are unacceptably high, even in temperate climates. as antibiotic prophylaxis has been shown to be helpful for other dermatological highrisk areas, further research experimenting with different antibiotic prophylactic regimens is worthwhile. acknowledgments we thank trial recruiting doctors (drs. alan poggio, jeremy hudson, robert teunisse, lauren barcley, sandra steele, michael khong, and abid vitani), the trial clinical nurse (lyndie terry), and data collection personnel (lorraine fisher, lynne kelly, and angela byers). we also thank dr pranav divakarum and dr leanne hall for their help in preparing the manuscript. references 1. haas af, grekin rc. antibiotic prophylaxis in dermatologic surgery. j am acad dermatol. 1995;32(2 pt 1):155-176. 2. dettenkofer m, wilson c, ebner w, norgauer j, rüden h, daschner fd. surveillance of nosocomial infections in dermatology patients in a german university hospital. br j dermatol. 2003;149(3):620-623. 3. dixon aj, dixon mp, askew da, wilkinson d. prospective study of wound infections in dermatologic surgery in the absence of prophylactic antibiotics. dermatol surg. 2006;32(6):819-826. 4. culver dh, horan tc, gaynes rp, et al. surgical wound infection rates by wound class, operative procedure, and patient risk index. am j med. 1991;91(3):s152-s157. 5. cruse pje, foord r. the epidemiology of wound infection: a 10year prospective study of 62,939 wounds. surg clin north am. 1980;60(1):27-40. 6. maragh sl, otley cc, roenigk rk, phillips pk. antibiotic prophylaxis in dermatologic surgery: updated guidelines. dermatol surg. 2005;31(1):83-91. 7. rosengren h, dixon a. antibacterial prophylaxis in dermatologic surgery: an evidence-based review. am j clin dermatol. 2010;11(1):35-44. 8. wright ti, baddour lm, berbari ef, et al. antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. j am acad dermatol. 2008;59(3):464-473. 9. del rosso jq. wound care in the dermatology office: where are we in 2011? j am acad dermatol. 2011;64(3 suppl):s1-s7. 10. penington a. ulceration and antihypertensive use are risk factors for infection after skin lesion excision. anz j surg. 2010;80(9):642-645. 11. dixon aj, dixon mp, dixon jb. prospective study of skin surgery in patients with and without known diabetes. dermatol surg. 2009;35(7):1035-1040. the recruited cases for this study were at particularly high infection risks, and we postulate that this was the reason for the failure of antibiotic prophylaxis in our study. first, the anatomical site studied was below the knee, which has been shown to have higher risk of infection than other anatomical sites [13,16]. second, only flap and graft surgery was included, which is known to be of higher ssi risk than simpler surgical techniques [20]. third, the study was conducted in a tropical setting, where infection rates have previously been shown to be increased (8.6% and 11.7% in studies in the mackay region) [35,36]. the reason for this remains unclear, but might be related to tropical humidity. we hypothesize that a single-dose antibiotic prophylaxis was simply insufficient in dose and duration to prevent ssi in these circumstances. minimizing antibiotic dose and duration is an increasingly important focus of research [37]. given the advantages of prophylactic antibiotics in reducing morbidity, and potentially reducing the total amount of antibiotic prescribed [17], we would recommend that future research investigate other prophylactic regimens, such as larger or multiple preor perioperative doses of antibiotic or antibiotic mixed with local anesthetic and injected directly into the wound site preoperatively [38,39]. the strengths of our study were a blind, randomized design with placebo control, a standardized protocol for excision and follow-up, as well as the collection of a large amount of demographic, medical, and excision-related data for comparison of groups. we must, however, acknowledge some limitations to our study. infection may have been underreported, with participants presenting to doctors outside the study practice after surgery. various characteristics influence ssi, and although information on as many variables as possible was recorded, it is difficult to ensure that all possible variables are comparable at baseline. despite the intention to take swabs for microscopy culture and sensitivity for all cases of clinical ssi, only 21 swabs were taken in 31 suspected ssi cases. there may also be limitations to generalizing our findings. this study included complex procedures only, and we do not know the effect of this regimen for elliptical excisions albeit that few nasal and aural skin cancers can be effectively excised with an ellipse. the climate in north queensland is hot and humid, with a mean daily maximum temperature ranging between 24.2°c and 30°c during the summer months and a relative humidity of 75%-79%. the results may not necessarily be generalizable to a temperate climate with a lower baseline infection rate. the diagnosis of infection, even when guidelines are used, is subjective, and interobserver and intraobserver variation may occur [40]. however, the definition we used is the most widely implemented standard definition of wound infection [27]. research | dermatol pract concept 2019;9(1):8 35 27. garner js, jarvis wr, emori tg, horan tc, hughes jm. cdc definitions for nosocomial infections, 1988. am j infect control. 1988;16(3):128. 28. altman d, moher d, schulz kf; the consort group. consort 2010 statement. http://www.consort-statement.org/consort-2010. 2014. accessed june 1, 2018 29. altman dg. confidence intervals for the number needed to treat. bmj. 1998;317(7168):1309. 30. paul sp. “halo” grafting: a simple and effective technique of skin grafting. dermatol surg. 2010;36(1):115-119. 31. amland pf, andenaes k, samdal f, et al. a prospective, doubleblind, placebo-controlled trial of a single dose of azithromycin on postoperative wound infections in plastic surgery. plast reconstr surg. 1995;96(6):1378-1383. 32. rosengren h, heal cf, buttner pg effect of a single prophylactic preoperative oral antibiotic dose on surgical site infection following complex dermatological procedures on the nose and ear: a prospective, randomised, controlled, double-blinded trial. bmj open. 2018;8:e020213. 33. kuijpers di, smeets nwj, lapière k, thissen mrtm, krekels gam, neumann ham. do systemic antibiotics increase the survival of a full thickness graft on the nose? j eur acad dermatol venereol. 2006;20(10):1296-1301. 34. zhang y, dong j, qiao y, he j, wang t, ma s. efficacy and safety profile of antibiotic prophylaxis usage in clean and cleancontaminated plastic and reconstructive surgery: a meta-analysis of randomized controlled trials. ann plast surg. 2014;72(1):121130. 35. heal c, buettner p, raasch b, et al. can sutures get wet? prospective randomised controlled trial of wound management in general practice. bmj. 2006;332(7549):1053-1056. 36. heal c, buettner p, cruickshank, et al. does single application of topical chloramphenicol to high risk sutured wounds reduce incidence of wound infection after minor surgery? prospective randomised placebo controlled double blind trial. bmj. 2009;338:a2812. 37. llewelyn mj, fitzpatrick jm, darwin e, et al. the antibiotic course has had its day. bmj. 2017;358:j3418. 38. griego rd, zitelli ja. intra-incisional prophylactic antibiotics for dermatologic surgery. arch dermatol. 1998;134(6):688-692. 39. huether mj, griego rd, brodland dg, zitelli ja. clindamycin for intraincisional antibiotic prophylaxis in dermatologic surgery. arch dermatol. 2002;138(9):1145-1148. 40. bruce j, russell em, mollison j, krukowski zh. the quality of measurement of surgical wound infection as the basis for monitoring: a systematic review. j hosp infect. 2001;49(2):99-108. 12. wahie s, lawrence cm. wound complications following diagnostic skin biopsies in dermatology inpatients. arch dermatol. 2007;143(10):1267-1271. 13. heal c, buettner p, browning s. risk factors for wound infection after minor surgery in general practice. med j aust. 2006;185(5):255-258. 14. lathlean s. skin cancer in general practice in south australia: a five year study. aust fam physician. 1999;(28 suppl 1):s28-s31. 15. bordeaux js, martires kj, goldberg d, pattee sf, fu p, maloney me. prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. j am acad dermatol. 2011;65(3):576-583. 16. heal cf, buettner pg, drobetz h. risk factors for surgical site infection after dermatological surgery. int j dermatol. 2012;51(7)796-803. 17. smith sc, heal cf, buttner pg. prevention of surgical site infection in lower limb skin lesion excisions with single dose oral antibiotic prophylaxis: a prospective randomised placebo-controlled double-blind trial. bmj open. 2014;4(7):e005270. 18. sylaidis p, wood s, murray ds. postoperative infection following clean facial surgery. ann plast surg. 1997;39(4):342-346. 19. rosengren h, heal c, smith s. an update on antibiotic prophylaxis in dermatologic surgery. curr dermatol rep. 2012;1(2):5563. 20. amici jm, rogues am, lasheras a, et al. a prospective study of the incidence of complications associated with dermatological surgery. br j dermatol. 2005;153(5):967-971. 21. rossi am, mariwalla k. prophylactic and empiric use of antibiotics in dermatologic surgery: a review of the literature and practical considerations. dermatol surg. 2012;38(12):1898-1921. 22. goossens h, ferech m, vander stichele r, elseviers m; esac project group. outpatient antibiotic use in europe and association with resistance: a cross-national database study. lancet. 2005;365(9459):579-587. 23. costelloe c, metcalfe c, lovering a, mant d, hay ad. effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. bmj. 2010;340:c2096. 24. moorhead c, torres a. i prevent bacterial resistance: an update on the use of antibiotics in dermatologic surgery. dermatol surg. 2009;35(10):1532-1538. 25. burke jp. maximizing appropriate antibiotic prophylaxis for surgical patients: an update from lds hospital, salt lake city. clin infect dis. 2001;33 suppl 2:s78-s83. 26. classen dc, evans rs, pestotnik sl, horn sd, menlove rl, burke jp. the timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. n engl j med. 1992;326(5):281-286. dermatology: practical and conceptual 52 letter | dermatol pract concept 2019;9(1):12 dermatology practical & conceptual introduction chondrodermatitis nodularis chronica helicis (cnch) is a benign inflammatory disorder. it is characterized by a 4to 5-mm large, painful, solitary nodule or papule on the helix. the pathogenesis of cnch remains elusive. differential diagnosis includes cutaneous malignancies such as squamous cell carcinoma (scc) [1]. diagnosis is mostly made clinically, but histopathological examination is recommended. dermoscopy can help in the diagnosis of many tumoral or inflammatory skin disorders. to date, dermoscopic features of cnch have not been defined. we sought to describe the dermoscopic findings in a series of patients with cnch. case presentation five patients (2 men and 3 women) with biopsy-proven, untreated cnch were included. median age was 72 years (range, 46-83 years). clinical and dermoscopic photographs were taken before the biopsy, using a canon powershot g16 camera with a dermlite foto epiluminescence system (3gen, inc, san juan capistrano, ca). these images were evaluated independently by 4 dermatologists, 3 with 3 years of experience in dermoscopy and 1 with more than 15 years and considered an expert in the field. the process was not blind, as the final diagnosis (cnch) was known by the evaluators. the final dermoscopic descriptions were achieved through a consensus among the evaluators. five lesions were analyzed. two were located on the right helix, 1 on the left helix, and 2 on the left anthelix. clinically, all the lesions were erythematous hyperkeratotic papules (figures 1a and 2a), one of them eroded (figure 2d). on dermoscopy, the lesions were round; 4 lesions presented with structureless white areas and irregular, ill-defined vessels at the periphery; the fifth had multiple erosions (figure 2d). at the center, 1 lesion had keratin and a yellow-brown flat crust (figure 1b), 1 had a central erosion (figure 1c), 2 had a raised yellowish keratotic crust (figure 2b and 2d), and 1 had a structureless yellowish area (figure 2c). none of the dermatologists found any useful clue to differentiating cnch from scc by dermoscopy. conclusions differentiating cnch from scc is crucial, as clinical presentation can be very similar, and the ear is considered a high-risk dermoscopic features of chondrodermatitis nodularis chronica helicis: a case series daniel morgado-carrasco1, xavier fustà-novell1, sebastian podlipnik 1, lara ferrandiz1 1 department of dermatology, hospital clínic de barcelona, universitat de barcelona, spain key words: chondrodermatitis nodularis chronica helicis, chondrodermatitis, ear, squamous cell carcinoma, dermoscopy citation: morgado-carrasco d, fustà-novell x, podlipnik s, ferrandiz l. dermoscopic features of chondrodermatitis nodularis chronica helicis: a case series. dermatol pract concept. 2019;9(1):52-53. doi: https://doi.org/10.5826/dpc.0901a12 published: january 31, 2019 copyright: ©2019 morgado-carrasco et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: lara ferrandiz, md, department of dermatology, hospital clínic de barcelona, villarroel 170, 08029 barcelona, spain. email: lferrandiz@e-derma.org letter | dermatol pract concept 2019;9(1):12 53 figure 1. chondrodermatitis nodularis chronica helicis. (a) clinical image: erythematous hyperkeratotic papule on the left anthelix. (b,c) dermoscopy: structureless white areas and irregular, ill-defined vessels at the periphery. at the center, keratin and a yellow-brown flat crust (b), an erosion (c). [copyright: ©2019 morgado-carrasco et al.] and ill-defined vessels. these characteristics did not allow the differentiation of cnch from scc. histopathological examination is recommended. cnch belongs to the group of dermatoses in which the diagnosis demands an integrated clinico-dermoscopic and histological diagnostic approach. references 1. wagner g, liefeith j, sachse mm. clinical appearance, differential diagnoses and therapeutical options of chondrodermatitis nodularis chronica helicis winkler. j dtsch dermatol ges. 2011;9(4):287-291. 2. rosendahl c, cameron a, argenziano g, zalaudek i, tschandl p, kittler h. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. 2012;148(12):1386-1392. location in scc. it has been suggested that pain can be an important sign when diagnosing cnch [1]. however, pain can also be associated with scc and it may be a powerful patient-reported warning signal for invasive sccs. moreover, painful sccs can be associated with increased mortality, at least in organ transplant recipients. dermoscopic features of well-differentiated scc include yellow scales, structureless white areas, and a central mass of keratin or yellow keratotic follicular plugs surrounded by a white rim and irregular vessels [2]. these dermoscopic characteristics are practically the same as those described for cnch in this report. the main limitation of our study is the small number of lesions analyzed. cnch presented dermoscopically with central keratin or an erosion surrounded by structureless white areas figure 2. chondrodermatitis nodularis chronica helicis. (a) clinical image: erythematous hyperkeratotic papule on the right helix. (b-d) dermoscopy: structureless white areas and irregular, ill-defined vessels at the periphery. a raised yellowish keratotic crust at the center (b). structureless yellowish area (c). yellowish crusts and erosions (d). [copyright: ©2019 morgado-carrasco et al.] aa b c a b c d dermatology: practical and conceptual letter to editor | dermatol pract concept. 2023;13(2):e2023172 1 subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase besiana p. beqo1, emir q. haxhija1 1 department of pediatric and adolescent surgery, medical university of graz, graz, austria citation: beqo bp, haxhija eq. subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase. dermatol pract concept. 2023;13(2):e2023172. doi: https://doi.org/10.5826/dpc.1302a172 accepted: march 20, 2023; published: april 2023 copyright: ©2023 beqo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: emir haxhija md phd febps, department of paediatric and adolescent surgery, medical university of graz, auenbruggerplatz 34, a-8036 graz, austria. phone: +43-(0)316 – 38513762 fax: +43-(0)316 – 38513775 email: emir.haxhija@medunigraz.at dear editor, we are writing in response to the article “subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase” (doi: https://doi.org/10.5826/ dpc.1204a156) that was recently published in your esteemed journal [1]. as the topic of subcutaneous granuloma annulare (sga) is of particular interest to us, we would like to offer  our comments regarding the case presented in the article. upon review of the clinical and histopathological features described, we respectfully suggest that the case presented in the article appears to be more compatible with the diagnosis of generalized granuloma annulare (gga), rather than sga. gga is characterized by the presence of 10 or more skin plaques with a circular appearance “affecting at least the trunk and either upper or lower, or both extremities” [2], with smaller or larger subdermal extensions of the granulomas beneath these skin lesions, sometimes seen in a patchy pattern [3]. gga is more common in adults. although its etiology is still unknown, various triggering mechanisms, including infectious diseases, have been reported [4], which could have been the case in the report presented by kaur et al. in contrast, sga is almost exclusively seen in children and presents as immobile, solid, non-tender, non-inflammatory subcutaneous lumps that often appear as single or multiple lesions with rare overlying cutaneous abnormalities. these lumps are asymptomatic and attached to the deep fascia with a clear epifascial extension, and they spontaneously regress without any treatment over a period of 1-2 years [5]. the histopathologic images presented in the report by kaur et al do not appear to reveal typical sga histopathology as it is classically seen in children but rather suggest gga with a patchy pattern of small granulomatous islands. our recent research has shown that sga can be recognized by the epifascial cap shape of the subcutaneous lesions on ultrasound and mr imaging, which can aid in the accurate diagnosis of sga [5]. this new imaging sign may help avoid unnecessary examinations and specialist consultations for children with sga and enable accurate diagnosis through imaging alone (figure 1). finally, it is worth noting that sga lumps typically self-resolve in up to 2 years, while lesions described by kaur 2 letter to editor | dermatol pract concept. 2023;13(2):e2023172 et al disappeared within 15 days after intralesional injection of triamcinolone acetonide (10 mg/ml), as commonly observed in patients with localized or generalized variants of granuloma annulare. references 1. kaur l, chakraborty d, dayal s, singh s, yadav k. subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase. dermatol pract concept. 2022;12(4):e2022156. doi: 10.5826/dpc.1204a156. pmid: 36534560. pmcid: pmc9681236. 2. piette ew, rosenbach m. granuloma annulare: clinical and histologic variants, epidemiology, and genetics. j am acad dermato.l 2016;75(3):457-465. doi: 10.1016/j.jaad.2015.03.054. pmid: 27543209. 3. tsuruta d, sowa j, hiroyasu s, ishii m, kobayashi h. concomitant occurrence of patch granuloma annulare and classical granuloma annulare. j dermatol. 2011;38:(5):482-485. doi: 10.1111/j.1346-8138.2010.01070.x. pmid: 21352310. 4. piette ew, rosenbach m. granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. j am acad dermatol. 2016;75(3):467-479. doi: 10.1016/j.jaad .2015.03.055. pmid: 27543210. 5. beqo bp, gasparella p, flucher c, tschauner s, brcic i, haxhija eq. subcutaneous granuloma annulare vs. subcutaneous vascular malformations in children: a diagnostic challenge. children (basel). 2023;10(2):362. doi: 10.3390/children10020362. pmid: 36832491. pmcid: pmc9955411. figure 1. this composite figure shows a clinical picture of the frontal location of multiple subcutaneous granuloma annulare (sga) lumps (a). note the epifascial cap sign in the ultrasound image of two sga lesions marked with multiple white arrows (b), and in another ultrasound image showing mild peripheral hypervascularization (c). the histopathology of the sga lesions is characterized by pathognomonic mucin positive staining of necrobiotic collagen (stars) which is surrounded by inflammatory histiocytes and lymphocytes, ordered in palisades (black arrows). untitled observation | dermatol pract concept 2015;5(4):1 1 dermatology practical & conceptual www.derm101.com case reports case 1. a male 36-year-old active smoker was treated surgically for a painful ingrown nail on his right toe. although he had no complications when he was seen one week after the surgery, at a three-week follow-up, he was admitted to the outpatient clinic complaining of unbearable pain. on inspection, necrosis was observed on the toe that was operated on (figure 1). the pulse of the dorsalis pedis artery was not palpable when the man was examined. a color doppler ultrasonography (usg) and angiogram showed a low blood flow in the posterior tibial artery and an occlusion in the dorsalis pedis artery. the patient was diagnosed with buerger’s disease, leading to the amputation of his right toe. the wound healed sufficiently, but slowly. case 2. a 35-year-old woman presented to our outpatient clinic with an ingrown nail at the left hallux that appeared swollen, and had been for three months. she had used antibiotics for a month and there was no sign of infection. still, common surgery, uncommon complication hande akdeniz1, kadri ozer1, adile dikmen1, uger kocer1 1 plastic, reconstructive and aesthetics surgery department, ankara training and research hospital. ankara, turkey key words: nails, ingrown nails, nail amputation, nail complications, ambulatory surgical procedures, minimally invasive surgical procedures citation: akdeniz h, ozer k, dikmen a, kocer u. common surgery, uncommon complication. dermatol pract concept 2015;5(4):1. doi: 10.5826/dpc.0504a01 received: july 5, 2015; accepted: july 25, 2015; published: october 31, 2015 copyright: ©2015 akdeniz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: hande akdeniz, md, ankara training and research hospital. plastic, reconstructive and aesthetics surgery department, 06100, ankara, turkey. tel:+90 312 5953653. e-mail: hakdenizw@gmail.com ingrown nail surgery is the one of the most common surgeries in outpatient clinics that are generally perfomed in response to patient complaints. still, making simple observations, taking patient histories and conducting further tests are often neglected by outpatient clinics. consequently, it is important to be aware if ingrown nail is associated with any underlying diseases that can lead to major complications. in this article, we report on two cases ending in amputation that were performed with winograd’s partial matrix excision procedure for ingrown nails. such a complication is rare, unexpected, and most unwanted in forefoot surgery. after a detailed analysis of the situation, we discovered that both patients were smokers, and one of them had buerger’s disease. these conditions led to the ingrown nails in addition to poor wound healing. this case report emphasizes the fact that even when performing minor procedures, obtaining a detailed history and conducting an examination are of paramount importance. patient selection is also a considerable factor, especially for patients who are smokers, who may experience a worst case surgical scenario. abstract mailto:hakdenizw@gmail.com 2 observation | dermatol pract concept 2015;5(4):1 conclusion ingrown nail or onychocryptosis is a common nail pathology prevalent in 20% of the population seeking foot care [1]. patients are usually treated conservatively, but the presence of a sharp nail edge in the ulcer may prevent wound healing. treatments that involve surgery are assumed to be minimally invasive and an option for patients who have not not benefit from the more conservative treatments. the surgeries are mostly perfomed in outpatient clinics without involving further tests or history and examination. complications are uncommon with the exception of recurrence and infection [2]. having an ingrown nail is a frequent health problem that causes pain and difficulty in walking that may lead to diminished daily activities. the big toe is the most commonly affected toe and a second toe’s adjacent border may be involved [3]. the inflammation of the soft tissue along the side of the toenail very often accompanies this problem. the tissue may become infected easily, if it is not treated properly. many modalities have been used for treating ingrown nails. conservative management includes warm soaks and cottonwick elevations of the affected nail corner. antibiotic therapy can be used for infections in their early stages. a gutter splint is another conservative treatment approach; either adhesive tape or cyanoacrylate is used to isolate the sharp edges of the nail from the ulcer bed [4]. in the later stages, granulation tissue and lateral wall hypertrophy are formed and surgical treatment is needed. the objective of these surgical techniques is removal of the lateral nail plate and lateral matricectomy [5]. winograd’s procedure is one of the most commonly performed procedure among ingrown nail surgeries. in this technique, after local anesthesia is given and digital tourniquets are prepared, a longitudinal incision is made in the eponychium. the lateral nail border, hypertrophied tissue, and germinal and sterile matrix are removed. this procedure requires no special equipment. therefore, it can be performed easily in outpatient clinics [6]. some risk factors associated with development include tight-fitting shoes, improper nail trimming, infections, ischemia, trauma, excessive sweating, hypertrophy of the nail folds, etc, but the specific etiology is still unknown. diabetes and obesity, as well as thyroid, cardiac, and renal disorders may cause edema in the lower extremities and predispose individuals to the disease [4] it is important to be aware of underlying diseases and if they are the cause of an ingrown nail. such conditions can eventually affect the healing process and increase complication rates. toybenshlak et al. (2005) reported two similar cases that were diagnosed as buerger’s disease. the researchers mentioned that buerger’s disease can cause an ingrown nail, also a factor in poor postoperative healing [2]. in our first patient, buerger’s disease was assumed as the cause of the she was an active smoker with a 10-pack-a-year smoking history. a winograd’s partial matrix excision procedure was performed. at the woman’s two-month follow-up visit, swelling, rubor, warmth, and partial necrosis were exhibited on the operated toe (figure 2). a color doppler usg did not show any abnormality, but she was hospitalized for antibiotherapy. in the patient’s records, there was a cranial magnetic resonance imaging (mri) report that had been suspected of vasculitis three years prior to her surgery. further tests were performed, but no positive marker related situation was found. after surgical debridement, circulatory insufficiency was observed intraoperatively. thus, the wound was left open for secondary healing, and platelet rich fibrin was applied as a biological dressing. the wound did not heal for five months, so the toe was amputated after all pursuant to the patient’s choice. figure 1. a) male 36-year-old, active smoker, at three-week followup; necrosis was observed on his operated toe. amputation of right toe was performed. b) the wound healed sufficiently, but slowly. [copyright: ©2015 akdeniz et al.] figure 2. a) 35-year-old woman with 10 pack-year smoking history, at two-month follow-up; swelling, rubor, warmth and partial necrosis were exhibited at the operated toe. b) after five months the wound had not healed and the bone was exposed. [copyright: ©2015 akdeniz et al.] observation | dermatol pract concept 2015;5(4):1 3 references 1. reyzelman am, trombello ka, vayser dj, et al. are antibiotics necessary in the treatment of locally infected ingrown toenails? arch fam med. 2000;9(9):930–2. 2. toybenshlak m, elishoov o, london e, et al. major complications of minor surgery: a report of two cases of critical ischaemia unmasked by treatment for ingrown nails. j bone joint surg br. 2005;87:1681–3. 3. misiak p, terlecki a, rzepkowska-misiak b, wcisio s, brocki m. comparison of effectiveness of electrocautery and phenol application in partial matricectomy after partial nail extraction in the treatment of ingrown nails. pol przegl chir. 2014; 86(2):89–93. 4. heidelbaugh jj, lee h. management of the ingrown toenail. am fam physician. 2009;79(4):303–8. 5. zuber tj. ingrown toenail removal. am fam physician. 2002;65 (12):2547–52, 2554. 6. ali sm, ahmed gs, tahir sm. outcome of partial nail plate and matrix removal (winograd technique) for ingrown toe nail. j liaquat uni med health sci. 2013;12:182–5. 7. bettin cc, gower k, mccormick k, et al. cigarette smoking increases complication rate in forefoot surgery. foot ankle int. 2015;36(5):488-93. necrosis, but in the second patient there were no symptoms of buerger’s. although we focused on vasculitis, the clinical and laboratory tests were negative. it is universally acknowledged that smoking has negative effects on wound healing. bettin et al. (2015) reported that active smokers and patients with a smoking history were 4.3 and 1.9 times more likely to have foot surgery complications [7]. we recommend that surgeons warn patients who are active smokers about the increased risk of complications before forefoot surgery. in conclusion, our two cases show once again that taking a patient’s history is essential before any surgical procedure. more attention should be paid to patients in the clinic who are to undergo any procedure, even if it is a minor one. as far as we know, aside from technical complications, ours is the first report that reveals amputation as a possible complication of ingrown nail surgery. in light of our experience, our decision to check peripheral pulses in our clinic before performing ingrown nail surgery hinges on the possibility of necrosis and patients must be informed of such risks. finally, we are convinced that unless patients are willing to quit smoking, they should not undergo ingrown nail surgery. dermatology: practical and conceptual 214 review | dermatol pract concept 2018;8(3):13 dermatology practical & conceptual www.derm101.com recent trends in teledermatology and teledermoscopy katie j. lee1, anna finnane1,2, h. peter soyer1,3 1 dermatology research centre, the university of queensland diamantina institute, translational research institute, brisbane, australia 2 the university of queensland, school of public health, herston, australia 3 department of dermatology, princess alexandra hospital, brisbane, australia key words: teledermatology, teledermoscopy, mobile teledermoscopy, melanoma, skin cancer citation: lee kj, finnane a, soyer hp. recent trends in teledermatology and teledermoscopy. dermatol pract concept. 2018;8(3):214-223. doi: https://doi.org/10.5826/dpc.0803a13 received: january 18, 2018; accepted: march 21, 2018; published: july 31, 2018 copyright: ©2018 lee et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this funding was supported by the australian national health and medical research council (centre for research excellence for the study of naevi app1099021). competing interests: prof. h. peter soyer is a shareholder of e-derm consult gmbh and molemap by dermatologists ltd pty. he provides teledermatological reports regularly for both companies. ms. katie j. lee and dr. anna finnane have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: h. peter soyer, md, facd, fahms, the university of queensland diamantina institute, level 5, translational research institute, 37 kent street, woolloongabba, qld, australia 4102. email: p.soyer@uq.edu.au. teledermatology is a useful alternative where specialized dermatological assistance is not available and has been used successfully to support health professionals in a wide range of settings worldwide, in either an asynchronous store-and-forward format or a real-time video conferencing format. teledermoscopy, which includes dermoscopic images in the teleconsultation, is another addition that improves remote assessments of pigmented lesions. a more recent variant is mobile teledermoscopy, which uses a smartphone to deliver the same type of service. teledermoscopy’s greatest strength may be as a triage and monitoring tool, as it can reduce the number of unnecessary referrals, wait times, and the cost of providing and receiving dermatological care. while face-to-face (ftf) care remains the gold standard for diagnosis, drawbacks of not using ftf care as the primary method can be mitigated if teleconsultants are willing to refer to ftf care whenever there is uncertainty. teledermatology has generally been well accepted by patients and practitioners alike. barriers to the large-scale use of teledermatology remain. assigning medicolegal responsibility and instituting a reimbursement system are critical to promoting widespread use by medical professionals, while privacy and security features and a mechanism to link teleconsultations to patients’ existing health records are essential to maximize patient benefit. direct-to-consumer services also need attention from regulators to ensure that consumers can enjoy the benefits of telemedicine without the dangers of unregulated or untested platforms. abstract review | dermatol pract concept 2018;8(3):13 215 europe, with several studies conducted in brazil, australia, new zealand, and turkey, and fewer elsewhere in the world. recent studies continue to examine teledermatology for a wide variety of disorders (table 1); teledermoscopy has been mostly studied for assessing melanocytic and keratinocytic lesions [11-25]. accuracy and interobserver concordance most studies show comparable diagnostic accuracy between teledermatology and face-to-face (ftf) care [55,64,66,71,72], although 3 earlier studies reviewed by lee and english [71] found teledermatology either significantly superior [9] or inferior [73,74]. more specifically, finnane et al [75] reviewed accuracy of diagnosis for skin cancer; most studies showed that ftf consultations were more accurate than teledermatology (67%-85% vs 51%-85%); however, some studies found teledermatology was more accurate. interobserver agreement between ftf consultants and teledermatologists ranged from 45% to 96% for diagnosis [33,38,42,48,58,61,67] and 66% to 96% for management recommendations, rising to 80% to 90% for skin cancer introduction one of the earliest telemedicine specialties, teledermatology is now integrated into several public health systems [1-3] and has been used to support military personnel on deployment [4], staff on commercial ships [5], and care providers in nursing homes [6]. teledermoscopy is also increasingly popular, using images taken with a digital dermatoscope or a standard digital camera with a dermoscopic attachment with magnification and polarized light, to show the lesion in more detail. studies of teledermatology have assessed its usefulness in triage and referral by primary care providers (pcps), consultation with patients or health professionals in remote or medically undersupplied locations, and monitoring patients with chronic skin conditions [6]. teledermatology can also be a useful educational tool for dermatologists and other health care providers, who can send an image of a difficult rash or lesion to a more experienced colleague for diagnostic assistance and instruction [7-10]. teledermatology can be delivered as a real-time video consultation (rt-td) or as an asynchronous store-and-forward (saf) service. mobile teledermatology and teledermoscopy are extensions of these services, where a smartphone is used with or without a dermatoscopic attachment, to deliver the same type of service from a pocket-sized device. while rt-td consultations have the advantage of allowing the teleconsultant to ask clarifying questions and providing direct instructions and education to the patient, the image quality of the video is usually inferior to static images used in saf consultations. teledermoscopy in particular relies on saf technology, as its main usefulness lies in the superior detail and clarity of dermatoscopic images over clinical images. in addition, saf consultations allow the teleconsultant to work at a time convenient to them, which is especially useful for consultations in different time zones. methods we searched the pubmed database for reviews and original articles, restricted to human research published in english between 2015 and 2017. the search terms dermatolog*, dermoscop*, dermatoscop*, teledermatolog*, teledermoscop*, teledermatoscop*, remote consult, and remote consultation were combined in the appropriate method for pubmed. studies were included if the primary focus was on teledermatology or teledermoscopy; studies focusing on computer-assisted diagnosis or teledermatopathology were excluded. results a 2018 [6] literature review of teledermatology use found that the majority of studies were published in the us, uk, and table 1. conditions examined by teledermatology condition references acne [26-40] acneiform/drug eruption [1,41-48] alopecia [32,33,37,39,41,42,44] benign lesions including nevi, seborrheic keratoses, hemangiomas, and scars [11-16,19-23,27,32,33,35, 38-41,44-46,48-61] premalignant neoplasms [15,16,20,22,38-42,46,49, 50,52,58,60] malignant neoplasms [1,11-22,32,35,38,40,41, 44-46,48-53,55-58,60-66] atypical or dysplastic nevi [15,16,20-22,24,25,33,60] papulosquamous dermatoses [31-36,38,39,41,42,4448,58,59,67] dermatitis/eczema [1,28,31-49,67,68] inflammatory conditions [26,27,31,35,45,48,56-58] infections [1,26,28,31,32,34-37,40, 42-48,56-59] hair or nail conditions [26,27,44,49,59] wounds [42,44] other [1,21,26-29,31,32,34,42,43, 46-48,53,57-59,67,69,70] 216 review | dermatol pract concept 2018;8(3):13 other studies have found that interobserver concordance when using teledermoscopy is moderate (fleiss kappa = 0.52) [16] to excellent (prevalence-adjusted, bias-adjusted kappa = 95) [12], with the exception of very difficult lesions [18]. triaging numerous studies found that saf teledermatology is highly effective as a triaging tool. it can reduce ftf referrals by 31% to 88%, surgery waiting times, and the number of no-shows at ftf clinics [11,13,14,29,31,32,35,42,46,53-57,64,67,71,7680], although some studies report no difference in time to treatment [51] or number of secondary referrals [52]. teledermatology can also improve access to dermatological care in lower income groups, such as medicaid enrollees in the us [39]. inclusion of dermatoscopic images also improves triaging decisions, including shorter waiting times and low number needed to excise for both melanomas (1.59) and other skin cancers (1.32) [13,42]. in a study comparing paper referrals without dermatoscopic images to digital referrals including dermoscopy, 43% of patients with benign lesions in the teledermoscopy arm were returned to a pcp without a ftf dermatologist appointment, compared to 1% from the paper referrals arm [16]. inclusion of dermatoscopic images can also allow more cancers to be booked directly to surgery [16,50,64]. one drawback to the reduced number of patients being referred to ftf appointments is the risk of so-called “unimaged melanomas.” these lesions are not initially noted by the referring pcp but rather discovered by the dermatologist management [58,61,71]. between referring pcps and teledermatologists, interobserver diagnostic agreement ranges from 21% to 60% [34,45,46,49,59,65], suggesting that teledermatology provides useful assistance to pcps who lack specialist dermatological training. still images can also be combined with video (called hybrid teledermatology); one study found that this improved management accuracy compared to assessments with still images alone (87.6% vs 71.7%, respectively). this may be because the video provides additional information about the patient’s behavior not captured by the referring doctor’s history [27]. an important recent study examined teledermatology interobserver concordance rates in patients with either fitzpatrick i-iii or iv-vi skin types. concordance between ftf and teledermatology diagnosis and management were the same in both lighter and darker skin groups, suggesting that teledermatology is reliable for diagnosis in patients of all fitzpatrick skin types [41]. as is the case in ftf dermatology, including dermatoscopic images (figure 1) in a teleconsultation appears to improve the reliability of telediagnoses, reportedly improving both sensitivity (0.93-1.0 with teledermatology vs 0.6-1.0 without) and specificity (0.85-0.97 vs 0.72-0.81) [14,55,64]. while including dermoscopy added 1 to 2 minutes to a consultation, 9 minutes (95% ci 8.3-9.5) with dermoscopy vs 7 minutes (95% ci 6.7-7.6) without dermoscopy, the teleconsultant’s evaluation time was almost the same for both groups, at 1.09 minutes (95% ci 1.04-1.14) with dermoscopy and 1.02 minutes (95% ci 1.0-1.04) without [14]. figure 1. a dermoscopic image provides greater clarity and detail for melanocytic lesions. [copyright: ©2018 lee et al.] review | dermatol pract concept 2018;8(3):13 217 sometimes concerned about the service’s ability to meet patient demand, technical complications, and an increased workload. consulting dermatologists were also concerned about the lack of ability to palpate lesions, reliability of teledermatology, legal liability, and financial reimbursement [21,57,80,87-90,92]. a survey of attitudes to teledermoscopy particularly found that 71% of dermatologists surveyed were in favor of pcps using teledermatology to seek advice, provided there was dermoscopy training for the pcps, or in the case of long travel distances or long waiting times [93]. barriers to routine use there are a number of barriers to the effective use of teledermatology. reimbursement is a major issue to integrating teledermatology into the health care system, as is defining who is ultimately medically responsible for diagnosis and treatment decisions; these issues are complicated further if the referring doctor and consultant are in different jurisdictions [1,3,72,84,88,94,95]. privacy and security while transmitting patient images and information are critical, as well as integration into electronic health records for maximum effectiveness [3,42,43,84,94,96]. international standards for encryption and data protection, such as international organization for standardization (iso) standards iso/ts 13131:2014 on telehealth services [97] or iso/iec 27001:2013 on information technology security [98], should be consulted when setting up a teledermatology service. finally, referring health care providers will require training on what elements of the patient’s history are useful to the teledermatologist, appropriate image acquisition, especially how to use a dermatoscope effectively, and on effectively using the selected teledermatology platform [72,84,99] (see example in figure 2). there are successful models for new services to draw on, including the dutch health care system, where teledermatology is fully reimbursed and integrated in the health system, with electronic records available to all system users [3]; the teledermatology service of the us veterans health administration [100]; an ngo-led teledermatology service in toledo, belize, where a collaboration between the medical college of wisconsin and hillside healthcare international has addressed technological requirements, training for pcps, and ongoing adjustments to the service to optimize its usability [101]; and the australian tele-derm national service, which provides consultations and education to rural and remote general practitioners [49]. mobile teledermatology and teledermoscopy mobile teledermatology is the use of a smartphone to take and send images and information to a teleconsultant; mobile as an incidental part of the ftf examination. with reduced ftf appointments, there is a real risk of these lesions going unnoticed [62,63]. however, the reverse can also be true: one study focusing on aesthetic dermatology concerns also identified 5 skin cancers and 2 actinic keratoses by teledermatology [38]. cost effectiveness while some studies found teledermatology to be more expensive than conventional care, in most studies teled e r m a t o l o g y w a s e q u i v a l e n t o r m o r e e c o n o m i c a l [6,13,14,54,67,71,81,82]. teledermatology consultations usually took longer than ftf consultations [14,83], but economic benefits for the health system stemmed from fewer ftf specialist referrals, and for patients from reduced travel time, costs, and time away from work and faster delivery of treatments [57,72,77,84,85]. rt-td is generally more expensive than saf modalities due to more expensive video conferencing technology and difficulty organizing suitable times for multiple clinicians, but can still be more cost-effective than ftf visits, particularly when the patient lives a long way from specialist dermatology care [26,72]. cost-effectiveness studies have been limited by addressing only a few economic principles in each study; randomized clinical trials and other studies that include a comprehensive economic evaluation are still needed [77]. in terms of quality of life (qol), there are relatively few studies about the effectiveness of teledermatology for improving qol. a 2015 review found that teledermatology does improve qol due to improvements in disease severity [86], but the only 2 studies comparing saf teledermatology to ftf dermatology found that teledermatology and ftf care were equally effective at improving patients’ qol [68,86]. user attitudes patient and doctor attitudes to teledermatology are generally reported as neutral to good, with patients in rural areas often more positive than urban areas [26,35,38,52,54,57,59,60,72,82,8791]. a study in which each participant was assessed ftf, by saf and by rt-td found that while patients preferred ftf assessment, they were still generally satisfied with teledermatology, and were evenly divided between preferring saf and rt-td [92]. drivers of patient satisfaction included convenience, less travel, shorter waiting times, lower cost, and good quality of health care [21,26,87,92]. some areas of patient dissatisfaction with teledermatology include poor follow-up or communication by their referring physician, feeling uncomfortable being photographed, or wishing to directly ask the teledermatologist questions [59,72,87]. referring health care providers generally found teledermatology easy to use but were 218 review | dermatol pract concept 2018;8(3):13 several studies suggest that pcp and dermatology staffs are able to capture good-quality images with a mobile phone [55,58]. of note, a study of pcps found they were able to provide mobile teledermoscopy images of similar quality to images taken in a dermatology department despite having little training in dermoscopy [11,15]. images taken by study participants themselves are generally of sufficient quality for teleconsultations. a study of mobile dermoscopy with instructions on skin self-examination found that the images were generally good quality, with substantial agreement between mobile teledermoscopy and ftf diagnoses (kappa = 0.9), although 22% of participants did not choose to image lesions that were later selected for imaging by the clinician [22]. similarly, a study of parenttaken images for a pediatric dermatology service found there was good correlation between telediagnoses and in-person diagnoses (82%) [33]. another study of high school students found that 98% were able to take good-quality overview images of another person, and 66% were able to take in-focus dermoscopic images on the first try [23]. mobile teledermoscopy is also a useful triaging tool for pcps, having been used successfully in mass screening events [20], in underserved areas remote from ftf dermatologists [103], and for reducing waiting time for surgery compared to paper referrals [11]. mobile teledermatology has also been explored as a relatively low-cost way to extend dermatological assistance to rural health services. a study of a service in uganda and guatemala, with us-based dermatologists, found that 89% of the teledermatology consultations changed the treatment plan initially suggested by the pcp, with the added benefit of pcps improving their diagnostic accuracy over the course of the study [44]. finally, there is an increasing number of direct-to-consumer websiteor app-based dermatology services, which can be very popular with patients: a trial of one app for pediatric dermatology found 83% of parents said that, had the app been unavailable, they would have sought ftf appointments with a pcp, an urgent care clinic, or a dermatologist [28]. review of such services in 2014-2015 found that there teledermoscopy is performed with a smartphone that has a dermoscopic attachment (figure 3), usually in conjunction with an app to facilitate saf teledermatology. this emerging technology is particularly useful for ongoing monitoring of chronic conditions that require frequent follow-up and changes to optimize treatment. in addition, in developing countries, mobile phone networks are well developed and often more reliable than other electronic communications [45,84]. a survey of australian dermatologists and dermatology trainees found that mobile teledermatology was common, with more than 50% saying they sent or received clinical images using a smartphone at least weekly (rising to 89% of junior practitioners) [102]. however, it was also poorly regulated, with limited security measures, documentation of patient consent, or transfer of images to a patient’s permanent medical record. dermatologists reported taking mobile phone images to obtain advice from a colleague, monitor patient progress, communicate with the patient’s other doctors, and for educational purposes [102]. similarly, 47% of british dermatologists surveyed had used a mobile to take images for teledermatology, and 75% of these were aware of guidelines on data storage and transfer [89]. there are few studies comparing diagnostic and management concordance between mobile teledermoscopy and ftf assessment, but existing studies are generally positive, with 81% to 91% full or partial diagnostic concordance [40,48,58]. a german study found that accuracy of the clinical diagnosis, as compared to histopathological diagnosis, was 72.2% for ftf and 55.6% for teledermatologists [40]. figure 2. sequential monitoring of a clinically dysplastic nevus using the molemap teledermoscopy platform. the 2 larger images in the top row compare dermoscopic images of the same lesion taken 4 years apart. the images in the middle row are clinical images of the same lesions taken over 4 years, and the images in the bottom row are the corresponding dermoscopic images. (supplied by authors; h. peter soyer is a shareholder and consultant of molemap pty ltd.) [copyright: ©2018 lee et al.] figure 3. mobile teledermoscopy with a handyscope dermoscopic attachment (fotofinder systems gmbh, bad birnbach, germany). [©2018 fotofinder systems] review | dermatol pract concept 2018;8(3):13 219 drawbacks were requiring assistance to image hard-toreach areas like the back [19], uncertainty about privacy and accuracy [69], uncertainty about completely trusting a telediagnosis [19], and uncertainty about whether insurance would cover such a service [24]. a discrete choice survey of mobile teledermoscopy patients found that patients preferred involvement of a doctor to skin self-examinations, but also strongly preferred having their concerning lesions assessed by a dermatologist rather than a gp, which is more easily achieved via mobile teledermoscopy [108]. there are very few studies of clinician attitudes about mobile teledermatology. a survey of nurses in arizona, which included an introduction to mobile teledermoscopy, example images, and case studies, found that although most had not used mobile teledermoscopy, they perceived it to have the ability to improve diagnosis and positively affect their practice, with moderate scores for perceived ease of use. however, this study may be influenced by self-selection bias [109]. barriers to use of mobile teledermatology while modern smartphones enable patients to take and forward their own images, patient-acquired images have drawbacks such as teleconsultants having difficulty confirming patient identity and coordinating with pcps [72]. the proliferation of poorly regulated direct-to-consumer teledermatology apps may also have adverse outcomes for consumers who rely on them rather than professional, individual medical advice, particularly where the service relies on algorithms to diagnose or suggest treatment plans, without oversight by a trained health care provider [29,106,107,110]. conclusions teledermatology is a useful alternative where specialized dermatological assistance is not available, and has generally been accepted by patients and practitioners alike. its greatest strength may be as a triage and/or monitoring tool, in both underserved areas and busy metropolitan dermatology clinics, by reducing both the number of unnecessary referrals and wait times. while ftf care remains the gold standard for diagnosis, this drawback can be mitigated if teleconsultants are willing to refer to ftf care whenever there is uncertainty. despite these advantages, barriers remain to incorporating teledermatology into large-scale use. privacy and security features are essential to any telemedicine system, and teledermatology records need to be linked to patients’ health records for maximum effectiveness. assigning medicolegal responsibility and instituting a reimbursement system are also critical to persuading greater numbers of health profeswere up to 29 available to us patients, with some restricting their advice to acne or anti-aging, while others were treating patients for any condition [29, 104,105]. there is also a number of services aimed at pediatric patients [106]. as for general teledermatology, this form of mobile teledermatology can substantially reduce the waiting period to access care, but services are poorly regulated, frequently do not require proper verification of patient identity, and provide little continuity of care or integration with the patient’s official medical record [29,105-107]. however, there are examples that avoid these pitfalls, usually by being associated with a regulated health care provider, such as the stanford health care ecare direct program [91] or a trial giving direct-to-consumer access to existing members of a commercial health plan [36]. ongoing monitoring one major advantage of mobile teledermatology is that patients themselves may collect images for short-term monitoring, without requiring a ftf appointment. a study of 29 patients found that 97% were able to collect suitable baseline and follow-up images of nevi with a mobile dermatoscope, with a good diagnostic concordance (kappa = 0.87) between ftf consultations and teledermatology [24]. a study of a smartphone saf service for facial laser resurfacing patients, allowing them to send daily images of their skin to monitor healing after the procedure, found that patients using the service required fewer ftf consultations. as well as detecting any adverse reactions requiring medical treatment, the teleconsultant was able to reassure participants about reactions that were an expected part of the healing process, such as swelling, exudation, or crusting [69]. a randomized control trial examining ongoing monitoring of isotretinoin acne treatment also found that the mobile teledermatology patients had equivalent treatment success and fewer adverse events than the ftf patients [30]. user attitudes there are few studies of consumer or professional acceptance of mobile teledermatology and dermoscopy, but existing studies indicate favorable attitudes. patients generally expressed satisfaction with mobile services, citing improved waiting times, convenience, comfort, reassurance, and privacy [24,30,69]. one study found that a high number of participants believe that mobile teledermoscopy would improve their skin self-examinations for cancer and motivate them to check their skin more often [19], and in other studies parents were willing to use a pediatric teledermatology service for their children [28,33]. participants generally reported feeling comfortable and competent with taking dermoscopic images after minimal instructions [19,23]. 220 review | dermatol pract concept 2018;8(3):13 14. ferrándiz l, ojeda-vila t, corrales a, et al. internet-based skin cancer screening using clinical images alone or in conjunction with dermoscopic images: a randomized teledermoscopy trial. j am acad dermatol. 2017;76(4):676-682. doi: 10.1016/j. jaad.2016.10.041. 15. dahlén gyllencreutz j, johansson backman e, terstappen k, paoli j. teledermoscopy images acquired in primary health care and hospital settings a comparative study of image quality. j eur acad dermatol venereol. 2018;32(6):1038-1043. 16. dahlén gyllencreutz j, paoli j, bjellerup m, et al. diagnostic agreement and interobserver concordance with teledermoscopy referrals. j eur acad dermatol venereol. 2017;31(5):898-903. doi: 10.1111/jdv.14147. 17. daniel cl, armstrong gt, keske rr, et al. advancing survivors’ knowledge (ask) about skin cancer study: study protocol for a randomized controlled trial. trials. 2015;16(1):109. doi: 10.1186/s13063-015-0637-x. 18. de giorgi v, gori a, savarese i, et al. teledermoscopy in doubtful melanocytic lesions: is it really useful? int j dermatol. 2016;55(10):1119-1123. doi: 10.1111/ijd.13281. 19. horsham c, loescher lj, whiteman dc, soyer hp, janda m. consumer acceptance of patient-performed mobile teledermoscopy for the early detection of melanoma. br j dermatol. 2016;175(6):1301-1310. doi: 10.1111/bjd.14630. 20. hue l, makhloufi s, sall n’diaye p, et al. real-time mobile teledermoscopy for skin cancer screening targeting an agricultural population: an 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10.1089/tmj.2014.0225. dermatology: practical and conceptual letter to the editor | dermatol pract concept. 2023;13(2):e2023173 1 author’s reply to letter to the editor “subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase” lovleen kaur1, surabhi dayal1 1 department of dermatology, venereology and leprology, pandit bhagwat dayal sharma post graduate institute of medical sciences, rohtak, haryana, india citation: kaur l, dayal s. author’s reply to letter to the editor “subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase”. dermatol pract concept. 2023;13(2):e2023173. doi: https://doi.org/10.5826/dpc.1302a173 accepted: march 30, 2023; published: april 2023 copyright: ©2023 kaur et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: lovleen kaur, md, department of dermatology, venereology and leprology, pandit bhagwat dayal sharma post graduate institute of medical sciences, rohtak, haryana, india; contact: +917888661584; e-mail: dr.lovleen555@gmail.com dear editor, we appreciate the commenter’s interest shown for our article  [1]. we agree that generalized granuloma annulare (gga) affects at least the trunk and either upper and/ or lower extremities as first described by dabski and winkelmann who studied 100 cases of gga. however, it is important to note that the lesional morphology was either annular plaques in ring-like configuration or non-annular papules in their study [2]. gga clinically presents as widespread macules or papules or annular plaques on the trunk and limbs unlike our case which had a single type of clinical morphology of painless subcutaneous nodules [3,4]. subcutaneous granuloma annulare (sga) usually presents as skin-colored subcutaneous nodules with minimal to absent cutaneous surface changes. a slight erythema in very few lesions (3 out of 23 nodules) in our case was seen, similar to the faint erythema noticeable in the clinical photograph of sga in the article cited by the commenters themselves and previously observed in other studies too[4,5]. regarding the issue raised on mobility of nodules reported in our case, we would like to bring reader’s attention to the study on 47 pediatric sga cases [5]. among 53 total subcutaneous nodules, 25 were in fact freely mobile, while 23 were not or slightly mobile. immobility or fixity occurs more commonly when sga extends and attaches to underlying periosteum as in the cases of lesions over scalp and forehead [5]. interpreting our case as gga rather than sga may have been caused by the erythematous lesion pointed with red arrow labelled as ‘biopsy site’ instead of ‘attempted biopsy site’ (indicating post-surgical wound after suture removal), which might be misinterpreted as an annular plaque of gga. sga is usually an authentic and exclusive panniculitic process with no dermal involvement, however, 25% cases may have coexistent findings of granuloma annulare in the 2 letter to the editor | dermatol pract concept. 2023;13(2):e2023173 dermis [6]. histopathologically, sga should have areas of basophilic degeneration of collagen bundles with peripheral palisading granulomas involving connective tissue septae of the subcutis [6]. the histopathology in our case revealed necrobiotic granulomas exclusively involving subcutaneous septae while in gga upper and middle dermis shows predominant participation [6]. as our case presented very early, within 7 days from onset, the biopsied nodule might be purely subcutaneous without upper dermal participation yet, causing relatively smaller granulomas on histopathology. although imaging alone may be preferred in children being non-invasive, its utility as substitute for biopsy in adults needs to be confirmed with further imaging studies in adult sga. we emphasize that sga does not occur exclusively in children but can be observed in adults as well, although it is rare and may follow a different disease course in comparison to the children one. further contemplating, our case might fit into a generalized form of sga, as generalized form of perforating ga [3]. in conclusions, since the primary and the only lesions in our case were subcutaneous nodules, the term gga as diagnosis of our case should be discouraged. references 1. kaur l, chakraborty d, dayal s, singh s, yadav k. subcutaneous granuloma annulare in an atypical age group in immediate post-covid-19 phase.  dermatol pract concept. 2022;12(4):e2022156. doi: 10.5826/dpc.1204a156. pmid: 36534560. pmcid: pmc9681236. 2. dabski k, winkelmann rk. generalized granuloma annulare: clinical and laboratory findings in 100 patients. j am acad dermatol. 1989;20(1):39-47. doi:10.1016/s0190-9622(89)70005-0. pmid: 2913080. 3. bourke j. granulomatous disorders of the skin. in: griffiths cem, barker j, bleiker t, chalmers r, creamer d, ed. rook’s textbook of dermatology. 9th ed. uk: john wiley & sons; 2016:97.1-7. 4. piette ew, rosenbach m. granuloma annulare: clinical and histologic variants, epidemiology, and genetics. j am acad dermatol. 2016;75(3):457-465. doi:10.1016/j.jaad.2015.03.054. pmid: 27543209. 5. felner ei, steinberg jb, weinberg ag. subcutaneous granuloma annulare: a review of 47 cases. pediatrics. 1997;100(6):965-967. doi:10.1542/peds.100.6.965. pmid: 9374565. 6. requena l. panniculitis. in: griffiths cem, barker j, bleiker t, chalmers r, creamer d, ed. rook’s textbook of dermatology. 9th ed. uk: john wiley & sons; 2016:99.13-14. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(2):19 165 dermatology practical & conceptual introduction recurrent melanocytic nevus (rmn) is the name given to melanocytic lesions that grow after previous partial excision, usually by shaving. it presents a proliferation of melanocytes whose clinical aspect may be difficult to differentiate from melanoma, being therefore denominated pseudomelanoma [1]. case presentation a 6-year-old girl was referred for evaluation of a melanocytic lesion in the right lower limb, noted 5 months after a thirddegree burn in the same area and with progressive growth, according to a family member. clinical examination revealed a hyperchromic macula, with 2 cm in the largest diameter and presence of light and dark brown areas and irregular borders (figure 1). the dermoscopic features found were light brown and dark brown blotches, border asymmetry, and streaks at the periphery of the lesion (figure 2). confocal microscopy revealed single bright, nucleated cells of varying sizes and shapes in the suprabasal epidermis (figure 3). after 3 months, lesion growth was verified by means of comparative analysis of dermoscopy images (figure 4). we opted for excision of the lesion and the specimen was sent for histopathological analysis, which revealed hyperkeratosis traversed by well-defined melanin pigment columns, atypical melanocytic proliferation in the lower layers of the epidermis, and a cicatricial fibrosing inflammatory process occupying the reticular dermis. the histological picture was consistent with junctional rmn associated with extensive scarring (figure 5). no pagetoid migration of melanocytes or mitotic figures was observed. discussion many theories have been proposed to clarify the possible origin of rmn. among them, the proliferation of melanocytes in the adjacent epidermis, the proliferation of melanocytes from remnant adnexal structures, or the growth from residual intradermal melanocytic nevi are highlighted. it is known that 50% of recurrences are noted within 6 months of the surgical procedure. in a series of 80 cases studied by king et al., the recurrent nevus after burn injury raquel nardelli de araujo1, marcelle klein de araújo2, juan piñeiro-maceira1,3, carlos baptista barcaui1,3 1 department of dermatology, pedro ernesto university hospital, university of the state of rio de janeiro, rio de janeiro, brazil 2 ipanema federal hospital, rio de janeiro, brazil 3 dermatology, faculty of medical sciences, state university of rio de janeiro, brazil key words: recurrent nevus, burn injury citation: nardelli de araujo r, klein de araújo m, piñeiro-maceira j, baptista barcaui c. recurrent nevus after burn injury. dermatol pract concept. 2019;9(2):165-167. doi: https://doi.org/10.5826/dpc.0902a19 accepted: february 5, 2019; published: april 30, 2019 copyright: ©2019 nardelli de araujo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: raquel nardelli de araujo, md, department of dermatology, pedro ernesto university hospital, university of the state of rio de janeiro, boulevard 28 de setembro, 77. vila isabel, rio de janeiro rj, brazil, 20551-030. email: raquelnardelli@yahoo. com.br 166 letter | dermatol pract concept 2019;9(2):19 lesions seemed to be completely excised, which would suggest that the regrowth from residual nevus was unlikely [1]. in our case, no previous lesion in the right lower limb was referred before the burn injury. melanocytic lesions in large burns configure a challenge for dermatologists due to clinical and dermoscopic aspects. they can be classified clinically and histologically in reactive cicatricial pigmentation, recurrent nevus, incompletely excised melanoma, or metastatic melanoma [1,2]. no rmn descriptions were found in large burns. however, the authors emphasize that rmn should be remembered as a possibility due to tissue injury and scarring caused by burns. c o n s i d e r i n g t h a t m o r p h o l o g ical changes of pigmented lesions are described as significant predictors of malignancy, it has been suggested that rmn would be an exception to this rule, since the continuous clinical modifications may occur over time as evidenced in the case described. however, it does not increase the risk for melanoma development. as a general rule, in these cases the pigment will not extend beyond the scar and the majority remain stable for years [2]. figure 1. pigmented macula, with 2 cm in the largest diameter and with light and dark brown areas and irregular borders. [copyright: ©2019 nardelli de araujo et al.] figure 2. dermoscopy shows light brown and dark brown blotches, border asymmetry, and streaks in the periphery of the lesion. [copyright: ©2019 nardelli de araujo et al.] figure 3. confocal microscopy shows single bright, nucleated cells of varying sizes and shapes in the suprabasal epidermis. [copyright: ©2019 nardelli de araujo et al.] figure 4. dermoscopy performed 3 months after the first dermoscopy evaluation shows progressive enlargement beyond the burn scar with an increase in the irregular streaks. [copyright: ©2019 nardelli de araujo et al.] figure 5. histopathological analysis. atypical melanocytic proliferation in the lower layers of the epidermis and the intradermal component with a cicatricial inflammatory process (hematoxylin and eosin, ×200). [copyright: ©2019 nardelli de araujo et al.] letter | dermatol pract concept 2019;9(2):19 167 references 1. king r, hayzen ba, page rn, googe pb, zeagler d, mihm mc jr. recurrent nevus phenomenon: a clinicopathologic study of 357 cases and histologic comparison with melanoma with regression. mod pathol. 2009;22(5):611-617. 2. longo c, moscarella e, pepe p, et al. confocal microscopy of recurrent naevi and recurrent melanomas: a retrospective morphological study. br j dermatol. 2011;165(1):61-68. conclusions we emphasize the importance of clinical, dermoscopic, and histopathological evaluation of melanocytic lesions in large burns by dermatologists to avoid possible diagnostic errors and unnecessary interventions. untitled observation | dermatol pract concept 2015;5(2):13 75 dermatology practical & conceptual www.derm101.com introduction reactive perforating collagenosis (rpc) is the most common type of acquired perforating dermatoses (apd), [1] and is characterized by umbilicated papules and plaques with central crusted ulceration. pruritus is the most common symptom of rpc, and the lesions are most commonly found on the extensor surfaces of the extremities. this entity is histopathologically characterized by invagination of the epidermis and transepidermal elimination of collagen bundles. the pathogenesis of rpc is still somewhat unclear, but it has been reported that trauma resulting from scratching may induce damage to the epidermis or dermal collagen [1,2]. moreover, rpc is commonly found in association with chronic renal failure and diabetes mellitus. dermoscopy is a noninvasive technique that has been used in the diagnosis of apd [3], especially for perforating folliculitis (pf). however, to our knowledge, the dermoscopic features of rpc have not been previously described in the literature. here, we report the dermoscopic features and their histological correlations in rpc as a means to improve the diagnosis of this condition. case presentation a 46-year-old thai woman presented with a one-month history of multiple pruritic ulcerated papules and plaques with yellowish crust on the upper and lower extremities (figure 1). differential diagnoses included prurigo nodularis, perforating granuloma annulare, factitious disorder, and dermoscopic findings in a case of reactive perforating collagenosis payapvipapong kittisak1, masaru tanaka2 1 division of dermatology, department of medicine, phramongkutklao hospital, bangkok, thailand 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan key words: reactive perforating collagenosis, dermoscopy citation: kittisak p, tanaka m. dermoscopic findings in a case of reactive perforating collagenosis. dermatol pract concept 2015;5(2):13. doi: 10.5826/dpc.0502a13 received: december 15, 2014; accepted: february 4, 2015; published: april 30, 2015 copyright: ©2015 kittisak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors declare no conflict of interest. authorship: all authors have contributed significantly to this publication. corresponding author: masaru tanaka, md, phd, department of dermatology, tokyo women’s medical university medical center east, 2-1-10 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: tanaka.twmu@gmail.com figure 1a. multiple ulcerated papules and plaques with yellowish crust on the upper and lower extremities. [copyright: ©2015 kittisak et al.] 76 observation | dermatol pract concept 2015;5(2):13 non-ulcerating red papules and nodules as main features and factitious disorder would show more linearly or irregularly shaped lesions. however, dermoscopic features of these conditions were not previously reported. a biopsy from an ulcerated papule on the thigh showed perforation through the epidermis forming a tunnel filled with cellular debris, covered with scale-crust. thick collagen fibers were observed perforating through this tunnel. the area of perforation was not connected to the hair follicles. other acquired reactive perforating dermatosis. dermoscopy showed a yellowish-brown structureless area in the center, a whitish rim and pink-white structureless area, and hairpin vessels observed at the periphery (figure 2). she had several underlying diseases, including diabetes mellitus and chronic renal failure. she was on hemodialysis three times a week. a perforating disorder seemed to be the most probable because of these clinical and dermoscopic findings. prurigo nodularis and perforating granuloma annulare would show figure 1b. a close up photo of the lesion. [copyright: ©2015 kittisak et al.] figure 2. dermoscopy showing a yellowish-brown structureless area in the center and a white rim with an erythematous halo at the periphery of the lesion. [copyright: ©2015 kittisak et al.] figure 3. (a) cup–shaped ulceration with basophilic crust (hematoxylin and eosin, ×4). (c) perforation through the epidermis forming a tunnel filled with cellular debris, covered with scale-crust. thick collagen fibers were perforating through this tunnel (hematoxylin and eosin, ×10). (b, d) transepidermal elimination of the collagen bundles (masson-trichrome stain, ×4 and ×10). [copyright: ©2015 kittisak et al.] observation | dermatol pract concept 2015;5(2):13 77 [4]. although recent reports suggest that allopurinol might be a good therapeutic option for rpc in some patients, treatment of rpc is difficult and still no standard therapy is available [4-6]. the present case was treated with antihistamine and emollients and relieved the symptom. in the present case report, the dermoscopy-pathology correlations were evaluated in rpc (figure 4). the homogeneous yellowish-brown structureless area observed at the center of the lesion was found to correspond to the scalecrust; the whitish rim to the epidermal invagination, the thickness of which varied in some areas; and the pink-white halo seemed to correspond to a combination of small blood vessels surrounding the lesion. further, the hairpin vessels at the periphery corresponded to the irregular vessels in the papillary dermis at the periphery of the lesion. ramirez-fort et al. first described the dermoscopic feature of apd in 2013, and confirmed the diagnosis of pf by clinical and histopathological examinations [3]. the dermoscopic features described included bright white clods and a structureless gray area surrounded by brown reticular lines. although rpc is included in apd, the clinical, dermoscopic, and histological features are substantially different from those of pf. we speculate that the differences between apd and pf reported by ramirez-fort and those between rpc and pf reported herein are mainly owing to the different sizes of the lesion and due to the differences in ethnicity between the reported cases. in conclusion, the dermoscopic features of rpc include central yellowish-brown structureless areas and a whitish rim with a pinkish white halo, as well as some hairpin vessels at the periphery. these features seem to contribute to the diagnosis of rpc. references 1. kim sw, kim ms, lee jh, et al. a clinicopathologic study of thirty cases of acquired perforating dermatosis in korea. ann dermatol 2014;26(2):162-71. 2. wagner g, sachse mm. acquired reactive perforating dermatosis. j dtsch dermatol ges 2013;11(8):723-9. 3. ramirez-fort mk, khan f, rosendahl co, et al. acquired perforating dermatosis: a clinical and dermoscopic correlation. dermatol online j 2013;19(7):18958. 4. tilz h, becker jc, legat f, et al. allopurinol in the treatment of acquired reactive perforating collagenosis. an bras dermatol 2013;88(1):94-7. 5. rüger k, tebbe b, krengel s, et al. acquired reactive perforating dermatosis. successful treatment with allopurinol in 2 cases. hautarzt 1999;50(2):115–20. 6. karpouzis a, giatromanolaki a, sivridis e, kouskoukis c. acquired reactive perforating collagenosis: current status. j dermatol 2010;37(7):585–92. the dermis showed proliferation of small blood vessels and mild perivascular inflammatory cell infiltrate comprising lymphocytes and a few neutrophils (figure 3). masson-trichrome staining showed transepidermal elimination of the collagen bundles. based on these clinical and histological features, a diagnosis of rpc was established. conclusions the pathogenesis of rpc is still unknown but it has been hypothesized that inherited susceptibility, diabetic vasculopathy, and hypoxic conditions may be the predisposing factors figure 4. the homogeneous yellowish-brown structureless area at the center of the lesion corresponding to the scale-crust; the whitish ring-shaped rim to the epidermal invagination (ei), the thickness of which varied; and the pink-white halo seemed to correspond to a combination of small blood vessels surrounding the lesion. [copyright: ©2015 kittisak et al.] dermatology: practical and conceptual supplement | dermatol pract concept 2016;6(2):11 57 dermatology practical & conceptual www.derm101.com what follows are the abstracts presented at the joint meeting of the international confocal group (icg), the international dermoscopy society (ids), and the international society for digital imaging of the skin (isdis). the meeting was held on march 5, 2016, in washington, dc, usa, in conjunction with the annual meeting of the american academy of dermatology (figure 1). the abstracts appear in the order in which they were presented. low-cost smartphone confocal microscope dongkyun (dk) kang1 1 wellman center of photomedicine, massachusetts general hospital, boston, ma, usa spectrally encoded confocal microscopy (secm) is a highspeed reflectance confocal microscopy technology. secm utilizes a stationary optical element, a diffraction grating, and a broadband light source to illuminate a line on the tissue with multiple spectrally-encoded spots, which enables scan-less line confocal imaging. in order to conduct two-dimensional confocal imaging, however, secm still needs to use a beam scanning device or needs to mechanically translate the device. when a slit aperture is used, secm can image a rectangular area of the tissue with multiple spectrally-encoded lines, which enables two-dimensional confocal imaging without using any beam scanning devices. resulting confocal images are directly projected on a two-dimensional imaging sensor. this new approach, slit-secm, can uniquely enable development of a smartphone confocal microscope, in which an optics module is attached to a smartphone to conduct confocal imaging and the smartphone imaging sensor is used to acquire two-dimensional confocal images. due to its low cost, portability, and inherent network connectivity, smartphone confocal microscopy has a potential to provide an in vivo diagnostic tool in resource-poor countries and also to increase clinical adaptation of confocal imaging in developed countries. we present preliminary results of imaging human skin in vivo with slit-secm. we developed a slit-secm bench system with an inexpensive, battery-powered led ($25) and a low-cost color cmos sensor ($355). the bench system achieved lateral resolution of 1.3 µm and axial resolution of 6 µm. confocal images of human skin were acquired at the speed of 10 frames/sec. acquired confocal images clearly visualized characteristic cellular features of human skin down to the dermal-epidermal junction, including cell nuclei in spinous layer and dermal papilla. results from this preliminary study show feasibility of conducting skin confocal imaging using inexpensive optical and electrical components and suggest that slit-secm may be developed into a low-cost smartphone confocal microscope. melanocytic hyperplasia – so what? lilian rocha1, pascale guitera2,3 1 department of dermatology, medical school, university of são paulo, são paulo, brazil 2 melanoma institute australia, the university of sydney, sydney, australia abstracts from the 2016 joint meeting of the international confocal group (icg), the international dermoscopy society (ids), and the international society for digital imaging of the skin (isdis) citation: abstracts from the 2016 joint meeting of the international confocal group (icg), the international dermoscopy society (ids), and the international society for digital imaging of the skin (isdis). dermatol pract concept 2016;6(2):11. doi: 10.5826/dpc.0602a11 copyright: ©2016 dermatology practical & conceptual. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 58 supplement | dermatol pract concept 2016;6(2):11 not be retrieved. there was a significant female predominance (25 cases) and mainly located on upper face (front, peri-oricular and scalp) and lower face (cheeks, peri-oral and chin). the most frequent dermoscopic feature was asymmetric hyperpigmented follicular opening and on rcm most cases showed <5 atypical cells in 3 fields and mild cellular pleomorphism. we discuss correlation with pathology and outcomes. new developments in rcm of skin: imaging-guided ablation, computational modeling of dej morphologic patterns, integration with widefield imaging heidy sierra1, kivanc kose1, gary peterson1, milind rajadhyaksha1, alican bozkurt2, setareh ariafar2, jennifer dy2, dana brooks2, david dickensheets3 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 2 northeastern university, cdsp center, ece department, boston, ma, usa 3 department of electrical and computer engineering, montana state university bozeman, mt, usa 3 sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, australia the differentiation of melanocytic hyperplasia in severe sundamaged skin (mh) from early stages of lentigo maligna (elm) may be very difficult. some histopathologic criteria have been proposed helping to classify lesions as malignant or not. but, more distinctive changes of melanoma may not occur for years (pagetoid cells, adnexal spreading, formation of nests of melanocytes and descent of neoplastic cells into the dermis). the exact threshold for malignancy is still controversial and so the management of these lesions remain discussed. we retrospectively evaluated consecutive cases of pigmented lesions with pathology report as mh or elm from the confocal databases of the main melanoma centre of sydney, australia from 2005 and 2015. only cases with > 1 year follow up and recorded dermoscopic and rcm images were reviewed. we reviewed 11 histopathologic features that were correlated to 13 rcm features and sensitivity and specificity for each rcm criterion were studied. we also analysed the dermoscopic features of each lesion using previously described criteria for lm. 51 cases were retrieved in this period. 40 cases had > 1 year follow up but in 3 cases the dermoscopic images could figure 1. agenda of the joint meeting of the icg / ids / isds, 2016. [copyright: ©2016 dermatol pract concept.] supplement | dermatol pract concept 2016;6(2):11 59 recent advances in microbiopsy technology and the future of dermoscopy-guided microbiopsy. principles of inflammatory dermoscopy dimitrios ioannides1, aimilios lallas1 1 first department of dermatology, aristotle university, thessaloniki, greece although traditionally used for evaluation of skin tumors, dermoscopy continuously gains appreciation in other fields of dermatology. the dermoscopic patterns of several inflammatory and infectious skin diseases have already been described, and the technique has been shown to improve clinical performance in terms of differential diagnosis in the daily practice. the increasing use of dermoscopy in general dermatology was significantly enhanced by the development of the new generation hand-held dermatoscopes, which can be easily placed in every dermatologist’s pocket and do not require use of immersion fluid. four main categories of dermoscopic criteria should be considered when applying the technique in inflammatory diseases: 1) vascular features, including purpuric structures (morphology distribution); 2) color variegations; 3) follicular abnormalities and 4) specific features. nowadays, the dermatoscope should not be regarded a second-level diagnostic equipment, but an irreplaceable diagnostic tool in every-day clinical setting, similarly to the stethoscope in general medicine. we provide an up-to-date summary of data on dermoscopy in general dermatology, attempting to assist clinicians to profitably utilize and apply the available knowledge in the everyday practice. management of surgical margins of basal cell carcinoma using high frequency ultrasound a. freites-martinez1, p. pasquali2, a. fortuño-mar3 1 university hospital of fuenlabrada, dermatology, madrid, spain 2 pius hospital de valls, department of dermatology, tarragona, spain 3 eldine pathology laboratory, pathology, tarragona, spain introduction & objectives: high frequency ultrasound (hfus) is a non-invasive technique that allows visualizing skin tumors in vivo to obtain size, shape and tumor volume. in this study, we sought to measure the correlation between ex vivo hfus and histopathology surgical margins of basal cell carcinoma. material & methods: this was a prospective, single-blinded study. all patients had been sent for tumor excision. hfus reflectance confocal microscopy (rcm) has advanced from merely a research tool for diagnosis of skin cancer to being used in the clinic to guide patient care. here we present three technology solutions that will further impact clinical advances: an rcm imaging guided-laser ablation approach has been developed for treatment of basal cell carcinomas (bccs). initial testing in 48 lesions using an er:yag or an co2 lasers shows feasibility on patients. twenty of the lesions, assessed with post-ablation histopathology, show 85% agreement with rcm imaging for detection of residual or clearance of bccs. tumor clearance of the remaining 28 lesions has been confirmed with imaging and these are currently being followed-up with additional imaging. an image analysis based automated tool for quantitative analysis of rcm mosaics of melanocytic lesions collected is being developed. the method can distinguish patterns, at dermal-epidermal junction level, of benign (ring, meshwork, clod) from non-specific (potentially malignant) and background non-lesional skin using their textural appearance. preliminary analysis on 20 rcm mosaics shows classification with 80-67% sensitivity and 99-78% specificity in distinguishing these patterns. an innovative solution has been developed, that integrates a miniature color camera into the objective lens of our microscope, providing simultaneous widefield dermoscopy images of the skin surface and rcm images of the subsurface cellular structure. initial in vivo testing on 15 volunteers shows feasibility of the approach. advances in dermoscopy-guided microbiopsy for biomarker analysis tarl w. prow1, van hoang1, lynlee lin1, jean-marie tan1, mitch s. stark1, h. peter soyer1 1 dermatology research centre, the university of queensland, school of medicine, translational research institute, brisbane, australia the refining of clinico-pathologic correlation using dermoscopy by scope et al in the area of dermatology has led to “a plea for a combined diagnostic approach of histopathologic and dermoscopic evaluation of melanocytic lesions”. integration between dermoscopy and histology was only effective in a limited number of scientific works despite its promising premise. we propose that a sub-millimetre skin biopsy device known as the microbiopsy for minimally invasive and suture-free skin sampling for molecular diagnosis be used for this purpose. to this end we are integrating microbiopsy based sampling into dermoscopy to enable dermoscopy guided microbiopsy for molecular diagnosis. we discuss our 60 supplement | dermatol pract concept 2016;6(2):11 publications to date that are in press and/or under review. it is hoped that the efforts of the working groups will serve as the basis for convening a successful dicom process for dermatologic imaging with an initial focus on melanoma. the isic archive: current efforts in melanoma education and automated diagnosis typically rely on convenience samples of small numbers of images that vary in quality and annotation. the isic archive is a partnership of leading international melanoma centers to provide a large public repository of clinically annotated high quality skin images. the isic archive software is open source and the images in the archive are publicly available through a creative commons zero license (cc0). the individual lesion images in the archive are annotated with clinical (e.g., pathology diagnosis) and technical (e.g., exif header content) attributes. in addition, a process has been developed to append morphologic annotations to the images at the lesion level (e.g., symmetry) and at the sub-lesion level (e.g., the presence of pigment network in a specific region within a lesion). the initial focus of the archive and annotations has been on dermoscopic images, as these are most diagnostic for melanoma. the archive has been selected for an ongoing 2016-2017 image analysis challenge (for automated lesion segmentation and classification) by the international symposium of biomedical imaging. ohsu/apple mole mapper researchkit project sancy leachman1, dan webster1 1 department of dermatology, oregon health and science university, portland, or, usa mobile technologies are revolutionizing medicine. smart phones are being leveraged by the ‘quantified self’ movement and major health systems to empower individuals to take a bigger and more direct role in their own health and medical care. skin cancer is no exception. there is an ongoing proliferation of apps to educate and assist the public in skin cancer recognition. in october 2015, oregon health & science university released an iphone app “mole mapper” designed to advance melanoma research by giving users the ability to accurately measure and monitor moles, and contribute photos of the evolution of their moles over time to apple’s open source ‘researchkit’. sage bionetworks, a nonprofit research institute is a key partner in managing and analyzing the melanoma data and images for this project. in this presentation, drs. leachman and webster provide a brief overview of the current state of consumer apps for melanoma detection and the progress of the researchkit melanoma project. was performed with a 22 mhz ultrasound (taberna promedicum, lüneburg, germany®) before and immediately after excision to determine length and depth. tumor measurements and surgical margins (sm) were evaluated. sm were established by observing echogenicity differences and tumor shape. the pathologist was blinded to hfus measurements and sm. results: a total of 79 basal cell carcinoma (bcc) (56 nodular, 15 superficial and 8 with more than one histological subtype) were included. out of 79 bcc, 76 (96.2%) had a correspondence between ex vivo hfus and histology (72 had negative and 4 had positive sm by ex vivo hfus and histology). of the remaining 3 tumors, one had uncertain and 2 had negative sm by ex vivo hfus while positive sm by histology. in this study, ex vivo hfus allowed correct visualization of negative sm in 72/79 bcc (91.1%). conclusions: other non invasive techniques such as dermoscopy and confocal microscopy allow an accurate diagnosis in most bcc cases. however, the information related to depth and tumor volume is limited. hfus devices are portable and give extra valuable information for bcc surgical management. future studies are needed to compare ex vivo hfus with other non-invasive technique such optical coherence tomography and confocal microscopy. international skin imaging collaboration (isic) update allan halpern1 1 dermatology service, memorial sloan kettering cancer center, new york, new york, usa overview: the international skin imaging collaboration is an academia/industry partnership designed to facilitate the application of digital skin imaging to help reduce melanoma mortality. the mobile era presents an exciting opportunity for the application of digital photography as an aid to early diagnosis of melanoma. isic is designed to address two barriers to the broad successful implementation of mobile solutions for melanoma diagnosis: a lack of standards for dermatologic imaging, and limited access of educators and developers to large numbers of high quality clinically annotated skin lesion images. standards: there are currently no dicom standards for dermatologic imaging. through the efforts of 5 working groups comprised of international melanoma thought leaders from academia and industry we are using the delphi method to propose standards related to 5 areas of skin cancer imaging: technology, terminology, techniques, privacy, and metadata. the working groups have prepared several http://www.apple.com/researchkit/ dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review of atlas of vulvar pathology. 3rd ed. by ej wilkinson, ik stone françois milette1 1 centre hospitalier pierre-boucher, longueuil, canada citation: milette f. review of atlas of vulvar pathology. 3rd ed. by ej wilkinson, ik stone. dermatol pract concept. 2014;4(2): 17. http:// dx.doi.org/10.5826/dpc.0402a17 copyright: ©2014 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: françois milette m.d., centre hospitalier pierre-boucher, longueuil, canada. email: francois.milette@cssspb.qc.ca review by françois milette this atlas of vulvar disease (sic) is the result of a collaboration between a gynecologist and a pathologist who benefited from the advice of a colleague, dr. ann church, dermatologist and dermatopathologist. the difficulties inherent to the dialogue between clinicians and pathologists are apparent in that two different classifications of the diseases discussed in the book are given: “one which the reader can search under specific disease headings and another in which the clinical presentation is the guide,” as stated in the preface. the second classification based on clinical presentation is the one on which the structure of the whole book is based. it includes the following categories, a chapter being devoted to each successively: (1) cysts; (2) maculae; (3) papillae; (4) papules; (5) plaques; (6) tumors, benign; (7) ulcers; (8) verrucae; (9) vesicles/bullae; (10) pediatrics; (11) trauma; (12) tumors, malignant; and (13) vulvodynia and vestibulodynia. the logic of this classification is certainly questionable, as the various categories are neither exclusive nor complete. moreover, lesions are distributed in these various categories and chapters in a bizarre and completely arbitrary manner. malignant melanoma, for instance, is classified in the chapter about papules and not in the chapter on malignant tumors. a melanoma certainly can present as a papular lesion, but it can also occur as a macule, a plaque or an ulcer and it certainly is a malignant tumor. another evident flaw in this classification is exemplified by verrucous carcinoma, which is addressed book review | dermatol pract concept 2014;4(2):17 81 figure 1. wilkinson ej, stone ik atlas of vulvar pathology. 3rd ed. philadelphia: lippincott williams & wilkins, 2012. isbn: 1451132182. 274 pages. list price: $164.99. in the chapter on verrucae as if it were not the malignant neoplasm that it is. the “specific disease headings” referred to in the preface are dispersed almost randomly throughout the book. moreover, this histologic classification, although purportedly referring to specific headings, is presented as only a “crossreference” to the clinical presentation classification and it, too, is flawed (for example, lichen planus is classified as a “non-neoplastic epithelial disorders” and not as the noninfectious inflammatory disorder that it is). this having been said concerning the general organization of this book, if one can overcome the reservations induced by the limitations apparent in the table of contents, one will discover a very good chapter devoted to the anatomy, macroscopic and microscopic, of the vulva and to a practical discussion of the general approach to vulvar problems. following this introduction to vulvar problems, the following chapters, enumerated earlier, are each introduced by an algorithm, the algorithmic nature of which is not always evident. for instance, the ulcer algorithm on page 121 is only a list of confirmatory tests of presumed diagnoses and not, as one would expect, a tool for evaluation of a vulvar ulcer (figure 2). following the algorithm, each chapter presents various lesions that are discussed in a constant and well-structured succession of paragraphs devoted to: (1) definition; (2) general features; (3) clinical presentation; (4) adjunctive studies; (5) differential diagnosis; (6) microscopic features; (7) clinical behavior and treatment; and (8) progressive therapeutic options. 82 book review | dermatol pract concept 2014;4(2):17 figure 2. ulcer algorithm, page 121, atlas of vulvar pathology. as a pathologist, i was somewhat deceived by the relatively superficial treatment of histology. in the discussion of psoriasis, for instance, the stereotypical histopathology of the disease is presented and little attention is given to the fact that vulvar psoriasis is most often not stereotypical histologically and therefore is often difficult to diagnose. this may lead to a false impression of facility in the mind of the student. some definitions given in this book are questionable. for example, seborrhea (seborrheic dermatitis) is as a chronic inflammatory disease associated with a characteristic distribution in areas of sebum production, particularly the face and scalp defined (page 90). in fact, the microscopic description on page 100 is a much better definition: seborrheic dermatitis is a spongiotic dermatitis affecting the hair follicle. seborrheic dermatitis has nothing to do with sebum production and the term seborrheic is a misnomer in the context of this dermatitis. therefore the legend to figure 6.24: “note the loss of pubic hair related to excess sebum production,” states a falsity. the therapeutic options are presented in a progressive way, thus aiding a student and the patient to plan therapy adapted to the severity of the clinical condition. last, i must add a word concerning the images in this book. the quality of the clinical photographs are excellent and in fact much better than that of the microphotographs. this is probably because the authors are primarily clinicians. do you like atlases? personally, i have often been deceived by atlases and have concluded that they are more useful to their authors than to their readers. the present book is no exception. nevertheless it certainly has value either as an introduction to vulvar diseases for residents in gynecology, dermatology or pathology or as a synthetic review of vulvar pathology for the practicing clinician or pathologist. untitled observation | dermatol pract concept 2015;5(4):12 47 dermatology practical & conceptual www.derm101.com case report a 57-year-old man with a history of melanoma, two basal cell carcinomas (bcc) and several dysplastic nevi presented for a routine skin check. the patient had an asymptomatic pigmented lesion on the left side of his back that he had not noticed before (figure 1), measuring 0.6 cm in diameter with a flat and smooth surface, irregular borders and different colors. the suspected clinical diagnosis was melanoma and a dysplastic nevus. under dermoscopic examination (figure 2) we could identify three different parts in the lesion. on the left side, there was an atypical pigment network and some globules. in the central area, we found an intensification of the pigment network, which looked darker brown. on the right side of dermoscopic findings in a collision tumor composed of a dermatofibroma and a melanocytic nevus mimicking melanoma carolina marcucci1, emilia cohen sabban2, paula friedman1, rosario peralta1, ricardo sánchez marull3, horacio cabo2 1 dermatology, buenos aires, argentina 2 dermatology section, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina 3 dermatopathology, buenos aires, argentina key words: dermoscopy, collision tumor citation: marcucci c, cohen sabban e, friedman p, peralta r, sánchez marull r, cabo h. dermoscopic findings in a collision tumor composed of a dermatofibroma and a melanocytic nevus mimicking melanoma. dermatol pract concept 2015;5(4):12. doi: 10.5826/ dpc.0504a12 received: april 15, 2015; accepted: july 13, 2015; published: october 31, 2015 copyright: ©2015 marcucci et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: carolina marcucci, md, 72 ambrosetti st., buenos aires, argentina. tel. 0541149021487. email: caromarcucci@ hotmail.com collision tumors consist of two different neoplasms occurring concurrently in the same lesion. this association has been described for both benign and malignant neoplasms that may be difficult to identify. therefore, dermoscopy is a valuable tool to make a correct diagnosis. we report a very unusual collision tumor composed of both a dermatofibroma and a melanocytic nevus mimicking melanoma. abstract figure 1. pigmented 0.6 cm diameter lesion, with irregular borders and different colors, located in the back of a 57-year-old male patient. [copyright: ©2015 marcucci et al.] mailto:caromarcucci@hotmail.com mailto:caromarcucci@hotmail.com 48 observation | dermatol pract concept 2015;5(4):12 comments the coexistence of two different neoplasms in the same biopsy specimen is defined as a collision tumor. this entity has been widely reported in the literature, and a bcc and an sk (seborrheic keratosis) [1,2] is the most common combination. in general, the association between the two lesions is fortuitous, although some of them may involve related cell types [3]. the clinical diagnosis of a collision tumor is extremely difficult to make. in these cases, dermoscopy becomes a necessary and useful tool to identify different structures and then make a correct diagnosis [4]. pigment network and globules are two criteria of melanocytic lesions. in the case we presented, we could find these two features both on the left side and the central area of the lesion. we believe that this correlated to the melanocytic part of the lesion (left side) and also to the area where the nevus and the dermatofibroma overlapped. white shiny structures were also noticed in our patient. these structures can be observed in a large variety of entities, such as in df, spitz nevus, melanoma, bcc and scars [5]. in our patient, we could see multiple white shiny structures on a pink the lesion, we found a pink-colored area with multiple white shiny structures. considering that this was a suspicious lesion in a high-risk patient, the lesion was excised and histopathology confirmed the presence of two different contiguous neoplasms: a melanocytic nevus with mild dysplasia (left side of the lesion) and fusocellular proliferation (right side of the lesion) (figure 3). the immunohistochemical stains were negative for hmb 45, melan a and smooth muscle actin (figure 4). a diagnosis of dermatofibroma (df) was made. figure 2. dermoscopic examination of the lesion showing the following features: an atypical pigment network (black stars), globules (red star), darker brown atypical pigmented network (black line area), and white shiny structures (black arrow) in a pink background (dotted line area). original magnification x 10. [copyright: ©2015 marcucci et al.] figure 3. melanocytic nevus with mild dysplasia (left side of the lesion) and fusocellular proliferation (right side of the lesion). hematoxylin & eosin x 4. [copyright: ©2015 marcucci et al.] figure 4. the immunohistochemical stains were negative for hmb 45, melan a and smooth muscle actin were negative. [copyright: ©2015 marcucci et al.] observation | dermatol pract concept 2015;5(4):12 49 2. cabo h, cohen sabban e. combined lesions. in: cabo h. dermatoscopía, 2nd edition, buenos aires; ediciones journal, 2012:30915. 3. martorell a, botella-estrada r, nagore e, guillen-barona c. dermoscopic features of a collision tumour composed of a pigmented basal cell carcinoma and a melanoma. j eur acad dermatol venearol. 2010;24:974-85. 4. álvarez-cuesta c, vázquez-lópez f, pérez-oliva n. dermatoscopy in the diagnosis of cutaneous collision tumour. clin exper dermatol. 2004;29:196–205. 5. ferrari a, argenziano g, buccini p, et al. typical and atypical dermoscopic presentations of dermatofibroma. j eur acad dermatol venearol. 2013;27:1375-80. background on the right side of the lesion, which corresponded to the df. identifying a collision tumor may be challenging for dermatologists. we described a case of a very unusual collision tumor composed of df and a dysplastic nevus. as in our experience, the importance of recognizing these cases relies not only on ruling out a melanoma, but also avoiding misdiagnosing a melanoma. references 1. de giorgi v, massi d, sestini s, et al. cutaneous collision tumour (melanocytic naevus, basal cell carcinoma, seborrhoeic keratosis): a clinical, dermoscopic and pathological case report. br j dermatol. 2005;152:787–90. untitled review | dermatol pract concept 2015;5(3):9 35 dermatology practical & conceptual www.derm101.com zosteriform impetigo: wolf’s isotopic response in a cutaneous immunocompromised district philip r. cohen1 1 department of dermatology, university of california san diego, ca, usa key words: cutaneous, dermatome, dermatomal, district, herpes, immunocompromised, impetigo, infection, isotopic, response, skin, staphylococcal, staphylococcus aureus, wolf, zoster, zosteriform citation: cohen pr. zosteriform impetigo: wolf’s isotopic response in a cutaneous immunocompromised district. dermatol pract concept 2015;5(3):9. doi: 10.5826/dpc.0503a09 received: april 26, 2015; accepted: may 5, 2015; published: july 31, 2015 copyright: ©2015 cohen. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: impetigo can result from staphylococcus aureus (s. aureus). wolf’s isotopic response is the occurrence of a new cutaneous disorder at the site of a previously healed disease. a cutaneous immunocompromised district is an area of skin that is more vulnerable than the rest of the individual’s body. purpose: to describe a man with impetigo localized to a unilateral dermatome and review the clinical features of other patients with zosteriform staphylococcus aureus cutaneous infection. methods: pubmed was used to search the following terms, separately and in combination: cutaneous, dermatome, dermatomal, district, herpes, immunocompromised, impetigo, infection, isotopic, response, skin, staphylococcal, staphylococcus aureus, wolf, zoster, zosteriform. all papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. results: crusted, eroded and intact, erythematous papules and nodules acutely presented localized to the mandibular branch of the left trigeminal nerve on the face of a 66-year-old man; he did not recall a prior episode of varicella-zoster virus infection in that area. a bacterial culture isolated methicillinsusceptible s. aureus. viral cultures and direct fluorescent absorption studies were negative for herpes simplex and herpes zoster virus. all of the lesions resolved after oral treatment with cefdinir. impetigo and/or furunculosis in a zosteriform distribution have also been described in 3 additional patients. the bacterial culture showed either methicillin-susceptible or methicillin-resistant s. aureus; the skin infection resolved after treatment with oral antibiotics; however one man experienced 2 recurrences in the same area. conclusions: zosteriform cutaneous staphylococcal impetigo may be an example of wolf’s isotopic response in a cutaneous immunocompromised district abstract 36 review | dermatol pract concept 2015;5(3):9 discussion non-bullous impetigo is caused by either s. aureus or streptococcus pyogenes. it typically presents as a superficial ulcer covered by a purulent exudate that dries into an adherent yellow to honey-colored crust. lesions are frequently found introduction impetigo is a bacterial infection that can be caused by staphylococcus aureus (s. aureus) [1]. herpes zoster is a viral infection caused by varicella-zoster virus [2]. occasionally, non-viral conditions—including bacterial infections—can morphologically mimic herpes zoster by presenting with skin lesions in a dermatomal distribution [3]. a man who presented with zosteriform facial skin lesions of impetigo is described and the clinical features of previously reported patients with dermatomal s. aureus infection are summarized. case report a 66-year-old healthy afebrile man presented for evaluation of skin lesions that had developed on the left side of his face. his cutaneous past medical history was remarkable for cryotherapy-treated actinic keratoses, excision of two basal cell carcinomas (on the left chest in 2004 and the right cheek in 2009), and genital herpes simplex virus type 2 infection. he had chicken pox as a child and no episode of herpes zoster; he had received the varicella vaccine 2 years ago. a week earlier, he noticed that facial skin lesions began to appear. initially the site was pruritic and then a crust would develop; there were no blisters. the lesions were first noted on the left side of his chin; subsequently, they developed on his left cheek and left neck, near his jaw. based on the distribution and morphology of his skin lesions, his wife diagnosed him to have a shingles. cutaneous examination showed crusted, eroded and intact, erythematous papules and nodules—ranging in size from 3 to 5 mm in diameter—restricted to only the left side of his face. there were about 12 lesions. they were located on his chin, cheek, and neck in a distribution that corresponded to the third division of the fifth cranial nerve (figure 1). the unilateral and dermatome location of the skin lesions raised the possibility of herpes zoster. however, the appearance of the individual crusted erosions was consistent with impetigo. additional laboratory studies were performed and he was empirically treated for both herpes zoster (with 1 gram of oral valacyclovir three times daily for 10 days) and impetigo (with 300 mg of oral cefdinir twice daily for 10 days and topical mupirocin 2% ointment three times daily for 10 days). all of the facial skin lesions resolved within 1 week; no residual crusts were present at his 1-month follow up examination. a tzanck smear taken from one of the lesions at presentation was negative for multinucleated epidermal giant cells. in addition, not only the direct fluorescent absorption studies, but also the viral cultures were negative for both herpes zoster virus and herpes simplex virus. the bacterial culture from a crusted erosion was positive for methicillin susceptible s. aureus; the bacteria was also susceptible to cefazolin. figure 1 (a, b, and c). distant (a) and closer (b and c) views of zosteriform impetigo located on facial skin innervated by the mandibular branch of the left trigeminal nerve; the lesion appear as crusted, eroded and intact, erythematous papules and nodules on the left side of the chin (b) and neck (c). [copyright: ©2015 cohen. a b c review | dermatol pract concept 2015;5(3):9 37 zoster virus infections. these not only include fungal and other viral infections, but also acneiform lesions, dysimmune reactions, granulomatous reactions, leukemia and lymphomatous infiltrates, malignant tumors and other conditions [3,11,12]. bacterial infections, such as furunculosis and s. aureus-associated nonbullous impetigo have each only been observed in 4 individuals (table 1) [3,10-13]. a cutaneous immunocompromised district is an area of skin that—for either genetic or acquired reasons—is more vulnerable than the rest of the individual’s body. this vulnerable site often facilitates the onset of skin disorders or immunity-related eruptions at that area because of the local dysregulation of immune control. the immunocompromised district in dermatology is a designation that is intended to include all possible etiologies potentially involved in a local immune destabilization of the affected area of mucosa or skin [20,21]. zosteriform impetigo is favored to represent wolf’s postherpetic isotopic response in a cutaneous immunocompromised district [3,8,11,12]. the absence of a definitive history of preceding varicella-zoster virus infection in 75 percent of the individuals (3 of the 4 patients) may reflect a prior subclinical varicella-zoster virus infection, such as an episode of asymptomatic zoster sine herpete [7,8]. alternatively, and often similar in presentation with a dermatomal distribution, is the possibility of a blascho linear arrangement due to skin mosaicism [22]. conclusion impetigo and herpes zoster are common bacterial and viral infections, respectively. concurrent s. aureus infection or impetinization of varicella-zoster virus infectious skin lesions may occur; however, cultures of the skin lesions are typically positive for both bacteria and virus. however, similar to the described patient, the skin lesions of zosteriform impetigo are only culture positive for s. aureus; viral studies—including tzanck smear, culture, direct fluorescent absorption, and polymerase chain reaction—are negative. wolf’s isotopic postherpetic response in a cutaneous immunocompromised district is not uncommon; however, bacterial infection is seldom reported in this setting. some of individuals with zosteriform cutaneous staphylococcal infections did not recall a prior herpes zoster infection at that site raising the possibility that they had previously experienced an episode of asymptomatic zoster sine herpete. similar to non-dermatomal s. aureus infection, zosteriform impetigo promptly responded to antibiotics to which the bacteria are susceptible. on the face and extremities. satellite lesions are common, resulting from self-inoculation [1,4-6]. herpes zoster occurs when there is reactivation of a latent varicella-zoster infection. skin lesions typically present as unilateral, erythematous-based vesicles in a dermatomal distribution. less commonly, disseminated herpes zoster can present as multiple, widely distributed, individual vesicles—with or without—associated dermatomal skin involvement. in addition to a positive viral culture for varicella-zoster virus, bacterial culture can concurrently be positive for s. aureus when the vesicular, ulcerated or crusted lesions become colonized or secondarily infected by the bacterial organism [2,7-9]. zosteriform impetigo represents the development of nonbullous impetigo, to date caused by s. aureus infection, in which the cutaneous lesions appear in a dermatomal distribution. varicella-zoster virus is absent from the bacterial skin lesions. in addition to the reported patient, zosteriform s. aureus cutaneous infection has been described in 3 other individuals (table 1) [3,10-13]; however, one might speculate that zosteriform cutaneous staphylococcal infection is probably more common than the paucity of reported individuals would suggest. there were 3 men and 1 girl; the latter was 17 years old. the men ranged in age from 63 to 76 years; the median age was 66 years. dermatomes were affected equally on the right and left side of the body; two of the men had involvement of the same area: the facial skin innervated by the mandibular branch of the trigeminal nerve. the infection presented with clinical features of furunculosis (2 patients), impetigo (1 patient) or both (1 patient). bacterial cultures of the skin lesion were positive for either methicillin-susceptible (2 patients) or methicillin-resistant (1 patient) s. aureus [14]. viral culture, at this time of s. aureus infection, was negative for varicella-zoster virus; in addition, 3 of the 4 patients did not have a history of clinically significant herpes zoster (either in the affected area or elsewhere on their body). the bacterial infection was successfully treated with oral antibiotic in all patients; however one man experienced 2 recurrences in the same area. wolf’s isotopic response designates the occurrence of a new cutaneous disorder at the location of a previously healed skin disease [15]. it was originally termed “isoloci response” by wolf and wolf in 1985 [16]. a decade later, ruocco suggested changing the name to “isotopic response” [10,17,18]. however, since the latter designation generated hundreds of references linked with radioactive isotopes during computerobtained literature searches, it was subsequently changed to “wolf’s isotopic response” [19]. several types of postherpetic isotopic responses have been observed following either herpes simplex virus or varicella38 review | dermatol pract concept 2015;5(3):9 3. ruocco v, ruocco e, ghersetich i, bianchi b, lotti t. isotopic response after herpesvirus infection: an update. j am acad dermatol 2002;46:90-94. [pmid = 11756952] 4. hartman-adams h, banvard c, juckett g. impetigo: diagnosis and treatment. am fam physician 2014;90:229-235. [pmid = 25250996] references 1. darmstadt gl, lane at. impetigo: an overview. pediatr dermatol 1994;11:293-303. [pmid = 7899177] 2. kawai k, gebremeskel bg, acosta cj. systematic review of incidience and complications of herpes zoster: towards a global perspective. bmj open 2014;4:e004833. [pmid = 24916088] table 1. characteristics of patients with zosteriform cutaneous staphylococcal infections [a,b] c a ra s location morphology cp bact cult vc prior vzv other conditions tx ref 1 17 w f breast, upper flank, & back r t4 multiple erythematous pustules, papules, & nodules i & f mrsa men 2b metastatic medullary thyroid cancer [c] 13c2 2 63 w m abdomen r t11 tender red nodules x 3 with intact, ulcerated, and pustular centers f mssa scc: l temple [d] 13c1 3 66 w m face l cnv-3 12 crusted, eroded & intact, red papules & nodules i mssa ak bcc x 2: r cheek & l chest hsv 2: genital [e] cr 4 76 nd m face l cnv-3 furuncles [f] f nd nd + [f] colon carcinoma [f] [f] 10 [a] abbreviations: a, age (in years); ak, actinic keratosis; bact cult, bacterial culture; bcc, basal cell carcinoma; c, case; cnv-3, third division (mandibular branch) of fifth cranial (trigeminal) nerve dermatome; cp, clinical presentation; cr, current report; f, furunculosis; hsv 2, herpes simplex virus, type 2 infection; i, impetigo; l, left; men 2b, multiple endocrine neoplasia, type 2b (also known as either mucosal neuroma syndrome or multiple endocrine adenomatosis, type 2b; an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities); mrsa; methicillin-resistant staphylococcus aureus; mssa, methicillin susceptible staphylococcus aureus; nd, not done; r, right; ra, race; ref, references; s, sex; scc, squamous cell carcinoma; t, thoracic dermatome; tmp/smx ds, trimethoprim/sulfamethoxazole double strength; tx, treatment; vc, viral culture (for vzv); vzv, varicella-zoster virus infection (herpes zoster); &, and; -, negative or none, + positive, %, percent. [b] furunculosis has been reported as a postherpetic isotopic response in 3 individuals; however, for 2 of the people, it is not definitively defined whether the herpetic infection was caused by herpes simplex virus or varicella-zoster virus in each of these individuals [5,10,11,12]. [c] treatment included oral tmp/smx ds twice daily for 15 days; topical therapy included cleaning with povodine iodine (betadine) 10% cleanser and mupirocin 2% ointment 3 times daily to lesions, nostrils and umbilicus. [d] treatment included oral tmp/smx ds twice daily for 4 weeks; topical therapy included cleaning with chlorhexidine (hibiclens) 4% solution and mupirocin 2% ointment 3 times daily to lesions and nostrils. [e] treatment included oral cefdinir 300 mg twice daily for 10 days; topical therapy included mupirocin 2% ointment 3 times daily to lesions. [f ] the diagnosis of colon cancer occurred at the same time as his initial episode of herpes zoster. the herpes zoster virus infection occurred 1 month prior to his zosteriform furunculosis and presented as numerous small, solitary and grouped vesicles that were successfully treated with oral acyclovir 800 mg 5 times daily. he had 3 episodes of zosteriform furunculosis; the second and third episodes occurred 2 months and 5 months after the initial episode. each episode was confined to the same area of his face and the “furuncles were not arranged in groups, thus a recurrent herpes simplex could easily be excluded clinically.” the initial and second episodes were each treated with oral cefaclor 500 mg twice daily for 5 days. review | dermatol pract concept 2015;5(3):9 39 14. cohen pr. community-acquired methicillin-resistant staphylococcus aureus skin infections: a review of epidemiology, clinical features, management, and prevention. int j dermatol 2007;46:111. [pmid = 17214713] 15. wolf r, wolf d, ruocco v, ruocco e. wolf’s isotopic response: the first attempt to introduce the concept of vulnerable areas in dermatology. clin dermatol 2014;12:557-560. [pmid = 25160096] 16. wolf r, wolf d. tinea in a site of healed herpes zoster (isoloci response?) [letter]. int j dermatol 1985;24:539. [pmid = 4066096] 17. wolf r, ruocco v, filioli fg. isotopic response [letter]. br j dermatol 1997;136:466-467. [pmid = 9115937]. 18. wolf r, lotti t, ruocco v. isomorphic versus isotopic response: data and hypotheses. j eur acad dermatol venereol 2003;17:123125. [pmid = 12705738] 19. wolf r, wolf d, ruocco e, brunetti g, ruocco v. wolf’s isotopic response. clin dermatol 2011;29:237-240. [pmid = 21396564] 20. ruocco v. the immunocompromised district: how the pieces of the puzzle gradually fell into place [commentary]. clin dermatol 2014;32:549-552. [pmid = 25160094] 21. ruocco v, ruocco e, piccolo v, et al. the immunocomporomised district in dermatology: a unifying pathogenic view of the regional immune dysregulation. clin dermatol 2014;32:569-576. [pmid = 25160098] 22. ruocco v, ruocco e, brunetti g, saniuliano s, wolf r. opportunistic localization of skin lesions on vulnerable areas. clin dermatol 2011;29:483-488. [pmid = 21855722] 5. pereira lb. impetigo-review. an bras dermatol 2014;89:293-299. [pmid = 24770507] 6. bangert s, levy m, hebert aa. bacterial resistance and impetigo treatment trends: a review. pediatr dermatol 2012;29:243-248. [pmid = 22299710] 7. gilden d, nagel ma, cohrs rj. varicella-zoster. handb clin neurol 2014;123:265-283. [pmid = 25015490] 8. staikov i, neykov n, marinovic b, lipozencic j, tsankov n. herpes zoster as a systemic disease. clin dermatol 2014;32:424-429. [pmid = 24767191] 9. kim sr, khan f, ramirez-fort mk, downing c, tyring sk. varicella zoster: an update on current treatment options and future perspectives. expert opin pharmacother 2014;15:61-71. [pmid = 24289750] 10. wolf r, brenner s, ruocco v, filioli fg. isotopic response. int j dermatol 1995;34:341-348. [pmid = 7607796] 11. ruocco v, brunetti g, puca rv, ruocco e. the immunocompromised district: a unifying concept for lymphoedematous, herpesinfected and otherwise damaged sites. j eur acad dermatol venereol 2008;23:1364-1373. [pmid = 19548975]. 12. ruocco v, ruocco e, brunetti g, et al. wolf’s post-herpetic isotopic response: infections, tumors, and immune disorders arising on the site of healed herpetic infection. clin dermatol 2014;32:561568. [pmid = 25160097] 13. schepp ed, cohen pr. zosteriform staphylococcus aureus cutaneous infection: report of two patients with dermatomal bacterial infection. skinmed 2015;13:275-81. dermatology: practical and conceptual commentary | dermatol pract concept 2019;9(3):8 211 dermatology practical & conceptual introduction in a majority of cutaneous disorders, while a specific tissue pattern constitutes the predominant basis for histopathological diagnosis, the presence of special structures or cells serves as an adjuvant or supportive attribute that may enhance the probability of that diagnosis in specific conditions. dermoscopy as a diagnostic tool in general dermatology is still in a developmental and impressionable phase, and its current “diagnostic” accuracy is limited by the lack of uniform standardized criteria/algorithm of structures or features defining a particular condition owing to paucity of published literature, particularly properly designed trials. pending the establishment of such criteria while anecdotal reports remain an important source of advancing our dermoscopic cognition of a dermatosis, the presence of an odd or singular structure on dermoscopy reported in a particular condition warrants careful evaluation and interpretation by experts, evidencebased reinforcement from multiple cases, and clarity on its absence in close clinicopathological differentials before labeling it “diagnostic” for that condition. the situation becomes further complicated by the understated but very relevant differences observed in the dermoscopic features of the same cutaneous lesion in different skin types [1]. in our opinion, the observation “dermoscopy of chromoblastomycosis,” by subhadarshani and yadav [2] published in this journal, highlights the relative limitation rather than the merit of dermoscopy in diagnosing granulomatous disorders, especially in skin of color (soc). they reported reddish pink background with multiple yellow-orange ovoid structures, along with interspersed brown dots, crusts, and scales as the dermoscopic features in their clinically and pathologically confirmed case of chromoblastomycosis. notwithstanding the confounding issue of using the terms brown and blackish red interchangeably for supposedly the most diagnostic dermoscopic feature for the authors, the dermoscopic characterization in pigmented skin: interpret “pigmented” structures carefully sidharth sonthalia1, abhijeet kumar jha2, mohamad goldust3, abhishek omchery4, johannes f. dayrit5 1 skinnocence: the skin clinic, gurgaon, india 2 department of skin & v.d., patna medical college and hospital, patna, bihar, india 3 mazandaran university of medical sciences, sari, iran 4 kaya clinic, sohna road, gurugram, india 5 department of dermatology, research institute for tropical medicine, muntinlupa city, philippines key words: dermoscopy, skin of color, granulomatous, inflammatory, chromoblastomycosis, lupus vulgaris, sarcoidosis, dots, globules citation: sonthalia s, kumar jha a, goldust m, omchery a, dayrit jf. dermoscopic characterization in pigmented skin: interpret “pigmented” structures carefully. dermatol pract concept. 2019;9(3):211-213. doi: https://doi.org/10.5826/dpc.0903a08 accepted: april 10, 2019; published: july 31, 2019 copyright: ©2019 sonthalia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. sidharth sonthalia, skinnocence: the skin clinic & research centre, c-2246, sushant lok-1, block-c, gurugram 122009, india. email: sidharth.sonthalia@gmail.com 212 commentary | dermatol pract concept 2019;9(3):8 case presentation the first case is that of a 21-year-old indian woman with a 2-year-old erythematous facial plaque with a “moth-eaten” appearance (figure 1a). polarized dermoscopy (figure 1b) revealed reddish pink background with yellow-orange ovoid structures, crusts, scales, and interspersed irregular brown dots (similar to the case in question). peripheral branching vessels were additional features. lupus vulgaris was confirmed by histopathology and molecular diagnostics. in the second case, a 40-year-old indian man had asymptomatic erythematous clustered papules over the right forearm that developed 8 months previously (figure 2a). polarized dermoscopy revealed pale pink background with yellowish orange areas and white scales. interspersed irregular pigmented dots and globules were observed in this case as well (figure 2b). cutaneous sarcoidosis was confirmed on lack of clarification on the patient’s skin type renders the issue more complicated (although we presume indian origin and skin type iv-v based on authors’ work affiliation and clinical image). although the majority of features on inflammoscopy are indistinguishable in different skin phototypes, as per our reported experience the observation of “pigmented” structures on dermoscopy of any dermatoses in darker skin types warrants cautious interpretation since such brownish dots, granules, globules, and clods are observed very commonly during different phases of evolution of the majority of pigmentary and inflammatory skin disorders in soc [3]. while in the case under question the brown or blackish red structures may indeed represent the clinically visible black dots stemming from transepithelial elimination of inflammatory exudate and hemorrhage, labeling them as “the most useful sign in diagnosing chromoblastomycosis” seems to be an overstatement. we support our contention with 2 cases. figure 1. (a) infiltrated plaque of lupus vulgaris with a “moth-eaten” appearance on the face of an indian woman. (b) polarized dermoscopy revealed reddish pink background with yellow-orange ovoid structures, crusts, scales and interspersed irregular brown dots (arrows) with focal clustering (circle). peripheral branching vessels were the additional feature (dermlite 4, ×10). (c) histopathology showing caseating granulomas and other features diagnostic of lupus vugaris. note the presence of numerous melanophages (yellow arrows) in the upper dermis (hematoxylin and eosin, ×400). [copyright: ©2019 sonthalia et al.] a b c figure 2. (a) erythematous clustered papules over the right forearm of an indian man. (b) polarized dermoscopy revealed pale pink background with yellowish orange areas, white scales, and interspersed pigmented irregular dots and globules (arrows) (dermlite 4, ×10). (c) histopathology showing noncaseating granulomatous inflammation in the dermis suggestive of sarcoidosis. note the presence of many melanophages (yellow arrows) in the upper dermis (hematoxylin and eosin, ×400). [copyright: ©2019 sonthalia et al.] a b c commentary | dermatol pract concept 2019;9(3):8 213 typical histopathology; pulmonary involvement and elevated angiotensin-converting enzyme levels were found. interestingly, in both cases, apart from the typical granulomatous picture, numerous papillary dermal melanophages were visible (figures 1c and 2c), possibly contributing to the dermoscopic brownish structures. the yellowish green “apple jelly” nodules or “grains of sand” were not appreciable in either case on diascopy. conclusions without any intended criticism, we wish to highlight that while there is a huge void of dermoscopic characterization of nonmelanocytic cutaneous disorders especially in soc, dermoscopy enthusiasts must exert extreme caution before labeling the presence or absence of a particular dermoscopic feature as “highly diagnostic.” a systematic approach for collection and banking of dermoscopic images of disorders in general dermatology from across the globe, especially from the darker skin types, is warranted. the preliminary suggestion of existence of minor but important differences in the dermoscopic features of the same inflammatory dermatosis in different skin types [3] makes a valid case for exploring this uncharted territory. references 1. sonthalia s, gupta a, jha ak, sarkar r, ankad bs. disorders of pigmentation. in: lallas a, errichetti e, ioannides d, eds. dermoscopy in general dermatology. 1st ed. london: crc press; 2018:282-294. 2. subhadarshani s, yadav d. dermoscopy of chromoblastomycosis. dermatol pract concept. 2017;7(4):23-24. 3. gupta v, sonthalia s, bhat yj, langar s, bosseila m. inflammatory and infectious conditions. in: lallas a, errichetti e, ioannides d, eds. dermoscopy in general dermatology. 1st ed. london: crc press; 2018:295-309. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):3 9 dermatology practical & conceptual www.derm101.com case 1 a 60-year-old male presented with depigmented scaly lesions on the scalp and anterior neck, which he had noticed for four months. the lesions were asymptomatic and stationary. a detailed cutaneous examination revealed faint hyperpigmented borders surrounding the depigmented patches. dermoscopy showed white structureless areas, branching telangiectasia, and blue-gray globules sprinkled in a few places on the white areas and white rosettes in many places (figure 1). white rosettes in discoid lupus erythematosus: a new dermoscopic observation balachandra s. ankad1, swapnil d. shah2, keshavmurthy a. adya3 1 department of dermatology, s. nijalingappa medical college, karnataka, india 2 skin and laser clinic, solapur, india 3 blde university’s shri m b patil medical college, vijayapura, india key words: white rosette, discoid lupus erythematosus, dermoscopy citation: ankad bs, shah sd, adya ka. white rosette in discoid lupus erythematosus: a new dermoscopic observation/ dermatol pract concept 2017;7(4):9-11. doi: https://doi.org/10.5826/dpc.0704a03 received: june 27, 2017; accepted: august 17, 2017; published: october 31, 2017 copyright: ©2017 ankad et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. balachandra s. ankad, professor, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587103, karnatka, india. email: drbsankad@gmail.com figure 1. depigmented patches of discoid lupus erythematosus (left panel). dermoscopy shows white rosette (black circle), telengiectasia (yellow arrow), patulous follicular openings (red circle), blue-gray globules (red arrow), and brownish areas at the periphery (right panel). [copyright: ©2017 ankad et al.] white rosettes are shiny white structures seen as four oval-shaped points that come together in the center. they resemble four-leaf clover [1]. earlier it was thought they were specific for actinic keratosis and squamous cell carcinoma, but they are noted in many other conditions [2]. with polarized light dermoscopy, it is evident that rosettes are seen only and they are due to the optical effect between polarized light and follicular structures [3]. here, authors describe cases of discoid lupus erythematosus (dle) demonstrating rosettes under polarized dermoscopy. abstract mailto:drbsankad@gmail.com 10 observation | dermatol pract concept 2017;7(4):3 to the optical effect of polarized light. it is postulated that rosettes are formed by narrowing of infundibula or blockage by keratin [3]. others suggest that rosettes correspond to an alternating focal hyperkeratosis and normal corneal layer and keratin-filled acrosyringeal openings [4]. these are described in actinic keratosis, squamous cell carcinoma, basal cell carcinoma, seborrheic keratosis, and lichen planus like keratosis [3]. haspeslagh et al performed ex vivo dermoscopic examinations of 6,108 consecutive biopsy specimens and reported that many conditions, including basal cell carcinoma, dermatofibroma, nevus, squamous cell carcinoma, melanoma, molluscum contagiosum, and lichen planopilaris demonstrate rosettes. however, there was no mention of dle. in their study, transverse sections proved that smaller rosettes are mainly caused by polarizing horny material at the infundibular level in adnexal openings and larger rosettes mainly by concentric perifollicular fibrosis [3]. this implies that rosettes are seen in the conditions wherein hair follicle and perifollicular involvement is present. this observation is compounded by the fact that polarization of the infundibular keratin layer results in four segments that appear as rosettes when out of focus [3]. recently gonzalez-alvarez et al described rosettes in pigmented melanoma and stated that rosettes are not angular dependent, which means that they do not change orientation when dermoscopy is rotated around its vertical axis [4]. this is in contrast to white shiny lines observed due to fibrotic changes, which alter their orientation [5]. in dle, rosettes do not change the angle of orientation. case 2 a 45-year-old male had lesions on the right cheek, upper chest, nose and forehead that had been present for two months. the lesions were slightly itchy and progressive in nature. cutaneous examination showed well-defined plaques with adherent scales and atrophy in a few places. dermoscopy demonstrated brownish structureless areas surrounded by white striations. in areas of the scalp, dermoscopy showed white rosettes erupting in brownish structureless areas (figure 2). case 3 a 69-year-old male presented with an itchy lesion on the scalp that had been present for six months. the itch was aggravated with exposure to sunlight. cutaneous examination revealed a well-defined plaque on the vertex of scalp with slight, adherent scales. dermoscopic examination revealed whitish structureless areas surrounded by red dots and globules, white scale, and follicular plugs. white rosettes were also noted both in the center and periphery. brown globules were found at the periphery of whitish areas (figure 3). skin biopsy showed features suggestive of dle in all three cases. white rosettes are white shiny points seen under polarized dermoscopy. they vary in size from 0.2 mm to 0.5 mm, and they can be oriented in the same angulations or in different angulations [4]. the exact morphologic correlate is not known. many authors believe that it is due figure 2. well-defined, erythematous plaques (left panel). dermoscopy reveals brownish structureless area in the center and white striations at periphery. white rosettes (black circle) are seen in brown areas (right panel). [copyright: ©2017 ankad et al.] figure 3. scaly plaques on the scalp (left panel). dermoscopy shows white structureless areas (yellow star), white rosette (yellow circle), patulous follicles (red arrow), red dots and globules, brown areas at periphery, and follicular scale and plugs (black arrows) (right panel). [copyright: ©2017 ankad et al.] observation | dermatol pract concept 2017;7(4):3 11 references 1. cuellar f, vilalta a, puig s, palou j, salerni g, malvehy j. new dermoscopic pattern in actinic keratosis and related conditions. arch dermatol. 2009;145:732. 2. liebman tn, rabinovitz hs, dusza sw, marghoob aa. rosettes may be observed in a range of conditions. arch dermatol. 2011;147:1468. 3. haspeslagh m, noe m, de wispelaere i, et al. rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation. j eur acad dermatol venereol. 2016;30(2):311-313. 4. gonzalez-alvarez t, armengot-carbo m, barriero a, et al. dermatoscopic rosettes as a clue for pigmented incipient melanoma. dermatology. 2014;228:31–33. 5. marques-da-costa j, campos-do-carmo g, ormiga p, et al. rosette sign in dermatoscopy: a polarized finding. skinmed. 2011;9:392. 6. weedon d. the lichenoid reaction pattern. in: weedon d, strutton g. (editors). skin pathology. 2nd ed. elsevier; china: 2002:31-74. 7. liebman tn, rabinovitz hs, balagula y, jaimes-lopez n, marghoob aa. white shiny structures: dermoscopic features revealed under polarized light. j eur acad dermatol venereol. 2012;26:1493–1497. there are no reports of rosettes in dle in the literature. in this report, three patients with dle showed white rosettes. in all cases, the orientation angle of white rosettes was in the same plane. rosettes were of the same size and shape in all three cases. histopathology of dle shows changes mainly midway of hair, and heavy infiltration is seen around the sebaceous gland insertion [6]. this explains the appearance of rosettes in dle. it should be noted that rosettes are seen only in early phases of dle because follicles are still preserved and not destroyed by fibrosis. finally, rosettes are the result of the pathological process involving the follicular and perifollicular areas. rosettes should not be confused with other white structures like white chrysalis strands or white lines, which correspond to collagen bundles in the dermis [2,7]. the authors could not find morphological differences in rosettes in color of the skin (brown) from other types of skin. to conclude, this is the first report of dle demonstrating white rosettes under polarized dermoscopy. thus this report proves that white rosettes are not specific dermoscopic patterns to any particular condition. they are the result of theoptical effect of crossed polarization in the follicular and perifollicular structures. https://www.ncbi.nlm.nih.gov/pubmed/25786770 dermatology: practical and conceptual dermatoscopy | dermatol pract concept 2014;4(4):14 71 dermatology practical & conceptual www.derm101.com below find the answer to the quiz by şenel presented in the previous issue of dermatology practical & conceptual (http:dx.doi.org/10.5826/dpc0403a14). diagnosis: pigmented basal cell carcinoma. discussion basal cell carcinoma (bcc) is the most frequent type of skin cancer in humans. non-pigmented bccs are much more prevalent than pigmented bccs. sometimes it could be difficult to distinguish a pigmented bcc from a melanoma [1]. menzies et al. suggested a dermatoscopic method with a sensitivity of 93% and a specificity of 89% for diagnosing pigmented bccs (see table) [2,3]. the correct answer to the dermatoscopy quiz in the april 2014 issue (http://dx.doi.org/10.5826/dpc.0403a14) is pigmented basal cell carcinoma congratulations to dr. urmi khanna, who was the first to send us the correct answer! references 1. şenel e. dermatoscopy of non-melanocytic skin tumors. indian j dermatol venereol leprol. 2011;77(1):16-21; quiz 22. 2. menzies sw, westerhoff k, rabinovitz h, et al. surface microscopy of pigmented basal cell carcinoma. archiv dermatol 2000; 136:1012-6. 3. menzies sw. dermoscopy of pigmented basal cell carcinoma. clin dermatol. 2002;20:268-9. dermatoscopy: a multicolored lesion on the forehead—quiz answer engin şenel citation: şenel e. dermatoscopy: a multicolored lesion on the forehead—quiz answer. dermatol pract concept. 2014;4(4):14. http:// dx.doi.org/10.5826/dpc.0404a14 copyright: ©2014 şenel. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: engin şenel, m.d., bba, hitit university faculty of medicine, department of dermatology, 19200 çorum, turkey. tel.: +90 364 2230300. fax: +90 364 2230323. e-mail: enginsenel@enginsenel.com table. dermatoscopic criteria for pigmented bccs (adapted) [2,3]. negative feature: absence of pigmented network + at least one of the following: focal ulceration spoke wheel-like areas leaf-like areas or structureless areas in the periphery lesion multiple blue-gray globules large blue-gray ovoid nests linear and arborizing vessels dermatology: practical and conceptual research | dermatol pract concept 2017;7(2):6 31 dermatology practical & conceptual www.derm101.com introduction vitiligo is characterized by circumscribed depigmented macules and patches of skin. it is a multifactorial disorder due to genetic and environmental factors. vitiligo affects approximately 0.5-2% of the general population worldwide [1]. the disease can affect all age groups, but studies have shown that most patients seem to develop the disease about the age of 20. it also occurs more often in individuals with dark or tanned skin [2]. different theories have been proposed for the pathogenesis of vitiligo in which autoimmunity in genetically susceptopical mycophenolate mofetil in the treatment of vitiligo: a pilot study farhad handjani1, 2, shahin aghaei3, iman moezzi1, 2, nasrin saki1, 2 1 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran 2 department of dermatology, school of medicine, shiraz university of medical sciences, shiraz, iran 3 dermatology department, school of medicine, iran university of medical sciences, tehran, iran key words: vitiligo, mycophenolate mofetil, repigmentation citation: handjani f, aghaei s, moezzi i, saki n. topical mycophenolate mofetil in the treatment of vitiligo: a pilot study. dermatol pract concept. 2017;7(2):6. doi: https://doi.org/10.5826/dpc.0702a06 received: october 10, 2016; accepted: december 23, 2016; published: april 30, 2017 copyright: ©2017 handjani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nasrin saki, md, molecular dermatology research center, shiraz university of medical sciences, shiraz, iran 7134844119. email: nasrinsa85@yahoo.com background: vitiligo is a multifactorial disease that is characterized by circumscribed depigmented macules and patches. autoimmune reactions may play an important role in the pathogenesis of the disease. mycophenolate mofetil is a drug that inhibits dna synthesis in lymphocytes and has been used in autoimmune diseases such as immunobullous skin diseases, lupus erythematosus, and autoimmune hepatitis. objectives: the objective of this study was to show the efficacy of topical mycophenolate mofetil in the treatment of vitiligo. methods: thirty patients with limited vitiligo were enrolled in this study. the patients applied a topical preparation of mycophenolate mofetil 15% twice daily for three months and at the end of every month, repigmentation was assessed using the vitiligo area scoring index (vasi). results: at the end of the third month, 36.6 % (n=11) of the patients showed about 25% repigmentation of the lesions. no side effects were observed throughout the study. conclusion: this study showed that topical mycophenolate mofetil can be somewhat effective in the treatment of vitiligo; however, it seems to be inferior to potent topical steroids in inducing repigmentation. abstract mailto:nasrinsa85@yahoo.com 32 research | dermatol pract concept 2017;7(2):6 medical sciences and all patients signed the informed consent form. statistical analysis was performed with the spss 19.0 statistical package (spss inc., chicago, il, usa), using paired t-test and descriptive methods. the criterion for statistical significance was at a = 0.05. results thirty patients were included in this study with a mean age of 32.8 years (with an age range from 17 to 51 years). eight of them were male (27%) and the rest were females (73%). the mean duration of the disease was 9.4 months (ranging from 1 to 48 months). nine patients had acrofacial vitiligo and the rest had the segmental type of the disease. most of lesions were located on the hands (41.2%), followed by the face (32.3%), while the remaining lesions were located in other regions of the body (26.5%). at the end of third month, 36.6 % (n=11) of patients achieved approximately 25% repigmentation. at the end of first month, only one patient had dramatic response with 40% repigmentation, but at the end of second month, five patients (16.6%) had achieved 25% repigmentation. thirteen patients had a history of previous treatment with topical corticosteroids and/or topical calcineurin inhibitors. five of them had shown a good response to previous treatment but had presented with new lesions. one of the patients which had shown a good response to previous treatments, showed no response to mmf therapy, whereas the other four showed some repigmentation (28.8%). there were eight patients who were resistant to previous topical therapy, who also showed no response to mmf therapy. two of them had a positive family history of vitiligo in their firstor second-degree relatives. one patient with a positive family history of vitiligo in her mother had a good response to mmf therapy, while the other patient with history of vitiligo in his aunt did not respond to therapy. this patient was also resistant to previous topical steroid therapy. all lesions that responded to mmf therapy were in sunexposed areas, except for one lesion, which was on the thigh area. comparing the overall pigmentation at the end of the second month with the first month showed a statistically significant difference (p.value= 0.027). comparing the overall pigmentation at the end of the third month with the first month showed a statistically significant difference (p.value= 0.0.005) (table 1). none of the patients presented with any adverse side effects while using the topical medication. discussion this study was a pilot study investigating the therapeutic effects of topical mmf on vitiligo patients. tible individuals is considered to play an important role [3,4]. the autoimmune mediated destruction of melanocytes is a well accepted theory and currently is the leading hypothesis in vitiligo pathogenesis. this immune reaction is mediated by cellular and humoral immunity and cytokines [5]. various treatment modalities, including topical therapy, phototherapy and systemic therapy have been used [6-10], but no single treatment has been shown to be successful in all cases, hence a search for a new drug continues. mycophenolate mofetil (mmf) is a purine antagonist that selectively inhibits proliferation of activated lymphocytes. mmf is converted to mycophenolic acid in the human body which then inhibits inosine monophosphate dehydrogenase. this enzyme converts inosine monophosphate to guanosine monophosphate. in fact, mmf inhibits dna synthesis in lymphocytes, and inhibits the production of antibody by b-cells. the drug prevents glycosylation and expression of binding molecules and the summoning of lymphocytes and monocytes into sites of inflammation [11]. mmf can induce apoptosis of activated lymphocytes and decrease the recruitment of lymphocytes (both cd4 and cd8) and monocytes into inflammation sites [12]. lee yf et al showed that the recruitment of cd8 lymphocytes to the skin was significantly decreased after mmf therapy [13]. therefore, the use of it could theoretically help in the management of vitiligo. objective the objective of this study was to assess the efficacy of topical mmf in the treatment of vitiligo. to our knowledge, there is no such study in the literature to date. methods this study was conducted at the department of dermatology, shahid faghihi university hospital, shiraz, iran over a 14-month period. thirty patients were enrolled in this pilot study. all patients had limited vitiligo (less than 5% of total body surface area) and had either received no previous treatment or three months had elapsed since their last treatment plan. patients with mucosal vitiligo, pregnant and lactating women, children and neutropenic patients were excluded due to probable side effects of mmf on these patients. the patients were instructed to apply topical mmf 15% preparation twice daily for three months, and at the end of every month repigmentation was assessed using the vitiligo area scoring index (vasi) for every patient. the reason for choosing a 15% concentration of mmf was that this was the maximum concentration that could be obtained by dissolving the mmf tablets (500 mg tablet, actoverco company, iran) in eucerin®. this study was approved by the ethical committee of shiraz university of research | dermatol pract concept 2017;7(2):6 33 it seems that although the use of topical mmf in the treatment of vitiligo can be effective, its use may not be warranted in cases resistant to topical steroids. however, due to its safety, it can be considered in cases where the use of topical steroids is contraindicated or can cause significant atrophy. acknowledgements the present article was extracted from the thesis written by dr. iman moezzin and was financially supported by shiraz university of medical sciences grant no.92-01-01-6771. references 1. alikhan a, felsten lm, daly m, petronic-rosic v. vitiligo: a comprehensive overview. part 1. introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. j am acad dermatol. 2011;65(3):473-491. 2. hamzavi ih , mahmoud bh, isedeh pn. handbook of vitiligo: basic science and clinical management. jp medical ltd: london 2015:1-21. 3. westerhof w, d’ischia m. vitiligo puzzle the pieces fall in place. pigment cell res. 2007;20(5):345-359. 4. passeron t, ortonne jp. physiopathology and genetics of vitiligo. j autoimmun. 2005;25 suppl:63-68. 5. abreu ac, duarte gg, miranda jy, ramos dg, ramos cg, ramos mg. immunological parameters associated with vitiligo treatments. a literature review based on clinical studies. autoimmune dis. 2015;2015:196537. 6. jalel a, soumaya gs, hamdaoui mh. vitiligo treatment with vitamins, minerals and polyphenol supplementation. indian j dermatol. 2009;54(4):357-360. 7. taieb a, alomar a, bohm m, et al. guidelines for the management of vitiligo: the european dermatology forum consensus. br j dermatol. 2013;168:5-19. 8. gawkrodger dj, ormerod ad, shaw l, et al. guideline for the diagnosis and management of vitiligo. br j dermatol. 2008; 159:1051-1076. 9. yones ss, palmer ra, garibaldinos tm, hawk jl. randomized double-blind trial of treatment of vitiligo: efficacy of psoralenuv-a therapy versus narrowband-uv-b therapy. arch dermatol. 2007;143(5): 578-584. 10. gupta d, kumari r, thappa dm. depigmentation therapies in vitiligo. indian j dermatol venereol leprol. 2012;78:49-58. 11. ransom jt. mechanism of action of mycophenolate mofetil. ther drug monit. 1995;17(6):681-684. 12. chapuis ag, paolo rizzardi g, d’agostino c, et al. effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. nat med. 2000;6(7):762-768. 13. lee yf, cheng cc, lan jl, et al. effects of mycophenolate mofetil on cutaneous lupus erythematosus in (nzb × nzw) f1 mice. j chin med assoc. 2013;76(11):615-623. 14. wohlrab j, jahn k, plaetzer m, neubert r, marsch wc. topical application of mycophenolate mofetil in plaque-type psoriasis. br j dermatol. 2001;144(6):1263-1264. 15. amnuaikit t, songkram c, pinsuwan s. enhancement of mycophenolate mofetil permeation for topical use by eucalyptol and n-methyl-2-pyrrolidone. scientifica (cairo). 2016;2016:9672718. autoimmune destruction of melanocytes is currently the leading hypothesis in vitiligo pathogenesis. the immune system involved in this destruction includes the cellular and humoral immunity and various cytokines. the presence of several antibodies against different melanocyte-associated antigens was confirmed in vitiligo. elimination of melanocytes by cytotoxic t cells is also another mechanism involved in vitiligo. cytokines also play an important role in vitiligo. increased levels of tumor necrosis alpha (tnf-α) and interferon-gamma (ifn-γ) are important arms in vitiligo pathogenesis [5]. mmf inhibits dna synthesis in lymphocytes, and inhibits the production of antibody by b-cells. the drug prevents glycosylation and expression of binding molecules and the infiltration of lymphocytes and monocytes into sites of inflammation [11]. in this study, the maximum concentration of topical mmf, using its 500 mg tablet, was utilized. at the end of first month, only one patient had dramatic response with 40% repigmentation, but at the end of second month 16.6% of the patients had achieved 25% repigmentation, and in the third month, 36.6 % of patients achieved 25% repigmentation. this study showed that mmf may be an alternative and safe topical drug therapy for vitiligo. topical mmf is also used in plaque type psoriasis with success. pure mmf 2% was compared to 0.1% betamethasone-17-valerate cream. no difference was seen between the therapeutic efficacies of both topical drugs in psoriasis [14]. nearly all the lesions that showed a good response to mmf therapy were in sun-exposed areas; this may be due to the synergistic effects of natural ultraviolet light in the repigmentation of vitiligo lesions. there are some limitations in this study. firstly, because it was a pilot study, the number of cases was few and there was no control group. further studies with larger sample sizes and in the form of randomized clinical trials are needed to assess the efficacy of topical mmf in the treatment of vitiligo. secondly, because of the difficulty in skin penetration of topical drugs, using skin permeation enhancers, such as eucalyptol (eul) and n-methyl-2-pyrrolidone (nmp) suggested by amnuaikit et al may increase the therapeutic efficacy of topical mmf [15]. table 1. overall pigmentation at the end of each month with mmf therapy. [copyright: ©2017 handjani et al.] time (at the end of each month) pigmentation (mean +/sd) 1st month 1.33+/1.33 2nd month 4.16+/2.19 3rd month 10 +/2.82 dermatology: practical and conceptual 20 letter | dermatol pract concept 2019;9(1):5 dermatology practical & conceptual a 56-year-old woman presented with a 5-year history of a single, painless, bluish swelling (figure 1) over the inner aspect of the upper lip that began as a pea-sized lesion and gradually increased to the present size. there was no history of trauma or spontaneous bleeding. on examination, a single, violaceous, soft, compressible, nonindurated, nonpulsatile papule was present on the inner aspect of the upper lip. on diascopy, the lesion could be emptied of most of its blood content. mucoscopy (polarized, 10×) revealed few red and blue lacunae with whitish veil (figure 2). a diagnosis of venous lake was made. mucoscopy of a venous lake abhijeet kumar jha1, juhi pathak2 1 department of skin & v.d., patna medical college and hospital, patna, bihar, india 2 department of conservative dentistry and endodontics, buddha institute of dental sciences and hospital, patna, bihar, india key words: mucoscopy, venous lake citation: jha ak, pathak j. mucoscopy of a venous lake. dermatol pract concept. 2019;9(1):20-21. doi: https://doi.org/10.5826/ dpc.0901a05 published: january 31, 2019 copyright: ©2019 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & v.d., patna medical college and hospital, patna, bihar, india. email: drabhijeetjha@gmail.com figure 1. single bluish swelling on the inner aspect of the upper lip. [copyright: ©2019 jha and pathak.] figure 2. mucoscopy (polarized, 10×) reveals few red and blue lacunae with whitish veil. [copyright: ©2019 jha and pathak.] letter | dermatol pract concept 2019;9(1):5 21 of the lacuna, resulting in half-and-half lacuna [3]. to the best of our knowledge, this is the first report on mucoscopy in venous lake. references 1. james w, berger t, elston d, eds. andrews ’diseases of the skin: clinical dermatology. 10th ed. philadelphia: saunders; 2005:588. 2. rapini rp, bolognia jl, jorizzo jl, eds. dermatology. vol. 2. st. louis: mosby; 2007:1624. 3. jha ak, lallas a, sonthalia s. dermoscopy of cutaneous lymphangioma circumscriptum. dermatol pract concept. 2017;7(2):37-38. venous lakes, also known as “phlebectases” [1], are small (0.2-1 cm), generally solitary, soft, compressible, violaceous papules commonly found on sun-exposed areas, predominantly the vermilion border of the lips and ears. lesions generally occur among the elderly [2]. dermoscopically, venous lake can mimic cutaneous lymphangioma circumscriptum that displays 2 distinct patterns: yellow lacunae surrounded by pale septa without inclusion of blood and yellow to pink lacunae alternating with dark red or bluish lacunae, due to the inclusion of blood. few lacunae can contain blood, which was characteristically accumulated in the lowest part untitled quiz | dermatol pract concept 2015;5(3):7 27 dermatology practical & conceptual www.derm101.com below is the answer to the quiz by dr. oliveira et al presented in the previous issue of dermatology practical & conceptual [2015;5(2):15]. congratulations to dr. darshan karia (email:darshan karia3@gmail.com), who was the first to send us the correct answer! answer diagnosis: extradigital solitary glomus tumor clinical course the patient had no evidence of recurrence during 12 months of follow-up. answer and explanation glomus tumors are neoplasms of the normal glomus body. this structure is a neuromyoarterial body composed of an afferent arteriole and an efferent venule with multiple interconnections. contractility of glomus cells occurs after temperature changes are sensed by nerves within the glomus body, hence its importance in local blood flow regulation [1,2]. glomus tumors are rare corresponding to 1,6% of all soft tissue tumors. they are usually solitary, presenting as a blue to pink, soft nodule associated with a classic triad of symptoms: pain, pinpoint tenderness and cold sensitivity. these tumors are frequently located on the extremities, mostly in the subungueal areas of the digits. extradigital locations include upper and lower extremities, trunk and less commonly the face. therefore, glomus tumors in extradigital locations may represent a diagnostic challenge resulting in misdiagnosis of these lesions [3,4]. dermoscopy features of extradigital glomus tumors have rarely been documented [5]. in our case, central purple homogeneous area correlates to enlarged vessels and surrounding white patch probably corresponds to fibrous structures. while not specific, theses findings may represent an additional clue to complement the difficult diagnosis of glomus tumors in a less common location. accurate diagnosis of extradigital glomus tumors is important to avoid long diagnostic delays, providing an early adequate surgical treatment and diminishing associated local chronic pain. references 1. schiefer tk, parker wl, anakwenze oa, amadio pc, inwards cy, spinner rj. extradigital glomus tumors: a 20-year experience. mayo clin proc 2006; 81:1337-44. 2. naverson dn, trask dm, watson fh, burket jm. painful tumors of the skin: “lend an egg”. j am acad dermatol 1993;28:298300. 3. lee dw, yang jy, chang s, et al. clinical and pathological characteristics of extradigital and digital glomus tumours: a retrospective comparative study. j eur acad dermatol 2011;25:1392-97. 4. chun js, hong r, kim ja. extradigital glomus tumor: a case report. mol clin oncol 2014;2:237-39. 5. ito t, yoshida y, furue m, yamamoto o. solitary nodule on the nose. acta derm venereol 2013;93:379-81. painful purple nodule on the right thigh—answer andré oliveira1, susana brás1, adelaide milheiro2, jorge cardoso1 1 department of dermatology, hospital de curry cabral—centro hospitalar de lisboa central, lisboa, portugal 2 department of pathology, hospital de curry cabral—centro hospitalar de lisboa central, lisboa, portugal citation: oliveira a, brás s, milheiro a, cardoso j. painful purple nodule on the right thigh—answer. dermatol pract concept 2015;5(3):7. doi: 10.5826/dpc.0502a07 copyright: ©2015 oliveira et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: andré oliveira, md, department of dermatology, hospital de curry cabral—centro hospitalar de lisboa central, rua da beneficência nº8, 1069-166, lisboa, portugal. tel. +35 1912561666; fax. +35 1217924392. e-mail: andre.oliveira@sapo.pt dermatology: practical and conceptual quiz | dermatol pract concept 2014;4(4):6 37 dermatology practical & conceptual www.derm101.com case a 50-year-old african-american female with a past medical history significant for human immunodeficiency virus (hiv) and non-adherence to haart therapy, was admitted for failure to thrive and a generalized, pruritic skin eruption. the patient first noticed the eruption on her feet a few months prior to admission. within days, it had spread to her torso, upper extremities, and scalp. on physical examination, she had well-demarcated, erythematous and scaly, confluent plaques involving the torso, upper and lower extremities (figure 1). in addition, she had thick, hyperkeratotic plaques on the palms and soles as well as dystrophic fingernails (figure 2). skin scrapings were performed and histopathology evaluation was obtained (figure 3). what is your diagnosis? generalized, pruritic skin eruption in an immunocompromised patient stephanie wang1, juliana basko-plluska1, maria m. tsoukas1 1 department of dermatology, university of illinois at chicago, chicago, usa citation: wang s, basko-plluska j, tsoukas mm. generalized pruritic skin eruption in an immunocompromised patient. dermatol pract concept. 2014;4(4):6. http://dx.doi.org/10.5826/dpc.0404a06 received: june 20, 2014; accepted: june 25, 2014; published: october 31, 2014 copyright: ©2014 wang et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: maria m. tsoukas, md, phd, department of dermatology, university of illinois at chicago, chicago, usa. tel. 312.996.6966. email: tsoukasm@uic.edu figure 1. well-demarcated, erythematous and scaly, confluent plaques on the patient’s back. (copyright: ©2014 wang et al.) 38 quiz | dermatol pract concept 2014;4(4):6 diagnosis given the clinical and histopathological findings, a diagnosis of tinea corporis in an immunocompromised patient was made. clinical course the patient was treated with fluconazole 100 mg daily for 3 months. her eruption improved within days of starting the therapy. discussion tinea corporis is a dermatophyte infection of the skin. factors that determine severity of clinical disease include the immune system of the host, the inhibitory effect of sebum, the presence of mannans in the cell walls of dermatophytes and their immune-inhibitory effects, as well as keratinases, which allow invasion of fungi into the stratum corneum. differential diagnosis included and was not limited to crusted scabies, psoriasis and sebo-psoriasis, nutritional deficiency. extensive tinea corporis requires systemic therapy with antifungal medications. standard treatments include terbinafine 250 mg daily for a week, fluconazole 150-200 mg per week for 2-4 weeks, itraconazole 200 mg daily for 1 week, or griseofulvin 500–1000 mg/day (microsize) or 375–500 mg/day (ultramicrosize) for 2–4 weeks. in immunocompromised patients, a longer course of therapy may be indicated. figure 2. thick, hyperkeratotic plaques on the palms and dystrophic fingernails. (copyright: ©2014 wang et al.) figure 3. punch biopsy, skin at the back: numerous hyphae in the stratum corneum and a superficial, mixed perivascular infiltrate were evident on histopathologic examination. (copyright: ©2014 wang et al.) dermatology: practical and conceptual 36 letter | dermatol pract concept 2019;9(1):9 dermatology practical & conceptual introduction we present a case of an epidermal cyst on the face of a child, clinically and dermoscopically mimicking pilomatricoma. pilomatricoma, also called pilomatrixoma or calcifying epithelioma of malherbe, is a benign skin tumor and one of the most common causes of superficial head and neck masses in children and young adults [1]. it usually manifests as a solitary, asymptomatic, firm nodule on the face (especially eyelids and eyebrows), scalp, neck, or arms [1]. common differential diagnoses for head and neck pilomatricoma include sebaceous cyst, ossifying hematoma, giant cell tumor, chondroma, dermoid cyst, foreign body reaction, degenerating fibroxanthoma, metastatic bone formation, and osteoma cutis [1]. pilomatricoma-like changes have been described in epidermoid cysts in patients with gardner syndrome [1]. surgical excision of the pilomatricoma is the treatment of choice, with wide resection margins to minimize the risk of recurrences [2]. case presentation in our case, a 6-year-old girl presented clinically with a preauricular, firm, solitary lesion that had been growing slowly for the 2 months before the first visit (figure 1). dermoscopy epidermal cyst on the face of a child, clinically and dermoscopically mimicking pilomatricoma jelena krtanjek1, ivana ilic2, mateja kendel3, ruzica jurakic toncic4 1 division of dermatology and venereology, general hospital varazdin, varazdin, croatia 2 department of pathology and cytology, university hospital centre zagreb, zagreb, croatia 3 division of dermatology and venereology, county hospital cakovec, cakovec, croatia 4 university department of dermatology and venereology, university hospital centre zagreb, university of zagreb school of medicine, zagreb, croatia key words: pilomatricoma, epidermal cyst, dermoscopy citation: krtanjek j, ilic i, kendel m, jurakic toncic r. epidermal cyst on the face of a child, clinically and dermoscopically mimicking pilomatricoma. dermatol pract concept. 2019;9(1):36-37. doi: https://doi.org/10.5826/dpc.0901a09 published: january 31, 2019 copyright: ©2019 krtanjek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, university department of dermatology and venereology, university hospital centre zagreb, university of zagreb, school of medicine, salata 4 10000 zagreb, croatia. email: rjtoncic@gmail.com figure 1. clinical presentation of a preauricular, firm, solitary lesion on the face of a 6-year-old girl. [copyright: ©2019 krtanjek et al.] letter | dermatol pract concept 2019;9(1):9 37 its frequent incidence, this diagnosis should be considered when evaluating similar skin lesions, to avoid unnecessary surgical excision. references 1. ghigliotti g, cinotti e, parodi a. usefulness of dermoscopy for the diagnosis of epidermal cyst: the ‘pore’ sign. clin exp dermatol. 2014;39(5):649-650. 2. fernández atuan r, álvarez garcía n, gonzález ruiz y, siles hinojosa a, rihuete heras ma, elías pollina j. the diagnosis of pilomatrixoma in children is not as easy as it may seem: a review of 126 cases [in spanish]. cir pediatr. 2017;30(1):46–49. revealed erythematous border, irregular white structures, and brown-blue central pigmentation (figure 2). based on the clinical and dermoscopic examination, the initial diagnosis was pilomatricoma with differential diagnosis of foreign body reaction. after 1 month, the lesion enlarged quickly; therefore, excision was advised. histopathology report demonstrated a cyst lined by an epidermislike epithelium including a granular cell layer, filled with laminated keratin, compatible with a diagnosis of epidermal cyst (figure 3). conclusions we believe that this is the first report of an epidermal cyst on the face of a child with these dermoscopic features. given figure 2. dermoscopy image of the lesion (dermlite 3gen pro hr ii, nikon coolpix). erythematous surrounding skin, irregular white structures, and brown-blue central pigmentation. [copyright: ©2019 krtanjek et al.] figure 3. a cyst lined by an epidermis-like epithelium including a granular cell layer, filled with laminated keratin. [copyright: ©2019 krtanjek et al.] dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023100 1 folliculitis decalvans in father and son – genes, environment or both? shekhar neema1, senkadhir vendhan1, biju vasudevan1, lekshmipriya krishnan1 1 armed forces medical college, pune, india key words: folliculitis decalvans, familial, genetic, trichoscopy citation: neema s, vendhan s, vasudevan b, krishnan l. folliculitis decalvans in father and son – genes, environment or both? dermatol pract concept. 2023;13(2):e2023100. doi: https://doi.org/10.5826/dpc.1302a100 accepted: september 15, 2023; published: april 2023 copyright: ©2023 neema et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr shekhar neema, md, febdv, assoc prof (dermatology), armed forces medical college, pune, india. email: shekharadvait@gmail.com introduction folliculitis decalvans (fd) is a chronic recurrent inflammation of the scalp leading to cicatricial alopecia, which predominantly occurs in young individuals. staphylococcus aureus infection and abnormal alteration of the patient immune response play important role in the etiopathogenesis of fd. we hereby report a rare case of fd that occurred in both father and son. case presentation a 37-year-old male presented with a history of patchy loss of hair over the scalp of 12 years. examination showed involvement of vertex and occiput in the form of a well-defined patch of scarring alopecia with erythematous to violaceous boggy plaque over mid occiput measuring 8 × 8 cm with tufted hairs and pustules in the periphery ( figure 1a). dermoscopy showed loss of follicular ostia, pustules, tufted hairs and perifollicular erythema (figure 2a). histopathology was consistent with the diagnosis of fd and pus swab culture grew staphylococcus aureus. the patient was treated with oral rifampicin and clindamycin 300 mg twice daily with good response. a 8-year-old male, son of the index case presented with asymptomatic patch loss of hair over the vertex of the scalp for 3 years. dermatological examination showed vertex involvement with patchy scarring alopecia with (figure 1b). dermoscopy showed loss of follicular ostia, tufted hairs and perifollicular erythema (figure 2b). the patient was also treated with rifampicin and clindamycin with significant improvement. conclusions fd is a predominantly neutrophilic, chronic, and recurrent cicatricial alopecia of the scalp that predominantly occurs in young and middle-aged men [1]. staphylococcus aureus acts as superantigens and stimulate t-cells. genetic predisposition may play a role as colonization with staphylococcus aureus is common while fd is an uncommon disease [2]. it is characterized by alopecia surrounded by crops of follicular 2 research letter | dermatol pract concept. 2023;13(2):e2023100 pustules with pain, itching, and burning sensations. vertex and occipital areas of the scalp are the most common areas affected, although beard, trunk, axilla, and pubic region can also be involved. tufted folliculitis is characterized by multiple hairs (5-20) emerging from the single dilated follicular orifice and is a common finding in fd. trichoscopy is helpful in diagnosis and shows the absence of follicular ostia, tufted folliculitis, follicular hyperkeratosis, follicular pustules, yellow tubular scaling, yellow crusts, perifollicular erythema, and perifollicular hemorrhages. bacterial culture and sensitivity from the intact pustule may identify staphylococcus aureus reservoir. histopathological examination shows follicular neutrophilic abscesses in the infundibula, destruction of sebaceous glands in early lesions and dermal lymphocytes, destruction of follicles and dermal scarring in advanced lesions [3]. oral antibiotics, corticosteroids and isotretinoin have been reported to be effective. rifampicin -clindamycin combination has the best evidence for effectiveness. other figure 1. (a) clinical image of case 1 during presentation showing scarring alopecia over the vertex and occipital regions of the scalp with tufted hairs and pustules. (b) clinical image of case showing patchy scarring alopecia over vertex with tufted hairs. figure 2. (a) dermoscopy of case 1 shows background erythema, loss of follicular ostia, follicular pustules, perifollicular erythema, perifollicular hemorrhage and crust (blue star), perifollicular white scale (blue arrow) and tufted hair (yellow circle) (dermlite dl4, x10, polarized). (b) dermoscopy of case 2 showing loss of follicular ostia, perifollicular scale (blue arrow) and tufted hairs (yellow circle) (dermlite dl4, x10, polarized). research letter | dermatol pract concept. 2023;13(2):e2023100 3 treatments are intra-lesional triamcinolone acetonide, adalimumab, infliximab, secukinumab, nd:yag laser, and photodynamic therapy [4]. a novel traf3ip2 variant has been reported to cause scarring alopecia with mixed features of discoid lupus erythematosus and fd [5]. folliculitis decalvans has also been reported in a 32-year-old, identical male twins staying apart, exploring possible genetic links. fd occurs due to immune response to staphylococcus aureus that may have a genetic basis as illustrated in our cases. this occurrence may be due to chance, however, genetic basis of this rare disorder requires further evaluation. references 1. rambhia ph, conic rrz, murad a, atanaskova-mesinkovska n, piliang m, bergfeld w. updates in therapeutics for folliculitis decalvans: a systematic review with evidence-based analysis. j am acad dermatol. 2019;80(3):794-801.e1. doi: 10.1016/j .jaad.2018.07.050. pmid: 30092322. pmcid: pmc6363910. 2. brooke rc, griffiths ce. folliculitis decalvans. clin exp dermatol. 2001;26(1):120-122. doi: 10.1046/j.1365-2230. 2001.00746.x. pmid: 11260200. 3. uchiyama m, harada k, tobita r, irisawa r, tsuboi r. histopathologic and dermoscopic features of 42 cases of folliculitis decalvans: a case series. j am acad dermatol. 2021;85(5):11851193. doi: 10.1016/j.jaad.2020.03.092. pmid: 32272176. 4. otberg n, kang h, alzolibani aa, shapiro j. folliculitis decalvans. dermatol ther. 2008;21(4):238-244. doi: 10.1111/j .1529-8019.2008.00204.x. pmid: 18715292. pmid: 18715292. 5. nemer g, el-hachem n, eid e, et al. a novel traf3ip2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans. clin genet. 2020;98(2):116-125. doi: 10.1111/cge.13767. pmid: 32350852. 6. douwes ke, landthaler m, szeimies rm. simultaneous occurrence of folliculitis decalvans capillitii in identical twins. br j dermatol. 2000;143(1):195-197. pmid: 10886161. dermatology: practical and conceptual 148 letter | dermatol pract concept 2019;9(2):12 dermatology practical & conceptual introduction seborrheic keratosis-like melanomas (sk-like melanomas) are difficult to diagnose and easily overlooked, especially among elderly patients with multiple clinically typical sks which are usually not dermoscopically assessed and are removed with destructive measures without histopathological confirmation [1]. therefore, systematic dermoscopic evaluation of all sklike lesions should be made in order to avoid misdiagnoses, delayed treatment, and medicolegal consequences. the term sk-like melanoma refers to melanoma that clinically and/or dermoscopically looks like sk, even if it is verrucous on histopathology report [1]. comedo-like openings are predominantly found in sk, less frequently in unna nevi, and very rarely in malignant melanoma, and they histopathologically correlate with keratin plugs within dilated follicular openings [1]. case presentation we present a case of a 65-year-old woman with a lesion on her back that presented as ugly duckling sign. it was asymmetrical, nonulcerated, 5 mm in diameter, and slightly elevated with 3 different colors (dark brown, light brown, and gray; figure 1). dermoscopy showed striking asymmetry in shape, color, and structure, with gray-brown blotches, large light brown and pinkish structureless area, and unevenly distributed and sharply defined brown globules of varying size and shape grouped in asymmetrical clusters which resembled comedo-like openings (figure 2). complete excision was performed and histopathology revealed melanoma, breslow thickness 1 mm with sk-like features and no signs of perineural or intravascular invasion (figure 3). conclusions sk-like melanoma can be dermoscopically very challenging and in case of any suspicion, histopathological confirmation is mandatory [1]. although dermoscopic criteria have been described for differentiating melanocytic and nonmelanocytic skin lesions, some features can be confusing if simultaneously present in the same lesion [1]. since comedo-like openings represent a typical feature of sk, they might mislead the clinician to a wrong diagnosis. in a study of melanomas melanoma with comedo-like openings: a rare dermoscopic finding zorica đorđević brlek1, jaka radoš2, mirna bradamante2, ružica jurakić tončić2 1 department of dermatology and venereology, pula general hospital, pula, croatia 2 university of zagreb school of medicine, department of dermatology and venereology, university hospital centre zagreb, zagreb, croatia key words: melanoma, dermoscopy, comedo-like openings citation: đorđević brlek z, radoš j, bradamante m, jurakić tončić r. melanoma with comedo-like openings: a rare dermoscopic finding. dermatol pract concept. 2019;9(2):148-149. doi: https://doi.org/10.5826/dpc.0902a12 accepted: october 22, 2018; published: april 30, 2019 copyright: ©2019 đorđević brlek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ružica jurakić tončić, md, university of zagreb school of medicine, department of dermatology and venereology, university hospital centre zagreb, šalata 4, 10000 zagreb, croatia. email: rjtoncic@gmail.com letter | dermatol pract concept 2019;9(2):12 149 2. braga jc, scope a, klaz i, mecca p, spencer p, marghoob aa. melanoma mimicking seborrheic keratosis: an error of perception precluding correct dermoscopic diagnosis. j am acad dermatol. 2008;58(5):875-880. resembling sk, carrera et al [1] found the presence of comedo-like openings in 30.6% cases, as well as milia-like cysts in 22.4%, yellowish keratin in 31.3%, and scaly and hyperkeratotic surface in 33.6% [1]. dermoscopy allows correct diagnosis of melanoma in more than 80% of clinically sk-like melanomas [1]. the main dermoscopic features identified as helpful are blue-black sign, blue-white veil, pseudopods or streaks, and pigment network [1]. combining features of polarized light and nonpolarized light dermoscopy is beneficial since nonpolarized permits visualization of structures located in the upper skin layers, while polarized permits visualization of deeper structures which then enhances the conspicuity of different structures and may help reduce the rate of diagnostic errors [2]. i n o u r c a s e t h e d i a g n o s i s w a s straightforward due to melanomasuggestive dermoscopic clues. sk-like melanomas represent a potential diagnostic pitfall; therefore, dermatologists should be aware of “errors of perception,’’ referring to a possibility of being drawn to one prominent but potentially misleading sk dermoscopic feature, while other subtle clues of melanoma in the visual field can be overlooked [2]. complete dermoscopic evaluation of all quadrants of the lesion and careful analysis of all criteria should be undertaken to ensure that they are all consistent with the final diagnosis [2]. references 1. carrera c, segura s, aguilera p, et al. dermoscopic clues for diagnosing melanomas that resemble seborrheic keratosis. jama dermatol. 2017;153(6):544-551. figure 1. clinical finding of malignant melanoma: asymmetrical, nonulcerated, 5 mm in diameter, and slightly elevated with 3 different colors (dark brown, light brown, and gray). [copyright: ©2019 đorđević brlek et al.] figure 2. dermoscopic finding of malignant melanoma: asymmetrical in shape, color, and structure, with gray-brown blotches, large light brown and pinkish structureless area, unevenly distributed and sharply defined brown globules of varying size and shape grouped in asymmetrical clusters that resemble comedo-like openings. [copyright: ©2019 đorđević brlek et al.] figure 3. histopathology of malignant melanoma: proliferation of atypical melanocytes singly and in nests within the epidermis, papillary and superficial portion of reticular dermis with smaller nests of atypical melanocytes located within follicular ostia filled with keratin plugs (hematoxylin and eosin, ×10). [copyright: ©2019 đorđević brlek et al.] dermatology: practical and conceptual research | dermatol pract concept 2019;9(3):3 187 dermatology practical & conceptual disseminate recurrent folliculitis and hidradenitis suppurativa are associated conditions: results from a retrospective study of 131 patients with down syndrome and a cohort of 12,351 pediatric controls andrea sechi1, alba guglielmo1, annalisa patrizi1, francesco savoia1, guido cocchi2, miriam leuzzi1, marco a. chessa1 annalucia virdi1, iria neri1 1 division of dermatology, sant’orsola-malpighi polyclinic, department of experimental, diagnostic and specialty medicine, university of bologna, italy 2 neonatology unit, sant’orsola-malpighi polyclinic, department of medical and surgical sciences, university of bologna, italy key words: hidradenitis suppurativa, folliculitis, down syndrome, pediatric, hair follicle disease citation: sechi a, guglielmo a, patrizi a, savoia f, cocchi g, leuzzi m, chessa ma, virdi a, neri i. disseminate recurrent folliculitis and hidradenitis suppurativa are associated conditions: results from a retrospective study of 131 patients with down syndrome and a cohort of 12,351 pediatric controls. dermatol pract concept. 2019;9(3):187-194. doi: https://doi.org/10.5826/dpc.0903a03 accepted: may 3, 2019; published: july 31, 2019 copyright: ©2019 sechi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: annalisa patrizi, md, division of dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti, 1 – 40138 bologna, italy. email: annalisa.patrizi@unibo.it background: hidradenitis suppurativa (hs) is a chronic, inflammatory, recurrent skin disease of the pilosebaceous unit characterized by protean manifestations. several studies have found an increased incidence and earlier presentation of this disease in patients carrying trisomy 21. patients with down syndrome (ds) have a higher risk of developing a wide range of cutaneous manifestations, including hs and chronic folliculitis. recently, disseminate recurrent folliculitis (drf) has been reported as an atypical monosymptomatic feature of hs at its onset. objective: to assess the prevalence of hs and drf by comparing a cohort of patients carrying trisomy 21 vs pediatric controls. methods: a retrospective 2-year monocentric clinical study was performed by collecting clinical data of 131 patients with ds, aged 4-36 years, followed at the dermatology unit and down syndrome regional center of bologna university. data were matched with those coming from 12,351 pediatric controls. results: in ds patients, drf and hs showed a prevalence of, respectively, 6.8% and 24.4%, while 5.3% of patients presented both diseases. in the control group the prevalence for hs+ and drf+ was 0.5% and 1.2%, respectively, with a 0.14% of overlap cases. the association between hs and drf abstract 188 research | dermatol pract concept 2019;9(3):3 where a more than 5-fold higher risk of developing hs has been reported [8]. the primary endpoint of this study was to investigate the prevalence of hs and drf of any body area in patients with ds. the second endpoint was to evaluate the clinical features (including anatomical distribution, disease severity) of these 2 conditions in the affected population and to verify whether there was a statistically significant correlation. materials and methods medical records were used to perform a 2-year single-center retrospective study on 131 patients with ds followed at the down syndrome regional center and referred to the dermatology unit of the sant’ orsola malpighi university hospital of bologna from january 1, 2016, to december 31, 2018. a second cohort of 12,351 patients served as the control group. this population consisted of all patients aged between 0 and 18 years who were referred to the pediatric dermatology unit during the same 2-year period. this choice was determined by the possibility to retrieve diagnoses and/ or clinical images of the patients visited from the database. patients lacking written parental consent for the collection of images were excluded. iconographic and dermoscopic data were reviewed to detect skin signs of drf and hs in order to identify 4 different cohorts in the studied population: patients with cooccurrence of hidradenitis and folliculitis (hs+f+), those presenting only drf (hs–f+), those with hs alone (hs+f–), and those with neither of the 2 conditions (hs–f–). drf was defined as a noninfectious inflammatory reaction of hair follicles presenting with multiple papules, pustules, papulopustules, or follicular papules with keratotic plug and perifollicular scarring affecting any body area and characterized by a chronic relapsing course lasting more than 6 months. the spectrum of kp was excluded by taking into account the following factors: morphological features, anatomical distribution, and dermoscopic pattern [9]. spiny keratotic papules presenting with variable perifollicular keratosis and degrees of inflammation, mainly scattered on extensor surfaces, favors the diagnosis of kp. evaluation of dermoscopic images in kp shows short hair shafts or coiled vellus hair within widened follicular openings in most cases. introduction down syndrome (ds) is the most common chromosomal disorder and is characterized by congenital heart defects, endocrinological disorders, neurological abnormalities, immunological disturbances, and a wide range of cutaneous manifestations. the cutaneous diseases associated with ds include alopecia areata, vitiligo, atopic dermatitis, psoriasis, elastosis perforans serpiginosa, syringomas, xerosis with palmoplantar hyperkeratosis, and folliculitis [1]; folliculitis was found to be the most common dermatological manifestation in patients with ds [2]. folliculitis is an inflammatory reaction of hair follicles with possible involvement of the follicular opening and the perifollicular area. its classification is based on histopathological or laboratory features, infectious agents, topographic distribution, recognized mechanism, disease duration, and localization within the pilosebaceous compartments [3]. chronic, relapsing folliculitis with secondary anetoderma has been widely reported in patients affected by ds [4]. the recalcitrant course of the folliculitis, in synergy with the congenital malformation of elastic fibers in patients with ds, can lead to irreversible elastolysis, which is responsible for the anetodermal scarring [2]. the exact etiology is still a matter of discussion. some authors have postulated the role of infective triggers such as staphylococcus aureus or malassezia [5], while others have suggested a link between chronic folliculitis and keratosis pilaris (kp), as the follicular expressions of a generalized xerotic condition [6]. patients with ds are probably more susceptible to cutaneous infections including bacterial folliculitis, furuncles, abscesses, and secondary impetigo [1]. long-term disseminate folliculitis of noninfectious etiology is difficult to frame in dermatology [7]. several skin disorders such as atopic dermatitis, psoriasis, pityriasis rubra pilaris, and hidradenitis suppurativa (hs) often show follicular lesions, variably associated with other typical skin signs. disseminate recurrent folliculitis (drf) has been proposed as one of the presenting features of an atypical monosymptomatic form of hs. a population-based cross-sectional analysis found a 2.1% prevalence of hs in patients with ds vs a 0.3% in nonaffected controls. this association was stronger in the ds population aged between 18 and 29 years, proved to be statistically significant in both groups (p < 0.05). in the ds cohort the mean age of symptoms onset was 15.67 (sd: 2.29) years for hs and 13.11 (sd: 4.93) years for drf. buttocks were the most frequently affected body area for drf followed by the inguinocrural area, while in hs buttocks were less frequently involved than groins and upper thighs. conclusions: because of the later onset of hs, patients with drf at an early age should be monitored for the possible onset of hs in the apocrine-bearing areas. abstract research | dermatol pract concept 2019;9(3):3 189 moreover, patients presenting recalcitrant folliculitis with positive cutaneous swab for bacteria or fungi were not included. hs was identified according to the diagnostic criteria provided by the european consensus guidelines for the treatment of hs: history of recurrent suppurating lesions (including inflammatory nodules, sinus tracts, abscess, and subsequent scarring) in the apocrine gland-bearing areas, occurring at least twice in a 6-month period [10]. past medical and family history of dermatological conditions was recorded in patients affected by hs to establish disease duration and age at hs symptom onset. for each patient the following data were collected: age, sex, anatomical pictures of affected body segments, elementary lesions and their anatomical distributions, and disease severity of hs according to hurley’s classification [11]. statistical analysis associations between hs and drf, expressed as dichotomous variables, were assessed using chi-square test calculated on contingency tables. proportions were estimated with 95% exact confidence interval based on the binomial distribution. the risk ratio was estimated by the odds ratio together with 95% approximate confidence interval. statistical tests were 2-sided and p < 0.05 was considered statistically significant. all analyses were performed using spss for mac v22.0 (ibm corp, armonk, ny). results patients with ds the collection of clinical and iconographic data identified the following 4 cohorts of ds patients: hs+f+, presenting with both hs and drf (7/131 patients, 5.3%); hs+f–, characterized only by hs (2/131 patients, 1.52%); hs–f+, displaying features of drf (32/131 patients, 24.42%); and hs–f–, without either disease (90/131, 68.70%). a femaleto-male ratio of 1:1 was found in hs+f– patients, while a male prevalence was detected in the other groups. patient’s age was recorded at the first consultation and at onset of symptoms. the distribution of age at first visit varied considerably in the 4 identified groups. hs–f– presented the lowest age (mean: 9 years; sd: 7.29), while hs+f+ had the highest (mean: 22.98 years; sd: 3.78); intermediate values were found in hs+f– (mean: 16.41 years; sd: 3.67) and hs–f+ (mean: 13.48 years; sd: 6.13). age range reached the lowest value in hs–f–, where the youngest patient was aged 1 year, while the highest extremity of 36 years belonged to hs–f+. age at onset of hs symptoms was established in both hs+f+ and hs–f+, being, respectively, 16 (sd: 2.38) and 14.5 (sd: 2.12) years. age at drf onset could be established in 18/32 hs–f+ and in 7/7 hs+f+ patients. the mean age at onset of symptoms was 15.67 (sd: 2.29) years for hs and 13.11 (sd: 4.93) years for drf. disease severity of hs was assessed using hurley’s classification score [11]. in the hs+f+ group the disease severity was classified as stage i in 2/7 patients (28.6%) and stage ii in 5/7 patients (71.4%). the 2 patients belonging to the hs+f– cohort were staged with hurley severity score i. medical history was accurately recorded in all cases: no patient had undergone hs-related surgery or had a positive family history for hs (table 1). disease location was assessed for both drf and hs by identifying the following anatomical body areas: upper limbs, lower limbs, scalp, armpit, inguinocrural, thorax (including inframammary folds), posterior trunk, buttocks, abdomen, and genitals (figure 1). with regard to drf localization, the hs+f+ group showed a decreasing involvement of the following areas: inguinocrural (100%), buttocks and abdomen (85.7%), posterior trunk (57.1%), inferior limbs, genitals, and scalp (14.3%). affected body areas in the hs– f+ group were, in order of decreasing frequency: buttocks (93.7%), inguinocrural (46.9%), thorax (18.7%), abdomen (15.6%), armpit and posterior trunk (9.4%), and lower and upper limbs (3.1%). in the hs+f+ group hs lesions were localized in the following areas: the inguinocrural area was involved in the totality of cases, followed by armpits (71.4%), buttocks and thorax (42.9%), genitals and scalp (14.3%). the hs+f– cohort presented the sole involvement of the inguinocrural area in one case and buttocks in the other (figure 2). control group this group consisted of 12,351 patients and was thus highly heterogeneous. the reported clinical conditions of the control subjects were, in order of decreasing frequency: atopic dermatitis (23.6%), vascular tumors and malformations (16.6%), infective and postinfective etiology (11.8%), melanocytic nevus (10.5%), inherited skin disorders (6%), urticaria and drug adverse event (5.7%), exogenous dermatitis (4.1%), contact irritant or allergic dermatitis (3.9%), psoriasis (3%), epidermal nevus (2.3%), autoimmune disorders (2.3%), lichen planus (2%), appendageal abnormalities (0.8%), and photodermatoses (0.2%). the frequencies of the studied disease were as follows: 1.2% (142/12,351) for drf and 0.5% (63/12,351) for hs; 0.14% (18 patients) presented both diseases. the remaining 5.5% belonged to conditions (including unknown etiologies) other than those mentioned. overall data were partially lacking in important details, such as age at onset of symptoms and associated clinical pictures in some cases (table 1). the association between hs and drf, assessed by chisquare test, was statistically significant both in ds and control groups (p value: 0.0039 and 0.00027, respectively). the odds ratio indicates that patients affected by ds and showing drf have a 9.8 higher risk of developing hs vs patients without drf. 190 research | dermatol pract concept 2019;9(3):3 table 1. demographic data of the studied ds and control cohorts ds patients hs+f+ hs−f+ hs+f− hs−f− sex n = 7 (5.3%) n = 32 (24.4%) n = 2 (1.5%) n = 90 (68.7%) male 4 (57.1%) 17 (53.1%) 1 (50%) 54 (60%) female 3 (42.9%) 15 (46.9%) 1 (50%) 36 (40%) age at first consultation n = 7 n = 32 n = 2 n = 90 mean age (sd) 22.98 (sd: 3.78) 13.48 (sd: 6.13) 16.41 (sd: 3.67) 9 (sd: 7.29) range 18-28 4-36 14-19 1-35 disease severity n = 7 — n = 2 — hurley i 2 (28.6%) — 2 (100%) — hurley ii 5 (71.4%) — 0 (0%) — hurley iii 0 (0%) — 0(0%) — age at drf onset n = 7 n = 18 n = 2 — mean age (sd) 12.85 (sd: 2.96) 13.20 (sd: 5.57) — range 8-16 4-23 — age at hs onset n = 7 — n = 2 — mean (sd) 16 (sd: 2.38) — 14.5 (sd: 2.12) — range 13-20 — 13-16 — controls hs+f+ hs−f+ hs+f− hs−f− sex n = 18 (0.14%) n = 148 (1.2%) n = 55 (0.44%) n = 12130 (98.2%) male 8 (44%) 61 (41%) 19 (35%) 7,626 (63%) female 10 (56%) 87 (59%) 36 (65%) 4,504 (37%) age at first consultation n = 18 n = 148 n = 55 n = 12,130 mean age (sd) 17.6 (sd: 2.0) 14.5 (sd: 4.2) 16.8 (sd: 6.3) 7.1 (sd: 8.6) disease severity n = 18 — n = 55 — hurley i 7 (39%) — 31 (56%) — hurley ii 11 (61%) — 24 (44%) — hurley iii 0 (0%) — 0 (0%) — figure 1. clinical presentation of hs and drf in patients carrying trisomy 21. (a) painful suppurating nodules were detected in close proximity of the intergluteal fold, while the lateral aspects of the buttocks display signs of diffuse folliculitis in an hs+f+ patient. (b) case of hs–f+ with the gluteal involvement of drf presenting with active follicular-based papules and pustules, in the absence of inflammatory nodules, abscess, sinus tracts, or scarring. [copyright: ©2019 sechi et al.] a b research | dermatol pract concept 2019;9(3):3 191 none of the patients had clinical evidence of any of the occlusion tetrad syndrome signs associated with hs (pilonidal cyst, dissecting cellulitis of the scalp, acne conglobata) [12]. discussion in the general population, the prevalence of hs varies from 0.00033% [13] to 4% [14]. cosmatos et al recently assessed the hs prevalence at 0.053%, with a rate for women almost triple that of men [15]. in our retrospective analysis the prevalence of hs reached 6.8% of the ds population, which is even higher than what is already reported in the literature on patients with ds [8,16]. compared to the control group the prevalence was 13.6and 20-fold higher for hs and drf, respectively. it is also known that hs starts earlier in life in ds, with the highest incidence occurring in the group aged 18-29 compared with the general hs population [8,16]. many efforts have aimed to better investigate the pediatric onset of hs, and, to date, there are only 14 cases published in the literature [17]. palmer and keefe investigated early hs in the general hs population, assessing a 2% prevalence below the age of 11 years [18], whereas different data come from a more recent study, which found a prepubertal onset of hs in 7.7% of the studied hs cohort, by setting the cutoff point at 13.5 years [19]. the prevalence of hs in our control group was 0.5% (63/12,351), which is much higher than the supposed 1% prevalence under 18 years of age in a previously studied hs cohort [20]. the median age at onset of hs symptoms in our ds sample was 16 years (range 13-20) in the hs+f+ group and 14.5 years in the hs+f– group. in all cases, patients with hs had reached the pubertal growth, which is associated with an increased end-organ sensitivity of the pilosebaceous unit to androgens [21]. the mean age at diagnosis of hs in the ds population was quite different in the 2 groups: a mean age of 22.98 years was found in hs+f+ patients and 16.41 years in the hs+f– cohort. similar results were obtained in the controls, showing a mean age of 17.6 years in the hs+f+ cohort, 14.5 years in hs+f– group, and 16.8 years in hs–f+ patients; however, several not-ds hs+ patients had a prepubertal onset of hs. a possible bias is the relatively low age of controls, due to the fact that all patients were recruited from the pediatric dermatology outpatient service. the male-to-female ratio in our ds hs+ groups was 5:4, so a slightly higher male prevalence was detected. the male prevalence of hs in patients with ds is also confirmed by a wide cross-longitudinal study published in the literature [8]; this trend is reversed in the hs population not associated with ds, presenting a female prevalence (female-to-male figure 2. bar graph illustration of anatomical distribution of drf and hs lesions compared among the 4 study cohorts. [copyright: ©2019 sechi et al.] 192 research | dermatol pract concept 2019;9(3):3 ratio 2.8:1), with a peak in patients aged 30-39 years [22]. in fact, in the hs+ control group a female-to-male ratio of 1.7:1 was found. hs severity was assessed using hurley score: 71.4% of ds patients showing both follicular and hs alterations had hurley score ii, while the remaining ds patients (28.6%) had hurley i, as well as the totality of hs+f– ds subjects. the severity assessment was not biased by previous hs-related surgery. these findings from the 2 hs+ cohorts differ from the severity distribution among the general hs population, where stage i is detected in 68% of patients, while stage ii occurs only in 28% [23]. in the not-ds control subjects the hurley stage i was identified in 39% of hs+f+ patients and 56% of hs+f– patients. hurley stage ii was detected in 61% and 44% of controls belonging to the hs+f+ and hs+f– subcohorts. it may be speculated that presenting drf in association with hs is a risk factor of a more severe disease. in ds a scarcely considered factor is the alteration of the collagen component. recent in vitro and ex vivo studies have demonstrated an overexpression of the genes encoding the collagen type vi in human skin fibroblast cultures and nuchal skin of ds fetuses [24,25]. type vi collagen is an extracellular matrix molecule abundantly expressed in the dermis, which plays a key role in the processes of hair follicle cycling and wound healing, tissue repair through the regulation of the dermal matrix assembly, and fibroblastic motility [24,26]. it has a heterotrimeric structure, consisting of 3 distinct polypeptide chains: α1, α2, and α3. the increase in collagen vi is due to an upregulation of the transcription of the col6a1 and col6a2 genes located in the chromosome 21, respectively, encoding for the α1 and α2 chains, due to a gene dosage effect [24]. two diseases associated with impairment of type vi collagen are ullrich congenital muscular dystrophy and bethlem myopathy, which are also characterized by abnormal skin findings, including follicular hyperkeratosis, hypertrophic and keloid scarring, and cutaneous xerosis [26]. it is possible to hypothesize that a mechanical stress exerted on compromised follicular units can activate abnormal extracellular remodeling, leading to scarring evolution. this might explain, in the hs+f+ cohort, the progression of drf into tract formation and cicatrization at intertriginous sites, bypassing the hs severity stage i. as suggested by revuz, drf is a gray area in the field of dermatology, as it cannot be associated univocally with a specific disease or etiology [7]. even though drf belongs to the clinical spectrum of hs, it is not mentioned among the diagnostic criteria. as a consequence, a diagnosis of hs cannot be postulated on the basis of drf presenting as painful papulopustules with a lack of closed comedones or microcysts. assuming that drf may represent a mode of presentation of hs [7], in some patients belonging to the hs–f+ group, drf possibly represents the initial pre-hurley stage i of hs. this hypothesis could represent the key to explain not only the statistical correlation between hs and drf, but also the age mismatch at symptom onset between the hs+f+ and hs+f– cohorts. disease location of drf in the hs+f+ ds group favored the inguinocrural area, which was involved in all patients, followed by the buttocks and abdomen detected in 6/7 cases. on the other hand, the buttocks represent the most frequent localization of drf in hs–f+ ds patients: this frequency remains stable regardless of the age range. other body areas such as the groin, thigh, armpit, and back are affected mainly in postpubertal patients, whereas prepubertal patients show a constant involvement of the buttocks with minimal involvement of other anatomical sites. hs lesions in subjects with ds were located, with decreasing prevalence, at the inguinocrural area, armpits, buttocks, thorax (including inframammary folds), genitals, and scalp. as suggested by giovanardi et al [27] in a recent study, there is no difference in disease distribution of hs in patients with ds vs not-ds. also, there is no strict overlap between drf and hs lesion distribution in ds patients showing both affections (hs+f+). as a result, it can be affirmed that the follicular papulopustules of drf may be the hallmark of a follicular inflammatory disease, which predisposes to develop hs in typical areas. the mechanical friction in the intertriginous area probably remains the main trigger in generating hs lesions in predisposed ds patients. another possible predisposing factor in both hs and drf is obesity, which has also been frequently associated with ds [28]. weight gain leading to obesity usually occurs after puberty, causing an increase of mechanical friction in the areas of skin-to-skin contact. moreover, it causes a proinflammatory state through increased levels of resistin and chemerin, which are responsible for insulin resistance and upregulation of the follicular androgen receptor, leading to follicular occlusion [29]. in addition, the intrinsic immunodeficiency of ds [30] facilitates microbial growth and proliferation in the superficial segments of hair follicles and in the perifollicular space. as a consequence, bacterial infections may contribute to hs progression leading to disease extension and scarring evolution [31]. the pathogenesis of hs is multifactorial, with both genetic and environmental factors involved. considering the genetic factors, an important role is played by loss-of-function mutations of the component of the γ-secretase complex, which results in reduced notch signaling [32]. impaired notch signaling causes alterations of the hair follicle structure and insufficient feedback suppression of tlr-mapk-activated innate immunity, leading to immune deregulation. the main environmental factors are obesity, smoking, mechanical traumatism, and bacteria. furthermore, pathogen-associated research | dermatol pract concept 2019;9(3):3 193 molecular patterns, microbe-associated molecular patterns, and damage-associated molecular patterns activate the autoinflammatory and inflammasome pathway [33]. the higher prevalence of hs in patients with ds can be explained by the impaired notch-mkp signaling: in trisomy21, the increased level of amyloid precursor protein (app) reduces notch signaling, acting as a competitive substrate of γ-secretase [34], resulting in the persistence of autoinflammation [35]. furthermore, app and its cleavage product (secretory n-terminal ectodomain of app) promote keratinocyte migration, adhesion, and proliferation [36]. this results in the plugging and dilation of hair follicles, which leads to follicular hyperkeratosis, hyperplasia of the follicular epithelium, and rupture of hair follicles with consequent perifolliculitis and cyst formation [36]. this study has several limitations due to the lack of validation criteria for the drf diagnosis, the lack of a longterm prospective study regarding the hs-drf association, and the lack of ethnicity variability, since the great majority of the enrolled population consists of caucasians. a higher incidence of hs has, in fact, been reported in the african american ethnic group in 2 studies [37,38]. garg et al demonstrated a 2.5-fold higher incidence of hs in this population [37], while vlassova et al identified african american women as being exposed to the highest risk of developing hs [38]. to sum up, trisomy 21 carries genetic alterations that are responsible for hair follicle imbalances and consequent occlusion. the follicular plugging acts in synergy with other promoting factors such as obesity, mechanical stress, pubertal increase in circulating androgens, and insulin resistance. added to this is the promoting role of the alteration of the collagen component, which may be responsible for the evolution toward profibrotic phenotype. conclusions both drf and hs are commonly detected in patients carrying trisomy 21 and might be considered 2 associated features of the same syndromic condition [39]. on the other hand, there are no studies concerning the prevalence of drf in the general pediatric population, since the validity of drf as a separate entity is still debated. drf is also thought to be associated with a variant of kp, which also occurs under the follicular occlusion disease spectrum [9]. in our clinical practice, we identify pediatric patients at risk of developing hs by taking into account several parameters, which are reported in table 2; positivity for 2 or more parameters leads us to follow up patients at risk every 6 months, to identify early signs of hs. although this is not a validated tool, it might be useful to recognize patients eligible for hs screening. to determine more accurately whether drf is a separate entity or an early pre-hurley stage i of hs, it will be useful to follow drf lesions longitudinally through photographic and ultrasound evaluation. the latter has become a very promising, widely available imaging modality for hs, able to detect subclinical changes occurring in early stages, as well as the initial hair follicle dilation, increased thinning, or abnormal echogenicity of the dermal layer [40]. references 1. national board of health and welfare. cancer incidence in sweden 2017 [in swedish]. 2018. retrieved from: https://www. socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf. accessed march 5, 2019. 2. schepis c, barone c, siragusa m, pettinato r, romano c. an updated survey on skin conditions in down syndrome. dermatology 2002;205(3):234-238. table 2. illustration of the 8 parameters that are assessed to perform a risk stratification of developing hs in pediatric patients recommendation criteria for hs screening in pediatric patients familial background: family history positive for hs in at least 1 first-degree relative. genetics: syndromes with known genetic abnormalities (bazex-dupré-christol syndrome, dowling-degos disease, ds, keratitis-ichthyosis-deafness syndrome), dent disease 2. ethnicity: descent from african and hispanic populations. clinical findings: history of disseminate recurring folliculitis lasting more than 6 months, involving at least 2 body areas (either monoor bilaterally) not attributable to known etiological factors. endocrinological abnormalities: clinical and laboratory findings of insulin resistance, peripheral hyperandrogenism, polycystic ovarian syndrome. follicular occlusion signs: clinical evidence of at least 1 of the occlusion tetrad syndrome signs associated with hs (pilonidal cyst, dissecting cellulitis of the scalp, acne conglobata). smoking: smoking habits or smoke exposure in indoor environments (secondhand smoke). ultrasound: detection of any of the sonographic features suggestive for subclinical follicular abnormalities, including widening of the hair follicles, thickening or abnormal echogenicity of the dermis, and dermal pseudocystic nodules. https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-12-50.pdf 194 research | dermatol pract concept 2019;9(3):3 3. luelmo-aguilar j, santandreu ms. folliculitis:  recognition and management. am j clin dermatol. 2004;5(5):301-310. 4. schepis c, siragusa m. secondary anetoderma in people with down’s syndrome. acta derm venereol. 1999;79(3):245. 5. kavanagh gm, leeming jp, marshman gm, reynolds nj, burton jl. folliculitis in down’s syndrome. br j dermatol. 1993;129(6):696-699. 6. finn oa, grant pw, mccallum di, raffle ej. a singular dermatosis of mongols. arch dermatol. 1978;114(10):1493–1494. 7. revuz j. disseminate recurrent folliculitis as the presenting picture of hidradenitis suppurativa. ann dermatol venereol. 2017;144(11):715-718. 8. garg a, strunk a, midura m, papagermanos v, pomerantz h. prevalence of hidradenitis suppurativa among patients with down syndrome: a population-based cross-sectional analysis. br j dermatol. 2018;178(3):697-703. 9. wang jf, orlow sj. keratosis pilaris and its subtypes: associations, new molecular and pharmacologic etiologies, and therapeutic options. am j clin dermatol. 2018;19(5):733-757. 10. zouboulis cc, desai n, emtestam l, et al. european s1 guideline for the treatment of hidradenitis suppurativa/acne inversa. j eur acad dermatol venereol. 2015;29(4):619-644. 11. hurley hj. axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach. in: roenigk rk, roenigk hh, eds. dermatologic surgery. new york: marcel dekker; 1989:729-739. 12. plewig g, kligman am. acne conglobata. in: acne. berlin, heidelberg: springer; 1975:168-203. 13. lookingbill dp. yield from a complete skin examination: findings in 1157 new dermatology patients. j am acad dermatol. 1988;18(1 pt 1):31-37. 14. jemec gb, heidenheim m, nielsen nh. the prevalence of hidradenitis suppurativa and its potential precursor lesions. j am acad dermatol. 1996;35(2 pt 2):191-194. 15. cosmatos i, matcho a, weinstein r, montgomery mo, stang p. analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the united states. j am acad dermatol. 2013;68(3):412-419. 16. denny g, anadkat mj. hidradenitis suppurativa (hs) and down syndrome (ds): increased prevalence and a younger age of hidradenitis symptom onset. j am acad dermatol. 2016;75(3):632-634. 17. liy-wong c, pope e, lara-corrales. hidradenitis suppurativa in the pediatric population. j am acad dermatol. 2015;73(5 suppl 1):s36-s41. 18. palmer ra, keefe m. early-onset hidradenitis suppurativa. clin exp dermatol. 2001;26(6):501-503. 19. deckers ie, van der zee hh, boer j, prens ep. correlation of early-onset hidradenitis suppurativa with stronger genetic susceptibility and more widespread involvement. j am acad dermatol. 2015;72(3):485-488. 20. scheinfeld n. hidradenitis suppurativa in prepubescent and pubescent children. clin dermatol. 2015;33(3):316-319. 21. ebling fjg. hidradenitis suppurativa: an androgen-dependent disorder. br j dermatol. 1986;115:259-262. 22. garg a, kirby js, lavian j, lin g, strunk a. sexand age-adjusted population analysis of prevalence estimates for hidradenitis suppurativa in the united states. jama dermatol. 2017;153(8):760764. 23. canoui-poitrine f, le thuaut a, revuz je, et al. identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. j invest dermatol. 2013;133(6):15061511. 24. karousou e, stachtea x, moretto p, et al. new insights into the pathobiology of down syndrome—hyaluronan synthase-2 overexpression is regulated by collagen vi α2 chain. febs j. 2013;280(10):2418-2430. 25. quarello e, guimiot f, moalic jm, shnoneau m, ville y, delezoide al. quantitative evaluation of collagen type vi and sod gene expression in the nuchal skin of human fetuses with trisomy 21. prenat diagn. 2007;27(10):926-931. 26. theocharidis g, drymoussi z, kao ap, et al. type vi collagen regulates dermal matrix assembly and fibroblast motility. j invest dermatol. 2016;136(1):74-83. 27. giovanardi g, chiricozzi a, bianchi l, et al. hidradenitis suppurativa associated with down syndrome is characterized by early age at diagnosis. dermatology. 2018;234(1-2):66-70. 28. o’ shea m, o’ shea c, gibson l, leo j, carty c. the prevalence of obesity in children and young people with down syndrome. j appl res intellect disabil. 2018;31(6):1225-1229. 29. melnik bc, plewig g. impaired notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa). br j dermatol. 2013;168(4):876-878. 30. kusters ma, verstegen rh, gemen ef, de vries e. intrinsic defect of the immune system in children with down syndrome: a review. clin exp immunol. 2009;156(2):189-193. 31. highet as, warren re, weeks aj. bacteriology and antibiotic treatment of perineal suppurative hidradenitis. arch dermatol. 1988;124(7):1047–1051. 32. melnik bc, plewig g. impaired notch-mkp-1 signalling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology. exp dermatol. 2013;22(3):172-177. 33. schlapbach c, hänni t, yawalkar n, hunger re. expression of the il-23/th17 pathway in lesions of hidradenitis suppurativa. j am acad dermatol. 2011;65(4):790-798. 34. berezovska o, jack c, deng a, gastineau n, rebeck gw, hyman bt. notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage. j biol chem. 2001;276(32):30018-30023. 35. blok j, jonkman m, horváth b. the possible association of hidradenitis suppurativa and down syndrome: is increased amyloid precursor protein expression resulting in impaired notch signalling the missing link? br j dermatol. 2014;170(6):1375-1377. 36. herzog v, kirfel g, siemes c, schmitz a. biological roles of app in the epidermis. eur j cell biol. 2004;83(11-12):613-624. 37. garg a, lavian j, lin g, strunk a, alloo a. incidence of hidradenitis suppurativa in the united states: a sexand age-adjusted population analysis. j am acad dermatol. 2017;77(1):118-122. 38. vlassova n, kuhn d, okoye ga. hidradenitis suppurativa disproportionately affects african americans: a single-center retrospective analysis. acta derm venereol. 2015;95(8):990-991. 39. gasparic j, theut riis p, jemec gb. recognizing syndromic hidradenitis suppurativa: a review of the literature. j eur acad dermatol venereol. 2017;31(11):1809-1816. 40. wortsman x, moreno c, soto r, arellano j, pezo c, wortsman j. ultrasound in-depth characterization and staging of hidradenitis suppurativa. dermatol surg. 2013;39(12):1835–1842. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2014;4(2):1 1 the compendium (part 4) – d – dark cells: of eccrine glands are secretory and characterized ultrastructurally by numerous vacuoles that contain mucin. the name “dark” comes from the electron-dense appearance of the cells in contrast to the electron-lucid character of light cells of eccrine glands. the terms dark cell and light cells (also known as clear and pale cells) are used also to contrast two populations of cells within a particular neoplasm, i.e., spiradenoma, wrongly designated “eccrine spiradenoma” because differentiation of that neoplasm is apocrine. in most instances, a dark appearance results from scant cytoplasm, which causes nuclei to appear crowded, as much as from dense nuclear chromatin. light cells have abundant glycogen in their cytoplasm. at scanning magnification lymphocytes appear dark in color even “black.” this is helpful in diagnosis. decapitation secretion: describes apical portions of cytoplasm of secretory cells that project prominently as buds into a lumen. the buds often contain eosinophilic granules. the neck of a bud becomes progressively thinner and eventually is lost into the lumen, giving the impression of having been “pinched off’ or decapitated. in the realm of hamartomas and neoplasms, the finding of definitive “decapitation secretion” is specific for apocrine differentiation. the terms apocrine secretion, “decapitation” secretion, “pinching-off’ secretion, and snouts are synonyms. degeneraton: in classic pathology, particular alterations detectable microscopically either in cells or in extracellular tissue, i.e., hydropic degeneration of cells and degeneration of collagen. the term is applied incorrectly to “liquefaction degeneration” of the basal layer, those changes consisting only of vacuoles situated immediately above and below the basement membrane, and to “mucinous degeneration” of a neural neoplasm where “degeneration” is employed as a synonym for deposits of mucin. “fatty degeneration” of neutrophils has been reputed to be responsible for the yellow color of pus, a claim that probably is without merit. elastotic material that results from longstanding injury to skin by the effects of ultraviolet light is not a degeneration of collagen, as it is purported to be, but rather a faulty product of fibrocytes. degeneration of cells designates injury that may not necessarily be fatal; that is, the cells are not yet dead and, therefore, are able to recover fully, as in examples of ballooning degeneration early in its course, i.e., before spinous cells have swollen dramatically and before reticular alteration has come into being. once, however, either of those two latter changes has eventuated as a consequence of ballooning severely, necrosis of keratocytes is inevitable and invariable. degeneration of collagen: loss of the normal structure of collagen bundles as a result of anoxemia or of the action of lysosomal enzymes from leukocytes; seen as granular basophilic change in tissue sections stained by hematoxylin and eosin and should not be referred to as necrosis of collagen, because collagen is a fiber and not a cell. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 4 bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 4. dermatol pract conc. 2014;4(2):1. http://dx.doi.org/10.5826/dpc.0402a01 copyright: ©2014 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@aol.com 2 review | dermatol pract concept 2014;4(2):1 in addition, degeneration of collagen refers to structural and tinctorial alterations in bundles as a consequence of injury to them. in sections stained by hematoxylin and eosin, such degeneration is recognized by loss of outlines of bundles, i.e., they appear to have a smudged appearance, and by change in quality of staining, i.e., the usual red hue becomes blue. these changes in collagen are seen in conditions as unalike as necrobiosis lipoidica, necrobiotic xanthogranuloma, and severe burns of any cause, and as a consequence of the effects of neutrophils, in large number, on collagen, as occurs in “churg-strauss granulomas,” and on elastic fibers in elastosis perforans serpiginosa, and of numerous eosinophils on collagen, as happens in “flame figures.” the term degeneration, rather than necrosis, is proper for these changes because necrosis is possible only for cells that are viable; fibrocytes, i.e., viable cells, can undergo necrosis, but collagen, i.e., fibrous tissue, cannot. dendritic melanocyte: a melanocyte that is as thin as a reed and nearly always heavily pigmented. deposit: a significant quantity of a substance in an organ where that is not a normal occurrence such as a quantity of mucin, amyloid, or urate in the skin. dermal papillae: comprise the uppermost portion of the dermis situated between epidermal rete ridges in sections oriented vertically and characterized, when viewed in three dimensions, by the appearance of nipple-like projections of connective tissue into hollows of the undersurface of the epidermis. dermal papillae constitute most of the papillary dermis, i.e., the relatively thin superficial part of the dermis that is continuous with the much thicker reticular dermis. bundles of collagen and fibers of elastic tissue are more delicate in the papillary dermis than they are in the reticular dermis. the papillary dermis also is more richly vascularized by capillaries and contains more mucin than does the reticular dermis. a dermal papilla should not be confused with a follicular papilla, to wit, the spade-shaped, mucin rich, capillary-invested connective tissue structure that invaginates the bulb of a follicle in full-fledged anagen and has different appearances at other phases of the follicular cycle. dermatitis: inflammatory disease in which the infiltrate of inflammatory cells is present in the dermis, a definition that is applied scrupulously throughout this work, in contrast to the way the term “dermatitis” is used in virtually every text of dermatology and dermatopathology, namely, as a synonym for “eczema,” a term that we employ only for purposes of decrying it. dermatoscopy (not dermoscopy): is a special procedure that may help define whether a skin lesion is benign or malignant clinically. it has other related uses. the procedure uses a dermatoscope there are no “true” words “dermoscopy” and “dermoscope;” the words correct are “dermatoscopy” and “dermatoscopic.” and that is precisely why disciplines are named dermatology, not dermology, and dermatopathology, not dermopathology. the entry for dermat-, dermatoin a dictionary of dermatological words, terms, and phrases by leider and rosenblum (dome laboratories, west haven, conn. 1976 revised edition) reads as follows: combining forms from the stem of the greek word, derma; skin, dermatos; of the skin.” not surprisingly, there is no entry in that dictionary for dermobecause no such stem exists. it is not too late to banish dermoscopy and dermoscopic in favor of dermatoscopy and dermatoscopic. dermatosis: refers to any condition of the skin, by implication an abnormal one, among those being inflammation, i.e., dermatitis. confusingly, some authors use “dermatosis,” in contradistinction to “dermatitis,” for skin conditions that are not characterized by inflammation clinically. in our judgment, the term “dermatitis” or “inflammatory disease of the skin” is preferable to “inflammatory dermatosis” because it is more direct, “dermatosis” being generic, not specific, and employed for diseases other than inflammatory ones. dermis: refers to the connective tissue of the skin that is situated between the epidermis and the subcutaneous fat (which is really not part of the skin [the skin being the epidermis and the dermis]). it is divided roughly into two components: a thin adventitial dermis composed of a superficial papillary dermis and a continuous periadnexal dermis, and a thick reticular dermis. both the adventitial dermis and the reticular dermis are composed of cells (fibrocytes, dendrocytes, and mast cells), bundles (collagen), fibers (elastic), and ground substance (mucin). within the dermis reside epithelial (folliculosebaceous-apocrine and eccrine) and nonepithelial (blood vessels, nerves, and smooth muscles) structures of adnexa. dermoepithelial interface: the junction between dermis and epithelial structures contiguous with it, i.e., epidermis (surface and infundibular) and adnexal (folliculosebaceous apocrine and eccrine). what transpires at the interface between dermis and epidermis especially is important for diagnosis by conventional microscopy of those inflammatory diseases of the skin designated “interface dermatitides.” the interface also is important in other highly circumscribed circumstances, such as a perceptibly thickened basement membrane there, an evidence of either discoid lupus erythematosus or dermatomyositis. the thickened basement membrane is denoted as “smudged” by some dermatopathologists. desmoplasia: refers to fibroplasia that develops in response to certain proliferations. desmoplastic melanoma is truly desmoplastic because a proliferation of fibrocytes, which produce fibrous tissue, accompanies the proliferation review | dermatol pract concept 2014;4(2):1 3 malignant of melanocytes. in contrast, desmoplastic trichoepithelioma is not truly desmoplastic because the number of fibrocytes in the stroma is not increased notably and fibrosis is not discernable readily. differentiation: denotes a change whereby things become unlike in structure, function, and specialization and, in biology, the process by which, in the course of development, cells become modified into a form specific, structurally and functionally. for example, differentiation occurs in an embryo as germinative cells at loci of surface ectoderm evolve into apocrine-sebaceous-follicular units, each component of which having distinctive attributes morphologic, and differentiation occurs in proliferations postnatal as cells of them attempt to recapitulate events in life embryonic by forming elements of them, as in trichoblastoma where follicular germs often are contiguous with a follicular papilla, sebaceoma in which sebocytes at one or more stages various of maturation and structures akin to sebaceous ducts are nearly invariable, and papillary apocrine adenoma in which cells that line lumina sport signs of “decapitation secretion.” when structures that seem to be normal are evident, a proliferation is judged to be well differentiated; when there are only hints vague of structures normal, a proliferation is regarded as poorly differentiated; when no sign of a structure normal is apparent, a proliferation is considered to be undifferentiated. maturation is a kind of differentiation, namely, that specific of cells as they age, i.e., a basal keratocyte of the epidermis into a corneocyte and an immature sebocyte at the periphery of a lobule into a mature one in the center of it. (see maturation) digitated: refers to the shape of a type of epidermal proliferation that expresses itself as finger-like projections above the skin surface, as may be seen in verruca vulgaris or solar keratosis. mammillated differs from digitated by having rounded, rather than pointed, protuberances. dopa: is an acronym for dihydroxphenylalanine, which is oxidized by dopaoxidase in a positive dopa reaction, i.e., one in which melanogenesis occurs. duct: is a discrete structure tubular lined by epithelial cells and specialized for transport of substances secretory or excretory. most ducts, such as dermal ones of eccrine units, serve purposes other than mere transport, such as exchange of substances, mostly of electrolytes, and concentration of secretions or excretions. the ducts of apocrine and eccrine glands are indistinguishable from one another morphologically, but sebaceous ducts possess a surface crenulated that stamps them incontestably for what they are. dull pink globules (kamino bodies): globules that are stained very light red by hematoxylin and eosin, bright red by periodic acid schiff (and resistant to diastase), and blue with masson’s trichrome, and present in the epidermis of about 50% of all junctional and compound examples of “classic” spitz’s nevi. they are found in other kinds of nevi, such as reed’s, and, uncommonly, in clark’s. they do occur in melanoma. the number of them varies greatly in “classic” spitz’s nevus, from but a single globule too many globules disposed as solitary units and in clusters. when present in other kinds of nevi and in melanomas, they tend to be few. the globules in “classic” spitz’s nevi, and presumably in melanomas, consist of material that composes basement membrane, namely, laminin and type iv collagen. in short, the finding of these globules almost always signifies “classic” spitz’s nevus or “reed’s nevus,” but they are not a signs unequivocal of them. dusty melanin: fine granules of melanin of uniform size usually evenly dispersed throughout the cytoplasm of melanocytes or keratocytes. dyskeratosis: cornification abnormally of individual keratocytes within the epidermis and epithelial structures of adnexa. dyskeratotic cells have pyknotic nuclei and eosinophilic cytoplasm, the latter, as visualized by electron microscopy, being jammed with filaments of keratin in perinuclear aggregation. those prematurely cornified cells are encountered in inflammatory diseases, such as grover’s disease and the verrucous stage of incontinentia pigmenti, in neoplastic diseases, such as bowen’s disease and the squamous cell carcinoma called subungual keratoacanthoma; in darier’s disease; acantholytic dyskeratosis acanthoma, and in cystic conditions such as warty dyskeratoma. in all instances, dyskeratosis is an expression of unexpectedly early, but slow, death of keratocytes. in contrast, those keratocytes that die rapidly have no time to cornify, a fact made manifest by the presence of a normal basket-weave configuration of the stratum corneum met with above necrotic cells, mostly spinous ones, in conditions such as erythema multiforme and fixed drug eruption, and in processes in which necrosis occurs even more suddenly and diffusely, such as burns of all kinds. because keratocytes that die slowly undergo cornification, rather than become necrotic, the stratum corneum above them bears testimony to that in the form of either parakeratosis or compactly organized orthokeratosis, as occurs in the squamous cell carcinoma of the bowen’s type and lichen planus, respectively. dyskeratotic cell: a cell that cornified prematurely or abnormally with a pyknotic nucleus and brightly eosinophilic cytoplasm, as in darier’s disease, warty dyskeratoma, and squamous-cell carcinoma in situ. dysplasia: in classic virchowian pathology, an abnormality that results from an aberration in the embryological anlage. 4 review | dermatol pract concept 2014;4(2):1 in the past four decades, general pathologists have perverted the definition original of dysplasia and in its place have introduced a bevy of new definitions for it, those being as disparate as “cytologic atypia,” “atypical hyperplasia,” “abnormal growth,” “aberrant differentiation,” and “architectural and cytologic atypia.” because no single definition, intelligible and repeatable, exists for dysplasia, use of that term serves only to impede communication between and among pathologists, to say nothing of discourse rational between pathologists and clinicians. for that reason, the term “dysplasia” should be avoided scrupulously. dysplastic nevus: as it is “pictured” it is the most common of all nevi, it being characterized clinically by variability in size (from a few millimeters to more than a centimeter) and in hue, it usually being tan and flat at the periphery and darker brown and only slightly elevated in the center, but sometimes displaying more than two shades of brown. when compound, it is typified histopathologically by having the silhouette of a benign neoplasm (i.e., symmetrical, well circumscribed, etc.), being only slightly elevated, if at all, and displaying small nests of melanocytes at the dermoepidermal junction and, in the very center of the lesion, a few nests small in the papillary dermis, the nuclei of those melanocytes being small, oval, and monomorphic. the concept of dysplastic nevus is predicated on the notion of melanocytic dysplasia, a term that has yet to be defined in a crisp, comprehensible, repeatable way. we eschew the term “dysplasia” and “dysplastic nevus,” the former because it is unnecessary in general and for diagnosis with specificity in particular, and the latter because we name nevi eponymically, in the case of so called dysplastic nevus for clark, of so-called juvenile melanoma for spitz, and of so-called pigmented spindle-cell tumor for reed. last, dysplastic nevi were said, over and over again, by clark and acolytes to be a “precursor” of melanoma and a “marker” for persons at risk for melanoma. they are neither. less than 10% of all melanomas in the world, i.e., in persons of all races, develop in association with a preexisting nevus of any kind, and then the most common nevus, by far, is a congenital one that affects markedly the thickened papillary dermis (superficial) or the upper part of the reticular dermis (superficial and “deep”), not an acquired “dysplastic” one. moreover, no relationship has been proven between the presence of so-called dysplastic nevi and risk for developing melanoma. it is true that episodically a melanoma may develop in continuity with a clark’s nevus, just as it may in association with any kind of melanocytic nevus. dysplastic nevus syndrome: a misconception based on misperceptions, namely, of “melanocytic dysplasia” and “dysplastic nevus.” the so-called syndrome consists of a single element, to wit, dysplastic nevi, and, therefore, does not fulfill criteria for a syndrome, which is a constellation of signs and symptoms that constitute a disorder. furthermore, no agreement exists about how many of those nevi are requisite for diagnosis of the “syndrome,” some authors insisting that “only a single nevus” is sufficient, whereas others contend that more than 100 of them are necessary. – e – ecchymosis: a broad, flat purpuric lesion that results from bleeding into the upper part of the dermis. eccrine: designates a type of secretion or a gland responsible for that secretion in which the cells remain intact during the manufacture and release of the resulting chemical substance, the mechanism of secretion being called merocrine. eccrine glands are situated normally everyplace on the integument, but they are especially numerous on palms and soles, sites where apocrine glands and hair follicles are absent. ectoderm: all constituents of human skin are derived from either ectoderm or mesoderm. the epithelial structures, i.e., epidermis (surface and infundibular), apocrine units, sebaceous units, hair follicles, eccrine units, and nail units, come from ectoderm. melanocytes, nerves, and specialized sensory receptors develop from neuroectoderm. the other elements of skin, i.e., langerhans’ cells, macrophages, mast cells, fibrocytes, blood vessels, lymph vessels, muscles, and adipocytes originate from mesoderm. eczema: a nonspecific term for various unrelated inflammatory diseases, one that has not been defined in a repeatable way after nearly 150 years of usage. some sense for the frustration a student of inflammatory skin diseases must feel in regard to comprehending the meaning of the term can be gleaned from the definition offered by hebra, the great austrian dermatologist of the 19th century, namely, “eczema is that which looks like eczema,” a profundity that continues to be mouthed smugly in some quarters to this day. the “eczemas” are said to include diseases as disparate as allergic contact dermatitis (and nummular dermatitis, dyshidrotic dermatitis, and “id” reactions), atopic dermatitis, lichen simplex chronicus, and seborrheic dermatitis. perhaps the best attempt at lucid definition of eczema is a papular or papulovesicular disease characterized histopathologically by spongiosis. that definition, however, excludes a paragon of eczema in most classifications of it, i.e., lichen simplex chronicus (because that condition is devoid of spongiosis) and atopic eczema (which also is bereft of spongiosis). some manifestations of atopic dermatitis may show spongiosis within an infundibulum and a superficial perivascular predominately lymphocytic infiltrate (spongiotic infundibulitis). it also includes pityriasis rosea, erythema annulare centrifugum, and miliaris rubra, to mention but three spongiotic dermatitides that no textbook of dermatology and no dermatologist consider to be among review | dermatol pract concept 2014;4(2):1 5 the eczemas. in short, there is no need for dermatologists to continue to squander time and thought in an effort vainly to define eczema; in reality, it cannot be done and, furthermore, there is no need for the term at all. each of the diseases reputed to be eczema can be diagnosed with specificity for what it is based on both clinical features and histopathologic findings, i.e., allergic contact dermatitis, nummular dermatitis, dyshidrotic dermatitis, “id” reaction, and seborrheic dermatitis. in short, the word eczema, like dysplasia, is an impediment to communication among physicians and should be jettisoned, along with variations on the theme of it such as eczematoid, eczema-like, eczematous, eczematous dermatitis, eczematization, eczematogenic, and eczematosis. elastophagocytosis: is the process by which a macrophage engulfs altered fragments of elastic or elastotic tissue. elastotic material: solar elastosis, i.e., the altered, basophilic, spaghetti-like connective tissue produced by fibrocytes that have been exposed for many years to the damaging effects of ultraviolet light. embryo: refers to an early or developing stage of any organism, in particular, the developing product of fertilization of an egg. in humans, embryo designates a developing organism from 1 week after conception to the time that a crownrump length of 30 mm is attained by about 55 or 56 days after fertilization. during the embryonic period, formation of organs (organogenesis) is accomplished. the embryonic period is followed by fetal development, which continues until birth and during which development of specific tissues (histogenesis) and initiation of specific functions is achieved. endophytic: growing inward, as from the surface of the skin, like a morpheaform basal-cell carcinoma. epidermal hyperplasia: an increased number of cells, especially spinous ones, in a thickened epidermis. we employ it as a synonym for acanthosis because the latter is a parochial term restricted in scope to cutaneous pathology. because dermatopathology and general pathology are one pathology, one language should be used for both. strictly speaking epidermal hyperplasia applies also to an increased number of cells in the cornified layer, but by convention that abnormality is termed hyperkeratosis. so, too, epidermal hyperplasia includes an increased number of granular cells, but, by custom, that phenomenon is designated hypergranulosis. for the aforementioned reasons, we use epidermal hyperplasia as a synonym for spinous cell hyperplasia of the epidermis. epidermal nevus: hamartoma characterized by papillated or digitated proliferation of epidermal keratocytes and associated almost always with hyperkeratosis. epidermolytic hyperkeratosis: refers to a pattern within an epithelium, especially epidermis, characterized by enlarged, markedly vacuolated keratocytes with feathery borders, within whose cytoplasm are numerous coarse keratohyaline granules and on occasion, trichohyalin granules. the boundaries between the keratocytes appear to be lysed. visualization of the cells by electron microscopy reveals that there actually is no lysis: the cells are cohesive. all of these changes occur in association with marked orthokeratosis. epidermopoiesis: the making of epidermis; the process of maturation of epidermal basal cells into cornified cells. epidermotropic: (see epidermotropism) epidermotropically metastatic: traditionally used to describe metastases to skin that involve the epidermis as well as the upper part of the dermis. neoplastic cells of a metastasis destined to become epidermotropic emerge from cutaneous vessels, usually in the upper part of the dermis, and migrate to epidermis and sometimes to epithelial structures of adnexa. the most common epidermotropic metastasis to skin is melanoma. these metastases are usually in the epidermis or the upper part of the dermis but may be in the epidermis alone. porocarcinomas, carcinomas of the genital tract in women, and carcinomas of the gastrointestinal tract are sometimes metastatically epidermotropic. sarcomas practically never metastasize to epidermis. it would be better not to use this term. (see epidermotropism for an explanation) epidermotropism: a biological phenomenon that indicates growth or turning movement of a cell or a collection of cells toward the epidermis. in a strictly morphologic sense, it is not definable. adj. epidermotropic. the following term is suggested instead: intraepidermal: being present within the epidermis. the word epidermotropic is not defined in any of the main medical dictionaries, nor is it in textbooks of dermatology or dermatopathology. as for epidermotropism, it is only defined in a minority of dictionaries and in some textbooks. strictly speaking, the suffix tropism implies a movement; the best example is the turning or bending phenomenon plants undergo in response to light as the environmental stimulus. this response is called phototropism. literally, epidermotropism means a “turning towards the epidermis or having an affinity for the epidermis.” when checking the words “epidermotropism” and “epidermotropic” in dictionaries, textbooks, and journals, it is hard to find them unassociated with mycosis fungoides. in the rest of the cases, those words are used almost exclusively for other lymphomas, especially the t-cell lymphomas. it is difficult to find other diseases with “epidermotropic” alterations, but when that happens, interestingly they are almost always malignant processes, i.e., carcinomas such as paget’s disease 6 review | dermatol pract concept 2014;4(2):1 or porocarcinomas, or metastatic melanomas. last, there are only isolated usages of the words “epidermotropism” or “epidermotropic” in inflammatory conditions in part because, as it can be inferred from literature, those words are apparently synonymous with malignancy. in addition, epidermotropism and epidermotropic seem to imply the diagnosis of mycosis fungoides, and vice versa. equally and for the same reason, epidermotropism is linked to an infiltrate of lymphocytes, and it is not used when the infiltrate is made of other cells. what dermatopathologists call “epidermotropism” most of the time is the presence of lymphocytes in the epidermis. however, in more than half of the routine cases in a dermatopathology laboratory, there are lymphocytes within the epidermis, as in any spongiotic psoriasiform, or interface dermatitis, even in epidermal or melanocytic “tumors”, and none of these infiltrates are usually referred to as epidermotropic; other words, like exocytosis, are employed. nor is the presence of cells other than lymphocytes in the epidermis referred to as epidermotropism, even though those cells move from dermal vessels to the epidermis, just as lymphocytes do in mycosis fungoides. it seems as if dermatopathologists, when looking at lymphocytes within the epidermis, made the choice between using as a designation either exocytosis or epidermotropism only after having decided whether the condition is benign or malignant or, more specifically, “nonlymphoma” or lymphoma. even in those few cases in which the term epidermotropism is used for diseases that are not lymphomatous, it is only employed for malignant conditions, i.e., histiocytosis or metastatic melanoma. in addition, there is no agreement universally on what each author means by epidermotropism. some use it exclusively for the lymphocytes of mycosis fungoides others extend it to lymphocytes of lymphomas in general, still others use it for the presence in the epidermis of carcinoma or melanoma cells themselves and yet others for any inflammatory cell present in the epidermis, notwithstanding whether the process is malignant or benign. moreover, the suffix tropism designates a movement that cannot be seen on the static tissues of a slide. a pathologist, however, should limit himself to describing the changes and their location with regard to normal structures and should avoid interpretations in regard to “movement.” for all these reasons, the words epidermotropism and epidermotropic are best avoided in description of microscopic findings on sections of tissue. epithelial mucin: refers to mucopolysaccharides characterized by high content of neutral glycoprotein produced by epithelial cells. in skin, infundibulum of the surface epidermis is the major source of epithelial mucin, but sebaceous and eccrine cells also are capable of making mucin. dermal mucin differs from epithelial mucin by being constituted mainly of acid mucopolysaccharides. epithelial structures of adnexa: derivatives of germinative cells of surface ectoderm in an embryo, one type of germ giving rise to hair follicles, sebaceous glands and ducts, and apocrine glands and ducts, and another type of germ to eccrine glands and ducts, those four structures epithelial being ones adnexal. epithelioid: the oval shape of nonepithelial cells (the nucleus being oval and the cytoplasm being discernible readily) arranged in a synctium that has a resemblance faint to cohesive cells of an epithelium. in histopathology of the skin, the word is applied to histiocytes of inflammatory diseases, such as sarcoidosis, and melanocytes of noninflammatory processes, such as melanocytic nevi, in which cells, with plump oval shape appear to touch one another like epithelial cells. epithelioid histiocytes characterized by plump oval nuclei and abundant eosinophilic cytoplasm are disposed snugly in collections of sarcoidal and turberculoid granulomas, in contrast to nonepitheloid macrophages, which tend to be disposed as solitary units. epithelioid melanocytes, typified by plump oval nuclei and abundant eosinophilic cytoplasm, are seen, for example, in ovoid aggregations and fascicles in one of the numerous variants of “classic” spitz’s nevus. they may be also seen in melanoma. epitheliod melanocyte: (see epitheloid) epithelioma: is a french word for carcinoma, but which is employed by english-speaking dermatologists and pathologists in ways various, such as in trichoepithelioma (known also as “epithelium adenoides cysticum”), which is a benign proliferation of follicular germinative cells, basal cell epithelioma, which is a malignant proliferation of germinative follicular cells, and squamous cell epithelioma, which is a malignant proliferation of spinous cells, the latter two proliferations malignant qualifying as carcinomas. epithelioid tubercle: a collection of epithelioid histiocytes. when not surrounded by lymphocytes, they are referred to colloquially as naked tubercles and are a characteristic feature of the granulomas of sarcoidosis and its simulators; when surrounded by dense infiltrates of lymphocytes, they are called tuberculoid. epithelium: denotes a layer of cells that covers surfaces of the body and membranes that line it. epithelia are derived from all three germ layers, although most arise from ectoderm and endoderm. epithelia are classified on the basis of layers into simple and stratified, and on the basis of cellular review | dermatol pract concept 2014;4(2):1 7 characteristics into squamous, cubical, and columnar. simple squamous epithelium consists of a single layer of flat cells such as those found in air spaces of the lungs. epithelium that lines the lumen of blood vessels and body cavities is similar morphologically to simple squamous type but is categorized separately as endothelium and mesothelium, respectively. simple cubical epithelium may be observed on the surface of the ovary. simple columnar epithelium appears in portions of many ducts and glands, such as apocrine ones. specialized columnar epithelium with capability to secrete mucus is typical of the lining of the stomach, the cervical canal of the uterus, and the conjunctiva. pseudostratified columnar epithelia present in the male urethra and in large excretory ducts of a parotid gland consist of a single layer of tall cells whose nuclei are situated at different levels and thereby create the impression of being arranged in several layers. stratified columnar epithelium may be seen in large ducts of exocrine glands. stratified epithelium that does not cornify is typical of mucous membranes of the mouth, upper part of the esophagus, and vagina. stratified epithelium that cornifies covers the surface of the skin, i.e., the epidermis, and lines ducts of adnexa, such as those of sebaceous glands. transitional epithelium is seen only in the urinary bladder. epithelial cells appear histologically cohesive. erosion: loss of part or all of an epidermis without any loss of dermis. in contrast, ulcer denotes loss of entire epidermis and at least part of the dermis. stereotypical erosion is the denuded lesion of pemphigus vulgaris in which a layer of basal cells remains intact beneath the blister. the most common cause of erosions in skin is lively excoriation by long, sharp fingernails that act like talons. because erosion does not involve the dermis, it heals without a scar, unless infection has supervened and, with it, ulceration. erythroderma: redness often accompanied by scaling of the entire skin such as occurs in psoriasis, mycosis fungoides, and so-called atopic dermatitis and numerous other skin diseases. proper biopsy, dermatopathologic interpretation and clinicopathologic correlation can often help one come to a diagnosis. exo-endophytic: means growing outward and inward from the skin surface, as in fully developed squamous cell carcinoma of the keratoacanthomatous type. exophytic: growing outward, as from the skin surface, like a filiform verruca. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023175 1 can stria gravidarum predict surgical fluid loss in cesarean section? seyma banu arslanca1, ozgur sahin2, ugurkan erkayıran3, zehra ozturk basarır4, tufan arslanca4 1 department of obstetrics and gynecology, etlik zübeyde hanım maternity and women’s health teaching and research hospital, ankara, turkey 2 department of obstetrics and gynecology, canakkale state hospital, canakkale turkey 3 department of obstetrics and gynecology, sutcu imam university, faculty of medicine, kahramanmaras, turkey 4 department of gynecologic oncology, ankara city hospital, university of health sciences, ankara, turkey key words: stria gravidarum, surgical fluid loss, cesarean section, davey score citation: arslanca sb, sahin o, erkayıran u, basarır zo, arslanca t. can stria gravidarum predict surgical fluid loss in cesarean section? dermatol pract concept. 2023;13(3):e2023175. doi: https://doi.org/10.5826/dpc.1303a175 accepted: november 7, 2022; published: july 2023 copyright: ©2023 arslanca et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: tufan arslanca, department of gynecologic oncology, ankara city hospital, university of health sciences, ankara, turkey. orcid:0000-0001-9686-1603 e-mail: drtufanarslanca@hotmail.com introduction: alterations in collagen subtypes and matrix can potentially cause fluid loss in surgery which is important in terms of liquid loss. objectives: the study aimed to analyze stria gravidarum (sg) and its severity in pregnant women who had undergone cesarean section (cs) and to evaluate surgical fluid loss (sfl) that occurred during cs operation. methods: the research was designed as a prospective clinical cohort study to compare the amount of sfl in the second cesarean section with the severity of sg at 34-37 weeks pregnant (n 308). the severity of sg was evaluated in the preoperative period using the davey scoring. all patients were defined none, mild stria and severe stria. the sfl was calculated by weighing the pre-and post-operative weights of the sponges. results: the weight gain (p = 0.008) and body mass index (bmi, p = 0.017) gradually increased toward severe sg. in correlation analysis of sfl, a positive correlation was found with davey (r=0.791; p = 0.0001), weight gained during pregnancy (r=0.328; p = 0.0001), bmi (r=0.453; p = 0.001) and newborn weight (r=0.139; p = 0.003). in the receiver operating characteristic for the predictability of sg severity on sfl, severe sg showed a potential for sfl with 95.1% specificity and 93.2% sensitivity at 791 cut-offs (area under the curve:0.987; p = 0.00001; 95% confidence interval: 0.977-0.997). abstract 2 original article | dermatol pract concept. 2023;13(3):e2023175 introduction as a result of immunological, metabolic, endocrine, and vascular changes that occur during pregnancy, various physiological and pathological processes occur in the skin and skin appendages of the pregnant woman [1,2]. among the physiological skin changes seen in pregnant women such as weight gain [3], stria gravidarum (sg) is considered to be the most common skin change [4]. after birth, the skin color is characterized by bands that turn into hypopigmented, atrophic lines, and appear on the abdomen, thighs, distal femoral areas, inguinal region, and breasts after an average of 24 weeks of gestation [2,5]. these lesions, whose exact cause is unknown, are thought to develop as a result of connective tissue changes such as a decrease in the amount of elastin and fibrillin in the dermis [6,7]. after birth, it is less visible with a pale and cream-colored, atrophic appearance over time, but it does not disappear completely [8,9]. although striae are not a serious condition that will risk health, they can cause complaints such as itching and burn on the skin, and these physical changes can cause serious anxiety in pregnant women [10]. local retinoic acids, glycolic acid, and vitamin c may be beneficial after pregnancy [11]. benefiting from these supplements is one of the strongest indications of how critical a collagen deficiency or disorder plays in sg [12,14]. collagen is not only the crucial component of the extracellular-matrix, maintaining the dermis structure but also an important molecule for coagulation systems [15-17]. although the formation of the vascular tube takes place in a polymerized 3d collagen lattice, endothelial cells cannot be organized into capillary-like structures on a hard plastic surface [18]. it is unclear how damage to the collagen matrix triggers endothelial cell organization in a vascular network and what factor might be involved. cellto-cell interactions in the vascular structure are essential for the endothelial cell organization to transform into a luminal structure and may be associated with sg due to altered collagen fibers and a collagen matrix [19]. objectives we acknowledged that alterations in collagen subtypes and matrix can potentially cause fluid loss and this issue has not been investigated in terms of sg and its severity. the present study aimed to analyze the sg data and its severity in pregnant women who had undergone cesarean section (cs) and to evaluate the relationship of these values with the surgical fluid loss (sfl) that occurred during cs operation. thus, we focused to understand the relationship between the severity of sg and the amount of sfl during the cs. methods study design the study was designed as a prospective clinical cohort study to compare the amount of sfl in the second cesarean section with the severity of sg in 34-37 weeks pregnant women. the study included healthy pregnant women over the age of 18 who gave birth to a single newborn in their second cs at the medical center between 2020 and 2022. the study was approved by the review board of the institution (14.10.202207-363) and conducted following the helsinki declaration, a set of ethical principles regarding human experimentation. all the participants read and signed the informed consent about the study. study participants all pregnant women who attended the hospital and were scheduled for cs were invited to enroll in the study. inclusion criteria were to be admitted for the second cesarean section with the severity of sg in 34-37 weeks pregnant women who had a history of only one cesarean section. reluctance to participate in the study, not meeting the admission criteria, having a chronic disease, and having any complications in the previous cesarean section were accepted as exclusion criteria. in addition to 7 women who were not willing to participate in the study for various personal reasons, 42 people with a midline incision, suspected preoperative placenta accreta, using corticosteroids, history of abdominopelvic surgery and/or wound infection, endometriosis or pelvic inflammatory disease were excluded from the study. stria-davey scoring and groups for study planning, one of the researchers consulted all eligible participants to obtain detailed anamnesis; cs history, age, body mass index, gestational age, parity, previous miscarriage, etc. the severity of sg was evaluated in the preoperative period using the four body regions (abdominal, hip, hip, and breast) where sg is most common and using conclusions: the sg severity and sfl showed a very strong relationship, which was a very important finding that would affect the approach of the surgeons to the patients with sg in terms of fluid loss in cs. original article | dermatol pract concept. 2023;13(3):e2023175 3 the davey scoring system. the abdomen was divided into 4-quadrants concerning a line drawn horizontally from the midline and the navel, and each quadrant was given a score: score 0=clear skin, score 1=moderate (1–3), and score 2=many striae (4 and more). according to this calculation, the scores of all four quadrants were added together to obtain the total, and patients with none (score 0) were defined as the group i, mild (score1-2) were defined as ii and severe (score 3-8) were defined as iii. c/s operation and sfl amount all cs included in the study was performed and the data were recorded by two experienced residents and blinded to the results of the davey score assessment. surgeons were asked to measure and report the amount of sfl after performing the surgery. they calculated the amount of sfl by weighing the pre-and post-operative weights of the sponges we used in the cesarean section in the operating room and looking at the hemoglobin difference. we used sponges after the delivery of the baby and placenta and thus, excluded amnion and bleeding due to c/s. in addition, the amount of blood measured with sponge was considered to be insignificant, since there was no difference at preoperative and postoperative values of the hemoglobin and hematocrit. in this way, the weight difference between sponges reflects the amount of sfl. statistical analysis after the data were collected, they were turned into an excel spreadsheet and the data were transferred to spss©statistics v22 (ibm© corp.) and analyzed with proper methods. while quantitative data were presented as mean and standard deviation, qualitative data were presented as frequency and percentage. the mann-whitney test compared the skewed data while the unpaired t-test evaluated the normally distributed quantitative data such as sfl amount. categorical data were compared using the chi-square test or fisher exact test if appropriate. correlation analysis of the amount of sfl and severity was performed in the groups determined according to the davey score. in addition, we performed a stepwise linear regression model for predictors. the receiver operating characteristics (roc) curve was constructed to determine the best cut-off value for the amount of sfl and sg severity diagnostic fit. the best cut-off in the roc curve has the highest true positive rate along with the lowest false positive rate. a p-value less than 0.05 was considered significant. results three hundred fifty-seven women were evaluated to participate and 49 cases did not join the present study due to not meeting the inclusion/exclusion criteria. the 308 pregnant were defined by davey score into three subgroups: group-i included 71 as none, group ii included 107 as mild, and group iii included 130 women as severe. the mean age was 28.7± 6.07 years and did not differ for groups (p = 0.566). the weight gain (p = 0.008) and body mass index (bmi, p = 0.017) gradually increased toward severe sg. hemoglobin (pre/postoperative), platelet, pt, aptt, ast, alt, bun, creatinine, and fibrinogen were similar for groups. there was no significant difference in the baseline characteristics of both study groups, as seen in table 1. in the correlation analysis performed with the amount of sfl, a positive correlation was found with davey (r=0.791; p = 0.0001), weight gained during pregnancy (r=0.328; p = 0.0001), bmi (r=0.453; p = 0.001) and newborn weight (r=0.139; p = 0.003). other parameters we analyzed did not show a significant relationship with the sfl. the stepwise linear regression analysis of sfl showed davey score-sg severity as the most dominant parameter (62.2±3.3; beta:0.67, p = 0.0001, adjusted r2= 0.68) affecting its linearity as seen in table 2. bmi, alt, weight gain, age, and creatine were the other strongest parameters effective over sfl after sg severity. in the roc analysis, we did for the predictability of sg severity on sfl, severe sg showed a predictive potential for sfl with 95.1% specificity and 93.2% sensitivity at 791 cutoff value (area under the curve:0.987; p = 0.00001; 95% confidence interval: 0.977-0.997). bmi and delta hemoglobin were also analyzed for the predictability of sg severity, as seen in figure 1. although the delta hemoglobin did not predict the sg severity (p = 0.696), the bmi showed a potential for it (area under the curve:0.744; p = 0.008; 95% confidence interval: 0.689-0.798). conclusions the present research assessed stria severity in pregnant women with cs and its relationship with the amount of sfl that occurred during cs operation. although the difference in punch weights before and after the operation was inconsistent with blood parameters indicating the bleeding status, the sg severity and the fluid loss measured during the operation showed a very strong relationship, which was a very important finding that would affect the approach of the surgeons to the patients with sg in terms of fluid loss in cs. the emergence of sg in pregnant individuals occurs as a result of pathological and histological changes as a result of mechanical tissue tension, mast cell degranulation due to elastolysis in the mid-dermis, and macrophage stimulation [7,17]. gradual changes occur and collagen, elastin, and fibrillin fibers are markedly reduced. as the epidermis thins and flattens, the distance between the collagen bundles 4 original article | dermatol pract concept. 2023;13(3):e2023175 table 2. the stepwise linear regression analysis of surgical fluid loss (sfl). model b se beta t p value lower upper constant 87.4 63.13 1.38 0.167 -36.7 211.7 davey score 62.2 3.33 0.67 18.63 0.0001 55.6 68.7 bmi, kg/m2 8.5 1.84 0.16 4.59 0.0001 4.86 12.1 alt, u/l 2.18 1.09 0.06 2.002 0.046 0.03 4.33 weight gain, kg 4.11 1.64 0.08 2.506 0.013 0.88 7.33 age, years 3.43 1.37 0.08 2.491 0.013 0.72 6.14 creatine, mg/dl -8.73 4.03 -0.07 -2.16 0.031 -16.67 -0.79 alt = alanine aminotransferase; bmi = body mass index; se = standard error. dependent: the amount of sfl was defined thgrough pre/postop measurements of punches. predictors: age, pregnancy week, davey score, family history, bmi, weight gained during pregnancy, smoking, baby gender, baby weight, hemoglobin, pulse, diastolic/sistolic blood pressure, platelet, protrombin time, active partial tromboplastine time, inr, ast, alt, bun, creatinine, fibrinogen. table 1. demographics and clinical details of the participants. variables none mild severe p value age, years 27.4±5.3 29.3±6.1 30.0±6.0 0.566 bmi, kg/m2 26.9±3.7 29.9±4.0 32.5±4.4 0.017 weight gain, kg 9.2±3.6 11.2±4.5 13.7±5.3 0.008 pregnancy, week 38.4±1.1 38.4±1.5 38.3±1.2 0..874 newborn weight, kg 3110±487.5 3161±566.2 3345±596 0.302 newborn gender, m/f 34 / 37 61 / 46 71 / 59 0.478 stria history, n/m/s 37 / 31 / 3 44 / 44 / 19 13 / 42 /75 0.001 term status, p/e/f/l 1 / 39 / 28 / 3 6 / 54 /37 /10 3 / 76 / 44 / 7 0.401 hb – preoperative 11.6±1.4 11.6±1.5 11.8±1.5 0.121 hb – postoperative 10.2±1.4 10.1±1.5 10.4±1.6 0.407 platelet count x103 238±74 246±75 240±76 0.714 pt, sec 9.7±1.47 9.72±1.5 9.78±1.78 0.847 aptt, sec 27.7±4.4 28.2±4 27.3±4 0.622 ast, u/l 17.8±6.9 19.2±11.5 18.7±5.4 0.609 alt, u/l 9.15±4.96 11.2±9.86 11.9±6.71 0.297 bun, mg/dl 10.1±9.2 8.8±5 8.9±5.3 0.438 creatinine, mg/dl 0.5±0.15 0.5±0.12 0.49±0.14 0.899 fibrinogen, g/l 390±52 401±58 415±73 0.856 alt = alanine aminotransferase; aptt = activated partial thromboplastin time ast = aspartate aminotransferase; bun = blood urea nitrogen; hb = hemoglobin; n/m/s = none/moderate/severe; p/e/f/l = pre/early/full/late term; plt = platelet; pt = prothrombin time. increases with the dilatation of the blood vessels, and the elastic fibers are separated [2]. as collagen and elastin are the two major components of the arterial wall, they are passive mechanical components of soft tissues and their molecular structures regulate the characteristic response of tissues to mechanical effects [20]. previous studies reported that women with sg have problems such as adhesion and prolapsus [21,22]. however, the effects of these problems on the vessel wall in these individuals were not investigated. surgeons should take into consideration this issue in surgical approaches such as sc where sfl is in higher amounts. physiologically, the formation of the vascular tube occurs in a polymerized 3d collagen lattice. however, the organization of vascular endothelial cells into capillary-like structures does not occur on a hard surface, even if the surface is covered with a suitable matrix component [23,24]. the study by wang et al, investigating changes in collagen fibrils, reported increased prominence of dermal blood vessels in the early period of sg [20]. this alteration, branching, and widening of vessels, involving increased numbers, promote clinical erythema and explains how the appearance of striae can be improved [25]. according to them, type-i collagen original article | dermatol pract concept. 2023;13(3):e2023175 5 loss in individuals with sg in cs operations. as the most important point, the relationship between these losses and the severity of sg was independent of bleeding. although it is novel research in its field, it had strengths and limitations. first, the main strength is that it is the first research to analyze the association between the severity of sg and sfl in pregnant, with a large sample size. second, demographics such as the age, bmi, and fetal weight of all pregnant were similar which may lessen the bias when comparing the sg groups. because we performed the current analysis as a prospective design, we were able to compare blood data such as hb concentration, platelets, and rbc before and immediately after the cs to understand sfl content. however, the study proceeded without any long-term follow-up. among the participants, a collagen measurement could be made in neither the blood nor the sfl. severe sg according to davey score was positively associated with the sfl and evaluation of sg status is a quick method that may be used for the prediction of sfl. the severity of sg and the sfl measured during the operation showed a very strong relationship, which was a very important finding that would affect the approach of the surgeons to the patients with sg in terms of fluid loss in cs. nevertheless, multicenter studies with more participants are needed in clinical and surgical applications to follow the classification of sg severity and thus predict the possible amount of sfl. reference 1. brennan m, young g, devane d. topical preparations for preventing stretch marks in pregnancy. cochrane database syst rev. 2012;1111(11):cd000066. doi: 10.1002/14651858. cd000066.pub2. pmid: 23152199. pmcid: pmc10001689. 2. yu y, wu h, yin h, lu q. striae gravidarum and different modalities of therapy: a review and update. j dermatolog treat. 2022;33(3):1243-1251. doi: 10.1080/09546634.2020.1825614. pmid: 33003983. 3. ağar m, güngör k, güngör nd, kavrut m, madenli aa. vitamin d supplementation inhibits nf-kß signaling pathway in lean and obese women with pcos. eur rev med pharmacol sci. 2022;26(11):3973-3977. doi:10.26355/eurrev_202206_28967.   pmid: 35731068. 4. rabinerson d, melzer h, gabbay-ben-ziv r. [striae gravidarum etiology, prevalence and treatment]. harefuah. dec 2018;157(12):787-790. 5. farahnik b, park k, kroumpouzos g, murase j. striae gravidarum: risk factors, prevention, and management. int j womens dermatol. 2017;3(2):77-85. doi:10.1016/j.ijwd.2016.11.001. pmid: 28560300. pmcid: pmc5440454. 6. korkmaz n, aydin aa. relationship of myonectin with insulin resistance in patients with polycystic ovary syndrome a cross-sectional prospective clinical study. the journal of reproductive medicine. 2021;66(7-8):183-188. 7. çintesun e, aydoğdu m, akar s, çelik ç. is striae gravidarum a sign of spontaneous premature birth? j matern fetal neonatal fibril fragmentation, and decreased density of the collagenous extracellular matrix, can induce endothelial structures to form vascular tubes [18]. although it is unclear which alterations at the collagen matrix trigger endothelial cell organization, there may be a decrease in the density of collagen. a study by xu et al reported that damage to type-iv-collagen reveals cryptic regions that alter interactions with vascular endothelial cells [26]. although not addressed in the studies of xu and wang, it is a crucial point to be investigated that these changes in the vascular endothelium may cause results in the form of leakage from the vessel wall. in the present study, we proved a very strong correlation between sg severity and sfl during cs. as an important finding, there was no correlation between parameters such as blood cells and hemoglobin values and sg severity in this relationship. the results supported that there was no bloodborne effect on the sfl content that we detected during the surgery and that it was only due to a liquid leak. as it is known, the decrease in elastic fibers and weakening of collagen support together with the dilatation of the vessel walls can increase the permeability of the vessel wall and facilitate the passage of intravascular fluid into the extravascular space. this may lead to the weakening of vascular resistance in pregnant women who develop sg and increase fluid accumulation in the third chambers, leading to more fluid and blood loss during the operation, and consequently to the need for more isotonic fluid replacement and hypovolemia, especially in those who delivered by cesarean section. as a result, we predicted that this situation may cause systemic bleeding and fluid loss. with our results, we supported our hypothesis based on the fact that there may be excessive fluid figure 1. the roc analysis for prediction of severe stria gravidarum. bmi = body mass index; hb = hemoglobin; sfl = surgical fluid loss. 6 original article | dermatol pract concept. 2023;13(3):e2023175 tract collagen. biophys j. 2016;111(1):57-68. doi:10.1016/j .bpj.2016.05.049. pmid: 27410734. pmcid: pmc4944529. 18. varani j, perone p, warner rl, et al. vascular tube formation on matrix metalloproteinase-1-damaged collagen. br j cancer. 2008;98(10):1646-1652. doi:10.1038/sj.bjc.6604357. pmid: 18443597. pmcid: pmc2391116. 19. yucel t, mutnal a, fay k, et al. matrix metalloproteinase expression in basal cell carcinoma: relationship between enzyme profile and collagen fragmentation pattern. exp mol pathol. 2005;79(2):151-160. doi:10.1016/j.yexmp.2005.05.003. pmid: 16004981. 20. wang f, calderone k, do tt, et al. severe disruption and disorganization of dermal collagen fibrils in early striae gravidarum. br j dermatol. 2018;178(3):749-760. doi:10.1111/bjd.15895. pmid: 28815554. 21. elprince m, taha ot, ibrahim zm, et al. prediction of intraperitoneal adhesions using striae gravidarum and scar characteristics in women undergoing repeated cesarean sections. bmc pregnancy childbirth. 2021;21(1):286. doi:10 .1186/s12884-021-03763-z. bpmid: 33836692. pmcid: pmc8033650. 22. kan o, gorkem u, alkilic a, cetin m. efficacy of striae gravidarum extension and localization on predicting intraperitoneal adhesion risk. j obstet gynaecol res. 2019;45(12):2358-2363. doi:10.1111/jog.14125. pmid: 31531933. 23. carnevale e, fogel e, aplin ac, et al. regulation of postangiogenic neovessel survival by integrins in collagen and fibrin matrices. j vasc res. 2007;44(1):40-50. doi: 10.1159/000097976. pmid: 17167269. 24. wang j, milner r. fibronectin promotes brain capillary endothelial cell survival and proliferation through alpha5beta1 and alphavbeta3 integrins via map kinase signalling. j neurochem. 2006;96(1):148-159. doi: 10.1111/j.1471-4159.2005.03521.x. pmid: 16269008. 25. al-himdani s, ud-din s, gilmore s, bayat a. striae distensae: a comprehensive review and evidence-based evaluation of prophylaxis and treatment. br j dermatol. 2014;170(3):527-547. doi: 10.1111/bjd.12681. pmid: 24125059. 26. xu j, rodriguez d, petitclerc e, et al. proteolytic exposure of a cryptic site within collagen type iv is required for angiogenesis and tumor growth in vivo. j cell biol. 2001;154(5): 1069-1079. doi: 10.1083/jcb.200103111. pmid: 11535623. pmcid: pmc2196184. med. 2022;35(18):3467-3472. doi:10.1080/14767058.2020.1 821642. pmid: 32957847. 8. korgavkar k, wang f. stretch marks during pregnancy: a review of topical prevention. br j dermatol. 2015;172(3):606-15. doi:10.1111/bjd.13426. pmid: 25255817. 9. kream e, boen m, fabi sg, goldman mp. nonsurgical postpartum abdominal rejuvenation: a review and our experience. dermatol surg. 2021;47(6):768-774. doi:10.1097/dss .0000000000003003. pmid: 33867470. 10. karhade k, lawlor m, chubb h, johnson trb, voorhees jj, wang f. negative perceptions and emotional impact of striae gravidarum among pregnant women. int j womens dermatol. 021;7(5part b): 685-691. doi:10.1016/j.ijwd.2021.10.015. pmid: 35028366; pmcid: pmc8714569. 11. costa e, okesola bo, thrasivoulou c, et al. cx43 mediates changes in myofibroblast contraction and collagen release in human amniotic membrane defects after trauma. sci rep. 2021;11(1):16975. doi:10.1038/s41598-021-94767-4. pmid: 34408164. pmcid: pmc8373966. 12. findik rb, i̇lkaya f, guresci s, guzel h, karabulut s, karakaya j. effect of vitamin c on collagen structure of cardinal and uterosacral ligaments during pregnancy. eur j obstet gynecol reprod biol. 2016;201:31-5. doi:10.1016/j.ejogrb.2016.03.022. pmid: 27042769. 13. gedikbasi a, yücel b, arslan o, giris m, gedikbasi a, abbasoglu sd. dynamic collagen changes in cervix during the first trimester and decreased collagen content in cervical insufficiency. j matern fetal neonatal med. 2016;29(18):2968-2972. doi:10 .3109/14767058.2015.1109623. pmid: 26594899. 14. gomez hm, pillar al, brown ac, et al. investigating the links between lower iron status in pregnancy and respiratory disease in offspring using murine models. nutrients. 2021;13(12):4461. doi 10.3390/nu13124461. pmid: 34960012. pmcid: pmc8708709. 15. drobnik j, pietrucha k, kudzin m, mader k, szymański j, szczepanowska a. comparison of various types of collagenous scaffolds applied for embryonic nerve cell culture. biologicals. 2017;46:74-80. doi:10.1016/j.biologicals.2017.01.001. pmid: 28108210. 16. duckert f, nyman d. factor xiii, fibrin and collagen. suppl thromb haemost. 1978;63:391-396. pmid: 262335. 17. dhital b, gul enf, downing kt, hirsch s, boutis gs. pregnancy induced dynamical and structural changes of reproductive dermatology: practical and conceptual 188 letter | dermatol pract concept 2018;8(3):8 dermatology practical & conceptual www.derm101.com challenging facial pigmented lesions: values and limits of confocal microscopy marina agozzino1, teresa russo1, marco ardigò2, vincenzo piccolo1, massimo mascolo3, stefania staibano3, roberto alfano4, giuseppe argenziano1 1 dermatology unit, university of campania luigi vanvitelli, naples, italy 2 department of dermatological clinic, san gallicano dermatological institute-irccs, rome, italy 3 department of advanced biomedical sciences, pathology section, university of naples federico ii, naples, italy 4 department of anesthesiology, surgery and emergency, university of campania luigi vanvitelli, naples, italy key words: in vivo reflectance confocal microscopy, pigmented facial lesion, lentigo maligna, seborrheic keratosis citation: agozzino m, russo t, ardigò m, piccolo v, mascolo m, staibano s, alfano r, argenziano g. challenging facial pigmented lesions: values and limits of confocal microscopy. dermatol pract concept. 2018;8(3):188-190. doi: https://doi.org/10.5826/dpc.0803a08 received: january 12, 2018; accepted: march 7, 2018; published: july 31, 2018 copyright: ©2018 agozzino et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: teresa russo, md, c/o ii policlinico, edificio 9, primo piano, via pansini 5 80131 naples, italy. email: russo. teresa87@gmail.com. introduction pigmented facial lesions (pfl) may be difficult to diagnose clinically and dermoscopically. nowadays, reflectance confocal microscopy (rcm) offers the possibility to assess in vivo pfl, although in challenging cases histopathology remains mandatory [1,2]. herein a series of 3 patients with ambiguous pfl are reported. discussion clinically, all lesions were flat and brownish in color (figures 1a-1c), while dermoscopically they revealed brownblack thickened pseudonetwork, grayish color, and rhomboidal structures (figures 1a and 1b). only one also exhibited scattered milia-like cysts (figure 1c). rcm examination of the 3 lesions, performed using a vivascope 1500 (lucid, rochester, ny, usa), showed elongated bright tubular cords with bulbous projections (lesion a, figure 2a), keratinocyte disarray and atypical cell aggregates around adnexal structures (lesion b, figure 2b), and dendritic cell infiltration of adnexal structures with numerous reflective atypical roundish cells at the dermoepidermal junction (lesion c, figure 2c). features seen in the second and third lesions were interpreted as suggestive of lentigo maligna (lm). histopathology performed on excisional biopsies for all 3 lesions confirmed the diagnosis of an irritated, pigmented seborrheic keratosis (sk) of lesion a (figure 3a); a diagnosis of melanoma in situ was made in lesion b (figure 3b); and histopathologic features of lesion c were suggestive of an irritated sk and were partially in contrast with rcm findings (figure 3d). these examples underline how the diagnosis of flat pfl on chronically sun-damaged skin represents one of the most challenging scenarios for dermatologists treating skin cancer. in particular, facial lm and sk may show overlapping morletter | dermatol pract concept 2018;8(3):8 189 sible rcm pitfall in the differentiation of pfl (figure 2d). a detailed evaluation of the components of the folliculotropism in facial macules may help to improve the diagnostic accuracy of rcm findings [3]. the infiltration of the hair follicle was found to be indicative of lm/lmm compared to nonmelanocytic skin neoplasms, with an overall sensitivity of 96% and specificity of 83% [3]. a few bright dendrites in the epiderphological features. irritated or regressive sk is particularly challenging when it shows clinical (eg, irregular borders, presence of multiple colors, asymmetry) and dermoscopic features (such as focal or diffuse pink or gray hue) that overlap with those of facial melanoma. moreover, the presence in lesion c of perifollicular inflammatory cells and langerhans cells, resembling dendritic melanocytes in rcm, represents a posfigure 1. dermoscopic images. (a) lesion a and (b) lesion b show a thickened pseudonetwork and gray color in the middle area. (c) lesion c shows sharply demarcated borders, a milia-like cyst, and looped vessels. rcm mosaics. [copyright: ©2018 agozzino et al.] figure 2. (a) the majority of lesion a displays elongated tubular structures (cords) and bulbous projections indicative of sk. (b) rcm images of lesion b show non-edged papillae with aggregates of atypical large nucleated cells around adnexal structures. in lesion c, the epidermis reveals (c) a disarrayed honeycomb pattern with multiple atypical reflective cells around follicular openings (red arrows) and keratin-filled invaginations in the upper left part of the image, (d) numerous cells with dendritic processes around follicles, and (e) melanophages inside dermal papillae. [copyright: ©2018 agozzino et al.] figure 3. histopathology. (a) lesion a shows acanthosis, parakeratosis, and horn cysts (hematoxylin and eosin [h&e] staining, original magnification ×50). (b) nested atypical melanocytes, pagetoid spread cells, and some perifollicular atypical melanocytes in lesion b (h&e staining, original magnification ×50). (c) lesion c reveals horn cysts, subepidermal chronic inflammation, and melanin deposits (h&e staining, original magnification ×50). (d) staining for s100 protein highlights only some melanocytes (s100 protein, original magnification ×50). [copyright: ©2018 agozzino et al.] 190 letter | dermatol pract concept 2018;8(3):8 references 1. russo t, piccolo v, lallas a, et al. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. doi: 10.1159/000472253. 2. guitera p, pellacani g, crotty ka, et al. the impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. j invest dermatol. 2010;130(8):2080-2091. doi: 10.1038/ jid.2010.84. 3. persechino f, de carvalho n, ciardo s, et al. folliculotropism in pigmented facial macules: differential diagnosis with reflectance confocal microscopy. exp dermatol. 2018;27(3):227-232. doi: 10.1111/exd.13487. mis, but not infiltrating the hair follicle predominantly, have estimated specificity for pigmented actinic keratosis (53%) [3]. therefore, further studies of distribution and amount of cells, and the presence of bulging around the follicles, are necessary and could represent an important tool to help in differentiating pfl. conclusions nowadays, confocal examination provides increasingly useful information for the interpretation of doubtful facial lesions. however, histopathologic examination remains mandatory in special cases to avoid overtreatment. dermatology: practical and conceptual letter | dermatol pract concept 2018;8(3):15 227 dermatology practical & conceptual www.derm101.com use of dermatoscopy in the detection of squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa ruzica jurakic toncic1, mikela petkovic2, slobodna murat susic1, romana ceovic1, giuseppe argenziano3 1 department of dermatology and venereology, university hospital centre zagreb, university of zagreb school of medicine, zagreb, croatia 2 polyclinic nola, zagreb, croatia 3 dermatology unit, university of campania, naples, italy key words: severe generalized recessive dystrophic bullous epidermolysis, squamous cell carcinoma, dermoscopy, nonmelanoma skin cancer citation: jurakic toncic r, petkovic m, murat susic s, ceovic r, argenziano g. use of dermoscopy in the detection of squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa. dermatol pract concept. 2018;8(3):227-230. doi: https://doi. org/10.5826/dpc.0803a15 received: december 5, 2017; accepted: march 6, 2018; published: july 31, 2018 copyright: ©2018 jurakic toncic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, department of dermatology and venereology, university hospital centre zagreb, university of zagreb school of medicine, zagreb 10000, croatia. email: rjtoncic@gmail.com. case presentation epidermolysis bullosa (eb) is a heterogeneous group of disorders. inherited eb is classified into eb simplex, junctional, and dystrophic [1]. we present a case of a 33-year-old female patient with severe generalized recessive dystrophic epidermolysis bullosa (rdeb-sg) who, since birth, has received follow-up in our department and referral centre of the ministry of health and social welfare of the republic of croatia for hereditary bullous epidermolysis. she presented with 5 non-healing lesions on the scalp, which were clinically very suggestive of squamous cell carcinoma (scc). a year ago, the patient underwent surgical removal of a well-differentiated scc in the occipital region and moderately differentiated scc in the left parietotemporal region. clinically, in the occipital region, next to the margin of cutaneous flap of previously excised scc, exophytic lesions and ulcerations were found. in the left parietotemporal region, an erosion measuring 3 cm in diameter with an elevated margin was found (figure 1). dermoscopy was performed on 5 regions that clinically presented as ulcerations and revealed a red background. lesions presented with an amorphous whitish or pinkish background along with polymorphous atypical vessels (figure 2). in some areas, erosions were clearly seen. histopathology confirmed diagnosis of moderately differentiated scc in all 5 lesions. discussion inherited ebs are rare disorders that, according to data published in 2016, have an overall incidence and prevalence during a 5-year period of 19.60 and 8.22 in 1 million live births, respectively [1-4]. recessive dystrophic epidermolysis bullosa (rdeb) is a rare genodermatosis characterized by generalized severe blistering, atrophic scarring, milia formation, pseudosyndactyly, mutilation, and development of severe disability [2]. these patients have multiple comorbidities and their life 228 letter | dermatol pract concept 2018;8(3):15 wounds or skin lesions, a biopsy guided by experienced dermoscopist should be performed. an advantage of dermoscopy is that it is a noninvasive diagnostic tool, and use of non-contact dermoscopy is absolutely preferred. this is important because rdeb patients often suffer from chronic pain. in order to obtain good visualization, persistent crusts should be removed [1]. dermoscopic criteria for scc are well established; therefore, dermoscopy and photo documentation should be routinely used in detection of scc. dermoscopic features of early and advanced scc, as well as dermoscopic criteria of well vs poorly differentiated scc, have been described [6,7]. the most common pattern seen in poorly differentiated scc is a red predominant color and randomly distributed small vessels, which can be dotted or irregular. dermatoscopy of invasive well-differentiated scc shows a white color, presented as an amorphous area or white perifollicular circles, white perivascular halos, and a polymorphous vessel pattern [6-8]. in dermoscopy of undifferentiated scc, only atypical vessels could be expected, which can help differentiate scc from surrounding ulcerated skin that is found in patients with rdeb [6]. conclusions due to the high risk of development of scc in patients with rdeb, it is recommended to follow-up with these patients on a regular 6-month basis [1]. although it is time-consuming and inconvenient for the patient (due to discomfort and pain), it is absolutely necessary to remove and reapply all the dressings to complete a full body checkup [1]. regional lymph node examination is recommended in all patients [1]. development of multiple primary tumors has been described in more than 60% of the patients with rdeb, therefore meticulous lifelong surveillance for additional scc is a requisite in expectancy is shortened, with mean age of death of 23.35, and median of 22.09 years [3,5]. death can occur during infancy or early childhood due to sepsis, pneumonia, renal failure, occlusion of the upper airway, or failure to thrive, but the leading cause of death in adults is cutaneous scc [3,5]. cutaneous scc most commonly occurs in rdeb and represents the leading cause of death of these patients [1,5]. these patients have a 51.68% cumulative risk of developing scc by the age of 30, with cumulative risk of death at 42.26% by that age [3]. eb-associated scc is more aggressive, has high metastatic potential, and presents a significant cause of mortality and morbidity. these tumors arise in chronic non-healing skin wounds during mid to late adolescence [5]. death from distant metastases occurs in the majority of patients within 5 years of diagnosis of the primary tumor [3,5]. the pathogenesis of scc in rdeb is still unknown. these tumors preferentially occur on limbs, especially on bony prominences where the blistering and scarring are the most pronounced [1,2]. there is no obvious relationship to sun exposure, and the most common sites are long-term non-healing wounds or scars [1,3]. presence of the chronic scar tissue in eb patients cannot itself fully explain this phenomenon because tumors in scars or radiodermatitis are not characterized with such an aggressive biological behavior [3]. to date, there is no convincing evidence that rdeb scc is different from non-rdeb scc, but it is speculated that rdeb scc has a permissive tumor microenvironment [2]. in rdeb, early diagnosis of scc can be difficult as it can present similarly to typical chronic ulceration with scarring and crusting [1]. in these patients, sccs, similarly to burn scar tumors, usually start as an ulcer margin, with the possibility that only one portion of the ulcer undergoes malignant transformation, while the rest remains as a non-healing inflamed area [1]. knowing this, if a rdeb patient presents with non-healing a b figure 1. clinical findings. (a) alopecia of the scalp with exophytic lesions and ulcerations in the occipital region next to the margin of cutaneous flap. (b) erosion measuring 3 cm in size with elevated margin in the left parietotemporal region. [copyright: ©2018 jurakic toncic et al.] letter | dermatol pract concept 2018;8(3):15 229 2. kim m, murrell df. update on the pathogenesis of squamous cell carcinoma development in recessive dystrophic epidermolysis bullosa. eur j dermatol. 2015;25(suppl 1):30-32. 3. fine jd, johnson lb, weiner m, li kp, suchindran c. epidermolysis bullosa and the risk of life-threatening cancers: the national eb registry experience, 1986-2006. j am acad dermatol. 2009;60(2):203-211. doi: 10.1016/j.jaad.2008.09.035. 4. fine jd. epidemiology of inherited epidermolysis bullosa based on incidence and prevalence estimates from the national epidermolysis bullosa registry. jama dermatol. 2016;152(11):1231-1238. doi: 10.1001/jamadermatol.2016.2473. 5. fine jd, johnson lb, weiner m, suchindran c. cause-specific risks of childhood death in inherited epidermolysis bullosa. j pediatr. 2008;152(2):276-280. doi: 10.1016/j.jpeds.2007.06.039. 6. lallas a, pyne j, kyrgidis a, et al. the clinical and dermoscopic features of invasive cutaneous squamous cell carcinoma depend all rdeb patients [1,3]. most eb-associated sccs are well differentiated; however, it is not possible to predict biological behavior of a tumor simply on the basis of histological grade [1,3]. because sccs in this group of patients present with a more aggressive biological behavior, early diagnosis of this type of tumor is mandatory and we strongly encourage the experts dealing with this special group of patients to acquire necessary dermoscopic skills for early recognition of these tumors [3,9]. references 1. mallipeddi r. epidermolysis bullosa and cancer. clin exp dermatol. 2002;27(8):616-623. doi: 10.1046/j.1365-2230.2002.01130.x. a b dc e figure  2. dermatoscopic findings of rdeb-associated scc. (a) white amorphous area with pinkish background, atypical vessels, and erosions. (b) red background with polymorphic atypical vessels. (c) red, pink, and white background with polymorphic atypical and tortuous vessels. (d) white area on pinkish background. (e) pinkish background with white areas and polymorphic atypical vessels. [copyright: ©2018 jurakic toncic et al.] 230 letter | dermatol pract concept 2018;8(3):15 8. zalaudek i, argenziano g. dermoscopy of actinic keratosis, intraepidermal carcinoma and squamous cell carcinoma. curr probl dermatol. 2015;46:70-76. doi: 10.1159/000366539. 9. mellerio je, robertson sj, bernardis c, et al. management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines. br j dermatol. 2016;174(1):56-67. doi: 10.1111/bjd.14104. on the histopathological grade of differentiation. br j dermatol. 2015;172(5):1308-1315. doi: 10.1111/bjd.13510. 7. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377-386. doi: 10.1016/j.jaad.2009.11.697. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):10 43 dermatology practical & conceptual www.derm101.com case report a 69-year-old woman was referred to the skin cancer unit for a solitary pink lesion of the trunk of two months’ duration (figure 1). because of the rapid growth of the lesion, the site involved and the age of the patient, a medical consult was requested to rule out malignancy. no relevant medical history was recorded. dermoscopy and reflectance confocal microscopy (rcm) studies were performed and the lesion was finally biopsied. dermoscopic examination revealed the predominance of a homogeneous pink color on the background, with prominent shiny whitish structures, arranged in a reticulated pattern (figure 2). at the periphery, areas of peppering were present. rcm imaging acquired on vivascope 1500 system (caliber i.d., andover, ma, usa) showed a regular honeycombed pattern without pagetoid cells at the spinous-granular layer. only a few dendritic, inflammatory cells and some keratinocytes with highly refractile cell contours could be detected (figure 3a). a prominent and widespread inflammatory infiltrate obscuring the dermo-epidermal junction was also present, without melanocytic features (figure 3b). at the papillary dermis more inflammatory cells with a few melanophages could be observed (figure 3c). histopathology from the excised lesion showed a prominent lichenoid dermal infiltrate with hyperkeratosis, hypergranulosis and dyskeratinocytes in the epidermis. all findings were in keeping with the final diagnosis of lichen planus (figure 4). a solitary pink lesion: dermoscopy and rcm features of lichen planus claudia pezzini1, simonetta piana2, caterina longo1,3, elisa benati3, stefania borsari3, francesca specchio3, elvira moscarella3 1 department of dermatology, university of modena and reggio emilia, modena, italy 2 pathology unit, arcispedale s. maria nuova, irccs, reggio emilia, italy 3 dermatology and skin cancer unit, arcispedale s. maria nuova, irccs, reggio emilia, italy key words: lichen planus, dermoscopy, reflectance confocal microscopy, solitary lesion citation: pezzini c, piana s, longo c, benati e, borsari s, specchio f, moscarella e. a solitary pink lesion: dermoscopy and rcm features of lichen planus. dermatol pract concept 2017;7(4):43-45. doi: https://doi.org/10.5826/dpc.0704a10 received: june 9, 2017; accepted: september 5, 2017; published: october 31, 2017 copyright: ©2017 pezzini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, arcispedale s.maria nuova, irccs viale risorgimento 80, 42100 reggio emilia, italy. tel. 0522295611. email: elvira.moscarella@gmail.com we present an unusual onset of cutaneous lichen planus (lp) in a middle-aged patient. the initial presentation as solitary, indolent pink lesion required further investigations to rule out malignancy, especially amelanotic melanoma. dermoscopy and reflectance confocal microscopy findings were found to be helpful in our case in addressing the correct diagnosis. abstract mailto:elvira.moscarella@gmail.com 44 observation | dermatol pract concept 2017;7(4):10 the patient developed multiple similar cutaneous lesions one week later. systemic steroid therapy led to complete healing. discussion reports on alternative applications of dermoscopy in general dermatology are an increasing phenomenon, suggesting its usefulness beyond the oncologic field. this diagnostic tool has allowed the identifications of several skin diseases, both neoplastic and non-neoplastic [1-3]. regarding inflammatory conditions in dermatology, specific dermoscopic patterns have been well defined for a non-invasive diagnosis [3]. these peculiar clues are somehow easy to identify when the history, distribution and morphology of lesions are evocative for a specific disease. however, things are less straightforward when we face unusual clinical scenarios [4]. reflectance confocal microscopy, providing a non-invasive imaging at a histologic resolution, has repeatedly proved its reliability in the recognition of different skin diseases, assisting in the identification of difficult to diagnose cases. solitary pink lesions are often a major challenge for dermatologists, amelanotic melanoma being the diagnosis not to miss. lichen planus is a relatively common inflammatory disorder of the skin, often affecting middle-aged patients. in its typical form, pruritic widespread papules develop over weeks. the oral mucosa may be also involved, showing the diagnostic hallmark of the disease, the wickham striae [5]. the figure 1. clinical picture of the patient. (a) solitary and asymptomatic pink lesion of the chest of a 69-year-old woman. (b) close-up of the clinical image. [copyright: ©2017 pezzini et al.] figure 2. dermoscopy. homogeneous pink color on the background, with prominent shiny whitish structures, arranged in a reticulated pattern. at the periphery areas of peppering are present. [copyright: ©2017 pezzini et al.] current case showed rather atypical initial clinical features of lp, simulating a possible malignancy, such as basal cell carcinoma, squamous cell carcinoma or melanoma, at clinical examination. however, the observation on dermoscopy of shiny white structures in a reticular arrangement suggested the diagnostic hypothesis of lichen planus. these structures represent the wellknown and characterized dermoscopic counterpart of wickham striae, which are dermoscopically visible in “nonmucosal” skin and specific for lp [6]. rcm in pinkish lesions has already been applied to discriminate between different skin tumors [7]. its application in our case proved to be complementary to dermoscopy, revealing “in vivo” the lichenoid infiltrate of lp obscuring the dermo-epidermal junction [8,9], with strong histologic correlation. even if this confocal feature is not exclusive of lp, and is possibly observed in other interface dermatitides or in lichen planus-like keratosis [9], the final integration of clinical-dermoscopical and confocal investigations led to the correct diagnostic hypothesis. as shown in our case, difficult lesions in everyday clinical practice benefit from a synergistic diagnostic approach. dermoscopic and rcm investigations may support our diagnostic hypothesis, improving its accuracy especially when faced with atypical presentations of common inflammatory skin conditions. observation | dermatol pract concept 2017;7(4):10 45 references 1. borsari s, pampena r, lallas a, et al. clinical indications for use of reflectance confocal microscopy for skin cancer diagnosis. jama dermatol. 2016;152:1093-1098. 2. lallas a, zalaudek i, argenziano g, et al. dermoscopy in general dermatology. dermatol clin. 2013;31:679-694. 3. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166:1198–1205. 4. papageorgiou c, apalla z, lazaridou e, et al. atypical case of lichen planus recognized by dermoscopy. dermatol pract concept. 2016;6:39-42. 5. usatine rp, tinitigan m. diagnosis and treatment of lichen planus. am fam physician. 2011;84:53-60. 6. vázquez-lópez f, manjón-haces ja, maldonado-seral c, et al. dermoscopic features of plaque psoriasis and lichen planus: new observations. dermatology. 2003;207:151–156. 7. braga jc, scope a, klaz i, et al. the significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. j am acad dermatol. 2009;61:230-241. 8. moscarella e, gonzález s, agozzino m, et al. pilot study on reflectance confocal microscopy imaging of lichen planus: a realtime, non-invasive aid for clinical diagnosis. j eur acad dermatol venereol. 2012;26:1258-1265. 9. agozzino m, gonzález s, ardigò m. reflectance confocal microscopy for inflammatory skin diseases. actas dermosifiliogr. 2016;107:631-639. figure 3. rcm imaging. (a) rcm single image taken at the spinous granular layer. a regular honeycombed pattern is visible with a few dendritic inflammatory cells. (b) rcm mosaic image taken at the level of the dermo-epidermal junction with the widespread inflammatory infiltrate obscuring the junction. (c) rcm mosaic at the level of the papillary dermis, in an area of dense inflammatory infiltrate. [copyright: ©2017 pezzini et al.] figure 4. histological examination. hyperkeratosis and hypergranulosis of the epidermis with scattered dyskeratinocytes are present. in the dermis a dense lichenoid infiltrate obscures the dermo-epidermal junction framed by the red square, h&e stain). [copyright: ©2017 pezzini et al.] dermatology: practical and conceptual quiz | dermatol pract concept 2015;5(1):9 51 dermatology practical & conceptual www.derm101.com the patient a 30-year-old woman presented to our hospital in manacor, mallorca, with a new lesion on the thorax that had appeared three to four months earlier, had gradually enlarged and was slightly itchy. the patient was otherwise healthy. physical examination revealed a tender, brownish papule or plaque contacting the elastic band of the underwear under the right breast (figure 1). the remaining physical exam showed no other relevant lesions. dermoscopic examination showed an ill-defined redyellowish background with a small, pigmented, structureless area. tiny, dotted and comma vessels were barely visible. remarkable were numerous rounded or droplet-shaped, whitish structures spread all over the lesion (figure 2). a 3 mm punch biopsy was obtained showing epidermal acanthosis and an intense superficial dermal inflammatory infiltrate. the infiltrate was composed by neutrophils, eosinophils and plasma cells, intermingled with bigger epithelioid cells, some of them containing tiny, round, basophilic structures in their cytoplasm (figure 3). what is your diagnosis? answer cutaneous leishmaniasis an itching plaque juan garcias-ladaria1, karel lópez-brito2, marta pascual-lópez1, vicenç rocamora1 1 department of dermatology, hospital de manacor, islas baleares, spain 2 department of pathology, hospital de manacor, islas baleares, spain citation: garcias-ladaria j, lópez-brito k, pascual-lópez m, rocamora v. an itching plaque. dermatol pract concept 2015;5(1):9. http://dx.doi.org/10.5826/dpc.0501a09 received: june 29, 2014; accepted: july 2, 2014; published: january 31, 2015 copyright: ©2015 garcias-ladaria et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: juan garcias-ladaria, md, department of dermatology, hospital de manacor, carretera manacor-alcudia, sin número, 07500 manacor, balearic islands, spain. tel. +34660418877. email: jgarcila@gmail.com figure 1. a brownish papule or plaque contacting the elastic band of the underwear under the right breast. (copyright: ©2015 garcias-ladaria et al.) 52 quiz | dermatol pract concept 2015;5(1):9 clinical course the patient was scheduled to receive intralesional antimonials. answer and explanation leishmaniasis is an infectious disease caused by several species of the genus leishmania trasmitted by sandflies of the genera phlebotomus and lutzomiya. it is a major health problem, endemic in more than 70 countries worldwide, probably widely underreported, with estimated global annual incidence of 0.2 to 0.4 million cases for visceral leishmaniasis (vl), and 0.7 to 1.2 million cutaneous leishmaniasis (cl) [1]. while 90% of vl concentrate in six countries—india, bangladesh, sudan, south sudan, brazil and ethiopia, cl is widely distributed in the americas, the mediterranean basin, and western asia from the middle east to central asia. spain is a hypoendemic country with 0.41 new cases per 100,000 inhabitants annually [1]. the disease is specially diagnosed on the mediterranean basin, but a recent flare of the disease around madrid, far from the coast, has raised concern and shows how leishmaniasis is still nowadays an important issue in public health and is far from eradication [2,3]. leishmaniasis is generally regarded as a zoonotic infection, although antroponotic contagion has been also reported. reservoirs are mammal hosts (mainly marsupials, rodents, edentates, and carnivores). more than 20 species of leishmania are infectious to the human being. they are in turn transmitted by more than 30 species or subspecies of sandflies. vector-related factors, like their saliva, have been shown to contribute to the viability and morphology of the infection [3]. additionally, host factors like an effective th1 response has been shown to be capital in controlling and destructing infection on the skin [3]. immunosuppression, particularly hiv co-infection, has been regarded as a matter of concern. hiv and leishmania can both share the transmitting source (basically contaminated needles) and are synergistic pathogens. cl can be divided in disseminated cl, localized cl and mucous leishmaniasis. while disseminated and mucous cl, like vl, are life-threatening conditions, localized cl tends to self-resolution. still, it can lead to permanent scarring and disfigurement, especially in cosmetic areas, and correct diagnosis and early treatment is paramount. combined with variability in host response, parasitic and vector factors result in a myriad of skin lesions that can be challenging, even for experienced clinicians. the typical lesion starts with erythema at the site of a bite of an infected sand-fly. the erythema develops into a papule, then a nodule that progressively ulcerates in a variable time frame raging from weeks to months. they are usually found in exposed areas, especially the face and arms and can be solitary or multiple. atypical presentations are hyperkeratotic, verrucous or papillomatous papules or plaques, with eczematiform, zosteriform, erysipeloid or sporotrichoid configurations. the skin lesions can also simulate connecting tissue diseases (lupus erythematosus, dermatomyositis) or tumors [4,5]. figure 2. numerous rounded or droplet-shaped, whitish structures spread all over the lesion. (copyright: ©2015 garcias-ladaria et al.) figure 3. epidermal acanthosis and an intense superficial dermal inflammatory infiltrate. (copyright: ©2015 garcias-ladaria et al.) quiz | dermatol pract concept 2015;5(1):9 53 as in other inflammatory and infectious diseases [6,7], dermoscopy has emerged as a valuable tool for the bedside diagnosis of cutaneous leishmaniasis. in 2008, a spanish group described the dermoscopic criteria of cutaneous leishmaniasis for the first time [8]. they described four patterns. pattern 1 (early lesions) more often showed vascular structures (comma-shaped vessels, linear irregular vessels and polymorphous ⁄atypical vessels) and “yellow tears,” while pattern 2 (later lesions) displayed a central erosion⁄ulceration and hyperkeratosis surrounded by “white starburst-like pattern” and vascular structures on the periphery. pattern 3 was a combination of patterns 1 and 2, and pattern 4 consisted of vascular structures alone. vascular morphology appeared to be varied: comma-shaped vessels, linear irregular vessels, dotted vessels, polymorphous⁄atypical vessels, hairpin vessels, arborizing telangiectasia, corkscrew vessels, and glomerular vessels are described. eighty-eight percent of the lesions had two or more vascular patterns and no specific pattern or arrangement was found. more recently changes in reflectance confocal microscopy (rcm) of cl have been described [9], namely linear and comma-shaped vessels, follicular plugging, presence of multinucleated giant cells and mixed inflammatory infiltrate, and the more specific “brick-like structures” which are bright polygonal structures, not described elsewhere. however, diagnosis confirmation still relies on visualization of the parasite under the microscope by culture, smears or biopsy [3]. biopsy samples show a polymorphous infiltrate with plasma cells and variable epidermal response (acanthosis/atrophy/ulceration). while late lesions show well organized, tuberculoid granulomas, early lesions show spread macrophages intermingled within the infiltrate, containing amastigotes, the so-called leishman-donovan bodies. to ensure that the visualized structures are amastigotes an experienced observer should look for the characteristic size (2–4 µm), shape (round to oval), and internal organelles (the nucleus and kinetoplast). cl is frequently misdiagnosed in countries where it is not endemic, particularly if organisms are not seen [10]. histological differential diagnoses are sarcoidosis, foreign body reaction, granulomatous rosacea and granuloma annulare. cultures show the growth of promastigotes, the flagellated infective form, found in vectors. polymerase chain reaction (pcr) can be performed on biopsy samples with high specificity. serology is not generally performed in cl. first-line treatment, according to the who, are parenteral pentavalent antimonial drugs at 20 mg/kg per day for 20-28 days. however, for localized cl, periodic intralesional injections every four weeks are widely accepted as the standard treatment and achieve high rates of cure [3]. other treatment options include other antibiotics, physical therapies (cryotherapy, thermotherapy, co2 laser therapy), surgery and imiquimod. in conclusion, we present a case of localized cutaneous leishmaniasis in an atypical location. constant rubbing of the underwear gave the lesion the appearance of an irritated tumor, in our view easy to misdiagnose as an irritated melanocytic nevus or an irritated seborrheic keratosis. dermoscopy was determinant in the decision to take a biopsy. leishmaniasis is a common disease in extensive parts of the world, currently far from epidemiological control, and dermatologists and dermatopathologists should be familiar with it. references 1. alvar j, vélez id, bern c, et al. leishmaniasis worldwide and global estimates of its incidence. plos one 2012;7(5):e35671. 2. aguado m, espinosa p, romero-maté a, et al. outbreak of cutaneous leishmaniasis in fuenlabrada, madrid. actas dermosifiliogr 2013;104:334-42. 3. reithinger r, dujardin jc, louzir h, et al. cutaneous leishmaniasis. lancet infect dis 2007;7:581-96. 4. herwaldt bl. leishmaniasis. lancet 1999;354:1191-99. 5. garcía-almagro d. leishmaniasis cutánea. actas dermosifiliogr 2005;96:1-24. 6. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology 2006;212:7-18. 7. zalaudek i, giacomel j, cabo h, et al. entodermoscopy: a new tool for diagnosing skin infections and infestations. dermatology 2008;216:14-23. 8. llambrich a, zaballos p, terrasa f, et al. dermoscopy of cutaneous leishmaniasis. br j dermatol 2009;160:756-61. 9. alarcon i, carrera c, puig s, et al. in vivo confocal microscopy features of cutaneous leishmaniasis. dermatology 2014;228:121-24. 10. böer a, blödorn-schlicht n, wiebels d, et al. unusual histopathological features of cutaneous leishmaniasis identified by polymerase chain reaction specific for leishmania on paraffinembedded skin biopsies. br j dermatol 2006;155:815-19. dermatology: practical and conceptual observation | dermatol pract concept 2018;8(3):1 163 dermatology practical & conceptual www.derm101.com bullous pemphigoid induced by hijama therapy (cupping) arghavan azizpour1, maryam nasimi1, safoura shakoei2, fariba mohammadi1, arsalan azizpour3 1 autoimmune bullous diseases research center, tehran university of medical sciences (tums), tehran, iran 2 department of dermatology, imam khomeini hospital, tehran university of medical sciences (tums), tehran, iran 3 tehran university of medical sciences (tums), tehran, iran key words: bullous pemphigoid, hijama, trigger factor, trauma citation: azizpour a, nasimi m, shakoei s, mohammadi f, azizpour a. bullous pemphigoid induced by hiama therapy (cupping). dermatol pract concept. 2018;8(3):163-165. doi: https://doi.org/10.5826/dpc.0803a01 received: november 4, 2017; accepted: february 11, 2018; published: july 31, 2018 copyright: ©2018 shakoei et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: safoura shakoei, md, department of dermatology, imam khomeini hospital, tehran university of medical sciences, tehran, iran, 1419733141. email: dr.shakoei@gmail.com. introduction bullous pemphigoid (bp) is a common subepidermal blistering disease. it is a generalized skin disorder that appears as tense bullae on the extremities, flexures, and trunk. trauma is considered a rare triggering factor for this disease [1]. hijama therapy (cupping), as mentioned in islamic hadiths, is a traditional procedure that employs special cups for pain alleviation. in wet cupping, after the removal of the cups, several small incisions are made at different points of the body and vacuums are used to harvest blood [2]. herein, we present the case of a female patient (41 years old) with bp lesions at the site of hijama therapy, which became generalized later on. this case is significant, as this is the first report of bp exacerbated mainly at the site of hijama therapy. case presentation a 41-year-old woman was referred to our hospital with pruritic blisters and erosions at the site of hijama therapy on her back. a few days earlier, she had undergone cupping without heat on her back that resulted in the local formation of bulbullous pemphigoid (bp) is described as a subepidermal blistering disorder, which is commonly reported among the elderly, particularly those older than 60 years of age. in this report, we present the case of a 41-year-old female patient with bp lesions that were initially detected at the site of hijama therapy with a subsequent generalized spread. punch biopsy from the lesions and perilesional direct immunofluorescence (dif) demonstrated features of bp. the anti-bp180 level was 178 ru/ml, and the anti-bp230  level was negative. bp antigens at the site of hijama caused an antibody response, which led to widespread blistering over the trunk due to epitope spreading. in a comprehensive review of the literature, a total of 22 bp patients with lesions due to physical trauma were studied, and clinical, immunological, and epidemiological information was gathered. this article is the first report on the occurrence of bp induced by hijama therapy. abstract 164 observation | dermatol pract concept 2018;8(3):1 and humoral responses against the cutaneous basement membrane zone. it is commonly reported among the elderly, particularly those older than 60 years of age [1]. hijama is a complementary therapy used in the treatment of hypertension, polycythemia, headache, migraine, drug intoxication, acne, cough, dyspnea, facial paralysis, lumbar sprain, arthritis, lae immediately afterward. the lesions then became generalized, involving the anterior and posterior aspects of the trunk. the patient had similar lesions on her trunk 8 months ago; however, she had not consulted a doctor. those lesions had spontaneously resolved within 2 months. the patient’s medical and drug histories were insignificant. the physical examination revealed multiple tense bullae and erosions on the trunk, with predominance over the hijama therapy site (figure  1). the bullae were about 10-15 mm in size and filled with a clear fluid; there was no mucosal involvement. the histopathological examination of the bullae at the hijama therapy site revealed poor cell subepidermal blistering with a mild perivascular lymphocytic infiltration, as well as eosinophils (figures 2a-2b). in the basement membrane zone, direct immunofluorescence (dif) of the perilesional skin revealed the linear c3  deposition (figure  3). the anti-bp180 level was 178 ru/ml (positive >20), and the anti-bp230 level was  7.2  ru/ml (positive >20). the anti-desmoglein 1 level was 2 u/ml (negative <14), whereas the anti-desmoglein 3 level was 1.7 u/ml (negative <14). the complete blood cell count, as well as other laboratory findings, was in the normal range. after reviewing the histopathological and clinical findings at the hijama therapy site, a diagnosis of bp was confirmed. the patient was started on topical clobetasol propionate 0.05% ( 3   t u b e s p e r d a y ) t h a t w a s t o b e applied on normal skin. skin lesions improved and no new lesions appeared after 2 weeks. this was followed by tapering of topical corticosteroids over 20 weeks with no signs of relapse. discussion bp is described as an autoimmune blistering disease, which involves cellular fibromyalgia, soft tissue damage, myofascitis, chronic muscle pain, neurological pain, and chronic nonspecific neck pain [2,3]. various types of cupping include wet cupping, retained cupping, flash cupping, moving cupping, medicinal cupping, and needle cupping. the islamic sayings (hadiths) of prophet muhammad emphasize the effectiveness of hijama therapy for figure 1. tense bullae on the trunk, with a preference for the hijama therapy site. [copyright: ©2018 shakoei et al.] figure 2. histopathological features. (a) subepidermal bulla and eosinophilic infiltrate in the dermis. (b) severe dermal eosinophilic infiltrate with papillary dermis edema (hematoxylin and eosin stain; magnifications: a×40; b×100). [copyright: ©2018 shakoei et al.] observation | dermatol pract concept 2018;8(3):1 165 matrix metallopeptidase-9, degrade the bp180 extracellular domain and can lead to the formation of bullae [4]. physical factors, including uv radiation, radiotherapy, and irradiation, can alter the basal membrane and expose modified antigens, leading to the stimulation of autoantibody formation, complement activation, and blister formation [6]. uv radiation and/or radiotherapy decrease t-cell immune reactivity and lead to the development of antibodies targeted against the proteins [4]. the epitope spreading phenomenon explains the extension of bp lesions. the targets of immune responses can even be other epitopes of the same protein or proteins from the same tissue [4]. according to the review by dănescu, the most common factor inducing bp lesions is radiotherapy. the findings showed that the interval between the onset of bp lesions and activity of the trigger factor was less than 1 month, similar to our report [4]. the onset of new lesions may be only limited to the site of trauma, or it may spread to other body parts, as seen in our patient [4]. conclusion this article is the first report on the occurrence of bp lesions induced by hijama therapy. despite hijama therapy-induced bp lesions being an uncommon presentation, physicians should be cautious about the risks and consider the diagnosis of bp in patients with blisters arising from hijama therapy. references 1. nguyen t, kwan jm, ahmed ar. relationship between radiation therapy and bullous pemphigoid. dermatology. 2014;229:88-96. doi: 10.1159/000362208. 2. sajid mi. hijama therapy (wet cupping)—its potential use to complement british healthcare in practice, understanding, evidence and regulation. complement ther clin pract. 2016;23: 9-13. doi: 10.1016/j.ctcp.2016.01.003. 3. vakilinia sr, bayat d, asghari m. hijama (wet cupping or dry cupping) for diabetes treatment. iran j med sci. 2016;41:s37. 4. dănescu s, chiorean r, macovei v, sitaru c, baican b. role of physical factors in the pathogenesis of bullous pemphigoid: case report series and a comprehensive review of the published work. j dermatol. 2016;43:134-140. doi: 10.1111/1346-8138.13031. 5. korfitis c, gregoriou s, georgaia s, christofidou e, danopoulou i. trauma-induced bullous pemphigoid. indian j dermatol venereol leprol. 2009;75:617-619. doi: 10.4103/0378-6323.57732. 6. isohashi f, konishi k, umegaki n, et al. a case of bullous pemphigoid exacerbated by irradiation after breast conservative radiotherapy. jpn j clin oncol. 2011; 41:811-813. doi: 10.1093/jjco/ hyr049. health [3]. due to their religious beliefs, iranians are interested in hijama treatment. many cupping procedures are performed in iran; however, only 13% of people consult a doctor prior to hijama therapy [3]. wet cupping is performed to ease the pain through local suctioning with special cups on the selected areas, which are often the sites of pain. following the removal of the cup, a sterile scalpel is used to make small skin incisions. the cup is then placed on the incision site in order to draw blood and remove toxins [2]. trauma (both sucking and abrasions) can change the vascular permeability and trigger deposition of autoantibodies in patients with subclinical bp [4]. various factors, including trauma, friction, insect bites, surgical wounds, burns, skin grafting, radiotherapy, photo chemotherapy, and venous access procedures, have been reported to induce lesions [5]. there are several theories for the induction of bp lesions due to trauma. first, disruption of the skin due to trauma might increase the expression of the basement membrane zone antigens, leading to the initiation of an inflammatory process with lower titers of circulating antibodies. due to the increased storage of circulating autoantibodies, besides inflammatory cell recruitment (particularly granulocytes), tissue damage can improve vascular permeability [4,6]. by attaching to granulocytes, autoantibodies stimulate the complement system and initiate a loop of inflammatory stimuli [4]. proteolytic enzymes of activated granulocytes, such as figure  3. direct immunofluorescence shows continuous linear deposition of c3 along the basement membrane zone (magnification ×400). [copyright: ©2018 shakoei et al.] dermatology: practical and conceptual letter to our readers | dermatol pract concept 2016;6(1):2 1 dermatology practical & conceptual www.derm101.com sharing our knowledge and insights with others remains a cornerstone of the medical profession. publishing case reports that highlight unusual and interesting diseases, contributing original research that brings attention to new information, and writing review articles that shed different perspectives on previously published works has always been and continues to be the foundation for the dissemination of medical knowledge. the aforementioned, in turn, ignites the fuel that leads to change, which ultimately benefits our patients through improvements in diagnosis, therapy and management. while some may question the need for yet another journal, given the plethora of journals already in circulation, there is in fact a need for them all since each has its own target audience and fills its own unique niche. the journal dermatology practical & conceptual (dpc) is no different. it was the vision of dr. harald kittler to create an online openaccess journal for clinicians interested in practical issues and concepts relevant to the care of dermatologic conditions. with this in mind the first issue of dpc, with dr. harald kittler as its first editor (2011-2013), was launched october 2011. dpc quickly garnered a loyal following of readers and was embraced by the international dermoscopy society as its official organ for publication. under harald kittler’s stewardship there was a steady increase in the number and in the quality of articles submitted to dpc. it is a testament to the quality of the submissions that 79% of articles submitted between 2011-2013 were accepted, after peer review, for publication. on february 5, 2013, due in no small part to the efforts of the first editor of dpc, the reviewers, authors, and the derm101 staff, pubmed central endorsed dpc by accepting all issues of the journal, staring with the october 2011 issue, to be indexed in pubmed. after his tireless work and dedication to dpc, dr. harald kittler decided that “new blood” was required to continue to improve the journal. it was obvious to all involved in dpc that the ideal person to take over the reins of editorship of dpc was dr. iris zalaudek. it was fortunate for us all that dr. zalaudek, who is the undisputed “queen of dermoscopy,” accepted the challenge. she served as editor of dpc from 2013-2015 and she was instrumental in widening dpc readership and in soliciting authors to submit their work to dpc. under her leadership, dpc experienced a 48% increase in submissions, many of which highlight novel findings and continue to be referenced by others. in 2015 dr. iris zalaudek decided to step down as editor of the journal. now arose the challenge of finding a successor to take over the editorship of dpc. it was common knowledge to all prospective editors that drs. kittler and zalaudek had sunk their hearts and souls into the journal by working extremely hard and allocating much of their free time to ensuring its success. thus, it was with trepidation that we (dr. ashfaq a. marghoob and dr. michael a. marchetti) jointly applied for the about-to-be-vacant editorship seat. after deliberation, the dpc committee accepted our offer of joint editorship of dpc. truth be told, while we are honored to have been named editors of dpc starting in 2016, we remain extremely nervous since we know the work involved and acknowledge that we can never fill the shoes of the previous editors. with that said, we have made a pledge to do our utmost at moving dpc forward and in continuing the vision of the previous editors. we have already made strides by implementing a system for the electronic submission and review of articles. while we acknowledge that there will be some bumps in the road, ultimately the electronic submission process should changing of the guard ashfaq a. marghoob1, michael a. marchetti1 1 department of dermatology, memorial sloan kettering skin cancer center, new york, ny, usa citation: marghoob aa, marchetti ma. changing of the guard [editorial]. dermatol pract concept 2016;6(1):1. doi: 10.5826/dpc.0601a01 copyright: ©2016 marghoob et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: ashfaq a. marghoob, md, memorial sloan kettering skin cancer center, 16 east 60th street, new york, ny, usa. email: dpc@derm101.com 2 letter to our readers | dermatol pract concept 2016;6(1):1 and understanding of the readership, authors and reviewers, we will succeed. we thank you for trusting us with the task of editorship of dpc and look forward to working with all of you at improving dpc, educating our colleagues and helping take better care of our patients. ashfaq a. marghoob, md editor-in-chief michael a. marchetti, md co-editor-in-chief prove more effective, organized and efficient. together with the reviewers we will continue to strive to bring to press insightful, novel, impactful, and relevant articles; if successful, our efforts should result in increased citations of dpc articles in other journals. we intend to track the number of citations to articles in proportion to the number of articles published, and as this proportion improves, we hope to eventually submit dpc to thomson reuters for evaluation with the intent of obtaining an official journal impact factor. needless to say, much work remains before we can accomplish this task; however, we are confident that with the help dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2014;4(1):1 1 optimization and securing of medical practices and procedures has always been very challenging in medicine. however, the real-life clinical settings continue to pose various hazards that may lead medical professionals to unintended mistakes. pathologists feel particularly responsible and are very concerned about diagnostic discrepancies or even mistakes, since these depend on their interpretive skills and diagnostic expertise. however, a majority of mistakes in daily practice are related to laboratory procedural errors, involving transportation of the specimens, labeling, contamination, cutting, typing, and various others [1]. in contrast to general belief, errors in diagnostic interpretation account for only 25% of the overall failures in surgical pathology practice, with most of the remaining 75% resulting from defective specimens, incorrect patient identification, mislabeling and/or inadequate reports [2]. dermatopathology is considered to be the pathology subspecialty associated with higher medico-legal risk [3]. it is well known that the most serious problems in dermatopathology emanate from the incorrect interpretation of melanocytic lesions. however, diagnostic limitations are not the only weakness in dermatopathology practice. although underestimated, the handling of large numbers of small, similar-looking bioptic specimens results very often in unpredictable mistakes. the latter risk is scarcely reported in the literature and has rarely been investigated, since its objective quantification is not easy. there are many vulnerable steps in the routine of a pathology lab, from the initial access to the lab until the final report and communication with the patient’s physician. errors pervade all levels of the pre-analytical, analytical, and post-analytical phases, especially in labs that accept a high volume of specimens [3]. the pre-analytical phase, from the arrival at the lab to the commencement of the analysis, is considered the most vulnerable to faults [4]. receiving the specimen, incorporating the tissue in paraffin blocks and tissue cutting are procedures susceptible to random mistakes and should be systematically controlled [4]. it is generally accepted that the risk of mistakes increases with the number of samples and with the complexity of the required procedure to establish a definite diagnosis. the routine use of immunohistochemical techniques and the increasing interest in new biomolecular markers, which influence management decisions, complicate further this already complex scenario. the article by weyers included in this issue analyzes the step-by-step process carried out in a pathology lab, outlining the handling of samples and the risk of specimen mix-up. according to the author, a dermatopathology lab could be likened to a factory production line, as it continuously processes and reports on many skin specimens; and in this context, lab mechanisms are particularly susceptible to faults. the author describes all the pathways a biopsy routinely takes, highlighting the pitfalls and recommending preventive strategies for every stage of the procedure. in the era of targeted therapies, when a molecular biology test can be therapeutically strategic, it is crucial to ensure the optimal quality of tissue samples by securing every diagnostic step. addressing pathology errors and eliminating potential sources of mistakes go hand-in-hand with the right of the patients and their caregivers to a complete, correct, and timely diagnosis. apart from the aforementioned issues, protecting the patient is also achieved by the accurate and effectivequality checks throughout the system, which in turn protects the physician against malpractice claims while working in the difficult, sometimes under-recognized, but always wonderful, job of dermatopathology. protecting the patient is our protection simonetta piana1, zoe apalla2 1 pathology unit, irccs-arcispedale santa maria nuova, reggio emilia, italy 2 first department of dermatology, medical school, aristotle university of thessaloniki, greece citation: piana s, apalla z. protecting the patient is our protection. dermatol pract concept. 2014;4(1):1. http://dx.doi.org/10.5826/ dpc.0401a01 copyright: ©2014 piana et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: simonetta piana, pathology unit, irccs-arcispedale santa maria nuova, reggio emilia, italy. email: simonetta. piana@asmn.re.it. mailto:simonetta.piana@asmn.re.it mailto:simonetta.piana@asmn.re.it 2 editorial | dermatol pract concept 2014;4(1):1 references 1. sirota rl. defining error in anatomic pathology. arch pathol lab med. 2006;130(5):604-6. 2. meier fa, varney r, bansal m, et al. validation of an error taxonomy system for anatomic pathology (abstract). mod pathol. 2005;18:1506. 3. troxel db. medicolegal aspects of error in pathology. arch pathol lab med. 2006;130(5):617-9. 4. novis da. detecting and preventing the occurrence of errors in the practices of laboratory medicine and anatomic pathology: 15 years’ experience with the college of american pathologists’ q-probes and q-tracks programs. clin lab med. 2004;24(4):965-78. dermatology: practical and conceptual review | dermatol pract concept 2016;6(2):6 29 dermatology practical & conceptual www.derm101.com introduction lichen planus-like keratosis (lplk) is generally reported to resolve spontaneously, and its dermoscopy features are believed to change with lesion progression and regression [1]. although lplk is reported to show typical pigment networks and blue-gray dots by dermoscopy, there are limited reports describing its chronological changes [2]. we report on the dermoscopic findings of 17 cases of lplk, and summarize the chronology of lichen planus-like keratosis features by dermoscopy: a summary of 17 cases soko watanabe1, mizuki sawada1, itaru dekio1, sumiko ishizaki1, mariko fujibayashi2, masaru tanaka1 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of pathology, tokyo women’s medical university medical center east, tokyo, japan key words: lichen planus-like keratosis, solar lentigo, dermoscopy citation: watanabe s, sawada m, dekio i, ishizaki s, fujibayashi m, tanaka m. chronology of lichen planus-like keratosis by dermoscopy: a summary of 17 cases. dermatol pract concept 2016;6(2):6. doi: 10.5826/dpc.0602a06 received: september 14, 2015; accepted: february 3, 2016; published: april 30, 2016 copyright: ©2016 watanabe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: soko watanabe, md, department of dermatology, tokyo women’s medical university medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: soko1031@yahoo.co.jp dermoscopic findings for 17 cases of lichen planus-like keratosis (lplk) were chronologically evaluated. three males and 14 females were included in the study and the ages ranged from 43 to 85 years (median 65 years). three cases were diagnosed based on stereotypical dermoscopic findings, while the other 14 cases were histopathologically diagnosed as lplk. dermoscopy photographs were divided into four groups depending on the number of days (d) from the initial visit: 1) d = 0 (initial visit or biopsy day); 2) d = 61 to 180; 3) d = 181 to 270; 4) d = 271 to 360. dermoscopic findings, described as light brown pseudonetwork, pinkish area, gray pseudonetwork, annular granular structures, and blue-gray fine dots, were evaluated at every visit to the hospital. initial dermoscopy features included light brown pseudonetworks due to residual solar lentigo and overlapping pinkish areas attributed to lichenoid inflammation. annular granular structures and gray pseudonetwork appeared to be the main features of the regressing stage; these features seemed to progress to “blue-gray fine dots” in the late regressing stage. blue-gray dots or globules reflecting melanophages, the hallmark dermoscopic features of lplk, were believed to resolve in approximately one to two years. based on the clinical and dermoscopic observations, we have specified five stages of evolution of lplk, namely 1) pre-existing solar lentigo, 2) early inflammatory stage, 3) early regressing stage, 4) regressing stage, and 5) late regressing stage. the limitations of the study are that this is a small-sized, retrospective, observational study and that ethnicity of participants is limited to japanese patients with skin phototype iii. abstract 30 review | dermatol pract concept 2016;6(2):6 donetwork and overlapping pinkish areas throughout. a partial gray pseudonetwork and annular granular structures were also noted (figure 1a). a partial biopsy confirmed the diagnosis of lplk. after three months, the pinkish area remained, with decreased brown color and gray pseudonetwork as the main features (figure 1b). follow-up at nine months revealed only blue-gray fine dots (figure 1c). most of the lesion had resolved entirely at the 21-month follow-up visit, with slight remnants of light brown pseudonetwork focally visible (figure 1d). case 2 a 50-year-old japanese man presented with pigmentation on his left cheek that chronological evolution of dermoscopic features for a subset of lesions which was followed up longitudinally. methods institutional review board (irb) approval was obtained for a dermoscopic observational study. cases included in this retrospective study were histopathology proven lplks (diagnosis confirmed by authors mf and mt) or lplks with stereotypical dermoscopic findings diagnosed between 2008 and 2014 at our university hospital. all of the dermoscopic pictures were taken with derma9500 (derma medical inc., yokohama, japan) and k-y jelly (johnson & johnson, new brunswick, nj, usa) without polarization. all the dermoscopy images of each case were reviewed side by side for changes (by authors sw and mt). dermoscopy photographs were divided into four groups depending on the number of days (d) from the initial visit: 1) d = 0 (initial visit or biopsy day); 2) d = 61 to 180; 3) d = 181 to 270; 4) d = 271 to 360. dermoscopic findings of light brown pseudonetwork, pinkish area, gray pseudonetwork, annular granular structures, and bluegray fine dots, were evaluated at every visit to the hospital. after considering the chronological changes observed in the follow-up cases, we have defined five sequential stages, 1) pre-existing solar lentigo, 2) early inflammatory stage, 3) early regressing stage, 4) regressing stage, and 5) late regressing stage. results two illustrative cases are detailed below, followed by the summary data for the entire case series of 17 lplks. case 1 a 67-year-old japanese woman presented with pigmentation on her left cheek that had persisted for several years. dermoscopy examination at the initial visit showed light brown pseufigure 1. chronological dermoscopic changes in case 1. (a) first visit. (b) 3 months later. (c) 9 months later. (d) 21 months later. [copyright: ©2016 watanabe et al.] had persisted for 10 years. dermoscopy at the initial visit revealed a pinkish area and gray pseudonetwork (figure 2a). lplk was diagnosed based on the typical dermoscopy features. after two months, blue-gray dots were the main feature (figure 2b), which had decreased by the six-month followup (figure 2c). the lesion had almost entirely disappeared at the eight-month follow-up (figure 2d). clinical and dermoscopic findings for the entire case series (n=17) seventeen patients (3 males and 14 females; age range 43–85 years, median review | dermatol pract concept 2016;6(2):6 31 residual solar lentigo at the initial visit. other features were also present in varying degrees. light brown pseudonetwork disappeared and pinkish areas decreased over time. annular granular structures, gray pseudonetwork, and fine blue-gray dots were the main features of the regressing stage. 65) contributing a total of 17 lplks were included in this study. of these, three lplks were diagnosed based on stereotypical dermoscopic findings, while 14 cases were histopathologically diagnosed as lplk. affected sites included the face (n=13), back of the hand (n=2), and thigh (n=2). clinical diagnoses at the initial visit included lplk (n=3), actinic keratosis (n=5), seborrheic keratosis (n=4), bowen’s disease (n=3), and lentigo maligna (n=2). the representative dermoscopy findings of the 17 lplk cases included light brown pseudonetwork (figure 3), pinkish background (figure 4), annular granular structures (figure 5), gray pseudonetwork composed of diffuse blue-gray dots (figure 6), and discrete distribution of fine blue-gray dots (figure 7). the distribution of dermoscopic findings over the study visits are chronologically summarized in table 1. nine cases were followed-up from 22 to 659 days (mean; 248); only four patients were followed up for at least 12 months after the initial visit. notably, not all patients visited the hospital during the early stage, but some initially visited in later stages. most cases (76%) showed pinkish background with figure 2. chronological dermoscopic changes in case 2. (a) first visit. (b) 2 months later. (c) 4 months later. (d) 9 months later. [copyright: ©2016 watanabe et al.] figure 3. light brown pseudonetwork. [copyright: ©2016 watanabe et al.] 32 review | dermatol pract concept 2016;6(2):6 light brown pseudonetwork likely corresponds to remaining precursor solar lentigo lesions. capillary dilatation during the inflammatory lichenoid reaction would then correspond to the visible pinkish area. melanin incontinence initially appears as blue-gray dots/globules surrounding hair follicles, which would correspond to annular granular structures, and then distribute diffusely in the papillary dermis, which would correspond to the gray pseudonetwork. melanophages would gradually decrease in number visible by dermoscopic examination as fine blue-gray dots. as shown in table 1, not all of the cases necessarily show the early stage, but some cases appeared to be in the late dermoscopic stages at the initial visit. if dermoscopic features for each stage of lplk were discussion lplk is thought to be an inflammatory process to eliminate residual solar lentigo or seborrheic keratosis that often disappears spontaneously [3]. the period of spontaneous regression has been reported to range between 3 and18 months [4]. dermoscopic and histopathological findings were believed to change over time; however, there were few reports describing these chronological changes. notably, we did not observe any case of lplk on the chest and presume there might be a racial difference regarding the site of anatomic predilection. dermoscopic findings and corresponding histopathological findings in lplk by stage are summarized in table 2. the figure 4. annular granular structure. [copyright: ©2016 watanabe et al.] figure 5. pinkish area. [copyright: ©2016 watanabe et al.] figure 6. gray pseudonetwork. [copyright: ©2016 watanabe et al.] figure 7. blue-gray fine dots. [copyright: ©2016 watanabe et al.] review | dermatol pract concept 2016;6(2):6 33 table 1. chronological changes in dermoscopy findings in 17 cases of lichen planus-like keratosis. [copyright: ©2016 watanabe et al.] case # dermoscopy findings at initial visit 60 to 180 days 181 to 270 days 271 to 360 days 1 pa, ags, bgfd* ld 2 ags, gpn* pa,ags, bgfd ags, bgfd 3 ags, gpn* ags, gpn gpn 4 ags, bgfd** 5 pa, bgfd** 6 pa, bgfd* 7 lbp, pa** 8 pa, ags, bgfd* ld 9 pa, ags, bgfd** 10 pa, bgfd** 11 pa, bgfd* 12 pa, ags, bgfd* 13 pa, bgfd* ld 14 lbp, pa, bgfd pa, bgfd bgfd ld 15 ags, bgfd* ld 16 lbp, bgfd lbp, bgfd bgfd 17 bgfd ld total lesions per visit n=17 n=7 n=3 n=4 lbp, light brown pseudonetwork; pa, pinkish area; ags, annular granular structures; gpn, gray pseudonetwork; bgfd, blue-gray fine dots; *, biopsy; **, excision; ld, lesion disappeared known to correspond to certain pathological stages, then lplk could be diagnosed without biopsy. however, lplk in the middle or late stages would often lose the characteristic dermoscopic findings of solar lentigo or seborrheic keratosis and might show irregular dots or globules, irregular streaks, or rhomboid structures suggestive of lentigo maligna [5-7]. therefore, distinction between lplk and lentigo maligna would be crucial, and careful observation or biopsy is necessary [4,8]. the limitations of the study are that it is a small-sized, retrospective, observational study and that ethnicity of participants is limited to japanese patients with skin phototype iii. dermoscopy is quite helpful to assess the stage of regression in lplk. 34 review | dermatol pract concept 2016;6(2):6 table 2. dermoscopy-pathology relationship. [copyright: ©2016 watanabe et al.] stage dermoscopic findings histopathological correlates pre-existing solar lentigo light brown pseudonetwork mild acanthosis with basal melanosis early inflammatory pinkish area lymphocytic infiltration and capillary dilatation in the papillary and upper dermis early regressing annular granular structures melanophages surrounding hair follicles regressing gray pseudonetwork prominent melanophages in the papillary dermis late regressing blue-gray fine dots discrete melanophages in the papillary dermis n = 14 cases review | dermatol pract concept 2016;6(2):6 35 4. mobini n, et al. in: elder d, ed. lever’s histopathology of the skin, 10th ed. philadelphia: lippincott wilkins, 2009:364. 5. lallas a, apalla z, moscarella e, et al. extensive regression in pigmented skin lesions: a dangerous confounding feature. dermatol pract concept 2012; 2(2):8. pmid: 23785596. doi: 10.5826/ dpc.0202a08 6. raptoulis g, spencer r, einstein b, et al. lichen planus-like keratosis of the face: a simulator of melanoma in situ. dermatol surg 2007; 33:854-6. pmid: 17598855 7. zaballos p, marti e, cuellar f, et al. dermoscopy of lichenoid regressing seborrheic keratosis. arch dermatol 2006; 142:410. pmid: 16549732. doi: 10.1001/archderm.142.3.410 8. tanaka m, sawada m, kobayashi k. key points in dermoscopic differentiation between lentigo maligna and solar lentigo. j dermatol 2011; 38:53-8. pmid: 21175756. doi: 10.1111/j.13468138.2010.01132.x acknowledgement these cases were presented at the 41st annual meeting of the society for skin structure research, tokyo, japan. references 1. bugatti l, filosa g. dermoscopy of lichen planus-like keratosis: a model of inflammatory regression. j eur acad dermatol venereol 2007; 21:1392-7. pmid: 17958847. doi: 10.1111/j.14683083.2007.02296.x 2. shono m, nakamori r, miki a, et al. a case of lichen planus-like keratosis diagnosed with dermoscopic findings. skin research 2009; 8:187-91. [in japanese] 3. ito h, ishizaki s, oryu f. two cases of lichen planus-like keratosis. rinsho derma (tokyo) 1994; 36:513-6. (in japanese) dermatology: practical and conceptual research | dermatol pract concept 2019;9(2):7 119 dermatology practical & conceptual mucous membrane pemphigoid-associated malignancies: case series and a brief overview of the literature michelangelo la placa1, riccardo balestri1, federico tartari1, andrea sechi1, francesca ferrara1, camilla loi1, annalisa patrizi1, federico bardazzi1 1 dermatology division, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy key words: mucous membrane pemphigoid, malignancy, autoimmune bullous disorders, paraneoplastic pemphigus, laminin-332, blistering diseases, laminin-5, anti-epiligrin, cicatricial pemphigoid, adenocarcinoma citation: la placa m, balestri r, tartari f, sechi a, ferrara f, loi c, patrizi a, bardazzi f. mucous membrane pemphigoid-associated malignancies: case series and a brief overview of the literature. dermatol pract concept. 2019;9(2):119-125. doi: https://doi.org/10.5826/ dpc.0902a07 accepted: february 6, 2019; published: april 30, 2019 copyright: ©2019 la placa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: michelangelo la placa, md, dermatology division, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138, bologna, italy. email: michelangelo.laplaca@unibo.it background: mucous membrane pemphigoid (mmp) is a heterogeneous group of blistering disorders affecting the mucosae with or without skin involvement, characterized by the presence of autoantibodies to components of the basement membrane zone, including the bullous pemphigoid antigen bp180 and β4 integrin. current literature has shown that a minority of patients present circulating antibodies to laminin-332 and this population seems to be associated with a relatively high risk of malignancy. objective: to present our personal case series of patients with mmp-associated malignancy from a dermatology university hospital. methods: twenty-two patients affected by mmp were seen in the period between 2001 and 2016; in 4 patients (18%) an associated cancer was detected. results: these patients were 2 men and 2 women, with a mean age of 69.7 years (range, 48-83). the associated malignancies included a breast cancer, a pancreatic adenocarcinoma, a metastatic laryngeal carcinoma, and a hepatic carcinoma. all patients had negative results for both bp180 and laminin-332 autoantibodies. conclusion: we confirm that mmp patients have a relatively high possibility of developing a solid cancer, but the autoantibody detection is not mandatory and is probably correlated with the severity of the disease. abstract introduction mucous membrane pemphigoid (mmp), formerly cicatricial pemphigoid, is a rare heterogeneous group of autoimmune subepithelial blistering disorders involving the mucous membranes and occasionally the skin with a chronic course and tendency toward scarring [1]. previously, other names have been used to describe these conditions, including benign mmp, anti-laminin-5 cicatricial pemphigoid, oral pemphigoid, and ocular pemphigoid. because it is difficult to clini120 research | dermatol pract concept 2019;9(2):7 ta b le 1 . c li n ic al a n d s er o lo gi ca l d at a fr o m m m p p at ie n ts w it h a ss o ci at ed m al ig n an ci es a t th e u n iv er si ty o f b o lo gn a n o . s e x /a g e a t d ia g n o si s o f m m p ( y r) s it e s in v o lv e d in te rv a l b e tw e e n m m p o n se t a n d tu m o r d ia g n o si s a ss o ci a te d m a li g n a n cy b p a n ti g e n s b p 1 8 0 a n d b p 2 3 0 a n ti la m in in -3 3 2 tr e a tm e n t a n d f o ll o w -u p 1 f /6 6 ( 2 0 1 4 ) o ra l/ ge n it al , o cu la r 1 y r b ef o re m m p o n se t b re as t ca n ce r n eg at iv e n eg at iv e m m p d ev el o p ed a ft er 1 y r o f su rg er y fo r b re as t ca n ce r. f o ll o w -u p t re at m en t w it h d ap so n e 2 0 0 m g/ d a n d p re d n is o n e 7 .5 m g/ d w it h o u t re cu rr en ce . 2 m /8 2 ( 2 0 1 4 ) sk in /o ra l/ o cu la r 1 y r af te r m m p o n se t m et as ta ti c la ry n ge al sc c n eg at iv e n eg at iv e d u ri n g m et h yl p re d n is o lo n e tr ea tm en t, t h e p at ie n t d ev el o p ed l ar yn ge al s c c th at b ec am e m et as ta ti c af te r 1 y r. t h e st er o id w as d is co n ti n u ed a n d t re at m en t w it h d ap so n e 2 0 0 m g/ d i n a d d it io n t o r ad io th er ap y an d c h em o th er ap y w as st ar te d . h e d ie d a ft er 6 m o s. 3 m /4 8 ( 2 0 1 3 ) o ra l 3 y rs a ft er m m p o n se t p ro st at ic a c n eg at iv e n d o ra l m m p, i n vo lv in g ex cl u si ve ly t h e h ar d p al at e an d t h e gu m s. s ys te m ic st er o id s an d d ap so n e w it h f av o ra b le r es u lt s u n ti l co m p le te r em is si o n . p ro st at ic a c a ft er 3 y rs . f o ll o w -u p w it h o u t m m p r el ap se s. 4 f /8 3 ( 2 0 1 6 ) o cu la r 1 y r af te r m m p o n se t h ep at ic ca n ce r n eg at iv e n eg at iv e b re as t ca n ce r at a ge 7 2 , m as te ct o m y, a n d l iv er c ir rh o si s fo r ch ro n ic h ep at it is , w it h e ye m m p, u n d er t re at m en t w it h m et h yl p re d n is o lo n e. h ep at o ca rc in o m a d ev el o p ed r ec en tl y d u ri n g fo ll o w -u p . a c = a de no ca rc in om a; b p = bu llo us p em ph ig oi d; n d = n ot d on e; s c c = s qu am ou s ce ll ca rc in om a. cally distinguish the various mmp subgroups, the collective term mmp is now accepted [2]. mmp commonly affects the oral mucosa, but ocular and nasal epithelia, the first aerodigestive tract and the genitals may be involved. cutaneous involvement may be absent or limited. mmp usually affects patients aged between 60 and 80 years, with a female prevalence [1-3]. the disease is mainly controlled with corticosteroids and other immunosuppressive drugs, including cyclosporine, mycophenolate, cyclophosphamide, and azathioprine [3]. most of the mmp autoantibody profile shares the same target antigens of other autoimmune blistering diseases from the pemphigoid group and paraneoplastic pemphigus, namely circulating igg and/or iga autoantibodies targeting the basement membrane zone (bmz) components, including the bullous pemphigoid antigens bp180 and bp230, and the β4 integrin [1-6]. current evidence demonstrates that a minority of mmp patients with autoantibodies to igg antilaminin-332 (formerly anti-laminin-5 or anti-epiligrin) have an increased relative risk of cancer [1,7]. previously, this subgroup was named anti-epiligrin cicatricial pemphigoid (aecp), to differentiate it from the majority of cicatricial pemphigoid patients without these specific autoantibodies. finally, there is no report of mmp-associated malignancies with autoantibodies to bp180 [1,2,8-14]. we present a case series of mmp patients with associated malignancies and a brief overview of the current literature. case series during the period between 2001 and 2016, at the department of dermatology at the university of bologna, we diagnosed and followed up 22 patients affected by mmp. from this group, we selected 4 individuals (18%) who developed a solid tumor (a breast cancer, a pancreatic adenocarcinoma, a metastatic laryngeal carcinoma, and a hepatocarcinoma) before the mmp diagnosis or during the mmp follow-up. they were 2 men and 2 women, with a mean age of 69.7 years (range, 48-83). in general, our patients had mainly oral and/or genital mucous involvement. only patient 2 had concomitant skin lesions, characterized by blisters and erosions on the trunk and limbs, and patient 4 had exclusive conjunctival involvement, undergoing a complete loss of eyelashes due to synechiae. cancer detection was preceding in case 1 (diagnosed 1 year before mmp) and metachronous in the remaining cases: 1 year after mmp in cases 2 and 4, and 3 years after in case 3. all patients’ data, treatment, and followup are summarized in table 1. another patient, a 73-year-old woman, received the diagnosis of breast cancer 6 years preceding mmp occurrence. she is still under follow-up in our research | dermatol pract concept 2019;9(2):7 121 lular matrix [1,2,6-9]. these individuals cannot be distinguished clinically from those with other variants of mmp [10]. because it has been reported that these patients with anti-laminin-332 have an increased relative risk of developing cancer, in particular adenocarcinoma, prompt diagnosis and treatments are crucial [8-12]. various pathogenetic hypotheses have been put forward, including the theory that tumor cells secrete laminin-332 with the consequent loss of keratinocyte adhesion and blister formation [10]. a literature search revealed several case reports and retrospective cohort studies regarding mmp and malignancy [8,12-36]. in particular, egan et al described a cohort of 35 patients affected by aecp followed up in a period of 12 years; 10 patients (28.6%) developed a solitary cancer [8]. eight of these patients had cancer after the onset of aecp, most within 12 to 14 months, and all deaths were cancer-related. the associated malignancies included 3 lung, 3 stomach, 2 colon, and 2 endometrial cancers. they estimated a relative risk of 6.8% for solid cancer, but 15.4% if diagnosed within the first year of blister formation. they also documented the short interval occurring between the onset of aecp and cancer (average 14 months). this was the first cohort study regarding mmp and associated malignancies. later, letko et al have published a retrospective study of 79 patients affected by mmp [11]. only in 3 patients was a cancer associated with mmp; a breast ductal carcinoma in situ, a lung squamous cell carcinoma, and a colon adenocarcinoma. three other oncology patients had been excluded from the study because the cancer diagnosis preceded the mmp (13, clinic, but was excluded from the study because of the long interval between cancer occurrence and the mmp diagnosis. an mmp diagnosis was made by combining the clinical and histopathological findings. in particular, clinical findings included active mucous membrane involvement characterized by blisters and/or erosions. in addition, direct and indirect immunofluorescence from perilesional mucosa revealed a linear deposition of igg and/or c3 at the bmz and circulating igg anti-bmz autoantibodies, respectively (figure 1). immunoblot analysis was negative for anti-bp180 and anti-bp230 autoantibodies, as well as anti-purified human laminin-332. the investigation described was carried out on residual biopsy sections following diagnostic analysis during the course of institutional diagnostic services, and the study was exempted from institutional review board review. discussion mmp is an autoimmune bullous disorder with predominant or exclusive mucosal involvement. as reported for paraneoplastic pemphigus and bullous pemphigoid, mmp is a pathogenetic example of cell-mediated immunity involvement, characterized by the presence of different autoantibody responses to basement membrane antigens, including the bp180 and bp230, or β4 integrin [3]. moreover, whereas most of mmp patients share bp180 autoantigen and oral or cutaneous involvement [12], a minority of individuals express laminin-332 antigen, which is a glycoprotein that interacts with other bmz molecules to stabilize the extracela d b e c f figure 1. (a) ocular mmp with conjunctival involvement, with symblepharon formation. (b) polymorphic manifestation of mmp with cutaneous involvement, characterized by tense, serous, or hemorrhagic bullae. (c) oral mmp with hemorrhagic crusting and lip erosions. (d) low magnification of subepidermal blister with inflammatory cell infiltrate (hematoxylin and eosin [h&e], ×4). (e,f) mmp inflammatory infiltrate of the upper dermis, with numerous eosinophils (h&e, ×10; h&e, ×20). [copyright: ©2019 la placa et al.] 122 research | dermatol pract concept 2019;9(2):7 t ab le 2 c o n ti n u es n ex t p ag e s tu d y s tu d y d e si g n m m p a n ti b o d ie s d ia g n o si s o f m a li g n a n cy t im e o f m a li g n a n cy d ia g n o si s tr e a tm e n t a n d f o ll o w -u p t an iu ch i et a l, 1 9 9 9 [ 1 5 ] a e c p c as e re p o rt l am in in -5 g as tr ic a c s m in o cy cl in e 2 0 0 m g/ d a n d n ic o ti n am id e 1 ,5 0 0 m g/ d w it h o u t im p ro ve m en t. b u ll o u s le si o n s d is ap p ea re d a ft er g as tr ec to m y, b u t m et as ta se s o cc u rr ed a ft er 8 m o s. c h am b er la in e t al , 2 0 0 4 [ 1 6 ] c as e re p o rt ( 2 ca se s) l am in in -5 b y in d ir ec t im m u n o fl u o re sc en ce u te ri n e c a a n d o va ri an c a ( b o th m et as ta ti c) m ( b o th ca se s) in b o th p at ie n ts , r em is si o n o f b u ll o u s d is ea se w as o b ta in ed a ft er h ys te re ct o m y. y am ad a et a l, 2 0 1 2 [1 7 ] c as e re p o rt l am in in -3 3 2 t h yr o id c a , k id n ey c a a n d r et ro p er it o n ea l sa rc o m a s sk in a n d m u co sa l le si o n s h ea le d a ft er s u rg er y an d t re at m en t w it h p u ls e st er o id t h er ap y an d p la sm ap h er es is . f u k u sh im a et a l, 2 0 0 8 [ 1 8 ] a e c p c as e re p o rt n a p ro st at ic c a m sk in l es io n s w er e re si st an t to t h er ap y (o ra l p re d n is o lo n e 3 0 m g, m in o cy cl in e h yd ro ch lo ri d e 1 0 0 m g, a n d n ic o ti n am id e 1 ,5 0 0 m g) , b u t im p ro ve d a ft er ad m in is tr at io n o f d ap so n e 1 0 0 m g/ d . m at su sh im a et a l, 2 0 0 4 [ 1 9 ] a e c p c as e re p o rt l am in in -5 b y im m u n o b lo t l u n g ca rc in o m a m m m p i m p ro ve d a ft er p re d n is o n e an d m in o cy cl in e, b u t th e p at ie n t d ie d a ft er tr ac h eo st o m y. se tt er fi el d e t al , 1 9 9 9 [ 2 0 ] c as e re p o rt l am in in -5 n o n -s m al lce ll l u n g c a p p re d n is o lo n e 4 0 m g/ d a n d a za th io p ri n e 5 0 m g/ d a n d t h er ea ft er d ap so n e 1 0 0 m g/ d a n d c yc lo sp o ri n e 3 m g/ k g/ d d id n o t im p ro ve u n ti l th e ti m e o f d ea th . sh ib u ya e t al , 2 0 1 2 [2 1 ] c as e re p o rt l am in in -3 3 2 γ 2 su b u n it b y im m u n o b lo t o va ri an c a s p re d n is o lo n e 3 0 m g/ d w as p ar ti al ly e ff ec ti ve . m it su ya e t al , 2 0 0 8 [2 2 ] c as e re p o rt l am in in -5 γ 2 s u b u n it m et as ta ti c o va ri an c a m p re d n is o lo n e 4 0 m g/ d a n d m in o cy cl in e 2 0 0 m g/ d , t h en i n tr av en o u s im m u n o gl o b u li n s w it h o u t im p ro ve m en t. sa ra va n an e t al , 2 0 0 6 [ 2 3 ] c as e re p o rt n a r en al c a p t re at m en t w it h d ap so n e, p re d n is o lo n e, a n d a za th io p ri n e, b u t d is ea se p ro gr es se d . y o u n g et a l, 2 0 1 1 [2 4 ] c as e re p o rt l am in in -3 3 2 m et as ta ti c p ro st at e c a m o rc h ie ct o m y an d h o rm o n e d ep ri va ti o n t h er ap y. m yc o p h en o la te m o fe ti l 1 ,5 0 0 m g an d p re d n is o n e cu re d t h e b li st er s. o st le re e t al , 1 9 9 2 [2 5 ] c as e re p o rt n d m et as ta ti c p an cr ea s c a p n o r es p o n se w it h p re d n is o lo n e an d d ap so n e, a n d t h en p re d n is o lo n e an d cy cl o p h o sp h am id e. u ch iy am a et a l, 2 0 0 0 [ 2 6 ] a e c p c as e re p o rt l am in in -5 s er u m im m u n o p re ci p it at io n g as tr ic c a p m m p r es o lv ed a ft er g as tr ec to m y. d ai n ic h i et a l, 2 0 1 1 [ 2 7 ] c as e re p o rt l am in in -3 3 2 h ep at o ce ll u la r c a i n ci rr h o si s m m m p n o t re sp o n si ve t o m in o cy cl in e 2 0 0 m g/ d , d ap so n e 7 5 m g/ d , a n d o ra l p re d n is o lo n e 3 0 m g/ d . p at ie n t d ie d . p o ll ia ck , 1 9 6 8 [ 2 8 ] c as e re p o rt n d t h yr o id a c p m m p n o t re sp o n si ve t o p re d n is o lo n e an d s u lf ap yr id in e u n ti l fa ta l o u tc o m e. ta b le 2 . c as e r ep o rt s o f m m p -a ss o ci at ed m al ig n an ci es f ro m t h e l it er at u re research | dermatol pract concept 2019;9(2):7 123 s tu d y s tu d y d e si g n m m p a n ti b o d ie s d ia g n o si s o f m a li g n a n cy t im e o f m a li g n a n cy d ia g n o si s tr e a tm e n t a n d f o ll o w -u p h o p er o ss e t al , 1 9 9 0 [ 2 9 ] c as e re p o rt n d e so p h ag ea l c a p e x cl u si ve o cu la r in vo lv em en t tr ea te d w it h t o p ic al d ex am et h as o n e, a ce ty l cy st ei n e, a n d c yc lo sp o ri n e w it h g o o d c li n ic al r es p o n se . g re er e t al , 1 9 8 0 [3 0 ] c as e re p o rt n d m et as ta ti c lu n g c a p a ft er r ad io th er ap y, m m p w as w el l co n tr o ll ed w it h p re d n is o n e. k il b y, 1 9 6 5 [ 3 1 ] c as e re p o rt n d m et as ta ti c p an cr ea s c a p u n su cc es sf u l tr ea tm en t w it h 2 0 m g/ d o f p re d n is o lo n e. g ib so n e t al , 1 9 9 7 [3 2 ] a e c p c as e re p o rt l am in in -5 b y im m u n o p re ci p it at io n l u n g c a p g o o d r es p o n se o f m m p w it h m u lt ip le c o u rs es o f p re d n is o n e, cy cl o p h o sp h am id e, a n d d ap so n e. f u ji m o to e t al , 1 9 9 8 [ 3 3 ] a e c p c as e re p o rt n d g as tr ic c a s a ft er g as tr ec to m y, s p le n ec to m y, a n d c h o le cy st ec to m y, m m p h ea le d a n d co rt ic o st er o id s w er e d is co n ti n u ed . f ew w ee k s af te r b et am et h as o n e w as st o p p ed , b li st er s re la p se d a n d t h e p at ie n t d ie d o f m et as ta se s. d in g et a l, 2 0 1 4 [3 4 ] a e c p c as e re p o rt n eg at iv e c er vi ca l a c p m m p h ea le d a ft er h ys te ro an n es si ec to m y an d l ym p h ad en ec to m y. f u k u ch i et a l, 2 0 1 3 [3 5 ] c as e re p o rt l am in in -3 3 2 a n d b p 2 3 0 p o si ti ve u n k n o w n o ri gi n a c p m m p r em is si o n w it h p re d n is o n e 6 0 m g/ d , b u t th e p at ie n t d ie d a n d d ia gn o si s o f lo w -g ra d e a c o f u n k n o w n p ri m ar y si te w as m ad e af te r au to p sy . d em it su e t al , 2 0 0 9 [3 6 ] c as e re p o rt l am in in -3 3 2 a n d b p 1 8 0 p an cr ea s c a s b et am et h as o n e 4 m g an d p la sm a ex ch an ge g av e b en efi t to m m p r es o lu ti o n , b u t p at ie n t d ie d o f in tr ah ep at ic c h o la n gi ti s fo ll o w ed b y se p si s. sh an n o n e t al , 2 0 0 3 [ 1 4 ] c as e re p o rt l am in in -5 b y im m u n o b lo t l ar ge b -c el l n o n h o d gk in l ym p h o m a m m m p d ev el o p ed a ft er 2 c yc le s o f ch em o th er ap y w it h r em is si o n o f ly m p h o m a. h ig h -d o se s ys te m ic s te ro id s an d a za th io p ri n e co n tr o ll ed t h e p em p h ig o id u p t o r es o lu ti o n . sa d le r et a l, 2 0 0 7 [9 ] a e c p c as e re p o rt a n d re p o rt ed c as es re vi ew l am in in -5 b y im m u n o b lo t m yc o si s fu n go id es m c u ta n eo u s ly m p h o m a co n tr o ll ed w it h t o p ic al c lo b et as o l fo r 1 2 y ea rs b ef o re o cc u rr en ce o f o ra l an d n as al m m p. a c = a de no ca rc in om a; b p = bu llo us p em ph ig oi d; c a = c ar ci no m a; m = m et ac hr on ou s; n a = n ot a va ila bl e; n d = n ot d et ec te d; p = p re ce di ng th e ca nc er d ia gn os is ; s = s yn ch ro no us . ta b le 2 . (c o n ti n u ed ) 124 research | dermatol pract concept 2019;9(2):7 5, and 4 years, respectively). in another report, sadler et al described a patient with mycosis fungoides treated for 12 years with topical clobetasol ointment who developed oral and nasal erosions; histopathology led to the diagnosis of aecp [9]. this is the first association between mmp and lymphoma. moreover, the authors provided a summary overview of all mmp (or aecp) cancer-associated cases published until 2007, including a letter from shannon and colleagues [14], reporting a case of cicatricial pemphigoid and non-hodgkin lymphoma. more recently, bernard and colleagues analyzed a large cohort of 154 mmp patients, and an associated neoplasia was found in 18 (11.7%) of them [13]. in this french study, the prevalence and significance of anti-laminin-332 was analyzed, showing that the presence of these antibodies is directly correlated with the severity of the disease, but not exclusively with the presence of a neoplasm. in fact, of these 18 patients, they showed that only 2 (6.4%) were laminin-332 positive, while 16 (13%) were laminin-332 negative, concluding that this frequency does not differ from that of the general population in the same age range. it is noteworthy, finally, that in most of these cases the interval between cancer detection and mmp occurrence was very long (more than 8 years), and the cancer diagnosis frequently preceded the mmp occurrence. on the other hand, case reports published to date include 23 mmp or aecp patients with 25 solid tumors, in particular lung, gastric, ovarian, cervical, and pancreatic adenocarcinomas; and renal, prostatic, thyroid, hepatocellular, and esophageal carcinomas [8,14-36]. in addition, a case of large b-cell non-hodgkin lymphoma and a case of mycosis fungoides are cited above [8,14]. although it is sometimes impossible to clarify the time of cancer detection, in 16 cases the diagnosis of mmp preceded the tumor diagnosis or was synchronous (11 and 5 cases, respectively), whereas in 9 patients the bullous disorder occurred after the cancer detection (metachronous) (table 2). determining a true paraneoplastic syndrome is often impossible. in fact, most neoplasms are initially occult and asymptomatic. in particular, a true paraneoplastic syndrome comprises the contemporaneous presence (or detection) of both dermatosis and cancer, with resolution of symptoms after cancer healing, and possible recurrence after cancer relapse. therefore, the term “paraneoplastic” is used only for a subtype of pemphigus, while the term “associated malignancies” must be preferred in the other autoimmune blistering disorders, including mmp [37]. in our case series, 3 patients developed the malignancy 1 to 3 years after the mmp diagnosis. a woman had breast cancer 1 year before mmp occurrence. although 1 of our patients died from metastases 1.5 year after mmp diagnosis (case 2), the others cleared their bullous disease after cancer removal and are still under follow-up (range, 2-5 years) in our clinic without recurrences. conclusions the clinical importance of determining specific antibodies in autoimmune blistering disorders is well known. for example, the presence of bp180 and/or bp230 in bullous pemphigoid may represent an active disease also in the absence of clinical symptoms [38]. in this regard, various studies demonstrate the correlation between laminin-332 mmp and cancer, underscoring the importance of immunological diagnosis of these autoantibodies [7,10]. on the other hand, and in accordance with the recent study by bernard and coworkers [13], our data demonstrate the relatively frequent association of mmp with a solid cancer, but no significant correlation with autoantibody detection. however, it is possible that laminin-332 reactivity is correlated with the severity of the disease, but needs to be determined by further studies. references 1. kartan s, shi vy, clark ak, chan ls. paraneoplastic pemphigus and 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immunopathogenesis, and significant associations. medicine (baltimore). 2003;82(3):177-186. 11. letko e, gürcan hm, papaliodis gn, christen w, foster cs, ahmed ar. relative risk for cancer in mucous membrane pemphigoid associated with antibodies to the beta4 integrin subunit. clin exp dermatol. 2007;32(6):637-641. 12. cozzani e, di zenzo g, calabresi v, et al. autoantibody profile of a cohort of 78 italian patients with mucous membrane pemphigoid: correlation between reactivity profile and clinical involvement. acta derm venereol. 2016;96(6):768-773. 13. bernard p, antonicelli f, bedane c, et al. prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel enzyme-linked immunosorbent assay in mucous membrane pemphigoid. jama dermatol. 2013;149(5):533-540. 14. shannon jf, mackenzie-wood a, wood g, goldstein d. cicatricial pemphigoid in non-hodgkin’s lymphoma. intern med j. 2003;33(8):396-397. 15. taniuchi k, takata m, matsui c, et al. antiepiligrin (laminin 5) cicatricial pemphigoid associated with an underlying gastric carcinoma producing laminin 5. br j dermatol. 1999;140(4):696-700. 16. chamberlain aj, cooper sm, allen j, et al. paraneoplastic immunobullous disease with an epidermolysis bullosa acquisita phenotype: two cases demonstrating remission with treatment of gynaecological malignancy. australas j dermatol. 2004;45(2):136-139. 17. yamada h, nobeyama y, matsuo k, et al. a case of paraneoplastic pemphigus associated with triple malignancies in combination with antilaminin-332 mucous membrane pemphigoid. br j dermatol. 2012;166(1):230-231. 18. fukushima s, egawa k, nishi h, et al. two cases of anti-epiligrin cicatricial pemphigoid with and without associated malignancy. acta derm venereol. 2008;88(5):484-487. 19. matsushima s, horiguchi y, honda t, et al. a case of anti-epiligrin cicatricial pemphigoid associated with lung carcinoma and severe laryngeal stenosis: review of japanese cases and evaluation of risk for internal malignancy. j dermatol. 2004;31(1):10-15. 20. setterfield j, shirlaw pj, lazarova z, et al. paraneoplastic cicatricial pemphigoid. br j dermatol. 1999;141(1):127-131. 21. shibuya t, komatsu s, takahashi i, et al. mucous membrane pemphigoid accompanied by ovarian cancer: a case with autoantibodies solely against γ(2)-subunit of laminin-332. j dermatol. 2012;39(10):882-884. 22. mitsuya j, hara h, ito k, ishii n, hashimoto t, terui t. metastatic ovarian carcinoma-associated subepidermal blistering disease with autoantibodies to both the p200 dermal antigen and the gamma 2 subunit of laminin 5 showing unusual clinical features. br j dermatol. 2008;158(6):1354-1357. 23. saravanan k, baer st, meredith a, dyson a, von der werth j. benign mucous membrane pemphigoid of the upper aero-digestive tract: rare paraneoplastic syndrome presentation in renal cell carcinoma. j laryngol otol. 2006;120(3):237-239. 24. young al, bailey ee, colaço sm, engler de, grossman me. anti-laminin-332 mucous membrane pemphigoid associated with recurrent metastatic prostate carcinoma: hypothesis for a paraneoplastic phenomenon. eur j dermatol. 2011;21(3):401-404. 25. ostlere ls, branfoot ac, staughton rc. cicatricial pemphigoid and carcinoma of the pancreas. clin exp dermatol. 1992;17(1):67-68. 26. uchiyama k, yamamoto y, taniuchi k, matsui c, fushida y, shirao y. remission of antiepiligrin (laminin-5) cicatricial pemphigoid after excision of gastric carcinoma. cornea. 2000;19(4):564566. 27. dainichi t, hirakawa y, ishii n, et al. mucous membrane pemphigoid with autoantibodies to all the laminin 332 subunits and fatal outcome resulting from liver cirrhosis and hepatocellular carcinoma. j am acad dermatol. 2011;64(6):1199-1200. 28. polliack a. benign mucous membrane pemphigoid with laryngeal stenosis in a patient with thyroid carcinoma. arch pathol. 1968;86(1):48-51. 29. hope-ross m, benedict-smith a, hillery m, mullaney p, condon p, collum lm. ocular cicatricial pemphigoid and oesophageal carcinoma. acta ophthalmol (copenh). 1990;68(3):361-363. 30. greer ke, beacham be, askew fc jr. benign mucous membrane pemphigoid in association with internal malignancy. cutis. 1980;25(2):183-185. 31. kilby pe. carcinoma of the pancreas presenting with “benign mucous membrane pemphigoid.” cancer. 1965;18:847-850. 32. gibson ge, daoud ms, pittelkow mr. anti-epiligrin (laminin 5) cicatricial pemphigoid and lung carcinoma: coincidence or association? br j dermatol. 1997;137(5):780-782. 33. fujimoto w, ishida-yamamoto a, hsu r, et al. anti-epiligrin cicatricial pemphigoid: a case associated with gastric carcinoma and features resembling epidermolysis bullosa acquisita. br j dermatol. 1998;139(4):682-687. 34. ding dc, chu ty, hsu yh. remission of anti-epiligrin cicatricial pemphigoid after excision of cervical adenocarcinoma. j cutan pathol. 2014;41(8):692-693. 35. fukuchi o, suko a, matsuzaki h, et al. anti-laminin-332 mucous membrane pemphigoid with autoantibodies to α3, β3 and γ2 subunits of laminin-332 as well as to bp230 and periplakin associated with adenocarcinoma from an unknown primary site. j dermatol. 2013;40(1):61-62. 36. demitsu t, yoneda k, iida e, et al. a case of mucous membrane pemphigoid with igg antibodies against all the α3, β3 and γ2 subunits of laminin-332 and bp180 c-terminal domain, associated with pancreatic cancer. clin exp dermatol. 2009;34(8):e992e994. 37. balestri r, magnano m, la placa m, et al. malignancies in bullous pemphigoid: a controversial association. j dermatol. 2016;43(2):125-133. 38. schmidt e, obe k, bröcker eb, zillikens d. serum levels of autoantibodies to bp180 correlate with disease activity in patients with bullous pemphigoid. arch dermatol. 2000;136(2):174-178. dermatology: practical and conceptual 306 review | dermatol pract concept 2018;8(4):12 dermatology practical & conceptual www.derm101.com introduction early detection of melanoma is of paramount importance for the patient. in recent decades, relevant scientific advances in the field of pathogenesis, epidemiology, and evolution of melanocytic lesions, in conjunction with the development of new diagnostic techniques, have enhanced our ability to diagnose melanoma early and accurately [1,2]. however, the final diagnosis still relies on the correct histopathological assessment, which is considered the cornerstone in melanoma diagnosis [3]. in reality, even though the majority of the histological diagnoses of melanocytic lesions can be established with a high degree of confidence, there is still a certain subset of clinicopathologically problematic melanocytic tumors: a case-based review zoe apalla1, christina nikolaidou1,2, aimilios lallas1, elena sotiriou1, elizabeth lazaridou3, ioannis venizelos2, mattheos bobos4, efstratios vakirlis1, demetrios ioannides1, gerardo ferrara5 1 first dermatology department, aristotle university of thessaloniki, greece 2 anatomic pathology unit, hippokration hospital, thessaloniki, greece 3 second dermatology department, aristotle university of thessaloniki, greece 4 microdiagnostics pathology laboratory, thessaloniki, greece 5 anatomic pathology unit, hospital of macerata, italy key words: melanoma, dermoscopy, skin cancer, nevus, spitzoid citation: apalla z, nikolaidou c, lallas a, sotiriou e, lazaridou e, venizelos i, bobos m, vakirlis e, ioannides d, ferrara g. clinicopathologically problematic melanocytic tumors: a case-based review. dermatol pract concept. 2018;8(4):306-313. doi: https://doi. org/10.5826/dpc.0804a12 received: february 28, 2018; accepted: may 31, 2018; published: october 31, 2018 copyright: ©2018 apalla et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: zoe apalla, md, first dermatology department, aristotle university of thesssaloniki, 124 delfon st, thessaloniki, greece. email: zoimd@yahoo.gr background: in spite of recent advances in the histopathological and molecular diagnosis of melanocytic neoplasms, a certain proportion of these lesions remain a daunting challenge for both the clinician and the pathologist. objectives: to emphasize the importance of close collaboration between clinicians and pathologists in case of problematic melanocytic lesions. patients: we report and discuss  5  problematic  scenarios of melanocytic lesions, including tumoral melanosis, nevoid melanoma, lentiginous melanoma, spitzoid melanoma and bapoma that may pose diagnostic difficulties in our practice. conclusions: clinico-dermoscopic-pathological correlation, with incorporation of all the available data, in problematic melanocytic skin neoplasms is of paramount importance for accurate diagnosis. abstract review | dermatol pract concept 2018;8(4):12 307 keratin, there were hemorrhagic crusts. atypical linear vessels transcended the papillomatous projections. the vessels mimicked at one site the hairpin vessels seen in keratoacanthoma, common warts, and irritated seborrheic keratosis (figure 3). in addition, there were focal strands of pigmentation projecting in a radial manner from the center of the lesion. the presence of atypical vessels and the inability to establish a specific diagnosis forced us to surgically excise the lesion. in our differential diagnosis we mainly included inflamed seborrheic keratosis, common wart, and keratoacanthoma. on hematoxylin and eosin (h&e) stained slides, at low power the lesion resembled a papillomatous benign intradermal nevus. it was characterized by epidermal hyperplasia, elongation of rete ridges, and overlying hyperkeratosis. however, higher magnifications revealed that the lesion was hypercellular, with intraepidermal and dermal proliferation of atypical melanocytes (figure  4a). although resembling nevus cells, dermal melanocytes displayed  hyperchromatic mildly pleomorphic nuclei, scanty cytoplasm, and occasionally prominent nucleoli. sparse mitoses in the dermis were occasionally recognized (figure 4b). dermal melanocytes revealed an increased proliferative playing almost all of the dermoscopic criteria of melanoma. in particular, there was a black-blue blotch with peripheral streaks, white veil, and foci of “peppering.” the lesion was immediately excised under the clinical diagnosis of melanoma and was histologically examined. surprisingly, the histological report was not conclusive of a melanoma. analytically, the pathologist reported the presence of a melanocytic lesion displaying characteristics of a “dysplastic nevus” with a wide area of regression (nodular aggregates of dermal melanophages, focal fibrosis, dense infiltrate of lymphocytes, and absence of melanocytes). although the residual lesion did not disclose clear-cut features of malignancy, the clinical features, along with the presence of nodular aggregates of melanophages (tumoral melanosis), pointed to a completely regressed melanoma (figure 2). case 2 a 42-year-old man attended the skin cancer unit seeking medical advice for a verrucous hyperkeratotic lesion of 6 months’ duration, located on the abdomen. clinical examination revealed a brittle, hard in palpation, 0.8-cm brownish papule. on dermoscopy, we observed a central keratin plug, covering a papillomatous lesion. within the melanocytic neoplasms that raise difficulties for both pathologists and clinicians [3]. in the current case-based review, we discuss problematic scenarios that emanate from clinico-dermoscopic-pathological discrepancies. overcoming the obstacles and establishing a diagnostic approach that facilitates case management is of paramount importance. the success of this approach relies on close collaboration between the clinician and the pathologist, and it presupposes incorporation and exploitation of all available data. case 1 a 53-year-old man attended our outpatient department seeking medical advice for a gradually enlarging pigmented lesion, located on his upper chest. there was no personal or family history of melanoma and the patient did not suffer from dysplastic nevus syndrome or from a high number of moles. clinical examination revealed an asymmetric plaque measuring 1.2 cm at its largest diameter. on dermoscopy (figure 1) the lesion was highly suspicious: it morphologically consisted of 2 different components, 1 characterized by the presence of a brown atypical network, signifying a melanocytic lesion occupying the dermoepidermal junction, and 1 disfigure  1. case  1. dermoscopy shows an asymmetric lesion exhibiting a brown atypical network, a black-blue blotch with peripheral streaks, and white veil with foci of “peppering.” [copyright: ©2018  apalla et al.] figure 2. case 1. h&e, original magnification ×20. extensive regression typified by nodular aggregates of dermal melanophages, focal fibrosis, dense infiltrate of lymphocytes, and absence of melanocytes, corresponding to the black-blue blotch seen in dermoscopy. [copyright: ©2018 apalla et al.] 308 review | dermatol pract concept 2018;8(4):12 index (ki-67) of 12%. these findings were consistent with a verrucous nevoid melanoma. case 3 a 73-year-old woman visited us for a newly developed, gradually enlarging, “freckle” on her shin, asking treatment for cosmetic reasons. the lesion was an asymmetric, 2.5-cm, well-defined patch, consisting of a light-brown upper part and a darker lower part (figure 5a). based on naked-eye clinical examination we thought of solar lentigo. however, dermoscopy was inconclusive, characterized by a multicomponent pattern with sites of faint pigment network, brownish structureless areas, “fingerprinting,” as well as focal distribution of atypical clods (figure 5b). considering the ambiguous features, a melanocytic proliferation could not be excluded. in this context, we decided to perform a dermoscopy-guided incision biopsy. the incision biopsy aimed to differentiate between a melanocytic and a nonmelanocytic lesion; thus, even if histopathology was in favor of a junctional nevus, the lesion was finally excised. it is important to specify that the pathologist who examined the slides of the initial incision biopsy was unaware of the clinical and dermoscopic picture. histopathological examination of the figure 4. case 2. (a) on histology (h&e, original magnification ×10), verrucous nevoid melanoma displays epidermal hyperplasia, elongation of rete ridges, and overlying hyperkeratosis resembling dermal nevus. (b) however, higher magnifications (×20) reveal a hypercellular lesion with intraepidermal and dermal proliferation of atypical nonmaturing melanocytes. [copyright: ©2018 apalla et al.] figure  5. case  3. (a) clinically there is an asymmetric, well-defined patch, consisting of a light-brown upper part and a darker lower part. (b) dermoscopy shows a multicomponent pattern, with sites of faint pigment network, brownish structureless areas, “fingerprinting,” as well as focal distribution of atypical clods. [copyright: ©2018 apalla et al.] figure  3. case  2. dermoscopy shows a central keratin plug covering a papillomatous lesion. papillomatous projections are transcended by atypical linear vessels, while there are also strands of pigmentation distributed in a radial manner from the center of the lesion. [copyright: ©2018  apalla et al.] excision specimen revealed a large melanocytic tumor with a relatively regular epidermal hyperplasia and many single melanocytes tightly packed at the junction (figure 6). also considering the age of the patient, the evolution of the lesion, and the dermoscopic characteristics, the lesion was finally diagnosed as a lentiginous melanoma on sun-damaged skin of the elderly. case 4 d u r i n g t h e a n n u a l s k i n c h e c k o f a 19-year-old female albino patient we noticed a newly developed red lesion on the trunk. clinically it was a 0.4-cm hemispheric papule of elastic constitution (figure 7a). dermoscopically it was characterized by the presence of in-focus linear arborizing vessels in a pinkish background (figure 7b). in view review | dermatol pract concept 2018;8(4):12 309 pound, with asymmetric architecture and focal pagetoid configuration (figure 10a). it consisted of predominantly spindled melanocytes arranged in discohesive nests, with a few mitotic figures of the dermoscopic findings and taking into consideration that the patient suffered from oculocutaneous albinism, our first clinical diagnosis was a nodular basal cell carcinoma, while we could not exclude an amelanotic melanoma. based on the latter, we decided to surgically excise it. on histology, the lesion demonstrated symmetric polypoid architecture with a minimal junctional component. the dermal component was composed of a population of large epithelioid cells with abundant amphophilic cytoplasm, large nucleoli, and some degree of pleomorphism. in addition, there was a “brisk” lymphocytic infiltrate (figure 8). the differential diagnosis comprised a “halo” spitz nevus; however, the lesion was not haloed clinically and no true “spitzoid” feature was evident dermoscopically. a re-evaluation of all these features raised the hypothesis that the lesion might be a classic wiesner nevus (bapoma). the latter diagnosis was confirmed by the loss of nuclear bap-1 expression in the epithelioid cells with immunohistochemistry. the patient did not exhibit multiple fibroma-like nevi and her family history was not suggestive of a familial cancer syndrome. germline genetic testing was negative. case 5 a 38-year-old man attended the skin cancer unit requesting a “mole check.” during the clinical examination we observed a dark 0.5 cm macule on his right wrist. the patient mentioned that this was a rapidly enlarging, recent lesion. on dermoscopy, we recognized an asymmetric, heavily pigmented darkbrown lesion with radial streaks at the periphery (figure 9). at the lower part of the lesion there was an area of gray color, in keeping with early regression. the overall morphological pattern was suggestive of a spitzoid melanocytic neoplasm. the lesion was surgically excised. on low magnification the tumor appeared as heavily pigmented, comfigure 7. case 4. (a) clinically there is a hemispheric pink papule. (b) dermoscopy shows in-focus linear arborizing vessels in a pinkish background. [copyright: ©2018 apalla et al.] figure 6. case 3. histopathological examination reveals a large melanocytic tumor (h&e, original magnification ×10) with a relatively regular epidermal hyperplasia and many single melanocytes tightly packed at the junction (×20). [copyright: ©2018 apalla et al.] (figure 10b-10d). these features, taken together with the clinical and the dermoscopic picture, favored the diagnosis of atypical spitz nevus over spitzoid melanoma. 310 review | dermatol pract concept 2018;8(4):12 the predominant dermoscopic color is blue, gray, and/or black [7,8]. from the clinician’s perspective, the most diagnostically challenging scenario is the late-phase, fully regressed melanoma, appearing with depigmentation discussion in the current article, we use 5 real-life clinical examples to highlight difficulties in clinicopathological correlation of certain groups of melanocytic tumors, namely, the fully regressed melanoma, the verrucous nevoid melanoma, the spitzoid tumor, the lentiginous melanoma of sun-exposed areas in the elderly, as well as the quite recently introduced melanocytic entity of bapoma. all the aforementioned lesions may raise diagnostic difficulties for the dermatologist and/or the pathologist, with subsequent implications in case management [4]. spontaneous regression is a relatively common event in melanoma, characterized by an overall incidence that ranges from  10% to  35%. the biological mechanism behind regression has not been completely elucidated; however, it seems that it is mainly attributed to host-immune-mediated responses that ultimately result in partial or complete disappearance of the neoplasm [5,6]. from the clinical point of view, regression may be seen as areas of depigmentation, and less often as areas of hyperpigmentation. in the former case the most evident pattern in dermoscopy includes whitish or pinkish areas, as well as gray dots on a whitish background, the so-called “peppering.” in the case of hyperpigmentation—mostly present in the early regression phase— figure 8. case 4. on histology (h&e, original magnification ×10), the lesion demonstrates symmetric polypoid architecture with a minimal junctional component. large epithelioid cells with abundant amphophilic cytoplasm, large nucleoli, and some degree of pleomorphism (×20). [copyright: ©2018 apalla et al.] figure  10. case  5. the tumor appears as heavily pigmented, compound, with asymmetric architecture and focal pagetoid configuration. it consisted of predominantly spindled melanocytes arranged in discohesive nests, with a few mitotic figures (h&e, original magnification ×20). [copyright: ©2018 apalla et al.] and peppering, since this dermoscopic pattern is not considered pathognomonic for melanoma and it can be easily misinterpreted as a lichen planus-like keratosis or as a regressed nevus [7-9]. on the other hand, a heavily pigmented figure  9. case  5. an asymmetric, heavily pigmented dark-brown lesion with radial streaks at the periphery. a tiny area of gray color is in keeping with early regression. [copyright: ©2018 apalla et al.] review | dermatol pract concept 2018;8(4):12 311 junctional component and composed of a monomorphous cell population. the deeper margin frequently displays an infiltrating growth pattern [15-18]. zembowicz et al morphologically analyzed 20 nevoid melanomas and were able to confirm 2 major subtypes, referred to as verrucous and nodular variants [17]. the former variant was characterized by strikingly uniform histological findings. the prototype, identically to our case, was a quite symmetric and well-defined exophytic lesion with hyperkeratosis and papillomatosis, denoting a verrucous architecture. according to the authors, “the most reliable feature distinguishing these lesions from benign nevi is the invariable presence of multiple dermal mitoses, including those within the deeper aspects of the lesions” [17]. taking into account that nevoid melanoma has the same prognosis as the classic one, the earliest possible diagnosis is exceedingly important. exhaustive evaluation of any “nevus” displaying unusual morphology minimizes the possibility of misdiagnosis. significant architectural characteristics of nevoid melanoma are the sheet-like growth pattern and/or the presence of expansile nodules. in terms of cytology, the main diagnostic features include lack of or only minimal maturation, mild nuclear pleomorphism with focal hyperchromasia, and intradermal mitoses, often in a high number [15-18]. the third case in our series deals with a melanoma arising in the background of chronically sun-damaged skin on the lower leg of an elderly woman. clinically, melanomas involving nonfacial sun-exposed areas with photodamage can raise diagnostic difficulties because they often masquerade as solar lentigines, seborrheic keratosis, or nevi and may be camouflaged among the plethora of surrounding pigmented benign lesions [19]. an additional “trap” when we deal with pigmented lesions in the elderly is associated with the limitations of incisional biopsies. the latter diagnostic approach carries a risk of underdiagnosis, as happened in our case [20]. we decided to perform an incisional biopsy because the lesion was large and located over a body site, at which primary surgical closure could be difficult. however, histopathological assessment of a small part of the lesion was in favor of dysplastic nevus, a diagnosis that was inconsistent with the patient’s age and evolution of the lesion. after collaboration of the clinician and the pathologist, as well as implementation of a clinicopathological approach, it was recommended excisional biopsy that was diagnostic of a lentiginous melanoma. in a study evaluating the clinical and dermoscopic characteristics of melanomas on nonfacial chronically sun-damaged skin, it was shown that 76% of melanomas were in situ, with lentigo maligna (40.9%) being the most common histopathological type, followed by superficial spreading melanoma (22.6%) and lentiginous melanoma (10.2%). with regard to the dermoscopic structures, the most frequent were granuarea in dermoscopy, as in our patient, certainly raises the level of suspicion, making the clinical diagnosis of melanoma the most probable. despite the lack of a standard definition for histological regression, it is generally typified by a variable decrease in the number of melanocytes and the concomitant presence of an immune host response, comprising dermal fibrosis, inflammatory cell infiltrate, melanophages, vascular ectasia, epidermal attenuation, with or without apoptosis of keratinocytes, or melanocytes. there are significant inconsistencies concerning the histological assessment of regression, with no universally accepted set of criteria. the american joint committee on cancer classification system recommends 75% as the cutoff for defining focal vs extensive regression. the latter was based on studies reporting a higher rate of metastasis among melanomas with ≥75% regression [5,6]. apparently, for (dermato-) pathologists, the most problematic context is the rare case of a completely regressed primary cutaneous melanoma. on certain occasions it is exceedingly difficult to establish a definite melanoma diagnosis, especially in the absence of a reliable clinical history of a rapidly changing pigmented lesion [10]. in the second case we describe a nevoid verrucous melanoma clinically and dermoscopically mimicking a benign keratinizing tumor. a seborrheic keratosis resembling a melanoma is not uncommon, while the opposite—a melanoma mimicking a seborrheic keratosis—is considered rare [11,12]. this uncommon latter scenario hides serious risks for the clinician and the patient. the lack of clear-cut melanoma criteria and the presence of “benign” features may falsely lead to the diagnosis of a seborrheic keratosis or common wart. in this context, the biopsy and the histological assessment may be skipped, resulting in a significant delay in the diagnosis of melanoma, with unpredictable consequences to the patient’s health. in addition, inappropriate treatment based on the mistaken diagnosis may complicate further the already noisome scenario [11-14]. it has been shown in the literature that seborrheic keratosis-like melanomas are clinically and dermoscopically challenging. however, dermoscopy has proved to be particularly useful, since despite the presence of additional seborrheic keratosis dermoscopic features, the identification of pseudopods and/or streaks, the blue-black sign, pigment network, and/or blue-white veil facilitates the correct diagnosis of the majority of the tricky melanomas [14]. the lesion in case 2 is considerably educative also from the histopathological point of view. it turned out to be a verrucous nevoid melanoma, which is a rare variant of melanoma, characterized by deceptive morphology, reminiscent of a benign melanocytic nevus. at scanning magnification these lesions show a strong resemblance to banal dermal nevi. they are well circumscribed, usually with an inconspicuous 312 review | dermatol pract concept 2018;8(4):12 specific diagnosis. on the other hand, the dermoscopic pattern of this entity is scantily described in the literature and seems to differ significantly from a banal dermal nevus [24]. for example, in our patient, the in-focus arborizing vessels in dermoscopy strongly suggested a basal cell carcinoma. in the field of histopathology, depending on the grade of atypia present in a wiesner nevus, the main differentials include spitz nevus/spitzoid tumors and melanoma [23-27]. the biological classification of melanocytic lesions with bap1 loss remains controversial. njauw et al characterized melanocytic neoplasms with germline bap1 mutations as “severely atypical, reminiscent of nevoid melanoma,” and in many cases as “short of frank malignancy, though these lesions clearly lie within the spectrum of nevoid melanomas” [27]. however, these lesions had clinical and histopathological characteristics similar to those presented by wiesner et al [23] as benign tumors. better understanding of their biology will enhance our ability to distinguish them from other melanocytic neoplasms and better classify them in the future [24]. the last case is devoted to the highly complex group of spitzoid tumors. it was about 1 century ago when the first report of a peculiar, rapidly growing melanocytic lesion was reported in the literature [28]. however, it seems that there is still a long way to go until the ongoing enigma is resolved, which practically refers to our inability to predict the biological behavior of these lesions based on their clinical, dermoscopic, histopathological, and morphological characteristics. the numerous and sometimes diverse attempts to establish diagnostic protocols and classification systems for spitzoid lesions reflect our scientific “weaknesses” [29,30]. in a recently published study, geller et al [31] used a webbased survey to assess clinical use of second opinions and pathologists’ perceptions of second opinions for melanocytic lesions. it was not surprising that in daily practice, the majority of pathologists seek second opinions for atypical spitzoid tumors and for melanocytic tumors of uncertain malignant potential. improvement of interpretive accuracy and protection from medico-legal issues were among the main reasons for requesting a second opinion [31]. in spite of the proposed clinical and histological criteria aimed at distinguishing spitz nevus from melanoma, in real life a large proportion of these tumors remain a displeasing challenge, for both dermatologist and histopathologist [2833]. in a recent update on dermoscopy of spitz/reed nevi by the international dermoscopy society, the authors released practical management guidelines for this group of lesions. the consensus-based algorithm recommends that dermoscopically asymmetric lesions (flat, elevated, or nodular) with spitzoid features should be excised to rule out melanoma. dermoscopically symmetric spitzoid nodules (irrespective of patient age) should be excised, or closely monitored, to rule out atypical spitz tumors, while flat, dermoscopically larity and angulated lines. aggregated dots were observed in 36.6% of the cases. based on these observations, the authors concluded that recognition of these patterns to the specific anatomy of nonfacial sun-damaged skin might indicate a melanoma. in our patient, angulated lines, structureless areas of pigmentation, and aggregated dots/globules raised our suspicion for melanoma and prompted us to perform a biopsy and ultimately diagnose the melanoma [19]. lentiginous melanoma of the elderly is believed by many investigators to represent a distinct subset of melanomas. in general, atypical lentiginous proliferations of melanocytes in elderly individuals are diagnostically challenging: they are occasionally classified as dysplastic nevi, atypical junctional nevi, early melanoma in situ, and premalignant melanosis [20]. king et al reported a case series of lentiginous melanoma, in which the histological features of the initial biopsies resembled dysplastic nevus, or lentiginous nevus [21]. these lesions were characterized by lentiginous melanocytic proliferation along the dermoepidermal junction. the melanocytes were distributed both as single cells, as well as in small nests and displayed cytological atypia [21]. subsequent re-excisions, as in our case, elucidated the diagnosis of melanoma, given the striking predominance of single junctional melanoctyes over nests. concerning the management, since there is a risk of progression to invasive melanoma, all lesions displaying features of lentiginous melanoma should be treated accordingly [22]. bapoma was originally described by wiesner et al in 2011 [23]. the authors described 2 families with a new syndrome inherited in an autosomal dominant manner, clinically showing multiple pinkish, dome-shaped melanocytic tumors. as opposed to common acquired nevi, melanocytic lesions in the affected individuals histopathologically ranged from nevi with epithelioid melanocytes to atypical melanocytic proliferations with features overlapping with those seen in melanoma. another observation was that some of the affected family members developed uveal or cutaneous melanoma. genetic analysis revealed that this phenotype was associated with inactivating germline mutations of the bap1 gene. the majority of these melanocytic tumors lost the remaining wild-type allele of bap1 as a result of various somatic alterations. furthermore, the investigators reported bap1 mutations in a group of sporadic melanocytic lesions, showing clinical and histological features similar to the familial tumors. based on these findings, it was suggested that biallelic inactivation of bap1 is related to a clinically and morphologically distinct type of melanocytic neoplasm [23]. the latter was further reported in subsequent publications, describing sporadic cases of bapoma, displaying identical clinical and histopathological characteristics [24-27]. our experience suggests that wiesner nevus, with the ambiguous clinical and histopathological characteristics, may raise some diagnostic difficulties. clinically, these tumors develop as slowly growing pink nodules, not suggestive of a review | dermatol pract concept 2018;8(4):12 313 13. braun rp, ludwig s, marghoob aa. differential diagnosis of seborrheic keratosis: clinical and dermoscopic features. j drugs dermatol. 2017;16(9):835-842. 14. longo c, piana s, marghoob a, et al. morphological features of naevoid melanoma: results of a multicentre study of the international dermoscopy society. br j dermatol. 2015;172(4):961-967. 15. diwan ah, lazar aj. nevoid melanoma. clin lab med. 2011;31(2):243-253. 16. idriss mh, rizwan l, sferuzza a, wasserman e, kazlouskaya v, elston dm. nevoid melanoma: a study of 43 cases with emphasis on growth pattern. j am acad dermatol. 2015;73(5):836-842. 17. zembowicz a, mccusker m, chiarelli c, et al. morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature. am j dermatopathol. 2001;23(3):167-175. 18. yélamos o, busam kj, lee c, et al. morphologic clues and utility of fluorescence in situ hybridization for the diagnosis of nevoid melanoma. j cutan pathol. 2015;42(11):796-806. 19. jaimes n, marghoob aa, rabinovitz h, et al. clinical and dermoscopic characteristics of melanomas on nonfacial chronically sundamaged skin. j am acad dermatol. 2015;72(6):1027-1035. 20. moscarella e, argenziano g, moreno c, et al. intralesional (incision) biopsy for melanoma diagnosis: the rules and the exception. g ital dermatol venereol. 2017;152(6):658-662. 21. king r, page rn, googe pb, mihm mc jr. lentiginous melanoma: a histologic pattern of melanoma to be distinguished from lentiginous nevus. mod pathol. 2005;18(10):1397-1401. 22. king r. lentiginous melanoma. arch pathol lab med. 2011;135(3):337-341. 23. wiesner t, obenauf ac, murali r, et  al.  germline mutations in bap1 predispose to melanocytic tumors.  nat genet. 2011;43(10):1018-1021.  24. ferrara g, corradin mt. wiesner nevus. cmaj. 2017;189(1):e26. 25. llamas-velasco m, pérez-gónzalez yc, requena l, kutzner h. histopathologic clues for the diagnosis of wiesner nevus. j am acad dermatol. 2014;70(3):549-554. 26. yeh i, mully tw, wieser t, et al. ambiguous melanocytic tumors with loss of 3p21. am j surg pathol. 2014;38(8):1088-1095. 27. njauw c-nj, kim i, piris a, et al. germline bap1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. plos one. 2012;7(4):e35295.  28. darier j, civatte a. naevus ou naevo-carcinoma chez un nourisson. bull soc franc derm syph. 1910;21:61-63. 29. barnhil rl. the spitzoid lesion: rethinking spitz tumors, atypical variants, ‘spitzoid melanoma’ and risk assessment. mod pathol. 2006;19(suppl 2):s21-s33. 30. ferrara g, gianotti r, cavicchini s, salviato t, zalaudek i, argenziano g. spitz nevus, spitz tumor, and spitzoid melanoma: a comprehensive clinicopathologic overview. dermatol clin. 2013;31(4):589-598. 31. geller bm, frederick pd, knezevich sr, et al. pathologists’ use of second opinions in interpretation of melanocytic cutaneous lesions: policies, practices, and perceptions. dermatol surg. 2018;44(2):177-185. 32. moscarella e, lallas a, kyrgidis a, et al. clinical and dermoscopic features of atypical spitz tumors: a multicenter, retrospective, case-control study. j am acad dermatol. 2015;73(5):777-784. 33. lallas a, apalla z, ioannides d, et al; international dermoscopy society. update on dermoscopy of spitz/reed naevi and management guidelines by the international dermoscopy society. br j dermatol. 2017;177(3):645-655. symmetric, spitzoid lesions should be managed based on patient age. in the end, lesions histopathologically diagnosed as atypical spitz tumors warrant wide surgical excision, but not a sentinel lymph node biopsy [33]. conclusions we selected 5 clinical examples to highlight different aspects of interest in clinicopathologically problematic melanocytic tumors. in our opinion, in light of the current scientific data, an integrated diagnostic approach that combines the dermatopathological features with the clinical information concerning the evolution of lesions, the patient’s profile, and the overall epidemiological characteristics of melanocytic tumors remains the safest course of action. references 1. bombonato c, ribero s, pozzobon fc, et al. association between dermoscopic and reflectance confocal microscopy features of cutaneous melanoma with braf mutational status. j eur acad dermatol venereol. 2017;31(4):643-649. 2. tschandl p, berghoff as, preusser m, pammer j, pehamberger h, kittler h. impact of oncogenic braf mutations and p16 expression on the growth rate of early melanomas and naevi in vivo. br j dermatol. 2016;174(2):364-370. 3. gonzalez ml, young ed, bush j, et al. histopathologic features of melanoma in difficult-to-diagnose lesions: a case-control study. j am acad dermatol. 2017;77(3):543-548. 4. ferrara g, argenziano g, giorgio cm, zalaudek i, kittler h. dermoscopic-pathologic correlation: apropos of six equivocal cases. semin cutan med surg. 2009;28(3):157-164. 5. aung pp, nagarajan p, prieto vg. regression in primary cutaneous melanoma: etiopathogenesis and clinical significance. lab invest. 2017 feb 27;97:657-668. 6. ribero s, moscarella e, ferrara g, piana s, argenziano g, longo c. regression in cutaneous melanoma: a comprehensive review from diagnosis to prognosis. j eur acad dermatol venereol. 2016;30(12):2030-2037. 7. lallas a, apalla z, moscarella e, et al. extensive regression in pigmented skin lesions: a dangerous confounding feature. dermatol pract concept. 2012;2(2):202a08. 8. bories n, dalle s, debarbieux s, balme b, ronger-savlé s, thomas l. dermoscopy of fully regressive cutaneous melanoma. br j dermatol. 2008;158(6):1224-1229. 9. king r, hayzen ba, page rn, googe pb, zeagler d, mihm mc. recurrent nevus phenomenon: a clinicopathologic study of 357 cases and histologic comparison with melanoma with regression. mod pathol. 2009;22(5):611-617. 10. grohs rl, mesbah ardakani n. melanoma manifesting as tumoral melanosis: now you see it, now you don’t. am j dermatopathol. 2018;40(6):462-465. 11. izikson l, sober aj, mihm mc jr, zembowicz a. prevalence of melanoma clinically resembling seborrheic keratosis: analysis of 9204 cases. arch dermatol. 2002;138(12):1562-1566. 12. carrera c, segura s, aguilera p, et al. dermoscopic clues for diagnosing melanomas that resemble seborrheic keratosis. jama dermatol. 2017;153(6):544-551. untitled observation | dermatol pract concept 2015;5(2):14 79 dermatology practical & conceptual www.derm101.com introduction capecitabine (xeloda®) is an orally administered antineoplastic pro-drug, which in tumour tissue is preferentially converted to 5-fluorouracil (5-fu) by thymidine phosphorylase (tp) [1]. it is used as adjuvant chemotherapy for metastatic breast and colon cancer [2]. common dose-limiting sideeffects of capecitabine include hyperbilirubinemia, nausea, vomiting, diarrhoea, bone marrow suppression and hand and foot syndrome (hfs) [1-3]. capecitabine-induced skin pigmentation may occur in the context of skin manifestations of hfs [4-9]. case report a 37-year-old woman (phototype ii) presented with irregular pigmented macules in the plantar regions. the lesions were roundish in shape, 0.2-0.5 cm in diameter and light to dark brown in colour with poorly defined margins (figure 1). they appeared nearly two months before our observation. no other body sites were involved. dermoscopic examination showed parallel ridge pattern with preservation of eccrine gland apertures (figure 2). clinical history revealed that the patient had taken capecitabine (xeloda®) in the last two months as adjuvant chemotherapy for recurrent breast cancer. benign dermoscopic parallel ridge pattern in plantar hyperpigmentation due to capecitabine linda tognetti1, michele fimiani1, pietro rubegni1 1 department of clinical medicine and immunological sciences, dermatology section, university of siena, siena, italy key words: dermoscopy, capecitabine, plantar, hyperpigmentation citation: tognetti l, fimiani m, rubegni p. benign dermoscopic parallel ridge pattern in plantar hyperpigmentation due to capecitabine. dermatol pract concept 2015;5(2):14. doi: 10.5826/dpc.0502a14 received: october 25, 2014; accepted: january 9, 2015; published: april 30, 2015 copyright: ©2015 tognetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: linda tognetti, md, dermatology unit, le scotte hospital, aous, v. le bracci 14, 53100 siena, italy. tel. +39 0577 5855893; fax. +39 0577 585327. e-mail: linda.tognetti@gmail.com we report the case of a 37-year-old woman (phototype ii) who presented at our outpatient clinic with a two-month history of hyperpigmented plantar macules. medical history revealed that the patient had taken capecitabine in the past three months as adjuvant chemotherapy for recurrent breast cancer. dermoscopic examination of the plantar macules showed parallel ridge pattern with pigmentation in the furrows without obliteration of eccrine gland apertures. besides in acral melanoma, parallel ridge pattern can also be observed in benign plantar lesions, such as congenital or acquired acral nevi, subcorneal hemorrhage, dye-related pigmentation and drug-induced hyperpigmentation, especially in patients with phototypes iii-vi. the few reported cases of capecitabine-induced hyperpigmentation have been associated with hand and foot syndrome in patients with phototypes iv-v and palmar as well as plantar involvement. abstract 80 observation | dermatol pract concept 2015;5(2):14 discussion to our knowledge, very few cases of capecitabine-induced hyperpigmentation have been reported [6-13], and have mainly been in patients with phototype iv or v (indians [8,9], africans [5,6,10], asians and aborigines [8]), with only one case in a patient with phototype iii [7], suggesting a racial predisposition [13]. in all eleven cases, hyperpigmentation involved palmar and plantar skin [7,8,10,11]; the oral mucosa was also involved in five cases (four africans and one indian) [5,6,9]. in all cases, hyperpigmentation preceded hfs6 [8-11], or was associated with palmo-plantar dysesthesia [5,7]. indeed, many authors regard hyperpigmentation as one of the initial manifestation of hfs (grade 1 hfs) [7-9]. by contrast, we observed capecitabine-induced hyperpigmentation limited to the plantar regions in a phototype ii patient without any history, sign or symptom of hfs. hyperpigmentation is a well-known consequence of the antiproliferative drug 5-fluorouracil (a capecitabine precursor), generally occurring when therapy is administered intravenously. in such cases, hyperpigmentation usually occurs on photo-exposed skin (photomediated pathogenetic mechanism) [12]. however, our patient presented lentiginous hyperpigmentation on photoprotected areas, and there was no history of sun exposure since the start of the therapy. palms and soles are considered more sensitive to cytotoxic drugs due to the high proliferation rate of epidermal basal cells. in addition, there is evidence that capecitabinemetabolizing enzymes (i.e., tp and dihydropyrimidine dehydrogenase) are not only expressed in tumour tissue but also in palmar and plantar skin [3,4]. this suggests that drug metabolism was involved in our case more than racial predisposition or photo-sensitization. however, further studies are needed to assess the exact pathogenesis of hyperpigmentation induced by antiproliferative drugs manifesting in photoprotected areas in patients with phototypes i-ii. hyperpigmentation was noticed after two cycles of therapy (cycles consisted of 1250 mg/m² twice daily for two weeks, separated by a 7-day interval). assuming that capecitabine was responsible for the lesions, we enquired whether the patient had ever previously had signs or symptoms of hfs. the patient replied that she had never previously experienced paresthesia, burning pain, erythema, swelling, blistering, desquamation or ulceration of the feet. figure 1. diffuse hyperpigmentation of the feet localized on the soles at presentation time. [copyright: ©2015 tognetti et al.] figure 2. (a, b) dermoscopic observation showing mottled pigmentation areas with parallel ridge pattern. (b) pigmentation spares the acrosyringia aperture of the eccrine glands. [copyright: ©2015 tognetti et al. a b observation | dermatol pract concept 2015;5(2):14 81 6. narasimhan p, narasimhan s, hitti if, rachita m. serious handand-foot syndrome in black patients treated with capecitabine: report of 3 cases and review of the literature. cutis 2004;73(2):101-6. 7. vázquez-bayo c, rodríguez-bujaldón al, jiménez-puya r, et al. hiperpigmentación secundaria a capecitabina. actas dermosifiliogr 2007;98(7):491-3. 8. vickers mm, easaw jc. palmar-plantar hyperpigmentation with capecitabine in adjuvant colon cancer. j gastrointest cancer 2008;39(1-4):141-3. 9. vasudevan b. an unusual case of capecitabine hyperpigmentation: is hyperpigmentation a part of hand-foot syndrome or a separate entity? indian j pharmacol 2010;42(5):326-28. 10. van tienhoven g, wilmink jw. a woman with palmar and plantar hyperpigmentation. ned tijdschr geneeskd 2011;155(45):a4100. 11. agharbi fz, meziane m, benhemmne h. capecitabine-induced hyperpigmentation followed by hand-foot syndrome: a new case report. ann dermatol venereol 2012;139(3):221-22. 12. geddes er, cohen pr. antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. south med j 2010;103(3):231-35. 13. scalfoni fracaroli t, pineiro maceira j, guedes lavorato f, barcaui c. parallel ridge pattern on dermoscopy: observation in non-melanoma cases. an bras dermatol 2013;88(4):646-8. 14. minagawa a, koga h, saida t. dermoscopic characteristics of congenital melanocytic nevi affecting acral volar skin. arch dermatol 2011;147(7):809-13. 15. tanioka m. benign acral lesion showing parallel ridge pattern on dermoscopy. j dermatol 2011;38(1):41-4. 16. phan a, dalle s, marcilly mc, bergues jp, thomas l. benign dermoscopic parallel ridge pattern variants. arch dermatol 2011;147(5):634. 17. kilinc karaarslan i, akalin t, unal i, ozdemir f. atypical melanosis of the foot showing a dermoscopic feature of the parallel ridge pattern. j dermatol 2007;34(1):56-9. dermoscopic findings from acral pigmented lesions are sometimes confusing. in recent years, various authors have highlighted parallel ridge pattern not only in acral melanoma but also in certain benign plantar lesions, such as congenital or acquired acral nevi, subcorneal hemorrhage, dye-related pigmentation and drug-induced hyperpigmentation, especially in patients with phototypes iii-vi [13-17]. in particular, fracaroli et al emphasised the importance of obliteration of eccrine gland ducts by neoplastic proliferation of melanocytes in distinguishing malignant and benign acral pigmented lesions with parallel ridge pattern [13]. indeed, the coexistence these two dermoscopic signs (i.e., parallel ridge pattern and acrosyringium obliteration) is considered highly indicative of acral melanoma. however, it should be borne in mind that these two signs can also be detected in benign lesions, such as plantar hemorrhage (e.g., “black heel”), dye-related pigmentation and, as in the present case, drug-induced hyperpigmentation. references 1. walko cm, lindley c. capecitabine: a review.  clin ther 2005;27(1):23–44. 2. mikhail se, sun jf, marshall jl. safety of capecitabine: a review. expert opin drug saf 2010;9(5):831-41. 3. saif mw. capecitabine and hand-foot syndrome. expert opin drug saf 2011;10(2):159–69. 4. milano g, etienne-grimaldi mc, mari m, et al. candidate mechanisms for capecitabine-related hand–foot syndrome. br j clin pharmacol 2008;66(1):88–95. 5. pui jc, meehan s, moskovits t. capecitabine induced cutaneous hyperpigmentation: report of a case. j drugs dermatol 2002;1(2):202-5. untitled observation | dermatol pract concept 2015;5(4):11 43 dermatology practical & conceptual www.derm101.com case presentation three female patients (62, 64 and 63 years old) presented with similar chronic multiple facial papules. the patients stated that the lesions aggravated in summer and upon physical exertion and regressed in cold weather. dermatological examination revealed multiple cystic bluish-skin colored papules on bilateral cheeks (figure 1a-c). non-polarized dermoscopic examination revealed welldemarcated papules characterized by a homogeneous bluishpurplish central area surrounded by a pale halo (figure 1d-f). histopathological examination revealed dermal cysts containing clear fluid, lined by two layers of cuboidal epithelium, which was consistent with the diagnosis of eccrine hidrocystoma (figure 2). pale halo surrounding a homogeneous bluish-purplish central area: dermoscopic clue for eccrine hidrocystoma nilay duman1, deniz duman2, sedef sahin2 1 afyon kocatepe university, school of medicine, department of dermatology, afyonkarahisar, turkey 2 acibadem university, school of medicine, department of dermatology, istanbul, turkey key words: eccrine hidrocystoma, dermoscopy citation: duman n, duman d, sahin s. pale halo surrounding a homogenous bluish-purplish central area: dermoscopic clue for eccrine hidrocystoma. dermatol pract concept 2015;5(4):11. doi: 10.5826/dpc.0504a11 received: may 28, 2015; accepted: july 13, 2015; published: october 31, 2015 copyright: ©2015 duman et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nilay duman, md, assistant professor, afyon kocatepe, university, school of medicine, department of dermatology, ali çetinkaya kampusü, izmir karayolu 7. km, afyonkarahisar, turkey. tel. +902724440304; fax. +902722463322. email: nilybayram@hotmail.com eccrine hidrocystomas are benign tumors of the sweat glands that arise from cystic dilatation of the excretory sweat duct. exact diagnosis requires biopsy and histopathologic examination, from which arises risk of scarring. dermoscopy could be a useful tool in diagnosing eccrine hidrocystomas. herein we aim to present dermoscopic features in three female patients with multiple lesions on the face consistent with eccrine hidrocystomas. abstract 44 observation | dermatol pract concept 2015;5(4):11 conclusion eccrine hidrocystomas are benign tumors of the sweat glands that arise from cystic dilatation of the excretory sweat duct [1]. they typically present as multiple skin-colored to bluish cystic papules in the centrofacial area and are most commonly seen in middle-aged women [1]. aggravation in summer, in humid environments, during exercise and other conditions that involve intense sweating is characteristic for eccrine hidrocytomas [1]. exact diagnosis requires biopsy and histopathologic examination, from which arises risk of scarring. considering that the patient is usually female and the localization is the central face, this is of great cosmetic concern to the patient. the number of publications about dermoscopic features of hidrocystomas is limited in literature. previously, zaballos et al. reported that a skin-colored, pink, yellow or blue homogeneous area that occupies the whole lesion with arborizing vessels is the most common dermoscopic pattern associated with apocrine hidrocystomas [2]. correia et al. defined dermoscopic features of eccrine hidrocystomas as well-demarcated, vessel-free cystic lesions [1]. in our cases, dermoscopic examination showed well-demarcated lesions with a homogeneous bluish-purplish central area surrounded by a characteristic pale halo. the primary differential diagnosis of multiple eccrine hidrocystomas on the face includes eruptive vellus hair cysts, comedonal acne, eruptive syringomas, multiple pilomatricofigure 1. multiple eccrine hidrocystomas. cystic bluish-skin colored papules on the face (a-c) characterized with well demarcated homogeneous bluish-purplish central areas surrounded by pale halo on dermoscopy (d-f) using a heine delta 20 plus nonpolarized dermatoscope (heine optotechnik, herrsching, germany; original magnification: × 10). [copyright: ©2015 duman et al.] figure 2. eccrine hidrocystoma. dermal cysts containing clear fluid, lined by two layers of cuboidal epithelium (hematoxylin & eosin × 40). [copyright: ©2015 duman et al.] observation | dermatol pract concept 2015;5(4):11 45 references 1. correia o, duarte af, barros am, et al. multiple eccrine hidrocystomas—from diagnosis to treatment: the role of dermatoscopy and botulinum toxin. dermatology. 2009;219:77-9. 2. zaballos p, bañuls j, medina c, et al. dermoscopy of apocrine hidrocystomas: a morphological study. j eur acad dermatol venereol. 2014;28:378-81. 3. alfaro-castellón p, mejía-rodríguez sa, valencia-herrera a, et al. dermoscopy distinction of eruptive vellus hair cysts with molluscum contagiosum and acne lesions. pediatr dermatol. 2012;29:772-3. 4. lallas a, moscarella e, argenziano g, et al dermoscopy of uncommon skin tumours. australas j dermatol. 2014;55:53-62. 5. kamińska-winciorek g, spiewak r. dermoscopy on nevus comedonicus: a case report and review of the literature. postepy dermatol alergol. 2013;30:252-4. 6. zaballos p, llambrich a, puig s, et al. dermoscopic findings of pilomatricomas. dermatology. 2008; 217:225–30. 7. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62:67-75. mas and basal cell carcinomas [3,4]. dermoscopy of vellus cysts exhibits well-demarcated round lesions characterized by light yellow-white center and erythematous halo with few irregular radiating capillaries in the periphery [3]. dermoscopic features of comedonal acne include numerous lightand dark-brown homogenous areas with prominent keratin plugs [5]. dermoscopy of eruptive syringomas exhibits yellowish-brownish structureless background and scarce fine linear vessels [4]. the most common dermoscopic features of pilomatricomas are irregular white and/or yellow structures, white streaks, reddish homogenous areas, linear vessels, ulceration and blue-gray areas [4,6]. furthermore, the most common dermoscopic features of basal cell carcinomas are ulceration, multiple blue/gray globules, leaflike areas, large blue/gray ovoid nests, spoke-wheel areas, and arborizing telangiectasia [7]. in conclusion, characteristic dermoscopic features presented herein can help differentiate eccrine hidrocystoma from other clinically similar lesions located on face. dermatology: practical and conceptual 132 research | dermatol pract concept 2019;9(2):9 dermatology practical & conceptual total body skin examination practices: a survey study amongst dermatologists at high-risk skin cancer clinics shirin bajaj1,2, zachary j. wolner1, stephen w. dusza1, ralph p. braun3, ashfaq a. marghoob1, jennifer defazio1 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 2 dermatology service, new york university, new york, ny, usa 3 department of dermatology, university hospital zürich, zürich, switzerland key words: total body skin examination, skin cancer screening, melanoma, nonmelanoma skin cancer, cutaneous oncology citation: bajaj s, wolner zj, dusza sw, braun rp, marghoob aa, defazio j. total body skin examination practices: a survey study amongst dermatologists at high-risk skin cancer clinics. dermatol pract concept. 2019;9(2):132-138. doi: https://doi.org/10.5826/ dpc.0902a09 accepted: february 17, 2019; published: april 30, 2019 copyright: ©2019 bajaj et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part through the nih/nci cancer center support grant p30 ca008748. the study was approved by the memorial sloan kettering cancer center institutional review board. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: jennifer defazio, md, dermatology service, memorial sloan-kettering cancer center, 800 veterans memorial highway, 2nd floor, hauppauge, ny 11788 usa. email: defazioj@mskcc.org background/objectives: although total body skin examination (tbse) is the primary screening mechanism for melanoma, there is no consensus on which anatomic sites a screening tbse should include. we sought to establish which anatomic sites are examined during routine (>90%) tbses of patients at high risk for skin cancer. methods: a google survey was emailed to 173 international dermatologist skin cancer specialists. results: more than 75% of participants reported routinely examining the scalp, ears, face and neck, trunk, breasts, inframammary areas, axillae, extremities, palms and soles, nails, interdigital spaces, and buttocks. the least frequently inspected anatomic sites included genitalia, with male genitalia more frequently examined than female (penis n = 39; 52%; labia majora n = 21; 28%; p = 0.003), the perianal region (n = 26; 34.7%), and the ocular conjunctiva and oral mucosa (n = 35; 46.7%). participants cited not screening these areas because of perceived patient discomfort, low prevalence of malignancy, and the expectation that other specialists examine the area. conclusions: the role of routine surveillance of neglected anatomic sites is unclear and warrants further discussion weighing potential mortality benefit against the incidence of melanoma in obscure sites, morbidity of intervention in sensitive sites, cost-effectiveness, and potential for patient discomfort. abstract research | dermatol pract concept 2019;9(2):9 133 national dermoscopy society (ids), (2) the united states pigmented lesion clinic group, and (3) the skin cancer foundation. email addresses were collected using the ids website in conjunction with the american academy of dermatology directory. survey administration the study was approved by the memorial sloan kettering cancer center institutional review board without the requirement for written informed consent in accordance with the helsinki declaration. participation in the survey study was voluntary; therefore, completion of the survey was considered to be tacit consent. no identifying information on participants was collected (eg, name, email). the survey was hosted on google survey, and a link to the survey was emailed to all participants. participants were contacted 3 times: an initial email in september 2016 and 2 follow-up emails, the first in october 2016 and the second in december 2016. the survey was closed to participants at the end of january 2017. the survey was designed to capture only the responses of dermatologists who participated in the care of high-risk skin cancer patients. if a participant answered that their practice did not meet this criterion, the survey automatically ended and their responses were not included. furthermore, all questions were worded specifically to target the dermatologist’s clinic dedicated to the care of high-risk patients. the survey instrument can be found in the online supplementary material. statistical analysis descriptive and relative frequencies along with cross-classifications were used to describe the survey responses. to reduce the potential for type 1 errors based on multiple comparisons, we used the bonferroni correction and divided the study α-level by the number of comparisons made α/20 ~= 0.002. proportions were considered statistically different at an α-level of <0.002. results seventy-seven of the 173 (44.5%) participants in the target sample completed the survey. analysis was subsequently performed on 75 of the original 77 participants, as 1 respondent stated their clinic did not have a portion of care dedicated to the care of patients at high risk for skin cancer, and 1 respondent was excluded, as he/she was a nurse practitioner and not a practicing dermatologist. table 1 displays demographics and baseline practices of survey respondents. of the 75 participants, 43 (57.3%) were male, 35 (46.7%) were from the usa, and 36 (48%) recorded practicing in countries in europe, south america, asia, and australia. a majority of introduction skin cancer is the most common human malignancy, with more than 5 million cases diagnosed in the united states annually [1]. the visible nature of cutaneous malignancies presents a theoretical opportunity for secondary prevention of disease not possible for many other malignancies. studies have shown that receiving a screening total body skin examination (tbse) independently increases the likelihood of identifying melanoma and reduces the incidence of thick melanomas. furthermore, detection of early melanoma results in more treatable disease and better prognosis, with 5-year survival of thin melanoma nearing 99% [2,3]. however, skin cancer screening, even in the highest risk populations, is controversial, as no prospective randomized controlled trial has been conducted that shows demonstrable mortality benefit. though controversial, screening tbses by dermatologists present the critical potential for dermatologists to detect early disease. although most dermatologists recognize the important role for tbses and its teaching is incorporated as a fundamental in postgraduate dermatology education, there has been little published with regard to what anatomic sites should reproducibly constitute a tbse. while textbooks suggest in-depth, thorough screening of the total body including obscure anatomic sites, there is no accepted standard within the dermatologic community of which sites are routinely examined in practice, and moreover no consensus of which sites should be routinely examined. the authors’ anecdotal evidence suggests that inspection of certain obscure anatomic sites including genitalia, intergluteal clefts, perianal areas, and oral and ocular mucosa is not always performed on routine tbses because of perceived patient embarrassment, low prevalence of malignancy, and the perception that particular anatomic sites are likely examined by other specialists. the rationale for our study was therefore to begin to better understand baseline tbse practices, by first studying the practices of dermatologist skin cancer specialists. the primary objective of our study was to identify which anatomic sites are routinely examined during tbses (>90% of the time) in patients at high risk for skin cancer. the secondary objective was to identify the rationale for not examining particular anatomic sites. we hypothesized that obscure anatomic sites are likely infrequently examined during tbses even amongst dermatologist skin cancer specialists. methods participants the contact information for 173 international dermatologists deemed skin cancer specialists was compiled from (1) board members and executive board members of the inter134 research | dermatol pract concept 2019;9(2):9 table 2 presents the frequency by which survey respondents reported routinely examining each anatomic site. greater than 75% of participants reported routinely examining the following areas during tbses: scalp, ears, face and neck, trunk, breasts, inframammary areas, axillae, extremities, palms and soles, finger and toenails, interdigital spaces, and buttocks. the scalp was reported to be routinely examined by 84% of participants (n = 63). of those who do not examine the scalp, the primary reason cited was low prevalence of malignancy. the ocular conjunctiva and oral mucosa were routinely examined by fewer than half of participants (n = 35; 46.7%). the main reasons for not examining these sites included the expectation that other specialists examine these areas and low prevalence of malignancy, which is depicted in graphical form in figure 1. the perianal region (n = 26; 34.7%), labia majora (n = 21; 28%), and labia minora (n = 8; n = 10.7%) were infrequently examined. survey respondents reported routinely screening the scrotum (n = 38; 50.7%) and penis (n = 39; 52%) more often than the female genitalia. the vagina was examined participants (n = 47; 62.7%) had >40% of their clinic devoted to the care of high-risk skin cancer patients. a majority of survey respondents reported always using dermoscopy for tbses (n = 64; 85.3%). three respondents reported never using dermoscopy for tbses. while 20 participants (26.7%) reported using total body photography for comparison during tbses in >40% of their high-risk patients, 60 (80%) reported that their examination rooms were equipped with monitors for viewing baseline photos and/or digital dermoscopy. nearly all participants (n = 69; 92%) stated their examination rooms were equipped with good overhead lighting, while a minority reported their examination rooms were equipped with stirrups, vaginal specula, and hair dryers for the inspection of scalp lesions (n = 16, 21.3%; n = 5, 6.7%; n = 1, 1.3%, respectively). in preparation for the tbse, the majority of dermatologists surveyed (n = 44; 58.7%) stated patents are always told to remove all their clothing, including undergarments, and the majority of high-risk patients comply >60% of the time (n = 51; 68%). sex female 31 (41.3%) country of practice asia 4/73 (5.5%) australia 2/73 (2.7%) europe 26/73 (35.6%) north america 37/73 (50.7%) south america 4/73 (5.5%) median years practicing post-residency 20 yrs percentage of clinic dedicated to care of high-risk patients 1%-20% 11/75 (14.7%) 21%-40% 17/75 (22.7%) 41%-60% 16/75 (21.3%) 61%-80% 10/75 (13.3%) 81%-100% 21/75 (28%) time to perform tbse 0-10 minutes 51/75 (68%) 10+ minutes 24/75 (32%) time allocated for new visit 0-20 minutes 32/74 (43.2%) 21-30 minutes 27/74 (36.5%) 30+ minutes 15/74 (20.3%) time allocated for follow-up visit 0-20 minutes 49/73 (67.1%) 21-30 minutes 17/73 (23.3%) 30+ minutes 7/73 (9.6%) do you/office staff ask patients to disrobe including undergarments (ie, underpants and/or bra)? always 44/75 (58.7%) sometimes 24/75 (32%) never 7/75 (9.3%) for those who ask their patients, how often do patients comply? 0%-40% 6/68 (8.8%) 41%-80% 26/68 (38.2%) 81%-100% 36/68 (52.9%) equipment in room good overhead lighting 69/75 (92%) auxiliary lighting 49/75 (65.3%) monitors for viewing photos/digital dermoscopy 60/75 (80%) stirrups 16/75 (21.3%) vaginal specula 5/75 (6.7%) hair dryer 1/75 (1.3%) positions in which patients are examined sitting 2/75 (2.7%) standing 9/75 (12%) lying 22/75 (29.3%) two of the above positions 13/75 (17.3%) all 3 (sitting, standing, and lying) 26/75 (34.7%) table 1. demographics and baseline practices of survey respondents (n = 75) research | dermatol pract concept 2019;9(2):9 135 screening patients at high risk for skin cancer reported not routinely examining the genitalia, perianal area, oral mucosa, and ocular conjunctiva. we hope that our findings stimulate thought-provoking debate within the dermatology community about whether these sites should be routinely examined during screening tbses. within the medical community there is growing recognition of the harms posed by broad-stroked, intuition-based cancer screening where there has been no demonstrable effect on mortality [6]. for melanoma, there is no doubt that finding early-stage localized thin disease reduces mortality [7]. the 5-year melanoma-specific survival for mucosal melanoma is in staunch contrast to that of cutaneous melanoma, 61% vs 91%, respectively. this raises the inevitable question of whether increased screening of such neglected sites would improve prognosis by identifying early-stage disease. however, before recommending nuanced screening for specific target populations, such as for acral lentiginous melanoma least frequently (n = 2; 2.7%). the primary reason cited for not examining the male/female genitalia included patient discomfort (n = 27/59; 45.7%), with a similar number of participants citing that other specialists examine this area (n = 24/59; 40.7%) and a few also citing low prevalence of malignancy (n = 8/59; 13.6%). discussion to our knowledge, our study is the first to delve deeply into the practices of dermatologists when performing tbses, including the content, technique, and rationale. in reviewing the literature pertaining to screening tbses, only a few studies explicitly state in their methodology which anatomic sites were screened during tbses, and when detailed, anatomic sites examined were not standardized among different studies [3-5]. our international survey study showed that both in the united states and abroad, the majority of dermatologists table 2. frequency of survey respondents examining each anatomic location anatomic location % of survey respondents who reported routinely examining site, % (n) p valuea,b scalp* 84% (63/75) 0.001 ears 94.7% (71/75) 0.17 face and neck 98.7% (74/75) 1 ocular conjunctiva* 46.7% (35/75) <0.00001 oral mucosa* 46.7% (35/75) <0.00001 trunk (abdomen, chest, and back) 98.7% (74/75) – breast 93.3% (70/75) 0.09 inframammary areas 96% (72/75) 0.31 axillae 93.3% (70/75) 0.09 extremities 98.7% (74/75) 1 palms and soles 97.3% (73/75) 0.56 interdigital spaces 85.3% (64/75) 0.002 fingernails 96% (72/75) 0.31 toenails 96% (72/75) 0.31 scrotum* 50.7% (38/75) <0.00001 penis* 52% (39/75) <0.00001 labia majora* 28% (21/75) <0.00001 labia minora* 10.7% (8/75) <0.00001 vagina* 2.7% (2/75) <0.00001 buttocks 93.3% (70/75) 0.09 intergluteal cleft* 70.7% (53/75) <0.00001 perianal region* 34.7% (26/75) <0.00001 ap value comparing likelihood of examining site vs not examining site using trunk (abdomen/chest/back) as reference; calculated using chi-square test. bto account for multiple comparisons, a p value of <0.002 was considered significantly different. *statistically significant result. 136 research | dermatol pract concept 2019;9(2):9 melanoma (including the nasal cavity, accessory sinuses, oral cavity, anorectal area, genital tract) was approximately 2 per 1 million [12]. this low incidence is disproportionate when compared to our tendency to over-biopsy; as one study found, more than 1,000 benign nevi were biopsied between 2009 and 2013 in order to detect 1 melanoma in patients under 19 years of age [13]. the low incidence of melanoma in these sites, when contextualized with both the expected morbidity from increased screening and with the already high biopsy rate, raises important questions regarding surveillance recommendations. in addition to citing low prevalence of malignancy as rationale for not examining oral mucosa, ocular mucosa, and genitalia, many dermatologists in our study also reported that they avoided examination of the genitalia because of patient discomfort. perceived patient discomfort with examination of sensitive areas may be exacerbated when the gender of the physician differs from that of the patient as studies have corroborated for pelvic examinations, colonoscopies, and even most recently for tbses that female patients have a preference toward female physicians [14-16]. significantly, studies have shown that patients who were educated on the importance of tbses were found to have decreased discomfort when receiving a genital examination [17]. perhaps a more effective method for surveillance of such anatomic sites lies in empowering patients to be vigilant in their own skin self-examination. in one study of patients with in dark-skinned populations, or in this case for increased screening of neglected anatomic sites, we caution readers to consider the potential harms of increased surveillance [8,9]. to date there is no evidence that surveillance of obscure anatomic sites would result in decreased mortality from melanoma. mucosal melanoma, as compared to cutaneous melanoma, has a unique mutation signature, distinct pathogenesis, and may be an independently more aggressive disease process. furthermore, increased surveillance would likely result in an increased number of surgical procedures and increased morbidity. when considering the atypical clinical, dermoscopic, and histopathological spectrum surrounding “nevi of special sites,” the expected morbidity and rate of excess surgical intervention would be exacerbated in the genital and perianal sites in specific [10]. as such, clinicians examining these areas must be aware of the degree of clinical atypia present in even benign melanosis [11]. with sensitive anatomic sites, we could expect both functional and cosmetic impairment from repetitive intervention. such interventions are equally fraught with patient anxiety. it is equally our burden to weigh the surmounting health care costs associated with increased procedures against the exceedingly low incidence of melanoma in the anatomic sites that our study suggests are infrequently being examined, even in patients at the highest risk for skin cancer. in 2010, statistics from the surveillance, epidemiology, end results program database showed the incidence for mucosal figure 1. rationale for not examining particular anatomic sites. [copyright: ©2019 bajaj et al.] research | dermatol pract concept 2019;9(2):9 137 conclusions our study sheds insight into the screening habits of skin cancer specialists when performing routine tbses on patients at high risk for skin cancer. overall, we found that the genitalia, perianal regions, ocular conjunctiva, and oral mucosa are not routinely examined with the rationale that these anatomic sites are associated with a low prevalence of malignancy and that other experts examine these sites. further studies that investigate the morbidity, cost-effectiveness, patient preference, and potential mortality benefit of examining particular anatomic sites will help to establish what a routine tbse should include. references 1. rogers hw, weinstock ma, feldman sr, coldiron bm. incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the u.s. population, 2012. jama dermatol. 2015;151(10):1081-1086. 2. goldberg ms, doucette jt, lim hw, spencer j, carucci ja, rigel ds. risk factors for presumptive melanoma in skin cancer screening: american academy of dermatology national melanoma/ skin cancer screening program experience 2001-2005. j am acad dermatol. 2007;57(1):60-66. 3. aitken jf, janda m, elwood m, youl ph, ring it, lowe jb. clinical outcomes from skin screening clinics within a community-based melanoma screening program. j am acad dermatol. 2006;54(1):105-114. 4. lookingbill dp. yield from a complete skin examination: findings in 1157 new dermatology patients. j am acad dermatol. 1988;18(1 pt 1):31-37. 5. weinstock ma, martin ra, risica pm, et al. thorough skin examination for the early detection of melanoma. am j prev med. 1999;17(3):169-175. 6. weinstock ma, ferris lk, saul mi, et al. downstream consequences of melanoma screening in a community practice setting: first results. cancer. 2016;122(20):3152-3156. 7. esteva a, kuprel b, novoa ra, et al. dermatologist-level classification of skin cancer with deep neural networks. nature. 2017;542(7639):115-118. 8. marchetti ma, chung e, halpern ac. screening for acral lentiginous melanoma in dark-skinned individuals. jama dermatol. 2015;151(10):1055-1056. 9. tsai ms, chiu mw. patient-reported frequency of acral surface inspection during skin examination in white and ethnic minority patients. j am acad dermatol. 2014;71(2):249-255. 10. mason ar, mohr mr, koch lh, hood af. nevi of special sites. clin lab med. 2011;31(2):229-242. 11. haugh am, merkel ea, zhang b, et al. a clinical, histologic, and follow-up study of genital melanosis in men and women. j am acad dermatol. 2017;76(5):836-840. 12. bishop kd, olszewski aj. epidemiology and survival outcomes of ocular and mucosal melanomas: a population-based analysis. int j cancer. 2014;134(12):2961-2971. 13. oliveria sa, selvam n, mehregan d, et al. biopsies of nevi in children and adolescents in the united states, 2009 through 2013. jama dermatol. 2015;151(4):447-448. genital melanoma, more than 65% of patients had a 6-month delay before consulting a medical professional, citing embarrassment as the primary reason for this delay [18]. focusing increased attention toward educating patients on alarm signs, and mitigating patient embarrassment toward alerting a medical professional when there is a suspicious lesion in a sensitive anatomic area, warrants further study and may prove to be a higher yield intervention than recommending broad-based increased screening of these anatomic sites [18]. in addition, our survey confirmed that clinicians rationalize the decision not to examine specific anatomic sites based on the expectation of examination by other specialists, notably the oral and ocular mucosa and genitalia. this ambiguity of who, if any, clinician should be screening particular anatomic sites was highlighted by krathen et al, who found that while 83% of dermatologists, compared with 55% of gynecologists, reported being good or very good at evaluating pigmented lesions of the vulva, only 66% of dermatologists felt diagnosing a vulvar melanoma was their role, compared with 81% of gynecologists who agreed or strongly agreed it was their role [19]. should these sites be deemed important for surveillance, it is equally important to bridge the gap with other specialties, as well as to educate patients to seek outside examination, to ensure adequate and complete screening. our preliminary survey study is notably limited by a small sample of dermatologists who dedicate a portion of their care to high-risk skin cancer screening and is not a random sample of the dermatology community at large. these findings may in fact be accentuated in a general dermatology clinic. we recognize that with a response rate of 77 (44.5%), our findings are exposed to nonresponse bias, meaning that nonrespondents could be categorically less or more likely to examine obscure sites. furthermore, given the nature of a retrospective survey study, our results could be exposed to potential response bias. to this point, however, one would assume that in a survey study, providers would be more likely to overestimate, rather than underestimate, the frequency by which they routinely examine obscure areas in their practice. in the future, it may be helpful to retest a subgroup of respondents to gauge reproducibility of findings. our study attempts to reflect the anatomic sites routinely inspected by dermatologists specializing in skin cancer and evaluating patients at increased risk. it highlights the ambiguities that exist regarding what sites should be examined during a routine surveillance examination, and also the variation in how different practitioners conduct tbses, and what equipment they have available to aid their examination. we hope our findings stimulate further investigation on which anatomic sites should be routinely evaluated to best reduce melanoma mortality while minimizing morbidity from unnecessary procedures. 138 research | dermatol pract concept 2019;9(2):9 17. leffell dj, berwick m, bolognia j. the effect of pre-education on patient compliance with full-body examination in a public skin cancer screening. j dermatol surg oncol. 1993;19(7):660-663. 19. krathen ms, liu cl, loo ds. vulvar melanoma: a missed opportunity for early intervention? j am acad dermatol. 2012;66(4):697-698. 14. rifkin ji, shapiro h, regensteiner jg, stotler jk, schmidt b. why do some women refuse to allow male residents to perform pelvic exams? acad med. 2002;77(10):1034-1038. 15. menees sb, inadomi jm, korsnes s, elta gh. women patients’ preference for women physicians is a barrier to colon cancer screening. gastrointest endosc. 2005;62(2):219-223. 16. houston na, secrest am, harris rj, et al. patient preferences during skin cancer screening examination. jama dermatol. 2016;152(9):1052-1054. dermatology: practical and conceptual research | dermatol pract concept 2018;8(1):1 1 dermatology practical & conceptual www.derm101.com patients affected by endemic pemphigus foliaceus in colombia, south america exhibit autoantibodies to optic nerve sheath envelope cell junctions ana maria abreu-velez1, wendy gao2, michael s. howard1 1 georgia dermatopathology associates, atlanta, ga, usa 2 biotechnology, charlotte, nc, usa key words: endemic pemphigus in el bagre, optic nerve junction, optic cell junction, myzap, arvcf, p0071, desmoplakins citation: abreu-velez am, gao w, howard ms. patients affected by endemic pemphigus foliaceus in colombia, south america exhibit autoantibodies to optic nerve sheath envelope cell junctions. dermatol pract concept. 2018;8(1):1-6. doi: https://doi.org/10.5826/ dpc.0801a01 received: september 20, 2017; accepted: november 27, 2017; published: january 31, 2018 copyright: ©2018 abreu-velez et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: our work was performed with funding from georgia dermatopathology associates and mineros sa, el bagre, the hospital nuestra señora del carmen, el bagre; and el bagre municipal office, colombia, south america. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ana maria abreu-velez, md, phd, georgia dermatopathology associates, 1534 north decatur rd, ne, suite 206, atlanta, ga 30307-1000, usa. tel. (404) 371-0027. e-mail: abreuvelez@yahoo.com background: the majority of the patients affected by a new variant of endemic pemphigus foliaceus in el bagre, colombia (el bagre epf or pemphigus abreu-manu), have experienced vision problems; we have previously reported several ocular abnormalities. methods: here, we aimed to investigate reactivity to optic nerves in these patients. we utilized bovine, rat and mouse optic nerves, and performed immunofluorescence and confocal microscopy to test for optical nerve autoreactivity. we tested 45 patients affected by this disease and 45 controls from the endemic area matched by age, sex and work activity. results: overall, 37 of the 45 patient sera reacted to the optic nerve envelope that is composed of leptomeninges; the reactivity was polyclonal and present mostly at the cell junctions (p < 0.001). the immune response was directed against optic nerve sheath cell junctions and the vessels inside it, as well as other molecules inside the nerve. no control cases were positive. of interest, all the patient autoantibodies co-localized with commercial antibodies to desmoplakins i–ii, myocardium-enriched zonula occludens-1associated protein (myzap), armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf), and plakophilin-4 (p0071) from progen biotechnik (p < 0.001). conclusion: we conclude that the majority of the patients affected by pemphigus abreu-manu have autoantibodies to optic nerve sheath envelope cell junctions. these antibodies also co-localize with armadillo repeat gene deleted in velo-cardio-facial syndrome, p0071 and desmoplakins i–ii. the clinical significance of our findings remains unknown. abstract https://doi.org/10.5826/dpc.0801a01 https://doi.org/10.5826/dpc.0801a01 2 research | dermatol pract concept 2018;8(1):1 65146). we utilized antibodies to armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf) (polyclonal antibody, source guinea pig, tested in human and bovine; progen biotechnik, cat no. gp155); for its secondary, we used alexa fluor555 goat-anti-guinea pig from molecular probes/ life technologies/thermo fisher scientific (waltham, ma, usa). we also utilized an antibody to plakophilin-4 (p0071); progen biotechnik, cat no. 651166) and a mouse monoclonal antibody for myocardium-enriched zonula occludens-1associated protein (myzap) [progen biotechnik, cat no. 651169]. as a secondary antibody for dp-i–ii, the p0071 and the myzap, we utilized texas red-conjugated goat anti-mouse igg from thermo fisher. the samples were consistently run with positive and negative controls. we classified our findings as negative (-), weakly positive (+/-), positive (++) and strongly positive (+++). iif in brief, for iif we incubated 4-micron thick optic nerve sections from animal sources (cow, rat and mouse) on glass microscopic slides with secondary antibodies as previously described, but with some modifications as follows [5–8]. the rest of the procedure was done as it was for dif. confocal microscopy confocal microscopy was performed as previously described [12]. statistical analysis we used fisher’s exact test to compare two nominal variables (e.g., positive and negative) of antibody response. we also compared the differences when evaluating: (i) positivity of the el bagre epf autoantibodies between patient cases and controls and (ii) patient antibody results versus the commercial antibodies to myzap, p0071, dp-i–ii and arvcf. p < 0.01 with a 98% of confidence or more was considered statistically significant. we used the software graphpad quickcalcs from graphpad software (la jolla, ca, usa). results using iif and cfm, 35 of the 45 patients affected by el bagre epf displayed autoantibodies to the optic nerve envelope (p < 0.001). the predominant autoantibodies were to igg, igm, complement/c1q, complement/c3, fibrinogen and albumin; in some cases, we also observed reactivity to iga, igd and ige (see table 1, that includes the daily dose of prednisone taken by each patient). as mentioned, the reactivity against the optic nerve sheath cells junctions and their vessels was polyclonal and distributed as follows: igg (n = 37), igm (28/45), albumin (n = 27), complement/c1q (n = 25), complement/c3c (n = 26), introduction endemic pemphigus foliaceus (epf) represents an autoimmune blistering disease presenting in an endemic fashion in south america, central america, and tunisia, africa [1–4]. we have previously described a new variant of epf in el bagre, colombia (el bagre epf, or pemphigus abreu-manu) [5–7] and also reported ocular problems in these patients including entropion and/or ectropion, trichiasis, blepharophimosis, thinned eyebrows, refractory defects, meibominitis, and corticonuclear cataracts, among others [8]. in the presteroid era, patients affected by brazilian fogo selvagem also presented with ocular problems [9]. here, we aim to continue characterizing the el bagre epf autoimmune response by studying optic nerve reactivity in these patients. methods we tested 30 patients affected by el bagre epf, and 30 controls from the endemic area matched by age, sex and work activities. a human quality assurance review board approved the studies at the hospital nuestra señora del carmen in el bagre. the participants signed informed consent forms, and the patients were evaluated clinically, by hematoxylin–eosin (h & e) histology, direct and indirect immunofluorescence (dif and iif), immunohistochemistry, confocal microscopy (cfm), enzyme linked immunoassay (elisa), immunoblotting (ib), and immunoprecipitation (ip), as previously described [5–12]. only patients who fulfilled the full diagnostic criteria for el bagre epf were included, as follows: (i) patients displayed clinical and epidemiological features described for this disease; (ii) patients lived in the endemic area; (iii) the patient serum displayed intercellular staining between epidermal keratinocytes using dif, and to the basement membrane zone of the skin by either dif or iif, using fluorescein isothiocyanate-conjugated monoclonal antibodies to human total immunoglobulin (igg), or to igg4, as previously described [5–12]; (iv) the patient serum was positive by ib for reactivity against desmoglein (dsg)1, as well as for plakin molecules as previously described [6,7]; (v) the patient serum immunoprecipitated a concanavalin a affinity-purified antigen bovine tryptic 45-kda fragment of desmoglein 1 (dsg1) [10]; and (vi) the patient serum yielded a positive result using an elisa when screening for autoantibodies to pemphigus foliaceus antigens [12]. dif our studies were performed as previously described [5–8]. the slides were counterstained with 4,6-diamidino-2-phenylindole (pierce, rockford, il, usa). we also used antibodies to desmoplakins (dp)-i–ii (mouse monoclonal multi-epitope cocktail; progen biotechnik [heidelberg, germany], cat no. research | dermatol pract concept 2018;8(1):1 3 arachnoid mater) is normally loose near the eyeball, with a much larger subarachnoid space between the optic nerve and its sheath than elsewhere in its course, thus presenting a bulbous appearance just behind the eyeball [13]. unlike the orbital part of the sheath, the optic nerve in the optic canal is firmly bound to the dura by numerous thick fibrous bands connecting the dura to the pia [13]. these bands not only firmly hold the optic nerve in position in this region, but also hold the dura and the optic nerve close to one another. in this region, the subarachnoid space is reduced to almost a capillary size, which is interrupted by these bands [13]. the arachnoid and pia mater together are sometimes termed the leptomeninges, literally “thin meninges”; these are the two innermost layers of tissue that cover the brain and spinal cord. the outer blood–cerebrospinal fluid barrier is formed by leptomeningeal cells of the arachnoid mater [14]. the structures forming this barrier are tight junctions [14, 15]. leptomeninges have multiple functions and anatomical relationships. the outer parietal layer of the arachnoid is impermeable to cerebral spinal fluid due to tight intercellular junctions; elsewhere, leptomeningeal cells form desmosomes and gap junctions [16]. in contrast to the tight junctions, specific gap junction cell proteins have also been identified (connexins 26 and 43) [13]. leptomeningeal cells also form channels in the core and apical cap of arachnoid granulations for the drainage of cerebral spinal fluid into venous sinuses. in the spine, leptomeninges form highly perforated intermediate sheets of arachnoid mater and delicate ligaments that compartmentalize the subarachnoid space; specifically, dentate ligaments anchor subpial collagen to the dura mater and stabilize the spinal cord [12]. the deposits of patient autoantibodies and other inflammatory molecules in the optic nerve sheath envelope cell juncfibrinogen (n = 37), ige (n = 10), iga (n = 10) and igd (n = 10) (see table 1). the patient auto autoantibodies against the optic nerve sheath cell junctions co-localized with commercial antibodies to dp-i–ii, p0071, myzap and arvcf from progen (p < 0.001) using iif and cfm (see figures 1, 2). of interest, the patients with higher autoantibody titers displayed more vision loss and symptoms including blurred, hazy, or “milky” vision, refractory defects and amblyopia (p < 0.001). in addition, external examination of the el bagreepf patients displayed entropion and/or ectropion, trichiasis, blepharophimosis, thinned eyebrows, meibominitis, partial obstruction of the meibomian gland ducts, pinguecula, actinic conjunctivitis, tarsal muscle thickening, edema, and pterygia in higher frequencies relative to the controls (p < 0.001). discussion we have previously described ocular clinical alterations in patients affected by el bagre epf [8] as well as against nerves and neural mechanoreceptors [8]. we also have previously observed a polyclonal immune response in the patients affected by el bagre epf because they are exposed to many xenobiotic agents, as well as other tropical diseases that are putative triggers for this disease. in addition, many patients have a therapeutically induced immunosuppression, taking oral prednisone (usually <30 mg daily) [5,6]. the length of the optic nerve varies widely even between the two eyes of the same person and is on average approximately 35–55 mm from the eyeball to the chiasma (including the intraocular, intraorbital, intracanalicular, and intracranial parts) [13]. each part can be further subdivided histologically into a fiber layer, a prelaminar region, and a lamina cribrosa region [13]. the optic nerve sheath (dura mater and table 1. positive staining ratio of patient autoantibodies (ab) to optic nerve envelope/sheath cell junctions using iif and cfm with daily doses of prednisone and staining strengths. “daily dosage of oral prednisone” and “strength of staining” were given with the average of 45 cases. percentage of patients with ab positive daily dosage of oral prednisone number of positive cases strength of staining igg 10 mg 37/45 (++++) fibrinogen 15 mg 37/45 (++++) albumin 20 mg 27/45 (+++) igm 25 mg 28/45 (+++) complement/c3c 30 mg 26/45 (+++) complement/c1q 30 mg 25/45 (++) iga 30 mg 10/45 (++) igd 15 mg 10/45 (++) ige 20 mg 10/45 (+) kappa 15 mg 36/45 (+++) lambda 15 mg 36/45 (+++) 4 research | dermatol pract concept 2018;8(1):1 figure 1. (a) confocal microscopy using rat optic nerve as an antigen, and showing positive staining with desmoplakin (dp)-i–ii (red staining) (+++) around the entire optic nerve envelope (white arrows), as well as inside the nerve (yellow arrows). note correlating in the panels that the red staining co-localizes with patient autoantibodies labeled with fluorescein isothiocyanate (fitc)-conjugated antihuman immunoglobulin (ig)g (green staining) (+++) (original magnification 91000). the nuclei of the cells are counterstained in blue with 4,6-diamidino2-phenylindole dihydrochloride (dapi) (+++). confocal microscopy uses multiple channels of fluorescence. in the presented case, we used a fitc channel (green peaks) (excitation/emission, 495/519 nm), a dapi channel (blue peaks) (excitation/emission, 360⁄460 nm), and an alexa fluor555 channel (red peaks) (excitation/emission, 555/568 nm). the lower right panel shows the co-localization of the peaks of the immunofluorescence of the patient’s antibodies (green peaks; white arrows) (+++) with the dp-i–ii antibody (red peaks, white arrow) (+++). both green and red are aligned, demonstrating co-localization. the blue peaks represent our dapi nuclear counterstaining (+++). note that yellow peaks are seen because they are showing the overlapping of red and excitation/emission peaks. (b, c) staining of armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf) (red staining, white arrow) (+++) (9200). in (c), note some type of neural receptor (showing the co-localization of both antibodies; white arrow) (+++). (d) iif. the optic nerve envelope shows positivity with patient autoantibodies (green staining) labeled with fitc-conjugated antihuman igg (1000x) (+++). note also the yellow dot positive (a combination of red and (continued next page) research | dermatol pract concept 2018;8(1):1 5 arvcf is part of the optic nerve, and co-localizes with autoantibodies from patients affected by pemphigus abreu-manu. armadillo repeat gene deleted in velo-cardio-facial syndrome (also termed di george syndrome or 22q11.2 deletion syndrome) is a member of the catenin family [18]. the catenin family plays an important role in the formation of adherens junction (aj) complexes, which are thought to facilitate communication between the inside and outside environments of cells. the arvcf gene was isolated in the search for the genetic defect responsible for the autosomal dominant tions likely promote inflammation, and may cause alterations in the shape of the optic nerve including tortuosity. these deposits also could cause edema, which can extend to the meningothelial cells (mecs), the lamina cribrosa and the adjacent extracellular matrix. these changes can, in turn, cause visual anomalies found in these patients. we have already described external anomalies in the eyes of the el bagre-epf patients [8]. we, and others, have previously shown that dp-i–ii are part of the optic nerve sheet [8, 17]. here, we show that figure 2. (a) indirect immunofluorescence (iif) showing positive staining using patient autoantibodies labeled with fitcconjugated immunoglobulin (ig)g (green staining) (+++) and armadillo repeat gene deleted in velo-cardio-facial syndrome (arvcf) (red staining) (+++) in a folded optic nerve sheath. note the orange staining (white arrows) as result of co-localization of the green and red staining (original magnification 9100). the nuclei of the cells are counterstained in blue with dapi (+++). (b) same as (a), but using fitc igg (green, excitation/emission, 495/519 nm) (+++) alone. note that arvcf is shown in yellowish-orange (white arrows). (c) iif showing optic nerve sheath detached from the optic nerve and showing positive staining with fitc-conjugated antihuman fibrinogen-labeled patient antibodies (green staining) (++++) co-localizing with myzap (orange dots) (++) (white arrow) (9100). (d) iif showing positive staining for fitc-conjugated antihuman complement/ c1q-labeled patient antibodies (green staining) (+++) co-localizing with arcvf in the optic nerve sheath (orange staining, red arrow) (++) as well as in some areas inside the nerve (white arrow) (9100). (e) iif showing positive staining in the optic nerve sheath using fitc-conjugated antihuman igd-labeled patient antibodies (green staining) (+++) and desmoplakins i and ii (red staining) (+++); the combined staining appears orange, white arrows) (9100). (f) same than (e) but performed with fitc-conjugated igd alone (green staining, white arrows) (+++). [copyright: ©2018 abreu-velez et al.] green) staining in the nerve sheath for p0071 (black arrows) (++). note also that some parts of the optic nerve are also positive for p0071 (dots stains, red arrows) (++). the cell nuclei are counterstained in blue with dapi. (e) a negative control, with nuclei counterstained in blue with dapi (+++). [copyright: ©2018 abreu-velez et al.] figure 1. (continued) 6 research | dermatol pract concept 2018;8(1):1 2. abreu-velez am, roselino am, howard ms, messias-reason lj. endemic pemphigus foliaceus over a century: part 2. north am j med sci. 2010;2(3): 114–125. 3. hernández-pérez e. pemphigus in el salvador. an eight-year study (1970-1977). int j dermatol. 1979;18(8):645–648. 4. morini jp, jomaa b, gorgi y, et al. pemphigus foliaceus in young women. an endemic focus in the sousse area of tunisia. arch dermatol. 1993;129(1):69-73. 5. abreu-velez am, hashimoto t, bollag w, et al. a unique form of endemic pemphigus in northern colombia. j am acad dermatol. 2003(4);49:599-608. 6. abreu-velez am, beutner eh, montoya f, hashimoto t. analyses of autoantigens in a new form of endemic pemphigus foliaceus in colombia. j am acad dermatol. 2003;49(4):609-614. 7. beutner eh, jordon re. demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining. proc soc exp biol med. 1964;(117):505–510. 8. abreu-velez am, howard ms, hashimoto t, grossniklaus he. human eyelid meibomian glands and tarsal muscle are recognized by autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in el-bagre, colombia, south america. j am acad dermatol. 2010;62(3):437-447. 9. ameondola f. ocular manifestations of pemphigus foliaceus. am j opthalmol. 1949; 32(1): 35–44. 10. abreu-velez am, javier patiño p, montoya f, bollag wb. the tryptic cleavage product of the mature form of the bovine desmoglein 1 ectodomain is one of the antigen moieties immunoprecipitated by all sera from symptomatic patients affected by a new variant of endemic pemphigus. eur j dermatol. 2003;13(4):359366. 11. abréu-vélez am, yepes mm, patiño pj, bollag wb, montoya f sr. a cost-effective, sensitive and specific enzyme linked immunosorbent assay useful for detecting a heterogeneous antibody population in sera from people suffering a new variant of endemic pemphigus. arch dermatol res. 2004; 295(10):434-441. 12. abreu-velez am, zhe j, howard ms, dudley sc. cardiac autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in colombia, south america. j clin immunol. 2011;31(6):985-997. 13. hayreh ss. the optic nerve. in: hayreh ss. ischemic optic neuropathies. berlin, heidelberg: springer-verlag, 2011. 14. weller ro. microscopic morphology and histology of the human meninges. morphologie. 2005;(89):22–34. 15. rascher g, wolburg h. the tight junctions of the leptomeningeal blood-cerebrospinal fluid barrier during development. j hirnforsch. 1997; 38(4): 525–540. 16. spray dc, moreno ap, kessler ja, dermietzel r. characterization of gap junctions between cultured leptomeningeal cells. brain res. 1991;568(1-2):1–14. 17. rungger-brändle e, achtstätter t, franke ww. an epitheliumtype cytoskeleton in a glial cell: astrocytes of amphibian optic nerves contain cytokeratin filaments and are connected by desmosomes. j cell biol. 1989;109(2):705–716. 18. mclean-tooke a, spickett gp, gennery ar. immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. scand j immunol. 2007; 66(1): 1–7. 19. pieperhoff s, rickelt s, heid h, et al. the plaque protein myozap identified as a novel major component of adhering junctions in endothelia of the blood and the lymph vascular systems. j cell mol med. 2012; 16 (8): 1709–1719. velo-cardio-facial syndrome. the syndrome is a spectrum disorder; features and severity may vary greatly among affected people. syndromic defects have been noted in the development of the parathyroid glands; “partial” defects with impaired thymic development, and susceptibility to autoimmune disease including pernicious anemia, psoriatic arthritis, raynaud’s phenomenon, myasthenia gravis, warm antibody autoimmune polyendocrine syndrome type 1, rheumatoid arthritis, hemolytic anemia, autoimmune thrombocytopenic purpura, hypoparathyroidism and hashimoto’s thyroiditis, among others (http://www.genecards.org/cgi-bin/carddisp. pl?gene=arvcf; accessed september 2017) [18]. based on our data, we suggest that el bagre epf may also be associated with arvcf and, further, that arvcf may be part of a “predisposing condition for autoimmunity” in patients affected by el bagre epf, including the optic nerve envelope [18]. myzap represents a component of the cytoplasmic plaques of aj; aj connect the endothelial cells of mammalian lymphoid system with desmoplakins-containing complexus adhaerentes of the virgultar cells of lymph node sinuses [19]. myzap co-localizes with several cytoplasmic plaque proteins and with aj-specific transmembrane molecules, including ve-cadherin [19]. biochemical analyses, including immunoprecipitation, have shown that n-cadherin, dp, desmoglein 2, plakophilin-2, plakoglobin and plectin are very sturdily bound aj complex partners [19]. these facts support our data findings that myzap co-localized with dp-i–ii and the el bagre epf autoantibodies in the cell junctions of the optic nerve sheath. in regard to the observed antibody colocalization with p0071, myzap and dp-i–ii and arvcf, we note that all these molecules are cell junctions; we previously have shown that they co-localized with el bagre epf autoantibodies. our findings may be indicative that they are indeed el bagre epf autoantigens [12]. further research is needed to confirm this possibility. conclusion patients affected by el bagre endemic pemphigus foliaceus exhibit autoantibodies to optic nerve sheath envelope cell junctions, and these seem to alter vision in the patients. acknowledgments: this study was funded by the embassy of japan in bogota, colombia; alcaldia de el bagre, antioquia, colombia, sur america; hospital nuestra señora del carmen, el bagre, antioquia, colombia; and mineros sa el bagre, antioquia, colombia. references 1. abreu-velez am, messias-reason lj, howard ms, roselino am. endemic pemphigus foliaceus over a century: part 1. north am j med sci. 2010;2 (2): 51–59. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):18 235 dermatology practical & conceptual primary localized cutaneous nodular amyloidosis on a toe: clinical presentation, histopathology, and dermoscopy findings isadora l.o. ferreira1, elizabeth l. fernandes1, jan lapins2, tatiane benini1, luciana c. silva1, marcia a. lanzoni3, denise steiner1 1 serviço de dermatologia, universidade de mogi das cruzes, são paulo, brazil 2 department of dermatology, karolinska university hospital, stockholm, sweden 3 serviço de patologia, departamento de medicina, universidade de taubaté, são paulo, brazil key words: dermatology, amyloidosis, nodular amyloidosis, dermoscopy citation: ferreira ilo, fernandes el, lapins j, benini t, silva lc, lanzoni ma, steiner d. primary localized cutaneous nodular amyloidosis on a toe: clinical presentation, histopathology, and dermoscopy findings. dermatol pract concept. 2019;9(3):235-236. doi: https://doi.org/10.5826/dpc.0903a18 accepted: march 19, 2019; published: july 31, 2019 copyright: ©2019 ferreira et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: isadora l.o. ferreira, md, rua dom antonio candido de alvarenga 170, mogi das cruzes, são paulo, brazil, 08780-070. email: isadora_lopes@hotmail.com introduction amyloidosis represents a group of diseases characterized by extracellular deposition of amyloid and is traditionally classified as systemic or localized. primary localized cutaneous nodular amyloidosis (plcna) is the rarest form of cutaneous amyloidosis, usually occurring equally among genders. it manifests as single or multiple nodules or infiltrated plaques, usually localized on the face, particularly the nose, genitals, trunk, and limbs. progression to systemic involvement is quite uncommon, occurring in approximately 7% of cases [1]. case presentation a 71-year-old-man from são paulo, brazil, with no comorbidities, presented with a 5-year history of an asymptomatic single, soft, large, elongated pink nodule in the toe web along the fourth left toe (figure 1, a and b). polarized contact dermoscopy showed white shiny streaks on orange-pink background (figure 1c). a local ultrasound examination revealed a hypoechoic tumor measuring 2.3 × 1.3 × 1.2 cm that extended to subcutaneous tissues. differential diagnostic possibilities as acral manifestations of soft tissue tumors including superficial acral fibromyxoma, inclusion body fibromatosis, and acral fibrokeratoma were considered. histopathology from a punch biopsy showed an epidermis with focal mild spongiosis, parakeratosis, and lymphocyte exocytosis together with a proliferation of desmoplastic spindle cells with a nonspecific lymphoplasmocytic inflammatory process. immunohistochemical examination was inconclusive. histopathology from complete excision showed that throughout the dermis, there were nodular deposits of hyaline and eosinophilic material, with spindle-shaped cells (figure 1d). hyaline-like, eosinophilic material was also seen in the walls of small vessels and subcutaneous 236 letter | dermatol pract concept 2019;9(3):18 long-term follow-up study. br j dermatol. 2001;145(1):105-109. 2. arnold sj, bowling jc. “shiny white streaks” in lichen amyloidosis: a clue to diagnosis. australas j dermatol. 2012;53(4):272-273. 3. rongioletti f, atzori l, ferreli c, et al. a unique dermoscopy pattern of primary cutaneous nodular amyloidosis mimicking a granulomatous disease. j am acad dermatol. 2016;74(1):e9-e10. dermoscopic findings of plcna have not been extensively described in the literature, and we suggest that polarized dermoscopy can be a complementary and useful aid for noninvasive diagnosis. references 1. woollons a, black mm. nodular localized primary cutaneous amyloidosis: a tissue. congo red staining showed the presence of a brick-red deposit in the dermis (figure 1e), which under polarizing microscopy showed apple-green birefringence. the diagnosis of plcna was established based on clinical findings and histopathology in the absence of systemic manifestations of amyloidosis. beside the lesion on the foot, the patient was asymptomatic. complete blood cell count, b-glucose, electrophoresis, ana test, urine test, and bence jones protein test results were normal. abdominal ultrasound and chest x-ray showed nothing remarkable. no systemic manifestations of amyloidosis were identified. the patient is undergoing 6-month follow-up intervals with clinical and laboratory examinations. after 1 year no recurrence was detected. conclusions we describe a rare presentation of primary cutaneous amyloidosis located on an uncommon body site. polarized dermoscopy examination could have contributed to the clinical suspicion of the correct diagnosis in this case. skin lesions with an altered composition or orientation of collagen will often reveal, under polarized dermoscopy, shiny white streaks [2]. in polarized dermoscopy of lichen amyloidosis, the deposition of amyloid substance with birefringent properties in the dermis is reported to be visualized as shiny white streaks [2]. a case report of dermoscopy of plcna described an orange hue, otherwise seen in dermal granulomatous skin disorders, as a clue for diagnosis [3]. the dermoscopic pattern of polarization-specific white structures in a background of orange-pink color, present in our case, could be an additional feature that can contribute to the plcna diagnosis. figure 1. (a, b) clinical presentation of a single, soft, pink nodule on the fourth left toe. (c) polarized contact dermoscopy of the lesion showing birefringent properties present as shiny white structures on orange-pink background. (d) histopathological examination of the lesion shows hyaline eosinophilic nodular deposits, with spindle-shaped cells throughout the dermis. (e) histopathological characteristics of the lesion, using congo red staining evidencing presence of a brick-red deposit in the dermis. [copyright: ©2019 ferreira et al.] a c d e b dermatology: practical and conceptual 150 letter | dermatol pract concept 2019;9(2):13 dermatology practical & conceptual introduction pigmented squamous cell carcinoma (pscc) is a rare variant of squamous cell carcinoma (scc), generally described in oral mucosa, conjunctiva and cornea, but only rarely found on the skin. histopathologically, it is characterized by a proliferation of atypical keratinocytes associated with nonneoplastic dendritic melanocytes and melanophages in the surrounding stroma [1]. clinically and dermoscopically pscc diagnosis is very difficult because of overlapping features with benign and malignant lesions, including basal cell carcinoma (bcc), melanoma, pigmented actinic keratosis, and seborrheic keratosis. only 22 cases of pscc have been reported in the literature (table 1). we searched our image database from 2011 to 2018 and found 899 histopathologically diagnosed sccs, with only 3 of them being pigmented (prevalence of 0.33% of all sccs). we present 1 of these 3 cases, showing clinical and dermoscopic characteristics of pigmented bcc. case presentation a 77-year-old white man presented with a 12-mm lesion of the chest, which had been noticed 1 year before. clinically, the lesion appeared as a pigmented nodule with central ulceration (figure 1a). dermoscopically, it showed blue areas at the periphery and white polymorphous vessels surrounding a central hyperkeratotic area (figure 1b). histopathological examination showed epidermis with hyperkeratosis and full-thickness cellular atypias. in some fields, solid nests were evident in the superficial dermis, constituted by atypical cells with abundant, slightly eosinophilic cytoplasms and intercellular bridges. the dermis was diffusely infiltrated by a dense lichenoid lymphocytic population. a final diagnopigmented squamous cell carcinoma: is the reported prevalence real? paola corneli1, elvira moscarella2, eugenia v. di brizzi2, andrea ronchi3, iris zalaudek1, roberto alfano4, giuseppe argenziano2 1 dermatology unit, university of trieste, trieste, italy 2 dermatology unit, university of campania, naples, italy 3 anatomo-pathology unit, university of campania, naples, italy 4 department of anesthesiology surgery and emergency, university of campania, naples, italy key words: squamous cell carcinoma, pigmented squamous cell carcinoma, prevalence, dermoscopy, blue pigmentation citation: corneli p, moscarella e, di brizzi ev, ronchi a, zalaudek i, alfano r, argenziano g. pigmented squamous cell carcinoma: is the reported prevalence real? dermatol pract concept. 2019;9(2):150-151. doi: https://doi.org/10.5826/dpc.0902a13 accepted: august 30, 2018; published: april 30, 2019 copyright: ©2019 corneli et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: giuseppe argenziano, md, dermatology unit, university of campania, nuovo policlinico (edificio 9c), via pansini 5, 80131 naples, italy. email: g.argenziano@gmail.com letter | dermatol pract concept 2019;9(2):13 151 sis of infiltrating (0.9-mm) scc with g2 differentiation was rendered (figure 1, c and d). conclusions dermoscopy alone does not allow differentiating pscc from other pigmented skin lesions. the present case highlights how overlapping features with pigmented bcc are possible in pscc. the majority of keratinizing tumors, and scc in particular, are nonpigmented. dermoscopic examination of these tumors generally reveals the presence of hairpin or atypical vessels, often surrounded by a whitish halo associated with the keratinizing process. our case showed blue areas and linear polymorphous vessels surrounding a central hyperkeratotic area. zalaudek et al described a similar case of pscc with a bluish diffuse pigmentation with central ulceration [2]. others reported cases of pscc with overlapping dermoscopic features of melanocytic lesions with radial brown streaks and globules. the real prevalence of pscc is unclear, with the english literature reporting an incidence of about 0.01% to 7% of all sccs, whereas the nonenglish literature describes an incidence of approximately 25% [1]. the rate we found in our population, 0.33% of all sccs, is between these 2 values. these variability in incidence rates may be due to factors related to the skin type of the population included. however, further studies are needed to support this hypothesis. references 1. satter ek. pigmented squamous cell c a r c i n o m a . a m j d e r m a t o p a t h o l . 2007;29(5):486-489. 2. zalaudek i, citarella l, soyer hp, hofmann-wellenhof r, argenziano g. dermoscopy features of pigmented squamous cell carcinoma: a case report. dermatol surg. 2004;30(4 pt i):539-540. figure 1. (a) clinical image of a nodular lesion on the right chest of a 77-year-old man. (b) dermoscopic examination shows blue areas and polymorphous vessels surrounding a central hyperkeratotic area. (c) histopathological examination (×20) shows hyperkeratosis and full-thickness cellular atypias. in some fields, some solid nests were evident in the superficial dermis, constituted by atypical cells with abundant slightly eosinophilic cytoplasms and intercellular bridges. the dermis was diffusely infiltrated by a dense lichenoid lymphocytic population. (d) higher magnification (×40) of panel c. [copyright: ©2019 corneli et al.] table 1. all described cases of pscc in the literature with associated author author, year site no. of cases described becker, 1934 not stated 3 kossard, 1997 ear 1 jurado, 1998 frontotemporal and nose 2 matsubo, 1999 scrotum 1 kamiya, 1999 external auditory canal 1 morgan, 2000 right helix, left temple, left eyebrow, right cheek, right temple 5 chapman, 2000 middle forehead 1 terada, 2003 right cheek 1 zalaudek, 2004 chest 1 satter, 2007 left cheek 1 chung, 2015 back 1 de giorgi, 2009 upper lip 1 verdú-amorós, 2016 head 1 savoia, 2013 nose 1 namiki, 2015 cheek 1 total 22 a c b d dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023170 1 evaluation of the knowledge of primary care physicians about important nail diseases before and after a short online training pauline greco1,2, félix pham1,2, gérard duru2, xavier lainé2, stéphane dalle1,2,3, luc thomas1,2,3 1 dermatology department, hôpital lyon sud, hospices civils de lyon, lyons, france 2 claude bernard lyon-1 university, lyon, france 3 cancer research center of lyon, lyons, france key words: nail, primary care physician, education, general practitioner, melanoma citation: greco p, pham f, duru g, lainé x, dalle s, thomas l. evaluation of the knowledge of primary care physicians about important nail diseases before and after a short online training. dermatol pract concept. 2023;13(3):e2023170. doi: https://doi.org/10.5826 /dpc.1303a170 accepted: february 1, 2023; published: july 2023 copyright: ©2023 greco et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this work was supported in part by grants from lyon 1 claude bernard university (to lt), the hospices civils de lyon (to lt) and the association vaincre le mélanome (to lt) competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: luc thomas, md, phd, service de dermatologie, hôpital lyon sud, 165 chemin du grand revoyet, 69310 pierre-bénite, france. fax number: +33478865706 email: luc.thomas@chu-lyon.fr irb approval status: reviewed and approved by the institutional ethical committee of lyons (n°20-63) introduction: nail diseases are often diagnosed late with a potential prognostic and functional impact. this could be partly due to knowledge gaps among primary care physicians (pcps). objectives: to evaluate the knowledge about diagnosis and management of ten common/important nail conditions in a population of french pcps and its improvement after a 31-minute online training session. methods: we submitted 10 pre-test and post-test clinical cases and an educative online course on the diagnosis and the management of nail diseases to 138 volunteer pcps; 73 completed the whole training path. results: compared to pre-test, more pcps in the post-test required an urgent second opinion to dermatologist for pigmented melanoma (100% versus 80.3%; p <0.05) and use of inappropriate/dangerous systemic treatment for trauma-induced nail changes was reduced after the training program (0% versus 6.8%; p <0.05). a lack of knowledge remained after training for amelanotic melanoma with an increase of mycological/bacteriological tests (9.6% versus 0%; p <0.05). conclusions: management of nail diseases by our panel of pcps was suboptimal and was improved after a short online training. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023170 introduction nail disorders are very common but might not be very well-known by primary care physicians (pcps). although 50% of nail conditions are due to fungal infection, other diseases affecting the nail unit are neoplastic, inflammatory, congenital, traumatic, or related to a systemic disease. because some of these non-fungal conditions clinically look alike onychomycoses, their diagnosis is often missed. patients may be then exposed to diagnostic delays with important prognostic significance especially in malignant tumors such as subungual melanoma (sum) or subungual squamous cell carcinoma (sscc) [1]. moreover, they are often submitted to inappropriate treatments. many publications underline that diagnosis of sum can be delayed from 9 months to 2.2 years after occurrence of the first symptoms [2,3]. these diagnostic delays are responsible in part of the apparent worse prognosis of sum yet, for an equivalent breslow index, their prognosis is not different from that observed in melanoma occurring elsewhere on skin [4]. confounding various nail conditions with fungal infection also led to an inappropriate use of medical resources such as urgent dermatology consultations, imaging, mycology tests and to unnecessary use of antifungal drugs. this is particularly true with repetitive trauma-induced toenail changes due to the conflict between the shoe and the tiptoes. this condition not only looks like fungal infection but is also frequently contaminated with fungus, therefore identifiable by laboratory tests [5]. in such cases, antifungal treatment may show some improvement that is rarely complete and often followed by a relapse since the real cause of the nail change is underestimated. moreover, subungual glomus-cell tumor (sgct), a sometimes very painful benign tumor, is known to be frequently left untreated for as long as 1 to 9 years with significant risk of disability and depression [6,7]. objectives the main objectives of our study were to evaluate the potential lack of knowledge of pcps about common or prognostically/functionally important nail diseases, to propose an online teaching session and to evaluate its improvement, particularly under the perspective of a better use of medical and therapeutic resources. our secondary goal was to evaluate pieces of knowledge where the improvements were the most significant and to identify topics in which our teaching program could be improved. methods study design we conducted a blinded anonymous study on 138 pcps over a three-month period from november 2020 to january 2021. this study was approved by the ethical committee of the université claude bernard lyon 1 (institutional review board n°2020-07-07-08, on july the 7th in 2020). we sent by e-mail a web link leading to our online educative path to all pcps members of the urps union of auvergne/rhone-alpes region and grand est region hosted by claroline®, the official educational website of lyon 1 claude bernard university. it was first composed of a 10-clinical-case pre-test, followed by a 31-minute educative video (https://clarolineconnect.univ-lyon1.fr/resource/open/ file/4776658 in french) and lastly a distinct 10-case post-test. the link for the post-test was only available when the applicant had validated the pre-test and completely watched the educative video. preand post-test, for each case, included a multiple-choice question with pre-determined answers about management and a single choice question with pre-determined answer for the diagnostic orientation. both preand post-test included distinct cases of one pigmented sum, one amelanotic sum, one sscc, one trauma-induced nail change, one onychomycosis, one nail unit psoriasis, one sgct, one nail case of alopecia areata, one periungual viral wart and one subungual hemorrhage. management proposals for each case were (one or more answer boxes could be ticked): “clinical follow-up”, “radiology imaging”, “mycological or bacteriological test”, “non-urgent dermatologist second opinion”, “orthopedic surgeon second opinion”, “podiatrist consultation”, “topical antifungal”, “other topical treatment”, “systemic treatment”, and “urgent dermatologist second opinion”. the diagnostic proposal for each case (only one answer box could be ticked) were the 10 conditions listed above. during the teaching video, all these conditions were covered by vocal explanations and images of several examples and five simple rules to improve diagnostic strategy in nail disease was taught : (1) thinking about nail tumor when a condition is monodactylic, (2) referring to dermatologist for brown or black but also red or white-yellowish longitudinal nail band, (3) spontaneous nail plate erosion is not banal, (4) referring to dermatologist for non resolutive and painful nail condition and (5) evaluate the static and the dynamic of feet for toenail disease. the answers to the preand the post-test were pre-determined before the launch of the educative program by a consensus of nail diseases experts and were classified as “compulsory” (+15 points), “correct” (0 points), “acceptable” (-5 point), “inappropriate” (-10 points) or “dangerous” (-30 points). an example of “compulsory” answer was an urgent dermatologist second opinion for pigmented or amelanotic sum or podiatrist consultation in case of trauma-induced nail change. an example of “dangerous answer” was clinical follow-up for sscc. for onychomycosis and psoriasis, no “dangerous” management were considered. an example of “acceptable” answer was an orthopedic original article | dermatol pract concept. 2023;13(3):e2023170 3 surgeon second opinion for sum, an example of “inappropriate” answer was imaging for nail psoriasis. although our study was more focused on the management of the cases, diagnostic orientation was also evaluated during preand post-tests. a correct answer was given 5 points. rating for all answers was discussed with our biostatistician (gd). some other common nail conditions were also briefly covered during the course (ingrown nail, pyogenic granuloma, mucoid pseudocyst, ungual changes in systemic disease, onychotillomania and some benign nail tumors). all cases shown during the pre-test were included in the teaching examples during the video course and expected answers to the questionnaire were then disclosed for each. indeed, none of the cases used for the post-test were included in the video as examples. study population participating pcps were asked about their gender, age, geographic setting (urban, suburban, or rural area), number of years after initial medical certification, attendance to post-university training session dermatology during the last 2 years. although we had the results of the pre-test of all the enrolled population, we only retained for statistical analysis the 73 for whom we had the complete sequence of tests and training. the 65 pcps who did not completed the entire study were only compared to the 73 others to determine if the two populations could be any different. statistics statistical analysis was performed by an independent biostatistician (gd) who also reviewed the questionnaire before its online launch. statistical unit was the pcp. statistical analysis was conducted using the ibm ipss statistic software, version 19 (ibm). distribution comparisons were made by the chi-2 test, fisher test for qualitative variables, student t test or paired student t test for quantitative variables. p value <0.05 was considered significant. results training path web link was sent to 10,205 pcps. one hundred and thirty-eight pcps were initially enrolled in the study and finished the pre-test. however, only 73 (52.9%) among them completed the whole training program. comparison with national statistics disclosed that our tested population, as usual in many medical surveys, included a slightly higher number of female (51/73 (69.3%); p = 0.0007) and younger (<40 years-old) (40/73 (54.7%); p = 1.0 10-12) pcps than found in their general population in france. comparing each pcp with himself, we demonstrated that the pre-test mean score was 15.2/20 and raised to 16.9/20 in the post-test (p = 2.25 10-18). comparison of the pre-test scores of the participants who did not complete the whole training path to the others did not show significant difference. when comparing pre and post-test, the number of compulsory and correct answers was significantly higher in the post-test. for management, the correct answer (ie “clinical follow up”) raised from 6/73 (8.2%) to 19/73 (26%) in warts (p=0.002), from 16/73 (21.9%) to 33/73 (45.2%) in trauma-induced nail changes (p = 0.002; table 1). a podiatrist consultation for trauma-induced nail changes was proposed in only 13/73 (17.8%) of the pre-test but raised to 55/73 (75.3%) in the post-test (p < 0.001). for pigmented sum, 59/73 (80.3%) of pcps required an urgent dermatologist second opinion in the pre-test whereas all recommended it 73/73 (100%) in the post-test (p < 0.001; table 1). in onychomycosis, the choice of a systemic treatment was made by 16/73 (21.9%) pcps in the pre-test while 54/73 (74%) prescribed it in the post-test (p < 0.001). for sgct, the use of radiology imaging raised from 18/73 (24.7%) in the pre-test to 43/73 (58.9%) in the post-test (p < 0.001; table 1). we also observed a decrease of using dangerous management in the post-test especially in malignant tumors. seven dangerous managements were initially proposed in the pretest (4/73 in sscc, 2/73 in amelanotic sum and 1/73 in pigmented sum) then was reduced to 3 after completion of the training program (3/73 in amelanotic sum), (p = 0.324; table 3). the use of inappropriate/dangerous systemic treatment was reduced after the training program: from 4/73 (5.5%) to 1/73 (1.4%) in warts (p = 0.085); and from 18/73 (24.7%) to 10/73 (13.7%) in alopecia areata (p = 0.045; table 3). a decrease in the unnecessary consumption of medical resources was also observed (table 4). mycological/bacteriological tests decreased after the training program: from 29/73 (39.7%) to only 3/73 (4.1%) in warts (p < 0.001) and from 40/73 (54.8%) to 4/73 (5.5%) in trauma-induced nail changes (p < 0.001). moreover, emergency referral (urgent second opinion) to dermatologists decreased from 20/73 (27.4%) to 5/73 (6.2%) (p < 0.001) and from 6/73 (8.2%) to 0% (p = 0.005) in subungual hemorrhage and alopecia areata respectively. of note, the number of mycological/bacteriological tests slightly increased in the post-test (table 4): 0/73 versus 7/73 (9.6%) in case of amelanotic sum (p = 0.03). similarly, the number of prescriptions of topical antifungals as well as the number of urgent dermatologist referrals slightly increased in the post-test in case of nail psoriasis (table 4): 4/73 (5.5%) versus 1/73 (1.4%) (p = 0.085) and 2/73 (2.7%) versus 0/73 (p = 0.076) respectively, which was not statistically significant. we can however observe that the post-test 4 original article | dermatol pract concept. 2023;13(3):e2023170 delay to initial treatment often long, from 15 months to 30 years [8,9]. sscc, s also often diagnosed late, from 2 to 480 months (mean : 55 months) [10]. these important delays might be partially responsible of an apparent worse prognosis of sum with a 33% overall survival rate at 15 years. moreover, since conservative surgical treatments can be offered to early-stage sum and sscc, these delays could also result in a higher number of amputations and subsequent disabilities [11,12]. part of the problem could be initial wrong management strategies by pcps [13]. however, little is known in the literature about the global knowledge of pcps about common or functionally important nail diseases [14-16]. for unknown reasons, the most widely acknowledged nail conditions by health professionals are fungal infections. indeed, many onychomycoses do exist since it is claimed that about 10 to 50% of all nail diseases could be due to dermatophytic nail bed case of psoriasis nail could have been found more difficult to identify by the panel of pcps since it was correctly diagnosed in only 45/73 (61.6%) versus 72/73 (98.6%) for the pre-test (p < 0.001) (table 2). lastly, in case of nail unit wart, the rate of urgent dermatologist referral increased from 12/73 (16.4%) to 23/73 (31.5%) (p = 0.015) after the training as well as the use of radiology imaging which increase from 3/73 (4.1%) to 13/73 (17.8%) (p = 0.003) (table 4). conclusions most of the studies about sum, sscc and, to a lesser extent, sgct, underline that diagnostic delay is often long and generates losses of chance for curative and functional surgery in the two cancers and an unnecessary long delay towards functional and pain relief in the latter case. sum is frequently discovered at advanced stage and the average reported table 1. pre-to-post-test evolution of correct or compulsory management answers in the panel. correct or compulsory answers, n (%) p valuenail disorders pre-test (n = 73) post-test (n = 73) wart clinical follow-up 6 (8.2) 19 (26.0) 0.002 trauma-induced nail change clinical follow-up 16 (21.9) 33 (45.2) 0.001 podiatrist consultation 13 (17.8) 55 (75.3) 0.001 onychomycosis mycological or bacteriological test 36 (49.3) 53 (72.6) 0.001 non-urgent dermatologist second opinion 27 (37.0) 13 (17.8) 0.004 systemic treatment 16 (21.9) 54 (74.0) < 0.001 squamous cell carcinoma radiology imaging 16 (21.9) 22 (30.1) 0.128 urgent dermatologist second opinion 56 (76.7) 66 (90.4) 0.012 amelanotic nail melanoma radiology imaging 39 (53.4) 14 (19.7) <0.001 urgent dermatologist second opinion 71 (97.3) 68 (93.2) 0.122 glomus tumor radiology imaging 18 (24.7) 43 (58.9) <0.001 non-urgent dermatologist second opinion 43 (58.9) 41 (56.2) 0.369 subungual hemorrhage clinical follow-up 52 (71.2) 60 (82.2) 0.057 pigmented subungual melanoma urgent dermatologist second opinion 59 (80.3) 73 (100) <0.001 alopecia areata non-urgent dermatologist second opinion 53 (72.6) 61 (83,6) 0.053 psoriasis non-urgent dermatologist second opinion 58 (79.5) 60 (82,2) 0.337 systemic treatment 11 (15.1) 10 (13,7) 0.407 original article | dermatol pract concept. 2023;13(3):e2023170 5 table 3. pre-to-post test evolution of “dangerous” management in the panel. “dangerous” answer, n (%) p valuepre-test (n = 73) post-test (n = 73) wart systemic treatment 4 (5.5) 1 (1.4) 0.085 trauma-induced nail change systemic treatment 5 (6.8) 0 0.010 squamous cell carcinoma clinical follow-up 2 (2.7) 0 0.076 topical antifungal 0 0 na other topical treatment 1 (1.4) 0 0.157 systemic treatment 1 (1.4) 0 0.157 amelanotic nail melanoma clinical follow-up 0 0 na non-urgent dermatologist second opinion 2 (2.7) 3 (4.1) 0.324 topical antifungal 0 0 na other topical treatment 0 0 na systemic treatment 0 0 na glomus tumor systemic treatment 0 0 na subungual hemorrhage systemic treatment 0 0 na pigmented nail melanoma clinical follow-up 1 (1.4) 0 0.157 alopecia areata systemic treatment 18 (24.7) 10 (13.7) 0.045 na = not applicable. table 2. pre-to-post test evolution of correct diagnosis in the panel. correct diagnosis, n (%) pre-test (n = 73) post-test (n = 73) p value wart 19 (26.0) 31 (42.5) 0.017 trauma-induced nail change 24 (32.9) 70 (95.9) <0.001 onychomycosis 44 (60.3) 72 (98.9) <0.001 squamous cell carcinoma 12 (16.4) 28 (38.4) 0.001 amelanotic subungual melanoma 12 (16.4) 34 (46.6) <0.001 glomus tumor 49 (67.1) 56 (76.7) 0.097 subungual hemorrhage 53 (72.6) 68 (93.2) <0.001 pigmented subungual melanoma 62 (84.9) 71 (97.3) 0.004 alopecia areata 49 (67.1) 48 (65.8) 0.430 psoriasis 72 (98.6) 45 (61.6) <0.001 invasion [17]. however, many authors believe that this condition is often not the primary nail disease and that many of them in fact complicate a pre-existing nail disease or injury [18]. damaged nail by inflammatory nail disease like psoriasis are often secondarily contaminated by dermatophytes that can subsequently be evidenced in the nail table by mycological laboratory tests [19,20]. trauma-induced nail changes are much more common on toenails with the exception of onychotillomania. evaluation of nail disease must always be done keeping in mind that any trouble of the foot static or any use of traumatizing shoes can result in nail injury and chronic changes too often confused with nail fungal infection. 6 original article | dermatol pract concept. 2023;13(3):e2023170 and painful nail condition and (5) evaluate the static and the dynamic of feet for toenail disease and eventually refer to a podiatrist. our study showed a global poor level of knowledge with a relatively high frequency of inappropriate proposed management. we also observed a misuse of medical resources in we believe that a wider diffusion of five simple rules can avoid many misdiagnoses: (1) thinking about nail tumor when a condition is monodactylic, (2) referring to dermatologist for brown or black but also red or white-yellowish longitudinal nail band, (3) spontaneous nail plate erosion is not banal, (4) referring to dermalogist for non resolutive table 4. pre-to-post-test evolution of inappropriate use of medical resources in the panel. incorrect answer, n (%) pre-test (n = 73) post-test (n = 73) p-value wart radiology imaging 3 (4.1) 13 (17.8) 0.003 mycological or bacteriological test 29 (39.7) 3 (4.1) <0.001 urgent dermatologist second opinion 12 (16.4) 23 (31.5) 0.015 trauma-induced nail change radiology imaging 0 0 na mycological or bacteriological test 40 (54.8) 4 (5.5) <0.001 topical antifungal 37 (50.7) 1 (1.4) <0.001 urgent dermatologist second opinion 1 (1.4) 1 (1.4) 0.500 onychomycosis radiology imaging 3 (4.1) 1 (1.4) 0.154 orthopedic surgeon second opinion 0 0 na urgent dermatologist second opinion 4 (5.5) 2 (2.7) 0.202 squamous cell carcinoma mycological or bacteriological test 9 (12.3) 1 (1.4) 0.004 amelanotic nail melanoma mycological or bacteriological test 0 7 (9.6) 0.003 glomus tumor mycological or bacteriological test 1 (1.4) 0 0.157 topical antifungal 0 0 na subungual hemorrhage radiology imaging 6 (8.2) 2 (2.7) 0.071 mycological or bacteriological test 1 (1.4) 0 0.157 orthopedic surgeon second opinion 1 (1.4) 0 0.157 urgent dermatologist second opinion 20 (27.4) 5 (5.8) <0.001 pigmented nail melanoma mycological or bacteriological test 1 (1.4) 0 0.157 alopecia areata radiology imaging 1 (1.4) 1 (1.4) 0.500 mycological or bacteriological test 14 (19.2) 8 (11) 0.081 topical antifungal 3 (4.1) 0 0.038 urgent dermatologist second opinion 6 (8.2) 0 0.005 psoriasis radiology imaging 2 (2.7) 0 0.076 topical antifungal 1 (1.4) 4 (5.5) 0.085 urgent dermatologist second opinion 0 2 (2.7) 0.076 na = not applicable. original article | dermatol pract concept. 2023;13(3):e2023170 7 references 1. lipner sr, scher rk. onychomycosis – a small step for quality of care. curr med res opin. 2016;.;32(5):865-867. doi: 10.1185/03007995.2016.1147026. pmid: 26807603. 2. nguyen jt, bakri k, nguyen ec, johnson ch, moran sl. surgical management of subungual melanoma: mayo clinic experience of 124 cases. ann plast surg. 2013;71(4):346-354. doi: 10.1097/sap.0b013e3182a0df64. pmid: 24025653. 3. wollina u, tempel s, hansel g. subungual melanoma: a single center series from dresden. dermatol ther. 2019;32(5):e13032. doi: 10.1111/dth.13032. pmid: 31344289. 4. phan a, touzet s, dalle s, ronger-savlé s, balme b, thomas l. acral lentiginous melanoma: a clinicoprognostic study of 126 cases. br j dermatol. 2006;155(3):561-569. doi: 10.1111/j.1365 -2133.2006.07368.x. pmid: 16911282. 5. natarajan v, nath ak, thappa dm, singh r, verma sk. coexistence of onychomycosis in psoriatic nails: a descriptive study. indian j dermatol venereol leprol. 2010;76(6):723. doi: 10.4103/0378-6323.72468. pmid: 21079333. 6. girisha bs, shenoy mm, mathias m, mohan r. glomus tumor of the nail unit. indian j dermatol. 2011;56(5):583-584. doi: 10.4103/0019-5154.87163. pmid: 22121286. pmcid: pmc3221231. 7. jawalkar h, maryada vr, brahmajoshyula v, kotha gk. subungual glomus tumors of the hand: treated by transungual excision. indian j orthop. 2015;49(4):403-407. doi: 10.4103/0019 -5413.159611. pmid: 26229160. pmcid: pmc4510793. 8. chakera ah, quinn mj, lo s, drummond m, et al. subungual melanoma of the hand. ann surg oncol. 2019;26(4):10351043. doi: 10.1245/s10434-018-07094-w. pmid: 30565042. 9. talavera-belmonte a, bonfill-ortí m, martínez-molina l, et al. subungual melanoma: a descriptive study of 34 patients. actas dermosifiliogr (engl ed). 2018;109(9):801-806. doi: 10.1016/j. ad.2018.06.010. pmid: 30082026. 10. dijksterhuis a, friedeman e, van der heijden b. squamous cell carcinoma of the nail unit: review of the literature. j hand surg am. 2018;43(4):374-379.e2. doi: 10.1016/j .jhsa.2018.01.010. pmid: 29482957. 11. sureda n, phan a, poulalhon n, balme b, dalle s, thomas l. conservative surgical management of subungual (matrix derived) melanoma: report of seven cases and literature review. br j dermatol. 2011;165(4):852-858. doi: 10.1111/j.1365 -2133.2011.10477.x. pmid: 21812768. 12. topin-ruiz s, surinach c, dalle s, duru g, balme b, thomas l. surgical treatment of subungual squamous cell carcinoma by wide excision of the nail unit and skin graft reconstruction: an evaluation of treatment efficiency and outcomes. jama dermatol. 2017;153(5):442-448. doi: 10.1001/jamadermatol.2017.0014. pmid: 28384651. pmcid: pmc5817490. 13. papachristou dn, fortner jg. melanoma arising under the nail. j surg oncol. 1982;21(4):219-222. doi: 10.1002 /jso.2930210405. pmid: 7144198. 14. iorizzo m. tips to treat the 5 most common nail disorders: brittle nails, onycholysis, paronychia, psoriasis, onychomycosis. dermatol clin. 2015;33(2):175-183. doi: 10.1016/j.det.2014.12.001. pmid: 25828710. many benign conditions. in our view, the rate of pre-test misdiagnoses does not reflect the current practice of nail consultations in our department and cannot completely explain the observed management delays especially for nail unit cancers. this might be due to a recruitment bias since we cannot exclude that the volunteer participants chose to enter the study because of their specific interest in onychology. however, we observed significant improvement in the management strategies of most tested conditions. some points could deserve a revision of our teaching strategy: more thorough training for amelanotic sum seems to be necessary. however, this diagnosis often remains difficult even for trained dermatologists. high level of prescription of radiology imaging and urgent dermatology consultation in nail unit viral warts appears to be an unexpected unwanted effect of the sensibilization of our public about the diagnosis of sscc. we do not consider this as a poor outcome of our training program since it is always better to insist on the possible malignant counterpart. maybe an age and disease-duration threshold could be proposed in our teaching to help counter this effect. our study has several possible biases. our sample did not reflect the general population of french pcps since women were overrepresented and our population was younger. this is a common finding in medical practice surveys and probably reflect the greater interest for online educational tools of young health professionals, who are more often women in our country. as mentioned earlier, we cannot exclude a selection bias, yet our questionnaire revealed that only few of them had received a specific training in dermatology in general and on nail diseases during the two previous years. a framing bias cannot be excluded since our teaser message to enter the study specifically mentioned the risk of misdiagnosing nail unit cancer in general and sum in particular. in conclusion, correct diagnosis of a nail disease can be delayed especially in primary care. onychomycosis is often over-diagnosed, since there is a lot of commercial communication about it. a short online training focusing on five simple rules significantly improved the management abilities of several nail conditions including life threatening ones by pcps. acknowledgements this work is supported in part by grants from lyon 1 university (to lt), the hospices civils de lyon (to lt) and by the foundation “vaincre le mélanome” (to lt). we thank the urps for its help in the diffusion of our questionnaire and training path. we thank mr anthony masson administrator of claroline web site. we thank 138 volunteers who accepted to enter the study. 8 original article | dermatol pract concept. 2023;13(3):e2023170 study of 35 cases. br j dermatol. 2007;156(5):871-874. doi: 10.1111/j.1365-2133.2006.07744.x. pmid: 17263801. 19. elewski be. onychomycosis: pathogenesis, diagnosis, and management. clin microbiol rev. 1998;11(3):415-429. doi: 10.1128/cmr.11.3.415. pmid: 9665975. pmcid: pmc88888. 20. summerbell rc, cooper e, bunn u, jamieson f, gupta ak. onychomycosis: a critical study of techniques and criteria for confirming the etiologic significance of nondermatophytes. med mycol. 2005;43(1):39-59. doi: 10.1080/13693780410001712043. pmid: 15712607. 15. schneider sl, tosti a. tips to diagnose uncommon nail disorders. dermatol clin. 2015;33(2):197-205. doi: 10.1016/j .det.2014.12.003. pmid: 25828712. 16. maddy aj, tosti a. what’s new in nail disorders. dermatol clin. 2019;37(2):143-147. doi: 10.1016/j.det.2018.12.004. pmid: 30850036. 17. thomas j, jacobson ga, narkowicz ck, peterson gm, burnet h, sharpe c. toenail onychomycosis: an important global disease burden. j clin pharm ther. 2010;35(5):497-519. doi: 10.1111/j.1365-2710.2009.01107.x. pmid: 20831675. 18. dalle s, depape l, phan a, balme b, ronger-savle s, thomas l. squamous cell carcinoma of the nail apparatus: clinicopathological dermatology: practical and conceptual review | dermatol pract concept 2018;8(1):4 15 dermatology practical & conceptual www.derm101.com glutathione for skin lightening: a regnant myth or evidence-based verity? sidharth sonthalia1, abhijeet k. jha2, aimilios lallas3, geraldine jain4, deepak jakhar5 1 skinnocence: the skin clinic & research centre, gurugram, india 2 department of skin & vd, patna medical college, patna, india 3 first department of dermatology, aristotle university, thessaloniki, greece 4 punarnawah medical & research centre, jaipur, india 5 consultant dermatologist & cosmetologist, new delhi, india key words: glutathione, skin lightening, intravenous, gsh, gssg citation: sonthalia s, jha ak, lallas a, jain g, jakhar d. glutathione for skin lightening: a regnant myth or evidence-based verity? dermatol pract concept. 2018;8(1):15-21. doi: https://doi.org/10.5826/dpc.0801a04 received: june 6, 2017; accepted: november 12, 2017; published: january 31, 2018 copyright: ©2018 sonthalia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. sidharth sonthalia, skinnocence: the skin clinic & research centre, c-2246, suhridaya, sunshant lok-1, block c, gurgaon, 122009, haryana, india. email: sidharth.sonthalia@gmail.com the recent hype surrounding the antimelanogenic properties of glutathione has resulted in physicians frequently administering it as a “wonder” drug for skin lightening and treatment of hyperpigmentation, especially in ethnic populations with darker skin tones. this phenomenon has seen a recent surge owing to aggressive marketing and capitalization of pharma-cosmeceutical companies. however, the unbridled and prodigal use of it, especially as a parenteral formulation, seems unjustified, given the lacunae in our knowledge about its antimelanogenic potential, limited clinical evidence favoring its role in skin lightening, and the statutory ban/advisory issued by certain federal agencies. even though parenteral glutathione is approved only for severe liver disorders and for prevention of chemotherapy associated neurotoxicity, the lack of statutory laws governing the use of systemic glutathione in most countries has contributed to its unchecked use for skin lightening. the current clinical evidence of intravenous glutathione for skin lightening is limited to a single study with a dubious study design and apparently flawed analysis of results, casting doubt on the drug’s efficacy and reported adverse effects. two studies evaluating oral/sublingual administration and one trial involving the use of topical glutathione reported good safety profile and appreciable but reversible results on skin tone. in this article, we shall review and discuss the current status of glutathione as a skin lightening agent and address the sundry unanswered queries regarding the dosage, duration of use and longevity of accrued effects based on clinical evidence and recent insights into its antimelanogenic mechanism. abstract mailto:sidharth.sonthalia@gmail.com 16 review | dermatol pract concept 2018;8(1):4 hailed for generations as a “magical skin whitening” molecule in countries like the republic of philippines, glutathione has seen a rapid spread in its popularity across the globe in a short duration of time. this has been the outcome of ardent manufacturer supported media campaigns about the almost preposterous effects of this molecule as a wonder drug for not only disorders of hyperpigmentation such as melasma, but also for general “skin whitening.” this article is meant to update healthcare professionals about the current status of efficacy, safety, and evidence of different formulations of glutathione for skin tone lightening. for more detailed background information regarding the basic and applied physiology of glutathione, readers may refer to a previously published exhaustive article on this aspect [6]. it is important to know that glutathione exists in a reduced form (gsh) and an oxidized form (gssg). the reduced form, gsh, seems to be instrumental in the depigmenting properties of this unique molecule. apart from these two major forms, gsh may be esterified to form glutathione esters [7]. an evidence-update on glutathione as a skin-lightening agent at the time of authoring this article, there were only four published studies that evaluated the efficacy of oral, topical, and parenteral glutathione as a skin-whitening agent (table 1) [10-13]. the two trials on oral gsh, conducted in thai population by arjinpathana and asawanonda, and in filipino women by handog et al. involved administering 500 mg/day of gsh in two divided doses to the study population, the difference being the use of a buccal lozenge (instead of oral capsules) in the latter study to enhance systemic absorption of glutathione [10,11]. the primary efficacy outcome in both the trials was to evaluate the preand post-treatment melanin indices. both trials employed a mexameter mx 18 (courage+khazaka electronic gmbh, cologne, germany) introduction the preoccupation with exploration of treatment options that may help attain a lighter skin tone or fairer complexion has been an ongoing phenomenon in people with skin of color (soc). the direct implication of this craze is the exploitation of topical agents originally developed for treatment of hyperpigmentation, such as skin lightening therapies. topicals containing hydroquinone, alpha and beta hydroxy acids, tretinoin, mequinol, arbutin, vitamin c, soy extracts and concoctions of multiple ingredients, including newer cosmeceuticals, are now in vogue for treatment of facial melanoses especially melasma [1] and for general skin lightening, at least of the face, neck and other exposed parts. the local adverse effects of these agents [1] and the quantity required for large surface area application constitute major limitations of this approach. understandably, the effect of such locally applied topicals remains limited to the application site alone without any notable systemic skin lightening effect. the quest for a systemic skin-whitening agent ensues. oral antioxidants, such as vitamin c, vitamin e, tranexamic acid, flavonoids, and various botanical extracts have been tried in melasma and disorders of hyperpigmentation, but none has proven to provide an overall skin lightening effect [1,2]. glutathione, being a strong antioxidant with additional anti-melanogenic properties, has recently become the most popular “systemic skin lightening molecule.” the most “popular” and controversial route of administration of glutathione for skin lightening has been intravenous (iv). glutathione (gsh), a low molecular weight thiol-tripeptide is central to the maintenance of intracellular redox balance [3]. currently, to the best of our knowledge, iv gsh has been approved by different statutory drug regulatory authorities for specific systemic disorders. the indications approved by the central drugs standard control organization (cdsco) in india are: 1) alcoholic fatty liver, 2) alcoholic liver fibrosis, 3) alcoholic liver cirrhosis, and 4) alcoholic hepatitis [4]. the philippines food and drug administration (fda) has approved its use as an adjunctive treatment to reduce neurotoxicity associated with cisplatin chemotherapy [5]. in addition to it being one of the richest antioxidants, it is being promoted as a skin-lightening agent, following the discovery of its antimelanogenic properties [7]. amongst the many mechanisms postulated to contribute to its antimelanogenic properties (figure 1), inhibition of tyrosinase enzyme, skewing of melanogenesis from the darker eumelanin to the lighter phaeomelanin, and scavenging of free radicals seem to be the most important [8]. unfortunately, there is a clear contradiction between the exact evidence supporting its efficacy and safety, and the hype around its depigmentary properties, with pharma-cosmeceuticals inundating dermatology therapeutics with glutathione tablets, capsules, topical preparations and parenteral preparations across the globe [9]. • inhibition of tyrosinase (the key enzyme of melanogenesis): – direct inhibition: thiol group binding with the copper-containing active site of the enzyme – indirect inactivation: exerted via the antioxidant effect of glutathione that leads to quenching of free radicals and peroxides • switching production of eumelanin to phaeomelanin • modulation of the depigmenting properties of other antimelanogenic principles figure 1. mechanisms postulated to be responsible for the skin lightening effect of glutathione. [copyright: ©2018 sonthalia et al.] review | dermatol pract concept 2018;8(1):4 17 tion in melanin index at both sun-exposed and sun-protected sites in all the subjects and moderate skin lightening observed by 90% of the subjects on global evaluation [11]. the tolerance to gsh was excellent in both the studies. the singular randomized, double-blind, placebo-controlled clinical trial by watanabe et al., conducted in 30 healthy filipino women aged 30-50 years has provided virginal evidence favoring efficacy of topical gssg 2% lotion (applied twice daily for 10 weeks) in producing temporary skin whitening [12]. the results of this split-face, protocol-based study revealed statistically to evaluate the primary efficacy outcome. the randomized, double-blind, two-arm, placebo-controlled study conducted by arjinpathana and asawanonda in 60 healthy medical students showed a consistent reduction in the melanin indices at all the six sites evaluated in the gsh group subjects, with a statistically significant reduction over placebo at two sites [10]. the open-label, single-arm pilot study conducted by handog et al. in 30 healthy filipino women (aged 22-42 years) with fitzpatrick skin types iv or v, using buccal lozenges instead of capsules of gsh, reported significant reductable 1. evidence of glutathione as a skin lightening agent: current summary of studies conducted to date glutathione formulation topical (gssg cream) oral (capsules) oral / buccal lozenges intravenous authors watanabe et al. [12] arjinpathana & asawanonda [10] handog et al. [11] zubair et al. [15] study subjects • 30 healthy filipino women • ages: 30-50 years • 60 healthy medical students • ages: 19-22 years • 30 healthy women • ages: 22–42 years • fitzpatrick skin types iv or v • 50 healthy pakistani women • ages: 25-47 years • skin type not mentioned study design randomized, doubleblind, placebocontrolled, split-face study randomized, doubleblind, placebo controlled study open-label, singlearm, pilot study open-label, placebocontrolled study methodology split-face study; application of 2% (w/w) gssg lotion and placebo lotion, twice daily for 10 weeks oral glutathione (500 mg) or placebo capsules daily, in 2 divided doses on an empty stomach for 4 weeks one buccal lozenge (500 mg) per day, for 8 weeks. injection glutathione 1200 mg or normal saline (placebo) injected over 30 minutes frequency of evaluation baseline; weekly for 10 weeks baseline; and at 4 weeks baseline, twice weekly for 8 weeks baseline, twice weekly for 8 weeks primary outcome melanin index—by mexameter mx18 melanin index—by mexameter melanin index—by mexameter visual taylor hyperpigmentation scale subjective parameters global evaluation on a 7-point rating scale global evaluation s on a 4-point rating scale global evaluation on a 5-point rating scale none results melanin index • melanin index reduction significant in gssg group vs. placebo • other parameters such as skin moisture, curvature index, keratin index also improved in the gssg group melanin index • melanin index reduction significant at all six sites in oral gsh group vs. placebo melanin index • melanin index reduction significant at all sites in buccal gsh group vs. placebo • global assessment: 27 subjects (90%) noted moderate skin lightening taylor scale • improvement (iv gsh vs placebo): completion of 12 injections—37.5% vs. 18.7% • after 2 months: 18.7% vs. 12.5% • after 4 months: 18.7% vs, 0% • after 6 months: 6.2% vs. 0% tolerance & safety • very well tolerated • no significant adverse effects in either group • very well tolerated • no significant adverse effects in either group • very well tolerated • no significant adverse effects in either group • adverse effects in all gsh treated patients • serious—liver dysfunction in 32% (8) patients and anaphylactic shock in 1 patient. (continued next page) 18 review | dermatol pract concept 2018;8(1):4 taylor scale for preand post-treatment evaluation of change in skin hue and tone and lack of mention of statistical tests applied. the taylor scale is an unreliable tool for observing subtle changes in skin pigmentation with a very high interinvestigator variability in its interpretation [16]. results based on taylor scale, rather than a reliable objective parameter like the melanin index using a mexameter mx-18, at best, are speculative. further, the major adverse effect reported in the iv gsh treated group was liver dysfunction, which was neither qualified nor quantified. development of liver dysfunction in healthy individuals receiving iv gsh is surprising, since the medication is approved by the cdsco for the treatment of various liver disorders mentioned earlier [4]. the researchers also did not evaluate baseline or post-treatment renal nor thyroid function of the subjects, both of which were reported to be adversely affected by iv glutathione in the position paper by the fda, department of health, republic of the philippines [5]. the controversy surrounding absorption of oral glutathione and adverse effects of iv glutathione and statutory status glutathione-based oral dietary supplements have been accorded the status of “generally recognized as safe (gras)” consistent with section 201(s) of the federal food, drug, and cosmetic act of the united states food and drug administration (us-fda) [16]. there is no restriction on its significant reduction of skin melanin index with glutathione compared to placebo, with no adverse drug effects. however, the results of these studies need to be interpreted with caution owing to certain limitations in their study design. the major limitations of these studies included: small sample size, cohort consisting of healthy volunteers, extremely short study period with an even shorter follow-up, and lack of measurement of blood levels of glutathione [10-12]. details of the inclusion criteria, methodology, results and specific limitations of these studies have been comprehensively catalogued in table 1. despite the rampant use of intravenous (iv) glutathione injections for skin lightening in certain countries, evidence favoring such a practice remains elusive. for years, the strong lobby of proponents of iv glutathione for skin lightening, including manufacturers, distributors, many skin clinics, and med spas, have been recommending arbitrary dosage schedules, despite complete lack of evidence [13,14]. it is only recently, that zubair et al. studied the efficacy and safety of iv gsh for skin tone lightening in 25 patients of pakistani origin in a placebo-controlled trial (1,200 mg given iv twice a week for 6 weeks in the treatment group versus normal saline in control group) [15]. although the results from this singular trial did not favor iv glutathione as an effective or lasting treatment for skin tone lightening, the inherent flaws of the study design mandate cautious analysis. the small sample size (n=25 in each group), complicated with a high dropout rate from the treatment group (9 out of 25) in this trial exhorts a cautious interpretation of the results. the methodology was flawed due to the employment of a highly subjective visual glutathione formulation topical (gssg cream) oral (capsules) oral / buccal lozenges intravenous follow-up after completion of study none none none done on 3 occasions—2nd, 4th, 6th month after treatment completion study limitations • small sample size • short duration of study • subjects: healthy filipino women • no post-study follow up • small sample size • short duration of study • subjects: healthy young adults • no post-study follow up • serum gsh levels not measured • small sample size • short duration of study • subjects: healthy women • no post-study follow up • serum gsh levels not measured. • small sample size • poor study design • no mention of statistical analysis • only two sites evaluated • unreliable method of efficacy evaluation • no information on baseline bio-chemical parameters • no details on hepatic adverse effects, nature, severity and recovery • serum gsh levels not measured *modified from table 1 published in: sonthalia s, daulatabad d, sarkar r. glutathione as a skin whitening agent: facts, myths, evidence and controversies. indian j dermatol venereol leprol. 2016;82:262. table 1. evidence of glutathione as a skin lightening agent: current summary of studies conducted to date (continued) review | dermatol pract concept 2018;8(1):4 19 gsh for skin lightening, the extremely high cost of injection vials constitutes another compelling deterrent to its use. the important limitations of iv gsh have been enumerated in figure 4. the pharmacological game changer: recent insights from research on the effect of gsh versus esterified gsh in tyrosinase inhibition a reasonable intracellular concentration of gsh and its unimpeded transportation into the melanosomes are essenavailability in this form in the us, philippines and japan. oral gsh is also easily available over-the-counter (otc) in india and many other asian countries. since oral gsh is known to have a low bioavailability in humans [9], manufacturers of iv injections of gsh “recommend” this route of administration to achieve desired therapeutic levels in the blood and skin rapidly to produce “instant” skin whitening results. however, as emphasized above, the literature evaluating the efficacy of iv gsh is still lacking. furthermore, the duration of therapy and long-term efficacy is yet to be established. despite the lack of evidence, manufacturers of iv gsh have been “recommending” a dose of 600-1200 mg, to be injected weekly or twice a week, with no specified net duration of the therapy [8]. although the overall safety of iv gsh, extrapolated from studies evaluating its use for male infertility and liver disorders seems to be convincing [18,19], several adverse effects of iv gsh have been documented in the philippines (figure 2), detailed in the position paper by the fda, department of health, republic of the philippines [5] with a warning for the public on the subject of the safety of the off-label use of glutathione solution for injection (figure 3). the reported adverse effects include adverse cutaneous eruptions including potentially fatal stevens-johnson syndrome (sjs) and toxic epidermal necrolysis (ten), severe abdominal pain, thyroid dysfunction, renal dysfunction, and lethal complications such as air embolism, or potentially fatal sepsis due to incorrect/ unsterile method of iv administration and use of counterfeit gsh [5,9]. apart from the lack of evidence favoring iv 1. cutaneous—ranging from skin rashes to serious and potentially fatal stevens-johnson syndrome (sjs) and toxic epidermal necrolysis (ten). 2. severe abdominal pain in patients receiving twice-weekly iv glutathione 3. thyroid dysfunction 4. kidney dysfunction with potential for development of renal failure 5. liver dysfunction—reported in 32% of the treated subjects in the iv gsh trial by zubair et al. [7] 6. lethal complications—air embolism, bloodborne infections and potentially fatal sepsis stemming from incorrect technique of injections by untrained staff, use of unsterile or used needles, and use of counterfeit intravenous glutathione figure 2. adverse effects reported with intravenous glutathione injections by the food and drug administration, department of health, republic of the philippines [5] and the intravenous gsh trial by zubair et al. [15] [copyright: ©2018 sonthalia et al.] figure 4. limitations of intravenous glutathione as a skin lightening agent. [copyright: ©2018 sonthalia et al.] 1. lack of any published or reliable source of evidence supporting the efficacy of intravenous glutathione in skin whitening 2. undefined dose and duration of intravenous injections, excepting the recommendations of manufacturers which has no apparent scientific basis 3. need for indefinite, perhaps lifelong maintenance with either oral or intravenous gsh, even if the “desirable” skin whitening has been attained 4. barrage of adverse effects reported with intravenous administration 5. lack of approval from us fda and warning against the use of intravenous glutathione by the fda of philippines 6. high cost of injectable glutathione vials us – united states; fda – food and drug administration figure 3. public warning issued by the food and drug administration, department of health, republic of the philippines [5] (may 12, 2011). [copyright: ©2018 sonthalia et al.] “the alarming increase in the unapproved use of glutathione administered intravenously as a skinwhitening agent at very high doses is unsafe and may result in serious consequences to the health of users. there is inadequate safety documentation on the use of high doses of glutathione administered at 600 mg to 1.2 grams once weekly and even up to twice weekly. the only approved indication of the intravenous format of glutathione is an adjunctive treatment to reduce neurotoxicity associated with cisplatin chemotherapy.” 20 review | dermatol pract concept 2018;8(1):4 4. cdsco list of approved drug from 01-01-2011 to 31-12-2011. http://www.cdsco.nic.in/writereaddata/listof-approveddrug-from-2011.pdf. accessed on april 26, 2017. 5. lazo sh. safety on the off-label use of glutathione solution for injection (iv). food and drug administration, department of health, republic of the philippines; 2011. http://www.doh.gov.ph/sites/ default/files/advisories_cosmetic_doh-fda%20advisory% 20no.%202011-004.pdf. accessed on february 26, 2017]. 6. sonthalia s, sarkar r. glutathione for skin lightening: an update. pigment int. 2017;4:3-6. 7. exner r, wessner b, manhart n, roth e. therapeutic potential of glutathione. wien klin wochenschr. 2000;112:610-616. 8. villarama cd, maibach hi. glutathione as a depigmenting agent: an overview. int j cosmet sci. 2005;27:147-153. 9. sonthalia s, daulatabad d, sarkar r. glutathione as a skin whitening agent: facts, myths, evidence and controversies. indian j dermatol venereol leprol. 2016;82:262-272. 10. arjinpathana n, asawanonda p. glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. j dermatolog treat. 2012;23:97-102. 11. handog eb, datuin ms, singzon ia. an open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in filipino women. int j dermatol. 2016;55:153-157. 12. watanabe f, hashizume e, chan gp, kamimura a. skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. clin cosmet investig dermatol. 2014;7:267-274. 13. oskin med spa website. http://www.oskinmedspa.com/portfolio/ iv-glutathione-injections/ accessed on september 8, 2017. 14. magic beauty website. http://www.magicbeauty.in/product/gshultima-1500mg. accessed on september 8, 2017]. tial for gsh to inhibit tyrosinase and switch melanogenesis from eumelanin to pheomelanin. trans-melanosomal transportation can be achieved through a membrane channel or diffusion, both of which seem to be lacking for gsh, a fact well established in previous research [20,21]. chung et al. recently evaluated the in vitro antimelanogenic effects and cytotoxicity of gsh and its three esterified derivatives—gsh monoethyl ester (gsh-mee), gsh diethyl ester (gsh-dee), and gsh monoisopropyl ester (gsh-mipe)—in three cell culture lines [22]. the results of their research demonstrated significant inhibitory effect of gsh-mee and gsh-mipe, but not gsh, on intracellular tyrosinase activity and melanin production. the authors attributed this effect to the lipophilicity of the esterified derivatives of gsh. of the three esters, gsh-dee and gsh-mipe demonstrated additional cytotoxic activity, rendering them unsuitable for clinical use. given in vitro efficacy and lack of cytotoxicity of gsh-mee, the researchers suggested the development of gsh-mee, instead of gsh, as an efficacious and safe molecule for the treatment of hyperpigmentation [22]. however, these results need further validation in both in vitro and clinical trials before drawing definitive conclusions. conclusion there is little convincing evidence in favor of glutathione as a therapy for hyperpigmentation at the present time, and there are many unresolved controversies that surround its use (figure 5). the trials available to date that have evaluated the role of glutathione in skin lightening administered through different modes have numerous limitations. although the safety of topical and oral gsh seems to be good, their efficacy (especially long-term) remains questionable. the extant evidence to support or discourage use of iv gsh as a therapeutic modality for improving skin tone or pigmentation is minimal and contradictory; notwithstanding the austere concern regarding the potential adverse effects associated with this mode of administration. more evidence in the form of high quality trials with better study design, larger sample size, and long-term follow-up is vital, before our patients are subjected to glutathione-based treatments. references 1. sarkar r, chugh s, garg vk. newer and upcoming therapies for melasma. indian j dermatol venereol leprol. 2012;78:417-428. 2. dickinson da, forman hj. glutathione in defense and signaling: lessons from a small thiol. ann n y acad sci. 2002;973:488-504. 3. murray rk. metabolism of xenobiotics. in: murray rk, bender da, botham km, kennelly pj, rodwell vw, weil pa, eds. harper’s illustrated biochemistry. 28th ed. michigan: mcgraw-hill; 2009:612-613. figure 5. controversial aspects of glutathione as a potential skin lightening therapy. [copyright: ©2018 sonthalia et al.] • paucity of high quality, well-designed controlled trials with large sample size and long follow-up duration • controversial aspects of absorption of orally administered glutathione and plasma levels achieved in different studies involving animal models as well as human volunteers • tendency to quick reversal of any skin benefit after stoppage of oral/topical/parenteral glutathione • no well-defined dosage and/or safe duration of administration of systemic glutathione • adverse effects reported with intravenous glutathione • prohibitory or ill-defined statutory laws on the use of intravenous glutathione for skin lightening in different countries • the recent finding of discordant effect of gsh vs. esterified gsh over inhibiting melanogenesis http://www.cdsco.nic.in/writereaddata/listof-approved-drug-from-2011.pdf http://www.cdsco.nic.in/writereaddata/listof-approved-drug-from-2011.pdf review | dermatol pract concept 2018;8(1):4 21 19. cook gc, sherlock s. results of a controlled clinical trial of glutathione in cases of hepatic cirrhosis. gut. 1965;6:472-476. 20. potterf sb, virador v, wakamatsu k, et al. cysteine transport in melanosomes from murine melanocytes. pigment cell res. 1999;12:4–12. 21. wellner vp, anderson me, puri rn, jensen gl, meister a. radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts. proc natl acad sci usa. 1984;81:4732–4735. 22. chung by, choi sr, moon ij, park cw, kim yh, chang se. the glutathione derivative, gsh monoethyl ester, may effectively whiten skin but gsh does not. int j mol sci. 2016;27;17:629. 15. zubair s, hafeez s, mujtaba g. efficacy of intravenous glutathione vs. placebo for skin tone lightening. j pak ass dermatol. 2016;26:177-181. 16. taylor sc, arsonnaud s, czernielewski j; hyperpigmentation scale study group. the taylor hyperpigmentation scale: a new visual assessment tool for the evaluation of skin color and pigmentation. cutis. 2005;76:270-274. 17. gras notice for glutathione. (2009) url http://www.fda. gov/ucm/groups/fdagov-public/@fdagov-foods-gen/documents/ document/ucm269318.pdf . accessed on april 26, 2017. 18. lenzi a, lombardo f, gandini l, culasso f, dondero f. glutathione therapy for male infertility. arch androl. 1992;29:65-68. http://www.ncbi.nlm.nih.gov/pubmed/?term=lenzi%2520a%255bauthor%255d&cauthor=true&cauthor_uid=1503526 dermatology: practical and conceptual 246 letter | dermatol pract concept 2019;9(3):23 dermatology practical & conceptual introduction fibroepithelioma of pinkus (fep), a rare subtype of basal cell carcinoma, classically presents on the trunk as a pink, light brown, or skin-colored papule or plaque. dermoscopy is a tool that can be utilized by dermatologists to correctly diagnose fep. the dermoscopic features of fep include polymorphous vessels, crystalline structures, milia-like cysts, ulceration, gray-brown areas, and gray-blue dots [1]. we present a case of fep with negative network. case presentation a 74-year-old man presented to our clinic with a 6-month history of a slowly growing, scaly, and irritated lesion on the left flank. on examination he was found to have a roughly 1-cm, ovoid, bright pink, scaling papule (figure 1). on dermoscopy, the lesion was noted to have a negative network, polymorphous blood vessels, white crystalline structures, and white scale (figure 2). the biopsy pathology was consistent with a superficial basal cell carcinoma, fep type (figure 3). with a histological stain for melanin, the tumor showed focal zones of hypopigmentation at the sites of the tumor’s attachment to the epidermis. these hypopigmented zones at the tumor “stalks” alternated with intervening zones of normally pigmented epidermis (figure 4). the lesion was subsequently destroyed with electrodesiccation and curettage. conclusions classically, fep presents as a pink, light brown, or skincolored papule or plaque on the trunk. due to nonspecific clinical findings and misdiagnosis, fep may be more common than previously thought. clinically, it may resemble benign growths such as dermal nevus, seborrheic keratosis, or soft fibroma [1]. on histology, fep has distinct tumor islands with basaloid (often palisading) cells within a fibromatous stroma (figure 3) [1]. negative network consists of a relatively light reticulated pattern that mimics a pigmented network, except that the light network surrounds darker areas that fill the spaces between the lines (figure 2) [2,3]. negative network has previously been associated with malignant melanoma, acquired and congenital nevi, spitzoid lesions, and dermatofibromas dermoscopic description of fibroepithelioma of pinkus with negative network yousif yonan1, connor maly1, david dicaudo1, aaron mangold1, mark pittelkow1, david swanson1 1 department of dermatology, mayo clinic arizona, scottsdale, az, usa key words: fibroepithelioma of pinkus, inverse network, dermoscopy, basal cell carcinoma citation: yonan y, maly c, dicaudo d, mangold a, pittelkow m, swanson d. dermoscopic description of fibroepithelioma of pinkus with negative network. dermatol pract concept. 2019;9(3):246-247. doi: https://doi.org/10.5826/dpc.0903a23 accepted: february 27, 2019; published: july 31, 2019 copyright: ©2019 yonan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: david l. swanson, md, 13400 east shea blvd., scottsdale, az 85259. email: swanson.david@mayo.edu. letter | dermatol pract concept 2019;9(3):23 247 references 1. reggiani c, zalaudek i, piana s, et  al. fibroepithelioma of pinkus: case reports and review of the literature. dermatology. 2013;226(3):207-211. 2. bassoli s, ferrari c, borsari s, et al. negative pigment network identifies a peculiar melanoma subtype and represents a clue to melanoma diagnosis: a dermoscopic study of 401 melanomas. acta derm venereol. 2013;93(6):650-655. 3. kornreich da, lee jb. white network in fibroepithelioma of pinkus. jaad case rep. 2016;2(5):400-402. [2]. in our fep case, the hypopigmented tumor stalks were likely the edges of vertical planes surrounding and enveloping stroma; this created the appearance of a negative network on surface dermoscopy (figure 4). one prior case report also described the association of fep with a negative network that resulted from strands of epithelial cells emerging from the underside of the epidermis [3]. given the overlapping clinical and dermoscopic features of fep with benign and malignant melanocytic and nonmelanocytic tumors, the conservative approach of biopsy is recommended. figure 1. clinical photograph of fep. [copyright: ©2019 yonan et al.] figure 3. anastomosing basaloid epithelial strands enclosing round islands of fibrous stroma (hematoxylin and eosin, ×40). [copyright: ©2019 yonan et al.] figure 2. contact polarized dermoscopic image showing features of negative network, white crystalline structures, polymorphous vessels, and white superficial scale. [copy right: ©2019 yonan et al.] figure 4. melanin stain demonstrating hypopigmented tumor stalks (thin arrows) alternating with intervening zones of normally pigmented epidermis (thick arrowheads). the network of hypopigmented tumor stalks creates the appearance of a negative network on dermoscopy (fontana stain, ×100). [copyright: ©2019 yonan et al.] dermatology: practical and conceptual review | dermatol pract concept 2014;4(4):1 1 dermatology practical & conceptual www.derm101.com – i – ichthyosis: a generic term for skin conditions characterized by what are said to be fishlike scales, i.e., scales that are broad and polygonal with free edges, as are seen in ichthyosis vulgaris (and its look-alike, acquired ichthyosis), x-linked ichthyosis, and lamellar ichthyosis. conditions reputed to be ichthyosis, such as ichthyosis hystrix and ichthyosis linearis circumflexa, do not qualify because they are not associated with broad polygonal scales. id: a suffix employed by dermatologists in such an inconsistent way that no unifying theme can be identified for it. for example, “-id” appears in words that reflect wholly diverse pathologic processes, such as eczematoid, syphilid, dermatophytid, monilioid, and leukemid. sometimes, the suffix is used alone as in “id reaction,” which has been invoked traditionally by dermatologists for what is known, equally confusingly, as “autoeczematization” and “autosensitization.” these fuzzy concepts were spawned more than three quarters of a century ago, when it was common practice in dermatology to use treatments such as autohemotherapy for a host of inflammatory diseases, injections intravenously of calcium gluconate for intractable pruritus, and radiation therapy for epilation of hairs harboring the organisms of tinea capitis. just as those three modes of therapy have disappeared, so, too, should the concept of “-ids.” we use the term “id reaction” only for a spongiotic dermatitis manifested by tiny vesicles on the hands of patients with florid dermatophytosis at another site, usually the feet, or for an analogue of that phenomenon such as widespread vesicles that appear subsequent to injudicious treatment, i.e., with gentian violet (known sardonically in times past as “gentian violent”) of an exuberant spongiotic dermatitis, usually on the feet, such as an allergic contact dermatitis. a time-honored explanation for an “id” reaction is hematogenous dissemination of antigen, such as a component of a dermatophyte or a contact allergen (i.e., used to add explanatory information or to state something in different words). immature sebocyte: is a sebaceous cell with a round nucleus and scant cytoplasm devoid of vacuoles, such as, is present at the very periphery of a normal sebaceous gland and in proliferations with sebaceous differentiation, i.e., the benign sebaceoma and the malignant sebaceous carcinoma. in a normal sebaceous gland (see lobule), an immature sebocyte travels from the outermost boundary of a lobule to the very center of it where, nearby, resides a sebaceous duct. in the course of the journey, the cytoplasm enlarges greatly as more and more vacuoles laden with lipid come to bloat it, the nucleus becoming scalloped as a result of pressure on it by cytoplasm ever-expanding by virtue of the presence of ever more vacuoles filled increasingly with lipid. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 6 (i-l) bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 6 (i-l). dermatol pract concept. 2014;4(4):1. http://dx.doi.org/10.5826/dpc.0404a01 copyright: ©2014 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@aol.com 2 review | dermatol pract concept 2014;4(4):1 immunohistochemistry: denotes the study of tissues by analysis of their chemicals and, more specifically, by methods of immunology in which an antigen-antibody reaction is fundamental. for instance, immunoperoxidase is an immunohistochemical method in which determination of the chemical composition of a tissue uses an antigen-antibody reaction as a pivotal marker. related methods are enzyme histochemistry, which employs an enzymatic reaction as the main process by which the chemical composition of a tissue is determinated, and radio labeling, which utilizes radioisotopes to that end. immunohistochemistry is an adjunctive procedure to h & e. it is meant to help as one other histopathologic “tool.” impetiginization: secondary infection of a lesion by bacteria, usually by virtue of animated scratching. lesions that are impetiginized simulate impetigo clinically because of the presence of vesiculopustules or pustules, both of which eventuate in crusts. they resemble impetigo histopathologically because bacteria, often in clumps, are seen to adorn crusts and scale-crusts. pruritic spongiotic dermatitides, such as allergic contact dermatitis and nummular dermatitis, often undergo impetiginization as a consequence of excoriation animatedly. incontinence of pigment: loss of pigment from the epidermis that is due to damage of epidermal melanocytes and basal keratocytes and ingestion of the melanin by macrophages within the dermis. in some conditions, however, transfer of pigment to dermal macrophages may result from phagocytosis of the terminal portions of dendritic processes that have protruded through the basal lamina. indian-file arrangement of neoplastic cells: epithelial cells with atypical nuclei arranged as single cells (strands) between collagen bundles; especially common in metastatic carcinomas and in certain leukemias and can also be seen in melanoma among others. inferior segment of a hair follicle: is bounded above by the site of insertion of muscle of hair erection above and below by the base of the follicle. this can be stated in more detail. in a longitudinal section, a mature follicle may be divided histologically into (1) an upper segment constituted of a single part, i.e., the isthmus which is delimited above by the entry of the sebaceous duct into the base of the infundibulum and below by desquamation of cornified cells of the inner sheath, and (2) a lower segment that consists of two parts, i.e., the stem, which stretches from the base of the isthmus to the end of the keratogenous zone at adamson’s fringe, and the bulb, which is the part of a follicle that resides below the adamson’s fringe. adamson’s fringe is the boundary between nucleated cells of a hair in the bulb of a follicle and enucleated cells of the hair in the stem of a follicle. the infundibulum is epidermal and not part of the hair follicle. infiltrate: elements present in tissue in a quantity greater than normal. an infiltrate may be cellular or noncellular. when it is cellular, an infiltrate may be composed of inflammatory cells, i.e., lymphocytes, or neoplastic cells, i.e., those of metastatic carcinoma. when it is largely noncellular, an infiltrate may consist, for example, of mucin, amyloid, colloid, or urate. noncellular infiltrates are referred to as deposits. an infiltrate made up of a single type of cell is considered to be monomorphous, examples of that being small lymphocytes in the inflammatory disease called polymorphous light eruption, abnormal lymphocytes in some lymphomas, and mast cells in the benign neoplasm urticaria pigmentosa. an infiltrate that is polymorphous, known also as mixed-cell, is composed of several types of cells that are present concurrently. for example, polymorphous infiltrates of neutrophils, eosinophils, lymphocytes, plasma cells, and histiocytes are seen in plaques of granuloma faciale/erythema elevatum diutinum. “polymorphous” should not be confused with “pleomorphic,” which refers to variation in size and shape of nuclei of neoplastic cells. infiltrating margins: an animistic term applied to the interposition of neoplastic cells between collagen bundles; intended to mean a poorly circumscribed (usually malignant) neoplasm. this cannot be seen under a microscope. it is similar to “invasion.” inflammation: changes in tissue that occur typically as a reaction to injury of any kind (i.e., mechanical, actinic, chemical, allergic, infectious, and effects of neoplasms) and characterized clinically be redness especially and swelling, and histopathologically by vasodilation and infiltrates of inflammatory cells, those especially being neutrophils, eosinophils, lymphocytes, plasma cells, and histiocytes. inflammatory dermatosis: a dermatosis is any pathologic condition of the skin. dermatologists and dermatopathologists sometimes speak of “inflammatory dermatosis” when “dermatitis” is preferable. general pathologists do not allude to “acute appendicosis” or to “ulcerative colossi,” but to appendicitis and colitis. the term “dermatitis” or the phrase “inflammatory disease of the skin” is preferable to “inflammatory dermatosis” because the word dermatosis is generic, not specific, and is employed by some authors for conditions other than inflammatory ones. inflammatory disease: a disorder characterized histopathologically by an infiltrate of inflammatory cells and, at times, by changes secondary to the effects of them such as spongiosis, acanthosis, and fibroplasia, but that infiltrate being unaffiliated with cells of any other fundamental pathologic process, (i.e., neoplastic, hamartomatous, cystic, etc.) infundibular tunnels: are dilated, tortuous channels of infundibular epithelium filled with cornified cells usually review | dermatol pract concept 2014;4(4):1 3 in laminated array, within the substance of some seborrheic keratosis. they are known also and inaccurately as “horn pseudocysts” but they are not true cysts because they communicate with the skin surface through patulous ostia. infundibulum of the epidermis: an infundibulum, as its name denotes, has the shape of a funnel. the upper two-thirds of it consists of the cone of the funnel, whereas the lower one-third—sometimes referred to inaccurately as the infra-infundibulum—is formed by the narrow tube of funnel. the infundibulum is not part of the outer sheath, but is integral to epidermis; histologically, it is not epidermoid, as often is said, but epidermal. although the epithelium of the lower tubular part of an infundibulum differs from that of the upper cone-like portion by having walls parallel to one another, slightly thinner granular zone, and fewer corneocytes, for practical purposes, infundibular epidermis is identical morphologically to surface epidermis, with which it is continuous. the length of infundibula varies greatly on different anatomic sites, being particularly long and dwarfing vellus follicles on a face, and being much shorter on a leg, for example. on one anatomic site, infundibula are unaffiliated with a follicle, namely, the nipple where a lactiferous (apocrine) duct enters directly into infundibula. inner sheath or inner root sheath: of a hair follicle is the part that actually encloses a hair along its course until the isthmus is reached. it consists of three layers: henle’s layer, huxley’s layer, and cuticle. the inner sheath cornifies in a distinctive fashion with formation first of bright red trichohyalin granules that disappear in time, a prelude to emergence of compactly arranged blue-gray corneocytes. the inner sheath comes into being through differentiation of matrical cells (one of seven separate paths of its differentiation). in situ: is a term used to denote neoplasms that are confined to their site of origin. this usage presumes in speaking of malignant neoplasms that, untreated, the process could eventuate in metastatic carcinoma. this prediction of biologic behavior by a histopathologist is based on retrospective analysis of similar lesions. cells of a malignant neoplasm that are confined to epithelium need not eventuate in metastases; they may remain in situ for the life of a person, and even regress. unfortunately, a histopathologist cannot predict the behavior of those cells and, for that reason, malignancy in situ must be removed completely to insure that it will never progress to the point that it may prove fatal. the concept of in-situ malignancy of the skin is accepted for neoplasms with squamous differentiation, i.e., bowen’s disease (see below), and for glandular differentiation, i.e., extramammary paget’s disease. superficial basal-cell carcinoma is seated beneath the epidermis and therefore is not considered to be truly in situ, i.e., intra-epidermal. melanoma in situ is a proliferation of abnormal melanocytes, confined to the epidermis and epithelial structures of adnexa, that fulfills all of the intra-epithelial criteria for melanoma. virtually all primary cutaneous melanomas begin within the epidermis, i.e., in situ. parenthetically, the above contains two egregiously flawed concepts; the concept of “in situ” squamous cell carcinoma and also “invasive” squamous cell carcinoma and these should be jettisoned. unlike the situation for apocrine carcinoma in situ (extra mammary paget’s disease) and melanoma in situ in which neoplastic apocrine cells and neoplastic melanocytes, respectively, actually move in vivo from the epidermis into the dermis and can be identified morphologically for what they are at both sites, that is not the case for so called squamous cell carcinoma in situ; neoplastic keratocytes do not descend as individual units or as discrete aggregations from the epidermis into the dermis, but rather the epidermis made up of abnormal keratocytes advances as a phalanx ever deeper. that being so, no normal epidermis is residual in a lesion of bowen’s disease (or solar keratosis), unlike the situation in extramammary paget’s disease which begins as apocrine carcinoma in situ and in melanoma in situ and furthermore, no clear distinction can be made by conventional microscopy between so called in situ squamous cell carcinoma and so called invasive squamous cell carcinoma; it is continuum, in contradistinction to the situation in extramammary paget’s disease and in melanoma where, at a moment in time, a plain distinction can be made between the component of the malignant neoplasm in the epidermis and the component of that same neoplasm in the papillary dermis. a discussion of why this “phalanx” occurs follows. when neoplastic cells other than keratocytes are present within the epidermis and its adnexal epithelium, those cells often are separated from their surroundings by clefts. in apocrine carcinoma in-situ and melanoma in-situ spaces between neoplastic cells and adjacent keratocytes are encountered commonly. the clefts represent artifacts that come into being during the process of fixation of specimens as a consequence of poor attachment of neoplastic cells that are not keratocytes to contiguous normal epidermal keratocytes. in contrast, the neoplastic cells of what is squamous cell carcinoma in-situ, being the keratocytes that they are, are linked to seemingly unaffected keratocytes at the circumference of the neoplasm, and even within it, as well as to one another, by intercellular bridges. moreover, the epidermis of “squamous cell carcinoma in-situ” tends to be largely replaced by neoplastic keratocytes, those cells usually making up the bulk of the effected surface epithelium. the situation for apocrine carcinoma in-situ and melanoma in-situ is different from that of “squamous cell carcinoma in-situ”; keratocytes often predominate over neoplastic nonkeratocytes in the affected surface epithelium of those incipient malignant neoplasms. 4 review | dermatol pract concept 2014;4(4):1 it is rather easy to distinguish neoplastic apocrine cells and melanocytes from normal keratocytes within the epidermis, and that is also true after the neoplastic cells of those conditions have left the epidermal compartment and come to reside within the dermis, the reason being that the epidermis is so sharply demarcated from the dermis. but the neoplastic keratocytes of “squamous cell carcinoma in-situ” do not advance from the epidermis into the dermis in the same manner as do neoplastic apocrine cells and melanocytes. the reason is that nearly the entire epidermis of “squamous cell carcinoma in-situ” is composed of abnormal keratocytes and those neoplastic cells cause the surface epithelium to thicken progressively; the neoplastic keratocytes remain in continuity with the surface (and/or adnexal) epithelium in which the pathologic process began. neoplastic keratocytes of so called squamous cell carcinoma in-situ do not transverse the dermo-epidermal junction to enter the dermis in the fashion of neoplastic apocrine cells and melanocytes but rather are part of steadily advancing mass of epithelium. in fact, in bowen’s disease, the stereotypical expression of “squamous cell carcinoma in-situ” in skin, the usual undulate pattern formed by rete ridges and dermal papillae is preserved, albeit altered markedly; even when the carcinoma has become so thick that it fills the upper half of the dermis. in sum, a clear distinction can be made between apocrine and melanoma in-situ on one hand and “squamous cell carcinoma in-situ” on the other. when neoplastic cells of apocrine carcinoma in-situ and melanoma in-situ enter the dermis, the intradermal component is readily perceived as being separate from both the intraepidermal component of it and from epidermal keratocytes. that is not the case for what is called squamous cell carcinoma in-situ; that malignant neoplasm, no matter how thick it becomes, remains continuous with the surface and/or adnexal epithelium within which it originated. if neoplastic keratocytes of squamous cell carcinoma in the dermis or subcutaneous fat actually detach from the carcinoma above it, a metastasis has then come into being. another misguided idea is embodied in the cliché said to characterize what is purported to be squamous cell carcinoma in-situ, (this is a flawed concept) namely, “full thickness atypia” of surface epithelium. before there can be involvement of the entire thickness of surface epithelium by changes of squamous cell carcinoma, earlier there must be involvement of the epithelium in only part of the thickness, much of the thickness, or the entire thickness. that circumstance, i.e., partial involvement, is no less a squamous cell carcinoma than involvement of the epithelium completely. an analogous situation obtains for melanoma in-situ; abnormal melanocytes of that neoplastic process disposed as solitary units only and stationed at the dermoepidermal junction exclusively is no less melanoma in-situ than when the entire thickness of the epidermis, including the cornified layer, is riddled by abnormal melanocytes. it seems that a “lot of time” is spent in differentiating solar (actinic) keratosis from the flawed concept of “squamous cell carcinoma in-situ” by this search for “full thickness atypia” when actually solar (actinic) keratosis in its course may involve the entire thickness of the epidermis. most dermatopathologists popularly but incorrectly equate “squamous cell carcinoma in-situ” and “full thickness atypia” with bowen’s disease (including bowenoid papulosis, erythroplasia of queyrat) and lack of full thickness atypia with solar (actinic) keratosis (including radiation keratosis, arsenical keratosis, actinic chelitis). interestingly, what is wrongly called “squamous cell carcinoma in situ” as a synonym for bowen’s disease is very different clinically and histopathologically from actinic keratosis. consider the following discussion: bowen’s disease, referred to conventionally and synonymously as squamous cell carcinoma in-situ, and bowenoid papulosis are as much very superficial squamous cell carcinomas as solar keratosis, radiation keratosis, and arsenical keratosis. the same abnormal keratocytes make up each of those conditions, only the silhouette of solar keratosis and its two analogues, bowen’s disease and bowenoid papulosis, are different; the cytopathologic attributes of all of them are the same. bowen’s disease, as a rule, appears in middle age or adulthood as a reddish plaque covered by adherent scale. when bowen’s disease occurs on the glanus penis, it is called erythroplasia of queyrat. cytopathologically, the cells that constitute bowen’s disease are indistinguishable from those that make up solar keratosis, but the architectural pattern of bowen’s disease, as assessed at low magnification of a conventional microscope, is different from that of solar keratosis. in bowen’s disease, the abnormal keratocytes form rectangles whereas in solar keratosis they form nubbins. in bowen’s disease, part of the thickness, much of the thickness, or the entire thickness of an epidermis that usually is thickened displays findings of squamous cell carcinoma, in contrast to solar keratosis in which only the lower part of the epidermis, that is, the nubbins, is affected in most instances but this may not be the case as noted earlier. moreover, in bowen’s disease, never are there suprabasal clefts that contain acantholytic, dyskeratotic cells whereas in solar keratosis that distinctive pattern is common. it is not surprising; therefore, that “pseudoglandular” squamous cell carcinoma in the skin represents an advanced stage in the progression of solar keratosis but never of bowen’s disease. integument: is synonymous with the entire skin. including both hair-bearing and hairless parts. intercellular: means between adjacent cells. it often is used in the phrases “intercellular bridges,” a synonym for review | dermatol pract concept 2014;4(4):1 5 desmosomes, and “intercellular edema,” which is synonymous with spongiosis. intercellular bridges, or spines, are seen to traverse intercellular spaces of epidermis and epithelial structures of adnexa in sections of skin visualized by conventional light microscopy. intradermal melanocytic nevus: a nevus in which nests or fascicles of melanocytes are positioned in the dermis wholly. the term instructs only about where the melanocytes of a particular nevus are stationed; it conveys nothing about the kind of nevus, i.e., clark’s, spitz’s, reed’s, miescher’s, or unna’s. intradermal vertical growth phase: (see radial growth phase) intraepidermal growth phase (lateral or horizontal growth phase: (see radial growth phase) intravasation: the entrance of foreign material into a blood vessel. this term is used by some, while others would use “intravascular.” invasion: through a microscope, no rational judgment can be made about “invasion” of neoplastic cells despite the insistence of histopathologists on making assessments of it. in fact, all such determinations are predicated entirely on thinking in post hoc ergo propter hoc fashion; first a histopathologist decides whether a neoplasm, for example of melanocytes, is benign or malignant and, if benign and involving both the epidermis and dermis, i.e., “classic” spitz’s nevus, the pronouncement is “not invasive,” but if the decision about the very same neoplasm changes to malignant, i.e., melanoma affecting both the epidermis and dermis, then the declaration becomes “invasive”: the “noninvasive” neoplasm suddenly becomes “invasive.” in the ultimate analysis, “noninvasive” and “invasive” are irrelevant to histopathological diagnosis; criteria for diagnoses turn on morphological findings in regard both to silhouette and to character of constituent cells and not at all to mystical and fictitious concepts such as “invasion.” in addition, “invasion” cannot be seen through a microscope. no movement of any kind can be seen on “fixed” tissue specimens. iris lesions: ring-shaped papules with a central purpuric punctum and a peripheral rim of dusky erythema, nearly specific for erythema multiforme. named for iris, the goddess of the rainbow in greek mythology, for whom the iris of the eye also was named. irregularly psoriasiform: denotes elongated rete ridges of uneven lengths, but with preservation of the normal undulating pattern between rete ridges and dermal papillae, as is seen in lichen simplex chronicus. this is strictly a descriptive term. isthmic portion of a hair follicle: the portion of a hair follicle that is a bridge between the infundibular epidermis above and the stem below, bounded by the entry of the duct of the sebaceous gland above and the site of desquamation of corneocytes of the inner sheath below. there is no inner sheath there, the disappearance if it being responsible for the very creation of it. isthmus: the isthmus is delimited by desquamation of corneocytes of the inner sheath below and the entrance of the sebaceous duct at the base of the infundibular epidermis above, isthmus means a narrow strip that connects two larger masses and, in cutaneous histology, the term is applied aptly to that short narrow strip of a follicle that is continuous with the stem of the follicle below and with the infundibular epidermis above. the isthmus is distinctive morphologically, fashioned as it is of epithelial cells arranged in a pattern unique to normal skin, except for that in follicles during the involutional phase of their cycle (catagen) when an appearance indistinguishable from that of isthmic epithelium is assumed by them. that epithelium, both of the isthmus and a follicle well advanced in catagen, is characterized by (1) a basal layer, (2) a spinous zone that is not truly “spinous” because intercellular “spines” are barely detectable between cells replete with pink cytoplasm, (3) absence of a granular zone, and (4) a prominent, brightly eosinophilic cornified layer whose cells are arranged compact and the surface of which is decorated by corrugations. the isthmus, which is the uppermost part of the follicle, lacks an inner sheath, but is a conduit for a hair en route from its origin as matrical cells in a bulb to the ostium of the infundibular epidermis and beyond it. bulges from the lower half of the isthmus and the uppermost part of the stem are protrusions of the follicle to which muscles of hair erection are tethered by a tendon of fibrous tissue. another important anatomic boundary alluded to previously is that marked by the entry of a sebaceous duct; that site demarcates the isthmus from the infundibular epidermis above. the isthmus alone forms the permanent “upper” segment of the hair follicle, the infundibulum being part of the epidermis. isthmus-catagen cyst: is a cyst that occurs nearly always on a scalp and is lined by epithelium just like that at the isthmus of a normal follicle and that of a follicle well advanced in catagen. the name “isthmus-catagen cyst” is in synchrony with a method for naming cysts according to the normal epithelial structure of adnexa that the lining of the cyst most closely resembles, i.e., infundibular cyst, apocrine gland cyst. synonyms for isthmus-catagen cyst are pilar cyst and tricholemmal cyst. “pilar” means “hair,” yet these cysts are devoid of hair. tricholemmal refers to the entire outer sheath as it courses from the isthmus above through the stem to the bulb below, yet the lining of these cysts resembles only 6 review | dermatol pract concept 2014;4(4):1 a discrete part of the outer sheath, to wit, that at the isthmus and that at the base of a follicle advanced in catagen. – j – jentigo: refers to a combination of simple lentigo and junctional melanocytic nevus. its use now is passé. each entity can be named accordingly. jigsaw puzzle pattern: describes resemblance vaguely to a jigsaw puzzle completed, that by virtue of proximity close of aggregations of epithelial cells of a proliferation benign, as occurs in cylindroma, but also at times in trichoblastoma of the type large nodular and in sebaceoma. junctional activity: a term introduced in the 1940s by arthur allen, but that lacks cogency because it pertains to a dynamic which cannot be visualized through a microscope, namely, activity of cells positioned mostly at the dermoepidermal junction. allen believed that those cells, which in his view eventually were to become ones of melanoma, derived from epidermal keratocytes, an idea that long have been discredited. junctional melanocytic nevus: a melanocytic nevus in which nests or fascicles of melanocytes are confined to the epidermis, especially to the dermoepidermal junction but the -term communicates nothing about the particular kind of nevus, i.e., clark’s, “spitz’s,” or “reed’s,” only about where histologically aggregations of melanocytes are situated. juvenile melanoma: the term introduced by sophie spitz for a melanoma in children that has come to be proven benign and now is known as “classic” spitz’s nevus. spitz insisted in her publication seminal of 1948 that by melanoma she meant malignant melanoma and she reiterated that in publications subsequent, only to acknowledge benignancy of it 3 years prior to her death in 1956. actually in this article (according to ackerman et al. “spitz’s nevus”: reassessment critical, revision radical. new york: ardor scribendi, ltd., 2007) sophie spitz was dealing with two different nevi, not just one. one was a “classic” spitz’s nevus and the second was a combined congenital nevus with spitz’s cells and a third was what she called “spindle cell tumor.” – k – karyolysis: disappearance of nuclei from cells during the process of cell death. karyolysis (ghosts of nuclei), karyorrhexis (fragmentation of nuclei), and pyknosis (shrinkage and darkening of nuclei) are the three cardinal signs of necrosis. karyolysis may be observed whenever necrosis occurs in the skin, i.e., ghosts of nuclei of severely ballooned keratocytes in general and ghosts of multinucleate epithelial giant cells in lesions induced by herpes virus, as one example, in particular. karyolysis also may be noted in neoplastic diseases, i.e., “shadow” cells of pilomatricoma. the “shadows” referred to in that later benign neoplasm of follicular matrix cells actually represent ghosts of nuclei of cornified cells that fail in their attempt to produce a normal hair. karyolysis is thought to result from progressive dissolution of chromatin as a consequence of the hydrolytic action of the dna of lysosomes. karyorrhexis: dot-like debris of nuclei, know also as nuclear “dust,” one of a triad of pivotal signs in nuclei, cells that are necrotic, namely, karyorrhexis, karyolysis, and pyknosis of cells that are necrotic. a synonym for karyorrhexis of white blood cells is leukocytoclasis, as is seen in leukocytoclastic vasculitis and in a host of other conditions as unrelated to one another as sweet’s syndrome and bullous lupus erythematosus. because apoptosis is characterized by karyorrhexis and pyknosis, it qualifies as a type of necrosis. karyorrhexis of lymphocytes is common in the subcutaneous fat of lupus profundus and karyorrhexis of lymphocytes ingested subsequently by histiocytes is known as “tingible bodies,” as occurs in some examples of lymphocytoma cutis. karyorrhexis of neoplastic lymphocytes occurs in subcutaneous t-cell lymphoma, the macrophages that gobble up the debris being dubbed beanbag cells. keratin: consists of a group of 25 to 30 water-soluble, cytoskeletal proteins that form filaments 10 nm (intermediate size) in diameter. these filaments are characterized by their molecular weights (range of 40 to 70 kd) and their composition, namely, two types of keratin, one relatively larger and more basic, and the other smaller and more acidic. keratins although related to one another biologically, are different from each other immunologically. they are found in all cutaneous epithelia and in the cornified layer of the epidermis. keratins account for about 85% of the cellular protein. keratins also are present in eccrine glands, apocrine glands, and sebaceous glands and their respective ducts. keratins are found, too, in the epithelium of hair follicles and nail units. keratins in hair and nails are considered to be “hard,” characterized as they are by lack of formation of keratohyaline granules and by higher content of sulfhydryl. all other keratins are considered to be “soft.” histologists in the past used the term “keratin layer” as a synonym for the cornified layer of the epidermis, a use that is imprecise because it is incomplete. keratocyte: an epithelial cell of epidermal surface and infundibular epithelium, including basal, spinous, granular, and cornified layers, and of neoplasms made up of spinous cells, such as the benign pale-cell acanthoma and the malignant squamous-cell carcinoma. in a generic sense, all cells that contain keratin are keratocytes, but in actuality, the term has review | dermatol pract concept 2014;4(4):1 7 a more circumscribed meaning. conventionally, the cells are called keratinocytes, but that is as wrong semantically as melaninocytes. the greek root is “kerato” denoting horn. however, despite the above “keratinocyte” is still used by most. keratogenous zone: refers to the zone in the lower segment of a follicle between noncornified and fully cornified elements, whose upper border is where the roof of a bulb meets the base of a stem, a boundary known also an adamson’s fringe (a-fringe). keratohyaline: refers to granules of different sizes and shapes that appear purple in sections stained by hematoxylin and eosin, and that are situated in the granular zone of the surface epidermis; the infundibular epidermis, and the sebaceous duct. products of keratohyaline granules are essential to normal cornification of those epithelial structures. an increased quantity of abnormal keratohyaline granules is found in a variety of diseases (i.e., in the infundibula of verrucae vulgaris, lichen planopilaris, and prurigo nodularis). keratohyaline granules: are deeply basophilic large granules found within spinous cells as they proceed to complete cornification in surface and infundibular epidermis and sebaceous duct. keratosis: refers to non-inflammatory hyperplasias and benign or malignant proliferations typified clinically and histopathologically by hyperkeratosis, i.e., orthokeratosis, parakeratosis, or both. the stereotypical examples of keratoses are verruca vulgaris (hyperplasia), seborrheic keratosis (benign neoplasm), and solar keratosis (malignant neoplasm). a lichen planus-like keratosis is merely a seborrheic keratosis in the process of undergoing regression secondary to the effects upon it of a band-like infiltrate of lymphocytes. koebner phenomenon: known also as isomorphic phenomenon, the induction by various types of trauma of lesions that are indistinguishable from lesions of the same disease that developed ab initio (from the beginning). the event is particularly common in psoriasis and lichen planus. it is to be differentiated from autoinoculation in infectious diseases, such as occurs in verrucae vulgaris and molluscum contagiosum. – l – labyrinthean: is a pattern resembling the appearance of a labyrinth, i.e., a place constructed of intricate passageways and blind alleys, compels extremely in arrangement. a labyrinthean pattern is encountered sometimes in sebaceomas and rarely in trichoblastic (basal cell) carcinoma. lamellar fibroplasia: collagen bundles aligned parallel to one another and seated just beneath nests of melanocytes lodged at the base of epidermal rete ridges that often are long and thin. the findings may be observed in association with any proliferation of melanocytes at the dermoepidermal junction of an epidermis that exhibits long, rete ridges, as is the situation in simple lentigines, in junctional and compound nevi of certain kinds, and in some melanomas. clark and co-workers consistently contrasted “lamellar fibroplasia” with “concentric eosinophilic fibroplasia,” but, in actuality, the two are merely different names for bundles of collagen continous in array lamellar. lamina densa: synonym for basal lamina. when the interface between dermis and an epithelium is studied by electron microscopy, the findings are as follows: within a basal keratocyte, tonofilaments are attached to a hemidesmosome that parallels the cytoplasmic leaflet of the plasma membrane. the lamina lucida, an electron-lucent zone, separates the lower border of a plasma membrane from the electron-dense basal lamina densa (basal lamina). within the lamina lucida, a sub-basal dense plaque is situated beneath a hemidesmosome and is traversed by fine anchoring filaments that extend in perpendicular fashion from the plasma membrane to mesh with the lamina densa. cross-banded anchoring fibrils and bundles of dermal microfibrils extend downward from the lamina densa, where they interweave with type iii collagen fibers in the papillary dermis. laminated orthokeratosis: describes a distinctive arrangement of corneocytes in which thin plates lie parallel to one another. the configuration is met within the stratum corneum of conditions such as ichthyosis vulgaris and x-linked ichthyosis, thin plates of corneocytes in those conditions being disposed parallel to the skin surface, as well as to one another. laminated orthokeratosis is found, too, in a type of epidermal cyst, i.e., an infundibular cyst, and in a “pseudocyst,” i.e., an infundibular tunnel in a lesion of seborrheic keratosis. infundibular hyperkeratosis is the sine qua non for diagnosis of keratosis pilaris and the variant of it, lichen spinulosus, and is observed in diseases encountered not uncommonly, such as pityriasis rubra pilaris, lichen planopilaris, and discoid lupus erythematosus, and in ones that are encountered only rarely, such as scurvy, phrynoderma, and “avitaminosis” secondary to severe alcoholism. hyperkeratosis of the upper part of eccrine ducts occurs in diseases such as lichen sclerosis et atrophicus and in milia that form after reeepithelialization has occurred beneath some subepidermal blistering diseases, i.e., porphyria cutanea tarda and bullous pemphigoid. most milia, however, represent tiny infundibular cysts. (see hyperkeratosis, basket woven orthokeratosis, compact orthokeratosis) langer’s lines: lines along which surgical incisions gape or fall together; depending on whether they are made across or parallel; charted by langer, who pierced the skin of cadavers with an awl. 8 review | dermatol pract concept 2014;4(4):1 language: the method of human communication either spoken or written consisting of the use of words in a structured and conventional way. leukocytoclasis: fragmentation of leukocytes, i.e., karyorrhexis, with formation of nuclear “dust.” the word usually refers to nuclei of polymorphonuclear leukocytes that become shattered into dust like particles in a variety of circumstances. nuclei of lymphocytes or of any other inflammatory or neoplastic cell also may undergo karyorrhexis. nuclear “dust” of neutrophils is the sine qua non for diagnosis of leukocytoclastic vasculitis, but it may be noted in other conditions as different as dermatitis herpetiformis and pyoderma gangrenosum. the stereotypic situation for appearance of nuclear “dust” of lymphocytes is lupus profundus, in which patchy lymphoplasmacytic infiltrates in lobules of the subcutaneous fat are accompanied by nuclear debris of lymphocytes in variable amount. tingible bodies in germinal centers of some expressions of lymphocytoma cutis represent nuclear “dust” of lymphocytes that has been ingested by macrophages. in short, if the meaning of the word “leukocytoclasis” is to be understood clearly, it must be modified always by “of neutrophils” or “of lymphocytes.” level of invasion: the depth of extension into the skin of a melanoma according to clark and his associates. they have defined five levels of extension. level i. melanocytes of melanoma confined to the epidermis. (melanoma in situ) level ii. melanocytes of a melanoma in the papillary dermis, but not the reticular dermis. level iii. melanocytes of a melanoma at the interface between the papillary and reticular dermis, filling the papillary dermis but not yet within the reticular dermis. level iv: melanocytes of a melanoma in the reticular dermis. level v. melanocytes of a melanoma in the subcutaneous fat. levels of invasion are approximations of thicknesses of melanomas, and because seriousness of prognosis tends to vary nearly directly with thickness, levels of invasion have some validity as prognostic indices. in practice, however, determination of level is often difficult, particularly in anatomic areas where it is difficult to discern the interface between papillary and reticular dermis. moreover, there is poor agreement in assessment of levels of invasion by pathologists in examination of given melanomas. measurement of thickness of a melanoma by means of an ocular micrometer is more precise and repeatable. it therefore has supplanted determination of levels as a guide to prognosis. someday it to will probably “disappear.” it is only a “number” and does not take into account the “host” response and many other factors that determine the prognosis. lichenification: thickening of the skin secondary to rubbing forcefully for many months or years. the condition is typified clinically by accentuation of normal skin markings, hyperpigmentation, and induration of variable extent, a constellation of findings designated lichen simplex chronicus. histopathologically, the surface epidermis of lichenified skin is compactly orthokeratotic, hypergranulotic, and unevenly acanthotic in psoriasiform fashion. the infundibular epidermis and upper part of the eccrine duct within the dermis sometimes show evidences of proliferation in pseudocarcinomatous fashion, the papillary dermis being thickened markedly by coarse bundles of collagen arranged in vertical streaks aligned parallel to rete ridges and perpendicular to the skin surface. another expression of lichenification, one seen particularly on the scalp, genitalia, and mucous membranes, is characterized by compact orthokeratosis and hypergranulosis so extensive that at first glance the epidermis resembles that of normal palm or sole. in that circumstances in which the epidermis, at first blush, looks just like that of normal volar skin, a clue to the correct diagnosis of lichen simplex chronicus is the presence of folliculosebaceous units (“hairy palm sign”). parenthically, folliculosebaceous units are not found on volar skin except in bulldogs. (ackerman et al,.histologic diagnosis of inflammatory skin diseases, 3rd ed. new york: ardor scribendi, ltd., 2005.) other classic examples of lichenification besides plaques of lichen simplex chronicus are papules and nodules of prurigo nodularis, the former (lichen simplex chronicus) brought into being by rubbing the skin, usually with knuckles, to and fro, in contrast to the latter (prurigo nodularis), which develops consequent to rubbing for a long time and with the ball of a first finger, a particular discrete site. should prurigo nodularis become eroded or ulcerated following scratching energetically, the condition then is named picker’s nodule. lichenification can be produced in skin that is normal clinically or it can be imposed on a variety of chronic pruritic dermatitides, such as allergic contact dermatitis or nummular dermatitis, and on neoplastic processes, such as, mycosis fungoides and leukemia cutis. all lesions of atopic dermatitis are the result of the effects of rubbing (lichenification) and scratching (erosions and ulcers); none of those lesions “erupt.” lichenoid: clinically, flat-topped papules and histopathologically, a band like infiltrate, usually of lymphocytes mostly, in a papillary dermis thickened by it. nearly always, lichenoid infiltrates of an inflammatory process consist of lymphocytes, as in lichen planus, lichenoid discoid lupus erythematosus, and lichenoid purpura of gougerot and blum. lymphocytes of a neoplastic process, to wit, mycosis fungoides in the plaque stage of the disease, also tend to be arrayed in band like fashion. as a rule, lichenoid infiltrates of inflammatory diseases obscure the dermoepidermal interreview | dermatol pract concept 2014;4(4):1 9 face where they are accompanied by vacuolar alternation and necrotic keratocytes, but that is not the case invariably, i.e., in some examples of the lichenoid purpura of gougerot and blum where the band like infiltrate of lymphocytes may not impinge on the epidermis. lichenoid infiltrates may be diffuse, i.e., across the entire expanse of a lesion, as in lichen planus or lichenoid purpura, or focal (patchy), i.e., confined to one or more spots along the front of a lesion, as in lichen nitidus or in one expression of lichen striatus. lichen nitidus exemplifies the focal nature of some lichenoid dermatitides and illustrates that a single lichenoid process may be made up mostly of lymphocytes (at an early stage) and mostly of epithelioid histiocytes (at a late stage), at one period the two types of inflammatory cells being present in equal measure, concurrently. a band like infiltrate of leukocytes in a thickened papillary dermis is responsible for the appearance clinically of a papule whose surface is flat, the prime example of that being the basic lesion of lichen planus. not all diseases marked by flat-topped papules, however, exhibit band like infiltrates in the papillary dermis, as is the case in longstanding lesions of lichen sclerosis et atrophicus, lichen simplex chronicus, and lichen myxedematosus. lipochrome: is an insoluble pigment composed of polymers of lipids and phosolipids in association with protein. histopathologically, lipochrome is a yellow-brown, finely granular, intracytoplasmic pigment. it represents the indigestible residues of autophagic vacuoles formed during long-standing injury to cells or aging of them, and forms as a result of damage by free radicals and by perodixation of polyunsaturated lipid. lipochrome is synonymous with “lipofuscin,” “carotid,” and “wear and tear” pigment. lobular panniculitis: an inflammatory process in the panniculus adiposis recognizable at scanning magnification of a conventional microscope, in which the infiltrate of inflammatory cells is situated mostly in the lobules rather than in the septa. lobule: denotes a discrete unit of cells bounded by fibrous tissue. lobules in the subcutaneous fat are rectangular, comprised nearly entirely of adipocytes, and bounded by fibrous septa (trabeculae). lobules of sebaceous, eccrine, and apocrine units consist of glandular segments surrounded by distinctive stroma, i.e., (sebaceous lobule). the epithelial units and nonepithelial components of cutaneous adnexal epithelia form a recognizable morphologic and functional unit. the term “lobule” also is applied to each of many similar-appearing units that make up entire neoplasms considered to be multilobular, i.e., tubular adenoma and cylindroma. lumen: designates a channel within a tubule or within an endothelium. in normal skin, there are three distinct types of lumen within adnexal epithelium, namely, those of eccrine glands and ducts, apocrine glands and ducts, and sebaceous ducts. normal apocrine glands are recognizable by distinctive signs of apocrine secretion, eccrine glands by presence of pale and dark cells, and sebaceous ducts by a thin, crenulated cornified layer. ducts of apocrine and eccrine glands cannot be distinguished from one another morphologically. the presence of lumina within an epithelial proliferation indicates that cells around them have differentiated to make (glandular) or to transport (ductal) secretory or excretory products. most lumina in skin, however, are vascular channels lined by endothelial cells. lymphoid follicles: collections of tightly packed lymphoid cells that form oval to spherical nodules. they are called primary follicles when they are composed of small lymphocytes and secondary follicles when germinal centers form after primary follicles have been stimulated by antigen. dermatology: practical and conceptual research | dermatol pract concept 2014;4(4):18 81 dermatology practical & conceptual www.derm101.com introduction although skin is the largest organ of the body there are no standardized reproducible methods for assessing skin function or severity of skin disease [1]. during recent years several scoring systems have been introduced to help clinical practice and clinical research on many skin diseases, which mainly compare inter-individual differences in disease activity [1,2]. the most known dermatologic tool is the psoriasis area severity index (pasi), which is currently the gold standard score for the assessment of severity of psoriasis. it combines the severity (erythema, induration and desquamation) and percentage of affected area [3,4]. a free online application helping physicians and patients in the computation of the pasi is available as well [5]. vitiligo is an acquired depigmentary disorder characterized by the loss of functioning epidermal melanocytes [6] it would be important to have accurate measurement of the size of vitiligo surface areas to assess treatment efficacy [1,7]. recently some new score systems were proposed. the vitiligo european task force (vetf) was proposed a system combining analysis of extent, stage of disease and disease progression. the vitiligo area scoring index (vasi) is another score system offering accurate measures of disease severity indexes and treatment evaluation criteria [1,8,9]. its name is conceptually derived   from pasi score. nevertheless both scores are not comprehensive, have some limitations: they do vitiligo extent tensity index (veti) score: a new definition, assessment and treatment evaluation criteria in vitiligo amir feily1 1 department of dermatology, jahrom university of medical sciences, jahrom, iran keywords: vitiligo, score, assessment criteria citation: feily a. vitiligo extent tensity index (veti) score: a new definition, assessment and treatment evaluation criteria in vitiligo. dermatol pract concept. 2014;4(4):18. http://dx.doi.org/10.5826/dpc.0404a18 received: july 22, 2014; accepted: august 23, 2014; published: october 31, 2014 copyright: ©2014 feily. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: amir feily, md, department of dermatology, honari clinic, motahari street, jahrom, iran. tel. +00989177204638. email: dr.feily@yahoo.com although skin is the largest organ of the body, there are no standardized reproducible methods for assessing severity of many skin diseases. due to lack of consensus, methods of assessment and inexistence of precise scoring system, there is no application for vitiligo estimation in real practice. in this paper the author describes veti score as a new treatment evaluation criteria and severity assessment method for vitiligo. this new tool, as does the pasi score in psoriasis, may be able to produce a constant and reproducible number and to help clinical research on vitiligo patients. additionally it has a potential to be a source of any computed application for researchers working on vitiligo patients. abstract http://en.wikipedia.org/wiki/psoriasis_area_severity_index http://en.wikipedia.org/wiki/erythema http://en.wikipedia.org/wiki/induration http://en.wikipedia.org/wiki/induration mailto:dr.feily@yahoo.com 82 research | dermatol pract concept 2014;4(4):18 score based on patients’ opinion divided in 6 stages: grading is as follows. vida score: • +4: activity of 6 weeks or less period • +3: activity of 6 weeks to 3 months • +2: activity of 3 to 6 months • +1: activity of 6 to12 months • 0: stable at least for 1 year and • -1: stable at least for 1 year with spontaneous repigmentation lower vida scores indicate less activity [10]. potential repigmentation index (pri) benzekari et al. in 2013 demonstrated a new index (pri) for prediction of potential repigmentation in non-segmental vitiligo and showed that the patients with higher pri were more prone to obtain higher pigmentation [8]. new system for assessment of vitiligo: vitiligo extent tensity index (veti) score the veti score is a new system that proposes to measure the extent of vitiligo by a numerical score and combines analysis of extensity and severity of vitiligo and produce a constant and reproducible number like pasi. the percentage of extension involvement (p) evaluates using the rule of nines (figure 1) not produce a constant total number with discrepancy and inter-individual variations [1,7,8]. reasonably it would make sense to combine the vasi with the vetf system and make a system much more similar to pasi score with constant total number and less inter-individual differences [8]. the purpose of this manuscript was to combine vetf and vasi system and develop a practical and standardized scoring system similar to pasi score with the aim to assess the treatment response and evaluate changes in affected area. additionally it has a potential to be a source of any computed application for researchers who work on vitiligo patients. scores designed for the assessment of vitiligo: vitiligo european task force (vetf) vetf is a system that incorporates three components of vitiligo: extent, stage and progression of disease [3]. extent is based on rule of nines [6]. staging is based on cutaneous and hair pigmentation in vitiligo patches and divided in three stages: • stage 0: normal pigmentation • stage 1: incomplete depigmentation • stage 2: complete depigmentation (hair whitening less than 30% (<30%) • stage 3: complete depigmentation plus hair whitening more than 30% (>30%) “spreading” in vetf is (+1: progressive; 0: stable; −1: regressive) [4]. vitiligo area severity index (vasi) its name is an adoption from pasi score in psoriasis. the percentage of vitiligo involvement is calculated in terms of hand units. one hand unit is approximately equivalent to 1% of the total body surface area. the degree of pigmentation is estimated to the nearest of one of the following percentages: 100% complete depigmentation, no pigment is present; 90% specks of pigment present; 75% depigmented area exceeds the pigmented area; 50% pigmented and depigmented areas are equal; 25% pigmented area exceeds depigmented area; and 10% only specks of depigmentation present [1,3]. the vasi for each body region is determined by the product of the area of vitiligo in hand units and the extent of depigmentation within each hand unit measured patch. total body vasi = s all body sites [hand units] ´ [residual depigmentation] [1]. vitiligo disease activity score (vida) vida score is a six-point scale for evaluating vitiligo activity. individuals own opinion is the base in vida score. vida figure 1. rule of nines in burn assessment. (copyright: ©2014 feily.) research | dermatol pract concept 2014;4(4):18 83 already used in burn assessment [11]. five sites affected, head (h), upper limbs (u), trunk (t) and lower limbs (l) and genitalia (g) are separately scored by using five stages of disease tensity (t): • stage 0: normal skin • stage 1: hypopigmentation (including trichrome and homogeneous lighter pigmentation) (figure 2) • stage 2: complete depigmentation with black hair and with perifollicular pigmentation (figure 3) • stage 3: complete depigmentation with black hair and without perifollicular pigmentation (figure 4) • stage 4: complete depigmentation with compound of white and black hair with/without perifollicular pigmentation (figure 5) • stage 5: complete depigmentation plus significant hair whitening (figure 6) figure 2. hypopigmentation (including trichrome, and homogeneous lighter pigmentation). (copyright: ©2014 feily.) figure 3. complete depigmentation with black hair and perifollicular pigmentation. (copyright: ©2014 feily.) figure 4. complete depigmentation with black hair and without perifollicular pigmentation. (copyright: ©2014 feily.) figure 5. complete depigmentation with compound of white and black hair with/without perifollicular pigmentation. (copyright: ©2014 feily. figure 6. complete depigmentation plus significant hair whitening. the area where hair does not exist normally, as in the extremities, is very resistant to treatment and placed in grade 5. (copyright: ©2014 feily.) 84 research | dermatol pract concept 2014;4(4):18 combine the vasi, vetf and some parts of the pri systems and invent a system much more similar to the pasi score with constant total number and less inter-individual differences [10]. veti score is a new treatment evaluation criteria and assessment method for vitiligo which can be easily handled in clinical practice. although it is difficult to compare different modalities in vitiligo [14], we think veti score is more like the pasi score for psoriasis, and unlike other vitiligo scores, produces a constant and reproducible number and would greatly help clinical research on vitiligo patients. notably, it has the potential to be a source of any computed application for researchers who work on vitiligo patients. i hope advantages of this tool to be confirmed by future observations. references 1. bhor u, pande s. scoring systems in dermatology. indian j dermatol venereol leprol. 2006;72:315-21. 2. pfütze m, niedermeier a, hertl m, eming r. introducing a novel autoimmune bullous skin disorder intensity score (absis) in pemphigus. eur j dermatol. 2007;17:4-11. 3. hamzavi i, jain h, mclean d, shapiro j, zeng h, lui h. parametric modeling of narrowband uv-b phototherapy for vitiligo, using a novel quantitative tool: the vitiligo area scoring index. arch dermatol. 2004;140:677–683. 4. taïeb a, picardo m. the definition and assessment of vitiligo: a consensus report of the vitiligo european task force. pigment cell res. 2007;20:27–35. 5. pasi calculator. http://pasi.corti.li/ psoriasis area severity index (pasi) calculator (1.7.1). accessed december 30, 2013) 6. wong pc, leung yy, li ek, tam ls. measuring disease activity in psoriatic arthritis. int j rheumatol. 2012;2012:839425. 7. fredriksson t, pettersson u. severe psoriasis—oral therapy with a new retinoid. dermatologica, 1978, 157:238-44. 8. benzekri l, ezzedine k, gauthier y. vitiligo potential repigmentation index: a simple clinical score that might predict the ability of vitiligo lesions to repigment under therapy. br j dermatol. 2013;168:1143-6. 9. aydin f, senturk n, sahin b, et al. a practical method for the estimation of vitiligo surface area: a comparison between the point counting and digital planimetry techniques. eur j dermatol. 2007;17:30-2. 10. njoo md, das pk, bos jd, westerhof w. association of the köbner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. arch dermatol. 1999;135:407-13. 11. wachtel tl, berry cc, wachtel ee, frank ha. the inter-rater reliability of estimating the size of burns from various burn area chart drawings. burns. 2000; 26:156-70. 12. feily a, baktash d, mohebbipour a, feily a. potential advantages of simvastatin as a novel anti-vitiligo arsenal. eur rev med pharmacol sci. 2013;17:1982-3. 13. feily a, namazi mr. silymarin as a potential novel addition to the limited anti-vitiligo weaponry: an untested hypothesis. int j clin pharmacol ther. 2011;49:467-8. 14. kawakami t, hashimoto t. disease severity indexes and treatment evaluation criteria in vitiligo. dermatol res pract. 2011;2011:750342. notably an area where hair does not exist normally, like the extremities, is very resistant to treatment and placed in grade five. the total body veti is calculated using the following formula that includes contributions from all body regions: veti score: (percentage of head involvement × grade of tensity) + (percentage of trunk involvement × grade of tensity) 4+ (percentage of upper limbs involvement × grade of tensity) 2+ (percentage of lower limbs involvement × grade of tensity) 4+ (percentage of genitalia involvement × grade of tensity) 0.1 the coefficients reported in this formula are based on percent of skin surface by the rule of nines. accordingly the coefficient of head is 1 (9:9=1), trunk and lower limb is 4 (36:9=4), upper limb is 2 (18:9=2) and genitalia is almost 0.1(1:9= 0.1). percentage of involvement: p tensity: t veti: (ph×th)+(pt×tt)4+(pu×tu)2+(pl×tl)4+ (pg×tg)0.1 5+20+10+20+0.5=55.5 the maximum score of veti is 55.5. for example, in figure 3 if just the anterior of the body is involved, the veti is calculated as follows: veti: (0× 0) + (0.25 × 2)4+ (0×0)2+ (0×0)4+ (0×0) 0.1 = 2 discussion vitiligo is an acquired depigmentary disorder characterized by the loss of functioning epidermal melanocytes [12] and affects more than 0.5–1% of the worldwide population with devastating psychological and social consequences [13,14]. current lack of consensus on methods of assessment of this conundrum and inexistence of precise scoring to the extent that pasi does makes it principally impossible to evaluate the efficacy of new drugs or perform meta-analyses on the results of different studies of the same treatment [1,14]. several scores have been proposed to surmount this problem and offer more accurate measures of disease severity indexes and inter-individual variations. among the above scores designed for assessment of vitiligo, vasi provides a relatively simple method analogous to the psoriasis area severity index (pasi) and vitiligo european task force (vetf) is a more complex system that incorporates three components of vitiligo: extent, stage and progression of disease, but these scores have some limitations with discrepancy in results and, unlike the pasi score do not make a constant total number [1,9,14]. regarding the other two scores, it should be pointed out that the vida score is based on the patient’s opinion [10] resulting in eventual discrepancy as a result. pri is a predictive index for repigmentation in non-segmental vitiligo [8] not a numerical index for measuring the extent and severity of vitiligo. since the vida score is based on patient opinion, it makes sense to http://www.ncbi.nlm.nih.gov/pubmed?term=pf%c3%bctze%20m%5bauthor%5d&cauthor=true&cauthor_uid=17324820 http://www.ncbi.nlm.nih.gov/pubmed?term=niedermeier%20a%5bauthor%5d&cauthor=true&cauthor_uid=17324820 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http://www.ncbi.nlm.nih.gov/pubmed?term=kawakami%20t%5bauthor%5d&cauthor=true&cauthor_uid=21747840 http://www.ncbi.nlm.nih.gov/pubmed?term=hashimoto http://www.ncbi.nlm.nih.gov/pubmed/?term=disease+severity+indexes+and+treatment+evaluation+criteria+in+vitiligo untitled research | dermatol pract concept 2015;5(3):10 41 dermatology practical & conceptual www.derm101.com introduction hair restoration is a safe procedure and most of its associated complications are preventable; however, they usually arise from variables that are directly controlled by the surgeon and/or the patient. donor site adverse reactions include: scarring, keloid formation, wound dehiscence, necrosis, donor site depletion, hypoesthesia, neuralgia, arteriovenous fistula formation, telogen effluvium, infection, hiccups, pyogenic granuloma formation, and hematoma formaton [1]. recipient site adverse reactions include poor hairline restoration, hair color mismatch, chronic folliculitis, in-grown hairs, cysts, and necrosis [1,2]. recipient area necrosis is a rare but dangerous complication that arises when an increased number of recipient grafts are utilized and de-vascularization of the scalp occurs as a result of dense splitting of recipient skin that results in large wound areas. although in the literature it has been mentioned that this complication is rare [1], our survey in iran determined that many hair transplant centers face this complication but do not officially report these cases. accordfeily’s method as new mode of hair grafting in prevention of scalp necrosis even in dense hair transplantation amir feily1, fatemeh moeineddin2 1 department of dermatology, jahrom university of medical sciences, jahrom, iran 2 skin and stem cell research center, tehran university of medical sciences, tehran, iran key words: scalp necrosis, hair grafting, dense hair transplantation, feily’s method citation: feily a, moeineddin f. feily’s method as a new mode of hair grafting in prevention of scalp necrosis even in dense hair transplantation dermatol pract concept 2015;5(3):10. doi: 10.5826/dpc.0503a10 received: february 11, 2015; accepted: april 20, 2015; published: july 31, 2015 copyright: ©2015 feily et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this study was supported by a grant from jahrom university of medical sciences, jahrom, iran. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: amir feily, md, department of dermatology, honari clinic, motahari street, jahrom, iran. email: dr.feily@ yahoo.com hair restoration is a safe procedure and most of its associated complications are preventable by the surgeon and/or the patient. recipient area necrosis is rare but arises when an increased number of recipient grafts are utilized and de-vascularization of the scalp occurs. the aim of this study was to investigate and compare all cases and pictures reported in main search engines and iranian centers of hair transplant to find the dangerous zone of necrosis and to provide a new method for prevention of necrosis. pictorial analysis of this study revealed that the majority of necrosis (14 of 18) occurs in central region of the scalp and is inclined, particularly, to the right parietal aspect of the scalp. accordingly, a case series was done and a new method for prevention of scalp necrosis even in dense packing transplantation was discussed. abstract 42 research | dermatol pract concept 2015;5(3):10 part 1: determining the danger zone the “danger zone” of scalp necrosis is the area on the scalp most vulnerable to necrosis. interestingly there were many unofficial pictures of recipient scalp necrosis on google and from iranian hair transplant centers; however, we could not find even one formal case report in literature. accordingly, we decided to determine the “danger zone” based on informal reported pictures from google and from iranian hair transplant centers. an extensive literature and google search was carried out to find out the likely sites of recipient area necrosis [7]. eighteen pictures were found and examined, but due to copyright restrictions, we only present pictures from the iranian hair transplant centers in this manuscript (figures 1-9). we drew a straight line on all of the pictures from the nose to the vertex and decided to draw a line from the back of one ear to the back of the other ear allowing the scalp to be divided into four equal regions. due to poor picture quality, we could not draw the second line on most pictures. necrosis was compared in all of the identified pictures in which vertical division of scalp from the nose to the vertex of the scalp was conducted. pictorial analysis revealed that most of the necrosis (14 of 18) occurred in central region of the scalp and was inclined to the right parietal region of the scalp (figures 1-7 and 10). from others two cases occurred in central scalp without any inclination (figure 8) and two cases occurred in central of scalp and was inclined to the left parietal region (figure 9). because mean velocities of blood flow do not differ significantly between the left and right hemisphere [8], it is not clear why the most of recipient scalp necrosis in our survey occurred on the right part of the central scalp region. part 2 we noticed that after slitting, some patients were troubled by dark areas on some parts of the recipient site. we hypothesize that the darkness can be a predisposing factor for scalp necrosis and may outline potential danger zones. based on this information, a prospective case series was designed in which 16 consecutive patients undergoing dense slit hair transplant procedures were troubled by dark areas on the recipient site after slitting. on the first day all 16 patients underwent dense slitting in the recipient zone resulting in dark areas on the some part of scalp. in patient 1 we put dense grafts in one dark zone and zero grafts in the other dark zone (figure 11 a-c). after one day necrosis was evident in the region where grafts were placed but no necrosis in the non-transplanted region (figure 12). of note, transplantation in patient 1 composed of slitting and hair grafting in both dangerous and non-dangerous regions on the first day with subsequent engrafting of the remaining slits on the second day (figures 11, 12). however, in the other 15 patients, ingly, after describing the standard methods of prevention of scalp skin necrosis used so far, we decided to locate these cases from the literature and iranian hair transplant centers to determine the dangerous zone in an effort to develop a method for prevention of scalp necrosis in dense packing transplantation. predisposing factors of skin necrosis: recipient-site necrosis is a result of vascular compromise. predisposing influence composed of patient’s factors and technical factors are as follows: • patient’s factors: smoking, atrophic skin damage, diabetes mellitus, scarring of the recipient site or a history of scalp surgery [3]. • technical factors: dense packing, megasessions, large openings, use of solutions with high epinephrine concentration, and deep recipient incisions [3]. methods of hair grafting / hair transplantation techniques and the risk of the recipient site skin necrosis: • follicular unit transplantation (fut): the donor strip can be harvested with a knife, after the strip has been harvested, the gap can be closed either with staples or sutures. the grafts are placed into the recipient slits/holes using fine-angled forceps [4]. • follicular unit extraction (fue): fue is a type of hair transplantation in which the method of extraction is different but implantation is the same as fut. it is a sutureless method of hair restoration in which hair follicles are extracted from the back of the head under local anesthesia with the help of special micropunches that are then implanted in the bald area [5]. • automated fue hair transplantation or s.a.f.e.r [suction assisted follicular extraction and reimplantation]: the fue matic machine (medicamat; malakoff, france) is an automated hair transplant machine that seeks to assist the doctor in performing a hair transplant using the fue technique [5,6]. it claims a faster extraction rate of grafts in a limited time. however, there is greater pulling and twisting of grafts, which puts the graft at risk of damage, resulting in greater transection [5]. notably these techniques have almost the same graft insertion but with a different donor harvesting process, and all of them have the same risk of donor site necrosis according to the above-mentioned risk factors. material and methods our study was composed of two parts: 1. comparing all case reports in the literature, from search engines and from hair transplant centers in iran to determine the danger zone of the scalp. 2. performing a case series to identify a method to decrease scalp necrosis in dense packing transplantation. research | dermatol pract concept 2015;5(3):10 43 results pictorial analysis in part one of this study revealed that the majority of necrosis (14 of 18) occurred in the central region of the scalp and was inclined, particularly, to the right parietal aspect of the scalp. our experimental study determined transplantation on the first day composed of just slitting of the entire scalp and engraftment in the non-dangerous area in a horseshoe-shaped pattern in which the left arm was wider than the right with subsequent graft insertion of remaining slits on the second day (figures 13-19). figures 1-7. in the majority, necrosis occurred in the central region and was inclined to the right parietal region of the scalp. [copyright: ©2015 feily et al.] 1 2 3 4 5 7 figure 8. necrosis occurred in central region without any inclination. [copyright: ©2015 feily et al.] figure 9. necrosis occurred central of the scalp and was inclined to the left parietal region. [copyright: ©2015 feily et al.] figure 10. necrosis occurred in central region and is inclined to the right parietal region of the scalp. [copyright: ©2015 feily et al.] 6 44 research | dermatol pract concept 2015;5(3):10 a b c figure 11a-c. putting dense grafts in one dark zone and zero grafts in the other dark zone. we enhanced the dark area for better evaluation. [copyright: ©2015 feily et al.] a figure 12. after one day necrosis was evident in the region grafts were placed with no necrosis in the non-transplanted region. [copyright: ©2015 feily et al.] b figure 13. first day composed of just slitting of all of the scalp and engraftment in non-dangerous area in a horseshoe shape pattern in which the left arm was wider than the right and in the second day, grafts were placed on the remained slits. [copyright: ©2015 feily et al.] figure 14. first day composed of darkness after slitting and engraftment just in non-dangerous zone and letting the dark area to reperfusion at least for 24 hours. [copyright: ©2015 feily et al.] figure 15. every dark area fades after 24 hours. [copyright: ©2015 feily et al.] figure 16. first day composed of darkness after slitting and engraftment just in non-dangerous zone and letting the dark area to reperfusion at least for 24 hours. [copyright: ©2015 feily et al.] research | dermatol pract concept 2015;5(3):10 45 and secondary ischemia revealed that flap survival significantly decreased due to a decreased reperfusion time (the time between primary and secondary ischemia). a longer period of primary ischemia and/or decreased reperfusion time lowers the tolerance of that flap to subsequent ischemic insults and secondary ischemia [9]. based on this information, we could describe the ischemia timeline for the scalp in the hair transplant process. the process is composed of three phases: primary and secondary ischemia, and reperfusion time. dense slitting cause’s primary ischemia in the scalp, following which the scalp skin begins to reperfuse until engraftment. hair follicle insertion in the slits causes secondary ischemia due to an increased demand of blood. basically, slitting is primary ischemia, engraftment is secondary ischemia and the period of time in between these two phases of ischemia is the reperfusion time. we believe that by increasing the reperfusion time after slitting, the tolerance of scalp to secondary ischemia insult and ultimately necrosis would decrease (table 1). another that patient 1 had necrosis localized to the dark area that was grafted immediately following slitting without resultant necrosis in the dark area that was not grafted on the first day of transplantation (figure 12) interestingly there was no evidence of necrosis following engraftment on the remaining 15 patients with dark areas on the scalp after slitting, which was grafted in the dangerous zone on the second day and subsequent days after the procedure (figures 13-19). discussion to better elucidate the chain of events, we describe some facts regarding flaps that is connected to our commentary on scalp necrosis. with regard to free tissue transfer surgery, a major problem that surgeons face is the rescuing of a flap that is at risk of failing due to ischemic complications in the postoperative period (postoperative vascular compromise leading to secondary ischemia). a study performed on mouse skin flaps subjected to combinations of primary ischemia, reperfusion, figure 17. every dark area fades after 24 hours. [copyright: ©2015 feily et al.] figure 18. first day composed of darkness after slitting and engraftment only in non-dangerous zone and letting the dark area to reperfusion at least for 24 hours. [copyright: ©2015 feily et al.] figure 19. every dark area fades after 24 hours. [copyright: ©2015 feily et al.] table 1. summary of feily’s method [copyright: ©2015 feily et al.] 46 research | dermatol pract concept 2015;5(3):10 packing hair transplantation processes without any vascular compromise. acknowledgements: a very special thanks goes to my hair transplant team: ahmad and arezoo feily and lida daghigh for their efforts, support and participation in this study. references 1. salanitri s, goncalves aj, helene a jr, lopes fh. surgical complications in hair transplantation: a series of 533 procedures. aesthetic surg journal; 2009;29(1):72-6. 2. unger w, shapiro r, unger r, et al. hair transplantation. 5th ed. informa healthcare, 2011. 3. konior rj. complications to hair restoration surgery. facial plast surg clin north am. 2013 aug;21(3):505-20. 4. khanna m. hair transplantation surgery. indian j plast surg 2008;41(suppl):s56-63. 5. dua a, dua k. follicular unit extraction hair transplant. j cutan aesthet surg 2010;3(2):76-81. 6. rassman wr. new instruments for automation. hair transplant forum intl 2004;14:131. 7. google search. recipient area necrosis after hair transplant. https://www.google.com/search?q=recipient+area+necrosis+after +hair+transplant&biw=1366&bih=625&source=lnms&tbm=isc h&sa=x&ei=ykxvmhynollat7ugjgn&ved=0cayq_auoaq 8. lin tk, ryu s, hsu pw. interhemispheric comparisons of cerebral blood flow velocity changes during mental tasks with transcranial doppler sonography. j ultrasound med 2009;28(11):1487-92. 9. babajanian m, zhang wx, turk jb, et al. temporal factors affecting the secondary critical ischemia of normothermic experimental skin flaps. arch otolaryngol head neck surg 1991;117(12):13604. 10. angel mf, mellow cg, knight kr, o’brien bm. the effect of time of vascular island skin flap elevation on tolerance to warm ischemia. ann plast surg 1989;22(5):426-8. study on flaps demonstrated that a reperfusion time of 24 hours before a complete ischemic episode had the best result in tolerance to ischemia [10]. in our study we dense-slit the scalp and put some of the grafts in the non-dangerous zone on the first day in a horseshoe pattern, and after 24 hours of reperfusion time for the dangerous zone and the other dark areas we continued to engraft the remaining slits. with this method we have not faced any recipient necrosis as of yet. if colleagues decide to graft hair follicles in one session, we recommend slitting the scalp as the first step in the session, followed by a rest period of a few hours, with subsequent engraftment because more reperfusion time would decrease the ischemic insults that most likely occur as a result of angina of the scalp skin where demand of oxygen is greater than the supply to implanted hair follicles. based on our knowledge, this is the first study regarding the recipient scalp necrosis which compares several cases of necrosis and provides a method for prevention of this vascular catastrophe. conclusion in order to prevent development of recipient area necrosis following a hair transplant procedure, graft insertion ideally should occur 24 hours following dense slitting. in our method, we recommend dense slitting the scalp with some engraftment in the non-dangerous zones on the first day in a horseshoe pattern with a 24-hour rest reperfusion time for danger zones and other dark areas. following this, we recommend engrafting of the slits. adequate reperfusion time is required to allow for appropriate development of implanted hairs and prevents development of necrosis. in our experience, with this method we have performed many dense https://www.google.com/search?q=recipient+area+necrosis+after+hair+transplant&biw=1366&b https://www.google.com/search?q=recipient+area+necrosis+after+hair+transplant&biw=1366&b https://www.google.com/search?q=recipient+area+necrosis+after+hair+transplant&biw=1366&b dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):10 55 dermatology practical & conceptual www.derm101.com introduction the term “clonal nevus” is used to describe a variant of benign melanocytic nevus that histologically exhibits a localized proliferation of pigmented epithelioid dermal melanocytes within an otherwise ordinary nevus [1]. alternative names for these nevi include inverted type a nevus and nevus with focal clonal hyperplasia. clonal nevi have been described as variants of combined nevi [2]. clonal nevi have been well described histologically and huyhn et al have published several clinical photographs of a clonal nevus [2]. a search of the literature has not discovered any previously published dermatoscopic images, however. there are certainly no serial dermatoscopic images of a clonal nevus arising from a previously banal nevus over time. case presentation a 30-year-old woman presented for a routine annual skin check in a primary care skin cancer clinic in the outer south eastern suburbs of melbourne, australia. she gave no personal or first-degree family history of melanoma or nonmelanoma skin cancer. she had worked on the ski fields in australia for three seasons during the preceding five years. an irritated benign acral nevus had been excised from the third/ fourth webspace of her right foot the previous year. a whole body skin examination was undertaken with the aid of a heine delta 20 nonpolarizing dermatoscope (heine optotechnik, herrshing, germany). digital clinical and dermatoscopic images were taken with a medicam 800 fotofinder non-polarizing camera (fotofinder systems gmbh, evolving clonal nevus—case report with serial digital dermatoscopy and dermatopathology mike inskip1, jill magee2 1 sun patrol skin care cancer clinic, berwick, australia 2 dorevitch pathology, heidelberg, australia key words: dermoscopy, dermatoscopy, clonal nevus, serial digital dermatocopy citation: inskip m, magee j. evolving clonal nevus—case report with serial digital dermatoscopy and dermatopathology. dermatol pract concept. 2015;5(1):10. doi: 10.5826/dpc.0501a10 received: 2014; accepted: 2014; published: january 30, 2015 copyright: ©2015 inskip et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr mike inskip mbchb (uk) fracgp, sun patrol skin cancer clinic, 48 van der haar avenue, berwick, victoria 3806, australia. tel. (03) 9769 3358; fax. (03) 9769 3357. e mail: sunpatrol.scc@bigpond.com we present a case of a clonal nevus arising from a previously banal melanocytic nevus over a 15-month period on the central back of a 30-year-old woman in a primary care skin cancer practice in melbourne, australia. clinical, dermatoscopic and dermatopathologic images are presented. a search of the literature has discovered no previously published dermatoscopy images of an evolving clonal nevus. abstract mailto:sunpatrol.scc@bigpond.com 56 observation | dermatol pract concept 2015;5(1):10 aichner, birnbach, germany), the dermatoscopy images being at 20x magnification. examination showed fitzpatrick skin type 2 with solar lentigines of the face, upper trunk and distal limbs. there were 5-10 benign pattern melanocytic nevi on her skin surface. the lesion in question was located on the central back, was slightly domed and measured 6 mm diameter. it was a uniform pale tan color with a centrally located blue, grey circular area 1mm in diameter (figure 1). this was consistent with the clinical description of a clonal nevus by huynh et al, “tan with a focus of blue/grey to blue/black pigmentation” [2]. however, on referring to the digital dermoscopic image of the same lesion taken 15 months earlier, there was no central focus of pigmentation of any kind in this image. there had just been a clinically banal benign melanocytic nevus (figure 2). the central focus of pigmentation had appeared over the last 15 months. the differential diagnosis thus consisted of benign clonal nevus or possible melanoma in view of the documented changes on serial digital dermatoscopy. in one study, bolognia et al concluded that “a small percentage of ‘small dark dots’ within melanocytic nevi are due to melanoma”, finding 3 (5%) of 59 such nevi to be melanoma [3]. an excisional biopsy was performed using an 8 mm punch excision, and the specimen was submitted for assessment by a specialist dermatopathologist. histology examination of the histological sections revealed an intradermal proliferation comprised predominantly of bland nevus cells that matured with descent and tracked down around adnexal structures consistent with a congenital pattern. centrally, there was a small population of somewhat more epithelioid appearing cells surrounded by pigmented melanophages. the cells did not exhibit marked pleomorphism, and no mitotic activity was noted. the findings were consistent with a benign clonal nevus (figures 3 to 6). figure 1. june 2014—dermatoscopy showing a central focus of blue/grey pigmentation consistent with a clonal nevus. (copyright: ©2014 inskip, magee.) figure 2. march 2013—dermatoscopy of the same lesion 15 months previous. clinically this is a homogeneous benign melanocytic nevus with no trace of central blue/grey pigmentation. (copyright: ©2014 inskip, magee.) figure 3. low power image shows a well circumscribed, wedgeshaped intradermal melanocytic proliferation comprised predominantly of bland nevus cells, however, with a central zone of more epithelioid cells, surrounded by a rim of hyperpigmented melanophages. (copyright: ©2014 inskip, magee.) figure 4. intermediate power view of central clone of epithelioid cells rimmed by melanophages and background of ordinary bland nevus cells. (copyright: ©2014 inskip, magee.) observation | dermatol pract concept 2015;5(1):10 57 conclusion a search of the literature has discovered no previously published dermatoscopy images of an evolving clonal nevus. the images we present thus add a further small piece of information to our overall knowledge base of this melanocytic nevus variant. in the case we present the clonal nevus appears to have arisen from a pre-existing clinically banal melanocytic nevus over some 15 months. it is noted that the five cases of clonal nevi presented by huyhn et al were between the ages of 37 and 80 years, all older than the case we present [2]. it is postulated that this dynamic process of evolution may occur in the first three decades of life. a recent case report of clonal nevus on the back of a 9-year-old girl is consistent with this hypothesis [3]. clonal nevi are important, as they can be confused with melanoma [4]. serial digital dermatoscopy is a relatively new diagnostic tool and appears helpful in recording the dynamic nature of melanocytic nevi. the authors feel it is important to publish dermatoscopic images such as ours to as wide an audience as possible to aid in greater understanding of this particular variant of benign melanocytic nevi in the future. references 1. ball nj, golitz le. melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases. j am acad dermatol 1994;30(5):724–29. 2. huynh pm, glusac ej, bolognia jl. the clinical appearance of clonal nevi (inverted type a nevi). int j dermatol 2004;43(12):88285. 3. balagula y, erdag g, alhariri j. dermoscopy of a clonal (inverted type a) nevus in a child. j am acad dermatol 2014;71(5):187-89. 4. bolognia jl, lin a, shapiro pe. the significance of eccentric foci of hyperpigmentation (“small dark dots”) within melanocytic nevi. arch dermatol 1994;130(8):1013–17. figure 5. higher power view of more eosinophilic epithelioid central clone of melanocytes with interspersed melanophages. background smaller basophilic nevus cells are seen at the periphery. (copyright: ©2014 inskip, magee.) figure 6. further higher power view of more eosinophilic epithelioid central clone of melanocytes with interspersed melanophages. (copyright: ©2014 inskip, magee.) dermatology: practical and conceptual 218 letter | dermatol pract concept 2019;9(3):11 dermatology practical & conceptual introduction riga-fede disease (rfd) is a benign lingual ulceration caused by repetitive trauma. it was described initially by riga in 1881 and by fede in 1890. it is usually caused by the sharp edges of newly erupted teeth. therefore, the disease is usually seen in infants and may result in malnutrition and lack of weight gain due to the difficulty in breastfeeding the baby. rfd can also occur as a result of teething in childhood. the disease can be incorrectly diagnosed as malignancy [1]. for this reason it is important to diagnose the disease correctly, to avoid radical treatment. for treatment, destruction of the trauma source is targeted. here we report a 9-year-old boy with chronic lingual ulceration diagnosed as rfd based on clinical features. rfd is usually caused by recurrent dental trauma effects of natal or neonatal teeth within the first month after birth. however, it has been reported that the disease can be seen in childhood as well, just as it was in our patient. because of its macroscopic and microscopic features, many lesions are confused with rfd. differential diagnosis includes squamous cell carcinoma, ulcerative candidiasis, fungal and bacterial infection, primary syphilis, tuberculosis, lymphoma, sarcoma, and agranulocytosis. thus it is important to diagnose the disease and prescribe the correct treatment. case presentation a 9-year-old boy presented at our clinic with chronic lingual ulceration (figure 1). the lesion was on the ventral surface of the tongue. there was no evidence of erythema or bleeding at the lesion base. he had used several treatment options such successfully treated riga-fede disease aslan yürekli1, didem dinçer2 1 bayburt state hospital dermatology department, bayburt, turkey 2 ufuk university dermatology department, ankara, turkey key words: riga-fede disease, lingual ulcer, trauma citation: yürekli a, dinçer d. successfully treated riga-fede disease. dermatol pract concept. 2019;9(3):218-219. doi: https://doi. org/10.5826/dpc.0903a11 accepted: november 21, 2018; published: july 31, 2019 copyright: ©2019 yürekli and dinçer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: aslan yürekli, md, bayburt state hospital dermatology department, bayburt, turkey. email: aslanyurekli03@ hotmail.com figure 1. chronic lingual ulceration on the ventral surface of the tongue. [copyright: ©2019 yürekli and dinçer.] letter | dermatol pract concept 2019;9(3):11 219 (60% of cases) observed on the tongue [2]. although oral lesions seen in rfd may be self-limited and may spontaneously recover, false or delayed diagnosis and ineffective treatment can cause long-term persistent tongue damage, malnutrition, and growth retardation. as a result, ulcers seen in the oral mucosa may be easily confused with other malignant lesions and may lead to aggressive interventions, so a more conservative treatment may be used to avoid unnecessary radical therapies as in our case. references 1. li j, zhang yy, wang nn, bhandari r, liu qq. riga-fede disease in a child. clin exp dermatol. 2016;41(3):285-286. 2. hong p. riga-fede disease: traumatic lingual ulceration in an infant. j pediatr. 2015;167(1):204. habit. laboratory investigations such as complete blood cell count and routine biochemistry analysis were within normal values. neurological examination did not reveal any findings. no febrile illnesses or other severe diseases were found in the medical history of the patient. the patient was diagnosed with rfd based on clinical features. because it was thought that the sharp tooth may have been the chronic trauma source, the patient visited an oral diagnosis and treatment clinic to have the left lower canine rasped. lingual ulceration resolved after 6 months (figure 2). conclusions rfd was defined in 1881 by italian physician riga. in 1890, fede performed histological studies of this lesion and identified it as a benign and noncommon mucosal disease. it is most frequently as topical steroid and antiseptic mouthwashes, but there was no response to these treatments. in his oral examination the left lower canine looked quite sharp. the patient had no licking figure 2. lingual ulceration resolved after 6 months of treatment. [copyright: ©2019 yürekli and dinçer.] dermatology: practical and conceptual observation | dermatol pract concept 2017;7(3):12 55 dermatology practical & conceptual www.derm101.com introduction syphilis is well known as “the great imitator” as it can present with a wide range of clinical manifestations mimicking other diseases. in addition, atypical manifestations are common and different stages can overlap. among the signs of secondary syphilis, syphilitic alopecia (sa) is traditionally considered infrequent, with a prevalence ranging from 2.9 to 22.2% [1-3]. however, its prevalence could be underestimated due to its possible subtle presentation and difficult diagnosis. sa is defined essential when alopecia is the only manifestation and symptomatic when mucocutaneous signs are [2-6]. according to its clinical appearance, sa is further classified into three forms: 1) moth-eaten, or patchy alopecia characterized by small alopecic patches irregularly distributed over the scalp; 2) diffuse alopecia, characterized by a diffuse hair loss; and 3) mixed form (i.e., combination of diffuse hair loss and alopecic moth-eaten patches) [2-7]. the trichoscopic findings of sa reported to date are based on the observation of six cases only: five cases of moth-eaten sa [4,5] and one case of diffuse sa [5]. we here report a case of a mixed sa form, highlighting the presence of some new trichoscopic features that have not been previously observed. syphilitic alopecia: uncommon trichoscopic findings linda tognetti1,2, elisa cinotti1, jean-luc perrot3, marco campoli1, pietro rubegni1 1 dermatology unit, department of medical, surgical and neuro sciences, university of siena, siena, italy 2 department of medical biotechnologies, university of siena, siena, italy 3 service de dermatologie, hôpital universitaire de saint-etienne, saint-etienne, france key words: secondary syphilis, moth-eaten and diffuse syphilitic alopecia, trichoscopy citation: tognetti l, cinotti e, perrot j-l, campoli m, rubegni p. syphilitic alopecia: uncommon trichoscopic findings. dermatol pract concept 2017;7(3):12. doi: https://doi.org/10.5826/dpc.0703a12 received: april 11, 2017; accepted: may 15, 2017; published: july 31, 2017 copyright: ©2017 tognetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: linda tognetti, md, department of dermatology, division of medical, surgical and neuro-sciences, university of siena, le scotte hospital, viale bracci 16, 53100 siena (italy). tel.: +39-0577 585428; fax. +39 0577 44238. email: linda.tognetti@gmail. com syphilitic alopecia (sa) is considered an uncommon manifestation of secondary syphilis. sa can present in a diffuse form, resembling telogen effluvium, or in a moth-eaten form that mimics a variety of conditions (i.e., alopecia areata, trichotillomania, lichen planus pilaris or tinea capitis). when the two forms coexist, we observe a mixed pattern. essential sa manifests without evidence of mucocutaneous syphilis manifestations and its diagnosis is often delayed. to date, trichoscopic description of sa forms are based on very few cases (i.e., five patients with moth-eaten sa and one with diffuse sa). this is the first report of a mixed pattern of essential sa: some new trichoscopic features—such as tapered bended hairs, erythematous background, diffuse scaling and perifollicular hyperkeratosis—are described in a 32-year-old man. in the absence of secondary syphilis manifestations, dermoscopy can be a useful tool that helps suspect and differentiate sa from its common mimickers. abstract 56 observation | dermatol pract concept 2017;7(3):12 leukocytosis, raised erythrocyte sedimentation rate, and c-reactive protein. serological tests for hiv and hepatitis b and c virus were negative. the patient received benzathine penicillin g 2.4 million units intramuscularly. hair regrowth occurred after two months. vdrl titer was 1:64 after four months and 1:16 after eight months. discussion alopecia could be an important sign for orienting the clinical diagnosis towards secondary syphilis, as in our case. the tropism of treponema pallidum for the hair bulge epithelium and peribulbar capillaries was demonstrated by scalp biopsies detecting spirochetes in the peribulbar region and penetrating into the follicle matrix [8]. the current hypothesis supporting the pathogenesis of sa is a vasculitis of peribulbar capillaries causing a perifollicular lymphocytic infiltration with scattered plasma cells that stops the hair cell cycle [6,7]. sa may clinically mimic a wide range of hair disorders, including alopecia areata (aa) [7], trichotillomania, lichen planus pilaris, tinea capitis, telogen effluvium, and androgenetic alopecia [2-10]. thus, the diagnosis may be delayed, especially when sa is the unique manifestation of secondary syphilis and primary syphilis signs are absent or not reported (i.e., essential sa). scalp dermoscopy can help in diagnosing sa: the trichoscopic findings of moth-eaten sa were recently described, based on the observation of five patients [4,5]. in particular, ye et al. observed black dots, focal atrichia, hypopigmentation of hair shaft and yellow dots in the center of the alopecic patches along with few black dots at the periphery of the clinical case a 34-year-old man presented for alopecia of the scalp and eyebrows for one month. he was under treatment with neuroleptic drugs for bipolar disease, anxiety and obsessive traits. he described a mild erythematous rash involving the trunk and headache and malaise for some weeks. clinical history was otherwise unremarkable. he denied having any genital lesions before hair loss started. on clinical examination, scattered small alopecic patches of 0.8 to 1.5 cm in diameter were present on the parietal-temporal-occipital areas of the scalp (figure 1) with a moth-eaten appearance. diffuse hair loss of the entire scalp was also evident. the eyebrows showed mild diffuse reduction in hairs rather than clear alopecic patches (figure 1a). the scalp appeared diffusely erythematous and scaling. neither trichodynia nor itching was present. gentle pull test was negative. trichoscopic examination of the motheaten alopecic patches revealed a nonscarring alopecia (figure 2). yellow dots were detected in the center of the patches, along with few black dots. diffuse whitish scaling, erythematous background, and focal follicular hyperkeratosis were also observed. vellus hairs were detected at the periphery of the alopecic patches. interestingly, we could observe some variously bent tapering hairs; in some cases a double-bending was visible, resulting in a serpiginous appearance. clinical history along with physical and trichoscopic findings suggested a diagnosis of secondary syphilis with a sa of mixed pattern. serological screening was performed, revealing a positive venereal disease research laboratory (vdrl) at a titer of 1:256 and a reactive treponema pallidum particle hemoagglutination assay. routine blood analysis revealed figure 1. clinical aspect. diffuse alopecia involving the scalp and the eyebrows, with moth-eaten patches on the temporal, parietal and occipital regions. diffuse fine scaling is present on the scalp. [copyright: ©2017 tognetti et al.] observation | dermatol pract concept 2017;7(3):12 57 tapered bended hairs are likely to be the expression of the chronic peribulbar sparse lymphocytic infiltration elicited by t. pallidum [6-8]. the diffuse fine scaling and the erythematous background that we observed in our case was in favor of a large involvement of the scalp (diffuse type of sa) and can be regarded as part of the exanthema of the secondary syphilitic infection. interestingly, hyperkeratosis was found both around the proximal part of some hair shafts and within some empty follicular ostia. clinically, moth-eaten sa is considered the main simulator of aa [2,3,7] (figure 3), and a scalp biopsy of moth-eaten sa forms may be required to exclude aa in doubtful cases [6,7]. trichoscopy helps to differentiate between these two conditions; exclamation point hairs (3-5 mm short, wide at the top and very thin as they enter the scalp) are considered the hallmark of aa, along with numerous yellow and black dots and vellus hairs [9,10]. in addition, vellus hairs are usually observed in the center of the aa patch, whereas in sa they appear at the periphery [9.10]. unbended tapering hairs are seldom observed in aa and mainly in the subacute phase [10]. trichotillomania can clinically simulate both sa and aa, presenting with irregularly shaped alopecic patches distributed mainly on the occipital, parietal and vertex region, over an patches [4]. piraccini et al. described reduction in the number of terminal hairs and the presence of empty hair follicles, vellus hairs, red-brown background and irregularly dilated capillaries with small blood extravasation in four patients [5]. diffuse sa involves the whole scalp as telogen effluvium, but the alopecic areas are more evident. the trichoscopic observation of one patient did not show any significant alterations [5]. our patient presented a clinical aspect of mixed pattern sa, about which the dermoscopic appearance has never been described. we identified some of the features previously observed in moth-eaten sa cases (i.e., reduction of terminal hairs, yellow dots, black dots, erythematous background, dilated capillaries and vellus hair) [4,5]. moreover, we observed additional features, including tapering hairs, diffuse scaling and focal follicular hyperkeratosis. the tapering hairs were detected at the periphery of the moth-eaten patches and were single or double bending; thus we defined them as “tapered bended hairs.” tapered bended hairs were of normal length and gradually narrowed from the proximal to the distal part. when detected in aa patients, tapering hairs without bending were considered the result of a sudden cessation of hair follicle production by the matrix due to the hair follicle inflammation [9,10]. in our case, figure 2. dermoscopy of the scalp. empty ostia and yellow dots are visible in the center of the alopecic patches over an erythematous background. tapered bent hairs (arrows) are present at the periphery of the alopecic patches. vellus hair are visible at the periphery (a,b,d). scales appear to be thin and withish; perifollicular hyperkeratosis is focally visible (b,c,d). [copyright: ©2017 tognetti et al.] 58 observation | dermatol pract concept 2017;7(3):12 manifestations, a condition that is increasing nowadays, likely due to an improper concomitant antibiotic treatments [1-6]. dermoscopy represents a useful, noninvasive, rapid, and inexpensive tool that helps the physician to suspect sa [10]. further descriptions are necessary to confirm these trichoscopic findings of the mixed pattern of sa, a rare condition where moth-eaten and diffuse alopecia coexist. references 1. vafaie j, weinberg jm, smith b, mizuguchi rs. alopecia in association with sexually transmitted disease: a review. cutis. 2005;76:361-366. erythematous background. on dermoscopy, trichotillomania patches show broken hairs of varying length and occasionally a few black dots [2-5,9]. in some cases, sa could also simulate scalp manifestations of lichen planus pilaris, especially when scarring is not clinically evident [3,9]. however, in lichen planus pilaris, scarring areas are present and hyperkeratosis is more severe and usually limited to hair follicles (figure 4). finally, tinea capitis can also clinically mimic sa manifestations [2-5,9]. however, dermoscopic examination of tinea capitis reveals black dots and commas, corkscrew, zigzag and morse code hairs irregularly distributed within the alopecic patches. physicians should be aware of the possibility of secondary syphilis with sa in the absence of clear primary syphilis figure 3. clinical (a) and dermoscopic (b) appearance of alopecia areata. multiple black and yellow dots and vellus hairs are observable at the periphery of the alopecic patch (a,b) along with some exclamation mark hairs (b). [copyright: ©2017 tognetti et al.] figure 4. clinical (a) and dermoscopic (b) aspect of lichen planus pilaris alopecia. confluent small alopecic patches of the parietal area are present on an erythematous scalp (a). dermoscopy shows dilated capillaries and severe follicular hyperkeratosis at the periphery of the patch and absence of follicular ostia in the center (b). [copyright: ©2017 tognetti et al.] observation | dermatol pract concept 2017;7(3):12 59 syphilis. a histopathological study of 12 patients. am j dermatopathol. 1995;17:158. 7. lee jy, hsu ml. alopecia syphilitica, a simulator of alopecia areata: histopathology and differential diagnosis. j cutan pathol. 1991;10:87. 8. nam-cha sh. alopecia syphilitica with detection of treponema pallidum in the hair follicle. j cutan pathol. 2007;34(1):37-40. 9. miteva m, tosti a. hair and scalp dermatoscopy. j am acad dermatol. 2012;67(5):1040-1048. 10. inui s, nakajima t, nakagawa k, itami s. clinical significance of dermoscopy in alopecia areata: analysis of 300 cases. int j dermatol. 2008;47:688-693. 2. hernandez-bel p, unamuno b, sanchez-carazo jl, et al. syphilitic alopecia: a report of 5 cases and a review of the literature. actas dermosifiliogr. 2013;104:512-517. 3. bi my, cohen pr, robinson fw, gray jm. alopecia syphilitica— report of a patient with secondary syphilis presenting as motheaten alopecia and a review of its common mimickers. dermatol online j. 2009;15:6. 4. ye y, zhang x, zhao y, et al. the clinical and trichoscopic features of syphilitic alopecia. j dermatol case rep. 2014;3:78-80. 5. piraccini bm, broccoli a, starace m, et al. hair and scalp manifestations in secondary syphilis: epidemiology, clinical features and trichoscopy. dermatology. 2015;231(2):171-176. 6. jordaan hf, louw m. the moth-eaten alopecia of secondary dermatology: practical and conceptual 98 review | dermatol pract concept 2019;9(2):4 dermatology practical & conceptual dermoscopy use in primary care: a scoping review jonathan a. fee1, finbar p. mcgrady1, cliff rosendahl2,3, nigel d. hart1 1 centre for medical education, queen’s university belfast, uk 2 school of medicine, the university of queensland, brisbane, australia, brisbane, australia 3 school of medicine, tehran university of medical sciences, iran key words: dermoscopy, general practice, primary health care, melanoma, cancer citation: fee ja, mcgrady fp, rosendahl c, hart nd. dermoscopy use in primary care: a scoping review. dermatol pract concept. 2019;9(2):98-104. doi: https://doi.org/10.5826/dpc.0902a04 accepted: october 15, 2018; published: april 30, 2019 copyright: ©2019 fee et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: dr. fee’s study fees and maintenance come from hsc r&d division, public health agency’s gp academic research training scheme and eat/5336/17. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. jonathan a. fee, centre for medical education, queen’s university, belfast, uk. email: jfee03@qub.ac.uk background: patients in many countries with new or changing skin lesions will first consult a primary care physician, often called a general practitioner (gp). with the dramatic rise in melanoma incidence over recent decades, dermoscopy offers a tool with an evidence base supporting its use in skin lesion assessment. how gps use dermoscopy is unclear. objectives: a scoping literature review was carried out to examine the current state of published evidence about dermoscopy use in primary care. methods: the methodological steps taken in this review followed those developed by arksey and o’malley, as revised by levac and colleagues. four electronic databases were searched for evidence published up to january 2018 describing the use of dermoscopy in a generalist primary care setting. seven articles were identified for analysis. results: all included articles have been published since 2007. most were questionnaire studies and revealed that generally a small minority of gps use dermoscopy, although some jurisdictions such as australia report greater use. dermoscopy is generally used only for the assessment of pigmented skin lesions, but is not used consistently. several perceived barriers to dermoscopy use, including the need for training, have been reported. conclusions: there is a paucity of data on dermoscopy use among gps, and diversity in questionnaire items prevents comparison between jurisdictions. perceived barriers to dermoscopy use require more in-depth exploration, potentially including qualitative data, to evaluate them more fully. understanding these factors, including how gps train in dermoscopy, will be crucial in widening dermoscopy use in primary care. abstract review | dermatol pract concept 2019;9(2):4 99 gps. the expertise of a medical librarian was sought to ensure that there was adequate coverage of relevant databases for formal literature searches. formal literature searches were carried out between january and february 2018. four electronic databases were searched: embase, medline, scopus, and web of science. minor adaptations in search terms were made between databases to account for the different database subject headings. the embase search strategy is shown in table 1. step 3: study selection j.a.f. screened abstracts from citations identified in database searches. where this was insufficient to make a decision, the whole article was read. in the event of ambiguity the article was referred for full-text assessment for eligibility. articles available only in the form of conference abstracts were excluded at this point, as is standard in scoping review methods. articles written in languages other than english were also excluded. introduction for the majority of patients in many countries with a new or changing skin lesion, their first consultation with a health care professional will be with a primary care physician, often called a general practitioner (gp). dermoscopy has been shown to be an effective tool for the detection of melanoma in primary care [1]. dermoscopy in primary care is a relatively new tool, and little is known about how gps use dermoscopy. given the role of dermoscopy in the early detection of melanoma and other skin cancers, understanding how it is used in the primary care setting, as well as identifying what is not yet clear, is important in directing future research and in helping to expand its use. scoping literature reviews, usually called scoping reviews, have become an increasingly common approach to providing a descriptive outline of evidence from published literature [2]. they are useful particularly when the aim is to map an area of research for its main concepts, sources, and types of evidence [3]. in the relatively unexplored area of dermoscopy use in a primary care setting, a scoping review was undertaken to examine the extent of research in this area and to identify where gaps in the existing literature appear. methods methodological approaches to conducting scoping reviews have been published in the literature. arksey and o’malley developed a framework for scoping reviews, and this was refined by levac and colleagues [3,4]. this was the framework followed in this review. research team the research team comprised a general practice specialty trainee (j.a.f.) and 3 gps (f.p.m., c.r., and n.d.h.) involved in clinical teaching and medical education research. research ethics no ethical approval was required for this work, as this was a secondary analysis of published literature within the public domain. step 1: identifying the research question while the use of dermoscopy has become more commonplace among doctors who specialize in skin cancer care, such as dermatologists, the aim of this review was to investigate the use of dermoscopy in primary care. for this reason an open and inclusive question was formed: what can be known from the literature about how dermoscopy is used in general practice? step 2: identifying relevant studies initial informal literature searches were carried out to identify the various terms used in the literature for dermoscopy and table 1. embase search terms 1. epiluminescence microscopy/ 2. dermoscop*.mp 3. dermatoscop*.mp 4. “epiluminescence microscop*”.mp 5. “surface microscop*”.mp 6. “incident light microscop*”.mp 7. general practice/ 8. “general practice*”.mp 9. general practitioner/ 10. “general practitioner*”.mp 11. gp*.mp 12. family medicine/ 13. “family medic*”.mp 14. “family practice*”.mp 15. “family physician*”.mp 16. “family practitioner*”.mp 17. primary medical care/ 18. “primary medical care*”.mp 19. primary health care/ 20. “primary health care*”.mp 21. primary healthcare*”.mp 22. “primary care*”.mp 23. “primary care physician*”.mp 24. 1 or 2 or 3 or 4 or 5 or 6 25. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 26. 24 and 25 100 review | dermatol pract concept 2019;9(2):4 collaboration centres was used in reporting the results [6]. a flowchart of the study selection process is shown in figure 1. results we identified 783 citations from the database searches. database searches were carried out sequentially. the search of the fourth database (embase), after the exclusion of conference abstracts, produced only 4 new citations, none of which passed the screening stage, and database searches were deemed to be sufficient. a large number of additional records were identified through searching reference lists. however, very few were relevant to the review question. seven articles were included in the review analysis, all of which were observational studies. of these, 5 were questionnaire studies and 2 reviewed medical records. all had gps as their subjects. one study included some gps who did not have generalist practices but were dedicated to skin cancer care; however, as the majority of the participants in the study (73.6%) were gps who maintained generalist practices (albeit some of them had a special interest in skin cancer), this study was included in the review [7]. origins of research articles describe work that has been carried out in 4 different countries, as is shown in figure 2. australia, the netherlands, at this stage j.a.f. and n.d.h. met to discuss the articles. full-text articles were read by both researchers and were considered for inclusion according to the criteria set out in table 2. discussion resolved any discrepancies in opinion between the researchers, and consensus was reached. whether included in the final analysis or not, the reference lists of all articles reaching this stage were searched, and additional new citations were screened by j.a.f. articles accepted from reference lists for full-text assessment also had their reference lists searched in an iterative process, until no additional new citations were generated that passed the screening stage. step 4: charting the data j.a.f. created a data extraction sheet using microsoft excel (microsoft, redmond, wa, usa) and extracted onto it details from the included papers. data extracted from each article included authors, year of publication, origin of the research, study design, outcome measures, and key findings that related to the review question. step 5: collating, summarizing, and reporting the results preferred reporting items for systematic reviews and metaanalyses (prisma) guidance [5] and guidance published by members of the joanna briggs institute and joanna briggs table 2. inclusion and exclusion criteria for article selection inclusion criteria • studies examined some aspect of the use of dermoscopy in everyday primary care practice. • participants were mainly gps (or in countries where the term gp is not in common use, primary care physicians working in a generalist community setting to whom patients self-refer). exclusion criteria • expert reviews of dermoscopy, commentaries or editorials discussing other articles. • articles focused on gps working in a specialist or secondary care setting. • gps recruited to training interventional studies in dermoscopy. • gps participating in screening programs. • teledermoscopy studies in which dermatologists interpret the images. • dermoscopy interpreted by artificial intelligence. figure 1. prisma flowchart of study selection process [5]. review | dermatol pract concept 2019;9(2):4 101 and the united states have contributed 2 articles each to the field. all of the research has been conducted in countries with high-income and advanced economies [8,9], and with very high human development in the human development index [10]. year of publication the first article included in the review was published in 2007. figure 3 shows a cumulative frequency chart of publication dates. all included articles were published over a 10-year period, and the majority were published in 2016 or 2017. use of dermoscopy by gps f i v e q u e s t i o n n a i r e s t u d i e s a n d 2 records-based observational studies have described dermoscopy use in primary care. the results are summarized in table 3. dermoscopy use varies widely between jurisdictions. dermoscopy use is well established in australia, where between 34% and 42% of gps in generalist practices reported using dermoscopy and where research into the use of dermoscopy in primary care has been undertaken since 2007 [7,11]. high levels of dermoscopy use were also table 3. studies reporting use of dermoscopy by gps study year country no. of participants response rate use of dermoscopy morris et al [15] 2017 usa 768 gps not reported 6% currently use; 15% have ever used dermoscopy morris et al [16] 2017 usa 705 gps not reported 8.3% currently use; 19.5% have ever used dermoscopy secker et al [12] 2017 netherlands 309 gps not reported 37% use dermoscopy ahmadi et al [14] 2017 netherlands 11 gps; 580 consultations not applicable 8.4% of consultations use dermoscopy chappuis et al [13] 2016 france 425 gps 10.5% 8% have access to a dermatoscope rosendahl et al [7] 2012 australia 193 gps not applicable 42.6% of generalist gps use; 89.4% of gps with skin cancer special interest use; and 95.9% of gps dedicated to skin cancer care use dermoscopy at least weekly chamberlain et al [11] 2007 australia 223 gps >90% 34% ever use dermoscopy figure 2. origins of review articles. figure 3. year of publication of review articles by cumulative frequency. 102 review | dermatol pract concept 2019;9(2):4 more than 400 patients per month, were more likely to use dermoscopy [16], although another study by the same authors did not confirm this [15]. one study demonstrated that gps subspecializing in skin cancer care were more likely to use dermoscopy than gps working in generalist gp practices [7]. perceptions of dermoscopy use three questionnaire studies asked participants to rank their perceptions of barriers to dermoscopy use from a list of suggestions. a pattern emerged across the studies that revealed common perceived barriers. the costs of dermoscopy—both the equipment cost and the insufficient reimbursement for its use in practice—were a clear barrier to its use. the other most commonly cited barriers were the need for dermoscopy training and the time needed both for training and to use dermoscopy in practice [13,15,16]. one of the studies also asked participants to rank their perceptions of the advantages of dermoscopy from a list of suggestions. the most common responses were that it helped to diagnose melanoma earlier, that it helped to reduce dermatology referrals, and that it reduced patients’ anxiety [13]. two questionnaire studies asked about confidence. confidence was significantly higher among dermoscopy users than nonusers in both studies: for the analysis of pigmented skin lesions generally in one study [13] and for differentiating between cancerous and noncancerous skin lesions in the other [15]. one study asked about how dermoscopy affects clinical decision-making; 75% of dermoscopy users felt that it influenced their diagnoses in practice [11]. discussion principal findings this review identified 7 observational studies that have investigated the use of dermoscopy in general practice, mostly by means of questionnaires. the use of dermoscopy by gps varies between jurisdictions; however, because of the paucity and heterogeneity of data it is difficult to draw any firm conclusions. in general, it is a small minority of gps who use dermoscopy, and only where gps have subspecialized in skin cancer care do a majority use dermoscopy [7]. those gps who use dermoscopy do not do so consistently for all pigmented skin lesions [7], and most use it only for the assessment of pigmented skin lesions [13]. this raises a concern that the dermoscopic features of skin cancers such as amelanotic melanomas may be overlooked. gps who used dermoscopy reported feeling more confident in analyzing pigmented skin lesions [13] and in differentiating between cancerous and noncancerous skin lesions [15]. what is unclear is whether dermoscopy makes gps feel more confident, or whether gps with more confidence in dermatology are more likely to embrace a new tool for reported among gps in the netherlands [12]. in contrast to this, dermoscopy use seems to be lower among gps in the united states and france, at 6%-8%. one study found that the use of dermoscopy by gps increases as they either develop a special interest in skin cancer or enter a practice dedicated to skin cancer care. however, when other variables such as practice type were controlled for, no association was found between dermoscopy use and the number of suspicious lesions excised per melanoma diagnosis [7]. however, the authors acknowledge that it was difficult to study dermoscopy use and subspecialization into skin cancer care in isolation, as the two are highly correlated. how studies reported dermoscopy use varied. current and previous use of dermoscopy by gps, gps’ access to a dermatoscope, and consultations that have used dermoscopy were all variably described. one study reported participants’ use of dermoscopy as low, medium, or high, with “low” including those who used dermoscopy less than once a week or not at all [7]. one questionnaire simply reported whether participants had ever or never used dermoscopy [11]. these differences prevent clear comparisons between studies and jurisdictions. patterns of dermoscopy use two studies reported specific information about frequency of dermoscopy use and for what purpose dermoscopy is used in clinical practice. in one study, 20% of gps working in generalist practices reported using dermoscopy for all pigmented lesions and 22% reported using it most days [7]. another study reported that of 8% of gps with access to a dermatoscope, 52% used it more than once a week [13]. this suggests that gps who use dermoscopy are not using it consistently; this was highlighted in another study, which found that dermoscopy was used in only 8.4% of consultations involving skin lesions suspected of malignancy [14]. one study suggested that dermoscopy seems to be used mostly for consultations involving pigmented skin lesions: 82% of dermoscopy users reported using dermoscopy for the assessment of pigmented skin lesions, 68% for nonpigmented lesions, and 8% to allow for digital data transmission, such as teledermoscopy [13]. characteristics of dermoscopy users three studies subanalyzed their questionnaire data to explore whether certain groups of gps are more likely to use dermoscopy. results were conflicting. one study found that male gps were more likely to use dermoscopy than female gps [13], although other studies did not support this finding [15,16]. two of the studies found that older gps were more likely to use dermoscopy [13,16], while another reported that younger gps were more likely to be using the tool [15]. one study reported that gps in busier practices, who saw review | dermatol pract concept 2019;9(2):4 103 all of the studies included in this review were observational, and there have been no long-term or follow-up studies that have looked at how the use of dermoscopy has changed in general practice over time. while this is partly due to the relatively novel status of dermoscopy as a tool for gps, it means that trends in dermoscopy use in primary care are currently unknown or unpublished. furthermore, because questionnaire studies have not used identical questions, comparison of dermoscopy use between different health care systems and countries, such as has been done in a survey of dermatologists [17], is not yet possible for gps. this review highlights a concerning absence of qualitative research into gps’ use of dermoscopy. while questionnaires have attempted to highlight gps’ perceptions of the advantages of dermoscopy and the barriers to its use, they inevitably do so at a superficial level. questions such as why most gps do not use dermoscopy and whether specific perceptions or barriers are preventing them from doing so have not been addressed. understanding these factors is crucial to understanding how dermoscopy can be translated from a new tool for lesion recognition into a standard technique for the assessment of skin lesions in primary care. notably, one of the perceived barriers to the use of dermoscopy in primary care highlighted by this review is the need for training. one of the papers included in this review reported on how gps train in dermoscopy, and found that only a minority of dermoscopy users had undertaken training [13]. it is unsurprising that many gps are unwilling to incorporate dermoscopy into their clinical practice without undertaking training, and understanding how to train gps in dermoscopy will be important in expanding use of dermoscopy among the gp workforce. conclusions this scoping literature review found research from several countries that demonstrates that dermoscopy is used by a minority, often a small minority, of gps. commonly perceived barriers to the use of dermoscopy include equipment costs and the time and training required to use it. no published qualitative research has explored these perceptions, and further research in this area could help to lay foundations for more widespread uptake of dermoscopy among gps. in particular, understanding how gps train in dermoscopy will be important in improving patient access to dermoscopy in primary care. references 1. herschorn a. dermoscopy for melanoma detection in family practice. can fam physician. 2012;58(7):740-745 [in english, french]. skin lesion assessment. insights such as these are not readily uncovered in questionnaire studies. gps perceive the barriers to dermoscopy use to include the cost of the equipment, the need for training, and the time required for training and using dermoscopy in practice. gps perceived the advantages of dermoscopy to be the earlier diagnosis of melanoma, reducing dermatology referrals, and reducing patient anxiety. limitations although this review was carried out according to a recognized scoping review methodology, it was exploratory in nature. databases and reference lists were searched using a comprehensive set of search terms; however, it is impossible to guarantee that other papers of relevance were not overlooked. as only published articles are included in search databases, any unpublished data, or data that exist in the form of conference abstracts, were not included in the review. by limiting the searches to english language articles for pragmatic reasons, it is also possible that published work exists in other languages but did not come to the attention of the reviewers. only 2 studies reported response rates; one was low at 10.5% [13] and raises the prospect of responder bias. another study reported a response rate of more than 90% [11]; however, the survey was distributed to attendees at a dermatology conference for gps and may not be representative of the gp population. one study reviewed data from a skin cancer audit database used by gps, and doctors selfselect to participate in this tool [7]. it is therefore difficult to assess how well these data reflect the use of dermoscopy among gps generally. the focus of the review was narrowed to looking at gps within a primary care, generalist setting. this inevitably excluded articles reporting on gps working in specialist skin cancer care or in a hospital setting. presumably some gps working in specialist settings may also work in a generalist setting at times and would bring their dermoscopy skills with them to this role. however, most patients in health care systems where gps play a “gate-keeping” role for secondary care will attend a gp without these enhanced skills. therefore, it was important for our team to understand how a gp working in a generalist setting uses dermoscopy. implications several important gaps in the literature were uncovered in this review. from the authors’ perspective, the absence of published data from the uk or ireland means that there is currently no clear understanding of how many gps use dermoscopy in these jurisdictions. all health care systems vary, and if an expansion of the use of dermoscopy in primary care were to be planned, having some baseline data on the use of dermoscopy would be highly desirable. 104 review | dermatol pract concept 2019;9(2):4 available at: http://hdr.undp.org/sites/default/files/2016_ human_ development_ report.pdf. accessed september 12, 2018. 11. chamberlain aj, kelly jw. use of dermoscopy in australia. med j aust. 2007;187(4):252-253. 12. secker lj, buis paj, bergman w, kukutsch na. effect of a dermoscopy training course on the accuracy of primary care physicians in diagnosing pigmented lesions. acta derm venereol. 2017;97(2):263-265. 13. chappuis p, duru g, marchal o, girier p, dalle s, thomas l. dermoscopy, a useful tool for general practitioners in melanoma screening: a nationwide survey. br j dermatol. 2016;175(4):744750. 14. ahmadi k, prickaerts e, smeets jge, joosten v, kelleners-smeets nwj, dinant gj. current approach of skin lesions suspected of malignancy in general practice in the netherlands: a quantitative overview. j eur acad dermatology venereol. 2018;32(2):236241. epub 2017 aug 16. 15. morris jb, alfonso sv, hernandez n, fernández mi. dermascope use by osteopathic primary care physicians. j am osteopath assoc. 2017;117(3):158-164. 16. morris jb, alfonso sv, hernandez n, fernández mi. examining the factors associated with past and present dermoscopy use among family physicians. dermatol pract concept. 2017;7(4):6370. 17. forsea am, tschandl p, zalaudek i, et al. the impact of dermoscopy on melanoma detection in the practice of dermatologists in europe: results of a pan-european survey. j eur acad dermatol venereol. 2017;31(7):1148-1156. 2. pham mt, rajić a, greig jd, sargeant jm, papadopoulos a, mcewen sa. a scoping review of scoping reviews: advancing the approach and enhancing the consistency. res synth methods. 2014;5(4):371-385. 3. arksey h, o’malley l. scoping studies: towards a methodological framework. int j soc res methodol. 2005;8(1):19-32. 4. levac d, colquhoun h, o’brien kk. scoping studies: advancing the methodology. implement sci. 2010;5:69. pmid: 20854677. 5. moher d, liberati a, tetzlaff j, et al. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. plos med. 2009;6(7):e1000097. 6. peters md, godfrey cm, khalil h, mcinerney p, parker d, soares cb. guidance for conducting systematic scoping reviews. int j evid based healthc. 2015;13(3):141-146. 7. rosendahl c, williams g, eley d, et al. the impact of subspecialization and dermatoscopy use on accuracy of melanoma diagnosis among primary care doctors in australia. j am acad dermatol. 2012;67(5):846-852. 8. world bank country and lending groups. the world bank. available at: https://datahelpdesk.worldbank.org/knowledgebase/ articles/906519#high_income. accessed september 12, 2018. 9. international monetary fund. 2018. world economic outlook: cyclical upswing, structural change. washington, dc, april. available at: http://www.imf.org/en/publications/weo/ issues/2018/03/20/world-economic-outlook-april-2018. accessed september 12, 2018. 10. united nations development programme. human development report 2016: human development for everyone. 2016. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(2):e2023124 1 a case of xanthoma disseminatum in a progressive form with bladder involvement effectively treated with 2-chlorodeoxyadenosine elçin akdaş1, burcu beksaç2, esra adışen1, özlem erdem3, murat orhan öztaş1 1 department of dermatology, faculty of medicine, gazi university, ankara, turkey 2 department of dermatovenereology, university of health sciences, gulhane research and training hospital, ankara, turkey 3 department of pathology, faculty of medicine, gazi university, ankara, turkey key words: xanthoma disseminatum, bladder, 2-chlorodeoxyadenosine, cladribine citation: akdaş e, beksaç e, adışen e, erdem ö, öztaş mo. a case of xanthoma disseminatum in a progressive form with bladder involvement effectively treated with 2-chlorodeoxyadenosine. dermatol pract concept. 2023;13(2):e2023124. doi: https://doi.org/10.5826/dpc.1302a124 accepted: november 14, 2022; published: april 2023 copyright: ©2023 akdaş et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: elçin akdaş, department of dermatology, gazi medical university, yenimahalle tr–06500, ankara, turkey. tel: +905469757697 e-mail: mdelcinakdas@gmail.com introduction xanthoma disseminatum (xd) is a rare non-langerhans cell histiocytosis that is difficult to treat [1]. in rare progressive forms of the disease, organ dysfunctions may occur [2]. we report a case of xd with bladder involvement, with an excellent response to 2-chlorodeoxyadenosine. case presentation a 47-year-old male patient presented with a 5-year history of numerous skin lesions on the oral mucosa, head, neck, trunk, and upper limbs (figure 1, a and c). his personal and family history was unremarkable. he denied  any  systemic symptoms. dermatological examination demonstrated numerous symmetrical yellow to brown papules and nodules that enlarged into plaques and tumoral lesions, especially in the intertriginous areas. laboratory tests were normal except for moderate leukocytosis and a slightly elevated erythrocyte sedimentation rate. electrocardiography and chest x-ray were also normal. histopathologic examination revealed diffuse dermal infiltration by histiocytic cells, foamy cells, and touton-type giant cells. immunohistochemical studies showed positive staining for cd68, factor xiiia, and fascin, and negative staining for s100 (figure 2, a-c). the patient was diagnosed with xd based on clinicopathological and immunohistochemical findings. abdominal ultrasound examination for possible systemic involvement revealed grade 2 hydronephrosis in the right kidney and an irregular 18 mm echogenic mass behind the bladder that prevented the opening of the right ureter. the mass in the bladder was also confirmed by an abdominopelvic ct scan. magnetic resonance imaging of the brain did not find any abnormality and serum protein electrophoresis did not show any m band. 2 research letter | dermatol pract concept. 2023;13(2):e2023124 figure 1. the appearance of lesions before (a,c) and after (b,d) treatment with 2-chlorodeoxyadenosine. histopathological and immunohistochemical findings of the specimen obtained through transurethral resection of the bladder were also consistent with xd (figure 2, d and e). we initiated 2-chlorodeoxyadenosine (cladribine) 0.14 mg/ kg/d for five consecutive days, repeated monthly. the treatment was well tolerated, and no serious side effects developed. after three cycles of treatment, improvement in skin lesions was remarkably evident, with more flattening and fading, although a complete resolution was not achieved (figure 1, b and d). also, the tumoral lesion in the bladder and hydronephrosis also completely regressed in the control ct scan. no new lesions developed during our follow-up of 48 months. conclusions xanthoma disseminatum is characterized by erythematous, reddish-brown papules, plaques, and nodules that are typically symmetrical and tend to coalesce in intertriginous areas [1,2]. histopathologic findings include diffuse dermal infiltration by histiocytes and touton giant cells. immunohistochemical evaluation shows histiocytes staining positive with cd68, cd163, factor xiiia, and fascin, and negative with s-100 and cd1a (langerin) [3 4]. although xd is generally considered a benign disease, in extremely rare progressive forms, mechanical mucosal complications and progressive organ dysfunction can cause research letter | dermatol pract concept. 2023;13(2):e2023124 3 significant morbidity and mortality [2]. many treatments including steroids, azathioprine, cyclophosphamide, electrocoagulation, or surgical excision, have been tried in xd, but recently the most satisfactory results have been obtained with 2-chlorodeoxyadenosine [5,6]. the excellent response to 2-chlorodeoxyadenosine was remarkable in this case with the progressive form of xd with bladder involvement. we emphasize the need for appropriate treatment with careful evaluation of the disease and close follow-up to prevent significant morbidity in progressive disease. acknowledgements: the patient in this manuscript has given written informed consent to the publication of his case details. references 1. altman j, winkelmann r. xanthoma disseminatum. arch dermatol. 1962;86(5):582-596. doi:10.1001/archderm. 1962. 01590110018003 2. caputo r, veraldi s, grimalt r, et al. the various clinical patterns of xanthoma disseminatum. dermatology. 1995;190(1):19-24. doi: 10.1159/000246628. pmid: 7894090. 3. zelger b, cerio r, orchard g, fritsch p, wilson-jones e. histologic and immunohistochemical study comparing xanthoma disseminatum and histiocytosis x. arch  dermatol. 1992;128(9):1207-1212. pmid: 1519935. 4. weitzman s, jaffe r. uncommon histiocytic disorders: the non-langerhans cell histiocytoses. pediatr  blood  cancer. 2005;45(3):256-264. doi: 10.1002/pbc.20246. pmid: 15547923. 5. khezri f, gibson le, tefferi a. xanthoma disseminatum: effective therapy with 2-chlorodeoxyadenosine in a case series. arch dermatol. 2011;147(4):459-464. doi: 10.1001/archdermatol.2010.378. pmid: 21173305. 6. adışen e, aladağ p, özlem e, gürer m. cladribine is a promising therapy for xanthoma disseminatum. clin exp dermatol. 2017;42(6):717-719. doi: 10.1111/ced.13116. pmid: 28544144. figure 2. histopathological appearance of skin and bladder biopsy specimens showing intense dermal infiltration of histiocytes and foamy cells (a and d, respectively) with tauton giant cells (d, yellow arrow). h&e original magnifications ([(a] × 40; [d] × 100). immunohistochemical examination, the cells in the skin and bladder stained positive for cd68 (b and d, respectively) and negative for cd1a (c and e, respectively). original magnification x40 for b,c,e and f. dermatology: practical and conceptual letters | dermatol pract concept 2016;6(1):8 25 dermatology practical & conceptual www.derm101.com we read with interest the article published by blum and giacomel, describing the low-cost dermatoscope designed using a mobile phone, immersion fluid and transparent adhesive tape. the method described by the authors has the advantage that it does not require any magnifying device [1]. we earlier described a technique where a low-cost jeweler’s loupe can be used as a dermoscopy device [2], and a modification of this where the loupe can be attached to any mobile phone and be used for mobile dermatoscopic imaging [3]. we used a jeweler’s loupe with an inbuilt led lighting system (figure 1), and we used alcohol gel as the fluid, which is used to reduce the reflection from the stratum corneum. in our apparatus, too, the imaging is done from a distance without actual contact with the fluid. the loupe is held at a distance of about 5 cm from the skin after a sufficiently thick layer of alcohol gel is applied over the skin (figure 2). the technique is not “true” dermoscopy as such, but helps to visualize basic dermoscopic features. compared to the technique described by blum and giacomel [1], we feel that the magnification actually adds to the quality of the image (and here it is true magnification, not comment on “‘tape dermatoscopy’: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape” feroze kaliyadan1, kt ashique2 1 department of dermatology, king faisal university, hofuf, saudi arabia 2 kims al shifa super specialty hospital, perinthalmana, kerala, india citation: kaliyadan f, ashique kt. comment on “‘tape dermatoscopy’: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape.” dermatol pract concept 2016;6(1):8. doi: 10.5826/dpc.0601a08 copyright: ©2016 kaliyadan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: feroze kaliyadan, md, dnb, mnam, department of dermatology, king faisal university, hofuf, saudi arabia 31982. tel. +966544710168. email: ferozkal@hotmail.com figure 1. jeweller’s loupe with inbuilt led lighting attached to the camera of a samsung note 3® mobile phone. [copyright: ©2016 kaliyadan et al.] figure 2. imaging of the lesion with the mobile phone. [copyright: ©2016 kaliyadan et al.] mailto:ferozkal@hotmail.com 26 letters | dermatol pract concept 2016;6(1):8 all the same, these devices can definitely be used as a costeffective means for understanding the basics of dermoscopy, especially for trainee dermatologists and medical students. there are probably two main factors which limit the regular use of dermoscopy as a diagnostic tool in many developing countries—one is a relatively lower incidence of skin cancers, specifically melanoma, and the other is the cost. most standard dermoscopes are not easily affordable for medical students or residents. at the same time, dermoscopy is increasingly being used to aid in the diagnosis in general dermatology, especially trichology. low-cost techniques, like the one described by us, can help in giving an initial handson exposure to residents and medical students regarding the basic physics of dermoscopy and also to understand the dermoscopic patterns of normal skin. more studies with a larger sample size are required to validate the actual effectiveness of these low-cost dermatoscopes vis-à-vis standard devices in the context of actual skin pathology. it would obviously not be prudent to use such a method for triaging in the context of conditions like melanoma. references 1. blum a, giacomel j. “tape dermatoscopy”: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape dermatol pract concept. 2015;5(2):87-93. 2. kaliyadan f. using a simple jeweler’s loupe as a dermoscopic instrument. indian j dermatol venereol leprol. 2011;77(5):617-20. 3. kaliyadan f, ashique kt. a simple and cost-effective device for mobile dermoscopy. indian j dermatol venereol leprol. 2013;79(6):817-9. digital zoom). the inbuilt lighting also makes it convenient, as we do not need to be dependent on an external light source or ambient lighting. jeweler’s loupes with inbuilt lights are easily available on online shopping platforms; these devices are quite cheap and it is very easy to assemble this apparatus using just simple adhesive tape. however, our method also has the same disadvantages as in the method described by blum and giacomel—focusing the camera is not very easy and there are limitations in analyzing finer details, especially vascular patterns (figure 3). better quality of lighting and adjusting the angle of the light in a jeweler’s loupe might further improve the quality of the imaging. we would like to emphasize that these low-cost techniques are in no way a substitute for standard dermoscopy. figure 3. melanocytic nevus dermoscopy. contact fluid used was alcohol gel: (a) with a jeweler’s loupe attached to a samsung galaxy note 3 mobile phone camera and (b) standard dermoscopy (dermlite foto ii pro, 3 gen inc, san juan capistrano, ca). [copyright: ©2016 kaliyadan et al.] http://www.ncbi.nlm.nih.gov/pubmed/26114061 _goback untitled quiz | dermatol pract concept 2015;5(2):15 83 dermatology practical & conceptual www.derm101.com the patient a 65-year-old caucasian man presented to our clinic with a 10-year history of a slow-growing, painful nodular lesion on the right thigh that was sensitive to cold. the physical examination revealed a well-defined, smooth, purple nodule, 7 mm in diameter, with a peripheral brown rim (figure 1). the lesion was tender to light touch. dermoscopy disclosed a multicolored structureless pattern: a purple center surrounded by a whitish area and an outer brown pigmentation (figure 2). an excisional biopsy of the lesion was performed. further histopathological examination revealed intradermal sheets of monomorphic round cells, interrupted by enlarged vessels with varying size (figure 3, hematoxylin-eosin, x40). a fibrous pseudocapsule surrounding sheets of cells with an eosinophilic cytoplasm and central nuclei was also seen (figure 4, hematoxylin-eosin, x100). immunohistochemically, tumor cells were reactive for smooth muscle actin (figure 5). painful purple nodule on the right thigh andré oliveira1, susana brás1, adelaide milheiro2, jorge cardoso1 1 department of dermatology, hospital de curry cabral—centro hospitalar de lisboa central, lisboa, portugal 2 department of pathology, hospital de curry cabral—centro hospitalar de lisboa central, lisboa, portugal citation: oliveira a, brás s, milheiro a, cardoso j. painful purple nodule on the right thigh. dermatol pract concept 2015;5(2):15. http://dx.doi.org/10.5826/dpc.0502a15 copyright: ©2015 oliveira et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: andré oliveira, md, department of dermatology, hospital de curry cabral—centro hospitalar de lisboa central, rua da beneficência nº8, 1069-166, lisboa, portugal. tel. +35 1912561666; fax. +35 1217924392. e-mail: andre.oliveira@sapo.pt figure 1. a well-defined, smooth, purple nodule, 7 mm in diameter, with a peripheral brown rim. [copyright: ©2015 oliveira et al.] figure 2. dermoscopy: a multicolored structureless pattern, a purple center surrounded by a whitish area and an outer brown pigmentation. [copyright: ©2015 oliveira et al.] 84 quiz | dermatol pract concept 2015;5(2):15 what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical & conceptual. figure 3. histopathological examination revealed intradermal sheets of monomorphic round cells, interrupted by enlarged vessels with varying size. [copyright: ©2015 oliveira et al.] figure 4. histopathological examination revealed a fibrous pseudocapsule surrounding sheets of cells with an eosinophilic cytoplasm and central nuclei. [copyright: ©2015 oliveira et al.] figure 5. tumor cells were reactive for smooth muscle actin. [copyright: ©2015 oliveira et al.] dermatology: practical and conceptual 4 research | dermatol pract concept 2019;9(1):2 dermatology practical & conceptual comparing the efficacy of intralesional triamcinolone acetonide with verapamil in treatment of keloids: a randomized controlled trial nasrin saki1, raya mokhtari2, farnoosh nozari3 1 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran 2 dermatology department, shiraz university of medical sciences, shiraz, iran 3 student research committee, shiraz university of medical sciences, shiraz, iran key words: keloid, verapamil, triamcinolone, vancouver scar scale, scar citation: saki n, mokhtari r, nozari f. comparing the efficacy of intralesional triamcinolone acetonide with verapamil in treatment of keloids: a randomized controlled trial. dermatol pract concept. 2019;9(1):4-9. doi: https://doi.org/10.5826/dpc.0901a02 published: january 31, 2019 copyright: ©2019 saki et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: farnoosh nozari, student research committee, shiraz university of medical sciences, shiraz, iran. email: farnoosh.nozari.7391@gmail.com background: keloid management remains a challenging clinical problem despite numerous therapies reported until now. the efficacy of corticosteroids in the treatment of keloids has been well established. the most commonly used corticosteroid is intralesional triamcinolone. sporadic reports on the use of intralesional verapamil suggest its efficacy. aim: since there is not sufficient evidence to support the role of intralesional verapamil as an effective alternative modality, it was decided to undertake a randomized study to determine its efficacy as a treatment for keloids. methods: a randomized, single-blind, single-group comparison with 15 patients (30 scars) was carried out to compare the effects of intralesional triamcinolone with verapamil injections. injections were scheduled every 3 weeks accompanied by cryotherapy until complete flattening of the scar or maximum 8 sessions, whichever came earlier. scar evaluation at each stage was done by serial photographic records as well as by vancouver scar scale. statistical analysis was done by wilcoxon and mann-whitney u tests using spss version 19. results: in both study groups there was a reduction in height and pliability at the end of the study. better improvement in height and pliability was seen with triamcinolone in comparison with verapamil. however, a desired change in vascularity and pigmentation was not seen with either of the drugs. conclusion: verapamil is not as effective as triamcinolone in the treatment of keloids. abstract research | dermatol pract concept 2019;9(1):2 5 of prior treatment with any intralesional injections were excluded from the study. the minimum sample size of 15 patients with at least 2 scars (30 scars) was calculated for this trial, where triamcinolone was considered as the standard treatment and verapamil was regarded as the experimental drug. fifteen consecutive patients who fulfilled our inclusion criteria entered the study using simple randomization technique. two similar keloid scars of each patient were randomly selected, using simple randomization by random number table. deciding on putting which lesion into which therapeutic arm was randomly made by flipping a coin. a lidocaine 2 injection with ring block technique was used to anaesthetize the site of injection before starting the treatment. the injections were made with an insulin syringe, 27-gauge needle. one of the scars received intralesional tac (exir pharmaceutical co, borujerd, iran), while the other received intralesional verapamil hydrochloride (verahexal, knoll ag, ludwigshafen, germany) every 3 weeks for a maximum of 8 sessions or until complete flattening of the scar. each intralesional session was preceded by cryotherapy using cryospray technique for 20 seconds at 1 cm distance from the lesion. the maximum volume of triamcinolone (20 mg/ ml) and verapamil (2.5 mg/ml) at each session was 1.5 cc. we used multiple intralesional injections until the lesion was blanched. detailed history and demographic parameters including age, sex, duration of the scar, and prior treatments were recorded. scar evaluation at each stage was done by vancouver scar scale (vss) [8]. the mentioned scale scores the scars on 4 parameters: height, vascularity, pliability, and pigmentation. scar height was accurately measured with a ruler in millimeters. scar vascularity and pigmentation were assessed by visual inspection. scar pliability was subjectively assessed by palpation. for study parameters in each group, the mean value and standard deviation (sd) were calculated. the decreasing values reflect the clinical improvement of the scar. the wilcoxon test was used to test the significant improvement of vss parameters in each group. the vss scores were compared between the 2 groups using mann-whitney u test. p value <0.05 was considered to be statistically significant. statistical analysis was done using spss version 19. results thirty scars were studied in 15 randomly selected patients who met our inclusion criteria (15 scars treated with verapamil; 15 scars treated with triamcinolone). among 15 participants, 14 were female and 1 was male. the mean age of the patients was 31.53 ± 12.58 years (mean ± sd) and the mean duration of the disease was 11.46 ± 7.06 months. introduction characterized by firm, tender nodules or plaques, keloids occur more frequently on shoulders, chest, neck, upper arms, and face [1]. they are benign overgrowth of fibrous tissue, usually developing after healing of a skin injury due to trauma, inflammation, surgery, or burns and extend beyond the original defect [2]. the uncontrolled growth of keloids can lead to cosmetic disfigurement and functional impairment, which might adversely affect the quality of life [3]. a variety of treatment modalities such as silicone gel sheeting, intralesional injections, surgical manipulation, laser, and radiotherapy have been used, but no particular treatment has been shown to be effective for all cases [4]. drugs like bleomycin and 5-fluorouracil have better efficacy, but they are costly and cause severe drug reactions. surgery and laser therapy have their own limitations, while radiotherapy can cause malignancy [5]. corticosteroids seem to be effective in the treatment of keloids as they diminish collagen and glycosaminoglycan synthesis, inhibit fibroblast growth, enhance collagen and fibroblast degeneration, and have a powerful anti-inflammatory effect. triamcinolone acetonide (tac) is the most commonly used intralesional corticosteroid for keloid treatment. tac is cost-effective and practical and has become first-line treatment for keloids, in spite of some local adverse effects such as dermal atrophy, telangiectasia, and hypopigmentation [2]. it has been demonstrated that calcium channel blockers decrease extracellular matrix production in scars. furthermore, they depolymerize actin filaments to modify fibroblast morphology by a consequent increased secretion of pro-collagenase [6]. intralesional verapamil hydrochloride has already been successfully applied for the treatment of keloids [7]. this study was hence conducted to assess the efficacy of intralesional verapamil in the treatment of keloids by its comparison with the effects of intralesional triamcinolone. methods the study was conducted at the department of dermatology, faghihi hospital, shiraz, iran, from december 2017 to december 2018. this study was approved by the local ethics committee of shiraz university of medical sciences and registered in the iranian clinical trial registry. all patients signed the informed consent form prior to initiation of the trial. this study is a randomized, single-group, single-blind comparison between triamcinolone and verapamil injection. inclusion criteria involved patients aged between 18 and 70 years old, with at least 2 scars with duration of less than 2 years. patients with evidence of any infection (in or near the scar area), those with a history of cardiovascular problems, pregnant women, and patients with a history 6 research | dermatol pract concept 2019;9(1):2 figures 2 and 3 represent the beforeafter photographs of a patient in the triamcinolone and verapamil groups, respectively. discussion despite numerous developed therapies, keloid treatment has remained a challenging clinical problem. this might be due to the fact that the mechanisms of development of keloids have not been completely understood [9]. laser therapy, surgical removal, radiation therapy, silicone gel, cryosurgery, intralesional injection of various agents, and occlusive dressing have all been used either alone or in various combinations [10]. however, evolution of different therapies has not significantly improved their success rates. in addition, each method has its own limitations such as high cost, poor efficacy, recurrence, and adverse effects (such as malignancy). the vss parameters for both treatment groups are presented in table 1. at the beginning of the study, there was no significant difference in parameters of the 2 groups (p > 0.05). in both study groups, there was a reduction in height and pliability at the end of the study as determined by wilcoxon test (table 2). using mann-whitney u test, statistically better improvement in height and pliability was observed in the triamcinolone-receiving group compared with the verapamil-receiving group (p < 0.001). however, a desired change in vascularity and pigmentation was not seen with either of the drugs (table 2). scar vascularity became worse in 1 out of 15 scars in the triamcinolone group. it can be observed that 12 out of 15 scars in both groups had normal pigmentation at the start of the study. after 24 weeks, 1 out of 3 hyperpigmented scars in the verapamil group regained normal pigmentation while the other 2 scars remained hyperpigmented. however, out of 3 hyperpigmented scars in the triamcinolone group, 1 regained normal pigmentation while the other 2 scars became hypopigmented at the end of our trial (table 3). no significant difference was detected in vascularity and pigmentation in the 2 groups (p > 0.05). the changes in vss score parameters within 24 weeks of follow-up in both groups are shown in figure1. table 1. mean vss scores during 24 weeks of follow-up intralesional injection interval in weeks with mean vss scores ± sd vss parameters drug 0 wks 3 wks 6 wks 9 wks 12 wks 15 wks 18 wks 21 wks 24 wks height v 4.11±1.90 4.11±1.90 4.04±1.92 3.90±1.95 3.77±1.94 3.77±1.94 3.71±1.99 3.43±2.04 3.10±1.85 t 4.25±1.94 3.98±1.92 2.97±2.07 1.97±2.06 1.16±1.91 0.82±1.95 0.55±1.12 0.34±0.90 0.21±0.56 vascularity v 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 0.87±0.74 t 0.87±0.74 0.93±0.70 0.93±0.70 0.93±0.70 0.93±0.70 0.93±0.70 0.93±0.70 0.93±0.70 0.93±0.70 pliability v 2.87±0.35 2.87±0.35 2.87±0.35 2.80±0.41 2.73±0.46 2.73±0.46 2.60±0.51 2.27±0.46 2.07±0.26 t 2.87±0.35 2.73±0.46 1.93±0.70 1.20±1.01 0.67±0.90 0.47±0.83 0.47±0.83 0.27±0.59 0.20±0.41 pigmentation v 0.40±0.83 0.40±0.83 0.40±0.83 0.40±0.83 0.40±0.83 0.40±0.83 0.40±0.83 0.27±0.70 0.27±0.70 t 0.40±0.83 0.40±0.83 0.20±0.56 0.13±0.35 0.13±0.35 0.13±0.35 0.13±0.35 0.13±0.35 0.13±0.35 wks = weeks; v = verapamil; t = triamcinolone; sd = standard deviation. table 2. mean vss scores ± sd before and after treatment in triamcinolone and verapamil groups vss parameters drug week 0 week 24 p value height v 4.11±1.90 3.10±1.85 <0.001 t 4.25±1.94 0.21±0.56 <0.001 vascularity v 0.87±0.74 0.87±0.74 1 t 0.87±0.74 0.93±0.70 0.32 pliability v 2.87±0.35 2.07±0.26 <0.001 t 2.87±0.35 0.20±0.41 <0.001 pigmentation v 0.40±0.83 0.27±0.70 0.32 t 0.40±0.83 0.13±0.35 0.10 v = verapamil; t = triamcinolone; sd = standard deviation. table 3. improvement in the pigmentation of scars in both groups 0 week 24 weeks pigmentation normal hypohypernormal hypohyperverapamil 12 0 3 13 0 2 triamcinolone 12 0 3 13 2 0 research | dermatol pract concept 2019;9(1):2 7 production. they suggested that calcium antagonists depolymerize actin filaments and alter the shape of fibroblast cells from bipolar to spherical, which may result in increased procollagenase production [12]. shanthi et al showed a reduction in vascularity, pliability, and height of the scars with both triamcinolone and verapamil injections [5]. it has also been found that this reduction is faster by triamcinolone injection. however, a desired change in pigmentation was not observed with either of the drugs. they found that similar to triamcinolone, verapamil significantly improved the clinical parameters of the scars; keloids are overgrowth of dense fibrous tissue developing after trauma to the skin [11]. although the basis of keloid formation has not been fully understood, an imbalance of matrix degradation and collagen biosynthesis, which could result in excess accumulation of collagen in wound, has been considered the primary biochemical feature of these skin lesions [10]. furthermore, inflammation or alteration of growth factors may contribute to keloid formation [11]. as cellular secretion of macromolecules is known to be a calcium-dependent process, lee and ping in 1990 examined the effects of calcium antagonists on extracellular matrix figure 1. line charts for scar height, pliability, vascularity and pigmentation in both groups. [copyright: ©2019 saki et al.] 8 research | dermatol pract concept 2019;9(1):2 compared with those treated with verapamil. in contrast to studies of shanthi et al [5] and ahuja and chatterjee [6], the scars of both groups in our study did not reach complete flattening and normal pliability at the end of the study. the possible reason could be the higher initial mean scores of height and pliability in both groups relative to the mentioned studies. however, no significant difference was found in the pigmentation of the scars before and after treatment in both groups. it could be due to the fact that most of the scars had normal pigmentation at the beginning of our study. this finding is compatible with previous studies. however, in contrast to previous works, scar vascularity did not show significant difference with both treatments at the end of our study [5,6]. the results of the present study suggest that verapamil can be considered a safe treatment for patients with keloids, but it is not as effective as triamcinolone. to date, corticosteroid injection is the core treatment available for keloid management. corticosteroids suppress keloid formation by 3 different mechanisms. first, they suppress inflammation by inhibition of leukocyte and monocyte migration and phagocytosis. second, corticosteroids are potent vasoconstrictors that reduce delivery of oxygen and nutrients to the wound. third, the antimitotic effect of corticosteroids inhibits proliferation of keratinocytes and fibroblasts, slowing reepithelialization and new collagen formation. corticosteroid injection decreases collagen and glycosaminoglycan synthesis by several mechanisms including decline of inflammatory process in the wound, decreasing fibroblast proliferation, and hypoxia enhancement. they also lead to decreased levels of endogenous vascular endothelial growth factor (vegf), transforming growth factor beta (tgf-β), and interleukin-1 (il-1), which play important roles in the process of keloid formation [13]. however, calcium antagonists merely affect this process by reduction of collagen production in the extracellular matrix and stimulation of collagenase synthesis, which will decrease fibrous tissue production [7]. conclusions in conclusion, given the anti-inflammatory and antimitotic effects of triamcinolone plus its vasoconstrictor properties, triamcinolone would be an effective treatment for keloids in comparison to verapamil. however, further studies involving a higher number of participants with a longer period of observation are encouraged to shed more light on this subject. references 1. lee ss, yosipovitch g, chan yh, goh cl. pruritus, pain, and small nerve fiber function in keloids: a controlled study. j am acad dermatol. 2004;51(6):1002-1006. hence, it can be a suitable alternative to triamcinolone for treatment of hypertrophic scars and keloids [5]. ahuja and chatterjee showed that a faster rate of improvement in scar height, vascularity, and pliability is achievable with triamcinolone. however, the difference in the rate of pigmentation change by the 2 agents was not statistically significant [6]. the present study was a randomized, single-blind clinical trial comparing the efficacy of intralesional verapamil with intralesional triamcinolone in the treatment of keloids. a significant improvement was observed in the height and pliability of the scars in both groups. in agreement with the literature, the improvement of these parameters was significantly higher in the scars treated with triamcinolone figure 2. before and after photographs of a patient in the triamcinolone group. [copyright: ©2019 saki et al.] figure 3. before and after photographs of a patient in the verapamil group. [copyright: ©2019 saki et al.] research | dermatol pract concept 2019;9(1):2 9 8. sullivan ta, smith j, kermode j, mclver e, courtemanche d. rating the burn scar. j burn care rehabil. 1990;11(3):256-260. 9. mofikoya bo, adeyemo wl, abdus-salam aa. keloid and hypertrophic scars: a review of recent developments in pathogenesis and management. nig q j hosp med. 2007;17(4):134-139. 10. manuskiatti w, fitzpatrick re. treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. arch dermatol. 2002;138(9):1149-1155. 11. leventhal d, furr m, reiter d. treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. arch facial plast surg. 2006;8(6):362-368. 12. lee rc, ping ja. calcium antagonists retard extracellular matrix production in connective tissue equivalent. j surg res. 1990;49(5):463-466. 13. roques c, téot l. the use of corticosteroids to treat keloids: a review. int j low extrem wounds. 2008;7(3):137-145. 2. garg am, shah ym, garg a, et al. the efficacy of intralesional triamcinolone acetonide (20mg/ml) in the treatment of keloid. int surg j. 2018;5(3):868-872. 3. robles dt, berg d. abnormal wound healing: keloids. clin dermatol. 2007;25(1):26-32. 4. gauglitz gg, korting hc, pavicic t, ruzicka t, jeschke mg. hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. mol med. 2011;17(1-2):113. 5. shanthi fm, ernest k, dhanraj p. comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. indian j dermatol venereol leprol. 2008;74(4):343. 6. ahuja rb, chatterjee p. comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. burns. 2014;40(4):583-588. 7. d’andrea f, brongo s, ferraro g, baroni a. prevention and treatment of keloids with intralesional verapamil. dermatology. 2002;204(1):60-62. dermatology: practical and conceptual review | dermatol pract concept 2019;9(2):1 75 dermatology practical & conceptual nonsurgical options for the treatment of basal cell carcinoma john paoli1,2, johan dahlén gyllencreutz3, julia fougelberg1,2, eva johansson backman1,2, maja modin1,2, sam polesie1,2, oscar zaar1,2 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 3 department of dermatology and venereology, skaraborg hospital, skövde, sweden key words: basal cell carcinoma, destructive therapy, topical drugs, radiotherapy, hedgehog inhibitors citation: paoli j, dahlén gyllencreutz j, fougelberg j, johansson backman e, modin m, polesie s, zaar o. nonsurgical options for the treatment of basal cell carcinoma. dermatol pract concept. 2019;9(2):75-81. doi: https://doi.org/10.5826/dpc.0902a01 accepted: november 15, 2018; published: april 30, 2019 copyright: ©2019 paoli et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: john paoli, md, assoc. prof, department of dermatology and venereology, sahlgrenska university hospital, 413 45 gothenburg, sweden. email: john.paoli@vgregion.se objectives: the aim of this review article is to summarize the effectiveness, potential adverse events, and indications of the main nonsurgical treatment alternatives for basal cell carcinoma. methods: an extensive literature review was carried out. the most relevant articles were discussed and selected by the authors in order to provide a brief but evidence-based overview of the most common nonsurgical methods used for treating basal cell carcinoma. results: although surgery and mohs micrographic surgery are often considered the optimal treatment options for basal cell carcinoma, these tumors can also be treated successfully with destructive techniques (eg, curettage alone, cryosurgery, or electrodesiccation), photodynamic therapy, topical drugs (eg, 5-fluorouracil, imiquimod, or ingenol mebutate), radiotherapy, or hedgehog pathway inhibitors. when choosing between these alternatives, physicians must take into consideration the tumor’s size, location, and histopathological subtype. special care should be taken when treating recurrent tumors. furthermore, physician experience is of great importance when using destructive techniques. finally, patient preference, potential adverse events, and cosmetic outcome should also be considered. conclusions: dermatologists and physicians treating basal cell carcinoma should have knowledge of and experience with the large arsenal of therapeutic alternatives available for the successful, safe, and individualized management of patients with basal cell carcinoma. abstract introduction basal cell carcinoma (bcc) is by far the most common cancer type in humans [1]. in europe, reports show bcc incidence rates between 77 and 158 per 100,000 person-years age-standardized to the european standard population [1]. exposure from ultraviolet radiation is believed to be the main risk factor for developing bccs. this belief is supported by the fact that the majority of bccs are found on sun-exposed body parts in middle-aged to elderly people [1,2]. the exact 76 review | dermatol pract concept 2019;9(2):1 inoperable bccs may benefit from radiotherapy or hedgehog pathway inhibitors (hpis) [1,16,17]. the aim of this review is to summarize the effectiveness, potential adverse events, and indications of the main nonsurgical treatment alternatives for bcc. destructive methods curettage alone bccs amenable to treatment with curettage alone are primary tumors with a superficial or nodular growth pattern with well-defined borders not involving the free margin of the eyelid, mucosal lip, or subcutaneous fat. for nbccs, the size is recommended to be <6 mm in high-risk areas, and below 20 mm elsewhere. the few studies on curettage alone were carried out many years ago and did not use a unifying technique. in some countries, including the usa, a shave biopsy is performed first, removing the tumor almost completely prior to curettage. in other countries, including sweden, curettage is performed directly, removing the entire tumor with the curette. nevertheless, 3 retrospective studies have reported similar clearance rates of 89.9%-96.0% after 5 years of follow-up. better cosmesis with minimal hypopigmentation or scarring was observed in patients treated with curettage alone compared with those treated with curettage and electrodesiccation (c&ed) [18-20]. curettage and electrodesiccation although c&ed has been used for decades as a simple and easily performed therapy for low-risk bccs, there is a lack of randomized controlled studies on the method. several retrospective studies show its effectiveness for correctly selected lesions (93.0%-96.9% clearance rates after 5 years of followup), but many studies fail to provide precise descriptions on the materials and technical protocols that are used [21,22]. in the latest american academy of dermatology guidelines, c&ed is one of the recommended treatment options for carefully selected low-risk primary lesions [16]. in terminal hair-bearing skin, with a potential follicular extension of the tumor (scalp, pubic, and axillary regions as well as the beard area in men), c&ed is considered less effective [17]. the effectiveness depends heavily on the physician’s skills and technique, and therefore proper training is important [23,24]. furthermore, the cosmetic outcome is regarded as inferior compared with standard excision and therefore it is best avoided in cosmetically sensitive areas [25]. cryotherapy cryotherapy with liquid nitrogen (−196.5°c) has been used to treat nonmelanoma skin cancer since the early 1960s [26]. it is a well-established treatment method for small, well-defined origin of bcc is not established, but they are considered to arise from keratinocyte cells located in the basal layer and in the dermo-epidermal junction zone [3]. the world health organization classification of bcc includes superficial, nodular, micronodular, and infiltrating basal cell carcinoma. moreover, the group includes fibroepithelial basal cell carcinoma with adnexal differentiation, basosquamous carcinoma, and keratotic basal cell carcinoma [4]. the infiltrative, morpheaform, and micronodular subtypes grow in a more aggressive way, whereas superficial and nodular subtypes generally have a less aggressive course and generally respond better to treatment [5]. clinically, dermoscopy can assist physicians in the correct diagnosis of bcc, including the histopathological subtype, with relatively high diagnostic accuracy [6-8]. the first articles on bcc focused on pigmented bccs showing a lack of pigment network in combination with blue-gray ovoid nests, multiple blue-gray dots/globules, leaf-like areas, spoke wheel/concentric areas, ulceration, and/or arborizing vessels [6,7,9]. in nodular bcc (nbcc), arborizing vessels are a common finding, sometimes together with ulceration [10]. under polarized light, shiny white lines can also be found [11]. superficial bccs (sbccs) characteristically show fine, short telangiectasias on a whitish-red background and multiple erosions [7,8,12]. the dermoscopic findings in more aggressive forms of bcc are less well studied. in infiltrative bccs, arborizing vessels are usually thinner than in nbccs. other findings include white-red structureless areas and ulceration. the morpheaform variant is often feature-poor, even when using dermoscopy. a white background can often be seen, sometimes together with a smaller number of thin arborizing vessels [13]. during the latest decades, insights into genetic and molecular changes behind the origin of bcc have increased. these understandings have to some extent been derived from studying patients with different genetic syndromes predisposing them to bcc development (eg, gorlin syndrome) who have a higher risk of developing bccs [14]. individuals with gorlin syndrome develop multiple bccs starting at an early age and the responsible mutation lies in the hedgehog (hh) receptor patched 1 (ptch1) gene that mediates sonic hh signaling. research has reported abnormal function and mutations in ptch1 in up to 90% of bccs, making it a target for drug development [3]. with regard to the management of bcc, surgery (including mohs micrographic surgery) is considered the gold standard [1,15,16]. nevertheless, with the rising number of patients with bcc, increasing health care costs, and the lack of access to dermatologists in many countries, nonsurgical options may be considered. many low-risk tumors can be successfully managed with destructive methods, photodynamic therapy (pdt), or topical medications, while advanced or review | dermatol pract concept 2019;9(2):1 77 [37,44], while the photosensitizing prodrug used does not seem to influence the outcome [45,46]. the histopathological subtype influences the result of pdt as pigmented, morphoeic, and infiltrative bccs are more resistant to treatment. the clearance rates following pdt for sbccs range from 76% to 82% in several studies [37,38,42], but could be as low as 58% [47]. the success rate is slightly lower for nbccs in general (53%-76%) [36,39-41]. debulking nbccs with curettage prior to pdt provides long-term clearance rates of 62%-73% [36,41,43] compared with light curettage without debulking, which provides more varying clearance rates of 33%-76% [38,40]. fewer recurrences have been observed when patients with nonaggressive bccs receive pdt in 2 sessions (91%) compared with only 1 session of pdt (68%) with a follow-up of 6 years [48]. three randomized controlled trials have compared the efficacy of aminolevulinic acid pdt and methyl aminolevulinate (mal) pdt for bccs, showing comparable effectiveness [45,46,49]. modifications to pdt have been tested to decrease the recurrence rate for bcc. daylight pdt may provide similar clearance rates compared with conventional pdt, but with less pain [50]. however, larger studies with longer follow-up times are needed to confirm its effectiveness. treating bccs with a fractional laser prior to pdt may improve the depth of penetration of the prodrug and has shown lower recurrence rates than conventional pdt for high-risk bccs (19% vs 44%) [51].  a meta-analysis by wang et al showed no significant differences in recurrence rates when comparing pdt to either cryotherapy or pharmacological treatment. however, surgery proved to have significantly lower risk of failure when compared with pdt. the same analysis showed a “good to excellent” cosmetic result comparing pdt to surgery or cryotherapy, but no significant differences when comparing it to other medical treatments [52]. topical medication 5-fluorouracil topical 5-fluorouracil (5-fu) 5% inhibits dna synthesis and was the first topical therapy approved for the treatment of sbcc [53]. however, compared with pdt and imiquimod, fewer well-designed studies evaluating this indication have been published [47,54]. in a prospective, single-arm, clinical study, 29 patients with 31 histopathologically confirmed sbccs were treated with 5-fu applied twice daily for up to 12 weeks. the lesions were excised 3 weeks after treatment with a histopathological clearance rate of 90% [53]. a single-blind, noninferiority, randomized controlled trial with 601 histopathologically confirmed sbccs compared the use of pdt (2 sessions with an interval of 1 week) with topical imiquimod (once daily, 5 times/week for 6 weeks) and primary bccs without sclerosing or infiltrative growth patterns. location below the knee is a relative contraindication because of prolonged wound healing [27]. large treatment series have shown clearance rates of 97%-99% after at least 5 years of follow-up [28,29]. as for c&ed, there are few prospective randomized trials on cryotherapy for bccs and different techniques and protocols are used, making comparisons difficult. most studies on cryotherapy involve prior curettage. curettage is regarded as a help in delineating the lateral extension and depth of the tumor and also to diminish the amount of tumor mass that has to be sloughed off during the healing process following cryotherapy. three prospective studies using a standardized curettage and cryotherapy protocol have reported very high clearance rates of >98% for bccs located in the face and scalp area, especially on the nose and ear [29-31]. the protocol in all 3 studies involves curettage followed by a double freeze-thaw cycle. thorough curettage with different sized curettes is first used to debulk the tumor and to identify the lateral and deep extension. following hemostasis with a 50% iron chloride solution, a 3-mm thick, open and appropriately sized neoprene cone is placed around the ulcerated area. subsequently, freezing takes place with maximal continuous liquid nitrogen spray using a hand-held cry-ac (brymill corp., ellington, ct, usa) through a size b nozzle, held horizontally and at a distance of approximately 1 cm while moved in circular motions over the treatment area. freezing is interrupted when the lateral spread of freeze (halo) has reached a minimum of 5 mm outside the tumor border or 1.0-1.5 mm outside the neoprene cone. the thaw time of the halo should last at least 60 seconds. after complete thawing, the freeze-thaw cycle is repeated. cryotherapy in a double freeze-thaw cycle as described above but without previous curettage has also shown excellent clearance rates for well-defined bccs of the eyelids with a 10-year recurrence rate of <0.5% [32]. photodynamic therapy pdt is an alternative approach to treat superficial nonmelanoma skin cancer, including bcc [33]. pdt for bcc is often well tolerated, but pain and/or a burning sensation is often experienced during the illumination phase [34]. after pdt, localized erythema and edema are common, followed by the formation of erosions and crusts with healing over a period of 2-6 weeks [1]. pdt is considered an interesting alternative treatment because it is noninvasive, it targets neoplastic cells selectively, it is cost-effective, and it offers a good cosmetic outcome [35,36]. there are many different treatment protocols for pdt and results vary depending on the bcc subtype [36-42], prior curettage [36,38,40,41,43], and number of pdt sessions 78 review | dermatol pract concept 2019;9(2):1 treatment of actinic keratosis through induction of primary necrosis of tumor cells, and neutrophil-mediated, antibodydependent cellular cytotoxicity of residual malignant cells [60]. im comes in 2 concentrations: 0.015% for the face and 0.05% for the trunk. recently, several case reports of successful off-label treatment of sbcc with topical im have been reported [61-65]. in a retrospective study, including 7 patients with sbcc treated with im gel 0.05% once daily for 2-7 days, there were no clinical signs of recurrence after 2-14 months [66]. a phase iia study including 60 patients with safety as the primary endpoint evaluated the treatment of sbcc with im at concentrations of 0.01/0.025/0.05% applied for 2 consecutive days or on day 1 and 8. the incidence of adverse events was generally low. the efficacy (secondary endpoint) appeared to be dose-related with up to 63% histopathological clearance with the highest dosage after 12 weeks [60]. another phase i/ii clinical study including 28 bccs (6 nbccs and 22 sbccs), which were unresponsive to earlier treatment or unsuitable for surgery, treated with sap from e peplus once daily for 3 days, showed complete clinical clearance in 82% after 1 month and 57% after 2-31 months, while sbccs smaller than 16 mm (n = 9) had a 78% clearance after a mean follow-up of 15 months [67]. for sbccs unsuitable for conventional treatment, im can offer an alternative treatment strategy in selected patients, but close follow-up is advised. radiotherapy the vast majority of bccs are treated with surgery or the destructive methods listed above. although rare, some bccs are neglected and/or are inaccessible to standard treatments. in these rare cases, radiotherapy (rt) may be considered. patients unwilling to undergo surgery or with significant comorbidities might also be candidates for this treatment option. there are 3 different radiation modalities: low-energy x-rays, brachytherapy, and high-energy rt. treatment success is generally 90%, which is in line with surgical treatment [68]. however, only a few clinical trials have been conducted, and there is no consensus on optimal treatment duration and which radiation modality should be selected [69]. rt is given in fractions of 30-70 gy over 2-7 weeks, which requires multiple visits to a specialized clinic. a prospective randomized trial selecting patients for surgery or rt with a subrandomization to long and short rt would be helpful to clarify which radiation modality is superior with regard to recurrence rates. due to long-term consequences such as radiodermatitis and the risk of secondary malignancies, mainly patients over 60 years should be considered for rt. in a canadian study, the cost of managing high-risk facial bccs with rt was higher than that of mohs micrographic surgery [70]. moreover, prior to initiation, a multidisciplinary decision with an experienced radiation oncologist and thorough patient information is topical 5-fu (twice daily for 4 weeks). in this study, topical 5-fu was noninferior to pdt and imiquimod was superior to pdt. furthermore, topical 5-fu and imiquimod were more often associated with mild to moderate adverse events in the treatment area than was pdt [55]. a 5-year follow-up on the study recently declared the probability of tumor-free survival to be 62.7% for pdt, 80.5% for imiquimod, and 70.0% for 5-fu [56]. in summary, 5-fu is approved for treatment of sbcc, appears to be noninferior to pdt, and is generally well tolerated. therefore, it can be considered a therapeutic option in the treatment of sbcc. imiquimod imiquimod works as an immunomodulator by activating toll-like receptor 7, resulting in stimulation of dendritic cells residing in both the epidermis and dermis to attract natural killer cells and produce cytokines via proliferation of b lymphocytes. the treatment regimen is classically topical imiquimod 5% applied once daily, 5 days per week for 6 weeks in sbcc and 12 weeks in nbcc. jansen et al recently presented 1-, 3-, and 5-year efficacy data on imiquimod in more than 100 histopathologically confirmed sbccs. after 1 year, 83.5% of the sbccs were successfully treated and at 5 years 80.5% still showed no recurrences [56]. similar findings were made by bath-hextall et al, who treated 254 bcc lesions (both superficial and nodular) with imiquimod with clearance rates of 85.1% for sbccs and 81.8% for nbccs at 3 years [57]. williams et al later presented 5-year results from the same cohort with an 83.8% success rate for sbcc and 81.1% for nbccs [58]. in these 2 studies, the recurrences were based on clinical assessment and were not histopathologically confirmed. with regard to aesthetic outcome, arits et al reported in a large randomized controlled trial that imiquimod and mal-pdt have similar results with good to excellent outcomes in 61.4% and 62.4% of the cases, respectively [55]. a cost-effectiveness study on topical treatments for bcc show that imiquimod and 5-fu are superior to mal-pdt at 12 months but longer follow-up time is needed to assess the costeffectiveness between imiquimod and 5-fu [59]. when compared with mal-pdt for sbccs, imiquimod is known to be superior in general but a subgroup analysis performed by roozeboom et al in a randomized controlled trial with 200 lesions in each treatment arm revealed that pdt might outperform imiquimod. also, in patients over 60 years of age with sbcc on the lower extremities, mal-pdt was significantly more effective than imiquimod at 1-year follow-up [47]. ingenol mebutate ingenol mebutate (im) gel is a topical agent derived from sap from the plant euphorbia peplus, which is approved for review | dermatol pract concept 2019;9(2):1 79 ence with the techniques; the expected adverse events; patient preference; and cosmetic outcome. references 1. trakatelli m, morton c, nagore e, et al. update of the european guidelines for basal cell carcinoma management. eur j dermatol. 2014;24(3):312-329. 2. el ghissassi f, baan r, straif k, et al. a review of human carcinogens, part d: radiation. lancet oncol. 2009;10(8):751-752. 3. kasper m, jaks v, hohl d, toftgard r. basal cell carcinoma: molecular biology and potential new therapies. j clin invest. 2012;122(2):455-463. 4. leboit pe. pathology and genetics of skin tumours. iarc press; 2006. 5. weinstock ma. epidemiology of nonmelanoma skin cancer: clinical issues, definitions, and classification. j invest dermatol. 1994;102(6):4s-5s. 6. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62(1):67-75. 7. lallas a, tzellos t, kyrgidis a, et al. accuracy of dermoscopic criteria for discriminating superficial from other subtypes of basal cell carcinoma. j am acad dermatol. 2014;70(2):303-311. 8. suppa m, micantonio t, di stefani a, et al. dermoscopic variability of basal cell carcinoma according to clinical type and anatomic location. j eur acad dermatol venereol. 2015;29(9):1732-1741. 9. menzies sw, westerhoff k, rabinovitz h, kopf aw, mccarthy wh, katz b. surface microscopy of pigmented basal cell carcinoma. arch dermatol. 2000;136(8):1012-1016. 10. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermatol. 2004;140(12):1485-1489. 11. liebman tn, jaimes-lopez n, balagula y, et al. dermoscopic features of basal cell carcinomas: differences in appearance under non-polarized and polarized light. dermatol surg. 2012;38(3):392-399. 12. giacomel j, zalaudek i. dermoscopy of superficial basal cell carcinoma. dermatol surg. 2005;31(12):1710-1713. 13. lallas a, apalla z, argenziano g, et al. the dermatoscopic universe of basal cell carcinoma. dermatol pract concept. 2014;4(3):11-24. 14. castori m, morrone a, kanitakis j, grammatico p. genetic skin diseases predisposing to basal cell carcinoma. eur j dermatol. 2012;22(3):299-309. 15. bath-hextall f, bong j, perkins w, williams h. interventions for basal cell carcinoma of the skin: systematic review. bmj. 2004;329(7468):705. 16. kim jys, kozlow jh, mittal b, moyer j, olencki t, rodgers p. guidelines of care for the management of basal cell carcinoma. j am acad dermatol. 2018;78(3):540-559. 17. national comprehensive cancer center. nccn clinical practice guidelines in oncology. basal cell skin cancer (version 1.2018). 2017. https://www.nccn.org/professionals/physician_gls/pdf/ nmsc.pdf . accessed august 7, 2018. 18. barlow jo, zalla mj, kyle a, dicaudo dj, lim kk, yiannias ja. treatment of basal cell carcinoma with curettage alone. j am acad dermatol. 2006;54(6):1039-1045. mandatory. finally, recurring bcc after rt is a surgical challenge and this should be carefully considered. hedgehog pathway inhibitors hpis have emerged as an important treatment option for locally advanced bcc or in the rare event of metastatic bcc [71]. there are 2 commercially available hpis: vismodegib and sonidegib. in a systematic review investigating vismodegib, 65% of patients with locally advanced bcc experienced complete or partial response, whereas 31% had a complete response rate. the corresponding numbers for metastatic bcc were 34% and 4%, respectively. however, among 803 patients, 31% discontinued the treatment because of side effects [72]. muscle spasms, dysgeusia, fatigue, weight loss, and alopecia are common. in addition, treatment with hpi is associated with high costs (approximately €4500/month). neoadjuvant treatment with hpis prior to surgery for selected cases has been evaluated with positive results [73], but prospective randomized controlled trials are lacking. when selecting this treatment option there is risk for multifocal remaining disease, which might complicate surgery. although there is no consensus, concurrent treatment with rt and hpis may be evaluated in selected cases [74]. conclusions this review shows that several effective nonsurgical therapeutic alternatives exist for the successful, safe, and individualized management of bcc. physicians managing patients with bccs need to be aware of the indications, effectiveness, and potential adverse events of this wide range of treatment methods so that they are able to select the most adequate method for each patient and clinical scenario. physicians also need specific training in each method in order to reproduce the same clinical outcome seen in the aforementioned studies. furthermore, physicians should be aware of the lack of randomized controlled trials for many of the nonsurgical procedures mentioned, even though they are regularly carried out by the dermatological community. more extensive guideline documents for the general management of bccs have been published by associations such as the european dermatology forum [1], the american academy of dermatology [16], and the national comprehensive cancer network [17], and this review does not intend to substitute any of them. however, the techniques mentioned herein can provide excellent results for the ever-growing number of patients who can benefit from nonsurgical approaches to managing bcc as long as the treating physician takes into account tumor size, location, and histopathological subtype; whether the tumor is primary or recurrent; their own experi80 review | dermatol pract concept 2019;9(2):1 38. fantini f, greco a, del giovane c, et al. photodynamic therapy for basal cell carcinoma: clinical and pathological determinants of response. j eur acad dermatol venereol. 2011;25(8):896-901. 39. peng q, warloe t, berg k, et al. 5-aminolevulinic acid-based photodynamic therapy: clinical research and future challenges. cancer. 1997;79(12):2282-2308. 40. rhodes le, de rie ma, leifsdottir r, et al. five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. arch dermatol. 2007;143(9):1131-1136. 41. soler am, warloe t, tausjo j, berner a. photodynamic therapy by topical aminolevulinic acid, dimethylsulphoxide and curettage in nodular basal cell carcinoma: a one-year follow-up study. acta derm venereol. 1999;79(3):204-206. 42. szeimies rm, ibbotson s, murrell df, et al. a clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up. j eur acad dermatol venereol. 2008;22(11):1302-1311. 43. berroeta l, clark c, dawe rs, ibbotson sh, fleming cj. a randomized study of minimal curettage followed by topical photodynamic therapy compared with surgical excision for low-risk nodular basal cell carcinoma. br j dermatol. 2007;157(2):401403. 44. wang i, bendsoe n, klinteberg ca, et al. photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase iii clinical trial. br j dermatol. 2001;144(4):832-840. 45. kuijpers di, thissen mr, thissen ca, neumann mh. similar effectiveness of methyl aminolevulinate and 5-aminolevulinate in topical photodynamic therapy for nodular basal cell carcinoma. j drugs dermatol. 2006;5(7):642-645. 46. schleier p, berndt a, kolossa s, zenk w, hyckel p, schultzemosgau s. comparison of aminolevulinic acid (ala)-thermogelpdt with methyl-ala-thermogel-pdt in basal cell carcinoma. photodiagnosis photodyn ther. 2007;4(3):197-201. 47. roozeboom mh, arits ah, mosterd k, et al. three-year followup results of photodynamic therapy vs. imiquimod vs. fluorouracil for treatment of superficial basal cell carcinoma: a single-blind, noninferiority, randomized controlled trial. j invest dermatol. 2016;136(8):1568-1574. 48. christensen e, skogvoll e, viset t, warloe t, sundstrom s. photodynamic therapy with 5-aminolaevulinic acid, dimethylsulfoxide and curettage in basal cell carcinoma: a 6-year clinical and histological follow-up. j eur acad dermatol venereol. 2009;23(1):5866. 49. morton ca, dominicus r, radny p, et al. a randomized, multinational, noninferiority, phase iii trial to evaluate the safety and efficacy of bf-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy. br j dermatol. 2018;179(2):309-319. 50. wiegell sr, skodt v, wulf hc. daylight-mediated photodynamic therapy of basal cell carcinomas: an explorative study. j eur acad dermatol venereol. 2014;28(2):169-175. 51. haak cs, togsverd-bo k, thaysen-petersen d, et al. fractional laser-mediated photodynamic therapy of high-risk basal cell carcinomas: a randomized clinical trial. br j dermatol. 2015;172(1):215-222. 52. wang h, xu y, shi j, gao x, geng l. photodynamic therapy in the treatment of basal cell carcinoma: a systematic review 19. mcdaniel we. therapy for basal cell epitheliomas by curettage only: further study. arch dermatol. 1983;119(11):901-903. 20. reymann f. 15 years’ experience with treatment of basal cell carcinomas of the skin with curettage. acta derm venereol suppl (stockh). 1985;120:56-59. 21. knox jm, lyles tw, shapiro em, martin rd. curettage and electrodesiccation in the treatment of skin cancer. arch dermatol. 1960;82:197-204. 22. williamson gs, jackson r. treatment of basal cell carcinoma by electrodesiccation and curettage. can med assoc j. 1962;86:855862.. 23. kopf aw, bart rs, schrager d, lazar m, popkin gl. curettageelectrodesiccation treatment of basal cell carcinomas. arch dermatol. 1977;113(4):439-443. 24. sweet rd. the treatment of basal cell carcinoma by curettage. br j dermatol. 1963;75:137-148. 25. rodriguez-vigil t, vazquez-lopez f, perez-oliva n. recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation. j am acad dermatol. 2007;56(1):91-95. 26. copper is. cryogenic surgery: a new method of destruction or extirpation of benign or malignant tissues. n engl j med. 1963;268:743-749. 27. zacarian sa. cryosurgery of cutaneous carcinomas. an 18-year study of 3,022 patients with 4,228 carcinomas. j am acad dermatol. 1983;9(6):947-956. 28. kuflik eg. cryosurgery for skin cancer: 30-year experience and cure rates. dermatol surg. 2004;30(2 pt 2):297-300. 29. lindemalm-lundstam b, dalenback j. prospective follow-up after curettage-cryosurgery for scalp and face skin cancers. br j dermatol. 2009;161(3):568-576. 30. nordin p, larko o, stenquist b. five-year results of curettagecryosurgery of selected large primary basal cell carcinomas on the nose: an alternative treatment in a geographical area underserved by mohs’ surgery. br j dermatol. 1997;136(2):180-183. 31. nordin p, stenquist b. five-year results of curettage-cryosurgery for 100 consecutive auricular non-melanoma skin cancers. j laryngol otol. 2002;116(11):893-898. 32. lindgren g, larko o. cryosurgery of eyelid basal cell carcinomas including 781 cases treated over 30 years. acta ophthalmol. 2014;92(8):787-792. 33. morton ca, szeimies rm, sidoroff a, braathen lr. european guidelines for topical photodynamic therapy part 1: treatment delivery and current indications—actinic keratoses, bowen’s disease, basal cell carcinoma. j eur acad dermatol venereol. 2013;27(5):536-544. 34. ibbotson sh. adverse effects of topical photodynamic therapy. photodermatol photoimmunol photomed. 2011;27(3):116-130. 35. caekelbergh k, annemans l, lambert j, roelandts r. economic evaluation of methyl aminolaevulinate-based photodynamic therapy in the management of actinic keratosis and basal cell carcinoma. br j dermatol. 2006;155(4):784-790. 36. foley p, freeman m, menter a, et al. photodynamic therapy with methyl aminolevulinate for primary nodular basal cell carcinoma: results of two randomized studies. int j dermatol. 2009;48(11):1236-1245. 37. basset-seguin n, ibbotson sh, emtestam l, et al. topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. eur j dermatol. 2008;18(5):547-553. review | dermatol pract concept 2019;9(2):1 81 in the treatment of pigmented and non-pigmented basal cell carcinomas. dermatol ther. 2017;30(1). 63. izzi s, sorgi p, piemonte p, carbone a, frascione p. successfully treated superficial basal cell carcinomas with ingenol mebutate 0.05% gel: report of twenty cases. dermatol ther. 2016;29(6):470-472. 64. jung ys, lee jh, bae jm, kim gm. superficial basal cell carcinoma treated with two cycles of ingenol mebutate gel 0.015. ann dermatol. 2016;28(6):796-797. 65. stieger m, hunger re. ingenol mebutate treatment in a patient with gorlin syndrome. dermatology. 2016;232(suppl 1):29-31. 66. bettencourt ms. treatment of superficial basal cell carcinoma with ingenol mebutate gel, 0.05%. clin cosmet investig dermatol. 2016;9:205-209. 67. ramsay jr, suhrbier a, aylward jh, et al. the sap from euphorbia peplus is effective against human nonmelanoma skin cancers. br j dermatol. 2011;164(3):633-636. 68. rowe de, carroll rj, day cl jr. long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. j dermatol surg oncol. 1989;15(3):315328. 69. cho m, gordon l, rembielak a, woo tc. utility of radiotherapy for treatment of basal cell carcinoma: a review. br j dermatol. 2014;171(5):968-973. 70. lear w, mittmann n, barnes e, breen d, murray c. cost comparisons of managing complex facial basal cell carcinoma: canadian study. j cutan med surg. 2008;12(2):82-87. 71. von hoff dd, lorusso pm, rudin cm, et al. inhibition of the hedgehog pathway in advanced basal-cell carcinoma. n engl j med. 2009;361(12):1164-1172. 72. jacobsen aa, aldahan as, hughes ob, shah vv, strasswimmer j. hedgehog pathway inhibitor therapy for locally advanced and metastatic basal cell carcinoma: a systematic review and pooled analysis of interventional studies. jama dermatol. 2016;152(7):816-824. 73. ally ms, aasi s, wysong a, et al. an investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. j am acad dermatol. 2014;71(5):904-911.e901. 74. pollom el, bui tt, chang al, colevas ad, hara wy. concurrent vismodegib and radiotherapy for recurrent, advanced basal cell carcinoma. jama dermatol. 2015;151(9):998-1001. and meta-analysis. photodermatol photoimmunol photomed. 2015;31(1):44-53. 53. gross k, kircik l, kricorian g. 5% 5-fluorouracil cream for the treatment of small superficial basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction. dermatol surg. 2007;33(4):433-439; discussion 440. 54. love we, bernhard jd, bordeaux js. topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. arch dermatol. 2009;145(12):1431-1438. 55. arits ah, mosterd k, essers ba, et al. photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. lancet oncol. 2013;14(7):647-654. 56. jansen mhe, mosterd k, arits a, et al. five-year results of a randomized controlled trial comparing effectiveness of photodynamic therapy, topical imiquimod, and topical 5-fluorouracil in patients with superficial basal cell carcinoma. j invest dermatol. 2018;138(3):527-533. 57. bath-hextall f, ozolins m, armstrong sj, et al. surgical excision versus imiquimod 5% cream for nodular and superficial basalcell carcinoma (sins): a multicentre, non-inferiority, randomised controlled trial. lancet oncol. 2014;15(1):96-105. 58. williams hc, bath-hextall f, ozolins m, et al. surgery versus 5% imiquimod for nodular and superficial basal cell carcinoma: 5-year results of the sins randomized controlled trial. j invest dermatol. 2017;137(3):614-619. 59. arits ah, spoorenberg e, mosterd k, nelemans p, kellenerssmeets nw, essers ba. cost-effectiveness of topical imiquimod and fluorouracil vs. photodynamic therapy for treatment of superficial basal-cell carcinoma. br j dermatol. 2014;171(6):15011507. 60. siller g, rosen r, freeman m, welburn p, katsamas j, ogbourne sm. pep005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase iia trial. australas j dermatol. 2010;51(2):99-105. 61. cantisani c, paolino g, cantoresi f, faina v, richetta ag, calvieri s. superficial basal cell carcinoma successfully treated with ingenol mebutate gel 0.05%. dermatol ther. 2014;27(6):352354. 62. diluvio l, bavetta m, di prete m, orlandi a, bianchi l, campione e. dermoscopic monitoring of efficacy of ingenol mebutate dermatology: practical and conceptual letter | dermatol pract concept 2018;8(4):9 297 dermatology practical & conceptual www.derm101.com introduction chronic recurrent multifocal osteomyelitis (crmo) is a rare, noninfectious, inflammatory bone disease, which occurs mainly in childhood [1]. we present a case of crmo and palmoplantar psoriatic skin lesions in a 12-year-old girl. case presentation a 12-year-old girl presented with recurrent erythematous palmoplantar plaques and pustules. she also complained about pain in her left ankle that started 7 months earlier. previous magnetic resonance imaging (mri) had consistently revealed a multifocal bone edema of the left foot. symptoms of weakness, fever, and morning stiffness were absent. the family history was unremarkable. physical examination revealed well-demarcated erythematous plaques with remnants of dried pustules in a palmoplantar distribution (figure 1). the active range of motion of the left upper ankle joint was painfully decreased by 50%. laboratory results showed a slight increase of inflammation parameters, including c-reactive protein level and erythrocyte sedimentation rate. antinuclear antibody level, rheumatoid factor, hla-b27, and lyme disease testing were negative. serial mris revealed fluctuating t2 hyperintensities and t1 hypointensities involving the left talus, calcaneus, and chronic recurrent multifocal osteomyelitis with psoriatic skin manifestations in a 12-year-old female andreas epple1, judith e. paffhausen1, christine fink1, alexander enk1, oliver sedlaczek2, holger a. haenssle1 1 department of dermatology, university hospital heidelberg, ruprecht karls university heidelberg, germany 2 department of diagnostic and interventional radiology, university hospital heidelberg, ruprecht karls university heidelberg, germany key words: childhood, chronic recurrent multifocal osteomyelitis, palmoplantar pustular psoriasis, diagnosis citation: epple a, paffhausen je, fink c, enk a, sedlaczek o, haenssle ha. chronic recurrent multifocal osteomyelitiswith psoriatic skin manifestations in a 12-year-old female. dermatol pract concept. 2018;8(4):297-298. doi: https://doi.org/10.5826/dpc.0804a09 received: february 8, 2018; accepted: march 15, 2018; published: october 31, 2018 copyright: ©2018 epple et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: prof. dr. holger haenssle, department of dermatology, university hospital heidelberg, ruprecht karls university heidelberg, neuenheimer feld 440, 69120 heidelberg, germany. e-mail: holger.haenssle@med.uni-heidelberg.de figure 1. well-demarcated erythematous scaly plaques with remnants of dried pustules on the left sole of the patient. [copyright: ©2018 epple et al.] 298 letter | dermatol pract concept 2018;8(4):9 accumulation of neutrophils. thus il-1β seems to play a key role in both crmo and pppp. conclusion crmo should be treated interdisciplinarily, and nsaids should be the medication of first choice. skin lesions may be alleviated by topical steroids. moreover, bisphosphonates, tnf antagonists, il-1-inhibitors, sulfasalazine or methotrexate have been described as effective. fortunately, our patient showed a complete remission 2 years after the onset of symptoms, which is also observed in 30% to 40% of reported cases. in summary, we describe a rare case of crmo initially presenting as pppp with joint pain. dermatologists and pediatricians should be familiar with the association of crmo and pppp in children to lead the way to correct diagnosis and treatment. references 1. giedion a, holthusen w, masel lf, vischer d. [subacute and chronic “symmetrical” osteomyelitis]. ann radiol (paris). 1972;15(3):329-342. 2. bissonnette r, fuentes-duculan j, mashiko s, et al. palmoplantar pustular psoriasis (pppp) is characterized by activation of the il17a pathway. j dermatol sci. 2017;85(1):20-26. metatarsal bones with undulating discrete joint effusion in the left upper ankle joint (figure 2a-d). additionally, synovial thickening of the left talocalcaneonavicular joint was noticed. t1-weighted images after contrast application were acquired at several mr-measurements over the course of 1 year, mainly reflecting the edema seen as t2 hyperintensities. based on these results, the diagnosis of crmo accompanied by palmoplantar pustular psoriasis (pppp) was made. treatment with oral nonsteroidal anti-inflammatory drugs (nsaids) and topical mometasone furoate 0.1% cream was initiated. crmo was first described by giedion et al in 1972. it primarily occurs in the distal metaphyses of long tubular bones [1]. the involvement of the calcaneus, as described herein, was rarely reported. pppp is found in approximately 15% of crmo patients. the pathophysiology of crmo is not well understood. recent studies of crmo patients described a reduced production of interleukin (il) 10 by monocytes. this impairment may result in an increased activation of the nod-like receptor family pyrin domains containing protein 3 inflammasome (nlrp3) leading to an enhanced expression of il-1β, which has a role in osteoclast activation via receptor activator of nuclear factor kappa-b ligand (rankl) stimulation. bissonnette et al [2] described high levels of il-1β and il-17a in patients with pppp leading to a secondary chemokine production of keratinocytes with figure 2. serial mris over the course of 12 months (a-d) with fat suppressed t2-weighted images showing the fluctuating hyperintensities of the left ankle involving the calcaneus, talus, and metatarsal bones with an undulating joint effusion in the left upper ankle joint. the date of each mri is indicated in the top row of images. [copyright: ©2018 epple et al.] untitled observation | dermatol pract concept 2015;5(4):9 37 dermatology practical & conceptual www.derm101.com the patient a 26-year-old man presented with a one-week history of lesions on the glans penis. the patient also stated that he had recurrent episodes of genital warts, which had been electrocauterized on previous occasions. he denied trauma, medication and history of another skin disorder. physical examination revealed remarkably thick and hard, hyperkeratotic, oyster-shaped scales adherent to multiple erythematous lesions on the glans penis. hyperpigmented, clustered verrucous papules, which coalesced to form plaques, were also detected on the shaft of his penis (figure 1). a shave biopsy from a hyperkeratotic lesion on the glans penis was performed; photomicrographs are presented in figure 2a, b. what is your diagnosis? answer and explanation psoriasis verrucosa of the glans penis, in association with condyloma acuminatum on histopathological examination, marked hyperkeratosis, parakeratosis and neutrophilic clusters in the stratum corneum were noted. papillomatosis and acanthosis of the epidermis with neutrophilic collections in the upper stratum malpighii along with vascular dilatation and perivascular lymphocytic infiltration of the dermis were also detected. oyster-shaped hyperkeratotic plaques on the penis engin sezer1, julia s. lehman2, özben yalçın3, i̇lter tüfek4, selçuk keskin4, emel öztürk durmaz1, sedef sahin1 1 department of dermatology, acıbadem university school of medicine, istanbul, turkey 2 department of dermatology, mayo clinic, rochester, mn, usa 3 department of pathology, sisli etfal training hospital, istanbul, turkey 4 department of urology, acıbadem university school of medicine, istanbul, turkey key words: psoriasis verrucosa, condyloma acuminatum, penis citation: sezer e, lehman js, yalçın ö, tüfek i, kekson s, durmaz eo, sahin s. oyster-shaped hyperkeratotic plaques on the penis. dermatol pract concept 2015;5(4):9. doi: 10.5826/dpc.0504a09 received: june 3, 2015; accepted: july 29, 2015; published: october 31, 2015 copyright: ©2015 sezer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: engin sezer, md, acıbadem university school of medicine, department of dermatology, buyukdere caddesi no: 40, istanbul, 34457, turkey. tel. + 902123044626; fax. +902123044440. email: eseze@yahoo.com figure 1. thick, hyperkeratotic plaques on an erythematous base on the glans in association with warty, hyperpigmented papules on the shaft, of the penis. [copyright: ©2015 sezer et al.] mailto:eseze@yahoo.com 38 observation | dermatol pract concept 2015;5(4):9 with munro’s microabscesses, kogoj’s spongiform pustules in the stratum malpighii, and dilated blood vessels in the upper dermis with lymphocytic inflammation [2,3]. although condyloma acuminatum lesions, characterized by hyperpigmented, verrucous papules, were identified elsewhere on the penis in our patient, the lesion on the glans lacked koilocytosis, clumped keratohyalin granules, and negative immunohistochemistry for hpv, as well as neutrophilic microabscesses in the stratum corneum and epidermis, therefore arguing against a diagnosis of genital wart in this instance. associated features of pv such as obesity, cardiac dysfunction, lymphatic congestion and psychosis were absent in our case [1-4]. some authors have suggested that local lymphatic disturbances and phlebitis may cause increased venous and lymphatic pressure, leading treponemal tests, namely vdrl and tpha as well as immunohistochemical staining for the human papillomavirus (hpv), were negative. psoriasis verrucosa (pv) is a rare form of psoriasis, with only a few cases reported in the literature. lesions are characterized by hard and thick hyperkeratotic plaques on the top of an erythematous base (as in our case). the lesions are located mainly on the trunk and extremities and, until now, penile involvement has not been reported. there is a male predominance (5:1), including our patient, and a history of long-term psoriasis (5-25 years) in all patients, excluding our case, who had rapid onset without previous psoriatic lesions [1-5]. histopathological examination revealed combined features of psoriasis and verrucae, namely, marked papillomatosis with acanthosis, massive hyperkeratosis/parakeratosis figure 2. (a) marked papillomatosis, hyperkeratosis and congested blood vessels are observed at low magnification (hematoxylin and eosin stain; original magnification, x100). (b) neutrophilic collections in the epidermis and stratum corneum (hematoxylin and eosin stain; original magnification, x400). [copyright: ©2015 sezer et al.] to leakage of plasma and proteins from blood, resulting in collagen fibrosis and epidermal hyperplasia [3]. we hypothesize that previous electrocauterization procedures for condyloma acuminatum may have resulted in lymphatic disturbances and activate pv via koebnerization. the treatment approaches for pv include oral retinoids, adalimumab, topical calcipotriol, corticosteroids and 5% crude coal tar [1-5]. we achieved marked regression of the lesions with a combination regimen of topical 5% salicylic acid and corticosteroid ointment including betamethasone valerate. finally we suggest that a diagnosis of pv should be kept in mind in cases with oyster-like, hard, hyperkeratotic plaques on an erythematous base and histopathological findings including marked papillomatosis and neutrophilic microabscesses in the epidermis and stratum corneum. references 1. wakamatsu k, naniwa k, hagiya k, ichimiya m, muto m. psoriasis verrucosa. j dermatol. 2010;37(12):1060-2. 2. okuyama r, tagami h. psoriasis verrucosa in an obese japanese man: a prompt clinical response observed with oral etretinate. j eur acad dermatol venereol. 2006;20(10):1359-61. 3. nakamura s, mihara m, hagari y, shimao s. psoriasis verrucosa showing peculiar histologic features. j dermatol. 1994;21(2):102-5. 4. maejima h, katayama c, watarai a, nishiyama h, katsuoka k. a case of psoriasis verrucosa successfully treated with adalimumab. j drugs dermatol. 2012;11:74-5. 5. erkek e, bozdogan o. annular verrucous psoriasis with exaggerated papillomatosis. am j dermatopathol. 2001;23(2):133-5. dermatology: practical and conceptual 200 research | dermatol pract concept 2019;9(3):5 dermatology practical & conceptual value of dermoscopy in a population-based screening sample by dermatologists isabelle hoorens1, katrien vossaert 1,2, sven lanssens2, laurence dierckxsens3, giuseppe argenziano4, lieve brochez1 1 department of dermatology, university hospital ghent, belgium 2 private practice, maldegem, belgium 3 department of dermatology, az sint-lucas, ghent, belgium 4 department of dermatology, second university of naples, italy key words: dermoscopy, screening, melanoma, basal cell carcinoma, squamous cell carcinoma citation: hoorens i, vossaert k, lanssens s, dierckxsens l, argenziano g, brochez l. value of dermoscopy in a population-based screening sample by dermatologists. dermatol pract concept. 2019;9(3):200-206. doi: https://doi.org/10.5826/dpc.0903a05 accepted: june 3, 2019; published: july 31, 2019 copyright: ©2019 hoorens et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: isabelle hoorens, md, phd, department of dermatology, ghent university hospital, corneel heymanslaan 10, 9000 gent, belgium. email: isabelle.hoorens@uzgent.be background: the use of dermoscopy improves the diagnosis of skin cancer significantly in trained dermatologists. however, to evaluate its cost-effectiveness in daily practice, not only sensitivity but also the excision rate is important. objective: we examined the diagnostic accuracy of cases from a true population-based sample scored by general dermatologists. methods: one hundred twenty-six dermatologists were randomly assigned to  145  digital cases of lesions detected at a skin cancer screening. this resulted in 4,655 case evaluations using a web application. accuracy of diagnosis and treatment was correlated with the histological diagnosis or expert opinion. results: the larger portion (89.7%) of the participating dermatologists reported using their dermatoscope daily. the odds of making a correct diagnosis of melanoma using dermoscopy was 5.38 compared with naked-eye examination (nee). dermoscopy increased sensitivity for skin cancer diagnosis from  70.6% to  84.6%, but this was associated with a small but significant decrease in specificity of  3.5%. to detect  1  skin cancer, 5.23  lesions had to be biopsied/excised in this sample and this was not significantly improved by dermoscopic evaluation. dermoscopy significantly increased the confidence about making a correct diagnosis, especially in seborrheic keratosis, bowen disease, and melanoma. conclusions: dermoscopy significantly improved diagnostic accuracy, the sensitivity of skin cancer detection, and the confidence in diagnosis especially for seborrheic keratosis, bowen disease, and melanoma. however, this finding was not reflected in a significant reduction in the number needed to excise in this sample. abstract research | dermatol pract concept 2019;9(3):5 201 cal or dermoscopy image. this study was approved by the flemish government and by the medical ethical committee of the university hospital ghent. all screenees provided written informed consent. as a histological diagnosis was not available for most of the lesions, the following surrogate reference diagnosis was used in a hierarchical order: diagnosis of the pathologist in case of excision or biopsy of the lesion (n = 5; 3.4%), concordant diagnosis by 2 blinded expert dermoscopists (k.v., l. b. [n = 100; 68.5%]); in case of discordance in diagnosis by these 2 experts, a third independent and blinded expert dermoscopist (g.a.) was asked and the most concordant diagnosis was chosen (n = 41; 28.1%). the gold standard diagnoses of all cases are listed in table 1. recruitment of dermatologists a personal invitation to participate in this study was sent to all 384 flemish certified dermatologists. one hundred twenty-six (32.8%) dermatologists were included in the study. participants were asked to register online and to evaluate 1 or more series of 25 cases each. case series were presented randomly to each registered dermatologist. upon registration, general information concerning their practice, previous training in dermoscopy, and the frequency of use of dermoscopy in routine practice was elicited. case evaluation each online case mentioned brief clinical information (age, gender, and location of the lesion). first dermatologists were introduction the skin cancer epidemic has an important impact on health care budget. early detection and treatment is assumed to give better cure rates and subsequently a more cost-effective treatment. dermoscopy is a well-established technique for diagnosis of melanoma and nonmelanoma skin cancer. several meta-analyses have shown that dermoscopy, in the hands of experienced dermatologists, is superior to naked-eye examination (nee) to detect melanoma [1-3]. dermoscopy also significantly increases the diagnostic accuracy of nonmelanoma skin cancer diagnosis [4]. for basal cell carcinoma (bcc) the dermoscopic diagnostic accuracy is up to 95%-99% [5-7]. it is known that the diagnostic accuracy of dermoscopy depends significantly on training of the examiners [8]. in the hands of untrained practitioners, dermoscopy provides no better diagnostic accuracy for melanoma than nee [1]. most of the studies on the additional diagnostic value of dermoscopy have been performed in a well-selected set of lesions, in which melanomas and other malignant lesions are usually overrepresented. since skin cancer prevalence in real-life setting is usually much lower, this can influence the number of false-positive diagnoses and their related cost in an important way (bayes’ theorem). for this reason we examined diagnostic accuracy and treatment allocation by nee alone and additional dermoscopy among dermatologists in a population-based screening sample in belgium. methods study design cases and determination of reference diagnosis the cases were collected during a population-based lesiondirected skin cancer screening. screenees could register for a free-of-charge skin cancer check-up if they had a lesion meeting 1 or more of the following criteria: abcd rule, ugly duckling sign, a new lesion lasting more than 4 weeks, or red nonhealing lesions. all the index lesions presented by the screenees were checked and photographed both clinically and dermoscopically, respectively with an eos 1200 d camera (canon, giessen, germany) and the dermlite photo system (3gen, san juan capistrano, ca, usa). following this lesiondirected screening, a total body check was offered to all participants for ethical reasons. we did not photograph any lesions during this second phase of the screening. in total 248 lesions were screened and 8 of them were histologically proven to be skin cancers (3.2%). further details on this screening initiative have been published elsewhere [9]. in total 145 of the 248 cases (58%) were selected for a web application. exclusion of cases was due to suboptimal quality of the photographs or a missing clinitable 1. specific diagnoses of lesions in the 145 cases no. % diagnosis melanoma 1 0.69 bcc 4 2.76 scc/bowen 1 0.69 actinic keratosis 3 2.07 angioma 5 3.45 dermatofibroma 4 2.76 atypical nevus 6 4.14 blue nevus 3 2.07 congenital nevus 6 4.14 benign nevus 53 36.55 solar lentigo 12 8.27 seborrheic keratosis 40 27.69 other 7 4.82 total 145 100 scc = squamous cell carcinoma. 202 research | dermatol pract concept 2019;9(3):5 shown the clinical picture and were asked to select a clinical diagnosis (multiple choice), to score the certainty of their diagnosis on a visual analogue scale from 0 to 100%, and to choose the best treatment action (no treatment, biopsy, surgical excision, curettage, cryotherapy, and other); after registration of these answers they were shown the dermoscopy photograph and were asked to complete the same questions. sample size calculation and statistical analysis a sample size of 1,630 case evaluations was required to achieve a power of 80% to detect a difference in specificity of 5% in the group of clinical evaluation compared with the group of additional dermoscopy evaluation with a significance level of 5%. a specificity of 85.4% for the clinical diagnosis was expected and an interclass correlation of 0.814 was assumed (based on pilot data). sample size calculation was adjusted for the clustered nature of the design by applying the method described by killip et al [10]. descriptive statistics were used to describe the cases and dermatologists participating. the related samples wilcoxon signed rank test was used for continuous variables. because of the clustered nature of the data, mixed logistic regression models were used to calculate sensitivity, specificity, and number needed to excise (nne) and their relation to experience and training of the dermatologist. all statistical tests were 2-tailed and p values <0.05 were considered statistically significant. the analyses were conducted in spss version 21.0 (ibm, armonk, ny, usa). outcomes the primary outcome of this study was to evaluate the diagnostic accuracy of dermoscopy compared with nee in a population-based setting. furthermore, we wanted to evaluate whether dermoscopy can increase certainty of the correct diagnosis. results participant characteristics in total 126 dermatologists randomly evaluated 1 or more series of cases with a mean of 32.1 evaluations per case. this resulted in 4,655 case evaluations; 80.2% of the participants were female and 19.8% were male. the median age was 45 years (interquartile range [iqr]: 38-52). the majority of dermatologists worked in a private practice (54.8%), 38.9% in a university center and 6.3% in a hospital setting. the reported median number of patients seen in routine practice was 100 per week (iqr: 70-130). dermoscopy was used at least once a day in 89.7%, once a week but not daily in 7.9%, once a week up to once a month in 1.6%, and not at all in 0.8%. thirty-seven (29.4%) used a nonpolarized dermatosope. training in dermoscopy varied among participants: only 3 dermatologists (2.4%) had no training in dermoscopy, whereas 25 (19.8%) had 1-5 hours, 42 (33.3%) had 5-10 hours, and 44.4% had more than 10 hours of training. diagnostic accuracy and certainty of diagnosis dermoscopy increased sensitivity for skin cancer diagnosis significantly from 70.6% to 84.6% (binomial generalized linear mixed model, p = 0.002; table 2), associated with a small but significant decrease in specificity (96.9% for nee vs 93.5% for dermoscopy, binomial generalized linear mixed model, p < 0.001; figure 1). the sensitivity for the diagnosis table 2. diagnostic performance of dermoscopy according to level of training of the dermatologist clinical dermoscopy sens spec 1 − spec sens spec 1 − spec all 0.706 (0.625-0.775)* 0.969 (0.959-0.977)** 0.031 0.846 (0.781-0.894) 0.935 (0.915-0.950)** 0.065 training < 5 hrs 0.645 (0.461-0.795)1 0.915 (0.886-0.938)2 0.085 0.774 (0.593-0.890)3 0.861 (0.810-0.900)4 0.139 5-10 hrs 0.702 (0.588-0.796)1 0.921 (0.903-0.935)2 0.079 0.829 (0.726-0.899)3 0.885 (0.854-0.910)4 0.115 > 10 hrs 0.704 (0.593-0.795)1 0.940 (0.927-0.951)2 0.060 0.852 (0.755-0.915)3 0.887 (0.861-0.909)4 0.113 sensitivity and specificity, binomial generalized linear mixed models. * p = 0.002 (odds ratio: 0.43 [95% confidence interval: 0.26-0.73]). ** p < 0.001 (or: 2.18 [95% confidence interval: 1.84-2.58]). 1,2,3,4 p = ns. research | dermatol pract concept 2019;9(3):5 203 of melanoma with the use of dermoscopy increased even more from 76.0% to 94.0% (binomial generalized linear mixed model, p = 0.028). the odds for making a correct diagnosis of melanoma using dermoscopy was 5.38 (95% ci: 1.22-23.81) compared with nee. dermoscopy also increased sensitivity for diagnosis of bcc and squamous cell carcinoma/bowen from 71.5% to 74.6%, and 58.9% to 71.0%, respectively, but this failed to reach statistical significance. a trend to increasing sensitivity/specificity was observed with increasing training level (figure 2). the confidence about a correct diagnosis significantly increased from a median of 70% (iqr: 60-80) using nee to 83.7% (iqr: 70-90) with dermoscopy (related samples wilcoxon signed rank test (p < 0.001)). this increase was most pronounced for seborrheic keratosis, bowen disease, and melanoma (figure 3). number needed to excise dermoscopy resulted in 43 additional excisions for skin cancer and 252 extra excisions for benign lesions (on a total of 1,675 excisions or biopsies performed) compared with the clinical evaluation without dermoscopy. this resulted in a nne of 4.77 for clinical evaluation alone and 5.23 when using dermoscopy (binomial generalized linear mixed model, p = not significant [ns]). the nne did not seem to be influenced by training level (0-5 hours, nne 5.15; 5-10 hours, nne 4.89; and >10 hours, nne 5.62; binomial generalized linear mixed model, p = ns; table 3). also for specific subcategories of lesions (melanocytic lesions and bcc) the nne did not change significantly between clinical diagnosis and dermoscopy diagnosis (table 3). figure  1. sensitivity and 1  minus specificity for a malignant diagnosis made clinically and using dermoscopy. dermoscopy increased sensitivity for skin cancer diagnosis significantly from  70.6% to  84.6% (binomial generalized linear mixed model, p = 0.002), associated with a small but significant decrease in specificity (96.9% for nee vs 93.5% for dermoscopy, binomial generalized linear mixed model, p < 0.001). [copyright: ©2019 hoorens et al.] figure  2. sensitivity and  1  minus specificity for a malignant diagnosis according to level of training of the dermatologist. sensitivity and specificity for skin cancer diagnosis increased with advanced level of training, although this failed to reach statistical significance (binomial generalized linear mixed model, p = ns). [copyright: ©2019 hoorens et al.] 204 research | dermatol pract concept 2019;9(3):5 discussion in this study the additional value of dermoscopy over nee diagnosis by 126 dermatologists was evaluated in a population-based series of 145 cases. in the past many similar studies have used very selected case series in which skin cancer was usually overrepresented. although the intention is not to miss any skin cancer (100% sensitivity), especially in melanoma, the importance of not overdiagnosing skin cancer (high specificity) may also be an important issue to avoid the individual (fear, unnecessary intervention) and societal (cost) disadvantages of false-positive diagnoses. in non–highrisk populations the specificity will have a higher impact on cost-effectiveness. in this study we therefore included a case series based on a population-based lesion-directed skin cancer screening program, in which skin cancer prevalence was only 6/145 (4.1%). nearly one third of all flemish dermatologists evaluated at least 25 of the 145 cases. cases were randomly presented to the participants, leading to a total of 4,655 case evaluations. in this way this study reflects the additional value of dermoscopy in the hands of general dermatologists in a population-based setting. the results of this study demonstrate that dermoscopy is frequently used in belgian dermatology practice: almost 90% of participants use their dermatoscope daily. this is comparable with large studies performed in france and australia (94.6%-98%) [11,12]. in accordance with other studies, we observed that dermoscopy significantly increases sensitivity for malignant lesions [1-4,6]. however, this results also in a small but significant decrease in specificity, thus increasing the number of false-positive diagnoses. in this study dermoscopy resulted in 43 additional excisions for skin cancer and 252 extra excisions for benign lesions over clinical diagnosis. the sensitivity/specificity tended to increase with increased level of training, confirming the results of previous studies [1-4,6]. confidence about making a correct diagnosis was significantly higher using dermoscopy, especially in melanoma, seborrheic keratosis, and bowen disease. however, this did not result in a reduction of unnecessary excisions as the nne did not significantly differ between clinical diagnosis and dermoscopy nor did it seem to be influenced by training. subanalyses with years of dermoscopy experience, daily use, in addition to level of training taken into account, also could not reveal a significant difference in the nne. however, the nne of the experts in the real-life setting on the screening (k.v., l.b.) was clearly lower than the nne reached in the online case evaluation (ie, nne 1.25 in reallife screening) [9]. the use of both clinical and dermoscopic photographs with the added information of gender, age, and lesion location to evaluate pigmented skin lesions remains somewhat artificial. in the absence of a total body inspection, individual lesions may be interpreted in a different way. an individual with multiple nevi, for instance, usually displays similar lesions (signature nevi); on the other hand there should be caution about lesions with a different pattern (ugly duckling sign). this was illustrated by 2 prominent nevi that were considered nonsuspicious by the 2 experts (k.v., l.b.) on the screening and were scored as potential melanoma in the online case series by at least 2 of 3 experts (g.a., k.v., l.b.). digital follow-up of these lesions by means of new clinical and dermoscopy photographs about 20 months after screenfigure 3. median certainty of diagnosis clinically vs dermoscopy per diagnostic group. certainty diagnosis median on visual analogue scale from 0 to 100%. ak = actinic keratosis; vs = seborrheic keratosis. [copyright: ©2019 hoorens et al.] research | dermatol pract concept 2019;9(3):5 205 ing showed no change, hence suggesting that these lesions have a benign behavior. this finding illustrates that some of the false-positive skin cancer diagnoses may have been due to the artificial conditions in which these lesions were evaluated. compared with previous studies, a nne of 1 out of 6 was obtained in this study. evaluation of the large screen campaign in germany in a partially nonspecialized setting not using dermoscopy resulted in 17 excisions of melanocytic lesions for the detection of 1 melanoma [13]. our data are comparable with those of a large multicentric study examining excision rates over a period of 10 years in specialized clinical settings, with a nne of 6.8 [14]. table 3. nne dermoscopy vs clinical situation according to level of training all lesions level of training excision/biopsy malignant excision/biopsy benign total excisions (nne) method clinical <5 hrs 31 100 131 (4.22) 5-10 hrs 58 230 288 (4.96) >10 hrs 61 235 296 (4.85) total 150 565 715 (4.77)* dermoscopy <5 hrs 33 137 170 (5.15) 5-10 hrs 81 315 396 (4.89) >10 hrs 79 365 444 (5.62) total 193 817 1010 (5.23)* melanocytic lesions level of training excision/biopsy malignant excision/biopsy benign total excisions (nne) method clinical <5 hrs 14 51 65 (4.57) 5-10 hrs 22 126 148 (6.73) >10 hrs 29 136 165 (5.69) total 65 313 378 (5.81)* dermoscopy <5 hrs 15 79 94 (6.26) 5-10 hrs 36 195 231 (6.41) >10 hrs 43 240 283 (6.58) total 94 514 608 (6.46)* bcc level of training excision/biopsy malignant excision/biopsy benign total excisions (nne) method clinical <5 hrs 10 32 42 (4.20) 5-10 hrs 18 71 89 (4.94) >10 hrs 17 54 71 (4.18) total 45 157 202 (4.49)* dermoscopy <5 hrs 13 28 41 (3.15) 5-10 hours 27 62 89 (3.30) >10 hrs 20 47 67 (3.35) total 60 137 197 (3.28)* nne to find 1 confirmed skin cancer, melanoma, or bcc, binomial generalized linear mixed models. *p = ns. 206 research | dermatol pract concept 2019;9(3):5 there was a trend toward increased sensitivity and specificity with increased training; however, training of >10 hours did not reach statistically significant superior results. in the recent nice guidelines it is recognized that dermoscopy is unequivocally useful in the diagnosis of melanoma, but only in the hands of trained users [15]. the required amount of training, however, is a topic of debate. it has been shown that despite the frequent use of dermoscopy, training seems to be insufficient and that even among dermatologists who consider themselves experienced in dermoscopy, repeated training can increase diagnostic accuracy [8,11]. in addition, currently a lot of training courses in dermoscopy mainly focus on red flags (increased sensitivity for melanoma). however, when used in low-prevalence populations, it could be interesting to put more focus on green flags (recognition of harmless lesions), thereby reducing the number of false-positive diagnoses and hence unnecessary excisions. conclusions the current study evaluated the additional value of dermoscopy in the hands of general dermatologists in a populationbased setting using a series of photos in a web application. these results demonstrate that dermoscopy clearly increases sensitivity for malignant lesions in a population-based setting at the expense of a small but significant decrease in specificity. although dermoscopy significantly increased confidence about a diagnosis, especially in melanoma, seborrheic keratosis and bowen disease, this did not result in a reduction of nne. there was a trend toward higher sensitivity and specificity according to training level (<5 hours, 5-10 hours, or >10 hours). we suggest that continuous training for dermoscopy is necessary and that training courses should also pay enough attention to the recognition of benign lesions to avoid unnecessary excisions and in that way benefit costeffectiveness ratios. references 1. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. 2. bafounta ml, beauchet a, aegerter p, et al. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137(10):13431350. 3. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. 4. pehamberger h, binder m, steiner a, et al. in vivo epiluminescence microscopy: improvement of early diagnosis of melanoma. j invest dermatol. 1993;100(3):356s-362s. 5. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62(1):67-75. 6. menzies sw, westerhoff k, rabinovitz h, et al. surface microscopy of pigmented basal cell carcinoma. arch dermatol. 2000;136(8):1012-1016. 7. pan y, chamberlain aj, bailey m, et al. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268274. 8. chevolet i, hoorens i, janssens a, et al. a short dermoscopy training increases diagnostic performance in both inexperienced and experienced dermatologists. australas j dermatol. 2015;56(1):52-55. 9. hoorens i, vossaert k, pil l, et al. total-body examination vs lesion-directed skin cancer screening. jama dermatol. 2016;152(1):27-34. 10. killip s, mahfoud z, pearce k. what is an intracluster correlation coefficient? crucial concepts for primary care researchers. ann fam med. 2004;2(3):204-208. 11. breton al, amini-adle m, duru g, poulalhon n, dalle s, thomas l. overview of the use of dermoscopy in academic and nonacademic hospital centres in france: a nationwide survey. j eur acad dermatol venereol. 2014;28(9):1207-1213. 12. venugopal ss, soyer hp, menzies sw. results of a nationwide dermoscopy survey investigating the prevalence, advantages and disadvantages of dermoscopy use among australian dermatologists. australas j dermatol. 2011;52(1):14-18. 13. waldmann a, nolte s, geller ac, et al. frequency of excisions and yields of malignant skin tumors in a population-based screening intervention of 360,288 whole-body examinations. arch dermatol. 2012;148(8):903-910. 14. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10-year multicenter survey. j am acad dermatol. 2012;67(1):54-59. 15. national institute for health and care excellence. melanoma—assessment and management of melanoma. (ng14) 2015. availible at: http://www.nice.org.uk/guidance/ng14. accessed march 15, 2019. dermatology: practical and conceptual 54 observation | dermatol pract concept 2018;8(1):12 dermatology practical & conceptual www.derm101.com case report a 62-year-old woman presented with complaints of asymptomatic tortuous purplish to black swellings on the undersurface of the tongue for 8 months (figure 1). she first noticed a few red to purple small outpouching of the veins on the undersurface of tongue. the lesion has increased progressively in due course of time. on mucosal examination, dilated tortuous vessels were seen along the lateral portions of undersurface of the tongue. examination of the skin, hair and other mucosal surfaces were normal. there was no history of bleeding from the site and there was no evidence of any associated systemic disease. dermoscopy [polarized, 10x] showed red lacuna with whitish veil at a few places, and based on location, age, clinical and dermoscopic appearance, it was diagnosed as lingual varicosities. discussion caviar tongue, also known as lingual varicosities and sublingual varices, is considered as a physiological change associated with advancing age, usually developing due to senile elastolytic degeneration of sublingual veins [1,2]. it is mostly seen at the undersurface of the tongue along the sublingual glands where the mucosal surface is thin and translucent which permits visualisation of submucosal vascular structures [1]. mucoscopy in lingual varicosities abhijeet k. jha1, m. d. zeeshan1, amar k. jha amar1 1 department of skin & vd, patna medical college and hospital, patna, bihar, india key words: mucoscopy, dermoscopy, lingual varicosity, caviar tongue citation: jha ak, zeeshan md, jha amar ak. mucoscopy in lingual varicosities. dermatol pract concept. 2018;8(1):54-55. doi: https://doi. org/10.5826/dpc.0801a12 received: september 22, 2017; accepted: october 26, 2017; published: january 31, 2018 copyright: ©2018 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin &vd, patna medical college and hospital, patna, bihar, india. email: drabhijeetjha@gmail.com figure 1. tortuous purplish to black swellings on the undersurface of the tongue. [copyright: ©2018 jha et al.] observation | dermatol pract concept 2018;8(1):12 55 lowest part of the lacuna, resulting in an appearance similar to the so-called “hypopyon” of the eye, a new “dermatologic” metaphoric term has been used to describe this peculiar feature as half-and-half lacuna [5]. the patient was counseled about the benign nature of the diseaseand that is common in the elderly; no treatment was given. sclerotherapy, surgery, or photocoagulation with high intensity diode laser or ndyag laser has been tried in few lesions on unusual locations, such as the lips or buccal mucosa. in conclusion, dermoscopy can be an auxiliary tool in the diagnosis of lingual varicosities. to the best of our knowledge, this is the first report on dermoscopy of caviar tongue. references 1. lazos jp, piemonte ed, panico rl. oral varix: a review. gerodontology. 2015;32:82-89. 2. kocsard e, ofner f, d’abrera vse. the histopathology of caviar tongue ageing changes of the undersurface of the tongue. dermatologica. 1970;140:318–322. 3. campos-do-carmo g, ramos-e-silva m. dermoscopy: basic concepts. int j dermatol. 2008;47:712–719. 4. zaballos p, llambrich a, cuéllar f, puig s, malvehy j. dermoscopic findings in pyogenic granuloma. br j dermatol. 2006;154:1108– 1111. 5. jha ak, lallas a, sonthalia s. dermoscopy of cutaneous lymphangioma circumscriptum. dermatol pract concept. 2017;7(2):8. on dermoscopy, dark-blue lacunae (figure 2) suggest vessel thrombosis and red lacunae suggest absence of it [2]. dermoscopically, hemangiomas also show red-bluish lacunae but lack the sharp dermarcation seen in angiokeratoma of fordyce [3]. pyogenic granuloma reveals whitish veils, but lack the red-blue lacunae [4]. cutaneous lymphangioma circumscriptum displays two distinct patterns: yellow lacunae surrounded by pale septa without inclusion of blood and yellow to pink lacunae alternating with dark-red or bluish lacunae, due to the inclusion of blood. a few lacunae contained blood, which was characteristically accumulated in the figure 2. dermoscopy [polarized, 10x] showed red lacuna with whitish veil at few places. [copyright: ©2018 jha et al.] dermatology: practical and conceptual 68 observation | dermatol pract concept 2018;8(1):17 dermatology practical & conceptual www.derm101.com learning points • dermoscopy can help the clinical diagnosis of vulvar basal cell carcinoma showing linear and arborizing telangiectasia, pinkish background, blue ovoid nests, blue globules, white shiny structures and brown dots. • reflectance confocal microscopy can be used to confirm the clinical diagnosis of vulvar basal cell carcinoma and to identify its surgical margins. case presentations case 1 an 82-year-old woman was referred to our clinic with complaints of itching and of bleeding from the vulva. she was otherwise healthy and denied a personal history of skin cancers, sexually transmitted diseases, and irradiation. a physical examination revealed a 3 x 2 cm ulcerated plaque involving the anterior vulvar commissure (figure 1a). the rest of the genital and pelvic examination did not reveal any other pathological findings. dermoscopic examination performed with dermlite foto system (dermlite, 3 gen, san juan capistrano, ca, usa) coupled with a camera (sony cybershot digital still camera 7.2 megapixels, sony corporation, tokyo, japan) and applying a disposable sterile transparent film (visulin; paul hartmann ag, heidenheim, germany) on the tip of the instrument, showed the presence of reddish and well-focused arborizing vessels on a pinkish background associated with whitish homogeneous areas (figure 1b,c). these features suggested the diagnosis of ulcerated bcc and dermoscopic and reflectance confocal microscopy features of two cases of vulvar basal cell carcinoma elisa cinotti, md1, giulia tonini1, jean luc perrot2, cyril habougit3, stefano luisi4, pietro rubegni1 1 department of medical, surgical and neuro-sciences, dermatology unit, university of siena, siena, italy 2 dermatology department, university hospital of saint etienne, saint etienne, france 3 pathology department, university hospital of saint etienne, saint etienne, france 4 department of molecular and developmental medicine, obstetrics and gynecology, university of siena, siena, italy key words: basal cell carcinoma, dermoscopy, imaging, reflectance confocal microscopy, vulva citation: cinotti e, tonini g, perrot jl, habougit c, luisi s, rubegni p. dermoscopic and reflectance confocal microscopic features of two cases of vulvar basal cell carcinoma. dermatol pract concept. 2018;8(1):68-71. doi: https://doi.org/10.5826/dpc.0801a17 received: july 21, 2017; accepted: september 14, 2017; published: january 31, 2018 copyright: ©2018 cinotti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: giulia tonini, md, dermatology section, university of siena, s. maria alle scotte hospital, 53100 siena, italy. tel : 00 39 3292063153; fax. 00 39 0577 44238. email: giuliatonini19@gmail.com basal cell carcinoma (bcc) is the most common malignant skin cancer. its genital localization is rare, and the diagnosis in this site could be challenging. here, we report two patients with vulvar bcc and describe their clinical, dermoscopic and in vivo and ex vivo reflectance confocal microscopic (rcm) features. dermoscopy and rcm can be useful tools for helping the clinical diagnosis of vulvar bcc and for identifying the correct surgical margins. abstract observation | dermatol pract concept 2018;8(1):17 69 control of the surgical margins (figure 4d) that resulted in being tumor-free. the histopathologic examination showed a nodular bcc and confirmed that the margins were free of disease (figure 5a and b). no relapse was observed during the maximum follow-up of 48 months. discussion basal cell carcinoma (bcc) is the most common malignant skin cancer, and in almost 85% of cases it is located in head and neck areas [2]. its genital localization is rare: vulvar bcc accounts for less than 1% of all bccs and represents only 2-5% of all vulvar cancers [3-7]. usually, a single vulvar lesion is observed, although bilateral, multifocal or disseminated forms are possible [5]. vulvar bcc may present with superficial, nodular, infiltrative, vegetating, ulcerated and pedunculated lesions [5]. the tumor usually appears as a pink or flesh-colored lesion with a pearly and translucent sheen [7]. pigmentation of vulvar bcc has been detected in only 3% of caucasian patients and in up to 81% of chinese supported the necessity of surgical treatment. the tumor was excised with a 1 cm margin previously identified by the dermoscopic examination. a histopathologic examination of the lesion confirmed the diagnosis of ulcerated bcc and showed a nodular subtype (figure 2). no relapse was observed during the maximum follow-up of six months. case 2 a 79-year-old woman presented with a history of an itchy lesion of the vulva. on clinical examination, an erythematouswhitish plaque with focal erosions was found on the right labium major. the periphery of the plaque had an irregular gray-blue pigmentation (figure 3a). dermoscopy performed with the high-definition dermoscope (dermlite; 3 gen, san juan capistrano, ca, usa) coupled with canon powershot g10 camera (canon inc., tokyo, japan) revealed fine linear telangiectasia, blue ovoid nests, a blue globule and white shiny structures on a pinkish background (figure 3b, c). areas of brown dots surrounded by a grayish pigmentation were also seen (figure 3d). all these features were strongly suggestive of nodular bcc. for hygienic purposes, a disposable sterile transparent film (visulin; paul hartmann ag, heidenheim, germany) was applied on the tip of the camera. in vivo rcm performed with vivascope 3000 (caliber, new york, ny, usa, distributed in europe by mavig gmbh, munchen, germany) showed dark silhouettes corresponding to tumor islands and numerous medium reflective large cells corresponding to melanophages in the papillary dermis (figure 4a-c). the lesion was excised with a 3 mm margin previously identified by the dermoscopic and in vivo rcm examination. ex vivo rcm (vivascope 2500, generation 3, caliber, new york, usa, distributed in europe by mavig gmbh, munich, germany) with a horizontal scanning of the fresh surgical specimen without prior preparation (“en face” technique) [1] was also performed for the perioperative figure 1. clinical (a) and dermoscopic examination (b, c) of the first case of vulvar basal cell carcinoma. clinical examination (a) shows an ulcerated plaque (green circle) involving the anterior vulvar commisure. dermoscopy (b, c) shows a reddish and well-focused arborizing vessel (black arrow) on a pinkish background associated with whitish homogeneous areas (yellow arrows). magnified dermoscopic image (c) of arborizing vessel (black arrows). [copyright: ©2018 cinotti et al.] figure 2. histopathologic examination shows a nodular basal cell carcinoma, a superficial ulceration and enlarged vessels (hematoxylin and eosin, 5x). [copyright: ©2018 cinotti et al.] 70 observation | dermatol pract concept 2018;8(1):17 figure 3. clinical (a) and dermoscopic examination (b, c, d) of the second case of vulvar basal cell carcinoma. clinical examination (a) shows an erythematous-whitish plaque (green circle) with focal erosions and an irregular gray-blue pigmentation at the periphery (red arrow) on the right labium major. dermoscopy (b, c, d) shows fine linear telangiectasia (black arrows), blue ovoid nests (red arrows), a blue globule (red dashed arrow), white shiny structures (yellow arrows) on a pinkish background and areas of brown dots (red asterisk) surrounded by a grayish pigmentation (blue circle). [copyright: ©2018 cinotti et al.] figure 4. in vivo (a,b,c) and ex vivo (d) reflectance confocal microscopy of the second case of vulvar basal cell carcinoma. in vivo reflectance confocal microscopy (920 x 920 μm) reveals small dark silhouettes (red asterisks) in connection to the basal layers of the epidermis (a) and larger tumor islands with peripheral clefts (red asterisks) in the superficial dermis (b). in some areas, abundant melanophages (blue arrows) are also visible in the superficial dermis around tumor islands (c). ex vivo reflectance confocal microscopy (single images of 750 x 750 μm) performed with the en face technique shows the tumor islands (red asterisks) (d). patients [2]. the tumor is usually larger than 1 cm at presentation indicating a late diagnosis [2]. subjective symptoms and clinical signs are often present for a prolonged period before the diagnosis. they include itching, irritation, discomfort, palpable vulvar mass, pain, and bleeding [2,4,5]. the last sign is related to ulcerated lesions, which represent 28% of all vulvar bccs [2,5]. vulvar bcc can mimic inflammatory diseases such as eczema, psoriasis, and infections (chronic candidiasis). it can also simulate bowen disease, paget disease, squamous cell carcinoma, leukoplakia, lichen ruber planus, lichen sclerosus, melanocytic nevus, melanoma, seborrheic keratosis, angioma, and other pigmented and non-pigmented tumors [6]. therefore, the diagnosis is frequently delayed and it is usually performed after inappropriate treatment [2,3]. dermoscopic features of vulvar bcc have been reported in only two cases, but rcm features have not been reported yet [6,8]. non-invasive imaging techniques, such as dermoscopy and rcm, are of great interest since they orient the diagnosis of this rare tumor in this sensitive area. the dermoscopic features of our cases and of the previously reported two patients with vulvar bcc [6,8] showed blue ovoid nests and telangiectasia as extragenital bcc. the previously published cases were both pigmented [6,8], whereas one of our cases was a non-pigmented bcc. in the case of pigmented bcc, ovoid nests allow for diagnosis of this tumor easily. non-pigmented lesions can be more difficult to identify because they can mimic inflammatory and infectious diseases. in the cases presented here, the presence of reddish and well-focused arborizing telangiectasia was a relevant clue to the diagnosis. interestingly, both of our cases and one previously reported [6] showed prominent homogeneous whitish areas, which could be an additional clue for vulvar bcc. we hypothesize that these whitish areas could correlate with a peritumoral fibrosis that could observation | dermatol pract concept 2018;8(1):17 71 confirm that the excision was complete. in vivo and ex vivo rcm have been reported to have a good diagnostic accuracy for cutaneous bcc [1,10], and our case suggests that they could also be used for genital bcc. in conclusion, vulvar bcc should be considered in the differential diagnosis of both pigmented and non-pigmented vulvar lesions. dermoscopy and rcm can be useful tools for its diagnosis and treatment and for the identification of its surgical margins. also, ex vivo rcm could be used in the perioperative setting of genital bcc. in our two cases, dermoscopic and rmc features were similar to extragenital bcc, except for the peculiar aspect of brown dots surrounded by grayish pigmentation that was observed on dermoscopic examination (figure 2c). references 1. espinasse m, cinotti e, grivet d, et al. ‘en face’ ex vivo reflectance confocal microscopy to help the surgery of basal cell carcinoma of the eyelid. clin exp ophthalmol. epub 2017 jan 31. 2. de giorgi v, salvini c, massi d, et al. vulvar basal cell carcinoma: retrospective study and review of literature. gynecol oncol. 2005;97:192–194. 3. fleury ac, junkins-hopkins jm, diaz-montes t. vulvar basal cell carcinoma in a 20-year-old: case report and review of the literature. gynecol oncol case rep. 2011; 2: 26-27. 4. mulayim n, foster silver d, tolgay ocal i, et al. vulvar basal cell carcinoma: two unusual presentations and review of the literature. gynecol oncol. 2002; 85: 532-537. 5. chokoeva aa, tchernev g, castelli e, et al. vulvar cancer: a review for dermatologists. wien med wochenschr. 2015;165:164177. 6. dobrosavljevic vukojevic d, djurisic i, lukic s, et al. dermatoscopy in vulvar basal cell carcinoma. j eur acad dermatol venereol. 2017;31:e180-181. 7. venkatesan a. pigmented lesions of the vulva. dermatol clin. 2010;28:795-805. 8. de giorgi v, massi d, mannone f et al. dermoscopy in vulvar basal cell carcinoma. arch dermatol. 2007;143:426–427. 9. bichakjian ck, olencki t, aasi sz, et al. basal cell skin cancer, version 1.2016, nccn clinical practice guidelines in oncology. j natl compr canc netw. 2016;14(5):574-597. 10. cinotti e, jaffelin c, charriere v, et al. sensitivity of handheld reflectance confocal microscopy for the diagnosis of basal cell carcinoma: a series of 344 histologically proven lesions. j am acad dermatol. 2015;73:319-320. be more visible on mucosa compared to the skin due to the absence of the stratum corneum and to the thinner epithelium. in vivo rcm showed similar features of cutaneous bcc and allowed us to understand some dermoscopic findings better. one of our cases showed brown dots at dermoscopy that correlated with the superficial tumor islands in connection with the epidermis that were well visualized under rcm. the grayish pigmentation around the dots visible at dermoscopy correlated with the presence of pigmented melanophages under rcm. the presence of melanophages could be explained by the possible trauma in the genital area. vulvar bcc requires surgical margins wider than 4 mm because it is high risk for recurrence [9] and its extension can be difficult to identify by clinical examination due to the pinkish color of the mucosa [6]. in fact, the erythema associated with bcc could be difficult to differentiate from the normal color of the mucosa. in our cases, both dermoscopy and rcm were used to identify the tumor margins before surgery. in vivo rcm examination allowed us to use narrow lateral surgical margins thanks to their precise identification. moreover, the perioperative ex vivo rcm examination allowed us to figure 5. histopathologic examination (a,b) of the second case of vulvar basal cell carcinoma. histopathologic examination shows a nodular basal cell carcinoma (a, hematoxylin and eosin, 2x) surrounded by an inflammatory reaction with melanophages (b, hematoxylin and eosin, 10x). [copyright: ©2018 cinotti et al.] dermatology: practical and conceptual 152 letter | dermatol pract concept 2019;9(2):14 dermatology practical & conceptual introduction pustular psoriasis (pp) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis, with clinically visible sterile pustules. acrodermatitis continua of hallopeau (ach), which is now considered to be a variant of pp, is characterized by primary and persistent (>3 months) pustules affecting the nail bed/matrix [1]. here we report a patient with pp manifesting itself with acute subungual abscesses involving all fingers. case presentation a 51-year-old woman presented with rapidly developed yellow discoloration of fingernails, accompanied by severe throbbing pain. dermatological examination revealed subungual abscesses involving all fingers, and periungual erythematous, edematous, and scaly changes extending to the proximal interphalangeal joint (figure 1, a and b). some fingernails showed distal onycholysis and oil spots, while distal subungual hyperkeratosis and thickening were evident on all toenails. aerobic bacterial culture of the purulent specimen yielded proteus spp, which was sensitive to almost all conventional antibiotics. a 1-week course of amoxicillin-clavulanate 2 g/day and fusidic acid ointment was unsuccessful. proximal shedding of nails started in some of the fingers (figure 2a), while erythematosquamous patches with superimposed grouped pustules developed on the legs (figure 2b). skin biopsy specimens showed parakeratosis, elongation of rete ridges, neutrophilic exocytosis, and intraepidermal pustules (figure 3). oral methotrexate 15 mg/week was started. in 2 weeks, a dramatic improvement was noted (figure 4a). at the eighth week of treatment, periungual inflammation subsided and all fingernails started to regrow (figure 4b). conclusions in ach, pustular eruptions tend to remain restricted to 1 or 2 digits, most commonly the thumb, for months or years, and may extend slowly to the dorsum of hands and feet. there are very limited reports of ach involving more than 2 digits. longstanding lesions may lead to anonychia and destruction of the underlying bones [1,2]. an atypical case of pustular psoriasis presenting with severe subungual abscesses involving all fingers a. tulin mansur1 1 dermatology department, baskent university istanbul hospital, istanbul, turkey key words: acrodermatitis continua, diagnosis, psoriasis, pustular psoriasis, subungual abscess citation: mansur at. an atypical case of pustular psoriasis presenting with severe subungual abscesses involving all fingers. dermatol pract concept. 2019;9(2):152-154. doi: https://doi.org/10.5826/dpc.0902a14 accepted: october 31, 2018; published: april 30, 2019 copyright: ©2019 mansur. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: prof. dr. a. tulin mansur, baskent university istanbul hospital, dermatology department, kısıklı cad, oymacı sok, no:7, 34662 altunizade, istanbul, turkey. email: tulinmansur@gmail.com letter | dermatol pract concept 2019;9(2):14 153 an acute, severe course involving almost all fingernails and causing rapid onychomadesis is unusual for ach, and in this context, infectious paronychia may be considered. however, bacterial abscesses developing simultaneously beneath several nails, resistant to oral and topical antibiotic therapy, should be extremely rare. therefore, we think that in our patient the culture result merely represents a contamination or secondary infection. very rarely ach may evolve into generalized pp in 1-2 years, mostly in elderly patients [2]. in contrast, the presented patient showed a rapid development of pustular lesions in relatively remote areas. the widespread and intense involvement of nails in addition to rapid progression and generalization does not support considering this case a typical example of ach. the phenotypes of pp are not well defined, and attempts to constitute a better classification of the subgroups are ongoing [1]. the number of digits involved and the rate of progression that would ensure a precise diagnosis of ach is not definite yet. types of pp may not always be clearly sepafigure 3. histopathological features of the lesions (hematoxylin and eosin, ×100). [copyright: ©2019 mansur.] figure 1. (a,b) subungual abscesses on fingernails, with periungual erythema and scaling. [copyright: ©2019 mansur.] a b figure 2. (a) proximal shedding in some nails. (b) small groups of pustules on erythematous patches. [copyright: ©2019 mansur.] a b figure 4. (a) prominent periungual erythema and edema with total loss of fingernails. (b) regrowth of nails after total shedding. [copyright: ©2019 mansur.] a b rated from each other, and at least some patients may represent an overlapping. accurate diagnosis and treatment is imperative for pp to avoid its detri154 letter | dermatol pract concept 2019;9(2):14 references 1. navarini aa, burden ad, capon f, et al. eraspen network. european consensus statement on phenotypes of pustular psoriasis. j eur acad dermatol venereol. 2017;31(11):1792-1799. 2. kim kh, kim hl, suh hy, et al. a case of acrodermatitis continua accompanying with osteolysis and atrophy of the distal phalanx that evoluted into generalized pustular psoriasis. ann dermatol. 2016;28(6):794-795. mental effects. in cases of subungual abscesses resistant to antibiotic therapy, pp involving nail apparatus should be considered. acknowledgment the author thanks tülay zenginkinet, md, pathologist, for helping to prepare the photomicrographs of the lesions. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):7 39 dermatology practical & conceptual www.derm101.com the role of dermoscopy and digital dermoscopy follow-up in the clinical diagnosis of melanoma: clinical and dermoscopic features of 99 consecutive primary melanomas gabriel salerni1,2, teresita terán3, carlos alonso1,2, ramón fernández-bussy1 1 hospital provincial del centenario de rosario, argentina, & faculty of medicine, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina 3 faculty, department of veterinary medicine, universidad nacional de rosario, argentina keywords: melanoma, dermoscopy, atypical mole syndrome, follow-up, imaging techniques citation: salerni g, terán t, alonso c, fernández-bussy r. the role of dermoscopy and digital dermoscopy follow-up in the clinical diagnosis of melanoma: clinical and dermoscopic features of 99 consecutive primary melanomas. dermatol pract concept. 2014;4(4):7. http://dx.doi.org/10.5826/dpc.0404a07 received: may 31, 2014; accepted: june 13, 2014; published: october 31, 2014 copyright: ©2014 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. corresponding author: gabriel salerni, md, phd, urquiza 3100. cp: s2002kdr, rosario, argentina. tel. +54 341 4398586.email: gabrielsalerni@hotmail.com background: early recognition is the most important intervention to improve melanoma prognosis. objective: to report the value of dermoscopy and digital dermoscopy in the clinical diagnosis of malignant melanoma (mm). methods: retrospective analysis of 99 consecutive primary mms diagnosed between 2010 and 2013. the mms were divided into 3 groups: 1) the mm was the reason for consultation (mmc), 2) the mm was detected during routine control of nevi (mmrc), and 3) the mm was detected due to changes observed during digital dermoscopy follow-up (mmdfu). clinical, dermoscopic and histologic features were assessed. results: a total of 99 mms were diagnosed in 89 patients (55% male) with a mean age of 50.8 (1893) years. of all the mms, 35 were the reason for patient consultation (mmc), 52 were detected during routine control of nevi (mmrc) and 12 were diagnosed due to changes observed with digital dermoscopy (mmdfu). on clinical examination, 74.2 % of mmc met the 4 abcd criteria, while only 30.7 % of mmrc and 8.3 % of mmdfu. most mmc were correctly classified as malignant according to dermoscopy, but 44.2% of mmrc and only 16.7% of mmdfu. 22.9% of mmc, 50% of mmrc and 58.3% of mmdfu were in situ. mean breslow thickness was significantly lower in the mmdfu group (0.52 mm) than in the mmrc and mmdfu groups (0.77 and 1.43 mm respectively). conclusions: the use of dermoscopy and digital dermoscopy allows the detection of mms in early stages, even in the absence of specific criteria for malignancy. abstract 40 original research | dermatol pract concept 2014;4(4):7 early recognition is the most effective intervention for improving the prognosis of patients with primary malignant melanoma (mm) [1]. dermoscopy has shown to increase the sensitivity in the clinical diagnosis of melanoma from 60 to 90% with specificity as high as 95% [2]. however, melanoma may be clinically but also dermoscopically indistinguishable from melanocytic nevi making early recognition a diagnostic challenge [3], especially in incipient lesions. furthermore, overlap of clinical features may lead to overlooking mms and excising an excessive number of benign lesions [4]. dermoscopic documentation of melanocytic lesions for the comparison of current and previous images in search of subtle changes over time, namely digital follow-up (dfu), has shown to be helpful in the diagnosis of early melanomas which might lack of specific criteria for malignancy. this approach has proved to be efficient in detecting early mms without increasing the number of unnecessary excisions [5-7]. the use of baseline regional photographs, so-called total body photography (tbp), might facilitate the detection of new lesions, and visual changes in pre-existing lesions, by providing a comparative reference for subsequent examinations [8]. the combined use of tbp and digital dermoscopy, called the ‘‘two-step method’’ of digital follow-up [9], has been proposed an approach for the assessment of individuals at high risk, being potentially more accurate than the two strategies separately since it allow not only for the detection of mm with few dermoscopic criteria by comparison of dermoscopy records, but also for the detection of melanoma either presented as new lesions or arising from nevi that were not monitored by dermoscopy [10]. the inclusion of patients who are at high risk for melanoma in follow-up programs allows the detection of melanomas in early stages, with good prognosis, even in the absence of clinical and dermoscopic features of melanoma [11]. the aim of this study was to assess the clinical, dermoscopic and histologic features of melanomas diagnosed with the use of dermoscopy during routine skin examinations and the use of digital dermoscopy monitoring, compared with those melanomas that led to patient’s consultation. methods we conducted a retrospective analysis of clinical and dermoscopic characteristics of 99 melanomas consecutively diagnosed over a 4-year period at the dermatology department of the hospital provincial del centenario de rosario, a third level hospital, and at the skin cancer department of a private diagnostic center. the study included primary lesions with clinical and dermoscopic pictures of acceptable quality to allow reliable evaluation. patients who were referred with diagnosis of melanoma after excision or biopsy (incisional or excisional) were excluded from the study as well as melanoma recurrences or cutaneous metastases of prior melanomas. all melanomas diagnosed between january 2010 and december 2013 that met inclusion criteria for the study were collected from both databases. the mms were divided into 3 groups: 1) the mm was the reason for consultation (melanoma consultation, mmc), 2) the mm was detected during routine control of nevi using dermoscopy (melanoma routine control, mmrc) and 3) the mm was detected due to changes observed during digital dermoscopy follow-up (melanoma digital follow-up, mmdfu). clinical data such as age and gender of the patients and the localization and size of the lesions were incorporated along with the clinical and dermoscopic images in a powerpoint presentation (microsoft corp, redmond, washington). this collection was presented to two dermatologists with experience in dermoscopy (g.s. and c.a.) who performed both clinical and dermoscopic evaluation while blinded to the way of detection (mmc, mmrc or mmdfu), identity of the patients, and histologic features of the lesions. for the clinical evaluation of the lesions, the abcd clinical acronym for early detection of melanoma was used [11]. the dermoscopic evaluation was performed using the abcd rule of dermoscopy proposed by stolz, which is based on the evaluation of 4 criteria: asymmetry (a), abrupt borders (b), colors (c), and different dermoscopic structures (d) [13]. the total dermoscopy score (tds) was calculated in each lesion, and they were classified as benign, suspicious or malignant. as standard practice, patients who presented for nevi control undergo full clinical examination with a handheld dermatoscope (dermlite dl100 and dermlite ii pro hybrid; 3gen llc, dana point, california). those lesions with clear criteria for melanoma or those highly atypical are excised and sent for histopathology evaluation; suspicious lesions but with no criteria for melanoma alternatively can be scheduled for short-term follow-up. high-risk patients are included in a follow-up program with total-body photographs and digital dermoscopy, according to the 2-step method previously described [9], with follow-up visits once or twice a year. the latter evaluation aided with a digital dermoscopic device (fotofinder dermoscope, fotofinder systems gmbh, germany). the criteria for inclusion in the follow-up program include moderate to severe atypical mole syndrome (ams), presence of a congenital nevus of medium to giant size, ams and previous melanoma, familial melanoma, presence of genetic mutations related to melanoma risk, and syndromes associated with melanoma risk. significant changes leading to excision of melanomas during digital dermoscopic monitoring were any of the following: symmetric enlargement, change in shape, focal changes in structure, regression, and changes in coloration. all new lesions observed during follow-up and exhibiting atypical observation | dermatol pract concept 2014;4(4):7 41 dermoscopic features but no criteria for melanoma were registered and included in follow-up or excised according to the personal risk of the patient, and the criteria of the investigator. each patient’s written consent was obtained for all invasive procedures. statistical analysis the x2 test was used to compare qualitative variables, applying fisher correction when needed because of the small sample size in tables of 2x2, and the t test was used to compare means. differences were considered to be statistically significant at p ≤ .05. results of the melanomas diagnosed between january 2010 and december 2013, 99 fulfilled the inclusion criteria of the study, 35 (35.3%) were the reason for patient consultation (mmc), 52 (52.5%) were detected during routine control of nevi using dermoscopy (mmrc), and 12 (12.2%) were detected due to changes observed during digital dermoscopy follow-up (mmdfu). population the study population consisted of 40 female (45%) and 49 male (55%), with a mean age of 50.8 (18-93) years. the distribution according to gender was homogeneous among the three groups. clinical evaluation most of the mm that led to patient’s consultation (mmc) were clinically asymmetric, had irregular borders and multiple colors, and had a diameter larger than 6 mm (table 1). of the mmrc, near 60% were asymmetric and had multiple colors, half had irregular borders, and more than 70% were 6 mm or larger. a quarter of the mmdfu were asymmetric, only 16.6% had irregular borders, about 40% had multiple colors and half of them were larger than 6 mm. almost 75% of the mmc fulfilled the 4 abcd criteria, while a third of the mmrc and just 8% of the mmdfu (figure 1). all differences were statistically significant. dermoscopic evaluation classification according to the abcd rule of dermoscopy is shown in table 2. of mmc, 82.9% were correctly classified as malignant, 11.4% as suspicious and 5.7% as benign. in the mmrc group, 44.2% of mmrc were correctly classified as malignant, 46.2% as suspicious and 9.6% as benign. in the mmdfu group, only 33.3% were correctly classified as malignant, 16.7% as suspicious and 50% as benign. most of mmc (n=25, 71.4%) displayed multicomponent pattern according to pattern analysis, followed by reticular pattern in 7 (15%), 2 lesions had starburst pattern and 1 unspecific pattern. in the mmrc group, more than half had reticular pattern (n=28), while only 19 (36.5%) display multicomponent pattern. in this group, globular and unspecific pattern where seen in 2 and 3 cases respectively. among the melanomas detected due to changes during digital follow-up (mmdfu), almost 60% (n=7) had reticular pattern and 25% (n=3) multicomponent pattern, 16.6% (n=2) showed globular pattern (figure 2). the most frequent morphological change was asymmetric enlargement in 6 out of 12 mmdfu, focal changes in structure were seen in 3 of 12 of the cases and regression in 1 of 12. one mm was excised because of symmetric enlargement and absence of other significant changes (figure 3). one mm was excised because was noted as a new lesion in the comparative analysis of consecutive total body photographs. histology evaluation the percentages of in situ melanoma among the groups were as follows: 22.9% in the mmc, 50% in the mmrc, and 58.3% in the mmdfu. 22.9% of the mmc were ulcerated, only 3.8% of the mmrc and none of the mmdfu. of the invasive melanomas, the mean breslow thickness was 1.43 table 1. clinical characteristics according to abcd acronym clinical criteria melanoma consultation (mmc) n=35 melanoma routine control (mmrc) n=52 melanoma digital follow-up (mmdfu) n=12 p* asymmetry 82.8% 61.5% 25% <0.05 irregular borders 80% 50% 16.6% multiple colors 85.7% 57.6% 41.6% diameter > 6mm 97.1% 71.1% 50% a+b+c+d 74.2% 32.6% 8.3% 42 original research | dermatol pract concept 2014;4(4):7 figure 1. (a-d) clinical images of melanomas that led to patient’s consultation (mmc), (e-h) melanomas detected during routine control (mmrc), and (i-l) melanomas detected due to changes during digital dermoscopy follow-up (mmdfu). (copyright: ©2014 salerni et al.) table 2. dermoscopic characteristics melanoma consultation (mmc) n=35 melanoma routine control (mmrc) n=52 melanoma digital follow-up (mmdfu) n=12 p* dermoscopy pattern <0.05 reticular atypical 15% 53.8% 58.3% globular atypical — 3.8% 16.7% starburst 5.7% — unspecific 2.8% 5.7% multicomponent 71.4% 36.5% 25% tds 6.2 5 4.77 classification according to the tds <0.05 benign 5.7% 9.6% 50% suspicious 11.4% 46.2% 16.7% malignant 82.9% 44.2% 33.3% observation | dermatol pract concept 2014;4(4):7 43 mm in the mmc group, 0.77 mm in the mmrc and 0.52 mm in the mmdfu. all these differences were statistically significant (table 3). clinical stage at diagnosis the clinical stage of the melanomas was classified according to the american joint committee on cancer staging system [14]. of the mmc, 8 (22.8%) presented as stage 0 at diagnosis and 14 (40%) as stage ia, 5 (14.2%) presented as stage ib, 6 (17.1%) as stage ii and 2 (5.7%) as stage iii, none of the mmc presented as stage iv. in the mmrc group, 26 (50%) presented as stage 0, 21 (40.3%) as stage ia, 3 (5.7%) as stage ib and 2 (3.8%) as stage ii; none of the mmrc presented as stage iii or iv. among the mmdfu, 7 (58.3%) presented as stage 0 and 5 (41.7%) as stage ia, none presented as stage ib, ii, iii or iv. differences among the different groups were statistically significant. of the mmc, 13 (37.1%) required sentinel node biopsy, while only 5 among the 52 mmrc (9.4%) and none of the mmdfu. discussion early recognition is the most effective intervention to improve melanoma prognosis [1]. over the past decades, efforts in secondary prevention have contributed to the stabilization of melanoma mortality. the abcd acronym was designed almost 30 years ago to provide the general public and primary care professionals a memorable and useful tool to aid in the early recognition of melanoma [12]. the parameters asymmetry, border irregularity, color (multiple colors), and diameter larger than 6 mm are used globally in medical education and in the lay press to provide simple parameters for evaluation of pigmented skin lesions which may require a more comprehensive examination by a specialist. while the a, b, and c criteria have been widely accepted, the emergence of reports with a significant proportion of melanomas with a diameter < 6 mm [15,16], has generated controversy around the criterion d, questioning its usefulness in recognizing incipient lesions. in our study, the vast majority of the melanomas that led to patient’s consultation (mmc) fulfilled the 4 abcd criteria with a 97% of lesions with a diameter > 6 mm. more than 70% of the mmrc had a diameter > 6 mm; one third of theses melanomas fulfilled the 4 abcd criteria simultaneously. in the mmdfu group, melanomas most melanomas were symmetric and did not have irregular borders, only 40% had multiple colors and only half had a diameter > 6 mm. less than 10% of the mmdfu fulfilled the 4 abcd criteria simultaneously. figure 2. dermoscopic images. mmc (a-d): (a) superficial extensive melanoma, breslow 2.5 mm, clark iv; (b) superficial extensive melanoma, breslow 0.49 mm, clark iii; (c) superficial extensive melanoma, breslow 1.7 mm, clark iv; (d) nodular melanoma, breslow 3.7 mm, clark v. mmrc (e-h): (e) superficial extensive melanoma, breslow 0.75 mm, clark iii; (f) superficial extensive melanoma, breslow 0.35 mm, clark ii; (g) in situ melanoma; (h) superficial extensive melanoma, breslow 0.7 mm, clark iii. mmdfu (i-l): (i) in situ melanoma; (j) in situ melanoma; (k) superficial extensive melanoma, breslow 0.7 mm, clark iii; (l) superficial extensive melanoma, breslow 0.6 mm, clark iii. (copyright: ©2014 salerni et al.) 44 original research | dermatol pract concept 2014;4(4):7 table 3. histologic characteristics melanoma consultation (mmc) n=35 melanoma routine control (mmrc) n=52 melanoma digital follow-up (mmdfu) n=12 p* in situ melanoma 22.9% 50% 58.3% <0.05 invasive melanoma 77.1% 50% 41.7% ulceration 22.9% 3.8% 0% breslow (mean) 1.43 mm 0.77 mm 0.52 mm figure 3. melanomas detected during digital dermoscopy follow-up (mmdfu) and changes that led to excision. changes correspond to the lesions i (first row), j (second row), k (third row) and l (fourth row) in figure 2. (copyright: ©2014 salerni et al.) observation | dermatol pract concept 2014;4(4):7 45 in 2004, the abcd acronym was revised, the addition of e, for evolution, has substantially improved the ability of clinicians and the general population to detect melanomas at an early stage by recognizing their natural dynamics. the latter criterion is especially important for the diagnosis of nodular melanoma, which frequently, at least initially, is symmetrical, with regular borders and few colors [17]. dermoscopy has been shown to improve the diagnostic accuracy for early melanoma detection [18-20], and currently training and utilization of dermoscopy is recommended for clinicians routinely examining pigmented skin lesions [21]. most melanomas that led to patient’s consultation were already clinically suspicious (3/4 fulfilled the 4 abcd criteria) and more than 80% were correctly classified as malignant according to abcd rule of dermoscopy, with less than 6% misclassified as benign. in the mmrc group, near 40% of the melanomas were correctly classified as malignant, with a significant proportion of melanomas misclassified and benign or suspicious (almost 10% and 50% respectively). these findings support the recommendation that dermoscopy should be used for all lesions, and not just for those suspicious from the clinical point of view [22], since melanomas detected in this group corresponded to lesions that the patient was unaware of at the time of consultation or lesions that didn’t caught patient’s attention previously. in a recent study, salerni et al [11] compared melanomas detected in a follow-up program with melanomas referred to a melanoma unit, they found 36% of melanomas detected during surveillance of patients at risk for melanoma misclassified as benign according to the abcd rule of dermoscopy with a significantly lower mean tds than the referred melanomas. they conclude that the surveillance of patients who are at high-risk for melanoma aided by dermoscopy allows the detection of melanomas low index of suspicion according to dermoscopy. it has been reported that melanoma may simulate benign melanocytic nevi even under dermoscopy examination [3]. on the basis that benign lesions remain stable whereas melanoma tend to change over time, digital follow-up of melanocytic lesions has been proposed as a strategy to recognize melanomas that may lack distinct dermoscopic features at baseline [23]. in our study, 11 of the 12 mmdfu where detected only due to changes observed during digital followup. in this group, only one third of the melanomas were correctly classified as malignant according to the abcd rule of dermoscopy, with a mean tds of 4.77 (significantly lower than the mmc and mmrc group), pointing out that digital follow-up allow for the detection of early melanoma, when specific structures or criteria for malignancy may not be present yet. similarly, in the ten-year experience in the surveillance of high-risk melanoma patients in a melanoma unit [10,24], 98 melanomas were diagnosed, with less than half correctly classified as malignant according to dermoscopy algorithm. breslow thickness of the primary tumor is the dominant prognostic factor in melanoma. criscione and weinstock [25], analyzed data from the surveillance epidemiology and end result (seer) program of the national cancer institute, they found that the most substantial change across the past decades occurred in the proportion of melanoma in situ, which rose from 25% in 1988 to 38% in 2006. in our study, proportion of melanoma in situ varies according to the observed group: less than one quarter among the melanomas that led to patient’s consultation, but rising to 50% almost 60% with the use of dermoscopy and digital dermoscopy respectively; highlighting the benefits of the latter approaches in the recognition of melanoma at early stages. regarding this issue, a meta-analysis was recently conducted to assess the evidence of follow-up of melanocytic skin lesions with digital dermoscopy in the management of individuals at risk for melanoma [26]. this analysis provided evidence that digital dermoscopy follow-up of melanocytic skin lesions with digital dermoscopy demonstrated the early detection of melanomas with a low rate of excisions. with the use of this diagnostic strategy, the proportion of in situ melanoma and thin melanomas were higher than expected in general population. almost 60% melanomas of the melanomas detected due to changes during digital follow-up were in situ; they were thinner among invasive ones than the mmc and mmrc; and none were ulcerated. none of the mmdfu and less than 10% of the mmrc required sentinel lymph node biopsy (snlb), while almost 40% of the mmc have indication for slnb, with a 6% of the patients in this group classified as stage iii at the time of diagnosis. in this study we report the value of dermoscopy examination and digital follow-up in the clinical diagnosis of melanoma in a series of consecutive melanomas. our findings confirm prior observations that the clinical abcd acronym might only allow for the detection of evolved melanomas, since most melanomas that led to patient’s consultation were already invasive. in this setting, the current efforts in public and medical education might have no substantial effect. the routinely use of dermoscopy in diary practice allow for the detection of melanomas with low index of suspicion of which the patients are unaware. in the context of high-risk patients, the use of digital follow-up enables the detection of incipient melanomas that lack not only clinic but also dermoscopic criteria for malignancy. references 1. kopf aw, welkovich b, frankel re, et al. thickness of malignant melanoma: global analysis of related factors. j dermatol surg oncol. 1987;13:345-20. 2. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j amacad dermatol. 2003;48(5):679-93. 46 original research | dermatol pract concept 2014;4(4):7 3. puig s, argenziano g, zalaudek i, et al. melanomas that failed dermoscopic detection: a combined clinicodermoscopic approach for not missing melanoma. dermatol surg. 2007;33(10):1262-73. 4. lindelöf b, hedblad ma. accuracy in the clinical diagnosis and pattern of malignant melanoma at a dermatological clinic. j dermatol. 1994;21:461-4 5. carli p, de giorgi v, crocetti e et al. improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150:687-92. 6. carli p, de giorgi v, chiarugi a et al. addition of dermoscopy to conventional naked-eye examination in melanoma screening: a randomized study. j am acad dermatol. 2004;50:683-9. 7. kittler h, binder m. follow-up of melanocytic skin lesions with digital dermoscopy: risks and benefits. arch dermatol. 2002;138:1379. 8. halpern ac. total body skin imaging as an aid to melanoma detection. semin cutan med surg. 2003;22:2-8. 9. malvehy j, puig s. follow-up of melanocytic skin lesions with digital total-body photography and digital dermoscopy: a twostep method. clin dermatol. 2002;20:297-304. 10. salerni g, carrera c, lovatto l et al. benefits of total body photography and digital dermoscopy (“two-step method of digital follow-up”) in the early diagnosis of melanoma in high-risk patients. j am acad dermatol. 2012;67(1):e17-27. 11. salerni g, lovato l, carrera c, et al. melanomas detected in follow-up program compared with melanomas referred to a melanoma unit. arch dermatol. 2011;147(5):549-55. 12. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin. 1985;35(3):130-51. 13. stoltz w, braun-falco o, bilek p, et al. a color atlas of dermoscopy. berlin, germany: blackwell science, 1994. 14. balch cm, buzaid ac, soong sj, et al. final version of the american joint committee on cancer staging system for cutaneous melanoma. j clin oncol. 2001;19(16):3635-48. 15. goldsmith sm, solomon ar. a series of melanomas smaller than 4 mm and implications for the abcde rule. j eur acad dermatol venereol. 2007;21(7):929-34. 16. gonzalez a, west aj, pitha jv et al. small-diameter invasive melanomas: clinical and pathologic characteristics. j cutan pathol. 1996;23(2):126-32. 17. abbasi nr, shaw hm, rigel ds, et al. early diagnosis of cutaneous melanoma: revisiting the abcd criteria. jama. 2004;292(22):2771-6. 18. bafounta ml, beauchet a, aegerter p, et al. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137:1343-50. 19. kittler h, pehamberger h, wolff k, et al. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159-65. 20. vestergaard me, macaskill p, holt pe, et al. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159:669-76. 21. australian cancer network (acn). clinical practice guidelines for the management of melanoma in australia and new zealand (2008). available from: http://www.nhmrc.gov.au/_files_nhmrc/ publications/attachments/cp111.pdf. accessed may 2014. 22. seidenari s, longo c, giusti f, et al. clinical selection of melanocytic lesions for dermoscopy decreases the identification of suspicious lesions in comparison with dermoscopy without clinical preselection. br j dermatol. 2006;154: 873–8. 23. stolz w, schiffner r, pillet l, et al. improvement of monitoring of melanocytic skin lesions with the use of a computerized acquisition and surveillance unit with a skin surface microscopic television camera. j am acad dermatol. 1996;35:202–7. 24. salerni g, carrera c, lovatto l, et al. characterization of 1152 lesions excised over ten years using total body photography and digital dermatoscopy in the surveillance of patients at high-risk for melanoma. j am acad dermatol. 2012;67(5):836-45. 25. criscione vd, weinstock ma. melanoma thickness trends in the united states, 1988–2006. j invest dermatol. 2010;130:793–7. 26. salerni g, terán t, puig s, et al. meta-analysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on behalf of the international dermoscopy society. j eur acad dermatol venereol. 2013; 27(7):805-14. dermatology: practical and conceptual letter to the editor | dermatol pract concept. 2023;13(3):e2023162 1 dermatology receives fewer grants versus other specialties but excels in citation impact in a cross-sectional analysis of r01 grants 2000-2022 jade conway1, jose w. ricardo2, shari r. lipner2 1 new york medical college, valhalla, new york, usa 2 department of dermatology, weill cornell medicine, new york, new york, usa citation: conway j, ricardo jw, lipner sr. dermatology receives fewer grants vs. other specialties but excels in citation impact in a crosssectional analysis of r01 grants 2000-2022. dermatol pract concept. 2023;13(3):e2023162. doi: https://doi.org/10.5826/dpc.1303a162 accepted: january 21, 2023; published: july 2023 copyright: ©2023 conway et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: ms. conway and dr. ricardo have no conflicts of interest. dr. lipner has served a consultant for orth-dermatologics, hoth therapeutics, and belle torus corporation authorship: all authors have contributed significantly to this publication. corresponding author: shari r. lipner, md phd, department of dermatology, weill cornell medicine, 1305 york avenue, 9th floor, new york, ny 10021 phone: 646-962-3376 e-mail: shl9032@med.cornell.edu to the editor, grant funding is essential for conducting high-impact biomedical research, and the national institutes of health (nih) research project grant r01 remains the benchmark non-industry funding mechanism. we aimed to characterize number and citation impact of r01 grants awarded to dermatology compared to other fields. the nih research portfolio online reporting tools database was retrospectively reviewed for new r01 grants issued to dermatology and other specialties, 2000-2022. primary investigators with md or md-phd were defined as “physician-scientists,” and those with phd or equivalent as “research-scientists.” nih icite database was searched for relative citation ratio (rcr), measuring fieldand time-independent citation rate for each publication per grant.1 reviews and articles without rcr were excluded. weighted rcr for each grant, defined as sum of grant-associated manuscript rcrs, represented the overall grant impact, and mean rcr represented the average rcr of grant-associated publications. there were 396 new r01 dermatology grants (total grant money: $153,057,895), resulting in 3,975 publications and 10.04 articles/grant 2000-2022. number of dermatology grants/year was stable (m of best fit line 0.087, variance 16.72, supplemental table 1). average number of grants/physician was 0.032 for dermatology and 0.052 for all specialties (table 1). most primary investigators were physician-scientists (220 grants, 55.5%). mean weighted rcr for physician-scientist grants (27.49, 95% confidence interval [ci], 20.95-34.03) was greater than for research-scientist grants (15.05, 95% ci, 12.17-17.93) (0 = .0017) (figure 1). mean rcr for physician-scientist publications (1.81, 95% ci, 1.57-2.04) was greater (p = 0.02) than for research-scientist publications (1.44, 95% ci, 1.241.63) (supplemental figure 1). 2 letter to the editor | dermatol pract concept. 2023;13(3):e2023162 our study demonstrated that nih-funded dermatology research is highly impactful, considering the high mean rcr value versus a field-normalized rcr standard value of 1.0 for nih-funded research. while dermatology performed above average for number of articles/grant (10.4 versus 7.36) [2], average grants/physician was lower compared to other specialties, suggesting limited allocation of nih funds to dermatology or dermatology investigators applying for few grants. despite numerous challenges, physician-scientists produced significantly more impactful research than research-scientists. in a retrospective study of all nih grants table 1. number of new national institute of health r01 grants and associated publications by specialty, 2000-2022 specialty # grants #publications average # grants/physician* internal medicine 12,168 192,553 0.101 psychiatry 3,742 55,754 0.096 pediatrics 2,722 38,114 0.045 radiology 2,150 36,192 0.077 neurology 1,973 33,818 0.139 general surgery 1,572 26,169 0.061 ophthalmology 1,065 17,307 0.055 obstetrics and gynecology 693 8,108 0.016 dermatology 396 3,975 0.032 family medicine 315 3,221 0.003 urology 277 3,525 0.027 physical medicine and rehabilitation 166 2,291 0.017 emergency medicine 144 1,280 0.003 all specialties 27,383 422,307 0.052 *number of grants/physician was calculated with the number of active physicians per specialty, obtained from the association of american medical college (aamc) physician specialty data report, as the denominator. figure 1. mean weighted relative citation ratio for r01 grants issued to department of dermatology investigators from 2000-2022, calculated using graphpad unpaired 2-tailed t test. the lines inside both blue bars represent the confidence intervals for the t test. rcr = relative citation rate letter to the editor | dermatol pract concept. 2023;13(3):e2023162 3 awarded to dermatology departments, 2009-2014, r01 grants for md investigators decreased by $1.4 million/year (p<0.001), and was stable for md/phds ($0.34 million/year, p=.25), and phds ($0.20 million/year, p = 0.53) [3]. furthermore, in a retrospective study of 106,368 r01 grant applications, 2000-2006, inclusion of human subjects significantly decreased likelihood of receiving nih funding (p < 0.001), suggesting nih inclination for basic over translational science [4]. physician-scientists must balance patient care and research responsibilities, with only 28% of md-phd dermatologists spending >50% of their time on research, in a survey-based study of 6,786 md-phd graduates, 19752014 [5]. dermatology physician-scientists have excelled in research output and deserve to be equally supported by funding agencies. institutional, philanthropic and industry-based funding mechanisms were not assessed, and rcrs might not fully capture influence of r01 grants, limiting our analysis. in sum, dermatology performs above average for citation impact of r01-funded research, but receives fewer grants, on average, than other specialties. in addition, dermatology physician-scientists demonstrate higher citation impact than research-scientists. we encourage dermatology investigators to apply for nih funding and persuade funding agencies to allocate resources supporting dermatology physician-scientists. references 1. janssens acjw, goodman m, powell kr, gwinn m. a critical evaluation of the algorithm behind the relative citation ratio (rcr). plos biol. 2017;15(10):e2002536. doi: 10.1371/journal .pbio.2002536. pmid: 28968388. pmcid: pmc5624566. 2. li d, agha l. research funding. big names or big ideas: do peer-review panels select the best science proposals?.  science. 2015;348(6233):434-438. doi:10.1126/science .aaa0185. pmid: 25908820. 3. cheng my, sukhov a, sultani h, kim k, maverakis e. trends in national institutes of health funding of principal investigators in dermatology research by academic degree and sex. jama dermatol. 2016;152(8):883-888. doi:10.1001/jamadermatol.2016 .0271. pmid: 27191545. 4. ginther dk, haak ll, schaffer wt, kington r. are race, ethnicity, and medical school affiliation associated with nih r01 type 1 award probability for physician investigators? acad med. 2012;87(11):1516-1524. doi: 10.1097/acm .0b013e31826d726b. pmid: 23018334; pmcid: pmc3485449. 5. brass lf, akabas mh. the national md-phd program outcomes study: relationships between medical specialty, training duration, research effort, and career paths.  jci insight. 2019;4(19):e133009. doi: 10.1172/jci.insight.133009. pmid: 31578310. pmcid: pmc6795497. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2014;4(2):2 9 introduction squamous cell carcinoma (scc) is the second most common cutaneous malignancy after basal cell carcinoma (bcc), with an increasing incidence worldwide [1,2]. it may present in a variety of morphologies, including as a keratinizing nodule, which may be clinically indistinguishable from keratoacanthoma (ka). although traditionally diagnosed clinically, dermoscopic characteristics of nodular squamous cell carcinoma and keratoacanthoma matthew j. lin1 , yan pan1, chris jalilian1, john w. kelly1 1 victorian melanoma service, alfred hospital, melbourne, australia keywords: dermoscopy, diagnosis, nodules, squamous cell carcinoma, keratoacanthoma citation: lin mj, pan y, jalilian c, kelly jw. dermoscopic characteristics of nodular squamous cell carcinoma and keratoacanthoma. dermatol pract concept. 2014;4(2):2. http://dx.doi.org/10.5826/dpc.0402a02 received: december 20, 2013; accepted: january 20, 2014 published: april 30, 2014 copyright: ©2014 lin et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. matthew lin, victorian melanoma service, alfred hospital, commercial rd, prahran, victoria, 3181, australia. tel. +61 (03) 9276 2000, fax. +61 (03) 9530 5940. email: drmatthewlin@gmail.com background: nodular squamous cell carcinoma (scc) and keratoacanthoma (ka) may mimic a variety of other benign and malignant non-pigmented nodules. objectives: to analyze the dermoscopic characteristics of nodular scc and ka. patients/methods: retrospective analysis of 50 nodular sccs and 8 kas collected from a tertiary dermatology referral center and a private dermatology practice in melbourne, australia, between 1 september 2009 and 1 october 2012. all lesions were nodules; defined as firm, elevated, round, palpable tumors with a diameter of 5 mm or more. clinical and dermoscopic images were evaluated by two examiners in consensus. results: signs of keratinization were frequently observed and included keratin crust/scale (90% of sccs, 100% of kas), central keratin mass (32% of sccs, 88% of kas), white structureless areas (66% of sccs, 50% of kas), white circles (32% of sccs, 38% of kas) and white keratin pearls (14% of sccs, 12% of kas). hemorrhage was present in 72% of sccs and 88% of kas and preferentially occurred centrally and in areas of keratinization. for nodular sccs and kas, we observed glomerular vessels (42% and 25% respectively), linear irregular vessels (36% and 25% respectively), atypical vessels (30% and 38% respectively) and hairpin vessels (30% and 25% respectively). conclusions: hemorrhage, keratinization and vascular features (glomerular, hairpin and linear irregular morphologies) are useful in diagnosing both nodular scc and ka. further research on the comparative dermoscopic characteristics of a range of amelanotic nodules is important in order to improve diagnosis of these clinically challenging tumors. abstract mailto:drmatthewlin@gmail.com 10 research | dermatol pract concept 2014;4(2):2 consensus on the criteria and consistency of reporting. all clinical and dermoscopic images were then evaluated by two examiners in consensus (y.p. and m.j.l.) who were aware of the histopathologic diagnosis. vessel morphology was defined as glomerular, dotted/pinpoint, linear irregular, hairpin, comma or corkscrew according to criteria described by menzies et al [21]. atypical vessels were defined as those vessels not fitting into any characteristic morphology. the pattern of vessel arrangement was then scored as radial, branched, clustered, centered, serpiginous, reticular or linear according to the criteria of kittler et al [22]. we evaluated for the presence of keratin crust/scale, central keratin mass, collarette, white circles, white pearls, white lines, white structureless areas and hemorrhage. dermoscopic colors were scored as white, yellow, pink, red, purple, blue, tan, brown, gray, blue or black. finally, we assessed for the presence of pigmented structures and blue-gray veil. dermoscopic features of nodular scc and ka were compared. the fisher exact test was used and analysis was performed using stata (statacorp 2011, stata statistical software: release 12, college station, texas). results fifty cases of nodular scc and 8 cases of ka were collected. of the nodular sccs, 54% were well differentiated, 38% were moderately differentiated and 6% were poorly differentiated. the median diameter was 8 mm (range 6-28 mm) for nodular sccs and 9 mm (range 6-16 mm) for kas. keratin crust/scale was observed in the vast majority of cases (90% of sccs and 100% of kas) (table 1). a central keratin mass was present in 32% of nodular sccs and 88% of kas. white structures were common, in decreasing frequency we observed; white structureless areas (66% of sccs and 50% of kas), white circles (32% of sccs and 38% of kas) and white keratin pearls (14% of sccs and 12% of kas). we observed that the keratin pearls were often clustered, forming a mosaic pattern of indented round foci of keratin. hemorrhage was observed in 72% of sccs and 88% of kas and tended to be present centrally in areas of keratinization. collarette surrounded 12% of sccs and 25% of kas. the vascular pattern was polymorphic in 50% of nodular sccs and 38% of kas. vessels were not seen in 4% of sccs. glomerular vessels were the most common vessel type and were observed in 42% of sccs and 25% of kas. for nodular sccs and kas, we also commonly observed linear irregular vessels (36% and 25% respectively), atypical vessels (30% and 38% respectively) and hairpin vessels (30% and 25% respectively); 71% of hairpin vessels were positioned peripherally with a radial arrangement. nodular scc and ka may mimic a variety of other benign and malignant nodules. in the context of a new or growing non-pigmented nodule, the differential diagnosis may include nodular bcc, hypertrophic intraepidermal carcinoma, atypical fibroxanthoma, merkel cell carcinoma and nodular or desmoplastic melanoma. the differing prognostic and therapeutic implications of each of these diagnoses make their distinction important. however, misdiagnosis is common, and a recent study found that misdiagnosed nodular melanoma was mistaken for nodular scc in 38% of cases [3]. dermoscopy is an important in-vivo, non-invasive diagnostic technique that permits visualization of morphological features not visible with the naked eye. it greatly enhances the diagnostic accuracy for pigmented skin lesions [4-6]. recent studies have shown that it also aids in the diagnosis of non-pigmented keratinizing skin lesions, including actinic keratosis and bowen’s disease [7-15]. however, relatively few studies have reported on the dermoscopic features of non-pigmented invasive scc and keratoacanthoma and better understanding of their presenting dermoscopic features may help in differentiating them from other nodules [16-18]. as non-pigmented nodules are a commonly encountered clinical diagnostic dilemma, this study sets out to describe the dermoscopic features of nodular scc and ka. materials and methods between 1 september 2009 and 1 october 2012, clinical and dermoscopic images for a series of 50 nodular sccs and 8 kas were collected from a single tertiary dermatology referral center and a single private dermatology practice (j.w.k.) in melbourne, australia. data were obtained from the medical records for all cases including age at diagnosis, sex, nodule diameter, site and tumor differentiation. institutional ethics committee approval was obtained. all lesions were excised and histopathology was reviewed to confirm the diagnosis. the diagnosis of ka was based on histopathological architecture and pattern of cell differentiation [19]. all lesions were nodules; defined as firm, elevated, round, palpable tumors with a diameter of 5 mm or more [20]. digital dermoscopic images were captured with a dermatoscope (dermlite dl3 dermatoscope, heine, herrsching, germany) mounted on a digital camera (cyber-shot dsc-w290, sony corporation, tokyo, japan). tenfold magnification was used. alcohol gel was used for immersion and precautions were taken to reduce compression artifact. lesions were excluded if the image quality was unsatisfactory. clinical and dermoscopic images were reviewed retrospectively. an initial meeting was held where a sample of 15 cases was scored and the literature reviewed to establish a research | dermatol pract concept 2014;4(2):2 11 tiple colors were present in all lesions, with 41% having 5 or 6 colors. pigmented structures or blue-gray veil were not seen. for nodular sccs and kas, the primary dermoscopic color was pink (62% and 75% respectively), white/yellow (32% and 25% respectively) and red (6% of sccs). multable 1. clinical and dermoscopic features of nodular squamous cell carcinoma and keratoacanthoma features nodular squamous cell carcinoma (n=50) keratoacanthoma (n=8) p age, median (range), y 79 (53-103) 72 (58-88) 0.70 male:female ratio 1.50 1.67 1 site head and neck 17 (34%) 2 (25%) 0.90 trunk 4 (8%) 1 (12%) upper extremity 13 (26%) 2 (25%) lower extremity 16 (32%) 3 (38%) keratinization keratin crust/scale 45 (90%) 8 (100%) 0.60 central keratin mass 16 (32%) 7 (88%) <0.01 collarette 6 (12%) 2 (25%) 0.58 white circles 16 (32%) 3 (38%) 1 white keratin pearls 7 (14%) 1 (12%) 1 white structureless areas 33 (66%) 4 (50%) 0.44 white lines 3 (6%) 0 (0%) 1 hemorrhage 36 (72%) 7 (88%) 0.44 vascular pattern monomorphic 23 (46%) 5 (62%) 0.61 polymorphic 25 (50%) 3 (38%) vessels absent 2 (4%) 0 (0%) vessel morphology dotted/pinpoint 7 (14%) 0 (0%) 0.58 glomerular 21 (42%) 2 (25%) 0.56 linear irregular 18 (36%) 2 (25%) 0.7 hairpin 15 (30%) 2 (25%) 1 atypical 15 (30%) 3 (38%) 0.69 vessels absent 2 (4%) 0 (0%) 1 vessel arrangement no specific arrangement 33 (66%) 3 (38%) 0.26 radial 7 (14%) 2 (25%) branched 8 (16%) 3 (38%) vessels absent 2 (4%) 0 (0%) pigmented structures 0 (0%) 0 (0%) 1 blue-gray veil 0 (0%) 0 (0%) 1 12 research | dermatol pract concept 2014;4(2):2 a common therapeutic dilemma with nodular scc is distinguishing it from ka. the results of our study show considerable similarity and overlap in the dermoscopic appearance of nodular scc and ka. for clinicians who encounter a growing keratinizing nodule that is clinically suspicious for either scc or ka, it appears that dermoscopy does not help to reliably distinguish between the two lesions. the exception to this was the presence of a central keratin mass, which was more common in ka than in scc (88% vs. 32%, p < 0.01). however, this is not surprising given that the central keratin plug is part of the architectural criteria for the histopathologic discussion in this study we have identified useful clues that may aid in the diagnosis of nodular scc and ka. dermoscopic signs of keratinization were present in the vast majority of nodular sccs and in all kas (figure 1). the frequent observation of keratin scale, central keratin mass, white structureless areas, white circles, white keratin pearls and hemorrhage in our series is comparable to two recent studies (table 2) [16,17]. the results of our study support the notion that dermoscopic features of keratin are the most useful features in identifying nodular scc and ka [17]. figure 1. clinical and dermoscopic images of 6 nodular squamous cell carcinomas (lesions a-c and g-i) and 3 keratoacanthomas (lesions d-f). lesions a-f are clinically keratinizing nodules which exhibit central keratin mass surrounded by radially oriented hairpin vessels (a,b,f) and/or linear irregular vessels (a,b,d,e). white structureless areas (c,f) and hemorrhagic areas (a,e,f) are also seen. lesions g-i lack obvious clinical clues of keratinization, however dermoscopy reveals white circles (h,i), hemorrhage (h), coiled glomerular vessels (g,h) and branched linear irregular vessels (i). [copyright: ©2014 lin et al.] research | dermatol pract concept 2014;4(2):2 13 cell carcinomas [24]. given that collarette is not uncommonly seen in rapidly growing nodules, it is probably not a useful distinguishing feature. vascular features are important clues in the diagnosis of non-pigmented nodules. glomerular vessels, linear irregular vessels, radially oriented hairpin vessels and atypical vessels were commonly present in our series. these vessel types are often found in other keratinizing lesions, including actinic keratosis and bowen’s disease [16,17]. however, compared to actinic keratosis and bowen’s disease, invasive sccs and diagnosis of ka. rosendahl et al concluded from their data that dermoscopy did not improve the ability to confidently differentiate between scc and ka [17]. indeed, dermatopathologists continue to debate whether ka is a highly differentiated form of scc or a benign involuting tumor [23]. another feature of keratinization not reported in other dermoscopic series of scc or ka is collarette, which we found in 12% of nodular sccs and 25% of kas. this is compared with an incidence of collarette found in 74% of pyogenic granulomas, 11% for melanomas and 5% for basal table 2. comparison of studies investigating dermoscopic features of squamous cell carcinoma and keratoacanthoma present study rosendahl et al16 zalaudek et al17 nodular scc (n=50) ka (n=8) scc (n=60) ka (n=43) scc (n=78) ka (n=24) keratinization   keratin crust/scale 90% 100% 70.0% 79.1% 48.7% 41.6%   central keratin mass 32% 88% 30.0% 51.2% 39.4% 58.3%   white circles 32% 38% 60.0% 25.6% 41.0% (targetoid hair follicles) 41.6% (targetoid hair follicles)   keratin pearls 14% 12% 16.7% (white clods) 25.6% (white clods) n/a n/a   white structureless areas 66% 50% 40.0% 55.8% 42.3% 50.0%   white lines 6% 0% n/a n/a n/a n/a   collarette 12% 25% n/a n/a n/a n/a vessel morphology   glomerular 42% 25% 75.0% (coils) 55.8% (coils) 14.1% (dotted/ glomerular) 12.5% (dotted/ glomerular)   linear irregular 36% 25% 23.3% (serpentine) 32.6% (serpentine) 17.90% 70.8%   hairpin 30% 25% 21.7% (looped) 11.6% (looped) 38.50% 37.5%   dotted/pinpoint 14% 0% 3.3% 2.3% 14.1% (dotted/ glomerular) 12.5% (dotted/ glomerular)   atypical 30% 38% n/a n/a n/a n/a   vessels absent 4% 0% 13.3% 18.6% n/a n/a hemorrhage 72% 88% 41.7% (blood spots) 51.2% (blood spots) 29.5% (microerosions) 62.5% (microerosions) n/a refers to criteria not described 14 research | dermatol pract concept 2014;4(2):2 the study was not designed to determine whether dermoscopy would alter the diagnosis. conclusion hemorrhage, keratinization, pink color and vascular structures (glomerular, hairpin and linear irregular morphologies) are useful dermoscopic features in diagnosing nodular scc and ka. there is considerable similarity and overlap in the dermoscopic appearance of these lesions. further research on the dermoscopic characteristics of a range of amelanotic nodules is important in order to improve the diagnosis of these clinically challenging tumors. prior presentation this study was presented in part at the 8th world congress of melanoma, hamburg, germany, july 17-20, 2013. references 1. alam m, ratner d. cutaneous squamous-cell carcinoma. n engl j med. 2001;344(13):975-83. 2. lomas a, leonardi-bee j, bath-hextall f. a systematic review of worldwide incidence of nonmelanoma skin cancer. br j dermatol. 2012;166(5):1069-80. 3. lin mj, mar v, mclean c, wolfe r, kelly jw. diagnostic accuracy of malignant melanoma according to subtype. australas j dermatol. 2014;55(1)35-42. 4. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-76. 5. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-65. 6. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137(10):1343-50. 7. zalaudek i, argenziano g, leinweber b, et al., dermoscopy of bowen’s disease. br j dermatol. 2004;150(6):1112-6. 8. felder s, rabinovitz h, oliviero m, kopf a. dermoscopic differentiation of a superficial basal cell carcinoma and squamous cell carcinoma in situ. dermatol surg. 2006;32(3):423-5. 9. zalaudek i, di stefani a, argenziano g. the specific dermoscopic criteria of bowen’s disease. j eur acad dermatol venereol. 2006;20(3):361-2. 10. peris k, micantonio t, piccolo d, fargnoli mc. dermoscopic features of actinic keratosis. j dtsch dermatol ges. 2007;5(11): 970-6. 11. bugatti l, filosa g, de angelis r. the specific dermoscopical criteria of bowen’s disease. j eur acad dermatol venereol. 2007;21(5):700-1. 12. mogensen m, jemec gb. diagnosis of nonmelanoma skin cancer/ keratinocyte carcinoma: a review of diagnostic accuracy of nonmelanoma skin cancer diagnostic tests and technologies. dermatol surg. 2007;33(10):1158-74. kas developed a more polymorphic vascular pattern with an increased frequency of hairpin and linear irregular vessels. when faced with a pink or red nodule, one of the most important diagnostic decisions to make is the distinction between a nodular scc and a clinically non-pigmented nodular melanoma. pigmented structures and blue-gray veil are important positive dermoscopic features that strongly favor the diagnosis of hypomelanotic nodular melanoma and these were both negative dermoscopic features in our series of nodular sccs and kas [25,26]. however, the diagnosis of truly amelanotic nodular melanoma becomes particularly challenging because it also lacks dermoscopic features of pigmentation. although none of the cases in our series contained pigmented structures, pigmented scc is a recognized entity. the clinical and dermoscopic diagnosis of this rare tumor have been described in several case reports and the presence of keratin scale might be useful clue for the diagnosis [27-32]. another common differential diagnosis of nodular scc is nodular bcc. in our series, cases did not display the characteristic arborizing vessels associated with bcc [33,34]. conversely, bcc rarely contains the glomerular, hairpin or linear irregular vessels, which were frequently observed in nodular scc and ka. seborrheic keratosis may also be confused with nodular scc. dermoscopically, keratin and hairpin vessels are common to both, however, hairpin vessels have been found to be more predictive of seborrheic keratosis [33]. seborrheic keratosis may also be pigmented and have milia-like cysts and comedo-like openings which aid diagnosis [35]. merkel cell carcinoma is a rare tumor that may also mimic nodular scc. both are non-pigmented nodules that commonly contain linear irregular vessels [36,37]. however, other vascular features may help discriminate, with hairpin vessels favoring the diagnosis of scc and arborizing vessels favoring the diagnosis of merkel cell carcinoma. hyperkeratosis is typically absent from merkel cell carcinomas, which also tend to have a shinier cherry red appearance [38]. there were several limitations to this study. firstly, the two examiners of images were not blinded to the diagnosis of scc or ka. secondly, we did not include nodules other than scc and ka and the study was not designed to test the sensitivity nor specificity of dermoscopic criteria in differentiating nodular scc and ka from other nodular lesions. finally, the study was not designed to determine if dermoscopy alters the naked eye diagnosis of a nodular scc or ka. for example, in figure 1, lesions a-f appear as clinically keratinizing nodules, where the major differential diagnosis on naked eye examination would be scc or ka and it is unlikely that dermoscopy would alter diagnosis in these cases. on the other hand, lesions g-i lack clinical clues of keratinization and it is here that dermoscopy may become useful in diagnosis. however, research | dermatol pract concept 2014;4(2):2 15 26. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-7. 27. kossard s, cook d. pigmented squamous cell carcinoma with dendritic melanocytes. australas j dermatol. 1997;38(3):145-7. 28. zalaudek i, citarella l, soyer hp, hofmann-wellenhof r, argenziano g. . dermoscopy features of pigmented squamous cell carcinoma: a case report. dermatol surg. 2004;30(4 pt 1):539-40. 29. ohnishi t, nakai k, nagayama t, et al. pigmented squamous cell carcinoma of the skin. report of a case with epiluminescence microscopic observation. br j dermatol. 2003;149(6):1292-3. 30. yoshida y, yamasaki a, shiomi t, et al. ulcerative pigmented squamous cell carcinoma in a 101-year-old japanese woman. j dermatol. 2009;36(4):241-4. 31. de giorgi v, alfaioli b, papi f, et al. dermoscopy in pigmented squamous cell carcinoma. j cutan med surg. 2009;13(6):326-9. 32. rosendahl c, cameron a, bulinska a, weedon d. cutaneous pigmented invasive squamous cell carcinoma: a case report with dermatoscopy and histology. dermatol pract concept. 2011;36(4):241-244. 33. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermatol. 2004;140(12):1485-9. 34. menzies sw, westerhoff k, rabinovitz h, et al. surface microscopy of pigmented basal cell carcinoma. arch dermatol. 2000;136(8):1012-6. 35. braun rp, rabinovitz hs, krischer j, et al. dermoscopy of pigmented seborrheic keratosis: a morphological study. arch dermatol. 2002;138(12):1556-60. 36. dalle s, parmentier l, moscarella e, et al. dermoscopy of merkel cell carcinoma. dermatology. 2012;224(2):140-4. 37. harting ms, ludgate mw, fullen dr, johnson tm, bichakjian ck. dermatoscopic vascular patterns in cutaneous merkel cell carcinoma. j am acad dermatol. 2012;66(6):923-7. 38. jalilian c, chamberlain aj, haskett m, et al. clinical and dermoscopic characteristics of merkel cell carcinoma. br j dermatol. 2013;169(2):294-7. 13. pan y, chamberlain aj, bailey m, et al. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268-74. 14. cuellar f, vilalta a, puig s, et al. new dermoscopic pattern in actinic keratosis and related conditions. arch dermatol. 2009;145(6):732. 15. zalaudek i, giacomel j, argenziano g, et al. dermoscopy of facial nonpigmented actinic keratosis. br j dermatol. 2006;155(5):951-6. 16. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2012;66(4):589-97. 17. rosendahl c, cameron a, argenziano g, et al. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. 2012:1-7. 18. pyne j, sapkota d, wong jc. squamous cell carcinoma: variation in dermatoscopic vascular features between well and non-well differentiated tumors. dermatol pract concept. 2012;2(4):5. 19. weedon d. keratoacanthoma. in: weedon d (ed). skin pathology. london: churchill livingstone, 2010:702-8. 20. cox nh, coulson ih. diagnosis of skin disease. in: burns t (eds). rook’s textbook of dermatology. oxford, uk: wiley blackwell,2010:5.7. 21. menzies s, crotty k, ingvar c, et al. dermoscopy: an atlas. 3rd ed. nsw, australia: mcgraw-hill, 2003. 22. kittler h, rosendahl c, cameron a, et al. dermatoscopy: an algorthmic method based on pattern analysis. vienna, austria: facultas, 2011. 23. weedon d, malo j, brooks d, williamson r. keratoacanthoma: is it really a variant of squamous cell carcinoma? anz j surg. 2010;80(3):29-30. 24. zaballos p, carulla m, ozdemir f, et al. dermoscopy of pyogenic granuloma: a morphological study. br j dermatol. 2010;163(6):1229-37. 25. kalkhoran s, milne o, zalaudek i, et al. historical, clinical, and dermoscopic characteristics of thin nodular melanoma. arch dermatol. 2010;146(3):311-8. dermatology: practical and conceptual review | dermatol pract concept 2018;8(2):8 109 dermatology practical & conceptual www.derm101.com introduction ex vivo confocal microscopy (evcm) is a an emerging imaging technique that allows real-time microscopic examination of freshly excised cutaneous tissue that eliminates the need for standard embedding, processing, and sectioning that is necessary for conventional histology [1]. it enables a rapid examination of an entire skin sample directly in the surgical room. it has been mainly applied to the perioperative analysis of the surgical margins of basal cell carcinoma (bcc) during micrographic mohs surgery (mms). notably, evcm does not alter the tissue and does not prevent subsequent histopathological examination. many possible applications are under investigation, such as the study of skin tumors other than bcc, the evaluation of skin appendages, and the diagnosis of skin infections. we aim to give an overview of the current available applications for this new device. the review was performed using the pubmed database. search terms employed were ‘‘ex vivo,’’ ‘‘reflectance confocal microscopy,’’ “confocal laser scanning microscopy,” ‘‘fluorescence confocal microscopy,’’ “skin,” “dermatology,” and “surgery.” ex vivo confocal microscopy: an emerging technique in dermatology elisa cinotti1, jean luc perrot2, bruno labeille2, frédéric cambazard2, pietro rubegni1 1 department of medical, surgical and neurological science, dermatology section, university of siena, s. maria alle scotte hospital, siena, italy 2 department of dermatology, university hospital of saint-étienne, saint-étienne, france key words: confocal microscopy, dermatology, ex vivo, fluorescence, skin, reflectance citation: cinotti e, perrot jl, labeille b, cambazard f, rubegni p. ex vivo confocal microscopy: an emerging technique in dermatology. dermatol pract concept. 2018;8(2):109-119. doi: https://doi.org/10.5826/dpc.0802a08 received: july 3, 2017; accepted: january 18, 2018; published: april 30, 2018 copyright: ©2018 cinotti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elisa cinotti, phd. department of medical, surgical and neurological science, dermatology section, university of siena, s. maria alle scotte hospital, viale bracci 16, 53100 siena, italy. tel: 0039-0577 585428. fax: 0039 0577585484. email: elisacinotti@gmail.com this review aims to give an overview of the current available applications of ex vivo confocal microscopy (evcm) in dermatology. evcm is a relatively new imaging technique that allows microscopic examination of freshly excised unfixed tissue. it enables a rapid examination of the skin sample directly in the surgery room and thus represents an alternative to the intraoperative micrographic control of the surgical margins of cutaneous tumors by standard microscopic examination on cryopreserved sections during mohs surgery. although this technique has mainly been developed for the margin’s control of basal cell carcinoma, many other skin tumors have been studied, including melanoma. use of evcm is continuing to evolve, and many possible applications are under investigation, such as the study of nails and hair diseases and the diagnosis of skin infections. abstract 110 review | dermatol pract concept 2018;8(2):8 in reflectance mode, the images appear in grayscale with dark hypo reflective structures (black and dark gray) and bright hyper reflective structures (white and light gray) with an identical appearance to in vivo reflectance confocal microscopy (figure 1). in the fluorescence mode, the nonfluorescent structures are dark (black and dark gray) and the fluorescent structures are white (figure 2). using acridine orange, the nuclei of the cells are fluorescently stained in white with an increase in contrast of keratinocytes, hair follicle epithelium, sebaceous and eccrine glands, fibroblasts (figure 2), and tumor cells (figure 3) relative to the surrounding tissue. different from in vivo reflectance confocal microscopy, muscle and adipose tissue can be seen, given the opportunity to observe the sample from its lateral sides (figures 1, 2) and its bottom. it should be noted that fat tissue is usually modified by fixation during classical histology, whereas fat remains intact under evcm. interestingly, the same specimen can be observed both under the reflectance and fluorescence mode and the combination of the two techniques can give complementary information on the architectural and cellular features. applications evcm has been shown to be a reliable diagnostic method with good histological correspondence for both normal and pathological skin [5,6,10]. it has been developed as an alternative to the optical microscopy examination of frozen sections stained with hematoxylin and eosin (h&e) for the intraoperative control of surgical margins of cutaneous tumors during mms [4,7,10-13]. evcm has also been used for intraoperative examination of nails [14,15] and can be employed for the evaluation of hair morphology [16] (figure 4) and disease of the mucosa [17,18]. mosaicing may offer a means to perform rapid histology at the bedside. several future applications are possible, such as the identification of fillers in the skin [19] and the diagnosis of inflammatory and infectious diseases [20-22]. evcm cannot replace conventional histological examination because the cytological and architectural details cannot always be clearly identified, and to date, there is no specific staining that allows us to distinguish between different cell types. however, evcm could be useful in some conditions in which the cellular and architectural abnormalities are more characteristic (figure 5). recently, evcm has extended to other disciplines that might require extemporaneous examination of tumors, such as brain, breast and thyroid tumors [6,23-25]. a possible barrier to more widespread use of evcm is that the mosaics are based on a single mode of grayscale contrast and appear black and white, whereas histology is based on two stains (hematoxylin for nuclei and ex vivo confocal microscopy examination microscope only one device is commercially available (vivascope 2500(r), new version of vivascope 2000, produced by caliber, new york, usa and distributed in europe by mavig gmbh, munich, germany). the ex vivo confocal microscope works in reflectance mode (laser wavelength of 830 nm) or fluorescence mode (laser wavelength of 488 nm or 658 nm). processing in reflectance mode no staining is required. however, aluminum chloride, acetic acid, or citric acid can be used to enhance the reflectance of nuclei [2-4]. when using the fluorescence mode, the entire surgical specimen is dipped in a solution of a fluorescent agent (e.g., acridine orange, methylene blue, fluorescein, nile blue, or patent blue v) for 10-20 seconds and rinsed in physiological saline, acetic acid or phosphate buffered saline in order to remove the excess of the fluorescent agent. the most used fluorescent agent is acridine orange that targets nuclear dna [2]. several studies showed that acridine orange immersion does not affect subsequent frozen sections and formalin-fixed histopathology quality [5-7]. cutting in thin slices is not necessary. the skin specimen can be observed entirely, or the tumor’s margins can be vertically cut as for conventional histology [8]. in order to prevent sample deformation and movement during the examination, the skin sample should be mounted between two thick microscopy glass slides attached together by a small amount of silicon glue or modeling clay [9]. to facilitate the contact of the outer surface of the specimen with the glass slide facing the microscope objective, aqueous gel (e.g., carbomer gel, gel larmes thea laboratories, clermont-ferrand, france) or silicone can be applied [9]. a “tissue press” can be used to better flatten the sample [9] and avoid to artifacts that result from the inhomogeneous contact between the sample’s surface and the glass slide in the case of a specimen with a inhomogeneous thickness. the skin sample is then settled on the microscope stage. ex vivo confocal microscopy images the microscope produces horizontal images of 750 x 750 µm of the different layers of the skin up to a thickness of 200 µm. single images are automatically stitched together into a reconstructed mosaic image to a maximum size of 20 x 20 mm (12 x12 mm for the previous generation of the device, the one that is most utilized). the depth of observation is manually adjusted. the acquisition time for a single image of 750 x 750 µm is 0.68 seconds (2 minutes/cm2) for the third generation of the device [8]. according to the manufacturer’s data, the lateral and axial spatial resolutions are 1 µm and 3 µm respectively. review | dermatol pract concept 2018;8(2):8 111 figure 1. normal skin under the ex vivo confocal microscope in the reflectance mode. epidermis (red bracket), dermis (yellow bracket), and fat tissue (yellow asterisks) are visible in a vertical section. [copyright: ©2018 cinotti et al.] figure 2. normal skin under ex vivo confocal microscope in fluorescence mode with acridine orange. epidermis (red bracket), dermis (yellow bracket), fat tissue (yellow asterisk), and adnexa (pink asterisks) are visible in a vertical section. [copyright: ©2018 cinotti et al.] 112 review | dermatol pract concept 2018;8(2):8 figure 3. superficial basal cell carcinoma under ex vivo confocal microscope in fluorescence mode with acridine orange in a vertical section. tumor islands (blue circles) are easily recognizable because they are brighter (fluorescent) than the surrounding tissue. [copyright: ©2018 cinotti et al.] figure  4. normal hair shafts under ex vivo reflectance confocal microscopy. [copyright: ©2018 cinotti et al.] review | dermatol pract concept 2018;8(2):8 113 proposed for other epithelial tumors [32,33], melanocytic tumors [6,17,34,35] (figure 7), and paget’s disease [36] (figure 8). the overall sensitivity and specificity of fluorescencemode evcm for detecting bcc with narrow or incomplete margins were 88–96.6% and 89.2–99% respectively [4,7,10,27,30]. the largest study performed by bennàssar and colleagues on 80 carcinomas demonstrated an overall sensitivity and specificity for residual bcc of 88% and 99% respectively [10]. possible false positive results can be caused by the presence of hair follicles and eccrine glands or sebaceous glands that may be confused with bcc islands. however, the former reveals no palisading, less fluorescence, and smaller nuclei. furthermore, it could be difficult to distinguish the infiltrative cords of bcc from the surrounding peritumoral stroma, although the latter show no tendency to cluster. a few case series reported the use of evcm for controlling the surgical margins of scc. concerning the reflectance mode, an initial study found a positive correlation with histopathology in 13 out of 23 sccs [11], whereas a sensitivity of 95% and a specificity of 96% for the identification of scc were achieved in a second study on 10 lesions [37]. only one study has been performed in the fluorescence mode, and eosin for cellular cytoplasm and dermis) and appears purple and pink [1]. in the future, digital staining could be used in order to change the grayscale into a color scale that mimics the appearance in histology [1]. ex vivo confocal microscopy for the control of surgical margins of cutaneous tumors different from mms, evcm enables the evaluation of the resection margins immediately after excision without freezing the specimen, thereby reducing the investment of time by two-thirds [10]. to date the analysis of surgical margins has been carried out by cutting the deep and lateral margins (“tübingen torte” [26]) and analyzing them in vertical plane, perpendicular to the surface of the skin, as is done in conventional histology. our group proposed an analysis of the entire specimen in horizontal plane, parallel to the surface of the skin (“en face” technique), without cutting the lateral and deep margins [8]. the “en face” technique provides images similar to in vivo reflectance confocal microscopy and is particularly suitable for horizontal spreading tumors [8]. (figure 6). most of the evcm studies were conducted on bccs [3-5,7,10,27-31] (figure 3). subsequently, evcm has been figure  5. ex vivo reflectance confocal microscopy examination of a skin biopsy from a plaque of sweet’s syndrome. dense infiltrate of hyper-reflective cells in the upper half of the dermis corresponding to leukocytes (red circle) and severe edema (hypo-reflective areas, green asterisks) of the upper dermis with strands of dermal collagen stretched across the pseudobullous spaces (yellow arrows) are visible. [copyright: ©2018 cinotti et al.] 114 review | dermatol pract concept 2018;8(2):8 because the endogenous autofluorescence from the dermis is relatively weak (figure 3). the reported criteria that enable identification of bcc islands under fluorescence confocal microscopy are [38]: 1. demarcated fluorescent areas with a higher nuclear density than the surrounding epidermis and adnexal structures (nuclear crowding) 2. peripheral palisading (peripheral polarized and aligned fluorescent cells) 3. clefting (black fluorescence-free area around the tumor mass) 4. nuclear pleomorphism 5. enlarged nucleus/cytoplasm ratio 6. modified stroma around the tumor (more densely nucleated dermis with fluorescent dots within a black background, corresponding to inflammatory cells and activated fibroblasts) bcc subtypes can also be identified [7]. in superficial bcc tumor islands are connected to the epidermis and separated from the dermis by some clefts (figure 3). in nodular evcm agreed with histopathology in 41 out of 43 mosaics obtained from 34 tumor margins of 13 sccs [32]. false negative results can be caused by incorrect imaging of the sample due to the presence of artifacts [32] and the inability to properly flatten the fresh tissue [9]. moreover, a discrepancy with histology can arise when preparing the specimen for standard histological examination and lateral slices are removed from the paraffin-embedded specimen before obtaining definitive sections. the material that is removed could contain tumor tissue seen under evcm and not under histology. basal cell carcinoma in reflectance mode, large bccs are easily detected [8]. however, tiny strands of micronodular infiltrating bccs could remain hidden because of the hyper-reflectivity of the surrounding normal dermis [10]. in fluorescence mode with a contrast agent that stains nuclei, such as acridine orange, bcc islands are highly fluoresecent and are distinguishable from the surrounding tissue figure 6. superficial basal cell carcinoma of the eyelid under ex vivo reflectance confocal microscope and horizontal section. tumor islands (blue circles) are hyper-reflective and separated from the stroma by clefting. [copyright: ©2018 cinotti et al.] review | dermatol pract concept 2018;8(2):8 115 packed and irregularly distributed nuclei [11,37]. in situ scc is more difficult to identify because of the difficulty of accurately detecting dyskeratotic cells and nuclear atypia [11,37]. improved quality of images has been obtained by using acridine orange as fluorochrome [14,32]. a study of 13 sccs demonstrated that evcm with the fluorescence mode could also be used to grade this tumor [32]. a well-defined tumor silhouette, numerous keratin pearls, keratin formation, and bcc tumor islands are larger and disconnected from the epidermis. in micronodular bcc tumor islands are smaller, and in infiltrative bcc tumor islands are small, elongated, and deep located. squamous cell carcinoma using the reflectance mode, squamous cell carcinomas (scc) can be identified by the presence of keratinocytes with densely figure 7. clinical (a) and ex vivo reflectance confocal microscopy (b, c) aspects of melanoma. melanoma thickness is marked by the red line (c) and melanoma nests (b, inset in c marked by the blue rectangle) are very easily recognizable because of their brightness (hyper-reflectivity). [copyright: ©2018 cinotti et al.] 116 review | dermatol pract concept 2018;8(2):8 of six melanomas with similar features to in vivo reflectance confocal microscopy [6]. a pilot study on 10 melanomas suggested that evcm could also be used to measure melanoma thickness [34] (figure 7) with the possible future benefit of being able to choose the correct size of the surgical margins before the surgical excision. ex vivo confocal microscopy and nails evcm could be particularly useful for nail tumors in order to confirm intraoperatively the diagnosis of the biopsy specimen and to proceed to the final excision without waiting for the histological examination. notably, evcm is more suitable than the optical examination of frozen sections of this site because nail tumors are often very small in size, and it is desirable that no material be wasted in producing sections that subsequently cannot be submitted to conventional pathology. in a pilot study on six malignant epithelial tumors of the nail apparatus, debarbieux et al [16] showed that evcm in fluorescence mode could be a useful tool for the diagnosis scarce nuclear pleomorphism correlate with the diagnosis of well-differentiated scc. conversely, an ill-defined tumor silhouette, paucity or absence of keratin pearls, and marked nuclear pleomorphism is observed in poorly differentiated tumors. sccs that are moderately differentiated reveal an intermediate pattern of growth with the presence of keratin formation. syringomatous carcinoma evcm in the fluorescent mode with acridine orange has been performed in only two syringomatous carcinomas [33]. they appeared as highly fluorescent neoplastic cords of monomorphous cells in the dermis. melanoma recently, melanoma has been imaged by evcm [6,17,34]. proliferation of atypical melanocytes in the epidermis and consumption of the epidermis and nests of atypical melanocytes in the dermis were observed under evcm in a study figure 8. clinical (a), fluorescence (b), and reflectance (c) ex vivo reflectance confocal microscopy aspect of paget’s disease. paget’s cells in the epidermis (red bracket; stratum corneum is marked by orange star) are visualized better (b, pink arrows) under fluorescence mode with acridine orange than under reflectance mode when comparing images from the same area. [copyright: ©2018 cinotti et al.] review | dermatol pract concept 2018;8(2):8 117 tamination because the examination is made concomitantly, just after the specimen collection [22]. evcm has the great advantage over conventional microscopy in that the sample is left intact with the subsequent possibility of localizing the infectious agent directly in the whole tissue. this could be particularly useful for the fast and precise identification of a fungus in a case of a deep fungal infection such as mucormycosis [22]. to date there is only one study that compares evcm to conventional microscopy and fungal culture for the identification of dermatophytes, and this study includes only three cases of hair infection [16]. as in vivo confocal microscopy, evcm can show viral cytopathic effect [20,31]. evcm has also been used successfully in fluorescence mode with anti-herpes virus simplex 1 (hsv1) antibodies coupled with fluorescein isothiocyanate for the identification of hsv1 from the roof of six vesicles from three different patients [20]. this application is an example of how this device has the potential to identify any pathogen disposing of specific antibodies conjugated with any fluorescent agent that can be excited by a wavelength of 488 nm or 658 nm. studies of comparison with standard methods such as tzanck-test, histopathology, or pcr for hsv infection should be performed. conclusions in conclusion, evcm is a relatively new imaging technique that can analyze whole skin samples of up to 2 cm in diameter without the need to cut it into thin sections. data for clinical use of evcm is only available for the intraoperative control of tumor margins in bcc. however, many other tumors are in the evaluation phase, as well as non-tumor diseases such as skin infections. in the future, evcm could be used in order to quickly obtain architectural and cytological details of any skin sample to orient the clinical diagnosis before definitive histological examination. a promising field seems to be the intraoperative nail evaluation, and a new domain that could be explored is hair shaft examination. at the present time, the main limitation of this technique is the high cost of the device, which limits its widespread use. references 1. bini j, spain j, nehal k, hazelwood v, dimarzio c, rajadhyaksha m. confocal mosaicing microscopy of human skin ex vivo: spectral analysis for digital staining to simulate histology-like appearance. j biomed opt. 2011;16:076008. 2. que skt. research techniques made simple: noninvasive imaging technologies for the delineation of basal cell carcinomas. j invest dermatol. 2016;136:e33–38. 3. rajadhyaksha m, menaker g, flotte t, dwyer pj, gonzález s. confocal examination of nonmelanoma cancers in thick skin of invasive scc, invasive onycholemmal carcinoma, and bowen’s disease showing marked nuclear and cytological atypia and the presence of numerous dyskeratotic cells. in particular, well-demarcated epithelial nests deeply invading the dermis, nuclear pleomorphism (variable size and shape of the nucleus), and densely packed and irregularly organized nuclei have been observed in invasive scc and onycholemmal carcinoma [14,39,40]. therefore, in these cases it would be possible to perform wide excision of the tumors just after the observation of a biopsy specimen under evcm, shortening the management. however, in situ scc and minimally invasive well-differentiated scc were more difficult to diagnose, showing only focal epithelial acanthosis and not cytological atypia [14]. the same study of debarbieux et al [14] included three benign epithelial tumors (two onychomatricomas and one onychopapilloma) that were differentiated from scc because their cellular density was similar to the adjacent nail bed and because the cells had small monomorphic nuclei. onychomatricomas showed acanthotic and papillomatous epithelium with no identified atypia under evcm [14]. interestingly, the dermal papillae embedded within the epithelial proliferation contained numerous spindle cells corresponding to fibroblastas [14]. onychopapilloma is a very circumscribed epithelial tumor of the nail bed, characterized by thin digitiform epithelial projections within the upper dermis that were visible under evcm [14]. in our experience, not only can nonpigmented epithelial tumors be recognized under evcm, but also other amelanotic non-epithelial tumors such as glomus tumor and neurinoma [40]. evcm seems to be less useful for subungual melanoma because the in vivo device that is used directly on the nail matrix performs well in this special site [15]. moreover, with evcm amelanotic melanocytes cannot be distinguished from epithelial cells or dermal inflammatory cells in fluorescence, and their reflectance can be low [14]. debarbieux et al [41] also used the in vivo device for the ex vivo examination of nail biopsies of pigmented subungual melanoma in a series of eight cases. however, this procedure has limitations in that the specimen is not fixed, tends to move, and is difficult to orient, unlike when using the ex vivo device. ex vivo confocal microscopy and infections evcm in reflectance mode has been used to identify the hyphae and/or conidia in onychomycosis [40], tinea capitis [16], and tinea barbae [16]. in reflectance mode hyphae are highly reflective, thick linear structures, and conidia are hyper-reflective roundish bodies with the same aspect of in vivo reflectance confocal microscopy [42-43]. in fluorescence mode with acridine orange, hyphae are bright [22]. compared to fungal culture, evcm is faster and does not have the problem of false positive results due to environmental con118 review | dermatol pract concept 2018;8(2):8 microscopy during herpetic skin infections. clin exp dermatol. 2015;40:421-425. 21. cinotti e, labeille b, douchet c, et al. role of in vivo and ex vivo confocal microscopy and of optical coherence tomography as aids in the diagnosis of molluscum contagiosum. ann dermatol venereol. 2016;143:564–566. 22. leclercq a, cinotti e, labeille b, perrot jl, cambazard f. ex vivo confocal microscopy: a new diagnostic technique for mucormycosis. skin res technol. 2016;22:203–207. 23. forest f, cinotti e, yvorel v, et al. ex vivo confocal microscopy imaging to identify tumor tissue on freshly removed brain sample. j neurooncol. 2015;124:157–164. 24. ragazzi m, piana s, longo c, et al. fluorescence confocal microscopy for pathologists. mod pathol. 2014;27:460–471. 25. ragazzi m, longo c, piana s. ex vivo (fluorescence) confocal microscopy in surgical pathology: state of the art. adv anat pathol. 2016;23:159–169. 26. kopke lf, konz b. micrographic surgery. a current methodological assessment. hautarzt. 1995;46:607–614. 27. gareau ds, patel yg, li y, et al. confocal mosaicing microscopy in skin excisions: a demonstration of rapid surgical pathology. j microsc. 2009;233:149–59. 28. ziefle s, schüle d, breuninger h, schippert w, moehrle m. confocal laser scanning microscopy vs 3-dimensional histologic imaging in basal cell carcinoma. arch dermatol. 2010;146:843–847. 29. al-arashi my, salomatina e, yaroslavsky an. multimodal confocal microscopy for diagnosing nonmelanoma skin cancers. lasers surg med. 2007;39:696–705. 30. larson b, abeytunge s, seltzer e, rajadhyaksha m, nehal k. detection of skin cancer margins in mohs excisions with highspeed strip mosaicing confocal microscopy: a feasibility study. br j dermatol. 2013;169:922–926. 31. schüle d, breuninger h, schippert w, dietz k, moehrle m. confocal laser scanning microscopy in micrographic surgery (threedimensional histology) of basal cell carcinomas. br j dermatol. 2009;161:698–700. 32. longo c, ragazzi m, gardini s, et al. ex vivo fluorescence confocal microscopy in conjunction with mohs micrographic surgery for cutaneous squamous cell carcinoma. j am acad dermatol. 2015;73:321–322. 33. longo c, ragazzi m, gardini s, moscarella e, argenziano g. ex vivo fluorescence confocal microscopy of eccrine syringomatous carcinoma: a report of 2 cases. jama dermatol. 2015;151:1034– 1036. 34. hartmann d, krammer s, ruini c, ruzicka t, von braunmühl t. correlation of histological and ex-vivo confocal tumor thickness in malignant melanoma. lasers med sci. 2016;31:921–927. 35. cinotti e, perrot j-l, labeille b, et al. contribution of reflectance confocal microscopy in the diagnosis of eyelid dermal nevus. ann dermatol venereol. 2015;142:226–228. 36. debarbieux s, dalle s, depaepe l, jeanniot py, poulalhon n, thomas l. extramammary paget’s disease of the scalp: examination by in vivo and ex vivo reflectance confocal microscopy. skin res technol. 2014;20:124–126. 37. horn m, gerger a, koller s, et al. the use of confocal laserscanning microscopy in microsurgery for invasive squamous cell carcinoma. br j dermatol. 2007;156:81–84. 38. bennàssar a, carrera c, puig s, vilalta a, malvehy j. fast evaluation of 69 basal cell carcinomas with ex vivo fluorescence confocal microscopy: criteria description, histopathological excisions to potentially guide mohs micrographic surgery without frozen histopathology. j invest dermatol. 2001;117:1137–1143. 4. karen jk, gareau ds, dusza sw, tudisco m, rajadhyaksha m, nehal ks. detection of basal cell carcinomas in mohs excisions with fluorescence confocal mosaicing microscopy. br j dermatol. 2009;160:1242–1250. 5. gareau ds, li y, huang b, eastman z, nehal ks, rajadhyaksha m. confocal mosaicing microscopy in mohs skin excisions: feasibility of rapid surgical pathology. j biomed opt. 2008;13:054001. 6. hartmann d, ruini c, mathemeier l, et al. identification of ex-vivo confocal laser scanning microscopic features of melanocytic lesions and their histological correlates. j biophotonics. 2017;10:128–142. 7. longo c, rajadhyaksha m, ragazzi m, et al. evaluating ex vivo fluorescence confocal microscopy images of basal cell carcinomas in mohs excised tissue. br j dermatol. 2014;171:561–570. 8. espinasse m, cinotti e, grivet d, et al. “en face” ex vivo reflectance confocal microscopy to help the surgery of basal cell carcinoma of the eyelid. clin exp ophthalmol. 2017;45(50):442-447. 9. cinotti e, grivet d, labeille b, et al. the “tissue press”: a new device to flatten fresh tissue during ex vivo confocal microscopy examination. skin res technol. 2017;23:121–124. 10. bennàssar a, vilata a, puig s, malvehy j. ex vivo fluorescence confocal microscopy for fast evaluation of tumour margins during mohs surgery. br j dermatol. 2014;170:360–365. 11. chung vq, dwyer pj, nehal ks, et al. use of ex vivo confocal scanning laser microscopy during mohs surgery for nonmelanoma skin cancers. dermatol surg. 2004;30:1470–1478. 12. gerger a, horn m, koller s, et al. confocal examination of untreated fresh specimens from basal cell carcinoma: implications for microscopically guided surgery. arch dermatol. 2005;141:1269–1174. 13. patel yg, nehal ks, aranda i, li y, halpern ac, rajadhyaksha m. confocal reflectance mosaicing of basal cell carcinomas in mohs surgical skin excisions. j biomed opt. 2007;12:034027. 14. debarbieux s, gaspar r, depaepe l, dalle s, balme b, thomas l. intraoperative diagnosis of nonpigmented nail tumours with ex vivo fluorescence confocal microscopy: 10 cases. br j dermatol. 2015;172:1037–1044. 15. fattouh k, debarbieux s, depaepe l, amini-adle m, balme b, thomas l. routine use of perioperative in vivo reflectance confocal microscopy of the nail matrix in melanonychia striata: about 30 cases. br j dermatol. 2017;177:570-573. 16. cinotti e, perrot jl, labeille b, raberin h, flori p, cambazard f. hair dermatophytosis diagnosed by reflectance confocal microscopy: six cases. j eur acad dermatol venereol. 2015;29:22572259. 17. cinotti e, haouas m, grivet d, perrot jl. in vivo and ex vivo confocal microscopy for the management of a melanoma of the eyelid margin. dermatol surg. 2015;41:1437-1440. 18. iovieno a, longo c, de luca m, piana s, fontana l, ragazzi m. fluorescence confocal microscopy for ex vivo diagnosis of conjunctival tumors: a pilot study. am j ophthalmol. 2016;168:207– 216. 19. cinotti e, perrot jl, labeille b, boukenter a, ouerdane y, cosmo p, et al. identification of a soft tissue filler by ex vivo confocal microscopy and raman spectroscopy in a case of adverse reaction to the filler. skin res technol. 2015;21:114–118. 20. cinotti e, perrot jl, labeille b, et al. first identification of the herpes simplex virus by skin-dedicated ex vivo fluorescence confocal review | dermatol pract concept 2018;8(2):8 119 41. debarbieux s, hospod v, depaepe l, balme b, poulalhon n, thomas l. perioperative confocal microscopy of the nail matrix in the management of in situ or minimally invasive subungual melanomas. br j dermatol. 2012;167:828–836. 42. forest f, cinotti e, habougit c, et al. rapid characterization of human brain aspergillosis by confocal microscopy on a thick squash preparation. cytopathology. 2016;27:221–222. 43. cinotti e, perrot jl, labeille b, cambazard f. reflectance confocal microscopy for cutaneous infections and infestations. j eur acad dermatol venereol. 2016;30:754-763. correlation, and interobserver agreement. jama dermatol. 2013;149:839–847. 39. fernandes massa a, debarbieux s, depaepe l, dalle s, balme b, thomas l. pigmented squamous cell carcinoma of the nail bed presenting as a melanonychia striata: diagnosis by perioperative reflectance confocal microscopy. br j dermatol. 2013;169:198– 199. 40. cinotti e, fouilloux b, perrot jl, labeille b, douchet c, cambazard f. confocal microscopy for healthy and pathological nail. j eur acad dermatol venereol. 2014;28:853-858. untitled quiz | dermatol pract concept 2015;5(2):16 85 dermatology practical & conceptual www.derm101.com below is the answer to the quiz by dr. rishpon presented in the previous issue of dermatology practical & conceptual [2015;5(1):13]. answer balloon cell nevus discussion balloon cell changes in a nevus correspond to nests of vacuolated melanocytes, caused by enlargement and disintegration of melanosomes [1]. dermoscopic correlation has been reported as white or yellow globules [2-4]. these globules were confirmed to correlate with junctional and dermal melanocytic nests seen on reflectance confocal microscopy, similar in size and location to the balloon cell nests in histology [2]. it is important to differentiate the white/yellow globules from other structures similar in color and shape, including milialike cysts and sebaceous glands [3]. this case highlights how clinical and dermoscopic primary morphology serves as a direct correlate of unique histologic features. congratulations to dr. akhilesh shukla (drakhilesh89@ gmail.com), who was the first to send us the correct answer! references 1. martinez-casimiro l, sánchez carazo jl, alegre v. balloon cell naevus. j eur acad dermatol venereol 2009;23(2):236–7. 2. jaimes n, scope a, welzel j, et al. white globules in melanocytic neoplasms: in vivo and ex vivo characteristics. dermatol surg 2012;38(1):128–32. 3. jaimes n, braun rp, stolz w, et al. white globules correlate with balloon cell nevi nests. j am acad dermatol 2011;65:e119–20. 4. cinotti e, perrot jl, labeille b, et al. yellow globules in balloon cell naevus. australas j dermatol 2013;54(4):268-70. a pigmented lesion with yellow-white globular-like structures—answer ayelet rishpon1 1 department of dermatology, tell-aviv sourasky medical center, tel-aviv, israel citation: rishpon a. a pigmented lesion with yellow-white globular-like structures—answer. dermatol pract concept 2015;5(2):16. doi: 10.5826/dpc.0502a16 copyright: ©2015 rishpon. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: ayelet rishpon, department of dermatology, tel-aviv sourasky medical center, tel-aviv, israel. tel. 972 542 195 569 email: arishpon@gmail.com. untitled observation | dermatol pract concept 2015;5(2):21 105 dermatology practical & conceptual www.derm101.com case presentation a 5-month-old israeli jewish male of lithuanian and kazakh descent with no family history of neurocutaneous or dermatological disease was referred to our outpatient pediatric dermatology clinic for evaluation of skin folds on the lower back, which had been present since birth (figure 1a). on physical examination, a mildly erythematous, poorly demarcated soft plaque on the right side of the lower back was noted with sensory change. the plaque consisted of excessive skin folds. on the lateral border of the plaque, a 3 cm cluster of café-au-lait spots was present. a firm raised area on the scalp (present since birth, according to the patient’s parents) was also palpated. ultrasonographic examination of the lower back was negative for cysts, bony involvement, or muscular abnormalities. ultrasound of the skull confirmed the presence of a benign bony prominence consistent with exostosis. segmental neurofibromatosis presenting with congenital excessive skin folds alexander m. helfand1, ariella nouriel 1, jonah zisquit1, aviv barzilai1, shoshana greenberger1,2 1 department of dermatology, sheba medical center, tel hashomer, ramat gan, israel, affiliated with the sackler school of medicine, tel aviv university, tel aviv, israel 2 pediatric dermatology clinic, edmond and lily safra children’s hospital, the chaim sheba medical center, tel aviv, israel key words: neurofibromatosis, skin folds, congenital citation: helfand am, nouriel a, zisquit j, barzilai a, greenberger s. segmental neurofibromatosis presenting with congenital excessive skin folds. dermatol pract concept 2015;5(2):21. doi: 10.5826/dpc.0502a21 received: october 22, 2014; accepted: january 21, 2014; published: april 30, 2015 copyright: ©2015 helfand et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: shoshana greenberger, md, phd, department of dermatology, sheba medical center, tel hashomer, ramat gan, israel 52621. tel. +972 54 7584934; fax. +972 3 5305842. email: shoshana.greenberger@sheba.health.gov.il segmental neurofibromatosis (snf) is a rare type of neurofibromatosis (nf-1) resulting from postzygotic somatic mutations in the neurofibromin gene that leads to mosaicism. reported manifestations of snf include neurofibromas, freckling, or café-au-lait spots limited to a single body region or limb. we present a 5-month-old male referred to our clinic for evaluation of congenital excessive skin folds on the back. a mildly erythematous, poorly demarcated soft plaque was noted, consisting of excessive skin folds. a cluster of light brown hyperpigmented macules was seen overlying the plaque. a punch biopsy of the plaque confirmed a diagnosis of neurofibroma. further investigation ruled out other manifestations of nf-1. the early onset of our patient’s neurofibroma and its gross appearance with redundant skin folds are all unusual features. to our knowledge, congenital excessive skin folds found in a single tumor have not been previously described in the literature as a manifestation of snf. clinicians should be educated about the possibility of congenital localized skin folds in association with snf in order to identify the disease in infancy and monitor any changes in neurofibroma pathology. abstract 106 observation | dermatol pract concept 2015;5(2):21 of the neurofibromatosis phenotype in these snf patients signified a somatic mutation [2]. in 2000, tinschert, et al confirmed that snf was a consequence of a spontaneous post-zygotic somatic mutation in the neurofibromin tumor suppressor gene leading to a mosaic pattern of the disease [3]. intragenic deletions in nf1 can occur early or late in fetal development, giving rise to somatic mosaicism that can manifest as highly localized neurofibromatosis (late mutation) or diffuse phenotypic findings (early mutation) difficult to differentiate clinically from germ-line nf-1 [4]. snf has been divided into four subtypes: true segmental, localized with deep involvement, hereditary, and bilateral [5]. snf can present with only pigmentary changes, only neurofibromas, isolated plexiform neurofibromas, or both pigmentary changes and neurofibromas, as in our patient [6,7]. the frequency of neurofibromatosis type 1 (nf-1) in israeli jews (1.04/1000) [8] has been reported to be 2-5 times that of the prevalence in the overall population, approximately 1/3000-1/5000 [9], though the prevalence of snf in israeli jews has not been described. moreover, the prevalence of nf-1 among israeli jews of asian descent (like our patient) (0.95/1000) is 50% greater than in jews of european or north american origin [8]. punch biopsy of the soft plaque on the lower back revealed a proliferation of spindle cells in the dermis, arranged in fascicles. the majority of fascicles were wavy and surrounded by stroma consisting of thin, delicate connective tissue fibers (figure 2a). cells throughout the dermis stained positive for s-100 (figure 2b) and negative for melana (not shown), compatible with the diagnosis of a neurofibroma. as segmental neurofibromatosis (snf) was suspected, a workup was ordered. the patient was found to have normal development and age-appropriate neurological function. he had no myopathy or muscle wasting. no lisch nodules were seen and doppler ultrasonography of the renal arteries detected no abnormalities. at follow-up consultation at 3 years of age, the plaque appeared to have grown proportionally with the child to a width of 20 cm (figure 1b, c). no axillary freckling was present. the parents were not interested in further genetic work-up. yearly follow-up surveillance was recommended. conclusions the first cases of segmental neurofibromatosis were reported in 1931 by gammel [1]. it was postulated that the localization figure 1. clinical photographs of the patient at the age of 5 months (a) and at a follow-up visit at the age of 3 years (b, c) showing a large plaque consisting of congenital skin folds on an erythematous base with a cluster of café-au-lait spots on the right side of the plaque. [copyright: ©2015 helfand et al.] figure 2. (a) h&e stained tissue section from snf lesion on the lower back at 10x magnification, showing proliferation of spindle cells in the dermis, arranged in fascicles. the majority of fascicles are wavy and surrounded by stroma consisting of thin, delicate connective tissue fibers. (b) s100 stained tissue section from snf lesion on the lower back at 10x magnification, with cells throughout the dermis staining positive for s100. [copyright: ©2015 helfand et al.] a b observation | dermatol pract concept 2015;5(2):21 107 found in a single location on the lower back with rapid proportional growth throughout early childhood have not been previously described in the literature on mosaic snf. while café-au-lait spots may be suggestive of the diagnosis, the alert clinician should be aware that segmental neurofibromatosis might present as localized excessive skin folds. references 1. gammel ja. localized neurofibromatosis. arch dermatol syphilol 1931;24:712-5. 2. miller rm, sparkes rs. segmental neurofibromatosis. arch dermatol 1977;113(6):837-8. 3. tinschert s, naumann i, stegmann e, et al. segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (nf1) gene. eur j hum genet 2000;8(6):455-9. 4. ruggieri m, huson sm. the clinical and diagnostic implications of mosaicism in the neurofibromatoses. neurology 2001;56(11):1433-43. 5. roth rr, martines r, james wd. segmental neurofibromatosis. arch dermatol 1987;123(7):917-20. 6. gabhane sk, kotwal mn, bobhate sk. segmental neurofibromatosis: a report of 3 cases. indian j dermatol 2010;55(1):105-8. 7. listernick r, mancini aj, charrow j. segmental neurofibromatosis in childhood. am j med genet a 2003:121a(2):132-135. 8. garty bz, laor a, danon yl. neurofibromatosis type 1 in israel: survey of young adults. j med genet 1994;31(11):853-7. 9. friedman jm. epidemiology of neurofibromatosis type 1. am j med genet 1999. 89(1):1-6. 10. kehrer-sawatzki h, kluwe l, sandig c, et al. high frequency of mosaicism among patients with neurofibromatosis type 1 (nf1) with microdeletions caused by somatic recombination of the jjaz1 gene. am j hum genet 2004;75(3):410-23. 11. korf, br. plexiform neurofibromas. am j med genet 1999;89(1):31-7. 12. folpe al, inwards cy. neurofibroma, neurofibromatosis type i, and early malignant change in neurofibroma. in: goldblum jr, ed. bone and soft tissue pathology: a volume in the series foundations in diagnostic pathology. 1st ed. philadelphia, pa: saunders, 2010:199-206. 13. kawachi y, maruyama h, ishitsuka y, et al. nf1 gene silencing induces upregulation of vascular endothelial growth factor expression in both schwann and non-schwann cells. exp dermatol 2013;22(4):262-5. snf has been estimated to be approximately 10-30 times rarer than nf-1. ruggieri and huson estimated snf prevalence as 1/36,000 to 1/40,000 [4]. kehrer-sawatzki et al, however, found somatic mosaicism in 40% of patients with sporadic nf-1 [10], suggesting the possibility of much higher snf prevalence. further study into the true prevalence of snf remains necessary. neurofibromatosis was suspected in our patient because of the café-au-lait spots found on the plaque. the other differential diagnoses of our patient’s cutaneous findings initially included nevus lipomatosus cutaneous superficialis, smooth muscle cell hamartoma, and nevus sebaceous. in addition, plexiform neurofibromas, sometimes present as loose, redundant skin folds [11,12]. however, histology findings precluded this diagnosis in our patient. the unusual appearance of excessive skin folds was mildly reminiscent of the congenital circumferential skin folds found in the ‘michelin tire baby syndrome,’ although these folds were not circumferential. the pathogenesis of such skin folds is unclear. some hypothesize that growth factors secreted by the schwann cells in the tumor, such as vascular endothelial growth factor, lead to overgrowth of the adjacent tissues [13]. the bony exostosis on the patient’s skull may be a random finding. alternatively, it may represent mosaicism. systemic nf-1 is much less probable, especially in light of the patient’s lack of systemic signs of neurofibromatosis. it should be noted, however, that lisch nodules and axillary freckling occur at older ages and thus their absence in the age of three cannot exclude systemic nf-1. in compliance with the wishes of the patient’s family, genetic analysis was not performed. nonetheless, the combination of localized neurofibroma and café-au-lait spots makes the diagnosis of snf highly likely. in summary, we report a case of snf in a 5-month-old male manifesting in excessive skin folds limited to a large plaque on the lower back that has grown proportionally with the child. café-au-lait spots are present on the right side of the plaque. the early onset of our patient’s neurofibroma and its gross appearance with redundant skin folds are all unusual features. to our knowledge, congenital excessive skin folds dermatology: practical and conceptual quiz | dermatol pract concept 2015;5(1):13 75 dermatology practical & conceptual www.derm101.com a pigmented lesion with yellow-white globular-like structures ayelet rishpon1 1 department of dermatology, tell-aviv sourasky medical center, tel-aviv, israel citation: rishpon a. a pigmented lesion with yellow-white globular-like structures. dermatol pract concept 2015;5(1):13. doi: 10.5826/ dpc.0501a13 received: may 8, 2014; accepted: may 10, 2014; published: january 30, 2015 copyright: ©2015 rishpon. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: ayelet rishpon, department of dermatology, tel-aviv sourasky medical center, tel-aviv, israel. tel. 972 36973585. email: arishpon@gmail.com. figure 1. skin of right upper back showing a hyperpigmented papule. (copyright: ©2015 rishpon.) figure 2. close-up revealing subtle yellow areas at the central and upper part of the lesion. (copyright: ©2015 rishpon.) the patient a 28-year-old caucasian woman with skin type ii, multiple nevi, and a family history of melanoma presented with a pigmented lesion on the right upper back. clinically a hyperpigmented papule was seen (figure 1). close-up revealed subtle yellow areas in the central and upper part of the lesion (figure 2). 76 quiz | dermatol pract concept 2015;5(1):13 dermoscopy with a contact polarized dermoscope re vealed a slightly asymmetric homogenous-reticular pattern. within the lesion distinct yellow-white polygonal globularlike structures were seen (figure 3). histology revealed melanocytic nests at the dermo-epidermal junction and upper papillary dermis, showing vacuolated melanocytes (figure 4). figure 4. histopathology of the lesion with h&e staining showing melanocytic nests at the dermo-epidermal junction and papillary dermis and, within them, showing vacuolated melanocytes. original magnification x40. [acknowledgement: andrea gat, md] (copyright: ©2015 rishpon.) figure 3. dermoscopy with dermlite dl3 (3gen, inc., san juan capistrano, ca) shows a melanocytic lesion with a slightly asymmetric homogenous reticular pattern. within the lesion distinct yellow-white polygonal globularlik e structures are seen. (copyright: ©2015 rishpon.) what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical & conceptual. dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(2):1 1 dermatology practical & conceptual www.derm101.com the patient a 64-year-old white female presented with an asymptomatic brown-to-black nodular lesion located on her back in proximity (about 1.7 cm) to a surgical scar; indeed, the patient had developed a melanoma in situ on her back in 2010. she reported that the lesion had been present for two years (figure 1). family history of melanoma or other skin cancers were negative. on dermatoscopy, the lesion showed an atypical starburst pattern, characterized by a blue-white veil and blue globules in the center, and a peripheral polymorphous vascular pattern showing the presence of dotted, linear and irregular vessels (figure 2). a milia-like cyst was also observed in the inferior part of the lesion. an excisional biopsy was performed with 2 mm margins. the diagnosis proposed to the pathologist was spitz-reed nevus or melanoma. histology revealed interconnected small nests of basaloid cells attached to the epidermis, embedded in a fibrous stroma. focally, melanin pigment was seen in tumor nests (figure 3). appearances may be deceiving matteo megna1, maddalena napolitano1, claudia costa1, massimo mascolo2, massimiliano scalvenzi1 1 department of dermatology, university of naples federico ii, naples, italy 2 department of advanced biomedical sciences, pathology unit, university of naples, federico ii, naples, italy citation: megna m, napolitano m, costa c, mascolo m, scalvenzi m. appearances may be deceiving. dermatol pract concept 2016; 6(2):1. doi: 10.5826/dpc.0602a01 received: september 15, 2015; accepted: january 10, 2016; published: april 30, 2016 copyright: ©2016 megna et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. matteo megna, department of dermatology, university of naples federico ii, via pansini, 5, 80131 napoli, italy. tel. +39.081.7462412; fax. +39.081.7462442. e-mail: mat24@libero.it figure 1. clinical aspect of the lesion. [copyright: ©2016 megna et al.] figure 2. dermatoscopic examination of the lesion. [copyright: ©2016 megna et al.] http://www.wordreference.com/enit/polymorphous mailto:mat24@libero.it 2 quiz | dermatol pract concept 2016;6(2):1 ized our case where the potential appearance of a pigmented network did not allow us to follow the dermatoscopic model for the diagnosis of the pigmented variant of bcc [6]. hence, considering patient’s medical history and both clinical and dermatoscopic features of the lesion, a diagnosis of melanoma or spitz-reed nevus was performed. a complete excision of the lesion was performed. histological examination showed a proliferation of abnormal trichoblasts in continuity with the surface and infundibular epidermis with cleft-like spaces (stromal retraction) within a widened papillary dermis that are responsible for the dermatoscopic structures observed in the center of the lesion such as blue-white veil-like area and blue globules. small nests of growing basaloid cells attached to the epidermis were seen in the periphery of the lesion that are responsible for the dermatoscopic structures of multiple maple leaf-like structures observed at lesions’ margins and that had been erroneously interpreted as an atypical starburst pattern previously. melanin pigmentation of the epithelium and in the histiocytes in the subjacent stroma was seen. the diagnosis was superficial pigmented basal cell carcinoma. this diagnostic pitfall results from the fact that bcc may exhibit a large variety of clinical and dermatoscopic what is your diagnosis? answer basal cell carcinoma discussion basal cell carcinoma (bcc) is the most common skin cancer [1]. nevertheless, detailed information regarding its incidence and prevalence are scarce since cancer registries usually do not collect bcc data. a population-based study in rochester, minnesota, usa, estimated the annual standardized incidence in caucasian subjects to be 146 cases per 100,000 persons [2]. clinicopathologic appearances of bccs are various and include nodular, superficial, morphoeic, and pigmented variants, making bccs common stimulants of different cutaneous lesions [3,4]. particularly, pigmented bccs can be a diagnostic challenge since they can demonstrate dermatoscopic features suggestive of melanocytic lesions, such as blue-white veil, brown to black dots and globules, pseudopods, radial streaming, as well as polymorphous vascular pattern [5]. some of these features also characterfigure 3. histological examination: hematoxylin and eosin, original magnification, x5 (a), x10 (b), x20 (c), x40 (d). [copyright: ©2016 megna et al.] quiz | dermatol pract concept 2016;6(2):1 3 2. chuang ty, popescu a, su wp, chute cg. basal cell carcinoma. a population-based incidence study in rochester, minnesota. j am acad dermatol 1990; 22(3):413-7. pmid: 2312827 3. roewert-huber j, lange-asschenfeldt b, stockfleth e, kerl h. epidemiology and etiology of basal cell carcinoma. br j dermatol 2007; 157:47-51. pmid: 18067632. doi: 10.1111/j.13652133.2007.08273.x 4. leiter u, garbe c. epidemiology of melanoma and non-melanoma skin cancer—the role of sunlight. adv exp med biol 2008; 624:89103. pmid: 18348450. doi: 10.1007/978-0-387-77574-6_8 5. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol 2010; 62(1):67-75. pmid: 19828209. doi: 10.1016/j.jaad.2009.05.035 6. menzies sw, ingvar c, crotty ka, mccarthy wh. surface microscopy of pigmented basal cell carcinoma. arch dermatol 2000; 136:1012-6. pmid: 10926737. doi: 10.1001/archderm.136.8.1012 7. kaminska-winciorek g, wydmanski j. benign simulators of melanoma on dermoscopy—black colour does not always indicate melanoma. jpccr 2013; 1(7):612. 8. white ea, rabinovitz hs, greene rs, oliviero m, kopf a. pigmented basal cell carcinoma simulating melanoma in a burn scar. cutis 2003; 71(5):404-6. pmid: 12769409 characteristics as a result of the wide range of combinations of histopathological features [6]. moreover, it should be taken also into account that among pigmented bccs, the heavily pigmented variant represents the most difficult type to differentiate from both melanocytic nevi and melanomas, confirming that the global aspect should always be evaluated in the dermatoscopic interpretation of the lesions [5]. there are a few studies in the literature that describe bccs simulating melanoma [7,8], although we did not find any reports depicting bccs simulating atypical starburst pattern such as in spitz-reed nevus. we report this case to highlight the fact that bccs may simulate melanocytic lesions both clinically and dermatoscopically, particularly when underlying the unusual spitz-reed like presentation of our case. references 1. marzuka ag, book se. basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. yale j biol med 2015; 88(2):16779. pmid: 26029015. dermatology: practical and conceptual image letter | dermatol pract concept. 2023;13(2):e2023111 1 violaceous macules on the auricles: a clinical sign of dermatomyositis lluís corbella-bagot1, francesc alamon-reig1, daniel morgado-carrasco1 1 department of dermatology, hospital clínic de barcelona, university of barcelona, barcelona, spain citation: corbella-bagot l, alamon-reig f, morgado-carrasco d. violaceous macules on the auricles: a clinical sign of dermatomyositis. dermatol pract concept. 2023;13(2):e2023111. doi: https://doi.org/10.5826/dpc.1302a111 accepted: october 26, 2022; published: april 2023 copyright: ©2023 corbella-bagot et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, dermatology department, hospital clínic de barcelona, c/ villarroel, 170, 08036, barcelona, spain. tel: (+34) 93 227 54 00; fax: (+34) 932275438 e-mail: morgadodaniel8@gmail.com case presentation a 66-year-old male with a recently diagnosed metastatic bladder carcinoma presented with muscle weakness and generalized pruritic rash. physical examination revealed heliotrope erythema, v-neck sign, shawl sign, gottron papules and dilated nailfold capillary loops. interestingly, several purpuric macules, together with ulcers and crusting were observed in both auricles (figure 1). blood tests showed high muscle enzymes (creatine-kinase 5954 u/l [normal value <300 u/l] and aldolase 43.5 u/l [normal range 0.3-6.0 u/l]), and anti-transcriptional intermediary factor 1 gamma (tif1-γ) antibody positivity. the remaining myositis-specific antibodies were negative. skin and muscle biopsies confirmed the diagnosis of dermatomyositis. treatment with prednisone 120 mg/ day (1 mg/kg/day) and hydroxychloroquine 400 mg/day was initiated with progressive improvement of muscle weakness and cutaneous involvement. the patient also started chemotherapy with gemcitabine and cisplatin and is currently under follow-up in the oncology and dermatology departments. teaching point dermatomyositis can present with a myriad of cutaneous manifestations. violaceous macules on the ears have recently been described in anti-melanoma differentiation-associated gene 5 (mda-5) dermatomyositis and may correlate with a poor prognosis [1]. as the violaceous macules and ulcers are predominantly located in anatomic protuberances in the auricle, a pressure-induced microangiopathy has been proposed as the pathogenic mechanism [2]. we have not found any described case presenting with positive anti-tif1-γ antibodies, which have been associated with malignancies. we report a case of a paraneoplastic anti-tif1-γ positive dermatomyositis presenting with violaceous macules in both auricles. clinicians should be aware of this recently described clinical sign since it may be related to a poor prognosis. a written consent form signed by the patient has been obtained. 2 image letter | dermatol pract concept. 2023;13(2):e2023111 references 1. intapiboon p, siripaitoon b. erythematous auricular papules in the fatal cases of anti-mda5 antibody-positive interstitial lung disease. respir med case rep. 2020;19;31:101299. doi: 10.1016/j.rmcr.2020.101299. pmid: 33294359. pmcid: pmc7695884. 2. okiyama n, inoue s, saito a. et al. antihelix/helix violaceous macules in japanese patients with anti-melanoma differentiation-associated protein 5 (mda5) antibody-associated dermatomyositis. br j dermatol. 2019;180(5):1226-1227. doi: 10.1111/bjd.17431. pmid: 30431155. figure 1. (a, b) violaceous macules, crusting and ulcers on both auricles. the lesions are more evident in anatomical protuberances such as the helix and antihelix. dermatology: practical and conceptual review | dermatol pract concept 2018;8(3):9 191 dermatology practical & conceptual www.derm101.com obligate and facultative paraneoplastic dermatoses: an overview stefano caccavale1, gabriella brancaccio1, marina agozzino1, paola vitiello1, roberto alfano2, giuseppe argenziano1 1 dermatology unit, university of campania luigi vanvitelli, naples, italy 2 department of anesthesiology, surgery and emergency, university of campania luigi vanvitelli, naples, italy key words: dermatological paraneoplastic syndromes, obligate paraneoplastic dermatoses, facultative paraneoplastic dermatoses, malignancy, oncological dermatology citation: caccavale s, brancaccio g, agozzino m, vitiello p, alfano r, argenziano g. obligate and facultative paraneoplastic dermatoses: an overview. dermatol pract concept. 2018;8(3):191-197. doi: https://doi.org/10.5826/dpc.0803a09 received: january 15, 2018; accepted: march 9, 2018; published: july 31, 2018 copyright: ©2018 caccavale et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: stefano caccavale, md, dermatology unit, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy. email: stefano85med@gmail.com introduction the skin is the most accessible organ of the body and can be easily examined using noninvasive techniques, providing the doctor with clues that can be suggestive of systemic disturbances, thus contributing to the diagnosis of many diseases, including malignancies [1,2]. the skin may be directly or indirectly involved in malignancies. direct involvement is due to the presence of tumor cells in the skin caused by direct tumor extension or metastasis. indirect involvement of the skin can be determined by a variety of polypeptides, hormones, cytokines, antibodies, or growth factors related to the neoplasia. these inflammatory, proliferative, or metabolic factors act as mediators, interfering with cell communication and, consequently, with its activity. in this case, there is no presence of neoplastic cells in the skin, and this involvement is considered a dermatological paraneoplastic syndrome [1]. thus, paraneoplastic syndromes are a group of diseases associated with a malignancy, but not directly related to the primary tumor itself or to its metastases. it is not always easy to determine the correlation between a dermatologic finding and an internal neoplasm. the following criteria, defined by mclean in 1986 [3], should be verified to assess the causal relationship between the dermatosis and the potential underlying malignancy: (1) development of a dermatosis only after the development of a malignant dermatological paraneoplastic syndromes are a group of cutaneous diseases associated with malignancy, but not directly related to the primary tumor itself or to its metastases. it is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. in this overview, skin conditions that are highly correlated with malignancy, whose recognition implies a mandatory investigation of internal cancer, are described. abstract 192 review | dermatol pract concept 2018;8(3):9 showing a genetic pattern (genodermatoses)—are described [1]. acanthosis nigricans maligna acanthosis nigricans (an) can be classified as benign or malignant [1]. benign an is relatively common; it may be familial or occur in association with drug use, obesity, and/or endocrinopathy, thus being regarded as a sign of hyperinsulinism and insulin resistance. it is characterized by the presence of hyperpigmented, velvety plaques most often seen on the sides and nape of the neck (“dirty neck” appearance) and other flexural (antecubital, popliteal fossae) or intertriginous areas (inguinal, axillae, inframammary folds). acrochordons frequently arise on the plaques of an [11]. by contrast, acanthosis nigricans maligna (anm) can be distinguished by its severity and its rapid and extensive spread. sudden-onset an is often associated with malignancy, especially in adult (average age 40 years) nonobese patients [1]. anm may be more widespread or generalized and involve atypical areas (interdigital, knuckles, soles, palmar, eyelids, perioral) and even mucosal surfaces, including neoplasm and (2) both the dermatosis and the malignant neoplasm follow a parallel clinical course, so the cutaneous symptoms disappear when the tumor is treated and reappear in cases of recurrence or metastasis [3]. paraneoplastic syndromes occur in about 7% to 15% of patients with cancer and may be the presenting sign of an unknown neoplasm, precede the diagnosis of malignancy, occur late in the course of illness, or be the first sign of recurrence. their recognition may result in earlier diagnosis and better prognosis for the patient, prolonging life expectancy [4-8]. a few rare paraneoplastic dermatoses are consistently associated with malignancies in almost 100% of the cases (obligate paraneoplastic dermatoses) [1-29]; others are more common skin disorders, associated with tumors in only 3% to 30% of the cases, so the coexistence of these dermatoses and neoplasms may be coincidental and the causal link is more controversial (facultative paraneoplastic dermatoses) [9,10,30] (table 1). in this overview, dermatoses that highly correlate with malignancy and that, when recognized, require mandatory investigation of internal cancer—excluding those disorders table 1. association of main facultative paraneoplastic dermatoses with systemic neoplasms main facultative paraneoplastic dermatoses main associated neoplasms [1,4,30] leser-trélat sign gastrointestinal (gi), lymphoma, breast, lung dermatomyositis bronchogenic adenocarcinoma, ovary, genital, breast, cervix carcinoma, gi palmoplantar keratoderma esophageal carcinoma pyoderma gangrenosum myelodysplastic syndrome, myeloma, leukemia, lymphoma sweet syndrome acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, lymphoproliferative disorders trousseau’s syndrome pancreas, lung, stomach vasculitis leukemia, lymphoma, lung, multiple myeloma pruritus hodgkin and non-hodgkin lymphoma extramammary paget’s disease gi, genitourinary (gu) digital clubbing lung, mesothelioma raynaud’s phenomenon testicle, gu, gi multicentric reticulohistiocytosis hematologic malignancies, breast, stomach amyloidosis multiple myeloma, hodgkin lymphoma, kidney flushing carcinoid, medullary carcinoma of thyroid, leukemia, kidney linear iga dermatosis lymphoproliferative malignancies, esophagus, renal cell, thyroid, bladder mucous membrane pemphigoid chronic lymphocytic leukemia, non-hodgkin lymphoma, acute myeloid leukemia, pancreas, lung, ovary, cervix, liver, gi, thymoma bullous pemphigoid breast, prostate, lung, thyroid, larynx, gi, cervix, uterus, bladder, lymphoreticular system, kidney, melanoma, and squamous cell carcinomas review | dermatol pract concept 2018;8(3):9 193 other areas may be affected such as the elbows, knees, legs, arms, cheeks, and scalp, with centripetal distribution of the lesions. nails may also be involved with subungual hyperkeratosis, onycholysis, and dystrophy. bullous lesions, mainly in the hands and feet, have been described [1]. biopsies are nonspecific. histologically, some psoriasiform features are present including hyperkeratosis, parakeratosis, and a superficial lymphohistiocytic infiltrate, but other non-psoriasiform changes also exist (vacuolar degeneration with melanin-containing macrophages in the dermis and dyskeratotic keratinocytes) [11]. almost all the cases cited in the literature were associated with malignancy. this syndrome typically precedes the diagnosis of malignancy by approximately 2 to 6 months in 65% to 70% of patients. about 80% of cases are associated with tumors of the upper aerodigestive tract (oral cavity, larynx, pharynx, trachea, esophagus, and lung), commonly squamous cell carcinomas (scc) or metastasis to cervical lymph nodes. in a retrospective study, 49% of cancers involved the oropharynx and larynx, followed by the lung (17%) and esophagus (10.6%) [1]. additional isolated cases associated with breast cancer, cholangiocarcinoma, colon adenocarcinoma, and hodgkin lymphoma have been reported [1]. case reports also describe sccs of the thymus, vulva, and skin [13,14]. its underlying mechanism is not well understood. immunological factors with antibodies directed against the tumor in a cross-reaction with the epidermis or basement membrane have been considered. possibly, a tumor production of a keratinocyte growth factor such as tgf-α may be involved [1]. paraneoplastic acrokeratosis generally responds to successful treatment of the underlying tumor, and fails to improve when the neoplasm persists. topical corticosteroids and systemic retinoids may be helpful. the physician should inquire regarding risk factors for malignancy (smoking habits, alcohol consumption, weight loss, family history) and perform a complete physical examination, including head and neck and endoscopic and pelvic examination in women [13,14]. the palate. palmar and plantar keratoderma with prominent fingerprint markings known as pachydermatoglyphy or tripe palms may be seen [10,11] (figure 1). skin biopsy is rarely necessary. common histopathologic findings are hyperkeratosis, papillomatosis, acanthosis alongside epidermal atrophy, and absence of an inflammatory infiltrate. nearly all malignancies associated with anm are adenocarcinomas (most commonly gastrointestinal adenocarcinomas). many others have been reported, including adrenal, bile duct, bladder, breast, cervical, endometrium, liver, larynx, lung, lymphoid hematological malignancies, ovary, pituitary, prostate, kidney, testicle, thyroid, and sarcomas [11]. anm can precede or occur simultaneously or after the diagnosis of cancer [1]. in a review study, this dermatological finding was observed in 58% of patients before tumor diagnosis [1,12]. the pathogenesis for the development of anm is debated (insulin-like growth factors or transforming growth factor alpha (tgf-α) may be responsible for the epidermal proliferation) [10]. depending on the clinical scenario, an extensive search for visceral malignancy may be warranted (fecal occult blood testing, endoscopy, imaging, etc.). in the case of anm, as for all paraneoplastic dermatoses, skin lesions may regress after systemic chemotherapy or radical surgery. acrokeratosis paraneoplastica (bazex syndrome) patients affected by acrokeratosis paraneoplastica are typically men older than 40 years [11]. cutaneous lesions are psoriasiform and manifest as asymptomatic, symmetrical erythematous-violaceous scaly patches. however, their distribution is not typical of psoriasis: in initial stages, the dermatosis involves the bridge of the nose, auricular helices, and distal ends of the extremities. as the disease progresses, desquamation may affect the dorsal and palmoplantar regions, producing a violaceous keratoderma. in advanced stages, figure 1. acanthosis nigricans maligna: clinical and dermatoscopical pictures. [copyright: ©2018 caccavale et al.] 194 review | dermatol pract concept 2018;8(3):9 in patients with egr who did not have an underlying internal cancer, nonneoplastic conditions including tuberculosis, pregnancy, calcinosis, esophageal dysmotility, sclerodactyly, sjögren’s syndrome, and crest syndrome may be rarely associated [1,17,18]. histopathology is nonspecific, showing mild hyperkeratosis, parakeratosis, acanthosis, and spongiosis with a perivascular mononuclear inflammatory infiltrate in the dermis [1]. its pathophysiology remains unknown. immune mechanisms are probably involved since immunosuppression accompanies the resolution of egr [1]. in paraneoplastic cases, therapy is aimed at treating the underlying malignancy. systemic corticosteroids have been tried with only partial success. necrolytic migratory erythema or glucagonoma syndrome necrolytic migratory erythema (nme) is more common in women more than 45 years of age, with an average age of onset of 52 years [1]. nme presents as a pruritic and sometimes painful mucocutaneous eruption with a pinkish, maculopapular erythema with irregular edges and annular or arciform lesions that tend to coalesce and adopt a polycyclic pattern. lesions are prominent in areas of pressure or trauma, commonly in intertriginous areas, groin, perineum, buttocks, distal extremities, and the central face. sometimes there is formation of flaccid blisters that rupture easily, forming erosions and crusts, while new vesicles continue to develop along the edges. residual hyperpigmentation at sites previously affected is common [1,19]. the disease has a waxing and waning course. the eruption may resemble such dermatoses as pemphigus foliaceus, acrodermatitis enteropathica, chronic mucocutaneous candidiasis, psoriasis, and severe seborrheic dermatitis [11]. erythema gyratum repens erythema gyratum repens (gyrate from the greek, meaning “a circle”; repens from the latin, meaning “to creep”) (egr) is a rare paraneoplastic dermatosis, usually occurring in patients older than 40 years, with a mean age of about 60 years; the male-to-female ratio is 2:1 [1,11,15]. the primary lesion is a pruriginous, macular erythema. numerous serpiginous bands are arranged in a parallel configuration of red swirls over most of the body, producing concentric figures that resemble a wood surface (“wood-grained” appearance) (figure 2). the edges of the lesions migrate at a rapid rate, about 1 cm/day. a slight scale can be found along the trailing edge of erythema. the hands, feet, and face are often spared [1,15]. peripheral eosinophilia is frequent. the presentation of egr is so typical that a differential diagnosis is difficult to generate. another gyrate erythema, erythema annulare centrifugum (eac), demonstrates polycyclic erythematous rings with a trailing edge of scale. similarly, this eruption can be pruritic. unlike egr, eac migrates slowly and is usually localized to smaller areas on the trunk and extremities [11,16] (figure 2). other figurate erythemas are erythema chronicum migrans and erythema marginatum. patients with egr should be mandatorily evaluated for the presence of malignancy because the disease is virtually always associated with an internal cancer [1]. malignant neoplasms are found in 82% of patients with egr. lung cancer is the most common (32%), followed by cancer of the esophagus (8%) and breast (6%). other malignancies have been associated, such as colon, stomach, bladder, prostate, uterine, rectal, and pancreatic cancer and multiple myeloma. the diagnosis of egr precedes the diagnosis of the neoplasia in approximately 80% of patients, on average from 4 to 9 months [13]. figure 2. erythema gyratum repens (left) and erythema annulare centrifugum (right). [copyright: ©2018 caccavale et al.] review | dermatol pract concept 2018;8(3):9 195 interferon, minoxidil, phenytoin, spironolactone, and cetuximab) [1,20]. an extensive clinical history and physical examination are necessary, in conjunction with blood tests, laboratory screening, and imaging (chest radiography, ct, colonoscopy, and, in women, mammography) [1]. pathogenesis of ahl is unclear. prolongation of the anagen phase of vellus hairs by a tumor-induced serum growth factor has been hypothesized [1,10]. ichthyosis acquisita ichthyosis acquisita is a cutaneous keratinization disorder, characterized by small white or brownish rhomboidal scales that rise above the skin surface, particularly localized symmetrically on the extensor surfaces of the extremities and on the trunk and scalp. the dry scales may be also thickened and widespread [13]. flexures, palms, and soles are spared [21]. ichthyosis may be due to systemic diseases (eg, leprosy, hypothyroidism, lymphoma, and aids) or to drug intake (eg, nicotinic acid, triparanol, and butyrophenones) [13]. new onset of ichthyosis in adult life is often related to an underlying malignancy [13,21]. ichthyosis acquisita is mostly seen in association with hodgkin lymphoma, non-hodgkin lymphoma (including mycosis fungoides), other lymphoproliferative diseases (eg, reticulolymphosarcoma, multiple myeloma), and nonlymphoproliferative diseases (kaposi sarcoma, leiomyosarcoma, breast, ovarian, lung, liver, and cervical carcinomas) [21,22]. acquired ichthyosis usually appears several weeks or months after detection of the cancer [2]. it has been suggested that tgf-α secreted from the tumor cells, may be implicated in the pathogenesis [22]. treatment of ichthyosis includes removal of exacerbating factors and of related systemic diseases, as well as applying moisturizers and keratolytics [13]. pityriasis rotunda p a t i e n t s o f t e n m a n i f e s t p i t y r i a s i s r o t u n d a ( p r ) between 20 and 45 years of age (range of 2 to 89) [23], except among the sardinian cohort, in which patients presented during childhood [24]. incidence is equal among men and women. the disease lasts from several months to more than 20 years, with reports of exacerbation during winter months [25]. pr is a rare disease characterized by round or oval, well-defined, scaly, hypoor hyperpigmented patches or thin plaques typically found on the trunk, back, buttocks, or arms, but that can occur in every area of the body. lesions number ranges in number from 1 to over 100, and the diameter from 1-10 cm. the hands, feet, and face are usually spared. lesions are asymptomatic but may be associated with minimal pruritus [13]. nme is typically associated with glucagonoma syndrome. glucagonoma is a rare endocrine, usually slow-growing, tumor of pancreatic alpha cells. glucagon-secreting tumors of the pancreas are responsible of the triad hyperglucagonemia, whose levels are greater than 1000 pg/ml, diabetes or glucose intolerance and nme [1,19]. other common manifestations are glossitis, angular cheilitis, weight loss, diarrhea, steatorrhea, abdominal pain, normocytic anemia, hypoaminoacidemia, thromboembolic disease, and psychiatric disturbances [1,19]. nme can be associated also with non-glucagon-secreting tumors (small-cell lung cancer, liver cancer, insulin-secreting tumors, and duodenal neoplasms), and in malabsorption syndromes, liver failure, inflammatory bowel disease, and celiac disease, leading to pseudoglucagonoma syndrome [1]. a ct scan may be useful in the diagnosis. about 95% of glucagonomas are positive in somatostatin receptor scintigraphy. somatostatin positivity may be useful in the treatment of the symptoms and signs of glucagonoma (octreotide, a somatostatin analogue, inhibits glucagon production) [1]. celiac arteriography is considered most sensitive to locate the tumor because of its vascularity [10]. histological findings of nme are nonspecific (edema and epidermal acanthosis with basal cell hyperplasia, spongiosis, parakeratosis with vacuolated epidermal cells associated with necrosis of the upper epidermis, cleft-like detachment from the deeper epidermis and loss of the granular cell layer, mild to moderate perivascular inflammatory infiltrate) [1,10]. the pathogenesis is poorly understood. various metabolic abnormalities and nutritional deficiencies have been implicated, including hypoaminoacidemia, zinc, and essential fatty acid deficiencies [10]. acquired hypertrichosis lanuginosa acquired hypertrichosis lanuginosa (ahl) is a rare paraneoplastic condition characterized by the sudden appearance of long, thin, soft, unpigmented, lanugo-like hair initially on the face and ears and then on the trunk, axillae, and extremities, with sparing of the palms, soles, and genital area [2]. it is more common in women than in men. other symptoms are painful glossitis, angular cheilitis, and papillary hypertrophy of the tongue [2, 20]. in men, ahl is most commonly associated with lung cancer, followed by colorectal cancer. in women, the most common neoplasms are, in order of frequency, colorectal cancer, lung cancer, and breast cancer. however, ahl has also been described in association with other cancers (ovary, uterus, bladder, pancreas, kidney, lymphomas, and leukemia) [2,20]. ahl must be differentiated from hypertrichosis associated with endocrine or metabolic alterations and use of medication (cyclosporine, penicillamine, glucocorticoids, 196 review | dermatol pract concept 2018;8(3):9 ing [1]. the diagnostic criteria for pnp can be distinguished into major criteria and minor criteria (table 2) [29]: 3 major criteria or 2 major and 2 minor are needed [1,11]. contrary to pemphigus vulgaris, in which direct immunofluorescence shows only intercellular deposition in epithelial cells, both basement membrane and epidermis are affected in pnp [1]. two-thirds of patients have a recognized neoplasia at the onset of pnp. approximately, 80% of associated malignancies are of hematological origin (non-hodgkin b-cell lymphoma, chronic lymphocytic leukemia, hodgkin lymphoma, t-cell lymphoma, castleman disease, thymoma, waldenström’s macroglobulinemia). in children and adolescents, association with castleman disease is the most frequent [1]. other neoplasms associated with pnp include kaposi’s sarcoma and carcinomas of the breast, skin, mucous membranes, lung, uterus, ovary, stomach, liver, and gastrointestinal tract [13]. pnp is characterized by production of autoantibodies directed against proteins of the plakin and cadherin families involved in cell architecture maintenance and tissue cohesion. autoantibodies immunoprecipitate keratinocyte antigens at 250 kd (desmoplakin i), 230 kd [bullous pemphigoid antigen i (bpag1)], 210 kd (desmoplakin ii and envoplakin), and 190 kd (periplakin) in all samples and at 170 kd in some samples. the production of autoantibodies that bind epidermal proteins is responsible of skin and mucosal displacement [13,27,28]. conclusions skin, being the most visible and external organ of the body, may be considered as a mirror for many systemic diseases [7]. it is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. references 1. silva ja, mesquita kc, igreja ac, et al. paraneoplastic cutaneous manifestations: concepts and updates. an bras dermatol. 2013;88(1):9-22. doi: 10.1590/s0365-05962013000100001. one-third of patients have an underlying disease, including tuberculosis, leprosy, and liver, kidney, heart, and lung diseases. associated neoplasms include hepatocellular, gastric and esophageal carcinoma, prostate cancer, chronic lymphocytic leukemia, and multiple myeloma [1]. pr has been classified into  2  distinct subtypes. type 1 occurs predominantly in elderly patients of asian and african descent and is frequently associated with systemic illness, infections, or malignancy. lesions are often hyperpigmented and generally fewer than 40. type 1 pr often improves with treatment of underlying systemic illness [26]. type 2 occurs in younger patients of northern european descent. it has a strong hereditary predisposition and it is believed to belong to the spectrum of congenital ichthyoses. lesions are typically hypopigmented and more numerous. type 2 pr is often self-limiting and improves through adulthood [26]. pr can be treated with retinoids, salicylates, or lactate emollients. paraneoplastic pemphigus paraneoplastic pemphigus (pnp) is a severe acantholytic mucocutaneous syndrome characterized by painful mucosal erosions, ulcerations, and polymorphous skin lesions that progress to blistering eruptions on the trunk and extremities [27,28]. oral involvement with persistent, painful stomatitis is seen in almost all cases and can often be the first symptom. oral lesions may be severe, and affect the entire mouth, with diffuse areas of shallow ulceration, and lips, with hemorrhagic crusting, and also the hypopharynx and esophagus; they may also involve other mucosa (conjunctival and anorectal) with ulcers and erosions. contrary to pemphigus vulgaris, acral and paronychial involvement is common in pnp. cutaneous manifestations can be classified in several groups: (1) pemphigus-like, (2) bullous pemphigoid-like, (3) erythema multiforme-like, (4) graft-versus-host disease, and (5) lichen planus-like [27,28]. the prognosis of pnp is severe. some patients have respiratory complications, such as bronchiolitis obliterans, responsible for dyspnea and respiratory failure. the high mortality rate of pnp (75%-80%) is also secondary to sepsis and bleedtable 2. diagnostic criteria for paraneoplastic pemphigus (proposed by camisa and helm) [29] major criteria minor criteria polymorphous skin eruption histological evidence of intraepithelial acantholysis concurrent internal neoplasia positive direct immunofluorescence (dif) with deposits both intercellularly and at the basement membrane zone with igg and c3 deposition antibodies with an immunoprecipitation specific pattern positive indirect immunofluorescence (iif) on rat bladder epithelium review | dermatol pract concept 2018;8(3):9 197 18. rongioletti f, fausti v, parodi a. erythema gyratum repens is not an obligate paraneoplastic disease: a systematic review of the literature and personal experience. j eur acad dermatol venereol. 2014;28(1):112-115. doi: 10.1111/j.1468-3083.2012.04663.x 19. john am, schwartz ra. glucagonoma syndrome: a review and update on treatment. j eur acad dermatol venereol. 2016;30(12):2016-2022. doi: 10.1111/jdv.13752 20. slee ph, van der waal ri, schagen van leeuwen jh, et  al. paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked? br j dermatol. 2007;157(6):1087-1092. doi: 10.1111/j.1365-2133.2007.08253.x 21. patel n, spencer la, english jc iii, zirwas mj. acquired ichthyosis. j am acad dermatol. 2006;55(4):647-656. doi: 10.1016/j. jaad.2006.04.047 22. kleyn ce, lai-cheong je, bell hk. cutaneous manifestations of internal malignancy: diagnosis and management. am j clin dermatol. 2006;7(2):71-84. doi: 10.2165/00128071-20060702000001 23. friedmann ac, ameen m, swale vj. familial pityriasis rotunda in black-skinned patients; a first report. br j dermatol. 2007;156(6):1365-1367. doi: 10.1111/j.1365-2133.2007. 07874.x 24. aste n, pau m, aste n, biggio p. pityriasis rotunda: a survey of  42  cases observed in sardinia, italy. dermatology. 1997;194(1):32-35. doi: 10.1159/000246053 25. batra p, cheung w, meehan sa, pomeranz m. pityriasis rotunda. dermatol online j. 2009;15(8):14. 26. grimalt r, gelmetti c, brusasco a, tadini g, caputo r. pityriasis rotunda: report of a familial occurrence and review of the literature. j am acad dermatol. 1994;31(5 pt 2):866-871. doi: 10.1016/s0190-9622(94)70248-9 27. kartan s, shi vy, clark ak, chan ls. paraneoplastic pemphigus and autoimmune blistering diseases associated with neoplasm: characteristics, diagnosis, associated neoplasms, proposed pathogenesis, treatment. am j clin dermatol. 2017;18(1):105-126. doi: 10.1007/s40257-016-0235-z 28. wieczorek m, czernik a. paraneoplastic pemphigus: a short review. clin cosmet investig dermatol. 2016;9:291-295. doi: 10.2147/ccid.s100802 29. camisa c, helm tn. paraneoplastic pemphigus is a distinct neoplasia-induced autoimmune disease. arch dermatol. 1993;129(7):883-886. doi: 10.1001/archderm.1993. 01680280071014 30. caccavale s. the association of bullous pemphigoid and malignancy: a case control study. g ital dermatol venereol. 2015;150(6):764-765. 2. yuste chaves m, unamuno pérez p. cutaneous manifestations of systemic malignancies: part 2. actas dermosifiliogr. 2013;104(7):543-553. doi: 10.1016/j.adengl.2012.05.026. 3. mclean di. cutaneous paraneoplastic syndromes. arch dermatol. 1986;122(7):765-767. doi: 10.1001/archderm.1986. 01660190043013. 4. brenner s, tamir e, maharshak n, shapira j. cutaneous manifestations of internal malignancies. clin dermatol. 2001;19(3):290297. doi: 10.1016/s0738-081x(01)00174-2. 5. moore rl, devere ts. epidermal manifestations of internal malignancy. dermatol clin. 2008;26(1):17-29, vii. doi: 10.1016/j. det.2007.08.008. 6. pipkin ca, lio pa. cutaneous manifestations of internal malignancies: an overview. dermatol clin. 2008;26(1):1-15, vii. doi: 10.1016/j.det.2007.08.002. 7. vora rv, kota rs, diwan ng, jivani nb, gandhi ss. skin: a mirror of internal malignancy. indian j med paediatr oncol. 2016;37(4):214-222. doi: 10.4103/0971-5851.195730. 8. miyashiro d, sanches ja. paraneoplastic skin disorders: a review. g ital dermatol venereol. 2016;151(1):55-76. 9. károlyi z. [paraneoplastic dermatoses]. orv hetil. 2002;143(31): 1827-1833. 10. thomas i, schwartz ra. cutaneous paraneoplastic syndromes: uncommon presentations. clin dermatol. 2005;23(6):593-600. doi: 10.1016/j.clindermatol.2005.01.006. 11. stone sp, buescher ls. life-threatening paraneoplastic cutaneous syndromes. clin dermatol. 2005;23(3):301-306. doi: 10.1016/j. clindermatol.2004.06.011. 12. ehst bd, minzer-conzetti k, swerdlin a, devere ts. cutaneous manifestations of internal malignancy. curr probl surg. 2010;47(5):384-445. doi: 10.1067/j.cpsurg.2010.01.003. 13. abreu velez am, howard ms. diagnosis and treatment of cutaneous paraneoplastic disorders. dermatol ther. 2010;23(6):662675. doi: 10.1111/j.1529-8019.2010.01371.x. 14. räßler f, goetze s, elsner p. acrokeratosis paraneoplastica (bazex syndrome) a systematic review on risk factors, diagnosis, prognosis and management. j eur acad dermatol venereol. 2017;31(7):1119-1136. doi: 10.1111/jdv.14199. 15. boyd as, neldner kh, menter a. erythema gyratum repens: a paraneoplastic eruption. j am acad dermatol. 1992;26(5 pt 1):757762. doi: 10.1016/0190-9622(92)70107-q. 16. tyring sk. reactive erythemas: erythema annulare centrifugum and erythema gyratum repens. clin dermatol. 1993;11(1):135139. doi: 10.1016/0738-081x(93)90110-x. 17. lo schiavo a, caccavale s, orlando i, tirri r. erythema gyratum repens and rheumatoid arthritis: an unrecognized association? indian j dermatol venereol leprol. 2012;78(1):122. doi: 10.4103/0378-6323.90974. untitled observation | dermatol pract concept 2015;5(4):6 23 dermatology practical & conceptual www.derm101.com introduction acral (lentiginous) melanoma (alm) is the most prevalent subtype in the asian and mexican mestizo populations [1,2]. acral lentiginous melanoma is most often diagnosed at an advanced stage and associated with a poor outcome [2-4]. dermoscopy is a noninvasive diagnostic technique that allows early recognition and increases diagnostic accuracy of pigmented skin lesions on acral volar skin [1-8]. congenital melanocytic nevi (cmn) are defined as melanocytic nevi that are present at birth or become apparent shortly after. acral cmn tend to show a greater size and a greater variability in color and shape than acquired nevi [1,8]. therefore, a histopathologic examination is sometimes required for differentiating acral cmn from alm, especially when the lesion has a large diameter and/or is clinical and dermoscopically atypical. according to previous studies, acral cmn show characteristic dermoscopic features such as a atypical dermoscopic presentation of an acral congenital melanocytic nevus in an adult: parallel ridge pattern and its histologic correlation rodrigo roldán-marín1,2, ana cecilia gonzález-de-cossío-hernández2, lorena lammoglia-ordiales2, eduwiges martínez-luna3, sonia toussaint-caire3, gerardo ferrara4 1 faculty of medicine, “universidad nacional autónoma de méxico”, mexico city, mexico 2 dermatology department, hospital general “dr. manuel gea gonzález”, mexico city, mexico 3 dermatopathology, dermatology department, hospital general “dr. manuel gea gonzález”, mexico city, mexico 4 dermatopathology, anatomic pathology unit, gaetano rummo general hospital, benevento, italy key words: congenital, acral, nevi, dermoscopy, histopathology citation: roldán-marín r, gonzález-de-cossío-hernández ac, lammoglia-ordiales l, martínez-luna e, toussaint-caire s, ferrara g. atypical dermoscopic presentation of an acral congenital melanocytic nevus in an adult: parallel ridge pattern and its histologic correlation. dermatol pract concept 2015;5(4):6. doi: 10.5826/dpc.0504a06 received: april 27, 2015; accepted: september 21, 2015; published: october 31, 2015 copyright: ©2015 roldán-marín et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rodrigo roldán-marín, md, faculty of medicine, research division, “ciudad universitaria”, coyoacan 04510, mexico city, mexico. tel: +52-55-56012818. email: roroderm@yahoo.com acral melanoma is the most frequent subtype in the asian and mexican mestizo populations. dermoscopy is a noninvasive diagnostic technique that helps the differential diagnosis of pigmented skin lesions on acral volar skin. we, herein, present a case of acral congenital melanocytic nevus with a parallel ridge dermoscopic pattern. since the parallel ridge pattern in a melanocytic lesion of the acral skin is classically ascribed to melanoma, the present case can be definitely labeled as “atypical” and worth of being elucidated in its histopathological correlates. abstract mailto:roroderm@yahoo.com 24 observation | dermatol pract concept 2015;5(4):6 figures 1 and 2. a 12 mm pigmented lesion on the plantar arch. [copyright: ©2015 roldán-marín et al.] had appeared shortly after birth and had been progressively enlarging in the course of the last years. under polarized dermoscopy, the melanocytic lesion was polychromatic with a central blue-grey area and dark and light brown colors in the periphery; a central parallel ridge pattern blended with a peripheral lattice-like pattern associated with few asymmetric dots and globules. the furrows at the periphery were relatively devoid of pigmentation (figure 3). based on the large size and the atypical dermoscopic presentation, the lesion was excised. histologic examination revealed a very bland compound melanocytic neoplasm with clear-cut congenital-like features (figure 4a). the central area of the lesion was mainly an intradermal combination of type c and dendritic (blue nevus-like) melanocytes (figure 4b), with a striking acrosyringial and periductal distribution (figure 4c); the junctional component was mainly peripheral, with regularly arranged nests without cytologic atypia (figure  d) and melanin columns under the surface furrows. this last histologic finding was also seen in the crista profunda intermedia (figures 4d and 4e) under the surface ridge in accordance with the dermoscopic appearance of the lesion. the final histopathological diagnosis was acral compound melanocytic nevus with congenital features. discussion dermoscopy is a powerful, noninvasive, diagnostic tool, which helps the clinical differential diagnosis between benign and malignant melanocytic lesions on volar skin [1,6,7]. alm is the most prevalent subtype in mexican population [2]. it is commonly diagnosed at an advanced stage and associated with a poor outcome [2-4]. combination of the crista dotted and parallel furrow patterns [1]; interestingly they tend to fade during childhood [1,5]. dermoscopically, the parallel ridge pattern is most commonly associated with alm in situ showing a high sensitivity (86%) and specificity (99%) for its diagnosis [6,7]. nevertheless, 4-8% of acral cmn do show a parallel ridge pattern [1,8]. we, herein, present a case of acral cmn nevus with a parallel ridge dermoscopic pattern along with its histopathological correlates. case presentation a 37-year-old, male patient, skin phototype iv, while being hospitalized for the treatment of schizophrenia, was seen for a 12 mm, pigmented skin lesion on his plantar arch (figures 1 and 2). according to the patient’s mother, the lesion figure 3. polarized dermoscopy revealed a polychromatic lesion with a central blue-grey area and dark and light brown colors in the periphery. a central parallel ridge pattern blended with a peripheral lattice-like pattern associated with few asymmetric dots and globules. the furrows at the periphery were relatively devoid of pigmentation. [copyright: ©2015 roldán-marín et al.] observation | dermatol pract concept 2015;5(4):6 25 tion along the ridges (where acrosyringia emerge). it has been recently proposed by some authors that eccrine melanocytic precursor cells may be the source of acral melanomas [8,9]. the junctional component was mainly peripheral and responsible for the lattice-like pattern, a quite common finding in melanocytic nevi of the plantar arch. recently, chuah et al. [10] confirmed that acral congenital melanocytic nevi tend to be larger and more asymmetrical than acral aquired melanocytic nevi. furthermore, they tend to be polychromatic and approximately 50% have a bluegrey coloration in the central portion of the lesion, which may be associated with the intradermal component [1,10]. other authors have also recorded a parallel ridge pattern in other benign conditions such as lentiginosis, racial melanosis, melanocytic nevi, drug-induced hyperpigmentation, subcorneal hemorrhage and dye-related pigmentation, particularly in darker skin phototypes [11,12]. our case is an example of acral cmn with a parallel ridge pattern observed in an adult. acral cmn may be larger and dermoscopically, the parallel ridge pattern is highly specific of alm. however, it has also been described to occur in acral cmn as a relatively rare finding [1,8]. in the latter occurrence, anamnestic data and stable clinicodermoscopic features on digital follow-up support the diagnosis of benignity. in our case, the lesion was reported as “congenital,” but seemed to have been enlarging even in recent times. this was interpreted as an atypical feature, inasmuch as cmn on acral volar skin commonly tend to fade over years [1,5] or, at least, do not commonly reveal a parallel ridge pattern. dermoscopically, the pattern was atypical also because it was characterized by pigmentation along the ridges. furthermore, the patient suffered schizophrenia and could not commit with follow-up evaluation. for these reasons, the final decision was to excise. histopathologically, a dermal dendritic cell component was found as responsible for the central bluish area; the striking growth of melanocytes surrounding the ductal compartment of the eccrine sweat glands might be considered as a further histopathological correlate for the central pigmentafigure 4. (a) histopatology (10x hematoxylin & eosin [h&e] stain) revealed a very bland compound melanocytic neoplasm with clear-cut congenital-like features. (b) (40x h&e stain) an intradermal combination of type c and dendritic (blue nevus-like) melanocytes. (c) (40x h&e stain) striking acrosyringial and periductal distribution. (d) (20x h&e stain) mainly peripheral regularly arranged melanocytic nests at the dermo-epidermal junction, but areas with melanin columns from melanocytes located in the crista profunda intermedia. (e) (40x h&e stain) columnar melanin depositions (melanin columns) arrayed under the surface furrow. [copyright: ©2015 roldán-marín et al.] 26 observation | dermatol pract concept 2015;5(4):6 5. suzaki r, ishizaki s, iyatomi h, tanaka m. age-related prevalence of dermatoscopic patterns of acral melanocytic nevi. dermatol pract concept. 2014;4:53-7. 6. saida t, miyazaki a, oguchi s, ishihara y, et al. significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in japan. arch dermatol. 2004;140:1233-8. 7. oguchi s, saida t, koganehira y, okubo s, kawachi s. characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin: a videomicroscopic analysis. arch dermatol. 1998;134:563-8. 8. okamoto n, aoto t, uhara h, et al. a melanocyte-melanoma precursor niche in sweat glands of volar skin. pigment cell melanoma res. 2014;27:1039-50. 9. grichnik jm. the cell of origin of acral melanomas may be hiding in the sweat glands. dermatol ther. 2015;28:105-6. 10. chuah sy, tsilika k, chiaverini c, et al. dermoscopic features of congenital acral melanocytic naevi in children: a prospective comparative and follow-up study. br j dermatol. 2015;172(1): 88-93. 11. fracaroli ts, lavorato fg, maceira jp, barcaui c. parallel ridge pattern on dermoscopy: observation in non-melanoma cases. an bras dermatol. 2013;88:646-8. 12. sano t, minagawa a, koga h, uhara h, okuyama r. melanocytic naevus shows parallel ridge pattern due to the melanin columns under the ridges. acta derm venereol. 2015;95:95–6. more asymmetrical and polychromatic than acral acquired melanocytic nevi, but tend to fade or to become architecturally organized in adulthood. thus, if the patient is uncertain whether the lesion has recently changed/enlarged and/or if follow-up cannot be completed, histopathological examination may be required. in the final dermoscopic-pathologic evaluation of the case, one must remember that the dermoscopic features of an acral melanocytic lesion are best evaluated at its periphery. references 1. minagawa a, koga h, saida t. dermoscopic characteristics of congenital melanocytic nevi affecting acral volar skin. arch dermatol. 2011;147:809-13. 2. káram-orantes m, toussaint-caire s, domínguez-cherit j, veja-memije e. clinical and histopathological characteristics of malignant melanoma cases seen at “dr. manuel gea gonzález” general hospital. gac med mex. 2008;144:219-23. 3. ito t, wada m, nagae k, et al. acral lentiginous melanoma: who benefits from sentinel lymph node biopsy? j am acad dermatol. 2015;72:71-7. 4. bello dm, chou jf, panageas ks, et al. prognosis of acral melanoma: a series of 281 patients. ann surg oncol. 2013;20:3618-25. dermatology: practical and conceptual research | dermatol pract concept 2018;8(4):6 283 dermatology practical & conceptual www.derm101.com onychoscopy: an observational study in 237 patients from the kashmir valley of north india yasmeen j. bhat1, muzafar a. mir1, abid keen1, iffat hassan1 1 postgraduate department of dermatology, std & leprosy, government medical college, srinagar, university of kashmir, jammu & kashmir, india key words: nail, dermoscopy, onychoscopy, inflammatory nail disorders, melanonychia citation: bhat yj, mir ma, keen a, hassan i. onychoscopy: an observational study in 237 patients from the kashmir valley of north india. dermatol pract concept. 2018;8(4):283-291. doi: https://doi.org/10.5826/dpc.0804a06 received: december 9, 2017; accepted: april 6, 2018; published: october 31, 2018 copyright: ©2018 bhat et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: yasmeen jabeen bhat, md, facp, associate professor, postgraduate department of dermatology, std & leprosy, government medical college, srinagar, university of kashmir, jammu & kashmir, india-190010. email: yasmeenasif76@gmail.com background: nail disorders comprise approximately10% of all dermatological conditions. because diagnosis is not always possible by clinical means alone, additional diagnostic procedures may be required at times. dermoscopy of nails (onychoscopy) has shown promising results in diagnosing various nail disorders and also avoids time-consuming investigations such as culture and biopsy. objective: to study the dermoscopic features of various nail disorders to determine the correlation between koh examination and onychoscopic patterns in patients with the clinical suspicion of onychomycosis, and to differentiate benign pigmented lesions from malignant ones. methods: an open, observational and cross-sectional study of 237 patients was conducted. all patients underwent clinical examination and the affected nails were examined with a dermatoscope. the onychoscopic patterns were identified and recorded. results: the study included 237 patients with the following diagnoses: 81 onychomycosis, 63 psoriasis, 27 lichen planus, 30 longitudinal melanonychia, 24 connective tissue disorders, 5 onychophagia and nail tics, 3 subungual verrucae, 2 glomus tumor, 1 darier disease, and 1 enchondroma. the most common onychoscopic findings were spiked pattern in cases of onychomycosis, dilated and tortuous capillaries in cases of psoriasis, longitudinal streaks and nail fragmentation in cases of lichen planus, and enlarged capillaries in cases of connective tissue diseases. limitations: the study was only observational and did not compare the results to biopsy and culture. conclusions: onychoscopy may be used as an important diagnostic tool when evaluating nail disorders. it should be used to aid in the diagnosis of various nail disorders and to avoid unnecessary and time-consuming investigations. abstract 284 research | dermatol pract concept 2018;8(4):6 nonpolarized and polarized modes were used initially without and then with the fluid. nonpolarized and dry mode helps in detection of nail plate changes, whereas polarized mode with or without fluid is best for nail bed changes. the linkage fluid used was ultrasound gel in most of the cases. diagnosis of onychomycosis was made with koh examination, and the presence of fungal elements was considered positive for the diagnosis. at times the sample was cultured. our study was approved by the institutional ethics committee, and written informed consent was obtained from all patients enrolled in the study. results a total of 237 patients (140 females and 97 males) were screened for onychoscopic findings. patients’ ages ranged from 1 year to 80 years (mean age: 30.72 years ±8.5). most of the patients, that is 151 (63.71%)were from rural areas, whereas 86 (36.29%) patients were from urban areas. systemic illnesses in the form diabetes mellitus, hypertension, and hypothyroidism were seen in 8, 6, and 2 patients, respectively (not statistically significant). the various nail disorders in decreasing order of frequency were as follows: onychomycosis (81), psoriasis (63), lichen planus (27), longitudinal melanonychia (30), connective tissue disorders (24), nail tics (5), subungual verrucae (3), glomus tumor (2), darier disease (1), and calcified enchondroma (1). the study included 81 (34.18%) patients with clinical suspicion of onychomycosis. among these patients, 69 had positive direct koh examination for onychomycosis and all 12 remaining patients had positive fungal culture. the most common clinical pattern of onychomycosis was distal and lateral subungual onychomycosis and was seen in 62 (76.54%) patients, whereas 19 (23.46%) patients had total dystrophic onychomycosis. onychoscopic findings in these patients showed proximal jagged edge, spikes, and longitudinal striae as shown in table 1 (table 1; figures 1 and 2). the next common nail disorder was nail psoriasis, which was seen in 63 patients (28%). the diagnosis was based solely on clinical examination, and only 1patient needed nail biopsy. the changes affected both nail plate and nail bed. the nail plate changes observed were pitting that was irregular in size and shape, both longitudinal and transverse ridging and nail plate crumbling. the nail bed changes were onycholysis, which was surrounded by an erythematous border proximally; red to orange salmon patches, which were irregular in size and shape; splinter hemorrhages with color ranging from brown, black, or purple; dilated tortuous capillaries in the hyponychium and proximal nail fold; subungual hyperkeratosis; and pustules in pustular psoriasis (table 2; figures 3 and 4). introduction nail disorders constitute approximately 10% of all dermatological conditions, and the diagnosis is still a challenge [1]. keeping in mind the various clinical difficulties in diagnosing nail disorders, and since some dermoscopic patterns are observed consistently with certain diseases, this study was conducted to evaluate various nail changes by using a dermatoscope. a dermatoscope is a noninvasive diagnostic tool that visualizes subtle clinical patterns of skin lesions, hair disorders, and various nail changes not normally visible to the unaided eye [2]. in addition to diagnosis of common nail disorders, dermoscopy of nails (onychoscopy) provides useful information in the differential diagnosis of longitudinal melanonychia [3-5].the evaluation of longitudinal melanonychia should include personal and family history, clinical examination, and dermoscopic examination. all these together aid in making the differential diagnosis of the nail pigmentation and also help render a decision of whether to biopsy, where to biopsy, and how to biopsy [5,6]. irregularities in the thickness, parallelism, spacing, and color of the brown–black bands are strongly suggestive of malignant melanoma. these patterns are highly specific and sensitive and may help in the diagnosis, selection of the type of surgery, and management [7]. we studied the dermoscopic features of various nail disorders to determine the correlation between koh examination and onychoscopic patterns in patients with clinical diagnosis of onychomycosis and to differentiate various benign and malignant pigmented lesions. materials and methods this cross-sectional observational study was conducted in the dermatology outpatient department of a tertiary care hospital. patients who either presented with nail disorders per se or were having nail involvement associated with various dermatoses were recruited for onychoscopic evaluation over a period of 1 year, from february 2016 through january 2017. relevant laboratory investigations such as koh, culture of nail clippings, and nail biopsy were also carried out in selected patients wherever there was diagnostic difficulty. patients of all age groups who consented to participate were included in the study; there were no exclusion criteria as such. all patients were subjected to clinical examination and dermoscopic examination. in all cases the affected nails were examined by a handheld dermatoscope (dermlitedl3n; 3 gen, inc, san juan capistrano, ca), with a magnification of 10×. higher magnification of upto 30× was used wherever deemed necessary. images were recorded directly by the digital camera of the dermatoscope with an attachment for iphone 6. both research | dermatol pract concept 2018;8(4):6 285 clinical examination, and in 6 patients nail matrix biopsy was also done. two patients had features of irregular melanocyte proliferation and their nail biopsy showed features of melanoma, while 4 showed regular proliferation and had benign melanocytic nevus. the other 24 patients had features of melanocytic activation only. two patients had fungal melanonychia. the onychoscopic changes observed in the benign group were blood spots in 21 patients and regular, parallel, uniform lines in 18 patients. in the melanoma group, irregular lines and micro-hutchinson sign were seen in both patients (table 4; figures 7-9). onychoscopic examination of the nail fold capillaries was done in patients with connective tissue disorders by mdad approach (morphology, diameter, architecture, and density). in this study we examined 24 patients with connective tissue diseases: 11 with systemic sclerosis, 10 with systemic lupus erythematosus (sle), and 3 with dermatomyositis. in systemic sclerosis early changes (few enlarged capillaries and few hemorrhages), active disease (frequently enlarged capillaries and frequent hemorrhages), and late changes (irregular enlargement, severe loss of capillaries and avascular areas) were seen. nail lichen planus, another common disorder, was observed in  27 (12%) patients. of these, 18  patients were diagnosed on the basis of clinical examination only and 9 patients needed nail biopsy, which showed sawtooth acanthosis, hyperkeratosis, hypergranulosis, degeneration of the basal layer, and bandlike lymphocytic infiltrate. the nail pattern changes that were seen on onychoscopy included chromonychia, subungual hyperkeratosis, onycholysis, and nail plate changes (table 3; figures 5 and 6). longitudinal melanonychia was seen in 30 (13.33%) patients. fifteen patients had involvement of a single nail of great toe or thumb, only 6 had involvement of both great toes and thumbs, and 3 had involvement of multiple nails. all patients were subjected to a proper history-taking and table 1. onychoscopic findings in different types of onychomycosis spiked pattern longitudinal striae pattern distal irregular termination pattern total 69 63 33 no. % no. % no. % dlso 48 69.57 45 71.43 24 72.73 tdo 21 30.43 18 28.57 9 27.27 p > 0.05; chi-square statistic = 0.122 dlso = distal and lateral subungual onychomycosis; tdo = total dystrophic onychomycosis. figure 1. proximal jagged edge, spikes, and longitudinal striations with different colors (aurora pattern). [copyright: ©2018  bhat et al.] figure  2. distal pulverization characteristic of the thickening of the nail plate in total dystrophic onychomycosis. [copyright: ©2018 bhat et al.] 286 research | dermatol pract concept 2018;8(4):6 in sle, we observed capillary dilatations, hemorrhages, telangiectasias, enlarged tortuous capillaries, and normal density. in dermatomyositis, enlarged ramified/bushy capillaries, capillary loss, twisted capillaries, and hemorrhages were seen (table 5; figures 10-12). we found 2 patients with subungual bluish nodules, tender to touch. usg doppler confirmed the diagnosis of glomus tumor after onychoscopy was done (figure 13). discussion the use of dermoscopy in nail disorders is quite recent. initially its use was limited to nail pigmentations, but nowadays it is frequently being utilized for the diagnosis of other nail disorders as well. in our study, the most common nail disorder observed was onychomycosis and the commonest pattern was distal and lateral subungual onychomycosis. onychomycosis forms the most common nail disorder and accounts for nearly 50% of all onychopathies [8]. since the treatment of onychomycosis can be long-standing and the morphology of the nail changes can vary, diagnosis cannot rely on clinical examination only. therefore, we use koh examination followed by culture of the samples [9,10]. because culture is a time-consuming process and to decrease the number of samples to be sent for culture, we can utilize a dermatoscope, which is a noninvasive procedure that can aid in the diagnosis of onychomycosis. piraccini et al [11] retrospectively analyzed 57 digital dermoscopic images with clinical diagnosis of onycholysis; they identified and described specific dermoscopic signs for onychomycosis. dermoscopic findings described for onytable 2. onychoscopic findings in 63 patients with psoriasis onychoscopic findings no. of patients percentage nail matrix involvement pitting 54 85.71 ridging (longitudinal or transverse) 54 85.71 nail plate crumbling 21 33.33 nail bed dilated and tortuous capillaries in nail bed and hyponychium 57 90.48 onycholysis 51 80.95 subungual hyperkeratosis 27 42.86 salmon patch 27 42.86 splinter hemorrhages 15 23.81 pustules (in pustular psoriasis) 1 1.58 figure 3. coarse pits irregular in size and shape, yellowish discoloration, distal onycholysis, capillary changes in proximal nail fold. [copyright: ©2018 bhat et al.] figure  4. distal onycholysis with proximal regular and erythematous border, salmon spot (orange to red), and splinter hemorrhages (purplish linear streaks). [copyright: ©2018 bhat et al.] research | dermatol pract concept 2018;8(4):6 287 nonychia, and atrophy; nail bed involvement shows subungual hyperkeratosis, chromonychia, and onycholysis [16,17]. in our experience with biopsy-confirmed nail lichen planus, the observed dermoscopic findings were chromonychia, whitish striations, nail fragmentation, trachonychia, onycholysis, and nail plate destruction; in clinically suspected cases, the observed dermoscopic findings were trachonychia, pitting, anonychia, pterygium, red lunula, chromonychia, subungual hyperkeratosis, onycholysis, striations, nail fragmentation, splinter hemorrhages, and nail plate destruction. another nail change that can be of concern in most patients is longitudinal melanonychia. this may represent a benign melanocytic nevus, lentigo, racial/ethnic melachomycosis were jagged proximal edge with spikes of the onycholytic area and longitudinal striae [11]. nakamura et al [8] performed dermoscopy in 500 cases of nail disorders, and in onychomycosis they identified chromonychia, onycholysis, opacity, and longitudinal stripes. in our study, the dermoscopic findings observed in onychomycosis showed jagged pattern of the proximal margin of the onycholytic area, spikes that were directed to the proximal fold, white-yellow longitudinal striae in the onycholytic nail plate (aurora borealis pattern), and distal irregular termination pattern. the next common onychopathy in our study was nail psoriasis. psoriasis can involve any structure of the nail apparatus, and accordingly there are different clinical manifestations [12]. so far the dermoscopic findings that have been observed in nail psoriasis include pitting, onycholysis, salmon spot, dilated blood vessels, splinter hemorrhages, dilated and tortuous capillaries in the hyponychium, and subungual hyperkeratosis [13,14]. fine pits could be appreciated well with a dermatoscope[15]. we divided the nail unit changes in our patients into nail matrix and nail bed changes. the nail matrix changes include pitting, both longitudinal and transverse ridging, and nail plate crumbling. the nail bed changes are dilation and tortuosity of capillaries, onycholysis, subungual hyperkeratosis, salmon patch, and splinter hemorrhages. dermoscopy is also a complementary tool in the diagnosis of nail lichen planus. since nail lichen planus affects both nail matrix and nail bed, the clinical signs also vary. dermoscopy findings that have been observed with matrix involvement include fissuring, pitting, trachyonychia, longitudinal ridging, dorsal pterygium, erythematous patches in the lunula, melatable 3. onychoscopic findings in 27 patients with nail lichen planus onychoscopic findings no. of patients percentage nail matrix longitudinal streaks 24 88.89 pitting 12 44.44 anonychia 12 44.44 pterygium 9 33.33 red lunula 6 22.22 trachyonychia 4 14.81 nail bed nail fragmentation 24 88.89 chromonychia 18 66.67 onycholysis 9 33.33 subungual hyperkeratosis 6 22.22 splinter hemorrhages 3 11.11 figure  5. longitudinal fissures, fragmentation, thinning of nail plate. [copyright: ©2018 bhat et al.] figure  6. dorsal pterygium formation. [copyright: ©2018  bhat et al.] 288 research | dermatol pract concept 2018;8(4):6 nonychia, drug-induced hyperpigmentation, or at times a malignant melanoma. the most common site involved in melanonychia is the thumb, followed by the great toe and the index finger [18]. to distinguish benign causes of longitudinal melanonychia from malignant ones, dermoscopy appears to be helpful to clinicians. it allows the visualization and evaluation of morphological features that are otherwise not visible to the unaided eye and thus forms a link between macroscopic clinical dermatology and microscopic dermatopathology [19]. in a study conducted by ronger et al [20], investigators observed 7 dermoscopic patterns in longitudinal melanonychia: (1) blood spots, (2) brown coloration of the background, (3) regular lines,(4) irregular lines, (5) grayish background and thin gray lines, (6) micro-hutchinson sign, and (7) microscopic grooves. among these patterns, brown-black background hue, irregular longitudinal lines, and micro-hutchinson sign table 4. onychoscopic findings in longitudinal melanonychia blood spots regular lines irregular lines micro-hutchinson sign no. % no. % no. % no. % total 21 70 18 60 2 6.67 2 6.67 p > 0.05; chi-square statistic = 0.083. figure  7. longitudinal melanonychia due to melanocytic activation with regular, parallel, and uniform gray bands. [copyright: ©2018 bhat et al.] figure 8. longitudinal melanonychia due to benign melanocytic nevus showing regular, parallel, and uniform brown–black bands with negative hutchinson sign. [copyright: ©2018 bhat et al.] are more often seen in malignant melanoma [20]. in this study we observed blood spots and regular lines in patients with benign cause and irregular lines and micro-hutchinson sign in patients with malignant melanoma. proximal nail fold changes are also common in connective tissue diseases. although most nail fold changes in connective tissue diseases are not specific, they may give an important clue to the diagnosis. a dermatoscope can help to detect these findings, which are difficult to see with the unaided eye. a case-control study compared nail changes in patients with connective tissue diseases and 2 healthy groups [21]. in this study, capillary loops and splinter hemorrhages were frequent significantly in patients with scleroderma. other studies have shown an association between the degree of nail fold capillary abnormalities and internal organ involvement and mortality in patients with scleroderma [22,23]. in our study the onychoscopic findings observed research | dermatol pract concept 2018;8(4):6 289 various studies have investigated nail changes in dermatomyositis; nail changes were observed in the form of splinter hemorrhages, red lunula, cuticular changes, and capillary loops in proximal nail folds [24-26]; in our study we noticed enlarged and ramified capillaries, capillary loss, twisted capillaries, and hemorrhages. also in previous studies, nail changes observed in patients with sle were proximal nail fold erythema, longitudinal ridging, splinter hemorrhages, bluish-black discoloration of the nail plate, onycholysis, subungual hyperkeratosis, and red lunula. splinter hemorrhage in fingernails of patients with sle was found to be associated significantly with disease activity [27]. we found nail changes in the form of capillary dilations and enlarged tortuous capillaries with normal density. glomus tumors are painful benign hamartomas with increased sensitivity to cold that arise from myoarterial apparatus [28,29]. we found 2 such patients, who showed pinkish blush in the nail plate with onychoscopy. limitations onychoscopy can be used as a diagnostic tool for nail disorders; however, it cannot replace the histopathological examination when there is a diagnostic dilemma. in our study, the sample size for various disorders was too small to allow interpretation that onychoscopy can be used as a diagnostic tool for those disorders. to validate these findings, therefore, further studies with larger sample sizes are needed. in patients with systemic sclerosis were enlarged capillaries, loss of capillaries, avascular areas, hemorrhages, and irregular enlargement. table 5. onychoscopic findings in patients with connective tissue disorders disease onychoscopic findings no. of patients percentage systemic sclerosis nail fold changes enlarged capillaries 8/11 72.73 irregular enlargement of the capillaries 7/11 63.64 loss of capillaries 6/11 54.54 avascular areas 6/11 54.54 nail bed changes hemorrhages 5/11 45.45 systemic lupus erythematosus nail fold changes capillary dilations 8/10 80 enlarged tortuous capillaries 8/10 80 periungual telangiectasia 6/10 60 nail bed changes hemorrhages 4/10 40 dermatomyositis nail fold changes enlarged capillaries 3/3 100 capillary loss 2/3 66.67 twisted capillaries 2/3 66.67 nail bed changes hemorrhages 2/3 66.67 figure 9. longitudinal melanonychia due to melanoma showing irregular black-gray-brown bands which are not parallel and are not uniform in color. micro-hutchinson’s sign is positive. [copyright: ©2018 bhat et al.] 290 research | dermatol pract concept 2018;8(4):6 conclusions onychoscopy is an easier, noninvasive, and cost-effective diagnostic tool that can allow detection of subtle nail changes not visible to the unaided eye. it can aid in diagnosing nail disorders earlier so that we can treat them before the disease progresses. in addition, it can help in differentiating benign lesions from malignant ones and accordingly guide us to figure  12. proximal nail fold capillaries in dermatomyositis: enlarged ramified/bushy capillaries with capillary loss. [copyright: ©2018 bhat et al.] figure 13. glomus tumor presenting as pinkish vascular area in nail bed. [copyright: ©2018 bhat et al.] figure  10. proximal nail fold capillaries in systemic sclerosis: enlarged capillaries, cuticular hemorrhages, and loss of capillaries leading to avascular areas. [copyright: ©2018 bhat et al.] figure 11. proximal nail fold capillaries in sle: enlarged tortuous capillaries and normal density. [copyright: ©2018 bhat et al.] research | dermatol pract concept 2018;8(4):6 291 15. farias dc, tosti a, chiacchio nd, hirata, sh. dermoscopy in nail psoriasis [in portuguese]. an bras dermatol. 2010;85(1):101103. 16. nakamura r, broce aa, palencia dp, ortiz ni, leverone a. dermatoscopy of nail lichen planus. int j dermatol. 2013;52(6):684687. 17. goettmann s, zaraa i, moulonguet i. nail lichen planus: epidemiological, clinical, pathological, therapeutic and prognosis study of 67 cases. j euro acad dermatol venereol. 2012;26(10):13041309. 18. koga h, saida t, uhara h. key point in dermoscopic differentiation between early nail apparatus melanoma and benign longitudinal melanonychia. j dermatol. 2011;38(1):45-52. 19. argenziano g, soyer hp. dermoscopy of pigmented skin lesions— a valuable tool for early diagnosis of melanoma. lancet oncol. 2001;2(7):443-449. 20. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138(10):1327-1333. 21. nabil pa, rao r, shenoi sd, balachandran c. nail unit in collagen vascular diseases: a clinical, histopathological and direct immunofluorescence study. indian j dermatol. 2006;51(4):265268. 22. ingegnoli f, ardoino i, boracchi p, cutolo m; eustar coauthors. nailfold capillaroscopy in systemic sclerosis: data from the eular scleroderma trials and research (eustar) database. microvasc res. 2013;89:122-128. 23. smith v, decuman s, sulli a, et al. do worsening scleroderma capillaroscopic patterns predict future severe organ involvement? a pilot study. ann rheum dis. 2012;71(10):1636-1639. 24. dourmishev la, dourmishev al. dermatomyositis: advances in recognition, understanding and management. berlin, heidelberg: springer-verlag; 2009. 25. samitz mh. cuticular changes in dermatomyositis. arch dermatol. 1974;110(6):866-867. 26. tosti a, de padova mp, fanti p, et al. unusual severe nail involvement in dermatomyositis. cutis. 1987;40(3):261-262. 27. ekmekc tr, ucak s, aslan k, et al. exaggerated cuticular changes in a patient with dermatomyositis. j euro acad dermatol venereol. 2005;19(1):135-136. 28. mcdermott em, weiss ap. glomus tumors. j hand surg am. 2006;31(8):1397-1400. 29. baran r, richert b. common nail tumors. dermatol clin. 2006;24(3):297-311. avoid unnecessary biopsies. however, the interpreter needs to have a thorough knowledge of the nail anatomy and its disorders; onychoscopy should not be used as the only diagnostic tool for confirming the diagnosis. references 1. samman pd. the nail in disease. 2nd ed. london: heineman w; 1972:1-176. 2. campos-do-carmo g, ramos-e-silva m. dermoscopy: basic concepts. int j dermatol. 2008;47(7):712-719. 3. koga h, saida t, uhara h. key point in dermoscopic differentiation between early nail apparatus melanoma and benign longitudinal melanonychia. j dermatol. 2011;38(1):45-52. 4. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138(10):1327-1333. 5. braun rp, baran r, le gal fa, et al. diagnosis and management of nail pigmentations. j am acad dermatol. 2007;56(5):835-847. 6. jellinek n.nail matrix biopsy of longitudinal melanonychia: diagnostic algorithm including the matrix shave biopsy. j am acad dermatol. 2007;56(5):803-810. 7. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002;138(10):1327-1333. 8. nakamura rc, costa m. dermatoscopic findings in the most frequent onychopathies: descriptive analysis of 500 cases. int j dermatol. 2012;51(4):483-496. 9. richert b, lateur n, theunis a, et al. new tools in nail disorders. semin cutan med surg. 2009;28(1):44-48. 10. harvey ck, richardson a. techniques for obtaining specimens for culture to confirm onychomycosis. j am podiatr med assoc. 2000;90(8):394-396. 11. piraccini bm, balestri r, starance m, et al. nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. j eur acad dermatol venereol. 2013;27(4):509-513. 12. sánchez-regaña m, umbert p. diagnosis and management of nail psoriasis [in spanish]. actas dermosifiliogr. 2008;99(1):34-43. 13. piraccini bm, bruni f, starace m. dermoscopy of non-skin cancer nail disorders. dermatol ther. 2012;25(6):594-602. 14. iorizzo m, dahdah m, vincenzi c, et al. videodermoscopy of the hyponychium in nail bed psoriasis. j am acad dermatol. 2008;58(4):714-715. dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):11 59 dermatology practical & conceptual www.derm101.com case presentations case 1 a 61-year-old man presented with multiple small, reddish, eroded papules located on his chest (figure 1a). histodermoscopic clues to diagnose acantholytic dyskeratosis francesca specchio1, giuseppe argenziano2, danica tiodorovic-zivkovic3, elvira moscarella2, aimilios lallas2, iris zalaudek4, caterina longo2 1 department of dermatology, university of rome, tor vergata, italy 2 dermatology and skin cancer unit, arcispedale s. maria nuova, irccs, reggio emilia, italy 3 clinic of dermatovenerology, clinical center of nis, medical faculty, university of nis, serbia 4 department of dermatology, medical universiy of graz, graz, austria key words: acantholytic dyskeratosis, dermoscopy citation: specchio f, argenziano g, tiodorovic-zivkovic d, moscarella e, lallas a, zalaudek i, longo c. dermoscopic clues to diagnose acantholytic dyskeratosis. dermatol pract concept 2015;5(1):11. doi: 10.5826/dpc.05011 received: september 8, 2014; accepted: october 16, 2014; published: january 30, 2015 copyright: ©2015 specchio et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. drs. specchio and longo wrote the manuscript. all authors revised it critically for important intellectual content. all authors gave the final approval of this version to be published. corresponding author: caterina longo, md, phd, dermatology and skin cancer unit, arcispedale santa maria nuova-irccs, viale risorgimento, 80, 42100 reggio emilia, italy. tel. 390522295612; fax. 390594224271. email: longo.caterina@gmail.com figure 1. (a) clinical examination of case 1 showed multiple confluent erythematous papules in a patient with grover’s disease. (b) clinically, multiple reddish papules were observed on the chest of a patient with stage iv melanoma treated with vemurafenib. (copyright: ©2015 specchio et al.) pathologic examination revealed the typical findings of grover’s disease. case 2 a 47-year-old woman was treated with vemurafenib for stage mailto:longo.caterina@gmail.com 60 observation | dermatol pract concept 2015;5(1):11 benign and malignant lesions, such as cutaneous squamouscell carcinoma, verrucal keratosis, plantar hyperkeratosis, hair follicle changes, panniculitis, and photosensitivity [2], along with widespread eruptions with histologic features of acantholytic dyskeratosis [3]. acantholytic dyskeratoma has been previously reported in association with other chemotherapeutics, including the epidermal growth factor receptor inhibitor cetuximab; however, the pathogenesis of acantholytic dyskeratosis is still unclear. two hypotheses have been postulated. one theory is that the accumulation in the skin of chemotherapy metabolites by sweating may be related to the development of dyskeratosis and acantholysis; another theory supposes that acantholytic dyskeratosis may represent an off-target effect of small-molecule kinase inhibitors [1]. recognition of cutaneous side effects occurring during braf-inhibitor therapy is essential for patient management. acantholytic dyskeratomas can be easily diagnosed by using dermoscopy. in fact, in acantholytic lesions, dermoscopy allows the visualization of a stereotypical pattern [4], which also assists in the differentiation of these benign lesions from malignancy, such as keratoacanthoma or invasive squamous cell carcinoma that may also occur as a complication of braf inhibitor therapy. typically, these papules display a central star-like pattern of brown scales that are otherwise not detectable at clinical examination. this dermoscopic pattern has been described to be peculiar for grover’s disease and solitary acantholytic dyskeratoma [4]. interestingly, our study shows the characteristic dermoscopic star-like pattern can be observed in acantholytic dyskeratotic lesions occurring during treatment with braf-inhibitors, as previously reported [3]. in conclusion, our case underlines the importance of dermoscopy to improve the recognition of acantholytic dyskeratomas (in grover’s disease and in patients under vemurafenib therapy), a skin eruption that is usually difficult to diagnose by naked eye. references 1. gupta m, huang v, linette g, cornelius l. unusual complication of vemurafenib treatment of metastatic melanoma: exacerbation of acantholytic dyskeratosis complicated by kaposi varicelliform eruption. arch dermatol 2012;148(8):966-68. 2. anforth r, fernandez-peñas p, long gv. cutaneous toxicities of raf inhibitors. lancet oncol 2013;14(1):e11-8. 3. chu ey, wanat ka, miller cj, et al. diverse cutaneous side effects associated with braf inhibitor therapy: a clinicopathologic study. j am acad dermatol 2012;67(6):1265-72. 4. giacomel j, zalaudek i, argenziano g. dermatoscopy of grover’s disease and solitary acantholytic dyskeratoma shows a brown, star-like pattern. australas j dermatol 2012;53(4): 315-16. iv melanoma, having been referred because of the recent onset of multiple asymptomatic reddish papules located on her chest (figure 1b). these lesions represented a skin rash of acantholytic dyskeratoma occurring while under vemurafenib treatment that spontaneously disappeared over the next few weeks. the dermoscopic evaluation of the lesions in both cases showed a central yellowish to brown star-like pattern overlying a pinkish homogeneous structureless area (figure 2a and b). conclusions treatment with vemurafenib, a small-molecule braf inhibitor, has led to significant improvement of prognosis in patients with advanced melanoma. similar to other kinase inhibitors, the use of vemurafenib has been accompanied by several dermatologic adverse events [1]. these include both figure 2. (a) dermoscopic evaluation of case 1 displayed a central yellowish to brown star-like pattern overlying a pinkish homogeneous structureless area similarly to the ones observed in case 2 (b). (copyright: ©2015 specchio et al.) dermatology: practical and conceptual practical, conceptual, educational note | dermatol pract concept 2014;4(4):16 75 dermatology practical & conceptual www.derm101.com introduction the number of yearly deaths from melanoma continues to increase, and the overall melanoma mortality rate is one of the few cancer mortality rates not on the decline [1,2]. these realities combined with increasing evidence of the lack of efficacy of the abcde criteria have necessitated ongoing efforts to enhance the earlier clinical detection of melanoma [3-8]. most approaches to melanoma diagnosis have included some predominant emphasis or combination of emphases on recognition of changing lesions, recognition of outlier (“uglyduckling”) lesions, and specific melanoma characteristics, with the most utilized criteria being the abcde criteria (“a” for “asymmetry,” “b” for “border irregularity,” “c for color variation,” “d for 6 mm diameter,” and “e” for “evolving lesions”) [8]. many recently published strategies have rejected the diameter criterion as well as abandoned all or portions of the abcde mnemonic [3,5,9-12]. many of these proposed strategies, including the “d” for “dark” proposal i offered, have also added emphasis on recognition of darkness as a particular feature of concern in pigmented lesions [5,10-12]. i have recently reviewed the compelling rationale for both an increased emphasis on darkness and rejection of the diameter criterion in the clinical diagnosis of melanoma [13]. the georgia approach to melanoma diagnosis uniquely incorporates many elements of these strategies in a complementary manner to increase the sensitivity of diagnosis of early melanoma [13,14] (figure 1). a unifying approach to the clinical diagnosis of melanoma including “d” for “dark” in the abcde criteria stuart m. goldsmith1 1 dermatology, emory university school of medicine citation: goldsmith sm. a unifying approach to the clinical diagnosis of melanoma including “d” for “dark” in the abcde criteria. dermatol pract concept. 2014;4(4):16. http://dx.doi.org/10.5826/dpc.0404a16 received: june 9, 2014; accepted: september 8, 2014; published: october 31, 2014 copyright: ©2014 goldsmith et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: stuart m. goldsmith, md, 2401 osler court, albany, ga, 31707, usa email: smg@swgaderm.com current clinical approaches to melanoma diagnosis have not been associated with a decrease in mortality from this cancer. the components of the new approach presented are, first, a screening examination to look for any lesion that stands out because of being dark, different, or changing; second, when a single lesion is recognized to be of concern for any reason, that lesion is then evaluated in more detail utilizing the abcde criteria, with the “d” signifying “dark” and not “6 mm diameter” in this mnemonic; and, third, additional discussion of the “ugly duckling” sign and of the recognition of nodular melanomas. since the georgia society of dermatology and dermatologic surgery was the first state or national society to endorse this approach, i refer to it as the georgia approach. abstract 76 practical, conceptual, educational note | dermatol pract concept 2014;4(4):16 tify lesions of possible concern and then the specific lesion assessment that follows [15]. this distinction is important because the screening examination determines the sensitivity of melanoma recognition, and it is the screening examination that really describes how most practitioners examine patients and how patients examine each other. first, the georgia approach places increased emphasis on the screening examination by initial, distinct discussion and clarification of its function. second, the approach includes both of the two screening strategies that have been used in most melanoma educational materials, change and ugly duckling identification. third, the approach adds the easily perceived, easily communicated, highly sensitive, specific (compared to change and ugly duckling identification) screening feature of darkness. a major tenet of physical diagnosis, particular for early diagnosis, is that one sees what one looks for. a strategy based on recognition only of any lesion that changes or differs from other lesions inadequately considers this principle. the added benefit of looking specifically for dark lesions as part of a screening examination for melanoma cannot be overstated; many melanomas, particularly small melanomas, can be recognized because of, and only because of, their intensity of pigment [16]. nonetheless, with melanoma, as with screening features for nearly every disease, no one feature has 100% sensitivity. the description of the screening examination for melanoma detection includes the instruction to examine the skin in order to detect any lesion that stands out because of being dark, different, or changing. each of the three screening features has non-redundant as well as complementary importance in the recognition of melanoma. the screening examination should usually include two looks, one for any lesion that stands out at all, which should allow detection of changed or ugly duckling lesions, and a second look to identify lesions of any size that stand out because of appearing, even focally, dark. consequently, the emphasis on darkness as a screening feature should only enhance the sensitivity of diagnosis of melanoma. second component: application of the abcde criteria to specific lesions, either those lesions identified to be of concern on the screening examination or specific lesions being examined for any reason, with “d” for “dark” in the abcde criteria though the impact of the abcde criteria on melanoma detection has been uncertain, the publication and utilization of these criteria are ubiquitous, and the criteria have many supporters. as marghoob and scope help elucidate, however, the role of the abcde criteria is not as a screening approach, as they have been utilized, but as a spot evaluation, and the criteria can also help to assess the level of concern when comparing similar lesions [15]. thus, the criteria have discussion of the approach first component: screening examination for dark, different, or changing lesions in their review of melanoma diagnosis, marghoob and scope discuss the concepts of a screening examination to idenfigure 1. the georgia approach presented as a patient information card (actual card size is 8½ inches x 3½ inches). (copyright: ©2014 goldsmith et al.) practical, conceptual, educational note | dermatol pract concept 2014;4(4):16 77 summary whatever changes occur in terms of melanoma diagnosis because of screening recommendations or technology, no strategy will reach its potential without the earliest possible clinical recognition of melanoma. the components of the georgia approach accomplish the following: first component: clarifies and emphasizes the role of a screening examination; adds dark to both change and ugly duckling identification as screening features; communicates the screening features simply and succinctly. second component: continues to utilize but more precisely defines the role of the abcde criteria and changes the meaning of the “d” to “dark.” third component: discusses both the ugly duckling sign as a general rule as well as specific issues relevant to the diagnosis of nodular melanomas. each of these three components has non-redundant potential to enhance the diagnosis of melanoma. by unifying and integrating all of the components in a logical manner, however, the georgia approach uniquely prioritizes and maximizes the sensitivity of diagnosis of early melanomas. during this period of transition in the clinical diagnosis of melanoma, i encourage other practitioners, departments, and societies to consider and adapt the georgia approach, as well. references 1. cancer facts & figures 2014. cancer.org web site. http://www. cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/ index. accessed june 5, 2014 2. howlader n, noone am, krapcho m, et al. seer cancer statistics review, 1975-2010. bethesda, md: national cancer institute, 2013. http://seer.cancer.gov/csr/1975_2010/, based on november 2012 seer data submission, posted to the seer web site, april 2013. 3. yagerman s, marghoob a. the abcds and beyond. the skin cancer foundation journal. 2013; 31:61-3, 94. 4. maley a, rhodes ar. cutaneous melanoma: preoperative tumor diameter in a general dermatology outpatient setting. dermatol surg. 2014;40:446-54. 5. manganoni am, pavoni l, calzavara-pinton p. patient perspectives of early detection of melanoma: the experience at the brescia melanoma centre, italy. g ital dermatol venereol. 2014 may 14. [epub ahead of print] 6. robertson k, mcintosh rd, bradley-scott c, et al. image training, using random images of melanoma, performs as well as the abc(d) criteria in enabling novices to distinguish between melanoma and mimics of melanoma. acta derm venereol. 2014;94(3):265-70. 7. de giorgi v, papi f, giorgi l, et al. skin self-examination and the abcde rule in the early diagnosis of melanoma: is the game over? br j dermatol. 2013;168:1370-1. 8. yagerman s, marghoob a. melanoma patient self-detection: a review of efficacy of the skin self-examination and patient-directed educational efforts. expert rev anticancer ther. 2013;13:1423-31. value, but one that requires this more precise explanation. the meanings of the a, b, c, and e in the georgia approach are unchanged from usual use: “a” for “asymmetry,” “b” for “border irregularity,” “c” for “color variation,” and “e” for “evolving” unlike other lesions. what is critical to the utility of the abcde criteria, however, is the change of the “d” to signify “dark” and not “6 mm diameter.” with this change, and without altering the familiar mnemonic, the criterion never present in the earliest melanomas is replaced by the single criterion that characterizes many early melanomas [11,16,17]. it can now be stated more accurately that most melanomas have one or more of the abcde criteria and that the criteria are relevant to the diagnosis of early melanomas. as a criterion of an individual lesion, similar to its utilization as a screening feature, the characteristic of darkness has nonredundant value and, in addition, enhances the application of other criteria. third component: discussion of the “ugly duckling” rule and specific discussion of nodular melanoma recognition there is increasing support for the strategy of melanoma recognition based on the concept that a melanoma will differ in appearance from one’s usual moles, referred to as the “uglyduckling” rule. the possible utility in this concept is reflected in the georgia approach both as a screening feature (“different”) and in the “e” for “evolving” description (“has a mole . . . changed . . . unlike others on your body?”). in the third component of the georgia approach, the “ugly-duckling” sign is specifically defined, conveying additional emphasis on and understanding of this strategy and its application. nodular melanomas represent a minority of melanomas but contribute disproportionately to melanoma mortality, and the final portion of the georgia approach is devoted to specific education about the diagnosis of this melanoma subtype. the varied presentations of nodular melanomas, including as amelanotic lesions, are specifically discussed, as is the particular relevance of change and ugly duckling recognition to the diagnosis of these melanomas. the inclusion of the nodular melanoma pictured adds further emphasis on both the diagnosis of nodular melanomas and of the relevance of change recognition to their diagnosis. nonetheless, as nodular melanomas have metastatic potential both in a shorter time frame and when smaller in diameter than other melanomas, the previously discussed addition of dark as a screening feature and the “d” for “dark” change may have particular impact on decreasing mortality by enhancing the earlier diagnosis of this melanoma subgroup. in addition to the potential impact on the diagnosis of earlier nodular melanomas by removing any diameter consideration, many early nodular melanomas, similar to other melanoma subtypes, are characterized by their dark pigment [18,19]. 78 practical, conceptual, educational note | dermatol pract concept 2014;4(4):16 9. yagerman se, chen l, jaimes n, et al. ‘do uc the melanoma?’ recognising the importance of different lesions displaying unevenness or having a history of change for early melanoma detection. australas j dermatol. 2014;55:119-24. 10. luttrell mj, hofmann-wellenhof r, fink-puches r, et al. the ac rule for melanoma: a simpler tool for the wider community. j am acad dermatol. 2011;65:1233-4. 11. goldsmith sm, solomon ar. a series of melanomas smaller than 4mm and implications for the abcde rule. j eur acad dermatol venereol. 2007;21:929-34. 12. shore rn, shore p, monahan nm, et al. serial screening for melanoma: measures and strategies that have consistently achieved early detection and cure. j drugs dermatol. 2011;10:244-52. 13. goldsmith sm. increased emphasis on darkness and rejection of a diameter criterion represent paradigm shifts in the clinical diagnosis of melanoma. br j dermatol. 2013;169:474-6. 14. website of the georgia society of dermatology and dermatologic surgery, gaderm.org, accessed august 16, 2014. 15. marghoob aa, scope a. the complexity of diagnosing melanoma. j invest dermatol 2009;129:11-3. 16. ferrari c, seidenari s, borsari s, et al. dermoscopy of small melanomas: just a miniaturized dermoscopy? br j dermatol. 2014. 17. bono a, bartoli c, baldi m, et al. micro-melanoma detection. a clinical study on 22 cases of melanoma with a diameter equal to or less than 3 mm. tumori. 2004;90:128-31. 18. bono a, tolomio e, carbone a, et al. small nodular melanoma: the beginning of a life-threatening lesion. a clinical study on 11 cases. tumori. 2011;97:35-8. 19. geller ac, elwood m, swetter sm, et al. factors related to the presentation of thin and thick nodular melanoma from a population-based cancer registry in queensland australia. cancer. 2009;115:1318-27. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2014;4(1):2 3 the compendium (part 3) – c – cancer: a term generic for a neoplasm malignant, i.e., a carcinoma or sarcoma. carcinoembryonic antigen: abbreviated cea, is a glycoprotein found in certain normal epithelial tissues, and in some neoplasms composed of epithelial cells, especially adenomas and adenocarcinomas. common neoplasms that contain carcinoembryonic antigen are adenocarcinomas of the gastrointestinal tract, lung, breast, ovary, endometrium, and cervix, medullary carcinoma of the thyroid, and, less frequently, squamous-cell carcinomas of the lung and cervix. within normal eccrine and apocrine units, carcinoembryonic antigen is demonstrable in luminal cells of ducts and secretory cells in glands. some authors maintain, incorrectly in our view, that investigation of carcinoembryonic antigen by immunoperoxidase techniques is helpful for distinguishing proliferations with eccrine differentiation from those with apocrine differentiation. carcinoma: denotes a proliferation malignant of epithelial cells. carcinomas may be classified histopathologically by aspects cytopathologic (i.e., germinative in trichoblastic (basal cell) carcinomas, spinous in squamous cell carcinoma, and polygonal and plasmacytoid in some apocrine carcinomas) and by differentiation or lack of it (i.e., apocrine or sebaceous for the former, they being adenocarcinomas in contrast to basal cell, squamous cell, and neuroendocrine carcinoma, and undifferentiated carcinoma or sarcoma for the latter). trichoblastic (basal cell) carcinoma is considered, conventionally, to be the most common carcinoma in skin, but squamous cell carcinoma is more common by far, the reason being that solar keratosis is more common incomparably than trichoblastic (basal cell) carcinoma and solar keratosis is one type of superficial squamous cell carcinoma, other types superficial of squamous cell carcinoma being arsenical keratosis, radiation keratosis, bowen’s disease, and so called actinic cheilitis. catagen: designates the involutional stage of a follicular cycle, during which the inferior segment of a follicle shrivels and shrinks as it ascends along a fibrous track to the base of an isthmus. catagen is characterized morphologically by the appearance of numerous individual necrotic keratinocytes, referred to popularly as apoptotic cells; (a term we eschew) a thickened, corrugated, glassy membrane; and release of melanin from melanocytes in the bulb into macrophages in the follicular papilla. cholesterol clefts: long, needle-like spaces that represent sites from which crystals of cholesterol have been dissolved in tissue by the agents used in processing specimens of tissue in preparation for examination of sections by conventional microscopy. chondroid stroma: is supporting tissue of a proliferation that bears a resemblance close to that of cartilage, it usually signifying differentiation toward cartilage. chondroid is homogeneous material that in sections stained by hematoxydermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 3 bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 3. dermatol pract conc. 2014;4(1):2. http://dx.doi.org/10.5826/dpc.0401a02 copyright: ©2014 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@att.net 4 review | dermatol pract concept 2014;4(1):2 lin and eosin is basophilic in some foci, eosinophilic in others, and amphophilic in still others. the appearance distinctive of chondroid is attributed to the presence of large amounts of chrondoid sulfate. “chondroid syringoma,” for example, is reputed to be a proliferation in which abnormal eccrine glandular structures reside in stroma that resembles cartilage. the term “chondroid syringoma” is a misnomer, however, because that mixed tumor of the skin usually shows apocrine, rather than eccrine (most authors regard syringoma wrongly as being eccrine), differentiation, as well as differentiation infundibular, sebaceous, and follicular, and may be devoid of chrondoid, consisting as it does most often of mucin alone. chondromyxoid stroma: describes connective tissue that resembles both chondroid and mucin. chondroid consists of homogeneous material that, in sections stained by hematoxylin and eosin, is basophilic in some foci, eosinophilic in others, and amphophilic in still others. the appearance of chondroid is caused by the presence of large amounts of chondroitin sulfate. myxoid tissue consists of finely granular basophilic material. large quantities of chondroid and myxoid are present together in the stroma of cutaneous mixed tumors, i.e., those with apocrine and those with eccrine differentiation. civatte bodies: necrotic keratocytes that can be seen in the epidermis (and the upper part of epithelial structures of adnexa) on one hand and in the dermis immediately adjacent to them on the other. also termed colloid bodies, hyaline bodies, and “apoptotic” bodies. clear cells: in dermatopathology as well as in general pathology, the term “clear cell” appears in designations of a number of proliferations and is also applied in descriptions of a broad variety of conditions such that the meaning of clear cells is unclear. it appears in the term “clear cell acanthoma” to designate keratocytes with a pale staining cytoplasm. in “clear cell papulosis” the “clear cells” are most likely of apocrine differentiation and scattered among basal cells. in the terms “clear cell eccrine porocarcinoma,” “clear cell porocarcinoma in-situ,” and “eccrine syringofibroadenoma of clear cell variant, pale neoplastic cells are also of glandular differentiation, either eccrine or apocrine. in “clear cell trichoblastoma” clear cells have been confirmed to represent an attempt at differentiation toward the outer sheath at the bulb. carcinomas as well as sarcomas have been told to be typified by “clear cells,” which actually did not have a clear cytoplasm but were filled with granular material. the “prefix” “clear cell” has also been added to dermatofibroma with pale spindle cells, to fibrous papule with dermal aggregates of clear cells with finely granular to vacuolated cytoplasm and to atypical fibroxanthoma with pleomorphic spindled and polygonal cells with clear cytoplasm. a type of seborrheic keratosis with “basal clear cells” has been described. hemangioblastomas have been told of having clear cells staining positive for neuron-specific enolase but not cytokeratin or epithelial membrane antigen. from the conditions just mentioned, it is obvious that the term “clear cell” is applied to cells of completely unrelated differentiations. there are examples of cells that seem to have a clear cytoplasm but to which the term “clear cells” is usually not applied. it is important to identify clearly, what the meaning is of “clear cell differentiation” in dermatopathology. the following examples demonstrate compellingly that the term “clear cell” has been applied to very different types of cells: epithelial cells of apocrine differentiation, epithelial cells of eccrine differentiation, epithelial cells of tricholemmal differentiation, benign epithelial cells of spinous differentiation, malignant epithelial cells of spinous differentiation, malignant mesenchymal cells of unknown differentiation, and foamy macrophages. all these cells have one feature in common, namely, that their cytoplasm does not stain well with h & e. in most of the cell types, the cytoplasm actually stains, though faintly or in a granular or vacuolated fashion. apart from that, however, the cells are very different from one another and they can be told apart either by their cytologic features or by the context in which they appear. the reasons for cytoplasms not staining with h & e are as various as are the types of cells designated “clear.” some cells are filled with mucin, some with glycogen, and some with lipids that are resolved completely during processing. actually, the term is best avoided. instead, cells and tissues should be described precisely; taking into account the context in which they appear in order to identify the differentiation of a tissue with near surety. cells should be described precisely as polygonal, round, or spindled; the cytoplasm should be named as being homogenous, granular, or vacuolated; nuclei should be identified as centered or excentric, round, scalloped, or flat, pleomorphic or monomorphic; and a tissue should be designated as being cohesive or loose. moreover, careful note should be taken of the context in which such cells appear, i.e., the presence together with tubules (i.e., hidradenoma), with cells arranged in a palisade (i.e., trichilemmoma), with proliferations of vessels (i.e., metastasis of renal cell carcinoma), or with spinous cells (i.e., bowen’s disease.) those features will in most instances permit identification of the differentiation with near surety, whereas the observation of “clear cells” does not allow any differentiation. cleft: denotes an empty space, i.e., one that does not contain fluid, in contrast to a blister, i.e., of bullous pemphigoid, to some cysts, i.e., apocrine hidrocystoma, and to some cystic hamartomas, i.e., steatocystomas. a cleft may appear in the epidermis, i.e., as in focal acantholytic dyskeratosis of darier’s review | dermatol pract concept 2014;4(1):2 5 disease; immediately below the epidermis, i.e., a max joseph space of lichen planus; between epithelial cells and adjacent stroma, i.e., in trichoblastic (basal cell) carcinoma; and between stroma peculiar of a benign proliferation and contiguous normal connective tissue, i.e., in trichoblastoma. the spaces in each of these circumstances are thought to result from retraction of tissue during fixation or processing of a biopsy specimen. in fact, in the differentiation of benign from malignant proliferations by pattern analysis and particularly their silhouettes the aforementioned concept can be used. in benign proliferations usually there are clefts between compactly arranged fibrous tissue of altered stroma and fibrous tissue of normal skin. in malignant proliferations usually there are clefts between neoplastic cells and altered stroma. cliché (and platitude): phrase or opinion that is over used and lacks original thought. avoid clichés! a person who employs clichés becomes a cliché! and clichés are ubiquitous in dermatology and pathology in general and in dermatopathology in particular, the realm of inflammatory skin diseases being no exception. platitudes like “plasma cells are not seen in lichen planus and in discoid lupus erythematous,” “parakeratosis does not occur in discoid lupus erythematosus “and“touton giant cells are necessary for diagnosis of juvenile xanthogranuloma” lead, inevitably, to misdiagnosis because each of those assertions is dead wrong. trite questions like “is it dle (discoid lupus erythematosus) or sle (systemic lupus erythematosus)?” “is it morphea or scleroderma?” and “is it small plaque parapsoriasis or mycosis fungoides?” are predicated on woefully faulty premises and invoke answers given reflexly that are plain incorrect. images like “corps ronds and grains” (don’t think of darier’s disease only!), “dilapidated brick wall” (don’t think of hailey-hailey disease only), “tombstone pattern” (don’t think of pemphigus vulgaris only!), “festooning” (don’t think of porphyria cutanea tarda only!), “flame figures” (don’t think of wells syndrome [which is a response to assaults by an arthropod] only!), “ground-glass cytoplasm” (don’t think of reticulohistiocytic granuloma only!), and “saw tooth pattern” (don’t think of lichen planus only!) may be picturesque, but none of them lend themselves to definition meaningfully by those who mouth them. moreover, not a single one of those whimsical mental pictures has specificity. coarse collagen bundles in vertical streaks: collagen bundles thicker than normal for the papillary dermis and oriented parallel to one another and to elongated rete ridges (as well as to exaggerated infundibula), and perpendicular to the surface of the skin, the papillary dermis being thickened markedly. the “streaks” signify persistent forceful rubbing of skin, as occurs in lichen simplex chronicus and its variant, prurigo nodularis. those conditions are typified also by compact orthokeratosis, hypergranulosis, acanthosis, and proliferation of infundibular and sometimes eccrine ductal, keratocytes. distinctive changes of lichen simplex chronicus may be produced in pruritic skin that, prior to the effects of prolonged rubbing of it, was normal clinically, or they may be imposed on a variety of itchy inflammatory skin diseases, such as lichen planus, i.e., hypertrophic lichen plasmas, allergic contact dermatitis, and dermatophytosis, deposits as in macular amyloidosis, i.e., amyloidosis and neoplastic diseases like mycosis fungoides. coarse melanin: large granules of melanin of irregular sizes and shapes usually found within the cytoplasm of macrophages or keratocytes. collagen: designates an albuminoid substance of white fibers in connective tissue and bone that yields gelatin on boiling. it is the most common protein in the animal world, the major product of fibrocytes, and the extracellular framework for all multicellular organisms. collagen, when viewed through a conventional microscope in sections of skin stained by hematoxylin and eosin, is seen to be arranged in two different patterns, namely, thin bundles in the papillary and periadnexal dermis and thicker bundles in the reticular dermis and septa of the subcutaneous fat. by electron microscopy, collagen fibers, irrespective of whether they are arranged in thin or thick bundles, have characteristic cross striations with a periodicity of 68 nm. a score or more types of collagen, different in composition of amino acids and in antigenicity, are recognized currently. collagen accounts for approximately 75% of the dry weight of skin and provides it with both tensile strength and elasticity. collagenization: means formation of collagen within growing or healing tissue. in dermatopathology, the term also is used to describe the markedly thickened bundles of collagen in the stroma of some neoplasms such as some congenital nevi colloquially called blue nevi and carcinoma from a breast metastatic to skin. collarette of epithelium: describes bowing inward of epithelial structures superficial in skin, i.e., infundibula and eccrine ducts, in a manner that encloses partially a variety of processes pathologic, i.e., the hyperplasia of small blood vessels of pyogenic granuloma, the epidermal keratocytes of verrucae vulgares, the benign proliferations of epidermal keratocytes in seborrheic keratosis and pale cell acanthoma, and the benign proliferations of cells adnexal in trichoblastoma and apocrine mixed tumor. colloid bodies: are necrotic keratocytes, also known as civatte bodies, hyaline bodies, and apoptotic bodies. column: a row of more than two cells, either ones epithelial or nonepithelial, as may occur, for example, in a 6 review | dermatol pract concept 2014;4(1):2 hamartoma, i.e., giant hairy congenital nevus, or neoplasm, i.e., melanoma. comedo: a dilated infundibulum stuffed by cornified cells arranged compactly or in laminated fashion and containing sebaceous secretion, and microorganisms, to wit, bacteria, yeasts, and mites of the normal skin flora. the ostium of a comedo is said, colloquially, to be either “open” or “closed.” in reality, all comedones are “open,” some more than others, because each comedo has access directly to the surface of the skin through an ostium at the summit of infundibular epidermis. if a comedo ruptures, its contents are discharged into the dermis and sometimes, into the subcutaneous fat, too, where ensues a suppurative, then granulomatous and, sometimes, fibrosing response. comedones are nearly invariable in acne vulgaris, where they are characterized clinically by dark casts of dilated infundibula dubbed by the laity “blackheads.” comedones may develop secondary to occlusion (such as by machine oils) and to severe longstanding damage by sunlight (“senile” comedones, better termed “solar” comedones). groups of solar-induced comedones in the midst of prominent elastotic material in the skin above the zygoma constitute nodular elastoidosis (favre-racouchot syndrome). steroid acne refers to comedones and pustules that are induced by prolonged administration of corticosteroids systemically or by application topically. compact orthokeratosis: describes the arrangement cohesive of orthokeratotic cells in a stratum corneum as it is viewed through a microscope conventional. the term does not apply to the normal pattern formed by corneocytes on palms and soles, but to the abnormal arrangement of them elsewhere on the integument, i.e., as occurs in response to vigorous, long standing rubbing of skin in lichen simplex chronicus or as an effect expected of the inflammatory process of lichen planus. in actuality, the term should be compact orthohyperkeratosis, but the word is clumsy; compact orthokeratosis has come to imply orthohyperkeratosis and, therefore, it suffices. compound nevus: a nevus in which aggregations of melanocytes are present in both the epidermis and the dermis. the term conveys information about where in the skin collections of melanocytes are situated, but it tells nothing about the character of the nevus itself as does naming the nevus when possible. (i.e., clark’s, spitz’s, reed’s, miescher’s, or unna’s, etc.). (see atypical melanocytic hyperplasia) compressed fibrous tissue: the appearance of amalgamation of bundles of collagen in a rim that encircles a structure whose border is circumscribed sharply and is smooth, such as a cyst, a benign proliferation solid cystic or a benign proliferation solid, the signs of compression being a consequence, in vivo, of the expansion very slowly over a long period of time of the structure epithelial. concentric eosinophilic fibroplasia: a description of wiry bundles of collagen that are arrayed parallel to one another and to elongated epidermal rete ridges, and situated immediately beneath a proliferation of melanocytes disposed mostly as solitary units and/or in tiny nests at the dermoepidermal junction. the finding usually is mentioned in the context of “lamellar fibroplasia,” the latter consisting of wiry bundles of collagen parallel to one another at the base of rete ridges and positioned immediately beneath nests of melanocytes there. in actuality, concentric and lamellar fibroplasias are a continuum, being the same phenomenon viewed differently by virtue of orientation different. moreover, although “concentric eosinophilic fibroplasia” and “lamellar fibroplasia” were asserted repeatedly by clark to be two of five criteria requisite for diagnosis histopathologic of the so-called dysplastic nevus (the other three being “persistent lentiginous melanocytic hyperplasia,” “atypical melanocytic hyperplasia” [melanocytic dysplasia], and “lymphocytes”), wiry bundles of collagen in “concentric” and “lamellar” array also are encountered at times in nevi of other types, such as “classic” spitz’s nevus, and in some melanomas. congenital: literally means present at birth and it is the opposite of acquired. the term, in dermatology and dermatopathology, is used figuratively because some congenital lesions are not apparent at birth. certain clinical and histopathologic findings are characteristic of nevi that, without a doubt, are present at birth. when those criteria are fulfilled, a nevus can be affirmed as congenital, no matter when it appears. in other words, although not all congenital nevi are apparent at birth, they surely are not becoming melanized markedly until puberty. that circumstance fulfills an essential criterion for the term congenital as defined in the oxford english dictionary—namely, “dating from one’s birth,” not necessarily being evident at one’s birth. that distinction is crucial to resolving the apparent contradiction of congenital nevi that seem to be acquired, and an understanding of this concept is essential if a classification of nevi predicated on their being congenital or acquired is to be logical. a congenital abnormality may result from genetic factors, i.e., down syndrome, hailey-hailey disease, epidermolysis bullosa simplex, or environmental factors that exert their effects in utero, i.e., hypoxia; infections such as syphilis, hepatitis, and human immunodeficiency virus (hiv); amniotic bands; or a combination of these. connective tissue: refers to tissues that originate from mesenchyme. it consists of a cellular component (undifferenreview | dermatol pract concept 2014;4(1):2 7 tiated mesenchymal cells, fibrocytes, adipocytes, mast cells, etc), an extracellular component replete with fibers (elastin and collagen), and a ground substance or matrix (highly sulfated glycosaminoglycans especially). the term “connective tissue diseases”, applied to the constellation of systemic lupus erythematosus, dermatomyositis, scleroderma, rheumatoid arthritis, and sjogren syndrome, is accurate because those diseases are abnormalities of connective tissue, but so, too, are a host of other conditions, such as pseudo xanthoma elasticum, ehlers-danlos syndrome, and hurler syndrome; all of them are “connective tissue diseases.” connective tissue mucin: pertains to mucinous substances produced by connective tissue cells, in contrast to similar substances that are manufactured by epithelial cells. epithelial mucins in the skin are characterized by their high content of neutral glycoproteins, whereas connective tissue mucins contain highly sulfated glycosaminoglycans. the mucin in focal mucinosis, myxedema, pretibial myxedema, scleromyxedema, discoid lupus erythematosus, and dermatomyositis, to mention but a few examples, is made by fibrocytes and, therefore, is connective tissue mucin. mast cells usually are numerous in connective tissue mucin, but not in epithelial mucin. connective-tissue nevus: a hamartoma of the dermis and/or subcutaneous fat. when the papillary dermis is involved mostly, the lesion resembles numerous “skin tags”; when the reticular dermis is involved mostly, the abnormality may be of collagen, elastic tissue, acid mucopolysaccharides, or any combination of them, as in shagreen patch and elastic tissue nevus. when the subcutaneous fat is the site, the result is nevus lipomatosis. conventional microscopy: is synonymous with light microscopy, in contrast to electron microscopy. cord: when employed clinically, designates a string-like or rope-like structure in or beneath the skin, and, when used histopathologically, a row of cells, two in width. in contrast to a cord, a strand is cells in a single file and a column is more than two cells wide. examples of a cord visible clinically are a vein affected by thrombophlebitis and “a rope” formed by an infiltrate composed of mostly epithelioid histiocytes in interstitial granulomatous dermatitis with arthritis. examples of cords observable through a microscope conventional are those epithelial (mantle cells) in fibrofolliculomas and those nonepithelial (glomus cells) in glomangiomas. strands of cells (abnormal melanocytes) are “splayed” between bundles of collagen in the reticular dermis in conditions such as the superficial and “deep” type of congenital melanocytic nevus and they (abnormal apocrine cells) are interposed between bundles of collagen in a metastasis of carcinoma from the breast. cord of melanocytic nevus cells: a column of nevus cells usually two cells wide and of variable length. cornification: is a process normal whereby epidermal, follicular, and ungual cells generative (germinative or matrical) mature to become corneocytes. in the process of maturation, germinative cells of the epidermis assume different appearances as they evolve from basal through spinous and granular stages to eventually becoming cornified fully. the increased number and density of keratin intermediate filaments and the organization of them into tonofilaments, the development of tonofilaments desmosomes complexes and formation of keratohyaline granules contribute to the flattening of the cells as they move away from the basal layer en route to death and desquamation. the cornified cells of the epidermis, surface and infundibular, constitute the stratum corneum; those in a follicle, the hair itself and the inner sheath; those in the nail unit, the nail itself. cornified cell or corneocyte: is the end product of the process of cornification. a normal cornified cell is anucleate, thin, flat, and eosinophilic when stained by hematoxylin and eosin and viewed by conventional microscopy. by electron microscopy, the cytoplasm of a normal corneocyte is characterized by densely packed tonofilaments and is devoid of cellular organelles. cornified cells of the stratum corneum protect an organism by acting as a barrier against noxious agents of various kinds. cornified cells in hair follicles are present in the inner sheath, and hair shaft, and in the nail unit they are found in the nail plate. the uppermost parts of eccrine and apocrine ducts also cornify; squames are corneocytes that have become detached from one another, as happens in an infundibular type of follicular cyst, especially after that cyst ruptures. keratin, a fibrous protein, is present in all cells of cornifying epithelium. cornified cells are composed almost entirely of keratin. it is inaccurate, however, to use keratinized cells as a synonym for cornified cells, because although corneocytes are made up of keratin, not all cells that contain keratin are corneocytes. horn cells and horny cells are imprecise designations for cornified cells. cornoid lamellation: a column of parakeratosis that derives from epidermis, including the infundibular epidermis, or eccrine ducts, with vacuolated and dyskeratotic cells just beneath it. it is a requisite for histopathologic diagnosis of porokeratosis in any of its different expressions. it may appear in other proliferations and dermatoses. corrugated: means wrinkled by parallel alternations of ridges and grooves. a normal basement membrane of an inferior segment of a follicle becomes corrugated markedly in the course of catagen. a normal sebaceous duct is stamped by a corrugated, crenulated, scalloped, or notched appearance. 8 review | dermatol pract concept 2014;4(1):2 corymbiform: conveys the sense clinically of a group of lesions that resembles a cluster of flowers, specifically, having a central pistil (i.e., “mother lesion”) and surrounding petals (i.e., “daughter lesions”), as may be seen in warts and molluscum contagiosum. the term also may be applied histopathologically (e.g., to the pattern formed by proliferation of cells in some trichoblastomas and trichoblastic carcinomas). cribriform: characterizes a pattern like that of a sieve formed by a mesh of cords of epithelial cells and by stroma fibrotic or mucinous, the latter being the equivalent of perforations. the example consummate of pattern cribriform is met with in trichoepithelioma, a type of trichoblastoma in which fibrous tissue serves as the “perforations”, and in cribriform carcinoma, a variant of apocrine carcinoma, in which small holes of fibrous tissue seem to “perforate” cords of epithelial cells. the pattern formed by adenoid cystic carcinoma, another variant histopathologic of apocrine carcinoma, and by adenoidcystic trichoblastic (basal cell) carcinoma also is cribriform, but in those two conditions, mucin fills the “holes” in the “sieve.” the term “cribriform” has application clinical too, i.e., the appearance sieve-like of nevus comedonicus, of atrophoderma vermicularis, and of scars atrophic in lesions long-standing of discoid lupus erythematosus. critical line: refers to the boundary between the bulbar matrix below and the bulbar supramatrical zone above. it was described first by auber, in 1852, and refers to an imaginary line drawn across the bulb at the site where a follicular papilla is widest. crust: a collection of serum that contains white blood cells, red blood cells, or both. the honey-colored crusts of impetigo consist of serum and leukocytes. a hemorrhagic scab of an abrasion is made up of serum, some leukocytes, and many erythrocytes. vegetations are heaped-up crusts that may come to pass in diseases such as pemphigus vegetans and pyoderma vegetans. necrotic keratocytes, parakeratotic cells, fibrin, and bacteria may be found in crusts of any kind, but particularly in those termed vegetations. cuboidal: polygonal cell. different cells in the epidermis and dermis may assume this shape (i.e., suprabasal keratocytes, melanocytes, apocrine, and eccrine ductal). cuticle: applies to more than one structure in the skin. there are two cuticles in a follicle, one being at the innermost margin of the inner sheath and the other being the cuticle of the hair. both cuticles are derived from matrical cells that differentiate into flat imbricated cells that resemble tiles on a roof. cuticular cells of the inner sheath point down, whereas those of the hair are directed up. these sets of apposed cornified cells interdigitate and lock a hair firmly in a follicle. when hair and inner sheath are separated from each other in the processing of sections of tissues, the cuticles are seen to have a distinct sawtoothlike appearance. cuticular cells of the inner sheath possess trichohyalin granules before cornification, whereas cuticular cells of the hair do not. cuticular cell: is one with a round nucleus and abundant eosinophilic cytoplasm that lines a duct of an apocrine or eccrine gland and is a component expected in aggregations of poromas and porocarcinomas (apocrine and eccrine) in which tubules form (the other component of the proliferation being a poroid cell.) (see poroid cell) cylindroid: means resembling a cylinder, as in the shape of aggregations of cells in a cylindroma. cylinder-like aggregations of epithelial cells also may be found in other proliferations, such as spiradenoma and some trichoblastic (basal cell) carcinomas. cyst: signifies an epithelium-lined round or oval sac that houses fluid, cells, or both. in the skin, epithelium of a cyst almost always is of an adnexal structure, and the contents of the cyst represent the maturation product of that epithelium, for example: infundibular cyst (also termed epidermoid cyst) lined by epithelium that resembles the infundibular portion of a follicle which is indeed part of the epidermis because of its basal, spinous, granular, and cornified layers, the cornified cells of the latter forming the contents of the cyst and being arranged in basket-woven or laminated pattern; isthmiccatagen cyst (also termed sebaceous cyst and tricholemmal cyst) lined by epithelium that includes the isthmic portion of an outer sheath of a follicle and the outer sheath at the base of a follicle advanced somewhat in catagen, because it lacks a granular zone, but possesses a corrugated inner surface and houses cornified cells arranged compactly; and apocrine gland cyst (also termed apocrine hidrocystoma) lined by epithelium that shows “decapitation secretion” like that of a normal apocrine gland and encloses apocrine secretion. only rarely are true epidermal cysts formed in skin, and they are thought to be inclusion cysts that result from penetrating injuries to a palm or sole. cystic means resembling a cyst. a true cyst is non-neoplastic. cystic: means resembling a cyst. by implication, a cystic structure is not a true cyst because it is not a non-neoplastic epithelium-lined sac that houses fluid, cells, or both. syringocystadenoma papilliferum, apocrine cystoadenoma, and apocrine cystoadenocarcinoma are examples of cystic conditions, but none of them qualifies as an authentic cyst. neither does steatocytoma, which is a cystic hamartoma. cystule: is a neologism coined by ackerman and böer for the purpose of designating, small structures histopathologic typified by a lumen round and an epithelium enveloping, in contrast to structures characterized by a lumen long with a review | dermatol pract concept 2014;4(1):2 9 lining epithelial more or less parallel to it, the latter being termed by us, generically, “tubule.” the only word extant currently equivalent to cystule is “microcyst,” but that is not an analogue of tubule and, moreover, everything observed through a microscope is “micro.” cystules are encountered in proliferations benign and malignant, the former being exemplified by those in syringoma and the latter by those in syringomatous carcinoma. papillations may project from the lining into the lumen of a cystule, as occurs in apocrine papillary adenoma and apocrine papillary carcinoma. tubules predominate overwhelmingly in tubular adenoma and tubular carcinoma. cytokeratins: is a family of intracellular, water-insoluble, fibrous proteins present in almost all epithelia. they are markers of epithelial differentiation in neoplasms that exhibit endodermal, neuroectodermal, mesenchymal, or germ-cell character. cytology: refers to the study of normal cells, in contrast to histology, which is the study of normal tissues. cytopathology: is the study of abnormal cells. undue emphasis on cytopathologic features in histopathologic examination of a proliferation may lead to misinterpretation of benign ones as malignant, and vice versa. cytoplasm: is the protoplasm of a cell exclusive of the nucleus. the entire cellular mass, called protoplasm consists of nucleoplasm (nuclear mass) and the residual volume, i.e., cytoplasm. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(1):4 9 dermatology practical & conceptual www.derm101.com introduction the neutrophilic dermatoses are a group of disorders characterized by skin lesions for which histological examination reveals intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils without evidence of infection [1]. cutaneous findings of neutrophilic dermatoses vary; lesions can present as nodules, plaques, ulcerations, or vesiculopustules and can be localized or widespread. in some cases, extracutaneous involvement may occur [2,3]. while the exact pathogenesis of neutrophilic dermatoses is unknown, these disorders may represent a state of immunologic reactivity [4]. in patients who have an underlying malignancy, neutrophilic dermatoses may occur as an anti-neoplastic therapy-related disorder, a paraneoplastic syndrome, or, less commonly, as an idiopathic condition [5]. the group of disorders that comprise neutrophilic dermatoses includes behçet’s disease, bowel (intestinal) bypass syndrome, erythema elevahistiocytoid sweet’s syndrome in a patient with myelodsyplastic syndrome: report and review of the literature michael m. shalaby1, ryan r. riahi2, les b. rosen3, erik j. soine2,4 1 medical school, louisiana state university health sciences center, new orleans, la, usa 2 department of dermatology, louisiana state university, new orleans, la, usa 3 dermpath diagnostics, pompano beach, fl, usa 4 soine dermatology & aesthetics, new orleans, la, usa key words: histiocytoid sweet’s, myelodysplasia, myelodysplastic, sweet, sweet’s, syndrome citation: shalaby mm, riahi rr, rosen lb, soine ej. histiocytoid sweet’s syndrome in a patient with myelodysplastic syndrome: report and review of the literature. dermatol pract concept 2016;6(1):4. doi: 10.5826/dpc.0601a04 received: september 10, 2015; accepted: october 6, 2015; published: january 31, 2016 copyright: ©2016 shalaby et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: michael shalaby ba, department of dermatology, louisiana state university, new orleans, la, usa. tel. 504417-0249 . email: mshal3@lsuhsc.edu the neutrophilic dermatoses are a group of disorders characterized by skin lesions for which histological examination reveals intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils without evidence of infection. the myelodysplastic syndromes consist of a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and inadequate blood cell production with a variable risk of transformation to acute leukemia. rarely, histiocytoid sweet’s syndrome occurring in patients with myelodysplastic syndrome has been described. we present a case of a 66-year-old woman with a history of myelodysplastic syndrome who developed histiocytoid sweet’s syndrome. we also review the literature and characterize patients with myelodysplastic syndrome who have developed histiocytoid sweet’s syndrome. abstract 10 observation | dermatol pract concept 2016;6(1):4 tender. the patient reported she had not started any new medications. complete blood count at time of diagnosis demonstrated: white blood cell count 1.5, hemoglobin 8.2, hematocrit 24.1, and platelets 26. tum diutinum, neutrophilic dermatosis of the dorsal hand, neutrophilic eccrine hidradenitis [6], pyoderma gangrenosum, and sweet’s syndrome (ss) [1]. the myelodysplastic syndromes (mds) consist of a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and inadequate blood cell production and a variable risk of transformation to acute leukemia. mds may occur de novo or may arise years after exposure to potentially mutagenic therapy (i.e., chemotherapy, radiation exposure). the patients’ inability to properly produce normal erythrocytes, mature granulocytes, and platelets, often results in an array of systemic consequences such as anemia, bleeding, and an increased risk of infection [7]. evidence from cancer databases suggests that there are approximately 10,000 new cases of mds diagnosed annually in the united states [8]. mds occurs most commonly in older adults with a median age at diagnosis of 65 years and a male predominance. review of the literature reveals six cases of histiocytoid sweet’s syndrome with mds [9-14]. when sweet’s syndrome is present, it portends a poor prognosis in patients with mds [12]. histiocytoid sweet’s syndrome is a rare variant of ss. histologically, histiocytoid sweet’s syndrome can present with an infiltrate containing predominantly mononuclear cells with large, slightly eccentric kidney-shaped or elongated nuclei with single indistinct nucleoli and slightly eosinophilic cytoplasm accompanied by numerous mature neutrophils and some mature lymphocytes; these cells may be misinterpreted as histiocytes. we present the case of a 66-year-old woman with a history of myelodysplasia who developed violaceous papules, some with central ulceration, on her face, bilateral upper extremities, and bilateral lower extremities, which later spread to include her right cheek and center of her chest. subsequent biopsy of the left posterior forearm confirmed the diagnosis of histiocytoid sweet’s syndrome. herein we describe patients with myelodysplastic syndromes who developed histiocytoid sweet’s syndrome and discuss the therapeutic options for the treatment of ss. case report a 66-year-old woman presented to the dermatology clinic with a one-month history of a rash. the patient reported she was diagnosed with mds via bone marrow biopsy one year prior; she was started on azacitidine and continued this therapy with minimal improvement. the patient was receiving blood transfusions for anemia and thrombocytopenia. she had not received granulocyte colony-stimulating-factor (g-csf) at any point during her treatment. physical exam revealed violaceous papules and plaques involving the face (figure 1), upper extremities (figure 2), and lower extremities (figure 3). the lesions were slightly figure 1. frontal view of the patient’s face demonstrating deeply erythematous to violaceous, edematous plaques on the bilateral cheeks and right upper eyelid. [copyright: ©2016 shalaby et al.] figure 2. multiple erythematous, edematous papules and plaques involving the left upper extremity. [copyright: ©2016 shalaby et al.] figure 3. lower extremities demonstrating ecchymosis and violaceous plaques bilaterally. [copyright: ©2016 shalaby et al.] observation | dermatol pract concept 2016;6(1):4 11 is precipitated by the patient having received a dermatosisassociated medication, most notoriously g-csf [4]. ss may also result from a hypersensitivity reaction to a bacterial or viral antigen [16]. it has been postulated that photosensitivity may also play a role in the pathogenesis of ss, although the mechanism is unknown [17]. furthermore, an alteration in the gene encoding protein tyrosine phosphatase nonreceptor 6 appears to be involved in the pathogenesis of ss and other subsets of neutrophilic dermatoses [18]. while the pathogenesis of mds remains poorly understood, studies suggest that the cell of origin has acquired multiple mutations resulting in dysplasia and ineffective hematopoiesis [19]. mds genomes are characterized by global dna hypomethylation with concomitant hypermethylation of gene-promoter regions relative to normal controls [20]. the underlying mechanism of altered dna methylation in mds genomes is unclear; however, studies have implicated mutations in genes that encode enzymes, such as tet2 (10,11 translocation), idh1 (isocitrate dehydrogenase-1), and idh2 (isocitrate dehydrogenase-2), that influence dna methylation directly or indirectly [21]. histiocytoid sweet’s syndrome is a histopathologic variant of ss characterized by an infiltrate of mononuclear cells that have a histiocytic appearance and represent immature granulocytes [22-25]. rarely, histiocytoid sweet’s syndrome has been associated with mds. a pubmed search was performed using the keywords: histiocytoid sweet’s, myelodysplasia, myelodysplastic, sweet, syndrome, which yielded six patients with histiocytoid sweet’s syndrome and mds. to the best of our knowledge, our patient is the seventh patient with mds to develop histiocytoid sweet’s syndrome [9-14]. these patients have been characterized in [table 1] [9-14]. four of the seven patients a 3 mm punch biopsy was performed on the left posterior forearm which showed papillary dermal edema in association with a diffuse dermal infiltrate consisting of lymphocytes, histiocytes, few neutrophils with leukocytoclasis, and occasional eosinophils (figures 4 and 5). the biopsy was consistent with histiocytoid sweet’s syndrome. our patient was initially treated with 90 mg of oral prednisone daily and dapsone 5% gel. the patient experienced resolution of many of her lesions. after four weeks of this regimen, prednisone was tapered and finally stopped. discussion ss was first described in 1964 by robert sweet as a constellation of clinical and laboratory findings he had observed in eight women as an “acute febrile neutrophilic dermatosis” [4,15]. ss skin lesions are typically tender, red to violaceous papules or nodules. sites frequently involved include the face, neck, and upper extremities [16]. salient features of ss include: pyrexia, elevated neutrophil count, painful erythematous cutaneous lesions characterized by an infiltrate of mature neutrophils typically located in the upper dermis, and prompt clinical improvement following the initiation of corticosteroid therapy [4]. arthralgias, malaise, headache, and myalgia are other symptoms associated with ss. subtypes of ss have been described and include: (i) the “classic” presentation, which may be associated with upper respiratory tract or gastrointestinal infection, inflammatory bowel disease, and pregnancy; (ii) the “malignancy-associated” presentation, in which the dermatosis is either the presenting manifestation of a previously undiagnosed cancer or the recurrence of malignancy in an oncology patient; and (iii) the “drug-induced” presentation, when the condition figure 4. 10x view demonstrating focal compact parakeratosis with marked edema of the papillary dermis bordering on vesiculation. a superficial and deep perivascular, interstitial and periadnexal infiltrate consisting of lymphocytes, red blood cells and histiocytoid cells is present. [copyright: ©2016 shalaby et al.] figure 5. 63x view demonstrating showing a perivascular and interstitial infiltrate consisting of lymphocytes, red blood cells and histiocytoid cells. [copyright: ©2016 shalaby et al.] 12 observation | dermatol pract concept 2016;6(1):4 known as neutrophilic dermatoses, which are characterized by skin lesions, which histologically consist of intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils without evidence of infection [1]. the myelodysplastic syndromes consist of a group of malignant hematopoietic stem cell disorders which result in impaired blood cell production and which pose a risk of transformation to acute leukemia. ss has been shown to be associated with gastrointestinal or upper respiratory tract infection, hematopoietic malignancy, and various drugs, notably g-csf [25]. first-line treatment for ss is systemic corticosteroids. herein we have presented the case of a 66-year-old woman with a history of myelodysplastic syndrome who developed histiocytoid sweet’s syndrome. references 1. callen jp. neutrophilic dermatoses. dermatol clin. 2002;20(3): 409-19. pmid: 12170875 2. jorizzo jl, solomon ar, zanolli md, leshin b. neutrophilic vascular reactions. j am acad dermatol. 1988;19(6):983-1005. pmid: 3060489 3. moschella sl. review of so-called aseptic neutrophilic dermatoses. australas j dermatol. 1983;24(2):55-62. pmid: 6362643 described were women; the average age of patients with mds who developed histiocytoid sweet’s syndrome was 65 years (range 44-75 years of age). systemic corticosteroids are the mainstay of therapy for ss. prednisone, at a dosage of 1 mg/kg/day, may be given as a single morning dose. intravenous pulse administration of methylprednisone sodium succinate (up to 1000 mg/day) over 1 or more hours, daily for three to five days, may be utilized for patients whose condition is refractory to other therapies [4]. other therapies include: clofazimine, colchicine, cyclosporine, dapsone, high-potency corticosteroids (such as clobetasol propionate 0.05%), indometacin, intralesional corticosteroids, lugol’s solution, and potassium iodide [4]. metronidazole has been effective in patients whose dermatosis is related to inflammatory bowel disease [4]. tumor necrosis factor (tnf) antagonists such as etanercept, infliximab, and thalidomide have been shown to be effective [4,23]. conclusion histiocytoid sweet’s syndrome is a rare variant of ss, which was originally described by robert sweet and is sometimes associated with mds. ss belongs to a group of conditions table 1. cases of concomitant sweet’s syndrome and myelodsyplastic syndrome in the same patient [9-14] case age/ sex clinical appearance time period to progression of leukemia after diagnosis of sweet’s syndrome mds present at time of diagnosis of sweet’s syndrome ref 1 44w multiple papules, plaques, and nodules on the face and extremities n/a yes [14] 2 66w violaceous papules and plaques involving the face, upper extremities, and lower extremities 16 months yes [cr] 3 68w 20 scattered 0.5-2 cm, pink to pinkpurple firm, non-tender nodules on the legs and left arm no progression yes [9] 4 73w multiple red tender plaques on trunk and upper extremities varying in size from 0.5 to 5 cm no progression yes [10] 5 57m multiple tender, raised, annular erythematous lesions on ankles and trunk. no progression yes [12] 6 71 m multiple, slightly tender, erythematous nodules and plaques scattered over the neck, thighs, and trunk, and confluent erythematous indurated plaques on the forearms no progression yes [11] 7 75m burning, maculopapular, erythematous, sharp-edged lesions, affecting abdomen, arms, back, and face leukemia at time of diagnosis yes [13] legend: cr = current report; m = male; mds—myelodysplastic syndrome; n/a—not available; w = woman; observation | dermatol pract concept 2016;6(1):4 13 tentially related to decitabine in a patient with myelodysplastic syndrome; eur j dermatol. 2012;22(6):811-2. pmid: 23178879 15. sweet rd. an acute febrile neutrophilic dermatosis. br j dermatol. 1964 ;76:349-56. pmid: 14201182 16. anzalone cl, cohen pr. acute febrile neutrophilic dermatosis (sweet’s syndrome). curr opin hematol. 2013;20(1):26-35. pmid: 23207661 17. meyer v, schneider sw, bonsmann g, beissert s. experimentally confirmed induction of sweet’s syndrome by phototestin. acta derm venereol 2011;91(6):720-1. pmid: 21681361 18. nesterovitch ab, gyorfy z, hoffman md, et al. alteration in the gene encoding protein tyrosine phosphatase nonreceptor 6 (ptpn6/shp1) may contribute to neutrophilic dermatoses. am j pathol. 2011;178(4):1434-41. pmid: 21406173 19. pang ww, pluvinage jv, price ea, et al. hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. proc natl acad sci usa. 2013;110(8):3011-6. pmid: 23388639 20. xu w, yang h, liu y, et al. oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. cancer cell. 2011;19(1):17-30. pmid: 21251613 21. cazzola m. idh1 and idh2 mutations in myeloid neoplasms— novel paradigms and clinical implications. haematologica. 2010;95;(10):1623-7. pmid: 20884716 22. wilson tc, stone ms, swick bl. histiocytoid sweet’s syndrome with haloed myeloid cells masquerading as a cryptococcal infection. am j dermatopathol. 2014;36(3):264-9. pmid: 23739245 23. maalouf d, battistella m, bouaziz jd. neutrophilic dermatosis: disease mechanism and treatment. curr opin hematol. 2015;22(1):23-9. pmid: 25394310 24. peroni a, colato c, schena d, rongioletti f, girolomoni g. histiocytoid sweet syndrome is infiltrated predominantly by m2-like macrophages. j am acad dermatol. 2015;72(1):131-9. pmid: 25440433 25. so jk, carlos ca, frucht cs, cohen pr. histiocytoid giant cellulitis-like sweet’s syndrome: case report and review of the literature. dermatology online journal. 2015: in press. 4. cohen pr. neutrophilic dermatoses: a review of current treatment options. am j clin dermatol. 2009;10(5):301-12. pmid: 19658442 5. cohen pr. neutrophilic dermatoses occurring in oncology patients. int j dermatol. 2007;46(1):106-11. pmid: 17214733 6. harrist tj, fine jd, berman rs, murphy gf, mihm mc jr. neutrophilic eccrine hidradenitis. a distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. arch dermatol. 1982;118(4):263-66. pmid: 6950689 7. steensma dp, bennet jm. the myelodysplastic syndromes: diagnosis and treatment. mayo clin proc. 2006;81(1):104-30. pmid: 16438486 8. ma x, does m, raza a, mayne st. myelodysplastic syndromes: incidence and survival in the united states. cancer. 2007;109(8): 1536-42. pmid: 17345612 9. lin j, zhang q, chen m. subcutaneous histiocytoid sweet’s syndrome in a patient associated with myelodysplastic syndrome-refractory anemia. j dermatol. 2012;39(1):99-101. pmid: 22007966 10. ten oever j, kuijper ph,, kuijpers al, dercksen mw, vreudgenhil g. complete remission of mds raeb following immunosuppressive treatment in a patient with sweet’s syndrome. neth j med. 2009;67(8):347-50. pmid: 19767665 11. pinal-fernandez i, ferrer fabrega b, ramentol sintas m, solans laque r. histiocytoid sweet syndrome and cutaneous polyarteritis nodosa secondary to myelodysplastic syndrome. int j rheum dis. 2013;16(6):777-9. pmid: 24382288 12. kaiser r, connolly k, linker c, maldonado j, fye k. stem cell transplant for myelodysplastic syndrome-associated histiocytoid sweet’s syndrome in a patient with arthritis and myalgias. arthritis rheum. 2008 ;59(12):1832-4. pmid: 19035416 13. srisuttiyakorn c, reeve j, reddy s, imaeda s, lazova r. subcutaneous histiocytoid sweet’s syndrome in a patient with myelodysplastic syndrome and acute myeloblastic leukemia. j cutan pathol. 2014;41(5):475-9. pmid: 24877196 14. park jy, park js, kim yc. histiocytoid sweet’s syndrome podermatology: practical and conceptual review | dermatol pract concept 2015;5(1):4 25 dermatology practical & conceptual www.derm101.com case presentation a man in his eighties with a past medical history notable for 4 primary cutaneous melanomas (all ajcc stage ia or 0), squamous cell skin cancer, and severe actinic damage presented for routine skin cancer surveillance follow-up. on the left dorsal forearm, a new 8 mm bluish nodule was detected during photographically assisted examination using total body photography digital images (figure 1). the patient was unaware of the lesion and denied the presence of any symptoms, including pain, itching, or bleeding. non-polarized contact dermatoscopic examination revealed a central bluewhite veil, scale, sparse atypical blue and black dots focally at the periphery, and a surrounding pink vascular blush with focal irregular tan-brown pigmentation (figure 2). no lymphadenopathy was present in the bilateral epitrochlear, axillary, supraclavicular, or cervical nodal basins, and there were no systemic symptoms. clinical concern for melanoma prompted an excisional biopsy. histopathologic examination of the biopsy specimen revealed a nodular basaloid tumor abutting from the epidermis with mucinous stroma, stromal retraction, and small cysmelanoma in situ colonizing basal cell carcinoma: a case report and review of the literature silvia e. mancebo1, michael a. marchetti1, travis j. hollmann2, ashfaq a. marghoob1, klaus j. busam2, allan c. halpern1 1 dermatology service, department of medicine, memorial sloan kettering cancer center, new york, new york, usa 2 dermatopathology service, department of pathology, memorial sloan kettering cancer center, new york, new york, usa key words: basal cell carcinoma, malignant melanoma, colonized tumors citation: mancebo se, marchetti ma, hollmann tj, marghoob aa, busam kj, halpern ac. melanoma in situ colonizing basal cell carcinoma: a case report and review of the literature. dermatol pract concept 2015;5(1):4. doi: 10.5826/dpc.0501a04 received: september 22, 2014; accepted: october 27, 2014; published: january 30, 2015 copyright: ©2015 mancebo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: michael a. marchetti, md, dermatology service, department of medicine, memorial sloan kettering cancer center, 16 east 60th street, room 4302, new york, ny 10022, usa. tel. 646 888 6016; fax: 646 227 7274. email: marchetm@mskcc.org colonization of basal cell carcinoma (bcc) by melanoma cells is a unique and uncommonly reported cutaneous entity. we describe a bluish nodule on the left forearm found during routine skin cancer surveillance examination with suspicious dermatoscopic findings including central-blue-white veil, sparse atypical dots, and a surrounding pink vascular blush with focal irregular tan-brown pigmentation at the periphery. histopathology demonstrated a pigmented bcc with an overlying and adjacent melanoma in situ (mis), as well as colonization of the bcc nodule by melanoma cells. we performed a review of the literature on the topic and discuss other presentations of cutaneous neoplasms composed of both bcc and melanoma, including collision, combined, and biphenotypic tumors. the prognostic and management challenges inherent to this distinctive neoplasm are summarized. abstract mailto:marchetm@mskcc.org 26 review | dermatol pract concept 2015;5(1):4 tic spaces filled with mucin and melanin pigment (figure 3). many atypical melanocytes were identified within the tumor as well as in the adjacent epidermis (figures 3 and 4). the nodular basaloid tumor stained with berep4 (figure 5). the figure 1. (a) clinical overview image of a new 8 mm bluish nodule (black arrow). (b) close-up image reveals a pink halo and peripheral tan pigmentation. (copyright: ©2015 mancebo et al.) figure 2. nonpolarized contact dermoscopic image showing central blue-white veil, scale, sparse atypical blue and black dots focally at the periphery, and a surrounding pink vascular blush with irregular tan-brown pigmentation. (copyright: ©2015 mancebo et al.) figure 3. histopathologic examination revealed a nodular basaloid tumor island budding from the epidermis, stromal retraction, and small cystic spaces filled with mucin and pigment (hematoxylin-eosin, x40). (copyright: ©2015 mancebo et al.) atypical melanocyte population within the tumor and along the dermal-epidermal junction stained with hmb-45 (figure 6a and 6b), a103, and sox10. no invasive melanoma was identified in the dermal stroma outside the basaloid nodule. these findings were interpreted as melanoma in situ (mis) colonizing a nodular basal cell carcinoma (bcc). surgical excision with 1 cm margins was performed and revealed residual mis at a peripheral margin. two additional excisions, each with 5 mm margins, were required to achieve negative histopathologic margins. discussion cutaneous neoplasms with two or more distinct cell populations are rare but well documented entities that frequently pose a diagnostic challenge to both clinicians and pathologists. multiple unique presentations regarding the specific co-existence of bcc with melanoma or melanocytic nevi figure 4. histopathologic examination also demonstrated atypical melanocytes as single cells and clusters within the basaloid nodule and along the dermal-epidermal junction (hematoxylin-eosin, x400). (copyright: ©2015 mancebo et al.) figure 5. berep4 labeled the nodular basaloid tumor, consistent with a diagnosis of basal cell carcinoma (x40). (copyright: ©2015 mancebo et al.) review | dermatol pract concept 2015;5(1):4 27 have been reported, often with confusing, overlapping, or imprecise nomenclature. based on a review of the literature, satter et al proposed simplifying the terminology used for these lesions and classifying them as collision, combined, colonized, or biphenotypic tumors [1]. collision tumors are defined as two distinct neoplasms that occur within close proximity of each other but maintain sharp distinct boundaries [1,2]. pierard et al retrospectively searched a histopathologic case series of 78,000 primary cutaneous cancers and identified 11 collision tumors of melanoma with bcc [3]. case reports have similarly documented other examples of collisions between bcc and melanoma [4-10], but also with melanocytic nevi [8,11-15] and blue nevi [16,17]. boyd and rapini performed a retrospective evaluation of 40,000 cutaneous biopsies and found 69 examples of collision tumors. bcc with melanocytic nevus (n=14) was the most frequently identified collision tumor in their series [11]. the coexistence of bcc and melanoma was not found. neoplasms consisting of two phenotypically different, yet imperceptibly intertwined populations of malignant cells are referred to as combined tumors [1,2,18]. often immunohistochemical stains are required to appreciate the intermingling of two tumor cell populations. using the above definition, authors have suggested reclassifying some neoplasms previously reported as collision or colonized tumors, as examples of combined bcc and melanoma lesions [1,2,10,19-30]. figure 6. hmb45 highlighted the atypical melanocytes present in the (a) bcc tumor island as well as the (b) dermal-epidermal junctional (a, x40; b, x200). (copyright: ©2015 mancebo et al.) biphenotypic tumors are exceptionally rare neoplasms that arise from a common stem cell precursor that undergoes divergent differentiation. the tumor cell populations that arise exhibit overlapping immunohistochemical and molecular properties, such as cytoplasmic organelles normally seen in two different cell lines [1]. rodriguez et al described two cases of cutaneous neoplasms with combined phenotypical features of bcc and melanoma, employing the term “basomelanocytic” tumor [20]. nonetheless, the authors could not conclusively demonstrate tumor cells showing combined staining for keratinocytic and melanocytic markers, and these tumors are likely better classified at present as combined neoplasms [1]. in contrast, there is a report of a biphenotypic squamomelanocytic tumor reported by rosen et al in which dual expression of both s-100 and keratin could be detected, along with expression of both premelanosomes and keratin tonofilaments in the cytoplasm of cells by electron microscopy [31]. a unique situation arises when mis permeates an adjacent or underlying bcc tumor. in these cases, atypical melanocytes from an adjacent mis are found interspersed among, but always restricted to basaloid epithelial cell aggregates (i.e., no invasive melanoma component exists). the case presented herein represents an example of such a phenomenon (table 1) [32-36]. care must be used with the term “colonization” as this term has also been used to describe the situation where large dendritic non-neoplastic melanocytes populate various neoplasms [2,37-39]. the discovery of colonization of bcc by melanoma cells specifically led florell et al to analyze nests of bcc using immunohistochemistry. they found that all 10 bcc tumors studied were populated by either dendritic melanocytes at the periphery (5/10) or evenly throughout the tumor (5/10) [37]. the authors further compared the density of melanocytes in bcc tumor islands to a single example of bcc colonized by mis and found that when bcc is infiltrated by melanoma cells, the melanocyte density is higher and clusters of melanocytes can be observed [37]. including the case presented herein, the majority of patients who have developed colonization of bcc by mis have been males (5/6), often with significant risk factors for melanoma including a history of prior invasive melanomas [32-34], severe actinic damage [32,33], cdkn2a gene mutation [32], or xeroderma pigmentosum variant [33]. anatomic sites with chronic ultraviolet light exposure including the face, ears, forearm, and scalp are most frequently affected. dermatoscopy or reflectance confocal microscopy (rcm) was rarely used in the evaluation of these neoplasms. recently, these two diagnostic technologies have emerged as valuable tools for the diagnosis of cutaneous neoplasms with two or more distinct cell populations [8,15,32,40,41]. in one study of 20 benignmalignant collision tumors, dermatoscopy and rcm was successful in identifying the malignant tumor in 14 and 19 28 review | dermatol pract concept 2015;5(1):4 ta b le 1 . su m m ar y o f r ep o rt ed c as es o f c o lo n iz at io n o f b as al c el l c ar ci n o m a by m el an o m a in s it u ( c o py ri gh t: © 2 0 1 5 m an ce b o e t al .) a u th o r a g e s e x a n a to m ic s it e p a st m e d ic a l h is to ry c li n ic a l d e sc ri p ti o n d e rm a to sc o p ic f e a tu re s r c m f e a tu re s tr e a tm e n t a n d /o r o u tc o m e b u rk h al te r an d w h it e [3 5 ] 6 9 m e ar n o m el an o m a ir re gu la r p ig m en te d l es io n — — c o n se rv at iv e lo ca l ex ci si o n w an g et a l [3 4 ] 7 2 m e ye li d b as al c el l ca rc in o m a 1 c m s ca ly re d d is h -b ro w n n o d u le — — l o ca l ex ci si o n w it h n eg at iv e sl n b io p sy sa le rn i et a l [3 2 ] 6 0 m b ac k c d k n 2 a m u ta ti o n ; 2 p ri o r m el an o m as ; at yp ic al m o le s yn d ro m e; se ve re a ct in ic d am ag e 2 .6 × 1 .6 c m b ro w n t o b lu e p la q u e a sy m m et ri c m u lt ic o m p o n en t le si o n w it h a ty p ic al n et w o rk , ir re gu la r gl o b u le s, m u lt ip le c o lo rs , a n d b lu e co lo r in c en te r d is ar ra n ge d e p id er m al ar ch it ec tu re w it h b ri gh t ro u n d is h n u cl ea te d c el ls i n t h e sp in o u s la ye r; n o n -e d ge d d er m al p ap il la e an d r o u n d is h a ty p ic al c el l ag gr eg at es ; d er m al n o d u le s w it h p er ip h er al c le ft -l ik e d ar k s p ac es n o t p ro vi d ed sm it h a n d h u sa in [ 3 3 ] 5 4 f f o re ar m x er o d er m a p ig m en to su m va ri an t; m u lt ip le i n va si ve m el an o m as ; m u lt ip le n m sc s 2 c m k er at o ti c n o d u le — — l o ca l ex ci si o n ; d ie d o f m et as ta ti c m el an o m a (u n k n o w n p ri m ar y b u t h is to ry o f m u lt ip le p ri o r in va si ve m el an o m as ) g o es er a n d d im ai o [ 3 4 ] 8 3 m sc al p d es m o p la st ic m el an o m a p ig m en te d l es io n — — n o t p ro vi d ed c u rr en t c as e 8 0 s m f o re ar m 4 p ri o r m el an o m as ; m u lt ip le s c c s; s ev er e ac ti n ic d am ag e 8 m m b ro w n t o b lu e n o d u le w it h p in k h al o b lu ew h it e ve il ; sc al e; ir re gu la r b lu e/ b la ck d o ts ; p er ip h er al v as cu la r b lu sh a n d i rr eg u la r ta n b ro w n p ig m en ta ti o n — n o e vi d en ce o f d is ea se a ft er 3 lo ca l ex ci si o n s r c m = r efl ec ta nc e co nf oc al m ic ro sc op y; c d k n 2a = c yc lin -d ep en de nt k in as e in hi bi to r 2a ; n m sc = n on -m el an om a sk in c an ce r sc c = s qu am ou s ce ll ca rc in om a review | dermatol pract concept 2015;5(1):4 29 cases, respectively [8]. in our case, the dermatoscopic features observed correlated well with histopathologic findings. the blue-white veil and blue-black dots are due to melanin and aggregates of pigmented neoplastic cells within the dermal nodule. the irregular tan-brown color at the periphery of the lesion corresponds to lentiginous proliferation of in-situ neoplastic melanocytes along the dermal-epidermal junction. colonization of bcc by mis raises important etiologic, prognostic, and therapeutic questions. currently, the mechanism of colonization is not well elucidated. we suggest an “interaction theory” [2] may be a contributing factor for the colonization of bcc by mis. we believe that increased secretion of cytokines and growth factors from the bcc may create a favorable environment for the unrestrained proliferation of melanoma cells [2]. furthermore, it is plausible that a bcc may be populated by melanoma due to poor physical cohesion of bcc cells, allowing melanoma cells to proceed without mechanical resistance. with regards to prognosis, the biologic significance of the breslow depth of melanoma cells colonizing, but restricted within a bcc tumor island remains unclear. burkhalter and white originally suggested that the bcc simply acts as a conduit for the extension of neoplastic melanocytes, similar to that seen when mis extends along adnexa, and therefore does not represent true invasion [35]. we agree with previous authors who have similarly stated that these lesions are unlikely true invasive melanomas with metastatic potential [32-36]. nonetheless, the following two cases highlight the caution that should be exercised before issuing a diagnosis of bcc colonization by mis. belisle et al report a case of an 82-year old woman where the initial biopsy of a papule on the nose demonstrated lentigo maligna with permeation of bcc nests by melanoma cells [21]. no atypical melanocytes were detected in the dermis outside the bcc epithelium or between collagen bundles. a subsequent re-excision, however, demonstrated true dermal melanoma invasion beyond the limits of the bcc, suggesting invasion of melanoma into the dermis from the overlying epidermis. in a similar case, taibjee et al report the presentation of a bcc with an overlying lentigo maligna on the nose of a 78-year old man [29]. atypical melanocytes, both as single cells and clusters, were additionally present in basaloid islands but also throughout the surrounding bcc dermal stroma. it remains unclear in this later case whether melanoma cells entered the dermis through invasion of the epidermis or via the epithelia of the basaloid tumor islands. in summary, we report a case that may best be interpreted as a melanoma in situ colonizing a bcc. we are of the opinion that these tumors developed independent of each other and the bcc served as a conduit for the extension of melanoma cells. the alternate hypothesis of a biphenotypic tumor with a common precursor diverging towards both epithelial and melanocytic differentiation seems less plausible. given the absence of adequate prospective data on outcomes, we suggest that these neoplasms should be treated on an individual case-by-case basis, taking into account the adequacy of the original biopsy, the anatomic site of the lesion, and the age and underlying comorbidities of the patient. new technologies, particularly rcm, may be useful in accurately identifying these tumors prior to skin biopsy. references 1. satter ek, metcalf j, lountzis n, et al. tumors composed of malignant epithelial and melanocytic populations: a case series and review of the literature. j cutan pathol 2009;36(2):211-19. 2. cornejo km, deng ac. malignant melanoma within squamous cell carcinoma and basal cell carcinoma: is it a combined or collision tumor?—a case report and review of the literature. am j dermatopathol 2013;35(2):226-34. 3. pierard ge, fazaa b, henry f, et al. collision of primary malignant neoplasms on the skin: the connection between malignant melanoma and basal cell carcinoma. dermatology 1997;194(4):37879. 4. martorell a, botella-estrada r, nagore e, et al. dermoscopic features of a collision tumour composed of a pigmented basal cell carcinoma and a melanoma. j eur acad dermatol venereol 2010;24(8):982-84. 5. miori l, bellosta m, del forno c, et al. pigmented bcc and lmm in a single lesion. j dermatol surg oncol 1989;15(12):1301-2. 6. sina b, samorodin c. basal cell carcinoma surrounded by lentigo maligna. cutis 1989;44(1):81-2. 7. bhawan j, mehregan ah, jung-legg y, et al. pigmented basal cell carcinoma and superficial spreading malignant melanoma: an unusual combination. j cutan pathol 1984;11(6):471-75. 8. moscarella e, rabinovitz h, oliviero mc, et al. the role of reflectance confocal microscopy as an aid in the diagnosis of collision tumors. dermatology 2013;227(2):109-17. 9. hirakawa e, miki h, kobayashi s, et al. collision tumor of cutaneous malignant melanoma and basal cell carcinoma. pathol res pract 1998;194(9):649-53. 10. king r, lyons j, meyers al, et al. primary invasive melanoma and basal cell carcinoma (collision tumor) with blue nevus-like cutaneous metastases. j cutan pathol 2007;34(8):629-33. 11. boyd as, rapini rp. cutaneous collision tumors. an analysis of 69 cases and review of the literature. am j dermatopathol 1994;16(3):253-57. 12. taira jw, flaming ja, weigand da. basal cell carcinoma and melanocytic nevus in the same lesion. cutis 1992;49(1):40-2. 13. de giorgi v, massi d, sestini s, et al. cutaneous collision tumour (melanocytic naevus, basal cell carcinoma, seborrhoeic keratosis): a clinical, dermoscopic and pathological case report. br j dermatol 2005;152(4):787-90. 14. schellander f, marks r, jones ew. basal cell hamartoma and cellular naevus: an unusual combined malformation. br j dermatol 1974;90(4):413-19. 15. zaballos p, llambrich a, puig s, et al. dermoscopy is useful for the recognition of benign-malignant compound tumours. br j dermatol 2005;153(3):653-56. 16. litak j, behroozan d, binder s. co-existing basal cell carcinoma and blue nevus in an african-american woman. j cutan pathol 2009;36(10):1114-16. 30 review | dermatol pract concept 2015;5(1):4 17. betti r, inselvini e, crosti c. blue nevi and basal cell carcinoma within a speckled lentiginous nevus. j am acad dermatol 1999;41(6):1039-41. 18. miteva m, herschthal d, ricotti c, et al. a rare case of a cutaneous squamomelanocytic tumor: revisiting the histogenesis of combined neoplasms. am j dermatopathol 2009;31(6):599-603. 19. erickson la, myers jl, mihm mc, et al. malignant basomelanocytic tumor manifesting as metastatic melanoma. am j surg pathol 2004;28(10):1393-96. 20. rodriguez j, nonaka d, kuhn e, et al. combined high-grade basal cell carcinoma and malignant melanoma of the skin (“malignant basomelanocytic tumor”): report of two cases and review of the literature. am j dermatopathol 2005;27(4):314-18. 21. belisle a, gautier ms, ghozali f, et al. a collision tumor involving basal cell carcinoma and lentigo maligna melanoma. am j dermatopathol 2005;27(4):319-21. 22. busam kj, halpern a, marghoob aa. malignant melanoma metastatic to a basal cell carcinoma simulating the pattern of a basomelanocytic tumor. am j surg pathol 2006;30(1):133-36. 23. de almeida barbosa a, jr., sales guimaraes n, de lourdes lopes m, et al. malignant melanoma and basal cell carcinoma in a combined tumour. br j dermatol 1999;140(2):360-61. 24. cowley gp, gallimore a. malignant melanoma metastasising to a basal cell carcinoma. histopathology 1996;29(5):469-70. 25. braun-falco m. combined malignant melanoma and basal cell carcinoma tumor of the intermingled type. j cutan pathol 2007;34(9):731-35. 26. coskey rj, mehregan ah. the association of basal cell carcinomas with other tumors. j dermatol surg oncol 1987;13(5):553-55. 27. hanson im, banerjee ss, menasce lp, et al. a study of eleven cutaneous malignant melanomas in adults with small-cell morphology: emphasis on diagnostic difficulties and unusual features. histopathology 2002;40(2):187-95. 28. charlton re. a melanomatous carcinoma. a case report and commentary. am j dermatopathol 1984;6 suppl:221-9. 29. taibjee sm, gee bc, sanders ds, et al. lentigo maligna involving the tumour nests and stroma of a nodular basal cell carcinoma. br j dermatol 2007;157(1):184-88. 30. papa g, grandi g, pascone m. collision tumor of malignant skin cancers: a case of melanoma in basal cell carcinoma. pathol res pract 2006;202(9):691-94. 31. rosen lb, williams wd, benson j, et al. a malignant neoplasm with features of both squamous cell carcinoma and malignant melanoma. am j dermatopathol 1984;6 suppl:213-9. 32. salerni g, lovatto l, carrera c, et al. correlation among dermoscopy, confocal reflectance microscopy, and histologic features of melanoma and basal cell carcinoma collision tumor. dermatol surg 2011;37(2):275-79. 33. smith lj, husain ea. colonisation of basal cell carcinoma and actinic keratosis by malignant melanoma in situ in a patient with xeroderma pigmentosum variant. clin pract 2012;2(2):e47. 34. goeser m, dimaio dj. a colonization of basal cell carcinoma by malignant melanoma in situ resembling a malignant basomelanocytic tumor. am j dermatopathol 2014;36(11):e179-82. doi:10.1097/dad.0000000000000047 35. burkhalter a, white wl. malignant melanoma in situ colonizing basal cell carcinoma. a simulator of invasive melanoma. am j dermatopathol 1997;19(3):303-7. 36. wang h, benda pm, piepkorn mw. parasitism of basal cell carcinoma by lentigo maligna melanoma. j am acad dermatol 2003;48(5 suppl):s92-4. 37. florell sr, zone jj, gerwels jw. basal cell carcinomas are populated by melanocytes and langerhans [correction of langerhan’s] cells. am j dermatopathol 2001;23(1):24-8. 38. satter ek. pigmented squamous cell carcinoma. am j dermatopathol 2007;29(5):486-89. 39. schubert b, rudolph p. basal cell carcinoma: a natural milieu for melanocytes? am j dermatopathol 2001;23(6):558-60. 40. menezes n, rita g, ines l, et al. letter: collision tumor: importance of the new auxiliary tools for diagnosis (an illustrative case report). dermatol online j 2011;17(7):12. 41. fernandez-canedo i, blazquez n, de troya m, et al. [collision tumor detected by dermatoscopy]. actas dermosifiliogr 2009;100(7):617-9. dermatology: practical and conceptual letter | dermatol pract concept 2018;8(4):8 295 dermatology practical & conceptual www.derm101.com introduction skin tags are benign tumors and are very common in the general population. skin friction can cause skin rupture and can represent an access for pathogens such as hpv. this mechanism could explain a more frequent localization of skin tags in anatomical sites such as the neck or armpits. mechanical friction and possible presence of hpv dna were suggested as significant cofactors in the pathogenesis of soft fibromas [1]. dianzani et  al [1] highlighted the presence of hpv type 6 and 11 dna in 88% of the 49 soft fibromas. other studies reported a positive hpv dna in 71.4% of biopsies from soft fibromas, whereas hpv detection rate was 13.3% in normal skin samples. thereafter, al-shaiji and al-buainian [3] reported that 30 individuals with soft fibromas showed positivity for hpv 6 and 11 dna in 77% of cases. other studies reported that 48.6% of 37 skin fibrous specimens were positive for hpv 6 and 11 dna but they did not report any relationship between hpv and soft fibromas of patients. these conflicting reports might reflect differences in material source, sample size, geographical distribution, and methods sensitivity. thus, the possible association between fibromas and hpv was revised in the present work in the light of new experimental procedures [2]. case presentation twenty patients were enrolled at the dermatological clinic of the “campus biomedico” in rome. the study was approved by institutional review board and all patients gave informed consent to participate in this study. anamnestic and clinicalhistological data, as well as information about risk factors such as a smoking habit and body mass index (bmi), were collected in a specially designed database and are illustrated in table 1. the results revealed detection of cutaneous hpv and mucosal hpv in all 20 of the tested subjects. excisional biopsies were performed in all patients with skin tags, completely removing the lesion. samples were stored at +4°c in thinprep(r) and utilized for dna and rna extraction by commercial kits [2]. human papillomavirus in skin tags: a case series caterina dianzani1, francesca paolini2, claudio conforti1,3, maria silvestre1, francesca flagiello1, aldo venuti2 1 department of plastic, reconstructive and cosmetic surgery, campus bio-medico university hospital, rome, italy 2 hpv unit, uosd tumor immunology and immunotherapy, regina elena national cancer institute, rome, italy 3 dermatology clinic, hospital maggiore, piazza dell’ospitale 1, trieste, italy key words: human papillomavirus, skin tags, fibromas, virology, hpv, skin cancer citation: dianzani c, paolini f, conforti c, silvestre m, flagiello f, venuti a. human papillomavirus in skin tags: a case series. dermatol pract concept. 2018;8(4):295-296. doi: https://doi.org/10.5826/dpc.0804a08 received: march 8, 2018; accepted: april 6, 2018; published: october 31, 2018 copyright: ©2018 dianzani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, hospital maggiore, piazza dell’ospitale 1, trieste, italy. email: dermatologiaconforti@gmail.com 296 letter | dermatol pract concept 2018;8(4):8 references 1. dianzani c, calvieri s, pierangeli a, imperi m, bucci m, degener a. m the detection of human papillomavirus dna in skin tags. br j dermatol. 1998;138:(4):649-651. 2. dianzani c, paolini f, conforti c, riva e, beninati e, venuti a. human papillomavirus expression in immunocompetent patients with actinic keratosis: a case series. j am acad dermatol. 2017;77(4):770-772. 3. al shajii a, al buainain h. skin tag in relation with human papilloma virus. the gulf journal of dermatology. 2005;12:31-33. the presence of hpv dna was detected by the polymerase chain reaction (pcr) and rolling circle amplification (rca). nested pcr with cp65/cp70 outer-cp66/cp69 inner, and my09/my11 outer-gp5+/gp6+inner primers was performed for the detection of cutaneous hpv and mucosal hpv, respectively. amplified products were subjected to direct sequencing in an automated apparatus. same primers were utilized for reverse-transcriptase and real-time pcr on extracted rna. these techniques are standardized procedures that were already utilized in a previous work [2]. hpv dna analyses showed presence of hpv in 50% of patients. the hpv genotype distribution is showed in figure 1. all hpvs were episomal, as indicated by rca, whereas hpv rna transcripts were undetectable, at least with the sensitivity of the test. conclusion data from our study confirms the presence of hpv dna in skin tags, suggesting the possible role of these viruses in their development. on the other hand, the lack of viral transcripts could indicate a latent infection by hpv. furthermore, our data have highlighted the presence of high risk hpvs (types 18 and 16). given that we examined only 20 patients, we can only hypothesize that skin tags may represent a reservoir of carcinogenic hpvs. table 1. clinical and anamnestic data of patients patient sex age (years) anatomical site mucosal hpv cutaneous hpv 1 m 77 back 2 f 72 back 3 f 66 right hip 4 f 77 left ear 18 5 f 89 neck 6 f 43 armpit 18 7 f 60 back 6 8 m 64 back 18 9 f 65 neck 10 m 40 neck 6 11 m 71 armpit 93 12 m 57 armpit 5 13 f 59 armpit 14 f 41 armpit 15 f 55 armpit 16 16 f 45 neck 17 m 20 back 18 f 58 back 16 19 f 45 armpit 20 m 24 neck 174 figure 1. hpv genotypes. percentages refer to the total number of hpvs plus samples. [copyright: ©2018 dianzani et al.] dermatology: practical and conceptual letter | dermatol pract concept 2019;9(2):16 157 dermatology practical & conceptual introduction we present an atypical case of keratoacanthoma centrifugum marginatum (kcm) that spontaneously regressed without treatment. case presentation a caucasian man in his 70s presented with a 3-month history of a large asymptomatic lesion of his left arm. he reported that it initially started as a pinpoint lesion but rapidly grew and stabilized. it was initially biopsied by his primary care physician and read by an outside facility pathologist as a moderately differentiated squamous cell carcinoma (scc). physical examination revealed a 6 × 6 cm, nontender, malodorous plaque with a heaped-up friable tissue rim with clinically normal skin in the center (figure 1). lymph node examination was unremarkable. fungal culture was negative. a punch biopsy for histopathological analysis was performed, showing epithelial fragments and fibrosis, consistent with the diagnosis of a central portion of a kcm (figure 2). however, the patient subsequently noticed flattening and reduction in size of the lesion. three months after initial presentation, physical examination showed a 4 × 5 cm, nontender, nonmalodorous thin plaque with a minor amount of friable tissue and clinically normal skin in the center (figure 3). it was biopsied in the center and on the periphery to confirm regression, which showed a keratin-filled cystic epithelial invagination and scar, consistent with a regressing kcm (figure 4). because of its spontaneous regression, the patient was closely monitored for complete resolution of the lesion. physical examination 6 months after initial presentation showed a 4 × 5 cm, nontender, thin pink plaque without friable tissue (figure 5). discussion keratoacanthomas (kas) are epidermal tumors characterized by rapidly growing, firm, symmetric, dome-shaped nodules with central keratin-filled craters that tend to regress spontaneously [1]. approximately 98% of kas are of the classic, solitary type [2]. rare variants of solitary ka include subungual ka, giant ka, and kcm. kcm is a very rare variant of ka characterized by progressive peripheral growth with concomitant central healing and atrophy [3]. it was first described by miedzinski and kozakiewicz in 1962 [4], and the term keratoacanthoma centrifugum marginatum was coined by belisario in 1965 [5]. the etiology of kcm is mulspontaneous regression of a keratoacanthoma centrifugum marginatum yesul kim1, klaus f. helm2, elizabeth m. billingsley2, charlene lam2 1 pennsylvania state college of medicine, hershey, pa, usa 2 department of dermatology, penn state hershey medical center, hershey, pa, usa key words: keratoacanthoma, squamous cell carcinoma, keratoacanthoma centrifugum marginatum, treatment, management citation: kim y, helm kf, billingsley em, lam c. spontaneous regression of a keratoacanthoma centrifugum marginatum. dermatol pract concept. 2019;9(2):157-159. doi: https://doi.org/10.5826/dpc.0902a16 accepted: november 26, 2018; published: april 30, 2019 copyright: ©2019 kim et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: charlene lam, md, mph, 100 campus drive, entrance 3, suite 100 hershey, pa 17033 usa. email: clam@ pennstatehealth.psu.edu 158 letter | dermatol pract concept 2019;9(2):16 tifactorial, including chronic uv light exposure, smoking, and exposure to chemical carcinogens [2]. histologically, kcm is similar to ka, with a central keratin-filled crater, overhanging lips of epithelium, sharp delineation between tumor nests and stroma, and lack of anaplasia and stromal desmoplasia [6]. kcms are locally aggressive tumors due to their progressive peripheral expansion. although they may be locally disfiguring, they are generally benign, with no reported cases of metastasis. kcm is often confused with scc. perineural and periadnexal extension may be seen in both entities, but kcm rarely extends beyond the sweat glands [3]. furthermore, pseudoepitheliomatous hyperplasia and hypergranulosis of the hair follicles occur in the central portion of early kas but only at the periphery of sccs [3]. conclusions kcms, in contrast to the classic solitary ka, do not tend to spontaneously regress [3]. however, we present a case figure 1. initial clinical presentation. [copyright: ©2019 kim et al.] figure 3. follow-up clinical presentation 3 months after initial visit. [copyright: ©2019 kim et al.] figure 5. follow-up clinical presentation 6 months after initial visit. [copyright: ©2019 kim et al.] of kcm that spontaneously regressed without intervention and serial biopsies to confirm complete regression. typically, surgical excision is the preferred therapy for kcm [3]. however, owing to the large size of the lesion in kcm, surfigure 4. histopathological examination of the lesion biopsied in the center and on the periphery to confirm regression. it showed keratin-filled cystic epithelial invaginations and scar, consistent with regressing kcm. hematoxylin and eosin, ×2 (a), ×20 (b). [copyright: ©2019 kim et al.] a b figure 2. histopathological examination of the initial biopsy done by the primary care physician and read at an outside facility was interpreted as a moderately differentiated scc. hematoxylin and eosin, ×2 (a), ×10 (b), ×20 (c). [copyright: ©2019 kim et al.] a b c letter | dermatol pract concept 2019;9(2):16 159 2. attili s, attili vr. keratoacanthoma centrifugum marginatum arising in vitiligo: a case report. dermatol online j. 2006;12(2):18. 3. georgescu t, oproiu am, radasan mg, et al. keratoacanthoma centrifugum marginatum: an unusual clinical and histopathological diagnostic pitfall. rom j morphol embryol. 2017;58(2):561-555. 4. miedzinski f, kozakiewicz j. das keratoakanthoma centrifugum— eine besondere varietät des keratoakanthoms [keratoacanthoma centrifugum—a special variety of keratoacanthoma]. hautarzt. 1962;13:348-352. 5. belisario jc. brief review of keratoacanthomas and description of keratoacanthoma centrifugum marginatum, another variety of keratoacanthoma. aust j dermatol. 1965;8(2):65-72. 6. v’ickova-laskoska mt, laskoski ds. keratoacanthoma centrifugum marginatum: a rare atypical variant of keratoacanthoma. clin exp dermatol. 2008;33(3):259-261. gical excision may result in increased morbidity. therefore, other modalities of therapies have been used, including oral retinoids, topical 5-fluorouracil, intralesional methotrexate, interferon alfa or bleomycin, cryotherapy, and mohs micrographic surgery [3]. in conclusion, although kcms do not typically spontaneously regress, this case of kcm spontaneously regressed without treatment. sccs can be similar in clinical appearance with dangerous consequences in cases with no treatment; therefore, close monitoring and serial biopsies are paramount to diagnosis and clinical decision-making in kcms. references 1. cerroni l, kerl h. keratoacanthoma. in: wolff k, goldsmith la, katz si, et al, eds. fitzpatrick’s dermatology in general medicine. 7th ed. new york: mcgraw hill; 2008:1049-1053. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):4 17 dermatology practical & conceptual introduction cutaneous pseudolymphoma is a group of skin disorders with aggravated immunological reaction to known/unknown stimulus [1]. it is a rare complication characterized by inflammatory reaction to tattoo dyes and clinically presents as an erythematous or violaceous pruritic nodule or collection of small nodules in the vicinity of or within the culprit tattoo [1]. phenotypically, it is a tor b-cell infiltration and takes a prolonged course to develop, typically several months to years after tattooing [2]. the histopathology of pseudolymphoma often mimics lymphoma. the leading histologic finding is mixed dermal infiltrate of lymphocytes, plasma cells, and eosinophils. immunohistochemical staining provides a clue showing a polyclonal lymphocyte population (usually found in benign, reactive processes) in contrast to monoclonality found in lymphomas [2]. although it is a benign skin condition, there have been reports of a malignant transformation due to persistent antigenic stimulation, so careful follow-up is mandatory [2]. case presentation we report the case of a 35-year-old woman presenting with multiple small, firm, erythematous to violaceous nodules at the periphery of the flower-shaped, multicolored tattoo at her left chest (figures 1 and 2). the tattoo was made 14 months before skin changes occurred. based on clinical features, the usual complications of tattoo were suspected, such as keloid, sarcoid granuloma, and foreign body granuloma. dermoscopy revealed a nonspecific homogenous violaceous pattern, with nonsharp border at the periphery. few lesions showed follicular accentuation (follicular whiteyellow halo). lesions were negative for yellow-orange background typical of the diagnosis of granulomatous skin disorders, allowing us to exclude them from differential diagnosis. lesions had a violet pink color, but without criteria for vascular lesions (figures 3-6). differential diagnosis also included lymphoma and cutaneous metastases; therefore, an excision of one nodule was done. histology showed thin epidermis with orthokeratosis, dermoscopy of a tattoo pseudolymphoma mateja kendel1, ruzica jurakic toncic2, mirna bradamante2, ivana ilic3, davorin loncaric2, jaka rados2, daniela ledic drvar2 1 department of dermatology and venereology, county hospital cakovec, croatia 2 university department of dermatology and venerology, university hospital centre zagreb, university of zagreb, school of medicine, zagreb, croatia 3 university hospital centre zagreb, department of pathology and cytology, zagreb, croatia key words: pseudolymphoma, tattoo, dermoscopy citation: kendel m, jurakic toncic r, bradamante m, ilic i, loncaric d, rados j, ledic drvar d. dermoscopy of a tattoo pseudolymphoma. dermatol pract concept. 2019;9(1):17-19. doi: https://doi.org/10.5826/dpc.0901a04 published: january 31, 2019 copyright: ©2019 kendel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, university department of dermatology and venerology, university hospital centre zagreb, university of zagreb, school of medicine, salata 4 10000, zagreb, croatia. email: rjtoncic@gmail.com 18 letter | dermatol pract concept 2019;9(1):4 few scattered cd20+ b cells. the plasma cell population showed a polytypic pattern of immunoglobulin light-chains. the histological architectural pattern, lack of atypia, and immunohistochemistry suggested the diagnosis of t-cell pseudolymphoma (figures 7 and 8). overlying a dense dermal infiltrate of lymphocytes of small and medium size, without nuclear atypia. in addition to lymphocytes, the mixed infiltrate also contained histiocytes and exogenous red pigment. immunohistochemistry confirmed the infiltrate mostly of cd3+ t lymphocytes with figure 1. clinical presentation of a tattoo pseudolymphoma (image taken with canon power shot sx520hs). [copyright: ©2019 kendel et al.] figure 3. dermoscopic image of a tattoo pseudolymphoma (dermlite photo nikon aw1). [copyright: ©2019 kendel et al.] figure 5. dermoscopic image of a tattoo pseudolymphoma (dermlite photo nikon aw1). [copyright: ©2019 kendel et al.] figure 2. clinical presentation of a tattoo pseudolymphoma (image taken with canon power shot sx520hs). [copyright: ©2019 kendel et al.] figure 4. dermoscopic image of a tattoo pseudolymphoma (dermlite photo nikon aw1). [copyright: ©2019 kendel et al.] figure 6. dermoscopic image of a tattoo pseudolymphoma (dermlite photo nikon aw1). [copyright: ©2019 kendel et al.] letter | dermatol pract concept 2019;9(1):4 19 references 1. kluger n, vermeulen c, moguelet p, et al. cutaneous lymphoid hyperplasia (pseudolymphoma) in tattoos: a case series of seven patients. j eur acad dermatol venereol. 2010;24(2):208–213. 2. bergman r. pseudolymphoma and cutaneous lymphoma: facts and controversies. clin dermatol. 2010;28(5):568-574. conclusions tattoo pseudolymphoma is considered as a rare benign disease and can be treated with topical/intralesional corticosteroids, surgical excision, or laser treatment [2]. because the clavicular region is prone to the development of keloids, we chose close follow-up. keeping in mind the popularity of tattoos, we can expect more complications related to them, one of which is certainly pseudolymphoma development. figure 7. histological findings in a tattoo pseudolymphoma. [copyright: ©2019 kendel et al.] figure 8. immunohistochemical analysis of a tattoo pseudolymphoma. [copyright: ©2019 kendel et al.] dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2013;4(3):1 1 – f – fascicles: a collection fusiform of oval or spindle-shaped cells, such as that which occurs in some “spitz’s nevi,” in virtually all reed’s nevi, and in some melanomas. also these may be found in the interweaving storiform pattern of kaposi’s sarcoma. fenestrated: refers to a window-like pattern, the panes being formed of connective tissue (i.e., fibrous and sometimes mucinous), and the struts by cords and columns of epithelium. in cutaneous pathology; this pattern is observed most commonly in fibrofolliculoma and in fibroepithelial trichoblastic carcinoma. festooning: refers to the undulating pattern of the dermal papillae that are seen beneath subepidermal blisters of diseases like bullous pemphigoid and that resemble the folds of a curtain. fetal: designates a period intra-uterine development that begins when the product of conception reaches a crown-rump length of 30 mm, usually by 55 or 56 days after fertilization, and ends at the moment of birth. the product of conception during this period is called a fetus. the period before fetal is embryonic, and the product of conception during that earlier period is termed an embryo. formation of tissues and development of their functions occur mostly during the fetal period. fetus: refers to the developing human or other animal, during the period in utero that extends from the end of the embryonic period, at the beginning of ninth week, to term. many systems that began to develop in the embryonic period continue to advance during the fetal one. the rates of growth and gain in weight of a fetus are phenomenal. (see fetal) fiber: a slender, elongated structure like that of a thread. by conventional microscopy, collagen is organized into bundles, whereas elastin is arranged in fibers. by electron microscopy, collagen is seen to be composed of fibers. fibrillar: manifesting a condition like fibrils, i.e., delicate slender stands of connective tissue, as do the collagen bundles in a neurofibroma. fibrin: is a filamentous protein derived from fibrinogen by the action of thrombin during coagulation of the blood. it is seen in histologic sections stained by hematoxylin and eosin as fibrillary eosinophilic material. fibrocyte: refers to a cell that produces fibers of fibrous and elastic tissue and ground substance of nonfibrous connective tissue. it is derived from mesenchyme and can differentiate toward other mesenchymal cells such as those that manufacture bone, cartilage, and muscle. in normal skin, a fibrocyte is characterized histologically by an oval nucleus and scant cytoplasm. fibrocytes are responsible not only for synthesis of connective tissue proteins but for their repair and degradation. a single fibrocyte is able to synthesize, simultaneously, more than one type of collagen and elastin. fibrodermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 5 bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 5. dermatol pract conc. 2014;4(3):1. http://dx.doi.org/10.5826/dpc.0403a01 copyright: ©2014 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@aol.com 2 review | dermatol pract concept 2014;4(3):1 cytes are important constituents of long-standing inflammatory conditions such as dermatofibromas, hamartomas such as fibrous papules, benign neoplasms such as infantile digital fibromas, and malignant neoplasms such as malignant fibrous histiocytomas. strictly speaking, the term “fibroblast” refers to the stage of a mesenchymal cell when it is highly active and capable of dividing, in contrast to “fibrocyte,” which denotes the same cell at a later stage when, although fully functional, it is incapable of dividing. for practical purposes, in the realms of cutaneous histology and pathology, the designation fibrocyte is preferable to fibroblast because it is in synchrony with other names for cells in normal skin and in tissues beneath it, such as keratocyte, melanocyte, histocyte, adipocyte, and chondrocyte. no other cell in the skin is given the suffix blast (yet, at one stage, each of the types is dividing actively), and there is no compelling reason why cells that make fibers, i.e., fibrocytes, should be named differently from the others. last, when viewed through a conventional microscope, it is not always possible on the basis of morphologic attributes to determine the stage of activity or the capability for division of the particular mesenchymal cell names “fibroblast” or “fibrocyte.” fibroepithelial units: are a combination of elements epithelial and fibrous that form a complex discrete, such combinations being separated from one another by clefts encircling, the pattern itself being indicative of benignancy. an example stereotypical of fibroepithelial units throughout a proliferation is found in trichofolliculoma, but also in trichoblastoma. fibrosis: literally, means a condition of fibers and, figuratively, as it is used in surgical pathology, a condition of abnormal fibrous tissue that early in its sequence chronological tends to be accompanied by an increase in number of fibrocytes, those cells producing altered bundles of collagen and often an increase in the amount of ground substance. later in its “life,” fibrosis may take the form of sclerosis in which fibrocytes are decreased in number and collagen bundles no longer are discernible as discrete units, a condition termed misleadingly “homogenization of collagen.” fibrosis is a consequence of any process pathologic that causes reduction in the amount of parenchyma and the framework of it, as occurs in acute inflammatory processes such as those that follow electrodessication and curettage, longstanding inflammatory processes such as caseous tuberculosis and gummatous syphilis and proliferations such as nodular trichoblastic (basal cell) carcinoma in which there may be extensive necrosis en masse of cells constituent. in general, the quantity of fibrosis is proportional to the extent of loss of tissue. fibroplasia is a synonym for fibrosis. when fibroplasia occurs in response to a proliferation benign or malignant, the phenomenon is known as “desmoplasia.” as noted, fibrosis/fibroplasia may be present in the late stages of certain inflammatory skin diseases and also proliferative ones. in addition, it may come into being in other pathologic processes such as the devolution of a verrucae vulgaris (a proliferation of epidermal keratocytes that fulfills the classic definition of “hyperplasia”) located on a palm or sole, the residuum of that warty lesion being a kind of fibrotic papule; in a clark’s nevus (a “benign neoplasm” of abnormal melanocytes) in which “lamellar”/ “concentric” fibroplasia tends to develop immediately beneath the proliferation of melanocytes situated at the dermoepidermal junction of thin, elongated rete ridges; in certain examples of an intradermal spitz’s nevus (a benign neoplasm of abnormal melanocytes), they being marked by striking desmoplasia; in melanoma (a malignant neoplasm of abnormal melanocytes) that also may be characterized episodically by extensive desmoplasia, and in some carcinomas metastatic to skin in which desmoplasia may be rife. fibrous septa: are struts formed of bundles of collagen and fibrocytes that separate compartments, such as lobules of adipose tissue, from one another. in sections of normal subcutaneous tissue, fibrous septa are thin and outline rectangles of fat lobules. fibrous tissue: refers to a type of connective tissue that consists of bundles of collagen manufactured by fibrocytes. fibrocytes produce both the fibrillar and nonfibrillar components of fibrous tissue, such as mucosubstances. fibrous tracts: linear bands of fibrous tissue that form normally behind hair follicles that have retracted in telogen. figurate: the term “figurate” refers to particular shapes of lesions clinically (those often being present together in the same patient at the same time), namely, arciform, annular, and polycyclic. figurate erythemas: the diseases designated “socalled” figurate erythemas are not related to one another; the diseases so designated have in common only the presence, clinically of lesions with arcuate, annular, and polycyclic shape. the “figurate erythemas” as usually conceived consist of erythema annulare centrifugum (darier)-deep type, deep gyrate erythema, deep figurate erythema, palpable migratory and arciform erythema, erythema figuratum, erythema perstans, erythema annulare centrifugum, and many others. these are nothing more than patterns that may be formed by infiltrates of various condition, all of which may sometimes present clinically with annular, arcuate, gyrate, or figurate lesions review | dermatol pract concept 2014;4(3):1 3 and at other times not. therefore figurate erythemas as such are not a distinctive clinicopathologic entity and the term need not be used. (it should be noted however that erythema annulare centrifugum is a distinctive disease, which is totally unrelated to the non-diagnostic designation erythema annulare centrifugum, deep type.) in addition, the group should include other equally dissimilar conditions such as subacute cutaneous lupus erythematous, erythema a marginatum, the urticarial stage of bullous pemphigoid, some plaques of mycosis fungoides, and one expression of psoriasis, none of those being found as a rule in classifications of the figurate erythemas in standard textbooks; all of the “figurate erythemas” are different from one another histopathologically because they are different from one another fundamentally and, that being the case, the notion of a category of “figurate erythemas” is as unuseful as that of “papulosquamous disease.” (that is, not very useful.) further more, in any patient who presents with annular or figurate macules, papules, or plaques that show superficial and deep lymphocytic infiltrates, additional examinations and investigations need to be performed in order to diagnosis lupus tumidus, erythema migrans of borreliosis, herpetic infection, polymorphous light eruption, or even leukemia cutis, with specificity. they include clinicopathologic correlation, serology for antinuclear antibodies, pcr for herpes viruses and/or borrelia on paraffin embedded biopsy specimens, and lymphocyte clonality investigations. fish: fluorescence in situ hybridization. based upon genomic sites of interest identified via comparative genomic hybridization (cgh), commercially available probe sets have been developed that enable screening of paraffin-embedded tissue for chromosomal copy number changes that are closely associated with the diagnosis of melanoma. fissure: a linear defect that extends from the surface of the skin into the dermis. fissures tend to occur over flexural creases, especially of palms and soles affected severely by hyperkeratotic conditions such as psoriasis, pityriasis rubra pilaris, and chronic allergic contact dermatitis to ingredients of cement, as occurs in laborers such as hod carriers. the intergluteal cleft is another site favored for formation of a fissure in a lesion of psoriasis. flame figures: stellate shaped collections made up of granules of eosinophils that cluster around one or more bundles of collagen. floret cell: refers to a type of multinucleated giant cell in which fibrocytic or adipocytic hyperchromatic nuclei assume arrangements that resemble petals of a flower. foam cells: are lipid-laden macrophages in which the pale cytoplasm contains numerous vacuoles from which lipids had been extracted during fixation in formalin and subsequent processing in alcohols of different grades. the lipid nature of the droplets can be demonstrated in frozen sections by fat stains such as scarlet red, oil red 0, or sudan black. foam cells are not specific for a single pathologic process, but predominate in lipidoses and xanthomatoses, a broad category of diseases characterized by deposits of excessive amounts of lipids in various organs of the body, including the skin. any resolving inflammatory process associated with degradation of red blood cells consequent to extravasations of numerous erythrocytes, as well as inflammatory processes that involve adipose tissue with necrosis of adipocytes, i.e., lupus erythematosus profundus, may be accompanied by foam cells. (see clear cells) focal acantholytic dyskeratosis: a focus that consists of a suprabasal cleft above which there are acantholytic, dyskeratotic cells in the spinous and granular layers and, above them, a column of parakeratosis, some of the cells of which may have become acantholytic. this is a pattern and not a specific disease entity. there are several types. (see acantholytic dyskeratosis) follicle: means a very small sac of which there are many types in the body, i.e., hair follicles, thyroid follicles, lymphoid follicles, and ovarian follicles. in embryology and histology of the skin, and in the realms of cutaneous proliferations of all kinds, the word “follicle” pertains to “hair follicle” alone. the follicle of a hair includes matrical epithelium of the bulb that matures to become the hair itself, the inner sheath that envelops the hair, and the outer sheath that forms a sleeve around the inner sheath. in short, a follicle in anagen consists of two segments: a transitory lower segment of bulb and stem, and a permanent upper segment, the isthmus. the infundibulum is epidermal, not follicular. every follicle, whether terminal or vellus, is surrounded by connective tissue, i.e., perifollicular sheath. follicular bulb: incorrectly termed hair bulb, refers to the pyriform lower end of a follicle whose boundaries are the base of the follicle below and the high-arched border known as adamson’s fringe above. that fringe also marks the lower boundary of the stem. the designation bulb derives from the morphologic similarity of a follicular bulb to a bulb of a tulip or an onion. a bulb consists mostly of matrical and supramatrical cells that mature to become cells of inner sheath and hair shaft. signs of inner sheath differentiation are seen in the bulb in the form of trichohyalin granules and blue-gray corneocytes, and of impending hair in the form of a keratogenous zone. in addition to these constituents, strikingly dendritic melanocytes are disposed as solitary units in crescentic array at the base of a bulb above a follicular papilla. the melanin that they produce imparts color to hair. 4 review | dermatol pract concept 2014;4(3):1 follicular germ: imprecisely termed hair germ, is a primordium not only of a follicle, but of an entire folliculosebaceous-apocrine unit. it is a crescentic collection of germinative cells whose nuclei are crowded and are situated at the base of an embryonic epidermis, below which are equally crowded nuclei of mesenchymal cells of an embryonic follicular papilla. the basal cells of a follicular germ are columnar and are aligned in a palisade. follicular germinative cells consist mostly of nucleus, their cytoplasm being scant. some nuclei are in mitosis. folliculitis/perifolliculitis: an inflammatory disease in which the infiltrate of inflammatory cells is present either in or around follicular epithelium, that is, epithelium of the isthmus, stem, and bulb. (see infundibulitis/periinfundibulitis) folliculo-sebaceous-apocrine unit: refers to the entire structures that result from maturation and differentiation of a follicular germ in an embryo, to wit, a hair follicle in continuity with its adnexal sebaceous and apocrine units. as a follicular germ elongates and then differentiates, a hair follicle comes into being, and concurrent with it develop three bulges, the upper a putative apocrine gland and duct, the middle a future sebaceous gland and duct, and the lowest a place for attachment of smooth muscles of hair erection. folliculotropism: adj. folliculotropic. a biological phenomenon that indicates growth or turning movement of a cell or a collection of cells toward a hair follicle. in a strictly morphologic sense, it is not definable since movement cannot be seen in the static tissues of a slide. the following terms would be better: intrafollicular—present within a hair follicle and perifollicular—present around a hair follicle. folliculotropism is not definable in medical dictionaries, or in textbooks of dermatopathology. however, it is constantly used in articles, especially in those about the histopathology of mycosis fungoides. folliculotropism and folliculotropic are employed, in general, for the mycosis fungoides in which “neoplastic” lymphocytes are mostly found in hair follicles. in fact, these criteria have led to two subtypes of mycosis fungoides, namely, the socalled folliculotropic and syringotropic. there are only occasional exceptions in the usage in reference to entities other than mycosis fungoides, but interestingly nearly all are malignant: melanoma, bowenoid carcinoma, skin metastases of other carcinomas, etc. descriptions of benign conditions with this term are extremely rare. apart from this term not being defined, there is no agreement among authors on its meaning. despite the frequency with which folliculotropism is employed in mycosis fungoides, there is no agreement on whether lymphocytes should be in hair follicles only, if they could be intraepidermal too, or whether they should be accompanied by mucin in follicles. what dermatopathologists intend to describe by the word folliculotropic is those biopsies in which the lymphocytes are placed mostly in the epithelium of the hair follicle surface and infundibular, i.e., those specimens in which cells have a clear affinity for this adnexa, but this is not exclusive of mycosis fungoides. many other diseases, much more common and benign, display cells with tendency for adnexa. any type of folliculitis, lupus erythematosus, lichen planopilaris, or fox-fordyce disease has a clear affinity for hair follicles, and neutrophilic hidradenitis or lichen striatus a tendency to affect sweat glands, to mention but some of them. the reason why none of these are described by words that finish with tropism or tropic is that dermatopathologists use these words only for malignant conditions. confronted with exactly the same morphologic finding, namely, lymphocytes in hair follicles, folliculotropism is used only after having decided already on a malignant condition, usually mycosis fungoides. when the diagnosis of a benign condition, i.e., lupus erythematosus or neutrophilic hidradenitis, is made the cell infiltrates are not termed tropic. the term seems only to apply to lymphocytes, not to eosinophils or neutrophils. (see syringotropic) fringe: describes the luminal border of a cell characterized by very fine filamentous projections. in a neoplasm, a fringelike border of luminal cells indicates apocrine differentiation. fusiform: tapering toward each end, as is the situation with certain melanocytes that are constituents of “classic” spitz’s nevi. one type of melanocyte cytopathologic is a spindle truly, its shape being like that of a stick with ends tapered because of a thin oval nucleus and scant cytoplasm. another type is fusiform, but rather than being thin, is distinguished by girth notable because of a plump oval nucleus and copious cytoplasm. in order to distinguish between those types of melanocytes in “classic” spitz’s nevi, we refer to the former as “spindle” and the latter as “fusiform,” cognizant fully of the limitations of those designations. parenthetically, nuclei of melanocytes of reed’s nevus are small and usually thin oval, and cytoplasm rich in melanin often is dendritic strikingly. – g – germ: is a term descriptive of a cluster of generative cells that in skin of an embryo gives rise to infundibular-apocrinesebaceous-follicular units and to eccrine units. those units derive from two different germs, both of which are situated at the base of surface ectoderm, the “follicular” germ being crescentic and apposed to a cluster of primitive mesenchymal cells of the future follicular papilla, and the eccrine germ review | dermatol pract concept 2014;4(3):1 5 being shaped like a nubbin and devoid of any papilla of mesenchymal cells accompanying. germinal centers: characteristic discrete round structures within lymphoid follicles, consisting of lymphocytes and macrophages that house nuclear debris of lymphocytes (tingible bodies). they occur as simulators of normal structures in inflammatory processes stimulating lymphomas and as abnormal structures in lymphomas such as giant follicular lymphoma (a malignant proliferation.) germinative cells: in a proliferation are analogues of those in a germ in an embryo that gives rise to the entire infundibular-apocrine-sebaceous-follicular unit, they being encountered in proliferations benign, i.e., trichoblastomas, and in ones malignant, i.e., trichoblastic (basal cell) carcinomas. “follicular germinative cells” is the phrase employed as an abbreviation for cells germinative of the “future infundibular-apocrine-sebaceous-follicular unit.” germ-like: means resembling the germ in an embryo of the future infundibular-apocrine-sebaceous-follicular unit as occurs in trichoblastic (basal cell) carcinoma of types various, including superficial, nodular, fibroepitheliomatous, and infundibulocystic. germ and papilla: represent an association in an embryo of a germ at first crescentic but soon elongate and a papilla contiguous with it. that duo forms a unit responsible for giving rise to an entire future infundibular-apocrinesebaceous-follicular unit. simulations of the unit appear in proliferations various, ranging from trichoepithelioma to fibroepitheliomatous trichoblastic (basal cell) carcinoma, from fibrous papule of the face to nevus sebaceous, and from panfolliculoma to adamantinoid trichoblastoma. giant melanocyte: this term denotes not only cell size, but also implies that the cell contains several nuclei. giant cells may be found in melanocytic nevi and in melanomas. giant cells in melanocytic nevi are round and contain many small nuclei in the form of a rosette when clustered centrally. less frequently the nuclei are arranged in a ring like configuration at the periphery. giant melanosome: a large, globular pigmented mass that may be seen with the conventional light microscope and is an abnormal melanosome many times larger than an ordinary melanosome. gland: denotes a single epithelial cell or a group of cells, in a tissue or organ, specialized to elaborate and discharge substances that are used elsewhere in the body (secretion) or are eliminated from it (excretion). glands that contain no excretory ducts, such as those of the adrenals and the thyroid, are referred to as endocrine glands, whereas those with excretory ducts, such as eccrine glands, apocrine glands, and sebaceous glands, are known as exocrine glands. the products of endocrine secretion enter blood or lymph directly, whereas those of exocrine secretion move directly onto body surfaces. the glands in skin are eccrine, apocrine, and sebaceous. eccrine glands are distributed over most of the body surface and promote cooling by evaporation of their secretion, i.e., sweat, which is produced by a method known as merocrine secretion. the long ducts of eccrine glands lead directly to the epidermis. apocrine glands, vestiges of pheromone-secreting glands in lower animals, are situated in certain specific regions of the body, such as perianal and axillae. the long ducts of these glands connect to the mid portion of infundibular epidermis of follicles. the appearance of the distinctive secretion of apocrine glands as viewed by conventional microscopy has been likened to “decapitation” or “pinching off” because the tops of luminal cells appear to be severed from the remainder of them. “decapitation” secretion and “pinching-off’ secretion are synonyms for apocrine secretion. sebaceous glands are found wherever there are follicles, mostly on the face, scalp, chest, and back. the glands consist of lobules composed of vacuolated cells and of ducts. the short ducts of sebaceous glands lead to the base of the infundibular epidermis. sebaceous secretion is holocrine, which means that entire contents of sebaceous cell are discharged into a sebaceous duct. glassy membrane: is a synonym for the pas (periodic acid-schiff) -positive basement membrane that surrounds the inferior segment of a hair follicle and is analogous to the basement membrane that separates epidermis from dermis. the follicular basement membrane thickens and becomes corrugated during the course of catagen. globule: refers to a small spherical shape. globules of melanin: are small, spherical masses of melanin that are larger than the granules of melanin present in melanocytes and melanophages. some term these “macroglobules” and others giant melanosomes. they are seen commonly in simple lentigines and in nevus spilus and uncommonly in a variety of other melanocytic lesions. glomeruloid: means an appearance that resembles the glomerulus of a kidney, a structure that is formed by invagination of a capillary-rich mass of mesenchyme into a sac of epithelium. in the skin, some hemangiomas of poems syndrome are glomeruloid in foci. grading of melanoma: a scale of the degrees of “aggressiveness” in the biologic behavior of neoplasms based on cellular atypia or prevalence of mitotic figures. many investigators have attempted to correlate the biologic activity of melanomas with the number of mitotic figures per unit area. the results they have reported are contradictory. 6 review | dermatol pract concept 2014;4(3):1 in practice, measurement of thickness of a melanoma with an ocular micrometer in the eyepiece of the microscope has proved to be the most reliable gauge of grade and therefore of prognosis. the above was written by maize and ackerman in 1987. now instead of grading, a staging system is used. it is the tnm system of the ajcc. however, it should be realized that prognostic “numbers” are only “statistics” and do not take into account the host that bears the “melanoma”. therefore assigning a prognosis to a patient based on a “number” in any field is a disservice to the patient. granulation tissue: highly vascular edematous connective tissue laced with a mixture of inflammatory cells. in skin, granulation tissue forms in response to trauma, such as incisions and puncture wounds, and below ulcers. granulation tissue has been described clinically as “proud flesh,” i.e., ulcerated, shiny, pink, sometimes moist tissue. the consummate example of granulation tissue in skin is seen in pyogenic granuloma at an early stage of it, that title being a misnomer because the condition is neither pyogenic nor a granuloma; it, fundamentally, is a proliferation of venules and capillaries secondary to trauma inflicted on a larger vessel, usually one situated in the deep reticular dermis or the upper part of the subcutaneous fat. granuloma: a collection of histiocytes, usually epithelioid ones. epithelioid histiocytes (so termed because of their resemblance to epithelial cells, namely, oval nuclei, readily discernable eosinophilic cytoplasm, and some tendency to seeming cohesiveness) are predominant in granulomas of tuberculoid leprosy, whereas foamy histiocytes monopolize in granulomas of lepromatous leprosy; both epithelioid histiocytes and foamy histiocytes are present together in granulomas of dimorphous leprosy. foamy histiocytes, known also as foam cells and lipophages, are nearly invariable in lobular panniculitides as a consequence of necrosis of adipocytes and are a finding, consistently, in xanthomas and xanthogranulomas. multinucleate histiocytes, as well as mononuclear ones, may be found in a granuloma, and they have been given different names depending on nuances of them cytopathologically in regard especially to where nuclei are dispersed, for example, langerhans, touton, and foreign body, none of which has either specificity or is pathognomonic for any disease. a granuloma devoid of inflammatory cells other than epithelioid histiocytes is termed sarcoidal (“naked” tubercle), and that surrounded by a dense mantle of lymphocytes, and sometimes plasma cells, is designated tuberculoid. sarcoidal granulomas are found not only in sarcoidosis, but also in foreign body responses to materials such as silica and beryllium. tuberculoid granulomas are encountered in infectious diseases besides tuberculosis, among those being tuberculoid leprosy and the recidivans manifestation of leishmaniasis, and in noninfectious diseases such as rosacea and its variant, perioral/periocular dermatitis. curiously, the granulomas of subcutaneous sarcoidosis tend to be tuberculoid in character and, episodically, granulomas of sarcoidosis restricted to the dermis may be tuberculoid. when epithelial histiocytes are aligned in the manner of stakes in a stockade, the arrangement is referred to as palisaded, as occurs in granuloma annulare, necrobiosis lipoidica, necrobiotic xanthogranuloma, and rheumatoid nodule. when histiocytes are dispersed between and among bundles of collagen, the pattern is designated interstitial, the exemplar of it being the interstitial manifestation of granuloma annulare. when an abscess is present in a collection of epithelioid histiocytes, as is common in infectious processes such as those initiated by atypical mycobacteria and deep fungi, the granuloma is known as suppurative. the term granuloma is employed clinically for smooth-surfaced, yellow-orange (“apple jelly”) papules that house epithelioid histiocytes in tuberculoid pattern, as is seen in lupus vulgaris, or in sarcoidal pattern, as is observed in sarcoidosis, and for vegetations that represent suppurative granulomas of infectious cause, as is witnessed in chromomycosis and blastomycosis. granulomatous dermatitis: an infiltrate of inflammatory cells in which histiocytes predominate (in at least one high-power field). (see granuloma) ground substance: is the finely granular intercellular material of loose connective tissue in which cells and fibers are embedded. the ground substance is composed partly of glycoproteins and mucopolysaccharides, but mainly of nonsulfated hyaluronic acid. all of the cutaneous mucinoses are diseases of ground substance, i.e., focal mucinosis, pretibial myxedema, and myxedema guttate: drop-sized and-shaped. usually applied to eruptive lesions of psoriasis (eruptive psoriasis may not be “guttate”) and to one of the several manifestations of mycosis fungoides, i.e., the one (“guttate parapsoriasis”) that is a variant of digitated dermatosis and is known also as small-plaque parapsoriasis, a flat manifestation of mycosis fungoides. – h – hair: is a thread of compactly arranged corneocytes that represents the ultimate maturation of matrical cells situated at the base of a follicular bulb. hair normally extends through an infundibular ostium and for various distances above the surface of the skin (i.e., far above the scalp of young persons and just above the margin of the eyelid). hairs generally are of two types: terminal, which are relatively broad, long, and dark; and vellus, which are thin, short, and light. review | dermatol pract concept 2014;4(3):1 7 hair disc or haarscheibe: is a type of nerve ending purported to be positioned at the dermoepidermal junction by f. pinkus in 1902. it is said to be a slow-adapting touch receptor present in mammalian skin. it is not visible, however, in sections of human skin stained by hematoxylin and eosin and viewed by conventional microscopy. no clear picture of this structure has ever been shown in any textbook of cutaneous histology, dermatology, general pathology, or dermatopathology. hamartoma: is a lesion identifiable by microscopy conventional as being characterized by an arrangement abnormal of tissues indigenous to a particular organ. the tissues in array aberrant appear to be normal at first glance, but may be abnormal slightly. the example stereotypical of hamartoma in the skin is nevus sebaceus, but conditions such as trichofolliculoma, fibrofolliculoma/ trichodiscoma, fibrous papule of the face, steatocystoma, and apocrine and eccrine nevi also are hamartomas. because a hamartoma results from an error in development embryonic, the term “hamartoma” should not be applied to proliferations cellular that begin after tissues have reached maturity structural. for example, congenital melanocytic nevi of the deep type are hamartomas, whereas acquired melanocytic nevi such as those named eponymically for spitz and reed, are not, they being neoplasms benign. the distinction just made is supported by differences clinical, histopathologic, and biologic between melanocytic nevi that are present at or shortly after birth and those that become manifest long after birth. for practical purposes the term “proliferation” has been proposed to subsume the word hamartoma. (see proliferation) hematoma: a nodule that is formed by bleeding into the lower part of the dermis, subcutaneous fat, or both regions, usually as a consequence of trauma. henle’s layer: is the outer component of the inner sheath of a follicle. in humans, it consists of only a single layer of cells, and it is the first layer of the inner sheath to display trichohyalin granules and to lose them in consequence of cornification. the layer is named for the early nineteenth century german histologist, t. henle, who was the first to describe it. heterchromasia: a difference in coloration in two or more structures or two or more parts of the same structure that under normal circumstances is alike in color, as is the case often in nuclei of a malignant neoplasm, such as melanoma, and at times in a benign neoplasm, such as “classic” spitz’s nevus. histochemical: denotes the study of particular tissues by analysis of their chemicals. histochemical reactions result in colored products that indicate particular substances. for example, naphthol asd-chloracetase esterases (leder’s stain) are used in cutaneous histopathology to localize esterases in granules of mast cells and in cells of myelogenous nature. histogenesis: refers to evolution of tissue from inception to full development. the term is used commonly by general pathologists to denote origin of proliferations, when, in actuality, the origin of most proliferations is not known. for that reason, it is advisable to name the proliferations according to the composition of their cells and/or the differentiation of those cells. we, in the spirit of classic virchowian pathology, advocate naming benign and malignant proliferations according to either; the specific type of cells of which they are composed of, and/or the specific differentiation of the cells themselves. benign and malignant epithelial proliferations, for example, may be composed of keratocytes (i.e., seborrheic keratosis and squamous cell carcinoma), and benign and malignant nonepithelial proliferations may be made up of mast cells (i.e., urticaria pigmentosa and malignant mastocytosis). benign and malignant epithelial proliferations may exhibit follicular, sebaceous, apocrine, and eccrine differentiation, and benign and malignant nonepithelial proliferations may show neural, muscular, vascular, fibrous, and adipose differentiation. most epithelial and nonepithelial proliferations seem to represent faulty attempts at recapitulation of a homologous normal structure as it developed during the course of embryogenesis. all of these attempts fail, but some are more successful than others. those neoplasms that fail totally are considered to be undifferentiated, whereas those that succeed are deemed to be welldifferentiated. by using repeatable and reliable criteria, specific, accurate diagnosis of benign and malignant epithelial and nonepithelial proliferations may be made histopathologically, except for those that are undifferentiated. there are exceptions. for example, some trichoblastomas, trichoblastic carcinomas of nodular type, and neuroendocrine carcinomas are undifferentiated, but each may be diagnosed with confidence at scanning magnification by virtue of particular characteristics. holocrine: literally means, “separating entirely” and designates a gland or a secretion made by a gland in which the cells responsible for producing it rupture and release wholesale the materials (in the case mature sebocytes they being lipids) manufactured by them. homogenization: of collagen refers to a uniform appearance of collagen as a consequence of seeming amalgamation of bundles with loss of the distinctive orthogonal pattern of them. the term is inaccurate because collagen cannot become homogenized. there can be sclerosis, as in late lesions of necrobiosis lipoidica, or packing of bundles of collagen, as in fully developed lesions of scleroderma, but not homogenization. 8 review | dermatol pract concept 2014;4(3):1 honeycomb appearance: describes a pattern checkered made up of small aggregations of epithelial cells surrounded by mucin in abundance, that combination of elements forming units distinct separated from one another by thin fibrous septa, the overall architecture resembling a honey comb built by honeybees, the example quintessential of it in pathology cutaneous being mucinous carcinoma. horn pseudocysts: whorls of delicate, laminated orthokeratotic cells that form in tunnels of infundibula, as within some seborrheic keratoses. huxley’s layer: is the middle component of an inner sheath of a follicle. it is two cells thick. trichohyalin granules appear in huxley’s layer later than in henle’s layer, and they disappear from it later, too. that loss of trichohyalin granules occurs at adamson’s fringe and is accompanied by signs of cornification. the layer was discovered by zoologist, t.h. huxley, in the mid-nineteenth century while he was still a medical student in london. hyaline: a substance that, when stained with hematoxylin and eosin and viewed by conventional microscopy, has a “glassy” homogeneous eosinophilic appearance. for almost a century; histopathologists used the term hyaline as a synonym for a substance considered by them to be specific and diagnostic of certain diseases, i.e., “toxic hyaline” for erythema clevatum diutinum. it is now appreciated that “toxic hyaline” is just fibrin. “hyaline globules” is a name given to degenerating erythrocytes lodged in lysosomes of endothelial cells in some lesions of kaposi’s sarcoma. “hyaline bodies” are necrotic keratocytes. the “hyaline” of hyalinasis cutis et mucosae (lipoid proteinosis) is largely hyaluronic acid. in short, the term hyaline is confusing because it does not convey specificity; and, for that reason, it should be avoided in favor of appellations for specific, definable substances, such as fibrin, erythrocytes, keratocytes, amyloid, and colloid. hyaline bodies: necrotic keratocytes; also termed colloid bodies, civatte bodies, and apoptotic bodies. hyperchromasia (overcoloration): i.e., an increase in intensity of staining of nuclei as is seen often in a malignant neoplasm, such as melanoma. the three characteristics of nuclei said, conventionally, to be indicative of malignancy are large size, pleomorphism, and hyperchromasia. none of the three, however, is a sign unequivocal of malignancy. “classic” spitz’s nevi, for example, often exhibit nuclei that are large and pleomorphic and, episodically, ones that are hyperchromatic. surely a lymphoma cannot be distinguished from an inflammatory disease that simulates it, i.e., lymphocytoma cutis, by virtue of hyperchromasia of lymphocytes alone; whether lymphocytes are those of an inflammatory or neoplastic process, nuclei of them are so dark blue that they verge on black, which is as dark as they can get. a trio of changes more indicative of malignancy is crowding, pleomorphism, and heterochromasia dramatic of nuclei. hypergranulosis: increased thickness of the granular zone (stratum granulosum) of an epidermis, surface and/or infundibular, or of the upper part of an eccrine (or theoretically, an apocrine) duct as a consequence of an increased number of keratocytes whose cytoplasm contains keratohyaline granules either in loci or in continuity. hypergranulosis is a finding stereotypical for lichen planus, in which the granular zone tends to assume a wedge shape as a result of accentuation of keratohyaline-containing keratocytes in infundibula and acrosyringia. hypergranulosis is a finding, consistently, in a variety of conditions as unlike as lichen simplex chronicus and bullous congenital ichthyosiform erythroderma. as a rule, hypergranulosis is coupled with a cornified layer marked by arrangement compactly of corneocytes. two exceptions to that “rule” are (1) pityriasis rubra pilaris, in which hypergranulosis is associated with both orthokeratosis and parakeratosis, and (2) plane warts, in which hypergranulosis is covered by orthokeratosis arrayed in a basket-weave pattern. hyperkeratosis: a thickened cornified layer of an epithelium, usually an epidermis (surface and infundibular), but sometimes the upper part of an eccrine duct (and, theoretically, an apocrine duct). hyperkeratosis may be classified as either orthokeratosis in which no nuclei are visible in cornified cells or parakeratosis, in which nuclei are retained overtly by cornified cells. a more precise term for orthokeratosis is orthohyperkeratosis, the number of cornified cells actually being increased. the latter designation is awkward, however, and orthokeratosis being equivalent to parakeratosis in number of syllables and being the antonym of it, we invoke that term as license taken on behalf of simplification. orthokeratosis may be subdivided into several types on the basis of pattern of arrangement of corneocytes, i.e., basket-weave, laminated (see laminated orthokeratosis), compact (see compact orthokeratosis), or a combination of them. basket-weave orthokeratosis refers to a thickened cornified layer whose cells are arrayed in a criss-cross fashion that resembles the pattern in a woven basket, it is the same configuration, only thickened, assumed by the stratum corneum of normal skin anywhere on the integument except for palms and soles, where corneocytes are organized compactly. two states pathologic in which the cornified layer may be thickened but still maintains its basketweave character are the infections diseases tinea versicolor (caused by the fungus malassezia furfur or glabrosum) and verrucae plana (caused by papillomavirus). review | dermatol pract concept 2014;4(3):1 9 hyperplasia: in classic pathology denotes a proliferation of cells that involutes when the stimulants for it ceases, such as occurs in verrucae vulgares. unfortunately, the definition just set forth is not applicable to proliferations as they are assessed by microscopy conventional; as a rule, a histopathologist cannot identify in sections of tissue the stimulus responsible for a proliferation and moreover, in the majority of instances the stimulus is not known. therefore, it is more useful to advise that the term hyperplasia characterize an increase in number of normal cells in arrangement relatively normal as is seen for example in so called syringofibroadenoma, i.e., a hyperplasia of epithelium of eccrine ducts that is induced by adjacent stroma altered markedly, such as fibrosis consequent to the effects of lymphedema long-standing, it being very different from apocrine fibroadenoma which is a benign proliferation of the type referred to conventionally as a neoplasm. in skin, most hyperplasias pseudocarcinomatous represent proliferation of epithelium of infundibular epidermis and of eccrine ducts. because for purpose of diagnosis with specificity it matters not a whit whether a particular condition is termed neoplasm, hyperplasia, hamartoma, malformation, etc., the word “proliferation” as generic for all of them is used frequently in this work. hypogranulosis: a thinned granular zone as a consequence of a decreased number of cells containing keratohyaline granules. it may occur across the entire front of a lesion, such as in ichthyosis vulgaris or in foci of diseases as different as psoriasis, inflammatory linear verrucous epidermal nevus, and solar keratosis. untitled observation | dermatol pract concept 2015;5(4):3 7 dermatology practical & conceptual www.derm101.com introduction the most common endocrine malignancy is thyroid cancer. papillary and follicular thyroid carcinoma are the most frequent subtypes. metastatic thyroid carcinoma usually appears in the local lymph nodes. indeed, distant metastases of papillary and follicular thyroid carcinoma are uncommon. when these occur, the sites typically include lung and bone. metastatic papillary thyroid carcinoma to the nose: report and review of cutaneous metastases of papillary thyroid cancer philip r. cohen1 1 department of dermatology, university of california san diego, san diego, ca, usa key words: basal, cancer, carcinoma, cell, cutaneous, kinase, inhibitor, metastases, nose, papillary, rearranged during transfection, receptor, ret, thyroid, tyrosine, vandetanib citation: cohen pr. metastatic papillary thyroid carcinoma to the nose: report and review of cutaneous metastases of papillary thyroid cancer. dermatol pract concept 2015;5(4):3. doi: 10.5826/dpc.0504a03 received: august 9, 2015; accepted: september 29, 2015; published: october 31, 2015 copyright: ©2015 cohen. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: metastatic papillary thyroid carcinoma typically appears in local lymph nodes. skin metastases are rare. purpose: a man with progressive metastatic papillary thyroid carcinoma who developed a cutaneous metastasis on his nose is described. the clinical manifestations of metastatic papillary thyroid carcinoma to skin are reviewed. methods: pubmed was used to search the following terms, separately and in combination: basal, cancer, carcinoma, cell, cutaneous, kinase, inhibitor, metastases, nose, papillary, rearranged during transfection, receptor, ret, thyroid, tyrosine, vandetanib. results: pathologic changes observed on the biopsy of the man’s nose lesion were similar to those of his original cancer. genomic evaluation of the tumor revealed an aberration involving the rearranged during transfection (ret) receptor tyrosine kinase. the residual tumor was excised. treatment with vandetanib, a ret inhibitor was initiated; his metastatic disease has been stable, without symptoms or recurrent cutaneous metastasis, for 2 years following the discovery of his metastatic nose tumor. conclusions: papillary thyroid carcinoma with skin metastases is rare. nodules usually appear on the scalp or neck; the thyroidectomy scar is also a common site. metastatic tumor, albeit infrequently, can present as a nose lesion. the prognosis for patients with cutaneous metastases from papillary thyroid carcinoma is poor. however, with the ability to test the tumor for genomic aberrations, molecular targeted therapies—such as tyrosine kinase inhibitors—may provide extended survival in these individuals. abstract mailto:mitehead@gmail.com 8 observation | dermatol pract concept 2015;5(4):3 on the right nasal tip (figure 1). microscopic examination of a 2 mm punch showed scale crust and parakeratosis overlying an atrophic epidermis. in the dermis, there were multiple nodules composed of large cells forming papillary projections. the papillae were composed of a stratified lining of cuboidal and columnar tumor cells with eosinophilic cytoplasm and a central fibrovascular core that contained occasional lymphocytes. focally, there were tumor cells with altered nuclear morphology. some cells showed crowding and overlapping of enlarged and elongated nuclei. other cells demonstrated intranuclear cytoplasmic pseudoinclusions (figure 2). the tumor cells stained positive for thyroid transcription factor-1 (ttf-1) and paired box gene 8 (pax8). correlation of the clinical history and pathology established a diagnosis of metastatic papillary thyroid carcinoma to skin. the residual tumor on the nose was excised without recurrence. however, within 6 months, he had progressive shortness of breath; follow up studies showed progressive chest disease. his tumor was sent for genomic studies (foundation one, cambridge, ma). an aberration in the rearranged during transfection (ret) receptor tyrosine kinase was identified: an in-frame fusion of coiled-coil domain containing 6 (ccdc6) up to intron 1, with ret from intron 11 to the end. treatment was initiated and maintained with the ret inhibitor vandetanib; he has had stable metastatic disease without symptoms 1.5 years after starting this drug. discussion cutaneous metastases may develop in patients with an established diagnosis of cancer. in this setting, they typically herald the onset of either relapsing or progressive disease in an oncology patient. however—albeit less commonly—they can be the initial presentation of an unsuspected internal malignancy in a previously cancer-free individual. however, albeit rare, papillary and follicular thyroid carcinoma have both been associated with skin metastases [1,2]. cutaneous metastases from papillary thyroid carcinoma are reported in less than 1 in 1,000 patients with this cancer [2]. the scalp is the most frequent site [3-7]. a man with progressing metastatic papillary thyroid cancer to lung who developed a cutaneous metastasis on the nose mimicking a basal cell carcinoma is described and the various clinical presentations of metastatic papillary thyroid cancer to skin are reviewed. case report a 72-year-old man was referred by his oncologist for evaluation of a lesion on his nose that was suspected to be a basal cell carcinoma. the lesion was painless and had appeared 3 weeks earlier. his past medical history was significant for metastatic papillary thyroid carcinoma diagnosed 6.5 years earlier. a total thyroidectomy and neck dissection was followed by adjuvant radioactive iodine-131. when lung nodules were discovered 1.25 years later, he received another treatment with iodine-131. he subsequently developed progressive chest disease 0.75 years later and received an additional treatment of iodine-131 in combination with capecitabine. he received stereotactic radiosurgery to lung metastases 1 year later; 2 years and 3.3 years later, he had excision of enlarged chest lymph nodes that showed tumor. restaging, 3 months prior to his nose lesion, showed not only intrathoracic metastatic disease (with pulmonary nodules and enlarged mediastinal lymph nodes), but also metastases to the right adrenal gland and bone. he was experiencing progressive fatigue. however, there was neither cough nor difficulty breathing. cutaneous examination showed an asymptomatic 7 x 7 mm violaceous non-telangiectatic nodule with central erosion figure 1. lateral (a) and upward (b) views of cutaneous metastatic papillary thyroid carcinoma presenting as an asymptomatic nodule with central erosion on the right nasal tip that morphologically mimicked a basal cell carcinoma. [copyright: ©2015 cohen.] a b observation | dermatol pract concept 2015;5(4):3 9 (a type ii keratin found in the follicular cells of the thyroid gland) [11] and paired box gene 8 (pax8, a nephric-lineage transcription factor that is a crucial transcription factor for the organogenesis of the kidney, the mullerian system and the thyroid gland) [12]. the nose is an unusual site for cutaneous metastases. in addition to thyroid carcinoma, other cancers with metastatic lesions on the nose include solid tumors originating from the breast, cervix, liver, lung and testes [13]; immunohistochemical markers can be used to differentiate the organ of origin of these metastatic tumors (table 1). the described patient was referred for evaluation of a suspected basal cell carcinoma. morphologic features of the nodule that suggested the possibility of metastatic tumor included its violaceous appearance and the absence of telangiectasias. in addition to the patient in this report, another man with papillary thyroid carcinoma also had a cutaneous metastasis on his nose; in this individual, the nose lesion was the initial presentation of his metastatic disease [14]. he was a 73-yearold caucasian man who developed a raised, non-pigmented lesion on his left nasal ridge; biopsy revealed papillary thyroid carcinoma. in addition to a thyroid mass, he had metastases to his lungs, bone and liver. management included a partial thyroidectomy, palliative radiotherapy (to the neck and cervical spine to treat tracheal invasion of the tumor and spinal cord compression, respectively), doxorubicin and radioactive the morphology of cutaneous metastases is variable. the lesions can present as patches, plaques, papules or nodules. they can mimic other conditions such as alopecia, infections (erysipelas and paronychia), benign cysts (epidermoid or pilar), pyogenic granuloma and cutaneous malignant neoplasms (basal cell carcinoma and keratoacanthoma) [4,5,7]. common skin manifestations of metastatic papillary thyroid cancer, in addition to scalp nodules, include neck nodules [3,4,8] and lesions on the thyroidectomy scar [1]. metastatic tumor at the fine-needle aspiration biopsy site has been observed [8]. also, lesions of cutaneous papillary thyroid carcinoma metastases have been described on the abdominal wall [6,9], arm [6], buttock [9], chest wall [3], face [3,6], shoulder [6] and thigh [9]. microscopic examination of papillary thyroid carcinoma cutaneous metastases shows similar pathology features as the primary cancer. immunohistochemical stains can also be helpful to confirm the diagnosis and exclude tumors originating from other organs. papillary thyroid carcinoma typically expresses thyroid transcription factor-1 (ttf-1, a 38-kd homeodomain containing dna binding nuclear protein expressed in the follicular cells of the thyroid and present in 93% of thyroid tumors) [4,10] and thyroglobulin (a 670-kd glycoprotein synthesized in the cytoplasm of follicular thyroid epithelial cells and detected in 95% of papillary thyroid carcinomas) [3,4]. it also usually expresses cytokeratin 7 a b c figure 2. low (a), medium (b), and high (c) magnification views of the papillary thyroid carcinoma metastasis shows aggregates of tumor cells in the dermis that are similar to those of the primary thyroid neoplasm. cuboidal and columnar cells line the lymphocyte-containing fibrovascular cores of tumor papillae. the cells have eosinophilic cytoplasm; some of them also have nuclear changes including enlarged and enlongated nuclei that are crowded and overlapping and nuclear pseudoinclusions [hematoxylin and eosin; a = x10, b = x20, c = x40]. [copyright: ©2015 cohen.] 10 observation | dermatol pract concept 2015;5(4):3 table 1. immunohistochemistry markers of solid tumors that metastasize to the nose tumor origin immunohistochemical marker breast er (estrogen receptor) gata3 (gata binding protein 3) gcdfp-15 (gross cystic protein fluid protein 15) her2 (human epithelial growth factor 2) mgb (mammaglobin) ny-br-1 (ankyrin repeat domain 30a) pr (progesterone receptor) tff1 (thyroid transcription factor 1) tff3 (thyroid transcription factor 3) cervix ca-125 (cancer antigen 125) cea (carcinoembryonic antigen) cytokeratin 17 human papilloma virus mybl2 (myeloblastosis family transcription factor-like 2) p16 (p16ink4a = cyclin-dependent kinase inhibitor 2a, multiple tumor suppressor 1) liver arg1 (arginase 1) cd10 (cluster of differentiation 10) cd34 (cluster of differentiation 34) heppar1 (hepatocyte paraffin 1) gpc3 (glypican 3) lung nsclc sclc cytokeratin ae1/ae3 (pan-cytokeratin) cam5.2 (cytokeratin 8 and cytokeratin 18) desmocollin a genomic aberrations alk (anaplastic lymphoma kinase) rearrangement egfr (epidermal growth factor receptor) mutation hmwk (high molecular weight cytokeratin) cytokeratin 5/6 cytokeratin 34betae12 napsin-a p63 (p53 family of nuclear transcription factors) ttf1 (thyroid transcription factor 1) cytokeratin ae1/ae3 (pan-cytokeratin) neuroendocrine markers cd56 (cluster of differentiation 56 = ncam, neural cell adhesion molecule) chromogranin synaptophysin testes gct sc/st cytokeratin ae1/ae3 (pan-cytokeratin) nanog oct4 (octomer-binding transcription factor 4) plap (placenta-like alkaline phosphatase) sall4 (sal-like 4) calret (calretinin) inha (inhibin a) vlm (vimentin) thyroid braf (b-isoform of raf kinase) v600e mutation-specific antibodies anti-b-raf mouse monoclonal antibody ve1 cit-ed1 (cbp/p300-interacting transactivator with glu/asp-rich carboxy-terminal domain, 1) cytokeratin 7 cytokeratin 19 gal-3 (galectin-3) hbme-1 (hector battifora mesothelioma-1) pax8 (paired box gene 8) thyroglobin tpo (thyroperoxidase) trop2 (trophoblastic cell surface antigen 2 = tac-std2, tumor associated calcium signal transducer 2) ttf1 (thyroid transcription factor 1) ttf2 (thyroid transcription factor 2 = foxe1, forkbend box e1) abbreviations: gct, germ cell tumor; nsclc, non-small cell lung cancer; sclc, small cell lung cancer; sc/st, sex cord/stromal tumor. observation | dermatol pract concept 2015;5(4):3 11 may not only occur several years following the diagnosis of the primary cancer, but also can occur on the nose or mimic basal cell carcinoma or both. cutaneous metastases of papillary thyroid carcinoma have previously been associated with a poor prognosis; however, some of the patients have indolent neoplastic disease and survive for several years. similar to the described patient, whose genomic evaluation of the tumor showed an aberration involving the rearranged during transfection (ret) receptor tyrosine kinase, the use of molecular targeted therapies may provide extended survival for individuals diagnosed with cutaneous metastatic papillary thyroid carcinoma. references 1. bruglia m, palmonella g, silvetti f, et al. skin and thigh muscle metastasis from papillary thyroid cancer. singapore med j. 2009;50:e61-e64. 2. koller ea, tourtelot jb, pak hs, et al. papillary and follicular thyroid carcinoma metastatic to the skin: a case report and review of the literature. thyroid. 1998;8:1045-50. 3. dahl pr, brodland dg, goellner jr, hay id. thyroid carcinoma metastatic to the skin: a cutaneous manifestation of a widely disseminated malignancy. j am acad dermatol. 1997;36:531-7. 4. alwaheeb s, ghazarian d, boerner sl, asa sl. cutaneous manifestations of thyroid cancer: a report of four cases and review of the literature. j clin pathol. 2004;57:435-8. 5. makris a, goepel jr. cutaneous metastases from a papillary thyroid carcinoma [letter]. br j dermatol. 1996;135:860-1. 6. horiguchi y, takahashi c, imamura s. cutaneous metastasis from papillary carcinoma of the thyroid gland: report of two cases. j am acad dermatol. 1984;10:988-92. 7. aghasi mr, valizadeh n, soltani s. a 64 year-old female with scalp metastasis of papillary thyroid cancer. indian j endocr metab. 2011;15(s2):s136-7. 8. tamiolakis d, antoniou c, venizelos j, et al. papillary thyroid carcinoma metastasis most probably due to fine needle aspiration biopsy. a case report. acta dermatoven apa. 2006;15:169-72. 9. loureiro mm, lette vh, boavida jm, et al. an unusual case of papillary carcinoma of the thyroid with cutaneous and breast metastases only. eur j endocrinol. 1997;137:267-9. 10. ordonez ng. value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. appl immunohistochem mol morphol, 2012;20:429-44. 11. chu pg, lau sk, weiss lm. keratin expression in endocrine organs and their neoplasms. endocr pathol. 2009;20:1-10. 12 laury ar, perets r, piao h, et al. a comprehensive analysis of pax8 expression in human epithelial tumors. am j surg pathol. 2011;35:816-26. 13. chun sm, kim yc, lee j-b, et al. nasal tip cutaneous metastases secondary to lung carcinoma: three case reports and a review of the literature. acta derm venereol. 2013;93:569-72. 14. khan oa, roses df, peck v. papillary thyroid carcinoma metastatic to skin may herald aggressive disease. endocr pract. 2010;16:446-8. 15. prescott jd, zeiger ma. the ret oncogene in papillary thyroid carcinoma. cancer. 2015 [epub ahead of print] iodine. three years later, his lung and pleural lesions progressed; pathology demonstrated anaplastic transformation of his tumor [14]. similar to the reported patient, other investigators have commented that since “ . . . the natural history of thyroid cancer is one of slow progression skin metastases may be confused with other skin neoplasms such as basal cell carcinoma . . .” [5] indeed, their patient—a 70-year-old man—presented with a enlarged thyroid gland and cervical lymphadenopathy; pathology from his total thyroidectomy and neck dissection established a diagnosis of papillary thyroid carcinoma. three years after receiving adjuvant treatment with radioactive iodine ablation and external beam radiotherapy, he developed a 1 cm nodular scalp lesion that was clinically thought to be a basal cell carcinoma; however, excisional biopsy showed papillary thyroid carcinoma. within four months, he died [5]. cutaneous metastasis of papillary thyroid carcinoma may be the presenting manifestation of previously undiagnosed malignancy [3,14]. the described patient’s nose lesion of metastatic papillary thyroid carcinoma occurred 6.5 years following his initial diagnosis of cancer and in the setting of progressive metastatic disease that had been treated with iodine-131 (on three occasions, without or with concurrent capecitabine) and stereotactic radiosurgery. similar to this patient, many of the individuals who develop skin metastases from papillary thyroid carcinoma typically present with cutaneous lesions several years (ranging from less than 2 years to 20 years) following the diagnosis of their original cancer [1,3,4,6-8]. the prognosis for patients with metastatic papillary thyroid carcinoma to the skin, in general, is unfavorable [3,5]. however, there are several individuals with metastatic papillary thyroid carcinoma who survive several years after diagnosis with indolent disease [1,3,9]. also, similar to the described patient, with the advent of molecular targeted therapies, such as tyrosine kinase inhibitors, the prognosis for patients with metastatic disease—and particularly those with rearranged during transfection (ret) proto-oncogene aberrations—is better than that observed in individuals with papillary thyroid carcinoma who were treated prior to the discovery of these agents [15]. conclusion papillary thyroid carcinoma with skin metastases is rare. cutaneous metastases of papillary thyroid carcinoma most commonly occur as nodules on the scalp, neck, and thyroidectomy scars. a man with progressive metastatic papillary thyroid carcinoma developed a cutaneous metastasis on his nose; the lesion morphologically mimicked a basal cell carcinoma. cutaneous papillary thyroid carcinoma metastases dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):9 51 dermatology practical & conceptual www.derm101.com introduction infundibulocystic basal cell carcinoma is a rare subtype of the most frequent form of human skin cancer (basal cell carcinoma). it was first described in 1987 and proposed as a new basal cell carcinoma (bcc) variant by ackerman and walsh in 1990 [1,2]. this unusual variant has been described to occur as a solitary entity or as part of nevoid basal cell carcinoma syndrome [3]. histopathologically it is a well circumscribed, superficially located, basaloid cell tumor with hyperchromatic, pleomorphic nuclei and rare mitoses, multiple tiny cysts containing cornified cells lined by infundibular epithelium. it typically lacks follicular bulbs and papillae or papillary mesenchymal bodies. the stroma usually has abundant connective tissue mucin [4]. dermoscopy is a non-invasive diagnostic technique that has become an integrative part of the clinical approach of skin tumors since it significantly improves the early diagnosis of melanoma and non-melanoma skin cancer (nmsc) compared to the naked eye examination [5]. dermoscopy has also been used to improve pre-operative margin evaluation and monitoring treatment response to topical therapy [6,7]. dermoscopic criteria for bcc have been clearly established infundibulocystic basal cell carcinoma: dermoscopic findings and histologic correlation rodrigo roldán-marín1, sergio leal-osuna1, lorena lammoglia-ordiales1, sonia toussaint-caire1 1 dermatology department, hospital general “dr. manuel gea gonzález,” mexico city, mexico keywords: infundibulocystic, basal cell carcinoma, dermoscopy, histopathology citation: roldán-marín, r, leal-osuna s, lammoglia-ordialis l, toussaint-caire s. infundibulocystic basal cell carcinoma: dermoscopic findings and histologic correlation. dermatol pract concept. 2014;4(3):9. http://dx.doi.org/10.5826/dpc.0403a09 received: february 18, 2014; accepted: march 15, 2014; published: july 31, 2014 copyright: ©2014 roldán-marín et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rodrigo roldán-marín, md, dermatology department, hospital general “dr. manuel gea gonzález,” calzada de tlalpan 4800, col. sección xvi, tlalpan 14080, mexico city, mexico. tel: +52-55-56043636. e-mail: roroderm@yahoo.com infundibulocystic basal cell carcinoma is a rare variant. it was first described in 1987 and proposed as a new basal cell carcinoma (bcc) subtype by ackerman and walsh in 1990. dermoscopy is a noninvasive diagnostic technique that allows prompt identification of many types of bcc. however, dermoscopic findings for the infundibulocystic variant have not been reported. in our patient the dermoscopic findings were maple leaf-like areas in the periphery of the tumor, multiple scattered blue-gray dots and globules, short, fine telangiectasia and chrysalis or white-shiny streaks. all these structures had an underlying anatomopathological correlation. conclusion: according to our case report, dermoscopy findings may aid to clearly diagnose this unusual bcc variant with proper histopathological correlation. abstract 52 observation | dermatol pract concept 2014;4(3):9 and its value in discriminating superficial bcc from other subtypes was recently reported [8]. however, there is no previous dermoscopic description of the infundibulocystic variant. case presentation a 49-year-old, female patient, skin phototype v, presented to the outpatient dermatology clinic for evaluation. the dermatological examination revealed a 4 mm, well-circumscribed, pigmented skin tumor affecting the medial aspect of her anterior right thigh. the neoplasm had a pale center with a peripheral pigmented rim with superficial scale, and it was firm to palpation. clinically, the lesion resembled a dermatofibroma (figure 1). dermoscopic evaluation revealed the presence of maple leaf-like areas on the periphery, multiple scattered blue-gray dots and globules, short, fine telangiectasia and chrysalis or white-shiny streaks (figure 2). figure 1. clinical examination revealed a 4 mm, well-circumscribed, pigmented skin tumor affecting the medial aspect of her anterior right thigh. the neoplasm had a pale center with a peripheral pigmented rim with superficial scale, and it was firm to palpation. [copyright: ©2014 roldán-marín et al.] figure  2. dermoscopy revealed the presence of maple leaf-like areas on the periphery, multiple scattered blue-gray dots and globules, short, fine telangiectasia and chrysalis or white-shiny streaks. [copyright: ©2014 roldán-marín et al.] figure 3. at low magnification histopathological showed a well circumscribed, superficially located tumor, formed by anastomosing cords of basaloid keratinocytes with several tiny cornifying cysts. [copyright: ©2014 roldánmarín et al.] observation | dermatol pract concept 2014;4(3):9 53 due to the inconsistency between the clinical appearance and the dermoscopic findings, an excisional biopsy was performed. the histopathological examination at low magnification showed a well circumscribed, superficially located tumor, formed by anastomosing cords of basaloid keratinocytes with several tiny cornifying cysts (figure 3). at higher magnification, tumor cells had scant cytoplasm with hyperchromatic, pleomorphic nuclei with rare mitoses and few necrotic cells. some keratinocytes had granular melanin in their cytoplasm. there was a lymphocytic peritumoral inflammatory infiltrate. at the upper reticular dermis there was an increased number of collagen bundles horizontally arranged and aligned parallel to the epidermis. lateral and deep margins were tumor free. discussion we present a case of infundibulocystic basal cell carcinoma, meaning a bcc with upper follicular differentiation. basal cell carcinoma rarely shows differentiation toward epithelial figures 4 and 5. maple leaf-like areas in the periphery as well as the scattered blue-gray dots and globules linked to the presence of pigmented epithelial nests in the papillary dermis. [copyright: ©2014 roldán-marín et al.] structures of adnexa including follicular, sebaceous, eccrine and apocrine. bcc was originally considered a neoplasm derived from the basal cells of the epidermis. later, it was proposed that it could derive from primary epithelial germ cells or from any part of the equipotential ectoderm of the skin in combination with organized mesodermal stroma [9]. thus basaloid cells in bcc have the potential for differentiation toward various epidermal appendages. a combination of different kinds of follicular differentiation toward infundibula and follicular germ cells is unique in the infundibulocystic variant of bcc. histopathologically, differential diagnosis includes basaloid follicular hamartoma and trichoepithelioma [2]. dermoscopy is a powerful, non-invasive, diagnostic tool, which greatly increases diagnostic accuracy. it has demonstrated to help diagnose bcc and its various subtypes with high sensitivity and specificity [5,7]. in our patient, dermoscopy clearly showed criteria compatible with basal cell carcinoma. the maple leaf-like areas in the periphery as well as the scattered blue-gray dots and globules were due to the presence of pigmented epithelial nests in the papillary dermis (figures 4 and 5). short, fine telangiectasia was consistent with the presence of dilated blood vessels in the superficial dermis (figure 6). the presence of chrysalis or white shiny structures was in agreement with the presence of an increased number of collagen bundles horizontally disposed and aligned parallel to the epidermis [10] (figure 7). this case illustrates the benefit of dermoscopy in establishing the diagnosis of basal cell carcinoma, even in this rare subtype. it also serves to exemplify how dermoscopy clearly aids the approach in the differential diagnosis between trichoepithelioma and bcc, which histologically can sometimes only be determined with immunohistochemistry staining. however, the most prominent dermoscopic findings in trichoepithelioma are arborizing telangiectasia and in desmoplastic lesions, an ivory-white background throughout [11,12]. conclusion this case report clearly exemplifies the usefulness of dermoscopy in the detection of bcc, even in this unusual subtype. it also serves to demonstrate once more how dermoscopy may bridge the gap between clinical and histopathological correlation, since 54 observation | dermatol pract concept 2014;4(3):9 each dermoscopic structure is related to a specific underlying anatomopathological correlate. references 1. tozawa t, ackerman ab. basal cell carcinoma with follicular differentiation. am j dermatopathol. 1987;9:474-82. 2. walsh n, ackerman ab. infundibulocystic basal cell carcinoma: a newly described variant. mod pathol. 1990;3:599-608. 3. requena l, fariña mc, robledo m, et al. multiple hereditary infundibulocystic basal cell carcinomas: a genodermatosis different from nevoid basal cell carcinoma syndrome. arch dermatol. 1999;135:1227-35. 4. kato n, ueno h. infundibulocystic basal cell carcinoma. am j dermatopathol. 1993;15:265-7. 5. lallas a, argenziano g, zendri e, et al. update on non-melanoma skin cancer and the value of dermoscopy in its diagnosis and treatment monitoring. expert rev anticancer ther. 2013;13:541-58. 6. caresana g, giardini r. dermoscopy-guided surgery in basal cell carcinoma. j eur acad dermatol venereol. 2010;24:1395-9. figure  6. short, fine telangiectasia due to the presence of dilated blood vessels in the superficial dermis. [copyright: ©2014 roldánmarín et al.] figure 7. white shiny structures related to the presence of an increased number of collagen bundles horizontally arranged and aligned parallel to the epidermis. [copyright: ©2014 roldán-marín et al.] 7. fargnoli mc, kostaki d, piccioni a, micantonio t, peris k. dermoscopy in the diagnosis and management of non-melanoma skin cancers. eur j dermatol. 2012;22:456-63. 8. lallas a, tzellos t, kyrgidis a, et al. accuracy of dermoscopic criteria for discriminating superficial from other subtypes of basal cell carcinoma. j am acad dermatol. 2014;70:303-11. 9. lever wf, schaumburg-lever g. basal cell epithelioma. in: lever wf, schaumburg-lever g. (eds.). lever’s histopathology of the skin. 7th ed. philadelphia: jb lippincott, 1990:622-34. 10. liebman tn, rabinovitz hs, balagula y, jaimes-lopez n, marghoob aa. white shiny structures in melanoma and bcc. arch dermatol. 2012;148:146. 11. ardigo m, zieff j, scope a, et al. dermoscopic and reflectance confocal microscope findings of trichoepithelioma. dermatology. 2007;215:354-8. 12. khelifa e, masouyé i, kaya g, le gal fa. dermoscopy of desmoplastic trichoepithelioma reveals other criteria to distinguish it from basal cell carcinoma. dermatology. 2013;226:101-4. dermatology: practical and conceptual observation | dermatol pract concept 2018;8(1):7 33 dermatology practical & conceptual www.derm101.com introduction syringocystadenoma papilliferum (scap) is a rare benign hamartomatous adnexal tumor that originates from the apocrine or the eccrine sweat glands [1]. it is a relatively rare neoplasm presenting at birth in 50% of the cases. in around 15-30% of the cases, it develops around puberty [2]. the lesions evolve either de novo or from a preexisting nevus sebaceous. there are three recognized clinical forms of it i.e., plaque, solitary nodular, and linear. most of the lesions localize over the head and neck region [3]. we hereby present a rare case of de novo congenital linear scap over the chest. we also describe the dermoscopic findings observed in our case. case presentation a 12-year-old girl presented with slowly growing multiple, itchy, red and raised lesions over her chest just below the left clavicle which were present since birth. the lesions had significantly increased in size and number in the previous two years. serous non-foul-smelling discharge from the lesions was occasionally noticed. associated symptoms suggestive of neurological, ocular or skeletal abnormality were not reported. on clinical examination, multiple grouped domeshaped papules and nodules with central umbilication were noted to be present in a linear array over the upper part of chest. the surface of the lesions showed central ulceration and crusting (figure 1). dermoscopic examination with a dermlite ii hybrid m (3gen, san juan capistrano, ca, usa; 10× magnification) was performed which revealed milky red papillomatous projections with a central ulceration. at places, white circles were seen over the rim of the milky red areas. polymorphic vessels were seen within the darker ulcerated areas. yellowish areas within the ulceration may represent sites of secretion (figure 2). dermoscopy of a rare case of linear syringocystadenoma papilliferum with review of the literature payal chauhan1, rishabh kumar chauhan1, amrita upadhyaya1, sanjeev kishore2 1 department of dermatology, venereology & leprology, all india institute of medical sciences, rishikesh, india 2 department of pathology, all india institute of medical sciences, rishikesh, india key words: linear syringocystadenoma papilliferum, adnexal tumor, dermoscopy citation: chauhan p, kumar chauhan r, upadyaya a, kishore s. dermoscopy of a rare case of linear syringocystadenoma papilliferum with review of the literature. dermatol pract concept. 2018;8(1):33-38. doi: https://doi.org/10.5826/dpc.0801a07 received: july 22, 2017; accepted: november 7, 2017; published: january 31, 2018 copyright: ©2018 chauhan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rishabh kumar chauhan, md, department of dermatology, venereology & leprology, all india institute of medical sciences, rishikesh, india. email: dr.rishabhchauhan@gmail.com syringocystadenoma papilliferum (scap) is a benign hamartomatous tumor arising from pluripotent cells with either apocrine or eccrine differentiation. we report a rare case of de novo linear scap in a 12-year-old female child with lesions over the chest along with the dermoscopic findings. abstract 34 observation | dermatol pract concept 2018;8(1):7 thirteen cases of linear scap were females and the majority of patients had onset at birth or in early childhood. only two cases of late-onset linear scap have been reported; one at 19 years and another 21 years old. surprisingly, the majority of the cases arose de novo. only three cases of linear scap have been reported to be associated with nevus sebaceous [21], tubular apocrine adenoma [8], and apocrine cystadenoma and hidrocystoma [10]. hitherto, only three cases of linear scap over the chest have been described [6,8,20]. of these, one case of linear scap in a 12-year-old male was associated with tubular apocrine adenoma[8]. the remaining two were cases of de novo linear scap over the left side of the chest in one [6] and over the left breast in the second case [20]. to the best of our knowledge, our patient represents the third case of de novo linear scap over chest. all the published cases of linear scap were histopathologically proven. however, there is a lack of documentation of dermoscopic findings in linear scap, as none has been previously reported. we also highlight the dermoscopic features of scap as the actual potential of dermoscopy has not been tapped in the diagnosis of adnexal tumors. in 2011, bruno et al. [22], described the dermoscopic features in scap associated with nevus sebaceous for the first time. the authors described a histopathological examination of the umbilicated papule was done and showed an endophytic tumor with several papillary infoldings lined by glandular epithelium, which consisted of two rows of cells. the inner row had high columnar cells with oval nuclei and faint eosinophilic cytoplasm. the outer row was comprised of small cuboidal cells with round nuclei and scant cytoplasm. focal areas of decapitation secretion were noted. the core of papillae had many plasma cells, lymphocytes and few polymorphic cells (figure 3). the diagnosis of linear syringocystadenoma papilliferum was made on the basis of clinical, dermoscopic and histopathologic examinations. the patient was referred to the department of pediatric surgery for surgical excision. discussion syringocystadenoma papilliferum (scap) is a rare benign cutaneous hamartoma seen to arise from the pluripotent cells with the potential to exhibit either apocrine or eccrine lineage, although apocrine differentiation is more common. it usually involves the head and neck area, taking its origin either de novo or from a preexisting nevus sebaceous in 30% of the cases [1]. the unusual anatomical sites of involvement include arms, breast, eyelids, axilla, scrotum, and inguinal and perineal regions [3]. three clinical types of scap have been described: a) plaque type: presenting as an alopecic patch on the scalp which may enlarge during puberty to become nodular, verrucous or crusted. b) linear type: consisting of multiple reddish pink firm papules or umbilicated nodules 1-10 mm in size commonly occurring over face and neck. c) solitary nodular type: which are domed pedunculated nodules 5-10 mm in size with a predilection for the trunk, shoulder, and axillae [4]. the linear presentation of scap is extremely rare with less than 20 cases reported in the literature [5-21] (table 1). figure 1. multiple grouped dome shaped papules and nodules with central umblication present over the chest just below the left clavicle. [copyright: ©2018 chauhan et al.] figure 2. milky red papillomatous projections (black circle) with central ulceration (black arrow). white circles (red circle) over the milky red rim. polymorphic vessels (green arrows) were also seen. [copyright: ©2018 chauhan et al.] observation | dermatol pract concept 2018;8(1):7 35 surrounding pinkish-white rim and peripheral hairpin like vessels. these findings are also similar to that seen in our case. the dermoscopic morphology of the other adnexal tumors of apocrine origin needs to be elucidated. recently, dermoscopic features of 22 cases of apocrine hidrocystoma were reported [25]. a homogenous area that occupies the whole lesion with arborizing vessels was found to be the most common dermoscopic pattern in apocrine hidrocystoma. similarly, tubular apocrine adenoma (taa) is another adnexal tumor of apocrine origin whose dermoscopy is hitherto unclear. ito et al, [26] noted coexistence of short fine telangiectasias and large blue-gray ovoid nests arranged in a floriform pattern to be the specific dermoscopic finding in taa. the present report aims to emphasize that the dermoscopic examination can act as an extremely valuable, noninvasive and inexpensive tool in the diagnosis of scap especially in children when a traumatic procedure like a biopsy can raise the apprehension and discomfort of the child and the parents. however, further studies are needed to corroborate the dermoscopic findings seen in our case. moreover, polymorphous vascular pattern comprised of irregular linear and glomerular vessels, some of which were surrounded by a whitish halo and others grouped in a horseshoe arrangement on a pinkish-white background. the dermoscopic findings in our case are similar and corroborate the earlier findings of bruno et al. [22] to the best of our knowledge, ours is the first case describing dermoscopic findings of de novo linear scap. dermoscopy findings in seven cases of scap associated with nevus sebaceous located in the head and neck regions documented by zaballos et al. [23] are noteworthy. the authors noted that the most common dermoscopic pattern associated with their scap cases was a symmetric erythematous lesion with “exophytic papillary structures,” followed by a central depression, ulceration and vessels (hairpin vessels, polymorphous vessels and comma vessels). similarly, dumen et al., [24] have also documented dermoscopic features in a case of scap with nevus sebaceous. the dermoscopic examination in the aforementioned case revealed central yellowishwhite discoloration, polymorphic vessels including irregular dotted, hairpin-like, glomerular and linear vessels with a a b c d figure 3. (a) scanner view showing an endophytic tumor with several papillary infoldings in the upper dermis (h&e, x40). (b) histopathological examination showing invagination of surface epithelium and irregular papillary projections protruding into the lumen (h&e, x100). (c) several papillary infoldings lined by glandular epithelium consisting of two rows of cells with inner row of high columnar cells having oval nuclei and faint eosinophilic cytoplasm and outer row having small cuboidal cells with round nuclei and scanty cytoplasm. (d) higher magnification showing core of papillae having many plasma cells, lymphocytes and few polymorphic cells. decapitation secretion is appreciated in the luminal layer (black arrow) (h&e, x400). [copyright: ©2018 chauhan et al.] 36 observation | dermatol pract concept 2018;8(1):7 ta b le 1 . su m m ar y o f th e h is to p at h o lo gi ca lly p ro ve n c as es o f li n ea r sc a p a g e / s e x a g e a t o n se t s y m p to m lo ca ti o n o f th e le si o n s c li n ic a l m o rp h o lo g y a ss o ci a ti o n a u th o r, y e a r o f p u b li ca ti o n r e f 1 0 , f si n ce b ir th u p p er p ar t o f th e le ft ar m m u lt ip le y el lo w is h -r ed p ap u le s, w it h c en tr al u m b il ic at io n i n s ev er al o f th e p ap u le s r o st an e t al , 1 9 7 6 5 1 6 , f si n ce b ir th l ef t si d e o f ch es t sk in -c o lo re d , fi rm p ap u le s an d n o d u le s f ew w er e u lc er at ed d is ch ar gi n g a se ro sa n gu in o u s m at er ia l p re m la th a et a l, 1 9 8 5 6 2 , m si n ce b ir th p o st er io r n ec k b el o w h ai rl in e 7 w ax y er yt h em at o u s o va l p ap u le s g o ld b er g et a l, 1 9 8 5 7 1 2 , m si n ce b ir th o cc as io n al ly m il d ly p ru ri ti c u p p er c h es t g ro u p ed s h in y er yt h em at o u s p ap u le s fo ca ll y co al es ci n g in to p la q u es t a a e p st ei n e t al , 1 9 9 0 8 1 1 , f si n ce b ir th r ig h t th ig h 4 p la q u es c o n si st in g o f a d o ze n p ea -s iz ed p in k p ap u le s an d s m al l n o d u le s w it h c ru st ed s u rf ac e. c en tr al u m b il ic at io n i n s o m e. d e b li ek e t al , 1 9 9 9 9 1 4 , f e ar ly c h il d h o o d p ru ri tu s l ef t in n er t h ig h 6 d is cr et e, e ry th em at o u s p ap u le s a p o cr in e cy st ad en o m a, h id ro cy st o m a p at te rs o n e t al , 2 0 0 1 1 0 2 0 , f si n ce b ir th su d d en g ro w th i n le si o n , r ec en t o n se t o f p ai n n ap e o f n ec k sk in -c o lo re d a n d e ry th em at o u s w ar ty p ap u le s ar ra n ge d v er ti ca ll y d aw n e t al , 2 0 0 2 1 1 5 , f 6 m o n th s o f ag e sc al p g ro u p ed s k in -c o lo re d , u m b il ic at ed p ap u le s al o n g w it h c au li fl o w er -l ik e m o is t re d d is h al o p ec ia p la q u e l ax m is h a et a l, 2 0 0 7 1 2 5 1 , m ea rl y ch il d h o o d n ap e o f n ec k 3 u lc er at ed n o d u le s (2 -3 c m ) sm al l, sk in co lo re d a n d y el lo w p ap u le s in c lo se p ro x im it y to t h e n o d u le s n ar an g et a l, 2 0 0 8 1 3 1 9 , f a t b ir th e x te n so r si te o f p ro x im al p ar t o f ri gh t u p p er e x tr em it y m u lt ip le d is cr et e, e ry th em at o u s, 0 .5 -1 c m s iz ed p se u d o ve si cu la r p ap u le s g ö n ü l et a l, 2 0 0 8 1 4 2 0 , f a t 1 9 y ea rs p ru ri tu s, h is to ry o f b le ed in g l ef tsi d ed o cc ip it al p ar t o f th e sc al p e x te n d in g to t h e n ap e o f n ec k h ig h ly e le va te d , m o is t, f et id , v eg et at ed a n d p in k is h l es io n y ag h o o b i et a l, 2 0 0 9 1 5 (c o n ti n u ed n ex t p ag e) observation | dermatol pract concept 2018;8(1):7 37 a g e / s e x a g e a t o n se t s y m p to m lo ca ti o n o f th e le si o n s c li n ic a l m o rp h o lo g y a ss o ci a ti o n a u th o r, y e a r o f p u b li ca ti o n r e f 4 0 , f si n ce b ir th r ig h t lo w er a b d o m en m u lt ip le e ry th em at o u s p ap u le s an d n o d u le s w it h e ro si o n o n t h e su rf ac e o f so m e o f th e le si o n s y ap e t al , 2 0 1 0 1 6 1 8 , f e ar ly c h il d h o o d r ig h t in gu in al & p u b ic re gi o n 3 l ar ge fl es h y er yt h em at o u s, e x u b er an t ve rr u co u s p la q u es w it h a d h er en t w h it is h s lo u gh sk in -c o lo re d , d is cr et e p ap u le s w it h s li gh t u m b il ic at io n p ah w a et a l, 2 0 1 1 3 1 5 , f e ar ly c h il d h o o d o cc as io n al ly p ru ri tu s l ef t si d e o f n ec k 2 0 d is cr et e er yt h em at o u s ve si cl eli k e p ap u le s m ar to re ll -c al at ay u e t al , 2 0 1 1 1 7 1 2 , m si n ce b ir th l o w er b ac k f le sh y ca u li fl o w er -l ik e er yt h em at o u s p ap u lo n o d u la r le si o n w it h i n cr ea se i n va sc u la ri ty a n d o o zi n g o f se ro sa n gu in o u s fl u id k ar e t al , 2 0 1 2 1 8 3 6 , m 2 1 y ea rs o f ag e r ig h t in gu in al f o ld m u lt ip le s k in -c o lo re d , d o m esh ap ed , fi rm , n o n te n d er n o d u le s g h o sh e t al , 2 0 1 2 1 9 1 0 , f 2 m o n th s r ig h t lo w er a b d o m en m u lt ip le e ry th em at o u s p ap u le s, c o al es ce n t p la q u es c h au h an e t al , 2 0 1 3 1 3 5 , f si n ce 8 m o n th s m il d i rr it at io n l ef t b re as t 2 e ry th em at o u s, m u lt il o b u la r ex u b er an t p la q u es b an d o p ad h ya y, 2 0 1 4 2 0 1 2 , m si n ce b ir th b ac k o f th e le ft e ar ex te n d in g to s ca lp m u lt ip le , s k in -c o lo re d v er ru co u s p ap u le s an d n o d u le s, s h o w in g er o si o n o n s o m e si te s n s e k in ci e t al , 2 0 1 6 2 1 1 2 , f si n ce b ir th o ve r ch es t ju st b el o w le ft c la vi cl e m u lt ip le g ro u p ed d o m es h ap ed p ap u le s an d n o d u le s w it h c en tr al u m b li ca ti o n , u lc er at io n an d c ru st in g p re se n t ca se a bb re vi at io ns : f , f em al e; m , m al e; n s, n ev us s eb ac eu s; r ef , r ef er en ce ; t a a , t ub ul ar a po cr in e ad en om a ta b le 1 . su m m ar y o f th e h is to p at h o lo gi ca lly p ro ve n c as es o f li n ea r sc a p ( co n ti n u ed ) 38 observation | dermatol pract concept 2018;8(1):7 12. laxmisha c, thappa dm. mishra mm, verma sk. linear syringocystadenoma papiliiferum ofthe scalp. j eur acad dermatol venereol. 2007;21(2):275-276. 13. narang t, de d, dogra s, saikia un, handa s. linear papules and nodules on the neck. syringocystadenoma papilliferum (sp). arch dermatol. 2008;144(11):1509-1514. 14. gönül m, soylu s, gül u, kaya i, albayrak l, unal t. linear syringocystadenoma papilliferum of the arm: a rare localization of an uncommon tumour. acta derm venereol. 2008;88(5):528529. 15. yaghoobi r, zadeh sh, zadeh ah. giant linear syringocystadenoma papilliferum on scalp. indian j dermatol venereol leprol. 2009;75(3):318‐319. 16. yap fb, lee br, baba r. syringocystadenoma papilliferum in an unusual location beyond the head and neck region: a case report and review of literature. dermatol online j. 2010; 16(10):4. 17. martorell-calatayud a, sanz-motilva v, garcia-sales ma, calatayud-blas a. linear syringocystadenoma papilliferum: an uncommon event with a favorable prognosis. dermatol online j. 2011;17(8):5 18. kar m, kar jk, maiti s. giant linear syringocystadenoma papilliferum of the back. indian j dermatol venereol leprol. 2012;78(1):123. 19. ghosh sk, mandal rk, bandyopadhyay d, mukhopadhyay sm. adult-onset linear syringocystadenoma papilliferum over the inguinal fold: a case report with emphasis on mast cell staining pattern. dermatol online j. 2012;18(11):16. 20. bandyopadhyay d, saha a, kumar d. linear syringocystadenoma papilliferum on female breast: a rare appendageal tumour on an uncommon location. dermatol online j. 2014:21(2). 21. ekinci ap, buyukbabani n, mehdi l, yazganoglu kd, baykal c. linear syringocystadenoma papilliferum on the retroauricular area associated with nevus sebaceous. dermatol online j. 2016;22(11). 22. bruno cb, cordeiro fn, soares fdo e, takano gh, mendes ls. dermoscopic aspects of syringocystadenoma papilliferum associated with nevus sebaceous. an bras dermatol. 2011;86(6):1213– 1216. 23. zaballos p, serrano p, flores g, et al. dermoscopy of tumours arising in naevus sebaceous: a morphological study of 58 cases. j eur acad dermatol venereol. 2015;29(11):2231-2237. 24. duman n, ersoy-evans s, erkin özaygen g, gököz ö. syringocystadenoma papilliferum arising on naevus sebaceus: a 6-yearold child case described with dermoscopic features. australas j dermatol. 2015; 56(2):e53-54. 25. zaballos p, bañuls j, medina c, salsench e, serrano p, guionnet n. dermoscopy of apocrine hidrocystomas: a morphological study. j eur acad dermatol venereol. 2014; 28(3):378-381. 26. ito t, nomura t2, fujita y, abe r, shimizu h, et al. tubular apocrine adenoma clinically and dermoscopically mimicking basal cell carcinoma. j am acad dermatol. 2014; 71(2):e45-46. we wish to encourage the incorporation of dermoscopy as an integral part of clinical skin examination so that the dermoscopic patterns can be defined and established for benign adnexal tumors thus averting the need for biopsy as a routine procedure in these patients. conclusion in this report, we describe clinical, histopathological features along with dermoscopic findings of scap in a 12-year-old girl. we wish to highlight the dermoscopic features of scap and emphasize that dermoscopy can contribute significantly to reaching a diagnosis of this rare entity. as far as we are aware, our patient represents the third case of de novo linear scap over the chest. references 1. chauhan a, gupta l, gautam rk, bhardwaj m, gopichandani k. linear syringocystadenoma papilliferum: a case report with review of literature. indian j dermatol. 2013;58(5):409. 2. karg e, korom i, varga e, ban g, turi s. congenital syringocystadenoma papilliferum. pediatr dermatol. 2008;25(1):132–133. 3. pahwa p, kaushal s, gupta s, khaitan bk, sharma vk, sethuraman g. linear syringocystadenoma papilliferum: an unusual location. pediatr dermatol. 2011;28(1):61-62. 4. pinkus h. life history of naevus syringocystadenomatous papilliferus. arch dermatol syphil. 1954;69(3):305-322. 5. rostan se, waller jd, syringocystadenoma papiliiferum in an unusual location: report of a case. arch dermatol. 1976;112(6):835836. 6. premalatha s, rao nr. yesudian p, razack a, zahra a. segmental syringocystadenoma papiliiferum in an unusual location. int j dermatol. 1985;24(8):520-521. 7. goldberg ns, esterly nb. linear papules on the neck of a child: syringocystadenoma papillifenim. arch dermatol. 1985;12(9):1198-1201. 8. epstein ba, argenyi zb, goldstein g, whitaker d. an unusual presentation of a congenital benign apocrine hamartoma. j cutan pathol. 1990;17(1):53-58. 9. de bliek jp, starink tm. multiple linear syringocystadenoma papiliiferum. j eur acad dermatol venereol. 1999;12(1):74-76. 10. patterson jw. straka bf, wick mr. linear syringocystadenoma papiliiferum of the thigh. j am acad dermatol. 2001; 45(1):139141. 11. dawn g, gupta g. linear warty papules on the neck of a young woman: syringocystadenoma papiliiferum (sp) in a sebaceous nevus (sn). arch dermatol. 2002;138(8):1091-1096. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):10 215 dermatology practical & conceptual introduction pemphigus vulgaris (pv) without mucosal involvement is quite rare. the scalp is commonly affected at presentation in pv and is frequently the first site of the disease [1]. case presentation we present a case of pv mimicking folliculitis decalvans clinically and dermoscopically on its first presentation. a 40-yearold male patient presented with patchy alopecia, erythema, and follicular pustules on the scalp of 3 months’ duration (figure 1a). the patient gave a history of treatment with antibiotics and antifungals, with no improvement. there were no other lesions involving the skin or mucous membranes at the time of presentation. on using a handheld dermatoscope (×10 magnification), many of the characteristic trichoscopic features of folliculitis decalvans such as tufted folliculitis, perifollicular erythema, crusting, and follicular pustules were seen in this case (figure 1b). the diagnosis of folliculitis decalvans was suggested, although the presence of skin erosions and excessive peripilar casts did not coincide with this diagnosis. histopathological examination revealed suprabasal acantholysis of surface epidermis and adnexal epithelium consistent with the diagnosis of pv that was confirmed using direct immunofluorescence. two weeks later, the patient developed extensive alopecia as well as acute widespread papules, erosions, and few blisters on his neck, axillae, inguinal folds, and arms. mucous membranes were not affected (figure 2a). dermoscopically alopecia with evident erosions, tufted folliculitis, and extensive peripilar casts were seen (figure 2b). “tufted folliculitis,” “tufting,” or “polytrichia” is the manifestation of a fibrosis-induced gathering of adjacent follicular structures, as well as a follicular retention of telogen phase hairs over multiple cycles, seen clinically as “doll’s hairs” [2]. it was speculated that due to persistent bacterial infection superimposed on erosions of pv, an ongoing inflammatory process was induced, leading to tufted folliculitis [1]. this pattern has been previously reported in patients with longscalp pemphigus vulgaris mimicking folliculitis decalvans: a case report manal bosseila1, eman a. nabarawy1, mostafa a. latif1, sally doss1, mona elkalioby1, marwah a. saleh1 1 dermatology department, cairo university, egypt key words: pemphigus vulgaris, scalp, folliculitis decalvans, tufted folliculitis, dermoscopy, trichoscopy citation: bosseila m, nabarawy ea, latif ma, doss s, elkalioby m, saleh ma. scalp pemphigus vulgaris mimicking folliculitis decalvans: a case report. dermatol pract concept. 2019;9(3):215-217. doi: https://doi.org/10.5826/dpc.0903a10 accepted: december 10, 2018; published: july 31, 2019 copyright: ©2019 bosseila et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. manal bosseila, dermatology department, kasr alainy hospital, manial, cairo, egypt. email: manal.bosseila@ kasralainy.edu.eg 216 letter | dermatol pract concept 2019;9(3):10 patients, as reported previously in the literature [2,3] and in our case as well. the peripilar casts sign was reported previously as movable tubular structures that envelop the hair shafts in pv. it was suggested that acantholytic hair casts should be considered as a dermoscopic diagnostic feature of outer root sheath separation in cases of pv of the scalp and to indicate disease activity as well [1]. on the other hand, using standing disease duration [2]. our patient had scalp lesions for only 3 months at the time of presentation. conclusions it is noteworthy that the dermoscopic finding of multiple hair tufting in pv of the scalp was documented only in male figure 1. (a) patchy alopecia with yellow crusting over the vertex and frontal parts of the scalp. (b) by trichoscopy: follicular tufting (red circles) with follicular pustules and acantholytic hair casts (red arrows). erosions are minimal (green arrows) (×10). [copyright: ©2019 bosseila et al.] a b figure 2. (a) extensive hair loss 2 weeks later with visible erosions of the scalp. (b) by trichoscopy: multiple follicular tufting (red circles), acantholytic peripilar casts (red arrows) with larger areas of erosions on a pale pink background. few shiny white localized areas of fibrosis are seen (blue arrows) (×10). [copyright: ©2019 bosseila et al.] a b letter | dermatol pract concept 2019;9(3):10 217 20to 70-fold magnification to examine 26 cases of pv of the scalp, well-circumscribed hair casts were found in only 1 case, whereas other trichoscopic findings were observed, such as extravasations, yellow hemorrhagic crusts, and white diffuse scaling [3]. we propose that early cases of pv of the scalp may mimic clinically and dermoscopically the picture of folliculitis decalvans. the additional presence of tiny erosions and cylindrical casts around hair shafts by dermoscopy should draw the attention to the possibility of cutaneous pv. references 1. hadayer n, ramot y, maly a, zlotogorski a. pemphigus vulgaris with loss of hair on the scalp. int j trichology. 2013;5(3):157-158. 2. ko dk, chae is, chung kh, park js, chung h. persistent pemphigus vulgaris showing features of tufted hair folliculitis. ann dermatol. 2011;23(4):523-525. 3. sar-pomian m, rudnicka l, olszewska m. trichoscopy—a useful tool in the preliminary differential diagnosis of autoimmune bullous diseases. int j dermatol. 2017;56(10):996-1002. untitled observation | dermatol pract concept 2015;5(4):7 27 dermatology practical & conceptual www.derm101.com case report a 50-year-old male was urgently referred to our unit by his family doctor, who sought a specialist’s opinion about an asymptomatic pigmented lesion on the second toe of the right foot (figure 1a); the general practitioner wished to exclude the possibility of plantar melanoma. the patient was unable to reliably establish when the lesion appeared. examination showed pigmentation involving almost the entire nail and extending into the surrounding skin. dermatoscopy revealed uniform brownish-black pigmentation of the nail bed, involving the eponychium, lunula (suggestive of hutchinson sign) and lateral nail folds. in the hyponychium, pigmentation was mostly distributed on the ridges, forming a parallel-ridge pattern (figure 1b). these dermatoscopic features raised the differential diagnosis of acral lentiginous melanoma. however, examination of the left foot showed less evident but clinically and dermatoscopically similar findings on the second, third and fourth toes (figure 1c). detailed medical history revealed that the patient had run two marathons in recent months. we therefore performed partial scraping of the lesion on the right foot, which confirmed the clinically suspected diagnosis of purpura traumatica pedis. discussion marathon runners experience a range of dermatological conditions and tissue-related injuries caused by mechanical trauma, infectious pathogens, inflammatory processes and environmental factors [1]. sports medicine specialists, family parallel-ridge pattern on dermatoscopy: observation in a case of purpura traumatica pedis luca feci1, michele fimiani1, pietro rubegni1 1 dermatology section, department of clinical medicine and immunological sciences, siena university, italy key words: purpura traumatica pedis, dermatoscopy, parallel-ridge pattern, acral melanoma citation: feci l, fimiani m, rubegni p. parallel-ridge pattern on dermatoscopy: observation in a case of purpura traumatica pedis. dermatol pract concept 2015;5(4):7. doi: 10.5826/dpc.0504a07 received: january 15, 2015; accepted: june 30, 2015; published: october 31, 2015 copyright: ©2015 feci et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: luca feci, md, dermatology section, department of clinical medicine and immunology, siena university, viale bracci 1, 53100 siena, italy. tel. 0577 585482. email: lucafeci84@gmail.com dermatologists are often referred urgent cases of acral hematoma by general practitioners and sports medicine specialists for the purpose of excluding warts, nevi or melanoma. acral hematoma is often a cause of anxiety to patients and their families. here, we report a case of purpura traumatica pedis, referred to us as suspected plantar melanoma because of the finding of parallel-ridge pattern on dermatoscopic examination. to avoid unnecessary and costly procedures, doctors should inquire about any episode of physical exertion before the onset of purpura, recording the lesion’s anatomic site (e.g., unilateral vs. bilateral involvement) and clinical features. abstract 28 observation | dermatol pract concept 2015;5(4):7 mechanical dermatoses, such as post-traumatic punctate skin hemorrhage, friction bullae, callosities and onycho-cryptosis, are the most frequent skin disorders in runners. these injuries physicians, dermatologists and coaches should be familiar with these skin conditions to ensure timely and accurate diagnosis and correct management of affected athletes [2]. figure 1. (a) asymptomatic pigmented lesion on second toe of right foot; (b) dermatoscopy revealed uniform brownish-black pigmentation of the nail bed; in the hyponychium, pigmentation was distributed prevalently on the ridges (parallel-ridge pattern); (c) bilateral lesions having similar clinical and dermatoscopic appearance. [copyright: ©2015 feci et al.] result from friction, shear forces, chronic pressure and collisions with surfaces that occur when athletes endure repetitive jump landings, accelerated starts and stops and other maneuvers during rigorous training and competition. among these conditions, “purpura traumatica pedis” (black heel), frequently observed in young athletes, may be difficult to differentiate from acral lentiginous melanoma (table 1). this explains the anxiety with which these patients and their equally worried accompanying parents seek medical advice. diagnosis of traumatic purpura is often easy if sports come up during the medical history intake. in other cases, dermatoscopy may prove useful (table 1). indeed, dermatoscopic evidence of subcorneal hemorrhage in the form of reddish globules makes diagnosis easy in the case of recent lesions [3-5]. however, in some cases of older lesions, dermatoscopy does not enable acral melanoma to be distinguished from frictional purpura (figure 2), as both may show a parallel-ridge pattern [6,7]. in these patients, the bilateral distribution of acral lesions, as was seen in our case, indicates the correct diagnosis. in conclusion, to avoid unnecessary and costly procedures, doctors should inquire about any physical exertion by the patient before onset of the black macules on the feet, and should record the anatomic site of the lesions, as well as clinical and dermatoscopic features. if purpura traumatica pedis is suspected, partial scraping of the lesion may be a simple and minimally invasive way of confirming the diagnosis. references 1. adams bb. dermatologic disorders of the athlete. sports med. 2002;32:309-21. 2. de luca jf, adams bb, yosipovitch g. skin manifestations of athletes competing in the summer olympics: what a sports medicine physician should know. sports med. 2012;42:399-413. 3. zalaudek i, argenziano g, soyer hp, saurat jh, braun rp. dermoscopy of subcorneal hematoma. dermatol. surg. 2004;30:1229–32. figure 2. (a) acral lentiginous melanoma of the right toe. the square indicates the area from which the dermatoscopic image was obtained; (b) parallelridge pattern on dermatoscopy. [copyright: ©2015 feci et al.] observation | dermatol pract concept 2015;5(4):7 29 6. fracaroli ts, lavorato fg, maceira jp, barcaui c. parallel ridge pattern on dermoscopy: observation in non-melanoma cases. an bras dermatol. 2013;88:646-8. 7. bernabeu-wittel j, domínguez-cruz j, zulueta t, quintana j, conejo-mir j. hemorrhagic parallel-ridge pattern on dermatoscopy in “playstation fingertip”. j am acad dermatol. 2011;65:238-9. 4. saida t, koga h, uhara h. key points in dermoscopic differentiation between early acral melanoma and acral nevus. j dermatol. 2011;38:25-34. 5. rubegni p, burroni m, andreassi a, fimiani m. the role of dermoscopy and digital dermoscopy analysis in the diagnosis of pigmented skin lesions. arch dermatol. 2005;141:1444-6. table 1. acral hemorrhage versus acral melanoma: clinical and dermatoscopic clues acral hemorrhage acral melanoma clinical clue clinical aspect well-demarcated, roundish or irregularly shaped, sometimes linear or punctuated macules, with colors varying form blue-black to reddish-brown early acral melanoma appear as a spreading pigmented patch with varying degrees of pigment intensity. as the lesion evolves, it may appear as a large, black, mounded, ulcerated, and bleeding lesion distribution multiple toes single toe duration of lesion transient persistent   anamnesis history of physical trauma, sport activity, and/or treatment with anticoagulant medications patient usually denied physical trauma, sport activity, and/or treatment with anticoagulant medications dermoscopic clues red-black to grayish color whit a homogeneous pattern of pigmentation and red-black globules especially seen as satellites at the periphery of the lesion. present usually absent parallel-ridge pattern present in about 40% of cases (“pebbles on the ridges”) present (the pigmentation following the ridges, with hypopigmentation of the furrows, is the only clue of early acral melanoma) irregular diffuse pigmentation with variable shades, irregular dots and globules absent present in more locally advanced acral melanoma, along with brownish or black parallel ridge pattern blue-white veil and ulceration absent present in far-advanced acral melanoma, along with dark parallel ridge pattern   parallel-furrow and fibrillar patterns mostly absent (only 1 case reported in literature) rarely present dermatology: practical and conceptual observation | dermatol pract concept 2018;8(1):15 63 dermatology practical & conceptual www.derm101.com case report bowen’s disease (bd) is an in situ variant of cutaneous squamous cell carcinoma (scc). the pigmented variant is an important entity in the clinical differential diagnosis of pigmented melanocytic lesions. in most cases of pigmented bd, it is possible to have an accurate preoperative diagnosis with the typical dermoscopic features. rarely, there may be challenging cases hard to diagnose even with dermoscopic aid [1-3]. in such lesions, reflectance confocal microscopy (rcm) may play an important role as an additional in vivo diagnostic technique [4]. the rcm features of pigmented bd are scarcely in the literature [4-7]. herein, we report on a case of pigmented bd with atypical clinical and dermoscopic features that mimics a melanoma and describe its rcm features. a 67-year-old male with skin phototype iii presented to our clinic with an enlarging lesion on the pubis. clinically it was a light and dark brown flat plaque with 10 x 7 mm in diameter (figure 1a, inset). the patient had a history of cryosurgery for genital warts in the same region two years ago. the clinical differential diagnosis included a pigmented wart, seborrheic keratosis, pigmented bowen’s disease (bd), and melanoma. on dermoscopy, pigment network diversity of different colors (brown, black, gray), scar-like depigmentation, gray areas, dotted vessels on an erythematous base, and a few linear irregular vessels were seen (figure 1a). these dermoscopic features were compatible with a melanoma. on rcm (vivascope 1500 multilaser; lucid, rochester, ny, usa), at the stratum corneum some polygonal nucleated cells were seen focally. atypical honeycomb pattern was obvious (figure 1b). characteristic large, targetoid dyskeratotic cells at the spino-granular layer were observed (figure 2a). there were some dendritic cells also. at the dermo-epidermal junction (dej), dermal papillae were edged and seen as bright rings due to the pigmented keratinocytes (figure 2b). in addithe role of reflectance confocal microscopy in a case of bowen’s disease difficult to diagnose isil karaarslan1, sibel tepret, seda yildiz1, banu yaman2, fezal ozdemir1 1 department of dermatology, faculty of medicine, university of ege, izmir, turkey 2 department of pathology, faculty of medicine, university of ege, izmir, turkey key words: bowen’s disease, reflectance confocal microscopy, melanoma citation: karaarslan i, tepret s yildiz s, yaman b, ozdemir f. the role of reflectance confocal microscopy in a case of bowen’s disease difficult to diagnose. dermatol pract concept. 2018;8(1):63-65. doi: https://doi.org/10.5826/dpc.0801a15 received: june 15, 2017; accepted: september 20, 2017; published: january 31, 2018 copyright: ©2018 karaarslan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: seda yildiz, md, department of dermatology, faculty of medicine, university of ege, 35100, bornova, izmir, turkey. tel. +902323902698. email: yildizsda@gmail.com there have been limited reports describing reflectance confocal microscopy (rcm) features of bowen’s disease (bd). herein, we describe the rcm features of a pigmented bd with atypical dermoscopic features, mimicking a melanoma. this case highlights the importance of rcm in a challenging bd. abstract 64 observation | dermatol pract concept 2018;8(1):15 on histopathology, overlying parakeratosis and full-thickness atypia of epidermis with acanthosis were seen. increased melanin pigmentation at the basal cell layer was observed (figure 2d). these histopathologic features were compatible tion, tightly coiled characteristic vessels, some with s-shape, were seen in the center of dermal papillae throughout the lesion (figure 2c). these rcm findings were consistent with a bd. figure 1. (a) pigment network diversity (brown, black, gray), scar-like depigmentation, gray areas, dotted vessels on an erythematous base, and a few linear irregular vessels on dermoscopy (inset: clinical image). (b) atypical honeycomb pattern (keratinocytes with varying size and shape) at rcm (mosaic, 1 x 1.8 mm). inset: dendritic cells (red arrows) at a closer view. [copyright: ©2018 karaarslan et al.] figure 2. (a) dyskeratotic cells (large, round nucleated cells) at the spino-granular layer (mosaic, 0.6 x 1.1 mm). (b) small close-set edged papillae at the dej (mosaic, 6 x 6 mm) and (c) tightly coiled vessels, some with s-shape in the center of dermal papillae (mosaic, 1 x 1.5 mm). (d) histopathology: parakeratosis and full-thickness atypia of epidermis with acanthosis and increased melanin pigmentation at the basal cell layer (h&ex100). inset: sparse dendritic cells with cd1ax400. [copyright: ©2018 karaarslan et al.] observation | dermatol pract concept 2018;8(1):15 65 presence of small bright circles, namely, edged papillae, were sufficient to rule out a melanoma. this case highlights the importance of rcm in challenging bd. references 1. stante m, de giorgi v, massi d, chiarugi a, carli p. pigmented bowen’s disease mimicking cutaneous melanoma: clinical and dermoscopic aspects. dermatol surg. 2004;30(4 pt 1):541-544. 2. hayashi y, tanaka m, suzaki r, mori n, konohana i. dermoscopy of pigmented bowen’s disease mimicking early superficial spreading melanoma. case rep dermatol. 2009;1(1):11-15. 3. inoue t, kobayashi k, sawada m, et al. dermoscopic features of pigmented bowen’s disease in a japanese female mimicking malignant melanoma. dermatol res pract. 2010;2010. 4. blumetti tp, scope a, de macedo mp, et al. dermoscopic and reflectance confocal microscopy findings in extra-genital hpv16associated pigmented squamous cell carcinoma in situ. acta derm venereol. 2016;96(6):836-837. 5. cao t, oliviero m, rabinovitz hs. squamous cell carcinoma. in: hofmann-wellenhof r, pellacani g, malvehy j, soyer hp (eds). reflectance confocal microscopy for skin diseases. 1st ed. berlinheidelberg: springer-verlag; 2012:297-307. 6. fraga-braghiroli n, stephens a, oliviero m, rabinovitz h, scope a. small brown circles: an important diagnostic clue for pigmented squamous cell carcinoma. j am acad dermatol. 2013;69:e1611616113. 7. debarbieux s, perrot jl, cinotti e, et al. reflectance confocal microscopy of pigmented bowen’s disease: misleading dendritic cells. skin res technol. 2017;23(1):126-128. with a pigmented bd. the dendritic cells demonstrated by cd1a staining were sparse (figure 2d, inset). the diagnosis of pigmented scc on rcm rely on the presence of the scale crust, markedly atypical honeycomb or disarranged pattern, round nucleated cells (dyskeratotic keratinocytes) at the spino-granular layer, a ringed pattern composed of small close-set edged papillae at the dej, and the presence of tightly coiled vessels in the dermal papillae [4-6]. the diagnosis may sometimes be challenging because of the presence of numerous bright, large, round or dendritic cells infiltrating the epidermis, which may be interpreted as atypical cells seen in melanoma. indeed these cells represent pigmented keratinocytes, langerhans cells, or melanocytes [5]. recently, debarbieux et al. reported on three challenging cases of pigmented bowen’s disease that were falsely diagnosed melanomas due to the high density of misleading dendritic cells seen on rcm [7]. it is important to clearly visualize the entire dej with its characteristic small, close-set edged papillae to be able to rule out a melanoma [4]. in the present case, the dendritic cells were not numerous (figure 2d, inset), and the characteristic small, close-set edged papillae at the dej were clearly demonstrated. therefore, it was not difficult to rule out a melanoma. in summary, in the present case, the rcm findings were concordant with the diagnosis of pigmented bd. although there was an atypical honeycomb pattern with some dendritic cells suspicious for melanoma, the presence of dyskeratotic cells, edged papillae, and characteristic vessels warranted the diagnosis of bd. in reality, at first glance at the dej, the untitled review | dermatol pract concept 2015;5(3):11 47 dermatology practical & conceptual www.derm101.com introduction sport participants may experience activity-associated dermatoses. some of these cutaneous manifestations in athletes are unique to specific sports or the equipment used in these sports or both. a young girl is described who developed targetoid erythema at the locations where the ball contacted her body during a racquetball tournament and the “ball site (sportsinduced targetoid erythema) sign” is introduced to name this pathognomonic skin presentation secondary to impact of a the ball site sign: ball sports-induced targetoid erythema in a racquetball player philip r. cohen1 1 department of dermatology, university of california san diego, ca, usa key words: ball, erythema, floorball, paint, ping pong, player, purpura, racquetball, sign, site, sport, sports, squash, target, targetoid citation: cohen pr. the ball site sign: ball sports-induced targetoid erythema in a racquetball player. dermatol pract concept 2015;5(3)11. doi: 10.5826/dpc.0503a11 received: april 26, 2015; accepted: may 5, 2015; published: july 31, 2015 copyright: ©2015 cohen. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: cutaneous injury following impact of a high velocity ball to the skin may result in either erythema or purpura or both. the lesion typically appears as an annular ring of erythema with or without accompanying ecchymosis when the skin is contacted by a paintball, a ping pong ball, a racquetball or a squash ball. purpose: to describe a girl with targetoid erythema following impact of a racquetball on her flank and back and to review other sports associated with this response to skin injury. methods: pubmed was used to search the following terms, separately and in combination: ball, erythema, paint, ping pong, purpura, racquetball, sign, site, sports, squash, targetoid. all papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. results: a 13-year-old girl developed an annular red ring surrounding a central area of normal appearing skin on her right flank and upper back where a racquetball traveling at a high velocity contacted her skin. similar appearing lesions of targetoid erythema have been described at the cutaneous impact sites of either paintballs, ping pong balls, squash balls; in addition to erythema, purpura may also concurrently appear or subsequently develop at the contact location of the ball with the skin. conclusions: targetoid erythema is a pathognomonic cutaneous presentation resulting from the impact of either a paintball, ping pong ball, racquetball or squash ball—that is traveling at a high velocity—with a sport participant’s skin. the ball site (sports-induced targetoid erythema) sign is suggested as a unifying nomenclature to designate this unique, ball sport-associated, cutaneous dermatosis in athletes participating in sports in which high velocity impact of the ball with the skin may occur. abstract mailto:mitehead@gmail.com 48 review | dermatol pract concept 2015;5(3):11 site of impact, there was targetoid erythema: an annular red ring surrounding a central area of normal-appearing skin— approximately the diameter of the racquetball (figures 2 and 3). the erythema was flat on the back (figure 3) and raised on the right flank (figure 2). the tenderness resolved with in 24 hours. neither site developed purpura. the targetoid erythema at both locations spontaneously resolved within 7 to 10 days. discussion a distinctive cutaneous lesion from high velocity ball-to-skin impact has only been observed, to date, in association with five sports: floorball, paintball, ping pong, racquetball, and squash [1-16]. nomenclature, specific to each of the individual sports, has been proposed (table 1) [1-16]. however, the reference to these lesions as “sports purpura” is not always accurate since only erythema—without the sequential development of purpura—may occur [2,9,16]. the initial description of this phenomenon—using alliteration to eloquently emphasize the extraordinary entity—was reported by seigel et al in 1986 as “paint pellet purpura: a peril for pistol-packing paramilitary personnel” [3]; however, the initial lesions immediately after injury had not evaluated and may have shown targetoid erythema prior to the development of purpura. additional reports regarding this form of dermatosis in paintball competitors were eventually published [4]. subsequently, the terminology was modified and the “paint pellet” became known as the “paintball”; thereafter, several authors incorporated the new name of the dermatosis-causing object when describing similar lesions: paintball purpura [5-7]. high velocity contact from either a paintball, a ping pong ball, a racquetball or a squash ball to the skin. case report a 13-year-old healthy girl presented for evaluation of skin lesions that had occurred during a racquetball match. during the competition, on two separate occasions, a racquetball traveling at a high velocity contacted her skin instead of the wall. each episode was accompanied by pain localized to the site of impact. examination of the affected areas on her right flank and upper central back showed similar lesions (figure 1). at the figure 1. the “ball site (sports-induced targetoid erythema) sign” presenting as erythematous annular lesions surrounding normalappearing skin at the sites of high velocity contact of a racquetball with the skin on the right upper flank and the upper central back of a 13-year-old female racquetball player. [copyright: ©2015 cohen.] a b c figure 2 (a, b, and c). distant (a) and closer (b and c) views of the right upper flank show a “racquetball associated targetoid erythema (rate) sign” consisting of a central area of normal-appearing skin corresponding to the site of the racquetball contact with the skin and a broad surrounding raised annular red ring. [copyright: ©2015 cohen.] review | dermatol pract concept 2015;5(3):11 49 individual sport—that have previously been associated with this phenomenon, a unifying term, the “ball site (sportsinduced targetoid erythema) sign,” is introduced to designate this unique cutaneous pattern of injury. there are multiple components that contribute to the mechanism of injury. these include not only the velocity at which the ball is traveling, but also other characteristics of the ball such as the composition, the diameter, and the weight (table 2) [6-8,14,17-24]. scott and scott have hypothesized that the ping pong ball—traveling at a high velocity— becomes indented after it strikes the skin. once the contour of the ball has changed and maximum indentation has occurred, a targetoid lesion of erythema (or purpura) results when the circular edge of the indented ball impinges, with considerable pressure, against the skin [8]. however, the pathogenesis of injury resulting in targetoid erythema from skin contact with a high velocity paintball, racquet ball or squash ball may be different than that from a ping pong ball. it is possible that the faster, larger, and heavier paintball and racquetball produce centrally located, impact-associated, blanching with a peripheral zone of dermal changes characterized morphologically by macular or indurated erythema; in some circumstances, impactassociated vessel damage and extravasated erythrocytes in skin immediately adjacent to the contact site of the ball may subsequently result in clinical purpura. the point-of-contact injury from the faster and heavier squash ball is of sufficient impact to cause disruption of vessels with subsequent ecchymosis or destruction of epidermis and superficial dermis with resultant erosion or both; the adjacent tissue damage results not only in zones of circumferential blanching and erythema, but also—in some individuals—additional annular rings of blanching and purpura. scott and scott reported, “ping pong patches” on the thigh of a table tennis participant and mentioned that “similar annular, but larger, lesions may occur . . . by the balls used for racquetball and squash” [8]. barazi and adams provided an illustration of this pathognomonic targetoid erythematous pattern of injury in a racquetball player in a correspondence titled “sports purpura” [9-11]; however, similar to the girl in this report and the player described by barazi and adams, not all of the racquetball players developed purpura at the site of contact by ball with the skin. this unique dermatosis secondary to the high velocity impact of a squash ball with the skin has also been observed [12-15]. impact-associated injuries also occur in floorball players [16]. in contrast to the concentric annular lesions that occur following high velocity contact of the ball and the skin in participants of paintball, ping pong, racquetball and squash, ecchymotic patches of purpura have been described at the cutaneous impact site of the ball in floorball players [1,2]. the patch initially corresponds to the diameter of the holes in the ball; the lesion may subsequently enlarge and display a swiss cheese-like pattern with discrete white-round areas within the patch [1,2,10]. targetoid erythema resulting from the impact of a high velocity ball with the skin is a sports-related injury that has been observed in participants of paintball, ping pong, racquetball, and squash; subsequently, in some of the individuals, purpura may also develop. this distinctive lesion has not been noted in sports associated with either smaller balls (such as hand ball, perhaps because they do not travel at as fast a velocity) or larger balls (such as tennis balls, since they may not be altered on impact with the skin or because they may result in damage not only to the skin but also to the subcutaneous structures including fat, muscle and possibly bone). in contrast to the several names—related to each figure 3 (a and b). distant (a) and closer (b) views of the upper central back targetoid erythema associated resulting from contact of a racquetball with the skin appearing as normal skin at the impact site surrounded by an annular zone of macular erythema. [copyright: ©2015 cohen.] a b 50 review | dermatol pract concept 2015;5(3):11 table 1. sports-specific nomenclature of the cutaneous lesion resulting from the impact of a high velocity contact of the ball to the skin [a,b] floorball [c] floorball ecchymotic patches [1,2] floorball purpura [current report] paintball paintball purpura [5-7] paint pellet erythema [d] [4] paint pellet purpura [e] [3] ping pong ping pong patches [f] [8] racquetball annular erythematous (and occasionally purpuric) patches [g] [9] annular lesion [8] rate (racquetball-associated targetoid erythema) sign [current report] squash annular erythematous (and occasionally purpuric) patches [h] [9] annular lesion [8] teas (targetoid erythema associated with squash) sign [current report] [a] the term “sports purpura” has been used by some authors to describe the observed clinical lesions. however, erythema may: (1) only develop, or (2) concurrently present with purpura, or (3) initially appear and be followed subsequently by purpura [11]. [b] the “ball site (sports-induced targetoid erythema) sign” is a proposed new unifying terminology— regardless of the specific ball sport—to define the unique and pathognomonic cutaneous lesion resulting from high velocity impact contact of the ball to the skin. [c] floorball is also referred to as either innebandy (in sweden and norway), salibandy (in finland) and unihockey (in germany and switzerland); “bandy” refers to a team winter sport played on ice in which the skaters use sticks to hit a ball into the opposing team’s goal and “inne” and “sali” translates to “indoor”. the floorball ball is white, 72 mm in diameter, and 23 grams in weight and made of plastic; it is hollow and has 26 holes each of 11 mm in diameter. the fastest ball speed has been recorded at a velocity of 204 kilometers per hour (which is equivalent to 127 miles per hour) [1,2,10]. impact-associated injuries from the floorball were recorded in 3% of 172 injuries (occurring in 4 of 133 injured women) among a study group of 374 female floorball players [16]. ecchymotic patches of purpura occur at the cutaneous impact site of the ball in floorball players [1,2]. the patch is initially annular, confluent, and corresponds to the diameter of the holes in the ball; in some circumstances, the lesion enlarges and displays a swiss cheese-like pattern with discrete white-round areas within the patch [1,2,10]. [d] rahbari and nabai described “paint pellet erythema” in a 19-year-old man with “three nonpruritic, annular, erythematous lesions [on the upper back] . . . that developed after the patient was hit by several paint pellets two days earlier” [4]. [e] seigel et al described a “targetoid lesion” on both the arm and back of a 32-year-old woman that occurred at the “sites in which she was hit on bare flesh by paint bullets while enjoying a survival game outing two days previously”. the individual “irislike lesions had an ecchymotic margins surrounding a central clear zone and a ‘bullseye’superficial erosion” [3]. [f ] scott and scott observed that the lesions “are uniformly circular, 12 to 15 mm in diameter, with clear centers and an annular 3 mm border that is generally erythematous but may be purpuric”. they also included a figure of an “annular popliteal lesion from a racquet ball” [8]. [g] barazi and adams, in a correspondence titled “sports purpura,” include an accompanying figure legend that describes a “large, erythematous, annular patch created by the impact of a racquet ball.” the authors comment, “initially, the lesions demonstrate an annular, urticarial plaque, but progress to exhibit purpura” and that “the purpura may take one week to resolve [9]. [h] subsequent to the high velocity impact of a squash ball with the skin there is a central ecchymosis surrounded by a white ring and then an erythematous targetoid zone [12,13]. in some patients, additional zones of white (normal-appearing skin) and purpura are observed [14]. indeed, two brothers—camaron and morgan pilley—decided to confirm the clinical consequence to a participant’s back following contact of a high velocity squash ball with the skin. cameron, at a distance of 2 meters, served a squash ball directed toward his brother morgan’s back; an ecchymosis-lined erosion resulted at the point of contact that was surrounded by a white ring (or normal appearing skin) and a broad annular target of erythema [15]. review | dermatol pract concept 2015;5(3):11 51 the clinical differential diagnosis of the ball site sign includes annular or targetoid lesion with either flat or raised erythematous borders (table 3) [4-7,9]. the lesion may appear purpuric a few days after the causative event. however, a focused medical history readily suggests the correct diagnosis of a cutaneous injury secondary to contact of the skin with either a paint ball, ping pong ball, racquet ball or squash ball. symptomatic treatment for localized symptoms may be necessary. the ball site sign is accompanied by acute pain at the site of contact of the ball to the skin. macular or edematous erythema appears shortly after the traumatic event. impact-associated contusion to the underlying tissue may result in the affected area remaining mildly tender to palpation for the next few days; acetaminophen or nonsteroidal anti-inflammatory drugs may reduce the pain. the erythema (and occasional associated purpura) resolves spontaneously in approximately seven to 14 days. conclusion a distinctive cutaneous lesion occurs following high velocity ball-to-skin impact in participants of paintball, ping pong, racquetball and squash. targetoid erythema presents as an annular red ring surrounding a central normal-appearing area of skin at the site of contact of the paintball, ping pong ball or racquetball. in some of these individuals purpura may concurrently or subsequently develop; purpura alone may also occur following skin contact with a paintball. impact injury of a squash ball with the skin is associated with a central area of ecchymosis surrounded by a concentric white ring and an erythematous targetoid area. descriptive terms associated with each sport, often incorporating either alliteration or acronyms, have previously been used to name the lesion: paintball purpura, ping pong patches, racquetball-associated targetoid erythema (rate) sign, and targetoid erythema associated with squash (teas) sign. the “ball site (sports-induced targetoid erythema) sign,” is introduced as a unifying term to designate this unique cutaneous pattern of injury in athletes participating in sports in which high velocity impact of the ball with the skin may occur. table 2. characteristics of balls that can produce targetoid erythema following high velocity contact impact of the ball to the skin [a,b] ball paintball ping pong ball racquetball squash ball composition gelatin [c] plastic [d] rubber rubber [e] weight (gm) 3.2-3.3 2.5-2.7 56.7-58.5 23-25 diameter (mm) 17 38-40 57 39.5-40.5 speed (kph) [f] 307-330 161 124-241 >241 references 6,7,17,18 6,8,19 14,20-22 14,23,24 [a] abbreviations: gm, grams; kph, kilometers per hour; mm, millimeters; mph, miles per hour [b] the paintball is smaller (more than half the diameter) and heavier (about 25%) than a ping pong ball [6-8,18,19]. in contrast, the squash ball is the essentially the same diameter as a ping pong ball, but ten times heavier [8,19,24]. and, the racquetball is nearly 1½ times larger in diameter and more than twenty times heavier than a ping pong ball [8,10,19,20]. all of these balls potentially travel 1½ to twice as fast as a ping pong ball [6-8,14,17-24]. [c] spherical gelatin capsules containing primarily polyethylene glycol, other non-toxic and water-soluble substances and dye. [d] air filled, celluloid or similar plastics material. [e] the squash ball consists of two pieces of rubber compound, glued together to form a hollow sphere and buffed to a matte finish. [f ] the speed of the ball can also be calculated in miles per hour: paintball = 191-205, ping pong ball = 100, racquetball = 77-150, and squash ball = >150. racquetball speeds have ranged from: (1) 124 kph (77 mph) to 145 kph (90 mph) during matches with women and (2) 209 kph (130 mph) to 241 kph (150 mph) during matches with men; the fastest recorded speed is 307 kph (191 mph) [14,2022]. the fastest recorded squash ball speed is 204 kph (127 mph) [14,23,24]. table 3. clinical differential diagnosis of the ball site sign [a] cupping (application of suction cups) dermatitis medicamentosa erythema annulare centrifugum erythema chronicum migrans erythema multiforme factitial dermatitis fixed drug eruption granuloma annulare gyrate erythemas insect bite reaction majocchi’s disease (purpura annularis telangiectoides) physical abuse tinea corporis urticaria [a] the “ball site sign,” is the “ball sports-induced targetoid erythema sign.” 52 review | dermatol pract concept 2015;5(3):11 15. bednall j. serve on sibling an internet hit. in: the advertiser. posted november 6, 2011. http://www.adelaidenow.com.au/sport/ serve-on-sibling-an-internet-hit/story-e6frecj3-12226186684669 accessed may 9, 2015. 16. pasanen k, parkkari j, kannus p, et al. injury risk in female football: a prospective one-season follow-up. scand j med sci sports 2008;18:49-54. [pmid = 17490461] 17. conn jm, annest jl, gilchrist j, ryan gw. injuries from paintball game related activities in the united states, 1997-2001. injury prevention 2004;10:139-43. [pmid = 15178668] 18. woodward a. how paintball is made-material, making, history, used, product, industry, machine, history, raw materials, the manufacturing process of paintball, quality control, byproducts/ waste. http://www.madehow.com/volume-6/paintball.html accessed may 9, 2015. 19. the ball (version for 40mm balls) technical leaflet t3. in: the international table tennis federation. posted may, 2011. http:// www.ittf.com/stories/pictures/t3_ball40mm_bod2011.pdf accessed may 9, 2015. 20. what are the dimensions of a racquetball ball? http://www.answers.com/q/what_are_the_dimensions_of_a_racquetball_ball accessed may 9, 2015. 21. cox n: racquetball speed. in: squash & racquetball. posted april 17, 2011. http://en.allexperts.com/q/squash-racquetball1548/2008/4/f/racquetball-speed.htm accessed may 9, 2015. 22. 1996-97 aara official rules of racquetball. in: the garden state racquetball association official aara racquetball rules. http:// www.math.rutgers.edu/~sontag/racquetball-rules.html accessed may 9, 2015. 23. horton l. big-banging aussie clocks up 176 mph raising the bar by . . . one. in: squash mad. posted may 9, 2014. http:// squashmad.com/breaking-news/cameroin-pilley-breaks-his-ownworld-speed-record/ accessed may 9, 2015. 24. balls-the name of the game. in: squash player. http://www.squashplayer.co.uk/squash_balls.htm accessed may 9, 2015. references 1. kluger n. sports purpura from football, indoor climbing, and archery [case letter]. cutis 2015;95:e3-e4. [pmid = in progress] 2. kluger n. sports purpura. presse med 2012;41:899-906. [pmid = 22386284] 3. siegel dm, goldberg lh, altman ar, kalter dc. paint pellet purpura: a peril for pistol-packing paramilitary personnel [letter]. jama 1986;255:3367. [pmid = 3712695] 4. rahbari h, nabai h. paint pellet erythema [letter]. pediatr dermatol 1996;13:174-5. [pmid = 9122082] 5. metelitsa a, barankin b, lin an. diagnosis of sports-related dermatoses. int j dermatol 2004;43:113-9. [pmid = 15125501] 6. levsky me, crowe m. what is your diagnosis? paintball purpura. cutis 2005;75:148,157-8. [pmid = 15839357] 7. aboutalebi s, stetson cl. paintball purpura [letter]. j am acad dermatol 2005;53:901-902. [pmid = 16243154] 8. scott mj jr, scott mj 3rd. ping pong patches. cutis 1989;43:363-4. [pmid = 2731441] 9. barazi h, adams bb. sports purpura. int j dermatol 2006;45:1443. [pmid = 17184253] 10. what’s floorball? in: australian floorball association. posted july 6, 2009. http://www.floorball.org.au/index.php?option=com_co ntent&view=category&id=3&layout=blog&ltemid=5 accessed may 9, 2015. 11. aguayo-leiva i, vano-galvan s, arrazola jm. a purpuric rash. aust fam physician 2009;38:889-90. [pmid = 19893836] 12. powell r. howick squash: hit by a squash ball. posted thursday, 28 april 2011. http://howicksquash.blogspot.com/2011/04/hitby-squash-ball.html accessed may 9, 2015. 13. reed l. my worse sports injury—abc wa—australian broadcasting corrporation (abc). in: saturday breakfast with pat hagan. posted june 17, 2010. http://blogs.abc.net.au/wa/2010/06/ my-worse-sports-injury.html?site=kimberley&program=kimberl ey_saturday_breakfast accessed may 9, 2015. 14. nair d. squash or tennis, which one is the harder sport? in: racquet social. http://racquetsocial.com/squash-or-tennis-whichone-is-the-harder-sport/ accessed may 9, 2015. http://www.adelaidenow.com.au/sport/serve-on-sibling-an-internet-hit/story-e6frecj3-12226186684669 http://www.adelaidenow.com.au/sport/serve-on-sibling-an-internet-hit/story-e6frecj3-12226186684669 http://www.madehow.com/volume-6/paintball.html http://www.ittf.com/stories/pictures/t3_ball40mm_bod2011.pdf http://www.ittf.com/stories/pictures/t3_ball40mm_bod2011.pdf http://www.answers.com/q/what_are_the_dimensions_of_a_racquetball_ball http://www.answers.com/q/what_are_the_dimensions_of_a_racquetball_ball http://en.allexperts.com/q/squash-racquetball-1548/2008/4/f/racquetball-speed.htm http://en.allexperts.com/q/squash-racquetball-1548/2008/4/f/racquetball-speed.htm http://www.math.rutgers.edu/~sontag/racquetball-rules.html http://www.math.rutgers.edu/~sontag/racquetball-rules.html http://squashmad.com/breaking-news/cameroin-pilley-breaks-his-own-world-speed-record/ http://squashmad.com/breaking-news/cameroin-pilley-breaks-his-own-world-speed-record/ http://squashmad.com/breaking-news/cameroin-pilley-breaks-his-own-world-speed-record/ http://www.squashplayer.co.uk/squash_balls.htm http://www.squashplayer.co.uk/squash_balls.htm http://www.floorball.org.au/index.php?option=com_content&view=category&id=3&layout=blog&ltemid=5 http://www.floorball.org.au/index.php?option=com_content&view=category&id=3&layout=blog&ltemid=5 http://howicksquash.blogspot.com/2011/04/hit-by-squash-ball.html http://howicksquash.blogspot.com/2011/04/hit-by-squash-ball.html http://blogs.abc.net.au/wa/2010/06/my-worse-sports-injury.html?site=kimberley&program=kimberley_saturday_breakfast http://blogs.abc.net.au/wa/2010/06/my-worse-sports-injury.html?site=kimberley&program=kimberley_saturday_breakfast http://blogs.abc.net.au/wa/2010/06/my-worse-sports-injury.html?site=kimberley&program=kimberley_saturday_breakfast http://racquetsocial.com/squash-or-tennis-which-one-is-the-harder-sport/ http://racquetsocial.com/squash-or-tennis-which-one-is-the-harder-sport/ dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):10 297 dermatology practical & conceptual introduction eumycotic mycetoma is a localized suppurative, granulomatous infection of subcutaneous tissue, which is characterized by the triad of painless mass, discharging sinuses, and grains/ granules. it develops after a penetrating injury causing inoculation of the organism that eventually results in a local disease, followed by spread of the infection to the surrounding soft tissues and osseous structures [1]. dermoscopy has become a very important noninvasive tool to assist in the diagnosis of many infectious diseases and infestations. there are few reports demonstrating the utility of dermoscopy in the diagnosis of subcutaneous fungal infections such as chromoblastomycosis [2] and eumycotic mycetoma [1]. here we report the dermoscopic patterns of a case of eumycotic mycetoma caused by madurella species in a patient with skin type 5. case presentation a 46-year-old man presented with a 2-year history of skin lesions on the left wrist that developed after a thorn prick. a dermoscopy of eumycotic mycetoma: a case report balachandra s. ankad1, r. manjula1, trilokraj tejasvi2, balakrishna p. nikam3 1 department of dermatology, s. nijalingappa medical college, karnataka, india 2 michigan medicine dermatology, university of michigan, ann arbor, mi, usa 3 krishna institute of medical sciences, karad, maharashtra, india key words: dermoscopy, eumycotic mycetoma, yellow globules, patterns citation: ankad bs, manjula r, tejasvi t, nikam bp. dermoscopy of eumycotic mycetoma: a case report. dermatol pract concept. 2019;9(4):297-299. doi: https://doi.org/10.5826/dpc.0904a10 accepted: april 1, 2019; published: october 31, 2019 copyright: ©2019 ankad et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: balachandra s. ankad, md, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot 587103, karnataka, india. email: drbsankad@gmail.com figure 1. clinical image of eumycotic mycetoma showing slightly indurated mass with discharging sinuses on the wrist (a) before and (b) after treatment. [copyright: ©2019 ankad et al.] a b 298 letter | dermatol pract concept 2019;9(4):10 surgeon had previously excised the thorn. the patient reported extrusion of black particles from the lesion initially. examination revealed a mildly indurated mass with multiple discharging sinuses (figure 1a). dermoscopic examination, using dermlite 3 with ×10 magnification in contact polarized mode, showed yellow globules, white superficial scales, telangiectasia and dotted vessels, blood spots, and whitish structureless areas (figures 2a and 3a). histopathology was consistent with eumycotic mycetoma with demonstration of granulomatous reaction and granules in mid dermis (figure 4). madurella grisea species was isolated on culture. the patient was treated with itraconazole 100 mg twice daily for 2 months, resulting in complete resolution of skin lesions (figure 1b). after the therapy, dermoscopic assessment revealed a reduction in yellow globules, white superficial scales, and dotted vessels, while figure 4. histopathology of eumycotic mycetoma shows suppurative granuloma composed of neutrophils in the dermis (h&e, ×10). [copyright: ©2019 ankad et al.] figure 2. dermoscopy of eumycotic mycetoma; lesion 1: (a) before treatment, yellow globules (black arrows) and white superficial scales (red arrows) are seen. (b) after treatment, yellow globules (yellow arrow), white superficial scales (red arrows), white globules (blue arrow), and red structureless areas (black arrows) are observed. note the reduction of structures except whitish structureless areas (black stars). [copyright: ©2019 ankad et al.] a b figure 3. dermoscopy of eumycotic mycetoma; lesion 2: (a) before treatment, yellow globules (black arrows), whitish structureless areas (red stars), telangiectasia and dotted vessels (yellow arrows), white superficial scales (red arrows), and blood spots (yellow star) are seen. (b) after treatment, reduction in yellow globules (yellow arrows), white superficial scales (red arrows), and dotted vessels (black arrows) are observed. note the prominent whitish structureless areas (black stars) after treatment. [copyright: ©2019 ankad et al.] a b letter | dermatol pract concept 2019;9(4):10 299 reduced significantly after the therapy, thereby emphasizing that their resolution can be helpful when monitoring treatment response. conclusions besides poorly specific findings (white structureless areas, telangiectasias, blood spots, and white scales), eumycotic mycetoma due to madurella species may feature yellow globules. these structures may be related to the granulomatous reaction, and their detection might be of aid, along with clinical and anamnestic data, in suspecting such a condition and guiding the clinician in taking samples for microbiological analysis in order to reach a definitive diagnosis. since this is a single case based on observation, further studies involving larger samples are recommended to elucidate and validate our findings. references 1. reis lm, lima bz, zillo fda c, rezende cm, fabricio lh, pinto ca. dermoscopy assisting the diagnosis of mycetoma: case report and literature review. an bras dermatol. 2014;89(5):832-833. 2. subhadarshani s, yadav d. dermoscopy of chromoblastomycosis. dermatol pract concept. 2017;7(4):23-24. whitish structureless areas were more pronounced compared with the initial picture (figures 2b and 3b). discussion from a dermoscopic-pathological correlation point of view, yellow globules detected in our case could correspond to dermal granulomas caused by madurella. generally, granuloma demonstrates orange-yellow globules. here, yellow color probably is due to granulomatous reaction with many neutrophils. whitish structureless areas and white superficial scales were other unspecific dermoscopic findings, which represent dermal fibrosis and hyperkeratosis, respectively. finally, blood spots represented dried blood. in a previous report, dermoscopy of eumycetoma showed white and yellow structures, which were similar to the present case [1]. in addition, white superficial scales and telangiectasia, blood spots, and dotted vessels were seen in our instance. in chromoblastomycosis, dermoscopy shows yellow globules, black dots, crusting, and white areas, which are [2] similar to mycetoma patterns, so the only difference from eumycetoma is the detection of black dots. interestingly, many of the dermoscopic findings (yellow globules, telangiectasias, blood spots, and white scales) were dermatology: practical and conceptual observation | dermatol pract concept 2018;8(2):2 75 dermatology practical & conceptual www.derm101.com introduction pseudoxanthoma elasticum (pxe) is a rare inherited disease of connective tissue causing fragmentation and mineralization of elastic fibers that primarily affects the skin, retina, and cardiovascular system [1]. classically it is characterized by multiple asymptomatic small (1–5 mm in size), yellowish coalescing papules that are symmetrically distributed on the neck and flexural body areas, such as the axillae, antecubital fossae, periumbilical, inguinal and popliteal areas [2]. periumbilical perforating pseudoxanthoma elasticum (pppxe) is considered a localized variant of inherited pxe based on the presence of angioid streaks (22% of cases) and flexural lesions [3]. some believe it to be an acquired dermatosis secondary to cutaneous trauma caused by multiple pregnancies, obesity, and multiple abdominal surgeries or trauma resulting in elastic fiber degeneration in these patients [4,5]. sapadin et al considered pppxe a bridge between the pure acquired form and the pure inherited form [6]. we report on a case of acquired pppxe with dermoscopic features. case presentation a 68-year-old multiparous woman presented with multiple yellowish, asymptomatic periumbilical lesions. the lesions had appeared two years ago and had slowly enlarged to form yellowish papules coalescing to form a plaque along with a few red-brown colored papules with central keratotic material (figure 1). there was no history of similar disease in the family. there was no history of any abdominal surgery. on examination, the patient was obese and had no evidence of any associated systemic disease. on cutaneous examination, multiple yellowish, asymptomatic periumbilical papules and periumbilical perforating pseudoxanthoma elasticum: a rare case report abhijeet k. jha1, md zeeshan1, binod k. sinha, anupama singh, pallavi agrawal2 1 department of skin & vd, patna medical college and hospital, patna, bihar, india 2 department of pathology, patna medical college and hospital, patna, bihar, india key words: periumbilical perforating pseudoxanthoma elasticum (pppxe), dermoscopy citation: jha ak, zeeshan md, sinha bk, singh a, agrawal p. periumbilical perforating pseudoxanthoma elasticum: a rare case report. dermatol pract concept. 2018;8(2):75-77. doi: https://doi.org/10.5826/dpc.0802a02 received: september 25, 2017; accepted: october 24, 2017; published: april 30, 2018 copyright: ©2018 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & v.d, patna medical college and hospital, patna, pin-800004, bihar, india. tel. +00919631444797. email: drabhijeetjha@gmail.com periumbilical perforating pseudoxanthoma elasticum (pppxe) usually presents with well-defined periumbilical yellowish atrophic plaques with keratotic papules at the periphery. it is considered a variant of hereditary pseudoxanthoma elasticum or a localized acquired cutaneous dermatosis. the lesions usually occur in the periumbilical area in obese, multiparous women. here, we report an additional case of periumbilical perforating pseudoxanthoma elasticum with its dermoscopic features. abstract 76 observation | dermatol pract concept 2018;8(2):2 gested to describe this condition [9]. on dermoscopy, a yellowish hue may be due to the elastolysis of elastic fibers or the presence of calcium deposits as in pxe [10,11]. there is no established treatment of pppxe. dietary calcium restriction plaques were present with few red-brown colored papules. dermoscopy (polarized, 10x, dermlite dl 4; 3gen, san juan capistrano, ca) revealed yellowish brown structureless areas along with semicircular, curved/serpiginous yellowish-brown lines, with few linear vessels along with a keratotic plug with central crater (figure 2 a, b). on histopathology the yellowish papule showed an increased number of elastic fibers in the upper and mid reticular dermis. the elastic fibers were fragmented and curled giving the appearance of raveled wool. a focus of calcification was also seen (figure 3). histological examination was consistent with the diagnosis of pppxe. cardiologic evaluation (normal electrocardiogram and echocardiogram) and ophthalmoscopic examination did not show any changes. routine laboratory tests and serum lipid profile were all within normal range. discussion the term pppxe was first used in 1979 by hicks [4]. earlier it was described as pseudoxanthoma elasticum (pxe) with coexisting elastosis perforans serpiginosa (eps). lund and gilbert were the first to establish it as a separate entity [7]. the term “localized acquired cutaneous pseudoxanthoma elasticum” was also proposed, as pppxe was believed to be “acquired” and lacked “systemic involvement.” [8] recently, the term “perforating calcific elastosis (pce)” has been sugfigure 1. periumbilical yellowish-white plaque with reddish brown keratotic papules at the periphery. [copyright: ©2018 jha et al.] figure 2. (a) dermoscopy (polarized, 10x) showed yellowish brown structureless areas along with semicircular, curved/serpiginous yellowish-brown lines, with few linear vessels. (b) dermoscopy (polarized, 10x) showed yellowish brown structureless areas along with semicircular, curved/serpiginous yellowish-brown lines with few linear vessels and keratotic plug with central crater. [copyright: ©2018 jha et al. a b observation | dermatol pract concept 2018;8(2):2 77 references 1. neldner kh. pseudoxanthoma elasticum. clin dermatol. 1988;6:1–159. 2. ko jh, shih yc, huang yh, yang ch. pseudoxanthoma elasticum. lancet. 2013;381:565. 3. woo ty, rasmussen je. disorders of transepidermal elimination. part 1. int j dermatol. 1985;24:267–269. 4. hicks j, carpenter cl jr, reed rj. periumbilical perforating pseudoxanthoma elasticum. arch dermatol. 1979;115:300-303. 5. kazakis am, parish wr. periumbilical perforating pseudoxanthoma elasticum. j am acad dermatol. 1988;19:384–388. 6. sapadin an, lebwohl mg, teich sa, phelps rg, dicostanzo d, cohen sr. periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks—apparent regression with hemodialysis. j am acad dermatol. 1998;39:338-344. 7. lund hz, gilbert cf. perforating pseudoxanthoma elasticum: its distinction from elastosis perforans serpiginosa. arch pathol lab med. 1976;100:544-546. 8. neldner kh, martinez-hernandez a. localized acquired cutaneous pseudoxanthoma elasticum. j am acad dermatol. 1992;26:642-644. 9. lopes lc, lobo l, bajanca r. perforating calcific elastosis. j eur acad dermatol venereol. 2003;17:206-207. 10. oiso n, kato m, kawada a. fibroelastolytic papulosis in an elderly woman with a 30-year history: overlapping between pseudoxanthoma elasticum-like papillary dermal elastolysis and white fibrous papulosis of the neck. eur j dermatol. 2014;24:688-689. 11. nasca mr, lacarrubba f, caltabiano r, verzı ae, micali g. perforating pseudoxanthoma elasticum with secondary elastosis perforans serpiginosa-like changes: dermoscopy, confocal microscopy and histopathological correlation. j cutan pathol. 2016;43:10. 12. sherer dw, singer g, uribarri j, et al. oral phosphate binders in the treatment of pseudoxanthoma elasticum. j am acad dermatol. 2005;53:610-615. (800 mg/day) and oral phosphate binder have been reported to have significant clinical improvement in pxe [12]. these treatment modalities may be tried in pppxe, as the pathological process involved in pxe and pppxe is similar. we report pppxe with calcinosis cutis in a rare presentation along with dermoscopic findings. figure  3. the elastic fibers are fragmented and curled giving appearance of raveled wool with a focus of calcification. (h&e, 40x). [copyright: ©2018 jha et al.] dermatology: practical and conceptual quiz | dermatol pract concept 2015;5(1):14 77 dermatology practical & conceptual www.derm101.com below is the answer to the quiz by dr. şenel et al presented in the previous issue of dermatology practical & conceptual [2014;4(4):13]. diagnosis: kaposi sarcoma. kaposi sarcoma (ks) was first described by kaposi in 1872. there are four clinical types of the disease: classic, endemic, epidemic and iatrogenic [1]. iatrogenic ks develops in patients taking immunosuppressive treatment. bluish-reddish coloration is seen in 84% of ks lesions in dermatoscopy. rainbow pattern and scaly surface are other dermatoscopic features of ks (36% and 15%, respectively) [2]. multicolored rainbow pattern is the most diagnostic appearance of ks in dermatoscopic evaluation and is associated with vascular lumen-rich histological sub-type [3]. this pattern can be rarely seen in the dermatoscopy of melanoma [4]. congratulations to dr. arina vashkevich (aavashk@mail. ru), who was the first to send us the correct answer! references 1. ahmadpoor p. human herpesvirus-8 and kaposi sarcoma after kidney transplantation: mechanisms of tumor genesis. iran j kid dis 2009;3(3):121-26. 2. hu sc, ke cl, lee ch, et al. dermoscopy of kaposi’s sarcoma: areas exhibiting the multicoloured ‘rainbow pattern’. j eur acad dermatol venereol 2009;23(10):1128-32. 3. şenel e. dermatoscopy of non-melanocytic skin tumors. indian j dermatol venereol leprol 2011;77(1):16-21; quiz 22. 4. cheng st, ke cl, lee ch, et al. rainbow pattern in kaposi’s sarcoma under polarized dermoscopy: a dermoscopic pathological study. br j dermatol 2009;160(4):801-9. what is your diagnosis? a solitary purple papule on the arm—answer engin şenel1, yasemin yuyucu karabulut2 1 hitit university faculty of medicine, department of dermatology, çorum, turkey 2 mersin university faculty of medicine, department of pathology, mersin, turkey citation: şenel e. karabulut yy. what is your diagnosis? a solitary papule on the arm dermatol pract concept. 2015;5(1):14. doi: 10.5826/dpc.0501a14 copyright: ©2015 şenel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: engin şenel, md, bba, assistant professor of dermatology, hitit university faculty of medicine, department of dermatology, 19200 çorum, turkey. tel. +90 364 2230300; fax +90 364 2230323. email: enginsenel@enginsenel.com mailto:aavashk@mail.ru mailto:aavashk@mail.ru mailto:enginsenel@enginsenel.com dermatology: practical and conceptual research | dermatol pract concept 2014;4(4):8 47 dermatology practical & conceptual www.derm101.com introduction the soles of the feet are the sites of predilection for acral lentiginous melanoma (alm) in the colored races [1]. approximately 7% of the japanese population has acral melanocytic nevus [1]. alm often shows a parallel ridge pattern (prp), with a specificity of 99% and a sensitivity of 86% [1,4]. in contrast, the acral melanocytic nevus shows a parallel furrow pattern (pfp, 54%), lattice-like pattern (21%), or fibrillar pattern (fp, 15%) [5,6]. comparison of dermatoscopic images of acral lentiginous melanoma and acral melanocytic nevus occurring on body weight-bearing areas soko watanabe1, mizuki sawada1, sumiko ishizaki1, ken kobayashi2, masaru tanaka1 1 department of dermatology, tokyo woman’s medical university medical center east, tokyo, japan 2 kobayashi dermatology clinic, tokyo, japan keywords: acral lentiginous melanoma, acral melanocytic nevus, negative fibrillar pattern, dermatoscopy citation: watanabe s, sawada m, ishizaki s, kobayashi k, tanaka m. comparison of dermatoscopic images of acral lentiginous melanoma and acral melanocytic nevus occurring on body weight-bearing areas. dermatol pract concept. 2014;4(4):8. http://dx.doi. org/10.5826/dpc.0404a08 received: april 21, 2014; accepted: june 15, 2014; published: october 31, 2014 copyright: ©2014 watanabe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors declare no conflict of interest. contribution: all authors have contributed significantly to this publication. corresponding author: soko watanabe, md, department of dermatology, tokyo women’s medical university medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111; fax: +81 3 3894 1441. e-mail: soko1031@yahoo.co.jp background: because body weight-bearing produces a shift in the horny layer, acral melanocytic nevus on the body weight-bearing area of the sole showed a regular fibrillar pattern (fp) due to slanting of the melanin columns in the horny layer. on the other hand, acral lentiginous melanoma (alm) on the body weight-bearing area of the sole tended to show irregular fibrillar pattern showing rather structureless pigmentation instead of a parallel ridge pattern, which is due to the shift of the horny layer. objective: to elucidate the subtle difference between the regular fp of nevus and irregular fp in alm. methods: in this study, the dermatoscopic features of five cases of alm and five cases of acral melanocytic nevus on the weight-bearing area of the sole were compared. results: all the cases with nevi showed regular fp showing regular distribution of fibrils, whereas all the melanomas showed irregular distribution of fibrils and colors. fibrils in nevi tended to be clear at the furrows and dim at the ridges. white fibrils corresponding to the eccrine ducts in the horny layer were more often present on the ridges in alm, which showed negative fp. conclusion: differentiating between the regular and irregular fp, including negative fp, might be helpful for the discrimination of melanoma from nevus. abstract 48 research | dermatol pract concept 2014;4(4):8 results the results are summarized in table 1. the four cases of acral melanocytic nevus showed regular distribution of colors with an exception of the case 3 nevi, which showed negative fp and was confirmed histopathologically as a nevus. all the alm cases showed irregular distribution of colors. all the nevus showed regular distribution of fibrils, whereas all the alm cases showed irregular distribution. all the fibrils terminated at the furrows in all cases of acral nevus. one alm case showed termination of the fibrils at the furrows only partially. most of alm cases showed dark and diffuse background and therefore white lines, which correspond to eccrine openings, were well observed. only in case 3 did the nevus show dark and diffuse background and white lines, namely negative fp. the other four cases of nevus did not show white lines. in these four nevi, there were hypopigmented spaces between the fibrils. the white lines corresponding to eccrine ducts were distinguishable from the hypopigmented spaces between the fibrils. discussion fp is regarded as a benign pattern [8]. however, alm on the body weight-loading area of the sole also shows fibrillar area at least partly and often shows irregular fp. we have recently noted the difference between the fp in nevi and irregular fp in alm, namely that the background is much darker and more diffuse in irregular fp in alm than in regular fp in nevi and eccrine openings are more distinct in alm (figure 1). we defined the “negative fp” as white lines corresponding to the bearing of body weight produces a shift in the horny layer; therefore, acral melanocytic nevus in the weight-bearing area of the sole often shows a regular fibrillar pattern (fp) due to slanting of the melanin columns in the horny layer. the fibrils tend to be clear at the furrows and dim at the ridges. the length of the fibrils is dependent on the thickness of the horny layer or the extent of weight-bearing. their thickness likely depends on the amount of melanin present. however, on the weight-bearing area of the feet, alm often shows structureless pigmentation instead of prp and 10% of acral melanocytic nevi show an atypical pattern [5,7]. alm sometimes shows whitish fibrils corresponding to eccrine ducts in the horny layer of the ridge of the structureless pigmentation, which we term “negative fp” (figure 1). negative fp is composed of whitish fibrils, corresponding to the elongated eccrine ducts, and the diffuse pigmentation as a background. this is often observed in alm on the weightbearing area, although it is seldom found in acral nevus in the same area. the reason for negative fp is probably due to the much darker background in alm than that in nevus. materials and methods five cases of alm (age: 39-68, median 67; 2 males and 3 females; histopathology: 4 cases were in situ, 1 case was invasive with tumor thickness of 1.6 mm) and five cases of acral melanocytic nevi (age: 7-38, median 16; 2 males and 3 females; 4 cases showed typical regular fibrillar pattern on dermatoscopy and histopathology of 1 as junctional nevus) with fp, on the body weight-bearing area of the sole, were used to compare the frequency of dermatoscopic features, including fp, negative fp, distribution of colors and fibrils, and whether the fibrils terminated at the furrows. figure 1. dermatoscopy of acral lentiginous melanoma located alm on the left sole near the fifth toe. the non-loaded area showed the typical parallel ridge pattern and regular white dots corresponding to the eccrine pores on the center of the ridges. the loaded area showed a more homogeneous brown pigmentation and a short negative fibrillar pattern was observed. (copyright: ©2014 watanabe et al.) table 1. comparison of dermatoscopic features between acral lentiginous melanoma and acral nevus occurring on the body weightbearing area of the sole cases alm (5) acral nevus (5) fibrillar pattern 5 5 regular distribution of colors 0 4 regular distribution of fibrils 0 5 fibrils terminatingending at the furrows 1 5 negative fibrillar pattern 5 1 alm, acral lentiginous melanoma research | dermatol pract concept 2014;4(4):8 49 eccrine intraepidermal ducts on the dark background, which is observed in nevi or more often in alm on the body weightloading area of the sole. negative fp was more commonly observed in alm (figures 2 and 3), however, only one case of acral melanocytic nevus showed these findings. negative fp could be observed when the background was dark. alm often shows prp, which is characterized by rather diffuse pigmentation divided by whitish lines at the furrows. when body weight-bearing produces a shift in the horny layer, the pigmentation of the prp might become more diffuse, thus darkening the background. the eccrine ducts are usually whitish and therefore not conspicuous on a lighter background, but when the background became dark, the eccrine dust could be seen more clearly as whitish fibrils, thus indicating a negative fp. acral melanocytic nevus also shows hypopigmented spaces between the fibrils, simulating negative fp, however, these figure 2. dermatoscopy of acral lentiginous melanoma on the loaded area, case 1. on the gray-blue to dark brown structureless background, a negative fibrillar pattern was conspicuous at the 12 to 6 o’clock position (black arrowhead). (copyright: ©2014 watanabe et al.) figure 3. dermatoscopy of acral lentiginous melanoma alm on the loaded area, case 2. a negative fibrillar pattern was observed on the light brown background. (copyright: ©2014 watanabe et al.) figure 4. dermatoscopy of acral melanocytic nevus on the loaded area, case 1. the double dotted line variant seemed to change into the short fibrillar pattern due to the body weight loading. the distribution of the dark brown fibrils was sparse and regular. there was no negative fibrillar pattern, fp but there were hypopigmented spaces between the fibrils. (copyright: ©2014 watanabe et al.) figure 5. dermatoscopy of acral melanocytic nevus on the loaded area, case 2. each fibril was densely arranged and the hypopigmented spaces between fibrils simulated negative fibrillar pattern. however, they terminated randomly and were light brown in color. (copyright: ©2014 watanabe et al.) figure 6. dermatoscopy of acral melanocytic nevus on the loaded area, case 3. this exceptional case of acral melanocytic nevus showed a negative fibrillar pattern, but the fibrils were regular and terminated at the furrows. (copyright: ©2014 watanabe et al.) 50 research | dermatol pract concept 2014;4(4):8 2. bellows cf, belafsky p, forgang is, beech dj. melanoma in african-americans: trends in biological behavior and clinical characteristics over two decades. j surg oncol. 2001;78:10-16. 3. ishihara k, saida t, yamamoto a. updated statistical data for malignant melanoma in japan. int j clin oncol. 2001;6:109-16. 4. saida t, miyazaki a, oguchi s, et al. significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in japan. arch dermatol. 2004;140:1233-8. 5. saida t, oguchi s, ishihara y. in vivo observation of magnified features of pigmented lesions on volar skin using video macroscope. usefulness of epiluminescence techniques in clinical diagnosis. arch dermatol. 1995;131:298-304. 6. oguchi s, saida t, koganehira y, et al. characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin. a videomicroscopic analysis. arch dermatol. 1998;134:563-568. 7. tanaka m, kimoto m, saida t. acral nevus. in: soyer hp et al, ed. color atlas of melanocytic lesions of the skin. new york: springer, 2007:66-74. 8. braun rp, thomas l, dusza sw, et al. dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society. dermatology. 2013;227:373-80. hypopigmented spaces were not as thin and white as the eccrine ducts. furthermore, these hypopigmented spaces did not terminate at the center of the ridges and were distributed more irregularly (figures 4 and 5). acral melanocytic nevus also showed negative fp, when it produced more melanin than usual and demonstrated long and dense fibrils (figure 6). the distribution of the fp is also important for the differentiation of alm from acral nevus. alm has the tendency to show an irregular overall distribution of colors and thickness of each fibril. in contrast, acral melanocytic nevus shows a regular distribution of fibrils that terminate at the furrows. irregular prp is an important finding indicative of alm, but when this feature is unclear owing to the body weightbearing and structureless pigmentation, a finding of negative fp or irregular fibril distribution might be helpful for the diagnosis of alm. this study was presented at the 77th annual meeting of the tokyo division of the japanese dermatological association. references 1. saida t, koga h, yamazaki y, tanaka m. acral melanoma. in: soyer hp et al, ed. color atlas of melanocytic lesions of the skin. new york: springer, 2007:196-203. dermatology: practical and conceptual 308 letter | dermatol pract concept 2019;9(4):15 dermatology practical & conceptual introduction we read with great interest a case report by chessa et al [1], which seems to be the first case describing the distinct clinical and dermoscopic features of favre-racouchot disease (frd). we present another patient with similar features. case presentation a 71-year-old man, retired bricklayer, presented with an asymptomatic, erythematous plaque with agminated whitish waxy and hyperkeratotic papules within the right malar area (figure 1a). the lesion had developed several months before. a case of unilateral inflamed plaques with comedones on the face: another case of an uncommon clinical presentation of favre-racouchot disease michał sobjanek1, martyna sławińska1, wojciech biernat2 1 department of dermatology, venereology and allergology, medical university of gdańsk, poland 2 department of pathomorphology, medical university of gdańsk, poland key words: favre-racouchot disease, comedones, nodules and cysts, solar elastosis, yellowish lobular-like pattern citation: sobjanek m, sławińska m, biernat w. a case of unilateral inflamed plaques with comedones on the face: another case of an uncommon clinical presentation of favre-racouchot disease. dermatol pract concept. 2019;9(4):308-309. doi: https://doi.org/10.5826/ dpc.0904a15 accepted: april 10, 2019; published: october 31, 2019 copyright: ©2019 sobjanek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: martyna sławińska, md, department of dermatology, venereology and allergology, medical university of gdansk, smoluchowskiego 17 st, 80-214 gdańsk, poland. email: mslawinska@gumed.edu.pl figure 1. (a) clinical presentation: an erythematous plaque with agminated whitish waxy and hyperkeratotic papules within the right malar area. (b,c) dermoscopic presentation: pinkish white globular structures intersected with the yellowish structureless areas corresponding with the presence of a crust. [copyright: ©2019 sobjanek et al.] a b c letter | dermatol pract concept 2019;9(4):15 309 and to our knowledge not typical of any known dermatosis. references 1. chessa ma, filippi f, ferrara f, patrizi a, baraldi c. a case of unilateral inflamed plaques with comedones of the face. dermatol pract concept. 2018;8(4):292-294. 2. paganelli a, mandel vd, kaleci s, pellacani g, rossi e. favre-racouchot disease: systematic review and possible therapeutic strategies. j eur acad dermatol venereol. 2019;33(1):32-41. conclusions frd is a relatively common disorder, and usually the diagnosis can be simply made based on clinical presentation [2]. the unique morphology and unilateral location in both discussed cases made the diagnosis more difficult. the presence of disseminated comedones and signs of photo-damage could serve as a clue to diagnosis. dermoscopic presentation in both cases was very similar in addition, disseminated individual comedones, small cysts, solar elastosis, and telangiectasia were present on both cheeks and nose. the patient had a history of basal cell carcinoma, hidradenitis suppurativa, type 2 diabetes, permanent atrial fibrillation, 25 packyears of cigarette smoking, and chronic professional as well as recreational sun exposure. dermoscopy showed pinkish white globular structures intersected with the yellowish structureless areas corresponding with the presence of a crust (figure 1, b and c). in differential diagnosis frd, pyoderma vegetans, sarcoidosis, tuberculosis, and papillated variant of bowen disease were considered. histopathological examination revealed cryptic invagination of the infundibular portion of the hair follicle filled with the horny material with overhanging polypoid protrusion of the skin with comedo-like dilation of the other infundibulum, confirming the diagnosis of frd (figure 2). figure 2. (a) cryptic invagination of the infundibular portion of the hair follicle filled with the horny material with overhanging polypoid protrusion of the skin with comedo-like dilation of the other infundibulum. (b) one of the follicles shows suppurative inflammation and dense lymphoplasmacellular infiltrate in the stroma. [copyright: ©2019 sobjanek et al.] a b dermatology: practical and conceptual 126 research | dermatol pract concept 2019;9(2):8 dermatology practical & conceptual total body photography and sequential digital dermoscopy in pregnant women gabriela m. martins-costa1, renato bakos1,2 1 postgraduate program in medical sciences, universidade federal do rio grande do sul (ufrgs), brazil 2 department of dermatology, hospital de clínicas de porto alegre (hcpa), universidade federal do rio grande do sul (ufrgs), brazil key words: dermoscopy, melanocytic nevi, pregnancy, digital monitoring, total body photography citation: martins-costa gm, bakos r. total body photography and sequential digital dermoscopy in pregnant women. dermatol pract concept. 2019;9(2):126-131. doi: https://doi.org/10.5826/dpc.0902a08 accepted: january 30, 2019; published: april 30, 2019 copyright: ©2019 martins-costa and bakos. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: gabriela m. martins-costa, msc, rua goncalo de carvalho, 221/301, floresta, porto alegre, rs, brazil, 900350170. email: gmynarskimc@gmail.com background: melanocytic nevi can vary in size and number in pregnant women, and the differential diagnosis with melanoma may be challenging. objectives: to describe changes in total body photography of pregnant women and dermoscopy aspects of their nevi. methods: a prospective cohort study with 703 melanocytic nevi from 18 women was performed, comparing them in the first and third trimester of pregnancy. images were analyzed between the 2 periods for changes in dermoscopic aspects. results: total body photography images indicated that 44% of patients had new lesions. regarding the observed changes, there were symmetric or regular changes of the network (23% of cases), occurrence of new globules/dots (12.4%), new vascular structures (3.2%), new streaks (1.7%), and new structureless area (1.0%). moreover, 55.0% of the nevi increased in size. enlarging of the nevi was observed mostly on the abdomen (87.1%; p < 0.001) and showed more network changes (27.1%; p = 0.014) and formation of new globules and dots (16.0%; p < 0.001). patients with a risk of developing melanoma presented more frequently enlarged nevi (45%; p = 0.019). the association between streak formation and skin type was significant (p = 0.012) and was more frequent in skin type ii (2.7%), when compared with skin types iii (1.3%) and iv (0%). conclusions: development of new melanocytic nevi may occur in pregnant women. the majority of the preexisting melanocytic nevi showed enlarging, and most of them presented with benign dermoscopic changes. the appearance of new streaks is more frequent in fair skin types. patients with a personal or family history of melanoma in first-degree relatives presented more nevi with changes in size. abstract research | dermatol pract concept 2019;9(2):8 127 or without darkening and thickening in a symmetric distribution. the other dermoscopic structure changes were also considered to be physiological when they occurred also in a symmetric or regular distribution. lesions that presented network and other dermoscopic structures changing in an asymmetric or irregular distribution were considered for excision. in addition, we tested the association of total body photography and dermoscopic changes with patients’ clinical features, such as skin type, presence of relevant melanoma risk factors (high-risk patients for melanoma were those with personal or family history of melanoma in first-degree relatives), and age. descriptive statistics were obtained for continuous data using mean and standard deviation with chi-square tests. for the categorical data, the numbers and percentages were analyzed with t test and wald chi-square tests. at the data crossing, we used the contingency tables with the chi-square test adjusted with generalized estimating equations. the study significance level was set at α = 0.05 (p < 0.05). data were analyzed with spss version 22.0. results we evaluated total body photography of 18 pregnant women and digital dermoscopy of 703 melanocytic nevi. we observed a mean of 43.5 nevi per patient (ranging from 9 to 69). patients’ ages ranged from 28 to 44 years. the mean age was 33 years (sd = 3.49). the mean number of pregnancies was 1.44 (sd = 0.70). four patients (4/18; 22.2%) had a positive family history of melanoma and one patient had a personal history of melanoma. regarding skin types, 9/18 patients (50%) had skin type iii, 7/18 patients (33.3 %) had type ii, and 3/18 patients (16.6%) had type iv. thirteen patients had some degree of freckling and solar lentigines (13/18; 72.2%). the most frequent global dermoscopic pattern was the reticular global pattern, present in approximately 16/18 (88.9%) patients. when comparing total body photography images between the first and third trimester, 8/18 (44%) patients presented new melanocytic nevi, ranging from 1 to 5 new lesions per patient. several body sites were involved, but all patients with new lesions presented at least one of them on the upper limbs. patients younger than 30 years of age presented more frequently new melanocytic nevi formation when compared with patients older than 30 (6/16; 37.5%; p < 0.001) (table 1). regarding sequential dermoscopic evaluation of nevi, 55% (387/703) of the nevi enlarged when the first and third trimesters were compared. seventy-three of 703 (10.4%) had increased pigmentation. considering baseline dermoscopic structures in preexisting nevi, pigmented network was the structure most frequently showing changes (163/703; introduction pregnancy is known as one of the clinical scenarios capable of inducing dynamic dermoscopic changes in melanocytic nevi [1,2]. some other factors are age, skin type, and ultraviolet radiation exposure. a few studies on dermoscopic alterations in melanocytic nevi during pregnancy have already showed an increase in size, darkening and/or lightening of lesions, variations of pigmented network, appearance of dots or globules, and increased vascularization as possible changing features [2,3]. recently, melanoma in pregnant women has been reported to be associated with increased mortality when compared with nonpregnant women [4-6]. therefore, it is crucial to recognize physiological or benign dermoscopic changes in melanocytic nevi and differentiate them from potential malignant transformation. most studies that have been published on dermoscopic changes of nevi during the gestational period have evaluated only a few lesions from each patient [2,7,8-15]. as far as we know there are no reports of total body photography in pregnant women. the aim of the present study was to evaluate the occurrence of new melanocytic lesions in pregnant women and to describe dermoscopic changes in preexisting nevi using total body photography and digital dermoscopy follow-up. methods pregnant women with a minimum of 10 nevi were consecutively recruited to the study. the patients were invited to participate after a regular visit at our department or a regular prenatal visit at the department of gynecology and obstetrics. informed consent was obtained at the beginning of the observational period according to an institutional review board-approved protocol. the visits were performed in the first and third trimesters of gestation. total body photography and digital dermoscopy from the majority of the patient’s melanocytic nevi were taken, using a nonpolarized light video dermatoscope (fotofinder; fotofinder systems, tübingen, germany). digital images between the two evaluations were then compared by one of the authors; equivocal lesions were also analyzed by a second observer. melanocytic nevi were defined as pigmented lesions 2 mm or more in size and presenting a nevus-compatible dermoscopic pattern. a total of 703 melanocytic nevi were evaluated and analyzed for changes in size and for changes in dermoscopic features (network, streaks, globules and dots, new structureless area, pigment pattern, and vascularization). changes in size and shape were evaluated by the automated fotofinder moleanalyzer system and were given in square millimeters. we considered pigment network changes associated with the pregnancy-nevus behavior: expansion (increase in size) with 128 research | dermatol pract concept 2019;9(2):8 women. meanwhile, few reports have described pigmentary changes in lesions that were further diagnosed as melanomas [9,15]. the authors emphasized that during follow-up these lesions presented asymmetric changes in shape and size as well as occurrence of new dermoscopic structures such as starburst pattern, streaks, black dots, dark red areas, and blue-gray pigmentation that increased the suspicion of a malignant behavior. we demonstrated that nevi may go through changes during pregnancy. the changes occur generally in a symmetric and regular fashion. we observed in our study that 55% of preexisting nevi enlarged in the third trimester, mainly on the abdomen in comparison with other body sites (p < 0.001) (figure 2). in line with our data, strumia et al evaluated nevi of 12 pregnant women and found a major enlargement 23.2%). we observed new vascular structures in 23 lesions; they were dotted or comma-like vessels, regularly distributed. new streaks were visualized in only 12 lesions, also symmetrically distributed in the lesion or at the periphery. data on new melanocytic lesions and modifications in preexisting nevi are shown in table 2. when analyzing an association between enlargement of nevi with clinical aspects and presence of dermoscopic structures, we observed that the majority of the enlarged nevi were located at the abdomen (88/101; 87.1%; p < 0.001) in comparison with other body locations. we could not find an association between enlargement of nevi and skin types (p = 0.959) and age (p = 0.867). patients with a risk of developing melanoma presented with more nevi that increased in size (99/220; 45%; p = 0.019). enlarged nevi presented typical network changes (105/387; 27%; p = 0.014) and globule/dot formation (62/387; 16%; p < 0.001) (table 3). regarding the association of dermoscopic changes in preexisting nevi and association with skin types, patients with the fair skin type had more streak formation than did those with dark skin types iii and iv (p = 0.012). there was no correlation between different skin types and other dermoscopic changes. there was no association between high-risk patients for melanoma and occurrence of new dermoscopic structures or changes, such as network change (p = 0.915), globule/dot formation (p = 0.816), or streaks (p = 0.320) (data not shown). discussion the use of digital follow-up and dermoscopy to evaluate pigmented lesion changes in pregnancy is certainly the best approach in early detection of melanoma in pregnancy in high-risk patients for melanoma. they are noninvasive tools and do not carry any fetal risk [13,16]. pigmentary changes, such as melasma and enlargement of nevi, are frequently reported by pregnant women [17]. in our study we observed an occurrence of new melanocytic nevi in 44% of the patients. in all pregnant women with new lesions, at least one of them occurred on the upper limbs (figure 1). despite pregnancy effects, we suggest that sun exposure may play a major role in this association. previous reports described single nevus modifications during pregnancy [8,13,16,17]. duarte et al reported a new lesion in the nipple of a pregnant woman that involuted to its baseline size 2 months after delivery [8]. zampetti et al described modifications of a preexisting nevus on the nose [13]. although we had only 2 patients younger than 30 years, we could observe that pregnant women at this age presented more new lesions than older women. to our knowledge, this is the first study to report the occurrence of new benign melanocytic lesions evaluated by total body photography in a series of pregnant table 1. clinical characteristics of new lesions during total body photography clinical characteristics n (%) patients with new lesions 8 (44.4) no. of new lesions per patient 1 lesion 2 (11.0) 2 lesions 2 (11.0) ≥ 3 lesions 4 (17.0) location of new lesions (n = 21) upper limbs 8 (100.0) chest 3 (37.5) abdomen 3 (37.5) lower limbs 3 (37.5) back 2 (25.0) head 1 (12.5) neck 1 (12.5) table 2. frequencies of dermoscopic changes between first and third trimester observed in 703 melanocytic nevi dermoscopic aspects n (%) enlargement 387 (55.6) pigmentation hyperpigmentation 73 (10.4) hypopigmentation 41 (5.8) dermoscopic structures network changes 163 (23.2) new dots/globules 87 (12.4) new vascular structures 23 (3.2) new streaks 12 (1.7) new structureless areas 7 (1.0) research | dermatol pract concept 2019;9(2):8 129 the first and third trimester (p = 0.001). the enlargements were more significant on the anterior portion of the body, although they did not reach a statistically significant difference. they observed, however, a statistically significant increase in nevus total dermoscopy score (tds) mean when comparing the first and third trimesters (p = 0.008) [9-11]. of nevi in pregnancy-related expanding areas, showing that body site is the most significant factor for nevus enlargement in pregnancy [7]. moreover, zampino et al studied only nevi on the back of 47 pregnant women and they did not observe alteration in size [10]. aktürk et al noticed a statistically significant difference between the mean diameters of nevi in table 3. association of nevus enlargement with body location, skin type, melanoma risk, presence of dermoscopic structures, and age group (n = 703) n (%) p value body location abdomen 88/101 (87.1) <0.001 back 100/178 (56.2) anterior chest 79/146 (54.1) lower limbs 58/114 (50.9) neck 19/39(48.7) face 10/28 (35.7) upper limbs 29/93 (31.2) skin type iv 32/54 (59.3) ii 142/255 (55.7) 0.959 iii 213/394 (54.1) high-risk patients for melanomaa 99/220 (45.0) 0.019 dermoscopic structures network changes 105/387 (27.1) 0.014 globules/dots formation 62/387 (16.0) <0.001 streaks 6/387 (1.6) 0.765 age group (n = 18) <30 yrs old 1/2 (50.0) 0.867 >30 yrs old 9/16 (56.3) apatients presenting with personal or family history of melanoma in first-degree relatives. figure 1. (a) baseline image of the anterior portion of the trunk and arms of a patient during the first trimester. (b) the development of a new lesion in the right arm in the third trimester (red square) is highlighted in the left upper corner. blue arrows are not relevant for this evaluation. they are markers in the system that we used which are necessary to number nevi that will be evaluated by dermoscopy. [copyright: ©2019 martins-costa and bakos] a b 130 research | dermatol pract concept 2019;9(2):8 and increase of globules/dots (in number and in size), thickening of the pigmented network, and radial streaming formation [12]. zampino et al observed a progressive lightening of the nevi at the end of pregnancy and after delivery. the lesions showed persisting changes in network. at the end of pregnancy, vessels increased and a higher tds was observed, with a significant reduction in both after delivery [10]. although not frequent, we observed streaks and structureless area formation in our study [12-16]. it is important to state that new structures occurred in a symmetric and regular distribution. patients with fair skin usually have more nevi than those with dark skin types. we observed that new streaks were more frequent among pregnant women with fair skin, although we did not observe any other association regarding dermoscopic changes of preexisting nevi and skin types [19]. during the follow-up period we decided to remove only 1 lesion. it was a new, fast-growing, atypical melanocytic lesion in the third trimester in a patient with a family history of melanoma and a history of progesterone use during the first weeks of gestation (figure 4). the histopathological analysis reported dysplastic melanocytic nevi (figure 4). irregular hyperpigmentation areas have recently been described as one of most relevant dermoscopic structures in differentiating atypical nevi from in situ melanoma. therefore, we reinforce the need for removing lesions with this kind of dermoscopic picture during pregnancy [23]. conclusions the limitation of this study is the low number of patients included, although we believe that the results presented can be representative of melanocytic nevi during pregnancy. moreover, pregnancy occurs usually in young women. it is known that melanocytic nevi may vary in size and number at this age. although we did not include a control group of nonpregnant women paired by age, we also believe that our data reflect dynamic changes in melanocytic nevi associated with pregnancy and not high-risk patients for melanoma also presented more changing nevi in comparison with low-risk patients. several studies have reported that those patients show more “unstable” nevi. this finding reinforces that pregnant women with multiple nevi and past or family history of melanoma should be closely monitored during pregnancy [17-20]. moreover, the occurrence of new or changing melanocytic lesions in pregnancy showing an irregular or asymmetric pattern should be prompted for excision to rule out melanoma [6,13,20]. pigmented network symmetric thickening/enlargement and new development of globules/dots in a regular distribution were the most common dermoscopic alterations found in the study (figure 3). homogeneous network enlargement and well-distributed globules and dots may be associated with physiological changes in melanocytic nevi of young people. these are dermoscopic features generally associated with growth in melanocytic nevi [20-24]. regarding these dermoscopic changes, rubegni et al observed a more prominent pigment network with architectural disorder and darkening of globules [14]. in the postpartum period the globules faded, but the lesions showed persisting changes in network. moreover, gunduz et al studied the nevi of 21 pregnant women and reported a tds increase of 19% in the lesions. major dermoscopic changes were darkening figure 4. dermoscopic image showing a new irregular pigmented lesion in the third trimester on the left buttock (20 × original magnification). histopathological examination revealed an atypical nevus. [copyright: ©2019 martins-costa and bakos] figure 2. (a) dermoscopic image (20 × original magnification) of a melanocytic lesion in the first trimester on the lateral trunk. (b) image from the same nevus in the third trimester showing enlargement with a symmetric and homogeneous network distribution. [copyright: ©2019 martins-costa and bakos] a b figure 3. (a) dermoscopic image (20 × original magnification) of a melanocytic lesion in the first trimester on the middle of the torso. (b) image from the same nevus in the third trimester showing a rim of symmetric and homogeneous distributed dots in the periphery of the lesion. [copyright: ©2019 martins-costa and bakos] a b research | dermatol pract concept 2019;9(2):8 131 9. sato t, ishiko a, saito m, tanaka m, ishimoto h, amagai m. rapid growth of malignant melanoma in pregnancy. j dtsch dermatol ges. 2008;6(2):126-129. 10. zampino mr, corazza m, costantino d, mollica g, virgili a. are melanocytic nevi influenced by pregnancy? a dermoscopic evaluation. dermatol surg. 2006;32(12):1497-1504. 11. aktürk as, bilen n, bayramgurler d, et al. dermoscopy is a suitable method for the observation of the pregnancy-related changes in melanocytic nevi. j eur acad dermatol venereol. 2007;21(8):1086-1090. 12. gunduz k, koltan s, sahin mt, e filiz e. analysis of melanocytic naevi by dermoscopy during pregnancy. j eur acad dermatol venereol. 2003;17(3):349-351. 13. zampetti a, feliciani c, landi f, et al. management and dermoscopy of fast-growing nevi in pregnancy: case report and literature review. j cutan med surg. 2006;10(5):249-252. 14. rubegni p, sbano p, burroni m, et al. melanocytic skin lesions and pregnancy: digital dermoscopy analysis. skin res technol. 2007;13(2):143-147. 15. canosa jm, brechtbühl er, duprat neto jp, rezze gg. dermatoscopy in pregnancy [in portuguese]. surg cosmet dermatol [internet]. 2011;3(3):261-263. available at: http://www.redalyc. org/articulo.oa?id=265522087016. accessed may 24, 2018. 16. campos-do-carmo g, ramos-e-silva m. dermoscopy: basic concepts. int j dermatol. 2008;47(7):712-719. 17. kar s, krishnan a, shivkumar pv. pregnancy and skin. j obstet gynaecol india. 2012;62(3):268-275. 18. haenssle hamn, ngassa a, buhl t, et al. association of patient risk factors and frequency of nevus-associated cutaneous melanomas. jama dermatol. 2016;152(3):291-298. 19. tuma b, yamada s, atallah an, araujo fm, hirata sh. dermoscopy of black skin: a cross-sectional study of clinical and dermoscopic features of melanocytic lesions in individuals with type v/vi skin compared to those with type i/ii skin. j am acad dermatol. 2015;73(1):114-119. 20. fikrle t, pizinger k, szakos h, et al. digital dermatoscopic followup of 1027 melanocytic lesions in 121 patients at risk of malignant melanoma. j eur acad dermatol venereol. 2013;27(2):180186. 21. enninga ea, holtan sg, creedon dj, et al. immunomodulatory effects of sex hormones: requirements for pregnancy and relevance in melanoma. mayo clin proc. 2014;89(4):520-535. 22. holtan sg, creedon dj, haluska p, markovic sn. cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. mayo clin proc. 2009;84(11):985-1000. 23. lallas a, longo c, manfredini m, et al. accuracy of dermoscopic criteria for the diagnosis of melanoma in situ. jama dermatol. 2018;154(4):414-419. 24. mackie rm, english j, aitchison tc, fitzsimons cp, wilson p. the number and distribution of benign pigmented moles (melanocytic naevi) in a healthy british population. br j dermatol. 1985;113(2):167-174. only with age. these observations are probably transitory due to physiological changes and might not affect lifetime nevus count [24]. finally, pregnancy is clearly the major clinical scenario in which melanocytic nevi might present clinical and dermoscopic changes. in this paper we point out some modifications that pregnant women may present in total body photography and sequential dermoscopy. we demonstrate that a significant portion of pregnant women develop new lesions. in addition, symmetric and regular enlargement in the size, network changes, and new formation of globules/dots were the major alterations observed in preexisting nevi. further studies comparing total body photography and dermoscopic images of melanocytic nevi in pregnant women and nonpregnant control women might help in elucidating the impact of other factors for dynamic changes in nevi during pregnancy. acknowledgments the authors thank dr. inês alencar de castro (in memoriam) for her valuable contribution to this work. references 1. zalaudek i, docimo g, argenziano g. using dermoscopic criteria and patient-related factors for the management of pigmented melanocytic nevi. arch dermatol. 2009;145(7):816-826. 2. borges v, puig s, malvehy j. melanocytic nevi, melanoma, and pregnancy [in spanish]. actas dermosifiliogr. 2011;102(9):650657. 3. sanchez jl, figueroa ld, rodriguez e. behavior of melanocytic nevi during pregnancy. am j dermatopathol. 1984;6 suppl:89-91. 4. stensheim h, moller b, van dijk t, fossa sd. cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. j clin oncol. 2009;27(1):4551. 5. moller h, purushotham a, linklater km, et al. recent childbirth is an adverse prognostic factor in breast cancer and melanoma, but not in hodgkin lymphoma. eur j cancer. 2013;49(17):36863693. 6. byrom l, olsen c, knight l, khosrotehrani k, green ac. increased mortality for pregnancy-associated melanoma: systematic review and meta-analysis. j eur acad dermatol venereol. 2015;29(8):1457-1466. 7. strumia r. digital epiluminescence microscopy in nevi during pregnancy. dermatology. 2002; 205(2):186-187. 8. duarte af, correia o. pregnancy breast lesions: the role of dermoscopy [abstract p1703]. j am acad dermatol. 2009; 60(suppl): ab89. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):9 295 dermatology practical & conceptual introduction basal cell carcinoma (bcc) is the most common malignancy in western populations. metastatic bcc (mbcc), however, is extremely rare and occurs in only 0.0028%-0.55% of cases. despite the recent introduction of hedgehog pathway inhibitors, the prognosis for mbcc remains poor [1]. case presentation a 73-year-old previously healthy caucasian woman was admitted to uddevalla hospital because of her impaired general condition. her hemoglobin level was 40 g/l and she had experienced significant weight loss. physical examination revealed a 37× 14-cm ulcerated tumor from the cervical region vertebra c7 to the level of vertebrae l1-l2 (figure 1a). the tumor had been growing on her back for the last decade. biopsies of the tumor showed an infiltrative bcc. three firm subcutaneous nodules could be visualized and palpated along the in-transit route toward the right axilla with 2 nodules located 1 and 7 cm, respectively, from the ulcerated tumor and a third in the right axilla. mri showed infiltrative tumor growth into the underlying subcutaneous tissues including muscles and spinous processes. the presence of metastases was difficult to assess with computed tomography (ct) because of the large amount of pleural fluid (figure 2a). plastic surgeons were consulted, but the tumor was considered inoperable. multidisciplinary consultation resulted in a recommendation of systemic therapy with the hedgehog pathway inhibitor vismodegib 150 mg per os per day. during the first 3 months of treatment, the tumor shrank significantly to 24 × 12 cm. however, a new ct scan revealed a suspected metastasis 20 mm in diameter in the inferior lobe of the right lung and 4 smaller metastases in the inferior lobe of the left lung. oncologists were consulted, but since the side effects of vismodegib were considered moderate (mild muscle cramps, diffuse alopecia, and ageusia), it was recommended that the patient continue with vismodegib. after 7 months of treatment, a third ct scan detected several new 2to 3-mm metastases in both lungs, and the neglected basal cell carcinoma with fatal outcome jenna pakka1, joanna holm2, annika m. börjesson3, christina b. halldin1, john paoli1 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 department of dermatology and venereology, uddevalla hospital, uddevalla, sweden 3 department of radiology, sahlgrenska university hospital, gothenburg, sweden key words: basal cell carcinoma, metastasis, patient delay, hedgehog inhibitor citation: pakka j, holm j, börjesson am, halldin cb, paoli j. neglected basal cell carcinoma with fatal outcome. dermatol pract concept. 2019;9(4):295-296. doi: https://doi.org/10.5826/dpc.0904a09 accepted: march 7, 2019; published: october 31, 2019 copyright: ©2019 pakka et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: jenna pakka, md, department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gröna stråket 16, 41345 gothenburg, sweden. email: jenna.pakka@vgregion.se 296 letter | dermatol pract concept 2019;9(4):9 ry of published cases from 1981 through 2011. jama dermatol. 2013;149(5):615616. the management of basal cell carcinoma. j am acad dermatol. 2018;78(3):540-559. 2. wysong a, aasi sz, tang jy. update on metastatic basal cell carcinoma: a summasmall metastases that were detected in previous ct scans had increased in size (figure 2b). furthermore, the healing process of the large bcc on the back had ceased (figure 1b). the decreasing effect of vismodegib was suspected to be caused by resistance development. the treatment was finally discontinued after 12 months. the patient died 6 months later, which was 1 year and 10 months after the diagnosis. conclusions this rare case is a reminder of the potential of bccs to metastasize and even cause a fatal outcome. mbcc has been associated with a high mortality rate, with median survival of only 8-10 months after the diagnosis [2]. the tumor size was considered the only risk factor for mbcc in this patient. because of the patient’s unwillingness and the general palliative approach, biopsies were not taken to confirm that the lung metastases were from the bcc. however, the patient had no other known cancers or symptoms suggesting other origins. although vismodegib showed good effect initially, the response was only partial. the response rate of this relatively new medicine in patients with mbcc has varied between 30.0% and 37.9% [1]. references 1. kim jys, koslow jh, mittal b, moyer j, olencki t, rodgers p. guidelines of care for figure 1. clinical picture showing a massive tumor on the patient’s back (a) before and (b) 6 months after the initiation of treatment with vismodegib. [copyright: ©2019 pakka et al.] a b figure 2. computed tomography scan showing the progression of the metastases (a) before and (b) 6 months after the initiation of treatment with vismodegib. initially, the lung metastases were difficult to assess because of the large amount of pleural fluid. [copyright: ©2019 pakka et al.] a b dermatology: practical and conceptual 244 letter | dermatol pract concept 2018;8(3):18 dermatology practical & conceptual www.derm101.com giant clear cell acanthoma with dermatoscopic white lines omid zargari1, seyyede zeinab azimi2, siamak geranmayeh3 1 dermatology, dana clinic, rasht, iran 2 department of dermatology, guilan university of medical sciences, rasht, iran 3 sina pathobiology laboratory, rasht, iran key words: clear cell acanthoma, dermatoscopy, epidermal tumor citation: zargari o, azimi sz, geranmayeh s. giant clear cell acanthoma with dermatoscopic white lines. dermatol pract concept. 2018;8(3):244-246. doi: https://doi.org/10.5826/dpc.0803a18 received: december 9, 2017; accepted: february 2, 2018; published: july 31, 2018 copyright: ©2018 zargari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: seyyede zeinab azimi, md, department of dermatology, guilan university of medical sciences, razi hospital, rasht, iran, 41448. email: sz.azimi@yahoo.com. introduction clear cell acanthoma (cca) was first described by degos in 1962 [1] and has been referred to as degos’ acanthoma. it is a benign epidermal tumor that commonly emerges as a solitary dome-shaped lesion on the legs with no gender predilection [1]. however, eruptive forms and involvements of other areas such as inguinal region, scrotum, vermilion mucosa, scalp, palm, nipple, and hallux have been reported [2,3]. case presentation a 73-year-old caucasian man presented with an asymptomatic strawberry-like plaque on his right ankle, reportedly present for several years. the plaque was approximately 4 cm in diameter, colored red and purple, and surrounded by a fine collarette of scale (figure 1). there was no history of pigmented skin changes or melanoma among his family members. past medical history was notable for ischemic heart disease, diabetes mellitus, and hypertension. his regular medications included aspirin, warfarin, metformin, and atorvastatin. dermatoscopic examination revealed a variegated red/ purple-colored lesion with curved white lines and with dot vessels in a serpiginous (“string of pearls”) pattern (figure 2). there were no colors to indicate melanin (black, figure 1. an asymptomatic erythematous vascular plaque on right ankle present for several years. [copyright: ©2018 zargari et al.] zenaidavega inserted text skin research center, department of dermatology, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran zenaidavega cross-out letter | dermatol pract concept 2018;8(3):18 245 tumor, a more recent hypothesis suggests that cca is a reactive inflammatory dermatosis [5]. the higher incidence of cca in lower limbs of elderly patients favors a reactive nature, probably induced by stasis dermatitis [6]. shalin et al demonstrated that the concurrence of cca with syringofibroadenomatous changes also suggests that both of these entities may share derivation from the eccrine apparatus [7]. the clinical variants of cca include giant, polypoid or pedunculated, pigmented, eruptive, atypical, and cystic patterns [8]. the giant type of cca measures more than 40 mm. until now, there are only 5 reports of giant cca in the english literature, these being located on the foot, buttock, and perineum. due to the variable clinical presentations of cca, it frequently is mistaken for several other lesions, including bowen’s disease, squamous cell carcinoma, malignant melanoma, kaposi sarcoma, and angiosarcoma [9,10]. indeed, the diagnosis is rarely made before skin biopsy, and frequently it can be misdiagnosed. dermatoscopy can improve the accuracy in diagnosing cca [9,11]. the dermatoscopic pattern of cca was first described by blum in 2001 as partly homogenous, symmetrically or bunch-like arranged pinpointlike capillaries [12]. cca usually has a brown, gray, or blue). a biopsy was performed. histopathological examination showed an acanthotic epidermis with pale-appearing keratinocytes full of a glycogen-rich cytoplasm positive to periodic-acid-schiff (pas) staining, consistent with cca (figure 3). the lesion was treated with cryotherapy and curettage. in follow-up, the patient had not developed new ccas after 1 year. discussion cca is frequently presented as a solitary, slowly growing nodule or plaque on the legs of elderly persons. its size usually varies from 3 to 20 mm [4]. perhaps, the original description of fine and chernosky is still the most comprehensive one: “cca has the stuck on appearance of seborrheic keratosis, the vascular look of pyogenic granuloma, the scale and exudation of an eczematous process and advancing rounded border of an epithelioma” [4]. the pathogenesis of cca remains unknown. there is not significant evidence to support a traumatic or druginduced origin. although it was primarily considered to be a benign epidermal figure  2. dermoscopy of the lesion shown in figure 1 showing a variegated red/purplecolored lesion with curved white lines and with dot vessels in a serpiginous pattern. [copyright: ©2018 zargari et al.] figure 3. dermatomicrographs of the lesion in figures 1 and 2. (a) hematoxylin and eosin (h&e) stain demonstrating pale-appearing cytoplasm of plump keratinocytes with elongated rete ridges. (b) pale keratinocytes full of a glycogen-rich cytoplasm positive to periodic acid-schiff (pas) staining. (original magnification: h&e stain ×100, pas ×40). [copyright: ©2018 zargari et al.] unique appearance on dermatoscopy, characterized by red dots, globules, and, sometimes, coiled (glomerular) vessels, arranged in a serpiginous pattern. when fully developed, these serpiginous arrangements are strikingly symmetric. however, in some cases the serpiginous vascular pattern is incomplete or partly developed, either showing a forme fruste or a compression artifact but is still clearly recognizable. dot or coiled (glomerular) vessels can also be a characteristic of inflammatory dermatoses, such as psoriasis, pityriasis lichenoides, and discoid eczema. nevertheless, in these diseases, the red dots or coiled vessels are uniformly distributed and do not join together to form serpiginous vascular arrays [1216]. other uncommon dermatoscopic features of cca include the presence of areas of hemorrhage, orange crusts, and a peripheral collarette of translucent scales. a new finding recently described in the literature is the frequent presence of crystalline structures when polarized dermatoscopy is used for the evaluation of cca [17]. cca is a benign tumor, and when the diagnosis can be made with confidence due to the characteristic serpiginous vascular pattern, treatment is not indicated for small asymptomatic lesions. if treatment is desired, surgical 246 letter | dermatol pract concept 2018;8(3):18 7. shalin sc, rinaldi c, horn td. clear cell acanthoma with changes of eccrine syringofibroadenoma: reactive change or clue to etiology? j cutan pathol. 2013;40(12):1021-1026. doi: 10.1111/cup.12232. 8. ko cj, subtil a. clear (pale) cell acanthosis as an incidental finding. j cutan pathol. 2009;36(5):573-577. doi: 10.1111/j.16000560.2008.01069.x. 9. tiodorovic-zivkovic d, lallas a, longo c, moscarella e, zalaudek i, argenziano g. dermoscopy of clear cell acanthoma. j am acad dermatol. 2015;72(1)(suppl):s47-s49. doi: 10.1016/j. jaad.2014.06.039. 10. tempark t, shwayder t. clear cell acanthoma. clin exp dermatol. 2012;37(8):831-837. doi: 10.1111/j.1365-2230.2012.04428.x. 11. ardigo m, buffon rb, scope a, et al. comparing in vivo reflectance confocal microscopy, dermoscopy, and histology of clear-cell acanthoma. dermatol surg. 2009;35(6):952-959. doi: 10.1111/j.1524-4725.2009.01162.x. 12. blum a, metzler g, bauer j, rassner g, garbe c. the dermatoscopic pattern of clear-cell acanthoma resembles psoriasis vulgaris. dermatology. 2001;203(1):50-52. doi: 10.1159/000051703. 13. pan y, chamberlain aj, bailey m, chong ah, haskett m, kelly jw. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268-274. doi: 10.1016/j.jaad.2008.05.013. 14. vázquez-lópez f, manjón-haces ja, maldonado-seral c, rayaaguado c, pérez-oliva n, marghoob aa. dermoscopic features of plaque psoriasis and lichen planus: new observations. dermatology. 2003;207(2):151-156. doi: 10.1159/000071785. 15. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermatol. 2004;140(12):1485-1489. doi: 10.1001/archderm.140.12.1485. 16. bowling j. diagnostic dermatology: the illustrated guide. oxford: wiley-blackwell; 2012. 17. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67:194 e1–e8. excision may be the treatment of choice for single lesions. however, cryosurgery remains a very useful alternative, especially for multiple lesions [10]. conclusions giant forms of cca are extremely rare and confident clinical diagnosis is not always possible. despite the nonspecific clinical presentation, the giant cca reported herein had the known specific dermatoscopic feature of dot vessels distributed in a serpiginous arrangement as well as a new feature of curved white lines, not previously reported. references 1. degos r, delort j, civatte j, poiares baptista a. epidermal tumor with an unusual appearance: clear cell acanthoma. ann dermatol syphiligr (paris). 1962;89:361-371. 2. posligua a, mercy k, sable k, amin s, gerami p, brieva jc. disseminated eruptive clear cell acanthoma: a case report of a rare entity. j am acad dermatol. 2016;74(5):ab51. doi: 10.1016/j. jaad.2016.02.203. 3. wang sh, chi cc. clear cell acanthoma occurring on the hallux: the first case report. j eur acad dermatol venereol. 2006;20(9):1144-1146. doi: 10.1111/j.1468-3083.2006.01640.x. 4. fine rm, chernosky me. clinical recognition of clear-cell acanthoma (degos’). arch dermatol. 1969;100(5):559-563. doi: 10.1001/archderm.1969.01610290043009. 5. park sy, jung jy, na ji, byun hj, cho kh. a case of polypoid clear cell acanthoma on the nipple. ann dermatol. 2010;22(3):337340. doi: 10.5021/ad.2010.22.3.337. 6. zedek dc, langel dj, white wl. clear-cell acanthoma versus acanthosis: a psoriasiform reaction pattern lacking tricholemmal differentiation. am j dermatopathol. 2007;29(4):378-384. doi: 10.1097/dad.0b013e31806f46f2. dermatology: practical and conceptual 120 observation | dermatol pract concept 2018;8(2):9 dermatology practical & conceptual www.derm101.com case presentation a 44-year-old fair-skinned male presented with a several-year history of a slowly enlarging asymptomatic nodule on his right forearm. he had an extensive sun exposure history and prior history of basal cell carcinomas but was otherwise in good general health. there was no family history of cancer. the physical examination revealed a 1 x 1 cm solid, wellcircumscribed, white, firm nodule on the extensor aspect of his right forearm (figure 1). dermoscopy showed a homogeneous white background with some peripheral arborizing vessels and mild erythematous halo (figure 2). a complete excisional biopsy was performed. histology revealed a well-circumscribed polypoid lesion covered by an atrophic epidermis. the dermis contained sclerotic bundles of collagen with a storiform pattern and scattered fibroblasts; no collagen bundles with plywoodlike or concentrically lamellar pattern were identified. no depressed surface, dermal atrophy, infiltrative edges, vascular proliferation, dermal spindle-shaped or dendritic melanocytes were seen (figure 3). diagnosis solitary storiform collagenoma (sclerotic fibroma) discussion the solitary storiform collagenoma (sclerotic fibroma) is a rare benign soft tissue tumor presenting as a slowly enlarging well-circumscribed solid, fibrous, pink, white or flesh-colored papule or nodule in young and middle-aged adults of both sexes [1]. it is more commonly found on the face and limbs but has also been described on the scalp, trunk, oral mucosa and nail bed [2]. the presence of multiple storiform collagenomas is considered as a cutaneous marker of cowden syndrome [3]. histology of sclerotic fibromas reveals a wellcircumscribed non-encapsulated dermal nodule with hypocellular storiform collagen bundles showing prominent clefts [4], sometimes with accumulation of collagen bundles in biphasic growth and arranged in a plywood-like or concentrically lamellar patterns [5]. dermoscopy of a solitary storiform collagenoma mona ebadian1, luigi citarella1, damian collins1, salvador diaz-cano2, lucia pozo-garcia1 1 lewisham and greenwich nhs trust, london, uk 2 kings college hospital, london, uk key words: collagenoma, storiform collagenoma, sclerotic fibroma, cowden syndrome citation: ebadian m, citarella l, collins d, diaz-cano s, pozo-garcia l. dermoscopy of a solitary storiform collagenoma. dermatol pract concept. 2018;8(2):120-122. doi: https://doi.org/10.5826/dpc.0802a09 received: january 16, 2018; accepted: february 20, 2018; published: april 30, 2018 copyright: ©2018 ebadian et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: lucia pozo-garcia, md, phd, lewisham and greenwich nhs trust, stadium road, london, greater london, se18 4qh, united kingdom. tel. +44 20 88365261 fax. +44 20 88366935. email:  lpozo@doctors.org.uk the dermoscopic features of solitary storiform collagenomas (sclerotic fibromas) have not been described previously, as these are rare cutaneous soft tissue tumors. the presence of multiple lesions is considered a marker of cowden syndrome. they can also present as single firm cutaneous nodules. we present an unusual single nodule with distinct dermoscopic and histologic features. abstract observation | dermatol pract concept 2018;8(2):9 121 with peripheral arborizing vessels; this pattern has not been described previously. some atypical forms of dermatofibromas [6], late stages of sclerotic dermatofibromas and amelanotic blue nevi, may occasionally present with similar dermoscopic features [7]. a sclerotic fibroma-like dermatofibroma has also been described as an uncommon variant of dermatofibroma [8]. it is unclear if storiform collagenomas represent we present an unusual solid, single nodule in a fairskinned patient with prior history of basal cell carcinomas. dermoscopy showed a homogeneous white background figure 1. well-circumscribed, white, firm nodule with erythematous halo and superficial vascularization. [copyright: ©2018  ebadian et al.] figure 2. dermoscopy shows a homogeneous structureless white lesion with erythema and arborizing vessels in peripheral distribution (polarized contact dermoscopy, x10). [copyright: ©2018  ebadian et al.] figure 3. well-circumscribed polypoid lesion contained collagen bundles separated by prominent clefts with scattered fibroblasts. hematoxylin-eosin stained sections (a. 40x, b. 100x, c. 200x). [copyright: ©2018 ebadian et al.] 122 observation | dermatol pract concept 2018;8(2):9 4. lo wl, wong ck. solitary sclerotic fibroma. j cutan pathol. 1990 oct;17(5):269-273. 5. nakashima k, yamada n, adachi k, yoshida y, yamamoto o. solitary sclerotic fibroma of the skin: morphological characterization of the ‘plywood-like pattern’. j cutan pathol. 2008 oct;35 suppl 1:74-79. 6. coelho de sousa v, andré oliveira a. nodular lesion with polymorphous vascular pattern. dermatol pract concept. 2017;7(4):81-83. 7. ma c, chambers cj, kiuru m, marsee dk, silverstein m. amelanotic blue nevus. jaad case rep. 2017 mar;3(2):93-94. 8. gonzalez-vela mc, val-bernal jf, martino m, gonzalez-lopez ma, garcia-alberdi e, hermana s. sclerotic fibroma-like dermatofibroma: an uncommon distinctive variant of dermatofibroma. histol histopathol. 2005 jul;20(3):801-806. 9. donati p, amantea a, carducci m, balus l. sclerotic (hypocellular) fibromas of the skin. br j dermatol. 1991 apr;124(4):395-396. a fibrous tissue hamartoma or a genuinely fibrohistyocitic neoplasm; some storiform collagenomas may correspond to involuting dermatofibromas [9]. storiform collagenomas should be considered in the differential diagnosis of acquired white firm papules or nodules. histology is needed to confirm the diagnosis. references 1. metcalf js, maize jc, leboit pe. circumscribed storiform collagenoma (sclerosing fibroma). am j dermatopathol. 1991 apr;13(2):122-129. 2. tosti a, cameli n, peluso am, fanti pa, peserico a. storiform collagenoma of the nail. cutis. 1999 sep;64(3):203-204. 3. al-daraji wi, ramsay hm, ali rb. storiform collagenoma as a clue for cowden disease or pten hamartoma tumour syndrome. j clin pathol. 2007 jul;60(7):840-842. dermatology: practical and conceptual research letter | dermatol pract concept. 2023;13(3):e2023163 1 cardiovascular complications are common in patients with juvenile dermatomyositis in a cross-sectional analysis of the 2016 kids inpatient database amar d. desai1, aman m. patel1, vraj p. shah1, shari r. lipner2 1 rutgers new jersey medical school, newark, new jersey, usa 2 weill cornell medicine, department of dermatology, new york, new york, usa key words: dermatomyositis, pediatric, cardiovascular, management, outcomes citation: desai ad, patel am, shah vp, lipner sr. cardiovascular complications are common in patients with juvenile dermatomyositis in a cross-sectional analysis of the 2016 kids inpatient database. dermatol pract concept. 2023;13(3):e2023163. doi: https://doi.org/10.5826/dpc.1303a163 accepted: february 1, 2023; published: july 2023 copyright: ©2023 desai et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: mr. desai, mr. patel, and mr. shah have no conflicts of interest. dr. lipner has served as a consultant for orth-dermatologics, verrica, and hoth therapeutics. authorship: all authors have contributed significantly to this publication. corresponding author: shari r. lipner, md phd, department of dermatology, weill cornell medicine, 1305 york avenue, 9th floor, new york, ny 10021 phone: 646-962-3376 e-mail: shl9032@med.cornell.edu introduction juvenile dermatomyositis (jdm) is an uncommon inflammatory disease (incidence 2-4 per 1 million children) with frequent cardiovascular complications (cvcs). incidence of cvcs in jdm varied widely from 2.9% to 37.5% in a meta-analysis of single-institution studies [1]. we aimed to assess for differences in presentation, treatment, and outcomes of jdm pediatric inpatients with cvcs. the 2016 kids inpatient database (kid), an all-payer in-patient pediatric database [2], was queried for jdm patients using international classification of diseases, tenth revision (icd-10), clinical modification jdm code “m33.” cvcs were collected using codes “a52.0/e08–e16/e66/e78/ i00–i99/q2/z95.” chi-squared tests compared frequencies by cvc status. multivariable logistic regression identified predictors of cvcs (p < 0.05). case presentation there were 836 pediatric jdm cases and 222 (26.6%) had cvcs (table 1). patients with cvcs were older (14.0 versus 11.4 years) and more often black (29.1% versus 21.6%), hispanic (35.5% versus 27.7%), in the lowest income quartile (36.1% versus 29.3%), and medicaid-insured (52.3% versus 41.9%) (all p < 0.05). overall treatment nonadherence was more common for patients ages 14-20 (71.4% versus 44.2%), females (96.4% versus 78.1%), and blacks (48.3% versus 22.7%) (p < 0.025) (supplementary table 1). 2 research letter | dermatol pract concept. 2023;13(3):e2023163 table 1. demographic data of dermatomyositis by cardiovascular complication status. no cardiovascular complications cardiovascular complications total pn = 613 (73.4%) n = 222 (26.6%) n = 836 age age, years (mean [se]) 11.42 [0.21] 14.04 [0.31] 12.12 [0.18] < 0.001 sex male 22.2% 19.3% 21.4% 0.365 female 77.8% 80.7% 78.6% race white 44.5% 29.1% 40.4% 0.002 black 21.6% 29.1% 23.6% hispanic 27.7% 35.5% 29.8% other 6.1% 6.4% 6.2% median income quartile patient zip code 0 – 25% 29.3% 36.1% 31.1% 0.038 26 – 50% 25.6% 25.1% 25.5% 51 – 75% 24.6% 26.5% 25.1% 76 – 100% 20.5% 12.3% 18.3% primary payer status medicare 0.2% 1.4% 0.5% 0.005 medicaid 41.9% 52.3% 44.7% private insurance 49.4% 39.6% 46.8% self-pay 2.8% 0.5% 2.2% no charge 0.2% 0.0% 0.1% other 5.5% 6.3% 5.7% hospital region northeast 15.2% 8.1% 13.3% < 0.001 midwest 22.5% 15.8% 20.7% south 40.6% 40.1% 40.5% west 21.7% 36.0% 25.5% severity of illness subclass (loss of function) minor lof 36.4% 10.3% 29.4% < 0.001 moderate lof 43.6% 43.5% 43.5% major lof 16.0% 34.5% 20.9% extreme lof 4.1% 11.7% 6.1% comorbidity anemia 15.2% 27.5% 18.4% < 0.001 fluid & electrolyte disorder 10.8% 23.3% 14.1% < 0.001 aphagia & dysphagia 9.5% 6.8% 8.7% 0.222 asthma 7.7% 10.8% 8.5% 0.154 heartbeat abnormalities at initial presentation 5.1% 11.7% 6.8% < 0.001 coagulation defect 4.2% 12.6% 6.5% < 0.001 gastro-esophageal reflux disease 3.4% 11.3% 5.5% < 0.001 liver disease 1.6% 6.8% 2.9% < 0.001 perinatal chronic respiratory disease 0.7% 3.2% 1.3% 0.005 treatment nonadherence 1.6% 8.1% 3.4% < 0.001 lof = loss of function; se = standard error. research letter | dermatol pract concept. 2023;13(3):e2023163 3 supplementary table 1. demographics of dermatomyositis by treatment adherence status. treatment adherence treatment nonadherence total pn = 808 (96.6%) n = 28 (3.4%) n = 836 age 0-6 years 17.9% 3.6% 17.5% 0.0127-13 years 37.9% 25.0% 37.4% 14-20 years 44.2% 71.4% 45.1% sex male 21.9% 3.6% 21.3% 0.020 female 78.1% 96.4% 78.7% race white 41.1% 20.7% 40.3% 0.006 black 22.7% 48.3% 23.7% hispanic 29.8% 31.0% 29.8% other 6.4% 0.0% 6.2% table 2. management and outcomes of dermatomyositis by cardiovascular complication status. no cardiovascular complications cardiovascular complications total p total charges charges ($) (mean [se]) 52,432.22 [3,579.96] 110,743.53 [15,989.20] 67,956.85 [5,076.36] < 0.001 length of stay number of days (mean [se]) 4.51 [0.34] 8.54 [1.07] 5.58 [0.39] < 0.001 number of procedures number of procedures (mean [se]) 1.27 [0.08] 1.58 [0.19] 1.36 [0.08] 0.137 time until 1st procedure number of days (mean [se]) 2.00 [0.46] 2.81 [0.42] 2.21 [0.36] 0.320 sepsis complication (%) 4.7% 4.0% 4.5% 0.670 respiratory failure complication (%) 3.1% 5.0% 3.6% 0.202 urinary tract infection complication (%) 2.4% 4.5% 3.0% 0.123 acute kidney injury complication (%) 1.3% 5.8% 2.5% < 0.001 hypoxemia complication (%) 0.5% 2.7% 1.1% 0.006 mortality complication (%) 0.2% 0.0% 0.1% 0.547 transfusion procedure (%) 20.2% 17.1% 19.4% 0.320 imaging procedure (%) 10.1% 7.7% 9.5% 0.284 se = standard error. jdm patients with vs. without cvcs had higher incidence of acute kidney injury (aki) (5.8% versus 1.3%, p  < 0.001) (table 2). on multivariable analysis, cvcs were associated with increasing age (or 1.12, 95% ci  1.07–1.16) and heartbeat abnormalities at initial presentation (or 2.67, 95% ci 1.37–5.17) (p < 0.005) (supplementary table 2). conclusions we found that jdm inpatients with cvcs were most often black or hispanic, of lower income, and medicaid-insured. similarly, in a national study of 16,097 pediatric inpatients, blacks vs. whites were 20% more likely to die within 30 days of surgery, which were attributed to lack specialized care access, poor physician-parent communication, and systemic racism [3]. therefore, social determinants likely influence the development of cvcs in jdm patients. we found that jdm patients with cvcs had greater total charges, los, and incidence of aki, but no difference in the number of procedures performed, suggesting worse inpatient disease courses for jdm patients with cvcs. in a 10-year 4 research letter | dermatol pract concept. 2023;13(3):e2023163 references 1. cantez s, gross gj, maclusky i, feldman bm. cardiac findings in children with juvenile dermatomyositis at disease presentation. pediatr rheumatol online j. 2017;15(1):54. doi: 10.1186 /s12969-017-0182-0. pmid: 28693511. pmcid: pmc5504613. 2. bliss-holtz j. the kids’ inpatient database (kid) and data mining in nursing. issues compr pediatr nurs. 2012;35(1):1-3. doi: 10.3109/01460862.2012.648829. pmid: 22250963. 3. chen c, mpody c, sivak e, tobias jd, nafiu oo. racial disparities in postoperative morbidity and mortality among high-risk pediatric surgical patients. j clin anesth. 2022;81:110905. doi: 10.1016/j.jclinane.2022.110905. pmid: 35696873. 4. yen th, lai pc, chen cc, hsueh s, huang jy. renal involvement in patients with polymyositis and dermatomyositis. int j clin pract. 2005;59(2):188-193. doi: 10.1111/j.1742-1241 .2004.00248.x. pmid: 15854195. 5. hilty m, oldrati p, barrios l, et al. continuous monitoring with wearables in multiple sclerosis reveals an association of cardiac autonomic dysfunction with disease severity. mult scler j exp transl clin. 2022;8(2):20552173221103436. doi: 10.1177/20552173221103436. pmid: 35677598. pmcid: pmc9168869. 6. aamc. data & reports / diversity in medicine: facts and figures 2019 / table 12. practice specialty, females by race/ ethnicity, 2018. available from: https://www.aamc.org/data -reports/workforce/data/table-12-practice-specialty-females -race/ethnicity-2018. accessed 27, 2022, supplementary table 2. binary logistic regression analysis of factors associated with cardiovascular complications in dermatomyositis. odds ratio 95% ci pa age 1.12 1.07-1.16 < 0.001 west vs. northeast 3.80 1.82-7.91 < 0.001 fluid and electrolyte disorders 1.93 1.14-3.28 0.015 heartbeat abnormalities at initial presentation 2.87 1.48-5.57 0.002 gastro-esophageal reflux disease 3.72 1.77-7.82 < 0.001 perinatal chronic respiratory disease 6.17 1.60-23.73 0.008 treatment nonadherence 5.31 1.98-14.22 < 0.001 ci = confidence interval. amultivariable analysis with age, race, income quartile, primary payer status, hospital region, anemia, fluid and electrolyte disorders, heartbeat abnormalities, coagulation defects, gastro-esophageal reflux disease, liver disease, perinatal chronic respiratory disease, and treatment nonadherence. single institution registry study, 1992-2002, aki incidence was 21.5% among 65 jdm patients, while overall incidence of aki was 2.5%. therefore, cvcs may be contributory to cost differences and los in jdm patients [4]. cvcs were associated with tachycardia, bradycardia, and palpitations at initial presentation. continuous monitoring with wearables in multiple sclerosis patients accurately showed trend-based heart rate variability and general dysregulation [5]. therefore, screening for heartbeat abnormalities might detect undiagnosed cvcs and preventing disease progression in jdm patients. older, female, and black children had higher incidence of treatment nonadherence, which may explain the age and cvc association with multivariable analysis. given the predominance of united states white dermatologists [6], physician/patient race discordance may be partially responsible for this nonadherence. limitations include retrospective design and lack of data regarding medications administered and procedures performed. we conclude that for jdm patients with cvcs, there are significant disparities in income, race, and insurance status. dermatologists treating pediatric jdm patients should screen for cvcs with appropriate cardiologist referral to improve outcomes for these patients. dermatology: practical and conceptual quiz | dermatol pract concept 2018;8(1):11 51 dermatology practical & conceptual www.derm101.com the patient a 51-year-old man with a history of recurrent primary cutaneous marginal zone lymphoma involving his back returned for a follow-up visit at our cutaneous lymphoma clinic. he complained of a several-month history of a new asymptomatic papule on the mid-thoracic back. he denied fevers, chills, night sweats or fatigue. clinical examination identified a 3 to 4 mm red to orange-colored papule on the middle back (figure 1a). dermoscopic examination of the lesion revealed an erythematous border encircling an orange-yellow area with white linear streaks and few dotted vessels (figure 1b). a biopsy and histopathological examination performed to exclude recurrence of skin lymphoma demonstrated a nodular dermal infiltrate of histiocytes with vacuolated foamy xanthomatous cytoplasm and touton-type multinucleated giant cells (figure 2). the histiocytes stained positively for cd68 and were negative for sox10. what is your diagnosis? solitary orange papule on the back of a middle-aged man shamir geller1, melissa pulitzer2, patricia l. myskowski1 1 dermatology service, department of medicine, memorial sloan kettering cancer center and weill cornell medicine, new york, ny, usa 2 department of pathology, memorial sloan kettering cancer center and weill cornell medicine, new york, ny, usa citation: geller s, pulitzer m, myskowski pl solitary orange papule on the back of a middle-aged man. dermatol pract concept. 2018;8(1):51-53. doi: https://doi.org/10.5826/dpc.0801a11 received: july 13, 2017; accepted: october 3, 2017; published: january 31, 2018 copyright: ©2018 geller et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part through the nih/nci cancer center support grant p30 ca008748. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: shamir geller, md, dermatology service, memorial sloan kettering cancer center, 16 east 60th street, new york, ny 10022, usa. email: shamirgeller@gmail.com figure 1. clinical image of the red to orange-colored papule on the patient’s upper back marked with a black triangular sticker (a). polarized, non-contact dermoscopy images of the lesion revealing a structureless orange-yellow area with erythematous border. white linear streaks and few dotted vessels are seen in the center of the lesion; 10x original magnification (b). [copyright: ©2018 geller et al.] mailto:shamirgeller@gmail.com 52 quiz | dermatol pract concept 2018;8(1):11 of cutaneous b-cell lymphoma was highly suspected, but the dermoscopic setting sun pattern was quite different from the typical dermoscopic features of the salmon-colored area and linear-irregular vessels typically seen in such a type of cutaneous lymphomas [10,11] (table 1). reflectance confocal microscopy (rcm) and high-definition optical coherence tomography (hd-oct) features of jxg and adult-onset xanthogranuloma were reported recently. highly refractive atypical large cells of variable diameter were seen in the dermis, and some of them had pleomorphic nuclei, corresponding to touton-type giant cells that were seen in histopathologic examination [9,12]. jxg and adult-onset xanthogranuloma can present with characteristic dermoscopic features of an orange-yellow structureless pattern with an erythematous border (setting sun sign) and white streaks. dermoscopy can be helpful in diagnosing these benign skin conditions in a noninvasive manner. answer adult-onset xanthogranuloma (juvenile xanthogranuloma presenting in an adult) discussion juvenile xanthogranuloma (jxg) is the most common nonlangerhans cell histiocytosis, which presents either as a single lesion or as multiple asymptomatic pink to red–brown dome-shaped papules or nodules (2 mm to 2 cm in diameter) that become yellow-brown as they mature. jxg most often affects infants and young children; however, it can appear in adults in their 20s and 30s and can even present in the elderly. jxg’s course is usually self-limited in the pediatric population and treatment is not necessary, although, in adults, in whom the term adult-onset xanthogranuloma is favored, it may not regress spontaneously [1]. histologically, jxg shows a dense histiocytic infiltration involving the dermis but sometimes extending subcutaneously. monomorphous histiocytes with eosinophilic cytoplasm are seen in the early lesions, while in mature jxg the histiocytes acquire a foamy and xanthomatous appearance, touton giant cells are identified, and lymphocytes, eosinophils, and plasma cells can be found throughout the infiltrate. regressing lesions show a proliferation of fibroblasts and fibrosis. the dermoscopic pattern of jxg was first described in 2007 by palmer et al., who described a characteristic orange-yellow “setting sun” appearance [2]. other dermoscopic features that have been reported in jxg cases include clouds of pale yellow globules, subtle pigment network, whitish streaks, and branched linear or dotted vessels [3,4]. song et al. studied the correlation between dermoscopic appearance and histopathological findings and found that the dermoscopic features correlated with the histologic level of maturation of the jxg lesions. the setting sun appearance was found in early evolutionary and in fully developed jxg. in fully developed lesions, the surrounding erythema decreased, and yellow globules became more evident as the histiocytes transformed to more xanthomatous cells, while in late regressive lesions, prominent whitish streaks were identified and were suggested to correspond to fibrosis [5]. it was suggested that dermoscopy might be helpful in differentiating jxg from other conditions that appear as solitary yellow-orange lesions [6,7]. the main differential diagnoses of jxg include sebaceous tumors [8], xanthomatous dermatofibroma, basal cell carcinoma, granulomatous dermatoses, and nonpigmented spitz nevus [4,9]. table 1 shows the dermoscopic features of all such conditions. in the present case, the clinical diagnosis figure 2. histopathology. circumscribed nodular dermal infiltrate effacing rete ridges and elevating and attenuating epidermis; hematoxylin-eosin stain, 40x original magnification (a). foamy histiocytes and touton-type multinucleated giant cells (asterisks) comprise the majority of the infiltrate. lymphocytes percolate through the histiocytic tumor; hematoxylin-eosin stain, 100x original magnification (b). [copyright: ©2018 geller et al.] quiz | dermatol pract concept 2018;8(1):11 53 8. moscarella e, argenziano g, longo c, et al. clinical, dermoscopic and reflectance confocal microscopy features of sebaceous neoplasms in muir-torre syndrome. j eur acad dermatol venereol. 2013;27(6):699-705. 9. lovato l, salerni g, puig s, carrera c, palou j, malvehy j. adult xanthogranuloma mimicking basal cell carcinoma: dermoscopy, reflectance confocal microscopy and pathological correlation. dermatology. 2010;220(1):66-70. 10. geller s, marghoob aa, scope a, braun rp, myskowski pl. dermoscopy and the diagnosis of primary cutaneous b-cell lymphoma. j eur acad dermatol venereol. 2017. 11. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol venereol. 2013;27(5):617621. 12. koku aksu ae, turgut erdemir av, gurel ms, bagci is, leblebici c. in vivo evaluation of juvenile xanthogranuloma with highresolution optical coherence tomography and reflectance confocal microscopy and histopathological correlation. skin res technol. 2015;21(4):508-510. 13. errichetti e, lallas a, apalla z, di stefani a, stinco g. dermoscopy of granuloma annulare: a clinical and histological correlation study. dermatology. 2017;233(1):74-79. 14. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. 15. lallas a, apalla z, ioannides d, et al. update on dermoscopy of spitz/reed naevi and management guidelines by the international dermoscopy society. br j dermatol. 2017;177(3):645-655. acknowledgments dr. shamir geller is a recipient of a supplemental grant from the american physicians and friends for medicine in israel (apf). references 1. hernandez-martin a, baselga e, drolet ba, esterly nb. juvenile xanthogranuloma. j am acad dermatol. 1997;36(3 pt 1):355367; quiz 368-359. 2. palmer a, bowling j. dermoscopic appearance of juvenile xanthogranuloma. dermatology (basel, switzerland). 2007;215(3):256259. 3. rubegni p, mandato f, fimiani m. juvenile xanthogranuloma: dermoscopic pattern. dermatology. 2009;218(4):380; author reply 381. 4. cavicchini s, tourlaki a, tanzi c, alessi e. dermoscopy of solitary yellow lesions in adults. archiv dermatol. 2008;144(10):1412. 5. song m, kim sh, jung ds, ko hc, kwon ks, kim mb. structural correlations between dermoscopic and histopathological features of juvenile xanthogranuloma. j eur acad dermatol venereol. 2011;25(3):259-263. 6. pretel m, irarrazaval i, lera m, aguado l, idoate ma. dermoscopic “setting sun” pattern of juvenile xanthogranuloma. j am acad dermatol. 2015;72(1 suppl):s73-75. 7. hussain sh, kozic h, lee jb. the utility of dermatoscopy in the evaluation of xanthogranulomas. pediatr dermatol. 2008;25(4):505-506. table 1. dermoscopic clues for the differential diagnosis of the studied solitary orange colored papule. diagnosis dermoscopic features juvenile xanthogranuloma [5] erythematous border circling an orange-yellow area (“setting sun”), white linear streaks and linear/branched vessels basal cell carcinoma [9] arborizing vessels with a pink background, ulcerations, leaf-like structures, blue-gray ovoid nests and white shiny streaks cutaneous b-cell lymphoma [10] salmon-colored background/area and serpentine (linear-irregular) vessels granulomatous dermatoses [13,14] structureless yellow-orange area with linear or branching vessels sebaceous tumors [8] • radially arranged, elongated crown vessels surrounding structureless yellow areas • yellow comedo-like globules and branching arborizing vessels nonpigmented spitz nevus [15] regularly distributed dotted vessels (coiled, hairpin or linear-irregular in elevated/nodular nevi) with reticular depigmentation (inverse white network) xanthomatous dermatofibroma [4] homogeneous yellow area with peripheral delicate pigment network dermatology: practical and conceptual letter | dermatol pract concept 2018;8(4):19 337 dermatology practical & conceptual www.derm101.com case presentation a 70-year-old woman presented with an asymptomatic pigmented lesion located on the right shoulder that had first been noticed about 1 year prior. she reported no previous trauma. on examination, there was a depressed, smooth, firm, white and bluish plaque that measured about 15 mm in diameter (figure 1). the dimple sign was present; it was not painful. immediately after clinical palpation, the plaque started to grow in size and became painful (figure 2). on dermoscopy, a blue-violaceous homogeneous area was observed in the center of the lesion surrounded by a whitish homogeneous area (figure 3). a delicate pigment network was found at the periphery of the lesion, over the whitish area, and scattered dotted and linear vessels were also present. the lesion was completely excised. histopathologic examination revealed a very cellular dermal neoplasm composed of interlacing spindle cells with vesicular nuclei and eosinophilic cytoplasm within collagen bundles arranged in a storiform pattern. blood-filled spaces that lacked an endothelial lining, multifocal hemorrhage and hemosiderin deposition were intermixed with the collagen bundles. (figure 4). spindle cells were positive for factor xiiia and negative for cd34, actin, desmin, s-100, melan-a and hmb45. a diagnosis of aneurysmal dermatofibroma was established. a white-bluish plaque with rapid growth after palpation belén lozano-masdemont1, isabel polimón-olabarrieta1, berta pérez-tato1, cristina diego-hernández2 1 department of dermatology, hospital universitario de móstoles, móstoles, madrid, spain 2 department of pathology, hospital universitario de móstoles, madrid, spain key words: dermatofibroma, fibrous histiocytoma, aneurysmal dermatofibroma, dermoscopy citation: lozano-masdemont b, polimón-olabarrieta i, pérez-tato b, diego-hernández c. a white-bluish plaque with rapid growth after palpation. dermatol pract concept. 2018;8(4):337-339. doi: https://doi.org/10.5826/dpc.0804a19 received: march 16, 2018; accepted: june 3, 2018; published: october 31, 2018 copyright: ©2018 lozano-masdemont et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: belén lozano-masdemont, md, department of dermatology, hospital universitario de móstoles, río júcar, s/n, 28935 móstoles, madrid, spain. email: belenmasdemont@gmail.com figure 1. clinical image. a depressed, smooth, firm, white and bluish plaque, about 15 mm in diameter, on the right shoulder. the dimple sign was present. [copyright: ©2018 lozano-masdemont et al.] 338 letter | dermatol pract concept 2018;8(4):19 discussion dermatofibroma is a benign dermal fibrohistiocytic tumor, mainly found on the lower limbs that presents with raised, hyperkeratotic nodules smaller than 2 cm, with a reddishbrown surface. it may be solitary, multiple, clustered and giant. aneurysmal dermatofibroma represents about 1.7% of all dermatofibromas, commonly presenting as a solitary nodule on the limbs of middle-aged adults [1]. it is usually larger than a typical dermatofibroma (0.5-4 cm). it may be associated with pain or rapid growth due to hemorrhage. the characteristic histological feature is the presence of hemorrhagic, cleft-like, and cystic spaces without an endothelial lining. adjacent solid areas show the usual features of dermatofibroma, often more cellular. multifocal interstitial hemorrhage and intraand extracellular hemosiderin deposition are prominent [1]. hemosiderotic dermatofibroma could be a precursor stage in its formation, due to slow, continuous extravasation of blood from capillaries, especially in the highly cellular areas containing a poorly developed reticulin network [1]. dermoscopically, hemosiderotic and aneurysmal dermatofibromas are characterized by a blue-yellowish to redbrownish pigmented homogeneous area. the histopathological correlation could be the prominent blood-filled spaces and intraand extracellular hemosiderin deposition. a yellowish homogeneous area seen at the periphery of the lesion could be caused by hemosiderin deposits or foamy giant cells and macrophages [2]. other reported dermoscopic features are white linear and homogeneous structures caused by pronounced fibrosis within the papillary dermis [2]. moreover, a delicate pigment network, scaly surface, and dotted, comma, and linear irregular and dilated vessels may be present [2]. figure 2. clinical image. the same plaque grew in size after clinical palpation. [copyright: ©2018 lozano-masdemont et al.] figure 3. dermoscopic image. a blue-violaceous homogeneous area surrounded by a whitish homogeneous area were the main features. a delicate pigment network was found at the periphery of the lesion over the whitish area and scattered dotted and linear vessels were also present. [copyright: ©2018 lozano-masdemont et al.] figure  4. histopathologic examination (hematoxylin and eosin stain, 4x) revealed a dermal neoplasm, composed of interlacing spindle cells with vesicular nuclei and eosinophilic cytoplasm within collagen bundles arranged in a storiform pattern. blood-filled spaces that lacked an endothelial lining, multifocal hemorrhage and hemosiderin deposition were intermixed with the collagen bundles. [copyright: ©2018 lozano-masdemont et al.] letter | dermatol pract concept 2018;8(4):19 339 references 1. ferrari a, argenziano g, buccini p, et al. typical and atypical dermoscopic presentations of dermatofibroma. j eur acad dermatol venereol. 2013;27(11):1375-1380. 2. zaballos p, llambrich a, ara m, olazarán z, malvehy j, puig s. dermoscopic findings of haemosiderotic and aneurysmal dermatofibroma: report of six patients. br j dermatol. 2006;154(2):244250. the most important differential diagnosis is melanoma, since there is a significant association with a melanoma-like pattern/vascular tumor-like pattern on dermoscopy [1]. due to diagnostic uncertainty and painful episodes of hemorrhage, a complete surgical excision of aneurysmal dermatofibroma is the norm. the rate of recurrence is around 19% [1]. dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):12 71 dermatology practical & conceptual www.derm101.com case presentation a 23-year-old female presented with an asymptomatic, erythematous, atrophic macule on the upper right side of her back that increased gradually in size within the last four years without any symptoms (figure 1a). on physical examination the surface of the lesion was smooth and no induration was examined on palpation. there was no history of trauma. dermatoscopic evaluation of the lesion using 3gen dermlite-ii pro hr and documented with dermlite-foto 3gen (llc, dana point, ca, usa) showed a homogenous pigment network on a purplish erythematous background (figure 1b). a skin biopsy was taken with the preliminary diagnosis of morphea and cutaneous mastocytosis. histopathological examination of h&e (hematoxylin and eosin) stained sections revealed epidermal atrophy, increase in melanin in basal keratinocytes and heavy dermal cellular infiltrate composed of spindle-shaped cells arranged in a storiform pattern that extended into the subcutaneous tissue (figure 2). immunhistochemical staining for cd34 was positive, while factor xiiia was negative (figure 3a, b). the diagnosis of dermatofibrosarcoma protuberans (dfsp) was made according to these findings. the patient was referred to department of plastic and reconstructive surgery for total excision. excision was dermatoscopic findings of atrophic dermatofibrosarcoma protuberans bengu nisa akay1, ezgi unlu2, cengizhan erdem1, aylin okcu heper3 1 ankara university faculty of medicine, department of dermatology, ankara, turkey 2 zekai tahir burak women’s health education and research hospital, department of dermatology, ankara, turkey 3 ankara university faculty of medicine, department of pathology, ankara, turkey key words: atrophic variant, dermatofibrosarcoma protuberans, dermatoscopy, mesenchymal tumor citation: akay bn, unlu e, erdem c, heper ao. dermatoscopic findings of atrophic dermatofibroma protuberans. dermatol pract concept 2015;5(1)12. doi: 10.5826/dpc.0501a12 received: september 8, 2014; accepted: october 5, 2014; published: january 30, 2015 copyright: ©2015 akay et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. ezgi unlu, zekai tahir burak women’s health education and research hospital, department of dermatology, samanpazarı-ankara, turkey. tel. 90 (312) 3065000; fax. 90 (312) 3124931. e-mail: drezgiyalcin@yahoo.com dermatofibrosarcoma protuberans (dfsp) is an uncommon locally aggressive mesenchymal tumor with a high local recurrence rate. atrophic dfsp is a rare variant of dfsp characterized by a nonprotuberant lesion. we report on a 23-year-old female, who presented with an atrophic, asymptomatic macule on the right side of her back 2 cm in diameter. dermatoscopic examination revealed homogenous pigment network on a purplish erythematous background. the histopathological finding of the incisional biopsy material was consistent with dfsp. to our knowledge, this is the second case of atrophic dfsp discussing the dermatoscopic features of this relatively rare condition. abstract mailto:drezgiyalcin@yahoo.com 72 observation | dermatol pract concept 2015;5(1):12 tive for cd34 and negative for factor xiiia, atrophic dermatofibroma cells are usually negative for cd34 and both of cd34 and factor xiiia are positive in the medallion-like dermal dendrocyte hamartoma [3, 4]. dermatoscopic studies of dfsp are very rare in the literature. in 2013, bernard et al reported the first study of dermatoscopic analysis of dfsp in 15 cases. delicate pigment network, vessels, structureless light brown areas, shiny white streaks, pink background coloration and structureless hypopigmented or depigmented areas were defined as six main dermatoscopic features of dfsp [5]. in 2014, dermatoscopic features such as peripheral dilated vessels forming a mesh-like pattern, milky-red areas, whitish linear structures and fine pigment network were reported in a series of four cases of dfsp [6]. to our knowledge, only one case of atrophic dfsp was presented with dermatoscopic features in the literature [4]. the reported dermatoscopic findings of that case were branching vessels on a yellowish background without pigment network. the authors suggested that the dermatoscopic features might be the result of dermal atrophy and close approximation the subcutis to the epidermis. in contrast, our case showed made with 3 cm safe surgical margins. no recurrence has been observed for one year. conclusion dfsp is a rare, slow growing, locally invasive cutaneous neoplasm of fibrohistiocytic origin with intermediate grade malignancy with an incidence between 0.8–5.0 cases per 1 million persons per year [1]. it often shows typically protuberant morphology. the atrophic presentation of dfsp is the rarest variant of this infrequent neoplasm, which was first described in 1985 [2]. the non-protuberant dfsp can be considered the early clinical stage of dfsp before developing the typical protuberant feature unless it remains as a non-protuberant tumor that is called atrophic dfsp. it occurs as an atrophic, asymptomatic plaque that can be difficult to distinguish from morphea, morphea like basal cell carcinoma, scar, lipoatrophy and atrophic dermatofibroma [3]. although the clinical appearance of atrophic dfsp is different from common protuberant type, histopathological features are similar. atrophic presentation of the lesions may be due to the marked cellularity of the tumor cells in the dermis and infiltration to the subcutaneous fat [1]. immunhistochemical staining is important to distinguish dfsp from atrophic dermatofibroma and medallion-like dermal dendrocyte hamartoma. while dfsp cells are posifigure 1. (a) erythematous, atrophic macule on the right side of upper aspect of the back; (b) dermatoscopic evaluation that shows homogenous pigment network on a purplish erythematous background. (copyright: ©2015 akay et al.) figure 3. (a) positive immunhistochemically staining for cd34 (x200); (b) negative immunhistochemically staining for factor xiiia (x200). (copyright: ©2015 akay et al.) figure 2. heavy dermal cellular infiltrate composed of spindle shaped cells arranged in a storiform pattern that extended into the subcutaneous tissue (h&e, x25). (copyright: ©2015 akay et al.) observation | dermatol pract concept 2015;5(1):12 73 dermatoscopically regular brown lines reticular on a purplish erythematous background. homogenous brown lines reticular seen in our case correspond to the accumulation of melanin in basal keratinocytes, while the erythematous background is the result of dilated vessels in the dermal plexus. here, the smooth surface reflects the stratum corneum being normal. the most frequent dermatoscopic pattern associated with dermatofibromas, a well-known and benign cousin of dfsp, is the central white scar-like patch and peripheral delicate pigment network [7]. the histopathologic correlation of white scar-like patch in dermatofibroma is pronounced fibrosis within the papillary dermis. contrary to dermatofibromas, fibroplasia in the upper half of the dermis is uncommonly observed in dfsp which may explain the absence of white scar-like areas in our case. in conclusion, we have presented the dermatoscopic findings in an unusual case of atrophic dfsp. atrophic dfsp should be kept in the differential diagnosis for atrophic and depressed skin lesions, particularly those seen on the trunks of women. dermatoscopy, a noninvasive method, may not only help to differentiate atrophic dfsp from other skin diseases but may also indicate the need for histopathological examination since the disease has prognostic significance. references 1. hanabusa m, kamo r, harada t, et al. dermatofibrosarcoma protuberans with atrophic apperance at early stage of the tumor. j dermatol 2007;34:336-39. 2. lambert wc, abramovits w, gonzalez-sevra a, et al. dermatofibrosarcoma nonprotuberans: description and report of five cases of a morpheaform variant of dermatofibrosarcoma. j surg oncol 1985;28:7-11. 3. wu jk, malik mm, egan ca. atrophic dermatofibrosarcoma protuberans: an uncommon and misleading variant. aus j dermatol 2004;45:175-77. 4. gungor s, buyukbabani n, buyuk m, et al. atrophic dermatofibrosarcoma protuberans: are there specific dermatoscopic features? j dtsch dermatol ges 2014;12:425-27. 5. bernard j, poulalhon n, argenziano g, et al. dermoscopy of dermatofibrosarcoma protuberans: a study of 15 cases. br j dermatol 2013;169:85-90. 6. avilés-izquierdo ja, conde-montero e, barchino-ortiz l, et al. dermoscopic features of dermatofibrosarcoma protuberans. aus j dermatol 2014;55:125-27. 7. zalballos p, puig s, llambrich a, et al. dermoscopy of dermatofibromas: a prospective morphological study of 412 cases. arch dermatol 2008;144:75-83. http://www.ncbi.nlm.nih.gov/pubmed?term=avil%c3%a9s-izquierdo%20ja%5bauthor%5d&cauthor=true&cauthor_uid=24720426 dermatology: practical and conceptual 292 letter | dermatol pract concept 2019;9(4):8 dermatology practical & conceptual introduction lentigo maligna (lm) is a type of in situ melanoma that usually arises in elderly people with sun-damaged skin. the accurate diagnosis of these lesions is difficult because, besides having other pigmented macules in the differential diagnosis, the histopathology has subtle features that can be confused with junctional melanocytic nevi (jmn). case presentation we present 4 cases of patients who had lm on the face, initially being misdiagnosed as jmn by biopsy of the lesions. patient 1, a 59-year-old man, presented with a brown lesion on the face at the same spot where he had a lesion removed previously (figure 1, a and c). asymmetric pigmentation with gray dots around the follicle was seen on dermoscopy (figure 1b). patient 2, aged 74 years, presented with new lesion on the face, revealing asymmetric gray pigment around the follicle and rhomboidal structures on dermoscopy (figure 2). patient 3, aged 58 years, presented with a lesion on the face that had been present for 3 years. multiple gray dots, some of them distributed around the follicle, were seen on dermoscopy (figure 3). patient 4, aged 60 years, presented with a lesion on the forehead that had been gradually growing. it presented asymmetric gray pigmentation around the follicle, rhomboidal structures, and circle-within-circle structures on dermoscopy (figure 4). conclusions when evaluating pigmented macules on the face, one should keep in mind the differential diagnosis, such as solar lentigo, seborrheic keratosis, pigmented actinic keratosis (pak), and lichen planus-like keratosis (lplk). dermoscopy can give some clues to help with the accurate diagnosis. stolz et al described a model of the dermoscopy progression for lm: it initially has asymmetric pigmentation and dots around the follicle, evolving to rhomboidal structures and then forming homogeneous pigmented areas and obliteration of the folliclentigo maligna of the face: the importance of clinical, dermoscopic, and histological correlation giovana serrão fensterseifer1, ana paula lodi1, manuela lima dantas1, ana letícia boff2, louise lovatto3 1 dermatology, santa casa de porto alegre, brazil 2 dermatopathology, santa casa de porto alegre, brazil 3 pigmented lesions clinic, santa casa de porto alegre, brazil key words: lentigo maligna, pigmented lesions of the face, dermoscopy, histopathology citation: serrão fensterseifer g, lodi ap, lima dantas m, boff al, lovatto l. lentigo maligna of the face: the importance of clinical, dermoscopic, and histological correlation. dermatol pract concept. 2019;9(4):292-294. doi: https://doi.org/10.5826/dpc.0904a08 accepted: july 21, 2019; published: october 31, 2019 copyright: ©2019 serrão fensterseifer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. giovana serrão fensterseifer, rua professor annes dias, 135-hospital santa clara, santa casa porto alegre, brazil. email: gfensterseifer@gmail.com letter | dermatol pract concept 2019;9(4):8 293 ular openings [1]. the existence of gray pigmentation (that can be arranged in an annular-granular pattern) is also an important criterion for the suspicion of lm. nevertheless, many lm dermoscopy criteria can also be seen in other lesions of the face, especially in pak and lplk. the histopathology of lm is characterized, initially, by subtle proliferation of slightly larger-dimensioned melanocytes at the basal layer of the epidermis of photo-damaged skin. these melanocytes are not equidistant from each other; they can be agglomerated and involve adnexa. at the next stage, there are more features of a malignant melanocytic lesion: pagetoid proliferation, melanocytes with hyperpigmented and angulated nucleus aligned in the basal layer, and involvement of the deeper portion of the follicles. at the third stage, the melanocytes can be arranged in nests, resembling a junctional nevus. at this stage, it is important to pay attention to the involvement figure 1. patient 1. (a) clinical image. (b) dermoscopy. (c) the first excisional biopsy was initially misdiagnosed as junctional melanocytic nevi. histopathology (×40 and ×400) shows lentiginous proliferation of atypical melanocytes (pleomorphic and hyperchromic nucleus) involving acrosyringia and some pagetoid proliferation. some melanocytes are arranged in nests. there are melanophages in the papillary dermis. (d) biopsy of the recurrent lesion. histopathology (×40 and ×400) shows even more subtle findings than the first one: lentiginous proliferation of melanocytes with bigger, hyperchromic, and irregular-shaped nucleus; melanocytes arranged in nests; and melanophages in the papillary dermis. [copyright: ©2019 serrão fensterseifer et al.] figure 2. patient 2. (a) clinical image. (b) dermoscopy. (c) histopathology examination (×40) shows continuous lentiginous proliferation and some melanocytes arranged in junctional nests. (d) higher magnification (×400) shows atypical and a few pagetoid melanocytes. [copyright: ©2019 serrão fensterseifer et al.] a c b d 294 letter | dermatol pract concept 2019;9(4):8 of adnexa, to the discrete pagetoid proliferation, to the disposal of the nests parallel to the epidermis, and to the shape of the melanocytes [2]. moreover, it is well known that nevi on sun-exposed skin of elderly people are usually intradermal nevi, being pink, domeshaped papules. in conclusion, the differential diagnosis of recent pigmented macules on sun-exposed skin of elderly individuals is usually between lm and nonmelanocytic lesions; it is always prudent to reevaluate pathology reports of jmn, followed by an excisional biopsy of these lesions. references 1. stolz w, schiffner r, burgdorf wh. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002;20(3):276278. 2. massi g, leboit pe. lentigo maligna. in: massi g, leboit pe. histological diagnosis of nevi and melanoma. 2nd ed. london: springer; 2014:437-444. figure 3. patient 3. (a) clinical image. (b) dermoscopy. (c) histopathology examination (×40) shows continuous lentiginous proliferation and some pagetoid melanocytes. (d) insert shows atypical melanocytes arranged in nests. [copyright: ©2019 serrão fensterseifer et al.] a c b d figure 4. patient 4. (a) clinical image. (b) dermoscopy. (c) histopathology shows lentiginous proliferation and junctional nests. (d) higher magnification (×400) shows atypical melanocytes arranged in nests. [copyright: ©2019 serrão fensterseifer et al.] a c b d dermatology: practical and conceptual practical, conceptual, educational note | dermatol pract concept 2014;4(4):15 73 dermatology practical & conceptual www.derm101.com malignant melanoma is the most common cancer among women and men aged 25-29 [1]. unfortunately, the incidence of melanoma far surpasses the rate of any other malignancy in this demographic. due to the growing trends of tanning and advanced nail art, the incidence of melanoma may increase in the coming years. less than a quarter of patients examine their own skin on a regular basis [2]. an austrian study concluded that patients deemed physicians as the fourth most reliable source for skin health information behind print media, television, and family members [3]. with this in mind, physicians must develop non-traditional melanoma prevention strategies to increase early detection. in a society where the majority of the population uses the internet, non-traditional screening tools for melanoma recognition include implementation of an electronic health system designed for regular self-evaluation of skin and nevi surveillance. e-health tools may detect melanoma at an earlier stage, reducing overall morbidity and mortality from disease [4]. however, experts are concerned that inaccurate readings may lead patients to neglect a physician consult, which could thwart early diagnosis of treatable melanocytic lesions [4]. other non-traditional strategies for early detection of melanoma in young women and men are also noteworthy. for example, hair stylists may aid in early detection of scalp lesions since young women and men frequently visit the same stylist. training stylists to recognize the signs of skin cancer in the scalp may increase rates of early detection of head and neck lesions that would have otherwise been discovered in later stages due to their inconspicuous locations [5]. these locations represent 6% of all melanomas, but are responsible for 10% of all deaths from melanomas [5]. similarly, massage therapists who see the same client on a regular basis may be able to report new neoplasms and changes in nevi on the body. nail artists represent another demographic that can be trained to recognize nail melanoma between appointments and alert their clients of pathologic nail changes. only 66% of patients address melanocytic changes observed in nails [6]. women will often use nail polish, various gel techniques, and wrapping procedures to conceal nails for prolonged periods of time. training these professionals may be an effective population-based strategy to increase rates of early stage melanoma detection. a survey of 206 hair professionals found that only 28.1% had received formal skin cancer education, but almost fifty percent of hair professionals were interested in a skin cancer education program [7]. about 37% looked at greater than non-traditional melanoma prevention strategies in the young adult and adolescent population collin m. blattner1, karan lal2, jenny e. murase3,4 1 des moines university, des moines, ia, usa 2 new york college of osteopathic medicine, old westbury, ny, usa 3 department of dermatology, palo alto foundation medical group, palo alto and mountain view, ca, usa 4 department of dermatology, university of california, san francisco, san francisco, ca, usa citation: blattner cm, lal k, murase je. non-traditional melanoma prevention strategies in the young adult and adolescent population. dermatol pract concept. 2014;4(4):15. http://dx.doi.org/10.5826/dpc.0404a15 received: june 5, 2014; accepted: august 12, 2014; published: october 31, 2014 copyright: ©2014 blattner et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: jenny e. murase, m.d., department of dermatology, palo alto foundation medical group, 701 east el camino real (31-104), mountain view, ca 94040. tel. 650-934-7676; fax. 650-934-7696. email: jemurase@gmail.com 74 practical, conceptual, educational note | dermatol pract concept 2014;4(4):15 50% of their customers’ scalps, 29% looked at greater than 50% of their customers’ necks, and 15% looked at greater than 50% of their customers’ faces for concerning lesions during the preceding month.7 hair professionals’ personal health practices corresponded with frequency of observation of customers’ lesions (p < .001) [7]. this study led to development of the skinny on skin, an educational program designed to aid in the early detection and prevention of melanoma by beauty industry professionals. counseling the young demographic can be difficult due to the pressure the media places on young women and men to enhance their appearance. with this in mind, appeals to the negative cosmetic impact of sun and indoor tanning may be more effective than health-based appeals [8]. it is important to explain to patients that intermittent periods of excessive sun exposure early in life may lead to an increase in fine lines, wrinkles, lentiginous proliferations, and rapidly evolving nevi that may develop into melanoma [9]. although counseling against tanning bed use may be successful in some patients, it has been shown that even after learning the associated risks, patients continue to tan [10]. the use of tanning beds has been associated with addictive behavior and may contribute to a compulsive desire to tan [11]. the brain of a person who habitually tans exhibits activity similar to that of a substance abuser and can experience tolerance, dependence, and withdrawal [11]. the brain responds to ultraviolet radiation (uvr) and can differentiate uvr from non-uvr tanning beds.11 when counseling these patients, it may be beneficial to use screening tools including the cage questionnaire (table 1) to determine the motivation and goals associated with excessive tanning [12]. understanding these desires will improve the ability of a provider to suggest appropriate alternatives to tanning [12]. for example, individuals who tan for relaxation may substitute yoga as an appropriate alternative, while those who tan for aesthetic purposes may choose to use dihydroxyacetone, the active ingredient in sunless tanners, as an alternative. it is also pertinent to discuss tanning in the pediatric and teenage populations to fully understand familial beliefs about tanning. children whose parents tan indoors are more likely to do the same compared to children whose parents do not tan; a population based survey found that indoor tanning was 30% in the twelve to eighteen year old age group when the caregiver personally tanned compared to only 10% when the caregiver did not tan [13]. in conclusion, primary care providers and dermatologists should continue to educate women and men about the major modifiable risk factors for melanoma, including unprotected sun exposure and monitoring of existing nevi. education of hair stylists, nail artists, and massage therapists may expedite a referral to health-care professionals. through the institution table 1. the cage questionnaire • have you ever felt the need to cut down on your tanning? • have you ever felt annoyed by criticism of your tanning? • have you ever felt guilty about your tanning? • have you ever felt the need to tan every morning? of both traditional and non-traditional melanoma prevention strategies, patients and physicians may achieve greater awareness, early detection, and prevention of disease. references 1. lim hw, james wd, rigel ds, et al. adverse effects of ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan. j am acad dermatol. 2011;64(5):893-902. 2. pollitt ra, geller ac, brooks dr, et al. efficacy of skin selfexamination practices for early melanoma detection. cancer epidemiol biomarkers prev. 2009;18(11):3018–23. 3. haluza d, cervinka r. perceived relevance of educative information on public (skin) health: a cross-sectional questionnaire survey. j prev med public health. 2013;46(2):82-8. 4. tyagi a, miller k, cockburn m. e-health tools for targeting and improving melanoma screening: a review. j skin cancer. 2012;2012:437502. epub 2012 dec 2013. 5. roosta n, wong mk, woodley dt, norris comprehensive cancer center melanoma working group. utilizing hairdressers for early detection of head and neck melanoma: an untapped resource. j am acad dermatol. 2012;66(4):687-8. 6. carreño am, nakajima sr, pennini sn, candido junior r, schettini ap. nail apparatus melanoma: a diagnostic opportunity. an bras dermatol 2013;88(2): 268-71. 7. bailey ee, marghoob aa, orengo if, et al. skin cancer knowledge, attitudes, and behaviors in the salon: a survey of working hair professionals in houston, texas. arch dermatol. 2011;147(10):1159-65. 8. diao dy, lee tk. sun-protective behaviors in populations at high risk for skin cancer. psychol res behav manag. 2014(7): 9-18. 9. dahl c, guldberg p. the genome and epigenome of malignant melanoma. apmis 2007; 115: 1161–76. 10. knight jm, kirincich an, farmer er, hood af. awareness of the risks of tanning lamps does not influence behavior among college students. arch dermatol. 2002;138(10):1311–5. 11. harrington cr, beswick tc, leitenberger j, et al. addictive-like behaviours to ultraviolet light among frequent indoor tanners. clin exp dermatol. 2011;36(1):33-8. 12. schneider s, diehl k, bock c, et al. sunbed use, user characteristics, and motivations for tanning: results from the german populationbased sun-study 2012. jama dermatol. 2013;149(1):43-9. 13. cokkinides ve, weinstock ma, o’connell mc, thun mj. use of indoor tanning sunlamps by us youth, ages 11-18 years, and by their parent or guardian caregivers: prevalence and correlates. pediatrics. 2002;109(6):1124–30. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020083 1 dermatology practical & conceptual introduction leprosy reactions are immunological reactions due to the changes in a patient’s immune status in response to mycobacterium leprae that may occur before, during, or even after the completion of multidrug therapy. leprosy reactions are divided into 2 types. type 1 lepra reaction (reversal reaction) is characterized by the development of acute erythema and swelling of existing skin lesions or by the appearance of new lesions and/or neuritis [1,2]. type 2 lepra reaction (erythema nodosum leprosum) is the appearance of skin nodules due to the immune complex–mediated complication of leprosy [3]. t1r is a type iv hypersensitivity reaction that occurs mostly in borderline leprosy patients [4]. clinically, t1r may present with similar morphology to other granulomatous skin conditions such as lupus vulgaris (lv), sarcoidosis, and granuloma faciale. as we know, dermoscopy can be used to facilitate the differential diagnosis of granulomatous skin conditions [5]. the present study aims to describe dermoscopic patterns in t1r according to the severity of lesions and the type of leprosy. case presentation the present work was designed as a prospective, tertiary urban hospital–based, observational study during the period from august 2016 to january 2017. institutional ethical clearance was obtained, and patients clinically and histopathologically diagnosed as having t1r were included. leprosy patients were classified using the ridley-jopling classification [1]. dermoscopy was performed by 2 independent dermoscopists (experience 7 years and 5 years, respectively). dermoscopy (polarized, ×10) was done using dermlitedl4 (3gen, san juan capistrano, ca), and photographs were captured by apple iphone 7 from the same site where biopsy was done (facial lesion)and sent for histopathology. dermoscopic features for lepra diagnosis included background color and type of vessels. a total of 14 patients with type 1 reaction were included in the study. type 1 lepra reaction was seen mostly in patients who were treated with multidrug therapy for leprosy for less than 6 months. among the 14 cases, 8 patients (57.14%) were previously diagnosed as having borderline tuberculoid leprosy (figures 1a, 2a, 3a) and 6 cases (42.85%) as having borderline lepromatous lepdermoscopy of type 1 lepra reaction in skin of color abhijeet kumar jha,1 m.d. zeeshan,1 pankaj tiwary,1 anupama singh,1 prasoon kumar roy,1 r.k.p. chaudhary1 1 department of skin & v.d., patna medical college and hospital, patna, bihar, india key words: leprosy, type 1 lepra reaction, dermoscopy in skin of color, erythema nodosum leprosum, dermoscopy citation: jha ak, zeeshan md, tiwary p, singh a, roy pk, chaudhary rkp. dermoscopy of type 1 lepra reaction in skin of color. dermatol pract concept. 2020;10(3):e2020083. doi: https://doi.org/10.5826/dpc.1003a83 accepted: december 28, 2018; published: june 29, 2020 copyright: ©2020 jha et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: abhijeet kumar jha, md, department of skin & v.d., patna medical college and hospital, patna, bihar, india. email: drabhijeetjha@gmail.com https://doi.org/10.5826/dpc.1003a83 mailto:drabhijeetjha@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020083 appearance [10]. in conclusion, dermoscopic features such as linear blurry vessels within reddish or orangish areas could typify t1r. that in sarcoidosis and lv, the granulomatous infiltrates are dense, thus pushing the vessels upward, closer to the surface with a consequent sharper rosy. nine male (64.28%) and 5 female patients (35.71%) were included, with age ranging from 21 to 47 years. at our dermoscopic examination, yellowish orange areas were observed in 6 cases (42.85%) and particularly reddish orange areas were seen in 8 cases (57.14%); arborizing vessels (figure 1b), fine short linear vessels (figure 2b), and linear blurry vessels (figure 3b) were detected in 10 cases (71.42%) and in 4 cases (28.57%), respectively; white scales were present in 1 case (7.14%). conclusions dermoscopy is a noninvasive tool widely used in the diagnosis of skin tumors and inflammatory skin disorders [6]. it is also helpful in assessment of vascular structures and color variations, which are not clinically visible to the naked eye. thus, dermoscopy may be considered between clinical examination and histopathology [7]. in the study conducted by ankad and sakhare [8], the dermoscopic features of the patients with borderline tuberculoid leprosy characteristically showed white areas, yellow globules, and linear branching telangiectasia. in our study, patients with borderline tuberculoid leprosy with severe t1r [8] showed reddish background and white structureless areas with fine short linear blurry vessels, probably due to an increased number of lymphocytes and loss of normal granuloma organization. yellow globules were seen in 6 cases of t1r. orange-yellow globules with telangiectasia are generally considered to be the hallmark of dermal granulomas. however, yellow translucent globules with branching telangiectasia could be also seen in lv and sarcoidosis [9]. the vessels in t1r were mostly blurry in contrast to sarcoidosis and lv, where the vessels appear usually quite sharp. this may be due to the fact figure 1. (a) erythematous plaque on the face. (b) dermoscopy (polarized, ×10) showing yellowish orange area with arborizing vessels. figure 2. (a) erythematous plaque on the face. (b) dermoscopy (polarized, ×10) showing reddish yellow area with linear vessels. figure 3. (a) erythematous plaque on the face. (b) reddish areas along with white structureless areas with fine short linear blurry vessels. letter | dermatol pract concept 2020;10(3):e2020083 3 5. bombonato c, argenziano g, lallas a, moscarella e, ragazzi m, longo c. orange color: a dermoscopic clue for the diagnosis of granulomatous skin diseases. j am acad dermatol. 2015;72(1 suppl):s60–s63. https://doi.org/10.1016/j.jaad.2014.07.059 6. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198–1205. https:// doi.org/10.1111/j.1365-2133.2012.10868.x 7. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology. 2006;212(1):7–18. https:// doi.org/10.1159/000089015 8. ankad bs, sakhare ps. dermoscopy of borderline tuberculoid leprosy. int j dermatol. 2018;57(1):74-76. https://doi.org/10.1111/ ijd.13731 9. lallas a, zaballos p, zalaudek i, et al. dermoscopic patterns of granuloma annulare and necrobiosis lipoidica. clin exp dermatol. 2013;38(4):424–429. 10. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. references 1. ridley ds, jopling wh. a classification of leprosy according to immunity: a fivegroup system. int j lepr other mycobact dis. 1966;34(3):255-273. pmid: 5950347 2. van brakel wh, nicholls pg, das l, et al. the infir cohort study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy: methods and baseline results of a cohort of multibacillary leprosy patients in north india. lepr rev. 2005;76(1):14-34. pmid: 15881033 3. pocaterra l, jain s, reddy r, et al. clinical course of erythema nodosum leprosum: an 11-year cohort study in hyderabad, india. am j trop med hyg.2006;74(5):868-879. https://doi. org/10.4269/ajtmh.2006.74.868 4. van brakel wh, khawas ib, lucas sb. reactions in leprosy: an epidemiological study of 386 patients in west nepal. lepr rev. 1994;65(3):190-203. https://doi.org/10.5935/03057518.19940019 https://doi.org/10.1016/j.jaad.2014.07.059 https://doi.org/10.1111/j.1365-2133.2012.10868.x https://doi.org/10.1111/j.1365-2133.2012.10868.x https://doi.org/10.1159/000089015 https://doi.org/10.1159/000089015 https://doi.org/10.1111/ijd.13731 https://doi.org/10.1111/ijd.13731 https://doi.org/10.4269/ajtmh.2006.74.868 https://doi.org/10.4269/ajtmh.2006.74.868 https://doi.org/10.5935/0305-7518.19940019 https://doi.org/10.5935/0305-7518.19940019 dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):6 23 dermatology practical & conceptual www.derm101.com case presentation a 58-year-old female presented to us with a gradually progressive erythematous scaly plaque over dorsum of right hand for eight months. there was a single round, tender 2 x 2 cm well defined plaque, with multiple black dots, scaling and crust (figure 1). potassium hydroxide mount from the black dots showed multiple refractile, round, grouped coppery structures (medlar bodies). dermoscopy showed a reddish pink background with multiple yellow-orange ovoid structures, along with interspersed brown dots, crusts and scales. skin biopsy from the plaque showed acanthotic epidermis with mixed cell infiltrate and microabscess with pigmented spherical spores. mycological culture from the tissue showed growth of fonsecaea pedrosoi. based on clinical, dermoscopic and histopathological features, a diagnosis of chromoblastomycosis was made. oral itraconazole 200 mg twice daily was started. conclusion chromoblastomycosis is a chronic fungal infection involving skin and subcutaneous tissue of the extremities. it is mostly caused by trauma [1]. commonly isolated fungal species are fonsecaea, phialophora and cladophialophora. clinically it presents as an erythematous papule and nodule progressing to form a verrucous plaque with central clearing. other common presentations include tumoral, cicatricial and sporotrichoid forms. direct microscopy shows presence of 5-12 μm sized, thick-walled, dark-colored structures called medlar bodies. histopathology shows pseudoepitheliomatous hyperplasia with intraepidermal abscess and medlar bodies [2]. isolation of the fungus on culture confirms the diagnosis of chromoblastomycosis. treatment includes either oral itraconazole (400 mg/day) or terbinafine (500 mg/day) with or without physical modalities such as thermotherapy. dermoscopy of chromoblastomycosis sweta subhadarshani1, deepika yadav1 1 department of dermatology and venereology all india institute of medical sciences, new delhi, india key words: chromoblastomycosis, dermoscopy citation: subhadarshani s, yadav d. dermoscopy of chromoblastomycosis. dermatol pract concept 2017;7(4):23-24. doi: https://doi. org/10.5826/dpc.0704a06 received: june 18, 2017; accepted: july 9, 2017; published: october 31, 2017 copyright: ©2017 subhadarshani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sweta subhadarshani, md, department of dermatology and venereology, all india institute of medical sciences, ansari nagar, new delhi: 110049, india. tel. 919868386876. email: shweta.aiims07@gmail.com chromoblastomycosis is a chronic cutaneous fungal infection commonly caused by fonsacea and cladophialophora spp. dermoscopy is a non-invasive, real-time diagnostic tool for rapid bedside diagnosis of various inflammatory and non-inflammatory disorders and can be an excellent modality for evaluation of cutaneous mycosis, for which it shows characteristic brown dots, crust, scales and yellow orange structures. abstract mailto:shweta.aiims07@gmail.com 24 observation | dermatol pract concept 2017;7(4):6 dermoscopy is an excellent bedside real-time tool for the diagnosis of chromoblastomycosis. references 1. torres-guerrero e, isa-isa r, isa m, arenas r. chromoblastomycosis. clin dermatol. 2012;30:403-408. 2. uribe f, zuluaga ai, leon w, restrepo a. histopathology of chromo blastomycosis. mycopathologia. 2013;175:477-488. 3. arguello-guerra l, gatica-torres m, dominguez-cherit j. chromomycosis. bmj case rep. 2016 may 20;2016. 4. zaias n, rebell g. a simple and accurate diagnostic method in chromoblastomycosis. arch dermatol. 1973;108:545-546. 5. tang j, zhuang k, ran x, dai y, ran y. chromoblastomycosis caused by cladophialophora carrionnii. indian j dermatol venereol leprol. 2017;83:482-485. dermoscopy of chromoblastomycosis shows irregular blackish red dots and white and pink areas along with scaling, crusting [3]. the blackish red dots correspond to the black dots observed clinically. these represent transepithelial elimination of the inflammatory cells and fungal elements along with hemorrhage [4]. this transepithelial elimination is thought to be an important defense mechanism in restricting the fungal infection. white and pink areas correspond to uneven areas [5]. yellow, ovoid structures on dermoscopy represent granulomas. these can be seen in any granulomatous pathology either infective or non-infective. out of the above-mentioned dermoscopic features, the presence of irregular blackish red dots is the most useful sign in making a diagnosis of chromoblastomycosis. in fact, resolution of blackish red dots has been noted with the clinical and pathological clearance of the lesion [5]. figure 1. (a) well-defined, erythematous, scaly, crusted plaque studded with black dots (arrow) over the dorsum of the hand. (b) dermoscopy (polarized, 16x; heine delta 20t, heine optotechnik, herrsching, germany) shows pink and white background with yellowish orange ovoid structures (circle), brown dots (asterisk), scale and crust. (c) potassium hydroxide mount (400x) shows medlar bodies (arrow). [copyright: ©2017 subhadarshani et al.] dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):10 55 dermatology practical & conceptual www.derm101.com introduction cutaneous leishmaniasis is caused by transmission of the leishmania spp. through the bite of the female sandfly [1]. while most of the clinical manifestations are characteristic and pose no diagnostic difficulties [2], there are several infrequent and atypical features of the disease which can delay correct diagnosis and proper treatment [3]. here we report on a case of zosteriform cutaneous leishmaniasis, which was diagnosed with the help of dermoscopy. case report a 55-year-old female, without known health-related problems, presented with an upper right chest and upper right back eruption for six weeks. the eruption was accompanied with mild to moderate itching and pain. she did not receive any treatment for these symptoms. the patient had traveled to an endemic area for cutaneous leishmaniasis inside israel a month before the rash appeared. on examination, two erythematous nodules, with a central ulcer covered with a yellow zosteriform cutaneous leishmaniasis diagnosed with the help of dermoscopy yuval ramot1, krassimira nanova2, ruslana alper-pinus1, abraham zlotogorski1 1 department of dermatology, hadassah-hebrew university medical center, jerusalem, israel 2 kupat holim leumit, jerusalem, israel citation: ramot y, nanova k, alper-pinus r, zlotogorski a. zosteriform cutaneous leishmaniasis diagnosed with the help of dermoscopy. dermatol pract concept. 2014;4(3):10. http://dx.doi.org/10.5826/dpc.0403a10. received: february 16, 2014; accepted: march 5, 2014; published: july 31, 2014 copyright: ©2014 ramot et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: abraham zlotogorski, md, department of dermatology, hadassah-hebrew university medical center, jerusalem 9112001, israel. tel. +972 2 6777111. e-mail: zloto@cc.huji.ac.il cutaneous leishmaniasis is usually easy to recognize; however, several atypical features exist, which may pose a diagnostic challenge. here we report a 55-year-old female patient, who presented with an itchy and painful eruption localized in a dermatomal distribution along the right upper chest. although the clinical appearance of the lesions suggested the diagnosis of herpes zoster, dermoscopic evaluation revealed erythema, hyperkeratosis, burst star whitish appearance and hairpin vessels, compatible with the diagnosis of cutaneous leishmaniasis. indeed, leishmania amastigotes were detected by smear from the lesions. zosteriform presentation of cutaneous leishmaniasis, as exemplified by our patient, is especially rare. in our case dermoscopy has proven to be an accessible and easy tool to diagnose such atypical presentation of cutaneous leishmaniasis, and dermatologists in endemic areas should be familiar with its typical dermoscopic features. abstract 56 observation | dermatol pract concept 2014;4(3):10 crust, were evident on the upper right back (figure 1a). an erythematous papule was evident as a satellite lesion. three similar additional lesions were found on the right upper chest (figure 1b), forming a seemingly dermatomal distribution of lesions, leading to the clinical impression of herpes zoster. however, dermoscopic examination revealed erythema, hyperkeratosis, burst star whitish appearance and hairpin vessels (figure 1c, d), compatible with cutaneous leishmaniasis. leishmania amastigotes were detected by smear from the lesions. discussion while several uncommon presentations of cutaneous leishmaniasis have been reported [3], a zosteriform presentation is especially rare, and has been described only anecdotally in the literature [3-6]. our case posed a special challenge, since the patient reported on pain in the relevant region, while leishamania lesions are usually asymptomatic. the lesions were also arranged in a seemingly dermatomal distribution, without crossing of the midline. however, the chronic course of the rash raised the suspicion of a different diagnosis than herpes zoster, and dermoscopy proved to be a useful diagnostic tool. several dermoscopic findings have been described in cutaneous leishmaniasis, the most common ones include erythema, a large number of different vascular structures, white starburst-like patterns, central ulcers, yellow tears and hyperkeratosis [7-9]. since erythema, hyperkeratosis and hairpin vessels can be observed in many dermatological conditions, they are not considered to be very useful or specific for diagnosing cutaneous leishmania [7]. however, the presence of a whitish starburst pattern was a strong indicator for cutaneous leishmaniasis in our patient. our case demonstrates the importance of including cutaneous leishmaniasis in the differential diagnosis of herpes zoster in endemic areas. furthermore, since dermoscopy can be easily utilized to diagnose this condition, dermatologists in endemic areas should be familiar with its typical dermoscopic features. references 1. rassi y, gassemi mm, javadian e, et al. vectors and reservoirs of cutaneous leishmaniasis in marvdasht district, southern islamic republic of iran. east mediterr health j. 2007;13(3):686-93. 2. farahmand m, nahrevanian h, shirazi ha, naeimi s, farzanehnejad z. an overview of a diagnostic and epidemiologic reappraisal figure 1. (a, b) clustered erythematous nodules with a central crust arranged in a dermatomal distribution. (c, d) dermoscopic features of the lesions, including erythema, hyperkeratosis, burst star whitish appearance and hairpin vessels. [copyright: ©2014 ramot et al.] observation | dermatol pract concept 2014;4(3):10 57 of cutaneous leishmaniasis in iran. braz j infect dis. 2011;15 (1):17-21. 3. bari au, rahman sb. many faces of cutaneous leishmaniasis. indian j dermatol venereol leprol. 2008;74(1):23-7. 4. raja km, khan aa, hameed a, rahman sb. unusual clinical variants of cutaneous leishmaniasis in pakistan. br j dermatol. 1998;139(1):111-3. 5. omidian m, mapar ma. chronic zosteriform cutaneous leishmaniasis. indian j dermatol venereol leprol. 2006;72(1):41-2. 6. momeni az, aminjavaheri m. clinical picture of cutaneous leishmaniasis in isfahan, iran. int j dermatol. 1994;33(4):260-5. 7. yucel a, gunasti s, denli y, uzun s. cutaneous leishmaniasis: new dermoscopic findings. int j dermatol. 2013;52(7):831-7. 8. taheri ar, pishgooei n, maleki m, et al. dermoscopic features of cutaneous leishmaniasis. int j dermatol 2013;52(11):1361-6. 9. llambrich a, zaballos p, terrasa f, et al. dermoscopy of cutaneous leishmaniasis. br j dermatol. 2009;160(4):756-61. dermatology: practical and conceptual practical, conceptual & educational notes | dermatol pract concept 2015;5(1):5 31 dermatology practical & conceptual www.derm101.com the so-called dysplastic nevus first entered medical parlance in 1980 [1], originally known as the b-k mole in 1978, only to evolve over the next 34 years into a variety of names including familiar and atypical sporadic mole, melanocytic nevus with persistent lentiginous melanocytic hyperplasia, junctional or compound nevus with architectural atypia/disorder with or without cytological atypia, and clark’s nevus, to mention but a few [2-6]. it is common knowledge that there is significant discordance and diagnostic uncertainty among consultants in the histopathologic diagnosis of difficult melanocytic neoplasia, i.e., benign or malignant [7]. the fact is there is disagreement among the experts [8,9] as to what constitutes the so-called dysplastic nevus clinically and histopathologically [10]. this is so because there is inadequate and conflicting clinical and histopathologic criteria for a so-called dysplastic nevus. both a melanoma and a dysplastic nevus have the same clinical features of the notorious abcd’s (asymmetry, border irregularity, color variability, diameter greater than 6 mm) what was and still is most disturbing and concerning, is the fact that there were reports, studies, theories and beliefs suggesting that the so-called dysplastic nevus is pre-malignant or a precursor of melanoma. furthermore, it is said that the so-called dysplastic nevus may evolve into a malignant melanoma in either the patient or in family members, or both. overlapping criteria in melanocytic neoplasia are features that are seen in both benign melanocytic nevi and superficial melanoma, such as seen in some nevi on occasion shortly after birth, persistent (recurrent) nevi, or traumatized nevi. in addition, overlapping criteria may be seen in nevi on special sites such as the palm/sole, genitalia (especially vulva of young women), umbilicus, perianal, scalp, and intertriginous folds. “although the diagnosis of cutaneous malignant melanoma is usually based on histopathologic criteria may at times be inadequate in differentiating melanoma from certain types of benign nevi.” [11] collectively, overlapping melanocytic criteria may well be the answer for such confusion between a so-called dysplastic nevus, melanocytic nevus and a superficial melanoma [12]. unfortunately, when a physician labels a nevus as socalled dysplastic, or used as a hedge when unsure whether the lesion is benign or malignant, and therefore, “premalignant,” there are consequences as this diagnosis evokes considerable the mythical concept and untoward consequences of a diagnosis of dysplastic nevus: an overdue tribute to a. bernard ackerman, md robert m. hurwitz1, morton e. tavel2 1 cutaneous and maxillofacial pathology laboratory, pc, indianapolis, in, usa 2 professor emeritus, indiana university school of medicine, department of medicine, indianapolis, in, usa key words: dysplastic nevus, consequences, melanoma, myth, overlapping criteria, discordance, melanocytic neoplasia citation: hurwitz rm, tavel me. the mythical concept and untoward consequences of a diagnosis of dysplastic nevus: an overdue tribute to a. bernard ackerman, md. dermatol pract concept. 2015;5(1):5. doi: 10.5826/dpc.0501a05 received: september 12, 2014; accepted: october 2, 2014; published: january 30, 2015 copyright: ©2015 hurwitz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: robert m. hurwitz, md, 9292 north meridian street, suite 210, indianapolis, indiana 46260, usa. email: bobbyhur@aol.com mailto:bobbyhur@aol.com 32 practical, conceptual & educational notes | dermatol pract concept 2015;5(1):5 apprehension, concern and anxiety in patients and their families. furthermore, reports mushroomed forth suggesting genetic transmission [13], but nowhere is there objective evidence that links the so-called dysplastic nevus or the socalled dysplastic nevus syndrome to malignant melanoma genetically or familial [14]. what is most distressing about the assumption that such dysplasia presages frank malignancy is that the assumption lacks sufficient objective validation, and is likely erroneous. the fact is that in melanocytic neoplasia, there are a variety of melanocytic nevi [15] and a variety of melanomas, e.g., melanoma in situ, superficial melanoma, and melanoma, but there is no dysplastic nevus. likely causes for the formation of false mythical conclusions operative in this untoward and ill-fated issue are the following [16]: 1) simple “logic,” that is, a conclusion based upon something that seems reasonable, e.g., heavy objects will fall faster then lighter ones. 2) notions provided by (respected?) teachers and, therefore, assumed to be “valid,” but later shown to be mythical. 3) a false belief arises when a condition is named in such a way that implies future progression, e.g., “pre-cancerous” lesion. treatments for this so-called dysplastic nevus and socalled dysplastic nevus syndrome regrettably have had the support and are promoted by many in the medical community, and sorry to say, in the legal community as well. what’s more, there is disagreement among experts regarding screening guidelines for high-risk characteristics of cutaneous melanoma [17]. among others, management includes repeated total body skin exams, repeated total body photographs, and aggressive avoidance of sun exposure. these procedures often lead especially and above all to the re-excision with margins of the so-called dysplastic nevus. along these lines, excision of additional so-called dysplastic nevi (figure 1) must also figure 1. scar on the right deltoid of a 40-year-old woman with numerous scattered melanocytic nevi on the trunk and extremities, following a 5 mm margin re-excision of a so-called spark’s nevus (features of a dysplastic and spitz nevus). (copyright: ©2015 hurwitz et al.) be considered meaningless. sentinel lymph node biopsy is often considered in so-called dysplastic nevi with severe architectural disorder and/or cytologic atypia. this procedure is indeed unbelievable, extremely alarming, if not outright shocking. they result in traumatic psychological e.g., worry anxiety and fear, as well as physical e.g., unsightly cutaneous scars. the consequences for these far-reaching therapeutics and prognostications for the so-called dysplastic nevus are barely credible, if not potentially tragic. (figure 2) [18,19]. rarely, regrettably and inappropriately to some, additional procedures are thought to avoid future litigation, and/or are thought to be good for business. these surgical maneuvers are reminiscent of other myths originating years ago, such as the mythical theory promoted dogmatically by halsted—respected for his status—at johns hopkins hospital. he postulated that attacking even small cancers with aggressive local surgery was the best way to achieve a cure, e.g., radical surgery for breast cancer, which included breast tissue, bone, muscle and lymph nodes, in the late 1890’s and early 1900’s [20]. similar radical surgery was performed in new york with wide and deep surgery including amputation for melanoma [21]. yet surprisingly, only about 50% of halsted’s mutilated radical mastectomy patients survived over three years, which was not superior to simpler procedures such as lumpectomy, introduced later. credible academic dermatologists and dermatopathologists have disagreed with the theories surrounding the socalled dysplastic nevus [22-25], that they inevitably evolve into malignancy, another example of mythical thinking. medical history is replete with examples of destroyed myths. for instance, it was believed for decades that peptic ulcer disease was simply a result of stress and anxiety, but now we figure 2. source of cartoon unknown; text modified by author. practical, conceptual & educational notes | dermatol pract concept 2015;5(1):5 33 understand from barry marshall and robin warren that the problem is the result of the bacterium helicobacter pylori [26], and from harald zur hausen that cervical squamous cell carcinoma is not due to sexual promiscuity, but in point of fact to the human papillomavirus, hpv16/18 [26]. myths regarding the over diagnosis of breast cancer are yet another [27,28]. furthermore, the myths of blood letting, cataract formation with uv light, extraterrestrial aliens, goblins, bigfoot, and remedies of questionable repute (snake oil) exist are often impossible to prove or disprove, because if truth be told, they do not exist, akin to the mythical dysplastic nevus [29]. in summary, branding the so-called dysplastic nevus as tantamount to a malignancy is clearly another, unacceptable devastating myth. as a result, we are creating needless fear and anxiety to patients and physicians alike, as well as placing patient lives in jeopardy. if we are to maintain any sort of ethics in the medical profession, then this myth of the so-called dysplastic nevus must be stopped. it is imperative that the discussion herein be a stimulus for sincere and genuine re-thinking and dialogue, of what has been a disastrous policy, and should not be flippantly dismissed as rhetoric or hyperbole without due consideration [30]. the late a. bernard ackerman, md, for thirty years, strongly believed in this point of view, and so consequently lectured, published scores of videos and articles repeatedly stating that the idea surrounding a so-called dysplastic nevus is in fact a myth. to him, and too many informed, knowledgeable and well-versed colleagues, the so-called dysplastic nevus clearly is mistaken for a one of a variety of different types of melanocytic nevi, or a misdiagnosis of what is in reality a superficial melanoma. in the sincere and respectful words of the late a. bernard ackerman, md, “the so-called dysplastic nevus has had thirty-one synonyms over the past thirty years, and thus this term should be relegated to the scrap heap.” [31] references 1. elder de, goldman li, goldman sc, greene mh, clark wh jr. dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma. cancer 1980;46(8):1787-94. pmid: 7427881 2. ackerman ab, massi d, nielson ta. dysplastic nevus, atypical mole or atypical myth. philadelphia, pa: ardor scribendi, ltd., 1999. 3. shoo a, sagebiel rw, kaslani–sabet m. discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. j am acad dematol 2010;62(5):751-63. pmid: 20303612 4. chen s. the dysplastic nevus controversy: it is not about the nevus per se but one’s belief in the multistept tumorigenesis theory. am j dermatopathol 2010;32(8):858. pmid: 20802304 5. hurt m. response of mark a. hurt, md, to dr. dumas on “uncertainty in diagnosis”. am j dermatopathol 2010;32(8):860. 6. mccalmont th. believe it or not: a truism or an entrenched paradigm? j cutan pathol 2013;40(12):993-95. pmid: 24274423 7. lodha s, saggar s, celebi jt, silvers dn. discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. j cutan pathol 2008;35(4):349-52. pmid: 18333894 8. hurwitz rm. letters to the editor. melanoma: experts disagree. dermatopathology: practical and conceptual 1996;2(1). 9. farmer er, gonin r, hanna mp. discordance in the histopathologic diagnosis of melanoma and melanocytic neoplasms betweem expert pathologists. hum pathol 1996;27(6):528-31. pmid: 24655081 10. hurt ma, milette f. correspondence: a letter to the editor not published in a well-known pathology journal, dysplastic nevusvoices of dissent! a response to dr.elder. dermatopathology: practical & conceptual 2010;16(3):17. 11. abbas o, miller dd, bhawan j. cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers. am j dermatopathol 2014;36(5):363-79. pmid: 24803061 12. hurwitz,rm, buckel lj, summerlin dj. melanocytic nevi and melanoma:overlapping criteria—the degree is the key. dermatol pract concept 2014;4(2):5. 13. decarlo k, yang s, emley a, et al. oncogenic braf–positive dysplastic nevi and the tumor suppressor igfbp7—challenging the concept of dysplastic nevi as a precursor lesions? hum pathol 2010;41(6):886-94. pmid: 20233623 14. dediol i, bulat v, zivkovic mv, markovic bm, situm m. dysplastic nevus—risk factor or disguise for melanoma. coll antroopol 2011 sept;35 suppl 2:311-3. pmid: 22220461 15. hurwitz rm, buckel lj, eads tj. histologic patterns of melanocytic nevi: a proposal for a new classification. j drugs dermatol 2007;6(5):487-92. 16. tavel me. snake oil is alive and well. the clash between myths and reality. reflections of a physician. chandler, arizona: brighton publishing llc, 2012. 17. watts cg, dieng m, morton rl, et al. clinical practice guidelines for identification, screening and follow-up of individuals at high risk of primary cutaneous melanoma: a systemic review. br j dermatol 2014 sep 10. doi: 10.1111/bjd. 13403 (epub ahead of print) 18. comfere ni, peters ms. reply to ‘surgical margins for possibly malignant melanocytic lesions’. j am acad dermatol 2014;71(3):589-90. pmid: 25128109 19. piepkorn mw, barnhill rl, elder de. reply: surgical margins for possible malignant melanocytic lesions and the over diagnosis of melanoma. j am acad dermatol 2014, 71(3):590. pmid: 25128110 20. mukherjee s. the emperor of all maladies: a biography of cancer. new york, ny: scribner, 2010. 21. ackerman ab. “exploding myths: melanocytic neoplasms.” video library lecture series. http://www.derm101.com/videolibrary/lecture-series/. accessed september 12, 2014. 22. maden r, chen s. the so-called dysplastic nevus in not dysplastic at all. dermatol pract concept 2013;3(1):1. doi:10.5826/30c.0301a01 23. ackerman ab. “dysplastic nevus: message or massage?” video library lecture series. http://www.derm101.com/video-library/ lecture-series/. accessed september 12, 2014. 24. mccalmont th. red alert or red herring? j cutan pathol 2014:41(4):337-39. pmid: 24655081 25. hurwitz rm. consequences of a diagnosis of dysplastic nevus. j cutan pathol 2014;41(4):407. pmid: 24655082 http://www.derm101.com/video-library/lecture-series/ http://www.derm101.com/video-library/lecture-series/ http://www.derm101.com/video-library/lecture-series/ http://www.derm101.com/video-library/lecture-series/ 34 practical, conceptual & educational notes | dermatol pract concept 2015;5(1):5 26. cornwall c. catching cancer: the quest for its viral and bacterial causes. plymouth, united kingdom: rowman & littlefield publishers, inc., 2013. 27. elmore jg, fletcher sw. overdiagnosis in breast cancer screening: time to tackle an underappreciated harm. ann intern med 2012;156(7):536-37. pmid: 22473439 28. kalager m, adami ho, bretthauer m, tamimi rm. overdiagnosis of invasive breast cancer due to mammography screening: results from the norwegian screen program. ann intern med 2012;156(7):491-99. pmid: 22473436 29. ackerman ab. “dysplastic nevus: message or massage?” part 1: resolution at last of controversy. video library lecture series. http://www.derm101.com/video-library/lecture-series/. accessed september 12, 2014. 30. hurwitz rm. have the lessons of munich been lost on american physicians? dermatopathology practical & conceptual 1999;5(1). 31. ackerman ab. “dysplastic nevus: message or massage?” part 2: resolution at last of controversy. video library lecture series. http://www.derm101.com/video-library/lecture-series/. accessed september 12, 2014. http://www.derm101.com/video-library/lecture-series/ http://www.derm101.com/video-library/lecture-series/ untitled note | dermatol pract concept 2015;5(2):7 55 dermatology practical & conceptual www.derm101.com in the journal dermatopathology: practical & conceptual in 1999 [1], there appeared an article “have the lessons of munich been lost on american physicians?” because of its ethical content, this manuscript was strongly supported and edited by the then founder and editor in chief, the late dr. a. bernard ackerman. during the late 19th and 20th centuries, europe, including austria and germany, were considered to be within the realm of medical excellence. knowledgeable physicians commonly came for months on end for study and intensive tutorials with the nationally well-known professors in areas such as pathology and cardiology. these enthusiastic young physicians came from around the world, commonly from countries such as the united states. emphasis within the introduction of the manuscript, “have the lesions of munich been lost on american physicians?” [1] focused on chamberlain and halifax, their connection to world war ii, and the disastrous effect that appeasement played. in addition, american medicine’s development is examined regarding the shaping of american medicine with physicians such as oliver wendell holmes (1809-1894) and william osler (1849-1919), among many others, and the faculty of johns hopkins instituting a fouryear graduated curriculum, including basic science and specialization. these brilliant alterations and achievements greatly influenced medical institutions throughout the world. because of the outcry for cheaper medicine, unfortunately, progressive medical excellence did not last in the united states. the deterioration of medicine involved their takeover by a variety of institutions, including government, hospitals and health care facilities, and managed care programs, such as the hmo (health maintenance organization), and the ppo (preferred provider organization), capitation shenanigans and the destructive and corrosive attitude of hospital against hospital, doctor against doctor, along with turf battles regarding contracts, all in the name of cheaper medicine. these issues are emboldened to this day. appeasement has progressed and elevated to wholesale of physicians, as well as elevation of the paramedical personnel to replace the physician. in other words, doctor’s offices and hospital attendance have now become “clinics.” patients are shuffled in and out of them quickly, oftentimes their rarely spending more than a few minutes with their physician, including a history and physical examination, thus eliminating any kind of meaningful doctor patient relationship. in addition, the sensitive personal relationship between the patient and his/her physicians has been compromised by physicians alternating schedules, and technicians, nurse assistants, nurse/practitioners are frequently used to replace the doctor’s personal visit. these medical practitioners are found in doctor’s offices and hospitals, but now shockingly in so-called walk-in clinics, minute clinics, drug and grocery stores, often without direct physician supervision. specialists and knowledgeable trained physicians such as dermatologists, among others, are often bypassed. unquestionably, specialists are essential in those tricky diagnostic dilemmas such as those with serious consequences, for example, distinguishing cutaneous melanocytic lesions and neoplasia, extensive rashes and those with markedly elevated fevers, and mild viral eruption versus septicemia. in conclusion, continued use of appeasement in medicine is truly demoralizing, devastating, unfortunate and a disaster for medicine and for both patient and physicians. as appeasement continues to grow, there will be progressive loss of astute, accurate medical diagnoses and treatment. interest appeasement never works robert m. hurwitz1 1 cutaneous and maxillofacial pathology laboratory pc, indianapolis, in, usa citation: hurwitz rm. appeasement never works. dermatol pract concept 2015;5(2):7. http://dx.doi.org/10.5826/dpc.0502a07 copyright: ©2015 hurwitz. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: robert m. hurwitz, md, cutaneous and maxillofacial pathology laboratory pc, 9292 north meridian street, suite 210, indianapolis, in, usa. email: bobbyhur@aol.com 56 note | dermatol pract concept 2015;5(2):7 and a disregard for the obnoxious concept of appeasement. appeasement never works! references 1. hurwitz rm. have the lessons of munich been lost on american physicians? dermatopathology: practical & conceptual 1999;5(1):7. in students to make a career in medicine as a physician will wane. in essence, appeasement never works! isn’t it time that physicians get back to practicing medicine, where doctors are actively in contact and in charge of the patient care as well as in the organization of medical and hospital practices? physicians and patients alike are aware of what is really going on! the time is overdue for a change of complacence dermatology: practical and conceptual book review | dermatol pract concept 2015;5(1):15 79 dermatology practical & conceptual www.derm101.com review by christian lefebvre i am a dermatologist in private practice and have worked in a university hospital environment for many years. i am glad of having been given the opportunity to review dr. hayes’ book on clinical diagnosis and treatment of skin cancers. the title of the book is inviting, as it suggests that its aim is to serve practicing dermatologists, generalists and all interested students of dermatology. moreover, the fact that its author is australian induced special expectations for me. since this country is known to be one of the most affected by the purported epidemics of melanoma, its practitioners, i thought, should have acquired a particular expertise worth being communicated. the ambition of the author is to cover cutaneous neoplasms from both the (clinical) diagnostic and therapeutic point of view. in reading the text, one rapidly understands that dr. hayes is addressing physicians with various backgrounds. the “army” fighting skin cancers in australia seems to count in its ranks many general practitioners having acquired the necessary expertise. this could be an inspiration for practitioners in other countries where dermatology is mastered rather exclusively by dermatologists, a practice that soon will become overwhelmed. the measures taken in australia seem to be efficient in controlling these epidemics. apart from the treatment techniques well presented in the book, i would have appreciated a short discussion of the public health policies existing in australia. the format of the book is adequate. the concise and synthetic mind governing its redaction makes rapid consultation on a specific topic is easy reading. the size of the book (482 pages) is very reasonable considering the extent of the subject. the practical aspect of each chapter is never neglected. the book gives preference to frequently occurring lesions and teaches efficient ways of recognizing them. for example, the illustrations pertaining to actinic keratosis are better than those found in most textbooks. many clinical photographs support the text and are essential to proper learning of dermatology. highlighted text zones aside the main text summarize the important points and are very welcome. rarer lesions and, most importantly, malignant lesions, are thoroughly treated. the chapter on melanoma is particularly well illustrated and developed. for those interested by review: skin cancer, melanoma and mimics. practical diagnosis and non-surgical treatments. the definitive reference text by mileham hayes christian lefebvre1 1 dermatology, montreal, canada citation: lefebvre c. review: skin cancer, melanoma and mimics. practical diagnosis and non-surgical treatments. the definitive reference text by mileham hayes. dermatol pract concept 2015;5(1):15. doi: 10.5826/dpc.0501a15 copyright: ©2015 lefebvre. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: christian lefebvre, md, dermatology, montreal qc, canada. email: christian.lefebvre7@sympatico.ca. hayes m. skin cancer, melanoma and mimics. practical diagnosis and non-surgical treatments. the definitive reference text. morningside, qld, australia: skin cancer books, 2013. 482 pages. isbn: 978-0987234353 80 book review | dermatol pract concept 2015;5(1):15 dermatoscopy, a complete chapter is present, covering the essential practical notions pertaining to it. many tables and algorithms are given allowing a highlighted approach. in summary, this book, this book fulfills its promises. it is a very good guide to diagnosis and treatment of cutaneous tumors. the author shows a remarkable practical sense and certainly benefits from a extensive experience, which will benefit all his readers. response from dr. mileham hayes your reviewer is absolutely correct in that, worldwide, dermatologists are in short supply, and it would be a tragedy if a melanoma were missed by a general practitioner or a dermatologist’s time wasted by having benign lesions referred to him. to counter the epidemic of both melanoma and skin cancers confirmed by audited histopathology, australian general practitioners responded by establishing private skin clinics and embarked on progressive examined specific training by two universities and the skin cancer college of australasia, thus “raising the bar” and best utilising dermatologists’ and plastic surgeons’ expertise. the aim of my text was to equip the “army,” uniquely in one book, with the full spectrum of practical essentials, not only for the melanomas and skin cancers, but also the many look-alike benign lesions. after all, 90% of cutaneous lesions are benign, and further, as my companion volume practical skin cancer surgery (churchill livingstone, 2014) points out, “well over 90% of skin cancers and melanomas can be diagnosed and completely excised in the medical practitioner’s clinic, office or rooms, under local anaesthetic to the world’s best standards and technical proficiency.” i cannot say if our methods “seem to be efficient in controlling these epidemics,” but i can say we have the best survival figures in the world, due to early detection. i regard this as a most satisfactory response and, without any implied arrogance, may be worth a look by other countries, especially where, as detailed in my book, melanomas are so much thicker when diagnosed. note from book review editor i am glad to welcome dr. christian lefebvre, dermatologist, a collaborator to the book review section of this journal. i would like to remind all readers that if they would like to propose a review of their own, they would be welcome. françois milette dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2014;4(1):15 89 introduction it is not without some apprehension that i submit my first book review to the readership of dermatology practical & conceptual. the challenge of succeeding my colleague and friend, mark hurt, as book review editor is great. in fact, i am certain that i will not be able to fulfill it alone for any length of time. therefore i want to begin by inviting readers of the journal to participate actively by suggesting titles they would like to see reviewed, submitting their own reviews and/ or in any other way that might come to their mind. i would be extremely grateful to receive your contributions. i can be contacted at: francois.milette@cssspb.qc.ca. the format that mark used to apply to his reviews (submitting the books to two reviewers, obtaining responses from the authors when possible and only thereafter writing is own text) is ideal and should be maintained. however since i have accepted only very recently to the opportunity of book review editor, i could not proceed that way this time. rather, i have chosen to present a book that i had the pleasure to read and found unexpected and interesting surprises. let me now humbly present my first contribution as book review editor of the journal. review by françois milette i bought the pigmentary system a few years ago because at the time i was wondering what was the scientific basis review of the pigmentary system: physiology and pathophysiology (2nd ed) by james j. nordlund, raymond e. boissy, vincent j. hearing, et al. françois milette1 1 centre hospitalier pierre-boucher, longueuil, canada citation: milette f. review of the pigmentary system (2nd ed) by james j. nordlund, raymond boissy, vincent j. hearing et al. dermatol pract concept. 2014;4(1):15. http://dx.doi.org/10.5826/dpc.0401a15 copyright: ©2014 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: françois milette, m.d., centre hospitalier pierre-boucher, longueuil, canada. email: francois.milette@cssspb.qc.ca. figure 1. the pigmentary system (2nd edition) by james j. nordlund, raymond boissy, vincent j. hearing, richard a. king, william oetting (ed.), jean-paul ortonne (ed.). hardcover: 1229 pages. publisher: blackwell. isbn: 1405120347. list price: $359.95. that sustained the argument according that the presence of benign melanocytes in lymph nodes was the result of “migration arrest” during embryogenesis. the subtitle of this book: physiology and pathophysiology appeared promising. unfortunately, i did not find a satisfactory answer to my question, but after reading through its many pages i found, on page 1016, the following paragraph that i considered as a conclusion to my quest: the pathogenesis of persistent dermal melanocytes is uncertain. dermal melanocytes are presumed by analogy with epidermal melanocytes to arise in the neural crest and migrate onto the skin. it has been suggested that dermal melanocytes are simply melanocytes destined for the epidermis that have remained in the dermis. because of the lack of information on the 90 book review | dermatol pract concept 2014;4(1):15 determinants of normal migration of epidermal melanocytes, our understanding of these lesions is poor. if this is true of dermal melanocytes, needless to say, it can only be truer for nodal melanocytes. my a priori intuition that the affirmation that nodal melanocytes were “migration arrested” was essentially speculative was confirmed. however, as is often the case in life, the point of arrival was less interesting than the road followed. i had made a wonderful journey through the pages of this book that purported to be nothing less than the definitive text of its time! in fact this rather vain statement has some truth in it. the book is a team effort to which nearly 120 authors from all around the world collaborated. it covers all aspects of the “pigmentary system” that can come to mind. even the contemptible notion of skin color based racism is evoked (on page 5): the furious pace of forward progress was slowed somewhat in the early part of the nineteenth century when skin color scientists in both europe and america were drawn into acrimonious debates over social issues, especially slavery and the place of “peoples of color” in the family of man. as its subtitle indicates, the book is divided in two parts: i. physiology and ii. pathophysiology. part i is particularly interesting for a dermatologist or a dermatopathologist curious to explore the basic science foundations of his specialty. everything is addressed: the history of science, comparative anatomy, general biology, embryology, biochemistry and biogenesis of melanin and melanosomes, metabolism and regulation of melanin formation and “trafficking,” genetics, etc. in the various chapters of part i, the reader will be amazed by the far-reaching extent the study of pigmentation can take. part ii concerns pathophysiology. it is divided into six sections. the first section is interesting as it begins by an overview of the disorders of pigmentation in humans. in it are discussed the various mechanisms by which pigmentation can be altered. it also proposes a series of clear definitions supporting a coherent classification of pigmentary disorders (tables 26.5 and 26.6 on p 502): table 26.5. some essential definitions. achromia: a type of leukoderma; totally white skin from any cause. amelanocytosis: total absence of all melanocytes in the epidermis that will result in amelanosis. depigmentation (amelanosis): a type of leukoderma also called amelanosis caused by total absence of melanin in the epidermis from any cause. dermatomal: following the distribution of a cutaneous sensory nerve. hyperchromia: skin color that is darker than normal from any cause. hypermelanocytosis: a higher than normal population density of melanocytes in the skin, in the epidermis, the dermis, or both, resulting typically in hypermelanosis. hypermelanosis: a type of hyperchromia that results from increased melanin in the skin, in the epidermis, dermis, or both. hypochromia: a type of leukoderma; skin color that is lighter than normal from any cause. hypomelanocytosis: a lower than normal population density of melanocytes in the epidermis typically resulting in hypomelanosis. hypomelanosis: a type of leukoderma caused by decreased melanin in the epidermis. hypopigmentation (hypomelanosis): a type of leukoderma caused by partial absence of melanin in the epidermis. leukoderma: skin with a white discoloration from any cause or by any mechanism. pigmentary system: all melanocytes and their product melanin at all sites within the body. pigmentation: of or pertaining to melanocytes or melanin. segmental: one portion of the integument, usually unilateral. skin color: the color of the skin is determined by two distinct groups of chromophores (cells, structural agents, chemicals that impart color to the skin), those of the pigmentary system (i.e. melanin and melanocytes) and those composed of other elements (chromatics) of the skin such as collagen, blood, carotenes, etc. table 26.4. a classification of the disorders of skin color. a) hyperchromia i) melanotic types of hyperchromia (hyperpigmentation) a) hypermelanosis (increased melanin only and normal population density of melanocytes) 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable, or generalized book review | dermatol pract concept 2014;4(1):15 91 ii) epidermal, dermal, or mixed b) hypermelanocytosis (increased melanocytes and melanin) 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable or generalized ii) epidermal, dermal or mixed ii) nonmelanotic types of hyperchromia 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable, or generalized ii) epidermal, dermal, or mixed b) hypoor achromia (leukoderma) i) melanotic types of leukoderma (hypoor depigmentation) a) hypomelanosis or amelanosis (decreased melanin only) 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable, or generalized ii) epidermal, dermal, or mixed b) hypoor amelanocytosis (partial or total absence of melanocytes) 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable, or generalized ii) epidermal, dermal, or mixed ii) nonmelanotic hypochromia 1) congenital i) localized, variable, or generalized ii) epidermal, dermal, or mixed 2) acquired i) localized, variable, or generalized ii) epidermal, dermal, or mixed the following two sections explore respectively hypopigmentation and hyper-pigmentation disorders from the most common to the rarest and exotic entities. each is presented in a coherent manner going through historical perspective, terminology, epidemiology, clinical findings, associated disorders, histopathology, laboratory investigations, diagnostic criteria, differential diagnosis, pathogenesis, treatment and prognosis. iconography of these two sections can be considered remarkable especially if one considers the rarity of many entities treated. the following section addresses the pigmentary disorders of nails and mucous membranes. it is not clear to me why placing those entities affecting nails and mucosae apart appeared necessary to the authors and editors of the book. in my opinion it creates some confusion, as in the preceding sections extracutaneous disorders of pigmentation affecting the meninges or the eyes were included with disorders of the skin. the next section concerns benign neoplasms. this is probably, at least to the eye of a pathologist, the weakest part of the book. the section is divided in two parts devoted respectively to frequent and rare neoplasms. the designation “rare” should probably be replaced by “controversial,” as at least some entities discussed in this section captioned “rare benign neoplasms of melanocytes” are clearly malignant. consider, for instance, the so-called “melanotic neuroectodermal tumor of infancy” described on pages 1148 to 1157. can it be reasonably considered benign when it is acknowledged that it has significant metastatic potential and is lethal in a significant number of cases impossible to differentiate from nonmetastatic tumors? my late friend bernie ackerman would have cut short this debate: this is melanoma! incidentally, it is perhaps regrettable and largely unexplainable that there is no chapter devoted to malignant tumors (that is, melanoma) of melanocytes in this book. perhaps is it better that way, though, judging from the unconditional adoption of the dysplastic nevus theory presented in chapter 24 devoted to the genetics of melanoma. the mythology of precancers surrounding the concept of melanocytic neoplasia physiolopathology could only have been spread by a chapter such as this. the last section of the book concerns treatment of pigmentary disorders. i humbly admit that, since i am a pathologist, i skipped this section. pardon me! as an excuse i may say that the book already is seven years old and i suspect that many things probably have evolved during these years so. since i cannot judge, i leave it to the interested reader to decide. i will conclude by admitting that this second edition is already dated and it is possible and even probable that some notions presented have evolved. to my knowledge there has been no further edition of this book. nevertheless, this second edition is so large in its scope that i am convinced any curious scientist interested by the subject will still find valuable things in it. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023127 1 characterization and prognostic significance of cutaneous immune-related adverse events in indian patients on immune checkpoint inhibitor therapy prasanna duraisamy1, vinitha varghese panicker1, wesley mannirathil jose2 1 department of dermatology, amrita institute of medical sciences, kochi, india 2 department of medical oncology and hematology, amrita institute of medical sciences, kochi, india key words: immune checkpoint inhibitors, cutaneous immune related adverse events, reactions, immunotherapy citation: duraisamy p, panicker vv, jose wm. characterization and prognostic significance of cutaneous immune related adverse events in indian patients on immune checkpoint inhibitor therapy. dermatol pract concept. 2023;13(3):e2023127. doi: https://doi.org/10.5826/ dpc.1303a127 accepted: december 15, 2022; published: july 2023 copyright: ©2023 duraisamy et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vinitha v panicker, department of dermatology, amrita institute of medical sciences, ponnekara, kochi. tel: 0484-2858590, 9847179964 email: varghesevinitha@yahoo.com, vinithavpanicker@aims.amrita.edu introduction: cutaneous immune-related adverse-events (ciraes), commonly seen in cancer patients receiving immune checkpoint inhibitors (ici) are reported to be associated with better patient survival; however, they have seldom been studied in indian population. recent reports suggest racial differences in iraes and also in survival outcomes. objectives: to study the various ciraes in indian patients on ici therapy and to analyze the association between ciraes and patient survival outcomes. methods: we conducted a retrospective cohort study of 86 cancer patients receiving immunotherapies in a tertiary care hospital in india and studied incidence, nature and grades of cutaneous immune-related adverse events and the association of ciraes with the patient survival outcomes. results: eighty-six patients were included, of whom 16 patients (18.6%) developed ciraes, with pruritus (12.8%) and maculopapular eruption (8.1%) being the most common. kaplan–meier plot with log-rank test showed that patients developing any type of cirae had longer progression-free survival than those without (p = 0.023) and a better objective-response-rate (50% versus 18.5%, p = 0.008). abstract 2 original article | dermatol pract concept. 2023;13(3):e2023127 introduction immune checkpoint inhibitors (ici) are a class of immunotherapeutic agents which act upon the immune check points programmed cell death 1 (pd-1), programmed cell death ligand 1 (pd-l1) and cytotoxic t lymphocyte antigen 4 (ctla-4), that regulate t-cell activity [1]. under normal circumstances, immune check points protect the host cells from immune response. however, these pathways are also utilized by cancers to escape the host immunity and their inhibition results in enhancement of immune response and prevents tumor escape causing tumor destruction. this enhanced immune response is non-specific and can have collateral effects on the normal cells leading to a new spectrum of adverse events called immune-related adverse events (iraes). iraes can potentially involve any system and in severe cases can lead to treatment discontinuation or even death. cutaneous iraes (ciraes) are one of the most common iraes and can have myriad presentations [2]. since both tumor regression and iraes are a result of enhanced immune response, the presence of iraes may correlate with greater antitumor response and studies have shown that iraes, particularly ciraes may be associated with better patient survival outcomes [3–6]. however, much of the available literature on immune checkpoint inhibitors and their iraes is based on trials and data from western countries and there is an inadequate representation of other populations particularly the indian population. reports suggest that immune checkpoint inhibitors can variation in activity and toxicity spectrum among various ethnicities such as lower incidence of iraes and poorer survival outcomes in hispanics compared to caucasian populations [7–10]. thus, there is a need for further data on the use of ici and various iraes in under-represented population groups. in our study, we aim to study the real-world incidence and manifestations of ciraes seen in indian patients on immune checkpoint inhibitor therapy and investigate the relationship between ciraes and patient survival. objectives to study the various ciraes in indian patients on ici therapy and to analyze the association between ciraes and patient survival outcomes. methods this was a single-institution retrospective study of patients receiving icis (nivolumab, pembrolizumab, atezolizumab and ipilimumab) from january 2017 to september 2021. the study was approved by the hospital institution review board. medical records of all patients with cancers treated with at least one dose of pd-1 antibodies (nivolumab or pembrolizumab), pd-l1 antibodies (atezolizumab) or ctla-4 antibodies (ipilimumab) during the study period were drawn from the hospital medical records database and analyzed. information regarding patient demographics and characteristics, nature of the malignancies, ici used, total duration of treatment, any adverse events during ici therapy, grade of the adverse events, time till progression, time till death were retrieved from medical records. treatments given for cutaneous adverse events and their outcomes were recorded. wherever possible, telephonic follow-up was performed to complete missing records. responses were assessed clinically and radiologically and classified according to standard tumor response evaluation criteria the response evaluation criteria in solid tumors (recist) version 1.1 and positron emission tomography response evaluation criteria in solid tumors (percist) version 1.0. adverse events during immunotherapy were documented and graded using the common terminology criteria for adverse events (ctcae) v 5.0. in the patients with ciraes, response of ciraes to their respective dermatological treatment was graded as no improvement, partial improvement (an improvement by one ctcae grade) or significant improvement (an improvement by two or more ctcae grades or improvement to grade 0). data censoring was done in october 2021. overall-response-rates (orr), overall survival (os) and progression-free-survival (pfs) were calculated and compared between patients having cutaneous adverse events and those not having cutaneous adverse events. tumor response was graded as complete response (cr), partial response (pr), progressive disease (pd) and stable disease (sd) based on standard tumor response evaluation criteria – recist and percist. overall response rate (orr) was defined as the proportion of patients who have a partial or complete response to therapy, excluding stable disease. progression free survival (pfs) was defined as the time conclusions: most common ciraes in our study were pruritus and maculopapular rash. the incidence of ciraes was lower in our indian cohort compared to that reported in caucasian cohorts. development of cutaneous immune-related adverse event in cancer patients on ici was associated with a longer progression-free-survival and a better objective-response-rate. thus, ciraes may serve as a surrogate marker for better patient outcomes. original article | dermatol pract concept. 2023;13(3):e2023127 3 elapsed since treatment initiation until disease progression or death from any cause, whichever comes first. progression was defined as clinical worsening of the disease or radiological progression as per recist v 1.1 / percist v 1.0 or death due to any cause. overall survival (os) is defined as the time as the time elapsed since treatment initiation until death from any cause. patients were censored at the date of last follow-up if still alive at the time of the analysis. statistical analysis was performed using ibm spss version 20.0 software (spss inc, chicago, usa). categorical variables were expressed using frequency and percentage. continuous variables are expressed as mean ± sd or the median and interquartile range [iqr]. chi-square test with continuity correction was used to test the statistical significance of differences in overall response rate between patients with and without adverse events. to compute the survival probability and the survival comparison between patients with and without adverse events, kaplan–meier analysis with logrank test was used. multivariable analysis of both pfs and os was performed with cox proportional hazard regression models. a p value of <0.05 was considered to be statistically significant. results a total of 86 patients (m:f 64:22) of median age 60.5 years (iqr:18 –83) were included. this was an umbrella study comprising of multiple malignancies, with lung cancer being the most common malignancy (26 patients, 30.2%). other common malignancies included hepatocellular carcinoma (12 patients, 13.9%), renal cell carcinoma (10 patients, 11.6%) and oropharyngeal squamous cell carcinoma (10 patients, 11.6%). the median duration of ici therapy was three months (iqr 2-6) with a median of five cycles (iqr 3-8.75). fifty-one patients (59.3%) were treated with nivolumab, 29 (33.7%) with pembrolizumab, five (5.8%) with atezolizumab and one (1.2%) with combination of ipilimumab and nivolumab. patient demographics are presented in table 1. a total of 42 iraes of any grade occurred in 28 patients (32.5%) with six patients (6.97%) having adverse events involving more than one organ system. cutaneous (18.6%) table 1. patient characteristics. clinical characteristics n (%) median age at ici initiation 60.5 (iqr:48-71) gender (male) 64 (74.4%) cancers lung cancer 26 (30.2%) hepatocellular carcinoma 12 (13.9%) renal cell carcinoma 10 (11.6%) oropharyngeal scc 10 (11.6%) melanoma 8 (9.3%) hodgkin lymphoma 7 (8.1%) endometrial cancer 3 (3.5%) urothelial carcinoma 2 (2.3%) esophageal adenocarcinoma 2 (2.3%) othersa 6 (7.2%) ici nivolumab 51 (59.3%) pembrolizumab 29 (33.7%) atezolizumab 5 (5.8%) combination (nivolumab + ipilimumab) 1 (1.2%) grade of adverse events 1 13 (15.1%) 2 20 (23.2%) 3 8 (9.3%) 4 1 (1.2%) aother cancers includes metastatic breast cancer, carcinoma stomach, pineal anaplastic astrocytoma, head and neck squamous cell carcinoma, nasal adenoid cystic carcinoma and testicular germ cell tumor accounting for 1 patient (1.2%) each. ici = immune checkpoint inhibitors; scc = squamous cell carcinoma. and endocrinological adverse events (15.1%) were the most common iraes noted. median time of onset of iraes of any type was two months. the various iraes are represented in table 2. twenty-four ciraes of any grade occurred in 16 patients (18.6%) pruritus in 11 patients (12.8%, 4 with isolated pruritus and 7 with pruritis in addition to other table 2. immune-related adverse events (iraes) and their grades. irae grade 1 grade 2 grade 3 grade 4 total cutaneous 9 9 6 0 24 thyroid disorders 1 11 1 0 13 neurological 1 0 1 0 2 conjunctivitis 1 0 0 0 1 diarrhea 1 0 0 0 1 intracranial hypertension 0 0 0 1 1 4 original article | dermatol pract concept. 2023;13(3):e2023127 of one month. in one patient with psoriasiform eruption – nivolumab dosing was changed from once in two weeks to once in four weeks. of the 15 patients treated for ciraes, 12 patients experienced significant improvement following treatment, one patient had partial improvement, two patients had no improvement. patients with iraes had a longer median pfs (6 months versus 3 months, p = 0.016) and a longer median os (15 months versus 8 months, p = 0.03) compared to patients without any adverse events. orr was also significantly higher (39.2% versus 17.2%, p = 0.02). kaplan-meier curves (pfs and os) comparing patients with and without iraes are represented in figure 1. median pfs (8 months versus 3 months, p = 0.023) and orr (50% versus 18.5%, p = 0.008) were significantly higher in patients with ciraes compared to those without ciraes (inclusive of patients who had aes in organs other than skin). median os was also longer (15 months versus 10 months). however, this association was not statistically significant (p = 0.246). kaplan-meier curves (pfs and os) comparing patients with and without ciraes are represented in figure 2. cutaneous lesions), maculopapular rash in 7 (8.1%), vitiligo in 2 (2.3%) and erythema multiforme, exfoliative dermatitis, psoriasiform eruption, mucositis in one patient each (1.2%). no hair or nail changes were noted. there were 9 grade 1 ciraes (37.5%), 9 grade 2 events (37.5%) and 6 grade 3 events (25%). no grade 4 ciraes were noted. the different ciraes and their grades are represented in table 3. of the 16 patients, ten (62.5%) received nivolumab, five (31.25%) pembrolizumab and one (6.25%) received a combination of ipilimumab and nivolumab. ciraes occurred after median of 2.75 months (iqr 2-3) from the initiation of ici (median cycles of ici: 4; iqr: 3-6). of the 16 patients with ciraes, 11 (68.75%) were managed with topicals, antihistamines or a combination of both. four patients required systemic immunosuppression. in addition to medical management, four patients (25%) with grade 3 maculopapular rash (2), exfoliative dermatitis (1) and erythema multiforme with mucositis (1) required an interruption in ici therapy until the resolution of lesions. the patient with erythema multiforme developed further grade 4 complications (intracranial hypertension) and icis were stopped. the other patients were restarted on ici therapy under careful observation after a drug-free period table 3. nature and grades of cutaneous immune-related adverse events (ciraes). cutaneous iraes no. of patients (%) total ciraes nature grade 1 grade 2 grade 3 grade 4 16 (18.6%) 24 pruritus 5 5 1 0 maculopapular rash 3 2 2 0 vitiligo like depigmentation 1 1 0 0 psoriasiform eruption 0 1 0 0 erythroderma 0 0 1 0 erythema multiforme 0 0 1 0 mucositis 0 0 1 0 figure 1. kaplan meier survival curves comparing (a) progression free survival and (b) overall survival between patients with and without immune-related adverse events (iraes). original article | dermatol pract concept. 2023;13(3):e2023127 5 malignant melanoma. though other studies have reported adverse events like bullous pemphigoid, lichenoid eruption, acneiform eruptions, neutrophilic disorders and sarcoid like lesions, we did not see any such reactions. we also did not encounter any scars like sjs/ten, dress and agep that have been reported in other studies [17]. ciraes occurred at a median duration of 2.75 months after initiation of ici therapy whereas other iraes (other than skin) occurred earlier (median duration: 2 months). in a previous study on the characteristics of ciraes and non-cutaneous iraes, ciraes were found to precede and increase the risk of other organ involvement in the same patient on ici therapy [18]. in our study, of the six patients who developed both cutaneous and non-cutaneous iraes, only two patients had cutaneous involvement prior to the extracutaneous adverse events, whereas it was the reverse in the other four. ciraes were well tolerated. the majority of the cutaneous toxicities were mild and were managed with topicals and antihistamines. grade 1 and 2 ciraes formed 75 % of the total. grade 4 dermatological iraes –were not seen in our cohort. of the 15, 14 had improvement in their symptoms with 13 having significant improvement (fall of two grades or fall to grade 0). one patient with psoriasiform eruption had only moderate improvement – however, this patient was not treated with any immunomodulatory agents. two patients with vitiligo like depigmentation did not request any treatment. however, these patients had only grade 1 and grade 2 vitiligo like depigmentation with limited area of involvement. one of these patients had associated pruritus which was treated with antihistamines. the occurrence of any irae was associated with a higher orr and a longer pfs and os. thus, the appearance of any irae in itself may be an indicator of better patient survival, similar to findings reported in other studies [3,19]. patients cox proportional hazard regression showed any irae (hazard ratio: 0.558, p = 0.033) and ciraes (hazard ratio: 0.698, p = 0.046) to have a significant association with increased pfs. development of any irae was also associated with significantly increased os (hazard ratio: 0.453, p = 0.028), whereas ciraes were not. conclusions icis are effective in treating various cancers and have revolutionized cancer treatment, however, studies and trials on ici safety and efficacy have inadequate representation of indian population. we have conducted a real-world study characterizing the ciraes seen in an indian cohort on ici therapy. ici response rates can be variable and reports have indicated that the presence of iraes maybe associated with a better therapeutic effect especially in lung cancer and malignant melanoma. identification of predictors of ici response are important especially in lowand mid-income countries where financial constraints and accessibility to advanced diagnostic procedures can be hurdles. we have studied the association between the presence of iraes and ciraes and treatment efficacy in terms of tumor response and survival outcomes. the incidence rates of ciraes can be variable with high incidences of up-to 70% being reported in patients [11]. a recent population level analysis of ciraes in patients receiving icis in the united states has observed an incidence of 25.1% [12]. similar incidence has been observed in a large taiwanese cohort (27.4%) [13]. compared to this, we observed a relatively lower incidence of ciraes (18.6%). with regard to the individual types of ciraes, the majority noted in our study were pruritus and maculopapular rash similar to prior literature focusing on ici associated cutaneous reactions [13–15]. vitiligo like depigmentation has been commonly reported in melanoma patients treated with ici [16]. this was also seen in our study, in two patients with figure 2. kaplan meier survival curves comparing (a) progression free survival and (b) overall survival between patients with and without cutaneous immune-related adverse events (ciraes). 6 original article | dermatol pract concept. 2023;13(3):e2023127 2020;12(7):3796–803. doi:10.21037/jtd.2019.08.29. pmid: 32802459. pmcid: pmc7399433. 8. florez ma, kemnade jo, chen n, et al. persistent ethnicity associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access. cancer res commun. 2022;2022(8):806–813. doi: 10.1158/2767-9764.crc-21-0143 . pmid: 35966167. pmcid: pmc9367161. 9. resnick k, zang p, travis larsen t, et al. impact of ethnicity and immune-related adverse events (irae) on outcomes for non-small cell lung cancer (nsclc) patients treated with immune checkpoint inhibitors. j clin oncol.  2022;40:16:suppl,  e21115-e21115. doi: 10.1200/jco.2022.40.16_suppl.e21115. 10. peravali m, gomes-lima c, tefera e, et al. racial disparities in immune-related adverse events of immune checkpoint inhibitors and association with survival based on clinical and biochemical responses. world j clin oncol. 2021;12(2):103114. doi:10.5306/wjco.v12.i2.103. pmid: 33680877. pmcid: pmc7918525. 11. schneider bj, naidoo j, santomasso bd, et al. management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: asco guideline update. j clin oncol. 2021;39(36):4073-4126. doi:10.1200/jco.21 .01440. pmid: 34724392. 12. wongvibulsin s, pahalyants v, kalinich m, et al. epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: a united states population-level analysis.  j am acad dermatol. 2022;86(3):563-572. doi:10.1016/j.jaad.2021.03.094. pmid: 33819538. 13. cho yt, lin yt, yang cw, chu cy. cutaneous immune-related adverse events among taiwanese cancer patients receiving immune checkpoint inhibitors link to a survival benefit. sci rep. 2022;12(1):7021. doi: 10.1038/s41598-022-11128-5. pmid: 35487955. pmcid: pmc9055047. 14. geisler an, phillips gs, barrios dm, et al. immune checkpoint inhibitor—related dermatologic adverse events. j am acad dermatol. 2020;83(5):1255–1268. doi:10.1016/j. jaad.2020.03.132. pmid: 32454097. pmcid: pmc7572894. 15. wang e, kraehenbuehl l, ketosugbo k, kern ja, lacouture me, leung dym. immune-related cutaneous adverse events due to checkpoint inhibitors. ann allergy asthma immunol. 2021;126(6):613–622. doi:10.1016/j.anai.2021.02.009. pmid: 33609771. pmcid: pmc8165024. 16. larsabal m, marti a, jacquemin c, et al. vitiligo-like lesions occurring in patients receiving anti-programmed cell death–1 therapies are clinically and biologically distinct from vitiligo. j am acad dermatol. 2017;76(5):863-870. doi:10.1016/j. jaad.2016.10.044. pmid: 28094061. 17. malviya n, tattersall iw, leventhal j, alloo a. cutaneous immune-related adverse events to checkpoint inhibitors. clin dermatol. 2020;38(6):660–678. doi:10.1016/j.clindermatol.2020. 06.011. pmid: 33341200. 18. thompson ll, krasnow na, chang ms, et al. patterns of cutaneous and noncutaneous immune-related adverse events among patients with advanced cancer. jama dermatol. 2021;157(5):577–582. doi:10.1001/jamadermatol.2021.0326. pmid: 33760001. pmcid: pmc7992016. 19. fujii t, colen rr, bilen ma, et al. incidence of immune-related adverse events and its association with treatment outcomes: the md anderson cancer center experience. invest new drugs. with any ciraes had a significantly longer median pfs and a higher orr. multivariable analysis also showed ciraes to be associated with a longer pfs. they were also associated with a longer os; however, it was not statistically significant. this is in contrast with other studies where in ciraes were associated with better survival outcomes with regard to both pfs and os [4,20–22]. limitations of the study are its retrospective design and small sample size. six out of the 16 patients with cutaneous iraes also had other organ iraes which may be a confounding factor. in conclusion, pruritus and maculopapular rash were the most common ciraes seen in our study of indian patients on ici therapy which is similar to the profile of ciraes seen in other populations. however, the incidence of ciraes was lower. ciraes were found to be associated with a superior orr and pfs. compared to adverse events in other organ systems, cutaneous adverse events are readily evident on a simple physical examination and do not usually require any investigations. thus, ciraes may serve as an easily accessible and actional clinical surrogate marker for predicting the tumor response. this can especially be important in resource poor settings. references 1. lee l, gupta m, sahasranaman s. immune checkpoint inhibitors: an introduction to the next-generation cancer immunotherapy. j clin pharmacol. 2016;56(2):157–169. doi:10.1002 /jcph.591. pmid: 26183909. 2. ramos-casals m, brahmer jr, callahan mk, et al. immune-related adverse events of checkpoint inhibitors. nat rev dis primers. 2020;6(1):38. doi:10.1038/s41572-020-0160-6. pmid: 32382051. pmcid: pmc9728094. 3. rogado j, sánchez-torres jm, romero-laorden n, et al. immune related adverse events predict the therapeutic efficacy of anti-pd-1 antibodies in cancer patients. eur j cancer. 2019;109:21-27. doi:10.1016/j.ejca.2018.10.014. pmid: 30682533. 4. thompson ll, chang ms, polyakov nj, et al. prognostic significance of cutaneous immune-related adverse events in patients with melanoma and other cancers on immune checkpoint inhibitors.  j am acad dermatol. 2022;86(4):886-889. doi:10.1016/j.jaad.2021.03.024. pmid: 33722547. 5. haratani k, hayashi h, chiba y, et al. association of immune related adverse events with nivolumab efficacy in nonsmall-cell lung cancer.  jama oncol. 2018;4(3):374-378. doi:10.1001/jamaoncol.2017.2925. pmid: 28975219. pmcid: pmc6583041. 6. sanlorenzo m, vujic i, daud a, et al. pembrolizumab cutaneous adverse events and their association with disease progression.  jama dermatol. 2015;151(11):1206-1212. doi:10 .1001/jamadermatol.2015.1916. pmid: 26222619. pmcid: pmc5061067. 7. lee j, sun jm, lee sh, ahn js, park k, ahn mj. are there any ethnic differences in the efficacy and safety of immune checkpoint inhibitors for treatment of lung cancer? j thorac dis. original article | dermatol pract concept. 2023;13(3):e2023127 7 21. phillips gs, wu j, hellmann md, et al. treatment outcomes of immune-related cutaneous adverse events. j clin oncol. 2019;37(30):2746–2758. doi:10.1200/jco.18.02141. pmid: 31216228. pmcid: pmc7001790. 22. gault a, anderson ae, plummer r, et al. cutaneous immune related adverse events in patients with melanoma treated with checkpoint inhibitors. br j dermatol. 2021;185(2):263–271. doi:10.1111/bjd.19750. pmid: 33393076.original article 2018;36(4):638–646. doi: 10.1007/s10637-017-0534-0. pmid: 29159766. pmcid: pmc5962379. 20. rose lm, deberg ha, vishnu p, et al. incidence of skin and respiratory immune-related adverse events correlates with specific tumor types in patients treated with checkpoint inhibitors. front oncol. 2021;10:570752. doi: 10.3389/fonc.2020.570752. pmid: 33520695. pmcid: pmc7844139. dermatology: practical and conceptual 220 letter | dermatol pract concept 2019;9(3):12 dermatology practical & conceptual introduction symmetrical peripheral gangrene (spg) is a rare but severe complication of disseminated intravascular coagulation (dic) characterized by symmetrical distal ischemic damage that leads to gangrene at 2 or more sites [1]. it occurs in the absence of large blood vessel obstruction, with vasoconstriction rather than thrombosis being implicated as the underlying pathophysiology. dic arising from sepsis results in uncontrolled activation of the coagulation pathway, and the use of vasopressors simultaneously involves the creation of spasms that affect the vessels; these spasms aggravate microcirculation problems which result in gangrene [2]. case presentation a 64-year-old man with no known comorbidities presented to the emergency department with fever, acute-onset right abdominal pain, and decreased urine output for the preceding 3 days. he had a fever (38°c), tachycardia (102 beats/minute), tachypnea (29 breaths/minute), hypotension (88/56 mm hg), and epigastric tenderness. ultrasound of the abdomen revealed choledocholithiasis. cholangitis was diagnosed. the patient was started on parenteral antibiotics and inotropic agents, and percutaneous transhepatic biliary drainage was performed. however, his condition continued to deteriorate and purpuric lesions developed on the skin. on examination he had spg of the fingers (figure 1a) along with retiform purpura on the feet (figure 1b). hematological examination revealed thrombocytopenia (14,000 cells/mm3), raised prothrombin time (patient: 17 seconds, control: 13 seconds) and elevated d-dimer level (>0.5). blood cultures were obtained and were positive for acinetobacter. the diagnosis of sepsis-induced dic with spg and purpura fulminans was established. the patient was managed in the intensive care unit with antibiotics, blood components, and inotropes, but he succumbed to his condition in the next 4 days. symmetrical peripheral gangrene due to disseminated intravascular coagulation sweta subhadarshani1, manik aggarwal1, vinod kumar2 1 department of dermatology and venereology, all india institute of medical sciences, new delhi, india 2 department of medicine, all india institute of medical sciences, new delhi, india key words: symmetrical peripheral gangrene, disseminated intravascular coagulation, sepsis, cholangitis, digital ischemia citation: subhadarshani s, aggarwal m, kumar v. symmetrical peripheral gangrene due to disseminated intravascular coagulation. dermatol pract concept. 2019;9(3):220-221. doi: https://doi.org/10.5826/dpc.0903a12 accepted: february 17, 2019; published: july 31, 2019 copyright: ©2019 subhadarshani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship statement: all authors have contributed significantly to this publication. corresponding author: sweta subhadarshani, md, mrcp(sce), department of dermatology and venereology, all india institute of medical sciences, new delhi, india. email: shweta.aiims07@gmail.com letter | dermatol pract concept 2019;9(3):12 221 references 1. davis mdp, dy km, nelson s. presentation and outcome of purpura fulminans associated with peripheral gangrene in 12 patients at mayo clinic. j am acad dermatol. 2007;57(6):944-956. 2. joynt g, doedens l, lipman j, bothma p. high-dose adrenaline with low systemic vascular resistance and symmetrical peripheral gangrene. s afr j surg. 1996;34(2):99-101. conclusions spg carries very high mortality rates and is almost always associated with dic. in a brief review of the literature we did not find any cases of spg occurring in a setting of cholangitis with acinetobacter. figure 1. (a) spg of fingers. (b) purpura over the patient’s leg in a reticular pattern. [copyright: ©2019 subhadarshani et al.] a b dermatology: practical and conceptual editorial | dermatol pract concept 2018;8(4):1 249 dermatology practical & conceptual www.derm101.com having spent most of our waking hours of the last decades working on, thinking and writing about, teaching, and discussing skin cancer diagnosis, this is the first time that we feel compelled to address a question that is so often asked: are we (doctors) going to be left out of the game by artificial intelligence (ai)? this question is usually asked in combination with an expression strongly suggestive of an underlying feeling: fear. this is absolutely understandable, to be honest. what kinds of feelings should we expect of a doctor who has spent a lifetime trying to improve his/her capacity to diagnose melanoma and who then reads that “machines perform at expert level or above” in recognizing melanoma? joy? happiness? hope? let’s be realistic—they are confusion, fear, and anger. the resistance of professionals to technological developments that threaten to replace them might sound similar to what happened at the time of the industrial revolution. one could argue that now, like then, if machines can indeed perform better than humans, the reluctance of doctors to accept this will not be reason enough to delay the advance of this new development. going back to the key question about whether doctors will be replaced by automated algorithms for skin cancer diagnosis, our honest answer is, we don’t know. we don’t think so, but we are not sure. in contrast, many other scientists are much more confident: melanoma in the future will be diagnosed by ai, the only question is how soon it will happen. but with all the tremendous efforts of scientists and the investments of huge companies, it should be quite soon. in fact, never before have we seen so many researchers in our field focusing their efforts on the same topic. never before have we seen so many studies published in such a short period of time with the same aim: to develop algorithms that diagnose melanoma equally as or better than doctors. most of them succeed in demonstrating this is so. without aiming to shake the confidence of those who foresee algorithms replacing doctors, we think that they might benefit by taking into account the following considerations: 1. what has been shown to date: all studies comparing melanoma diagnosis by ai with diagnosis by humans have been conducted in an experimental setting. to be clear, these studies were conducted in front of a computer, tablet, or smartphone and were based on evaluation of images. none of these algorithms has been tested in a real clinical setting (though the reason is not known). comparing a game with images played in front of a computer with a diagnosis made in a clinical setting is like comparing a car racing video game with a live formula 1 race. the clinical artificial intelligence and melanoma diagnosis: ignoring human nature may lead to false predictions aimilios lallas1, giuseppe argenziano2 1 first department of dermatology and venereology, aristotle university, thessaloniki, greece 2 dermatology unit, university of campania, naples, italy citation: lallas a, argenziano g. artificial intelligence and melanoma diagnosis: ignoring human nature may lead to false predictions. dermatol pract concept. 2018;8(4):249-251. doi: https://doi.org/10.5826/dpc.0804a01 published: october 31, 2018 copyright: ©2018 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: aimilios lallas, md, first department of dermatology and venereology, aristotle university, 124 delfon street, 54623, thessaloniki, greece. email: emlallas@gmail.com 250 editorial | dermatol pract concept 2018;8(4):1 and nuclear weapons was a great innovation that killed millions of people. it goes without saying that these 2 discoveries did not produce results with the same value. in fact, the results were polar opposites: extremely beneficial and extremely detrimental. if we can agree that the principal value of our ethical system is human life, then the value of research is assessed by the impact on it. in our field, for example, the research on epidemiology of melanoma has been of high value because it identified high-risk groups, positively affecting humanity. the research on histopathology of melanoma has been of high value because it identified prognostic factors, positively affecting humanity. the research on dermoscopy of melanoma has been of high value because it allowed for earlier detection, positively affecting humanity. the research on genetics of melanoma has been of high value because it identified mutations that might be potential targets of drugs. the research on drugs for metastatic melanoma has been of high value because it prolonged the survival of patients. the research on melanoma diagnosis with ai has not, as of this date, had a positive effect on humans. the only system that attempted to enter the clinical practice (that one with 98.5% sensitivity but 10% specificity) was never adopted by clinicians because it would have resulted in the unnecessary excision of millions of nevi [2]. what is good and what is bad is decided by the ethics of a society and not by mathematical models. ai recognizes no ethics—only mathematical models. are we so sure that we are (or will be) able to protect our ethics if ai takes the lead? 5. the nature of humans: humans like to interact with humans, in general, and even more in medicine. the moment that a physician examines a patient is a unique interaction during which a human being uses all available knowledge and mental effort to help another human being. there is a lot of interchange of energy in this procedure. this is very much superior to a simple judgment on the benign or malignant nature of a lesion. the result of a medical consultation is not measured only by the absolute improvement of the patient’s physical health. think for a moment about patients with end-stage metastatic cancer, those not responsive to treatment, or patients with diseases with no available treatments. they build a strong relationship with their doctor, which is not measurable or explainable by the absolute improvement of their physical health. to think that medical care can be simply conducted by mathematical models is tantamount to ignoring human nature. even if someday it will be possible to satisfactorily address points 1 through 4 made above, ignoring human nature and investing against it is very likely a prelude to failure. we are convinced that ai has the potential, in several ways, to become an additional precious tool in the hands of doctors struggling to reduce melanoma mortality. the main examination of patients is a much more multifactorial, unpredictable, and complicated process, as compared to evaluation of a clinical or dermoscopic photograph in front of a computer. this is quite clear for any doctor who works in clinical practice even for a short period. 2. the accuracy of diagnosis: most of the algorithms are fed by images of histopathologically diagnosed lesions. therefore, their great performance always has histopathology as a reference point and presupposes that the histopathological diagnosis was correct. however, it has been well documented that the interpretation of histopathology, especially for “borderline” melanocytic lesions, is far from what we would expect from a “gold standard” method. last year, in the bmj, elmore et al reported a disagreement rate among different pathologists up to 75% (!) when trying to differentiate between nevi with moderate to severe dysplasia and early melanoma [1]. therefore, ai algorithms are supplied with images of melanomas that might have been diagnosed as nevi by another pathologist and nevi that might have been diagnosed as melanomas by another pathologist. can we imagine the potential effects of this? clinicians are able to deal with this problem because they are aware of this limitation. they also know that morphology (clinical, dermoscopic, histopathological) does not always accurately predict biology. melanomas that look like nevi do exist and the inverse is true as well. for this reason, clinical management decisions are not made only on the basis of morphology. for ai, all this is not comprehensible. ai requires clear endpoints (benignmalignant). “don’t know” does not exist for ai, and this creates a huge risk. 3. the usefulness of mistakes: throughout history, scientific knowledge has improved principally by learning from human error. humans learn from their mistakes, and this has proved to be the foundation for progress. as soon as a doctor identifies a mistake, he/she tries to explain why it happened and what should be done to avoid repeating it. ai systems train themselves, without human guidance. they learn fast—much faster than we do—and we are unable to fully understand the way they become so accurate so quickly. as much as we fail to understand how an algorithm is able to accurately classify a lesion when humans do not, we also fail to adequately explain why ai is wrong when it is wrong. therefore, we will never really know why a mistake happened, and it is quite likely that ai will repeat the same mistakes because we cannot train it to avoid them. 4. the value of research: innovation is great, but the value of research is not measured by how innovative it is or by the impact factor of the journal in which it is published. the value of research is measured by its impact on humans. the discovery of penicillin was a great innovation that saved millions of people. the discovery of atomic bombs editorial | dermatol pract concept 2018;8(4):1 251 2. monheit g, cognetta ab, ferris l, et al. the performance of melafind: a prospective multicenter study. arch dermatol. 2011;147(2):188-194. aimilios lallas, md deputy editor giuseppe argenziano, md editor-in-chief obstacles of this goal are the misconceptions about our role as doctors. maybe by rereading and rethinking what hippocrates said 2,500 years ago we could find the way. references 1. elmore jg, barnhill rl, elder de, et al. pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. bmj. 2017 jun 28;357:j2813. dermatology: practical and conceptual observation | dermatol pract concept 2018;8(2):5 85 dermatology practical & conceptual www.derm101.com case presentation rosacea is a common skin condition of unknown cause with a prevalence of up to 22% in adults [1] that mainly affects women [2]. although the precise prevalence of rhinophyma is unknown, in one study of 108 patients with rosacea, 15 were noted to have rhinophyma, almost all of whom were men [3]. rosacea is classified into four stages: pre-rosacea and stages i to iii. in stage iii, large inflammatory nodules, furunculoid infiltrations, and connective tissue hypertrophy appear [4]. stage iii is dominated by sebaceous gland hypertrophy of the nose resulting in the characteristic cauliflower-like appearance called rhinophyma. the skin hypertrophy typical of rhinophyma may also be present in other facial areas. recently a new rhinophyma severity index (rhisi) was introduced [5]. the rhisi scale ranges from 1 to 6; lobules are seen in stages 3-6. although topical antibiotics or retinoids are often effective for rosacea, they have not been shown to improve rhinophyma. therefore, several surgical treatments have been developed, including tangential excision, electroscalpel, dermabrasion, laser ablation, scissor sculpting, radiofrequency electrosurgery, cryosurgery and wire loop electrosurgery [6-9]. rhinophyma is often extremely disfiguring, and surgical correction was reported to improve the quality of life in the majority of patients [10]. carbon dioxide laser surgery scanner-assisted carbon dioxide laser correction of severe rhinophyma: case report of a quality-of-life intervention easily learned jakob d. wikström1,2, jan lapins1.2 1 dermato-venereology clinic, karolinska university hospital, stockholm, sweden 2 dermatology and venereology unit, department of medicine, karolinska institutet, stockholm, sweden. key words: rhinophyma, laser correction, rosacea, laser surgery, scanner-assisted carbon dioxide laser citation: wikström jd, lapins j. scanner-assisted carbon dioxide laser correction of severe rhinophyma: case report of a quality-of-life intervention easily learned. dermatol pract concept. 2018;8(2):85-88. doi: https://doi.org/10.5826/dpc.0802a05 received: september 25, 2017; accepted: november 8, 2017; published: april 30, 2018 copyright: (c)2018 wikström et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. ethical disclosure: both patients provided written informed consent for publishing their photographs. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: jakob d wikström, md, phd, assistant professor, dermato-venereology clinic, karolinska university hospital / karolinska institutet, karolinska vägen, 17176 stockholm, sweden. email: jakob.wikstrom@ki.se. rhinophyma is a severe complication of rosacea that has been treated with multiple different surgical modalities over the years. here we present two cases of rhinophyma that demonstrate the cosmetic results of scanner-assisted carbon dioxide laser correction and how this method can be easily learned and managed. we conclude that scanner-assisted carbon dioxide laser is an excellent treatment alternative for rhinophyma. abstract 86 observation | dermatol pract concept 2018;8(2):5 was assessed to have active disease, as the nose was erythematous, and papulopustular rosacea was evident on his cheeks and chin. eight weeks prior to surgery, the patient was given oral doxycycline (100 mg daily) to reduce the inflammation to optimize surgical conditions following clearance of the papulopustular rosacea. no prophylactic antiviral treatment or other forms of oral or local antibiotics were given. the patient was treated in a single teaching session lasting one hour. the nose was anesthetized by injections of lidocaine 1% with epinephrine (1:100 000), followed by scanner-assisted pulsed carbon dioxide laser (unilas touch, limmer laser gmbh, germany) evaporation of excess tissue. the following settings were used: 3-4 mm diameter spot-size, effect 25-50 w and 0.3 ms pauses in continuous mode. all personnel and the patient wore laser protective glasses. a vacuum suction device was used to clear the smoke consisting of evaporated tissue. photographs from the patient’s youth were used as a reference when reshaping the nose to its original contour (figure 1). these photographs also illustrated the rhinophyma development over time. the selected area, delineated by ink, is gradually ablated by the laser beam when it passes over the tissue repeatedly. devitalized tissue is removed gently by cleansing the surface with swabs soaked in 0.9% sodium chloride solution. the depth of the vaporization is controlled by the selection of power, focal length, scannercontrolled spot size, and the movements of the handheld has become increasingly popular, because sharp margins and good hemostasis can be obtained with good intraoperative surgical field visibility [11]. the scanned carbon dioxide laser is a laser with a focusing hand-piece attached to a miniature optomechanical flash scanner delivery system that generates multiple focal beams. the laser moves rapidly and homogeneously in spiral scans and covers a round area on tissue at the focal plane that minimizes the tissue laser exposure time and thus reduces the risk of excessive tissue thermal necrosis and subsequent scarring. the area selected is gradually ablated by the laser beam when it passes over the tissue repeatedly. thus, scanner assisted carbon dioxide laser treatment of rhinophyma may require less training and may be more easily taught to dermatology residents who can practice independently. here we present one patient successfully treated in a teaching setting by both authors followed by a second patient that was independently treated by the resident dermatologist (jdw). patient 1 is a 54-year-old, otherwise healthy, man with a 30-year history of rosacea. he presented with facial redness and a large bulbous nose (rhinophyma stage iii or rhisi 6), which had increasingly affected his quality of life (figure 1). medical treatment previously administered 25 years previous had been unsuccessful and he had since been without treatment. the diagnosis of rhinophyma was evident, as the skin of the nose appeared thickened with irregular nodularities. he figure 1. preand post-surgery photographs of patient 1 with rhinophyma treated with scanner-assisted carbon dioxide laser. rhinophyma develops slowly over time as indicated by the timeline photographs (years are indicated). the surgical result 3 months post-surgery resembles the original nose profile of year 1981. at the 15 months follow up, papulopustular rosacea had returned which required topical treatment. note that this patient was a teaching case. [copyright: (c)2018 wikström et al.] observation | dermatol pract concept 2018;8(2):5 87 laser. the knowledge added by this report is three-fold: 1) we demonstrate that this method can be easily learned; 2) we show that even after decades of progression, rhinophyma can be treated successfully; and 3) we provide an instructive photographic timeline of rhinophyma development. while we did not compare scanner-assisted carbon dioxide laser to other methods, other authors have noted that scannerassisted carbon dioxide laser treatment requires less training, scanner. the vaporization is continuously shaping the nose into its desired form. the therapeutic endpoint is satisfaction with nasal shape and preservation of the deep portion of the sebaceous follicles, which aid re-epithelialization (figure 3). a honeycomb appearance and expressible sebum is useful for ensuring that the ablation is not carried out too deeply [12]. post-surgery, the nose was covered with a simple dressing and the patient immediately discharged. the dressings are initially left on for one or two days without changing to prevent early bleeding. thereafter, the wound is cleaned and rinsed with tap water, and the bandage is changed as often as necessary, preferentially on a daily basis, pending complete healing.  seven days post-surgery, areas of early re-epithelialization were observed. follow up visits after 3 months and 15 months revealed a maintained cosmetic result. the patient was very satisfied with the treatment outcome. the recurrent papulopustular rosacea was later managed by topical metronidazole gel (0.75%) followed by topical ivermectin cream (10 mg/g), which cleared the remaining symptoms. patient 2 is a 67-year old man with high blood pressure and rosacea of unknown duration, who presented with a moderate rhinophyma (stage iii or rhisi 3) for one year (figure 2). oral tetracycline had limited success in treating the symptoms and the patient expressed a strong wish for surgical correction. the rhinophyma diagnosis was clinically evident despite the disease appearing less active than in patient 1. the surgery was performed in a similar manner to patient 1 with the exception that the patient was operated on by the resident dermatologist (jdw) only. follow up visits after 12 months showed a good cosmetic result and the patient was very satisfied. the patient continued topical metronidazole treatment. conclusions rhinophyma stands out as a severe dermatological condition that can be treated straightforwardly in an outpatient setting. here we present two cases of rhinophyma that were successfully treated with scanner-assisted carbon dioxide figure  2. preand post-surgery photographs of patient  2  with rhinophyma treated with scanner-assisted carbon dioxide laser. note that this patient was independently operated on. [copyright: (c)2018 wikström et al.] figure  3. peroperative photograph during carbon dioxide laser vaporization of rhinophyma visualizing the different surgical layers. white or yellow granularity or honeycomb appearance, representing deep sebaceous follicular structures necessary to preserve normal texture and nasal follicular openings and avoid atrophic scarring. [copyright: (c)2018 wikström et al.] 88 observation | dermatol pract concept 2018;8(2):5 6. pelle mt, crawford gh, james wd. rosacea: ii. therapy. j am acad dermatol. 2004;51(4):499-512; quiz 513-494. 7. husein-elahmed h, armijo-lozano r. management of severe rhinophyma with sculpting surgical decortication. aesthetic plast surg. 2013;37(3):572-575. 8. prado r, funke a, bingham j, brown m, ramsey mellette j. treatment of severe rhinophyma using scalpel excision and wire loop tip electrosurgery. dermatol surg. 2013;39(5):807-810. 9. lazzeri d, larcher l, huemer gm, et al. surgical correction of rhinophyma: comparison of two methods in a 15-year-long experience. j craniomaxillofac surg. 2013;41(5):429-436. 10. schweinzer k, kofler l, spott c, et al. surgical treatment of rhinophyma: experience from a german cohort of 70 patients. eur j dermatol. 2017;27(3):281-285. 11. madan v, ferguson je, august pj. carbon dioxide laser treatment of rhinophyma: a review of 124 patients. br j dermatol. 2009;161(4):814-818. 12. goon pk, dalal m, peart fc. the gold standard for decortication of rhinophyma: combined erbium-yag/co2 laser. aesthetic plast surg. 2004;28(6):456-460. is reproducible and is potentially a lower-risk procedure in inexperienced hands [11]. references 1. abram k, silm h, oona m. prevalence of rosacea in an estonian working population using a standard classification. acta derm venereol. 2010;90(3):269-273. 2. berg m, lidén s. an epidemiological study of rosacea. acta derm venereol. 1989;69(5):419-423. 3. sibenge s, gawkrodger dj. rosacea: a study of clinical patterns, blood flow, and the role of demodex folliculorum. j am acad dermatol. 1992;26(4):590-593. 4. crawford gh, pelle mt, james wd. rosacea: i. etiology, pathogenesis, and subtype classification. j am acad dermatol. 2004;51(3):327-341; quiz 342-324. 5. schüürmann m, wetzig t, wickenhauser c, ziepert m, kreuz m, ziemer m. histopathology of rhinophyma a clinical-histopathologic correlation. j cutan pathol. 2015;42(8):527-535. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):15 75 dermatology practical & conceptual www.derm101.com introduction mammary paget disease (mpd) is an intraepidermal adenocarcinoma of the nipple area usually characterized by a welldemarcated eczema-like plaque. it may be associated with an underlying malignancy of the breast. reflectance confocal microscopy (rcm) is an in vivo noninvasive diagnostic tool with high-resolution imaging of the skin, almost comparable to conventional histology [1-4]. in this report, we aimed to evaluate the confocal microscopic findings of the mammary paget disease. report a 65-year-old woman was admitted with a one-year history of an erythematous, asymptomatic, slowly enlarging plaque on the left nipple area. she had a history of hemorrhagic discharge 13 years ago from the left breast. the subsequent mammography had revealed segmental microcalcification behind the areola extending to the periphery; thus, surgery was performed in 2001. the histopathology revealed ductal intraepithelial neoplasia ia (intraductal hyperplasia). six months later the hemorrhagic discharge recurred. surgery reflectance confocal microscopy of mammary paget disease fezal ozdemir1, bengu g. turk1, banu yaman2, giovanni pellecani3, necmettin ozdemir2, isil karaarslan1, francesca farnetani3 1 department of dermatology and venereology, ege university medical faculty, izmir, turkey 2 department of pathology, ege university medical faculty, izmir, turkey 3 department of dermatology, university of modena and reggio emilia, modena, italy key words: paget disease, reflectance confocal microscopy, mammary citation: ozdemir f, turk bg, yaman b, pellecani g, ozdemir n, karaarslan i, farnetani f. reflectance confocal microscopy of mammary paget disease. dermatol pract concept 2017;7(4):75-80. doi: https://doi.org/10.5826/dpc.0704a15 received: july 27, 2017; accepted: august 31, 2017; published: october 31, 2017 copyright: ©2017 ozdemir et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. bengu gerceker turk, ege university, medical faculty department of dermatology and venereology, 35100, bornova, izmir, turkey. tel. +90 2323902698. email: bengugerceker@yahoo.com mammary paget disease is the intraepidermal adenocarcinoma of the nipple area which is characterized usually by a well-demarcated eczematous plaque. reflectance confocal microscopy (rcm), is an in vivo noninvasive diagnostic tool with a high-resolution imaging of the skin, almost comparable to conventional histology. rcm findings of paget disease are limited in the literature. most of the reported cases are the extramammary type. in this report, we aimed to evaluate the rcm findings of a non-pigmented mammary paget disease in a 65 year-old woman. abstract mailto:bengugerceker@yahoo.com 76 observation | dermatol pract concept 2017;7(4):15 on dermatologic examination there was an erythematous plaque with multiple punctate hemorrhagic crusts and minimal scales, 4.0 x 2.6 cm in diameter involving some of the nipple of the left breast (figure 1a). before the biopsy, the lesion was examined using dermoscopy (dermlite dl3; was repeated, and a histopathological diagnosis of atypical ductal hyperplasia and atypical intraductal papilloma was made periodic follow-up examinations with mammography and ultrasonography have been performed yearly without any pathologic findings. figure 1. (a) erythematous plaque with punctate hemorrhagic crusts and minimal scales, 4.0 x 2.6 cm in diameter on the nipple. (b) background erythema (vascular blush) separated with whitish reticulation in most of the lesion and some linear and comma-like vessels. [copyright: ©2017 ozdemir et al.] figure 2. reflectance confocal microscopy: (a) dense tumor nests, simulating dark silhouettes that varied in size and shape in the partially spared honeycomb pattern of the epidermis (mosaic, 2 x 2 mm). (b) one of these nests; composed of hyporeflective tumor cells (paget cells), larger than the keratinocytes with abundant, pale cytoplasm and small, mildly bright nuclei (black arrows) (mosaic, 0.5 x 0.5 mm). [copyright: ©2017 ozdemir et al.] observation | dermatol pract concept 2017;7(4):15 77 tumor cells were arranged in small groups and focally with glandular formation. the epidermis was hyperplastic and a few scattered single tumor cells were seen in the upper epidermis; however, most of tumor cell groups were in the lower epidermis (figure 4). with immunoperoxidase techniques, the tumor cells stained diffuse positive for mfgp-1, ema, e-cadherin, and c-erbb2. they were negative for melan-a, and hmb-45. with these histological and immunohistochemical findings, paget disease was diagnosed. mammography and breast ultrasonography were normal. the patient had breast surgery, after which the pathology revealed paget disease without any associated malignancy of the breast. 3gen llc, san juan capistrano, ca, usa) and in vivo rcm (vivascope 1500 multilaser, lucid, rochester, ny, usa, distributed by mavig, munich). on dermoscopy, the background erythema (vascular blush) was separated with whitish reticulation due to the sulci of the areola in most of the lesion. some linear and commalike vessels were present (figure 1b). rcm images were recorded at different levels to a maximum depth of 200 μm on the mostly infiltrated part of the lesion with three mosaics (vivablocks) (epidermal layer, dermal-epidermal junction, and upper dermis) with the maximum area of 8 x 8 mm. the epidermal layers were characterized by partially spared honeycomb pattern with bright reflective dots (inflammatory cell groups) and dense tumor nests, simulating dark silhouettes that varied in size and shape (figure 2a). these nests were composed of hyporeflective tumor cells that were larger than the keratinocytes with abundant, pale cytoplasm and small, mildly bright nuclei (figure 2b). in addition, pagetoid spread of single tumor cells was scattered focally within the epidermis. some of the single cells were big and poorly reflected, and some were smaller and darker (figure 3a). at the lower epidermis, close to the dermo-epidermal junction, many large, dense tumor nests simulating dark silhouettes were present also; however, these tumor nests were more abundant than the ones in the upper epidermis (figure 3b). at the papillary dermis, there was increased vascularity due to horizontal and looped vessels with rapid blood flow, and some perivascular inflammatory cells were observed. histopathology of the shave biopsy revealed epidermal infiltration of tumor cells with abundant pale cytoplasm. figure 3. reflectance confocal microscopy: (a) pagetoid spread of single tumor cells scattered focally within the epidermis, some big and poorly reflected (black arrows), and some smaller and darker ones (white arrows) (mosaic, 0.65 x 0.5 mm). (b) numerous, large tumor cell nests simulating dark silhouettes (yellow arrows) at the lower epidermis, close to dermoepidermal junction level (mosaic, 1.0 x 0.8 mm). figure 4. a few scattered single tumor cells in the upper epidermis, and tumor cell groups mostly in the lower epidermis (h&e, x100) [copyright: ©2017 ozdemir et al.] 78 observation | dermatol pract concept 2017;7(4):15 paget cells contain intracytoplasmic mucin [9-12], a mixture of acid mucopolysaccharides. fraga-braghiroli et al. have shown that mucin located areas in dermal mucinosis were seen as darker areas on rcm [13]. likewise, ulrich et al. have shown that the peritumoral cleft-like spaces seen in bcc on histopathology exist in vivo, and correspond to the peritumoral mucin deposition which also demonstrates that mucin appear dark on rcm [14]. this may be due to the lower refractive index (ri) of mucin compared to melanin (1.72), keratin (1.51) or collagen (1.43) all of which have much higher refractive index than water (1.33) and, therefore they are hyper-reflective and appear brighter under rcm. we think this may be the reason of the hyporeflective nests of paget’s cells in our case. this case was more likely to be a mammary paget disease considering the history and required early surgical intervention. however, the clinical differential diagnosis of solitary erythematous patch on the breast may range from inflammatory lesions such as eczema to malignancy such as amelanotic melanoma, bowen’s disease or superficial bcc [15]. in this case, unfortunately, dermoscopic findings were nonspecific also for the differential diagnosis. at first glance on rcm the presence of numerous large, and dense nests simulating dark silhouettes excluded the diagnosis of eczema. in detailed examination, together with numerous dense nests, hyporeflective cells with pale cytoplasm and bright nuclei seen all through the epidermis made it possible to exclude a melanoma characterized by atypical cells with bright cytoplasm and dark nuclei. large, round nucleated cells representing dyskeratotic cells at the spinogranular layer, and tightly coiled vessels are characteristic features of bowen’s disease on rcm. however, neither dyskeratotic cells nor coiled vessels were seen in this case. the dense tumor nests we have seen on rcm were actually similar to the morphology of dark silhouettes of bcc. however, the lack of typical peritumoral cleft-like spaces and localization of the nests through the epidermal layer were the features opposing this diagnosis. the main limitation of rcm in the diagnosis of paget’s disease may be due to the hyporeflective cells. if the tumor cells are not abundant, and arrange in smaller groups with lesser glandular formation, rcm features may not be as obvious as they are in this case. so it may not always be possible to reach an accurate diagnosis easily. surely histopathological examination will be the gold standard in challenging rcm features. in conclusion, this case highlights the confocal findings of a typical mpd, which is similar to extramammary counterpart. the characteristic appearance of paget cells and their distinctive nest formation on rcm, may aid the clinical differential diagnosis by discerning it from inflammatory imitators like eczema. in addition, rcm is likely to improve discussion rcm findings of paget disease are limited in the literature [1-8]. some of the reported cases are extramammary type [3,4,6,7]. rcm findings of mammary paget disease were reported in four articles [1,2,5,8] in total of eight cases. the first case reported by longo et al. was a 70-year-old woman with pigmented mpd. in this report, paget cells were described as large, round cells with reflective cytoplasms and dark nuclei, similar to pagetoid melanocytes suggestive of melanoma [1]. richtig et al. described these cells as scattered bright nucleated cells in different sizes and shapes and varying reflectivity at the epidermal level, and pointed out that they resembled the pagetoid cells reported by longo et al. and to melanoma [2]. however, later, pan et al. described paget cells in extramammary lesions as large cells having dark cytoplasm and mild bright nuclei, each separated from the surrounding by a black halo. in addition, they observed that nests of paget cells formed dark glandular structures at the basal layer. they also suggested that paget cells could be discriminated from the pagetoid cells of melanoma by their low refractivity and round to oval shape [3]. a further report by guitera et al. clarified that paget cells of extramammary type were poorly reflective cells observed as dark “holes.” sometimes, single or small clusters of these cells appeared as “target” structures with round, bright centers and surrounding dark halos. some nested cells appeared as “palisading” nodules also, similar to nodular basal cell carcinoma (bcc) [4]. cinnoti et al. have also described the isolated paget cells as hyper-reflective cells with a dark halo in a targetoid appearance at the superficial layers together with hyporeflective, roundish, large cells at the basal layer [5]. oliveira et al. have also described rcm findings of five cases of mpd, similar to the report by guitera et al, as target structures and dark holes [8]. they reported that on rcm, paget cells were seen as 1.5–2 times larger the keratinocytes and explained that these cells observed as dark holes were poorly reflective due to their abundant pale cytoplasm, and that the bright central area seen in target structures were related with their pleomorphic nuclei [8]. all the mpd cases are summarized in table 1. in our case, hyporeflective paget cells with abundant, pale cytoplasm and small, mildly bright nuclei within dense tumor nests or scattered as single cells observed on rcm were in accordance with the recent literature [3,4,8]. they were clearly different from the pagetoid cells of melanoma, which have bright cytoplasm and dark nucleus. the single, hyporeflective cells scattered focally within the epidermis seen on rcm corresponded to the single tumor cells scattered in the upper epidermis on histology. paget cells forming large, dense tumor nests simulating dark silhouettes on rcm corresponded to tumor cell groups with glandular formation mostly in the lower epidermis. observation | dermatol pract concept 2017;7(4):15 79 table 1. all the cases of mammary paget disease case number presentation dermoscopy rcm findings of paget disease longo et al, 2007 1 1 case partially pigmented plaque on the superior quadrant of the breast lighter portion: whitish-pink area with irregular linear vessels darker portion: light brown diffuse pigmentation with irregular black dots and small gray-blue structures superficial epidermal layers: disarranged pattern, large, round, atypical cells with reflective cytoplasms and dark nuclei together with bright reflective particles + within the stratum corneum numerous large, reflective cells with long dendritic branches richting et al, 2011 2 1 case erosion on the center of the mamilla glomerular, linearirregular and commalike vessels disorganized epidermal architecture with multiple bright, nucleated cells of varying size, shape and reflectivity seen focally guitera et al, 2013 4 1 case (the same case in longo et al, 2007, the coauthor of this article) + 9 extramammary cases partially pigmented plaque the pigmented part is described as light brown pigmentation, some irregular black dots and small grayblue structures dense nests in the epidermal layer and some dendritic structures, dark round-oval areas, probably representing nuclei in some cells cinotti et al, 2013 5 1 case 2 mm, papular lesion non-specific findings hyper-reflective cells with a dark halo corresponding to isolated paget cells in the epidermal layers + roundish, large, hyporeflective cell groups at the basal layer oliveira et al, 2016 8 5 cases eczema-like plaques in 4 cases, and in patient #5 partially pigmented nodule pink-whitish to red background (in all cases), polymorphous vessels, erosions, yellow scales, and shiny-white streaks (in some cases), and in patient # 5: polymorphous vessels within red-yellowwhitish background, brown dots and structureless areas of grey pigmentation loss of epidermal architecture and pagetoid spread of poorly reflective round cells (paged cells), surrounded by a dark stroma seen as dark holes, + single cells or small nests of cells with a bright central area and a peripheral large dark halo seen as target structures ozdemir et al, 2017 (this article) 1 case eczematous reddish plaque involving some of the nipple area background erythema mostly separated with whitish reticulation, together with some linear and comma-like vessels partially spared honeycomb pattern with dense tumor nests, simulating dark silhouettes, composed of hyporeflective tumor cells, larger than keratinocytes with abundant, pale cytoplasm and small, mildly bright nuclei + pagetoid spread of single tumor cells, some big and poorly reflected and some smaller and darker, scattered focally 80 observation | dermatol pract concept 2017;7(4):15 tion by in vivo and ex vivo reflectance confocal microscopy. skin res technol. 2014;20(1):124-126. 7. suppa m, marneffe a, miyamoto m, rorive s, boone m, del marmol v. contribution of reflectance confocal microscopy in the diagnosis of extra-mammary paget’s disease. ann dermatol venereol. 2015;142(1):70-73. 8. oliveira a, zalaudek i, arzberger e, massone c, hofmannwellenhof r. reflectance confocal microscopy for diagnosis of mammary paget’s disease. acta derm venereol. 2016;96(7):980982. 9. karakas c. paget’s disease of the breast. j carcinog 2011; 10: 31 10. marques-costa jc, cuzzi t, carneiro s, parish lc, ramos-e-silva m. paget’s disease of the breast. skinmed. 2012;10(3):160-165. 11. neuhaus im, grekin rg. mammary and extramammary paget disease. in: wolff k, goldsmith la, katz si, et al, eds. fitzpatrick’s dermatology in general medicine. 7th ed. philadelphia, pa: mcgraw hill; 2008:1094–1098. 12. calonje e. tumours of the skin appendages. in: burns t, breathnach s, cox n, griffiths c, eds. rook’s textbook of dermatology. 8th ed. oxford, uk: wiley & blackwell; 2010:53.38-53.39. 13. fraga-braghiroli na, merati m, rabinovitz h, swanson d, scope a. reflectance confocal microscopy features of focal dermal mucinosis differ from those described for basal cell carcinoma: report of two cases. dermatology. 2015; 231(4): 326-329. 14. ulrich m, roewert-huber j, gonzalez s, rius-diaz f, stockfleth e, kanitakis j. peritumoral clefting in basal cell carcinoma: correlation of in vivo reflectance confocal microscopy and routine histology. cutan pathol. 2011; 38(2):190-195. 15. braga jc, scope a, klaz i, mecca p, gonzález s, rabinovitz h, marghoob aa. the significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. j am acad dermatol. 2009;61(2):230-241. the accuracy of the clinical diagnosis especially in patients who refuse biopsy in this sensitive area, the mammilla. this noninvasive technique can be also used to outline the surgical margins of mpd when necessary. as a summary, rcm may be applied as an adjuvant diagnostic tool for the diagnosis and management of mpd. references: 1. longo c, fantini f, cesinaro am, bassoli s, seidenari s, pellacani g. pigmented mammary paget disease: dermoscopic, in vivo reflectance-mode confocal microscopic, and immunohistochemical study of a case. arch dermatol. 2007;143(6):752-754. 2. richtig e, ahlgrimm-siess v, arzberger e, hofmann-wellenhof r. non invasive differentiation between mammillary eczema and paget disease by in vivoreflectance confocal microscopy on the basis of two case reports. br j dermatol. 2011;165(2):440-441. 3. pan zy, liang j, zhang qa, lin jr, zheng zz. in vivo reflectance confocal microscopy of extramammary paget disease: diagnostic evaluation and surgical management. j am acad dermatol. 2012 ;66(2):e47-53. 4. guitera p, scolyer ra, gill m, et al. reflectance confocal microscopy for diagnosis of mammary and extramammary paget’s disease. j eur acad dermatol venereol. 2013;27(1):e24-29. 5. cinotti e, perrot jl, labeille b, cambazard f. groupe imagerie cutanée non invasive de la société française de dermatologie [the contribution of reflectance confocal microscopy in the diagnosis of paget’s disease of the breast]. ann dermatol venereol. 2013;140(12):829-832. 6. debarbieux s, dalle s, depaepe l, jeanniot py, poulalhon n, thomas l. extramammary paget’s disease of the scalp: examinadermatology: practical and conceptual 10 review | dermatol pract concept 2019;9(1):3 dermatology practical & conceptual familial melanoma: diagnostic and management implications mariarita rossi1, cristina pellegrini1, ludovica cardelli1, valeria ciciarelli1, lucia di nardo1,2, maria concetta fargnoli1 1 department of dermatology, discab, university of l’aquila, l’aquila, italy 2 institute of dermatology, catholic university, rome, italy key words: familial melanoma, cdkn2a, cdk4, genetic testing, genetic counseling, cancer screening citation: rossi m, pellegrini c, cardelli l, ciciarelli v, di nardo l, fargnoli mc. familial melanoma: diagnostic and management implications. dermatol pract concept. 2019;9(1):10-16. doi: https://doi.org/10.5826/dpc.0901a03 published: january 31, 2019 copyright: ©2019 rossi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: prof. maria concetta fargnoli, department of dermatology, discab, university of l’aquila, via vetoio, coppito 2, 67100 l’aquila, italy. email: mariaconcetta.fargnoli@univaq.it background: an estimated 5%-10% of all cutaneous melanoma cases occur in families. this review describes susceptibility genes currently known to be involved in melanoma predisposition, genetic testing of familial melanoma patients, and management implications. results: cdkn2a is the major high-penetrance susceptibility gene with germline mutations identified in 20%-40% of melanoma families. a positive cdkn2a mutation status has been associated with a high number of affected family members, multiple primary melanomas, pancreatic cancer, and early age at melanoma onset. mutations in the other melanoma predisposition genes—cdk4, bap1, tert, pot1, acd, terf2ip, and mitf—are rare, overall contributing to explain a further 10% of familial clustering of melanoma. the underlying genetic susceptibility remains indeed unexplained for half of melanoma families. genetic testing for melanoma is currently recommended only for cdkn2a and cdk4, and, at this time, the role of multigene panel testing remains under debate. individuals from melanoma families must receive genetic counseling to be informed about the inclusion criteria for genetic testing, the probability of an inconclusive result, the genetic risk for melanoma and other cancers, and the debatable role of medical management. they should be counseled focusing primarily on recommendations on appropriate lifestyle, encouraging skin self-examination, and regular dermatological screening. conclusions: genetic testing for high-penetrance melanoma susceptibility genes is recommended in melanoma families after selection of the appropriate candidates and adequate counseling of the patient. all patients and relatives from melanoma kindreds, irrespective of their mutation status, should be encouraged to adhere to a correct ultraviolet exposure, skin self-examination, and surveillance by physicians. abstract review | dermatol pract concept 2019;9(1):3 11 ing, the probability of an inconclusive result, the genetic risk for melanoma and other cancers, and the debatable role of medical management. this review describes susceptibility genes known to be involved in melanoma predisposition, genetic testing of familial melanoma patients, and management implications. melanoma susceptibility genes unlike other cancer predisposition syndromes, melanoma is not linked to a single gene, but several highand intermediatepenetrance melanoma susceptibility genes have been identified to date (table 1). penetrance relates to the lifetime risk for a mutation carrier of developing melanoma and reflects the overall contribution of a specific gene alteration to the risk of melanoma. high-penetrance genes cdkn2a was the first familial melanoma predisposition gene to be identified and is mutated in approximately 20%40% of high-risk families, depending on selection criteria and on geographic region of the families [12,13,27-32]. the cdkn2a tumor suppressor gene is located at the 9p21 locus and encodes 2 different proteins, p16ink4a (p16) and p14arf (p14), both regulating cell cycle (figure 1a). the p16 promotes cell cycle arrest in the g1 phase by inhibiting retinoblastoma (rb) protein phosphorylation through cyclindependent kinase 4 (cdk4). p14 is also a tumor suppressor and acts through the p53 pathway inducing cell cycle arrest or favoring apoptosis [33]. the cdkn2a gene is the major melanoma susceptibility gene with more than 60 germline mutations identified to date, the majority of which are missense mutations in the p16 transcript [6,34]. cdkn2a mutation penetrance varies introduction cutaneous melanoma is one of the most aggressive human cancers, with an increasing incidence worldwide [1]. when detected at an early stage, high survival rates are reported 5 years after diagnosis [2]. although new therapies are currently available for metastatic disease, survival for patients with advanced disease is still poor. melanoma pathogenesis is complex and heterogeneous, with environmental, phenotypic, and genetic factors contributing to its development. the main risk factors involved in the etiopathogenesis of cutaneous melanoma are a large number of common acquired melanocytic nevi, atypical melanocytic nevi, light skin phenotype, exposure to ultraviolet (uv) radiation, and a family history of melanoma [3-5]. an estimated 5%-10% of all cutaneous melanoma cases occur in families. familial melanoma is defined as a family in which either 2 first-degree relatives or 3 or more melanoma patients on the same side of the family (irrespective of degree of relationship) are diagnosed with melanoma [5]. in these families the pattern of heritability is consistent with an autosomal dominant inheritance with incomplete penetrance. germline susceptibility has been associated with mutations in high-penetrance melanoma predisposition genes, cdkn2a (cyclin-dependent kinase 2a) and less frequently in cdk4 (cyclin-dependent kinase 4), bap1 (breast cancer associated protein-1), tert (telomerase reverse transcriptase), and pot1 (protection of telomeres 1), or with variants in intermediate-risk genes, mc1r (melanocortin 1 receptor) and mitf (microphthalmia-associated transcription factor) [6-9]. currently, genetic testing is recommended in high-risk melanoma patients and families to improve early detection and reduce mortality. individuals from high-risk melanoma families must receive genetic counseling so that they receive full information about the inclusion criteria for genetic testtable 1. overview of highand intermediate-penetrance genes involved in melanoma susceptibility gene penetrance gene encoded protein role mutation prevalence references high-penetrance cdkn2a p16ink4a cell cycle regulator ~20%-40% of families 10-13 p14arf cell cycle regulator ~1% of families 9,14,15 cdk4 cdk4 cell cycle regulator 17 families 16,17 tert catalytic subunit of telomerase telomere elongation 2 families 18,19 pot1 pot1 telomere maintenance 14 families 20-22 intermediatepenetrance mc1r mc1r melanin synthesis and melanocyte proliferation na 23,24 mitf mitf melanocyte development and differentiation na 25,26 cdk4 = cyclin-dependent kinase 4; cdkn2a = cyclin-dependent kinase 2a; mc1r = melanocortin 1 receptor; mitf = microphthalmia associated transcription factor; na = not applicable; pot1 = protec tion of telomeres 1; tert = telomerase reverse transcriptase. 12 review | dermatol pract concept 2019;9(1):3 between geographical areas, according to the population incidence rate of melanoma, ranging from 58% in europe to 76% in the united states and to 91% in australia by age 80 years [35]. the likelihood of detecting a cdkn2a mutation in melanoma families increases with the number of affected members (approximately 10% for 2-case melanoma families and 30%40% for families with 3 or more cases of melanoma), with the presence within the family of relatives with multiple primary melanoma (mpm), pancreatic cancer, or early age at melanoma onset [36]. in addition, cdkn2a mutations are also detected in individuals with mpm in the absence of a family history of melanoma in 8.3%, 15%, and 57% in united states, north america, and greece, respectively [37,38]. the association between pancreatic cancer and melanoma is often observed in cdkn2a-mutated melanoma families figure 1. pathways of high-risk genes involved in melanoma susceptibility. (a) cdkn2a encodes 2 proteins: p16ink4a and p14arf. mutations in cdkn2a gene allow the cells to escape from cell cycle arrest. in detail, p16ink4a inhibits cyclin d1/cdk4/6 complex to release e2f through rb phosphorylation. p14arf interacts with mdm2 to block p53 ubiquitination, thus promoting apoptosis. when mutated, cdkn2a produces 2 dysfunctional proteins inducing cell cycle progression and avoiding p53 degradation. (b) mutations in cdk4 promote the g1 to s phase transition, escaping the p16ink4a inhibition. (c) tert encodes the telomerase reverse transcriptase, involved in the maintenance of telomere length. mutations in the promoter region of tert increase telomerase activity resulting in chromosomal instability. pot1 interacts with the shelterin complex acting as protective structure which prevents access of tert to telomeres. the s270n mutation in the pot1 gene has been associated with familial melanoma. cdk = cyclin-dependent kinase; cdkn2a = cyclin-dependent kinase inhibitor 2a; mdm2 = mouse double minute 2; pot1 = protection of telomeres 1; rb = retinoblastoma. [copyright: ©2019 rossi et al.] and has been proposed as a hereditary cancer syndrome [39-45]. annual surveillance for pancreatic cancer is therefore warranted in high-risk melanoma families with cdkn2a mutations [46]. besides pancreatic cancer, families with cdkn2a mutations have been reported to also have an increased risk of developing breast, lung, and other tobacco-related cancers [42]. few melanoma kindreds worldwide have been found to carry mutations of b a c review | dermatol pract concept 2019;9(1):3 13 intermediate-penetrance genes in almost half of highly dense melanoma families, the underlying genetic basis is still unexplained. besides the possibility of rare mutations in a few additional unknown high-penetrance genes, a polygenic susceptibility as result of coinheritance of multiple intermediateand/or low-risk alleles or an interplay between susceptibility genes and genetic modifiers (other genes, phenotypic characteristics, and/or environmental risk factors) has been suggested. two intermediate-penetrance genes, mc1r and mitf, predisposing to melanoma have been identified to date (table 1). the mc1r gene, encoding a g-protein coupled receptor with a high affinity for the α-melanocyte-stimulating hormone (αmsh), has a key role in cutaneous pigmentation. binding of αmsh to mc1r stimulates camp-induced tyrosinase activity resulting in eumelanin synthesis. mc1r is a highly polymorphic gene in the caucasian population, with more than 100 variants identified [55,56]. specific mc1r variants (r142h, r151c, r160w, and d294h) resulting in a reduced receptor function with a switch from eumelanin to pheomelanin synthesis are classified as red hair color (rhc) or “r” variants and have been strongly associated with fair skin, freckling, uv radiation sensitivity, and inability to tan [24,57]. mc1r variants, mainly r alleles, have been associated with an increased risk of melanoma independently of phenotypic features [56]. notably, a stronger risk has been reported for patients with darkly pigmented skin [23]. it is indeed recognized that mc1r influences melanoma risk not only through its effect on pigmentation and uv sensitivity but also through additional biological pathways, including induction of antioxidant defenses, dna repair mechanisms, and melanocyte proliferation, regulation, and differentiation [58]. in addition, inheritance of mc1r variants with cdkn2a mutations has been shown to increase penetrance of melanoma in families carrying cdkn2a mutations [23,24]. finally, carrying r variants has been associated with specific clinicodermoscopic features of melanoma such as hypopigmentation, structureless areas, atypia, and vessels [59-61]. the mitf gene is a master regulator of melanocyte homeostasis encoding a lineage-specific transcription factor, involved in cell survival, differentiation, and proliferation [62]. a rare functional variant p.e318k in the mitf gene has been implicated in familial melanoma and in melanoma/renal cell carcinoma susceptibility [25,26]. the p.e318k mutation alters mitf sumoylation, increasing the mitf transcriptional activity with upregulation of downstream genes. clinically, a high nevus count, development of mpm, onset of melanoma before the age of 40, and nonblue eye color are phenotypic characteristics that have been associated with the p.e318k mutation [25,63,64]. the cdk4 oncogene, the second identified high-risk melanoma susceptibility gene, encoding one of the binding partners of p16. the cdk4 oncogene plays an important role at the g1/s phase cell cycle checkpoint (1b). when cdk4 is mutated, p16 cannot inhibit the cdk4 kinase activity resulting in increased phosphorylation of rb bound to e2f transcription factors with higher e2f release. e2f activates the transcription of pro-s phase cell cycle genes, promoting g1/s phase transition. all cdk4 pathogenetic mutations cluster in codon 24 of exon 2, a critical site for p16 binding [16,47]. the phenotype of cdk4-mutated families is indistinguishable from the cdkn2a phenotype, with early-onset cutaneous melanoma, development of mpms, and presence of atypical nevi [48]. in families negative for mutations in known high-risk genes, the introduction of next-generation sequencing methodologies led to the identification of germline mutations in a small number of novel high-penetrance melanoma susceptibility genes involved in pathways other than those mediated by known melanoma risk factors. the bap1 gene regulates differentiation of melanocytes and is part of the dna damage response. cutaneous melanoma is considered as part of the phenotype associated with the bap1 cancer susceptibility syndrome, characterized by multiple skin-colored spitzoid melanocytic tumors, uveal melanoma, and cutaneous melanoma, recently expanded to include mesothelioma, renal cell carcinoma, and basal cell carcinoma [49-53]. the elevated number of cancers in bap1mutated families suggests that this gene is a critical regulator of oncogenesis. telomere maintenance has been recently discovered as a key pathway in melanoma predisposition (figure 1c). the tert gene encodes the catalytic subunit of telomerase, which is the ribonucleoprotein complex that maintains telomere length. tert mutations induce increased expression of telomerase, thus promoting telomere stabilization and acting on cell aging, turnover, and senescence. a novel mutation occurring in the promoter region of the tert gene, encoding the catalytic subunit of telomerase, has been recently identified in 2 melanoma families [18,19]. pot1 is a crucial member of the shelterin complex proteins, important for telomere maintenance. mutations in the pot1 gene have been recently identified in a total of 12 cdkn2a-negative melanoma families [20,21]. additional shelterin complex genes, such as acd and terf2ip, were later found to be mutated in familial melanoma patients [54]. overall, germline mutations in pot1, acd, and terf2ip are detected in approximately 9% of high-density families without mutations in known high-penetrance genes. families carrying pot1, acd, and terf2ip mutations often present with mpm and early-onset melanoma. 14 review | dermatol pract concept 2019;9(1):3 ing the results and the potential limited impact on clinical management. in patients with a strong family history but negative for cdkn2a and cdk4 mutations, testing for other melanomaassociated genes can be performed: bap1 in the presence of typical cutaneous melanocytic lesions, ocular melanoma, or other associated cancers described in the bap1-cancer susceptibility syndrome or mitf in the presence of renal cell carcinoma. panel testing of melanoma predisposition genes is an attractive option for hereditary melanoma, especially for high-penetrance genes, and by now numerous panel tests are available at the same cost as a single gene test. however, routine screening of intermediateor low-penetrance genes is questionable because of the uncertainty of predicting clinical outcome of disease development. however, a tailored genetic testing approach with multigene panels based on the cancer profile observed in the family could be performed if in the families there are cases of breast cancer, prostate cancer, ovarian cancer, and/or colon cancer [45]. management of familial melanoma patients carriers of a cdkn2a mutation are at high risk of developing multiple melanomas and, in some families, pancreatic cancer [12,13]. the identification of a deleterious cdkn2a mutation suggests that carriers should be included in intensive skin surveillance programs with skin examination, also including scalp, oral and genital mucosa, performed every 6 months. however, the frequency of dermatological visit (3-month, 6-month, or 1-year intervals) should be planned on the basis of the patient’s risk factors; digital dermoscopy and clinical photography would be helpful for monitoring these patients. with regard to pancreatic cancer, patients should be aware of the current lack of effective screening guidelines [46,66]. overall, cdkn2a carriers are candidates for annual genetic counseling and testing genetic counseling should be offered to melanoma patients with hereditary predisposition so that they may better understand the meaning of the disease, pattern of inheritance, option of genetic testing, possible results and implications for other family members, and recommendations for primary and secondary prevention of melanoma and for psychological assessment [34,65]. to date, cdkn2a and cdk4 are the only genes recommended to be tested as single genes for genetic screening of melanoma predisposition [8,31,45]. genetic testing of the cdkn2a gene has been available for a long time and can be offered to patients with familial melanoma and/or mpm who are likely to carry a cdkn2a mutation. however, its use in clinical practice has been controversial because of the reported variation in the estimates of cdkn2a mutation penetrance, depending on selection criteria of patients, ethnic background, environmental exposure, and coinheritance of low-intermediate predisposing genes such as mc1r variants. leachman et al [31] proposed a useful rule to select appropriate candidates eligible for genetic testing in melanoma with regard to the specific population or geographic area (table 2): the rule of 2 for countries with a low incidence of melanoma (southern europe) and the rule of 3 for countries with a moderate–high incidence of melanoma (united states and northern europe). a rule of 4 for countries with a very high incidence of melanoma (australia) has been suggested [65]. to reduce the risk of uninformative negative results, it is important to identify the best candidate in the family for genetic testing, usually an individual with a personal presentation most suggestive of a cdkn2a mutation, such as young-onset or mpm patients [34]. if a cdkn2a mutation is detected in a family, screening of other family members is recommended. if no cdkn2a mutation is identified within a melanoma family, it should be stressed that the family is still at increased risk of melanoma on the basis of the family history. patients should be aware of the difficulty of interprettable 2. selection criteria for cdkn2a genetic testing according to melanoma incidence [31] geographic area/population with low melanoma incidence geographic area/population with moderate–high melanoma incidence • two (synchronous or metachronous) primary melanomas in an individual and/or • families with the following clinical features in firstor second-degree relatives on the same side of the family: — two cases of melanoma (one invasive) or — one case of melanoma and one case of pancreatic cancer • three primary melanomas in an individual and/or • families with the following clinical features in firstor second-degree relatives on the same side of the family: — three cases of melanoma (one invasive) or — two cases of melanoma and one case of pancreatic cancer or — one case of melanoma and two cases of pancreatic cancer review | dermatol pract concept 2019;9(1):3 15 15. pellegrini c, maturo mg, martorelli c, et al. characterization of melanoma susceptibility genes in high-risk patients from central italy. melanoma res. 2017;27(3):258-267. 16. zuo l, weger j, yang q, et  al. germline mutations in the p16ink4a binding domain of cdk4 in familial melanoma. nat genet. 1996;12(1):97-99. 17. puntervoll he, yang xr, vetti hh, et al. melanoma prone families with cdk4 germline mutation: phenotypic profile and associations with mc1r variants. j med genet. 2013;50(4):264-270. 18. horn s, figl a, rachakonda ps, et al. tert promoter mutations in familial and sporadic melanoma. science. 2013;339(6122):959961. 19. harland m, petljak m, robles-espinoza cd, et al. germline tert promoter mutations are rare in familial melanoma. fam cancer. 2016;15(1):139-144. 20. robles-espinoza cd, harland m, ramsay aj, et al. pot1 lossof-function variants predispose to familial melanoma. nat genet. 2014;46(5):478-481. 21. shi j, yang xr, ballew b, et al. rare missense variants in pot1 predispose to familial cutaneous malignant melanoma. nat genet. 2014;46(5):482-486. 22. müller c, krunic m, wendt j, von haeseler a, okamoto i. germline variants in the pot1-gene in high-risk melanoma patients in austria. g3 (bethesda). 2018;8(5):1475-1480. 23. pasquali e, garcía-borrón jc, fargnoli mc, et al. mc1r variants increased the risk of sporadic cutaneous melanoma in darker-pigmented caucasians: a pooled-analysis from the m-skip project. int j cancer. 2015;136(3):618-631. 24. fargnoli mc, gandini s, peris k, et al. mc1r variants increase melanoma risk in families with cdkn2a mutations: a metaanalysis. eur j cancer. 2010;46(8):1413-1420. 25. yokoyama s, woods sl, boyle gm, et al. a novel recurrent mutation in mitf predisposes to familial and sporadic melanoma. nature. 2011;480(7375):99-103. 26. bertolotto c, lesueur f, giuliano s, et al. a sumoylationdefective mitf germline mutation predisposes to melanoma and renal carcinoma. nature. 2011;480(7375):94-98. 27. begg c, orlow i, hummer a, et al. lifetime risk of melanoma in cdkn2a mutation carriers in a population-based sample. j natl cancer inst. 2005;97(20):1507–1515. 28. bruno w, ghiorzo p, battistuzzi l, et al. clinical genetic testing for familial melanoma in italy: a cooperative study. j am acad dermatol. 2009;61(5):775-782. 29. maubec e, chaudru v, mohamdi h, et al. familial melanoma: clinical factors associated with germline cdkn2a mutations according to the number of patients affected by melanoma in a family. j am acad dermatol. 2012;67(6):1257-1264. 30. harland m, cust ae, badenas c, et al. prevalence and predictors of germline cdkn2a mutations for melanoma cases from australia, spain and the united kingdom. hered cancer clin pract. 2014;12(1):20. 31. leachman s, carucci j, kohlmann l, et al. selection criteria for genetic assessment of patients with familial melanoma. j am acad dermatol. 2009;61(4):677.e1-14. 32. lang j, boxer m, mackie rm. cdkn2a mutations in scottish families with cutaneous melanoma: results from 32 newly identified families. br j dermatol. 2005;153(6):1121. 33. chudnovsky y, khavari pa, adams ae. melanoma genetics and the development of rational therapeutics. j clin invest. 2005;115(4):813-824. pancreatic cancer screening via endoscopic ultrasonography or magnetic resonance cholangiopancreatography. the recommendation of avoiding smoking in cancer prevention programs has been recently suggested for cdkn2a mutation carriers after the description of an increased prevalence of tobacco-associated cancers in cdkn2a-mutated families [67]. first-degree relatives (parents, siblings, children) will have a 50% chance of harboring the same mutation and risk. it is also prudent for children from familial melanoma kindreds to undergo routine skin examinations beginning at puberty. increased skin cancer screening, patients’ skin self-examination education, and 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mutation: phenotypic profile and associations with mc1r variants. med genet. 2013;50(4):264-270. 49. aoude lg, wadt k, bojesen a, et al. a bap1 mutation in a danish family predisposes to uveal melanoma and other cancers. plos one. 2013;8(8):e72144. 50. abdel-rahman mh, pilarski r, cebulla cm, et al. germline bap1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. j med genet. 2011;48(12):856859. 51. carbone m, ferris lk, baumann f, et al. bap1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and mbaits. j transl med. 2012;10:179. dermatology: practical and conceptual review | dermatol pract concept 2014;4(4):2 11 dermatology practical & conceptual www.derm101.com when all you have is a dermatoscope— start looking at the nails holger a. haenssle1,2, andreas blum3, rainer hofmann-wellenhof4, juergen kreusch5, wilhelm stolz6, giuseppe argenziano7, iris zalaudek3, franziska brehmer1 1 department of dermatology, venereology and allergology, university medical center göttingen, göttingen, germany 2 department of dermatology, venereology and allergology, university medical center heidelberg, heidelberg, germany 3 private dermatology practice, konstanz, germany 4 department of dermatology, medical university of graz, graz, austria 5 private dermatology practice, luebeck, luebeck, germany 6 clinic of dermatology and allergology, hospital munich-schwabing, munich, germany 7 dermatology and skin cancer unit, arcispedale santa maria nuova (irccs), reggio emilia, italy keywords: nail unit, dermatoscopy, melanoma, nevus, melanonychia striata, acral pigmentation, nail alteration citation: haenssle ha, blum a, hofmann-wellenhof r, kreusch j, stolz w, argenziano g, zalaudek i, brehmer f. when all you have is a dermatoscope—start looking at the nails. dermatol pract concept. 2014;4(4):2. http://dx.doi.org/10.5826/dpc.0404a02. received: may 4, 2014; accepted: may 16, 2014; published: october 31, 2014 copyright: ©2014 haenssle et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: pd dr. med. holger andreas haenssle, department of dermatology, venereology and allergology, im neuenheimer feld 440, 69120 heidelberg, germany. email: holger.haenssle@med.uni-heidelberg.de pigmented and non-pigmented nail alterations are a frequent challenge for dermatologists. a profound knowledge of clinical and dermatoscopic features of nail disorders is crucial because a range of differential diagnoses and even potentially life-threatening diseases are possible underlying causes. nail matrix melanocytes of unaffected individuals are in a dormant state, and, therefore, fingernails and toenails physiologically are non-pigmented. the formation of continuous, longitudinal pigmented streaks (longitudinal melanonychia) may either be caused by a benign activation of matrix melanocytes (e.g., as a result of trauma, inflammation, or adverse drug reactions) or by a true melanocytic proliferation (e.g., in a nevus or melanoma). in general, non-continuous nail alterations, affecting only limited parts of the nail apparatus, are most frequently of non-melanocytic origin. important and common differential diagnoses in these cases are subungual hemorrhage or onychomycosis. in addition, foreign bodies, bacterial infections, traumatic injuries, or artificial discolorations of the nail unit may less frequently cause non-continuous nail alterations. many systemic diseases that may also show involvement of the nails (e.g., psoriasis, atopic dermatitis, lichen planus, alopecia areata) tend to induce alterations in numerous if not all nails of the hands and feet. a similar extensive and generalized alteration of nails has been reported after treatment with a number of systemic drugs, especially antibiotics and cytostatics. benign or malignant neoplasms that may also affect the nail unit include glomus tumor, bowen’s disease, squamous cell carcinoma, and rare collision tumors. this review aims to assist clinicians in correctly evaluating and diagnosing nail disorders with the help of dermatoscopy. abstract 12 review | dermatol pract concept 2014;4(4):2 introduction the clinical and dermatoscopic evaluation of nail alterations is often a diagnostic challenge for dermatologists in their daily practice. regarding the variety of different patterns, it is helpful to follow a standardized diagnostic algorithm (figure 1a) and to memorize the dermatoscopic features of the most frequent nail disorders as depicted by the schematic icons in figure 1b [1]. in agreement with the evaluation of pigmented lesions elsewhere on the skin, a multi-step diagnostic procedure has proven to be successful [2]. a first step is dedicated to the differentiation of a melanocytic origin (longitudinal melanonychia) from a non-melanocytic origin of the nail pigmentation (non-continuous discoloration). figure 1. (a) algorithm for the dermatoscopic evaluation on the nail unit. in a first step, a differentiation between melanocytic and non-melanocytic alterations is made. in a second step, the alterations of melanocytic origin, that normally present as longitudinal melanonychia, need to be separated into benign (activation or proliferation) or malignant lesions. (b) the icons depict the most common dermatoscopic criteria of six frequent nail alterations in a much simplified manner. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) a b for all non-melanocytic nail disorders, a diagnosis should be made based on typical dermatoscopic criteria (figure 1b, e.g., subungual hematoma). in most of these cases, the clinical picture and dermatoscopic criteria will lead to a final diagnosis and further diagnostic measures will not be necessary [3-5]. however, a follow-up examination with comparison of clinical/dermatoscopic findings to baseline images may be useful to safely confirm the initial diagnosis [1]. in case of a longitudinal melanonychia, the distinction between a benign activation of melanocytes (figure 1b, lentigo, mostly grayish background with longitudinal homogeneous gray lines) and a true melanocytic proliferation ensues in a second step. if a melanocytic proliferation is present, the differentiation between nevus and melanoma is required (figure 1b) [6,7]. the confident diagnosis of melanoma in situ or early invasive melanoma by clinical appearance and dermatoscopy may especially cause difficulties, and a biopsy of the nail matrix should be performed in any case of doubt [8]. the solid surface of the nail unit with its convexities and concavities may prevent the exact optical attachment of the dermoscope to the nail by immersion oil or disinfectant agents. we recommend the use of ultrasound gel as a contact medium or the use of dermatoscopes with polarized light in the nail region. figure 2. onychomycosis, disto-lateral pattern of the left thumb of a 40 year-old male. (a) overview. (b) dermoscopy. the whitish brightening with parallel striation, proximal jags, and nail discolorations with yellow colors are dermatoscopically detectable. (copyright: ©2014 haenssle et al.) figure 3. mycotic/traumatic-impaired nail with secondary pseudomonas superinfection. (a) overview. (b) dermatoscopy. an intense green color of the nail neighboring a fissure is seen dermatoscopically. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) review | dermatol pract concept 2014;4(4):2 13 non-continuous (non-melanocytic) nail alterations onychomycosis the most common clinical form of onychomycosis shows a distolateral pattern that often involves the nails of the first and/or fifth toe. dermatoscopic examination typically reveals: (i) a whitish discoloration of the nail, (ii) superimposed longitudinal parallel striation, and (iii) jagged proximal edges with spikes (figure 2a, b). moreover, small splinter hemorrhages and various nail discolorations (chromonychia) with green, yellow or brown colors may occur [5,9]. of note, an intense green color of the nail plate severely affected by a mycotic infection often indicates a secondary infection with pseudomonas species (figure 3a, b). after a clinical and dermatoscopic examination the causative dermatophytes (mostly trichophyton rubrum, epidermophyton or microsporum species) may be differentiated by cultural techniques. subungual hemorrhage/subungual hematoma in addition to the subcorneal hemorrhage, the subungual hemorrhage (also called subungual hematoma) is one of the most frequent differential diagnoses of acral pigmented lesions. a detailed documentation of the lesion history should give first evidences for the causes of the subungual hemorrhage (e.g., trauma, anticoagulation). it usually appears as a reddish-blue to blue-black pigmentation that does not longitudinally involve the whole nail. the characteristic dermatoscopic findings of subungual hemorrhage are homogeneous or globular patterns, streaks, peripheral fading and also periungual hemorrhages of adjacent skin [10]. moreover, small, globular blood dots directed towards the distal end of the nail plate are a highly characteristic dermatoscopic feature that often leads to the correct diagnosis (figure 4a-c). importantly, a proximal subungual hematoma may be visible through the widely transparent cuticula; this should not be confused with the (micro-) hutchinson sign characterizing a subungual melanoma. subungual hemorrhage will continuously be transferred towards the distal edge of the nail at the figure 4. subungual hematoma after trauma. (a) overview. (b-c) dermatoscopy. the characteristic red-blue to blue-black homogeneous color, numerous satellite droplets towards the distal nail edge and the jagged margins are depicted. (copyright: ©2014 haenssle et al.) speed of the nail growth. sequential digital dermatoscopy follow-up may confidently be used to document the progressive “growing-out” of a subungual hemorrhage. any subungual hemorrhage that persists and eventually forms a longitudinal pigmentation involving the complete nail apparatus requires further diagnostic procedures including biopsy. systemic diseases involving the nail unit nail psoriasis with pitted and thickened nails, onycholysis and psoriatic crumbling of the nail plate can easily be inspected with the naked eye. dermatoscopy can be helpful for the diagnosis when the typical clinical features are absent or subtle. in patients with psoriatic onycholysis, dermatoscopy helps to visualize the inflammatory, erythematous border surrounding the distal edge of the detached nail plate [4]. the accuracy of the evaluation of psoriatic splinter hemorrhages and subungual hyper-/parakeratosis is increased. similar to nail psoriasis, patients with atopic diathesis or manifest atopic dermatitis may have pitted nails without further characteristics (figure 5a, b). onychopapilloma and subungual viral wart onychopapilloma is a benign neoplasms, that originates from the distal nail matrix and/or the nail bed [11,12]. it typically presents with longitudinal leukonychia or longitudinal erythronychia that does not continuously involve the whole nail, but that leaves an unaffected interval at the proximal nail matrix. importantly, cases of onychopapilloma presenting as longitudinal melanonychia of grayish color have been figure 5. pitted nails in a patient with atopic eczema. (a) overview. (b) dermatoscopy. dermatoscopically, small, circular punctate depressions within the nail plate are discernable. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) 14 review | dermatol pract concept 2014;4(4):2 reported [13]. the dermatoscopic view from the free distal margin of the nail plate typically reveals a wedge-shaped hyperkeratotic notch (figure 6a-d). the diagnosis of acral viral warts is often easily made by a clinical inspection. however, dermatoscopic examination may be useful for the diagnosis of small, subclinical or subungual warts or for the assessment of the therapeutic success after treatment. a yellowish, rough-verrucous surface with multiple, brown-red dots and/or streaks, which correspond to dilated capillaries and small hemorrhages are characteristic dermatoscopic criteria [14,15]. a decrease of the capillary density within viral warts is often observed in lesions responding to treatment. figure 7. artificial discoloration of the nail by staining of moist leather shoes. (a) overview. (b-c) dermatoscopy. the dermatoscopic examination of the distal free nail edge in ( c) clearly shows the superficial location of the pigment. (d-e) artificial nail discolorations may usually be easily removed with a scalpel. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) figure 8. artificial discolorations of all toenails after repetitive application of self-tanning lotion. (a) overview. (b) dermatoscopy. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) artifacts and foreign bodies of the nail unit artificial changes of the nail unit occasionally arise and may be quite worrisome for patients. in the summer, moist leather of shoes may cause irregular dark-brown discolorations of some toenails, which can easily be removed mechanically (figure 7a-e). additionally, the use of self-tanning lotions or tanning showers may lead to a homogeneous yellow-brownish discoloration of all nails (figure 8a, b). occasionally, foreign body injuries of the nail unit, accompanied by subungual hemorrhage, subungual serumand air-inclusions may be observed, especially in patients walking barefoot (figure 9a, b). other neoplasms of the nail unit glomus tumor glomus tumors represent approximately 1 to 5% of the soft tissue tumors of the hand. they are a subtype of benign venous malformations characterized by rows of glomus cells that surround distorted, thin-walled vascular channels. figure 6. onychopapilloma. (a-b) overview. (c-d) dermatoscopy. longitudinal erythronychia that does not continuously involve the whole nail but that leaves an unaffected interval at the proximal nail matrix. few reddish-black streaks represent hemorrhages and serous inclusions with yellowish background pigmentation. dermatoscopy of the distal nail margin reveals the typical rough verrucous surface of a wedge-shaped notch with red-black dots. (copyright: ©2014 haenssle et al.) review | dermatol pract concept 2014;4(4):2 15 glomus tumors of the nail unit are painful, vascular proliferations with an increased sensitivity to cold temperatures and pressure. they arise from myoarterial structures (hoyer-grossersche organs) of the nail unit [16]. nearly two-thirds of glomus tumors are localized on the hands, particularly the subungual region. in addition to numerous clinical tests that examine the painfulness and the increased sensitivity to cold, the use of dermatoscopy helps to localize the tumors and to visualize the vascular pattern of the lesion. furthermore, the use of dermatoscopy facilitates the delimitation of surgical margins before treatment (figure 10a, b) [16]. bowen’s disease and squamous cell carcinoma in the aging population tumors with increasing incidences (bowen’s disease, squamous cell carcinoma) may also arise in less common localizations including the nail bed or the skin below the distal nail plate. the clinical presentation of these tumors is often atypical and they are usually non-pigmented; therefore, their diagnosis is often missed or delayed. moreover, these tumors may be misinterpreted as other benign conditions such as verruca vulgaris, onychomycosis or trauma-induced nail dystrophy [14]. dermatoscopically, the characteristic pattern of pigmented bowen’s disease with its typical brownish dots along imaginary lines can frequently figure 9. splinter injury with insertion of a foreign body. (a) overview. (b) dermatoscopy. a subungual hemorrhage with subungual inclusions of serum and air are detectable. no remnants of a foreign body are visible. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) be observed (figure 11a, b) [17]. in contrast, non-pigmented bowen’s disease or squamous cell carcinoma may often show dot-like to glomerular vessels clustering in groups (up to vascular polymorphism) [18]. the potential risk of misdiagnosing subungual bowenoid squamous cell carcinoma as verruca vulgaris is exemplified in figure 12 (figure 12a-c) and 13 (figure 13a, b). collision tumors (squamomelanocytic tumor) a collision tumor is a cutaneous proliferation composed of closely intermingled cells of two independent tumor entities at the same location, e.g., of a melanoma and a squamous cell carcinoma. a squamomelanocytic tumor is such a collision tumor that mostly occurs in sun-exposed skin of the face and neck area of older patients [19,20]. recently, a first squamomelanocytic tumor of the nail unit has been reported [21]. the clinical and dermatoscopic examination revealed an advanced dystrophy of the nail plate with brown to slategray periungual pigmentation (corresponding to invasive melanocytes of the melanoma) and several keratin cysts of the figure 10. glomus tumor of the proximal nail unit (diffuse redblue color, artifact: bright-red residues of nail polish. (a) overview. (b) dermatoscopy shows an oval, homogeneous red-blue tumor. the patient complains of tenderness especially to pressure and sensitivity to cold temperatures. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) figure 11. advanced bowen carcinoma of the nail unit. (a) overview. (b) dermatoscopy. the nail unit is widely destroyed. dermatoscopically the “dots along lines,” that are characteristic of pigmented bowen’s disease are clearly observable. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) figure 12. bowen’s disease beneath the distal nail margin with accumulation of parakeratotic material. (a) overview. (b) dermatoscopy of the nail surface and (c) the distal nail edge. in this slightly pigmented keratotic tumor distal onycholysis and subungual hemorrhage are visible. differentiation from verruca vulgaris is very difficult since a number of characteristic criteria are present (yellowish, rough to verrucous surface with brown-red streaky hemorrhages). (copyright: ©2014 haenssle et al.) 16 review | dermatol pract concept 2014;4(4):2 adjacent skin (corresponding to areas of keratinization of the squamous cell carcinoma) (figure 14 a, b). continuous (melanocytic) nail alterations (longitudinal melanonychia) in contrast to the direct inspection of a localized melanocytic proliferation in case of a nevus or melanoma on the skin, the site of melanocytic proliferation within the nail matrix or proximal nail bed is not accessible for a direct dermatoscopic inspection. this means that the examination of longitudinal melanonychia is limited to the inspection of pigment that was deposited in the nail plate weeks to months earlier [22]. continuous longitudinal pigmented bands within the nail plate may represent melanocytic nevus, lentigo, racial/ethnic melanonychia, drug-induced hyperpigmentation, or malignant melanoma [6]. benign longitudinal melanonychia is rare in caucasians—only 1.4% of the population is affected. interestingly, the thumb, followed by the great toe and the index are involved most frequently [6]. figure 13. invasive subungual bowen carcinoma with profound accumulation of parakeratotic material. (a-b) overview. (c) dermatoscopy of the nail surface and (d) the distal nail edge. again, as already visualized in figure 12, a slightly pigmented keratotic tumor causes a distal onycholysis and deformation of the nail plate. the history of a long-standing nail alteration with progressive growth pattern should raise suspicion of a malignant tumor, namely, subungual squamous cell carcinoma or bowen carcinoma. (copyright: ©2014 haenssle et al.) figure 14. squamomelanocytic tumor of the nail unit as a genuine collision tumor of a squamous cell carcinoma and melanoma. (a) overview. (b) dermatoscopy. the nail unit is completely destroyed and shows yellowish keratotic as well as reddish erosive areas. plugs of keratin (similar to the keratotic pseudocysts of a seborrheic keratosis) in the periungual skin may be considered a marker of a keratinizing tumor. the irregular gray-brown discoloration of the periungual skin corresponded to invasive melanoma cells in the histopathological evaluation. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) figure 15. nail alteration after chemotherapy with docetaxel. (a) overview. (b) dermatoscopy. the dermatoscopic view reveals a diffuse yellow-red discoloration of multiple nails indicative of an increased vascularization of the nail matrix and a diffuse transient extravasation of erythrocytes. multiple dot-shaped hemorrhages (distal nail edge) are a further marker of toxic changes of the nail unit. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) drug-induced melanocytic activation a range of drugs has been associated with the formation of nail alterations. however, only a few drugs are regularly responsible for toxic effects on the nail matrix, the nail bed or the periungual skin [23]. these drugs predominantly include retinoids and chemotherapeutics like docetaxel (taxotere) (figure 15a, b) [24]. besides diffuse dark pigmentations of all nails and beau’s lines (lines appearing as horizontal and deep grooves of all fingernails), subungual hemorrhage, orange discolorations, acute painful paronychias, onycholysis, subungual hyperkeratosis and transverse loss of the nail plate are described for docetaxel, in which the type of nail alteration is related to the number of administered cycles. additionally, minocycline was repeatedly associated with gray-blue longitudinal melanonychias that are clinically very similar to ethnic subungual lentigo [25,26]. pigmentations usually occur after prolonged minocycline treatment, however, not always in a dose-dependent manner and mostly after treatment intervals of more than a few years, and may coincide with other pigmented sites. review | dermatol pract concept 2014;4(4):2 17 ethnic-type nail pigmentation (nevoid lentigo of the nail unit) the ethnic subungual lentigo predominantly occurs in humans with a darker skin type categorized according to fitzpatrick skin classification (e.g., indian skin type, skin type v). multiple nails are frequently affected and the color is homogeneous gray-brown. the thin longitudinal lines that might be discriminated within the pigmented band are regular in their coloration, thickness and spacing (figure 16a, b) [7,8]. the lateral margin of pigmentation is often diffuse. occasionally, the pigmented band of a subungual ethical lentigo is very subtle and pale and therefore may be difficult to separate from the uninvolved nail-plate in a clinicaldermatoscopic examination. benign nevus of the nail unit characteristics for subungual benign nevi are their appearance in children and young adults and their regular pattern of the longitudinal lines. the width of the pigmented band of subungual nevi is rather low (normally ≤3 mm) and regular in thickness and spacing of striation. the color of different subungual nevi varies from light brown to dark brown to black [3]. the pigmentation within one lesion is mostly homogeneous or is composed of evenly distributed thinner figure 16. ethnic lentigo of the right great toenail. (a) overview. (b) dermatoscopy. dermatoscopically there is a homogeneous grayish-pale longitudinal melanonychia affecting the whole nail with a slightly diffuse demarcation of the lateral margin. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) figure 17. benign nevus of left index finger after multiple years of digital monitoring and matrix biopsy. (a) overview. (b) dermatoscopy reveals a pigmented band composed of multiple light brown parallel lines and light brown dots. the pigmented band measures four millimeters and affects the whole nail (longitudinal melanonychia). (copyright: ©2014 haenssle et al.) lines of the same color (figure 17a, b). congenital acral nevi may also involve an increased melanocytic pigmentation of the nail unit (figure 18a, b). many congenital nevi at acral sites may clinically look suspicious at first sight and should thoroughly be inspected by using dermatoscopy. the double dotted parallel furrow pattern depicted in figure 18 was described as a typical acral volar skin pattern in younger individuals [27]. over the course of time when examined by sequential digital dermatoscopy the degree of pigmentation of the longitudinal line may increase or decrease depending on the uv exposure, whereas the width of the lesion should remain unchanged (figure19a, b) [28]. early and late invasive melanoma of the nail unit in epidemiological studies, melanoma of the nail unit frequently appeared in patients older than 50 years and, interestingly, was mostly localized at the nail unit of the thumb or the great toe. approximately 50% of patients with nail melanoma recollect a preceding trauma [3]. the width of the longitudinal pigmentation in melanoma in situ or early invasive melanoma frequently measures more than 5 mm and shows lines of variable thicknesses, spacing, and coloration figure 18. benign congenital nevus involving plantar acral skin and the nail of the right second toe in a 4-year-old girl. (a) overview. (b) dermatoscopy reveals a double dotted parallel furrow pattern in acral skin and a homogeneous brown pigmented band continuously affecting half of the nail width (longitudinal melanonychia). (copyright: ©2014 haenssle et al.) figure 19. benign nevus over the course of time (interval of approximately six months). (a) overview. (b) dermatoscopy. due to an irregular, intensive brownish striation a digital dermatoscopic follow-up examination was performed. the follow-up image reveals a decrease in pigmentation that may vary with the level of sunexposure and a constant width of the longitudinal melanonychia. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) 18 review | dermatol pract concept 2014;4(4):2 [3,7,8]. a feature significantly associated with the diagnosis of subungual melanoma is the microor macro-hutchinson sign defined by the visibility of a pigmentation of the periungual cuticula only by dermatoscopy or by naked eye inspection respectively (figure 20a, b) [29]. of note, in a number of early invasive subungual melanomas specific criteria may still be absent. in these cases a thorough investigation of the lesional evolution may raise enough suspicion to schedule a matrix biopsy (figure 21a, b). for other cases, sequential digital dermatoscopy may help to detect dynamic changes in color as well as an increase in width of the whole longitudinal pigmentation over the course of time. in far advanced invasive melanomas of the nail unit, the diagnosis may be easily made by naked eye examination. the nail unit then often reveals a severe dystrophy of the nail apparatus with ulceration, hemorrhage, or even loss of the overall nail plate. further criteria for a late invasive melanoma of the nail unit are loss of parallelism, multiple colors and localized invasion of malignant melanoma cells into the adjacent skin (figure 22a-d, 23a, b). the listed criteria should prompt the clinician to take at least one biopsy of the nail matrix without further delay. the prognosis of nail matrix melanoma is generally less favorable than for melanoma in other sites due to the frequent delay in diagnosis. further indications for dermatoscopy of the nails another useful indication for dermatoscopy of nails is the examination of the nail fold capillaries in patients with connective tissue diseases like systemic sclerosis (figure 24a-b) [30]. in patients suffering from sclerodactyly, the evaluation figure 20. subungual melanoma in situ. (a) overview. (b) dermatoscopy. the whole nail unit is affected by a continuous pigmentation composed of parallel lines showing an inhomogeneous color (brown to blue-gray) and pigment intensity (unpigmented followed by heavily pigmented streaks). a hutchinson sign, being indicative of an invasion of melanoma cells into the periungual skin, is better visualized by dermatoscopy (arrows at proximal nail fold). (copyright: ©2014 haenssle et al.) figure 21. early invasive subungual melanoma, thickness 0.2 mm. (a) overview. (b) dermatoscopy. dermatoscopically, a homogeneous gray-brown band is visible, measuring approximately 6 mm across and continuously affecting the whole nail (longitudinal melanonychia). sharply demarcated globular structures correspond to drop-like subungual hemorrhage. the macro-hutchinson sign, being indicative of an invasion of melanoma cells into the periungual skin, is (still) negative (proximal nail fold). (copyright: ©2014 haenssle et al.) figure 22. advanced subungual melanoma in a 30-year old male with skin type v (indian skin type). (a-b) overview. (c-d) dermatoscopy. the complete nail unit and also the adjacent skin are heavily pigmented with black-brown colors. the nail plate shows a severe onychorrhexis with multiple longitudinal fissures and ridges. the macro-hutchinson sign is positive at the proximal nail fold as well as at the distal tip of the toe. (d) dermatoscopy of the distal tip of the toe reveals the typical parallel ridge pattern of acral melanoma. (copyright: ©2014 haenssle et al.) figure 23. far advanced subungual melanoma of the right great toe. (a) overview. (b) dermatoscopy. the complete nail unit is destroyed by a black to pink colored, ulcerated melanoma. dermatoscopy reveals black-blue to red colors with a cloud-like texture. (copyright: ©2014 haenssle et al.) review | dermatol pract concept 2014;4(4):2 19 of nail fold capillaries should include the degree of dilated capillaries, the extent of nail fold hemorrhage as well as avascular areas. the dermatoscopic documentation of dilated capillaries and/or nail fold hemorrhage is a sensitive and specific strategy for the diagnosis of systemic sclerosis [30]. summary besides the clinical examination, dermatoscopy plays an important role in the evaluation of nail disorders. the dermatoscopic criteria for a valid diagnosis have been developed and assessed in numerous clinical trials. in all nail alterations that are suspicious or potentially malignant, a surgical intervention with subsequent histopathological evaluation should be performed. despite the investment of huge amounts of money for the development of diagnostic medical devices that should help clinicians to diagnose cutaneous melanoma with higher sensitivity and specificity, there is no such device suitable for the application in the case of nail pigmentations. quite the contrary, numerous manufacturers (e.g., melafind®/melasciences, nevisense®/scibase) explicitly exclude the usage of their devices for the nail unit. therefore, an extensive training of clinicians in dermatoscopy for lesions in the nail region is essential. international dermoscopy society (ids) the international dermoscopy society (ids) offers a valuable panel for further education in this important technique for all colleagues that are interested in dermatoscopy. after registration (free of cost) on the ids homepage (http://www. dermoscopy-ids.org), a range of tutorials and presentations of cases from all over the world are available. in the discussion forum, the user can upload digital images of uncertain cases and will receive comments from the most prestigious international experts of dermatoscopy within a few days. figure 24. capillaroscopy with a dermatoscope. dilated capillaries of the proximal nail fold and small hemorrhages of the cuticula (ehring’s rhexis bleeding) in a young woman with mild sclerodactyly and suspected crest syndrome. (a) overview. (b) dermatoscopy. (copyright: ©2014 haenssle et al.; first published in der hautarzt, 2014, 65(4):301-11.) note: a version of this manuscript was published in the german language in der hautarzt, 2014;65(4):301-11. references 1. tosti a, argenziano g. dermoscopy allows better management of nail pigmentation. arch dermatol. 2002;138(10):1369-70. 2. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-93. 3. braun rp, baran r, le gal fa, et al. diagnosis and management of nail pigmentations. j am acad dermatol. 2007;56(5):835-47. 4. piraccini bm, bruni f, starace m. dermoscopy of non-skin cancer nail disorders. dermatol ther. 2012;25(6):594-602. 5. piraccini bm, balestri r, starace m, et al. nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. j eur acad dermatol venereol. 2013;27(4):509-13. 6. koga h, saida t, uhara h. key point in dermoscopic differentiation between early 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malignant neoplasm with features of both squamous cell carcinoma and malignant melanoma. am j dermatopathol. 1984;6 suppl 213-9. 21. haenssle ha, buhl t, holzkamp r, et al. squamomelanocytic tumor of the nail unit metastasizing to a sentinel lymph node: 20 review | dermatol pract concept 2014;4(4):2 a dermoscopic and histologic investigation. dermatology. 2012;225(2):127-30. 22. hirata sh, yamada s, almeida fa, et al. dermoscopy of the nail bed and matrix to assess melanonychia striata. j am acad dermatol. 2005;53(5):884-886. 23. piraccini bm, iorizzo m. drug reactions affecting the nail unit: diagnosis and management. dermatol clin. 2007;25(2):215-21, vii. 24. correia o, azevedo c, pinto fe, et al. nail changes secondary to docetaxel (taxotere). dermatology. 1999;198(3):288-90. 25. ban m, kitajima y. nail discoloration occurring after 8 weeks of minocycline therapy. j dermatol. 2007;34(10):699-701. 26. tavares j, leung ww. discoloration of nail beds and skin from minocycline. cmaj. 2011;183(2):224. 27. suzaki r, ishizaki s, iyatomi h, et al. age-related prevalence of dermatoscopic patterns of acral melanocytic nevi. dermatol pract concept. 2014;4(1):53-57. 28. haenssle ha, krueger u, vente c, et al. results from an observational trial: digital epiluminescence microscopy follow-up of atypical nevi increases the sensitivity and the chance of success of conventional dermoscopy in detecting melanoma. j invest dermatol. 2006;126(5):980-5. 29. sladden mj, mortimer nj, osborne je. longitudinal melanonychia and pseudo-hutchinson sign associated with amlodipine. br j dermatol. 2005;153(1):219-20. 30. ohtsuka t. dermoscopic detection of nail fold capillary abnormality in patients with systemic sclerosis. j dermatol. 2012;39(4):331-5. dermatology: practical and conceptual 292 letter | dermatol pract concept 2018;8(4):7 dermatology practical & conceptual www.derm101.com introduction we report on a case of a 82-year-old woman referred to us with a 2-month history of comedones and multiple yellowcolored cysts, ranging from 0.5 to 5 mm in diameter, located within erythematous plaques on her right malar region (figure 1a). the left side was spared (figure 1b). the patient had a history of smoking. she had been a factory worker indoors for 40 years and she denied significant sun exposure. case presentation dermatoscopy showed yellowish lobular-like structures with rare peripheral telangiectasia (figure 1c). actinic keratosis, lentigo solaris and seborrheic keratosis were also detected on her face, mainly on her forehead, nose and periorbital areas. a punch biopsy was performed and histopathology revealed massive dermal elastosis and cystic-like spaces. the cystic-like spaces were lined by a flattened epithelium and were filled with layered horny material. the sebaceous glands were atrophic (figure 1d). considering clinical, dermoscopic and histological findings was diagnosed unilateral favre-racouchot disease (frd). discussion frd is characterized by nodules and cysts associated with the clinical signs of actinic-related skin damage and solar elastosis of the face. in 1888 thin et al. described grouped comedones occurring in solar-damaged skin of elderly individuals for the first time. in 1951, favre and racouchot extended this description to include nodular elastosis and cysts [1]. frd occurs in up to 6% of patients aged from 40 to 60 years, and most are caucasian men [1]. sun exposure, smoking, and therapeutic radiation are considered important risk factors. in this disease, 3 pathogenetic steps are described: 1) loss of functional elastic tissue network and reduction of tensile strength; 2) distension of the infundibular canal of the sebaceous follicles; and 3) retention of sebum with consequent comedones formation [1]. a case of unilateral inflamed plaques with comedones of the face marco a. chessa1, federica filippi1, francesca ferrara1, annalisa patrizi1, carlotta baraldi1 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: favre-racouchot syndrome, comedones, nodules and cysts, solar elastosis, yellowish lobular-like pattern citation: chessa ma, filippi f, ferrara f, patrizi a, baraldi c. a case of unilateral inflamed plaques with comedones of the face. dermatol pract concept. 2018;8(4):292-294. doi: https://doi.org/10.5826/dpc.0804a07 received: march 18, 2018; accepted: march 28, 2018; published: october 31, 2018 copyright: ©2018 chessa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: federica filippi, md, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138, bologna, italy. email: federicafilippi8@gmail.com letter | dermatol pract concept 2018;8(4):7 293 the skin areas usually involved are the lateral canthi of the eyes, the malar regions, as in our patient, temples, cheeks or neck and the posterior auricular skin. usually, this disease has a symmetrical distribution even though some cases of unilateral frs have been reported in the literature [2]. clinically, the skin involved is characterized by slowly progressive waxy and soft plaques with open or closed comedones. the surrounding skin may be thickened and shows deep furrows, isolated papules, nodules and rough and waxy plaques from 2 to 6 cm in diameter. figure 1. (a) inflamed plaque with comedones and yellow cysts localized on right malar region; (b) left side of face was spared by favreracouchot disease; (c) yellowish lobular-like structures with rare telangiectasia were detected at dermatoscopy; (d) thinning of the epidermis, massive dermal elastosis and cystic-like spaces. the sebaceous glands are atrophic (h&e 4×). [copyright: ©2018 chessa et al.] figure 2. (a) inflamed plaque with comedones on the right malar region; the black rectangle indicates the site where the skin biopsy was performed; (b) reduction of inflammation with improvement of the skin appearance after application of fusidic acid and tretinoin 0.05% for 2 months. [copyright: ©2018 chessa et al.] 294 letter | dermatol pract concept 2018;8(4):7 conclusion our patient refused both surgical and laser therapy, so a topical treatment was started. fusidic acid and tretinoin 0.05% creams were applied on the lesion once a day for 2 months, achieving a reduction of inflammation and a clinical improvement of the disease (figure 2 a,b). references 1. patterson wm, fox md, schwartz ra. favre-racouchot disease. int j dermatol. 2004;43(3):167-169. 2. vogel s, mühlstädt m, molin s, ruzicka t, schneider j, herzinger t. unilateral favre-racouchot disease: evidence for the etiological role of chronic solar damage. dermatology. 2013;226(1):32-34. clinical and histopathological findings usually play a pivotal role in coming to the diagnosis and ruling out chloracne, sebaceous adenoma, and syringoma [1]. the dermoscopic features of frd have not been reported in the literature before. histopathologically, frd is characterized by an alteration of the pilosebaceous unit; dilated infundibulum and large, round cystic like spaces are present. regression or absence of sebaceous glands is often detected. in addition, solar elastosis could be pronounced, but it may also be slight or absent [1]. sunscreen and cessation of smoking can arrest the progression of the disease. besides these measures, pharmacological and surgical approaches could be effective. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):12 1 author queries: aq1: we changed 6,20 to 6.20. is this correct? 302 letter | dermatol pract concept 2019;9(4):12 dermatology practical & conceptual introduction mastocytosis is characterized by accumulation of clonally proliferated, morphologically and immunophenotypically abnormal mast cells in the skin or the other organs [1]. solitary mastocytoma in infants is an uncommon disease that presents as 1-5 cm minimally elevated yellow-to-brown plaque with a smooth, shiny surface mostly located on the arms, limbs, neck, and trunk [1]. cutaneous mastocytosis in children follows a benign self-limiting clinical course; therefore, the treatment is only symptomatic and does not alter the natural course of the disease [1]. case presentation a 37-day-old male infant presented with an asymptomatic bullous lesion on his left thigh. it was first noticed 7 days after cesarean section delivery as a flat infiltration without any surface change. there was no significant family or antenatal history. the parents were referred to our clinic because of the recognition of first whitening then a bulla formation in the morning. on dermatological examination, a 1.5× 1-cm brown-purple bulla presented on a nonurticarial base surrounded by a yellow hue was seen (figure 1a). during dermoscopy imaging, the bulla was ruptured and a clear fluid was released. dermoscopic examination showed vascular structures with peripheral yellowish discoloration (figure 1b). the infant did not have any physical or psychomotor disturbances, and the physical examination did not reveal any systemic symptoms. the routine laboratory tests (complete blood cell count, biochemistry) were within normal limits. informed consent was obtained from the parent of the patient for publication of the photographs. the lesion was completely excised, with a differential diagnosis of mastocytoma, juvenile xanthogranuloma, and congenital self-healing reticulohistiocytosis. the histopathological examination demonstrated a dense mast cell infiltration in the dermis. these cells contained eosinophilic granular cytoplasm which stained positively with toluidine blue. the immunohistochemical study demonstrated the expression of proto-oncogene c-kit proteins in these cells using cd117 antibody. with regard to dermatological and solitary bullous mastocytoma with dermoscopic features in a neonate: neonatal solitary bullous mastocytoma özge gündüz1, dilsun yıldırım1, f. gülru erdoğan1, başar kaya2, handan doğan3 1 ufuk university faculty of medicine, department of dermatology, ankara, turkey 2 ufuk university faculty of medicine, department of plastic and reconstructive surgery, ankara, turkey 3 ufuk university faculty of medicine, department of pathology, ankara, turkey key words: neonate, solitary mastocytoma, mast cells, dermoscopy citation: gündüz ö, yıldırım d. erdoğan fg, kaya b, doğan h. solitary bullous mastocytoma with dermoscopic features in a neonate: neonatal solitary bullous mastocytoma. dermatol pract concept. 2019;9(4):302-303. doi: https://doi.org/10.5826/dpc.0904a12 accepted: may 21, 2019; published: october 31, 2019 copyright: ©2019 gündüz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: özge gündüz, md, ufuk university faculty of medicine, department of dermatology, 06520 balgat, ankara, turkey. email: drozgegunduz@yahoo.com letter | dermatol pract concept 2019;9(4):12 303 references 1. meni c, bruneau j, georgin-lavialle s, et al. paediatric mastocytosis: a systematic review of 1747 cases. br j dermatol. 2015;172(2):642-651. 2. vano-galvan s, alvarez-twose i, de las heras e, et al. dermoscopic features of skin lesions in patients with mastocytosis. arch dermatol. 2011;147(8):932-940. histopathological examination, the diagnosis of solitary mastocytoma was made; the patient healed uneventfully. an additional laboratory test of blood tryptase level was within normal limits (6.20 ng/ml). we prescribed an antihistamine suspension (hydroxyzine) and advised the parents to avoid stimuli or agents that may precipitate mediator release. three months have passed since the diagnosis of mastocytoma, and the patient has not shown any other cutaneous and systemic symptoms or signs consistent with systemic mastocytosis. discussion a clear association of cutaneous mastocytosis subtypes and dermoscopic patterns has been reported. four dermoscopic patterns have been identified, namely light-brown and yellow-orange blots, pigment network, and reticular vascular forms [2]. our case showed a central vascular structure surrounded by a yellow hue under dermoscopy, which is not consistent with previously described dermoscopic patterns. however, none of the patients in the aforementioned study showed a bullous reaction. in our case, the peripheral yellow hue might be representative of yellow-orange blot pattern, and the central vascular structure might reflect the detachment of epidermis due to the bullous reaction. conclusions we report the dermoscopic features with vascular structures surrounded with a yellow hue of solitary bullous mastocytoma in a neonate. acknowledgment the authors gratefully acknowledge the manuscript review of prof. dr. deepak modi. aq1 figure 1. (a) a brown-purple bulla surrounded by a yellow hue; (b) vascular structures with peripheral yellowish discoloration on dermoscopy (×10). [copyright: ©2019 gündüz et al.] a b dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):9 39 dermatology practical & conceptual www.derm101.com introduction inverted follicular keratosis (ifk) is an uncommon diagnosis, occasionally issued by the dermatopathologist. it refers to a benign tumor that typically originates on the face, with middle-aged men affected twice as often as females [1]. clinically, ifk is described as a tan or pink papule. the clinician will frequently diagnose the lesion as a verruca vulgaris or irritated seborrheic keratosis, with a differential diagnosis of squamous cell carcinoma (scc) and basal cell carcinoma [2]. many dermatopathologists are of the opinion that ifk actually represents an endophytic, follicularly oriented seborrheic keratosis or verruca [3]. armengot-carbo et al describe the dermoscopic findings in ifk as radial peripheral hairpin vessels surrounded by a whitish halo arranged around a central white-yellowish amorphous area [2]. histopathologically, ifk has been described as an exo-endophytic proliferation of keratinocytes that is sharply circumscribed; the proliferation has a lobular arrangement showing basaloid cells at the periphery and keratinocytes with more squamous differentiation at the center. some of the keratinocytes form concentric configurations termed “squamous eddies.” hyperand/ reflectance confocal microscopy of an inverted follicular keratosis mimicking a squamous cell carcinoma sarah hocker1, harold s. rabinovitz2, margaret oliviero2, jane grant-kels3, alon scope4 1 skin and cancer associates, plantation, fl, usa 2 department of dermatology, university of miami miller school of medicine, miami, fl, usa 3 department of dermatology, university of connecticut, farmington, ct, usa 4 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel key words: dermoscopy, inverted follicular keratosis, squamous cell carcinoma, reflectance confocal microscopy citation: hocker s, rabinovitz hs, oliviero m, grant-kels j, scope a. reflectance confocal microscopy of an inverted follicular keratosis mimicking a squamous cell carcinoma. dermatol pract concept 2017;7(4):39-42. doi: https://doi.org/10.5826/dpc.0704a09 received: march 31, 2017; accepted: june 26, 2017; published: october 31, 2017 copyright: ©2017 hocker et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: harold s. rabinovitz, md, and margaret oliviero, arnp, msn, are clinical investigators for caliber i.d. all authors have contributed significantly to this publication. corresponding author: sarah hocker, do, skin and cancer associates, 201 nw 82nd ave, ste 103, plantation fl 33324, usa. email: s.n.hocker@gmail.com distinguishing between benign and malignant neoplasms of the skin is a daily challenge to dermatologists. with the use of a dermatoscope and other imaging devices, the diagnosis is often more precise. the confocal microscope is a device that uses a near-infrared laser to perform noninvasive imaging of the skin. the benefit is that the images immediately provide additional, cellular-level information that can assist in diagnosis. however, lesions may share overlapping characteristics on confocal microscopy, and hence, benign lesions can still display confocal features concerning for a cancerous process, justifying a biopsy. here, we present a case of an inverted follicular keratosis imitating a squamous cell carcinoma on confocal microscopy. abstract 40 observation | dermatol pract concept 2017;7(4):9 the differential diagnosis included scc, irritated seborrheic keratosis, and verruca vulgaris. rcm imaging of the lesion demonstrated an overall lobular arrangement of the epidermis. at closer examination, there was an irregular honeycomb pattern of the granular and spinous layers, with variability in the brightness and thickness of the lines and size of the holes composing the honeycomb. the corneal layer did not display a thick scale or parakeratosis. the dermal papillae were well demarcated and occasionally showed edged papillae and some bright dots (compatible with inflammatory cells) (figure 3a, b). an area showed widening of the interpapillary spaces, consistent with acanthosis. the rcm findings were equivocal—the irregularity of the honeycomb pattern raised concern for scc, while the lack of scale/parakeratosis did not support that diagnosis. to reach a definitive diagnosis, a biopsy was performed. histopathology revealed exo-endophytic epidermal hyperplasia, with hyperkeratosis, hypergranulosis, and a slightly disorganized and crowded proliferation of basaloid and squamous keratinocytes with occasional squamous eddies. in the underlying papillary dermis, the blood vessels were dilated and tortuous. (figure 4a, b, c). the dermatopathologist’s diagnosis was ifk. comment controversy exists regarding the recognition of ifk as a distinct entity, or a variant of verruca vulgaris or irritated seborrheic keratosis. herein, we presented a case of an isolated lesion on the right forearm that mimicked a scc with rcm examination. weedon posited that the endophytic portion of ifks helps to differentiate between ifks and seborrheic keratoses and that human papillomavirus is not identified in most cases of ifk [5]. in contrast, ackerman concluded that, “inverted follicular keratosis is a resolving verruca vulgaris usually positioned on a face and associated with squamous or parakeratosis can also be seen [4]. reflectance confocal microscopy (rcm) features of ifk have been previously described by armengot-carbo et al. these include epidermal projections, broadened honeycomb pattern, disarranged dermoepidermal junction, and looped vessels in the dermis [2]. the authors added that these findings could also be observed in other lesions, such as scc. herein, we present the dermoscopic and rcm features of a single forearm lesion that was diagnosed by the pathologist as ifk. report of a case a 43-year-old male presented to the clinic for an evaluation of an isolated lesion on the right forearm, which he had noted three weeks prior. clinically, this was a 7 mm pink to erythematous papule with a verrucous surface (figure 1a, b). dermoscopy revealed a lobular arrangement with multiple ridges and fissures, whereby lobules were white with central coiled vessels or twisted-loop vessels (figure 2). figure 1a. clinical photograph demonstrating a red papule on the right volar forearm near the antecubital fossa. [copyright: ©2017 hocker et al.] figure 1b. clinical close-up photograph showing a 7 mm red papule. [copyright: ©2017 hocker et al.] figure 2. contact non-polarized dermoscopy demonstrating hairpin vessels surrounded by a white structureless area. [copyright: ©2017 hocker et al.] observation | dermatol pract concept 2017;7(4):9 41 eddies” [6]. he also wrote that human papillomavirus has been demonstrated in ifk. based on the clinical and dermoscopic appearance of our case, we believe this case diagnosed as ifk may actually represent an irritated seborrheic keratosis. while the rcm pattern observed in this lesion can also be seen in an irritated seborrheic keratosis, the irregularity of the honeycomb pattern posed a diagnostic pitfall that required a biopsy to exclude scc. references 1. bolognia jl, jorizzo jl, rapini rp. benign epidermal tumors and proliferations. in: bolognia j, jorizzo jl, rapini rp, et al. dermatology. 2nd ed. london: mosby elsevier; 2008:1666. 2. armengot-carbo m, abrego a, gonzalez t, et al. inverted follicular keratosis: dermoscopic and reflectance confocal microscopic features. dermatology. 2013;24;227(1):62–66. figure 3a. rcm mosaic (1.5 x 1.5 mm2) at the spinous and granular layers displaying an irregular honeycomb pattern. [copyright: ©2017 hocker et al.] figure 3b. rcm image (1x1mm2) at the dermo-epidermal junction showing bright-edged papillae. an irregular honeycomb pattern was identified in the adjacent spinous layer. [copyright: ©2017 hocker et al.] figure 4a. histopathology image at scanning magnification revealing an exo-endophytic epidermal proliferation. [copyright: ©2017 hocker et al.] figure 4b. histopathology image at higher magnification demonstrating an acanthothic epidermis with slight squamous disarray, squamous eddies and crowded basaloid cells. there are dilated, tortuous vessels in the dermal papillae. [copyright: ©2017 hocker et al.] figure 4c. histopathology image at higher magnification showing squamous eddies, dyskeratotic keratinoyctes, and a predominantly lymphocytic inflammatory infiltrate. (a, b, and c, hematoxylineosin stain.) [copyright: ©2017 hocker et al.] 42 observation | dermatol pract concept 2017;7(4):9 5. weedon d, strutton g, rubin ai. tumors of cutaneous appendages. in: weedon d, strutton g, rubin ai. weedon’s skin pathology. edinburgh: churchill livingstone/elsevier; 2010:765-766. 6. ackerman ab. inverted follicular keratosis, tricholemmoma, and desmoplastic tricholemmoma? in: resolving quandaries in dermatology, pathology & dermatopathology. volume ii. new york, ny: ardor scribendi, ltd., 2003 3. spielvogel rl, austin c, ackerman ab. inverted follicular keratosis is not a specific keratosis but a verruca vulgaris (or seborrheic keratosis with squamous eddies. am j dermatopathol. 1983;5(5):427442. 4. azzopardi jg, laurini r. inverted follicular keratosis. j clin pathol. 1975;28(6):465-471. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):14 225 dermatology practical & conceptual introduction owing to a somatic nras mutation at the stage of neural crest formation, patients with congenital melanocytic nevi (cmn) may have coexisting central nervous system (cns) abnormalities. this risk of cns abnormalities is higher in cmn with multiple satellite nevi [1]. frequent cns abnormalities include melanin deposits, melanocytic proliferations (neurocutaneous melanocytosis [ncm]), dandy-walker malformation, and spinal or cranial arachnoid cysts. moreover, cmn with a diameter >40 cm projected adult size are classified as giant congenital melanocytic nevi (gcmn) and carry an increased melanoma lifetime risk. case presentation we report a 33-year-old male patient with a gcmn covering his lower trunk and upper legs accompanied by large numbers of disseminated and partially hypertrichotic “satellite” nevi (figure 1, a-d). there was a history of seizures at the age of 3 years, but no medical reports were available. the patient’s current neurological status was unremarkable. magnetic resonance imaging (mri) scans of the brain and spinal cord revealed a large arachnoid cyst in the posterior cranial fossa (figure 1, e-g). the cerebellum appeared compressed but no structural aberrations suggestive of a dandy-walker malformation were found (figure 1, e-g). the brain parenchyma and leptomeninges showed no melanocytic proliferations. we scheduled the patient for dermatological examinations every 6 months including sequential total body imaging, dermoscopy, and palpation of skin and lymph nodes. we recommended follow-up mri scans of the brain and spine at 2-year intervals to monitor the arachnoid cyst and to detect any new cns abnormalities. the patient was instructed to present immediately in case of any new neurological symptoms. conclusions cns involvement in cmn was termed neurocutaneous melanocytosis (ncm) and has long been assigned an unfavorable prognosis. recent observations showed a dichotomy between “classic” ncm (showing widespread leptomeningeal involvement) and other cns manifestations, including focal melanin deposits of the brain parenchyma and cysts [1]. importantly, giant congenital melanocytic nevus accompanied by an intracranial arachnoid cyst sara dusel1, nina trenkler1, christine fink1, ferdinand toberer1, sven krengel2, alexander enk,1 holger a. haenssle1 1 department of dermatology, venerology, and allergology; university medical center, ruprecht-karls university, heidelberg, germany 2 dermatologische gemeinschaftspraxis, lubeck, germany key words: giant congenital melanocytic nevus, arachnoid cyst, neurocutaneous melanocytosis, melanoma risk citation: dusel s, trenkler n, fink c, toberer f, krengel s, enk a, haenssle ha. giant congenital melanocytic nevus accompanied by an intracranial arachnoid cyst. dermatol pract concept. 2019;9(3):225-227. doi: https://doi.org/10.5826/dpc.0903a14 accepted: february 8, 2019; published: july 31, 2019 copyright: ©2019 dusel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: holger a. haenssle, md, department of dermatology, venerology and allergology, university medical center, ruprecht-karls-university, im neuenheimer feld 440, 69120 heidelberg, germany. email: holger.haenssle@med.uni-heidelberg.de 226 letter | dermatol pract concept 2019;9(3):14 brospinal fluid resorption pathways, resulting in the formation of posterior fossa or spinal arachnoid cysts. table 1 lists previous publications reporting the rare association of gcmn with or without ncm and cerebral or spinal arachnoid cysts. however, in our patient mri scans revealed no melanocytic in the case of “classic” ncm the risk of severe complications is considerably higher. arachnoid cysts are frequent incidental findings in cns imaging and for the most part do not require any medical intervention. it has been hypothesized that leptomeningeal melanosis may interfere with the formation of cerefigure 1. clinical presentation and mri scans of the brain. the lower trunk and both upper legs are covered by a gcmn (a). a second large melanocytic lesion is situated on the thoracic posterior midline (b). many accompanying heterogeneous, partially hypertrichotic and nodular “satellite” nevi are spread over the whole body (c, d). sagittal t1-weighted magnetization-prepared rapid gradient-echo (mp-rage) mri of the brain revealed a large arachnoid cyst in the posterior cranial fossa (e). axial t1-weighted mp-rage mri scan of the brain (f) and axial t2-weighted turbo spin-echo (tse) mri of the brain (g) showed compression of the cerebellum but no structural aberrations. [copyright: ©2019 dusel et al.] a c e b d f g table 1 author, year [reference] observation frieden et al, 1994 [2] case series of 20 neurologically asymptomatic patients with gcmn; brain abnormalities in 9 patients, 1-month-old girl without ncm but left middle cranial fossa arachnoid cyst foster et al, 2001 [3] case series of 46 neurologically asymptomatic patients with gcmn; brain abnormalities in 14 patients, 1 patient without signs of ncm by mri but middle cranial fossa arachnoid cyst holmes et al, 2001 [4] 43-year-old woman with gcmn and increasing thoracic pain, mri without signs of ncm but spinal arachnoid cyst acosta et al, 2005 [5] 5-month-old girl, gcmn, ncm, symptomatic hydrocephalus, spinal arachnoid cyst ramaswamy et al 2012 [6] case series of 14 patients with gcmn and ncm; 3 patients had extensive dorsal spinal arachnoid cysts letter | dermatol pract concept 2019;9(3):14 227 deposits of leptomeninges [2-6]. further studies are needed to establish whether there is a true pathogenic association between gcmn and arachnoid cysts. in a large, prospective cohort published by kinsler et al [7], the risk of melanoma (cns or cutaneous) was 12% in the group of children with an abnormal baseline mri, compared with 2% in those with an unremarkable mri. when stratified according to the largest diameter of the cutaneous nevus, the melanoma risk was 8% for cmn >60 cm and 1% for cmn of all other sizes. mri screening is justified in infants with cmn >40 cm in diameter and/or >20 satellite nevi at birth. the clinical management of cmn patients with symptomatic cns abnormalities includes neurosurgery, anticonvulsant therapy, and shunt placement in cases of increased intracranial pressure. in general, problematic melanocytic lesions in children include large congenital nevi and spitz nevi that may be viewed as either potential melanoma precursors or melanoma simulators, respectively [8]. recommendations for management of the cmn and satellite nevi itself should incorporate the risk of malignant transformation as well as psychological implications of any disfigurement. because of the limited benefit of any prophylactic excisions for melanoma prevention, dermatological follow-up examinations alone are a valuable option in many cases. references 1. waelchli r, aylett se, atherton dj, thompson dj, chong wk, kinsler va. classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies magnetic resonance imaging as the best predictor of clinical outcome. br j dermatol. 2015;173(3):739-750. 2. frieden ij, williams ml, barkovich aj. giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. j am acad dermatol. 1994;31(3):423-429. 3. foster rd, williams ml, barkovich aj, hoffman wy, mathes sj, frieden ij. giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children. plast reconstr surg. 2001;107(4):933-941. 4. holmes g, wines n, ryman w. giant congenital melanocytic naevus and symptomatic thoracic arachnoid cyst. australas j dermatol. 2001;42:124-128. 5. acosta fl jr, binder dk, barkovich aj, frieden ij, gupta n. neurocutaneous melanosis presenting with hydrocephalus: case report and review of the literature. j neurosurg. 2005;102(1 suppl):96-100. 6. ramaswamy v, delaney h, haque s, marghoob a, khakoo y. spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. dev med child neurol. 2012;54(6):563-568. 7. kinsler va, o’hare p, bulstrode n, et al. melanoma in congenital melanocytic naevi. br j dermatol. 2017;176(5):1131-1143. 8. moscarella e, piccolo v, argenziano g, et al. problematic lesions in children. dermatol clin. 2013;31(4):535-547. dermatology: practical and conceptual observation | dermatol pract concept 2018;8(3):5 177 dermatology practical & conceptual www.derm101.com an eruption of yellow-red papules on the trunk, arms, and legs of an adult l. claire hollins1, grace w. weyant2, mark b. gibbs3, elizabeth v. seiverling1,4 1 department of dermatology, penn state health, milton s. hershey medical center, hershey, pa, usa 2 department of pathology, lancaster general health, lancaster, pa, usa 3 lebanon va medical center, lebanon, pa, usa 4 department of family and community medicine, penn state health, milton s. hershey medical center, hershey, pa, usa key words: dermoscopy, eruptive adult xanthogranuloma, xanthogranuloma, setting sun sign citation: hollins lc, weyant gw, gibbs mb, seiverling ev. an eruption of yellow-red papules on the trunk, arms, and legs of an adult. dermatol pract concept. 2018;8(3):177-179. doi: https://doi.org/10.5826/dpc.0803a05 received: december 14, 2017; accepted: february 26, 2018; published: july 31, 2018 copyright: ©2018 hollins et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: l. claire hollins, md, 500 university drive, suite 100, hershey, pa 17033 usa. email: lhollins@pennstatehealth. psu.edu. case presentation a 68-year-old caucasian man presented with a 6-month history of firm skin papules, starting on his face then gradually moving caudally, progressing to his arms, trunk, and legs (figure 1). many of his lesions were asymptomatic. however, a few of the papules were pruritic. the itching was alleviated by topical steroids. on physical exam, multiple yellow-brown to red firm papules and small nodules were noted on the face, trunk, and proximal extremities. dermoscopic examination demonstrated orange-yellow color surrounded by an erythematous border with occasional linear branched vessels (figure 2). histopathologic evaluation of 4 of the lesions revealed spindle cells in the upper dermis (figure 3). all 4 specimens had similar findings. immunohistochemical studies showed positivity for cd163, as well as factor xiiia. there was no significant positivity for cd34. laboratory data revealed a hemoglobin a1c of 9.3% and triglycerides of 461 mg/dl. an ophthalmology consult was obtained and no ocular pathology was found. a serum protein electrophoresis was negative. with this information, a diagnosis of adult eruptive xanthogranulomas was made. discussion a xanthogranuloma (xg) is a type of non-langerhans cell histiocytosis that most commonly presents in infancy and childhood; however, several cases have been described in adults. xanthogranulomas present as dome-shaped papules or nodules on the skin. the condition typically presents with a solitary yellow to reddish-brown growth. however, several cases have been described of eruptive xgs in adults, or adult xanthogranulomas (axgs) [1-3]. the differential diagnosis of xgs is extensive and is based on clinical appearance, associated comorbidities, histology, and immunohistochemistry. given the patient’s elevated hg a1c, eruptive xanthomas (exs) were considered. in addition to diabetes mellitus, exs 178 observation | dermatol pract concept 2018;8(3):5 axg. to rule out nxgs, a serum protein electrophoresis was ordered and found to be negative for monoclonal gammopathy. additionally, while nxg can be seen on the trunk and extremities, it is typically seen primarily in the periorbital region, and our patient had papules over his trunk and are associated with dramatically increased low-density lipoprotein (ldl) levels and hypertriglyceridemia. our patient had ldl levels around 100 at the time of biopsy. his triglycerides were only moderately elevated at 461 mg/dl, whereas serum triglyceride levels typically exceed 1500 to 2000 mg/ dl in ex, leading us to favor other diagnoses. two other diagnoses included in the differential are necrobiotic xanthogranulomas (nxgs) and progressive nodular histiocytosis (pnh), both of which can mimic eruptive figure  2. the “setting sun” sign of an adult xanthogranuloma on dermoscopy. [copyright: ©2018 hollins et al.] figure  3. dermal proliferation of predominantly spindle-shaped histiocytes (hematoxylin and eosin [h&e] staining ×100). inset: foamy histiocytes and touton giant cells are also present (h&e ×400). [copyright: ©2018 hollins et al.] figure 1. yellow-red papules on the face, right arm, and trunk. [copyright: ©2018 hollins et al.] observation | dermatol pract concept 2018;8(3):5 179 also have clouds of pale yellow dispersed through the papule (figure 1). in one study, 90.9% of confirmed xgs had this “setting sun” finding [5]. if suspicion is still high for a bcc, look for other findings of bcc such as leaf-like structures, blue-gray ovoid nests or globules, spoke-wheel structures, shiny white areas, or ulceration. conclusions our case represents the somewhat rare diagnosis of axg. the diagnosis was suspected based on dermoscopy and clinical morphology and was confirmed by histopathology (and laboratory ruled out other, similar diagnoses). xgs will usually resolve in children, while only approximately half of adult xgs regress [1]. our patient was treated with shave removal of symptomatic xgs with good results; however, isotretinoin can also be used, with possible recurrence of lesions with discontinuation. currently, the etiology of axg in otherwise healthy adults is unclear. dermoscopy can help with diagnosis and will show a characteristic yellow-orange hue, called the “setting sun” sign, and is sometimes accompanied by linear, branched vessels around the border (figure 4). this can be reassuring to both patients and physicians to help rule out skin carcinoma in which the color is not yellow and vessels tend to arborize across the lesion. finally, while most cases of adult eruptive xgs are idiopathic, reports have linked them with hematologic and rarely solid organ malignancy; therefore, close monitoring of patients with eruptive axgs is warranted [6]. references 1. saad n, skowron f, dalle s, forestier jy, balme b, thomas l. multiple adult xanthogranuloma: case report and literature review. dermatology. 2006;212(1):73-76. doi: 10.1159/000089027. 2. chang se, cho s, choi jc, et al. clinicohistopathologic comparison of adult type and juvenile type xanthogranulomas in korea. j dermatol. 2001;28(8):413-418. doi: 10.1111/j.1346-8138.2001. tb00002.x. 3. whitmore se. multiple xanthogranulomas in an adult: case report and literature review. br j dermatol. 1992;127(2):177-181. doi: 10.1111/j.1365-2133.1992.tb08053.x. 4. lovato l, salerni g, puig s, carrera c, palou j, malvehy j. adult xanthogranuloma mimicking basal cell carcinoma: dermoscopy, reflectance confocal microscopy and pathological correlation. dermatology. 2010;220(1):66-70. doi: 10.1159/000264670. 5. song m, kim sh, jung ds, ko hc, kwon ks, kim mb. structural correlations between dermoscopic and histopathological features of juvenile xanthogranuloma. j eur acad dermatol venereol. 2011;25(3):259-263. doi: 10.1111/j.1468-3083.2010.03819.x. 6. vadeboncoeur s, provost n. multiple xanthogranulomas in an adult: known entity, new association. j cutan med surg. 2016;20(5):474-477. doi: 10.1177/1203475416640795. extremities, in addition to his face. histopathology was also not consistent with nxg. finally, nxg can have ocular involvement, which we ruled out with an ophthalmologic examination. pnh was thought to be a less likely diagnosis, given the clinical features that are usually seen with this disease, such as facies leonina, and its progressive nature. our patient has normal facies and to date has not experienced progression of the disease, but will continue to be monitored. finally, generalized eruptive histiocytosis was also on the differential as a type of symmetric papular eruption of the skin on the trunk and proximal extremities. however, this diagnosis was less likely given the histopathologic findings. our patient had multiple foamy spindle-shaped histiocytes and touton giant cells. we favored the diagnosis of eruptive axgs, described previously as the presence of more than 5 yellowish papules and nodules over the body [2]. axg usually occurs in men, at a ratio of 1.6:1, and more than 90% of the time, the lesions are found on the trunk, followed by the head and neck. it has been reported on the extremities, albeit rarely. the demographic fits our patient well, and the biopsied specimen confirms the diagnosis of axg. because xg in adults is uncommon, the diagnosis might not be immediately obvious. dermoscopy can be employed to help differentiate it from other diagnoses on the differential, such basal cell carcinoma or sebaceous hyperplasia [4]. on dermoscopy, xgs, particularly the juvenile type, have been described as looking like a “setting sun” [5]. this orangeyellow color is not typical of the yellow “popcorn” appearance of sebaceous hyperplasia. the vessels in sebaceous hyperplasia also differ from xgs. sebaceous hyperplasia has crown vessels [4]. furthermore, xgs may have what look like arborizing vessels, as seen in basal cell skin cancer. however, xgs will have a more yellow-orange hue on dermoscopy than one might find in a basal cell carcinoma (bcc) and may figure 4. linear, branched vessels on the edge may mimic basal cell carcinoma on dermoscopy. [copyright: ©2018 hollins et al.] dermatology: practical and conceptual book review | dermatol pract concept 2014;4(4):17 79 dermatology practical & conceptual www.derm101.com review by françois milette lorenzo cerroni is the sole author of the fourth edition of this wonderful book on a most difficult, complex and confusing subject: cutaneous lymphoma. the former three editions were co-authored by helmut kerl, who recently retired, and kevin gatter, who now focuses on his work on bone marrow diagnosis. i do not doubt for a single second that dr. cerroni’s task has been, as stated by him, “herculean.” the book is remarkably organized and presented. its reading is easy and its iconography outstanding, both clinically and histopathologically. it is very “user friendly,” its size being reasonable (425 pages). most of all (and this is the main reason for buying a book!) it is easily, efficiently and usefully consulted when one is facing a difficult case. for many years i have used regularly the former editions of this guide and i am certain i will continue to use this new edition for many more years. last and not least, many chapters are supplemented with very instructive teaching cases that illustrate the never overestimated importance of clinico-pathological correlations and of open-mindedness in dealing with cutaneous lymphomas. the structure of cerroni’s book is similar to that of the preceding editions. the various lesions are grouped under the following headings: (1) nk/t-cell lymphomas, (2) b-cell lymphomas, (3) lymphomas in immunosuppressed individuals, (4) leukemias and precursor hematologic neoplasms, (5) hodgkin’s lymphoma, (6) lymphomas in children and adolescents, (7) pseudolymphomas and (8) “atypical lymphoid review: skin lymphoma. the illustrated guide, 4th edition, by lorenzo cerroni françois milette1 1 centre hospitalier pierre-boucher, longueuil, canada citation: milette f. review: skin lymphoma. the illustrated guide, 4th edition, by lorenzo cerroni. dermatol pract concept. 2014;4(4):17. http://dx.doi.org/10.5826/dpc.0404a17 copyright: ©2014 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: françois milette, md, centre hospitalier pierre-boucher, longueuil, québec, canada. email: francois.milette@ cssspb.qc.ca figure 1. cerroni l. skin lymphoma. the illustrated guide. 4th ed. wiley-blackwell 2014. isbn 978-1-118-492499. 425 pages. $219.95 proliferation.” in this last section, neoplasms and lesions hard to categorize are discussed. these neoplasms either do not fit into a defined category or their benignancy/malignancy is undecidable. although this classification is not entirely coherent, being based sometimes on histological, sometimes on clinical, sometimes on prognostic data, it certainly has some pertinence in relation with day-to-day practice. the subtle differences between the table of content of this new edition and that of the third edition illustrate well the subjectivity of any classification. for example, intravascular large cell lymphomas of the b, t and cd30 lineages are included in section 2 on b-cell lymphomas, whereas in the third edition they were classified, together with lymphomas in immunosuppressed individuals, in section 3 devoted to “other cutaneous lymphomas” (a section that no longer exists, having been replaced by a new section 3 devoted to 80 book review | dermatol pract concept 2014;4(4):17 lymphomas [b-cell and t-cell] developed in immunosuppressed individuals). for these types of lymphomas, the intravascular ones, vascular dissemination of cells was considered determinant of their conceptualization. perhaps, in a later edition, these intravascular variants will be redeployed in the sections corresponding to their cell types. as coauthor of a book on a single type of cutaneous lymphoma [1] and detractor of imprecision in language, i know well how difficult it is to bring order of any kind in the confused and controversial field of cutaneous lymphomas. these conceptual problems are admitted by dr. cerroni, as he recognized the existence of “a grey zone between clearly benign and clearly malignant neoplasms, a cloudy area where conventional definitions and criteria do not always work.” everybody would admit the existence of these cloudy areas and grey zone, but it is no reason to accept definitions that are non-definitions, definitions that defy understanding, such as the following definition of “indolent cd8+ lymphoid proliferation of the ear (face)” (page 166): a cd8+/ cd4variant of cd4+ small-medium t-cell lymphoma that is not confined to the ears or face! there is a name for such a statement: oxymoron. and what should one think of this “definition” of mycosis fungoides to be found on page 11: mycosis fungoides is the most common type of cutaneous lymphoma, representing almost 50% of all lymphomas arising primarily in the skin. it is defined as [emphasis mine] a tumor composed of small/ medium-sized, epidermotropic t-helper lymphocytes (but t-cytotoxic variants are not uncommon and tumor cells may be medium/large in advanced stages). after comparing this definition with that proposed in our opus [1], the reader is invited to conclude: mycosis fungoides is a disease systemic from the outset, neoplastic, malignant, composed of t-lymphocytes (i.e.: a lymphoma) with affinity special to the skin, with presentation protean, clinically, histopathologically, and biologically, of cause unknown. although our definition can be and has been criticized as overly inclusive, the protean character of mycosis fungoides is acknowledge by dr. cerroni, who lists the following variants of mf, clinical and histological: parapsoriasis, folliculotropic (with or without follicular mucinosis), syringotropic, localized pagetoid, unilesional, granulomatous, slack skin, erythrodermic, interstitial, poikilodermic, hypopigmented, hyperpigmented, purpuric, papular, bullous, anetodermic, pleva-like, “invisible,” etc. incidently, one should rejoice since it is clearly admitted at last (pages 34-35) that parapsoriasis, be it of the small or large plaque type, is mycosis fungoides even though the author continues to insist on the fact that “regardless of the academic discussion, it is important to underline that patients with small plaque parapsoriasis should not be aggressively treated.” this is evident and true not only for small-plaque parapsoriasis but also for any clinically indolent lymphoma, even for any indolent neoplasm of any type. where is the limit to the protean character of mf to be set? considering unilesional t-cell lymphoma, for instance, is it justified, as does cerroni, to subdivide it into (1) pagetoid reticulosis (with massive epidermotropism), (2) cd4+ small and medium t-cell lymphoma (with very little or no epidermotropism and diffuse dermal infiltration), (3) “genuine” unilesional mf (defined clinically), and (4) solitary mf with large cell transformation (teaching case 2.2, page 63), a supposedly “worrying feature” even if the patient remains in complete remission, one year after treatment? and is it reasonable to exclude from the spectrum of mf the leukemic variant of it (sézary syndrome) on the basis of the presence of more than 1,000 malignant circulating cells per cubic millimeter of blood and of purportedly specific molecular characteristics? isn’t it very probable that such molecular or genetic changes exist for each and every variant accepted as parts of the spectrum of mf? if one insists on genetic profiling of tumors, isn’t it to be feared that there will soon be as many lymphomas as there are patients harboring lymphomas? these questions merit reflection. many other concepts addressed in this otherwise wonderful book could be discussed at length, but that would clearly take us beyond the limits of a book review. as a conclusion, i would say that although this book continues to be plagued with some of the conceptual weaknesses surrounding the study of cutaneous lymphoma, it is a very good book and its author cannot be held responsible for all the “tossed salads of words” that for years have been feeding the minds of hematopathologists in search of, not proper diagnosis, but of precise prognostication. in a word, i warmly recommend this book that deals exhaustively with a very difficult subject. it can be very useful on a day-to-day basis but certainly has to be read with discernment. reference 1. ackerman ab, denianke k, sceppa j, asgari m, milette f, sanchez j. mycosis fungoides: perspective historical allied with critique methodical for the purpose of illumination maximal. atlas and text. new york: ardor scribend, ltd., 2008. untitled review | dermatol pract concept 2015;5(3):1 1 dermatology practical & conceptual www.derm101.com the compendium (part 9) – t – target lesions: papules or plaques consisting of concentric rings that display shades of red, among them dusky erythema; named for the marksman’s target. the lesions are virtually pathognomonic of erythema multiforme. tbse: the abbreviation for the total body skin examination. this exam of patients, performed by dermatologists is requested by all the major skin (i.e., aad, etc.) and skin cancer organizations (acs, scf, etc.) however, only 30% of dermatologists actually perform them routinely according to a recent article in the melanoma letter in 2007. in fact most dermatologists examine patients only for their chief complaint. hopefully, someday this exam combined with the skin self exam of the total body and including the genitalia (i.e. vagina, penis, and anus) and the “folds” in the genital area, at intervals, will become routine. some dermatologists include the genitalia and the folds of the genital area in the tbse. others stress that the patient do it as part of the self-exam or have other physicians do this part instead. (i.e., ob-gyn) considering the objections to the genital exam in the female, self-exams or “other doctor’s” exam may be “better,” though not “ideal,” it screens a much larger number of patients in a “regular” practice. telangiectasia: a condition typified by abnormal, permanent dilation of venules mainly but also, at times, of capillaries and arterioles. telangiectases may be a manifestation of an inflammatory process, such as rosacea, a noninflammatory process, such as a neoplasm, i.e., nodular trichoblastic (basal cell) carcinoma, and a degenerative process, such as skin injured severely by ultraviolet light. telangiectasia may be a sign of specific diseases such as acrosclerosis, a form of mastocytosis (telangiectasia macularis eruptiva perstans), or osler-weber-rendu syndrome (hereditary hemorrhagic telangiectasia). telangiectasia is an essential component of poikiloderma, i.e., atrophy, hyperpigmentation and hypopigmentation, and telangiectasia. histopathologically, telangiectasia is manifested usually as widely dilated venules in the upper part of the dermis of a variety of conditions that are representations of virtually every fundamental type of pathologic process in skin. telangiectasis: a dilated end of a vessel, usually a dilated capillary and venule. telogen: a period of duration intermediate in which a follicle, having involuted completely, comes to a standstill and rests, leaving only an isthmus at the base of which are undifferentiated cells residual of the lower segment and that will serve as ones germinative at the outset once again of anagen. terminal follicle: designates a hair follicle with some features different from a vellus follicle, namely, it is wider, longer, and seated deeper, often in the subcutaneous fat, and associated with a hair that is wider, longer, and darker. terminal follicles are distributed on the scalp, axillae, and genitalia. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 9 (t-z) bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 9 (t-z). dermatol pract concept 2015;5(3):1. doi: 10.5826/dpc.0503a01 copyright: ©2015 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, md, 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@aol.com mailto:bjhookerman@aol.com 2 review | dermatol pract concept 2015;5(3):1 also appears episodically in bullous congenital ichthyosiform erythroderma and in all other conditions cutaneous characterized histopathologically by epidermolytic hyperkeratosis. tricholemmal differentiation: denotes a circumstance in which cells resemble those of the outer (tricholemmal) sheath by virtue of having; (1) pale or clear cytoplasm), those at the periphery being columnar, arranged in a palisade, and resting on a prominent basement membrane like cells of the outer sheath at the bulb do normally, or (2) abundant pink cytoplasm, like the cells of the outer sheath at the stem or the isthmus. tricholemmal differentiation at the isthmus also is typified by compact orthokeratosis, a finding constant in epithelium of a normal isthmus (and in the analogue of it, namely, the lower segment of a follicle well advanced in catagen. the pallor of cells authentic of the tricholemmal sheath and of cells with tricholemmal differentiation is attributed to abundant glycogen within their cytoplasm. tricholemmal differentiation that stimulates the outer sheath at the bulb may be found in resolving verrucae vulgaris on the face (so-called tricholemmoma); in a benign proliferation that develops rarely, in nevus sebaceous; and, in instances uncommon of trichoblastic (basal cell) carcinoma. tricholemmal differentiation that resembles the outer sheath at the isthmus is expressed in the tumor of follicular infundibulum and in pilar sheath acanthoma. all examples of so-called proliferating tricholemmal cyst and proliferating tricholemmal cystic squamous cell carcinoma are really examples of tricholemmal cystic carcinoma. this must be differentiated from proliferating tricholemmal cystic acanthoma and squamous cell carcinoma. tricholemmal sheath: describes the outer sheath of a follicle. the outer sheath courses from the base of a bulb through the stem and the isthmus to terminate at the bottom of an infundibulum. cells in the lower part (bulb) of the outer sheath are clear and pale, those in the mid portion (stem) are pink, and those in the upper part of the isthmus are slightly redder. a basement membrane observable readily is present along the length of the outer sheath. it must be stressed that the outer sheath that forms at the end of telogen, i.e., the beginning of anagen, is a product of matrical differentiation. those matrical cells come into being rapidly following the revivification of germinative cells at the base of an isthmus, they being the sole residuum of the follicle that involuted, and being the ones responsible for generating an anagen follicle anew. trichomalacia: literally means “softening of hair.” histopathologically, it means pleated hair shafts that contain clumps of melanin as a result of twisting hairs in trichotillomania. tubercle: is a term in gross pathology for potato-like structures that, on histopathologic examination are seen to consist mostly of epithelioid histiocytes. the components of terminal and vellus follicles are the same, however. this contrasts with “vellus” which denotes a puny hair follicle and situated superficially, i.e., the upper part of the reticular dermis. terminal hairs: are thick, long hairs, in contrast to thin, short vellus hairs. as a rule, vellus hairs are lighter in color than terminal ones. terminal hairs are housed in large follicles seated deep in the reticular dermis or in the subcutaneous fat, and are situated on the scalp, beard, axillae, and pubis. vellus hairs reside in small follicles located superficially in the reticular dermis. they are distributed throughout the remaining skin, except for palms, soles, clitoris, and glans penis. touton giant cells: are multinucleated histiocytic giant cells with a central dark-staining core surrounded by nuclei in a rim and a periphery of pale foamy appearance. the cells can be found in a variety of inflammatory diseases, the best known of which is juvenile xanthogranuloma. trabecula: a fibrous septum, as in the normal subcutaneous fat. trabecular: means resembling small bars that tend to interconnect, that structure being exemplified by elements epithelial of neuroendocrine (merkel cell) carcinoma (presented originally under the title “trabecular carcinoma”) and occurring episodically in various benign proliferations epithelial with adnexal differentiation. tricho-: is a prefix in greek meaning hair and is a synonym for piloin latin. the prefix is used correctly, as in trichotillomania, a condition that results from twisting and pulling hairs, but often it is used improperly when what really is intended is folliculo(e.g., in trichoepithelioma, trichoblastoma), infundibulo-, (e.g., trichoadenoma) or sebaceo(e.g., trichodiscoma). trichoblast: is a cell analogous to that in a germ of an embryo (see germ) that eventuates in the infundibularapocrine-sebaceous-follicular unit and is a synonym for “follicular germinative cell.” trichoblasts abnormal make up trichoblastoma and trichoblastic (basal cell) carcinoma. trichohyalin: refers to a granule that appears bright red when stained by hematoxylin and eosin, it being analogous to keratohyalin, a purple granule present in the upper part of epithelium epidermal and sebaceous ductal. unlike keratohyalin, however, trichohyalin is specific for the inner sheath of follicles, appearing in that sheath at the bulb in both henle’s and huxley’s layers and in the cuticle. it is as essential to cornification normal of hair as keratohyalin is to cornification normal of stratum corneum. when trichohyalin granules are noted in a proliferation, they are evidences incontrovertible of follicular (inner sheath) differentiation. trichohyalin review | dermatol pract concept 2015;5(3):1 3 tzanck smear: refers to search for acantholytic keratocytes in smears from bullae of diseases such as pemphigus vulgaris and for multinucleated keratocytes from vesicles caused by herpes viruses. – u – ulcer: loss of the entire epidermis and at least some of the dermis, sometimes even extending into the subcutis. erosion, by contrast, results from partial or total loss of the epidermis, but none of the dermis. ulcers can result from diseases such as venous insufficiency (i.e., stasis ulcer), vasculitis (i.e., erythema gangrenosum in pseudomonas septicemia), chronic infection (i.e., leishmaniasis), and neoplasms (i.e., basal-cell carcinoma). ulcers can be factitious, i.e., self-induced by caustics, sharp instruments, or a person’s own fingernails. excoriation can produce erosion or ulceration, depending on how forcefully fingernails are wielded. ecthyma is an ulcer caused usually by beta-hemolytic streptococci. ulcers, if they destroy the normal pattern of collagen bundles in the papillary dermis, heal inevitably with a scar. ultrastructure: refers to morphologic observations that cannot be achieved by conventional microscopy but necessitate the resolving power of an electron microscope. there are many examples of structures in normal or diseased skin that cannot be discerned through a conventional microscope but that can be visualized readily through an electron microscope, among them specific causative organisms of viral diseases, langerhans granules, and weibel-palade bodies. undifferentiated: means lacking differentiation entirely and refers to absence of any evidence of specialization of a proliferation as it is visualized through a microscope conventional. new methods and techniques have enabled the anonymity of some proliferations to become identifiable with specificity. for instance, what may appear by microscopy conventional to be a primary proliferation malignant and seemingly undifferentiated may turn out to be an adenocarcinoma when glandular or ductal structures are identified by electron microscopy or to be a melanoma when immunoperoxidase positivity to s-100 protein is demonstrated. unevenly psoriasiform: having elongated rete ridges of uneven length; associated with preservation of the normal undulating pattern between rete ridges and dermal papillae. urticaria: evanescent pink papule or plaque that often has pseudopods at its periphery and blanches on diascopy, i.e., viewing of the skin through a firm transparent instrument, such as a glass slide, pressed against a lesion. a true hive cannot always be differentiated clinically from a hive-like lesion, as occurs in “urticarial vasculitis” (an early, nonpurpuric, edematous papule of leukocytoclastic vasculitis), but the tuberculoid: in general pathology refers to histopathologic findings that resemble those of tuberculosis and, in cutaneous pathology, of lupus vulgaris in particular. tuberculoid granulomas also occur, for example, in tuberculoid leprosy, the recidivans expression of leishmaniasis, infections by “atypical” mycobacteria, and, uncommonly, in sarcoidosis. tubular: means “like a tube” and refers to elongated epithelial lumen containing structures present in a variety of benign and malignant proliferations. nearly always, very elongated tubules in those conditions in the skin indicate apocrine differentiation, but tubules of other lengths and characters are found in proliferations that exhibit eccrine or sebaceous differentiation. prominent papillations within tubules also signify apocrine differentiation. tubule: in general denotes tiny hollow cylinders that convey a fluid or that functions as a passage. in histopathology, it indicates ductal and/or glandular differentiation in an organ or a proliferation. when a lumen is formed by cells and a histopathologist is unable to identify that structure as either ductal or glandular, the generic term “tubule” may be applied. epithelial neoplasms that form tubules are named adenomas when they are benign and adenocarcinomas when they are malignant. in skin, tubular differentiation of primary neoplasms may be sebaceous ductal, apocrine glandular or ductal, and eccrine glandular or ductal. in skin a tubule cornifying lined by stratified squamous epithelium is sebaceous ductal and one lined by cells that exhibit “decapitation secretion” is apocrine glandular. tumid: means swollen and is used for example to describe a form of discoid lupus erythematosus in which clinically there are indurate reddish plaques with no scales, follicular plugs, or signs of atrophy. histopathologically, there are no changes in the epidermis or at the dermo-epidermal interface in the tumid form of discoid lupus erythematosus only a perivascular lymphocytic infiltrate accompanied by abundant mucin within the reticular dermis. tumor: means a swelling and in dermatology has both implications clinical and histopathologic. in clinical dermatology, tumor denotes a solid protuberance more than 2.0 cm in greatest diameter, a nodule being a smaller version that measures no more than 2.0 cm in diameter and a papule being an even smaller analogue that is less than 1.0cm in diameter. a tumor may be comprised mostly of cells, such as in a carcinoma, of bundles of collagen, such as in a neurofibroma, or of deposits specific, such as of urates in a tophus of gout. in histopathology, the term tumor is used as a synonym for neoplasm, but that leads to the silly designation “tumor cells.” in short, there is a place proper for the word “tumor” clinically, but not for it histopathologically. 4 review | dermatol pract concept 2015;5(3):1 all interface dermatitides, both vacuolar and lichenoid types. in the vacuolar type of interface dermatitis, i.e., erythema multiform, vacuolar alteration is conspicuous because only a sprinkling of lymphocytes is noticeable along the dermoepidermal interface. in the lichenoid type of interface dermatitis, i.e., lichen planus, vacuolar alteration also is present, but it is overshadowed in lesions that are developed fully by a prominent band of lymphocytes that fills the upper part of the dermis and extends just beyond it, thereby obscuring the dermoepidermal junction. confluence of vacuoles in interface dermatitides may result in formation of a cleft at the dermoepidermal junction. all diseases marked by extensive vacuolar alteration may become vesicular or bullous, among those being lichen sclerosus at atrophicus, lichen planus, and erythema multiform. what constitutes the vacuoles has yet to be determined. vacuole: in the parlance of microscopy conventional refers to a small space that may be intraor extracellular. vacuoles intracellular are tiny units discrete bounded by a membrane, they serve as storage for fat, glycogen, precursors of secretions, as well as a dump for debris. that description is apt for lipid vacuoles in skin, such as in normal sebaceous cells and in lipophages, i.e., macrophages that have ingested particles of fat. vacuoles in proliferations eccrine or apocrine correspond ultrastructurally to intracellular structures glandular or ductal. they are found often in cuticular cells of poromas and, episodically in immature sebocytes of sebaceoma and sebaceous carcinomas. vacuoles extracellular are seen in inflammatory diseases of the interface type in which lymphocytes especially, obscure the dermo-epidermal junction either in the form of infiltrates sparse (vacuolar type) or of one dense and band-like (lichenoid type). vacuoles in interface dermatitis seem to form on either side of the epidermal (surface and infundibular) basement membrane, i.e., in the basal layer and in the uppermost part of the papillary dermis. changes similar may occur along the interface between the upper part of the eccrine dermal duct and the dermis. vacuoles in a ring: is descriptive of the small clear spaces that separate the inner margin of a tubule from homogenous pink material secretory housed in the lumen of it, the material having an outline scalloped by virtue of the indentation of it by tiny spaces, they representing sites of “decapitation” secretion and the pattern itself being indicative of apocrine differentiation. vasculitis: small-vessel vasculitis, fully developed, is typified by fibrin in the wall of venules (and rarely arterioles) and/ or thrombi in the lumen of them in the context of an infiltrate of inflammatory cells. large-vessel vasculitis is characterized by inflammatory cells in the wall of a vein or artery. vasculitis must be distinguished from the inordinately more common course of the two lesions is very different; a hive is transitory, usually waning in hours, whereas a hive-like lesion tends to last for days at least. by contrast, true urtica, (denotes a single lesion) when fully developed histopathologically, shows changes that are specific for it, namely, a sparse perivascular and interstitial mixed-cell infiltrate in which lymphocytes, neutrophils, and eosinophils ring venules and neutrophils and eosinophils are scattered in the interstitium. contrariwise, so-called urticarial vasculitis exhibits stereotypical changes of leukocytoclastic vasculitis, the essential element for that diagnosis being neutrophilic nuclear “dust” in conjunction with intact neutrophils, in time, those being joined by fibrin in the wall of venules. urticarial lesions, that is, ones not those of authentic urtica, display findings histopathologic typical of the disease they are in actuality, i.e., dermatitis herpetiformis, bullous pemphigoid, and insect bites. as stated above, urtica pertains to an individual lesion of the condition known as urticaria. urticarial: describes a hive-like appearance of lesions, that is, pink, edematous papules and plaques. urticarial lesions are differentiated clinically from true hives by the tendency of them to persist for longer periods of time (days rather than hours). urticarial lesions are seen in many conditions, i.e., responses to insect bites, dermatitis herpetiformis, bullous pemphigoid, leukocytoclastic vasculitis, and early lesions of allergic contact dermatitis. biopsy of these five conditions reveals histologic changes that are diagnostic of each of them. biopsy of a lesion of true urticaria reveals a sparse perivascular and interstitial mixed-cell infiltrate containing neutrophils and eosinophils. – v – vacuolar: means characterized by, pertaining to, or being like tiny cavities. vacuoles may be seen through a conventional microscope in both normal and diseased skin. in normal skin, vacuoles are found in sebaceous cells. in pathologic states, vacuoles are present in neoplasms that show sebaceous differentiation, macrophages that have ingested lipid (foam cells), and on either side of the epidermal (surface and infundibular) basement membrane in interface dermatitides (vacuolar alteration). when along that junction the infiltrate of inflammatory cells is sparse, the interface dermatitis is designated “vacuolar type.” when, in a thickened papillary dermis, the infiltrate of inflammatory cells is dense in bandlike array, the interface dermatitis is termed “lichenoid type.” vacuolar alteration: tiny spaces on either side of a basement membrane situated at the dermoepidermal junction and at the junction of dermis and epithelial structures of adnexa. “liquefaction degeneration” is a fanciful, but inaccurate, synonym. vacuolar alteration occurs in nearly review | dermatol pract concept 2015;5(3):1 5 appearance of a verrucous lesion changes markedly in time. long-standing verrucae vulgaris on the face are not verrucous at all, but are domed papules commonly misinterpreted clinically as trichoblastic carcinomas and histopathologically as tricholemmomas (because of largely endophytic character and tricholemmal differentiation of infundibular epithelium) and as inverted follicular keratosis (because of largely endophytic character and presence of “squamous eddies” within hyperplastic infundibula). vertical growth phase: the notions of “vertical growth phase” and “radial growth phase” of melanoma are bereft conceptually and useless practically. first, “vertical” and “radial” are not contrasting. vertical is a component of radial. second, what is called the “radial growth phase” involves the epidermis and the papillary dermis, an indication that that phase, too, has a dimension vertical. third, criteria that have been offered for the purpose of distinguishing a “radial” from a “vertical” growth phase of melanoma are abstruse, highly subjective, and not workable with repeatability. in short, it is mere conjecture on the part of a histopathologist where the “radial growth phase” ends and the “vertical growth phase” begins. one criterion alleged to allow recognition of the so-called vertical growth phase is detection of an “expansile nodule” in the upper part of the dermis. both words, namely, “expansile” and “nodule,” are flawed in that setting particular. nodules, clinically and histopathologically, are large structures, yet the “nodule” of the supposed “vertical growth phase” is said to be a small collection of neoplastic melanocytes situated in the upper part of the dermis. to prove that the “nodule” is “expansile,” it would have to be measured at different points in time; nothing can be appreciated as being expansile when viewed through a microscope conventional where everything in tissue is static. last, the concept of “radial” and “vertical” growth phases is not relevant either to diagnosis of melanoma or to management of it. diagnosis of melanoma, clinical and histopathologic, is based on criteria morphologic and does not turn at all on “growth phases,” and neither does treatment proper of melanoma, which is complete excision surgical with a margin sufficient to ensure that this has been accomplished. vesicle: a small blister, i.e., one that is up to 1.0 cm in diameter. a vesicle may be intraepidermal, as in an infection by herpes virus, subepidermal, as in dermatitis herpetiformis, or both intraepidermal and subepidermal in the same section, as in erythema multiforme, fixed drug eruption, and muchahabermann disease. clinically, it often is impossible to distinguish an intraepidermal from a subepidermal vesicle. the “rule” that a subepidermal vesicle is more firmly distended than an intraepidermal vesicle is violated often, as evidenced by tense vesicles that are standard in varicella, miliaria crystallina, and an “id” reaction. moreover, a subepidermal blisperivasculitides and peri-infundibulitides / perifolliculitides. in the latter circumstances, there is neither fibrin in the wall nor thrombi within the lumen of vessels. the most common vasculitis of small vessels is leukocytoclastic vasculitis, and much less common are septic vasculitis and livedo vasculitis. vasculitis of large vessels occurs in septa of the panniculus adiposa, not the skin, and is much less common than vasculitis of small vessels, it taking the form of phlebitis and arteritis. vasculopathy: a disorder of blood vessels. the term is generic, and yet it is employed often by dermatologists and pathologists for particular kinds of disorders of blood vessels, such as vasculitis or a disease characterized by vaso-occlusion (i.e., consumptive coagulopathy) or vaso-intrusion (i.e., systemic amyloidosis). in theory, the vasculopathy is applicable equally to increase in number of vessels in a proliferation of them that involutes (i.e., pyogenic granuloma), in a benign neoplasm that does not involute (i.e., cherry hemangioma), and in a malignant neoplasm (i.e., angiosarcoma) as well as to aberrations in structure of blood vessels, such as a malformation (i.e., arteriovenous shunt), and an ectasia (i.e., osler-weber-rendu syndrome). for these reasons, there is no need ever to employ the term vasculopathy; the particular pathologic process that involves blood vessels should be identified for what it is precisely. vegetation: a heaped-up collection of scale crusts-sometimes hemorrhagic, often purulent, as occurs in pemphigus vegetans. vellus follicle: is applied to a hair follicle whence spring delicate hair that covers much of the body, i.e., the face, arms, and trunk. in contrast, a terminal follicle houses hair that is broader and longer, and found mostly on the scalp, in the axillae, and in the public region. vellus hair: is applied to fine, delicate hair found on much of the body, i.e., the face, arms, and trunk, in contrast to terminal hair, which is broader and longer, and found mostly on the scalp, in the axillae, and in the pubic region. at scanning magnification a microscopist should endeavor to determine the age of the patient by noting signs distinctive such as puny vellus hair follicles, this along with diminutive sebaceous glands situated high in the dermis is a clue that the patient is an infant. verrucous: means like a fully developed verruca, a rough, finger-shaped lesion clinically, and a digitate proliferation of epidermal (and on a face infundibular) keratocytes histopathologically. besides verrucae vulgaris, verrucous patterns may be seen in verrucous seborrheic keratoses, verrucous epidermal nevi, verrucous solar keratoses, and the surface of keratoacanthoma, verrucous carcinoma, and even verrucous lesions of psoriasis. as is true of all diseases in skin, the 6 review | dermatol pract concept 2015;5(3):1 randomly in the upper part of the dermis, often in conjunction with patchy lichenoid infiltrates of lymphocytes there. just as coarse bundles of collagen in vertical streaks indicate lichen simplex chronicus, so, too, wiry bundles of collagen in haphazard array signify, for practical purposes, mycosis fungoides at a patch/subtle plaque stage of the disease (small plaque parapsoriasis and large-plaque parapsoriasis). as always, there are exceptions; wiry bundles of collagen in haphazard array may be encountered, episodically, in other circumstances, in which band-like infiltrates of lymphocytes are longstanding, among those being the lichenoid purpura of gougerot and blum and some instances of lichen planus. – z – zone: refers to each of three morphologic and functional units in a follicular bulb, namely, matrix at the bottom, supramatrical in the middle, and keratogenous at the top. zosteriform: means the belt-like distribution of lesions along a dermatome, such as those of herpes zoster. this concludes the 9-part series from bruce j. hookerman, md, “an abridged compendium of words. a discussion of them and opinions about them”, published in this journal. ter may be flaccid, as in that severe expression of erythema multiforme, termed badly “the adult type of toxic epidermal necrolysis.” blisters, whether intraepidermal or subepidermal, house serum, which, when it ascends to the surface of the skin, takes the form of a crust. vesiculobullous: having small and large blisters, i.e., vesicles and bullae. vesiculopustule: a lesion that has features of a small blister (containing serum) and a pustule (containing innumerable neutrophils). villous: having papillated projections that resemble intestinal villi, as do the dermal papillae in pemphigus vulgaris. vitreous membrane: (see glassy membrane) – w – wickham’s striae: refer to the whitish cross-hatchings seen on the surface of some lesions of lichen planus that result from zones of more prominent hyperkeratosis above foci of wedge-shaped hypergranulosis in the epidermis. wiry bundles of collagen in haphazard array: collagen bundles that resemble wires arranged dermatology: practical and conceptual observation | dermatol pract concept 2017;7(4):4 13 dermatology practical & conceptual www.derm101.com in vivo intraoral reflectance confocal microscopy of an amalgam tattoo oriol yélamos1,2, miguel cordova1 , gary peterson1, melissa p. pulitzer3, bhuvanesh singh4, milind rajadhyaksha1, jennifer l. defazio5 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 2 dermatology department, hospital clínic, universitat de barcelona, barcelona, spain 3 pathology department, memorial sloan kettering cancer center, new york, ny, usa 4 head and neck cancer center, memorial sloan kettering cancer center, hauppauge, ny, usa 5 dermatology service, memorial sloan kettering cancer center, hauppauge, ny, usa key words: reflectance confocal microscopy, amalgam tattoo, melanoma, oral, mucosa citation: yélamos o, cordova m, peterson g, pukitzer mp, singh b, rajadhyaksha m, defazio jl. in vivo intraoral reflectance confocal microscopy of an amalgam tattoo. dermatol pract concept 2017;7(4):13-16. doi: https://doi.org/10.5826/dpc.0704a04 received: july 11, 2017; accepted: august 10, 2017; published: october 31, 2017 copyright: ©2017 yélamos et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was funded in part by nih/nci grant r01ca156773, nih/nci grant r01ca199673, nih/nibib grant r01eb020029, the nih/nci cancer center support grant p30 ca008748 and the beca excelencia fundación piel sana. competing interests/disclosures: milind rajadhyaksha is a former employee of and owns equity in caliber imaging and diagnostics (formerly lucid inc.), the company that manufactures and sells the vivascope confocal microscope. the vivascope is the commercial version of an original laboratory prototype that he had developed at massachusetts general hospital, harvard medical school. the other authors have no disclosures or conflicts of interest to report. all authors have contributed significantly to this publication. corresponding author: jennifer defazio, md, dermatology service, memorial sloan kettering cancer center, 800 veterans highway, hauppauge, ny, usa. tel. +1 631-863-5118. email: defazioj@mskcc.org introduction the majority of oral pigmentations are benign lesions such as nevi, melanotic macules, melanoacanthomas or amalgam tattoos [1,2]. conversely, mucosal melanomas are rare, but often lethal [2]. reflectance confocal microscopy (rcm) allows imaging with cellular resolution and has excellent diagnostic accuracy to diagnose cutaneous melanoma [3]. however, rcm can be challenging to perform in the oropharynx using the current probes. the majority of oral pigmentations are benign lesions such as nevi, melanotic macules, melanoacanthomas or amalgam tattoos. conversely, mucosal melanomas are rare but often lethal; therefore, excluding oral melanomas in this setting is crucial. reflectance confocal microscopy is a non-invasive, in vivo imaging system with cellular resolution that has been used to distinguish benign from malignant pigmented lesions in the skin, and more recently in the mucosa. however, lesions located posteriorly in the oral cavity are difficult to assess visually and difficult to biopsy due to their location. herein we present a patient with previous multiple melanomas presenting with an oral amalgam tattoo in the buccal mucosa, which was imaged using an intraoral telescopic probe attached to a commercially available handheld rcm. in this case report we describe this novel probe, the first rcm description of an amalgam tattoo and we discuss its differences with the findings described in oral melanomas. abstract mailto:defazioj@mskcc.org 14 observation | dermatol pract concept 2017;7(4):4 during imaging, the patient was awake and tolerated the procedure well. superficially, rcm showed an overall normal epithelium with focal areas of epithelial disarray (figure 2a, b). deeper, we identified increased vascularity (figure 2c) and numerous large dendritic cells admixed with plump cells and bright dots (figure 2d). in light of her past medical history, the lesion was biopsied to exclude a primary or metastatic melanoma. histopathologic analysis revealed fine black granular pigment within the dermis suggestive of an amalgam tattoo (figure 2e). conclusions in the last decade, rcm imaging has expanded its use beyond the skin and has been applied to the oral and genital mucosa, specifically to distinguish mucosal melanomas from benign lesions [1,6,7]. indeed, rcm features suggesting mucosal melanomas include suprabasal dendritic or large round cells, dendritic cells in the epithelial-connective tissue junction, and epithelial disarray [1,6,7]. in our case, rcm showed numerous suprabasilar dendritic cells along with epithelial disarray. however, these findings occurred focally, and we also noted numerous bright dots and plump cells suggesting a reactive lymphohistiocytic infiltrate. to better characterize these findings, immunohistochemical stains for melanocytes and langerhans cells were performed. these showed normal numbers of melanocytes within the basal and suprabasilar epithelium (figure 2f) herein we present a patient with previous multiple melanomas presenting with an oral amalgam tattoo in the buccal mucosa, which was imaged using a novel intraoral telescopic probe attached to a commercially available handheld rcm. case a woman in her 70s was referred by her dentist for a pigmented lesion on the oral mucosa. she had a history of four cutaneous melanomas —three in situ and one invasive (breslow 0.25 mm)— excised four years prior. at physical examination, she presented with a 3 mm asymptomatic bluish papule on the left buccal mucosa (figure 1a, asterisk). to evaluate this location, a handheld rcm (vivascope3000, caliber id, rochester, ny) fitted with a telescopic probe was used (figure 1b). the probe was designed to be sufficiently small (12 mm) and long (~150 mm) to allow access inside the oral cavity [4]. the probe consists of a telescope and an objective lens of numerical aperture 0.7, providing a ~0.75 x 0.75 mm field of view, ~4 μm optical sectioning and ~1 μm lateral resolution, allowing imaging to a depth of ~300 μm. enclosing the lens there is a cap with a coverslip, which provides contact to the mucosa and keeps the tissue gently flattened and still during the imaging procedure (figure 1b, arrowheads). two caps are used: a shorter cap allows for imaging in the deeper epithelium/mucosal-submucosal junction and a longer cap in the superficial lamina propria. we acquired images and videos that were converted into videomosaics [5]. figure 1. (a) clinical image of pigmented lesion located on the left buccal mucosa (asterisk). note the presence of a dental filling in the third left lower molar. (b) this lesion was imaged with a telescopic probe attached to a handheld reflectance confocal microscope. attached to the probe is a small objective lens, which is enclosed in a small cap with a coverslip (arrowhead). the approach of using caps with different lengths allows for imaging at different depths in oral tissue. [copyright: ©2017 yélamos et al.] observation | dermatol pract concept 2017;7(4):4 15 no previous studies have reported the rcm findings of amalgam tattoos. although the presence of amalgam granules may not be visible with rcm since they are located deeper than 200-300 μm, the presence of bright dots (lymphocytes) and plump cells (macrophages), with suprabasal dendritic cells, is suggestive of a reactive process, such as an amalgam tattoo. to conclude, we have presented the first case of amalgam tattoo imaged with rcm using a new telescopic probe. and numerous langerhans cells extending into the upper epithelium (figure 2g). langerhans cells are difficult to distinguish from melanocytes on rcm [8], and have a low specificity on the oral mucosa since they occur in normal mucosa and in reactive processes such as amalgam tattoos [1]. histologically amalgam tattoos reveal small granules deposited between the collagen fibers and can present with a foreign-body reaction [2]. figure 2. reflectance confocal microscopy images (panels a – d) and its histopathologic correlates (panels e – f). superficial confocal videomosaic showing normal epithelial cells with prominent nucleoli (panel a, white rectangle and inset), and a focal area of epithelial disarray (panel b). confocal videomosaic obtained at the epithelial junction showing increased vascularity (arrowheads, panel c) and an area with numerous large atypical dendritic cells (panel d). hematoxylin and eosin stain of the lesion showed fine black granular pigment within the stroma in the dermis (panel e, original magnification x 40). immunohistochemical stain for a103 showed scattered melanocytes in the basal layer and in the epidermis (panel g, original magnification x 20). immunohistochemical stain for cd1a highlighted numerous langerhans cells throughout the epidermis (panel f, original magnification x 20). [copyright: ©2017 yélamos et al.] 16 observation | dermatol pract concept 2017;7(4):4 3. pellacani g, guitera p, longo c, avramidis m, seidenari s, menzies s. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759-2765. 4. peterson g, zanoni dk, migliacci j, cordova m, rajadhyaksha m, patel s. progress in reflectance confocal microscopy for imaging oral tissues in vivo. proceedings of spie photonics west. 2016;9689. 5. kose k, cordova m, duffy m, flores es, brooks dh, rajadhyaksha m. video-mosaicing of reflectance confocal images for examination of extended areas of skin in vivo. br j dermatol. 2014;171(5):1239-1241. 6. debarbieux s, perrot jl, erfan n, et al. reflectance confocal microscopy of mucosal pigmented macules: a review of 56 cases including 10 macular melanomas. br j dermatol. 2014;170(6):12761284. 7. uribe p, collgros h, scolyer ra, menzies sw, guitera p. in vivo reflectance confocal microscopy for the diagnosis of melanoma and melanotic macules of the lip. jama dermatol. 2017. 8. hashemi p, pulitzer mp, scope a, kovalyshyn i, halpern ac, marghoob aa. langerhans cells and melanocytes share similar morphologic features under in vivo reflectance confocal microscopy: a challenge for melanoma diagnosis. j am acad dermatol. 2012;66(3):452-462. although the presence of epidermal disarray and suprabasilar dendritic cells on rcm was suggestive of melanoma, the coexisting presence of bright dots and plump cells brings into consideration the differential diagnosis a reactive process such as an amalgam tattoo. however, since the rcm features of mucosal melanomas and other mucosal conditions are limited, larger studies are needed to increase the meaning of using this new probe with high-resolution images. acknowledgements we would like to thank dr. marco ardigò for his thoughtful feedback regarding this case. references 1. maher ng, solinas a, scolyer ra, guitera p. in vivo reflectance confocal microscopy for evaluating melanoma of the lip and its differential diagnoses. oral surg oral med oral pathol oral radiol. 2017;123(1):84-94. 2. lundin k, schmidt g, bonde c. amalgam tattoo mimicking mucosal melanoma: a diagnostic dilemma revisited. case rep dent. 2013;2013:787294. dermatology: practical and conceptual review | dermatol pract concept 2018;8(3):16 231 dermatology practical & conceptual www.derm101.com sequential digital dermatoscopic imaging of patients with multiple atypical nevi philipp tschandl1 1 vidir group, department of dermatology, medical university of vienna, austria key words: dermatoscopy, monitoring, melanoma, nevi, digital, screening citation: tschandl p. sequential digital dermatoscopic imaging of patients with multiple atypical nevi. dermatol pract concept. 2018;8(3):231-237. doi: https://doi.org/10.5826/dpc.0803a16 received: december 29, 2017; accepted: march 3, 2018; published: july 31, 2018 copyright: ©2018 tschandl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: priv. doz. philipp tschandl, md, phd, vidir group, department of dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. email: philipp.tschandl@meduniwien.ac.at. introduction dermatoscopy has progressed to a state-of-the art technique not only to distinguish melanoma from nevi [1,2], but also to diagnose all kinds of pigmented and nonpigmented skin tumors [3]. this is due to its proven increase in diagnostic accuracy compared to the unaided eye [4], an improvement that recently has also been shown to be present in nonpigmented lesions that are inherently more difficult to diagnose [5]. but there is a specific aspect of pigmented and nonpigmented skin lesion diagnosis with dermatoscopy that stands apart, namely, screening high-risk patients. why is this different? not only are these patients much more likely to be diagnosed with melanoma [6,7], they are also more difficult to diagnose [8]. this is partially because early melanoma can be featureless, but also because nevi on those patients can have a worrisome morphology. some approaches have been proposed to tackle these problems. the morphologic differentiability can be overcome partly by comparing nevi clusters of the same pattern in a patient [9,10], which has become well known as the comparative approach set forth by argenziano [11]. this comparative approach has its limitations though; for example, in an experimental setting, dermatologists were not able to distinguish melanomas and nevi well in lesions of high-risk patients [8,12]. total-body imaging is widely used for screening high-risk patients, but because pigmented skin lesions can change or occur, especially in young patients [13-15], it is most commonly not applied solely but in combination with other diagnostic methods [16,17]. patients with multiple atypical nevi are at higher risk of developing melanoma. among different techniques, sequential digital dermatoscopic imaging (sddi) is a state-of-the art method to enhance diagnostic accuracy in evaluating pigmented skin lesions. it relies on analyzing digital dermatoscopic images of a lesion over time to find specific dynamic criteria inferring biologic behavior. sddi can reduce the number of necessary excisions and finds melanomas in an early—and potentially curable—stage, but precautions in selecting patients and lesions have to be met to reach those goals. abstract 232 review | dermatol pract concept 2018;8(3):16 most likely will not benefit from it at all; instead, it may even do harm, as recent literature shows a positive association of false positive findings with a number of monitored lesions in a patient [30]. compliance an often-underestimated drawback is lack of patient compliance [29,31]; that is, patients do not show up for the followup appointments. the reason this is an issue is changed sensitivity at the baseline visit [32]. one basic mechanism of the increased diagnostic accuracy of digital dermatoscopic monitoring is that one increases specificity by leaving a lesion untouched in good faith, the lesion—on the patient—will come back after a specified interval. this increased specificity comes at the price of lower sensitivity, which can only be overcome by finding missed melanomas at a second examination. thus, the physician has to ensure the patient returns to the office. while the lack of compliance is not without dispute [33], an italian group [28] found compliance was higher for shorter intervals and that long-term monitoring may be started with shorter periods. lesions previous studies have shown that in high-risk patients one cannot estimate at baseline which of the lesions on the patient is more prone to become a melanoma [8,12]. while other authors argue that only lesions with some sign of atypia should be followed over time [34], those results suggest a possible benefit in integrating inconspicuous lesions. one should not follow, though, that all lesions on a patient have to be monitored at every visit. taking photographs of all lesions at every visit is not only impossible to do in a reasonable amount of time, but it may also decrease diagnostic accuracy as more monitored lesions per patient are positively correlated with false positive findings [30]. a survey showed that the majority of experts in the field in fact do not perform dermatoscopic monitoring of every single lesion on a patient [35], and indirect evidence indicates this is truly not necessary. in a retrospective analysis of our own high-risk center, where only a random subset of lesions is monitored at every visit with monitoring being stopped after no change has been seen for 2 (or 3) years, almost half of melanomas were in situ and mean invasion depth was well below 1 mm for 10 years [30]. therefore, because we cannot estimate which pigmented skin lesion turns out to be a melanoma, selection of lesion monitoring has to be random and can be incremental to save resources (incremental sddi, figure 1). one cannot choose which lesions specifically should be monitored, but there are rules as to which lesions should not be. important exclusion criteria are: (1) nodular (black, brown, gray, red or blue) lesions, as thick melanomas would progress to higher invasion depths more quickly [36,37]; a german group presented a rather innovative method in which they removed the skin of the entire back of a patient to reduce his melanoma risk [18]. though seemingly promising, this approach may not be a solution for usual high-risk patients: the removed nevi are most likely not the precursors of a potential melanoma [19], and possible melanoma risks due to germline mutations [20] would still be present. finally, such an overwhelming surgical procedure defeats the purpose of a screening method, namely reducing invasive procedures. rather, a noninvasive and more specific method has to be chosen for that purpose. one technique that fulfills those requirements, and overcomes some drawbacks mentioned previously, is digital dermatoscopic follow-up, or sequential digital dermatoscopic imaging (sddi) [21,22]. by comparing 2 images of a lesion taken at different time points, additional information about the dynamics, and thus biologic behavior, can be obtained. this additional information has gained interest when being added as an additional “e” criterion to the classic “abcds” [23]. in a study of patients with a high risk of melanoma [24], about 20% to 50% of melanomas could only be detected with the help of digital follow-up, but not with a single dermatoscopic examination. in addition to monitoring multiple nevi, digital dermatoscopy is also used to enhance specificity on individual suspicious lesions. here, a shorter interval (2-3 months [25]; short-term follow-up) is usually chosen [26] for single lesions and even small dermatoscopic changes are regarded as suspicious, whereas in the screening of patients with many nevi an interval of 6-12 months (long-term follow-up) is more common. in the following sections, general rules for practical application of sddi are discussed. selection risk factors the first consideration in applying digital dermatoscopic monitoring is the patient collective, as it has to meet certain criteria [27]. a previous report [24] has shown that digital dermatoscopy is particularly useful for patients with a familial atypical mole and multiple melanoma (fammm) syndrome and an atypical mole syndrome (ams; >50 nevi and >3 atypical nevi) in a strict sense. conversely, conventional dermatoscopy was sufficient for the detection of melanomas in patients with solely a large number of (inconspicuous) nevi: in this patient group, more than 80% of melanomas were diagnosed over a period of 10 years by means of a single dermatoscopic examination or other clinical information. in 2 additional studies with a shorter period of time, no melanoma was found in patients with low risk among the dermatoscopically monitored lesions [28,29]. thus, there is no compelling evidence for applying digital dermatoscopic monitoring to low-risk patient groups. they review | dermatol pract concept 2018;8(3):16 233 for 2-3 years because a diagnosed single melanocytic nevus is at very low risk of transforming into a melanoma at 0.0005% to 0.003% per year [42]. evaluation melanocytic nevi generally grow symmetrically and follow 1 of 3 variants: a reticular pattern (slow growth), a surrounding rim of clods (moderate to fast growth), or peripheral pseudopodia and radial lines (fast growth) [43]. the following changes (summarized in table 1 and figures 2-4 and adapted from kittler et al [44]) have been associated with melanoma in previous studies [45,46] and should lead to the removal of a lesion: (1) changed architecture; (2) asymmetric increase in size; (3) new colors, depigmentation, and focal color change; and (4) the appearance of melanoma criteria such as black dots or regression. (2) blue lesions [38], as monitoring cannot reliably evaluate changes in the dermis; (3) regressive lesions, as a potential melanoma may be completely regressed at follow-up; (4) lesions with a dermatoscopic clod pattern, as they show a faster growth [39]; and (5) spitzoid lesions [40], not including reed nevi [41], as the latter can show fairly symmetric growth and stabilization. lesions with these characteristics should be removed immediately, unless they are clearly benign at the baseline visit. finally, what should lesions selected for sddi look like? ideally, they are medium-sized, flat, and show a dermatoscopic reticular pattern. but, as with any recommendation, the preceding recommendations are due to change with new findings, specifically in the advent of automated full-body imaging, where monitoring of every single lesion of a patient seems feasible in the future. until then, it is justifiable to discard monitoring a single lesion if no change has occurred table 1. differentiation of nevus and melanoma with follow-up images* change nevus melanoma change in size none or symmetrical growth asymmetrical growth change in color no change or even lighter/darker brown or erythema new colors, especially focally and depigmentation change in structure no or subtle changes such as accentuation of existing structures architecture changes and the appearance of new structures including classical melanoma criteria and regression and signs of regression *adapted from kittler et al [50]. figure 1. incremental sddi. because with current methods it is not feasible to image every lesion at every visit, we selected a random sample of new lesions at every visit (gray), which were imaged in subsequent visits (yellow), but were discarded from follow-up after showing no change for 2 years (green). with this method, we were able to map all lesions eventually, to suggest if one lesion has occurred in the last interval even without tbp (red). [copyright: ©2018 tschandl.] 234 review | dermatol pract concept 2018;8(3):16 and (4) age. first, with shorter intervals between 2 images, less change indicates a probable melanoma [26,48], whereas nevi generally change more slowly and in a limited fashion [39,49,50]. in contrast, recurrence of a benign nevus may occur earlier than recurring melanoma [51]. second, new checkpoint inhibitors such as dabrafenib [52] or vemurafenib [53] may lead to drastic changes in nevi. notably, all criteria rely heavily on asymmetry (chaos), which is one of the most (interrater) reliable features in dermatoscopy [47], but evaluation of the necessary extent of change still relies on the subjective judgment of the examining physician. additionally, many additional factors have to be taken into account and these are (1) time, (2) medication, (3) anatomic location, figure  2. a compound nevus (a) with peripheral clods showing (b) symmetrical growth after 1 year. nevi with peripheral clods very commonly show symmetric enlargement over time [70]. [copyright: ©2018 tschandl.] figure 3. this histopathologically verified lentigo maligna initially presented with only structureless brown areas (a) at the baseline visit. (b) after 14 months of follow-up, the pigment has become darker, grown asymmetrically, and an additional pink structureless area can be seen. [copyright: ©2018 tschandl.] figure  4. while this lesion (a) initially appears inconspicuous, after (b) 6  months it shows additional black dots and asymmetric growth. histopathological evaluation revealed a superficially spreading melanoma with an invasion depth of 0.4 mm. [copyright: ©2018 tschandl.] third, congenital nevi of the nail apparatus may show growth and involution [54]. fourth, growing lesions raise more suspicion in older patients, as nevi are expected to change in younger patients to some extent [14,15]. general considerations effectiveness regarding diagnostic accuracy, a metaanalysis has shown that by using sddi, 54.6% of melanomas can be excised in situ. the number of lesions needed to monitor differs significantly between studies (31-1 008), most possibly reflecting different methods of executing sddi. undeniably, this number is the lowest for short-term sddi [21,48] because it is mainly used for increasing specificity (ie, avoiding excision of single suspicious lesions rather than scanning all lesions on a patient). it therefore does not have the identical purpose as longterm sddi and is commonly combined with other screening methods such as total-body photography, conventional skin examination, and dermatoscopy [16,17]. the number of needed excisions (nne) to find a melanoma under longterm sddi is low (1:12; melanoma: benign nevi as diagnosed by histopathology), but here also short-term sddi is lower (1:5) [21], as it includes only suspicious lesions, decreasing the pretest probability of false positive findings. the low nne for any kind of sddi is thought to be one of the main reasons the nne has decreased in recent years in specialized centers [55]. for every screening method, not only diagnostic accuracy, but also immediate and follow-up costs have to be taken into account. literature suggesting that even skin cancer awareness interventions can increase costs alongside even lower quality-adjusted life years [56] show the importance of being careful and constantly critical of population-wide decisions about any kind of screening method [57]. when limiting interventions to high-risk patients, there review | dermatol pract concept 2018;8(3):16 235 5. sinz c, tschandl p, rosendahl c, et al. accuracy of dermatoscopy for the diagnosis of nonpigmented cancers of the skin. j am acad dermatol. 2017;77(6):1100-1109. doi: 10.1016/j. jaad.2017.07.022. 6. fusaro rm, lynch ht, kimberling wj. familial atypical multiple mole melanoma syndrome (fammm). arch dermatol. 1983;119(1):2-3. doi: 10.1001/archderm.1983.01650250006002. 7. clark wh jr, reimer rr, greene m, ainsworth am, mastrangelo mj. origin of familial malignant melanomas from heritable melanocytic lesions. the b-k mole syndrome. arch dermatol. 1978;114(5):732-738. doi: 10.1001/archderm. 1978.01640170032006. 8. tschandl p, hofmann l, fink c, kittler h, haenssle ha. melanomas vs. nevi in high-risk patients under long-term monitoring with digital dermatoscopy: do melanomas and nevi already differ at baseline? j eur acad dermatol venereol. 2017;31(6):972-977. doi: 10.1111/jdv.14065. 9. grob jj, bonerandi jj. the “ugly duckling” sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. arch dermatol. 1998;134(1):103-104. doi: 10.1001/archderm.134.1.103-a. 10. wazaefi y, gaudy-marqueste c, avril m-f, et al. evidence of a limited intra-individual diversity of nevi: intuitive perception of dominant clusters is a crucial step in the analysis of nevi by dermatologists. j invest dermatol. 2013;133(10):2355-2361. doi: 10.1038/jid.2013.183. 11. argenziano g, catricalà c, ardigo m, et al. dermoscopy of patients with multiple nevi: improved management recommendations using a comparative diagnostic approach. arch dermatol. 2011;147(1):46-49. doi: 10.1001/archdermatol.2010.389. 12. skvara h, teban l, fiebiger m, binder m, kittler h. limitations of dermoscopy in the recognition of melanoma. arch dermatol. 2005;141(2):155-160. doi: 10.1001/archderm.141.2.155. 13. banky jp, kelly jw, english dr, yeatman jm, dowling jp. incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma. arch dermatol. 2005;141(8):998-1006. doi: 10.1001/ archderm.141.8.998. 14. zalaudek i, schmid k, marghoob aa, et al. frequency of dermoscopic nevus subtypes by age and body site: a cross-sectional study. arch dermatol. 2011;147(6):663-670. doi: 10.1001/ archdermatol.2011.149. 15. scope a, marchetti ma, marghoob aa, et al. the study of nevi in children: principles learned and implications for melanoma diagnosis. j am acad dermatol. 2016;75(4):813-823. doi: 10.1016/j. jaad.2016.03.027. 16. malvehy j, puig s. follow-up of melanocytic skin lesions with digital total-body photography and digital dermoscopy: a twostep method. clin dermatol. 2002;20(3):297-304. doi: 10.1016/ s0738-081x(02)00220-1. 17. salerni g, carrera c, lovatto l, et al. benefits of total body photography and digital dermatoscopy (“two-step method of digital follow-up”) in the early diagnosis of melanoma in patients at high risk for melanoma. j am acad dermatol. 2012;67(1):e17-e27. doi: 10.1016/j.jaad.2011.04.008. 18. brod c, schippert w, breuninger h. dysplastic nevus syndrome with development of multiple melanomas. a surgical concept for prophylaxis. j dtsch dermatol ges. 2009;7(9):773-775. 19. pampena r, kyrgidis a, lallas a, moscarella e, argenziano g, longo c. a meta-analysis of nevus-associated melanoma: is repeated evidence for cost-effectiveness of screening in general [58,59], and sddi specifically [60]. combinations sddi is never applied alone, but is at a minimum combined with a total-body exam from a physician with or without a handheld dermatoscope. combinations with other examination techniques have been shown to be effective in skin cancer screening of high-risk patients. total-body photography (tbp): by comparing clinical images of 2 time points, tbp itself may reduce the number of excised lesions in pigmented lesion clinics [61,62] by detecting clinically new or changing lesions. especially with the advent of high-resolution photography and automated detection of new lesions [63], tbp has the ability to become even more important in screening a large number of patients. the evidence and use of tbp for screening are promising, but an in-depth review is beyond the scope of this review. regarding digital dermatoscopy, tbp performs very well when combined with sddi in screening programs, as both possibly detect distinct subsets of melanoma [16,17]. reflectance confocal microscopy (rcm): to further reduce the number of unnecessary excisions, rcm has been applied as a “second-level” exam for doubtful lesions found by digital dermatoscopy [64]. though repeatedly found helpful in further studies [65-67], application is currently limited to highly specialized centers with access to this technique. limitations at the time of publication, this review may be outdated. it gives a current review of state-of-the art knowledge about digital dermatoscopic monitoring, but screening and monitoring high-risk melanoma patients may change in the future. new methods such as automated skin lesion tracking [63,68] as well as 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through a specialized clinic for patients at high risk of melanoma. j clin oncol. 2017;35(1):6371. doi: 10.1200/jco.2016.68.4308. dermatology: practical and conceptual research | dermatol pract concept 2020;10(1):e2020011 1 dermatology practical & conceptual detection of malignant melanoma using artificial intelligence: an observational study of diagnostic accuracy michael phillips,1 jack greenhalgh,2 helen marsden,2 ioulios palamaras3 1 royal perth hospital, perth, australia; harry perkins institute for medical research, perth, australia; and centre for medical research, university of western australia, perth, australia 2 skin analytics ltd., london, uk 3 barnet and chase farm hospitals, royal free nhs foundation trust, london, uk key words: melanoma, artificial intelligence, primary care, detection, identification citation: phillips m, greenhalgh j, marsden h, palamaras i. detection of malignant melanoma using artificial intelligence: an observational study of diagnostic accuracy. dermatol pract concept. 2020;10(1):e2020011. doi: https://doi.org/10.5826/dpc.1001a11 accepted: july 10, 2019; published: december 31, 2019 copyright: ©2019 phillips et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: michael phillips, mmedsci, mrf biostatistics unit, 6th floor mrf building, royal perth hospital, gpo box x2213, perth, wa 6847, australia. email: michael.phillips@perkins.uwa.edu.au background: malignant melanoma can most successfully be cured when diagnosed at an early stage in the natural history. however, there is controversy over screening programs and many advocate screening only for high-risk individuals. objectives: this study aimed to evaluate the accuracy of an artificial intelligence neural network (deep ensemble for recognition of melanoma [derm]) to identify malignant melanoma from dermoscopic images of pigmented skin lesions and to show how this compared to doctors’ performance assessed by meta-analysis. methods: derm was trained and tested using 7,102 dermoscopic images of both histologically confirmed melanoma (24%) and benign pigmented lesions (76%). a meta-analysis was conducted of studies examining the accuracy of naked-eye examination, with or without dermoscopy, by specialist and general physicians whose clinical diagnosis was compared to histopathology. the meta-analysis was based on evaluation of 32,226 pigmented lesions including 3,277 histopathology-confirmed malignant melanoma cases. the receiver operating characteristic (roc) curve was used to examine and compare the diagnostic accuracy. results: derm achieved a roc area under the curve (auc) of 0.93 (95% confidence interval: 0.920.94), and sensitivity and specificity of 85.0% and 85.3%, respectively. avoidance of false-negative results is essential, so different decision thresholds were examined. at 95% sensitivity derm achieved a specificity of 64.1% and at 95% specificity the sensitivity was 67%. the meta-analysis showed primary care physicians (10 studies) achieve an auc of 0.83 (95% confidence interval: 0.79-0.86), abstract mailto:michael.phillips@perkins.uwa.edu.au 2 research | dermatol pract concept 2020;10(1):e2020011 such as the recent cochrane reviews of skin cancer. methods derm was designed and developed using deep learning techniques that identify and assess features of pigmented lesions that are associated with mm [23-28]. deep learning differs from earlier machine learning methods by learning features that are associated with mm directly from the data, rather than using features predetermined by a researcher. the algorithm was trained and validated against a dataset of archived dermoscopic images of skin lesions, using 10-fold cross-validation. this approach allows every image to be tested once, while ensuring the same image does not appear in the training and test datasets. cross-validation is performed by splitting the dataset into several (10) “folds” (datasets). the algorithm is tested against each fold, with the remainder used for training. the results for each fold are then averaged so that the overall performance can be assessed. the image dataset was collated from several different sources including the ph2 dataset [29], interactive atlas of dermoscopy [30], and isic archive [31]. an additional 672 dermoscopic lesion images were collected from a variety of other sources. the isic archive contains a large number of images obtained from children, which are easy to classify as benign. their inclusion in the dataset was found to optimistically bias results so they were excluded from the development work. the isic archive also contains a large number of identical and near-identical images which were removed from the dataset. the involved smartphone photography and 4 provided an estimate of the probability of malignancy. none of these apps had been assessed for diagnostic accuracy [17]. understandably there is concern about the possible harm to patients that poorly designed, inaccurate, and/or misleading consumer apps may cause [1820]. however, with appropriate development and suitable evaluation there is no reason why modern electronic technology could not improve diagnostic accuracy. recently, an artificial intelligence (ai) algorithm categorizing photographs of pigmented lesions has been shown to be capable of classifying mm with a level of competence comparable to that of dermatologists [21]. as obermeyer and emanuel state in a recent review, “machine learning has become ubiquitous and indispensable for solving complex problems in most sciences. the same methods will open up vast new possibilities in medicine” [22]. however, there are ethical issues associated with the clinical applications of ai in medicine that do not apply to current business applications, astronomy, or chemistry, and these cannot be ignored [23]. the primary aim of this study was to evaluate the diagnostic accuracy of an ai algorithm (deep ensemble for recognition of melanoma [derm]) developed by skin analytics limited. the secondary aim was to improve the methodology for evaluating an ai diagnostic tool by comparing derm’s performance with clinical examination by physicians and stratification based on level of expertise and use of dermoscopy using a meta-analysis of diagnostic studies. but it should be noted that this was not designed to be a systematic review introduction malignant melanoma (mm) is less common than basal and squamous cell skin cancer; however, the incidence of mm is increasing faster than that of other forms of cancer and it is responsible for the majority of skin cancer deaths [1]. early diagnosis of mm (stage 1) has more than 95% five-year relative survival rate compared with 8% to 25% for mm diagnosed at later stages [2]. current practice guidelines in the united kingdom recommend appropriately trained health care professionals assess all suspect pigmented lesions using dermoscopy [1,3]. diagnosis is confirmed with biopsy, histological examination, and specialist pathological interpretation. pressure to diagnose mm early leads to a high proportion of benign pigmented lesions being referred from primary care to specialist care, and a large proportion of biopsied lesions are found to be benign [4,5]. this creates increased demands on overburdened secondary care and pathology service resources [6]. improved accuracy of pigmented lesion review in primary care would help reduce this pressure. techniques such as dermoscopy with classification algorithms, reflectance confocal microscopy, and teledermatology have been reported to improve diagnostic accuracy of mm [7-15]. however, the diagnostic accuracy is still dependent on the degree of experience of the examiners and the equipment required is costly [16]. a large number of smartphone applications for mm detection have been released recently. however, there is little evidence of clinical validation. kassianos et al reviewed 39 apps that addressed skin cancer issues; 19 with sensitivity and specificity of 79.9% and 70.9%; and dermatologists (92 studies) 0.91 (0.88-0.93), 87.5%, and 81.4%, respectively. conclusions: derm has the potential to be used as a decision support tool in primary care, by providing dermatologist-grade recommendation on the likelihood of malignant melanoma. abstract research | dermatol pract concept 2020;10(1):e2020011 3 number of mm diagnoses confirmed by histology, from which the counts could be derived. the reports were also examined for information concerning physician experience (general vs specialist physician) and context of use (primary care, secondary care). a meta-analysis from this data was conducted. the stata user-written packages metandi [42] and midas [43] were used, and a meta-regression was used to examine associations between diagnostic accuracy and year of study report, level of care, and expertise of the practitioner. many of the dermoscopy studies reported multiple results for each lesion using different dermoscopic algorithms (eg, abcd, 7-point checklist, etc. [44]); all of these results were included in the dataset. since this produces a clustered dataset, violating the statistical assumption of the independence of observations, we conducted a sensitivity analysis. multiple datasets were generated in which 1 estimate only was randomly included for each study where there were multiple estimates. the results indicated that the initial estimates were not sensitive to the clustering (details of this analysis are not reported here). and a meta-analysis enables comparison to a variety of different clinician experiences and evaluation techniques. this analysis was not intended to be systematic review, but the prisma guidelines were followed when appropriate. a literature search was conducted for studies reporting diagnostic accuracy data of naked-eye clinical examination, with or without dermoscopy, compared with histologically confirmed diagnosis. medline (413), web of science (707), and embase (322) were searched for the period from january 1, 1990, to september 30, 2017, using terms “accuracy pigmented lesions plus melanoma pigmented lesions plus detection,” “dermoscopy pigmented lesions plus melanoma pigmented lesions plus accuracy,” and “melanoma pigmented lesions plus diagnosis pigmented lesions plus primary care.” studies included in previous systematic reviews were also included [2,15,39-41]. the prisma flow diagram is shown in figure 2. one author (m.p.) conducted the literature search and extracted counts of true negative; true positive; false negative; false positive; or estimates of sensitivity, specificity, number of lesions examined, and final dataset consists of a total of 7,102 unique pigmented lesion images, 24% being confirmed as mm by histopathology, though subtype information was not available, the rest being made up of benign and nonbenign lesions. derm generates a continuous response to an image with limits of 0 and 1, which reflects its “confidence” that the lesion is mm: a value close to 1 indicates mm and near 0 indicates a benign lesion. a nonparametric receiver operating characteristic (roc) curve analysis was used to examine the overall diagnostic accuracy of the result using pepe’s nonparametric methods with bootstrapped estimation [32]. the gold standard for mm was histopathology. we examined different cut-points used by derm to categorize lesions as positive or negative, ie, illustrating alternative diagnostic rules from the diagnostic model [33]. the methods of youden [34] and liu [35] were used, as well as the values that maximized the roc area, resulted in a sensitivity and a specificity of 95%, and generated less than 1% false negative. the area under the curve (auc) of the roc curve, specificity/sensitivity, and diagnostic odds ratios were calculated for each of these cut-points. the roc auc is not a perfect assessment measure for diagnostic methods when the standard error of the estimator is quite different for the diagnostic alternatives (benign pigmented lesions vs mm), as is the case for derm (see figure 1) [36]. this issue was addressed by constructing the lorenz curve (a mirror image of the roc curve) with the associated gini index [37]. to compare the accuracy of derm with that of current diagnostic practices, we decided to conduct a meta-analysis of studies of diagnostic accuracy for mm rather than have a limited panel of dermatologists conduct parallel assessments, as has been done in other studies [21,38]. we chose this approach because biopsy-based histopathology provides the gold standard for mm diagnosis, figure 1. level of confidence of deep ensemble for recognition of melanoma (derm) algorithm by lesion type. 4 research | dermatol pract concept 2020;10(1):e2020011 the empirical roc curve analysis showed that derm has a high level of accuracy with an auc of 0.928 (95% confidence interval: 0.922-0.935) and an acceptable goodness-of-fit χ2 = 6,078 (p = 0.98) (figure 3). the lorenz curve analysis gave a gini index of 0.857. the gini index has an upper limit of 1 and the high value is indicative of high inequality estimated the median level of confidence as 0.059 (interquartile range: 0.016-0.171) when the lesion was a benign pigmented lesion and 0.651 (interquartile range: 0.417-0.849) when the lesion was mm. the equality of the 2 medians was compared by fisher exact test and found to be significantly different (p < 0.0001). all analysis was conducted by m.p. using the stata statistical package (statacorp. 2015. stata statistical software: release 15. college station, tx: statacorp lp). most of the data used to create the algorithm were based on anonymous, publicly available images, and an additional 672 anonymized dermoscopic lesion images were generously made available by clinical dermatologists. the meta-analysis data were derived from published papers that did not include individual patient data. there was no requirement for ethics approval, but the ethics committee of royal perth hospital was informed of the study as a courtesy. results histograms showing the distribution of the derm value for mm and for benign lesions are shown in figure 1. the histograms show that the value does not follow a normal distribution and there is a different dispersion of data for the 2 types of lesion. derm figure 3. the receiver operating characteristic curve of deep ensemble for recognition of melanoma (derm) results. shaded area shows 95% confidence interval. figure 2. prisma flow diagram of publications searched for the meta-analysis. research | dermatol pract concept 2020;10(1):e2020011 5 table 1. indices of diagnostic accuracy (±95% ci) at different cut-points of the derm confidence value cut-point derm value sensitivity (%) specificity (%) diagnostic odds ratio optimum (maximum auc) 0.272 85.0 (83.2-86.7) 85.3 (84.4-86.3) 33.0 (28.3-38.4) confidence ≥0.50 0.50 67.3 (65.0-69.5) 95.5 (94.9-96.0) 43.7 (37.1-51.5) 80% sensitivity 0.35 80 (fixed) 90.8 (90.0-91.5) 37.1 (32.1-42.9) 95% sensitivity 0.11 95.0 (93.8-96.0) 64.1 (62.8-65.4) 33.6 (26.8-42.1) high sensitivity 0.05 98.6 (98.0-99.1) 46.5 (45.2-47.9) 62.9 (41.7-95.0) 80% specificity 0.21 88.2 (86.6-89.7) 80 (fixed) 32.7 (27.9-38.4) 95% specificity 0.795 66.9 (64.3-69.3) 95% (fixed) 38.3 (32.1-45.7) auc = area under the curve; ci = confidence interval; derm = deep ensemble for recognition of melanoma. between mm and benign lesions, which supports the roc analysis. the youden, liu, and maximum auc methods estimated the same optimum cut-point at a value of 0.272 (95% confidence interval: 0.232-0.313) (table 1). as the sensitivity increases, the expected loss of specificity occurs, but when the sensitivity is fixed at 95%, specificity is still 64%. the summary of 82 studies that investigated the diagnostic accuracy of naked-eye examination (n = 29) or dermoscopy (n = 53) for pigmented lesions and mm between 1990 and 2017 is shown in table 2. a visual guide to the study accuracy is provided in the forest plots in figures 4 and 5. table 3 shows the pooled and weighted values of sentable 2. studies for meta-analysis of diagnostic accuracy author [ref] date total lesions no. of malignant melanomas (%) sensitivity (%) specificity (%) country of patients annessi [47] 2007 198 96 (48.5) 81.3 69.6 italy argenziano [48] 1998 309 106 (34.3) 95.0 75.0 italy argenziano [49] 2006 2,528 12 (0.475) 79.2 71.8 spain, italy argenziano [50] 2011 283 78 (27.6) 87.8 74.5 italy ascierto [51] 2010 54 12 (22.2) 66.6 76.2 italy barzegari [52] 2005 122 6 (4.92) 100 90.0 iran benelli [53] 1999 401 60 (15.0) 85.0 89.1 italy benelli [54] 2000 600 76 (12.7) 68.8 86.0 italy binder [55] 1995 100 37 (37.0) 73.0 74.0 austria binder [56] 1997 240 58 (24.2) 63.0 91.0 austria blum [57] 2004 269 84 (31.2) 95.2 77.8 germany bono [58] 2002 313 125 (39.9) 88.5 75.5 italy bono [59] 2006 206 76 (36.9) 63.0 80.0 italy carli [60] 1998 15 4 (26.7) 58.5 83.5 italy carli [61] 2003 200 44 (22.0) 91.9 35.2 italy carli [62] 2003 311 28 (9.00) 100 88.5 italy cristofolini [63] 1994 220 33 (15.0) 86.5 77.0 italy dal pozzo [64] 1999 713 168 (23.6) 94.6 85.5 italy doliantis [65] 2005 40 20 (50.0) 84.6 77.7 australia dreiseitl [66] 2009 458 146 (31.9) 96.0 72.0 germany dummer [67] 1993 824 25 (3.03) 80.5 95.5 germany feldmann [68] 1998 500 30 (6.00) 88.0 64.0 austria fueyo-casado [69] 2009 303 16 (5.28) 100 97.0 brazil gereli [70] 2010 96 48 (50.0) 89.6 31.2 turkey (table continues next page) 6 research | dermatol pract concept 2020;10(1):e2020011 and nonexperts both for naked-eye visual clinical examination (p < 0.001) and dermoscopy (p < 0.001), which is reflected in the estimated values shown in table 3, where experts have both higher sensitivity and specificity than nonexperts, and is most marked for specificity for both methods and for sensitivity only for dermoscopy (figure 6). the contrast in accuracy is most obvious for primary vs secondary care (p < 0.0001) with the auc differing by 8% specificity = 83%, β = 0.048, p = 0.81; and for dermoscopy the pooled results are as follows: auc = 0.91, sensitivity = 86%, specificity = 81%, β = 0.397, p = 0.005. meta-regression for the year of publication showed no significant association assessed by the combination of sensitivity and specificity for either visual clinical examination (p = 0.25) or dermoscopy (p = 0.18). there was a significant difference between experts sitivity, specificity, and diagnostic odds ratio for the studies. the pooled results for all studies are as follows: auc = 0.90, sensitivity = 85%, and specificity = 82%. the beta value (an indicator of asymmetry of the summary roc curve) is statistically significant (β = 0.263, p = 0.022), indicating that the diagnostic odds ratio shows variation across the summary roc curve. for naked-eye examination the pooled results are as follows: auc = 0.88, sensitivity = 79%, table 2. studies for meta-analysis of diagnostic accuracy (continued) author [ref] date total lesions no. of malignant melanomas (%) sensitivity (%) specificity (%) country of patients glud [71] 2009 83 12 (14.5) 92.0 81.0 denmark haenssle [72] 2010 1,219 127 (10.4) 62.0 97.0 germany har-shai [73] 2005 400 53 (13.3) 86.0 74.0 israel henning [74] 2008 150 50 (33.3) 92.0 38.0 usa keefe [75] 1990 222 11 (4.95) 85.7 66.5 scotland krähn [76] 1998 80 39 (48.8) 90.0 93.0 germany kreusch [77] 1992 317 96 (30.3) 98.9 94.1 germany lorentzen [78] 1999 232 49 (21.1) 59.0 92.0 denmark lorentzen [79] 2000 258 64 (24.8) 70.7 88.0 denmark luttrell [80] 2012 200 25 (12.5) 91.2 94.0 austria mackie [81] 2002 126 69 (54.8) 97.0 55.0 scotland mcgovern [82] 1992 237 16 (6.75) 44.0 94.0 usa menzies [83] 1996 385 107 (27.8) 92.0 71.0 australia menzies [84] 2008 497 105 (21.1) 95.0 80.0 australia menzies [85] 2013 465 217 (46.7) 93.0 70.0 australia nachbar [86] 1994 172 69 (40.1) 92.8 91.2 germany nilles [87] 1994 260 72 (27.7) 90.0 85.0 germany perrinaud [88} 2007 90 78 (86.7) 98.0 37.0 switzerland piccolo [89] 2014 165 33 (20.0) 91.0 52.0 italy rao [90] 1997 72 51 (70.8) 91.5 59.3 usa rosendahl [9] 2011 246 79 (32.1) 82.6 80.0 australia skvara [91] 2005 325 63 (19.4) 31.7 87.3 austria soyer [92] 1995 159 65 (40.9) 94.0 82.0 italy soyer [93] 2004 231 68 (29.4) 96.3 32.8 italy stanganelli [94] 2000 3,372 55 (1.63) 80.0 99.5 italy unlu [95] 2014 115 24 (20.9) 91.6 64.8 turkey walter [96] 2013 1,436 36 (2.51) 91.7 33.1 england westerhoff [97] 2000 100 50 (50.0) 54.6 56.1 australia zalaudek [98] 2006 150 44 (29.3) 94.0 71.9 multiple youl [99] 2007 11,116 49 (0.441) 60.0 98.0 australia all studies (n = 55) 32,226 3,277 (10.2) research | dermatol pract concept 2020;10(1):e2020011 7 figure 4. forest plot for naked-eye examination. figure 5. forest plot for dermoscopy. 8 research | dermatol pract concept 2020;10(1):e2020011 results confirm that clinician experience and use of dermoscopy improve accuracy. derm achieves an auc of 0.93, sensitivity and specificity of 85% and 85%, respectively, when using the estimated optimum value of 0.28. this is higher than naked-eye visual assessment (0.88, 80% and 71%), and similar to findings for dermatologists with dermoscopy (0.91, 85% and 82%). this is illustrated by plotting a roc curve of the data from studies in the meta-analysis, and superimposing the derm data from 4 cut-points (figures 6 and 7). a recent comprehensive series of cochrane reviews concluded that visual inspection alone had a specificity of 42% at a fixed sensitivity of 80% and a sensitivity of 76% at a fixed specificity of 80%, whereas dermoscopy plus visual inspection had a specificity of 92% at a fixed sensitivity of 80% and a sensitivity of 82% at a fixed specificity of 80% (0.83 vs 0.91) (figure 7). there was no association between the auc and year of study publication, suggesting that diagnostic accuracy is not improving over time (p = 0.63). discussion summary herewith we present an extensive evaluation of the ability of derm to identify mm from dermoscopic images of skin lesions. this preliminary analysis demonstrates the ability of an ai-based system to learn features of a skin lesion that are associated with mm, which can then be applied to the identification of mm. we conducted a meta-analysis of mm diagnostic accuracy to generate comparative values from current primary care and specialist dermatologist practices. these table 3. meta-analysis results subgroup no. of estimatesa no. of lesions no. of malignant melanoma sensitivity (%) (95% ci) specificity (%) (95% ci) sroc area (95% ci) all studies naked eye 29 23,930 2,140 79 (72-85) 83 (76-88) 0.88 (0.85-0.91) dermoscopy 79 33,749 5,031 86 (83-89) 81 (76-86) 0.91 (0.88-0.93) all studies nonexperts 20 22,580 1,630 82 (73-89) 73 (60-83) 0.85 (0.82-0.88) experts 65 29,767 3,812 84 (79-87) 85 (80-89) 0.91 (0.88-0.93) all studies primary care 10 19,152 867 80 (65-89) 71 (52-85) 0.83 (0.79-0.86) secondary care 87 36,673 5,480 85 (82-88) 82 (77-87) 0.91 (0.88-0.93) nonexperts naked eye 9 16,304 1,045 78 (60-90) 74 (54-88) 0.83 (0.80-0.86) dermoscopy 11 6,279 585 83 (76-89) 72 (55-84) 0.86 (0.83-0.89) experts naked eye 16 7,115 922 79 (70-86) 86 (79-91) 0.90 (0.87-0.92) dermoscopy 49 22,652 2,890 85 (79-89) 85 (77-90) 0.91 (0.89-0.94) primary care naked eye 6 14,822 595 78 (52-92) 74 (43-91) 0.83 (0.80-0.86) dermoscopy 4 4,330 272 82 (74-87) 66 (57-74) 0.83 (0.79-0.86) secondary care naked eye 19 8,597 1,372 79 (71-86) 85 (78-90) 0.89 (0.86-0.91) dermoscopy 68 28,076 4,108 87 (83-90) 82 (75-87) 0.91 (0.88-0.93) athe number of estimates exceeds the number of studies because multiple estimates are made using dermoscopy with alternative diagnostic algorithms. ci = confidence interval; sroc = summary receiver operating characteristic.   research | dermatol pract concept 2020;10(1):e2020011 9 strengths and limitations we trained our algorithm using archived images that have been published to train clinicians. it is likely that biases exist in the datasets (eg, patient demographics, mm subtypes, image capture methods), but it is very difficult to determine whether such biases exist and thus have been introduced into derm during its development. in addition, it must be [45]. our meta-analysis showed for visual inspection alone specificity of 83% when sensitivity was 80%; sensitivity of 78% when specificity was 80%; specificity of 86% when sensitivity was 80%; and sensitivity of 87% when specificity was 80%. derm gave comparable indices of specificity of 89% at sensitivity of 80% and a sensitivity of 90% at specificity of 80%. figure 7. summary receiver operating characteristic curves for primary and secondary care overlaid with the deep ensemble for recognition of melanoma (derm) sensitivity and specificity at cut-points from table 1 (the shaded rectangle shows the summary point from the meta-analysis). figure 6. summary receiver operating characteristic curves for naked eye and dermoscopic diagnosis overlaid with the deep ensemble for recognition of melanoma (derm) sensitivity and specificity at cut-points from table 1 (the shaded rectangle shows the summary point from the meta-analysis). auc = area under the curve. 10 research | dermatol pract concept 2020;10(1):e2020011 false-negative and false-positive results have equal importance. this is not the case when dealing with a life-threatening disease, such as mm, where a cut-point that maximizes sensitivity—thus reducing the number of false-negative cases— should be adopted. however, this results in a higher false-positive rate, which has health care and patient costs associated with further investigations. the most appropriate cut-point for use in a clinical setting will need to be determined by consensus agreement taking into account both clinical and economic factors and is likely to be different for different clinical settings and levels of care. at high levels of sensitivity, derm offers comparable specificity to dermatologists with dermatoscopes. derm could therefore provide dermatologist-grade advice on likelihood of mm to general practitioners without the cost and training requirements of dermoscopy. while diagnostic accuracy plays a pivotal role in the clinical evaluation of diagnostic tests, it does not prove that the test improves outcomes in relevant patient populations or that it enhances health care quality, efficiency, and cost-effectiveness. the only way to truly determine a test’s utility in the real-life decision-making setting of clinics is by conducting prospective clinical trials. we are currently conducting clinical validation studies of derm. to our knowledge, no other ai-based mm diagnostic test is undergoing such extensive clinical utility testing [23,46,47]. conclusions our study demonstrates the ability of an ai-based system to learn features of a skin lesion photograph that are associated with mm. derm has the potential to be used in primary care to provide dermatologist-grade decision support. it is too early to say deployment of derm would reduce onward referral, but such clinical validation is ongoing. references 1. marsden jr, newton-bishop ja, burrows l, et al. revised u.k. guidelines for the management of cutaneous melanoma 2010. br j dermatol. 2010;163(2):238-256. 2. wernli kj, henrikson nb, morrison cc, nguyen m, pocobelli g, whitlock ep. screening for skin cancer in adults: an updated systematic evidence review for the us preventive services task force [internet]. u.s. preventive services task force evidence syntheses, formerly systematic evidence reviews. rockville, md: agency for healthcare research and quality (us); 2016. 3. national collaborating centre for cancer (uk). melanoma: assessment and management. national institute for health and care excellence: clinical guidelines. london: national institute for health and care excellence (uk); 2015. 4. welch hg, woloshin s, schwartz lm. skin biopsy rates and incidence of melanoma: population based ecological study. bmj. 2005;331(7515):481. emphasized that the algorithm was trained predominantly using images of images rather than images created in a clinical setting. we are currently collecting such images during a clinical trial and plan to report the results in the near future. by using postbiopsy histology as the gold standard for both derm and the inclusion criteria for our meta-analysis, images of nonsuspicious lesions have not been included when training or evaluating derm. we have therefore not shown the ability of derm (or clinicians) to accurately classify nonsuspicious lesions, which could lead to verification bias as was observed by a study of cancer registry data during a prospective follow-up [46]. however, this bias will apply to both the evaluation of derm and the meta-analysis results, so it seems unlikely that the comparison of the 2 would be affected, but it remains a possibility. a strength of our study is that the use of a meta-analysis of naked-eye examination and dermoscopy, the most common current diagnostic methods for mm used in primary care, is based on evaluation of 32,226 pigmented lesions including 3,277 histopathology-confirmed mm. comparison with existing literature recently, 2 other groups who retooled versions of google’s inception network for the identification of melanoma showed accuracy equivalent to or better than that of a panel of dermatologists [22,23]. however, this approach is likely to generate issues such as overfitting (because of the small size of the review panel) and a lack of generalization (because of the selected nature of the voluntary reviewers). a recent addition to the literature was the publication of an extensive systematic review by the cochrane collaboration skin group [45]. four studies were conducted on melanoma diagnosis in adults by visual inspection, dermoscopy with and without visual inspection, reflectance confocal microscopy, and smartphone applications for triaging suspicious lesions. the dates of publication were slightly different from our study dates (up to august 2016 compared with september 2017), they searched more databases, and they did not limit themselves to histology-confirmed pathology as the diagnostic outcome but also included clinical follow-up of benign-appearing lesions, cancer registry follow-up, and “expert opinion with no histology or follow-up.” despite these differences, the number of studies is very similar. we identified 108 studies (29 visual and 79 dermoscopy) and they identified 104 (24 visual and 86 dermoscopy). implications for research and practice using different cut-points at which derm defines a lesion as mm, the sensitivity and specificity 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med j aust. 2007;187(4):215-220. 77. kreusch j, rassner g, trahn c, pietsch-breitfeld b, henke d, selbmann hk. epiluminescent microscopy: a score of morphological features to identify malignant melanoma. pigment cell res. 1992;suppl 2:295-298. 78. lorentzen h, weismann k, petersen cs, larsen fg, secher l, skødt v. clinical and dermatoscopic diagnosis of malignant melanoma: assessed by expert and non-expert groups. acta derm venereol. 1999;79(4):301-304. 79. lorentzen h, weismann k, kenet ro, secher l, larsen fg. comparison of dermatoscopic abcd rule and risk stratification in the diagnosis of malignant melanoma. acta derm venereol. 2000;80(2):122-126. 80. luttrell mj, mcclenahan p, hofmann-wellenhof r, fink-puches r, soyer hp. laypersons’ sensitivity for melanoma identification is higher with dermoscopy images than clinical photographs. br j dermatol. 2012;167(5):1037-1041. 81. mackie rm, fleming c, mcmahon ad, jarrett p. the use of the dermatoscope to identify early melanoma using the three-colour test. br j dermatol.2002;146(3):481-484. 82. mcgovern twm, litaker msm. clinical predictors of malignant pigmented lesions: a comparison of the glasgow seven-point checklist and the american cancer society’s abcds of pigmented lesions. j dermatol surg oncol. 1992;18(1):22-26. 83. menzies sw, ingvar c, crotty ka, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):1178-1182. 84. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol. 2008;144(9):1120-1127. 85. menzies sw, moloney fj, byth k, et al. dermoscopic evaluation of nodular melanoma. jama dermatol. 2013;149(6):699-709. 86. nachbar f, stolz w, merkle t, et al. the abcd rule of dermatoscopy: high prospective value in the diagnosis of doubtful melanocytic skin lesions. j am acad dermatol. 1994;30(4):551-559. 87. nilles m, boedeker rh, schill wb. s. surface microscopy of naevi and melanomas—clues to melanoma. br j dermatol. 1994;130(3):349-355. 88. perrinaud a, gaide o, french le, saurat j-h, marghoob aa, braun rp. can automated dermoscopy image analysis instruments dermatology: practical and conceptual editorial | dermatol pract concept 2019;9(1):1 1 dermatology practical & conceptual in 1985, ackerman said: “with big enough hopes and serious enough convictions, no human being need die of malignant melanoma” [1]. during the previous years, he had introduced the concept of “melanoma in situ” and proposed that melanoma can be histopathologically diagnosed when still confined within the epidermis. based on this, he hypothesized that all melanomas could be diagnosed before invading the dermis and acquiring metastatic potential and, therefore, melanoma mortality would be eliminated. it seems, however, that ackerman was a bit ahead of his time. even if melanoma could be histopathologically diagnosed before invading the dermis, how could such early melanomas be clinically recognized and excised? in that era, many melanomas were diagnosed only when ulcerating or bleeding. the abcd clinical rule, which was introduced in the mid 80s, significantly helped clinicians to recognize melanoma earlier and patients to seek medical advice earlier. but even the abcd rule is not usually sufficient to uncover melanoma in situ. this is because when the natural asymmetry of melanoma becomes visible to the naked eye, it is quite likely that the tumor has already invaded the dermis. in the years that followed, a new diagnostic revolution occurred in the field of skin cancer: dermoscopy. the investigation of the sub-macroscopic morphology enabled the recognition of melanomas that did not have macroscopically detectable criteria. with the improvement of knowledge of dermoscopic morphology, thinner and thinner melanomas became recognizable. therefore, approximately 30 years after ackerman expressed his vision, it seems that clinicians are now equipped with the necessary tools and knowledge to realize it. today, melanoma can finally be recognized when still in situ or minimally invasive and, as such, people might stop dying from it. however, the harsh reality is that, although the incidence of thin melanoma has dramatically increased over the last decades, the incidence and mortality rates of thick melanoma seem to remain stable. what are the main barriers to ackerman’s vision becoming reality? whose fault is it that people still die of melanoma, and what can be done? no one should die of melanoma: time for this vision to be realized? teresa russo1, aimilios lallas2, gabriella brancaccio1, vincenzo piccolo1, roberto alfano3, giuseppe argenziano1 1 dermatology unit, university of campania, naples, italy 2 first department of dermatology and venereology, aristotle university, thessaloniki, greece 3 department of anesthesiology, surgery and emergency, university of campania, naples, italy citation: russo t, lallas a, brancaccio g, piccolo v, alfano r, argenziano g. no one should die of melanoma: time for this vision to be realized? dermatol pract concept. 2019;9(1):1-3. doi: https://doi.org/10.5826/dpc.0901a01 published: january 31, 2019 copyright: ©2019 russo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: teresa russo, md, ii policlinico, edificio 9c, primo piano, via pansini 5 80131 naples, italy. email: russo. teresa87@gmail.com 2 editorial | dermatol pract concept 2019;9(1):1 2. the patient’s fault! in everyday practice, many melanomas are very easy to recognize clinically. to a certain extent, this is because they are so advanced and display all the typical morphologic characteristics of melanoma. many patients presenting with advanced melanomas report not to have sought medical advice earlier even if the tumor had been present for several months or even years. this thoughtless behavior can be attributed to a lack of awareness and to the widespread and popular misconceptions. characteristically, a survey among 1,024 adult italian women showed that 82% believed that excising a mole is dangerous because the surgical procedure could turn a benign mole into a malignant one [8]. another survey performed in the us reported that approximately 20% of the participants “always thought that melanoma was not very serious.” an association between the socio-economic status and melanoma thickness has been reported in several populationbased studies. for example, pollitt et al studied 566 patients with newly diagnosed melanoma and confirmed that a low socioeconomic status was associated with increased melanoma thickness and decreased survival [9]. in 2008, schneider et al showed that an employee education and screening program at lawrence livermore national laboratory resulted in a significant reduction of melanoma mortality [10]. screening programs are considered the main solution to increased public awareness. indeed, widely applied screening strategies for breast or prostate cancer seem to have succeeded in increasing awareness, even though it is not always clear if they also succeed in reducing mortality. for skin cancer, screening programs are not so well established, but they do exist. an example was the screen project, during which a population-based skin cancer screening was performed in one state in germany. then, melanoma incidence was compared to that in another state, where the screening was not performed. as expected, the investigators found an increased melanoma incidence in the state where the screening took place. the major differences between the 2 states occurred among women, the group with the greatest screen participation. these results are consistent with the impact of effective screening for other cancers [11,12]. however, screening programs for skin cancer might not be equally effective in increasing awareness if they are not combined with a systematic effort to dispel widespread misconceptions. we need to realize that a significant proportion of patients with advanced melanoma delay seeking medical attention, not because they do not see their melanomas, but because they think that it is not dangerous or, even worse, that it would be dangerous to excise it. therefore, a dual effort is required to improve public behavior concerning melanoma detection. first, improved and widespread screening programs should be available and 1. the tumor’s fault! the melanoma family is comprised of tumors with different potentials to grow and metastasize. fortunately, the great majority of melanomas grow superficially (slow-growing melanoma) for years before acquiring the biologic attitude of growing vertically (nodular component) and metastasizing [2]. however, rapidly growing melanomas do also exist (about 10% of melanomas diagnosed histopathologically) [2]. this type of biologically aggressive melanoma is largely responsible for melanoma mortality because it invades the dermis in only a few months, giving patients and doctors less of a chance to diagnose it at an early stage. evidence suggests that nodular melanoma might grow vertically up to 0.5 mm per month [3]. this means that after only 3–4 months the lesion is already 1.5 –2 mm in thickness, thus rapidly acquiring the potential to metastasize [4–6]. in fact, the problem of aggressive tumor biology might be even more difficult to solve, since it has been hypothesized that purely nodular melanoma might originate from dermal melanocytes. in 2008, segura et al [7] investigated the morphologic features of melanomas with a nodular component and correlated in vivo reflectance confocal microscopy findings with histopathologic alterations. they found that, while superficial spreading melanomas with a nodular component displayed marked epidermal disarrangement and pagetoid infiltration, purely nodular melanomas showed a preserved epidermis with only a few pagetoid cells. these observations, along with the report of “primarily dermal melanomas” a few years earlier revisited the conventional concept that melanoma develops only from transformed epidermal melanocytes, proposing instead that some melanomas might originate from dermal stem cells. the problem of “purely nodular,” “primary dermal,” or rapidly growing melanoma becomes even more complicated in the light of evidence suggesting that these melanomas develop in patients with a low nevus count and without other known risk factors. given that most screening strategies are designed on the basis of known risk factors, it seems that they fail to target individuals that will develop fast-growing melanomas. although purely nodular tumors represent a small proportion of all melanomas, they seem to have a definite impact on melanoma mortality. eliminating this impact is probably impossible, especially if it is true that some of these tumors originate in the dermis. reducing the impact could be possible by reviewing the screening strategies so as to better target individuals at risk and by promoting self-examination. the rapidly developing artificial intelligence diagnostic software could potentially help to improve and expand populationbased screening. editorial | dermatol pract concept 2019;9(1):1 3 conclusions we strongly believe that people still die of melanoma for reasons that are related to culture, general education, and habits of doctors and patients rather than reasons related to the lack of scientific knowledge or insufficiency of diagnostic tools. realizing this might help the medical community and health authorities to better target their efforts. references 1. ackerman ab. no one should die of malignant melanoma. j am acad dermatol. 1985;12(1 pt 1):115-116. 2. greenwald hs, friedman eb, osman i. superficial spreading and nodular melanoma are distinct biological entities: a challenge to the linear progression model. melanoma res. 2012;22(1):1-8. 3. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol. 2006;142(12):1551-1558.{ 4. brancaccio g, russo t, lallas a, moscarella e, agozzino m, argenziano g. melanoma: clinical and dermoscopic diagnosis. g ital dermatol venereol. 2017;152(3):213-223. 5. russo t, piccolo v, lallas a, et al. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. 6. russo t, piccolo v, ferrara g, et al. dermoscopy pathology correlation in melanoma. j dermatol. 2017;44(5):507-514. 7. segura s, pellacani g, puig s, et al. in vivo microscopic features of nodular melanomas: dermoscopy, confocal microscopy, and histopathologic correlates. arch dermatol. 2008;144(10):1311-1320. 8. piccolo v, russo t, giacomel j, lallas a, alfano r, argenziano g. dispelling myths concerning pigmented skin lesions. j eur acad dermatol venereol. 2016;30(6):919-925. 9. pollitt ra, swetter sm, johnson tm, patil p, geller ac. examining the pathways linking lower socioeconomic status and advanced melanoma. cancer. 2012;118(16):4004-4013. 10. schneider js, moore dh 2nd, mendelsohn ml. screening program reduced melanoma mortality at the lawrence livermore national laboratory, 1984 to 1996. j am acad dermatol. 2008;58(5):741-749. 11. swetter sm, pollitt ra, johnson tm, brooks dr, geller ac. behavioral determinants of successful early melanoma detection: role of self and physician skin examination. cancer. 2012;118(15):3725-3734. 12. waldmann a, nolte s, weinstock ma, et al. skin cancer screening participation and impact on melanoma incidence in germany—an observational study on incidence trends in regions with and without population-based screening. br j cancer. 2012;106(5):970974. 13. argenziano g, zalaudek i, hofmann-wellenhof r, et al. total body skin examination for skin cancer screening in patients with focused symptoms. j am acad dermatol. 2012;66(2):212-219. 14. hoorens i, bossaert k, pil l, et al. total-body examination vs lesion-directed skin cancer screening. jama dermatol. 2016;152(1):27-34. 15. federman dg, kravetz jd, kirsner rs. skin cancer screening by dermatologists: prevalence and barriers. j am acad dermatol. 2002;46(5):710-714. 16. grange f, woronoff as, bera r, et al. efficacy of a general practitioner training campaign for early detection of melanoma in france. br j dermatol. 2014;170(1):123-129. easily accessible. screening will allow clinicians to recognize early melanomas that patients themselves cannot detect. second, the population should be better educated to perform self-examination and, mainly, to immediately seek medical advice for melanomas that they do detect but neglect because of misconceptions. 3. the doctor’s fault! the likely reason why doctors miss melanoma is not their inability to recognize it, but the fact that they do not give themselves the chance to see and examine it. it has been shown that a big proportion of melanomas are “diagnosed” by the patients themselves, meaning that the patients seek medical advice precisely because they are worried about a lesion that finally proves to be melanoma. the remaining melanomas, however, remain to be discovered by clinicians. to do so, clinicians have to examine clinically and dermoscopically all the patient’s moles. they do so when patients ask for it, but when patients come in for other focused symptoms, evidence suggests that clinicians usually do not offer a total body mole check. it has been reported that up to 63% of patients diagnosed with melanoma had visited their general practitioner within the year prior to the diagnosis for another medical problem. dermatologists do not do much better, with only 30% of them performing a total body skin examination on all their patients. although this is understandable within the frame of a busy daily practice, clinicians should take into consideration data suggesting that 1 skin cancer is found every 50 patients examined with total body skin check, and 1 melanoma is uncovered every 400 patients. reading these data inversely, a clinician would realize that with every 50 patients he/she examines without a total body check, 1 skin cancer is missed, and with every 400 patients 1 melanoma is overlooked. although the safest proposal would be to offer a totalbody skin examination to all patients seeking dermatologic consultations, it might be unrealistic to apply in the real practice. however, a total-body skin check should be offered at least to individuals belonging to high-risk groups [13-15]. the epidemiologic evidence is well known: high-risk groups include individuals with (1) personal history of skin cancer; (2) more than 20 nevi on the arms, which is predictive of a high total nevus count; and (3) sun-damaged skin on uncovered areas. the strategy of total-body skin checks would be fruitful if applied not only by dermatologists, but also by appropriately trained general practitioners (gps). grange et al [16] found that training gps on skin cancer diagnosis and encouraging them to perform systematic skin examinations might reduce the mean breslow thickness of diagnosed melanomas and the incidence of very thick melanomas. dermatology: practical and conceptual 12 observation | dermatol pract concept 2018;8(1):3 dermatology practical & conceptual www.derm101.com case presentation a 14-year-old boy presented with an asymptomatic solitary skin-colored plaque on the frontal area that had been present for five years. in the beginning, the plaque was small but gradually progressed to a large 4 x 4 cm plaque on the forehead (figure 1a). on the dermatological examination, two café-au-lait macules on the trunk were found. general physical examination was normal. the patient’s past medical history revealed no significant findings, such as seizure, neurological deficit, or abnormal development, and trauma and manipulation were absent. family history for similar problem was also negative. brain ct showed that the lesion was limited to the outside of the skull bones without intracranial extension. routine laboratory tests, comprising of liver function test, urine analysis, and complete blood count were all normal. he was very unhappy with the lesion and had developed depression due to his classmates’ insults. an incisional skin biopsy was performed which showed increased normal collagen bundles in dermis, mild hyperkeratosis, acanthosis, minimal perivascular inflammation in the upper dermis, and dermal thickening (figure 2a, b). verhoeff’s elastic stain (veg) revealed elastorrhexis, that is, fragmentation and thinning of the elastic fibers within the reticular dermis (figure 2c). therefore, an isolated cutaneous collagenoma was diagnosed. due to the large size and poor cosmetic result of the surgery and the great impact of the lesion on quality of life, satisfactory treatment of a large connective tissue nevus with intralesional steroid injection nasrin saki1,2, azadeh dorostkar1,2, alireza heiran3, fatemeh sari aslani1,4 1 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran 2 dermatology department, shiraz university of medical sciences, shiraz, iran 3 student research committee, shiraz university of medical sciences, shiraz, iran 4 pathology department, shiraz university of medical sciences, shiraz, iran key words: collagenoma, isolated collagenoma, connective tissue nevus, steroid citation: saki n, dorostkar a, heiran a. sari aslani f. satisfactory treatment of a large connective tissue nevus with intralesional steroid injection. dermatol pract concept. 2018;8(1):12-14. doi: https://doi.org/10.5826/dpc.0801a03 received: june 26, 2017; accepted: october 8, 2017; published: january 31, 2018 copyright: ©2018 saki et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nasrin saki, md, molecular dermatology research center, dermatology department, shiraz university of medical sciences, shiraz, iran. postal code: 7134844119. e-mail: nasrinsa85@yahoo.com collagenoma is a type of connective tissue nevi, a rare hamartomatous malformation characterized by the predominant proliferation of normal collagen fibers and normal, decreased, or increased elastic fibers. collagenomas present as multiple or solitary, hereditary or sporadic, asymptomatic, skin-colored papules, nodules, and plaques with variable sizes, and are usually located on the trunk, arm, and back. here, we report on a 14-year-old boy who presented with an isolated giant collagenoma of the frontal area that dramatically responded to intralesional triamcinolone acetonide. abstract mailto:nasrinsa85@yahoo.com observation | dermatol pract concept 2018;8(1):3 13 conclusion connective tissue nevi are benign, well-defined hamartomas of the dermis categorized as collagenomas, elastomas, and nevi mucinosis based on the prevailing element of extracellular matrix of dermis. collagenomas are divided into inherited and acquired types. the inherited form consists of familial cutaneous collagenoma and shagreen patch of tuberous sclerosis, which is autosomal dominant. familial cutaneous collagenoma presents with multiple lesions and is accompanied by we decided to treat it with four monthly sessions of intralesional triamcinolone acetonide injections. triamcinolone acetonide 10 mg/ml was injected into the bulk of the connective tissue nevus in the first session and 20 mg/ml in the other three sessions. the patient was regularly followed and showed remarkable response with good results after the third injection. at follow-up, eight months after the last session, only the medial border of the lesion had relapsed, which was resolved with a single injection of triamcinolone acetonide 10 mg/ml (figure 1b, c, d). figure 1. trend on the improvement of the collagenoma over one year achieved by four intralesional triamcinolone acetonide injections. [copyright: ©saki et al.] cardiac disorders such as cardiomyopathy and conduction abnormalities [1-5]. acquired collagenoma includes eruptive collagenoma and isolated collagenoma. eruptive collagenoma is described as discrete, firm, skin-colored, and elevated papules, nodules, or plaques distributed on the trunk and extremities symmetrically [6]. isolated collagenoma exhibits numerable lesions localized on the palms, soles, and rarely other parts of the body [7,8]. the pathogenesis of collagenoma is ambiguous; however, sporadic collagenoma might be related to trauma, since it appears in areas subjected to friction. in addition, collagenomas might be associated with pseudohypoparathyroidism, hypogonadism, and down syndrome [9-11]. apparently, underproduction of collagenase and the consequent diminished collagen degradation is the key event underlying collagenoma pathogenesis [12]. additionally, the required time for fibroblasts mitosis, abundant within collagenoma, is reduced and this contributes to the increase in the collagen bundles [13]. histologically, in all types of collagenoma, coarse and dense collagen fibers accumulate in the dermis and the content of elastic fibers is diminished [14]. to the best of our knowledge, there is no conclusive effective therapy for cutaneous collagenoma except for surgical removal of the lesions [15]. three studies investigating the therapeutic effect of triamcinolone acetonide on familial cutaneous collagenoma [16], acquired linear nodular collagenoma [17], and isolated corymbose collagenoma [18] reported the improvement of the lesions in varying degrees. the therapeutic effects of triamcinolone acetonide might be the result of the underproduction of transforming growth factor β1 (tgfβ1) in the fibroblasts and overproduction of basic fibroblast growth factor (bfgf), which in turn inhibits fibroblast mitosis and collagen synthesis [19]. in the present case we tried intralesional triamcinolone acetonide and observed 14 observation | dermatol pract concept 2018;8(1):3 10. kakinoma y, endo h, tsukahara t, futoeda t, saito y, shinkai h. collagenoma with pseudohypoparathyroidism. br j dermatol. 2000;143(5):1122-1124. 11. sacks hn, crawley is, ward ja, fine rm. familial cardiomyopathy, hypogonadism, and collagenoma. ann intern med. 1980;93(6):813-817. 12. nico mm, valente ny, machado ka. isolated plantar collagenoma. acta derm venereol. 2003;83(2):144. 13. uitto j, bauer ea, santa cruz dj, holtmann b, eisen az. decreased collagenase production by regional fibroblasts cultured from skin of a patient with connective tissue nevi of the collagen type. j invest dermatol. 1982;78:136–140. 14. romiti r, romiti n. papulolinear collagenoma. j am acad dermatol. 2004;50:797-798. 15. al-breiki sh, bukhari ia. childhood solitary collagenoma. saudi med j. 2006;27(3):395-396. 16. dawn me, deng ac, petrali j, wessely c, jaffe d, gaspari aa. familial cutaneous collagenoma. skinmed. 2008;7:43–45. 17. sardana k, bansal s, garg vk, khurana n. linear nodular collagenoma – successful treatment with intralesional triamcinolone acetonide. pediatr dermatol. 2009; 26:626–628. 18. yadav s, khullar g, saikia un, dogra s. isolated corymbose collagenoma responding to intralesional triamcinolone acetonide and hyaluronidase injections. dermatol ther. 2013;26(5):419423. 19. robles dt, berg d. abnormal wound healing: keloids. clin dermatol. 2007; 25(1):26-32. a dramatic response. hence, intralesional triamcinolone acetonide may be a promising therapy for non-operable forms of collagenoma. references 1. botella-estrada r, alegre v, sanmartin o, ros c, aliaga a. isolated plantar cerebrifirm collagenoma. arch dermatol. 1991;127(10):1589-1590. 2. jones ms, helm kf. a solitary warty plaque. isolated cerebriform collagenoma. arch dermatol. 1997; 133(7):911-912. 3. kumar s, singh sk, banasal a, banasal m. isolated collagenoma on the scalp: a rare presentation. int j tricology. 2013;5(2):88. 4. amato l, mei s, gallerani i, moretti s, cipollini em, palleschi gm, et al. familial cutaneous collagenoma: report of an affected family. int j dermatol. 2005;44(4):315-317. 5. boente mdel c, primc nb, asial ra, winik bc. familial cutaneous collagenoma: a clinicopathologic study of two new cases. pediatr dermatol. 2004;21(1):33-38. 6. ju q, song n, sun j. eruptive cutaneous collagenoma in a chinese patient. j dermatol. 2011;38(4):399-401. 7. yahya h, rafindadi ah. eruptive collagenoma in nigerian girl. int j dermatol. 2006;45(11):1344-1346. 8. madke b, doshi b, nayak c, prasannan r. isolated pedunculated collagenoma (collagen nevi) of the scalp. indian j dermatol. 2013;58(5):411. 9. togawa y, nohira g, shinkai h, utani a. collagenoma in down syndrome. br j dermatol. 2003;148(3):596-597. figure 2. microscopic findings: (a) increased normal collagen bundles in the dermis, mild hyperkeratosis, acanthosis, minimal perivascular inflammation in upper dermis, and dermal thickening (h&e x40). (b) partial replacement of the subcutaneous fat by broad collagen bundles (h&e x200). (c) elastorrhexis within reticular dermis (verhoeff’s elastin stain x200). [copyright: ©saki et al.] dermatology: practical and conceptual review | dermatol pract concept 2014;4(4):3 21 dermatology practical & conceptual www.derm101.com epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection philip r. cohen1, taraneh paravar1, robert a. lee1 1 division of dermatology, university of california san diego, san diego, california keywords: acantholytic, cell, dermatoses, dermatosis, disease, epidermis, epithelial, giant, grover, herpes, infection, multinucleated, pemphigus, transient, virus, vulgaris citation: cohen pr, paravar t, lee ra. epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection. dermatol pract concept. 2014;4(4):3. http://dx.doi.org/10.5826/dpc.0404a03 received: july 22, 2014; accepted: july 24, 2014; published: october 31, 2014 copyright: ©2014 cohen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, m.d., division of dermatology, university of california, san diego, ca, usa. email: mitehead@ gmail.com background: multinucleated giant cells in the epidermis can either be epithelial or histiocytic. epithelial multinucleated giant cells are most often associated with herpes virus infections. purpose: to review the histologic differential diagnosis of conditions with epithelial and histiocytic multinucleated giant cells—since multinucleated giant cells in the epidermis are not always pathognomonic of a cutaneous herpes virus infection—and to summarize dermatoses in which herpes virus infection has been observed to coexist. methods: two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection are reported. using the pubmed database, an extensive literature search was performed on multinucleated giant cell (and epidermis, epithelial, and histiocytic) and herpes virus infection. relevant papers were reviewed to discover the skin conditions with either multinucleated giant cells in the epidermis or coincident cutaneous herpes virus infection. results: initial skin biopsies from patients with either pemphigus vulgaris or transient acantholytic dermatosis mimicked herpes virus infection; however, laboratory studies and repeat biopsies established the correct diagnosis of their acantholytic dermatosis. hence, epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection. indeed, epithelial multinucleated giant cells in the epidermis can be observed not only in the presence of infection (herpes virus), but also acantholytic dermatoses and tumors (trichoepithelioma and pleomorphic basal cell carcinoma). histiocytic multinucleated giant cells in the epidermis can be observed in patients with either giant cell lichenoid dermatitis or lichen nitidus of the palms. (continued next page) abstract 22 review | dermatol pract concept 2014;4(4):3 introduction herpes virus infection of the skin is characterized by the finding of multinucleated giant cells in the epidermis. we report two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection; however, all viral studies were negative and subsequent biopsies of their lesions demonstrated pathognomonic features of either pemphigus vulgaris or transient acantholytic dermatosis. the histologic differential diagnosis of conditions with multinucleated giant cells in the epidermis is reviewed and dermatoses in which herpes virus infection has been observed to coexist are summarized. case reports case 1 a 24-year-old caucasian woman presented with painful oral sores that persisted after a short tapering course of oral corticosteroids (methylprednisolone dose pack) that was stopped after 5 days. her past medical history was significant for type 1 diabetes mellitus and genital herpes simplex virus infection. she subsequently developed tender fluid-filled blisters of her axilla and groin and was empirically treated with oral valacyclovir 1000 mg twice daily without improvement. examination of the oral cavity showed ulcers on the hard palate, the buccal mucosa and the mucosa of the gingiva and labia. pustules, vesicles, and bullae were observed within the right axillae (figure 1) and the labia majora. a lesional skin biopsy from the right axilla was performed; specimens for bacterial culture, direct fluorescent antibody studies and viral cultures were also obtained. microscopic examination showed epidermal necrosis and ulceration surmounted by basophilic debris; rare cocci-shaped bacteria were seen within the inflammatory scale crust. focal reticular degeneration, intraepidermal neutrophilic pustules forming a suprabasilar cleft, and numerous multinucleated conclusions: epithelial and histiocytic multinucleated giant cell can occur in the epidermis. keratinocyte-derived multinucleated giant cells are most commonly associated with herpes virus infection; yet, they can also be observed in patients with skin tumors or acantholytic dermatoses. cutaneous herpes simplex virus infection can coexist in association with other conditions such as acantholytic dermatoses, benign skin tumors, bullous disorders, hematologic malignancies, inflammatory dermatoses, and physical therapies. however, when a herpes virus infection is suspected based upon the discovery of epithelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be considered and additional lesional skin biopsies performed. also, because hematoxylin and eosin staining is not the golden standard for confirmation of autoimmune bullous dermatoses, skin biopsies for direct immunofluorescence should be performed when a primary bullous dermatosis is suspected since the histopathology observed on hematoxylin and eosin stained sections can be misleading. abstract (continued) figure 1. the right axilla of a woman with pemphigus vulgaris shows pustules and vesicles on a faint erythematous base. (copyright: ©2014 cohen et al.) keratinocyte giant cells demonstrating nuclear molding were noted. there was a perivascular infiltrate in the upper dermis consisting of neutrophils and eosinophils (figure 2). the pathology was consistent with a herpes virus infection. the patient was hospitalized and treated for disseminated herpes virus infection with intravenous acyclovir at a dose of 10 mg per kilogram every 8 hours. the bacterial culture grew methicillin-resistant staphylococcus aureus and intravenous vancomycin was added. she continued to develop similar-appearing new lesions not only in her mouth, axilla and groin, but also on her arms and abdomen; in addition, earlier pustules and vesicles had enlarged and/or ruptured (figure 3). the direct fluorescence antibody studies and the viral cultures were negative for both herpes simplex virus and varicella-zoster virus. repeat skin biopsies were performed for routine staining and direct immunofluorescence. microscopic examination showed an intraepidermal blister containing acantholytic keratinocytes, numerous eosinophils, and occasional neutrophils; the adjacent epithelium showed spongiosis with eosinophils. perivascular inflammation, consisting of prominent eosinophils and occasional lymreview | dermatol pract concept 2014;4(4):3 23 phocytes, was present in the upper dermis (figure 4). direct immunofluorescence showed positive intercellular staining in the epidermis for igg and c3. subsequently, enzyme-linked immunosorbent assay (elisa) testing demonstrated that the serum igg titers were elevated for both desmoglein 1 and desmoglein 3. figure 2. (a) distant, (b) close and (c) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (a) basophilic debris is seen within the inflammatory scale crust overlying necrosis and ulceration of the epidermis. (b) there is a suprabasilar cleft showing an intraepidermal neutrophilic pustule; multinucleated keratinocyte giant cells are noted in the pustule. (c) nuclear molding can also be noted within several of the multinucleated keratinocyte giant cells (hematoxylin and eosin; a= x4, b=20, c=x40). (copyright: ©2014 cohen et al.) a b c figure 3. enlargement and/or rupture of pustules and vesicles in the right axilla of the women with pemphigus vulgaris. (copyright: ©2014 cohen et al.) figure 4. (a) distant and (b) closer views of the repeat biopsy specimen that establish the diagnosis of pemphigus vulgaris. acantholytic keratinocytes, numerous eosinophils, and occasional neutrophils are present in an intraepidermal blister; eosinophilic spongiosis is present in the adjacent epithelium. prominent eosinophils and occasional lymphocytes compose the perivascular infiltrate in the upper dermis (hematoxylin and eosin; a= x20, b=x40). (copyright: ©2014 cohen et al.) a b 24 review | dermatol pract concept 2014;4(4):3 figure 5. (a) distant, (b) close and (c) closer view of the left upper chest of a woman with transient acantholytic dermatosis presenting as pruritic erythematous papules. (copyright: ©2014 cohen et al.) a b c figure 6. (a) distant, (b) close and (c) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (a) an intraepidermal vesicle with suprabasilar epidermal acantholysis and cleft formation is noted. (b and c) closer views show neutrophils and eosinophils in both the intraepidermal vesicle and the dermis; in the blister cavity, multinucleated keratinocyte giant cells with nuclear molding are also noted (hematoxylin and eosin; a= x4, b=x20, c=x40). (copyright: ©2014 cohen et al.) a b c correlation of the clinical findings, laboratory studies, and repeat skin biopsies established a diagnosis of pemphigus vulgaris. initial management included 60 mg daily of oral prednisone. she also received intravenous rituximab, 2 doses of 1000 mg each separated by 2 weeks, prior to tapering her daily prednisone over the next 6 months. her skin lesions resolved without recurrence. case 2 a healthy 40-year-old caucasian woman presented with a recurrent itchy rash on her chest and abdomen of more than one-year duration. her past medical history was negative for herpes virus infection. cutaneous examination revealed discrete pruritic erythematous and crusted papules on her chest and abdomen (figure 5). a lesional biopsy was performed. empiric topical treatment was initiated with triamcinolone 0.1% ointment. review | dermatol pract concept 2014;4(4):3 25 microscopic examination showed suprabasilar epidermal acantholysis and cleft formation with neutrophils and eosinophils in both the intraepidermal vesicle and the dermis. multinucleated keratinocyte giant cells with nuclear molding were also seen in the blister cavity (figure 6). the pathologic findings were interpreted as a herpes virus infection. the clinical features and improvement with topical corticosteroid therapy did not correlate with the observed pathologic findings. direct fluorescence antibody studies and viral cultures did not demonstrate herpes virus infection. a repeat skin biopsy was performed of a new lesion on her upper chest. the second biopsy specimen showed acanthosis with focal acantholysis and dyskeratosis; viral cytopathic changes were absent. lymphocytic inflammation was present in the upper dermis (figure 7). correlation of the clinical presentation, laboratory studies, and pathologic changes established the diagnosis of transient acantholytic dyskeratosis (grover’s disease). discussion multinucleated giant cells can be observed in the epidermis (table 1) [1-10]. the etiology of the giant cells can either be epithelial or histiocytic. histiocytic epidermal multinucleated giant cells have been noted in giant cell lichenoid dermatitis [7,8] and lichen nitidus of the palms [9,10]. table 1. conditions with multinucleated giant cells in the epidermis epithelial cell origin acantholytic dermatosis pemphigus vulgaris [current report] transient acantholytic dermatosis [current report] infection herpes virus infection [1-3] tumors benign trichoepithelioma [4] malignant pleomorphic basal cell carcinoma [5,6] histiocytic cell origin giant cell lichenoid dermatitis [7,8] lichen nitidus of the palms [9,10] figure 7. (a) distant, (b) close and (c) closer views of the repeat biopsy specimen that establish the diagnosis of transient acantholytic dermatosis. acanthosis, with focal acantholysis and dyskeratosis, is noted in the epidermis and lymphocytic inflammation is present in the upper dermis; viral cytopathic changes are absent (hematoxylin and eosin; a= x4, b=x20, c=x40). (copyright: ©2014 cohen et al.) a b c epithelial multinucleated giant cells are most often associated with herpes virus infections [1-3]. however, they occasionally occur in either benign or malignant tumors of epidermal cell origin such as trichoepitheliomas or basal cell carcinomas, respectively [4-6]. we recently observed multinucleated giant cells of keratinocyte origin, which mimicked those noted in herpes virus infection, in the epidermis of patients with acantholytic dermatoses: pemphigus vulgaris [11-15] and transient acantholytic dermatosis [16-21]. herpes virus infections of the skin usually present as erythematous-based vesicles. microscopic examination of a 26 review | dermatol pract concept 2014;4(4):3 lesional biopsy often shows multinucleated ballooned keratinocyte giant cells in the epidermis containing steel-gray nuclei with accentuation of nucleoplasm at their periphery; acantholytic, sometime necrotic, keratinocytes within intraepidermal blisters can also be noted. the diagnosis of herpes virus infection can be confirmed by direct fluorescent antibody testing or viral culture [1-3,22-25]. herpes simplex virus infection can coexist in association with other skin conditions; this likely represents the coincident development of this viral infection in an immunocompromised district—an area of skin that have been made vulnerable by a previous or concurrent cutaneous disorder [26]. in addition to acantholytic dermatoses and bullous disorders (table 2) [27-33], herpes simplex virus can also occur in association with hematologic malignancies [27,34,35], inflammatory dermatoses [27,35], and physical therapies [27,35,36]. rarely, herpes virus infection has been discovered in benign skin tumors, such as seborrheic keratoses [37]. our patients had acantholytic dermatoses that were initially interpreted to represent a herpes virus infection based on the presence of multinucleated epithelial giant cells in the epidermis of lesional skin biopsies. however, additional evaluation (including direct fluorescent antibody studies and viral cultures) was negative for a viral infection. in addition, one patient failed to improve after oral or intravenous treatment with antiviral therapy. subsequently, repeat biopsies for direct immunofluorescence and/or routine histology established the correct diagnosis for both patients. conclusion epithelial and histiocytic multinucleated giant cell can occasionally be found in the epidermis. although keratinocytetable 2. acantholytic or bullous dermatoses in which herpes simplex virus infection has been demonstrated to be present in the skin lesion [27-33] bullous pemphigoid epidermolysis bullosa familial benign chronic pemphigus (hailey-hailey disease) keratosis follicularis (darier’s disease) pemphigus foliaceus pemphigus vulgaris staphylococcus scalded skin syndrome transient acantholytic dermatosis (grover’s disease) derived multinucleated giant cells are most commonly caused by a herpes virus infection, they can also be observed in either benign or malignant skin tumors or in patients with acantholytic dermatoses. indeed, our patients presented with vesicular skin lesions that showed epidermal multinucleated giant cells on their initial biopsy specimens and were initially interpreted to represent a herpes virus infection. however, direct fluorescent antibody and culture studies did not confirm the diagnosis of a viral infection. subsequently, repeat lesional skin biopsies revealed pathologic features that were able to establish the correct diagnosis of either pemphigus vulgaris or transient acantholytic dermatosis. therefore, when a herpes virus infection is suspected based upon the discovery of epithelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be 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[letter] acta derm venereal (stockh). 1997;77:412-13. 21. guana al, cohen pr. transient acantholytic dermatosis in oncology patients. j clin oncol. 1994;12:1703-9. 22. whitley rj, roizman b. herpes simplex virus infections. lancet. 2001;357:1513-18. 23. cather jc, cohen pr. herpes simplex virus type 1 infections. j gt houst dent soc. 1998;69(6):12-13. 24. cohen pr, kazi s, grossman me. herpetic geometric glossitis: a distinctive pattern of lingua herpes simplex virus infection. south med j. 1995;88:1231-5. 25. grossman me, stevens aw, cohen pr. herpetic geometric glossitis. n engl j med. 1993;329:1859-60. 26. ruocco v, ruocco e, brunetti g, sangiuliano s, wolf r. opportunistic localization of skin lesions on vulnerable areas. clin dermatol. 2011;29:483-8. 27. bunce pam, stanford dg. grover’s disease secondarily infected with herpes simples virus and staphylococcus aureus: case report and review. australas j dermatol. 2013;54:e88-e91. 28. pantazi v, potouridou i, katsarou a, papadogiorgaki h, katsambas a. darier’s disease complicated by kaposi’s varicelliform eruption due to herpes simplex virus. j eur acad dermatol venereol. 2000;14:209-11. 29. lee gh, kim ym, lee sy, et al. a case of eczema herpeticum with hailey-hailey disease. ann dermatol. 2009;21:311-314. 30. kosann mk, fogelman jp, stern rl. kaposi’s varicelliform eruption in a patient with grover’s disease. j am acad dermatol. 2003;49:914-5. 31. rubin ai, garson mc, morel kd. herpetic infection in epidermolysis bullosa. pediatr dermatol. 2006;23:355-7. 32. niederecker c, tappeiner g, wolff k. generalized herpes simplex infection complicating bullous pemphigoid. br j dermatol. 1995;132:484-6. 33. nikkels af, delvenne p, herfs m, pierard ge. occult herpes simplex virus colonization of bullous dermatitides. am j clin dermatol. 2008;9:163-8. 34. fukuzawa m, oguchi s, saida t. kaposi’s varicelliform eruption of an elderly patient with multiple myeloma. j am acad dermatol. 2000;42:921-922. 35. wollenberg a, zoch c, wetzel s, plewig g, przybilla b. predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. j am acad dermatol. 2003;49:198205. 36. manders sm, chetty bv. eczema herpeticum occurring in autografted skin. j am acad dermatol. 1991;24:509-10. 37. george pb, king r. herpesvirus infection of seborrheic keratosis. am j dermatopathol. 2001;23:146-8. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com commentary | dermatol pract concept 2014;4(1):5 43 have we really concluded what a large cell acanthoma is? is it a distinct entity, a solar lentigo, a subtype of seborrheic keratosis, or an hpv-induced acanthoma? in 1970, large cell acanthoma (lca) was first described by pinkus, as a sharply demarcated, hyperkeratotic patch, often on sun-exposed skin, characterized by extraordinarily large cells with polyploidy [1]. lca presents sharply demarcated hyperorthokeratosis, hypergranulosis, and enlarged keratinocytes without signs of atypical mitoses or nuclear dysplasia. pinkus separated actinic keratosis from lca by its tendency towards invasion, and postulated that lca may be a variant of lentigo senilis or that lentigo senilis may evolve into an lca [1]. the prevalence of this, by that time, newly described entity seemed to be low, according to a retrospective histopathologic analysis held at the department of dermatology, university of cologne, in which 4 cases of lca out of 4268 cases of actinic and seborrheic keratoses were identified [2]. since its original description, a debate in the literature has occurred as to whether lcas are distinctive lesions or solar lentigos with large nuclei. in 1988, sánchez yus et al. discussed that the nature of lca, mostly based on the frequent disordered arrangement of the malpighian cells, the nuclear variability and the occasional finding of dyskeratoses and suprabasal mitoses, and concluded that lca is probably a cytologic variant of bowen’s disease [3]. in 1992, there was a long, constructive series of papers published in the april issue of the american journal of dermatopathology, analyzing the concepts for the origin of lca. rabinowitz and inghirami claimed that lca was a distinctive keratosis, different from solar lentigo on the basis of the lack of color, absence of elongated hyperpigmented hockey-stick-shaped buds, and presence of hyperploid keratinocytes [4]. sánchez yus et al. concluded that lca is a distinctive entity with various stages of development, probably related to stucco keratosis, but histologically separate from solar lentigo [5]. on the other hand, roewert and ackerman stated that lca is a variant of solar lentigo and that solar lentigo (including the large cell variant) is a stage in the evolution of reticulated seborrheic keratosis and of lichen planus-like keratosis [6]. the origin of lca still remains unclear or not well understood. during the last decade, in a small series of papers, a large cell acanthoma: a debate throughout the decades aikaterini patsatsi1, elizabeth lazaridou2, christina fotiadou2, aikaterini kyriakou1, dimitrios sotiriadis1 1 second department of dermatology, aristotle university school of medicine, thessaloniki, greece 2 first department of dermatology, aristotle university school of medicine, thessaloniki, greece keywords: acanthoma, large cell acanthoma, solar lentigo citation: patsatsi a, lazaridou e, fotiadou c, kyriakou a, sotiriadis d. large cell acanthoma: a debate throughout the decades. dermatol pract concept. 2014;4(1):5. http://dx.doi.org/10.5826/dpc.0401a05 received: august 31, 2013; accepted: october 23, 2013; published: january 31, 2014 copyright: ©2014 patsatsi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aikaterini patsatsi, m.d., plagiari po box 461, 57500 thessaloniki, greece. tel. +302313323291; fax. +302310991473. email: katerinapatsatsi@gmail.com mailto:katerinapatsatsi@gmail.com 44 commentary | dermatol pract concept 2014;4(1):5 lca is still in question. in most cases, clinically, lca may be difficult to be differentiated from a solar lentigo, a pigmented actinic keratosis, or a flat and pigmented seborrheic keratosis. in 2003, mehregan et al., having studied 19 cases of lca, defined as histological characteristics of lca the presence of epidermal keratinocytes with nuclei roughly twice the size of adjacent epidermal or adnexal keratinocytes and with minimal nuclear pleomorphism. the authors concluded that on the basis of clinical, histologic, and immunohistochemical staining similarities, lca should be considered as a reaction pattern, possibly related to solar lentigo [11]. in the same study, solar lentigo and large cell acanthoma showed statistically significant increased numbers of melanocytes compared with both normal skin and actinic keratosis. the number of melanocytes did not differ significantly between lca and solar lentigo. in the era of dermoscopy, dermoscopic features of a large series of lcas have not been defined yet. our unpublished experience supports the option that lca is a solar lentigo. discussion around a possible link of lca origin with hpv infection has started. may hpv infection serve as a cofactor, possibly in conjunction with solar ultraviolet irradiation, in the generation of lcas, based on the detection of hpv dna in lesional skin? [7-9] if the reader scrutinizes the clinical and histological features of the hpv–induced lcas, many questions arise on whether the described lesions are lcas or plane warts, as well opposed by the correspondence paper of lora et al. in 2009. the authors suggest that in ambiguous cases, immunohistochemistry and/or in-situ hybridization (along with pcr) must be performed so as to precisely localize hpv-infected cells within the lesion, thus avoiding misdiagnosis of plane warts as lca [10]. moreover, most of the hpv–associated lcas are multiple and non-pigmented. as noted in most papers, lcas are hyperpigmented macules or plaques on sun-damaged skin. whether the hyperpigmentation is a stable finding of a true figure 1a. a sharply demarcated patch on sun exposed skin. [copyright: ©2014 patsatsi et al.] figure 1b. hyperorthokeratosis, enlarged keratinocytes without signs of atypical mitoses, increased number of melanocytes (h&e x40). [copyright: ©2014 patsatsi et al.] figure 1c. a brown, “broken up” pseudonetwork, scattered gray, brown dots and foci of surface scale. [copyright: ©2014 patsatsi et al.] commentary | dermatol pract concept 2014;4(1):5 45 4. rabinowitz ad, inghirami g large-cell acanthoma. a distinctive keratosis. 5. am j dermatopathol. 1992;14(2):136-8. 6. sánchez yus e, del rio e, requena l. large-cell acanthoma is a distinctive condition. am j dermatopathol. 1992;14(2):140-7. 7. roewert hj, ackerman ab. large-cell acanthoma is a solar lentigo. am j dermatopathol. 1992;14(2):122-32. 8. berger t, stockfleth e, meyer t, kiesewetter f, funk jo. multiple disseminated large-cell acanthomas of the skin associated with human papillomavirus type 6. j am acad dermatol. 2005;53(2):335-7. 9. garrido-rios aa, sanz-munoz c, aragoneses-fraile mh, et al. human papillomavirus detection in multiple large-cell acanthomas. j eur acad dermatol venereol. 2009;23(4):454–5. 10. wu yf, ko jh, kuo t, et al. large cell acanthoma manifesting as multiple white papules on extremities. dermatologica sinica. 2011;29:144-6. 11. lora v, kanitakis j. hpv detection in ‘large-cell acanthomas’: a word of caution. j eur acad dermatol venereol. 2009;23(12):1468-9. 12. mehregan dr, hamzavi f, brown k. large cell acanthoma. int j dermatol. 2003;42(1):36-9. 13. ackerman ab. response to drs rabinowitz and inghirami. am j dermatopathol. 1992;14(2):139. dermoscopy may reveal pseudofollicular openings, gray and brown dots and globules, yellow opaque homogeneous areas, surface scale and a delicate, light brown, pseudonetwork commonly seen in solar lentigos. the prominent dermoscopic features in a case of ours were a brown, “broken up” pseudonetwork, scattered gray, brown dots and foci of surface scale (figure 1a-c). should we agree, instead of a conclusion, with the statement of dr ackerman, in one of the response letters regarding the lca origin, in 1992, that “ we insist that every large cell acanthoma has long had a place in the sun—and that is precisely how it came to be a solar lentigo!’’ [12] references 1. pinkus h. epidermal mosaic in benign and precancerous neoplasia (with special reference to large cell acanthomas). acta dermatol (kyoto). 1970;65(2):75-81. 2. scholl w. large cell acanthoma. z hautkr. 1982;57(13):1002-5. 3. sánchez yus e, de diego v, urrutia s. large cell acanthoma. a cytologic variant of bowen’s disease? am j dermatopathol. 1988;10(3):197-208. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(1):16 93 case presentations case 1 a 39-year-old japanese man presented with 6-month history of a group of papules on the chest (figure 1a). the patient had no specific symptoms, such as itching or tenderness, but visited the clinic worried about the long duration of the lesions. physical examination showed pinkish white, firm papules of 5 to 10 mm in diameter with sharply demarcated borders. the surface of the papules was smooth and shiny. dermoscopic examination demonstrated aggregation of yellowish-white clods with linear vessels between or above the clods exhibiting reticular distribution as a whole (figure 1b). other papules also showed similar features. high dynamic range (hdr) [1,2] conversion of the dermoscopy photograph further clarified the multi-lobulated clods with a central opening (figure 1c). histopathological examination of the biopsied lesions established the diagnosis of sebaceous hyperplasia (sh) (figure 1d). based on the clinical, dermoscopic and histopathological findings, the final diagnosis was linear sh on the chest. case 2 a 32-year-old japanese woman presented with a 5-year history of linearly arranged papules on the upper chest (figure 2a). the patient was asymptomatic, including itching or tenderness. physical examination showed yellowish-white, firm papules up to 5 mm in diameter with a clear border. the surface of the papules was smooth and shiny. dermoscopic examination demonstrated aggregation of yellowish-white clods with vague linear vessels surrounding the clods (figure 2b). all other papules showed similar features. hdr image conversion of the dermoscopy photograph further clarified the multi-lobulated clods and the surrounding vessels (figure 2c). based on the clinical and dermoscopic findings, a diagnosis of linear sh on the chest was established. discussion sh represents benign proliferation of the sebaceous gland and tends to appear on the forehead and temples of middle-aged or elderly people [3]. it has also been reported in the vulva, penis and areola [4]. familial forms have also been reported [4]. to our knowledge, this is the second and the third cases of linear sh on the chest, but the sh in our cases are not on the midline of the anterior chest as described in the first report [5]. our cases were sporadic and not familial but the distribution of the papules seems to be along the blaschko line, suggesting that sh in our cases might have occurred as a result of mosaic mutation. linear sebaceous hyperplasia on the chest toshitsugu sato1, masaru tanaka2 1 sato dermatology clinic, tokyo, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan keywords: sebaceous hyperplasia, linear arrangement, chest, dermoscopy, high dynamic range, image conversion citation: sato t, tanaka m. linear sebaceous hyperplasia on the chest. dermatol pract concept. 2014;4(1):16. http://dx.doi.org/10.5826/ dpc.0401a16 received: june 9, 2013; accepted: june 14, 2013; published: january 31, 2014 copyright: ©2014 sato et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: toshitsugu sato, m.d., sato dermatology clinic, 1-7-3 kami-ogi, suginami-ku, tokyo 167-0043, japan. tel. +81 3 5397 3663; fax: +81 3 5397 3663. email: sato3663@gmail.com 94 observation | dermatol pract concept 2014;4(1):16 accurate diagnosis of sh is necessary, although no treatment is required in most cases. references 1. sato t, tanaka m. improved detection of dermoscopic structures by high dynamic range image conversion. jpn j dermatol. 2013;123:121-31. 2. “high dynamic range imaging.” http://en.wikipedia.org/wiki/ high_dynamic_range_imaging, 2013. accessed june 1, 2013. 3. layton am. disorders of the sebaceous glands. in: rook’s textbook of dermatology. 8th ed. west sussex: wiley-blackwell, 2010. 4. ahmed tss, preore jd, seykora j. tumors of the epidermal appendages. in: lever’s histopathology of the skin. 10th ed, philadelphia: lww, 2009:872. 5. jeong tj, shin mk, lee mh. linear sebaceous hyperplasia on the chest. clin exp dermatol. 2009;34(7):e366-7. 6. kato n, yasuoka a. “giant” senile sebaceous hyperplasia. j dermatol. 1992;19(4):238-41. several more variants of sh have been reported. for example, a giant form of 10 mm in diameter has been reported on the cheek [6] and four cases with a linear arrangement have been reported on the preand retro-auricular, neck and chin areas. each papule in these four cases ranged from 2 to 5 mm in diameter and formed a plaque measuring up to 1.5 cm wide x 8 cm long [7]. in another case of the linear type, the papules appeared on the juxta-clavicular beaded lines. they were small in size, 0.5-1.5 mm in diameter, and exhibited a linear arrangement on the supraor subclavicular areas [8]. the exact pathological mechanism of sh is unknown though the condition is associated with advanced age, ultraviolet irradiation and immunosuppression therapy especially cyclosporine a alone or in combination with corticosteroids [9]. sh is not directly associated with malignant disorders, although sebaceous neoplasms have been reported to be association with internal malignancy in the setting of muirtorre syndrome [10]. a b c d figure 1. case 1. (a) a group of papules on the chest with linear distribution pattern. (b) dermoscopy of sebaceous gland hyperplasia. note the aggregation of yellowish-white clods with linear vessels between or above the clods. (c) dermoscopy of sebaceous gland hyperplasia followed by hdr image conversion. note the multi-lobulated clods with central openings. (d) hematoxylin and eosin staining of biopsied lesion of sebaceous gland hyperplasia: note the multiple, mature sebaceous lobules attached to the central dilated duct in the upper dermis. original magnification x25. [copyright: ©2014 sato et al.] http://en.wikipedia.org/wiki/high_dynamic_range_imaging http://en.wikipedia.org/wiki/high_dynamic_range_imaging observation | dermatol pract concept 2014;4(1):16 95 9. zouboulis cc, boschnakow a. chronological ageing and photoageing of the human sebaceous gland. clin exp dermatol. 2001;26(7):600-7. 10. schwartz ra, torre dp. the muir-torre syndrome: a 25-year retrospect. j am acad dermatol. 1995;33(1):90-104. 7. fernandez n, torres a. hyperplasia of sebaceous glands in a linear pattern of papules. report of four cases. am j dermatopathol. 1984;6(3):237-43. 8. franco g, donati p, muscardin l, maini a, morrone a. juxtaclavicular beaded lines. australas j dermatol. 2006;47(3):204-5. a b figure 2. case 2. (a) multiple papules on the chest showing linear arrangement. (b) dermoscopy of sebaceous gland hyperplasia. note the aggregation of yellowish-white clods with vague linear vessels surrounding the clods. (c) dermoscopy of sebaceous gland hyperplasia followed by hdr image conversion. note the multi-lobulated clods with central openings and surrounding vessels. [copyright: ©2014 sato et al.] c untitled note | dermatol pract concept 2015;5(2):17 87 dermatology practical & conceptual www.derm101.com importance: medical professionals and indeed the general public have an increasing interest in the acquisition of dermatoscopic images of suspect or ambiguous skin lesions. to this end, good dermatoscopic image quality and low costs are important considerations. observations: images of seven lesions (seborrheic keratosis, melanoma in-situ, blue and dermal nevus, basal cell carcinoma and two squamous cell carcinomas) were taken. a novel technique of “tape dermatoscopy” involved: 1. using immersion fluid (i.e., water, olive oil, disinfectant spray) placed on the flat or slightly elevated lesion; 2. covering the lesion with transparent adhesive tape with lateral tension; 3. using ambient indoor or outdoor lighting for illumination (rather than flash photography); 4. positioning a photographic device at an angle of approximately 45° from the side of the lesion to avoid light reflection; 5. recording a focused image with a mobile phone or digital camera at a distance of approximately 25-30 cm from the lesion; and 6. enlarging the image on the screen of the device. essential dermatoscopic features enabling a correct diagnosis were visible in 6 of the 7 lesions. ‘tape dermatoscopy” images of the lesions were compared to standard dermatoscopy (using a fotofinder handyscope® in combination with a mobile phone). the latter confirmed the dermatoscopic features in six of seven lesions. conclusions and relevance: “tape dermatoscopy” images can be recorded by medical personnel and even the general public without a dermatoscope. however, the limitations of this method are that images may be unfocused, exophytic tumors may be difficult to assess, excess pressure on tumoral blood vessels may lead to compression artefact, dermatoscopic features that are only visible under polarized light are unable to be detected (particularly “crystalline” or “chrysalis” structures) and tumors in certain anatomic locations may be difficult to assess (e.g., edges of nose, ears [demonstrated in one case], nails). comparative prospective studies are necessary in order to test reproducibility of these preliminary findings, to establish special indications for the technique, and to develop guidelines for its effective use. abstract “tape dermatoscopy”: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape andreas blum1, jason giacomel2 1 public, dermatology, konstanz, germany 2 skin spectrum medical services, como, western australia, australia key words: low-cost, dermoscopy, dermatoscopy, simplified dermatoscopy, tape dermatoscopy, tape dermoscopy, transparent adhesive tape, mobile phone citation: blum a, giacomel j. “tape dermatoscopy”: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape. dermatol pract concept 2015;5(2):17. doi: 10.5826/dpc.0502a17 received: september 21, 2014; accepted: march 3, 2015; published: april 30, 2015 copyright: ©2015 blum et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: andreas blum, md, dermatology, seestrasse 3a, 78464, konstanz, germany. tel. +49 7531 643 11; fax. +49 7531 600 54. e-mail: a.blum@derma.de 88 note | dermatol pract concept 2015;5(2):17 revealed the dermatoscopic features of comedo-like openings, milia-like cysts, gyri, sulci and homogeneous yellowish to brownish colors, suggestive of a seborrheic keratosis. on the following day standard dermatoscopic images were taken with a fotofinder handyscope (fotofinder systems, bad birnbach, germany) attached to an iphone 5 (apple inc., cupertino, ca, usa). the latter confirmed the dermatoscopic features and “tape dermatoscopy” diagnosis (figure 2b), and no histology was considered necessary. case 2 an 88-year-old man noticed a change in a flat lesion on his left arm. a “tape dermatoscopy” image was taken (by a.b.) using disinfectant spray as immersion fluid, clear adhesive tape, indoor ambient light, and a mobile phone with an 8 megapixel camera (iphone 5). a thin melanoma was suspected, as the image showed the “tape dermatoscopy” features of atypical homogeneous brownish, whitish and pinkish areas, multiple grey dots, and some asymmetric, patchy, tan-brown pigmentation (figure 3a). a subsequent standard dermatoscopic image was taken with a fotofinder handyscope, confirming the dermatoscopic features and provisional diagnosis (figure 3b). histopathology revealed lentigo maligna on actinic damaged skin. case 3 a 78-year-old woman presented with an unchanged flat, pigmented lesion on her left forearm. a “tape dermatoscopy” image was taken (by a.b.) with a mobile phone (iphone 5) in ambient indoor lighting, using disinfectant spray as immerintroduction diagnosing skin cancer with the naked eye can be difficult, especially for early tumors. for this purpose dermatoscopy is extremely helpful [1-3]. medical professionals and, indeed, the general public have an increasing interest in the acquisition of dermatoscopic images of suspect or ambiguous skin lesions. preferably, this could be achieved at low cost without compromising image quality. saweda and tanaka have developed a low-cost dermatoscopic device using echo-gel on the skin lesion, mounting a glass slide, illuminating the lesion at an angle from above using a torch, and examining the lesion using a microscope eyepiece (ocular) lens [4]. however, a procedure to record images is not provided by this technique. in the current pilot study, an approach is presented for a useful, simplified and inexpensive “tape dermatoscope.” seven flat or slightly elevated skin lesions were examined. transparent adhesive tape was applied to each lesion with lateral tension after covering the lesion with immersion fluid. finally, images were recorded using a mobile phone or digital camera (figure 1). report of the cases case 1 a 48-year-old female sent an e-mail image of an enlarging, slightly elevated lesion on her right breast. “tape dermatoscopy” was subsequently performed by a family member instructed in the technique. after applying olive oil and transparent adhesive tape on the lesion, images were taken in outdoor daylight using a 5 megapixel iphone 4 mobile phone (apple inc., cupertino, ca, usa) (figure 2a). the image figure 1. schematic drawing demonstrating the “tape dermatoscopy” technique: (1) covering the lesion with immersions fluid (e.g., water, olive oil or disinfectant spray), (2) applying transparent adhesive tape over the lesion with lateral tension, (3) using ambient indoor or outdoor light for illumination, (4) approaching the lesion with the recording device at an angle of approximately 45° to avoid light reflection from the tape, and (5) recording a sharp image with a mobile phone or digital camera (with good macro capability) at a distance of approximately 20 to 30 cm. [copyright: ©2015 blum et al.] note | dermatol pract concept 2015;5(2):17 89 camera (iphone 5) (by a.b). disinfectant spray as an immersion fluid and transparent adherent tape were used, and the photographs were taken in ambient indoor light (figure 5a). standard dermatoscopic images of the same lesion were later recorded with a fotofinder handyscope (figure 5b). in both images the atypical arborizing vessels of a basal cell carcinoma (lower part), the milia-like cysts, and homogeneous yellowish to brownish colors of a seborrheic keratosis (upper part) were clearly visible. histopathology confirmed this collision tumor. sion fluid and transparent adherent tape. a homogeneous blue color was seen, suggestive of a blue nevus (figure 4a). a subsequent standard dermatoscopic image (taken with fotofinder handyscope) revealed the same feature (figure 4b). histologic confirmation was deemed unnecessary. case 4 a 90-year-old female presented with a recent onset of a reddish-brown, slightly elevated lesion on her left temple. a “tape dermatoscopy” image was taken using a mobile phone a figure 2. seborrheic keratosis on the right breast. (a) enlarged “tape dermatoscopy” image of the lesion. the lesion had been covered with immersion fluid (olive oil) and a tensioned transparent adhesive tape applied. (b) standard non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] b a figure 3. lentigo maligna on actinic damaged skin of the left arm. (a) enlarged “tape dermatoscopy” image of the flat lesion which had been covered with immersion fluid and tensioned transparent adhesive tape. photograph taken using an iphone 5 camera. (b) normal non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] b 90 note | dermatol pract concept 2015;5(2):17 dermatoscopy” revealed some (albeit unfocused) atypical vessels, ulcerations, whitish circles, and white lines (figure 6b and c). in the normal dermatoscopic image taken with a fotofinder handyscope linear irregular and hairpin-like vessels were clearly visible. in addition, there were ulcerations with blood spots, whitish circles and white lines (figure 6d). histopathologic examination confirmed an invasive squamous cell carcinoma. case 5 a 77-year-old woman presented with a reddish exophytic tumor on the left zygomatic area. clinical (figure 6a) and “tape dermatoscopy” images (figure 6b and c) were recorded (by a.b.). disinfectant spray was employed as an immersion fluid, and transparent adherent tape, ambient indoor lighting, and an iphone 5 were used. subsequent standard dermatoscopy images were taken with a fotofinder handyscope (figure 6d), during a regular office consultation. ‘tape a figure 4. blue nevus on the left forearm. (a) enlarged “tape dermatoscopy” image of the lesion after covering with immersion fluid and a tensioned transparent adhesive tape. (b) standard non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] b a figure 5. collision tumor of a basal cell carcinoma (lower part) and seborrheic keratosis (upper part) on the left temple. (a) enlarged “tape dermatoscopy” image of the lesion taken after applying immersion fluid and a tensioned transparent adhesive tape. (b) regular non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] b note | dermatol pract concept 2015;5(2):17 91 case 7 a 38-year-old man presented with a soft, elevated tumor on the scalp (figure 8a). low-cost “tape dermatoscopy” was performed (by a.b.) using disinfectant spray as an immersion fluid, transparent adherent tape, indoor ambient lighting, and an iphone 5. “tape dermatoscopy” revealed aggregated brownish globules (figure 8b). standard dermatoscopic photographs were subsequently taken with a fotofinder handyscope (figure 8c). the latter confirmed the presence of aggregated light-brown globules (“cobblestone pattern”) but also disclosed a few comma vessels (figure 8c). the diagnosis of dermal nevus was confirmed by histopathologic examination. discussion the current pilot study demonstrates the simple, cost-effective technique of “ tape dermatoscopy.” “tape dermatoscopy” images of flat or slightly elevated skin lesions can be recorded case 6 a 75-year-old man presented with an exophytic tumor on the lower antihelix of the right ear (figure 7a). low-cost “tape dermatoscopy” was carried out (by a.b.) using disinfectant spray as an immersion fluid, transparent adherent tape, indoor ambient lighting, and an iphone 5 (figure 7b). however, the “tape dermatoscopy” technique was not effective for the exophytic tumor at this anatomic area (left side of figure 7b) and the image of the surface of the tumor was unfocused (right side of figure 7b). standard dermatoscopy images were then recorded using a fotofinder handyscope (figure 7c). it was only possible to take a standard dermatoscopic image from the lateral aspect of the exophytic tumor. the latter revealed whitish circles, white-to-yellow keratotic areas, blood spots, and linear vessels in the upper part of the image (figure 7c). histopathologic examination confirmed an invasive squamous cell carcinoma. a b c d figure 6. (a) clinical image of invasive squamous cell carcinoma on the left zygomatic area. (b) “tape dermatoscopy” image taken with a mobile phone after the lesion was covered with immersion fluid and a tensioned transparent adhesive tape. (c) enlarged image of figure 6b. (d) normal non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] 92 note | dermatol pract concept 2015;5(2):17 (1) images may be unfocused, especially if the camera has an insufficient macro capability to record images close to the lesion; (2) markedly exophytic tumors are difficult to record (figure 6a-d); (3) tumoral blood vessels [5,6,13] can potentially be compressed while attaching and tensioning the adhesive tape (figure 8b); (4) diagnostic helpful features such as “crystalline” (“chrysalis”) structures are not visible with this non-polarized method [14,15]; and (5) tumors in difficult locations (e.g., convex surfaces of the nose, ears, and nails) may not be able to be recorded with adequate image quality (figure 7a-c). however, for many types of skin lesions located on relatively flat anatomic areas (including the scalp), the “ tape dermatoscopy” method is easily applicable and potentially effective. prospective studies of this proposed new technique are required, using large comparative series. the latter would involve comparing “ tape dermatoscopy” images recorded by non-professionals with standard dermatoscopic images taken by professionals with a standard dermatoscope. such studies may elucidate special indications for the technique and develop practicable guidelines for public use. references 1. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol 2002;3(3):159-65. by medical professionals and even untrained persons without the need of a standard dermatoscope. the technique may be useful for several types of skin lesions, including seborrheic keratosis, dermal nevus, blue nevus, invasive squamous cell carcinoma, lentigo maligna (highlighting diagnostically useful features such as multiple grey dots and pink areas) [5,6], and basal cell carcinoma. “tape dermatoscopy” images can be recorded and immediately scrutinized on the screen of a mobile phone, camera or computer and may be transmitted worldwide in a teledermatoscopical setting [7-10]. furthermore, the method may enable a triage system for skin cancer detection by patients themselves [11]. this could result in early cure of both non-melanoma skin cancer as well as melanoma, with reduced morbidity and even mortality [12]. however, the “ tape dermatoscopy” technique does have several limitations: figure 7. (a) exophytic invasive squamous cell carcinoma located on the antihelix of the right ear. (b) the transparent adhesive tape could not be applied satisfactorily on the exophytic tumor at this anatomic area (left side) and the “tape dermatoscopy” image was out of focus (right side). (c) standard non-polarized dermatoscopic image taken with a fotofinder handyscope was only possible from the lateral side. [copyright: ©2015 blum et al.] a b c note | dermatol pract concept 2015;5(2):17 93 ence on 690 austrian patients. j eur acad dermatol venereol 2014;28(8):1103-8. 10. karavan m, compton n, knezevich s, et al. teledermatology in the diagnosis of melanoma. j telemed telecare 2014;20(1):18-23. 11. börve a, gyllencreutz jd, terstappen k, et al. smartphone teledermoscopy referrals: a novel process for improved triage of skin cancer patients. acta derm venereol. 2015 jan 15; 95(2):186-90. 12. ferrándiz l, ruiz-de-casas a, martin-gutierrez fj, et al. effect of teledermatology on the prognosis of patients with cutaneous melanoma. arch dermatol 2012;148(9):1025-8. 13. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol 2008;144(9):1120-27. 14. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol 2012;67(2):194. e1-8. 15. wang sq, dusza sw, scope a, et al. differences in dermoscopic images from nonpolarized dermoscope and polarized dermoscope influence the diagnostic accuracy and confidence level: a pilot study. dermatol surg 2008;34(10):1389-95. 2. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol 2008;159(3):669-76. 3. argenziano g, giacomel j, zalaudek i, et al. a clinico-dermoscopic approach for skin cancer screening: recommendations involving a survey of the international dermoscopy society. dermatol clin 2013;31(4):525-34. 4. sawada m, tanaka m. self-assembly of a simple low-cost dermoscope for examination of skin lesions. dermatol pract concept 2013:3(4):35. 5. fabbrocini g, balato a, rescigno o, et al. telediagnosis and faceto-face diagnosis reliability for melanocytic and non-melanocytic ‘pink’ lesions. j eur acad dermatol venereol 2008;22(2):229-34. 6. giacomel j, zalaudek i. pink lesions. dermatol clin 2013;31(4): 649-78. 7. tan e, yung a, jameson m, oakley a, rademaker m. successful triage of patients referred to a skin lesion clinic using teledermoscopy (image it trial). br j dermatol 2010;162(4):803-11. 8. lim d, oakley am, rademaker m. better, sooner, more convenient: a successful teledermoscopy service. australas j dermatol 2012;53(1):22-5. 9. massone c, maak d, hofmann-wellenhof r, soyer hp, frühauf j. teledermatology for skin cancer prevention: an experifigure 8. (a) “tape dermatoscopy” image of an elevated dermal nevus on the scalp. the lesion had been covered with immersion fluid (disinfectant spray) and tensioned transparent adhesive tape. (b) enlarged image of figure 8a. (c) normal non-polarized dermatoscopic image taken with a fotofinder handyscope. [copyright: ©2015 blum et al.] a b c untitled observation | dermatol pract concept 2015;5(2):8 57 dermatology practical & conceptual www.derm101.com case report a 75-year-old male farmer presented to a primary care skin cancer practice in west australia with a 6-month history of an enlarging painless lesion on his left cheek with no history of any possible precursor lesion. the patient was of italian parentage with fitzpatrick skin photo-type 3. there was a past history of treatment of two separate squamous cell carcinomas in-situ, one on the forehead and the other on an ear, in the previous two years. other comorbidities included asthma, coronary heart disease, chronic obstructive pulmonary disease and arthritis. there was no history of nevus sebaceous and there was neither history nor clinical signs suggestive of cowden’s syndrome. examination showed a single small non-pigmented nodular lesion located on the left cheek in continuation with a small, pigmented macular lesion (figure 1). dermatoscopy (figure 2) revealed a raised pink lesion, 3.5 mm in diameter, with a radial arrangement of vessels peripherally, with centered blood vessels in the middle of the lesion, these vessels being centered in skin-colored clods. no keratin structures (keratin scale, white structureless areas or white circles) were seen. at one edge of this lesion, in direct contact with it, was a heavily pigmented flat lesion, 1 mm in trichilemmoma in continuity with pigmented basal cell carcinoma; with dermatoscopy and dermatopathology moayad al kaptan1, joseph kattampallil2, cliff rosendahl3 1 molescan clinic, cooloongup, wa, australia 2 clinipath pathology, osborne park, wa, australia 3 school of medicine, the university of queensland, australia key words: trichilemmoma, pigmented basal cell carcinoma, dermatoscopy, dermoscopy, dermatopathology citation: al kaptan m, kattampallil j, rosendahl c. trichilemmoma in continuity with pigmented basal cell carcinoma; with dermatoscopy and dermatopathology. dermatol pract concept 2015;5(2):8. doi: 10.5826/dpc.0502a08 received: february 12, 2015; accepted: march 3, 2015; published: april 30, 2015 copyright: ©2015 al kaptan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, phd, 5 larbonya crescent, capalaba, queensland, australia 4157. tel. +61 419 769 970; fax. +617 3245 3011email: cliffrosendahl@bigpond.com a case of trichilemmoma in continuity with a pigmented basal cell carcinoma is presented with dermatoscopy and dermatopathology. the distinction between the two lesions was evident dermatoscopically and was confirmed dermatopathologically. while trichilemmoma has been reported in association with basal cell carcinoma and dermatoscopy images of four previous cases of trichilemmoma have been published, no previous dermatoscopy image has been published of trichilemmoma associated with basal cell carcinoma. abstract mailto:cliffrosendahl@bigpond.com 58 observation | dermatol pract concept 2015;5(2):8 high power an eosinophilic mantle of thickened basement membrane, mimicking the outer root sheath of the hair follicle infundibulum, was seen. peripheral palisading was evident adjacent to the basement membrane and extending from that there were clear cells which were banal cytologically, lacked mitosis or individual cell necrosis (apoptosis) and contained an abundant amount of glycogen within their cytoplasm. the bcc component (figure 3 b1 and b2) showed superficial bcc at the dermo-epidermal junction. in the high power view melanin pigment could be seen. diameter with a pattern of pigmented lines radial, converging (figure 2). the lesion was subjected to an excision biopsy with a 4 mm peripheral margin and submitted for dermatopathological evaluation. dermatopathology (figure 3) showed both the trichilemmoma and bcc (basal cell carcinoma) components. the trichilemmoma (figure 3 a1 and a2) was a well-circumscribed, sharply demarcated lesion with surface papillomatosis, horn cysts and a degree of central desmoplasia. under figure 1. clinical image of a focally pigmented nodular lesion on the left cheek of a 75-year-old man. [copyright: ©2015 al kaptan et al.] figure 2. dermatoscopy images (polarized left, non-polarized right) of the lesion shown in figure 1. there is a focal pigmented macular component with lines radial converging and a larger nonpigmented nodule with a radial arrangement of vessels peripherally and a centered arrangement of vessels centrally. [copyright: ©2015 al kaptan et al.] figure 3 a and b. dermatopathology images of the lesion shown in figures 1 and 2. a1: low power view of the trichilemmoma component showing a well-circumscribed, sharply demarcated lesion with surface papillomatosis, three horn cysts and a degree of desmoplasia centrally. a2: higher power view) shows a thickened basement membrane (black arrow), peripheral palisading (yellow arrow) and clear cells (green arrow). b1: low power view of the bcc component showing superficial bcc at the dermo-epidermal junction. b2: higher power view of the bcc with low light, showing melanin pigment (arrow). [copyright: ©2015 al kaptan et al.] observation | dermatol pract concept 2015;5(2):8 59 sented here are consistent with those published previously, with a radial pattern of vessels peripherally and centred vessels centrally. association with a bcc is a previously reported, unusual variation, consistent with both lesions having hairfollicle derivation. this case demonstrates the utility of using a decision algorithm in esoteric cases with the final diagnosis to be delivered by the gold standard of dermatopathology. references 1. tsai j-h, huang w-c, jhuang j-y, et al. frequent activating hras mutations in trichilemmoma. br j dermatol 2014;171(5):1073– 77. 2. sano dt, yang jjh, tebcherani aj, bazzo la de pm. a rare clinical presentation of desmoplastic trichilemmoma mimicking invasive carcinoma. an bras dermatol 2014;89(5):796–98. 3. ackerman ab. trichilemmoma. arch dermatol 1978:114(2):286. 4. brownstein mh. trichilemmoma. benign follicular tumor or viral wart? am j dermatopathol 1980:2(3):229–31. 5. sellheyer k. basal cell carcinoma: cell of origin, cancer stem cell hypothesis and stem cell markers. br j dermatol 2011;164(4): 696–711. 6. wang y, bu w-b, chen h, zhang m-l, et al. basal cell carcinoma, syringocystadenoma papilliferum, trichilemmoma, and sebaceoma arising within a nevus sebaceus associated with pigmented nevi. dermatol surg 2011;37(12):1806–10. 7. yoon dh, jang ig, kim ty, kim ho, kim cw. syringocystadenoma papilliferum, basal cell carcinoma and trichilemmoma arising from nevus sebaceus of jadassohn. acta derm venereol 1997;77(3):242–43. 8. crowson an, magro cm. basal cell carcinoma arising in association with desmoplastic trichilemmoma. am j dermatopathol 1996;18(1):43–8. 9. lallas a, moscarella e, argenziano g, et al. dermoscopy of uncommon skin tumours. australas j dermatol 2014;55(1):53–62. 10. horcajada-reales c, avilés-izquierdo ja, ciudad-blanco c, et al. dermoscopic pattern in facial trichilemmomas: red iris-like structure. j am acad dermatol 2015;72(1 suppl):s30–2. 11. rosendahl c, cameron a, tschandl p, et al. prediction without pigment: a decision algorithm for non-pigmented skin malignancy. dermatol pract concept 2014;4(1):9. 12. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice— “chaos and clues.” aust fam physician 2012;41(7):482–87. conclusions trichilemmoma is a benign tumor derived from the external sheath cells of pilosebaceous units [1] and desmoplastic trichilemmoma is a rare variant, which can present clinically with features suggesting invasive malignancy [2]. there has been controversy as to whether trichilemmomas are actually aged warts, this belief being proposed by well-known dermatopathologist bernie ackerman [3] but vigorously opposed by others including marty brownstein [4]. basal cell carcinoma is a malignant tumor, of trichoblast differentiation but uncertain origin, although it is probably of follicular derivation [5], predilection for non-glabrous skin being consistent with this. trichilemmoma has previously been reported in association with bcc in the context of lesions arising in a preexisting nevus sebaceous [6,7]. in addition, three cases of desmoplastic trichilemmoma arising in association with bcc without a preexisting nevus sebaceous have been reported [8]. the dermatoscopy of four trichilemmomas has been reported [9,10] with images being presented for three of them [10]. in the first case reported, without a photograph, the dermatoscopic features were described as “keratin masses; perivascular whitish halos” [9]. the other three were reported together, with the first two described as having a hyperkeratotic central area with peripheral erythematous radial lines, the third having a “peripheral radiated red area.” all three were then presented as depicting what the authors called a “red iris like structure.” examination of the photographs published in fact displayed a non-pigmented lesion in each case with a radial arrangement of vessels peripherally and structureless white centrally with some centred vessels [11]. in the case we report, the clinician interpreted the lesion as a pigmented lesion and assessed it using the chaos and clues decision-algorithm [12]. the lesion was regarded as chaotic (asymmetrical) with the clues of an eccentric structureless (pink) area as well as lines radial segmental, which lead to a clear decision to do an excision biopsy. the pathologist, as is often the case with esoteric lesions, was able to deliver the answer to which particular type of malignancy this was. the dermatoscopic features of the trichilemmoma predermatology: practical and conceptual 222 letter | dermatol pract concept 2019;9(3):13 dermatology practical & conceptual a case of lepromatous leprosy clinically masquerading as vasculitis ali sadeghinia1, shadi azizzadeh-roodpishi1, maryam daneshpazhooh1, kambiz kamyab2, amin kiani1, hamidreza mahmoudi1 1 department of dermatology, autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran 2 department of dermatopathology, razi hospital, tehran university of medical sciences, tehran, iran key words: leprosy, vasculitis, skin lesions, misdiagnosis citation: sadeghinia a, azizzadeh-roodpishi s, daneshpazhooh m, kamyab k, kiani a, mahmoudi h. a case of lepromatous leprosy clinically masquerading as vasculitis. dermatol pract concept. 2019;9(3):222-224. doi: https://doi.org/10.5826/dpc.0903a13 accepted: february 14, 2019; published: july 31, 2019 copyright: ©2019 sadeghinia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: hamidreza mahmoudi, md, autoimmune bullous diseases research center, razi hospital, vahdate-eslami square, 11996, tehran, iran. email: hr_mahmoody@yahoo.com introduction leprosy is a chronic infectious disease caused by mycobacterium leprae affecting mostly skin and nervous system. it can have different clinical manifestations and can even mimic diseases of autoimmune origin and of vasculitis [1, 2]. here, we discuss a patient with an 8-year misdiagnosis of vasculitis that turned out to be leprosy. clinical presentation a 32-year-old man was referred to the dermatology clinic at razi hospital, tehran, iran, complaining of erythematous lesions for 8 months and a history of distal peripheral neuropathy for 8 years. he suffered from recurrent chronic punched-out ulcers on extremities with scar formation. he was diagnosed with vasculitis, most likely polyarteritis nodosa, because of the presence of lower limb ulcers, peripheral neuropathy, and livedoid-like skin changes. no skin biopsy was done at the time to help confirm the diagnosis. he was under treatment by rheumatologists before referral to our clinic and had been treated for 1 year with azathioprine (100 mg/day) and prednisolone (10 mg/day) to control neuropathy. physical examination revealed diffuse erythematous urticarial plaques on the patient’s trunk. poikilodermic changes were evident on his face and neck. he had bilateral hand and foot muscle atrophy and paresthesia. a few healing ulcers were evident on his ankles (figure 1). the lesions were not painful and he had no associated joint pain. neural examination revealed profound sensory impairment. laboratory examination only showed an elevated erythrocyte sedimentation rate of 56 mm/hour. no previous biopsy had been done. in the context of these findings, vasculitis, autoimmune connective tissue disease (actd), mycosis fungoides, and leprosy were the most likely differential diagnoses. a punch biopsy was taken from urticarial trunk lesions. microscopic view revealed perivascular, perifollicular, and perineural infiltration of mononuclear inflammatory cells and histiocytes. in addition, hypertrophied nerve bundles were seen. no signs of vasculitis were evident. acid-fast organisms were detected in ziehl-neelsen stain, especially letter | dermatol pract concept 2019;9(3):13 223 conclusions leprosy is a neglected tropical disease. it still infects a considerable population in developing countries. it has cutaneous and neurological manifestations and can also present with clinical manifestations resembling vasculitis [1]. there are some previous reports of leprosy mimicking vasculitis and actd clinically. hsieh and wu [2] reported a man with arthritis, joint deformities, paresthesia, malar rash, photosensitivity, and laboratory test results indicative of systemic lupus erythematous, treated for 3 years with no disease control. he had generalized, ill-defined skin lesions with peripheral sensorimotor neuropabeen documented. screening implementations were performed for his family members. invading cutaneous nerves and arrector pili muscles (figures 2 and 3). the density of bacilli in the patient’s smears (bacterial index) was 4+ (10100 bacilli in average field) and morphological stain was solid-stained (living). with the presence of erythematous skin lesions, neuropathy, and muscle atrophy; histopathological features, especially perineural involvement; and detection of acid-fast bacilli, our final diagnosis was leprosy and most likely borderline lepromatous form. following diagnosis, multidrug therapy against mycobacterium leprae (ml) was started. rifampin (600 mg/month), clofazimine (300 mg/month and 50 mg/ day), and dapsone 100 mg/day were prescribed for a 12-month treatment course. after 1 year, the patient’s skin is clear and no disease progression has figure  3. multiple acid-fast organisms, ziehl-neelsen stain (red staining) (original magnification ×100). [copyright: ©2019 sadeghinia et al.] figure 2. perivascular, perifollicular, and perineural infiltration of mononuclear inflammatory cells and histiocytes (loose granuloma); hematoxylin and eosin staining (original magnification ×4 and 40) (a-d); acid-fast organisms in ziehl-neelsen stain (red staining) (original magnification ×40) (e, f). [copyright: ©2019 sadeghinia et al.] a c e d f b figure 1. poikilodermic change (a); urticarial patches/plaques on trunk (b); atrophy of foot muscles and chronic ulcer, ankle (c). [copyright: ©2019 sadeghinia et al.] a c b 224 letter | dermatol pract concept 2019;9(3):13 early detection of leprosy is critical in order to prevent its sequels. physicians should have a higher clinical awareness about ml clinical features. it is important to consider it as a differential diagnosis of atypical cases of neuropathy or suspicious cases of vasculitis and actd. references 1. sampaio l, silva l, terroso g, et al. hansen’s disease mimicking a systemic vasculitis. acta reumatol port. 2011;36(1):61-64. 2. hsieh tt, wu yh. leprosy mimicking lupus erythematosus. dermatologica sinica. 2014;32(1):47-50. case of leprosy with mostly neural features. a probable cause of skin lesions could be the immunosuppression caused by azathioprine and prednisolone consumption. the recurrent leg ulcers may have been due to neuropathy directly caused by ml infection and trauma and the lucio leprosy phenomenon, which is a rare reaction in untreated lepromatous leprosy and is characterized by recurrent crops of leg ulcers due to direct invasion of ml to the vessels’ wall [1]. if a recent onset ulcer had been available for biopsy, the histopathological features of this phenomenon could have been noted. thy. after skin biopsy the diagnosis of leprosy was made. sampaio et al [1] reported a woman with symmetric polyarthritis, subcutaneous nodules, leg ulcers, and paresthesia of the distal extremities. first impression was primary vasculitis or actd, but biopsy showed ml infection. our patient had a history of chronic sensorimotor neuropathy with new urticarial trunk lesions. his condition was mistreated as neuropathy due to vasculitis for a long time before skin manifestations, possibly caused by the use of immunosuppressive drugs, became apparent. this patient had a neglected dermatology: practical and conceptual editorial | dermatol pract concept 2018;8(2):1 73 dermatology practical & conceptual www.derm101.com in his opinion piece, wolfgang weyers (2018) suggests that the practice of biopsying small lesions (<6 mm in diameter) without conspicuous clinical and/or dermoscopic features of melanoma is a key contributing factor to the so-called epidemic of melanoma overdiagnosis. he contends that these clinically non-diagnostic lesions often lack histopathologic criteria that allow precise classification, which leads to falsepositive diagnoses. he proposes delaying biopsy of lesions that are suspicious, but not diagnostic, for melanoma until features consistent with malignancy arise, the aim being to decrease diagnostic and biologic uncertainty and thereby minimize the potential for melanoma overdiagnosis together with its associated cost and morbidity. the view expressed by dr. weyers is intriguing, and the overarching concept raises important questions relevant to the diagnosis of melanoma. 1. what is the optimal sensitivity and specificity threshold for melanoma diagnosis? while taking a watch-and-wait approach until melanoma unequivocally declares itself will increase specificity and possibly decrease the likelihood of overdiagnosis, this approach implies a concomitant decrease in sensitivity for melanoma detection. this, in turn, may result in some individuals developing advanced stage melanomas due to the missed opportunity of early detection. this is not an uncommon scenario occurring in patients with difficult to detect melanoma subtypes, such as nodular, desmoplastic, nevoid, amelanotic, or spitzoid melanoma. further research is needed to determine if the benefits of a reduction in overdiagnosis and unnecessary biopsies outweigh the harm that may result from missed early melanoma detection. 2. which patient population is most amenable to watchful waiting of suspicious but not overtly malignant lesions? the concept of waiting until melanoma declares itself before performing a biopsy is contingent upon (a) patient and physician acceptance of monitoring as a reasonable choice, and (b) patient vigilance and periodic physician based follow-up. regarding the former, the idea of observing a suspicious lesion that may be an early melanoma may not be acceptable to certain patients, such as those with significant anxiety, a personal history of melanoma, or a family history of lethal melanoma. in some countries, the practice may also be associated with increased legal liability to the physician. regarding the latter, although there are some patients who are meticulous about regularly examining their skin, others lack the needed confidence or are unwilling or unable to consistently perform selfexaminations. even if patients are monitoring their own skin, the ability to detect subtle (and occasionally seemingly obvious) changes indicative of melanoma progression is not always possible. finally, a significant number of patients fail to keep their follow-up appointments, and some of these patients may go on to develop aggressive melanomas. 3. how are small equivocal lesions best monitored? to some extent, the concepts alluded to by dr. weyers are already implemented in clinical practice. total body photography comment on: screening for malignant melanoma— a critical assessment in historical perspective ashfaq a. marghoob1, michael marchetti1, allan c. halpern1, klaus j. busam1 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa citation: marghoob aa, marchetti m, halpern ac, busam kj. comment on: screening for malignant melanoma--a critical assessment in historical perspective. [editorial]. dermatol pract concept. 2018;8(2):73-74. doi: https://doi.org/10.5826/dpc.0802a01 published: april 30, 2018 copyright: ©2018 marghoob et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: ashfaq a. marghoob, md. dermatology service, department of medicine, memorial sloan kettering cancer center, 16 e 60th st, new york, ny 10065. email: marghooa@mskcc.org. 74 editorial | dermatol pract concept 2018;8(2):1 of melanoma only if there is compelling evidence from microscopic review (e.g., marked asymmetry, florid and chaotic pagetoid spread, and severe atypia) or ancillary studies. the same is true for small and partial biopsies. it is not our experience that pathologists issue a diagnosis of melanoma as a default option when the diagnosis is difficult; instead, they usually admit diagnostic uncertainty. while the biopsy of small lesions and small partial biopsies of lesions have undoubtedly contributed to an inflation of descriptive pathology reports (e.g., “atypical melanocytic proliferation”), such evasive diagnoses should not enter melanoma statistics and therefore cannot be responsible for the increase in the reported incidence of melanoma. we agree with dr. weyers that wholesale biopsy (especially partial biopsies) of small, non-palpable, equivocal lesions should be discouraged. we also agree that if a lesion has compelling clinical or dermoscopic features for melanoma, then a biopsy should be performed, irrespective of the lesion’s diameter. however, while there are benefits to the watch-and-wait approach for small equivocal lesions as outlined by dr. weyers, there are also potential pitfalls and unanswered questions that require further study. we posit that a combined approach using morphologic (clinical examination, dermoscopy, confocal microscopy, etc.), comparative (e.g., ugly duckling sign), temporal (monitoring using tbp, dermoscopy, confocal microscopy), and genomic data (e.g., non-invasive molecular assays obtained via microbiopsies, tape-stripping, etc.), augmented someday by machine learning approaches, will likely address some of the core issues described in the opinion piece by dr. weyers. furthermore, as our understanding of the biology of melanocytic neoplasms continues to expand, the prevalence of lesions with diagnostic and biologic uncertainty will decrease, but complete knowledge of the potential nature of every lesion over the course of each individual’s life will, of course, remain elusive. (tbp) and digital dermoscopic monitoring is one standard of care used in many clinics that screen patients at high risk for melanoma. the aim of digital monitoring is to actively follow banal and equivocal flat lesions with the aim of biopsying only those lesions that are changing in a concerning manner. however, while this timeand costintensive approach can improve the yield for diagnosis of melanoma, in our experience it does not always eliminate the biopsy of lesions that prove to be histopathologically equivocal. in fact, borderline lesions and nevi with unusual features appear to be enriched. among biologically dynamic, small, equivocal lesions, how certain do we need to be before performing a biopsy? if our threshold is too high, some patients may die from advanced disease because lesions were not biopsied at an earlier point in time. in practical terms, however, tbp and digital dermoscopic monitoring are not always available to patients, and the best approach to monitoring lesions without access to these technologies remains unclear. 4. what is the most appropriate interval for follow-up, and until what time point should small equivocal lesions be monitored? based on currently available data, there are no clear answers to these questions. 5. finally, does the removal of small equivocal lesions truly result in the overdiagnosis of melanoma? it is worth highlighting that there is no solid evidence and no study referenced to support dr. weyers’ claim that dermatopathologists’ interpretation of smaller lesions contributes to overdiagnosis. in fact, the opposite may be true. since most small lesions are captured in their entirety by a biopsy, all available diagnostic criteria can be applied, and if needed, modern ancillary methods are available to support the correct diagnosis. furthermore, most pathologists hesitate to establish a diagnosis of melanoma because of the small diameter of a lesion and usually render a diagnosis dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020014 1 dermatology practical & conceptual introduction early diagnosis of skin cancer is associated with a reduction in morbidity/mortality and in treatment costs [1]. the benefits of screening programs (especially for melanoma), however, have not been conclusively demonstrated. methods during this 6-month-long, observational study, data were prospectively collected in the dermatology department of a university hospital. patients included in the study had a pathology-confirmed diagnosis of basal cell carcinoma, squamous cell carcinoma, melanoma, or keratoacanthoma. those who suffered from cognitive decline or loss of sensory perception that impeded their noticing a skin tumor were excluded. the data collected included risk factors for skin cancer, personal and family background regarding skin tumors, sunburn events, phototype (i/ii), multiple atypical nevi, whether the patient had undergone solid organ transplantation, and demographic data. information was also collected on who first noticed the lesion: the patient, a family member or some other person, a dermatologist, or a doctor specializing in another field. results the study population totaled 184 patients, 12 of whom had 2 skin malignancies. the most commonly detected was basal cell carcinoma (60.7%, 119 tumors), followed by melanoma (19.4%, 38), squamous cell carcinoma (17.4%, 34), and keratoacanthoma (2.5%, 5). tumor duration had 2 main peaks, one at 6-12 months (25%) and one at more than 24 months (26%). figure 1 shows the risk factors detected. the patient was the first to detect the lesion in 54.3% of cases (100/184 patients), someone in the patient’s environment was first in 15.2% of cases (28/184 patients), a dermatologist in 22.3% of cases (41/184 patients), and a doctor specialwho detects skin cancer? factors associated with the suspicion of malignancy in patients with skin tumors alberto conde-taboada,1 laura croissier1, elena gonzález-guerra1, lucía campos1, beatriz aranegui2, eduardo lópez-bran1 1 dermatology department, hospital clínico san carlos, madrid spain 2 dermatology department, hospital infanta cristina parla, madrid, spain key words: skin cancer, early detection, dermatology education, melanoma, basal cell carcinoma, squamous cell carcinoma citation: conde-taboada a, croissier l, gonzález-guerra e, campos l, aranegui b, lópez-bran e. who detects skin cancer? factors associated with the suspicion of malignancy in patients with skin tumors. dermatol pract concept. 2020;10(1):e2020014. doi: https://doi. org/10.5826/dpc.1001a14 accepted: august 28, 2019; published: december 31, 2019 copyright: ©2019 conde-taboada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alberto conde-taboada, md, c/ prof. martín lagos s/n, madrid 28023, spain. email: condetaboada@aedv.es mailto:condetaboada@aedv.es 2 letter | dermatol pract concept 2020;10(1):e2020014 references 1. aviles izquierdo ja, molina i, rodriguez e, marquez-rodas i, suarez-fernandez r, lazaro-ochaita p. who detects melanoma? impact of detection patterns on characteristics and prognosis of patients with melanoma. j am acad dermatol. 2016;75(5):967-974. 2. graells j, ojeda rm. ability of non-melanoma skin cancer patients to self detect second tumours. j eur acad dermatol venereol. 2009;23(2):180-181. established. strategies are in place in western countries for such follow-up by dermatologists. however, no prospective clinical trials have been performed to determine what the best follow-up strategy might be. diagnosis was delayed more than 2 years in 26% of the present patients. this delay is associated with greater morbidity/mortality and higher treatment costs, justifying efforts to detect problems earlier. izing in another area in 8.2% of cases (15/184 patients). patients who had had a previous skin tumor were more likely to be the first to have detected their present tumor. having undergone solid organ transplantation was also significantly associated with the tumor being first detected by a dermatologist. no association was seen between who first identified the lesion and age, family background of skin cancer, sunburn events, the presence of multiple atypical nevi, phototype, or tumor duration. discussion the present self-detection rate of this study is similar to those reported for melanoma in other publications [1]. graells and ojeda reported 42% of patients with a second basal cell or squamous cell carcinoma to be the first to detect it [2]. our results confirm that the knowledge gained from previous episodes of skin cancer increases the likelihood of self-detection. on the other hand, patients who have undergone solid organ transplantation are at greater risk of developing skin cancer; the present results show dermatologists are more likely to be the first to detect skin malignancies in such patients, likely as a result of the monitoring protocols figure 1. risk factors for development of skin cancer detected in the patients. dermatology: practical and conceptual 198 research | dermatol pract concept 2018;8(3):10 dermatology practical & conceptual www.derm101.com dermatoscopy of flat pigmented facial lesions— evolution of lentigo maligna diagnostic criteria miguel costa-silva1, ana calistru1, ana margarida barros1, sofia lopes1, mariana esteves1, filomena azevedo1 1 department of dermatology and venereology, centro hospitalar são joão, epe porto, portugal key words: dermatoscopy, lentigo maligna, flat pigmented lesions, face citation: costa-silva m, calistru a, barros am, lopes s, esteves m, azevedo f. dermatoscopy of flat pigmented facial lesions—the evolution of lentigo maligna. dermatol pract concept. 2018;8(3):198-203. doi: https://doi.org/10.5826/dpc.0803a10 received: january 20, 2018; accepted: april 14, 2018; published: july 31, 2018 copyright: ©2018 costa-silva et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: miguel costa e silva, md, department of dermatology and venereology, centro hospitalar são joão, epe porto, alameda prof. hernâni monteiro, 4200-319 porto, portugal. email: miguelcostaesilva.dermato@gmail.com introduction flat pigmented facial lesions (fpfl) on chronic sun-damaged skin include a variety of melanocytic and nonmelanocytic, benign and malignant conditions with a similar clinical appearance presenting as a diagnostic challenge to physicians [1,2]. in many cases, diagnostic uncertainty is not resolved by clinical inspection, leading to biopsy or excision to rule out lentigo maligna (lm) [1]. recognition of facial melanoma is often difficult, particularly in the early stages. pigmented lesions of the face do not show the classic dermatoscopic findings characteristically observed elsewhere on the skin. a conventional pigment network is rarely found [2]. instead, they are dermatoscopically characterized by the presence of a specific feature called a pseudonetwork [2-4]. the well-known “abcde rule” cannot be applied to facial locations [5,6]. differential diagnosis includes solar lentigo (sl), postinflammatory hyperpigmenrecognition of facial lentigo maligna (lm) is often difficult, particularly at early stages. algorithms and multivariate diagnostic models have recently been elaborated on the attempt to improve the diagnostic accuracy. we conducted a cross-sectional and retrospective study to evaluate dermatoscopic criteria aiding in diagnosis of flat pigmented facial lesions (fpfl). we examined 46 fpfl in 42 caucasian patients and found that 4 of 20 dermatoscopic criteria reached the significance level required for features indicating malignancy namely, hyperpigmented follicular openings, obliterated follicular opening, annular-granular structures, and pigment rhomboids. concomitant presence of at least 2 or 3 of the 4 mentioned criteria was significantly more frequent in lm than in pigmented actinic keratosis (pak). however, despite more frequently seen in lm, these features were also displayed in some of the pak and other fpfl, so we found them not specific for lm. although dermatoscopy enhances the diagnostic accuracy in evaluating fpfl, histopathology remains the gold standard for correct diagnosis, making evident the need for improvements in early noninvasive diagnosis of lm.  abstract research | dermatol pract concept 2018;8(3):10 199 • obliterated follicular opening (ofo), when obliterated hair follicles were seen; • pigment rhomboids, interfollicular lines that form a polygon (most commonly a rhomboid); • moth-eaten borders, defined as concave areas at the edge of the lesion; • sharp border when there was abrupt cessation of pigmentation; • scale , evaluated from the dermatoscopic not the clinical image after application of fluid or gel; • fingerprint-like structures, corresponding to different types of fissures which can be described as ridges, “fat fingers,” or cerebriform pattern; • annular-granular structures, were considered when granules were found regularly around the follicles; • red rhomboidal structure, defined as lozenge-shaped vascular pattern occurring in the area separating the hair follicles from each other; and • increased density of the vascular network, defined as a vascular network of higher density within the lesion than in peripheral skin. data analysis all features were treated as binary values (present or absent). statistical methods chi-squared and fisher’s exact tests were used to evaluate possible associations. values of p ≤ 0,05 were considered significant. data analysis was performed using the statistical software program spss 20.0 for windows (spss inc, chicago, il). results we examined 46 fpfl in 42 caucasian patients (30 women and 12 men; age range 30–94 years, mean 65,2). lm was diagnosed in 5 (10.9%), pak in 15 (32.6%), sl in 19 (41.3%), sk in 5 (10,9%), lplk in 1 (2.2%) and pih in 1 (2.2%) lesion—all of them histopathologically confirmed. examples of sl, lm, and pak are shown in figure 1a-d. table 1 demonstrates the frequency of detected dermatoscopic features in our series. the most striking pattern in 34 of 46 (73.9%) fpfl was brown structureless areas, followed by hfo (24/46 52.2%). streaks and milia were not present in any of the lesions observed. in lm, hfo (5/5, 100%), annular-granular structures (4/5, 80%), brown structureless areas (4/5, 80%), dots (4/5, 80%), ofo (3/5, 60%), pigment rhomboids (3/5, 60%) and increased density of the vascular network (3/5, 60%) were present in most of the lesions. four features namely, hfo, ofo, annular-granular structures, and pigment rhomboids were significantly associated with tation (pih), seborrheic keratosis (sk), pigmented actinic keratosis (pak), and lichen planus-like keratosis (lplk) [2]. dermatoscopy has been demonstrated to be an efficient noninvasive technique for the preoperative assessment, as well as for differential diagnosis of pigmented lesions [5]. for all of these reasons, algorithms and multivariate diagnostic models have recently been elaborated on the attempt to improve the diagnostic accuracy [1,2,5,7]. the aim of the present study was to evaluate dermatoscopic criteria aiding in diagnosis of pigmented skin lesions on the face by blinded evaluation of a consecutive series of dermatoscopic images in order to emphasize their diagnostic value in the differentiation between lm and other fpfl. methods we conducted a cross-sectional and retrospective study of the fpfl in patients attending one author’s office over a 24-month period, from january 2014 to december 2015. we excluded those lesions with equivocal histopathology reports, raised lesions, and lentigo maligna melanoma (lmm) lesions. concerning this study, the authors refer to the entity as lm when confined to the epidermis (in situ) and as lmm when it invaded the dermis. the gold standard for diagnosis used in this study was the histopathologic report. clinical and dermatoscopic images of each lesion were documented by a fotofinder (fotofinder systems, inc, bad birnbach, germany) non-polarized, videodermatoscope and in some cases by a handyscope (fotofinder systems, inc, bad birnbach, germany) polarized, dermatoscope. in the case of lesions larger than 14 mm in diameter, multiple dermatoscopic images of different areas of the lesion were obtained to provide data for all topographical areas. immersion fluid, either 70% ethanol hand wash gel, or ultrasound gel, was always used when taking the photographs. all dermatoscopic images were assessed digitally and reviewed by 3 dermatologists (mcs, ac, amb) before reviewing the histopathologic report. dermatoscopic features were positively scored when a consensus of at least 2 of the 3 observers was achieved. twenty dermatoscopically detectable criteria related to different structures and combinations of colors and structures were analyzed, including scar-like areas, dots, yellow clods, globules, streaks, brown structureless areas, gray structureless areas, milia and comedones [1,2,5,7-10]. additionally we included other more controversial structures namely: • rosettes, also called four-dot clods, which are defined as 4 white dots arranged in a square; • hyperpigmented follicular openings (hfo), considered when fine, irregular, semi-, signet ring or double circles were present; 200 research | dermatol pract concept 2018;8(3):10 lm (p < 0.05). all lms presented at least 2 out of these 4 features and 4 (80%) lms had 3 of the 4. hfo (9/15, 60%), brown structureless areas (9/15, 60%), and annulargranular structures (8/15, 53.3%) were the most common dermatoscopic findings in pak. despite being present in only 20% (3/15), rosettes were solely observed in pak, and this difference was statistically significant when compared to all other fpfl (p < 0.05). no other dermatoscopic criteria were statistically associated with the diagnosis of pak (p > 0.05). concerning premalignant (pak) a n d m a l i g n a n t l e s i o n s ( l m ) a l l together and compared to benign fpfl (namely sl, sk, lplk and pih), hfo (70% vs 38.5%, p < 0.05), annulargranular structures (60% vs 23.1%, p < 0,05), rosettes (15% vs 0%, p < 0.05), and increased density of the vascular network (50% vs 15.4%, p < 0.05) were significantly more frequent in the former. distinguishing between lm and pak lesions, pigment rhomboids and ofo were significantly more frequent in the former (60% vs 6.7% and 60% v s   6 , 7 % , r e s p e c t i v e l y, p < 0 . 0 5 ) . concerning features indicating lm namely, hfp, ofo, annular-granular structures, and pigment rhomboids, the concomitant presence of  2  of the 4 mentioned criteria was significantly more frequent in lm than in pak (100% vs 40%, p < 0,05). similarly, the concomitant presence of 3 of the 4 mentioned criteria was significantly more frequent in lm than in pak (80% vs 6.7%, p < 0,05). discussion caucasian skin chronically exposed to the sun is susceptible to both benign and malignant fpfl [1]. lentigo maligna is the most common subtype of melanoma on the face with increasing incidence [5]. despite a frequent delay in diagnosis, its prognosis at the time of diagnosis is globally good [5]. the high frequency of pak observed in our study mainly reflects its relatively high frequency in the population when compared with lm [9]. although dermatoscopic characteristics of lm on the face have been described before, knowledge of the significance of dermatoscopic patterns with regard to the differentiation of lm from other fpfl is limited and may be a challenge even for experienced clinicians [1,3,5,7-10]. schiffner et al [8], found that using a combination of 4 features, asymmetric pigmented follicular openings, dark rhomboidal structures, slate-gray dots, and slate-gray globules resulted in a classification rate of 93% for lm, with a specificity of 96% and a sensitivity of 89%. these criteria differ fundamentally from those of steiner et al [11], who reported that radial streaming, peripheral black dots, and an irregular prominent pigment network that stops abruptly and thins out at the periphery, were the characteristic features for lm. according to the former findings, a progression model of lm was developed which differentiates 4 steps of the lm invasion of the hair follicles observed by dermatoscopy. initially hfo appear, then, fine gray dots and globules appear around the follicles, producing the annular-granular pattern. next, rhomboid pigmented areas are formed in the areas located around the hair follicle openings. lastly, with progression of the malignant cells within all follicular anatomical structures, the hyperpigmentation coalesces, and ofo emerge [8,12]. later, pralong et al [5], confirmed the diagnostic value of the classic stolz dermatoscopic critefigure  1. (a) solar lentigo with brown structureless areas, (b) lentigo maligna with rhomboids (arrowhead) and annular-granular structures (arrow), (c) pigmented actinic keratosis with rosettes (arrow), (d) pigmented actinic keratosis with hyperpigmented follicular openings (arrow) and obliterated follicular opening (arrowhead). [copyright: ©2018 costa-silva et al. research | dermatol pract concept 2018;8(3):10 201 table 1. dermatoscopic features in a series of 46 fpfl feature lm n = 5 pak n= 15 lm + pak n=20 benign lesions n= 26 lm + pak vs benign lesions p* lm vs pak p* lm vs fpfl p* pak vs fpfl p* age (years, median, range) 66.6 (30-87) 71 (45-92) 69.9 (30-92) 61.6 (30-94) 0.515 0.172 0.090 0.501 sex male female 2 (40%) 3 (60%) 5 (33.3%) 10 (66.7%) 7 (35%) 13 (65%) 8 (30.8%) 18 (69.2%) 0.762 0.787 0.079 0.942 hfo 5 (100%) 9 (60%) 14 (70%) 10 (38.5%) 0.034 0.091 0.023 0.460 annular-granular structures 4 (80%) 8 (53.3%) 12 (60%) 6 (23.1%) 0.011 0.292 0.047 0.170 pigment rhomboids 3 (60%) 1 (6.7%) 4 (20%) 2 (7.7%) 0.219 0.010 0.001 0.372 ofo 3 (60%) 1 (6.7%) 4 (20%) 4 (15.4%) 0.682 0.010 0.008 0.182 combination of 2/4† lm features 5 (100%) 6 (40%) 11 (55%) 5 (19.2%) 0.012 0.020 0.001 0.605 combination of 3/4‡ lm features 4 (80%) 1 (6.7%) 5 (25%) 2 (7.7%) 0.105 0.001 0.001 0.261 scar-like areas 1 (20%) 1 (6.7%) 2 (10%) 0 0.099 0.389 0.069 0.592 dots 4 (80%) 6 (40%) 10 (50%) 10 (38.5%) 0.434 0.121 0.081 0.741 scale 0 6 (40%) 6 (30%) 5 (19.5%) 0.396 0.091 0.184 0.072 yellow clods 1 (20%) 6 (40%) 7 (35%) 4 (15.4%) 0.122 0.417 0.828 0.075 rosettes 0 3 (20%) 3 (15%) 0 0.041 0.278 0.532 0.010 globules 2 (40%) 2 (13.3%) 5 (25%) 3 (11.5%) 0.232 0.132 0.087 0.613 streaks 0 0 0 0 brown structureless areas 4 (80%) 9 (60%) 12 (60%) 22 (84.6%) 0.159 0.292 0.743 0.075 fingerprint-like structures 0 1 (6.7%) 1 (25%) 7 (26.9%) 0.052 0.554 0.277 0.182 sharp border 2 (40%) 5 (33.3%) 7 (35%) 11 (42.3%) 0.615 0.787 0.966 0.575 moth-eaten borders 0 3 (20%) 3 (15%) 8 (30.8%) 0.214 0.278 0.184 0.665 milia 0 0 0 0 comedo 0 0 0 1 (3.8%) 0.375 0.724 0.482 red rhomboidal structure 0 1 (6.7%) 1 (5%) 0 0.249 0.554 0.724 0.146 increased vascular network 3 (60%) 7 (46.7%) 10 (50%) 4 (15.4%) 0.011 0.606 0.128 0.096 gray structureless areas 1 (20%) 3 (20%) 4 (20%) 3 (11.5%) 0.428 1 0.752 0.530 hfohyperpigmented follicular openings; ofoobliterated follicular opening; lm – lentigo maligna; pak – pigmented actinic keratosis; fpflflat pigmented facial lesions * chi-squared and fisher’s exact tests were used to evaluate possible associations. † combination of 2 out of the 4 features significantly associated to lm (hfo, ofo, annular-granular structures, and pigment rhomboids). ‡ combination of 3 out of the 4 features significantly associated to lm (hfo, ofo, annular-granular structures, and pigment rhomboids). 202 research | dermatol pract concept 2018;8(3):10 this study reviewed retrospectively a relatively small series of lesions and a larger number of patients and found that facial lesions are important to give more definite results. also, the lack of a uniform dermatoscopic nomenclature makes it difficult to compare different studies. conclusions although dermatoscopy improves diagnostic accuracy in evaluating fpfl, it remains a challenge. histopathology remains the gold standard for correct diagnosis. improvements in early noninvasive diagnose of lm are needed. using combinations of dermatoscopic structures may enhance the diagnosis value of dermatoscopy of fpfl. references 1. tschandl p, rosendahl c, kittler h. dermatoscopy of flat pigmented facial lesions. j eur acad dermatol venereol. 2015;29(1):120127. doi: 10.1111/jdv.12483. 2. carbone a, ferrari a, paolino g, et al. lentigo maligna of the face: a quantitative simple method to identify individual patient risk probability on dermoscopy. australas j dermatol. 2017;58(4):286-291. doi: 10.1111/ajd.12595. 3. pehamberger h, binder m, steiner a, wolff k. in vivo epiluminescence microscopy: improvement of early diagnosis of melanoma. j invest dermatol. 1993;100(3)(suppl):356s-362s. doi: 10.1038/ jid.1993.63. 4. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-693. doi: 10.1067/ mjd.2003.281. 5. pralong p, bathelier e, dalle s, poulalhon n, debarbieux s, thomas l. dermoscopy of lentigo maligna melanoma: report of 125 cases. br j dermatol. 2012;167(2):280-287. doi: 10.1111/j.1365-2133.2012.10932.x. 6. thomas l, tranchand p, berard f, secchi t, colin c, moulin g. semiological value of abcde criteria in the diagnosis of cutaneous pigmented tumors. dermatology. 1998;197(1):11-17. doi: 10.1159/000017969. 7. goncharova y, attia eas, souid k, vasilenko iv. dermoscopic features of facial pigmented skin lesions. isrn dermatol. 2013;2013:546813. doi: 10.1155/2013/546813. 8. schiffner r, schiffner-rohe j, vogt t, et al. improvement of early recognition of lentigo maligna using dermatoscopy. j am acad dermatol. 2000;42(1 pt 1):25-32. doi: 10.1016/s01909622(00)90005-7. 9. akay bn, kocyigit p, heper ao, erdem c. dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. br j dermatol. 2010;163(6):1212-1217. doi: 10.1111/j.13652133.2010.10025.x. 10. stante m, giorgi v, stanganelli i, alfaioli b, carli p. dermoscopy for early detection of facial lentigo maligna. br j dermatol. 2005;152(2):361-364. doi: 10.1111/j.1365-2133.2004.06328.x. 11. steiner a, pehamberger h, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. ii. diagnosis of small pigria and described 4 additional features, such as the increased density of the vascular network, red rhomboidal structures, target-like pattern, and darkening at dermatoscopic examination. akay et al [9], found that 3 dermatoscopic criteria were statistically significant for malignant growth, namely, dark rhomboidal structures, dark streaks, and black blotches. on the other hand, slate-gray globules, annulargranular structure, hfo, and black globules were not statistically significant for either benign or malignant growth. all dermatoscopic findings, except for black blotches, were observed in pak, leading the authors to conclude that the value of dermatoscopy in differentiating between melanocytic lesions and pak was limited [3,9]. recently, tschandl et al [1], confirmed this assertion, noting that pak and lm are similar in clinical and dermatoscopic features, sharing the presence of a gray color, although a pattern of pigmented circles is the most common pattern in early lm, while the presence of scales, white circles, and a sharply demarcated border were more in favor of pak. tschandl et al [1] saw the presence of gray color in lesions on the face as a strong clue to a malignant process, which is in accordance with the findings of tiodorovic-zivkovic et al [13], who postulated that gray color, regardless of the pattern, was the single most sensitive feature for the dermatoscopic recognition of early facial melanoma that can be detected even before the formation of the characteristic lm structures, such as circles or rhomboids. they concluded that its presence should always prompt the clinician to perform a biopsy. lastly, carbone et al [2] developed a scoring system to improve the diagnosis of lm with 7 dermatoscopic criteria: hfo, rhomboidal structures, target-like pattern, perifollicular gray color, dark blotches, moth-eaten border, and fingerprint-like structures. our analysis is in accordance with the first findings of schiffner et al and stolz et al [8,12]. four of 20 dermatoscopic criteria for analysis of facial pigmented skin lesions reached the significant level required for features indicating malignancy namely, hfo, ofo, annular-granular structures, and pigment rhomboids. the concomitant presence of 2 or 3 of the 4 dermatoscopic criteria enhances the diagnostic value of dermatoscopy in differentiating lm from pak or from other fpfl. however, despite more frequently seen in lm, these features were also displayed in some of the pak and other fpfl, so we found them not specific for lm. rosettes were solely observed in pak. however, they can also be found in other non-melanocytic fpfl [1,9]. it must be emphasized that most dermatoscopic images were taken with non-polarized dermatoscope. because rosettes are mainly visible with polarized light, we might have underestimated the presence of this structure. we found that pigment rhomboids and ofo were significantly more frequent in lm then in pak but, again, were not specific. research | dermatol pract concept 2018;8(3):10 203 13. tiodorovic-zivkovic d, zalaudek i, lallas a, stratigos aj, piana s, argenziano g. the importance of gray color as a dermoscopic clue in facial pigmented lesion evaluation: a case report. dermatol pract concept. 2013;3(4):37-39. doi: 10.5826/dpc.0304a09. mented skin lesions and early detection of malignant melanoma. j am acad dermatol. 1987;17(4):584-591. doi: 10.1016/s01909622(87)70240-0. 12. stolz w, schiffner r, burgdorf wh. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002;20(3):276-278. doi: 10.1016/s0738-081x(02)00221-3. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):14 63 dermatology practical & conceptual introduction dermoscopy can be a useful tool to help clinicians in the diagnosis of cutaneous b-cell lymphomas. case presentation a 61-year-old man presented with an irregularly growing erythematous plaque measuring 28 × 35 mm, which had appeared on the left thigh a few months before (figure 1a). he was otherwise healthy and could not recall an arthropod bite or a trauma in the same area. he was not taking any drugs and did not report weight loss, fever, or night sweating. the physical examination was normal. upon polarized noncontact dermoscopy, we observed a diffuse salmon-colored area with focally white areas (figure 1b). the lesion was totally excised with differential diagnosis of granulomatous dermatosis, amelanotic melanoma, cutaneous lymphoma, sarcoma, or metastasis. histopathology showed a dense nodular dermal lymphocytic infiltrate extendsalmon-colored and white areas on dermoscopy as supportive findings in the diagnosis of primary cutaneous marginal zone lymphoma giovanni biondo1,2, simona sola3, carlotta pastorino2, cesare massone2 1 dermatology and sexually transmitted disease unit, p. giaccone hospital, university of palermo, palermo, italy 2 dermatology unit, galliera hospital, genoa, italy 3 surgical pathology, galliera hospital, genoa, italy key words: dermoscopy, lymphoma, cancer citation: biondo g, sola s, pastorino c, massone c. salmon-colored and white areas on dermoscopy as supportive findings in the diagnosis of primary cutaneous marginal zone lymphoma. dermatol pract concept. 2019;9(1):63-66. doi: https://doi.org/10.5826/ dpc.0901a14 published: january 31, 2019 copyright: ©2019 biondo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: cesare massone, md, dermatology unit, ospedali galliera, via volta 6, 16128, genova, italy. email: cesare. massone@galliera.it figure 1. (a) irregular erythematous plaque on the left thigh. (b) polarized noncontact dermoscopy: a diffuse salmon-colored area on the background, together with focally white areas (marked with black arrows) and white circles (marked with asterisks). [copyright: ©2019 biondo et al.] b a 64 letter | dermatol pract concept 2019;9(1):14 discussion pcmzl is a low-grade malignant primary cutaneous b-cell lymphoma (pcbcl). clinically, patients present with solitary or multiple, asymptomatic, rarely ulcerative pink-violet to red-brown papules, plaques, and nodules localized preferentially on the extremities or trunk. mascolo et al. described the dermoscopic features of 10 pcbcl cases, observing white circles with a salmon-colored area in 9/10 cases, scales in 7/10 cases, and arborizing vessels or a polymorphous vascular pattern in 5 and 2 cases, respectively [2]. piccolo et al. also described the same features in 2 additional patients [3]. geller et al. expanded the study, examining 58 dermoscopic images of pcbcls, and reported a salmon-colored area (79.3%) and prominent blood vessels (77.6%), mostly of serpentine (linear-irregular) morphology (67.2%) [4]. ghahramani observed ing to the subcutaneous fat composed of reactive lymphoid follicles surrounded by a diffuse infiltrate composed by small to medium sized cells (marginal zone cells). in addition, plasma cells (at the margins of the infiltrate), lymphoplasmacytoid cells, small reactive lymphocytes, and occasional eosinophils were observed. a clear-cut grenz zone between the infiltrate and the epidermis was present (figure 2). neoplastic cells stained positive for cd20 and cd79a; cells stained negative for bcl-6, bcl-2, cd5, and cd10; reactive t lymphocytes were cd3+. a monoclonal expression of kappa chain was found. further complete staging investigations were negative for nodal or systemic involvement. following who criteria [1], primary cutaneous marginal zone lymphoma (pcmzl) was diagnosed. figure 2. (a) below a clear-cut grenz zone in the papillary dermis, there is a dense nodular dermal lymphocytic infiltrate composed of reactive lymphoid follicles surrounded by small to medium-sized cells (marginal zone cells). no dilated vessels in the papillary dermis are seen; areas of reactive fibrosis in the dermis are present (hematoxylin and eosin [h&e], ×20). (b) focally, the grenz zone is reduced due to patchy, nodular, more superficial infiltrate in the papillary dermis (h&e, ×100). (c) marginal zone cells, plasma cells, lymphoplasmacytoid cells, and slight increase of vessels within the infiltrate (h&e, ×200). (d) plasma cells and lymphoplasmacytoid cells (h&e, ×400). [copyright: ©2019 biondo et al.] letter | dermatol pract concept 2019;9(1):14 65 ta b le 1 . d er m o sc o p ic , c li n ic al , a n d h is to lo gi ca l fe at u re s o f p c b c l s r ep o rt ed i n t h e l it er at u re d e rm o sc o p ic , c li n ic a l a n d h is to lo g ic a l fe a tu re s o f p c b c ls r e p o rt e d i n t h e l it e ra tu re a u th o rs n u m b e r o f c a se s s e x a g e lo ca li za ti o n c li n ic a l fe a tu re s d e rm o sc o p ic f e a tu re s h is to lo g ic f e a tu re s m as co lo m et a l 2 0 1 6 [ 2 ] 6 p c m z l 2 p c f c l 2 p c l b c l 7 m 3 f 5 1 .9 (2 0 -7 3 ) 3 t ru n k 2 a rm 1 f o re ar m 1 t h ig h 1 r et ro au ri cu la r 1 n ec k 1 a x il la ry so li ta ry r ed /p in k is h n o d u le s (9 /1 0 ) w h it e ci rc le s (6 /1 0 ) sa lm o n -c o lo re d a re a (7 /1 0 ) sc al es (5 /1 0 ) a rb o ri zi n g ve ss el s (2 /1 0 ) p o ly m o rp h o u s va sc u la r p at te rn 6 p at ch y, n o d u la r o r d if fu se i n fi lt ra te o f sm al l ce n tr o cy te -l ik e ce ll s c d 2 0 + , c d 7 9 a+ , b cl 2 + , b cl 6 -, c d 1 0 2 d if fu se i n fi lt ra te o f sm al lm ed iu m cl ea ve d c el ls c d 1 0 + , b cl 6 + , b cl 2 2 d en se , d if fu se i n fi lt ra te o f la rg e ro u n d ce ll s, f re q u en t m it o se s, e le va te d k i6 7 , b cl 2 + , m u m 1 + , c d 1 0 g el le r s et a l 2 0 1 8 [ 4 ] 3 1 p c m z l 1 4 p c f c l 1 0 i n d o le n t p c b c l 3 p c l b c l n r n r 3 2 t ru n k 1 8 e x tr em it ie s 8 h ea d a n d n ec k r ed /v io la ce o u s p ap u le s, p la q u es , n o d u le s, s o li ta ry , t ru n k / ex tr em it ie s (p c m z l ) p in k /v io la ce o u s p ap u le s, n o d u le s h ea d ( p c f c l ) r ed /b lu is h i n fi lt ra te d p la q u es , n o d u le s o r tu m o r lo w er ex tr em it ie s (p c l b c l ) (4 6 /5 8 ) sa lm o n -c o lo re d a re a (4 5 /5 8 ) b lo o d v es se ls (6 /5 8 ) sc al e (4 /5 8 ) u lc er at io n n r p ic co lo v et a l 2 0 1 6 [ 3 ] 2 p c m z l 1 m 1 f 7 5 .5 (7 4 -7 7 ) b re as t b ac k p at ch y in fi lt ra te d o va l er yt h em at o u s le si o n m u lt ip le r ed d is h , v ar ia b ly s iz ed , fi rm n o d u le (2 /2 ) a rb o ri zi n g ve ss el s (2 /2 ) sa lm o n -c o lo re d a re a (2 /2 ) w h it e ar ea s/ ci rc le s d en se , d if fu se , l ym p h o id i n fi lt ra te w it h in th e d er m is a n d t h e su b cu ta n eo u s fa t, co n si st in g o f sm al lcl ea ve d l ym p h o cy te s an d l ym p h o p la sm ac yt ic c el ls a d m ix ed w it h p la sm a ce ll s, m ai n ly l o ca te d a t th e p er ip h er y o f th e in fi lt ra te c d 2 0 + , c d 7 9 a+ , b cl 2 + , c d 5 -, c d 1 0 , b cl -6 g h ah ra m an i et a l 2 0 1 8 [ 5 ] 1 p c f c l 1 p c m z l n r n r h el ix e ye b ro w s n r sp er m at o zo ali k e st ru ct u re s (p c f c l ) o ra n ge -y el lo w is h p at ch y ar ea s (p c f c l ) c ry st al li n e st ru ct u re s (p c f c l ) p se u d o p o d -l ik e ve ss el s (p c f c l ) d u ll r ed b ac k gr o u n d st ru ct u re le ss p at ch es p se u d o p o d -l ik e ve ss el s re fl ec t d il at ed ec ta ti c ve ss el s su rr o u n d in g th e n eo p la st ic f o ll ic le s n r = n ot re po rt ed ; p c b c l= p ri m ar y cu ta ne ou s b -c el l l ym ph om a; p c fc l = pr im ar y cu ta ne ou s fo lli cl e ce nt er ly m ph om a; p c lb c l = pr im ar y cu ta ne ou s la rg e b -c el l l ym ph om a; p c m z l = pr im ar y cu ta ne ou s m ar gi na l z on e ly m ph om a. 66 letter | dermatol pract concept 2019;9(1):14 supporting clinicians in recognizing primary lesions and recurrences [11], moreover identifying correct site of biopsy. references 1. cook jr, isaacson pg, chott a, et al. extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (malt lymphoma). in: swerdlow sh, campo e, harris nl, et al, eds. who classification of tumours of haematopoietic and lymphoid tissues. 4th ed. lyon cedex: iarc; 2017:259-262. 2. mascolo m, piccolo v, argenziano g, et al. dermoscopy pattern, histopathology and immunophenotype of primary cutaneous bcell lymphoma presenting as a solitary skin nodule. dermatology. 2016;232(2):203-207. 3. piccolo v, mascolo m, russo t, staibano s, argenziano g. dermoscopy of primary cutaneous b-cell lymphoma (pcbcl). j am acad dermatol. 2016;75(4):e137-e139. 4. geller s, marghoob aa, scope a, braun rp, myskowski pl. dermoscopy and the diagnosis of primary cutaneous b-cell lymphoma. j eur acad dermatol venereol. 2018;32(1):53-56. 5. ghahramani gk, goetz ke, liu v. dermoscopic characterization of cutaneous lymphomas: a pilot survey. int j dermatol. 2018;57(3):339-343. 6. bombonato c, argenziano g, lallas a, moscarella e, ragazzi m, longo c. orange color: a dermoscopic clue for the diagnosis of granulomatous skin diseases. j am acad dermatol. 2015;72(1 suppl):s60-s63. 7. brasiello m, zalaudek i, ferrara g, et al. lupus vulgaris: a new look at an old symptom—the lupoma observed with dermoscopy. dermatology. 2009;218(2):172-174. 8. errichetti e, lallas a, apalla z, di stefani a, stinco g. dermoscopy of granuloma annulare: a clinical and histological correlation study. dermatology. 2017;233(1):74-79. 9. bañuls j, arribas p, berbegal l, deleón fj, francés l, zaballos p. yellow and orange in cutaneous lesions: clinical and dermoscopic data. j eur acad dermatol venereol. 2015;29(12):2317-2325. 10. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. . how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy, part i: melanocytic skin tumors. j am acad dermatol. 2010;63(3):361-374. 11. piccolo v, russo t, agozzino m, et al. dermoscopy of cutaneous lymphoproliferative disorders: where are we now? dermatology. 2018;234(3-4):131-136. spermatozoa-like structures, orange-yellowish patchy areas, crystalline structures, and pseudopod-like vessels in primary cutaneous follicle center lymphoma, but not in pcmzl [5]. these findings are summarized in table 1. our observation confirms that a salmon-colored area upon dermoscopy is typical even if not exclusive of pcbcl. in fact, it brings to mind the orangish-yellowish areas observed in granulomatous dermatoses such as sarcoidosis, lupus vulgaris, and granulomatous rosacea, where also linear branching vessels are seen [6,7], while granuloma annulare shows peripheral structureless reddish-yellowish-orange areas with variable blurry vessels [8,9]. it is difficult to correlate the salmon color of pcbcl with pathology; an explanation could reside in the increased vascularization inside the dense nodular neoplastic lymphoid infiltrate in the mid and deep dermis (figure 2c). white areas probably correlate with areas of reactive fibrosis in the dermis or might correlate with focally reduced grenz zone due to patchy, nodular, more superficial infiltrate in the papillary dermis (figure 2b). recently, pseudopod-like vessels have been correlated with dilated ectatic vessels surrounding the neoplastic follicles [5]. as further dermoscopic differential diagnosis, amelanotic melanoma shows dotted vessels, linear-irregular vessels, hairpin-irregular vessels, serpentine vessels, or a combination of them (polymorphic vessels); also milky-red areas can be frequently visualized [10]. contrary to previous experiences [2,3], in our patient prominent vessels with serpentine morphology were not observed. also on dermoscopic-pathologic correlation, no dilated vessels were observed in the superficial dermis; prominent blood vessels have been correlated with neoangiogenesis, a phenomenon that in our case probably did not occur yet in the superficial dermis because it might be correlated with a different stage of the disease. conclusions in conclusion, a salmon-colored area and white areas on dermoscopy might be suggestive, even if not unique, of pcbcl, dermatology: practical and conceptual 82 review | dermatol pract concept 2019;9(2):2 dermatology practical & conceptual introduction in recent years there has been growing interest in investigating the link between anthropometric measures and cancer risk and progression. height is included among these measures and has been suggested to contribute to the risk of several selected malignancies, although it has not been implicated as a real cause per se. adult attained height might indeed be an indirect marker resulting from shared mechanisms within the complex interplay between genetic, hormonal, nutritional, and other environmental factors [1]. epidemiological studies have also connected the risk of skin cancer to multiple anthropometric parameters, including height, but the results appear to be still controversial and the possible mechanisms underlying the positive association remain unclear. cutaneous melanoma is a potentially lethal malignancy derived from melanocytes, whose incidence has steadily increased worldwide over recent decades. the main risk factors include exposure to ultraviolet rays (uvr), number of common and atypical nevi, uvr sensitivity-related phenotypic characteristics, genetic susceptibility, and a family history of melanoma [2]. we conducted a narrative review to summarize the epidemiological data regarding the association between melanoma risk and height. underlying mechanisms that might explain this association are also discussed. association between melanoma risk and height: a narrative review gino a. vena1,2, nicoletta cassano1,2, stefano caccavale3, giuseppe argenziano3 1 dermatology and venereology private practice, bari, italy 2 dermatology and venereology private practice, barletta, italy 3 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: cutaneous melanoma, height, cancer, risk, association citation: vena ga, cassano n, caccavale s, argenziano g. association between melanoma risk and height: a narrative review. dermatol pract concept. 2019;9(2):82-89. doi: https://doi.org/10.5826/dpc.0902a02 accepted: february 22, 2019; published: april 30, 2019 copyright: ©2019 vena et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: stefano caccavale, md, dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy. email: stefano85med@gmail.com the link between anthropometric indices, including height, and cancer risk and/or progression has attracted considerable interest in recent years. adult height results from the complex interplay between genetic, hormonal, nutritional, and other environmental factors and has been found to contribute to the risk of several selected malignancies, although it has not been implicated as a real cause per se. a number of studies have investigated the height-melanoma relationship, showing controversial results so far. in this review, we summarize the epidemiological data regarding the association between height and melanoma risk and analyze the potential underlying mechanisms. abstract review | dermatol pract concept 2019;9(2):2 83 had the highest hazard ratio in both women (1.17, 95% ci 1.11-1.24) and men (1.12, 95% ci 1.08-1.19). height was considered an important explanatory factor accounting for 33.8% of the excess risk of incident cancer for men vs women overall and for specific anatomical sites, and this was particularly evident also for melanoma, where the proportion mediated by height was 57.3% [3]. influence on mortality adult height appears to have opposite relationships with risk of death from various major causes of chronic diseases and cancer [11]. in the pooled cohort study carried out by wirén et al [4], height was associated with a nonsignificant increase in the risk of death from cutaneous melanoma in both men and women (hazard ratio per 5-cm increment in height of 1.10 [95% ci 0.99-1.21] and 1.09 [95% ci 0.92-1.29], respectively). an analysis of multiple prospective cohorts involving more than 1 million adults, mostly from europe and north america, showed a hazard ratio per 6.5-cm greater height of 1.26 (95% ci 1.12-1.42) for risk of melanoma death, corresponding to the highest relative risk of cancer death in women and men combined [11]. in a prospective study, more than 18,000 london-based male government employees were followed up for mortality for a maximum of 35 years [12]. following adjustment for covariates, taller men experienced elevated mortality rates from cancer of combined sites and from certain organ-specific malignancies. there was a significant association between height and mortality rate from skin cancer, defined as “malignant melanoma of skin” combined with “other malignant neoplasms of skin” (hazard ratio per 5-cm increase in height 1.35, 95% ci 1.06-1.70). studies specifically focusing on melanoma various case-control and cohort studies analyzed the relation between anthropometric factors, including height, and melanoma risk selectively. table 1 reports the general characteristics of the studies that focused on the risk of melanoma in association with adult height [13-25]. all these studies analyzed the risk of melanoma only, with the exception of one [24] that evaluated the risk of keratinocyte cancers and melanoma. table 2 summarizes the results concerning the association between melanoma risk and height. despite their methodological heterogeneity, many reports suggested an increased risk of melanoma with increasing height [13-15,18,21-23,25]. methods literature searches were performed in pubmed and google scholar databases up to september 30, 2018, using the terms “skin cancer,” “melanoma,” and “height.” case-control and cohort studies that investigated the association between cutaneous melanoma risk and height were considered and selected after reading the title and abstract and, when appropriate, the full text. only articles written in english were chosen. additional studies were found among the references of the retrieved articles. results are described in separate sections depending on whether they were obtained from studies evaluating the risk of cancer at multiple sites, also including melanoma, or analyzing the risk of melanoma only. studies assessing cancer at multiple sites, including melanoma several studies have examined the cancer-height relationship and disclosed a significant positive association of adult height with both the overall cancer risk and the incidence of cancer at various anatomical sites, also highlighting a significant association between height and melanoma in both men and women [3-6]. results from a prospective cohort study in subjects living in the area of washington state indicated a hazard ratio for melanoma per 5 inches of height of 1.28 with a 95% confidence interval (ci) of 1.05-1.55, after adjustment for age, sex, and race [3]. in the institutes of health-aarp diet and health study, the hazard ratio per 10-cm increase of height was 1.18 (95% ci 1.13-1.23) in males and 1.14 (95% ci 1.05-1.24) in females, after adjustment for covariates (age at entry, education, race, smoking status, and body mass index) [5]. other authors corroborated the existence of this association in particular groups, such as middle-aged women and postmenopausal women [7-10]. the relation between height and cumulative relative risk of cancer appeared to be similar in different populations, with little difference across north america, europe, australasia, and asia [7]. when height was handled as a time-dependent covariate, the results for all cancers combined and melanoma did not differ from those obtained using only baseline height [8]. melanoma was among the highest ranking sites across the studies that included women and also among men, even after controlling for potential confounding variables, such as body mass index [4,7,9]. in a large prospective study involving 7 cohorts in austria, norway, and sweden [4], increased height (per 5-cm increment) was associated with a higher global cancer risk and, among the different cancer types, melanoma 84 review | dermatol pract concept 2019;9(2):2 ta b le 1 . g en er al c h ar ac te ri st ic s o f th e st u d ie s fo cu si n g sp ec ifi ca lly o n m el an o m a r is k a u th o rs c o u n tr y s tu d y d e si g n a n d s p e ci a l n o te s s tu d y p o p u la ti o n m e a n fo ll o w -u p a d ju st m e n t fo r c o v a ri a te s v ei er ø d e t al [ 1 3 ] n o rw ay p ro sp ec ti ve c o h o rt s tu d y; li n k ag e to n c r a n d c en tr al st at is ti cs b u re au 5 0 ,7 5 7 s u b je ct s ag ed 1 6 -5 6 y rs at te n d in g a h ea lt h s cr ee n in g in 1 9 7 7 -1 9 8 3 1 2 .4 y rs g en d er , a ge a t in cl u si o n a n d a tt ai n ed a ge , c o u n ty o f re si d en ce c u tl er e t al [ 1 4 ] c an ad a h o sp it al -b as ed c as eco n tr o l st u d y 1 5 9 c as es a n d 1 5 9 c o n tr o ls — a ge a t m en ar ch e, p re se n ce o f n ev i (m an y/ fe w ), e as e o f b u rn in g, h is to ry o f ca n ce r in a fi rs td eg re e re la ti ve t h u n e et al [ 1 5 ] n o rw ay p ro sp ec ti ve c o h o rt s tu d y; li n k ag e to n c r 1 .3 m il li o n i n d iv id u al s fr o m a sc re en in g su rv ey i n 1 9 6 3 -1 9 7 5 1 7 .6 y rs a ge , b m i, b ir th c o h o rt , g eo gr ap h ic r eg io n a t ti m e o f m ea su re m en t f re ed m an et a l [1 6 ] u sa p ro sp ec ti ve c o h o rt st u d y; s el fad m in is te re d q u es ti o n n ai re s 6 8 ,5 8 8 s u b je ct s (7 9 % f em al e) f ro m th e u s r ad io lo gi c t ec h n o lo gi st s st u d y 1 0 y rs a ge , w ei gh t, g en d er , s m o k in g d u ra ti o n , a lc o h o l in ta k e, e d u ca ti o n , d ec ad e o f em p lo ym en t b eg an a s a ra d ia ti o n t ec h n o lo gi st , s k in a n d h ai r co lo r, p er so n al h is to ry o f n o n m el an o m a sk in c an ce r, p ro x y m ea su re s fo r re si d en ti al c h il d h o o d a n d a d u lt s u n li gh t ex p o su re sh o rs e t al [1 7 ] u sa c as eco n tr o l st u d y; te le p h o n e su rv ey 3 8 6 n ew c as es o f p ri m ar y cu ta n eo u s m el an o m a in 1 9 9 7 a n d 7 2 7 c o n tr o ls — a ge , s ex , h ai r co lo r, su n e x p o su re i n d ic at o rs , f ru it a n d v eg et ab le i n ta k e d u b in e t al [ 1 8 ] u sa c as eco n tr o l h o sp it al -b as ed st u d y 1 ,1 0 3 c as es a n d 5 8 5 c o n tr o ls — a ge , s ex g al lu s et al [ 1 9 ] it al y h o sp it al -b as ed c as eco n tr o l st u d y 5 4 2 c as es a n d 5 3 8 c o n tr o ls — a ge , s ex , e d u ca ti o n , s m o k in g, h is to ry o f su n b u rn , p ro p en si ty t o su n b u rn , n o . o f n ev i, n o . o f fr ec k le s, s k in , h ai r, an d e ye c o lo r d en n is e t al [ 2 0 ] u sa p ro sp ec ti ve c o h o rt s tu d y; st u d ysp ec ifi c q u es ti o n n ai re s 4 4 ,0 8 6 p es ti ci d e ap p li ca to rs a n d th ei r sp o u se s en ro ll ed i n 1 9 9 3 -1 9 9 7 8 .2 y rs a ge , g en d er , t en d en cy t o b u rn , r ed h ai r co lo r, p er so n al o r fa m il y h is to ry o f sk in c an ce r, h o u rs i n t h e su n , s u n sc re en a n d s u n p ro te ct io n u se l ev in e et al [ 2 1 ] is ra el p ro sp ec ti ve c o h o rt s tu d y; li n k ag e to n c r 1 ,0 8 6 ,5 6 9 m al es a ge d 1 6 -1 9 y rs ex am in ed b ef o re m il it ar y se rv ic e in 1 9 6 7 -2 0 0 5 1 7 .8 y rs y ea r o f b ir th , c o u n tr y o f o ri gi n , y ea rs o f sc h o o li n g, r es id en ti al so ci o ec o n o m ic p o si ti o n , r u ra l/ u rb an d w el li n g o ls en e t al [2 2 ] u k , c an ad a, a u st ra li a, d en m ar k , u sa , i ta ly p o o le d a n al ys is o f 8 c as eco n tr o l st u d ie s 2 ,0 8 3 c as es a n d 2 ,7 8 2 c o n tr o ls (w o m en ) — a ge , h ai r, ey e an d s k in c o lo r, fr ec k li n g, f am il y h is to ry o f m el an o m a in a fi rs td eg re e re la ti ve , e th n ic it y, n o . o f n ev i o n t h e ar m s, s k in s en si ti vi ty t o su n e x p o su re , s u n e x p o su re h is to ry , e d u ca ti o n al l ev el k va sk o ff et a l [2 3 ] f ra n ce p ro sp ec ti ve c o h o rt s tu d y; b as el in e an d f o ll o w -u p s el fad m in is te re d q u es ti o n n ai re s 9 8 ,9 9 5 w o m en b o rn i n 1 9 2 5 -1 9 5 0 an d e n ro ll ed i n 1 9 8 9 -1 9 9 1 1 8 y rs a ge , h ai r an d s k in c o lo r, n o . o f n ev i, n o . o f fr ec k le s, s k in s en si ti vi ty t o su n e x p o su re , m ea n u v r e x p o su re i n c o u n ti es o f b ir th a n d o f re si d en ce at b as el in e, p h ys ic al a ct iv it y l ah m an n et a l [2 4 ] a u st ra li a c o m m u n it yb as ed p ro sp ec ti ve s k in c an ce r st u d y* 1 ,1 7 1 s u b je ct s 1 6 y rs a ge , t re at m en t al lo ca ti o n ( b et aca ro te n e su p p le m en ts a n d /o r d ai ly su n sc re en ), h is to ry o f n o n m el an o m a sk in c an ce r, el as to si s o f th e n ec k , fr ec k li n g o f th e b ac k , s m o k in g st at u s st en eh je m et a l [2 5 ] n o rw ay p ro sp ec ti ve c o h o rt s tu d y; li n k ag e to n c r 2 9 2 ,8 5 1 s u b je ct s re cr u it ed i n 1 9 7 2 -2 0 0 3 2 7 y rs a ge , b m i, h ei gh t, a m b ie n t u v r o f re si d en ce , a ve ra ge i n te n si ty o f su n b u rn s, o cc u p at io n , p h ys ic al a ct iv it y, e d u ca ti o n , s m o k in g st at u s (i n w o m en , a ls o a ve ra ge i n te n si ty o f so la ri u m s es si o n s) b m i = b od y m as s in de x; n c r = n at io na l c an ce r r eg is tr y; u v r = ul tr av io le t r ad ia tio n. * c on co m ita nt a ss es sm en t o f k er at in oc yt e ca nc er s. review | dermatol pract concept 2019;9(2):2 85 curve appeared to support an exponential increase. the risk according to height increased with statistical significance until 195 cm in men and from approximately 170 to 180 cm in women, and then declined. results from a cohort of french women indicated that melanoma risk was positively associated with height in age-adjusted models only, as well as with sitting-to-standing height ratio in multivariable models, while no significant association with sitting height or leg length was observed [23]. in the pooled analysis of melanoma in women performed by olsen et al [22], there was an increased risk of melanoma in the highest quartile of height compared with the lowest quartile for women overall (pooled odds ratio 1.3, 95% ci 1.1-1.6). after stratification by age, the association was limited to women <50 years of age (pooled odds ratio 1.4, 95% ci 1.1-1.9). elevated odds ratios in the highest quartile of height were found for superficial spreading melanoma (pooled odds ratio 1.3, 95% ci 1.0-1.7), and to a lesser extent for nodular melanoma (pooled odds ratio 1.2, 95% ci 0.7-2.1), whereas no association with lentigo maligna melanoma was observed. furthermore, increased risks associated with the highest quartile of height were on the contrary, other studies failed to disclose a significant association [16,19,20,24]. shors et al observed no association between melanoma and height in women but found an increased risk for men in the highest vs the lowest quartile (odds ratio 2.4, 95% ci 1.3-4.5), although these results were attenuated after adjustment for weight (odds ratio 1.9, 95% ci 0.9-3.8) [17]. it is interesting that prospective studies involving large cohorts linked to national cancer registries and followed up for many years consistently reported a significant trend in melanoma-height association [13,15,21,25]. stenehjem et al recently published the results of a prospective study aimed at assessing the risk of melanoma according to anthropometric factors, adjusted for exposure to uvr, in a large population-based cohort in norway, linked to the national cancer registry, over an average follow-up period of 27 years [25]. they found significant positive associations for height, with greater than 50% increased melanoma risk for the highest quintile compared with the lowest quintile in both sexes. height above the median was estimated to account for 10% of the male and 6% of the female melanoma cases, respectively. the authors also used restricted cubic splines for the assessment of melanoma risk. the shape of the risk table 2. studies focusing specifically on melanoma risk: summary of results regarding association with height study main results veierød et al [13] increased risk with increasing height (p < 0.01, test for linear trend) cutler et al [14] height as a significant risk factor (difference of mean heights in cases vs controls of only 2 cm, p = 0.009) thune et al [15] significant increase of risk with increasing height in both sexes (rr 1.6, 95% ci 1.4-1.8 in the highest quintile) freedman et al [16] no association in men and women shors et al [17] increased risk for men in the highest vs the lowest quartile (or 2.4, 95% ci 1.3-4.5); no association in women dubin et al [18] increasing linear trend in risk for increasing height (p < 0.005); rr 1.62 (95% ci 1.01-2.6) in the highest quintile gallus et al [19] no significant association dennis et al [20] no significant association (results not further specified) levine et al [21] increasing trend in risk for increasing height; hr in the highest quintile 2.42 (95% ci 2.06-2.83) in univariate analysis, 1.40 (95% ci 1.191.65) in multivariable analysis olsen et al [22] increased risk in the highest quartile (pooled or 1.3, 95% ci 1.1-1.6) kvaskoff et al [23] positive association in age-adjusted models only (rr 1.27, 95% ci 1.05-1.55 for ≥164 cm vs <160 cm, p for trend = 0.02) lahmann et al [24] positive association in men (rr per 5-cm increment 1.55, 95% ci 0.972.47), though not significant stenehjem et al [25] positive association in both men and women (p trend < 0.001); hr in the highest quintile 1.55 (95% ci 1.36-1.77) for men and 1.52 (95% ci 1.31-1.76) for women in multivariable analysis ci = confidence interval; hr = hazard ratio; or = odds ratio; rr = relative risk. 86 review | dermatol pract concept 2019;9(2):2 ment of height after the occurrence of cancer in case-control studies [22,25]. it is relevant to underline that a recent systematic review and meta-analysis gave evidence for the relationship between height and melanoma risk [26]. the authors included 12 prospective studies, most of which enrolled caucasian populations with a total of 4,723,739 participants and 20,049 cases of melanoma. different potential confounding factors were taken into account for multi variate regression analyses in the included studies. in brief, the cumulative findings of this meta-analysis indicated that subjects in the top category of height had increased risk of melanoma (random-effects relative risk 1.46, 95% ci 1.24-1.73; p < 0.001) compared with the lowest category. per 10-cm increment in height was positively correlated with increased melanoma risk (randomeffects relative risk 1.27, 95% ci 1.19-1.35; p < 0.001), with significant results seen in both women and men using a subgroup analysis by gender. childhood height meyle et al examined anthropometric parameters in childhood (measured at ages 7-13 years) in relation to future risk of melanoma. for this purpose, they analyzed the data of 372,636 danish children from the copenhagen school health records register, during approximately 11 million person-years of follow-up [27]. relevant strengths of this study were the large sample size, the minimal loss to followup, the absence of selection bias, the inclusion of carefully recorded height measurements, and the identification of melanoma cases via linkage to the national cancer registry. greater childhood height at the ages of 7 and 13 years was shown to be significantly associated with an increased risk of melanoma in adulthood. melanoma risk was also associated with birth weight. therefore, the authors concluded that associations between body size and melanoma may initiate early in life and can be related to height and birth weight, without any apparent influence of body mass index or body surface area [27]. a further analysis of the same cohort revealed the positive and significant association of childhood height with the majority of melanoma variants in adulthood (superficial spreading melanoma, nodular melanoma, melanoma not otherwise specified), but not with lentigo maligna melanoma [28]. putative mechanisms underlying height-melanoma relationship in various analyses, positive height–cancer gradients were disclosed for many cancer types, including melanoma [3-10], suggesting that factors related to height might contribute noticed for melanomas of the head/neck, lower limbs, and upper limbs [22]. according to thune et al [15], there was a positive association with height for melanomas localized on the face and trunk in both sexes, and for those of the lower limbs only in females. stenehjem et al described significant positive trends for trunk, head, and neck melanomas in men, and for melanomas of the upper and lower limbs in women, and, as concerns the relation between height and histological subtype, they observed significant dose-related risks for superficial spreading melanoma and nodular melanoma in both sexes [25]. with regard to the studies shown in table 1, a great heterogeneity is recognizable among them, in terms of design, sample size and characteristics, as well as adjust ed confounding factors. limitations of most studies were the lack of complete information on several variables known to be risk factors for cutaneous melanoma and consequently the inability to adjust for the potential confounding effect of such variables. for instance, only some studies included adjustment for sunlight exposure, sun sensitivity (eg, sunburn) and/or uvr indicators, hair color and/or other pigmentary traits, and number of nevi (table 1). nevertheless, such information was categorized using nonstandardized and heterogeneous definitions, especially in the case of nevi count and sunlight exposure. lahmann et al took into account in their model clinical elastosis of the neck as an indicator of sun sensitivity and cumulative sun exposure [24]. in very few studies, data on family history of melanoma, other skin cancers or malignancies, or personal history of nonmelanoma skin cancer were available and taken into consideration (table 1). in the analysis performed by kvaskoff et al [23], the positive association between height and melanoma, detected in age-adjusted models only, was weakened and lost any statistical significance after full adjustment for age and also for other known risk factors for melanoma. in particular, the factors that decreased the strength of this association were number of nevi and hair color. the associations revealed by olsen et al were instead unaffected by adjustment for other known melanoma risk factors, such as sun exposure-related features [22]. many other factors may act as confounders, including ethnicity, socioeconomic status, education, outdoor activity, smoking, tanning habit, use of sunbeds, and other lifestyle factors, and these were taken into consideration occasionally (table 1). moreover, the majority of studies have relied on selfreported height, thus impairing the accurateness and precision of data entry [1]. in fact, only a limited number of reports clearly indicated that measurement of height was obtained by trained staff [15,21,24,25]. inaccuracy of estimates might also be related to recall bias, when the self-reporting of height was done in different periods of time, or to the assessreview | dermatol pract concept 2019;9(2):2 87 spurt, and the peak in height velocity at adolescence is driven by a cascade of hormones, primarily initiated by a rise in sex steroids and followed by increases in gh and the related igf-1 [34]. igf-1 level in children was found to be positively associated with growth in height [35]. moreover, the gh–igf-1 axis can be influenced by nutritional status [36]. igf and gh have been implicated not only in tissue growth and development, but also in carcinogenesis [37]. results from prospective studies of individuals with acromegaly have reported increased risks of melanoma [38]. gh exerts multiple biological effects directly or through igf-1 action and can interfere with many intracellular signaling pathways known to be implicated in oncogenesis [37]. of interest, human melanoma cells have been found to express gh receptors and also human metastatic melanoma cells were shown to possess active gh receptors that can modulate multiple signaling pathways capable of promoting tumor progression [39-41]. in addition, experimental data have supported the regulatory role of igf axis in human melanoma, particularly in the proliferation of early-stage melanoma cells [41-43]. previous case-control studies have examined the association between circulating igf-1 concentrations and the risk of melanoma with inconsistent results [44,45], while a nested case-control study in a prospective cohort from 10 european countries did not find any significant association between circulating igf-1 concentration measured in adulthood and melanoma risk [46]. however, these findings do not necessarily rule out the influence of igf-1, especially during childhood, on the future risk of melanoma. as previously mentioned, the achieved height can be correlated with the level of serum igf-1 in puberty, but later any correlation may be lost. growth-influencing exposures during childhood, which operate also through effects on igf-1 levels, may have long-term influences on disease risk, without, however, conditioning igf-1 levels throughout life [47]. in this context, prepubertal age is likely to be a crucial period in determining the risk of melanoma in adulthood, as suggested by the effects of sunburn and uvr exposure at these ages on nevogenesis and melanomagenesis [48]. a recent hypothesis has taken into consideration bodyresonant radiation that may affect both cancer incidence and body height. radio-waves might influence body height through hormonal disturbances. it has been speculated that individuals who sleep in a bed that acts as a radio-wave antenna can be particularly prone to the harmful effects of radiation. therefore, a correlation between melanoma incidence, mean body height, the number of fm broadcasting transmitters, as well as the use of metal spring mattresses has been hypothesized [49]. to cancer development in adulthood. the observations that height can be associated with selected cancers but not others seem to imply the existence of biological and behavioral mechanisms that vary depending on the anatomical site but may be shared by different cancer sites and/or types [3,8]. a number of hypotheses have been proposed to explain the association between height and melanoma. human growth is a complex phenomenon influenced by genetic, hormonal, nutritional, and other environmental factors from fetal life to puberty. the growth hormone (gh)–insulin-like growth factor (igf)-1 axis plays a central role in growth. nevertheless, numerous genes are involved in the control of stature, the large part of which are outside the gh–igf-1 system, and many other molecules, as well as multiple intracellular molecular pathways, are involved in growth processes [29]. for instance, a meta-analysis of genome-wide association studies identified nearly 700 variants, reflecting 423 loci, that contribute to normal adult stature variation in individuals of european ancestry and can explain nearly 20% of the heritability for adult height [30]. adult attained height is thought to be the consequence of the interplay of genetic factors and many early-life experiences and exposures that may have an impact on cancer or other pathological events occurring much later in life. stature may be an indirect indicator of nutritional status or caloric intake during childhood or adolescence [31]. a few data have suggested that caloric restriction during development can have lasting beneficial effect on the future risk of malignancy [32]. it has been postulated that cancer risk is proportional to organ cellularity and the number of proliferating cells within tissues [3,31]. height is directly correlated with the number of cells that can be susceptible to convert into neoplastic cells, and, for melanoma, the number of melanocytes is relevant, as well as the total body area. some authors detected a positive association between melanoma risk and high body surface area [15,25], while others noted no relation with body surface area [22,23]. as concerns nevus number, ribero et al highlighted the importance of growth in melanoma susceptibility based on the results of a study in the twinsuk cohort that disclosed the positive association between nevus count, an important risk factor for melanoma, and height [33]. moreover, their study also revealed that nevus count was unrelated to weight and positively associated with bone mineral density. adjustment for leukocyte telomere length, known to be linked to both bone mineral density and nevus count, did not modify the significance of the association between height and nevus count, thereby ruling out a direct influence of leukocyte telomere length on the results [33]. height is correlated with hormones and growth factors that may also be involved in carcinogenesis. the igf system plays an important role during the peripubertal growth 88 review | dermatol pract concept 2019;9(2):2 12. batty gd, shipley mj, langenberg c, et al. adult height in relation to mortality from 14 cancer sites in men in london (uk): evidence from the original whitehall study. ann oncol. 2006;17(1):157-166. 13. veierød mb, thelle ds, laake p. diet and risk of cutaneous malignant melanoma: a prospective study of 50,757 norwegian men and women. int j cancer. 1997;71(4):600-604. 14. cutler c, foulkes wd, brunet js, et al. cutaneous malignant melanoma in women is uncommonly associated with a family history of melanoma in first-degree relatives: a case-control study. melanoma res. 1996;6(6):435-440. 15. thune i, olsen a, albrektsen g, tretli s. cutaneous malignant melanoma: association with height, weight and body-surface area. a prospective study in norway. int j cancer. 1993;55(4):555-561. 16. freedman dm, sigurdson a, doody mm, et al. risk of melanoma in relation to smoking, alcohol intake, and other factors in a large occupational cohort. cancer causes control. 2003;14(9):847857. 17. shors ar, solomon c, mctiernan a, white e. melanoma risk in relation to height, weight, and exercise (united states). cancer causes control. 2001;12(7):599-606. 18. dubin n, moseson m, pasternack bs. epidemiology of malignant melanoma: pigmentary traits, ultraviolet radiation, and the identification of high-risk populations. recent results cancer res. 1986;102:56-75. 19. gallus s, naldi l, martin l, et al; oncology study group of the italian group for epidemiologic research in dermatology (gised). anthropometric measures and risk of cutaneous malignant melanoma: a case-control study from italy. melanoma res. 2006;16(1):83-87. 20. dennis lk, lowe jb, lynch cf, alavanja mc. cutaneous melanoma and obesity in the agricultural health study. ann epidemiol. 2008;18(3):214-221. 21. levine h, afek a, shamiss a, et al. country of origin, age at migration and risk of cutaneous melanoma: a migrant cohort study of 1,100,000 israeli men. int j cancer. 2013;133(2):486-494. 22. olsen cm, green ac, zens ms, et al. anthropometric factors and risk of melanoma in women: a pooled analysis. int j cancer. 2008;122(5):1100-1108. 23. kvaskoff m, bijon a, mesrine s, et al. anthropometric features and cutaneous melanoma risk: a prospective cohort study in french women. cancer epidemiol. 2014;38(4):357-363. 24. lahmann ph, hughes mc, williams gm, green ac. a prospective study of measured body size and height and risk of keratinocyte cancers and melanoma. cancer epidemiol. 2016;40:119-125. 25. stenehjem js, veierød mb, nilsen lt, et al. anthropometric factors and cutaneous melanoma: prospective data from the population-based janus cohort. int j cancer. 2018;142(4):681690. 26. yu d-j, li x-j, morice a, et al. height and risk of melanoma: a systematic review and meta-analysis. int j clin exp med. 2018;11(5):4426-4435. 27. meyle kd, gamborg m, sørensen tia, baker jl. childhood body size and the risk of malignant melanoma in adulthood. am j epidemiol. 2017;185(8):673-680. 28. meyle kd, gamborg m, hölmich lr, baker jl. associations between childhood height and morphologically different variants of melanoma in adulthood. eur j cancer. 2016;67:99-105. 29. baron j, sävendahl l, de luca f, et al. short and tall stature: a new paradigm emerges. nat rev endocrinol. 2015;11(12):735-746. conclusions accumulating evidence suggests the relation between anthropometry and cancer. a positive association between height and melanoma risk has been suggested, although results appear to be still controversial. however, the existence of a significant association has been highlighted in a recent systematic review and meta-analysis [26]. further research is, however, required to confirm a heightmelanoma relationship and better understand the underlying mechanisms. an intriguing aspect is the identification of the possible shared genetic factors and pathomechanisms, as well as exposures occurring early in life that are capable of influencing both growth process and future cancer risk. references 1. bandera ev, fay sh, giovannucci e, et al; world cancer research fund international continuous update project panel. the use and interpretation of anthropometric measures in cancer epidemiology: a perspective from the world cancer research fund international continuous update project. int j cancer. 2016;139(11):2391-2397. 2. rastrelli m, tropea s, rossi cr, alaibac m. melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification. in vivo. 2014;28(6):1005-1011. 3. walter rb, brasky tm, buckley sa, et al. height as an explanatory factor for sex differences in human cancer. j natl cancer inst. 2013;105(12):860-868. 4. wirén s, häggström c, ulmer h, et al. pooled cohort study on height and risk of cancer and cancer death. cancer causes control. 2014;25(2):151-159. 5. kabat gc, kim my, hollenbeck ar, rohan te. attained height, sex, and risk of cancer at different anatomic sites in the nih-aarp diet and health study. cancer causes control. 2014;25(12):1697-1706. 6. jiang y, marshall rj, walpole sc, et al. an international ecological study of adult height in relation to cancer incidence for 24 anatomical sites. cancer causes control. 2015;26(3):493-499. 7. green j, cairns bj, casabonne d, et al; million women study collaborators. height and cancer incidence in the million women study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. lancet oncol. 2011;12(8):785794. 8. kabat gc, anderson ml, heo m, et al. adult stature and risk of cancer at different anatomic sites in a cohort of postmenopausal women. cancer epidemiol biomarkers prev. 2013;22(8):13531363. 9. kabat gc, heo m, kamensky v, et al. adult height in relation to risk of cancer in a cohort of canadian women. int j cancer. 2013;132(5):1125-1132. 10. yang to, reeves gk, green j, et al; million women study collaborators. birth weight and adult cancer incidence: large prospective study and meta-analysis. ann oncol. 2014;25(9):1836-1843. 11. emerging risk factors collaboration. adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. int j epidemiol. 2012;41(5):1419-1433. review | dermatol pract concept 2019;9(2):2 89 and respond to gh treatment. biochem biophys res commun. 2013;441(1):144-150. 41. basu r, wu s, kopchick jj. targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways. oncotarget. 2017;8(13):21579-21598. 42. satyamoorthy k, li g, vaidya b, et al. insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and betacatenin pathways. cancer res. 2001;61(19):7318-7324. 43. capoluongo e. insulin-like growth factor system and sporadic malignant melanoma. am j pathol. 2011;178(1):26-31. 44. park sl, setiawan vw, kanetsky pa, et al. serum insulin-like growth factor-i and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma. cancer causes control. 2011;22(9):1267-1275. 45. kucera r, treskova i, vrzalova j, et al. evaluation of igf1 serum levels in malignant melanoma and healthy subjects. anticancer res. 2014;34(9):5217-5220. 46. bradbury ke, appleby pn, tipper sj, et al. circulating insulinlike growth factor i in relation to melanoma risk in the european prospective investigation into cancer and nutrition. int j cancer. 2019;144(5):957-966. 47. gunnell d, oliver se, donovan jl, et al. do height-related variations in insulin-like growth factors underlie the associations of stature with adult chronic disease? j clin endocrinol metab. 2004;89(1):213-218. 48. green ac, wallingford sc, mcbride p. childhood exposure to ultraviolet radiation and harmful skin effects: epidemiological evidence. prog biophys mol biol. 2011;107(3):349-355. 49. hallberg o. cancer and body height. pathophysiology. 2014;21(2):177-181. 30. wood ar, esko t, yang j, et al. defining the role of common variation in the genomic and biological architecture of adult human height. nat genet. 2014;46(11):1173-1186. 31. albanes d, winick m. are cell number and cell proliferation risk factors for cancer? j natl cancer inst. 1988;80(10):772-774. 32. frankel s, gunnell dj, peters tj, et al. childhood energy intake and adult mortality from cancer: the boyd orr cohort study. bmj. 1998;316(7130):499-504. 33. ribero s, glass d, aviv a, et  al. height and bone mineral density are associated with naevus count supporting the importance of growth in melanoma susceptibility. plos one. 2015;10(1):e0116863. 34. murray pg, clayton pe. endocrine control of growth. am j med genet c semin med genet. 2013;163c(2):76-85. 35. rogers i, metcalfe c, gunnell d, et al. avon longitudinal study of parents children study team. insulin-like growth factor-i and growth in height, leg length, and trunk length between ages 5 and 10 years. j clin endocrinol metab. 2006;91(7):2514-2519. 36. hawkes cp, grimberg a. insulin-like growth factor-i is a marker for the nutritional state. pediatr endocrinol rev. 2015;13(2):499511. 37. chhabra y, waters mj, brooks aj. role of the growth hormone–igf-1 axis in cancer. expert rev endocrinol metab. 2011;6(1):71-84. 38. gunnell d, okasha m, smith gd, et al. height, leg length, and cancer risk: a systematic review. epidemiol rev. 2001;23(2):313342. 39. lincoln dt, sinowatz f, kölle s, et al. up-regulation of growth hormone receptor immunoreactivity in human melanoma. anticancer res. 1999;19(3a):1919-1931. 40. sustarsic eg, junnila rk, kopchick jj. human metastatic melanoma cell lines express high levels of growth hormone receptor dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):16 71 dermatology practical & conceptual www.derm101.com reticular telangiectatic erythema: case report and literature review bryce d. beutler1, philip r. cohen2 1 university of nevada, las vegas, school of allied health sciences, las vegas, nevada, usa 2 division of dermatology, university of california san diego, san diego, california, usa key words: cardioverter, defibrillator, erythema, implantable, pacemaker, reticular, subcutaneous, telangiectasia, telangiectatic citation: beutler bd, cohen pr. reticular telangiectatic erythema: case report and literature review. dermatol pract concept 2015;5(1):16. doi: 10.5826/dpc.0501a16 received: september 1, 2014; accepted: october 23, 2014; published: january 30, 2015 copyright: ©2015 beutler et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: bryce d. beutler, bs, 1060 wiegand road, encinitas, ca 92024, usa. tel. 760 271 8901. email: brycebeutler@ hotmail.com background: reticular telangiectatic erythema is a benign cutaneous reaction that may occur in patients who have received a subcutaneous implantable cardioverter-defibrillator. reticular telangiectatic erythema is characterized by asymptomatic telangiectasias, blanchable erythematous patches, or both overlying and/or adjacent to the subcutaneous implantable cardioverter-defibrillator. purpose: we describe a man who developed reticular telangiectatic erythema after receiving a subcutaneous implantable cardioverter-defibrillator and review the salient features of this condition. we also summarize the conditions that can mimic reticular telangiectatic erythema. materials and methods: the features of a man with reticular telangiectatic erythema are presented and the literature on reticular telangiectatic erythema is reviewed. results: our patient developed reticular telangiectatic erythema within one month of subcutaneous implantable cardioverter-defibrillator insertion. the subcutaneous manifestations were asymptomatic. the patient concurred to have periodic clinical follow up and his condition will be monitored for any changes. conclusion: reticular telangiectatic erythema is a benign condition characterized by the development of erythema, telangiectasia, or both following insertion of a subcutaneous implantable cardioverter-defibrillator. other subcutaneous implantable cardioverter-defibrillator-related side effects, such as pressure dermatitis and contact dermatitis, can mimic the condition. reticular telangiectatic erythema can also be observed following insertion of other devices or, rarely, in the absence of inserted devices. local microcirculatory changes and subcutaneous implantable cardioverter-defibrillatorrelated obstruction of blood flow have been suggested as possible mechanisms of pathogenesis. the diagnosis can usually be established by clinical presentation. therefore, patch testing can usually be omitted. reticular telangiectatic erythema is typically asymptomatic and thus removal of the device is not required. abstract mailto:brycebeutler@hotmail.com mailto:brycebeutler@hotmail.com 72 observation | dermatol pract concept 2015;5(1):16 within four weeks, the patient noticed the onset of new blood vessels appearing around and encroaching upon the borders of the subcutaneous implantable cardioverter-defibrillator. cutaneous examination revealed a prominent scar at the insertion site of the subcutaneous implantable cardioverter-defibrillator. beneath the scar and approaching the subcutaneous implantable cardioverter-defibrillator there was minimal erythema and numerous telangiectasias. the skin surface was intact without any evidence of dermatitis or erosion (figures 1-3). based on correlation of the clinical history and the lesion morphology, a diagnosis of reticular telangiectatic erythema was established. the patient was reassured of the benign nature of the condition. he will have periodic follow up to monitor for any changes. discussion reticular telangiectatic erythema was first identified in 1981 by gensch and schmitt [2]. subsequently, this condition has introduction the subcutaneous implantable cardioverter-defibrillator is a subcutaneously implanted defibrillator that is used to detect and treat ventricular arrhythmias in at-risk patients [1]. reticular telangiectatic erythema is a benign cutaneous condition that may occur in patients who have received a subcutaneous implantable cardioverter-defibrillator. we describe a man who developed reticular telangiectatic erythema within one month of insertion of a subcutaneous implantable cardioverterdefibrillator and discuss the salient features of this condition. we also summarize other disorders that can mimic reticular telangiectatic erythema. case report a 54-year-old man presented with light-headedness and syncope. workup showed a left bundle branch block with bradycardia and a depressed ejection fraction of 40%. the patient received a biventricular implantable cardioverter-defibrillator and the symptoms have not reoccurred. figure 1. frontal (a) and side (b) views of chest show normal-appearing right chest and outline of a subcutaneous implantable cardioverterdefibrillator with reticular telangiectatic erythema on the left chest of a 54-year-old man. (copyright: ©2015 beutler et al.) a b figure 2. distant (a) and closer (b) views of reticular telangiectatic erythema on the left chest show the insertion site scar and superior border of the subcutaneous implantable cardioverter-defibrillator; telangiectasias and minimal erythema are noted. (copyright: ©2015 beutler et al. a b observation | dermatol pract concept 2015;5(1):16 73 implantable cardioverter-defibrillator and spread inward, as in our patient. alternatively, it can begin as an erythematous patch overlying the device with telangiectasias spreading in a peripheral manner. the lesions are asymptomatic. the diagnosis is essentially based upon clinical history and lesion morphology. a confirmatory biopsy is not usually necessary [15]. however, when tissue examination was performed, the lesional biopsies revealed telangiectasias and a perivascular lymphohistiocytic infiltrate in the superficial dermis [19,20]. the clinical differential diagnosis is listed in table 2 [3,10,14,15,21-33]. it includes potential cutaneous side effects from the subcutaneous implantable cardioverter-defibrillator as well as other local conditions and systemic disorders. allergic contact dermatitis (typically associated with metal sensitivity and pressure dermatitis) is a subcutaneous implantable cardioverter-defibrillator-associated dermatological side effects that may initially mimic reticular telangiectatic erythema. however, in allergic contact dermatitis, eczematous changes in the overlying epithelium may be observed in addition to erythema. if clinically suspicious, patch testing may be helpful to establish a diagnosis. pressure dermatitis may initially present as erythema; yet there is subsequent erosion of the overlying skin. similar to subcutaneous implantable cardioverter-defibrillator-associated reticular telangiectatic erythema, the same phenomenon has been observed following the insertion of other devices [10]. in 2005, mercader-garcía et al described reticular telangiectatic erythema in a 50-year-old man who had an intrabeen described in additional patients under various descriptive terms (table 1) [2-18]. reticular telangiectatic erythema presents in patients following insertion of a subcutaneous implantable cardioverterdefibrillator. the appearance of reticular telangiectatic erythema can occur within weeks of device implantation [18]; however, the onset of reticular telangiectatic erythema has been reported as late as four years after subcutaneous implantable cardioverter-defibrillator insertion [14]. the mean onset of reticular telangiectatic erythema following subcutaneous implantable cardioverter-defibrillator insertion is 30 months [10]. lesions initially appear as erythema, telangiectasia, or both. they may begin at the borders of the subcutaneous figure 3. distant (a) and closer (b) views of reticular telangiectatic erythema on the left chest show telangiectasias along the lateral border of the subcutaneous implantable cardioverter-defibrillator. (copyright: ©2015 beutler et al.) a b table 1. descriptive terminology for reticular telangiectatic erythema (copyright: ©2015 beutler et al.) annular erythema [3] circumscribed erythema [4,5] circumscribed reticular telangiectatic erythema [2] erythema [6,7] erythema with telangiectases [8] persistent telangiectatic erythema [9] post-implantation erythema [10] postsurgical sternal erythema [11-13] reticular telangiectatic erythema [14-16] telangiectatic erythema [17] telangiectatic erythematous cutaneous reaction [18] 74 observation | dermatol pract concept 2015;5(1):16 thecal infusion pump implanted in his left flank. the lesions appeared 15 days after the device was inserted and persisted with no significant changes for more than a year. however, approximately two years after insertion of the device, a cutaneous erosion developed over the implant site. the device was removed and the lesions disappeared shortly thereafter [34]. heat-triggered reticular telangiectatic erythema has also been reported. investigators described a patient in whom a defective spinal cord stimulator induced localized hyperthermia and subsequent reticular telangiectatic erythema. notably, the lesions began to dissipate several days after the device was switched off [35]. reticular telangiectatic erythema also occurred in patients following orthopedic implants [10]. in 2013, do and mousdicas described two men who developed reticular telangiectatic erythema following total knee arthroplasty. in both of these men, the reticular telangiectatic erythema appeared adjacent to the surgical scar and spontaneously resolved fully or partially within one year [36]. it has been postulated that the presence of any foreign body can cause reticular telangiectatic erythema. armengotcarbo et al describe a 61-year-old woman who developed reticular telangiectatic erythema one month after undergoing a lumpectomy for breast cancer. the lesion persisted for three months, until a long non-absorbable intradermal suture was detected and removed. two weeks later, the reticular telangiectatic erythema had disappeared [28]. a definitive pathogenesis for reticular telangiectatic erythema has yet to be identified. more than one etiology may cause the condition to occur. it may be device-related or siterelated. in addition, reticular telangiectatic erythema may be the result of anatomic factors [18]. wimmershoff et al proposed that device-generated electric or magnetic fields might play a causative role in the development of reticular telangiectatic erythema [7]. however, there are several reported cases in which reticular telangiectatic erythema developed in the absence of electrical devices [34,36]. while metal sensitivity has also been suggested as a possible mechanism of pathogenesis for reticular telangiectatic erythema, the clinical and histological features of reticular telangiectatic erythema are distinct from those of allergic contact dermatitis. nevertheless, patch testing may be useful if metal sensitivity is suspected. other investigators have postulated that reticular telangiectatic erythema results from changes to the microcirculatory environment. these changes may occur secondary to healing or result from device-related obstruction of blood flow [20]. reticular telangiectatic erythema is asymptomatic and does not have any adverse associated sequelae. therefore, reassurance of the benign nature of the condition and observation are reasonable alternatives to management. if the patient is concerned about the cosmetic features of reticular telangiectatic erythema, sclerotherapy may provide a potential therapeutic alternative. conclusion reticular telangiectatic erythema is a benign cutaneous condition that occurs within weeks, months, or years of subcutaneous implantable cardioverter-defibrillator insertion. the vascular lesion tends to persist and may progress with time. other subcutaneous implantable cardioverter-defibrillatorassociated adverse events, such as allergic contact dermatitis and pressure dermatitis, may initially mimic reticular telangiectatic erythema. occasionally, reticular telangiectatic erythema may occur in patients with spinal cord stimulators, infusion pumps, or other implantable devices. postulated mechanisms for the pathogenesis of reticular telangiectatic erythema include site-related anatomic factors and deviceassociated changes to the microcirculatory environment. management of reticular telangiectatic erythema typically includes reassurance and observation. references 1. grace a. the subcutaneous implantable cardioverter-defibrillator. curr opin cardiol 2014;29:10-19. 2. gensch eg, schmitt cg. circumscribed reticular telangiectatic erythema following implantation of a heart pacemaker. hautarzt 1981;32(12):651-54. table 2. clinical differential diagnosis of reticular telangiectatic erythema. (copyright: ©2015 beutler et al.) dermatitis pacemaker dermatitis [21,22] pressure dermatitis [10,23] erythema annular erythema [3] erythema ab igne [24] reticular telangiectatic erythema* [14,15] other conditions reticulated erythematous mucinosis [10,25] wells syndrome [26] vascular lesions angiosarcoma-like vascular proliferation [27] cutaneous reactive angiomatoses** [28-32] livido reticularis (localized) [10] telangiectasias [33] *subcutaneous implantable cardioverter-defibrillator-related ** cutaneous reactive angiomatoses include the following conditions: acroangiodermatitis, angiopericytomatosis, diffuse dermal angiomatosis, glomeruloid angioendotheliomatosis, intralymphatic histiocytosis, reactive angioendotheliomatosis (copyright: ©2015 beutler et al.) observation | dermatol pract concept 2015;5(1):16 75 3. gerdsen r, kaiser hw, fredrick k, rabe e, bieber t. annular erythema caused by impending pacemaker extrusion. acta derm venereol 1999;79(5):385-87. 4. maushagen e, reichle b, simon h. circumscribed erythema after cardiac pacemaker implantation. z kardiol 1994;83:340-342. 5. cierpka r, trappe hj, pfitzner p, lichtlen pr. circumscribed defibrillator erythema: a differential diagnostic and therapeutic problem in differential occult defibrillator infection diagnosis. z kardiol 1996;85(5):312-18. 6. sorhage b, glowania h. erythema after implantation of a cardiac pacemaker. z hautkr 1991;66:458-62. 7. wimmershoff mb, landthaler m, stolz w. the artificial pacemaker erythema. dtsch med wochenschr 1998;123:441. 8. kopera d, auer-grumbach p, cerroni l, smolle j. pacemaker erythema with telangiectasias. hautarzt 1994;45(10):716-718. 9. krasagakis k, vogt r, tebbe b, goerdt s. persistent telangiectatic erythema associated with an automatic implantable cardioverter defibrillator. br j dermatol 1997;136(4):633. 10. aneja, s, taylor js, billings sd, honari g, sood a. post-implantation erythema in 3 patients and a review of reticular telangiectatic erythema. contact dermatitis 2011;64(5):280-88. 11. morgan mb, scalf la, hanno r. sternal erythema: a distinctive postsurgical eruption. j am acad dermatol 2005;53(5):893-96. 12. chiu m. is postsurgical sternal erythema synonymous with reticular telangiectatic erythema? j am acad dermatol 2006;55(1):180. 13. bowers jw, morgan mb. is postsurgical sternal erythema synonymous with reticular telangiectatic erythema? reply. j am acad dermatol 2007;56(5):892-93. 14. dinulos jg, vath b, beckmann c, welch mp, piepkorn m. reticular telangiectatic erythema associated with an implantable cardioverter defibrillator. arch dermatol 2001;137:1259-61. 15. herbst r, weiss j. reticular telangiectatic erythema associated with an implantable cardioverter defibrillator: an underpublished entity? arch dermatol 2003;139(1):100-1. 16. kint a, vermander f. reticular telangiectatic erythema after implantation of a pacemaker. dermatologica 1983;166(6):322-24. 17. lin yc, chiu hc, chu cy, sun cc. telangiectatic pacemaker erythema. clin exp dermatol 2003;28(4):447-48. 18. ferringer t, mowad c. telangiectatic erythematous cutaneous reaction to an implantable cardioverter defibrillator. am j contact dermatitis 2003;14:37-40. 19. rodríguez-lojo r., verea mm, godoy j, barja jm. reticular telangiectatic erythema in a patient with a cardioverter defibrillator. actas dermo-sifiliográficas 2010;101(2):183-84. 20. pitarch g, mercader p, torrijos a, martínez-menchón t, fortea jm. reticular telangiectatic erythema associated with an implantable cardioverter defibrillator. cutis. 2006;78(5):329-31. 21. buchet s, blanc d, humbert p, et al. pacemaker dermatitis. contact dermatitis 1992;26(1):46-7. 22. peters ms, schroeter al, van hale hm, broadbent jc. pacemaker contact sensitivity. contact dermatitis. 1984;11(4):214-18. 23. wilkerson mg, jordan wp jr. pressure dermatitis from an implanted pacemaker. dermatol clin 1990;8(1):189-92. 24. dissemond j, grabbe s. erythema ab igne. intern med j 2008;38(8):675. 25. thareja s, paghdal k, lien mh, fenske na. reticular erythematous mucinosis—a review. int j dermatol 2012;51(8):903-9. 26. cashin b, allan n, kang c. wells syndrome. west j emerg med. 2010;11(1):95-6. 27. ringrose js, banerjee t, hull pr. angiosarcoma-like presentation of pacemaker-related vascular proliferation. clin exp dermatol 2012;37(2):143-45. 28. armengot-carbo m, sabater v, botella-estrada r. reticular telangiectatic erythema: a reactive clinicopathological entity related to the presence of foreign body. j eur acad dermatol venereol. 2014 aug 29. doi: 10.1111/jdv.12707. [epub ahead of print]. 29. o’grady jt, shahidullah h, doherty vr, al-nasuffi a. intravascular histiocytosis. histopathology 1994;24(3):265-68. 30. grekin s, mesfin m, kang s, fullen dr. intralymphatic histiocytosis following placement of a metal implant. j cutan pathol 2011;38(4):351-53. 31. requena l, farina mc, renedo g, et al. intravascular and diffuse dermal reactive angioendotheliomatosis secondary to iatrogenic arterioveous fistulas. j cutan pathol 1999;26:159-64. 32. mcmenamin me, fletcher cd. reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum. am j surg pathol. 2002;26(6):685-97. 33. blume je. generalized essential telangiectasia: a case report and review of the literature. cutis. 2005;75(4):223-24. 34. mercader-garcía p, torrijos-aguilar a, de la cuadra-oyanguren j, vilata-corell jj, fortea-baixauli jm. telangiectatic reticular erythema unrelated to cardiac devices, arch dermatol 2005;141(1):106-7. 35. inzinger m, tilz h, komericki p, schuster c, wolf p, kranke b. heat-triggered reticular telangiectatic erythema induced by a spinal cord stimulator. mayo clin proc 2013;88(1):117-19. 36. do hk, mousdicas n. reticular telangiectatic erythema after total knee replacement surgery. jbjs case connector 2013;3(2):e49. dermatology: practical and conceptual original article | dermatol pract concept. 2023;13(3):e2023125 1 dermoscopic pattern of basal cell carcinoma in hand non-h-zones joanna pogorzelska-dyrbuś1, natalia salwowska2, beata bergler-czop2 1 estevita” specialist medical practice, tychy, poland 2 department of dermatology, school of medicine in katowice, medical university of silesia, katowice, poland key words: dermoscopy, h-zone, basal cell carcinoma, ulceration, skin cancer citation: pogorzelska-dyrbuś j, salwowska n, bergler-czop b. dermoscopic pattern of basal cell carcinoma in hand non-h-zones. dermatol pract concept. 2023;13(3):e2023125. doi: https://doi.org/10.5826/dpc.1303a125 accepted: december 12, 2022; published: july 2023 copyright: ©2023 pogorzelska-dyrbuś et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: joanna pogorzelska-dyrbuś, md phd “estevita” specialist medical practice, 43-100 tychy, silesia, poland, phone: +48 32 227 96 30 e-mail: jpogorzelskadyrbus@gmail.com introduction: basal cell carcinoma (bcc) localized in the h-zone, the region of fusion of embryonic masses, has been associated with a higher risk of deeper invasion and more frequent recurrence. objectives: the aim of the study was to compare dermoscopic features of bcc in h and non-h zone that may most appropriately characterize those two locations. methods: dermoscopy images of histopathologically confirmed bccs from 120 patients were retrospectively analyzed. dermoscopy features of bcc in hand non-h zone were described and a comparative study of the dermoscopic pattern of bcc between the two locations was performed. results: of 120 bcc cases included in this study, 41 (34.2%) were located in the h-zone. the most frequent histological type was nodular (51.3% in hzone and 61.6 % in non-h-zone) followed by superficial (5.1% and 19.8 % in h and non-h-zone respectively). in dermoscopy, there was a higher prevalence of ulceration (73.2% versus 43.6%, p < 0.001) in h-zone and a lower prevalence of brown globules (26.8% versus 53.2%; p = 0.01), when compared with the non-h-zone. conclusions: our results show that dermoscopic features of bcc on the face fulfill a typical pattern regardless of the region, except for the prevalence of the ulceration which is significantly more frequent in h-zone and the brown globules present significantly more often in the non-h-zone it can be hypothesized that h-zone might predispose to more aggressive course of bcc complicated by ulceration and consequently deeper tissue destruction. abstract 2 original article | dermatol pract concept. 2023;13(3):e2023125 introduction basal cell carcinoma (bcc) is the most often diagnosed cancer in the fair-skinned population and its prevalence has increased dramatically over the last years [1]. although bcc has generally a good prognosis, due to its high prevalence, it generates significant medical and economic problems worldwide. the most important risk factor of bcc is exposure to ultraviolet radiation, which is why it arises most frequently de novo on the face [1,2]. bcc has a generally slow-growing pattern, however, lesions located on the face appear to be more aggressive [3,4]. the facial area called the h-zone, consisting of the nose, eye and ear region correspond to the locations of fusion of embryonic masses of mesoderm and the ectoderm. this zone is related to the higher risk of occurrence of bcc and its more aggressive expansion [5-7]. clinically, the accuracy of bcc diagnosis is approximately 60%, while dermoscopy, as an easily available and noninvasive diagnostic technique, can increase this quotient to over 90% [8,9]. the dermoscopy pattern of bcc has been extensively studied, including the differences depending on the anatomical location, however, the diagnostic criteria are continuously updated [10,11]. objectives taking into consideration the reported differences in the clinical course of the bccs located in the h-zone, the aim of the study was to compare dermoscopic features of bcc in the h-zone and non-h-zone that may most appropriately characterize those two locations. methods dermoscopy images of 120 bccs of patients with skin phototype ii recruited from the department of dermatology, medical university of silesia in katowice, and “estevita” specialist medical practice between 2017 and 2020, were analyzed. the location and histological type of the lesion, age and gender of each patient, were analyzed. patients with genetic disorders predisposing to bcc were excluded from the analysis. the anatomic location of tumors was classified as h-zone (nose, ear, eye) and non-h-zone (forehead, cheek, chin and the rest of the face and neck) based on the decision of two separate authors. if the lesion had been located in the border zone between the aforementioned anatomical locations or there was a discordance in the authors decision, its eventual classification was based on the discussion of all three authors. classical dermoscopic features of bcc like arborizing telangiectasias, leaf-like structures, blue-gray ovoid nests, blue-gray non-aggregated globules, spoke-wheel structures, ulceration and less specific features like milia cysts, brown globules and short fine telangiectasias (sft) and shiny white areas were assessed by two independent authors. all features were classified as present or absent and then comparison between h and non-h zone was made. dermoscopic evaluation with light pressure and solely with ultrasound gel was performed with medicam 1000 fotofinder systems gmbh camera by 3 experienced observers. statistical analysis the categorical variables were presented in both absolute numbers and percentages, while the due to non-normal distribution of the continuous variables, their results were summarized using the median with a quartile 1 and 3. normality of distribution was tested using the shapiro-wilk test. between-group comparisons of continuous variables were conducted using the mann–whitney  u test, while pearson chi-squared test was used to evaluate the categorical variables. the interval of two-sided p < 0.05 was considered statistically significant. statistica 10 (starsoft inc.) was used for all calculations. the approval of the bioethics committee was not required, based on the pcn/0022/kb/34/21 decision of the bioethics committee of the medical university of silesia in katowice. all patients gave an informed written consent to participate in the study. results of 120 bcc cases included in this study, 41 (34.2%) were located in the h-zone as presented in table 1 and the figure 1. the most frequent histological type was nodular (51.3% in the high-risk zone and 61.6 % in the non-h-zone) followed by the superficial (5.1% and 19.8% in hand non-h-zone respectively) as demonstrated in table 2. arborizing telangiectasias and short fine telangiectasias were the most frequently seen dermoscopy features in both face regions, with similar prevalence in the h and non-h zone. arborizing telangiectasias were present in 78.0% and 77.2 % and short fine telangiectasias in 78.0% and 84.8 % in h-zone and non-h-zone respectively. the features of pigmentation such as leaf-like structures, blue-gray ovoid nests blue-gray globules were present in comparable incidence in both groups, with exception of brown globules, which were present significantly more often in the non-hzone (53.2% versus 26.8%, p = 0.01). moreover, there was a significantly higher prevalence of ulceration in the h-zone than in the non-h-zone (73.2% versus 43.6 %, p < 0.001). conclusions bcc develops mainly as a result of interactions between environmental and genetic factors. however, disorders during original article | dermatol pract concept. 2023;13(3):e2023125 3 the process of embryogenesis and their consequences on the clinical course of bcc still remain incompletely examined. h-zone, the region corresponding to places of fusion of embryonic masses, is considered a region of higher occurrence and recurrence of bcc, although it is uncertain, whether the location of the tumor plays a similar role in the development and prognosis of bcc as other, already established risk factors such as histologic subtype, the diameter of the lesion, and the patient health condition [7,12]. dermoscopic criteria of bcc, which include arborizing telangiectasias, large blue/gray ovoid nests, multiple blue/ gray globules, short fine telangiectasia, leaflike areas, multiple in-focus blue/gray dots, ulceration were proposed by menzies et al [9]. the main results of our analysis are: 1) the dermoscopic image of the bcc cases differs depending on their development in the h-zone and non-h-zone 2) the prevalence of ulceration in the h-zone is significantly higher than in the non-h zone 3) the bccs located in the non-h-zone tend to present brown globules in a significantly higher percentage than bccs from the h-zone. according to the literature, ulceration is a characteristic feature associated with worse clinical behavior, typically in nodular bcc [10,13,14]. in our study, it was nodular bcc that dominated the analyzed tumors, as it constituted 61.6% of tumors in the non-h-zone and 51.3% of tumors in the h-zone. these facts may indicate that a higher incidence of ulceration in the h-zone in our study does not solely reflect the histological subtypes of the tumors. on the basis of our results, one could hypothesize that tissue interference during mesenchymal fusion in embryogenesis might predispose to a more aggressive course of bcc complicated by ulceration table 1. comparison of dermoscopic features in hand non-h-zones*. analysed dermoscopic features h-zone (n=41) non-h-zone (n=79) p arborizing teleangiectasias, n (%) 0.91 absent 9 (22.0%) 18 (22.8%) present 32 (78.0%) 61 (77.2%) leaf-like structures, n (%) 0.14 absent 33 (80.5%) 52 (65.8%) present 8 (19.5%) 27 (34.2%) blue-gray ovoid nests, n (%) 0.22 absent 28 (68.3%) 45 (57.0%) present 13 (31.7%) 34 (43.0%) blue-gray non-aggregated globules, n (%) 0.055 absent 29 (70.7%) 40 (50.6%) present 12 (29.3%) 39 (49.4%) spoke-wheel structures, n (%) 0.13 absent 39 (95.1%) 67 (84.8%) present 2 (4.9%) 12 (15.2%) milia cysts 0.16 absent 21 (51.2%) 51 (64.6%) present 20 (48.8%) 28 (35.4%) short fine teleangiectasias, n (%) 0.45 absent 9 (22.0%) 12 (15.2%) present 32 (78.0%) 67 (84.8%) brown globules, n (%) 0.010 absent 30 (73.2%) 37 (46.8%) present 11 (26.8%) 42 (53.2%) ulceration, n (%) <0.001 absent 11 (26.8%) 44 (56.4%) present 30 (73.2%) 35 (43.6%) shiny white areas, n (%) 0.37 absent 12 (29.3%) 29 (36.7%) present 29 (70.7%) 50 (63.3%) 4 original article | dermatol pract concept. 2023;13(3):e2023125 cases [11]. moreover, the cited manuscript did not divide the bccs on the basis of embryological origin, as has been done in our manuscript. although in some studies, a significant increase in the recurrence rate of bccs located in the h-zone was demonstrated, no such results were confirmed in the other analyses including the study of yalcin, or armstrong et al, who did not find any association between bcc location and the risk of invasion, ulceration and recurrence rate [15-17]. we found a significantly higher frequency of brown globules, not reported before in the literature. it should be noted in the h-zones. it has been proved that bcc located in fusion planes may demonstrate a deeper tissue invasion, due to the perpendicular arrangement of fibrous connective tissue favorable to infiltration [15-16]. the influence of the location of bcc on the prognosis, including the recurrence rate is still debated. even though a recent, thorough analysis of 291 cases of bcc by conforti et al evaluated their dermoscopy patterns with reference to the anatomical location, the authors included tumors located on the whole-body surface, thus the cancers located on the head/neck constituted approximately 47% of all analyzed figure 1. comparison of the dermoscopic features in h-zone and non-h-zone. in the lesions located in the h-zone, there is a higher prevalence of ulceration, and brown globules are more frequently observed in the non-h-zone. table 2. comparison of histological subtypes in hand non-h-zones. histological subtype, n (%) h-zone (n=39) non-h-zone (n=73) p nodular 20 (51.3%) 45 (61.6%) 0.03 superficial 2 (5.1%) 14 (19.8%) infiltrative 3 (7.7%) 1 (1.4%) micronodular 0 (0.0%) 2 (2.7%) morpheiform 2 (5.1%) 0 (0.0%) pigmented 3 (7.7%) 2 (2.7%) multifocal 7 (18.0%) 7 (9.6%) other 2 (5.1%) 2 (2.7%) original article | dermatol pract concept. 2023;13(3):e2023125 5 3. ramachandran s, fryer aa, smith a, et al. cutaneous basal cell carcinomas: distinct host factors are associated with the development of tumors on the trunk and on the head and neck. cancer. 2001;92(2): 354-358. doi: 10.1002/1097-0142(20010715)92:2<354::aidcncr 1330>3.0.co;2-f. pmid: 11466690. 4. scrivener y, grosshans e, cribier b. variations of basal cell carcinomas according to gender, age, location and histopathological subtype. br j dermatol. 2002;147(1):41-47. doi: 10.1046/j .1365-2133.2002.04804.x. pmid: 12100183. 5. nicoletti g, tresoldi mm, malovini a, prigent s, agozzino m, faga a. correlation between the sites of onset of basal cell carcinoma and the embryonic fusion planes in the auricle. clin med insights oncol. 2018;12:1179554918817328. doi: 10.1177/1179554918817328. pmid: 30559599. pmcid: pmc6293364. 6. newman jc, leffell dj. correlation of embryonic fusion planes with the anatomical distribution of basal cell carcinoma. dermatol surg. 2007;33(8):957-964. doi: 10.1111/j.15244725.2007.33198.x. pmid: 17661939. 7. panje wr, ceilley ri. the influence of embryology of the mid-face on the spread of epithelial malignancies. laryngoscope. 1979;89(12):1914-1920. doi: 10.1288/00005537-19791200000003. pmid: 513913. 8. reiter o, mimouni i, gdalevich m, et al. the diagnostic accuracy of dermoscopy for basal cell carcinoma: a systematic review and meta-analysis. j am acad dermatol. 2019;80(5):1380-1388. doi: 10.1016/j.jaad.2018.12.026. pmid: 30582991. 9. menzies sw, westerhoff k, rabinovitz h, kopf aw, mccarthy wh, katz b. surface microscopy of pigmented basal cell carcinoma. arch dermatol. 2000;136(8):1012-1016. doi: 10.1001 /archderm.136.8.1012. pmid: 10926737. 10. lallas a, apalla z, argenziano g, et al. the dermatoscopic universe of basal cell carcinoma. dermatol pract concept. 2014;4(3):11-24. doi: 10.5826/dpc.0403a02. pmid: 25126452. pmcid: pmc4131992. 11. conforti c, pizzichetta ma, vichi s, et al. sclerodermiform basal cell carcinomas vs. other histotypes: analysis of specific demographic, clinical and dermatoscopic features. j eur acad dermatol venereol. 2021;35(1):79-87. doi: 10.1111/jdv.16597. pmid: 32401364. 12. welsch mj, troiani bm, hale l, deltondo j, helm kf, clarke le. basal cell carcinoma characteristics as predictors of depth of invasion. j am acad dermatol. 2012;67(1):47-53. doi: 10.1016/j.jaad.2011.02.035. pmid: 22507669. 13. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62(1):67-75. doi: 10.1016/j.jaad.2009.05.035. pmid: 19828209. 14. reiter o, mimouni i, dusza s, halpern ac, leshem ya, marghoob aa. dermoscopic features of basal cell carcinoma and its subtypes: a systematic review. j am acad dermatol. 2021;85(3):653-664. doi: 10.1016/j.jaad.2019.11.008. pmid: 31706938. pmcid: pmc9366765. 15. armstrong lt, magnusson mr, guppy mp. the role of embryologic fusion planes in the invasiveness and recurrence of basal cell carcinoma: a classic mix-up of causation and correlation. plast reconstr surg glob open. 2016;3(12):e582. doi: 10.1097/gox.0000000000000571. pmid: 26894007. pmcid: pmc4727691. that these structures were more often visible in the non-h zones (26.8% versus 53.2% p=0.01). this observation may be at least partially explained by the fact that the visibility of dermoscopic features is significantly instrument-dependent, therefore the same high-resolution device, namely the medicam 1000 (fotofinder systems gmbh) used throughout the diagnostic process made detection of such petite structures possible [12,18]. finally, an explanation for a lower incidence of brown globules in the h-zone can be the fact that in the presence of ulcerations, most often dominating the optical field of the dermoscopic image of the lesion, the visibility of the other structures may be worse. it could be speculated that the differences between the dermoscopic features of bccs present in hand non-h-zones, which at the present state of knowledge of uncertain significance, may gain further importance with the increasing use of high-resolution equipment, including the use of optical super-high magnification dermoscopy or confocal dermoscopy, which could shed additional light on the dermoscopic diagnostics in bcc [19]. according to our results, the dermoscopic features of bcc on the face fulfil a typical pattern regardless of the region, except the ulceration, which is significantly more frequent in h-zone. moreover, we found brown globules in a greater frequency than previously described in the literature. compliance of our results with literature in terms of remaining pigmented and vascular structures can confirm that our study was conducted according to the generally accepted algorithm, moreover that this algorithm applies for hand non-h-zone as well. finally, it can be hypothesized that, within the limitations of our study, the location of bcc in the h-zone may predispose to its more aggressive course complicated by ulceration and consequently to deeper tissue destruction but further research is necessary to confirm these hypotheses. precisely conducted dermoscopy, can be useful in the early detection of bcc and consequently can have a clinical implication in the selection of less invasive treatment options which is of highest importance considering its face localization. references 1. verkouteren jac, ramdas khr, wakkee m, nijsten t. epidemiology of basal cell carcinoma: scholarly review. br j dermatol. 2017;177(2):359-372. doi: 10.1111/bjd.15321. pmid: 28220485. 2. pelucchi c, di landro a, naldi l, la vecchia c; oncology study group of the italian group for epidemiologic research in dermatology (gised). risk factors for histological types and anatomic sites of cutaneous basal-cell carcinoma: an italian case-control study. j invest dermatol. 2007;127(4):935-944. doi: 10.1038/sj.jid.5700598. pmid: 17068478. 6 original article | dermatol pract concept. 2023;13(3):e2023125 18. seidenari s, bellucci c, bassoli s, arginelli f, magnoni c, ponti g. high magnification digital dermoscopy of basal cell carcinoma: a single-centre study on 400 cases. acta derm venereol. 2014;94(6):677-682. doi: 10.2340/00015555-1808. pmid: 24682274. 19. pogorzelska-dyrbuś j, szepietowski jc. optical super-high magnification dermoscopy of pigmented and nonpigmented nodular basal cell carcinoma. j cosmet dermatol. 2022;21(11):64586460. doi: 10.1111/jocd.15082. pmid: 35567508. 16. granström g, aldenborg f, jeppsson ph. influence of embryonal fusion lines for recurrence of basal cell carcinomas in the head and neck. otolaryngol head neck surg. 1986;95(1):76-82. doi: 10.1177/019459988609500115. pmid: 3106899. 17. yalcin o, sezer e, kabukcuoglu f, et al. presence of ulceration, but not high risk zone location, correlates with unfavorable histopathological subtype in facial basal cell carcinoma. int j clin exp pathol. 2015;8(11):15448-15453. pmid: 26823913. pmcid: pmc4713699. dermatology: practical and conceptual review | dermatol pract concept 2014;4(3):2 11 dermatology practical & conceptual www.derm101.com following the first descriptions of the dermatoscopic pattern of basal cell carcinoma (bcc) that go back to the very early years of dermatoscopy, the list of dermatoscopic criteria associated with bcc has been several times updated and renewed. up to date, dermatoscopy has been shown to enhance bcc detection, by facilitating its discrimination from other skin tumors and inflammatory skin diseases. furthermore, upcoming evidence suggests that the method is also useful for the management of the tumor, since it provides valuable information about the histopathologic subtype, the presence of clinically undetectable pigmentation, the expansion of the tumor beyond clinically visible margins and the response to non-ablative treatments. in the current article, we provide a summary of the traditional and latest knowledge on the value of dermatoscopy for the diagnosis and management of bcc. abstract introduction following the first descriptions of the dermatoscopic pattern of bcc that go back to the very early years of dermatoscopy, gradually gathering evidence significantly enriched our knowledge on the topic [1-12]. up to date, the value of dermatoscopy in improving the diagnosis of bcc has been extensively demonstrated, while the method continuously gains appreciation as a useful tool in the management of the tumor [1,9,13-17]. dermatoscopy for diagnosis of bcc the list of dermatoscopic criteria associated with bcc has been several times updated and renewed. an analytic description of the bcc-related dermatoscopic criteria and their histopathologic correlation is quoted in table 1, while a characteristic example of each one of them is presented in figures 1 and 2 [1,9,12,18,19]. figure 3 illustrates representative examples of histopathologic alterations corresponding to bcc-related dermatoscopic criteria. the dermatoscopic variability of bcc is a result of different combinations of these criteria, depending on several factors. apart from the histopathologic subtype, which represents the most important determinant of the dermatoscopic pattern of bcc, there is upcoming evidence that the dermatoscopic aspect of the tumor is influenced also by factors related to the patient, such as gender, age and pigmentary the dermatoscopic universe of basal cell carcinoma aimilios lallas1, zoe apalla2, giuseppe argenziano2, caterina longo1, elvira moscarella1, francesca specchio1, margaritha raucci1, iris zalaudek3 1 skin cancer unit, arcispedale santa maria nuova, irccs, reggio emilia, italy 2 dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, italy 3 department of dermatology, medical university of graz, austria keywords: basal cell carcinoma, diagnosis, dermoscopy, dermatoscopy, non-melanoma skin cancer, management citation: lallas a, apalla z, argenziano g, longo c, moscarella e, specchio f, raucci m, zalaudek i. the dermatoscopic universe of basal cell carcinoma. dermatol pract concept. 2014;4(3):2. http://dx.doi.org/10.5826/dpc.0403a02. received: january 7, 2014; accepted: march 8, 2014; published: july 31, 2014 copyright: ©2014 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: study supported in part by the italian ministry of health (rf-2010-2316524). competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aimilios lallas, m.d., skin cancer unit, arcispedale santa maria nuova irccs, viale risorgimento 80—42100 reggio emilia, italy. email: emlallas@gmail.com 12 review | dermatol pract concept 2014;4(3):2 table 1. definition and histopathologic correlation of the dermatoscopic criteria of basal cell carcinoma. [copyright: ©2014 lallas et al.] dermatoscopic criteria definition histopathologic correlation arborizing vessels stem vessels of large diameter, branching irregularly into finest terminal capillaries. their color is bright red, being perfectly in focus due to their location on the surface of the tumor dilated vessels in the dermis, representing the supportive neovasculature of the tumor cells superficial fine telangiectasia short, fine, focused linear vessels with very few branches telangiectatic vessels located in the papillary dermis blue-gray ovoid nests well circumscribed, confluent or near confluent pigmented ovoid or elongated configurations, larger than globules and not intimately connected to pigmented tumor body large well-defined tumor nests with pigment aggregates, invading the dermis multiple blue-gray globules numerous, loosely arranged round to oval wellcircumscribed structures, which are smaller than the nests small, roundish tumor nests with central pigmentation, localized to the papillary dermis and/or reticular dermis in-focus dots loosely arranged well-defined small gray dots, which appear sharply in focus free pigment deposition along the dermo-epidermal junction, and/or melanophages and/or small aggregates of pigmented neoplastic cells in the papillary and reticular dermis maple leaf-like areas translucent brown to gray/blue peripheral bulbous extensions that never arise from pigmented network or from adjacent confluent pigmented areas multifocal tumor nests containing pigment aggregates, connected to each other by lobular extensions. they are mainly localized in the epidermis and less frequently in the papillary dermis spoke wheel areas well-circumscribed radial projections, usually tan but sometimes blue or gray, meeting at an often darker (dark brown, black, or blue) central axis tumor nests arising and connected to the epidermis, characterized by finger-like projections and centrally located pigmentation concentric structures irregularly shaped globular-like structures with different colors (blue, gray, brown, black) and a darker central area. they possibly represent variations or “precursors” of the spoke wheel areas small tumor nests arising and connected to the epidermis with centrally located pigmentation ulceration one or more large structureless areas of red to black-red color loss of the epidermis, usually covered by hematogenous crusts multiple small erosions small brown-red to brownyellow crusts thin crusts overlying superficial loss of the epidermis shiny white-red structureless areas translucent to opaque white to red areas diffuse dermal fibrosis or fibrotic tumoral stroma short white streaks (chrysalis) orthogonal short and thick crossing lines seen only with polarized dermoscopy presence of collagenous stroma and fibrosis in the dermis review | dermatol pract concept 2014;4(3):2 13 trait. studies report on a higher frequency of superficial bcc (sbcc) on the trunk and lower legs of women, whereas the majority of nodular bcc occur on the head and neck of men [20,21]. pigmentation is present in more than 50% of the tumors in skin of color, whereas less than 10% of bccs in fair skinned individuals are pigmented (figure 4) [22-26]. furthermore, the concept of the signature pattern of bcc has been recently introduced, referring to the observation that multiple bccs in an individual usually display a repetitive dermatoscopic pattern [27]. dermatoscopy improves the clinical diagnosis of bcc, enabling its detection even at an early stage, when the tumor is still clinically inconspicuous (figure 5). dermatoscopy has also been assessed as a valuable method to differentiate bcc from other skin tumors and inflammatory skin diseases [1,9,13]. the reported diagnostic accuracy of dermatoscopy for bcc diagnosis has been reported to range from 95% to 99%, depending on bcc subtype and the set of diseases included in the control group [1,9,12,13]. indeed, various entities constitute the differential diagnosis of different bcc sub-types. for example, the classical nodular non-pigmented bcc has to be discriminated from squamous cell carcinoma (scc), amelanotic melanoma and other non-pigmented tumors, while heavily pigmented variants have to be differentiated mainly from melanoma and nevi. instead, the differential diagnosis of superficial bcc includes both skin figure 1. the dermatoscopic criteria of non-pigmented bcc: (a) arborizing vessels, (b) superficial fine telangiectasia, (c) ulceration, (d) multiple small erosions, (e) shiny white-red structureless areas and (f) short white streaks. [copyright: ©2014 lallas et al.] figure 2. pigmented bcc may display, in addition to the criteria shown in figure 1, one or more of the following features: (a) blue-gray ovoid nests, (b) multiple blue-gray dots/globules, (c) in-focus dots, (d) maple leaf-like areas, (e) spoke wheel areas (arrow) and (f) concentric structures (arrows). [copyright: ©2014 lallas et al.] 14 review | dermatol pract concept 2014;4(3):2 tumors, like actinic keratosis or bowen’s disease (bd), and inflammatory skin diseases, such as psoriasis or dermatitis. the diagnostic accuracy of dermatoscopy has been mainly tested in the field of pigmented bcc, with the well-known menzies method achieving a sensitivity of 97% and a specificity of 92% and 93% for differentiating pigmented bcc from melanoma and nevi, respectively (figure 6) [1]. according to the latter model, the diagnosis of pigmented bcc is based on the dermatoscopic absence of pigment network and the figure 3. (a) large dilated vessels in the dermis, corresponding to the arborizing vessels seen in dermatoscopy; (b) fine telangiectatic vessels located in the papillary dermis in a sbcc, dermatoscopically seen as superficial fine telangiectasias; (c) thick hematogenous crust overlying ulceration, dermatoscopically seen as structureless area of black-red color; (d) strands of neoplastic cells in the background of a collagenous fibrotic stroma, corresponding to shiny whitish areas in dermatoscopy (e) large well-defined tumor nests with pigment aggregates, invading the dermis, recognized as blue-gray ovoid nests in dermatoscopy; (f) multiple melanophages in the papillary and reticular dermis, dermatoscopically seen as blue-gray dots; (g) small, roundish tumor nests with central pigmentation localized in the dermis, dermatoscopically corresponding to multiple blue-gray globules; (h) tumor nests arising and connected to the epidermis, characterized by finger-like projections and centrally located pigmentation, that represent the histopathologic correlate of spoke-wheel areas; and (i) multifocal tumor nests containing pigment aggregates, connected to each other by lobular extensions, evoking the dermatoscopic criterion of maple leaf-like areas. [copyright: ©2014 lallas et al.] figure  4. the clinical and dermatoscopic aspect of bcc is influenced by the pigmentary trait of the patient. fair skin individuals usually develop non-pigmented tumors (a), while the frequency of pigmented variants is much higher in patients with darker skin (b). [copyright: ©2014 lallas et al.] figure  5. (a) a 2 mm clinically incospicuous papule can be easily interpreted as bcc with dermatoscopic examination. (b) dermatoscopy of this shuttle hypopigmented macule on sun-damaged skin reveals short fine telangiectasia, blue-gray dots and peripheral maple leaf-like areas, allowing a straight-forward diagnosis of bcc. [copyright: ©2014 lallas et al.] detection of one of six positive criteria: arborizing vessels, ulceration, large blue-gray ovoid nests, maple leaf-like areas, spoke wheel areas or multiple blue-grey dots/globules [1]. the substantial reproducibility of these criteria has been appropriately assessed, with arborizing vessels, maple leaf-like areas and large blue-gray ovoid nests representing the most robust and reliable bcc specific parameters [9]. altamura et al. recently validated menzies method in a study including more than 600 bccs, 96.5% of which exhibited at least one review | dermatol pract concept 2014;4(3):2 15 of the six positive dermatoscopic criteria [9]. of interest, 40% of the bccs in the latter study displayed criteria suggestive of melanocytic lesions, including dots/globules, blue-whitish veil and vascular structures. the frequency of the latter criteria linearly increased with pigmentation, highlighting the diagnostic challenge in differentiating heavily pigmented bcc from melanocytic tumors (figure 7). however, even heavily pigmented bccs were diagnosed with a high accuracy based on the aforementioned absence of pigment network and presence of at least one positive criterion [9]. although the diagnostic accuracy of dermatoscopy for non-pigmented nodular bcc has not been assessed up to date, several lines of evidence suggest that the detection of arborizing vessels is highly predictive of the diagnosis of bcc, enabling its differentiation from scc and other nonpigmented skin tumors (figure 8). in the study by altamura figure 6. pigmented nodular bcc has to be discriminated from melanoma and nevi. the diagnosis of bcc (a) is based on the absence of pigment network and the presence of at least one of the bcc-related criteria (in this case arborizing vessels, blue-gray ovoid nests and multiple blue-gray dots). in contrast melanoma (b) and nevi (c), as a rule, exhibit an atypical or a typical pigment network, respectively. [copyright: ©2014 lallas et al.] figure  7. two clinically similar pigmented nodular tumors. the bcc can be dermatoscopically recognized by the absence of pigment network and the presence of arborizing vessels and blue-gray ovoid nests (a). although nor the second nodule displays a pigment network, it exhibits dotted vessels and its pigmented structures are irregular brown/black globules and irregular peripheral streaks, in contrast to the well-circumscribed large blue-gray ovoid nests of the bcc. as strongly suggested by its dermatoscopic pattern, the second tumor is a nodular melanoma (b). [copyright: ©2014 lallas et al.] figure 8. the differential diagnosis of non-pigmented nodular tumors includes bcc, scc and other less frequent entities. dermatoscopically, the first nodule exhibits focused arborizing vessels, highly predictive of the diagnosis of bcc (a). dermatoscopy of the second tumor reveals dotted and linear irregular vessels, keratin masses and perifollicular white circles, overall suggestive of the diagnosis of scc (b). [copyright: ©2014 lallas et al.] 16 review | dermatol pract concept 2014;4(3):2 et al, the characteristic vascular pattern of bcc and the presence of ulceration or erosions were the most useful criteria for the diagnosis of non-pigmented bcc [9]. rosendahl et al investigated the dermatoscopic pattern of scc in a study that included a large set of non-pigmented skin tumors with 20 different diagnoses. in addition to their primary findings, the authors found a strong association between the presence of arborizing vessels and the diagnosis of bcc [28]. superficial bcc has to be differentiated from other skin tumors (mainly in-situ scc) and inflammatory skin diseases (figure 9). the clinical discrimination between sbcc and bd can be enhanced by dermatoscopy, which typically reveals shiny white/red structureless areas and superficial fine telangiectasia in the former and glomerular vessels in the latter [13]. recently, pan et al assessed the diagnostic accuracy of dermatoscopy for differentiating among sbcc, bd and solitary psoriatic plaques and found the following criteria to be associated with bcc: scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background and brown dots/globules. the authors reported a diagnostic probability of 99% if four of these six features were identified [13]. the dermatoscopic diagnosis of pigmented sbcc is usually straightforward even in small and clinically inconspicuous lesions (figure 10). this is because pigmented sbcc displays dermatoscopic criteria corresponding to dermo-epidermal melanin deposition (maple leaf-like areas, spoke wheel areas, concentric structures), which are highly specific for the diagnosis of bcc. in contrast to its usefulness for discriminating bcc from keratinocyte skin cancer, dermatoscopy seems insufficient to differentiate between bcc and adnexal tumors [29]. the latter group comprises sebaceous, follicular, eccrine and apocrine neoplasms, several of which have been characterized as dermatoscopic “mimickers” of bcc [30]. trichoblastoma, trichoepithelioma, pilomatrichoma, cylindroma and eccrine poroma are only some of the entities reported to dermatoscopically exhibit linear branching vessels and blue-gray globules, similar to those seen in bcc [29,31-35]. in this context, it has been suggested that the differential diagnosis might be facilitated by the observation that the vessels of adnexal tumors are usually less focused, or by the detection of whitish or yellowish structures that have been associated with follicular and sebaceous tumors, respectively [29]. however, the validity and usefulness of the latter dermatoscopic clues and the possible value of dermatoscopy for differentiating between bcc and adnexal tumors require further elucidation. dermatoscopy for management of bcc in addition to its well-documented value for the diagnosis of bcc, dermatoscopy continuously gains an essential role in the management of the tumor. in our era, the therapeutic armamentarium of clinicians for bcc includes several surgical methods as well as non-surgical modalities [36]. the figure 9. three clinically similar erythematous and slightly scaly flat lesions. dermatoscopy of the first case revals superficial fine telangiectasia and few blue-gray dots, suggestive of the diagnosis of superficial bcc (a). the second lesion dermatoscopically displays dotted and glomerular vessels and yellow crusts, which indicate the diagnosis of bowen’s disease (b). dermatoscopy of the third plaque reveals the typical pattern of psoriasis, consisting of regularly distributed dotted vessels and white scales (c). [copyright: ©2014 lallas et al.] review | dermatol pract concept 2014;4(3):2 17 choice of the appropriate treatment depends on several factors including the histopathologic subtype, the presence of pigmentation or ulceration, the tumor depth, the anatomical site and the presence of residual disease or recurrence [36,37]. dermatoscopy has been shown to provide valuable information for several of the aforementioned parameters. dermatoscopy for predicting the histopathologic subtype the histopathologic subtype is the most crucial factor influencing the treatment choice for bcc [36,38]. this is because the response rates of different tumor subtypes to a given treatment modality vary significantly. superficial bcc, despite of its overall indolent physical course, has been classified in the past among high-risk subtypes, on the basis of its high recurrence rates after surgery [38-40]. this can be explained by the natural tendency of the tumor to expand peripherally beyond clinically visible margins, which often results in incomplete surgical excision and subsequent recurrence. in the recent years, sbcc has been shown to respond perfectly to non-ablative treatments such as imiquimod or photodynamic therapy, prompting experts to recommend the latter modalities as first-line therapeutic options for this subtype [41-46]. in contrast, nodular bcc is associated with high response rates to surgery (up to 98%), while non-surgical treatments are much less effective [36,47-49]. management of infiltrative and sclerodermiform bcc are more troublesome, since they are characterized by considerable recurrence rates following surgery (up to 40%) while they respond poorly to non-surgical modalities [36,45,47-49]. mohs’ surgery is suggested as the treatment of choice for the latter subtypes [50,51]. dermatoscopy has been shown to provide valuable information for the pre-operative classification of bcc, since several lines of evidence suggest that different histopathologic subtypes exhibit different dermatoscopic patterns (table 2, figure 11) [1,4,7,9,11,12]. the latter observation is reasonable, since the dermatoscopic criteria of bcc correspond to underlying histopathologic alterations [18,19]. dermatoscopy of non-pigmented nodular bcc, which is the commonest subtype, typically reveals a translucent pinkish tumor. arborizing vessels represent the dermatoscopic hallmark of nodular bcc, while ulceration is also a common finding. pigmented nodular bcc is dermatoscopically typified by blue-grey ovoid nests or multiple blue-gray dots/globules, usually associated with arborizing vessels. structures corresponding to dermo-epidermal pigmentation, including maple leaf-like areas, spoke wheel areas and concentric structures are less frequently observed in nodular tumors, being typically distributed at the peripheral, more superficial part of the lesion [1,9,11]. infiltrative and sclerodermiform bcc also display branching vessels under dermatoscopy. however, they are usually finer, more scattered and show fewer branches compared to the classic vessels of nodular bcc. in addition, in contrast to the global translucent pinkish color of nodular bcc, infiltrative bcc often exhibits white/red structureless areas, while the underlying fibrosis of sclerodermiform bcc results in a dermatoscopically whitish background [11,12]. in contrast, superficial bcc usually lacks the classic arborizing vessels, typically displaying superficial fine telangiectasia with relatively few ramifications. multiple small erosions figure 10. pigmented superficial bcc can be dermatoscopically recognized at an early stage, based on the characteristic morphology of the dermo-epidermal pigmented structures. (a) although typical maple leaf-like areas have not been formed yet, the brown peripheral projections of this slightly pigmented sbcc can be easily recognized. (b) a pigmented sbcc arising within a solar lentigo, dermatoscopically typified by small blue-gray dots (black arrow). (c) another collision of a solar lentigo and a small pigmented sbcc, the latter dermatoscopically exhibitng spoke wheel areas (white arrow). [copyright: ©2014 lallas et al.] 18 review | dermatol pract concept 2014;4(3):2 table 2. dermatoscopic criteria of basal cell carcinoma according to subtype. [copyright: ©2014 lallas et al.] dermoscopic criteria definition superficial pigmented superficial fine telangiectasia multiple small erosions shiny white-red structureless areas maple leaf-like areas spoke wheel areas concentric structures multiple blue-gray dots in-focus dots ^ detection of blue-gray ovoid nests excludes the diagnosis of superficial bcc nodular pigmented arborizing vessels ulceration short white streaks^^ blue-gray ovoid nests multiple blue-gray dots in-focus dots maple leaf-like areas* spoke wheel areas* concentric structures* ^^ seen only with polarized dermoscopy * typically detected at the peripheral, superficial parts of the lesion morpheaform pigmented arborizing vessels** ulceration whitish background blue-gray ovoid nests multiple blue-gray dots in-focus dots **usually finer, more scattered and with fewer branches comparing to the vessels of nodular bcc infiltrative pigmented arborizing vessels^^^ ulceration white-red structureless areas blue-gray ovoid nests multiple blue-gray dots in-focus dots ^^^usually finer, more scattered and with fewer branches comparing to the vessels of nodular bcc fibroepithelioma of pinkus white-pinkish background fine arborizing vessels in the center dotted vessels at the periphery basosquamous carcinoma pigmented arborizing vessels keratin masses white structureless areas superficial scale ulceration/blood crusts blood spots in keratin masses blue-gray ovoid nests multiple blue-gray dots review | dermatol pract concept 2014;4(3):2 19 and shiny white/red structureless areas represent common additional dermatoscopic criteria of non-pigmented superficial bcc. when pigmentation is present in superficial tumors it is located at the level of dermo-epidermal junction, being dermatoscopically seen as translucent light brown to grayish concentric structures, spoke-wheel areas or maple leaf-like areas. instead, detection of blue-gray ovoid nests signifies the presence of dermal pigmented basaloid nests, indicating that the tumor is not superficial [4,7,12]. fibroepithelioma of pinkus is an uncommon variant of bcc, dermatoscopically typified by a white-pinkish background color with fine arborizing vessels in the center and dotted vessels at the periphery [52,53]. basosquamous carcinoma (bsc) was traditionally described as an uncommon aggressive variant of bcc. however, its biologic course and some clinical and epidemiologic data are rather similar to scc. heretofore, bsc is considered to represent a complex of tumors characterized by both basaloid and squamoid differentiation, in an apparent continuum between bcc and scc [54-56]. the dermatoscopic characteristics of bsc have been recently reported to mirror its peculiar histopathology, since the tumor shares dermatoscopic criteria of both bcc and scc [57]. in detail, the most frequent dermatoscopic criteria of bsc are unfocused (peripheral) arborizing vessels, keratin masses, white structureless areas, superficial scale, ulceration or blood crusts, blue-grey blotches and blood spots in keratin masses. notably, nearly all bsc were reported to exhibit at least one bcc-related plus one scc-related dermatoscopic feature [57]. figure  11. representative examples of the dermatoscopic pattens of different bcc subtypes: (a) superficial, exhibiting superficial fine telangiectasia, multiple small erosions and maple leaf-like areas; (b) nodular, displaying arborizing vessels, ulceration, blue-gray ovoid nests and multiple blue-gray dots; (c) infiltrative, showing a yellowish-red background and arborizing vessels with small calliber and few ramifications and; (d) morpheaform, exhibiting a whitish backround, few fine arborizing vessels and multiple brown dots. (e) fibroepithelioma of pinkus, typified by the combination of fine arborizing vessels in the center and dotted vessels at the periphery; and (f) basosquamous carcinoma characterized by unfocused, peripheral arborizing vessels, a large whitish structureless area in the center and blue-gray ovoid nests at the lower part. [copyright: ©2014 lallas et al.] figure 12. dermatoscopy of nevoid basal cell carcinomas (a-c) and palmar pits (d) in patient with gorlin-goltz syndrome. although the brown pigmentation is similar to the one seen in nevi, the diagnosis of bcc can be based on the presence of blue-gray nests and arborizing vessels (a), multiple blue-gray globules (b), and multiple bluegray dots and superficial fine telangiectasia (c), respectively. dermatoscopy of the palmar pits reveals linearly arranged dotted vessels (d). [copyright: ©2014 lallas et al.] nevoid bcc is an uncommon variant of the tumor, typically associated with patients with gorlin-golz syndrome. although dermatoscopy of nevoid bcc may show brown pigmentation similar to the one seen in nevi, it also typically reveals bluegray dots, globules or nests, often combined with arborizing vessels. in the context of gorlin-goltz syndrome, dermatoscopy facilitates also the recognition of the characteristic palmar pits, by revealing lineary arranged dotted vessels (figure 12). 20 review | dermatol pract concept 2014;4(3):2 a recent study investigated the accuracy of dermatoscopic criteria for discriminating superficial from the other subtypes of bcc [58]. this is particularly relevant in clinical practice, since the possible misinterpretation of a nodular or infiltrate tumor as superficial bcc could lead the clinician to the inappropriate choice of a non-surgical treatment modality. according to the results of the latter study, the presence of short fine telangiectasia, multiple small erosions and structures corresponding to dermo-epidermal pigmentation predict the superficial subtype. in contrast, detection of ovoid nests should lead clinicians to exclude the diagnosis of superficial bcc, while arborizing vessels and large ulcerations are also suggestive of nodular, sclerodermiform or infiltrative tumors. the sensitivity and specificity of this algorithm for the diagnosis of superficial bcc were 81.9% and 81.8%, respectively [58]. dermatoscopy for assessing the presence of pigmentation the frequency of pigmentation in bcc varies significantly among different races, since pigmented bcc accounts for less than 10% of bccs in caucasians, while the majority of bccs in hispanics and asians and virtually all bccs in black individuals are pigmented [22-26]. notably, histopathological studies found trace amounts of pigment in a considerable percentage of clinically non-pigmented bccs [24]. this is explained by the fact that when only scarce foci of pigmentation are present, they might be insufficient to result in clinically evident pigmentation. the presence of pigmentation is not routinely reported in histopathologic reports, since in the past it was not considered to influence the management and prognosis of the tumor [38,39]. however, the induction of pdt in bcc treatment restored the importance of pigmentation, since its presence was shown to influence the tumor’s response. in detail, case series studies reported a poor response of pigmented bcc to pdt, compared to non-pigmented variants (14% versus 62-100%) [43,59]. this was incorporated in recent guidelines on the use of pdt, suggesting that the method is generally not recommended for pigmented tumors [43,60]. the low efficacy of pdt in pigmented tumors has been attributed to melanin, which appears to act as a competitive light-absorbing pigment, decreasing response rates. effectively, the presence of clinically undetectable pigmentation might represent a diagnostic pitfall for clinicians, forcing them to apply an ineffective treatment on a subset of bccs. this problem seems to be, at least partially, solved by the application of dermatoscopy, which was recently shown to reveal clinically undetectable pigmentation in approximately 30% of macroscopically non-pigmented bccs, enhancing clinicians to better select tumors potentially sensitive to pdt and minimize treatment failures (figure 13) [61]. dermatoscopy for assessing excision margins positive surgical margins represent the most potent predictor of bcc recurrence [62,63]. incomplete surgical excision usually follows removal of tumors located on the face, while recurrence is also associated with bcc subtypes that are characterized by a tendency to expand beyond clinically-visible margins [36,63]. the most reliable method to overcome the problem of positive surgical margins is mohs’ surgery, which is suggested as the optimal treatment for aggressive tumor subtypes (e.g, morpheaform bcc) and for bccs located on the face [50,51]. however, with the exception of highly figure 13. (a) the presence of pigmentation in this bcc is both clinically and dermatoscopically evident. (b) macroscopically, a few pigmented dots can be hardly seen in this bcc. dermatoscopy reveals clear-cut pigmented structuress, namely blue-gray globules and nests. (c) on clinical grounds, this bcc is judged as non-pigmented. dermatoscopy reveals clinically undetectable pigmentation (blue-gray dots/globules). [copyright: ©2014 lallas et al.] review | dermatol pract concept 2014;4(3):2 21 specialized clinical settings, the traditional surgical excision remains the choice treatment in the majority of bccs. using the recommended lateral excision margins of 3mm, the conventional surgery has been associated with recurrence rates up to 17% [48,49,62]. dermatoscopy, by providing a more accurate assessment of the true extension of the tumor, allows a more precise estimation of the required surgical margins, helping to minimize the recurrence rate. specifically, carducci et al. suggested that the margins of the perilesional healthy skin can be defined by the absence of the well-known dermatoscopic criteria of bcc [14]. the discrimination of bcc vessels from the dermal plexus vasculature of the surrounding healthy skin can be based on the blurred appearance and dark red-to-purple color of the surrounding sun-damaged skin, in contrast to the bright-red and focused vessels of the tumor (figure 14) [12,14]. while the diagnostic significance of pigmented structures, such as blue-gray ovoid nests, blue-gray globules or maple leaf-like areas is unquestionable, the usefulness of vascular structures in defining the surgical margins is controversial. mun et al. suggested that arborizing vessels and superficial fine telangiectasia do not directly correspond to bcc cells, but represent feeding vessels of the tumor and may extend also to the perilesional skin [64]. subsequently, if vessels are considered helpful in defining excision margins, there is the risk of unnecessarily removing healthy skin surrounding the bcc [64]. although mun’s hypothesis seems reasonable, it was supported by only one published case and, accordingly, the question whether vascular structures should figure  14. defining the surgical margins of this bcc developing on telangiectatic, sun-damaged skin is troublesome. dermatoscopy facilitates the determination of tumor margins, by enhancing the discrimination between tumoral vessels and telangiectasia of the healthy skin. specifically, the bcc vessels are bright red, appear sharply in focus and exhibit evident ramifications to finer capillaries (black arrows). instead, the telangiectatic vessels of the surrounging skin are more blurred, unfocused and show few, if any, branches (white arrows). [copyright: ©2014 lallas et al.] be considered for defining surgical margins of bcc remains to be further elucidated. dermatoscopy for monitoring response to non-ablative treatments as mentioned above, non-ablative modalities have become very popular among dermatologists for the treatment of superficial bcc, achieving high response rates [46,65]. a common problem associated with non-ablative modalities is the post-treatment evaluation, since at the end of a treatment cycle, the clinical morphology of the lesion often does not allow a reliable estimation of the possible presence of residual disease. in this context, clinicians have to choose among the more conservative “wait and see” strategy, the safe option of performing a new diagnostic biopsy or the more aggressive approach of proceeding to a second therapeutic course or to another treatment modality. these scenarios are associated with the risk of under-treating a persisting tumor, overtreating a healed tumor and prolonging patient’s morbidity and economic costs, respectively. dermatoscopy was recently shown to improve the posttreatment evaluation of bcc following non-ablative procedures; dermatoscopy facilitates the accurate assessment for the presence or absence of residual disease and minimizes the aforementioned risks of underor over-treatment of bcc [66]. specifically, the disappearance of the dermatoscopic criteria of bcc after treatment was shown to accurately predict histopathologic clearance, while the persistence or new appearance of some bcc criteria correlates well with persistence and relapse, respectively. according to the results of a recent study, the presence of arborizing vessels, ulceration or pigmented structures (e.g., blue-gray ovoid nests and maple leaf-like areas) accurately predicts residual disease, and should prompt the clinician to continue the treatment. instead, red/white structureless areas and/or superficial fine telangiectasia might represent equivocal features, since they do not always correspond to residual disease [66]. effectively, detection of the latter criteria warrants close monitoring to recognize a possible recurrence of the bcc (figure 15). of note, in a series of bccs treated with imiquimod, arborizing vessels, maple leaf-like areas and spoke-wheel areas were reported to decrease in size and number at an early stage after treatment initiation, while ovoid nests and multiple blue-gray globules persisted for a longer period of time [17]. detection of blue-gray globules has also been reported to be valuable for early diagnosis of disease recurrence. conclusion while in the past dermoscopy was considered a second-level tool for evaluation of clinically equivocal skin tumors, in our era it represents an irreplaceable part of clinical examination. 22 review | dermatol pract concept 2014;4(3):2 for bcc, dermoscopy not only augments the clinical differential diagnosis, but also seems to provide additional significant information for guiding the 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2017;7(4):5 17 dermatology practical & conceptual www.derm101.com a spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebocontrolled, double-blind study fabio rinaldi1, barbara marzani2, daniela pinto2, yuval ramot3 1 international hair research foundation, milan, italy 2 giuliani s.p.a. r&d, milan, italy 3 department of dermatology, hadassah—hebrew university medical center, jerusalem, israel key words: hair, polyamines, spermidine, anagen, randomized clinical trial citation: a spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebocontrolled, double-blind study dermatol pract concept 2017;7(4):17-21. doi: https://doi.org/10.5826/dpc.0704a05 received: july 26, 2017; accepted: september 4, 2017; published: october 31, 2017 copyright: ©2017 rinaldi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: giuliani s.p.a., milan, italy. competing interests: fabio rinaldi, md, serves as a consultant for giuliani s.p.a. yuval ramot, md, has received travel support from giuliani s.p.a. barbara marzani, phd, and daniela pinto, phd, are employed by giuliani s.p.a. all authors have contributed significantly to this publication. corresponding author: fabio rinaldi, md, international hair research foundation, viale bianca maria 19, 20100 milan, italy. tel: +39-276006089, fax: +39-2-89059053. e-mail: fabio.rinaldi@studiorinaldi.com background: spermidine has been shown both in vitro and in mice models to have an anagen-prolonging effect on hair follicles (hfs). objectives: to evaluate the effects of a spermidine-based nutritional supplement on the anagen phase of hfs in healthy human subjects in a randomized, double-blind, placebo-controlled trial. methods: one hundred healthy males and females were randomized to receive a tablet containing a spermidine-based nutritional supplement or a placebo once daily for 90 days. at the beginning and the end of the treatment period, 100 hfs were plucked and subjected to microscopic evaluation to determine the number of anagen v-vi hfs, and immunohistochemical examination was performed to quantify the ki-67 and c-kit levels in the hair bulbs. pull test was performed after three and six months. results: the spermidine-based nutritional supplement increased the number of anagen v-vi hfs after three months of treatment, accompanied by increased ki-67, a marker for cellular proliferation, and decreased c-kit, a marker for apoptosis, levels. all results were also significantly better when compared to the placebo group. the pull test remained negative after six months in all patients receiving the spermidine supplement, while 68% of the subjects in the placebo group had a positive pull test. conclusions: this preliminary study shows that a spermidine-based nutritional supplement can prolong the anagen phase in humans, and therefore might be beneficial for hair loss conditions. further studies are needed to evaluate its effects in specific different clinical settings. abstract 18 research | dermatol pract concept 2017;7(4):5 or acquired diseases affecting the hair shaft; the use of any topical and/or systemic therapy for hair loss in the previous three months; regular treatment with corticosteroids, hormone therapies, anti-androgenic acting products (e.g., spironolactone, cimetidine, ketoconazole) or anticoagulants; infections or other active disease up to three months prior to beginning the study; organic diseases affecting the kidneys, liver, cardiovascular system, lungs or the central nervous system; diabetes mellitus; alcohol or recreational drug abuse in the year preceding the start of the study; and clinical history of sensitivity or allergic reaction. all patients were evaluated and enrolled to the study in the rinaldi dermatologic clinic, milan, italy. study design this study was a single center, parallel group, double-blinded, randomized, placebo-controlled trial with 1:1 allocation to treatment groups. all subjects signed an informed consent form in accordance with the ich and good clinical practice (gcp) guidelines, prior to undergoing any study related procedures. each patient was randomly allocated to either of two groups (n = 50 in each group): a treatment group receiving a tablet containing a spermidine-based nutritional supplement, taken once daily after the main meal, and a placebo group. the treatment was given for 90 days. assessment criteria all patients were evaluated at three time points: t0 = beginning of the study, t1 = 3 months after the beginning of the study, and t2 = 6 months after the beginning of the study. identification of hf lifecycle phase by means of epiluminescence imaging (trichogram to verify normal cycling status, based on the presence of anagen for at least 80% of hair follicles) was performed at t0 and t1. at both visits, 100 hair bulbs were plucked from the occipital area of all subjects. the occipital area was chosen because hair bulbs in this area are not affected by androgen receptor changes typical of androgenetic alopecia, thus avoiding enrollment into the study of subjects suffering from as yet clinically undetectable androgenetic alopecia. the plucked hair bulbs were immersed in saline solution and evaluated microscopically to select anagen phase v–vi hfs (differentiating from previous phases and above all from initial catagen phase hair bulbs). standardized parameters reported and proposed by kloepper et al. were used [19]. the levels of ki-67, a marker of cellular proliferation, and of c-kit, a marker of apoptosis, were determined immunohistochemically on the plucked hfs as described previously [25]. the extent of hair loss was also assessed by the hair pull test on t0, t1 and again on t2 to check for possible onset of physiological telogen effluvium, typical of the autumn season [26]. introduction the polyamines, consisting of putrescine, spermidine and spermine, are straight chain aliphatic compounds that are ubiquitously found in living organisms [1,2]. their levels are strictly controlled by complex metabolic pathways incorporating polyamine biosynthesis, catabolism, and transport [3,4]. they are essential for the survival and growth of eukaryotic cells by regulating gene expression and protein synthesis, affecting a large variety of cellular processes, including cell growth, differentiation, and regulation [5-7]. the hair follicle (hf), one of the most highly proliferative organs in mammals, has also been shown to be dependent on polyamines for its normal growth, function and cycling. this has been demonstrated in several mouse models, where changes in polyamine metabolism led to hair loss due to alteration in the proliferation of the hf keratinocytes [8-18]. spermidine, the prototypic polyamine in humans, is especially important for normal hair growth. indeed, topical administration of eflornithine, which inhibits ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis pathway of polyamines, is used to treat excessive hair growth in females [17,18]. it has also been shown to decrease the anagen phase and induce apoptosis in human hfs in vitro [19]. spermidine and its metabolically stable analog, n1-methylspermidine, were demonstrated to prolong anagen and affect epithelial stem cell functions in human hfs in vitro [5,20,21]. in vivo, topical application of α-methylspermidine, a stable analogue of spermidine, enhanced hair growth in telogen phase mice [22]. previous preliminary studies have shown the effectiveness of spermidine-containing nutritional supplements for the treatment of telogen effluvium [23,24]. however, the effect of spermidine on the anagen phase in normal subjects has never been studied in humans. therefore, we conducted a randomized, double-blind, placebo-controlled trial on 100 patients, to evaluate the effects of a spermidine-based nutritional supplement on the anagen phase of hfs in healthy human subjects. patients and methods subjects a total of 100 healthy men and women were recruited into the study after giving written consent. the participants were randomized into the treatment group (31 men and 19 women, 36.08 years of age on average, age range 23-50) or placebo group (36 men and 14 women, 35.6 years of age on average, age range 22-48). all participants in the study had unremarkable dietary and lifestyle habits. exclusion criteria included initial signs of androgenetic alopecia demonstrated by miniaturization of the hair shaft as observed in the occipital region; a family history of androgenetic alopecia; congenital research | dermatol pract concept 2017;7(4):5 19 by decreased levels of the apoptosis marker, c-kit (table 2). at the same time, in the placebo group, ki-67 levels were decreased and c-kit levels increased. there was a statistically significant difference between the spermidine-treated group and the placebo group. pull test at baseline, all subjects had a negative pull test (table 3). there was a gradual increase in the number of subjects that had a positive pull test in the placebo group, with 14 subjects at t1 (28%), and 34 subjects at t2 (68%) having a positive test (table 3). this was in contrast to the subjects in the spermidine-treated group, where only one subject was found to have a positive test at t1 (table 3), and none at t2. the difference between the groups was statistically significant at both time points. discussion our results provide preliminary evidence that a spermidinebased nutritional supplement, when given orally once daily for 90 days, can promote anagen prolongation, and reverse the transition between anagen to catagen and to telogen. part student’s t test was used for comparing the number of anagen hair bulbs and ki-67 and c-kit levels at baseline and at t1, and the change from baseline was compared between groups using the paired t-test. comparison of the pull test results between t1 and t2 was performed using the chisquare test or fisher’s exact test. the statistical analyses were performed on all subjects enrolled (n=100) by means of a two-tailed test and on a significance level of 0.05 (p-value). results number of anagen v-vi hair bulbs the number of anagen hair bulbs increased in the spermidine treatment group between t0 and t1 (more than 50% increase), while in the placebo group there was a significant decrease in the number of anagen hair bulbs of approximately 20% (table 1). there was a highly statistically significant difference in the change in anagen hair bulb number between the spermidine-treated group and the placebo group (p<0.0001). ki-67 and c-kit assessments treatment with spermidine increased the levels of the proliferation marker ki-67 after 3 months of treatment, accompanied table 1. number of anagen phase v-vi hair bulbs placebo mean (s.d.) n=50 spermidine mean (s.d.) n=50 p value (between treatment groups, student’s t-test) t0 25.54 (4.05) 24.64 (4.45) 0.29 (n.s.) t1 20.24 (3.14) 37.44 (3.84) absolute change between t1 and t0 -5.3 (2.3)* 12.8 (6.87)* <0.0001 *p<0.0001 within treatment group, change from t0, paired t-test. n.s. non significant; s.d. standard deviation. table 2. expression of ki-67 and c-kit placebo mean (s.d.) n=50 spermidine mean (s.d.) n=50 p value (between treatment groups, student’s t-test) ki-67 t0 91.58 (8.83) 90.08 (12.12) 0.48 (n.s.) t1 86.63 (7.66) 102.77 (10.75) absolute change between t1 and t0 -4.96 (6.76)* 12.69 (8.1)* <0.0001 c-kit t0 9.19 (1.08) 9.67 (1.12) 0.03 t1 10.99 (1.14) 7.52 (1.22) absolute change between t1 and t0 1.8 (1.07)* -2.16 (1.24)* <0.0001 *p<0.0001 within treatment group, change from t0, paired t-test. n.s. non significant; s.d. standard deviation. 20 research | dermatol pract concept 2017;7(4):5 the last administration of the pill, as demonstrated by the negative pull test in the treatment group. these preliminary results can serve as a proof of principle to the fact that oral spermidine can exert functional effects on human hfs and further strengthen previous results that showed its effectiveness for the treatment of telogen effluvium [23,24]. the possible beneficial effects of this compound for telogen effluvium and other hair disorders, such as pattern hair loss, need to be further confirmed in larger controlled studies. references 1. alcazar r, altabella t, marco f, et al. polyamines: molecules with regulatory functions in plant abiotic stress tolerance. planta. 2010;231:1237-1249. 2. nahar k, hasanuzzaman m, suzuki t, fujita m. polyamines-induced aluminum tolerance in mung bean: a study on antioxidant defense and methylglyoxal detoxification systems. ecotoxicology. 2017;26:58-73. 3. casero ra, jr., marton lj. targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. nat rev drug discov. 2007;6:373-390. 4. ou y, wang sj, li d, chu b, gu w. activation of sat1 engages polyamine metabolism with p53-mediated ferroptotic responses. proc natl acad sci usa. 2016;113:e6806-e6812. 5. gerner ew, meyskens fl, jr. polyamines and cancer: old molecules, new understanding. nat rev cancer. 2004;4:781-792. 6. tabor cw, tabor h. polyamines in microorganisms. microbiol rev. 1985;49:81-99. 7. yerra a, mysarla dk, siripurapu p, jha a, valluri sv, mamillapalli a. effect of polyamines on mechanical and structural properties of bombyx mori silk. biopolymers. 2017;107:20-27. 8. coleman cs, pegg ae, megosh lc, guo y, sawicki ja, o’brien tg. targeted expression of spermidine/spermine n1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis. carcinogenesis. 2002;23:359-364. 9. megosh l, gilmour sk, rosson d, et al. increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase. cancer res. 1995;55:4205-4209. 10. panteleyev aa, christiano am, o’brien tg, sundberg jp. ornithine decarboxylase transgenic mice as a model for human atrichia with papular lesions. exp dermatol. 2000;9:146-151. 11. pietila m, alhonen l, halmekyto m, kanter p, janne j, porter cw. activation of polyamine catabolism profoundly alters tissue of these effects could probably be attributed to an increased proliferation and decreased apoptosis in the hair bulb cells, as assessed by determining ki-67 and c-kit levels. the potential beneficial effects of spermidine on human hfs have been suggested previously, based on several mice model studies [27]. this assumption has received additional support from two recent in vitro studies, using human hf organ cultures and cell cultures [20,21]. in the first study, spermidine was found to enhance hair shaft elongation and prolong anagen, accompanied by increased human hair matrix and epidermal keratinocyte proliferation [21]. the anti-apoptotic and anagen-promoting effects of spermidine were recapitulated when n1-methylspermidine, a metabolically stable spermidine, was used [20]. the relevance of the human hf culture model for polyamines research has been demonstrated previously, when eflornithine, which is being used in clinical practice for the treatment of excess facial hair growth [17,18], also induced catagen in vitro [19]. the exact mechanism by which spermidine exerts its beneficial effects on the human hf is still not entirely clear. it has been shown previously that spermidine can differentially modulate the gene expression profile of hfs, which can have functional relevance to human hair growth and cycle [21]. furthermore, n1-methylspermidine can exert anti-oxidative and anti-inflammatory effects on human cells in vitro [20], which are both relevant to the human hf growth and function. polyamines, and among them spermidine, might also be linked to the hairless protein [28,29], which has an important role in controlling normal hair function and cycle [20,31]. the fact that spermidine was found to enhance longevity supports the anagen-promoting effects observed in this study, as the duration of anagen is a good indicator for the hf vitality [32-34]. this study shows that oral spermidine can enhance anagen prolongation in humans. anagen prolongation has significant clinical implications for different hair disorders, as it directly affects the amount of hair that is shed and therefore the number of hfs located on the scalp. furthermore, although spermidine-containing tablets were given for only 90 days, the effect was still evident at least three months after table 3. pull test results t0 t1 t2 placebo n (%) spermidine n (%) placebo n (%) spermidine n (%) placebo n (%) spermidine n (%) 50 50 36 (72) 49 (98)* 16 (32) 50 (100)# + 14 (28) 1 (2)* 19 (38) ++ 12 (24) +++ 3 (6) *p<0.0001 by fisher’s exact test; #p<0.0001 by chi-square test research | dermatol pract concept 2017;7(4):5 21 21. ramot y, tiede s, biro t, et al. spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions. plos one. 2011;6:e22564. 22. fashe tm, keinanen ta, grigorenko na, et al. cutaneous application of alpha-methylspermidine activates the growth of resting hair follicles in mice. amino acids. 2010;38:583-590. 23. rinaldi f, sorbellini e, bezzola p, marchioretto di. biogenina® based food supplement: hair growth enhancer. nutrafood. 2003;2:1-7. 24. rinaldi f, bezzola p, sorbellini e, giuliani g. the effect of polyamines on hair cycle clock. j plast dermatol. 2009;5:163-167. 25. trink a, sorbellini e, bezzola p, et al. a randomized, double-blind, placebo and active-controlled, half-head study to evaluate the effects of platelet rich plasma on alopecia areata. br j dermatol. 2013;169:690-694. 26. grover c, khurana a. telogen effluvium. indian j dermatol venereol leprol. 2013;79:591-603. 27. ramot y, pietila m, giuliani g, rinaldi f, alhonen l, paus r. polyamines and hair: a couple in search of perfection. exp dermatol. 2010;19:784-790. 28. luke ct, casta a, kim h, christiano am. hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. exp dermatol. 2013;22:644-649. 29. ramot y, vardy la. commentary on: hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. exp dermatol. 2013;22:697-698. 30. ramot y, horev l, smolovich i, molho-pessach v, zlotogorski a. marie unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript. exp dermatol. 2010;19:e320322. 31. ramot y, zlotogorski a. molecular genetics of alopecias. curr probl dermatol. 2015;47:87-96. 32. eisenberg t, abdellatif m, schroeder s, et al. cardioprotection and lifespan extension by the natural polyamine spermidine. nat med. 2016;22:1428-1438. 33. kaeberlein m. spermidine surprise for a long life. nat cell biol. 2009;11:1277-1278. 34. eisenberg t, knauer h, schauer a, et al. induction of autophagy by spermidine promotes longevity. nat cell biol. 2009;11:13051314. polyamine pools and affects hair growth and female fertility in transgenic mice overexpressing spermidine/spermine n1-acetyltransferase. j biol chem. 1997;272:18746-18751. 12. pietila m, parkkinen jj, alhonen l, janne j. relation of skin polyamines to the hairless phenotype in transgenic mice overexpressing spermidine/spermine n-acetyltransferase. j invest dermatol. 2001;116:801-805. 13. pietila m, pirinen e, keskitalo s, et al. disturbed keratinocyte differentiation in transgenic mice and organotypic keratinocyte cultures as a result of spermidine/spermine n-acetyltransferase overexpression. j invest dermatol. 2005;124:596-601. 14. smith mk, trempus cs, gilmour sk. co-operation between follicular ornithine decarboxylase and v-ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin. carcinogenesis. 1998;19:1409-1415. 15. soler ap, gilliard g, megosh lc, o’brien tg. modulation of murine hair follicle function by alterations in ornithine decarboxylase activity. j invest dermatol. 1996;106:1108-1113. 16. suppola s, pietila m, parkkinen jj, et al. overexpression of spermidine/spermine n1-acetyltransferase under the control of mouse metallothionein i promoter in transgenic mice: evidence for a striking post-transcriptional regulation of transgene expression by a polyamine analogue. biochem j. 1999;338 ( pt 2):311-316. 17. hamzavi i, tan e, shapiro j, lui h. a randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. j am acad dermatol. 2007;57:54-59. 18. wolf je, jr., shander d, huber f, et al. randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine hcl 13.9% cream in the treatment of women with facial hair. int j dermatol. 2007;46:94-98. 19. kloepper je, sugawara k, al-nuaimi y, gaspar e, van beek n, paus r. methods in hair research: how to objectively distinguish between anagen and catagen in human hair follicle organ culture. exp dermatol. 2010;19:305-312. 20. ramot y, marzani b, pinto d, kloepper je, paus r. n(1)-methylspermidine, a stable spermidine analog, prolongs anagen and regulates epithelial stem cell functions in human hair follicles. arch dermatol res. 2015;307:841-847. dermatology: practical and conceptual editorial | dermatol pract concept 2015;5(1):6 45 dermatology practical & conceptual www.derm101.com introduction the clinicopathologic classification, diagnosis, and management of spitzoid melanocytic lesions is one of the most problematic topics in dermato-oncology and dermatopathology. after earlier anecdotal reports [1,2], the controversial history of these controversial lesions began in 1948 when sophie spitz described 13 cases of what she called “juvenile melanoma,” underlining its presumably good prognosis because only one case of her series had proven fatal [3]. during the following forty years, however, the entity described by sophie spitz was thought to be completely benign, with metastasizing cases being intuitively considered as cases of melanomas simulating spitz nevus (spitzoid melanoma) [4]. in 1989, smith and co-worker described the so-called “spitz nevus with atypia and metastasis” or “malignant spitz nevus,” i.e., a kind of lesion showing histopathologic features not enough for a diagnosis of malignancy, yet capable of nodal metastasis, usually with no further dissemination [5]. this apparently contradictory concept was then set forth by barnhill with the diagnostic category of “metastasizing spitz tumor” [6], or “atypical spitz nevus/tumor” [7]. to date, while some opinion leaders maintain that there are only two diagnostic categories (nevus and melanoma) and that every “abnormal” behavior is simply a diagnostic mistake [8], some others suggest that spitzoid lesions are indeed a “morpho-biologic spectrum” of lesions ranging from benignity to full-blown malignancy [9], and sharing a peculiar genetic profile, with chromosome rearrangements involving kinase fusions [10]. intermediate lesions within such a spectrum eventually show: i) an equivocal histomorphology, featuring a diagnostic agreement among experts which is consistently lower than for “conventional” (non-spitzoid) melanocytic neoplasms [7,11]; ii) peculiar clinical features and behavior with a relatively high incidence in prepubescent patients [12] and a higher incidence of regional (sentinel) node involvement [13] but a better prognosis than “conventional” (non-spitzoid) melanoma of the same thickness/stage [14] (possible lowgrade malignancies [11]). hypopigmented atypical spitzoid neoplasms (atypical spitz nevi, atypical spitz tumors, spitzoid melanoma): a clinicopathological update gerardo ferrara1, stefano cavicchini2, maria teresa corradin3 1 department of oncology, anatomic pathology unit, gaetano rummo hospital, benevento, italy 2 dermatology unit, fondazione irccs ca’ granda ospedale maggiore, milan, italy 3 department of dermatology, santa maria degli angeli hospital, pordonenone, italy key words: spitz nevus, spitz tumors, spitz melanoma, dermoscopy, histopathology citation: ferrara g, cavicchini s, corradin mt. hypopigmented atypical spitzoid neoplasms (atypical spitz nevi, atypical spitz tumors, spitzoid melanoma): a clinicopathological update. dermatol pract concept 2015;5(1):6. doi: 10.5826/dpc.050106 received: september 2, 2014; accepted: october 5, 2014; published: january 30, 2015 copyright: ©2015 ferrara et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gerardo ferrara, md, department of oncology, anatomic pathology unit, gaetano rummo hospital, via dell’angelo 1, i-82100 benevento, italy. email: gerardo.ferrara@libero.it 46 editorial | dermatol pract concept 2015;5(1):6 we have already pointed out that dermoscopy seems to allow clinicians to increasingly identify and excise pigmented spindle cell spitz nevus and reed nevus (which are basically the same clinicopathological entity), to such an extent that the brown-black plaque-like “variant” is surprisingly becoming the most common (and therefore “typical”) spitz nevus encountered in clinico-dermoscopic-pathologic studies [1517]. the present paper will focus on the clinicopathological features of papulonodular hypopigmented spitzoid lesions, which are “atypical” with a much greater frequency than their plaque-like heavily pigmented counterpart [16,17]. the proposed classification systems for spitzoid neoplasms the dermatopathologist’s mission is to provide an accurate, specific, and comprehensive diagnosis, thereby enabling the clinician to estimate the prognosis and develop the optimal plan of treatment and follow up for any single patient. there is little doubt that the simple designation “benign” vs “malignant” provides the clinician with all of the necessary information for the patients’ care. a. bernard ackerman taught us that each pigmented lesion may have only three diagnoses: “melanoma,” “nevus” or “i don’t know,” with the “i don’t know” cases to be referred to an expert who will be finally able to place them into either of the first two entities. according to this view, the adjective “atypical” is redundant and useless, because any spitz nevus is “atypical” by definition; nevertheless, it can be differentiated from its malignant simulator (i.e., spitzoid melanoma) according to a well defined set of histologic criteria; every spitzoid (and non-spitzoid) melanocytic proliferation behaves as either a benign or a malignant neoplasm which we can be unable to correctly categorize simply because our brain can fail to correctly apply the diagnostic criteria [8]. a.b. ackerman’s approach delivers a clear-cut message to the clinicians; nevertheless, it carries at least two major problems, which are still waiting to be overcome. the first problem is purely morphologic: by assuming that spitz nevus is a simulator of melanoma (spitz nevus as a pseudomalignancy) and that melanoma resembling spitz nevus is a simulator of its simulator (spitzoid melanoma as a pseudopseudomalignancy), it is not surprising that the diagnosis of such lesions is a quandary even among experts who may be indeed unable to place an “i don’t know” lesion into a either “nevus” or “melanoma” category [7,11,18]. the second problem with a.b. ackerman’s approach is biological. a tutorial held in graz, austria, in 2008 evaluated 57 melanocytic tumors of uncertain malignant potential, 35 of which being thick spitzoid neoplasms: a panel of expert was unable to differentiate cases with favourable and unfavourable behaviour on morphologic grounds; therefore, it was concluded that the cases were all malignant, albeit clearly different from “conventional” melanoma because of a great thickness associated with a relatively low metastatic rate [18]. because of all these uncertainties and under medicolegal pressure, a dichotomic “benign vs malignant” approach unavoidably leads to a frequent overdiagnosis of melanoma or, else, to the cautious suggestion of a management as per melanoma for lesions that, even if malignant, are biologically different from “conventional” melanoma. these reasons led barnhill to set forth a three-tiered classification system by assuming an “intermediate” category (“atypical spitz nevus/tumor”) between spitz nevus and melanoma [6,7]. within barnhill’s “intermediate” category, the risk of malignancy of each lesion was considered as allegedly proportional to its “deviance” from the conventional stereotype of the spitz nevus. as an extreme consequence of this view, in 2006 barnhill proposed that every spitzoid lesion could be actually classified “intermediate” and thereby designated as “tumor” (without or with atypical features) [19]: more explicitly, all spitzoid lesions could be virtually “non-benign,” with the new dichotomic approach thus being “tumor vs melanoma.” the message to the clinician, which stems from barnhill’s approach is that basically all spitzoid lesions represent a harmful occurrence, and in our opinion, this is too much. in keeping with the concept of spitzoid neoplasms as a morpho-biological spectrum, we have adopted a four-tiered classification system proposed by da forno [20] and encompassing: i) spitz nevus; ii) atypical spitz nevus; iii) (atypical) spitz tumor; iv) spitzoid melanoma [17]. the histopathologic criteria for the differential diagnosis between the two “intermediate” categories of the spectrum—atypical spitz nevus and spitz tumor—are provided in table 1. briefly, a spitz tumor is—by definition—“tumorigenic,” i.e., it is characterized by a nodular silhouette made by confluent sheets of cells in the dermis without intervening collagen, and/or (nontraumatic) ulceration, and/or relevant mitotic activity [17]. the decision-making process following a diagnosis based on our classification system is itemized in the “guidelines for management” section. an algorithm for the clinical diagnosis of spitzoid neoplasms it is commonly said that spitz nevus can show all the “local” dermoscopic features of melanoma, but in a more or less tidy fashion [15,17]. the occurrence of an atypical (melanomalike) dermoscopic pattern in spitz nevus is also possible. however, the relationship between dermoscopic and histopathologic atypia is not absolute, inasmuch as dermoscopically atypical lesions are not necessarily histopathologically atypical as well; conversely, it is well known that amelanotic editorial | dermatol pract concept 2015;5(1):6 47 melanoma can show a tidy (“spitz nevus-like”) dermoscopic appearance [21]. since a fully reliable clinico-dermoscopic distinction between spitz nevus and melanoma is not possible, surgical excision is warranted for all lesions with spitzoid features. there is, however, a remarkable exception to this rule: since in pre-puberty spitz nevus is relatively common [12] whereas melanoma is exceedingly rare [22], a spitzoid lesion in patients younger than 12 years can be managed conservatively unless it stands as atypical on clinical and/or on dermoscopic grounds, either at the baseline or during follow up [12]. for the above, the clinical evaluation of such lesions can be accomplished according to the following algorithm: 1. recognition of a spitzoid melanocytic lesion on dermoscopy: this is enough to warrant surgical excision after puberty. 2. recognition of atypical clinicodermoscopic features in a spitzoid melanocytic lesion: this is the threshold for surgical excision in prepubescent patients. 3. recognition of atypical clinicodermoscopic features during follow up of a spitzoid melanocytic lesion in prepubescent patients. the following sections will focus on hypopigmented spitzoid lesions; nevertheless, the above-specified algorithm must be implemented for all spitzoid lesions, irrespective of the amount of their pigmentation. recognition of a hypopigmented spitzoid lesion a hypopigmented spitzoid melanocytic neoplasm can be typified by at least one of the following: 1. homogeneous pink color: sometimes associated with a brownish hue or remnant(s) of brown pigmentation. 2. dotted vascular pattern: short capillary loops visible as pinpoint dots, best appreciated with non-contact dermoscopy. 3. “starburst” vascular pattern: long centrifugal capillary loops visible as regular lines radiating toward the periphery of the lesion, easier to be observed with non-contact dermoscopy. 4. reticular depigmentation: a grid of whitish areas delineating pink (homogeneous or “dotted”) areas representing the holes of the net. 5. chrystalline (chrysalis-like) structures (with polarized dermoscopy only): a variation on the theme of reticular depigmentation, featuring white shiny parallel or orthogonal or disordered linear streaks or short lines which can be seen only with polarized light dermoscopy. these features can consistently help the clinical differential diagnosis with hypopigmented clark nevus, pyogenic granuloma, juvenile xanthogranuloma, molluscum contagiosum, and viral wart. any single above-listed feature can be seen also in melanoma. symmetric and plaque-like or slightly raised (dometable 1. proposed histopathologic criteria for the differential diagnosis between atypical spitz nevus and spitz tumor (copyright: ©2015 ferrara et al.) microscopic features atypical spitz nevus atypical spitz tumor size 7-10 mm >10 mm tumorigenicity (nodule) + asymmetry superficial deep +/superficial sharp circumscription, intraepidermal +/+/ sharp circumscription, lateral dermal -/+ sharp circumscription, deep dermal +/++ epidermal atrophy -/+ +/++ ulceration -/+ large dermal nests superficial deep +/superficial dermal sheets of cells +/++ deep extension + melanin in the depth -/+ cytologic atypia focal (‘random’) widespread maturation + mitotic figures few numerous and/or close to the base 48 editorial | dermatol pract concept 2015;5(1):6 table 2. histomorphologic criteria for metastasizing atypical spitz nevi/tumors (urso, 2005 [23]) with their clinico-dermoscopic correlates (copyright: ©2015 ferrara et al.) histopathologic features clinico-dermoscopic correlates expansile dermal nodule (large) nodule deep extension (large) nodule deep mitoses nodule abundant melanin in depth gray-blue or pink color great nuclear pleomorphism no correlate asymmetry asymmetry (when superficial) necrosis no correlate epidermal atrophy prominent vascular pattern, ulceration cells within the lymph vessels no correlate shaped) cutaneous lesions showing these dermoscopic features in a tidy fashion are most commonly spitz nevi; nevertheless, a histopathologically atypical spitzoid proliferation can be dermoscopically quite tidy and symmetric (figure 1), thereby underlining once again the need to excise all lesions with spitzoid features after puberty. recognition of atypical clinico dermoscopic features in a spitzoid melanocytic lesion this topic is of paramount importance in prepubescent patients. in 2005, urso [23] performed a review of 19 papers reporting 62 spitzoid neoplasms showfigure 1. a lesion of the right thigh in a 22-year-old woman. the lesion is clinically (a, inset) reddish and sharply circumscribed; on dermoscopy (a) its main feature is reticular depigmentation, which is associated with regularly distributed light brown dots/globules. overall, the lesion is very symmetric. nevertheless, it is slightly atypical histopathologically. the silhouette is dome-shaped, with a sharp lateral circumscription (b) but also with a central exaggerated confluence of nests within the superficial dermis (c) at this level, cytomorphology is very bland and monomorphic, with no mitotic figure (d). histopathological diagnosis: spitz nevus according to ackerman’s classification [8]; spitz tumor with atypical features according to barnhill’s classification, 2006 [19]. our histopathological diagnosis was atypical compound spitz nevus and a narrow re-excision was advised. (copyright: ©2015 ferrara et al.) ing an aggressive biological behavior in spite of histopathologic features not enough for a diagnosis of clear-cut malignancy. nine criteria were thus found to be predictive of metastatic potential: notably, such criteria were not the very same as for “conventional” melanoma and, most important, they had to be used in a completely different manner, because even the presence of one criterion could be virtually incompatible with benignity. urso’s [23] criteria are listed in table 2, along with their expected clinico-dermoscopic counterpart. by accepting urso’s approach [23], atypical (possibly malignant) spitzoid neoplasms are most often: a. large, commonly >7 mm in diameter; b. nodular: more or less irregularly raised, palpable, firm, sometimes polypoid and/or ulcerated; c. hypo-amelanotic: pink-reddish in color, with a nondescript or, else, with a prominent and/or polymorphous vascular pattern. the above listed features have been summarized in the clinicopathologic definition “red spitz tumors,” as opposite to the “blue spitz tumors” [12], the latter histopathologically corresponding to epithelioid (spitzoid) proliferations intermingled with heavily pigmented dendritic melanocytes (so-called “pigmented epithelioid melanocytomas” [24]). the two cases of red spitz tumors shown in figure 2 demonstrate that such lesions sometimes disclose unspecific dermoscopic features with a clinical picture which is, however, definitely worrisome. the unique banal cutaneous lesion, which cannot be differentiated from a red spitz tumor on the basis of dermoscopy, is pyogenic granuloma: this is the reason why always submit to histopathologic examination the curetted material of any pyogenic granuloma look-alike lesion. the quality of the vascular pattern is of paramount importance for the differential diagnosis of “red spitz tumors” from more common and banal lesions, such as viral warts (figure 3) and molluscum contagiosum (figure 4). in our experience, a diagnoeditorial | dermatol pract concept 2015;5(1):6 49 figure 3. a dome-shaped red lesion with a light verrucous surface (a) located on the back in a 7-year-old girl. dermoscopy (b) suggests that the lesion is probably not a viral wart, because of the presence of a thick reticular depigmentation surrounding linear irregular vessels; some small white scales and a peripheral light brown symmetric pigmentation are visible as well. histopathologically, the lesion is very atypical, with an asymmetric involvement of the epidermis (c, arrow) and a deep dermal component made by epitheloid (spitzoid) cells with a confluent pleomorphomism and a larger size than the overlying melanocytes (d). histopathological diagnosis: spitzoid melanoma, according to ackerman’s classification [8]; spitz tumor with atypical features, according to banhill’s classification, 2006 [19]. our histopathological diagnosis was (atypical) spitz tumor. in this case, a sentinel node biopsy disclosed few parenchymal aggregates of pleomorphic melanocytes; no completion lymph node dissection was performed. the patient is alive with no evidence of disease after six years. (copyright: ©2015 ferrara et al.) sis of spitz nevus in the presence of a polymorphous vascular pattern must be made only under a compelling histopathological evidence of benignity; we have also suggested that when a given spitzoid lesion is histopathologically atypical but its “grading” is uncertain, the presence of a highly atypical vascular pattern could point toward its management as a “tumor” instead of an “atypical nevus” [17]. recognition of atypical clinico dermoscopic features during followup of a spitzoid melanocytic lesion in prepubescent patients. dermoscopic monitoring of spitzoid proliferations can be recommended only for plaque-like or dome-shaped dermoscopically symmetric lesions before puberty [12]: the suggested protocol is based on clinico-dermoscopic controls every three to six months [25]. a completely benign hypopigmented lesion is expected to enlarge, even very rapidly but always very symmetrically, and then to slowly involute, either completely [26] or up to a “dermal nevus-like” homogeneous light brown pattern [27,28]. abnormal dermofigure 2. two examples of “red tumors” which are not easily recognizable as “spitzoid” on clinicodermoscopic grounds. on the top, a multinodular polypoid neoplasm of the external ear (a) in a 9-year-old boy. the neoplasm is dermoscopically typified by a prominent ad atypical vascular pattern (diffuse reddish areas, dotted vessels, peripheral thick linear irregular vessels); a few light brown areas are also visible and can dermoscopically suggest that this highly atypical lesion is melanocytic (b). on the bottom, a raised multinodular pink-reddish lesion of the buttock (c) in an 11-year-old boy; dermoscopy (d) shows whitish-pink lobules with a polymorphous vascular pattern (diffuse pink-red areas, thin and elongated linear-irregular vessels, hairpin vessels), peripheral white globules, and light brown structureless areas. also in this case dermoscopy discloses remnants of pigmentation, which are not clinically evident and, again, can suggest that the lesion is melanocytic. in both cases our histopathological diagnosis was (atypical) spitz tumor. (copyright: ©2015 ferrara et al.) 50 editorial | dermatol pract concept 2015;5(1):6 scopic digital follow up findings (an example is given in figure 5) include: a. asymmetric growth b. nodular/polypoid growth c. ulceration d. increased atypia in the vascular pattern. any of the above features warrant immediate surgical excision. spitzoid melanoma: a clinicopathological reassessment while adult spitzoid melanoma is often clinically and dermoscopically indistingiuishable from “conventional” melanoma, pediatric spitzoid melanoma shows very peculiar clinicopathologic features. histopathologically, it differs from atypical spitz nevus or spitz tumor by showing a non-spitzoid cytomorphologic clone arising in the context of a spitzoid lesion. such a highly unusual occurrence can be detected even clinically and dermoscopically. in figure 6 the “clone” is the red nodule with a nondescript vascular pattern; the nodule was initially treated as per pyogenic granuloma, but histopathologically disclosed a highly atypical proliferation of pleomorphic epithelioid cells. on the excision specimen, the “shoulder” of the neoplasm disclosed a bland morphology, featuring monomorphic spindle cells, probably representing a benign background (spitz nevus) in which spitzoid melanoma had been developing. based on the very few exceptional cases we have seen, pediatric spitzoid melanoma is a malignancy figure 4. a melanocytic neoplasm removed from the forearm of a 10-yr-old girl. clinically (a) the lesion is firm red nodule with a central depression. dermoscopically (b), a central yellow crust could resemble the umbilication of a molluscum contagiosum; however, vessels around the crust are atypical; in addition there is a peripheral reddish area with dotted vessels which suggest that the lesion is melanocytic. histopathologically the neoplasm is strikingly cellular and focally eroded with large dermal sheets of cells (c); several mitotic figures (d; arrows) are detected in the mid-dermal component. histopathological diagnosis: melanoma according to ackerman’s classification [8]; spitz tumor with atypical features according to barnhill’s classification, 2006 [19]. our histopathological diagnosis was (atypical) spitz tumor. histologic images kindly provided by prof. raffaele gianotti, department of pathophysiology and transplantation, university of milan, milan, italy. (copyright: ©2015 ferrara et al.) figure 5. dermoscopic digital monitoring of a red lesion of the arm in a melanocytic lesion of the leg in a 5-year-old girl. at the baseline (a), the lesion is typified by a quite symmetrical ‘starburst’ vascular pattern associated with a reticula depigmentation; rare coiled vessels are also present. after 17 months (b), there is evidence of early nodular growth in the central area, which appears homogeneous pinkish-red with some dotted vessels and thin linear vessels. a brownish peripheral hue is also evident. histopathologically, the silhouette is nodular (c), with wide areas of epidermal atrophy (d) and crops of dermal mitotic figures (e; arrows). histopathological diagnosis: melanoma according to ackerman’s classification [8]; spitz tumor with atypical features according to barnhill’s classification, 2006 [19]. our histopathologic diagnosis was (atypical) spitz tumor. (copyright: ©2015 ferrara et al.) editorial | dermatol pract concept 2015;5(1):6 51 arising in the background of a spitz nevus [17], just like already suggested for melanoma arising in spitz tumor [29]. guidelines for management surgical excision is recommended for all lesions with spitzoid dermoscopic features detected after puberty. before puberty, plaque-like or dome-shaped dermoscopically symmetric lesions with spitzoid features can undergo dermoscopic digital monitoring [12]. large (>1cm), nodular, ulcerated, rapidly growing/changing, or otherwise atypical spitz nevi of the childhood must be excised. the management of patients with a histopathologic diagnosis of atypical spitz nevus and spitz tumor should be decided with a multidisciplinary approach and on an informed consent basis. a narrow re-excision can be considered for atypical spitz nevi and must be recommended for all incompletely excised lesions, as well as for spitz tumors. the opportunity of a sentinel node biopsy for spitz tumors should be evaluated case by case. the decision must be made by preliminarily considering that in spitz tumors the presence of isolated tumor cells in the sentinel node is not an unequivocal sign of malignancy [30,31] and is not an indication to completion lymphadenectomy, based on the ambiguity of the primary. it must be also underlined that, in a recent meta-analysis, 98-99% of young patients with spitz tumors had no evidence of disease after a median follow-up of 59 months, regardless the sentinel node positivity [14]; therefore, the diagnostic and prognostic information given by a positive sentinel node in young patients seems to be negligible. if this is true, an echotomographic monitoring of the regional nodes (and an echotomography-guided fine needle aspiration biopsy cytology) can even replace sentinel node biopsy, because it allows to efficiently detect massive replacement of the node(s) by neoplastic cells, thereby addressing selected patients to election lymphadenectomy [31]. such a follow up protocol is probably the best choice in patients younger than 10 years, especially for lesions located in the head/neck area, a region in which surgical procedures are aesthetically relevant and are hampered by a sizable failure rate [32]. the prognosis of spitz tumors is age-dependent [33]. adult patients, who are expected to be at greater risk, could be managed more aggressively. the risk stratification for atypical spitzoid melanocytic proliferations has been recently addressed with the use of a new four-probe fluorescence insitu hybridization (fish) assay for 6p25 (rreb1), 11q13 (ccnd1), 9p21 (cdkn2a), and 8q24 (myc) [34]. the following categories have been individuated: i) spitzoid melanoma with homozygous 9p21 deletion (high risk); ii) spitzoid melanoma with 6p25 and/or11q13 gain (intermediate to high risk); iii) atypical spitz tumor with isolated 6q23 deletion (low risk); iv) atypical spitz tumor with no fish abnormality (low to very low risk). so far, the number of investigated cases is too low to validate the above-detailed risk stratification system. however, the use of fish techniques for prognostic—rather than for diagnostic—purposes seems to be a very promising tool. in adult patients, cases of spitz tumor with homozygous deletion of 9p21, best evaluated using a dual color fish test targeting cdkn2a (spectrumorange) and cep9 (spectrumgreen), might be managed as per melanoma. figure 6. an atypical neoplasm of the face in an 11-year-old girl. dermoscopically (a) the lesion is biphasic: a flat portion shows reticular depigmentation along with structureless and globular brown areas; a nodular area discloses a non-descript vascular pattern, featuring a diffuse reddish area. the lesion was clinically diagnosed as a pyogenic granuloma associated with a spitz nevus. for aesthetic reasons, the nodular portion was thus curetted. histopathologically, the nodule showed a widespread derma atrophy (b) with large sheets of epithelioid cells at the junction (c); cytomorphologically, dermal melanocytes were epithelioid but devoid of true ‘spitzoid’ features (d). the excision specimen showed a bland junctional proliferation of spindle cells (e), which were clearly different from epithelioid melanocytes of the previously curetted nodule (f). histopathological diagnosis: melanoma according to ackerman’s classification [8]; spitzoid melanoma according to barnhill’s classification, 2006 [19]. our histopathological diagnosis was pediatric spitzoid melanoma (melanoma over a spitz nevus). the dermoscopic differential diagnosis between pyogenic granuloma and nodular melanoma is virtually impossible; nevertheless, histopathologically we have never seen a pyogenic granuloma associated with a melanocytic nevus. (copyright: ©2015 ferrara et al.) 52 editorial | dermatol pract concept 2015;5(1):6 the suggested management for both pediatric-type and adult-type spitzoid melanoma is obviously the same as for “conventional” melanoma. conclusions the introduction of dermoscopy has significantly changed the clinical diorama of spitzoid lesions. since there are still many controversial points in the histopathologic categorization of these lesions, clinicopathologic correlation must be the mainstay for their diagnosis and proper management. references 1. darier fj, civatte a. naevus ou naevo-carcinoma chez on nourisson? bull soc franc dermatol syphilol 1910;21:61–3. 2. pack gt. pre-pubertal melanoma of the skin. surg gynecol obstet 1948;86:374-75. 3. spitz s. melanoma of childhood. am j pathol 1948;24:591-609. 4. kernen ja, ackerman lv. spindle cell nevi and epithelioid cell nevi (so-called juvenile melanomas) in children and adults: a clinicopathologic study of 27 cases. cancer 1960;13:612-25. 5. smith kj, barrett tl, skelton hg 3rd, lupton gp, graham jh. spindle cell and epithelioid cell nevi with atypia and metastasis (malignant spitz nevus). am j surg pathol 1989;13:931-39. 6. barnhill rl, flotte tj, fleischli m, perez-atayde a. cutaneous melanoma and atypical spitz tumors in children. cancer 1995;76:1833-45. 7. barnhill rl, argenyi zb, from l, et al. atypical spitz nevi/tumor: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. hum pathol 1999;30:513-20. 8. mones jm, ackerman ab. “atypical” spitz’s nevus, “malignant” spitz’s nevus, and “metastasizing” spitz’s nevus: a critique in historical perspective of three concepts flawed fatally. am j dermatopathol 2004;26:310-33. 9. casso em, grin-jorgensen cm, grant-kels jm. spitz nevi. j am acad dermatol 1992;27:901-13. 10. wiesner t, he j, yelensky r, et al. kinase fusions are frequent in spitz tumors and spitzoid melanomas. nat commun 2014;5:3116. 11. ferrara g, de vanna a. f1000prime recommendation of gerami p et al’s histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up. am j surg pathol 2014, 38(7):934-40, 15 jul 2014. website. f1000prime.com. doi: 10.3410/f.718306130.793497130. f1000prime.com/71830 6130#eval793497130 12. ferrara g, zalaudek i, savarese i, scalvenzi m, argenziano g. pediatric atypical spitzoid neoplasms. a review with emphasis on ‘red’ (‘spitz’) tumors and ‘blue’ (‘blitz’) tumors. dermatology 2010;220:306-10. 13. ludgate mw, fullen dr, lee j, et al. the atypical spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. cancer 2009;115:631. 14. lallas a, kyrgidis a, ferrara g, et al. atypical spitz tumours and sentinel lymph node biopsy: a systematic review. lancet oncol 2014;15:e178. 15. ferrara g, argenziano g, soyer hp, et al. the spectrum of spitz nevi: a clinicopathologic study of 83 cases. arch dermatol 2005;141;1381-87. 16. ferrara g, zalaudek i, argenziano g. spitz nevus: an evolving clinicopathologic concept. am j dermatopathol. 2010;32:410-14. 17. ferrara g, gianotti r, cavicchini s, et al. spitz nevus, spitz tumor, and spitzoid melanoma: a comprehensive clinicopathologic overview. dermatol clin 2013;31:589-98. 18. cerroni l, barnhill r, elder d, et al. melanocytic tumors of uncertain malignant potential: results of a tutorial held at the xxix symposium of the international society of dermatopathology in graz, october 2008. am j surg pathol 2010;34:314-26. 19. barnhill rl. the spitzoid lesion: the importance of atypical variants and risk assessment. am j dermatopathol 2006;28:75-83. 20. da forno pd, fletcher a, pringle jy, saldanha gs. understanding spitzoid tumours: new insights from molecular pathology. br j dermatol 2008;158:4-14. 21. pizzichetta ma, talamini r, stanganelli i, et al. amelanotic/ hypomelanotic melanoma: clinical and dermoscopic features. br j dermatol 2004;150:1117-24. 22. moscarella e, zalaudek i, cerroni l, et al. excised melanocytic lesions in children and adolescents—a 10-year survey. br j dermatol 2012;167;368-73. 23. urso c. a new perspective for spitz tumors? am j dermatopathol 2005;27:364-65. 24. zembowicz a, scolyer ra. nevus/melanocytoma/melanoma: an emerging paradigm for classification of melanocytic neoplasms? arch pathol lab med 2011;135:300-6. 25. brunetti b, nino m, sammarco e, scalvenzi m. spitz naevus: a proposal for management. j eur acad dermatol venereol 2005;19:391. 26. argenziano g, zalaudek i, ferrara g, lorenzoni a, soyer hp. involution: the natural evolution of pigmented spitz and reed nevi? arch dermatol 2007;143:549-51. 27. ferrara g, moscarella e, giorgio cm, argenziano g. spitz nevus and its variants. in: soyer hp, argenziano g, hoffmannwellenhof r, johr r (eds). color atlas of melanocytic lesions of the skin. berlin-heidelberg: springer-verlag 2007:151-163. 28. scalvenzi m, francia mg, palmisano f, costa c. long term clinical and dermoscopic follow-up of a child with a spitz nevus. open j ped 2012;2:253-6. 29. magro cm, yaniv s, mihm mc. the superficial atypical spitz tumor and malignant melanoma of the superficial spreading type arising in association with the superficial atypical spitz tumor: a distinct form of dysplastic spitzoid nevomelanocytic proliferation. j am acad dermatol 2009;60:814-23. 30. leboit pe. what do these cells prove? am j dermatopathol 2003;25:355-6. 31. ferrara g, errico me, donofrio v, zalaudek i, argenziano g. melanocytic tumors of uncertain malignant potential in childhood: do we really need sentinel node biopsy? j cutan pathol 2012;39:1049-51. 32. jones el, jones ts, pearlman nw, et al. long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel node biopsy result. jama surg 2013; 16:1-6. 33. pol-rodriguez m, lee s, silvers dn, celebi jt. influence of age on survival in childhood spitzoid melanoma. cancer 2007;109:157983. 34. gerami p, scolyer ra, xu x, et al. risk assessment for atypical spitzoid melanocytic neoplasms using fish to identify chromosomal copy number aberrations. am j surg pathol 2013;37:676-84. http://www.ncbi.nlm.nih.gov/pubmed?term=pizzichetta%20ma%5bauthor%5d&cauthor=true&cauthor_uid=15214897 http://www.ncbi.nlm.nih.gov/pubmed?term=talamini%20r%5bauthor%5d&cauthor=true&cauthor_uid=15214897 http://www.ncbi.nlm.nih.gov/pubmed?term=stanganelli%20i%5bauthor%5d&cauthor=true&cauthor_uid=15214897 http://www.ncbi.nlm.nih.gov/pubmed/22428965 http://www.ncbi.nlm.nih.gov/pubmed/22428965 http://www.ncbi.nlm.nih.gov/pubmed/23388126 http://www.ncbi.nlm.nih.gov/pubmed/23388126 http://www.ncbi.nlm.nih.gov/pubmed/23388126 dermatology: practical and conceptual 22 letter | dermatol pract concept 2019;9(1):6 dermatology practical & conceptual case presentation a 26-year-old man presented with a 6-month history of distortion of the right thumbnail and crusting under the nail. on examination, there was yellowish discoloration of the nail along with subungual hyperkeratosis with hemorrhagic spots visible through the nail plate (figure 1). dermoscopy (heine delta 20t, polarized, 16×) of the nail plate showed yellowish white irregular discoloration of the nail bed along with broad, dark red clods suggestive of hemorrhage (figure 2a), while that of the hyponychium showed yellowish brown keratotic areas with horizontal and vertical fractures, multiple dark red and black dots, some of which had white halo (figure 2b). histopathology showed hyperkeratosis, parakeratosis, papillomatosis, acanthosis, hemorrhage in the stratum corneum, and prominent keratohyalin granules compatible with a diagnosis of subungual wart. conclusions onychoscopy is a recent real-time diagnostic aid in the diagnosis of benign and malignant nail disorders and shows characteristic features of a specific dermatosis. subungual wart can be seen on dermoscopy as thick adherent whiteyellow scales, fissures, and dotted dilated vessels (with intermingled hemorrhagic dots) which may be surrounded by a white halo [1,2]. it can be readily differentiated from other subungual pathologies on dermoscopy such as subungual exostosis or infective conditions such as onychodermoscopy of subungual wart sweta subhadarshani1, jayati sarangi2, kaushal k. verma1 1 department of dermatology and venereology, all india institute of medical sciences, new delhi, india 2 department of pathology, all india institute of medical sciences, new delhi, india key words: dermoscopy, wart, nail, onychoscopy citation: subhadarshani s, sarangi j, verma kk. dermoscopy of subungual wart. dermatol pract concept. 2019;9(1):22-23. doi: https:// doi.org/10.5826/dpc.0901a06 published: january 31, 2019 copyright: ©2019 subhadarshani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sweta subhadarshani, md, department of dermatology and venereology, all india institute of medical sciences, ansari nagar, new delhi 110049, india. email: shweta.aiims07@gmail.com figure 1. yellowish discoloration of nail; subungual hyperkeratosis and hemorrhagic spots visible through nail plate. [copyright: ©2019 subhadarshani et al.] letter | dermatol pract concept 2019;9(1):6 23 references 1. piccolo v, argenziano g, alessandrini am, russo t, starace m, piraccini bm. dermoscopy of subungual exostosis: a retrospective study of 10 patients. dermatology. 2017;233(1):80-85. 2. piraccini bm, bruni f, starace m. dermoscopy of non-skin cancer nail disorders. dermatol ther. 2012;25(6): 594–602. mycosis, which can result in subungual hyperkeratosis. subungual exostosis shows hyperkeratosis, vascular ectasia, and ulceration, while onychomycosis shows a jagged edge of the proximal margin of the onycholytic area with sharp structures (spikes) directed to the proximal fold and aurora borealis pattern. figure 2. (a) dermoscopy (heine delta 20t, polarized, 16×) of nail plate shows yellowish white irregular discoloration of nail bed along with broad, dark red clods (black arrow) suggestive of hemorrhage. (b) dermoscopy (heine delta 20t, polarized, 16×) of hyponychium shows yellowish brown keratotic areas with horizontal and vertical fractures (red arrow), multiple dark red and black dots (black arrow), some of which have white halo. [copyright: ©2019 subhadarshani et al.] a b dermatology: practical and conceptual 228 letter | dermatol pract concept 2019;9(3):15 dermatology practical & conceptual introduction the wide spectrum of insect-induced cutaneous manifestations ranges from localized irritant contact dermatitis to life-threatening anaphylactic reaction, with morphology and severity being dependent on the involved subset of insects. burrowing bugs have generally been considered harmless to humans, excepting anecdotal reports of inflammatory plaques [1]. recently, a peculiar pattern of tiny pigmented macules caused by cydnidae insects was described [1]. in this case report, the clinico-dermoscopic features of such pigmentation encountered in an adult indian woman. case presentation a 42-year-old woman, head chef of a restaurant centered in a heavily vegetated pasture, presented with an asymptomatic cluster of tiny brown macules in a streaky pattern over the dorsomedial aspect of the left forefoot (figure 1a) that had developed 1 week previously, during the monsoon season in north india. her workplace dress included the chef hat, long polythene gloves for hands and forearms, and perforated rubber clogs as footwear. her coworkers admitted developing similar evanescent lesions over the forearms. the patient admitted having observed a few winged, low-flying insects in her kitchen that became more noticeable with the onset of the monsoons. dermoscopy revealed a healthy pink background with a cluster of numerous oval to bizarre-shaped shiny brown globules, clods, and a few granules that demonstrated a superficial “stuck-on” appearance (figure 1b). after firmly rubbing with acetone, the lesions nearly disappeared clinically (figure 2a), and dermoscopy revealed that the majority of pigmented structures had disappeared with only a few residual globules and clods (figure 2b). suspecting pigmentation due to insects of cydnidae family, the author procured 2-3 insects from the restaurant that a medical entomologist confirmed to be chilocoris assmuthi breddin, 1904. a final diagnosis of cydnidae pigmentation (cp) was made. conclusions to the author’s knowledge, this is the second report of cp and the first to show dermoscopic features. as recently described in 3 index cases by malhotra et al [1], cp presents with superficial staining of the human skin produced dermoscopy of cydnidae pigmentation: a novel disorder of pigmentation sidharth sonthalia1 1 skinnocence: the skin clinic & research centre, gurugram, india key words: dermoscopy, pigmentation, cydnidae, arthropod, chilocoris, swab test citation: sonthalia s. dermoscopy of cydnidae pigmentation: a novel disorder of pigmentation. dermatol pract concept. 2019;9(3):228229. doi: https://doi.org/10.5826/dpc.0903a15 accepted: january 23, 2019; published: july 31, 2019 copyright: ©2019 sonthalia. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: sidharth sonthalia, md, dnb, mnams, skinnocence: the skin clinic & research centre, c-2246, sushant lok-1, block-c, gurugram-122009, india. email: sidharth.sonthalia@gmail.com letter | dermatol pract concept 2019;9(3):15 229 the abrupt appearance of asymptomatic pigmented macules can be perplexing. although dermatitis neglecta, postinflammatory hyperpigmentation following viral exanthems, lentigines, and pigmented purpuric dermatoses constitute differentials, the clinical clues for suspicion of cp in this case were abrupt onset, rainy season, involvement of exposed area, lesions affecting workplace contacts, bizarre and streaky configuration of macules, and removal with acetone swab. dermoscopy may confirm the diagnosis with the cluster of oval to bizarre-shaped brown and shiny globules and clods with a superficial “stuck on” appearance. references 1. malhotra ak, lis ja, ramam m. cydnidae (burrowing bug) pigmentation: a novel arthropod dermatosis. jama dermatol. 2015;151(2):232-233. 2. lis ja. burrower bugs of the old world: a catalogue (hemiptera: heteroptera: cydnidae). genus (wrocław). 1999;10(2):165-249. by secretions of the burrowing bug chilocoris spp (family, cydnidae; order, hemiptera; suborder, heteroptera; superfamily, pentatomoidea). the species implicated in the first report and in this case was the same: chilocoris assmuthi breddin, 1904 [1]. although the natural habitat of cydnidae is soil or sand [2], these insects are often seen in vegetation-rich areas and adjoining human dwellings with an apparent tendency to proliferate in rainy season. essentially harmless to humans, their odorous secretions can stain the human skin, producing oval to bizarre pigmented lesions, especially over exposed areas. the patient developed the clustered cydnidae pigmented macules over a small area of her left foot left exposed by a window in her footwear at that site. maturation of lesions over time leads to darkening of pigmentation. curiously, these macules can be rubbed off with acetone, but not with soap and water. if untouched, the pigment reportedly fades away over a week [1]. figure 1. cp in a 42-year-old chef: (a) over the medial aspect of right foot, with the inset showing close-up view of the pigmented macules with streaky and bizarre margins; and (b) dermoscopy revealing healthy pink background with a cluster of numerous oval to bizarre-shaped shiny brown globules, clods, and a few granules. the pigmented structures have a superficial “stuck-on” appearance (escope videodermoscope, polarized, ×20). [copyright: ©2019 sonthalia.] a b figure 2. after forceful manual swabbing with acetone-soaked gauze: (a) the pigmentation seems to have been almost completely “rubbed off”; and (b) dermoscopy revealing disappearance of the majority of pigmented structures with only a few residual globules and clods (escope videodermoscope, polarized, ×20). [copyright: ©2019 sonthalia.] a b dermatology: practical and conceptual review | dermatol pract concept 2018;8(2):6 89 dermatology practical & conceptual www.derm101.com noli me tangere noli me tangere, do not touch me, is a phrase from the bible. in the latin translation of the gospel according to john, jesus spoke those words to mary magdalene after his resurrection to prevent her from touching him. over the centuries, that phrase was transferred from the biblical tale to other spheres, such as sensitive issues that were dangerous to tackle, as in the novel noli me tángere by josé rizal, one of the national heroes of the philippines. the novel portrayed corruption and abuse by the spanish colonial government and the catholic church, and rizal was executed a few years after its publication for the crime of rebellion. in medicine, noli me tangere warned of touching malignant neoplasms, especially malignant melanoma for which noli me tangere became a synonym. in the screening for malignant melanoma—a critical assessment in historical perspective wolfgang weyers1 1 center for dermatopathology, freiburg, germany key words: melanoma, screening, overdiagnosis citation: weyers w. screening for malignant melanoma—a critical assessment in historical perspective. dermatol pract concept. 2018;8(2):89-103. doi: https://doi.org/10.5826/dpc.0802a06 received: november 6, 2017; accepted: december 19, 2017; published: april 30, 2018 copyright: ©2018 weyers. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: wolfgang weyers, md, center for dermatopathology, engelbergerstr. 19, 79106 freiburg, germany. tel. 01149761-31696; fax. 01149-761-39772. email: ww@zdpf.de screening for melanoma has been advocated for many years because early detection and excision have been regarded as the most important measure to lower mortality from that neoplasm. in the past decade, concern has been raised by epidemiologists that screening might result in excision chiefly of “inconsequential cancer,” i.e., melanomas that would never have progressed into life-threatening tumors, a phenomenon referred to by the misleading term “overdiagnosis.” without any firm evidence, that speculation has been embraced worldwide, and incipient melanomas have been trivialized. at the same time, efforts at early detection of melanoma have continued and have resulted in biopsy of pigmented lesions at a progressively earlier stage, such as lesions with a diameter of only 2, 3, or 4 mm. those tiny lesions often lack sufficient criteria for clinical and histopathologic diagnosis, the result being true overdiagnoses, i.e., misdiagnoses of melanocytic nevi as melanoma. this is especially true if available criteria for histopathologic diagnosis are diminuished even further by incomplete excision of lesions. the reliability of histopathologic diagnosis is far higher in excisional biopsies of lesions that were given some more time to develop changes that make them recognizable. biopsy of pigmented lesions with a diameter of 6 mm has been found to result in a far higher yield of melanomas. in addition to better clinical judgment, slight postponement of biopsies bears the promise of substantial improvement of the reliability of histopathologic diagnosis, and of alleviating true overdiagnoses. abstract 90 review | dermatol pract concept 2018;8(2):6 [5] four years later, lund and kraus alluded to nests at the dermo-epidermal junction of melanoma that were “often large, confluent, horizontally extended, and loosely cellular” [6]. in 1976, price, rywlin and ackerman advanced criteria for histopathologic diagnosis of melanoma “on the basis of proven metastases.” most of those criteria pertained to changes in the epidermis, such as “poor circumscription of the intraepidermal melanocytic component of the lesion with lateral extension of individual melanocytes” and “marked variation in shape and size of the melanocytic nests” [7]. in subsequent publications by ackerman, additional criteria were established, e.g., asymmetry and extension of melanocytes deep down adnexal epithelia [8]. those criteria not only enabled melanoma to be diagnosed at an early stage but also resulted in marked improvement of clinico-pathologic correlation. in 1952, martin swerdlow of chicago deplored the “recurring discrepancy between the clinical and pathologic diagnosis of nevus or pigmented mole.” of 57 lesions diagnosed clinically as melanoma, only 16 (28%) were said to be melanomas histopathologically, and of 27 melanomas diagnosed histopathologically, only 59% had been diagnosed clinically as melanoma [9]. because of new criteria for histopathologic diagnosis established in subsequent decades, the correct clinical diagnosis was confirmed far more often histopathologically, and the more dependable histopathologic diagnoses drew the attention of clinicians to clinical aspects of melanoma that had been neglected previously. in 1985, friedman, rigel, and kopf advanced the “abcd” rule for “early detection of malignant melanoma”: a for “asymmetry,” b for “border irregularity,” c for “color variegation,” and d for “diameter generally greater than 6 mm” [10]. those criteria were not very specific because they were also fulfilled, in moderate degree, by many melanocytic nevi. their sensitivity, however, was higher because most melanomas display irregularities in their general architecture, outline, and coloration, once having reached a diameter of 6 mm. more importantly, melanomas at that stage are nearly always thin and often still confined to the epithelium so that a simple excision results in permanent cure. the early detectability and treatability of melanoma prompted ackerman to demand in 1985 that “no one should die of malignant melanoma” [11]. introduction of screening for melanoma because of direct visibility and detectability at an early stage and usually slow growth, melanoma came to be viewed as a “model for cancer education and prevention” and an “ideal screening tumor” [12,13]. criteria for diseases qualifylate 19th century, any active treatment of melanoma was discouraged. for example, moriz kaposi cautioned that, “according to experience, extirpation even of the very first nodules cannot arrest further progress. hence, the procedure is carried out only rarely, and the very first symptom of pigmented cancer is regarded as an ominous sign of a rapidly deleterious course” [1]. in 1933, guido miescher noted that surgical treatment for melanomas was “more and more abandoned at least for primary tumors because the danger of acute dissemination is doubtlessly high, and cases with acute aggravation following surgical procedures have been observed repeatedly” [2]. as late as in the 1960s, those fears had not been overcome. as stated in gottron’s handbook of dermatalogy and venerology, “until recently, management followed the principle of ‘noli me tangere’ that regarded any therapeutic procedure as malpractice. today, treatment has entered an active stage but an agreed-upon therapeutic approach has not emerged” [3]. establishment of clinical and histopathologic criteria for recognition of incipient melanoma the last decades of the 20th century witnessed a radical paradigm shift. therapeutic restraints were replaced by the conviction that melanomas must be detected and exstirpated as early as possible, not as an exophytic nodule but as a tiny papule, not as a papule but as a macule. for decades, the macular stage of melanoma had been misinterpreted as a benign nevus that, according to accepted wisdom, underwent “malignant transformation” when a nodule of melanoma developed on it. for example, in 1953, allen and spitz described typical histopathologic signs of melanoma in situ, including: “(1) the general features of nuclear anaplasia such as hyperchromatism, increase in nuclear and nucleolar size, irregular nuclear vacuolization, and mitotic figures; (2) subepithelial inflammatory reaction consisting prepoderantly of lymphocytes; and (3) cytoplasmic vacuolization and fine melanin pigmentation reaching to the uppermost layers, that is, to the stratum granulosum and stratum corneum.” they concluded, nonetheless, that “the decision as to whether or not a given lesion is to be diagnosed an active junctional nevus or a melanocarcinoma must ... depend on this single fact: the presence or absence of dermal invasion” [4]. it took many years to realize that the vast majority of melanomas start in the anatomic structure that harbors melanocytes physiologically, namely, the epidermis, and that they can be recognized there. in a histopathologic study of melanoma in 1958, lane et al described melanoma in situ under the name “purely junctional malignant melanoma.” review | dermatol pract concept 2018;8(2):6 91 at primary prevention, i.e., prevention of the development of skin cancer, but also included efforts at secondary prevention, i.e., early detection and treatment. several other campaigns followed [18,19]. after a continuous rise in the incidence of age-specific melanoma for many decades, together, these campaigns likely were responsible for a decrease in the age-specific melanoma incidence in australia, the first country worldwide to note a decrease. however, those effects are still shrouded by an absolute increase in the number of detected melanomas due to demographic aging [20] (figure 1). the australian model was copied in the southern united states, where jack redman of albuquerque in 1977 started the new mexico melanoma project [21]. as in australia, the population was informed through leaflets and tv spots about the risks associated with uv exposure and the identifying features of melanoma. cartoon characters like “sid seagull” in australia and a mole in new mexico (reflecting the synonymous use of the word for pigmented lesions) targeted especially children and youth (figures 2, 3). in 1979, the skin cancer foundation was founded in new york city and it released a series of publications that alerted physicians and the laity to the danger of excessive exposure to ultraviolet light as the most important influenceable risk factor for melanoma and to criteria for early recognition of melanoma in a booklet titled, the many faces of malignant melanoma and a leaflet about the “abcds of moles & melanomas” (figure 4). the rising incidence of melanoma also led to efforts at prevention and early detection in other countries with a predominantly fair-skinned population. for example, in 1982, a skin cancer comic book distributed in hawaii resulted in a more reserved attitude toward sun exposure [22]. similar effects were seen in sweden and england following educational campaigns ing for screening procedures had been formulated by wilson and jungner in a “public health paper” of the world health organization in 1968, namely: “(1) the condition sought should be an important health problem. (2) there should be an accepted treatment for patients with recognized disease. (3) facilities for diagnosis and treatment should be available. (4) there should be a recognizable latent or early symptomatic stage. (5) there should be a suitable test or examination. (6) the test should be acceptable to the population. (7) the natural history of the condition, including development from latent to declared disease, should be adequately understood. (8) there should be an agreed policy on whom to treat as patients. (9) the cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. (10) case-finding should be a continuing process and not a ‘once and for all’ project” [14]. those criteria were subsequently supplemented and specified: the disease must have serious consequences and a high prevalence in order to justify screening efforts, and it must progress slowly and not be immediately life threatening [15,16]. all those conditions are fulfilled by melanoma. by that time, the first campaigns for prevention and early detection of melanoma were already under way. in 1963, neville davis of princess alexandra hospital in brisbane started the “queensland melanoma project,” a clinical and histopathologic study with long-term follow-up of patients and an associated public campaign for melanoma prevention [17]. because of the high prevalence of skin cancer among the fair-skinned population exposed to a tropical climate, australia pioneered efforts at skin cancer prevention. in 1981, the cancer council of victoria started the “slip! slop! slap!” campaign (“slip on a shirt! slop on a sunscreen! slap on a hat!”) that aimed figure 1. poster of the sydney melanoma unit in the 1990s. figure 2. “sid seagull” as a teacher of cautious sun exposure in the australian “sunsmart” campaign. figure 3. “getting to know your moles”. first american publication for melanoma education by the new mexico melanoma project in the late 1970s. 92 review | dermatol pract concept 2018;8(2):6 [33]. when patients with early-stage melanomas came to consultation hours following the first german melanoma campaign in giessen in the early 1980s, they were said to “probably owe their life to the campaign” [25], and this [23, 24]. in germany, the giessen melanoma group started an educational campaign in 1980, referring to melanoma as “black cancer” and “a wolf in sheep’s clothing” [25] (figure 5). those activities were pursued at a national level by the commission for early detection and prevention of skin cancer that was founded in 1987 [26]. in addition to educational efforts in numerous brochures and leaflets, the commission inaugurated a oneyear pilot study of population-based skin cancer screening in the state of schleswig-holstein that began in 2003 aimed at “preponing the point of diagnosis as far as possible... through population-based, area-wide skin cancer screening, in order to reduce morbidity and mortality and costs in the health care system” [27]. eventually, 19% of the population made use of the offer of free screening examinations, leading to a rise in the incidence of melanoma of about one third and to a significant reduction in mortality after five years. the results of that study contributed to the decision to implement populationbased skin cancer screening in germany. since mid-2008, free skin cancer screening is offered to all adults over 34 years of age every two years under the scope of public health insurances [28]. most studies about melanoma screening failed to detect a positive effect on mortality, and in germany, the positive trend could not be substantiated in follow-up studies [29]. however, mortality remained at least relatively stable despite a marked increase in the incidence of melanoma. the latter was attributed to factors such as greater sun exposure during recreational activities, use of solariums, travel to tropical countries, and depletion of the ozone layer of the stratosphere [28,30,31]. in the united states, an increase in the incidence of melanoma between 1975 and 2010 of almost 200% contrasted with an increase of only 32% in mortality [32]. that discrepancy was perceived as a success of cancer screening was probably true for some of them. the conclusion seemed obvious: if one succeeded at detecting an even higher percentage of melanoma at an early stage, this would eventually lead to a decrease in mortality. figure 4. “the abcds of moles & melanomas”. leaflet of the american skin cancer foundation in 1985. figure 5. “fight against black cancer”. leaflet of the giessen melanoma group in the mid 1980s. review | dermatol pract concept 2018;8(2):6 93 [45]; the “menzies method” that considered symmetry and monochromacity to be exclusion criteria for melanoma [46]; a “7-point checklist” with three major and four minor criteria [47]; a simplified “3-point checklist” [48]; and the cash algorithm that emphasized the importance of “color, architecture, symmetry, and homogeneity” for the assessment of melanocytic neoplasms [49]. moreover, dermatoscopy enabled assessment of the development of lesions by following their natural course—far more precise a technique than conventional clinical examination or anamnestic data [50]. irrespective of the recognition scheme, dermatoscopy has the potential of enhancing the sensitivity and specificity of clinical diagnosis of melanoma substantially. however, it requires some experience, and without it, it may lead to undesired results [51]. in order to overcome subjectivity and lack of experience in the assessment of dermatoscopic images, computer-based evaluation programs have been developed. computers with deep convolutional neural networks trained by thousands of images and corresponding diagnoses have been found to reach a performance that matches the level of experienced dermatologists [52,53]. such programs may assist especially in the laborious evaluation of images obtained by total body photography in patients with myriad pigmented lesions [54]. additional techniques employed to enhance precision in clinical diagnosis include confocal laser microscopy that enables high resolution imaging of the epidermis and upper dermis down to the level of individual cells, optical coherence tomography with lower resolution but greater depth of penetration, electrical impedance spectroscopy that provides a score for the cellular irregularity of the skin based on electrical conductivity of the tissue, and multispectral analysis that involves illumination of the skin with different wavelength and likewise results in the computation of a score for structural irregularity [55]. especially if used in combination, these techniques enhance the precision of the clinical diagnosis of melanoma (figure 6a-c). specificity and, especially, sensitivity have been claimed to exceed 90% with these techniques. those numbers, however, have little significance because they depend strongly on the experience of the investigator and, especially, on the type of lesions examined. at very early stages, diagnosis is far less precise than in more advanced lesions, no matter which technique is employed. increase in the number of biopsies the rationale for the use of adjunctive techniques for clinical diagnosis is the desire to reduce the frequency of biopsies for suspicious pigmented lesions. in fact, numerous studies have demonstrated a decrease in biopsies following dermatoscopic assessment of pigmented lesions. however, some studies also improvement of methods for early clinical recognition of melanoma those considerations led to enhanced efforts at early detection of melanoma. the latter included not only educational campaigns and screening examinations but also improvement of clinical diagnosis. clinical examination of the skin by a trained physician fulfilled the screening requirement of “a suitable test or examination ... acceptable to the population” [14], but sensitivity and specificity were limited; most studies revealed a sensitivity of about 80% and a specificity of about 70% [34-36]. the abcd criteria were criticized because many nevi and seborrheic keratoses fulfilled them, and they did not encompass the early stage of nodular melanomas [37]. for the latter, change of a pigmented lesion was the most important identifying feature. this led to supplementation of the abcd rule by another letter, namely, “e” for “enlargement,” “elevation,” or “evolving.” the latter term came to be preferred because it included any type of change [38]. in order to detect changes of moles in patients with myriad pigmented lesions, total body photography was introduced in 1988, rendering possible a comparison with the previous state at each new consultation [39]. in addition to the abcde rule, other formulas were advanced for clinical detection of melanomas, such as the “three cs” (“color, contour, change”) or the “glasgow 7-point checklist” of 1990 that included, as major criteria, change in size, change in shape, and change in color, along with four minor criteria, namely, diameter ≥ 7 mm, inflammation, crusting or bleeding, and sensory change [40]. because of its more complex nature, the “7-point checklist” did not become as popular and widely used as the abcde rule [41]. a criterion not pertaining to the individual lesion is the “ugly duckling sign.” first described in 1998, the sign implies that a pigmented lesion differing from all other lesions of a given patient is likely to be a melanoma [42]. the importance of that “intrapatient comparative analysis” has been substantiated by several studies [43]. in addition to refinement of criteria for clinical diagnosis of melanoma, several technical advances enhanced precision of diagnosis. most important was the introduction of the dermatoscope that enabled the surface of lesions to be studied in ten-fold magnification and with reduced scatter of light (application of fluid enables immediate contact of the lens to the skin surface). hence, anatomic structures could be assessed down to the papillary dermis, and the distribution of pigment and vessels could be assessed far better than by the naked eye. among the criteria established for dermatoscopy were assessment of different dermatoscopic patterns in “pattern analysis” [44]; the “abcd rule of dermatoscopy” that assessed asymmetry, borders, coloration, and “different structural components” according to a point rational scheme 94 review | dermatol pract concept 2018;8(2):6 has resulted in a significant decrease of biopsy rates [60]. on the other hand, if a lesion shows changes during follow-up, this alone may prompt a biopsy to be performed— although less than 10% of changing lesions have been found to be melanomas [61]. the number of nevi excised for each melanoma has been referred to as the “number needed to treat” and varies significantly in different studies; in a recent review numbers ranged between 4 and 29.9 [62]. the lower numbers may reflect the ratio in specialized centers but, in general, the higher numbers are probably closer to reality. in our own material, i.e., specimens examined in a big dermatopathology laboratory in germany under the conditions of population-based skin cancer screening, the “number needed to treat” was 36.4 in three successive months of 2016. epidemiologists are right to deplore that “biopsy samples are taken from hundreds of thousands of benign lesions ... in addition to needless morbidity, these interventions cost billions of dollars” [63]. the substantial increase in biopsies was associated not only with an increase in the number of excised nevi but also of melanomas. the latter paralleled the rise in biopsies. for example, in the united states, the number of biopsies increased between 1986 and 2001 by 154% and the number reported the opposite, namely, an increase in the number of lesions found to be suspicious dermatoscopically, compared to examination of them with the naked eye, that were found to be nevi histopathologically [56]. likewise, data for confocal laser microscopy are contradictory. some studies reported a significant decrease in biopsy rates [57], whereas others found that the enhanced sensitivity of diagnosis of melanoma was associated with a decrease in specificity that resulted in biopsy of melanocytic nevi [58]. the same obtains for multispectral analysis [59]. one reason may be the occasional presence in nevi of changes normally indicating malignancy, such as melanocytes in the upper reaches of the epidermis that are an expected finding in irritated nevi and in nevi on “special sites” such as palms and soles. histopathologic examination allows those findings to be assessed in the context of many other criteria that helps to avoid overdiagnoses. in contrast, melanocytes in the upper reaches of the epidermis found by confocal laser microscopy result in the lesion being classified as suspicious and selected for biopsy. lack of change of a lesion during follow-up indicates benignancy because melanocytic nevi are very stable once they have reached the stage of senescence. accordingly, follow-up of patients with myriad pigmented lesions through total body photography figure 6a-c. clinical, dermatoscopic, and confocal microscopic presentation of lentigo maligna demonstrating the potential of adjunctive techniques in the clinical diagnosis of melanoma (courtesy of harald kittler, vienna). a b c review | dermatol pract concept 2018;8(2):6 95 mas that would never have been noticed had they not been biopsied, implies the assumption that such melanomas also existed in the past without being treated and without resulting in higher morbidity and mortality. there are two possible explanations for that assumption. first, patients could have died of other causes before being bothered by their melanoma. considering the advanced age of many patients with melanoma, that explanation is plausible. however, it does not explain the rise in the incidence of melanoma in children and young adults. if there were also melanomas in that age group that were never diagnosed and that never caused any trouble, they must have regressed spontaneously [68]. the second explanation, spontaneous regression, is also plausible considering the common occurrence of that phenomenon in melanoma. most melanomas are associated with a marked inflammatory cell infiltrate as an expression of an immunologic response to them. that response often leads to partial regression of the neoplasm. in the center or, more often, at the edge of melanomas, melanocytes are diminished in number or absent entirely and, as a result of the preceding inflammatory process, the papillary dermis is fibrotic and contains melanophages and blood vessels with prominent endothelia arranged perpendicularly to the skin surface. if there are numerous melanophages, zones of regression are difficult to distinguish clinically from other areas of the neoplasm, whereas cases with marked fibrosis of the papillary dermis and few melanophages present themselves as poorly pigmented or whitish zones. histopathologically, signs of regression may be apparent readily but may also be very subtle, sometimes consisting of nothing but slight fibrosis with an occasional melanophage. those subtle signs of regression can be overlooked easily and may result in recurrences of the primary tumor in cases in which the latter seems to have been removed completely with a generous margin. if regression continues, it may lead to complete disappearance of the neoplasm. according to the literature, no primary melanoma can be detected in 2 to 8% of all metastasizing melanomas [69], a phenomenon caused most commonly by complete regression of it. if advanced melanomas that have caused metastases regress so often, how much more common must be complete regression in early melanomas that have not metastasized and that will never be noticed, unless a biopsy is taken prior to their complete disappearance [68]? the latter circumstance has become much more common because of efforts to detect them early-on; when confronted with melanomas in nearly complete regression, one sometimes wishes that the clinician had postponed his biopsy by half a year (figure 7a-c). that some melanomas “would never have developed into a clinically manifest tumour” is beyond dispute [67]. however, to attribute the rise in the incidence of melanomas entirely to that phenomenon is just as one-sided as the tale of melanomas by 140% [63]. the parallel increase in biopsies and melanomas raised doubts concerning the tale of a “melanoma epidemic” that had been accepted wholesale for many years. the “incredibly rising incidence of malignant melanoma” [64] suddenly seemed to be incredible. a moderate rise in the incidence could be expected, if only because of increased longevity, but the dramatic increase seemed to be artificial and could be explained by a variety of other factors, such as increased reporting of melanomas to tumor registries and more reliable criteria for histopathologic diagnosis [65]. in the old literature, there are scores of pictures of clear-cut melanoma misdiagnosed as melanocytic nevus. if lesions had been excised in toto and had not metastasized, patients would have never learned that they had been afflicted by a potentially life threatening neoplasm. misleading use of the term “overdiagnosis” most melanomas accountable for the rise in incidence were lesions at an early stage. formerly celebrated as a triumph of cancer screening, that fact suddenly raised doubts concerning the expedience of it. in 2005, welch and coworkers noted that “the incidence of melanoma is associated with biopsy rates. that the extra cases diagnosed were confined to early stage cancer while mortality remained stable suggests overdiagnosis—the increased incidence being largely the result of increased diagnostic scrutiny and not an increase in the incidence of disease” [66]. the term “overdiagnosis” was not employed as in the traditional meaning of misdiagnosis. a new definition of that term had been advanced by epidemiologists in 1989 for breast cancer, namely, “a histologically established diagnosis of invasive or intraductal breast cancer that would never have developed into a clinically manifest tumour during the patient’s normal life expectancy if no screening examination had been carried out” [67]. although highly prone to be misunderstood, that definition has been embraced by epidemiologists worldwide and has been extended to all types of cancer. the definition, however, refers to a statistical variable exclusively and not to neoplasms in the real world because patients may outlive their “normal life expectancy” and nobody knows in advance whether or not an “invasive or intraductal ... cancer ... would ... have developed into a clinically manifest tumour” [67]. failure of melanoma to develop into a “clinically manifest tumor” the hypothesis that the rise in the incidence of melanoma is caused primarily by “inconsequential cancer,” i.e., melano96 review | dermatol pract concept 2018;8(2):6 cytic nevi [50]. a study of 50 incipient melanomas followed dermatoscopically demonstrated a mean growth rate of 5.3 mm2 per year [72]. following incomplete removal of melanomas, recurrences are common, probably even the rule, a characteristic that caused melanomas to become the most frequent source of medical malpractice suits in the united states [73]. curtailment of screening for a potentially life threatening tumor nonetheless, the hypothesis that the increased incidence of melanoma is “largely the result of increased diagnostic scrutiny and not an increase in the incidence of disease” [66] has found wide acceptance and has resulted in demands to curtail diagnostic scrutiny. in recent years, it has been suggested by epidemiologists that “screening guidelines should be revised to lower the chance of detection of ... inconsequential cancers with the same energy traditionally used to increase the sensitivity of screening tests” [63]. the cost of population-based screening for melanoma has been criticized, and it is estimated that 25,000 screening examinations are necessary to prevent a single death from melanoma, whereas other cancers show a far more favorable ratio, of a true “melanoma epidemic.” obviously, various factors play a role: an increase in detection and treatment melanomas that would have progressed and caused death in the absence of treatment, an increase in melanomas that would have remained “inconsequential” without such measures, and a real rise in the incidence of melanoma. that the latter exists is suggested by an increase in the number of thick melanomas in populations not participating in cancer screening [70]. moreover, only a real rise in the incidence of melanoma explains the sustained high mortality rates because it is fallacious to assume that excision of many more melanomas at an early stage has no beneficial effect at all. after all, we are not entirely ignorant about how melanomas behave biologically. although, for obvious ethical reasons, there have been no long-term prospective studies concerning their natural biologic course; experience of many decades suggests that melanomas, irrespective of stage, tend to progress. photokatamnestic studies of patients with advanced melanomas demonstrated their slow but inexorable growth over many years [71]. dermatoscopic follow-up studies of suspicious lesions that eventually proved to be melanoma demonstrated their slow but continuous expansion and a behavior of growth that differed clearly from that of melanoa b c figure 7a. exophytic melanoma in nearly complete regression. neoplastic cells have given way to granulation tissue in the exophytic nodule and to superficial fibrosis adjacent to it. in the nodule, small aggregations of neoplastic cells have remained. [copyright: ©2018 weyers.] figure 7b. a dense lichenoid infiltrate of lymphocytes is present beneath remnants of epithelioid melanoma cells with pronounced nuclear atypia. beneath the infiltrate, neoplastic cells have been substituted by granulation tissue. [copyright: ©2018 weyers.] figure 7c. in the periphery, only moderate fibrosis of the papillary dermis with dilated, thick-walled blood vessels, some colloid bodies, and a few melanophages signify that the melanoma was once far larger. [copyright: ©2018 weyers.] review | dermatol pract concept 2018;8(2):6 97 of an oxymoron” [79], and juan rosai, in 2008, spoke of it as an “obsolete, untenable concept” [80]. although clark himself had been among the first to emphasize that most melanomas do not arise in association with a nevus, that “the junction nevus has no formal histogenetic relationship to malignant melanoma,” and that “most malignant melanomas pass through a long phase of superficial growth during which the process differs in appearance from junctional nevi” [81], he subsequently presented melanoma as a model for the theory of multistep carcinogenesis, according to which malignant neoplasms arise from “precursor lesions” through accruing genetic alterations and came “to view melanocytic neoplasia as a paradigm for all neoplastic systems” [82]. in 1984, clark and coworkers postulated a stepwise “tumor progression” from the “common acquired melanocytic nevus” via nevi with increasing “melanocytic dysplasia” to primary and metastatic melanoma. the “dysplastic nevus” was said to be the “histogenetic precursor of melanoma,” and early stages of melanoma, including thin invasive lesions, were claimed not to be fully malignant because the authors “hypothesized that such tumors do not have competence for metastases,” the latter being conferred to them through additional genetic alterations that launched melanoma into the “vertical growth phase” [82]. incipient melanomas that fulfilled all histopathologic criteria for diagnosis were no longer diagnosed as melanoma but as nevi with “severe dysplasia” in order to adhere to the concept of tumor progression through successive “precursor lesions” [83]. that old concept has been reanimated recently by the demonstration of mutations shared by melanocytic nevi and melanomas, with additional mutations accumulating in the course of melanoma development. in principle, each and every mutation among the many hundreds detectable in advanced melanomas may be viewed as a new step of tumor progression, but the genetic findings were interpreted in accordance with concepts of the 1980s. once again, melanoma in situ was said not to be malignant. together with “intermediate lesions,” including dysplastic nevi, it was referred to as a “precursor lesion” and was distinguished explicitly from melanoma [84]. some authors even contended that in-situ melanomas are biologically distinct from invasive melanoma and that they are a different type of neoplasm affecting other age groups and different anatomic sites, and “not in themselves ... precursor lesions, but perhaps ... instead markers for increased risk of development of invasive melanomas” [85]. the tendency to deny the malignant nature of incipient melanomas coalesced with speculations concerning “overdiagnosis” of melanoma in precarious fashion—precarious because it may be dangerous to trivialize melanoma in situ. in-situ melanomas are no less melanomas than the same type of lesion at a slightly later stage. their appearance, clinically and histopathologically, is identical to the macular component of advanced melanomas, e.g., only 800 examinations are necessary arithmetically to prevent one fatality in colon carcinoma [74]. accordingly, it has been suggested that screening be confined to individuals with an enhanced risk of developing melanoma, such as those with myriad nevi and a family history of melanoma; however, most melanomas occur in patients not belonging to such risk groups. the importance of screening also depends on the level of knowledge of melanoma in the population. if the risk associated with an unsual or changing mole is known, and patients with such a lesion would attend a physician anyhow, regular screening is less effective because it results in only slight preponement of the time of diagnosis and treatment. hence, “shortening the delay in the diagnosis by intensifying education and screening of the whole population may not lead any longer to a strong improvement of prognosis” [75]. in fact, numerous studies have shown that the majority of melanomas are self-detected or detected by family members [76-78]. because of direct visibility, screening for skin lesions is less urgent than for neoplasms such as colon carcinoma that cannot be noticed at an early stage by patients themselves. denial of the malignant nature of melanoma at an early stage the unhesitant acceptance of the speculation that the rise in melanoma incidence is caused primarily by removal of basically harmless lesions, and the dominant role that speculation acquired, in the absence of any sound evidence, in subsequent debates about screening can be explained only by its coincidence with another development commencing at that time, namely, a renaissance of concepts in dermatopathology that seemed to have been overcome. by acknowledging that most criteria for histopathologic diagnosis of melanoma pertain to changes in the epidermis, diagnosis of melanoma had become possible at the in situ stage. although diagnosis may be difficult at that stage, it is straightforward and undisputable in cases in which all criteria are fulfilled, including asymmetry; poor circumscription by solitary melanocytes; uneven distribution of solitary melanocytes, nests, and pigment; focal predominance of solitary melanocytes over nests; variation in size and shape of nests; and presence of pagetoid melanocytes in all reaches of the epidermis. however, melanomas detected at that stage are still harmless biologically; in the new terminology of epidemiologists, they qualify as “indolent cancer” or “inconsequential cancer.” it is the very purpose of screening to detect and to remove “inconsequential” lesions in order to prevent them from becoming “consequential.” nonetheless, the logic of screening was turned upside-down by arguing that melanoma in situ cannot cause death and, therefore, is not malignant. for example, clark, in 1990, referred to melanoma in situ as “a contradiction in terms, the prototype 98 review | dermatol pract concept 2018;8(2):6 [88]. there is no marker that allows one to predict future behavior reliably, and such as marker will probably never emerge because behavior is not only determined by the lesion itself but by many unrelated factors, such as the immune response to it. in patients of advanced age, it may be justifiable to ignore a melanoma, but it is risky if one cannot gauge how much lifetime they have left. to count on spontaneous regression of melanoma in young and middle-aged patients would be negligent. the problem of “true” overdiagnosis: misdiagnosis of nevi as melanoma in addition to death of patients from other causes and complete regression, there is yet another explanation for “melanomas” that “would never have developed into a clinically manifest tumour,” namely, overdiagnosis—not “overdiagnosis” by epidemiologists but overdiagnosis in the traditional meaning of that term, i.e., misdiagnosis of melanocytic nevi as melanoma. such overdiagnoses probably contribute substantially to the alleged rise in the incidence of melanoma [89,90]. although diagnosis of melanoma is usually reliable thanks to numerous well-established criteria, there are exceptions. among them are melanocytic neoplasms in which criteria are conflicting, such as spitz’s nevi which are usually symmetrical and sharply circumscribed but harbor melanocytes with pronounced nuclear atypia in all reaches of the epidermis. depending on the degree of those changes, distinction from melanoma may be extremely difficult. the same is true for nevi “in special sites,” such as acral skin or genitalia, that may display features normally indicating malignancy, such as pronounced confluence of nests and melanocytes above the junction. in addition to those problems of differential diagnosis caused by conflicting criteria, there are problems caused by lack of criteria. the latter have become much more common in recent years and are more relevant for the problem of overdiagnosis. one of the chief reasons for that detrimental development are efforts to detect and remove melanomas as early as possible. more and more biopsies are being performed in lesions measuring only 2, 3, or 4 mm in diameter. clinically, those lesions present themselves as a dark-brown or black macule that does not allow for a clear distinction between nevus and melanoma because it was not given the time to develop features that make it recognizable. dermatoscopy and confocal laser microscopy may reveal more distinctive features, but those adjunctive techniques also reach their limits in lesions of that size. because a clear-cut distinction between a nevus and a melanoma is often impossible in such lesions, the latter are biopsied, and histopathologists are confronted with the same problem: the lesions did not have enough time to develop features crucial for histopathologic differential diagnosis, just and the morphologic correlates of biologic behavior—from high cellularity to uneven distribution of cells, extension of melanocytes deep down adnexal epithelia, and scatter of them through all levels of the epidermis—suggest that the decisive steps in cancerogenesis responsible for the malignant nature of the lesion have already occurred even if many additional clinical, histopathologic, and molecular changes may follow as the lesion progresses (figure 8). lesions may also regress, but occasional regression of incipient melanomas does not militate against malignancy; spontaneous regression has also been reported in cases of melanoma with disseminated metastases [86]. in early lesions, that phenomenon is doubtlessly more common, but experience suggests that complete regression is an exception rather than the rule. at an early stage, there is usually no urgency in diagnosis, and lesions can be followed clinically for some time until the diagnosis can be made with confidence. however, at least in young patients, one cannot expect untreated melanomas to remain “inconsequential” for their lifetime. and even if a substantial share of melanomas currently detected early on would remain “inconsequential,” early diagnosis and treatment cannot be discarded as superfluous as long as the future course cannot be foretold. although epidemiologists have demanded “to focus on distinguishing indolent from aggressive disease” [87] and to reserve the designation “cancer” for “lesions with a reasonable likelihood of lethal progression if left untreated” [32], no prescription has been offered on how to accomplish this. even welch conceded that “the conundrum in overdiagnosis is that clinicians can never know who is overdiagnosed at the time of cancer diagnosis” figure 8. melanoma in situ fulfilling all criteria for malignancy, namely, high cellularity, irregular size and form of nests, irregular distribution of nests and of solitary melanocytes, focal predominance of solitary melanocytes over nests, and many melanocytes in the upper reaches of the epidermis. this is melanoma and not a “precursor,” irrespective of whether or not additional step sections reveal some melanocytes in the papillary dermis. [copyright: ©2018 weyers.] review | dermatol pract concept 2018;8(2):6 99 of melanoma in situ: pathologists employed different criteria for diagnosis in different areas of the country [92]. in a study of melanomas measuring 4 mm in diameter or less, only half were unanimously diagnosed as melanoma upon review by each of three dermatopathologists. the authors suggested adopting “a ‘consensus diagnosis’ approach among histopathologists, because these lesions have no true gold standard” [93]. incomplete excision as an important cause of overdiagnosis of melanoma the reliability of histopathologic diagnosis is diminished even further if lesions are not excised completely because, in that as an embryo at an early stage does not allow for distinction between male and female or between mouse and man. for example, one criterion for malignancy, focal predominance of solitary melanocytes over nests, cannot be employed if nests have not yet formed. likewise, poor circumscription by solitary melanocytes rather than nests is a criterion for malignancy, but if there are no nests, it is fulfilled by all melanocytic lesions (figure 9a-d). it is not surprising, therefore, that the reliability of histopathologic diagnosis in small pigmented lesions is poor. a larger study with a participation of 187 american pathologists found that “diagnoses of melanoma in situ and early stage invasive melanoma ... were neither reproducible nor accurate” [91]. a study from austria revealed marked regional differences in the diagnosis a b c d figure 9a. small melanocytic neoplasm measuring 2 mm in diameter. at this early stage, a definite clinical distinction between clark’s nevus and melanoma in situ is not yet possible because, in the latter instance, the lesion did not have enough time to develop features indicating malignancy, such as an irregular border or irregular distribution of pigment. [copyright: ©2018 weyers.] figure 9b. the lesion was removed. histopathologically, it is composed of solitary melanocytes only. predominance of solitary melanocytes over nests is a criterion for malignancy that cannot be applied to such early lesions. [copyright: ©2018 weyers.] figure 9c. the regular distribution for solitary melanocytes is in favor of benignancy. however, presence of numerous melanocytes above the basal layer in the absence of signs of irritation is unusual for a melanocytic nevus. a melanoma in situ cannot be excluded with confidence. [copyright: ©2018 weyers.] figure 9d. the lesion was probably excised completely, but it comes close to one lateral margin. incomplete excision cannot be excluded. if this is a nevus, excision of it qualifies as “overtreatment” in the first place. because a melanoma in situ cannot be ruled out, and the lesion may have been excised incompletely, a re-excision was performed, probably “double overtreatment.” [copyright: ©2018 weyers.] 100 review | dermatol pract concept 2018;8(2):6 excision. not uncommonly, only fragments of epithelium are provided. the most likely explanation for that phenomenon is a low degree of suspicion on the part of clinicians because lesions of that size also lack clinical criteria for malignancy. with a lesion considered to be probably benign, physicians may flinch from taking a generous biopsy and may attach greater importance to a favorable cosmetic result. furthermore, the generous execution of biopsies—with biopsies being taken from lesions measuring only 2 or 3 mm in diameter—often leads to removal of many lesions and attempts to perform biopsies as simply and quickly as possible. the diligence attached to each biopsy, and the appraisal of the importance of diligence, are lower than with a more reserved approach. diagnosed “too early” in other words, the formula of “the earlier, the better” that has replaced the old conviction of noli me tangere cannot be accepted without reservation. there is also such a thing as “too early” in which an active approach may be detrimental, rather than beneficial. linking the indication for biopsy to the old abcd rule for clinical recognition of melanoma has been suggested recently. in a retrospective analysis of lesions biopsied under the clinical suspicion of melanoma, “lesions larger than 6 mm in size had higher positive predictive value,” and restriction of biopsies to those lesions would result in a substantial reduction of the “number needed to treat” [94]. additional advantages not noted in that study include a substantial improvement of the reliability of histopathologic diagnosis and, possibly, greater diligence in performing the biopsy, again resulting in specimens easier to evaluate. the incidence of melanomas smaller than 6 mm in diameter that have already invaded the dermis is not precisely known. several studies suggest that about one-third of such small melanomas possess a dermal component. the latter, however, is nearly always superficial so that a simple excision results in permanent cure in the vast majority of patients [93,95,96]. recent studies suggest that the delay in diagnosis caused by clinical observation of vaguely suspicious lesions of small diameter has no significant effect on the thickness of lesions at the time of biopsy and, therefore, is unlikely to affect prognosis [97,98]. there are rare exceptions of fatal small melanomas, but in the latter cases, lesions usually show a different biologic behavior from the outset: they often grow rapidly and present themselves as a small, firm papule that may not be pigmented clinically. because of those qualities, such melanomas are usually not detected at an early stage [74], and they often evade screening efforts and are noticed by patients themselves as “interscreening cancers.” scrutiny for melanoma should focus on those case, additional criteria for diagnosis cease to be available, such as symmetry and circumscription. unfortunately, partial biopsies are becoming more and more common. despite demands that incisional biopsies should be performed only for distinction of melanocytic from non-melanocytic neoplasms, and not for distinguishing nevi from melanomas, they are being performed indiscriminately for all kinds of melanocytic neoplasms by an ever increasing number of dermatologists; in the united states, most melanomas are currently diagnosed on the basis of partial biopsies. this course of action reduces the dependability of diagnosis substantially and cannot be corrected by subsequent re-excision because most re-excision specimens show no or only small remnants of the neoplasm that defy meaningful interpretation. moreover, the previous procedure may result in signs of irritation, such as presence of melanocytes above the junction, impeding diagnosis even more. incomplete excisions with a markedly reduced chance of correct diagnostic interpretation may be the most important cause of overdiagnosis. the reason is the disparity in the consequences of an incorrect diagnosis. if a benign lesion is misinterpreted as malignant, the mistake is hardly ever uncovered, whereas a malignant lesion misinterpreted as benign may recur and, in addition to damage to the patient, may have a legal aftermath for the histopathologist. in cases lacking sufficient criteria for diagnosis, this is a strong incentive to err on the malignant side [89,90]. of course, histopathologists may choose to acknowledge uncertainty and abstain from a specific diagnosis. in general, however, there is no fallback for them, as for clinicians who, in the case of doubt, perform a biopsy and delegate responsibility to the histopathologist. traditionally, histopathology is considered to be the “gold standard” for the diagnosis of neoplasms. in the past decades, numerous studies have shown how far from “gold” this standard is. nonetheless, despite many limitations, histopathology is better suited to fulfill that role than other techniques, although clinical or dermatoscopic findings may be more revealing in individual cases. histopathologic diagnosis of a neoplasm is only rarely overruled by other considerations. having the last word, histopathologists are pressed to offer a final conclusion, usually in the form of a clear-cut diagnosis. if the latter is not provided, they must at least utter some judgment leading, most often implicitly, to a suggestion concerning management of the patient. in the case of doubts being spelled out, the consequences are usually identical to those produced by a diagnosis of malignancy, such as a re-excision, and the emotional burden for the patient is comparable. overdiagnoses and evasive diagnoses are most common in very small lesions. the reason, in addition to diagnostically important features not yet having emerged, is the disproportionate number of inappropriate biopsies of those lesions that, in principle, should be those most suitable for complete review | dermatol pract concept 2018;8(2):6 101 conceptual. 2002;8:4. https://www.derm101.com/dpc-archive/ october-december-2002-volume-8-no-4/dpc0804a12-criteriafor-diagnosis-of-melanoma-histopathologically-in-historicalperspective/. accessed november 6, 2017. 9. swerdlow m. nevi; a problem of misdiagnosis. am j clin path. 1952;22:1054-1060. 10. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin. 1985;35:130-151. 11. ackerman ab. no one should die of malignant melanoma. j am acad dermatol. 1985:12:115-116. 12. robinson wa. malignant melanoma as a model for cancer education and prevention. 1989 harvey lecture american association for cancer education. j cancer educ. 1990;5:85-89. 13. paul e. das melanom – ein idealer vorsorgetumor. bayer ärztebl. 2004;7-8:400-402. 14. wilson j, jungner g. principles and practice of screening for disease. geneva: world health organization. 1968: 26f. 15. cole p, morrison as. basic issues in population screening for cancer. j natl cancer inst. 1980;64:1263-1272. 16. mcdonald cj. status of screening for skin cancer. cancer. 1993;72:1066-1070. 17. davis nc, herron jj. queensland melanoma project: organization and a plea for comparable surveys. med j aust. 1966;1:643644. 18. marks r. two decades of the public health approach to skin cancer control in australia: why, how and where are we now? australas j dermatol. 1999; 40: 1-5. 19. montague m, borland r, sinclair c. slip! slop! slap! and sunsmart, 1980-2000: skin cancer control and 20 years of population-based campaigning. health educ behav. 2001;28:290-305. 20. whiteman dc, green ac, olsen cm. the growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. j invest dermatol. 2016;136:1161-1171. 21. redman jc, mora db. malignant melanoma of the skin diagnosed and treated in albuquerque, new mexico, in 1980. j dermatol surg oncol. 1982;8:40-43. 22. putnam gl, yanagisako kl. skin cancer comic book: evaluation of a public educational vehicle. cancer detect prev. 1982;5:349356. 23. boldeman c, jansson b, holm le. primary prevention of malignant melanoma in a swedish urban preschool sector. j cancer educ. 1991;6:247-253. 24. hughes br, altman dg, newton ja. melanoma and skin cancer: evaluation of a health education programme for secondary schools. br j dermatol. 1993;128:412-417. 25. illig l, paul e, hundeiker m. [public and professional melanoma education. a german model for improved early detection of melanomas by journalistic methods—based on corrected views on melanoma and nevus]. z hautkr. 1983;58:73-112. 26. breitbart ew, christophers e. arbeitsgemeinschaft dermatologische prävention (adp) e.v. j dtsch deratol ges. 2014; 12 (suppl. 4):42 27. greinert r, volkmer b, wende a, et al. prävention von hautkrebs. notwendigkeit, durchführung und erfolg. hautarzt. 2003;54:1152-1163. 28. breitbart ew, waldmann a, nolte s, et  al. systematic skin cancer screening in northern germany. j am acad dermatol. 2012;66:201-211. lesions, and if a small, rapidly growing firm papule is noted, it should be biopsied without delay, especially if pigment can be detected dermatoscopically, even if it is smaller than 6 mm in diameter [99,100]. there may also be other reasons to deviate from the rule to refrain from biopsies in lesions smaller than 6 mm in diameter. if dermatoscopy, confocal laser microscopy or other techniques reveal findings highly suggestive of malignancy, histopathologic evaluation is warranted. in such cases, however, histopathologists should be alerted to the high degree of suspicion because histopathologic criteria for malignancy may drag behind clinical ones. as long as histopathologic examination serves as a gold standard for diagnosis of melanocytic neoplasms, and very small melanomas “have no true gold standard” histopathologically in a substantial proportion of cases [93], biopsy of small pigmented lesions should not be the rule but an exception. if clinicians follow pigmented lesions until they develop obvious signs of malignancy or reach a diameter of 6 mm, the reliability of histopathologic diagnosis can be improved substantially. moreover, a less generous approach to biopsy might result in more diligence devoted to that procedure, further enhancing the reliability of diagnosis. by allowing pigmented lesions to play themselves out until they reach a stage that makes 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mcpherson m, elwood jm, aitken jf. the relationship between melanoma thickness and time to diagnosis in a large population-based study. arch dermatol. 2006;142:1422-1427. 98. rosina p, tessari g, giordano mv, girolomoni g. clinical and diagnostic features of in situ melanoma and superficial spreading melanoma: a hospital based study. j eur acad dermatol venereol. 2012;26:153-158. 99. menzies sw, moloney fj, byth k, et al. dermoscopic evaluation of nodular melanoma. jama dermatol. 2013;149:699-709. 100. cicchiello m, lin mj, pan y, mclean c, kelly jw. an assessment of clinical pathways and missed opportunities for the diagnosis of nodular melanoma versus superficial spreading melanoma. australas j dermatol. 2016;57:97-101. 67. peeters phm, verbeek alm, straatman h, et al. evaluation of overdiagnosis of breast cancer in screening with mammography: results of the nijmegen programme. int j epidemiol. 1989;18:295-299. 68. weyers w. the ‘epidemic’ of melanoma between underand overdiagnosis. j cutan pathol. 2012;39:9-16. 69. savoia p, fava p, osella-abate s, et al. melanoma of unknown primary site: a 33-year experience at the turin melanoma centre. melanoma res. 2010;20:227-232. 70. linos e, swetter sm, cockburn mg, colditz ga, clark ca. increasing burden of melanoma in the united states. j invest dermatol. 2009;129:1666-1674. 71. paul e. wachstumsdynamik maligner melanome. fortschr med. 1989; 107: 97-102. 72. beer j, xu l, tschandl p, kittler h. growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings. dermatol pract concept. 2011;1(1): 59-67. 73. rayess hm, gupta a, svider pf, et al. a critical analysis of melanoma malpractice litigation; should we biopsy everything? laryngoscope. 2017; 127:134-139. 74. gilmore s. melanoma screening: informing public health policy with quantitative modelling. plos one. 2017;12(9):e0182349. 75. richard ma, grob jj, avril mf, et al. melanoma and tumor thickness: challenges of early diagnosis. arch dermatol. 1999;135:269274. 76. richard ma, grob jj, avril mf, et al. delays in diagnosis and melanoma prognosis (i): the role of patients. int j cancer. 2000;89:271-279. 77. carli p, de giorgi v, palli d, et al. self-detected cutaneous melanomas in italian patients. clin exp dermatol. 2004; 29: 593-596. 78. lee kb, weinstock ma, risica pm. components of a successful intervention for monthly skin self-examination for early detection of melanoma: the “check-it-out” trial. j am acad dermatol. 2008;58:1006-1012. 79. clark wh jr, malignant melanoma in situ. hum pathol. 1990;21:1197-1198. 80. rosai j. [lecture]. melanoma in situ: an attractive, obsolete, untenable concept. graz: 29th symposium of the international society of dermatopathology, oct 4, 2008. 81. clark wh jr, from l, bernardino ma, mihm mc. the histogenesis and biologic behavior of primary human malignant melanomas of the skin. cancer res. 1969;29:705-727. 82. clark wh jr, elder de, guerry d iv, epstein mn, green mh, van horn m. a study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. hum pathol. 1984;15:1147-1165. 83. reed rj, clark wh jr, mihm mc. premalignant melanocytic dysplasias. in: ackerman ab (ed.) pathology of malignant melanoma. new york: masson. 1981:159-183. 84. shain ah, yeh i, kovalyshyn i, et al. the genetic evolution of melanoma from precursor lesions. n engl j med. 2015;373:19261936. untitled note | dermatol pract concept 2015;5(2):18 95 dermatology practical & conceptual www.derm101.com is the early introduction of dermatology beneficial? students are presented with vast amounts of medical information prior to clinical training. students learn anatomy of the body, physiology of the heart, and the inner workings of the nervous system. yet, dermatology has become an increasingly overlooked aspect of medical school curricula in the preclinical years. many schools fail to offer a dermatology course, and those that do often fail to adequately prepare primary care residents for treating basic dermatologic disease [1]. these shortfalls in medical education should no longer be ignored since more than 3.5 million skin cancers are treated annually in the united states at an estimated cost of over 8.1 billion dollars [2,3]. on july 29, 2014, the united states surgeon general issued a landmark call to action to prevent skin cancer, calling it a major public health problem [3]. medical schools should meet the challenge and provide an appropriate dermatology curriculum for students to reduce future morbidity, mortality, and healthcare associated cost from skin cancer. academic dermatologists and other clinical staff members in partnership with the american academy of dermatology (aad) can play a pivotal role in educating future physicians by developing creative ways to engage preclinical students (table 1). a recent article in the journal of the american academy of dermatology (jaad) highlighted the positive impact that performing a skin biopsy on a cadaver had on first-year medical students [4]. this self-directed exercise aptly named “the cadaveric skin biopsy project” (csbp) simulated skin biopsy specimen collection and provided a realistic setting for students to learn basic skin histology [4]. faculty, residents, and histotechnologists at the university of west virginia school of medicine assisted with skin lesion identification, biopsy, slide preparation, and diagnosis. although the csbp requires a multidisciplinary approach and presents practical challenges, it could be integrated into a preclinical dermatology curriculum and serve as a valuable introduction to clinical skin examination. this would allow preclinical students a chance to identify and describe skin lesions, perform biopsies, and practice proper handling of tissue [4]. the majority of students demonstrated a positive response to the way the csbp impacted their appreciation of dermatology, performance of dermatologic procedures, understanding of benign versus malignant skin lesions, and awareness of the skills necessary to work effectively in teams [4]. another study by hansra et al asked primary care residents if their medical school understanding the importance of dermatology training in undergraduate medical education jenny e. murase1 1 department of dermatology, palo alto foundation medical group, mountain view, california, usa citation: murase je. understanding the importance of dermatology training in undergraduate medical education. dermatol pract concept 2015;5(2):18. http://dx.doi.org/10.5826/dpc.0502a18 copyright: ©2015 murase. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: jenny e. murase, md, department of dermatology, palo alto foundation medical group, 701 east el camino real (31-104), mountain view, ca 94040, usa. tel. 650 934 7676; fax. 650 934 7696. e-mail: jemurase@gmail.com table 1. proposed curriculum and timeline for medical student dermatology training suggested activity suggested timeline cadaver skin biopsy project preclinical medical student training dermatology seminar course preclinical medical student training aad online basic dermatology curriculum modules clinical medical student training 2-week required clerkship clinical medical student training 96 note | dermatol pract concept 2015;5(2):18 riculum into a two-week dermatology rotation for fourth-year medical students [11]. all participants enhanced their dermatology knowledge (p < .001), and most students found the modules worth their time (93%) and easy to navigate (95%) [11]. all respondents also supported the continuation of the modules as part of the fourth-year dermatology clerkship [11]. despite the results, there was no control group in the study, and more research must be done to draw definitive conclusions. early didactic and clinical exposure of dermatology in the medical school setting may heighten a future physician’s awareness of challenges in dermatology. the aad’s online curriculum for medical students should be considered a compulsory component of undergraduate medical education that may assist learners in developing a differential diagnosis and a well-rounded approach to skin problems. hopefully, this will achieve the goal of early accurate diagnosis and treatment to reduce overall morbidity and mortality of skin disease. references 1. hansra nk, o’sullivan p, chen cl, berger tg. medical school dermatology curriculum: are we adequately preparing primary care physicians? j am acad dermatol. 2009 jul;61(1):23-29.e1. 2. rogers, hw, weinstock, ma, harris, ar, et al. incidence estimate of nonmelanoma skin cancer in the united states, 2006. arch dermatol 2010; 146(3):283-7. 3. u.s. department of health and human services. the surgeon general’s call to action to prevent skin cancer. washington, dc: u.s. dept of health and human services, office of the surgeon general, 2014. 4. baker mg, bradley eb, mccollum ma, russell ma. the cadaveric skin biopsy project: description and student evaluation of an innovative approach to dermatology instruction in the preclerkship medical school curriculum. j am acad dermatol. 2014 aug;71(2):314-9. 5. mcclesky p, gilson r, devillez r. medical student core curriculum in dermatology. chicago: dermatology teachers exchange group; 2007. 6. fleischer a, herbert c, feldman s, o’brien f. diagnosis of skin disease by nondermatologists. am j manag care 2000;6:1149-56. 7. steele k. primary dermatological care in clinical practice. j r coll gen practice. 1984 jan; 34(258):22-3. 8. lowell ba, froehlich cw, federman dg, kirsner rs. dermatology in primary care: prevalence and patient disposition. j am acad dermatol 2001 aug; 45(2):250-5. 9. clayton r, perera r, burge s. defining the dermatological content of the undergraduate medical curriculum: a modified delphi study. br j dermatol 2006;155:137-44. 10. the aamc project on the clinical education of medical students: clinical skills education, 2005. retrieved from www.aamc.org/ initiatives/clinical skills/ 11. cipriano sd, dybbro e, boscardin ck, shinkai k, berger tg. online learning in a dermatology clerkship: piloting the new american academy of dermatology medical student core curriculum. j am acad dermatol. 2013 aug;69(2):267-72. training in dermatology was inadequate, appropriate, or excessive in preparation for residency [1]. less than 40% of primary care residents felt that their medical school curriculum adequately prepared them to diagnose and treat common skin disorders, but the study only looked at family practice and internal medicine from a few geographic locations [1]. primary care residents were also asked to compare their knowledge of dermatologic disease to other commonly taught diseases, and it was determined that dermatology was not adequately taught when compared to asthma and diabetes [1]. this reflects a need to increase the amount of curricular time devoted to dermatology in comparison to other content areas [1,5]. there were several areas of dermatology that primary care residents believed were sufficiently taught. these areas included • melanoma/moles, • atopic dermatitis/contact dermatitis • non-melanoma skin cancer/sun damage • herpes simplex/zoster • urticaria/hives • psoriasis/seborrhea • acne/rosacea, and warts there were several topics that primary care physicians (pcps) identified as very important in their practices, but which residents deemed inadequately taught in their medical school dermatology curricula. these include • skin infections • leg ulcers/wound care • cutaneous drug eruptions • infestations • viral exanthems • vasculitis/purpura • connective tissue disease • alopecia, and • hiv dermatology these topics should be prioritized in dermatology curricula and further implemented into the aad’s online curriculum for medical students. some medical schools do not require a dermatology rotation during the third or fourth year, even though dermatologic complaints account for 5 to 8.2% of all primary care visits [6,7], and a study by lowell et al found that 35.5% of patients who presented to primary care had at least one skin problem [8]. residents who completed a dermatology rotation as students were more likely to report that vasculitis, connective tissue disease, and alopecia were adequately taught during medical school [1]. clinical skills taught in medical school should include shave biopsy, punch biopsy, and cryotherapy, since more than 60% of pcps perform one or more of these procedures routinely [9,10]. another recent publication in the jaad sought to determine the impact of the integration of the aad’s online curdermatology: practical and conceptual dermatology practical & conceptual www.derm101.com granuloma annulare has been associated with systemic disease including diabetes mellitus. we report a case of a 62-year-old japanese woman with generalized erythematous granuloma annulare who showed remission after substantial improvement in hyperlipidemia following a strict lipid-lowering diet. the lesion appeared in the lower abdomen one year before current presentation and subsequently spread to other areas of the trunk despite treatment with topical steroid and oral epinastine hydrochloride. physical examination showed a well-demarcated erythematous plaque measuring 10 cm in diameter with fine scales on the left abdomen, and slightly indurated pinkish plaques of up to 5 cm in diameter on the right side of the abdomen and axillae. clinical laboratory tests showed mild glucose intolerance (hba1c 6.2%), mild liver dysfunction (ast: 86 iu/l, alt: 76 iu/l), slight hypercholesterolemia (total cholesterol: 235 mg/dl), and severe hyperlipidemia (triglyceride: 962 mg/ml). histopathological examination of the lesions showed homogenization of collagen fibers and granulomatous infiltrates between fibers in the upper and middle dermis. a diagnosis of generalized erythematous granuloma annulare was established based on the clinical and histopathological findings, especially with the distribution on more than one anatomic site. a lipid-lowering diet for three months resulted in major improvement of hyperlipidemia and remission of the skin lesions. a review of generalized erythematous granuloma annulare in the japanese literature indicated a wellknown association of granuloma annulare with diabetes mellitus, however, the relation with hyperlipidemia was described only recently. this case suggests a possible relationship between granuloma annulare and hyperlipidemia, with possible improvement of granuloma annulare with a lipid-lowering diet. abstract observation | dermatol pract concept 2014;4(1):17 97 remission of generalized erythematous granuloma annulare after improvement of hyperlipidemia and review of the japanese literature soko watanabe1, masaru tanaka1 ken kobayashi1, mizuki sawada1 sumiko ishizaki1, koji tsurui3, mariko fujibayashi2 1 departments of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of pathology, tokyo women’s medical university medical center east, tokyo, japan 3 tsurui clinic of internal medicine3, tokyo, japan key words: generalized erythematous granuloma annulare, glucose intolerance, hyperlipidemia citation: watanabe s, tanaka m, kobayashi k, sawada m, ishizaki s, tsurui k, fujibayashi m. remission of generalized erythematous granuloma annulare after improvement of hyperlipidemia and review of the japanese literature. dermatol pract concept. 2014;4(1):17. http://dx.doi.org/10.5826/dpc.0401a17 received: june 18, 2013; accepted: july 23, 2013; published: january 31, 2014 copyright: ©2014 watanabe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: soko watanabe, md, department of dermatology, tokyo women’s medical university medical center east, 2-1-10 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: soko1031@yahoo.co.jp 98 observation | dermatol pract concept 2014;4(1):17 laboratory tests showed hba1c 6.2% (normal: 4.3-5.8), aspartate aminotransferase (ast) 76 iu/l (normal: 5-40), alanine aminotransferase (alt) 258 iu/l (normal: 5-35), total cholesterol (t-chol) 235 mg/dl (normal: 110-210), and triglyceride 962 mg/dl (normal: 55-129) (table 1). histopathological examination of biopsy material obtained from the left and right abdomen and stained with hematoxylin and eosin (h&e) showed similar changes, including homogenized but poorly stained collagen fibers and granulomatous infiltration of histiocytes, lymphocytes and giant cells between the fibers in the upper and middle dermis. histiocytes were also scattered among the collagen fibers (figure 2a). elasticavan-gieson staining showed diminished fractured elastic fibers, but no phagocytosis of giant cells. alcian-blue staining confirmed the presence of mucin deposition between collage fibers (figure 2b). immunostaining for cd68 demonstrated many histiocytes and langhans giant cells (figure 2c). a diagnosis of a generalized erythematous papular type of granuloma annulare was established based on the clinical and histopathological findings together with the distribution pattern of the lesion (on more than one anatomic site). treatment with topical diflorasone diacetate ointment was started. consultation with the department of internal medicine regarding glucose intolerance, liver dysfunction introduction granuloma annulare manifests various skin lesions, such as erythematous, plaque, papular, nodular and ulcerative forms, in addition to the typical annular lesion [1]. we report a case of generalized erythematous granuloma annulare with a remission after lipid-lowering diet. case presentation a 62-year-old japanese woman presented with itchy erythematous skin lesions on the left lower abdomen, the right side of the chest and both axillae. the family history was negative for similar skin lesions. the past history was negative apart from mild liver dysfunction on routine blood tests. the skin lesions were first noticed one year earlier, and subsequently spread to the chest and back in spite of treatment with topical steroid and oral epinastine hydrochloride. physical examination showed a well-demarcated erythema of approximately 10 cm in diameter with limited fine scales on the left lower abdomen (figure 1a). some of the macules on the chest and axillae measured up to 5 cm and were palpable pinkish erythemata surrounded by small red papules at the periphery (figure 1b, c). a b c figure 1. clinical photographs. note the presence of large erythematous plaque measuring 10 x 10 cm in diameter, with limited scaling and well-demarcated border on the left lower abdomen, surrounded by (a) several small erythemata. (b) erythemata up to 5 cm in diameter were seen on the right abdomen. (c) erythemata grouped into small red papules were seen in the axillae. [copyright: ©2014 watanabe et al.] observation | dermatol pract concept 2014;4(1):17 99 site [2]. the generalized form of granuloma annulare also tends to exhibit various types of skin lesions [3]. the present case demonstrated generalized skin lesions of erythematous type together with papular type. the frequency of the erythematous type is reported to be approximately 16%, and 14 japanese cases, including the present case, have been reported since 1966 [4-15]. the age distribution of the reported japanese cases ranged from 50 to 70, with no gender difference, with a distribution mainly on the extremities (table 2). the association of granuloma annulare with diabetes mellitus is well documented, together with other less frequent complications of autoimmune disorders and internal malignancy [14]. the association of granuloma annulare with dyslipidemia was recently reported [16]. in the study by wu et al, dyslipidemia was more common in generalized than localand hyperlipidemia was followed by a lipid-lowering diet for a period of three months. strict adherence to the latter resulted in marked improvement of hyperlipidemia. one month later, the skin lesions showed clear remission, together with improvement in laboratory data (table 1). discussion granuloma annulare often shows generalized distribution of the skin manifestations that cover more than one anatomic table 1. results of laboratory tests before and after lipid-lowering diet. initial visit at the end of lipid-lowering diet for 1 month 3 months aspartate aminotransferase (iu/l) 86 33 33 alanine aminotransferase (iu/l) 76 26 29 -glutamyl transpeptidase (iu/l) 267 252 243 total cholesterol (mg/dl) 235 281 294 triglyceride (mg/dl) 962 331 366 hba1c 6.2% 5.8% 5.8% a b c figure 2. histopathological findings. (a) a high power view of hematoxylin-eosin stained biopsy section showing infiltrates forming a granuloma composed mainly of histiocytes and giant cells intermingled with lymphocytes. (b) alcian-blue staining confirmed mucin deposition between collagen fibers. (c) immunostaining for cd68 demonstrated many histiocytes and giant cells. [copyright: ©2014 watanabe et al.] 100 observation | dermatol pract concept 2014;4(1):17 granuloma annulare and dermatologists should be aware of the relation between granuloma annulare and various internal diseases. we should also be aware of generalized lesions, which can be easily overlooked as non-specific skin lesions, and conduct skin biopsy to establish a definitive diagnosis. this case was presented at the 74th tokyo division meeting of the japanese dermatological association. references 1. katsuoka k et al. granuloma annulare in a patient with diabetes mellitus. [article in japanese]. hifubyo shinryo. 1989;11:35. 2. izumi h et al. two cases of non-annular type generalized granuloma annulare. [article in japanese]. rinsho hifuka. 1996;9:71921. 3. dicken ch, carrington sg, winkelmann rk. generalized granuloma annulare. arch dermatol. 1969;99(5):556-63. 4. nagai r et al. granuloma annulare. [article in japanese]. hifu rinsho. 1966;8:544. 5. miyake k el al. a case of generalized granuloma annulare. [article in japanese]. rinsho hifuka. 1969; 23:911. 6. sato y et al. generalized granuloma annulare. [article in japanese]. rinsho hifuka. 1970;24:353. 7. maumi f. atypical granuloma annulare. [article in japanese]. rinsho hifuka. 1969;23:1019. 8. shimada y. four cases of granuloma annulare. [article in japanese]. rinsho hifuka. 1974;28:685. 9. ogino a, tamaki e. atypical granuloma annulare. transition from erythema to multiple type. dermatologica. 1978;156(2):97. 10. araki t et al. generalized granuloma annulare with atypical clinical features. [article in japanese]. hifu rinsho. 1981;23:1789. 11. okusa y et al. erythematous granuloma annulare. [article in japanese]. hifu rinsho. 1986;28:359. 12. tsutsui k et al. a case of atypical granuloma annulare. [article in japanese]. hifu rinsho. 1989; 31:855. 13. ebihara t et al. a case of erythematous granuloma annulare. [article in japanese]. jpn j dermatol. 1991;101:900. 14. nakama t et al. a case of generalized form of atypical granuloma annulare. [article in japanese]. rinsho hifuka. 1998;52:337. 15. konohana i et al. a case of erythematosus granuloma annulare. [article in japanese]. rinsho hifuka. 1993;47:479. 16. wu w, robinson-bostom l, kokkotou e, jung hy, kroumpouzos g. dyslipidemia in granuloma annulare: a case-control study. arch dermatol. 2012;148(1):1131-6. ized/disseminated disease, and the annular lesion morphology was associated with hypercholesterolemia. our review of the japanese literature on generalized erythematous granuloma annulare showed that 6 out of 14 had glucose intolerance, 1 had rheumatoid arthritis, and 1 had internal malignancy. the distinct features of the present case were the following: 1) the skin lesions were mainly noted on the trunk, 2) high serum triglyceride level (962 mg/dl), 3) mild glucose intolerance, and 4) liver dysfunction. in this regard, there has been little information in the literature on hyperlipidemia in erythematous granuloma annulare. moreover, granuloma annulare often spontaneously resolves after a biopsy especially in the erythematous type [15]. the clinical improvement noted in the present case could have been triggered by the biopsy, topical application of the steroid ointment and/or beneficial changes in both glucose intolerance and hyperlipidemia following lipid-lowering diet. however, one cannot dismiss the possible involvement of hyperlipidemia in the activity of granuloma annulare. therefore, the presented case suggests the possible relationship between granuloma annulare and hyperlipidemia, with possible improvement of granuloma annulare by lipid-lowering diet. with the increased concern on adult lifestyle-related diseases in recent years, physicians need to pay attention to table 2. summary of japanese cases with generalized erythematous granuloma annulare reported in the literature between 1966 and 2013. age 49 – 92 (median 59.5) gender males 6, females 8 location trunk 7, arms 12, legs 11 complications diabetes mellitus 6, rheumatoid arthritis, 1, malignancy 1 treatments topical steroid 9, none 1 prognosis remission 5, partial remission 3, stable 3 dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):21 93 dermatology practical & conceptual www.derm101.com introduction tinea versicolor, also known as pityriasis versicolor, is a common cutaneous fungal infection characterized by superficial scaling and a mild disturbance of skin pigmentation. it classically presents as round to oval macules that can be hypopigmented, hyperpigmented, or erythematous (hence the name versicolor) and typically affects the chest, upper back, and shoulders. however, involvement of more unusual regions of the body such as the face and scalp, arms and legs, intertriginous sites, genitalia, areolae, and palms and soles [1-6] has been reported. this report details two cases observed at our institution in which the infection occurred in uncommon distributions. cases case 1 a 32-year-old asian woman presented with an asymptomatic, tan colored, scaly plaque over the left popliteal fossa (figure 1). she had no systemic complaints and her past medical history was unremarkable. at the time of the visit, she had been taking oral doxycycline for 1 month to treat folliculitis of the legs. potassium hydroxide (koh) prepauncommon presentations of tinea versicolor sowmya varada1, tushar dabade1, daniel s. loo1 1 tufts medical center, department of dermatology, boston, ma, usa keywords: tinea versicolor, pityriasis versicolor, malassezia, groin, flexures citation: varada s, dabade t, loo ds. uncommon presentations of tinea versicolor dermatol pract concept. 2014;4(3):21. http://dx.doi. org/10.5826/dpc.0403a21 received: april 11, 2014; accepted: may 11, 2014; published: july 31, 2014 copyright: ©2014 varada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sowmya varada, bs, department of dermatology, tufts medical center, 14th floor biewend building, 800 washington st., boston, ma 02111, usa. tel. 617-636-0156; fax. 617-636-8316. email: sowmya.varada@jefferson.edu tinea versicolor (tv) is a common cutaneous fungal infection characterized by superficial scaling and a mild disturbance of skin pigmentation. it typically affects the chest, upper back, and shoulders. however, involvement of more unusual regions of the body such as the face and scalp, arms and legs, intertriginous sites, genitalia, areolae, and palms and soles has been reported. this report details two such cases observed at our institution: a 32-year-old woman with involvement of the popliteal fossa and a 16-year-old boy with involvement of the groin. the clinician must be aware of these variations in location and perform the appropriate diagnostic workup when lesions have the characteristic morphology of tv despite an unusual location. the etiology, pathophysiology, and epidemiology of tv are reviewed and current literature describing other instances of tv in uncommon locations is discussed. abstract 94 observation | dermatol pract concept 2014;4(3):21 preparation of a lesion demonstrated yeast forms and short, septate, hyphal forms. he was subsequently treated with oral ketoconazole 400 mg once daily for 3 days, followed by ketoconazole 2% shampoo once a week for prophylaxis. discussion the incidence of tinea versicolor varies by season and geographic location and is likely underreported, but it is one of the most common superficial mycoses worldwide. prevalence ranges from as low as 1% in dry and temperate climates to 50% in the tropics [4]. the implicated pathogens are dimorphic saprophytes of the genus malassezia (formerly pityrosporum) currently comprising twelve known species, of which m. globosa, m. sympodialis, and m. furfur are the most commonly cultured [7]. the yeast forms, which exist commensally in the stratum corneum as part of human skin flora [4], are obligatorily lipophilic and therefore prefer regions of the body with the highest concentrations of sebaceous fatty acids such as the face, scalp, chest, and back [8]. development of the clinical disease requires conversion of the yeast into the pathogenic mycelial form, an event that is likely provoked by many factors including malnutrition, hyperhidrosis, oral contraceptive use, and an altered immune response (such as corticosteroid use, aids, and solid organ transplant).4 other risk factors for acquiring tv are: (1) age—the infection is most common in teens and young adults when sex hormones increase sebaceous secretions [9], (2) heat and humidity—it is more prevalent in tropical than temperate and dry regions, in the summer rather than winter, and in areas of the body covered by clothing [8], (3) use of topical oils which provide additional lipid substrate for yeast development [7], and (4) pregnancy. the disease is not contagious and factors such as gender, race, socioeconomic status, and skin hygiene are not implicated [4,7]. ration of the scaly plaque demonstrated spores and short hyphae (figure 2). the patient was treated with ketoconazole 2% cream once to twice daily for three weeks. case 2 a 16-year-old healthy caucasian boy presented with a 1-year history of a mildly pruritic truncal rash that, over the past 3 months, had spread over the arms, legs, and groin. the lesions consisted of 1-2 cm salmon colored, round to oval, scaly papules coalescing into plaques (figure 3). in the past, he was treated with an unknown prescription cream and selenium sulfide shampoo, which did not resolve the infection. koh figure  2. potassium hydroxide (koh) preparation demonstrating spores and short hyphae. [copyright: ©2014 varada et al.] figure 3. multiple 1-2 cm salmon colored, round to oval, thin scaly plaques over the groin and medial thighs. [copyright: ©2014 varada et al.] figure 1. multiple tan plaques with fine scale over the posterior left popliteal fossa. [copyright: ©2014 varada et al.] observation | dermatol pract concept 2014;4(3):21 95 the largest single institution studies analyzing the anatomical distributions of tv show that the vast majority of infections involve the same locations. of 25 patients from the united kingdom, roberts et al. [10] found the chest, upper back, shoulders, upper arms, and abdomen to be the most commonly affected. in this study, the two most frequently involved nonclassical locations were the scalp and groin, affecting 25% and 19% of patients respectively [11]. in a similar analysis of 47 patients studied by bumgarner et al. [11], only two did not exhibit the classic distribution of trunk or upper arm involvement. it is unclear which factors predispose to the development of tinea versicolor in nonclassical distributions. case series and reports have further described these associations. tinea versicolor of the flexures, as seen in one of our patients, is not entirely uncommon. aljabre et al. reported an 11.8% (13 of 110 patients) incidence of flexural involvement at their institution but no statistically significant correlation with age, sex, immune status, infection duration, or infection relapse rate. they also noted that of flexures, the axillary vault and inguinal crease were the least frequently involved and were often spared even in cases of widespread infection [5,12] however, another report describes two cases solely affecting the axillae and inguinal regions respectively [2]. several case reports have described a total of ten instances of tinea versicolor involving the penis including nine involving the penile shaft and one involving the glans [13-17]. two of these occurred in renal transplant recipients receiving systemic immunosuppression [13,14], but the rest have involved healthy males lacking any of the above-mentioned risk factors other than age and geographic location. all of the reported cases were accompanied by extensive involvement of the chest, back, or other regions with no instances involving the penis alone. other case reports have described tv affecting the head and neck [15,18-21]. several cases of tv of the face have been found more commonly in children than adults, with children exhibiting more extensive facial involvement and less involvement of other body regions [1,5]. also, it has been found to occur more frequently in the tropics [10], although boralevi et al. [19] report a more severe presentation occurring in two caucasian patients in a temperate climate. most of the reported cases have been in otherwise healthy patients without systemic illness and immune compromise—only one patient studied by hughes et al [20] was immunocompromised from chemotherapeutic treatment of acute lymphoblastic leukemia. although uncommon, eruptions confined to the areola and periareolar areas have also been noted. two patients had bilateral involvement of the areolae—one case occurred in a pubescent male with mild gynecomastia and one in an adult female, suggesting that localized seborrhea (perhaps hormone mediated) or increased heat and humidity from occlusion against clothing may play a role [22,23]. another unilateral case was reported in a healthy male and was isolated to the left areola with no other skin involvement [24]. conclusion while the factors that predispose to development of tv are generally known, it remains unclear if there are specific etiological factors responsible for unusual variations in location. while these distributions occur more often in conjunction with the typical areas than alone, this is not necessarily so, as demonstrated in our first case. the clinician must be aware of this variability and consider performing a koh preparation if the lesions have characteristic morphology despite an unusual location. as both topical and oral medications are highly effective in treating this mycosis, neglecting the full scope and distributions of tinea versicolor may result in suboptimal management; the patient may be prescribed topicals when oral medications may have been more appropriate, or may be unaware of all areas requiring topical application, resulting in incomplete resolution of the infection. references 1. terragni l, lasagni a, oriani a. pityriasis versicolor of the face. mycoses. 1991;34(7-8):345-347. 2. rudolph ri, holzwanger jm. letter: inverse tinea versicolor. arch dermatol. 1975;111(9):1213. 3. kaur i, handa s, kumar b. tinea versicolor: involvement of unusual sites. int j dermatol. 1996;35(8):604-605. 4. gupta ak, bluhm r, summerbell r. pityriasis versicolor. j eur acad dermatol venereol. 2002;16(1):19-33. 5. aljabre sh. intertriginous lesions in pityriasis versicolor. j eur acad dermatol venereol. 2003;17(6):659-662. 6. huang ww, tharp md. a case of tinea versicolor of the eyelids. pediatr dermatol. 2013;30(6)-e242-3. epub apr 17 2012. 7. s c h w a r t z r a . s u p e r f i c i a l f u n g a l i n f e c t i o n s . l a n c e t . 2004;364(9440):1173-1182. 8. gupta ak, batra r, bluhm r, faergemann j. pityriasis versicolor. dermatol clin. 2003;21(3):413-429, v-vi. 9. mendez-tovar lj. pathogenesis of dermatophytosis and tinea versicolor. clin dermatol. 2010;28(2):185-189. 10. roberts so. pityriasis versicolor: a clinical and mycological investigation. br j vener dis. 1969;81(5):315-326. 11. bumgarner fe, burke rc. pityriasis versicolor; atypical clinical and mycologic variations. arch dermatol syphilol. 1949;59(2):192195. 12. aljabre sh. sparing of the upper axillary area in pityriasis versicolor. rev iberoam micol. 2005;22(3):167-168. 13. ryu hw, cho jw, lee ks. pityriasis versicolor on penile shaft in a renal transplant recipient. anna dermatol. 2012;24(3):345-347. 14. daneshvar sa, hashimoto k. an unusual presentation of tinea versicolor in an immunosuppressed patient. j am acad dermatol. 1987;17(2 pt 1):304-305. 96 observation | dermatol pract concept 2014;4(3):21 15. khaddar rk, cherif f, ben hadid r, mokni m, ben osman a. penile shaft involvement in pityriasis versicolor. acta dermatovenerol alp pannonica adriat. 2008;17(2):86-89. 16. nia ak, smith el. pityriasis versicolor of the glans penis. br j vener dis. 1979;55(3):230. 17. smith el. pityriasis versicolor of the penis. br j vener dis. 1978;54(6):441. 18. sandhu k, kanwar aj. extensive pityriasis versicolor of the face. j dermatol. 2004;31(3):258-259. 19. boralevi f, marco-bonnet j, lepreux s, buzenet c, couprie b, taieb a. hyperkeratotic head and neck malassezia dermatosis. dermatology. 2006;212(1):36-40. 20. hughes br. tinea versicolor in immunosuppressed patients. j am acad dermatol. 1988;19(2 pt 1):357-358. 21. el-gothamy z, ghozzi m. tinea versicolor of the scalp. int j dermatol. 1995;34(8):533-534. 22. sardy m, korting hc, ruzicka t, wolff h. bilateral areolar and periareolar pityriasis versicolor. journal der deutschen dermatologischen gesellschaft [journal of the german society of dermatology]. 2010;8(8):617-618. 23. smith bl, koestenblatt ek, weinberg jm. areolar and periareolar pityriasis versicolor. j eur acad dermatol venereol. 2004;18(6):740-741. 24. anthony jl, schosser rh, gross dj. unilateral areolar and periareolar tinea versicolor. int j dermatol. 1991;30(8):600. dermatology: practical and conceptual observation | dermatol pract concept 2015;5(2):25 125 dermatology practical & conceptual www.derm101.com introduction the term infantile perianal pyramidal protrusion (ippp) was first proposed by kayashima et al in 1996 to describe a rare benign condition characterized by a pyramidal protrusion on the midline of the perineum, anterior to the anus [1]. since its initial description, 108 cases have been reported in the literature. the condition is not believed to be as rare, but it is often erroneously interpreted as a vascular or anatomical anomaly or sometimes even an outcome of sexual abuse [2]. here we report a case of ippp in baby girl studied by dermoscopy and ultrasonography. case report a healthy 9-month-old caucasian girl presented with a two-month history of edematous perianal protrusion. no anatomical defect was present at birth. medical history included intermittent constipation that was untreated. there was no suspicion of sexual abuse and no history of maternal cervical dysplasia or condyloma. family history was positive for ulcerative colitis (father). physical examination revealed a solitary, edematous, light-red, tongue-like, sessile projection with diameters of 3x5 mm, located on the midline, just anterior to the anus. it had soft elastic consistency to palpation infantile perianal pyramidal protrusion: a case report with dermoscopy and ultrasound findings arianna lamberti1, georgios filippou2, antonella adinolfi2, michele fimiani1, pietro rubegni1 1 department of medicine, surgery and neurosciences, dermatology section, university of siena, italy 2 department of medicine, surgery and neurosciences, rheumatology section, university of siena, italy key words: dermoscopy, perianal, protrusion citation: lamberti a, filippou g, adinolfi a, fimiani m, rubegni p. infantile perianal pyramidal protrusion: a case report with dermoscopy and ultrasound findings. dermatol pract concept 2015;5(2):25. doi: 10.5826/dpc.0502a25 received: september 8, 2014; accepted: december 28, 2014; published: april 30, 2015 copyright: ©2015 lamberti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. arianna lamberti, department of medicine, surgery and neurosciences, dermatology section, viale bracci, 16-azienda ospedaliera universitaria senese “santa maria alle scotte,” 53100, siena, italy. tel. +39 0577 585420; fax. +39 0577 44238. e-mail: ariannalamberti@virgilio.it infantile perianal pyramidal protrusion, it is a rare benign cutaneous condition described in relatively recent times. it is considered to be under-reported in the pediatric literature because it is often mistaken for other conditions. the unawareness of this lesion may be responsible for an excessive concern both in physician and in parents, which leads to overly aggressive and unnecessary treatments. thus its recognition has many implications regarding proper management and treatment. we report a typical presentation of ippp in which the diagnosis was based on the use of non-invasive diagnostic tools and in particular of dermoscopy and ultrasonography. abstract 126 observation | dermatol pract concept 2015;5(2):25 a) constitutional ippp (congenital and/or familial), b) acquired ippp, and c) ippp due to lichen sclerosus et atrophicus (lsa) [3]. to better understand this classification, it is useful to report some basic anatomical concepts. the perineum is a muscle-fascial formation, which closes the bottom of the pelvic floor. it is characterized by points of weakness both median and on the side, represented by spaces existing between the muscle bundles. according to the rhomboidal shape of perineum, we can distinguish two triangular portions divided by the transverse perinei muscle. the anterior perineal triangle, or urogenital perineum, differs widely in the two sexes; the posterior triangle, or anal perineum is very similar in both males and females [5]. constitutional ippp develops due to a pelvic floor and perineal weak points. congenital ippp may be a remnant of a projecting tip of the urogenital septum. sometimes it may be found in other members of the family [2]. in acquired ippp, constipation seems to play a relevant role because the lesion regresses after appropriate management, though it is not clear whether regression is due to cessation of constipation or whether constipation causes development of ippp. diarrhea, fistulas and fissures may also be implicated in the formation of ippp through mechanical stimulation of (figure 1). there was no inguinal lymphadenopathy, pain or other symptoms. dermoscopic evaluation showed patchy structureless white areas and a vascular pattern composed of red globular and dotted vessels (figure 2). ultrasound examination of the lesion with a high frequency linear probe (18 mhz, esaote mylab 70xvg device, genoa, italy), gray scale and power doppler analysis revealed a thick hypoechoic area of skin under which increased power doppler signal indicated hypervascularization (figure 3). vascular and anatomical anomalies were therefore excluded. we diagnosed infantile perianal pyramidal protrusion and no treatment was suggested, but only dietary modifications and laxatives to facilitate intestinal transit. two months later the lesion had completely regressed. discussion infantile perianal pyramidal protrusion (ippp) typically appears as a skin protuberance, usually situated anterior to the anus. location and shape vary widely and may be peanutlike, tongue-like or leaf-like, posterior or concomitantly anterior and posterior to the anus [3,4]. size ranges from 5 to 30 mm2 and the overlying skin is usually pink or pale red with a smooth surface. it is distinguished from acrochordons or skin folds on the basis of clinical features. ippp is most often observed at birth, with strong female predominance, presumably related to being more visible in females. the pathogenesis of ippp is unclear. three types are currently recognized: figure 1. clinical appearance: a solitary pyramidal light-red skin protrusion, located anterior to the anus. [copyright: ©2015 lamberti et al.] figure 2. dermoscopic image: patchy structureless whitish areas and a vascular pattern composed of red globular and dotted vessels. [copyright: ©2015 lamberti et al.] figure 3. (a) gray-scale ultrasound image clearly showing a thickened hypoechoic area (asterisk) due to inflammation. the deep margins of the lesion are not well defined (arrows), nor is the dermalsubdermal interface. arrowheads indicate the epidermal interface. (b) power doppler ultrasound image showing an evident increase in pd signal in the hypoechoic area, confirming high blood flow, probably due to vessel dilation due to inflammation. [copyright: ©2015 lamberti et al.] observation | dermatol pract concept 2015;5(2):25 127 laries [13,18,19]. the dermoscopic appearance, in addition to excluding the presence of vascular tumors, is different from that observed in lichen sclerosus involving perineum, which some authors believe is involved in the pathogenesis of ippp. in particular, in the latter cases, linear vessels appear as anastomosing, branching dull red telangiectasias of different caliber and size, whereas dotted vessels appear as randomly arranged and loosely aggregated red dots. moreover, scales and keratotic plugs are often seen in cases of lichen sclerosus which involve the perineum [9]. dietary modification may be tried and no other treatment is required for functional ippp. a conservative approach is indicated because ippp usually resolves spontaneously within several weeks [6,7]. in conclusion, if physicians are aware of ippp as a distinct cutaneous condition, unnecessary or invasive investigation procedures can be avoided. references 1. kayashima k, kitoh m, ono t. infantile perianal pyramidal protrusion. arch dermatol 1996;132(12):1481-4. 2. zavras n, christianakis e, tsamoudaki s, et al. infantile perianal pyramidal protrusion: a report of 8 new cases and a review of the literature. case rep dermatol 2012;4(3):202-6. 3. fleet sl, davis ls. infantile perianal pyramidal protrusion: report of a case and review of the literature. pediatr dermatol 2005;22(2):151-2. 4. leung ak. concomitant anterior and posterior infantile perianal protrusions. j natl med assoc 2010;102(2):135-6. 5. kravarusic d, swartz m, freud e. perineal hernias in children: case report and review of the literature. afr j paediatr surg. 2012;9(2):172-5. 6. miyamoto t, inoue s, hagari y, et al. infantile perianal pyramidal protrusion with hard stool history. br j dermatol 2004;151(1):229. 7. mérigou d, labrèze c, lamireau t, et al. infantile perianal pyramidal protrusion: a marker of constipation? pediatr dermatol 1998;15(2):143-4. 8. cruces mj, de la torre c, losada a, et al. infantile pyramidal protrusion as a manifestation of lichen sclerosus et atrophicus. arch dermatol 1998;134(9):1118-20. 9. a. larre borges, tiodorovic-zivkovic d, lallas a, et al. clinical, dermoscopic and histopathologic features of genital and extragenital lichen sclerosus. j eur acad dermatol 2013;27:1433–39. 10. theiler m, wälchli r, weibel l. vascular anomalies—a practical approach. j dtsch dermatol ges 2013;11(5):397-405. 11. vaid rm, cohen ba. cutaneous crohn’s disease in the pediatric population. pediatr dermatol 2010;27(3):279-81. 12. kleinerman r, whang tb, bard rl, et al. ultrasound in dermatology: principles and applications. j am acad dermatol 2012;67(3). 13. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol 2014;170(3):514-26. 14. jasaitiene d, valiukeviciene s, linkeviciute g, et al. principles of high-frequency ultrasonography for investigation of skin pathology. j eur acad dermatol venereol 2011;25(4):375-82. the perineum [6,7]. lichen sclerosus et atrophicus associated ippp is a skin protrusion similar to those observed in other types mentioned above but is histopathologically different. some authors suggested that ippp might be a peculiar form of lsa, probably an early manifestation, although in other cases it might coexist with lsa [8,9]. histologic findings of ippp, except in patients with lsa associated ippp (in which were observed features suggestive of lichen sclerosus, such as patchy lichenoid infiltrates with vacuolar alteration and homogenization areas of the collagen in the papillary dermis), may show epidermal acanthosis, upper dermal edema, dilated capillaries with fibrous tissue elements infiltrated by lymphocytes and eosinophils in the dermis (especially upper), or an almost normal picture [2,9]. the differential diagnosis of ippp includes rectal prolapse, perianal lesions of crohn’s disease, hemangiomas and hemorrhoids or even sexual abuse [2,10,11]. in our opinion, the majority of cases can be resolved by medical history and physical examination. in doubtful cases ultrasonography (us) and dermoscopy may offer additional help in that biopsy and histological examination could be avoided [12,13]. in particular, us remains the most useful modality for imaging pediatric genital organs. doppler us and color doppler imaging allow rapid identification of normal vessels and abnormal vascular structures [14,15]. with sonography, hemangiomas are usually poorly defined solid masses that vary in their echogenicity and vascularization according to their phase. in the early phase, they tend to be hypoechoic and hypervascular, showing arterial and venous flow and sometimes arteriovenous shunts [15]. vascular malformations can usually be detected as anechoic tubules (e.g., arterial or venous), pseudocystic spaces (e.g., venous or lymphatic), or hyperechoic areas (e.g., capillary) depending on the type of vessel [16]. perianal fluid collections/abscesses can be detected as oval shaped hypoto anechoic masses, which were demarcated off the regular tissue by a hypoechoic seam. in addition, a fistulous connection to the rectum could clearly be visualized [16,17]. in our case, the hypoechoic area associated with increased power doppler signal (indicating increased blood flow, suggested by the dermoscopy image) is a sign of intense inflammation of presumably functional origin. dermoscopy is a simple, non-invasive method enabling observation in vivo of superficial morphological skin characters, impossible to observe with the naked eye. its applications have multiplied in recent years, extending to non-pigmented skin lesions as well as infectious and inflammatory skin diseases [13]. it has therefore gained a more prominent position in routine clinical practice and now increasingly accompanies clinical examination [18,19]. in our case, dermoscopy revealed patchy structureless white areas consistent with fibrosis and a vascular pattern composed of red globular and dotted vessels correlating to the variably dilated capil128 observation | dermatol pract concept 2015;5(2):25 18. haliasos ec, kerner m, jaimes n, et al. dermoscopy for the pediatric dermatologist, part ii: dermoscopy of genetic syndromes with cutaneous manifestations and pediatric vascular lesions. pediatr dermatol 2013;30(2):172-81. 19. oiso n, kawada a. the dermoscopic features in infantile hemangioma. pediatr dermatol 2011;28(5):591-3. 15. ziereisen f, guissard g, damry n, avni fe. sonographic imaging of the paediatric female pelvis. eurradiol 2005;15:1296 –1309. 16. dubois j, patriquin hb, garel l, et al. soft-tissue hemangiomas in infants and children: diagnosis using doppler sonography. ajr 1998;171:247-52. 17. son jk, taylor ga. transperineal ultrasonography. pediatr radiol 2014;44:193–201. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):10 57 dermatology practical & conceptual www.derm101.com introduction shortto medium-term (i.e., 3–6 months) digital dermoscopic monitoring is recommended for the early detection of featureless melanomas [1-3]. high dynamic range (hdr) conversion of dermoscopic images is useful for the identification of dermoscopic structures, even by newly trained dermoscopists [4]. a case of a superficial spreading melanoma in situ diagnosed via digital dermoscopic monitoring with high dynamic range conversion toshitsugu sato1, masaru tanaka2 1 sato dermatology clinic, tokyo, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan keywords: melanoma, short-term digital monitoring, dermoscopy, high dynamic range conversion citation: sato t, tanaka m. a case of a superficial spreading melanoma in situ diagnosed via digital dermoscopic monitoring with high dynamic range conversion. dermatol pract concept. 2014;4(4):10. http://dx.doi.org/10.5826/dpc.0404a10. received: april 8, 2014; accepted: june 18, 2014; published: october 31, 2014 copyright: ©2014 sato et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: toshitsugu sato, m.d., sato dermatology clinic, 1-7-3 kami-ogi, suginami-ku, tokyo 167-0043, japan. tel: +81 3 5397 3663; fax: +81 3 5397 3663. email: sato3663@gmail.com a 48-year-old woman presented with a 3 mm, pigmented macule at her first visit to our clinic. the macule, which showed complete symmetry and a typical network, was tentatively diagnosed as a clark nevus; a 6-month follow-up was recommended, and the patient returned 7 months later. at the second visit, the lesion had enlarged to a diameter of 5 mm, and dermoscopy revealed that it had maintained its typical pigment network. at this point, evidence-based monitoring would have led to excision but the decision was made to continue monitoring. owing to poor compliance, the patient went another 2 years without follow-up. when we assess small lesions, such as this, the usefulness of dermoscopy is apparent. additionally, we examined the benefits and drawbacks of high dynamic range (hdr) conversion of the dermoscopy images and their helpfulness for inspecting small lesions. although the delicate structures present in the lesion can be recognized by a dermoscopy expert and hdr image conversion has a capacity to highlight important structures, there is also a risk that hdr image conversion may mask some of the structural changes. however, a comparison of the original dermoscopy images with the hdr-converted images provides newly trained dermoscopists the opportunity to recognize new findings and to distinguish the differences in the findings between both the types of images. therefore, such comparisons might be useful for obtaining an accurate diagnosis by using dermoscopy and hdr image conversion. abstract 58 observation | dermatol pract concept 2014;4(4):10 enlarged to 5 mm diameter. dermoscopic examination of the lesion revealed that it still had a typical pigment network at the periphery as well as structureless, dark-brown, central pigmentation (figure 2a). hdr conversion of the dermoscopy image also showed the entire pigment network (figure 2b). there were no obvious findings suggestive of a melanoma apart from the fact that the lesion had more than doubled in size. this would have lead to excision according to evidence based guidelines for short-term monitoring, but in fact a decision was made to continue monitoring for a further 6 months. however, the patient did not present for a follow-up examination for 2 years. at the time of her third clinical visit, the patient’s lesion had further enlarged to 7 mm in diameter (figure 3a-c). dermoscopy revealed an atypical pigment network with multifocal thickening of the mesh, color asymmetry, and the presence of bluish-white structures. the hdr conversion continued to reveal the entire pigment network, case report a 48-year-old japanese woman presented with a 6-month history of a pigmented macule on her left chest. her family history was unremarkable, but her medical history indicated the excision of a facial basal cell carcinoma 3 years earlier. a physical examination during the initial visit showed a flat, pigmented 3 mm macule on the patient’s left chest. dermoscopy revealed a typical pigment network at the periphery, with structureless, dark-brown pigmentation in the center (figure 1a). hdr conversion of the dermoscopic image showed the pigment network more clearly (figure 1b). the lesion demonstrated complete symmetry in both color and structure, but was darker in the center and paler at the periphery. therefore, the macule was tentatively diagnosed as a clark nevus, and a 6-month follow-up was recommended. when the patient presented 7 months later, the lesion had figure 1a. a dermoscopic image obtained during the initial presentation, showing a typical pigment network at the lesion’s periphery and structureless dark-brown pigmentation in the center, with a diameter of 3 mm. (copyright: ©2014 sato et al.) a b figure 1b. a dermoscopic image with high dynamic range conversion clearly showing the entire pigment network. the lesion showed complete symmetry in both color and structure. (copyright: ©2014 sato et al.) figure 2a. a dermoscopic image obtained during the second presentation (7 months after the first image) showing the typical pigment network of the lesion, with a 5 mm diameter. despite the slight increase in lesion diameter, the overall reticular pattern of the lesion did not change. (copyright: ©2014 sato et al.) a b figure 2b. a dermoscopic image with high dynamic range conversion clearly showing the entire pigment network. (copyright: ©2014 sato et al.) observation | dermatol pract concept 2014;4(4):10 59 [1-3]. newly trained dermoscopists often find it difficult to identify structures revealed via dermoscopic examination, and hdr conversion of the images may be an effective method to facilitate identification of the structures [4]. hdr [5] is a set of methods used in imaging and photography to capture a greater dynamic range between the lightest and darkest areas of an image than permitted by standard digital imaging or photographic methods. hdr images can more accurately represent the range of intensity levels found in regular images, and are often captured by using a plurality of differently exposed pictures of the same subject matter. non-hdr cameras take pictures at a single exposure level within a limited contrast range. this results in the loss of detail in bright or dark areas of pictures at different exposure levels. however, intelligently placing these images together produces a picture that is representative of both the dark and bright areas. to avoid taking multiple pictures at different exposure levels, the use of hdr image conversion software (casio computers, tokyo, japan) is required. in the present case, dermoscopy at the first and second presentations did not reveal any suspicious findings apart from the increase in lesion size, therefore, short-term follow-up was recommended. evident thickening of the central network via dermoscopic examination at the patient’s second presentation may have been detected if a consultation occurred with a doctor who was an expert in dermoscopy. such a diagnosis may have led to excision of the lesion even though it was still symmetrical. at that time, there were two unequivocal reasons for excision, including the lesion having doubled in area by more than twice its original size and the pattern changes that were observed with thick, reticular lines being a clue to its malignancy. departures from evidence-based protocols must not be permitted during monitoring. kittler and menzies reported that identification of any morphologic changes seen after 3 months as well as the utility of sequenbut demonstrated multifocal darkening and thickening of the mesh on this occasion. these findings were highly suggestive of a melanoma, and the patient was advised to undergo a complete excision of the lesion. the patient was referred to the department of dermatology, tokyo women’s medical university medical center east, tokyo, japan for further assessment. the lesion was excised with a 3 mm margin, and a histological diagnosis of an in situ superficial spreading melanoma was established. discussion when dermoscopy reveals a melanocytic lesion with a multicomponent pattern, it should be considered highly suggestive of melanoma. however, early-onset melanoma lesions often show only a reticular pattern, and an evaluation for the presence of a typical or atypical pigment network is sometimes difficult. when an initial diagnosis, at the first visit, is difficult, short-term (3to 6-month) monitoring is recommended figure 3a. a clinical image obtained during the third presentation (30 months after the first presentation) showing a 7 mm diameter lesion. (copyright: ©2014 sato et al.) a figure 3c. a dermoscopic image with high dynamic range conversion clearly showing the entire pigment network with multifocal darkening and thickening of the network. (copyright: ©2014 sato et al.) c figure 3b. a dermoscopic image showing the atypical pigment network with multifocal thickening of the mesh, color asymmetry, and the presence of bluish-white structures. (copyright: ©2014 sato et al.) b 60 observation | dermatol pract concept 2014;4(4):10 tial imaging depends on patient compliance with follow-up visits [6]. for the present patient, lesion excision should have been recommended at the second visit, according to the evidence-based protocol, because of the lesion’s enlargement, regardless of the absence of color or structure changes. however, erroneously, a 2 mm change in diameter (from 3 mm to 5 mm) was not considered a significant change. therefore, the use of a ruler with 0.1 mm units to measure the length of lesion may have been useful to determine the exact change in the diameter. the change of 1.7 times the diameter (from 3 mm to 5 mm) of the lesion resulted in an increase of 2.8 times the area (from 28.3 mm2 to 78.5 mm2). because of attention only to the structures and colors observed by using dermoscopy, our mistake resulted in a departure from the protocol. further, when the appointment time had passed, it would have been prudent to have a protocol in place to actively contact the patient to return for a further examination. this case demonstrates the difficulty associated with prejudging a patient’s likely compliance. the patient failed to present for her third planned visit, but presented two years later, when the lesion showed suspicious dermoscopic features, including an atypical pigment network and bluish-white structures. when we compared the dermoscopic images obtained during the 3 visits, the first 2 images showed that the network was already thickened and partly obscured, although the distribution of the color and structures was regular. a comparison of the diameters of the hypopigmented areas and the thickness of the pigmented mesh might be important. an abrupt change in color in the pigmented network might also suggest an atypical pigment network. further accumulation of cases of early superficial spreading melanoma is needed to investigate the typical width of the pigment network although an objective definition such as given in revised pattern analysis “lines reticular where the lines are thicker than the holes they surround” may prove to be appropriate [7]. the present case illustrates the application of hdr conversion to clearly identify the pigment network, even in a structureless area, by using ordinary dermoscopy. the use of reference hdr images, even by dermoscopy beginners, enabled changes in a lesion to be noticed along with new findings, such as the visibility of the structureless area and the thickening of the line demarcating the pigment network. on the other hand, hdr converted images strongly increase image contrast. therefore, such changes may also obliterate valuable clues pertaining to the thickened network that make the holes in the network stand out in contrast to the lines. for newly trained dermoscopists, comparing the hdr-converted dermoscopy images with the original dermoscopy images is important. we must diagnose the lesions in a comprehensive manner via different methods, including examinations, dermoscopy images, and hdr-converted dermoscopy images. references 1. altamura d, avramidis m, menzies sw. assessment of the optimal interval for and sensitivity of short-term sequential digital dermoscopy monitoring for the diagnosis of melanoma. arch dermatol. 2008;144:502-6. 2. argenziano g, mordente i, ferrara g. dermoscopic monitoring of melanocytic skin lesions: clinical outcome and patient compliance vary according to follow-up protocols. br j dermatol. 2008;159:331-6. 3. menzies sw, gutenev a, avramidis m, batrac a, mccarthy wh. short-term digital surface microscopic monitoring of atypical or changing melanocytic lesions. arch dermatol. 2001;137:1583-9. 4. sato t, tanaka m. improved detection of dermoscopic structures by high dynamic range image conversion. jpn j dermatol. 2013;123:121-31. [japanese]. 5. high dynamic range imaging. wikipedia website. http:// en.wikipedia.org/wiki/high_dynamic_range_imaging. accessed 2013. 6. kittler h, menzies sw. follow-up of melanocytic skin lesions with digital dermoscopy. in: marghoob aa (eds). atlas of dermoscopy, 2nd ed. london: informa healthcare, 2012:354-361. 7. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—‘chaos and clues’. aust fam physician. 2012;41(7):482–7. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(1):6 47 introduction kikuchi-fujimoto disease (kfd) or histiocytic necrotizing lymphadenitis is a rare, benign, and self-limited disorder characterized by regional cervical lymphadenopathy, mild fever, and night sweats. it has a worldwide distribution, with higher prevalence among young asian females [1]. recognition of kfd is crucial especially because it can be mistaken for lymphoma, tuberculosis or even, for carcinoma. prognosis is favorable with spontaneous recovery occurring in 1 to 4 months. treatment is symptomatic and includes analgesicsantipyretics, non-steroidal anti-inflammatory drugs and, rarely, corticosteroids. kfd can occur isolated, or associated with severe and autoimmune diseases including mixed connective tissue diseases and systemic lupus erythematosus (sle). in particular kfd can precede, postdate or coincide with the diagnosis of sle [2]. here we report a case of necrotizing lymphadenitis preceding the occurrence of subacute cutaneous erythematosus lupus (scle) in a 42-year-old woman. subacute cutaneous lupus erythematosus onset preceded by kikuchi-fujimoto disease vito di lernia1, gianluigi bajocchi2, simonetta piana3 1 dermatology unit, arcispedale santa maria nuova-irccs, reggio emilia, italy 2 rheumatology unit, arcispedale santa maria nuova-irccs, reggio emilia, italy 3 pathology unit, arcispedale santa maria nuova-irccs, reggio emilia, italy keywords: kikuchi-fujimoto disease, skin, lymphadenitis citation: di lernia v, bajocchi g, piana s. subacute cutaneous lupus erythematosus onset preceded by kikuchi-fujimoto disease. dermatol pract concept. 2014;4(1):6. http://dx.doi.org/10.5826/dpc.0401a06 received: june 27, 2013; accepted: september 16, 2013; published: january 31, 2014 copyright: ©2014 di lernia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. vito di lernia, unit of dermatology, arcispedale s. maria nuova-irccs, viale risorgimento 80, 42100 reggio emilia, italy. email: vito.dilernia@asmn.re.it kikuchi-fujimoto disease (kfd) is an uncommon clinicopathological entity characterized by fever and lymphadenopathy, predominantly involving cervical lymph nodes, accompanied by chills and leukopenia. the diagnosis relies primarily on the presence of typical morphological features in the swelling lymph nodes. kfd can occur as a benign and self-limiting lymphadenopathy, but it can sporadically precede, postdate or coincide with the diagnosis of systemic lupus erythematosus (sle). the authors report a case of subacute cutaneous lupus erythematosus (scle) in a 42-year-old female preceded by prolonged fever, anemia, leukopenia, and cervical necrotizing lymphadenopathy. about two months later, the patient developed facial and scalp plaques suggestive of lupus skin disease. histologic and immunologic investigations lead to the diagnosis of scle. it is not clear whether kfd associated with lupus skin disease are true kfd or a histopathologic feature of sle. abstract 48 observation | dermatol pract concept 2014;4(1):6 papulo-squamous lesions on her scalp, ears, face, and trunk, she was referred to the dermatology department. skin examination showed papular and scaly plaques on the face, the scalp, the v-area of the neck, upper chest, back and shoulder in a photodistributed pattern. no malar rash was noted. skin lesions were biopsied with a presumptive diagnosis of lupus. at histology, the epidermis was thinned and displayed focal parakeratosis and vacuolar degeneration of basal keratinocytes, with occasional cytoid bodies. the dermis showed conspicuous interstitial mucin deposits, dense perivascular and perifollicular lymphocytic infiltrates with interface dermatitis (figure 2) and superficial nuclear debris with karyorrhexis. direct immunofluorescence failed to demonstrate immunoglobulin or complement deposits along the dermoepidermal junction or around the vessels. immunologic serum investigations showed absence of antinuclear antibodies, antibodies (anti)-la/ss-b, anti-ds dna, anti-phospholipids, anti-panca, anti-jo1, anti-scl-70, anti-rnp. antibodies anti-ro/ss-a (e.i.a) were 59 (normal value: 0-10), ena (e.i.a) 18.7 (normal value: 0-3). the patient’s complement levels were low with c3 71 mg/dl (normal values: 88–201 mg/dl), c4 5 mg/dl (normal values: 16–47 mg/dl). on the basis of clinical, laboratory and histology findings, a diagnosis of scle was made. the patient was given prednisone 25 mg per day and hydroxychloroquine. skin lesions improved rapidly and healed without scarring. the dosage of corticosteroids was gradually tapered without relapse of skin lesions. after case report a 42-year-old moroccan female was admitted to the hospital with fever lasting one month, night sweats and left cervical lymphadenopathy. laboratory exams showed leukocytes 3300/mm3, erythrocytes 4.370.000/mm3, hemoglobin 12.7 g/ dl, thrombocytes 156.000/mm3, ldh 843u/l (normal values: 230-460). other laboratory findings were all within normal ranges. serologic investigations excluded viral, bacterial and parasitic infections, including syphilis and cytomegalovirus, epstein-barr virus, hiv, rickettsia coronii, brucella spp, salmonella typhi, salmonella paratyphi, toxoplasma, leishmania donovani infections. blood and throat cultures were negative. quantiferon tb gold (esat-6, cfp-10, tb7.7 antigens) was negative. chest x-ray was normal. chest computed tomography (ct) showed multiple, small-sized bilateral hilar and mediastinal lymphadenopathies. abdominal ct revealed additional small interaortocaval, para-aortic mesentheric and iliac lymphadenopathies. due to the presence of multiple lymphadenopathies, a bone marrow biopsy was performed to exclude a lymphoma. bone marrow examination was considered normal. histology showed a mild reactive t lymphocytosis, consisting of a regular number of interstitial lymphocytes which showed mainly a cd3+, cd 20phenotype. bronchial aspiration with microbiologic cultures for mycobacterium tuberculosis were negative. a cervical lymph node biopsy was performed. the lymph node structure was completely effaced by diffuse necrotic areas with abundant karyorrhectic debris (figure 1); the search for dna of mycobacterium tuberculosis was negative. a mediastinal lymph node biopsy and a liver biopsy showed normal histological findings. at this time a definitive diagnosis was not available. after two months new laboratory investigations showed a leukocyte count of 3830/mm3, erythrocytes 3360000/mm3, hgb 9,2 g/dl, thrombocytes 353.000/mm3, ast 44 u/i, alt 45 u/i, ldh 138 u/l. since the patient developed recurrent figure 1. lymph node showing evident loss of architecture with widespread apoptosis and necrosis (inset, at high power). [copyright: ©2014 di lernia et al.] figure 2. at low power, the epidermis is hyperkeratotic and the basal membrane is focally thickened. the dermis shows scattered aggregates of granulocytes (a). interstitial mucin deposits are highlighted with alcian pas stain (b). [copyright: ©2014 di lernia et al.] observation | dermatol pract concept 2014;4(1):6 49 ies were not found. laboratory findings were unremarkable except for neutropenia, anemia and elevated ldh. two months later our patient developed a scle. she presented leukopenia and photosensitivity, but she did not fulfill acr (american college of rheumatology) criteria for the diagnosis of sle. however, since we have a 38-month follow-up, a clinical evolution of our patient’s scle toward sle in the future cannot be definitely excluded. scle has exceptionally been reported in association with kfd [11]. kfd may be the initial diagnosis in patients who go on to develop sle later on. a lag time of 10 months to 3 years has been observed between the diagnosis of kfd and the subsequent onset of sle [12]. pathological features of kfd and ll show significant overlap. thus patients with necrotizing lymphadenitis should be monitored long term for sle. it is suitable to test for autoimmune disease repeatedly even if anas are initially negative. references 1. onciu m, medeiros lj. kikuchi–fujimoto lymphadenitis. adv anat pathol. 2003;10(4):204-11. 2. santana a, lessa b, galräo l, lima i, santiago m. kikuchi– fujimoto’s disease associated with systemic lupus erythematosus: case report and review of the literature. clin rheumatol. 2005;24(1):60–3. 3. cramer jp, schmiedel s, alegre ng, et al. necrotizing lymphadenitis: kikuchi-fujimoto disease alias lupus lymphadenitis? lupus. 2010;19(1):89-92. 4. gordon jk, magro c, lu t, et al. overlap between systemic lupus erythematosus and kikuchi fujimoto disease: a clinical pathology conference held by the department of rheumatology at hospital for special surgery. hss j. 2009;5(2):169–77. 5. kuo tt. kikuchi’s disease (histiocytic necrotizing lymphadenitis). a clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and dna ploidy. am j surg pathol. 1995;19(7): 798–809. 6. kim sk, kang ms, yoon by, et al. histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (sle): is histiocytic necrotizing lymphadenitis in sle associated with skin lesions? lupus. 2011;20 (8):809-19. 7. hu s, kuo tt, hong hs. lupus lymphadenitis simulating kikuchi’s lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature. pathol int. 2003;53(4):221-6. 8. paradela s, lorenzo j, martinez-gómez w, et al. interface dermatitis in skin lesions of kikuchi-fujimoto’s disease: a histopathological marker of evolution into systemic lupus erythematosus? lupus. 2008;17(12):1127-35. 9. kucukardali y, solmazgul e, kunter e, et al. kikuchi–fujimoto disease: analysis of 244 cases. clin rheumatol. 2007;26(1):50–4. 10. yilmaz m, camci c, sari i, et al. histiocytic necrotizing lymphadenitis (kikuchi–fujimoto’s disease) mimicking systemic lupus erythematosus: a review of two cases. lupus. 2006;15(6):384–7. 11. ruiz beguerie j, fernandez penas p, sharma r. kikuchi-fujimoto disease with cutaneous presentation in a patient with subacute cutaneous lupus erythematosus. dermatol online j. 2012;18(9):8. 12. dorfman rf, berry gj. kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. semin diagn pathol. 1988;5(4):329-45. 38-month follow up the patient is free of skin and systemic symptoms. now she is taking hydroxychloroquine 400 mg/ day. laboratory investigations are all within normal value, except for persistent complement deficiency in c3 and c4. discussion the etiology of kfd is unknown and controversial. the viral origin remains still a hypothesis that has not definitely been proven. common presentation signs are acute symmetrical painful swelling of predominantly cervical lymph nodes, fever and systemic signs. the nature of the clinical and pathophysiological relationships between kfd and sle remains a matter of debate, in particular whether kfd can be considered an atypical manifestation of sle [3]. both conditions share the predilection for young females and similar clinical features, including lymphadenopathy, mainly in the cervical lymph nodes, fever, arthralgia, and leukopenia [4]. histopathologic findings of kfd are crucial in characterization of this condition. diagnosis is generally made upon on pathological examination of the excised lymph nodes. typical morphological features include apoptotic necrosis in paracortical areas with abundant karyorrhectic debris, infiltration of histiocytes, cd123+ plasmacytoid dendritic cells, cd8+ t cells, and the absence of neutrophils [5]. lupus lymphadenitis (ll) is characterized by prominent necrosis, strikingly similar to that described in patients with kfd. some histological findings, such as the presence of hematoxylin bodies, prominent plasma cells and neutrophils support the diagnosis of ll [6]. however histology alone may be not enough to distinguish between kfd and ll [7]. when kfd occurs with skin involvement, there are two major possibilities. the first one is a sle with cutaneous and lymph-node involvement, mainly if histopathology of skin lesions show interface dermatitis [8]. in this case kfd may in fact be a histopathologic characteristic of sle supporting the hypothesis that kfd is a rare manifestation of sle [3]. the second one is benign, self-limited kfd with transient cutaneous involvement. extra-nodal involvement in kfd is uncommon; skin manifestations are observed in 5–30% of patients [9]. various skin lesions, such as urticaria-like erythematous papules, nodules, plaques, and indurate lesions, have been reported. in addition, also lupus-typical skin manifestations, as malar rash and photosensitivity, have been observed [10]. in such cases, histopathology of skin lesions usually show lymphohistiocytic infiltrates accompanied by non-neutrophilic karyorrhetic debris, similar to those observed in the involved lymph nodes. in our patient a necrotizing lymphadenitis preceded the onset of lupus skin disease. the lymph node biopsy showed extensive necrosis suggesting the possibility of ll, however aggregates of nuclear debris or so-called hematoxylin boddermatology: practical and conceptual editorial | dermatol pract concept 2014;4(3):13 67 dermatology practical & conceptual www.derm101.com the incidence of melanoma has been on the rise for the last several decades, with a current us lifetime risk of developing melanoma estimated as 1 in every 60 individuals [1]. the key to preventing death from melanoma is the early detection of this cancer, at a stage where surgical excision is curative. however, in attempt to diagnose melanoma early, physicians are also removing many benign lesions, most of these being melanocytic nevi. the pursuit to improve our clinical sensitivity for melanoma diagnosis, while minimizing unnecessary skin biopsies, has led to the development of skin imaging techniques. among recent non-invasive imaging modalities, reflectance confocal microscopy  (rcm) stands out as particularly promising since it offers bedside imaging at cellular-level resolution. stevenson and coauthors [2] have reported in dermatology practical & conceptual on a systematic review of the diagnostic accuracy of rcm for melanoma diagnosis. they have identified five publications, including a total of about 900 lesions, a third of which were melanomas; most of these lesions were reportedly equivocal for diagnosis, clinically and dermatoscopically. based on these studies, the pooled sensitivity for melanoma diagnosis using rcm is 93% (range 91%-97%) and specificity is 76% (range 68%-86%). while the study by stevenson et al [2] did not address the exact contribution of rcm as an add-on test to dermatoscopy, the aforementioned data suggests that rcm can indeed increase diagnostic accuracy beyond clinical and dermatoscopic examination. to simulate the added contribution of rcm to dermatoscopy, stevenson et al [2] took a hypothetical case of 1000 dermatoscopically equivocal skin lesions, and based on the previously reported benign to malignant ratio of 4:1 for experts’ diagnosis of melanoma [3], they assume a ratio of 800 benign lesions to 200 melanomas. they estimate that rcm will prevent the unnecessary excision of 608 benign lesions that would be diagnosed as benign based on rcm, reflecting the specificity of 76%. if we were to formulate the best indications for using rcm as an add-on test to dermatoscopy, we would need to better point-out which lesions are included in this group of 608 benign lesions that are dermatoscopically equivocal, but rcm negative. in this editorial, we can only attest to our own impression and experience, as well as some literature reports, that this group of lesions could encompass the following examples: recognizing the benefits and pitfalls of reflectance confocal microscopy in melanoma diagnosis alon scope1, caterina longo2 1 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel 2 dermatology and skin cancer unit, arcispedale santa maria nuova, (istituto di ricovero e cura a carattere scientifico-irccs), reggio emilia, italy keywords: melanoma, reflectance confocal microscopy, dermatoscopy citation: scope a, longo c. recognizing the benefits and pitfalls of reflectance confocal microscopy in melanoma diagnosis. dermatol pract concept. 2014;4(3):13. http://dx.doi.org/10.5826/dpc.0403a13 received: april 9, 2014; accepted: april 12, 2014; published: july 31, 2014 copyright: ©2014 scope et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: dr. scope’s research is funded by the european commission marie curie fp7 reintegration grant (pirg07-ga-2010-268359) competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: alon scope, md, department of dermatology, sheba medical center, tel hashomer 52621, israel. tel. 972-35302419. email: scopea1@gmail.com 68 editorial | dermatol pract concept 2014;4(3):13 (1) nevi with irregular pigment pattern (e.g., irregular network, complex pattern) on dermatoscopy showing a regular pattern (e.g., ringed or meshwork patterns) on rcm (figures 1,2); (2) nevi with a hyperpigmented structureless pattern on dermatoscopy that display on rcm a cobblestone pattern of the epidermis (reflecting pigmented keratinocytes at the basal and suprabasal epidermis) or a dense infiltrate of melanophages in the dermis; (3) a dermatoscopically-equivocal lesion on sun-damaged skin with a differential diagnosis between solar lentigo and melanoma on sun-damaged skin, that presents a straightforward pattern of solar lentigo on rcm, without any findings concerning for melanoma; (4) a pink macule revealing only a vascular pattern on dermatoscopy, while rcm demonstrates a straightforward pattern of nevus; (5) a macule or patch displaying granularity or blue-gray hue on dermatoscopy, while showing on rcm features of lichen planus-like keratosis with melanophages and remnants of solar lentigo, in the absence of suspicious findings for melanoma [4]; (6) recurrent pigmentation in a scar, whereby rcm helps discriminate between a benign reactive pigmentation and an atypical melanocytic proliferation which would require a biopsy to exclude melanoma [5]. however, there is also a “price” associated with overriding dermatoscopic concern with rcm-based diagnosis. in the figure 1. (a) dermatoscopic image of a nevus showing an irregular network with thickened dark brown lines. (b) rcm mosaic (3.5 x 3.5 mm) acquired at dermo-epidermal junction level reveals a regular ringed and meshwork pattern. (c) higher magnification rcm image (1.5 x 1 mm) depicts well-outlined dermal papillae in the absence of atypical cells, features compatible with the diagnosis of a nevus. [copyright: ©2014 scope et al.] figure  2. (a) dermatoscopy image of a nevus typified by complex pattern with central bluish clods, structureless areas and peripheral network. (b) rcm overview image (5 x 6 mm mosaic) acquired at dermo-epidermal junction level reveals a regular meshwork pattern. (c) higher magnification rcm image (1.5 x 1 mm) shows junctional thickening and junctional nests in the absence of atypical cells, features compatible with the diagnosis of a nevus. [copyright: ©2014 scope et al.] editorial | dermatol pract concept 2014;4(3):13 69 still be strongly considered for digital dermatoscopic monitoring. in contrast, for nodular lesions a dichotomous decision, biopsy or not, should always be obtained; nodular lesions that do not show clear-cut benign findings on rcm in a way that correlates well and accounts for the dermatoscopicallyconcerning findings, should be strongly considered for biopsy. finally, in the simulated scenario discussed by stevenson et al [2], sensitivity for diagnosis was assumed to be set by dermatoscopy, as rcm examination is only performed on dermatoscopically-equivocal lesions that are otherwise deemed for excision. indeed, a common point of view is that rcm cannot impact sensitivity for melanoma diagnosis beyond clinical and dermatoscopic examination. however, management decisions in the clinic are more complex and influenced by the physician’s (a) interpretation of the lesion’s morphology, (b) diagnostic confidence and (c) threshold for biopsy, to name a few factors. in real life, not all lesions referred for rcm imaging would have evoked a biopsy based on clinical and dermatoscopic findings alone (figure 4). as rcm becomes more readily available at the bedside, in terms of cost, size of device, ease and speed of use, the clinical and dermatoscopic thresholds for referring lesions to rcm examination may be much lower than the thresholds, which prompt a biopsy. for example, in individuals with very fair skin where many skin lesions appear pink or non-pigmented, rcm can add diagnostic information and narrow the broad differential diagnosis between bcc, bowen’s disease, nevus, amelanotic melanoma and inflammatory lesions [8]; in this scenario, the handheld rcm device, which allows for more rapid screening of multiple lesions, can be particularly useful for guiding the clinician which of the pink lesions needs to be biopsied [9]. another example is a small-diameter pigmented lesion with few and equivocal dermatoscopic findings, while estimation by stevenson et al [2] among the 200 melanomas that are deemed for excision based on the dermatoscopic impression, 14 melanomas may be misdiagnosed as benign based on the rcm findings, reflecting an imperfect sensitivity of 93%. if we were to improve in recognizing the pitfalls of rcm, we would need to identify recurring patterns among these 14 melanomas. again, based on personal experience and literature reports, here are some potential examples of rcm-false negative melanomas: (1) nodular melanoma associated with hyperkeratosis or ulceration [6]; (2) fully ulcerated melanoma, a scenario where rcm should not be used, since secondary surface changes (e.g., blood, scale-crust) can obscure diagnostic findings; (3) nevoid type melanoma consisting cytologically of mostly of small-melanocytes [7]; and (4) melanoma in situ showing on rcm only focally suspicious findings for melanoma, while displaying equivocal reticular pattern on dermatoscopy (figure 3). we also need to develop strategies to minimize the rate of rcm false-negative melanomas. as a general rule, good agreement between clinical, dermatoscopic and rcm findings should be reached to minimize the risk of missing melanomas. we need to remember that rcm is an adjunct test that should be integrated with other diagnostic data. in this regard, there is a difference between flat and nodular equivocal lesions. flat lesions with significant clinical and dermatoscopic suspicion that are diagnosed as benign based on rcm imaging, should figure 3. (a) clinical image of a 10 mm asymmetric brown patch on the right leg. the patient is a 64-year-old female with prior history of melanoma, and the lesion has been present for several years without notable change. (b) dermatoscopic image showing an irregular reticular pattern. the differential diagnosis was between solar lentigo and melanoma on sun-damaged skin. (c) rcm mosaic image (1.5 x 1.5 mm) acquired at dermo-epidermal junction level reveals a ringed pattern. the initial rcm diagnosis was that of a nevus. however, more exhaustive imaging (akin to “step sectioning” on histopathology) was done as clinically and dermatoscopically, the lesion did not fit well with a nevus. (d) rcm image (0.5 x 0.5 mm) at the level of the basal layer of the epidermis showed foci with irregular infiltration of bright dendritic cells as solitary units (arrowhead) and as aggregates (arrow). the final rcm diagnosis was melanoma. (e) on histopathology (hematoxylin & eosin, 10x), there is a broad asymmetric junctional proliferation of melanocytes, compatible with a melanoma in situ. (f) higher magnification histopathology (hematoxylin & eosin, 20x) shows the tissue correlates of the rcm findings; atypical dendritic melanocytes are seen as crowded solitary units (arrowhead) and as aggregates (arrow). [copyright: ©2014 scope et al.] 70 editorial | dermatol pract concept 2014;4(3):13 rcm shows features that are highly suspicious for melanoma (figure 5) [10]. in conclusion, rcm is rapidly becoming an important addon tool in the armamentarium of dermatologists who screen patients for skin cancer. incorporating rcm as a diagnostic adjunct can increase specificity of melanoma diagnosis. however, we need to study more extensively the indications for using rcm, and equally importantly, the limitations of rcm. figure 4. (a) baseline back images of a 69-year-old male patient with a history of melanoma. (b) repeat back image, at 3-year follow-up, reveals a new pigmented macule on the left upper back (red arrow). of note, the arrows in (a) and (b) correspond to the same anatomic locations. (c) clinically (inset) the lesion is a symmetric 5 mm macule with 2 shades of brown. dermatoscopically, the lesion displays a homogenous pattern, with brown-gray dots. the suspicion for melanoma was very low at this juncture, but the patient was referred to rcm because the lesion was new. (d) rcm mosaic (2.5 x 2 mm) acquired at the level of the basal layer of the epidermis shows an irregular ringed (yellow arrow) and non-specific pattern (white asterisk). (e) on higher magnification rcm image (0.5 x 0.5 mm) at the spinous layer of the epidermis, dendritic cells in pagetoid pattern can be seen. the rcm diagnosis is melanoma. (f) on histopathlogy (hematoxylin and eosin, 20x), there are irregularly crowded nests of atypical melanocytes at the dej, lack of dermal maturation, and atypical melanocytes in pagetoid pattern (arrows). the diagnosis is melanoma 0.6 mm in breslow thickness. [copyright: ©2014 scope et al.] figure  5. (a) dermatoscopy image of a 3 mm pigmented lesion. dermatoscopy reveals a structureless brown-gray pigmentation with few dots. (b) rcm mosaic (3.5 x 2.5 mm) acquired at the level of the spinous-granular layers of the epidermis displays a disarrayed pattern of the epidermis with bright cells in pagetoid distribution at the periphery of the lesion (blue square). (c) on higher magnification rcm image (1.25 x 0.75 mm), large and bright nucleated cells in pagetoid pattern (arrows) can be easily detected. the rcm diagnosis for this lesion is melanoma. (d) on histopathology (hematoxylin and eosin, 20x), there is a junctional proliferation of atypical melanocytes as confluents nests and as solitary units, as well as melanocytes in pagetoid pattern. the diagnosis is melanoma 0.3 mm in breslow thickness. [copyright: ©2014 scope et al.] editorial | dermatol pract concept 2014;4(3):13 71 references 1. rigel ds. epidemiology  of  melanoma. semin cutan med surg. 2010;29:204-9. 2. stevenson ad, mickan s, mallett s, et al. systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. dermatol pract concept. 2013;3:19–27. 3. carli p, de giorgi v, crocetti e, et al. improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150:687-92. 4. bassoli s, rabinovitz hs, pellacani g, et al. reflectance confocal microscopy criteria of lichen planus-like keratosis. j eur acad dermatol venereol. 2012;26:578-90 5. longo c, moscarella e, pepe p, et al. confocal microscopy of recurrent naevi and recurrent melanomas: a retrospective morphological study. br j dermatol. 2011;165:61-8. 6. longo c, farnetani f, ciardo s, et al. is confocal microscopy a valuable tool in diagnosing nodular lesions? a study of 140 cases. br j dermatol. 2013;169:58-67 7. guitera p, menzies sw, longo c, et al. in vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. j invest dermatol. 2012;132:2386-94. 8. braga jc, scope a, klaz i, et al. the significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. j am acad dermatol. 2009;61:230-41. 9. fraga-braghiroli na, stephens a, grossman d, et al. use of handheld reflectance confocal microscopy for in vivo diagnosis of solitary facial papules: a case series. j eur acad dermatol venereol. 2013 [epub ahead of print] 10. pupelli g, longo c, veneziano l, et al. small-diameter melanocytic lesions: morphological analysis by means of in vivo confocal microscopy. br j dermatol. 2013;168:1027-33. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):19 85 dermatology practical & conceptual www.derm101.com introduction ophthalmomyiasis, also known as ocular myiasis, is the infestation of the eye or periorbital tissue by larvae of the insect order diptera. when larvae remain outside the eye it is called ophthalmomyiasis externa, while penetration of the eye is termed ophthalmomyiasis interna. the latter is caused by the larvae of dermatobia hominis, which can cause also blindness. ophthalmomyiasis externa in humans is often caused by the larvae of the sheep nasal botfly, oestrus ovis, and the russian botfly, rhinoestrus purpureus, which are found in sheep farming communities. often the victims have the sensation of being struck by a foreign body or insect. soon thereafter a painful inflammation develops, causing an acute catarrhal conjunctivitis [1,2]. oestrus ovis is a cosmopolitan fly whose females are larviparous, depositing a number of first instar larvae on the edge of, or just inside the nostrils of sheep and goats, while still in flight, whereas infestation in humans is rare [3]. ophthalmomyiasis produced in humans by o. ovis larvae is restricted to conjunctivae, sclera, eyelids, and lacrimal duct (external ophthalmomyiasis) or the eyeball (internal ophthalmomyiasis). hallmarks of this condition are a typical history associated with severe local conjunctival inflammation with diagnosis of ophthalmomyiasis externa by dermatoscopy sody a. naimer 1, kosta y. mumcuoglu2 1 department of family medicine, siaal research center for family medicine and primary care research; faculty of health sciences, bengurion university of the negev, beer-sheva; elon moreh clinic, clalit health services, shomron district, lev shomron, israel 2 parasitology unit, department of microbiology and molecular genetics, the kuvin center for the study of infectious and tropical diseases, the hebrew university—hadassah medical school, jerusalem, israel keywords: oestrus ovis, ophthalmomyiasis externa, conjunctivitis, dermatoscopy citation: naimer sa, mumcuoglu ky. diagnosis of ophthalmomyiasis externa by dermatoscopy. dermatol pract concept. 2014;4(4):19. http://dx.doi.org/10.5826/dpc.0404a19 received: june 1, 2014; accepted: august 30, 2014; published: october 31, 2014 copyright: ©2014 naimer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. sody naimer, department of family medicine, ben-gurion university of the negev, pob 653, beer-sheva 84105, israel. tel. +972.8.6477433; fax. +972.8.6477623. email: sodyna@clalit.org.il ophthalmomyiasis in humans caused by the larvae of the sheep nasal botfly (oestrus ovis) and is a rare phenomenon in israel. we describe the utilization of the dermatoscope as a diagnostic tool for the facilitation of early diagnosis of conjunctivitis due to the infestation of the eyes by the sheep nasal botfly in two patients. after the physical removal of the larvae with the help of a cotton swab applicator under a slit lamp examination and the topical use of antibiotics, the clinical symptoms improved within 1-2 days. undoubtedly the dermatoscope played a crucial role leading to the definitive diagnosis and immediate therapeutic intervention. abstract 86 observation | dermatol pract concept 2014;4(4):19 of the organisms precluded their removal under these conditions and therefore the patient was referred for a slit lamp examination at the emergency department of beilinson hospital, where 14 additional larvae were removed from the eye. the patient was released after application of chloramphenicol eye ointment with ocular covering. the following day he reported a sensation of something moving in the left posterior nasal region later migrating to the back of his throat. after intensive water gargling, all symptoms resolved and the eye recovered without any further sequelae. case 2 a 17-yearold teenager arrived at the clinic after spending the prior night and day hiking the hevron mountains. he recalled that previous day he had the sensation of suddenly being struck in the face by a fly. his left eye gradually became more and more irritated and he felt something moving around inside his eye. the findings were similar to those in the patient in case 1, except that in this patient, the time lapse between the infestation and diagnosis led to substantial accumulation of purulent secretion which hindered clear visualization of the complete conjunctival surface. upon examination with the dermatoscope, the smartphone screen displayed a number of larvae wriggling over the cornea and bulbar surface trying to evade discovery (figure 2). at the kedumim family health center, 15 larvae were manually removed with the tip of a a foreign body sensation, photophobia, lacrimation, erythema and marked periorbital edema. the patient may have the rare complaint of a sensation of motion within the eye [4-6]. in israel, cases of ophthalmomyiasis caused by o. ovis have been reported [7-9]. in addition, yeruham et al. [10] reported the case of a pharyngeal myiasis, while mumcuoglu and eliashar [11] reported a case of nasal myiasis caused by the larvae of this species. we describe the utilization of the dermatoscope as a diagnostic tool for the facilitation of early diagnosis of conjunctivitis due to the infestation of the eyes by the sheep nasal botfly in two patients. case reports case 1 a 27-yearold male was standing outdoors when suddenly he felt an insect hit his left eye at high velocity. soon afterwards he complained of a stinging sensation, pain and uncontrollable tearing. upon arrival at the clinic an hour after this incident, the patient seemed anxious. his eye was covered with his hand. physical examination disclosed a red left eye with swollen and erythematous palpebra and profuse epiphora. the conjunctivae were fiery red and the bulbar conjunctiva demonstrated significant flushing with ciliary injection. at first, with unassisted examination any trigger or cause leading to this condition was hardly discernible. however, after administering topical anesthetic drops and applying polarized dermatoscopic inspection, a number of larvae were observed escaping the light shone across the eye surface and crawling into the conjunctival fornices (figure 1). a smartphone was mounted onto the eyepiece of the dermatoscope and the zoom photography mode enabled further magnification. with a cotton swab applicator under the illumination of the device, six larvae were removed and placed in formalin. the abundance figure 1. solitary horizontal oestrus ovis larva in the conjunctival fornix of the left eye. zoom photography from smartphone mounted over a dermlite 3 (trademark) polarized dermatoscope. (copyright: ©2014 naimer et al.) figure 2. group of larvae gathered in the inner canthus of conjunctiva. notice the streak of pus accumulated to in the gutter to the left. (copyright: ©2014 naimer et al.) observation | dermatol pract concept 2014;4(4):19 87 summarizing 21 cases in which the maximum number of organism found were seven [17]. in conclusion, the observed cases represent one of several reports of ophthalmomyiasis in the middle east caused by o. ovis. however, we have introduced a novel, readily available tool to facilitate diagnosis and treatment. inhabitants and visitors in endemic regions are all vulnerable to eye infestation by fly larvae, and health care providers need to include this condition in their differential diagnosis of anterior segment inflammatory disorders. the dermatoscope can serve as a loyal companion to assist treating such cases especially in remote areas. references 1. smillie pk, gubbi hc. nasal and ophthalmomyiasis: case report. j laryngol otol. 2010;124(8):934–5. 2. cameron ja, shoukrey nm, al-garni aa. conjunctival ophthalmomyiasis caused by the sheep nasal botfly (oestrus ovis). am j ophthalmol. 1991;112 (3):331–4. 3. dunbar j, cooper b, hodgetts t, et al. an outbreak of human external ophthalmomyiasis due to oestrus ovis in southern afghanistan. clin infect dis. 2008;46(11):e124–6. 4. jenzeri s, ammari w, attia s, et al. external ophthalmomyiasis manifesting with keratouveitis. int ophthalmol. 2009;29(6):533–5. 5. thakur k, singh g, chauhan s, et al. vidi, vini, vinci: external ophthalmomyiasis infection that occurred and was diagnosed and treated in a single day: a rare case report. oman j ophthamol. 2009;2(3):130–2. 6. pather s, botha lm, hale mj, et al. ophthalmomyiasis externa: case report of the clinicopathologic features. int j ophthalmic pathol. 2013;18;2(2). 7. hadani a, rauchbach k, ilsar m. ophthalmomyiasis in a man caused by larvae of the sheep nasal bot fly (oestrus ovis linnaeus, 1785). refu vet. 1975;32:157–8. 8. garzozi h, lang y, barkay s. external ophthalmomyiasis caused by oestrus ovis. isr j med sci. 1989;25(3):162-3. 9. harvey jt. sheep botfly: ophthalmomyiasis externa. can j ophthalmol. 1986;21(3):92-5. 10. yeruham i, malnick s, bass d, et al. an apparently pharyngeal myiasis in a patient caused by oestrus ovis (oestridae: diptera). acta trop. 1997;68:361-3. 11. mumcuoglu ky, eliashar r. nasal myiasis due to oestrus ovis larvae in israel. isr med assoc j. 2011;13:379-80. 12. zumpt, f. myiasis in man and animals of the old world. london: butterworth, 1965:267. 13. naimer sa, urkin y. expanded use of the otoscope and dermatoscope in primary care. int j health med & med sci. 2013;5(12),535-545. 14. naimer sa, urkin j. enhancement of ophthalmologic diagnosis with hand held polarized dermatoscope. clin ped. 2014;53:579-84. 15. khurana rk. eye examination-induced syncope role of trigeminal afferents. clin auton res. 2002;12(5):399-403. 16. pandey a, madan m, asthana ak, et al. external ophthalmomyiasis caused by oestrus ovis: a rare case report from india. korean j parasitol. 2009;47(1):57–9. 17. mzm, elmazar hmf, essa ab. oestrus ovis as a cause of red eye in aljabal algharbi, libya. middle east afr j ophthalmol. 2011;18(4):305–8. cotton wool applicator using a full scale slit lamp. again an occlusive ocular dressing was left in position after antibiotic ointment application. the following day the patient reported that his symptoms had improved significantly. in both cases the larvae were examined under a stereo microscope and using morphological characteristics [12] they were identified as the first instar larvae of the sheep nasal botfly, oestrus ovis (figure 3). discussion despite its original indication for use in delineating and characterizing pigmented skin lesions, the recent introduction of the polarized dermatoscope allows thorough examination with full illumination of the eye. the further advantage of a convenient portable device, which can, in selected instances, be used instead of the slit lamp in these remote rural locations where such infestations most commonly opportune. dermatoscopy for use over the various surfaces of the body holds a vast number of advantages. in particular, the numerous uses of polarized dermatoscopy in ophthalmology have been reported [13,14]. for instance, a portable utensil in its format, as opposed to the slit lamp which is static and demands the patient sit in front of the examiner, will enable patient examination while lying on a bed. this is a great benefit specifically for subjects who react with fear to discomfort and eye manipulation and procedures with vasovagal syncopal reactions [15]. this is the first report of dermatoscopic use in diagnosis of this condition. slit lamp is the rule for diagnosis of ophthalmomyiasis in all reports in the past [16]. the consequences of a late and delayed diagnosis are obvious, therefore the clinical approach noted in previously reported cases highlight the importance of prompt diagnosis and speedy intervention. in our patients this is exemplified by the relatively mild clinical presentations before the onset of complications and their rapid recovery. furthermore a unique characteristic witnessed in the present cases was the staggering number of larvae involved after a very brief exposure to the fly itself. the largest recently reported series from libya figure 3. first instar larva of the sheep nasal botfly (oestrus ovis). (copyright: ©2014 naimer et al.) http://www.ncbi.nlm.nih.gov/pubmed/12420086 http://www.ncbi.nlm.nih.gov/pubmed/12420086 http://www.researchgate.net/researcher/39181248_anita_pandey http://www.researchgate.net/researcher/34974705_molly_madan http://www.researchgate.net/researcher/21393752_ashish_k_asthana http://www.ncbi.nlm.nih.gov/pubmed/?term=elmazar hm%5bauth%5d http://www.ncbi.nlm.nih.gov/pubmed/?term=essa ab%5bauth%5d dermatology: practical and conceptual observation | dermatol pract concept 2015;5(1):17 87 dermatology practical & conceptual www.derm101.com case presentation a 33-year old male presented with a 6-year history of brownish plaques on both legs. his medical and family histories were unremarkable. the patient reported that the plaques were occasionally painful and that the lesions produced more sweat than the surrounding skin. the patient also reported that there was no trauma preceding the appearance of the lesions. dermatological examination showed brownish indurated plaques at the medial sides of the bilateral popliteal fossa and posterior of the right leg (figure 1). the plaques were painful upon palpation. the starch-iodine test was performed to determine the presence of hyperhidrosis. to perform this test the plaque on the patient’s right leg was painted with iodine solution and allowed to dry thoroughly. then, a starch powder was sprinkled on the surface and the appearance of purple-black speckling was observed, indicating presence of hyperhidrosis. next, an incisional biopsy specimen was obtained from the same lesion. hematoxylineosin (h&e) staining of the biopsy specimen showed lobules with mucinous stroma in the deep dermis and subcutaneous tissue (figure 2). the lobules were composed of hyperplastic and proliferated eccrine glands, and numerous small blood vessels (figure 3). with the clinical and histopathological findings, a diagnosis of eccrine angiomatous hamartoma (eah) was made. multiple painful brownish plaques associated with local hyperhidrosis nilay duman1, gül erkin2, nilgün atakan2, özay gököz3 1 afyon kocatepe university, school of medicine, department of dermatology, afyonkarahisar, turkey 2 hacettepe university, school of medicine, department of dermatology, ankara, turkey 3 hacettepe university, school of medicine, department of pathology, ankara, turkey key words: hyperhidrosis, eccrine gland, hamartoma citation: duman n, erkin g, atakan n, gököz, ö. multiple painful brownish plaques associated with local hyperphidrosis. dermatol pract concept 2015;5(1):17. doi: 10.5826/dpc.0501a17 received: july 18, 2014; accepted: october 2, 2014; published: january 30, 2015 copyright: ©2015 duman et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nilay duman, md, assistant professor, afyon kocatepe university, school of medicine, department of dermatolology, ali çetinkaya kampusü, i̇zmir karayolu 7. km, afyonkarahisar, turkey. tel. 90 (272) 4440304; fax. 90 (272) 2463322. e-mail:nilybayram@hotmail.com eccrine angiomatous hamartoma is a rare hamartomatous lesion characterized by proliferation of eccrine glands and small blood vessels, and occasionally other elements. it generally arises congenitally or later in childhood, as solitary or multiple lesions on the distal extremities. adult-onset multiple lesions are very rare. herein we describe a 33-year-old male with symptomatic multiple eccrine angiomatous hamartoma lesions. abstract 88 observation | dermatol pract concept 2015;5(1):17 as eah is a benign, slow-growing lesion, aggressive treatment is not indicated. simple excision is currently the treatment of choice in patients with undesirable symptoms, such as pain or hyperhidrosis, those with cosmetic concerns, and in cases of progressive enlargement of the lesions [2]. botulinum toxin may be considered to treat lesions associated with hyperhidrosis [2]. as the lesions in the presented patient were symptomatic, they were excised. in conclusion, eah is a rare entity with a unique clinical and histopathological presentation that should be considered in the differential diagnosis of vascular and hamartomatous lesions. references 1. naik v, arsenovic n, reed m. eccrine angiomatous hamartoma: a rare multifocal variant with features suggesting trauma. dermatol online j 2009;15(9):6. pmid: 19930993 conclusion eah is a rare hamartomatous lesion characterized by proliferation of eccrine glands and small blood vessels, and occasionally other elements, such as adipose tissue, hair, and epidermis [1,2]. eah generally occurs congenitally or later in childhood as solitary or multiple lesions on the distal extremities, especially the legs; however, pubertaland adult-onset lesions, and trunk and head involvement were also reported [3,4]. to date, a gender predilection has not been reported. the clinical presentation of eah ranges from a simple angiomatous nodule to erythematous-purpuric plaques. it is generally asymptomatic, but occasionally can be associated with pain and hyperhidrosis, and less frequently hypertrichosis [1,4]. the etiopathogenesis of eah remains unknown. some researchers have suggested that faulty interaction between differentiating epithelium and the underlying mesenchyme gives rise to abnormal proliferation of adnexal and vascular structures in congenital forms. late onset lesions have been associated with recurrent trauma [2]. histopathological examination of eah is usually characterized by a circumscribed, non-encapsulated lobular lesion in the mid to deep dermis that is composed of mature-looking and occasionally dilated eccrine glands, and associated benign vascular proliferation. the vascular component is composed of small blood vessels exhibiting variable dilatation. occasionally, mucinous change, a lipomatous component, or pilar structures are observed [4]. the epidermis is usually normal, but occasionally verrucous changes are present. eah must be differentiated from vascular malformations, tufted angioma, smooth muscle hamartoma, glomus tumor, blue rubber bleb nevus, and macular telangiectatic mastocytosis [3]. definitive diagnosis of eah is based on clinicopathological correlation. figure 1. brownish indurated plaque at the medial side of the popliteal fossa. (copyright: ©2015 duman et al.) figure 2. proliferative lobules with mucinous stroma in the deep dermis and subcutaneous tissue (h&e, x10 original magnification). (copyright: ©2015 duman et al.) figure 3. proliferative eccrine glands and small blood vessels within the mucinous stroma (h&e, x40 original magnification). (copyright: ©2015 duman et al.) observation | dermatol pract concept 2015;5(1):17 89 4. calonje e, brenn t, lazar a, et al. tumors of the sweat glands. in: calonje e, brenn t, lazar a, mckee ph, eds. mckee’s pathology of the skin. 4th ed. china: elsevier-saunders, 2012:1529-30. 2. lin yt, chen cm, yang ch, chuang yh. eccrine angiomatous hamartoma: a retrospective study of 15 cases. chang gung med j 2012;35(2):167-77. pmid: 22537932 3. shin j, jang yh, kim sc, kim yc. eccrine angiomatous hamartoma: a review of ten cases. ann dermatol 2013;25(2):208-12. pmid: 23717013 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 11 foreword i decided to write this series of essays, “on the nature of thought processes and their relationship to the accumulation of knowledge” because it seems to me logical that if we do not understand the mechanisms that occur within our brains to generate thoughts (those thoughts underlying each and everything we do) we cannot begin to understand how or why events either occur according to plan or seem to go awry. the series looks at thought processes and the “knowledge” generated by them from a variety of perspectives. the goal is to better understand just how “true” items of knowledge are, or can be, and how that understanding might help us generate and communicate “knowledge” more accurately. this current essay about the nature of evidence was originally published in dermatopathology: practical & conceptual in october 2009, but because of a series of unlucky events the essay has been withdrawn shortly after its publication without being ever replaced for the readership. after now 4 years, the essay will be finally again available for the readers of dermatology practical & conceptual. further essays in the series are “in the works” and this essay is an important topic in the series overall, so i am pleased that it is to be republished. introduction how do we decide what to believe? this question is most important for us because we each believe many things. each of us assumes that what we believe is true, otherwise we would not believe it. and we are aware that we do not all believe all of the same things. if fact, we are convinced that many other people believe things which by definition they believe to be true, that are just plain wrong, or not true, because we do not believe those same things. of course we each have reasons for our beliefs. if someone asks us, “why to you believe that?” we can respond, “because. . . .” and we all believe that our reasons support adequately our decision to believe that item. so if all of my beliefs are true, and all of your beliefs are true, and all of our reasons collectively support our beliefs, why do we disagree so often? let us move on to the topic of this essay, the nature of evidence. the random house dictionary, second edition, defines “evidence” as “that which tends to prove or disprove something; ground for belief; proof” and “something that makes plain or clear.” serving as it does as a justification for belief, evidence is something we simply cannot live without. the definition implies that evidence must be true and unassailable, serving as a “ground for belief”, “belief” being something we assume to be true, and “proof”, which implies that there can be no argument. also, the definition implies that evidence serves to clarify an issue, serving to improve our understanding of it. when we hear the “evidence” we are supposed to say “aha! now i understand” and we all move on to the next item of interest. so the question arises, are “reasons for belief” the same as “evidence”? if we do consider them to be the same, should we consider them to be the same? in this essay we will look at the concept of evidence from a variety of perspectives and on the nature of thought processes and their relationship to the accumulation of knowledge, part xiii: the nature of evidence cris anderson1 1 pathology, southern illinois university school of medicine, carbondale, illinois, usa citation: anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xiii: the nature of evidence dermatol pract concept. 2014;4(1):3. http://dx.doi.org/10.5826/dpc.0401a03 copyright: ©2014 anderson. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: cris anderson, m.d., email: crisj@me.com 12 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 try to gain some insight into the powerful hold the very word “evidence” holds over us. we will examine reasons why evidence cannot be expected to be true and unassailable in each and every case. we will examine the question of whether or not the word “evidence” has become more of an instrument of persuasion than out-and-out “proof” and how this affects us in the day-to-day practice of medicine, which is supposed to be evidence-based. evidence—the ideal preston cloud, in oasis in space: earth history from the beginning, states, “a subject becomes a science when it is brought within the bounds of natural law and a body of ordering principles that make its hypotheses testable—where evidence takes priority over authority and revelation.” this statement implies that evidence is more than merely something that “justifies belief.” it implies that the justification of belief must be a sort of “proof.” that is to say, a body of evidence—that body which can be evaluated independently by one or more persons other than the person who puts forth that body—should lead a reasonable person to conclude the belief on his or her own. no doubt a person who accepts revelation as a reason for belief feels justified in believing what has come to him by means of revelation. encarta world english dictionary, first edition, defines “belief” as “acceptance by the mind that something is true or real, often underpinned by an emotional or spiritual sense of certainty.” that dictionary also defines “justify” as “to serve as an acceptable reason or excuse for something.” thus, using the term “evidence” as “that which justifies belief” does not necessarily imply “proof.” encarta defines “proof” as “evidence or an argument that serves to establish conclusively a fact or the truth of something.” however, i would argue that most of us infer “proof” when we hear the label “evidence” applied to some information given to us. in a similar vein, returning to cloud’s statement about science, “authority”, if we accept it as a reason to believe some item of information, it serves to justify our acceptance of that item and becomes “evidence.” in fact, “evidence” is not unique to science at all. what really makes science “science” is the “body of ordering principles that make its hypotheses testable” and the actual testing of those hypotheses. the “evidence” that we scientists use does require “proof.” we try to use “proof” formally in the sense of deductive logic or mathematical proof, in which each ensuing step is agreed upon by all as following its predecessor. evidence in practice we tend to use the term “evidence” rather freely, applying the term to a reason that we accept as justifying our belief, but without “thoroughly vetting” the term each time we use it to see if a rational person would accept necessarily our argument in the case at hand. we may do this without malice aforethought, being somewhat confused at the time as to our own argument; but occasionally a person might purposefully apply the term “evidence” in an attempt to prevent the audience from working through the argument themselves to see if the argument is actually a valid one. unfortunately, often there is no easy way to tell whether the arguer is being logical, is confused, or is trying to hoodwink the audience. many problems exist in this complex world in which we live for which legitimate disagreements occur. for some of the reasons to be discussed later in this essay, a formal, undeniable proof cannot be put forth. this does not mean that there are no rules available with which such a problem can be discussed in a meaningful and enlightening way. in fact, informal logic, or argumentation, is a discipline which recognizes that “proof” more often than not represents a consensus arrived at by the process of justifying and rebutting claims, refining through the process an understanding of the topic of the argument. david zarefsky, in argumentation: the study of effective reasoning, 2nd edition, an audio course produced by the teaching company, explains the five key assumptions that underlie the process of argumentation. first, argumentation takes place with an audience in mind and that audience judges ultimately the success or failure of the argument. second, argumentation takes place under the condition of uncertainty. third, argumentation involves justification of claims made by the arguers. fourth, argumentation is a cooperative exercise; although it may seem adversarial, the arguers share a common goal of arriving at the best decision under the prevailing circumstances. fifth, argumentation involves risks—an arguer may be shown to be wrong and lose the argument and the loser may lose face if s/he is perceived to have performed badly during the argument. “proof”, or justification, rests on being able to put forth and/or to recognize a “valid” argument. that is to say the argument follows logically and is thus consistent and without contradiction. a problem arises when we humans cannot, or do not make the attempt to, discern the difference between proof and persuasion. persuasion, in this sense, means that the words sound nice, but the argument is not valid in some way. recall from the earlier essay in this series reasoning the words of rick garlikov, in which he compares reasoning with a game of chess. garlikov writes, “if little children are playing with chess pieces and a chess board, but are making arbitrary moves in what they think is emulation of adults they have seen playing chess, it is not that they are playing chess badly. it is that they are not playing chess at all, regardless of what they think they are doing or what they call it.” if the rules are not followed, there is no argument in the true sense of the word. there is merely the melodious sound of words. practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 13 if i concede a point to you when you put forth an invalid argument, you have persuaded me, yes; but the proof or justification is not there. interlude about learning it is most important for us to understand how knowledge is gained. it is for the most part a painful process based entirely in trial-and-error. more involved discussions about concepts related to learning are to be found in earlier essays in this series, especially interpretation, causation, reasoning, and patterns. i will mention briefly a few salient points. what one is able to learn and conclude is dependent on how the problem is defined—that is to say, what boundaries are drawn that define the system being studied. different boundaries lead to different questions being asked, different types of data collected, and different interpretations of data. all learning of material previously discovered is based in ostensive definition, whereby someone is shown something by someone more knowledgeable about the object and the learner must try to figure out exactly what it is s/he is supposed to be looking at (more complete discussion of this in interpretation). abstract concepts are thought about and discussed in terms of metaphor. metaphors are based in everyday experience and are related to features of human embodiment, for example “happiness” is discussed in terms of “up”, the “future” in terms of “forward”, “life” is a “journey”, and the like (also discussed in interpretation). a metaphor chosen will necessarily highlight one aspect of the abstract concept, while simultaneously downplaying another aspect of that concept. this gets back to the problem of how boundaries are drawn around the abstract concept, or from what perspective the concept is examined. patterns are sought, which are converted mentally to rules that can then be applied to future situations. if an expected outcome ensues, we assume the rule must be correct. if we are surprised, if we see a contradiction unexpectedly or the like, we revise the rule and see if we can make a better prediction for the next event (trial-and-error at work). the rules we “discover” serve as boundaries for the system we are examining. we start by imagining some event and then trying, “by hook or by crook”, to get to where we imagine. it is very difficult to get somewhere without some inkling of where one might be going. serendipitous events occur, but only for the “prepared” mind. true to pattern, when we find something, a method or an approach perhaps, we try it again and again until we finally are forced to admit that some sorts of problems require a different approach (the rules applied routinely result in surprises or contradictions). this is discussed in more depth in the essay on reasoning. paradox and contradiction, if recognized, lead to the opportunity to redraw boundaries around a problem and try to “get it right.” an implicit assumption that we all hold is that, if we identify the pattern correctly and describe it with a precise and correct rule, we will avoid surprise and contradiction. we are slaves to expectation! knowledge and understanding basically, while we think we “know” and “understand” things, we only feel that way. in the earlier essay in this series on truth it was noted that when we think we know something, our “truth bell” rings in our brains. the “truth bell” is in the ventral striatum and associated with the nucleus accumbens and is associated with pleasure and motivation. in the earlier essay in this series on emotion, we learned that damasio posits that even the most objective thought we think we are having is run through various centers in the brain associated with feelings, including the somatosensory cortex. we evolved this way because being able to assess easily our feelings better enabled us to determine whether we were in danger imminently. when the “truth bell” rings for each of us, there is no assurance that the thought ringing the “truth bell” is actually true in the sense that it conforms with universal law. “evidence” is a similar concept, since it is that which justifies belief. “belief” is a personal feeling for each of us that what we believe is true. something that we accept as justifying for us a belief also rings the “truth bell” and, thus, is not necessarily true in the conforms-with-universal-law sense. “evidence” as an attribute applied during argument we all understand the world from a slightly different perspective. each of us thinks we are correct about many of the things we understand. it is human nature to share knowledge and understanding. often, however, the person with whom we are sharing our unique perspective requires convincing. to convince someone that our belief is justified, we offer them “evidence.” the evidence we offer them is the evidence that justifies our own belief. we assume that if the evidence is good enough for us, it should be good enough for anyone else and the evidence we are sharing should serve to justify belief in the mind of the other person. although at first blush we think of the word “evidence” as being associated with objectivity and science, the label “evidence” is laden intensely with feeling. if you reject my evidence, if you say my evidence is insufficient to justify your belief in what i believe, i infer that you are implying that my own belief is not justified and that i should not accept the 14 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 item i have labeled as “evidence” as sufficient to justify my own belief. the grip of “authority” from our earliest experiences we rely on other people to tell us “the truth.” our teachers, our parents initially, instruct us by first ostensive and then verbal definition. there is much to learn and learning from the experience of others saves us time and is often safer than direct experience. “don’t touch that hot stove!”, “don’t run into the street without looking both ways!”, we are told. if someone tells us this or that plant is safe to eat, we do not risk poisoning ourselves. to look to authority is natural to humans. following authority helps us to become more easily acculturated into our very complex society. as our lives become more complex and as we are bombarded from all sides by information coming with increasing frequency, our tendency naturally is to believe what we hear, since we humans look automatically to authority. it is only when we hear statements that we recognize as contradicting one another that we are prompted to examine situations more carefully and to make more reasoned decisions about what to accept as true. contradiction requires us to ask, “who really is an authority in this subject?” “who should we believe?” “how can we find out the truth?” in the end, we look for and evaluate information put forth as “evidence” and we evaluate carefully those items before we accept them internally as evidence, which justifies our belief. for most of us this means adhering to the “scientific method”, which is defined by encarta dictionary as “the system of advancing knowledge by formulating a question, collecting data about it through observation and experiment, and testing a hypothetical answer.” the problem here is that we must call up into working memory, which can only hold simultaneously about seven items, propositions that we can recognize as contradictory. we all have so many potential thoughts and memories stored in our brains, we often do not call up information that is contradictory and we continue to believe contradictory propositions; that is we all live with cognitive dissonance. finding the “best fit” definition of a system in the essay in this series on reasoning, we noted that lawrence slobodkin, in simplicity and complexity in games of the intellect, opined that complex problems require a look by both philosophers and mathematicians in order to gain a better understanding of those problems. “evidence” has been considered by both and we will see what each of them has to say. what sorts of things can be accepted as evidence—philosophers as with most abstract concepts, one’s conclusion depends ultimately on the boundaries one constructs around one’s system of thought concerning the concept. thomas kelly, in evidence published in the online stanford encyclopedia of philosophy, notes that most people think of evidence as “something that might be placed in a plastic bag”, such as a bloody knife, or an historical document, or the result obtained by biochemical analysis of a blood specimen. however, philosophers through the ages have applied variably the term evidence to mental items present in one’s consciousness (bertrand russell), stimulation of one’s sensory receptors (willard quine), or even the totality of propositions that one knows (timothy williamson). bayesians consider evidence to be those beliefs for which one is psychologically certain. should an item in my consciousness, say an idea i have for writing a story of science fiction (and, therefore, for which very little physical evidence is available) be considered as evidence? perhaps it could serve as evidence that i have an imagination. should the fact that i say i feel cold serve as evidence to support my action to turn up the thermostat? or should i wait until someone sees me shivering so that more than one person agrees that i feel cold? should the totality of propositions i “know” serve as evidence, even if all those propositions are not satisfiable with one another (some propositions contradict one another, if only i could bring them into my consciousness at the same time, i would see that they are contradictory and could act to resolve my cognitive dissonance)? kelly advises us that philosophers have offered “quite divergent theories of what sorts of things are eligible to serve as evidence.” he points out that, depending on one’s frame of reference, “the concept of evidence has often been called upon to fill a number of distinct roles”, and that, while sometimes the roles complement each other, sometimes tension is created. one interesting concept is that, in the minds of those who are skeptical about our knowledge of the external world, one’s evidence does not favor ordinary commonsense interpretations of one’s environment over unusual alternatives. for example, skeptics may point out that we do not sense what we think we are sensing; those skeptics posit that we could be hallucinating in an undetectable way. our evidence does not mean we see that tree, even if we pluck a leaf and feel the features of that leaf under our fingers. we could be hallucinating the entire episode. this has been dubbed the “brains in a vat” paradox. skeptics maintain that there is no way to be certain about anything we think we “know.” another interesting concept is that an item of evidence, e, can never be the ultimate evidence in support of a belief practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 15 because there is always the possibility that additional evidence, e’, may become known that defeats the prior evidence. evidence that is susceptible to being undermined is called “defeasible” evidence. kelly points out that there is controversy among philosophers whether “indefeasible” evidence could even exist. important to this discussion about the availability of additional evidence is whether one is considering a subset of evidence or a theoretical “total body of evidence.” i remember attending courses in dermatopathology given by a. bernard ackerman, m.d. often, when bernie was discussing his diagnosis of a particular case, a member of the audience would ask (this is a paraphrased quotation), “what if you just had this area—what would your diagnosis be then?” bernie would point out, “but you don’t just have a small area, you have the entire case. it makes no sense to consider a small part of the specimen in isolation; you must consider all the information available.” it is true that our brain power has limitations, but bernie insisted that we should not draw our boundaries around a problem more narrowly than necessary. we will return to the problem of narrow boundaries later. additionally, evidence supports a belief in relation to the number of hypotheses available. if there is only one hypothesis, then evidence supports only that hypothesis. but if there are multiple plausible competing hypotheses, evidence may support more than one of those hypotheses and not serve to differentiate between competing hypotheses. bayesians theorize that evidence can support an hypothesis only if one considers the probability that an hypothesis is correct. we physicians are all familiar with bayes theorem as it relates to diagnosis. if the prevalence of disease a is 30% and the prevalence of disease b is 3%, the presence of a symptom common to both diseases is more likely to be evidence of disease a than disease b. what we need is a symptom or sign or test result that will serve to differentiate between the two diseases. another consideration philosophically is whether additional confirmatory evidence provides a stronger argument than disconfirmatory evidence. karl popper developed the example using the premise “all swans are white.” he averred that evidence of each additional white swan provided little additional proof of the claim. he pointed out that a single black swan would disprove the hypothesis. he pointed out that the goal of science should be to “look for black swans.” scientific experiments should attempt to disprove an hypothesis. if the experiment failed to disprove the hypothesis, that hypothesis could still serve as a working hypothesis and as a (temporary) basis for further progress of knowledge about some aspect of our universe. victor difate, in his entry evidence on the internet encyclopedia of philosophy, describes carl hempel’s work on “the raven’s paradox.” hempel begins with the hypothesis “all ravens are black” and then draws a logically equivalent statement, “all non-black things are non-ravens.” hempel then points out that one could provide evidence that all ravens are black by merely looking around the room and saying, for example, “that book is green. it is a non-black thing and a non-raven. therefore it is evidence in support of my hypothesis.” he further points out that, using “evidence” to support a statement that is equivalent from a logical standpoint to the original premise does not do much to prove the hypothesis in a meaningful way and that a similar argument could be used to “prove” the hypothesis that “all ravens are white.” a way around this, points out difate, might be to “test severely” a hypothesis. it may be true that a green book provides evidence that all ravens are black, but the evidence is weak in the extreme. one should make a good faith effort to ensure that, if a non-black raven exists, one is likely to find it, just as karl popper has recommended. philosophers have spent much time and brain power on the problem of evidence. the main point i wish to make here is that how one frames the problem determines the sorts of conclusions one may draw ultimately. one cannot draw a system with infinite boundaries and, therefore, paradoxes and disagreements will arise that might suggest a better, or at least an alternate, way to draw boundaries in an effort to minimize the presence and effects of paradox. problem definition from a mathematical perspective lawrence slobodkin, in simplicity & complexity in games of the intellect, explains the role mathematicians play in our world. says slobodkin, “the work of mathematicians is to imagine new worlds and what their regularities might be. in their choice of difficult intellectual problems they can exclude questions that require physical apparatus for collecting information and knowledge or social history in their answers. in this sense they are free of the limitations placed on empirical scientists . . . the purpose of their activity is clarity and understanding only. while they are free to make new worlds, they carefully avoid dealing with the inconvenient parts of this one.” mathematicians draw up a set of rules, which are often represented symbolically by formulae, they then select a set of initial conditions (by defining some of the variables in the equations), and then set the whole process in motion by attempting to solve the equations to see what occurs. this is very like the concept of games discussed in the essay in this series on reasoning. slobodkin states of games, “basically, all good games involve a complete, circumscribed, and simplified model of a world, consisting of a clear playing 16 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 field with understandable and unchanging rules whose rich consequences are then developed by the players.” when mathematicians approach a problem, they set certain assumptions (which are some of the rules) and make certain predictions about what they expect will happen. if their predictions come to fruition, they accept that their assumptions are valid. if something unexpected occurs, they must consider whether their assumptions were correct or whether there could be some other reason for the unexpected occurrence. if a contradiction arises when the rules are executed flawlessly, there is a paradox. paradox as a clue to deficient knowledge thomas bolander, in self-reference in the online stanford encyclopedia of philosophy, writes of paradox “a paradox is a seemingly sound piece of reasoning based on apparently true assumptions that leads to a contradiction . . . the significance of a paradox is its indication of a flaw or deficiency in our understanding of the central concepts involved in it.” bolander describes semantic and set-theoretic paradoxes and explains, “in [the] case of the semantic paradoxes, it seems that it is our understanding of fundamental semantic concepts such as truth (in the liar paradox and grelling’s paradox) and definability (in berry’s paradox) that are deficient. in the case of set-theoretic paradoxes, it is our understanding of the concept of the set. if we fully understood those concepts, we should be able to deal with them without being led to contradictions.” for the purposes of this essay i am using the definitions, from encarta, of “truth” as “correspondence to fact or reality” and “definability” as ability to “give the precise meaning of a word or expression or to state or describe something clearly.” as for “reality”, i invoke the words of steven pinker (as discussed in the essay in this series on patterns), in the stuff of thought: language as a window into human nature, “but reality can’t be riddled with paradoxes and inconsistencies; reality just is.” you can see that, if we humans are deficient in our understanding of the concepts of “truth” and “definability.” it is only natural that we will have difficulty understanding the concept of “evidence.” parenthetically, the paradoxes mentioned by bolander are as follows. but first, a few more definitions. logic, as defined in encyclopedia britannica, 15th edition, is the study of propositions and of their use in argumentation. deborah bennett, in logic made easy: how to know when language deceives you, states, “a proposition is any statement that has the property of truth or falsity.” a proposition is composed of a subject and a predicate. as per the random house dictionary of the english language, second edition, the subject is the syntactic unit that is performing the action or being in the state expressed by the predicate and the predicate is the syntactic unit that expresses the action or state attributed to the subject. from the standpoint of logic, the predicate is that which is affirmed or denied by the subject . the liar sentence is the proposition (and thus having the property of truth or falsity) “this sentence is not true.” “sentence” is the subject and “true” is the predicate, which is denied by the subject in this example. when one tries to determine the truth of this proposition, one either starts out assuming the sentence is true or that the sentence is false. if one assumes it is true, then it cannot be true because the sentence itself (self-reference) states that it is not true. if one assumes the sentence is false, then it must be true since the “false” of “not true” is “true.” grelling’s paradox involves the use of a predicate defined in a self-referent way. states bolander, “say a predicate is heterological if it is not true of itself, that is if it does not itself have the property it expresses. [“hetero-” being a prefix meaning “different or other” and “logical” meaning “based on facts”] thus the predicate “german” is heterological, since it is not itself a german word, but the predicate “deutsch” is not heterological. the question that leads to the paradox now: ‘is “heterological” heterological?’” bolander continues his explanation, “it is easy to see that we obtain a contradiction independently of whether we answer ‘yes’ or ‘no’ to this question (the argument runs more or less like in the liar’s paradox). grelling’s paradox is self-referential, since the definition of the predicate heterological refers to all predicates, including heterological itself. definitions such as these, which depend on a set of entities, at least one of which is the entity being defined, are called impredicative. berry’s paradox is also based on an impredicative description. bolander explains, “some phrases of the english language are descriptions of natural numbers, for example, “the sum of five and seven” is a description of the number 12. berry’s paradox arises when trying to determine the denotation of the following description: ‘the least number that cannot be referred to by a description containing less than 100 symbols’. the contradiction is that this description containing 93 symbols denotes a number which, by definition, cannot be denoted by any description containing less than 100 symbols. the description is of course impredicative, since it implicitly refers to all descriptions, including itself.” russell’s paradox is a set-theoretic paradox. states bolander, “russell’s paradox arises from considering the russell set r of all sets that are not members of themselves . . . the contradiction is derived by asking whether r is a member of itself . . . if r is an element of itself, then by the definition of the russell set, it is not a member of itself. if r is not an element of itself, then by definition, r is an element of itself. practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 17 language can interfere with logic and evidence this section and the next few sections will address problems with language as we use language to attempt to provide logical reasons to support our claims and to use the term “evidence” in its ideal sense. the vast majority of us are well-intentioned. when we speak to each other and argue a point, we try very hard to follow the rules as described by garlikov and zarefsky and others. it is just that certain limitations in the system get in the way of our goals as we imagine those goals. some of these limitations were addressed briefly in the section in this essay on interlude about learning. another limitation is the way we are able to use language. language serves as an instrument of thought and thought serves as a means to understanding. thus language, which is composed of words and syntax, is the currency of understanding. encarta defines understanding as the ability to explain to oneself a concept and seems to imply some degree of precision since, in theory, we would explain to ourselves a concept in the same way each time we explain it, otherwise, we would not truly “understand” the concept if we kept changing our minds. when we explain to ourselves, we may well understand the “message” in exactly the same way each time we ponder it, but what happens when we try to explain the concept or message to another person? we assume that another person understands language the same way we do, but study after study has shown that people do not understand seemingly simple bits of language in the same way. we all know from practical experience that we are often surprised by what ensues when we have relayed a message to someone. thought and logic in earlier essays in this series, especially in reasoning, we learned that the rules of logic are not the rules of our “natural” thinking processes. we looked at the work of gerd gigerenzer, who in adaptive thinking and gut feelings, explains the concept of “fast and frugal” heuristics and the role of environment of evolutionary adaptation in the evolution of what are truly our “natural” thinking processes. our “natural” thinking processes often lead to errors, although usually not life-threatening errors, which is why we have survived to pursue our studies. perhaps because we find our errors discombobulating, if not downright embarrassing, we maintain steadfastly that we can “do better.” to that end, certain patterns of thought and language have been observed throughout the ages and studies have been made to understand rules that lead to consistent and noncontradictory thought. we will examine both the rules and common misunderstandings of the rules later in this essay. rules of logic as rules of communication rules exist so that we can know what to expect. humans, despite occasional protestations to the contrary, hate surprises. one very important set of rules that we have relate to communication. without communication we could not exist. and without rules, there can be no effective communication. bennett, in logic made easy, states, “there are certain principles of ordinary conversation that we expect ourselves and others to follow. these principles underlie all reasoning that occurs in the normal course of the day and we expect that if a person is honest and reasonable, these principles will be followed. the guiding principle of rational behavior is consistency. if you are consistently consistent, i trust that you are not trying to pull the wool over my eyes or slip one by me . . . [these principles of conversation are] consistency and noncontradiction [which were] recognized very early on to be at the core of mathematical proof.” so in a way we expect the same rigor of ordinary conversation that we expect from mathematical proof. in fact, as we shall see, although logic is a function of language (discussed in the essay in this series on reasoning) the rules of logic, and even messages themselves, can be written symbolically and the formulae and equations can even be manipulated by computer algorithms. parenthetically, this should not surprise us much since mathematics in its purest form is the language of relationships (patterns) and not merely a way to manipulate numbers. common symbols used are s for subject and p for predicate. for conditional propositions (if/then statements), p is the antecedent and q is the consequent. aristotle noted that form determines the validity of an argument, regardless of the truth or falsity of the propositions. this allows the simplicity of using symbols, which in some systems are manipulated according to mathematical rules, to determine validity since one will not be distracted by the subject matter. in fact, mathematical proofs are evaluated for validity by computer programs developed for that purpose since to determine validity “by hand” is tedious, time-consuming, and prone to human error. truth or falsity of propositions must be determined separately since only a true and valid argument is a sound argument (as discussed in the essay in this series on reasoning). logic as a means of evaluating evidence many things in life are not straightforward. it may be obvious that “b” follows from “a”, but it may be less obvious that “g” or “m” or “z” is a consequence ultimately of “a.” in order to get from “a” to a conclusion, “g,” we require some sort of 18 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 “proof.” encarta defines “proof” as “evidence or an argument that serves to establish a fact or truth of something.” keith devlin, in mathematics: the science of patterns, states, “in propositional logic, a proof, or valid deduction, consists of a series of propositions such that each proposition in the series is either deduced from previous ones by means of modus ponens, or else is one of the assumptions that underlie the proof.” modus ponens, as discussed in the essay in this series on reasoning, follows the form, “if p, then q.” bennett explains, “the basic steps in any deductive proof, either mathematical or metaphysical, are the same. we begin with true (or agreed upon) statements, called premises, and concede at each step that the next statement or construction follows legitimately from the previous statements. when we arrive at the final statement, called our conclusion, we know it must be necessarily true due to our logical chain of reasoning.” i want to point out early in this discussion that ultimately, despite all these rules we are going to examine, our decision as to valid or not valid, true or not true, is based in trial-and-error and common sense, which result from our experiences. we use rules, or at least attempt to use them, because we think rules will lead us necessarily to a correct conclusion, but if at the end of our intellectual labors we can think of a counterexample that shows our conclusion to be false in some instance, we know our thread of reasoning contains an error or that we have run into a paradox that exposes our lack of understanding. bennett discusses the work of douglas hofstadter, who, in the words of bennett, “said that the study of logic began as an attempt to mechanize the thought processes of reasoning. hofstadter pointed out that even the ancient greeks knew ‘that reasoning is a patterned process, and is at least partially governed by statable laws.’ indeed, the greeks believed that deductive thought had patterns and quite possibly laws that could be articulated . . . [troubled by the sophists, who used ‘deliberate confusion and verbal tricks in the course of a debate to win an argument’] aristotle . . . attempted to systematically lay out rules that all might agree dealt exclusively with correct usage of certain statements called propositions.” bennett describes aristotle’s basic work in logic. aristotle strived to develop methods “to reason from generally accepted opinions about any problem set before us and shall ourselves, when sustaining an argument, avoid saying anything contradictory.” aristotle’s two basic axioms were “the law of the excluded middle” and the “law of noncontradiction.” law of the excluded middle explains bennett, “the law of the excluded middle requires that a thing must either possess a given attribute or must not possess it. a thing must be one way or another; there is no middle. in other words, the middle ground is excluded. a shape is either a circle or not a circle . . . a statement is either true or not true.” bennett points out that this law cannot be applied reasonably to all situations, since “fuzzy logic” applies to circumstances when application of the law of the excluded middle is inappropriate. a common tactic in debate is to pretend that the law of the excluded middle applies, when it does not apply. an opponent is encouraged, thereby, to accept a position he does not hold. examples offered by bennett, “either you are with me or you are against me. either you favor assisted suicide or you favor people suffering a lingering death.” recall the discussion on fuzzy logic put forth by bart kosko and described in the essay in this series on reasoning. how many apples are entirely red or entirely green? how many people like their jobs 100% of the time? inappropriate use of the law of the excluded middle is called the “black-and-white fallacy.” law of noncontradiction bennett describes the law of noncontradiction, “ . . . a thing cannot both be and not be at the same time. a figure cannot be both a square and not a square. two lines in a plane cannot both intersect and not intersect.” using syllogisms logicians understand that the basis of argumentation is the syllogism. bennett states that aristotle defined the syllogism as “ . . . discourse in which, certain things being stated, something other than what is stated [a conclusion] follows of necessity from their being so.” adds bennett, “in other words, a syllogism accepts only those conclusions that are inescapable from the stated premises.” syllogisms, as series of premises related to each other in some way, are composed of words, and certain of those words appear consistently in syllogisms, defining as they do the relationship of the subject (s) to predicate (p) of the premises offered. these simple words are used often by us and we each assume that “the other guy” understands them in exactly the same manner that we understand them. but we do not understand words such as “all”, “a”, “any”, “some”, “not”, “if”, and “then” in the same way. states bennett, “in reasoning and language comprehension, there are several factors to consider. sentences take on meaning based on the denotative (dictionary) meaning, the linguistic structure (syntax and semantics), and the connotation. connotation includes the factual and experiential knowledge that we bring to the material at hand . . . if p, then q can be expressed as: p never without q; p only if q; q if p; p is a sufficient condition for q; p implies q; q is a necessary condition for p; q is implied by p; or q whenever p. though they are identical statements in logic, there is no reason to believe that individuals interpret these sentence forms in the same way.” practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 19 quantifiers may be universal or particular. for example, “all,” “every,” and “none” are universal and specific, applying to the entire class under discussion, but the quantifiers “some,” “few,” and “many” are particular and vague, applying to only some members of the class under discussion. in classifying valid conclusions, the symbols a and i are assigned to propositions that are affirmations (derived from the word affirmo), a for universal and i for particular, while e and o are assigned to propositions that are negations (derived from the word nego), e for universal and o for particular. aristotle discovered that for three line syllogisms there were sixty-four possible ways that the four types of quantifiers (a, i, e, and o) could be combined, but only four of those combinations resulted in valid conclusions. (it seems that aristotle had discovered the problems that are associated with the “combinatorial explosion” as described by gigerenzer and discussed more completely in the earlier essay in this series on reasoning.) each combination is referred to as a “mood.” the valid moods are aaa, eae, aii, and eio. examples of valid syllogisms are aaa—all birds are animals; all canaries are birds; therefore, all canaries are animals; eae—no beans are animals; all chickpeas are beans; therefore, no chickpeas are animals; aii—all biographers are authors; some curators are biographers; therefore, some curators are authors; eio—no bases are acids; some chemicals are bases; therefore, some chemicals are not acids. syllogisms were also classified as to “figure.” which referred to the arrangement of terms in the syllogism. the conclusion is symbolized as, for example, “all s (subject) are p (predicate).” between the two premises of the syllogism, one contains the subject and the other the predicate of the conclusion. both premises contain a common term, called m, the middle term. bennett gives the example using the syllogism, “all poodles are dogs (first premise); all dogs are animals (second premise); therefore, all poodles are animals (conclusion).” in the conclusion, “poodles” is s and “animals” is p. the first premise is s-m and the second premise is m-p, where “dogs” is the middle term, m. considering the possible arrangements, s-m or m-s, m-p or p-m, aristotle called the “first figure” s-m, and m-p, the “second figure” s-m and p-m, and the “third figure” m-s and m-p for the premises. only the “first figure” is valid, recognized aristotle (“all dogs are poodles.” or m-s, for instance, is not true). aristotle resolved these syllogistic moods by applying his law of noncontradiction and settled ultimately on the rules we now use. reductio ad absurdum as proof bennett describes the basic steps in any deductive proof. one begins with true or agreed upon premises and concedes at each step that the ensuing statement follows legitimately from the previous statement(s). the final statement is the conclusion. a common type of proof is one of reductio ad absurdum, by which one arguer begins by accepting the opponent’s premise as true and argues logically by refutation to a contradiction by exposing inconsistencies in the opponent’s original argument, causing the opponent to give up his original premise as false. in all systems, agreement on the rules and definitions used in the system of interest is essential to maintaining consistency, so that reasoning in that system can be valid. for example, there is a difference between contradictories and contraries. confusing one for the other can lead to invalid arguments and unsound conclusions. contradictories versus contraries contradictories are paired statements such that both statements cannot be true and both cannot be false. for contradictories, one statement is universal (affirmation or denial) and its contradictory is particular (denial or affirmation, respectively). for example, “every person has enough to eat” is a universal statement, applying as it does to an entire set. the contradictory must be a particular (and not a universal) denial—“some people do not have enough to eat.” a particular applies to a subset, not to the entire set (humans in this example). in another example, “no individuals are altruistic” serves as the universal denial, while “some people are altruistic” serves as the particular affirmation in this contradictory pair. aristotle pointed out that every affirmative statement has its own opposite negative and vice versa. for contradictories, one statement of the pair will always be true and the other false. contradictories are represented by a with o and e with i in affirmo/nego terminology. contraries consist of opposite pairs in which both the affirmation and denial are universal or both are particulars. for contraries, both cannot be true, but it is also possible that neither is true. for example, “all people are rich” and “no people are rich” are contraries. contraries are represented by a with e and i with o in the affirmo/nego terminology. bennett credits john stuart mill with noting that people frequently confuse contradictories with contraries and that this confusion also occurs in one’s private thoughts. he opined that if people made these pairs of statements aloud they may detect their errors. bennett gives as example the common plaint “nobody around here helps out.” the contradictory is that “some of us help out.” and the contrary is “we all help out.” how often is the appropriate affirmation used in the heat of complaint? using quantifiers in logic quantifiers, mentioned in an earlier section in this essay, may be expressed explicitly or implicitly, and this variation in usage can lead to alternate interpretations. consider the uni20 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 versal quantifier “all.” bennett gives the example, “members in good standing may vote.” “all” is implied. the article “a” may be used as a universal quantifier, as in the example, “a library is a place to borrow books.” implying “all” libraries. confusion may arise in deduction logically by using different universal quantifiers. bennett cites a study in 1989 by david o’brien in which people of various ages (second graders, fourth graders, eighth graders and adults) were tested for their understanding of the universality of “all,”, “any,”, and “a” used in propositional statements. states bennett, “without exception, in every age group the tendency to err was greatest when the indefinite article a was used, “if a thing . . .” for older children and adults, errors decreased when any was used, “if any thing . . . ,” and errors virtually vanished with the universality was made explicit, “all things . . .” with the youngest children, though the errors did not vanish, they were reduced significantly when the universality was made clear with the word all.” problems with converse statements beginning with the basic form of a propositional statement, “quantifier subject (s) predicate (p)”, the statements “all s are p” and “all p are s” are converse statements. people may think they mean the same thing, but that is not a correct interpretation. bennett states that conversion is a common error during argument. both statements may be true, but they are not equivalent statements. bennett gives examples “all mothers are parents” versus “all parents are mothers.” the first statement is true, but the second is not true. “all dogs love their owners” versus “all (dog) owners love their dogs.” possibly neither statement is true. bennett describes a study in which children of varying ages were asked about a series of drawings of squares and circles. the children were shown a picture in which, from left to right, were drawn a gray circle, a white square, a gray circle, a white square, a gray square, a gray circle, a gray circle, and a gray square. the children were then asked questions such as “are all the squares white?” (considered by the examiners an easy question), “are all the circles gray?”, and “are all the white ones squares?” (considered by the examiners a more difficult question). states bennett, “the youngest subjects converted the quantification 50% of the time, thinking ‘all the squares are white’ meant the same as ‘all the white ones are squares’. this may be explained in part by the less developed language ability of the youngest children (ages 5-6), but their mistakes may also be explained by their inability to focus their attention on the relevant information [such as just squares or just white things] . . . by ages 8 and 9, children were able to correctly answer the easier questions 100% of the time and produced the incorrect conversion on the more difficult questions only 10 to 20% of the time.” another factor involved in reasoning is that of familiarity, or lack thereof, with the subject being reasoned about. states bennett, “the rules of inference dictating how one statement can follow from another and lead to logical conclusions are the same regardless of the content of the argument. logical reasoning is supposed to take place without regard to either the sense or truth of the statement or the material being reasoned about. yet, often reasoning is more difficult if the material under consideration is obscure or alien.” recall from the essay in this series on reasoning gigerenzer’s comparison of performance of test subjects on the wason selection task. one group was asked to reason about the cards “d,” “e,” “3,” and “4.” while the other group was asked to reason about the cards “subway”, “arlington”, “cab”, and “boston.” gigerenzer’s hypothesis was that, if logic is “natural” thought, most test subjects should perform correctly whether the problem was abstract (as in the d, e, 3, 4 scenario) or whether the problem concerned social interactions (as in the subway, arlington, cab, boston scenario). the tests were quite similar from a logical viewpoint. when the four cards on the table read “d,” “e,” “3,” and “4.” the conditional statement to be evaluated logically was “if there is a ‘d’ on one side of the card, then there is a ’3’ on the other side.” the test subjects were instructed to turn over any cards necessary to test the validity of the conditional statement. logic would dictate that, faced with a statement “if p, then q,” one must rule out, “p and not q.” the appropriate cards to turn over are “d” and “4.” in other scenario, when the four cards on the table were “subway,” “arlington,” “cab,” and “boston”, the conditional statement to be evaluated was “if a person goes to boston, then he takes the subway.” the cards to turn over are p (boston) and not q (cab). gigerenzer found that 10% of test subjects answered correctly in the abstract scenario and 30-40% of test subjects answered correctly in the social scenario, a much better performance; however, one might be tempted to conclude from this study that, even under the best of circumstances, less than half of us can think logically. bennett points out that familiarity is not always a help. she describes a study performed in 1928 by m. c. wilkins. the premise put forth to wilkins’ students was “all freshman take history i.” states bennett, “ . . . only 8% of her subjects accepted the conversion, ‘all students taking history i are freshmen.’ however, 20% of them accepted the equally erroneous conclusion, ‘some students taking history i are not freshmen.’ with strictly symbolic material (all s are p), the errors ‘all p are s’ and ‘some p are not s’ were made by 25% and 14% of the subjects, respectively. one might guess that in the first instance students retrieved common knowledge about their world—given the fact that all freshmen take history i does not mean that only freshmen take it. in fact, practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 21 they may have themselves observed nonfreshmen taking history i. so their conclusion was correct and they were able to construct a counterexample to prevent making the erroneous conversion. however, as they continued thinking along those lines, knowledge about their own world encouraged them to draw a (possibly true) conclusion that was not based on correct logical inference. ‘some students taking history i are not freshmen’ may or may not be true, but it does not follow logically from ‘all freshmen take history i’.” negation the interplay between language and logic can prove especially troublesome. as bennett pointed out earlier, statements that are equivalent in meaning by logic are not always interpreted as equivalent by a human reasoner. negation, or saying that something is not, proves difficult at times for humans to process. bennett explains that aristotle recognized early on in his studies that propositions meaning the same thing can be explained as either an affirmation or a negation. for example, “all humans are imperfect” is the affirmation, while “no humans are perfect” is a negation with an equivalent meaning. it is possible to affirm the absence of something or to deny the presence of something; thus, the same set of facts can be presented by affirmation or negation. how facts are presented, however, affects how people understand them. bennett describes a study in which test subjects were asked to perform certain written tasks. test subjects were timed and their accuracy assessed. basically, the same instruction was written as an affirmative, an implicit negative, and an explicit negative. papers were given to the test subjects, each with the arabic numerals 1 through 8 listed consecutively at the top of the page. one instruction said, “mark the numbers 1, 3, 4, 6, 7.” the next instruction said, “do not mark the numbers, 2, 5, 8, mark all the rest.” the third instruction said, “mark all the numbers except 2, 5, 8.” states bennett, “the subjects performed the task faster and with fewer errors of omission following the affirmative instruction even though the list of numbers was considerably longer. subjects performing the task using ‘except’ were clearly faster than those following the ‘not’ instruction, signifying that the implicit negatives were easier to understand than the instructions containing the word ‘not’.” bennett adds about the understanding of implicit negatives, “some negatives do not have an implicit negative counterpart, and those negatives are more difficult to evaluate. the statement, ‘the dress is not red’ is harder to process than a statement like ‘seven is not even’, because the negation ‘not even’ can be easily exchanged for ‘odd’, but ‘not red’ is not easily translated [and very difficult to visualize]. the difficulties involved with trying to visualize something that is not may well interfere with one’s ability to reason with negatives. if i say that i did not come by car, what do you see in your mind’s eye? it may be that, wherever possible, we translate negatives into affirmatives to more easily process information.” double negatives can cause problems with processing information as well. in reasoning by reductio ad absurdum, we want to prove a proposition, p, but to do so we assume not-p and argue to a contradiction. we conclude “not-not-p” or “p.” bennett points out that referendum questions at the voting booth often use wording that makes one’s choice seem counterintuitive and confuses voters. her example is from a ballot managing her retirement funds. “proposal: to stop investing in companies supporting gun control . . . voting ‘for’ means you are against gun control [are for easily obtainable guns] and voting ‘against’ means you favor gun control [are against easily obtainable guns] . . . if the process of negation involves an extra mental step, a double negative can be mind boggling. ‘the probability of a false negative for the pregnancy test is 1%’ or ‘no non-new yorkers are required to complete form 203’ or ‘the statistical test indicates that you cannot reject the hypothesis with no difference’ can cause listeners to scratch their heads (or give them a headache).” in a line from a story from john mortimer’s rumpole of the bailey, horace rumpole, barrister at law, cross-examines an expert witness on the subject of bloodstains. the witness states, “the finding is not inconsistent with your hypothesis.” an exasperated rumpole counters, “does not ‘not inconsistent’, when translated to plain english, mean ‘consistent’?” the witness: “yes, it does.” common sense reigns, albeit temporarily, at last. a brief recap so far we have seen that, although rules have been discovered that assist us in reasoning logically so that we might evaluate “evidence” according to an ideal, problems with the use of language, resulting as it does in differences in interpretation, often interfere with the ideal of formal logic to which we aspire. also, speaking from the standpoint of philosophy, we may not even understand fully the concepts of “truth” and “definability” since paradoxes exist involving those terms. there is disagreement about what sorts of things should be allowed to be considered evidence. nonetheless, each of us on some level think we understand what “evidence” is and that “evidence” is, or at least should be, true and unassailable. this leads to a cognitive dissonance that simmers just under our awareness and causes problems for us as we interact with our fellow man. evidence based medicine the cognitive dissonance we all experience relative to evidence spills necessarily over into our professional lives. today, 22 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 we are all expected to practice so-called evidence based medicine. to do otherwise, we are told, is to risk unnecessarily patients’ lives and to cause too much money to be spent on healthcare. so what is meant by evidence in the case of evidence based medicine? despite a well-meaning start, pretty much “evidence” in medicine has come to mean the outcome of a clinical trial, that outcome having been interpreted by an expert in the field. at its outset, the premise underlying evidence based medicine was that each physician, having completed his or her studies of basic medical science (anatomy, physiology, pathology, pharmacology and the like), would determine for each patient the best course of action by doing his/her own research of the literature. by doing so, each physician would break the bond to “authority.” no longer would each physician “parrot” what s/he thought a mentor would do in a similar situation. s/he would find out the results of the latest studies and act according to the “best evidence.” what ensued, however, was a distortion of the ideal. maya goldenberg, in “iconoclast or creed? objectivism, pragmatism, and the hierarchy of evidence” in perspectives in biology and medicine, states, “objectivity is an epistemic virtue in science that stands for an aperspectival ‘view from nowhere’, certainty, and freedom from bias, values, interpretation, and prejudice. even if objectivity cannot be achieved, it is perceived to be an ideal worth striving for.” goldenberg explains that the idea for evidence based medicine arose from the “pragmatism” movement in philosophy, a movement founded by charles sanders peirce and william james. the doctrines underlying pragmatism are “(1) the meaning of concepts is to be sought in their practical bearings; (2) the function of thought is to guide action; and (3) truth is preeminently to be tested by the practical consequences of belief.” goldenberg quotes james stating that pragmatism stands for “the open air and possibilities of nature, as against dogma, artificiality and the pretense of finality in truth . . . [pragmatists] turn toward concreteness and adequacy, towards facts, towards action, and towards power. that means the empiricist temper regnant, and the rationalist temper sincerely given up . . . [pragmatism] does not stand for any special results [or doctrines]. it is a method only.” goldenberg agrees that the allegiance of evidence based medicine to the randomized controlled trial captures the tenor of pragmatism; however, the strict adherence of evidence based medicine to its hierarchy of evidence, which is based in a ranking of study designs based on the supposed rigor of their methodology, goes against the spirit of pragmatism. of hierarchies, kirstin borgerson, in “valuing evidence: bias and the evidence hierarchy of evidence-based medicine” in perspectives in biology and medicine, states that evidence based medicine advocates “are not just claiming that it is helpful to be able to distinguish, for instance, good from bad rcts [randomized controlled trials] or better from worse cohort studies. they have made an assumption about the necessity of ranking these methods against one another so that a critical review of the literature will produce one, hopefully decisive, answer . . . [there are multiple possible hierarchies] . . . no one has seriously (that is, explicitly and methodologically) argued for any particular hierarchy. hierarchies are more often asserted than argued for.” performance of randomized controlled trials (rcts) is a pragmatic methodology, writes goldenberg, since the purpose of them is to “temporarily suspend prior knowledge of human physiology, disease, and pharmacology, all of which might allow for inferences regarding the effectiveness of a particular drug in treating a given condition, and instead determine whether a treatment works by trying the treatment in a large number of cases under controlled conditions.” goldenberg explains that rcts are “ostensibly unhindered by the pre-theoretic expectations and commitments that can bias the deductive methods of basic science and the less systematic experimental methods of clinical experience and observational studies . . . absent the influence of anticipated outcomes, scientists faced with recalcitrant empirical data should be more open to revising even well-established views about treatment efficacy.” goldenberg points out that randomization and blinding are not always appropriate. small sample size renders randomization futile, for example, and blinding is not always possible, as in studying the negative effects of smoking. ethical considerations arise in studying effects of surgery, since sham surgical procedures would be required to truly blind interpretation of results. furthermore, some social contexts may result in bleeding of effects of the study if, for example, study patients share their medications with friends participating in the study, hoping that everyone will benefit from a new therapeutic agent. in a blinded study, subjects may have an incentive to lie about their actions, if they fear being reprimanded for breaking the blinding effect of the study. the hierarchy of evidence based medicine asserts that randomized controlled trials are always better evidence than alternative studies such as observational studies, even though different health research studies call for different designs so there really is no gold standard methodology. for example, robin bluhm, in “from hierarchy to network: a richer view of evidence for evidence-based medicine” in perspectives in biology and medicine, states of studies of epidemiology, “ . . . epidemiology is not generally an experimental science. the epidemiologist must try to identify causal factors ‘in the wild’ rather than in the controlled environment of the laboratory.” bluhm points out that progress in medicine requires the close interaction of epidemiologists, who attempt to establish causes of disease, and laboratory scientists, who can design practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 23 experiments to compare outcomes between study and control groups. the most common study design for epidemiology, asserts bluhm, is the cohort study, in which groups, similar in most ways, differ in a finding of interest, and are observed and compared over time to determine if the finding of interest leads to a different incidence of a separate finding at the later time. for example, is smoking associated with an increased incidence of lung cancer, or is a high cholesterol level associated with an increased incidence of myocardial infarction? cohort studies are similar to randomized controlled trials in that the populations are followed over time. in the cohort study one population is exposed to some factor, while in the rct one population receives an intervention, such as a drug or surgical procedure. other sorts of studies include case reports and cross sectional surveys. different types of studies have varying strengths and weaknesses. goldenberg discusses the work of upshur and tracy, “ . . . the entire edifice of evidence hierarchies is . . . based upon expert judgment or consensus. they charge that ‘the structuring of evidence according to hierarchy is by no means natural, intuitive, or even logically justified’ . . . upshur and tracy propose that the initial creation of an evidence hierarchy was intended to link the quality of evidence to the soundness of the recommendations based on the evidence . . . on the belief that these methods [rcts and meta-analyses] are less susceptible than observational designs to bias. the key is the ability of randomization to eliminate selection bias and the unprovable claim that randomization balances all relevant known and unknown factors in a probabilistic sense. the hierarchy attributes lower reliability to expert judgment, and specifically subordinates theory and pathophysiological reasoning to designs with randomization. the reasoning behind the latter subordination is unclear, as pathophysiology often provides more fundamental understanding of causation and is in no way scientifically inferior. thus, upshur and tracy conclude, the hierarchy has been advanced on the basis of expert opinion rather than reasoned argument—a move unbefitting of evidence-based thought and practice.” goldenberg asserts that adherents of evidence based medicine have failed to recognize the fallibility of scientific evidence, preferring instead to undertake a “sort of absolutist search for certainty.” she discusses the work of paul feyerabend who “described science as being obsessed with its own mythology of objectivity and universality.” goldenberg continues, “if the hierarchy of evidence was put in place to refute skepticism and ensure certainty, it stands as an example of what feyerabend abhorred: science making claims to truth well beyond its actual capacity.” mark tonelli, in “evidence-free medicine: forgoing evidence in clinical decision making” in perspectives in biology and medicine, opens his article, “at some time in the not-toodistant past, medicine was apparently practiced in the absence of evidence. i know this to be the case because a medline search for the term ‘evidence-based medicine’ prior to 1990 yields virtually no returns . . . by the time i had completed residency and fellowship in 1996, evidence-based medicine (ebm) had gone from ‘paradigm shifting’ concept to widely accepted dogma.” tonelli bemoans that establishing hierarchies of evidence has distracted the medical profession from its calling, which is to arrive at the best possible decision, be it diagnosis or treatment, for the individual patient. says tonelli, “ . . . the myriad attempts to define, categorize, and stratify evidence for use in clinical medicine have only resulted in a epistemic and linguistic morass . . . instead of arguing about what does or does not constitute evidence in support of a clinical decision, we should more carefully examine the central question regarding the legitimacy of various potential facts and warrants for clinical decision making.” tonelli notes that clinical medicine does not lend itself to formal, deductive logic, but utilizes the informal logic of argumentation. states tonelli, “clinical judgment requires the use of various kinds of reasoning. done well, clinical decision making closely resembles the structure of argumentation, with careful consideration of many facts, warrants, backings, and rebuttals, ultimately resulting in a conclusion that is only probably, never demonstrably, correct.” tonelli refers to the work of toulmin, the uses of argument, noting, “ . . . data, or basic facts, are often invoked as a foundation to a claim, but that facts alone are inherently insufficient to provide legitimate support to any claim. in arriving at or defending a particular conclusion, we must go beyond producing facts to providing warrants, more general and hypothetical propositions that are necessary to have the particular fact support a particular claim.” tonelli opines that proponents of evidence based medicine consider fact and warrant as a bundle—the fact serves as its own warrant. he gives the example that a certain pitcher may be considered the best based on a low earned run average (era)—the fact. but, maintains tonelli, the arguer of this claim must warrant that the era is superior to all other measures of pitching excellence to back his claim. physicians, asked about their evidence for a certain decision, often merely cite a reference. they do not then warrant their use of that reference-datum by explaining why it is superior to other possible choices in this particular patient at this time. tonelli insists that it is most important to show that the warrants that are invoked to support a claim based upon the facts in the reference are legitimate. he adds that establishing legitimacy of a warrant requires “an understanding of the underlying metaphysical and epistemic underpinnings of a healing discipline.” tonelli recognizes five broad classes of legitimate potential warrants: pathophysiologic rationale, results of clinical 24 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 research, clinical experience, patient goals and values, and system features. he notes that the relative importance of any warrant will depend on the specifics of the patient. a warrant from any of the five classes may be the most important in a particular case. since the classes of warrants “differ from one another in kind, not in degree . . . no meaningful hierarchies of potential warrants can exist across the [classes].” within a class, a basic hierarchy might be appropriate. for example, the clinical experience of a medical student would likely carry less weight than the experience of the attending generalist, whose experience would carry less weight than a specialist. however, even within a class of warrants, hierarchies “must be considered general and not prescriptive, serving only as guidelines, not clinical rules . . . often facts and warrants from each of the five classes are likely to be coherent, all supporting the same clinical decision . . . [but] when warrants conflict, supporting different conclusions regarding the right diagnosis or course of action . . . the clinician’s judgment is put to the test.” tonelli opines, “the demand for evidence distracts clinicians, requiring them to search outside of the clinician-patient relationship for answers to questions that are not directly applicable to the patient at hand . . . the answer to a great many important and interesting general medical questions can be discovered by searching, analyzing, and interpreting published clinical research. the answer to the question of what to do about the individual patient, however, does not exist outside of the clinician-patient relationship waiting to be discovered.” tonelli observes, “the consummate clinician is one who can identify all the relevant facts and warrants and, when necessary, negotiate between conflicting warrants by weighing each in the context of the particular patient at hand. the excellent clinician must, by necessity, have a well-developed knowledge base that includes understanding of biologic and physiologic concepts and principles, the relevant clinical research in her specialty, substantial personal experience, and, preferably, access to clinicians with even more. in addition to this knowledge base, the clinician must also have the skills and inclination to understand patient preferences, goals, and values, as well as an understanding of the facilitators and barriers to optimal care inherent in the system in which she practices. no wonder ebm’s simple five-step process has such appeal. training clinicians to practice an evidence-free medicine is significantly more challenging than training them to practice ebm.” parenthetically, the “simple five-step process” of evidencebased practice is as follows: 1) formulate a well-built question, 2) identify articles and other evidence-based resources that answer the question, 3) critically appraise the evidence to assess its validity, 4) apply the evidence, and 5) re-evaluate the application of evidence and areas for improvement. relative to step three, family practitioner ross upshur, in “looking for rules in a world of exceptions,” in perspectives in biology and medicine, noted that it had been estimated that “a physician would need to spend 627.5 hours just to read the 7,287 articles relevant to primary care each month. and that is just reading, never mind the “critically appraise” part. so evidence based medicine seems to be another distortion of the profession of medical practice, along with the expectation that no errors are tolerable or should occur while we care for our patients, that we can take care of the total needs of a patient in a seven minute office visit, and similar expectations with which we are all familiar. attributed to albert einstein is the saying “all things should be made as simple as possible, but not simpler.” slobodkin has pointed out, in simplicity & complexity in games of the intellect, that it is human nature to simplify some aspects of life and to complexify (for example by ritual) other aspects of life. we all decry “error” in the practice of medicine. but how much of the aggregate of unexpected and less than desired outcomes is really due to error per se, how much is due to unreasonable expectation on the part of patients and ourselves as medical practitioners, and how much is due to a lack of understanding (because we humans simply have not yet made the discoveries) of basic science, clinical medicine, and principles of complexity theory or system theory? it seems that perhaps evidence based medicine has evolved into an attempt to simplify the practice of medicine too much. conclusion in the end, it seems to me that “evidence” truly is, as defined, “that which justifies belief” and nothing more. we each feel justified in believing what we believe. if our belief comes to us by revelation or authority, we still consider it a belief and we feel justified in believing it. if this is true, then evidence is best considered just another word for a “reason” or “reasons.” attempts have been made throughout the ages to give “evidence” a “higher calling” by insisting on proof that something labeled as “evidence” is true and warrants any conclusions drawn from that evidence. but, as we have seen in this essay, there are so many factors involved, from language to education to paying attention to the proper things at the moment of reasoning, that the formal rules discovered are likely to never be our “natural” process of thinking. where most of us are concerned, the pretense of “evidence” to a scientific ideal is merely an illusion. as garlikov might say, we have not learned the rules of the game to use evidence as ideal. evidence is the aggregate of reasons we use to justify our belief in some fact or claim. those reasons may or may not follow the rules of argumentation and those reasons may not practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 25 actually lead an astute reasoner to conclude our claim. in the end, evidence does not guarantee truth or certainty. the label “evidence” applied to a fact does not make that fact any more likely to support a valid conclusion. what is important is the process we use to support a claim, the process of argumentation, by which we warrant why a piece of evidence is pertinent to the claim. we hold in our minds the ideal that evidence is true and unassailable, but we can never reach that ideal and for a number of reasons. we are limited by our understanding of basic concepts, such as “truth” and “definability”, that lead unavoidably to paradox. we cannot possibly ensure that we understand the same message in exactly the same way, nor do we understand the most basic concepts of our language in the same way, for example dealing with “if/then” hypotheses, negations, and the like. we all live unavoidably with cognitive dissonance, believing contradictory statements, most often because we cannot drag the contradictions into our working memories simultaneously to recognize that they are contradictory. nonetheless, in a manner analogous to discovering the rules of logical thought, a process begun in earnest by aristotle, following the principles of the scientific method, whereby hypotheses are tested according to a body of organizing principles and the test results are examined and interpreted independently by multiple investigators, seems to provide the best way to advance knowledge, while minimizing opportunities for inconsistency and contradiction. argumentation and science share the same basic principles in that people with differing views are willing to look at a problem from different perspectives and are willing to risk being proved wrong in the interest of acquiring a common understanding of an issue. reasons, properly warranted, comprise the best form of evidence, evidence serving as a means to the end of gaining knowledge. however, human nature being what it is, we sometimes “put the cart before the horse” and think that the end justifies the means. if we imagine a desired end and then create a “story” that we label as “evidence” for the purpose of persuasion only, if we put consistently the goal of winning an argument ahead of better understanding, as aristotle accused the sophists of doing, then we are lost. in a manner analogous to vaccination to minimize the spread of infectious disease, the vast majority of people should take the time to understand more fully the rules of logic and the common problems that interfere with thinking consistently and without contradiction. then the populace at large would be at least in a position to know a reasoned argument when confronted with such an animal. michael shermer, as discussed in the essay in this series on interpretation, has pointed out, “anecdotal thinking comes naturally; science requires training.” it is up to each of us to do our part to further the common cause of ensuring that our collective knowledge base is as consistent and noncontradictory as possible. upshur, in “making the grade: assuring trustworthiness in evidence” in perspectives in biology and medicine, quotes alfred north whitehead (1929), “the chief danger to philosophy is narrowness in the selection of evidence. this narrowness arises from the idiosyncracies and timidities of particular authors, of particular groups, of particular schools of thought, of particular epochs in the history of civilization. the evidence relied upon is arbitrarily biased by the temperaments of individuals, by the provincialities of groups, and by the limitations of schemes of thought.” when confronted with inconsistencies and contradiction, we must try to discover the source of inconsistency or contradiction. we may find, by reviewing and applying assiduously the known rules of logic, an error in our proof. we can be aware of our biases and try to think more broadly. we can ask ourselves if we are being a bit slavish to authority. if a true paradox arises, we can try to expand the scheme of our thought and try to look at the problem from a new perspective from which paradox disappears. parenthetically, as an example, for zeno’s paradox involving infinity, zeno proposed that achilles could never catch up to or pass the tortoise, who started with a 10-meter head start, in the race because he (achilles) would only close a certain percentage of the gap in what mathematically is represented by an infinite series. manipulating the formula mathematically gives a finite equation, showing that achilles draws level with the tortoise when the tortoise has moved 1 and 1/9 meters. a better understanding of infinite series eliminated the paradox. i am not sure we are yet ready to solve the liar’s paradox, but theoretically, as suggested by whitehead, we could look at the problem from another less limited perspective to solve the paradox. but, as bolander explains, that will require a new understanding of “truth.” until we better understand truth, we must stop thinking of “evidence” as true and unassailable. and we should understand that our collective knowledge base has necessarily items in it that will require revision in the future. i think it is most important that we learn more about the limitations of humans and to ensure that as many of us as possible have access to that knowledge. only then will we be able to design systems that are effective, including an effective healthcare system. that humans have imagination is both boon and bane. imagination has enabled us to survive, to prepare for the future, and to dream of a better world. but the downside of this is that we are tempted to believe that what we imagine is true and/or attainable, regardless of whether or not we truly understand “reality,” or principles of universal law. we are in danger, as goldenberg said of feyerabend’s words, of making claims to truth well beyond our capacity. 26 practical, conceptual or educational notes | dermatol pract concept 2014;4(1):3 learning to accept “evidence” for what it really represents instead of what we want it to represent will be a start. summary we tend to think of evidence that it must be of necessity true and unassailable, but that does not conform to reality. evidence is really just a reason or reasons that we use to justify our beliefs. we try to hold evidence to an ideal, but because of our innate fallibility, which occurs as a direct result of our evolution within the environment with which we have co-evolved, we cannot ensure evidence meets that ideal. the nature of language and the use of that language by us is a major impediment to maintaining consistency and avoiding contradiction in our communication with one another. additionally, our “natural” thought processes do not follow the rules of logic as discovered by logicians throughout the ages. this being the case, we must endeavor to understand better our human fallibility and learn to work within our capabilities. to do so, we must accept “evidence” as what it is instead of what we would like it to be. dr. anderson is a retired general pathologist, residing in carbondale, illinois, and teaching part-time at her alma mater, southern illinois university school of medicine. bibliography anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part ii: the role of emotion, feeling, and consciousness. dermatopathology: practical & conceptual. 2004;10(2):15. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part iii: the concept of truth. dermatopathology: practical & conceptual. 2004;10(3):20. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part viii: interpretation. dermatopathology: practical & conceptual. 2006;12(4):23. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part x: causation. dermatopathology: practical & conceptual. 2008;14(2):20. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xi: reasoning. dermatopathology: practical & conceptual. 2008;14(4):22. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xii: detecting and using patterns. dermatopathology: practical & conceptual. 2009;15(2):16. bennett d. logic made easy: how to know when language deceives you. new york: w. w. norton & co. 2004: pp 19-20, 30, 29, 31, 3536, 40, 49, 54-57, 66, 73-79, 102, bluhm r. from hierarchy to network: a richer view of evidence for evidence-based medicine. perspect biol med. 2005;48(4):535-47. bolander t. “self-reference.” stanford encyclopedia of philosophy (summer 2008). edward n. zalta (ed). url=<http://plato.stanford. edu/entries/self-reference/> borgerson k. valuing evidence: bias and the evidence hierarchy of evidence-based medicine. perspect biol med. 2009;52(2):218-33. cloud p. oasis in space: earth history from the beginning. new york: w. w. norton & co. 1988. p 47. devlin k. mathematics: the science of patterns. new york: w. h. freeman and company. 1994. p 47, 74. difate v. “evidence.” the internet encyclopedia of philosophy (2007). url=<http://iep.utm.edu/e/evidence.htm> goldenberg m. iconoclast or creed? objectivism, pragmatism, and the hierarchy of evidence. perspect biol med. 2009;52(2):168-87. kelly t. “evidence.” the stanford encyclopedia of philosophy (fall 2008 ed). edwardn. zalta (ed). url=<http://plato.stanford.edu/ archives/fall2008/entries/evidence/> pinker s. the stuff of thought: language as a window into human nature. new york: penguin books. 2007: 72, 154-5. slobodkin l. simplicity & complexity in games of the intellect. cambridge, massachusetts: harvard university press. 1992. p 74. tonelli mr. evidence-free medicine: forgoing evidence in clinical decision making. perspect biol med. 2009;52(2):319-31. upshur re. looking for rules in a world of exceptions: reflections on evidence-based practice. perspect biol med. 2005;48(4):477-89. upshur re. making the grade: assuring trustworthiness in evidence. perspect biol med. 2009;52(2):264-75. zarefsky d. argumentation: the study of effective reasoning. 2nd edition. audio course. chantilly, va: the teaching company. 2005. lecture 2. http://plato.stanford.edu/entries/self-reference/ http://plato.stanford.edu/entries/self-reference/ http://plato.stanford.edu/archives/fall2008/entries/evidence/ http://plato.stanford.edu/archives/fall2008/entries/evidence/ dermatology: practical and conceptual 214 commentary | dermatol pract concept 2019;9(3):9 dermatology practical & conceptual dermoscopy is a valuable tool in improving the accuracy of diagnosing skin lesions. slowly it has started to gain popularity among primary care physicians as a helpful tool in their practice; however, their ability to integrate dermoscopy is dependent on being suitably trained on how to use it [1]. primary care providers are often the first to examine new skin lesions on their patients, and having them skilled in dermoscopy would be advantageous in screening for potential skin cancers. the article “standard dermoscopy and videodermoscopy as tools for medical student dermatologic education” provides an innovative direction to make learning about skin pathology important in medical student education and more interactive for students [1]. having students use dermoscopy on live patients makes teaching the material more concrete and clear, compared to simply learning it from a textbook. it demonstrates in real time the impact dermoscopy can have on clinical assessments of skin lesions. when trying to bring a new technology to the general practitioner, it is best to start integrating the technology at the earliest level of training. if the idea of using dermoscopy is taught during the early years of medical school, then students will continue to build on their skills gradually over several years, similarly to how many schools teach the basic skills of otoscopy and fundoscopy. many medical schools are currently undergoing curriculum reform [2]. medical schools are looking for innovative ways to make their curriculum more interactive and engaging. this is a perfect time to integrate a technology like this into a medical school education. bringing in real-life examples will get students interested in learning about dermoscopy, and they will be able to see the direct impact it can have on their diagnostic skills. creating programs for teaching dermoscopy can help a medical school stand out on the forefront of education and attract students who are interested in incorporating this type of technology into their future practices. references 1. cho hg, sheu sl, chiang a, nord km. standard dermoscopy and videodermoscopy as tools for medical student dermatologic education. dermatol pract concept. 2018;8(1):39-42. 2. fischel je, olvet dm, iuli rj, lu wh, chandran l. curriculum reform and evolution: innovative content and processes at one us medical school. med teach. 2019;41(1)99-106. standard dermoscopy and videodermoscopy as tools for medical school education arjun d. saini1, edward prodanovic1 1 eastern virginia medical school, norfolk, va, usa key words: dermoscopy, medical school, education, reform, curriculum, student, learning, dermatology, videodermoscopy citation: saini ad, prodanovic e. standard dermoscopy and videodermoscopy as tools for medical school education. dermatol pract concept. 2019;9(3):214. doi: https://doi.org/10.5826/dpc.0903a09 accepted: january 2, 2019; published: july 31, 2019 copyright: ©2019 saini and prodanovic. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: arjun saini, ms, 270 w york street, apt. 3404, norfolk, va 23510. email: sainiad@evms.edu dermatology: practical and conceptual case report | dermatol pract concept 2016;6(2):3 9 dermatology practical & conceptual www.derm101.com hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective balachandra s. ankad1, savitha l. beergouder1 1 department of dermatology, s. nijalingappa medical college, bagalkot, karnataka, india key words: dermoscopy, hypertrophic lichen planus, prurigo nodularis, histopathology, patterns citation: ankad bs, beergouder sl. hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective. dermatol pract concept 2016;6(2):3. doi: 10.5826/dpc.0602a03 received: september 14, 2015; accepted: february 3, 2016; published: april 30, 2016 copyright: ©2016 ankad et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. balachandra s. ankad, associate professor, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587103, karnataka, india. tel. +91 9980410056; fax. 08354 235360. e-mail: drbsankad@gmail.com background: hypertrophic lichen planus (hlp) classically involves shin and ankles and is characterized by hyperkeratotic plaques and nodules. prurigo nodularis (pn) is a chronic neurodermatitis that presents with intensely pruritic nodules. histopathology of hlp and pn demonstrate epidermal hyperplasia, hypergranulosis, and compact hyperkeratosis. the dermis shows vertically arranged collagen fibers and an increased number of fibroblasts and capillaries in both conditions. moreover, basal cell degeneration is confined to the tips of rete ridges, and band-like infiltration is conspicuously absent in hlp. therefore, both conditions mimic each other clinically, which makes diagnosis difficult. hence, there is a need for a diagnostic technique to differentiate both conditions. objective: to evaluate dermoscopic patterns in hlp and pn and to study these patterns histopathologically. materials and methods: the study was conducted at s. nijalingappa medical college in bagalkot. it was an observational case series study. ethical clearance and informed consent was obtained. a dermlite 3 dermoscope (3gen, san juan capistrano, ca, usa) attached to a sony cyber shot camera dsc-w800 (sony electronics inc., san diego, california, usa) was employed. histopathology was done to confirm the diagnosis. results: there were 10 patients each with hlp and pn. hlp was seen in 8 males and 2 females. pn was observed in 7 females and 3 males. dermoscopy of hlp demonstrated pearly white areas and peripheral striations (100%), gray-blue globules (60%), comedo-like openings (30%), red dots (40%), red globules (10%), brownish-black globules (30%), and yellowish structures (90%). in pn, red dots (70%), red globules (60%), and pearly white areas with peripheral striations (100%) were observed under dermoscopy. conclusion: both hlp and pn demonstrated specific dermoscopic patterns which can be demonstrated on histopathologic findings. the authors propose that these patterns are hallmarks of each condition. thus, dermoscopy is a good diagnostic tool in the differentiation of hlp and pn. abstract mailto:drbsankad@gmail.com 10 case report | dermatol pract concept 2016;6(2):3 parakeratosis, and hypergranulosis. the papillary dermis shows fibrosis with vertically arranged collagen fibers and increased number of fibroblasts and capillaries [8]. hence, histopathologic differentiation of both hlp and pn is difficult in a few instances. the authors evaluated the dermoscopic patterns in both conditions and believe that these patterns were specific to each condition that would help in differentiating two diseases. materials and methods the study was conducted in the department of dermatology in a tertiary hospital attached to s. nijalingappa medical college at bagalkot in southern india from october 2014 to july 2015. it was an observational case series study. ten patients each with clinical signs and symptoms of hlp and pn were subjected to complete history and dermatological examination. ethical clearance was obtained by the institutional ethical committee. informed written consent was taken from patients. demographic data such as age, gender and disease duration were all documented. dermoscopic examination a dermlite 3 dermoscope (with 10x magnification) with both polarized and non-polarized lights was employed in the study. sony digital camera (14 megapixels) was attached to save the images. initially, ultrasound gel was applied either on the faceplate of the dermoscope or on the skin lesions and then lesions were observed through the eyepiece of the dermoscope. however, only the polarized light version was used in our study to appreciate color patterns in the dermis. although polarized dermoscopy was employed, ultrasound gel was applied for clarity of images and to lessen distortions associated with light [9]. introduction hypertrophic lichen planus (hlp) is the second most common cutaneous variant of lichen planus. it is characterized as extremely pruritic, and thick hyperkeratotic plaques are seen primarily on the shins or dorsal aspect of the foot and may be covered by a fine adherent scale. the lesions are usually symmetrical and tend to be chronic because of repetitive scratching. later, lesions become hyperkeratotic thickened elevated purplish or reddish plaques and nodules. the average duration of hlp in patients whose lesions had cleared was reported to be 6 years. chronic venous stasis frequently contributes to the development of this condition (figure 1a) [1,2]. prurigo nodularis (pn) is a chronic, benign neurodermatitis of unclear etiology characterized by excoriated, intensely pruritic nodules, which are secondary to an intense itchscratch cycle (figure 1b). it was first described by hardaway in 1880 and named by hyde and montgomery in 1909 [2]. it is found on exposed extensor surfaces of the lower extremities. vigorous scratching or rubbing results in lichenification, neurotic excoriations, and nodulation [3,4]. hlp and pn mimic each other clinically, especially when hlp affects the lower legs [3, 5]. histopathology of hlp reveals epidermal hyperplasia, acanthosis, hypergranulosis and compact and lamellated hyperkeratosis centered on follicular infundibula and acrosyringia. basal cell damage is usually confined to the tips of rete ridges and may be missed on casual observation [6]. bandlike infiltration is distinctly missing in the dermis [7]. these pitfalls in histopathology of hlp make it difficult to diagnose histopathologically, unlike classical lp. collagen bundles are oriented vertically in the papillary dermis in association with an increased number of eosinophils [6]. the characteristic histopathology of pn is the presence of thick, compact orthohyperkeratosis, irregular epidermal hyperplasia or pseudoepitheliomatous hyperplasia, focal figure 1. (a) hyperkeratotic, thickened, plaques and nodules on the legs in hypertrophic lichen planus. (b) hyperkeratotic papules, plaques and nodules on the legs and dorsum of feet in prurigo nodularis. [copyright: ©2016 ankad et al.] case report | dermatol pract concept 2016;6(2):3 11 results out of 10 hlp, 8 male and 2 female patients were present between the ages of 26 and 50 years (mean age 38 years). duration of disease was between 4 months and 48 months. dermoscopy demonstrated milky white structures at the center and grayish strands which were arranged peripherally. this was referred to as pearly white areas (wickham’s striae) and peripheral striations (figures 2-4). gray-blue globules were present diffusely in the center extending peripherally (figure 3). comedo-like openings (clo) were observed as regular dells filled with keratin on the surface and were situated diffusely over the lesions (figures 3, 4). yellowish structures observed were arranged in a lacy network over the lesions (figure 4). tiny pigmented areas referred to as brownish-black globules were present at the periphery of the lesions (figure 3). red dots and red globules were present at the center and periphery (figures 3, 4). histopathology of hlp demonstrated orthokeratosis, hypergranulosis, and elongation of rete ridges (figure 5a). dermoscopic patterns with corresponding histopathologic changes are tabulated in table 1. pn was observed in 7 female and 3 male patients with ages ranging from 20 to 54 years. mean duration of disease was 4 years (minimum 1 year and maximum 7 years). histopathology of pn showed orthokeratosis and hyperkeratosis, irregular acanthosis and elongated rete ridges (figure 5b). dermoscopy of pn demonstrated pearly white structures in the center with peripheral extensions. the pattern is described as “starburst” appearance. these white areas were surrounded by peripheral striations (figure 6). red dots and red globules (figures 6, 7) were located diffusely in the center. dermoscopic patterns and corresponding histopathologic changes are represented in table 2. frequencies of each dermoscopic pattern in hlp and pn are shown in figure 8. all new and old lesions of hlp and both excoriated and hyperkeratotic lesions of pn were examined under dermoscopy. data was tabulated in a microsoft excel® sheet. proportions and percentages were used for representing the data. histopathology was carried out in both hlp and pn to confirm the diagnosis by taking a punch biopsy from each type of lesion. inclusion criteria: 1. patients with signs and symptoms of hlp and pn. 2. patients who had not received or stopped treatment for hlp and pn 1 month prior to the study. exclusion criteria: 1. patients with secondary infection superseding hlp and pn. 2. patients who were receiving treatment 1 month prior to the study. figure 2. dermoscopy of hypertrophic lichen planus shows pearly white areas (stars), peripheral striations (arrows). [copyright: ©2016 ankad et al.] figure 3. dermoscopy of hypertrophic lichen planus shows grayblue globules (hexagons), comedo-like openings (arrows), brownishblack dots (circles) and red globules (stars). [copyright: ©2016 ankad et al.] figure 4. dermoscopy of hypertrophic lichen planus shows yellowish structure (black arrows), comedo-like openings (white arrows) and peripheral blood vessels (circles). [copyright: ©2016 ankad et al.] 12 case report | dermatol pract concept 2016;6(2):3 table 1. proposed dermoscopic patterns corresponding to histopathologic features in hypertrophic lichen planus. [copyright: ©2016 ankad et al.] dermoscopic patterns corresponding histopathologic changes 1 pearly white areas (wickham striae); and peripheral striations compact orthokeratosis above zones of wedge-shaped hypergranulosis, acanthosis, and dermal fibrosis. 2 gray-blue globules dermal melanophages 3 comedo-like openings hypergranulosis and hyperkeratosis of dilated infundibulum 4 red dots dermal capillaries 5 red globules dermal capillaries 6 brownish-black globules epidermal melanocytes 7 yellow structures spongiosis and vacuolar degeneration of basal cell figure 5. (a) histopathology of hypertrophic lichen planus with compact orthokeratosis, hypergranulosis and elongation of rete ridges. (b) histopathology of prurigo nodularis with orthokeratosis and hyperkeratosis; irregular acanthosis and elongated rete ridges. (hematoxylin & eosin, x4). [copyright: ©2016 ankad et al.] figure 6. dermoscopy of prurigo nodularis shows pearly white areas (stars), red globules (circle), red areas (white arrows) and peripheral striations (black arrows). [copyright: ©2016 ankad et al.] figure 7. dermoscopy of prurigo nodularis shows red globules (white arrows) and peripheral striations (black arrows). [copyright: ©2016 ankad et al.] case report | dermatol pract concept 2016;6(2):3 13 over the whole periphery of the lesion in pn and it was localized in the center with peripheral extensions in some areas in hlp. peripheral extensions were well defined in pn giving a “starburst” appearance. in classic lichen planus, pearly white areas are arranged in annular and arboriform pattern or circular, linear, globular, reticular and radial streaming [2,11]. however, there was no mention of hlp in these studies. different configurations and arrangements of pearly white areas help to differentiate hlp, pn, and classical lichen planus. pearly white areas correspond histopathologically to compact orthokeratosis above zones of wedge-shaped hypergranulosis and acanthosis discussion hlp develops during the course of a subacute attack, nevertheless, occasionally only hypertrophic or warty lesions are found. the most common site is the lower limbs, especially around the ankles. the development of hypertrophic lesions greatly lengthens the course of the disease, as they may persist for many years. hlp must be distinguished from lichen simplex chronicus, pn and lichen, amyloidosis [10]. dermoscopy of hlp and pn showed pearly white areas, which were more prominent in pn than in hlp. there was a slight difference in the appearance. white areas were spread table 2. proposed dermoscopic patterns corresponding to histopathologic features in prurigo nodularis. [copyright: ©2016 ankad et al.] dermoscopic patterns corresponding histopathologic changes 1 white areas and peripheral striations hyperkeratosis, hypergranulosis, acanthosis and dermal fibrosis 2 red dots dilated capillaries 3 red globules focal hemorrhages figure 8. frequency of dermoscopic patterns in hypertrophic lichen planus and in prurigo nodularis. [copyright: ©2016 ankad et al.] 14 case report | dermatol pract concept 2016;6(2):3 ogy [20]. arrangement and configuration of red globules give a clue to the condition. red dots were seen as red indistinct islands in the confines of pearly white structures in this study. they were observed in both hlp and pn. they were centrally located in pn in a “comma-like” pattern, whereas in hlp they were arranged diffusely in the lesions. in psoriasis, they appear as regular dotted vessels over a light red background, and in pityriasis rosea, arrangement of vessels is patchy on a yellow background. in classic lp, vessels are arranged peripherally in the confines of white crossing lines and they appear as clear red globules [20]. red globules are larger than the red dots. these were prominent in pn and were not evidently seen in hlp in this study. these correspond to enlarged blood vessels as well as focal hemorrhage in dermis. similar findings, in addition to brown-yellowish crusts and scales, were observed by errichetti et al in excoriated and hyperkeratotic lesions of pn [13]. however, yellow areas and crusts were not demonstrated in this study. description of dermoscopy of hlp with histopathologic correlation is well documented [21] and similar dermoscopic patterns were observed in the present study. histopathologic diagnosis of a condition depends on the characteristic features of that condition which may not be observed in all lesions submitted for histopathologic examination [22]. dermoscopy visualizes the color patterns in the epidermis, dermo-epidermal junction, and papillary dermis; when these patterns are observed consistently in a given disease, they could aid in its diagnosis [23]. although the same dermoscopic patterns are expected in hlp and pn due to a few similar histopathologic findings, dermoscopy demonstrated some different patterns which are specific in each condition. this is probably because of the few specific histopathologic features which are unique to hlp and pn. conclusion dermoscopy is an in vivo diagnostic technique enabling clinicians to visualize subsurface structures with appropriate configuration and color patterns. hlp and pn demonstrate specific dermoscopic patterns that correspond to histopathologic findings. gray-blue globules, clo and brownish-black globules were specific to hlp. hence, the authors propose that these patterns are a hallmark of each condition. thus, dermoscopy is helpful in the differentiation of hlp and pn. further studies involving large sample size are suggested for studying the validity (sensitivity, specificity) of dermoscopy in making the diagnosis. acknowledgement the authors wish to acknowledge the help of dr. vijay domble for his assistance with histopathology. [12]. peripheral striations were more pronounced in pn than in hlp, and this pattern corresponds to dermal fibrosis in histopathology [13]. other conditions which can be listed in the differential diagnosis of hlp and pn by dermoscopy include nodular scabies, keratoacanthoma, and reactive perforating collagenosis [14]. clo filled with yellow keratinous plugs referred to as corn pearls were observed in hlp by vazquez-lopez f et al [12]. clo correspond to dilatation, plugging and hypergranulosis of infundibulum and they are suggestive of transepithelial elimination. in hlp, histopathologic changes, namely, epidermal hyperplasia, acanthosis, hypergranulosis and compact and lamellated hyperkeratosis, are centered on follicular infundibula and acrosyringia [15]. hence, clo are very specific to hypertrophic lp and are not observed in pn. clo are also demonstrated in the early stages of lichen sclerosis and in basal cell carcinoma and seborrheic keratosis [16-18]. gray-blue globules observed in this study represent melanin pigment in the dermis due to melanin incontinence as a result of vacuolar degeneration. the configuration of gray-blue globules and dots is specific for each condition. gray-blue globules in lichen planus pigmentosus of the scalp appear as a “target” pattern. this suggests that pathology is around the perifollicular area and spares the interfollicular area. in discoid lupus erythematosus of the scalp, the pathologic process involves perifollicular and interfollicular areas, hence, gray-blue globules follow a “speckled” pattern [19]. gray-blue globules appear as ovoid and nest-like in basal cell carcinoma [17]. in this study, gray-blue globules in hlp were arranged in diffuse structureless pattern interspersed in pearly white areas indicating presence of melanin incontinence in perifollicular and interfollicular areas. gray-blue globules were not demonstrated in pn, suggesting absence of melanin incontinence in pn. yellow structures represent vacuolar degeneration of the basal layer and spongiosis [2]. yellow structures demonstrated in this study appear as a “lacy network” pattern, traversing the pearly white areas. the characteristic situation of clo along yellow structures confirms the fact that the pathological process in hlp is cornered in and around follicles. yellow structures were not demonstrated in pn. nevertheless, brown-yellowish crusts were noted in pn in one study [13]. melanocytes in the epidermis appear as brownish-black globules in dermoscopy and their arrangement is diffuse, annular or in dotted patterns in classical lp [2]. in hlp, brownish-black globules were diffusely arranged surrounding gray-blue dots. brownish-black dots were not observed in pn. red dots correspond to dilated capillaries in histopatholcase report | dermatol pract concept 2016;6(2):3 15 observations. dermatology 2003;207:151–6. pmid: 12920364. doi: 10.1159/000071785 13. errichetti e, piccirillo a, stinco g. dermoscopy of prurigo nodularis. j dermatol 2015;42:632–34. pmid: 25808786. doi: 10.1111/1346-8138.12844 14. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol. 2015; 150(5):533-46. pmid: 26086412. 15. busam kj, goldblum jr (eds). dermatopathology: a volume in a series: foundations in diagnostic pathology. philadelphia: saunders elsevier, 2010; 11-81. 16. shim wh, jwa sw, song m, et al. diagnostic usefulness of dermatoscopy in differentiating lichen sclerosus et atrophicus from morphea. j am acad dermatol 2012;66:690-1. pmid: 22421117. doi: 10.1016/j.jaad.2011.06.042 17. bowling j. non-melanocytic lesions. in: bowling j, (ed.). diagnostic dermoscopy: the illustrated guide. west sussex: wileyblackwell, 2012; 59-91. 18. braun rp, rabinovitz hs, krischer j, et al. dermoscopy of pigmented seborrheic keratosis: a morphological study. arch dermatol 2002; 138:1556-60. pmid: 12472342. doi: 10.1001/ archderm.138.12.1556 19. ankad bs, beergouder sl, moodalgiri vm. lichen planopilaris versus discoid lupus erythematosus: a trichoscopic perspective. int j trichol 2013; 5:204-7. pmid: 24778533. doi: 10.4103/0974-7753.130409 20. lallas a, kyrgidis a, tzellos tg, apalla z, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br journal dermatol 2012; 166:1198205. pmid: 22296226. doi: 10.1111/j.1365-2133.2012.10868.x 21. ankad bs, beergouder sl and sujana l. dermoscopy of hypertrophic lichen planus. austin j dermatolog 2014; 1(3):1013. http:// austinpublishinggroup.com/dermatology/fulltext/ajd-v1-id1013. php. accessed on august, 20, 2015 22. mobini n, toussaint s, kamino h. noninfectious erythematous, papules and squamous diseases. in: elder de (ed.). lever’s histopathology of the skin, 10th ed. philadelphia: lippincott-williams wilkins, 2009:169-203. 23. nischal kc, khopkar u. dermoscope. indian j dermatol venereol leprol 2005; 71:300-3. pmid: 16394450 references 1. shiohara t, kano y. lichen planus and lichenoid dermatoses. in: bolognia jl, jorizzo jl, schaffer jv (eds.). dermatology, 3rd ed. new york: elsevier saunders, 2012; 183-202. 2. doshi b, khopkar u. histopathology of lichen planus and its variants. in: khopkar u and valia a (eds.). lichen planus. new delhi: jaypee brothers medical publisher (p) ltd, 2013; 123-47. 3. vaidya dc, robert a. schwartz. prurigo nodularis: a benign dermatosis derived from a persistent pruritus. acta dermatovenerol croat 2008; 16:38-44. pmid: 18358109 4. lee mr, shumack s. prurigo nodularis: a review. aust j dermatol 2005; 46:211-20. pmid: 16197418. doi: 10.1111/j.14400960.2005.00187.x 5. berth-jones j. eczema, lichenification, prurigo and erythroderma. in: burns t, breathnach sm, cox n, griffiths c (eds.). rook’s textbook of dermatology, 8th ed. oxford: wiley-blackwell, 2010; 23.1-51. 6. weedon d. the lichenoid reaction pattern (interface dermatitis). in: weedon d (ed.). weedon’s skin pathology, 2nd ed. london: churchill livingstone, 2002; 31-74. 7. mobini n, toussaint s, kamino h. noninfectious erythematous, papular and squamous diseases. in: elder de (ed.). lever’s histopathology of the skin, 10th ed. philadelphia: lippincott williams and wilkins, 2010;169-204. 8. weigelt n, metze d, ständer s. prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients. j cutan pathol 2010; 37: 578-86. pmid: 20002240. doi: 10.1111/j.16000560.2009.01484.x 9. bowling j. introduction to dermoscopy. in: bowling j (ed.). diagnostic dermoscopy: the illustrated guide. west sussex: wiley-blackwell, 2012:2-14. 10. breathnach sm. lichen planus and lichenoid disorders. in: burns t, breathnach sm, cox n, griffiths c (eds.). rook’s textbook of dermatology, 8th ed. oxford: wiley-blackwell, 2010; 41.1-28. 11. gungor s, topal io, goncu ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept 2015;5(2):45–53. pmid: 26114051. doi: 10.5826/dpc.0502a06 12. vazquez-lopez f, manjon-haces ja, maldonado-seral c, et al. dermoscopic features of plaque psoriasis and lichen planus: new http://www.ncbi.nlm.nih.gov/pubmed/?term=errichetti%20e%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed/?term=stinco%20g%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed/26086412 http://www.ncbi.nlm.nih.gov/pubmed?term=shim%20wh%5bauthor%5d&cauthor=true&cauthor_uid=22421117 http://www.ncbi.nlm.nih.gov/pubmed?term=jwa%20sw%5bauthor%5d&cauthor=true&cauthor_uid=22421117 http://www.ncbi.nlm.nih.gov/pubmed?term=song%20m%5bauthor%5d&cauthor=true&cauthor_uid=22421117 http://www.ncbi.nlm.nih.gov/pubmed?term=braun%20rp%5bauthor%5d&cauthor=true&cauthor_uid=12472342 http://www.ncbi.nlm.nih.gov/pubmed?term=rabinovitz%20hs%5bauthor%5d&cauthor=true&cauthor_uid=12472342 http://www.ncbi.nlm.nih.gov/pubmed?term=krischer%20j%5bauthor%5d&cauthor=true&cauthor_uid=12472342 http://www.ncbi.nlm.nih.gov/pubmed/12472342 http://www.ncbi.nlm.nih.gov/pubmed/12472342 http://austinpublishinggroup.com/dermatology/fulltext/ajd-v1-id1013.php http://austinpublishinggroup.com/dermatology/fulltext/ajd-v1-id1013.php http://austinpublishinggroup.com/dermatology/fulltext/ajd-v1-id1013.php http://www.ncbi.nlm.nih.gov/pubmed?term=weigelt%20n%5bauthor%5d&cauthor=true&cauthor_uid=20002240 http://www.ncbi.nlm.nih.gov/pubmed?term=metze%20d%5bauthor%5d&cauthor=true&cauthor_uid=20002240 http://www.ncbi.nlm.nih.gov/pubmed?term=st%c3%a4nder%20s%5bauthor%5d&cauthor=true&cauthor_uid=20002240 http://www.ncbi.nlm.nih.gov/pubmed/20002240 http://www.ncbi.nlm.nih.gov/pubmed/?term=topal%20io%5bauth%5d dermatology: practical and conceptual review | dermatol pract concept 2014;4(4):3 21 dermatology practical & conceptual www.derm101.com epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection philip r. cohen1, taraneh paravar1, robert a. lee1 1 division of dermatology, university of california san diego, san diego, california keywords: acantholytic, cell, dermatoses, dermatosis, disease, epidermis, epithelial, giant, grover, herpes, infection, multinucleated, pemphigus, transient, virus, vulgaris citation: cohen pr, paravar t, lee ra. epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection. dermatol pract concept. 2014;4(4):3. http://dx.doi.org/10.5826/dpc.0404a03 received: july 22, 2014; accepted: july 24, 2014; published: october 31, 2014 copyright: ©2014 cohen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, m.d., division of dermatology, university of california, san diego, ca, usa. email: mitehead@ gmail.com background: multinucleated giant cells in the epidermis can either be epithelial or histiocytic. epithelial multinucleated giant cells are most often associated with herpes virus infections. purpose: to review the histologic differential diagnosis of conditions with epithelial and histiocytic multinucleated giant cells—since multinucleated giant cells in the epidermis are not always pathognomonic of a cutaneous herpes virus infection—and to summarize dermatoses in which herpes virus infection has been observed to coexist. methods: two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection are reported. using the pubmed database, an extensive literature search was performed on multinucleated giant cell (and epidermis, epithelial, and histiocytic) and herpes virus infection. relevant papers were reviewed to discover the skin conditions with either multinucleated giant cells in the epidermis or coincident cutaneous herpes virus infection. results: initial skin biopsies from patients with either pemphigus vulgaris or transient acantholytic dermatosis mimicked herpes virus infection; however, laboratory studies and repeat biopsies established the correct diagnosis of their acantholytic dermatosis. hence, epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection. indeed, epithelial multinucleated giant cells in the epidermis can be observed not only in the presence of infection (herpes virus), but also acantholytic dermatoses and tumors (trichoepithelioma and pleomorphic basal cell carcinoma). histiocytic multinucleated giant cells in the epidermis can be observed in patients with either giant cell lichenoid dermatitis or lichen nitidus of the palms. (continued next page) abstract 22 review | dermatol pract concept 2014;4(4):3 introduction herpes virus infection of the skin is characterized by the finding of multinucleated giant cells in the epidermis. we report two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection; however, all viral studies were negative and subsequent biopsies of their lesions demonstrated pathognomonic features of either pemphigus vulgaris or transient acantholytic dermatosis. the histologic differential diagnosis of conditions with multinucleated giant cells in the epidermis is reviewed and dermatoses in which herpes virus infection has been observed to coexist are summarized. case reports case 1 a 24-year-old caucasian woman presented with painful oral sores that persisted after a short tapering course of oral corticosteroids (methylprednisolone dose pack) that was stopped after 5 days. her past medical history was significant for type 1 diabetes mellitus and genital herpes simplex virus infection. she subsequently developed tender fluid-filled blisters of her axilla and groin and was empirically treated with oral valacyclovir 1000 mg twice daily without improvement. examination of the oral cavity showed ulcers on the hard palate, the buccal mucosa and the mucosa of the gingiva and labia. pustules, vesicles, and bullae were observed within the right axillae (figure 1) and the labia majora. a lesional skin biopsy from the right axilla was performed; specimens for bacterial culture, direct fluorescent antibody studies and viral cultures were also obtained. microscopic examination showed epidermal necrosis and ulceration surmounted by basophilic debris; rare cocci-shaped bacteria were seen within the inflammatory scale crust. focal reticular degeneration, intraepidermal neutrophilic pustules forming a suprabasilar cleft, and numerous multinucleated conclusions: epithelial and histiocytic multinucleated giant cell can occur in the epidermis. keratinocyte-derived multinucleated giant cells are most commonly associated with herpes virus infection; yet, they can also be observed in patients with skin tumors or acantholytic dermatoses. cutaneous herpes simplex virus infection can coexist in association with other conditions such as acantholytic dermatoses, benign skin tumors, bullous disorders, hematologic malignancies, inflammatory dermatoses, and physical therapies. however, when a herpes virus infection is suspected based upon the discovery of epithelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be considered and additional lesional skin biopsies performed. also, because hematoxylin and eosin staining is not the golden standard for confirmation of autoimmune bullous dermatoses, skin biopsies for direct immunofluorescence should be performed when a primary bullous dermatosis is suspected since the histopathology observed on hematoxylin and eosin stained sections can be misleading. abstract (continued) figure 1. the right axilla of a woman with pemphigus vulgaris shows pustules and vesicles on a faint erythematous base. (copyright: ©2014 cohen et al.) keratinocyte giant cells demonstrating nuclear molding were noted. there was a perivascular infiltrate in the upper dermis consisting of neutrophils and eosinophils (figure 2). the pathology was consistent with a herpes virus infection. the patient was hospitalized and treated for disseminated herpes virus infection with intravenous acyclovir at a dose of 10 mg per kilogram every 8 hours. the bacterial culture grew methicillin-resistant staphylococcus aureus and intravenous vancomycin was added. she continued to develop similar-appearing new lesions not only in her mouth, axilla and groin, but also on her arms and abdomen; in addition, earlier pustules and vesicles had enlarged and/or ruptured (figure 3). the direct fluorescence antibody studies and the viral cultures were negative for both herpes simplex virus and varicella-zoster virus. repeat skin biopsies were performed for routine staining and direct immunofluorescence. microscopic examination showed an intraepidermal blister containing acantholytic keratinocytes, numerous eosinophils, and occasional neutrophils; the adjacent epithelium showed spongiosis with eosinophils. perivascular inflammation, consisting of prominent eosinophils and occasional lymreview | dermatol pract concept 2014;4(4):3 23 phocytes, was present in the upper dermis (figure 4). direct immunofluorescence showed positive intercellular staining in the epidermis for igg and c3. subsequently, enzyme-linked immunosorbent assay (elisa) testing demonstrated that the serum igg titers were elevated for both desmoglein 1 and desmoglein 3. figure 2. (a) distant, (b) close and (c) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (a) basophilic debris is seen within the inflammatory scale crust overlying necrosis and ulceration of the epidermis. (b) there is a suprabasilar cleft showing an intraepidermal neutrophilic pustule; multinucleated keratinocyte giant cells are noted in the pustule. (c) nuclear molding can also be noted within several of the multinucleated keratinocyte giant cells (hematoxylin and eosin; a= x4, b=20, c=x40). (copyright: ©2014 cohen et al.) a b c figure 3. enlargement and/or rupture of pustules and vesicles in the right axilla of the women with pemphigus vulgaris. (copyright: ©2014 cohen et al.) figure 4. (a) distant and (b) closer views of the repeat biopsy specimen that establish the diagnosis of pemphigus vulgaris. acantholytic keratinocytes, numerous eosinophils, and occasional neutrophils are present in an intraepidermal blister; eosinophilic spongiosis is present in the adjacent epithelium. prominent eosinophils and occasional lymphocytes compose the perivascular infiltrate in the upper dermis (hematoxylin and eosin; a= x20, b=x40). (copyright: ©2014 cohen et al.) a b 24 review | dermatol pract concept 2014;4(4):3 figure 5. (a) distant, (b) close and (c) closer view of the left upper chest of a woman with transient acantholytic dermatosis presenting as pruritic erythematous papules. (copyright: ©2014 cohen et al.) a b c figure 6. (a) distant, (b) close and (c) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (a) an intraepidermal vesicle with suprabasilar epidermal acantholysis and cleft formation is noted. (b and c) closer views show neutrophils and eosinophils in both the intraepidermal vesicle and the dermis; in the blister cavity, multinucleated keratinocyte giant cells with nuclear molding are also noted (hematoxylin and eosin; a= x4, b=x20, c=x40). (copyright: ©2014 cohen et al.) a b c correlation of the clinical findings, laboratory studies, and repeat skin biopsies established a diagnosis of pemphigus vulgaris. initial management included 60 mg daily of oral prednisone. she also received intravenous rituximab, 2 doses of 1000 mg each separated by 2 weeks, prior to tapering her daily prednisone over the next 6 months. her skin lesions resolved without recurrence. case 2 a healthy 40-year-old caucasian woman presented with a recurrent itchy rash on her chest and abdomen of more than one-year duration. her past medical history was negative for herpes virus infection. cutaneous examination revealed discrete pruritic erythematous and crusted papules on her chest and abdomen (figure 5). a lesional biopsy was performed. empiric topical treatment was initiated with triamcinolone 0.1% ointment. review | dermatol pract concept 2014;4(4):3 25 microscopic examination showed suprabasilar epidermal acantholysis and cleft formation with neutrophils and eosinophils in both the intraepidermal vesicle and the dermis. multinucleated keratinocyte giant cells with nuclear molding were also seen in the blister cavity (figure 6). the pathologic findings were interpreted as a herpes virus infection. the clinical features and improvement with topical corticosteroid therapy did not correlate with the observed pathologic findings. direct fluorescence antibody studies and viral cultures did not demonstrate herpes virus infection. a repeat skin biopsy was performed of a new lesion on her upper chest. the second biopsy specimen showed acanthosis with focal acantholysis and dyskeratosis; viral cytopathic changes were absent. lymphocytic inflammation was present in the upper dermis (figure 7). correlation of the clinical presentation, laboratory studies, and pathologic changes established the diagnosis of transient acantholytic dyskeratosis (grover’s disease). discussion multinucleated giant cells can be observed in the epidermis (table 1) [1-10]. the etiology of the giant cells can either be epithelial or histiocytic. histiocytic epidermal multinucleated giant cells have been noted in giant cell lichenoid dermatitis [7,8] and lichen nitidus of the palms [9,10]. table 1. conditions with multinucleated giant cells in the epidermis epithelial cell origin acantholytic dermatosis pemphigus vulgaris [current report] transient acantholytic dermatosis [current report] infection herpes virus infection [1-3] tumors benign trichoepithelioma [4] malignant pleomorphic basal cell carcinoma [5,6] histiocytic cell origin giant cell lichenoid dermatitis [7,8] lichen nitidus of the palms [9,10] figure 7. (a) distant, (b) close and (c) closer views of the repeat biopsy specimen that establish the diagnosis of transient acantholytic dermatosis. acanthosis, with focal acantholysis and dyskeratosis, is noted in the epidermis and lymphocytic inflammation is present in the upper dermis; viral cytopathic changes are absent (hematoxylin and eosin; a= x4, b=x20, c=x40). (copyright: ©2014 cohen et al.) a b c epithelial multinucleated giant cells are most often associated with herpes virus infections [1-3]. however, they occasionally occur in either benign or malignant tumors of epidermal cell origin such as trichoepitheliomas or basal cell carcinomas, respectively [4-6]. we recently observed multinucleated giant cells of keratinocyte origin, which mimicked those noted in herpes virus infection, in the epidermis of patients with acantholytic dermatoses: pemphigus vulgaris [11-15] and transient acantholytic dermatosis [16-21]. herpes virus infections of the skin usually present as erythematous-based vesicles. microscopic examination of a 26 review | dermatol pract concept 2014;4(4):3 lesional biopsy often shows multinucleated ballooned keratinocyte giant cells in the epidermis containing steel-gray nuclei with accentuation of nucleoplasm at their periphery; acantholytic, sometime necrotic, keratinocytes within intraepidermal blisters can also be noted. the diagnosis of herpes virus infection can be confirmed by direct fluorescent antibody testing or viral culture [1-3,22-25]. herpes simplex virus infection can coexist in association with other skin conditions; this likely represents the coincident development of this viral infection in an immunocompromised district—an area of skin that have been made vulnerable by a previous or concurrent cutaneous disorder [26]. in addition to acantholytic dermatoses and bullous disorders (table 2) [27-33], herpes simplex virus can also occur in association with hematologic malignancies [27,34,35], inflammatory dermatoses [27,35], and physical therapies [27,35,36]. rarely, herpes virus infection has been discovered in benign skin tumors, such as seborrheic keratoses [37]. our patients had acantholytic dermatoses that were initially interpreted to represent a herpes virus infection based on the presence of multinucleated epithelial giant cells in the epidermis of lesional skin biopsies. however, additional evaluation (including direct fluorescent antibody studies and viral cultures) was negative for a viral infection. in addition, one patient failed to improve after oral or intravenous treatment with antiviral therapy. subsequently, repeat biopsies for direct immunofluorescence and/or routine histology established the correct diagnosis for both patients. conclusion epithelial and histiocytic multinucleated giant cell can occasionally be found in the epidermis. although keratinocytetable 2. acantholytic or bullous dermatoses in which herpes simplex virus infection has been demonstrated to be present in the skin lesion [27-33] bullous pemphigoid epidermolysis bullosa familial benign chronic pemphigus (hailey-hailey disease) keratosis follicularis (darier’s disease) pemphigus foliaceus pemphigus vulgaris staphylococcus scalded skin syndrome transient acantholytic dermatosis (grover’s disease) derived multinucleated giant cells are most commonly caused by a herpes virus infection, they can also be observed in either benign or malignant skin tumors or in patients with acantholytic dermatoses. indeed, our patients presented with vesicular skin lesions that showed epidermal multinucleated giant cells on their initial biopsy specimens and were initially interpreted to represent a herpes virus infection. however, direct fluorescent antibody and culture studies did not confirm the diagnosis of a viral infection. subsequently, repeat lesional skin biopsies revealed pathologic features that were able to establish the correct diagnosis of either pemphigus vulgaris or transient acantholytic dermatosis. therefore, when a herpes virus infection is suspected based upon the discovery of epithelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be considered and additional lesional skin biopsies performed. also, because hematoxylin and eosin staining is not the golden standard for confirmation of autoimmune bullous dermatoses, skin biopsies for direct immunofluorescence should be performed when a primary bullous dermatosis is suspected since the histopathology observed on hematoxylin and eosin stained sections can be misleading. references 1. cohen pr. tests for detecting herpes simplex virus and varicellazoster virus infections. dermatol clin. 1994;12:51-68. 2. huff jc, krueger gc, overall jc jr, copeland j, spruance sl. the histopathologic evolution of recurrent herpes simplex labialis. j am acad dermatol. 1981;5:550-7. 3. leinweber b, kerl h, cerroni l. histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella zoster): a broad spectrum of presentations with common pseudolymphomatous aspects. am j surg pathol. 2006;30:50-58. 4. kazakov dv, michal m. trichoepithelioma with giant and multinucleated neoplastic epithelial cells. am j dermatopathol. 2006;28:63-4. 5. tschen jp, cohen pr, schulze ke, tschen ja. pleomorphic basal cell carcinoma: case reports and review. south med j. 2006;99:296-302. 6. garcia ja, cohen pr, hertzberg aj, wallis me, rapini rp. pleomorphic basal cell carcinoma. j am acad dermatol. 1995;32:7406. 7. goldberg lj, goldberg n, abrahams i, et al. giant cell lichenoid dermatitis: a possible manifestation of sarcoidosis. j cutan pathol. 1994;21:47-51. 8. gonzalez jg, marcus md, santa cruz dj. giant cell lichenoid dermatitis. j am acad dermatol. 1986;15:87-92. 9. de eusebio murillo e, yus es, lens rn. lichen nitidus of the palms: a case with peculiar histopathologic features. am j dermatopathol. 1999;21:161-4. 10. weiss rm, cohen ad. lichen nitidus of the palms and soles. arch dermatol. 1971;104:538-0. review | dermatol pract concept 2014;4(4):3 27 11. damoiseaux j. bullous skin diseases: classical types of autoimmune diseases. scientifica (cairo). 2013;2013:457982. epub 2013 jan 8. 12. ruocco v, ruocco e, shiavo al, et al. pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. clin dermatol. 2013;31:374-81. 13. venugopal ss, murrell df. diagnosis and clinical features of pemphigus vulgaris. immunol allergy clin n am. 2012;32:233-43. 14. ruocco e, wolf r, ruocco v, et al. pemphigus: associations and management guidelines: facts and controversies. clin dermatol. 2013;31:382-90. 15. kasperkiewicz m, schmidt e, zillikens d. current therapy of the pemphigus group. clin dermatol. 2012;30:84-94. 16. weaver j, bergfeld wf. grover disease (transient acantholytic dermatosis). arch pathol lab med 2009;133:1490-4. 17. quirk cj, heenan pj. grover’s disease: 34 years on. australas j dermatol. 2004;45:83-8. 18. davis md, dinneen am, landa n, gibson le. grover’s disease: clinicopathologic review of 72 cases. mayo clin proc. 1999;74:229-34. 19. parsons jm. transient acantholytic dermatosis (grover’s disease): a global perspective. j am acad dermatol 1996;35:653-66. 20. cohen pr, kurzrock r. transient acantholytic dermatosis after treatment with 2-chlorodeoxyadenosine. [letter] acta derm venereal (stockh). 1997;77:412-13. 21. guana al, cohen pr. transient acantholytic dermatosis in oncology patients. j clin oncol. 1994;12:1703-9. 22. whitley rj, roizman b. herpes simplex virus infections. lancet. 2001;357:1513-18. 23. cather jc, cohen pr. herpes simplex virus type 1 infections. j gt houst dent soc. 1998;69(6):12-13. 24. cohen pr, kazi s, grossman me. herpetic geometric glossitis: a distinctive pattern of lingua herpes simplex virus infection. south med j. 1995;88:1231-5. 25. grossman me, stevens aw, cohen pr. herpetic geometric glossitis. n engl j med. 1993;329:1859-60. 26. ruocco v, ruocco e, brunetti g, sangiuliano s, wolf r. opportunistic localization of skin lesions on vulnerable areas. clin dermatol. 2011;29:483-8. 27. bunce pam, stanford dg. grover’s disease secondarily infected with herpes simples virus and staphylococcus aureus: case report and review. australas j dermatol. 2013;54:e88-e91. 28. pantazi v, potouridou i, katsarou a, papadogiorgaki h, katsambas a. darier’s disease complicated by kaposi’s varicelliform eruption due to herpes simplex virus. j eur acad dermatol venereol. 2000;14:209-11. 29. lee gh, kim ym, lee sy, et al. a case of eczema herpeticum with hailey-hailey disease. ann dermatol. 2009;21:311-314. 30. kosann mk, fogelman jp, stern rl. kaposi’s varicelliform eruption in a patient with grover’s disease. j am acad dermatol. 2003;49:914-5. 31. rubin ai, garson mc, morel kd. herpetic infection in epidermolysis bullosa. pediatr dermatol. 2006;23:355-7. 32. niederecker c, tappeiner g, wolff k. generalized herpes simplex infection complicating bullous pemphigoid. br j dermatol. 1995;132:484-6. 33. nikkels af, delvenne p, herfs m, pierard ge. occult herpes simplex virus colonization of bullous dermatitides. am j clin dermatol. 2008;9:163-8. 34. fukuzawa m, oguchi s, saida t. kaposi’s varicelliform eruption of an elderly patient with multiple myeloma. j am acad dermatol. 2000;42:921-922. 35. wollenberg a, zoch c, wetzel s, plewig g, przybilla b. predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. j am acad dermatol. 2003;49:198205. 36. manders sm, chetty bv. eczema herpeticum occurring in autografted skin. j am acad dermatol. 1991;24:509-10. 37. george pb, king r. herpesvirus infection of seborrheic keratosis. am j dermatopathol. 2001;23:146-8. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(2):15 155 dermatology practical & conceptual introduction there are only 4 previously published dermoscopic images of balloon cell melanoma (bcm) in the literature, 3 of primary tumors and 1 of bcm satellite metastasis. currently, data are restricted by a low number of reports and a definitive dermoscopic pattern of bcm is still not documented. we suggest some dermoscopic features to correctly diagnose this tumor. case presentation recently, an 84-year-old caucasian woman was referred to our skin cancer unit because of an asymptomatic nodule on the right leg for the preceding 4 months, with no personal or family history of melanoma or nonmelanoma skin cancer. physical examination showed a well-defined, reddish nodule measuring 1 cm in diameter (figure 1a). dermoscopy revealed yellowish structureless areas, white lines, and irregular, hairpin-shaped and curved vessels (figure1b). due to suspicions of melanoma, an excisional biopsy was performed for histopathological examination. hematoxylin and eosin (h&e) staining showed an atypical melanocytic proliferation, with an architecturally disorganized, predominantly intradermal component composed of cells containing hyperchromatic pleomorphic nuclei and a ballooned appearance with vacuolated cytoplasm, mitotic figures, and discrete areas of intradermal pagetoid spread (figure 2, a and b). no ulceration, lymphovascular and perineural invasion, satellitosis, or regression was noted. breslow thickness was 4.1 mm with moderate mitotic activity with 4 mitotic figures seen per square millimeter. immunohistochemical staining showed positive results for melanocytic markers s100 (figure 2c), hmb45 in the dermal component, and melan-a, confirming the diagnosis of bcm. ki67 ki67 staining was positive in balloon cells. conclusions in 2013, the first dermoscopy report described an amelanotic nodule with a structureless yellow lesion, central ulceration, presence of terminal hairs, and curved and dotted vessels in an elderly man with a history of local trauma [1]. balloon cell primary nodular melanoma: dermoscopy evidence fernanda s. seabra resende1, claudio conforti3, roberta giuffrida2, paola corneli3, serena fagotti3, ana custrin4, venus shaffiei4, iris zalaudek3, nicola di meo3 1 department of dermatology and venereology, university of brasilia, brasilia, brazil 2 department of clinical and experimental medicine, section of dermatology, university of messina, messina, italy 3 dermatology clinic, hospital maggiore, university of trieste, trieste, italy 4 clinical unit of pathological anatomy and histology, university of trieste, trieste, italy key words: balloon cell, dermoscopy, histology, melanoma, oncology, dermato-oncology citation: resende fss, conforti c, giuffrida r, corneli p, fagotti s, custrin a, shaffiei v, zalaudek i, di meo n. balloon cell primary nodular melanoma: dermoscopy evidence. dermatol pract concept. 2019;9(2):155-156. doi: https://doi.org/10.5826/dpc.0902a15 accepted: october 31, 2018; published: april 30, 2019 copyright: ©2019 resende et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, hospital maggiore, trieste, italy. email: claudioconforti@yahoo.com 156 letter | dermatol pract concept 2019;9(2):15 of a recent raised amelanotic nodular lesion with white lines and polymorphous vessels in dermoscopy suggested malignancy, although the diagnosis of bcm was histologically defined. we therefore suggest focusing on 4 dermoscopic criteria during the assessment of a nodular lesion to rule out bcm: (1) yellowish structureless areas, (2) white lines, (3) irregular hairpinshaped and (4) curved vessels. in 2014, a satellite metastasis of bcm was described as having a milky red structureless background, yellowish structureless areas, and a few irregular, linear, hairpin-shaped, and curved vessels. as balloon cells generally lack melanin, this study proposed the association of milky red and yellowish structureless areas as a considerable clue for the diagnosis of bcm [2]. we also reported the presence of yellowish structureless areas in our case. the dermatopathological diagnosis of bcm is reportedly challenging both careful clinical-pathological correlation as well as correctly interpreted immunohistochemical stains. clinically, bcm could be presented as a nodular, ulcerated, polypoid, or papillomatous lesion with the absence of pigmentation. dermoscopic evidence showed numerous aggregated white globular structures, which correspond to nests of pigmented melanocytes in the lower epidermis, papillary, and/or lower dermis in histology. in this case the presence figure 2. (a) h&e staining (×5) showing the radial phase of the melanoma. (b) h&e staining (×40) with cells containing hyperchromatic pleomorphic nuclei and a ballooned appearance with vacuolated cytoplasm, mitotic figures, and discrete areas of intradermal pagetoid spread. (c) immunohistochemical staining (×2.5, s100 positive). [copyright: ©2019 resende et al.] a b c figure 1. balloon cell melanoma, clinical and dermoscopic presentation. (a) erythematous nodule, 1 cm in diameter. (b) yellowish structureless areas (red thick arrow), white lines (black asterisks), hairpin-shaped, and curved vessels (black arrows). [copyright: ©2019 resende et al.] a b references 1. inskip m, magee j, barksdale s, weedon d, rosendahl c. balloon cell melanoma in primary care practice: a case report. dermatol pract concept. 2013;3(3):25-29. 2. duman n, sahin s, özaygen ge, gököz ö. dermoscopy of satellite metastasis of balloon cell melanoma. j am acad dermatol. 2014;71(1):e11-e12. untitled research | dermatol pract concept 2015;5(3):2 7 dermatology practical & conceptual www.derm101.com diagnostic utility of ki-67 and cyclin d1 immunostaining in differentiation of psoriasis vs. other psoriasiform dermatitis engin sezer1, almut böer-auer2, emel cetin3, fatma tokat3, emel durmaz1, sedef sahin1, umit ince3 1 department of dermatology, acibadem university school of medicine, istanbul, turkey 2 department of dermatology, dermatologikum, hamburg, germany 3 department of pathology, acibadem university school of medicine, istanbul, turkey keywords: psoriasis, psoriasiform dermatitis, proliferation, ki-67, cyclin d1 citation: sezer e, böer-auer a, cetin e, tokat f, durmaz e, sahin s, ince u. diagnostic utility of ki-67 and cyclin d1 immunostaining in differentiation of psoriasis vs. other psoriasiform dermatitis. dermatol pract concept 2015;5(3):2. doi: 10.5826/dpc.0503a02 received: october 31, 2014; accepted: may 3, 2015; published: july 31, 2015 copyright: ©2015 sezer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: engin sezer, md, acıbadem university school of medicine, department of dermatology, buyukdere caddesi no: 40, istanbul, 34457, turkey. tel. 902123044626; fax. 902123044440. email: eseze@yahoo.com background: differentiation of psoriasis from non-psoriasis psoriasiform dermatitis (nppd) may be difficult for dermatopathologists, as lack of distinctive histopathological features in a subset of cases may cause confusion in diagnosis. objective: as the prototype of psoriasiform dermatitis, psoriasis is a hyperproliferative skin disorder with increased epidermal turnover compared with nppd, we investigated the role of proliferation markers, ki-67 and cyclin d1 as diagnostic tools to differentiate psoriasis from other psoriasiform dermatitis. methods: histopathological specimens of psoriasis (n = 35) and nppd (n = 36, 14 pityriasis rubra pilaris, 12 pityriasis rosea and 10 lichen simplex) cases were reviewed and immunohistochemically stained for ki-67 and cyclin d1. ki-67 and cyclin d1 positive cells were counted for suprabasal, and total epidermal immunostaining per mm2. results: suprabasal and total epidermal cell counts for ki-67 were found to be significantly higher in the psoriasis group compared with the nppd group (p < 0.05). an important and interesting feature was the presence of a cut-off value for the suprabasal/total epidermal cell count ratio of 75% for ki-67 immunostaining, which was higher in all patients having psoriasis (range, 77.1% 92.4%) and lower in all nppd cases (range, 21.0% 73.3%). however, suprabasal cyclin d1 cell counts were higher in the psoriasis group compared with the nppd group (p < 0.05), total epidermal cyclin d1 cell counts were not statistically significant in either group (p = 0.167), and a cut-off value for suprabasal/total epidermal cell count ratio to distinguish these two entities was not detected using this immunostain. conclusions: we suggest that ki-67 is a more sensitive marker than cyclin d1 in terms of having a cutoff value of 75% for the suprabasal/total epidermal immunoreactive cell count ratio, which we believe could be useful for dermatopathologists in differentiating psoriasis from other psoriasiform dermatitis. abstract 8 research | dermatol pract concept 2015;5(3):2 materials and methods histopathological specimens of psoriasis (n = 35) and control nppd (n = 36, 14 pityriasis rubra pilaris, 12 pityriasis rosea, and 10 lichen simplex) cases were reviewed by a board certified dermatopathologist (e.s.) from the histopathology archives of the acibadem university school of medicine. immunohistochemical staining for ki-67 and cyclin d1 was performed on all specimens for microscopic analysis. the method used for immunostaining was the streptavidin-biotin-amplified system. the slides were submitted to subsequent steps of deparaffinization and rehydration. sections were sliced (6 µm thick) and air-dried for 30 minutes. then the sections were fixed in cold acetone for 10 minutes. after blocking endogenous peroxidase using 0.2% sodium azide for 5 minutes, they were washed with phosphate buffered saline for 15 minutes. subsequently, the sections were incubated with primary antibodies for 1 hour. the primary antibodies were ki-67 (dako, düsseldorf, germany) and cyclin d1 (dako, düsseldorf, germany) with a dilution of 1:100. after incubation, the sections were rinsed with distilled water and tap water. the tissue was counterstained with mayer’s hematoxylin. all slides were covered with a cover slip. introduction psoriasiform dermatitis histopathologically indicates the presence of epidermal hyperplasia with elongation of the rete ridges in a regular manner. however psoriasis is the prototype of psoriasiform dermatitis, various skin disorders such as pityriasis rubra pilaris, lichen simplex chronicus and pityriasis rosea may reveal psoriasiform epidermal hyperplasia and cause confusion in histopathological diagnosis. although characteristic and distinctive histopathological features such as munro’s microabscesses and tortuous, dilated capillaries in psoriasis; alternating horizontal and vertical parakeratosis in pityriasis rubra pilaris; mounds of parakeratosis with extravasation of erythrocytes in pityriasis rosea; and dermal, thickened vertical collagen bundles with orthokeratosis resembling acral skin in lichen simplex help us reach a specific diagnosis, unfortunately such is not the case in every instance, forcing the dermatopathologist to report as “non-specific psoriasiform dermatitis.” because psoriasis is a hyperproliferative skin disorder with increased epidermal turnover rate and mitotic index, we investigated the role of proliferation markers ki-67 and cyclin d1 as diagnostic tools to differentiate psoriasis from non-psoriasis psoriasiform dermatitis (nppd). figure 1. total epidermal and suprabasal cell counts/mm2 for ki-67 and cyclin d1 immunostaining; nppd, non-psoriasis psoriasiform dermatitis. [copyright: ©2015 sezer et al.] research | dermatol pract concept 2015;5(3):2 9 ki-67 were found to be significantly higher in the psoriasis group (462.2 ± 188.2 cells/mm2) compared with the nppd group (345.6 ± 193.7 cells/mm2) (p = 0.012, independent samples t test) (figure 2). suprabasal ki-67 cell counts were also higher in the psoriasis group (401.2 ± 169.0 cells/mm2) compared with the nppd group (181.6 ± 97.4 cells/mm2) (p < 0.001, independent samples t test) (figure 3). suprabasal/ total epidermal cell count ratio for ki-67 immunostaining was higher in the psoriasis group (mean: 86.0 ± 4.4%) compared with the nppd group (mean: 54.1 ± 13.8%) (p < 0.001, independent samples t test). an important and interesting feature was the presence of a cut-off value for the suprabasal/total epidermal cell count ratio of 75% for ki-67 immunostaining, which was higher in all psoriasis cases (range, 77.1% 92.4%) and lower in all nppd cases (range, 21.0% 73.3%) (table 1, figure 3). these features highlight that suprabasal ki-67 positive cells were more than three-fourths of the total epidermal ki-67 positive cells in the epidermis (including basal and suprabasal cell population) in psoriasis group, whereas this ratio was lower than threefourths in nppd group (figure 4). figure 2a demonstrates that most of the ki-67 positive staining cells were located on immunohistochemical scoring the ki-67 and cyclin d1 positive cells were counted for suprabasal and total epidermal immunostaining. for a more practical future use for the dermatopathologists, the immunostaining cells were counted per mm2. statistical analysis data from microscopic analysis were expressed as mean ± standard error. the independent samples t test was used to determine the statistical significance of the cell count/mm2 and the percentage of immunostaining suprabasal to the total epidermal cell ratio between psoriasis and nppd. p values of less than 0.05 were considered statistically significant. the statistical analysis was performed by using spss statistical software (ibm, armonk, ny, usa). results ki-67 and cyclin d1 cell counts for psoriasis and nppd are described in figure 1. total epidermal cell counts for figure 2. overall ki-67 cell count was marked in the psoriasis group (a) compared with that of the nppd group (b). [copyright: ©2015 sezer et al.] figure 3. predominance of suprabasal ki-67 immunostaining cells was observed in the psoriasis group (a) compared with the nppd group (b), which shows marked basal layer staining. [copyright: ©2015 sezer et al.] 10 research | dermatol pract concept 2015;5(3):2 discussion as the prototype of psoriasiform dermatitis, psoriasis is a chronic, relapsing, inflammatory skin disease characterized by epidermal hyperproliferation and disturbed differentiation of keratinocytes. differentiation of psoriasiform dermatitis can be challenging for dermatopathologists, as the distinctive features may not be present in every histopathologic specimen. the characteristic histopathological features for psoriasis include collection of neutrophils within the parakeratotic stratum corneum (i.e., munro’s microabscesses), spongiform pustules beneath the keratin layer (i.e., kogoj’s pustules), thin suprapapillary plates and tortuous, dilated capillaries in the superficial papillary dermis. the diagnostic signs for pityriasis rubra pilaris are alternating orthokeratosis and parakeratosis in both vertical and horizontal directions, thick suprapapillary plates, broad epidermal ridges, and narrow dermal papillae [1]. the presence of thickened collagen bundles arranged in vertical streaks in the dermal papillae, marked hypergranulosis and a thick layer of compact orthokeratosis resembling that seen on normal palms and soles (i.e., hairy palm sign) leans toward a diagnosis of lichen simplex [2]. angulated parakeratosis reminiscent of a teapot, pityriasiform vesicles, and extravasation of red blood cells is more characteristic of suprabasal layer in psoriasis samples (i.e., ki-67 positive 113 suprabasal and 29 basal cells with a suprabasal/total epidermal cell ratio of 79.6%) whereas most of the immunoreactive cells were located in basal layer in nppd samples (i.e., ki-67 positive 18 suprabasal and 53 basal cells with a suprabasal/ total epidermal cell ratio of 25.5%) as highlighted in figure 2b. we suggest that this phenomenon reflects the increased mitotic index in suprabasal layer of psoriatic lesions, related to hyperproliferative state. total epidermal cyclin d1 immunostaining cell counts were not statistically significant in the psoriasis group (422.3 ± 141.2 cells/mm2) compared with the nppd group (374.9 ± 144.7 cells/mm2) (p = 0.167, independent samples t test). suprabasal cyclin d1 cell counts were higher in the psoriasis group (389.2 ± 134.1 cells/mm2) compared with the nppd group (266.7 ± 113.8 cells/mm2) (p < 0.001, independent samples t test). however, the suprabasal/total epidermal cell count ratio for cyclin d1 immunostaining was higher in the psoriasis group (mean: 91.5 ± 5.0%) compared with the nppd group (mean: 69.6 ± 14.1%) (p < 0.001, independent samples t test), a cut-off value to distinguish between these two entities was not detected (i.e., the cyclin d1 ratio was as low as 76.6% in the psoriasis group and as high as 96.1% in the nppd group) (table 1, figure 5). table 1. suprabasal/total epidermal cell count (i.e., basal plus suprabasal cells) ratio ranges for ki-67 and cyclin d1 immunostaining psoriasis nppd cut-off value ki-67 77.1% 92.4% 21.0% 73.3% 75% cyclin d1 76.6% 99.6% 46.5% 96.1% n/a nppd, non-psoriasis psoriasiform dermatitis; n/a, not available. figure 4. a clear cut-off value for suprabasal/total epidermal cell count ratio could not be identified for cyclin d1 immunostaining, such as in this example of nppd specimen, in which a high suprabasal staining pattern was detected. [copyright: ©2015 sezer et al.] figure 5. suprabasal ki-67 positive cells were more than 75% of the total epidermal ki-67 positive cells in the epidermis (including basal and suprabasal cell population) in psoriasis group, whereas this ratio was lower than 75% in nppd group. [copyright: ©2015 sezer et al. research | dermatol pract concept 2015;5(3):2 11 nppd group, a cut-off point to obtain a clear differentiation as in our study could not be achieved in the reported research. overexpression of chemokines, interleukin-8 (il-8) and gro/melanoma growth-stimulatory activity (gro-α) are known to stimulate proliferation of keratinocytes in psoriasis [12]. il-8 is derived predominantly from keratinocytes and the associated neutrophils within the psoriatic plaques. gro-α is an additional neutrophil chemoattractant. we suggest that the hyperproliferative state in psoriasis compared with nppd may be related to the presence of neutrophils, which interact with these chemokines in keeping with the results of our study, as psoriasis is the only psoriasiform dermatitis with intraepidermal neutrophilic infiltration. neutrophil elastase (ne), a 30-kd weight cellular toxic molecule produced by neutrophils is participated in the proliferation of keratinocytes by transforming growth factor-α (tgf-α). a recent study revealed enhanced expression of ki-67 in a cultured transwell psoriasis organ model after ne treatment, thus strengthening the role of neutrophilic infiltration in the hyperproliferative state of psoriasis [13]. in contrast, tgf-β has an inhibitory effect on epithelial cell proliferation. downregulation of its receptor in a psoriatic epidermis has the effect of diminishing this inhibitory influence, thus resulting in overproliferation [14]. t-cadherin, e-cadherin, p-cadherin, and protein kinase d expression also appears to play a part in the regulation of epidermal growth in psoriasis [15]. ki-67 is a cell-cycle-associated antigen, expressed in all parts of the cell cycle except in g 0 and early g 1 , and therefore confined to the proliferative compartment of the epidermis [16]. ki-67 has proven to be of value as a marker of cell proliferation by recognizing the cell cycle-dependent expression of the ki-67 non-histone nuclear antigen [17]. psoriatic lesions have been shown to reveal a higher ki-67 index compared with normal appearing, nonlesional skin [18-20]. the ki-67 activity rate was found to be higher in the inner margin of the lesions, followed by the center and outer margins [20]. cyclin d1 is a component of cyclin-dependent kinase (cdks) complexes, regulating the function of retinoblastoma susceptibility gene production, which is necessary for cell-cycle progression into mitosis [21]. cell cycling and cell proliferation are regulated by sequential activation of cdks, which are activated by specifically binding to cyclins: cdk4/6 links with cyclin d1, and cdk2 with cyclin e [22]. these complexes phosphorylate retinoblastoma proteins, thereby inducing a release of e2f transcription factors, and thus starting the g 1 phase [23]. we believe that ki-67 is a more sensitive proliferation marker then cyclin d1, because a cut-off value for the suprabasal/total epidermal cell count ratio could not be identified for cyclin d1 and total epidermal immunostaining of cyclin d1 in psoriasis and nppd groups were statistically insignificant. pityriasis rosea [3]. however, these findings are exceedingly helpful for dermatopathologists in reaching a specific diagnosis, whereas a lack or overlap of these features may result in a nonspecific diagnosis of “psoriasiform dermatitis,” which may cause confusion in accurate diagnosis. because, as a prototype of psoriasiform dermatitis, psoriasis differs from nppd as being a hyperproliferative skin disorder with a 12-fold increase in the number of keratinocytes in cell cycling that results in a decreased turnover time for the epidermis from 13 days to 3 or 4 days, we hypothesized that proliferation markers such as ki-67 and cyclin d1 would be helpful in distinguishing psoriasis from nppd [4]. histopathologically, the presence of suprabasal mitotic figures leans toward a diagnosis of psoriasis in psoriasiform dermatitis [4]. thus we designed the study protocol to investigate the suprabasal staining pattern with proliferation markers as well as suprabasal-to-total epidermal cell ratio as a diagnostic and practical approach to differentiate psoriasis from nppd. suprabasal ki-67 and cyclin d1 cell counts were found to be higher in the psoriasis group than in the nppd. an important and practical finding for dermatopathologists in our research was the presence of a cut-off value for a suprabasal/total epidermal cell count ratio of 75% for ki-67 immunostaining, which was higher in all psoriasis cases and lower in all nppd cases. as far as we are aware, this phenomenon has not been described in the literature. however, suprabasal ki-67 staining in the epidermis may also be observed in nppd, resembling psoriasis, such as in the first and third rete ridges in figure 2b, we suggest that the most reliable distinction between the two entities is the cut-off value for suprabasal/total epidermal cell count ratio of 75%, which is higher in all psoriasis and lower in all nppd cases. we comment that this finding may be more useful for dermatopathologists in the differential diagnosis of psoriasis and nppd, because evaluation of this feature is more practical compared with counting ki-67 positive cells/mm2. increased keratin 16 and decreased keratin 10 expression in the suprabasal compartment of epidermis in psoriasis lesions also reflects the hyperproliferative state in this region, which supports the increased suprabasal ki-67 immunostaining rate in our study. however, ki-67 immunostaining was used as a prognostic tool to assess the efficacy of various treatment modalities for psoriasis such as acitretin, rambazole, ustekinumab, methotrexate, narrow band ultraviolet b phototherapy, photodynamic therapy, and topical tacrolimus, to the best of our knowledge, a study indicating the use of ki-67 as a diagnostic tool to differentiate psoriasis from nppd has not yet been reported [5-10]. in another study, hypoxia inducible factor 1 alpha (hif-1 alpha), which is linked to inflammation through reciprocal interactions with several cytokines, was used as an immunohistochemical marker to differentiate psoriasis from nppd [11]. however hif-1 alpha immunoreactivity scores were higher in the psoriasis group than in the 12 research | dermatol pract concept 2015;5(3):2 2. annessi g, petresca m, petresca a. pretibial pruritic papular dermatitis: a distinctive cutaneous manifestation in response to chronic rubbing. am j dermatopathol 2006;28(2):117-21. 3. sezer e, saracoglu zn, urer sm, bildirici k, sabuncu i. purpuric pityriasis rosea. int j dermatol 2003;42(2):138-40. 4. calonje e, brenn t, lazar a, mckee ph. spongiotic, psoriasiform and pustular dermatoses. in: calonje e (eds). mckee’s pathology of the skin. 4th ed. london, uk: elsevier saunders, 2012:206-10. 5. werner b, bresch m, brenner fm, lima hc. comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after acitretin. j cutan pathol 2008;35(3):302-10. 6. bowenschen hc, otero me, langewouters am, et al. oral retinoic acid metabolism blocking agent rambazole for plaque psoriasis: an immunohistochemical study. br j dermatol 2007;156(2): 263-70. 7. reddy m, torres g, mccormick t, et al. positive treatment effects of ustekinumab in psoriasis: analysis of lesional and systemic parameters. j dermatol 2010;37(5):413-25. 8. yazici ac, tursen u, apa dd, et al. the changes in expression of icam-3, ki-67, pcna, and cd31 in psoriatic lesions before and after methotrexate treatment. arch dermatol res 2005;297(6):249-55. 9. smits t, kleinpenning mm, van erp pe, van de kerkhof pc, gerritsen mj. a placebo-controlled randomized study on the clinical effectiveness, immunohistochemical changes and protoporphyrin ix accumulation in fractioned 5-aminolaevulinic acidphotodynamic therapy in patients with psoriasis. br j dermatol 2006;155(2):429-36. 10. vissers vh, van vlijmen i, van erp pe, de jong em, van de kerkhof pc. topical treatment of mild to moderate psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on sum score, epidermal proliferation, keratinization, t-cell subsets and hla-dr expression br j dermatol 2008;158(4):705-12. 11. simos g, roussaki-schulze av, koukoulis g. increased hif-1 alpha immunostaining in psoriasis compared to psoriasiform dermatitides. j cutan pathol 2009;36(12):1255-61. 12. gillitzer r, ritter u, spandau u, goebeler m, bröcker eb. differential expression of gro-alpha and il-8 mrna in psoriasis: a model for neutrophil migration and accumulation in vivo. j invest dermatol 1996;107(5):778-82. 13. yang x, yan h, zhai z, hao f, ye q, zhong b. neutrophil elastase promotes proliferation of hacat cell line and transwell psoriasis organ culture. int j dermatol 2010;49(9):1068-74. 14. doi h, shibata ma, kiyokane k, otsuki y. downregulation of tgfbeta isoforms and their receptors contributes to keratinocyte hyperproliferation in psoriasis vulgaris. j dermatol sci 2003; 33(1):7-16. 15. zhou s, matsuyoshi n, takeutchi t, ohtsuki y, miyachi y. reciprocal altered expression of t-cadherin and p-cadherin in psoriasis vulgaris. br j dermatol 2003;149(2):268-73. 16. sawhney n, hall. ki67-structure, function and new antibodies. j pathol 1992;168(2):161-62. 17. caldwell cj, hobbs c, mckee ph. the relationship of ki67 and involucrin expression in proliferative, pre-neoplastic and neoplastic skin. clin exp dermatol 1997;22(1):11-6. 18. doger fk, dikicioglu e, ergin f, et al. nature of cell kinetics in psoriatic epidermis. j cutan pathol 2007;34(3):257-63. 19.gudjonsson je, johnston a, sigmundsdottir h, valdimarsson h. immunopathogenetic mechanisms in psoriasis. clin exp immunol. 2004;135(1):1-8. a study investigating the role of matrix metalloproteinases (mmps) in the role of the proliferative status of psoriasis revealed that ki-67 immunostaining for proliferative keratinocytes was particularly intense adjacent to the mmp-19 positive cells, mainly in the rete ridges, and was thought to be associated with remodeling of the extracellular matrix during inflammation [24]. the majority of t cells in established psoriatic plaques express cell-surface cutaneous lymphocyteassociated antigen (cla). a correlation of cla-positive t cells in evolving psoriatic skin with ki-67 index was identified suggesting an additional function of the cla-positive t lymphocytes in the proliferation of psoriatic epidermis [25]. this phenomenon also supports the context of decreasing ki-67 activity in patients treated with ustekinumab, a human antiil-12 monoclonal antibody, as the cytokine il-12 upregulates the cla expression of activated t cells in vitro and its expression is increased in lesional psoriatic skin [7]. another molecule showing correlation with ki-67 activity in psoriatic lesions is 72 kda heat shock protein 72 (hsp72), which serves to protect cells from injury caused by oxidative stress, hypothermia, ultraviolet radiation, ionizing radiation, and metabolic poisons [26]. the damaged proteins produced by oxidative stress in psoriatic lesions have been thought to serve as stress signals in triggering hsp72. overexpression of src-family tyrosine kinases (sfks) was demonstrated in skin biopsy specimens of psoriasis controlled with normal skin [27]. because altered keratinocyte differentiation and hyperproliferation are associated with increased epidermal growth factor (egf) receptor activity, and because sfks are directly activated by egf in human keratinocytes, stimulation of egf receptor is believed to activate sfks in psoriasis [27]. suppression of apoptosis is also considered as the pathogenetic mechanism for the hyperproliferative state of psoriasis. expression of survivin, a member of the inhibitor of apoptosis protein family, mediating the apoptosis suppressive function by inhibition of the caspase pathway and nuclear factor kappa β (a transcription factor also responsible for inhibition of apoptosis) was investigated, revealing overexpression of both markers in the psoriasis group [28]. finally, we suggest that ki-67 is a more sensitive marker than cyclin d1 in terms of the presence of a cut-off value of 75% for the suprabasal/total epidermal cell count ratio, which we believe could be a useful tool for dermatopathologists to differentiate psoriasis from other psoriasiform dermatitis. references 1. hashimoto k, fedoronko l. pityriasis rubra pilaris with acantholysis and lichenoid histology. am j dermatopathol 1999;21(5):491-3. research | dermatol pract concept 2015;5(3):2 13 25. davison sc, ballsdon a, allen mh, barker jn. early migration of cutaneous lymphocyte-associated antigen (cla) positive t cells into evolving psoriatic plaques. exp dermatol 2001;10(4):280-5. 26. edwards mj, nazmi n, mower c, daniels a. hsp72 antigen expression in the proliferative compartment of involved psoriatic epidermis. j cutan pathol 1999;26(10):483-9. 27. ayli ee, li w, brown tt, et al. activation of src-family tyrosine kinases in hyperproliferative epidermal disorders. j cutan pathol 2008;35(3):273-7. 28. abdou ag, hanout hm. evaluation of survivin and nf-kappab in psoriasis, an immunohistochemical study j cutan pathol 2008;35(5):445-51. 20. vissers wh, arndtz ch, muys l, et al. memory effector (cd45ro+) and cytotoxic (cd8+) t cells appear early in the margin zone of spreading psoritiz lesions in contrast to cells expressing natural killer receptors, which appear late. br j dermatol 2004;150(5):852-9. 21. abou el-ela m, nagui n, mahgoub d, et al. expression of cyclin d1 and p16 in psoriasis before and after phototherapy. clin exp dermatol 2010;35(7):781-5. 22. pines j. cyclins and cyclin-dependant kinases: theme and variations. adv cancer res 1995;66(1):181-212. 23. sardet c, vidal m, cobrinik d, et al. e2f-4 and e2f-5, two members of the e2f family, are expressed in the early phase of the cell cycle. proc natl acad sci usa 1995;92(6):2403-7. 24. suomela s, kariniemi al, impola u, et al. matrix metalloproteinase-19 is expressed by keratinocytes in psoriasis. acta dermatoveneologica 2003;83(2):108-14. editorial | dermatol pract concept 2011;1(1):2 3 editorial: from the editor harald kittler, m.d. 1 1department of dermatology, division of general dermatology, medical university of vienna, austria citation: kittler h. from the editor [editorial]. dermatol pract concept 2011;1(1):2. http://dx.doi.org/10.5826/dpc.0101a02. copyright: ©2011 kittler. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: harald kittler, md, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18–20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. e-mail: harald.kittler@meduniwien.ac.at. hello, readers! this is the first issue of a new journal with a great tradition. what seems to be a contradiction is meant to be a fruitful synthesis. the critical and creative mind of a. bernard ackerman, the founder of the journal, was a catalyst for many sustainable reactions and there is still considerable afterglow! the half-life of ideas can be longer than the life span of a human being! under bernie’s patronage new ideas were conceived, and this journal is just one of them. after sustained contact with him, many of his students found themselves substantially altered. however, students are not merely reactants, and a good mentor will not only promote his own original ideas but also those of his students. some of bernie’s students became catalysts themselves. almut böer-auer, who succeeded bernie as the editor of this journal, is one of them. the journal, dermatopathology: practical & conceptual indubitably bears her stamp. when i took over the editorship i decided to strike a new path and to follow traditional trails at the same time. dermatopathology: practical & conceptual is now dermatology practical & conceptual. the change of the journal’s title intends to express the change in the scope of the journal. the fact that only one word was changed and the rest of the title will stay the same is a reference to the great tradition of the journal. this tradition will always remain our common ground and, from a historical point of view, the origin of our specialty. the common ground i mean is morphology. in dermatology, morphology has been put into second place. molecular biology has gained impact and importance, whereas morphology has lost it. nowadays morphologic studies are not even regarded as scientific research, and if so, it is labeled as low-impact research. it cannot be denied that we are living in the century of the molecular biology revolution and that medicine has made important progress in this regard. however, there are still many questions related to morphology that remain unanswered. i am convinced that the integration of morphology (the biologic world as we see it) and molecular biology (the matrix behind it) will serve as a medium for cutting edge research. neither of the two views alone can sufficiently explain biologic phenomena. even if one day biology and medicine can be fully reduced to a hidden code revealed only by molecular biology, we will still be living in a sensual world. in this way our common ground parallels common sense. dermatology practical & conceptual shall be a platform for any kind of dermatological research that advances the integration of morphology and common sense with “basic science.” dermatology practical & conceptual will be an open access online journal. no subscription to derm101.com will be needed to view the contents of the journal. it took some time and effort to perform the necessary modifications. the production teams of derm101 and silverchair were very supportive in this regard and i want to take this opportunity to thank them. the journal will continue to appear quarterly. after three issues have been published, we will apply for the inclusion of the journal in pubmed central (pmc), the u.s. national institutes of health (nih) free digital archive of biomedical and life sciences journals and literature. although the journal is now renamed dermatology practical & conceptual, dermatopathology will remain an important part of it. we will maintain a section dedicated fully to dermatopathology. regarding the new, broader scope of the journal, two new sections will be launched. one is dedicated to dermatoscopy and diagnostic imaging and dermatology practical & conceptual www.derm101.com 4 editorial | dermatol pract concept 2011;1(1):2 will be edited by alon scope. alon is widely known for his research in dermatoscopy and confocal imaging. it is also my pleasure to announce that the international dermoscopy society (ids) elected dermatology practical & conceptual as the official journal of their society. the ids has more than 3000 members worldwide. in this regard i want to thank the executive board of the ids and especially the president of the society, dr. argenziano, and his secretary, dr. zalaudek, for putting their trust in our journal. the other new section will be dedicated to dermatology in primary care. it reflects the growing importance that primary care physicians are attaching to dermatology especially in countries like australia and great britain. the editor of this section will be jeff keir, a primary care physician practicing in australia. jeff keir holds a master’s degree in family medicine and a diploma in practical dermatology from the university of cardiff. he is a distinguished academic lecturer and has performed and promoted research in the field of primary care and skin cancer. he is the secretary of the skin cancer college of australia and new zealand (scaanz). dermatology practical & conceptual will provide a forum to exchange views on primary care dermatology and clinical research and will become the official journal of scaanz. despite these substantial changes, i promise that the critical spirit of the journal will be maintained and that the content of the former journal, dermatopathology: practical & conceptual, will not be lost. we will maintain an electronic archive so that all articles published in the past will be available to our future readers. in addition to that we will relaunch certain articles under a new section termed “from our archives.” in this section we will challenge authors who had expressed opinions in original articles that were published some time ago, with the light of new evidence. it will be interesting to see whether their past views match up with their present views or to learn about the reasons that made them change their mind. there are more changes to come but they will be revealed in upcoming issues. i want to close this editorial with a reference to the founder of this journal. when the first issue of dermatopathology: practical & conceptual was launched in january 1995, dr. ackerman closed his editorial with the following words: this journal has no intention of being judged by its cover, as distinctive as it may be; it is to be judged by the power of the ideas that are housed temporarily within its lines and that await release by avid readers. the potential of those ideas knows no bounds. i can add nothing more. harald kittler, m.d. editor-in-chief dermatology practical & conceptual dermatology: practical and conceptual 208 research | dermatol pract concept 2018;8(3):12 dermatology practical & conceptual www.derm101.com potential utility of dermoscopy in the examination of ocular pigmentations nida kaçar1, cem yildirim2, nese demirkan3, yunus bulgu4 1 department of dermatology, faculty of medicine, pamukkale university, denizli, turkey 2 department of ophthalmology, faculty of medicine, pamukkale university, denizli, turkey 3 department of pathology, faculty of medicine, pamukkale university, denizli, turkey 4 department of ophthalmology, suhut public hospital, afyonkarahisar, turkey key words: dermoscopy, ocular pigmentation, impression cytology, melanoma, melanocytic lesion citation: kaçar n, yildirim c, demirkan n, bulgu y. potential utility of dermoscopy in the examination of ocular pigmentations. dermatol pract concept. 2018;8(3):208-213. doi: https://doi.org/10.5826/dpc.0803a12 received: february 2, 2018; accepted: may 7, 2018; published: july 31, 2018 copyright: ©2018 kaçar et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: prof. nida kaçar, md, pamukkale universitesi tip fakultesi, dermatoloji ad, e-309, kinikli, denizli, turkey. email: n_gelincik@yahoo.com. background: dermoscopy is a fundamental method in the examination of melanocytic neoplasms. limited data exist about the dermoscopic features of ocular pigmentations (ops). objectives: we aimed to investigate the usefulness of dermoscopy in the examination of ops. methods: dermoscopic images of ops of 20 consecutive patients were recorded. impression cytology (ic) was performed to these lesions. dermoscopic images were evaluated for specific dermoscopic structures and patterns without knowing the cytological examination results. results: fifteen percent (3/20) of the lesions presented with suspicious cytological findings. more of the suspicious lesions had 4 colors compared to benign lesions (66.7% vs 11.8%, p=0.088). this was also determined for blue-gray (66.7% vs 11.8%, p=0.088) and white (66.7% vs 17.7%, p=0.14) colors. at least 3 structures were observed in all suspicious lesions (100%), but were observed in only in 41.2% of benign lesions (p=0.105). besides, two-thirds of suspicious lesions had more than 4 structures, but none of the benign lesions reported this (p=0.016). most of the benign lesions showed asymmetry in one axis (93.3%), whereas all suspicious lesions showed asymmetry in 2 axes (p=0.004). conclusions: dermoscopy seems to be a useful method in the evaluation of ops. the existence of dermoscopic patterns, colors, and dermoscopic structure plurality and asymmetry raise suspicion in ops, similarly to skin pigmentations. dermatologists should be aware of the ocular area, and closer collaboration should be developed between dermatologists and ophthalmologists in the management of pigmented lesions. abstract research | dermatol pract concept 2018;8(3):12 209 handheld dermatoscope (3gen, san juan capistrano, ca) coupled with a sony cyber-shot dsc-w35 camera (sony corporation, zug, switzerland) after removing the glass faceplate. the polarizing technology of the dermatoscope used in the present study allowed us to take dermoscopic images from a distance of approximately 1 cm without contact with the lesions. impression cytology (ic) was performed on these lesions after dermoscopic imaging. sampling was performed as follows: the eye was anesthetized with 1-2 drops of 0.5% proparacaine hcl (alcaine) and the eyelids were opened for a few seconds to dry the conjunctiva to improve the adherence of cells to the cellulose acetate filter paper with a pore size of 0.45 (m. the cellulose acetate filter paper was pressed gently onto the surface of the op; after 3-5 seconds, it was removed. the procedure was repeated 2-3 times to increase the sensitivity of the technique. the cellulose acetate filter paper was immediately fixed in 95% ethanol for 15 minutes and stained by the papanicolaou method, which was performed on the same day of collection. at this stage, the filter paper was placed in position with the cell sample facing upward during staining, avoiding contamination and loss of material. after the coloration, it was mounted with entellan (millipore sigma, darmstadt, germany) and filter paper on the slide. ic samples were screened in terms of nuclear size, nuclearto-cytoplasmic ratio, irregular nucleus, irregular nuclear chromatin pattern, and prominent nucleoli, and subsequently graded into 4 different stages: 0 (insufficient material for diagnosis), 1 (normal epithelial conjunctival cells with or without melanin pigment, reactive conjunctival cells as seen in inflammation), 2 (melanocytes with mild atypia), 3 (melanocytes with moderate atypia), and 4 (melanocytes with severe atypia) [9]. the amount of cells collected (low, moderate, high, very high) was noted for all samples [10]. the lesions with grade 1 or 2 atypia on ic samples were regarded as benign and those with grade 3 or 4 atypia as suspicious. grade 0 ic samples were not taken under consideration [11]. dermoscopic images were evaluated for specific dermoscopic structures and patterns by one of the authors (nk) without prior knowledge of the cytological examination results. fisher’s exact test was used for statistical analyses with spss software (version 18.0; spss inc, chicago, il, usa). p values < 0.05 were considered significant. power analysis was performed according to these results (for more than 4 structures, suspicious 66.7% and benign 0%) and it was determined that the present study had more than 80% power with 95% confidence. for the present study approval was obtained from the medical research ethics committee of the faculty of mediintroduction the ocular surface includes the conjunctiva and the cornea. specifically, melanocytic lesions that arise in this area are melanocytic nevus, racial melanosis, primary acquired melanosis, and melanoma. melanocytic nevi are the most common melanocytic tumors of the conjunctiva. they generally become clinically evident during the first and second decade of life. typically, the conjunctival melanocytic nevi are pigmented, well defined, and elevated lesions. approximately 1% of melanocytic nevi evolve to melanoma. racial melanosis presents commonly on the limbus as bilateral congenital, circular pigmentation. ocular melanocytosis is also a congenital pigmentation status entertaining a melanoma risk; it emerges unilaterally and involves periocular skin, the sclera, and orbita, but typically spares conjunctiva. ocular melanocytosis is commonly confused with primary acquired melanosis, which is an acquired condition emerging in middle age that presents with diffuse, patchy, poorly defined, and flat pigmentation. thirteen percent of primary acquired melanosis lesions with atypia can also give rise to melanoma [1-3]. the reasons for conjunctival nevi excisions include fast growth, suspicious changes under biomicroscopic examination such as intrinsic vascularity and/or pigmentation increase, cosmetic reasons, and patient concerns about malignancy [1,2,4]. ocular melanoma arises from melanocytes within the eye, including the uveal tract, conjunctiva, and orbit; it constitutes less than 5% of all melanoma cases. conjunctival melanomas comprise only ~5% of ocular melanomas; however, the incidence has been increasing, as reported for cutaneous melanoma, which is being related to ultraviolet light exposure [5,6]. the rarity of conjunctival melanomas contributes to difficulties in their management. slit-lamp biomicroscopy, high-resolution anterior segment ultrasound, in vivo confocal microscopy, and optical coherence tomography constitute the noninvasive diagnostic technologies for evaluating ocular surface lesions [7]. dermoscopy is one of the most important noninvasive technologies being used in the diagnosis and follow-up of pigmented skin lesions [8]. in the present study, we aimed to investigate the usefulness of dermoscopy in the examination of ocular pigmentations (ops). materials and methods patients with ocular pigmentation older than 18 years old who presented to the departments of dermatology and ophthalmology of the faculty of medicine of pamukkale university between december 2010 and march 2012 were invited to participate in the study, prospectively. the lesions were examined clinically and dermoscopically. dermoscopic images were taken with a dermlite pro hr (polarizing) 210 research | dermatol pract concept 2018;8(3):12 (65%). only 1 pattern was found in 6 (all benign), 2 patterns in 13 (11 benign, 2 suspicious) and 3 patterns in 1 lesion (suspicious). we found 4 lesions with only a single color (all benign), 11 (10 benign, 1 suspicious) with 2 colors, 1 (benign) with 3 colors, and 4 (2 benign, 2 suspicious) with 4 colors. the most frequent color was light brown, which was present in 18 lesions (15 benign, 3 suspicious), followed by dark brown (16 lesions [13 benign, 3 suspicious]), white (5  lesions [3  benign, 2  suspicious]), blue-gray (4 lesions [2 benign, 2  suspicious]), and black (2  benign cine, pamukkale university, and all participants gave their informed consent. results t h e s t u d y e n r o l l e d   2 4   o p s f r o m to 23 patients. four lesions of 3 patients were excluded because ic samples were grade 0 (insufficient material for diagnosis). twenty ops of 20 patients (12 males, 8 females) were included in total. the clinical diagnoses, based on clinical features including the localization, onset time, and morphological characteristics of the lesion and biomicroscopic findings were primary acquired melanosis in 6 lesions, ota nevus in 1, melanocytic nevus in 12, and melanoma in 1 lesion. three lesions showed grade 3 atypia (figure 1). two of the 3 cytologically suspicious lesions were clinically diagnosed as melanocytic nevus; only 1 was suspicious from the clinical point of view. biopsy was planned for these lesions; however, the patients did not agree. two cytologically benign lesions could be followed up, and no change was observed in them when comparing their cytological diagnosis (figure 2). another cytologically benign lesion was removed at the request of the patient and the histopathological diagnosis was compound nevus. homogeneous and globular patterns were the dominant dermoscopic patterns in both benign lesions (seen in 14 and 13 lesions, respectively) and suspicious (3) lesions (figure 3). these patterns coexisted in most of the lesions lesions). more of the suspicious lesions showed 4 colors compared to benign lesions (66.7% vs 11.8%, p=0.088). this was also determined for blue-gray (66.7% vs 11.8%, p=0.088) and white (66.7% vs 17.7%, p=0.14) colors. the most prevalent dermoscopic structure was the structureless area observed in 17 lesions (14 benign, 3 suspicious), followed by dots (13 benign, 3 suspicious), globules (11 benign, 3 suspicious), pigment network (1  benign, 2 suspicious) and streaks (1 benign, 2 suspicious). only one dermoscopic structure was found in 1 lesion (benign), 2 strucfigure 1. cytological examination of the suspicious lesions of the 3 cases showing grade 4 atypia in the sheets of atypical melanocytes. (a) pap ×10 and grade 3 atypia. (b) and (c) pap ×20. [copyright: ©2018 kaçar et al.] figure 2. no dermoscopic changes were observed within 6 months in the 2 observed lesions. [copyright: ©2018 kaçar et al.] research | dermatol pract concept 2018;8(3):12 211 prognosis [11]. dermoscopy is a fundamental method in the examination of melanocytic neoplasms. it has been established that dermoscopic examination increases the diagnostic accuracy from 5% to 30% [10]. the whole skin, nails, and mucosa should be examined during melanoma screening. although nails and oral and genital mucosa lesions have been routinely examined in addition to skin, dermatologists generally do not show interest in ocular mucosa. therefore, there are not much data about the dermoscopic features of pigmentations on ocular mucosa in the literature. we observed light-brown-colored homogeneous pattern, a benign dermoscopic pattern [12], in the conjunctival pigmentation of a case of laugier-hunziker syndrome. ic of the pigmentation revealed melanocytes with only a mild atypia, suggesting a benign nature in accordance with the dermoscopic pattern we observed [13]. atypical pigment network, irregular dots/globules, regression structures, and blue-white veil, all of which are melanoma-specific dermoscopic features, were reported in a case of palpebral conjunctival melanoma. concordance was present between dermoscopic findings and diagnosis in that case as well [14]. tures in  9  lesions (all benign), 3  structures in  8  lesions (7 benign, 1 suspicious), 4 structures in 1 lesion (suspicious), and 5 structures in 1 lesion (suspicious). three or more structures were observed in all suspicious lesions (100%), but in only 41.2% of the benign lesions (p=0.105). twothirds of suspicious lesions had more than 4 structures, but none of the benign lesions had this (p=0.016). asymmetry was observed in all lesions except for 2 benign ones (90%). most of the benign lesions showed asymmetry in one axis (93.3%), whereas all suspicious lesions showed asymmetry in 2 axes (p=0.004). categorical comparisons are summarized in table 1. discussion the fields of dermatology and ophthalmology overlap in many ways, as a number of diseases involve both the eye and the skin. one of those diseases is melanoma. dermatologists have an important place in the management of skin melanoma. it has been established that the early detection of melanoma is the most effective intervention to improve figure 3. (a), (b), and (c) dermoscopic views of some ops (original magnification ×10): (a) homogeneous, (b) reticular, and (c) homogeneous-reticular dermoscopic patterns. (d), (e), and (f) clinical views of some ops. [copyright: ©2018 kaçar et al.] 212 research | dermatol pract concept 2018;8(3):12 changes in comparison to their cytological diagnosis; in addition, histopathological diagnosis of another cytologically benign lesion that was removed at the request of the patient was also benign. conclusions according to our knowledge, the present study is the first prospective study to investigate the dermoscopic features of ops. our results demonstrated that dermoscopy is a useful method in the examination of ops. dermatologists should be aware of the ocular area in terms of possible melanoma involvement, and closer collaboration should be developed between dermatologists and ophthalmologists in the management of pigmented lesions. acknowledgement the study was presented as a poster presentation at the 4th world congress of dermoscopy 2015 in vienna, austria. references 1. kheir wj, tetzlaff mt, pfeiffer ml, et  al. epithelial, non melanocytic and melanocytic proliferations of the ocular surface. semin diagn pathol. 2016;33(3):122-132. doi: 10.1053/j. semdp.2015.10.006. 2. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology. 2006;212(1):7-18. doi: 10.1159/000089015. 3. rayward o, moreno-martín p, vallejo-garcia jl, vano-galvan s. ophthaproblem. can you identify this condition? conjunctival nevus. can fam physician. 2011;57(10):1157, 1159-1160. 4. shields cl, shields ja. tumors of the conjunctiva and cornea. surv ophthalmol. 2004;49(1):3-24. doi: 10.1016/j.survophthal.2003.10.008. 5. blum es, yang j, komatsubara km, carvajal rd. clinical management of uveal and conjunctival melanoma. oncology (williston park). 2016;30(1):29-32, 34-43, 48. 6. shields cl, kels jg, shields ja. melanoma of the eye: revealing hidden secrets, one at a time. clin dermatol. 2015;33(2):183-196. doi: 10.1016/j.clindermatol.2014.10.010. 7. barros jn, almeida sr, lowen ms, cunha mc, gomes já. impression cytology in the evaluation of ocular surface tumors: review article. arq bras oftalmol. 2015;78(2):126-132. doi: 10.5935/0004-2749.20150033. 8. marino ml, carrera c, marchetti ma, marghoob aa. practice gaps in dermatology: melanocytic lesions and melanoma. dermatol clin. 2016;34(3):353-362. doi: 10.1016/j.det.2016.03.003. 9. levecq l, de potter p, jamart j. conjunctival nevi clinical features and therapeutic outcomes. ophthalmology. 2010;117(1):35-40. doi: 10.1016/j.ophtha.2009.06.018. 10. braun rp, rabinovitz hs, oliviero m, kopf aw, saurat jh. dermoscopy of pigmented skin lesions. j am acad dermatol. 2005;52(1):109-121. doi: 10.1016/j.jaad.2001.11.001. 11. breitbart ew, waldmann a, nolte s, et  al. systematic skin cancer screening in northern germany. j am acad dermatol. 2012;66(2):201-211. doi: 10.1016/j.jaad.2010.11.016. homogeneous, globular, starburst, and reticular patterns are the dermoscopic patterns seen most frequently in benign pigmented skin tumors. the presence of more than 2 dermoscopic patterns together suggests malignant nature. in addition, the presence of color and/or dermoscopic structure multiplicity and/or asymmetry also raises suspicion [12]. in the present study, we found that 4 colors, 3 or more dermoscopic structures, asymmetry in 2 axes, and blue-gray or white colors are the dermoscopic findings that indicate a suspicious lesion. according to our results, dermoscopic pattern, color, and dermoscopic structure plurality and asymmetry should arouse suspicion in ops, similarly to skin pigmentations. particular attention should be paid to lesions with more than 4 structures and/or asymmetry in 2 axes. there are 2 limitations of our study. first, the sample size of our study is relatively small. second, we only performed ic for the lesions. ic is an extensively used method to evaluate superficial epithelial layers of the ocular surface [7]. it was demonstrated that ic with cellulose acetate filters is able to sample deeper layers when performed repeatedly [15]. the major advantage of ic is to preserve the eye from unnecessary surgical procedures [7]. an increased nuclear-tocytoplasmic ratio, an irregular nuclear chromatin pattern, the presence of large nucleoli, and the observation of mitosis and anisokaryosis have been suggested as malignant cytological features in melanin-containing cells [16]. although the gold standard for diagnosis is histopathological examination, a 73% correlation was found between ic and histopathology in pigmented lesions from the conjunctiva, and biopore membrane ic was shown to accurately predict the outcome in 88% of the 127 histopathologically proven melanocytic lesions [16,17]. the positive and negative predictive accuracy of ic have been found to be 97.4% and 52.9%, respectively, when compared to histopathological findings in the diagnosis of ocular surface neoplasia [18]. in conclusion, ic was proposed to be a useful noninvasive method in evaluating conjunctival nevi [19]. in our study, the 2 observed lesions with benign cytological features showed no dermoscopic table 1. categorical comparisons dermoscopic features benign suspicious p value ≥4 colors 11.8 66.7 =0.088 blue-gray color 11.8 66.7 =0.088 white color 17.7 66.7 =0.14 ≥3 structures 41.2 100 =0.105 ≥4 structures 0 66.7 =0.016 asymmetry in 2 axes 5.9 100 =0.004 research | dermatol pract concept 2018;8(3):12 213 12. jaimes n, marghoob aa. the morphologic universe of melanoma. dermatol clin. 2013;31(4):599-613, viii-ix. doi: 10.1016/j. det.2013.06.010. 13. kaçar n, yildiz cc, demirkan n. dermoscopic features of conjunctival, mucosal, and nail pigmentations in a case of laugierhunziker syndrome. dermatol pract concept. 2016;6(1):23-24. doi: 10.5826/dpc.0601a07. 14. li k, xin l. palpebral conjunctiva melanoma with dermoscopic and clinicopathological characteristics. j am acad dermatol. 2014;71(2):e35-e37. doi: 10.1016/j.jaad.2013.11.011. 15. singh r, joseph a, umapathy t, tint nl, dua hs. impression cytology of the ocular surface. br j ophthalmol. 2005;89(12):16551659. doi: 10.1136/bjo.2005.073916. 16. paridaens ad, mccartney ac, curling om, lyons cj, hungerford jl. impression cytology of conjunctival melanosis and melanoma. br j ophthalmol. 1992;76(4):198-201. doi: 10.1136/ bjo.76.4.198. 17. keijser s, missotten gs, de wolff-rouendaal d, et al. impression cytology of melanocytic conjunctival tumours using the biopore membrane. eur j ophthalmol. 2007;17(4):501-506. doi: 10.1177/112067210701700404. 18. tananuvat n, lertprasertsuk n, mahanupap p, noppanakeepong p. role of impression cytology in diagnosis of ocular surface neoplasia. cornea. 2008;27(3):269-274. doi: 10.1097/ ico.0b013e31815b9402. 19. barros jn, lowen ms, mascaro vl, andrade tp, martins mc. impression cytology features of conjunctival nevi reported as more noticeable. arq bras oftalmol. 2009;72(2):205-210. doi: 10.1590/s0004-27492009000200014. untitled observation | dermatol pract concept 2015;5(2):9 61 dermatology practical & conceptual www.derm101.com case presentation an 83-year-old patient presented to the dermatologist numerous times with multiple lesions on the face, scalp and ears (figure 1). lesions were gradually excised (11 lesions were excised and studied from 2011-2013). histopathologically, two of the lesions were benign cylindromas, four were spiradenomas, and four others were combined lesions (cylindromas in conjunction with spiradenomas). the patient was diagnosed with brooke-spiegler syndrome. at the time of this biopsy, the patient presented with a rapidly enlarging nodule on the scalp. the biopsy of the scalp showed an adnexal neoplasm with poor circumscription, irregular borders and infiltrative growth pattern at the base (figure 2). it was composed of small irregular cylindroma-like aggregates, which had almost lost their malignant cylindroma in a patient with brooke-spiegler syndrome liliane borik1,2, patricia heller2, monica shrivastava3, viktoryia kazlouskaya2 1 division of immunology, allergy and infectious diseases, department of dermatology, medical university of vienna, vienna, austria 2 ackerman academy of dermatopathology, new york, ny, usa 3 advanced laser skin center, teaneck, nj, usa key words: adnexal neoplasm, apocrine neoplasm, cylindroma, cylindrocarcinoma citation: borik l, heller p, shrivastava m, kazlouskaya v. malignant cylindroma in a patient with brooke-spiegler syndrome. dermatol pract concept 2015;5(2):9. doi: 10.5826/dpc.0502a09 received: october 17, 2014; accepted: january 9, 2015; published: april 30, 2015 copyright: ©2015 kazlouskaya et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: viktoryia kazlouskaya, md, phd, ackerman academy of dermatopathology ,145 e 32 st, 10th fl, new york, ny 10036, usa. tel. 347-488-8058. e-mail: viktoriakozlovskaya@yahoo.com malignant cylindroma (cylindromatous carcinoma, cylindrocarcinoma) is the malignant counterpart of benign cylindroma. it is a rare neoplasm, more often developing in the setting of multiple preexisting benign neoplasms. herein we present an additional case of malignant transformation of the cylindroma diagnosed in an 83-year-old patient with known brooke-spiegler syndrome. abstract figure 1. multiple nodules in the central face. [copyright: ©2015 kazlouskaya et al.] mailto:viktoriakozlovskaya@yahoo.com 62 observation | dermatol pract concept 2015;5(2):9 figure 6. re-excision of cylindrocarcinoma showed infiltrative pattern with the involvement of the fat tissue and underlying structures. h&e stained section, ×20. [copyright: ©2015 kazlouskaya et al.] jigsaw pattern. hyaline sheaths were lost around some aggregates (figure 3). the cells of the tumor were mostly enlarged with striking nuclear pleomorphism. there was individual cell necrosis, but no necrosis en masse (figure 4). focal clear cell change was seen. s100 immunostain showed a patchy staining and was inconclusive. ki-67 immunostain showed relatively high proliferation rate (figure 5). the diagnosis of cylindrocarcinoma was made and the complete excision of the tumor was recommended. on the re-excision, the tumor showed the same pattern with the involvement of the fat with the small aggregates of the tumor (figure 6). a focus of spiradenoma was revealed in one of the sections of the re-excision specimen (figure 7a and b). no recurrences or metastases were observed in this patient after 12 months of follow up. after a year of follow up, the patient presented with two additional enlarging nodules on the scalp (different locations from the first one). both of tumors showed unusual features, including infiltrative growth pattern, asymmetry, figure 2. a cylindroma-like adnexal neoplasm with an irregular, infiltrative pattern. hematoxylin and eosin (h&e) stained sections, ×40. [copyright: ©2015 kazlouskaya et al.] figure 3. small irregular aggregates of the cylindrocarcinoma, some are without hyaline sheath. loss of jigsaw pattern. h&e stained sections, ×100. [copyright: ©2015 kazlouskaya et al.] figure 4. tumor aggregates composed of mostly enlarged cells with mitotic figures. lack of hyaline sheath around them. h&e stained sections, ×400. [copyright: ©2015 kazlouskaya et al.] figure 5. ki-67 immunostain in cylindrocarcioma. [copyright: ©2015 kazlouskaya et al.] observation | dermatol pract concept 2015;5(2):9 63 several authors have reported a greater tendency of malignant cylindroma formation in patients with multiple pre-existing benign lesions. rare sporadic solitary tumors are also described [3,4]. brooke-spiegler syndrome (bss) is the most frequently associated with malignant cylindromas. the syndrome has autosomal-dominant inheritance. the formation of multiple cylindromas in patients with this syndrome may be due to cyld gene located on 16 chromosome [5]. clinically, cylindrocarcinomas most commonly are localized on the head and neck. the malignant variant shows rapid enlargement, bleeding, ulceration, color change, fixation and pain. when the tumor develops from the longstanding benign neoplasm, it is possible to identify gradual or abrupt transition to the malignancy [6]. histopathologically, malignant cylindroma is characterized by loss of the jigsaw pattern, loss of the delicate hyaline sheaths, loss of peripheral palisading of and infiltration of subcutaneous tissue with small irregular tumor aggregates. one of the tumors also had areas resembling spiradenoma (figure 8a and b). the second tumor was curetted and presented with fragments of the tumor, involving subcutaneous fat tissue (figure 9a and b). although cytological abnormalities were not striking, both tumors were felt to have malignant differentiation based on their architectural characteristics. discussion malignant cylindroma (cylindrocarcinoma) is an extremely rare adnexal neoplasm. it was first described by wiedmann in 1929 on the scalp of a 63-year-old woman [1,2]. after the excision of the lesion, the patient died of visceral and lymph node metastases. so far, less than 50 cases of malignant cylindroma have been reported in literature. figure 7. re-excision of cylindrocarcinoma. (a) one of the sections showing a focus of spiradenoma. h&e stained sections, ×40. (b) high power of spiradenoma seen adjacent to cylindrocarinoma, h&e stained sections, ×200. [copyright: ©2015 kazlouskaya et al.] figure 8. tumor of the scalp, excised after one year of follow up. (a) assymmetrical tumor, composed of parts resembling cylindroma and spiradenoma. h&e stained sections, ×40. (b) infliltrative growth pattern of the tumor nests. h&e stained sections, ×200. [copyright: ©2015 kazlouskaya et al.] 64 observation | dermatol pract concept 2015;5(2):9 of basal cell adenoma and its malignant counterpart—basal cell adenocarcinoma of the salivary glands—may be indistinguishable from cutaneous cylindrocarcinomas. as well as cutaneous neoplasms, they may have similar hyaline deposits and share similar genetic abnormalities. both benign and malignant variants of salivary gland tumors may co-exist with cylindromas/cylindrocarcinomas [16,17]. several cases of the anal/rectum basaloid tumor with the features of cylindroma/ spiradenoma have been reported recently [18,19] presence of koiocytes, presence of squamous cell carcinoma (scc) in situ and identification of hpv allow to classify those tumors as hpv-induced scc in situ. when malignant cylindroma is diagnosed histopathologically as a solitary lesion, the treatment of choice is wide local excision because of the high recurrence rates and the potential to metastasize. in addition, laser ablation, mohs’ micrographic surgery, cryotherapy, retinoic acid, trichloroacetic acid, carbon dioxide laser and radiotherapy can be performed [20,21]. in extensive lesions, resurfacing with split skin-grafts is the method of choice for covering the defects [22]. aggressive behavior with frequent extensive local infiltrative growth and metastases is known for malignant cylindromas. to ensure a better prognosis, early diagnosis and close follow-up is mandatory especially in patients with multiple cylindromas. the prognosis and prognostic features of malignant cylindromas are not well described due to the low number of reported cases and insufficient follow up on the patients. in the summary of 24 reported cases of malignant cylindroma gerretsen et al reported that local recurrence was seen in 9 cases, metastases to the lymph nodes or viscera were seen in 11 cases and 11 patients died [23]. liver and vertebral column are particularly affected. metastases to thyroid, stomach and bones as well as intracranial invasion and transcranial erosion by cylindromas have been observed [24-26]. perineural involvement may occur [3]. the tumor islands at the periphery, and loss of the bimorphic cell composition. it exhibits nuclear pleomorphism, abnormal crowded nuclei, a high mitotic rate, stromal invasion and focal areas of necrosis. requena et al mentioned that asymmetry, poor circumscription, necrosis en masse may help to make a diagnosis even at low magnification. as its benign counterpart, malignant cylindroma may be associated with spiradenoma, forming so-called “spiradenocylindrocarcinoma” [8-10]. we have observed a focus of spiradenoma in the subsequent re-excision sections of the presented lesion, and in one of the tumors developed later, but there were no atypical cytological changes seen in the foci, and we concluded that the term “cylindrocarcinoma” is preferable. features of malignancy, mentioned above, may be scant and seen only in a few histopathological sections. several cases of well-differentiated malignant cylindromas were reported [3, 11, 12]. kazakov et al described several histopathological patterns of malignant tumors arising in the setting of pre-existent spiradenomas and cylindromas in patients with bss [6]. most frequently, neoplasms resembled salivary gland basal cell adenocarcinomas and had either low grade or high-grade malignant differentiation. infiltrative and sarcomatoid poorly differentiated pattern was seen in lesser amount of cases. no immunohistochemical markers help to perform a differential diagnosis between benign and malignant cylindromas with certainty. when the neoplasm in undifferentiated, the use of cytokeratins, carcinoembryonic antigen (cea), epithelial membrane antigen (ema) may help to define the tumor origin [13]. expression of s-100, laminin, collagen iv, fibronectin and cd-34 have been reported [14,15]. presence of estrogen receptors was shown by apostolou et al [8] ki-67 may be helpful to highlight a high proliferative rate [9]. cylindrocaricinoma must be distinguished with the benign cylindroma and spiradenoma. membranous variant figure 9. second tumor, excised after a year of follow up. (a, b) irregular cylindroma-like nests of tumor, extending into subcutaneous tissue. h&e stained sections, ×200, ×400. [copyright: ©2015 kazlouskaya et al.] observation | dermatol pract concept 2015;5(2):9 65 12. donner lr, ruff t, diaz ja. well-differentiated malignant cylindroma with partially preserved hyaline sheaths. a locally invasive neoplasm? am j dermatopathol 1995;17(2):169-73. 13. kazakov dv, michal m, kacerovska d, mckee ph. malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma. in: cutaneous adnexal tumors. philadelphia, pa: lippincott williams and wilkins, 2001:105-12. 14. tellechea o, reis jp, ilheu o, baptista ap. dermal cylindroma. an immunohistochemical study of thirteen cases. am j dermatopathol 1995;17(3):260-5. 15. meybehm m, fischer hp. spiradenoma and dermal cylindroma: comparative immunohistochemical analysis and histogenetic considerations. am j dermatopathol 1997;19(2):154-61. 16. antonescu cr, terzakis ja. multiple malignant cylindromas of skin in association with basal cell adenocarcinoma with adenoid cystic features of minor salivary gland. j cutan pathol 1997;24(7):449-53. 17. headington jt, batsakis jg, beals tf, et al. membranous basal cell adenoma of parotid gland, dermal cylindromas, and trichoepitheliomas. comparative histochemistry and ultrastructure. cancer 1977;39(6):2460-9. 18. chetty r, serra s, hsieh e. basaloid squamous carcinoma of the anal canal with an adenoid cystic pattern: histologic and immunohistochemical reappraisal of an unusual variant. am j surg pathol 2005;29(12):1668-72. 19. kacerovska d, szepe p, vanecek t, et al. spiradenocylindroma-like basaloid carcinoma of the anus and rectum: case report, including hpv studies and analysis of the cyld gene mutations. am j dermatopathol 2008;30(5):472-6. 20. retamar ra, stengel f, saadi me, et al. brooke-spiegler syndrome—report of four families: treatment with co2 laser. int j dermatol 2007;46(6):583-6. 21. lo js, peschen m, snow sn, oriba ha, mohs fe. malignant cylindroma of the scalp. j dermatol surg oncol 1991;17(11):897901. 22. fabian rl, shugar ma. florid dermal cylindroma (turban tumor). head neck surg 1981;4:165-9. 23. gerretsen al, van der putte sc, deenstra w , van vloten wa. cutaneous cylindroma with malignant transformation. cancer 1993;72:1618-23. 24. lotem m, trattner a, kahanovich s, rotem a , sandbank m. multiple dermal cylindroma undergoing a malignant transformation. int j dermatol 1992;31:642-4. 25. wyld l, bullen s, browning fs. transcranial erosion of a benign dermal cylindroma. ann plast surg 1996;36:194-6. 26. pingitore r, campani d. salivary gland involvement in a case of dermal eccrine cylindroma of the scalp (turban tumor). report of a case with lung metastases. tumori 1984;70:385-8. our case report represents one more example of this rare entity and widens our horizons of this unique tumor. it may be interpreted as “spiradenocylindrocarinoma.” some parts of the tumor, including spiradenoma did not show atypia, therefore we prefer the interpretation that the malignant tumor developed from the pre-existing benign tumor composed from cylindroma and spiradenoma. references 1. wiedmann a. weitere beitrage zur kenntnis der sogenannten zylindrome der kopfhaut. arch dermatol 1929;159:180-7. 2. wiedemann a. further contributions to the knowledge of the socalled cylindroma of the scalp. arch dermatol 1929;159:180-7. 3. navarro v, monteagudo c, calduch l, et al. well-differentiated malignant solitary dermal cylindroma. an immunohistochemical study. in: 19th colloquium of the international society of dermatopathology (isd). madrid, spain, november 5-7, 1998. abstracts. am j dermatopathol 1998;20(6):598. 4. akgul gg, yenidogan e, dinc s, et al. malign cylindroma of the scalp with multiple cervical lymph node metastasis-a case report. int j surg case rep 2013;4(7):589-92. 5. gerretsen al, beemer fa, deenstra w, hennekam fa, van vloten wa. familial cutaneous cylindromas: investigations in five generations of a family. j am acad dermatol 1995;33:199-206. 6. kazakov dv, zelger b, rutten a, et al. morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of brooke-spiegler syndrome. am j surg pathol 2009;33(5):705-19. 7. requena l, kiryu h, ackerman ab. cylindrocarcinoma. neoplasms with apocrine differentiation. philadelphia, pa: lippincott-raven publishers, 1997:733-50. 8. apostolou g, apostolou n, chatzipantelis p, biteli m. spiradenocylindrocarcinoma. report of a case with a low-grade component of spiradenocarcinoma and an immunohistochemical study. am j dermatopathol 2009;31(6):594-8. 9. carlsten jr, lewis md, saddler k, et al. spiradenocylindrocarcinoma: a malignant hybrid tumor. j cutan pathol 2005;32(2):16671. 10. dai b, kong yy, cai x, shen xx, kong jc. spiradenocarcinoma, cylindrocarcinoma and spiradenocylindrocarcinoma: a clinicopathological study of nine cases. histopathology 2014;65(5):65866. 11. donner lr. well-differentiated malignant cylindroma. am j dermatopathol 2012;34(6):677. dermatology: practical and conceptual 238 review | dermatol pract concept 2018;8(3):17 dermatology practical & conceptual www.derm101.com squamous cell carcinoma of the nail unit michela starace1, aurora alessandrini1, emi dika1, bianca maria piraccini1 1 department of specialized, diagnostic and experimental medicine, university of bologna, bologna, italy key words: squamous cell carcinoma, malignant nail tumor, nail surgery, nail unit, onychoscopy citation: starace m, alessandrini a, dika e, piraccini bm. squamous cell carcinoma of the nail unit. dermatol pract concept. 2018;8(3):238244. doi: https://doi.org/10.5826/dpc.0803a17 received: december 31, 2017; accepted: february 28, 2018; published: july 31, 2018 copyright: ©2018 starace et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: michela starace, md, phd, v. massarenti 1, 40138, bologna, italy. email: michela.starace2@unibo.it introduction squamous cell carcinoma (scc), together with bowen’s disease, the in situ form of scc, is the most common malignant tumor of the nail and is usually slow growing [1]. however, both have a very low incidence [2]. several factors have been proven to favor its development, such as exposure to ionizing radiation, high-risk hpv, and chronic trauma. scc tends to occur most commonly on the fingernails of elderly men and mainly in the thumb. scc has an indolent course and causes very mild symptoms. clinical manifestations depend on the site within the nail unit where it arises (most commonly from the nail bed), and they include lateral detachment (onycholysis) of the nail and a warty aspect, with a longitudinal band of melanonychia, erosion of the nail bed associated or not with a nodule, and, rarely, longitudinal erythronychia. there is often a substantial delay in the diagnosis of scc in the nail unit because is often misdiagnosed as chronic paronychia, onychomycosis, pyogenic granuloma, subungual squamous cell carcinoma (scc) of the nail apparatus is a rare malignant tumor that usually originates underneath the nail plate and grows slowly with possible bone invasion. the etiology remains unknown, although a strong association with different conditions, such as high-risk human papillomavirus (hpvs), trauma, or radiation exposure has been demonstrated. nail scc is called “the great mimicker nail tumor” because different clinical presentations may coexist, resembling benign or malignant nail lesions. for this reason, there is often a significant delay between the onset of nail scc and the diagnosis. clinical manifestation includes onycholysis and erythema, while in the advanced stages nail ulceration can be observed. the association with pain, swelling, and inflammation usually indicates an invasive scc with involvement of the underlying bone. metastasis is rare but possible with involvement of lymph nodes. a multidisciplinary approach to assessment, management, and follow-up is advised. using careful examination and modern diagnostic methods, including onychoscopy, biopsy, and histopathology, will help identify scc and prevent the invasive progression. x-ray is important to investigate the bone invasion to determine the best surgical approach that will have satisfying cosmetic and functional outcomes. nevertheless, local excision with sufficient surgical margins, best if using mohs surgery, is usually sufficient and superior to amputation of the distal phalanx. this review aims to highlight the correct approach in suspected scc of the nail unit. abstract review | dermatol pract concept 2018;8(3):17 239 although chronic inflammation and infections have been suggested as etiological factors in scc, it is still unclear whether these alterations could be trigger factors for a malignant transformation or if such association is just an occasional finding [10]. clinical manifestations scc runs an indolent course and causes very mild symptoms. the clinical history describes a long-standing lesion, as tumor growth is very slow. scc has a variety of clinical appearances that depend on the site within the nail unit where it arises, most commonly from the subungual region (nail bed) (57.4%), rarely from the proximal or lateral nail folds (31.5%), and exceptionally from the hyponychium (finger pulp skin) [5]. possible signs of presentation of subungual scc follow. 1. lateral detachment (onycholysis) of the nail and warty aspect of the exposed nail bed and lateral nail fold that tends to ulcerate associated with an adjacent thin band of longitudinal melanonychia, which result from melanocytic activation by the tumor (figure 1). this is typical of bowen’s disease, the hyperkeratoric variant of in situ scc. the warty aspect of the lesion explains why it is frequently misdiagnosed as viral wart (figure 2). 2. painless erosion of the nail bed, appearing as a distal area of onycholysis with yellow discoloration and oozing from under the nail. the erosion is not visible unless the nail plate is cut away (figure 3). 3. in long-standing lesions, the clinical aspect becomes that of a large nail bed erosion associated or not with a nodule (figure 4). 4. rarely (3% of the cases), scc can appear as a band of longitudinal erythronychia. all reported cases of this clinical presentation were in situ scc, clinically indistinguishable from the more common erythronychia due to onychopapilloma (figure 5) [11]. 5. scc involving multiple digits is an exceptional presentation, also known as synchronous scc [12]. 6. most commonly localized hyperkeratosis could be the first appearance of scc, partial or extensive. in this type, the nail bed is thickened and the nail plate is raised from the nail bed, inducing an onycholysis due to an accumulation of parakeratotic material [13]. compared with scc of the rest of the skin, nail scc tends to become invasive more quickly. bone involvement is seen in more than 20% of cases, ranging from 16% to 66% [6,13,14], with the frequency peaks increasing in immunocompromised patients, such as aids patients under highly active antiretroviral therapy [6,15]. pain may occur when bone invasion is present [4]. lymph nodal involvement is warts, subungual exostosis, keratoacanthoma, or amelanotic melanoma [3]. moreover, the majority of sccs of the nail unit originate from advanced bowen’s disease lesions, and it is therefore not surprising that lesions may be present for years, sometimes more than a decade [4]. onychoscopy can be useful for the diagnosis, showing onycholysis, irregular vascularity, or hemorrhages with a rough-to-verrucous surface, but the features of this tumor are not exclusive; histology is mandatory. surgical excision remains the mainstay treatment of scc: classical surgical removal is recommended for invasive scc, whereas mohs micrographic surgery is indicated for noninvasive scc. therefore, the diagnosis of the scc can be challenging and is often delayed, jeopardizing the possible use of a preserving surgical approach. bone invasion and metastases are, however, rare. epidemiology the prevalence of scc ranges from 0.0012% of hospital patients to 0.028% of dermatology outpatients [2]. the typical patient is a middle-aged man with an ulcerated nodule of the nail bed or lateral onycholysis that has not been cured by previous treatments. the peak incidence age is between 50 and 69 years, but the tumor can occur at any age during adulthood. the ratio of sex incidence for male to female is 2:1 [5]. scc usually involves one fingernail, especially the thumb (44% of cases), with the second and third fingers of the dominant hand and the big toenail being other possible locations [6]. only 16% of sccs are located on the toenails [1]. pathogenesis trauma, chronic sun or arsenic exposure, radiation, burning, genodermatoses, tobacco or immunosuppression, and hpv infection are considered to risk factors for the development of scc [7]. immune suppression has an important role in the development of scc: immunocompromised patients present with the tumor at a younger age and with a shorter history than those patients with normal immune function [7]. there is increasing evidence of the role of hpv in the pathogenesis of scc of the nail unit, as several types of hpv, especially type 16 detected on the nail unit as the only subtype, have been detected in several cases [8]. a possible method of transmission is from the genital area. the occurrence of multiple hpv-positive scc in several nails in immunosuppressed patients further underlines the importance of hpv. aggressive and extensive treatment and close follow-up are necessary in hpv-associated scc, due to its higher recurrence rate, possibility of metastasis, and proliferative activity compared to hpv-negative scc [9]. 240 review | dermatol pract concept 2018;8(3):17 less common, occurring in 2% of patients [16]. tendency to metastasize is low but has been reported in a few cases [17]. differential diagnosis scc is a rare neoplasm that often mimics other entities resembling benign or common infectious or inflammatory processes of the nail apparatus. the lack of awareness among physicians, its painless history, and the higher frequency of benign diseases than malignant conditions that simulate scc are responsible for the delay in its diagnosis [13]. differential diagnosis includes pyogenic granuloma [18], onychomycosis [10], onychopapilloma [11], longitudinal melanonychia [19], subungual exostosis, chronic paronychia, fibrokeratoma, and onychomatricoma [1]. the most important diagnosis to rule out in case of suspect scc is viral warts. hpv-induced warts appear as figure 5. scc with a longitudinal erythronychia and erosion of under nail bed. [copyright: ©2018 starace et al.] figure  4. scc long-standing subungual lesion, evolving in nail bed large erosion with disappearing of nail plate. [copyright: ©2018 starace et al.] figure  3. scc with eroded mass under the nail, characterized by onycholytic area with oozing from the nail in late stage due to subungual erosion. [copyright: ©2018 starace et al.] figure 1. scc with lateral detachment of the nail and a warty aspect of the exposed nail bed and lateral nail fold with black discoloration that tends to ulcerate with a scab formation. [copyright: ©2018 starace et al.] figure  2. scc with lateral verrucous lesion, frequently misdiagnosed as viral wart especially when the lesion is characterized by nail plate partial or total absence due to a hyperkeratotic nodule. [copyright: ©2018 starace et al.] review | dermatol pract concept 2018;8(3):17 241 surface with brown-red streaky hemorrhages [23]. the use of onychoscopy, however, reduces the difficulties for differential diagnosis versus onychopapilloma [24], onychomatricoma [25], and subungual exostosis [26]. the vascular polymorphism is the most important aspect seen by onychoscopy in scc producing eroded lesions of the multiple hyperkeratotic and exophytic papules or nodules, especially located on the palmar or dorsal side of the finger, but may also involve the periungual skin [20]. differential diagnosis with bowen’s disease is difficult in these cases. another important differential diagnosis is between scc presenting as eroded lesion of the nail bed and amelanotic melanoma [21,22]. diagnostic techniques the use of nail dermoscopy (onychoscopy), a noninvasive method to better observe the nail unit, has been described as a useful instrument as a preoperative method to evaluate nail diseases for a more accurate examination than the naked eye. under these circumstances, onychoscopy has been shown to decrease the number of unnecessary excisions of benign lesions. typical alterations visible in scc with onychoscopy are onycholysis, irregular vascularity, or hemorrhages with a rough to verrucous surface (figures 6 and 7). none of these signs is, however, exclusive or diagnostic for the tumor. differential diagnosis between periungual warts and scc is not helped by onychoscopy as well, as the 2 types of lesions share several signs, such as yellowish and rough to verrucous a b c d figure 6. clinical picture in (a) frontal view and (b) lateral view of scc and onychoscopy of typical alterations of scc: onycholysis, irregular vascularity, and erosion of nail bed (c) before and (d) after nail clipping onycholytic nail plate. [copyright: ©2018  starace et al.] figure 7. onychoscopy of a verruca-like aspect of scc: onycholysis, irregular vascularity, and hemorrhage, verrucous surface of nail bed. [copyright: ©2018 starace et al.] 242 review | dermatol pract concept 2018;8(3):17 in particular, be performed in any case of a recurrent and persistent periungual warty lesion in order to make an early diagnosis of scc and avoid extensive surgery and to preserve maximal function of the digit. histopathology a variable degree of irregular and incomplete keratinization and superficial ulceration is present. a high degree of atypia with large and hyperchromatic nuclei of the basal and spinous cells, single cell necrosis, and pathological mitoses are observed with frequent keratin pearls. the epidermis shows vacuolated superficial keratinocytes with pyknotic raisin-like nuclei. in the late stage, the deep invasion of the bone can observed, and this type of scc is negative for hpv dna [4, 30]. one of the most pertinent differential diagnoses of scc of the nail is subungual keratoacanthoma (ka). the main difference is that scc has a very irregular stratification, while keratoacanthoma has a normal maturation of the epithelial cells from the basal layer to the center. moreover, is possible to observe a lip formation in ka, but not in scc, as well as the presence of elastic fibers in ka, a sign of its rapid growth, which is not seen in scc [4]. treatment a variety of treatment options is available for scc, including surgical excision, microscopically controlled surgery (mohs surgery), therapeutic radiation, and nonsurgical alternatives. surgical excision remains the mainstay treatment of scc: classically, surgical removal is mandatory for invasive scc, whereas mohs micrographic surgery is indicated for noninvasive scc, as it allows excision of the diseased part of the nail with minimal residual scarring, reduces the number of unnecessary amputations, and preserves the quality of life of the patient [31]. mohs surgery also allows the evaluation of periosteal invasion to be distinguished from inflammation or compression [31]. wide surgical excision with no less than 4 mm of normal tissue from the margin of the tumor can be used for the lesions without bone involvement. the postsurgical reconstruction can be done with full thickness skin graft reconstruction. a recent paper described postoperative complications of mohs surgery: in the early phase, topin-ruiz et al observed graft infection and delayed wound healing with severe pain; late-stage complications included hypersensitivity to mechanical shock, mildly increased sensitivity to cold, loss of fine touch sensation, and epidermal inclusion cysts [32]. these sensitive alterations are compared to the “phantom limb pain” referred to after disarticulation and volar flap reconstructions [33]. nail bed and is characterized by dot-like to glomerular vessels clustering in groups [23]. in a recent paper, teysseire et al [27] described the clinical and dermoscopic presentations of scc finding irregular and unparalleled borders, hyperkeratosis underneath the nail plate, splinter hemorrhages, white longitudinal lines, nail thickening, and a polycyclic/fuzzy lesion edge. some presentations are not specific to scc, but are also observed in other diseases such as onychomatricoma or onychopapilloma, especially in the case of localized hyperkeratosis, parallel edges, sharp demarcation, and splinter hemorrhages. the onychoscopy criterion significantly associated with series of scc of this study is unparalleled lateral edges or fuzzy edges of the nail lesion. a method recently used to investigate nail tumors is ex vivo fluorescence confocal microscopy (fcm). debarbieux et al [28] described the excellent correlation of malignant epithelial tumors with the observation of marked cytological and architectural atypia, such as nuclear pleomorphism and densely packed and irregularly organized nuclei, typical of invasive scc. the while the correlation was less favorable for minimally invasive scc with slight cytological atypia and the “blurred cell pattern.” it is also suggested that this technique be used intraoperatively to make or confirm a diagnosis and to assess the surgical margins. it is defined as an alternative to classic mohs surgery. at ultrasonography, scc appears as a heterogeneously hypoechoic focal mass with irregular margins; in color doppler mode, low-resistance pulsatile flow signals within the tumor or at the periphery is evident [27]. radiological exam should be done to evaluate underlying bone involvement, which is an indicator for amputation, but is fortunately reported in less than 20% of patients [29 30]. more often, x-ray of the digit may show osteolysis due to compression and not to true bone invasion. x-ray and computed tomography (ct) are useful in showing scc as a crescent-shaped soft tissue mass with osteolytic defect of the associated phalanx, without periosteal reaction. a heterogeneous hypoechoic mass with irregular contours and posterior acoustic enhancement best represents the scc [2]. an mri is performed to investigate soft tissues or bone masses in the subungual area. an mri is superior to the other radiologic imaging methods for soft tissue masses, as it has the capability of identifying the exact location and extension and adds value in local staging for scc [2]. accurate diagnosis can only be made by performing an appropriate biopsy followed by histopathologic evaluation [27], but biopsy is painful and often leaves definitive dystrophic scars. therefore, many dermatologists are reluctant to perform biopsies and instead let the scc grow, treating it as a benign lesion. as a result, the patients are often misdiagnosed, leading to an average delay of 4 years for definitive treatment, as noted in the literature [13]. nail biopsy should, review | dermatol pract concept 2018;8(3):17 243 visualize the onycholytic nail plate and subungual hyperkeratosis with high magnification that permits observation of the aspect of the color and shape. it is not a specific method for diagnosis, but it is helpful in differential diagnosis in some conditions such as onychomatricoma and onychomycosis. another important role of dermoscopy can be the selection of the biopsy site [27]. pathological confirmation is necessary for early diagnosis and treatment effectiveness. the presence of pain indicates bone invasion by the tumor, and x-ray is mandatory in these patients to investigate the bone involvement. given the rarity of the condition, there is no consensus on the optimal treatment. no standardized therapeutic approach is described in scc, and the choice is selected on the basis of the extension of the tumor and the involvement of the underlying structures. microscopic surgery and local removal are advised in superficial lesions for the lower recurrence rate, while large excision until amputation are recommended for patients with bone infiltration. the tendency of recurrence is higher in the nail unit than in another part of the body, likely due to residual hpv in the surrounding area or an incomplete excision of the tumor, and for this reason a strict and long follow-up is recommended for scc. references 1. lecerf p, richert b, theunis a, andré j. a retrospective study of squamous cell carcinoma of the nail unit diagnosed in a belgian general hospital over a 15-year period. j am acad dermatol. 2013;69(2):253-261. doi: 10.1016/j.jaad.2013.02.008. 2. high wa, tyring sk, taylor rs. rapidly enlarging growth of the proximal nail fold. dermatol surg. 2003;29(9):984-986. 3. tambe sa, patil pd, saple dg, kulkarni uy. squamous cell carcinoma of the nail bed: the great mimicker. j cutan aesthet surg. 2017;10(1):59-60. doi: 10.4103/jcas.jcas_35_16. 4. haneke e. important malignant and new nail tumors. j dtsch dermatol ges. 2017;15(4):367-386. 5. d e b e r k e r da , d a h l m g , m a l c o l m aj, l a w r e n c e c m . micrographic surgery for subungual squamous cell carcinoma. br j plast surg. 1996;49(6):414-419. doi: 10.1016/s00071226(96)90013-2. 6. kelly kj, kalani ad, storrs s, et al. subungual squamous cell carcinoma of the toe: working toward a standardized therapeutic approach. j surg educ. 2008;65(4):297-301. doi: 10.1016/j. jsurg.2008.05.013. 7. ormerod e, de berker d. nail unit squamous cell carcinoma in people with immunosuppression. br j dermatol. 2015;173(3):701712. doi: 10.1111/bjd.13860. 8. dika e, venturoli s, patrizi a, et al. the detection of human papillomavirus-16 in squamous cell carcinoma of the nail unit: a case series. j am acad dermatol. 2017;76(2):354-356. doi: 10.1016/j. jaad.2016.08.063. 9. riddel c, rashid r, thomas v. ungual and periungual human papillomavirus-associated squamous cell carcinoma: a review. j am acad dermatol. 2011;64(6):1147-1153. doi: 10.1016/j. jaad.2010.02.057. given the rarity of scc, treatment guidelines have not been established. although surgical excision remains the mainstay treatment of scc, a variety of nonsurgical treatment options have also been trialed with varying success. these include photodynamic therapy, 5% fluorouracil cream, or 5% imiquimod cream after curettage; they are characterized by high incidence of relapses and absence of control of histological margins of the tumors. radiation therapy may be helpful in the case of polydactylous disease or where surgery is difficult, especially in immunocompromised patients, although the advantages must be weighed against its potential as a causative agent in these cancers [7]. radiation therapy has been suggested as an emerging alternative treatment option to preserve integrity of the distal finger. an alternative and underutilized approach to surgical excision in difficultto-treat cases of scc is the photon irradiation using a water bath. this technique is recommended in the case of extensive disease that can lead to unacceptable functional morbidity or cosmetic outcomes, but its use has been limited due to concerns regarding toxicity [34]. chemotherapy is indicated only in metastatic disease. amputation of the distal phalanx has the highest cure rate and is indicated in case of long-standing carcinoma or bony involvement. recurrence is reported in only 3.5% of patients after mohs surgery [31] and 4% after wide surgical excision [28] compared with conventional surgery or modified surgical procedures that vary from 28.5% to 56% according to different experiences [1]. moreover, the recurrence is higher than skin scc. there are several explanations for this discrepancy: most nail scc is associated with high-risk hpv, which remains in the nail and periungual tissue and may subsequently trigger oncogenic mutations. furthermore, the surgical procedure is more difficult in nail involvement than skin areas for margins, and the pathology can be more challenging to interpret [35]. conclusions scc presents with a variety of clinical appearances and course. physicians need to maintain heightened awareness, and chronic, non-healing lesions of the digits should be viewed with suspicion. rapidly growing ulcerative lesions should be considered as potential malignancy. the prognosis of scc is very good if it is recognized at an early stage, highlighting the need for clipping away the nail plate and taking a biopsy in patients with chronic or recurrent oozing from under the nail that fails to respond to any previous conservative treatment. nail dermoscopy is useful in looking for longitudinal melanonychia or erythronychia, irregular vascularity, and hemorrhages. moreover, it is helpful to better 244 review | dermatol pract concept 2018;8(3):17 23. haenssle ha, blum a, hofmann-wellenhof r, et al. when all you have is a dermatoscopestart looking at the nails. dermatol pract concept. 2014;4(4):11-20. 24. tosti a, schneider sl, ramirez-quizon mn, zaiac m, miteva m. clinical, dermoscopic, and pathologic features of onychopapilloma: a review of 47 cases. j am acad dermatol. 2016;74(3):521526. doi: 10.1016/j.jaad.2015.08.053. 25. lesort c, debarbieux s, duru g, dalle s, poulhalon n, thomas l. dermoscopic features of onychomatricoma: a study of 34 cases. dermatology. 2015;231(2):177-183. doi: 10.1159/000431315. 26. piccolo v, argenziano g, alessandrini am, russo t, starace m, piraccini bm. dermoscopy of subungual exostosis: a retrospective study of 10 patients. dermatology. 2017;233(1):80-85. doi: 10.1159/000471800. 27. teysseire s, dalle s, duru g, et al. dermoscopic features of subungual squamous cell carcinoma: a study of 44 cases. dermatology. 2017;233(2-3):184-191. doi: 10.1159/000479059. 28. debarbieux s, gaspar r, depaepe l, dalle s, balme b, thomas l. intraoperative diagnosis of nonpigmented nail tumours with ex vivo fluorescence confocal microscopy: 10 cases. br j dermatol. 2015;172(4):1037-1044. doi: 10.1111/bjd.13384. 29. peterson sr, layton eg, joseph ak. squamous cell carcinoma of the nail unit with evidence of bony involvement: a multidisciplinary approach to resection and reconstruction. dermatol surg. 2004;30(2 pt 1):218-221. 30. zavos g, karidis np, tsourouflis g, et al. nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. int j dermatol. 2011;50(12):14961500. doi: 10.1111/j.1365-4632.2011.04939.x. 31. dika e, fanti pa, patrizi a, misciali c, vaccari s, piraccini bm. mohs surgery for squamous cell carcinoma of the nail unit: 10 years of experience. dermatol surg. 2015;41(9):1015-1019. 32. topin-ruiz s, surinach c, dalle s, duru g, balme b, thomas l. surgical treatment of subungual squamous cell carcinoma by wide excision of the nail unit and skin graft reconstruction: an evaluation of treatment efficiency and outcomes. jama dermatol. 2017;153(5):442-448. doi: 10.1001/jamadermatol.2017.0014. 33. björkman a, weibull a, olsrud j, ehrsson hh, rosén b, björkman-burtscher im. phantom digit somatotopy: a functional magnetic resonance imaging study in forearm amputees. eur j neurosci. 2012;36(1):2098-2106. doi: 10.1111/j.14609568.2012.08099.x. 34. goodman cr, denittis a. photon irradiation using a water bath technique for treatment of confluent carcinoma in situ of the hand, digits, and nail bed: a case report. j med case reports. 2017;11(1):86. doi: 10.1186/s13256-017-1233-3. 35. tang n, maloney me, clark ah, jellinek nj. a retrospective study of nail squamous cell carcinoma at 2 institutions. dermatol surg. 2016;42(suppl 1):s8-s17. doi: 10.1097/dss.0000000000000521. 10. grigorov y, philipov s, patterson j, et al. subungual squamous cell carcinoma associated with long standing onychomycosis: aggressive surgical approach with a favourable outcome. open access maced j med sci. 2017;5(4):480-482. doi: 10.3889/ oamjms.2017.116. 11. jellinek nj, lipner sr. longitudinal erythronychia: retrospective single-center study evaluating differential diagnosis and the likelihood of malignancy. dermatol surg. 2016;42(3):310-319. doi: 10.1097/dss.0000000000000594. 12. abner s, redstone j, chowdhry s, kasdan ml, wilhelmi bj. synchronous squamous cell carcinoma in multiple digits. eplasty. 2011;11:e9. 13. meesiri s. subungual squamous cell carcinoma masquerading as chronic common infection. j med assoc thai. 2010;93(2):248251. 14. dalle s, depape l, phan a, balme b, ronger-savle s, thomas l. squamous cell carcinoma of the nail apparatus: clinicopathological study of 35 cases. br j dermatol. 2007;156(5):871-874. doi: 10.1111/j.1365-2133.2006.07744.x. 15. handisurya a, rieger a, bankier a, et al. human papillomavirus type 26 infection causing multiple invasive squamous cell carcinomas of the fingernails in an aids patient under highly active antiretroviral therapy. br j dermatol. 2007;157(4):788-794. doi: 10.1111/j.1365-2133.2007.08094.x. 16. zaiac mn, weiss e. mohs micrographic surgery of the nail unit and squamous cell carcinoma. dermatol surg. 2001;27(3):246251. 17. batalla a, feal c, rosón e, posada c. subungual squamous cell carcinoma: a case series. indian j dermatol. 2014;59(4):352-354. doi: 10.4103/0019-5154.135480. 18. khullar g, singh s, saikia un, kumar a, singh mp, kanwar aj. squamous cell carcinoma of the nail fold masquerading as pyogenic granuloma. indian j dermatol venereol leprol. 2016;82(5):555-557. doi: 10.4103/0378-6323.182975. 19. gatica-torres m, arguello-guerra l, manuel ruiz-matta j, dominguez-cherit j. subungual pigmented squamous cell carcinoma presenting as a grey longitudinal melanonychia in a young patient. bmj case rep. 2016;2016:2016. 20. inkaya e, sayit e, sayit at, zan e, bakirtas m. subungual squamous cell carcinoma of the third finger with radiologic and histopathologic finding: a report case. j hand microsurg. 2015;7(1):194-198. doi: 10.1007/s12593-014-0152-4. 21. richert b, lecerf p, caucanas m, andré j. nail tumors. clin dermatol. 2013;31(5):602-617. doi: 10.1016/j.clindermatol. 2013.06.014. 22. starace m, dika e, fanti pa, et al. nail apparatus melanoma: dermoscopic and histopathologic correlations on a series of 23 patients from a single centre. j eur acad dermatol venereol. 2018;32(1):164-173. dermatology: practical and conceptual letter | dermatol pract concept 2014;4(3):21 97 dermatology practical & conceptual www.derm101.com to the editor, in her essay, “on the nature of thought processes and their relationship to the accumulation of knowledge, part xiii: the nature of evidence” [1], cris anderson helps us to look at the question of why a person would choose an alternative treatment rather than a conventional scientific one. her essay also stimulates us to look at our own process of argumentation as well as our own biases and prejudices. (for example, why should we become angry when a patient decides to act against our best medical advice and choose complementary alternative medicine [cam].) despite the efforts of nine medical practitioners the patient in the case study, “application of black salve to a thin melanoma that subsequently progressed to metastatic melanoma: a case study,” the patient chose to treat her melanoma with black salve. she reluctantly agreed to conventional medical treatment only after the melanoma had clinically metastasized. i hypothesize that the patient suppressed the painful memories of the death of her son and her brother from metastatic melanoma. i believe she just did not want to think about melanoma. there are many personal testimonies and anecdotal reports of positive outcomes using black salve to treat cancer present on the internet [2]. so perhaps an easier, less emotionally painful choice was to choose to believe these anecdotal stories and use black salve. michael shermer has pointed out “anecdotal thinking comes naturally, science requires training.” [1] ernst [3] describes that complementary medicine [cm] tends to be built on untestable philosophies rather than on proven facts or testable hypotheses. the concept of cancer that prevails in cm is no exception; cancer is viewed as an expression or symptom of a deep-rooted underlying problem. therefore, cm cures often aim at treating this underlying problem rather than the cancer itself. thus, complementary therapies do not depend strongly upon a specific cancer diagnosis, but usually offer universal cures that are applicable for almost any malignancy. in addition a self-care element is central to many treatments; the patient is put in charge of his/her own health [every patient is his/her own physician]. the over simplification of the pathology and the self-care component in therapy constitute a large proportion of the attraction of cm cancer concept to the patient [3]. one study in south australia in 2004 revealed that complementary alternative medicines [cam] were used by 52.2% of the population. the conclusion of this study is: “australians continue to use high levels of cam and cam therapists. the public is often unaware that cam’s are not tested by the therapeutic goods administration for efficacy or safety” [4]. we all live with cognitive dissonance to some degree. cris anderson states in her essay, “we all have so many potential thoughts and memories stored in our brains we often do not call up information that is contradictory and we continue to believe contradictory propositions; that is we all live with cognitive dissonance” [1]. “imagination has enabled us to survive, to prepare for the future and to dream of a better world. but the downside of this is that we are tempted to believe that what we imagine is true” [1]. as medical practitioners we try to practice evidence-based medicine. we attempt to offer our patients the best “up to date” medical advice based on the outcomes of logical thought processes and the scientific method. “hypotheses are tested accordletter to the editor graham w. sivyer1 1 school of medicine, the university of queensland, australia citation: sivyer gw. letter to the editor. dermatol pract concept. 2014;4(3):22. http://dx.doi.org/10.5826/dpc.0403a22 received: february 17, 2014; accepted: february 18, 2014; published: april 30, 2014 copyright: ©2014 sivyer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: graham sivyer, mbbs(hons) fsccanz. email. graham.sivyer@ipnet.com.au 98 letter | dermatol pract concept 2014;4(3):21 ing to a body of organizing principles and the test results are examined and interpreted independently by multiple investigators” [1]. this seems to be “the best way to advance knowledge while minimizing opportunities for inconsistency and contradiction” [1]. “argumentation and science share the same principles in that people with differing views are willing to look at a problem from differing perspectives and are willing to risk being proved wrong in the interest of acquiring a common understanding of an issue…” [1] (however, before we rush to criticize other treatments we should bear in mind that it is estimated that as little as a quarter of conventional medicine is based on “level 1 evidence” [5].) the question is: can the use of black salve to treat melanoma and non-melanoma skin cancer with a potentially disastrous outcome be prevented? because we are all human beings at times using illogical thought processes, the answer to this question is “probably not.” however with adequate knowledge, i believe we can reduce the risk for our patients. we need to accept that the use of cam by our patients, according to surveys, is high. we need to have an understanding of the constituents of pastes such as black salve, and that these contain escharotics that will destroy normal tissue as well as cancerous tissue and we need to advise our patients of the dangers of self-treating diagnosed and un-diagnosed skin lesions. graham w. sivyer, mbbs lecturer, school of medicine university of queensland references 1. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge. part xiii: the nature of evidence. dermatol pract concept. 2014;4(1):3. 2. website. www.altcancer.com. accessed october 20, 2013. 3. ernst e. complementary cancer treatments: hope or hazard? clin oncol (r coll radiol). 1995:7:259-63. 4. maclennan ah, myers sp, taylor aw. the continuing use of complementary and alternative medicine in south australia: costs and beliefs in 2004. med j aust. 2006; 184(1):27-31. 5. albeni d, girardelli cr, masini c, et al. what proportion of dermatological patients receive evidence-based treatment? arch dermatol. 2001;137:771-6. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020017 1 dermatology practical & conceptual introduction rosettes are shiny white structures consisting of 4 white dots, similar to a 4-leaf clover. in dermoscopy, they can be seen with polarized light because of an optical phenomenon. small rosettes (0.1-0.2 mm) are associated with the presence of concentric keratin at the infundibular level of the annex openings, the largest (0.3-0.5 mm) with perifollicular concentric fibrosis. when multiple rosettes are present, they are usually oriented at the same angle. they have been reported mainly related to actinic keratosis and squamous cell carcinoma. nevertheless, they are not specific to any condition, as they have been described in a number of inflammatory and tumoral cutaneous lesions, including melanoma [1]. the latter is one of the main differential diagnoses of blue nevi. blue nevi are benign proliferations of dendritic melanocytes in the dermis. clinically they may be acquired or congenital, and they present preferentially in the extremities and face as a blue papule. on dermoscopy, the bluish or steel-blue homogeneous pattern and the absence of other structures are characteristic. however, sometimes it is possible to observe the presence of other structures such as globules, dots, pseudopods, streaks, pigment network, and network-like areas [2]. in these cases, a histopathological study should be performed to rule out melanoma. case presentation a 14-year-old male, diagnosed with xeroderma pigmentosum, has come to our center for total body photography every 12 months and digital dermoscopy follow-up every 6 months since he was 6 years old. in this follow-up, an asymptomatic pigmented lesion that had been present since early infancy on the medial region of the dorsum of the right foot was observed and registered. on physical examination it corresponded to a bluish, symmetrical pigmented papule, with a diameter of 5 mm (figure 1a). dermoscopy revealed a homogeneous steelblue pattern with areas of regular gray‐blue globules (figure 1b). in addition, on dermoscopy with polarized light, the lesion showed white rosettes distributed along the length of the whole nevus (figure 1c). a diagnosis of blue nevus was made, based on the clinical-dermoscopy characteristics. in blue nevus with rosettes on polarized light dermoscopy corina isabel salas-callo,1 josep riera-monroig,1 sebastian podlipnik,1,2 susana puig1,2,3 1 dermatology department, melanoma unit, hospital clínic of barcelona, barcelona university, spain 2 institut d’investigacions biomediques august pi i sunyer (idibaps), barcelona, spain 3 biomedical research networking center on rare diseases (ciberer), isciii, barcelona, spain key words: blue nevus, rosettes, dermoscopy, polarized light dermoscopy, shiny white structures citation: salas-callo ci, riera-monroig j, podlipnik s, puig s. blue nevus with rosettes on polarized light dermoscopy. dermatol pract concept. 2020;10(1):e2020017. doi: https://doi.org/10.5826/dpc.1001a17 accepted: september 21, 2019; published: december 31, 2019 copyright: ©2019 salas-callo et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: susana puig, md, melanoma unit, dermatology department, hospital clinic barcelona, villarroel 170. 08036, barcelona, spain. email: susipuig@gmail.com; spuig@clinic.cat mailto:susipuig@gmail.com mailto:spuig@clinic.cat 2 letter | dermatol pract concept 2020;10(1):e2020017 the digital dermoscopy follow-up, this lesion has not presented changes in size or pigment and new structures have not appeared, ruling out the diagnosis of melanoma. conclusions this description of rosettes in blue nevus draws attention to the importance of the clinical-dermoscopy correlation to establish the diagnosis. references 1. haspeslagh m, noë m, de wispelaere i, et al. rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation. j eur acad dermatol venereol. 2016;30(2):311-313. 2. di cesare a, sera f, gulia a, et al. the spectrum of dermatoscopic patterns in blue nevi. j am acad dermatol. 2012;67(2):199-205. figure 1. blue nevus on the dorsum of the right foot. (a) clinical image. (b) dermoscopy (×10) reveals global steel-blue homogeneous pattern with the presence of multiple white rosettes and the absence of pigment network, globules, and streaks. (c) with greater detail, the orientation of all the rosettes at the same angle. dermatology: practical and conceptual review | dermatol pract concept 2014;4(3):3 25 dermatology practical & conceptual www.derm101.com introduction the incidental finding of focal acantholytic dyskeratosis, first described by ackerman, is a common occurrence [1-4]. “papular acantholytic dyskeratoma” has been used to describe a solitary lesion on the lip [5], whereas, “papular acantholytic dyskeratosis” has been used to describe numerous lesions of genital location [6-16]. however, non-genital lesions characterized by acantholysis and dyskeratosis have been difficult to properly identify and interpret. solitary, non-genital lesions with prominent acantholysis and dyskeratosis without cup-shaped architecture or follicular involvement have been described as a distinct histologic entity: acantholytic dyskeratotic acanthoma [17,18]. we present a patient who developed an acantholytic acantholytic dyskeratotic acanthoma: case report and review of the literature alina goldenberg1, robert a. lee 2,3, philip r. cohen2 1 medical school, university of california san diego, california, usa 2 division of dermatology, university of california san diego, california, usa 3 dermatopathology, university of california san diego, california, usa keywords: acantholysis, acanthoma, cutaneous, dyskeratosis, nail, warty citation: goldenberg a, lee ra, cohen pr. acantholytic dyskeratotic acanthoma: case report and review of the literature. dermatol pract concept. 2014;4(3):3. http://dx.doi.org/10.5826/dpc.0403a03 received: february 15, 2014; accepted: march 19, 2014; published: july 31, 2014 copyright: ©2014 goldenberg et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. university of california, san diego, california, usa. email: mitehead@gmail.com background: focal acantholytic dyskeratosis has been described as an incidental finding and as a clinically distinct lesion. in both situations, a dimorphic histologic pattern is observed: acantholysis and dyskeratosis. solitary, non-genital lesions displaying such pathology have been difficult to classify. clinical and pathological characteristics of acantholytic dyskeratotic acanthomas are described. methods: the features of a patient with solitary, non-genital, acantholytic dyskeratotic acanthoma are presented and the literature on acantholytic dyskeratotic acanthomas is reviewed. using pubmed the following terms were searched and relevant citations assessed: acantholysis, acanthoma, cutaneous, dyskeratosis, nail, warty. results: we identified 30 cutaneous acantholytic dyskeratotic acanthomas, including our patient, most often found on the trunk and mimicking basal cell carcinoma, and three subungual acantholytic dyskeratotic acanthomas of the thumb, which mimicked onychopapilloma. conclusion: acantholytic dyskeratotic acanthomas are clinically and pathologically distinct lesions, which may morphologically present as either truncal plaques or subungual longitudinal erythronychia. abstract 26 review | dermatol pract concept 2014;4(3):3 dyskeratotic acanthoma and summarize the acantholytic dyskeratotic acanthomas (30 cutaneous and 3 subungual) that have been described in literature during the past 30 years. case report a 72-year-old white woman presented for evaluation of a painful lesion beneath her left breast. it appeared three months earlier as a non-healing, tender, raised area with central erosion. she had no personal or family history of keratosis follicularis (darier’s disease), transient acantholytic dermatosis (grover’s disease), non-melanoma skin cancer or melanoma. cutaneous examination revealed a 10 x 4 mm plaque beneath the left breast (figure 1). a 3 x 3 mm erosion was present in the center of the lesion. an excisional biopsy was performed. microscopic examination showed acanthosis with focal parakeratosis and dyskeratosis. focal areas of acantholysis, involving all layers of the epidermis, were also observed. in the dermis, there was mild superficial perivascular lymphocytic inflammation (figure 2). correlation of the clinical presentation and pathologic findings established the diagnosis of an acantholytic dyskeratotic acanthoma. the entire lesion had been removed during the biopsy. the biopsy site healed by second intention and her symptoms resolved spontaneously. discussion history focal acantholytic dyskeratosis was first coined by ackerman in 1972 in an attempt to describe a distinctive histologic pattern with parakeratotic hyperkeratosis, acantholytic dyskeratosis (at all levels of the epidermis), and focal suprabasilar clefts. he classified the lesions by size, number (single or multiple), and duration (persistent and transient) leading to six distinct classes: (1) incidental, (2) multiple lesions (darier’s disease), (3) nodular with follicular involvement (warty dyskeratoma), (4) papular, (5) systematized, and (6) transient (grover’s disease). the majority of his patients had lesions that were similar to those subsequently observed, clinically unapparent and histologically incidental (3]. figure 1. distant (a) and closer (b) views of an acantholytic dyskeratotic acanthoma. the lesion appears as an erythematous plaque with central area of erosion. [copyright: ©2014 goldenberg et al.] a b figure  2. (a) at low magnification, one portion of the lesions shows mild thickening of the epidermis with focal areas of acantholysis involving all layers of the epidermis; there is overlying parakeratosis and focal dyskeratosis. another portion of the same lesion (b) shows basket weave orthokeratosis, acanthosis, and horn pseudocyst formation (hematoxylin and eosin a, x10; b, x10). [copyright: ©2014 goldenberg et al.] a b review | dermatol pract concept 2014;4(3):3 27 two patients with the papular subtype of focal acantholytic dyskeratosis, diagnosed as seborrheic keratosis and basal cell carcinoma, appeared to have features that are similar to those now established as acantholytic dyskeratotic acanthomas [1]. subsequently, omulecki et al. described a patient who had a single plaque with bimodal histology of acantholysis and dyskeratosis, and introduced the term acantholytic dyskeratotic acanthoma [18]. thereafter, ko et al. did a retrospective study and described 28 patients who had a solitary, non-genital lesion with acantholysis and dyskeratosis; however, the lesion did not have a cup-shaped, cystic architecture or follicular involvement [17]. nail findings of focal acantholytic dyskeratosis were first described by isonokami and higashi in the japanese literature in 1990 [19]. however, it was not until nearly two decades later that sass et al. reported 3 patients with acantholysis and dyskeratosis of the thumb nail bed epithelium as acantholytic dyskeratotic acanthoma [20]. there is currently neither a world health organization statement nor an agreement in explicative dermatopathology whether acantholytic dyskeratotic acanthoma is a distinct entity. indeed, in lever’s histopathology textbook acantholytic dyskeratosis is described as a phenomena and not a separate entity [21]. in contrast, in weedon’s latest textbook some authors consider cutaneous acantholytic dyskeratotic acanthoma to be a separate entity, which usually clinically presents as a basal cell carcinoma [22]. we concur with ko et al. that cutaneous acantholytic dyskeratotic acanthoma is a separate entity with a distinctive clinical morphology and corresponding pathologic features. epidemiology our review includes 30 patients with cutaneous acantholytic dyskeratotic acanthoma and 3 patients with subungual acantholytic dyskeratotic acanthoma (table 1) [1,17-20,23]. their onset age ranged from 39 years to 84 years with a median of 54 years. cutaneous acantholytic dyskeratotic acanthoma is more common in women, whereas subungual acantholytic dyskeratoma is more common in men. the ratio of women to men who had cutaneous acantholytic dyskeratotic acanthomas was 3:2. in contrast, the ratio of women to men with subungual acantholytic dyskeratotic acanthoma was 1:2. clinical presentation the cutaneous lesions were between 2-9mm, with a median size of 5mm. they presented as flesh colored, red papules or plaques. the most common location (83%, 25 of 30) was the trunk; the other site included the extremities (17%, 5 of 30). all of the subungual lesions presented with monodactylous, solitary longitudinal erythronychia of the thumbnail. the solitary red band extended from the matrix to the distal part of the nail apparatus. pathology three histopathologic patterns of cutaneous acantholytic dyskeratotic acanthoma were observed. confluent acantholytic dyskeratosis affecting the entire thickness of the epidermis was noted in 19 patients [17]. confluent acantholytic dyskeratosis localized only to the granular and corneal layer of the epidermis was observed in 3 patients [17]. non-confluent focal sites of acantholytic dyskeratosis were present in 8 of the patients, including the patient reported herein and by omulecki et al [18]. specifically, our patient had two foci of intra-epidermal acantholysis with overlying parakeratosis and focal dyskeratosis; focal horn cyst formation was also noted. in addition, she had mild perivascular lymphocytic inflammation in the dermis. differential diagnosis clinical multiple clinical diagnoses were often submitted with the skin biopsy specimen. the most common clinical diagnoses of cutaneous acantholytic dyskeratotic acanthoma were either a nonmelanoma skin cancer (basal cell carcinoma in 15 patients or squamous cell carcinoma in 9 patients) or an actinic keratosis (5 patients). less common diagnoses were seborrheic keratosis (3 patients), nevus (2 patients), or wart (2 patients). onychopapilloma, which can morphologically present as a monodactylous single red band, was the suggested diagnosis, prior to biopsy, in the 3 patients with subungual acantholytic dyskeratotic acanthoma. other diagnoses of longitudinal erythronychia included glomus tumor, malignant neoplasms (such as melanoma and squamous cell carcinoma), and warty dyskeratoma [24]. pathological the co-existence of acantholysis and dyskeratosis is present in a few distinct conditions. keratosis follicularis (darier’s disease) has focal orthokeratotic plugs, full epidermal acantholysis leading to the formation of suprabasal clefts (lacuna), and corneal and granular dyskeratosis (corps ronds and grains) [25]. transient acantholytic dermatosis (grover’s disease) also can present with a “darier’s pattern” of acantholysis and dyskeratosis [26]. warty dyskeratoma typically has a cup-shaped invagination into underlying dermis and follicular involvement; in addition to clefting and corps ronds, prominent villi may also be observed [27]. table 2 summarizes the pathologic features that can differentiate acantholytic dyskeratotic acanthoma from warty dyskeratoma [17,18,27]. the absence of dyskeratosis permits differentiation of acantholytic dyskeratotic acanthoma from an acantholytic acanthoma. the absence multi-nucleated epidermal giant cells in acantholytic dyskeratotic acanthoma differentiates it from 28 review | dermatol pract concept 2014;4(3):3 table 1. clinical and pathologic characteristics of acantholytic dyskeratotic acanthomaa [copyright: ©2014 goldenberg et al.] category cutaneous (17,18, cr) subungual (20) number 30b 3c age: range/median 39-84/ 54 12-53/ 15 f:m 3:2 1:2 location . . . . . trunk 25 . . . . . extremities 5 . . . . . thumb 3 size: range/ median (mm) 2-9/ 5 3-5/4 morphology . . . . . papuled 10 . . . . . plaquee 20 . . . . . median longitudinal. . . hemorrhage, onycholysis 3 histopathology . . . . . confluentf 19 3g . . . . . confluent, gch 3 . . . . . focali 8 clinical differentialj . . . . . bcc 15 . . . . . scc 9 . . . . . ak 5 . . . . . sk 3 . . . . nevus 2 . . . . wart 2 . . . . onychopapilloma 1 3 treatment . . . . excision 30 3 [a] abbreviations: ak, actinic keratosis; bcc, basal cell carcinoma; cr, current report; f, female; gc, granular and corneal layers; m, male; scc, squamous cell carcinoma; sk, seborrheic keratosis [b] two patients with solitary papules with focal acantholytic dyskeratosis described by ackerman [1] and one patient described by barnette and cobb [21] with a solitary acantholytic acanthoma with mild dyskeratosis reported in the literature prior to the establishment of acantholytic dyskeratotic acanthoma yet showing some of the features observed in this lesion, have not been included in the table [12] [c] one patient with focal acantholytic dyskeratosis of the nail unit described by isonokami and higashi [19], reported in the literature prior to the establishment of acantholytic dyskeratotic acanthoma yet sharing some of the features observed in this lesion has not been included in the table [d] papule: the lesion is less than 5 mm [e] plaque: the lesion is greater than or equal to 5 mm [f ] confluent: epidermis with acanthosis and confluent acantholytic dyskeratosis involving multiple levels of epidermis [g] epidermal acanthosis with subungual hyperkeratosis lifting nail plate (parakeratosis with neutrophils); many suprabasal acantholytic clefts and dyskeratotic cells (corps ronds and grains) [h] gc: epidermis with acanthosis and confluent acantholytic dyskeratosis present mostly in the granular and corneal layers [i] focal, discrete foci of acantholytic dyskeratosis [j] total number may exceed number of patients due to multiple clinical differential diagnoses per each individual review | dermatol pract concept 2014;4(3):3 29 herpes simplex and varicella-zoster skin lesions [6]. incidental acanthosis or dyskeratosis may be occasionally noted in an actinic keratosis, basal cell carcinoma, or squamous cell carcinoma; however, the absence of nuclear atypia differentiates acantholytic dyskeratotic acanthoma from those conditions. in contrast to acantholytic dyskeratotic acanthoma, subungual warty dyskeratoma has a prominent papillomatous pattern; also, the acantholysis and dyskeratosis occur within a crater-like shape [28]. pathogenesis currently the pathogenesis of acantholytic dyskeratotic acanthoma remains to be established. none of the patients had family history of keratosis follicularis (darier’s disease); however, specific genetic studies had not been performed. testing for atp2a2 gene mutations is an emerging diagnostic tool for the distinction between darier’s and grover’s diseases [4,29]. evaluating for mutations in this gene may be useful in further elucidating the developmental pathway of acantholytic dyskeratotic acanthoma in patients with cutaneous or subungual lesions. treatment all cutaneous and subungual lesions were completely excised. our patient’s lesion was entirely excised at the time of biopsy and healed without evidence of recurrence at the subsequent visit. conclusion the term focal acantholytic dyskeratosis was originally used to describe incidental lesions with acantholysis and dyskeratosis; however, when these findings occur as a distinct, non-genital lesion of the skin or under the nail, we concur table 2. comparison of morphology and histology of acantholytic dyskeratotic acanthoma to warty dyskeratomaa [copyright: ©2014 goldenberg et al.] category ada wd morphology papule + + plaque + histology cup-shaped + follicular + [a] abbreviations: ada, acantholytic dyskeratotic acanthoma; wd, warty dyskeratoma; +, present; -, absent with current nomenclature of acantholytic dyskeratotic acanthoma. specifically, we consider acantholytic dyskeratotic acanthoma to be a clinically and pathologically distinct lesion, which may morphologically present as either truncal plaques or subungual longitudinal erythronychia. our patient was a 72-year-old woman with a non-healing eroded plaque underneath the breast. in our review of the literature, we were able to find 30 patients whose skin lesions presented as solitary, non-genital plaque, usually between 5 mm to 1 cm in size. cutaneous acantholytic dyskeratotic acanthoma most commonly occurred on the trunk of women. we also found 3 patients (2 men and 1 woman) with subungual acantholytic dyskeratotic acanthoma of the thumb. clinically, cutaneous acantholytic dyskeratotic acanthoma most resembled a nonmelanoma skin cancer or actinic keratosis and subungual acantholytic dyskeratotic acanthoma was suspected to be an onychopapilloma. three histological patterns of acantholytic dyskeratotic acanthoma were described: (1) confluent acantholytic dyskeratosis involving all layers of the epidermis seen in 19 patients, (2) confluent acantholytic dyskeratosis within granular and corneal layers seen in 3 patients, and (3) focal acantholytic dyskeratosis seen in 8 patients. the pathologic differential diagnosis of acantholytic dyskeratotic acanthoma includes darier’s disease, grover’s disease, and warty dyskeratoma; however, acantholytic dyskeratotic acanthoma can be differentiated from the solitary warty dyskeratoma by the absence of cup-shaped architecture and the absence of follicular involvement. the pathogenesis of acantholytic dyskeratoma remains to be discovered and excision appears to be the definitive treatment. acantholytic dyskeratotic acanthoma may be more common than noted in the literature. references 1. ackerman ab. focal acantholytic dyskeratosis. arch dermatol. 1972;106:702-6. 2. bogle ma, cohen pr, tschen ja. trichofolliculoma with incidental focal acantholytic dyskeratosis. south med j. 2004;97:773-5. 3. dimaio dj, cohen pr. incidental focal acantholytic dyskeratosis. j am acad dermatol. 1998;38:243-7. 4. kolbusz rv, fretzin df. focal acantholytic dyskeratosis in condyloma acuminate. j cutan pathol. 1987;16:44-7. 5. o’connell bm, nickoloff bj. solitary labial popular acantholytic dyskeratoma in an immunocompromised host. am j dermatopathol. 1987;9:339-42. 6. chorzelski tp, kudejko j, jablonska s. is popular acantholytic dyskeratosis of the vulva a new entity? am j dermatopathol 1984;6.557-60. 7. coppola g, muscardin lm, piazza p. papular acantholytic dyskeratosis. am j dermatopathol. 1986;8:364-5. 8. van der putte scj, oey hb, storm i. papular acantholytic dyskeratosis of the penis. am j dermatopathol. 1986;8:365-6. 9. warkel rl, jager rm. focal acantholytic dyskeratosis of the anal canal. am j dermatopathol. 1986;8:362-3. 30 review | dermatol pract concept 2014;4(3):3 10. schepers c, soler j, palou j, mascaró jm. papular acantholytic dyskeratosis of the genitocrural area simulating molluscum contagiosum. j cutan pathol. 1997;24:122. 11. coppola g, muscardin lm, piazza p. papular acantholytic dyskeratosis. am j dermatopathol. 1986;8:364-5. 12. cooper ph. acantholytic dermatosis localized to the vulvocrural area. j cutan pathol. 1989;16:81-4. 13. van joost th, vuzevski vd, tank b, menke he. benign persistent papular acantholytic and dyskeratotic eruption: a case report and review of the literature. br j dermatol. 1991;124:92-5. 14. bell hk, farrar cw, curley rk. papular acantholytic dyskeratosis of the vulva. clin exp dermatol. 2001;26:386-8. 15. sáenz am, cirocco a, avendaño m, gonzález f, sardi jr. papular acantholytic dyskeratosis of the vulva. pediatr dermatol. 2005;22:237-9. 16. grossin m, battin-bertho r, belaich s. another case of focal acantholytic dyskeratosis of the anal canal. am j dermatopathol. 1993;15:194-5. 17. ko cj, barr rj, subtil a, mcniff jm. acantholytic dyskeratotic acanthoma: a variant of a benign keratosis. j cutan pathol. 2008;35:298-301. 18. omulecki a, lesiak a, narbutt j, et al. plaque form of warty dyskeratoma—acantholytic dyskeratotic acanthoma. j cutan pathol. 2007;34:494-6. 19. isonokami m, higashi n. focal acantholytic dyskeratosis—a case report in nail lesion. hifu. 1990;32:507-10. 20. sass u, kolivras a, richert b, et al. acantholytic tumor of the nail: acantholytic dyskeratotic acanthoma. j cutan pathol. 2009;36:1308-1311. 21. kirkham n. tumors and cysts of the epidermis (chapter 29). in: elder de, elenitsas r, johnson bl, murphy gf. lever’s histopathology of the skin, 9th edition. lippincott williams and wilkins: philadelphia, 2005:805-66. 22. weedon d. disorders of epidermal maturation and keratinization (chapter 9). in: weedon d. weedon’s skin pathology, 3rd ed. london: churchill livingstone elsevier, 2010:247-79. 23. barnette dj jr, cobb m. a solitary, erythematous, hyperkeratotic papule. acantholytic acanthoma. arch dermatol. 1995;131:2112. 24. cohen pr. longitudinal erythronychia: individual or multiple linear red bands of the nail plate: a review of clinical features and associated conditions. am j clin dermatol. 2011;12:217-31. 25. frost k. dyskeratosis follicularis (darier’s disease). arch derm syphilol. 1935;31:508-11. 26. davis, md, dinneen am, landa n, gibson le. grover’s disease: clinicopathologic review of 72 cases. mayo. clinic. proc. 1999;74:229-34. 27. kaddu s, dong h, mayer g, kerl h, cerroni l.. warty dyskeratoma—‘follicular dyskeratoma’: analysis of clinicopathologic features of a distinctive follicular adnexal neoplasm. j am acad dermatol. 2002;47:423-8. 28. baran r, perrin c. focal subungual warty dyskeratoma. dermatology. 1997;195:278-80. 29. sakuntabhai a, ruiz-perez v, carter s, et al. mutations in atp2a2, encoding a ca2+ pump, cause darier disease. nat genet .1999;21:271-7. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):11 61 dermatology practical & conceptual www.derm101.com case report case 1 a 54 year-old-man, presented with multiple, small, well defined, gray-brown, papules and small papillomatous patches located on his penis, which had appeared over the last year (figure 1). genital warts, lichen planus, a verrucous nevus and bp were suspected among our clinical diagnosis. the dermoscopy revealed a pigmented papillomatous surface, brown-gray dots arranged in a linear distribution at the periphery of the lesion, and widespread dotted vessels (figures 2 and 3). a biopsy was done, and the histology showed mild hyperkeratosis, irregular acanthosis, dyskeratosis, cytological atypia and mitosis (figures 4 and 5), consistent with the diagnosis of bp. dermoscopic findings in bowenoid papulosis: report of two cases carolina marcucci1, emilia cohen sabban2, paula friedman1, rosario peralta1, ignacio calb3, horacio cabo4 1 dermatologist, buenos aires, argentina 2 dermatology section, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina 3 dermatopathologist, buenos aires, argentina 4 dermatology section, instituto de investigaciones médicas “a. lanari”, university of buenos aires, argentina keywords: dermoscopy, bowenoid papulosis citation: marcucci c, sabban ec, friedman p, peralta r, calb i, cabo h. dermoscopic findings in bowenoid papulosis: report of two cases. dermatol pract concept. 2014;4(4):11. http://dx.doi.org/10.5826/dpc.0404a11 received: june 19, 2014; accepted: august 18, 2014; published: october 31, 2014 copyright: ©2014 marcucci et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: carolina marcucci, m.d., 72 ambrosetti st., buenos aires, argentina. tel. +0541149021487. email: caromarcucci@hotmail.com bowenoid papulosis (bp) corresponds to an in situ squamous cell carcinoma (scc) located in the anogenital region. it is related to hpv, and presents with gray-brown elevated papules or plaques. a biopsy is needed to confirm the diagnosis; however, dermoscopy may be useful to differentiate this disease from other conditions, such as genital warts, seborrheic keratosis and lichen planus. in this paper we describe the dermoscopic findings in two patients with this disease. abstract figure 1. small gray-brown papules. (copyright: ©2014 marcucci et al.) 62 observation | dermatol pract concept 2014;4(4):11 case 2 a 31-year-old male patient with no relevant medical history presented with gray-brown asymptomatic small papules on his penis that had appeared a few months before (figure 6). the dermoscopy revealed multiple areas with grey-brown dots aligned in a linear fashion and a keratotic surface. no vascular pattern could be identified (figure 7). a skin biopsy was conducted and the histological examination confirmed the presence of bp. discussion bp represents a multifocal intraepithelial neoplasia located in the anogenital region [1]. the natural course of this disease is unpredictable: the lesions may increase, decrease, and even disappear spontaneously. although progression to an invasive scc is uncommon, it has been estimated in 2.6% of cases [2]. the most important differential diagnoses are genital warts, both clinically and dermoscopically [3]. figures 2 and 3. pigmented papillomatous surface. linear arrangement of brown-grey dots, at the periphery of the lesion (black arrow) and widespread dotted vessels (white arrow). original magnification x10. (copyright: ©2014 marcucci et al.) figure 4. mild hyperkeratosis, irregular acanthosis, dyskeratosis and mitosis (h&e x10). (copyright: ©2014 marcucci et al.) figure 5. cytological atypia, dyskeratosis and mitosis (h&e x40). (copyright: ©2014 marcucci et al.) figure 6. gray-brown asymptomatic small papules. (copyright: ©2014 marcucci et al.) to date and to our knowledge, no reports that specifically describe the dermoscopic findings of bp are available, and a few reports of dermoscopic examinations of this dermatosis observation | dermatol pract concept 2014;4(4):11 63 have been published in the literature. dong et al. [3] reported two cases of bp showing an unspecific pattern, and one of the lesions also showed dotted vessels and a keratotic surface as in our first case. in a study describing pigmented lesions of the vulva, ferrari et al. [4] also presented 2 cases of bp: one lesion revealed brown to gray structureless areas and glomerular vessels in a clustered and linear arrangement; the other lacked pigmentation and revealed multiple whitish-red exophytic papillary structures with central glomerular and hairpin vessels. the features of the two cases we presented were similar: brown-gray dots with a linear arrangement, located at the periphery of the lesion. these features remind us of pigmented bowen’s disease, an in situ variant of cutaneous squamous cell carcinoma, which needs to be differentiated from bp at histopathological level [5,6]. although more studies are needed to confirm these findings as criteria for bp, we think that in the presence of linear arrangement of brown-gray dots in a genital lesion, we should rule out bp among other diagnosis. references 1. campione e, centonze c, diluvio l, et al. bowenoid papulosis and invasive bowen’s disease: a multidisciplinary approach. acta derm venereol. 2013; 93:216–56. 2. kutlubay z, engin b, zara t, tüzün y. anogenital malignancies and premalignancies: facts and controversies. clin dermatol. 2013:31,362-73. 3. dong h, shu d, campbell tm, et al. dermoscopy of genital warts. j am acad dermatol. 2011; 64:859-64. 4. ferrari a, zalaudek i, argenziano g, et al. dermoscopy of pigmented lesions of the vulva: a retrospective morphological study. dermatol 2011; 222:157-66. 5. dirk m. elston. the diagnosis: bowenoid papulosis. cutis. 2010; 86:295-96. 6. cameron a, rosendahl c, tschandl p, riedl e, kittler h. dermatoscopy of pigmented bowen’s disease. j am acad dermatol. 2010; 62:597–604. figure 7. multiple gray dots aligned in a linear fashion (black arrow). original magnification x10. (copyright: ©2014 marcucci et al.) dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2014;4(1):7 51 the patient a 42-year-old caucasian man presented with a 15-year history of a widespread, persistent, pruritic eruption over his trunk and extremities. he was not on medication and had no relevant family history. on physical examination, multiple discrete, pinkish, hyperkeratotic 1 to 2 mm papules, arranged in a rippled pattern, were detected on the trunk and extremities (figure 1). widespread pruritic papules on the trunk and extremities engin sezer1, emel erkek1, sedef sahin1 1 department of dermatology, acıbadem university school of medicine, istanbul, turkey keywords: lichen amyloidosis, generalized, amyloid deposition citation: sezer e, erkek e, sahin s. widespread pruritic papules on the trunk and extremities. dermatol pract concept. 2014;4(1):7. http:// dx.doi.org/10.5826/dpc.0401a07 received: july 18, 2013; accepted: september 4, 2013; published: january 31, 2014 copyright: ©2014 sezer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: engin sezer, m.d., acıbadem university school of medicine, department of dermatology, buyukdere caddesi no: 40, istanbul, 34457, turkey. tel. + 902123044626; fax. + 902123044440. email: eseze@yahoo.com figure 1. multiple pinkish, hyperkeratotic papules are observed on the trunk. [copyright: ©2014 sezer et al.] a biopsy was performed; photomicrographs are presented in figure 2a, b. what is your diagnosis? figure 2. (a) histopathological examination revealed amorphous eosinophilic deposits in the papillary dermis with hyperkeratosis, hypergranulosis, and marked acanthosis. (b) crystal violet staining highlighted the eosinophilic deposits in the upper dermis. [copyright: ©2014 sezer et al.] a b 52 quiz | dermatol pract concept 2014;4(1):7 keratosis, as observed in the skin biopsied specimen of our patient, were detected. interface changes, including basal cell hydropic degeneration, colloid bodies, and rare satellite cell necrosis, have also been described. subepidermal vesicles with papillary dermal eosinophilic amyloid deposits have been reported in vesicular la. the etiology of la is unclear. chronic friction, rubbing, and scratching that result in discharge of epidermal keratinocytes into the dermis and conversion into amyloid deposition have been considered in the etiopathogenesis of la. the dermal amyloid material is thought to be derived from keratin peptides and other proteins such as apolipoprotein e2. immunohistochemically, reaction of amyloid deposits with antihuman keratin antibodies such as ck 5/6/18 and mnf 116 also supports this hypothesis [6]. the treatment results of la are disappointing. topical and intralesional corticosteroid injections, topical tacrolimus, topical and oral dimethyl sulphoxide, photo(chemo)therapy, retinoids, cryotherapy, and carbon dioxide laser ablation have all been tried with mixed results [7]. however, in our patient, pruritus was markedly improved with narrow-band ultraviolet b phototherapy even though the lesions persisted post-treatment. a trial treatment of photodynamic 5-aminolevulinic acid on a small abdominal area proved ineffective. finally, we suggest that the diagnosis of generalized la be considered in cases of widespread, pruritic, and hyperkeratotic papules over the trunk and extremities. references 1. brinster n, calonje e. degenerative and metabolic diseases. in: calonje e, brenn t, lazar a, mckee ph, eds. mckee’s pathology of the skin, 4th ed. new york: elsevier saunders, 2012: 537-41. 2. hongcharu w, baldassano m, gonzales e. generalized lichen amyloidosis associated with chronic lichen planus. j am acad dermatol. 2000;43(2): 346-8. 3. yalcin b, artuz f, gur toy g, et al. generalized lichen amyloidosis associated with chronic urticaria. dermatology. 2003;207(2): 203-4. 4. parsi k, kossard s. thermosensitive lichen amyloidosis. int j dermatol. 2004;43(12):925-8. 5. cho th, lee mh. a case of lichen amyloidosus accompanied by vesicles and dyschromia. clin exp dermatol. 2008;33(3):191-3. 6. apaydin r, gurbuz y, bayramgurler d, müezzinoglu b. bilen n. cytokeratin expression in lichen amyloidoisus and macular amyloidosis. j eur acad dermatol venereol. 2004;18(3):305-9. 7. grimmer j, weiss t, weber l, meixner d, scharffetter-kochanek k. successful treatment of lichen amyloidosis with combined bath puva photochemotherapy and oral acitretin. clin exp dermatol. 2007;32(1):39-42. answer and explanation generalized lichen amyloidosis on histopathological examination, epidermal changes including marked hyperkeratosis, hypergranulosis, and irregular acanthosis were observed. an additional finding was the presence of eosinophilic, hyaline, homogeneous deposits confined to the papillary dermis, which showed metachromatic staining with crystal violet. sparse melanophages were observed in the dermis. the vessels of the dermis and hypodermis were normal. a diagnosis of generalized lichen amyloidosis, based on clinical and histopathological findings, was made. lichen amyloidosis (la) is a form of primary cutaneous amyloidosis without systemic involvement, characterized by extracellular deposition of amyloid material in the papillary dermis [1]. la is mainly observed in adult patients, without gender predilection. although the disorder is rare in western countries, it is relatively common in asia and some south american countries, indicating a genetic background. on physical examination, discrete, shiny, hyperkeratotic papules are observed mainly in a localized fashion over the shins and extensor aspects of the arms. biphasic amyloidosis is characterized by overlap of lichen and macular amylodosis with tiny papules superimposed upon a background of hyperpigmented skin. in our case, lack of the hyperpigmented component helped us rule out biphasic amyloidosis. generalized la is vanishingly rare with only five cases reported in the english-language literature. compared with the conventional form, generalized la is characterized by widespread involvement of pruritic papules over the trunk and extremities. its association with pruritic disorders, including lichen planus and chronic urticaria in two reported cases, suggests that pruritus is a precipitating factor in generalized la [2,3]. compared with those cases, there was no history of a previous skin disorder in our patient. the duration of lesions in the reported cases varied between 3 and 19 years, which is in accordance with that of our patient (15 years). lack of involvement of the axillae and the antecubital and popliteal fossae, which correspond to areas of regionally elevated temperature (monitored by infrared thermography) in a patient with generalized la, raises the possibility of cutaneous temperature as a factor in the distribution of amyloid deposition of this entity [4]. transformation from amorphous aggregates toward mature amyloid fibrils has been shown as a temperature-dependent process. our patient’s condition was in keeping with previously reported cases, which have shown sparing of lesions over these anatomical sides. other atypical clinical presentations of la include blistering and dyschromic variants, characterized by vesicles and dotted, reticular hyper and hypopigmented spots [5]. histopathologically, eosinophilic deposits, together with marked epidermal acanthosis, hypergranulosis, and hyperdermatology: practical and conceptual 278 research | dermatol pract concept 2019;9(4):6 dermatology practical & conceptual relationship between level of serum 25-hydroxyvitamin d and risk of squamous cell carcinoma in an iranian population mahboobeh-sadat hosseini1, fereshteh salarvand2, amir houshang ehsani2, pedram noormohammadpour2, shadi azizzadeh2, mohaddese mousavi3, mona morsali3 1 health research center, lifestyle institute, baqiyatallah university of medical sciences, tehran, iran 2 department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 3 school of medicine, tehran university of medical sciences, tehran, iran key words: skin cancer, squamous cell carcinoma, vitamin d, cancer epidemiology, supplements citation: hosseini m-s, salarvand f, ehsani ah, noormohammadpour p, azizzadeh s, mousavi m, morsali m. relationship between level of serum 25-hydroxyvitamin d and risk of squamous cell carcinoma in an iranian population. dermatol pract concept. 2019;9(4):278-282. doi: https://doi.org/10.5826/dpc.0904a06 accepted: june 17, 2019; published: october 31, 2019 copyright: ©2019 hosseini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: fereshteh salarvand, md, department of dermatology, razi hospital, tehran university of medical sciences, razi dermatology hospital, vahdat-e-eslami square, tehran, iran. email: fsalarvand@razi.tums.ac.ir background: the relationship between vitamin d and skin squamous cell carcinoma (scc) is not well defined. objective: to investigate the relationship between vitamin d levels and the incidence of skin scc for the first time in iran. methods and study design: in this case-control study, 126 subjects were enrolled (63 in each group) out of referents to razi skin hospital in tehran in 2014. the risk factors for cancer gathered by self-reported questionnaires and blood samples were obtained to measure the level of 25-hydroxyvitamin d. multivariate logistic regression was used to neutralize the effect of confounding factors. results: cases of scc were more likely to be in men, older than 49 years and working in an outdoor environment, and with longtime exposure to sunlight and a personal history of skin cancers. family history of skin cancer and of cigarette smoking were not significantly related to scc. in the scc and control groups, 69.8% and 31.7%, respectively, had sufficient levels of vitamin d (p < 0.001). mean level of 25-hydroxyvitamin d was 40.99 ng/ml in the scc group and 26.34 ng/ml in the control group (p < 0.05). in the unadjusted model, the level of vitamin d as a continuous variable was positively related to scc risk. in the adjusted model, vitamin d did not independently predict the likelihood of scc. conclusion: vitamin d level and scc risk are directly related, although not in an independent fashion. indeed, this relation is severely confounded by exposure to sunlight, which was evidenced by an increased vitamin d level in the people working outside and the higher prevalence of scc in the same population. abstract research | dermatol pract concept 2019;9(4):6 279 methods the subjects were selected from referrals to the day clinic of razi dermatologic hospital (tehran university of medical sciences, tehran, iran) in the year 2014. based on previous studies [8] and available formulas for sample size calculation, to measure the difference between 2 means we entered 126 subjects into our study, 63 in each stem, considering the power of 80% and α = 0.05. thus, in our case-control study, 63 patients who attended our hospital clinic with a new-onset dermal lesion compatible with scc (determined by an expert dermatopathologist) were enrolled as the case group. those with a history of childhood radiotherapy for alopecia were excluded. we recruited another 63 persons without any malignant or premalignant skin lesions as the control group from the attendees to the clinic for reasons other than skin malignancy. the sampling method was convenient without matching. none of the subjects had received vitamin d supplements. primary information including age, sex, professional environment (outdoor/indoor), weekly exposure to sunlight (less than vs more than 6 hours), history of previous scc, family history of scc, and smoking status were gathered through self-reported questionnaires and kept confidential throughout the study. blood samples were drawn and immediately sent to the razi hospital laboratory to measure serum levels of 25-hydroxyvitamin d 3 (as ng/ml), which is the best available marker for estimating the level of vitamin d in the body. the definitions of 25(oh)d deficiency (30 ng/ml) were based on the recommendations of the european endocrine society [14]. all data were analyzed by spss statistical software, and a p value below 0.05 was considered significant. pearson chisquare and independent sample t test were applied. odds ratios (ors) and 95% confidence intervals (cis) were calculated. to counteract the unwanted effect of the confounding variables on the relationship between plasma 25(oh)d levels and scc, we utilized the hierarchical multivariate logistic regression models. results the mean age of the subjects was 50.2 years (sd = 19.01); the youngest and oldest patients were 19 and 86 years old, respectively. characteristics of all patients and controls are shown in table 1. the probability of working in the outdoor environment was significantly higher in the scc group. the scc patients were significantly more likely to have more prolonged exposure to the sun during the week. personal history of skin cancer was higher in scc patients. regarding the family history of skin cancer and smoking, there was no introduction squamous cell carcinoma (scc), after basal cell carcinoma, is the most common cancer in the white population and is associated with metastasis and considerable morbidity [1]. over the past 10 to 30 years, its incidence in north america has increased approximately 50% to 200%. also, the incidence of this cancer is doubled by each 8to 10-degree decrease in latitude, and it approaches its highest rate near the equator. the age-specific incidence rate among caucasians is 100 to 150 cases per 100,000 population, and this rate becomes 10 times higher among people older than 75 years [2]. regarding cancer epidemiology, uv radiation from sunlight is the most important known risk factor for scc of the skin. uvb is the main suspect (wavelength 290-320 nm), but uva (wavelength 320-400 nm) may be accused as well [3]. uv radiation can cause mutations in the dna of the skin cells, which is usually through the creation of thymine dimers in the p53 tumor suppressor gene. the inability of the immune system to repair the mutations leads to skin cancer [4]. over the last half-century, changes in lifestyle have increased the exposure of populations to sunlight [3]. people with fair skin are most at risk. occupational exposure to uv radiation is also known to have an effect. one of the potential risk factors for scc that has recently been brought to attention is vitamin d and its measurable serum marker 25-hydroxyvitamin d [25(oh)d] [5]. eighty to ninety percent of vitamin d is produced in sunlight-exposed skin. this photobiosynthetic process is mainly mediated by uv rays [6], the same component of sunlight that is the leading risk factor for scc. these interactions make a complicated relationship among vitamin d, skin cancer, and uv rays. so far, there is no conclusive evidence in this regard [7]. on the one hand, many clinical, epidemiological, animal, and in vitro investigations have suggested that vitamin d and its metabolites have a risk-reducing impact on nonmelanoma skin cancer. this protective role comes from inhibition of the hedgehog signaling pathway (basal cell carcinoma) and modulation of p53-mediated dna damage response (scc) [3]. on the other hand, many authors believe in a direct relationship between vitamin d and skin cancers, mainly because vitamin d level is a reflection of individual exposure to sunlight uv rays [8-10]. some believe the vitamin d endocrine system is also relevant in photocarcinogenesis through its receptor, vdr [11]. in summary, there is uncertainty about the association between vitamin d and skin cancer. so far, there is no available study in iran, considering very high rates of vitamin d deficiency in this country [12,13]. thus we conducted this study to help achieve a better understanding of the link between scc risk and vitamin d in an iranian population. 280 research | dermatol pract concept 2019;9(4):6 as shown in table 3, based on the results of logistic regression analysis, when 25(oh)d level was treated as a continuous variable, each unit increase in vitamin d corresponded with a 2.9% increase in the chance of the occurrence of scc (wald = 10.55, p value = 0.001). the or in this model for each level of vitamin d was approximately 1.03, or merely 1 unit increase equals a 1.03-time rise in the chance of scc. however, after adjusting for the effect of other variables— gender, age, work environment, prolonged sun exposure, personal history of skin cancer—vitamin d levels could not significantly predict the occurrence of scc (wald = 3.37, p value = 0.066), although an inverse association was found (b = −6.3%). discussion in this study, without controlling for the effect of undesired variables (including age, sex, and sunlight exposure), an increased level of 25(oh)d was associated with the risk of scc. however, after controlling for this effect by using statistical methods, there was no significant relationship between scc risk and vitamin d level. we found that the prevalence of scc was higher in people who worked in an open area (such as farmers and construction workers) and also with more prolonged contact with sunlight, compared with people who worked in closed statistically significant difference between patients and controls (p value > 0.05). in the scc group, 10 (15.9%), 9 (14.3%), and 44 (69.8%) were in deficiency, insufficiency, and sufficiency of vitamin d, respectively. in the control group, 32 (50.8%) had deficient, 11 (17.5%) had insufficient, and 20 (31.7%) had sufficient levels of vitamin d. these differences are statistically significant (p < 0.001). however, when looking at the quantitative variables, the mean 25(oh)d level in the total sample was 33.66 ng/ml (sd = 24.02). mean vitamin d levels were significantly higher in patients with scc than in the control group (40.99 ng/ml vs 26.34 ng/ml, p < 0.01). as shown in table 2, the average vitamin d levels had no statistically significant difference among subjects with regard to gender, personal family history of skin cancer, and smoking. however, the average vitamin d level was higher among the people who worked outdoors (such as farmers) than those who worked in closed environments (44.04 ng/ml vs 30.56 ng/ml, p = 0.008). people with prolonged contact with sunlight (>6 hours/week) had higher average levels of vitamin d (48.82 ng/ml vs 29.33 ng/ml, p = 0.000). as well, the average vitamin d levels among different age groups had a significant variation such that in the age group 67-86 years they were greater than in other groups, and in the age group 19-33 years average vitamin d levels were the lowest. table 1. characteristics of study subjects controls scc cases total no. % no. % no. % p value gender male 23 36.5 50 79.4 73 57.9 <0.05 female 40 63.5 13 20.6 53 42.1 occupational environment outdoor 4 6.3 25 39.7 29 23 <0.05 indoor 59 93.7 38 60.3 97 77 sunlight exposure (weekly) >6 hours 3 4.8 25 39.7 28 22.2 <0.05 <6 hours 60 95.2 38 60.3 98 77.8 family history of scc positive 0 0 5 7.9 5 4 >0.05 negative 63 100 58 92.1 121 96 personal history of scc positive 0 0 9 14.3 9 7.1 <0.05 negative 63 100 54 85.7 117 92.9 smoking yes 18 28.6 17 27 35 27.8 >0.05 no 45 71.4 46 73 91 72.2 total 63 50 63 50 126 100 research | dermatol pract concept 2019;9(4):6 281 is not a cause of skin cancer itself. in other words, sunlight exposure, the primary suspect for confounding the conclusions, is responsible for higher vitamin d levels and the higher chance of skin scc at the same time, especially in those who work outdoors. the strength of our study was in addressing the effect of confounding factors and moderating their impact on the relationship between vitamin d and scc. nevertheless, the most significant limitation was the failure in assessing all possible influencing factors on vitamin d level and the occurrence of scc such as seasonal changes, ethnicity and race, and skin pigmentation classification. environments or who had shorter contact with sunlight (respectively, or = 9.7 and or = 13.16, p value < 0.05). thus prolonged exposure to sunlight for any activity—including work, sport, and entertainment—greater than 6 hours per week was defined as a potent risk factor for being diagnosed with scc. this finding is consistent with the results of many studies showing that the uv beams of sunlight exposure are a known risk factor for scc, causing mutations in genes that inhibit carcinogenesis [3,15]. the average level of 25(oh)d in scc patients was more than that in the control group and was statistically significant (40.99 vs 26.34, p value < 0.05). the unadjusted model of multivariate logistic regression analysis showed a meaningful positive relationship between vitamin d level and the occurrence of scc (table 3). afzal et al also published similar results; he and his colleagues assessed the relationship of vitamin d and incident scc in a 28-year prospective study of 10,160 white danish people and showed a positive association [16]. eide et al reported similar findings among 3,223 people in the united states in a prospective study [9]. in brazil, with a high percentage of vitamin d deficiency and insufficiency resembling that in iran, the level of vitamin d was higher among those with nonmelanoma skin cancers compared with healthy individuals [17]. liang and colleagues reported analogous results among chinese women; they found a significantly positive association between plasma 25(oh) d levels and scc risk after adjusting for age at blood draw, season of blood draw, hair dye, burning tendency, the number of sunburns, and uvb flux of residence at blood collection (p for trend = 0.0002) [18]. conversely, van der pols et al, in a prospective study for 11 years in an australian subtropical community, following baseline assessment of serum 25(oh) d in 1,191 adults, claimed that scc incidence tended to be lower in those with higher serum levels of 25(oh)d (or = 0.67, 95% ci: 0.44-1.03, p=0.07) [10]. tang et al seemingly suggested the inverse association between vitamin d and the risk of nonmelanoma skin cancer among older men [19]. in our study, after adjustment for the effect of possible confounding factors in multivariate logistic regression, vitamin d level could not independently predict the occurrence of scc. it seems that, as winsløw et al noted, the level of vitamin d in our population not consuming supplements is a surrogate for their amount of sun exposure, which per se has an established role in skin cancer [20]. thus this vitamin table 2. mean level of 25 oh vitamin d within study variables mean (ng/ml) sd p value gender male 36.63 21.69 0.104 female 29.58 26.58 age group 15-32 years 18.24 16.11 0.000 33-50 years 30.56 22.99 51-63 years 38.57 22.10 64-89 years 48.67 24.53 occupational environment outdoor 44.04 20.05 0.008 indoor 30.56 24.32 sunlight exposure (weekly) >6 hours 48.82 22.37 0.000 <6 hours 29.33 22.78 family history of scc positive 44.92 28.77 0.287 negative 33.2 23.83 personal history of scc positive 36.53 14.10 0.712 negative 33.44 24.64 smoking yes 31.35 19.88 0.506 no 34.55 25.47 total 33.66 24.02 table 3. multivariate logistic regression analysis for the relationship between vitamin d and scc b wald or (95% ci) p value r2 unadjusted model 0.029 10.55 1.03 (1.012-1.048) 0.001 0.104 adjusted model −0.063 3.37 0.939 −0.878-1.004) 0.066 0.752 282 research | dermatol pract concept 2019;9(4):6 9. eide mj, johnson da, jacobsen gr, et al. vitamin d and nonmelanoma skin cancer in a health maintenance organization cohort. arch dermatol. 2011;147(12):1379-1384. 10. van der pols jc, russell a, bauer u, neale re, kimlin mg, green ac. vitamin d status and skin cancer risk independent of time outdoors: 11-year prospective study in an australian community. j invest dermatol. 2013;133(3):637-641. 11. reichrath j, saternus r, vogt t. endocrine actions of vitamin d in skin: relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond. mol cell endocrinol. 2017;453:96-102. 12. vatandost s, jahani m, afshari a, amiri mr, heidarimoghadam r, mohammadi y. prevalence of vitamin d deficiency in iran: a systematic review and meta-analysis. nutr health. 2018;24(4):269-278. 13. khosravi-boroujeni h, sarrafzadegan n, sadeghi m, et al. prevalence and trends of vitamin d deficiency among iranian adults: a longitudinal study from 2001-2013. j nutr sci vitaminol (tokyo). 2017;63(5):284-290. 14. holick mf, binkley nc, bischoff-ferrari ha, et al. evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. j clin endocrinol metab. 2011;96(7):1911-1930. 15. hussein mr. ultraviolet radiation and skin cancer: molecular mechanisms. j cutan pathol. 2005;32(3):191-205. 16. afzal s, nordestgaard bg, bojesen se. plasma 25-hydroxyvitamin d and risk of non-melanoma and melanoma skin cancer: a prospective cohort study. j invest dermatol. 2013;133(3):629-636. 17. soares am, szejnfeld vl, enokihara my, michalany n, castro ch. high serum 25-hydroxyvitamin d concentration in patients with a recent diagnosis of non-melanoma skin cancer: a case-control study. eur j dermatol. 2018;28(5):649-653. 18. liang g, nan h, qureshi aa, han j. pre-diagnostic plasma 25-hydroxyvitamin d levels and risk of non-melanoma skin cancer in women. plos one. 2012;7(4):e35211. 19. tang jy, parimi n, wu a, et al. inverse association between serum 25(oh) vitamin d levels and non-melanoma skin cancer in elderly men. cancer causes control. 2010;21(3):387-391. 20. winsløw uc, nordestgaard bg, afzal s. high plasma 25-hydroxyvitamin d and high risk of nonmelanoma skin cancer: a mendelian randomization study of 97 849 individuals. br j dermatol. 2018;178(6):1388-1395. conclusions the positive association between vitamin d and the occurrence of scc was obscured by modulating the effect of possible confounding factors including age, gender, work environment, and the most important one, sunlight exposure. it is interesting that the relationship was inverse in the adjusted model, although it was not significant. knowledge about the epidemiology of scc is very limited in iran. we recommend further studies, preferably prospective ones with larger sample sizes and addressing all factors that influence both the amount of vitamin d in the body and the incidence of scc at the same time. references 1. chinem vp, miot ha. epidemiology of basal cell carcinoma. epidemiologia do carcinoma basocelular [in english, portuguese]. an bras dermatol. 2011;86(2):292-305. 2. rogers hw, weinstock ma, harris ar, et al. incidence estimate of nonmelanoma skin cancer in the united states, 2006. arch dermatol. 2010;146(3):283-287. 3. reichrath j, reichrath s. the relevance of the vitamin d endocrine system (vdes) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (nmsc): present concepts and future perspectives. dermatoendocrinol. 2013;5(1):38-50. 4. tongkao-on w, gordon-thomson c, dixon km, et al. novel vitamin d compounds and skin cancer prevention. dermatoendocrinol. 2013;5(1):20-33. 5. bikle dd. vitamin d and skin cancer. j nutr. 2004;134(12 suppl):3472s-3478s. 6. tuohimaa p, pukkala e, scélo g, et al. does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin d as a possible explanation. eur j cancer. 2007;43(11):1701-1712. 7. zeeb h, greinert r. the role of vitamin d in cancer prevention: does uv protection conflict with the need to raise low levels of vitamin d? dtsch arztebl int. 2010;107(37):638-643. 8. asgari mm, tang j, warton me, et al. association of prediagnostic serum vitamin d levels with the development of basal cell carcinoma. j invest dermatol. 2010;130(5):1438-1443. dermatology: practical and conceptual research | dermatol pract concept 2019;9(2):10 139 dermatology practical & conceptual introduction dermatofibrosarcoma protuberans (dfsp) is a fibrohistiocytic tumor that arises from the dermis and invades deeper tissue [1,2]. classic dfsp clinically appears as an indurated plaque or nodule, exhibiting flesh to reddish brown color [1]. the tumor is locally aggressive and has a high rate of recurrence; however, it rarely metastasizes [1,2]. the diagnosis of dfsp is often delayed because of its rarity, slow progression, and lack of early clinical clues. therefore, dermoscopy may be a valuable tool in the recognition and prompt diagnosis of this tumor. few previous reports have addressed the dermodermoscopy of dermatofibrosarcoma protuberans: what do we know? gabriela f. escobar1, caroline k. ribeiro2, leandro l. leite1, carolina r. barone1, andré cartell2 1 department of dermatology, hospital de clínicas de porto alegre (hcpa), brazil 2 medical school, university of rio grande do sul (ufrgs), brazil 3 department of pathology, hospital de clínicas de porto alegre (hcpa), brazil key words: dermatofibrosarcoma protuberans, dermoscopy, nonmelanocytic skin cancer, malignant cutaneous tumor, soft tissue tumor citation: escobar gf, ribeiro ck, leite ll, barone cr, cartell a. dermoscopy of dermatofibrosarcoma protuberans: what do we know? dermatol pract concept. 2019;9(2):139-145. doi: https://doi.org/10.5826/dpc.0902a10 accepted: february 21, 2019; published: april 30, 2019 copyright: ©2019 fortes escobar et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gabriela fortes escobar, md, msc, rua ramiro barcelos, 2350, 90035-903 porto alegre, rs, brazil. email: gescobar@hcpa.edu.br background: dermatofibrosarcoma protuberans (dfsp) is an uncommon mesenchymal tumor of intermediate malignancy. its rarity and slow progression often imply a delayed diagnosis. there are few previous reports of dermoscopic features of dfsp and most are single case descriptions. objectives: to report 2 cases of dfsp and their dermoscopic features, as well as conduct a review of all previous cases published addressing the use of dermoscopy in this tumor. methods: we conducted a literature search for all dermoscopic cases of dfsp. in addition, we presented 2 additional cases and compared them to the earlier findings. results: we summarized the main dermoscopic findings of dfsp based on analysis from 32 patients. the most common features of this tumor are the presence of vessels (81%), followed by a pigmented network (78%) and a pinkish background (66%). conclusions: dfsp can mimic benign lesions and the diagnosis may be challenging. dermoscopy is an important tool that may enhance clinical suspicion toward the diagnosis of dfsp. abstract 140 research | dermatol pract concept 2019;9(2):10 tasis. the lesion was totally excised with 3-cm margins and there has been no recurrence in 2 years of follow-up. patient 2 a 50-year-old woman, fitzpatrick skin phototype iv, was referred to the dermatology department to evaluate the possibility of cowden syndrome, since she had been previously diagnosed with breast cancer and papillary thyroid carcinoma. after a thorough physical examination, the patient did not meet the clinical diagnostic criteria for the syndrome. however, an inframammary brownish plaque lesion was observed. there was no history of trauma or previous procedures to the area. the patient had noticed a gradual enlargement of the lesion in the preceding 2 years. physical examination showed a brown atrophic plaque on the left inframammary region, measuring 25 × 20 mm (figure 4). on palpation, the lesion was indurated and tender and resembled a morphea plaque. dermoscopy revealed a pigmented network, with areas with interruptions in the network, over a pinkish background. no vascular structures were visible (figure 5, a and b). a 5-mm punch biopsy was performed. histopathological examination revealed a storiform pattern of a dermal spindle cell proliferation infiltrating the subcutaneous fat tissue in a honeycomb pattern (figure 6a). immunohistochemistry using anti-cd34 scopic aspects of dfsp and its variants [3-11]. in this article, we present 2 cases of dfsp and their dermoscopic features, as well as a review of previously published dermoscopic descriptions of this rare neoplasm. case reports patient 1 a 73-year-old woman, fitzpatrick skin phototype iii, presented with a 5-year history of an asymptomatic, slowly enlarging, nodular lesion located on the abdomen. physical examination showed a solitary mesogastric erythematous tumor measuring 80 × 80 mm (figure 1). on palpation, the lesion was firm and not tender. dermoscopy revealed fine arborizing telangiectasias and linear vessels over structureless depigmented areas, surrounded by a pink background with unfocused vessels (figure 2, a and b). a 5-mm punch biopsy was performed. histopathological examination revealed spindle-shaped tumor cells in a storiform pattern (figure 3, a and b), suggesting dfsp. the diagnosis was confirmed by immunohistochemistry, with positive staining using anticd34 antibody (figure 3c). magnetic resonance imaging showed a homogeneous nodular lesion circumscribed to the subcutaneous tissue and a chest x-ray ruled out lung metasfigure  1.  erythematous tumor located on the abdomen. an ecchymotic hue post-biopsy could be visualized. [copyright: ©2019 escobar et al.] figure 3. (a) spindle-shaped cells arranged in a storiform pattern (h&e, ×100). (b) (h&e, ×400). (c) immunohistochemistry using anticd34 antibody revealed that spindle cells were positive. h&e = hematoxylin and eosin. [copyright: ©2019 escobar et al.] a b c figure 2. (a) fine arborizing telangiectasias and linear vessels over structureless depigmented areas, surrounded by a pink background with unfocused vessels (×20). (b) close-up to visualize the central vascular structures (×50). [copyright: ©2019 escobar et al.] a b research | dermatol pract concept 2019;9(2):10 141 (pdgfb) signaling pathway plays a central role in the proliferation of dfsp tumor cells [2]. the typical histopathological characteristics of dfsp are described as uniform spindle cells with elongated nuclei, showing minimal atypia or mitotic activity, resulting in a storiform pattern [2,12]. the tumor infiltrates into the subcutaneous tissue, creating the characteristic honeycomb pattern. other spindle cell tumors such as dermatofibroma, malignant fibrous histiocytoma, atypical fibroxanthoma, desmoplastic melanoma, kaposi sarcoma, and solitary fibrous tumor are the histological differential diagnoses [2,12]. the infiltrative pattern of dfsp helps to differentiate it from benign entities, even though it is usually not sufficient for a conclusive diagnosis. in these cases, immunohistochemistry becomes a useful resource, since dfsp reveals positivity for cd34 and negativity for s100 protein, factor xiiia, and desmin [1,2]. histological variants of dfsp have been described in the literature, such as the pigmented variant (bednar tumor), myxoid dfsp, juvenile form (giant cell fibroblastoma), fibrosarcomatous variant, sclerosing dfsp, and atrophic subtype [16,17]. dermoscopic findings of dfsp are limited in the literature [3-11]. we performed an extensive search in the pubmed database and found a total of 9 articles with 30 patients (table 1). the first report, conducted by bernard et al [3], antibody revealed that spindle cells were positive, confirming the diagnosis of dfsp (figure 6b). the lesion was totally excised with margins of 4 cm and there has been no recurrence in 2 years of follow-up. discussion dfsp is a slowly growing mesenchymal neoplasm, characterized by high morbidity due to its local invasion and high recurrence rate after surgical excision [12,13]. the peak age at onset is between 20 and 50 years, and incidence among women is 1.14 times higher than in men [14]. the tumor usually presents as a slowly growing, painless, reddish brown nodule or plaque. the trunk is the most common anatomic site, followed by proximal extremities [1,15]. furthermore, dfsp may present as a morphea-like, atrophic, sclerotic, violaceous plaque that may ulcerate as it gradually increases in size [2,11]. the main differential diagnoses include cutaneous melanoma and dermatological manifestations of metastatic carcinomas. also, dfsp may mimic benign lesions such as dermatofibromas, hypertrophic scars, and keloids [2,9,11]. a chromosome translocation is found in more than 90% of the cases, involving chromosomes 17q22 and 22q13 [1,2]. the constitutively activated platelet-derived growth factor-β figure 4. brown atrophic plaque on the left inframammary region. [copyright: ©2019 escobar et al.] figure 6.  (a) spindle-shaped cells  arranged in a  storiform pattern (h&e, ×100). (b) immunohistochemistry using anticd34 antibody revealed that spindle cells were positive. h&e = hematoxylin and eosin. [copyright: ©2019 escobar et al.] a b figure 5. (a,b) pigmented network, with areas with interruptions in the network, over a pinkish background. no vascular structures were visible (×20). [copyright: ©2019 escobar et al.] a b 142 research | dermatol pract concept 2019;9(2):10 ta b le 1 . su m m ar y o f th e d er m o sc o p ic f in d in gs o f d f sp s tu d y [ c it a ti o n ], y e a r o f p u b li ca ti o n n o . o f c a se s a g e (m e a n ), s e x lo ca ti o n o f le si o n s iz e ( lo n g e st d ia m e te r) ; p re se n ta ti o n d e rm o sc o p y b er n ar d e t al [ 3 ], 2 0 1 3 (p o la ri ze d c o n ta ct ) 1 5 ( 2 r ec u rr en t le si o n s an d 1 b ed n ar t u m o r) 4 6 y rs , 6 7 % f t ru n k ( 8 0 % ), u p p er l im b s (2 0 % ) 2 5 .6 m m ( m ea n d ia m et er ); 6 0 % n o d u le d el ic at e p ig m en te d n et w o rk ( 8 7 % ), v es se ls ( 8 0 % ), s tr u ct u re le ss l ig h t b ro w n ar ea s (7 3 % ), s h in y w h it e st re ak s (6 7 % ), p in k b ac k gr o u n d c o lo ra ti o n ( 6 7 % ), an d s tr u ct u re le ss h yp o o r d ep ig m en te d a re as ( 6 0 % ); c o ex is te n ce o f re ti cu la r p ig m en ta ti o n a n d u n fo cu se d a n d /o r fo cu se d a rb o ri zi n g ve ss el s (6 7 % ) a vi lé siz q u ie rd o e t al [ 4 ], 2 0 1 4 a 4 3 6 .5 y rs , 2 f , 2 m t ru n k ( 7 5 % ), u p p er l im b s (2 5 % ) 2 5 m m ( m ea n d ia m et er i n 3 le si o n s; 1 l es io n n i) ; 1 0 0 % p la q u e a re as o f fi n e p ig m en t n et w o rk ( 1 0 0 % ), m es h -l ik e ve ss el s (1 0 0 % ) th at a re m ai n ly p er ip h er al ly l o ca te d , m il k y re d a re as ( 7 5 % ), w h it is h l in ea r st ru ct u re s o r ar ea s (7 5 % ) e sd ai le e t al [ 5 ], 2 0 1 4 a 1 n i n i si ze n i; p la q u e f in e p ig m en t n et w o rk , p in k b ac k gr o u n d , s tr u ct u re le ss h yp o an d h yp er p ig m en te d ar ea s, n o n sp ec ifi c ve ss el s g ü n gö r et a l [6 ], 2 0 1 4 a 1 3 7 y rs , f u p p er l im b 1 5 m m ; p la q u e a rb o ri zi n g te la n gi ec ta si as a n d y el lo w is h b ac k gr o u n d c o lo ra ti o n , n o p ig m en t n et w o rk e h ar a et a l [7 ], 2 0 1 6 a 1 ( b ed n ar t u m o r) 7 1 y rs , f b u tt o ck 7 m m ; n o d u le h o m o ge n eo u s b la ck -b lu is h p ig m en ta ti o n a n d w h it is h v ei lli k e st ru ct u re s h ar tm an n e t al [ 8 ], 2 0 1 6 (n o n p o la ri ze d c o n ta ct ) 1 6 6 y rs , m t ru n k 2 2 m m ; p la q u e h yp o p ig m en te d a re as , l ig h t b ro w n p ig m en t n et w o rk , p al e p in k a re as , a rb o ri zi n g te la n gi ec ta si as , b lu egr ay o va l n es ts p ic co lo e t al [ 9 ], 2 0 1 6 a 1 2 4 y rs , m l o w er l im b 5 0 m m ; n o d u le a ty p ic al n et w o rk , s tr u ct u re le ss h yp er an d h yp o p ig m en te d a re as , s h in y w h it e st re ak s, u n fo cu se d l in ea rir re gu la r ve ss el s v en tu ri n i et a l [1 0 ], 2 0 1 6 a 1 ( re cu rr en t le si o n ) 5 4 y rs , f t ru n k 4 0 m m ; p la q u e c en tr al l in ea r w h it e an d p in k a re as , s tr u ct u re le ss l ig h t b ro w n a re as , f o ca l p ig m en te d re ti cu la r li n es c o st a et a l [1 1 ], 2 0 1 7 a 6 ( 1 c as e w as p re vi o u sl y re p o rt ed b y p ic co lo e t al [ 9 ]; th er ef o re , t h e d es cr ip ti o n w as n o t re p ea te d ) n i n i si ze n i; p ap u le , m as s p la q u e, n o d u le 5 p at te rn s d es cr ib ed : • c la ss ic d f sp : p ig m en t n et w o rk , w h it is h l in ea r st ru ct u re s, d il at ed v es se ls , p al e re d b ac k gr o u n d • a n gi o m ali k e: a rb o ri zi n g ve ss el s ar ra n gi n g in a c en tr if u ga l fa sh io n o n a p in k is h b ac k gr o u n d • k el o id -l ik e: p o ly m o rp h ic v es se ls o n a w h it eto -b lu is h b ac k gr o u n d , s tr u ct u re le ss w h it e ar ea s • m o rp h ea -l ik e: i n n er p o rt io n h yp o p ig m en te d s tr u ct u re s, s u rr o u n d ed b y a sl ig h tl y p ig m en te d n et w o rk w it h l in ea r ve ss el s • n o d u la r m o rp h ea -l ik e: s li gh tl y p ig m en te d n et w o rk , a rb o ri zi n g th in v es se ls , h yp o p ig m en te d u n st ru ct u re d a re as o n a p in k is h b ac k gr o u n d , d o tt ed v as cu la r p at te rn a n d w h it e st re ak s in t h e in n er n o d u la r p o rt io n e sc o b ar e t al [ th is ar ti cl e] , 2 0 1 9 ( fi rs t le si o n : n o n p o la ri ze d co n ta ct ; se co n d l es io n : p o la ri ze d n o n co n ta ct ) 2 6 1 .5 y rs , f t ru n k 8 0 m m a n d 2 5 m m ; n o d u le a n d p la q u e f ir st l es io n : ve ss el s (a rb o ri zi n g te la n gi ec ta si as a n d l in ea r ve ss el s) , s tr u ct u re le ss d ep ig m en te d a re as , p in k b ac k gr o u n d c o lo ra ti o n ; se co n d l es io n : p ig m en te d n et w o rk an d p in k b ac k gr o u n d c o lo ra ti o n , n o v as cu la r st ru ct u re s n i = n ot in fo rm ed . a n o de sc ri pt io n of th e de rm os co py m et ho d us ed . research | dermatol pract concept 2019;9(2):10 143 furthermore, hartmann et al [8] described a case of dfsp with clinical and dermoscopic features that resembled a basal cell carcinoma. in this case, dermoscopy showed 2 criteria used to diagnose basal cell carcinoma: arborizing telangiectasias and structures similar to blue-gray ovoid nests. in addition, hypopigmented areas, light brown pigment network, and pale pink areas could also be visualized. dfsp may also resemble keloids, particularly in patients with darker skin. piccolo et al [9] described the case of an african male patient with the following dermoscopic features: atypical network, structureless hyperand hypopigmented areas, shiny white streaks, and unfocused linear-irregular vessels. this report also highlights the dermoscopic multicomponent pattern, which should always raise a red flag for malignancy. recurrent dfsp may be very challenging to diagnose because it can resemble scar tissue. venturini et al [10] reported 1 case in which they observed linear white and pink areas surrounded by structureless light brown areas with focal pigmented reticular lines. these findings were similar to those described by bernard et al [3]. this article included 2 recurrent lesions and the authors did not identify differences between the dermoscopic patterns observed in patients with recurrent dfsp and those with primary lesions. recently, costa et al [11] analyzed dermoscopic findings in 5 clinical variants of dfsp (however, 1 was previously described [9]). the angioma-like dfsp displayed thick arborizing vessels arranged in a centrifugal fashion on a pinkish background. also presenting with vascular structures, the keloid-like dfsp had polymorphic vessels (linear and arborizing) on a white-to-bluish background and structureless white areas. moreover, a morphea-like plaque dfsp was reported, exhibiting a slightly pigmented network, structures, and linear vessels. however, nodule-plaque morphea-like dfsp presented with a pigmented network, arborizing thin vessels, and hypopigmented unstructured areas on a pinkish background in the plaque area, while the nodular portion exhibited a dotted vascular pattern and white streaks. regarding our cases presented in this report, patient 1 exhibited the multicomponent pattern described by bernard et al [3]. in this case, fine arborizing telangiectasias and linear vessels could be seen over structureless depigmented areas, which were surrounded by a pinkish background with unfocused vessels. despite the fact that a pigmented network was reported in 87% of the lesions [3], in patient 1 there were no pigmented structures. of interest, in patient 2 the only dermoscopic findings were a pigmented network with a pinkish background and no vessels could be observed. although this case clinically had a morphea-like aspect, our dermoscopic features differed from those described by costa et al [11] in their morphea-like variant in that we did not observe hypopigmented structures or vessels. therefore, analyzed 15 cases of dfsp, including 1 case of bednar tumor. in this study, 80% of the lesions were located on the trunk, while the remaining were on the upper limbs. in this article, 6 dermoscopic characteristics and their frequency were described: delicate pigmented network (87%), vessels (80%), structureless light brown areas (73%), shiny white streaks (67%), pink background coloration (67%), and structureless hypoor depigmented areas (60%). among the lesions with vessels, all had unfocused vessels and half had a mixture of unfocused and focused vessels. arborizing vessels were the most prevalent vascular structure, since it was found in 11 of 12 cases. therefore, the authors concluded that the most common dermoscopic pattern observed was the coexistence of reticular pigmentation and unfocused and/or focused arborizing vessels. another interesting finding was the high number of dermoscopic features per lesion (a median of 4), also called a multicomponent pattern, which is suggestive of malignant tumors [3,18,19]. subsequently, avilés-izquierdo et al [4] described the dermoscopic features in 4 cases of dfsp. all lesions consisted of plaques, located mainly on the trunk (75%). the most prominent dermoscopic features observed by the authors were mesh-like vessels, mostly located peripherally, which histologically corresponded to dilated vessels in the superficial dermis. in addition, all cases presented with a fine pigment network, histologically represented by hyperpigmentation in the basal cell layer. milky red areas were observed in 3 cases, as well as whitish linear structures or areas, which histologically corresponded to intersecting bands of tumor cells in the dermis, forming a storiform pattern. esdaile et al [5] also described a similar case with a fine pigment network over a pink background, with structureless hypoand hyperpigmented areas and nonspecific vessels. a further report by güngör et al [6] described 1 case of the atrophic variant of dfsp. in this patient, dermoscopic examination revealed arborizing telangiectasias and a yellowish background. the authors suggested that this particular background coloration could be explained by dermal atrophy and the close approximation of the subcutis to the epidermis. in addition, ehara et al [7] described 1 case of the pigmented variant of dfsp (bednar tumor), which clinically and dermoscopically mimicked a blue nevus. in this case, a homogeneous black-bluish pigmentation with white-veil structures was observed, while no vessels could be visualized. while the diffuse and intense pigmentation was attributed to melanin-laden spindle cells in the dermis and subcutaneous tissue, the white veil structures corresponded to collagen in the upper dermis. since the tumor had a deeper presentation, no vascular structures could be appreciated, which differed from the bednar case reported by bernard et al, which displayed vessels on dermoscopy [3]. 144 research | dermatol pract concept 2019;9(2):10 corroborate the earlier findings of most studies [3-,5,9-11]; however, atypical dermoscopic presentations have also been described [6-8]. since this tumor may mimic benign lesions, dermoscopy is a valuable tool, indicating the need for a prompt biopsy and contributing to the correct diagnosis. references 1. li y, wang c, xiang b, shen s, li l, ji y. clinical features, pathological findings and treatment of recurrent dermatofibrosarcoma protuberans. j cancer. 2017;8(7):1319-1323. 2. thway k, noujaim j, jones rl, fisher c. dermatofibrosarcoma protuberans: pathology, genetics, and potential therapeutic strategies. ann diagn pathol. 2016;25:64-71. 3. bernard j, poulalhon n, argenziano g, et al. dermoscopy of dermatofibrosarcoma protuberans: a study of 15 cases. br j dermatol. 2013;169(1):85-90. 4. avilés-izquierdo ja, conde-montero e, barchino-ortiz l, lázaro-ochaita p. dermoscopic features of dermatofibrosarcoma protuberans. australas j dermatol. 2014;55(2):125-127. 5. esdaile ba, matin rn. residents’ corner august 2014. clues in dermoscopy: dermoscopic features to aid earlier diagnosis? eur j dermatol. 2014;24(4):518-519. 6. güngör s, büyükbabani n, büyük m, tarıkçı n, kocatürk e. atrophic dermatofibrosarcoma protuberans: are there specific dermatoscopic features? j dtsch dermatol ges. 2014;12(5):425-427. 7. ehara y, yoshida y, shiomi t, yamamoto o. pigmented dermatofibrosarcoma protuberans and blue naevi with similar dermoscopy: a case report. acta derm venereol. 2016;96(2):272-273. 8. hartmann f, haenssle ha, seitz cs, kretschmer l, schön mp, buhl t. maculonodular lesion on the back of a 66-year-old man. hautarzt. 2016;67(10):845-847. 9. piccolo v, russo t, staibano s, et al. dermoscopy of dermatofibrosarcoma protuberans on black skin. j am acad dermatol. 2016;74(6):e119-e120. 10. venturini m, zanca a, manganoni am, pavoni l, gualdi g, calzavara-pinton p. in vivo characterization of recurrent dermatofibrosarcoma protuberans by dermoscopy and reflectance confocal microscopy. j am acad dermatol. 2016;75(5):e185-e187. 11. costa c, cappello m, argenziano g, piccolo v, scalvenzi m. dermoscopy of uncommon variants of dermatofibrosarcoma protuberans. j eur acad dermatol venereol. 2017;31(8):e366e368. even in the same dsfp clinical variant, the dermoscopic features may vary. in the attempt to summarize previously published data with the 2 new cases presented in this report (table 2), we found that the 3 most common dermoscopic findings were the presence of vessels (81%), followed by a pigmented network (78%) and a pinkish background (66%). vascular structures included arborizing, mesh-like, linear-irregular, or polymorphic vessels. in relation to the pigment network observed, it corresponds to the increased pigment in the epidermal basal cells, rather than melanocytic proliferation. therefore, it is an exception to the rule that the presence of a pigment network is a dermoscopic clue for the diagnosis of a melanocytic lesion [18]. furthermore, 50% displayed structureless hypoor depigmented areas and 44% presented structureless light brown areas. shiny white streaks, which were observed in more than half of the cases (53%), may have been underestimated since this finding is only seen under polarized dermoscopy [20]. unfortunately, not all previous studies described the dermoscopic acquisition method. this is an interesting issue to evaluate in future cases, since shiny white streaks have been related to malignant neoplasms, such as melanomas and basal cell carcinomas [20] and, therefore, could also be an indicator of dfsp. surgical excision remains the mainstay treatment for dfsp. because of its infiltrating growth pattern, a wide excision with margins of at least 3 cm of clinically uninvolved skin is strongly advised for the treatment of dfsp [13,21,22]. alternatively, mohs micrographic surgery has become the treatment of choice for most skin cancers on the head and neck, as well as for recurrent or histologically aggressive lesions [1,12,23]. adjuvant radiotherapy may be indicated when the resection margins are positive or when excision may result in significant aesthetic or functional damage [21]. based on the knowledge about the signaling mechanisms of tumor proliferation, imatinib mesylate has shown significant therapeutic value in the treatment of dfsp [1,12]. furthermore, predictors of poorer overall survival include older age at diagnosis, male sex, and large tumor size [15]. in addition, the pathological fibrosarcomatous variant is associated with an aggressive clinical course, with a higher rate of local recurrence and metastasis [24]. since recurrences usually occur within 3 years of primary excision, patients should be followed up every 6 months during this period and annually thereafter [21]. conclusions this current report illustrates dermoscopic features of 2 cases of dfsp, as well as a review of previous reports. our findings table 2. most common dermoscopic findings of dfsp and their frequency (total of 32 cases) dermoscopic featuresa frequency (n) pigmented network 78% (25) vessels 81% (26) structureless light brown areas 44% (14) shiny white streaks 53% (17) pink background 66% (21) structureless hypoor depigmented areas 50% (16) abernard et al [3]. research | dermatol pract concept 2019;9(2):10 145 cal hyper/hypopigmentation, and the multicomponent pattern in melanocytic lesions lacking specific dermoscopic features of melanoma. arch dermatol. 2008;144(11):1440-1444. 20. shitara d, ishioka p, alonso-pinedo y, et al. shiny white streaks: a sign of malignancy at dermoscopy of pigmented skin lesions. acta derm venereol. 2014;94(2):132-137. 21. saiag p, grob jj, lebbe c, et al. diagnosis and treatment of dermatofibrosarcoma protuberans: european consensus-based interdisciplinary guideline. eur j cancer. 2015;51(17):2604-2608. 22. wollina uwe, langner d, schönlebe j, frança k, lotti t, tchernev g. dermatofibrosarcoma protuberans: retrospective single center analysis over 16 years. j med sci. 2018;6(1):35-37. 23. lowe gc, onajin o, baum cl, et al. a comparison of mohs micrographic surgery and wide local excision for treatment of dermatofibrosarcoma protuberans with long-term follow-up: the mayo clinic experience. dermatol surg. 2017;43(1):98-106. 24. liang ca, jambusaria-pahlajani a, karia ps, elenitsas r, zhang pd, schmults cd. a systematic review of outcome data for dermatofibrosarcoma protuberans with and without fibrosarcomatous change. j am acad dermatol. 2014;71(4):781-786. 12. acosta ae, vélez cs. dermatofibrosarcoma protuberans. curr treat options oncol. 2017;18(9):56. 13. molina as, duprat neto jp, bertolli e, et al. relapse in dermatofibrosarcoma protuberans: a histological and molecular analysis. j surg oncol. 2018;117(5):845-850. 14. kreicher kl, kurlander de, gittleman hr, barnholtz-sloan js, bordeaux js. incidence and survival of primary dermatofibrosarcoma protuberans in the united states. dermatol surg. 2016;42 suppl 1:s24-s31. 15. criscito mc, martires kj, stein ja. prognostic factors, treatment, and survival in dermatofibrosarcoma protuberans. jama dermatol. 2016;152(12):1365-1371. 16. al barwani as, taif s, al mazrouai ra, al muzahmi ks, alrawi a. dermatofibrosarcoma protuberans: insights into a rare soft tissue tumor. j clin imaging sci. 2016;6:16. 17. lyu a, wang q. dermatofibrosarcoma protuberans: a clinical analysis. oncology lett. 2018;16(2):1855-1862. 18. soyer hp, argenziano g, chimenti s, ruocco v. dermoscopy of pigmented skin lesions. eur j dermatol. 2001;11(3):270-276. 19. arevalo a, altamura d, avramidis m, blum a, menzies s. the significance of eccentric and central hyperpigmentation, multifodermatology: practical and conceptual 132 research | dermatol pract concept 2018;8(2):13 dermatology practical & conceptual www.derm101.com introduction phototherapy is an effective treatment method for many skin diseases. the most important chronic side effect of phototherapy is carcinogenesis. according to the information available, although the carcinogenetic effects of narrowband ultraviolet b (nbuvb) treatment seems more moderate when compared to other forms of phototherapy, its long-term reliability is not known exactly [1]. dermoscopy is among the optical techniques with higher efficacy in the earlier diagnosis of skin cancer compared to naked-eye examination [2]. for this reason, total body examinations, both clinical and dermoscopic, are being performed in many centers before and during phototherapy. dermoscopic changes in melanocytic nevi covered with both opaque tape and sunscreen cream during narrowband ultraviolet b therapy derya ök kekeç1, nida kaçar2, işıl kılınç karaarslan3 1 denizli public hospital, denizli, turkey 2 department of dermatology, pamukkale university, denizli, turkey 3 department of dermatology, ege university, izmir, turkey key words: dermoscopy, sunscreen, melanocytic nevus, phototherapy, narrowband ultraviolet b citation: ök kekeç d, kaçar n, kilinç karaarslan i. dermoscopic changes in melanocytic nevi covered with both opaque tape and sunscreen cream during narrowband ultraviolet b therapy. dermatol pract concept. 2018;8(2):132-139. doi: https://doi.org/10.5826/ dpc.0802a13 received: january 25, 2018; accepted: february 20, 2018; published: april 30, 2018 copyright: ©2018 ök kekeç et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this study was financially supported by grant number 2015tpf011 from the scientific research projects foundation of pamukkale university. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nida kaçar, md, pamukkale universitesi tip fakultesi, dermatoloji anabilim dali, kırmızı bina, 3. kat kinikli, 20070 pamukkale denizli, turkey. tel. +902582965875. email: n_gelincik@yahoo.com background: ultraviolet (uv) light may cause dermoscopic changes on melanocytic nevi (mn). objectives: to investigate the effects of sunscreen cream (ssc) application on dermoscopic changes in mn during narrowband uvb (nbuvb) therapy. methods: half of the randomly selected mn in each patient were covered with opaque tape and ssc [ssc(+)], and the rest were covered with only opaque tape [ssc(-)] during nbuvb treatment sessions. results: more ssc(-) mn displayed dermoscopic changes at end of nbuvb therapy compared to the start of therapy (p=0.035). the number of the mn that decreased in size and showed loss of structure was significantly higher in ssc(-) mn (p=0.04 and p=0.026, respectively). conclusions: sunscreen in combination with opaque tape may contribute to some dermoscopic changes in melanocytic nevi, including decrease in size and loss of structure. abstract research | dermatol pract concept 2018;8(2):13 133 opaque tape—without ssc application ssc(-). ssc was applied approximately 20 minutes before the opaque tape was applied. spf 50 + ssc containing organic and inorganic filters against uva-uvb (solante; buergli pharma, inc., makati, philippines) was used. dermoscopic images of the selected mn were captured with a digital dermoscopy system at the beginning, at the end, and 3-6 months after the end of nbuvb therapy. at all follow-ups, total body mole mapping was performed with a fully automated body mole-mapping programme (body studio atbm; fotofinder systems inc, columbia, md, usa). dermoscopic photographing, total body mole mapping, and arrangement of photographs were performed by one researcher (dök). the evaluation of the images was done by another researcher (nk) without knowing whether the lesion was ssc(+) or ssc(-). the mn that showed unexpected dermoscopic findings, such as decrease in size or loss of structure, were further evaluated by another researcher (ikk). the data were analyzed with the spss statistics 21 packet programme. sustained variables were given as average ± standard deviation, minimum – maximum assets and categorical variables for numbers and percentages. in order to compare the independent group discrepancies, the mann-whitney u test was used. the differences between categoric variables were examined with chi-square test. for examination of risk factors, the logistic regression test was used. results of the 24 patients enrolled, a total of 165 mn were identified. excluded from the study were 6 patients with 34 mn, who were lost to follow-up and 11 mn of included patients that had poor image quality. in sum, the study included 120 mn belonging to  18  patients (mean age: 44.7±14.2  years; 13 women). the majority of patients were diagnosed with mycosis fungoides (n:5; 27.8%) and psoriasis (n:5; 27.8%); the remaining diagnoses were pruritus, granuloma annulare, pityriasis lichenoides chronica and perforating dermatoses. fitzpatrick skin type 3 was the most common skin type (n:14; 77.8%). the mean cumulative treatment dose was 32.9±33.3 joule/ cm2 (range 1.53-100.14 joule/cm2). one patient received acitretin treatment in addition to phototherapy. forty-two mn [18 ssc(+); 24 ssc (-)] were reexamined after a mean of 4.2±1.2 months (range: 3-6 months) after the end of nbuvb therapy. ssc(-) and ssc(+) groups constituted 68 (56.7%) and 52 (43.3%) patients, respectively. the most frequently observed dermoscopic pattern was reticular pattern (n=50; 41%), followed by homogenousreticular pattern (n=31; 25.8%), homogenous pattern (n=17; 14.2%), globular pattern (n=12; 10.0%), homogenousglobular pattern (n=8; 6.7%), and multicomponent pattern uv light can cause clinical, histopathologic and dermoscopic changes in melanocytic nevi (mn) [3-5]. the dermoscopic changes observed in mn after nbuvb or ultraviolet a1 (uva1) exposure did not occur in mn covered with opaque tape or sunscreen cream (ssc). in the direction of these findings, it was suggested that the dermoscopic changes induced by uva1 and ultraviolet b (uvb) can be prevented successfully with either opaque tape or highly protective factor ssc; however, no significant histologic and immunohistochemical changes were detected in mn showing dermoscopic changes [6]. although dermoscopic changes were recorded in a significantly few amount of covered mn during phototherapy sessions, they still occured in a noteworthy part of the covered mn [5,7,9]. the turkish dermatology society phototherapy guidelines advise covering big and atypical mn and premalignant lesions before phototherapy [9]. based on the above findings, we covered half of the selected mn with opaque tape and ssc and the rest with only opaque tape during all phototherapy sessions in order to investigate whether the use of ssc in addition to opaque tape has an additive effect in preventing dermoscopic changes induced by uv exposure. we also evaluated the development of new mn during follow-up. as far as we know, our study is the first study searching dermoscopic changes in covered mn with both opaque tape and ssc and new mn development during phototherapy. materials and methods all patients with a variety of dermatologic diseases were refered to our phototherapy unit for nbuvb therapy between january 28, 2015 and july 25, 2016 were evaluated in terms of eligibility for the study. the patients who were older than 1 year old and had at least two mn >2 mm size located on body and/or proximal extremity without melanoma suspicion were invited to participate in the study. exclusion criteria included personal or family history of melanoma or cutaneous malignant epithelial tumor, active infection, atypical mole syndrome, active or previous history of systemic inflammatory or neoplastic disease, immunosuppressive medication, phototherapy history, and artificial uv exposure. mn located on sun-exposed body parts such as the head, neck, and distal extremities were not taken into consideration. every study participant signed an informed consent form. phototherapy was given using a waldman uv 7001k (tl-01) device equipped with f85/100w-01 (tl01) philips fluorescent tubes. at least two mn sized >2 mm were selected randomly in each patient. half of the selected mn in each patient were covered with opaque tape after ssc application ssc(+), and the rest were covered only with 134 research | dermatol pract concept 2018;8(2):13 ssc(+) mn; but not at a significant level (p>0.05) (table 2). the ratio of ssc(+) mn that showed darkening pigmentation, darkening pigment network, increase in size, and decrease in the number of dot and/or globules were higher than ssc(-) mn (p>0.05) (table 3). t h e d e r m o s c o p i c ch a n g e s 3 6 months after the end of nbuvb therapy compared to the beginning and the (n=2; 1.7%). seventy percent of mn were located on the body, 25.8% on the arms, and 4.2% on the legs. new mn development was not established during the study. although the ratio of ssc(-) mn displaying dermoscopic changes was higher than ssc(+) mn at the end of nbuvb therapy compared to the beginning; the ratio of mn displaying dermoscopic changes was similar in both ssc(-) and ssc(+) groups  3-6  months after the end of nbuvb therapy compared to the beginning and the end of therapy (table 1). no differences in dermoscopic changes according to anatomic locations were detected between ssc(-) and ssc(+) groups (p>0.05). dermoscopic changes at the end of nbuvb therapy compared to the of therapy: the ratios of ssc(-) mn that showed decrease in size and loss of structure were higher than ssc(+) mn (p=0.04 and p=0.026, respectively) (figure 1). failure to apply ssc over mn increased the ratio of decrease in size 4,681 times compared to mn applied with ssc (exp(b): 4.681). the ratio of loss of structure was found to be increased 5.932 times in ssc(-) mn compared to ssc(+) mn (exp(b):5.932). the mean exposed joules were comparable between the ssc(-) and ssc(+) mn showing decrease in size and loss of structure (p>0.05). more ssc(-) mn showed fading in pigmentation, fading in pigment network, new structure and/ or color development, and increase in the number of dot and/or globules than table 1. mn showing dermoscopic changes at the beginning, at the end, and 3-6 months after end of therapy beginning vs. end end vs. 3-6 months after the end end vs. 3-6 months after the end ssc(+); n(%) 19 (15.8%) 6 (14.2%) 6 (14.2%) ssc (-); n(%) 38 (31.6%) 6 (14.2%) 3 (7.1%) p value =0.035 >0.05 >0.05 total n(%) 57 (47.5%) 12 (28.5%)* 9 (21.4%)* *these ratios were calculated within 42 mn that were reexamined after discontinuing therapy. figure 1. the nevi that showed fading in pigmentation and pigment network (b); fading in pigmentation together with decrease in size (d), and decrease in dots/globules together with increase in streaks and blue-gray color formation (f) at the end of therapy compared to the beginning (a, c and e, respectively). [copyright: ©2018 ök kekeç et al.] end of therapy: these analyses were performed in ssc(-) 24 mn and ssc(+) 18  mn that were reexamined after discontinuing therapy. dermoscopic changes persisted in 7 mn [4 ssc (+); 3 ssc(-)] and new dermoscopic changes (late onset) emerged in 2 mn [2 ssc (+)] 3-6 months after the end of therapy. when the dermoscopic changes were considered separately, it was observed that most returned to their former state research | dermatol pract concept 2018;8(2):13 135 discussion prevelance of mn changes according to age, genetic and environmental factors, and the number of mn, which are low in childhood can increase in time [10]. the most studied enviromental factor in terms of relevance with mn development is uv light. an animal model demonstrated that uvb and uva2 both induce mn development [11,12]. epidemiological and twin studies revealed a relationship between the number of mn and the intermittant intense uv exposure; however, no relationship was established between daily uv exposure and mn number [13,14]. it was shown that as the experienced sunburn number and severity increase, new mn or had a tendency to do so (table 4, figure 2). the dermoscopic changes and histopathologic results of excised mn are summarized in table 5. before starting the study, it was calculated with 80% power that 95% confidence could be achieved if 49 mn would be included in each group (at least 98 mn) when power analysis had been performed, assuming the obtainable ratios would be 10% and 30%. when the results of the study were examined, power analysis was performed according to these results [for size decrease ssc(+) 9.6% vs ssc(-) 33.8%, and for structure loss ssc(+) 3.8% vs. ssc(-) 19.1%], and it was determined that the present study had 95% and 86% power, respectively, with 95% confidence. table 2. more frequently observed dermoscopic changes in ssc(-) mn compared to ssc(+) mn at the beginning vs. end of nbuvb therapy** (n=120) ssc(+); n (%) ssc(-); n (%) p decrease in size 5 (9.6%) 23 (33.8%) =0.04 symmetric 5 19 >0.05 asymmetric 0 4 loss of construction 2 (3.8%) 13 (19.1%) =0.026 loss of pigment network 2 11 >0.05 dots/globules 0 1 branched streaks 0 1 fading in pigmentation 19 (34.6%) 33 (47.1%) p>0.05 symmetric-homogeneous 17 30 >0.05 asymmetric 0 2 central 2 0 peripheral 0 1 fading in pigment network 11 (21.2%) 19 (27.9%) p>0.05 symmetric-homogeneous 11 19 na new structure formation 1 (1.9%) 6 (8.8%) p>0.05 pigment network 0 3 na streaks 0 1 dot-globul 0 1 white scar-like depigmentation 1 1 structureless areas 1 0 ulcer 1 0 chrysalis structures 1 0 new color formation 1 (%1.9%) 4 (5.9%) p>0.05 blue 0 1 na white 1 1 blue-gray 0 2 loss of color 0 (0%) 1 (1,5%) na black 0 1 na increase of dots-globules 1 (1.9%) 1 (1.5%) na *na= no analysis **the above given mn and the dermoscopic parameter numbers do not match, because more than one dermoscopic parameter was observed in one mn. 136 research | dermatol pract concept 2018;8(2):13 treatment [16,17] and even in 43.2% of covered mn during psoralen-ultraviolet a (puva) and nbuvb treatment [7]. we observed dermoscopic changes in most of the mn (65%) despite being covered with opaque tape in all and with ssc in half of them. higher ratios that are found in our study may be related to the detailed dermoscopic evaluation parameters. lin et al recognized size changes in a larger proportion of the mn located on the abdominal region in comparison to the mn located on other body sites but noted no significant relation with skin type [16]. in our study, we did not detect any differences in dermoscopic changes between ssc(+) and ssc(-) mn groups according to anatomical location. kılınç karaaslan et al observed increase in size in uncovered mn but not in opaque tape-covered mn at the end of development increases [15]. these findings explain that the nevogenic effect of uv is dose dependent and is distinctive in areas where environmental uv is much more intense. we did not observe new mn development in our study. it can be related to other factors, including that almost all our patients were dark phenotype, all were over 18 years old, and we had short-term follow-up. in addition, the ones who had severe sunburn history were excluded from the study, and during treatment the uv dosage were raised gradually. there are genetic factors that have not been identified, yet might have a role. uv light can cause clinical, histopathologic and dermoscopic changes in mn by increasing melanin synthesis or inducing melanocyte proliferation [3-5]. dermoscopic changes were reported in 27-50% of mn during nbuvb table 3. more frequently observed dermoscopic changes in ssc(+) mn compared to ssc(-) mn at the beginning vs. at the end of nbuvb therapy (n=120) ssc(+); n (%) ssc(-); n (%) p* increase in size 3 (5.8%) 3 (4.4%) p>0.05 symmetric 2 3 na asymmetric 1 0 darkening in pigmentation 4 (7.7%) 4 (5.9%) p>0.05 symmetric –homogenous 4 4 na darkening in pigment network 4 (7.7%) 2 (2.9%) p>0.05 symmetric –homogenous 4 2 na decrease in the number of dots/globules 4 (7.7%) 4 (5.9%) p>0.05 *na= no analysis table 4. the course of dermoscopic changes 3-6 months after end of therapy* returned to the original state or tended to do so persisted or progressed late onset increase in size 9.5 [4.6:4.6] 2.3 [2.3:0] 4.6 [2.3:2.3] decrease in size 21.4 [0:21.4] 4.6 [2.3:2.3] 2.3 [2.3:0] darkening in pigmentation 9.5 [4.6:4.6] 4.6 [4.6:0] 0 fading in pigmentation 28.5 [6.9:21.4] 11.9 [4.6:6.9] 4.6 (4.6:0] darkening in pigment network 9.5 [4.6:4.6] 2.3 [2.3:0] 0 fading in pigment network 16.6 [4.6:11.9] 9.5 [2.3:6.9] 0 new structure development 6.9 [2.3:4.6] 2.3 [0:2.3] 4.6 [2.3:2.3] loss of structure 14.2 [2.3:11.9] 2.3 [0:2,3] 2.3 [2.3:0] increase in the number of dots/globules 0 2.3 [2.3:0] 2.3 [0:2.3] decrease in the number of dots/globules 6.9 [2.3:4.6] 0 0 new color development 2.3 [0:2.3] 2.3 [2.3:0] 0 loss of color 2.3 [0:2.3] 0 0 * %total [%ssc(+): %ssc(-)]; these ratios were calculated within 42 mn that were reexamined after discontinuing therapy research | dermatol pract concept 2018;8(2):13 137 nbuvb, uva1 and puva treatments for three months [17]. none of the above studies mention decrease in size in mn and it was not stated whether size decrease was taken into consideration. lin et al detected size change in 40% of mn during nbuvb treatment, and similar to our study, they evaluated mn size in terms of both decrease and increase. they a mean 9 weeks of nbuvb treatment [8]. similarly to their observation, ghani-nejad et al determined a significant increase in size in uncovered mn, but not in opaque tapecovered mn, after nbuvb treatment for 30-60 sessions [7]. contrary to these studies, karaca et al established a statistically significant mean area measurement increase in mn, despite being uncovered, in patient groups who received figure 2. darkening in pigmentation and pigment network (b, e) and fading in pigmentation and pigment network (h) at the end of therapy compared to the beginning (a, d, g) in three mn. it is seen that dermoscopic changes showing tendency to return back (c), increasing (f) and persisting (i) 3-6 months after the end of therapy. [copyright: ©2018 ök kekeç et al.] table 5. dermoscopic changes in excised mn dermoscopic changes mn1 mn2 mn3 mn4 structureless areas + ulcer + chrysalis structures + streaks formation + white scar-like depigmentation + + decrease in size + + increase in size + fading in pigmentation + + + darkening in pigmentation + fading in pigment network + decrease in the number of dots/globules + loss of pigment network + histopathologic diagnosis intradermal nevus junctional nevus junctional nevus dysplastic nevus 138 research | dermatol pract concept 2018;8(2):13 nbuvb exposure in both study groups. however, dermoscopic changes remained in some mn. in addition, dermoscopic changes emerged 3-6 months after the end therapy in some mn that did not show any dermoscopic changes at the end of therapy. those dermoscopic changes can be due to lateonset or persistent effects of nbuvb but can also be related to the natural evolution of mn, independent from nbuvb, as claimed by dobrosavljevic et al. long-term follow up studies may clarify this condition [18]. conclusion in conclusion, nbuvb treatment causse various dermoscopic changes in mn; some of these changes can be prevented with opaque tape. ssc in combination with opaque tape helps in preventing the development of dermoscopic changes in mn, including size decrease and structure loss. acknowledgments this study was financially supported by grant number 2015tpf011 from the scientific research projects foundation of pamukkale university. we thank hande s enol, lecturer, for her help and comments in statistical analyses. references 1. sokolova a, lee a, d smith s. the safety and efficacy of narrow band ultraviolet b treatment in dermatology: a review. am j clin dermatol. 2015;16(6):501-531. 2. seebode c, lehmann j, emmert s. photocarcinogenesis and skin cancer prevention strategies. anticancer res. 2016;36(3):13711378. 3. hofmann-wellenhof r, soyer hp, et al. ultraviolet radiation of melanocytic nevi: a dermoscopic study. arch dermatol. 1998;134(7):845-850. 4. stanganelli i, rafanelli s, bucchi l. seasonal prevalence of digital epiluminescence microscopy patterns in acquired melanocytic nevi. j am acad dermatol. 1996;34(3):460-464. 5. hofmann-wellenhof r, wolf p, smolle j, reimann-weber a, soyer hp, kerl h. influence of uvb therapy on dermoscopic features of acquired melanocytic nevi. j am acad dermatol. 1997; 37(4):559-563. 6. manganoni am, rossi mt, sala r, et al. dermoscopic, histological and immunohistochemical evaluation of cancerous features in acquired melanocytic nevi that have been repeatedly exposed to uva or uvb. exp dermatol. 2011;21(2):86-90. 7. ghani-nejad h, hallaji z, damavandi mr, et al. dermoscopic changes of melanocytic nevi after psoralen-ultraviolet a and narrow-band ultraviolet b phototherapy. indian j dermatol. 2016;61(1):118. 8. kilinc karaarslan i, teban l, dawid m, tanew a, kittler h. changes in the dermoscopic appearance of melanocytic naevi after photochemotherapy or narrowband ultraviolet b phototherapy. j eur acad dermatol venereol. 2007;21(4):526-531. observed size decrease and increase in 54% and 46% of mn that displayed size change, respectively [16]. dobrosavljevic et al evaluated dermoscopic changes in mn of patients using and not using ssc 28 days after uv exposure for a minimum of 7 days. they did not detect any significant change in mn in terms of size increase between the two groups. however, 28 days after the end of uv exposure they observed that the fading in pigmentation in a large proportion of mn belonged to the group that was not using ssc compared to other group who was using ssc (61.9% vs. 20.5%, respectively) [18]. in our study, we detected size change in the 27.5% of mn, 84.8% of which showed decrease in size. the ratios of mn that showed size decrease and structure loss were statistically significantly higher in the ssc(-) group compared to the ssc(+) group. in addition, we also found the ratios of mn that showed fading in pigmentation network and in pigmentation were also higher in the ssc(-) group, although the difference did not reach a statistically significant level. we excised one of the mn that showed size decrease, fading in pigmentation, and pigmentation network, but no other dermoscopic change, and we did not detect atypical histopathologicafindings. we thought that the above-mentioned dermoscopic findings might have emerged by induction of melanocyte apoptosis and blockage of melanin production from melanocytes by nbuvb [19,20]. according to our findings, it can be speculated that ssc application in combination with opaque tape may hinder the triggering effects of nbuvb over mn involution. hofmann–wellenhof et al detected significant darkening in brown color and total irregularity generation in uncovered mn during uvb treatment but no significant dermoscopic changes in those covered by opaque tape. however, when considering mn covered and uncovered with opaque tape together, they recognized that mn showed significantly more “total irregularity,” darker “brown color,” and increase in brown globules and pigment network width at the end of uvb treatment compared to the beginning. in all, they thought these changes may depend on the systemic effects of uv radiation on mn [5]. the emergence of dermoscopic changes in the majority of mn during our study, despite being covered with opaque type, supports the systemic effects of uv on mn. kılınç karaaslan et al established that the majority of dermoscopic changes arising after nbuvb and puva treatments were reversible [8]. lin et al observed that while enlarged mn after nbuvb treatment tended to revert to pretreatment size 3 months after the cessation of therapy, the trend for mn showing size decrease was for continued size reduction [16]. the majority of dermoscopic changes occured in our study showed a tendency to return to their former state at approximately a mean of 4.2 months after cessation of research | dermatol pract concept 2018;8(2):13 139 14. wachsmuth rc, turner f, barrett jh, et al. the effect of sun exposure in determining nevus density in uk adolescent twins. j invest dermatol. 2005;124(1):56-62. 15. harrison sl, maclennan r, buettner pg. sun exposure and the incidence of melanocytic nevi in young australian children. cancer epidemiol biomarkers prev. 2008;17(9):2318-2324. 16. lin cy, oakley a, rademaker m, hill s, yung a. effect of narrowband ultraviolet b phototherapy on melanocytic naevi. br j dermatol. 2013;168(4):815-819. 17. karaca f, öztaş m, gürer ma. effects of narrow band uvb, uva1 and puva treatments on dermoscopic features of melanocytic nevi. turkderm. 2014;48(1): 26-30. 18. dobrosavljevic d, brasanac d, apostolovic m, medenica l. changes in common melanocytic naevi after intense sun exposure: digital dermoscopic study with a 1-year follow-up. clin exp dermatol. 2009;34(6):672-678.  19. terushkin v, scope a, hofmann-wellenhof r, marghoob a. disappearance of melanocytic nevi. in: marghoob a, ed. nevogenesis. verlag berlin heidelberg: springer. 2012:145-153. 20. kittler h. evolution of nevi. in: marghoob a, ed. nevogenesis. verlag berlin heidelberg: springer. 2012:43-47. 9. akdeniz n. fototerapinin yan etkileri ve kontrendikasyonları. in: elçin g, karadag as, yılmaz e, eds. fotodermatoloji. 1st ed. istanbul: galenos yayınevi. 2015:315-333. 10. grichnik jm, rhodes ar, sober aj. benign neoplasias and hyperplasias of melanocytes. in: wolff k, goldsmith la, katz si, gilchrest ba, paller as, leffell dj, eds. fitzpatrick’s dermatology in general medicine. 7th ed. new york: mcgraw-hill. 2008:1099-1122. 11. gallagher rp, rivers jk, lee tk, bajdik cd, mclean di, coldman aj. broad-spectrum sunscreen use and the development of new nevi in white children: a randomized controlled trial. jama. 2000;283(22):2955-2960. 12. menzies sw, greenoak ge, abeywardana cm, crotty ka, o’neill me. uv light from 290 to 325 nm, but not broad-band uva or visible light augments the formation of melanocytic nevi in a guinea-pig model for human nevi. j invest dermatol. 2004;123(2):354-360. 13. dulon m, weichenthal m, blettner m, et al. sun exposure and number of nevi in 5to 6-year-old european children. j clin epidemiol. 2002;55(11):1075-1081. dermatology: practical and conceptual 262 research | dermatol pract concept 2018;8(4):3 dermatology practical & conceptual www.derm101.com the potential roles of herpesvirus and cytomegalovirus in the exacerbation of pemphigus vulgaris fariba mohammadi1, zahra khalili1, sayed mahdi marashi2, amirhoushang ehsani1, maryam daneshpazhooh1, majid teymoori-rad2, kamran balighi1, ahmad nejati2, shohreh shahmahmoodi2, shima izadidakhrabadi2, hamidreza mahmoudi1, pedarm noormohammadpour1 1 autoimmune bullous disease research center, department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 2 virology department, school of public health (sph), tehran university of medical sciences (tums), tehran, iran key words: pemphigus vulgaris, herpesvirus, cytomegalovirus citation: mohammadi f, khalili z, mahdi marashi s, ehsani a, daneshpazhooh m, teymoori-rad m, balighi k, nejati a, shahmahmoodi s, izadidakhrabadi s, mahmoudi h, noormohammadpour p. the potential roles of herpesvirus and cytomegalovirus in the exacerbation of pemphigus vulgaris. dermatol pract concept. 2018;8(4):262-271. doi: https://doi.org/10.5826/dpc.0804a03 received: march 19, 2018; accepted: july 18, 2018; published: october 31, 2018 copyright: ©2018 mohammadi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this research was supported by tehran university of medical sciences (tums), grant numbers 32855-30-03-95 and 30976101-04-94. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: pedarm noormohammadpour, md, autoimmune bullous disease research center, razi hospital, vahdate-eslami square, 11996, tehran, iran. email: normohamad@razi.tums.ac.ir background: among exogenous etiologies, the critical role of microbial agents such as herpesviruses (hsv1/2) and cytomegalovirus (cmv) in triggering and flaring autoimmune conditions such as pemphigus vulgaris (pv) has been recently discovered. objectives: the present study aimed to investigate the plausible role of these viruses in the exacerbation of pv using serological and molecular methods. patients/methods: sixty patients with pv (30 with relapse type and 30 with remission type) were recruited for the purpose of this case-control study. skin, mucosal, and throat specimens were obtained and examined for viruses by reverse transcriptase polymerase chain reaction. to determine the immunoglobulin g (igg) titer, enzyme-linked immunosorbent assay was used. results: desmoglein1-specific igg was positive in  56.7% of patients with the relapse form and in  20.0% of those with the remission form indicating a significant difference across the  2  groups (p = 0.003), but the rate of positivity for desmoglein3-specific igg in the relapse and remission types was  76.7% and  63.3%, respectively, with no significant difference (p = 0.260). there was no difference in the mean levels of hsv-igg and cmv-igg in the relapse and remission groups. hsv and abstract research | dermatol pract concept 2018;8(4):3 263 atypical hsv infections have been described in immunosuppressed patients [16]. several studies have suggested the activation or exacerbation of pemphigus after hsv or cmv infections [17]. more recently, japanese researchers have detected high levels of hsv in the saliva samples of pv patients [18]. in this regard, several studies have shown the benefits of adding antiviral therapies to an immunosuppressive therapy in recalcitrant disease [19,20]. several studies also failed to detect herpesviruses in pemphigus patient specimens [21,22], suggesting that viruses may have only a transient role for exacerbation of pemphigus disease, although yet to be further defined. the number of patients with pv in iran appears to be increasing, and little information is available with regard to the role of hsv1/2 and cmv in triggering pv among the iranian population. the present study aimed to investigate the plausible role of these viruses (hsv1/2 and cmv) in the exacerbation of pv using serological and molecular methods. materials and methods disease definitions in pv patients pv patients were categorized as follows: relapse (development of more than 3 new lesions/month that do not heal within a week without treatment, or development of established lesions in a patient whose disease was controlled) and complete remission (absence of new or established lesions in a patient whose all-systemic therapy is discontinued for ≥2 months, or while the patient is receiving minimal therapy) [23]. scoring of disease was recorded based on the pemphigus disease area index. study population sixty patients with pv (27 male, 33 female; mean age 46.3 ± 12.7 years) were recruited for the purpose of this case-control study. patients were selected among inpatients and outpatients who were referred to the pemphigus clinic of razi hospital (tehran, iran). the diagnosis of pemphigus had been confirmed by histology and direct immunofluorescence. among patient subjects, 30 were in complete remission as in the control group, whereas the rest (n = 30) were in relapse as in the case group. none of the patients had overt labial herpetic lesions at the time of sampling. all study participants introduction pemphigus disease is an autoimmune disease that is characterized by secretion of autoantibodies that act against surface glycoproteins of epithelial cells [1]. the immunological basis for pemphigus disease includes autoantibodies targeted against keratinocyte surface antigens desmoglein1 and desmoglein3 (dsg1, dsg3) [2]. these proteins are primarily involved in intercellular cell-to-cell adhesion structures. pemphigus vulgaris (pv) is a common type of pemphigus disease with painful blistering on the skin and mucous membranes [3]. overall, the close link between autoimmune diseases and both endogenous (genetic) and exogenous (environmental) factors has been clearly understood. exogenous factors include thiol drugs, physical trauma such as burn, ultraviolet exposure, x-ray, neoplasm, hormones and pregnancy, nutritional factors, and emotional stress [4-7]. among exogenous etiologies, the critical role of microbial agents such as viruses in triggering and flaring autoimmune conditions has been recently discovered. in this regard, the causative role of herpesviruses (hsvs) as the most important human pathogens in the pathogenesis of pv has been recently suggested [8]. thus, efforts have been made to clarify viral etiologies for pv and in this way the role of hsvs and cytomegalovirus (cmv) is taken into consideration [9,10]. the main common features of both pointed viruses include their ability to survive in the host body for a long time as well as activating periodically [11]. the human hsvs including herpesviruses 1 and 2 (hsv1/2) and cmv infect between 60% and 90% of the adult population worldwide [12,13]. after primary infection, the virus establishes lifelong latency, with periodic reactivations that are effectively controlled by a robust immune response in most infected individuals despite the virus-producing proteins that interfere with adaptive and innate immunity. the activation of t cells is the important aspect of adaptive immunity. tissue-resident memory (trm) t cells are a subtype of memory lymphocytes that enter nonlymphoid tissues such as skin and become permanently established without recirculating. local immune control of viruses can be mediated by trm t cells through direct killing of infected cells and recruiting circulating memory cd8+ to the skin. also, trm t cells maintain hsv1 latency by secreting granzyme b, which degrades the early protein icp4 that is important in viral replication [14,15]. cmv positivity in pv patients was independent of the site of the samples. using the multivariable linear regression model, the level of cmv-igg in pv patients was directly affected by female sex and advanced ages. conclusions: our study could not demonstrate the role of hsv1/2  and cmv as triggering factors for pv exacerbation. further studies are needed to evaluate the potential role of these viruses in pv exacerbation especially considering demographic variables. abstract 264 research | dermatol pract concept 2018;8(4):3 statistical analysis the results were presented as mean ± standard deviation for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. normality of data was analyzed using the kolmogorov-smirnoff test. categorical variables were compared using chi-squared test or fisher’s exact test when more than 20% of cells with an expected count of less than 5 were observed. quantitative variables were also compared with t test or mann-whitney u test. the association between quantitative variables was assessed using the pearson correlation test. to determine the main correlates of igg antibodies against viruses, multivariable linear regression analysis was used. for the statistical analysis, the statistical software spss version 16.0 for windows (spss inc., chicago, il) was used. p values of 0.05 or less were considered statistically significant. we used graphpad prism software (graphpad software, la jolla, ca) for plotting graphs. results in total, 30 patients with the relapse type of pv and 30 patients with the remission type were assessed. the demographic and clinical features of patients are presented in table 1. comparison of the baseline characteristics of the 2 groups (table 2) showed no difference in gender, mean age, subtypes of disease (mucous or mucocutaneous), or disease duration and oral medications. regarding medical history, hypertension and hyperlipidemia were more prevalent in those with relapse pv than in the remission group, while no difference was revealed in other underlying comorbidities including diabetes mellitus, history of smoking, coronary artery disease, or thyroid abnormalities. with regard to dsg-specific igg positivity in the relapse and remission forms of pv, dsg1-specific igg was positive in 56.7% of patients with the relapse form and in 20.0% of those with the remission form, indicating a significant difference across the 2 groups (p = 0.003), but the rate of positivity for dsg3-specific igg in the relapse and remission types was 76.7% and 63.3%, respectively, with no significant difference (p = 0.260). the mean hsv-igg in the relapse and remission groups was 154.47 ± 66.80 and 151.17 ± 62.73, respectively, with no significant difference (p = 0.844). moreover, the mean cmv-igg in the subgroups was 130.30 ± 47.88 and 127.93 ± 53.56, respectively, with no meaningful difference (p = 0.857). there was no correlation between prednisolone dose and hsv-igg (p = 0.373) or cmv-igg (p = 0.647). as shown in table 3, hsv and cmv positivity in pv patients was independent of the source of the samples. gave informed consent to provide samples for the study, which was approved by the local research ethics committee of tehran university of medical sciences (approval number: ir.tums.medicine.rec.1395.1017 and ir.tums. medicine.rec.1395.2472). sample preparation for viral detection and determination of specific antibodies, we used blood, skin biopsy, and throat swab samples from patients. after patient consent forms were obtained, one skin specimen or mucosal specimens were obtained by punch biopsy (3 mm) and blood samples were taken from all patients. in addition, a sample from the throat was collected by swabbing. all samples were transferred in cold chain conditions to the virology laboratory. as soon as samples were received, preparation and storage were carried out. sera (for serology) and buffy coat (for virus detection) were isolated from whole blood and stored at −20°c. dna extraction from buffy coat, skin biopsy, and throat swab were performed using dna isolation kit for cells and tissues according to the manufacturers’ instructions (roche, berlin, germany). after dna extraction, it was eluted in 50 µl of buffer and then adjusted to a definitive concentration of 500 ng/µl. virus-specific antibody responses hsv1/2and cmv-immunoglobulin g (igg) antibodies were determined using enzyme-linked immunosorbent assay (elisa). quantification of igg antibodies was determined by standard curve as ru/ml according to the manufacturer (values greater than 22 ru/ml were defined as seropositive). dsg-specific igg the levels of autoantibody to dsg1 and dsg3 were measured by elisa. the cutoff values were 20 u/ml for both. determination of viral load the absolute quantification of hsv1/2 and cmv-specific dna was performed by real-time polymerase chain reaction (pcr) using the realstar hsv pcr kit 1.0 and realstar cmv pcr kit 1.0, respectively (altona diagnostics; hamburg, germany). all stages of the amplification of the viruses’ specific target sequences for the detection and quantification of the amplified dna were carried out according to the manufacturer’s instructions. ten microliters of the dna extracted from samples in distilled water, and the 4 controls were included in each experiment as a template and a negative control and quantification standards, respectively. moreover, we performed internal control to identify possible pcr’s inhibitor and to confirm the reliability of all reagents of the kit used for each sample. finally, the concentration of the samples was calculated in copies per microliter and copies per milliliter. research | dermatol pract concept 2018;8(4):3 265 table 1. demographic and clinical characteristics of pemphigus vulgaris patients id sex age (years) type duration (years) activation pdn dose (mg/d) drug history dsg1 dsg3 pdai p1 f 72 mcpv 2 relapse 15 azathioprine positive positive 94 p2 f 41 mpv 2.5 remission 5 azathioprine negative positive 0 p3 f 47 mcpv 4 remission 5 mycophenolic acid, azathioprine negative positive 0 p4 f 48 mcpv 1.5 remission 5 mycophenolic acid negative positive 0 p5 f 31 mcpv 2 remission 5 azathioprine, rituximab positive positive 0 p6 f 28 mcpv 5 relapse 10 mycophenolic acid, azathioprine positive positive 12 p7 m 61 mcpv 4 remission 5 azathioprine, mycophenolic acid, rituximab, mtx negative positive 0 p8 m 67 mcpv 10 relapse 30 cyclophosphamide, mycophenolic acid, rituximab negative positive 34 p9 f 63 mcpv 3.5 remission 0 mycophenolic acid monotherapy negative negative 0 p10 m 41 mcpv 3 remission 0 mycophenolic acid positive negative 0 p11 m 60 mcpv 2.5 remission 5 azathioprine negative negative 0 p12 m 45 mcpv 7 remission 5 mycophenolic acid, azathioprine negative negative 0 p13 m 32 mcpv 10 remission 7.5 azathioprine negative positive 0 p14 m 41 mcpv 1.5 remission 5 azathioprine, rituximab negative negative 0 p15 m 38 mcpv 4 remission 10 azathioprine, mycophenolic acid, rituximab positive negative 0 p16 m 55 mpv 2 remission 7.5 azathioprine negative positive 0 p17 m 65 mcpv 2 relapse 5 azathioprine negative positive 14 p18 f 45 mcpv 2 relapse 10 azathioprine positive positive 12 p19 f 58 mcpv 2 remission 7.5 azathioprine negative positive 0 p20 m 39 mpv 2 remission 1.25 azathioprine negative negative 0 p21 f 45 mpv 2 relapse 7.5 mycophenolic acid negative positive 5 p22 m 21 mcpv 1 relapse 15 azathioprine positive positive 34 p23 f 65 mcpv 12 remission 5 none negative positive 0 p24 f 45 mcpv 10 remission 5 azathioprine negative positive 0 p25 f 33 mcpv 5 relapse 0 azathioprine 15 p26 m 44 mpv 19 remission 7.5 mycophenolic acid, azathioprine negative positive 0 p27 f 54 mcpv 2.5 remission 5 mycophenolic acid, rituximab positive positive 0 p28 f 62 mcpv 3 remission 2.5 azathioprine negative negative 0 p29 f 55 mcpv 1.5 remission 2.5 mycophenolic acid, mtx negative negative 0 p30 m 38 mcpv 1.5 remission 7.5 rituximab positive positive 0 p31 f 67 mcpv 11 remission 5 azathioprine, mycophenolic acid, rituximab, mtx negative positive 0 p32 f 46 mcpv 0.5 remission 7.5 rituximab negative negative 0 (continued next page) 266 research | dermatol pract concept 2018;8(4):3 id sex age (years) type duration (years) activation pdn dose (mg/d) drug history dsg1 dsg3 pdai p33 f 40 mcpv 12 remission 10 azathioprine negative positive 0 p34 m 40 mcpv 3 relapse 25 azathioprine, rituximab negative positive 5 p35 m 55 mcpv 6 remission 7.5 azathioprine negative negative 0 p36 m 35 mcpv 14 remission 7.5 mycophenolic acid, azathioprine, mtx, rituximab, ivig negative positive 0 p37 m 65 mcpv 5 relapse 0 mycophenolic acid, azathioprine positive negative 23 p38 f 74 mcpv 2 relapse 7.5 azathioprine positive positive 24 p39 f 32 mcpv 2 relapse 10 rituximab negative positive 14 p40 f 39 mcpv 8 relapse 2.5 mycophenolic acid, rituximab positive positive 3 p41 f 36 mcpv 5 relapse 5 mycophenolic acid, azathioprine positive positive 34 p42 f 54 mcpv 2 relapse 5 mycophenolic acid, azathioprine, mtx positive positive 12 p43 f 54 mcpv 6 relapse 25 rituximab, mycophenolic acid negative positive 11 p44 m 20 mcpv 1 relapse 15 rituximab negative negative 5 p45 f 42 mpv 1 remission 2.5 rituximab negative positive 0 p46 m 38 mpv 3 relapse 15 none negative positive 27 p47 f 46 mcpv 15 relapse 20 mycophenolic acid, azathioprine, mtx, rituximab, ivig, cyclophosphamide positive positive 0 p48 m 27 mcpv 1.5 relapse 30 mycophenolic acid, azathioprine positive positive 0 p49 m 42 mcpv 0.5 relapse 35 none negative negative 17 p50 f 34 mpv 1 relapse 10 mycophenolic acid, azathioprine, mtx, rituximab, ivig, cyclophosphamide 10 p51 f 34 mcpv 1 relapse 6.25 rituximab positive negative 38 p52 f 37 mcpv 2 relapse 25 azathioprine, rituximab positive positive 19 p53 m 57 mcpv 3 relapse 15 azathioprine positive positive 84 p54 m 54 mcpv 5.5 relapse 2.5 azathioprine, mycophenolic acid, rituximab, mtx positive negative 12 p55 f 54 mcpv 2 relapse 12.5 rituximab negative positive 8 p56 f 48 mcpv 1 relapse 10 azathioprine positive positive 23 p57 f 60 mcpv 10 remission 10 azathioprine negative positive 0 p58 m 29 mcpv 3 relapse 5 mycophenolic acid, rituximab positive positive 14 p59 m 45 mcpv 1 relapse 15 azathioprine positive positive 21 p60 f 39 mcpv 1.5 relapse 35 mycophenolic acid, azathioprine negative positive 15 abbreviations: mtx, methotrexate; dsg, desmoglein; mcpv, mucocutaneous pv; mpv, mucous pv; pdn dose, oral prednisolone dose at the time of the study; pdai, pemphigus disease area index table 1. demographic and clinical characteristics of pemphigus vulgaris patients (continued) research | dermatol pract concept 2018;8(4):3 267 46.60 vs 112.00 ± 50.86, p = 0.020). also, a direct correlation was revealed between patients’ age and the level of cmv-igg (r coefficient = 0.404, p = 0.001). discussion several studies have investigated the relationship between viral infections and the initiation or exacerbation of autoimmune as indicated in table 4 and figure 1 and using the multivariable linear regression model, the level of hsv-igg was not associated with the baseline characteristics including demographics, underlying comorbidities, disease duration, and form of pv. however, as shown in table 5 and figure 2, the level of cmv-igg in pv patients was affected by the gender and age factors. the mean cmv-igg was significantly higher in female than in male patients suffering from pv (142.21 ± table 2. comparing baseline characteristics between the patients with relapse and those in remission relapse type (n = 30) remission type (n = 30) p value male 12 (40.0) 14 (46.7) 0.602 mean age, years (±sd) 44.90 ± 14.30 47.83 ± 11.04 0.377 disease duration, years (±sd) 3.42 ± 3.14 5.23 ± 4.75 0.086 medical history history of hypertension 9 (30.0) 2 (6.7) 0.020 history of hyperlipidemia 5 (16.7) 0 (0.0) 0.050 history of diabetes mellitus 5 (16.7) 2 (6.7) 0.424 history of smoking 1 (3.3) 1 (3.3) 1.000 history of coronary disease 2 (6.7) 1 (3.3) 0.998 history of avn 2 (6.7) 0 (0.0) 0.492 history of hypothyroidism 2 (6.7) 0 (0.0) 0.492 form of disease 0.706 mucous 3 (10.0) 5 (16.7) mucocutaneous 27 (90.0) 25 (83.3) medication azathioprine 19 (63.3) 20 (66.7) 0.787 mycophenolic acid 13 (43.3) 13 (43.3) 1.000 rituximab 12 (40.0) 10 (33.3) 0.592 methotrexate 4 (13.3) 4 (13.3) 1.000 ivig 2 (6.7) 1 (3.3) 0.999 cyclophosphamide 3 (10.0) 0 (0.0) 0.237 unless noted otherwise, values represent number (percent). table 3. comparison of hsv and cmv detection based on reverse transcriptase polymerase chain reaction techniques according to the source of samples between the patients with relapse and those in remission relapse type (n = 30) remission type (n = 30) p value hsv skin 1 (3.3) 0 (0.0) 0.998 pbmc 1 (3.3) 2 (6.7) 0.898 throat 0 (0.0) 0 (0.0) 1.000 cmv skin 3 (10.0) 0 (0.0) 0.237 pbmc 5 (16.7) 0 (0.0) 0.052 throat 3 (10.0) 0 (0.0) 0.237 values represent number (percent). abbreviation: pbmc, peripheral blood mononuclear cell. 268 research | dermatol pract concept 2018;8(4):3 table 4. multivariable linear regression model to assess the main correlates of hsv-igg antibody in patients with pemphigus vulgaris unstandardized coefficients standardized coefficients t p value (constant) b std. error beta sex −35.727 164.984 −0.217 0.829 age −3.982 18.674 −0.031 −0.213 0.832 type 0.492 0.809 0.098 0.608 0.546 duration −10.558 26.124 −0.056 −0.404 0.688 form 0.825 2.345 0.053 0.352 0.726 hypertension −15.421 19.720 −0.121 −0.782 0.438 hyperlipidemia 0.185 34.852 0.001 0.005 0.996 diabetes 58.505 46.066 0.254 1.270 0.210 coronary disease −14.900 33.394 −0.075 −0.446 0.657 smoking −2.827 45.347 −0.010 −0.062 0.951 (constant) 67.297 54.454 0.190 1.236 0.222 figure 1. level of hsv-igg antibody (cut-off value: 22 ru/ml) according to baseline variables. research | dermatol pract concept 2018;8(4):3 269 table 5. multivariable linear regression model to assess the main correlates of cmv-igg antibody in patients with pemphigus vulgaris unstandardized coefficients standardized coefficients t p value (constant) b std. error beta sex −62.825 114.201 −0.550 0.585 age 28.334 12.926 0.281 2.192 0.033 type 1.196 0.560 0.303 2.135 0.038 duration 24.026 18.083 0.163 1.329 0.190 form −0.515 1.623 −0.042 −0.317 0.752 hypertension −2.244 13.650 −0.022 −0.164 0.870 hyperlipidemia −14.238 24.124 −0.110 −0.590 0.558 diabetes 12.675 31.886 0.070 0.397 0.693 coronary dis. 35.510 23.115 0.228 1.536 0.131 smoking −46.372 31.389 −0.202 −1.477 0.146 (constant) 39.650 37.693 0.142 1.052 0.298 figure 2. level of cmv-igg antibody (cut-off value: 22 ru/ml) according to baseline variables. 270 research | dermatol pract concept 2018;8(4):3 mati-roodsari et al, similar to our study, only 1 patient had a positive hsv pcr result for skin samples [32,33]. these values are less than the findings of the study by tufano et al, reporting positive hsv pcr in 5 of 7 skin specimens [29]. other pcr results show evidence of hsv1 infection in 10% of all blood samples and cmv infection in 16.6% of all blood samples, 10% of all skin samples, and 10% of all throat samples. on the other hand, several studies failed to detect herpes dna viruses in pemphigus patient specimens [26,27]. senger et al showed the role of hsv1 in exacerbation of pemphigus by using the elisa technique [31]. however, we found no correlation between hsv and cmv pcr results or igg antibody levels and disease activity (relapse or remission). these findings cannot rule out the role of these viruses in exacerbation of the disease; improvement in some patients, especially those with the mucosal form, after receiving antiviral therapy as well as exacerbation of pemphigus after hsv infection are clinical evidence of the possible role of viruses in disease exacerbation [22]. therefore, the role of viruses in exacerbation of pemphigus remains a hypothesis and requires further study. our study is unique for several reasons. first, we used both elisa and pcr techniques to find evidence of viruses, whereas most previous studies used only one technique. second, the samples were sourced from several sites including skin, throat, and blood. third, we evaluated virus status in relapse and remission pv patients to determine the role of viruses in the exacerbation of the disease, whereas most previous studies examined the status of viruses in newly diagnosed patients and healthy controls to determine the etiological role of viruses. however, this study had some limitations. we could not evaluate other types of pemphigus disease due to their lower prevalence. because of high costs of the techniques, we were able to investigate only the role of hsv1/2 and cmv in the exacerbation of disease. conclusions in conclusion, our study could not demonstrate the role of hsv1/2 and cmv as triggering factors for pv exacerbation. further studies are needed to evaluate the potential role of these viruses in pv exacerbation. references 1. kasperkiewicz m, ellebrecht ct, takahashi h, et al. pemphigus. nat rev dis primers. 2017;3:17026. 2. spindler v, waschke j. pemphigus: a disease of desmosome dysfunction caused by multiple mechanisms. front immunol. 2018;9:136. 3. kridin k. pemphigus group: overview, epidemiology, mortality, and comorbidities. immunol res. 2018;66(2):255-270. 4. tur e, brenner s. contributing exogenous factors in pemphigus. int j dermatol. 1997;36(12):888-893. diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and diabetes mellitus [24]. in this regard, efforts have been made to detect viral pathogens in blood samples and skin specimens of patients with pemphigus by techniques such as immunochemistry and pcr for dna particles. the association between onset or reactivation of pemphigus disease and viral infections may be causal, or as a result of drug-induced immunosuppression which can increase the likelihood of viral infections, or established on the pathogenic connection between viral infection and immune dysregulation leading to autoimmunity. the mechanism of viral induction of autoimmunity can be explained in several ways, including molecular mimicry (due to cross-reactions between pathogen-derived epitopes and self-derived epitopes); bystander activation (due to activation of preexisting autoreactive t cells as a result of the inflammatory environment); epitope spreading (when antigen-presenting cells recognize self-antigens which were not initially directed by the immune system); polyclonal activation (due to infection of b cells by lymphocytotropic viruses which lead to b cell proliferation and increased antibody production); and viral superantigens (encoded by some viruses, are able to activate polyclonal t cells) [25]. molecular mimicry is possibly the most acceptable explanation for the association of viral infections and pemphigus. further explanation is that viruses upregulate production of interferon and interleukins. high levels of interferon gamma lead to increased expression of hla2 on keratinocytes, making the pemphigus antigen structural site active. also, overproduction of il4 and il10 causes a shift of th1 to th2 response which potentiates antibody response [26,27]. the role of viruses in the pathogenesis of pemphigus has been assessed in some previous studies. ‘the importance of viral infections as an exacerbating factor of pv is neglected by some clinicians. concerning this, in our current case-control study, we evaluated the probable role of hsv1/2 and cmv in the exacerbation of pv. in our study, a significantly higher number of pv patients (regardless of disease activity) were positive for hsvand cmv-igg antibodies, similar to the studies by tufano et al and sagi et al [28,29]. this may show a history of hsv and cmv exposure in most patients and may indicate more frequent recrudescence of latent viruses [30]. a significant increase in igg antibody levels, discovered by comparing relapse and remission samples, indicates an active infection. according to a general consensus, relatively higher igg levels are associated with a higher probability of having an active viral infection and relatively lower igg levels represent a previous viral infection rather than an active viral infection. in this regard, senger et al showed higher levels of hsv1 antibody in patients in the active phase of disease than in remission patients [31]. in contrast to our study, there was no significant difference in antibody levels between relapse and remission patients. in the studies of marzano et al and rahresearch | dermatol pract concept 2018;8(4):3 271 20. oliveira-batista dp, janini me, fernandes nc, santos n. laboratory diagnosis of herpesvirus infections in patients with pemphigus vulgaris lesions. intervirology. 2013;56(4):231-236. 21. cohen ss, blauvelt a, weinstein md, herndier bg, anhalt gj. no evidence of human herpesvirus 8 infection in patients with paraneoplastic pemphigus, pemphigus vulgaris, or pemphigus foliaceus. j invest dermatol. 1998;111(5):781-783. 22. esmaili n, hallaji z, abedini r, soori t, mortazavi h, chamsdavatchi c. pemphigus vulgaris and herpesviruses: is there any relationship? int j dermatol. 2010;49(11):1261-1265. 23. murrell df, dick s, ahmed ar, et al. consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. j am acad dermatol. 2008;58(6):1043-1046. 24. ercolini am, miller sd. the role of infections in autoimmune disease. clin exp immunol. 2009;155(1):1-15. 25. lossius a, johansen jn, torkildsen ø, vartdal f, holmoy t. epstein-barr virus in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis: association and causation. viruses. 2012;4(12):3701-3730. 26. ruocco e, ruocco v, lo schiavo a, brunetti g, wolf r. viruses and pemphigus: an intriguing never-ending story. dermatology. 2014;229(4):310-315. 27. vercelli d, jabara hh, lauener rp, geha rs. il-4 inhibits the synthesis of ifn-gamma and induces the synthesis of ige in human mixed lymphocyte cultures. j immunol. 1990;144(2):570-573. 28. sagi l, baum s, agmon-levin n, et al. autoimmune bullous diseases: the spectrum of infectious agent antibodies and review of the literature. autoimmun rev. 2011;10(9):527-535. 29. tufano ma, baroni a, buommino e, ruocco e, lombardi ml, ruocco v. detection of herpesvirus dna in peripheral blood mononuclear cells and skin lesions of patients with pemphigus by polymerase chain reaction. br j dermatol. 1999;141(6):10331039. 30. hashido m, kawana t. herpes simplex virus-specific igm, iga and igg subclass antibody responses in primary and nonprimary genital herpes patients. microbiol immunol. 1997;41(5):415-420. 31. senger p, abidi n, lin dm, seiffert-sinha k, sinha aa. positive correlation of anti-herpes simplex type i virus antibody levels with pemphigus vulgaris disease status and activity in a large patient cohort. eur j dermatol. 2017;27(2):132-138. 32. marzano av, tourlaki a, merlo v, spinelli d, venegoni l, crosti c. herpes simplex virus infection and pemphigus. int j immunopathol pharmacol. 2009;22(3):781-786. 33. rahmati-roodsari m, rahmdar sr, alfaragi m, saeedi m, rahmati roodsari s, sajadi nia rs. association of hsv1/2 infection and pemphigus disease. arch pediatr infect dis. 2014;2(2):207210. 5. paolino g, didona d, magliulo g, et al. paraneoplastic pemphigus: insight into the autoimmune pathogenesis, clinical features and therapy. int j mol sci. 2017;18(12):e2532. 6. ruocco e, wolf r, ruocco v, brunetti g, romano f, lo schiavo a. pemphigus: associations and management guidelines: facts and controversies. clin dermatol. 2013;31(4):382-390. 7. tavakolpour s. pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. arch dermatol res. 2018;310(2):95-106. 8. ruocco e, ruocco v, lo schiavo a, brunetti g, wolf r. viruses and pemphigus: an intriguing never-ending story. dermatology. 2014;229(4):310-315.  9. brandão ml, fernandes nc, batista dp, santos n. refractory pemphigus vulgaris associated with herpes infection: case report and review. rev inst med trop sao paulo. 2011;53(2):113-117. 10. oliveira-batista dp, janini me, fernandes nc, santos n. laboratory diagnosis of herpesvirus infections in patients with pemphigus vulgaris lesions. intervirology. 2013;56(4):231-236. 11. marzano av, tourlaki a, merlo v, spinelli d, venegoni l, crosti c. herpes simplex virus infection and pemphigus. int j immunopathol pharmacol. 2009;22(3):781-786. 12. looker kj, magaret as, turner km, vickerman p, gottlieb sl, newman lm. global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. plos one. 2015;10(1):e114989. 13. swanson ec, schleiss mr. congenital cytomegalovirus infection: new prospects for prevention and therapy. pediatr clin north am. 2013;60(2):335-349. 14. schenkel jm, masopust d. tissue-resident memory t cells. immunity. 2014;41(6):886-897. 15. ariotti s, hogenbirk ma, dijkgraaf fe, et al. t cell memory. skin-resident memory cd8(+) t cells trigger a state of tissue-wide pathogen alert. science. 2014;346(6205):101-105. 16. desai dv, kulkarni ss. herpes simplex virus: the interplay between hsv, host, and hiv-1. viral immunol. 2015;28(10):546-555. 17. brandão ml, fernandes nc, batista dp, santos n. refractory pemphigus vulgaris associated with herpes infection: case report and review. rev inst med trop sao paulo. 2011;53(2):113-117. 18. takahashi i, kobayashi tk, suzuki h, nakamura s, tezuka f. coexistence of pemphigus vulgaris and herpes simplex virus infection in oral mucosa diagnosed by cytology, immunohistochemistry, and polymerase chain reaction. diagn cytopathol. 1998;19(6):446-450. 19. machado ardsr, la serra l, turatti a, machado am, roselino am. herpes simplex virus 1 and cytomegalovirus are associated with pemphigus vulgaris but not with pemphigus foliaceus disease. exp dermatol. 2017;26(10):966-968. dermatology: practical and conceptual letter to the editor | dermatol pract concept 2014;4(4):20 89 dermatology practical & conceptual www.derm101.com dear editor, we would like to discuss on the report on “zosteriform cutaneous leishmaniasis” [1] ramot et al. reported that “dermoscopy has proven to be an accessible and easy tool to diagnose such atypical presentation of cutaneous leishmaniasis, and dermatologists in endemic areas should be familiar with its typical dermoscopic features” [1]. in fact, cutaneous leishmaniasis is an important tropical dermatological infection. to diagnose it, the practitioner has to perform laboratory investigation to confirm the diagnosis [2]. the use of “in vivo confocal microscopy” is presently mentioned as a new noninvasive tool to diagnose cutaneous leishmaniasis [3,4]. as noted by taheri et al., the appearance by dermoscopy of cutaneous leishmaniasis is varied [4]. the “paronychial, annular, palmoplantar, zosteriform, erysipeloid, and sporotrichoid” appearance of cutaneous leishmaniasis is not common and can be easily missed. the limitation in diagnosis seems not due to limitation of the dermoscopy toll but the awareness of the practitioner on the disease, cutaneous leishmaniasis [5]. in endemic areas of cutaneous leishmaniasis, use of dermoscopy in the investigation of any cases of zosteriform cutaneous lesions to rule out cutaneous leishmaniasis is suggested. references 1. ramot y, nanova k, alper-pinus r, zlotogorski a. zosteriform cutaneous leishmaniasis diagnosed with the help of dermoscopy. dermatol pract concept. 2014;4(3):10. 2. wiwanitkit v. interest in paromomycin for the treatment of visceral leishmaniasis (kala-azar). ther clin risk manag. 2012;8:323-8. 3. alarcon i, carrera c, puig s, malvehy j. in vivo confocal microscopy features of cutaneous leishmaniasis. dermatology. 2014;228(2):121-4. 4. taheri ar, pishgooei n, maleki m, et al. dermoscopic features of cutaneous leishmaniasis. int j dermatol. 2013;52(11):1361-6. 5. omidian m, mapar ma. chronic zosteriform cutaneous leishmaniasis. indian j dermatol venereol leprol. 2006;72(1):41-2. zosteriform cutaneous leishmaniasis sim sai tin1, viroj wiwanitkit2 1 medical center, shantou, china 2 hainan medical university, china citation: tin ss, wiwanitkit v. zosteriform cutaneous leishmaniasis. dermatol pract concept. 2014;4(4):20. http://dx.doi.org/10.5826/ dpc.0404a20 received: june 9, 2014; accepted: september 8, 2014; published: october 31, 2014 corresponding author: sim sai tin, medical center, shantou, china. email: simsaitin@gmail.com dermatology: practical and conceptual book review | dermatol pract concept 2015;5(2):19 97 dermatology practical & conceptual www.derm101.com review by christian lefebvre this is an extremely practical book offered to all clinicians interested in dermatologic surgery. dr. hayes proposes an allinclusive package covering every aspect of an office practice of dermatologic surgery, froflm the design of the operating room and its lighting to technical aspects of surgical intervention, be it a simple biopsy or the most complicated operation. the reader is instructed by texts, figures and tables depicting details of the interventions. perhaps the only addition that might be desirable would be a series of videos showing the main or the most complicated interventions. this could conceivably be added to the electronic version of the book, which is the version i used for this review. the style of writing is such that a reader soon feels as if he were in a discussion with the author himself, as if being guided by him—as if looking over his shoulder! residents completing their formation in dermatology and wishing to practice surgery will find this book most useful. for the practicing dermatologist and dermatologic surgeon, it will deepen surgical knowledge by offering an easily consulted and very complete database. in my personal case, as a general dermatologist, the reading of this book was a powerful incentive and a good tool to improve my technical skills. everywhere in the book, one feels that dr. hayes masters the subject completely. it is evident that he has extensive experience and that he wants and knows how to share it. here in canada, and particularly in the province of quebec where i have my practice, dermatologists do mostly basic and simple interventions, relying largely on specialized colleagues, plastic surgeons and/or “mohs’ surgeons.” apparently the education of dermatologists in australia includes a larger part of surgery. my question may appear naïve but: review of hayes’ practical skin cancer surgery christian lefebvre1, françois milette2 1 dermatology, montreal, canada 2 centre hospitalier pierre-boucher, longueuil, canada citation: lefebvre c, milette f. review of hayes’ practical skin cancer surgery. dermatol pract concept 2015;5(2):19. doi: 10.5826/ dpc.0502a19 copyright: ©2015 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: christian lefebvre, md, dermatology, montreal qc, canada. email: christian.lefebvre7@sympatico.ca figure 1. hayes m. practical skin cancer surgery. churchill livingstone: london, 2014. isbn 9780729539326. 304 pages. do all dermatologists feel capable and self-confident enough to practice all the interventions described by dr. hayes in his book? last, i agree completely with dr. hayes when he insists on doing a biopsy before any possibly mutilating surgery. a surprising biopsy result is indeed always possible and a precise diagnosis remains the cornerstone on which to decide the most adequate intervention. in summary, i heartily recommend this book to any practitioner interested in dermatological surgery. the subject is ever more important as our ageing population of patients is at more risk every day of developing skin tumors for which treatment is possible and efficient. even if one does not practice surgery, it is apropos, in order to inform and reassure a patient, to have a precise idea of the situation to which a patient referred to a surgeon will be exposed. christian lefebvre dermatologist montreal, canada 98 book review | dermatol pract concept 2015;5(2):19 1. kim ys, choi dy, gil yc, et al. the anatomical origin and course of the angular artery regarding its clinical implications. dermatol surg 2014 40(10):1070-6. note from françois milette, md, book review editor the book review is the complement to dr. hayes’ opus reviewed in the preceding issue covering diagnosis and nonsurgical treatment of skin cancer. in this second book, the surgical approach to skin cancer therapy is covered exhaustively. as a dermatopathologist, i did not feel competent to review this book and am very glad to once again welcome dr. lefebvre’s collaboration. response from dr. mileham hayes i am glad for dr. lefebvre’s review and that my book seems to have achieved my objectives, which were not only to provide clear and logical steps, but to identify, “sign-post,” and solve those circumstances where the surgeon is not sure how to proceed. i have subsequently found two omissions from my work. firstly, i would recommend excising deeper in the glabella area as, for some reasons, bccs are deeper there in my experience; and secondly, re-excision is mandatory if there is not deep clearance—but observation may suffice if there is lateral involvement. finally, i also found it gratifying that my practical suspicion that “the lateral nasal branch of the facial artery (aka, angular) seems to wind around the base of the lateral ala” (p 208) has now been confirmed. [1] dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(1):10 37 case presentation an 81-year-old japanese woman presented with a pigmented skin lesion on the left heel (figure 1). it had been noticed for at least one to two years. she had no specific symptoms. she had a habit of rubbing her soles with pumice. physical examination revealed a dark brown-to-black hyperkeratotic plaque of 10 mm with a sharply demarcated, symmetrical border. dermoscopic examination demonstrated a scaly surface and regular brown-to-black dots/globules (figure 2). at first the diagnosis of a pigmented wart was made an incisional biopsy was performed. histopathologically the lesion was characterized by nests of melanocytes with considerable nuclear atypia and mitoses. we thus established a diagnosis of melanoma. a detailed inspection of the remaining lesion revealed surrounding pigmented macules with different shades of brown-to-black and diffuse irregular hypopigmentation (figure 1b). the pigmented macules showed the parallel ridge pattern on dermoscopy (figure 2b). we performed a re-excision with a 5 mm margin from all the surrounding pigmented macules. conventional histopathologic staining with hematoxylin and eosin of the central lesion revealed marked hyperkeratosis and proliferating nests composed of atypical melanocytes acral melanoma with hyperkeratosis mimicking a pigmented wart misaki ise, m.d.1, fumiyo yasuda, m.d.1, izumi konohana, m.d.1, keiko miura, m.d.2, masaru tanaka, ph.d.3 1 division of dermatology, hiratsuka city hospital, kanagawa, japan 2 division of diagnostic pathology, faculty of medicine, tokyo medical and dental university hospital, tokyo, japan 3 department of dermatology, tokyo woman’s medical university medical center east, tokyo, japan key words: acral, melanoma, hyperkeratosis, wart citation: ise m, yasuda f, konohana i, miura k, tanaka m. acral melanoma with hyperkeratosis mimicking a pigmented wart. dermatol pract conc. 2013;3(1):10. http://dx.doi.org/10.5826/dpc.0301a10. received: june 6, 2012; accepted: november 8, 2012; published: january 31, 2013 copyright: ©2013 ise et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: misaki ise, m.d., division of dermatology, hiratsuka city hospital, kanagawa, japan. tel. 0463320015; fax. 0463312847. e-mail. misakiku1005@yahoo.co.jp. acral lentiginous melanoma (alm) of the sole sometimes has a hyperkeratotic appearance and mimics a pigmented wart. we report a case of an 81-year-old woman with an alm on the left sole with hyperkeratosis. due to its presentation it was difficult to make a correct diagnosis at the beginning. finally we noticed several small, pigmented macules around the wart-like lesion with the parallel ridge pattern on dermoscopy, strongly suggesting acral melanoma. when a hyperkeratotic pigmented lesion on the sole is encountered, one should rule out melanoma by careful examination of the periphery of the lesion. dermoscopy is a helpful adjunct for the diagnosis of an unusual case like this. abstract 38 observation | dermatol pract concept 2012;3(1):10 son for hyperkeratosis might be that our patient had tinea pedis. coexistence of tylosis, clavus, human papilloma virus (hpv) infection, or other hyperkeratotic disorders may have an influence on keratinization of melanoma. we performed anti-hpv staining of the specimen but with a negative result. furthermore, similar to previous cases [2,4], hyperkeratosis was conspicuous since melanoma cells mainly proliferated in the epidermis rather than the dermis. melanoma cells may directly affect overlying epidermis and induce keratinization. hyperkeratotic cases of melanoma have often been misdiagnosed. for example, two cases [2,4] in japan showed amelanotic melanoma, one of which was diagnosed as a hematoma at first. an additional two cases [3] were diagnosed as warts at first and treated by curettage or cryotherapy. since misdiagnosis and inadequate treatment may lead to dissemination of the disease, it is essential to diagnose melanoma correctly without any delay. dermoscopic findings were very helpful for a correct diagnosis in this case. aggregated dots/globules strongly indicate melanocytic lesion. their color depends on the amount and depth of melanin. therefore we estimated that black dots/globules correspond to aggregated nests in the stratum within the epidermis (figure 3a). nests ascending into the stratum corneum were also seen (figure 3b). atypical melanocytes forming nests demonstrated substantial nuclear atypia and mitoses (figure 3c). eosinophilic structures resembling kamino bodies were also seen. the surrounding pigmented macules revealed atypical melanocytes proliferating singly or forming small nests. these atypical melanocytes were hardly observed in the hypopigmented areas that were characterized by lymphocytic infiltration, aggregated melanophages and sparse papillary dermal fibrosis. a hemorrhage in the stratum corneum or epidermis that could induce black or brown dots/ globules in dermoscopic observation was not seen histologically. the tumor cells stained positively for s-100 protein and hmb-45 antigen. we confirmed by melan-a staining that melanoma cells were confined to the epidermis both at the central and surrounding lesions. a diagnosis of acral lentiginous melanoma (alm) in situ was eventually made. computed tomography scan of the abdomen and thorax revealed no obvious metastasis. serum 5-s-cysteinyldopa level was normal. a full thickness skin graft from her abdomen was placed on the operative wound. the patient has been free of disease for eight months since the operation. discussion alm is the most common type of melanoma in the japanese population. in japan about one-half of cases of cutaneous melanoma affect acral skin and approximately 30% of them occur on the sole [1]. alm on the sole sometimes can be hyperkeratotic [2,3,4]. in previous reports, hyperkeratotic lesions were seen at sites on which acute pressure was exerted. our case was not necessarily at a site of acute pressure, but the patient had been habitually rubbing it. this might have caused hyperkeratosis in our case. another reafigure 1. (a) a dark brown-to-black hyperkeratotic plaque measuring 10 mm in diameter on the left sole. the border was well circumscribed and symmetrical. (b) a clinical examination after biopsy revealed several pigmented macules of different shades varying from brown to black around the central hyperkeratotic lesion. [copyright: ©2013 ise et al.] figure 2. dermoscopic examinations of: (a) a hyperkeratotic lesion—scaly surface and regular brown-to-black dots/globules. (b) surrounding macules—many brown-to-black macules. most of them showed parallel ridge pattern. [copyright: ©2013 ise et al.] observation | dermatol pract concept 2012;3(1):10 39 references 1. ishihara k, saida t, yamamoto a. japanese skin cancer society prognosis and statistical investigation committee. updated statistical data for malignant melanoma in japan. int j clin oncol. 2001;6:109-16. 2. yasuoka n, ueda m, ohgami y, hayashi k, ichihashi m. amelanotic acral lentiginous malignant melanoma. br j dermatol. 1999;141(2):370-2. 3. dalmau j, abellaneda c, puig s, zaballos p, malvehy j. acral melanoma simulating warts: dermoscopic clues to prevent missing a melanoma. dermatol surg. 2006;32(3):1072-8. 4. yamamoto m, kitoh a, tanioka m, et al. a case of amelanotic melanoma resembling verruca plantaris. japanese journal of clinical dermatology. 2003;57(6):516-8. corneum and brown dots/globules to nests in the epidermis. furthermore, surrounding pigmented macules exhibited the typical parallel ridge pattern, which played a key role in the correct diagnosis of this melanoma. conclusion alm on the sole sometimes shows the feature of hyperkeratosis. whenever we encounter a hyperkeratotic, pigmented macule on the sole, we should observe carefully not only the main lesion but also the circumference of the lesion so as not to miss subtle pigmentation with parallel ridge pattern on dermoscopy. dermoscopy often plays an important role in the diagnosis of pigmented skin lesions. figure 3. (a) hematoxylin and eosin staining revealed remarkable hyperkeratosis and many large nests of atypical melanocytes at the dermoepidermal junction. (b) nests of atypical melanocytes ascending into the stratum corneum. (c) the nests are composed of atypical cells, and mitoses were also observed. eosinophilic structures resembling kamino bodies were also seen. [copyright: ©2013 ise et al.] dermatology: practical and conceptual 168 research | dermatol pract concept 2018;8(3):3 dermatology practical & conceptual www.derm101.com cryotherapy versus co 2  laser in the treatment of plantar warts: a randomized controlled trial nahid hemmatian boroujeni1, farhad handjani1,2 1 department of dermatology, shiraz university of medical sciences, shiraz, iran 2 molecular dermatology research center, shiraz university of medical sciences, shiraz, iran key words: cryotherapy, dermatologic surgery, warts, plantar warts, randomized controlled trial citation: hemmatian boroujeni n., handjani f. cryotherapy versus co 2  laser in the treatment of plantar warts: a randomized controlled trial. dermatol pract concept. 2018;8(3):168-173. doi: https://doi.org/10.5826/dpc.0803a03 received: february 10, 2018; accepted: april 10, 2018; published: july 31, 2018 copyright: ©2018 hemmatian boroujeni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: farhad handjani, md, department of dermatology, faghihi hospital, zand blvd, shiraz, iran. email: hanjanif@ yahoo.com background: warts are one of the most common infections in humans. plantar warts are a subtype of non-genital warts, and several procedures and topical treatments have been used in its treatment. cryotherapy is one of the most popular modalities, but it is time-consuming and remission rates vary in different studies. co 2  laser was the first laser used for treating warts. to date, no clinical trial has been done to compare co 2  laser with cryotherapy in the treatment of plantar warts. patients and methods: this randomized controlled trial was performed in order to compare the efficacy and number of sessions needed to treat plantar warts in 60 patients who had received no previous treatment in the previous 3 months. they were randomly allocated to the cryotherapy or co 2  laser group. the number of sessions needed for response and the recurrence rate after a 3-month follow-up was compared in the 2 groups. results: sixty patients with plantar warts were randomly allocated to either the co 2  laser or cryotherapy groups. median age was 25 (range=18-53) and 27 (range= 18-75) years in the cryotherapy group and co 2  laser groups, respectively. both groups were matched for age and sex (56% male and 44% female in the cryotherapy group and 34% male and 66% female in the co 2  laser group). the median number of sessions needed for complete resolution of the warts in the co 2  laser and cryotherapy groups were 1 (range=1-2) and 3 (range=1-12), respectively. the difference in the number of sessions was statistically significant between the 2 groups (p-value≤0.001). recurrence rates after a 3-month follow-up was not statistically significant (p-value= 0.069). conclusion: the number of sessions needed to treat plantar warts was less using co 2  laser than cryotherapy; therefore, this modality can be a good addition to the already existing anti-wart armamentarium. abstract research | dermatol pract concept 2018;8(3):3 169 patients and methods this study was designed as a randomized controlled clinical trial (rct), and its protocol was approved by the ethics committee of shiraz university of medical sciences with reference number ir.sums.med.rec.1396.08. the rct was registered on the iranian registry of clinical trials website with code number 24482, and the study was done at the department of dermatology at faghihi hospital, shiraz, iran. inclusion criteria were: men and women aged 18 years or older with clinically diagnosed plantar warts who had not received any treatment in the previous 3 months prior to referral. pregnant and lactating woman and those with a history of keloid formation were excluded from the trial. sixty patients who fulfilled the above criteria were enrolled in the study after signing the written informed consent. the patients were randomly allocated into the cryotherapy or co 2  laser groups using computer-generated block randomization. during the first visit, complete medical history was taken and the number of lesions (on the plantar area and any other body site) as well as evidence of any concomitant systemic disease were documented, and photography was taken on each visit. the cryotherapy group received treatment weekly until clinical resolution of the lesions. in each session, 2 freezeand-thaw cycles of a 15-second duration was performed. patients were visited weekly for evaluation of response and any possible complications. the co 2  laser group received therapy weekly until clinical resolution of the lesions. co 2  laser (smartxide dot; deka, italy) was used as the modality of treatment for the plantar warts. each session consisted of 1 to 2 passes of co 2  laser on continuous mode with a power of 15-25 watts according to the depth of the lesion, estimated on physical examination. each pass had 2 components. first, the focused mode with a spot size of 1 mm, and second, the unfocused mode that was induced with a 5 cm distance between the laser probe and the lesion(s). m u p i r o c i n o i n t m e n t w a s p r e s c r i b e d f o r a l l t h e patients 2 times a day for 3 days. resolution of the lesions was considered as clearance of the lesion(s) on inspection and palpation and was documented by photography. persistence of the lesion(s) after 12 weeks of treatment with cryotherapy or 3 sessions of co 2  laser was considered as failure. three months after resolution of the lesions, the patients were re-evaluated for possible recurrence. results sixty patients were enrolled in the trial. twenty-seven in the cryotherapy group and 29 in the co 2  laser group completed introduction warts are one of the most common benign neoplasms. it is the third most common skin disease in childhood and is probably even more common in adulthood [1]. warts are induced by over 100 types of human papillomavirus (hpvs) and can affect any race [2]. they are subdivided into genital and non-genital types. in a study from india in 2016, the ratio of non-genital warts to the genital forms was 9 to 1 [3]. non-genital warts are subsequently subdivided into common, plane, palmoplantar, mosaic, filiform or digitate types [4]. palmoplantar warts are one of the most common types of non-genital warts [5]. following discovery of hpvs as the causative agent of warts, several treatment methods have been introduced. currently, there is no specific antiviral agent against hpvs. systemic cidofovir affects dna viruses such as hpv, but renal toxicity limits its use [6]. no curative standard definitive oral or topical treatment exists for warts [7]. current treatments are based on 2 mechanisms: destruction of the bulk of the neoplasm or stimulation of cellular immunity against hpvs [8,9]. topical immunomodulators (imiquimod [10]), topical and intralesional cytotoxic agents (5-fu, podophyllin [11]), immunotherapy (diphenylcyclopropenone [12]), topical and oral retinoids [13], and systemic immunomodifiers (cimetidine, interferons [14] have been used with some success. local destructive methods are used more often than immunomodifiers. they include cryotherapy [15], trichloroacetic acid [16], lactic acid, salicylic acid, electrosurgery, curettage, surgery with scalpel or scissors [17], photodynamic therapy [18], and various types of lasers [17]. in a cochrane review done in 2003 by gibbs et al [19], cryotherapy was reported to be the most commonly used therapy for warts. however, the treatment outcome with cryotherapy as compared to topical salicylic acid was not significant, and a higher morbidity was reported for cryotherapy. for bleomycin, 5fu, and intralesional interferon and photodynamic therapy, data was limited. this clinical trial challenges the use of cryotherapy in the treatment of warts. patients treated with cryotherapy face a higher cost, as stated by stamuli et al [20]. ablative and non-ablative lasers have been used in order to decrease the duration of the treatment course and recurrence of warts. the first laser that was used for warts was co 2  laser [21], followed by pulsed dye laser and er: yag laser [22,23]. co 2  laser has been used for recalcitrant warts with remission rates ranging from 50% to 100%, in only a few studies [24,25]. to our knowledge, no clinical trial in the english literature has compared cryotherapy with co 2  laser in the treatment of plantar warts [26]; hence, this study was designed to compare the efficacy of these 2 modalities in the treatment of plantar warts. 170 research | dermatol pract concept 2018;8(3):3 in the laser group and one in the cryotherapy group failed treatment (figure 4). after 3 months of treatment completion, 3 patients in the laser group and 8 patients in the cryotherapy group developed a recurrence. in other words, remission rate was 89.7% in the laser group and 70.4% in the cryotherapy group. the difference was evaluated by chi-square test and was not statistically significant (p-value=0.069). no clinical infection was detected in any of the patients. two episodes of moderate bleeding occurred during laser therapy, which was managed by coagulation with the co 2  laser unfocused mode. discussion there are several treatment options for treating plantar warts ranging from office-based therapy (such as cryotherapy) to treatments applied by the patient (such as salicylic acid) [27]. various lasers have been used for this purpose with different the trial. three patients in the cryotherapy group were lost to follow-up, and a patient in the laser group was withdrawn from the trial and had to be referred for skin biopsy because of a suspicious lesion on the plantar surface of his opposite foot that appeared to be melanoma. demographic characteristics of the patients are summarized in table 1. the 2 groups were matched according to sex and age. five patients in the laser group and 2 in the cryotherapy group had coexistent warts on their hands. two patients in the laser group and 3 in the cryotherapy group had diabetes mellitus type 2, and a patient in the laser group had hypothyroidism. the co 2  laser power used was 21±4 watts, both for focused and unfocused mode. the median number of sessions needed for complete treatment with co 2  laser was 1 (range= 1-2) while in the cryotherapy group, it was 3 (range=1-12). the number of required sessions for the 2 groups was compared by mann-whitney test, and the difference was statistically significant (p-value≤ 0.001) (figures 1-3). one patient table 1. characteristics of the patients parameter cryotherapy co 2 laser age (years), median 25 (range=18-53) 27 (range= 18-75) sex, number (percentage) male: 15 (56%) female: 12 (44%) male: 10 (34%) female: 19 (66%) number of warts in each group, median 1 (range= 1-20) 5 (range= 1-20) figure 1. phases of treatment in one patient who underwent co 2  laser therapy (a) before laser therapy; (b) immediately after therapy; (c) 1 week after therapy. [copyright: ©2018 hemmatian boroujeni et al.] figure 2. phases of treatment in another patient in the co 2  laser group (a) before laser therapy; (b) immediately after therapy; (c) 3 months after therapy). [copyright: ©2018 hemmatian boroujeni et al.] research | dermatol pract concept 2018;8(3):3 171 treatment, not the time interval between each session [32]. in some studies, 2 cycles of freeze-and-thaw had a better result than only 1 cycle in plantar warts, while this was not the case for warts on other parts of the body such as the hands [33]. we chose the 2-cycle freeze-and-thaw method using the spray gun with an interval of 1 week between each session. cryotherapy can destroy the bulk of the wart and induce inflammation and immune response but cannot kill hpvs. liquid nitrogen might become contaminated if direct contact devices are used; not so with spray guns [34]. the remission rate with this method in our study was 70%. in a study by ahmed et al, the authors noted a 44% and 47% cure rate with cryotherapy using the spray gun and cotton swab, respectively [35]. this difference between our results and the aforementioned article may be due to the difference in disease chronicity and follow up. to our knowledge, there is no study comparing co 2  laser with cryotherapy in the english literature, although comparisons of other lasers have been undertaken. in a study by akhyani et al, no superiority in remission rate for pdl laser was found when compared with cryotherapy. however, patients in the pdl group achieved remission sooner in the course of treatment [36]. in our study, we did not find a statistically significant difference in the recurrence rate between our 2 groups, and the p-value was 0.069. one main concern in this study was the issue of possible transmission of warts with co 2  laser plume to the dermatologist or patient and contamination of the laser device that could be a cause of transmission of the virus to other success rates. in this study, we compared co 2  laser and cryotherapy in order to determine their efficacy. our remission rate in the co 2  laser group was 89%. this is very similar to the result that mitsuishi found in his study [28]. mitsuishi et al reported the only prospective non-blinded, non-randomized study on plantar warts to date. they included 31 patients with a remission rate of 89%, after 3-12 months of follow-up. however, in other studies using lasers for plantar warts, the results were not as promising. in a retrospective survey by landsman et al, in 166 patients with plantar warts treated by co 2  laser, the remission rate was 75%, after a 3-72 month follow-up [29]. in another retrospective survey by sloan et al, in 92 patients with recalcitrant warts, remission rate was 64% at 12-month follow-up [30]. the difference in the remission rate between our study and the other studies cited above can be attributed to the different duration of follow-ups used and inclusion of recalcitrant cases. when recalcitrant cases are included in a study, the remission rate is usually lower. in the other arm of our study we used cryotherapy. there are several studies on the efficacy of cryotherapy and the adverse effects attributed to this method, although there is limited data comparing this method with other methods in the treatment of plantar warts [31]. liquid nitrogen with a temperature of -196˚ c was used for cryotherapy and was applied with spray gun, probe, or cotton swab. for choosing the best interval for applying cryotherapy, we did not find any difference between 1-week, 2-week, or 3-week intervals. it seems that the number of sessions determine efficacy of figure 4. phases of treatment in another patient in the cryotherapy group (a) before cryotherapy; (b) cryotherapy after 6 sessions; (c) cryotherapy after 12 sessions; failure of treatment. [copyright: ©2018 hemmatian boroujeni et al.] figure  3. phases of treatment in a patient who underwent cryotherapy (a) before cryotherapy; (b) cryotherapy after  6  sessions; (c) cryotherapy after 11 sessions. [copyright: ©2018 hemmatian boroujeni et al.] 172 research | dermatol pract concept 2018;8(3):3 10. ahn cs, huang ww. imiquimod in the treatment of cutaneous warts: an evidence-based review. am j clin dermatol. 2014;15(5):387-399. doi: 10.1007/s40257-014-0093-5. 11. sharma n, sharma s, singhal c. a comparative study of liquid nitrogen cryotherapy as monotherapy versus in combination with podophyllin in the treatment of condyloma acuminata. j clin diagn res. 2017;11(3):wc01-wc05. 12. park hk, kim js. factors contributing to the treatment duration of diphenylcyclopropenone immunotherapy for periungual warts. dermatol ther. 2016;29(2):114-119. doi: 10.1111/dth.12312. 13. joshipura d, goldminz a, greb j, gottlieb a. acitretin for the treatment of recalcitrant plantar warts. dermatol online j. 2017;23(3). 14. abdelmaksoud a. reply to “significance of interferon gamma in the prediction of successful therapy of common warts by intralesional injection of candida antigen.” int j dermatol. 2017;56(12):1505-1506. doi: 10.1111/ijd.13753. 15. walczuk i, eertmans f, rossel b, et al. efficacy and safety of three cryotherapy devices for wart treatment: a randomized, controlled, investigator-blinded, comparative study. dermatol ther (heidelb). 2018;8(2):203-216. doi: 10.1007/s13555-017-0210-5. 16. jayaprasad s, subramaniyan r, devgan s. comparative evaluation of topical 10% potassium hydroxide and 30% trichloroacetic acid in the treatment of plane warts. indian j dermatol. 2016;61(6):634-639. doi: 10.4103/0019-5154.193670. 17. ramírez-fort mk, sam h, manders ek. management of cutaneous human papillomavirus infection: surgery. curr probl dermatol. 2014;45:186-196. doi: 10.1159/000356070. 18. hu z, liu l, zhang w, et al. dynamics of hpv viral loads reflect the treatment effect of photodynamic therapy in genital warts. photodiagnosis photodyn ther. 2018;21:86-90. doi: 10.1016/j. pdpdt.2017.11.005. 19. gibbs s, harvey i, sterling jc, stark r. local treatments for cutaneous warts. cochrane database syst rev. 2003(3):cd001781. 20. stamuli e, cockayne s, hewitt c, evert team, et al. costeffectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts: economic evaluation alongside a randomised controlled trial (evert trial). j foot ankle res. 2012;5:4. doi: 10.1186/1757-1146-5-4. 21. mcburney ei, rosen da. carbon dioxide laser treatment of verrucae vulgares. j dermatol surg oncol. 1984;10(1):45-48. doi: 10.1111/j.1524-4725.1984.tb01172.x. 22. dmovsek-olup b, vedlin b. use of er: yag laser for benign skin disorders. lasers surg med. 1997;21(1):13-19. doi: 10.1002/ (sici)1096-9101(1997)21:13.0.co;2-0. 23. veitch d, kravvas g, al-niaimi f. pulsed dye laser therapy in the treatment of warts: a review of the literature. dermatol surg. 2017;43(4):485-493. doi: 10.1097/dss.0000000000001023. 24. lauchli s, kempf w, dragieva g, burg g, hafner j. co2 laser treatment of warts in immunosuppressed patients. dermatology. 2003;206(2):148-152. doi: 10.1159/000068459. 25. serour f, somekh e. successful treatment of recalcitrant warts in pediatric patients with carbon dioxide laser. eur j pediatr surg. 2003;13(4):219-223. doi: 10.1055/s-2003-42237. 26. nguyen j, korta dz, chapman lw, kelly km. laser treatment of nongenital verrucae: a systematic review. jama dermatol. 2016;152(9):1025-1034. doi: 10.1001/jamadermatol.2016.0826. 27. lipke mm. an armamentarium of wart treatments. clin med res. 2006;4(4):273-293. doi: 10.3121/cmr.4.4.273. patients who later undergo aesthetic procedures using the same device. it seems that the risk of viral transmission from co 2  laser plume after procedures on non-genital warts is not higher than the general population [37]. in our study, we did not see any clinically apparent warts in our cosmetic patients that used the same device and no warts were observed in the dermatologist performing the laser treatment in our cases. the absence of any clinical infection in both groups can be attributed to the topical application of mupirocin ointment. therefore, administering a topical ointment might help to reduce post-procedural infections. conclusion overall, co 2  laser can be an effective and timesaving treatment modality for plantar warts. however, studies with larger sample sizes and longer follow-up periods are advised in order to confirm the results of this study. references 1. afshar rm, mollaie hr, fazlalipour m, arabzadeh sa. prevalence and type distribution of human papillomavirus infection using the inno-lipa assay, kerman, southeast iran. asian pac j cancer prev. 2013;14(9):5287-5291. doi: 10.7314/ apjcp.2013.14.9.5287. 2. mallory sb, baugh ls, parker rk. warts in blacks versus whites. pediatr dermatol. 1991;8(1):91. doi: 10.1111/j.1525-1470.1991. tb00851.x. 3. ghadgepatil ss, gupta s, sharma yk. clinicoepidemiological study of different types of warts. dermatol res pract. 2016;2016:7989817. doi: 10.1155/2016/7989817. 4. vlahovic tc, khan mt. the human papillomavirus and its role in plantar warts: a comprehensive review of diagnosis and management. clin podiatr med surg. 2016;33(3):337-353. doi: 10.1016/j.cpm.2016.02.003. 5. silverberg nb. human papillomavirus infections in children. curr opin pediatr. 2004;16(4):402-409. doi: 10.1097/01. mop.0000128403.78839.3c. 6. grone d, treudler r, de villiers em, husak r, orfanos ce, zouboulis chc. intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome. j eur acad dermatol venereol. 2006;20(2):202-205. doi: 10.1111/j.1468-3083.2006.01380.x. 7. rivera a, tyring sk. therapy of cutaneous human papillomavirus infections. dermatol ther. 2004;17(6):441-448. doi: 10.1111/j.1396-0296.2004.04047.x. 8. arany i, tyring sk, stanley ma, et al. enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. antiviral res. 1999;43(1):55-63. doi: 10.1016/s0166-3542(99)00033-9. 9. oni g, mahaffey pj. treatment of recalcitrant warts with the carbon dioxide laser using an excision technique. j cosmet laser ther. 2011;13(5):231-236. doi: 10.3109/14764172.2011.606465. research | dermatol pract concept 2018;8(3):3 173 33. berth-jones j, bourke j, eglitis h, et  al. value of a second freeze-thaw cycle in cryotherapy of common warts. br j dermatol. 1994;131(6):883-886. doi: 10.1111/j.1365-2133.1994. tb08594.x. 34. tabrizi sn, garland sm. is cryotherapy treating or infecting? med j aust. 1996;164(5):263. 35. ahmed i, agarwal s, ilchyshyn a, charles-holmes s, berth-jones j. liquid nitrogen cryotherapy of common warts: cryo-spray vs. cotton wool bud. br j dermatol. 2001;144(5):1006-1009. doi: 10.1046/j.1365-2133.2001.04190.x. 36. akhyani m, ehsani ah, noormohammadpour p, shamsodini r, azizahari s, sayanjali s. comparing pulsed-dye laser with cryotherapy in the treatment of common warts. j lasers med sci. 2011;1(1):14-19. 37. gloster hm jr, roenigk rk. risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts. j am acad dermatol. 1995;32(3):436-441. doi: 10.1016/0190-9622(95)90065-90069. 28. mitsuishi t, sasagawa t, kato t, et al. combination of co laser therapy and artificial dermis application in plantar warts: human papillomavirus dna analysis after treatment. dermatol surg. 2010;36(9):1401-1405. 10.1111/j.1524-4725.2010.01648.x.  29. landsman mj, mancuso je, abramow sp. carbon dioxide laser treatment of pedal verrucae. clin podiatr med surg. 1992;9(3):659-669. 30. sloan k, haberman h, lynde cw. carbon dioxide laser-treatment of resistant verrucae vulgaris: retrospective analysis. j cutan med surg. 1998;2(3):142-145. doi: 10.1177/120347549800200306. 31. gibbs s, harvey i, sterling j, stark r. local treatments for cutaneous warts: systematic review. bmj. 2002;325(7362):461. doi: 10.1136/bmj.325.7362.461. 32. bourke jf, berth-jones j, hutchinson pe. cryotherapy of common viral warts at intervals of 1, 2 and 3 weeks. br j dermatol. 1995;132(3):433-436. doi: 10.1111/j.1365-2133.1995. tb08678.x. untitled research | dermatol pract concept 2015;5(4):8 31 dermatology practical & conceptual www.derm101.com introduction early detection of melanoma is crucial to improve survival [1]. melanoma may be clinically but also dermoscopically indistinguishable from other pigmented skin lesions, especially in incipient and small lesions [2]. several strategies such as the abcd(e) acronym [3,4], the “ugly duckling sign” [5] or the efg [6], just to mention a few, have been proposed to enhance clinical recognition of atypical lesions that should undergo excision or close monitoring, but it usefulness in the detection of melanoma at a curable stage is questionable since only evolved lesions fulfil clinical criteria [7,8]. dermoscopy has shown to improve melanoma detection by allowing the visualization of diagnostic criteria not visible to the naked eye, and its routine use for the evaluation of skin lesions is recommended in most of the clinical guidelines worldwide [9]. the use of sequential digital dermoscopy for the comparison of current and previous images in search of subtle changes over time has shown to be helpful in the diagnosis of early melanomas that might lack of specific criteria for malignancy [10]. herein we present a series of melanomas located on the leg with a diameter less than 5 mm measured on relaxed skin before excision. this study reports the dermoscopic clues for early recognition of these lesions and highlights importance of weighing the personal and familial history as well as the clinical context. case presentations the cases are presented in table 1. the 8 melanomas corresponded to 7 patients, most females (7/8), with a mean age of 42.5 years (range 35-53 years). four melanomas were detected during routine nevi control and 4 were detected due to changes during digital follow-up; the melanoma was not the reason for the patient´s consultation. cases 6 and 7 corresponded to the same patient, a 35-year-old female carrier of g101w mutation in cdkn2a. clinical characteristics are shown in table 2. all melanomas were located on the legs, 7 in the calf and 1 in the thigh. all melanomas have a diameter lower than 5 mm, with a mean of 3.7 mm (range 2.5-4.5 mm). according to naked eye examination only 2 of 8 melanomas had irregular borders, a series of small-diameter melanomas on the legs: dermoscopic clues for early recognition gabriel salerni 1,2, carlos alonso1,2, ramón fernández-bussy1 1 hospital provincial del centenario de rosario, argentina. faculty of medicine, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina key words: melanoma; dermoscopy; atypical mole syndrome; follow-up; imaging techniques citation: salerni g, alonso c, fernández-bussy r. a series of small-diameter melanomas on the legs: dermoscopic clues for early recognition. dermatol pract concept 2015;5(4):8. doi: 10.5826/dpc.0504a08 received: june 29, 2015; accepted: july 4, 2015; published: october 31, 2015 copyright: ©2015 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, urquiza 3100, cp: s2002kdr, rosario, argentina. tel. +54 341 4398586. email: gabrielsalerni@hotmail.com mailto:gabrielsalerni@hotmail.com 32 research | dermatol pract concept 2015;5(4):8 while case 8 additionally displayed changes in dermoscopic structures and colors (figure 3). all melanomas corresponded to superficial spreading histologic type. most melanomas (6/8) were in situ. two melanomas, corresponding to cases 1 and 8, were invasive with a breslow thickness of 0.2 (figure 4) and 0.35 mm respectively. discussion strategies aimed at recognition of suspicious lesions may have little impact in the diagnosis of small melanomas. the abcd rule [3], originally designed 30 years ago and revised in 2004 [11] when the e criterion (for evolution) was included, fails to recognize the existence of small-diameter melanoma, i.e., melanomas less than 6 mm in diameter. and 3 out of 8 were asymmetric and had multiple colors. in only 2 cases the patients were able to report a history of change, in both cases the lesions were reported as new. in 4 cases the patients referred the lesion as stable, and in 2 cases the patients were unaware of the lesion (figure 1). dermoscopy evaluation was based on pattern analysis; dermoscopic features are shown in table 3. upon dermoscopy 5 melanomas were asymmetric; 3 lesions displayed only 1 color, 2 melanomas had 2 colors and 3 displayed 2 or more colors. reticular pattern and the presence of atypical pigment network were the most frequent features, seen in 7 of 8 melanomas (figure 2). four melanomas were detected due to changes during digital follow-up (cases 5 to 8). in 3 melanomas (cases 5, 6 and 7) the only change detected was asymmetric enlargement, table 1. cases presentations case age gender form of diagnosis fh mm ph mm multiple mm ams mmc mmrc mmdd 1 44 f   ✓ ✓ ✓ 2 52 f   ✓ 3 35 f   ✓ ✓ 4 45 m   ✓ 5 43 f   ✓ ✓ ✓ ✓ 6 35 f   ✓ ✓ ✓ ✓ ✓ 7 35 f   ✓ ✓ ✓ ✓ ✓ 8 53 f   ✓ ✓ mmc: melanoma reason for consultation; mmrc: melanoma routine control; mmdd: melanoma digital dermoscopy; fh mm: familial history of melanoma; ph mm: personal history of melanoma; ams: atypical mole syndrome table 2. clinical characteristics case abcd (e) asymmetry (a) irregular borders (b) multiple colours (c) diameter (d) history of change (evolution, e)diameter >6 mm diameter (mm) 1 3.1 ✓ 2 ✓ ✓ 2.5 3 ✓ ✓ ✓ 4.5 unknown 4 3.6 ✓ 5 3.3 6 4.3 7 4.0 8 ✓ ✓ ✓ 4.5 unknown research | dermatol pract concept 2015;5(4):8 33 series, the melanoma was not the reason for patient’s consultation; the strict application of the abcd rule for appraisal of lesions that may need to be further examined by a specialist would have led to missing these melanomas. even though the inclusion of e, for evolution, has improved the recognition of melanoma by emphasizing change over time as an important the d criterion has been a matter of controversy since all melanomas are smaller than 6 mm in early stages and a significant proportion of melanomas may be smaller than 6 mm at the time of diagnosis. as stated by kittler, the limit of 6 mm is not a biological minimum size of melanomas, but the lower limit for the applicability of the abcd rule [12]. in our figure 1. clinical images of cases 1 to 8 (a to h). cases 1 to 4 (a to d) corresponded to melanomas detected during routine nevi control while cases 5 to 8 (e to h) corresponded to melanomas detected during digital follow-up; cases 6 and 7 (f and g) corresponded to the same patient. none of the lesions fulfilled clinical criteria for suspicion of melanoma. [copyright: ©2015 salerni et al.] 34 research | dermatol pract concept 2015;5(4):8 figure 2. dermoscopic features of cases 1 to 8 (a to h). reticular pattern was seen in all cases but in case 5 (e). in cases 1 to 4 (a to d) and in case 8 (h) the presence of atypical pigment network was observed. cases 1, 4 and 5 (a, d and e) showed pseudopods at the periphery. cases 6 and 7 displayed typical pigment network with hypo pigmented irregular areas. [copyright: ©2015 salerni et al.] additional criterion in the differentiation of melanoma from benign lesions, in only 2 cases the patients were able to report a history of change; in both cases the lesions were reported as new. we found that patients may find it difficult to detect the occurrence of new small lesions as well as clinical changes in pre-existing small lesions. unlike nodular type, superficial spreading and lentiginous melanomas usually experiment a variable radial growth phase before invading the underlying dermis. nevertheless, smalldiameter superficial spreading melanomas with vertical growth phase have been reported [13,14]. in our series, 2 invasive melanomas with a diameter of 3.1 and 4.5 mm were observed, highlighting that even very small lesions may have metastatic potential. the diagnosis of small-diameter melanomas poses difficulties because the dermoscopic features of small melanomas have been reported infrequently. according to our findings, even in small lesions dermoscopic clues might allow early recognition. reticular pattern and the presence of atypical pigment network was the most common dermoscopic feature (7/8) followed by radial streaks / pseudopods (2/8). it is recommended that dermoscopy should be performed in all lesions, and not just for those suspicious from the clinical point of view, since clinical pre-selection of lesions for dermoscopic examination is associated with a loss of lesions that might require either surgical excision or follow-up examinations [15]. four melanomas were detected due to changes during digital of high-risk melanoma patients, increase in size with no further significant change were observed in 3 cases; 1 case displayed changes in shape, structures and pigmentation. this supports the fact that digital follow-up allows for the detection of early melanoma, when specific structures or criteria for malignancy may not be present yet [7,8]. in a recent study carrera et al. [16] addressed special attention to melanomas of the legs. as in our series, in the dermoscopic analysis none of the cases showed a multi-component pattern, or marked asymmetry in structure or pigresearch | dermatol pract concept 2015;5(4):8 35 figure 3. dermoscopic changes leading to excision in cases 5 to 8. increase in size with no further significant change were observed in cases 5 to 7 (first, second and third row respectively). in case 8 (fourth row) dermoscopic changes were more evident, with changes in shape, structures and pigmentation. [copyright: ©2015 salerni et al.] 36 research | dermatol pract concept 2015;5(4):8 99 consecutive primary melanomas. dermatol pract concept. 2014;4(4):7. 8. salerni g, lovato l, carrera c, et al. melanomas detected in follow-up program compared with melanomas referred to a melanoma unit. arch dermatol. 2011;147(5):549-55 9. australian cancer network (acn). clinical practice guidelines for the management of melanoma in australia and new zealand (2008). available from: http://www.nhmrc.gov.au/_files_nhmrc/ publications/attachments/cp111.pdf. accessed june 2015. 10. salerni g, terán t, puig s, et al. meta-analysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on behalf of the international dermoscopy society. j eur acad dermatol venereol. 2013;27(7):805-14. 11. abbasi nr, shaw hm, rigel ds, et al. early diagnosis of cutaneous melanoma: revisiting the abcd criteria. jama. 2004;292(22):2771-6. 12. kittler h, rosendahl c, cameron a, tschandl p. dermatoscopy— an algorithmic method based on pattern analysis. austria: facultas.wuv, 2011. 13. pellizzari g, magee j, weedon d, et al. a tiny invasive melanoma: a case report with dermatoscopy and dermatopathology. dermatol pract concept. 2013;3(2):6. 14. bono a, tolomio e, trincone s, et al. micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm. br j dermatol. 2006;155(3):570-3. 15. seidenari s, longo c, giusti, et al. clinical selection of melanocytic lesions for dermoscopy decreases the identification of suspicious lesions in comparison with dermoscopy without clinical preselection. br j dermatol. 2006;154(5):873–9. 16. carrera c, palou j, malvehy j, et al. early stages of melanoma on the limbs of high-risk patients: clinical, dermoscopic, reflectance confocal microscopy and histopathological characterization for improved recognition. acta derm venereol. 2011;91(2):137-46. mentation, emphasizing the importance of finding other dermoscopic features in these early lesions. we report a series of small-diameter melanomas of the legs that did not meet the clinical criteria for suspicion. the routinely use of dermoscopy in the evaluation of skin lesions and digital dermoscopy in the monitoring of high-risk individuals provided crucial information for early recognition of these lesions that might have been overlooked assessed solely by the naked eye. references 1. kopf aw, welkovich b, frankel re, et al. thickness of malignant melanoma: global analysis of related factors. j dermatol surg oncol. 1987;13(4):345-20. 2. puig s, argenziano g, zalaudek i, et al. melanomas that failed dermoscopic detection: a combined clinicodermoscopic approach for not missing melanoma. dermatol surg. 2007;33(10):1262-73. 3. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin. 1985;35(3):130-51. 4. rigel ds, friedman rj. the rationale of the abcds of early melanoma. j am acad dermatol. 1993;29:1060-1. 5. grob jj, bonerandi jj. the ‘ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. arch dermatol. 1998;134(1):103-4 6. kelly jw, chamberlain aj, staples mp, et al. nodular melanoma. no longer as simple as abc. aust fam physician. 2003;32(9):706–9. 7. salerni g, terán t, alonso c, fernández-bussy r. the role of dermoscopy and digital dermoscopy follow-up in the clinical diagnosis of melanoma: clinical and dermoscopic features of figure 4. histologic image of case 1, showing proliferation of atypical melanocytes at the dermo-epidermal junction with pagetoid spread and focal invasion of dermis. diagnosis: superficial spreading melanoma, breslow 0.2 mm. histologic images courtesy of mario gorosito. [copyright: ©2015 salerni et al.] http://www.ncbi.nlm.nih.gov/pubmed/?term=pellizzari%20g%5bauthor%5d&cauthor=true&cauthor_uid=23785644 http://www.ncbi.nlm.nih.gov/pubmed/?term=magee%20j%5bauthor%5d&cauthor=true&cauthor_uid=23785644 http://www.ncbi.nlm.nih.gov/pubmed/?term=weedon%20d%5bauthor%5d&cauthor=true&cauthor_uid=23785644 http://www.ncbi.nlm.nih.gov/pubmed/3921200 untitled observation | dermatol pract concept 2015;5(2):26 129 dermatology practical & conceptual www.derm101.com the patient a 69-year-old postmenopausal woman consulted for frontal hair loss for two years. she had started menopause at the age of 50 years old and had been taking bisphosphonates for her osteoporosis for two years. her clinical history, including gynecological data, was otherwise negative. anamnestic data ruled out the possibility of traction alopecia. dermatological examination revealed a fitzpatrick skin type iii. she had a linear frontotemporal recession with perifollicular erythema, lonely hairs on the frontal region, and scarring alopecia (figure 1). the patient had a total loss of eyebrows but she did not have body hair loss. there were no other skin or mucosal abnormalities. thyroid hormone function was also normal. dermoscopy with a non-contact polarizing fotofinder dermatoscope x20 (fotofinder systems, inc, bad birnbach, germany) revealed perifollicular erythema and very mild perifollicular scaling in addition to hair shaft dystrophy and broken hair. furthermore, dermoscopy noted the presence of white dots coexisting with irregular white and pink areas devoid of hair follicular openings (figure 2). no prior topical treatment was used before our consultation. a 4 mm scalp punch biopsy from the frontal hairline was performed. hisfrontotemporal hairline recession in a postmenopausal woman anissa zaouak1, houda hammami ghorbel1, talel badri1, wafa koubaa2, samy fenniche1 1 department of dermatology, habib thameur hospital, faculty of medicine, university of tunis el manar, tunis, tunisia 2 department of anatomopathology, habib thameur hospital, faculty of medicine, university of tunis el manar, tunis, tunisia key words: frontal fibrosing alopecia, dermoscopy, menopausal, histology citation: zaouak a, ghorbel hh, badri t, koubaa w, fenniche s. frontotemporal hairline recession in a postmenopausal woman. dermatol pract concept 2015;5(2):26. doi: 10.5826/dpc.0502a26 received: september 27, 2014; accepted: january 9, 2015; published: april 30, 2015 copyright: ©2015 zaouak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: anissa zaouak, md, assistant professor, department of dermatology, habib thameur hospital, 8 street ali ben ayed, montfleury 1008, tunis, tunisia. tel. +21627952419; fax. +216 71399115. email: anissa_zaouak@yahoo.fr figure 1. scarring alopecia affecting the frontotemporal hairline. [copyright: ©2015 zaouak et al.] 130 observation | dermatol pract concept 2015;5(2):26 the hormonal imbalance caused by the decrease of estrogens associated with menopause could be the main trigger that creates the inflammatory scarring reaction of ffa in predisposed patients [2]. it is a disease that is diagnosed clinically in most cases. the progressive recession of the frontotemporal hairline is the most constant and characteristic clinical manifestation of ffa. it occurs symmetrically and bilaterally giving rise to a band of alopecia between 0.5 cm and 8 cm from the original hairline. hair loss from the lateral third of the eyebrows is also characteristic of ffa [3]. histologic features of ffa and lichen planopilaris are similar: both demonstrate a follicular lichenoid inflammatory infiltrate involving the isthmus and infundibulum, perifollicular fibrosis and fibrous tracts as seen in our patient [4]. typical dermoscopic findings, as seen in our patient, include mainly the absence of follicular openings, perifollicular scaling and perifollicular erythema [5,6]. trichoscopy appears to be a non-invasive diagnostic tool for the diagnosis and follow-up of ffa. in fact, in a recent study including 79 patients [5], the authors concluded that perifollicular erythema may represent a direct trichoscopic marker of disease activity in ffa. our patient had a scarring alopecia of the scalp margin and ffa was diagnosed mainly on clinical appreciations. however, in front of an early stage of ffa, dermoscopy appears to be helpful to establish differential diagnosis topathological examination revealed perifollicular lamellar fibrosis, loss of sebaceous glands and a lichenoid lymphocytic infiltrate targeting the infundibulum and isthmus (figure 3). what is your diagnosis? diagnosis frontal fibrosing alopecia clinical course the patient was treated with minoxidil 2% with a slight improvement of her scarring alopecia. discussion frontal fibrosing alopecia (ffa) is a relatively recently recognized condition of unknown origin and was first described in 1994 [1]. it is generally considered as a variant of lichen planopilaris primarily affecting postmenopausal women. figure 2a. perifollicular erythema, very mild perifollicular scaling, acquired hair shaft dystrophy and broken hair. [copyright: ©2015 zaouak et al.] figure 2b. white dots with irregular white and pink areas devoid of hair follicular openings. [copyright: ©2015 zaouak et al.] figure 3. perifollicular lamellar fibrosis, loss of sebaceous glands and a lichenoid lymphocytic infiltrate targeting the infundibulum and isthmus (h&e x40). [copyright: ©2015 zaouak et al.] observation | dermatol pract concept 2015;5(2):26 131 dermoscopy could improve diagnostic accuracy of hair and scalp disorders. references 1. kossard s. postmenopausal frontal fibrosing alopecia. arch dermatol 1994;130(6):770-4. 2. moreno-ramirez d, camacho martinez f. frontal fibrosing alopecia: a survey in 16 patients. j eur acad dermatol venereol 2005;19(6):700-5. 3. moreno-ramirez d, ferrandiz l, camacho fm. diagnostic and therapeutic assessement of frontal fibrosing alopecia. actas dermasifiliogr 2007;98(9):594-602. 4. macdonald a, clark c, holmes s. frontal fibrosing alopecia: a review of 60 cases. j am acad dermatol 2012;67(5):955-61. 5. toledo-padtrana t, garcia hernandez mj, camacho martinez fm. perifollicular erythema as a tricoscopy sign of progression in frontal fibrosing alopecia. int j trichology 2013;5(3):151-3. 6. inui s, nakajima t, shono f, itami s. dermoscopic findings in frontal fibrosing alopecia: report of four cases. int j dermatol 2008;47(8):796-9. 7. miteva m, tosti a. hair and scalp dermatoscopy. j am acad dermatol 2012;67(5):1040-8. 8. rubegni p, mandato f, fimiani m. frontal fibrosing alopecia: role of dermoscopy in differential diagnosis. case rep dermatol 2010;2(1):40-5. 9. rudnicka l, rakowska a, olszewska m. trichoscopy: how it may help the clinician. dermatol clin 2013;31(1):29-41. 10. goldberg lj. cicatricial marginal alopecia: is it all traction? br j dermatol 2009;160(1):62-8. 11. miteva m, tosti a. dermoscopic features of central centrifugal cicatricial alopecia. j am acad dermatol 2014;71(3):443-9. 12. vano-galvan s, molina-ruiz am, serrano-falcon c, et al. frontal fibrosing alopecia: a multicenter review of 355 patients. j am acad dermatol 2014;70(4):670-8. between traction alopecia, alopecia areata and cicatricial marginal alopecia. in fact, our patient had a cicatricial alopecia with the absence of yellow dots and dystrophic hairs, which are the most relevant dermoscopic findings in alopecia areata. anamnestic data ruled out the possibility of traction alopecia characterized by the absence of miniaturized hairs, white dots and fractured hair shafts at dermoscopic examination [7-9]. as for cicatricial marginal alopecia (cma), this entity is characterized by an area of permanent hair loss that involves mainly the crown and vertex and spreads centrifugally. cma is characterized dermoscopically by low hair density, loss of follicular ostia with a peripilar white gray halo around the emergence of hairs that were absent in our patient [10,11]. currently, no treatment protocols exist for ffa. stabilization of hair loss is occasionally observed with various topical or systemic therapies such as oral 5-α-reductase inhibitors, hydroxychloroquine, minoxidil and topical or intralesional corticosteroids. the aim of the treatment is to arrest hair loss. improvement of ffa was most often seen when treated with oral finasteride or dutasteride, but a spontaneous stabilization of the disease may also occur. the regrowth of hair is usually minimal and always located at the hairline [12]. some treatments may reduce inflammation, but the impact on progression of alopecia is uncertain. we report this case not only for the rarity of the disease but also to underline the role of dermoscopy as a very useful tool in the diagnosis of frontal fibrosing alopecia. in fact, the characteristic clinical presentation together with typical dermoscopic features could help in avoiding unnecessary biopsies in patients with frontal fibrosing alopecia. hence, dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2013;3(4):1 1 dear readers, mark a. hurt, the editor of the book review section of dermatology practical & conceptual has decided, after a decade of contributions, that the time has come to him to transition out of his role. mark was recruited by bernie ackerman and started working as book review editor in 2003. during these 10 years, mark contributed with his vivid and relevant reviews to this journal’s content, and his section became a regular part of the journal. i personally had the chance to work together with mark during the past five months since starting my editorship in may 2013. during these few and quite challenging months, i felt particularly grateful to mark for his timely and wellwritten contributions, which allowed me to concentrate on other issues that needed my attention. in my role as editor and in the name of the entire editorial board and our readers, i want to thank mark a. hurt for a decade of his dedication and contributions to the journal. this issue will contain his farewell to our readers and his last review, which i am sure you will enjoy reading, as i did. all our best to you, mark! while we have to say good bye to mark, i am happy to announce that we can say welcome to françois milette, who accepted to continue mark’s work and will be the new editor of the book review section. please let me briefly introduce françois here: françois graduated from the university of montreal in medicine in 1986 and in anatomic pathology in 1990. since then he has worked as general pathologist in gaspé, quebec, canada. in 1994, he went to the st. luc hospital of montreal university. he worked there for four years and progressively developed interest and expertise in dermatopathology, mainly through the close collaboration with a remarkable team of dermatologist and dermatopathologists. since the year 2000 he has worked at the hôpital pierre-boucher, longueuil in quebec, canada with a team of dermatologists and pathologists. from 2005 until the time of his death, françois collaborated closely with dr. bernard ackerman. during this time, françois was stimulated by the unique character of bernie ackerman, increased his expertise in dermatopathology and contributed with scientific works to the former journal, dermatopathology: practical & conceptual. i am confident that françois will successfully continue the book review section of the journal. françois, welcome in the team. besides the transitions of mark and francois, the journal also underwent its own transition during the past months. derm101 relaunched in september 2013 with a new look—a clean, modern design; simplified and more intuitive navigation; and robust content. this cosmetic procedure of derm101 affected the online and pubmed publication process of the july issue, which many of our contributors and readers noticed. for this delay, we sincerely apologize. looking forward, we at dermatology practical & conceptual are planning to implement a new online submission system for contributors, which will streamline the review process. irrespective of these many challenges during the past months, we receive a steadily increasing number of submissions, and i want to thank the contributors for their confidence in us. this october issue has exciting contents covering the many aspects of clinical morphology, including traditional histopathology, dermoscopy and in vivo reflectance confocal microscopy, but also research on surgical procedures for improving wound healing after excision of non-melanoma skin cancer. i am sure you will enjoy reading its content! with my best wishes, iris zalaudek editor-in-chief dermatology practical & conceptual about transitions iris zalaudek1,2 1 division of dermatology, medical university of graz, graz, austria 2 skin cancer unit, arcispedale santa maria nuova, irccs, reggio emilia, italy citation: zalaudek i. about transitions. dermatol pract conc. 2013;3(4): 1. http://dx.doi.org/10.5826/dpc.0304a01. copyright: ©2013 zalaudek. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: iris zalaudek, m.d., division of dermatology, medical university of graz, auenbruggerplatz 8, 8036 graz, austria. email: dpc@derm101.com dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):19 237 dermatology practical & conceptual an 8-year-old boy presented with a well-demarcated pigmented lesion localized 5 cm above his right knee. his parents reported that it had appeared approximately 5 months before as a small pink-red papule initially diagnosed as a wart. gradually, the lesion grew in size and developed a darker area in the center (figure 1). dermoscopically, the lesion showed a multicomponent pattern with blue to black dots and globules, blue-white veil, and pinkish color, especially visible at the periphery (figure 2). histological evaluation revealed a well-circumscribed dermoepidermal pigmented atypical melanocytic proliferation composed of epithelioid spindle cells (spitzoid cytology). a strange atypical spitz tumor andrea bassi1, vincenzo piccolo2, maurizio de martino1, teresa oranges1, cesare filippeschi1, giuseppe argenziano2 1 department of health sciences, university of florence & department of paediatric medicine, anna meyer children’s university hospital, florence, italy 2 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: dermoscopy, spitz tumor, histopathology, atypical spitz tumor citation: bassi a, piccolo v, de martino m, oranges t, filippeschi c, argenziano g. a strange atypical spitz tumor. dermatol pract concept. 2019;9(3):237-238. doi: https://doi.org/10.5826/dpc.0903a19 accepted: february 12, 2019; published: july 31, 2019 copyright: ©2019 bassi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, md, c/o ii policlinico, edificio 9, primo piano, via pansini 5 80131 napoli, italy. email: piccolo.vincenzo@gmail.com figure 1. small pink-red papule on the right knee (0.8  × 1 cm) with a cross shape distribution of the pigment. [copyright: ©2019 bassi et al.] figure 2. multicomponent pattern with blue to black dots and globules, blue-white veil, and pinkish color at the periphery of the lesion. [copyright: ©2019 bassi et al.] 238 letter | dermatol pract concept 2019;9(3):19 melanocytes were mostly arranged in confluent fascicles, with retraction artifacts. there was prominent central and lateral pagetoid spread (figure 3). a final diagnosis of atypical spitz tumor (ast), with free margins, was made. asts have been regarded as “borderline” melanocytic lesions with overlapping features with spitz nevus and spitzoid melanoma, but their true biological significance is still poorly understood. pediatric asts seem to be associated with minimal lethal potential. in our case the clinical diagnosis was not straightforward; the site and the patient’s age led us to suspect initially a spitz with an atypical presentation [1]. the atypical dermoscopy presentation and the atypical melanocytic proliferation of spitzoid cells led us to the final diagnosis. given the complexities in interpretation, great care should be given when dealing with spitzoid lesions that show any degree of deviation from the classic features of spitz nevus. reference 1. moscarella e, piccolo v, argenziano g, et al. problematic lesions in children. dermatol clin. 2013;31(4):535-547. figure 3. (a) histopathological examination shows a raised, well-circumscribed, slightly asymmetric dermoepidermal atypical melanocytic proliferation associated with marked hyperkeratosis and irregular hyperplasia (h&e, original magnification ×2.5). (b) there is prominent central and lateral pagetoid spread of melanocytes and no epidermal ulceration (h&e, original magnification ×10). (c) pigmented melanocytes display an epithelioid spindle (spitzoid) morphology and are mostly arranged in confluent fascicles with peripheral retraction artifacts (h&e, original magnification ×20). (d) melanocytes show mild pleomorphism and are intermingled with numerous melanophages (h&e, original magnification ×40). h&e = hematoxylin and eosin. [copyright: ©2019 bassi et al.] a c b d dermatology: practical and conceptual 304 letter | dermatol pract concept 2019;9(4):13 dermatology practical & conceptual introduction nevi in children undergo morphological changes characterized by a specific dermoscopic pattern. in the majority of cases childhood nevi present dermoscopically with a globular structure, but in older children they can present with a reticular and mixed pattern. the total number of nevi increases during childhood and decreases in adulthood and leads to almost complete disappearance of nevi in advanced age (with the exception of dermal and congenital nevi). nevi involute in 3 different pathways: via “halo” phenomenon, a regression pattern, and a gradual involution (no evidence of regression pattern or halo phenomenon). two different perilesional phenomena of melanocytic nevus can be observed: depigmentation, found in halo nevus (hn), and eczema, related to meyerson nevus. halo phenomenon is a result of an immunological mechanism in which nevocellular antigens are recognized by the immune system, both humoral and cell-mediated. hn, also known as sutton nevus, is a benign type of nevus commonly found in children that presents with a central pigmented part surrounded by a hypopigmented zone. case presentation we report an unusual presentation of hn in 11-year-old girl. a clinically heavily pigmented verrucous lesion localized on the back was found, measuring 5 × 5 mm, with 3 mm of surrounding hypopigmentation. clinically the lesion was verrucous, which is not common in hn (figure 1). dermoscopy showed criteria for a melanocytic lesion, central nonspecific an unusual presentation of halo nevus in a child mikela petkovic1, slobodna murat susic1, ruzica jurakic toncic1 1 university department of dermatology and venereology, university hospital center and school of medicine, zagreb, croatia key words: halo nevus, sutton nevus, inflammatory nevus, hyperkeratotic nevus citation: petkovic m, murat susic s, jurakic toncic r. an unusual presentation of halo nevus in a child. dermatol pract concept. 2019;9(4):304-305. doi: https://doi.org/10.5826/dpc.0904a13 accepted: april 24, 2019; published: october 31, 2019 copyright: ©2019 petkovic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, department of dermatology and venereology, university hospital center zagreb, school of medicine university of zagreb, salata 4, 10000 zagreb, croatia. email: rjtoncic@gmail.com figure 1. the patient presented with sharply demarcated peripheral hypopigmentation with central hyperkeratotic nevus. [copyright: ©2019 petkovic et al.] letter | dermatol pract concept 2019;9(4):13 305 figure 2. dermoscopy showed centrally nonspecific dermoscopic structure and peppering surrounded by intensive white color and keratin plugs. [copyright: ©2019 petkovic et al.] figure 3. on higher magnification atypical vessels were found, surrounded by a peripheral rim of intense hypopigmentation. [copyright: ©2019 petkovic et al.] figure 4. on magnification (×15), histopathology showed focally thinned, hyperkeratotic epidermis with small nests of nevus cells with abundant melanin in the basal layer of the epidermis. in the papillary dermis significant fibrosis and edema were found, along with evenly distributed lymphocytic infiltrate and clusters of pigmentophages. [copyright: ©2019 petkovic et al.] dermoscopic structure with peppering, suggesting regression of lesion. peripherally intensive white color and keratin plugs were found (more pronounced under nonpolarized dermoscopy) (figures 2 and 3). duration of the lesion was unknown. the clinical and dermoscopic presentation were primarily indicative of a benign lesion, but it was excised because of its atypical clinic appearance. histology showed focally thinned, hyperkeratotic epidermis. small nests of nevus cells with abundant melanin were found in the basal layer of the epidermis. in the papillary dermis, significant fibrosis and edema were found, along with evenly distributed lymphocytic infiltrate and clusters of pigmentophages (figure 4). after clinicohistopathological correlation, the diagnosis of “inflammatory and hyperkeratotic halo nevus of children” was established. conclusions this is a case of an unusual presentation of hn with hyperkeratotic changes of the epidermis. this observation was described by 1 group of authors [1]. the existence of this entity is still elusive, since there are no other described cases in children or adults to our knowledge. hyperkeratosis, an epidermal hyperplasia, is not a common finding in nevus, but it can be observed and hyperkeratotic changes found in nevus are thought to be a result of higher expression of ki 67 [2]. the first description and series of case reports of hyperkeratotic hn in children was done by patrizi et al [1]. halo phenomenon can be observed in some other benign or malignant entities; therefore, all lesions with depigmentation should be examined with caution. it remains elusive why only few halo nevi develop hyperkeratotic changes, which is observed in our case. awareness of its existence is important in order to avoid unnecessary surgery in children. references 1. patrizi a, neri i, sabattini e, rizzoli l, misciali c. unusual inflammatory and hyperkeratotic halo naevus in children. br j dermatol. 2005;152(2):357-360. 2. horenstein mg, prieto vg, burchette jl, shea cr. keratotic melanocytic nevus: a clinicopathologic and immunohistochemical study. j cutan pathol. 2000;27(7):344-350. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2013;3(4):5 19 systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions alexander d. stevenson1, sharon mickan2, susan mallett3, mekhala ayya1 1 university of oxford, oxford, england, united kingdom 2 centre for evidence-based medicine, department of primary care health sciences, university of oxford, oxford, england, united kingdom 3 department of primary care health sciences, university of oxford, oxford, england, united kingdom key words: reflectance confocal microscopy, melanoma, diagnosis, systematic review, meta-analysis, dermoscopy citation: stevenson ad, mickan s, mallett s, ayya m. systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. dermatol pract conc. 2013;3(4): 5. http://dx.doi.org/10.5826/ dpc.0304a05. received: june 5, 2013; accepted: august 25, 2013; published: october 31, 2013 copyright: ©2013 stevenson et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: alexander stevenson, fracgp, isabella plains medical centre, canberra act australia. email address: dradstevenson@gmail.com. background: melanoma is a cancer of the skin and is increasing in incidence in the uk and europe. melanoma is a condition that is often curable if detected at an early stage, which makes accurate diagnosis vital. reflectance confocal microscopy (rcm) is a tool used to image the skin. it gives high magnification images of the skin, which may provide more accurate diagnosis of lesions that are equivocal on clinical examination and dermoscopy. objective: to determine the diagnostic accuracy of reflectance confocal microscopy (rcm), for melanoma diagnosis, as an add-on test to clinical examination and dermoscopy in the diagnosis of equivocal pigmented skin lesions using histopathology as the reference standard. methods: a search was conducted of medline, embase and six other electronic databases from inception to present. forward citation searching and hand searching of reference lists were also conducted. diagnostic accuracy studies that assess rcm in the diagnosis of melanoma were included in the review. two contributors conducted the search, data extraction and assessment of methodological quality using quadas-2. statistical analysis was performed using hierarchical bivariate random effects meta-analysis. results: 951 titles and abstracts were screened. five studies comprising 909 lesions were eligible for meta-analysis. meta-analysis returned a per lesion sensitivity of 93% [95% ci 89-96] and a specificity of 76% [95% ci 68-83]. conclusions: the utility of reflectance confocal microscopy (rcm) as an add-on test for the diagnosis of melanoma depends on the trade off between over-excising benign lesions and misdiagnosing melanoma as benign. this becomes important when considering lesions on surgically difficult or cosmetically important areas of the body. abstract 20 review | dermatol pract concept 2013;3(4):5 the 1990’s. the devices are now small and ergonomically able to image most areas of the skin. the diagnostic features are easy to learn and reproducible [13,16]. the devices themselves are quite, they are in limited use in clinical practice [17] and combined with the time to assess each lesion, may restrict the use to specialist clinics. a comprehensive search found no systematic reviews or meta-analysis. systematic reviews are important as they allow for a more transparent and objective appraisal of the evidence. meta-analysis where appropriate can enhance the precision of the estimates of individual studies [18]. the objective for this review is to examine the diagnostic accuracy of rcm in the diagnosis of melanoma as an add-on test for lesions that are clinically and/or dermoscopically equivocal/suspicious for melanoma in cohort studies that have used a predefined threshold. this must be a pre-defined scoring system or system of diagnosis but there is no restriction on the system. metaanalysis will be conducted if there is sufficient consistency between studies in the way the thresholds are applied. methods search strategy electronic searches were conducted of medline, embase, cinahl, the cochrane register of diagnostic test accuracy studies, dare (database of abstracts of reviews of effects), health technology assessment (hta) database (the cochrane library), medion (the medion database) and nhs economic evaluation database (nhseed). the detailed search strategy for medline (pubmed) used the following terms, cslm, laser microscope*, confocal microscope*, confocal scanning microscope*, microscopy, confocal (mesh), melanoma (mesh), melanoma*, hutchinson* freckle, nevus, nevi, mole*, skin cancer*, cutaneous neoplasm*, skin neoplasms (mesh), skin neoplasms, nevus[mesh], melanocytes[mesh], skin tumour*, skin tumor*, skin lesion*, melanocytic. the terms were adapted for the other databases as appropriate. the searches were performed from database inception. the search was conducted by two independent reviewers. manual searches were conducted of the reference lists of the review articles and studies included in the final analysis. forward citation searching was performed on all relevant retrieved articles via scopus and science citation index. the ‘related articles’ function of pubmed was used to look at the first 20 articles retrieved. no language restriction was applied to the electronic searches. the search was restricted to studies on humans. all the major journals were indexed. the searching authors felt that there was sufficient information provided in the articles and therefore correspondence with authors was not performed. the studies were included if they met the following criteria: introduction melanoma is a cancer of the skin which is increasing in frequency both in the uk and europe1. cancer research uk (cruk) have calculated that in the 35 years from 1975-2010 the age standardized incidence rate in the uk rose from 3.2 per 100000 to 17.2 per 1000002. the biggest risk factor for developing melanoma is exposure to ultraviolet light [3]. prognosis for melanoma is very much dependent on the stage of the disease when it is diagnosed so early accurate diagnosis of melanoma is crucial. the five-year survival for stage 1a melanoma is 97%. the five-year survival drops rapidly to 10-15% for stage 4 metastatic disease [4]. this rapid decline in survival with higher stage is because the only potentially curative treatment is surgical excision [5]. adjuvant therapy for non-metastatic melanoma has not yet been demonstrated to provide a survival benefit [6] and no therapy has proven to extend survival for metastatic melanoma [7,8]. the currently accepted best diagnostic method for melanoma is dermoscopy [9]. a recent meta-analysis of dermoscopy in the diagnosis of melanoma pooled the sensitivities and specificities and found a sensitivity of 91% and a specificity of 86% [10]. most dermoscopy research has been conducted in white skinned populations however there is some evidence of the ability of dermoscopy to work equally well in non-white populations [11]. reflectance confocal microscopy (rcm) also known as confocal laser scanning microscopy (clsm) of the skin was first described in the early 1990s [12]. this technology uses a near infrared laser to obtain images of the top layers of the skin. these images are magnified such that they are “quasihistological.” from the images, information can be obtained regarding cell structure and the architecture of the surrounding tissues. the images are analyzed and combinations of features are assessed to give a positive or negative diagnosis of melanoma. several criteria have been developed to analyze images of rcm [13]. the test itself takes about ten minutes for imaging and evaluation of a skin lesion. the goal of diagnosing melanoma is to correctly identify melanomas, while at the same time, excising as few benign lesions as possible. the most appropriate first line examination for this is dermoscopy, which has been shown to be a more accurate diagnostic tool than unaided eye examination [9]. given the time needed to use rcm, it is most appropriate as a secondary examination add test to dermoscopy for lesions where dermoscopy does not give a confident diagnosis. this role has been suggested previously [14,15]. there have been many narrative reviews on the use of rcm in the diagnosis of melanoma. these articles have focused mainly on describing the technology and discussing its potential role in melanoma diagnosis. rcm technology has advanced since the first instruments were introduced in review | dermatol pract concept 2013;3(4):5 21 assessment of methodological quality two authors independently assessed methodological quality of the studies using the quadas-2 tool [23]. any disagreements were resolved by discussion. the results of the quality assessment are presented with a textural methodological quality summary and graphical representation. results search the search of the databases was conducted on february 8, 2012. after screening for duplicates 951 studies were examined. a flow diagram of the search can be found in figure 1. after examining titles and abstracts the full text of 39 articles were retrieved. there were five articles that met the inclusion criteria. these are shown in table 1. excluded studies there were five studies, which were derivation studies, or studies that did not validate on a new set of patients. there were 15 descriptive correlation studies, which only described which rcm features were associated with melanoma. there were four case reports or small case series, two narrative review articles, one editorial and one study looking at observer agreement of the rcm features associated with melanoma. methodological quality assessment the exclusion criteria for studies in the review included two major methodological quality criteria. the studies could not be case control studies nor could they be studies that set a diagnostic threshold i.e.: studies that developed a scoring system. case control studies have been demonstrated to overestimate diagnostic accuracy when compared to cohort studies that use an appropriate spectrum [24]. studies that derive/set a threshold use multivariable analysis to derive a score. these scores are derived on a certain population. it is very often the case that these scoring systems perform worse when they are validated in another population, however similar [25]. this resulted in a low risk of bias regarding the applicability of the included patients and the appropriateness of the index test. in this study, the reporting of patient selection was generally poor however all domains were graded as low risk of bias. the methodological quality assessment is shown graphically in table 2. findings five studies were identified comprising 909 lesions. the average prevalence of melanoma was 36.2% with a range from 29-39. three studies used the rcm diagnostic scortype of study cohort studies of diagnostic test accuracy with a predefined threshold that was established on separate data are eligible for inclusion. target condition melanoma of the skin. study population patients presenting with lesions suspicious for melanoma that were equivocal to clinical and dermoscopic diagnosis. no restriction was placed upon participant characteristics such as age, sex, ethnicity etc. index test reflectance confocal microscopy. there was no restriction on the type of algorithm or diagnostic process. reference standard histopathology of the excised skin lesion or long-term clinical follow-up. data extraction and management per lesion data was extracted onto a study specific data extraction sheet by two authors independently. the following data was collected: the details of the study population, details of the reference standard and index test, blinding of the reference standard and the index test. prevalence of melanoma, information to complete the 2 x 2 table. statistical analysis and data synthesis data were extracted by two reviewers independently. hierarchical bivariate random-effects meta-analysis [19] was used to perform the statistical meta-analysis as this has been demonstrated to be the most robust method [19]. if there appeared to be no or minimal threshold differences between the studies clinically or on the receiver operator characteristic (roc) plot then a summary statistic in the form of sensitivity and specificity was planned [20]. if there were, clinically and visually, the appearance of a threshold effect then the summary roc curve was planned as the most appropriate summary measure [20]. if a study presented several sensitivity and specificity estimates on a receiver operator characteristic curve (roc) then the point estimate used for meta-analysis was the point chosen by the author of the article. the results are presented graphically using revman5 [21]. the studies were combined in a statistical meta-analysis using the metandi function in stata [22]. subgroup analyses was intended for investigation of operator experience and algorithm method however there was an insufficient number of studies. 22 review | dermatol pract concept 2013;3(4):5 per lesion sensitivity and specificity are shown on a forest plot in figure 2. there appears to be minimal heterogeneity per lesion in sensitivity across the studies, with more heterogeneity in the specificity. based upon this a hierarchical summary receiver operator characteristic (hsroc) curve was obtained using the bivariate method. the diagnostic accuracy results are quite similar in all studies and there is no evidence of a threshold effect or apparent threshold effect. the plot of this is shown in figure 3. from meta-analysis the operating point had a sensitivity of 93.3% [95% ci 88.5-96.2, range 91% to 97%] and a specificity of 75.9% [95% ci 67.9-82.5, range 68% to 86%]. ing system developed by pellacani 200526 (curchin 2011, guitera 2009, pellacani 2007), two used a scoring system for lentigo maligna developed by guitera 201027 (guitera 2010, curchin 2011) and one did not use a specific diagnostic algorithm but made rcm diagnoses based upon pre-specified melanoma associated features (langley 2007). the operators were self identified as experienced in four out of the five studies and inexperienced in one (curchin 2011). there were no explicit differences in the spectrum of disease of patients being examined with rcm. all studies examined equivocal skin lesions. one study was exclusively limited to equivocal skin lesions on the face (guitera 2010) and two studies excluded lesions on the face (pellacani 2007 guitera 2009). figure 1. prisma flow diagram. [copyright: ©2013 stevenson et al.] review | dermatol pract concept 2013;3(4):5 23 patient outcomes compared to the existing diagnostic pathway. it is not enough just to measure the sensitivity and specificity [28]. duff et al. [29] and rampen et al. [30] followed patients after melanoma screening, searching for missed melanomas. duff found no missed melanomas from 1961 patients and rampen found seven invasive melanomas and two lentigo maligna (a type of melanoma in situ) from 9968 patients seen in the clinic. this data suggests that, in real clinical contexts using current diagnostic technology, few melanomas are missed. the purpose of this review was to evaluate rcm as an add-on test to existing diagnostic pathways, not to evaluate it as a replacement test. it has been suggested that rcm is more sensitive than dermoscopy [13]. if all lesions that were suspicious to the unaided eye examination were examined given the low number of studies included in the review, statistical subgroup analysis and covariate hierarchical modeling for investigation of heterogeneity were not performed due to low statistical power. discussion when examining the use of a new diagnostic test it is important to consider whether its introduction will improve table 1. characteristics of included studies first author and year country of study algorithm patient characteristics number of lesions reference standard number of patients melanoma frequency curchin 201117 australia pellacani 2005, guitera 2010 data not available 35 histology not available 37% guitera 200915 italy and australia pellacani 2005 median age and iqr 47(36-60). f:m 149:177 326 histology 326 37% guitera 201027 australia italy and usa guitera 2010 data not available 73 histology/ long term follow up not available 37% pellacani 200714 italy and australia pellacani 2005 median age and iqr 47.7(35.9-60.4). f:m 158:174 351 histology 332 37% langley 200733 canada no named diagnostic algorithm average age: 44 range: 16-84 125 histology 125 29% [copyright: ©2013 stevenson et al.] table 2. quadas-2 risk of bias assessment. study risk of bias applicability concerns patient selection index test reference standard flow and timing patient selection index test reference standard curchin 2011        guitera 2009        guitera 2010 ?       pellacani 2007 ?       langley 2007         low risk  high risk ? unclear risk [copyright: ©2013 stevenson et al.] figure 2. forest plot of the studies. [copyright: ©2013 stevenson et al.] 24 review | dermatol pract concept 2013;3(4):5 if the role of rcm is as an add-on test, all lesions that are examined with rcm have already been declared as positive by the existing pathway. using rcm in this way will not increase the detection rate of the few melanomas that are currently being misdiagnosed as benign as they will have already left the diagnostic pathway. it is possible that the availability of rcm may change clinician confidence and diagnostic threshold. instead of the clinical/dermoscopic diagnosis being the final step before a management decision is made, rcm would exist as an add-on test. the individual clinician might change his or her threshold to be more sensitive and less specific in order to capture more disease. this has not been addressed in these studies however it may change the sensitivity and specificity of rcm in actual clinical practice. another area where it may be helpful is if the clinician is suspicious of a lesion, especially featureless pink lesions, and are considering monitoring it the clinician may well use rcm and find that it is positive and proceed with excision. the risk here is if it is rcm negative and the clinician does not follow it up with some monitoring procedure they may miss a melanoma. to gauge the trade off between the reduction in unnecessary biopsies and the missed melanoma diagnoses the sensitivity and specificity can be applied to an estimated prevalence of melanoma in the spectrum of patients that would be selected for rcm examination. the average prevalence of melanoma in the studies included in the review was 36%. in a 2002 systematic review of dermoscopy the mean frequency of melanoma was 28%. previous research has suggested a malignant to benign ration of 1:4 with the expert use of dermoscopy [32]. this translates to a frequency melanoma in dermoscopy positive lesions of 20%. if we assume that in real clinical practice the clearly positive melanomas would not be examined with rcm, we can gauge an estimated frequency of disease in dermoscopy positive lesions would be slightly lower. figure 4 demonstrates a flow diagram of the impact of rcm in its proposed role as an add on test to dermoscopy using a sensitivity of 93% and a specificity of 75% as calculated in the meta-analysis and a melanoma frequency of 20%. for 1000 dermoscopy positive lesions, there would be 200 melanomas. rcm would correctly identify 186 of these and miss [14]. there would be 192 benign lesions excised and 608 benign lesions not excised. the only benefit of rcm in this pathway is to increase the specificity of diagnosis and reduce the number of benign lesions excised. the value of reflectance confocal microscopy as an add-on test in the diagnosis of melanoma depends on the trade off between the harms associated with excising benign lesions and the harms associated with misdiagnosing a melanoma as benign. if rcm is to be used in clinical practice a decision has to be made weighing up the consequences with dermoscopy and rcm then this is no doubt the case. this, however, is not helpful for clinical practice. it takes seconds to examine a lesion with dermoscopy and minutes to examine a lesion with rcm. rcm is not going to take on the role of dermoscopy. therefore it is not useful to compare rcm to the sensitivity and specificity of dermoscopy. instead, it should be considered as an add-on test to the best current clinical diagnostic tool, which in this case is dermoscopy. if rcm were to be used as an add-on test in clinical practice, the population examined with rcm would be the narrow pre-selected group of those in whom dermoscopy was not clearly positive or not clearly negative. the population of lesions being examined with rcm in these studies was not clear and reproducible. the terms “clinically suspicious” and “equivocal” do not give the reader sufficient information. it is not certain that the lesions examined by rcm in the studies were the same that would be examined by rcm in clinical practice. if the lesions examined in these studies included those that were clearly melanoma then the spectrum of disease would be different to that in clinical use and this could bias the result leading to an over estimate of sensitivity and specificity. these factors combined with the concept that diagnostic accuracy determined from laboratory condition studies may be different from the diagnostic accuracy in the real life clinical setting [31], mean that the external validity of these results has to be taken cautiously. figure 3. hierarchical summary receiver operator characteristic curve. [copyright: ©2013 stevenson et al.] review | dermatol pract concept 2013;3(4):5 25 in the images obtained. a study looking at the agreement between observers in identifying these features found high overall levels of reproducibility [16]. weaknesses a weakness of this review is that the current studies may not have focused on the pertinent patient populations to test the ability of rcm as an add-on test to dermoscopy. it is noted that in three of the five studies included in this review the main operators using rcm were giovanni pellacani and of missing a melanoma and the harms averted by avoiding performing un-necessary excisions. excision of skin lesions on most areas of the body is often a quick and easy process that does not carry a great risk of morbidity. the situations where this is not the case are when lesions are on cosmetically sensitive areas of the body such as the face, head and neck or where skin surgery becomes complex, involving the use of skin grafts or flaps. it is these lesions where the reduction in benign lesion excision would have the most impact. the algorithms that have been developed for use in melanoma diagnosis are based upon several features observed figure 4. proposed role of rcm in diagnostic pathway: hypothetical example based on 1000 lesions positive with dermoscopy. [copyright: ©2013 stevenson et al.] 26 review | dermatol pract concept 2013;3(4):5 13. gerger a, hofmann-wellenhof r, samonigg h, smolle j. in vivo confocal laser scanning microscopy in the diagnosis of melanocytic skin tumours. br j dermatol. 2009;160(3):475-81. 14. pellacani g, guitera p, longo c, et al. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759-65. 15. guitera p, pellacani g, longo c, et al. in vivo reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. j invest dermatol. 2009;129(1):131-8. 16. pellacani g, vinceti m, bassoli s, et al. reflectance confocal microscopy and features of melanocytic lesions: an internet-based study of the reproducibility of terminology. arch dermatol. 2009;145(10):1137-43. 17. curchin ces, wurm emt, lambie dlj, et al. first experiences using reflectance confocal microscopy on equivocal skin lesions in queensland. australas j dermatol. 2011;52(2):89-97. 18. egger m, smith gd, o’rourke k. rationale, potentials, and promise of systematic reviews. in: egger m, smith gd, altman dg (eds.). systematic reviews in health care: meta-analysis in context. 2nd ed. london: bmj books, 2001. 19. harbord rm, whiting p, sterne ja, et al. an empirical comparison of methods for meta-analysis of diagnostic accuracy showed hierarchical models are necessary. j clin epidemiol. 2008;61(11):1095-103. 20. macaskill p gatsonis c, deeks jj, harbord rm, takwoingi y. chapter 10: analysing and presenting results. in: deeks jj bossuyt pm, gatsonis c (eds.). cochrane handbook for systematic reviews of diagnostic test accuracy version 1.0. the cochrane collaboration, 2010. 21. copenhagen: the nordic cochrane centre tcc. review manager (revman). 5.1 ed, 2011. 22. harbord r. metandi: stata module to perform meta-analysis of diagnostic accuracy. statistical software components s456932, boston college department of economics, 2008. 23. whiting pf, rutjes aw, westwood me, et al. quadas-2: a revised tool for the quality assessment of diagnostic accuracy studies. ann int med. 2011;155(8):529-36. 24. lijmer jg, mol bw, heisterkamp s, et al. empirical evidence of design-related bias in studies of diagnostic tests. jama. 1999;282(11):1061-6. 25. buntinx f, aertgeerts b, aerts m, et al. chapter 8. multivariable analysis in diagnostic accuracy studies: what are the possibilities? in: knottnerus ja, buntinx f (eds.). the evidence base of clinical diagnosis: theory and methods of diagnostic research. 2nd ed. oxford: wiley-blackwell, 2009. 26. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy of pigmented skin lesions—improvement in melanoma diagnostic specificity. j am acad dermatol. 2005;53(6):979-85. 27. guitera p, pellacani g, crotty ka, et al. the impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. j invest dermatol. 2010;130(8):2080-91. 28. lord sj, irwig l, simes rj. when is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? ann int med. 2006;144(11):850-5. 29. duff cg, melsom d, rigby hs, kenealy jm, townsend pl. a 6 year prospective analysis of the diagnosis of malignant melanoma in a pigmented-lesion clinic: even the experts miss malignant melanomas, but not often. br j plas surg. 2001;54(4):317-21. pascale guitera. in addition the small number of studies and poor reporting in the primary studies limited the scope of the review. summary reflectance confocal microscopy may contribute to the diagnosis of melanoma as an add-on test in the diagnostic pathway to reduce over-diagnosis following dermoscopy. reduction in the excision rate of benign lesions that look suspicious on clinical examination may be important particularly where treatment by removal is potentially difficult or harmful. as no diagnostic test is 100% accurate, each clinician and patient will have to decide if the trade off between missing a small number of melanomas is worth the reduction in excision of benign lesions. references 1. de vries e, coebergh jw. cutaneous malignant melanoma in europe. eur j cancer. 2004;40(16):2355-66. 2. uk cr. melanoma statistics and outlook. [29/09/2012]; available from: http://cancerhelp.cancerresearchuk.org/type/melanoma/ treatment/melanoma-statistics-and-outlook. 3. lucas r, mcmichael t, smith w, armstrong bk. solar ultraviolet radiation: global burden of disease from solar ultraviolet radiation: world health organization; 2006. 4. balch cm, gershenwald je, soong sj, thompson jf, atkins mb, byrd dr, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199-206. 5. sladden mj, balch c, barzilai da, et al. surgical excision margins for primary cutaneous melanoma. cochrane database syst rev. 2009(4):cd004835. 6. wheatley k, ives n, hancock b, et al. does adjuvant interferonalpha for high-risk melanoma provide a worthwhile benefit? a meta-analysis of the randomised trials. cancer treat rev. 2003;29(4):241-52. 7. marsden jr, newton-bishop ja, burrows l, et al. revised u.k. guidelines for the management of cutaneous melanoma 2010. br j dermatol. 2010;163(2):238-56. 8. ives nj, stowe rl, lorigan p, wheatley k. chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. j clin oncol. 2007;25(34):5426-34. 9. menzies sw, zalaudek i. why perform dermoscopy? the evidence for its role in the routine management of pigmented skin lesions. arch dermatol. 2006;142(9):1211-2. 10. rajpara sm, botello ap, townend j, ormerod ad. systematic review of dermoscopy and digital dermoscopy/artificial intelligence for the diagnosis of melanoma. br j dermatol. 2009;161(3):591604. 11. de giorgi v, trez e, salvini c, et al. dermoscopy in black people. br j dermatol. 2006;155(4):695-9. 12. rajadhyaksha m, grossman m, esterowitz d, webb rh, anderson rr. in vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. j invest dermatol. 1995;104(6):946-52. review | dermatol pract concept 2013;3(4):5 27 nant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150(4):687-92. 33. langley rgb, walsh n, sutherland ae, et al. the diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of benign and malignant melanocytic lesions: a prospective study. dermatology. 2007;215(4):365-72. 30. rampen fh, casparie-van velsen ji, van huystee be, kiemeney la, schouten lj. false-negative findings in skin cancer and melanoma screening. j am acad dermatol. 1995;33(1):59-63. 31. gur d, bandos ai, cohen cs, et al. the “laboratory” effect: comparing radiologists’ performance and variability during prospective clinical and laboratory mammography interpretations. radiology. 2008;249(1):47-53. 32. carli p, de giorgi v, crocetti e, et al. improvement of maligdermatology: practical and conceptual review | dermatol pract concept 2019;9(3):1 169 dermatology practical & conceptual introduction dermoscopy is a fascinating bridge between clinical and histological examination that has become a key tool for the evaluation of pigmented and nonpigmented skin tumors because of its ability to reveal findings not visible to the naked eye [1,2]. besides this classic application, it is gaining appreciation in areas other than dermato-oncology, especially inflammatory dermatology (inflammoscopy) [1,2]. while a well-established and structured approach for the analysis of dermoscopic images is available in the field of tumoral diseases, criteria and terminology used for inflammatory dermatoses in the literature are often variable, metaphoric, and poorly comprehensible, with consequent lack of a systematic analytic approach [1,2]. for this reason, a set of 5 dermoscopic parameters (with a total of 31 subitems) has been proposed by a consensus document of the international dermoscopy society as a basic guide to use in general dermatology [3]: (i) vessels (including morphology and distribution); (ii) scales (including color and distribution); (iii) follicular findings; (iv) “other structures” (structures other than vessels/scales; including color and morphology); and (v) “specific clues” (features that, when present, are strongly suggestive of only 1 diagnosis due to a strict dermoscopicpathological correlation). as vascular structures and scales are the main characterizing dermoscopic features of inflammatory diseases, the selection of proper equipment is of utmost importance [1]. in this dermoscopy of inflammatory dermatoses (inflammoscopy): an up-to-date overview enzo errichetti1 1 institute of dermatology, santa maria della misericordia university hospital, udine, italy key words: dermoscopy, differential diagnosis, general dermatology, inflammoscopy citation: errichetti e. dermoscopy of inflammatory dermatoses (inflammoscopy): an up-to-date overview. dermatol pract concept. 2019;9(3):169-180. doi: https://doi.org/10.5826/dpc.0903a01 accepted: june 2, 2019; published: july 31, 2019 copyright: ©2019 errichetti. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: enzo errichetti, md, msc, institute of dermatology, santa maria della misericordia university hospital, piazzale santa maria della misericordia, 15, 33100 udine, italy. email: enzoerri@yahoo.it in addition to its use in pigmented and nonpigmented skin tumors, dermoscopy is gaining appreciation in assisting the diagnosis of nonneoplastic diseases, especially inflammatory dermatoses (inflammoscopy). in this field, dermoscopic examination should be considered as the second step of a “2-step procedure,” always preceded by the establishment of a differential diagnosis on the basis of clinical examination. in this paper, we sought to provide an up-to-date overview on the use of dermoscopy in common inflammatory dermatoses based on the available literature data. for practical purposes, the analyzed dermatoses are grouped according to the clinical presentation pattern, in line with the 2-step procedure principle: erythematous-desquamative and papulosquamous dermatoses, papulokeratotic dermatoses, erythematous facial dermatoses, sclero-atrophic dermatoses, and miscellaneous.  abstract 170 review | dermatol pract concept 2019;9(3):1 dermoscopic analysis): erythematousdesquamative and papulosquamous dermatoses, papulokeratotic dermatoses, erythematous facial dermatoses, scleroatrophic dermatoses, and miscellaneous. erythematousdesquamative and papulosquamous dermatoses psoriasis psoriasis is surely one of the dermatoses that benefits most from dermoscopic analysis as it usually displays a repetitive pattern, ie, uniformly distributed dotted vessels (histologically corresponding to dilated capillaries in regularly elongated dermal papillae) over a light or dull red background along with diffuse white scales (histologically corresponding to parakeratosis) (figure 1a) [1]. notably, psoriatic vessels are typically uniform in size, shape, and distance among each other [1,2]. in hyperkeratotic lesions, vascular structures may be poorly visregard, the use of noncontact polarized dermatoscopes is usually recommended as they preserve such findings; an interface fluid (eg, oil or gel) is sometimes required to enhance the visualization of structures covered by overlying scaling [1,2]. of note, dermoscopic assessment of inflammatory diseases should be considered as the second step of a “2-step procedure,” always preceded by the establishment of a differential diagnosis on the basis of clinical examination [1,2]. indeed, such conditions often display only poorly specific dermoscopic findings that, however, may be useful if used in the context of a specific differential diagnosis [1,2]. this paper aims to provide an up-todate overview on the use of dermoscopy in common inflammatory dermatoses based on the available literature data. for practical purposes, the analyzed dermatoses are grouped according to the clinical presentation pattern, in line with the 2-step procedure principle (ie, clinical differential diagnosis followed by figure 1. uniform dotted vessels and diffuse white scales in psoriasis (a). dotted vessels distributed in clusters and yellow scales and serocrusts in eczematous dermatitis (b). the typical wickham striae of lichen planus; brownish dots are also visible around wickham striae (c). lichen nitidus typically reveals roundish, well-defined, white areas devoid of physiological skin markings (d). [copyright: ©2019 errichetti.] a c b d ible and scale removal or the use of a fluid interface may facilitate their visualization [1,2]. in addition, scale removal may also display tiny red blood drops, the so-called dermoscopic “auspitz sign” [1,2]. of note, vessels may sometimes appear as red globules (defined as round vessels having a diameter more than 0.1 mm) on dermoscopic examination, especially on the legs (due to the higher hydrostatic pressure of this area) [1,2,4]. both dotted and globular vessels look like dilated, elongated, and convoluted (bushy) capillaries under higher magnifications (×100-×400) [1,2,4]. while differentiating dotted vessels from globular vessels has not been found to be of any help in the diagnostic accuracy in psoriasis, a recent study showed that the presence of globular vessels in psoriatic lesions is a negative response predictor to narrowband ultraviolet b (nb-uvb) phototherapy [4]. the association of uniform dotted vessels on a red background and diffuse white scales has been found to display good diagnostic accuracy for psoriasis, with a sensitivity of 84.9% and a specificity of 88.0% [5]. indeed, although dotted/globular vessels and white scaling also characterize bowen disease, in this condition vessels are more commonly distributed in a focal/clustered pattern and are different in size, shape, and distance among each other [6]. in addition, the presence of uniform dotted vessels vs short, fine telangiectasias is helpful in differentiating psoriatic patches from superficial basal cell carcinoma [7]. in this regard, a recent study introduced a dermoscopic diagnostic model for the differentiation of solitary psoriatic plaques from intraepidermal carcinoma and superficial basal cell carcinoma, stating that the concomitant presence of red dots, a homogeneous vascular pattern, and a light red background yields a diagnostic probability of 99% for psoriasis [7]. importantly, uniform dotted/globular vessels may also be seen in lichen review | dermatol pract concept 2019;9(3):1 171 fungoides show thin linear vessels alone or in combination with red dots, forming the so-called “spermatozoon-like” structures, while dermatitis typically lacks linear vessels, unless overtreated with topical steroids [13]. lichen planus the dermoscopic hallmark of lichen planus is represented by wickham striae (figure 1c), which histologically correspond to hypergranulosis [1,2]. in addition to their network-like appearance, wickham striae may less commonly display other morphologies on dermoscopy, including linear, “radial streaming,” annular, round, “leaf venation” (delicate secondary striae branching from the centered whitish venation, linked together at either end, mimicking the crystal structure of snow) and “starry sky” (clustered, follicular white dots) aspect [1,2]. notably, wickham striae are typically white, yet they may also appear yellow or blue, respectively, on palmoplantar areas and in darkskinned patients [1,2]. importantly, network-like white structures similar to wickham striae may also be seen in scarring/resolving lesions of several dermatoses (pseudowickham striae), eg, discoid lupus erythematosus, nodular scabies, and prurigo nodularis [1,2]. they are due to dermal fibrosis and may be distinguished from wickham striae on the basis of the vascular pattern as they usually show vessels that are significantly more dilated than those visible in wickham striae [1,2]. additional findings visible in active lesions include the following: (1) dotted, globular, and/or linear vessels, mainly detectable at the periphery of the lesion and less commonly showing a perifollicular or diffuse arrangement; (2) white/ yellow dots; and (3) pigmented structures (dots, globules, and/or reticular or cloud-like areas) [1,2]. although all the above-mentioned findings may sometimes coexist in a steroids by displaying telangiectatic vessels [1,2]. eczematous dermatitis eczematous dermatitis consists of several distinct clinical entities that share the presence of spongiosis on histology, eg, atopic dermatitis, allergic contact dermatitis, stasis dermatitis, and asteatotic eczema [1,2]. the dermoscopic hallmarks of eczematous dermatitis include dotted vessels distributed in clusters or randomly (unspecific arrangement), corresponding to dilated capillaries in irregularly elongated dermal papillae, and yellow scales and serocrusts, resulting from hyperkeratosis and spongiosis/ exocytosis (figure 1b) [1,2]. hemorrhages may also be seen as a result of intense itching [1,2]. of note, the dermoscopic pattern of eczematous dermatitis varies according to the disease stage [1,2]. in detail, in acute phases yellow serocrusts and dotted vessels distributed in clusters or randomly are typically seen, while more or less uniform dotted vessels surrounded by a white halo are the main dermoscopic features in chronic phases (lichenification) [1,2]. obviously, overlapping pictures are often seen in clinical practice [1,2]. importantly, some subtypes of eczematous dermatitis may display peculiar additional features. in particular, stasis dermatitis often displays globular or glomerular vessels due to the presence of a higher hydrostatic pressure, chronic hand eczema commonly shows brownish-salmon-colored dots/ globules (representing spongiotic vesicles), and asteatotic eczema frequently reveals white scales having a double free edge (“rail-like” appearance) [1,2,10]. a case-control study has demonstrated that dermoscopy may support the differential diagnosis between chronic, resistant-to-treatment or relapsing eczema and patch-stage mycosis fungoides [13]. in detail, patches of mycosis simplex chronicus and secondary lichenification [2]. unlike psoriasis, however, in these conditions vessels are typically surrounded by a white halo due to the presence of hypergranulosis [2]. the dermoscopic features seen in specific subtypes of psoriasis do not differ significantly [1,8]. in fact, the dermoscopic pattern of the disease in specific body sites is identical to that of plaque psoriasis, with variations in the amount of scaling depending on the localization of the lesions [8]. in psoriatic balanitis and inverse psoriasis, lesions lack scaling, but the typical vascular pattern of regularly distributed red dots is evident on dermoscopic examination [6,8]. little or absent scaling is also typical of guttate psoriasis as this form of psoriasis is eruptive, thereby having little hyperkeratosis [9]. conversely, in scalp or palmoplantar psoriasis, the thick hyperkeratotic surface of the plaques does not allow the visualization of the underlying vascular structures, which are highlighted after removal of the scales [8,10,11]. in pustular psoriasis, palmoplantar and generalized forms, yellow globules (pustules) and crusts are also visible along with dotted vessels and white scaling, while follicular psoriasis is characterized by white follicular keratotic plugs surrounded by uniform dotted vessels [1,2]. the “red globular ring” pattern, with vessels distributed in a networklike arrangement, is another less common (but specific) vascular pattern visible in plaque-type psoriasis lesions [1,2]. as mentioned above, dermoscopy may also be helpful in treatment evaluation and monitoring. apart from the negative predictive value of globular vessels when psoriasis is treated with nb-uvb phototherapy, it has been demonstrated that hemorrhagic dots are a positive predictive sign suggesting a favorable clinical outcome in psoriasis treated with biological agents [12]. finally, dermoscopy can reveal an otherwise not clinically evident skin atrophy following treatment with potent topical 172 review | dermatol pract concept 2019;9(3):1 visible as well [1,2,5]. interestingly, an eczematous reaction may occur on the background of pityriasis rosea, especially in atopic patients, with yellow serocrusts/scaling and clustered dotted vessels visible on dermoscopy along with the peripheral collarette scaling (figure 2b) [1,2,5]. pityriasis lichenoides the term pityriasis lichenoides encompasses a spectrum of diseases that includes 2 main variants, ie, pityriasis lichenoides et varioliformis acuta (pleva) and pityriasis lichenoides chronica, although intermediate or overlapping forms do exist [17,18]. dermoscopic features of pleva and pityriasis lichenoides chronica differ significantly. specifically, dermoscopic appearance of pleva varies according to the “lesion age,” with very early lesions commonly displaying a purpuric are more pronounced or deep in this district [16]. dermoscopic assessment may be helpful in differentiating lichen nitidus from its main differential diagnoses, including follicular eczema and frictional lichenoid dermatosis, respectively characterized by roundish, equidistant, keratotic, whitish areas with blurry margins and discrete, more or less defined, whitish areas with retention of the normal skin furrows and regularly arranged dotted vessels [16]. pityriasis rosea both the herald patch and secondary lesions of pityriasis rosea typically show a characteristic peripheral whitish scaling (“collarette” sign) as well as dotted vessels, which, unlike psoriasis, are distributed in an irregular or focal pattern (figure 2a); diffuse or localized yellowish orange structureless areas may be single lesion, dermoscopic patterns of lichen planus usually vary according to disease stage. [1,2]. indeed, while early papules usually show subtle wickham striae over a reddish background, mature lesions display well-represented wickham striae and peripheral vessels. [1,2]. both of such structures tend to fade over time, concomitantly to the gradual appearance of pigmented structures (figure 1c) [1,2]. in long-standing lesions, pigmentary findings are often the only visible clue [1]. some clinical variants of lichen planus may reveal peculiar features [1,14]. relevant examples include annular lichen planus, in which wickham striae appear as a peripheral annular white structure with capillaries or pigmentary findings (according to lesion duration), and hypertrophic lichen planus, typically displaying follicular keratotic plugs [1,14]. in this last variant, wickham striae are often not visible because they are covered by the overlying hyperkeratosis [1]. apart from diagnostic purposes, dermoscopic examination may also be used to assess the likelihood of postinflammatory pigmentation persistence, with homogeneous, structureless, and light brown areas devoid of granularity being correlated with a shorter duration and granular pigmentation being associated with a longer course, and to monitor the evolution of lesions after therapy [15]. lichen nitidus dermoscopic examination of lichen nitidus typically reveals roundish, welldefined, white areas devoid of physiological skin markings (figure 1d) [16]. the absence of skin markings is a very relevant dermoscopic clue to recognize such a dermatosis as it is related to a quite characteristic histological finding, ie, flattening of the epidermis overlying the inflammatory infiltrate [16]. however, lesions on the penis may retain skin markings, probably because they figure 2. dermoscopy of pityriasis rosea shows the characteristic peripheral whitish scaling (“collarette” sign). no vessels are seen (a); pityriasis rosea in an atopic patient displays yellow serocrusts/scaling along with the peripheral whitish scaling collarette (b). central amorphous brownish crust surrounded by a peripheral scaling collarette and a purpuric halo is visible in a case of pityriasis lichenoides et varioliformis acuta (c). dermoscopic examination of pityriasis lichenoides chronica reveals an orange structureless area along with nondotted vessels (linear-irregular and branching vessels), white scaling, and sparse dotted vessels (d). [copyright: ©2019 errichetti.] a c b d review | dermatol pract concept 2019;9(3):1 173 tinguish extrafacial discoid lupus erythematosus from subacute lupus erythematosus [1,2,19]. papulokeratotic dermatoses porokeratosis the dermoscopic hallmark of all variants of porokeratosis is the presence of a well-defined, annular, peripheral, white hyperkeratotic structure (“white track”) having 2 free edges which appears as similar to the outlines of a volcanic crater as observed from a high point (figure 4a) [1]. such a keratotic rim may be hyperpigmented in disseminated superficial actinic porokeratosis and in dark-skinned patients [1]. from a histological point of view, it corresponds to the “cornoid lamella.” in this regard, dermoscopy may be helpful even in treatment monitoring [1]. the center of the lesions is usually whitish or brownish and may exhibit circular and/or linear whitish and/or hyperpigmented tracks, blue-gray dots, and dotted, linear, or globular vessels [1]. darier disease and grover disease because they have a strict histological similarity, darier disease and darier-like grover disease share a similar dermokeratoderma is typified by orange structureless areas [1,2,11]. in erythrodermic stage, prp features orange blotches and islands of nonerythematous (spared) skin displaying reticular vessels; unspecific whitish scaling and scattered dotted vessels over a reddish background may also be seen [18]. dermoscopic assessment of lesions on elbows and knees in circumscribed juvenile prp often displays whitish keratotic follicular plugs with a yellow peripheral keratotic ring, surrounded by an erythematous halo with linear and/ or dotted vessels; whitish scaling is also visible [2]. palmoplantar keratoderma in this form of prp shows the same aspect as the classic variants [11]. subacute lupus erythematosus subacute cutaneous lupus erythematosus is characterized by 2 constant dermoscopic findings, namely whitish scales (diffusely or peripherally distributed) and a mixed vascular pattern (at least 2 types of vessels among dotted, linear-irregular, linear and branching vessels) over a pinkish-reddish background (figure 3b) [19]. focally distributed orange-yellowish structureless areas due to dermal hemosiderin deposits may also be seen less commonly [19]. unlike discoid lupus erythematosus, follicular plugs are typically not seen, and this finding may be helpful to disaspect (more or less diffuse hemorrhagic areas due to erythrocyte extravasation), mature lesions usually showing a central amorphous brownish crust (due to epidermal necrosis) (figure 2c), and healing lesions often featuring a central white area (due to fibrosis) [1,2,17]. a rim of pinpoint and/or linear vessels with a targetoid aspect may be seen at the periphery of the lesions [1,2,17]. these vascular structures appear as dilated and convoluted vessels at higher magnification, with some of them showing a glomerular pattern or linear aspect [1,2,17]. in addition, a peripheral scaling collarette having an inner free edge is often evident in all the stages, especially in mature (figure 2c) and healing lesions [1,2,17]. on the other hand, pityriasis lichenoides chronica typically displays orangeyellowish structureless areas (corresponding to hemosiderin deposits in the dermis due to erythrocyte extravasation) and nondotted vessels (including globular, linear-irregular, and/or branching vessels) (figure 2d); diffuse and/or peripheral whitish scaling, focally distributed dotted vessels, hemorrhagic spots, and hypopigmented areas are additional dermoscopic findings [9]. of note, the presence of hypopigmented areas is more common in long-standing lesions, which often display focal postinflammatory hypopigmentation. importantly, in dark-skinned patients, orangish areas are difficult to see [9]. pityriasis rubra pilaris dermoscopy has been found to be helpful in supporting the diagnosis of several clinical manifestations of both classic pityriasis rubra pilaris (prp) and circumscribed juvenile prp. in detail, papular lesions of classic prp usually reveal round/oval yellowish areas surrounded by vessels of mixed morphology (ie, linear and dotted) (figure 3a) and often centered by central keratin plugs, whereas palmoplantar figure 3. pityriasis rubra pilaris features a roundish, yellowish area surrounded by vessels of mixed morphology (ie, linear and dotted) (a). dermoscopy in subacute lupus erythematosus reveals white scales and a mixed vascular pattern (ie, dotted and linear vessels in this case; visualized more clearly in the box) over a pinkish-reddish background (b). [copyright: ©2019 errichetti.] a b 174 review | dermatol pract concept 2019;9(3):1 most typical dermoscopic findings of seborrheic dermatitis consist of dotted vessels in a patchy distribution and fine yellowish scales (in combination or not with white scales) [25], it is not uncommon to observe facial lesions displaying a different vascular pattern, ie, linear branching vessels (with or without dotted vessels) [1,2]. such a vascular pattern is even more common in scalp seborrheic dermatitis [1,2]. additional, unspecific features of facial seborrheic dermatitis include follicular plugs, orange-yellowish areas, and whitish structureless areas [25]. demodicosis demodicosis is an underrecognized facial dermatosis whose clinical presentation may mimic several dermatoses, mainly including rosacea and seborrheic dermatitis [27]. the dermoscopic hallmark of all clinical subtypes are the so-called erythematous facial dermatoses rosacea erythemato-telangiectatic subtype is the most studied variant of rosacea [25,26]. it typically features a quite constant and specific dermoscopic pattern, namely linear vessels characteristically arranged in polygonal networks (vascular polygons) (figure 5a) [25,26]. additional dermoscopic findings may be seen but are poorly specific, including rosettes, follicular plugs, white-yellowish scales, pigmentation structures, and dilated follicles [25,26]. pustules and orange structureless areas, often associated with vascular polygons, are typically seen in papulopustular and granulomatous rosacea, respectively [1,2,25,26]. seborrheic dermatitis although a study on facial inflammatory dermatoses concluded that the scopic pattern [20-22]. indeed, both are typically characterized by a central yellowish-brownish area having a starlike, branched polygonal or round-oval shape, resulting from compact hyperkeratosis and exocytosis (due to acantholysis), and a peripheral white halo corresponding to acanthosis (figure 4b) [20-22]. the same dermoscopic pattern is visible in braf-inhibitor-induced acantholytic dyskeratosis owing to their similar histological background [1]. on the other hand, spongiotic histological subtype of grover disease displays whitish scaling over a reddish-yellowish background [22]. dotted and/or linear/irregular vessels are additional findings visible in both darier disease and darier-like and spongiotic grover disease [20-22]. prurigo nodularis the dermoscopic pattern of prurigo nodularis (both hyperkeratotic and excoriated lesions) consists of radially arranged whitish lines or peripheral whitish halo with some centrifugal coarse projections on a brownish and/ or reddish background, the so-called “white starburst pattern” (figure 4c) [23]. in the center of the lesions, brownreddish or brown-yellowish crusts (figure 4c), erosions, and/or hyperkeratosis or scales may also be seen [23]. such a pattern is quite different from that of its main differential diagnoses, including hypertrophic lichen planus (see above), acquired reactive perforating collagenosis (arpc), and nodular scabies [1,23,24]. central round brownish-greenish/yellowish brown structureless area surrounded by a white keratotic collarette and an erythematous halo with or without dotted vessels (“trizonal concentric” pattern) is typically seen in arpc (figure 4d), while nodular scabies usually features dotted vessels, sometimes associated with the presence of mites (“hang glider sign”) and/or burrows (“jet with condensation trails”) [1,23,24]. figure 4. the typical white keratotic track having 2 free edges is visible in a case of porokeratosis (a). darier disease characteristically reveals a central star-like, yellowish area surrounded by a peripheral white halo (b). the “white starburst” pattern (peripheral radial white striae over a reddish-brownish background) is visible in a case of prurigo nodularis; a central yellow crust is also present (c). acquired reactive perforating collagenosis displays a central round brownish-greenish structureless area surrounded by a white keratotic collarette and an erythematous halo (“trizonal concentric” pattern) (d). [copyright: ©2019 errichetti.] a c b d review | dermatol pract concept 2019;9(3):1 175 the first 2 conditions display an indistinguishable dermoscopic pattern, which is typified by focal or diffuse orange structureless areas and well-focused linear or branching vessels, which are usually located over the orange areas (figure 5d) [30]. other possible findings include milia-like cysts, erythema, whitish lines or structureless areas, follicular plugs, dilated follicles, pigmentation structures, and white and/or yellow scales [30]. on the other hand, even though leishmaniasis is a granulomatous dermatosis, orange structureless areas are visible only in a minority of patients (approximately 15% of cases) because they are covered by the frequent overlying epidermal changes (ie, ulcerations/ erosions, crusting, or hyperkeratosis/ scaling) [30-32]. according to the available literature, white/yellow follicular keratotic plugs (previously called “yellow tears”) and white peripheral projections (“white starburst pattern”) are the most characterizing features [30-32]. granuloma faciale despite its name, granuloma faciale is a chronic leukocytoclastic vasculitis and not a granulomatous disease [1,25]. the presence of dilated follicular openings has been reported as the most characterizing dermoscopic feature of this condition [1,25]. linear and/or branching dilated vessels are also commonly seen [1,25]. in addition, purpuric spots and orange structureless areas, histologically corresponding to erythrocyte extravasation and hemosiderin dermal deposits, may also be observed [1,25,29]. less common, unspecific findings include perifollicular whitish halo, pigmentation structures, follicular plugs, yellowish scales, whitish streaks, and whitishgrayish structureless areas [1,25]. granulomatous facial diseases the main granulomatous dermatoses of the face include sarcoidosis, lupus vulgaris, and cutaneous leishmaniasis [30]. “demodex tails,” which are white-yellowish, protruding, follicular keratotic plugs due to the presence of a mixture of keratotic material and mites in the follicles (figure 5b) [27]. “demodex follicular openings,” which consist of round and coarse follicular openings containing white/yellow plugs surrounded by an erythematous halo, are also referred as typical of demodicosis and may represent nonprotruding demodex tails [27]. other unspecific dermoscopic findings may be observed (ie, diffuse erythema, scaling, pustules, and reticular dilated vessels) and their prevalence varies according to the subtypes of demodicosis [27]. discoid lupus erythematosus dermoscopy of facial (and extrascalp in general) discoid lupus erythematosus reveals different features according to the disease stage [1,25,28]. early lesions are typified by white scales and follicular findings, namely follicular red dots surrounded by whitish halos (“inverse strawberry” pattern) or follicular whitish-yellowish keratotic plugs (visible as white rosettes on polarized-light dermoscopy) over a more or less erythematous background (“strawberry” pattern) (figure 5c) [1,25,28]. vessels of variable morphology (dotted, linear-irregular, and/or branching) may also be seen, especially at the periphery of the lesions [1,25,28]. on the other hand, late lesions display white structureless areas, pigmentary structures, hair loss, and telangiectatic linear-irregular, branching vessels and/or dotted/glomerular vessels [1,25,28]. importantly, intermediatestage lesions may reveal a mixture of all the aforementioned features [1,25,28]. less common dermoscopic findings include diffuse hyperkeratosis (hypertrophic discoid lupus erythematosus), dilated follicles, and yellowish scales [1,25,28]. figure  5. erythemato-telangiectatic rosacea with its typical linear vessels arranged in polygonal networks (vascular polygons) (a). the so-called demodex tails (white-yellowish, protruding, follicular keratotic plugs) are visible in demodicosis (b). white keratotic plugs over a reddish background are the typical dermoscopic features of active discoid lupus erythematosus (c). dermoscopy of sarcoidosis reveals orange structureless areas with overlying focused linear vessels; white areas are also visible (d). [copyright: ©2019 errichetti.] a c b d 176 review | dermatol pract concept 2019;9(3):1 sclerotic and sclerotic lesions, thus underlining that such a dermoscopic clue is much more relevant and useful for active lesions than early inflammatory and late ones [33]. mucosal (anogenital) lichen sclerosus reveals the same features as the cutaneous lesions (especially bright white areas and well-focused vessels), apart from the lack of follicular keratotic plugs [33]. necrobiosis lipoidica dermoscopy of necrobiosis lipoidica lesions typically shows yellow-orange structureless areas (figure 6c), due to the presence of granulomatous inflammatory infiltrate and lipid deposits in the dermis, and well-focused vascular structures, whose morphology varies according to the disease stage, with dotted, globular, comma-shaped, and glomerular vessels more commonly seen in early stages or active lesional border, network-shaped, linear, and hairpin-like vessels more frequent in more developed (mature) lesions and branching-serpentine vessels being typical of advanced lesions [30]. of note, diameter of branching-serpentine vessels typically decreases from the center to the periphery of the lesion due to the more marked epidermal atrophy in central areas (figure 6c) [30]. additional less common and poorly specific dermoscopic findings include ulcerations, whitish-yellowish crusts, highlighting that lesions belonging to different clinical phases may display a dermoscopic (and histological) overlap [33]. lichen sclerosus the hallmarks of cutaneous lichen sclerosus are represented by keratotic follicular plugs, corresponding to follicular hyperkeratosis, and well-defined, bright white patches, resulting from superficial fibrosis (figure 6b) [33]. in addition, scaling and hemorrhagic spots have been shown to be quite specific for lichen sclerosus when compared to morphea [33]. less common features include erythematous areas, focused vessels (especially linear-irregular and dotted), crystalline structures, unfocused large purple vessels, yellowish areas, and pigmentary structures (reticular brown areas and brown dots) [33]. even in cutaneous lichen sclerosus there may be a variability of dermoscopic pattern according to the clinical disease stage, with erythematous areas and focused vessels being more common in inflammatory lesions and unfocused large purple vessels and yellowish areas being typical of atrophic stages, yet a dermoscopic overlap is possible as the prevalence of bright white areas does not differ significantly between inflammatory and sclerotic lesions [33]. interestingly, follicular keratotic plugs have been found more commonly in clinically inflammatoryin addition, cutaneous leishmaniasis is often typified by vascular structures having a variable morphology, including hairpin, comma, glomerular, and/or corkscrew vessels [30-32]. thrombotic vessels, yellowish hue, white scarring areas, milia-like cysts, pustules, and perilesional hypopigmented halo are further unspecific findings that may be seen [30-32]. sclero-atrophic dermatoses morphea the most specific dermoscopic feature of morphea consists of white clouds, which are ill-defined dull white areas corresponding to deep dermal fibrosis (figure 6a); erythematous areas, focused vessels (especially linear-irregular but also branching and dotted), crystalline structures, unfocused large purple vessels, yellowish areas, and pigmentary structures (structureless brown areas, reticular brown areas, and brown dots) are additional findings [33]. of note, dermoscopic features may vary according to the disease stage, with erythematous areas and focused vessels (especially linear-irregular) being indicative of inflammatory phases and unfocused large purple vessels typical of atrophic stages [33]. however, the prevalence of white clouds does not differ significantly among inflammatory, sclerotic, and atrophic stages, thereby figure 6. morphea is characterized by dull white areas with blurry margins (“white clouds”) (a). keratotic follicular plugs, white scales, and hemorrhagic spots over a white-pinkish background are visible in lichen sclerosus (b). necrobiosis lipoidica: yellow-orange structureless areas and branching-serpentine vessels whose diameter decreases from the center to the periphery of the lesion (c). [copyright: ©2019 errichetti.] a b c review | dermatol pract concept 2019;9(3):1 177 frequently seen in repigmenting or progressing lesions than stable lesions [1]. other possible features include intralesional pigmentary islands, perilesional hyperpigmentation, reversed pigmentary network, reticular pigmentation, and telangiectasias [1]. lichen pigmentosus vs ashy dermatosis both lichen pigmentosus and ashy dermatosis are characterized by pigmented dots (“peppering”) [38]. however, in the former dermatosis, dots are usually brownish and larger (figure 9a) than those seen in the latter condition, which typically displays smaller and graybluish dots over a bluish background (figure 9b) [38]. such differences are the result of the different level of melanophages/melanin deposits (superficial dermis in lichen pigmentosus and deep papillary and reticular dermis in ashy dermatosis) [38]. idiopathic guttate hypomelanosis vs vitiligo dermoscopy of idiopathic guttate hypomelanosis displays 2 main aspects, ie, the “cloudy sky-like” pattern (multiple small areas coalescing into irregular/polycyclic macules, with several white shades and both welland illdefined edges) and the “cloudy” pattern (wellor ill-defined roundish homogeneous whitish areas) (figure  8a), respectively more common in bigger and smaller lesions [37]. notably, in both cases, patchy hyperpigmented network typically surrounds white areas (figure 8a) [37]. on the other hand, well-demarcated, dense/glowing, white areas are the most common dermoscopic findings in vitiligo (figure 8b) [1]. although not present in all lesions, white hairs and perifollicular pigmentation (figure 8b) are considered the most specific features of vitiligo, with the latter finding more whitish scaling, brownish reticular structures, and whitish structureless areas, with this last feature being more common in long-standing lesions, which are characterized by pronounced dermal fibrosis [30]. miscellaneous common urticaria vs urticarial vasculitis dermoscopy of common urticaria and urticarial vasculitis frequently shows a homogeneous erythematous background (avascular areas), yet such a feature is less common in late lesions of urticaria vasculitis [2]. reticular/ linear vessels may be present in both diseases, but they are significantly more frequent in common urticaria [2]. conversely, purple-red dots/globules, often on an orange-brown background, are highly indicative of urticarial vasculitis, as they are very rare in common urticaria [2]. capillaritis (pigmented purpuric dermatoses) vs vasculitis the term capillaritis refers to a group of chronic, benign, cutaneous diseases that are characterized by extravasation of erythrocytes in the skin with consequent hemosiderin deposition, including schamberg disease, doucas-kapetanakis disease, majocchi disease, gougerot–blum syndrome, and lichen aureus [34,35]. all of them are typified by the presence of focused reddish purpuric dots and/or globules over a brownishcoppery background (figure 7a); in addition, peripheral telangiectatic vessels and yellow scales/crusts are seen in majocchi disease and doucas-kapetanakis disease, respectively [34,35]. unlike capillaritis, dermoscopy of small-vessel skin vasculitis may reveal blue-gray patches and purpuric globules/dots that are usually violaceous a n d b l u r r i e r ( f i g u r e   7 b ) b e c a u s e extravasated erythrocytes are located deeper [36]. figure  7. schamberg disease: focused reddish purpuric dots and globules over a coppery background (a). unlike capillaritis, dermoscopy of small-vessel skin vasculitis reveals blurrier violaceous purpuric globules (b). [copyright: ©2019 errichetti.] a b figure  8. idiopathic guttate hypomelanosis: well-defined roundish homogeneous whitish area (“cloudy” pattern) surrounded by patchy hyperpigmented network (a). vitiligo: white areas and perifollicular pigmentation (b). [copyright: ©2019 errichetti.] a b 178 review | dermatol pract concept 2019;9(3):1 appearance may be seen in mastocytoma, with the last 2 patterns more commonly visible in regressing phases [1,40]. granuloma annulare the main dermoscopic clue (prevalence rate of 88.0%) of granuloma annulare is represented by unfocused vessels having a variable morphology (dotted, linear-irregular, and/or branching) over a more or less evident pinkish-reddish background (figure 11a,b) [41]. whitish (irregular or globular) and yellowish subtype [1]. in detail, urticaria pigmentosa typically reveals either a homogeneous light-brown background or a coarse pigment network (figure 10a), while telangiectasia macularis eruptiva perstans (tmep) is mainly characterized by reticular or tortuous linear vessels on an erythematous/brownish base (figure 10b) [1]. a brownish network may sometimes be appreciated in tmep [1]. finally, diffuse/multifocal yellow-orange discoloration, diffuse light-brown discoloration, and brownish network-like pityriasis versicolor vs gougerotcarteaud syndrome distinguishing such conditions may be sometimes difficult on clinical grounds, and dermoscopy may provide some clues to facilitate their differential diagnosis [1,39]. in particular, pityriasis versicolor is characterized by fine whitish scales localized in the skin furrows and a brownish background, while gougerot-carteaud syndrome typically shows fine whitish scaling associated with brownish, homogeneous, more or less defined, polygonal, flat globules separated by whitish/pale striae creating a cobblestone appearance or brownish areas presenting a “sulci and gyri” pattern [1,39]. balanitis according to a recent study, dermoscopic examination may provide useful information on common forms of balanitis [6]. in particular, psoriatic balanitis and zoon balanitis are the most recognizable forms, with the former being characterized by homogeneous dotted vessels distributed in a uniform pattern and the latter typically displaying focal or diffuse orange areas along with focused linear curved vessels [6]. on the other hand, cottage cheese-like structures (representing sparse white coating corresponding to candida yeast colony growth) showed a strong correlation with candidal balanitis [6]. all the above-mentioned forms of balanitis may be distinguished from erythroplasia of queyrat, which features glomerular vessels distributed in a focal or diffuse pattern [6]. notably, differentiating dotted from globular vessels on hand-held dermoscopic examination may be challenging [6]. however, in erythroplasia of queyrat, vessels are typically more heterogeneous in shape, size, and distance among each other [6]. mastocytoses dermoscopic features of cutaneous mastocytoses vary according to the disease figure  10. coarse brownish network in urticaria pigmentosa (a). telangiectasia macularis eruptiva perstans reveals tortuous linear vessels on a brownish base (b). [copyright: ©2019 errichetti.] a b figure 11. in both “palisading granuloma” and “interstitial” histological variants of granuloma annulare, dermoscopy shows unfocused vessels having a variable morphology (dotted, linear-irregular, and/or branching) over a more or less evident pinkish-reddish background (a,b). however, the former variant also features yellowish orange areas (a). [copyright: ©2019 errichetti.] a b a figure 9. brownish dots in lichen pigmentosus (a). in ashy dermatosis dots are smaller and bluish (b). [copyright: ©2019 errichetti.] b review | dermatol pract concept 2019;9(3):1 179 21. errichetti e, maione v, pegolo e, stinco g. dermoscopy: a useful auxiliary tool in the diagnosis of type 1 segmental darier’s disease. dermatol pract concept. 2016;6(2):53-55. 22. errichetti e, de francesco v, pegolo e, stinco g. dermoscopy of grover’s disease: variability according to histological subtype. j dermatol. 2016;43(8):937-939. 23. errichetti e, piccirillo a, stinco g. dermoscopy of prurigo nodularis. j dermatol. 2015;42(6):632-634. 24. suh ks, han sh, lee kh, et al. mites and burrows are frequently found in nodular scabies by dermoscopy and histopathology. j am acad dermatol. 2014;71(5):1022-1023. 25. lallas a, argenziano g, apalla z, et al. dermoscopic patterns of common facial inflammatory skin diseases. j eur acad dermatol venereol. 2014;28(5):609-614. 26. lallas a, argenziano g, longo c, et al. polygonal vessels of rosacea are highlighted by dermoscopy. int j dermatol. 2014;53(5):e325-327. 27. segal r, mimouni d, feuerman h, pagovitz o, david m. dermoscopy as a diagnostic tool in demodicidosis. int j dermatol. 2010;49(9):1018-1023. 28. lallas a, apalla z, lefaki i, et al. dermoscopy of discoid lupus erythematosus. br j dermatol. 2013;168(2):284-288. 29. jardim mml, uchiyama j, kakizaki p, valente nys. dermoscopy of granuloma faciale: a description of a new finding. an bras dermatol. 2018;93(4):587-589. 30. errichetti e, stinco g. dermatoscopy of granulomatous disorders. dermatol clin. 2018;36(4):369-375. 31. taheri ar, pishgooei n, maleki m, et  al. dermoscopic features of cutaneous leishmaniasis. int j dermatol. 2013;52(11):1361-1366. 32. yücel a, günasti s, denli y, uzun s. cutaneous leishmaniasis: new dermoscopic findings. int j dermatol. 2013;52(7):831837. 33. errichetti e, lallas a, apalla z, di stefani a, stinco g. dermoscopy of morphea and cutaneous lichen sclerosus: clinicopathological correlation study and comparative analysis. dermatology. 2017;233(6):462-470. 34. zalaudek i, ferrara g, brongo s, et al. atypical clinical presentation of pigmented purpuric dermatosis. j dtsch dermatol ges. 2006;4(2):138-140. 35. zaballos p, puig s, malvehy j. dermoscopy of pigmented purpuric dermatoses (lichen aureus): a useful tool 8. lallas a, apalla z, argenziano g, et al. dermoscopic pattern of psoriatic lesions on specific body sites. dermatology. 2014;228(3):250-254. 9. errichetti e, lacarrubba f, micali g, piccirillo a, stinco g. differentiation of pityriasis lichenoides chronica from guttate psoriasis by dermoscopy. clin exp dermatol. 2015;40(7):804-806. 10. errichetti e, stinco g. dermoscopy in differential diagnosis of palmar psoriasis and chronic hand eczema. j dermatol. 2016;43(4):423-425. 11. errichetti e, stinco g. dermoscopy as a supportive instrument in the differentiation of the main types of acquired keratoderma due to dermatological disorders. j eur acad dermatol venereol. 2016;30(12):e229-e231. 12. lallas a, argenziano g, zalaudek i, et al. dermoscopic hemorrhagic dots: an early predictor of response of psoriasis to biologic agents. dermatol pract concept. 2016;6(4):7-12. 13. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol venereol. 2013;27(5):617-621. 14. güngör s, topal io, göncü ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept. 2015;5(2):45-53. 15. vázquez-lópez f, maldonado-seral c , l ó p e z e s c o b a r m , p é r e z o l i v a n. dermoscopy of pigmented lichen planus lesions. clin exp dermatol. 2003;28(5):554-555. 16. errichetti e, stinco g. comment on “dermatoscopic features of lichen nitidus.” pediatr dermatol. 2018;35(6):879-880. 17. lacarrubba f, verzì ae, dinotta f, scavo s, micali g. dermatoscopy in inflammatory and infectious skin disorders. g ital dermatol venereol. 2015;150(5):521531. 18. errichetti e, piccirillo a, stinco g. dermoscopy as an auxiliary tool in the differentiation of the main types of erythroderma due to dermatological disorders. int j dermatol. 2016;55(12):e616-e618. 19. errichetti e, piccirillo a, viola l, stinco g. dermoscopy of subacute cutaneous lupus erythematosus. int j dermatol. 2016;55(11):e605-e607. 20. errichetti e, stinco g, lacarrubba f, micali g. dermoscopy of darier’s disease. j eur acad dermatol venereol. 2016;30(8):1392-1394. orange (focally or diffusely distributed) areas represent the most common nonvascular findings [41]. of note, dermoscopic appearance of granuloma annulare significantly varies according to its histological subtype, with a strict association between yellowish orange structureless areas and palisading granuloma histological variant (figure 11a) as they are usually absent in lesions having an interstitial histological pattern (figure 11b) [41]. references 1. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. 2. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol. 2015;150(5):533-546. 3. errichetti e, zalaudek i, kittler h, et al. standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (non-neoplastic dermatoses): an expert consensus on behalf of the international dermoscopy society. br j dermatol. 2019 may 11. epub ahead of print. doi: 10.1111/bjd.18125. 4. errichetti e, stinco g. clinical and dermoscopic response predictors in psoriatic patients undergoing narrowband ultraviolet b phototherapy: results from a prospective study. int j dermatol. 2018;57(6):681-686. 5. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198-1205. 6. errichetti e, lallas a, di stefani a, et al. accuracy of dermoscopy in distinguishing erythroplasia of queyrat from common forms of chronic balanitis: results from a multicentric observational study. j eur acad dermatol venereol. 2019;33(5):966-972. 7. pan y, chamberlain aj, bailey m, chong ah, haskett m, kelly jw. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268274. 180 review | dermatol pract concept 2019;9(3):1 40. vano-galvan s, alvarez-twose i, de las heras e, et al. dermoscopic features of skin lesions in patients with mastocytosis. arch dermatol. 2011;147(8):932-940. 41. errichetti e, lallas a, apalla z, di stefani a, stinco g. dermoscopy of granuloma annulare: a clinical and histological correlation study. dermatology. 2017;233(1):74-79. 38. errichetti e, angione v, stinco g. dermoscopy in assisting the recognition of ashy dermatosis. jaad case rep. 2017;3(6):482-484. 39. errichetti e, maione v, stinco g. dermatoscopy of confluent and reticulated papillomatosis (gougerot-carteaud syndrome). j dtsch dermatol ges. 2017;15(8):836-838. for clinical diagnosis. arch dermatol. 2004;140(10):1290-1291. 36. choo jy, bae jm, lee jh, et al. bluegray blotch: a helpful dermoscopic finding in optimal biopsy site selection for true vasculitis. j am acad dermatol. 2016;75(4):836-838. 37. errichetti e, stinco g. dermoscopy of idiopathic guttate hypomelanosis. j dermatol. 2015;42(11):1118-1119. untitled quiz | dermatol pract concept 2015;5(3):3 15 dermatology practical & conceptual www.derm101.com case report a 56-year-old male patient was seen in the dermatology clinic for a 25-year history of an asymptomatic cluster of violaceous papules in a coalescing pattern on the right lateral thigh (figure 1). no other significant findings were found on physical exam and all laboratory results were within normal demographic ranges. the patient reported to have hypothyroidism that was diagnosed one year ago and trigeminal neuralgia for which he was taking carbamazepine and calcium for five years’ duration. an incisional biopsy from one of the lesions involving lesion and peri-lesional skin was performed. discussion dermatopathological examination revealed hyperkeratosis, an acanthotic epidermis with elongation of rete ridges, and a superficial to deep dermal inflammatory infiltrate (figure 2). an alcian blue stain at a ph of 2.5 was performed indicating the presence of mucin within the papillary dermis (figure 3). clinicopathologic examination confirmed the diagnosis of mucinous nevus. mucinous nevus is a benign hamartomatous lesion, first described by redondo bellian in 1993, is a rare type of primary cutaneous mucinosis [1]. its name stems from the lesion’s striking appearance to a nevus and the presence of dermal mucin [2]. histologically, two types of mn exist: connective tissue nevus of the proteoglycan (ctnp), and the asymptomatic cluster of violaceous papules reza yaghoobi1, karan lal2, amir feily3 1 department of dermatology, jundishapur university of medical sciences, ahvaz, iran 2 new york institute of technology college of osteopathic medicine, new york, ny, usa 3 skin and stem cell research center, tehran university of medical sciences, tehran, iran citation: yaghoobi r, lal k, feily a. asymptomatic cluster of violaceous papules. dermatol pract concept 2015;5(3):3. doi: 10.5826/ dpc.0503a03 copyright: ©2015 yaghoobi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: amir feily, md, skin and stem cell research center, tehran university of medical sciences, tehran, iran. email: dr.feily@yahoo.com figure 1. multiple violaceous papules on the right lateral thigh. [copyright: ©2015 yaghoobi et al.] figure 2. hematoxylin and eosin (100x) showing hyperkeratosis, acanthosis along with elongation of rete ridges, and a superficial to deep dermal inflammatory infiltrate. [copyright: ©2015 yaghoobi et al.] 16 quiz | dermatol pract concept 2015;5(3):3 various connective tissue nevi. other features such as dermal inflammation may be present as seen on the hematoxylin and eosin stained specimen from the biopsy of our patient’s lesion. although this moderately dense inflammatory infiltrate most likely represents exogenous irritation from pruritus, it may distract pathologists to focus on the inflammatory lesions as opposed to the background features favoring mucinous nevus. for this reason, biopsy with dermatopathological evaluation is necessary with the addition of alcian blue staining at a ph of 2.5 for identification of dermal mucin, along with von geison staining to determine the quantitative extent of elastin fibers within the papillary and reticular dermis. the benign nature of these lesions requires only excisionbased therapy. some authors have suggested the use of carbon dioxide laser therapy only for mn classified as combined epidermal ctnp [15]. references 1. redondo bellon p, vazquez-doval j, idoate m, quintanilla e. mucinous nevus. j am acad dermatol 1993;28 (5 pt 1):797-98. 2. perez-crespo m, lopez-navarro n, betlloch i, et al. acquired and familial mucinous nevus. int j dermatol 2011;50(10):1283-85. 3. rongioletti f, rebora a. mucinous nevus. arch dermatol 1996;132 (12):1522-23. 4. song bh, park s, park ej, et al. mucinous nevus with fat. am j dermatopathol 2012;34(8):e146-48. 5. brakman m, starink tm, tafelkruyer j, bos jd. linear connective tissue naevus of the proteoglycan type (‘naevus mucinosus’). br j dermatol 1994;131(9):368-70. 6. uitto j, santa cruz dj, eisen az. connective tissue nevi of the skin. clinical, genetic, and histopathologic classification of hamartomas of the collagen, elastin, and proteoglycan type. j am acad dermatol 1980; 3(5):441-61. 7. suhr kb, ro yw, kim kh, et al. mucinous nevus: report of two cases and review of the literature. j am acad dermatol 1997;37(2 pt 2):312-3. 8. lim jh, cho sh, kim ho, kim cw, park ym. mucinous naevus with atypical features. br j dermatol 2003;148(5):1064–66. 9. sahara ly, bastian bc, bruckner al. coalescing, nevoid papules in an infant. arch dermatol 2005;141(7):897– 902. 10. chen cw, tsai tf, chen yf, hung cm. familial mucinous nevus. pediatr dermatol 2008;25(2):288–9. 11. nayal b, mathew m, kumar p, nair rp. mucinous naevus: a rare variant of connective tissue naevus. j interdiscipl histopathol 2013;1(2):89-92. 12. chui hh, chang wy, chen gs. mucinous nevus—a case report and review of literature. dermatol sinica 2007;25:147-52. 13. tadini g, boldrini mp, brena m, et al. nevoid follicular mucinosis: a new type of hair follicle nevus. j cutan pathol 2013;40 (9):844-47. 14. esteves t, ferreira l, viana i, bordalo o. brown plaques on the lower back. dermatology online journal 2010;16(6):11. 15. chi cc, wang sh, lin py. combined epidermal-connective tissue nevus of proteoglycan (a type of mucinous nevus): a case report and literature review. j cutan pathol 2009;36(7):808-11. combined epidermal connective tissue nevus of the proteoglycan. ctnp is classified by the presence of dermal mucin whereas combined epidermal nevus of the proteoglycan has features consistent with epidermal nevi, hyperkeratosis, elongation of rete ridges, and an acanthotic epidermis [3]. a case has been reported of combined epidermal ctnp, with mature adipocytes within the superficial dermis that was misdiagnosed as nevus lipomatosis superficialis indicating the importance of alcian blue staining in suspicious lesions [4]. clinically the lesions may be congenital [1] or may develop later on in life [5,6,7], as they did in our patient and can vary in presentation most often appearing as papules, plaques, or even a pedunculated mass [8] in either a rare zosteriform pattern or a more commonly a unilateral linear nevoid pattern. the most common location for these lesions is the lower back4; however, cases have been reported on the abdomen [9], thighs [10], and face [11]. the pathogenesis of mucinous nevus remains uncertain; however, many theories exist regarding the origin of the mucin. the most supported theory is that the mucin is overproduced by abnormal fibroblasts within the superficial dermis [12] characteristically, due to positive staining with alcian blue, at a ph of 2.5, and not at 0.5, mucin is considered to be of hyaluronic acid origin [5]. due to the subtleties in its presentation and histology, differential diagnoses to consider include: nevoid follicular mucinosis [13], cutaneous mucinosis of infancy [14], cutaneous focal mucinosis [14], epidermal nevus [14], nevus lipomatosis superficialis [4], papular mucinosis [14], and the figure 3. alcian blue stain (100x) showing purple mucin deposits within the papillary dermis. [copyright: ©2015 yaghoobi et al.] dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020023 1 dermatology practical & conceptual introduction digital dermoscopy has an essential role in diagnosing a variety of skin lesions once it allows their follow-up over time. the diameter of the dermatoscope lenses limits the applicability of this tool in the diagnosis of large lesions. we present a case series of 3 congenital melanocytic nevi (cmn) documented by the wide area digital dermoscopy (wadd) technique, which allows a dermoscopic record of the entire lesion area.  as previously described [1], the wadd technique consists of merging multiple and overlapped separate dermoscopic images by using the “photomerge” feature of adobe photoshop cc software (adobe systems incorporated, san jose, ca, usa, v19.1.6). the final processed image comprises the full lesion at a high resolution. dermoscopic definition of every single separate image is completely preserved, allowing navigation throughout the lesion with pan and zoom capabilities. case presentation our case series comprised 3 patients with cmn. figure 1 shows cmn located on the plantar area in a 23-year-old patient. in figure 2 the cmn are located on the right malar area in a 20-month-old patient. figure 3 shows cmn located on the left gluteal region in a 37-year-old patient. conclusions clinical and dermoscopic follow-up studies of cmn are essential for early detection of malignant transformation. wadd technique may improve follow-up once it allows the comparison of an entire large area. applicability of this technique extends beyond cmn, as it can be useful in any situation involving digital dermoscopy of large lesions. as a limitation, scanning of ultra-large lesions can be challenging, demanding time to obtain the required image overlapping correctly. in the future, specific and user-friendly software may contribute to facilitating the process of image acquiring and processing. reference 1. dellatorre g, gadens ga. wide area digital dermoscopy. j am acad dermatol. 2019;80(6):e153. wide area digital dermoscopy for congenital melanocytic nevi: report of 3 cases guilherme a. gadens,1 gerson dellatorre1 1 department of dermatology & cutaneous oncology, hospital santa casa de curitiba, brazil key words: melanocytic nevi, image enhancement, dermoscopy, pigmented nevus citation: gadens ga, dellatorre g. wide area digital dermoscopy for congenital melanocytic nevi: report of 3 cases. dermatol pract concept. 2020;10(1):e2020023. doi: https://doi.org/10.5826/dpc.1001a23 accepted: october 23, 2019; published: december 31, 2019 copyright: ©2019 gadens and dellatorre. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: gerson dellatorre, md, alameda prudente de moraes, 1250, curitiba, paraná, brazil, 80430-220. email: dellatorre@gmail.com mailto:dellatorre@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020023 figure 1. (a) congenital melanocytic nevi measuring 6.3 × 3.4 cm located on the plantar area in a 23-year-old patient. (b) wide area digital dermoscopy obtained from merging of 20 separate dermoscopic images (dermlite dl4 3gen inc., san juan capistrano, ca, usa; attached to a smartphone; polarized, magnification ×10). figure 2. (a) congenital melanocytic nevi measuring 4.9 × 2.9 cm located on the right malar area in a 20-month-old patient. (b) wide area digital dermoscopy obtained after merging of 17 dermoscopic images. figure 3. (a) congenital melanocytic nevi measuring 3.3 × 2.2 cm located on the left gluteal region in a 37-year-old patient. (b) detail of zoom capability, preserving dermoscopic definition, of final wide area digital dermoscopy image obtained from 14 separate dermoscopic images. untitled quiz | dermatol pract concept 2015;5(2):10 67 dermatology practical & conceptual www.derm101.com the patient a 40-year-old white caucasian woman presented with a 20-year history of asymptomatic lesions on palmoplantar regions. physical examination revealed numerous keratotic papules with crateriform holes on the palms (figure 1) and yellow pits over the areas of soles exposed to pressure (figure 2). her father reported the same skin signs but he was less severely affected. the patient displayed no systemic symptoms and chest x-ray and routine laboratory testing showed no alteration. no arsenic exposure was reported. skin biopsy obtained from a lesion revealed marked orthokeratotic hyperkeratosis with hypergranulosis (figure 3). what is your diagnoisis? keratotic papules of palms and soles vincenzo maione1, giuseppe stinco1, maria orsaria2, enzo errichetti1 1 department of experimental and clinical medicine, institute of dermatology, university of udine, italy 2 institute of pathology, university of udine, italy citation: maione v, stinco g, orsaria m, errichetti e. keratotic papules of palms and soles. dermatol pract concept 2015;5(2):10. http:// dx.doi.org/10.5826/dpc.0502a10 copyright: ©2015 maione et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: vincenzo maione, md, institute of dermatology, university of udine, ospedale san michele, piazza rodolone, 1, 33013-gemona del friuli (udine), italy. tel. +39 0432989378; fax. +39 0432989209. e-mail: maionevincenzo@gmail.com figure 1. multiple keratotic crateriform papules over the palms. [copyright: ©2015 maione et al.] figure 2. numerous depressed pits of different sizes on the soles. [copyright: ©2015 maione et al.] figure 3. epidermal depression with hypergranulosis and marked orthokeratotic hyperkeratosis (h & e, magnification 2x). [copyright: ©2015 maione et al. 68 quiz | dermatol pract concept 2015;5(2):10 of the presence of hyperkeratotic polygonal papules on dorsum and lateral aspects of hands and feet. the histological features are pronounced orthohyperkeratosis and hyalinized and homogenous collagen, with the presence of elastorrhexis in acrokeratoelastoidosis, which is absent in focal acral hyperkeratosis [5]. degenerative collagenous plaques of hands instead affect sun-damaged skin with symmetrical papules and plaques clustered on thumb, first web space and side of index finger. this disease is characterized by the presence of hyperkeratosis associated with a thickened and distorted collagen zone with fragmentation of elastic fibers [6]. it is always important to keep in mind darier’s disease, nevoid basal cell carcinoma syndrome, cowden’s disease, porokeratotic eccrine ostial and dermal duct nevus, cole disease (guttate hypopigmentation with punctate keratoderma) and cantú syndrome. treatment is symptomatic, and the principal aim is to reduce hyperkeratosis. topical (urea, salicylic acid, retinoids) [7] and systemic (acitretin and alitretinoin) [8] therapies have been used widely, with variable results. references 1. oztas p, alli n, polat m, et al. punctate palmoplantar keratoderma (brauer-buschke-fischer syndrome). am j clin dermatol 2007;8(2):113-6. 2. giehl ka, eckstein gn, pasternack sm, et al. nonsense mutations in aagab cause punctate palmoplantar keratoderma type buschke-fischer-brauer. am j hum genet 2012;91(4):754-9. 3. zhang, xj, li m, gao tw, et al. identification of a locus for punctate palmoplantar keratodermas at chromosome 8q24.13-8q24.21. j invest derm 2004;122(5):1121-5. 4. alikhan a, burns t, zargari o. punctate porokeratotic keratoderma. dermatol online j 2010;16(1):13. 5. meziane m, senouci k, ouidane y, et al. acrokeratoelastoidosis. dermatol online j 2008;14(9):11. 6. abulafia j, vignale, ra. degenerative collagenous plaques of the hands and acrokeratoelastoidosis: pathogenesis and relationship with knuckle pads. int j dermatol 2000;39(6):424–32. 7. kong ms, harford r, o’neill jt. keratosis punctata palmoplantaris controlled with topical retinoids: a case report and review of the literature. cutis 2004;74(3):173-79. 8. raone b, raboni, patrizi a. alitretinoin: a new treatment option for hereditary punctate palmoplantar keratoderma (brauer-buschkefischer syndrome). j am acad dermatol 2014;71(2):e48-9. diagnosis buschke-fischer-brauer keratoderma (bfbk) discussion in 1910, buschke and fischer described a keratinization disorder with palmoplantar localization and named it “keratoderma maculosa disseminata palmaris et plantaris.” in 1913 brauer demonstrated the genetic origin of disease. bfbk is an autosomal dominant condition with late adolescence onset and an incidence rate of 1.7/100000/year [1]. this disease has an important genetic heterogeneity. two candidate regions were mapped: one on chromosome 15q22-24, where studies found mutations in aagab gene [2], and the other on chromosome 8q24.13-q24 [3]. bfbk is not associated with systemic illness, but recent reports signal an association with earlyand late-onset malignancies. clinically, numerous yellow-brown papules and small, depressed pits occur on palms and soles. the papules frequently lose their keratotic plugs leaving crateriform holes. lesions are usually asymptomatic, but pain and tenderness are occasionally reported. the histology results aspecific with circumscripted, massive orthokeratotic hyperkeratosis, depression of the underlying malpighian layer and devoid of dermic inflammation. hypergranulosis may be found. the differential diagnosis of bfbk includes verruca vulgaris, arsenic keratosis, palmoplantar porokeratosis, porokeratotic keratoderma, acrokeratoelastoidosis, focal acral hyperkeratosis and degenerative collagenous plaques of hands. arsenic keratosis is characterized by mild-to-moderate keratinocyte dysplasia, and the presence of koilocytes is the histological hallmark of verruca vulgaris. the differential diagnosis between bfbk, palmoplantar porokeratosis and porokeratotic keratoderma results more difficult. in porokeratotic keratoderma, the parakeratotic column above the orthokeratotic stratum corneum is similar to cornoid lamella but there is no evidence of dyskeratosis, vacuolated keratinocytes, or lymphocytic inflammation of the papillary dermis, as in porokeratosis [4]. marginal papular acrokeratoderma (acrokeratoelastoidosis and focal acral hyperkeratosis) differs from bfbk because untitled research | dermatol pract concept 2015;5(2):22 109 dermatology practical & conceptual www.derm101.com introduction “primum no nocere!”—hippocrates tinea capitis was a common disease in northern iran, where the majority of population still resides in rural areas. the first effective antifungal agent, i.e., griseofulvin, was introduced in 1959. up that time, there was no therapy available for patients with tinea capitis except radiation therapy (rt). it has been estimated that approximately 200,000 children worldwide received rt for tinea capitis [1]. there is no clear data on the number and method patients were treated in iran, but regarding the poor hygienic status of people, it can be imagined that probably thousands of patients, mostly children, have been treated with radiotherapy. unfortunately, many did not even have this privilege and were left untreated or had underwent non-efficient remedies. here, i will take a historical look at the issue followed by analyzing the clinical characteristics of bccs in irradiated patients. materials and methods in a retrospective study, the clinical records of all patients with bcc were reviewed. demographic details as well as clinical details and history of rt for treating tinea capitis was analyzed. data were analyzed using spss and p-values less than 0.05 were considered significant. radiation-induced basal cell carcinoma omid zargari1 1 consultant dermatologist, rasht, iran key words: basal cell carcinoma, radiotherapy, tinea capitis, iran, rasht citation: zargari o. radiation-induced basal cell carcinoma. dermatol pract concept 2015;5(2):22. doi: 10.5826/dpc.0502a22 received: december 8, 2014; accepted: january 26, 2015; published: april 30, 2015 copyright: ©2015 zargari. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: omid zargari, md, faad, 15, ave.103, golsar, rasht 41378, iran. tel. +98 13 33117520; fax. +98 13 33123438. e-mail: ozargari@gmail.com background: the treatment of tinea capitis using radiotherapy was introduced at the beginning of the twentieth century. a variety of cancers including basal cell carcinoma (bcc) are seen years after this treatment. objective: we sought to determine the clinical characteristics of bccs among irradiated patients. methods: the clinical records of all patients with bcc in a clinic in north of iran were reviewed. results: of the 58 cases of bcc, 29 had positive history for radiotherapy in their childhood. multiple bccs were seen in 79.3% and 10.3% of patients with history and without history of radiotherapy, respectively. conclusions: x-ray radiation is still a major etiologic factor in developing bcc in northern iran. patients with positive history for radiotherapy have higher rate of recurrence. abstract 110 research | dermatol pract concept 2015;5(2):22 humid climate and heavy rainfalls, is the center of rice and tea farms in iran. during the early years of twentieth century, this province and its capital, rasht, were the battlefield of civil wars and invasions by russians and the british. at that time, diseases such as malnutrition, cholera, tuberculosis, malaria, typhoid, leprosy and skin infections were common in this region. the american presbyterian mission started its mission in guilan in 1905, and the american christian hospital that was founded by this group was among the first hospitals made in northern iran circa 1917 and maybe the first hospital with x-ray facility (figure 1). the major figure in this hospital was dr. john davidson frame (1880-1942) who established the hospital and worked as a physician and surgeon in rasht for about 37 years (figure 2) [4,5]. the exact number of patients with tinea capitis who have been treated with radiotherapy in the american christian hospital and other centers in guilan is unknown, but we as dermatologists are still seeing signs of radiotherapy-induced tumors today. also, the dosage of rt was not clear, but the target dose was the induction of total depilation. the cutaneous symptoms after radiation exposure are based on a combination of inflammatory processes and alteration of cellular proliferation as a result of a specific pattern of results a total number of 69 patients with bcc were studied. the youngest one was a 27 years old man with gorlin’s syndrome that was excluded from the study. also, in 10 cases, the history for radiotherapy was not clear and therefore they were excluded from the study. of the remaining 58 patients, there were 23 women and 35 men with an age range from 34 to 85 years (mean age 60 years). twenty-nine out of 58 patients (50%) had positive history for rt in their childhood for treatment of tinea capitis. the demographic data of patients is shown in table 1. statistical analysis using chi-square test and t-test showed no significant difference from the point of gender and age between those who had history of rt and those who had not such history. in those who had positive history for rt, 23 out of 29 (79.3%) had multiple bccs. in 27 of them (93.1%), the site of involvement was scalp. fifteen out of 29 (51.7%) had recurrent lesions in this group. in contrast, in the group with negative history for rt, only three patients (10.3%) had multiple bccs, in only seven patients (24.1%), scalp was involved and only five patients (17.2%) had recurrent bccs. discussion non-melanoma skin cancers are the most common malignancies in iran, with an incidence of around 10-15 new cases per 100,000 of the population. bcc is the most common skin cancer and constitutes about three forth of all skin cancers in iran [2,3]. skin cancer, particularly bcc, presents a major problem for patients who have undergone irradiation for the treatment of tinea capitis. while ultraviolet radiation is the most common risk factor in bcc development, a significant number of the patients with bcc in northern iran, are still those who had radiation therapy for treating their tinea capitis. a bit of history! guilan is a province located in northern iran, nowadays with a population of around three million. guilan, with its table 1. demographic and clinical characteristics of patients. rt+ rtp. value gender, no (%) female male 29 9 (31.0) 20 (69.0) 29 14 (48.3) 15 (51.7) 0.104 age (mean) 60.31±7.85 59.57±9.86 0.87 number of lesions solitary, no (%) multiple, no (%) 6 (20.7) 23 (79.3) 26 (89.7) 3 (10.3) 0.0001 rt: radiotherapy. figure 1. medallion of american mission hospital in iran [5] (reproduced with permission). research | dermatol pract concept 2015;5(2):22 111 versity hospital, they found a relative risk (rr) of 3.6 for developing bcc in irradiated children [7], in 40% of whom the bccs were multiple. also, they found an inverse association between bcc risk and age of radiation exposure [7]. in another study, ron et al compared 10,834 patients irradiated for tinea capitis in their childhood in israel to a control group of 16,226, demonstrating an rr of 4.9 (95 % ci = 2.6–8.9) for bcc in the irradiated group [8]. the predominant type of bcc in our study was nodular type, which was in concordance with the study done in tunis [9]. bccs have been stratified as low-risk or high-risk according to their propensity for recurrence [10]. our study revealed a greater risk for recurrence among those who have had history for radiation. hassanpour et al compared the management and treatment characteristics of patients previously irradiated for tinea capitis as well as unexposed patients and found that the previously irradiated patients proved to be more difficult to treat, with more hospital admissions (p = 0.008), more operations (p = 0.01), and longer hospitalization period (p = 0.01) [11]. risk factors considered include histologic subtype, horizontal diameter, anatomic location, and patient health status. we believe that history of radiation should be considered as another independent risk factor for basal cell carcinoma in iran. the reason for higher recurrence rate and more aggressive natural history of these tumors is as yet unexplained. a recent study has revealed that mitochondrial d-loop instability is significantly higher in irradiated bccs than in the nonirradiated ones [12]. on the other hand, a genetic study failed to demonstrate any genetic differences (specifically, difference in p53 and ptch) between bcc in irradiated patients and bcc in non-irradiated patients [13]. therefore, it seems that the natural history is more host-related than tumor-related. an interesting question is whether uv radiation and ionizing radiation have a synergistic effect. this study is subject to several limitations. in addition to the problems inherent in any retrospective analysis, the sample size was small and lacking data on skin phototypes of patients and had no histopathologic comparison between the irradiated and non-irradiated patients. conclusions this study shows that x-ray radiation for treating tinea capitis is a significant cause of bcc development in northern iran. bccs in those who had history of radiation have a more aggressive behavior with higher rate of recurrence. references 1. cipollaro ac, brodey a. control of tinea capitis. ny state j med 1950;15;50:1931-4. transcriptionally activated pro-inflammatory cytokines and growth factors. the entire complex is referred to as cutaneous radiation syndrome and its severity depends on several factors such as the radiation dose, radiation quality, individual radiation sensitivity, the extent of contamination and absorption and amount of skin exposed [6]. clinical manifestations usually include a combination of hyperand hypopigmentations, epidermal thinning and sclerosis (figure 3). in a study done by shore et al on more than 2,000 children given x-ray therapy for tinea capitis at new york unifigure 2. dr. john davidson frame and nurses in front of american hospital in rasht [5] (reproduced with permission). figure 3. basal cell carcinoma on the background of old radiodermatitis. [copyright: ©2015 zargari.] 112 research | dermatol pract concept 2015;5(2):22 of the scalp after radiation therapy for tinea capitis: 33 patients. cancer radiother 2004;8(4):270-3. 10. sloane jr. the value of typing basal cell carcinomas in predicting recurrence after surgical excision. br j dermatol 1977;96(2): 127-33. 11. hassanpour se, kalantar-hormozi a, motamed s, moosavizadeh sm, shahverdiani r. basal cell carcinoma of scalp in patients with history of childhood therapeutic radiation: a retrospective study and comparison to nonirradiated patients. ann plast surg 2006;57(5):509-12. 12. boaventura p, pereira d, mendes a, et al. mithocondrial d310 dloop instability and histological subtypes in radiation-induced cutaneous basal cell carcinomas. j dermatol sci 2014;73(3): 31-9. 13. tessone a, amariglio n, weissman o, et al. radiotherapy-induced basal cell carcinomas of the scalp: are they genetically different? aesthetic plast surg 2012;36(6):1387-92. 2. iraji f, arbaby n, asilian a, et al. incidence of non-melanoma skin cancers in isfahan. iranian j of dermatology 2007;38:330-4. 3. noorbala mt, kafaie p. analysis of 15 years of skin cancer in central iran (yazd). dermatol online j 2007;13;13(4):1. 4. frame ma. passage to persia—writings of an american doctor during her life in iran, 1929-1957. england: summertime publisher, 2014. 5. taeb h. the hospitals of rasht. iran: nashr-e farhang-e ilia, 2005 6. gottlöber p, krähn g, peter ru. cutaneous radiation syndrome: clinical features, diagnosis and therapy. hautarzt 2000;51(8): 567-74. 7. shore re, moseson m, xue x, et al. skin cancer after x-ray treatment for scalp ringworm. radiat res 2002;157(4):410-8. 8. ron e, modan b, preston d, alfandary e, et al. radiationinduced skin carcinomas of the head and neck. radiat res 1991;125(3):318-25. 9. mseddi m, bouassida s, marrekchi s, et al. basal cell carcinoma dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020018 1 dermatology practical & conceptual introduction defining clinical margins of lentigo maligna (lm), lentigo maligna melanoma (lmm), and acral melanoma can be challenging when planning surgical excision. this is mainly due to the presence of pathology in normal-looking or lightly pigmented surrounding skin, which can result in incomplete excisions. the wood lamp has many useful applications in dermatology practice, including skin infections (erythrasma, tinea capitis), pigmentary changes (vitiligo, melasma), and porphyria. however, publications addressing its use in dermatology surgery are scarce. we present a case series of 5 patients who presented to our clinic with suspicious pigmented lesions. case presentation in our cohort of 5 patients (3 male, 2 female) the mean age was 77 years old (range 67-86). the lesions were on the face (n = 3), scalp (n = 1), and toe (n = 1). nikon d33s camera (nikon, tokyo, japan) was used for clinical photography and heine delta 20t dermatoscope (heine optotechnik, herrsching, germany) was used for dermoscopic images. all patients were examined under wood lamp (365 nm) in a dark, windowless room. digital photographs were captured and saved in the patients’ e-records to be reviewed before surgery. as seen in figure 1, a and b, wood light examination demonstrated hyperchromatic areas extending beyond the clinically/ dermoscopic discernible pigmentation. these findings guided the surgeon to determine the surgical margins (0.5 cm) using wood light. complete excision demonstrated by histological clearance was achieved in all 5 cases, confirmed by parallel sections of the margins. one patient who had lmm with breslow 0.3 mm required further wide local excision. two of the 5 patients were examined under wood lamp following previous incomplete excisions (with 0.5 cm margin) where no baseline wood lamp examination was undertaken. the site and extent of residual lm were clearly visible under wood lamp (figure 1, c and d), facilitating complete clearance in the re-excision. conclusions the presence of melanin can be difficult to observe by the naked eye because of melanin’s tendency to absorb radiation spanning the electromagnetic spectrum (350-1,200 mm), especially in the shorter wavelength [1]. wood light unique photo-interaction with melanin makes it ideal to assess the extent of pigmented lesions where areas of increased concentrations of epidermal melanin will appear darker by condefining surgical margins with wood lamp ausama a. atwan,1 stela ziaj,2 caroline m. mills1 1 department of dermatology, university hospital of wales, cardiff, uk 2 department of dermatology, royal gwent hospital, newport, uk key words: wood lamp, surgical margin, lentigo maligna, lentigo maligna melanoma citation: atwan aa, ziaj s, mills cm. defining surgical margins with wood lamp. dermatol pract concept. 2020;10(1):e2020018. doi: https://doi.org/10.5826/dpc.1001a18 accepted: october 24, 2019; published: december 31, 2019 copyright: ©2019 atwan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. stela ziaj, department of dermatology, university hospital of wales, cardiff, uk. email: stelaziaj@doctors.org.uk mailto:stelaziaj@doctors.org.uk 2 letter | dermatol pract concept 2020;10(1):e2020018 tients. j eur acad dermatol venereol. 2018;32(9):e366-e368. 4. champin j, parrot jl, cinotti e, et al. in vivo reflectance confocal microscopy to optimize the spaghetti technique for defining surgical margins of lentigo maligna. dermatol surg. 2014;40(3):247-256. melanoma in situ after excisional biopsy. dermatol surg. 2015;41(5):572-578. 3. couty e, tognetti l, labeille b, et al. in vivo reflectance confocal microscopy combined with the “spaghetti technique” for the identification of surgical margins of lentigo maligna: experience in 70 patrast to the normal skin. therefore, the value of wood light in defining surgical margins is limited in patients with photo-damaged skin and concurrent solar lentigines. in this report we have shown that wood light is very helpful in determining margins of lentiginous melanomas before surgical excision. walsh et al [2] also demonstrated that 11.7% of patients with melanoma in situ (n = 60) had wood light enhancement beyond the visible margins of biopsy and the use of wood lamp increased the average wound size in patients. a comparative study is warranted to examine surgical clearance between excisions based on wood lamp illumination vs clinical and dermoscopic examination alone. no long-term follow-up was needed for our cohort of patients following confirmed complete excisions. however, this should be considered in future research with a larger sample size to investigate recurrence rates. advances in technology will continue to modify the way we monitor and manage pigmented skin lesions. for example, in-vivo confocal microscopy has already proven beneficial in assessing surgical and medical approaches in the treatment of lm [3,4]. however, it is important not to forget the utility of simple yet helpful instruments such as wood light, which is widely available in our dermatology departments. references 1. paraskevas lr, halpern ac. utility of the wood’s light: five cases from a pigmented lesion clinic. br j dermatol. 2005;152(5):1039-1044. 2. walsh sb, varma r, raimer d, et al. utility of wood’s light in margin determination of figure 1. (a,b) a lentiginous melanoma on the left cheek. wood light illuminates the area lacking pigment anteriorly and superiorly. (c,d) wood lamp examination of a scar following incomplete excision of a lentigo maligna shows the residual lentigo maligna at the upper edge of the scar. dermatology practical & conceptual www.derm101.com conjectures and refutations | dermatol pract concept 2012;2(3):5 21 objective although conflicting with the concept of nevi being hamartomas, to date, spitz and reed nevi have been regarded as acquired melanocytic nevi, whereas many other types have already been accepted as being congenital. here, the reader will find a survey on clinical, dermatoscopic and histopathologic clues suggesting a congenital origin of authentic spitz nevi. relevant differences in respect to reed nevi are pointed out. what is a nevus? in classic pathology, the term nevus is usually related to a benign hamartomatous proliferation programmed during embryologic life, i.e., a malformation consisting of tissue elements normally found at the corresponding site, but which are growing in a disorganized mass (latin, naevus, birthmark) [1]. thus, per definition, a nevus has to be of congenital origin, e.g., as a consequence of post-zygotic mutation. however, to date, melanocytic nevi are dichotomized into congenital or acquired ones, although the denomination “acquired nevus” is an oxymoron, the term “congenital nevus” tautological. fittingly, the concept of nevi being hamartomas was recently weakened by happle, who suggested defining a nevus rather as a functional or genomic mosaicism, including congenital, but also acquired lesions [2,3]. which are the features of congenital nevi? there are several features suggesting a congenital origin of a melanocytic nevus. by clinical definition, a melanocytic nevus is of the congenital type if present since birth or appearing only shortly after, or if the lesion is of great extension [4]. additionally, from a pathogenetic point of view, any combined, agminated or systematized growth or the presence of terminal hair follicles should be regarded as indicative of a congenital lesion [1,4]. however, the true time of onset of a given melanocytic nevus may precede its visual perception on the skin surface by months or years and might be accelerated by uv-irradiation or hormonal influences, thus simulating a putatively acquired lesion [5-9]. pathologists commonly make the diagnosis of a congenital type nevus even in adults based on the presence of particular histopathologic features that may be found in definitely congenital nevi, in particular, infiltration of the reticular dermis or subcutis and involvement of cutaneous appendages, vessels or nerves. as a common finding, melanocytes splay between collagen bundles singly or in double rows [4,10,11]. recently, the presence of largish melanocytic nests has been identified as a further clue to congenital type nevi and their distinction from acquired ones [4,12,13], although largish nests might also be found in the periphery of growing clark nevi [14]. melanocytes of congenital nevi may be of largish spitz and reed nevi: acquired or congenital? michael bär, m.d.1 1 dermatology office, bautzen, germany key words: spitz nevus, reed nevus, congenital nevus, acquired nevus, melanocytic nevus, nevogenesis, classification citation: bär m. spitz and reed nevi: acquired or congenital? dermatol pract conc. 2012;2(3):5. http://dx.doi.org/10.5826/dpc.0203a05. history: received: february 28, 2012; accepted: april 30, 2012; published: july 31, 2012 copyright: ©2012 bär. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: michael bär, m.d., dermatology office, löbauer straße 17, 02625 bautzen, germany. email: info@hautarztpraxisbaer.de. 22 conjectures and refutations | dermatol pract concept 2012;2(3):5 size and comprise fusiform, epitheloid, or even balloonized or neuroid shapes. the overall silhouette of superficial and deep or deep congenital nevi like zitelli nevus, miescher nevus or blue type nevi is band-like or, more frequently, wedge-shaped [1]. from a dermatoscopic point of view, congenital type nevi frequently exhibit nuances of a globular pattern [4,9,15]. which are the features of acquired nevi? there is still no universally accepted classification of acquired melanocytic nevi [9]. traditionally, at least from a clinical point of view, any smaller nevus with an appearance after the first year of life is termed acquired, although, according to ackerman and other authors, melanocytes that constitute an acquired nevus must already have been present in the skin from the time of parturition and, almost certainly, those melanocytes do not migrate into the skin after birth [1,8,16]. thus, most acquired nevi might root on congenitally preformed depositions of melanocytes, as may be occasionally seen as an incidental finding in skin sections, thus actually representing tardive congenital nevi [1,17]. however, among clinicians, dermatoscopists and dermatopathologists, clark nevus, in particular, is unanimously accepted as an authentic acquired melanocytic proliferation and thus arbitrarily chosen as the prototype of an acquired melanocytic nevus [4,9,15]. interestingly, in contrast to most other types of nevi, clark nevi are flat, superficial and horizontally oriented proliferations that never involve the reticular dermis or subcutis [1,4,18,19]. in contrast to congenital nevi, the melanocytes of clark nevi are usually monomorphous and small with an oval shape [1]. from a dermatoscopic point of view, acquired melanocytic nevi like clark’s frequently exhibit a monotonous reticular pattern [4,15,20]. features of spitz nevi spitz nevi are rapidly growing red or brown papules or nodules usually developing in children or young adults [1,21]. up to 7% of spitz nevi have been reported to occur congenitally and may vary in size from a few millimeters to 2 cm or more [7,21-23]. they may occur in a systematized or agminated pattern and may occasionally be found as constituents of different variants of combined congenital nevi like speckled lentiginous nevi or in association with blue type nevi [21,22,24-38]. histopathologically, spitz nevi are dome-shaped superficial or wedge-shaped superficial and deep melanocytic proliferations with a nested, vertical growth pattern composed of largish, polymorphous, fusiform or epithelioid, in part multinuclear melanocytes (“spitz cells”) [1,21,39]. balloon cells may rarely be seen [40]. spitz nevi exhibit a prominent epidermal or infundibular hyperplasia possibly associated with syringoadnexotropism, neurotropism or myotropism [21]. in the center, melanocytes disposed as solitary units or in nests may be present above the dermoepidermal junction, here exhibiting a certain transepidermal maturation inversely to such usually seen in dermal melanocytic populations [41]. fibroplasia may be impressive, in particular in dermal variants of spitz nevi [22]. dermatoscopically, spitz nevi are typified by nuances of a globular pattern, frequently associated with a structureless center [4,42]. features of reed nevi reed nevi are rapidly growing brown or black, flat or slightly raised lesions usually developing in young adults. only few reed nevi have been noted at birth [43]. histopathologically, reed nevi are typified by a superficial horizontal fascicular growth pattern restricted to the epidermis and papillary dermis and a strong melanin pigmentation [44]. they consist of monomorphous fusiform or sometimes epithelioid melanocytes aggregated in rather largish nests [21,22,39,45,46]. an infiltration of the superficial portions of the eccrine ducts is commonly seen [21,39]. dermatoscopically, reed nevi start with a globular pattern. in a more developed stage they are typified by nuances of a unique starburst pattern consisting of circumferential radial lines or pseudopods and a structureless center. later, the starburst pattern may disperse into a rather reticular pattern [4]. discussion most types of melanocytic nevi like unna’s, miescher’s, clark’s or spitz’s were originally considered to be acquired melanocytic nevi [18,19]. meanwhile, several parallels between unambiguously congenital and apparently acquired nevi were recognized and, recently, at least blue type nevi, miescher nevus and unna nevus have been accepted as congenital type melanocytic nevi [1,4,9,21,47]. in contrast, although conflicting with the concept of nevi being hamartomas, to this day, spitz and reed nevi are still regarded as acquired melanocytic nevi [18,19,21]. however, in several descriptions of spitz nevus it has been noted to have features in common with superficial or superficial and deep congenital melanocytic nevi, too [21,22]. in 2000, harris et al compared congenital and acquired spitz conjectures and refutations | dermatol pract concept 2012;2(3):5 23 nevi with superficial congenital nevi from a clinical and histopathologic point of view, also recognizing many overlapping features [23]. although ackerman in 2007 distinguished congenital and acquired spitz nevi [21], harris et al seem to be the first and only so far seriously considering a congenital origin of any authentic, that is, not atypical, spitz nevus [23]. in point of fact, the burden of clues indicating a congenital origin of spitz nevi seems striking: spitz nevi have a preponderance for children or young adults, and up to 7% of the lesions have even been reported to occur congenitally [7,21-23]. they may vary in size from a few millimeters to 2 cm or more, an extension usually regarded as incompatible with the diagnosis of an acquired nevus [4,7]. spitz nevi may occur in a systematized or agminated pattern, including satellite lesions, strongly arguing for a predetermination early in embryologic life [21,22,24-32]. additionally, they may occasionally be found as constituents of different variants of combined congenital nevi like speckled lentiginous nevus or in association with blue type nevi [33-38]. according to ackerman, all constituents of a combined nevus should represent congenital type nevi [1,21]. thus, even from a clinical point of view, spitz nevi actually should be regarded as truly congenital melanocytic nevi, although their clinical manifestation may be obvious many years later, only if dormant nevi become abruptly activated upon hormonal stimulation during puberty or pregnancy [7]. interestingly, to date, there do not seem to be any consistent reports on combined nevi consisting of any truly acquired constituent like clark nevus. the unique report by marghoob et al on the case of agminated atypical seems to be based on a misinterpretation, as the provided figures exhibit the clinical, dermatoscopic and histopathologic features of an agminated superficial congenital nevus (ackerman nevus), incompatible with the considered diagnosis of agminated clark nevi [48]. in addition, ackerman described clark nevi as constituents of combined nevi in association with blue or spitz nevi [1]. here, in our opinion, the putative clark nevus most likely corresponds to an associated unna or ackerman nevus, respectively, as the melanocytes are either confined to the expanded papillary dermis or the junctional melanocytic nests are to large for an authentic clark nevus [1,12]. finally, the dysplastic compound nevi associated with agminated spitz nevi reported by hamm et al most likely represent associated (incipient) superficial congenital melanocytic nevi [26]. histopathologically, spitz nevi are superficial or superficial and deep melanocytic proliferations composed of largish, fusiform or epithelioid, in part multinuclear melanocytes (“spitz cells”) aggregated in largish, predominantly vertically oriented nests [1,21]. fittingly, melanocytes of congenital nevi are also largish and tend to a rather spindled shape than those of truly acquired clark nevi. additionally, multinucleate melanocytes are an expected finding in congenital type nevi like unna or miescher nevi, but virtually never seen in acquired nevi like clark’s [1]. thus, the occurrence of large and multinucleate melanocytes in about 25% of the lesions analyzed by requena et al might be another clue to the congenital nature of spitz nevi [49]. interestingly, those “spitz cells” also might occasionally be met with in combined congenital melanocytic nevi, miescher nevi, balloon cell nevi or deep penetrating nevi [21]. balloon cells, however, as occasionally found in other congenital nevi, may only rarely be seen [40]. the prominent epidermal or infundibular hyperplasia together with a possible adnexotropism (in particular, syringotropism), neurotropism or myotropism suggests spitz nevi to represent hamartomatous proliferations [21]. in the center, melanocytes disposed as solitary units or in nests may be present above the dermoepidermal junction, as may be seen in early congenital melanocytic nevi, here exhibiting a certain transepidermal maturation inversely to that usually seen in dermal melanocytic populations [1,41]. interestingly, spitz nevi may infiltrate the deeper reticular dermis and even the subcutaneous fat, paralleling the vertical and wedge-shaped growth pattern of miescher nevus [21]. rarely, however, spitz nevus may also present as a sessile or papillomatous papule, thus exhibiting a pattern reminiscent of that seen in unna nevus [21]. fibroplasia may be impressive in dermal variants of spitz nevi being reminiscent of that seen in blue type nevi [22]. dermatoscopically, as many other congenital type nevi, spitz nevi are typified by nuances of a globular pattern [4,42]. however, the initial rapid growth of spitz nevi, some overlapping features with melanoma as well as the lacking reports on terminal hair growing within spitz nevi, a finding generally indicating the congenital nature of a given melanocytic nevus [21], might be considered as clues to a rather acquired histogenesis. furthermore, some findings like fibroplasia, epidermal or infundibular hyperplasia, and infiltration of eccrine ducts or largish melanocytes may be a feature of both melanoma and spitz nevus, thus again relativizing their implication as clues to a congenital nature. according to ackerman, spitz nevus exhibits the silhouette of an acquired melanocytic nevus. ackerman, however, did not define precisely the criteria of the silhouette of an acquired nevus in contrast to such of a congenital one [21]. nonetheless, ackerman regarded agminated or systematized spitz nevi and those being present since birth as truly congenital, i.e., hamartomatous, the others as their acquired analogues [21]. this does not seem plausible to us, as a veritable spitz nevus is either congenital or acquired. otherwise acquired or congenital types must be differing entities with morphologic overlap only. obviously, the silhouette of some spitz nevi 24 conjectures and refutations | dermatol pract concept 2012;2(3):5 may be reminiscent of that of miescher nevus, blue nevus or even unna nevus, all the three representing nevi that have already been accepted as being of the congenital type. in contrast, reed nevi strongly imitate the silhouette of clark nevus, so far the only melanocytic nevus with even molecular clues to a truly acquired origin [50]. it has been assumed that a point mutation v600e in the b-raf gene corresponds to a somatic defect that can be induced by intermittent sun exposure and may be an early step in the genesis of melanoma and (acquired) melanocytic nevi [51]. interestingly, spitz nevi, blue nevi and classic congenital melanocytic nevi obviously do not possess that mutation, but harbor mutations in the c-kit, c-met or n-ras genes instead [9,52-54]. hence, the lack of b-raf mutations might be another indirect argument pointing towards a congenital nature of spitz nevi. unfortunately, for the time being there is no molecular data available explicitly referring to reed nevus. in contrast to spitz nevus, the indicators of a congenital origin of reed nevus are poor. the outstanding reports on agminated or systematized reed nevi, or reed nevus as constituent of a combined nevus, rather suggest a histogenetic event compatible with what is regarded to be a truly acquired melanocytic nevus and might represent another clue to reed and spitz nevi being different entities. finally, a review of the corresponding figures published in relevant reports did not result in identification of any agminated or combined nevus seriously suspicious for reed nevus. histopathologically, reed nevi are typified by a horizontal fascicular growth pattern restricted to the epidermis and papillary dermis [21,39,44], thus paralleling the pattern of clark nevus. however, the prevailing cytomorphologic feature of spindle-shaped or even epithelioid melanocytes seem to be more in favor of a congenital type nevus. however, as mentioned for spitz nevi, no terminal hair follicles have been reported to occur in reed nevi yet. reed nevi and spitz nevi have in common an infundibular accentuated epidermal hyperplasia and a frequent melanocytic infiltration of the upper eccrine ducts [21]. dermatoscopically, reed nevi start with a globular pattern indistinguishable from that of spitz or other congenital type nevi. in a more developed stage they are typified by nuances of a unique starburst pattern consisting of circumferential radial lines or pseudopods. later, the starburst pattern may disperse into a reticular pattern reminiscent of that seen in clark nevus [4]. in 2007, argenziano et al proposed a classification system for melanocytic nevi based on dermatoscopic features [15]. they distinguished congenital nevi present at birth or appearing before puberty with a globular pattern, whereas acquired nevi usually exhibit a reticular pattern. according to the dual concept of nevogenesis based on dermatoscopic observations, zalaudek and coworkers distinguished an endogenous, i.e., genetically determined pathway represented by a dermatoscopically globular pattern and a rather vertical growth and an exogenous or uv-dependent pathway with associated braf mutation dermatoscopically represented by a reticular pattern and a rather horizontal growth [9]. hence, all melanocytic nevi growing at non-uv-exposed localizations must be of the congenital type, including spitz nevus which has been reported to grow even at the palate [55]. on the other hand, the possible congenital onset of reed nevi argues against their uv-dependent acquired histogenesis. interestingly, largish junctional melanocytic nests are an expected finding not only in congenital type nevi but in growing lesions, particularly at the periphery of enlarging clark nevi [14]. as a consequence, the presence of a globular dermatoscopic pattern of reed and spitz nevi might only be an expression of their rapid growth and not a reliable proof of their acquired or congenital nature. a truly acquired origin of reed nevi would, however, implicate at least one more pathway within the dual concept of nevogenesis advocated by zalaudek et al [9], an additional uv-independent exogenous pathway. an alternative concept was recently suggested by happle, who proposed a functional or genomic mosaicism that might be congenital, but also acquired anytime during life, as origin of any nevoid growth. hence, the definition of nevus must not inevitably include the idea of a hamartomatous proliferation and, furthermore, an authentic nevus might be actually acquired, among other possible factors, such as following chronic or intermittent uv exposure [2,3]. to sum up, taking into consideration all the aforementioned clinical, dermatoscopic and dermatopathologic features of spitz and reed nevi (table 1), we propose a congenital origin for all authentic spitz nevi might be proposed. in contrast, reed nevi seem to exhibit several features favoring an acquired histogenesis. owing to the morphologic overlap with spitz nevus, however, it may be speculated that reed nevus corresponds to a morphologically distinctive, acquired analogue of spitz nevus. it might be presumed that both could share a similar genetic disorder acquired at different times during embryologic or postnatal life, which would explain the different clinical settings. however, this might not be a sufficient explanation for their horizontal or vertical growth patterns that, again, might depend on additional local factors. in conclusion, further comparative and molecular studies on congenital versus apparently acquired spitz and reed nevi are required to verify their true histogenetic origin. references 1. ackerman ab, cerroni l, kerl h. pitfalls in histopathologic diagnosis of malignant melanoma. philadelphia: lea & febiger, 1994. conjectures and refutations | dermatol pract concept 2012;2(3):5 25 table 1. clues to an acquired or congenital nature of spitz and reed nevi. reed nevus spitz nevus arguments pro congenital origin arguments pro acquired origin arguments pro congenital origin arguments pro acquired origin clinical • congenital onset possible, albeit rarely • predilection for children or young adults clinical • rapid growth • no reports on agminated growth • no reports on being constituent of a combined nevus • no reports on occurrence at non-uv-exposed anatomical sites clinical • congenital onset possible • predilection for children or young adults • agminated pattern possible • occasional constituent of combined nevi • large size up to more than 2 cm possible • occurrence at nonuv-exposed anatomical sites clinical • rapid growth • no reports on associated terminal hair growth dermatoscopy • initial globular pattern dermatoscopy • starburst pattern later tapering off into a reticular pattern like clark nevus dermatoscopy • globular pattern as seen in other congenital nevi dermatopathology • largish nests • fusiform melanocytes • epitheloid or multinuclear melanocytes possible • infundibular hyperplasia • infiltration of eccrine ducts • central pagetoid spread of melanocytes possible dermatopathology • silhouette reminiscent of clark nevus • horizontal growth pattern restricted to epidermis and papillary dermis, i.e., no consistent reports on dermal variants involving the reticular dermis • relatively small melanocytes • no reports on associated terminal hair growth • some features in common with melanoma dermatopathology • silhouette may be reminiscent of miescher or unna nevus • infiltrative vertical growth pattern with possible infiltration of the reticular dermis or subcutis • reports on dermal variants • largish nests • epithelioid / multinuclear melanocytes frequent • infundibular hyperplasia • infiltration of eccrine ducts • myotropism, neurotropism • fibroplasia • central pagetoid spread of melanocytes possible • no 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spitz nevi. j invest dermatol. 2004; 122(5):1325-6. 53. bauer j, curtin ja, pinkel d, bastian bc. congenital melanocytic nevi frequently harbor nras mutations but no braf mutations. j invest dermatol. 2007;127(1):179-82. 54. ross al, sanchez mi, grichnik jm. molecular nevogenesis. dermatol res pract. 2011;2011:463184. epub 2011 apr 6. 55. nikai h, miyauchi m, ogawa i, takata t, hayashi y, okazaki h. spitz nevus of the palate. report of a case. oral surg oral med oral pathol. 1990;69(5):603-8. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2012;3(2):13 75 does taping torso scars following dermatologic surgery improve scar appearance? helena rosengren, mbchb, fracpg1, deborah a. askew, ph.d., mhithsci2, clare heal, mbchb, ph.d.3, petra g. buettner, ph.d., msc4, william o. humphreys, mbbs, facscm5, lyndie a. semmens5 1 school of medicine, james cook university, townsville, queensland, australia 2 school of medicine, the university of queensland, queensland, australia 3 james cook university, townsville, queensland, australia 4 school of public health, tropical medicine and rehabilitation sciences, james cook university, townsville, queensland, australia 5 skin repair, townsville, queensland, australia key words: taping, trunk, torso, scars, dermatologic surgery citation: rosengren h, askew da, heal c, buettner pg, humphreys wo, semmens la. does taping torso scars following dermatologic surgery improve scar appearance? dermatol pract conc. 2013;3(2):13. http://dx.doi.org/10.5826/dpc.0302a13. received: november 4, 2012; accepted: february 1, 2013; published: april 30, 2013 copyright: ©2013 rosengren et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: helena rosengren received a research grant through the university of queensland by an australian commonwealth government initiative, primary health care research and evaluation and development (phcred). funding for the research nurse and assistant and for purchase of skin tapes came from the recruiting skin cancer clinics, skin alert and skin repair. otherwise authors had no financial support for the submitted work. the submitted work was not influenced in any way by funding bodies. competing interests: the authors have no conflicts of interest to disclose. all authors have made substantive intellectual contribution to the study. corresponding author: dr. helena rosengren, 66 mooney street, gulliver, queensland 4812, australia. tel. 61 414 881401/ 617 4779 0099; fax. 617 4779 0098. email: helenarosengren@ymail.com. background: studies show that patients are significantly less satisfied with torso scars than scars elsewhere. though not an uncommon practice, it is unknown if application of adhesive tapes following dermatological surgery help improve cosmesis. objective: to determine the effect of taping sutured torso wounds on overall scar appearance, scar width and patient satisfaction with the scar. patients/methods: participants having elliptical torso skin excisions in a primary care setting in regional australia were randomized in a single-blinded, controlled trial to 12 weeks taping (intervention) or usual care (control) following deep and subcuticular suturing. a blinded assessor reviewed scars at three and six months. results: of 195 participants recruited, 136 (63 taped, 73 controls) completed six months of follow-up. independent blinded assessment of overall scar appearance was significantly better in taped participants (p= 0.004). taping reduced median scar width by 1 mm (p=0.02) and when stratified by gender, by 3.0 mm in males (p=0.04) and 1.0 mm in females (p=0.2). high participant scar satisfaction was not further improved by taping. conclusion: taping elliptical torso wounds for 12 weeks after dermatologic surgery improved scar appearance at six months. abstract 76 research | dermatol pract concept 2012;3(2):13 researcher trained staff to ensure consistency of data collection and standardization of management. the study nurse phoned participants within five days of surgery and then fortnightly for 12 weeks to ascertain analgesia requirements, wound complications and intervention compliance. wound assessment was encouraged at three and six months even if participants had not been fully compliant with the intervention protocol. every participant gave signed informed consent and received written postoperative wound care information. eligibility criteria patients aged 18 to 80 years requiring elliptical skin excisions on the torso were eligible for the study provided they could easily reach the wound or had someone available to help with taping. exclusion criteria included known tendency to keloid scarring; allergy to the sutures or skin tapes; flap surgery; and prescribed immunosuppressive drugs. participants requiring a second wider excision for residual tumor or melanoma were subsequently excluded from the study. surgical wound management protocol we used a standardized surgical procedure (figure 1). in addition to deep and subcuticular sutures, an occasional superficial interrupted 3/0 nylon suture was used where necessary to improve wound edge apposition. melolin dressings (smith and nephew medical ltd, hull, uk), applied immediately after surgery, were changed after seven days (or sooner if soiled) and removed along with sutures 14 days postoperatively. a splash-proof dressing cover (opsite flexifix, smith and nephew medical ltd, hull, uk) was used, making showering easier for participants. in the hotter more humid months (november to february inclusive), however, we used non-waterproof dressing covers (fixomul stretch, bsn medical, hamburg, germany), allowing wounds to breathe better. intervention adhesive tapes 100 mm long and 10 mm wide (leukostrips, smith and nephew medical ltd, hull, uk) were applied perpendicularly to the sutured wound, in parallel without overlapping, prior to the dressing (figure 2). it has been shown that tapes adhere to skin for longer with this technique [15]. participants and carers were shown how to apply and remove tapes as well as receiving written instructions and a descriptive photo of the taping technique (figure 3). instructions were given to change tapes on the same day each week for 12 consecutive weeks and to trim tape ends if they lifted. if no more than 4 cm extending either side of the scar, instructions were given to replace this tape and still change all tapes on the scheduled weekday. introduction dermal postoperative repair produces scar tissue that can cause significant psychological and physical consequences [1,2]. with an estimated 55 million elective operations occurring each year in the developed world alone [3] and confirmation that most patients (irrespective of age, gender and ethnicity) believe that even a small improvement in scarring is worthwhile [4], any research that may help improve scar outcome is meaningful. research has confirmed a positive correlation between tension and increased scar tissue formation [5,6]. the great range of movement afforded by the spine renders scars on the trunk particularly vulnerable to tension and subsequent disfigurement. it may therefore not be surprising that patients are significantly more dissatisfied with torso scars than other scars [7-9]. dermatologic surgery on the trunk is common worldwide, and in australia 27% of all basal cell carcinomas (bccs), 8% of all squamous cell carcinomas (sccs), 25% of all invasive melanoma in men and 11% of all invasive melanoma in women are excised from the torso [10,11]. evidence shows that prolonged use of adhesive tapes applied along a scar following surgery may reduce scar volume and improve cosmetic outcome [12,13]. though shortterm taping following dermatological surgery may be standard protocol for many practices, the optimal duration and mechanism of action of this intervention remains unclear [12,14]. the aim of this study was to determine the impact of 12 weeks of tape application perpendicular to sutured torso wounds on overall aesthetic appearance and width of the scars, as well as patient scar satisfaction at six months following surgery. materials and methods this was a randomized controlled assessor blinded trial involving patients having elliptical skin excisions on the torso in a primary health care setting. the study was approved by the university of queensland ethics committee (approval number #2008000535 april 2008). all patients gave written informed consent. setting & participants consecutive eligible patients were recruited by two general practitioners (including the prin cipal researcher, hr), at a primary health skin cancer clinic in townsville, north queensland, australia from june 2008 to january 2010. baseline demographic data, relevant medical history, degree of torso movement anticipated during the study period and lesion histology were documented (table 1). excision sites were recorded on body maps. the principal research | dermatol pract concept 2012;3(2):13 77 table 1. baseline characteristics of participants by treatment group characteristic control group n=103 intervention group n=92 p age in years—mean (sd) 52.6 (15.4%) 51.4 (15.1%) 0.59 women 50 (48.5%) 56 (60.9%) 0.10 body mass index (kg/m2) – mean (sd) 27.0 (4.1%) 26.7 (4.5%) 0.61 diagnoses of diabetes 8 (7.8%) 7 (7.6%) 0.97 prescribed aspirin, clopidogrel and/or inhaled steroids 16 (15.5%) 9 (9.8%) 0.23 smoking status 0.28 ex-smoker 33 (32.0%) 27 (29.3%) current smoker 9 (8.7%) 15 (16.3%) level of activity at work 0.28 not working 43 (41.7%) 32 (34.8%) sedentary occupation 39 (37.9%) 30 (32.6%) moderate bending/ lifting 12 (11.7%) 16 (17.4%) strenuous bending/ lifting 9 (8.7%) 14 (15.2%) histology of skin lesion 0.12 basal cell carcinoma 42 (40.8%) 44 (47.8%) sqamous cell carcinoma 5 (4.9%) 9 (9.8%) cutaneous melanoma 11 (11.3%) 6 (6.5%) dysplastic naevus 34 (32.0%) 27 (29.3%) other naevus 3 (3.0%) 5 (5.4%) other lesion 8 (7.8%) 1 (1.1%) torso site 0.27 upper back (above waist) 67 (65.0%) 59 (64.2%) lower back/buttock 10 (9.7%) 11 (11.9%) chest 22 (21.4%) 21 (22.8%) abdomen 4 (3.9%) 1 (1.1%) median post-excision length of scar before suturing [mm] (iqr) 33 (25, 37) 33 (28, 37.5) 0.41 median post-excision width of scar before suturing [mm] (iqr) 19 (15, 22) 19 (15, 22.5) 0.72 iqr= inter-quartile range; sd = standard deviation moderate bending/ lifting<15kg (e.g. bowls/ gardening); strenuous bending/ lifting >15kg (e.g. rowing/ weight training) 78 research | dermatol pract concept 2012;3(2):13 randomization and blinding the allocation sequence was generated using a computerized randomization schedule at the discipline of general practice at the university of queensland. randomization was done in blocks of six to ensure roughly equal numbers in each study group. sequentially numbered opaque sealed envelopes containing details of group allocation were only opened following wound closure to ensure blinding to randomization during the surgical procedure. participants were asked not to reveal their group allocation to the blinded outcome assessor. scars were assessed 10 to 14 days after completion of the 12-week intervention so that there was no residual tape adhesive that might inadvertently reveal group allocation. outcome data entry was done at the university of queensland by a research assistant not directly involved in the trial. clinical outcomes maximal scar width was recorded to the nearest millimeter. overall scar appearance and participant satisfaction with their scar were both appraised using five-point categorical scales. outcome assessment was undertaken by an independent blinded research nurse three and six months postoperatively. overall scar appearance was evaluated and documented along with presence of scar elevation, depression and dyschromia. reference photographs taken and categorized by the principal investigator (hr) before commencement of the trial helped ensure consistency of this assessment. participants completed adapted questionnaires [16] at the assessment visits. participant satisfaction with the scar was ascertained as well as how perceived cosmetic results compared to their expectation and whether they would use tapes for future torso scars if our study results proved favorable. sample size it was hypothesized that a minimum mean difference of 2 mm in wound width between taped participants and controls would be clinically significant. to show this with statistical confidence (power in excess of 80%; significance level 0.05), 29 participants were required in each study group. for overall scar appearance and patient scar satisfaction (both measured on categorical scales), it was hypothesized that a difference of at least one category between the two figure 1. standardized surgical procedure. [copyright: ©2013 rosengren et al.] figure 2. randomization protocol. [copyright: ©2013 rosengren et al.] figure 3. taped torso wound—a descriptive photo. [copyright: ©2013 rosengren et al.] research | dermatol pract concept 2012;3(2):13 79 ments (p=0.343). analgesics used were paracetamol (38), paracetamol with 30 mg codeine phosphate (4) and ibuprofen (2), but 77.4% (151) patients required no pain relief. one participant developed allergy to the adhesive tapes and subsequently stopped taping. surgical complications (1 hematoma, 2 infection, 1 dehiscence, 2 stitch abscesses) were as infrequent in both study groups (p=0.804). characteristics of non-participants forty-five patients declined participation, mainly due to a lack of interest (73.3%). participants were more likely to be female (p=0.005), less likely to take anticoagulants or inhaled steroids (p=0.049) and reported more exercise in their leisure time (p=0.042) than non-participants. those who enrolled in but did not complete the study (41) were more likely to be younger (p<0.001), female (p=0.01) and more physically active at work (p=0.036). main outcome measures the overall scar rating given by the blinded assessor at six months was significantly better in the intervention group (p=0.004) (table 2) both for males (p=0.045) and females (p=0.045). wounds were rated as good or very good in 64.4% of taped participants and 38.4% controls, whereas they were rated as poor or very poor in 14.6% taped participants and 39.8% controls. median scar width at six months was 1 mm less in taped participants than controls (p=0.015). when stratified by gender, there was no significant difference in scar width for females (p=0.155), but for men there was a study groups would be clinically significant. to show this with statistical confidence (power in excess of 80%; significance level 0.05), 78 participants were required in each study group. for all outcomes to be assessed and allowing for a 25% drop out rate, we planned to enroll 204 patients. statistical analysis participant data were analyzed according to allocated study group, irrespective of protocol violation or non-compliance. success of randomization was ascertained by comparing baseline information between groups. this included age, gender, diabetes, smoking history, degree of torso movement at work and in leisure time, body mass index, histology of lesion, torso site and wound dimensions. numerical data were described using mean values and standard deviations when approximately normally distributed or median values and inter-quartile ranges when skewed. chi-square tests, t-tests and non-parametric wilcoxon tests were used for baseline comparisons between participants and non-participants and between the study groups. wound assessments and patient satisfaction scores were compared using non-parametric wilcoxon tests. statistical analysis was conducted using spss version 18 (pasw; spss inc., chicago, illinois). p-values of less than 0.05 were considered statistically significant. results baseline description of patients and skin lesions of 240 eligible patients, 195 opted to participate. excisions were for skin cancer (44.1% bccs, 7.2% sccs) or suspicious pigmented lesions (48.7%) (table 1). those with lesions requiring a second wider excision (16 melanoma; two incompletely excised bccs) were excluded from the study, leaving 177 participants (86 intervention; 91 control). one in-situ melanoma with adequate margins on primary excision remained in the study. forty-one participants withdrew or were lost to follow-up, leaving 63 (73.3% of 86) in the intervention and 73 (80.2% of 91) in the control group at six months (figure 4). at baseline there were no significant differences between study groups (table 1) with the mean age being 52 years (sd 15.2, range 18 to 80 years) and 53.3% (104) being female. other than gender there were no differences between the study groups at six months, with 38.4% (28) of controls and 58.7% (37) of intervention participants being female (p=0.013). treatment and complications there was no difference between study groups in the number of deep sutures used (p=0.93; median number three; range from two to ten) or postoperative pain relief requirefigure 4. randomization flow chart for participants. [copyright: ©2013 rosengren et al.] 80 research | dermatol pract concept 2012;3(2):13 discussion twelve weeks of taping torso scars postoperatively significantly improved independent assessment of overall scar appearance at six months. there was no significant difference in the number of participants with at least some scar depression, elevation or dyschromia in the two study groups. since degree of these three variables was not evaluated, however, these observations may have little clinical relevance. taping reduced median scar width by a modest 1 mm, which, though statistically significant, was thought not to be clinically relevant. when stratified by gender, however, the observed 3 mm reduction in scar width in taped males may be of clinical as well as statistical significance. in nontaped controls, scars were significantly wider in males than females, possibly because men subject the torso to more tension and stretch. this could explain why taping, which may help support the healing wound, had a greater impact on scar width in males. participant satisfaction was high in our study and not further improved by taping. a major limitation of this study, however, is that we did not have adequate power to show with statistical confidence whether taping affected patient satisfaction levels. due to time restrictions and a higher than predicted dropout rate, only 136, rather than the required 156 participants, attended for six-month assessment. furthermore there may have been under-reporting of dissatisfac3.0 mm difference in median width between the control (5.0 mm, iqr = 2.0, 10.0) and intervention groups (2.0 mm, iqr = 1.0, 5.5) (p=0.036) (table 2). there was no significant difference between study groups in the number of participants with at least some scar depression, elevation or dyschromia. the intervention was well tolerated with just one of 85 participants initially randomized to the intervention developing an allergy to the tapes. no other problems arose as a result of taping. subjective scar assessment at six months was the same in both study groups (p=0.649) even when stratified by gender (table 3). only one participant (control) reported the cosmetic outcome to be worse than expected; 98.6% (71) controls and 93.2% (55) of the intervention group would have opted to have the surgery done again (p=0.174) (table 2). the majority of participants (82.4% intervention group; 69.9% controls; p=0.148) even when stratified by gender (70.4% males; 81.5% females; p=0.221) indicated they would use tapes for a future scar if our results proved favorable (table 3). though trends suggested that median scar width and overall scar appearance was better in the intervention group three months postoperatively, this did not reach statistical significance. median scar width was 1 mm less in taped participants (3.0 mm, iqr = 2.0, 5.0) than controls (4.0 mm, iqr = 2.5,6.0) (p=0.064), while overall scar appearance rated good/ very good in 53% taped participants compared to 43% controls (p=0.259) at three months following surgery. table 2. independent blinded scar assessment at six months control n=73 taped n=63 p-value overall rating of scar appearance 0.004 very good 11 (15.1%) 10 (16.1%) good 17 (23.3%) 29 (46.8%) okay 16 (21.9%) 13 (21.0%) poor 25 (34.2%) 10 (16.1%) very poor 4 (5.5%) 0 median width of scar (iqr) [mm] 4.0 (2.0, 7.5) 3.0 (2.0, 5.0) 0.015 median length of scar (iqr) [mm] 36.0 (29.0,42.5) 35.0 (28.0,41.0) 0.39 scar elevation 8 (11.0%) 4 (6.5%) 0.55 scar depression 26 (35.6%) 22 (35. 5%) 0.99 discolouring 69 (94.5%) 57 (91.9%) 0.73 iqrinterquartile range research | dermatol pract concept 2012;3(2):13 81 similar to other studies [17,18], we found that the independent assessor was less satisfied with the scar than the participants themselves. participant satisfaction with torso scars was much higher in our study than in other studies, however [7-9]. reasons for this may include altered participant expectation and employment of a different suture technique in our study. on recruitment we informed participants that the study was being conducted because torso scars tend to look worse than scars elsewhere. preoperative expectations are known to be an important determinant of patient satisfaction [8]. only one participant reported a worse than expected outcome at six months. though there has not been sufficient research on the use of absorbable sutures [19], there is evidence that their tion, as many participants were well known to their primary health care surgeon and may have wished not to offend. additionally, almost two-thirds of the excisions were on the upper back, resulting in scars that would have been difficult for some participants to clearly visualize possibly leading to inappropriately high satisfaction scores. blinding the doctor to group allocation before wound closure helped ensure a uniform surgical technique for all participants. fortnightly phone calls may have helped improve compliance in taped participants. bias in reported satisfaction was prevented by contacting controls with equal regularity. bias in scar assessment was eliminated by blinding the independent assessor, who used a visual aid to help categorize scars and improve uniformity in scar rating. table 3. participant questionnaire outcome measures at 6 month follow-up control (n=73) taped (n=63) p-value how satisfied are you with how your scar looks? 0.65 very satisfied 33 (45.8%) 25 (43.1%) satisfied 26 (36.1%) 21 (36.2%) neutral 13 (18.1%) 11 (19%) dissatisfied 0 1 (1.7%) very dissatisfied 0 0 how does the scar compare with what you expected? 4.0 (2.0, 7.5) 3.0 (2.0, 5.0) 0.015 my scar is invisible to me 23 (31.9%) 18 (31.6%) my scar is better than i expected 28 (38.9%) 16 (28.1%) my scar is about what i expected 20 (27.8%) 23 (40.4%) my scar is worse than i expected 1 (1.4%) 0 given the scarring result would you make the same decision to have surgery? 0.17 yes 71 (98.6%) 55 (93.2%) if we find that taping does make a difference to the scar would you tape a future torso scar after surgery? 0.15 yes 51 (69.9%) 52 (82.4%) no 4 (5.5%) 3 (4.8%) don’t know 16 (21.9%) 6 (9.6%) not answered 2 (2.7%) 2 (3.2%) 82 research | dermatol pract concept 2012;3(2):13 conclusion this study has shown that 12 weeks taping of sutured torso scars is a safe, effective and well-tolerated intervention that may significantly improve scar appearance at six months. acknowledgements: we gratefully acknowledge the two recruiting townsville primary health skin cancer clinics, skin alert and skin repair, for funding a research nurse and the tapes used in this study. we would like to convey our appreciation to phcred for the research grant awarded to dr. helena rosengren. we would also like to thank sylvia scully for her invaluable assistance with data entry at department of general practice, university of queensland. ethical approval: the study was approved by the university of queensland ethics committee (approval number #2008000535 april 2008). all patients gave written informed consent. trial registration: australian new zealand clinical trials registry (actrn126080004963 may 2008) references 1. brown bc, mckenna sp, solomon m, wilburn j, mcgrouther da, bayat a. the patient-reported impact of scars measure: development and validation. plast reconstr surg. 2010;125(5):1439-49. 2. durani p, mcgrouther da, ferguson mw. the patient scar assessment questionnaire: a reliable and valid patient-reported outcomes measure for linear scars. plast reconstr surg. 2009;123(5):1481-9. 3. bayat a, mcgrouther da, ferguson mw. skin scarring. bmj. 2003;326(7380): 88-92. 4. young v, hutchison j. insights into patient and clinician concerns about scar appearance: semiquantitative structured surveys. plast reconstr surg, 2009;124(1):256-65. 5. su cw, alizadeh k, boddie a, lee rc. the problem scar. clin plast surg. 1998; 25(3):451-65. 6. ladin da, garner wl, smith dj jr, excessive scarring as a consequence of healing. wound repair regen. 1995;3(1):6-14. 7. dixon aj, dixon mp, dixon jb. prospective study of long-term patient perceptions of their skin cancer surgery. j am acad dermatol. 2007;57(3):445-53. 8. kearney cr, holme sa, burden ad, mchenry p. long-term patient satisfaction with cosmetic outcome of minor cutaneous surgery. australas j dermatol. 2001. 42(2):102-5. 9. lowe t, paoloni r. sutured wounds: factors associated with patient-rated cosmetic scores. emerg med australas. 2006;18(3):259-67. 10. staples m, elwood m, burton rc, williams jl, marks r, giles gg. non-melanoma skin cancer in australia: the 2002 national survey and trends since 1985. med j aust. 2006;184(1):6-10. 11. buettner pg, maclennan r. geographical variation of incidence of cutaneous melanoma in queensland. aust j rural health. 2008;16(5):269-77. 12. atkinson ja, mckenna kt,barnett ag, mcgrath dj, rudd m. a randomized, controlled trial to determine the efficacy of pause in high tension areas results in better scar cosmesis [20]. furthermore, the use of subcuticular surface sutures avoids additional scars associated with stretched interrupted epithelial suture marks. the two-layered (deep absorbable and subcuticular non-absorbable suture) closure we used may simply have given superior scar aesthetics (increasing participant scar satisfaction) compared to the simple interrupted suture closure used in other studies. few studies were found that assessed the cosmetic effect of taping scars. in a randomized prospective study of 39 caesarean section cases, atkinson et al were able to demonstrate a significant reduction of scar volume where paper tape was applied for 12 weeks along the scar postoperatively [12]. the odds of developing hypertrophic scars were 13.6 times greater in non-taped wounds. in a descriptive paper, reiffel presented two cases with photographic evidence showing significant improvement in scarring following surgical scar revision and use of paper tapes along the scar for at least two months [13]. it has been postulated that the following three interventions help prevent excessive scar formation: supporting the healing wound to reduce tension (which results in increased collagen synthesis); covering the wound to improve hydration and hasten scar maturity (by down regulating collagen and fibroblast production); and applying pressure to the wound (causing local hypoxia and subsequent fibroblast and collagen degradation) [12,14,19]. in our study long tapes applied close together perpendicular to the wound edges is likely to have reduced wound tension and provided at least intermittent wound pressure (with torso movement). though the tapes we employed were only partially occlusive, this may also have played a role in improving scar hydration. though the trend in our study suggested that taping torso wounds was beneficial at three months, statistical significance was only seen at six months. any intervention for torso scars might therefore be best followed up for at least six months before discounting its effectiveness. a longer term observational study mapping the natural progress of torso scars is needed to establish just how long they are vulnerable to stretch, as it may well be much longer than six months. the 12-week period of taping in our study was an arbitrary decision. perhaps a shorter period of taping is equally effective, or conversely, more prolonged taping gives a superior result. we have outlined several potential reasons for patient satisfaction being high and in particular being equally high in both study groups. despite this, 82.4% taped participants specified they would tape a future scar if our results proved favorable, indicating that many patients are motivated to improve scar appearance and that 12 weeks of taping is not too onerous. research | dermatol pract concept 2012;3(2):13 83 18. rissin y, fodor l, ishach h, oded r, ramon y, ullmann y. patient satisfaction after removal of skin lesions. j eur acad dermatol venereol. 2007;21(7):951-5. 19. tziotzios c, profyris c, sterling j. cutaneous scarring: pathophysiology, molecular mechanisms and scar reduction therapeutics part ii. strategies to reduce scar formation after dermatologic procedures. j am acad dermatol. 2012;66(1):13-24. 20. durkaya s, kaptanoglu m, nadir a, yilmaz s, cinar z, dogan k. do absorbable sutures exacerbate presternal scarring? tex heart inst j. 2005;32(4):544-8. 21. webster dj, davis pw. closure of abdominal wounds by adhesive strips: a clinical trial. br med j. 1975;3(5985):696-8. 22. taube m, porter rj, lord ph. a combination of subcuticular suture and sterile micropore tape compared with conventional interrupted sutures for skin closure. a controlled trial. ann r coll surg engl. 1983;65(3):164-7. per tape in preventing hypertrophic scar formation in surgical incisions that traverse langer’s skin tension lines. plast reconstr surg. 2005;116(6):1648-56; discussion 1657-8. 13. reiffel rs. prevention of hypertrophic scars by long-term paper tape application. plast reconstr surg. 1995;96(7):1715-8. 14. mustoe ta. a randomized, controlled trial to determine the efficacy of paper tape in preventing hypertrophic scar formation in surgical incisions that traverse langer’s skin tension lines. plast reconstr surg. 2005. 116(6): discussion 1657-8. 15. katz kh, desciak eb, maloney me. the optimal application of surgical adhesive tape strips. dermatol surg. 1999;25(9):686-8. 16. singer aj, arora b, dagum a, valentine s, hollander je. development and validation of a novel scar evaluation scale. plast reconstr surg. 2007;120(7):1892-7. 17. hoeller u, kuhimey a, bajrovic a, et al. cosmesis from the patient’s and the doctor’s view. int j radiat oncol biol phys. 2003;57(2):345-54. untitled quiz | dermatol pract concept 2015;5(4):14 57 dermatology practical & conceptual www.derm101.com the patient a 42-year-old male, phototype iii-iv, presented with an 8-month history of gradually enlarging pigmentation on the second finger of his left hand. he had no personal or familial history of skin cancer. no cryotherapy or other procedure was performed in this location. naked-eye examination revealed an irregular hyperpigmented plaque extending from proximal to lateral nail fold, which appeared irregularly shaped and with fuzzy borders (figure 1a). dermoscopy showed a brown-colored area displaying parallel pattern with pigment both in furrows and ridges and a white structureless area in the proximal nail fold; in the distal part of the lateral nail fold and in the hyponychia, a slightly verrucous area with irregular light brown pigmentation was noted (figure 1b). irregular pigmentation of acrosyringia was also observed. two punch biopsies were taken from the proximal and distal areas of the lesion. histopathology reported acanthosis, hyperkeratosis and full thickness atypia of epidermal keratinocytes, and melanin in the lower epidermis (figure 2). what is your diagnosis? a pigmented lesion on the finger gabriel salerni1,2, carlos alonso1,2, mario squeff1, mario gorosito3, ramón a. fernández-bussy1 1 dermatology department, hospital provincial del centenario de rosario and universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina 3 pathology department, universidad nacional de rosario, argentina citation: salerni g, alonso c, squeff m, gorosito m, fernández-bussy ra. a pigmented lesion on the finger. dermatol pract concept 2015;5(4):14. doi: 10.5826/dpc.0504a14 copyright: ©2015 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: gabriel e. salerni, md, phd, urquiza 3100. 2000 rosario, santa fe, argentina. tel. +54 341 4398586. email: gabrielsalerni@gmail.com figure 1. clinical image showing an irregular hyperpigmented plaque on the second finger of the left hand (a). dermoscopy showed a brown-colored area displaying a parallel pattern and a white-colored area in the proximal nail fold; in the distal part of the lateral nail fold and in the hyponychia, a slightly verrucous area with irregular light brown pigmentation was noted (b). irregular pigmentation of acrosyringia was also observed (b, arrows). [copyright: ©2015 salerni et al.] mailto:gabrielsalerni@gmail.com 58 quiz | dermatol pract concept 2015;5(4):14 dermoscopy may be considered as a helpful tool for increasing the diagnostic accuracy of bd. glomerular vessels plus a scaly surface was the most frequent combination of criteria in pigmented and non-pigmented bd. in pbd, small brown globules and/or homogeneous pigmentation can be seen in addition [1]. the correct classification of non-melanocytic origin of the lesion was therefore achieved only after histological evaluation. despite its rarity, pbd should be included among those lesions that may simulate cutaneous melanoma. references 1. zalaudek i, argenziano g, leinweber b, et al. dermoscopy of bowen’s disease. br j dermatol. 2004;150(6):1112-6. 2. gutiérrez-mendoza d, narro-llorente r, karam-orantes m, et al. dermoscopy clues in pigmented bowen’s disease. dermatol res pract. 2010;2010: 464821. 3. cameron a, rosendahl c, tschandl p, et al. dermatoscopy of pigmented bowen’s disease. j am acad dermatol. 2010;62(4):597-604. 4. firooz a, farsi n, rashighi-firoozabadi m, et al. pigmented bowen’s disease of the finger mimicking malignant melanoma. arch iran med. 2007;10(2):255-7. 5. saxena a, kasper da, campanelli cd, et al. pigmented bowen’s disease clinically mimicking melanoma of the nail. dermatol surg. 2006;32(12):1522-5. diagnosis pigmented bowen’s disease clinical course in a second procedure, the lesion was excised completely. polymerase chain reaction sampling was positive for human papillomavirus (hpv). answer and explanation bowen’s disease (bd) is an in situ squamous cell carcinoma of the skin and mucous membranes that typically presents as a scaly erythematous plaque. bd can be induced by sun exposure, chronic arsenic exposure, radiation, trauma and human papillomavirus (hpv) infection. pigmented bowen’s disease (pbd) is an unusual form of the disease, which generally presents as a hyperpigmented, well-demarcated plaque with a scaly or hyperkeratotic surface. pigmented bowen’s disease (pbd) may clinically present with a variable amount of pigmentation and simulate seborrheic keratosis, actinic keratosis, basal cell carcinoma, atypical nevus, or melanoma [1-3]. only few cases of pbd located on the finger have been reported in the literature [4,5]. figure 2. acanthosis, hyperkeratosis and full thickness atypia of epidermal keratinocytes. dilated capillaries in the dermal papillae and melanin pigment in the lower epidermis (a). hematoxylin & eosin (h&e) x20. large, round and hyperchromatic nuclei with mitoses were contained in dermal papillae (b). h&e x40. [copyright: ©2015 salerni et al.] dermatology: practical and conceptual image letter | dermatol pract concept 2019;9(3):7 209 dermatology practical & conceptual case presentation we propose the case of a 17-year-old female patient with multiple, soft, yellowish papules symmetrically distributed on the neck (figure 1a). dermoscopy showed a yellowish orange area associated with reddish and whitish areas [1] (figure 1b). optical coherence tomography (oct) revealed normal epidermis associated with clusters of horizontally oriented dermal aggregates with peripheral clefts (figure 1c). a biopsy was performed in the same site of previous noninvasive imaging techniques. histology disclosed the presence of altered elastic fibers in the upper and reticular dermis with extension to the papillary dermis stained with hematoxylin and eosin (figure 1d). pseudoxanthoma elasticum (pxe) is a rare disorder concerning elastolytic fibers due to a genetic mutation, with systemic alterations as mainly cardiac and ophthalmological complications due to abnormalities of elastic fibers. teaching point we believe that this is the first report of pxe with dermoscopy correlated to oct and histology. oct may be useful for pxe confirmation showing specific dermal features. reference 1. nasca mr, lacarubba f, caltabiano r, verzi ae, micali g. perforating pseudoxanthoma elasticum with secondary elastosis perforans serpiginosa-like changes: dermoscopy, confocal microscopy and histopathological correlation. j cutan pathol. 2016;43(11):1021-1024. dermoscopy, optical coherence tomography, and histological correlation of pseudoxanthoma elasticum flavia persechino1,2, domenico giordano3, chiara d. marini4, chiara franceschini2, marco ardigò2, severino persechino3 1 department of clinical and molecular medicine, sapienza university of rome, italy 2 clinical dermatology, san gallicano dermatological institute, irccs, rome, italy 3 nesmos department, dermatology unit, sant’andrea hospital faculty of medicine & department of psychology, sapienza university of rome, italy 4 surgical pathology units, department of clinical and molecular medicine, ospedale sant’andrea, sapienza university of rome, italy key words: dermoscopy, pseudoxanthoma elasticum, optical coherence tomography, histology, elastic fibers citation: persechino f, giordano d, marini cd, franceschini c, ardigò m, persechino s. dermoscopy, optical coherence tomography, and histological correlation of pseudoxanthoma elasticum. dermatol pract concept. 2019;9(3):209-210. doi: https://doi.org/10.5826/ dpc.0903a07 accepted: april 25, 2019; published: july 31, 2019 copyright: ©2019 persechino et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: severino persechino, md, nesmos department, dermatology unit, sant’andrea hospital faculty of medicine & department of psychology, sapienza university of rome, via di grottarossa, 1035, 00189 rome, italy. email: severino.persechino@ uniroma1.it 210 image letter | dermatol pract concept 2019;9(3):7 figure 1. (a) clinical photograph of pxe. (b) dermoscopy of pxe. (c) oct revealed normal epidermis associated with clusters of horizontally oriented dermal aggregates with peripheral clefts. (d) histology disclosed the presence of altered elastic fibers in the upper and reticular dermis with extension to the papillary dermis stained with hematoxylin and eosin. [copyright: ©2019 persechino et al.] a b d c dermatology: practical and conceptual 300 letter | dermatol pract concept 2019;9(4):11 dermatology practical & conceptual introduction concomitant cancers in psoriasis patients often pose significant limitations in treatment decision. in contrast to the majority of the available systemic antipsoriatic drugs, apremilast is not contraindicated in case of previous or concomitant malignancy [1]. we report a patient with psoriasis and lung adenocarcinoma who completely responded to apremilast. the patient provided written informed consent for the data reported in the current manuscript. case presentation a 67-year-old woman visited the outpatient unit for an exacerbation of psoriasis (psoriasis area and severity index [pasi] score at baseline visit: 18). in 2013 she received a diagnosis of lung adenocarcinoma, stage iiib. since then she received various treatments, including pemetrexed, carboplatin, cisplatin, and radiotherapy. progressive disease with liver metastases was detected in 2016. the patient received 6 courses of bevacizumab/docetaxel/carboplatin with documented partial response, and then nivolumab was started. the treatment was complicated by bacteremia. antibiotics resulted in a drug reaction successfully managed with systemic steroids. systemic drugs were discontinued, including nivolumab, despite an almost complete resolution of her metastatic disease. tapering of steroids led to exacerbation of psoriasis. clinical examination revealed symmetrically distributed, pruritic, scaly plaques (figure 1, a and b). the patient was not a good candidate for acitretin. after a thorough examination of her medical profile and in close collaboration with the oncologists, we decided to prescribe systemic apremilast (30 mg × 2, after dose titration from day 1 to day 5). the patient achieved pasi-75 in 16 weeks (pasi score at week 16: 4) (figure 1, c and d). nivolumab was concomitantly reinitiated, resulting in a documented response after 5 months. based on the results of imaging examinations, the laboratory tests, and the overall assessment by an oncologist, there was no indication that the course of the cancer or the response to nivolumab was influenced by apremilast treatment. after 12 months of treatment with apremilast, the patient remains free of psoriasis recurrence. psoriasis in patients with active lung cancer: is apremilast a safe option? zoe apalla1, eftychios psarakis1, aimilios lallas2, alexia koukouthaki1, athanassios fassas3, maria smaragdi1 1 state dermatology and venereology department, hippokration hospital, thessaloniki, greece 2 first dermatology department, aristotle university of thessaloniki, greece 3 oncology department, st. luke’s private hospital, thessaloniki, greece key words: psoriasis, adenocarcinoma, apremilast, phosphodiesterase inhibitor, treatment citation: apalla z, psarakis e, lallas a, koukouthaki a, fassas a, smaragdi m. psoriasis in patients with active lung cancer: is apremilast a safe option? dermatol pract concept. 2019;9(4):300-301. doi: https://doi.org/10.5826/dpc.0904a11 accepted: may 22, 2019; published: october 31, 2019 copyright: ©2019 apalla et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: zoe apalla, md, phd, 124 delfon str, pc 54643, thessaloniki, greece. email: zoimd@yahoo.gr letter | dermatol pract concept 2019;9(4):11 301 harmless when given in patients with psoriasis and concomitant lung adenocarcinoma. conclusions we report a favorable response of psoriatic lesions to apremilast in a patient suffering from metastatic lung adenocarcinoma, without any adverse event. definite conclusions cannot be extracted before further studies confirm the safety of apremilast in a larger number of patients with concurrent malignancies. references 1. paul c, cather j, gooderham m, et al. efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase iii, randomized controlled trial (esteem 2). br j dermatol. 2015;173(6):1387-1399. 2. pullamsetti ss, banat ga, schmall a, et al. phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with hif. oncogene. 2013;32(9):1121-1134. evidence on the safety of small molecules in the context of psoriatic patients with known concomitant malignancies is poor. apremilast is considered one of the safest options for the treatment of psoriasis. however, exclusion of patients with known malignancies from clinical trials does not allow safe conclusions for patients with solid organ malignancies. we decided to use apremilast based on the lack of contraindication, as per summary of product characteristics. furthermore, we were encouraged to follow this decision based on data about the pathophysiological role of phosphodiesterase 4 (pde4) in lung and other cancer, at a cellular level. analytically, in a previous study, investigators exposed different lung cancer cell lines to hypoxia and measured the activity and expression of pde4. interestingly, they found that pde4 is expressed in lung cancer cells, cross-talks with hypoxia-inducible factor signaling, and promotes lung cancer progression. based on this observation, they suggested that it could represent a potential therapeutic target [2]. whether a similar effect would occur in vivo remains to be investigated further. however, the reported effect on cell lines indicates that pde4 inhibition is quite likely—at the very least—to be figure 1. erythematous, scaly plaques involving the lower back (a) and both legs (b). complete clearance 16 weeks after apremilast initiation (c,d). [copyright: ©2019 apalla et al.] dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):12 65 dermatology practical & conceptual www.derm101.com introduction digital mucous cysts are benign ganglion cysts of the digits typically located at the distal interphalangeal (dip) joints or in the proximal nail fold [1]. usually the clinical diagnosis is straightforward, though sometimes it may mimic other lesions and diagnosis becomes a challenge [2,3]. dermatoscopy may be helpful in the clinical recognition of these benign lesions. report of cases case 1 a 29-year-old male presented with a 2-year history of a solitary, round, dome-shaped, fluctuant, asymptomatic nodule 8 mm in diameter located off the midline of the dorsal side of the third toe between the dip joint and the proximal nail fold (figure 1a). polarized light dermoscopy without compression (figure 1b) revealed flesh-colored aspect and linear branched and serpentine vessels originating from the periphery, while with compression (figure 1c) the lesion turned more translucent with the presence of bright white structures and less prominent vascularization. case 2 a 27-year-old male consulted because of a solitary fluctuant nodule of 6 mm, which appeared 8 months prior to consultation, located in the dorsum of the second toe, between dip joint and the proximal nail fold (figure 2a). upon polarized light dermoscopy examination without compression (figure dermatoscopic pattern of digital mucous cyst: report of three cases gabriel salerni1,2, roger gonzález3, carlos alonso1,2 1 hospital provincial del centenario de rosario, faculty of medicine, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina 3 faculty of medicine, universidad autónoma de nuevo león, monterrey, méxico keywords: dermoscopy, dermatoscopy, digital mucous cyst, vessels, diagnosis citation: salerni g, gonzález r, alonso c. dermatoscopic pattern of digital mucous cyst: report of three cases. dermatol pract concept. 2014;4(4):12. http://dx.doi.org/10.5826/dpc.0404a12 received: june 26, 2014; accepted: july 2, 2014; published: october 31, 2014 copyright: ©2014 salerni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, urquiza 3100. cp: s2002kdr, rosario, argentina. tel. +54 341 4398586. email: gabrielsalerni@hotmail.com digital mucous cysts are benign ganglion cysts of the digits typically located on the dorsal aspect of the interphalangeal joint and distal phalanx of the digits. usually the clinical diagnosis is straightforward, though sometimes it may mimic other lesions and diagnosis becomes a challenge. we present a series of three digital mucous cysts with a repeatable dermoscopic pattern consisted of linear branched and serpentine vessels when no compression is applied and translucent aspect with white bright areas and loss of vascular pattern when compression is applied. abstract 66 observation | dermatol pract concept 2014;4(4):12 lesion turned translucent with bright white structures and vascular pattern became almost invisible. discussion mucous cysts are small cystic lesions that occur intradermally on the dorsal aspect of the interphalangeal joint and distal phalanx of the digits. the diagnosis of digital mucous cyst is usually clinical and straightforward. unusual locations or presentations, however, may be difficult to identify [3]. digital mucous cysts are usually solitary, round-to-oval, domeshaped, firm-to-fluctuant papules or nodules, measuring 1-10 mm in diameter that have overlying skin that ranges from 2b) thick linear branched vessels running from the periphery and crossing the center of the lesion were observed, with compression (figure 2c) the lesion turned translucent and whitish with bright white structures. case 3 a 54-year-old female presented with a 6-month history of a solitary, fluctuant, painful nodule, with a diameter of 8 mm located the dorsal side of the fourth finger of the right hand, on the dip joint (figure 3a). polarized light dermoscopy without compression (figure 3b) revealed the presence of linear branched and serpentine vessels arranged from the periphery to the center; without compression (figure 3c) the figure 1. case 1. clinical image (a). polarized light dermoscopy without compression showing linear branched and serpentine vessels (b). translucent aspect upon polarized light dermoscopy with compression, with presence of bright white structures; decreased vascularization (c). (copyright: ©2014 salerni et al.) figure 2. case 2. clinical image (a). polarized light dermoscopy without compression revealed thick linear branched vessels running from the periphery and crossing the center of the lesion (b). dermoscopic aspect using polarized light dermoscopy with compression, translucent aspect with presence of bright white structures (c). (copyright: ©2014 salerni et al.) figure 3. case 3. clinical image (a). polarized light dermoscopy without compression showing linear branched and serpentine vessels arranged from the periphery to the center (b). translucent aspect upon polarized light dermoscopy with compression, with presence of bright white structures (c). (copyright: ©2014 salerni et al.) observation | dermatol pract concept 2014;4(4):12 67 linear, branched and serpentine arrangement of vessels is a specific arrangement of vessels typically seen in basal cell carcinoma. but, as stated by kittler, the specificity of this pattern for basal cell carcinoma is frequently overestimated [4]. it is true that basal cell carcinoma is the most common diagnosis in cases of non-pigmented nodular lesions with branched vessels, but in principle any invasive tumor in the dermis that lies below the superficial vascular plexus may have this pattern of vessels. histologically, there are two types of digital mucous cysts. the myxomatous, or superficial, type is located near the proximal nail fold and tends to fluctuate and resemble the focal mucinosis. the ganglion, or deep type, is located on the dorsum of a finger near the dip joint and is analogous to the ganglion [5]. histologically, digital mucous cysts do not have an epithelial lining (figure 4a); so, the term cyst, although commonly accepted, is a misnomer. we believe that the compression of the overlying dermis produced by the accumulation of mucin with a consequent flattening of the vascular plexus plus the thinning of the epidermis (figure 4b), are responsible for the vascular pattern of linear branched and serpentine vessels observed with dermoscopy. in summary, herein we present a series of three digital mucous cysts with a repeatable dermoscopic pattern consisted of linear branched and serpentine vessels when no compression is applied, and translucent aspect with white bright areas and loss of vascular pattern when compression is applied. even though diagnosis of digital mucous cyst is usually straightforward, our findings prove that dermoscopic examination might provide additional useful information. references 1. sonnex ts. digital mixoid cyst: a review. cutis. 1986;2:89-94. 2. salerni g, alonso c. images in clinical medicine. digital mucous cyst. n engl j med. 2012 apr 5;366(14):1335. 3. hur j1, kim ys, yeo ky, kim js, yu hj. a case of herpetiform appearance of digital mucous cysts. ann dermatol. 2010;22(2):194-5. 4. kittler h, rosendahl c, cameron a, et al. non-pigmented lesions. in: dermatoscopy—an algorithmic method based on pattern analysis. vienna: facultas verlags und buchhandels ag, 2011:179-193. 5. hernandez-lugo am, dominquez-cherit j, vega-memije me. digital mucoid cyst: the ganglion type. int j dermatol. 1999;38:533-5. very thin to moderately thick. the cysts contain a viscous, gelatinous fluid that may be clear or yellow-tinged. they may appear suddenly or develop over a period of months. grooving of the nail may precede the clinical manifestation of the cyst itself by up to 6 months. currently, it is believed that the cysts arise from mucoid degeneration of connective tissue and this process, in most cases, involves communication with the adjacent dip joint and possible coexistence of osteoarthritis. history of trauma has been documented in a small minority of cases. dermoscopic features of digital mucous cyst were first reported by two of us [2]. in the original observation, as well as the current series, the findings depended on whether or not pressure was applied in the examination with polarized light dermoscopy. when no pressure was applied, vascular pattern was predominant with the presence of linear branched and serpentine vessels in the 3 cases. when pressure is applied, vascular pattern become less prominent and the lesion becomes translucent with bright white areas. figure 4. histopathology evaluation: cystic space containing clear mucinous material in the dermis (a; h&e, ×40). the mucinous contents stained for acid mucopolysaccharides with alcian blue (b; h&e, ×200). (copyright: ©2014 salerni et al.) dermatology: practical and conceptual editorial | dermatol pract concept 2017;7(4):1 1 dermatology practical & conceptual www.derm101.com establishing the journal, dermatology practical & conceptual (dpc), has been a tremendous challenge for us. previously named dermatopathology practical & conceptual by bernie ackerman, who was the visionary founder, dpc became more and more relevant under the editorship of drs. kittler, zalaudek, marghoob and marchetti. when the journal became the official organ of the international dermoscopy society, dpc became a great arena to share the visions and experiences in the field of dermoscopy. research in dermoscopy is of uppermost importance, given that this technique is still relatively young, and its applications in the context of skin tumors, but especially of general dermatology, are growing day by day. however, dpc is not only that. it is indeed unique in that it is open access, free to both authors and readers. in other words, at dpc there are no fees for anyone who wants to read or publish scientific articles in the entire field of clinical and experimental dermatology! this is the same spirit that has guided the international dermoscopy society for the last 15 years, namely, an open access platform devoted to physicians, aiming exclusively to promote the science behind dermatology, to spread the available knowledge, and to assist doctors in improving their efficiency in diagnosing and treating patients with skin disorders. with this in mind, we feel privileged and deeply committed to take dermatology practical & conceptual in a brand new course aimed to further spread the readership, facilitate publication of important new ideas, and finally take the journal to the next step! giuseppe argenziano, md editor-in-chief gabriella brancaccio, md assistant editor teresa russo, md assistant editor aimilios lallas, md deputy editor a new direction for dermatology practical & conceptual giuseppe argenziano1, gabriella brancaccio1, teresa russo1, aimilios lallas2 1 dermatology unit, university of campania, naples, italy 2 first department of dermatology, aristotle university, thessaloniki, greece citation: argenziano g, brancaccio g, russo t, lallas a. a new direction for dermatology practical & conceptual. dermatol pract concept 2017;7(4):1. doi: https://doi.org/10.5826/dpc.0704a01 published: october 31, 2017 copyright: ©2017 argenziano et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: giuseppe argenziano, md. email: dpc.editor@gmail.com. dermatology: practical and conceptual quiz | dermatol pract concept 2014;4(3):14 73 dermatology practical & conceptual www.derm101.com turkey. tel.: +90 364 2230300. fax: +90 364 2230323. e-mail: enginsenel@enginsenel.com the patient a 48-year-old man presented with a two-year-history of a slowly growing pigmented lesion on his forehead. dermatological examination revealed an irregular, multi-colored papule with a diameter of 25 x 26 mm (figure 1). dermatoscopic examination disclosed blue-gray globules, leaf-like structures and structureless areas (figures 2, 3). dermatoscopy: a multicolored lesion on the forehead engin şenel1 1 hitit university faculty of medicine, department of dermatology, çorum, turkey keywords: cutaneous carcinoma, skin cancer, basal cell carcinoma, pigmented basal cell carcinoma, dermatoscopy, dermoscopy citation: senel e. dermatoscopy: a multicolored lesion on the forehead. dermatol pract concept. 2014;4(3):14. http://dx.doi.org/10.5826/ dpc.0403a14. received: december 20, 2013; accepted: december 20, 2013; published: july 31, 2014 copyright: ©2014 şenel. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: engin şenel, m.d., bba, hitit university faculty of medicine, department of dermatology, 19200 çorum, figure 1. pigmented lesion on forehead. [copyright: ©2014 senel.] figures 2, 3. dermatoscopy: blue-gray globules, leaf-like structures and structureless areas. [copyright: ©2014 senel. 74 quiz | dermatol pract concept 2014;4(3):14 what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical & conceptual. dermatology: practical and conceptual 180 observation | dermatol pract concept 2018;8(3):6 dermatology practical & conceptual www.derm101.com lichen planus-like keratosis: clinical applicability of in vivo reflectance confocal microscopy for an indeterminate cutaneous lesion nicole nagrani1, natalia jaimes1, margaret c. oliviero, harold s. rabinovitz2 1 department of dermatology and cutaneous surgery, university of miami miller school of medicine, miami, fl, usa 2 skin and cancer associates, plantation, fl, usa key words: lichen planus-like keratosis, reflectance confocal microscopy, lichenoid keratosis, lichenoid dermatoses citation: nagrani n, jaimes n, oliviero mc, rabinovitz hs. lichen planus-like keratosis: clinical applicability of in vivo reflectance confocal microscopy for an indeterminate cutaneous lesion. dermatol pract concept. 2018;8(3):180-183. doi: https://doi.org/10.5826/ dpc.0803a06 received: february 4, 2018; accepted: march 1, 2018; published: july 31, 2018 copyright: ©2018 nagrani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: nicole nigrani bs, department of dermatology and cutaneous surgery, university of miami miller school of medicine, 1600 nw 10th ave, rosensteil science medical building, rm 2023a, miami, fl 33136, usa. email: nxn237@miami.edu. case presentation a 66-year-old man with a history of melanoma and nonmelanoma skin cancers presented to the dermatology office after developing a new pigmented skin lesion on his right arm. clinical inspection revealed an 8 mm pink-brown papule on a background of sun-damaged skin (figure 1a). dermoscopic evaluation demonstrated a focal area of coarse grayish granules (box), a light brown structureless area (arrow), and shiny white structures with rosettes (circle) over a light brown background (figure 1b). these dermoscopic findings were suggestive of a melanoma in situ or lichen planus-like keratosis (lplk). normally a deep shave or excisional biopsy would be recommended. lichen planus-like keratosis (lplk) is an involuting cutaneous lesion often presenting between the fifth and seventh decades of life. these lesions typically appear abruptly as a solitary macule, papule, or plaque that continuously evolves as it undergoes regression. clinical and dermoscopic features of lplk can mimic both benign and malignant lesions, often prompting biopsy for accurate diagnosis. we describe a case of lplk developing in a patient with a history of multiple skin cancers, including melanoma. dermoscopy revealed peripheral granules and a central area with pinkish-brown pigmentation and a disorganized pattern with shiny white structures and rosettes. handheld reflectance confocal microscopy (rcm) showed a typical honeycomb pattern with millia-like cysts and comedolike openings, and lacked pagetoid and dendritic cells. based on the benign features seen with rcm, the lesion was followed until complete regression was observed. in conclusion, we describe a case of lplk with clinically and dermoscopically indeterminate features that was successfully monitored with rcm. we intend to highlight the utility of rcm as a diagnostic aid in equivocal lesions in order to prevent unnecessary excisional procedures. abstract observation | dermatol pract concept 2018;8(3):6 181 can become darker and violaceous and eventually evolve to become hyperor hypopigmented macules [4]. although not completely understood, the pathogenesis of lplk is thought to involve a chronic inflammatory reaction causing regression of a benign epithelial neoplasm, such as a solar lentigo or seborrheic keratosis [5]. the different stages of regression result in different appearances both clinically and dermoscopically, often making the diagnosis of lplk difficult. the clinical differential diagnoses include solar lentigo, seborrheic keratosis, actinic keratosis, bowen’s disease, basal cell carcinoma, and melanoma, this being the main concern in this specific case [6]. dermoscopically, lplk is characterized by granularity, which appears as coarse gray-brown granules. the 2 described dermoscopic patterns include the localized and diffuse granular patterns. the diffuse granular pattern is characterized by brownish-gray, reddish-brown, bluish-gray, or whitish-gray coarse granules with areas of tan pigmentation [7,8]. the localized pattern is associated with early regression stages of lplk and is characterized by the presence of granularity in association with an area or areas of the original epidermal lesion [5,6,9]. granularity is considered a feature of regression and can also be appreciated in other melanocytic or nonmelanocytic lesions; therefore lplk, in particular with diffuse granular pattern, can be difficult to diagnose and differentiate from malignant lesions, including melanoma [5]. in such cases, a skin biopsy is recommended to confirm the diagnosis. histopathology of lplk is characterized by a dense lichenoid inflammatory infiltrate of lymphocytes with interface involvement often obscuring the dermoepidermal junction [8]. additional histologic features within the epidermis include necrotic basilar layer keratinocytes, epidermal acanthosis, hypergranulosis, and hyperkeratosis [4,8]. in this case however, reflectance confocal microscopy (rcm) was used before making the final decision of performing a skin biopsy. rcm demonstrated a spinous granular layer of the epidermis with a typical honeycomb pattern, with several white oval structures, consistent with milia-like cysts, and dark round depressed structures, or comedo-like openings. no pagetoid cells or dendrites were present (figure 2a). at the dermoepidermal junction there were elongated cords, bulbous projections, and milia-like cysts. some bright round cells were also seen within the interpapillary spaces (figure 2b). these features were suggestive of an lplk, and the patient was treated with topical steroids with follow-up recommended. sequential digital monitoring at 3 months revealed that most of the lesion had resolved, revealing a light pink papule of 8 mm in diameter (figure 3a). dermoscopically, the lesion revealed shiny white structures, likely corresponding to a scar process, over a light pink background (figure 3b). at 6-month follow-up, the lesion had completely regressed and was hardly identifiable to the naked eye (figure 4a). using dermoscopy, there was only a scar-like area without dermoscopic features (figure 4b). discussion lplk usually appears as a rapidly evolving solitary lesion, ranging from 5 to 20 mm in diameter, with areas of predilection of the upper extremities, face, and anterior torso [1,2]. the lesion can appear as a papule or plaque with either a smooth or verrucous surface, and the color can range from pink to violaceous or tan to brown [1,3]. early lesions often present as erythematous papules; with progression, they a b figure  1a. clinical image of an  8  mm outlier pink/light brown papule on the right forearm of a  66-year-old man. [copyright: ©2018 nagrani et al.] figure  1b. dermoscopic image of the lesion showing a focal area of coarse grayish granules (rectangle), light brown featureless area (black arrow), and shiny white structures and rosettes focally distributed (arrows). with these findings, possible diagnoses included melanoma on sun-damaged skin or lplk. a skin biopsy or rcm was recommended. [copyright: ©2018 nagrani et al.] 182 observation | dermatol pract concept 2018;8(3):6 granular layer, elongated cords or bulbous projections at the dermal-epidermal junction, and numerous bright-stellate spots or plump bright cells in the superficial dermis, as rcm findings in lplk [10]. these features—in addition to the rcm represents an emerging technique in the noninvasive histomorphological analysis of skin, and has shown applicability in the diagnosis of lplk. bassoli et al reported the presence of typical honeycomb pattern of the spinous a b figure 3a. sequential digital monitoring showing clinical and dermoscopic images at  3-month follow-up. clinically the lesion appeared as a light pink papule. [copyright: ©2018 nagrani et al.] figure 3b. sequential digital monitoring showing clinical and dermoscopic images at  3-month follow-up. under dermoscopy, shiny white structures over a light pink background were observed. [copyright: ©2018 nagrani et al.] a b figure  2a. rcm image. typical honeycomb patter at the spinous and granular layers of the epidermis, with several white oval structures corresponding to milia-like cysts (white arrows), and dark round depressed structures suggesting comedo-like openings (arrow). there were not pagetoid or dendritic cells present. [copyright: ©2018 nagrani et al.] figure 2b. rcm image. at the dermoepidermal junction, there were elongated cords, bulbous projections, and milia-like cysts. within the interpapillary spaces, there were some bright round cells. with these findings, the clinical impression was a lplk and follow-up of the lesion was recommended. [copyright: ©2018 nagrani et al.] observation | dermatol pract concept 2018;8(3):6 183 2. maor d, ondhia c, yu ll, chan jj. lichenoid keratosis is frequently misdiagnosed as basal cell carcinoma. clin exp dermatol. 2017;42(6):663-666. doi: 10.1111/ced.13178. 3. kulberg a, weyers w. regressing basal-cell carcinoma masquerading as benign lichenoid keratosis. dermatol pract concept. 2016;6(4):13-18. doi: 10.5826/dpc.0604a03. 4. morgan mb, stevens gl, switlyk s. benign lichenoid keratosis: a clinical and pathologic reappraisal of  1040  cases. am j dermatopathol. 2005;27(5):387-392. doi: 10.1097/01. dad.0000175533.65486.84. 5. bugatti l, filosa g. dermoscopy of lichen planus-like keratosis: a model of inflammatory regression. j eur acad dermatol venereol. 2007;21(10):1392-1397. doi: 10.1111/j.14683083.2007.02296.x. 6. raptoulis g, spencer r, einstein b, oliviero m, braun r, rabinovitz h. lichen planus-like keratosis of the face: a simulator of melanoma in situ. dermatol surg. 2007;33(7):854-856. 7. zaballos p, blazquez s, puig s, et al. dermoscopic pattern of intermediate stage in seborrhoeic keratosis regressing to lichenoid keratosis: report of 24 cases. br j dermatol. 2007;157(2):266272. doi: 10.1111/j.1365-2133.2007.07963.x. 8. crotty ka, menzies sw. dermoscopy and its role in diagnosing melanocytic lesions: a guide for pathologists. pathology. 2004;36(5):470-477. doi: 10.1016/s0733-8635(05)70272-2. 9. elgart gw. seborrheic keratoses, solar lentigines, and lichenoid keratoses. dermoscopic features and correlation to histology and clinical signs. dermatol clin. 2001;19(2):347-357. doi: 10.1080/00313020412331283851. 10. bassoli s, rabinovitz hs, pellacani g, et al. reflectance confocal microscopy criteria of lichen planus-like keratosis. j eur acad dermatol venereol. 2012;26(5):578-590. doi: 10.1111/j.14683083.2011.04121.x. absence of bright nucleated or dendritic cells in the spinous granular layers, bright dendritic, spindle, or atypical cells at the dermoepidermal junction, and tumor islands in the superficial dermis—are proposed as diagnostic rcm criteria of lplk, and were shown to properly classify lplk in 71.4% of cases [10]. however, these features have not been analyzed on sun-damaged skin. in this case, the clinical and dermoscopic findings were indistinguishable and most concerning for melanoma. nevertheless, using the rcm criteria proposed by bassoli et al [10], malignant lesions such as melanoma were ruled out, and the diagnosis of lplk was made, allowing for observation over the course of 6 months. notably, rcm remained effective in accurately identifying the lplk in this patient with sundamaged skin. conclusions this case clearly illustrates the utility and value of rcm in the diagnosis of lplk on sun-damaged skin. even though histological analysis is diagnostic, we believe rcm is a useful noninvasive alternative in equivocal lesions when analyzed by experienced personnel and followed appropriately over time. references 1. abdulla fr, mutasim df. multiple benign lichenoid keratoses. j am acad dermatol. 2010;62(5):900-901. doi: 10.1016/j. jaad.2009.05.020. a b figure 4a. sequential digital monitoring of the lesion over 6 months after initial observation. clinically, the lesion appeared to have completely regressed. [copyright: ©2018 nagrani et al.] figure 4b. sequential digital monitoring of the lesion over 6 months after initial observation. dermoscopically, evaluation only showed a showed a scar-like area. dermatology: practical and conceptual research | dermatol pract concept 2020;10(2):e2020035 1 dermatology practical & conceptual dermoscopy training effect on diagnostic accuracy of skin lesions in canadian family medicine physicians using the triage amalgamated dermoscopic algorithm elizabeth a. sawyers,1 donald t. wigle,2 ashfaq a. marghoob,3 andreas blum4 1 community family practice, ottawa, canada 2 medical epidemiology, ottawa, canada 3 dermatology, memorial sloan kettering cancer center, new york, ny, usa 4 dermatology, eberhard karls universitat, tubingen, germany key words: dermoscopy, family/general practice, skin cancer, medical education, triage amalgamated dermoscopic algorithm citation: sawyers ea, wigle dt, marghoob aa, blum a. dermoscopy training effect on diagnostic accuracy of skin lesions in canadian family medicine physicians using the triage amalgamated dermoscopic algorithm. dermatol pract concept. 2020;10(2):e2020035. doi: https://doi.org/10.5826/dpc.1002a35 accepted: november 10, 2019; published: april 3, 2020 copyright: ©2020 sawyers et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: elizabeth a. sawyers, bsc, md, msc, 801-1081 carling avenue, ottawa, k1y 4g2, canada. email: lizsawyers@ me.com background: accurate identification of cutaneous lesions is an essential skill for family medicine physicians (fmps). studies show significant improvement in skin cancer detection with dermoscopy use. frontline fmps are an ideal target group for dermoscopy training. the 3-step triage amalgamated dermoscopic algorithm (tada) facilitates high sensitivity and specificity for pigmented and nonpigmented skin lesions. step i requires unequivocal identification of dermoscopic features for 1 of 3 benign skin lesions: angioma, dermatofibroma, or seborrheic keratosis. if absent, steps ii and iii are applied assessing for features of architectural disorder and malignancies with organized, symmetric patterns, respectively. objective: to assess fmps’ diagnostic accuracy of benign and malignant skin lesions before and after training in tada step i. methods: in this repeated-measures observational study, 33 dermoscopy-naive fmps attending an introductory dermoscopy workshop each assessed gross and corresponding dermoscopic photographic images of 50 pigmented and nonpigmented skin lesions (23 benign, 27 malignant) for features of tada step i lesions before and after training. analyses compared diagnostic accuracy in relation to training and baseline physician characteristics. abstract https://doi.org/10.5826/dpc.1002a35 mailto:lizsawyers@me.com mailto:lizsawyers@me.com 2 research | dermatol pract concept 2020;10(2):e2020035 moscopy workshop without compensation. incomplete data sets for 2 participants were excluded, leaving 31 for analyses. participant characteristics, potential barriers to dermoscopy use, and familiarity with canadian screening guidelines for diabetes mellitus, hypertension, cancers (breast, cervical, colorectal, prostate, skin), and osteoporosis were collected by questionnaire upon registration. tada step i teaching modules were written and presented live on microsoft power point for mac v15.33, 2017 (microsoft corporation). content introduced fundamental dermoscopy principles with emphasis on tada and review of published dermoscopic findings of the 3 target lesions (dermatofibroma, hemangioma, seborrheic keratosis) [10-12]. participants were provided a 25-minute session to complete each identical preand postteaching quiz of 50 randomly ordered cases projected onto a large screen for participant viewing and assessment, each containing clinical and corresponding dermoscopic images with a brief patient history (age, sex, lesion location, relevant clinical lesion features). cases included 27 malignant and 23 benign lesions: 7 basal cell carcinomas (5 nonpigmented, 2 pigmented), 4 squamous cell carcinomas (3 in situ, [bowen disease], 1 invasive; 2 nonpigmented, 2 pigmented), 16 melanomas (9 in situ, 1 nodular, 1 amelanotic, and 5 superficial spreading) with mean breslow tumor thickness of 1.24 mm, 8 nevi, 5 angiomas, 5 seborrheic keratoses, 4 dermatofibromas, and 1 clear cell acanthoma. lesion diagnosis was confirmed based on the presence of unequivocal clinical and/or dermoscopic criteria for those benign and by histopathology for those ambiguous and/or malignant. photographic images selected retrospectively from patient records were obtained with a canon rebel t1i eos 500d (canon canada, brampton, on, canada) and/or iphone 6 (apple) camera attachment using contact polarized dermoscopy (dermlite dl3n, 3gen inc.) with magnification ×10. four quiz images were provided by authors andreas blum (germany; a.b.), ashfaq a. marghoob (usa; a.a.m.), and contributor darshini persaude (canada; d.p.). presented material was preapproved by expert dermoscopists and authors a.b. and/or a.a.m. introduction skin cancer is the most common of all canadian cancers, with more than 80,000 cases diagnosed yearly [1]. in 2017, 7,200 of these were melanomas, the most lethal of subtypes [1]. while incidence and mortality rates persistently climb, canadians have difficulty accessing dermatological specialty care [2,3]. frontline family medicine physicians (fmps) are ideally positioned to identify cutaneous lesions with malignant potential. dermoscopy is an inexpensive, noninvasive tool shown to significantly improve diagnostic accuracies of benign and malignant skin lesions compared with naked eye examination among fmps and dermatologists [4-6]. the complex scoring systems and/or narrow focus of previously validated dermoscopic algorithms make them impractical for primary care setting integration [7-9]. triage algorithms, however, eliminate requirements for specific diagnoses, asking users to distinguish benign from potentially malignant lesions, the latter necessitating biopsy or referral [10,11]. the 3-step triage amalgamated dermoscopic algorithm (tada), unlike others, allows assessment of pigmented, nonpigmented, benign, and malignant skin lesions including melanomas demonstrating symmetric homogenous patterns [10,11]. step i looks to unequivocally identify dermoscopic criteria in any 1 of 3 benign lesions (angioma, dermatofibroma, or seborrheic keratosis). if absent, step ii is applied, assessing for features of architectural disorder, and similarly, step iii for malignancies with organized, symmetric patterns (figures 1 and 2) [10,11]. tada requires polarized light dermoscopy use and excludes facial, mucosal, nail unit, and glabrous skin lesion analysis [10,11]. as canadian dermoscopy training opportunities are sparse for fmps, our objective was to develop and test introductory educational modules for tada step i in a group of fmps. methods this repeated-measures study conducted in ottawa, canada, included 33 dermoscopy-naive fmps voluntarily responding to a mass mailing invitation to a 3.5-hour introductory derresults: diagnostic accuracy improved from 76.4% to 90.8% (p < 0.001) and from 85.0% to 90.0% (p = 0.01), respectively, for all lesions and for all tada i lesions. female sex was significant as a predictor of individual posttraining performance (all lesions combined, p = 0.02). conclusions: results show significant improvement in diagnostic accuracies for benign and malignant skin lesions with introductory dermoscopy training using tada step i. this will reduce unnecessary benign lesion excision and enhance referral sensitivity, conserving specialist resources. abstract research | dermatol pract concept 2020;10(2):e2020035 3 figure 1. the triage amalgamated dermoscopic algorithm [10-12]. figure 2. unequivocal features of skin lesions assessed in the triage amalgamated dermoscopic algorithm step i [10-12]. 4 research | dermatol pract concept 2020;10(2):e2020035 training time required to achieve proficiency (61.3%), and lack of accessible training programs (54.8%). more than 90% of participants were familiar with canadian clinical practice guidelines for diabetes mellitus, hypertension, targeted cancers, and osteoporosis, with just 12.1% aware of those for skin cancer (figure 4). discussion our results demonstrate that introductory dermoscopy training and application of tada step i significantly improved fmps’ diagnostic accuracy for both benign and potentially participants were instructed to choose 1 of 4 possible responses per case in provided quiz booklets to identify lesions possessing the published dermoscopic features of angioma, dermatofibroma, seborrheic keratosis (figure 2), or none of these. the latter category, in which no dermoscopic features of tada i lesions were identified, was deemed non-tada i lesions representing all malignant lesions, nevi, and clear cell acanthoma. participants’ preand postteaching quiz response data for a maximum possible total of 3,100 lesion assessments (31 participants × 50 cases × 2 assessments) were collected and coded numerically for each of the 4 questions (0 = did not answer; 1 = seborrheic keratosis; 2 = hemangioma; 3 = dermatofibroma; 4 = none of the these) and entered into microsoft excel for mac v15.33, 2017 for statistical analysis. sensitivity and specificity were defined, respectively, as the percentage of malignancies correctly identified as non-tada i and the percentage of tada i lesions correctly identified as such. preand postteaching accuracy scores for all skin lesions and subgroups were evaluated with a matched-pairs t test using wizard pro for mac [13]. postteaching accuracy scores for all lesions combined were assessed in relation to 5 independent participant characteristics: age (>50 vs up to 50 years old), sex (m, f), years in practice (>10 vs up to 10 years), medical teaching within their practice (yes vs no), and number of skin cancers diagnosed during the past 6 months (up to 5 vs ≥6) using a t test [13]. all scores were normally distributed except for preand postteaching for tada i lesions and postteaching for melanoma. given our study sample size over 30, the paired t test is valid for measuring statistical significance [14]. results table 1 lists participant characteristics. among these, only female sex was statistically significant as a predictor of postteaching diagnostic accuracy. the mean numbers of correct postteaching diagnoses for all lesions combined among men and women, respectively, were 44.5 and 45.9 (t test, p < 0.001). table 2 shows correct diagnoses for all skin lesions improved from 76.4% to 90.8% (paired t test, p < 0.001) after teaching (figure 3). for the tada i lesions, preto postteaching specificity, as defined, increased from 85.0% to 90.0% (paired t test, p = 0.01). thus the percentage of tada i lesions unnecessarily biopsied would decrease by one-third from 15% to 10% after training. sensitivity, as defined, for all malignancies increased from 78.1% to 94.8% (paired t test, p < 0.001) and for malignant melanoma subcategory from 76.9% to 95.0% (paired t test, p < 0.001). perceived barriers to fmps’ dermoscopy use were identified as lack of awareness regarding dermoscopy (67.7%), table 1. participant characteristics (n = 31) characteristic % (n) age up to 50 years 48.4% (15) 20-30 years 12.9% (4) 31-40 years 19.4% (6) 41-50 years 16.1% (5) >50 years 51.6% (16) 51-60 years 19.4% (6) >61 years 32.2% (10) sex male 35.5% (11) female 64.5% (20) years in practice up to 10 years 38.7% (12) <1 year 6.5% (2) 1-3 years 9.7% (3) >3-5 years 9.7% (3) >5-10 years 12.9% (4) >10 years 61.3% (19) >10-15 years 3.2% (1) >15 years 58.1% (18) teaching in practice yes 41.9% (13) no 54.8% (17) did not answer 3.2% (1) skin cancers diagnosed in past 6 months up to 5 61.3% (19) 6 or more 35.5% (11) 6-10 19.4% (6) 11-15 3.2% (1) 16-20 9.7% (3) >21 3.2% (1) did not answer 3.0% (1) research | dermatol pract concept 2020;10(2):e2020035 5 2011, 55% of melanoma patients had wait times exceeding the 2-week benchmark for assessment [15]. the royal college of physicians and surgeons of canada suggests a benchmark ratio of 1.5 dermatologists to 100,000 people, which is not achieved in 55% of the provinces and territories, with 18% and 73% having ratios <0.5 and ≤1.5, respectively [15,16]. with 46% of practicing canadian malignant lesions. this addresses the growing need for such training given current escalating strains on canadian dermatological resources. the canadian skin patient alliance reports failing grades in the standard-of-care benchmark for median wait times for any dermatological patient from 5 to 12 weeks from 2001 to 2011 and 23 weeks for 25% of patients in 2011 [15]. in figure 3. comparison of percent correct diagnosis by skin lesion group preand posttraining by participants using the triage amalgamated dermoscopic algorithm (tada) step i. table 2. comparison of preand posttraining percent correct responses for 1,550 skin lesion assessments by participants using the triage amalgamated dermoscopic algorithm (tada) step i skin lesion subgroup (n) percent correct diagnoses p value pretraining posttraining all lesions (50) 76.4 90.8 <0.001 all benign (23) 73.9 86.1 <0.001 angioma (5) 90.0 96.0 0.06 clear cell acanthoma (1) 60.0 90.0 0.005 dermatofibroma (4) 90.0 97.5 0.03 nevi (8) 56.3 77.5 <0.001 seborrheic keratosis (5) 74.0 78.0 0.50 all tada i lesions (14) 85.0 90.0 0.01 all malignant (27) 78.1 94.8 <0.001 basal cell carcinoma (7) 85.7 98.6 <0.001 bowen disease (3) 66.7 83.3 0.02 malignant melanoma (16) 76.9 95.0 <0.001 squamous cell carcinoma (1) 80.0 100.0 0.01 correct responses were classified as a specific tada i lesion (angioma, dermatofibroma, or seborrheic keratosis) or “other” if a non-tada i lesion. 6 research | dermatol pract concept 2020;10(2):e2020035 eye for melanoma [25], but fmps given even short training had improved clinical and dermoscopic diagnostic sensitivity [26]. a randomized controlled trial showed a 25.1% difference (54.1% vs 79.2%, p = 0.002) in referral sensitivity for lesions of malignant suspicion in fmps using dermoscopy compared with the naked eye, without compromising specificity [4]. a study using the complete tada found sensitivity and specificity rates of 94.6% (95% confidence interval = 93.4%-95.7%) and 72.5% (95% confidence interval = 70.1%-74.7%), respectively, after a 1-day training session for physicians, some of whom had previous dermoscopy experience [11]. our inclusion of only dermoscopy-naive fmps indicates tada’s utility in novices [10,11]. our results outperform those in a randomized controlled trial of fmps trained with the three-point checklist triage algorithm in identifying lesions of malignant potential (sensitivity 79.2%, specificity 71.8%) [4]. although studies report that time required for dermoscopy-assisted examinations is a barrier to uptake [27-29], we found no such evidence. a randomized, prospective multicenter analysis concluded that use is not a significant burden, with a median time difference of only 72 seconds (70 vs 142) for total body skin examination with and without dermoscopy [29]. we show potential for impactful clinical risk reduction with the 2-fold decrease in unnecessary benign lesion biopsy rates after training. tada i identifies only the 3 targeted benign skin lesions, leaving a potentially malignant group requiring analysis with subsequent steps ii and iii. our reported sensitivity and specidermatologists being ≥55 years old and a projected 3.4% annual attrition rate, the 6.2% annual increase in full-time dermatologists required for replenishment is unattainable at the existing 0.8% replacement rate [15,16]. strategic partnership with canada’s 43,500 fmps potentially could improve early skin cancer detection; however, several barriers exist [17]. dermatological training is underrepresented in medical education, nationally and internationally [18-20]. large proportions of new american graduates feel inadequately trained to evaluate skin conditions, while 82% of uk graduates report never being exposed to a single type of skin cancer [18]. designated hours of medical education for canada’s dalhousie university 2017 graduating class were 13 for dermatology compared with 107, 78.5, and 69 for neurology, cardiology, and respirology, respectively [18]. a 2017 survey from canadian medical schools showed 75% of dermatological core educational hours occurred in preclerkship years, with only 3 schools offering compulsory clinical exposure, a decrease from 12 in 1983 [21]. it is not surprising that most melanoma patients have had 1 or more physician visits the year before diagnosis, with only 20% receiving a screening examination [4,22]. our finding of low familiarity with clinical practice guidelines for skin cancer compared with other illnesses is consistent with other studies illustrating dermatological educational deficits [23,24]. the canadian professors of dermatology 2012 national core curriculum lists skin cancer recognition as an expected competency without mention of dermoscopy training to facilitate this goal [20]. inadequate dermoscopic training results in diagnostic outcomes that are inferior to those from the naked figure 4. participant familiarity with canadian clinical practice guidelines for common diseases seen in primary care. research | dermatol pract concept 2020;10(2):e2020035 7 associated with clinical examination of pigmented skin lesions. dermatology. 2000;200(1):11-16. 7. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—“chaos and clues.” australian fam physician. 2012;41(7):482-487. 8. carli p, quercioli e, sestini s, et al. pattern analysis, not simplified algorithms, is the most reliable method for teaching dermoscopy for melanoma diagnosis to residents in dermatology. br j dermatol. 2003;148(5):981-984. 9. dolianitis c, kelly j, wolfe r, simpson p. comparative performance of 4 dermoscopic algorithms by nonexperts for the diagnosis of melanocytic lesions. arch dermatol. 2005;141(8):10081014. 10. rogers t, marino ml, dusza sw, et al. a clinical aid for detecting skin cancer: the triage amalgamated dermoscopic algorithm (tada). j am board fam med. 2016;29(6):694-701. 11. rogers t, marino m, dusza sw, bajaj s, marchetti ma, marghoob a. triage amalgamated dermoscopic algorithm (tada) for skin cancer screening. dermatol pract concept. 2017;7(2):39-46. 12. jaimes n, marghoob aa. tada. from dermoscopedia. september 15, 2017, 11:29 utc. available at: https://dermoscopedia. org/w/index.php?title=tada&oldid=7815. accessed march 21, 2020. 13. wizard pro for mac, version 1.9.36, available at wizardmac.com. 14. mordkoff j t. the assumption(s) of normality. available at: http://www2.psychology.uiowa.edu/faculty/mordkoff/gradstats/ part%201/i.07%20normal.pdf. accessed oct 20, 2019. 15. canadian skin patient alliance. skin deep: a report card on access to dermatologic care and treatment in canada-2012. available at: http://www.canadianskin.ca/en/docman/report-card/english/ national/1-national-report-card/file. accessed september 15, 2017. 16. canadian medical association specialty profiles. dermatology. available at: https://www.cma.ca/sites/default/files/2019-01/ dermatology-e.pdf. accessed may 25, 2019. 17. canadian medical association specialty profiles. family medicine. available at: https://www.cma.ca/sites/default/files/2019-01/ family-e.pdf. accessed may 25, 2019. 18. borretta l, green p. dermatology in undergraduate medical education: are we underrepresented? available at: http://www. dermatology.ca/wp-content/uploads/2016/06/p3_06.pdf. accessed september 15, 2017. 19. kirshen c, shoimer i, wismer j, desgroseilliers jp, lui h. teaching dermatology to canadian undergraduate medical students. j cutan med surg. 2011;15(3):150-156. 20. national dermatology core curriculum and core competencies. july 2012. available at: http://www.dermweb.com/dermatology_ resources/national-dermatology-core-curriculum-competencies. htm. accessed september 15, 2017. 21. hu a, vender r. undergraduate dermatology education in canada: a national survey. j cutan med surg. 2017;22(1):31-37. 22. geller ac, o’riordan dl, oliveria sa, valvo s, teich m, halpern ac. overcoming obstacles to skin cancer examinations and prevention counseling for high-risk patients: results of a national survey of primary care physicians. j am board fam pract. 2004:17(6):416-423. 23. oliveria sa, christos pj, marghoob aa, halpern ac. skin cancer screening and prevention in the primary care setting: national ambulatory medical care survey 1997. j gen intern med. 2001;16(5): 297-301. ficity are not equivalent to those obtained from testing the full algorithm. however, we report significant improvements comparing favorably to those published [11]. improved diagnostic accuracy of step i lesions reduces the lesion pool progressing to steps ii and iii and the probability of false positives [10,11]. our results support this with greater changes in diagnostic accuracies realized for malignant vs tada i lesions, respectively, at 16.7% (p < 0.001) and 5.0% (p = 0.01). although participants did not directly examine patients, clinical information, skin lesion, and dermoscopic photographs were provided to simulate realistic clinical encounters [10,11]. acknowledging the limitation of a small number of self-selected participants, our conservative data assessment used a matched-pairs t test to assess statistical significance of preand posttraining diagnostic score changes. conclusions we show that introductory training of dermoscopy-naive fmps resulted in significant improvements in diagnostic accuracy of benign and malignant skin lesions, with potential for improved referral sensitivity and reduction in unnecessary benign lesion excisions. training in tada steps ii and iii is necessary to evaluate directly the diagnostic accuracy of nontada i lesions and is a planned future endeavor to provide fmps the required skill set to respond to current and future dermatological clinical demands. references 1. canadian cancer society. melanoma skin cancer statistics, 2018. available at: http://www.cancer.ca/en/cancer-information/ cancer-type/skin-melanoma/statistics/?region=on. accessed november 1, 2018. 2. canadian cancer society, statistics canada. canadian cancer statistics 2017. public health agency of canada/territorial registries. available at: http://www.cancer.ca/~/media/cancer.ca/cw/cancer %20information/cancer%20101/canadian%20cancer%20 statistics/canadian-cancer-statistics-2017-en.pdf?la=en. accessed september 15, 2017. 3. maguiness s, searles ge, from l, swiggum s. the canadian dermatology workforce survey: implications for the future of canadian dermatology—who will be your skin expert? j cutan med surg. 2004;8(3):141-147. 4. argenziano g, puig s, zalaudek i, et al. dermoscopy improves the accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877-1882. 5. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137(10):13431350. 6. stanganelli i, serafini m, bucchi l. a cancer-registry-assisted evaluation of the accuracy of digital epiluminescence microscopy https://dermoscopedia.org/w/index.php?title=tada&oldid=7815 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http://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/statistics/?region=on http://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/statistics/?region=on http://www.cancer.ca/~/media/cancer.ca/cw/cancer%20information/cancer%20101/canadian%20cancer%20statistics/canadian-cancer-statistics-2017-en.pdf?la=en http://www.cancer.ca/~/media/cancer.ca/cw/cancer%20information/cancer%20101/canadian%20cancer%20statistics/canadian-cancer-statistics-2017-en.pdf?la=en http://www.cancer.ca/~/media/cancer.ca/cw/cancer%20information/cancer%20101/canadian%20cancer%20statistics/canadian-cancer-statistics-2017-en.pdf?la=en 8 research | dermatol pract concept 2020;10(2):e2020035 27. federman dg, kravetz jd, kirsner rs. skin cancer screening by dermatologists: prevalence and barriers. j am acad dermatol. 2002;46(5):710-714. 28. apalla z, lallas a, argenziano g, et al. the light and the dark of dermatoscopy in the early diagnosis of melanoma: facts and controversies. clin dermatol. 2013;31(6): 671-676. 29. zaludek i, kittler h, marghoob aa, et al. time required for a complete skin examination with and without dermoscopy: a prospective randomized multicenter study. arch dermatol. 2008; 44(4):509-513. 24. federman dg, concato j, caralis pv, hunkele ge, kirsner rs. screening for skin cancer in primary care settings. arch dermatol. 1997;133(11):1423-1425. 25. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. 26. westerhoff k, mccarthy wh, menzies sw. increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy. br j dermatol. 2000;143(5):1016-1120. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020078 1 dermatology practical & conceptual introduction darier disease (dd) is an autosomal dominant genodermatosis belonging to the group of keratinization disorders that can affect epidermis, nails and mucous membranes, caused by a mutation in the atp2a2 gene on chromosome 12q2324.1, which has an important role in calcium signal transduction [1]. it is induced by haplo-insufficiency with variable expressivity, but with complete penetrance, in adults. case presentation we report a case of a 59-year-old woman with itching redbrown hyperkeratotic papules and plaques distributed on her left chest and left lumbar region, in blaschkoid distribution. the skin surrounding the lesions was normal (figure 1, a and b). dermoscopic examination revealed polygonal-shaped yellowish/brownish areas of various sizes surrounded by a thin whitish halo (figure 1c). the patient stated that these lesions presented in a chronic and relapsing course since adolescence (after puberty) and had treated her cutaneous disease with topical homeopathic therapies. she denied comorbidities and family history of dermatologic disease. we performed a punch biopsy, and histopathological examination revealed acanthosis with acantholysis and dyskeratosis in the basal and suprabasal epidermal layers with formation of corp ronds and grains (figure 2). based on clinical and histopathological evaluations, a diagnosis of segmental dd was made. conclusions dd is characterized by specific dermatologic findings such as symmetrical keratotic papules on the seborrheic regions. papules typically coalesce in plaques, usually localized in seborrheic areas of the trunk, scalp, forehead and flexures. lesions may fluctuate in severity and are often exacerbated by ultraviolet light, heat, occlusion or stress [1]. darier and white first described this disease independently in 1889; it is also known as keratosis follicularis. a localized manifestation of dd is a rare finding and was reported for the first time in 1906. this peculiar form is a peculiar case of darier disease in blaschkoid distribution francesca peccerillo1, sabrina longhitano1, barbara ferrari1, laura bigi1, giovanni pellacani1, giulia odorici1 1 department of surgical, medical, dental and morphological sciences, transplant, oncological and regenerative medicine; dermatology unit, university of modena and reggio emilia, modena, italy key words: segmental darier disease, blaschkoid distribution, atp2a2 mutation, dermoscopy, histopathology citation: peccerillo f, longhitano s, ferrari b, bigi l, pellacani g, odorici g. a peculiar case of darier disease in blaschkoid distribution. dermatol pract concept. 2020;10(4):e2020078. doi: https://doi.org/10.5826/dpc.1004a78 accepted: april 18, 2020; published: october 26, 2020 copyright: ©2020 peccerillo et al. this is an open-access article distributed under the terms of the creative commons attribution license, by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. giulia odorici, department of surgical, medical, dental and morphological sciences, transplant, oncological and regenerative medicine; dermatology unit, university of modena and reggio emilia, via del pozzo 71, 41124 modena, italy. email: giulai87@hotmail.com 2 letter | dermatol pract concept 2020;10(4):2020078 areas of more severe involvement. some authors estimate that these manifestations account for 10% of cases of dd with several variants: unilateral, linear, segmental or zosteriform. the localized forms may be clinically and histologically indistinguishable from nevi with acantholytic dyskeratosis. differential diagnosis included the dermatological manifestation of clinical lesions following blaschko lines, such as verrucous epidermal nevus, lichen striatus, and linear lichen planus. these peculiar clinical presentations reflect a de novo postzygotic somatic mutation in the heterozygous state [2]. in fact, over 100 different mutations have been identified in the classic form, and several of them have also been demonstrated in affected areas of mosaic dd patients [2]. in patients with unilateral localized disease, the distal nail manifestations of dd are often absent. our patient represents a peculiar case of segmental type 1 manifestation of dd. although the treatment consisted predominantly of topical therapy, the patient refused any kind of topical application because of her faith in homeopathy and the relapsing course of her disease. references 1. bardazzi f, odorici g, balestri r. darier disease. in: katsambas a, lotti t, dessinioti c, d’erme am ed. european handbook of dermatological treatment. 3rd ed. berlin: springer; 2015:183-188. 2. guerra l, pedicelli c, proto v, et al. a postzygotic atp2a2 novel mutation identified by next-generation sequencing in mosaic darier disease. acta derm venereol. 2019;99(1):115-116. doi: 10.2340/00015555-3018. pmid: 30085326. characterized by keratotic papules unilaterally distributed in streaks or whorls following blaschko lines. it typically has a late onset and is aggravated by sunlight [1]. in this peculiar rare manifestation of dd, 2 phenotypes are recognized: type 1 is characterized by unilateral distribution along blaschko lines, and type 2 presents widespread disease with localized figure 1. (a) clinical examination revealed hyperkeratotic, reddish brown papules, segmental distributed along the left chest region. (b) similar lesions were present on the back (lumbar region) following the blaschko lines. (c) dermoscopic examination showed polygonal-shaped brownish areas surrounded by a thin whitish halo (canon g 16 digital camera; dermlite foto, 3gen). figure 2. histopathologic examination showed hyperkeratotic areas with acantholytic dyskeratosis in epidermis (corps ronds) and in the stratum corneum (grains) and formation of suprabasal cleft. the dermis showed sparse superficial perivascular lymphohistiocytic infiltrate. (h&e, ×20). a b c dermatology: practical and conceptual case report | dermatol pract concept 2015;6(2):4 17 dermatology practical & conceptual www.derm101.com introduction fibroepithelioma of pinkus (fep) is generally considered a rare basal cell carcinoma subtype [1] although some consider it a variant of trichoblastoma [2,3]. fep was first described by pinkus in 1953 as a premalignant fibroepithelial tumor [4]. the clinical appearance of fep is typically that of a solitary, flesh-colored, dome-shaped sessile papule or plaque, but large pedunculated, polypoid or ulcerated cases have also been reported [5]. clinically it can resemble several benign skin tumors, including dermal nevus, pedunculated fibroma, acrochordon and seborrheic keratosis [1,5]. fep is more common in females and is most frequently located on the lumbosacral region, although it may occur anywhere on the body surface [6]. it typically develops after the fourth decade of life, but two pediatric cases have also been described [7,8]. the dermatoscopy of fep, since first described in 2005 [9] has been well summarized by reggiani et al. [1] as follows: • polymorphous vessels consisting mainly of fine, focused, short arborizing and dotted vessels, the latter mainly located at the periphery of the lesion • short white streaks—also called “chrysalis/crystalline structures” (visible only on polarized dermoscopy) two adjacent individual fibroepithelioma of pinkus of the umbilicus—one pink, one pigmented— a case report and review of the literature mike inskip1, caterina longo2, afaf haddad3 1 skin patrol skin cancer clinic, berwick, victoria, australia 2 skin cancer unit, arcispedale santa maria nuova-irccs, reggio emilia, italy 3 dorevitch pathology, heidelberg, victoria, australia key words: dermatoscopy, dermoscopy, fibroepithelioma of pinkus, basal cell carcinoma, pigmented, umbilicus citation: inskip m, longo c, haddad a. two adjacent individual fibroepithelioma of pinkus of the umbilicus—one pink, one pigmented—a case report and review of the literature. dermatol pract concept 2016; 6(2):4. doi: 10.5826/dpc.0602a04 received: december 31, 2015; accepted: february 3, 2016; published: april 30, 2016 copyright: ©2016 inskip et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: mike inskip mbchb, fracgp, sun patrol skin cancer clinic, 48 van der haar avenue, berwick, victoria 3806, australia. tel. +03 9769 3358; fax. +03 9769 3357. email: michaelinskip@bigpond.com we present a unique case of separate and independent adjacent fibroepitheliomas of pinkus (fep) arising from the umbilicus in an 83-year-old man. of further interest, one is pigmented and the other nonpigmented. clinical, dermatoscopic and histopathological images are provided. a review of the published literature is undertaken to attempt to assess the incidence of pigmented versus nonpigmented fep. of 24 published fep cases, 10 (41.7%) have been pigmented. thus to date pigmented fep comprise approaching one-half of all reported cases. abstract mailto:michaelinskip@bigpond.com 18 case report | dermatol pract concept 2016;6(2):4 an excisional biopsy of both lesions was performed and the specimens were submitted for assessment by a specialist dermatopathologist. • in pigmented fep, gray-brown areas and gray-blue dots in addition to dermatoscopy, reflectance confocal microscopic findings also have been well described [10]. the hallmark of fep is a fenestrated pattern constituted by “holes” that correspond to the fibrous stroma. in pigmented lesions, a variable amount of plump, bright cells corresponding to melanin-laden macrophages were also present. case report an 83-year-old man presented to a primary care skin cancer clinic in melbourne, australia for a routine skin cancer examination. he pointed out two adjacent soft, exophytic lesions arising from the superior aspect of his umbilicus. these had first appeared some seven years earlier and had been slowly growing in size since. these lesions had never been tender, irritated or bled at any time. he had a history of multiple non-melanoma skin cancer excisions since the age of 70. in the last five years, three separate basal cell carcinomas had been excised from his lumbar back and one from his left upper arm. a welldifferentiated squamous cell carcinoma had been excised from his left forearm six months previous. the umbilical lesions had been overlooked on several previous examinations as most likely dermal nevi or acrochordons. a whole body skin examination was undertaken with the aid of a heine delta 20 nonpolarizing dermatoscope (heine optotechnik, herrshing, germany). digital clinical and dermatoscopic images were taken with a medicam 800 fotofinder non-polarizing camera (fotofinder systems gmbh, aichner, birnbach, germany) the dermatoscopy images being at 20x magnification. there was severe actinic damage skin of face, upper trunk and distal limbs with multiple solar lentigines and scattered actinic keratoses. the lower trunk and proximal limbs were relatively spared. the lesions of interest were immediately adjacent and appeared to arise from the superior aspect of the umbilicus. each measured 10 x 12 mm diameter and were both of soft, polypoid nature. the right-hand lesion was pale pink with patchy yellow surface exudate. the left-hand lesion had no exudate and notable brown/gray pigmentation distally (figures 1 and 2). dermatoscopy dermatoscopy of the right-hand, nonpigmented lesion revealed the presence of multiple small erosions along with fine polymorphic peripheral vessels on a pink/white background (figure 3). dermatoscopy of the left-hand, pigmented lesion showed small ovoid gray structures, fine brown dots, arborizing vessels and a single erosion as might be found in a basal cell carcinoma (figure 4). figure 1. abdomen showing twin soft, polypoid lesions arising from the umbilicus. [copyright: ©2015 inskip.] figure 2. close-up of twin umbilical lesions. [copyright: ©2015 inskip.] figure 3. right-hand, nonpigmented umbilical lesion—dermatoscopy 20x magnification—non-polarized. note the multiple small erosions along with fine polymorphic peripheral vessels on a pink / white background. [copyright: ©2015 inskip.] case report | dermatol pract concept 2015;6(2):4 19 it is worth examining the progression of currently published literature on pigmented fep. the first case of a pigmented fep in the literature dates back to 2004. it was suggested by the authors at that time that a pigmented fep was “a statistically very unlikely event” [12]. a year later, in 2005, zalaudek presented the first published dermatoscopy image of an fep. this lesion was also pigmented and showed the most unusual feature of white peripheral leaf-like structures [13]. in 2006 the first case series detailing the dermatoscopic features of 10 histologically proven fep was published [5]. four of these 10 fep were pigmented. in the same year the first pediatric case of pigmented fep was published. this was a pigmented plaque fep in a 13-year-old girl, which had slowly been growing on her abdomen since the age of 3 years [7]. up to and including the reggiani et al. review of the literature in 2013 [1], the dermoscopy and reflectance confocal microscopy of 24 fep had been reported. of these, 14 (58.3%) histopathology two separate and independent tumours were apparent. these were not two clones of a single tumor. both lesions showed interconnecting and ramifying cords of basaloid epithelium set in a loose stroma, infiltrating through most of the dermis (figures 5 and 6). in the pigmented lesion, melanophages with distinct brown cytoplasmic granules were present within the stroma separating the basaloid trabeculae (figure 7). the infiltrative and arborizing pattern of both lesions was characteristic of fibroepithelioma of pinkus. conclusions the case we present is unique in that no previous case of two adjacent separate and independent adjacent fep has ever been described in the literature. the case is also most unusual in in two further respects: 1) only one previous case of fep arising from the umbilicus has been reported [11]. 2) of further interest, one lesion is pigmented and the other nonpigmented. figure 4. left-hand, pigmented umbilical lesion—dermatoscopy 20x magnification—non-polarized. note the small ovoid gray structures, fine brown dots, arborizing vessels and a single erosion as might be found in a basal cell carcinoma. [copyright: ©2015 inskip.] figure 5. 40x magnification (hematoxylin & eosin stain) showing ramifying trabeculae of basaloid epithelium. [copyright: ©2015 haddad.] figure 6. 100x magnification (hematoxylin & eosin stain) showing detail of the interconnecting trabeculae of basaloid epithelium and loose stroma. [copyright: ©2015 haddad.] figure 7. 200x magnification (hematoxylin & eosin stain) showing pigmented macrophages within the intervening stroma of the pigmented lesion. [copyright: ©2015 haddad.] 20 case report | dermatol pract concept 2016;6(2):4 6. su mw, fromer e, fung ma. fibroepithelioma of pinkus. dermatol online j 2006; 12:2. pmid: 16962017 7. scalvenzi m, francia mg, falleti j, balato a. basal cell carcinoma with fibroepithelioma-like histology in a healthy child: report and review of the literature. pediatr dermatol 2008; 25:359-63. pmid: 18577044. doi: 10.1111/j.1525-1470.2008.00683.x 8. pan z, huynh n, sarma dp. fibroepithelioma of pinkus in a 9-year-old boy: a case report. cases j 2008; 1:21. pmid: 18588684. doi: 10.1186/1757-1626-1-21 9. zalaudek i, leinweber b, ferrara g, et al. dermoscopy of fibroepithelioma of pinkus. j am acad dermatol 2005; 52:168-9. pmid: 15627105. doi: 10.1016/j.jaad.2004.06.033 10. longo c, soyer hp, pepe p, et al. in vivo confocal microscopic pattern of fibroepithelioma of pinkus. arch dermatol 2012; 148(4):556. pmid: 22508888. doi: 10.1001/archdermatol. 2011.945 11. lin tc, lee tl, lin ty, wu py. an infrequent case of neoplasm with fibroepithelioma of pinkus and hidradenomatous features arising at the umbilicus: a rare finding. am j dermatopathol 2011;33(7):750-2. pmid: 21885941. doi: 10.1097/ dad.0b013e31820978cf 12. strauss rm, edwards s, stables gi. pigmented fibroepithelioma of pinkus. br j dermatol 2004; 150(6):1208-9. pmid: 15214913. doi: 10.1111/j.1365-2133.2004.06018.x 13. zalaudek i, leinweber b, ferrara g, et al. dermoscopy of fibroepithelioma of pinkus. j am acad dermatol 2005; 52:168-9. pmid: 15627105. doi: 10.1016/j.jaad.2004.06.033 were nonpigmented and 10 (41.7%) were pigmented. thus, to date pigmented fep approaches one-half of all reported cases—not as statistically unlikely as first proposed in the sentinel case report of 2004. it is possibly not prudent to draw conclusions on incidence based on a single case. twenty-four published cases is statistically a very small number, however. more reports are needed to verify these observations. references 1. reggiani c, zalaudek i, piana s, et al. fibroepithelioma of pinkus: case reports and review of the literature. dermatology 2013;226(3):207-11. pmid: 26460228. doi: 10.1111/13468138.13142 2. bowen ar, leboit pe. fibroepithelioma of pinkus is a fenestrated trichoblastoma. am j dermatopathol 2005; 27:149-54. pmid: 15798442 3. gutte rm. fibroepithelioma of pinkus: a distinctive variant of trichoblastic carcinoma. indian j dermatol venereol leprol 2013; 79(5):725. pmid: 23974599. doi: 10.4103/0378-6323.116729 4. pinkus h. premalignant fibroepithelial tumors of skin. arch dermatol syphilol 1953; 67:598-615. pmid: 13050184 5. zalaudek i, ferrara g, broganelli p, et al. dermoscopy patterns of fibroepithelioma of pinkus. arch dermatol 2006; 142:1318-22. pmid: 17043187. doi: 10.1001/archderm.142.10.1318 http://dx.doi.org/10.1016/j.jaad.2004.06.033 http://www.ncbi.nlm.nih.gov/pubmed/22508888 http://www.ncbi.nlm.nih.gov/pubmed/22508888 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=lin tc%5bauthor%5d&cauthor=true&cauthor_uid=21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=lee tl%5bauthor%5d&cauthor=true&cauthor_uid=21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=lin ty%5bauthor%5d&cauthor=true&cauthor_uid=21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=wu py%5bauthor%5d&cauthor=true&cauthor_uid=21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/21885941 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=strauss rm%5bauthor%5d&cauthor=true&cauthor_uid=15214913 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=edwards s%5bauthor%5d&cauthor=true&cauthor_uid=15214913 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/?term=stables gi%5bauthor%5d&cauthor=true&cauthor_uid=15214913 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/15214913 http://dx.doi.org/10.1016/j.jaad.2004.06.033 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/23974599 http://www-ncbi-nlm-nih-gov.ezproxy.library.uq.edu.au/pubmed/23974599 dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;3(1):11 41 the patient an 83-year-old woman presented with a pigmented lesion on her nose, which she had noticed in the last year (figure 1). a close-up showed a small irregular papule about 5 mm in diameter (figure 2). dermatoscopy showed a chaotic pattern composed of brown, blue and gray clods and dots and structureless zones (figure 3). what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer that is received will receive a complimentary copy of the book dermatoscopy: an algorithmic method based on pattern analysis [facultas verlag, 2011]. dermatoscopy: what is your diagnosis? esther azizi, m.d.1 1 dermatology section, sackler faculty of medicine, tel aviv university, israel citation: azizi e. dermatoscopy: what is your diagnosis? dermatol pract conc. 2013;3(1):11. http://dx.doi.org/10.5826/dpc.0301a11. copyright: ©2013 azizi. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: esther azizi, m.d., dermatology section, sackler faculty of medicine, tel aviv university, ramat aviv, 69978, israel. email: esaz1@post.tau.ac.il. figure 1. clinical image. [copyright: ©2013 azizi.] figure 2. clinical close-up. [copyright: ©2013 azizi.] figure 3. dermatoscopy. [copyright: ©2013 azizi.] 42 quiz | dermatol pract concept 2012;3(1):11 please see article 8 of this issue of dermatology practical and conceptual for a detailed description of this case and other examples of recurrent nevi with dermatoscopic/ dermatopathologic correlation (http://dx.doi.org/10.5826/ dpc.0204a10). congratulations to dr. mohamad shizarpour who was the first to send us the correct answer to this quiz! the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. answer to october 2012 quiz the correct answer to the dermatoscopy quiz in the october 2012 issue is recurrent nevus. dermatology: practical and conceptual letter | dermatol pract concept 2019;9(3):21 241 dermatology practical & conceptual introduction two 15-year-old female monozygotic twins affected by alopecia areata (aa) and thyroiditis presented to our clinical attention. their family history was negative for thyroiditis. aa was localized on their occipital and parietal regions, forming an ophiasis pattern. case presentation dermatological examination of the first twin (gc, twin a, figure 1) showed wave-shaped hair-loss patches localized predominantly on the right side of the parieto-temporooccipital scalp. the disease started at age 4; alopecia was widespread to a large part of the scalp. beginning at age 14, twin a was treated with systemic and topical corticosteroids and today presents the current clinical features. the second twin (gg, twin b, figure 2), instead, since age 14 presented a framework of localized, round, small alopecia localized in the temporo-occipital area. during clinical examination, a patch of hair loss was evident on the occipital scalp of both twins, without other skin lesions or signs of inflammation; occasional itch was present. after our consultation, the twins underwent blood analysis. the results of the laboratory tests were suggestive of autoimmune thyroiditis in both patients, as the autoantibody values were very high (twin a: thyroglobulin antibodies 28.7 iu/ml, thyroperoxidase antibodies 617.46 iu/ml; twin b: thyroglobulin antibodies 44.51 iu/ml, thyroperoxidase antibodies >1,000.00 iu/ml); furthermore, twin a also had above-average blood test results: total antioxidant status 494 iu/ml, hemoglobin 11.6 g/dl, transferrin 398 mg/ml, and ferritin 6.67 ng/ml; twin b also had elevated total antioxidant status (407 iu/ml) and vitamin d (10 ng/ml) levels. the remaining tests were negative for both patients. treatment with oral betamethasone 2 mg/day was started for both twins for 1 month when they were 14 years old. it was then reduced to 2 mg twice a week in association with vasodilatory and antiseptic lotions of the scalp for 2 months. this therapy led to a partial remission of dermatological manifestations in both patients. an endocrinological consultation was also recommended to better evaluate thyroid malfunctioning. alopecia areata in twins with autoimmune thyroiditis: personal observations giusy schipani1, stefano dastoli1, elisabetta scali1, luigi bennardo1, martina silvestri1, steven paul nisticò1 1 dermatology unit, department of health sciences, magna graecia university, catanzaro, italy key words: autoimmune thyroiditis, alopecia areata, twins citation: schipani g, dastoli s, scali e, bennardo l, silvestri m, nisticò sp. alopecia areata in twins with autoimmune thyroiditis: personal observations. dermatol pract concept. 2019;9(3):241-243. doi: https://doi.org/10.5826/dpc.0903a21 accepted: january 23, 2019; published: july 31, 2019 copyright: ©2019 schipani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: luigi bennardo, md, via serra tancredi 2 87010 lattarico (cs), italy. email: luigibennardo10@gmail.com 242 letter | dermatol pract concept 2019;9(3):21 lating epithelial cells, fibroblasts, and macrophages. in addition, a role of treg lymphocytes has been hypothesized: they have an immunosuppressive effect and contribute to prevent autoimmune responses. therefore, defects in treg cell number and/or function may contribute to the development of autoimmune diseases such as aa [6]. different immune-cell lines including plasmocytic dendritic cells, natural killer (nk) cells, and t cells, along with key molecules such as interferon-γ, il-15, mica, and nkg2d, have been identified as contributing to the autoimmune process in aa [7]. genome-wide association studies provide evidence for the involvement of both innate and acquired immunity in the pathogenesis, and mechanistic studies in mouse models of aa have specifically implicated an ifn-γ-driven immune response, including ifnγ, ifn-γ-induced chemokines, and cytotoxic cd8 t cells as the main drivers of disease pathogenesis [8]. low expression of major histocompatibility complex class i and ii molecules and high expression of macrophage migration inhibitory factor, an nk cell inhibitor, prevent infiltration of a subset of t lymphocytes from the hair follicle of healthy individuals, but aggregations of cd56+/nkg2d+ nk cells are found around hair follicles from patients with aa [9]. based on the literature data, which suggest a common activation of different immune patterns, and on the data obtained by our clinical case, we can say that aa should be considered a warning manifestation for other distinct diseases such as ones that affect the thyroid. in this unusual case, a genetic study to support the relationship between aa and autoimmunity may be useful. references 1. lortkipanidze n, zlotogorski a, ramot y. two episodes of simultaneous identical alopecia areata in identical twins. int j trichology. 2016;8(1):47-48. 2. dogra d, sood a, khaitan bk. alopecia areata in identical twins. indian j dermatol venereol leprol. 1996;62(3):199. conclusions association between autoimmune disease and aa has been widely discussed. several studies have revealed a high prevalence of thyroid disorders in patients with aa. screening for autoimmune thyroiditis and thyroid function should be done in all patients with these cutaneous disorders for the early identification of this disease. recently lortkipanidze et al [1] described a case of aa and alopecia universalis occurring in identical twins in the same area of the scalp, forming an ophiasis pattern. previously dogra et al [2] focused their attention on the occurrence of aa in the members of the same family, supporting the hypothesis that the patients with aa are genetically predisposed to develop this kind of disease. in patients affected by autoimmune thyroid diseases, the functions of the different skin cell types may be affected not only by variation in thyroid hormone levels but also by the presence of thyroid-specific autoantibodies [3]. thyroid hormones act on epidermal differentiation and their effects are particularly important for the function of sebaceous, eccrine, and apocrine glands; growth of hair follicles; and synthesis of proteoand glycosaminoglycans by dermal fibroblasts [4]. thyroid hormones were found to induce differentiation and apoptosis and inhibit clonal growth of hair follicle epithelial stem cells [5]. moreover, the immunoregulatory genes that predispose to autoimmune thyroiditis (foxp3, cd25, cd40, ctla4, the hla genes, ptpn22, among other emerging immunoregulatory genes) have a critical role in the development of an effective immune response including self-tolerance, humoral immunity, and cell-mediated immunity. recent data show that the pathogenesis of autoimmune thyroiditis is mediated by th1, th2, and th17 subtypes. th17 lymphocytes are mainly characterized by the synthesis of interleukin (il)-17a, il-17f, il-21, il-22, and il-47, which contribute to the release of other proinflammatory mediators by stimufigure 1. aa in twin a. [copyright: ©2019 schipani et al.] figure 2. aa in twin b. [copyright: ©2019 schipani et al.] letter | dermatol pract concept 2019;9(3):21 243 3. cianfarani f, baldini e, cavalli a, et al. tsh receptor and thyroid-specific gene expression in human skin. j invest dermatol. 2010;130:93-101. 4. slominski at, zmijewski ma, skobowiat c, zbytek b, slominski rm, steketee jd. sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system. adv anat embryol cell biol. 2012;212: v, vii, 1-115. 5. tiede s, bohm k, meier n, funk w, paus r. endocrine controls of primary adult human stem cell biology: thyroid hormones stimulate keratin 15 expression, apoptosis, and differentiation in human hair follicle epithelial stem cells in situ and in vitro. eur j cell biol. 2010; 89(10): 769-777. 6. ramos-leví am, marazuela m. pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms. endocrinol nutr. 2016;63(8):421-429. 7. rajabi f, drake la, senna mm, rezaei n. alopecia areata: a review of disease pathogenesis. br j dermatol. 2018;179(5):10331048. 8. trüeb rm, dias mfrg. alopecia areata: a comprehensive review of pathogenesis and management. clin rev allergy immunol. 2018;54(1):68-87. 9. pratt ch, king le jr, messenger ag, christiano am, sundberg jp. alopecia areata. nat rev dis primers. 2017;3:17011. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(1):e2020009 1 dermatology practical & conceptual case presentation an otherwise healthy 5-year-old girl presented during the summer with painful shiny erythematous patches and some blisters on the finger pads of both hands and on the palms of 1 week’s duration (figure 1). on further questioning, her father mentioned that she had been playing and swimming all week in a swimming pool. a diagnosis of pool palms was made. avoidance of the swimming pool for a couple of days was recommended. no further treatment was indicated. pool palms daniel morgado-carrasco,1 hernán feola,2 pablo vargas-mora3 1 department of dermatology, hospital clínic de barcelona, universitat de barcelona, spain 2 department of dermatology, hospital san juan de dios, la plata, argentina 3 department of dermatology, faculty of medicine, universidad de chile, santiago, chile keywords: pool palms, swimming pool, frictional dermatitis, dermatitis, summertime citation: morgado-carrasco d, feola h, vargas-mora p. pool palms. dermatol pract concept. 2020;10(1):e2020009. doi: https://doi. org/10.5826/dpc.1001a09 accepted: november 3, 2019; published: december 31, 2019 copyright: ©2019 morgado-carrasco et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, md, department of dermatology, hospital clínic de barcelona, barcelona, spain. email: morgadodaniel8@gmail.com figure 1. pool palms. shiny erythematous patches and some blisters on the finger pads of both hands and on the palms of a 5-yearold girl. mailto:morgadodaniel8@gmail.com 2 image letter | dermatol pract concept 2020;10(1):e2020009 tendency to rub against the pool surface when playing [2]. cessation of the activity leads to rapid symptom resolution. references 1. wong lc, rogers m. pool palms. pediatr dermatol. 2007;24(1):95. 2. novoa a, klear s. pool palms. arch dis child. 2016;101(1):41. teaching point pool palms is a relatively frequent benign disorder, although scarcely described in the literature. it is a frictional dermatitis that affects the skin of the hands and feet after repeated contact with rough pool surfaces [1]. it is more frequent in childhood, probably because of children’s skin fragility and their dermatology: practical and conceptual observation | dermatol pract concept 2015;5(2):27 133 dermatology practical & conceptual www.derm101.com introduction tinea capitis is a fungal infection of hair and scalp that typically occurs in childhood and equally in both sexes that has recently increased in incidence in adults and the elderly [1,2]. it is typically caused by trichophyton and microsporum species. t. tonsurans infections may not be symptomatic and mostly infects children; however, it can also cause disease in adults who are close contact with those children [3]. thus, it is difficult to diagnose and it requires a high index of suspicion from the examination physician. tinea capitis has clinical features ranging from a noninflammatory scaling to a severe pustular eruption with alopecia, known as kerion. the clinical manifestations of t. tonsurans tinea capitis are variable. t. tonsurans infection commonly causes “black dot” tinea capitis. t. tonsurans performs an endothrix type of hair invasion, which causes hair to tinea capitis caused by trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use alita sombatmaithai1, penvadee pattanaprichakul1, papapit tuchinda1, theetat surawan1, chanai muanprasart1, lalita matthapan1, sumanas bunyaratavej1 1 department of dermatology, faculty of medicine siriraj hospital, mahidol university, bangkok, thailand key words: tinea capitis, trichophyton tonsurans, patchy hair loss, alopecia citation: sombatmaithai a, pattanaprichakul p, tuchinda p, surawan t, muanprasart c, matthapan l, bunyaratavej s. tinea capitis caused by trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use. dermatol pract concept 2015;5(2):27. doi: 10.5826/dpc.0502a27 received: january 23, 2015; accepted: march 8, 2015; published: april 30, 2015 copyright: ©2015 sombatmaithai et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sumanas bunyaratavej, md, department of dermatology, faculty of medicine siriraj hospital, mahidol university, 2 wanglang road, bangkok noi, bangkok 10700, thailand. tel. +6624197000; ext 4333; fax. +6624115031. email: sumbunyavej@ hotmail.com tinea capitis is unusual and often misdiagnosed in healthy adults. we report a case of a healthy woman with a several-year history of asymptomatic, bizarre-shaped, non-scarring alopecia. she had used overthe-counter ketoconazole shampoo regularly for a long time. an initial potassium hydroxide preparation showed negative result for fungal organism. the scalp biopsy revealed endothrix infection, and dermoscopic examination demonstrated the comma hair and corkscrew hair signs. the fungal culture showed trichophyton tonsurans. the daily use of antifungal shampoo could be the important factor to conceal clinical and laboratory findings for diagnosis of t. tonsurans tinea capitis in our case, which required high clinical suspicion and histopathology and dermoscopic examinations. abstract 134 observation | dermatol pract concept 2015;5(2):27 examination from hair and scalp was negative, and therefore, fungal culture was not performed. the clinician raised the possible diagnosis of this atypical, non-scarring alopecia as alopecia areata with the differential diagnosis of androgenetic alopecia, chronic telogen effluvium, and trichotillomania. betamethasone valerate scalp lotion was prescribed to apply twice daily on the affected scalp area but without any clinical improvement. two 4 mm punch biopsy specimens were taken from the peripheral edge of the alopecia for both vertical and transverse sections to evaluate the cause of non-scarring hair loss in this patient. the histopathology of the scalp biopsy specimens demonstrated an adequate number of terminal hair follicles without evidence of dermal fibrosis. there was minimal superficial perivascular and perifollicular mononuclear cell infiltrate in some of the follicles without definite peribulbar infiltration. an appropriate ratio of anagen to catagen/telogen hair was appreciated. numerous fungal hyphae and arthrospores within several hair shafts were demonstrated in both vertical and transverse sections. the epidermis remained intact with orthokeratosis of the keratin and no significant inflammation (figure 2a and b). koh examination of lesional hair under dermoscopy showed a positive endothrix result. dermoscopic examination revealed broken hair shafts, comma hair sign and a large number of corkscrew hairs (figure 3a and b). wood lamp’s test revealed a non-fluorescent result. a fungal culture from scalp biopsy and hair demonstrated colonies of t. tonsurans. based on clinical presentation, histopathology and fungal culture, the diagnosis was tinea capitis caused by t. tonsurans. the patient was treated with griseofulvin 500 mg twice daily in combination with ketoconazole shampoo once daily application for eight consecutive weeks. she achieved complete clinical cure. the followup mycological results were negative for both of koh examination and fungal culture. break easily [4]. in addition, it also leads to an inflammatory tinea capitis, which often leads to misdiagnoses. case report a 38-year-old primary school female teacher presented with a history of symptomless, patchy, slow, progressive hair loss for several years. she had been using over-the-counter ketoconazole shampoo regularly for a long time without any improvement. the patient did not have other skin lesions or other underlying diseases. the patient denied history of animal contact or history of pattern hair loss in her family. she had not taken any medications. no other family members had the same lesions. on physical examination, bizarre-shaped patches of hair loss with surrounding hair thinning on the vertex were observed (figure 1). there was no broken hair shaft, exclamation-point hair or significant scalp inflammation surrounding the area of alopecia. hair pulling test was negative. potassium hydroxide (koh) 10% figure 1. bizarre-shaped patchy alopecia on vertex scalp. [copyright: ©2015 sombatmaithai et al.] figure 2. (a) mild superficial perivascular and perifollicular lymphocytic infiltrate around some hair follicles without definite peribulbar infiltration (h&e x40). (b) numerous fungal hyphae and arthrospores inside hair shaft (h&e x400). [copyright: ©2015 sombatmaithai et al.] observation | dermatol pract concept 2015;5(2):27 135 conclusion this case demonstrated the unusual clinical manifestations of t. tonsurans tinea capitis. the patient had asymptomatic, dry and scaly patches of alopecia. physicians could not make a diagnosis due to the unclear clinical features, until histopathologic exam of the hair shaft showed endothrix fungal infection. the patient had been using over-the-counter ketoconazole shampoo regularly for a long period of time, which caused tinea capitis signs and symptoms unclear and a negative result in the first koh test. consequently, physicians did not diagnose tinea capitis on this patient at first. acknowledgement we acknowledge dr. manasmon chairatchaneeboon, division of dermatopathology, department of dermatology, faculty of medicine siriraj hospital, mahidol university, for the preparation of histopathological images and description and dr. nakaraj pluetrattanabha for dermoscopic examination and pictures. references 1. mohrenschlager m, bruckbauer h, seidl hp, ring j, hofmann h. prevalence of asymptomatic carriers and cases of tinea capitis in five to six-year-old preschool children from augsburg, germany: results from the miriam study. pediatr infect dis j 2005;24(8):749-50. 2. ginter-hanselmayer g, weger w, ilkit m, smolle j. epidemiology of tinea capitis in europe: current state and changing patterns. mycoses 2007;50:6-13. 3. hay rj, clayton ym, de silva n, midgley g, rossor e. tinea capitis in south-east london—a new pattern of infection with public health implications. br j dermatol 1996;135(6):955-8. 4. stein ll, adams eg, holcomb kz. inflammatory tinea capitis mimicking dissecting cellulitis in a postpubertal male: a case report and review of the literature. mycoses 2013;56(5): 596-600. 5. stefanato cm. histopathology of alopecia: a clinicopathological approach to diagnosis. histopathology 2010;56(1):24-38. 6. pinheiro am, lobato la, varella tc. dermoscopy findings in tinea capitis: case report and literature review. an bras dermatol 2012;87(2):313-4. 7. shim wh, jwa sw, song m et al. dermoscopic approach to a small round to oval hairless patch on the scalp. ann dermatol 2014;26(2):214-20. 8. bookstaver pb, watson hj, winters sd, carlson al, schulz rm. prophylactic ketoconazole shampoo for tinea capitis in a highrisk pediatric population. j pediatr pharmacol ther 2011;16(3): 199-203. 9. greer dl. successful treatment of tinea capitis with 2% ketoconazole shampoo. int j dermatol 2000;39(4):302-4. 10. elewski be. tinea capitis: a current perspective. j am acad dermatol 2000;42:1-20. discussion tinea capitis is predominantly seen in prepubertal children. this patient was not in a common age group and partially treated with ketoconazole shampoo. thus, the symptoms could be concealed, resulting in the delay of diagnosis. generally, the diagnosis of tinea capitis must be confirmed by koh preparation of infected hairs and a fungal culture. although scalp biopsy provides high sensitivity, this procedure is invasive and unable to identify the species of pathogen. therefore, the procedure is not in routine clinical use. scalp skin biopsy is performed in order to make a differential diagnosis of unidentified alopecia or another alopecia that is recalcitrant to treatment [5]. due to the obscure clinical presentation of tinea capitis in this patient, the definitive diagnosis was confirmed by biopsy and histopathology. the dermoscope, a non-invasive handheld device, could be useful for diagnosis. the appearance of lesional hair under the dermoscope were comma shape and corkscrew hairs, regardless of dermatophyte species [6,7]. tinea capitis treatment is mainly oral antifungals, but a topical antifungal shampoo is suggested as an adjuvant therapy [8]. there is a report that successfully used a topical antifungal shampoo as a monotherapy [9]. this patient used antifungal shampoo for several years that prolonged the disease without complete cured. using of antifungal shampoo probably caused the result to be negative in the first koh examination. additionally, this patient had been prescribed topical steroid medication, which caused a positive result in the following koh examinations. apart from treatment, physicians should consider disease prevention by screening for close-contact individuals and carriers especially in this particular case: the patient was a primary school teacher, who had contact with children [10]. figure 3. (a) koh examination of hair shaft presented a positive endothrix result. (b) dermoscopic examination revealed comma hair sign and large amount of corkscrew hair. [copyright: ©2015 sombatmaithai et al.] dermatology: practical and conceptual review | dermatol pract concept 2020;10(2):e2020028 1 dermatology practical & conceptual introduction the association of melanoma with a preexisting nevus is still a debated subject. histopathological data support an associated nevus in approximately 30% of all excised melanomas [1]. it must be acknowledged that these numbers do not reflect the true frequency of this event, as histopathological studies rely on selection bias of excised, suspicious lesions. in fact, the annual risk of an individual melanocytic nevus becoming malignant is extremely low and has been estimated to be approximately 0.0005% (or less than 1 in 200,000) before the age of 40 years, to 0.003% (1 in 33,000) in patients older than 60 years [2,3]. however, since many studies propose a direct correlation between the number of moles and melanoma development (roughly 2to 14-fold), efforts to curb the rise in melanoma have centered on the detection of early changes in melanocytic nevi [2]. is there more than one road to nevus-associated melanoma? roberta vezzoni,1 claudio conforti,1 silvia vichi,1 roberta giuffrida,2 chiara retrosi,1 giovanni magaton-rizzi,1 nicola di meo,1 maria antonietta pizzichetta,2,3 iris zalaudek1 1 dermatology clinic, hospital maggiore, university of trieste, italy 2 department of clinical and experimental medicine, section of dermatology, university of messina, messina, italy 3 division of oncology b, cro aviano national cancer institute, aviano, italy key words: nevus-associated melanoma, melanoma, melanogenesis, dermoscopy, eosinophilia citation: vezzoni r, conforti c, vichi s, giuffrida r, retrosi c, magaton-rizzi g, di meo n, pizzichetta ma, zalaudek i. is there more than one road to nevus-associated melanoma? dermatol pract concept. 2020;10(2):e2020028. doi: https://doi.org/10.5826/dpc.1002a28 accepted: november 20, 2019; published: april 3, 2020 copyright: ©2020 vezzoni et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: r. v. and c. c. contributed equally to this publication as first authors. all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, hospital maggiore, piazza dell’ospitale 1, 34125, trieste, italy. email: claudioconforti@yahoo.com the association of melanoma with a preexisting nevus is still a debated subject. histopathological data support an associated nevus in approximately 30% of all excised melanomas. the annual risk of an individual melanocytic nevus becoming malignant is extremely low and has been estimated to be approximately 0.0005% (or less than 1 in 200,000) before the age of 40 years, to 0.003% (1 in 33,000) in patients older than 60 years. current understanding, based on the noticeable, small, truly congenital nevi and nevi acquired early in life, is that the first develops before puberty, presents with a dermoscopic globular pattern, and persists for the lifetime, becoming later a dermal nevus in the adult. in contrast, acquired melanocytic nevi develop mostly at puberty and usually undergo spontaneous involution after the fifth decade of life. the purpose of this review is to analyze the data of the literature and to propose, on the basis of epidemiological and clinical-dermoscopic characteristics, a new model of melanogenesis of nevus-associated melanoma. abstract https://doi.org/10.5826/dpc.1001a28 mailto:claudioconforti@yahoo.com 2 review | dermatol pract concept 2020;10(2):e2020028 in some cases, it is extremely difficult to determine the original association with a preexisting nevus [1,3]. clinical and dermoscopic aspects currently, there is widespread agreement about certain clinical features of nam and its ageand sex-related incidence, whereas some discordance regarding the histological subtype and anatomic site is reported among different studies. in most studies, nam appears to be a superficial spreading type of melanoma generally occurring on the trunk. on the other hand, dnm is associated with a nodular subtype, as well as with an anatomic location on the extremities, which has better outcomes than on the trunk in several survival models [2,3]. in the meta-analysis of pampena et al, no relevant differences were observed between nam and dnm groups regarding the melanoma subtype and body site. superficial spreading melanoma was the most common frequent subtype, whereas the trunk and the extremities were the most common locations [1]. to our knowledge, it is difficult to distinguish nam and dnm based on dermoscopy, and moreover there are only a limited number of studies about this topic. stante et al found that an atypical pigment network and regression structures were associated with melanoma arising in a nevus [4]. to detect dermoscopic parameters, a further study by shitara et al was conducted [5]. a case-control test set of nam vs dnm, paired by breslow thickness and histopathological subtype, was analyzed by 2 blinded experienced dermoscopists, according to criteria such as presence of nevus, pattern analysis, and abcd dermoscopy score. the results showed that the presence of irregular globules, streaks, and a negative pigment network were significantly related to nam. in contrast, the presence of a blue-white veil was not associated with nam. no significant differences were found between the other dermoscopic criteria or in any global pattern in pattern analysis [5]. histopathological features nam is defined by the coexistence of nevus components and melanoma features in histopathological examination. a higher prevalence of invasive melanoma is reported for both nam and dnm groups; however, in situ melanomas are slightly more prevalent in nams [1]. cymerman et al reported that dnm was associated with mean breslow thickness greater than 1.0 mm, ulceration, and stage greater than i [3]; even pampena et al found a significantly lower mean breslow thickness in nams than observations imply that nevi undergo dynamic proliferations that appear and disappear throughout the lifetime. currently, nevi are merged into 2 categories, congenital and acquired. current understanding, based on the striking, small, truly congenital nevi and nevi acquired early in life, is that the first develops before puberty, presents with a dermoscopic globular pattern, and persists for the lifetime, becoming later a dermal nevus in the adult [3,4]. in contrast, acquired melanocytic nevi develop mostly at puberty and usually undergo spontaneous involution after the fifth decade of life. however, in the realm of acquired nevi, we can distinguish 2 types of nevi: compound nevi with a superficial or with a deep dermal component. while the former is dermoscopically characterized by a reticular pattern, the latter is typified by a central elevated part showing a structureless pattern (deep dermal component) and a flat peripheral, reticular component (lateral junctional shoulders) [4,5]. although the majority of both nevus types undergo spontaneous involution, some of the dermal components of deep compound nevi may also persist until advanced age. there is global agreement that in certain cases melanoma develops in conjunction with a preexisting melanocytic nevus. nevus-associated melanoma (nam) is diagnosed on the basis of the presence of histopathological evidence of nevus components and melanoma features. conversely, de novo melanoma (dnm) is defined as melanoma without histopathological evidence of a preexisting nevus [1]. comparative data on melanomas that arise from preexisting melanocytic nevi and those that arise de novo is limited, and the effect of the origin of melanoma on disease characteristics and prognosis remains unclear. currently available data from the literature about clinical, histological, dermoscopic, and molecular features and prognosis of nam are summarized in table 1. epidemiology the prevalence of nam varies across studies. only one-third of melanomas arise in association with a preexisting nevus. the literature describes a wide range of nam prevalence, from 4% to 72%. lin et al reviewed 25 studies and found that 36% of melanomas were associated with a preexisting nevus [2]. recently, pampena et al conducted a systematic review and a meta-analysis of published reports on the nam ratio in melanoma patients. they showed that 29.1% of melanomas developed in conjunction with a preexisting nevus and 70.9% developed de novo [1]. a possible reason for these discrepancies is that the thicker the melanoma, the higher the probability for nevus remnants to be obscured or destroyed by malignant proliferation; thus, review | dermatol pract concept 2020;10(2):e2020028 3 ta b le 1 . c u rr en tl y a va il ab le d at a fr o m t h e l it er at u re a b o u t c li n ic al , h is to lo gi ca l, d er m o sc o p ic , a n d m o le cu la r fe at u re s an d p ro gn o si s o f n a m s tu d y n a m / c a se s h is to ty p e d e rm o sc o p y n a m d e rm o sc o p y d n m m o le cu la r a n a ly se s n a m m o le cu la r a n a ly se s d n m p ro g n o si s k ad du e t al [ 9] 20 02 14 8/ 66 7 (2 2. 1% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d g oo d ou tc om e (5 -y ea r m et as ta si sfr ee s ur vi va l ra te 9 3. 75 % ) in 6 9 pa ti en ts w it h n a m b ev on a et a l [ 11 ] 20 03 42 1/ 16 06 (2 6. 2% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d st an te e t al [ 4] 20 03 35 /1 08 (3 2. 4% ) a ll a pn : 3 3 (9 4. 3% ) is : 2 6 (7 4. 3% ) ib g : 2 5 (7 1. 4% ) ib d : 1 5 (4 2. 8% ) b w v : ( 37 .1 % ) b lo tc he s: 6 ( 17 .1 % ) a v p: 5 ( 14 .3 % ) r eg re ss io n: 2 1 (6 0% ) a pn : 5 8 (7 9. 4% ) is : 5 3 (7 2. 6% ) ib g : 4 8 (6 5. 7% ) ib d : 3 6 (4 9. 3% ) b w v : 3 8 (5 2% ) b lo tc he s: 4 3 (5 8. 9% ) a v p: 2 7 (3 6. 9% ) r eg re ss io n: 2 9 (3 9. 7% ) n ot r ep or te d n ot r ep or te d n ot r ep or te d m an ga no ni e t al [ 16 ] 20 10 10 /9 5 (9 .5 % ) n m n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d b et ti e t al [ 17 ] 20 14 24 7/ 87 3 (2 8. 2% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d d n m : m r ≥ 6 m it os is / m m 2 ca n be a m or e im po rt an t in di ca to r of pr og no si s th an m r < 6 m it os is /m m 2 sh it ar a et a l [ 5] 20 15 39 0/ 11 90 (3 2. 7% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d k ak av an d et a l [ 10 ] 20 14 29 /5 7 (5 0. 8% ) a ll n ot r ep or te d n ot r ep or te d b r a f v 60 0e : 5 5% b r a f v 60 0e : 2 1% n ot r ep or te d l in e t [2 ] 20 15 23 5/ 85 0 (2 7. 6% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d n o su rv iv al d if fe re nc e h ae ns sl e et a l [ 15 ] 20 16 10 3/ 19 0 (5 4. 2% ) a ll n ot r ep or te d n ot r ep or te d >1 p re vi ou s m el an om a: 6 7 (6 5. 1% ) m ul ti pl e (> 50 ) co m m on a nd / or 3 o r fe w er a ty pi ca l n ev i: 25 (2 4. 3% ) a ty pi ca l m ol e sy nd ro m e: 7 2 (6 9. 9% ) f a m m m s yn dr om e: 6 ( 5. 8% ) >1 p re vi ou s m el an om a: 7 1 (8 1. 6% ) m ul ti pl e (> 50 ) co m m on a nd /o r 3 or f ew er a ty pi ca l n ev i: 12 /8 7 (1 3. 8% ) a ty pi ca l m ol e sy nd ro m e: 6 3 (7 2. 4% ) f a m m m s yn dr om e: 1 2 (1 3. 8% ) n ot r ep or te d (t ab le 1 c o n ti n u es ) 4 review | dermatol pract concept 2020;10(2):e2020028 in dnms [1]. possible reasons for these discrepancies include the possibility that nevus remnants might have been obscured by malignant cells in thicker melanoma with consequent difficulties in the measurement of the mean breslow thickness [1,3]. the majority of nams are associated with acquired nevi, but, with the exclusion of congenital nevi, they are also more frequently associated with intradermal nevi or compound remnants. whether or not the nevus had dysplastic features does not seem to influence the prevalence of nam. however, nam appeared to be slightly more frequently associated with nondysplastic nevi than with dysplastic nevi [1]. prognosis certain studies suggested a more favorable overall survival with nam, but they considered only a few factors such as age and thickness [6]. on the contrary, other authors investigated survival through kaplan-meier and multivariable analysis and reported no statistically significant differences in survival between patients with nam and patients with dnm [1-3,7-9]. lin et al found there was no correlation between nam and sentinel lymph node status, and the presence of a nevus associated with a melanoma has no prognostic implication in overall survival [2]. cymerman et al confirmed nam as an independent predictor of better survival through multivariable analysis [3]. dnm is more likely to possess adverse histopathological and molecular features in primary cutaneous melanoma and appears to be an independent factor of poor outcome in multivariable analysis. among patients with dnm, men had a statistically significant worse survival than women; there was no sex-related difference in survival among patients who were diagnosed with nam [3]. ta b le 1 . (c o n ti n u e d ) c ur re nt ly a va ila bl e d at a fr om t he l it er at ur e a bo ut c lin ic al , h is to lo gi ca l, d er m os co pi c, a nd m ol ec ul ar f ea tu re s an d pr og no si s of n a m s tu d y n a m / c a se s h is to ty p e d e rm o sc o p y n a m d e rm o sc o p y d n m m o le cu la r a n a ly se s n a m m o le cu la r a n a ly se s d n m p ro g n o si s c ym er m an e t al [ 3] 20 16 54 7/ 21 49 (2 5. 4% ) a ll n ot r ep or te d n ot r ep or te d n ot r ep or te d n ot r ep or te d d n m s ho rt er o ve ra ll su rv iv al : n y u 1 (h r = 1. 63 ); n y u 2 (h r = 2 .5 2) a lv ar ez m ar ti ne z et  a l [ 18 ] 20 18 20 /3 2 (6 2. 5% ) a ll sb w : 7 ( 35 .0 % ) sb b c : 3 ( 15 .0 % ) sb b e : 0 ( 0. 0% ) c lo ds : 4 ( 20 .0 % ) l r /p c : 0 ( 0. 0% ) l r /p s: 2 ( 10 .0 % ) w hi te li ne s: 8 (4 0. 0% ) g ra y/ bl ue s tr uc tu re s: 2 (1 0. 0% ) t l r /b l : 4 ( 20 .0 % ) a v p: 1 ( 5. 0% ) sb w : 3 ( 25 .0 % ) sb b c : 4 ( 33 .3 % ) sb b e : 4 ( 33 .3 % ) c lo ds 4 ( 33 .3 % ) l r /p c : 1 ( 8. 3% ) l r /p s: 0 ( 0. 0% ) w hi te li ne s: 1 ( 8. 3% ) g ra y/ bl ue s tr uc tu re s: 1  (8 .3 % ) t l r /b l : 1 ( 8. 3% ) a v p: 2 ( 16 .6 % ) n ot r ep or te d n ot r ep or te d n ot r ep or te d a p n = a ty p ic al p ig m en te d n et w o rk ; a v p = a ty p ic al v as cu la r p at te rn ; b w v = b lu ew h it e ve il ; d n m = d e n o vo m el an o m a; f a m m m s yn d ro m e = f am il ia l at yp ic al m o le a n d m u lt ip le m el an o m a sy n d ro m e; i b d = i rr eg u la r b la ck d o ts ; ib g = i rr eg u la r b ro w n g lo b u le s; i s = i rr eg u la r st re ak s; l r /p c = l in es r ad ia l o r p se u d o p o d s ci rc u m fe re n ti al ; l r /p s = l in es r ad ia l o r p se u d o p o d s se gm en ta l; m r = m it o ti c ra te ; n a m = n ev u sas so ci at ed m el an o m a; n m = n o d u la r m el an o m a; n y u 1 /2 = r ef er ri n g to 2 p at ie n t co h o rt s (s ee r ef er en ce 3 ); s b b c = s tr u ct u re le ss b ro w n -b la ck ce n te re d ; sb b e = s tr u ct u re le ss b ro w n -b la ck e cc en tr ic ; sb w = s tr u ct u re le ss b lu ew h it e; t l r /b l = t h ic k l in es r et ic u la r o r b ra n ch ed l o ca li ze d . review | dermatol pract concept 2020;10(2):e2020028 5 cal localizations are the lower or upper limbs and the back, and the prognosis is poorer as the breslow at diagnosis is on average more frequently elevated [11-16]. conclusions according to our experience, current literature, and clinical evaluation, it can be assumed that there are therefore 2 different types of nam: a melanoma that arises in the center of the mole and a melanoma that grows next to the mole. the first probably arises from a real congenital nevus, and the second instead comes from a compound-dysplastic acquired nevus. therefore, the clinical evaluation of a melanoma should consider the location and age, but also the dermoscopic pattern that allows differentiation of the cases of nam on congenital nevus from the cases of nam on acquired nevus. further studies are certainly necessary to highlight possible models of progression of these melanomas according to this new concept of nevogenesis, deepening the molecular and genetic aspects and possibly correlating them to the dermoscopic characteristics. references 1. pampena r, kyrgidis a, lallas a, moscarella e, argenziano g, longo c. a meta-analysis of nevus-associated melanomainly located in the upper region of the back and along the paravertebral area of young patients and usually are associated with a high number of nevi. on the contrary, “acquired” nevi develop during puberty, increase in number until the fourth decade of life, and thereafter decrease via involution, apoptosis, or regression. during their development, acquired nevi undergo morphological changes that are initially characterized by a globular and later peripheral globular pattern during the active phase of growth and by a reticular or reticular mixed pattern (central structureless and peripheral reticular) during their stable phase of life. d e r m o s c o p i c a l l y, i t h a s b e e n observed that in most cases melanomas arisen from a “congenital-like” nevus come from the central portion of the lesion surrounded by a predominantly globular pattern (figure 1a); this type of melanoma usually involves young patients (aged between 15 and 30 years) with prevalent localization on the trunk, with lower breslow and therefore with a better prognosis. on the other hand, the melanoma that arises on the acquired compound nevus originates from the peripheral portion of the melanocytic lesion that can be recognized through a predominantly reticular pattern (figure 1b). the population affected by this type of nam is typically elderly without a high number of nevi; the most typigenetics in melanoma, the most common mutation is represented by brafv600e, which occurs in 70%-95% of patients. kakavand et al reported that nam had a higher frequency of brafv600e mutations than dnm. indeed, 55% of nam cases were brafv600e mutant and only 21% of dnm cases were brafv600e mutant [10]. nevus and melanoma cells in nams share a similar mutational profile, which might suggest a common origin or even a malignant transformation of nevus melanocytes [3]. discussion based on daily practice, it appears that approximately 30% of melanomas are associated with a preexisting nevus, whereby it is currently impossible to predict which nevus type is at risk to undergo malignant transformation. tsao et al reported that the risk of an individual nevus to progress toward melanoma is higher in men aged 60+ years, who usually have few nevi [13]. however, this model does not justify the presence of melanomas in young patients with many moles. according to our experience, current literature, and clinical evaluation, it can be assumed that there are therefore 2 different types of nam: a melanoma that arises in the center of the mole and a melanoma  that grows next to the mole. the first probably arises from a real congenital nevus (also named “congenital-like nevi,” “early-onset nevi,” or “true small congenital nevi”); the second instead comes from a compound-dysplastic acquired nevus (“late-onset nevi” or “acquired nevus”). the “congenital-like nevi” are characterized by a globular or structureless brown pattern and, once developed, persist throughout the lifetime, acquiring finally the stereotypical shape and appearance of an intradermal nevus in the elderly. these types of nevi are figure 1. dermoscopic features of nevus-associated melanoma (nam). (a) nam from congenital nevi arises in the center of the mole, and (b) nam from acquired nevi grows next to the mole. 6 review | dermatol pract concept 2020;10(2):e2020028 plications for mutation testing of primary melanomas. pathology. 2014;46(3):193-198. 11. bevona c, goggins w, quinn t, fullerton j, tsao h. cutaneous melanomas associated with nevi. arch dermatol. 2003;139(12):1620-1624. 12. tucker ma, halpern a, holly ea, et al. clinically recognized dysplastic nevi: a central risk factor for cutaneous melanoma. jama. 1997;277(18):1439-1444. 13. tsao h, bevona c, goggins w, quinn t. the transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population-based estimate. arch dermatol. 2003;139(3):282-288. 14. lallas a, zalaudek i, cota c, et al. naevus-associated lentigo maligna: coincidence or continuum? hippokratia. 2011;15(4):373375. 15. haenssle ha, mograby n, ngassa a, et al. association of patient risk factors and frequency of nevus-associated cutaneous melanomas. jama dermatol. 2016;152(3):291-298. 16. manganoni am, farisoglio c, gavazzoni f, facchetti f, zanotti f, calzavara-pinton p. nodular melanomas associated with nevi. j am acad dermatol. 2010;63(5):e97. 17. betti r, santambrogio r, cerri a, et al. observational study on the mitotic rate and other prognostic factors in cutaneous primary melanoma arising from naevi and from melanoma de novo. j eur acad dermatol venereol. 2014;28(12):1738-1741. 18. alvarez martinez d, boehncke wh, kaya g, merat r. recognition of early melanoma: a monocentric dermoscopy follow-up study comparing de novo melanoma with nevus-associated melanoma. int j dermatol. 2018;57(6):692-702. ma: prevalence and practical implications. j am acad dermatol. 2017;77(5):938-945.e4. 2. lin wm, luo s, muzikansky a, et al. outcome of patients with de novo versus nevus-associated melanoma. j am acad dermatol. 2015;72(1):54-58. 3. cymerman rm, shao y, wang k, et al. de novo vs nevus-associated melanomas: differences in association with prognostic indicators and survival. j natl cancer inst. 2016;108(10):djw121. 4. stante m, carli p, massi d, de giorgi v. dermoscopic features of naevus-associated melanoma. clin exp dermatol. 2003;28(5):476-480. 5. shitara d, nascimento m, ishioka p, et al. dermoscopy of naevus-associated melanomas. acta derm venereol. 2015;95(6):671675. 6. rhodes ar, harrist tj, day cl, mihm mc jr, fitzpatrick tb, sober aj. dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas. j am acad dermatol. 1983;9(4):563-574. 7. cochran aj. histology and prognosis in malignant melanoma. j pathol. 1969;97(3):459-468. 8. friedman rj, rigel ds, kopf aw, et al. favorable prognosis for malignant melanomas associated with acquired melanocytic nevi. arch dermatol. 1983;119(6):455-462. 9. kaddu s, smolle j, zenahlik p, et al. melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis. melanoma res. 2002;12(3):271-278. 10. kakavand h, crainic o, lum t, et al. concordant brafv600e mutation status in primary melanomas and associated naevi: imuntitled quiz | dermatol pract concept 2015;5(4):2 5 dermatology practical & conceptual www.derm101.com the patient a 72-year-old man presented to our clinic with a 12-month history of a new, growing, asymptomatic, pigmented flat lesion on his right leg. the physical examination revealed an irregular, dark-brown patch with 8 mm of maximum diameter (figure 1). a pigmented flat lesion on the leg of a 72-year-old man virgínia coelho de sousa1, andré oliveira1 1 department of dermatology, hospital de santo antónio dos capuchos centro hospitalar de lisboa central, lisboa, portugal key words: clonal seborrheic keratosis, dermoscopy, melanoma citation: coelho de sousa v, oliveira a. a pigmented flat lesion on the leg of a 72-year-old man. dermatol pract concept 2015;5(4):2. doi: 10.5826/dpc.0504a02 copyright: ©2015 coelho de sousa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: andré oliveira, md, department of dermatology, hospital de santo antónio dos capuchos centro hospitalar de lisboa central, alameda santo antónio dos capuchos, 1169-050, lisboa, portugal. tel. +351912561666; fax. +351213562208. email: andre.oliveira@sapo.pt figure 1. an irregular, dark-brown patch with 8 mm. [copyright: ©2015 coelho de sousa et al.] figure 2. multiple small and loosely arranged brown globules (blue circles) resembling the so-called dermoscopic “concentric structures.” [copyright: ©2015 coelho de sousa et al.] dermoscopy disclosed a sharply demarcated lesion corresponding to the jelly-sign (red arrows). additionally, multiple small and loosely arranged brown globules (blue circles) resembling the so-called dermoscopic “concentric structures,” were seen (figure 2). a punch biopsy of the lesion was performed. histopathological examination revealed multiple heavily pigmented intra-epidermal nests of basaloid cells, corresponding to the borst-jadassohn phenomenon (figure 3, hematoxylin & eosin [h&e], x200). what is your diagnosis? 6 quiz | dermatol pract concept 2015;5(4):2 of clinical simulators of melanoma [2]. described criteria for melanocytic and non-melanocytic lesions are sometimes seen together in the same lesion [3]. common dermoscopic features of sk include fissures and ridges, comedo-like openings, milia-like cysts and sharply demarcated borders [4,5]. clonal sk is considered a rare variant characterized by proliferation of intra-epidermal clusters of basaloid cells known as borst-jadassohn phenomenon. dermoscopic features of clonal sk have previously been documented in few reports or small case series [6-10]. in our case, the patient’s history pointed towards the diagnosis of melanoma. however, jelly-sign favored a sk even if milia-like cysts and other frequently observed criteria were absent. globular structures are observed mainly in melanocytic tumors. clonal sk, basal cell carcinoma and epidermal nevi are few of the known exceptions. in the former, globules correspond to the epidermal nests of pigmented basaloid cells seen in histopathology. in conclusion, clonal sk represents a dermoscopic pitfall being difficult to differentiate from melanoma. both tumors are also increasingly more prevalent in the elderly. histopathological examination should always be performed in such confounding lesions. references 1. hafner c, vogt t. seborrheic keratosis. j dtsch dermatol ges. 2008;6:664-77. 2. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: result of a consensus meeting via internet. j am acad dermatol. 2003;48:679-93. 3. argenziano g, rossiello l, scalvenzi m, et al. melanoma simulating seborrheic keratosis: a major dermoscopy pitfall. arch dermatol. 2003;139:389-91. 4. braun rp, krischer j, saurat jh. the “wobble” sign in epiluminescence microscopy as a novel clue to the differential diagnosis of pigmented skin lesions. arch dermatol. 2000;136:940-42. 5. longo c, moscarella e, piana s, et al. not all lesions with a verrucous surface are seborrheic keratoses. j am acad dermatol. 2014;70:e121-3. 6. longo c, zalaudek i, moscarella e, et al. clonal seborrheic keratosis: dermoscopic and confocal microscopy characterization. j euro acad dermatol venereol. 2013;28:1397-400. 7. zalaudek i, ferrara g, argenziano g. clonal seborrheic keratosis: a dermoscopic pitfall. arch dermatol. 2004;140:1169-70. 8. popadic m. a hyperkeratotic clonal seborrheic keratosis accompanied by nodulocystic basal cell carcinoma. j am acad dermatol. 2015;72:e113-5. 9. fraga-braghiroli na, merati m, rabinovitz h, scope a. reflectance confocal microscopy features of a clonal seborrheic keratosis that clinically and dermoscopically simulates melanoma. dermatol surg. 2015;41:662-5. 10. yagerman se, marghoob aa. clonal seborrheic keratosis versus epidermal nevus. j am acad dermatol. 2013;69:e43-4. diagnosis clonal seborrheic keratosis clinical course as it is considered a benign non-melanocytic lesion, a conservative management was proposed. no further unnecessary therapeutic procedures were performed. answer and explanation seborrheic keratosis (sk) is one of the more common skin neoplasms seen by dermatologists. clinical and dermoscopic diagnosis of sk is straightforward in most of the cases. however, deeply pigmented lesions can resemble melanoma. sk may be grouped into seven histological subtypes, with acanthotic, hyperkeratotic and adenoid variants being the more representative [1]. dermoscopy is a fast, non-invasive technique that increases diagnostic accuracy for both melanocytic and nonmelanocytic skin tumors, allowing for a better differentiation figure 3. histopathological examination revealed borst-jadassohn phenomenon (h&e, x200). [copyright: ©2015 coelho de sousa et al.] research | dermatol pract concept 2011;1(1):3 5 background: progressive macular hypomelanosis (pmh) is a disease of unclear etiology. propionbacterium acnes (p. acnes) was claimed to be an etiological factor. objectives: the purpose of this study was to document the clinicopathological features of pmh in egyptian patients and to evaluate the therapeutic outcome. methods: patients with clinical features of pmh were recruited. wood’s lamp examination, skin scrapings for fungi, and skin biopsy specimens were obtained. biopsies were stained with hematoxylin and eosin, pas, fontana-masson, and s100 protein. patients received either narrow-band uvb (nbuvb) or nbuvb plus daily topical clindamycin 1% and benzoyl peroxide gel 5% (bcuvb). the period of active treatment was 14 weeks followed by a follow-up period of 24 weeks. results: twenty-nine patients were included. microscopic evaluation of skin biopsy specimens showed no significant differences between lesional and normal skin. fontana-masson stained sections showed overall reduction of melanin granules in the basal layer of lesional skin only and s100 staining did not detect significant differences in the number of melanocytes in lesional and normal skin. nearly complete repigmentation was reported in 10 patients treated with bcuvb compared to 9 patients treated with nbuvb with no significant differences between both groups after 14 weeks. only 2 patients in each group retained the pigmentation and the remaining patients returned to the baseline color before treatment. conclusions:  this study documented the clinicopathological features of pmh among egyptians. no permanently effective treatment is available. further studies are needed to prove or disprove the pathogenic role of p. acnes in pmh. abstract progressive macular hypomelanosis among egyptian patients: a clinicopathological study mohamed khaled selim, m.d.1, el-shahat farag ahmed, m.d.1, mamdouh morsy abdelgawad, m.d.1, mohammed fawzy el-kamel, m.d. 1 1department of dermatology, andrology and stds, mansoura university, egypt key words: progressive macular hypomelanosis citation: selim mk, ahmed ef, abdelgawad mm, el-kamel mf. progressive macular hypomelanosis among egyptian patients: a clinicopathological study. dermatol pract concept 2011;1(1):3. http://dx.doi.org/10.5826/dpc.0101a03. editor: harald kittler, m.d. received: october 1, 2010; accepted: february 11, 2011; published: october 31, 2011 copyright: ©2011 selim et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: mohamed khaled selim, m.d., department of dermatology, mansoura university, 60 el gomhoria street, mansoura, 35516 dakahlia, egypt. email: mkhaled4@yahoo.com. dermatology practical & conceptual www.derm101.com 6 research | dermatol pract concept 2011;1(1):3 introduction progressive macular hypomelanosis (pmh) is not a common skin disorder but it may be only rarely recognized. it is often mistaken for pityriasis versicolor and pityriasis alba. various authors have written about similar skin disorders, referring to them by different names, but we believe that all these similar disorders are part of the same entity. the current term “progressive macular hypomelanosis” was coined by guillet et al [1] following a study in the french west indies concerning this condition in black adults of mixed ethnic origin. subsequently, additional cases were reported from other parts of the world [2–4]. pmh is characterized by ill-defined nummular, non-scaly hypopigmented spots on the trunk, often confluent in and around the midline, and rarely extending to the proximal extremities and neck/head region. there is normal sensation without any history of itching, pain, or preceding infection, trauma or inflammation [1–5]. pmh has a worldwide distribution; however, it is more often identified in black people living in or originating from tropical countries [1–5]. it is also more often seen in young females [1, 2, 4, 5]. however, one study reported a higher frequency in males [3]. the natural history of pmh is stable disease or perhaps slow progression over decades, with spontaneous disappearance after mid-life [1, 2, 4]. however, others have reported that spontaneous regression does not occur and that the hypomelanosis remains stable for many years [3, 5]. extensive pityriasis alba is probably identical with pmh, and discontinuation of use of the former term was suggested on the grounds that extensive pityriasis alba is histologically and clinically different from classical pityriasis alba, which is basically an eczematous type of disorder [6]. pmh is characterized histologically by diminished pigment in the epidermis and a normal-looking dermis [1, 4]. electron microscopy shows a shift from large melanosomes in normal-looking skin to small aggregated, membranebound melanosomes in hypopigmented skin [1, 4]. pmh should be differentiated from other disorders with hypopigmentation on the trunk, such as pityriasis versicolor, mycosis fungoides, vitiligo, leprosy, pityriasis alba, and postinflammatory hypopigmentation [1–6]. the etiology of this condition is uncertain, although westerhof et al recently incriminated propionobacterium acnes [5]. pmh appears to progress to some extent over months to years and then becomes relatively static. in patients with dark skin types, pmh may be distressing because the contrast between normal skin and hypopigmented macules makes the lesions appear more prominent and the patients feel socially awkward [1–4]. no consistently effective therapy is known, but lesions may spontaneously be resolved. however, there are few reports of repigmentation after narrow band uvb [7, 8], combination of sunlight and oral tetracycline (case report) [9], combination of uva1 plus topical clindamycin and benzoyl peroxide (45 patients) [10], or combination of topical benzoyl peroxide and oral doxycycline (case report) [11]. the purpose of this study was to document the clinicopathological features of pmh in egyptian patients, and to evaluate the therapeutic outcome. material and methods patients, who were at least 16  years of age, presenting to dermatology clinic of mansoura university hospital, mansoura, egypt with acquired, hypopigmented, discrete or confluent macules larger than 1 cm in diameter, with normal sensation, consistent with the clinical features of pmh described by gullet et al [1, 2] were selected. thirty-five patients fulfilling these criteria were enrolled in this study during the period of february 2006 to january 2010. patients were excluded if their hypopigmentation was associated with or the result of a specific disease at the site, such as pityriasis versicolor, table 1: clinical characteristics characteristics n = 29 female 22 (76%) male 7 (24%) age, years (mean ± sd) 20.7 ±9.1 duration, years (mean ± sd) 7 ±2.1 former treatment puva 1 uvb 2 antimycotics 19 no treatment 7 research | dermatol pract concept 2011;1(1):3 7 hypopigmented macules of leprosy, hypopigmented mycosis fungoides, idiopathic guttate hypomelanosis, eczema, psoriasis, pityriasis lichenoides chronica, pityriasis rosea, injury, infection, or congenital disorders of pigmentation, such as piebaldism, nevus depigmentosus, ash leaf macules of tuberous sclerosis, pityriasis alba, and vitiligo. patients were also excluded if they had positive potassium hydroxide test results; were sensitive to any of the study medication ingredients or sunlight; were treated with chemical peeling or other treatments that could cause scaling of the trunk; or were pregnant or lactating. in addition, any previous treatment for pmh or any antibacterial treatment (both local and systemic) had to be stopped at least three months before study entry. details of the history and examination were recorded. patients were evaluated at eight-week intervals for 24 weeks after therapy. photographs taken at the first visit were compared with those obtained during follow-up evaluations. informed written consent was obtained from every patient or his guardian. we obtained two 4 mm punch biopsy specimens from comparable anatomic sites of lesional and normal-appearing skin. hematoxylin and eosin staining and periodic acid schiff staining were performed. fontana-masson stain for melanin was performed as well as immunohistochemical stain for s100 protein. potassium hydroxide (koh) examination of epidermal scrapings from hypopigmented lesions was performed. wood›s lamp examination in a completely dark room was also done. the patients were divided into two treatment groups. the first group received narrow-band uvb (nbuvb) treatment (starting dose 100mj/cm2, and increased dose by 50mj/cm2) twice weekly for 28 sessions. the other group received the same regimen of first group (nbuvb treatment) plus daily topical clindamycin solution 1% in the morning and benzoyl peroxide gel 5% in the evening (bcuvb group). the period of active treatment in both groups was 14 weeks followed by a follow-up treatment-free period for 24 weeks. subjective assessment of treatment result (repigmentation) was assessed by comparing pre-treatment and posttreatment photos. images of the trunk were taken at each visit. conditions were standardized throughout the study, including the same camera, lighting conditions, and distance between camera and patient, and the same external dermatologist for color assessment. the assessing dermatologist who was blinded for the assigned treatment independently scored treatment success by comparing photos before treatment with photos at the end of the active treatment period, i.e., after 14 weeks, and photos at the end of follow-up treatment free period of another 24 weeks (38 weeks after start of active treatment). repigmentation relative to the baseline situation was scored on a 3-point scale: ++ = total repigmentation, + = moderate repigmentation, 0 = no change. statistical analysis the subjective assessment scores of the patients’ dermatologists and assistants were analyzed by comparing the scores of both treatment groups. figure 1. non-scaly, ill-defined hypopigmented, discrete macules on the abdomen. figure 2. typical lesions on the back. figure 3. typical lesions on the buttocks and thighs. 8 research | dermatol pract concept 2011;1(1):3 figure 4. biopsy from the hypopigmented skin lesion shows decrease in the pigment intensity in the epidermis (hematoxylin & eosin [h & e], 20x). figure 7. normal skin: s100 stained section shows no difference in the number of melanocytes in the normal-appearing skin and the hypopigmented skin in figure 6 (s100, 20x). figure 5. biopsy from normal-appearing skin shows normal pigment intensity in the epidermis (h & e, 20x). figure 8. lesional hypopigmented skin biopsy: fontana-masson stained section shows reduction of melanin granules in the basal cell layer of the hypopigmented skin compared with normal pigment of the adjacent normal-appearing skin in figure 9 (fontana-masson, 10x). figure 6. lesional hypopigmented skin: s100 stained section shows normally intact melanocytes in the basal cell layer like those found in normal-appearing skin biopsy in figure 7 (s100, 20x). figure 9. normal-appearing skin biopsy: fontana-masson stained section shows normal melanin pigment of the biopsied normal-appearing skin compared with the reduction of the melanin granules in the basal cell layer of adjacent hypopigmented skin lesion in figure 8 (fontana-masson, 10x). research | dermatol pract concept 2011;1(1):3 9 results thirty-five patients met our inclusion criteria for diagnosis of pmh. six patients were lost in follow-up and excluded from the analysis. the remaining 29 patients (7 men and 22 women) completed all the investigations and treatment course (active treatment and follow-up). table 1 shows the demographic and clinical criteria of studied patients. all patients were egyptian of arabic descent with no racial mixing. the mean age of onset was 20.7 ± 9.1 years (range between 16 and 37 years). the mean duration of the disease was 7 ±2.1 years. the back (especially lumbar and lumbosacral areas) was the most common site of involvement followed by abdomen, buttocks, chest, and thighs (figures 1–3). all lesions fulfill the criteria of pmh with normal sensation and negative koh mounts of skin scrapings for malassezia furfur. under wood’s lamp examination, hypopigmented lesions demonstrated a follicular pink fluorescence in two patients only. normal and lesional skin biopsies were taken for comparison in all 29 patients. hematoxylin and eosin stained sections showed no significant difference between lesional and normal skin, except in five patients who showed subtle decrease in pigment intensity in lesional skin (figures 4, 5). there was no spongiosis, inflammatory infiltrate, or epidermotropism in any case. s100 staining did not detect significant differences in the number of melanocytes in lesional and normal-appearing skin (figures 6, 7). fontana-masson stained sections showed overall reduction of melanin granules in the basal cell layer of lesional skin compared to normal adjacent normal-appearing skin (figures 8, 9). sections stained with pas did not show any spores or hyphae in the stratum corneum or pilosebaceous ducts. the external dermatologist scored the bcuvb-treated group slightly higher than the nbuvb-treated group. complete or nearly complete repigmentation was reported in 10 patients in the bcuvb-treated group compared to 9 patients in the nbuvb-treated group with no significant differences between both treatment groups after 14 weeks of treatment (p > 0.05). at the end of follow-up (at 38 weeks), only two patients in the nbuvb-treated group and two patients in the bcuvb-treated group retained the pigmentation acquired by treatment, and the remaining patients (seven in the nbuvb group and eight in the bcuvb group) returned to baseline color with loss of pigmentation acquired by treatment. table 2: regimentation at the end of active treatment (week 14) and at the end of follow-up period (week 38) total repigmentation uvb+ anti acne (n=15) uvb (n=14) p-value at week 14 10 (66%) 9 (64%) ns at week 38 2 (13%) 2 (14%) ns discussion while several reports have documented progressive macular hypomelanosis of the trunk over the past two decades [1-5], it is not a well-recognized entity in clinical practice in many parts of the world, possibly because the initial publications on this subject were not in english. multiple synonyms, including pmh [1], progressive macular confluent hypomelanosis [3], cutis trunci variata [12], progressive and confluent hypomelanosis of the melanodermic metis [2] nummular and confluent hypomelanosis of the trunk [13], and idiopathic multiple large macules [14] add to the confusion. similarly, lernia and ricci [15] and relyveld et al [6] concluded that the condition described by zaynoun and coworkers [16] as extensive pityriasis alba cannot be differentiated from progressive and extensive hypomelanosis described by guillet et al [1, 2]. when occurring in dark-skinned individuals, pmh may be misdiagnosed as hypopigmentation associated with pityriasis versicolor, despite exclusion of malassezia furfur. in areas where leprosy is endemic, tuberculoid or borderline tuberculoid leprosy may be considered, but there is no sensory impairment, no textural change, and no histologic evidence of granulomas in lesions of pmh. hypopigmented mycosis fungoides differs from pmh in its asymmetrical distribution, poikiloderma, and textural changes [1–4]. progressive macular hypomelanosis is a disease of unknown etiology. several theories have been proposed regarding its etiology, including that of its being a genodermatosis [1, 2], or that it is related to p. acnes [5]. westerhoff, relyveld, and others published a study in 2004 demonstrating a relationship between the hypopigmented macules and p. acnes [5]. their study included eight patients with biopsy specimens taken of normal and affected skin, and the presence of bacteria was determined by examining fluorescent and non-fluorescent hair follicles using a wood’s lamp and by anaerobic culture. affected skin fluoresced on wood’s lamp evaluation in all eight patients and culture showed evidence of p. acnes on specimens in all but one patient. normal skin specimens did not show evidence of any bacteria [5]. successful treatment of pmh has eluded practitioners. topical steroids and anti-fungals were generally unsuccessful in many of our patients, similar to the findings in other reports. if westerhoff et al are correct about p. acnes playing a role, specifically that p. acnes inhibits melanogenesis, then antibiotics such as topical clindamycin or the oral tetracyclines should, in theory, be effective. in 2006 [10], relyveld 10 research | dermatol pract concept 2011;1(1):3 and others (including westerhoff) reported that uva irradiation in combination with benzoyl peroxide 5% hydrogel in the morning and clindamycin 1% lotion at night for 14 weeks was more effective than uva irradiation plus topical steroid for repigmentation in patients with pmh [10]. however, they limited the post-treatment follow-up period to 12 weeks only with no long-term follow-up data. to our knowledge, there is no available data about the prevalence of pmh in egypt. we think that it is not a rare condition in clinical practice, but commonly misdiagnosed and under-reported by treating physicians. in our hospital, the total number of patients with pmh was greater than the number recruited for the study, because several were excluded due to the refusal of a skin biopsy or due to the presence of unrelated concomitant diseases. we found that pmh is a disorder of adolescents and young adults with strong female preponderance (76%), as previously reported [1–5]. the age of our patients ranged between 16 and 37 years with no cases reported in the elderly, as noted in other studies. this finding supported that pmh is not a progressive disorder as expected from the nomenclature of the disease. therefore, the term “progressive” in pmh may be erroneous because the condition does not progress in most patients and regresses spontaneously after many years, as reported by other authors [4]. we could not identify any definite causative factor(s). exposure to natural sunlight may enhance the visual demarcation between lesional and nonlesional skin, indicating that pmh lesions tan poorly as reported in a study in singapore [4]. in contrast to this observation, temporary repigmentation after natural sun exposure or narrowband uvb has been reported in other studies, including our study [7–9]. all of our patients were egyptians with no parental consanguinity or racial mixing. thus, it is clear that pmh can occur in any race, and not only in mixed negroid subjects as reported previously by guillet et al [1]. in this study, histological examination demonstrated decreased melanization of the basal layer in lesions of pmh as compared to normal skin. this difference was illustrated with fontana–masson stain. s100 staining did not detect significant differences in the number of melanocytes in lesional and normal-appearing skin. there was no spongiosis, inflammatory infiltrate, or epidermotropism in any case. our results were consistent with previous studies [1–5]. histologic evaluation is sometimes important to exclude hypopigmented mycosis fungoides, vitiligo, and postinflammatory pigmentary changes. the observation that there was no decrease in numbers of melanocytes but only a decrease in melanin content suggests that there is probably a functional defect in pigmentation or a problem in melanin distribution. electron microscopic studies [4, 17] revealed that hypopigmentation in pmh seems to be the result of an altered melanogenesis based on a decrease in melanin formation and a change in the distribution of melanosomes. in lesional skin of pmh patients less melanized aggregated melanosomes instead of single, mature melanosomes are transferred from melanocytes to keratinocytes [4, 17]. this results in a decrease of epidermal melanin [4, 17]. a hypothetical factor produced by p. acnes may be responsible for abnormal melaogenesis, as suggested by the authors who claimed that this organism may have a role in pathogenesis of pmh [5, 17]. the clinical observations that pmh fades over time and that it is not found in the elderly suggest that the inhibitory effect on melanogenesis in the lesional skin of those patients is not permanent [4, 5]. pmh is known to be recalcitrant to treatment. few reports claimed the effectiveness of regimentation after narrow band uvb [7, 8], combination of sunlight and oral tetracycline (case report) [9], combination of uva1 plus topical clindamycin and benzoyl peroxide (45 patients) [10], or combination of topical benzoyl peroxide and oral doxycycline (case report) [11]. however, long-term follow-up data are lacking in all studies, and the maximum follow-up duration in most studies was three months. in our work, we divided the patients randomly into two groups: the first group received narrow-band uvb treatment and the other group received the same regimen of the first group (narrow-band uvb treatment) plus daily topical clindamycin solution 1% in the morning and benzoyl peroxide gel 5% in the evening. active treatment was continued for 14 weeks followed by a follow-up treatment-free period of 24 weeks, which is nearly double the follow-up period in the relyveld et al study [10]. at the end of active treatment period, total repigmentation was obtained in 10/15 patients in the bcuvb group compared to 8/14 in the nbuvb group with no significant difference between both groups. these results were nearly similar to relyveld et al [10] who used a combination of uva1 plus topical measures against p.acne (clindamycin and benzoyl peroxide). however, our results were dramatically different from the last authors at the end of follow-up period. relyveld et al [10] reported that most of their patients retained the pigmentation at the end of a follow-up period of 12 weeks. in our work, we extended the follow-up period to 24 weeks and we found that most of our patients in both groups lost the pigmentation acquired by treatment in both groups. these results do not support the pathogenic role of p. acnes in pmh as claimed by westerhoff and his team. however, regrowth of p. acnes may provide an explanation for loss of pigmentation acquired in treatment. research | dermatol pract concept 2011;1(1):3 11 conclusion progressive macular hypomelanosis is a disease of unclear etiology that is often misdiagnosed and difficult to treat. this study documented the clinicopathological features of pmh among egyptian patients. no permanently effective treatment is available. further studies on a larger number of patients are needed to prove or disprove the pathogenic role of p. acnes in pmh and to search for other cause(s) or other effective treatments for this disfiguring disease. references 1. guillet g, helenon r, gauthier y, surleve-bazeille je, plantin p, sassolas b. progressive macular hypomelanosis of the trunk: primary acquired hypopigmentation. j cutan pathol 1988;15(5):286–9. 2. guillet g, halenon r, guillet mh, gauthier y, menard n. [progressive and confluent hypomelanosis of the melanodermic metis]. ann dermatol venereol 1992;119(1):19–24. 3. lesueur a, gracia-granel v, halenon r, cales-quist d. [progressive macular confluent hypomelanosis in mixed ethnic melanodermic subjects: an epidemiologic study of 511 patients]. ann dermatol venereol 1994;121(12):880–3. 4. kumarasinghe spw, tan sh, thng s, thamboo tp, liang s, lee ys. progressive macular hypomelanosis in singapore: a clinicopathological study. int j dermatol 2006;45(6):737–42. 5. westerhof w, relyveld gn, kingswijk mm, de man p, menke he. propionibacterium acnes and the pathogenesis of progressive macular hypomelanosis. arch dermatol 2004;140(2):210–4. 6. relyveld g, menke h, westerhof w. progressive and extensive hypomelanosis and extensive pityriasis alba: same disease, different names? (letter). j eur acad dermatol venereol 2006;20(10):1363– 1364. 7. hwang sw, hong sk, kim sh, et al. progressive macular hypomelanosis in koreans: a clinicopathologic study. ann dermatol 2009;21(3):261-7. 8. chung yl, goo b, chung ws, lee gs, hann sk. a case of progressive macular hypomelanosis treated with narrow-band uvb (letter). j eur acad dermatol venereol 2007;21(7):1007-9. 9. perman m, sheth p, lucky aw. progressive macular hypomelanosis in a 16-year old. pediatr dermatol 2008;25(1):63-5. 10. relyveld gn, kingswijk m, reitsma jb, menke he, bos jd, westerhof w. benzoyl peroxide/clindamycin/uva is more effective than fluticasone/uva in progressive macular hypomelanosis: a randomized study. j am acad dermatol 2006;55(5):836–43. 11. tierney e, hamzavi i. progressive macular hypomelanosis in a young african-american woman: case report and review of the literature. j am acad dermatol 2007;56:2, (supplement 2) ab146. 12. borelli d. [cutis “trunci variata.” a new genetic dermatosis]. med cutan ibero lat am 1987;15(4):317–19. 13. menke he, doornweerd s, zaal j, et al. acquired nummular and confluent hypomelanosis of the trunk. paper presented at: second annual meeting of the european society for pigment cell research; june 18-21, 1989; uppsala, sweden. 14. sober aj, fitzpatrick tb. yearbook of dermatology. st louis, mo: mosby–year book, 1996:416–7.  15. di lernia v, ricci c. progressive and extensive hypomelanosis and extensive pityriasis alba: same disease, different names? j eur acad dermatol venereol 2005;19(3):370–2. 16. zaynoun st, aftimos bg, tenekjian kk, bahuth n, kurban ak. extensive pityriasis alba: a histological histochemical and ultrastructural study. br j dermatol 1983;108(1):83–90. 17. relyveld g, dingemans kp, menke he, bos jd, westerhof w. ultrastructural findings in progressive macular hypomelanosis indicate decreased melanin production. j eur acad dermatol venereol 2008;22(5):568–74. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020054 1 dermatology practical & conceptual introduction blastomycosis is a fungal infection caused by blastomyces dermatitidis. it is characterized by a chronic granulomatous and suppurative inflammatory reaction [1]. cutaneous blastomycosis (cb) usually develops after hematogenous dissemination from primary lung involvement. however, less commonly, blastomyces dermatitidis can be inoculated into the skin, causing primary cutaneous blastomycosis. the skin involvement in cb includes a wide variety of manifestations ranging from papulopustular and nodular lesions to verrucous and ulcerative lesions [2]. we report a case of cb initially misdiagnosed as pyoderma gangrenosum (pg). case presentation a 64-year-old woman with a nonhealing ulceration on the left leg was referred to us with a preliminary diagnosis of pg. the lesion first appeared 25 years ago and had grown in size without any response to many treatments, including topical and systemic antibiotics and corticosteroids. there was no history of a trauma to the area or a known inciting cause. there was also no history of a respiratory infection. dermatological examination revealed a painless vegetative ulceration 18 × 10 cm in size on the anterior aspect of the left leg (figure 1). on the dermoscopic examination, white to pinkish overlapping papillomatous structures, white and red structureless areas, blood spots, and polymorphous vessels including dotted, coiled, serpentine, and complex looped vessels with an annular arrangement were observed (figure 2). direct microscopic examination of the skin-scraping material revealed the fungal element. the histopathological examination showed ulceration, pseudoepitheliomatous hyperplasia, predominantly neutrophilic inflammatory infiltrate, and broad-based bugging yeasts consistent with blastomyces dermatitidis (figure 3). a detailed workup revealed no evidence of systemic involvement. a 200-mg daily dose of itraconazole was started; considerable improvement was observed after 3 months. conclusions cb is a rare and often misdiagnosed cause of persistent leg ulceration. the common misdiagnoses include scrofuloderma, granuloma inguinale, nocardiosis, cutaneous tuberculosis, as well as squamous cell carcinoma. our patient was initially a 25-year history of leg ulceration: cutaneous blastomycosis ömer faruk elmas,1 belkiz uyar,1 asuman kilitçi2 1 department of dermatology, faculty of medicine, kırşehir ahi evran university, kırşehir, turkey 2 department of pathology, faculty of medicine, kırşehir ahi evran university, kırşehir, turkey key words: cutaneous blastomycosis, dermoscopy, histopathology, pyoderma gangrenosum citation: elmas öf, uyar b, kilitçi a. a 25-year history of leg ulceration: cutaneous blastomycosis. dermatol pract concept. 2020;10(3):e2020054. doi: https://doi.org/10.5826/dpc.1003a54 accepted: march 12, 2020; published: june 29, 2020 copyright: ©2020 elmas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. ömer faruk elmas, department of dermatology, kırşehir ahi evran university, kırşehir, 40000, turkey. email: omerfarukmd@gmail.com https://doi.org/10.5826/dpc.1003a54 mailto:omerfarukmd@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020054 misdiagnosed with pg and underwent systemic corticosteroid treatment, which did not lead to remarkable improvement. pg is a neutrophilic dermatosis characterized by painful ulcerative lesions usually located on extremities. on histopathological examination, pg usually shows ulceration, pseudoepitheliomatous hyperplasia, and neutrophil-rich dermal inflammatory infiltration, which can also be seen in cb. the significant clinicopathological overlap between cb and pg may cause misdiagnosis. the diagnosis of recalcitrant leg ulcerations including pg is mainly based on the exclusion and histopathological examination is usually performed. in this context, pathology specimens submitted should always be examined carefully to rule out cb. it should also be kept in mind that in a case of cb, the misdiagnosis of pg followed by systemic corticosteroid therapy may cause fatal complications such as disseminated blastomycosis and acute respiratory distress syndrome [2,3]. references 1. mason ar, cortes gy, cook j, maize jc, thiers bh. cutaneous blastomycosis: a diagnostic challenge. int j dermatol. 2008;47(8):824-830. https://doi. org/10.1111/j.1365-4632.2008.03732.x. 2. azar mm, relich rf, schmitt bh, spech rw, hage ca. cutaneous blastomycosis masquerading as pyoderma gangrenosum. j clin microbiol. 2014;52(4):1298-1300. https://doi.org/10.1128/jcm.03356-13. 3. mak j, al habeed a, al kalabi m, alavi a. pyoderma gangranosum-like blastomycosis. j cutan med surg. 2018;22(5):519521. https://doi.org/10.1177/120347541 8760460. figure 1. vegetative ulceration 18 × 10 cm in size on anterior aspect of the left leg. figure 2. dermoscopy shows white to pinkish overlapping papillomatous structures, white and red structureless areas, blood spots, and polymorphous vessels including dotted, coiled, serpentine complex looped vessels with an annular arrangement. figure 3. (a) low-power histopathological view shows ulceration, pseudoepitheliomatous hyperplasia, and dermal inflammatory infiltration (h&e, ×100). (b) broad-based bugging yeasts consistent with blastomyces dermatitidis (h&e, ×400). https://doi.org/10.1111/j.1365-4632.2008.03732.x https://doi.org/10.1111/j.1365-4632.2008.03732.x https://doi.org/10.1128/jcm.03356-13 https://doi.org/10.1177/1203475418760460 https://doi.org/10.1177/1203475418760460 dermatology: practical and conceptual abstracts | dermatol pract concept 2014;4(3):23 1 dermatology practical & conceptual www.derm101.com impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions ivette alarcon, cristina carrera, josep malvehy, susana puig melanoma unit, dermatology department, hospital clinic and university of barcelona, spain dermoscopy is a non-invasive imaging technique that improves accuracy in the diagnosis of melanoma. it has been associated with a reduction in the false-positive detection rate and a subsequent decrease in unnecessary excisions. in vivo confocal microscopy is also a non-invasive technique which allows the examination of the skin at cellular resolution; its diagnostic accuracy has been evaluated by several studies concluding that the use of this novel technique provides a significant improvement in melanoma detection. the number-needed-to-treat (nnt) ratio is an effective method for measuring accuracy in melanoma detection. the aim of the present study was to assess the impact of rcm analysis on the number of dermoscopically equivocal pigmented lesions excised for every melanoma, in a clinical setting. three hundred and forty-three consecutive patients presenting with dermoscopically equivocal lesions, assumed to be melanocytic neoplasms based on clinical and dermoscopic features, were prospectively enrolled. dermoscopy and confocal microscopy diagnosis were made by dermatologists with expertise in both techniques. histopathological assessment was considered as the reference standard. the main outcome was nnt, calculated as the proportion of dermoscopically and rcm equivocal lesions excised for every melanoma. secondary outcomes included sensitivity, specificity, positive predictive value and negative predictive value of each technique for diagnosing melanoma. results: dermoscopy alone obtained a hypothetical nnt of 3.73; the combination of dermoscopy and rcm identified 264 equivocal lesions that qualified for excision, 92 of which were confirmed to be a melanoma, resulting in an nnt of 2.87, whereas the analysis of rcm images classified 103 lesions as melanoma, with a consequent nnt of 1.12. the difference in nnt was statistically significant between the three groups (p < 00001). there was no significant improvement in sensitivity when comparing the combination of dermoscopy and rcm with rcm alone (94.6% vs. 97.8%; p = 0.043). however, the differences between specificities were statistically significant (p < 1x106), favouring rcm alone. conclusions: the addition of rcm analysis to dermoscopy reduces unnecessary excisions with high diagnostic accuracy and could be a mean for reducing the economic impact associated with the management of skin cancer. abstracts from the joint meeting of the international society for digital imaging of the skin (isdis), the international confocal group (icg), and the international dermoscopy society (ids) in conjunction with the 2014 american academy of dermatology, march 22, 2014, denver, co, usa citation: abstracts from the joint meeting of the international society for digital imaging of the skin (isdis), the international confocal group (icg), and the international dermoscopy society (ids) in conjunction with the 2014 american academy of dermatology, march 22, 2014, denver, co, usa. dermatol pract concept. 2014;4(3):23. http://dx.doi.org/10.5826/dpc.0403a23 published: july 31, 2014 copyright: ©2014 alarcon et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 abstracts | dermatol pract concept 2014;4(3):23 eruptive facial post inflammatory lentigo-like reaction: clinical and dermatoscopic features raúl cabrera head and chairman, department of dermatology, universidad del desarrollo-clínica alemana, santiago de chile, chile we present 8 cases of an unusual presentation of a fixed drug eruption (fde) mimicking a clinical lentigo on the face. since brocq’s first and very detailed description of fde, we have not found any description in the literature of the special form of fde described herein. the sudden appearance of a lentigo on the face after the ingestion of nsaids can mimic other forms of lentigo and can easily be misdiagnosed. most of our patients presenting with this form of post inflammatory lentigo-like reaction (pillr) have a clinical lentigo like appearance on the face from the beginning. the appearance of these pillr usually lack strong local symptoms such as burning and itching, demonstrating that this is mainly a subclinical form of fde that later became a clinical pillr. only after specific questioning about mild burning or itching, required for the medical records, did patients remember having these symptoms. all of them had a history of previous nsaids intake, specifically of ibuprofen or ketoprofen. the majority of the patients had a pillr with different intensities of brown clinical color upon first clinical examination; with the exception of two patients whose pillr had also a pink color in the acute phase (fig 1). the clinical appearance of a pillr generally persisted for more than six months. under dermatoscopy, the lesions were generally asymmetric and the borders were ill-defined. all cases presented a brown uniform background color of different shades—from light brown to dark brown—that produced a pseudonetwork. in all patients a light pink area due to vessels arranged as red dots or short telangiectatic vessels accompanied the brown pseudonetwork. brown and/or brown-gray dots also distributed randomly or in focal areas of the lesion generated a dermatoscopic granular pattern. in those patients with darker skin, an annular granular pattern was observed in focal areas along symmetric follicular openings. the pink color present under dermoscopy (as the result of vessels associated with inflammation) is a strong indicator for a pillr diagnosis and is not found in the dermatoscopy of other forms of lentigo. the histopathologic analysis of pillr displays features of a mild form of fde. deconstructing skin: rcm and fcm interpretation with quantitative image analysis tools kivanc kose*, miguel cordova*, jennifer dy**, dana h. brooks**, milind rajadhyaksha* *dermatology service, memorial sloan kettering cancer center, new york, ny, usa ** electrical and computer engineering department, northeastern university, boston, ma, usa most skin cancers originate at and spread from the dermal epidermal junction. currently, biopsy followed by histology is the “gold standard.” however, this is an invasive procedure, which is painful, costly and time consuming. moreover, statistics show that, depending on the setting, up to 80% of these biopsies may turn out to be benign. with the aid of new imaging technologies, lesions may be diagnosed non-invasively and the number of the biopsies reduced [1]. reflectance confocal microscopy (rcm) is one these technologies, which is proven to be highly sensitive and specific in non-invasive diagnoses of melanomas [2,3] and basal cell carcinomas [4,5] with cellular-level resolution (0.5-1 um) and optical sectioning (1-3 um) capabilities. rcm provides images of enface sections down to the papillary dermis, which is often the depth that clinicians wish to examine. however, the current practice in rcm based diagnosis relies on visual examination, and therefore is subjective. in many cases, visually analyzing rcm images is more challenging compared to hematoxylin and eosin (h&e) stained histology, since the only source of contrast is reflectance (leading to gray scale images) contrary to the color contrast (purple and pink colors) in histology. moreover, due to speckle noise and optical aberrations, the image quality decreases as the depth increases. therefore, recognition tasks that are simple in histology can be challenging in rcm images. currently, only a relatively small group of “early adopter” clinicians can read and analyze these images reliably. training novice readers requires substantial effort and time and is currently a barrier against wider adoption of this technology. in order to address this need, machine learning based methods for quantitative analyses may be utilized. in this study, the development of tools such as automated dermal epidermal junction delineation and video-mosaicing are reported. in the first scenario, the problem of finding the dermal epidermal junction (dej), which is a trivial task in h&e stained histology but not in rcm images is addressed. this problem is particularly important because, most of the time, clinicians make their diagnostic decision using mosaics of rcm images collected at or around the dej level. in current practice, dej level is determined by the clinicians in a subjective manner, by going back and forth between the rcm images collected at different depths and examining abstracts | dermatol pract concept 2014;4(3):23 3 them. standardization of this procedure by automatically delineating the dej level in a quantitative manner will lead to the accuracy and repeatability of both image acquisition procedure and rcm based diagnosis. in order to automate dej delineation, we developed 2 algorithms, one for highlypigmented (type > iii) and another for lightly pigmented (type < iii) skin types, as they have different reflectance characteristics due to their varying melanin content. in stacks of dark skin, the algorithm aims to locate highly reflective basal cells at the dej level using an order statistics based filtering approach. in lightly pigmented skin, as the pigmentation level is lower, the basal cells are not bright enough to the detected reliably. in this case, we benefit from the fact that, blurring occurs in rcm images of deeper levels of skin, especially below the dej (due to optical aberrations). we model this phenomenon using a multi scale entropy filtering based method, and delineate the dej using this model. we tested the proposed dej delineation algorithms on 16 highly pigmented and 12 lightly pigmented skin stacks and compared our results against manual segmentation of expert readers. the algorithms can delineate dej with a mean ±std of 7.5±5 um in highly pigmented skin and 29±5.4 um in lightly pigmented skin. in another scenario, we showed the feasibility of creating mosaics out of rcm videos collected at a given level of skin, so called video-mosaicing6. video-mosaicing provides a tool for rapidly and adaptively imaging over large areas of skin which can be useful for examination of larger areas around dermal-epidermal and various other application such as delineating margins of lentigo maligna melanoma to guide surgical excision or non-melanoma skin cancer margins to guide mohs surgery. in our study, we showed that if (i) there is 25-50% overlap between consecutive frames and (ii) the imaging depth is kept constant, it is possible to convert these videos into high-quality mosaics of the imaged area. for this purpose we developed a computer program that can first find the identification tag in the video, crop out that region automatically and extract individual frames of the rcm video. then, we use freely available software (ice, microsoft) to stitch and blend the consecutive frames into a mosaic. we evaluated the proposed algorithm on videos of non-melanoma margins in mohs surgical wounds, lentigo maligna margins, malignant melanoma in situ, seborrheic keratosis, and benign lesions. a sample case of “malignant melanoma in situ” is presented in figure 1. several diagnostically-significant structures, such as atypical epidermal cells, epidermal disarray, perifollicular infiltration, roundish, dendritic, and pleomorphic pagetoid cells, dilated blood vessels and meshwork pattern with atypical cells can be clearly be identified in the resulting videomosaic. the results of this study suggest that in principle, a coverage rate of ~240-360 mm2/min is within reach for any confocal microscope with configuration similar to that (1 mm x 1mm fov, ~ 8 frames/ second) of the vivascope 3000. thus, video-mosaicing technology has the potential for much faster imaging of large areas compared to the current commercially-available rcm mosaicing approach, which typically images at ~14 mm2/ min. moreover, it enables the clinician to cover areas with any desired shape and along any desired path that may be determined real-time during acquisition. references 1. pellacani g, pepe p, longo c. reflectance confocal microscopy as a second-level examination in skin oncology improves diagnostic accuracy and saves unnecessary excisions: a longitudinal prospective study. br j dermatol 2014. epub ahead of print. doi: 10.1111/ bjd.13148, 2014 2. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy of pigmented skin lesions-improvement in melanoma diagnostic specificity. j am acad dermatol. 2005;53(6):979–85. 3. pellacani g, guitera p, longo c, et al. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol 2007;127(12):2759-65. 4. s. nori f, rius-díaz j, cuevas m. et al. sensitivity and specificity of reflectance-mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. j am acad dermatol 2004;51(6):923-30. 5. guitera p, menzies sw, longo c. in vivo confocal microscopy for diagnosis of melanoma and basal cell carcinima using a two-step method: analysis of 710 consecutive clinically equivocal cases. j invest dermatol. 2012;132(10):. management of bcc: is there a place for dermoscopy? aimilios lallas, 1 zoe apalla,2 giuseppe argenziano,1 caterina longo,1 elvira moscarella,1 iris zalaudek,3 1 skin cancer unit, arcispedale santa maria nuova, reggio emilia, italy. 2 first department of dermatology, aristotle university, thessaloniki, greece. 3 department of dermatology, university of graz, graz, austria. following the first descriptions of the dermatoscopic pattern of basal cell carcinoma (bcc) that go back to the very early years of dermatoscopy, the list of dermatoscopic criteria associated with bcc has been several times updated and renewed. up to date, the usefulness of dermatoscopy in differentiating pigmented and non-pigmented bcc from other skin tumors has been extensively demonstrated. in addition to its well-documented value in improving the diagnosis, dermatoscopy continuously gains an essential role in the management of bcc. 4 abstracts | dermatol pract concept 2014;4(3):23 dermatoscopy for choosing the appropriate treatment modality in our era, the therapeutic armamentarium of clinicians for bcc includes several surgical methods as well as non-surgical modalities. the choice of the appropriate treatment depends on several factors including the histopathologic subtype, the presence of pigmentation or ulceration, the tumor depth, the anatomical site and the presence of residual disease or recurrence. dermatoscopy has been shown to provide valuable information for several of the aforementioned parameters. the histopathologic subtype is the most crucial factor influencing the treatment choice for bcc. in the recent years, sbcc has been shown to respond perfectly to non-ablative treatments such as imiquimod or photodynamic therapy, prompting experts to recommend the latter modalities as first-line therapeutic options for this subtype. in contrast, conventional or mohs surgery is considered the choice treatment for nodular, infiltrative and sclerodermiform subtypes, while non-surgical treatments are much less effective. a recent study investigated the accuracy of dermatoscopic criteria for discriminating superficial from the other subtypes of bcc. this is particularly relevant in clinical practice, since the possible misinterpretation of a nodular or infiltrate tumor as superficial bcc could lead the clinician to the inappropriate choice of a non-surgical treatment modality. according to the results of the latter study, the presence of short fine telangiectasia, multiple small erosions and structures corresponding to dermo-epidermal pigmentation predict the superficial subtype. in contrast, detection of ovoid nests should lead clinicians to exclude the diagnosis of superficial bcc, while arborizing vessels and large ulcerations are also suggestive of nodular, sclerodermiform or infiltrative tumors. the presence of pigmentation is not routinely reported in histopathologic reports, since in the past it was not considered to influence the management and prognosis of the tumor. however, the use of pdt in bcc treatment restored the importance of pigmentation, since its presence was shown to influence the tumor’s response. in detail, case series studies reported a poor response of pigmented bcc to pdt, compared to non-pigmented variants (14% versus 62-100%). the low efficacy of pdt in pigmented tumors has been attributed to melanin, which appears to act as a competitive light-absorbing pigment, decreasing response rates. effectively, the presence of clinically undetectable pigmentation might represent a diagnostic pitfall for clinicians, forcing them to apply an ineffective treatment on a subset of bccs. this problem seems to be, at least partially, solved by the application of dermatoscopy, which was recently shown to reveal clinically undetectable pigmentation in approximately 30% of macroscopically non-pigmented bccs, enhancing clinicians to better select tumors potentially sensitive to pdt and minimizing treatment failures. dermatoscopy for assessing excision margins dermatoscopy, by providing a more accurate assessment of the true extension of the tumor, allows a more precise estimation of the required surgical margins, helping to minimize the recurrence rate. the discrimination of bcc vessels from the dermal plexus vasculature of the surrounding healthy skin can be based on the blurred appearance and dark red-topurple color of the surrounding sun-damaged skin, in contrast to the bright-red and focused vessels of the tumor. however, while the diagnostic significance of pigmented structures is unquestionable, the usefulness of vascular structures in defining the surgical margins is controversial. it has been suggested that arborizing vessels do not directly correspond to bcc cells, but represent feeding vessels of the tumor and may extend also to the perilesional skin. subsequently, if the extension of vessels is used to define the excision margins, there is the risk of unnecessarily removing healthy skin surrounding the bcc. although the latter hypothesis seems reasonable, it was supported by only one published case and, accordingly, the question whether vascular structures should be considered for defining surgical margins of bcc remains to be further elucidated. dermatoscopy for monitoring response to nonablative treatments a common problem associated with non-ablative modalities is the post-treatment evaluation, since at the end of a treatment cycle, the clinical morphology of the lesion often does not allow a reliable estimation of the possible presence of residual disease. dermatoscopy has the potential to improve the post-treatment evaluation of bcc following non-ablative procedures, minimizing therefore the risks of underor over-treatment of bcc. specifically, the disappearance of the dermatoscopic criteria of bcc after treatment has been shown to accurately predict histopathologic clearance, while the persistence of some bcc criteria correlates well with the presence of residual disease. according to the results of a recent study, the presence of arborizing vessels, ulceration or pigmented structures (e.g., blue-gray ovoid nests and maple leaf-like areas) accurately predicts residual disease, and should prompt the clinician to continue the treatment. instead, red/white structureless areas and/or superficial fine telangiectasia might represent equivocal features, since they do not always correspond to residual disease. effectively, detection of the latter criteria warrants close monitoring to recognize a possible recurrence of the bcc. abstracts | dermatol pract concept 2014;4(3):23 5 diagnosis of basal cell carcinoma with dermoscopy and reflectance confocal microscopy as the basis for direct referral to definitive surgery steven a. nelson, alon scope, ayelet rishpon, harold s. rabinovitz, margaret c. oliviero, susan d. laman, christine m. cole, yu-hui h. chang, david l. swanson background: in usual practice, the diagnosis of a suspected basal cell carcinoma (bcc) is typically confirmed by biopsy of the suspected lesion, followed by the histopathologic evaluation of tissue specimens via light microscopy, prior to referral to surgery. a physician’s presumptive diagnosis of bcc can be enhanced by identifying dermoscopic features typical for bcc. reflectance confocal microscopy (rcm) is also useful for diagnosis of bcc. it is conceivable a presumptive diagnosis of bcc supported by dermoscopic and rcm features could circumvent the need for biopsy prior to surgery, with confirmation of the diagnosis performed on the surgical specimen. objective: to investigate the feasibility of bypassing biopsy of suspected bcc and proceeding directly to excision or mohs surgery based on dermoscopic features alone, as well as when combined with rcm. in addition, we sought to compare the diagnostic accuracy for bcc based on prior rcm experience. methods: potential study subjects were identified during the routine office visit by the presence of one or more lesions for which bcc was suspected, thus warranting a biopsy. clinical, dermoscopic and rcm images were obtained prior to biopsy. eight clinicians with varying levels of expertise, each blinded to the histopathologic findings, individually interpreted the clinical, dermoscopic and rcm images. based on these interpretations, the clinicians chose between 4 hypothetical options: definite bcc (willing to send for definitive treatment without biopsy), other malignancy (perform biopsy for diagnosis), uncertain diagnosis (perform biopsy), and benign (do not biopsy). the choice decisions were made based on dermoscopy alone and subsequently on dermoscopy supplemented by rcm. results: of the 100 suspected lesions enrolled, 90 were verified as bcc on histopathology. the pooled sensitivity for direct referral to definitive surgery without biopsy was 67.59% for dermoscopy alone. adding rcm imaging increased the pooled sensitivity for direct referral to surgery to 76.53%. for the diagnostic decision to refer for treatment without biopsy, the pooled positive predictive value was 96.97% for dermoscopy alone and 98.64% for dermoscopy plus rcm. the sensitivities were generally higher for dermoscopy alone as the level of experience increased, although with a sacrifice to specificity. limitations: actual patient management was not affected in this study. physician behavior might be different if bona fide referrals were actually being made. the interpretations were made on image evaluation alone rather than at bedside, which might enhance accuracy. conclusions: dermoscopy provides a high positive predictive value for bcc diagnosis. the addition of rcm to dermoscopy increases diagnostic sensitivity. based on this study, from the standpoint of cost-effectiveness and patient convenience, dermoscopy and dermoscopy with rcm could be acceptable for direct-referral-to-surgery clinical decisions. what’s new in the diagnosis of lm? danica tiodorovic-zivkovic1, giuseppe argenziano2, aimilios lallas2, luc thomas3, a. ignjatovic4, md; harold rabinovitz5, elivra moscarella2, caterina longo2, rainer hofmann-wellenhof,6 iris zalaudek,6 1 clinic of dermatovenerology, clinical center of nis medical faculty, university of nis, serbia 2 skin cancer unit, arcispedale, s. maria nuova, irccs; reggio emilia, italy 3 lyon 1 university, dermatology department, centre hospitalier lyon sud, lyon, france 4 department of medical statistics, faculty of medicine, university of nis; nis, serbia 5 skin and cancer associates, plantation; florida, usa 6 department of dermatology and venerology, medical university of graz; graz, austria the term lentigo maligna (lm) refers to melanoma in situ arising on chronically sun-damaged skin with a flattened dermal-epidermal junction. it most commonly arises on the face although it is not limited to this anatomic region. little is currently known about the influence of age, gender and topography on the clinical and dermoscopic variability of lm. therefore, we retrospectively collected all consecutive cases of histopathologically proven facial and extra-facial lm diagnosed between january 2012 and january 2013 at 4 academic skin cancer clinics in france, italy, serbia and usa. the frequency of clinical and dermoscopic features of 201 cases of lm from 200 patients were assessed in correlation to specific anatomic sub-sites, patient’s age and gender. most cases were located on the face, with the cheeks being the most commonly affected sub-site. location on the cheek was significantly associated with female gender compared to all other sub-sites. dermoscopically, gray color irrespective of a specific pattern, was the most prevalent finding. the knowledge about the age, gender and site-related clinical features of lm associated with dermoscopic-gray colour may enhance the clinical recognition of lm. 6 abstracts | dermatol pract concept 2014;4(3):23 the elephant study philipp tschandl, harald kittler, iris zalaudek, giuseppe argenziano background: teaching dermatoscopy, or any other morphologic method, relies on two different approaches: a logical and a heuristic method. with the first, single elements are evaluated and results deducted to reach a decision; with the second, overall appearance is being rated and compared to other instances observed before. previous studies in the field of dermatology imply that a heuristic method may perform better when compared to strict algorithms such as the abcdrule when applied by lay people. it is not known whether in dermatoscopy comparing a heuristic to a more detailed logic teaching for medical students has any difference. aim: to compare the efficacy of two different teaching methods in regard to dermatoscopy. methods: medical students without prior contact to dermatoscopy were shown 50 lesions consisting of melanomas, nevi, basal cell carcinomas, seborrheic keratoses, dermatofibromas and benign vascular lesions and asked to diagnose and rate for chance of malignancy every lesion. afterwards the students were split into two groups and received either a logic or heuristic teaching within one hour. afterwards they were asked to do the same assessment of 50 lesions as in the beginning. diagnostic values as well as diagnostic accuracy (for malignancy) as measured by the auc of roc curves were compared. results: diagnostic accuracy improved by 0.21 (p<0.001) and 0.19 (p<0.001) in the heuristic and logic group respectively after the teaching, there was no difference between the two groups (p=0.585). percent of correct diagnoses increased similarly by +32.9% (p<0.001) and +35.7% (p<0.001) without difference between the groups (p=0.451). conclusion: only one hour of teaching is sufficient to largely improve diagnostic-dermatoscopic abilities of medical students. there is no significant difference in increase of diagnostic accuracy between teaching logic or heuristic when assessing classic dermatoscopic appearances of common lesions. untitled quiz | dermatol pract concept 2015;5(4):10 39 dermatology practical & conceptual www.derm101.com what is your diagnosis (figures 1-3)? a) verruca vulgaris b) actinic keratosis c) bowenoid papulosis d) seborrheic keratosis e) acanthoma high-grade squamous intraepithelial lesion of the oral commissure (bowenoid papulosis). a case and review erine a. kupetsky1, carlos a. charles2,3, joan mones4 1 palisades medical center dermatology, north bergen, nj, usa 2 derma di colore, new york, ny, usa 3 department of dermatology, weill medical college of cornell university, new york, ny, usa 4 ackerman academy of dermatopathology, new york, ny, usa citation: kupetsky ea, charles ca, mones j. high-grade squamous intraepithelial lesion of the oral commissure (bowenoid papulosis). a case and review. dermatol pract concept 2015;5(4):10. doi: 10.5826/dpc.0504a10 copyright: ©2015 kupetsky et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: erine a. kupetsky, do, msc, palisades medical center dermatology, graduate medical education, 7600 river road, north bergen, nj 07047. fax. 201 758-2740. email: eakderm@gmail.com figure 1. scanning magnification of the lesion on the oral commissure. [copyright: ©2015 kupetsky et al.] figure 2. higher magnification of the oral lesion. [copyright: ©2015 kupetsky et al.] figure 3. higher magnification of the slightly verrucous lesion shows hyperplasia with full-thickness atypia of squamous epithelial cells, evidence of loss of polarity, nuclear crowding, nuclear pleomorphism and increased mitotic figures indicative of high-grade squamous intraepithelial lesions. [copyright: ©2015 kupetsky et al.] mailto:eakderm@gmail.com 40 quiz | dermatol pract concept 2015;5(4):10 candidiasis [13] have also been described. histopathologically, lesions of oral bp were indistinguishable from squamous cell carcinoma in situ. a computerized search of the files of the ackerman academy of dermatopathology in new york, ny, from july 1999 through august 31, 2013, yielded 560 biopsies diagnosed as bp; however, only three patients with extragenital bp were identified, including the present case. this finding parallels that of the medical literature and indicates that extragenital bp is exceedingly rare. all three extragenital lesions from the ackerman academy were oral: two occurred on the lip and one, the present case, was located on the oral commissure. there were two males and one female, 22, 64 and 40 years of age, respectively. clinically, the lesions were thought to be lichen simplex chronicus, verruca vulgaris or pemphigus vulgaris, and bowenoid papulosis, respectively. histopathologically all lesions were indistinguishable from squamous cell carcinoma in situ. answer c) high-grade squamous intraepithelial lesion of the oral commissure (bowenoid papulosis) discussion bowenoid papulosis (bp) is characterized clinically by one or more small, verrucous papules usually located on the genitalia or thighs of younger patients [1]. rarely, bp has been reported on extragenital sites with or without concomitant genital lesions [2,3,4]. on the genitalia, bp clinically resembles condyloma acuminatum or lichen planus; however, histopathologically, bp is indistinguishable from squamous cell carcinoma in situ or bowen’s disease, hence, its designation “bowenoid papulosis,” a term coined by wade, kopf and ackerman, in 1978 [1]. bp has been shown to be associated primarily with the high-risk human papillomavirus (hpv) infection subtypes, 16 and 18; however, other high-risk subtypes, such as 31, 32 [5], 33, 35, 39, 53, and 67, have also been reported. many lesions of bp resolve with or without therapy and behave in a clinically benign fashion despite their malignant histology [7]; however, cases of squamous cell carcinoma in-situ and invasive squamous cell carcinoma have been reported to occur in association with lesions of bp, particularly in immunosuppressed patients [8,9.10]. risk of penile squamous cell carcinoma in men may be as high as 30% in patients with bp and increases incrementally with the duration of the disease [11]. patients with bp have also been reported to have concurrent hpv-associated dysplasia of the vulva and uterine cervix, of various degrees, including highgrade dysplasia, vin 3 and cin 3, respectively. our patient, a 22-year-old man, presented with verrucous papules centrally located within a central lichenified plaque on the oral commissure. the lesion was clinically thought to be a wart or a lesion of lichen simplex chronicus. histopathologically, the lesion showed full thickness epithelial atypia demonstrating increased numbers of mitotic figures, loss of polarity, and nuclear pleomorphism compatible with squamous cell carcinoma in situ (figures 1-3). in situ hybridization was positive for the high-risk subtypes 16/18 (figure 4). p16 immunoperoxidase stain demonstrated strong diffuse staining in the lower portion of the lesion with individually positive cells extending into the upper reaches of the epithelium (figure 5). oral bp is exceeding rare with only nine cases, to our knowledge, reported in the medical literature [11-19]. men were more commonly affected than women, and the ages ranged from 20 to 40 years. clinically, reported cases of oral lesions of bp in the medical literature are similar to those occurring on genital sites, namely, small verrucous papules [16]; however, erythematous velvety plaques [20], raised solitary nodules [11], leukoplakia or macules resembling figure 4. human papillomavirus in situ hybridization showing positive staining for the high-risk subtypes, 16/18 (red nuclear staining). [copyright: ©2015 kupetsky et al.] figure 5. p16 immunoperoxidase stain shows strong diffuse positive staining of the lower portion of the lesion with individually positive cells extending into the upper reaches of the epithelium (brown staining). [copyright: ©2015 kupetsky et al.] quiz | dermatol pract concept 2015;5(4):10 41 6. yoneta a, yamashita t, jin hy, et al. development of squamous cell carcinoma by two high-risk human papillomaviruses (hpvs), a novel hpv-67 and hpv-31 from bowenoid papulosis. br j dermatol. 2000;143(3):604-8. 7. de belilovsky c, lessana-leibowitch m. maladie de bowen et papulose bowénoide: données cliniques virologiques et évolutives comparatives. contracept fertil sex. 1993;21(3):231-6. 8. takayama a, ishiguro n, kawashima m. coexistence of bowenoid papulosis and bowen’s disease in a patient with systemic lupus erythematosus. j dermatol. 2012;39(7):646-9. 9. kreuter a, brockmeyer n, pfister h, altmeyer p, wieland u. increased human papillomavirus type 31 dna load in a verrucous high-grade intraepithelial neoplasia of a human immunodeficiency virus-infected patient with extensive bowenoid papulosis. br j dermatol. 2007;156:575-612. 10. del pino m, rodriguez-carunchio l, ordi j. pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma. histopathology. 2013;62(1):161-75. 11. daley t, birek c, wysocki g. oral bowenoid lesions: differential diagnosis and pathogenic insights. oral surg oral med oral pathol oral radiol endod. 2000;90(4):466-73. pmid 11027384 12. lookingbill dp, kreider jw, howett mk, olmstead pm, conner gh. human papillomavirus type 16 in bowenoid papulosis, intraoral papillomas and squamous cell carcinoma of the tongue. arch dermatol. 1987;123:363-6. 13. fornatora m, jones ac, kerpel s, freeman p. human papillomavirus-associated oral epithelial dysplasia (koilocytic dysplasia): an entity of unknown biologic potential. oral surg oral med oral pathol oral radiol endod. 1996;82:47-56. 14. kratochvil fj, cioffi ga, auclair pl, rathbun wa. virus-associated dysplasia (bowneoid papulosis?) of the oral cavity. oral surg oral med oral pathol. 1989;68:312-6. pmid 2549485 15. cox d, greenspan d, jordan rc, greenspan js. oral bowenoid papulosis in an hiv-positive male. oral surg oral med oral pathol oral radiol endod. 2006;102(4):431-2; author reply 432. 16. nakano e, kunisada m, ikeda t, et al. successful treatment with fluoropyrimidine ts-1 of human papillomavirus type 16-detected multiple oral bowenoid papulosis in an elderly woman. eur j dermatol. 2012;22(2):267-268. 17. rinaggio j, glick m, lambert wc. oral bowenoid papulosis in an hiv-positive male. oral surg oral med oral pathol oral radiol endod. 2006;101(3):328-32. 18. feldman sb, sexton fm, glenn jd, lookingbill dp. immunosuppression in men with bowenoid papulosis. arch dermatol. 1989;125(5):651-4. 19. pekar u, tilgen w, weidauer h, petzoldt d. [mucous membrane manifestations in hiv infection]. der hautarzt; zeitschrift fur dermatologie, venerologie, und verwandte gebiete. 1988;39(4):243-6. 20. lookingbill dp, kreider jw, howett mk, olmstead pm, conner gh. human papillomavirus type 16 in bowenoid papulosis, intraoral papillomas, and squamous cell carcinoma of the tongue. arch dermatol. 1987;123(3):363-8. 21. darragh tm, colgan tj, cox jt, et al. the lower anogenital squamous terminology standardization project for hpv-associated lesions: background and consensus recommendations from the college of american pathologists and the american society for colposcopy and cervical pathology. arch pathol lab med. 2012;136(10):1266-97. pmid 22742517 in 2012, a consensus panel of the college of american pathologists and the american society for colposcopy and cervical pathology recommended a change in terminology for bp from “bowenoid papulosis” to “high-grade squamous intraepithelial lesion.” they noted that bowenoid papulosis could be added to the diagnosis in parentheses if it could be verified that the lesion was small and had been excised. if verification could not be accomplished but the clinical setting was one of small papules, they wrote that, “a note stating that the differential diagnosis includes bowenoid papulosis may be warranted.” they also stated that, “bowenoid papulosis may have a lower risk of progression to cancer than cutaneous hsil [highgrade squamous intraepithelial lesion] found in larger plaques (bowen disease).” [21] treatment for oral bp is similar as that for genital bp and includes intralesional, topical or oral medication as well as surgical excision. fluoropyrimidine ts-1 (prodrug of 5-fu, gimestat (cdhp), and oteracil potassium (oxo)), 100 mg daily for three weeks was administered in one elderly woman with hpv-16 positive oral bp and resulted in regression of the lesion [16]. intralesional interferon alpha followed by topical imiquimod has also been reported as successful [17]. other treatments that have been used for genital bp and may be appropriate in oral lesions include 5-fu, podophylin, retinoic acid, and cidofovir. surgical modalities include simple excision, cryosurgery, laser vaporization, and electrodessication of small lesions. podophyllin is toxic in large amounts but has been used successfully for the treatment of oral hairy leukoplakia and could potentially be used to treat refractory bp [22,23]. our patient was treated successfully with 5-fluorouracil cream followed by imiquimod cream each applied five times per week for five weeks with two weeks between each medication. he remains lesion-free five months post treatment. references 1. wade tr, kopf aw, ackerman ab. bowenoid papulosis of the genitalia. arch dermatol. 1979;115(3):306-8. 2. johnson tm, saluja a, fader d, et al. isolated extragenital bowenoid papulosis of the neck. j am acad dermatol. 1999;41(5 pt 2):867-70. 3. olhoffer ih, davidson d, longley j, glusac ej, leffell d. facial bowenoid papulosis secondary to human papillomavirus type 16. br j dermatol. 1999;140(4):761-2. 4. purnell d, ilchyshyn a, jenkins d, et al. isolated human papillomavirus 18-positive extragenital bowenoid papulosis and idiopathic cd4+ lymphocytopenia. br j dermatol. 2001;144(3):61921. 5. degener am, laino l, pierangeli a, et al. human papillomavirus32-positive extragenital bowenoid papulosis (bp) in a hiv patient with typical genital bp localization. sex transm dis. 2004;31(10):619-22. pmid 15389001 42 quiz | dermatol pract concept 2015;5(4):10 podophyllin resin (25%) versus podophyllin resin (25%) together with acyclovir cream (5%) in the treatment of oral hairy leukoplakia. oral surg oral med oral pathol oral radiol endod. 2007;103;1:64-71. pmid 17178496 doi: 10.1016/j.tripleo. 2006.02.016 22. leitner j, hofbauer f, ackerl m. [poisoning with a podophyllincontaining wart-treating tincture]. dtsch med wochenschr. 2002;127(28-29):1516-20. 23. moura md, guimaraes tr, fonseca lm, et al. a random clinical trial study to assess the efficiency of topical applications of http://dx.doi.org/10.1016/j.tripleo.2006.02.016 http://dx.doi.org/10.1016/j.tripleo.2006.02.016 dermatology: practical and conceptual practical, conceptual or educational notes | dermatol pract concept 2014;4(3):4 31 dermatology practical & conceptual www.derm101.com actinic granuloma is a rare, idiopathic disorder of middleaged adults that always appears in sun-exposed skin [1,2]. it is a form of granulomatous dermatosis characterized by annular plaques with central atrophy and raised erythematous margins that are similar to those observed in granuloma annulare (ga) [3]. a 42-year-old man presented with a three-month history of an asymptomatic erythematous annular and serpiginous lesion on his forehead. there was no history of preceding trauma to the area. he was not on any medications. examination revealed an erythematous to brown annular to serpiginous plaque with central atrophy (figure 1). systemic examination revealed no abnormalities. results of full blood count and multiple biochemical analyses were unremarkable. skin biopsy showed normal epidermis with significant solar elastosis and granulomatous reaction in dermis, composed of numerous multinucleated giant cells. there was no area of necrobiosis. verhoeff von gieson stained sections revealed loss of elastic fiber in the center but the presence of fragments of elastin within the giant cells (figure 2). alcian blue staining was negative of mucin (figure 3). o’brien’s actinic granuloma is a chronic disease that affects middle-aged individuals of either sex who have a history of intense sun exposure [3]. it begins as small skinactinic granuloma reza yaghoob1, nastaran ranjbari2, amir feily3 1 department of dermatology, jundishapur university of medical sciences, ahvaz, iran 2 department of pathology, jundishapur university of medical sciences, ahvaz, iran 3 department of dermatology, jahrom university of medical sciences, jahrom, iran keywords: actinic granuloma, elastin fiber citation: yaghoob r, ranjbari n, feily a. actinic granuloma. dermatol pract concept. 2014;4(3):4. http://dx.doi.org/10.5826/ dpc.0403a04 received: april 1, 2014; accepted: june 5, 2014; published: july 31, 2014 copyright: ©2014 yaghoob et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: amir feily, department of dermatology, honari clinic, motahari st, jahrom, iran. tel. ++ 989177204638. email: dr.feily@yahoo.com figure  1. erythematous to brown annular-like plaque with signs of atrophy at the center. [copyright: ©2014 yaghoob et al.] colored or pink papules that quickly evolve into annular plaques. the border of the lesion extends slowly at the periphery while the center returns to a slightly atrophic appearance 32 practical, conceptual or educational notes | dermatol pract concept 2014;4(3):4 [1]. the pathogenesis of the condition is unknown; however, solar elastosis of sun damage is believed to be a triggering factor [1,3]. it is also reported in association with prolonged doxycycline [4]. o’brien, who initially described actinic granuloma in 1975 postulated that actinic damaged elastic fibers are the antigenic stimuli that trigger the inflammatory process leading to reparation of sun damaged connective tissue [5,6]. annular elastolytic giant cell granuloma (aegcg) was proposed by henke et al. and used to describe a clinically and histologically similar cutaneous eruption not limited to sun exposure and without solar elastosis [6]. these two conditions may represent a single diagnostic entity and have been grouped under the title “granular elastolytic giant cell granuloma” and proposed as a diagnosis for all annular lesions exhibiting a zonal histologic pattern that includes a granulomatous response with giant cells at the annular rim and centrally a loss of elastic fibers or solar elastotic material [7]. clinical differentials include facial lesions of granuloma annulare, necrobiosis lipoidica and annular sarcoid. these can be distinguished readily on histopathological features [8,9]. the characteristic histopathologic feature of actinic granuloma is multinucleated foreign body giant cells, which phagocytize the degenerated elastic fibers, a process known as elastophagocytosis. there is an absence of necrobiosis, such as facial necrobiosis lipoidica, or mucinosis, such as ga or sarcoid-like granuloma in the dermis at the solar elastosis level [1,3]. several forms of treatment with varying results have been reported, such as with chloroquine, cyclosporine, intralesional steroids, cryotherapy, methotrexate, isotretinoin, acitretin, pentoxiphylline, and retinoid psoralen + uva (repuva) [3,10]. spontaneous remission has been reported in some cases [3]. we report the present case of actinic granuloma because this condition is extremely rare, and patients often do not complain of it. consequently, any instances may not be brought to medical attention. our patient was advised to strictly sun protect. he was lost to follow up. references 1. gutierrez-gonzalez e, gomez-bernal s, alvarez-perez a, sanchezaguilar d, toribio j. elastolytic giant cell granuloma: clinic-pathologic review of twenty cases. dermatol online j. 2013;19(10):3. http://escholarship.org/uc/item/80q2b8gb. accessed june 5, 2014. 2. le corre y, steff m, prophette b, celerier p, maillard h. annular elastolytic giant-cell granuloma. ann dermatol venereol. 2010;137-532-5. 3. lazzarini r, rotter a, farias dc, muller h. o’brien’s actinic granuloma: an unusually extensive presentation. an bras dermatol. 2011;86:339-42. 4. lim ds, triscott j. o’brien’s actinic granuloma in association with prolonged doxycycline phototoxicity. australas j dermatol. 2003;442:67-70. 5. o’brien jp. actinic granuloma. an annular connective tissue disorder affecting sun and heat damaged (elastotic) skin. arch dermatol. 1975;111:460-6. 6. wang c-y, pujol rm, lee w-h, su w-p. annular elastolytic granuloma: a clinicopathologic study of 15 cases and a literature review. dermatol-sinica. 1996;14:51-64. 7. weedon d. elastolytic granulomas. in: weedon d. weedon’s skin pathology, 3rd ed. london: churchill-livingstone, 2010:188-9. 8. tee sl, chen qp, lim yl. necrobiosis lipoidica with elastophagocytosis on an unusual location. am j dermatopathol. 2014 apr 28 [epub ahead of print]. 9. kumari r, thappa dm, chougule a, adityan b. granuloma multiforme: a report from india. indian j dermatol venereol leprol. 2009;75_296-9. 10. stefanaki c, panagiotopoulos a, kostakis p, stefanaki k, petridis a. actinic granuloma successfully treated with acitretin. int j dermatol. 2005;44:163-6. figure 2. verhoeff von gieson stained sections revealed loss of elastic fiber in the center but presence of fragments of elastin within the giant cells. [copyright: ©2014 yaghoob et al.] figure  3. alcian blue staining was negative for mucinosis. [copyright: ©2014 yaghoob et al.] dermatology: practical and conceptual quiz | dermatol pract concept 2014;4(4):13 69 dermatology practical & conceptual www.derm101.com the patient a 54-year-old woman with immune thrombocytopenic purpura (itp) referred to our dermatology department with a three-week-history of a purple-colored lesion on her right arm. the patient was on treatment with oral prednisone at 20 mg/day for itp and levothyroxine at 25 mg/day for hypothyroidism. no topical treatment was prescribed or used before our consultation. dermatological examination revealed a 12.5 x 7.5 mm solitary purple papule located on the right upper extremity (figure 1). dermatoscopic examination disclosed bluish-red coloration (figure 2). surgical excision of the lesion was performed. histopathological examination of the lesion revealed nodular vascular proliferation in dermis, pronounced congestion and extravagated erythrocytes (figure 3). what is your diagnosis? what is your diagnosis? a solitary purple papule on the arm engin şenel1, yasemin yuyucu karabulut2 1 hitit university faculty of medicine, department of dermatology, çorum, turkey 2 mersin university faculty of medicine, department of pathology, mersin, turkey citation: şenel e. karabulut yy. what is your diagnosis? a solitary papule on the arm dermatol pract concept. 2014;4(4):13. http:// dx.doi.org/10.5826/dpc.0404a13 received: march 29, 2014; accepted: april 3, 2014; published: october 31, 2014 copyright: ©2014 şenel et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: engin şenel, md, bba, assistant professor of dermatology, hitit university faculty of medicine, department of dermatology, 19200 çorum, turkey. tel. +90 364 2230300; fax +90 364 2230323. email: enginsenel@enginsenel.com figure 1. a purple papule in the right upper extremity. (copyright: ©2014 şenel et al.) 70 quiz | dermatol pract concept 2014;4(4):13 please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical & conceptual. figure 2. bluish-red coloration in polarized dermatoscopy taken with dermlite ii pro hr, 3gen inc. (copyright: ©2014 şenel et al.) figure 3. nodular vascular proliferation in dermis, pronounced congestion and extravagated erythrocytes (h&e, x100). (copyright: ©2014 şenel et al.) dermatology: practical and conceptual 310 letter | dermatol pract concept 2019;9(4):16 dermatology practical & conceptual introduction basal cell nevus syndrome (bcns), also known as gorlin-goltz syndrome, is a rare autosomal dominantly inherited disorder characterized by the development of basal cell carcinomas (bccs) from a young age, multiple keratocysts, palmar and/or plantar pits, calcification of falx cerebri, and family aggregations. other criteria are skeletal anomalies, frontal bossing, cardiac and ovarian fibromas, medulloblastoma, glaucoma, and cleft lip/palate. the disorder is caused by an alteration of the sonic hedgehog signaling pathway, which results in constitutive activity and tumor cell proliferation. some germline pathogenic variants of these genes, including ptch1 and sufu, have been found and are responsible for clinical heterogeneity. only 2 case reports have described the occurrence of melanoma in patients with bcns, but neither reported the occurrence of collision lesions [1,2]. here we present clinical, dermoscopic, and histological features of a collision tumor of bcc and in situ melanoma in a patient with multiple bccs and bcns. case presentation a 48-year-old man came to our attention for multiple bccs of the face, arms, and trunk. family history revealed a sister with the genetic diagnosis of bcns and a history of ovarian fibromas and keratocysts. one brother with a cleft palate died at birth. the patient suffered from multiple kidney cysts, glaucoma, and scoliosis. at birth, he received the diagnosis of macrocephaly. palmar or plantar pitting was not evident. clinical examination revealed multiple lesions suggestive of bccs on the trunk. the patient also had multiple nevi. we observed an asymmetric partially pigmented lesion on in situ melanoma in collision with a basal cell carcinoma in a patient with basal cell nevus syndrome: clinical and dermoscopic features giulia briatico1, elvira moscarella1, andrea ronchi2, enrico maria procaccini1, giuseppe argenziano1 1 dermatology unit, university of campania, luigi vanvitelli, naples, italy 2 pathology unit, university of campania, luigi vanvitelli, naples, italy key words: basal cell carcinoma, melanoma in situ, basal cell nevus syndrome, collision tumors citation: briatico g, moscarella e, ronchi a, procaccini em, argenziano g. in situ melanoma in collision with a basal cell carcinoma in a patient with basal cell nevus syndrome: clinical and dermoscopic features. dermatol pract concept. 2019;9(4):310-312. doi: https://doi. org/10.5826/dpc.0904a16 accepted: april 25, 2019; published: october 31, 2019 copyright: ©2019 briatico et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, university of campania, luigi vanvitelli, dermatology unit, via sergio pansini, 5, naples, 80121, italy. email: elvira.moscarella@gmail.com letter | dermatol pract concept 2019;9(4):16 311 bcns prompted us to look dermoscopically at all lesions of the patient. we considered the development of melanoma in our patient as circumstantial, because melanoma and gorlin-goltz syndrome have different molecular pathogeneses. high prevalence in the caucasian population. when colliding with melanoma, the nodular component of a bcc could be misdiagnosed as a nodular component of the melanoma. in our case, the patient’s history of multiple bccs in the context of the lower back, approximately 1 cm in diameter, with a central amelanotic nodular component. upon dermoscopy, the lesion was asymmetrical, displaying a pink structureless area in the center with short, fine telangiectasias and an atypical network at the periphery (figure 1). histological examination showed a combined neoplasm. on one side, a proliferation of atypical melanocytes organized in a lentiginous pattern consistent with in situ melanoma was evident. on the other side, we observed a nodular bcc (figure 2). conclusions collision tumor of bcc and melanoma is an uncommon but well-described event. several cases of clinical and dermoscopic features of melanomas colliding with bccs have been reported in the literature. in fact, bcc is the more represented malignant tumor among collision lesions, simply because of its figure 1. (a) clinical appearance of the back of the patient, a 48-year-old man, showing multiple nevi and 1 asymmetrically pigmented lesion with a central amelanotic nodular component and brown pigmentation in the periphery. (b) dermoscopy, showing a pink structureless area in the center with short, fine telangiectasias and an atypical network at the periphery. [photograph by dermaview tre t medical. copyright: ©2019 briatico et al.] a b figure 2. (a) histological examination shows a combined neoplasm. (b) in detail, on one side, a proliferation of atypical melanocytes organized in a lentiginous pattern consistent with in situ malignant melanoma is evident. (c) on the other side, we see a nodular basal cell carcinoma (h&e, magnification ×10). [copyright: ©2019 briatico et al.] a b c 312 letter | dermatol pract concept 2019;9(4):16 references 1. gregoriou s,  kazakos c,  belyaeva h, et  al. hypomelanotic nail melanoma in a patient with gorlin syndrome. j cutan med surg. 2012;16(2):143-144. 2. kedem a, even-paz z, freund m. basal cell nevus syndrome associated with malignant melanoma of the iris. dermatologica. 1970;140(2):99-106. this case underlines once more the importance of total body clinical and dermoscopic examination. in situ melanoma in collision with bcc in bcns is an exceptional event; however, an accurate dermoscopic examination may serve to exclude concomitant malignancies, especially in view of systemic treatment for bccs. observation | dermatol pract concept 2012;2(1):8 45 primary adenomyoepithelioma of the skin – a variant of apocrine mixed tumor? elisabeth riedl, m.d.1,2, geoffrey j. gottlieb, m.d.3 1 department of dermatology, medical university of vienna, vienna, austria 2 department of dermatology, mount sinai school of medicine, new york, ny, usa 3 strata pathology services, lexington, ma, usa key words: adenomyoepithelioma, apocrine mixed tumor, myoepithelioma citation: riedl e, gottlieb gj. prmary adenomyoepithelioma of the skin – a variant of apocrine mixed tumor? dermatol pract conc. 2012;2(1):8. http://dx.doi.org/10.5826/dpc.0201a08. editor: harald kittler, m.d. received: november 3, 2011; accepted: december 6, 2011; published: january 31, 2012 copyright: ©2012 riedl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elisabeth riedl, m.d., department of dermatology, mount sinai school of medicine, one gustave l. levy place, box 1047, new york, ny 10029. email: elisabeth.riedl@meduniwien.ac.at. dermatology practical & conceptual www.derm101.com analogous to adenomyoepitheliomas of the breast, cutaneous adenomyoepithelioma is composed of two components, one being myoepithelial, the other ductal epithelial, and it lies in the spectrum of neoplasms having a “pure“ myoepithelioma at one end and a mixed apocrine tumor at the other. we present the case of a 53-year-old woman with a 3 cm nodular lesion on her left forearm that had been present for many years. histopathologic examination revealed a large lobulated neoplasm surrounded by a compressed fibrous pseudocapsule. most of the cells that constituted the lesion displayed myoepithelial differentiation arranged in solid sheets, cords, and solitary units. glandular and ductal structures with features of apocrine differentiation composed the second part of the neoplasm. the myoepithelial cellular component of the neoplasm stained for s100 protein and was negative for cytokeratin and carcinoembryonic antigen (cea). based on findings by conventional microscopy and immunohistochemistry, the neoplasm was classified as primary adenomyoepithelioma of the skin. abstract 46 observation | dermatol pract concept 2012;2(1):8 introduction adenomyoepithelioma has been described as a rare benign neoplasm that occurs almost exclusively in the breast. in the breast it is defined as a neoplasm composed of two structures, namely, tubules limited by an inner epithelial layer of ductlike cells and an outer layer with mostly clear myoepithelial cells [1]. apart from the breast, adenomyoepitheliomas have been described in the salivary glands and in the lung [2,3]. in the skin, these neoplasms seem to be exceedingly rare, with only few reports of adenomyoepitheliomas published to date [4-7]. we present the case of a 53-year-old woman with a clinically benign nodular cutaneous lesion that revealed histopathologic and immunohistochemical features of adenomyoepithelioma. case report a 53-year-old woman presented to her dermatologist with a 3 cm asymptomatic nodule on the left forearm. the lesion had been present for several years. a trauma at the site years previously was reported. the biopsy specimen consisted of a 2.5 x 1.9 x 1.5 cm tan ellipse of skin and contained a hard yellow nodule measuring 1.5 cm in greatest dimension. serial sections of tissue were prepared and stained with hematoxylin and eosin. examination of the sections at scanning magnification revealed beneath an intact epidermis a zone of fibrosis within the upper part of the dermis (figure 1 a, b). beneath the scar, there was a large, lobulated neoplasm, which for the most part was surrounded by a compressed fibrous pseudocapsule. each of the aggregates of neoplastic cells varied in sizes and shapes and some were large and nodular (figure 1a–c). at higher magnification, most of the cells that constituted the lesion displayed myoepithelial differentiation with polygonal and “plasmacytoid“ features (figure 2). the cells presented sometimes as solid sheets, but also as cords and solitary units. in places glandular and ductal structures were evident; in some areas apocrine-type secretion within glandular structures was found (figure 2 a–c). focally, the myoepithelial cells contained a clear cytoplasm (figure 2 d–f). in some areas cells were present within a myxoid stroma (figure 2 g–h). foci of cells with pleomorphic nuclei and mitotic figures were identified (figure 2 k–l). the myoepithelial cellular component of the neoplasm stained for s100 protein and was negative for cytokeratin and carcinoembryonic antigen (cea) expression. the positive cytokeratin stain highlighted the background epithelial/ glandular components of the neoplasm. stains for epithelial membrane antigen (ema) and hmb-45 were negative. conclusions we describe a cutaneous neoplasm composed of myoepithelial cells and a focal epithelial and glandular component. the s100 positivity indicates myoepithelial cells, while epithelial-glandular cells are negative for s100 protein expression. myoepithelial cells did not stain with anti-cytokeratin bodies. based on findings by conventional microscopy and immunohistochemistry, this neoplasm shows myoepithelial differentiation and focal epithelial lined tubules with features of apocrine secretion, findings that are consistent with the diagnosis of primary adenomyoepithelioma of the skin. while various adnexal neoplasms with a myoepithelial cellular component have been described in the skin, adenomyoepithelioma of the skin seems to be extremely rare. what are the criteria that distinguish adenomyoepithelioma from figure 1. histologic features of adenomyoepithelioma. the large lobulated neoplasm is located in the dermis and surrounded by a fibrous pseudocapsule (a). beneath an intact epidermis a superficial zone of fibrosis (b) is present. the neoplasm is composed of tubular and ductal structures as well as solid-appearing tumor areas set in a fibromyxoid stroma (c). [copyright: ©2012 riedl et al.] a b c observation | dermatol pract concept 2012;2(1):8 47 other benign cutaneous neoplasms with myoepithelial differentiation? while myoepithelioma is defined as a benign neoplasm consisting exclusively of myoepithelial cells embedded in a myxoid stroma, adenomyoepithelioma shows in addition to myoepithelial cells a second component displaying various degrees of epithelial-ductal differentiation [6,8]. mixed apocrine tumor, also termed ‘‘chondroid syringoma,’’ at the other end of the spectrum is a benign adnexal neoplasm that, in addition to apocrine epithelium, manifests various degrees of follicular and/or sebaceous differentiation [9]. clinically, myoepitheliomas occur usually in children and young adults and are located on the extremities, while mixed apocrine tumors affect older individuals and are usually found on the face [8,9]. the few cases of cutaneous adenomyoepitheliomas that have been described to date, including the present case, were described in older patients and were located on the extremities and on the trunk [6,7]. pleomorphic adenoma in the breast is regarded as the analogue to mixed apocrine tumor in the skin, while adenomyoepithelioma of the breast is defined as a neoplasm with nodular aggregations of clear myoepithelial cells that surround epithelial lined tubules. occasionally, the myoepithelial component predominates and loses the close association with epithelial structures [1]. figure 2. cutaneous adenomyoepithelioma is made up of different cellular components. in foci glandular and ductal structures are present; occasionally apocrine-type secretion within glandular structures is found (a–c). in other areas myoepithelial cells with clear cytoplasm predominate (d–f). in various areas cells are present within a myxoid stroma (g–h). within solid cell aggregation pleomorphic cells and mitotic figures are evident (k–l). [copyright: ©2012 riedl et al.] 48 observation | dermatol pract concept 2012;2(1):8 in the skin, the predominance of myoepithelial cells in relation to ductal epithelial structures lacking features of follicular and/or sebaceous differentiation separates this neoplasm from mixed apocrine tumor. therefore, myoepithelioma, adenomyoepithelioma and mixed apocrine tumor lie in the spectrum of neoplasms with pure myoepithelial differentiation at one end and apocrine-sebaceous-follicular differentiation at the other. the most important question for the patient is the biologic potential of such a lesion. while the chronic course in our patient and the majority of the histopathologic features suggest a benign neoplasm, foci of cells having pleomorphic nuclei and mitotic figures were present. both findings could indicate the potential for locally aggressive behavior and/or metastasis, as has been rarely described in adenomyoepitheliomas of the breast [2,10]. therefore, adenomyoepitheliomas of the skin should be completely excised, as has been recommended in the reported case. references tavassoli fa. myoepithelial lesions of the breast. myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. am j surg pathol. 1991;15(6):554–68. seifert g. are adenomyoepithelioma of the breast and epithelialmyoepithelial carcinoma of the salivary glands identical tumours? virchows arch. 1998;433(3):285–8. chang t, husain an, colby t, et al. pneumocytic adenomyoepithelioma: a distinctive lung tumor with epithelial, myoepithelial, and pneumocytic differentiation. am j surg pathol. 2007;31(4):562– 8. hartz ph. adenomyoepithelioma of sweat gland; report of a case. am j clin pathol. 1946;16(6):385–90. gubareva av. [adenomyoepithelioma of the skin]. arkh patol. 1965;27:32. wallis nt, banerjee ss, eyden bp, armstrong gr. adenomyoepithelioma of the skin: a case report with immunohistochemical and ultrastructural observations. histopathology. 1997;31(4):374–7. clarke le, seykora jt. primary cutaneous adenomyoepithelioma. j cutan pathol. 2007;34(8):654–7. hornick jl, fletcher cd. cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases. hum pathol. 2004;35(1):14–24. kazakov dv, belousova ie, bisceglia m, et al. apocrine mixed tumor of the skin (“mixed tumor of the folliculosebaceous-apocrine complex”). spectrum of differentiations and metaplastic changes in the epithelial, myoepithelial, and stromal components based on a histopathologic study of 244 cases. j am acad dermatol. 2007;57(3):467–83. huang cy, sheen-chen sm, eng hl, ko sf. adenomyoepithelioma of the breast. tumori. 2007;93(5):493–5. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(2):e2020042 1 dermatology practical & conceptual case presentation a single male in his twenties presented with itching and a foreign body sensation in his moustache. he reported active, oral sexual contact with a female acquaintance 3 days prior to the onset of symptoms. examination revealed yellowish deposits on the moustache and facial hair below the lower lip with erythema of the underlying skin (figure 1a). on dermoscopy, crab-shaped parasites with broad bodies and thick claws were spotted clutching the hair shafts. viable nits containing unhatched nymphs and empty translucent nit casings were also seen attached to proximal hair shafts (figure 1b). examination of the remaining hair-bearing skin including pubic area and eyelashes did not yield any findings. thus a diagnosis of phthiriasis of the facial hair was made. teaching point phthirus pubis or pubic louse can infest and survive in any hair-bearing skin [1]. entomodermoscopy serves as a rapid diagnostic tool [2]. references 1. chosidow o. scabies and pediculosis. the lancet. 2000;355(9206): 819-826. 2. chuh a, lee a, wong w, ooi c, zawar v. diagnosis of pediculosis pubis: a novel application of digital epiluminescence dermatoscopy. j eur acad dermatol venereol. 2007;21(6):837-838. pubic lice in facial hair puravoor jayasree,1 feroze kaliyadan,2 karalikkattil t. ashique3 1 dermatology, medical trust hospital, cochin, kerala, india 2 dermatology, college of medicine, king faisal university, saudi arabia 3 amanza health care, nahas skin clinic, perinthalmanna, kerala, india key words: lice infestations, pruritus, hair, phthirus, dermoscopy citation: jayasree p, kaliyadan f, ashique kt. pubic lice in facial hair. dermatol pract concept. 2020;10(2):e2020042. doi: https://doi. org/10.5826/dpc.1002a42 accepted: december 21, 2019; published: april 20, 2020 copyright: ©2020 jayasree et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. puravoor jayasree md, dnb, consultant dermatologist, medical trust hospital, cochin, kerala, india, 682016. email: jayasree5678@gmail.com figure 1. (a) facial hair showing yellowish deposits and erythema of underlying skin. (b) crab shaped pubic lice with thick claws grasping hair shafts along with brown (viable) and translucent (empty) nits seen on polarized dermoscopy. https://doi.org/10.5826/dpc.1002a42 https://doi.org/10.5826/dpc.1002a42 mailto:jayasree5678@gmail.com dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;2(2):1 1 binary world/bivalent logic it cannot be denied that the change from analog to digital technology had an enormous effect on how we communicate in daily life. for somebody who grew up within the last 20 years it is difficult to imagine a world without cell phones, email, or online communities. the digital revolution has not only changed our daily life, it also had a significant impact on the way we share information in medicine. we can share a huge amount of data conveniently and rapidly across vast distances. modern communication technologies eliminate distance barriers and permit the providing of health care from a distance (telemedicine). teledermatopathology, using digital pathology images (virtual microscopy), has been successfully launched for diagnosis, education, and research. however, the digital slide scanners that are required for virtual microscopy are expensive, and transmission of large digital images requires highspeed internet connections. ironically persons with limited access to expert dermatopathology services will benefit the most from telemedical applications but can afford it the least. the study by riedl et al in this issue of dermatology practical and conceptual explores the diagnostic accuracy of interactive teledermatopathology [1]. their method does not require that a dermatopathologist have physical “hands-on” involvement but provides real-time interactions between a technician and a dermatopathologist or between two dermatopathologists. it is an inexpensive and easy way to bring expert opinion to remote places either for education or for diagnosis (for example, to obtain a second opinion). apropos diagnosis it is amazing that a binary system of only two symbols, 0 and 1, that is used by all modern computers can replace complex analog data. the binary system is based on classic bivalent logic and the classic laws of thought, including the famous “law of the excluded middle,” which states that either any given proposition is true or its negation is true (“tertium non datur” or “no third possibility is given”). in the digital world it means that there is nothing between 0 and 1. a computer simply would not work if this logic principle is violated. if one applies this logic principle to semantics in general and to the language of dermatopathology in particular, it would mean that a neoplasm is either benign or malignant, it cannot be both at the same time. the statement that a lesion is a melanoma can be true or false, but it cannot be true and false at the same time. however, semantics is different from pure logic. statements made in natural language, especially when they predict events in the future or are open to interpretation, often defy the principles of bivalent logic. aristotle, the founder of bivalent logic, solved the problem by asserting that the principle of bivalence found its exception in propositions that predict events in the future: either there will be metastasis or there won’t, but today it is neither true nor false; but if one is true, then the other becomes false. according to aristotle, it is impossible to say today if the proposition is correct: we must wait for the contingent realization (or not). in other words, logic realizes itself afterwards. the complex of logical problems created by the attempt to predict future events by observing a piece of tissue under the microscope is explored in the readable essay by françois milette published in this issue of dermatology practical and binary world/bivalent logic harald kittler, m.d. citation: kittler h. binary world/bivalent logic [editorial]. dermatol pract conc. 2012;2(2):1. http://dx.doi.org/10.5826/dpc.0202a01. copyright: ©2012 kittler. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: harald kittler, md, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. e-mail: harald.kittler@meduniwien. ac.at. mailto:harald.kittler@meduniwien.ac.at. mailto:harald.kittler@meduniwien.ac.at. 2 editorial | dermatol pract concept 2012;2(2):1 conceptual [2]. however, we must not forget that making a diagnosis of melanoma in the absence of metastasis always includes prediction: by analogy we predict that a neoplasm with a given morphology will behave in an aggressive way. this means that even without counting mitosis or without measuring the invasion thickness we make a prognosis when we render the diagnosis of melanoma. this is problematic but unavoidable. there are different strategies to overcome this dilemma. one strategy is the application of 3-valued logic applied to vague or undetermined cases. in our example of melanoma it means that there are 3 categories: melanoma, nevus, and “ i do not know.” most of you will know that this was the strategy favored by bernie ackerman. another strategy is to apply a sort of “fuzzy logic” that allows for categories that are not well defined and open to interpretation. fuzzy logic is a form of many-valued logic; it is approximate rather than exact and may have truth values ranging between 0 and 1. in semantics fuzzy logic is often introduced by fuzzy terms such as “atypical spitz tumor” or “melanocytic tumor of uncertain malignant potential” (meltump). these terms are fuzzy purposely and have been established to prevent that a diagnosis is completely false. finally there is a third possibility to overcome the dilemma of uncertainty when predicting future events: to defy logic! the proponents of this solution apply terms like “metastatic spitz nevus” or “malignant blue nevus” defying the basic principle of logic that if one statement is true, then the other becomes false. everyone has to choose his own way of dealing with the dilemma of uncertainty and the choice will in part depend on your character. i am more inclined to choose solution 1 (which in part is idealistic and platonic) but i can understand the practical reasons of applying fuzzy logic (solution 2) to our problem, although i am convinced that this cannot be a final solution and one should try everything to remove the “fuzziness.” however, as a rational person i cannot choose an irrational solution like solution 3. reference 1. riedl e, asgari m, alvarez d, margaritescu i, gottlieb gj. a study assessing the feasibility and diagnostic accuracy of realtime teledermatopathology. dermatol pract conc. 2012;2(2):2. http://dx.doi.org/10.5826/dpc.0202a02. 2. milette f. predicting outcome: a fourfold delusion! dermatol pract conc. 2012;2(2):14. http://dx.doi.org/10.5826/dpc. 0202a14. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2013;3(4):1.2 3 the compendium (part 2) – b – balloon melanocyte: an abnormally large melanocyte that has abundant, clear cytoplasm and a normal nucleus. the ballooned appearance of these cells is due to abnormal melanosome development. ballooning: “intracellular edema” of epidermis and epithelial structures of adnexa, recognizably morphologically as swollen pale cytoplasm of affected spinous cells. rupture of decidedly ballooned keratocytes leads to formation of a pattern of epidermis that resembles a net and, therefore, is termed reticular alteration. when ballooning of keratocytes is extraordinary in itself or is so extensive that reticular alteration, has developed, necrosis of those cells is invariable, as is observed characteristically in infections by some viruses, such as those of herpes, pox, and coxsakie, but also of noninfectious diseases such as erythema multiforme, fixed drug eruption, and mucha haberman disease. the term ballooning, if unmodified, is enigmatic because ballooning refers also to the appearance of swollen cytoplasm in types of cells other than keratocytes, such as ballooned melanocytes of nevi and melanomas (balloon-cell nevus and balloon cell melanoma, respectively). basal lamina: is a structure, recognizable through an electron microscope, formed of extracellular material present along the basal surface of epithelial cells and around muscles, nerves, and capillaries. it separates these structures from adjacent connective tissue. basaloid cells: that by conventional microscopy, more or less resemble those of the basal layer of the epidermis. unfortunately, the term is applied to cells that look very different from one another such as germinative cells of trichoblastoma, and matrical cells of pilomatricoma. basement membrane: the term “basement membrane” derives from observations of findings by conventional microscopy in contrast to “basal lamina” (lamina densa), which pertains to changes discernible only by electron microscopy. the basement membrane is situated between dermis and epidermis, and is demonstrated most compellingly when stained by the method of periodic acid-schiff. basket-woven orthokeratosis: is a thickened cornified layer whose cells are arranged in a fashion that resembles the pattern in a woven basket. the pattern is the one observed in the stratum corneum of histologic sections taken from normal skin anywhere on the integument except for palms and soles, sites at which corneocytes typically are organized compactly. in patholologic states, a cornified layer may be thickened but still maintain its basket-woven character as happens secondary to infectious diseases like tinea versicolor (caused by the fungus malassezia furfur and/or glabrosum) and verruca plana (caused by papilloma virus). dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 2 bruce j. hookerman1 1 dermatology, st. louis, missouri, usa citation: hookerman j. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 2. dermatol pract conc. 2013;3(4):1.2. http://dx.doi.org/10.5826/dpc.0304a1.2. copyright: ©2013 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bhookerman@att.net. 4 review | dermatol pract concept 2013;3(4):1.2 basket-woven pattern of the stratum corneum: the normal appearance of the epithelial (and infundibular) cornified layer (except for that on the palms and soles) in sections of skin viewed by conventional microscopy. benign: refers to the behavior of a proliferation, namely, lack of capability to cause death either by destruction of tissue locally or by metastasis. the term should not be used to describe characteristics cytopathologic, i.e., “benign trichoblasts”, because cells examined by conventional microscopy can not be identified reliably as being benign or malignant. nuclei of those cells, however, can be described accurately as being either monomorphic or pleomorphic. a judgment about nature benign is made on the basis of both the pattern architectural (silhouette) and the attributes cytopathologic of it, that determination being predicated ultimately on experience previous with the behavior biologic of other proliferations of appearance similar. in general, the silhouette of a proliferation is the best gauge if its conduct biologic, the silhouette being the representation morphologic of that behavior. benign melanoma: an oxymoron because melanoma, by definition, is a malignant neoplasm, i.e., it has the potential to kill by metastasis or local destruction. in short, there is no benign melanoma. b-fringe: refers to the boundary between the bulbar supramatrical zone below and the bulbar keratogenous zone above. it is defined by loss of trichohyalin granules from henle’s layer. at this site, several characteristic morphologic changes occur in the bulb of a follicle, to wit, henle’s layer of the inner sheath begins to cornify, the cuticle of the inner sheath acquires trichohyalin granules, and the outer sheath becomes multilayered. it is at this site that preparation for cornification of the hair cortex begins. b-fringe is situated below a-fringe (adamson’s fringe), which marks the end of the keratogenous zone. “b” stands for “below” adamson’s fringe. biopsy: refers specifically to the removal of tissue from a living person and to examination by microscopy of sections cut from the specimen of that tissue, usually for purposes of diagnosis. there are several types of biopsy of skin, excision in toto, excision in parte (erroneously termed “incisional”), punch, and shave (also called horizontal or tangential) using a knife blade or razor blade and variants such as saucerization (a variant of shave using a razor blade which is bowed for deeper removals.) each of these biopsy techniques has value and lack there of. (see shave biopsy; see sauceratization) blister: a collection of fluid, irrespective of size, within the epidermis, i.e., pemphigus vulgaris, or immediately beneath the epidermis, i.e., bullous pemphigoid, or, episodically, in both sites concurrently, i.e., some examples of erythema multiforme. the terms, vesicle and bulla, are subsumed by the word, blister. borderline melanoma: a notion introduced by richard j. reed for a melanocytic proliferation deemed by him to elude diagnosis either as nevus or melanoma. “borderline” malignancy implies a state somewhere between “benign” and “malignant.” in our opinion, there is no such region and in the realm of melanocytic proliferations only four diagnoses are possible, to wit, nevus, melanoma, melanoma in association with a nevus, and “i don’t know and the lesion should be removed completely.” of course, an explanation of why one does not know should be included. “borderline melanoma” is a violation of principles fundamental to classic pathology and an evasion from admitting that one really does not know. in 1975, reed wrote that pigmented spindle cell nevus “may represent a variant of borderline melanoma.” bowen’s disease (see in-situ) bowenoid: means resembling bowen’s disease histopathologically, i.e., a squamous-cell carcinoma in situ characterized by the presence of atypical keratinocytes throughout much of the thickness of a thickened epidermis. nuclei are crowded and vary from small and monomorphous to large and strikingly pleomorphic; some keratocytes may be multinucleate, and others may be in mitosis. cytoplasm of neoplastic cells may be pale. bowenoid papulosis refers to histopathologic findings like those in bowen’s disease within a lesion, situated usually on genital skin, whose silhouette is that of condyloma acuminatum, the squamous-cell carcinoma in situ having been induced by papillomavirus. the designation “bowenoid” also is applied to sebaceous carcinoma in situ on an eyelid and to an uncommon expression of trichoblastic (basal-cell carcinoma). the problems with the word “in-situ” will be discussed under “in-situ”. bulbous: resembling a bulb in shape-as do the bulb of a flower or an onion, the lowest part of a hair follicle, and the aggregations of neoplastic cells in the lower part of a stereotypical verrucous carcinoma. bulge: denotes a protruding part, an outward curve, or a swelling. in cutaneous embryology and histology, each of three hemispherical protrusions that develop on a side of an embryonic follicle is referred to as a bulge. those protrusions, from top to bottom, represent a future apocrine gland and duct, a future sebaceous gland and duct, and a future site for attachment of smooth muscles of hair erection. in fetal and post-fetal life, the so-called bulge (this differs from “the bulge” referred to above relating to the “embryonic follicle”) of a follicle is actually several bulges of isthmic and stem epithelium, each of which acts as a site for attachment of review | dermatol pract concept 2013;3(4):1.2 5 a fascicle of muscle of hair erection. that distinctive structure, which is the one meant when the term “the bulge” is used colloquially and incorrectly, is known also as der wulst, which in german means “the bulge.” bulges seem to have no role in the follicular cycle. bulla: a blister that is more than 1.0 cm in greatest diameter. like its smaller analogue, i.e., a vesicle, a bulla may be situated within the epidermis, as in severe allergic contact dermatitis beneath the epidermis, as in cicatrical pemphigoid, or in both sites together in the same lesion, as in some responses to the “bite” of an insect. burrow: a tunnel, usually in the cornified layer or spinous zone of the epidermis, fashioned by a parasite. the female mite of sarcoptes scabiei deposits her eggs and dumps her feces in a burrow fashioned by her in the stratum corneum and from which site she dines on fluid sucked from the viable epidermis. the activity of the mite and progeny of it, namely, larvae and nymphs, conducted within a burrow of scabies, namely, ingestion and defecation, gives rise to intense pruritus. the larva or “creeper” of ancylostoma braziliense, the cause of cutaneous larva migrans, lives in a tunnel created by serpentine movements of it through the lower most part of the epidermis. dermatology: practical and conceptual quiz | dermatol pract concept 2014;4(3):15 75 dermatology practical & conceptual www.derm101.com below find the answer to the quiz by costa et al. presented in the previous issue of dermatology practical & conceptual (http:dx.doi.org/10.5826/dpc0402a13). diagnosis trichoepithelioma congratulations to dr. napolitano, who was the first to send us the correct answer! an atypical pigmented lesion—answer claudia costa1, franco palmisano1, massimiliano scalvenzi1 1 department of dermatology, university of naples federico ii, naples, italy citation: costa c, palmisano f, scalvenzi m. an atypical pigmented lesion. dermatol pract concept. 2014;4(3):15. http://dx.doi. org/10.5826/dpc.0403a15. copyright: ©2014 costa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: massimiliano scalvenzi, via pansini 5, 80129 naples. italy. email: scalvenz@unina.it dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2013;4(1):8 53 background and objectives zalaudek et al. [1] discussed the age-related prevalence of dermatoscopy patterns in acquired melanocytic nevi of the trunk and extremities excluding palms and soles. they concluded that the globular pattern predominated in the youngest age group, while the reticular and/or homogeneous patterns were more common in older individuals. in nonwhite populations including japanese people, acral volar skin is the most prevalent site for malignant melanoma. about half of all cutaneous melanomas in japanese patients are seen in acral skin [2]. because japanese media, including age-related prevalence of dermatoscopic patterns of acral melanocytic nevi reiko suzaki1, sumiko ishizaki1, hitoshi iyatomi2, masaru tanaka1 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of applied informatics, faculty of science and engineering, hosei university, tokyo, japan keywords: melanocytic nevi, palms, soles, age, dermatoscopy citation: suzaki r, ishizaki s, iyatomi h, tanaka m. age-related prevalence of dermatoscopic patterns of acral melanocytic nevi. dermatol pract concept. 2014;4(1):8. http://dx.doi.org/10.5826/dpc.0401a08 received: july 21, 2013; accepted: october 21, 2013; published: january 31, 2014 copyright: ©2014 suzaki et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: reiko suzaki, m.d., department of dermatology, tokyo women’s medical university medical center east, 2-1-10 nishi-ogu, arakawa-ku, tokyo, 116-8567, japan. tel: +81 3 3810 1111; fax: +81 3 3894 1441. e-mail: reikosa@rmail.plala.or.jp the objective of this study was to evaluate the relation between age and dermatoscopic features of acral nevi. we evaluated 159 dermatoscopic images of melanocytic nevi from 146 individuals filed at the dermatoscopy outpatient clinic of tokyo women’s medical university medical center east between april 2006 and march 2009. all images of melanocytic lesions on acral volar skin that showed a clear-cut dermatoscopic pattern of an acral nevus at the time of initial observation were included. the dermatoscopic patterns of all images were retrospectively examined in a blinded fashion according to the standard dermatoscopic classification criteria for acral melanocytic nevi. images were classified using 15 structural variants of the parallel furrow pattern. these variants were then re-classified into two groups; the “single” line group and “double” line group. patients of the double line group (age, 25.5 years) were significantly younger than those of the single line group (32.4 years). there was no significant difference in the age-related predominance between the solid line patterns and dotted line patterns. there was a significant age difference between patients with nevi showing the crista dotted pattern (mean age 24.9 years) and patients with nevi without the crista dotted pattern (mean age 34.6 years). we conclude that the double line variant of the parallel furrow pattern and crista dotted pattern, which probably correspond to the congenital type acral nevus, tend to be more common in young patients. abstract 54 research | dermatol pract concept 2013;4(1):8 nevus within each of the age groups, absolute numbers and percentages are provided as frequencies. results demographics of the study population and general results we examined 159 melanocytic nevi in a study population of 146 individuals consisting of 47 men (32.2%) and 99 women (67.8%). the mean age of the study population was 29.8 years (range, 1-80 years). the distribution of nevi in the different age groups was 46 nevi in 0-15 years group, 29 nevi in the 16-30 years group, 55 nevi in the 31-45 years group, 20 nevi in the 46-60 years group and 9 nevi in the > 60 years age group. the mean age of each age group was 7.3, 26.8, 36.9, 50.9 and 70.0 years, respectively. the number of nevi on the palm was 9 (5.7%) while number of nevi on the plantar surface of the foot was 150 (94.3%). in the parallel furrow group, the single solid line variant was identified in 74 lesions, of which 34 were prototypical single solid line variant only (figure 1a), 32 were associated with crista dotted pattern (regular dots/globules on the center of the ridges) (figure 1e), 1 was associated with crista reticulated pattern (reticular pigmentation on the ridges) (figure 1f) and 7 were associated with lattice-like pattern (figure 1g). the single dotted line variant was seen in 27 lesions, of which 12 were prototypical single dotted line variant only (figure 1b), 14 were associated with the crista dotted pattern and 1 was associated with the crista reticulated pattern. the double solid line variant was identified in 34 lesions, of which 17 were prototypical double solid line variant only (figure 1c) and 17 were associated with the crista dotted pattern. the double dotted line variant was seen in 22 lesions, of which 15 were prototypical double dotted line variant only (figure 1d) and 7 were associated with the crista dotted pattern. the crista dotted pattern was seen in only 2 lesions. the total numbers of each group were 101 nevi in the single line group and 56 nevi in the double line group. age-related distribution of the structural dermatoscopic types of acral melanocytic nevi the double line group pattern was the most predominant in the youngest age group (41.1%), but its frequency decreased with increasing age. on the other hand, the single line group was the most common (37.6%) in the third age group. the mean age of the double line group (25.5 years) was significantly lower than that of the single line group (32.4 years). age differences between subjects of the solid and dotted line patterns we also analyzed differences in the age of patients with the solid and the dotted line patterns. the mean age was 31.5 tv and printed media, often emphasize this fact, recent recognition of acral melanoma has been increasing among the japanese. one aspect of this awareness is wariness about the nature of any pigmented lesion that appears on the acral volar skin, with consequent increase in the number of consultations to dermatologists. on the other hand, acral melanocytic nevi are not rare and have an approximate incidence of 7 to 9% of the general japanese population [3]. therefore, it would be helpful to understand the dermatoscopic variations of acral melanocytic nevi. based on dermatoscopic examination of acral melanocytic nevi, four different variants of parallel furrow patterns (single solid line, single dotted line, double solid line, double dotted line) and other variations (crista dotted pattern, crista reticulated pattern) are recognized (figure 1). the purpose of the present study was to investigate the relationship between age and dermatoscopic features of acral nevi. methods in this epidemiological observational study, dermatoscopic images filed in the tokyo women’s medical university medical center east database (tokyo, japan) between april 2006 and march 2009 were evaluated. we retrieved all images of melanocytic lesions located on the acral volar skin that showed a clear-cut dermatoscopic pattern of an acral nevus at initial observation. dermatoscopic patterns of all images were retrospectively examined in a blinded fashion according to the standard dermatoscopic classification criteria for the acral melanocytic nevi. we classified the retrieved images into 15 structural patterns as shown in table 1. we then re-classified these 15 structural patterns into two groups, namely, the “single” line group and “double” line group. the single solid line (pigmented solid lines just on the furrow, figure 1a) and single dotted line variants (pigmented dotted lines just on the furrow, figure 1b) were classified into the “single” line group. the double solid line (pigmented solid lines facing each other right across the furrows, figure 1c) and double dotted line variants (pigmented dotted lines facing each other right across the furrows, figure 1d) were classified into the “double” line group. all cases of the lattice-like pattern (figure 1g) in this study included a single solid line in the furrow, and were therefore classified into the “single” line group. unclear images were excluded from subsequent analysis. cases with regular fibrillar patterns (figure 1h) were included in the study only when they demonstrated parallel furrow patterns by oblique view dermatoscopy. because the fibrillar pattern can be regarded as an artifactual expression of the parallel furrow pattern, as reported by maumi et al. [4], oblique view dermatoscopy alters the regular fibrillar pattern into a parallel furrow pattern. the study participants were categorized into one of five age groups: 0-15 years, 16-30 years, 31-45 years, 46-60 years and > 60 years. for each dermatoscopic type of melanocytic research | dermatol pract concept 2013;4(1):8 55 a b c d e g f h figure 1. the definitions and representative dermatoscopic images of the main structural patterns. (a) single solid line variant. (b) single dotted line variant. (c) double solid line variant. (d) double dotted line variant. (e) single solid line variant + crista dotted variant. (f) single solid line variant + crista reticulated variant. (g) latticelike variant. (h) fibrillar variant. [copyright: ©2014 suzaki et al.] 56 research | dermatol pract concept 2013;4(1):8 mean age for patients with nevi with crista dotted pattern was younger than those without the crista dotted pattern. these results showed significant age differences between nevi with crista dotted pattern and those without crista dotted pattern. discussion the following are the major findings of our study. first, the group of patients with the double pattern (solid or dotted) was significantly younger than the group of patients with the single pattern; 41.1% of patients in the double pattern group were the youngest in the entire study group. second, there were no significant differences in age-related prelavence between the solid line group and the dotted line group. third, patients displaying the crista dotted pattern were younger than those without the crista dotted pattern. based on these observations, we consider that the dermatoscopic patterns of the double solid line, double dotted line and crista dotted pattern are characteristic dermatoscopic features of early-onset nevi, including congenital nevi. the oblique view dermatoscopy at an angle could change the solid line pattern into a dotted line pattern. the solid line pattern can be considered a variant of the dotted line pattern. thus, there should be no significant difference in age-related predominance between the solid and dotted line patterns. miyazaki et al. [5] indicated that the fibrillar pattern is caused by an oblique arrangement of melanin pigment in the slanting cornified layer. the slanting is considered to be produced by mechanical pressure from body weight. of note, even in the fibrillar pattern, the nest of nevus cells is mainly located in the crista profunda limitans, as they are in the parallel furrow pattern. therefore, the fibrillar pattern can be regarded as an artifactual expression of the parallel furrow pattern. these are the reasons for considering the parallel furrow pattern as the prototype of major dermatoscopic patterns seen in acral nevi. in fact, the three major dermatoscopic patterns seen in acral nevi, namely the parallel furrow, latticelike and the fibrillar patterns, are essentially the same and are not related to the age of the patients but to the anatomic sites. our personal experience with acral melanocytic nevi, based on daily clinical practice, concurs that the double dotted line or crista dotted variants are observed more commonly in younger patients. in contrast, the single line variants are more frequent in older individuals. therefore, it is important to consider the age-related prevalence of the several parallel furrow pattern variants in acral melanocytic nevi. altamura et al. [6] reported their follow-up data of dermatoscopic patterns of acral nevi. in their study, they defined any change from a given benign pattern at baseline into a different pattern at the follow-up visit as substantial variation. a total of 230 acquired acral melanocytic nevi were followedup digitally for 6, 12, 18 and 24 months. dermatoscopic years for the group of patients showing the single solid line pattern and 34.9 years for the single dotted line pattern group, with no significant difference between the two groups. similarly, the mean age of patients showing the double solid line pattern (24.8 years) was not significantly different from that of the double dotted line pattern group (26.6 years). age differences between nevi with crista dotted pattern and nevi without crista dotted pattern we also analyzed the age differences between patients with nevi with crista dotted pattern and those without crista dotted patterns. the mean age was 24.9 years for the nevi with crista dotted pattern, and 34.6 years for the nevi without crista dotted pattern. for both the single and double groups, the table 1. number of structural patterns in all dermatoscopic images dermatoscopic pattern n % single solid line variant only 34 21.4 single dotted line variant only 12 7.5 double solid line variant only 17 10.7 double dotted line variant only 15 9.4 crista dotted pattern only 2 1.3 crista reticulated pattern only 0 0 single solid line variant with crista dotted pattern 32 20.1 single solid line variant with crista reticulated pattern 1 0.6 single dotted line variant with crista dotted pattern 14 8.8 single dotted line variant with crista reticulated pattern 1 0.6 double solid line variant with crista dotted pattern 17 10.7 double solid line variant with crista reticulated pattern 0 0 double dotted line variant with crista dotted pattern 7 4.4 double dotted line variant with crista reticulated pattern 0 0 latticelike pattern 7 4.4 total number of cases 159 100 research | dermatol pract concept 2013;4(1):8 57 the limitations of the present study are the relatively small sample size, single medical center based study, single ethnicity, referral bias in the data set, cross-sectional and retrospective designs. in conclusion, the double line variants of the parallel furrow pattern and crista dotted pattern, which probably correspond to the congenital type acral nevus, tend to be more common in young patients. references 1. zalaudek i, grinschgl s, argenziano g, et al. age-related prevalence of dermoscopy patterns in acquired melanocytic naevi. br j dermatol. 2006;154(2): 299-304. 2. ishihara k, saida t, yamamoto a. updated statistical data for malignant melanoma in japan. int j clin oncol. 2001;6(3):109-16. 3. saida t. malignant melanoma on the sole: how to detect the early lesions efficiently. pigment cell res. 2000;13 suppl;8:135-9. 4. maumi y, kimoto m, kobayashi k, et al. oblique view dermoscopy changes regular fibrillar pattern into parallel furrow pattern. dermatology. 2009;218(4): 385-6. 5. miyazaki a, saida t, koga h, et al. anatomical and histopathological correlates of the dermoscopic patterns seen in melanocytic nevi on the sole. j am acad dermatol. 2005;53(2):230-6. 6. altamura d, zalaudek i, sera f, et al. dermoscopic changes in acral melanocytic nevi during digital follow-up. arch dermatol. 2007;143(11):1372-6. changes over time were observed in 42 of the 230 acral nevi (18.3%), and the frequency of change increased linearly over time. minimal variations in the parallel furrow pattern were the most common dermatoscopic changes over time (seen in 10 of the changing 42 nevi, 24%). they also reported that one case changed over time from single solid line pattern to a double solid line variant, however, the authors did not provide a detailed description of these minimal changes, and it is not clear if some cases changed over time from a double to single pattern. the observations in this study raise further interesting questions regarding nevi evolution and age-related changes in histopathological findings in acral nevi. understanding age-related patterns of acral nevi could perhaps lead to better evaluation of dermatoscopic structures and should be helpful in the differential diagnosis from melanoma. based on the data of zalaudek et al. [1] and results of the present study, we conclude that the double line and the crista dotted acral patterns correspond to globular nevi seen on non-acral skin and that the single line acral pattern is equivalent to reticular nevi seen on non-acral skin. the double line variant of the parallel furrow pattern and crista dotted pattern seem to correspond to the congenital type nevi, similar to the suggestion of zalaudek et al. that the globular nevi correspond to congenital type nevi. untitled review | dermatol pract concept 2015;5(2):1 1 dermatology practical & conceptual www.derm101.com 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 8 (p-s). dermatol pract concept 2015;5(2):1. doi: 10.5826/dpc.0502a01 copyright: ©2015 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, md, 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@ aol.com the compendium (part 8) – p – paget cell: specific for mammary paget’s disease and extramammary paget’s disease, is typified by a large, round, or plump oval nucleus and pale-staining cytoplasm, the latter being more abundant in extramammary paget’s disease because there it is replete with acid mucopolysaccharides that are demonstrable by staining with hematoxylin and eosin and better yet with stains specialized for them. paget cells of mammary paget’s disease and extramammary paget’s disease have several attributes in common, but they are dissimilar, just as are mammary paget’s disease and extramammary paget’s diseases themselves, despite the fact that they share the word “mammary” and the name paget’s disease.” paget pattern: is scatter of cells constituent of mammary paget’s disease and extramammary paget’s disease throughout an epithelium, usually epidermal but also adnexal. pagetoid cell: is one that resembles the cell constituent of paget’s disease especially of extramammary paget’s disease by having a large roundish nucleus and abundant pale cytoplasm. it is found, for example, in some lesions of melanoma and of bowen’s disease. pagetoid melanocyte: an abnormal melanocyte with abundant pale cytoplasm, but less abundant than in a ballooned melanocyte and such cells may be dispersed singly or in nests within the epidermis. they resemble the pale cells found within the epidermis of lesions of mammary and extramammary paget’s disease. pagetoid melanocytes may contain dusty particles of melanin. if they do not, reliable differentiation from true paget cells depends on histochemical techniques. paget cells are dopa negative and contain either neutral mucopolysaccharides (in mammary disease) or sialomucin (in extramammary disease). pagetoid melanocytes are dopa-positive and do not contain mucin. they are usually seen in melanomas, especially those on the trunk and proximal parts of the extremities, but also are found in some melanocytic nevi, especially combined melanocytic nevi. pagetoid melanocytic proliferation: a phrase coined by wallace h. clark, jr. and advocated by a panel of dermatopathologists appointed by the national institutes of health to forge definitions of terms employed in the language of melanocytic neoplasia, they being published in 1992. in brief “pagetoid melanocytic proliferation” was yet another attempt at evasion from a diagnosis by microscopy conventional of “melanoma in situ” and, like all the others, has faded into oblivion. pagetoid pattern: is descriptive of scatter of cells proliferative throughout an epithelium, usually epidermal but also adnexal, in the manner, that it is seen in mammary paget’s disease and extramammary paget’s disease, e.g., in melanoma, bowen’s disease, and mycosis fungoides. thus pagetoid cells may or may not appear in pagetoid pattern in a given histopathologic section (i.e., melanoma). pale cell: is one, whose cytoplasm is deficient in intensity of color, i.e., pallid, as seen in some examples of apocrine (pale-cell) hidradenoma, in pale cell acanthoma, and in pale cell acanthosis. (see clear cells) dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 8 (p-s) bruce j. hookerman1 2 review | dermatol pract concept 2015;5(2):1 papilloma: refers to nipple-like projections above the skin surface as a consequence of extensions outward of dermal papillae (papillomatosis) that may or may not be covered by thickened epidermis. cutaneous papillomas include those that have fibrous cores, i.e., fibroepithelial papillomas, and those that consist mostly of papillated epithelium, i.e., condylomata. the term “verrucous” sometimes is used synonymously with papillomatous, but the tips of dermal papillae in verrucous lesions tend to be pointed (digitated), i.e., verruca vulgaris, rather than rounded (papillomatous), i.e., condyloma acuminatum. papillomatous: refers to a nipple-like projections above the skin surface seemingly as a consequence of extensions outward of dermal papillae (papillomatous) that may or may not be covered by thickened epidermis. cutaneous papillomas include those that have a fibrous core, e.g., fibroepithelial papillomas and those that consist mostly of epithelium papillate, e.g., condylomata acuminata. the term “verrucous” sometimes is used synonymously with papillomatous, but the tip of epidermal excrescences in lesions verrucous often are pointed (digitated), i.e., verrucae vulgares, rather than rounded (papillomatous), i.e., condyloma acuminatum. papule: a small, i.e., up to 1.0 cm, slightly raised, solid or cystic lesion. a papule may be formed by abnormalities mostly of surface epidermis, as in a plane wart, by changes mostly in infundibular epidermis and in the dermis adjacent to it, as in lichen planopilaris, by ones mostly in the papillary dermis, as in a lesion of lichen nitidus, by findings mostly in the reticular dermis, as in a small infundibular cyst (a milium), or by aberrations of both epidermis and dermis together, as in a lesion of conventional lichen planus. the surface of a papule maybe flat (i.e. lichenoid, as in lichen planus) as it presents itself usually, hemispherical, as in lichen nitidus, or conical, as in a variety of spongiotic dermatitides, such as allergic contact dermatitis. papules may be either smooth, like that of an incipient lesion of guttate psoriasis, or scaly, as in a later lesion of guttate psoriasis in which the original cornified layer that covers mounds of parakeratosis has been shed. the time-honored litany of “papulosquamous diseases” should be abandoned because the diseases said to constitute that assemblage are unrelated wholly to one another, i.e., seborrheic dermatitis and secondary syphilis, “guttate parapsoriasis” (one pattern of mycosis fungoides) and psoriasis, lichen planus and pityriasis rosea. moreover, many conditions that are typified by scaly papules are not included in the so called papulosquamous group, among those being a particular presentation of sarcoidosis on a leg, one manifestation of grover’s disease (the darier type), and some examples of dermatophytosis. pale-cell acanthosis: refers to a specific histopathologic pattern within a thickened epidermis in which there are discrete zones of large pale-staining keratinocytes separated widely from one another by prominent intercellular spaces traversed by elongated bridges. neutrophils usually pepper the foci of pale keratocytes. in short, the changes of pale-cell acanthosis are identical to those that constitute the benign neoplasm named pale-cell acanthoma. (see clear cells) palisade: refers to the appearance of cells aligned in the fashion of stakes like those that form a line of defense in a fortification, i.e., columnar cells at the periphery of an outer sheath at the bulb of a normal hair follicle; germinative cells at the periphery of a “follicular” germ in an embryo, of aggregations of cells in a trichoblastoma, and of aggregations of cells in trichoblastic (basal cell) carcinoma; histiocytes around a zone of mucin and of degenerated collagen in granuloma annulare and around a zone of fibrin in rheumatoid nodule, and nuclei of schwann cells apposed directly to one another at the distal end of their respective cytoplasm in verocay bodies of schwannomas. panniculitis: an inflammatory disease in which the infiltrate of inflammatory cells is present in the panniculus adiposa (subcutaneous fat). for purposes of facilitating diagnosis by conventional microscopy of panniculitis, the process is divided arbitrarily as “septal” and “lobular,” depending on whether the infiltrate of inflammatory cells, as seen at scanning magnification, mostly is in fibrous septa or mostly in fat lobules. sometimes, septa and lobules are affected equally. there can be significant overlap. papillary: means shaped like a nipple. the root “pap” appears in several names for cutaneous structures, i.e., papillary dermis, dermal papilla, follicular papilla, papilloma, papillomatosis, papillations, and papillated. nipple-like projections above the skin surface may be seen as an affect of proliferations of keratocytes as in condylomata acuminata and of extension outward of papillary dermis, i.e., papillomatosis, as in acanthosis nigricans. papillomatous and papillated are synonymous with papillary. papillary dermis: refers to the uppermost portion of the dermis that has nipple-like projections into hollows in the underside of the epidermis. collagen in the papillary dermis is seen as delicate fibrils in contrast to collagen in the reticular dermis, which is arranged in bundles. capillaries in the papillary dermis emerge from venules that are situated in the uppermost portion of the reticular dermis and, for that reason, this plexus is also known as the subpapillary plexus. papillations: are projections above the skin surface or into the lumen of a structure tubular or cystic and that may be seen as an effect of proliferations of epithelial cells alone or of fibrous core protrusive covered by epithelial cells. review | dermatol pract concept 2015;5(2):1 3 wrongly to interpret an inflammatory disease as a lymphoma. in fact, there, is no need for the term parapsoriasis because the actual diagnoses are either mucha-habermann disease or mycosis fungoides or whatever other named disease is being considered. parapsoriasis en plaques: is a synonym for one expression of the early patch stage of mycosis fungoides. it is a term that is no longer relevant. (see parapsoriasis) part of a follicle: is a term applied to each of two units that constitute each of the two segments of a follicle. each part has its own morphologic appearance, and each is delimited by distinct boundaries. from bottom up, the lower transient segment of a follicle is composed of two parts, namely, bulb and stem, and the upper permanent segment of isthmus. pas: is based on an acronym for periodic acid-schiff. periodic acid in a stain is used as an oxidizing agent. a solution of schiff reagent consists of basic fuchsine, hydrochloric acid, and sodium bisulfate and serves as the actual stain. pas stain is used to detect carbohydrates and mucoproteins. when material stained by pas is removed by diastase, that material must be glycogen. patch: a broad, i.e., more than 1.0 cm, flat lesion. a macule, in contrast to a patch, is a flat lesion less than 1.0 cm in greatest diameter. a patch may begin as a macule, as in vitiligo, or it may appear as a patch from the outset, such as a café au lait “spot.” alterations histopathologic that are responsible for patches are the same as those for macules. a café au lait spot of neurofibromatosis results from an increase in melanin within the epidermis, a purple patch of an ecchymosis from extravasation of erythrocytes in the dermis, and a reddish patch of a blush or of a sunburn from erythrocytes congested within dilated blood vessels of the superficial plexus. pattern: refers to a design or arrangement of figures or structures. in clinical dermatology, pattern includes distribution of lesions, arrangement of lesions, configuration of lesions, and outline of individual lesions themselves. in dermatopathology, pattern pertains mostly to distribution and arrangement of infiltrates of inflammatory cells and to silhouettes formed by neoplastic cells. they are the vehicles used to arrive at the correct diagnoses with specificity. in dermatopathology pattern usually refers to patterns of inflammatory cells. however, the concept of pattern is more far reaching. the following discussion illustrates this. rather than conceive of distinctive expressions of pathologic processes as specific diseases, it may be more accurate, and, therefore, more illuminating, to think of them as “patterns of disease.” for example, dermatologists understand, full well, that conditions like erythema multiforme, erythema nodosum, and leukocytoclastic vasculitis represent repeatable papulovesicle: describes a combination of a papule and a vesicle. parakeratosis: retention of nuclei in cornified cells. it results either from acceleration in epidermopoiesis (i.e., in psoriasis) or from faulty maturation of keratocytes (i.e., in bowen’s disease). within the epidermal cornified layer of different inflammatory diseases, parakeratosis may occur in mounds, as in guttate psoriasis, in alternation with orthokeratosis, both vertically and horizontally, as in pityriasis rubra pilaris, in broad zones of confluence, as in plaques of fully developed psoriasis, and in mounds that also contain serum, as in seborrheic dermatitis. parakeratosis may be observed in neoplasms such as solar keratosis (a superficial squamous-cell carcinoma of one type), in which the epidermis displays broad columns of parakeratosis that alternate at intervals with thin columns of orthokeratosis, the latter being stationed at sites of acrosyringia and infundibula (so-called acrotrichia), and in a much thicker squamous-cell carcinoma, where whorls of parakeratosis within aggregations of neoplastic keratocytes are referred to colloquially as “horn pearls.” one expression of epidermal nevus, i.e., inflammatory linear epidermal nevus, is typified by stubby, straight columns of parakeratosis, in contrast to the situation in disseminated superficial actinic porokeratosis, in which thin columns of parakeratosis tilt toward the center of the lesion. parapsoriasis: a term given to five cutaneous conditions, namely, parapsoriasis (pityriasis) lichenoides et varioliformis acuta, parapsoriasis (pityriasis) lichenoides chronica, parapsoriasis guttate, parapsoriasis en plaques, and parapsoriasis variegate. since brocq’s seminal article in 1902 devoted exclusively to parapsoriasis, those five conditions have been held to be vaguely related to one another in a “parapsoriasis group.” in actuality, pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica are morphologic variations of a single inflammatory process, namely, mucha-habermann disease, and parapsoriasis en plaques and parapsoriasis variegata (large-plaque parapsoriasis) and digitate dermatosis, and its smaller, rounder variant, guttate dermatosis (smallplaque parapsoriasis), are expressions morphologic of a single neoplastic process, to wit, mycosis fungoides. in short, both small-plaque parapsoriasis and large-plaque parapsoriasis are synonyms for flat lesions of mycosis fungoides. most patients with flat lesions of mycosis fungoides never develop elevated lesions of the disease (plaques, nodules, tumors), no matter the duration of it. that fact does not deny the authenticity of a diagnosis of mycosis fungoides for flat lesions of it, anymore than it would of kaposi’s sarcoma, melanoma, and angiosarcoma, each of which is diagnosable when lesions of them are flat. in sum, the descriptive term parapsoriasis should not be used unmodified because it is imprecise, confusing, and potentially harmful to patients; clinicians may be led 4 review | dermatol pract concept 2015;5(2):1 of a flower, as may be observed in some examples of trichoblastoma and trichoblastic (basal cell) carcinoma. petechia: a pinpoint punctum of extravasated red blood cells in the upper part of the dermis. phlegmon: cellulitis brought into being usually by microaerophilic streptococci. the process tends to extend throughout the dermis and subcutaneous fat to skeletal muscle and other soft tissues. histopathologically, it is seen to consist of a sparse, but diffuse, infiltrate of neutrophils, mostly. phlegmonous inflammation differs from suppurative inflammation, which also consists mostly of neutrophils, by displaying sparse polymorphs in diffuse distribution, as in erysipelas, rather than a dense discrete collection of them. pigment “incontinence”: the loss of pigment from the epidermis due to damage of epidermal melanocytes and basal keratocytes and its ingestion by macrophages within the dermis. in some conditions, however, pigment transfer to dermal macrophages may be due to phagocytosis of the terminal portions of dendritic processes of melanocytes that have protruded through the basal lamina. pigmentation: coloration caused by a variety of pigments. melanin is responsible for a great range of colors in skin, such as black (abundant melanin at all levels of the epidermis, including the cornified layer, as in some simple lentigines), blue (melanin within melanocytes and melanophages in the mid and deep parts of the dermis in many blue nevi), tan (sparse melanin in the epidermis of cafe au lait spots), gray (diffuse dermal melanosis associated with some metastases of melanoma), and ashy melanin increased within the epidermis and present in macrophages within the upper part of the dermis as in a clinical expression of post inflammatory hyperpigmentation known as erythema dyschromicum perstans. of course, erythema dyschromicum perstans (ashy dermatosis) is not an authentic disease just one manifestation of post-inflammatory pigment alteration. differences in coloration among peoples also are due to melanin. loss of epidermal melanin can be seen in diseases as diverse as vitiligo and post-inflammatory hypopigmentation. skin colors in tattoos result from pigments other than melanin, such as silver (slate gray), carotene (yellowish orange), cobalt (blue), cadmium (yellow), mercury (red), carbon (black or blue), and chromium (green). the brown color of hemochromatosis is a consequence mostly of melanin in keratinocytes rather than of sparse hemosiderin deposited in macrophages. pilar: like tricho-, pertains to hair, (the former latin and the latter greek), in contrast to follicular, which refers specifically to an entire follicle including a hair. the two terms pilar and tricho-, on the one hand, and follicular, on the other, often are used interchangeably and, therefore, incorrectly (i.e., pilar patterns of disease, clinically and histopathologically, and that each of those patterns can be brought into being by different causes, sometimes many of them, as in the case of erythema multiforme, in which causes are disparate as infection by herpes virus and a drug given systemically. and what has just been stated in regard to erythema multiform, erythema nodosum, and leukocytoclastic vasculitis obtains equally for urticaria, sweet’s syndrome, and pyoderma gangrenosum. on reflection further, the very same concept is applicable to psoriasis, lichen planus, and granuloma annulare as well as to all other apparently noninfectious inflammatory diseases of the skin and subcutaneous fat, from pityriasis rosea to nodular vasculitis. and reflection still further makes apparent that even so called infectious diseases really are patterns of disease! is suppurative granulomatous dermatitis and panniculitis in conjunction with pseudocarcinomatous proliferation of keratocytes brought about by any number of different “deep fungi” and “atypical mycobacteria” not a pattern? and is staphylococcal scalded skin syndrome that stimulates, exactly, the appearance of “superficial pemphigus” (foliaceus/ erythematosus) not a pattern? and is it not true that except for the presence of hyphae, dermatophytosis may mimic all of the patterns of psoriasis histopathologic? in sum and in short, pattern analysis (in conjunction with an algorithmic method) is the surest route to diagnosis of all “inflammatory diseases” of the skin and subcutaneous fat, each of which may be thought of as a pattern morphologic of disease. pautrier’s “microabscess”: a collection of abnormal lymphocytes within the epidermis or epithelial structures of adnexa of lesions of mycosis fungoides; a misnomer because abscess denotes a collection of neutrophils, and pautrier’s collections consist of abnormal lymphocytes. pedunculate: a polypoid excrescence that is attached to the skin or other flat surface by a stalk, as is the case in a fibroepithelial polyp or papilloma. “peppering” by lymphocytes: describes the scatter of lymphocytes as solitary units within an aggregation of epithelial cells of a proliferation, as occurs in spiradenoma and adamantinoid trichoblastoma, or within the epidermis as happens often in mycosis fungoides. persistence: in dermatopathology refers to the continuation of a proliferation benign or malignant, at a primary site after an attempt, usually surgical and unsuccessful, has been made to remove it. most proliferations described as “recurrent” actually are just persistent. recurrence should only be used when referring to true metastasis. (see recurrence of melanoma) petaloid: denotes the appearance histopathologic of aggregations of cells in a proliferation that resembles petals review | dermatol pract concept 2015;5(2):1 5 i.e., neutrophils, eosinophils, lymphocytes, plasma cells, and histiocytes in a section of granuloma faciale. polygonal cell: having the shape of a polygon that structure being a closed plane figure bounded by straight lines usually there are at least three sides and typically five or more. when a cell with such a shape is non-epithelial, it is likely to be an abnormal melanocyte (of “classic” spitz’s nevus or melanoma), and when epithelial, it is likely to be an abnormal myoepithelial cell (as in mixed tumor of apocrine type, that neoplasm benign really being infundibulo-apocrinesebaceousfollicular). polygonal cells are often met in company with plasmacytoid cells. polymorphic eruption: more than, one type of skin lesion occurring concurrently in an individual, i.e., a combination of macules, papules, vesicles, and so on, as occurs in mucha-habermann disease. polymorphous: in reference to infiltrates in lesions, composed of several types of cells, as are the mixed-cell infiltrates of granuloma faciale/erythema elevatum diutinum and of histiocytosis x. polypoid: resembling a polyp, an excrescence above the skin surface having a narrow base and a stalk, such as an acrochordon (i.e., fibroepithelial polyp) or as in an apocrine fibroadenoma. pop out: is a colorful description of the way some benign proliferations and cysts shoot from the skin after an incision made above is carried very near to them. the reason for ease of separation from surrounding tissue is that benign proliferations and cysts tend to compress adjacent fibrous tissue and, in the process, create a narrow space between them and adjacent nearly normal skin. the space, combined with the tract of the incision, becomes the route that a neoplasm or cyst takes as it flies from its haven. when a surgeon cradles some benign neoplasms and cysts in order to encourage them to “shell out,” the same space acts as the corridor for their release from the skin. poroid cell: is one with a round nucleus and scant cytoplasm situated lateral to a cuticular cell in a duct of a normal apocrine or eccrine gland, it usually being the component dominant (the other less conspicuous being a cuticular cell) in poromas and porocarcinomas, both ones apocrine and eccrine. precancer (premalignancy): the term precancerous implies a benign stage in development of an authentic cancer. skin lesions purported to be “precancerous” are solar keratosis, arsenical keratosis, radiation keratosis, bowen’s disease (and its analogue on genitalia, erythroplasia of queyrat), lentigo maligna, and extramammary paget’s disease. sheath acanthoma, trichoblastoma, and pilomatricoma). each of those proliferations consists of cells non-viable like those in a follicle, not simply of cells non-viable like those of hair. furthermore, there are no true pilar cysts (although hair shafts often are found in steatocystomas, eruptive vellus hair cysts, and some infundibular cysts), only ones epidermal (i.e., infundibular) and follicular (isthmic-catagen types). “pinching-off” secretion: describes picturesquely the appearance of the distal secretory portion of luminal cells that line apocrine glands. the terms “apocrine” secretion, “decapitation” secretion, “pinching off’ secretion, and “snouts” are synonyms. plaque: an elevated, broad, i.e., more than 1.0 cm in diameter, lesion. a plaque of psoriasis may come into being from extension centrifugally of a single papule or it may be a consequence of confluence of many papules. plaques usually are acquired, as is the case in lichen simplex chronicus, hypertrophic lichen planus, and lichen amyloidosis, but some of them are congenital, as in a garment type of congenital melanocytic nevus, an epidermal nevus like that known as ichthyosis hystrix, and a connective tissue nevus like a shagreen “patch.” plasma: is the fluid portion of circulating blood. it is distinguished from serum, which is the fluid obtained after coagulation. plasmocytoid: refers to a cell that exhibits cytologic features similar to those of a plasma cell, i.e., an eccentrically placed nucleus associated with abundant amphophilic cytoplasm. plasmocytoid cells are found often in some proliferations with apocrine differentiation such as apocrine hidradenoma and apocrine mixed tumor, (not uncommonly in conjunction with polygonal cells). these cells are also seen in benign proliferations, such as “classic” spitz’s nevus and in malignant proliferations, such as melanoma and malignant apocrine mixed tumor. platitude: (see cliché) pleomorphism: denotes variation in size and shape of cells, and particularly nuclei of them, in an infiltrate of a process proliferative. pleomorphism is the determinant most important of nuclear atypia, the other characteristics conventional of them being large size of nuclei and degree of staining inconsistent markedly of them. no direct correlations exist, however, between pleomorphism of nuclei and behavior biologic of a proliferation. nuclei may be strikingly pleomorphic in proliferations benign, such as in some “classic” spitz’s nevi, and even in some conditions inflammatory, such as “monster cells” in an expression distinctive of dermatofibromas. pleomorphism is not the same as polymorphism, which refers to different types of cells present together in a single infiltrate, 6 review | dermatol pract concept 2015;5(2):1 are present above the dermoepidermal junction, and nuclei of melanocytes that may be pleomorphic; that constellation of histopathologic findings signifies melanoma in-situ. biologically, some examples of so-called lentigo maligna, once having extended into the reticular dermis, eventuate in metastases of melanoma. in brief, lentigo maligna is not a “precanceroses,” but a melanoma that is confined to the epidermis and epithelial structures of adnexa. extramammary paget’s disease is not “precancerous,” but an apocrine carcinoma that begins within the epidermis and extends far down epithelial structures of adnexa (in the same manner as does melanoma). although many lesions of extramammary paget’s disease remain patches, i.e., in-situ, for the lifetime of the patient, some do not; neoplastic cells may descend into the dermis and from there metastasize. in conclusion, a clinician cannot determine by gross examination alone which solar keratosis will eventually become a metastasizing squamous cell carcinoma, which “lentigo maligna” will become a metastasizing melanoma, or which extramammary paget’s disease will metastasize as apocrine carcinoma. each of these conditions is cancer, and each must be removed completely. no clinician or histopathologist can predict which lesion of solar keratosis, arsenical keratosis, radiation keratosis, bowen’s disease, melanoma in-situ, or extramammary paget’s disease, left untreated, will cause death as a consequence of metastasis. clinicians should be educated further to appreciate the fact that radical surgery is not appropriate for any of these cancers; all that is required is total removal nothing more. by sanitizing cancers with such terms as solar keratosis, lentigo maligna, and extramammary paget’s disease, clinicians and pathologists sustain a belief in the erroneous concept of “precanceroses.” in actuality, solar keratosis is a squamous cell carcinoma, lentigo maligna is a melanoma, and extramammary paget’s disease is an apocrine carcinoma. in addition, there is neither need nor place for the word parapsoriasis in the language of dermatology and dermatopathology. the diseases now referred to as parapsoriasis can be diagnosed accurately as either mucha-habermann disease or mycosis fungoides. no disease termed parapsoriasis transforms into mycosis fungoides; it is either mycosis fungoides or it is mucha-habermann disease. this is a considerable advance beyond thinking of brocq, who spawned the concept of parapsoriasis and who wrote these lines about it in 1903: “it is then quite evident that the group of parapsoriasis, such as i define it, established bonds of union between psoriasis and seborrhea psoriasiform on one side, and between lichen planus and the mild form of pityriasis rubra and mycosis fungoides on the other.” leukoplakia is a generic term that traditionally has been used for precancerous of keratocytes on mucous membranes or mucocutaneous junctions. are the conditions just enumerated precancerous, or are they cancers? all are malignant neoplasms. histopathologically and biologically, solar keratoses, arsenical keratoses, radiation keratoses, and bowen’s disease are squamous cell carcinomas. histopathologically, all fulfill criteria for squamous cell carcinoma, namely, keratinocytes that display crowded nuclei, pleomorphic nuclei, nuclei in mitosis, and premature cornification in the form of dyskeratotic cells. biologically, each of those lesions may eventuate in metastases, a phenomenon that qualifies them as malignant. it is curious that dermatologists and pathologists the world over diagnose superficial basal cell carcinoma without hesitation but they name superficial squamous cell carcinomas by evasions such as “solar keratoses,” “arsenical keratoses,” “radiation keratoses,” and “bowen’s disease.” if superficial basal cell carcinoma is considered to be cancer and not precancerous then so should solar keratoses, arsenical keratoses, radiation keratoses, and bowen’s disease be regarded as cancers. they are all, types of squamous cell carcinoma. histopathologically, solar keratoses sometimes are associated with suprabasal clefts above which reside acantholytic dyskeratotic cells. when that type of solar keratosis becomes thicker, histopathologists term the lesion pseudoglandular squamous cell carcinoma. no distinct histopathologic boundary exists, however, between any variant of solar keratosis and squamous cell carcinoma. it is not surprising, therefore, that in no textbook of dermatology, dermatopathology, or general pathology can a statement be found where solar keratosis ends and squamous cell carcinoma begins. the reason is that solar keratosis is a squamous cell carcinoma, albeit an “embryologic one.” the decision about whether a particular neoplasm is a solar keratosis or a squamous cell carcinoma is the mere whim and fancy of histopathologists. because the judgment is entirely arbitrary, it is wholly without repeatability. what has just been written about solar keratosis applies equally to arsenic keratosis, radiation keratosis, bowen’s disease and bowenoid papulosis—-squamous cell carcinomas all. clinically, histopathologically, and biologically, lentigo maligna is melanoma. clinically, the lesion, irrespective of size, is asymmetrical with notched borders and variegated color, usually shades of brown. histopathologically, the neoplasm fulfills all of the criteria for melanoma in-situ, e.g. an increased number of melanocytes disposed as solitary units (and later in nests) within the epidermis (and epithelial structures of adnexa), solitary melanocytes that are not equidistant from one another (and neither are the nests), nests that usually have become confluent in foci, some melanocytes that review | dermatol pract concept 2015;5(2):1 7 bizarre-shaped, thin-walled vessel in a patch or plaque of kaposi’s sarcoma. pseudoacantholysis: the process whereby non-epithelial cells, melanocytes in particular of some examples of “classic” spitz’s nevi and of some melanomas, are separated from one another in a manner reminiscent to that of acantholysis in which epithelial cells are detached from one another. pseudocapsule: refers to simulation of a capsule, i.e., a structure that envelops a proliferation. in general pathology, disagreement considerable exists concerning the terms “capsule” and “pseudocapsule.” some histopathologists consider a capsule to be a membrane fibrous formed by stroma of normal tissue at the periphery of a proliferation that usually is benign. other histopathologists regard a proliferation as encapsulated when the layer of fibrous tissue that surrounds it is intrinsic to the proliferation itself. those latter pathologists contend that there are few truly encapsulated proliferations and they cite as examples of those few, schwannomas, thymomas, and thyroid adenomas. for them, the layer of fibrous tissue that surrounds most other proliferations may be ascribed to fibrous stroma of normal tissue and, therefore, qualifying as pseudocapsule. neither a “capsule” nor a “pseudocapsule” is requisite for any diagnosis with specificity in dermatohistopathology. the alterations fibrous in point nearly always are caused by compression of surrounding normal tissue by a benign proliferation or cyst. clefts tend to form between compressed fibrous tissue that surrounds a benign proliferation and the relatively normal tissue adjacent. as a consequence of such clefts encircling, a benign proliferation tends to “pop out” when incision is made sufficiently deep above it. the attributes just described are not seen as a rule in malignant proliferations. in sum, so-called capsule and pseudocapsule are merely compressed connective tissue. pseudocarcinomatous hyperplasia: is a proliferation of epithelial cells that, by silhouette, simulates a carcinoma, usually a squamous-cell carcinoma, but by cytologic features does not. the “pseudocarcinomatous” appearance results from marked hyperplasia of epithelial structures of adnexa, i.e., infundibular epidermis and eccrine ducts. those adnexal epithelial structures normally extend far into the dermis, and it is for that reason hyperplasia of them may result in simulation of an epithelial malignant neoplasm, i.e., a carcinoma. although some keratocytes in the pseudocarcinomatous hyperplastic epithelium may be in mitosis, nuclei are not strikingly crowded or pleomorphic, in contrast to the usual situation in many squamous-cell carcinomas. pseudocarcinomatous hyperplasia may be secondary to another pathologic process at that site, i.e., granular neoplastic cells in granular-cell schwannoma, infectious agents such as atypical mycobacteria in swimming-pool granuloma and proliferation: an increase in number, usually of cells. a proliferation of epithelial cells in skin may be divided into those that are epidermal and those that are adnexal. a proliferation of epidermal keratocytes may be psoriasiform evenly, i.e., elongated rete ridges of about equal length, those alternating with dermal papillae of about equal length, as in psoriasis at its apogee, psoriasiform unevenly i.e., elongated rete ridges that are not of uniform length but that alternate nonetheless with dermal papillae to create an undulate pattern, as in longstanding nummular dermatitis, jagged, i.e., serrations at the base of a thickened epidermis, as in lichen planus, and mammillated, papillated, or digitated, i.e., the surface of the epidermis resembling breasts, nipples, or fingers, respectively, as in some examples of nevus sebaceous, acanthosis nigricans, and verruca vulgaris, respectively. “verrucous” is a synonym for “digitate.” proliferation of cells of epithelial structures of adnexa, i.e., the upper part of eccrine ducts and of infundibular epidermis, may be slight or marked the latter sometimes simulating squamous cell carcinoma (pseudocarcinomatous), as seen in some examples of halogenodermas, infections by deep fungi and atypical mycobacteria, and the verrucous stage of incontinentia pigmenti. proliferation of melanocytes may be categorized according to an increase in the absolute number of normal appearing melanocytes per unit area of dermoepidermal junction or basal layer of epidermis, either as solitary units entirely or associated with nests. proliferation also may be a term generic for any increase in the number of cells other than ones inflammatory and, therefore, applicable to what are designated conventionally neoplasms (both benign and malignant), hyperplasias, hamartomas, malformations, structures ectopic, etc. no agreement has been reached after more than 150 years about definition of the above. moreover, and more important, these definitions are not essential to diagnosis with specificity. once the diagnosis with specificity has been accomplished by naming things for what they are such as in the case of verruca vulgaris with sebaceous differentiation, fibrofolliculoma/ trichodiscoma, nevus comedonicus, spiradenoma, and microcystic adnexal carcinoma, a knowledgeable clinician should understand immediately the implications biologic of the specific diagnosis just stated in regard to management of the patient. proliferation of atypical melanocytes: an increase in number of melanocytes whose nuclei are atypical those cells being present in, and sometimes above, the basal layer of the epidermis and of epithelial structures of adnexa. the phrase is descriptive and does not convey a diagnosis with specificity; such a proliferation may occur in melanoma in situ, as well as in a junctional “classic” spitz’s nevus. promontory sign: describes a projection of a normal venule into a larger space created by a newly formed, often 8 review | dermatol pract concept 2015;5(2):1 dense, diffuse infiltrates of histiocytes, some nuclei of which are pleomorphic and in mitosis, may resemble a poorly differentiated squamous cell carcinoma. what some authors consider to be “pseudocancerous,” i.e., florid oral papillomatosis, epithelioma cuniculatum, and giant condyloma, are really authentic verrucous carcinomas. “solitary” keratoacanthoma cannot be a pseudomalignancy because it sometimes metastasizes as the squamous cell carcinoma that it is. pseudocarcinomatous hyperplasia refers specifically to silhouettes that may simulate those of either a basal cell carcinoma or a squamous cell carcinoma. a simulator of superficial basal cell carcinoma is follicular germ induced by fibrohistiocytic elements of dermatofibroma, and a mimic of squamous cell carcinoma is the adnexal epithelial hyperplasia often associated with infections by deep fungi and atypical mycobacteria. a distinction must be made between the terms pseudocarcinoma, on one hand, and pseudocarcinomatous hyperplasia on the other. the former is a clumsy attempt to render a specific diagnosis, whereas the latter is a description of adnexal epithelial hyperplasia the outline of which resembles a carcinoma. the term pseudocarcinomatous hyperplasia is not meant to be a specific diagnosis. pseudocarcinomatous hyperplasia usually consists of a proliferation of infundibular and/or eccrine ductal epithelium that assumes the outline of a squamous cell carcinoma, but nuclei of spinous cells are neither crowded nor atypical. the same principle that obtains for pseudomalignancy in general applies equally to pseudolymphomas of the b-cell type in which the architectural pattern resembles roughly that of a lymphoma of the b-cell type, namely, nodular aggregations composed mostly of lymphocytes distributed throughout the dermis and sometimes in the subcutaneous fat, but the lymphocytes are small and devoid of prominent nuclear pleomorphism. it has become increasingly apparent that many lesions on faces diagnosed as pseudolymphomas have proved to be authentic lymphomas. lymphomatoid papulosis often is listed among the pseudolymphomas, but, in reality, it is a ki-1 lymphoma. actinic reticuloid, a persistent light reaction, does not mimic a lymphoma histopathologically, and neither does pityriasis lichenoides (mucha-habermann disease). the lymphocytes in actinic reticuloid and mucha-habermann disease are small and monomorphous. pseudosarcomas tend to have the silhouette of a benign neoplasm, but nuclei of neoplastic cells display pleomorphism, i.e., the mesenchymal cells (“floret cells”) of pleomorphic fibromas and pleomorphic lipomas. there are several “pseudomelanomas,” only one of which is accompanied, and only episodically, with striking pleomorphism of nuclei, namely, “classic” spitz’s nevus. that nevus, however, like all nevi, has the architectural pattern of a benign deep fungi in chromo mycosis, halogens in bromoderma, and persistent rubbing of the skin in prurigo nodularis. pseudoglandular: resembling (however vaguely) an authentic gland, as does the structure that may form in a solar keratotic type of squamous-cell carcinoma and is characterized by suprabasal clefts above, which are acantholytic, dyskeratotic cells. at its outset, a very superficial squamouscell carcinoma of this type is called a solar (actinic) keratosis. pseudomalignancy: malignancy is fundamentally a concept predicated on biologic behavior. a malignant neoplasm has the capability to kill either by destruction of tissue locally or by metastasis. the irrepressible behavior of malignant neoplasms is reflected in certain morphologic correlates, grossly (clinically) and histopathologically. viewed through a microscope, those morphologic attributes usually are expressed as a particular silhouette and as certain cytologic features. as a rule, malignant neoplasms tend to be asymmetrical and poorly circumscribed, and to be composed of neoplastic cells disposed in aggregations that vary markedly in size and shape, that may have jagged outlines, and that tend to become confluent to form sheets of cells. nuclei of cells that constitute malignant neoplasms often are pleomorphic, and some are in mitosis. some mitotic figures may be abnormal. the concept of pseudomalignancy is based on disparity between histopathologic appearance and biologic behavior of a condition. a pseudomalignancy has either the silhouette or the cytologic features usually associated with a malignant neoplasm, yet its behavior is uniformly and wholly benign. pseudomalignancies usually are benign neoplasms, but, rarely, they may be inflammatory diseases, such as dermatofibromas with “monster cells.” irrespective of the essential pathologic process, the term pseudomalignancy (pseudocarcinoma, pseudolymphoma, pseudosarcoma, and pseudomelanoma) is vague and descriptive of a benign condition; it is not a specific diagnosis framed in the language of clinical dermatology, i.e., trichoblastoma, response to the bite of a tick and “classic” spitz’s nevus. pseudomalignancies neither precede nor transform into authentic malignancies. the word should rarely be used. furthermore, pseudocarcinoma may refer to a benign neoplasm, a hyperplasia, or an inflammatory process that mimics a carcinoma, usually a basal cell carcinoma or a squamous cell carcinoma. for example, desmoplastic trichoepithelioma, a particular expression of trichoblastoma typified by columns of follicular germinative cells, often mimics a morpheaform basal cell carcinoma histopathologically; the hyperplasia of surface epithelium above a granular cell neoplasm may simulate squamous cell carcinoma, and a very early lesion of xanthogranuloma, an inflammatory process that consists of review | dermatol pract concept 2015;5(2):1 9 and/or the subcutaneous fat. purpura can be classified as subsequent to inflammatory disease, as in schamberg’s disease, leukocytoclastic vasculitis, and mucha-habermann disease, and as unaffiliated with an inflammatory disease, as is the case for solar purpura, thrombomcytopenia, and disseminated intravascular coagulopathy. pushing margins: an image used to convey the smooth, round borders of a well-circumscribed (usually benign) neoplasm that appears to grow centrifugally. this term is to be eschewed. it is a cliché since it cannot be seen under a microscope. (i.e., pushing). pustule: clinically, an elevated, circumscribed collection of pus (neutrophils and necrotic debris of neutrophils) and, histopathologically, a collection of neutrophils within an epidermis (surface and/or infundibular) and, much less often, an eccrine unit. a variety of names, some eponymic, have been given to types of pustules situated within cutaneous epithelia. discrete pustules in the mid-spinous zone of psoriasis are termed “munro’s micrabscesses”; sponge-like pustules in the upper reaches of the epidermis, particularly of psoriasis and variants of it, ranging from acrodermatitis continua (hallopeau) through keratoderma blenorrhagicum to subcorneal pustular dermatitis (sneddon and wilkinson), are known as spongiform pustules of kogoj; abscesses positioned beneath the cornified layer of an epidermis are referred to as subcorneal pustules. none of those types of pustules is specific for anyone disease. so-called munro’s micro abscesses also may be seen in dermatophytosis, spongiform pustules in halogenodermas, and subcorneal pustules in pyoderma gangrenosum. the various appearances of pustules histopathologically reflect a moment in time at which a biopsy interrupted migration of neutrophils from capillaries in dermal papillae to the cornified layer of the epidermis, which is their destination ultimately. for reasons not understood, neutrophils in eruptive (guttate) psoriasis hone to the summit of mounds of parakeratosis. most pustules in skin are infundibular epidermal rather than surface epidermal, and most of them are idiopathic. many of the remainder are infectious, i.e., bacterial (staphylococci), fungal (dermatophytes), viral (herpes), and spirochetal (treponema palladium). sometimes, what looks like a pustule in infundibular epidermis is seen by conventional microscopy to consist of countless eosinophils and many fewer neutrophils. examples of this phenomenon, termed badly “eosinophilic folliculitis” (the condition, actually, is an infundibulitis, not a folliculitis, and it is not eosinophilic, but rather is dominated by eosinophils), are encountered in ofuji’s disease and in some patients with hiv. the term pustule is reserved for any nonsolid lesion that clinically is filled with “pus” and pustule histopathologically only for collections of neutrophils in neoplasm, to wit, it is symmetrical and sharply circumscribed. some “classic” spitz’s nevi have several architectural features in common with melanoma, such as a scatter of melanocytes at all levels of the epidermis, a phenomenon that is also encountered in the other distinctive melanocytic nevi such as congenital nevi biopsied shortly after birth; some junctional and compound nevi situated on the palms and soles; junctional and compound nevi situated on particular anatomic sites such as the nipple and areola, genitalia, perianal region, intertriginous regions, and umbilicus; and junctional and compound nevi that persists after inadequate surgical removal. in sum, whenever possible the diagnoses should be made for what they are. the term “pseudo” anything has limited usefulness. psoriasiform: resembling a fully developed lesion of psoriasis clinically, i.e., a reddish plaque covered by scales, and/or histopathologically, i.e., elongated rete ridges of about equal length that alternate with long dermal papillae to form a strikingly undulate pattern. the concept of psoriasiform just stated is parochial, however, because it applies only to lesions formed fully of that remarkably protean disease. clinical expressions of psoriasis range from smooth-surfaced guttate papules devoid of scale to exfoliative erythroderma, from discrete pustules on palms and soles to widespread pustules accompanied by signs and symptoms of systemic character, and from plaques with slight scale to “extremely thick side.” each of these manifestations of psoriasis has an analogue histopathologically. in theory, therefore, simulation of any of the manifold expressions of psoriasis, clinically and histopathologically, is psoriasiform. punch biopsy: refers to a procedure used to obtain a cylindrical portion of skin that consists of epidermis and dermis, and even of subcutaneous tissue. the procedure is performed with an instrument known as a punch, the diameter of which may range from 2 to 8 mm and whose cutting edge is usually made of steel but sometimes of plastic. a sample of skin is taken by introducing the round blade of the punch into the skin, to which it is oriented perpendicularly, and, under pressure, rotating the instrument, back and forth, until it has penetrated the entire dermis and entered the subcutaneous fat. the procedure is simple and rapid and leaves a wound that is easy to close with a suture or that may heal with second intention and with little scar. of course, there are many indication and contraindications for the use of this procedure. (see biopsy, razor blade removals) purpura: a purple color caused by hemorrhage in the skin. petechiae are pinpoint hemorrhagic macules and ecchymoses are hemorrhagic patches. a hematoma is extensive hemorrhage in a somewhat discrete locus in the reticular dermis 10 review | dermatol pract concept 2015;5(2):1 razor blade removals: in this technique a razor blade which bends (it is usually the equivalent of a “gillette blue blade” cut in half or whole) is used to perform shave horizontal or tangential removals. the blade may also be bowed into different shapes to perform saucerization removal/excisions by a dermatologist who is experienced with it. some find this far superior to a “knife blade” to perform saucerization. some refer to saucerization as “scoop removals.” (see biopsy, shave removals, see sauceratization) recurrence of melanoma: the following applies to all other proliferations as well varying of course if the proliferations are benign or malignant. (i.e., benign proliferations can also persist) the issue of “recurrence of melanoma” is central to the matter of extent of margins for excisions of melanoma and to the issue of prognosis for a person who bears a melanoma. virtually every textbook of dermatology and of general surgery advocates wider excisions for thicker melanomas based on the assertion that the likelihood for recurrence of melanoma is enhanced by narrow margins of excision, especially for thicker lesions. that declaration is without validity. recurrence means to occur again, and in the realm of melanoma the phenomenon of recurrence may assume one of two forms, namely, persistence of a primary melanoma at the original local site, as a consequence of incomplete removal, or metastasis. the implications of those very different expressions of “recurrence” are profound, to wit, persistence of a primary melanoma may not spell a grave prognosis (i.e., re-excision may be curative, especially if the neoplasm is still very thin), whereas metastasis, for practical purposes, may signal a grave prognosis. unfortunately, all too many general pathologists and surgeons use the term recurrence indiscriminately, i.e., they fail to make a distinction between recurrence of a primary neoplasm at the initial local site (persistence) and recurrence that presents itself as neoplastic cells at a site some distance from the primary one (metastasis). (see persistence.) the literature of pathology and surgery with regard to “margins of excision for melanoma” is peppered by the word “recurrence,” yet rarely is an attempt made by authors to qualify the type of recurrence, i.e., persistence or metastasis. without such clarification, a reader is unable to judge the authenticity of the statement that recurrence of a melanoma is more likely if margins of the excision are narrow. if by recurrence the authors of these papers actually mean metastasis (as they usually do), then a patient’s prognosis is grim and could not have been altered, no matter how wide and deep the margins of excision because the metastasis must have occurred before the excision of the primary melanoma, assuming that the primary neoplasm was removed entirely. parenthetically, authors of an epithelium, usually, the epidermis; we do not use the word pustule for aggregations of eosinophils within an epithelium. pyknosis: one of the specific signs of necrosis marked by shrinkage and intense hyperchromasia of nuclei. during cell death, some nuclei may shrink as chromatin condenses to a solid, densely basophilic mass. that combination of findings constitutes pyknosis. pyriform: means having the form of a pear and, when applied to proliferation epithelial, refers usually to lobules of epithelial cells that assume the shape of a pear, such as normal lobules of a sebaceous gland and abnormal ones of nevus sebaceous. – r – racemiform: describes an appearance like a cluster of grapes or a bunch of berries formed by epithelial cells in some proliferations. in cutaneous pathology, the best example of racemiform arrangement of cells is found in trichoblastoma. radial growth phase: a concept introduced by richard reed and co-workers who stated that the “variants of malignant melanoma that grow radially at the dermoepidermal interface are expressions of an evolutionary process in which melanoma cells proliferate and spread along the dermal-epidermal interface or in the immediate subadjacent papillary dermis for a variable period of time before they acquire the capacity to survive and produce aggregates of tumor cells in the dermis (vertical growth phase).” those collaborators have suggested that the vertical growth phase, defined by them as the presence of an “expansile nodule” in the papillary dermis, may indicate potential for metastasis, whereas the radial growth phase is associated with no capability for metastasis. the terms radial and vertical, however, are not contrasting; vertical is a component of radial. vertical and horizontal are contrasting. moreover, “radial growth phase” and “vertical growth phase” of melanoma simply are replacements for the now abandoned concept of clark’s “levels of invasion of melanoma.” radial growth phase superseded clark’s levels i and ii, whereas vertical growth phase substituted for levels iii, iv, and v. notions of radial growth phase and vertical growth phase of melanoma are not relevant either to diagnosis or to management of melanoma. in reality, no histopathologist is able to determine truly where the so-called radial growth phase ends and the so-called vertical growth phase begins, and no surgeon’s hand should be guided by those “phases”; every melanoma, irrespective of thickness of it, should be removed with just enough normal skin around it to ensure that that goal has been achieved. in short, assignment of phases radial and vertical is engagement in mysticism and should be eschewed. review | dermatol pract concept 2015;5(2):1 11 the concepts stated above vary depending on the dermatopathologist. morphologically, the effects of the battle between lymphocytes and melanocytes of melanoma express themselves in three fashions: fibrosis, melanosis, and a combination of fibrosis and melanosis. these descriptive terms, i.e., fibrosis and melanosis, apply to the residual changes of complete and focal regression of primary melanoma in a thickened papillary dermis beneath an epidermis whose normal undulations have been muted or effaced. fibrosis refers to fibroplasia, usually of delicate fibrillary bundles of collagen, in a thickened papillary dermis. sometimes the papillary dermis may be more than five times its normal thickness and measures more than 1.0mm as a consequence of formation of new collagen by fibrocytes. fibrosis often is accompanied by diffuse deposits of mucin, sparse lymphocytic infiltrates, variable numbers of melanophages, i.e., from practically none to many, and telangiectases. in contrast, melanosis denotes a dense band of melanophages in a papillary dermis that may be as thickened by macrophages as it may be by fibroplasia. the epidermis above a zone of melanosis also shows diminution in the normal pattern of rete ridges and dermal papillae. in some specimens, sections exhibit features of fibrosis and melanosis in the same thickened papillary dermis. in those cases, fibrosis tends to be present in the upper part of the expanded papillary dermis and melanosis in the lower part. when melanosis is noted, a diagnosis of regression of melanoma may be issued without equivocation. the findings of melanosis are specific. that is not the case for fibrosis in regression of melanoma. changes indistinguishable from it may be found in regression of lichen planus like keratosis, a solar lentigo-reticulated seborrheic keratosis that attracts lichenoid infiltrates of lymphocytes to it and is subsequently destroyed by them. even the numerous necrotic keratocytes so often observed in the epidermis and papillary dermis of a regression of lichen planus like keratosis may be noted in some lesions of melanoma undergoing regression by fibrosis. regression of “halo” nevus as a result of the effects of lymphocytes on melanocytes also takes the form of fibroplasia but never of melanosis. a “halo” nevus that has regressed completely can be distinguished, usually, at scanning magnification from a melanoma that has regressed completely by fibrosis: the two have different silhouettes. in most instances, a regressed “halo” nevus has the silhouette of a clark’s nevus, i.e., it is small, symmetrical, and slightly domed, whereas a melanoma usually is broader, asymmetrical, and flattish. what is the significance of regression of primary melanoma? complete regression of melanoma, in our experience is synonymous with the existence of metastases from that primary melanoma. as we conceive it, prior metastasis to a regional lymph node is mandatory for occurrence of complete regrespapers about this subject often define local recurrence as the appearance of a melanoma within 2 to 5 cm of the primary site. those melanomas however represent satellite metastases, not persistent primaries. if, one day, dermatologists, pathologists, and surgeons are to communicate lucidly with one another about recurrence of melanoma and its implications for margins of excision of melanoma and for prognosis, then they must not employ the same word recurrence for two entirely different phenomena, i.e., persistence and metastasis. only then can meaningful studies be undertaken of the relationship between extent of margins of excision for primary melanomas and prognosis of those neoplasms. and only then can those studies be assessed critically. re-epithelialization: refers to a process by which a new epidermis is generated from infundibular and eccrine ductal epithelia. regression: in the realm of cutaneous neoplasia, refers to involution of a benign or a malignant proliferation, usually as a consequence of the effects of inflammatory cells on proliferations. the commonest benign proliferation that undergoes regression is solar lentigo (or its more advanced expression, reticulated seborrheic keratosis) to which a dense lichenoid infiltrate of lymphocytes is attracted. that lesion, known as a lichen planus-like keratosis, eventually disappears, leaving in its wake a papillary dermis thickened by fibroplasia, a sprinkling of lymphocytes, melanophages, and telangiectasias. solitary keratoacanthomas nearly always regresses after months as a consequence, in part, of a dense mixed infiltrate of inflammatory cells, leaving as residuum a dermal scar. regression of primary melanoma is a phenomenon that involves the superficial vascular plexus, a thickened papillary dermis, and the epidermis. requirements for induction of regression are: (1) melanocytes of melanoma in the epidermis and papillary dermis, and (2) lymphocytic infiltrates around the vessels of the superficial plexus, in lichenoid array within the “melanomatous” component of the papillary dermis, and scattered among neoplastic melanocytes of melanoma within the epidermis. in brief, cytotoxic products of lymphocytes kill neoplastic cells of melanoma situated in the papillary dermis and epidermis. rarely, all of the cells of the melanoma in the epidermis are destroyed by the effects of lymphocytes, a condition termed “complete regression” of melanoma. often, all of the melanocytes of melanoma in a discrete focus of the papillary dermis and epidermis are obliterated by the action of lymphocytes; a circumstance designated “focal regression” of melanoma. episodically, melanocytes of melanoma are eliminated partially in the papillary dermis and in the epidermis or entirely in the papillary dermis and not at all in the epidermis, a phenomenon known as “partial regression.” 12 review | dermatol pract concept 2015;5(2):1 composed of elements like those that constitute basement membranes normal in the skin and that is found around aggregations of cells in cylindroma and cylindrocarcinoma, as well as, at times, in spiradenoma. ripple pattern: for purposes practical the epithelial elements essential always being immature sebocytes, refers to an image histopathologic created by epithelial cells seemingly undifferentiated arrayed in lines wavy that gives the impression of the appearance of rippling of water, it being a sign specific of sebaceoma. round melanocyte: small, round, “lymphocytoid” melanocytes are commonly present in the middle or lower portions of intradermal melanocytic nevi. they are smaller in diameter than the more superficially situated cuboidal or epithelioid melanocytes, have centrally placed compact nuclei, and usually do not contain melanin. small round melanocytes with atypical nuclei sometimes are found in melanomas. in these cases there may be only a few nests of such cells or they may constitute the bulk of the neoplasm. large, seemingly round cells are seen in “classic” spitz’s nevi and some blue nevi as the result of section of spindle cells perpendicular to their long axes. large round cells with atypical nuclei are commonly found in melanomas. – s – sarcoma: a neoplasm malignant made up of cells nonepithelial. s-100 protein: is an acidic protein composed of a and b subunits. it was thought initially to be specific for neuroectodermal cells and tissues. subsequently, the protein has been shown to be ubiquitous in distribution, including tissues derived from ectoderm (i.e., astroglial cells, melanocytes, neuroblasts, schwann cells), mesoderm (i.e., langerhans’ cells, adipocytes), and endoderm (i.e., neuroendocrine cells of respiratory and gastrointestinal tracts). many neoplasms that differentiate toward those normal cells and tissues also react to this protein. s-100 protein is found in secretory cells of eccrine glands, but the presence of s-100 protein in a proliferation with adnexal differentiation does not necessarily signify eccrine differentiation. s-100 protein also is present in some proliferations with indubitable apocrine differentiation, evidenced by apocrine secretion, and in many neoplasms in the breast, probably because mammary glands and lactiferous ducts have capability for apocrine metaplasia. despite its lack of total specificity, antibodies directed against s100 protein continue to play a central role in establishing a diagnosis of melanoma in the skin. the routinely used, commercially available polyclonal antibodies are directed against both subunits of s100 protein and recognized protein sion of primary melanoma. sensitized lymphocytes return from the involved node to the skin where they “hone in” on the melanoma and destroy it. different authors have different interpretations concerning the significance of focal regression of primary melanoma. some aver that it is a good prognostic sign, whereas others claim that it has no prognostic significance. we are not certain of the meaning of focal regression of primary melanoma, biologically, but we infer that if complete regression signifies a grave prognosis focal regression probably does not herald a good one. however of this later point there is no certainty. last, there is the subject of regression of metastasis of melanoma to skin. that phenomenon is seen rarely, but when it is encountered, the setting tends to be a satellite metastasis in the same histopathologic section as a primary melanoma. when melanophages in discrete collections marked by jagged outlines are discerned in foci within reticular dermis and even within the subcutaneous fat, the diagnosis is melanosis as a consequence of regression of a metastasis of melanoma. reticular alteration: (see ballooning) reticulate: refers to one manifestation of a pattern net-like that can be visualized in the skin by both inspection gross and examination histopathologic. examples of patterns reticulated observable clinically are livedo reticularis, confluent and reticulated papillomatosis, and parapsoriasis reticulata (parakeratosis variegata), which is a manifestation of mycosis fungoides. patterns reticulate seen histopathologically result from interconnection of cells epithelial in conditions as diverse as trichoblastoma, mantle adenoma, and fibroepitheliomatous trichoblastic (basal cell) carcinoma. retiform: retiform is a synonym for reticulate. ribbons of collagen: describe the appearance of strips of collagen that resembles ribbons in proximity close to one another as is the situation in fibrofolliculoma/trichodiscoma, they being aligned perpendicular to struts of mantle epithelium that forms a pattern fenestrated at a stage “early” in that particular hamartoma (fibrofolliculoma) and being distributed haphazardly later in the course of the same hamartoma (trichodiscoma). richly fibrocytic stroma: in a proliferation of epithelial cells adnexal describes connective tissue in which fibrocytes are present in large number and in which bundles of collagen tend to be delicate and fibrillary, often being joined by mucin in quantity, as is the case in small nodular trichoblastoma, type racemiform of trichoblastoma, and fibroepitheliomatous trichoblastic (basal cell) carcinoma. rims of basement membrane material: describes a layer homogenous and eosinophilic of uniform thickness review | dermatol pract concept 2015;5(2):1 13 parakeratosis of darier’s disease and of porokeratosis), and greasy (i.e., the delicate, laminated, pigmented orthokeratosis of seborrheic keratosis). scale must be distinguished clinically from keratosis, i.e., a horny excrescence, which is not a flake of cornified cells, but which may be orthokeratotic in a lesion of isolated epidermolytic hyperkeratosis, parakeratotic in one of acantholytic dyskeratotic acanthoma, and both together in a solar keratosis. diagnosis histopathologic of many skin diseases can be accomplished by study of the epidermal cornified layer alone, using only low magnification of a conventional microscope. for example, mounds of parakeratosis that house neutrophils at their summit signify eruptive psoriasis or dermatophytosis, mounds of scale-crusts at lips of infundibular ostia indicate seborrheic dermatitis, alternation of short rectangular or square zones of orthokeratosis and parakeratosis in both horizontal and vertical directions telegraphs pityriasis rubra pilaris, marked compact orthokeratosis on hair bearing skin denotes lichen simplex chronicus, and a slice of orthokeratosis above a slice of parakeratosis, i.e., the “sandwich sign,” should call to mind dermatophytosis in which hyphae repose in orthokeratotic cells very near the middle of the sandwich. corneocytes in excessive number may cause infundibula to widen, as in keratosis pilaris and discoid lupus erythematosus, and even to become sac-like, as in an infundibular cyst. scale-crust: a combination of scale (cornified cells, usually parakeratotic ones) and crust (serum that contains blood cells, either, red, white, or both). scale-crusts cover spongiotic psoriasiform dermatitides, allergic contact dermatitis, and nummular dermatitis in particular, but they are found also at the lips of ostia of infundibula in seborrheic dermatitis. scale usually results from acceleration in epidermopoiesis that is associated with an increase in the number of spinous cells. crust usually is a consequence of spongiosis or of erosion secondary to excoriation, following which serum flows to the surface of the skin. scanning: in histopathology pertains to observing an entire section quickly, from one end to another, using an objective with the lowest magnification, i.e., between x 1.0 and x 2.5 objective of a conventional microscope. scanning magnification is crucial to accurate diagnosis in dermatopathology because it permits analysis of patterns formed by cells, i.e., infiltrates of inflammatory cells around vascular plexuses, in the interstitium, and within epithelial structures, and infiltrates of neoplastic cells as they have become arranged in distinctive silhouettes. architectural features visualized with scanning magnification are requisite if an algorithmic method based on pattern analysis for specific diagnoses of skin diseases is to be used effectively for inflammatory diseases and for proliferations of various kinds with expressed in melanocytes, langerhans cells, neutrophils, and nerves within the skin. in some settings, macrophages may also be detected with anti s100 protein antibodies. it is important to note that virtually all melanocytes, whether occurring singly in the epidermis, as benign nevus nests, or as melanoma cells, express s100 protein within their cytoplasms. reported sensitivity rates have been reported for less common subtypes including mucosal, sinonasal and desmoplastic melanomas. metastatic melanoma is also almost always detected with antis100 protein antibodies. melanomas may fail to express s100 protein, though this is exceedingly uncommon. when attempting to identify a subpopulation of cells within the epidermis, it is important to evaluate the immunostaining in concert with the routine histology in order to separate langerhans cells from melanocytes. (the addition of anti-cd1a antibody would further help in this distinction, as langerhans cells invariably express this antigen, while melanocytes do not). more commonly, dermatopathologists are asked to identify a population of poorly differentiated spindle-shaped cells within the dermis. in this setting, anti-s100 protein antibodies can be an invaluable aid. virtually all desmoplastic melanomas express this protein, and virtually none of the other neoplasms in this histologic differential diagnosis do so. thus, results from this test are very helpful in narrowing a differential diagnosis, and when used in conjunction with other antibodies, can help establish a diagnosis in most cases. satellite lesion: (see metastasis of melanoma) satellitosis: a metastasis within 5 centimeters of the primary neoplasm, which sometimes is apparent in the same tissue section; an evidence of distant metastases. the terms satellite, in-transit, regional and distant applied to metastasis are artificial and misleading and not necessary. saucerization: a variant of shave removal using a razor blade, which is bowed for deeper removals. (see razor blade removal) scale: a collection of cornified cells seen clinically as a dry, thin flake which may assume various sizes, shapes, and colors. scale may consist of orthokeratotic cells, parakeratotic cells, or both of them jointly, it being lodged usually atop surface epidermis but sometimes being contained within the invagination formed by infundibular epidermis. scale is described as micaceous (i.e., the confluent parakeratosis of psoriatic plaques), branny (i.e., the focal scale-crust of seborrheic dermatitis), powdery (i.e., the orthokeratosis of tinea versicolor in which the normal basket-weave pattern of the thickened cornified layer is preserved), adherent (i.e., the confluent compact and laminated orthokeratosis of ichthyosis vulgaris and x-linked ichthyosis), coarse (i.e., the focal vertical 14 review | dermatol pract concept 2015;5(2):1 a puny inferior segment, and one or more large sebaceous glands. sebaceous secretion: is holocrine secretion of overmature sebaceous cells. it represents the end product of maturation of sebocytes. sebocyte: is a synonym for sebaceous cell, a cell derived in embryonic life from a follicular germ. immature sebocytes have round nuclei and scant, slightly vacuolated cytoplasm; mature sebocytes have scalloped nuclei and markedly vacuolated cytoplasm. sebocytes in an embryo originate in the middle bulge at the junction of the infundibulum and isthmus. sebocytes are aggregated in lobules that, in conglomerate, form a gland; a duct collects sebaceous (holocrine) secretion and transports it to an infundibular epidermis, from whence it is carried, as sebum, through an ostium to the surface of the skin. seborrheic: purportedly relating to sebaceous glands or sebum. in actuality, however, conditions such as seborrheic dermatitis and seborrheic keratosis bear no direct relationship to sebaceous glands or to sebum. seborrheic distribution of lesions refers to sites like those involved by seborrheic dermatitis, to wit, the forehead, malar region, paranasal and nasolabial folds, retroauricular region, and sternal region. sebum: is constituted mostly of sebaceous secretion and other materials that are carried with it in its journey through a sebaceous duct and epidermal infundibulum to the skin surface, namely, squames, pityrosporum ovale and orbiculare, staphylococcus epidermidis, propionibacterium acnes, and demodex . secretion: is a process whereby a specific product is elaborated as a result of the activity of a gland. secretion also may refer to any substance that is produced by the act of secreting. the major kinds of secretion are those that are discharged on an internal or external surface of the body (i.e., by way of an exocrine gland) and those that secrete hormones that are dispatched into blood and lymph (i.e., by way of an endocrine gland). the glands in skin produce secretions of different types, i.e., merocrine by eccrine glands, apocrine by apocrine glands, and holocrine by sebaceous glands. merocrine, apocrine, and holocrine secretions are all exocrine. secretory: pertains to a process whereby a specific product is elaborated by cells of a gland. secretion and excretion are two processes by which cells extrude their products. if the extruded material is to be used by the organism, the process is called secretion; if the extruded material is waste, the process is called excretion. all three glands in skin, namely, eccrine, apocrine, and sebaceous, are secretory. regard to benign verses malignant proliferations the silhouette reflects the biologic behavior. there are exceptions. scar: a type of fibrosis that represents the end stage of an inflammatory process or the end result of a wound healing, that early in its course resulted in destruction of preexisting tissue, evolved through granulation tissue, and eventuated in fibroplasia. formation of granulation tissue, the scaffold on which fibroplasia usually proceeds, is a sign that healing of the wound has commenced. histopathologically, a scar rather early in its course is made up of altered bundles of collagen in conjunction with a marked increase in the number of fibrocytes, both of those elements being oriented mostly parallel to the skin surface, and in association with what seems to be an increase in the number of dilated venules aligned mostly perpendicular to that surface and in the amount of mucin. years later, the number of fibrocytes is so markedly decreased that sometimes they are identifiable with difficulty. in contrast, a keloid is a type of fibrosis that consists of strikingly thickened, brightly eosinophilic, homogeneous-appearing collagen bundles disposed randomly and affiliated with an increased number of plump fibrocytes that parallel the long axis of the thickened bundles. a dermatofibroma is another type of fibrosis in which coarse collagen bundles and many fibrocytes are arranged haphazardly, sometimes being joined by siderophages and lipophages that signify extravasation in the dermis previously of erythrocytes secondary to trauma at that particular site. other findings encountered commonly in a dermatofibroma are fibrocytes and/or histiocytes interspersed between distinctly thickened bundles of collagen at the periphery of the lesion, acanthosis, and hyperpigmentation of the epidermis. normal skin markings tend to be effaced when those three forms of fibrosing inflammation, i.e., scars, keloids, and dermatofibromas, encroach severely on the papillary dermis and impinge on the epidermis. sclerosis: clinically, a condition of hardness of the skin and, histopathologically, a type of fibrosis characterized by near obliteration of boundaries between bundles of collagen, the result being the appearance of the bundles having become blended (“homogenization”) and by marked decrease in the number of fibrocytes. sclerosis usually indicates that fibroplasia has been longstanding. examples of sclerosis are the thickened papillary dermis of lichen sclerosus et atrophicus and much, or all, of the dermis of chronic radiation dermatitis. morphea, other than the form of it confined to the upper part of the dermis and known as lichen sclerosus et atrophicus, is not typified by sclerosis; collagen bundles in a lesion of morphea formed fully are crowded but, nonetheless, discrete. at that stage, fibrocytes in morphea are decreased in number. “sebaceous follicle”: refers to a vellus-hair follicle on a face characterized by a prominent epidermal infundibulum, review | dermatol pract concept 2015;5(2):1 15 surface for the purpose of sampling exophytic lesions such as verrucae, seborrheic keratoses, fibroepithelial polyps, melanocytic nevi, and cherry hemangiomas. some flat lesions of melanoma-in situ in sites like the tip of the nose and in bowen’s disease and basal cell carcinomas are sometimes amenable to the shave technique. unfortunately, the procedure is abused when it is used to biopsy inflammatory diseases of all kinds, proliferations that are mostly endophytic, and elevated pigmented lesions suspected of being melanoma. these alltoo-common practices are to be deplored because they often harvest inadequate specimens that prevent histopathologists from using criteria effective for diagnosis, criteria that have been formulated on the basis of sections cut from satisfactory biopsy specimens taken by scalpel excision. this technique using a razor blade can be modified to perform saucerization which can provide satisfactory “biopsies” of pigmented and other lesions if used properly and selectively. (see razor blade removal, see saucerization) sheath: denotes a structure that encloses or surrounds a body. in skin, most sheaths are composed of fibrous tissue, the most notable being the perifollicular connective tissue sheath that extends along the entire outer sheath to the base of the infundibular epidermis. the follicular sheath is separated by a basement membrane from the epithelial component of a follicle. nerve fascicles in skin also are associated with three connective tissue sheaths, the epineurium, perineurium, and endoneurium. shell out: describes a method whereby certain benign proliferations and cysts are eased from their housings with a scalpel or other instrument and transported to the skin surface along a path formed by an artifactual cleft that developed between compressed encompassing fibrous tissue and normal skin or subcutaneous fat. siderophage: a macrophage that has ingested iron. signet-ring cell: describes a mucin producing adenocarcinomatous cell whose cytoplasm is filled completely with mucin and is distended by it. mucin causes the nucleus to be compressed and displaced to the side of a cell, thereby causing the entire cell to resemble a signet ring. the signet part is the nucleus at the side of the cell, the ring portion is the cytoplasm at the periphery of the cell, and the space reserved to accommodate a finger is the mucin. other proliferations have been said to have cells that simulate this appearance (i.e. signet ring cells in some melanomas). silhouette: is a representation of the outline of something, usually filled in with black or another solid color. in the mind’s eye of a histopathologist, the contours of a proliferation or a cyst can be filled in with solid colors and made into silhouettes. observation of a proliferation at scanning segment: refers to two fundamentally different parts of a hair follicle, namely, the upper and the lower. the upper segment consists of isthmus. it does not participate in the ever-repeating cyclic changes of a follicle. the lower segment is made up of two parts, namely, the stem above and the bulb below. the lower segment undergoes characteristic morphologic and functional changes during a follicular cycle that are designated growing (anagen), involuting (catagen), and resting (telogen). semantics: the meaning of a word, phrase, or text septa: refers usually to struts of connective tissue that divide a normal or pathologic structure into compartments, for example, fibrous septa that partition fat lobules of normal subcutaneous tissue, granulomatous and fibrotic septa that form fenestrations in subcutaneous fat of erythema nodosum, and fibrous septa that create units composed of clusters of proliferative apocrine cells and mucin in mucinous carcinoma. septal panniculitis: an inflammatory process in the panniculus adiposis in which, as viewed at scanning magnification, the infiltrate of inflammatory cells is situated mostly in the septa rather than in the lobules. in many instances the overlap with lobular may make distinction difficult. serum: is the fluid portion of the blood obtained after removal of the fibrin clot and blood cells, distinguished from plasma in circulating blood. sessile: means attached by a base broad, in contrast to a polyp which is attached by a peduncle. shadow cells: are ones cornified in which, as a consequence of karyolysis, nuclei have faded but an outline vague of them still can be recognized. these cells represent attempts faulty at differentiation toward hair and are found only in conditions in which some follicular matrical cells are present, examples of that being panfolliculoma, pilomatricoma, matricoma, matrical carcinoma, desmoplastic trichoepithelioma, and mixed tumors with apocrine, follicular and sometimes sebaceous differentiation. rarely, “shadows cells” may be present in trichoblastomas and trichoblastic (basal cell) carcinomas, both of those proliferations consisting mostly of germinative cells. “shadow cells” tend to become calcified, a phenomenon that is visualized at first as sprinkling of delicate particles basophilic within corneocytes arranged compactly and later as obscuration complete of corneocytes by material homogeneous and purple. in pilomatricoma, “shadow cells” often act as a nidus for osseous metaplasia by fibrocytes. shave (tangential, horizontal) biopsy technique: describes a procedure performed with a surgical blade or razor blade directed mostly parallel to the skin 16 review | dermatol pract concept 2015;5(2):1 cystoadenomas are mostly cystic. solid carcinoma designates a distinctive histopathologic variant of apocrine carcinoma. specimen: designates a sample of tissue taken by a surgical procedure in preparation for examination by conventional microscopy in order to determine particular characteristics of it from which inferences (diagnoses) may be drawn. a distinction exists· between a specimen of skin removed by a surgical instrument from a person and sections of skin that represent slivers cut by a microtome from a specimen. spindle-shaped cell: having the shape of a spindle, i.e., being like a stick with ends tapered used to form and twist yarn in spinning by hand. true spindle-shaped melanocytes are thin and are met with more often in melanoma than in the type of nevus paid heed most by spitz in 1948 and in which large cells constituent tend to be fusiform, often in conjunction with ones round, plump oval, polygonal, and plasmacytoid; never do spindle-shaped melanocytes arrayed in fascicles monopolize in “classic” spitz’s nevus, although they do predominate in what spitz in 1948 referred as a “spindle cell tumor.” last, it must be stressed that spindleshaped melanocytes do not qualify as “spitz’s cells,” the sine qua non for which is cytoplasm copious; a true “spindle cell” of any kind, including one melanocytic, has cytoplasm paltry. in short, although spindle-shaped melanocytes may appear among “spitz’s cells” in a “classic” spitz’s nevi, they are not, in themselves “spitz’s cells.” thus “true” spindle shaped cells contrast with fusiform shaped cells, whether referring to the above or those found in other melanocytic nevi, including “blue nevus.” solid cystic: describes the two elements that constitute various proliferations, benign and malignant, one of them being made up of cells arranged compactly (solid) and of the other cells that line a sac containing fluid or material (cystic), the example quintessential of the phenomenon being one presentation histopathologic of apocrine (solid cystic) hidradenoma. spir-: is a prefix used to convey a sense for relation to a structure that spirals. in dermatopathology, spirtraditionally has referred to the spiral of the component intraepidermal of an eccrine duct, i.e., to the acrosyringium, and perforce to proliferations thought to be eccrine in character. the terms eccrine spiradenoma and eccrine acrospiroma, however, are misnomers because both spiradenoma and some proliferations included under the rubric of acrospiroma (i.e., pale or clear-cell hidradenoma) show apocrine, rather than eccrine, differentiation. because the segment distal of an apocrine duct spirals through infundibular epidermis, the concept and the word acrosyringium is applicable equally to the apocrine, as well as the eccrine duct. magnification of a conventional microscope enables histopathologists to imagine, among other things, its silhouette. the silhouette of a proliferation is the morphologic representation of the biological behavior of that proliferation. for example, a silhouette that is symmetric, vertically oriented, wedgeshaped, and sharply circumscribed with smooth borders indicates that a proliferation, if primary in skin, is likely to be benign. a silhouette that is asymmetric, poorly circumscribed, and jagged in outline nearly always signifies that a proliferation, if primary in skin, is malignant. all too often, textbooks of general pathology emphasize cytologic details almost exclusively as criteria for differentiating benign from malignant proliferation, whereas, in actuality, features of silhouette are more compelling in regard to that distinction because they are more consistent morphologic reflections of biological behavior. in short, accurate diagnosis of cutaneous proliferation requires assessment of silhouette at scanning magnification and of cytologic features at higher magnifications. the entire range of magnifications, from scanning to high, is complementary in enabling a histopathologist to come to a specific, accurate diagnosis. sinus: an epithelium-lined channel in the skin that opens on the surface, usually through an infundibular ostium. in contrast to a fistula that is open on both ends, neither of which needs to be in continuity with an infundibulum, a sinus is open at one end only. examples of a cutaneous sinus are seen in lesions of the so-called follicular occlusion triad, all of which begin as explosive suppurative infundibulitides/folliculitides, namely, acne conglobata, hidradenitis suppurativa, and dissecting cellulitis of the scalp (to which should be added a fourth analogue, i.e., acne keloidalis). a sinus forms as a result of re-epithelialization of an infundibulum as it attempts to restore itself to its original state after having burst and ejected its contents, mostly of neutrophils, into the dermis, where those polymorphs are joined, in time, by histiocytes in company with lymphocytes and plasma cells, and, eventually, by fibrocytes. the failed attempt of an infundibulum to reconstitute itself in that setting is manifested as a sinus which invariably, is accompanied by fibrosis. sinus tract: (see sinus) solar elastosis: elastotic material, i.e., the altered, bluish, spaghetti-like connective tissue produced by fibrocytes that have been affected by sunlight over the course of decades. this is a sign of longstanding damage to the skin by the effects of ultraviolet light. solid: designates a substance or tissue that is not fluid, gaseous, or hollow. the term is applied in dermatopathology to proliferations that are neither tubular nor cystic. for example, poromas and cylindromas are mostly solid. apocrine hidradenomas are solid and cystic. apocrine papillary review | dermatol pract concept 2015;5(2):1 17 proliferations common, i.e., verruca vulgaris and seborrheic keratoses. squamoid cells: (see squamoid) squamous eddies: are whorls made up of spinous cells mostly, but also of granular and cornified cells, that presumably come into being as a consequence of the spiral of sebaceous ducts through infundibular epidermis. the circumstance most common for development of “squamous eddies” is verruca vulgaris, and the next most common is seborrheic keratosis. most of the time, “squamous eddies” are a sign of a benign condition and also of irritation of the lesion (i.e. seborrheic keratosis.) stage: usually refers to the extent of spread of a malignant proliferation. clinical stages for melanoma have been defined by the american joint committee on cancer and the new york university melanoma cooperative group. the value of these stagings is debatable by some. stellate: shaped like a star, arranged in a roset or rosets. stem: describes the upper part of the lower segment of a follicle that resembles the stem of a flower, a slender stalk that derives from a bulb and that supports a “flower” (upper segment of isthmus and infundibular epithelium). the course of a stem is from adamson’s fringe below to desquamation of corneocytes of the inner sheath above (from the top of the bulb to the base of the isthmus). in terminal follicles in anagen, the stem is the longest part. storiform: refers to a pattern created by the interweaving of fascicles of oval and spindle cells that causes it to resemble the intersecting intertwining pattern of a doormat. strand: refers to epithelial and nonepithelial cells arranged in single file, in contrast to a cord, in which cells are arranged in rows of two, and columns, in which cells are arranged in formations more than two cells wide. strands may be seen in benign conditions, such as melanocytes splayed in a single file between bundles of collagen of the reticular dermis in a superficial type of congenital nevus, and in malignant ones, such as metastatic carcinoma to the skin from a breast. stratified squamous epithelium: consists of cells of different shapes, i.e., columnar, cuboidal, and polygonal, that flattens progressively as they come nearer to the free surface. stratified squamous epithelium, such as the epidermis, may cornify completely and be free of nuclei in its outermost cells or, as in mucous membranes, may cornify partially and retain nuclei in its outermost cells. stroma: designates the connective tissue component of a proliferation of epithelial cells. it may be edematous, mucinous, or fibrous or it may contain globules of amyloid. some spitzoid: in general, any lesion that resembles histopathologically a “classic” spitz’s nevus. the term spitzoid melanoma has been applied to a melanoma that has some attributes histopathologic of that nevus. spitz’s cells: melanocytes of the size and shape of those pictured in most photomicrographs by spitz in her article seminal of 1948, they being ones of “classic” spitz’s nevus and having a large nucleus, abundant cytoplasm, and round, fusiform, and polygonal shapes especially. spongiform pustule: a collection of neutrophils in the spinous and granular zones of the epidermis. remnants of cell membranes give the pustule a sponge-like appearance. spongiosis (intercellular edema): of the epidermis and of epithelial structures of adnexa, expressed morphologically by widened spaces between spinous cells and by intercellular bridges that stretch across those extended spaces in company with a sprinkling of cells, usually inflammatory ones foreign normally to the epidermis. although spongiosis nearly always is mediated by inflammatory cells, particularly by lymphocytes but sometimes by eosinophils and even by neutrophils, it may be induced by neoplastic lymphocytes, such as those of mycosis fungoides. in short, spongiosis is a distinctive pattern of cutaneous epithelium brought into being usually by inflammatory cells and unusually by neoplastic ones. some spongiotic inflammatory processes may eventuate in vesicles clinically, such as allergic contact dermatitis, nummular dermatitis, dyshidrotic dermatitis, and “id” reactions, whereas others, such as seborrheic dermatitis, erythema annulare centrifugum, and pityriasis alba, do not progress to vesicles. practically never does spongiosis in mycosis fungoides culminate in a vesicle. spontaneous: means self-generated, which is incompatible with biologic processes. therefore, all so-called spontaneous phenomena like spontaneous keloids and spontaneous regression of melanoma are not spontaneous at all. the former results from external trauma and the latter from the effects of lymphocytes on the melanocytes. squame: designates a lone corneocyte, particularly one that has become detached from its neighbors, as happens, commonly following rupture of an infundibular type of follicular cyst. in that circumstance, squames often are found free in the dermis or subcutaneous fat, or within multinucleate histiocytic giant cells. the term “squame” does not apply to physiologic desquamation of clumps of epidermal corneocytes. squamoid: means resembling cells of the spinous zone of surface or the infundibular epidermis, in contrast to basaloid cells that look like basal cells of that epithelium. proliferations of basaloid and squamoid cells are found together in some 18 review | dermatol pract concept 2015;5(2):1 part of the reticular dermis. capillaries from the superficial plexus loop into the dermal papillae. supramatrical zone: designates the zone in a follicular bulb situated between the matrix below and the keratogenous zone above. it is bounded by the critical line at its base and by the b-fringe at its surface. multiplication of cells that originated in the matrix has almost stopped by the time the supramatrical zone has been reached, in preparation for formation of hair. (see keratogenous zone, see b fringe) suprapapillary plate: the portion of the epidermis situated immediately above the summit of dermal papillae. suppuration: formation and exudation of pus, i.e., a creamy viscous fluid that consists of a daunting collection of neutrophils mostly, but also debris, both cellular and non-cellular, that results from necrosis and degeneration consequent to the effects of destructive enzymes released from polymorphonuclear leukocytes. accumulation of pus in a cavity of a cavernous organ is called empyema. suppuration in skin may manifest itself as tiny pustules (i.e., munro’s micro abscesses and kogoj’s spongiform pustules) and as large abscesses (i.e., secondary to rupture of an infundibular cyst and in infectious processes, such as those caused by atypical mycobacteria and deep fungi). within cutaneous epithelium, foci of suppuration may appear in both surface and infundibular epidermis, and in eccrine glands and ducts. abscesses also may develop in the midst of the dermis or in the subcutaneous fat. syringo-: designates a tube such as is characteristic of some structures constituent of syringoma and of syringomatous carcinoma, but also of many other proliferations of character eccrine, apocrine, and sebaceous. syringotropism: a biological phenomenon that indicates growth or turning movement of a cell or a collection of cells toward an eccrine gland. in a strictly morphologic sense it is not definable. adj. syringotropic. the following terms would be better; intrasyringeal: placed within an eccrine gland; perisyringeal: present around an eccrine gland. syringotropic is not defined in medical dictionaries, or in textbooks of dermatopathology. however, it is constantly used in articles, especially in those about histopathology of mycosis fungoides. strictly speaking, the suffix tropism implies movement, the best example being the turning or bending phenomenon that plants undergo in response to light as the environmental stimulus, called phototropism. literally, syringotropism means a “turning toward the eccrine gland” or having an affinity for the eccrine gland respectively. a review of this word in the literature reveals a constant association with one condition only: mycosis fungoides. the proliferations may be associated with stroma copious, i.e., fibrofolliculoma/ trichodiscoma, trichoblastoma, and the fibroepitheliomatous type of trichoblastic (basal cell) carcinoma, whereas other proliferations are accompanied by little or no stroma, i.e., cylindroma, sebaceoma, and infundibulocystic trichoblastic (basal cell) carcinoma. understanding of stroma can be very helpful in determining whether a lesion is benign or malignant. stroma like that of perifollicular sheath in an embryo: refers to highly fibrocytic, richly vascular connective tissue made up chiefly of delicate fibrillary bundles of collagen in combination with mucin plentiful, the constellation of findings being reminiscent of that seen around a follicle developing in an embryo. subcorneal pustule: a collection of neutrophils situated immediately beneath the cornified layer of the epidermis. subcutaneous: denotes being situated beneath the dermis and therefore beneath the skin. the skin itself consists only of epidermis and dermis. the subcutaneous fat was known in times past as the hypodermis because it lies immediately beneath the skin. a distinction exists between subcutaneous fat and subcutaneous tissue. subcutaneous fat consists predominantly of adipocytes. at the base of the subcutaneous fat is fascia, or aponeurosis, and beneath it sits skeletal muscle. lesions that arise in or are situated in the dermis and subcutaneous fat are considered to be housed in superficial soft tissues, whereas those found below the fascia are regarded as being within deep soft tissues. dermatopathology overlaps with “soft tissue” pathology; although most regard it as a separate field of pathology. superficial atypical melanocytic proliferation of uncertain significance (sampus): a phrase employed for diagnosis by david elder, his associates, and followers of them to designate a “category” that “includes predominantly junctional melanocytic proliferations and melanocytic proliferations that are confined to the epidermis and papillary dermis, “without evidence of tumorigenic proliferation or mitotic activity there.” because the term is generic, rather than specific, it is not a diagnosis precise but a description recondite and, at the same time, an acknowledgment of doubt about behavior biologic, adding nothing to what should be an effort with determination to arrive at a diagnosis with precision based on an understanding profound of melanocytic proliferations. now is the time to jettison that phrase fuzzy before it becomes yet another example of gobbledygook in the language of general pathology and dermatopathology. superficial vascular plexus: refers to venules and arterioles situated beneath the papillary dermis in the upper review | dermatol pract concept 2015;5(2):1 19 are described by words that finish with tropism or tropic is that dermatopathologists use these words only for malignant conditions. confronted with exactly the same morphologic finding, namely, lymphocytes in eccrine glands, syringotropism is used only after having decided already on a malignant condition, usually mycosis fungoides. when the diagnosis of a benign condition, i.e., lupus erythematosus or neutrophilic hidradenitis, is made the cell infiltrates are not termed tropic. in addition, the term seems only to apply to lymphocytes, not eosinophils or neutrophils. systematic: concerning a system or organized according to a system. systemic: pertinent to a whole body rather than to one of its parts; somatic. systemization: the process of organizing something according to plan. systematized: arranged according to an organized system. words syringotropism and syringotropic are employed in the cases of mycosis fungoides in which neoplastic lymphocytes are found in the epithelia of eccrine glands. in fact, this criterion has led to two subtypes of mycosis fungoides, namely, the so-called syringotropic and folliculotropic. (see folliculotropism) there are only occasional exceptions in the usage of these words in reference to entities other than mycosis fungoides, but interestingly nearly all are malignant: melanoma, bowenoid carcinoma, skin metastases of other carcinomas, etc. occasionally, syringotropic is used for an inflammatory disease. what dermatopathologists intend to describe by the word syringotropic is the biopsies in which lymphocytes are placed mostly in the eccrine units, i.e., those specimens in which cells have a clear affinity for these adnexa. but this is not exclusive of mycosis fungoides. many other diseases, much more common and benign, display cells with tendency for adnexa. examples are neutrophilic hidradenitis or lichen striatus to mention but some of them. the reason why none of these research | dermatol pract concept 2011;1(1):13 59 objectives: the aim of this study was to calculate the horizontal growth rate of melanoma in vivo and to correlate it with morphologic findings. patients and methods: we searched our database for melanomas for which sequential dermatoscopic images and histopathologic slides were available. the final sample consisted of 50 melanomas of 48 patients (mean age: 50 ± 15 years, 62% females). we calculated the horizontal growth rate in mm2 per year by morphometric analysis of digital dermatoscopic images. dermatoscopic and dermatopathologic findings were assessed according to predefined criteria and correlated with the horizontal growth rate. results: the median time interval between baseline and follow-up image was 12 months (range: 2–100 months). the majority of melanomas were in situ (n=28, 56%). the mean horizontal growth rate of all melanomas was 5.3 mm2/year (sd: ± 5.8 mm2/year). the histopathologic findings of numerous and large epidermal nests were associated with rapid growth. this histopathologic pattern corresponded to a pattern of clods (“globules”) dermatoscopically. from a dermatoscopic point of view, melanomas with a main pattern of clods grew significantly faster (mean horizontal growth rate: 10.4 mm2/year, 95% ci: 6.4-14.4 mm2/year) than melanomas with mainly a reticular pattern (4.8 mm2/year, 95% ci: 2.7-7.0 mm2/year) or with other patterns (2.6 mm2/year, 95% ci: -0.5-5.6 mm2/ year, p=0.01). conclusion: morphologic characteristics of melanoma are associated with biologic behavior. large and numerous epidermal nests (corresponding to a pattern of clods dermatoscopically) indicate more rapid growth. abstract growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings jürgen beer, m.d.1, lina xu, m.d.1, philipp tschandl, m.d.1, harald kittler, m.d.1 1department of dermatology, division of general dermatology, medical university of vienna, austria key words: horizontal growth rate, melanoma in vivo, dermotoscopy citation: beer j, xu l, tschandl p, kittler h. growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings. dermatol pract concept 2011;1(1):13. http://dx.doi.org/10.5826/dpc.0101a13. editor: alon scope, m.d. received: february 1, 2011; accepted: june 21, 2011; published: october 31, 2011 copyright: ©2011 beer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: harald kittler, md, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. e-mail: harald.kittler@meduniwien.ac.at. dermatology practical & conceptual www.derm101.com 60 research | dermatol pract concept 2011;1(1):13 introduction little is known about the growth rate of melanoma in vivo, but it has been speculated that it varies between different types of melanomas. applying the classification of clark [1], nodular melanomas are believed to grow faster than superficial spreading or lentigo maligna melanomas. it is known that melanoma subtype per se is not associated with prognosis, but there is some evidence that the growth rate of melanoma is an independent predictor of survival [2]. as liu et al [3] pointed out there is also a potential indirect impact of the growth rate on prognosis that is related to the penalty associated with diagnostic delay that is particularly severe with rapidly growing melanomas and less severe with slowly growing melanomas. the growth rate of melanoma in vivo is difficult to measure. it is a dynamic process and neither its direction nor its magnitude can be assessed on a static image or slide. theoretically, it can be divided in a horizontal and in a vertical growth phase. the vertical growth rate has been estimated indirectly based on information provided by patients and their families, but this method is unreliable. the use of digital dermatoscopy to monitor melanocytic skin lesions has resulted in the availability of sequential dermatoscopic images of melanoma. these images may be used to obtain unbiased measurements of the horizontal growth rate of melanomas in vivo and to identify dermatoscopic and dermatopathologic characteristics that are associated with slow or rapid growth. identification of these factors would increase our knowledge on the biology of melanoma and would be a step forward towards an integrated classification. it would have important practical implications on early recognition and on the selection of lesions for digital monitoring. methods we included consecutive cases of histopathologically verified melanomas collected between january 1998 and december 2009 for which sequential dermatoscopic images were available. the study was approved by the internal review board of the medical university of vienna. all melanomas were initially monitored because of lack of melanoma specific criteria in the setting of patients with multiple nevi. the original sample consisted of 72 cases. twenty-two cases were excluded because of one of the following reasons: (1) histopathologic slides were not available (n=2), (2) the melanoma was larger than the maximum field of view of the digital camera or was only partly captured all so that the area covered by the lesion could not be calculated (n=9), and (3) review of the histopathologic slides by a board certified dermatopathologist did not result in an unequivocal diagnosis of melanoma (n=11). the final sample included 50 cases. the majority of cases were monitored only once and then excised because of significant changes over time. if melanomas were monitored more than once the observed changes at the first follow-up visit were not considered significant enough to warrant excision. one case was monitored more than once because the patient refused excision despite significant changes of the lesion after the first follow-up visit. all digital dermatoscopic images were captured with molemax ii ™ (derma medical systems, vienna, austria). the device offers a field of view of 10.8 x 8.1 mm. images were stored in bitmap format with a resolution of 640 x 480 pixels. to capture an image the device has to be in direct contact with the skin. the molemax ii ™ system uses cross-polarization. since only flat lesions are selected for monitoring, shearing or flattening, which may influence area measurements of raised or polypoid lesions, does not occur. operators were instructed not to stretch the skin during examination. the digital dermatoscopic images were analyzed with the image analysis software melanie (freely available from the corresponding author on request) that was specifically designed for the purpose of analyzing pigmented skin lesions. the program performs a semiautomatic segmentation of the lesion from the background and computes the area of the lesion in square pixels. after conversion of square pixels into square millimeters, we calculated the horizontal growth rate per year by subtracting the area of the baseline image from the area of the follow-up image and dividing the result by the follow-up time in years. assessment of dermatoscopic patterns for the purpose of this study we used the method of pattern analysis as described by kittler for dermatoscopic analysis [4]. this method uses a standardized description of pigmented lesions based on patterns, colors, and clues. a pattern is a collection of multiple basic elements of the same type that covers a significant part of the lesion. basic elements including dots, lines, clods, and circles are given objective geometric definitions. a dot is a tiny round spot (no length, no breadth). a line is a structure with parallel edges where the length is much greater than the breadth. a clod is any solid object larger than a dot and may have any shape. globules, therefore, are a variant of clods that are small and elliptical. a circle is a curved line equidistant from a fixed point. an area without any of the basic elements dominating is termed structureless. a pigmented lesion may have a single pattern or multiple patterns. we classified the melanomas into the following three categories according to their main patterns: (1) those with mainly reticular lines, (2) those with mainly clods, and (3) and those with other patterns (dots and/or structureless). baseline dermatoscopic images were evaluated research | dermatol pract concept 2011;1(1):13 61 by 2 observers (h.k. and j.b.) on a computer screen to define their pattern. assessment of dermatopathologic criteria histopathologic sections of melanomas were examined by a board certified dermatopathologist (h.k.) without knowledge of the dermatoscopic images. we rated four different criteria: upward scatter, nesting, nest size and cell size. with regard to upward scatter and nesting, we adopted the definitions as described by viros et al [5]. all four histopathologic criteria were defined in advance: 1. upward scatter was defined as the proportion of intraepidermal melanocytes present above the basal layer, irrespective of whether suprabasal melanocytes were arranged singly or as nests. it was graded from 0 to 3 using the following criteria: 0, essentially all melanocytes situated at the dermo-epidermal junction, with only rare melanocytes in higher epidermal layers; 1, the majority of melanocytes (75%–100%) situated at the dermoepidermal junction, with some present in higher epidermal layers; 2, roughly equal proportions of intraepidermal melanocytes present at the dermo-epidermal junction and in higher epidermal layers; and 3, most (>50%) of the intraepidermal melanocytes situated in the upper layers of the epidermis. 2. nesting was defined as collections of intraepidermal melanocytes that form clusters of five or more cells. the degree of nesting was quantified as: 0, intraepidermal melanocytes present almost exclusively as single cells with only rare nests; 1, intraepidermal melanocytes predominantly arranged as single cells with no more than 25% of cells in nests; 2, 25%–50% of the intraepidermal melanocytes in nests; and 3, >50% of the intraepidermal melanocytes in nests. a schematic drawing of nesting is shown in figure 1. 3. with regard to nest size we defined small nests as clusters of five to nine cells, whereas large nests were defined as clusters of ten or more cells. the proportion of large nests measured against the total number of nests was quantified as: 0, intraepidermal melanocytes present almost exclusively as single cells; 1, intraepidermal nests predominantly arranged as small nests with no more than 25% large nests; 2, 25%–50% of the intraepidermal nests are large nests; and 3, >50% of the intraepidermal nests are large nests. 4. to determine cell size, the diameter of basal keratinocytes was used as a size reference. cell size referred to the entire cell including the nucleus and cytoplasm. visual assessment of size was quantified on a continuous rating scale from 1 to 3 using the following definitions: 1, the diameter of tumor cells was similar to or smaller than that of basal keratinocytes; 2, the diameter was larger than that of basal keratinocytes, but not larger than twofold; and 3, the diameter was larger than the twofold diameter of basal keratinocytes. statistical analysis continuous data are given as mean and standard deviation (sd) unless otherwise specified. we used analysis of variance (anova) for the comparison of the horizontal growth rates figure 1. schematic drawing of scoring of nesting. a: intraepidermal melanocytes present almost exclusively as single cells with only rare nests (score=0); b: intraepidermal melanocytes predominantly arranged as single cells with no more than 25% of cells in nests (score=1); c: 25%–50% of the intraepidermal melanocytes in nests (score=2); d: >50% of the intraepidermal melanocytes in nests (score=3). figure 2. sequential dermatoscopic images of a melanoma with a pattern of clods. (a) baseline image; (b) follow up image. the baseline image was taken 5.1 months before the follow-up image. the size at baseline was 32.6 mm2 and after follow-up 38.9 mm2. the increase in size was 6.3 mm2, which corresponds to a horizontal growth rate of 1.1 mm2 per month. 62 research | dermatol pract concept 2011;1(1):13 table 1: melanomas according to observed pattern n % melanomas with a single pattern reticular 13 26% clods 2 4% dots 0 structureless 5 10% melanomas with multiple patterns reticular and clods 2 4% reticular and dots 8 16% reticular and structureless 7 14% clods and dots 2 4% clods and structureless 3 28% dots and structureless 5 10% others 3 6% total 50 100% table 2: histopathologic criteria by main dermatoscopic pattern reticular (n=28) dots/structureless (n=13) clods (n=9) scatter no scatter, almost all melanocytes at the dermo-epidermal junction 9 (32.1%) 6 (46.2%) 3 (33.3%) 75–100% of melanocytes at the dermo-epidermal junction, <25% in higher layers of the epidermis 13 (46.4%) 7 (53.8%) 6 (66.7%) 50–75% of melanocytes at the dermo-epidermal junction, <50% in higher layers of the epidermis 6 (21.4%) 0 0 more than 50% of melanocytes in higher levels of the epidermis 0 0 0 nesting almost all melanocytes arranged as single cells 8 (28.6%) 5 (38.5%) 0 < 25% of melanocytes arranged in nests 5 (17.9%) 2 (15.4%) 1 (11.1%) 25–50% of melanocytes arranged in nests 10 (35.7%) 3 (23.1%) 1 (11.1%) >50% of melanocytes arranged in nests 5 (17.9%) 3 (23.1%) 7 (77.8%) nest size intraepidermal melanocytes present almost exclusively as single cells 11 (39.3%) 7 (53.8%) 1 (11.1%) intraepidermal nests predominantly arranged as small nests with no more than 25% large nests 11 (39.3%) 1 (7.7%) 1 (11.1%) 25–50% of the intraepidermal nests are large nests 3 (10.7%) 3 (23.1%) 1 (11.1%) >50% of the intraepidermal nests are large nests 3 (10.7%) 2 (15.4%) 6 (66.7%) cell size smaller than that of basal keratinocytes 9 (32.1%) 8 (61.5%) 1 (11.1%) larger than that of basal keratinocytes, but not larger than twofold 18 (64.3%) 5 (38.5%) 7 (77.8%) larger than the twofold diameter of basal keratinocytes 1 (3.6%) 0 1 (11.1%) research | dermatol pract concept 2011;1(1):13 63 figure 3. micrographs of the melanoma shown in figure 2. the neoplastic melanocytes in the epidermis are mainly arranged in nests. more than 50% of these nests are large. a b c e g d f 64 research | dermatol pract concept 2011;1(1):13 between groups. we adjusted for size differences at baseline by including the size of the melanoma at baseline as a covariate. the pearson correlation coefficient was used for correlation of continuous data. all given p-values are 2-tailed and a p-value of <0.05 indicates statistical significance. results general data the final sample consisted of pairs of sequential images of 50 melanomas from 48 patients (mean age: 50 ± 15 years, 62% females). the median time interval between baseline and follow-up image was 12 months (range: 2–100 months). the majority of melanomas were in situ (n=28.56%). the median breslow thickness of invasive melanomas was 0.50  mm (range: 0.20 to 0.90 mm). twenty-six melanomas (52%) were located on the trunk, 12 (24%) on the lower extremities, 7 (14%) on the upper extremities, and 5 (10%) on the head and neck. the original histopathologic diagnosis was superficial spreading melanoma in 38 cases (76%) and lentigo maligna or lentigo maligna melanoma in 8 cases (16%). the remaining 4 cases (8%) were unclassified. twenty-one melanomas (42%) had one dermatoscopic pattern and 29 (58%) more than one pattern. the frequencies of dermatoscopic patterns are given in table 1. in 28 melanomas (56%) the main pattern was reticular, nine melanomas (18%) had mainly clods, and 13 melanomas (26%) had other patterns (dots and/or structureless). the mean area size at baseline was 22.6 mm2 (sd: ± 13.0 mm2). melanomas with a main pattern of clods were significantly larger at baseline than melanomas with other dermatoscopic patterns. dermatoscopic/dermatopathologic correlation the dermatopathologic characteristics by dermatoscopic patterns are given in table 2. the dermatoscopic pattern of clods was associated with nesting and nest size dermatopathologically (figures 2 and 3). nests dominated in 77.8% (n=6) of lesions with a pattern of clods and large nests were found in 66.7% (n=5). reticular melanomas or melanomas with other patterns on the other hand were characterized by a predominance of single cells or small nests (figures 4 and 5). horizontal growth rate the mean horizontal growth rate of all melanomas was 5.3  mm2 per year (sd: ± 5.8 mm2 per year). the annual growth rate did not correlate with patients’ age (pearson correlation coefficient=-0.22, p=0.13) and was similar for females (5.4 ± 5.5 mm2/year) and males (5.1 ± 6.4 mm2/ year, p=0.86). superficial spreading melanomas did not grow significantly faster than lentigo maligna or lentigo maligna melanomas (6.2 ± 5.8 mm2/year versus 3.9 ± 2.5 mm2/year, p=0.27). we observed no significant differences in the horizontal growth rates of in situ and invasive melanomas (4.3 ± 5.5 mm2/year for in situ versus 6.4 ± 6.1 mm2/year for invasive melanomas, p=0.21). anatomic site was also not associated with the horizontal growth rate. the horizontal growth rate was significantly related to the type of dermatoscopic pattern. it was highest for melanomas with a pattern of clods (9.6 ± 7.8mm2), followed by reticular melanomas (5.1 ± 3.9 mm2), and was lowest for melanomas with a structureless pattern and/or a pattern of dots (2.6 ± 6.4 mm2, p=0.012, figure 6). significant regression occurred in four melanomas, two with a pattern of clods and two with other patterns. the association between dermatopathologic findings and the horizontal growth rate is shown in figure 7. the scores for scatter, nesting, nest size and cell size were significantly associated with the horizontal growth rate. figure 4. sequential dermatoscopic images of a melanoma with a reticular pattern. (a) baseline image; (b) follow up image. the baseline image was taken 35.4 months before the follow-up image. the size at baseline was 12.6 mm2 and after follow-up 18.8 mm2. the increase in size was 6.2mm2, which corresponds to a horizontal growth rate of 0.2 mm2 per month. research | dermatol pract concept 2011;1(1):13 65 figure 5. micrographs of the melanoma shown in figure 4. the neoplastic melanocytes in the epidermis are mainly arranged as single cells. a b c e g d f 66 research | dermatol pract concept 2011;1(1):13 discussion to date, our knowledge of melanoma development has been based on static, not on dynamic observations. with the rare exceptions of patients who refused excision, it has not been possible to observe the growth rate of melanomas directly. indirect measurements of the vertical growth rate based on patient recall have been used instead but are believed to be unreliable. by reviewing sequential dermatoscopic images of 50 melanomas that were not excised at the patients’ first visit, mainly because of lack of melanoma specific criteria, we were able to obtain unbiased measurements of the horizontal growth rate by morphometric studies. as expected, the melanomas in our sample grew at different speeds. some grew relatively fast with a horizontal growth rate of up to 21.6 mm2 per year, others grew slowly or not at all. the horizontal growth rate as observed by us is a net effect of the horizontal spread of proliferating, pigmented melanoma cells minus antagonistic effects due to regression. on average the horizontal growth rate was 5.3 mm2 per year. this estimate has to be interpreted with caution because it is an extrapolation (some melanomas were monitored for less than one year). assuming that the growth curve of melanoma is exponential (disregarding the antagonistic effect of regression) we can estimate that it would take approximately 3.5 years for a typical melanoma in our sample to grow from a square with a side length of 0.5 cm to a square with a side length of 1 cm. since the range of growth rates was large in our sample, we looked for morphologic criteria that were associated with slow or rapid horizontal growth. in applying the classification of clark [1] we found that the horizontal growth rate of superficial spreading melanomas was higher than of lentigo maligna melanomas, but this difference was statistically not significant. with the limitation that nodular melanomas were not represented in our sample, the results of our analysis do not support the validity of the classification by clark, at least with respect to its significance with regard to biologic behavior. the significance of other histomorphologic features was much greater. nesting and nest size were strongly associated with the horizontal growth rate (figure 7). melanomas with numerous and large epidermal nests grew significantly faster than melanomas with mainly single cells or small nests. the significance of this finding is underlined by the fact that melanomas with numerous and large epidermal nests are characterized by a pattern of clods dermatoscopically. scatter and cell size were also associated with the horizontal growth rate, but these histopathologic characteristics are not associated with dermatoscopic findings and are therefore of limited clinical value. the melanoma with a pattern of clods shown in figure 2 grew more than 5 times faster than the melanoma with a reticular pattern shown in figure 4. although the increase in size was similar in both cases, the follow-up interval was more than five times longer in the case of the reticular melanoma. the finding that the growth rate of melanomas with a pattern of clods is significantly higher that of those with other dermatoscopic patterns is of great clinical importance. usually pigmented lesions are selected for monitoring because of diagnostic uncertainty. if lesions with a pattern of clods are selected for digital monitoring, it should be kept in mind that they may turn out to be rapid growing melanomas. since the penalty associated with diagnostic delay is particularly severe with rapid growing melanomas, digital monitoring for lesions with a dermatoscopic pattern of clods should be perfigure 6. horizontal growth rate by dermatoscopic pattern: the growth rate was highest for melanomas with a pattern of clods (p for difference: 0.012). figure 7. horizontal growth rate by dermatopathologic findings. the scores for scatter (p=0.035), nesting (p=0.009), nest size (p=0.012), and cell size (p=0.048) were significantly associated with the horizontal growth rate. all p-values are derived from analysis of variance (anova). research | dermatol pract concept 2011;1(1):13 67 formed with caution. the penalty associated with diagnostic delay is less severe with slow growing melanomas. slow growing melanomas in our sample had a reticular pattern, a structureless pattern, or a pattern of dots. this is in line with the observation of argenziano et al [6] who found out that the reticular pattern dominates in slow growing melanomas. according to our findings it is relatively unproblematic to select flat lesions with one of these patterns for monitoring. it is, however, indicated to choose a monitoring interval that reflects the slow growth of these types of melanomas. one year would be a reasonable choice. our study has several limitations. the most important one is selection bias due to the fact that all melanomas in our series were initially selected for monitoring because of lack of melanoma specific criteria. this may favor the selection of slow growing melanomas and may bias our results. another limitation is that the vertical growth rate could not be assessed. we consider this a minor limitation because there is no vertical growth as long as melanomas grow in situ. the basal membrane constitutes a natural boundary that impedes vertical growth. after the basal membrane has been penetrated by tumor cells they grow in all directions, and it probably makes no sense to differentiate between horizontal and vertical growth. it should also be kept in mind that the growth rate is a dynamic parameter that is most useful in vivo and to date only the horizontal growth rate but not the vertical growth rate can be measured in vivo. once a melanoma has been excised and the vertical tumor thickness has been measured, it is of limited value to know how long it took to get there. on the other hand, it would have important practical implications for early recognition and selection of lesions for digital monitoring if we are able to differentiate between rapidly and slowly growing melanomas in vivo by dermatoscopy. the integration of clinical, dermatoscopic, dermatopathologic, and biologic findings is the only way to profoundly increase our understanding of melanoma. taken by itself, each of these aspects alone will not be able to fully explain a complex neoplasm like melanoma. our study and those of others are important initial steps towards an integration of different aspects of melanoma. viros et al [5], for example, successfully correlated molecular and morphologic aspects of melanoma. with regard to the recent advances in molecular genetics it can be expected that future studies will also integrate molecular aspects, like, for example, the role of activating braf mutations, with dynamic biologic findings. references 1. clark wh jr, from l, bernardino ea, mihm mc. the histogenesis and biologic behavior of primary human malignant melanomas of the skin. cancer res 1969;29(3):705-27. 2. grob jj, richard ma, gouvernet j, et al. the kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study. int j cancer 2002;102(1):34-8. 3. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol 2006;142(12):1551-8. 4. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual 2007;13(1):3. 5. viros a, fridlyand j, bauer j, et al. improving melanoma classification by integrating genetic and morphologic features. plos med 2008;5(6):e120. 6. argenziano g, kittler h, ferrara g, et al. slow-growing melanoma: a dermoscopy follow-up study. br j dermatol 2010;162(2):26773. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2013;3(4):6 29 case presentation a 69-year-old japanese man presented with pigmented skin lesions on the inguinal regions (figure 1). the lesions were first noticed three years earlier, and they subsequently spread to the chest (figure 2) and back. the patient had no specific symptoms but reported that his father had had similar lesions. physical examination showed dark brown macules of up to 20 mm in diameter with partial confluence (figure 3). some of the macules were intermingled with atrophic whitish areas interiorly. the macules on the chest tended to be smaller (maximum diameter: 5 mm) and lighter in color than those on the back. dermoscopy demonstrated central brown pigmentation with many blue-gray dots surrounded by a single hypopigmented band, namely “white track” at the periphery (figure 4). the peripheral border of the white track showed light brown pigmentation, making the white track recognizable. there was no whitish linear structure corresponding to wickham’s striae often seen in lichen planus. a biopsy was taken from the peripheral ridge of a brown macule on the right inguinal area. inguinal porokeratosis in a japanese man yuka hayashi1, masahiko ozeki1, sumiko ishizaki1, mariko fujibayashi2, yoshihiko mitsuhashi3, miki izumi4, masaru tanaka1 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of pathology, tokyo women’s medical university medical center east, tokyo, japan 3 department of dermatology, tokyo medical university, tokyo, japan 4 department of medical education, tokyo medical university, tokyo, japan key words: porokeratosis, genital, inguinal, dermoscopy citation: hayashi y, ozeki m, ishizaki s, fujibayashi m, mitsuhashi y, izumi m, tanaka m. inguinal porokeratosis in a japanese man. dermatol pract conc. 2013;3(4):6. http://dx.doi.org/10.5826/dpc.0304a06. received: may 19, 2013; accepted: july 21, 2013; published: october 31, 2013 copyright: ©2013 hayashi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: masaru tanaka, m.d., department of dermatology, tokyo women’s medical university medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: masarutanaka@1984.jukuin. keio.ac.jp inguinal and genital porokeratosis are rare but seem to be more common in asians. we report a case of a 69-year-old japanese man with multiple lesions of porokeratosis in both inguinal regions. the lesions first appeared in the inguinal region and subsequently spread to the trunk. the patient reported that his father had had similar lesions. dermoscopy demonstrated central brown pigmentation and blue-gray dots surrounded by a single “white track” at the periphery. the exterior border of the white track also showed light brown pigmentation. genital or inguinal porokeratosis is uncommon and may be misdiagnosed as bowen’s disease, lichen planus or extramammary paget’s disease. however, awareness of this entity and the use of dermoscopy are helpful to establish a correct diagnosis. abstract 30 observation | dermatol pract concept 2013;3(4):6 histopathological examination showed a parakeratotic column, the so-called ‘cornoid lamella (figure 5). irregular arrangement of keratinocytes with pyknotic nuclei, in addition to perinuclear edema were noted in the epidermis underneath the parakeratotic column. no granular layer was found at the site of parakeratosis. a nonspecific perivascular lymphocytic infiltrate intermingled with melanophages was present in the upper dermis. the clinico-pathological features established the diagnosis of disseminated superficial porokeratosis. discussion porokeratosis is inherited in an autosomal dominant pattern. five different forms can be distinguished, including the plaque type of mibelli, disseminated superficial actinic porokeratosis (some lesions of this type are distributed mainly in areas not exposed to the sun or appear in patients on immunosuppresfigure 1. a 69-year-old japanese man presented with a three-year history of pigmented skin lesions in the inguinal regions. [copyright: ©2013 hayashi et al.] figure 3. dark brown macules of up to 20 mm in diameter were noted in the inguinal area with partial confluence in some areas. some of the macules intermingled with interiorly atrophic whitish areas. [copyright: ©2013 hayashi et al.] figure 5. histopathological examination showed a cornoid lamella and irregular arrangement of keratinocytes underneath the parakeratotic column. no granular layer was found at the site of parakeratosis. a nonspecific perivascular lymphocytic infiltrate intermingled with melanophages was present in the upper dermis. [copyright: ©2013 hayashi et al.] figure 4. dermoscopy demonstrated central brown pigmentation with many blue-gray dots surrounded by a single hypopigmented band, namely “white track” (between black arrows) at the periphery. [copyright: ©2013 hayashi et al.] figure 2. light brown, smaller macules subsequently appeared on the trunk. [copyright: ©2013 hayashi et al.] observation | dermatol pract concept 2013;3(4):6 31 conclusion because genital or inguinal porokeratosis is very rare, though more common in asians and often mimics extramammary paget’s disease, bowen’s disease or lichen planus, dermoscopic examination is useful when the “white track” structure is detected at the periphery of the macule. references 1. johnson bl, yan ac. porokeratosis. in: elder de, elenitsas r, johnson bl, murphy gf (eds.). lever’s histopathology of the skin, 10th ed. philadelphia: lww, 2009:139-41. 2. bunker cb, neill sm. male genital dermatology. in: burns t, breathnach s, cox n, griffiths c (eds.). rook’s textbook of dermatology, 8th ed. west sussex: wiley-blackwell, 2010:71.37. 3. chen tj, chou yc, chen ch, kuo tt, hong hs. genital porokeratosis: a series of 10 patients and review of the literature. br j dermatol. 2006:155(2);325-9. 4. delfino m, argenziano g, nino m. dermoscopy for the diagnosis of porokeratosis. j eur acad dermatol venereol. 2004:18(2);194-5. 5. zaballos p, puig s, malvehy j. dermoscopy of disseminated superficial actinic porokeratosis. arch dermatol. 2004:140(11);1410. sants), linear porokeratosis, porokeratosis plantaris palmaris et disseminata and punctuate porokeratosis [1]. genital porokeratosis is extremely rare, but classical lesions have been reported on the penis and scrotum [2,3]. chen et al [3] reported 10 cases of genital porokeratosis in asian patients and the lesions in three of their patients were in genital and adjacent areas, with one patient presenting with inguinal lesions. it seems that genital porokeratosis is more common in asian populations [2]. the lesions in our patient appeared first in the inguinal area and subsequently spread to the trunk. since the lesions on the trunk were relatively subtle compared to those in the inguinal area, the patient only complained of the latter lesions on the initial examination, thus the differential diagnosis included lichen planus linearis. however, dermoscopic examination demonstrated typical features characteristic of porokeratosis, namely a “white track” or “whitish-yellowish annular” structure [4,5]. as reported by chen et al [3], genital porokeratosis is extremely rare and some of their cases were clinically indistinguishable from extramammary paget’s disease, bowen’s disease or lichen planus. accordingly, dermoscopic examination is essential and of great help. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(2):e2020047 1 dermatology practical & conceptual case presentation a 55-year-old woman with a personal history of 2 previous melanomas was referred for assessment. full-skin examination revealed few nevi, mostly dome-shaped dermal subtype, cherry angiomas, and seborrheic keratosis. on her back, a clinically banal-looking lesion was found close to a melanoma scar (figure 1a). dermoscopy initially revealed typical findings pointing to intradermal nevus with cobblestone pattern and area of fibroses attributed to trauma; when lateral pressure was exerted, the basis of the lesion was exposed, revealing pseudopods and globules irregularly distributed at the periphery of the lesion (figure 1, b-d). the lesion was excised and histopathology reported in situ melanoma associated with dermal nevus. teaching point training and utilization of dermoscopy is recommended for clinicians routinely examining skin lesions. dermoscopy must be applied to all lesions and not just to those suspicious from a clinical point of view [1]. when facing raised or pedunculated lesions, the base of the lesion must be examined. in this case, dermoscopy additionally provided crucial information for early recognition of a melanoma that might have been overlooked if it had been assessed solely by the naked eye. reference 1. seidenari s, longo c, giusti f, pellacani g. clinical selection of melanocytic lesions for dermoscopy decreases the identification of suspicious lesions in comparison with dermoscopy without clinical preselection. br j dermatol. 2006;154(5):873-879. hidden melanoma gabriel salerni,1,2 carlos alonso2 1 dermatology department, hospital provincial del centenario de rosario, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina key words: melanoma, dermoscopy, melanoma incognito, diagnosis citation: salerni g, alonso c. hidden melanoma. dermatol pract concept. 2020;10(2):e2020047. doi: https://doi.org/10.5826/ dpc.1002a47 accepted: february 13, 2020; published: april 3, 2020 copyright: ©2020 salerni and alonso. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, bv. oroño 1441, cp 2000, rosario, argentina. email: gabrielsalerni@hotmail.com https://doi.org/10.5826/dpc.1002a47 https://doi.org/10.5826/dpc.1002a47 mailto:gabrielsalerni@hotmail.com 2 image letter | dermatol pract concept 2020;10(2):e2020047 figure 1. (a) banal-looking lesion, clinically consistent with dermal nevus, close to melanoma scar. (b-d) with lateral pressure, globules and pseudopods irregularly distributed at the periphery were observed in the base upon dermoscopy. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):9 39 dermatoscopic pattern dermatoscopic features of spiradenoma—a benign adnexal neoplasm—have not been described. we present a case of spiradenoma occurring on the occipital scalp (figure 1a, 1b) that showed a structureless pattern and blue clods on dermatoscopy. the vascular pattern of serpentine, branched vessels (figure 2) in combination with blue clods suggest a basal cell carcinoma (bcc) [1]. however, the blue clods in bcc represent nests of pigmented trichoblasts, whereas in this case of spiradenoma the blue clods correspond to hemorrhage, a frequent finding in spiradenoma. this example also demonstrates that branched vessels seen by dermatoscopy are not specific and that they can be found in any kind of adnexal neoplasm, not only in bcc. dermatoscopic pattern of a spiradenoma philipp tschandl, m.d.1 1 department of dermatology, division of general dermatology, medical university of vienna, austria key words: dermatoscopy, spiradenoma, adnexal neoplasm citation: tschandl p. dermatoscopic pattern of spiradenoma. dermatol pract conc. 2012;2(4)9:. http://dx.doi.org/10.5826/dpc.0204a09. received: april 4, 2012; accepted: july 3, 2012; published: october 31, 2012 copyright: ©2012 tschandl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: philipp tschandl, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. 43.1.40400.7700; fax. 43.1.408.1928. e-mail: philipp.tschandl@meduniwien.ac.at. figure 1. (a) clinical picture of the spiradenoma on the scalp. (b) clinical closeup image. [copyright: ©2012 tschandl.] figure 2. dermatoscopically, blue and orange clods as well as branched vessels can be seen. [copyright: ©2012 tschandl.] 40 observation | dermatol pract concept 2012;2(4):9 reference 1. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermtol. 2004;140(12):1485-9. figures 3 and 4 show the histopathologic images of this tumor. one can see large aggregations containing two cell populations, small basaloid cells on one side and large cuboidal cells on the other, and a prominent pas-positive eosinophilic band is visible at the periphery of the aggregations. the latter feature is reminiscent of a cylindroma but the aggregates of cells are too large. cylindroma-like features may be encountered in spiradenomas and sometimes these two entities occur together suggesting a common origin of these two adnexal neoplasms. figure 4. the aggregations in the dermis are made up of two cell populations, small basaloid cells on one side and large cuboidal cells on the other, and a prominent pas-positive eosinophilic band is visible at the periphery of the aggregations. [copyright: ©2012 tschandl.] figure 3. histopathologic image at scanning magnification reveals large aggregations of epithelial cells in the dermis and a hemorrhage in the deep reticular dermis. [copyright: ©2012 tschandl.] dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020052 1 dermatology practical & conceptual introduction regression within cutaneous melanoma has been previously described as a spontaneous or therapy-induced phenomenon, driven by the activation of the immune system [1]. however, simultaneous development of regression in both melanoma and multiple melanocytic nevi is an extremely rare event, having been reported only twice in the literature [1,2]. case presentation a 76-year-old caucasian man came to our attention for lymphadenopathy of a 3-cm right inguinal lymph node (figure 1a), subsequently diagnosed histopathologically as nodal melanoma metastasis. upon total body skin examination, multiple suspicious lesions on the trunk and limbs showed dermoscopic evidence of regression. four of the lesions met additional atypical dermoscopic criteria and were excised to rule out primary melanoma (figure 1, b-d). the excised lesions were flat and located on the right lower limb, right abdomen, and right upper arm. the histopathological diagnosis of the right lower limb lesion (ipsilateral to the nodal metastasis) was a primary melanoma with breslow thickness of 0.3 mm, no ulceration, wide regression (>75%), and fibrosis of the superficial dermis (figure 2, a and b). the remaining 3 lesions were dysplastic nevi with regression and fibrosis (figure 2, c and d). a total body ct scan showed brain, adrenal, lymphatic, and bone metastases. as the nodal metastasis proved braf (v600k, v600r, v600m) positive, combined target therspontaneous regression of primary melanoma and multiple melanocytic nevi in a patient with metastatic melanoma giovanni paolino,1,2 nathalie rizzo,3 riccardo pampena,4 pietro bearzi,1 alessandra bulotta,5 vanesa gregorc,5 pina brianti,1 elisa moliterni,2 santo raffaele mercuri1 1 unit of dermatology, irccs ospedale san raffaele, milan, italy 2 dermatologic clinic, la sapienza university of rome, italy 3 department of pathology, irccs ospedale san raffaele, milan, italy 4 centro oncologico ad alta tecnologia diagnostica, azienda unità sanitaria locale—irccs di reggio emilia, italy 5 department of medical oncology, irccs ospedale san raffaele, milan, italy key words: cutaneous melanoma, regression, dermoscopy, dysplastic nevi, dermatopathology citation: paolino g, rizzo n, pampena r, bearzi p, bulotta a, gregorc v, brianti p, moliterni e, mercuri sr. spontaneous regression of primary melanoma and multiple melanocytic nevi in a patient with metastatic melanoma. dermatol pract concept. 2020;10(3):e2020052. doi: https://doi.org/10.5826/dpc.1003a52 accepted: february 19, 2020; published: june 29, 2020 copyright: ©2020 paolino et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. pietro bearzi, unit of dermatology, irccs ospedale san raffaele, via olgettina, 60, 20132, milano, italy. email: pietro.bearzi@gmail.com https://doi.org/10.5826/dpc.1003a52 mailto:pietro.bearzi@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020052 we suggest that the presence of multiple metastases in our case induced a vigorous immune response, leading to regression of the primary melanoma (right lower limb) and other melanocytic lesions sharing the same antigens. this is confirmed by the presence of dermoscopic and histological regression in the primary melanoma and the excised dysplastic nevi. the role of regression in the prognosis of melanoma is debated [1]. indeed, there is still no consensus as to whether the regression is associated with a worse or better prognosis. on one hand, the presence of wide regression (>75%) may “hide” the primary melanoma, eventually delaying the diagnosis with a consequent worse prognosis [2]. furthermore, since melanoma cells can escape t-cell-mediated destruction by the production of immunosuppressive cytokines and the downregulation of hla class i [1], metastasis can easily apy with braf and mek inhibitors ensued. at 6 months follow-up, metastases showed mild regression and no other melanocytic nevi developed regression features. conclusions regression in melanoma occurs 6 times more often than in other malignancies and relates to melanocytes’ elevated immunogenicity [1]. indeed, circulating antibodies against melanocyte cytoplasmic proteins have been isolated in melanoma patients and tumor-specific cd8+ t cells are present in melanoma-associated vitiligo [1]. moreover, in vitro cytotoxic t lymphocytes from melanoma tissue have been shown to target differentiation antigens shared with normal melanocytes [1]. figure 1. (a) right inguinal lymphadenopathy with overlying inflammation. histology revealed it was a nodal melanoma metastasis. (b) pigmented lesion on the right calf (dimensions: 1.5 × 1 cm), with no sign of ulceration. upper left insert: dermoscopy revealed asymmetric pigmentation, white central areas with scar-like depigmentation and mild peppering. histopathological diagnosis: invasive malignant melanoma (see figure 2, a and b). (c) pigmented lesions on the right abdomen (diameter: 5 mm each) with clinical signs of regression. upper right insert: dermoscopy showed central scar-like depigmentation and asymmetric globules on the right part of the lesion. histological diagnosis: dysplastic nevus (see figure 2c). lower left insert: other pigmented lesion on the abdomen, showing similar clinical and dermoscopic features. histological diagnosis: dysplastic nevus. (d) pigmented lesion on the right upper arm (diameter: 1 cm) with signs of regression. upper left insert: dermoscopy revealed central scar-like depigmentation, with minimal central ectatic vessels and a peripheral brown pigmentation. histology: dysplastic nevus (see figure 2d). letter | dermatol pract concept 2020;10(3):e2020052 3 thickness underestimation and the capability of melanoma to escape tumor surveillance [1,2]. references 1. gualano mr, osella-abate s, scaioli g, et al. prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis. br j dermatol. 2018;178(2):357362. https://doi.org/10.1111/bjd.15552. 2. lallas a, apalla z, moscarella e, et al. extensive regression in pigmented skin lesions: a dangerous confounding feature. dermatol pract concept. 2012;2(2):8. https://doi.org/10.5826/dpc.0202a08. spread in melanomas with wide regression. on the other hand, t lymphocytes may proliferate until the antigenic trigger (melanoma cells) is present [2]. finally, as reported in the literature [2], the presence of regression increases the likelihood of a positive braf mutation. in conclusion, the simultaneous presence of regression in melanoma and benign melanocytic lesions results from the immune response against melanocytic antigens expressed by both cell lineages [1,2]. dermoscopic regression in multiple melanocytic lesions should increase awareness for malignancy. primary melanoma regression >75% in the primary melanoma increases the risk for metastasis, due to breslow figure 2. (a) the histology of the excised lesion on the right lower limb, revealed to be an invasive malignant melanoma. breslow thickness: 0.3 mm (h&e, ×100). (b) another histological specimen of the melanoma of panel a: regression >75%, signs of fibrosis in the superficial dermis, scattered melanophages, and patchy lymphocytic infiltration of the stroma (h&e, ×100). (c) the excised pigmented lesion on the right abdomen (upper right insert of figure 1c) resulted in a dysplastic nevus with signs of regression and fibrosis in the upper dermis (h&e, ×100). (d) the excised pigmented lesion on the right upper arm (figure 1d) resulted in a dysplastic nevus: signs of regression, fibrosis of the upper dermis, and scattered melanophages (h&e, ×100). https://doi.org/10.1111/bjd.15552 https://doi.org/10.5826/dpc.0202a08 untitled observation | dermatol pract concept 2015;5(2):23 113 dermatology practical & conceptual www.derm101.com proton pump inhibitor-induced sweet’s syndrome: report of acute febrile neutrophilic dermatosis in a woman with recurrent breast cancer philip r. cohen1 1 department of dermatology, university of california san diego, san diego, ca, usa key words: acute, breast, cancer, dermatosis, esomeprazole, febrile, inhibitor, neutrophilic, omeprazole, proton, pump, sweet, syndrome citation: cohen pr. proton pump inhibitor-induced sweet’s syndrome: report of acute febrile neutrophilic dermatosis in a woman with recurrent breast cancer. dermatol pract concept 2015;5(2):23. doi: 10.5826/dpc.0502a23 received: september 18, 2014; accepted: december 30, 2014; published: april 30, 2015 copyright: ©2015 cohen. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: sweet’s syndrome, also referred to as acute febrile neutrophilic dermatosis, can either occur as an idiopathic disorder or associated with another condition, including cancer, or induced by exposure to a drug. proton pump inhibitors selectively inhibit gastric parietal cell h+-k+-adenosine triphosphatase and are most commonly used for the treatment of gastroesophageal reflux disease. purpose: proton pump inhibitor-associated sweet’s syndrome is described in a woman with recurrent breast cancer. methods: pubmed was used to search the following terms, separately and in combination: acute febrile neutrophilic dermatosis, breast cancer, malignancy, paraneoplastic, proton pump inhibitor, and sweet’s syndrome. all papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. results: proton pump inhibitors have previously been associated with cutaneous adverse reactions including maculopapular rash, subacute cutaneous lupus erythematosus and toxic epidermal necrolysis. however, drug-induced sweet’s syndrome has not been observed in patients receiving proton pump inhibitors. the reported woman developed sweet’s syndrome after initial exposure and subsequent repeat challenge to proton pump inhibitors; subsequent studies also observed recurrence of her breast cancer presenting as metastases to her stomach and bone. conclusions: drug-induced sweet’s syndrome has most commonly been associated with granulocyte colony stimulating factor in oncology patients. malignancy-associated sweet’s syndrome has been observed in patients with solid tumors, including breast cancer. confirmation of proton pump inhibitorinduced sweet’s syndrome, by repeat challenge with another medication in the same class of drug, was observed in a woman with breast cancer; although the subsequent discovery of recurrent breast cancer presenting as gastric mucosa and vertebral metastases also raises the possibility of concurrent paraneoplastic sweet’s syndrome, her sweet’s syndrome symptoms and lesions resolved without recurrence while her recurrent metastatic visceral malignancy persisted. in summary, medication-associated sweet’s syndrome can occur in oncology patients and proton pump inhibitors should be added to the list of medications associated with the potential to cause drug-induced sweet’s syndrome. abstract 114 observation | dermatol pract concept 2015;5(2):23 hands recurred. cutaneous examination showed tender, erythematous to violaceous, pustules and pseudovesicular plaques, ranging in size from 5 mm to 3 cm in diameter, predominantly on the proximal palms of both hands (figures 1, 2 and 3). similar lesions were also noted on the distal left palm proximal to the left second digit and the left ventral thumb (figure 3), the lateral side of the left second digit (figures 4 and 5), and the dorsal left thumb (figures 4 and 6). microscopic examination of a biopsy from the left dorsal wrist showed parakeratosis with neutrophilic pustule formation in the epidermis. there was edema in the upper dermis and a dense interstitial inflammatory infiltrate in both the superficial and deep dermis. the infiltrate was comprised mostly of neutrophils; lymphocytes and histiocytes were also present. stains to detect bacteria, fungi and mycobacteria were negative for organisms; a separate lesional biopsy for tissue culture was also negative for these organisms and herintroduction sweet’s syndrome is an acute febrile neutrophilic dermatosis typically characterized by the sudden onset of pyrexia, increased number or percent of neutrophils, and painful red skin lesions that consist of a diffuse dermal infiltrate of neutrophils; in addition, the symptoms and lesions promptly respond to systemic corticosteroids [1]. the condition can occur in an idiopathic setting, most commonly in young women associated with a streptococcal pharyngitis [2]. alternatively, its onset can be associated with either other conditions—such as pregnancy, inflammatory bowel disease or cancer—or drugs [3]. a woman with recurrent breast cancer who developed her first episode of sweet’s syndrome after an initial exposure to omeprazole and a recurrence of the dermatosis immediately after receiving a single dose of esomeprazole is described. case report an 86-year-old hispanic woman presented for evaluation of tender lesions on her hands. her past medical history was significant for invasive lobular carcinoma (grade 2, t3n3 with lymphatic vessel invasion, estrogen receptor positive, progesterone receptor negative, and her2/neu negative) of the left breast that was diagnosed 1 year earlier. her initial treatments included mastectomy of the left breast with axillary lymph node dissection and 6 weeks of adjuvant radiation therapy; thereafter, 20 mg of tamoxifen citrate daily was started. follow up evaluation, 9 months after diagnosis, showed no evidence of disease. she presented to her primary care physician 3 weeks earlier with 2 months of loss of appetite, nausea, dyspepsia, and postprandial abdominal bloating. she had also lost 5 pounds. a clinical diagnosis of gastroesophageal reflux disease was made and she was started on 20 mg of omeprazole daily. within 6 days, she developed severe neck pain; 2 days later she had “blisters on her palms.” she was evaluated in the emergency department 8 days after initiating omeprazole; the medication was stopped and she received dilaudid (and subsequently ibuprofen) for her neck pain and ondansetron 4 mg every 8 hours, as needed, for her nausea. the next day her primary care physician prescribed prednisone (40 mg daily for 5 days) for the painful blisters on her hands. she returned for evaluation after completing the prednisone. her neck pain had improved and the lesions on her hands had resolved. however, her gastrointestinal symptoms persisted. the ondansetron was stopped and her primary care physician prescribed 20 mg of esomeprazole daily. within 6 hours after she took her first dose of esomeprazole, the neck pain returned and the skin lesions on her figure 1. distant view of the palms of an 86-year-old woman with proton pump inhibitor-induced sweet’s syndrome. the painful hand lesions appeared within 6 hours after she took an initial dose of esomeprazole. previously, she had developed similar hand lesions on day 8 of omeprazole that resolved after a short course of oral prednisone. [copyright: ©2015 cohen.] figure 2. the right ventral hand show tender erythematous-based pustules and pseudovesicular violaceous plaques on the proximal palm. [copyright: ©2015 cohen.] observation | dermatol pract concept 2015;5(2):23 115 used for monitoring a breast cancer patient’s response to treatment and to detect cancer recurrence. elevation of this marker is seen in oncology patients with therapy-resistant breast cancer or raises concern regarding the possibility of recurrent carcinoma in individuals with previously treatmentresponsive disease. computerized tomography scan of the abdomen with contrast showed a large gastric fundus and body with circumferential wall thickening at the antrum; these findings were compatible with metastatic cancer and postulated to be responsible for her clinical manifestations of gastric outlet obstruction and abdominal symptoms. there was also mild diffuse nodularity of the omentum consistent with peritoneal carcinomatosis. her computerized tomography scan of the chest showed sclerotic lesions in the t8 vertebral body consistent with thoracic skeletal metastases. biopsy of the stomach lining showed sheets of cohesive malignant cells with enlarged atypical nuclei and foamy cytoplasm invading into the gastric mucosa. immunohistopes virus infection. in summary, the pathology findings were those of a neutrophilic dermatosis. there was no history of sore throat, mucosal lesions, or other skin lesions. her leukocyte count was 8,400 cells per cubic millimeter with 72% neutrophils (upper limit of normal = 71%). the remainder of her complete blood counts, serum chemistries, thyroid function tests, urinalysis were normal. direct fluorescent antibody studies for herpes (simplex and varicella zoster) virus and urine culture were negative. correlation of her clinical history, lesion morphology, biopsy pathology and laboratory studies were consistent with the diagnosis of sweet’s syndrome. an association between her exposure to omeprazole and the initial episode of her skin lesions was retrospectively considered. the recurrence of her dermatosis within hours after receiving esomeprazole (a chemically-related proton pump inhibitor), confirmed the suspected diagnosis of drug-induced sweet’s syndrome. additional laboratory studies showed an elevated ca153 of 435.7 u/m (normal < 25.0 u/ml). ca153 is a tumor marker figure 3. the left ventral hand show painful erythematous-based pustules and violaceous plaques on the proximal palm and a similarappearing lesion on the distal palm proximal to the left second digit and the thumb. [copyright: ©2015 cohen.] figure 4. distant lateral view of the left hand shows sweet’s syndrome lesions on the index finger and thumb. [copyright: ©2015 cohen.] figure 5. closer view of the lateral left index finger shows a sweet’s syndrome lesion presenting as a pustule with surrounding erythema. [copyright: ©2015 cohen.] figure 6. closer view of the dorsal left thumb shows an erythematous-based pustular sweet’s syndrome lesion. [copyright: ©2015 cohen.] 116 observation | dermatol pract concept 2015;5(2):23 cancer patients—either in a paraneoplastic setting [7-14] or as an incidental dermatosis occurring in the individual’s lymphedematous arm following ipsilateral mastectomy and lymph node dissection [15-20]. the currently described woman had an established diagnosis of metastatic breast cancer that had been treated; she had achieved a clinical remission. however, the development of sweet’s syndrome and persistent symptoms suggestive of gastroesophageal reflux disease prompted additional investigation that discovered biopsy-confirmed recurrence of her breast cancer presenting with metastasis to the gastric mucosa [21-25]. diagnostic criteria for drug-induced sweet’s syndrome were introduced in 1996 [26]. subsequently, an increasing number of medications have been associated with the development of sweet’s syndrome [27]. granulocyte colony stimulating factor is the most frequently described agent to elicit the dermatosis; as expected, this usually occurs in patients with new or recurrent malignancy who are being treated with antineoplastic therapy and receive the granulocyte colony stimulating factor for treatment-related neutropenia [1,14]. the proton pump is a term that refers to the gastric parietal cell h+-k+-adenosine triphosphatase (atpase); proton pump inhibitors selectively inhibit this enzyme and thereby inhibit gastric acid secretion [28,29]. agents in this class of drugs include dexlansoprozole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, and tenatoprazole [29,30]. the drugs are primarily used to treat gastroesophageal reflux disease in children and adults [31,32]. cutaneous adverse reactions to proton pump inhibitors are uncommon [33]. a retrospective study performed in thailand discovered a prevalence of skin reactions ranging from three to 20 per 100,000 of the treated population. a “maculopapular rash” was the most frequently observed proton pump inhibitor-induced skin reaction [34]. proton pump inhibitor-associated subacute cutaneous lupus erythematosus was initially described in 2005 and its recognition is increasing [35]. a recently published retrospective series of 24 patients from denmark noted the skin rash was widespread with a tendency to bullous lesions and focal skin necrosis and that most individuals had anti-ro/sjogren syndrome a antibodies. twelve and a half percent (3/24) of the patients who developed drug-induced subacute cutaneous lupus erythematosus reacted to more than one proton pump inhibitor, similar to the described patient [36]. life threatening dermatoses secondary to proton pump inhibitors have also been described, albeit rarely [30,37,38]. to the best of my knowledge, proton pump inhibitor-induced sweet’s syndrome has not previously been observed. the currently reported woman had never previously been exposed to proton pump inhibitors; she experienced her initial episode of sweet’s syndrome 8 days after starting omeprazole and chemistry stains showed that the tumor cells were positive for brst-2—a monoclonal antibody that detects gross cystic disease fluid protein 15 (gcdfp-15) which is a specific marker for breast cancer in surgical specimens—and weakly positive (in approximately 10% of tumor cells) for estrogen receptor and progesterone receptor; the cells were negative for her2/ neu. these findings established a diagnosis of metastatic carcinoma and were consistent with a breast primary. treatment for the hand lesions included topical soaks— using a mixture of white vinegar (1 cup) and water (4 cups)— three times daily, followed by applying a thin layer of 0.05% clobetasol cream; topical application of a high potency corticosteroid cream was used for treatment of her skin lesions since she had experienced nausea and gastrointestinal irritation when she had previously received oral prednisone. the clinical presentation of her hand lesions raised the possibility of infection or impetiginization by a bacterial pathogen; therefore, prior to receiving negative tissue cultures from her skin biopsy, empiric therapy (capable of treating methicillin susceptible staphylococcus aureus) with oral cefdinir (300 mg twice daily for 10 days) was also initiated. within 1 week there was significant improvement of the skin lesions: they were no longer painful and had begun to heal. after an additional 7 days, the hand lesions had nearly resolved and the frequency of topical corticosteroid cream applications was progressively decreased and the medication was subsequently discontinued. there was no recurrence of the dermatosis. her metastatic breast cancer was treated with fulvestrant, 500 mg intramuscularly, every 2 weeks. she was also started on denosumab, 120mg subcutaneously, every month to prevent skeletal events. after 3 courses of antineoplastic therapy, her computerized tomography scans did not show any decrease in tumor and her ca153 had increased to 1098.0 u/ml (normal < 25.0 u/ml). in spite of the progression of her metastatic breast cancer, new lesions of sweet’s syndrome had not appeared. discussion malignancy-associated sweet’s syndrome can occur in patients with either hematologic cancer or solid tumors [4]. sweet’s syndrome in oncology patients can be idiopathic or related to a medication they are receiving either to treat the cancer or to manage a drug-induced neutropenia and/or associated with the discovery of a previously undiagnosed malignancy or recurrence of an established neoplasm [5]. paraneoplastic sweet’s syndrome is most commonly observed in patients with acute myelogenous leukemia [6]. solid tumor-associated sweet’ syndrome has most frequently been described in patients with carcinomas of the genitourinary organs, breast, and gastrointestinal tract [7]. however, sweet’s syndrome has also been described in breast observation | dermatol pract concept 2015;5(2):23 117 syndrome suggests the possibility of a drug-induced etiology. the subsequent prompt recurrence of the dermatosis within hours after a non-intentional repeat challenge with a different proton pump inhibitor established the diagnosis of medication-associated sweet’s syndrome. the initial episode cleared after a short treatment course of oral corticosteroid and her recurrence resolved after stopping the proton pump inhibitor and topical treatment with a high potency corticosteroid cream. although the detection of an unsuspected recurrence of her breast cancer with documented new metastatic disease to her stomach and bone raised the possibility of concurrent paraneoplastic sweet’s syndrome, the dermatosis remained in remission while her ca153 tumor marker increased and the antineoplastic therapy-treated metastatic tumor persisted. her second episode within 6 hours after receiving a single dose of esomeprazole. naranjo et al developed a method for estimating the probability of adverse drug reactions [39]. they not only created and studied an adverse drug reaction probability scale (table 1), but also found that their scale was reliable and valid for: (1) assessing a potential adverse drug reaction and (2) assigning a probability category. according to naranjo et al’s adverse drug probability scale, sweet’s syndrome developing as an adverse drug reaction induced by proton pump inhibitors would be assigned to a definite probability category in the reported patient (table 1). in summary, the temporal relationship between initially receiving a proton pump inhibitor and the onset of sweet’s table 1. adverse drug reaction probability scale [a-e] question pa ps are there previous conclusive reports on this reaction? answer score: yes = +1; no = 0 no 0 did the adverse event appear after the suspected drug was administered? answer score: yes = +2; no = -1 yes 2 did the adverse reaction improve when the drug was discontinued or a specifi c antagonist was administered? answer score: yes = +1; no = 0 yes 1 did the adverse reaction reappear when the drug was readministered? answer score: yes = +2; no = -1 yes 2 are there alternative causes (other than the drug) that could on their own have caused the reaction? answer score: yes = -1; no = +2 no [f] 2 did the reaction reappear when a placebo was given? answer score: yes = -1; no = +1 no [g] 1 was the drug detected in the blood (or other fl uids) in concentrations known to be toxic? answer score: yes = +1; no = 0 dnk 0 was the reaction more severe when the dose was increased, or less severe when the dose was decreased? answer score: yes = +1; no = 0 dnk 0 did the patient have a similar reaction to the same or similar drugs in any previous exposure? answer score: yes = +1; no = 0 yes 1 was the adverse event confi rmed by any objective evidence? answer score: yes = +1; no = 0 yes 1 total score 10 [a] abbreviations: dnk, do not know; pa, patient answer; ps, patient score [b] answer all questions and determine score to assess the adverse drug reaction. [c] an answer of “do not know” = 0 score. [d] from the total score, the adverse drug reaction is assigned a probability category: definite (greater than or equal to 9), probable (5 to 8), possible (1 to 4), doubtful (less than or equal to 0). [e] drug = proton pump inhibitor: omeprazole and esomeprazole. [f ] although the detection of recurrent breast cancer raised the possibility of paraneoplastic sweet’s syndrome, the dermatosis remained in remission: (1) after withdrawal of the proton pump inhibitor and either systemic or topical corticosteroid treatment and (2) as the patient’s ca153 tumor marker increased in association with the persistence of her antineoplastic therapy-treated metastatic malignancy. [g] the patient received oral medications for neck pain and nausea following the initial episode of sweet’s syndrome without recurrence of the dermatosis: dilaudid, ibuprofen, and ondansetron. 118 observation | dermatol pract concept 2015;5(2):23 10. verfara g, vargas-machuca i, et al. localization of sweet’s syndrome in radiation-induced locus minoris resistentae. j am acad dermatol 2003;49:907-9. 11. jacobi d, vidal c, gironet n, machet m-c, machet l. pancytopenia and macular rash in a woman with a history of breast cancer. la revue de medecine interne 2003;24:399-400. 12. teng jmc, draper bk, boyd as. sweet’s panniculitis associated with metastatic breast cancer. j am acad dermatol 2007;56:s61s62. 13. surovy am, pelivani n, hegyi i, et al. giant cellulitis-like sweet syndrome, a new variant of neutrophilic dermatosis. jama dermatol 2013;149:79-83. 15. pack jw, mehrotra b, barnett bo, baron ad, venook ap. the sweet syndrome during therapy with granulocyte colony-stimulating factor. ann intern med 1992;116:996-8. 15. petit t, frances c, marinho e, herson s, chosidow o. lymphoedema-area-restricted sweet syndrome during g-csf treatment. lancet 1996;347:690. 16. demitsu t, takaki t. atypical neutrophilic dermatosis on the upper extremity affected by postmastectomy lymphedema: report of 2 cases. dermatologica 1991;183:230-3. 17. garcia-rio i, perez-gala s, aragues m, et al. sweet’s syndrome on the area of postmastectomy lymphedema. j eur acad dermatol venereol 2006;20:401-405. 18. gutierrez-paredes e, gonzalez-rodriguez a, molina-gallardo i, jorda-cuevas e. neutrophilic dermatosis on postmastectomy lymphedema. actas dermosifiliogr 2012;103:649-51. 19. lee ch, le hc, et al. neutrophilic dermatosis on postmastectomy lymphoedema: a localized and less severe variant of sweet syndrome. eur j dermatol 2009;19:641-2. 20. lucas a, betlloch i. erythematous papules on the arm of a mastectomy patient. actas dermosifiliogr 2009;100:231-2. 21. ferri le, onerheim r, emond c. loinitis plastic as the first indication of metastatic lobular carcinoma of the breast: case report and literature review. can j surg 1999;42:466-9. 22. pera m, riera e, lopez r, et al. metaastatic carcinoma of the breast resembling early gastric carcinoma. mayo clin proc 2001;76:205-7. 23. kudo t, matsumoto t, nakamura s, et al. solitary minute metastasis from breast cancer mimicking primary intramucosal gastric signet-cell cancer. gastrointest endosc 2005;62:139-40. 24. arrangoioz r, papavasiliou p, dushkin h, farma jm. case report and literature review: metastatic lobular carcinoma of the breast an unusual presentation. int j surg case rep 2011;2:301-5. 25. fernandes gs, correa ts, carvalho ep, katz a, hoff pm. gastric and endobronchial metastases in a case of lobular breast cancer. 2013;6:555-60. 26. walker dc, cohen pr. timethoprim-sulfamethoxazole-associated acute febrile neutrophiic dermatosis: case report and review of drug-induced sweet’s syndrome. j am acad dermatol 1996;34:918-23. 27. yorio jt, mays sr, ciurea am, et al. case of vemurafenibinduced sweet’s syndrome. j dermatol 2014;41:1-4. 28. kierkus j, oracz g, korczowski b, et al. comparative safety and efficacy of proton pump inhibitors in paediatric gastroesophageal reflux disease. drug saf 2014 37:309-16. 29. ward rm, kearns gl. proton pump inhibitors in pediatrics. mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. pediatr drugs 2013;15:119-31. conclusion drug-induced sweet’s syndrome has been associated with antibiotics, antivirals, biotherapeutics, granulocyte growth factors, nonsteroidal anti-inflammatory drugs, psychotropes, vaccines, and other miscellaneous medications. cancerassociated sweet’s syndrome had been observed in oncology patients with not only hematologic malignancies but also solid tumors; the dermatosis may be either idiopathic, medication-related or paraneoplastic. the reported patient, a woman with a history of treated breast cancer, had never previously taken any proton pump inhibitors; she developed sweet’s syndrome after initial exposure and subsequent repeat challenge to proton pump inhibitors. the first episode of sweet’s syndrome occurred 8 days after starting omeprazole and promptly cleared following the oral administration of corticosteroid whereas the second episode of the dermatosis erupted within hours after a single dose of esomeprazole and gradually resolved after initiating topical treatment with a high potency corticosteroid cream. the diagnosis of sweet’s syndrome, associated with her symptoms of gastroesophageal reflux disease, prompted additional studies that resulted in the unexpected discovery of metastatic breast cancer to her stomach and vertebrae. therefore, in addition to druginduced sweet’s syndrome associated with proton pump inhibitors (which was confirmed by rechallenging the patient with the same class of medication), the woman described in this report may also coincidentally have concurrent paraneoplastic sweet’s syndrome; however, her symptoms and lesions of sweet’s syndrome have not recurred and her metastatic breast cancer has persisted in spite of antineoplastic therapy. references 1. analone cl, cohen pr. acute febrile neutrophilic dermatisis (sweet’s syndrome). curr opin hematol 2013;20:26-35. 2. burrall b. sweet’s syndrome (acute febrile neutrophilic dermatosis). dermatol online j 1999;5(1):8. 3. cohen pr. sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. orphanet j rare dis 2007;2:34. 4. cohen pr, talpaz m, kurzrock r. malignancy-associated sweet’s syndrome: review of the world literature. j clin oncol 1988;6:1887-97. 5. cohen pr, kurzrock r. mucocutaneous paraneoplastic syndromes. seminars in oncology 1997;24:334-59. 6. cohen pr, kurzrock r. paraneoplastic sweet’s syndrome. emergency med 1994;26(2):37-38. 7. cohen pr, holder wr, tucker sb, kono s, kurzrock r. sweet syndrome in patients with solid tumors. cancer 1993;72:2723-31. 8. antony f, holdern ca. sweet’s syndrome in association with generalized granuloma annulare in a patient with previous breast carcinoma. clin exp dermatol 2001;26:668-70. 9. coskun u, gunel n, senol e, et al. a case of sweet’s syndrome developed after the treatment of herpes simplex infection in a metastatic breast cancer patient. j cutan pathol 2002;29:301-4. observation | dermatol pract concept 2015;5(2):23 119 35. almebayadh m, regnier-rosencher e, carlotti a, et al. subacute cutaneous lupus erythematosus induced and exacerbated by proton pump inhibitors. dermatology 2013;226:119-23. 36. sandholdt lh, lauriaviciene r, byum a. proton pump inhibitorinduced subacute cutaneous lupus erythematosus. br j dermatol 2014;170:342-51. 37. kamann s, bauer c, fackler i, przybilla b. anaphylaxis caused by omeprazole. hautarzt 2006;57:1016-20. 38. thakor as, burke a, handfield-jones s, et al. toxic epidermal necrolysis and neutropaenia: complications of omeprazole. australasian j dermatol 2009;50:207-10. 39. naranjo ca, busto u, sellers em, et al. a method for estimating the probability of adverse drug reactions. clin pharmacol ther 1981;30:239-45. 30. bose s, guyer a, long a, banerji a. evaluation and management of hypersensitivity to proton pump inhibitors. ann allergy asthma immunol 2013;111:452-7. 31. tjon ja, pe m, soscia j, mahant s. efficacy and safety of proton pump inhibitors in the management of pediatric gastroesophageal reflux disease. pharmacotherapy 2013;33:956-71. 32. masclee gmc, sturkenboom mcjm, kulpers ej. a benefit-risk assessment of the use of proton pump inhibitors in the elderly. drugs aging 2014;31:263-82. 33. kardaun sh, tupker ra. symmetrical drug-related intertriginous and flexural exanthema (baboon syndrome) induced by omeprazole. int j dermatol 2012;51:1131-44. 34. chularojanamontri l, jiamton s, manapajon a, et al. cutaneous reactions to proton pump inhibitors: a case-control study. j drug dermatol 2012;11(10):e43-e47. dermatology: practical and conceptual commentary | dermatol pract concept 2020;10(1):e2020005 1 dermatology practical & conceptual melanocytic tumors are currently classified as nevi, considered benign; melanomas, considered malignant; and melanocytomas, considered borderline tumors [1]. however, recent studies on the genetic aberrations tend to make this classification problematic. in fact, the genomic analysis shows that both nevi and melanomas present mutations activating a certain number of growth-promoting signaling pathways. tumors labeled as nevi and considered to be benign generally have a single or a small number of pathogenic mutations, often activating the map-kinase pathway (driver mutations), but no apparent additional genomic alterations. tumors labeled as melanomas and considered to be malignant may harbor the same driver mutations detected in those labeled nevi, associated with a variable, generally high, number of additional mutations tending to ablate tumor-suppression mechanisms and to activate additional oncogenic pathways, including cdkn2a, pten, tp53, and tert-promoter mutations (promoting mutations). tumors histologically regarded as problematic, sometimes termed melanocytomas or meltumps, harbor the same driver mutations detected in “nevi” and in “melanomas,” but a lower number of promoting mutations than “melanomas” [1-4]. the study of the distribution of pathogenic mutations has suggested they may occur in certain characteristic sequences [1]. the initial event is often represented by a single mutation, which appears to be different in the different types of lesions: braf in common nevi; n-ras in some congenital and some acquired nevi; gnaq or gna11 in blue nevi; kinase fusions of alk, braf, ros1, ntrk1, ntrk3, met, ret, or map3k8 in spitz nevi; and kinase fusion of ntrk3 in spindle cell nevi of reed [1,5-15]. moreover, in some braf-mutated neoplasms, more specific histological and biological characteristics may be produced by a supervening driver mutation, just as bap1 mutation in bap1-inactivated nevus, ctnnb1 in deep penetrating nevus, and prkar1a in epithelioid blue nevus/ pigmented epithelioid melanocytoma [16-20]. subsequently, other driver and/or promoting mutations may be progressively acquired, because driver mutations tend to induce an increase of cellular proliferation and, consequently, an increase of the probability that additional mutations occur. these supervened genomic aberrations may be ineffective or capable to alter, lightly or severely, a certain number of cell proliferation control mechanisms. if effective, they may lead to an additional enhancement of cell proliferation and, consequently, to an additional probability that other mutations take place, and so forth [1-4]. therefore, in any given tumor, the total amount of the acquired mutations produces a certain risk of neoplastic progression, parallel to a certain risk of melanocytic skin tumors: genetic aberrations and clinicopathological classification carmelo urso1 1 dermatopathology study center of florence, florence, italy key words: melanocytic nevus melanoma, melanocytomas, genetic aberrations, classification citation: urso c. melanocytic skin tumors: genetic aberrations and clinicopathological classification. dermatol pract concept. 2020;10(1):e2020005. doi: https://doi.org/10.5826/dpc.1001a05 accepted: september 29, 2019; published: december 31, 2019 copyright: ©2019 urso. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: carmelo urso, md, dermatopathology study center of florence, via della cernaia, 88, i-50129 florence, italy. email: cylaur@libero.it mailto:cylaur@libero.it 2 commentary | dermatol pract concept 2020;10(1):e2020005 the only common denominators are that “nevi” harbor a single mutation or few more, producing a minimal malignant potential, the amount of which, however, can be different in the different histological types of nevus; “melanomas” show a variable, relatively high, number of additional promoting mutations, producing a high malignant potential, the amount of which, however, can be different in the different histological types of melanomas; “melanocytomas” harbor a relatively small number of additional promoting mutations, producing a relatively low malignant potential, the amount of which, however, can be different in the different histological types of melanocytomas. in short, rather than specific diagnoses, the current diagnostic categories nevus, melanoma, and melanocytoma emerge as generic terms encompassing a great number of heterogeneous unrelated tumors, different in their genetic profiles, in their clinical and histological morphology, and in their malignant potential. conclusions genetic studies suggest that the current classification of melanocytic tumors needs to be critically reevaluated and opportunely updated. in particular, 2 points seem to be put forward by genomic analyses and considered: (1) melanocytic neoplasms sharing the same driver mutations, and consequently having the same pathogenesis, show strong clinicopathological similarities and may constitute a single class of neoplasms or a unique neoplasm; and (2) the malignant potential of every single neoplasm could be potentially estimable, by matching the pathogenic mutational burden with the follow-up data of the patients. references 1. bastian bc, de la fouchardiere a, elder de, et al. genomic landscape of melanoma. in: elder de, massi d, scolyer ra, willemze r, eds. who classification of skin tumours. 4th ed. lyon, france: iarc; 2018:72-75. 2. potrony m, badenas c, aguilera p, et al. update in genetic susceptibility in melanoma. ann transl med. 2015;3(15):210. 3. shain ah, yeh i, kovalyshyn i, et al. the genetic evolution of melanoma from precursor lesions. n engl j med. 2015;373(20):19261936. 4. cancer genome atlas network. genomic classification of cutaneous melanoma. cell. 2015;161(7):1681-1696. 5. pollock pm, harper ul, hansen ks, et al. high frequency of braf mutations in nevi. nat genet. 2003;33(1):19-20. 6. ichii-nakato n, takata m, takayanagi s, et al. high frequency of braf600 mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium sized congenital nevi. j invest dermatol. 2006;126(9):2111-2118. 7. bauer j, curtin ja, pinkel d, bastian bc. congenital melanocytic nevi frequently harbor nras mutations but no braf mutations. j invest dermatol. 2007;127(1):179-182. unfavorable events (recurrences, local and distant metastases, or death). this dual risk can be considered the malignant potential of the tumor, definable as the probability that a certain number of adverse events may occur and directly proportional to the global pathogenic mutational burden. when genetic alterations are small in number, limited to the driver mutation or few more, this potential is low or very low, adverse events are rare or very rare, and, clinically, the tumor appears as benign. when genetic alterations are numerous, including driver and promoting mutations, the malignant potential is high, adverse events are frequent, and, clinically, the tumor appears as malignant. of course, all intermediate cases may exist, because the malignant potential may theoretically assume every value between a minimum value (>0) and a maximum one (=100). the lowest possible value is >0, because all melanocytic tumors harbor at least 1 genomic alteration affecting the proliferation control mechanisms, and this inevitably implies a certain risk (risk 0 is to be reserved to the healthy skin, in which melanocytes harbor no pathogenic mutations). in sum, there do not seem to exist tumors with no chromosomal aberrations and consequently with no risk (risk = 0) and, at the same time, there seem to exist very few, if any, tumors harboring the totality of the possible chromosomal aberrations and, consequently, with the maximum possible risk (risk = 100). tumors tend to show a certain variable number of pathogenic mutations and consequently may have all possible levels of risk, the malignant potential ranging between >0 and 100. sic stantibus rebus, the concept that melanocytic tumors can be only either benign or malignant, comes to be hardly applicable [1] because no tumor has malignant potential =0 and few, if any, have a malignant potential =100. this may produce 2 important conceptual and practical effects on the current clinicopathological classification of melanocytic skin tumors. the first is that the great majority of melanocytic tumors, having a malignant potential of intermediate value, ranging between these extremes, tend to appear as “borderline or intermediate,” between “fully benign” and “fully malignant” tumors. paradoxically, virtually all melanocytic neoplasms seem to be attributable to an “intermediate” category, currently considered only as a very small and very narrow area, between the much larger categories of nevi and melanomas. the second is that the categorization of melanocytic tumors into nevi and melanomas appears simplistic and/ or inadequate. in fact, the diagnostic categories of nevus, melanoma, and melanocytoma do not appear as 3 definite tumors with specific clinical, histological, and genetic characteristics, but as 3 large, heterogeneous assemblages of melanocytic tumors. each of these 3 categories encompasses a mixture of dissimilar tumors, different because they have different driver events and, therefore, different pathogeneses and different clinicopathological features. in each of these 3 categories, commentary | dermatol pract concept 2020;10(1):e2020005 3 15. vandenboom t, quan vl, zhang b, et al. genomic fusions in pigmented spindle cell nevus of reed. am j surg pathol. 2018;42(8):1042-1051. 16. wiesner t, murali r, fried i, et al. a distinct subset of atypical spitz tumors is characterized by braf mutation and loss of bap1 expression. am j surg pathol. 2012;36(6):818-830. 17. yeh i, lang ue, durieux e, et al. combined activation of map kinase pathway and β-catenin signaling cause deep penetrating nevi. nat commun. 2017;8(1):644. 18. zembowicz a, knoepp sm, bei t, et al. loss of expression of protein kinase a regulatory subunit 1α in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. am j surg pathol. 2007;31(11):1764-1775. 19. bahrami a, lee s, wu g, et al. pigment-synthesizing melanocytic neoplasm with protein kinase c alpha (prkca) fusion. jama dermatol. 2016;152 (3):318-322. 20. cohen jn, joseph nm, north jp, et al. genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in prkar1a, and prkca genes. am j surg pathol. 2017;41(10):1333-1346. 8. wiesner t, he j, yelensky r, et al. kinase fusions are frequent in spitz tumors and spitzoid melanomas. nat commun. 2014;5:3116. 9. yeh i, botton t, talevich e, et al. activating met kinase rearrangements in melanoma and spitz tumours. nat commun. 2015;6:7174. 10. yeh i, tee mk, botton t, et al. ntrk3 in spitz tumors. j pathol. 2016;240(3):282-290. 11. van raamsdong cd, bezrookove v, green g, et al. frequent somatic mutation of gnaq in uveal melanoma and blue nevi. nature. 2009;457(7229):599-602. 12. lamba s, felicioni l, buttitta f, et al. mutational profile of gnaqq209 in human tumors. plos one. 2009;4(8):e6833. 13. van raamsdong cd, griewank kg, crosby mb, et al. mutation in gna11 in uveal melanoma. n engl j med. 2010;363(23):21912199. 14. newman s, fan l, pribnow a, et al. clinical genome sequencing uncovers potentially targetable truncations and fusions of map3k8 in spitzoid and other melanomas. nat med. 2019;25(4):597-602. dermatology: practical and conceptual 252 research | dermatol pract concept 2018;8(4):2 dermatology practical & conceptual www.derm101.com subclinical oral involvement in patients with endemic pemphigus foliaceus ana maria abreu-velez1, michael s. howard1, héctor jose lambraño padilla2, sergio tobon-arroyave3 1 georgia dermatopathology associates, atlanta, ga, usa 2 dentist, el bagre, antioquia, colombia 3 school of dentistry, university of antioquia, medellin, colombia key words: endemic pemphigus foliaceus, oral mucosa, iga, cell junctions, salivary glands, secretory immunoglobulin a citation: abreu-velez am, howard ms, lambraño padilla hj, tobon-arroyave s. subclinical oral involvement in patients with endemic pemphigus foliaceus. dermatol pract concept. 2018;8(4):252-261. doi: https://doi.org/10.5826/dpc.0804a02 received: january 30, 2018; accepted: july 12, 2018; published: october 31, 2018 copyright: ©2018 abreu-velez et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this work was funded by georgia dermatopathology associates; mineros sa, medellin, colombia; hospital nuestra señora del carmen, el bagre, colombia; the embassy of japan in colombia; the school of dentistry, university of antioquia; and el bagre mayoral office. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ana maria abreu-velez, md, phd, georgia dermatopathology associates, 1534 north decatur road, ne, suite 206; atlanta, ga 30307-1000 usa. email: abreuvelez@yahoo.com background: we have described a variant of endemic  pemphigus  foliaceus (epf) in el bagre area known as pemphigus abreu-manu. our previous study suggested that colombian epf seemed to react with various plakin family proteins, such as desmoplakins, envoplakin, periplakin bp230, myzap, arvcf, p0071 as well as desmoglein 1. objectives: to explore whether patients affected by a new variant of endemic pemphigus foliaceus (el bagre-epf) demonstrated oral involvement. materials and methods: a case-control study was done by searching for oral changes in 45 patients affected by el bagre-epf, as well as 45 epidemiologically matched controls from the endemic area matched by demographics, oral hygiene habits, comorbidities, smoking habits, place of residence, age, sex, and work activity. oral biopsies were taken and evaluated via hematoxylin and eosin staining, direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and immunohistochemistry. results: radicular pieces and loss of teeth were seen in in  43  of the  45  el bagre-epf patients and 20 of the 45 controls (p < 0.001) (confidence interval [ci] 98%). hematoxylin and eosin staining showed 23 of 45 el bagre-epf patients had corneal/subcorneal blistering and lymphohistiocytic infiltrates under the basement membrane zone and around the salivary glands, the periodontal ligament, and the neurovascular bundles in all cell junction structures in the oral cavity; these findings were not seen in the controls (p < 0.001) (ci 98%). the direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and microarray staining displayed autoantibodies to the salivary glands, including their serous acini and the excretory duct cell junctions, the periodontal ligament, the neurovascular bundles and their cell junctions, striated muscle and their cell junctions, neuroreceptors, and connective tissue cell junctions. the autoantibodies were polyclonal. iga autoantibodies were found in neuroreceptors in the glands and were positive in 41 of 45 patients and 3 of 45 controls. abstract research | dermatol pract concept 2018;8(4):2 253 to human total igg or igg4, as described elsewhere [1-5]. furthermore, each patient had to be positive by immunoblotting for reactivity against dsg1 [2, 3], as well as for plakin molecules; each patient’s serum immunoprecipitated a concanavalin a affinity-purified bovine tryptic 45 kda fragment of dsg1 [4]; and each patient’s serum had to yield a positive result using an enzyme-linked immunosorbent assay test when screening for autoantibodies to pemphigus foliaceus antigens [5]. oral mucosa from the buccal mucosa was biopsied; 2 biopsies were taken, 1 for h&e staining and immunohistochemistry (ihc) and 1 for dif. the skin was tested as previously described [1-5]. dif, iif, and ihc we performed dif and iif as previously described [2, 3]. all samples were run with positive and negative controls. several years ago, the first [12] discovered new autoantigens to several organs other than the skin. because of the complexity of the immune response in these patients, we contacted other experts, including dr. e. h. beutner in the usa, dr. takashi hashimoto in japan, and dr. w. w. franke (formerly a professor at the university of heidelberg in germany). all agreed that our data indicated new autoantigens. we sent identical serum for study to these scientists, and all agreed this disorder was unique. a few months later, the primary owner of progen biotechnik (heidelberg, germany), dr. w. w. franke, commercialized these antibodies. thus, we used the following antibodies from progen: antiarcvf (armadillo repeat gene deleted in velocardiofacial syndrome; cat. no. gp155), anti-desmoplakin (dp) 1 and dp2 (cat. no. 65146), anti-p0071 (cat. no. 651166), and anti-myzap (myocardium-enriched zonula occludens1-associated protein; cat. no. 651169). secondary antibodies were obtained from thermo fisher scientific (waltham, ma, usa), for arcvf we used alexa fluor 555 goat anti-guinea pig, while for dp1, dp2, p0071, and myzap we used goat anti-mouse texas red-conjugated igg. we also used rabbit anti-junctional adhesion molecule 1 (jam-a) (thermo fisher scientific), as this antibody is positive against gap junction. we classified our findings as negative (-), weakly positive (+), moderately positive (++), and strongly positive (+++). for ihc, we utilized antibodies for α-1-antitrypsin, human matrix metalloproteinase 9 (mmp9), human tissue inhibitor of metalloproteinases 1 (timp-1), metallothionein, introduction we have described a new variant of endemic pemphigus foliaceus in el bagre, colombia, south america (el bagre-epf, or pemphigus abreu-manu) [1-5]. el bagre-epf differs from other types of epf clinically, epidemiologically, and immunologically. previous studies have shown that patients affected by epf in brazil have some oral findings [7, 8]. selected authors have described the presence of autoantibodies using hematoxylin and eosin (h&e) staining, direct and indirect immunofluorescence (dif, iif), and electron microscopy studies [9-11]. in the current study, our aim was to search for oral clinical lesions and an oral autoimmune response in patients affected by epf in el bagre, colombia (el bagre-epf) [1-5] and to compare our findings with those described in the medical literature for brazilian epf patients. materials and methods statement on ethics a human quality assurance review board approved the studies at the hospital nuestra señora del carmen in el bagre, and all participants provided signed consent. the studies have been approved by the appropriate institutional and/or national research ethics committee and have been performed in accordance with the ethical standards as established in the 1964 declaration of helsinki and its later amendments or comparable ethical standards. we tested 45 patients affected by el bagre-epf and 45 controls from the endemic area matched by age, sex, demographics, comorbidities, work activities, weight, exposure to chemicals, socioeconomic status and income, and food intake. thirty controls from the endemic area were healthy individuals. the other controls included patients with psoriasis, scleroderma, and chronic drug eruptions. all of the tests were performed in both cases and controls. the patients and controls were evaluated by h&e histology, dif, iif, confocal microscopy, immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay. only patients meeting diagnostic criteria for el bagre-epf were included; specifically, they had to display clinical and epidemiological features described for this disease, live in the endemic area [1,2], and have serum displaying intercellular staining (ics) between epidermal keratinocytes and the basement membrane zone (bmz) of the skin via either dif or iif using fluorescein isothiocyanate (fitc) conjugated monoclonal antibodies conclusions: patients affected by el bagre-epf have some oral anomalies and an immune response, primarily to cell junctions. the intrinsic oral mucosal immune system, including iga and secretory iga, play an important role in this autoimmunity. our data contradict the hypothesis that pemphigus foliaceus does not affect the oral mucosa due to the desmoglein 1-desmoglein 3 compensation. abstract 254 research | dermatol pract concept 2018;8(4):2 large varicosities were found in 10 of 45 patients at the base of the involved lingual renine veins or in vessels of the ventral surface of the tongue or the floor of the mouth, with no control varicosities recorded. small ulcers were seen in the palatal mucosa in 5 of 45 el bagre-epf patients. dental caries were also found in most participants. h&e staining the h&e staining showed that  23  of  45  el bagre-epf patients had corneal and/or subcorneal epidermal blisters and dermal edema and lymphohistiocytic infiltrates under the bmz and around the salivary glands (including their serous acini and the excretory duct cell junctions and the neurovascular bundles). these findings were not observed in the controls (p < 0.001) (ci 98%) (figure 1b). dif, confocal microscopy, and imgenex microarray studies in table  1, we present the results of our autoantibody findings in the skin and the oral mucosa, including their strength and colocalization with commercial antibodies to arvcf, myzap, dp i-ii, p0071, and jam-a. in both anatomic areas, autoantibodies were polyclonal in nature with a prevalence of igg and fibrinogen in the acute cases; in chronic cases (>2 years of disease), igm was most commonly seen (p < 0.001) (ci 98%) (figure 1). the controls were uniformly negative. the el bagre-epf patients’ periodontal ligaments have polyclonal autoantibodies on 43 of 45 compared to 0 of 45 controls. multiple structures in the oral mucosa displayed their strongest autoreactivity with iga compared with their anatomic correlates in the skin (p < 0.001) (ci 98%) (see table 1). the neuroreceptors in the salivary glands were very positive (+++) in most el bagre-epf patients compared with the controls (p < 0.001) (ci 98%). the controls demonstrated secretory iga in the salivary glands, including serous acini and the excretory duct cell junctions; these findings were also noted in the el bagreepf patients (p < 0.001) (ci 98%) (figures 1 and 2). the el bagre-epf autoantibodies colocalized 100% with the commercial antibodies to arvcf, p0071, dp i-ii, myzap, and arvcf (p < 0.001) (ci 98%). albumin autoantibodies also colocalized with jam-a used as control. when using antibodies to igg we observed neutrophil extracellular traps coming from the dermal vessels. in the bmzs of the salivary glands (including in serous acini and excretory duct cell junctions), igg was positive to some unique cells that may be stem cells. unique individual cells resembling lymphocytes were positive with c3c, c1q, ige, and igg in an opsonized manner. several cell junctions were positive in the epidermis but did not show the classic fishnet-like intercellular stain between keratinocytes commonly seen in pemphigus. rather the staining was dot-like and on cell junctions. and urokinase type plasminogen activator (all from dako; agilent technologies, santa clara, ca). questionnaires on oral habits deleterious oral habits include bruxism parasomnias, traumatic brain injury, neurological disabilities, nail biting, morphological factors, temporomandibular joint dysfunction, tongue thrusting, mouth breathing, smoking habits, and chewing on plants and/or gum. other questions included how often toothbrushes were changed, use of dental floss, dental visits, and frequency of brushing teeth. imgenex microarray iif using frozen normal oral organs our microarray work was performed as described for our iif; as our antigen source, we used a commercial human tissue microarray in duplicate from imgenex corporation (san diego, ca, usa). confocal microscopy confocal microscopy was performed as previously described [5,6]. statistical analysis we used the fisher exact test to compare 2 nominal variables (eg, positive and negative) of the antibody response. p < 0.01 with a 98% degree of confidence or more was considered statistically significant. we used the software graphpad quickcalcs (graphpad software inc., la jolla, ca, usa). results questionnaires on oral habits deleterious oral habits did not show any statistical significance between the cases and controls. the oral health habits were poor in all study participants (37/45 patients and 38/45 controls). most never visited the dentist for economic reasons (43/45 patients and 42/45 controls), brushed their teeth at most once or twice a week (32/45 patients and 33/45 controls), and rarely used dental floss (40/45 patients and 41/45 controls). overall, 42 of 45 el bagre-epf patients were taking oral prednisone in doses ranging from 5 to 40 mg/day. in addition, 3 of 45 controls were taking prednisone for systemic sclerosis or for psoriasis (p < 0.001) (confidence interval [ci] 98%). oral evaluation the most significant alteration in the el bagre-epf patients was the finding of multiple radicular pieces and loss of teeth in 43 of 45 el bagre-epf patients and in 17 of 45 controls (p <0.001) (ci 98%) (figure 1a). furthermore, 14 of 47 el bagre-epf patients had no teeth (figure 1). leukoedema was found in 6 of 45 el bagre-epf patients and in no controls. research | dermatol pract concept 2018;8(4):2 255 figure 1. (a) missing teeth in one el bagre–epf patient. (b) h&e staining of the oral mucosa, showing edema in the mucosa; in the dermis, a lymphohistiocytic infiltrate (black arrow) and dilation of a blood vessel (blue arrow) (200×). (c) dif showing positive staining with fitc conjugated anti-fibrinogen antibodies in intracorneal blister (light green staining; white arrow) and pericytoplasmic staining of the epidermal keratinocytes (light green staining; red arrow) (200×) and stain in the vessels (yellow-green staining; light blue arrow). (d) dif showing positive staining with fitc conjugated igg antibodies against the bmz (green staining; yellow arrow), as well as against upper dermal blood vessels with ulex (yellow staining, resulting from the colocalization of fitc [green] and texas red [red]; light blue arrow) (200×). (e) dif showing positive staining with fitc conjugated fibrinogen antibodies (green staining), colocalizing with myzap alexa fluor 555 against skeletal muscle (yellow arrow), as well as their cell junctions (red staining; white arrows) (200×). (f) dif showing positive staining with fitc conjugated c3c antibodies against the acini of the salivary glands (yellow staining; red arrow) and colocalizing with myzap in a salivary duct with alexa fluor 555 (white arrow; 400×). [copyright: ©2018 abreu-velez et al.] 256 research | dermatol pract concept 2018;8(4):2 table 1. dif autoantibody staining in the oral mucosal structures, compared with the skin and colocalization with dp i-ii, arvcf, and p0071 autoantibodies dif antibodies oral positivity strength of staining positivity to oral mucosa structures colocalization with arvcf, dp-i-ii, p0071, and myzap positivity in skin strength of staining igg 40/45 (+++) epithelial cell junction dot staining. some stem cells like at the bmz. the neurovascular bundles and salivary glands including their serous acini and excretory ducts, mainly their cell junctions. neutrophil extracellular traps. cell junctions in the dermal connective tissue. unique individual cells, resembling lymphocytes in shape with “opsonized” features. 100% 40/45 (+++) fibrinogen 39/45 (+++) intracorneal and subcorneal blisters. intracytoplasmic and pericytoplasmic staining on keratinocytes (uneven pattern). dot staining on cell junctions over the entire mucosa. cell junctions in the dermal connective tissue. skeletal muscle staining. bmz of the salivary glands, its serous acini, and the excretory ducts. neurovascular bundles. encapsulated neural receptors. 100% 39/45 (+++) igm 38/45 (+++) the mucosal corneal cell layer, dot staining on cell junctions. the bmz, neurovascular bundles, skeletal muscle, and some of their intracellular organelles. the bmz of salivary glands, including serous acini and excretory duct cell junctions. receptors linked with the glands. 100% 38/45 (+++) albumin 38/45 (+++) mucosal cell junction dot staining. salivary gland bmzs, their serous acini and excretory duct cell junctions. cell junctions in the dermal connective tissue. large neural receptors, colocalizing with jam-a. 100% and with jam-a 38/45 (+++) complement/ c3c 35/45 (+++) cell junctions between keratinocytes. mucosal bmz. neural receptors linked to the salivary glands. bmz of the salivary glands. neurovascular bundles. skeletal muscle cell junctions. cell junctions in the dermal connective tissue. unique individual cells resembling lymphocytes in shape with “opsonized” features. 100% and with jam-a 35/45 (+++) (continued next page) research | dermatol pract concept 2018;8(4):2 257 connective tissue (mainly against the cell junctions), and inside some striated muscle organelles. timp1 was positive in the corneal layer and the upper epidermal layers in some patients, and in others in the lower epithelial layers and in the cell junctions of the vessels and cell junctions of the salivary ducts (figure 3). ihc staining using metallothionein we observed patchy spot staining at the bmz, as well as in the neurovascular bundles, the salivary glands including serous acini and the excretory ducts, cell junctions, striated muscle, mesenchymal-endothelial cell junction dif antibodies oral positivity strength of staining positivity to oral mucosa structures colocalization with arvcf, dp-i-ii, p0071, and myzap positivity in skin strength of staining complement/ c1q 35/45 (++) cytoplasm of mucosal keratinocytes, patchy; dot staining in the bmz cell junctions and in the salivary glands and their ducts. striated muscle and its cell junctions. neural receptors in the salivary glands. cell junctions in the dermal connective tissue. unique individual cells resembling lymphocytes in shape lymphocytes, with “opsonized” features that colocalize with cd3. 100% and jam-a 35/45 (++) complement/ c4 17/45 epithelium, bmz, and striated muscle. 17/45 iga 17/45 (++) corneal layer, epithelial dot staining on cell junctions, and pericytoplasmic cell staining in the basaloid layer. salivary ducts as well as smooth muscle and skeletal muscle, and basal layer cells. connective tissue cell junctions. neural receptors in the glands. 100% 39/45 (++) igd 16/45 (++) skeletal muscle and its cell junctions. positive on neurovascular supply structures under the bmz. positive on ducts of the salivary glands. 100% 16/45 (++) ige 7/45 (++) receptors in the salivary glands. unique individual cells resembling lymphocytes in shape, with “opsonized” features that colocalize with cd3. 100% 7/45 (++) lambda 40/45 (+++) staining on subcorneal blisters and epithelial cell junctions. on salivary glands, including their serous acini and excretory ducts. skeletal muscle and its cell junctions and on connective tissue cell junctions. 100% 40/45 (+++) kappa 40/45 (+++) staining on subcorneal blisters and epithelial cell junctions. on salivary glands including their serous acini and excretory ducts. skeletal muscle and its cell junctions and on connective tissue cell junctions. 100% 40/45 (+++) table 1. dif autoantibody staining in the oral mucosal structures, compared with the skin and colocalization with dp i-ii, arvcf, and p0071 autoantibodies (continued) 258 research | dermatol pract concept 2018;8(4):2 figure 2. (a) dif showing positive dot staining with fitc conjugated igg antibodies against epithelial cell junctions (light green staining; white arrow) (200×) and in the corneal layer (light green staining; red arrow). (b) dif showing positive staining with fitc conjugated igg antibodies against the corneal layer (yellow staining; yellow arrow) and dot cell junction staining in epithelial cells (light green staining; white arrow). arvcf staining with alexa fluor 555 is noted in a salivary gland duct (red staining; white arrow) (200×) and in the corneal layer (red staining; yellow arrow). (c-f) confocal microscopy, using multiple channels of fluorescence. in c, we used antibody to igm fitc channel (excitation/emission, 495/519 nm); in (d) an antibody to p0071 (texas red, 555 channel) (excitation/emission, 555/568 nm); in (e) a dapi channel (blue) (excitation/emission, 360⁄460 nm); and in f, the combination of all showing a perfect colocalization against neuroreceptors in a salivary gland (in c-f, white arrows, 1,000×). [copyright: ©2018 abreu-velez et al.] research | dermatol pract concept 2018;8(4):2 259 figure 3. (a) ihc positive staining for metallothionein between oral mucosal cell junctions (black arrow) as well as at the bmz (brown staining; red arrow; 200×). (b) ihc positive staining for iga on neurovascular dermal structures (brown staining; red arrow) (100×). (c) ihc positive staining mesenchymal-endothelial junctions in dermal connective tissue cell junctions (brown staining; red arrow)(200×). (d) dif, showing positive staining with iga fitc conjugate on dermal connective tissue cell junctions (black arrow) colocalizing with arvcf conjugate with alexa fluor 555 (400×). (e) ihc positive staining with metallothionein in a salivary gland (brown staining; red arrow)(400×). (f) dif positive staining with fitc conjugated c1q, colocalizing with texas red dp i-ii in the oral mucosa (black arrow, 1,000×). [copyright: ©2018 abreu-velez et al.] 260 research | dermatol pract concept 2018;8(4):2 revealed fs in the acute and bullous phases of the disease and significant periodontal disease [26]. other authors studied 15 patients with fs reporting subcorneal acantholysis and no oral blisters or erosions, but dif demonstrated the presence of tissue-bound autoantibodies in both the epidermis and the oral epithelium of all patients [6]. other authors studied patients with fs and 4 control subjects, examining the oral mucosa using electron microscopy. in addition to showing clinically normal oral mucosa, electron microscopy showed widening of the intercellular spaces between keratinocytes [6-11]. we observed an autoimmune response to neural receptors in el bagre-epf patients’ oral mucosa and salivary glands; indeed, we have described autoreactivity to skin neurovascular structures and neural receptors in previous studies [27,28]. the neuronal/transmitter control of salivary glands is performed by both dopaminergic and serotonergic neurons and receptors [29]. both classes of transmitters elicit saliva secretion. the neurons contain γ-aminobutyric acid (gaba). gaba-positive fibers form a network around most salivary acinar lobules and a dense plexus in the interior of a minor fraction of acinar lobules. we conclude that patients affected by el bagre-epf have an autoimmune response in the oral mucosa. we suggest that this process results in loss of teeth; iga, and the mucosal immune system seem to play important roles. given our observations, the dsg1-dsg3 compensation theory offered to explain a “lack” of oral compromise in pemphigus foliaceus (including its endemic variants) may need reassessment. references 1. abreu velez am, hashimoto t, bollag w, et al. a unique form of endemic pemphigus in northern colombia. j am acad dermatol. 2003;49(4):599-608. 2. abreu velez am, beutner eh, montoya f, hashimoto t. analyses of autoantigens in a new form of endemic pemphigus foliaceus in colombia. j am acad dermatol. 2003;49(4):609-614. 3. hisamatsu y, abreu velez am, amagai m et al. comparative study of autoantigen profile between colombian and brazilian types of endemic pemphigus foliaceus by various biochemical and molecular biological techniques. j dermatol sci. 2003;32(1):33-41. 4. abreu velez am, javier patiño p, montoya f, et al. the tryptic cleavage product of the mature form of the bovine desmoglein 1 ectodomain is one of the antigen moieties immunoprecipitated by all sera from symptomatic patients affected by a new variant of endemic pemphigus. eur j dermatol. 2003;13(4):359-366. 5. abréu vélez am, yepes mm, patiño pj, bollag wb, montoya f sr. a cost-effective, sensitive and specific enzyme linked immunosorbent assay useful for detecting a heterogeneous antibody population in sera from people suffering a new variant of endemic pemphigus. arch dermatol res. 2004;295(10):434-441. 6. lacaz netto r, macedo nl. pemphigus foliaceus: a clinical histopathological study of the gingiva [in portuguese]. rev odontol unesp. 1983;12: 61-69. conclusions herein, we report for the first time that patients affected by a new variant of epf in el bagre, colombia, have oral manifestations. the main clinical finding was the asymptomatic loss of teeth, and the main pathological finding was subcorneal blistering. the asymptomatic autoimmune response is directed at multiple structures in the oral mucosa, primarily to cell junctions of the epithelia, dermis, salivary glands, and vessels. we also describe for the first time that the intrinsic oral mucosal immune system, including iga and secretory iga, appears to play an important role in this asymptomatic autoimmunity. previously, we showed that el bagre-epf patients have a polyclonal immune response in the skin and against other organs involving iga [12-15]. in this case-control study we found some clinical alterations such as loss of teeth in the el bagre-epf group. prednisone therapy and lack of oral hygiene can explain these findings. however, the controls have similar demographic factors, with the exception of the intake of prednisone. the autoantibodies to the periodontal ligament could contribute to weakness of the patients’ teeth. we previously reported autoantibodies to several smooth muscle structures including the arrector pili muscle in most el bagre-epf patients [13]. in theory, clinical involvement of the oral mucosa is not typically present in pemphigus foliaceus. previously published data indicate that in pemphigus foliaceus, desmoglein 1 (dsg1) and desmoglein 3 (dsg3) are expressed in a pathogenic distribution throughout the squamous mucosal epithelia and the skin [16-18]. in our data, we observed something completely different that contradicts this hypothesis, ie, the “theory of dsg1-dsg3 compensation.” measuring salivation in the endemic area is also difficult, but with use of multicolor immunofluorescence [19] we were able to observe positivity to neuroreceptors using high magnifications and color contrast. we also previously demonstrated that the el bagre-epf patients have autoantibodies to their palms and soles, as well as to their sweat glands with an iga response (immune-specific to these anatomic sites) [20,21]. our findings pointed us to an iga autoimmune response that is part of the mucosal innate immunity, including the saliva containing lysozymes, bacteriocidins, defensins, cationic proteins, and lactoferrin [22]. our findings brought our attention to the specific immunity that the oral mucosa has in comparison with the skin. tomasi and his colleagues in the mid-1960s originally documented oral “local immunity” with the presence of iga antibodies in secretions including saliva [23-25]. a group of brazilian authors performed a study of the oral cavity of 56 patients with fogo selvagem (fs). histopathological and clinical examination of the gingivae of 8 patients research | dermatol pract concept 2018;8(4):2 261 18. amagai m, tsunoda k, zillikens d, et al. the clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. j am acad dermatol. 1999;40(2 pt 1):167-170. 19. abreu velez am, upegui zapata ya, howard ms. periodic acid-schiff staining parallels the immunoreactivity seen by direct immunofluorescence in autoimmune skin diseases. n am j med sci. 2016;8(3):151-155. 20. abreu velez am, howard ms, hashimoto t. palms with a polyclonal autoimmune response in patients affected by a new variant of endemic pemphigus foliaceus in colombia, south america. eur j dermatol. 2010;20(1):74-81. 21. abreu velez am, howard ms, hashimoto k, et al. autoantibodies to sweat glands detected by different methods in serum and in tissue from patients affected by a new variant of endemic pemphigus foliaceus. arch dermatol res. 2009;301(10):711-718. 22. feller l, altini m, khammissa ra, et al. oral mucosal immunity. oral surg oral med oral pathol oral radiol. 2013;116(5):576583. 23. tomasi tb jr, zigelbaum s. the selective occurrence of gamma-1a globulins in certain body fluids. j clin invest. 1963 oct;42:15521560. 24. chodirker wb tomasi tb jr. gamma-globulins: quantitative relationships in human serum and nonvascular fluids. science. 1963;142(3595):1080-1081. 25. tomasi tb jr, tan em, solomon a, prendergast ra. characteristics of an immune system common to certain external secretions. j exp med. 1965 jan 1;121:101-124. 26. russel al. a system of classification and scoring for prevalence surveys of periodontal disease. j dent res. 1956;35(3):350-359. 27. abreu-velez am, howard ms, yi h, gao w, et al. neural system antigens are recognized by autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in colombia. j clin immunol. 2011;31(3):356-368.  28. abreu velez am, yi h, warfvinge g, howard ms. autoantibodies to full body vascular cell junctions colocalize with myzap, arvcf, desmoplakins i and ii and p0071 in endemic pemphigus in colombia, south america. int j dermatol. 2018;57(3):291298. 29. habre-hallage p, dricot l, hermoye l, et al. cortical activation resulting from the stimulation of periodontal mechanoreceptors measured by functional magnetic resonance imaging (fmri). clin oral investig. 2014;18(8):1949-1961. 7. sotto  mn, shimizu  sh, costa  jm, et al. south american pemphigus foliaceus: electron microscopy and immunoelectron localization of bound immunoglobulin in the skin and oral mucosa. br j dermatol. 1980;102(5):521-527. 8. marcucci  g, cucé  lc, sotto  mn, et al. contribuição ao estudo da ultra-estrutura da mucosa bucal em doentes de pênfigo foliáceo brasileiro. rev fac odontol univ são paulo. 1982;205-225. 9. hietanen j, salo op, kanerva l, et al. ultrastructure of uninvolved oral mucosa in pemphigus patients. acta derm venereol.1983;63(6):63491-63494. 10. rivitti  ea, sanches  ja, miyauchi  lm, et al. pemphigus foliaceus autoantibodies bind both epidermis and squamous mucosal epithelium, but tissue injury is detected only in the epidermis. j am acad dermatol. 1994;31(6):31954-31958. 11. guedes ac, rotta o, leite hv, et al. ultrastructural aspects of mucosas in endemic pemphigus foliaceus. arch dermatol. 2002;138(7):949-954. 12. abreu-velez am, howard ms, yi h,et al. patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with myzap, p0071, desmoplakins 1-2 and arvcf, causing renal damage. clin exp dermatol. 2018;43(6):692-702. 13. abreu-velez am, valencia-yepes ca, upegui-zapata ya, et al. patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with myzap, p0071, desmoplakins 1 and 2 and arvcf. clin exp dermatol. 2017;42(8):874-880. 14. abreu-velez am, gao w, howard ms.patients affected by endemic pemphigus foliaceus in colombia, south america exhibit autoantibodies to optic nerve sheath envelope cell junctions. dermatol pract concept. 2018; 31;8(1):1-6. 15. abreu velez am, howard ms, velazquez-velez je. cardiac rhythm and pacemaking abnormalities in patients affected by endemic pemphigus in colombia may be the result of deposition of autoantibodies, complement, fibrinogen, and other molecules. heart rhythm. 2018;15(5):725-731. 16. shirakata y, amagai m, hanakawa y, et al. lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1. j invest dermatol. 1998;110(1):76-78. 17. mahoney mg, wang z, rothenberger k, koch pj,  amagai m, stanley jr. explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. j clin invest. 1999;103(4):461-468. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020102 1 dermatology practical & conceptual introduction several guidelines recommend phototherapy, systemic agents, or biologic therapy for the treatment of moderate-to-severe psoriasis. sequential use of more than 1 biologic has become more common due to primary or secondary failure with this type of treatment and an increase in the number of drugs available. however, the order of usage of these drugs is still speculative. we report about a patient with severe psoriasis with primary failure to respond after treatment with ustekinumab and adalimumab who achieved psoriasis area and severity index (pasi) 100 score with secukinumab in 8 weeks. case presentation a 47-year-old woman presented with a 30-year history of psoriasis vulgaris without psoriatic arthritis or other comorbidities. she was previously treated with methotrexate and puva but had hepatotoxicity and minimal response with uvb narrowband. at first visit, the patient revealed pasi 23.7, dermatology life quality index (dlqi) 30, body surface area (bsa) 30, and body weight 80 kg (figure 1) and was subsequently secukinumab: rapid efficacy in psoriasis after primary failure with ustekinumab and adalimumab aline lissa okita1, tatiane benini1, denise reis longhi1 1 department of dermatology, universidade de mogi das cruzes, são paulo, brazil key words: severe psoriasis, biologics, secukinumab, adalimumab, ustekinumab citation: okita al, benini t, reis longhi d. secukinumab: rapid efficacy in psoriasis after primary failure with ustekinumab and adalimumab. dermatol pract concept. 2020;10(4):e2020102. doi: https://doi.org/10.5826/dpc.1004a102 accepted: may 28, 2020; published: october 26, 2020 copyright: ©2020 okita et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: aline lissa okita, md, department of dermatology from universidade de mogi das cruzes, ave dr cândido x de almeida e souza, 200, são paulo, brazil. email: alinelissaokita@gmail.com figure 1. clinical presentation prior to ustekinumab treatment. 2 letter | dermatol pract concept 2020;10(4):2020102 300 or 150 mg. the 3 groups were: patients with primary failure to anti-tnfα; patients with secondary failure to anti-tnfα; and patients who failed with more than one anti-tnfα. the patients in the 3 groups achieved statistically significant rates of pasi 75 using secukinumab 300 mg [2]. magnano et al reported on 16 psoriatic patients previously treated with more than 1 systemic or biologic agent, without control of skin lesions. these patients were treated with secukinumab, and 8 of them obtained a complete clearance (pasi 100), 6 patients presented pasi 90, and 2 patients showed pasi 75. all patients presented improvement in the dlqi [3]. in addition, a case of successful treatment with secukinumab in recalcitrant psoriatic arthritis treated previously with 2 anti-tnf drugs was reported [4]. the case reported here was exposed to multiple systemic treatments resulting in inadequate disease control and adverse events that led to discontinuation of therapies. she failed to respond to both anti-tnfα and anti-il12/23 drugs but reached pasi 100 in 8 weeks with secukinumab without any adverse effects. this indicates that each patient may have a specific behavior in the disease pathway and might respond better to certain drugs. further studies are needed to determine which factors are essential to define the biologic of choice. treated with ustekinumab 45 mg for 6 months with no response. then she received adalimumab, but symptoms worsened with an increased number of lesions and intense itching (pasi 33.6, dlqi 30, bsa 78) (figures 2a and 3a). after that, she received secukinumab 300 mg at weeks 0, 1, 2 and 3, 4 achieving pasi 75 at week 5 (figures 2b and 3b) and pasi 100 and dlqi 0 at week 8. conclusions studies on secukinumab have demonstrated rapid and high efficacy in the treatment of psoriasis, and bio-naïve patients achieved higher scores, pasi 90, than those previously exposed to treatment with biologics. however, many authors reported successful treatment with secukinumab after biological exposure. in one series of 6 patients, patients exhibited efficacy with secukinumab after failure with ustekinumab. four patients had primary failure with ustekinumab and 2 patients experienced secondary failure. after 12 weeks, 4 patients achieved pasi 90 with secukinumab [1]. another study of 235 patients randomized 3 groups of anti-tnf nonresponders to treatment with secukinumab at figure 2. clinical presentation. (a) after adalimumab treatment. (b) after 5 weeks of secukinumab treatment. a b figure 3. clinical presentation. (a) after adalimumab treatment. (b) after 5 weeks of secukinumab treatment. a b letter | dermatol pract concept 2020;10(4):2020102 3 acad dermatol. 2018;79(3 suppl 1): ab256. poster abstract. doi: 10.1016/j.jaad.2018.05.1018. 3. magnano m, loi c, patrizi a, et al. secukinumab in multifailure psoriatic patients: the last hope? j dermatolog, treat. 2018;29(6):583–585. doi: 10.1080/09546634.2018.1427206. pmid: 29334270. 4. pelechas e, memi t, voulgari pv, drosos aa. a case of recalcitrant psoriatic arthritis to tnf inhibitors improved after administration of secukinumab, an il-17a inhibitor. rheumatol ther. 2017;4(2):509–513. doi: 10.1007/s40744-017-0084-0. pmid: 29022197. references 1. morgado-carrasco d, riera-monroig j, fustà-novell x, alsina gibert m. response to secukinumab after treatment failure with ustekinumab in 6 patients with plaque psoriasis. actas dermosifiliogr. 2018;109(6):565-567. doi: 10.1016/j. ad.2017.07.019. pmid: 29169562. 2. warren rb, barker j, burden ad, et al. secukinumab has demonstrated efficacy and safety in hard-to-treat anti–tumor necrosis factor α failure patients from the united kingdom and republic of ireland: results of the signature study. j am dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(3):e2020062 1 dermatology practical & conceptual clinical presentation a 66-year-old man presented with 2 asymptomatic ulcerations on the right cheek (figure 1). these began as enlarging papules that ulcerated 2 weeks later. he had been treated for leishmaniasis a year previously, with an ulcer in the same location. diagnosis had been made by skin biopsy and polymerase chain reaction, identifying leishmania braziliensis. at that time, he was given intramuscular meglumine antimoniate; his lesions had healed completely within 1 month. teaching point leishmaniasis recidivans (lr) is a rare presentation of localized cutaneous leishmaniasis, recurring at the site of a previously healed ulcer [1], as in this case. it typically affects the face, often the cheek. leishmania braziliensis is one of the species linked to new world lr. while the pathogenesis of lr is not known, risk factors include parasite resistance and incomplete treatment. resistance to antimonials is increasingly a concern in some regions [2]. references 1. masood s, naveed s, alvi ru. infiltrated leishmaniasis recidivans cutis on the face: a rare clinical presentation. trop doct. 2012;42(2):120-121. https://doi.org/10.1258/td.2011.110396 2. ponte-sucre a, gamarro f, dujardin jc, et al. drug resistance and treatment failure in leishmaniasis: a 21st century challenge. plos negl trop dis. 2017;11(12):e0006052. https://doi.org/10.1371/ journal.pntd.0006052 leishmaniasis recidivans in rural venezuela ariadna perez sanchez1, rajani katta2 1 department of internal medicine, the university of texas health science center, san antonio, tx, usa 2 department of dermatology, mcgovern medical school, houston, tx, usa key words: leishmaniasis recidivans, leishmania braziliensis, localized cutaneous leishmaniasis, ulceration, antimonials citation: perez sanchez a, katta r. leishmaniasis recidivans in rural venezuela. dermatol pract concept. 2020;10(3):e2020062. doi: https://doi.org/10.5826/dpc.1003a62 accepted: april 16, 2020; published: june 29, 2020 copyright: ©2020 perez sanchez and katta. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: rajani katta, md, mcgovern medical school at ut health houston, 6800 west loop south, ste. #180, bellaire, tx 77401, usa. email: info@kattamd.com figure 1. two ulcerations on the right cheek, overlying scar from previous infection. https://doi.org/10.1258/td.2011.110396 https://doi.org/10.1371/journal.pntd.0006052 https://doi.org/10.1371/journal.pntd.0006052 https://doi.org/10.5826/dpc.1003a62 dermatology: practical and conceptual image letter | dermatol pract concept 2019;9(4):4 271 dermatology practical & conceptual case presentation a 4½-year-old boy presented with a delayed appearance of all fingernails and near absence of both thumbnails, present since birth, along with incomplete extension of the bilateral elbows. on examination, the bilateral thumbnails were hypoplastic and the index fingers of both hands showed tenting with triangular lunulae. flexion deformity was noted at the bilateral elbows. a roentgenogram of the pelvis showed bilateral iliac horns, while that of both knees showed absent patella. the rest of the examination was within normal limits. on the basis of the presence of bilateral iliac horns, triangular lunulae, webbing of elbow, and an absent patella (figure 1, a-d), a diagnosis of nail-patella syndrome was made. teaching point nail-patella syndrome presents with a classic tetrad of triangular lunulae, elbow pterygium, absent patellae, and posterior iliac horns. dermoscopy aids in better visualization of the triangular lunulae. nail-patella syndrome: a classic case sarita sanke1, taru garg1, rubina jassi1, apoorva maheshwari1 1 department of dermatology, lady hardinge medical college & associated hospitals, new delhi, india key words: nail patella, elbow pterygium, iliac horns, dermoscopy citation: sanke s, garg t, jassi r, maheshwari a. nail-patella syndrome: a classic case. dermatol pract concept. 2019;9(4):271. doi: https://doi.org/10.5826/dpc.0904a04 accepted: july 3, 2019; published: october 31, 2019 copyright: ©2019 sanke et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rubina jassi, md, dnb, mrcp (sce), department of dermatology, lady hardinge medical college, shaheed bhagat singh marg, new delhi 110001, india. email: jassi.rubina@gmail.com figure 1. nail-patella syndrome collage showing (a) triangular lunula on dermoscopy, (b) bilateral posterior iliac horns, (c) bilateral elbow pterygium, and (d) absent patella. [copyright: ©2019 sanke et al.] a c b d dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2012;3(2):15 87 review by mark a. hurt, md it has been just over 4 years, at this writing, since bernie ackerman died on december 5, 2008, in new york city. on that day, i lectured at the university of missouri-columbia, my alma mater, on why i disagreed with the concept of the dysplastic nevus. my lecture was titled: “dysplastic nevus: fact or fiction?” bernie was a big influence on what i discussed in that lecture, and it generated a number of questions from the audience, most of whom were residents in pathology who knew little about him or his ideas. as i was driving home to st. louis, my wife telephoned me about bernie’s passing. it was a long and quiet drive ackerman ab. a philosophy of practice of surgical pathology: dermatopathology as model. new york: ardor scribendi, ltd., 1999 citation: ackerman ab. a philosophy of practice of surgical pathology: dermatopathology as model. new york: ardor scribendi, ltd., 1999. dermatol pract conc. 2013;3(2):15. http://dx.doi.org/10.5826/dpc.0302a15. copyright: ©2013 hurt. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr., maryland heights, mo 63043, usa. tel. 314.991.4470. email: markhurt@aol.com. figure 1. ackerman ab. a philosophy of practice of surgical pathology: dermatopathology as model. new york: ardor scribendi, ltd., 1999. 470 pp with index. isbn-10: 1893357023. isbn-13: 978-1893357020. home. it was a moment of reflection about him, having spoken with him only a few days earlier, which could come only at such a time. the world changed for me that day. in the years since his passing, i have thought of him often, of his long career, of the controversies he caused— and clarified—and of the quality of ideological engagement he encouraged. it was invigorating, infuriating, challenging, sometimes baffling, but never dull. a few weeks ago, i decided to learn whether his book, a philosophy of practice of surgical pathology: dermatopathology as model, was ever reviewed. it was. michael b. morgan, md, reviewed it in the american journal of dermatopathology 2001; 26:554-555. bernie responded to the review, as was his custom. edward nikicicz provided very brief tribute to the the book in 2002 on the amazon.com website. to my knowledge, there are no others. this is the kind of book that, in my opinion, deserves an additional review, now some 12 years after the first review and 14 years after the book was published. so, here it is, and i hope that bernie would have wanted to respond to it, but, unfortunately, he cannot. —— • —— physically, this book looks more like a novel, and a wellanticipated one, it printed on 80# simpson teton, with pages bearing deckle edges, set in centaur, metro light, and trajan. the boards are in green cloth with a sewn-in bookmark. this book is composed of 44 chapters. there are 470 pages with a foreword, afterword, and an index. the dedication is to arkadi m. rywlin, md, and alberta szalita, md, two of his teachers—the first in pathology and the second in psychoanalysis. 88 book review | dermatol pract concept 2012;3(2):15 in the foreword, bernie lays out the purpose for his book in these words: . . . this book is a treatise about the intrinsic character and quality of the practice of pathology; that is, it is a system of ideas, concepts, and principles formed to enable and motivate the logical and analytical conduct of that practice for the purpose of achieving its raison d’être optimally, to wit, specific, accurate diagnosis. this book . . . endeavors to help students of pathology to inquire into the essence of the practice of pathology and, in the process, to forge a system for practice that is both reflective and effective. what follows is his treatise. these 44 chapters are a collection of vignettes about the practice of medicine and pathology, reflections on thought, and insights into a life well lived. if any reader of this review has read this book and knew the man, he or she will grasp immediately that these vignettes are classic bernie ackerman. i recall fondly his struggle to find just the right word to turn a phrase in just the right way, and the words in this book are the result of his struggle. a philosophy of life and a philosophy of practice are difficult to grasp and even more difficult to record in a coherent manner. bernie begins each chapter by laying out his thesis followed by excerpts from his own articles, or from other writers, with associated commentary. because readers of this review probably do not own a copy of this book, i think it should be of benefit to enumerate a list of the chapters with their titles to provide a global sense of it. afterward, i will concentrate on the issues i found most interesting. 1. the patient is the purpose; the purpose is the patient 2. the importance of historical perspective 3. comprehension of structure and function 4. open mind, accurate observation, profound knowledge, critical thought, reasonable interpretation 5. precision in language 6. indispensability of clinical dermatology to the mastery of dermatohistopathology 7. indispensability of dermatohistopathology to the mastery of clinical dermatology 8. general pathology and dermatopathology are one pathology 9. lives of lesions 10. variable expressions of a single process 11. criteria for diagnosis 12. illusion and reality 13. clues to diagnosis 14. pattern analysis 15. an algorithmic method for histopathologic diagnosis 16. histopathologic look-alikes 17. differential diagnosis 18. pitfalls in diagnosis 19. exceptions 20. mythology 21. clichés 22. clinical miscues as a clue to accurate histopathologic diagnosis 23. clinical implications of particular histopathologic findings 24. important or not? 25. unifying concepts 26. biopsy 27. the best special stain 28. minimizing errors in diagnosis 29. construction of an informative pathology report 30. limitations of the method 31. advantages and disadvantages of clinical history 32. the issues of alleged negligence and of behavior in matters medical-legal 33. individuality, imagination, and originality 34. skepticism, reflection, resistance, responsibility, and tenacity 35. taking the subject (not oneself) seriously 36. “i don’t know” and “i was wrong” 37. ethics, etiquette, and collegiality 38. i, myself, alone 39. collaboration and sharing 40. educare et docere 41. a profession is not a business 42. the master word in medicine 43. the magic word in medicine 44. farewell bernie ackerman was a master of the english language and of a method that he described as learning dermatopathology through “historical perspective.” i remember well when i first read his articles that employed this method. i was then a pathology resident at the university of missouricolumbia and fascinated with surgical pathology. his articles were unusual in that they presented case data but added a layer of cases from history, often including photographs of the original cases, that enriched the experience of reading about the disease in question. those of you who have read his articles on mycosis fungoides [1] or melanoma in situ [2] cannot have come away unmoved by the experience. historical perspective, precision in language, clearly established criteria for diagnosis, and excellent photography were the hallmarks of his work. chapter 2 of this book visits this approach with a recounting of textbooks written throughout the history of the discipline. those of you who have read and studied his books on adnexal proliferations know well that a study of structure book review | dermatol pract concept 2012;3(2):15 89 and function introduced the weighty subject matter of the sections of proliferations that followed. chapter 3 details the rudiments of ackerman’s thinking on the subject, and it is accompanied by drawings to aid his conceptual presentation. in chapter 4, bernie tackles one’s approach to preparing one’s mind for perception, conception, and evaluation. how many of you have read this kind of statement in the opening of a chapter of a philosophic treatise in dermatopathology? a fundamental precept of the ancient romans was “mens candida,” i.e., “open mind.” that idea is as valid today as it was at the time of virgil. without an open mind, there can be no receptivity to new observations, new ideas, and new concepts.” i add only one caveat to this statement, because i know dr. ackerman believed it; one must bring an active mind into all matters—the mind cannot be open to everything, as it will degenerate from the lack of ability to distinguish truth from propaganda. as he states, “an open mind must be exercised, not just left open like a sieve.” i disagree with bernie, however, on a crucial point, which we discussed on a number of occasions. he states the following (p 83): in the realm of morphology, a serious limitation to astute observation is the subjectivity inherent in the process itself. in actuality, the process is 100 percent subjective. for example, competent histopathologists might not be able to agree about whether a particular neoplasm is symmetric or asymmetric—one of the most important considerations in distinguishing benign from malignant neoplasms by silhouette—let alone to conclude whether the neoplasm is benign or malignant, or both together in the same biopsy specimen. my point of difference with bernie is not that there is disagreement between any two or among several observers on matters of what is observed morphologically or what it means—after all, there is an entire consultation industry in dermatopathology based on this fact. my disagreement with bernie centers on the issue of subjectivity. just because observers may not agree on a given set of data or a diagnosis does not mean that the process is a subjective one. in any given case, each can learn from one another until each understands precisely what the issues are, thus removing the subjective or the arbitrary from the realm of the discussion. in one sense of the meaning of subjective, however, he is right; the observer perceives the object only with his or her senses, and that process cannot be transferred. it can only be transmitted from one to another in the form of conceptual knowledge. this, then, is the meaning of bernie’s statement that “still, persons trained to make precise observations can do that with remarkable consistency and repeatability.” this statement is true, and it also the reason why the process is not subjective. precision in language (chapter 5) is one of the more important chapters, and bernie gives examples of problems in communication in pathology: misnomers, nouns without modifiers (e.g., “nevus” without “melanocytic”), superfluous synonymy (too many names for the same pathological process), redundancies, flawed concepts, and animism and anthropomorphism. he concludes with a few examples of what he considers proper definitions. i liked bernie’s examples of flawed concepts, especially his examples of how the term “dysplasia” has been used in pathology. he was right then, and he is still right; it is a hopeless concept that has no coherent definition and, in my opinion, should be dropped, expunged, jettisoned from the language of pathology. the sooner this occurs, the better we all will be. clinical dermatology and dermatopathology are two different perspectives on the same object. thus, in chapters 6 and 7, ackerman tackles these perspectives. i urge especially the reader to study chapter 7, which addresses fundamental lesions defined and illustrated diagrammatically. in 1984, bernie authored an entire book with anna ragaz, md, on the lives of lesions.[3]. what more does he add to this? in chapter 9, he reiterates the principle: “not only do diseases have lives, but individual lesions of those diseases have lives, too, just as human beings do.” i would characterize his sentiments this way: the “life” of a lesion is its natural history. to know dermatopathology (as well as any other aspect of pathology—see his chapter 8) requires a thorough understanding of the nature of the concept of a spectrum of lesions from the beginning of their evolution through and including their devolution (see chapter 10). moreover, it requires that one knows all of the differential diagnosis so as to understand the mimicry of the lesion in question with the natural history of other classes of lesions, however similar. in chapter 11, “criteria for diagnosis,” bernie’s introduction is a quotation by ludwig wittgenstein, one of the most unintelligible philosophers of the 20th century, if not of all time, second only to immanuel kant. this criticism aside, bernie addresses perhaps the most critical epistemological issue facing all of diagnostic pathology: how does one identify criteria that constitute a given diagnosis? in this, i differ from dr. ackerman, who stated explicitly that: every judgment made by a morphologist, whether a clinician or a histopathologist, is subjective—i.e., 100 percent subjective. i disagree profoundly with this point of view. just because one has direct access only to one’s own consciousness and 90 book review | dermatol pract concept 2012;3(2):15 no other does not mean that the judgments he or she draws are subjective. one cannot just “make up” criteria from the thin air; rather, one induces them by observation of the facts of reality, testing the hypothetical criteria against the facts of nature, and accepting valid criteria only when they pass muster. in defense of bernie on this issue, he is better than that which he professes explicitly. when he details the process of testing criteria in the arena of the facts of nature and rejecting them when they do not work, he gets it right. in my experience with him personally, he got it right most of the time—enough of the time to teach this student a few things! an illusion, according to merriam-webster (unabridged), is: . . . perception of something objectively existing in such a way as to cause or permit misinterpretation of its actual nature either because of the ambiguous qualities of the thing perceived or because of the personal characteristics of the one perceiving or because of both factors. of course, merriam-webster is not precise on this matter; there are no “ambiguous qualities” in nature; all qualities in nature are specific and concrete, but to be identified, they must be discovered by one’s mind. if that does not happen, an error is the result (although errors have wider causes that simply from illusion). it is the interpretation of these qualities that is often difficult and why error is so easy to make. this is not a trivial issue, as bernie places illusion into perception as such (chapter 12), not interpretation (conception and evaluation), of what is perceived. in my opinion, this is a critical point, because it explains why one might misinterpret the object of perception; say a melanoma, as though it were a melanocytic nevus. i regard illusion as having a basis in reality and perception but conditioned by conception. this explains why misidentification happens frequently and more commonly in those who are learning dermatopathology in the early years of their careers, but it happens to us all, eventually. bernie’s example of reviewing slides first without history is a good practice and can help remove bias: to make their competence and care serve patients optimally, histopathologists are obligated to resist the siren illusion by every means possible. one strategy that i employ, in imitation of odysseus, is to examine sections first without ‘benefit’ of even a syllable of history. . . . another is to reexamine, exactingly, all sections signed out by me to which a colleague in pathology or dermatology calls my attention in regard to any reservation whatsoever he or she may have about the correctness of my diagnosis. bernie makes a distinction between a clue and a criterion (chapter 13), the latter being more important, as it states a fundamental: “criteria for diagnosis are the fewest denominators that enable diagnosis to be made.” clues, in contrast, are pointers to the criteria but are not fundamental as such. he was right about both, and he taught generations of dermatopathologists how to identify them. he proceeds in the chapter by enumerating a few clues (p 221). this approach is absolutely correct and well worth considering. ackerman, for practical purposes, introduced dermatopathologists to the concept of pattern analysis for the purpose of an algorithmic approach to diagnosis. even if he did not originate the method, he made it so accessible and popular that he might as well have originated it. chapter 14 details some of this methodology beginning with his approach to inflammatory diseases of the skin, which he introduced in his famous “gold book,” [4] to his application of the method for the diagnosis of proliferations of melanocytes and adnexal proliferations. in a succinct few pages, bernie captures a life’s work, which newcomers to the field should note well. prior to understanding bernie’s algorithmic method of diagnosis (chapter 15), i and other colleagues found ourselves in precarious positions of method. how should one make a diagnosis? what was the approach? in my residency, i was told to start low and proceed to high, but i understood nothing about pattern recognition, how to use scanning magnification, and to avoid—as much as possible—higher magnifications. ackerman provided an approach, and he spells it out in basic concept here. a histopathologic look-alike (chapter 16) differs from an illusion in that a look-alike offers no histopathologic clue or criterion to come to a precise diagnosis without providing some other clinical or histopathological information to enable a narrowing of the differential diagnosis. bernie provides 15 examples that are worth knowing (pp 262-263); there are others. in chapter 17, ackerman expands this issue of look alikes, but now he emphasizes that most “look alikes” really are not alike at all once one knows the criteria for diagnosis. this is when a differential diagnosis is imperative, and why a deep understanding of criteria aids greatly in coming to a definitive diagnosis. bernie provides 15 examples of classic dilemmas (pp 269-271). perhaps this is the biggest pitfall (chapter 18) of all: without tabula rasa, a microscopist cannot utilize all of the faculties at his or her disposal to come to a specific, accurate diagnosis. when a histopathologist knows information of any kind about a patient prior to reading sections of a specimen taken from that patient, it becomes impossible to interpret the sections without prejudice. . . . it is after a histopathologist has come to a tentative diagnosis that reference should be made to any and all clinical data. i will add, this is true especially in medicolegal cases. when an attorney asks you to “weigh in” on a case, it is very book review | dermatol pract concept 2012;3(2):15 91 difficult not to have some kind of prejudice just by the nature of the situation at hand. a very important chapter (chapter 25) addresses unifying concepts in dermatopathology. bernie offers examples about melanoma, mycosis fungoides, squamous cell carcinoma, lupus erythematosus, etc. as readers of his other books and articles know well, he had particular views about unifying concepts, and he was successful at doing it well. he was not always successful, however, at convincing his readers that he was right about his opinions of them. that, he understood, was expected. what is the “best special stain” (chapter 27) in dermatopathology? i will leave it to the reader of this review to guess, but ackerman believed there was only one; if you know his works, you already know what it is. how can one minimize errors? dr. ackerman provided a list for how he thought best to operate (chapter 28), and he offered a single maxim: “the single most egregious act of omission is a failure to concentrate.” amen to that! in chapter 32, bernie addresses issues on alleged medical negligence in medical-legal matters. his principal point is that not all errors are negligent errors. in short, a mistake is an error, but an error is not always a consequence of carelessness or indifference. on the contrary, mistakes can be made when great care has been exercised . . . no pathologist gets them all right. making mistakes is inevitable in the course of a professional life. many mistakes will be made, especially by those who are privileged to act as consultants to colleagues about particularly difficult problems in diagnosis. a physician should attempt to avoid self flagellation for a mistake in diagnosis or even for negligence. the best adaptation is to do one’s very best each day with sections from every biopsy specimen, acknowledge error, learn from it, and go on. chapter 34 is an essay on how one’s position can change about the nature of a disease. on page 373, bernie lists a number of diseases in which he changed his opinion about their nature. the list spans the years 1967-1994, and he admits that it is not a complete list. i have changed my mind about many subjects on which i have written since i began practicing dermatopathology in 1969. each error in perception or in interpretation was corrected in a subsequent publication as soon as the misconception became apparent to me. some have yet to be rectified because i have yet to recognize them as being wrong. dr. ackerman concludes his book with chapters on admitting error, ethics, the joys of individual production and collaboration with others, education, the “business” of medicine versus the practice of the profession of medicine, the master-word of medicine (work), and the magic word of medicine (joy). finally, bernie, in a chapter titled “farewell,” lays out his plan for shifting his emphasis in the final phase of his career. he could not have known it, but that phase would last about 8 years, and in that time, he accomplished much of what he stated that he wanted to accomplish. it was a pleasure for me to share in some of that with him. —— • —— in the first decade of this century, i had the honor of spending time with bernie, perhaps in a way that many of his fellows did not. it began with a review of his second addition of neoplasms with follicular differentiation, [5] blossomed into my becoming editor of this section of dermatopathology practical and conceptual, and led to a friendship and a collegial relationship that was constant until his death. reading this book on bernie’s philosophy of practice brought back a flood of memories of the man, his ideas, and why he and they matter still and always will. it brought me back to one of the most challenging times, intellectually and emotionally, of my life. it is important that each new generation of dermatopathologists discovers a. bernard ackerman, md. love him or hate him, each one will have to make peace with his positions on ideas in this field. this book, written and published by him at the peak of his faculties, will aid in that desideratum. as bernie earned it, he gets the last word: of all human endeavors, none provides greater possibilities for fulfillment than the profession of medicine, and of all the specialties in medicine, none is more challenging and edifying that pathology. in order to practice medicine, including pathology, wisely and well, one must be guided by an encompassing philosophy. this volume shares such a philosophy about the practice of pathology, one that is rooted in reverence for the discipline and in respect for those who work at it. let those who read the lines in these pages be as enriched by the experience as was he who composed them. disce, doce, dilige! references 1. sanchez jl, ackerman ab. the patch stage of mycosis fungoides. criteria for histologic diagnosis. am j dermatopathol. 1979 spring;1(1):5-26. pubmed pmid: 549480. 2. kamino h, ackerman ab. malignant melanoma in situ: the evolution of malignant melanoma within the epidermis. in: ackerman ab. pathology of malignant melanoma. new york: masson publishing usa, inc., 1981:59-91. 92 book review | dermatol pract concept 2012;3(2):15 3. ackerman ab, ragaz a. the lives of lesions. chronology in dermatopathology. new york: masson, 1984. 4. ackerman ab. histologic diagnosis of inflammatory skin diseases. a method by pattern analysis. philadelphia: lea & febiger, 1978. 5. hurt ma. review of: neoplasms with follicular differentiation, 2nd ed, by ackerman ab, reddy vb, soyer hp. reviewed in am j dermatopathol 2002; 24(2):169-179. dr. hurt is the book review editor of dermatology: practical & conceptual. he practices dermatopathology in maryland heights, mo, usa, near st. louis. contact him at markhurt@aol.com. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020060 1 dermatology practical & conceptual introduction lichen planus is an idiopathic lichenoid dermatosis that has many variants, such as the follicular form, which is clinically and histologically characterized by follicle involvement. usually the most typical dermoscopic feature of lichen planus is the presence of whitish lines, also called wickham striae (ws), which histologically correlate with orthokeratosis above the zones of wedge-shaped hypergranulosis [1]. ws are seen as rounded, arboriform, reticular, or annular pearly whitish structures and are pathognomonic of lichen planus. ws can show different color patterns, such as homogeneous crystalline white, blue-white veil, and yellowish white pattern. the ws border can show thin spikes or arboriform ramifications, intermingled with linear vessels [1,2]. other features that can be observed at dermoscopic analysis are the presence of gray-blue dots, peppering, red lines due to the presence of vascular structures, comedo, milium-like cysts, and blue-white veils in the center [2]. case presentation a dark-skinned man of african origin, aged 33, who has been living in italy for the past 10 years, came to our attention after a 1-year history of a pigmented lesion on his face. this lesion was previously treated as actinic keratosis with diclofenac sodium 3% gel, but this treatment had not been successful. on examination, the area of concern showed irregularly flat, dark brown macules with defined limits on nasolabial folds. the lesion showed 2 slightly elevated darker infiltrated and palpable areas, 1 on the left side of the upper lip and 1 under the nostril (figure 1a). the patient did not report any symptoms. dermoscopy showed the typical pseudonetwork pattern with gray-brown perifollicular pigmentation, reticulated hyperpigmentation and 2 areas of darker irregular pigmentation, and obliteration of follicular openings (figure 1b). according to the dermoscopic features, the recent onset of the lesion, and its increased size, two 4-mm punch biopsies lichen planus mimicking atypical melanocytic lesion in a man with dark skin federica scarfì,1 luciana trane,1 flavia silvestri,1 federico venturi,1 teresa oranges,1 agata janowska,1 francesca portelli,2 vincenzo de giorgi1,3 1 department of dermatology, university of florence, florence, italy 2 division of pathological anatomy, department of surgery and translational medicine, university of florence, florence, italy 3 cancer research attilia pofferi foundation, pistoia, italy key words: lichen planus, melanoma, dark skin, dermoscopy citation: scarfi f, trane l, silvestri f, venturi f, oranges t, janowska a, portelli f, de giorgi v. lichen planus mimicking atypical melanocytic lesion in a man with dark skin. dermatol pract concept. 2020;10(3):e2020060. doi: https://doi.org/10.5826/dpc.1003a60 accepted: march 17, 2020; published: june 29, 2020 copyright: ©2020 scarfi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo de giorgi, md, department of dermatology, university of florence, viale michelangiolo 41, 50121 firenze, italy. email: vincenzo.degiorgi@unifi.it https://doi.org/10.5826/dpc.1003a60 mailto:vincenzo.degiorgi@unifi.it 2 letter | dermatol pract concept 2020;10(3):e2020060 sion: asymmetric pigmented follicular openings, dark rhomboidal structures, slate-gray globules, and slate-gray dots. this case shows the difficult clinical and dermoscopic differential diagnosis of pigmented lesions on the face, mostly with darker skins, and shows that it is important to consider also lichenoid dermatitis as a possible differential diagnosis in the management of pigmented lesions of the face. references 1. vázquez-lópez f, gómez-díez s, sánchez j, pérez-olivia n. dermoscopy of active lichen planus. arch dermat o l . 2 0 0 7 ; 1 4 3 ( 8 ) : 1 0 9 2 . h t t p s : / / d o i . org/10.1001/archderm.143.8.1092 2 . vá z q u e z l ó p e z f,   m a n j ó n h a c e s ja, maldonado-seral c, raya-aguado c, pérez-oliva n, marghoob aa. dermoscopic features of plaque psoriasis and lichen planus: new observations. dermatology. 2003;207(2):151-156. https://doi. org/10.1159/000071785 dermoscopic analysis of our case showed a gray pseudonetwork with asymmetrical pigmented follicular openings. this pattern, however, is common to numerous pigmented lesions, both melanocytic and not melanocytic lesions, which often makes a correct diagnosis difficult. moreover, the presence of a milky pink erythema in a part of the lesion and the obliteration of some follicular openings can mean a progression of malignant lentigo [2]. our case shows all typical dermoscopic features of a melanocytic lesion on the face. therefore, the preoperative clinical diagnosis was of an atypical melanocytic lesion. the presence within the lesion of a dermal nevus made the dermoscopic diagnosis even more difficult. in fact, the overall dermoscopic appearance of our lesion revealed the 4 most important features of malignant lentigo in progreswere taken for histopathological examination under the suspected diagnosis of atypical melanocytic lesion. the final clinical and histopathological diagnosis (figure 2) was follicular lichen planus with the presence of a dermal melanocytic nevus (figure 1c). conclusions the particular site of the face and the dark skin of our patient can hide some typical features of follicular lichen planus and can mimic some typical features of melanocytic lesions. the pathognomonic ws may not be visible in pigmented skin and ws may not be appreciated on lichen planus lesions when the patient has been receiving topical treatment such as topical steroids or salicylic acid. figure 1. (a) clinical and (b,c) dermoscopic features of the case. figure 2. (a,b) histopathological examination of 2 punch biopsies shows compact hyperkeratosis, irregular epidermal hyperplasia with vacuolar basal changes, and scattered apoptotic keratinocytes. there is a band-like inflammatory infiltrate in the dermis consisting of lymphocytes and histiocytes and scattered melanophages. delicate fibroplasia around adnexal follicles is also observed. (c,d) the second skin biopsy shows a common dermal nevus, with pigmented melanocytes in the superficial portions of the lesion; melanocytes do not show signs of cytological atypia. https://doi.org/10.1001/archderm.143.8.1092 https://doi.org/10.1001/archderm.143.8.1092 https://doi.org/10.1159/000071785 https://doi.org/10.1159/000071785 dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020065 1 dermatology practical & conceptual introduction tinea nigra is a rare superficial phaeohyphomycosis whose characteristic lesion is an asymptomatic, unilateral, well-delimited brown to black macule. differential diagnoses are melanocytic lesions, subcorneal hemorrhage, and exogenous pigmentation. we present 2 cases of tinea nigra where dermoscopy was helpful in making the correct diagnosis. case presentations an 8-year-old girl presented with a well-defined brown patch on the right palm (figure 1a). dermoscopy showed homogeneous “brown spicules” that did not follow the dermatoglyphic lines (figure 2a). a 5-year-old boy presented with an irregular patch on the left palm (figure 1b). dermoscopy showed “brown spicules” following the parallel ridge pattern (figure 2b). both patients were from porto alegre, brazil, and had the lesions for approximately 8 months. mycological examination showed dematiaceous septate hyphae (figure 3), and hortaea werneckii was identified in culture. both patients were treated with fenticonazole cream for 30 days and showed clinical improvement. conclusions tinea nigra is a superficial fungal infection that affects the stratum corneum. it is characterized by a single unilateral and asymptomatic brown to black patch that affects mainly the palms and, less frequently, the soles of young adults. it is caused by h. werneckii, a dematiaceous fungus found in tropical and subtropical climates, mainly in the sand at the beach. mycological examination shows brown and septate hyphae with thick walls. examination of the culture shows black, humid, and shiny colonies. clinically, tinea nigra can mimic benign and malignant acral melanocytic lesions. however, pigmented melanocytic nevi show a parallel furrow pattern that is not seen in tinea nigra. the dermoscopy pattern for tinea nigra was first described as “pigmented spicules,” which form an almost reticulated entodermoscopy in the diagnosis of tinea nigra: two case reports manuela lima dantas,1 giovana serrão fensterseifer,1 paulo henrique martins,2 irina a. paipilla hernandez,1 fernando eibs cafrune2 1 dermatology, porto alegre, brazil 2 dermatology department, santa casa hospital de porto alegre, brazil key words: entodermoscopy, superficial mycosis, tinea nigra, melanocytic lesions citation: lima dantas m, serrão fensterseifer g, henrique martins p, paipilla hernandez ia, eibs cafrune f. entodermoscopy in the diagnosis of tinea nigra: two case reports. dermatol pract concept. 2020;10(3):e2020065. doi: https://doi.org/10.5826/dpc.1003a65 accepted: april 17, 2020; published: june 29, 2020 copyright: ©2020 lima dantas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. giovana serrão fensterseifer, rua anita garibaldi, 1143/1203, porto alegre, brazil. email: gfensterseifer@ gmail.com https://doi.org/10.5826/dpc.1003a65 mailto:gfensterseifer@gmail.com mailto:gfensterseifer@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020065 patch [1]. however, noguchi et al recently described cases of tinea nigra with the parallel ridge pattern, featuring fine, wispy, brown “spicules” (characteristic of tinea nigra) and no color gradation (important clue for differentiation from melanoma) [2]. besides melanocytic lesions, we have to consider subcorneal hematoma and exogenous pigmentation as differential diagnoses. dermoscopy of subcorneal hematoma usually reveals reddish black homogeneous areas, often accompanied by satellite globules. in doubtful cases, a scraping test can be performed; gentle scraping off of the stratum corneum with a scalpel will result in partial or complete removal of the pigmentation in cases of subcorneal hematoma. exogenous pigmentation can present as a parallel ridge pattern on dermoscopy. previous exposition to some kind of material that can pigment the area, pigmentation favoring foot pressure points, and disappearance within 1 month are important clues for the correct diagnosis (table 1). table 1. dermoscopy findings of tinea nigra and its differential diagnosis tinea nigra “pigmented spicules” forming an almost reticulated patch or arranged in parallel ridge pattern with no color gradation benign acral melanocytic lesion parallel furrow pattern, fibrillar pattern, or lattice-like pattern malignant acral melanocytic lesion parallel ridge pattern subcorneal hematoma reddish black homogeneous areas, satellite globules; partial or complete removal of pigment with scrapping test exogenous pigmentation parallel ridge pattern; correlate with medical history clues figure 1. a brown, well-delimited patch on the palm. figure 3. mycological examination: dematiaceous septate and branched hyphae.figure 2. (a) “brown spicules” forming an almost reticulated patch. (b) “brown spicules” arranged in the parallel ridge pattern. letter | dermatol pract concept 2020;10(3):e2020065 3 references 1. kaminska-winciorek g, spiewak r. tips and tricks in the dermoscopy of pigmented lesions. bmc dermatol. 2012;12:14. https:// doi.org/10.1186/1471-5945-12-14 2. noguchi h, hiruma m, inoue y, miyata k, tanaka m, ihn h. tinea nigra showing a parallel ridge pattern on dermoscopy. j dermatol. 2015;42(5):518-520. https://doi.org/10.1111/13468138.12830 we present 2 cases of tinea nigra, one with the classic dermoscopy of “brown spicules” forming an almost reticulated patch and the other with the most recent dermoscopy pattern described, the parallel ridge pattern, featuring “brown spicules” and no color gradation. dermoscopy, a noninvasive technique broadly used in the evaluation of pigmented lesions, has shown to be a useful tool for the diagnosis of tinea nigra. https://doi.org/10.1186/1471-5945-12-14 https://doi.org/10.1186/1471-5945-12-14 https://doi.org/10.1111/1346-8138.12830 https://doi.org/10.1111/1346-8138.12830 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2014;4(1):4 27 every year, hundreds of thousands of pages are devoted to diagnostic problems in medicine. in books and medical journals, physicians constantly share their experiences, advance criteria for diagnosis, and alert to diagnostic pitfalls. one tremendous pitfall, however, probably the greatest of them all, is hardly ever mentioned, namely, specimen mix-up. the true size of that pitfall is unknown. there are only few articles about that subject and most deal with individual cases. this is not surprising because specimen mix-up would not occur if it could be recognized reliably and studied systematically. in laboratory medicine, analysis in the early 1970s of 5200 control cases smuggled into routine examinations revealed an error rate of 3.5%. the most common of those errors, occurring in 0.89% of all cases, was a specimen mix-up [1]. by contrast, in a survey conducted at hospitals of many countries, the rate of specimen mix-up was estimated confusion—specimen mix-up in dermatopathology and measures to prevent and detect it wolfgang weyers1 1 center for dermatopathology, freiburg, germany keywords: histopathology, biopsy, error, mix-up, patient safety, quality improvement citation: weyers w. confusion—specimen mix-up in dermatopathology and measures to prevent and detect it. dermatol pract concept. 2014;4(1):4. http://dx.doi.org/10.5826/dpc.0401a04 received: september 24, 2013; accepted: october 14, 2013; published: january 31, 2014 copyright: ©2014 weyers. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: wolfgang weyers, m.d., center for dermatopathology, engelbergerstr. 19, 79098 freiburg, germany. tel. +49-761-31696; fax. +49-761-39772. email: ww@zdpf.de maintaining patient identity throughout the biopsy pathway is critical for the practice of dermatology and dermatopathology. from the biopsy procedure to the acquisition of the pathology report, a specimen may pass through the hands of more than twenty individuals in several workplaces. the risk of a mix-up is considerable and may account for more serious mistakes than diagnostic errors. to prevent specimen mix-up, work processes should be standardized and automated wherever possible, e.g., by strict order in the operating room and in the laboratory and by adoption of a bar code system to identify specimens and corresponding request forms. mutual control of clinicians, technicians, histopathologists, and secretaries, both simultaneously and downstream, is essential to detect errors. the most vulnerable steps of the biopsy pathway, namely, labeling of specimens and request forms and accessioning of biopsy specimens in the laboratory, should be carried out by two persons simultaneously. in preceding work steps, clues must be provided that allow a mix-up to be detected later on, such as information about clinical diagnosis, biopsy technique, and biopsy site by the clinician, and a sketch of the specimen by the technician grossing it. awareness of the danger of specimen mix-up is essential for preventing and detecting it. the awareness can be heightened by documentation of any error in the biopsy pathway. in case of suspicion, a mix-up of specimens from different patients can be confirmed by dna analysis. abstract 28 review | dermatol pract concept 2014;4(1):4 to be about 0.5% [2]. the discrepancy between those data suggests a huge dark figure of cases. in addition to the dark figure whose true size, naturally, is shrouded in the dark, other factors hamper a systematic analysis of mistakes in the assignment of specimens. among them are different criteria employed in studies dealing with mistakes in laboratory medicine, some studies including only cases of specimen mix-up that were not recognized and corrected immediately, others many other types of mistakes, ranging from loss of specimens to incomplete labeling of them that could be amended easily [3,4]. even inappropriate biopsies and incorrect interpretation of reports by clinicians have been dubbed “laboratory errors,” in accordance with the definition of such errors as “any defect from ordering tests to reporting results and appropriately interpreting and reacting on these.” [5] moreover, data from one hospital or laboratory cannot be transferred readily to another, even if the same criteria are employed. methods of quality control in tests of blood or urine, mix-up of specimens can be recognized in follow-up examinations if one result is not compatible with all the others. in order to facilitate recognition of such mistakes, nosanchuk and gottman in 1974 introduced the “delta check” that compares any two consecutive results for a given test on the same patient by subtracting the later result from the prior result and then dividing by the prior result. the delta value is determined for every new test and is compared to previous values. each parameter has its own tolerance for deviation, and if the latter is exceeded, the respective case is submitted to further investigation [6,7]. because samples of blood or urine are generally used for analysis of several variables, the sensitivity of the method has been enhanced by introduction of a multivariate delta check 8,9]. another method advocated to detect laboratory errors is the “splitspecimen design,” according to which samples from the same patient are analyzed by two different laboratories, and one part is stored away and analyzed only in the case of contradictory results [10]. in addition, co-determination of the blood group with every test, and comparison of it with the known blood group of the patient, has been advocated as a routine measure of quality control, although it does not help to detect mix-up of specimens of patients with the same blood group [11]. given the rarity of specimen mix-up, the considerable costs and efforts associated with those methods of detection, and the limited sensitivity of them, the value of methods such as the delta check has been called in question [12]. a mix-up of biopsy specimens is even more difficult to recognize than a mix-up of samples of blood or urine, the reason being that results, in general, cannot be compared to previous or subsequent data on the same parameter. each biopsy specimen stands for itself. this is not only true for neoplasms excised completely but also for inflammatory dermatoses. depending on the stage of development of a given lesion, the histopathologic findings in two biopsy specimens of the same disease in the same patient may differ strikingly, and a modification of the histopathologic presentation by unrelated factors, such as irritation, venous hypertension, or another co-existing disease, must always be expected. even within the same biopsy specimen, histopathologic findings may vary considerably, precluding the “split-specimen design” as a method of quality control. moreover, splitting a specimen in several portions in order to have them examined by different laboratories, or to keep one portion in storage, would compromise severely the assessment of criteria for histopathologic diagnosis and, therefore, is not feasible for the vast majority of biopsy specimens in dermatopathology. the suspicion of a specimen mix-up is raised especially by divergent diagnoses on the same neoplasm in an incisional biopsy and the subsequent re-excision specimen. however, two different neoplasms in the immediate vicinity of one another are not rare, especially in skin damaged severely by sunlight. moreover, complete regression of a neoplasm following biopsy of it is a common phenomenon not only in basal-cell carcinoma, but also in squamous-cell carcinomas and melanocytic neoplasms [13-15]. therefore, failure to find remnants of a biopsy-proven neoplasm, coupled with detection of a different neoplasm, does not necessarily imply a specimen mix-up. it does, however, raise the suspicion of it. in order to prove or disprove that suspicion, studies can be performed to check the identity of the patient in both specimens. for that purpose, various methods have been proposed, ranging from immunohistochemical determination of the blood group or of the hla class 1 antigen profile to molecular studies [16-18]. immunohistochemical methods have advantages in complex cases. for example, in case of suspicion that some of many fragments of tissue in the same paraffin block come from a different patient, molecular analysis may be difficult, whereas differences in the immunohistochemical staining pattern of those fragments of tissue are detectable easily. however, identical blood groups are common, and even when studying the polymorphous hla class 1 complex with a panel of five antibodies, identical results of different patients must be expected in 1% of cases [17]. molecular identity testing is far more sensitive. it is performed by short tandem repeat analysis, i.e., analysis of repeating sequences of 2-6 base pairs of dna also known as “microsatellites.” because the latter show great variation in regard to the number of repeats and often many alleles at a microsatellite locus, they have been chosen for genetic fingerprinting in forensic medicine. with the use of commercially available kits for combined analysis of several loci, the probability of the review | dermatol pract concept 2014;4(1):4 29 same result in unrelated individuals is about 1 to 1 billion. since the late 1990s, short tandem repeat analysis has been employed increasingly for proving a mix-up of specimens in surgical pathology [18-22]. a mix-up of specimens from the same patient, however, cannot be detected by any of those methods. moreover, considering the rarity of specimen mix-ups, identity testing is far too laborious and costly to be performed as a routine measure. it is reserved for clarifying the suspicion of specimen mix-up, and the latter arises only if the result of an examination is not plausible. sometimes, a mix-up of specimens is obvious. for example, if a biopsy specimen from the buttock of a newborn under the clinical diagnosis of a strawberry hemangioma shows a solar keratosis and large sebaceous glands in severely sun-damaged skin, clinical data and histopathologic findings are incompatible. if the next specimen comes in as a solar keratosis from the nose but shows a hemangioma, the issue is resolved. usually, the question whether the mix-up occurred in the operating room or the laboratory cannot be decided, but all one needs to do for restoring order is to switch the numbers of both specimens. in general, however, it is not that easy. for example, if there is also a vascular neoplasm in the first biopsy specimen, the histopathologist must be extremely alert in order to identify the specimen mix-up on the basis of anatomical differences or presence or absence of solar elastosis. if the first patient is not a newborn but an adult, this becomes more difficult. it is even more difficult if findings in only a single specimen do not fit, whereas histopathologic findings in preceding and subsequent specimens and in all specimens submitted by the same physician on the same day are compatible with the respective clinical data. there is no chance at all to discover a specimen mix-up if clinical diagnoses and anatomy are similar, e.g., a melanocytic nevus from the chest and a melanoma from the shoulder. in such instances, the mix-up either goes unnoticed or manifests itself months or years later by a local recurrence of the melanoma at the site of the alleged nevus. the consequences may be dramatic, and they have been described in many case reports in the forensic medical literature. for example, in an elderly patient two biopsies were taken from the colon, one of which was reported as carcinoma and the other as normal bowel mucosa. because the precise biopsy site had not been specified on the request slip, a subtotal colectomy was performed on the wrong segment of colon. when histopathologic examination of it failed to reveal signs of malignancy, the mistake was clarified by another biopsy of the carcinoma that had been left untreated [23]. biopsy of a gastric ulcer in a middle-aged woman revealed a carcinoma and resulted in gastrectomy. no residual malignancy was found in the surgical specimen. in an elderly man, a biopsy from the stomach was performed on the same day under the clinical diagnosis of carcinoma. it revealed only a mild gastritis that was treated conservatively. one year later, the patient died from metastasizing gastric cancer. a molecular analysis revealed that the biopsy specimens of both patients had been mixed-up [19]. a middle-aged woman underwent a breast biopsy that was diagnosed as infiltrating carcinoma. based on this result, a total mastectomy and axillary lymph node dissection was performed. when histopathologic study of the specimens revealed no residual tumor, the original biopsy specimen was re-examined and failed to reveal carcinoma as well. the carcinoma was found in the preceding slide that the pathologist had taken inadvertently twice from tray, the second time giving the diagnosis of mammary carcinoma on the wrong patient [23]. a nostrum to prevent such catastrophes does not exist. methods of quality control in laboratory medicine, such as the delta check and the “split-specimen design,” cannot be applied. in order to prevent a mix-up of biopsy specimens, it has been proposed to ink all incoming specimens with six different colors in a defined sequence and to write down that color on the request form. in a study of 1000 breast core needle specimens, two mix-ups could be detected by a deviation of the color noted on the request form from the actual color of the specimen seen under the microscope. one of those mix-ups was caused by confusion of two paraffin blocks, the other by an incorrectly labeled specimen slide. in yet another case, a mix-up was faked by an incorrect declaration of the color on the request form; in that instance the additional measure caused confusion, rather than preventing it [24]. more importantly, the sensitivity of the method is low because a deviation of colors may be overlooked, a mix-up of specimens inked with the same color cannot be recognized, and a mix-up of specimens before or after procession of it in the laboratory cannot be detected. most mix-ups, however, occur before procession of the specimen [3,4]. despite the high effort associated with it, that method does not provide great benefits. standardization the best way to prevent and detect the mix-up of specimens seems to be good organization of all steps connected with a biopsy, from the surgical procedure itself to labeling of sample bottles and request forms in the operating room, accessioning of specimens in the laboratory, procession of specimens, assessment of histopathologic findings at the microscope, typing of dictations, transmission of reports, and, finally, assignment of reports to the respective patients in the medical practice or clinic. during that procedure, the specimen may pass through the hands of more than twenty individuals in several workplaces, and none of them can be expected to be focused fully on his or her duty in every minute of every day [25]. 30 review | dermatol pract concept 2014;4(1):4 one of the most effective means of reducing error in that complex procedure is standardizing processes wherever possible. the reason is that work is usually, and most effectively, performed on the basis of automatic, reflex-type behavior, the so-called “schematic control mode,” rather than controlled conscious thought or processing, the “attentional control mode.” conscious thought is activated by a seemingly new or novel problem for which no preconceived schema for solution exists; it is slow and effortful. with increasing experience, mental schemas to handle recurrent problems are developed and trained by repetitive behavior in myriad corresponding situations. the “schematic control mode” allows experts to function fast and effortless. once activated by conscious intention, subsequent actions are relatively automatic and usually reliable. however, if misconceived signals initiate a wrong action, the latter is likely to be carried through without being noticed. examples are slips in which the wrong automatic action is used, such as putting away a slide that has not been studied, and lapses, the omission of an automatic action, such as skipping a slide in a tray or leaving out a key word in a report (e.g., “malignancy” instead of “no malignancy”). any breach in routine standardized processes carries an enhanced risk of inducing slips and lapses. the latter are far more common than mistakes resulting from failures in conscious judgment and are less likely to be noted because they involve situations perceived as being non-problematic. in order to prevent signals that induce misguided automatic actions, standardization is crucial. in the operating room, sample bottles containing only formalin should always be taken from the same place, and sample bottles with specimens should be deposited at another place and always in the same way. in the laboratory, sample bottles, tissue cassettes, paraffin blocks, and slides should always be arranged in the same manner, the intend being to make it difficult for individuals to err by allowing them to function reliably without conscious thought [26,27]. computer-assisted work another means to prevent mistakes is automation of processes. for example, when labeling tissue blocks by hand, the same number may accidentally be accorded twice, digits may be interchanged, or they may not be written clearly and may be misread later on. automatic labeling of blocks or specimen slides in a printer prevents such mistakes (figure 1) [4,20]. the incorrect transcription of data, such as name or date of birth of the patient or number of the biopsy specimen, can be prevented by bar codes. once those data have been converted into a bar code, they do not need to be typed anew in subsequent work steps. in laboratory medicine, a dramatic decrease of specimen labeling mistakes has been reported from numerfigure 1. slides with handwritten and printed pathology numbers. even with clear handwriting, characters do not look exactly the same. for example, the lower horizontal bar of the number 2 on the middle slide is rather short; as a consequence, the number might be read erroneously as 7. among thousands of slides, there are always some handwritten characters that may be misread. printed numbers prevent such errors. [copyright: ©2014 weyers.] ous medical centers following adoption of a continuous bar code system [28]. in laboratories receiving specimens from external institutes, a continuous bar code system is difficult to implement, but bar codes should at least be used within the laboratory. in one study from a pathology department, adoption of a bar code system led to a reduction of specimen labeling mistakes by 98% [4]. ideally, bar codes should be used not only for labeling sample bottles and request forms but also for tissue cassettes, paraffin blocks, and slides, but the costs for establishing such a system may be prohibitive. moreover, it must be kept in mind that one-dimensional bar codes are not perfectly safe but may occasionally be misread. therefore, correct scanning should be confirmed by checking the patient’s name on the request slip. computer-based working processes have the advantage of a clear typeface. obviously, toners of printers should be replaced in time, as weak printing may lead to reading or scanning errors. with handwritten data reading errors are far more common. unfortunately, little value is attached to legible writing. any information that cannot be deciphered by downstream persons, not all of whom possess broad medical knowledge, is worthless. though readability is a great advantage of computerbased processes, it is not the most important one. without the facility to transfer a brief constellation of letters or numerals at the push of a button into an elaborate text, medical care in its modern form would be unthinkable. however, the tremendous easement provided by computers goes along with risks. a text typed or written traditionally may be replete with typing errors, but as a rule a word remains intelligible even in the case of incorrect typing. by contrast, the accidental review | dermatol pract concept 2014;4(1):4 31 transposition of letter characters or numerals in a computer code may create a completely different content, especially if that code is very brief. therefore, the striving for simplicity and brevity should not be exaggerated; a certain measure of redundancy is essential. a negative example in that regard are computer codes like “7a” or “10b” that have been used for decades at the world’s leading laboratory of dermatopathology by a. bernard ackerman in new york city. those brief codes are error-prone because a slip of the tongue or a minimal deviation of one finger on the computer keyboard suffice to turn a “7a” into an “8a,” thus creating a different diagnosis. by using codes that are slightly longer and reflect their content visibly, such as “pso-vulg” for psoriasis vulgaris or “gran-an” for granuloma annulare, those sources of error are mitigated. even with such codes, however, sources of error must be kept in mind. if two codes resemble one another in their visual presentation or phonetically, such as “gran-an” and “gran-ang,” the diagnosis of richly vascularized granulation tissue may be given for a case of granuloma annulare. recognition and elimination of such sources of confusion enhances the reliability of histopathologic diagnosis. redundancy also implies that at least two unrelated data should be provided side by side at each work step, such as the name of the patient and the date of birth or a unique patient identifier on all sample bottles and request slips. labeling bottles with the name only has been found to increase the rate of mistakes in specimen identification [29]. if the names of two patients are similar, as in married couples, siblings, or parents and their children, a special warning sign may be helpful, e.g., color marking of the forename. in the laboratory, the pathology number should be accompanied by the patient’s name. this is not always possible. for example, tissue blocks are too small to carry several data. in the absence of control by the patient’s name, diligence should be heightened, e.g., by double-check of the correct sequence of tissue blocks and by reading out pathology numbers in a low voice at the beginning of each new procedure. when pathology numbers are typed or scanned by histopathologists or secretaries, the name of the patient should always be controlled and either dictated or read in a low voice before dictating or typing the code of the diagnosis. the computer system should not allow two files of patients to be opened at the same time so that the accidental entry of data into the wrong file becomes impossible. a particularly helpful, but also risky, option provided by computers is the “copy and paste” function that allows an elaborate text to be copied into a different file. texts that have been marked are kept in the computer’s clipboard, and if the “paste” function is activated accidentally later on, the copied report may be issued for an unrelated biopsy specimen unless the clipboard has been cleared previously. order an essential requirement for every step in the biopsy pathway is order. the aura of a “creative chaos” cherished by some pathologists and created deliberately by piling up trays with innumerable slides in all corners of their room, intermingled with memos, medical journals, and used coffee cups, is dangerous. workplaces must be tidy, no matter whether in the operating room or at the computer, laboratory bench, or microscope. one of the chief rules is to keep only one procedure in sight. when typing down the data of patients or dictating or typewriting histopathology reports, requests slips may lie on top of one another so that only the uppermost one is visible, but never side-by-side (figure 2a, b). in the operating room, the file of the current patient should be separated from all other files. sample bottles should figure 2. entry of data from the request form in the computer. (a) correct: request forms lie on top of one another so that only the uppermost one is visible. after completion of the entry, the uppermost form is turned over and is placed back-side-up on the pile of finished forms on the left. (b) false: request forms of several specimens are scattered across the desk. in case of a distraction, e.g., through a telephone call, the risk is considerable that data from an unrelated request form will be entered when resuming work. [copyright: ©2014 weyers.] a b 32 review | dermatol pract concept 2014;4(1):4 be labeled and request forms completed immediately after the procedure and should be removed for postage before the next patient is called in. if this is not done, and several files with adhesive labels carrying different names are deposited on the same desk, or unmarked bottles with biopsy specimens of different patients are kept in the same room, there is a great risk of confusion. confusion may also be caused by labeling bottles and request forms prior to the biopsy because the course of action is often changed during the procedure, e.g., by performing an additional biopsy, by abstaining from a biopsy, or by changing the sequence of biopsies [20]. in such instances, empty bottles or request forms for biopsies that have not been performed are being posted, or the numbers or declarations of the biopsy site on bottles and request slips do not conform to one another. figure 3. in a patient in whom five biopsies were performed, specimens 3 and 4 cannot distinguished from one another because roman numerals were used for labeling sample bottles. the roman numeral 4 cannot be recognized clearly. [copyright: ©2014 weyers.] figure 4. because the top of one of those sample bottles was not closed tightly, formalin leaked out. the bottles were labeled with a permanent marker pen that was dissolved by formalin. as a consequence, the specimens in the sample bottles cannot be correlated reliably with the biopsy sites noted on the request forms. [copyright: ©2014 weyers.] figure 5. the adhesive labels used to mark those sample bottles did not adhere but became detached. as a result, sample bottles cannot be distinguished from one another. the only option to dissolve this dilemma is correlation of histopathologic findings with the diagnoses and biopsy sites noted on the request forms. if biopsy sites and diagnoses are similar, however, correlation of biopsy specimens and request forms becomes a guessing game. [copyright: ©2014 weyers.] if several biopsies are performed on the same patient, the bottles containing specimens should be put away in a defined, unchangeable sequence before labeling bottles and completing request forms after the procedure. numbered compartments into which bottles are being placed help to prevent confusion of them. when numbering consecutive bottles, arabic numerals are preferable to roman ones because the latter are prone to confusion. for example, the roman numeral “iii” may be read as “ii” if two bars are placed too close to one another, or as “iv” if one of the bars is written slightly obliquely (figure 3). before removing bottles for postage, it should be checked that all bottles contain a specimen, that they are labeled correctly with all requisite data, and that the covers are screwed down tightly. if covers are loose, and formalin leaks out, it may render labels illegible. this is the case especially if bottles are labeled with a permanent marker pen. the ink of marker pens is dissolved by formalin (figure 4). use of adhesive labels with written or printed data is preferable. depending on the batch, however, not all adhesive labels adhere firmly. therefore, firm adherence of them should be checked (figure 5). in addition, sample bottles and request forms should be checked for completeness and concordance in regard to names, numbers, and biopsy sites. bottles should then be placed in a closed plastic bag before being sent off in one envelope together with the corresponding request forms. according to a current survey among american dermatologists concerning medical error in dermatology practice, nine of ten assessment errors involved the biopsy pathway, and the most common of those errors accounting for 18% of them was incorrect information on the sample bottle or the request form [25]. review | dermatol pract concept 2014;4(1):4 33 those data are in accordance with the experience in general pathology. most errors in the assignment of specimens, according to the literature nearly three quarters, occur in the pre-analytic phase, i.e., in the practice of the submitting clinician or in the laboratory during unpacking of envelopes, correlation of sample bottles and request forms, and numbering of specimens [4,29,30]. especially in those phases, strict order is essential. the workspace for unpacking envelopes must be big enough to allow sample bottles and request forms from one envelope to be arranged in a clear fashion. sample bottles should be placed on top of the corresponding request forms. several specimens from the same patient should be compiled before labeling them with ascending pathology numbers corresponding to the sequence of biopsies indicated on bottles and request forms (figure 6). only one envelope should be unpacked at a time; all specimens of that envelope should be numbered and passed on for trimming before the next envelope is opened. any distraction during that vulnerable phase is associated with an enhanced risk of confusion. among such influences are missing, incomplete, illegible, or incorrect data on sample bottles or request forms that require consultation of the submitting practice. if specimens must be put on hold for those or other reasons, they should be removed from the work space before the next envelope is unpacked. there should be a separate space for such specimens and the corresponding request forms, if possible with compartments reflecting the reasons for postponement, such as consultation of the submitting practice, decalcification, or longer fixation time for large biopsy specimens. the order created during unpacking and numerical labeling of specimens must be maintained in all subsequent work steps, including entry of personal data of patients and clinical data in the computer, trimming of specimens using a scalpel to enable them to fit into appropriately labeled tissue cassettes, orderly alignment of tissue cassettes following procession of them in the tissue processor and before embedding specimens in paraffin blocks, orderly alignment of paraffin blocks on a refrigerated plate before cutting sections, cutting sections at the microtome, microscopy of slides holding sections of tissue, and typewriting of reports (figures 7-10). any deviation from the ascending sequence of pathology numbers, e.g., by commutation of two request forms in a pile or two slides on a tray, carries the risk of not being noticed and of leading to an error with potentially serious consequences. if there is an interruption in the ascending sequence of pathology numbers, e.g., if one slide has been broken and must be cut anew, the breach should be marked by a placeholder. other deviations from the rule should also be marked visibly, e.g., existence of several slides for a single specimen. clear marking of deviations reduces the risk that the histopathologist takes the wrong slide from the tray. if such mistakes happen, they are usually noticed and corrected readily. however, if associated figure 6. correlation of sample bottles and request forms in the laboratory. the envelopes contain sample bottles and request forms of several patients. a large workspace for laying out request forms and sample bottles helps to prevent confusion of them. sample bottles are placed on top of the corresponding request forms. subsequently, bottles and request forms are marked with adhesive labels containing the pathology number and a corresponding bar code. the correlation of specimens with request forms and the numbering of them should be carried out by two persons who can control one another mutually. [copyright: ©2014 weyers.] figure 7. once sample bottles and request forms have been numbered, they are arranged in a row, corresponding to a row of tissue cassettes carrying the same numbers. specimens are then dissected and put into tissue cassettes. the pathology numbers on sample bottles and tissue cassettes must be checked for concordance before taking out and dissecting the specimen. [copyright: ©2014 weyers.] with some other adverse influence, such as an interruption through a telephone call, the risk is considerable that the error will not be discovered when resuming work. cleanliness in addition to order, cleanliness is an essential requirement in all steps of the biopsy pathway. this is especially true for the operating room and the laboratory bench. specimens 34 review | dermatol pract concept 2014;4(1):4 sometimes fall down during handling of them. moreover, hard pieces of tissue may flip away when dissecting specimens with a scalpel and, in that instance, one may have to search for them on the floor. for that reason, the floor should be kept very clean, and there should be neither fluff nor other pieces of tissue lying around. because small pieces of tissue are difficult to see, the floor of a laboratory should be of a light uniform color without any fanciful decor. cupboards should go down to the floor without leaving narrow empty spaces beneath them that are difficult to clean and to inspect. specimens of tissue are moist and, therefore, they tend to adhere to instruments. when removing several lesions from figure 8. following dissection of specimens, many tissue cassettes with biopsy specimens of different patients are put in a basket and are processed in a tissue processor in order to dehydrate them and to prepare them for paraffin embedding. [copyright: ©2014 weyers.] figure 9. following procession of tissue, tissue cassettes are taken out of the tissue processor and are once again arranged in a row according to ascending pathology numbers. paraffin blocks are arranged in the same fashion. the pathology numbers on tissue cassettes and blocks must be checked for concordance before opening the next cassette. only one cassette should be opened at a time. pincers must be cleared before taking out the next specimen in order to prevent transmission of fragments of tissue into a wrong block. [copyright: ©2014 weyers.] the same patient, fragments of tissue of one lesion may be transferred easily to a wrong sample bottle if abrasors or pincers are not cleared after use. the same may happen in the laboratory when trimming specimens in order to place them into tissue cassettes or when embedding them in paraffin. subsequently, sections are cut from paraffin blocks at the microtome. because sections may adhere to the blade, the latter must be cleaned and changed at regular intervals. the tissue is cut in serial sections that usually have a thickness of 5 μm and are connected by paraffin, resulting in thin ribbons of tissue (figure 11). those ribbons are transferred to a warm water bath where they are allowed to float on the surface before being scooped up onto a slide placed under the water level (figure 12). if some sections become detached from the ribbon and are not scooped up, they remain on figure 10. before cutting sections at the microtome, blocks are cooled on a refrigerated plate. they are arranged in a row according to ascending pathology numbers and corresponding to a row of slides at the other side of the microtome. [copyright: ©2014 weyers.] figure 11. before clinching the next paraffin block to the microtome, the pathology number on the block and the slide must be checked for concordance and the blade of the microtome cleared from remnants of paraffin or tissue. by moving the block up and down across the blade, serial sections are cut that are connected by paraffin, resulting in thin ribbons of tissue. [copyright: ©2014 weyers.] review | dermatol pract concept 2014;4(1):4 35 the surface of the water bath and may be transferred onto another slide. in order to prevent such so-called “floaters,” the water bath must be kept clean, and the water must be changed at regular intervals (figure 13a, b). contamination of one specimen with fragments of another is one of the most common causes of misdiagnosis secondary to mix-up of tissue [16]. in one study, 0.6% to 2.9% of all slides were found to be contaminated by extraneous tissue. in most of those cases, contaminants were confined to single sections and, therefore, resulted from contamination after embedding of specimens in paraffin blocks [31]. figure 12. ribbons of tissue are transferred to a warm water bath where they are allowed to float on the surface before being scooped up onto a slide placed under the water level. if fragments of tissue become detached, they remain on the surface of the water bath and may be transferred onto another slide. in order to prevent such “floaters,” the water must be kept clean and must be changed at regular intervals. [copyright: ©2014 weyers.] mutual control because a mix-up of tissue cannot be prevented reliably, internal control is crucial. the latter may be exercised simultaneously or downstream. simultaneous control means that at least two persons are involved in the same action and can call attention instantly to any error of one another. it is indicated in the most vulnerable steps of the biopsy pathway, including the compilation of sample bottles and request forms in the medical practice before being posted. if bottles and request forms are controlled by two persons with respect to completeness and correct labeling and if that control is verified by countersigning, it will no longer happen that specimens are missing, superfluous, or not assignable when envelopes are unpacked in the laboratory. when compiling material for postage, sample bottles with biopsy specimens from the same patient should not be put in different envelopes. the accessioning of biopsy specimens in the laboratory, including unpacking of envelopes and sorting and numbering sample bottles and request forms, carries the greatest risk of specimen mix-up. in a study performed at more than 400 institutes of surgical pathology, accessioning accounted for nearly half of all deficiencies in specimen identification [29]. therefore, it should be carried out by two persons simultaneously. the same is true for the end control of slides, before slides with sections of tissue and the corresponding request forms leave the laboratory and are forwarded for microscopy. the control of the correct, identical sequence of pathology numbers on slides, paraffin blocks, and request forms, and of the concordance of the shape of specimens in paraffin blocks and on slides, by at least two persons is essential (figure 14). according to one study, the error rate figure 13. (a) biopsy from the chin of a 34-year-old patient showing typical signs of a verruca vulgaris, namely, acanthosis with elongated rete ridges bent toward the center of the lesion, papillomatosis, hypergranulosis with koilocytes, and compact orthokeratosis with narrow columns of parakeratosis above elongated papillae. in addition to two sections of the wart, there is another piece of tissue on the left. (b) the section of tissue on the left shows crowded nuclei in the lower layers of the epidermis, some hyperchromatic nuclei, loss of the granular layer, and parakeratosis with many nuclei per unit area. these are features of a solar keratosis. the piece of tissue does not belong on this slide but is presumably a “floater” from the water bath. [copyright: ©2014 weyers.] a b 36 review | dermatol pract concept 2014;4(1):4 could be reduced from 1% to 0.1% by reading out loud the numbers to another person [20]. even more important are downstream controls that allow detection and correction of errors of preceding work steps. downstream control starts with bagging specimens for postage. at this point, the absence of a sample bottle or any incomplete or incorrect labeling should be noted. in case of inconsistencies noted during unpacking of envelopes, sorting sample bottles and request forms, or trimming specimens in order to fit them in tissue cassettes, such as differences between the specimen in the bottle and a sketch on the request form, the submitting clinician should be contacted immediately. if inconsistencies between clinical data and histopathologic findings are noted at the microscope, the preceding and subsequent slides should be checked for another corresponding inconsistency that suggests a mix-up of specimens. if no corresponding inconsistency is found, slides and paraffin blocks should be compared in order to exclude the error most easy to detect, namely, use of a wrongly labeled slide. once the identity of the specimen on the slide and in the paraffin block has been confirmed, all specimens of the same submitting clinician of the same day should be checked for inconsistencies. if no other inconsistency is found, the reasons for the incongruity between clinical data and histopathologic findings can sometimes be clarified by consultation of the submitting clinician. when studying sections of tissue and dictating reports, histopathologists should not only check routinely the identity of numbers on slides and request forms, but also the names of patients on request forms and in the computer in order to detect keyboard entry errors. the secretaries typewriting reports should notice inconsistencies in them, such as discrepancies between the dictated report and data on the request form (e.g., a computer code for an inflammatory dermatosis in a specimen suspected to be a neoplasm clinically; attestation of complete removal in a biopsy declared as incomplete) or contradicting statements (e.g., “no evidence of malignancy” in a basal-cell carcinoma; “complete removal” together with a note that the neoplasm extends to one lateral margin). ideally, computerized systems should include a barrier for unusual or incompatible combinations of codes [26]. however, because elaborate computer systems for pathology laboratories with such functions are currently not available, control still depends mostly on the vigilance of the individuals involved, namely, secretaries and histopathologists. the latter should read typewritten reports and check them for mistakes before approving them by signature. the last link in the chain of downstream control is the clinician who should call the histopathologist in case of incongruities between the pathology report and the clinical picture. when errors are noted in the chain of downstream control, they should be corrected immediately. any error that is allowed to persist may be missed later on and may result in an incorrect report. severe mistakes rarely result from a single error but typically from a combination of “latent” and “active” errors [26]. even if the precipitating error is relatively trivial, e.g., correct designation but inverse listing of two biopsy specimens on a request slip (specimen 2 being listed above specimen 1), it should be corrected by filling out a new request form or by at least highlighting the inverse sequence by an eye-catching warning sign. any “latent” error corrected early on reduces the risk of more serious errors following it. clues for control the chain of downstream control is the most expedient mechanism to detect and correct errors in the biopsy pathway. however, it can only work if appropriate clues are provided in preceding work steps that allow inconsistencies to be detected later on. for example, the size and shape of biopsy specimens should be documented in the laboratory before dissecting specimens in order to fit them into tissue cassettes. if this is done, a subsequent mix-up can be detected by comparing those data with the histopathologic section on the slide. the precise way in which specimens are dissected should also be documented in order to enable technicians to note a missing or superfluous piece of tissue when preparing paraffin blocks. moreover, by describing precisely the size and shape of the obtained biopsy specimen to the submitting clinician, a mixup of specimens in the clinic or medical practice can often be verified. unfortunately, the latter option is being curtailed progressively by the ever-increasing number of very small and shallow shave biopsies. the specimens obtained by such biopsies usually cannot be told from one another. moreover, very small and narrow biopsy specimens preclude recognition figure 14. end control of slides in the laboratory. slides are laid out on trays according to ascending pathology numbers. before they are forwarded for microscopy, they are checked for the identical ascending sequence of pathology numbers on slides and request forms and for concordance of the shape of specimens in paraffin blocks and on slides. [copyright: ©2014 weyers.] review | dermatol pract concept 2014;4(1):4 37 of a mix-up on the basis of anatomical characteristics, such as sebaceous glands, apocrine glands, or solar elastosis, because those characteristics are often not exposed. the most important clues for downstream controls are provided by clinical information on the request form. the more comprehensive that information, the greater is the likelihood to detect a mix-up of specimens. among data that should never be omitted are at least one clinical diagnosis, a statement concerning the biopsy site without which a deviating anatomy cannot be noted, and a statement concerning the biopsy technique, such as shave, curettage, or punch (figure 15a-e). completing the request form is an important task that should be carried out by the physician himor herself. if it is delegated to an inexperienced assistant who does not understand the importance of those entries, the latter are often incomplete or wrong, such as the diagnosis of psoriasis in a biopsy for basal-cell carcinoma only because the patient also suffers from psoriasis and that diagnosis is the first to be mentioned in his file. if such misinformation is provided repeatedly by a particular medical practice or clinic, the histopathologist will eventually seize to inquire about discrepancies between clinical and histopathologic diagnoses, a b c d e figure 15. in a 58-year-old patient, two biopsies were performed under the clinical diagnosis of a melanocytic nevus. on the request form, specimen 1 was said to be an excisional biopsy from the right arm, and specimen 2 a punch biopsy from the cheek. (a, b) specimen 1 shows a punch biopsy of a melanoma in situ characterized by a proliferation of single melanocytes, many of which are present in the upper reaches of the epidermis. the dermis shows marked solar elastosis and a large sebaceous gland. (c, d) specimen 2 shows the compound stage of a clark’s nevus. the lesion is symmetrical and sharply circumscribed, melanocytes are distributed in regular fashion, and there are no melanocytes in the upper reaches of the epidermis. there is no solar elastosis. the lesion does not extend to lateral margins. those two specimens have been mixed-up. this can be concluded from type of excision (complete for the nevus, incomplete for the melanoma), the anatomy (the large sebaceous gland in figure 15a indicates the cheek as the biopsy site), and the association of the melanoma with marked solar elastosis (also indicating the cheek as the biopsy site). without the precise information on the request form, the mix-up of specimens would not have been detected. (e) even with this information, the mix-up would not have been detected in the case of a superficial shave biopsy including only epidermis and papillary dermis, but not the sebaceous gland and the pronounced solar elastosis in the upper reticular dermis. [copyright: ©2014 weyers.] 38 review | dermatol pract concept 2014;4(1):4 and the chances to detect a mix-up of specimens will decrease substantially. completeness and correctness of information provided on the request form, however, is not enough; that information must also be legible. there is a peculiar tendency among literate human beings to write less legibly in the case of uncertainty about what is being written. however, if a clinician is not sure about a diagnosis in a difficult case, undecipherable information on a request form does not contribute to resolving the conundrum. if previous biopsies exist of a given lesion or disease, they should be mentioned specifically with reference to the previous pathology number. commonly, entries concerning the same biopsy site differ from one another, such as “paranasal” and “cheek” for the very same spot, thus preventing the histopathologist from appreciating the identity of a lesion in the primary biopsy and the re-excision. abbreviations that are not generally used or whose meaning is ambiguous (e.g., “sk” for solar or seborrheic keratoses; “lp” for lichen planus or lymphomatoid papulosis) should be omitted on request forms. poor or missing communication among different health care providers is one of the greatest problems in the medical system. unfortunately, the pressure of work is so high that poor communication is often accepted tacitly [32]. in the practice of dermatopathology, missing, incomplete, or illegible entries on request forms are so common that systematic inquiries for every case are impossible considering the sheer mass of deficient forms. if deficient request forms were exceptional, inquiries for additional information would be much more common. the lack of inquiries, in turn, contributes to the perception of filling out request forms as a cumbersome table 1. mix-up of specimens in the medical practice/clinic source of error prevention of error detection of error 1 missing or incorrect data of patients on sample bottles or request forms laboratory: complete removal of old adhesive labels and thorough cleaning of sample bottles before re-use of them practice: mention principally of name and date of birth of patients on both, sample bottles and request forms; use of bar codes to prevent transcription errors; legible labeling of vials and request forms (including clinical diagnosis, site of biopsy, mention of previous biopsies with corresponding pathology number) immediately after the surgical procedure; removal of completed vials and request forms before calling in the next patient; separation of the file of the current patient from other files; heightened attention in the case of patients with similar or identical names practice: control of sample bottles and request forms after every surgical procedure; labeling of bottles and request forms in accordance with the sequence of biopsies; control of correct labeling of sample bottles and request forms before bagging them for postage laboratory: recognition of discrepancies between the specimen in the bottle and the description of it on the request form (e.g., shave, punch); immediate consultation of submitting clinicians in the case of inconsistencies or missing data on bottles or request forms histopathologist: recognition of discrepancies between clinical data and anatomical/histopathologic findings; in case of an inconsistency control of all biopsy specimens submitted by the same clinician for a corresponding inconsistency; in case of missing previous biopsies control of personal data of the patient by use of different variables (e.g., forename, surname, date of birth) to detect transcription mistakes 2 incorrect correlation of sample bottles and request forms; missing or incorrect numbering of bottles containing biopsy specimens from the same patient deposition of sample bottles from the same patient in a defined unchangeable sequence during the biopsy procedure; labeling of bottles and request forms immediately after the biopsy by the surgeon himor herself; use of attaching labels for labeling bottles instead of marker pens; labeling of bottles and request forms with arabic instead of roman numerals 3 loss of biopsy specimens/sample bottles control of the content of sample bottles before the cover is screwed down; secure fastening of the cover to prevent leakage of formalin; several bottles with specimens from the same patient always in the same envelope review | dermatol pract concept 2014;4(1):4 39 table 2. mix-up of specimens in the laboratory source of error prevention of error detection of error 1 incorrect correlation of sample bottles and request forms after unpacking envelopes practice: several bottles with specimens from the same patient always in the same envelope laboratory: deposition of sample bottles on top of the corresponding request form before numbering bottles and request forms; use of type-written pathology numbers and corresponding bar codes for labeling bottles and request forms; never unpacking several envelopes at the same time histopathologist: recognition of inconsistencies between clinical data and anatomical/histopathologic findings; in case of inconsistencies control of previous and subsequent slides and of all specimens of the same submitting clinician for other inconsistencies suggesting a mix-up 2 loss or confusion of pieces of tissue during dissection of specimens or in the tissue processor trimming of only a single specimen from the moment it is taken out of the sample bottle to the moment the tissue cassette is closed and put in the basket of the tissue processor; regular cleaning of pincers and scalpels in order to prevent adhesion of fragments of tissue to them; cleanliness in the laboratory and a floor of a light, uniform color in order to facilitate recovery of pieces of tissue that have fallen down; enwrapping of very small pieces of tissue in filter paper in order to prevent them from falling through tiny holes in the tissue cassette laboratory: comparison of a sketch of the specimen and the way it was dissected with the shape and number of fragments of tissue when embedding them in paraffin 3 use of a tissue cassette with a wrong number after dissection of specimens with a scalpel clear arrangement of both, sample bottles and pre-numbered tissue cassettes, in numerical sequence; control of numbers on the sample bottle, the request form, and the tissue cassette before dissecting specimens; enhanced care if additional tissue cassettes are needed for a single specimen (prevention of transcription mistakes such as transposed digits when labeling those cassettes) histopathologist: recognition of inconsistencies between clinical data and anatomical/histopathologic findings; if portions of tissue have not been processed and embedded, comparison of them with the pieces of tissue in the paraffin block; histopathologic examination of tissue that has been left in the sample bottle 4 transfer of tissue into the a wrong block when embedding specimens in formalin clear arrangement of both, tissue cassettes and pre-numbered blocks, in numerical sequence; control of numbers on the tissue cassette and the block before embedding specimens in paraffin; regular cleaning of pincers to prevent adhesion of fragments of tissue to them histopathologist: recognition of inconsistencies between clinical data and anatomical/histopathologic findings; recognition of pieces of tissue that do not correspond to other pieces of tissue on the same slide 5 transfer of tissue onto the wrong slide when cutting specimens at the microtome clear arrangement of both, paraffin blocks and pre-numbered slides, in numerical sequence; control of numbers on the block and the slide before clinching the block to the microtome and cutting sections; cleaning and change of the knife of the microtome at regular intervals; clean water bath to prevent “floaters” laboratory: comparison of size and shape of the sections of tissue on slides with the pieces of tissue in paraffin block before slides are forwarded for microscopy histopathologist: recognition of inconsistencies between clinical data and anatomical/histopathologic findings; in case of inconsistencies comparison of sections of tissue on the slides with those in paraffin blocks 40 review | dermatol pract concept 2014;4(1):4 and negligible duty. thus, deficiencies in communication are deepened structurally. however, structural deficiencies need to be addressed because they can be remedied much easier than individual human errors [33]. pitfalls individual errors caused by a short moment of abstraction of one of many persons involved in the biopsy pathway are unavoidable, considering the high number of patients managed day after day in medical practices and clinics and the enormous mass of biopsy specimens obtained. full concentration of all involved persons at all times is a desirable but unrealistic demand. concentration can be fostered, e.g., by sufficient rest periods and a quiet workplace. any abstraction, e.g., by loud conversation within earshot, diminishes concentration and may lead to mistakes. conversation, however, is essential for cooperation in a team. interruptions, e.g., by telephone calls, are also unavoidable and contribute to the quality of service. unnecessary interruptions concerning problems that could also be discussed at another time, however, should be avoided. any interruption is a potential source of error [27]. because short-term memory is a particularly fallible human faculty, requirement for it should be minimized [26]. in case of an interruption, work should not be stopped in the middle of a procedure, such as dictation or typewriting of a report, but should first be finished before responding to the new request, and doubled care is necessary when resuming work, e.g., by renewed control of the name of the patient and of the pathology number on the slide and request form. in addition to interruptions, there are other pitfalls in the biopsy pathway that should be known and respected, including similar or identical names of patients and deviation from the regular ascending sequence of pathology numbers. any empty space on a tray bears the risk that a slide is put back at a wrong position and the subsequent slide being grabbed does not correspond to the next request form. yet another pitfall is paperclips that attach some additional information to a request form. if such paperclips catch another request form, more than one form may be put aside after dictation, and the next report may be issued erroneously for the wrong patient. table 3. mix-up of specimens at the microscope source of error prevention of error detection of error 1 confusion of slides when taking them from the tray laboratory: meticulous control of the correct sequence of slides and request forms before slides are forwarded for microscopy; indication of breaks in the regular sequence by place holders for missing slides and an eye-catching marker for additional slides on the same biopsy specimen histopathologist: control of the numbers on the slides and request forms before dictating a report; care not to grab and put aside two request forms instead of a single one after dictation; heightened attention in the case of several slides on the same biopsy specimen; heightened attention following an interruption (e.g., by a telephone call) histopathologist: recognition of the missing concordance between pathology numbers on slides and request forms when checking those numbers prior to a new dictation or on the basis of inconsistencies between clinical data and histopathologic findings; control of a series of preceding slides, request forms, and dictations in order to detect the point of deviation secretary: consultation of the histopathologist in the case of inconsistencies between clinical data and the histopathology report practice/clinic: consultation of the histopathologist for clinicopathologic correlation 2 confusion of request forms habitual palpation of the paper of the request form to make sure that only one request form is taken from the pile and put aside after dictation of a report; heightened attention in the case of paperclips that may catch another, unrelated request form 3 slip of the tongue when dictating a computer code use of redundant codes; elimination of codes that can be confused easily because of similarities phonetically or in typeface review | dermatol pract concept 2014;4(1):4 41 safety measures designed to prevent or detect a specimen mix-up cannot always be implemented. for example, consultation of the submitting clinician in the case of an incompletely labeled specimen is only possible if the clinician can be reached. not uncommonly, all attempts at reaching clinicians are wrecked by a busy signal of the telephone. simultaneous control in the most vulnerable phases of the biopsy pathway may not be feasible in the case of an extraordinarily high workload or an unexpected shortage in personnel. the quality of downstream control depends not only on clues provided in preceding work steps, but also on the attentiveness and experience of the involved individuals and on the amount of stress under which they operate. most errors occur on days with a high workload [4]. the opposite extreme, a very low workload, is also error-prone because boredom leads to poor performance. performance is best at moderate levels of arousal [26]. documentation of errors if errors are uncovered, they should not only be corrected but also documented. documentation of errors heightens the awareness of problems and offers the chance to expose and resolve recurrent sources of error. in institutes with a formal plan for handling errors, errors are less common [29]. errors should be classified according to type and probable place of occurrence (e.g., labeling sample bottles in the medical practice, unpacking and numbering specimens in the laboratory, examining slides at the microscope). systematic documentation of errors in the computer facilitates analysis of them [4]. for an efficient analysis of errors, open handling of them in a matter-of-factly fashion without fear is indispensable. when errors are uncovered, the crucial question is not who was responsible for them, but why mechanisms for preventing them have failed [32]. documentation should not be restricted to severe errors with possible or real dramatic consequences but should also include minor errors because analysis of them reveals clues to prevent errors that are more serious [4]. this was already emphasized by the american industrial safety pioneer, herbert william heinrich, who emphasized that for every industrial accident that causes a major injury, there are 29 accidents that cause minor injuries and 300 accidents that cause no injuries [34]. a similar relationship can be assumed for “accidents” in the biopsy pathway. for every mix-up of specimens detected, many other mix-ups probably go unnoticed, and the vast majority of them do not cause any harm. in individual cases, however, consequences may be dramatic. therefore, knowledge of sources of error, appreciation of dangers associated with them, precautions to prevent them, mechanisms of control to detect them, a clear structuring of the work flow in the biopsy pathway, and the possibility to prove a mix-up in the case of suspicion are crucial factors to safeguard the quality of medical care (see tables 1, 2, 3, 4). references 1. grannis gf, grümer hd, edison ja, mccabe wc. proficiency evaluation of clinical chemistry laboratories. clin chem. 1972;18(3):222-36. 2. dzik wh, murphy mf, andreu g, et al. an international study of the performance of sample collection from patients. vox sang. 2003;85(1):40-7. 3. zarbo rj, meier fa, raab ss. error detection in anatomic pathology. arch pathol lab med. 2005;129(1):1237-45. 4. rakha ea, clark d, chohan bs, et al. efficacy of an incidentreporting system in cellular pathology: a practical experience. j clin pathol. 2012;65(7):643-8. 5. bonini p, plebani m, ceriotti f, rubboli f. errors in laboratory medicine. clin chem. 2002;48(5):691-8. table 4. mix-up of specimens by the secretary source of error prevention of error detection of error 1 entry of the data of the patient on a wrong pathology number use of a bar-code system for the entry of data; piling of request forms on top of one another so that only the uppermost one is visible, but never side to side; control of the pathology number and the patient’s name prior to any new entry; heightened attention after interruptions (e.g., telephone calls) histopathologist/secretary: comparison of data on the request form and in the computer before any dictation/entry histopathologist: control of clinical and histopathologic diagnoses before approval of reports practice/clinic: consultation of the histopathologist in case of inconsistencies between clinical findings and the histopathologic diagnosis 2 typewriting of a report on a wrong pathology number 3 entry of a wrong computer code use of redundant codes; elimination of codes that can be confused easily because of similarities phonetically or in typeface 42 review | dermatol pract concept 2014;4(1):4 6. nosanchuk js, gottman aw. cums and delta checks. a systematic approach to quality control. am j clin pathol. 1974;62(5):707-12. 7. ladenson jh. patients as their own controls: use of the computer to identify “laboratory error.” clin chem. 1975;21(11):1648-53. 8. sheiner lb, wheeler la, moore jk. the performance of delta check methods. clin chem. 1979;25(12):2034-7. 9. iizuka y, kume h, kitamura m. multivariate delta check method for detecting specimen mix-up. clin chem. 1982;28(11):2244-48. 10. shahangian s, cohn rd, gaunt ee, krolak jm. system to monitor a portion of the total testing process in medical clinics and laboratories: evaluation of a split-specimen design. clin chem. 1999;45(2):269-80. 11. suvisaari j, syrjälä m. practical method for estimating the frequency of specimen mix-up in clinical chemistry laboratories. clin chem. 2002;48(7):1133-5. 12. ovens k, naugler c. how useful are delta checks in the 21st century? a stochastic-dynamic model of specimen mix-up and detection. j pathol inform. 2012;3:5. 13. swetter sm, boldrick jc, pierre p, wong p, egbert bm. effects of biopsy-induced wound healing on residual basal cell and squamous cell carcinomas: rate of tumor regression in excisional specimens. j cutan pathol. 2003;30(2):139-46. 14. weyers w, diaz c, weyers i, borghi s. nichts mehr drin. das mysterium des tumorfreien nachexzidates. pink & blue. 2003;17:17-22. 15. weyers w. the “epidemic” of melanoma between underand overdiagnosis. j cut pathol. 2012;39(1):9-16. 16. ritter jh, sutton td, wick mr. use of immunostains to abh blood group antigens to resolve problems in identity of tissue specimens. arch pathol lab med. 1994;118(3):293-7. 17. laagaaij el, cramer-knijnenburg gf, van der pijl jw, et al. rapid verification of the identity of questionable specimens using immunohistochemistry with monoclonal antibodies directed against hla-class i antigens. histopathology. 1997;31(3):284-88. 18. hunt jl. identifying cross contaminants and specimen mix-ups in surgical pathology. adv anat pathol. 2008;15(4):211-7. 19. banaschak s, sibbing u, brinkmann b. [identification of tissue samples in suspected accidental specimen interchange]. [article in german] pathologe. 1997;18(5): 385-9. 20. banaschak s, witting c, brinkmann b. [confusing tissue samples: causes, consequences, prevention]. [article in german] pathologe. 1999;20(3):155-8. 21. pfeifer jd, zehnbauer b, payton j. the changing spectrum of dna-based specimen provenance testing in surgical pathology. am j clin pathol. 2011;135(1):132-8. 22. bell cg, wood dr, cheong sjh, et al. molecular confirmation of pathological specimen integrity in australasia. pathology. 2009:41(3):280-3. 23. canadian medical protective association. specimen and report mix-ups. is0776-w, cmpa 2008. 24. renshaw aa, kish r, gould ew. the value of inking breast cores to reduce specimen mix-up. am j clin pathol. 2007;127(2):271-2. 25. watson aj, redbord k, taylor js, et al. medical error in dermatology practice: development of a classification system to drive priority setting in patient safety efforts. j am acad dermatol. 2013;68(5):729-37. 26. leape ll. error in medicine. jama. 1994;272(23):1851-7. 27. sirota rl. error and error reduction in pathology. arch pathol lab med. 2005;129(10):1228-33. 28. howanitz pj. errors in laboratory medicine: practical lessons to improve patient safety. arch pathol lab med. 2005;129(10): 1252-61. 29. nakhleh re, zarbo rj. surgical pathology specimen identification and accessioning: a college of american pathologists qprobes study of 1004115 cases from 417 institutions. arch pathol lab med. 1996;120(3):227-33. 30. hollensead sc, lockwood wb, elin rj. errors in pathology and laboratory medicine: consequences and prevention. j surg oncol. 2004;88(3):161-81. 31. gephardt gn, zarbo rj. extraneous tissue in surgical pathology: a college of american pathologists q-probes study of 275 laboratories. arch pathol lab med. 1996;120(11):1009-14. 32. chassin mr, becher ec. the wrong patient. ann intern med. 2002;136(11):826-33. 33. reason j. human error: models and management. bmj. 2000;320(7237):768-70. 34. heinrich hw. industrial accident prevention: a scientific approach. new york: mcgraw-hill, 1931. untitled review | dermatol pract concept 2015;5(4):16 65 dermatology practical & conceptual www.derm101.com case report an 85-year-old man presented with an 8-month history of slowly increasing diffuse yellow skin lesions on the torso and upper arms. he had been unaware of the discoloration until his internist noted it and referred him to dermatology. the patient had been followed by a hematologist for paraproteinemia that had not been treated. the examination showed well-demarcated yellow patches and plaques covering large portions of his upper trunk with some islands of sparing (figure 1, 2). the dermoscopic evaluation showed a reticular pattern of yellow amorphous homogeneous structures with overlying branched and linear vessels (figure 3). a skin biopsy showed scattered foamy histiocytes within the reticular dermis, which were consistent diffuse normolipemic plane xanthoma associated with monoclonal gammopathy yoon k. cohen1, david j. elpern2 1 alta dermatology, mesa, az, usa 2 the skin clinic, williamstown, ma, usa key words: xanthoma, plane xanthoma, diffuse normolipemic plane xanthoma, multiple myeloma, lymphoproliferative disorder, monoclonal gammopathy, paraproteinemia citation: cohen yk, elpern dj. diffuse normolipemic plane xanthoma associated with monoclonal gammopathy. dermatol pract concept 2015;5(4):16. doi: 10.5826/dpc.0504a16 received: may 28, 2015; accepted: september 21, 2015; published: october 31, 2015 copyright: ©2015 cohen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: yoon k. cohen, do, 110 marginal way pmb 804, portland, me 04101, usa. email: mail@yooncohen.com diffuse normolipemic plane xanthoma (dnpx) was first described by altman and winkelmann in 1962. it is a rare and non-inherited form of xanthomatosis. clinically, the dermatosis is characterized by the presence of symmetric yellowish-orange plaques that favor the neck, upper trunk, flexural folds and periorbital region. it has been recognized to be associated with hematological diseases, especially with multiple myeloma and monoclonal gammopathy. we present a patient with diffuse plane xanthoma, normal lipid level, and monoclonal gammopathy. abstract figure 1. clinical view shows well-demarcated yellow patches and plaques covering large portions of the upper chest and shoulder with some islands of sparing. [copyright: ©2015 cohen et al.] 66 review | dermatol pract concept 2015;5(4):16 is characterized by the presence of symmetric yellowishorange plaques that favor the neck, upper trunk, flexural folds and periorbital region [1,2]. histologically, foam cells (macrophages that have engulfed lipid droplets) and variable numbers of touton giant cells, lymphocytes, and foamy histiocytes can be seen [3]. while not all cutaneous xanthomas are associated with systemic diseases, dnpx has been associated with systemic with a plane xanthoma (figures 4, 5, 6). a complete blood count, comprehensive metabolic panel, fasting lipid panel were within normal range. the serum protein electrophoresis showed elevated igg at 3780. there was an m-band present in the gamma region. discussion diffuse normolipemic plane xanthoma (dnpx) was first described by altman and winkelmann in 1962 [1]. it is an uncommon subtype of non-langerhans histiocytosis [15]. dnpx is characterized by xanthelasma palpebrarum; diffuse plane xanthoma of the head, neck, trunk, and extremities; and normal plasma lipid levels [2,4]. xanthelasma typically appears first, followed by involvement of the lateral parts of the neck and upper trunk [1]. clinically, the dermatosis figure 2. well-demarcated yellow plaques on the upper back. [copyright: ©2015 cohen et al.] figure 3. dermoscopic view shows a reticular pattern of yellow amorphous uniformed granules with overlying vascular structures. [copyright: ©2015 cohen et al.] figures 4, 5, 6. histology views show scattered foamy histiocytes within the papillary dermis with a normal overlying epidermis, which were consistent with a plane xanthoma. [copyright: ©2015 cohen et al.] review | dermatol pract concept 2015;5(4):16 67 2. lynch pj, winkelmann rk. generalized plane xanthoma and systemic disease. arch dermatol. 1966:93:639-46. 3. marcoval j, moreno a, bordas x, et al. diffuse plane xanthoma: clinicopathologic study of 8 cases. j am acad dermatol. 1998;39:439-42. 4. loo ds, kang s. diffuse normolipidemic plane xanthomas with monoclonal gammopathy presenting as urticarial plaques. j am acad dermatol. 1996;35:829-32. 5. hu ch, winkelmann rk. unusual normolipemic cutaneous xanthomatosis: a comparison of two cases illustrating the differential diagnosis. acta dermato-venereol. 1977:57:421-9. 6. groszek e, abrams jj, grundy sm. normolipidemic planar xanthomatosis associated with benign monoclonal gammopathy. metabolism. 1981:30:927-35. 7. jones rr, baughan asj, cream jj, et al. complement abnormalities in diffuse plane xanthomatosis with paraproteinmia. br j dermatol. 1979:101:711-6. 8. jordon re, mcduffie fc, good ra, et al. diffuse normolipidemic plane xanthomatosis: an abnormal complement component profile. clin exp immunol. 1974;18:407-15. 9. kodama h, nakagawa s, tanioku k. plane xanthomatosis with antilipoprotein autoantibody. arch dermatol. 1972;105:722-7. 10. wilson de, flowers cm, hershgold ej, et al. multiple myeloma, cryoglobulinemia and xanthomatosis: distinct clinical and biochemical syndromes in two patients. am j med. 1975;59:721-9. 11. waldorf ha, duncan lm, fitzpatrick tb. circumscribed areas of yellow pigmentation on the arms of a 67 year old man. fitzpatrick’s j clinic dermatol. 1994;2:27-9. 12. kim kj, lee dp, suh hs, et al. diffuse plane xanthomas in a patient with chronic myeloid leukemia. j dermatol. 2004;31:503-5. 13. bolognia jl, jorizzo jl, schaffer jv. dermatology. 3rd ed. new york: saunders, 2012. 14. lorenz s, hohenleutner s, hohenleutner u, et al. treatment of diffuse plane xanthoma of the face with the erbium: yag laser. arch dermatol. 2001;137:1413-5. 15. burgesser mv, calafat p, diller a. diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. findings of an autopsy. rev fac cien med univ nac cordoba. 2011;68:65-9. diseases, particularly multiple myeloma and monoclonal gammopathy [2,3]. however, other malignant hematological or lymphoproliferative disorders associated with dnpx include acute monoblastic leukemia, chronic myelomonocytic leukemia, chronic myloid leukemia, chronic lymphatic leukemia, non-hodgkin’s lymphoma, adult t-cell lymphoma/leukemia, sezary syndrome, waldenstrom’s macroglobulinemia, cryoglobulineimia and castleman’s disease [2,3,5-12]. the pathogenesis of dnpx has not been fully elucidated, however, in gammopathy-associated dnpx, monoclonal igg is thought to bind to circulating ldl, rendering the antibody– ldl complex more susceptible to phagocytosis by macrophages [13]. dnpx can precede such disorders by several years; therefore close follow-up with periodic laboratory tests for myeloproliferative disorders should be performed [4]. there are currently several treatment options available. in patients with limited involvement, the individual lesions can be excised. other options include chemabrasion, dermabrasion, and ablative laser therapy. the erbium:yag laser has been used successfully to treat facial xanthomas in one patient [14]. in this patient, currently there are no associated systemic symptoms. his hematologist was informed of the diagnosis. the patient will be evaluated for potential underlying malignancies. moreover, this case shows that dermatological lesions can be the first manifestation of important hematological diseases and so physicians should be familiarized with this rare entity. references 1. altman j, winkelmann rk. diffuse normolipemic plane xanthoma. arch dermatol. 1962;85:633-40. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020075 1 dermatology practical & conceptual introduction pigmented purpuric lichenoid dermatitis of gougerot and blum is an uncommon variant of pigmented purpuric dermatosis (ppd) characterized by confluent purpuric papules and plaques on the legs [1]. the overlap of the clinical features of the subtypes of ppd usually hinders its diagnosis. case presentation a 32-year-old black male, born in a west african country, reported the development of multiple asymptomatic brown-to-violaceous plaques on the legs in the previous 2 months. he was diagnosed with human immunodeficiency virus (hiv) type 1 infection 9 years before but had bad compliance with highly active antiretroviral treatment (haart). one month before noticing the development of skin lesions, haart was reinitiated with emtricitabine, tenofovir and dolutegravir. at the time of presentation, cd4+ lymphocyte count was 870 cells/mm3 and viral load was 22 copies/ml. serologies for syphilis and hepatitis b and c virus were negative. on skin examination, the patient had multiple red-brown nummular plaques with an oval-to-irregular outline on the legs (figure 1). the lesions measured 1 to 3 cm in diameter, had a lighter central area, and were surrounded by a narrow erythematous-violaceous border. dermoscopy revealed a diffuse coppery-red structureless background permeated by a brownish-to-gray network with ill-defined borders and a polymorphic pearly white central area with polygonal-to-oval red and gray dots, globules, and patches (figure 2). histopathologic examination revealed a dense band-like lymphocytic infiltrate in the upper dermis, endothelial cell swelling and extravasation of red blood cells with hemosiderin inside of macrophages. there was no visible vessel wall damage (figure 3). dermoscopy of pigmented purpuric lichenoid dermatitis of gougerot and blum in an hiv-infected patient pedro miguel garrido1, pablo espinosa-lara1, marta aguado-lobo1, luís soares-almeida1,2,3, joão borges-costa1,2,3,4 1 dermatology department, centro hospitalar universitário lisboa norte, epe (chuln), lisbon, portugal 2 dermatology university clinic, faculty of medicine, university of lisbon, portugal 3 dermatology research unit, instituto de medicina molecular, university of lisbon, portugal 4 instituto de higiene e medicina tropical (ihmt), universidade nova de lisboa, lisbon, portugal key words: dermoscopy, pigmented purpuric dermatosis, pigmented purpuric lichenoid dermatitis of gougerot and blum, human immunodeficiency virus citation: garrido pm, espinosa-lara p, aguado-lobo m, soares-almeida l, borges-costa j. dermoscopy of pigmented purpuric lichenoid dermatitis of gougerot and blum in an hiv-infected patient. dermatol pract concept. 2020;10(4):e2020075. doi: https://doi.org/10.5826/dpc.1004a75 accepted: april 21, 2020; published: october 26, 2020 copyright: ©2020 garrido et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: pedro miguel garrido, md, centro hospitalar lisboa norte epe, av. prof. egas moniz, lisboa 1649-035, portugal. email: pedro.mi.garrido@gmail.com 2 letter | dermatol pract concept 2020;10(4):2020075 figure 1. clinical findings: red-brown nummular plaques with a lighter central area surrounded by a narrow erythematous-violaceous border on the legs. figure 2. dermoscopic findings: diffuse coppery-red structureless background (black star) permeated by a brownish-to-gray network with ill-defined borders and a polymorphic pearly white central area (red star) with polygonal-to-oval red and gray dots (blue and yellow star, respectively), red globules (green arrow) and patches. figure 3. histopathologic findings. (a) dense band-like lymphocytic infiltrate in the upper dermis and increased number of dilated blood vessels. (b) endothelial cell swelling and extravasation of red blood cells with hemosiderin inside of macrophages. (c) hemosiderin deposition in the upper dermis. (a,b) h&e stain; original magnifications ×40, ×100. (c) perls prussian blue iron stain; original magnification ×40). a b c letter | dermatol pract concept 2020;10(4):2020075 3 hypertension, diabetes mellitus, and autoimmune diseases [1]. although the etiology of ppd remains unknown, previous reports suport a role for cell-mediated immunity on its pathogenesis [1]. in this case, skin lesions developed after initiation of haart, alongside viral suppression and immunity improvement. pigmented purpuric lichenoid dermatitis of gougerot and blum may therefore be a consequence of the immunity imbalance associated with the immune reconstitution inflammatory syndrome. references 1. kim dh, seo sh, ahn hh, kye yc, choi je. characteristics and clinical manifestations of pigmented purpuric dermatosis. ann dermatol. 2015;27(4):404–410. doi: 10.5021/ ad.2015.27.4.404. pmid: 26273156. 2. park my, shim wh, kim jm, et al. dermoscopic finding in pigmented purpuric lichenoid dermatosis of gougerot-blum: a useful tool for clinical diagnosis. ann dermatol. 2018;30(2):245– 247. doi: 10.5021/ad.2018.30.2.245. pmid: 29606831. conclusions the clinical diagnosis of pigmented purpuric lichenoid dermatitis of gougerot and blum is challenging, as this dermatosis can closely resemble kaposi sarcoma—an important differential diagnosis in hiv patients like ours—cutaneous vasculitis, and other ppds, particularly lichen aureus. dermoscopy is a noninvasive technique that may increase accuracy in the differential diagnosis. one previous report described its dermoscopic findings [2]. in comparison, our case stands out because of the coppery-red structureless background and the pearly white central area. the differences in the clinical presentation and dermoscopic findings correlate with the variability in histopathologic features: the presence of a coppery-red structureless background results from the lichenoid infiltrate and the extravasation of red blood cells with hemosiderin deposition in macrophages; the pearly white central area is explained by the increased number of hemosiderin-laden macrophages on the dermis. ppd has been associated with many conditions, such as dermatology: practical and conceptual observation | dermatol pract concept 2016;6(2):10 53 dermatology practical & conceptual www.derm101.com introduction in approximately 10% of cases, darier’s disease (dd) may present in a localized pattern as the result of a postzygotic mosaicism in the atp2a2 gene (type 1 segmental dd) [1]. such a variant is characterized by hyperkeratotic reddishbrownish papules having a linear distribution along blaschko’s lines, which frequently get worse during the summer [1]. since type 1 segmental dd usually lacks diagnostic clues typical of the generalized form, i.e., positive family history of the disease, nail and mucosal abnormalities, and/or acral involvement, its distinction from other acquired inflammatory blaschkolinear dermatoses may often be quite challenging, thus requiring histopathological examination to reach a definitive diagnosis [1]. we here describe for the first time the use of dermoscopy in a patient with type 1 segmental dd. case presentation a 25-year-old caucasian man presented with a two-year history of slightly itchy skin lesions on the right side of his abdomen, which were reportedly worse in the summer months. there was no family history of similar problems. physical examination showed numerous hyperkeratotic reddishbrownish papules in a blaschkoid distribution (figure 1a). no mucosal or nail lesions were present. on polarized light dermoscopy: a useful auxiliary tool in the diagnosis of type 1 segmental darier’s disease enzo errichetti1, vincenzo maione2, enrico pegolo3, giuseppe stinco1 1 department of experimental and clinical medicine, institute of dermatology, university of udine, italy 2 department of dermatology, “hôpital saint louis”, paris diderot university, france 3 department of medical and biological sciences, institute of anatomic pathology, university of udine, italy key words: darier’s disease, dermoscopy; differential diagnosis; mosaicism, type 1 segmental darier’s disease citation: errichetti e, maoine v, pegolo e, stinco g. dermoscopy: a useful auxiliary tool in the diagnosis of type 1 segmental darier’s disease. dermatol pract concept 2016;6(2):10. doi: 10.5826/dpc.0602a10 received: november 18, 2015; accepted: march 12, 2016 ; published: april 30, 2016 copyright: ©2016 errichetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: enzo errichetti, md, institute of dermatology, “santa maria della misericordia” university hospital, piazzale santa maria della misericordia, 15 –33100 udine, italy. tel. (+39) 0432559820. e-mail. enzoerri@yahoo.it type 1 segmental darier’s disease is a blaschkolinear variant of darier’s disease resulting from a postzygotic mosaicism. since it usually lacks diagnostic clues typical of the generalized form, including positive family history of the disease, nail and mucosal abnormalities, and/or acral involvement, its distinction from other acquired inflammatory blaschkolinear dermatoses may often be quite challenging, thus requiring histopathological examination to reach a definitive diagnosis. we report a case of type 1 segmental darier’s disease with its dermoscopic findings in order to show the usefulness of dermoscopy in assisting the noninvasive identification of this condition. abstract 54 observation | dermatol pract concept 2016;6(2):10 authors found a variable vascular pattern, including red dots, red lines, or erythema, and constant nonvascular structures, which they named “giant pseudocomedones,” consisting in dilated oval openings with raised or flat borders and central brown or yellowish hyperkeratotic plugs [7]. however, according to our recent study on 11 patients, dd may display a more complex dermoscopic pattern characterized by a centrally located polygonal, star-like or roundish-oval shaped yellowish/brownish area, surrounded by a more or less thin whitish halo, overlying a pinkish homogeneous structureless area, with or without whitish scales and dotted and/or linear vessels presenting a whitish halo [8]. indeed, we observed a similar appearance in the present “localized” instance. in terms of dermoscopicpathological correlation, the central yellowish-brownish area and its whitish halo would correspond to the compact hyperkeratosis and acanthosis (figure 1b, c), respectively, while the pinkish background and vessels would be due to the dermal inflammation [8-9]. by reporting the dermoscopy of this case of type 1 segmental dd, we would like to point out the usefulness of such dermoscopic examination (carried out with dermlite dl3 x10; 3gen, san juan capistrano, ca, usa), most papules displayed the same aspect, namely, centrally located, roundish or polygonal, yellowish/brownish areas of various sizes (often with a whitish halo) that were surrounded by a pinkish homogeneous structureless areas (with or without linear and/ or dotted vessels) (figure 1b). histology revealed compact hyperkeratosis, parakeratosis, acanthosis, foci of suprabasal acantholysis, dyskeratotic cells in the form of “corp ronds” and “grains,” and superficial dermal chronic inflammation (figure 1c), thus leading to the diagnosis of type 1 segmental dd. the patient was treated with tretinoin 0.05% cream (once a day) with moderate improvement of the clinical picture after three weeks. discussion during the last years, the use of dermoscopy in “general” dermatology has considerably increased [2-6]. the first dermoscopic description of dd dates back to 2004, when vázquez-lópez et al reported a study on five patients. the figure 1. physical examination shows numerous hyperkeratotic reddish-brownish papules in a blaschkoid distribution on the right side of the abdomen; unrelated sparse lesions of folliculitis and the scar at the biopsy site are also evident on the right subaxillary region and costal arch, respectively (a). polarized light dermoscopic examination (x10 magnification) of two contiguous papules displays centrally located, polygonal (outlined in black) or roundish (outlined in black), yellowish/brownish areas (black arrows) presenting a whitish halo (black stars), which are surrounded by a pinkish homogeneous structureless area with some dotted vessels (black arrowheads) (b). histology shows compact hyperkeratosis (black arrow), parakeratosis, acanthosis (black stars), foci of suprabasal acantholysis, dyskeratotic cells (better visible in the box) in the form of “corp ronds” and “grains”, and superficial dermal chronic inflammation (hematoxylin and eosin stain x100) (c). [copyright: ©2016 errichetti et al.] observation | dermatol pract concept 2016;6(2):10 55 3. errichetti e, lacarrubba f, micali g, piccirillo a, stinco g. differentiation of pityriasis lichenoides chronica from guttate psoriasis by dermoscopy. clin exp dermatol 2015; 40(7):804-6. pmid: 25682853. doi: 10.1111/ced.12580 4. errichetti e, stinco g. dermoscopy of idiopathic guttate hypomelanosis. j dermatol 2015; 42(11):1118-9. pmid: 26212033. doi: 10.1111/1346-8138.13035 5. errichetti e, stinco g. dermoscopy in differential diagnosis of palmar psoriasis and chronic hand eczema. j dermatol 2015 oct 13. [epub ahead of print] pmid: 26460228. doi: 10.1111/13468138.13142 6. errichetti e, piccirillo a, stinco g. dermoscopy of prurigo nodularis. j dermatol 2015; 42(6):632-4. pmid: 25808786. doi: 10.1111/1346-8138.12844 7. vázquez-lópez f, lopez-escobar m, maldonado-seral c, perezoliva n, marghoob aa. the handheld dermoscope improves the recognition of giant pseudocomedones in darier’s disease. j am acad dermatol 2004; 50(3):454-5. pmid: 14988691. doi: 10.1016/s0190-9622(03)02475-7 8. errichetti e, stinco g, lacarrubba f, micali g. dermoscopy of darier’s disease. j eur acad dermatol venereol 2015 aug 6. [epub ahead of print] pmid: 26248700. doi: 10.1111/jdv.13238 9. lacarrubba f, verzì ae, errichetti e, stinco g, micali g. darier disease: dermoscopy, confocal microscopy, and histologic correlations. j am acad dermatol 2015; 73(3):e97-9. pmid: 26282823. doi: 10.1016/j.jaad.2015.04.066 10. jackson sm, nesbitt lt. the diagnosis. in: jackson sm, nesbitt lt, eds. differential diagnosis for the dermatologist, 2nd ed. new york: springer, 2012; 857-8. a low-cost and noninvasive technique in assisting the recognition of this variant of dd. in fact, even though the definitive diagnosis of such a condition relies on histopathological analysis, dermoscopy may be used as an auxiliary tool to rule out the other major acquired inflammatory papular dermatoses which may present in a blaschkolinear fashion and enter into the differential diagnosis [10], including lichen planus, which is typically characterized by wickham striae (seen as round, linear, reticular or annular pearly-whitish structures) [2]; psoriasis, showing white scales and symmetrically/regularly distributed dotted vessels on a light or dull red background [2,3] and lichen striatus, displaying vessels of mixed morphology (dotted and/or linear) over a pinkish background, with or without whitish scales (personal observations). references 1. sanderson ea, killoran ce, pedvis-leftick a, wilkel cs. localized darier’s disease in a blaschkoid distribution: two cases of phenotypic mosaicism and a review of mosaic darier’s disease. j dermatol 2007; 34(11):761-4. pmid: 17973816. doi: 10.1111/j.1346-8138.2007.00379.x 2. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol 2015; 150(5):53346. pmid: 26086412 http://dx.doi.org/10.1016/s0190-9622(03)02475-7 observation | dermatol pract concept 2011;1(1):6 21 melanoma arising in a giant nevus spilus maculosus alexander stella, m.d.1, katharina ponholzer, m.d.1, jessika weingast, m.d.1, michael binder, m.d.1 1department of dermatology, division of general dermatology, university of vienna, vienna, austria key words: nevus spilus, large nevus spilus maculosus, malignant melanoma citation: stella a, ponholzer k, weingast j, binder m. melanoma arising in a giant nevus spilus maculosus. dermatol pract concept 2011;1(1):6. http://dx.doi.org/10.5826/dpc.0101a06. editor: harald kittler, m.d. received: october 1, 2010; accepted: december 31, 2010; published: october 31, 2011 copyright: ©2011 stella et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: alexander stella, m.d., department of dermatology, division of general dermatology, medical university of vienna, a-1090 vienna, austria. email: alexander.stella@meduniwien.ac.at. case report a 78-year-old caucasian woman presented with an ulcerated nodule in the right pretibial region (figure 1). the nodule measured 1 cm in diameter and was surrounded by an erythema. it had grown in a large pre-existing, congenital pigmented lesion that, according to the patient, existed since birth (figure 2). the gigantic nevus was flat and speckled. it extended over the right leg and the right side of the abdomen and the lower back, skipping the buttock and the back of the thigh, and crossed the midline (figure 3). close up it consisted of multiple dark-brown macules on a light brown, café-au-lait-like background (figure 4). a punch biopsy of the nevus showed elongation of rete ridges and hyperpigmentation of basal keratinocytes but no substantial proliferation of melanocytes (figure 5). histopathology of the nodule showed a nodular melanoma with an invasion thickness of 4.5 mm (figure 6). on the basis of the clinical and pathologic findings we made the diagnosis of a melanoma arising in a giant nevus spilus maculosus. figure 1. close-up of eroded nodule with surrounding erythema. melanoma arising in a nevus spilus is rare. there are two distinct types of nevus spilus characterized by macular or papular speckles, respectively. we report the case of a melanoma that arose in association with a giant nevus spilus maculosus. abstract dermatology practical & conceptual www.derm101.com 22 observation | dermatol pract concept 2011;1(1):6 figure 2. the nodule on the right leg appeared in association with a speckled lentiginous nevus (nevus spilus). figure 3. extension of the nevus spilus that crosses the midline. figure 4. close-up of nevus spilus maculosus. figures 5a–e. punch biopsy of the speckled lentiginous nevus. the biopsy was taken from the thigh. mild acanthosis and hyperpigmentation of basal keratinocytes is present but there is no marked proliferation of melanocytes. a b c d e observation | dermatol pract concept 2011;1(1):6 23 discussion malignant melanoma arising in association with a nevus spilus, also referred to as speckled lentiginous nevus, is rare [1,2]. in german, nevus spilus is also named “kiebitzeinaevus,” referring to the peculiar pattern of the nevus that resembles a lapwing’s egg (figure 7). according to happle there are two distinct types of nevus spilus [3,4]. nevus spilus maculosus is flat and characterized by dark brown spots on a light brown background. in this type of nevus spilus the background pigmentation histopathologically corresponds to hyperpigmention of basal keratinocytes, and the dark spots are believed to be typified by junctional melanocytes arranged in nests. in the presented case a punch biopsy of the nevus did not show a proliferation of melanocytes, but the biopsy was relatively small and sampling error cannot be excluded. papular nevus spilus, on the other hand, is characterized by dark brown papules or nodules on a light-brown background, although small dark spots may also be present [3]. histopathologically, this type of nevus spilus shows the pattern of a superficial and deep congenital nevus with the presence of melanocytes in the papillary and reticular dermis. the malignant potential of the papular type appears to figures 6a–g. histopathology of the ulcerated melanoma arising in the nevus spilus maculosus. large and pleomorphic tumor cells are arranged in irregular nests and sheets in the dermis. a b c d f e g be lower than that of macular type of nevus spilus [3]. it is possible that the two different types of nevus spilus originate from different mutations. this would also explain the dissimilar malignant potential of either type of nevus [4]. as a possible differential diagnosis we also considered a partial unilateral lentiginosis (pul), which seems to be a figure 7. four lapwing’s eggs [german: kiebitz eier]. picture courtesy of dr. ernst bauernfeind, head curator of the bird collection, museum of natural history, vienna, austria). 24 observation | dermatol pract concept 2011;1(1):6 mosaic manifestation of type 1 neurofibromatosis [5]. this rare condition was excluded on the basis of clinical findings because in pul the background is normal and not hyperpigmented and the body-midline is not crossed. in addition, our patient showed no signs of neurofibroma or café-au-lait macules [6,7]. phacomatosis spilorosea, a subtype of phacomatosis pigmentovascularis, could also be excluded because of the absence of telangiectasias [8]. we excluded the speckled lentiginous nevus syndrome that is characterized by a speckled lentiginous nevus of the papular type and ipsilateral neurological abnormalities such as hyperhidrosis, muscular weakness and dysesthesia because such abnormalities were not present in our patient [9]. this case of a melanoma arising in a nevus spilus maculosus suggests that this type of nevus should be regularly observed by a dermatologist and patients should be instructed to perform self-examinations to detect changes as early as possible. references 1. breitkopf c, ernst k, hundeiker m. neoplasms in nevus spilus. hautarzt 1996;47:759–62. 2. borrego l, hernandez santana j, baez o, hernandez hernandez b. naevus spilus as a precursor of cutaneous melanoma: report of a case and literature review. clin exp dermatol 1994;19(6):515– 17. 3. vidaurri-de la cruz h, happle r. two distinct types of speckled lentiginous nevi characterized by macular versus papular speckles. dermatology 2006;212(1):53–8. 4. happle r. speckled lentiginous naevus: which of the two disorders do you mean? clin exp dermatol 2009;34(2):133–5. 5. chen w, fan pc, happle r. partial unilateral lentiginosis with ipsilateral lisch nodules and axillary freckling. dermatology 2004;209(4):321–4. 6. serarsalan g. partial unilateral lentiginosis with ipsilateral ocular nevus. j eur acad dermatol venereol 2007;21(2):281–3. 7. happle r. nevus spilus maculosus vs. partial unilateral lentiginosis. j eur acad dermatol venereol 2007;21(5):713. 8. happle r. phacomatosis pigmentovascularis revisited and reclassified. arch dermatol 2005;141(3):385–8. 9. happle r. speckled lentiginous nevus syndrome: delineation of a new distinct neurocutaneus phenotype eur j dermatol 2002;12(2):133–5. dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(3):2 3 dermatology practical & conceptual www.derm101.com the patient a 50-year-old caucasian gentleman presented with a oneyear history of a gradually enlarging pigmented lump on the right forearm. on examination there was a 1 cm blue-purple nodule, which was hard in consistency (figure 1). a mobile dermal cystic component was palpated after lateral pressure. further dermoscopic examination revealed a homogeneous blue-purple pigmentation surrounded by a subtle brown hyperpigmentation and a central white area with fine linear whitish structures. no pigment network was noticed (figure 2). histopathological examination was performed to exclude melanoma. it revealed an ill-defined nodular dermal proliferation of spindle-shaped fibroblasts and myofibroblasts arranged as short intersecting bundles. there were multiple dilated vascular channels and numerous hemosiderin-laden macrophages (figure 3). a slowly enlarging purple nodule on the arm sheena ramyead1, salvador diaz-cano2, lucia pozo-garcia3 1 department of general medicine, homerton university hospital, east london, uk 2 department of histopathology, king’s college hospital, london, uk 3 department of dermatology, lewisham and greenwich nhs trust, london, uk citation: ramyead s, diaz-cano s, pozo-garcia l. a slowly enlarging purple nodule on the arm. dermatol pract concept 2016;6(3):2. doi: 10.5826/dpc.0603a02 copyright: ©2016 ramyead et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: sheena ramyead, mbbs, mrcp, 74 regency lodge, adelaide road, swiss cottage, london, nw3 5ed, uk. tel. +44 7920517226. email: sheena.ramyead@gmail.com figure 1. well-defined, blue-purple nodule on right forearm. [copyright: ©2016 ramyead.] figure 2. homogeneous bluish purple pigmentation under dermoscopy surrounded by a subtle brown hyperpigmentation and a central whitish area with fine shiny linear whitish structures. [copyright: ©2016 ramyead.] mailto:sheena.ramyead@gmail.com 4 quiz | dermatol pract concept 2016;6(3):2 at least 20 different histological variants of dermatofibromas have been described with the aneurysmal subtype being unusual (2% of all cases) [6-8]. aneurysmal dermatofibroma, also known as aneurysmal fibrous histiocytoma (afh) was initially described in 1981 [9]. it presents as single dark papules or nodules, most commonly located on the lower limbs, which occasionally grow quickly and may bleed. they are clinically alarming and are often confused with melanocytic or vascular neoplasms [10]. dermoscopy shows homogeneous pigmentation with different hues from blue-purple to red-brown colors. the presence of fine whitish linear structures corresponding to fibrosis is commonly seen, but these findings are non-specific and an excision biopsy is mandatory to exclude melanoma [10,11]. a rainbow pattern initially described in kaposi sarcomas [12] has also been reported in aneurysmal dermatofibromas [13]. it can only be observed under polarized dermoscopy and is a result of the passage of polarized light through increased dermal fibrosis. histologically, afh consists of blood-filled spaces lacking endothelium within the fibrohistiocytic tumor. perl’s stain is positive, identifying stromal hemosiderin deposition, while the spindle cells are negative for endothelial (cd34) and melanocytic (s100) markers [6]. the pathogenesis is unknown, however, the blood is thought to represent extravasation of erythrocytes from capillaries. important clinical differential diagnoses include malignant melanoma, hemangioma and kaposi’s sarcoma. what is your diagnosis? answer and explanation aneurysmal dermatofibroma dermatofibromas are benign fibrous histiocytomas, representing the second most common cutaneous fibrohistiocytic lesion after acrochordons (skin tags). they present as firm, dome-shaped papules, which are commonly hyperpigmented and are primarily seen in adults on the lower extremities [1]. the dimpling of the skin with lateral compression or “fitzpatrick’s sign” is considered by many to be pathognomonic for dermatofibromas. despite the description of this sign in all major textbooks, not all dermatofibromas dimple (as in our case), and all that dimple are not dermatofibromas. the exact etiology of dermatofibromas is unknown, however, they have been associated with trauma and insect bites [2]. they are usually solitary, but cases of multiple synchronous lesions (eruptive dermatofibromas) have been reported, especially associated with autoimmune disorders, in particular, systemic lupus erythematosus, atopic eczema and human immunodeficiency virus [3-5]. histologically, dermatofibromas are characterized by a nodular dermal proliferation of spindled fibroblasts and myofibroblasts, arranged in intersecting fascicles with entrapment of thick collagen bundles in the superficial and mid dermis. there is hyperplasia of the epidermis with flat confluent rete ridges. the proliferating cells are positive for vimentin, factor xiiia and cd68 and negative for cd34. figure 3. ill-defined dermal proliferation of spindle cells and blood vessels with numerous superficial siderophages (panel a, hematoxylin-eosin 40x). the spindle cells infiltrate around thick collagen bundles at the lesion periphery (panel b, he 200x) and it shows dilated blood vessels and siderophages in the upper part (panel c, he 400x). [copyright: ©2016 ramyead.] quiz | dermatol pract concept 2016;6(3):2 5 6. calonje e, fletcher cd. aneurysmal benign fibrous histiocytoma: clinicopathological analysis of 40 cases of a tumour frequently misdiagnosed as a vascular neoplasm. histopathology 1995;26(4):323-31. pmid: 7607620. doi: 10.1111/j.13652559.1995.tb00193.x. 7. kamino h, reddy v, pui j. fibrous and fibrohisticocytic proliferation of the skin and tendons. in: bolognia j, jorizzo j, schaffer j, eds. dermatology. 3rd ed. philadelphia: saunders, 2012:19621963. 8. luzar b, calonje e. cutaneous fibrohistiocytic tumours—an update. histopathology 2010;56(1):148-65. pmid: 20055912. doi: 10.1111/j.1365-2559.2009.03447.x. 9. santa cruz dj, kyriakos m. aneurysmal (“angiomatoid”) fibrous histiocytoma of the skin. cancer 1981;47(8):2053-61. pmid: 6261935 10. zaballos p, llambrich a, ara m, olazaran z, malvehy j, puig s. dermoscopic findings of haemosiderotic and aneurysmal dermatofibroma: report of six patients. br j dermatol 2006;154(2):24450. pmid: 16433792. doi: 10.1111/j.1365-2133.2005.06844.x. 11. blum a, jaworski s, metzler g, bauer j. lessons on dermoscopy: dermoscopic pattern of hemosiderotic dermatofibroma. dermatol surg 2004;30(10):1354-5. pmid: 15458535. doi: 10.1111/j.1524-4725.2004.30409.x. 12. cheng st, ke cl, lee ch, wu cs, chen gs, hu sc. rainbow pattern in kaposi’s sarcoma under polarized dermoscopy: a dermoscopic pathological study. br j dermatol 2009;160(4):801-9. pmid: 19067686. doi: 10.1111/j.1365-2133.2008.08940.x. 13. padilla-espana l, fernandez-canedo i, blazquez-sanchez n. fast-growing pigmented nodular lesions. actas dermosifiliogr 2015;106(6):505-6. pmid: 25770848. doi: 10.1016/j. ad.2015.01.009. in summary, in the presence of a gradually enlarging, blue-purple, hard nodule with homogeneity on dermoscopy, there should be a high index of suspicion for an aneurysmal dermatofibroma. the dermoscopic pattern which may include fine white lines may be identical to some nodular melanomas, however the slow growth and long term evolution indicates its benign nature. these tumors require histological confirmation. references 1. gonzalez s, duarte i. benign fibrous histiocytoma of the skin. a morphologic study of 290 cases. pathol res pract 1982;174(4):379-91. pmid: 6296802. doi: 10.1016/s03440338(82)80019-8. 2. mckee ph, calonje e, granter sr. fibrohistiocytic tumors. in: mckee ph, calonje e, granter sr, eds. pathology of the skin with clinical correlations. 3rd ed. philadelphia: elsevier mosby; 2005:1741-1760. 3. kanitakis j, carbonnel e, delmonte s, livrozet jm, faure m, claudy a. multiple eruptive dermatofibromas in a patient with hiv infection: case report and literature review. j cutan pathol 2000;27(1):54-6. pmid: 10660133. doi: 10.1034/j.16000560.2000.027001054.x. 4. massone c, parodi a, virno g, rebora a. multiple eruptive dermatofibromas in patients with systemic lupus erythematosus treated with prednisone. int j dermatol 2002;41(5):279-81. pmid: 12100703. doi: 10.1046/j.1365-4362.2002.01493.x. 5. yazici ac, baz k, ikizoglu g, koca a, kokturk a, apa dd. familial eruptive dermatofibromas in atopic dermatitis. j eur acad dermatol venereol 2006;20(1):90-2. pmid: 16405617. doi: 10.1111/j.1468-3083.2005.01357.x. dermatology: practical and conceptual research | dermatol pract concept 2020;10(1):e2020010 1 dermatology practical & conceptual serum total 25-hydroxyvitamin d levels in patients with cutaneous malignant melanoma: a case-control study in a low-risk southern european population angeliki befon,1 alexander c. katoulis,2 sofia georgala,1 andreas katsampas,1 vasiliki chardalia,1 aggeliki melpidou,3 vasiliki tzanetakou,1 vasiliki chasapi,1 dorothea polydorou,1 clio desinioti,1 micaela plaka,1 dimitris rigopoulos,1 alexandros j. stratigos1 1 first department of dermatology and venereology, national and kapodistrian university of athens, medical school, andreas syggros hospital for skin and venereal diseases, athens, greece 2 second department of dermatology and venereology, attikon general university hospital, national and kapodistrian university of athens, greece 3 biochemistry laboratory, evangelismos general hospital of athens, greece keywords: malignant melanoma, vitamin d, breslow thickness, ulceration, risk factors, prognosis. citation: befon a, katoulis ac, georgala s, katsampas a, chardalia v, melpidou a, tzanetakou v, chasapi v, polydorou d, desinioti c, plaka m, rigopoulos d, stratigos aj. serum total 25-hydroxyvitamin d levels in patients with cutaneous malignant melanoma: a casecontrol study in a low-risk southern european population. dermatol pract concept. 2020;10(1):e2020010. doi: https://doi.org/10.5826/ dpc.1001a10 accepted: september 24, 2019; published: december 31, 2019 copyright: ©2019 befon et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. angeliki befon, first department of dermatology and venereology, university of athens, andreas syggros hospital, 5 dragoumi str, athens 16121, greece. e-mail: drbefon@yahoo.gr background: recent data have shown an inverse association between serum 25-hydroxyvitamin d concentration and incidence of several cancers, including cutaneous malignant melanoma (cmm). in addition, lower serum 25-hydroxyvitamin d levels have been associated with thicker or higher stage melanomas and worse survival in observational studies. materials and methods: ninety-nine patients diagnosed with primary cmm and 97 matched healthy controls entered the study. demographic characteristics, risk factors for cmm, and clinical and histological characteristics were recorded for patients with primary cmm. total serum 25-hydroxyvitamin d levels of melanoma patients measured by fully automated chemiluminescent vitamin d total immunoassay (elecsys vitamin d total, roche) at the time of diagnosis were compared with those of healthy controls. in addition, we tested the association of serum total 25-hydroxyvitamin d levels at melanoma diagnosis with known risk and prognostic factors for cmm. results: of the melanoma patients, 49 (49.49%) had deficient serum total 25-hydroxyvitamin d levels (<20 ng/ml), 23 (23.23%) had insufficient levels (21-29 ng/ml), and 27 (27.27%) had adequate abstract mailto:drbefon@yahoo.gr 2 research | dermatol pract concept 2020;10(1):e2020010 of matched healthy controls. in addition, we tested the association of serum 25-hydroxyvitamin d levels at the time of melanoma diagnosis with known risk and prognostic factors for cmm, in an attempt to assess their prognostic value. materials and methods study design this prospective cohort study was conducted at the melanoma unit of the first department of dermatology and venereology, andreas syggros hospital, athens, greece. the study was approved by the ethics committee of the hospital. written informed consent was obtained for all entered patients and controls. patient recruitment took place from april 2011 to march 2014. consecutive patients diagnosed with primary invasive cmm of any stage were enrolled. the diagnosis of cmm was made on histological grounds. exclusion criteria included the following: patients with noncutaneous melanoma or metastatic melanoma of unknown primary; patients with self-reported preexisting conditions that could interfere with vitamin d metabolism, such as chronic liver or kidney disease; transplant recipients or those with other causes of immunosuppression; patients receiving high-dose calcium therapy; and patients receiving vitamin d supplementation during the previous 6 months. for all recruited melanoma patients, complete personal and family history was obtained and total body skin examination was performed. demographic characteristics such as age, sex, race, occupation; body measurements, ie, height and weight to calculate body mass index (bmi); risk factors for cmm including hair color, skin color, skin phototype, occupational and recreational sun exposure, sunburns during childhood; presence of dysplastic nevi, number of melanocytic nevi, personal or family history of cmm, have all been recorded. clinical type of cmm and localization in sun-exposed or sun-protected areas were assessed. breslow thickness and presence or absence of ulceration were obtained from the histology report at the time of diagnosis. for cmm staging, the seventh edition of the american joint committee on canintroduction the incidence of cutaneous malignant melanoma (cmm) has increased steeply over recent decades and continues to grow worldwide despite intense efforts at primary prevention. cmm results from complex interactions between genetic and environmental factors. excessive intermittent ultraviolet radiation (uvr) exposure and sunburns during childhood are considered as the principal causes of cmm insurgence in adults, with double the risk relative to a nonexposed population [1,2]. on the other hand, uvr stimulates the endogenous production of pre-vitamin d 3 in the skin, which supplies >90% of the body’s requirements [3]. in vivo vitamin d demonstrates pleiotropic effects. beyond its role in homeostasis of calcium and phosphorus, it modulates cellular functions, such as innate and adaptive immunity through the suppression of inflammation, cell proliferation, differentiation, apoptosis, and metastatic potential [4-8]. recent data have linked low serum vitamin d levels to a wide range of diseases, including cardiovascular disease, insulin resistance, autoimmune disease, and infection. most importantly, they have been linked with increased incidence of several malignancies, such as breast, colorectal, kidney, lung, and pancreatic cancer [6-10]. the relationship between vitamin d levels and cmm seems to be more intricate, compared with other malignancies [1]. vitamin d receptor is present in normal melanocytes and in certain cell lines of melanoma [11]. in vitro studies have shown that a proportion of melanoma cell lines in culture respond to the antiproliferative effect of active vitamin d analogs [12,13]. serum vitamin d levels have been examined as a marker for increased risk for cmm development. lower serum vitamin d levels have been associated with thicker or higher stage melanomas [14-20]. two recent large cohort studies have shown that vitamin d levels were significantly associated with overall survival, melanoma-specific survival, and disease-free survival [21,22].  in the present study, we sought to investigate serum total 25-hydroxyvitamin d levels in a cohort of patients diagnosed with primary cmm and compare them with those levels (>30 ng/ml). the median serum total 25-hydroxyvitamin d levels were significantly lower in melanoma patients (20.62 ng/ml) compared with healthy controls (24.71 ng/ml), but statistical significance was not reached (chi-square test, p = 0.051) no statistically significant association was found between serum total 25-hydroxyvitamin d levels and demographic characteristics; risk factors for cmm; prognostic factors, such as breslow thickness and ulceration; as well as clinical characteristics, such as melanoma stage, clinical type, and location. conclusions: lower serum 25-hydroxyvitamin d levels were found in our greek cohort of melanoma patients compared with healthy controls, without reaching, however, statistical significance; these levels were not statistically associated with established risk and prognostic factors for cmm. abstract research | dermatol pract concept 2020;10(1):e2020010 3 results a total of 105 patients were diagnosed with primary cmm at our academic department during the study period. six of them were excluded because they had been using oral vitamin d supplements; thus 99 patients were included in the study. of the 99 patients, 53 were female (53.54%). their age ranged from 37 to 64 years (median 50 years). the demographic characteristics of melanoma patients (n = 99) and healthy controls (n = 97) are presented in table 1. regarding risk factors for cmm among melanoma patients, there were 7 patients with skin phototype i (7.07%), 43 with type ii (43.43%), 34 with type iii (34.34%), and 15 with type iv (15.15%). twenty patients (20.20%) reported excessive nonintentional (occuwere used to describe the data. to test the relationship between serum levels of vitamin d and various demographic and prognostic factors, the chi-square test or the fisher exact test was used. in all the above comparisons vitamin d was used as a categorical variable with 3 levels. comparisons of baseline characteristics between the study groups were performed by using the chi-square test. for the comparison of serum vitamin d median between patients and controls, the nonparametric mann-whitney u test was used as 25-hydroxyvitamin d serum concentrations could not be assumed to be normally distributed (demonstrated by kolmogorov-smirnov test). the level of significance was set at 5% (p < 0.05). all statistical analyses were performed using the statistical package spss version 18 (ibm, usa). cer (ajcc) classification system (2010) was used. patients were followed for 42-78 months. during follow-up, recurrences and melanoma-related deaths were recorded. ageand sex-matched healthy subjects with nonrelated minor skin conditions from the outpatient dermatology service were recruited as healthy controls after they had given their informed consent. the same exclusion criteria as for melanoma patients were used. assessment of serum total 25-hydroxyvitamin d for all recruited melanoma patients, whole blood was sampled within 1 month from the time of diagnosis of cmm. in healthy controls, blood sampling was performed at the time of recruitment. to avoid the effect of seasonal variation of vitamin d levels, for each entered patient, a control subject was recruited at the same time. of our melanoma patients, 61 (61.61%) were diagnosed during spring and summer when sun exposure is high, and this is in accordance with other reports worldwide on the seasonality of melanoma diagnosis [20]. all blood samples were immediately processed and centrifuged. serum 25-hydroxyvitamin d levels were measured using a commercial, fully automated chemiluminescent vitamin d total immunoassay (elecsys vitamin d total, roche). measurements were performed at the biochemistry department of evangelismos general hospital of athens, greece. according to the endocrine society’s clinical guidelines, reference serum values for vitamin d were classified as follows: levels greater than 30 ng/ml were considered adequate; values between 21 and 29 ng/ml, insufficient; and levels lower than 20 ng/ ml, deficient. statistical analysis median values and interquartile ranges for continuous variables, or number and proportions for categorical variables, table 1. demographic characteristics and serum 25(oh)d levels for patients and controls melanoma patients controls p value n (%) n (%) sex 0.780a male 46 (46.46) 47 (48.45) female 53 (53.54) 50 (51.55) age 0.780a ≤40 years 31 (31.31) 34 (35.05) >40 years 68 (68.69) 63 (64.95) age, median (iqr) 50 (37-63.5) 51 (36-63) residence 0.493a urban 67 (67.68) 70 (72.2) rural 32 (32.32) 27 (27.8) serum 25(oh)d median (iqr) median (iqr) 0.051b 20.62 (13.22-29.67) 24.71 (15.37-34.65) n (%) n (%) 0.260a <20 ng/ml 49 (49.49) 42 (43.30) 21-29 ng/ml 23 (23.23) 18 (18.56) >30 ng/ml 27(27.27) 37 (38.14) bmi ≤25 42 (42.42) na >25 57 (57.58) na achi-square test. bmann-whitney u test. n (%) = frequency (percentage); 25(oh)d = 25-hydroxyvitamin d; bmi = body mass index; iqr = interquartile range; na = not available. 4 research | dermatol pract concept 2020;10(1):e2020010 serum total 25-hydroxyvitamin d (<20 ng/ml), 23 (23.23%) had insufficient levels (21-29 ng/ml), and 27 (27.27%) had adequate 25-hydroxyvitamin d levels (>30 ng/ml). two melanoma patients with serum total 25-hydroxyvitamin d levels between 20 and 20.9 ng/ml and 3 patients with values between 29 and 29.9 ng/ml were included in the insufficient class of the melanoma patients group. of the healthy controls, 42 (43.30%) had deficient serum levels of total 25-hydroxyvitamin d (<20 ng/ml), 18 (18.56%) had insufficient levels (2129 ng/ml), and 37 (38.14%) had adequate 25-hydroxyvitamin d levels (>30 ng/ml). the median serum total 25 hydroxyvitamin d levels were lower in melanoma patients (20.62 ng/ml vs 24.71 ng/ml) compared with those in healthy controls (p = 0.051). statistical analysis is presented in table 1. we tested the correlation of serum total 25-hydroxyvitamin d levels at melanoma diagnosis with demographic pational) sun exposure, while 52 (52.53%) reported excessive intentional (recreational) sun exposure. thirty-nine patients (39.39%) had experienced blistering sunburns during childhood and adolescence and 35 (35.35%) during adulthood. signs of photo-damaged skin—presence of elastosis, solar lentigines, actinic keratoses—were observed in 46 patients (46.46%). family history of cmm was reported by 8 patients (8.08%), and personal history by 1 (1.01%). atypical nevi were present in 32 patients (32.32%). risk factors for cmm among our melanoma patients are depicted in table 2, while clinical and histological characteristics of melanoma are presented in table 3. serum total 25-hydroxyvitamin d levels were measured in 99 melanoma patients at the time of diagnosis and in 97 ageand sex-matched healthy controls at the time of recruitment. of the melanoma patients, 49 (49.49%) had deficient n (%) p valuea sunburn during adulthood (>20 years) 0.408 no 64 (64.65) yes 35 (35.35) sunscreen use 0.845 never 32 (32.32) rarely 29 (29.29) during summer vacation 31 (31.31) usually throughout year 7 (7.07) nevi count 0.982 <10 41 (41.41) 10-50 40 (40.40) >50 18 (18.18) atypical mole 0.648 yes 32 (32.32) no 67 (67.68) family history of melanoma 0.977 yes 8 (8.08) no 91 (91.92) personal history of melanoma 0.999d yes 1 (1.01) no 98 (98.99) achi-square test (unless specified otherwise). bblue, green, and light brown eyes. cblonde, red, and light brown hair. dfisher exact test. n (%) = frequency (percentage). n (%) p valuea eye color 0.120 lightb 77 (77.78) dark 22 (22.22) hair color 0.948 lightc 52 (52.53) dark 47 (47.47) skin color 0.910 white 58 (58.59) light brown 38 (38.38) dark 3 (3.03) phototype 0.813 type i 7 (7.07) type ii 43 (43.43) type iii 34 (34.34) type iv 15 (15.15) occupational sun exposure 0.077 yes 20 (20.20) no 79 (79.80) recreational sun exposure 0.104 yes 52 (52.53) no 47 (47.47) photoaging 0.903 yes 46 (46.46) no 53 (53.54) sunburn during childhood (<20 years) 0.356 no 60 (60.61) yes 39 (39.39) (data continues next column) table 2. descriptive statistics of risk factors and association with serum 25-hydroxyvitamin d research | dermatol pract concept 2020;10(1):e2020010 5 at diagnosis and were independently protective of relapse and death [14]. among 2,182 participants in the leeds melanoma cohort, lower 25-hydroxyvitamin d levels and smoking were associated with ulceration of primary melanomas and poorer melanoma-specific survival [15]. in accordance with these findings, other authors have found significantly lower median serum 25-hydroxyvitamin d concentrations in melanoma patients compared with healthy controls and combined these lower serum 25-hydroxyvitamin d concentrations found in melanoma patients with greater breslow thickness characteristics and risk factors for cmm. no statistically significant association between serum total 25-hydroxyvitamin d levels and the tested parameters was found (table 2). we also tested the correlation of serum total 25-hydroxyvitamin d levels at melanoma diagnosis with prognostic factors, such as breslow thickness and ulceration, as well as with clinical characteristics, such as melanoma stage, clinical type, and location, after classifying patients into 2 groups: those with bmi >25 (n = 57) and those with bmi ≤25 (n = 42) (see table e1 of supplementary content). although no statistical difference was documented, we observed that a higher percentage (33.33%) of melanoma patients with ulceration and bmi >25 had insufficient serum total 25-hydroxyvitamin d levels compared with those (23.81%) without ulceration. moreover, breslow thickness was not associated with serum concentrations of 25-hydroxyvitamin d (p = 0.370), and the correlation remained nonsignificant even when the patients were classified into 2 subgroups of early-onset (<40 years, p = 0.295) and late-onset melanoma (>40 years, p = 0.284) (see table e2 of supplementary content). discussion in the present study, we found lower median serum total 25-hydroxyvitamin d levels among melanoma patients compared with healthy controls, but the difference did not reach statistical significance (p = 0.051). possible explanations for this finding may be the relatively small number of patients, though representative of the low incidence of melanoma in greece, and the narrow variations of the median (interquartile range) serum 25-hydroxyvitamin d levels between patients and healthy controls (table 1), as both groups had median values of serum total 25-hydroxyvitamin d in the range of vitamin d insufficiency (20.62 ng/ml for the melanoma patients and 24.71 ng/ml for the healthy controls. in contrast, no statistically significant associations were documented between serum total 25-hydroxyvitamin d levels at melanoma diagnosis and demographic characteristics, risk factors for cmm, clinical characteristics, and prognostic factors, such as breslow thickness, ulceration, and melanoma stage. to our knowledge this is the first study to assess serum total 25-hydroxyvitamin d at the time of melanoma diagnosis and examine its correlation with clinical and histological variables in a low-incidence southern european country with high year-round ambient uvr levels. in recent years, various studies have focused on the role of vitamin d status in cmm risk and progression. overall lower serum vitamin d levels at melanoma diagnosis have been associated with an increased incidence of cmm and worse prognosis. in a prospective study of 271 melanoma patients in uk, newton-bishop et al found that higher 25-hydroxyvitamin d 3 levels were associated with lower breslow thickness table 3. descriptive statistics of clinical and histological characteristics and association with serum 25-hydroxyvitamin d levels n (%) p valuea melanoma location 0.139b trunk 45 (45.45) extremities 43 (43.43) face and neck 11 (11.11) melanoma type 0.128b lmm 3 (3.03) ssm 76 (76.77) nm 16 (16.16) alm 2 (2.02) other 2 (2.02) stage 0.602b in situ 5 (5.05) i 63 (63.64) ii 19 (19.19) iii 11 (11.11) iv 1 (1.01) deaths 0.566 yes 4 (4.04) no 95 (95.96) recurrence 0.359b yes 6 (6.06) no 93 (93.94) breslow level 0.370 <1 mm 52 (52.53) 1-4 mm 33 (33.33) >4 mm 14 (14.14) ulceration 0.494 yes 31 (31.31) no 68 (68.69) achi-square test (unless specified otherwise). bfisher exact test. n (%) = frequency (percentage); lmm = lentigo malignant melanoma; ssm = superficial spreading melanoma; nm = nodular melanoma; alm = acral lentiginous melanoma. 6 research | dermatol pract concept 2020;10(1):e2020010 found deficient total 25-hydroxyvitamin d levels among our healthy controls, in agreement with previous greek experience in various settings. this raises the discussion on what is sufficient and necessary for different population types [31,32]. our findings are more consistent with the us institute of medicine cutoff levels for serum 25-hydroxyvitamin d sufficiency in almost the entire (97.5%) caucasian population (>20 ng/ml) and less consistent with the endocrine society standards (>30 ng/ml) [33,34]. the prognostic significance of serum 25-hydroxyvitamin d levels at melanoma diagnosis remains controversial. in the present study, no significant association with breslow thickness and melanoma stage was documented. a possible explanation for that could be that our sample consisted mostly of thin melanomas (52.38% of them had breslow thickness <1 mm) and there was only 1 stage iv case. it is of note that most studies showing significant association between serum 25-hydroxyvitamin d and breslow thickness and/or melanoma stage originate from countries with high melanoma incidence rates such as australia, united kingdom, germany, and italy [14,16-19]. in contrast, the incidence in greece is low and it is estimated to be about 4 (4.01 females and 4.05 males) cases/100,000/year [35]. it can be speculated that in countries with high melanoma rates, the prognostic significance of vitamin d status becomes more evident, possibly because of a complex and yet unknown interplay between genetic and environmental factors that affect simultaneously both vitamin d status and melanoma development and progression. the question remains: should serum vitamin d levels be determined in any newly diagnosed patient with melanoma? literature review provides contradicting evidence. moreover, a meta-analysis of studies that looked at serum vitamin d levels and the incidence of skin cancer—cutaneous melanoma and nonmelanoma skin cancer—found no association between vitamin d level and risk of melanoma development, although there was a clear association with nonmelanoma skin cancer risk [36]. as mentioned before, 25-hydroxyvitamin d concentration at melanoma diagnosis is influenced by many factors, and it is not by any means representative of the vitamin d status during the whole process of melanoma genesis. the use of “snapshot” single measurements of 25-hydroxyvitamin d when attempting to demonstrate health risks associated with vitamin d deficiency is in dispute. in addition, serum 25-hydroxyvitamin d level is not the sole determinant of vitamin d activity. vitamin d binding protein, polymorphisms in the vitamin d receptor, calcium ingestion, renal activation of vitamin d, among others, may also play an important part [37,38]. on the other hand, the large number of melanoma patients who have low or deficient vitamin d levels at diagnosis, combined with the routine recommendation for avoidance of unprotected sun exposure thereafter, and worse survival [16]; association between lower serum 25-hydroxyvitamin d levels, higher breslow thickness, and higher ajcc melanoma stage [17]; a nearly 4-fold increase in risk of having a thicker tumor that was associated with low serum vitamin d levels (<50 nmol/l) [18]; inversely associated breslow thickness with vitamin d levels [19]; and higher vitamin d in nonulcerated tumors and in tumors within mitotic rate <1/mm2 [23]. other studies, however, have argued against the prognostic value of serum 25-hydroxyvitamin d in cmm. in a cohort of 1,171 patients with invasive melanoma, saiag et al tested the prognostic value of serum 25-hydroxyvitamin d 3 concentrations and concluded that only variation during follow-up is an independent melanoma prognostic marker, but not levels at diagnosis [24]. previously reported associations between low 25-hydroxyvitamin d 3 at diagnosis and poor prognosis they believe to be due to insufficient adjustment for prognostic factors [24]. other authors found significantly higher levels of vitamin d 3 in melanoma patients than in healthy controls, but both inferior of normal values [25]; significantly reduced serum 25-hydroxyvitamin d levels only in the stage iv melanoma patients compared with stage i patients, suggesting that patients with low serum vitamin d levels may develop earlier distant metastatic disease [26]; and significantly lower serum vitamin d binding protein levels in melanoma patients compared with healthy controls, emphasizing the prognostic significance of vitamin d binding protein rather than of 25-hydroxyvitamin d levels [27]. in contrast to what one might expect, ie, the typical fair-skinned patient with melanoma with a history of excessive sun exposure would have normal vitamin d levels at diagnosis, a significant number of melanoma patients in the cohorts studied were serologically vitamin d-deficient [21]. τhis observation is difficult to interpret. although serum 25-hydroxyvitamin d concentration is the best determinant of vitamin d status because of its long half-life (more than 250 hours), its value is influenced by several factors, such as variation in sun exposure due to latitude, season, or time of day, clothing, sunscreen use, skin pigmentation, age, and obesity [28]. in addition, suboptimal serum 25-hydroxyvitamin d levels are common in adults in many countries and are highly prevalent in the middle east and asia [29]. serum 25-hydroxyvitamin d levels are higher in northern than in southern europe, and in western than in eastern europe, presumably owing to differences in skin phototypes among european populations [30]. in mediterranean countries such as spain, italy, and greece, low serum 25-hydroxyvitamin d may be attributed to darker skin pigmentation and reduced sun exposure resulting from urbanization [29]. also in greece dairy product fortification and vitamin d supplementation is not a usual practice, especially for younger age groups (median age of our melanoma patients was 50 years). we research | dermatol pract concept 2020;10(1):e2020010 7 4. guillot x, semerano l, saidenberg-kermanach n, falgarone g, boissier mc. vitamin d and inflammation. joint bone spine. 2010;77(6):552-557. 5. scaglione-sewell ba, bissonnette m, skarosi s, abraham c, brasitus ta. a vitamin d3 analog induces a g1-phase arrest in caco-2 cells by inhibiting cdk2 and cdk6: roles of cyclin e, p21waf1, and p27kip1. endocrinology. 2000;141(11):3931-3939. 6. lamprecht sa, lipkin m. cellular mechanisms of calcium and vitamin d in the inhibition of colorectal carcinogenesis. ann n y acad sci. 2001;952(1):73-87. 7. evans sr, shchepotin ei, young h, rochon j, uskokovic m, shchepotin ib. 25-dihydroxyvitamin d3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model. int j oncol. 2000;16(6):1249-1254. 8. aranow c. vitamin d and the immune system. j investig med. 2011;59(6):881-886. 9. atoum m, alzoughool f. vitamin d and breast cancer: latest evidence and future steps. breast cancer (auckl). 2017;11: 1178223417749816. 10. liu y, wang x, sun x, lu s, liu s. vitamin intake and pancreatic cancer risk reduction: a meta-analysis of observational studies. medicine (baltimore). 2018;97(13):e0114. 11. e g a n k m . vi t a m i n d a n d m e l a n o m a . a n n e p i d e m i o l . 2009;19(7):455-461. 12. reichrath j, rech m, moeini m, meese e, tilgen w, seifert m. in vitro comparison of the vitamin d endocrine system in 1,25(oh)2d3-responsive and -resistant melanoma cells. cancer biol ther. 2007;6(1):48-55. 13. piotrowska a, wierzbicka j, nadkarni s, brown g, kutner a, żmijewski ma. antiproliferative activity of double point modified analogs of 1,25-dihydroxyvitamin d against human malignant melanoma cell lines. int j mol sci. 2016;17(1):e76. 14. newton-bishop ja, beswick s, randerson-moor j, et al. serum 25-hydroxyvitamin d3 levels are associated with breslow thickness at presentation and survival from melanoma. j clin oncol. 2009;27(32):5439-5444. 15. newton-bishop ja, davies jr, latheef f, et al. 25-hydroxyvitamin d2/d3 levels and factors associated with systemic inflammation and melanoma survival in the leeds melanoma cohort. int j cancer. 2015;136(12):2890-2899. 16. gambichler t, bindsteiner m, hoxtermann s, kreuter a. serum 25-hydroxyvitamin d serum levels in a large german cohort of patients with melanoma. br j dermatol. 2013;168(3):625-628. 17. bade b, zdebik a, wagenpfeil s, et al. low serum 25-hydroxyvitamin d concentrations are associated with increased risk for melanoma and unfavourable prognosis. plos one. 2014;9(12):e112863. 18. wyatt c, lucas rm, hurst c, kimlin mg. vitamin d deficiency at melanoma diagnosis is associated with higher breslow thickness. plos one. 2015;10(5):e0126394. 19. cattaruzza ms, pisani d, fidanza l, et al. 25-hydroxyvitamin d serum levels and melanoma risk: a case-control study and evidence synthesis of clinical epidemiological studies. eur j cancer prev. 2019;28(3):203-211. 20. bianconi f, masanotti gm, liso a, la rosa f, duca e, stracci f. seasonal variation in skin cancer diagnosis. front public health. 2016;4:78. 21. sondak vk, mciver b, kanetsky pa. vitamin d and melanoma: what do we tell our patients? j clin oncol. 2016;34(15):17131714. along with the real possibility that patients with lower vitamin d levels may fare worse than those with higher levels, seems to provide strong rationale for routine determination of the 25-hydroxyvitamin d level at initial diagnosis, followed by oral supplementation and monitoring for patients with low or deficient levels [21]. in view of the well-established pathogenetic role of uvr in skin carcinogenesis and the controversy over vitamin d, changes in current recommendations for strict photo-protection as a major target of skin cancer prevention are not warranted [21]. most importantly, sun exposure alone does not guarantee vitamin d sufficiency [15,22,39]. nevertheless, an optimum balance between sun protection and exposure is advocated [1]. the present study has some limitations. the sample size of melanoma patients was relatively small and monocentric compared to other studies, although it originated from the largest referral center of melanoma patients in central greece. in addition, most cases were early-stage melanomas. it is known that serum total 25-hydroxyvitamin d levels are usually not affected until the bmi is >30 ng/ml. in our melanoma group no patient had bmi >30 so we divided our patients into 2 groups, one with bmi ≤25 and the other with overweight patients and bmi >25. another limitation of studies including ours, assessing serum 25-hydroxyvitamin d levels, is that the ideal levels are a matter of controversy and concentrations that would be beneficial for patients with melanoma are not adequately documented. conclusions we found lower serum total 25-hydroxyvitamin d levels among our melanoma patients in a case-control study performed in a low-risk southern european population. however, no statistically significant difference was documented, and these levels were not associated with established risk factors and prognostic variables for cmm. more studies are needed to elucidate the complex effect of vitamin d in the development and progression of cmm. better understanding of the role of vitamin d may provide new insights applicable to melanoma prevention and treatment. references 1. ombra mn, paliogiannis p, doneddu v, et al. vitamin d status and risk for malignant cutaneous melanoma: recent advances. eur j cancer prev. 2017;26(6):532-541. 2. savoye i, olsen cm, whiteman dc, et al. patterns of ultraviolet radiation exposure and skin cancer risk: the e3n-sunexp study. j epidemiol. 2018;28(1):27-33. 3. pilz s, trummer c, pandis m, et al. vitamin d: current guidelines and future outlook. anticancer res. 2018;38(2):1145-1151. 8 research | dermatol pract concept 2020;10(1):e2020010 32. katrinaki m, kampa m, margioris a, castanas e, malliaraki n. vitamin d levels in a large mediterranean cohort: reconsidering normal cut-off values. hormones. 2016;15(2):205-223. 33. ross ac, manson je, abrams sa, et al. the 2011 report on dietary reference intakes for calcium and vitamin d from the institute of medicine: what clinicians need to know. j clin endocrinol metab. 2011;111(4):524-527. 34. holick mf, binkley nc, bischoff-ferrari ha, et al. evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. j clin endocrinol metab. 2011;96(7):1911–1930. 35. lasithiotakis k, leiter u, krüger-krasagakis s, tosca a, garbe c. comparative analysis of incidence and clinical features of cutaneous malignant melanoma in crete (greece) and southern germany (central baden-württemberg). br j dermatol. 2006;154(6):1123-1127. 36. caini s, boniol m, tosti g, et al. vitamin d and melanoma and non-melanoma skin cancer risk and prognosis: a comprehensive review and meta-analysis. eur j cancer. 2014;50(15):2649-2658. 37. tagliabue e, raimondi s, gandini s. meta-analysis of vitamin d-binding protein and cancer risk. cancer epidemiol biomarkers prev. 2015;24(11):1758-1765. 38. orlow i, reiner as, thomas ne, et al. vitamin d receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study. carcinogenesis. 2016;37(1):30-38. 39. binkley n, novotny r, krueger d, et al. low vitamin d status despite abundant sun exposure. j clin endocrinol metab. 2007;92(6):2130-2135. 22. fang s, sui d, wang y, et al. association of vitamin d levels with outcome in patients with melanoma after adjustment for c-reactive protein. j clin oncol. 2016;34(15):1741-1747. 23. lim a, shayan r, varigos g. high serum vitamin d level correlates with better prognostic indicators in primary melanoma: a pilot study. australas j dermatol. 2018;59(3):182-187. 24. saiag p, aegerter p, vitoux d, et al. prognostic value of 25-hydroxyvitamin d3 levels at diagnosis and during follow-up in melanoma patients. j natl cancer inst. 2015;107(12):djv264. 25. oliveira filho rs, oliveira da, martinho va, antoneli cb, marcussi la, ferreira ce. serum level of vitamin d3 in cutaneous melanoma. einstein (sao paulo). 2014;12(4):473-476. 26. nürnberg b, gräber s, gärtner b, et al. reduced serum 25-hydroxyvitamin d levels in stage iv melanoma patients. anticancer res. 2009;29(9):3669-7364. 27. navarrete-dechent c, del puerto c, molgó m, et al. circulating vitamin d-binding protein and free 25-hydroxyvitamin d concentrations in patients with melanoma: a case-control study. j am acad dermatol. 2017;77(3):575-577. 28. tsiaras wg, weinstock ma. factors influencing vitamin d status. acta derm venereol. 2011;91(2):115-124. 29. van schoor nm, lips p. worldwide vitamin d status. best pract res clin endocrinol metab. 2011;25(4):671-680. 30. van der wielen rp, lowik mr, van den berg h, et al. serum vitamin d concentrations among elderly people in europe. lancet. 1995;346(8969):p207-p210. 31. manios y, moschonis g, hulshof t, et al. prevalence of vitamin d deficiency among school children in greece: the role of sex, degree of urbanisation and seasonality. br j nutr. 2017;118(7):550-558. research | dermatol pract concept 2020;10(1):e2020010 9 table e1. association of serum 25(oh)d levels with clinical and histopathological characteristics in different levels of bmi serum 25(oh)d, n (%) total p value <20 ng/ml 21-29 ng/ml >30 ng/ml patients with bmi ≤25 breslow 0.473a <1 mm 8 (40) 8 (40) 4 (20) 20 (100) 1-4 mm 9 (60) 2 (13.33) 4 (26.67) 15 (100) >4 mm 3 (42.86) 3 (42.86) 1 (14.29) 7 (100) total 20(47.62) 13(30.95) 9 (21.43) 42 (100) patients with bmi >25 breslow 0.338a <1 mm 14 (43.75) 9 (28.13) 9(28.13) 32 (100) 1-4 mm 7 (38.89) 5 (27.78) 6 (33.33) 18 (100) >4 mm 6 (85.71) 1 (14.29) 0 7 (100) total 27 (47.37) 15 (26.32) 15 (26.32) 57 (100) patients with bmi ≤25 ulceration 0.423 yes 6 (37.50) 5 (31.25) 5 (31.25) 16 (100) no 14 (53.85) 8 (30.77) 4 (15.38) 26 (100) total 20(47.62) 13 (30.95) 9 (21.43) 42 (100) patients with bmi >25 ulceration 0.735 yes 6 (40) 5 (33.33) 4 (26.67) 15 (100) no 21 (50) 10 (23.81) 11 (26.19) 42 (100) total 27(43.37) 15 (26.32) 15 (26.32) 57 (100) patients with bmi ≤25 melanoma located in sun-exposed body parts 0.943 yes 12 (46.15) 8 (30.77) 6 (23.08) 26 (100) no 8 (50) 5 (31.25) 3 (18.75) 16 (100) total 20 (47.62) 13 (30.95) 9 (21.43) 42 (100) patients with bmi>25 melanoma located in sun-exposed body parts 0.926 yes 13 (46.43) 8 (28.57) 7 (25) 28 (100) no 14 (48.28) 7 (24.14) 8 (27.59) 29 (100) total 27 (47.37) 15 (26.32) 15 (26.32) 57 (100) aresult derived from fisher exact test. sun-exposed body parts = extremities and head and neck; 25(oh)d = 25-hydroxyvitamin d; bmi = body mass index. 10 research | dermatol pract concept 2020;10(1):e2020010 table e2. association of serum 25(oh)d levels with breslow in different age groups serum 25(oh)d, n (%) total p value <20 ng/ml 21-29 ng/ml >30 ng/ml age ≤40 years breslow 0.295a <1 mm 8 (66.67) 0 4 (33.33) 12 (100) 1-4 mm 9 (64.29) 3 (21.43) 2 (14.29) 14 (100) >4 mm 4 (80) 1 (20) 0 5 (100) total 21 (67.74) 4 (12.90) 6 (19.35) 31 (100) age >40 years breslow 0.284a <1 mm 14 (35) 17 (42.50) 9 (22.50) 40 (100) 1-4 mm 7 (36.84) 4 (21.05) 8 (42.11) 19 (100) >4 mm 5 (55.56) 3 (33.33) 1 (11.11) 9 (100) total 26 (38.24) 24 (35.29) 18 (26.47) 68 (100) aresult derived from fisher exact test. 25(oh)d = 25-hydroxyvitamin d. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(1):3 5 dermatology practical & conceptual www.derm101.com introduction eccrine syringofibroadenoma (esfa) is a rare neoplasm that usually presents as a solitary, often large, hyperkeratotic nodular lesion with predilection for the extremities. histologically, there are thin anastomosing epithelial cords and strands forming a lattice and connected to the undersurface of the epidermis. ducts are presented within the tumor. between the strands, there is a rich fibrovascular stroma. eccrine syringofibroadenoma is typically a rare benign neoplasm. eccrine syringofibroadenoma (esfa) is of acrosyringeal or eccrine dermal duct differentiation. histologically, there are multiple anastomosing cords of benign epithelial cells surrounded by a loose fibrovascular stroma. the epithelial cords demonstrate ductal differentiation. occasional luminal eccrine ducts are noted within the anastomosing cords. the authors describe two cases with different subtypes of esfa, a solitary esfa and a reactive esfa with squamous cell carcinoma. case report patient 1 a 77-year-old thai male patient presented with asymptomatic erythematous plaques on both soles for a year. the lesions had slowly extended from the middle of his soles to heels and medial part of the feet (figure 1a). he denied history eccrine syringofibroadenoma (esfa): a report of two cases bhakinai temnithikul1, suthep jerasutus2, poonnawis sudtikoonaseth1, nataya voravutinon1, tanawatt kootiratrakarn1, pinnaree kattipathananpong1 1 institute of dermatology, department of medical services, ministry of public health, bangkok, thailand 2 department of dermatology, faculty of medicine, ramathibodi hospital, mahidol university, bangkok, thailand keywords: eccrine syringofibroadenoma (esfa), syringofibroadenoma, eccrine syringofibroadenomatous hyperplasia, acrosyringeal adenomatosis, squamous cell carcinoma citation: temnithikul b, jerasutus s, sudtikoonaseth p, voravutinon n, kootiratrakarn t, kattipathananpong p. eccrine synringofibroadenoma (esfa): a report of two cases. dermatol pract concept 2016;6(1):3. doi: 10.5826/dpc.0601a03 received: september 29, 2015; accepted: october 6, 2015; published: january 31, 2016 copyright: ©2016 temnithikul et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: bhakinai temnithikul, md, institute of dermatology, department of medical services, ministry of public health, bangkok, thailand. tel. +66 81719-2567. email: arumuab@hotmail.com figure 1a. the lesions slowly extended from the middle of the soles to the heels and medial part of the feet. [copyright: ©2016 temnithikul et al.] 6 observation | dermatol pract concept 2016;6(1):3 anastomosing slender elongated cords and strands of cuboidal cells embedded in fibrovascular stroma with a diagnosis of recurrent squamous cell carcinoma with eccrine syringofibroadenoma at the periphery of the specimen (figure 2b and c). immunohistochemical staining was done. positive staining was observed for epithelial membrane antigen (ema) and carcinoembryonic antigen (cea). discussion eccrine syringofibroadenoma (esfa) (synonym: syringofibroadenoma, eccrine syringofibroadenomatous hyperplasia [1], acrosyringeal adenomatosis [2]) is a rare benign adnexal of previous trauma. the patient had valvular heart disease and coronary artery disease. he had undergone valve and coronary bypass surgery 10 years ago. he is currently on oral warfarin treatment. physical examination revealed bilateral, well-defined, firm, cobblestone-like, erythematous plaques on both soles with keratoderma. histological examination was obtained. the histopathology showed thin reticular strands of proliferating cells connected to the epidermis and extending into the dermis, anastomosing irregularly. small eccrine ducts could be seen within the cords. the area between the strands was filled with richly vascular fibrous stroma. perivascular infiltration with lymphocytes, plasma cells and mast cells were noted (figure 1b and 1c). immunohistochemical staining was done. positive staining was observed for epithelial membrane antigen (ema) and carcinoembryonic antigen (cea). patient 2 a 52-year-old thai female patient presented with asymptomatic erythematous exophytic masses on the dorsum of her left foot (figure 2a). she had gradually developed asymptomatic erythematous exophytic masses on her left foot for several years. a surgical excision was performed on the lesions one year ago. histopathological diagnosis revealed squamous cell carcinoma. this patient had developed dome-shaped reddish exophytic masses on top of the surgical scar after surgery 6 months ago. she denied history of trauma and never had previous keloidal scars. physical examination revealed multiple well-defined firm dome-shaped exophytic erythematous masses on top of the surgical scar on the dorsum of her left foot. histological examination from the lesion was obtained and showed proliferation of atypical squamous cells extending to the superficial dermis. there was also aggregation of figure 1b. histopathologic findings. [copyright: ©2016 temnithikul et al.] figure 1c. histopathologic findings. [copyright: ©2016 temnithikul et al.] figure 2a. erythematous exophytic masses on dorsum of the left foot. [copyright: ©2016 temnithikul et al.] observation | dermatol pract concept 2016;6(1):3 7 sis. it may be the result of a somatic mutation in the early embryonic stage. 5. reactive esfa associated with inflammatory or neoplastic dermatosis is often in an acral location. this reactive change has been seen next to burn scar ulcer, erosive palmoplantar lichen planus [6], hidrotic ectodermal dysplasia, bullous pemphigoid [1], diabetes mellitus with polyneuropathy and chronic ulcer, inflammatory psoriasis or persistent local infection, lymphedema (elephantiasis), nevus sebaceous and squamous cell carcinoma. the pathogenesis may be associated with a specific type of eccrine duct remodeling or repair. the co-existence of esfa and squamous cell carcinoma has been reported [4,7]. it is unclear whether esfa develops in response to squamous cell carcinoma or squamous cell carcinoma represents a malignant degeneration of esfa. the incidence of squamous cell carcinoma arising in esfa is unknown. the histologic picture of coexistence of esfa and squamous cell carcinoma have appeared as squamous cell carcinoma with ductal differentiation impinged by benign esfa and squamous cell carcinoma surrounded by esfa. the malignant degeneration of esfa has been termed as eccrine syringofibrocarcinoma (esfac) [7-9]. the mechanisms of underlying malignant transformation remain unclear. it is recommended that esfa be completely excised to prevent malignant degeneration, although the risk of this occurrence is unknown. recurrences and metastatic disease have not been reported. excision appears to be the definitive treatment. trauner et al reported a patient with esfa successfully treated with a dual pulse width flashlamp pumped pulsed dye laser [10]. in conclusion, the authors show two rare cases of eccrine syringofibroadenoma (esfa) with different clinical manifestations. patient 1 was diagnosed with esfa by histological findings. the immunohistochemical demonstration was consistent with esfa. he had no associated findings or sign of ectodermal dysplasia and he was therefore classified as tumor arising most often on the extremities of elderly individuals with characteristic histopathology. the tumor consists of anastomosing cords of cuboidal epithelial cells surrounded by a fibrovascular stroma containing plasma cells and ductal structures [3]. although the exact site of origin of esfa remains controversial, it is believed to be derived from the acrosyringium or eccrine dermal duct. esfa stains positively with epithelial membrane antigen (ema) and carcinoembryonic antigen (cea). cytokeratin studies have been inconsistent [4]. human papillomavirus 10 (hpv-10) may also play a role in the development of eccrine syringofibroadenomas. cases of esfa have been divided into five distinct subtypes due to clinical manifestations: solitary lesions, multiple lesions associated with an ectodermal dysplasia, lesions with no additional cutaneous pathology, nevoid lesions, and reactive lesions: 1. solitary esfa is typically a nonhereditary solitary nodule or verrucous mass normally found on the lower extremities of the middle-aged and elderly. 2. multiple esfa without associated cutaneous finding (eccrine syringofibroadenomatosis) are nonfamilial palmoplantar lesions without significant associated cutaneous finding. 3. multiple esfa with hidrotic ectodermal dysplasia (hed) presents in two different variants, schöpf-schulz-passarge syndrome and clouston’s syndrome. schöpf -schulzpassarge syndrome (ssps) is a rare autosomal dominant ectodermal dysplasia, characterized by hypodontia, hypotrichosis, nail dystrophy, palmoplantar keratoderma, and periocular and eyelid margin apocrine hidrocystoma. clouston’s syndrome is autosomal dominant ectodermal dysplasia, characterized by dystrophic nails and sparse hair. hpv-10 has been detected in the lesions occurring in clouston’s syndrome [5]. 4. nevoid esfa (nonfamilial unilateral linear esfa) is a rare genetic mosaicism, producing diffuse plantar hyperkeratofigure 2b. histopathologic findings. [copyright: ©2016 temnithikul et al.] figure 2c. histopathologic findings. [copyright: ©2016 temnithikul et al.] 8 observation | dermatol pract concept 2016;6(1):3 5. carlson ja, rohwedder a, daulat s, schwartz j, schaller j. detection of human papillomavirus type 10 dna in eccrine syringofibroadenomatosis occurring in clouston’s syndrome. j am acad dermatol. 1999;40:259–62. 6. french le, masgrau e, chavaz p, saurat jh. eccrine syringofibroadenoma in a patient with erosive palmoplantar lichen planus. dermatology. 1997;195:399-401. 7. bjarke t, ternesten-bratel a, hedblad m, rausing a. carcinoma and eccrine syringofibroadenoma: a report of five cases. j cutan pathol. 2003;30:382-92. 8. gonzález-serva a, pró-rísquez ma, oliver m, caruso mg. syringofibrocarcinoma versus squamous cell carcinoma involving syringofibroadenoma: is there a malignant counterpart of mascaro’s syringofibroadenoma? am j dermatopathol. 1997;19:5865. 9. katane m, akiyama m, ohnishi t, watanabe s, matsuo i. carcinomatous transformation of eccrine syringofibroadenoma. j cutan pathol. 2003; 30:211-4. 10. trauner, ma, narurkar va, ruben bs. eccrine syringofibroadenoma treated with a dual pulse width flashlamp pumped pulsed dye laser. dermatol surg. 1999;25:418-20. multiple efsa without associated cutaneous findings. patient 2 was classified as reactive esfa and diagnosed as esfa with squamous cell carcinoma by typical histological and immunohistological findings. excision of the esfa was the definitive treatment to prevent the malignant degeneration. mohs surgery was done for squamous cell carcinoma. she has been evaluated with a complete skin examination every 6 months. references 1. nomura k, hashimoto i. eccrine syringofibroadenoma in two patients with bullous pemphigoid. dermatology. 1997;195:395-8. 2. hara k, mizuno e, nitta y, ikeya t. acrosyringeal adenomatosis (eccrine syringofibroadenoma of mascaro). a case report and review of the literature. am j dermatopathol. 1992;14:328-39. 3. starink tm. eccrine syringofibroadenoma: multiple lesion representing a new cutaneous marker of the schöpf syndrome, and solitary nonhereditary tumors. j am acad dermatol. 1997;36:569-76. 4. schadt cr, boyd as. eccrine syringofibroadenoma with coexistent squamous cell carcinoma. j cutan pathol. 2007;34:71-4. dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2012;2(2):15 75 review by heinz h. kutzner, m.d. this book definitely fills a gap. among the plethora of outstanding molecular pathology textbooks (e.g., molecular genetic pathology by liang cheng and david y. zhang, humana press, 2008; and molecular pathology by william b. coleman and gregory j. tsongalis, academic press, 2009), murphy’s book is a glittering diamond that should be read from cover to cover by every dermatologist and dermatopathologist. it is worth every dollar—and even more. michael murphy and his multi-author team have achieved the difficult task of putting together a concise and highly readable text that covers all molecular biology topics relevant to murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. citation: book review: murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. dermatol pract conc. 2012;2(2):15. http://dx.doi.org/10.5826/dpc.0202a15. copyright: ©2012 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr, maryland heights, mo, 63043, usa. tel. 314.991.4470; email: markhurt@aol.com. figure 1. murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. 478 pp with index. isbn 978-1-60761-170-7; upc 9781607611707; $239. dermatologists and dermatopathologists. each topic was researched in depth and is up to date. both neophytes and experienced dermatologists with a sound molecular background will profit equally from this book, which is full of details, surprises, new developments in the field, and data relevant to the daily professional lives of dermatologists and dermatopathologists. murphy’s 478-page book contains 23 chapters and 1 addendum (written by 32 authors): 1. introduction to molecular diagnostic testing in dermatology and dermatopathology 2. principles in molecular biology 3. technologies in the molecular diagnostics laboratory 4. cytogenetics of primary skin tumors 5. melanocytic neoplasms i: molecular diagnosis 6. melanocytic neoplasms ii: molecular staging 7. non-melanoma skin cancers and hereditary cancer syndromes 8. cutaneous sarcomas and soft tissue proliferations 9. molecular determination of soft tissue margins, clonal origin, and histogenesis of skin cancers 10. mycosis fungoides and related lesions 11. cutaneous non-mf t-cell and nk-cell lymphoproliferative disorders 12. cutaneous b-cell lymphomas 13. leukemia cutis 14. inflammatory disorders of the skin 15. infectious diseases of the skin i: dermatophytosis/ onychomycosis mailto: 76 book review | dermatol pract concept 2012;2(2):15 a beautiful chapter! encyclopedic definitely is a hyperbolic term, but in the context of molecular biology in conjunction with dermatology/dermatopathology, murphy’s book comes quite close to it. “primer” and “encyclopaedic manual” aside, is there something left for the experienced dermatologist and dermatopathologist with a profound background in molecular biology, or is this just another book for the shelf? not at all! this book is full of hidden surprises (which might be a euphemism for one’s many blind spots, i hate to admit); i loved to read about chronic wounds and biofilms, about the cytogenetic alterations associated with the leukemias (a very detailed a precise account), and many others. and what about the figures, tables, and photomicrographs? just the right dosage—and some of it is even in color. personally, i am more visually oriented and cannot get enough of long and detailed tables, figures, color photomicrographs, which help me to understand the written material much faster, particularly in a complicated field like this one. in general, the authors did a very good job here. the printed pictorial material is always a compromise: publishers hate it (costs and space!), while readers love it (particularly the visually oriented ones). a nice table and picture are always welcome. any serious criticism? none! any suggestions and wishes? yes, i sincerely hope dr. murphy will sell a million copies of it, or even more! and, needless to add, these copies should be read also! repeatedly! did i already mention the price? forget about money! this is a must-have! would this be “the book” for the lonely island? definitely yes! if you already read tolstoy’s war and peace, this would be the perfect time to grab the blue murphy! a word of caution? true story: at the recent asdp meeting in seattle, i overheard an enthusiastic young colleague approaching david weedon with the words, “dr. weedon, we love your book. we always use it as a prop!” never say this to dr. murphy! his book is “un-prop-able.” this book was made exclusively for reading. besides, you can carry it everywhere. dr. kutzner practices dermatology and dermatopathology at dermatopathologie friedrichshafen in germany. contact him at kutzner@ dermpath.de. review by wolfgang weyers, m.d. molecular dermatopathology is an evolving field of medicine that acquires rapidly increasing importance in the diagnosis and management of patients with skin diseases. there is a need, therefore, for a reference that imparts knowledge 16. infectious diseases of the skin ii: non-dermatophytic infections 17. wound healing disorders: chronic wounds and keloids 18. alopecias 19. genodermatoses: inherited diseases of the skin 20. molecular aspects of skin aging 21. pharmagogenetics and pharmacogenomics i: linking diagnostic classification to therapeutic decisions 22. pharmagogenetics and pharmacogenomics ii: genetic determinants of drug response and adverse drug reactions 23. regulatory, legal, coding, billing, reimbursement, and ethical considerations for molecular diagnostic testing in dermatology and dermatopathology 24. additional resources who can benefit from this book? everybody in the field of dermatology and dermatopathology in particular! molecular techniques and principles have been invading the field of dermatology and dermatopathology for many years with few doctors keeping pace with the deluge of new and exciting developments and findings in the world of molecular biology, molecular medicine, and pathology. one can use murphy’s molecular diagnostics both as an easy-to-follow textbook and as an encyclopedic reference manual (where, within a second, you can look up that particular important fact that you are looking for so desperately in a conference, or at the microscope, or at the computer writing a paper). can the neophyte really use this book as a “primer”? not exactly. it will definitely take some endeavor and stamina—but it is feasible, particularly for those who have been avoiding the field whenever and wherever possible and are now trying to catch up. besides, one does not have to read and know everything in molecular biology. some topics may slumber for a while and then suddenly become “hot” for informational value. there are three very well written introductory chapters on general molecular biology; they cover about everything one should know on basic molecular biology in medicine. additionally, each special chapter begins with a concise introduction that allows one to put facts and data into perspective, providing a perfect overview. can murphy’s book also be used as a reference manual? definitely yes! many chapters contain a remarkable wealth of information, e.g., the chapter on dermatophytosis (among many others), which would take hours or days to compile from other sources. the chapters on melanoma, soft tissue tumors, and lymphomas/leukemia are outstanding and make great reading, particularly for oncologists and dermatopathologists. if you are interested in the intricacies of targeted medicine of malignant melanoma, go to chapters 5 and 6. problems with genodermatoses? go to chapter 19: 31 pages and 14 detailed tables, as well as 97 references tell you all you need and want to know and may want to recheck later. mailto:kutzner@dermpath.de mailto:kutzner@dermpath.de book review | dermatol pract concept 2012;2(2):15 77 melanoma skin cancers and hereditary cancer syndromes,” the authors claim simplistically that keratoacanthoma “does not exhibit distinct histopathological features nor specific protein biomarkers that allow a definite discrimination from scc,” as if there were no histopathologic criteria for differentiation between keratoacanthoma and conventional squamous-cell carcinoma that work in the majority of cases. they go on to explain that, “a lower degree of chromosomal instability in ka compared to scc . . . provides a potential approach to genetically differentiate ka from scc,” but do not allude to the vagueness of those findings in ambiguous cases. in regard to melanoma, the authors allude correctly to the subjectivity entering into histopathologic diagnosis, e.g., in differentiation of spitz’s nevus from spitzoid melanoma, but do not acknowledge that in molecular methods, such as fish, evaluation is also subjective and that the establishment of certain cut-off points for fish signals, even if backed by profound studies, is by its very nature arbitrary. in many chapters, a word of caution vis-á-vis results of molecular studies is missing entirely. this impairs seriously the practical utility of the book. for example, in lymphomas, clonality is often detectable in one biopsy but not the other. nevertheless, the reproducibility of molecular studies is not addressed. in patients with leukemia who develop unrelated skin diseases, non-neoplastic inflammatory cells entering the skin are often accompanied by some leukemic cells that can be demonstrated immunohistochemically, a finding that has no prognostic significance. obviously, those cells can also be detected by molecular studies, and at even lower numbers. nevertheless, the editor of the book and author of the chapter about “leukemia cutis” adheres to the traditional separation between “(a) ‘leukemids’ . . . in which inflammatory lesions contain no neoplastic cells; and (b) leukemia cutis (lc) . . . in which leukemic cells (myeloid or lymphoid) infiltrate the skin,“ and avers that “prognosis for patients with acute lc is generally very poor” (pp. 263f). the problem of the great sensitivity of molecular studies, allowing for identification of infinitesimal numbers of neoplastic cells with no prognostic import at all, is not discussed. in regard to infectious diseases such as tuberculosis or borreliosis, no word is uttered concerning sensitivity and specificity of pcr studies. what does failure to detect dna of borrelia in formalinfixed tissue imply? should patients be treated nonetheless? and how dependable is a positive test? how common are false positive results? is it better to rely on molecular studies or other findings, such as histopathologic pattern? what is known about sensitivity of molecular tests in different manifestations of infection, such as erythema migrans and acrodermatitis chronica atrophicans in the case of borreliosis and lupus vulgaris and erythema induratum in the case of tuberculosis? obviously, these are questions of great importance for the management of patients, but physicians will not find about the pros and cons, possibilities and limitations of molecular techniques to physicians who are not experts in the field. michael murphy must be commended for having recognized this need and for having assembled a broad array of co-authors in order to create the first textbook of molecular diagnostics in dermatology and dermatopathology, a book that, according to its preface, is aimed at “any physician,” particularly dermatologists and dermatopathologists, and has been designed to be used “as a reference guide in their daily practice of medicine.” first attempts are always difficult, and hardly any pioneering effort is a complete success. this also applies to the book under discussion. however, first attempts are essential to create a platform from which to proceed. considering the rapid progress in molecular diagnosis, there soon will be need for a second edition, and the purpose of a review resides not only in representing the finished product but also, and especially, in indicating ways of improving it. the finished product is a multi-author book that covers many aspects of molecular dermatopathology, ranging from “principles of molecular biology” to “technologies in the molecular diagnostics laboratory” and from molecular aspects of specific inflammatory and neoplastic skin diseases to “pharmacogenetics and pharmacogenomics.” if physicians turn to this “reference guide in their daily practice of medicine,” they will find almost anything, and the knowledge conveyed will enable them to understand reports concerning molecular findings. as in all multi-author books, however, the emphasis varies from chapter to chapter. of 15 chapters dealing with specific diseases, some focus on diagnosis, others on prognosis, and still others on molecular techniques. some chapters are very practical, e.g., the one on “cutaneous non-mf t-cell and nk-cell lymphoproliferative disorders” in which clinical, histopathological, immunohistochemical, and molecular findings are presented and assessed in regard to their diagnostic value. this enables physicians to integrate different aspects into a meaningful diagnostic procedure that may differ from disease to disease. for example, demonstration of monocloncal integration of htlv-i proviral dna in tumor cells is important for diagnosis of adult t-cell leukemia/ lymphoma, whereas in regard to lymphomatoid papulosis, the authors acknowledge that “molecular studies add little value.” likewise, the chapter about “cutaneous sarcomas and soft tissue proliferations” considers molecular testing as one of several diagnostic avenues, alludes to new immunohistochemical markers based on the knowledge of specific molecular alterations, and discusses sensitivity and specificity of the respective methods. this is noteworthy because other chapters tend to trivialize or neglect the value of diagnostic methods other than molecular ones. for example, in the chapter about “non78 book review | dermatol pract concept 2012;2(2):15 genetically altered cells are “pre-neoplastic” rather than neoplastic, and what they mean by the terms “pre-neoplastic” and “overt malignancy.” those deficiencies are relevant because they are related to one of the most important challenges for molecular pathology, namely, reconsideration of current concepts of disease. for example, the question whether molecular alterations in normal-appearing cells in the vicinity of squamous-cell carcinomas are non-neoplastic consequences of chronic solar damage or part and parcel of the neoplastic process might be resolved by comparing molecular alterations in those cells with alterations in cells of normal-appearing, sun-damaged skin further away from the neoplasm. if one adheres to opaque concepts such as “pre-neoplastic” and “overtly malignant” lesions, however, one does not ask the question and cannot give the answer. studies concerning molecular differences between solar keratoses and squamous-cell carcinomas have demonstrated more similarities than differences, but in keeping with predominant wisdom the authors of the chapter about “cytogenetics of primary skin tumors” emphasize differences such as “higher frequency of loh in ak compared to scc” (p. 63), rather than considering the obvious conclusion that solar keratoses are early manifestations of squamous-cell carcinoma. the notion that recurrences of basal-cell carcinomas are evidence of greater “aggressiveness” has prompted molecular studies “to distinguish between aggressive and nonaggressive bcc” (p. 61). recurrences, however, are chiefly a result of the pattern of growth. recurrences are caused by incomplete excisions, and the latter are more common in poorly circumscribed lesions. although the pattern of growth may be linked to distinctive molecular alterations, recognition of the pattern suffices to predict the probability of recurrences. in this chapter, as in several others, data of studies are presented that are often equivocal and have little import. by contrast, many important issues are not being addressed. for example, it is a notorious problem to distinguish irritated seborrheic keratoses and irritated warts from squamous-cell carcinoma, especially in small biopsy specimens. there can be no doubt that worldwide thousands of re-excisions are performed daily for ostensible squamous-cell carcinomas that, in reality, are irritated examples of benign epithelial lesions. this is one of many examples in which molecular tests might have greater importance than for distinction between aggressive and nonaggressive basal-cell carcinoma or different stages of development of squamous-cell carcinoma. yet, they are not considered in this textbook. the utility of the book is compromised further by its lack of focus on a particular readership. although, according to the preface, the book has been written for “any physician,” some chapters are replete with technical details, such as precise amino acid sequences of primers that are interesting only an answer in this “reference guide in their daily practice of medicine.” in the daily practice of medicine, molecular techniques are employed most commonly for the detection of infectious agents. it is noteworthy that, in this textbook, the chapter concerning “non-dermatophytic infections” is one of the shortest, deals mostly with methodology, is replete with general statements concerning the current and potential importance of molecular diagnostic techniques, and has practically nothing to say about the reliability of specific methods for specific infections. in fact, common diseases such as tuberculosis and borreliosis, are hardly mentioned at all and, consequently, are not listed in the index. neither are other infectious diseases, such as orf, bartonellosis, and leprosy. parenthetically, fungal infections are covered in a separate chapter that is substantially longer than the chapter dealing with all other infectious diseases. this lack of balance, a common problem of multi-author textbooks, is also evident in other respects. for example, opaque concepts are presented without being defined consistently, in various chapters. in the chapter on “mycosis fungoides and related lesions,” the authors refer to so-called “cutaneous t-cell lymphoid dyscrasia” as “a group of idiopathic chronic dermatoses, with persistent cutaneous infiltrates of monoclonal or restricted oligoclonal t cells” that have “a potential, albeit low, for progression to ctcl,” whereas, in the chapter on “inflammatory disorders of the skin,” they note that “cutaneous t-cell dyscrasias (i.e., lymphomas) can occasionally masquerade . . . as inflammatory dermatoses.” in other words, according to one chapter, “t cell lymphoid dyscrasias” are distinguished from lymphoma, whereas, in another chapter, they are referred to as lymphomas. interestingly, the editor of the book, michael murphy, was the senior author of both chapters, indicating that he has no clear concept of what he is writing about. just as “cutaneous t-cell dyscrasias,” many other vague concepts and clichés are adopted wholesale and are presented without an attempt at integration. for example, in keeping with leaflets for the uninitiated laity, melanoma is said to be “the most deadly form of skin cancer” (p. 59), although other neoplasms of the skin, such as cutaneous angiosarcoma, are clearly more malignant. basal-cell carcinoma is said to account “for ~80% of all skin cancers” and squamous-cell carcinoma “for almost 20% of all skin cancers” (p. 60), although those numbers are invalid, based as they are on studies that include superficial basal-cell carcinomas but exclude superficial squamous-cell carcinomas, such as bowen’s disease and solar keratoses. field cancerization is said to be characterized by “a clonal proliferation of preneoplastic genetically altered, but morphologically normalappearing cells . . . prior to the development of overt malignancy” (p. 191), but the authors fail to explain why those book review | dermatol pract concept 2012;2(2):15 79 dr. weyers practices dermatopathology at the center for dermatopathology, freiburg, germany. contact him at ww@zdpf.de. comment by mark a. hurt, m.d. i thank my colleagues, drs. kutzner and weyers, for their insightful reviews of this book. i contacted dr. murphy to obtain his response to the reviewers; he read the reviews, but he declined to comment. i extend the offer for a reply should dr. murphy wish to respond in a later issue of the journal. when approaching such a weighty topic as molecular diagnostics in dermatology and dermatopathology, i am reminded of the difficulty in establishing a diagnosis based on the classical techniques of clinicopathological correlation. the process is from clinical to histopathological to correlation to diagnosis—with prognosis coming much later epistemologically. this method has been an enormous achievement for mankind, and it cannot be reversed in any meaningful way. with the introduction of molecular information, the process does not change, but it becomes more complex . . . because there is more data to correlate and more variables that introduce the possibility of error into the process of diagnosis. as with any multi-authored work, one expects some degree of uneven writing and presentation; that is the case in this arbeit. including the editor, there are 32 authors involved in the writing of 23 chapters. most authors write from institutions within the united states. a few other countries are represented; these include australia, taiwan, germany, the united kingdom, italy, canada, and france. there is one page of “additional resources” highlighting a number of websites to organizations involved in the molecular genetics of varying conditions. this is followed by an index of 12 pages. this book is rather small—not the usual journal size— and it is a throwback to the days of small monographs in pathology. such monographs, as azzopardi’s problems in breast pathology, were, as a rule, filled with photographs and relatively large type—often 12 point—usually in times roman. in contrast, the type font in this book is times roman, but it is very small, probably 8 or 9 point, which is considerably smaller than historical works, and this fact alone makes for difficult reading. the book is at its best when the text is combined with tables and photographs of the techniques and some of the relevant lesions in question. chapter 3 on molecular techniques by drs. elaba, murphy, and mnayer is a concise introduction to the applied technology that comprises the field of molecular testing in dermatology and dermatopathology (table 3.1); it is a solid overview. the tables are especially helpful for focusing in on the disease, the molecufor a limited audience and that are not provided in other chapters. some passages seem to have been written for politicians or health-care managers. an entire chapter is devoted to coding, billing, and reimbursement, and statements concerning financial aspects also pepper other chapters. in the first chapter, the editor claims that, “in view of the unsustainable health care expenditures in the usa (17% gdp), . . . potential savings . . . can come as a result of preventative and/or more accurate testing.” there can be little doubt that molecular diagnostics will raise, rather than curtail, costs in the health care sector because many tests do not substitute but supplement other methods of diagnosis. seductive statements such as these may serve to increase the acceptance of molecular diagnostics by credulous laymen but can hardly appeal to physicians “in their daily practice of medicine.” for the sake of the average physician, as the official target audience, “principles of molecular biology” and “technologies in the molecular diagnostics laboratory” are discussed in the introductory chapters. in those chapters, the structure of dna and rna, the composition of the human genome, and nearly all techniques of molecular diagnosis are discussed in brief sections. however, the impression is created that this discussion is a compulsory exercise. for somebody not particularly knowledgeable in molecular biology, many explanations are opaque. for example, why is there “need for dna from peri-lesional non-tumor cells” in tests for loss of heterozygosity? and how do primers work? when dna is polymerized following binding of the primer to one strand, why not the entire strand? why is the pcr product restricted to a short target sequence? the authors do not mention the fact that a pair of primers is required, binding to different loci adjacent to the two ends of the target sequence. these, and many other issues, are not explained in a way that an average physician with only rudimentary knowledge in molecular biology might have a chance to understand. another factor that impairs seriously the utility of the book for the average physician is the constant use of acronyms that are not being explained. here and there, one can find an explanation of acronyms, such as cep6, etbr, rflp, or rreb1, at the beginning of a section or chapter, but some acronyms are not explained at all or are at a place impossible to find. the book would profit greatly from a table in which acronyms are listed and explained in alphabetical order, possibly in different colors for acronyms referring to genes, proteins, diagnostic methods, and diseases. in sum, the book by murphy and co-workers is a premiere, the first textbook about molecular diagnosis in dermatopathology. as such, it is a worthwhile endeavor, but flaws are substantial, and there are two good reasons to look forward to a second edition, namely, (1) increasing knowledge in molecular dermatopathology and (2) improvement of many weaknesses that characterize the first edition. mailto:ww@zdpf.de 80 book review | dermatol pract concept 2012;2(2):15 pregnancy, respectively. this said, it is, indeed, exciting to consider that cells of a melanoma away from the obvious neoplasm (principally in situ lesions for practical purposes) might be detected in fields that look as though they are in a control field but are, in fact, areas of melanoma that mimic the control field (i.e., “field cells”). i believe that the identification of these kinds of cells will have impact in the future on how to plan for staged excisions of melanoma, provided that the costs of mapping are feasible. in my practice of evaluating staged excisions of melanomas and melanomas in situ for mohs surgeons, i have found that standard techniques are very useful, those using melan-a and comparing the peripheral margins to the prior biopsies and to the debulk specimens. perhaps only 1 to 2% of patients ever have persistence and regrowth (so-called “true local recurrence”) after using this technique; if molecular techniques for the evaluation of peripheral margins ever become realistic in practice, they might eliminate this 1 to 2% after the lesions are found to persist. the good news seems to be that even when this happens, the patient outcomes are usually not worsened [1]. i agree wholeheartedly with dr. murphy that differentiation between primary and metastatic neoplasms would be of great benefit diagnostically and prognostically for patients (page 196). he reviews the status of techniques, such as the detection of fusion genes for “signature” genetic abnormalities and reverse transcription sequencing identification, which seem promising. in sum, i recommend this book principally as a reference work that many will not be able to read easily unless they are involved in the daily work of the molecular evaluation of patients’ various conditions, especially genodermatoses and some neoplasms. it fills a niche in the arsenal of tools for dermatopathologists, and it is well worth the price. reference 1. brown cd, zitelli ja. the prognosis and treatment of true local cutaneous recurrent malignant melanoma. dermatol surg. 1995 apr;21(4):285-90. pubmed pmid: 7728476. dr. hurt is the book review editor for dermatology practical and conceptual, and he practices dermatopathology in maryland heights, mo, usa. contact him at markhurt@aol.com. lar technique necessary, the molecular findings in the skin or other organs (or both), and relevant literature related to the findings. a good example of this is dr. murphy’s chapter 13 on “leukemia cutis,” specifically table 13.2. this is the kind of tool that draws the reader into the problems encountered in practice and allows for differentiation and integration of the techniques and findings. another excellent example of the integration of diseases is that of drs. smith & mclean in chapter 19 on “genodermatoses: inherited diseases of the skin.” this chapter is rich in the explanation of patterns of inheritance, gene(s) involved, omim numbers, and clinical nomenclature. these kinds of presentations alone justify purchasing the book if nothing more than just to have all of this information in one relatively small, concise text. chapters relevant to the day-to-day problems confronting dermatopathologists are chapters 5 through 8, which address melanocytic neoplasia, non-melanocytic neoplasia, and soft tissue neoplasia. these are the core of the book, and the various authors address techniques relevant to diagnosis and, to some extent, prognosis. of note, there is the fact that the genetic testing in a given neoplasm centers on identifying abnormal genetic patterns in the lesions in question compared to known controls of abnormal patterns found in malignancy. as a rule, the problem in melanocytic neoplasia, at least in my experience, is whether the lesion in question is melanoma or not. in other kinds of lesions, whether carcinoma or sarcoma, it seems that the diagnosis of malignancy is often already established by other techniques before genetic analysis adds additional information for subclassification of those malignancies. one problem i encountered when reading this work was the concept of “pre-neoplasia,” which dr. murphy addressed in chapter 9 (“molecular determination of tissue margins, clonal origin, and histogenesis of skin cancers”). i reject this concept. one cannot find a meaningful use for it. it is similar to being a “little pregnant.” one is or is not pregnant—and a lesion is or is not neoplastic. molecular genetics will not “solve” this issue because it is philosophical in nature, and there is no gene for philosophy. it is true that one can identify the conditions in which a neoplasm arises, just as one can identify the conditions in which a pregnancy occurs, but the conditions are not the same as the actual neoplasm or the mailto:markhurt@aol.com dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(2):e2020038 1 dermatology practical & conceptual case presentation a male patient, 72 years old, had a history of melanoma (ajcc stage ib) located on the left leg. during a regular follow-up visit, we observed an asymmetric, brown, blue-gray plaque with 1.2 cm maximum diameter, sharply delimited on the right supraclavicular region. on dermoscopy, the lesion presented a multicomponent pattern, with 4 colors (brown, gray, blue, and white), a globular atypical pattern, pseudonetwork, and asymmetrical globules. in the left area of the image, it was possible to see a homogenous brown area, with overlapping gray and white shiny structures and ovoid nests which led to the suspicion of a collision tumor of seborrheic keratosis and basal cell carcinoma or melanoma, mainly because of these two distinctive patterns on the same area (figure 1). the lesion was excised, and the histology was compatible with a seborrheic keratosis. teaching point at times, the clinical and dermoscopic diagnosis of seborrheic keratosis is challenging because it can mimic other conditions including basal cell carcinomas or melanomas [1,2]. references 1. mansur at, yildiz s. a diagnostic challenge: inflamed and pigmented seborrheic keratosis. clinical, dermoscopic, and histopathological correlation. dermatol online j. 2019 mar 15;25(3). pii: 13030/ qt0w56m5hq. 2. carrera c. the many faces of seborrheic keratosis. actas dermosifiliogr. 2019;110(5):338. when seborrheic keratosis is wearing a mask cristina sousa,1,2 sebastian podlipnik,1 susana puig,1 josep malvehy1 1 dermatology department, hospital clínic, barcelona, spain 2 dermatology department, centro hospitalar de vila nova de gaia/espinho, vila nova de gaia, portugal key words: seborrheic keratosis, fusion tumor, dermoscopy, dermatology challenge citation: sousa c, podlipnik s, puig s, malvehy j. when seborrheic keratosis is wearing a mask. dermatol pract concept. 2020;10(2):e2020038. doi: https://doi.org/10.5826/dpc.1002a38 accepted: january 18, 2020; published: april 20, 2020 copyright: ©2020 sousa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ana cristina da silva sousa, rua conceição fernandes, 4434-502 vila nova de gaia, portugal. email: a.cristina. silvasousa@gmail.com figure 1. dermoscopy image of a cutaneous lesion presenting with a multicomponent pattern, with 4 colors, a globular atypical pattern, pseudonetwork, and asymmetrical globules. https://doi.org/10.5826/dpc.1002a38 mailto:a.cristina.silvasousa@gmail.com mailto:a.cristina.silvasousa@gmail.com dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020100 1 dermatology practical & conceptual case presentation an 82-year-old man presented with fever and an erythematoedematous left index finger. he had a history of myelodysplastic syndrome. he was placed on intravenous antibiotic (amoxicillin/clavulanic acid) due to suspicion of cellulitis. the condition gradually developed blisters and necrosis, and surgeons decided to amputate. in the following days, the clinical picture worsened with the development of ulcers with violaceous borders and surrounding edema on the dorsal hand and proximal metacarpophalangeal joints of the thumb and third and fourth fingers (figure 1). skin biopsy was compatible with a neutrophilic dermatosis, and the diagnosis of neutrophilic dermatosis of the dorsal hands (nddh) was made. he was immediately started on oral prednisone 80 mg per day and showed rapid improvement. teaching point nddh, a distributional variant of sweet syndrome, is an under-recognized entity. it is often clinically misdiagnosed as an infectious process. physicians should suspect this diagnosis in order to avoid unnecessary and damaging procedures. red plaque on the dorsal hand with necrosis: think before you amputate marc mir-bonafé1, javier aubán-pariente1, sheila requena-lópez1, celia gómez-de-castro1, yolanda hidalgo-garcía1 1 department of dermatology, hospital universitario central de asturias, oviedo, spain key words: cellulitis, neutrophilic dermatosis, neutrophilic dermatosis of the dorsal hands, sweet syndrome citation: mir-bonafé m, aubán-pariente j, requena-lópez s, gómez-de-castro c, hidalgo-garcía y. red plaque on the dorsal hand with necrosis: think before you amputate. dermatol pract concept. 2020;10(4):e2020100. doi: https://doi.org/10.5826/dpc.1004a100 accepted: april 19, 2020; published: october 26, 2020 copyright: ©2020 mir-bonafé et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: marc mir-bonafé, md, department of dermatology, hospital universitario central de asturias, avenida de roma s/n, spain. email: marcmir5@hotmail.com figure 1. ulcers with violaceous borders and surrounding edema present on the dorsal left hand and aspects of the thumb with proximal metacarpophalangeal joints of the third and fourth fingers. note the absence of the left index finger. dermatology practical & conceptual www.derm101.com cia would be easy and each biopsy would demonstrate the descriptions found in my new text. as my training progressed, i was fortunate to attend alopecia clinics in the dermatology department and see the corresponding biopsies during residency and in fellowship. usually, the biopsies were expertly performed, grossed, and diagnosed, again, making the process seem exciting and deceptively easy. in reviewing outside consultations, however, i also quickly learned that many cases would not be easily diagnosed. i entered private practice where i, again, have been fortunate enough to work with excellent clinicians and supported by helpful and experienced colleagues. i was lucky, in a way, when a majority of my first alopecia biopsies were to confirm central centrifugal cicatricial alopecia, and the biopsies usually corresponded to that diagnosis. rarely, a biopsy would arrive either without clinical information, an inadequate amount of tissue, or as a consultation on poorly oriented tissue, etc. i realized how frustrating it was for everyone involved when a specific diagnosis could not be rendered and especially for the patient for having to endure the pain of scalp biopsies. when a challenging case of alopecia presents itself, i always turn to my text and enjoy the brief, yet sufficient information. when i realized there was a second edition of my trusty alopecia text, i was both excited and a bit nervous. i have read the first edition several times, both continuously and intermittently. i liked that the first edition was succinct, and having nearly memorized some portions, i felt i had conquered many of the topics. i found it easy to get through book review | dermatol pract concept 2012;3(1):13 47 review by amy c. parsons, m.d. i commend the authors on a job well done. i appreciate the time and effort required by them to produce a text and for sharing their knowledge. overall, the text is well written and easy to understand. the most important feature of any pathology atlas is the inclusion of clear photomicrographs corresponding to key points in the text, and this was certainly accomplished. i purchased the first edition of the book as a pathology resident when i became interested in dermatopathology. i knew i would need to learn more about the diagnosis of alopecia, which has a reputation of being a more challenging part of the field. i was unsure what the anxiety was about when such a small atlas arrived and was so clearly written. after i read through the text, i felt that diagnosing alopesperling lc, cowper se, knopp ea. an atlas of hair pathology with clinical correlations. second edition. new york & london: informa healthcare, 2012 citation: sperling lc, cowper se, knopp ea. an atlas of hair pathology with clinical correlations. second edition. new york & london: informa healthcare, 2012. dermatol pract conc. 2013;3(1):13. http://dx.doi.org/10.5826/dpc.0301a13. copyright: ©2013 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr., maryland heights, mo 63043, usa. tel. 314.991.4470. email: markhurt@aol.com. figure 1. sperling lc, cowper se, knopp ea. an atlas of hair pathology with clinical correlations. second edition. new york & london: informa healthcare. 2012. 216 pp. isbn 978184184733-7. upc 9781841847337. $250 hardcover; $200 kindle version. 48 book review | dermatol pract concept 2012;3(1):13 the information without having to sift through volumes of unnecessary information. i tried not to panic as i opened the new edition. my first observation is that the book is a different in color and a bit thicker, while still a convenient size for handling and carrying around. i find some comfort in not having to refer to a large text for alopecia—i can at least easily handle the book when faced with the frustration of making a less than specific diagnosis based on the occasional biopsy without clinical information or with inadequate tissue. of course, i am a fan of the first edition, but i was sometimes wishing for more photomicrographs to correspond to the descriptions in the text. i was also hopeful that there might be a few algorithms in the second edition. my review will thus be a comparison of the first and second editions. the second edition includes a new first chapter, which is a guide to using the book. like a pep-rally for the weary or novice, the authors give the reader a title of “trichopathologist” and outline how following the text will lead easily to the correct diagnosis. the chapter of “normal hair anatomy and architecture” is similar to the first edition, with some improvement in the clarity of photos and labeling of the structures. a few additional photos are included, as well. this is a trend throughout the book and a definite improvement. the authors have maintained the chapter titled “distinctive or critical histological features and associated diseases” and have retained the lists of diseases with certain characteristics. i find this chapter quite useful; though not an algorithm, the lists help to narrow down the diagnosis. likewise, the “clinical correlation” chapter and clinical photos throughout the book are critical, especially when faced with a histological diagnosis that is incongruous with the clinical impression. the core of the text consists of the chapters addressing specific diagnoses. while retaining all the previous chapters, the authors have included several new chapters, including: psoriatic alopecia, tumor-necrosis factor-alpha inhibitor associated psoriasiform alopecia, folliculitis decalvans, fibrosing alopecia in a pattern distribution, erosive pustular dermatosis, trichodysplasia of immunosuppression, and chemotherapy induced alopecia. i find myself leaning toward the “lumper” side of dermatopathology and am wary of too many “distinct” entities placed easily in a single category. specifically, i do not see the need for three different chapters addressing lichen planopilaris (lichen planopilaris, frontal fibrosing alopecia, and fibrosing alopecia in a pattern distribution), when the reader could be presented the different clinical patterns in a single chapter, and perhaps in a table format with distinguishing characteristics. likewise, folliculitis decalvans was included in the central centrifugal cicatricial alopecia chapter in the first edition. however, the authors dedicated a separate chapter to the condition in the second edition, although they do consider it a clinical pattern of central centrifugal cicatricial alopecia. additionally, i am thrilled to have been reminded of “erosive pustular dermatosis” and can suggest the diagnosis in the proper clinical setting. however, i am not sure that it is correctly included in the book of hair pathology and might be better placed in a chapter covering other findings from scalp biopsies for alopecia, such as alopecia neoplastica, angiosarcoma, seborrheic dermatitis, etc. should the authors feel the need for such a chapter. i also noticed that the authors now include descriptions of a few therapeutic options for several entities. while the authors do not overwhelm the text with this information, the inclusion of this information places the text in danger of seeming antiquated, should better treatments emerge in the future. of course, this might warrant a third edition. the new chapters addressing psoriatic alopecia and tnf-alpha inhibitor associated psoriatic alopecia are helpful and point out the importance of the location of eosinophils and plasma cells to distinguish the two (deeper in drug induced alopecia). the text also highlights important points that psoriatic alopecia can have eosinophils and is often treated before biopsy making epidermal changes unnecessary for the diagnosis. another important point made is that alopecia areata often presents without peribulbar inflammation. there are many useful points throughout the text that readers are certain to discover for themselves. fortunately, the authors retained the summaries of each condition at the end of each chapter, and even expanded the information provided. several of the summaries at the ends of the chapters for specific entities now include a list of “pitfalls” which is incredibly helpful and alone is a reason to purchase the new edition. i will check these before rendering a diagnosis regularly until i have these potential pitfalls committed to memory. suggestions for the next edition, should there ever be one, include a series of photos or drawings showing the phases of the hair cycle in sequence in the normal hair anatomy chapter. this seems to be a confusing concept that could be easily illustrated. i would love to have a series of algorithms, although they might be difficult to generate, as several entities share so many characteristics. overall, i recommend adding the new edition to the collection of anyone diagnosing alopecia, including dermatologists, dermatopathologists, and residents. dermatologists will benefit from owning this book, as it has wonderful clinical photos, and can be helpful when the histopathology does not ‘fit” the clinical impression, especially, the summary boxes addressing differential diagnoses and pitfalls. the book is relatively inexpensive, especially considering the book review | dermatol pract concept 2012;3(1):13 49 number of color photomicrographs it contains, as well as the invaluable text. in summary, when compared to the first edition, the second edition contains new chapters covering: psoriatic alopecia, tumor-necrosis factor-alpha inhibitor associated psoriasiform alopecia, folliculitis decalvans, fibrosing alopecia in a pattern distribution, erosive pustular dermatosis, trichodysplasia of immunosuppression, and chemotherapy induced alopecia. the second edition also includes a brief description of treatments for several entities. most importantly, the new edition contains many additional photos, with better clarity, and the summaries at the ends of the chapters now include potential pitfalls to avoid. dr. parsons practices dermatopathology at cutaneous pathology, wcp laboratories, maryland heights, mo. contact her at amycparsons@gmail.com. response to the review from the authors we thank dr. parsons for providing a thoughtful and detailed review. her positive comments touched upon all of the goals that we set out to accomplish with the second edition of the atlas. regarding the segregation of certain diagnostic entities into separate chapters, we, too, tend to be “lumpers” rather than “splitters.” like dr. parsons, we believe that frontal fibrosing alopecia is a subset of lichen planopilaris. we also feel that folliculitis decalvans is most often a manifestation of central, centrifugal, cicatricial alopecia. we subdivided conditions into separate chapters as a practical strategy for streamlining the search for information, rather than to imply a change of classification. we anticipate that the reader will consult the table of contents or the index to locate the relevant text, and, once there, will find our proposal that the conditions are clinical subsets within a larger group. we designed the brief “treatment” paragraph at the end of some sections to introduce clinicians and pathologists to primary therapeutic approaches. we meant it not to be a comprehensive discussion of therapeutic options. we envisioned rather that clinicians would use this information (and the referenced citations) as a starting point from which to launch their own investigation of current treatment modalities. dr. parsons alludes to the possibility of a third edition of the atlas. we incorporated many suggestions from readers while creating the second edition. we appreciate feedback from any readers who wish to make suggestions for the next edition! leonard c. sperling, m.d., professor of dermatology and pathology, chair of dermatology uniformed services university, bethesda, md, usa. leonard.sperling@usuhs.edu. shawn e. cowper, m.d., associate professor of dermatology and pathology yale university, new haven, ct, usa. shawn.cowper@ yale.edu. eleanor a. knopp, m.d., fellow in dermatopathology and clinical dermatologist yale university, new haven, ct, usa. eleanorknopp@gmail.com. final words by mark a. hurt, m.d., book review editor i thank my colleague, amy c. parsons, m.d., for her insightful and extensive review of this book, from both of which (the review and the book) i learned a great deal. i appreciate also that drs. sperling, cowper, and knopp were willing to respond to dr. parsons’s review. a. bernard ackerman, m.d., advocated that a new edition of a book should be a new book. in this vein, drs. sperling, cowper, and knopp have succeeded in spades in their desideratum to bring a tome of hair (and follicular) pathology to the front. in essence, this is a book that addresses the clinicopathological diagnosis of diseases that result in alopecia, and it provides a detailed guide to the histopathological criteria that aid dermatopathologists in establishing the diagnosis of specific types of alopecia. theirs is, indeed, a new book, and a very good one at that. this is a serious, well-written work with excellent photographs throughout and with tables outlining differentials, criteria for diagnosis, and capsule summations of each diagnosis. also, a “pitfalls” section follows each capsule summary. there are updated references throughout. the book is 216 pages with a glossary (pages 209-212) and an index (pages 213-216). there are 36 chapters, the first 7 of which address background information necessary to set the context of the specific alopecias, which follow. the authors provide each kind of alopecia its own chapter. there is no specific algorithm, but the authors group the chapters, as a rule, so that alopecias with a similar differential diagnosis are close to each other. the general layout is similar to the 1st edition but with the addition of chapters on psoriatic alopecia, drug-induced psoriatic alopecia, folliculitis decalvans, fibrosing alopecia in a pattern distribution, erosive pustular dermatosis, trichodysplasia of immunosuppression, and chemotherapy-induced alopecia. the authors increased the number of clinical photographs compared to the 1st edition—welcomed by this reviewer, who rarely sees patients clinically with these conditions. there is also a sizable increase in the number of histopathological photographs, also welcomed. almost all photographs are in color, are color balanced, well focused, and labeled with relevant figure legends. in december 2005, seven years ago, i reviewed the first edition of this book in dermatopathology: practical and con50 book review | dermatol pract concept 2012;3(1):13 ceptual. in that review, i was critical from two perspectives: 1) it lacked an algorithm, and 2) it relied primarily on the use of horizontal sections in the evaluation of alopecia, rather than using a combination of vertical and horizontal sections. both of these criticisms seem less important to me today, although an algorithm would still be a welcomed feature to the next edition. furthermore, there are a number of vertical sections added in this new edition; i am glad to see them. who should buy this book? it seems somewhat trite to say everyone who practices dermatopathology. yet, this is true. i know of no better source to study and think about the problems of alopecia from the perspective of a dermatopathologist in a relatively busy practice. the first edition of this book saved me hours of work by preparing my mind for these conditions. this new edition promises even more to the student serious about the diagnosis of alopecia. dr. hurt is the book review editor of dermatology practical and conceptual. he practices dermatopathology in maryland heights, mo, usa. contact him at markhurt@aol.com. observation | dermatol pract concept 2012;2(1):9 49 glomangiosarcoma in the shoulder of a 51-year-old man arvind rishi, m.d.1; felix dulanto, m.d.2; sheng chen, m.d., ph.d.1 1 department of pathology and laboratory medicine, hofstra north shore-lij school of medicine, new york, usa 2 family medicine program at glen cove hospital, hofstra north shore-lij school of medicine, new york, usa key words: glomangiosarcoma, glomangioma, glomus tumor, malignant glomus tumor citation: rishi a, dulanto f, chen s. glomangiosarcoma in the shoulder of a 51-year-old man. dermatol pract conc. 2012;2(1):9. http://dx.doi.org/10.5826/dpc.0201a09. editor: harald kittler, m.d. received: december 1, 2011; accepted: december 10, 2011; published: january 31, 2012 copyright: ©2012 rishi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sheng chen, m.d., ph.d., department of pathology, 6 ohio drive, suite 202, lake success, ny 11042. tel. 516-304-7279; fax. 516-304-7270. email: schen@nshs.edu. glomangiosarcoma is a very rare type of soft tissue neoplasm. here we report such a case in the shoulder of a 51-year-old man. abstract dermatology practical & conceptual www.derm101.com case report a 51-year-old white hispanic man presented with a pruritic lesion on the back of his left shoulder. he first noticed it about two months ago. the patient was otherwise well with no constitutional symptoms. his past medical history was unremarkable. family history was significant for having older siblings with malignancy, one with multiple myeloma and another with thyroid cancer. physical examination showed an overweight middle aged male with multiple small freckles, skin tags and nevi over his trunk and neck. a 1 cm pink, firm, rubbery, non-tender nodule was present on the back of left shoulder. there was no lymphadenopathy. a shave biopsy of the left shoulder lesion was performed. histopathological findings shave biopsy showed a cellular neoplasm with a multinodular growth pattern in the dermis (figure 1a). the neoplasm was very cellular and consisted of round, ovoid and spindle cells with moderate nuclear atypia and frequent mitotic figures (up to 6 per 10 hpf) (figure 1b–c). focal areas showing histopathological features of glomangioma such as perivascular arrangement were noted (figure 1d). immunohistochemistry showed that the neoplastic cells were positive for smooth muscle actin (sma), smooth muscle myosin heavy chain (smmh), vimentin, and focally positive for caldesmon and negative for cd31, cd34, ae1/3, desmin, hmb45, melan-a and s100. the neoplastic cells stained focally for p53. based on these histological and immunohistochemical findings, a diagnosis of glomangiosarcoma was rendered. 50 observation | dermatol pract concept 2012;2(1):9 term of malignant glomus tumor to described a lesion located deep to the achilles tendon in a 24-year-old female with severe and persistent right distal lower extremity pain that finally required an above-knee amputation [1]. the first case series of glomangiosarcoma was reported by gould et al in 1990. the authors presented six cases of locally aggressive glomus neoplasm and proposed a three-tier classification for these lesions, namely, locally infiltrative glomus tumor, glomangiosarcoma arising in a benign glomus tumor and de novo glomangiosarcoma [2]. aiba et al suggested using the term glomangiosarcoma when a sarcomatous component arises in the background of a pre-existing glomangioma [3]. rodríguez-justo et al reported a clinico-pathological review of 19 cases of glomangiosarcoma and de novo glomangiosarcoma, including their case of glomangiosarcoma arising in benign glomus tumor [4]. kreutz et al reported the first metastatic glomangiosarcoma in 1987 in a 33-year-old male with a large lesion found superficially on the thigh with metastasis to maxilla [5]. since then, a few more cases with metastaimaging studies, including whole body pet scan revealed no evidence of metastatic lesions. subsequently wide excision was performed and showed a 0.9 cm tumor involving the dermis and subcutis. cytogenetic analysis showed no chromosomal abnormality. discussion although glomangioma and glomus tumor and glomangiosarcoma and malignant glomus tumor have been used interchangeably in the literature, we recommend the use of glomangioma and glomangisarcoma for benign and malignant glomus neoplasms, respectively, simply for consistency of terminology. for example, we do not call leiomyosarcoma malignant leiomyoma or angiosarcoma malignant hemangioma. glomangiosarcoma is very rare. the first case was reported by lumley and stansfeld in 1972, who used the figure 1. shave biopsy shows a cellular multinodular neoplasm with surface ulceration (a) (h&e (hematoxylin and eosin, 2x). the neoplasm consists of sheets of ovoid-spindle cells (b) (h&e, 10x). the neoplastic cells are ovoid, spindle and epithelioid with frequent mitotic figures (c) (arrows indicating mitotic figures, h&e, 40x). focal glomangioma-like areas are noted in the peripheral of the lesion (d) (h&e, 20x). [copyright: ©2012 rishi et al.] a c b d observation | dermatol pract concept 2012;2(1):9 51 sis have been reported and outcome in most of them was lethal [5-7]. in 2001, folpe et al, after analysis of 52 cases of atypical and malignant glomus tumors, proposed an empirical classification and three diagnostic criteria for malignancy in glomus neoplasm, namely, (1) deep location and a size of more than 2 cm; or (2) presence of atypical mitotic figures; or (3) moderate to high nuclear atypia with five or more mitotic figures/50 hpf [8]. based on the proposed criteria, 32 out of the 52 cases were classified by folpe et al as malignant glomus tumor, while the rest either as symplastic glomus tumor, glomus tumor of uncertain malignant potential, or glomangimatosis. this empirical classification as well as the proposed diagnostic criteria, are adopted in the current who publication on tumors of soft tissue and bone [9], although further validation and refinement are clearly needed. in the case we presented here, although the lesion was small (0.9 cm in size) and superficially located, it was cellular with ovoid-spindle morphology, moderate nuclear atypia, and many mitotic figures. in our opinion, these features are those of glomangiosarcoma. however, we understand that observation of nuclear atypia is subjective. one may argue that the current lesion showed only mild nuclear atypia and thus, according to the criteria proposed by folpe et al, it would be classified as glomus tumor of uncertain malignant potential. actually the latter is not a diagnostic entity, but rather a descriptive term used for those lesions when one is not sure if it is gloomangiosarcoma or not. in the present case, even in the absence of significant nuclear atypia, we believe the histopathologic findings, namely, high cellularity, ovoid-spindle morphology and increased mitotic activity, are best interpreted as glomangiosarcoma. microscopically glomangiosarcoma varies depending on the degree of differentiation. well differentiated ones have histology similar to glomangioma except that there are frequent mitotic figures and presence of cytological atypia. poorly differentiated ones resemble high-grade sarcoma and a definite diagnosis based solely on morphology can be challenging. histological differential diagnoses include epithelial, myoepithelial, melanocytic and smooth muscle tumors. immunohistochemistry can be helpful in differential diagnosis. immunohistochemically, glomangiosarcoma is positive for vimentin, sma, smmh, and collagen iv and negative for epithelial, vascular, melanocytic and neural markers. although myoepithelial lesions express sma, they are also positive for other markers, such as epithelial markers and s100, which are negative in glomangiosarcoma. leiomyosarcoma expresses desmin and caldesmon, which are usually negative in glomangiosarcoma. the treatment for glomangiosarcoma is complete surgical excision. no radiation or chemotherapy is recommended at this time for primary, recurrent or metastatic disease, although their use had been reported by several authors [8,9]. references 1. lumley js, stansfeld ag. infiltrating glomus tumour of lower limb. br med j. 1972; 1:484–5. 2. gould ew, manivel jc, albores-saavedra j, monforte h. locally infiltrative glomus tumors and glomangiosarcomas. a clinical, ultrastructural, and immunohistochemical study. cancer. 1990; 65(2):310–8. 3. aiba m, hirayama a, kuramochi s. glomangiosarcoma in glomus tumor. an immunohistochemical and ultrastructural study. cancer. 1988; 61(7):1467–71. 4. rodríguez-justo m, aramburu-gonzález ja, santoja c. glomangiosarcoma of abdominal wall. virchows arch. 2001;438(4):418– 20. 5. kreutz rw, christensen re jr, fish lr. glomangiosarcoma with metastasis to the maxilla. int j oral maxillofac surg. 1987;16(1):116–8. 6. brathwaite cd, poppiti rj jr. malignant glomus tumor. a case report of widespread metastases in a patient with multiple glomus body hamartomas. am j surg pathol. 1996; 20(2):233–8. 7. watanabe k, sugino t, saito a, kusakabe t, suzuki t. glomangiosarcoma of the hip: report of a highly aggressive tumour with widespread distant metastases. br j dermatol. 1998;139(6):1097– 101. 8. folpe al, fanburg-smith jc, miettinen m, weiss sw. atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. am j surg pathol. 2001;25(1):1–12. 9. fletcher cdm, unni kk, mertens f (eds). pathology and genetics of tumors of soft tissue and bone. world health organization classification of tumors.lyon, france: iarc press; 2002. dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;2(4):10 41 quiz a 30-year-old male patient presented with a small, brown papule on the calf (figure 1). by dermatoscopy one can see radial lines in some segments at the periphery and skincolored and pink structureless zones (figure 2). what is your diagnosis? dermatoscopy: what is your diagnosis? philipp tschandl, m.d.1 1 department of dermatology, division of general dermatology, medical university of vienna, austria citation: tschandl p. dermatoscopy: what is your diagnosis? dermatol pract conc. 2012;2(4):10. http://dx.doi.org/10.5826/dpc.0204a10. copyright: ©2012 tschandl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: philipp tschandl, m.d., department of dermatology, division of general dermatology,medical university of vienna,währinger gürtel 18-20,1090 vienna, austria. tel. +43 1 40400 7700; fax. +43 1 408 19 28. email: philipp.tschandl@ meduniwien.ac.at. figure 1. (a ) clinical picture of a small brown papule. (b) clinical closeup. [copyright: ©2012 tschandl] a b figure 2. (a) dermatoscopically, prominent radial lines can be seen at the periphery and skin colored and pink structureless zones. (b) dermatoscopic closeup. [copyright: ©2012 tschandl]’ a b 42 quiz | dermatol pract concept 2012;2(4):10 answer to july 2012 quiz the correct answer to the dermatoscopy quiz in the july 2012 issue is spiradenoma. please see article 9 of this issue of dermatology practical and conceptual for a detailed description of this quiz case with dermatoscopic/dermatopathologic correlation (http:// dx.doi.org/10.5826/dpc.0204a09). please send your answer to dpc@derm101.com. the first correct answer will receive a complimentary copy of the book, dermatoscopy. an algorithmic method based on pattern analysis [facultas verlag, 2011]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):16 77 dermatology practical & conceptual www.derm101.com case report in 2006 an otherwise healthy 76-year-old woman presented to her general practitioner (gp) with a pigmented skin lesion on her right calf below the popliteal fossa. the gp took a 5 mm biopsy of this lesion, which was reported as a superficial spreading melanoma with a breslow thickness of 0.6 mm. there was a family history of a brother age 80 and a son aged 23 both succumbing to melanoma with cerebral metastases. the patient was referred to a surgeon and wide margin excision was discussed, but she declined to undergo surgery and subsequently purchased black salve via the internet, applying it to the melanoma under a closed dressing for 24 hours. this caused localized inflammation and ulceration, and the ulcer reportedly healed over a period of six to eight weeks. in 2011, five years later, when the patient presented for a routine skin check, a small dark blue firm nodule with surrounding skin discoloration was noticed on her right calf at the site of the biopsied melanoma (figure 1a). arrangements were made for an excisional biopsy, but the patient did not attend. five months later the patient re-presented with a fungating nodular lesion in the right calf (figure 1b). a provisional diagnosis was made of melanoma with a nodular component and after discussion with the patient she was referred to a surgeon for excision of the lesion and consideration of sentinel node biopsy. the patient did not attend these appointments but purchased black salve via the internet and applied it to the lesion. three weeks later the patient re-presented to her gp with a large eschar on her right calf that was removed to reveal an ulcer and a pink nodule with surrounding erythema. application of black salve to a thin melanoma that subsequently progressed to metastatic melanoma: a case study graham w. sivyer1 cliff rosendahl1 1 school of medicine, the university of queensland, australia keywords: black salve, melanoma, metastatic citation: sivyer gw, rosendahl c. application of black salve to a thin melanoma that subsequently progressed to metastatic melanoma: a case study. dermatol pract concept. 2014;4(3): 16. http://dx.doi.org/10.5826/dpc.0403a16 received: november 25, 2013; accepted: december 27, 2013; published: july 31, 2014 copyright: ©2014 sivyer et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: graham sivyer, mbbs(hons) fsccanz. email. graham.sivyer@ipnet.com.au this is a case study of a female patient diagnosed with superficial spreading melanoma who decided to treat the lesion by the application of a preparation known as black salve. persistence of the melanoma was documented five years later with subsequent evidence of metastatic spread to the regional lymph nodes, lungs, liver, subcutaneous tissues and musculature. a literature search has revealed one other case study of the use of black salve for the treatment of melanoma. abstract 78 observation | dermatol pract concept 2014;4(3):16 in february 2013 (i.e., seven years after her original presentation with melanoma) the patient developed edema of her right lower leg and consulted with a different gp who referred her to a different surgeon. this surgeon found a hard craggy mass in her right inguinal region and was of the opinion that the mass was responsible for the lower leg edema by virtue of pressure on the inguinal veins and lymphatics. the patient agreed to surgical removal of the 60 x 50 mm fungating lesion on her right calf with a split skin graft to cover the defect. she also agreed to a fine needle aspiration (fna) of the mass in her right groin. histopathology of the mass removed from the right calf revealed ulcerated nodules of metastatic or in-transit malignant melanoma with apparent complete local excision. the fna of her right groin revealed histological appearances consistent with a melanoma deposit in a lymph node. four months later a nodular lesion on the scalp, which the patient regarded as a cyst (figures 1c and 1d), was removed surgically and histology revealed melanocytic proliferation with numerous dermal mitoses consistent with a metastatic deposit. the patient agreed to radiotherapy in an attempt to shrink the right inguinal mass to relieve the peripheral edema of figure 1. (a) a nodule on the right calf where a biopsy five years earlier discovered thin invasive melanoma; (b) image of the site shown in figure 1a five months later; (c) metastatic melanoma skin deposit on the scalp; (d) dermatoscopy image of the lesion shown in figure 1c. [copyright: ©2014 sivyer et al.] figure 2. pet ct scan of the chest showing lesions consistent with metastatic melanoma in the right lung. [copyright: ©2014 sivyer et al.] her right leg and underwent a course of 10 treatments with subsequent partial resolution of the edema. in august 2013 the patient agreed to further investigations and a ct pet scan was performed. this revealed lesions consistent with metastatic melanoma “…involving the lungs, liver, right groin, subcutaneous tissues and musculature…” (figure 2). evidence of persistent disease has continued with a large mass arising adjacent to the site of the original tumor on the right calf, photographed in november 2013 (figure 3). observation | dermatol pract concept 2014;4(3):16 79 conclusions one other case of black salve being used to treat melanoma has been reported in the literature. the male patient in that case treated a nodule on the right chest wall with the application of black salve. because the lesion continued to grow and ulcerate, he presented to a hospital emergency department eight months following the initial black salve application. biopsy of the lesion at that time confirmed melanoma. a ct scan showed a nodule in the lung, but metastatic melanoma was not confirmed histologically in that case study [1]. the exact composition of black salve varies but common ingredients are zinc chloride and powdered bloodroot from the bloodroot plant, sanguinaria canadensis [2]. during the 1930’s to 1950’s a similar compound was used by dr. fred mohs to fix tissue prior to surgical excision but this method has subsequently been replaced by fresh tissue excision [2]. mohs’ original formula included zinc chloride, bloodroot and antimony sulphide [3]. the ingredient zinc chloride is a strong escharotic and has been used for the debridement of chronic leg ulcers and for chemo-surgical debridement of osteolytic bone [4]. the other major ingredient sanguinaria canadensis is a perennial flowering plant native to north eastern america and the ingredient is known colloquially as bloodroot, indian paint and redroot [2]. when the root is harvested and cut, a red liquid drains which thickens to a paste. this paste is also a strong escharotic and has been used by indigenous americans to treat warts, polyps and moles [2]. the active ingredient in the bloodroot rhizome is a benzyl isoquinolone alkaloid [bia]. bia’s are a diverse group of specialized plant metabolites that includes approximately 2,500 known structures including the narcotic analgesics morphine and codeine. sanguinarine contains antimicrobial properties [5], and invitro studies show that it also contains potent anti-cancer properties [6]. a recently published research article has shown that sanguinariine is a rapid inducer of melanoma caspasedependent cell death that is mediated by oxidative stress [7]. figure 3. a photograph taken in november 2013, seven years after a thin melanoma on the patient’s right calf was treated with black salve, shows a large ulcerated mass adjacent to a skin graft marking the site of local excision performed in february 2013. [copyright: ©2014 sivyer et al.] despite arguable molecular rationale for the topical application of these natural compounds, preclinical and clinical data in this field are still scant and no controlled clinical trial has yet been published demonstrating any relevant clinical efficacy. one brand of black salve, cansema (manufacturer omega alpha labs), is marketed on the internet as “…a miraculous product with a miraculous history with roots that go back to the late 19th century.” the advertisement goes on to state: “only suppression and greed have prevented its enormous benefits from being made available to the mainstream” [8]. many testimonials praising the results of cansema are also listed on the internet [9]. it is likely that some patients researching cancer treatments on the internet might not be aware that testimonials are not valid scientific proof. it has been argued by one author that “when they read that the mohs technique offers the highest known cure rate for skin cancer and that the salve for sale is identical to dr. mohs’ original formula it is fair to assume that some will infer that the salve available for sale produces the stated cure rates” [3]. the australian government has issued warnings to consumers about the use of black and red salves in treating cancer and, in an authoritative warning, states, “the tga is not aware of any credible, scientific evidence which shows that any black or red salve preparation is effective in treating cancer” [10]. the case presented here involves a patient who, having had an initial diagnosis of thin invasive melanoma, decided to follow the option of an alternative cancer treatment rather than conventional evidence based treatment. the reason the patient gave for seeking alternative treatment in 2006 was the cost of immediate surgical management in the australian private health system. when she failed to attend this private appointment, her gp contacted her. the gp then arranged for her to be seen in the local public hospital at no cost, though there was going to be a delay of a couple of weeks for the appointment. once again the patient did not attend this appointment. at that time the patient was reportedly also encouraged by an acquaintance to use black salve. it is speculation, but perhaps having witnessed the death of her brother at age 80 and her own son at age 23 from cerebral metastatic melanoma, the patient was in denial of her own disease. as it turned out, there was a time delay of seven years before she agreed to conventional management of her melanoma. during this time there were consultations with three gps, three surgeons, one dermatologist, one radiologist and an oncologist. the patient exercised the undisputed right to follow the treatment regimen of personal choice. over a period of seven years the disease progressed both locally and systemically. it is not known whether distant metastases were already present at the time of original diagnosis, but based on 80 observation | dermatol pract concept 2014;4(3):16 the staging of the tumor (stage 1), the prognosis for 10-year disease-free survival was 87.9% [11]. ten-year survival prognosis for stage 4 melanoma (lung metastases) is 2.5% [11]. we believe it is essential that patients are adequately informed about evidence-based treatment and warned about the potential adverse consequences associated with an alternative treatment regimen but we also believe that support should continue to be provided regardless of choices made. references 1. cienki jj, zaret l. an internet misadventure: bloodroot salve toxicity. j altern complement med. 2010;16(10):1125-7. 2. mohs fe. origins and progress of mohs micrographic surgery. in: mikhail gr (ed.). mohs micrographic surgery. philadelphia: wb saunders,1991:1-3. 3. elston dm. escharotic agents, fred mohs, and harry hoxsey. j am acad dermatol. 2005;53:523-5. 4. jellinek n. escharotic and other botanical agents for the treatment of skin cancer: a review. j am acad dermatol. 2005;53:487-95. 5. mitscher la, park yh, clark d, et al. antimicrobial agents from higher plants. an investigation of hunnemannia fumariaefolia. pseudoalcoholates of sanguinarine and chelerythrine. lloydia. 1978;41; 145-50. 6. han mh, park c, clark d, et al. apoptosis induction of human bladder cancer cells by sanguinarine through reactive oxygen species-mediated up-regulation of early growth response gene-1. plos one. 8 [5]:e63425. doi: 10.1371/journal.pone. 0063425 7. burgeiro a. bento a, gajate c, et al. rapid human melanoma cell death induced by sanguinarine through oxidative stress. eur j pharmacol. 2013;705(1-3): 109-18. 8. cansema. www.altcancer.com /cansema htm. accessed october 20, 2013. 9. cansema. www.altcancer.com. accessed october 20, 2013. 10. australian government. department of health and ageing therapeutic goods administration. black and red salves in treating cancer. www.tga.gov.au/safety/alerts-medicine-black-salve-120203. htm. accessed october 20, 2013. 11. aitken jf, barbour a, burmeister b, et al. clinical practice guidelines for the management of melanoma in australia and new zealand. sydney, australia: cancer council australia; australian cancer network; ministry of health, new zealand. 2008:159. observation | dermatol pract concept 2016;6(3):9 47 dermatology practical & conceptual www.derm101.com case presentation a 72-year-old man with a history of melanoma in situ presented for his regular follow-up visit. the routine clinical examination revealed a pinkish-red nodule on the lower back. the nodule was not present in the previous visit held six months earlier (figures 1, a and b). the dermoscopic examination revealed a nonpigmented lesion characterized by a polymorphous vascular pattern, consisting of dotted and short curved linear vessels on a redpinkish background. the latter unspecific pattern did not allow a definite diagnosis, prompting us to excise the nodule (figure 2). on low power examination the lesion was well circumscribed and involved the reticular dermis (figure 3a). at higher magnification, the extensive myxoid change was evident; cellularity was inconspicuous and vascularity consisted of small, thin-walled vessels (figure 3b). the findings were diagnostic of superficial angiomyxoma. conclusions sa was initially described by carney et al. in 1985 in association with carney’s complex syndrome, a rare autosomal dominant disorder characterized by neoplasia involving the heart, central nervous system, and endocrine organs. in 1998 allen et al. reported several cases of sa without evidence of carney’s complex. in 1999 calonje et al. reported the clinicopathological and immunohistochemical features of sa as an independent disease [1,5]. in 2014 green et al. reported the superficial angiomyxoma of the skin alvaro abarzúa-araya1 aimillios lallas2 simonetta piana3 caterina longo2 elvira moscarella2, giuseppe argenziano4 1 department of dermatology, facultad de medicina, pontificia universidad católica de chile, santiago, chile 2 skin cancer unit, arcispedale santa maria nuova irccs, reggio emilia, italy 3 pathology unit, arcispedale santa maria nuova irccs, reggio emilia, italy 4 dermatology unit, second university of naples, naples, italy key words: superficial angiomyxoma, angiomyxoma, cutaneous tumor, dermoscopy citation: abarzúa-araya a, lallas a, piana s, longo c, moscarella e, argenziano g. superficial angiomyxoma of the skin. dermatol pract concept 2016;6(3):9. doi: 10.5826/dpc.0603a09 received: march 13, 2016; accepted: may 2, 2016; published: july 31, 2016 copyright: ©2016 abarzúa-araya et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aimillios lallas, md, skin cancer unit, arcispedale santa maria nuova, viale risorgimento 80, 42100, reggio emilia, italy. tel. 00390522295611; fax. 00390697625822. e-mail: emlallas@gmail.com superficial angiomyxomas (sa) of the skin are rare benign cutaneous tumors of soft tissue composed of prominent myxoid matrix and numerous blood vessels. sa are more common in males [1] and they are usually located on the trunk but can also appear on the lower limbs, head, neck and genitalia [2,3]. treatment is surgical, the total excision is curative, but local recurrence is possible [4]. herein we present a 72-year-old patient with a history of melanoma in situ, with a new lesion on the lower back. abstract 48 observation | dermatol pract concept 2016;6(3):9 dermoscopic features of sa for the first time and described “the red planet sign”—a red, translucent, globular exophytic lesion with arborizing vessels that looks like a blood moon during recent lunar eclipses [6]. in contrast, in our case, the patient presented with a pinkish-red nodule on the lower back, not a polypoid lesion. additionally, dermoscopy did not show the red planet sign, thus we believe that this sign may be highly unspecific or anecdotic. we did not perform an echocardiogram or other tests because our patient lacked skin pigmentation, mucosal lesion, other cutaneous tumors or family history of myxomas. although spitz nevus and amelanotic melanoma come first in the list of differential diagnoses of nonpigmented nodular lesions displaying predominantly dotted vessels under dermoscopy, several other less common tumors might exhibit a similar pattern. our case suggests that sa should be added in this list. however, since these dermoscopic findings are highly unspecific, a nodule dermoscopically characterized by predominantly dotted vessels should be promptly excised to rule out melanoma. figure 1. superficial angiomyxoma. clinical images. [copyright: ©2016 abarzúa-araya et al.] a b figure 2. superficial angiomyxoma. dermoscopic image. [copyright: ©2016 abarzúa-araya et al.] figure 3a & b. superficial angiomyxoma. histologic images. [copyright: ©2016 abarzúa-araya et al.] a b observation | dermatol pract concept 2016;6(3):9 49 4. diniz g, temir g, ortac r. angiomyxoma: always myxoid, sometimes aggressive. turk patoloji derg. 2012;28(2):162-4. pmid: 22627635. doi: 10.5146/tjpath.2012.01116. 5. calonje e, guerin d, mccormick d, fletcher cd. superficial angiomyxoma: clinicopatologic analysis of a series of a distinctive but poorly recognized cutaneous tumors with tendency for recurrence. am j surg pathol. 1999;23(8):910-7. pmid: 10435560. 6. green m, logemann n, sulit dj. myxoid stroma and delicate vasculature of a superficial angiomyxoma give rise to the red planet sign. dermatol online j. 2014;20(9). pmid: 25244175. references 1. lee cc, chen yl, liau jy, chen ca, cheng wf. superficial angiomyxoma on the vulva of an adolescent. taiwan j obstet gynecol. 2014;53(1):104-6. pmid: 24767658. doi: 10.1016/j. tjog.2013.08.001. 2. rodríguez-vásquez m, garcía-arpa m, delgado m, et al. angiomixoma superficial. actas dermosifiliogr. 2005;96(5):311-4. pmid: 16476394 3. nakamura m, tokura y. superficial angiomyxoma on the scrotum of a child. pediatr dermatol. 2011;28(2):200-1. pmid: 21504453. doi: 10.1111/j.1525-1470.2011.01389.x. observation | dermatol pract concept 2011;1(1):14 69 cutaneous pigmented invasive squamous cell carcinoma: a case report with dermatoscopy and histology cliff rosendahl, mbbs1, alan cameron, mbbs1, agata bulinska, m.d.1, david weedon, m.d.2 1school of medicine, the university of queensland, brisbane, australia 2sullivan and nicolaides pathology, brisbane, australia key words: pigmented, squamous cell carcinoma, invasive, dermatoscopy, histology citation: rosendahl c, cameron a, bulinska a, weedon d. cutaneous pigmented invasive squamous cell carcinoma: a case report with dermatoscopy and histology. dermatol pract concept 2011;1(1):14. http://dx.doi.org/10.5826/dpc.0101a14. editor: alon scope, m.d. received: january 27, 2011; accepted: june 21, 2011; published: october 31, 2011 copyright: ©2011 rosendahl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, po box 734, capalaba, queensland, australia, 4157. email: cliffrosendahl@bigpond.com. introduction cutaneous invasive pigmented squamous cell carcinoma (scc) is rare. there have previously been only a few case reports or small case series in the english literature [1-13]. in the largest published study there were five cases of pigmented invasive scc in 46,791 archived cases of invasive scc (approximately 0.01%) [2]. this compares to pigmented scc in-situ (pigmented bowen’s disease) in which the largest study found 52 of 951 (5.5%) consecutive cases of scc in-situ to be pigmented [14]. the differential diagnosis of pigmented invasive scc includes benign and malignant melanocytic neoplasms (melanoma and nevus) as well as pigmented types of benign and malignant epithelial neoplasms such as basal cell carcinoma (bcc), actinic keratosis (ak), scc in-situ, seborrheic keratosis and melanoacanthoma [1, 12]. our search has revealed five cases of pigmented invasive scc with a description of dermatoscopy features [1, 9, 10, 12, 13] and in none of those cases was the diagnosis predicted. case report an 80 year-old man with fitzpatrick type 2 skin, presented for a routine skin check. a new raised pigmented skin lesion 6 mm in diameter was discovered on his right cheek (figure 1). it had not been observed at his previous examination six months earlier. the patient migrated to australia at the age of 21. he had a long history of both occupational (bulldozer driver) and recreational (weekend fisherman) sun exposure. the past medical history of this patient included the treatment of multiple histopathologically confirmed skin malignancies including scc, scc in-situ, bcc, ak and one in-situ melanoma. none of the treated non-melanoma skin cancers had been pigmented. the majority of these skin lesions were on the head, neck and upper limbs with a minority on the back and lower limbs. close macroscopic examination of the lesion on his right cheek (figure 1) revealed that there was prominent surface scale overlying the posterior portion. a bluish discoloration was observed within the lesion; the clinician considered dermatology practical & conceptual www.derm101.com 70 observation | dermatol pract concept 2011;1(1):14 the source of this discoloration as the presence of melanin pigmentation. a smaller amount of scale was also present on peri-lesional skin. the lesion was raised and palpation revealed that it was nodular and slightly tender. the surface of the lesion was tape-stripped to remove surface scale and examined with a non-polarizing dermatoscope. a photograph was taken (figure 2) with a nonpolarizing dermlite fluid dermatoscope (3-gen, san juan capistrano, ca) coupled to a canon 50d single lens reflex camera(canon, tokyo, japan). dermatoscopic features are described according to revised pattern analysis [15, 16]. dermatoscopically (figure 2) the peri-lesional skin was white in between the red vascular plexus. the overall pattern of the lesion was structureless. the anterior (figure 2, right side) part of the lesion was blue superiorly with blue and white inferiorly and in these parts linear, serpentine, and coiled vessels were seen. posteriorly (figure 2, left side), denser blue pigment partially obscured the vessels. as an additional clue two white circles were present dermatoscopically (arrows, figure 2). the peripheral borders of the lesion blended into peri-lesional skin without sharp demarcation. the lesion was excised in toto. it was signed out by the reporting pathologist as a “focally pigmented, moderately well differentiated acantholytic squamous cell carcinoma extending to mid-dermis.” (figures 3–5). discussion a search of the literature reveals five previous reports with the dermatoscopic features of pigmented invasive scc [1, 9, 10, 12, 13]. in 1997 kossard et al reported a case of a 79-year-old man with a 5 mm pigmented invasive scc of the ear [1]. figure 1. clinical and macroscopic image of a raised pigmented lesion on the right cheek. figure 2. dermatoscopic view of the lesion shown in figure 1. arrows point to white circles. figure 3. histologic view (low power) of the lesion shown in figures 1 and 2 shows invasive squamous cell carcinoma with aggregations of neoplastic keratinocytes, signs of abnormal cornification (eosinophilic cytoplasm and numerous dyskeratotic cells) and prominent acantholysis. figure 4. additional low power histologic view. observation | dermatol pract concept 2011;1(1):14 71 they described the epiluminescent microscopy findings of “... a diffuse grey-blue colour, but the nodule lacked a peripheral pigment network and had no evident milia-like cysts.” they considered a differential diagnosis of nodular melanoma, pigmented bcc, irritated seborrheic keratosis and thrombosed hemangioma. in 2003 ohnishi et al reported a case of a 91-year-old man with a deeply pigmented ulcerated scc on the cheek [9]. inspection of the dermatoscopic images presented revealed an asymmetric structureless lesion with the added clue to malignancy of the color blue [17]. there was no recorded prediction of the diagnosis in this case. in 2004 zalaudek et al reported a case on the chest of an 80-year-old white male [10]. inspection of the dermatoscopic image presented showed a structureless blue lesion with white and grey areas corresponding to surface scale. the authors advised about the presence of ulceration but this is not evident in the dermatoscopic image. they considered the differential diagnosis of melanoma and pigmented bcc but not pigmented scc. in 2009 di giorgi et al reported a case on the upper lip of a 45-year-old woman [12]. dermatoscopically there were no blue structures but there was a central red and brown structureless area with radial lines at the periphery in a circumferential distribution. in this case a dermatologist had previously made a diagnosis of seborrheic keratosis. after dermatoscopic assessment the authors made a provisional diagnosis of a “suspect melanocytic lesion.” also in 2009, yoshida et al reported a 2.2 x 1.5 cm pigmented scc on the nose of a 101-year-old japanese woman [13]. they published dermatoscopic images which revealed a centrally ulcerated lesion with serpentine vessels and bordering the ulceration, a structureless pigmented area displaying predominantly blue color with some brown. blue radial lines project focally at the periphery. in the case we present here malignancy was predicted on the basis of the “chaos and clues” algorithm [17]: there was “chaos” (asymmetry) and the clues of “eccentric structureless zone (blue)” and “polymorphic vessels.” of the three pigmented malignancies (pigmented melanoma, pigmented bcc, and pigmented scc), pigmented scc should be considered because of the presence of surface scale (seen macroscopically) and white circles (seen dermatoscopically). the blue color was not consistent with pigmented scc in-situ; the color blue indicated the presence of melanin in the deep dermis [18]. therefore, invasive pigmented scc was considered, and this was confirmed histopathologically. conclusion pigmented cutaneous invasive scc is uncommon with few reports in the literature. four out of five previously reported cases with dermatoscopy had a blue structureless zone. the case we report, like previous cases, had clues to malignancy and in this case these included asymmetry, a blue structureless zone and polymorphic vessels. the presence of surface scale and the presence of white circles may be clues to squamous cell carcinoma. the dermatoscopic finding of white circles as a clue to invasive squamous cell carcinoma needs to be confirmed with the study of more cases. references 1. kossard s,  cook d. pigmented squamous cell carcinoma with dendritic melanocytes. australas j dermatol 1997;38(3):145-7. 2. morgan mb, lima-maribona j, miller ra, et al. pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases. j cutan pathol 2000;27(8):381-6. 3. jurado i, saez a, luelmo j, et al. pigmented squamous cell carcinoma of the skin. report of two cases and review of the literature. am j dermatopathol 1998;20(6):578–81. 4. matsumoto m, sonobe h, takeuchi t, et al. pigmented squamous cell carcinoma of the scrotum associated with a lentigo. br j dermatol 1999;141(1):132–6. figure 5. high power view of boxed area in figure 3 showing abnormal keratinocytes with large nuclei and prominent nucleoli, dyskeratotic cells, melanin (arrows) and acantholysis. 72 observation | dermatol pract concept 2011;1(1):14 5. kamiya m, maehara r, iizuka s, et al. pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal. pathol int 1999;49(10):909–12. 6. chapman ms, quitadamo mj, perry ae. pigmented squamous cell carcinoma. j cutan pathol 2000;27(2):93–5. 7. shields ja, shields cl, eagle rc jr, singh ad, demirci h, wolf ma. pigmented conjunctival squamous cell carcinoma simulating a conjunctival melanoma. am j ophthalmol 2001;132(1):104–6. 8. terada t, yamagami j, fugimoto a, tanaka k, sugiura m. pigmented squamous cell carcinoma of the cheek skin probably arising from solar keratosis. pathol int 2003;53(7):468–72. 9. ohnishi t, nakai k, nagayama t, sasaki m, suzuki t, watanabe s. pigmented squamous cell carcinoma of the skin. report of a case with epiluminescence microscopic observation. br j dermatol 2003;149(6):1292-3. 10. zalaudek i, citarella l, soyer hp, hofmann-wellenhof r, argenziano g. dermoscopy features of pigmented squamous cell carcinoma: a case report dermatol surg 2004;30(4 pt 1):539-40. 11. satter ek. pigmented squamous cell carcinoma. am j dermatopathol 2007;29(5):486-9. 12. de giorgi v, alfaioli b, papi f, et al. dermoscopy in pigmented squamous cell carcinoma. j cutan med surg 2009;13(6):326-9. 13. yoshida y, yamasaki a, shiomi t, suyama y, nakayama b, yamamoto o. ulcerative pigmented squamous cell carcinoma in a 101-year-old japanese woman. j dermatol 2009;36(4):241-4. 14. cameron a, rosendahl c, tschandl p, riedl e, kittler h. dermatoscopy of pigmented bowen›s disease. j am acad dermatol 2010;62(4):597-604. 15. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual 2007;13(1):3. 16. kittler h, riedl e, rosendahl c, cameron a. dermatoscopy of unpigmented lesions of the skin: a new classification of vessel morphology based on pattern analysis. dermatopathology: practical & conceptual 2007;14(4):3. 17. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and non-melanocytic pigmented lesions. j am acad dermatol 2011;64(6):1068-73. 18. weismann k, lorentzen hf. dermoscopic color perspective. arch dermatol 2006;142(9):1250. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):4 29 dermatology practical & conceptual www.derm101.com introduction herpetic eczema (he), also known as kaposi varicelliform eruption, is the dissemination of the herpes simplex virus in the same area of a pre-existing skin disease. hailey-hailey disease (hhd), or benign familial pemphigus, is autosomal dominant and manifests through erythematous plaques with flaccid blisters that rupture easily. it results in superficial linear erosions with crusts and maceration in intertriginous areas. the coexistence between he and hhd is a rare condihailey-hailey disease associated with herpetic eczema—the value of the tzanck smear test thomás de aquino paulo filho1, yara kelly rodrigues defreitas1, mylenne torres andrade da nóbrega1, carlos bruno fernandes lima1, barbara luiza medeiros francelino carriço1, maria aurora pinto leite e silva1, filipe lauria paulo1, pedro bezerra da trindade neto1 1 department of clinical medicine, dermatology center, rio grande do norte university, natal, brazil keywords: benign familial pemphigus, kaposi varicelliform eruption, hailey-hailey disease citation: paulo filho ta, defreitas yk, da nóbrega mt, lima cb, carriço bf, leite silva ma, lauria paulo f, trindade neto p. haileyhailey disease associated with herpetic eczema—the value of the tzanck smear test. dermatol pract concept. 2014;4(4):4. http://dx.doi. org/10.5826/dpc.0404a04 received: august 8, 2014; accepted: september 11, 2014; published: october 31, 2014 copyright: ©2014 paulo filho et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: thomas de aquino paulo filho, md, 240, deodoro avenue, 59012600, natal, rn, brazil. email: thomasfi@uol.com.br background: herpetic eczema is a herpetic superinfection of a preexisting skin disease. hailey-hailey disease is an autosomal dominant dermatosis that is clinically characterized by flaccid vesicles and rashes in intertriginous areas. the coexistence of those findings is a rare condition; only five cases have been published in literature. purpose: to report the rare coexistence between hailey-hailey disease and herpetic eczema and to highlight the importance of cytology for a quick diagnosis. case report: a 38-year-old man had been diagnosed with hailey-hailey disease for 13 years. his condition evolved into what could be herpetic eczema, which was later confirmed by skin cytology and histopathology. the man showed remission in the infection after 10 days under treatment with acyclovir. conclusion: research on the concomitance of infection by the herpes virus must be performed in the exacerbations of hailey-hailey disease, and, in those situations, the quick diagnosis through skin cytology makes the early treatment possible. abstract 30 observation | dermatol pract concept 2014;4(4):#4 tion with only five cases that have been described in literature [1,2]. the diagnosis should be clinically suspected as the showing up of monomorphic eruption of vesiculopustules in the areas that had previously been affected by the underlying disease. the diagnosis is confirmed by viral culture, direct immunofluorescence, polymerase chain reaction (pcr) procedure or by skin cytology (tzanck test); the last one is a rapid and practical method that shows giant viral multinucleated cells, which is an indirect piece of evidence of the presence of herpetic infection [1,2,3,6]. case report a 38-year-old male single driver has been diagnosed with hailey-hailey disease, which has affected his axillary and inguinal regions for 13 years. three months prior, he was being treated with acitretin 50 mg/day and desonide 0.05% alternating with tacrolimus 0.1% topically in the areas of exacerbation of lesions. a burning sensation, followed by redness, vesicles and subsequent ulcers in the inguinal region for about two days was reported. physical examination showed vesiculopustules and areas with ulcerations in the inguinal region (figure 1). skin cytology showed giant viral multinucleated cells and characteristic changes of the underlying disease—acantholytic cells, not only parabasal ones, but also those from upper layers of the epidermis, giving them the aspect of “crumbling wall” (figure 2). histopathology confirmed the diagnosis of hailey-hailey disease and herpetic eczema (figure 3). the treatment with acyclovir 400 mg three times daily for ten days was recommended with complete remission of the herpetic condition (figure 4). discussion hhd was first described in 1939. it normally appears in the third or fourth decade of a person’s life, but it may occur at any age. it is a rare entity, and a person may have multiple figure 1. presence of vesicopustules and ulcerations in an erythematosus base in the inguinal region. (copyright: ©2014 paulo filho et al.) figure 2. giant multinucleated cells and acantholytic cells in the same slide. giemsa stain, at 400x. (copyright: ©2014 paulo filho et al.) figure 3. (a) intraepidermal suprabasal acantholytic blisters with dyskeratosis of keratinocytes. (b) giant multinucleated cells. h&e, at 400x. (copyright: ©2014 paulo filho et al.) observation | dermatol pract concept 2014;4(4):4 31 relapses and remissions of the disease [1,4]. it occurs due to mutations on the atpc21 gene that causes failure in keratinocyte adhesion. the epidermal defect leads to spontaneous acantholysis or it might occur as a result of friction or infections [1]. infections caused by herpes simplex virus may lead to exacerbation of the lesions [2]. he is a viral infection caused by herpes simplex (potentially fatal) that appears in preexistent conditions such as atopic and contact dermatitis, darier disease, pemphigus, pityriasis rubra pilaris, skin lymphoma, and benign familial pemphigus among others. the risk factors in the pathogenesis include rupture of the epidermal barrier and the use of topical calcineurin inhibitors; some authors also describe the topical use of corticosteroids [2,5]. our patient appeared to be susceptible to the development of the condition presented since he had the main risk factors. the diagnosis of coexistence of those findings may be reached in a reliable way through skin cytology, which is a simple, quick and viable method that shows sensitivity higher than 80%, making the establishment of early treatment possible. to confirm he, the presence of giant viral multinucleated cells that might contain inclusion bodies is necessary. on the other hand, the parabasal and upper layers of the skin acantholytic cells may be observed, having the aspect of “crumbling wall” [1,3]. the current therapeutic strategies for hhd aim to reduce outbreaks and improve the patients’ quality of life. oral retinoids, antibiotics, corticosteroids, cyclosporine, topical vitamin d analogues, calcineurin inhibitors, botulinum toxin, surgical excision and co2 lasers may be utilized [4]. upon the occurrence of he, the treatment must be promptly provided. the early use of antiviral drugs—acyclovir, famciclovir and valacyclovir—is extremely important in order to avoid potentially fatal complications [1,2]. thus, it is important to stress the possibility of concomitant infection by the herpes virus in the frequent exacerbations of hailey-hailey disease and, in those cases, the quick diagnosis through skin cytology will allow the initiation of early treatment in order to avoid complications that can be potentially fatal. references 1. lee gh, kim ym, lee sy, et al. a case of eczema herpeticum with hailey-hailey disease. ann dermatol. 2009; 21:311-4. 2. olson j, robles dt, kirby p, colven r. kaposi varicelliform eruption (eczema herpeticum). 2008;14:18. 3. ruocco e, brunetti g, del vecchio m, ruocco v. the practical use of cytology for diagnosis in dermatology. jeadv. 2011; 25:125–9. 4. berger em, galadari hi, gottlieb ab. successful treatment of hailey-hailey disease with acitretin. j drugs dermatol. 2007; 6:734-6. 5. wollenberg a, zoch c, wetzel s, plewig g, przybilla b. predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. j am acad dermatol 2003;49:198-205. 6. paulo filho ta. citodiagnóstico prático em dermatologia. a pele. 2006;37:6. figure 4. post-treatment (presence of erythema with no signs of vesicopustules). (copyright: ©2014 paulo filho et al.) dermatology: practical and conceptual editorial | dermatol pract concept 2014;4(3):5 33 dermatology practical & conceptual www.derm101.com is aggressive digital papillary adenocarcinoma (adpa) really aggressive? does it only occur at digital location? does it always have microscopic papillary features? is it really adenocarcinoma? let’s us address these questions one by one. is adpa aggressive? from the term, namely, aggressive digital papillary adenocarcinoma, one would interpret this as high grade malignant tumor with grim prognosis. is this the case? let’s answer this question with historical literature review. in 1979 helwig from the armed force institute of pathology introduced a term called aggressive digital papillary adenoma and presented 22 cases under this term at the american academy of clinical and pathologic conference in chicago [1]. a brief written description of these cases was found as differential diagnosis in an article entitled “eccrine acrospiroma” published in 1984 [2]. helwig described the so-called aggressive digital papillary adenoma by these words: “i presented 22 examples of aggressive digital papillary adenoma of which 21 occurred on the digits and one on the sole… microscopically, nests and masses of cuboidal to columnar cells irregularly infiltrate the collagenous stroma. usually, pleomorphism is minimal. the epithelial patterns vary from solid foci to a more common picture of repeated acinar or glandlike structures fused into larger masses. the gland-like structures have minute or, occasionally, large lumens and often show a papillary configuration. small foci of squamous differentiation may occur. thirteen of the 22 tumors recurred at least once, some extended into subjacent bone and, occasionally, amputation of the digit was required. two tumors metastasized, one to the lung.” [2] as one can see from what was described, these lesions, some of them with recurrences and even metastasis, were not adenomas but carcinomas. for reasons unknown, helwig did not make straightforward diagnosis of these lesions as carcinoma even in the presence of metastasis, instead he called them “aggressive” adenoma. the term “aggressive” adenoma was used here by helwig to describe a lesion considered by him as an adenoma but showing recurrences and metastasis. in other word, if this lesion was called carcinoma, then the word “aggressive” would be redundant, since recurrence and metastasis are expected for carcinomas. decades later when these lesions were called rightly by duke et al. (also from armed force institute of pathology) as carcinomas, namely, aggressive digital papillary adenocarcinoma [3], the word “aggressive” was not removed and it remained in the term up to today. with the word “aggressive” remaining in the term, it gives a wrong impression that the lesion under consideration is aggressive digital papillary adenocarcinoma really aggressive digital papillary adenocarcinoma? sheng chen1, masoud asgari2 1 department of pathology & dermatology, hofstra north shore-lij school of medicine, new york, usa 2 department of pathology & laboratory medicine, staten island university hospital, staten island, new york, usa citation: chen s, asgari m. is aggressive digital papillary adenocarcinoma really aggressive papillary adenocarcinoma? dermatol pract concept. 2014;4(3):5. http://dx.doi.org/10.5826/dpc.0403a05 received: may 24, 2014; accepted: june 2, 2014; published: july 31, 2014 copyright: ©2014 chen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: sheng chen, md, phd, department of pathology & dermatology, hofstra north shore-lij school of medicine, 6 ohio drive, suite 202, lake success, ny 11042, usa. tel. 516-304-7284; fax. 516-304-7270. email: schen@nshs.edu 34 editorial | dermatol pract concept 2014;4(3):5 is a high-grade carcinoma. as a matter of fact, the lesion under consideration is not high-grade carcinoma. even duke et al. acknowledged that the lesions under discussion were low-grade malignant tumor [3]. in order to avoid confusion, we agree with suchak et al. who proposed to remove the word “aggressive” from the term aggressive digital papillary adenocarcinoma [4]. does adpa only occur at digital location? although most if not all cases reported in the literature were from digital or nondigital acral skin, there is no reason to believe that this kind of lesion only occurs on digits or is restricted to acral skin. this kind of lesion must have occurred at skin sites other than acral location and is simply called something other than adpa. the predominant digital location of those lesions documented in the literature was most likely due to selection bias. most, if not all, cases reported in the few large series were referring cases. lesions on digits are often difficult to excise completely without digital amputation, thus, it has a tendency to recur and calls for pathology consultation. furthermore, duke et al. did acknowledge that this kind of lesion might arise elsewhere other than acral location [3]. recently an example of such case was reported in thigh [5]. does adpa always have microscopic papillary features? according to duke et al., the typical adpa is “multinodular, solid, and cystic with papillary projections present in the cystic spaces… twelve (18%) of the neoplasms were essentially only solid, lacking cystic spaces. characteristic of all lesions was a pattern of fused back-to-back glands lined by cuboidal to low columnar epithelial cells in the solid portion of the tumors” [3]. as one can see, papillary features are not present in all cases of adpa. in contrast, solid component is a constant feature present in all cases of adpa. in this sense, it is better to call adpa solid adenocarcinoma rather than papillary adenocarcinoma. in our opinion, there is no need to include the word “papillary” in the term since some adpa may not have papillary feature at all. if one likes, he or she can simply call adenocarcinoma with solid and papillary features or adenocarcinoma with multinodular growth pattern. is adpa really adenocarcinoma? following the reports from the armed force institute of pathology, a few articles, mostly single case reports, under the term of adpa, were published by other authors [6-22]. many of these authors appeared to be confused and included different lesions under the term of adpa. for example, in 2006 crowson et al. illustrated a case (figures 15 and 16 in the article) under the term adpa and commented that histopathologically the lesion was “cognate to that of ductal carcinoma in situ of the breast” [21]. from the photomicrographs illustrated there, it appears that an intact peripheral myoepithelial cell layer was present, so we believe the case is actually adenocarcinoma in situ. in 2010 hsu et al. described an 8 mm nodule on the finger of a 28-year-old woman and diagnosed as aggressive digital papillary adenocarcinoma [22]. according to the authors, the lesion was excised with positive margin, and there was no evidence of disease progression at the six-year follow-up. the photomicrographs of h&e and p63 stain provided by the authors for their case (figures 2 and 3 in the article) showed clearly the presence of an intact myoepithelial cell layer. this led us to conclude that the lesion actually represented so-called papillary eccrine adenoma, which is a type of adenocarcinoma in situ in our opinion [23,24]. among the articles from armed force institute of pathology, only kao et al. mentioned the presence of myoepithelial cells in an abstract published in 1984 [25]. kao et al. described the myoepithelial cells in these words: “as in other eccrine tumors, three main cells types were identified, namely, clear and dark epithelial cells bordering on the tubular and ductal lumina and a third myoepithelial type forming the outer layer.” interestingly in subsequent full articles published in 1987 [26] and 2000 [3], the authors did not comment on whether the lesion under discussion had any myoepithelial component or not. in an article published in 2012, suchak et al. collected 31 cases from referral archives at three institutions and reported under the term of adpa [4]. besides the series of cases from the armed force institute of pathology, this report represented the only study with a large series of cases. by using immunocytochemical staining suchak et al. demonstrated the presence of myoepithelial cells in adpa. according to suchak et al. immunocytochemical staining was done in 8 out of 31 cases and the authors stated that: “the presence of sma-positive and calponin-positive myoepithelial cells around glandular structures has been thought of as a feature of benignity in the context of cutaneous adnexal tumors. five of 6 cases in this study showed positivity for sma in the outer myoepithelial layer (diffuse in 3, focal in 2), whereas all 6 cases were strongly positive for calponin. this, however, was not predictive of outcome: 1 of these cases had multiple recurrences eventuating in pulmonary metastases (with diffuse sma staining of myoepithelial cells throughout the tumor, illustrated in fig. 3), 2 cases had no adverse outcomes, and 2 were lost to follow-up. one case that was sma negative had no adverse outcome 20 months after complete excision of the tumor. the presence of tumor associated myoepithelial cells should not be construed as an indication of benignity but rather another indication for a primary adnexal tumor should metastasis be a clinical or diagnostic consideration.” [4] if what suchak et al. stated here is true, then adpa might not be adenocarcinoma but adenomyoepithelial tumor. in general, the presence of both epithelial and myoepithelial editorial | dermatol pract concept 2014;4(3):5 35 cells in a neoplasm indicates that the neoplasm under consideration is either benign or carcinoma in situ or adenomyoepithelial tumor. in our opinion, those cases reported by suchak et al. with the presence of both epithelial and myoepithelial cells are adenomyoepithelial tumors (either adenomyoepithelioma or adenomyoepithelial carcinoma). the case suchak et al. described (case #29) with multiple recurrences and later on pulmonary metastasis is clearly adenomyoepithelial carcinoma (also called malignant adenomyoepithelioma). according to suchak et al., the patient was 16 years old female who presented with a lesion in her big toe, which was excised with unknown marginal status. microscopically the lesion was that of multilobular predominantly solid tumor with tubules and focal cystic and papillary changes. mitotic rate was stated to be 6.5/mm2. immunohistochemical staining was done and clearly showed the presence of both epithelial and myoepithelial cells (figure 3 in the article). the patient had multiple local recurrences and metastasis to leg and lung over 21 years of follow up. this case, in our opinion, both clinically and histopathologically is undoubtedly that of adenomyoepithelial carcinoma. in summary, the so-called aggressive digital papillary adenocarcinoma is not an aggressive tumor. there is no reason to believe that it is restricted to digital location. it does not always have microscopic papillary feature and furthermore it might be adenomyoepithelial tumor rather than adenocarcinoma. thus, the so-called aggressive digital papillary adenocarcinoma, in our opinion, is not really aggressive digital papillary adenocarcinoma. references 1. helwig eb. aggressive digital papillary adenoma. unpublished data. am acad dermatol clin pathol conf, chicago: december 5, 1979. 2. helwig eb. eccrine acrospiroma. j cutan pathol. 1984;11:415 20. 3. duke wh, sherrod tt, lupton gp. aggressive digital papillary adenocarcinoma (aggressive digital papillary adenoma and adenocarcinoma revisited). am j surg pathol. 2000;24:775-84. 4. suchak r, wang wl, prieto vg, ivan d, lazar aj, brenn t, calonje e. cutaneous digital papillary adenocarcinoma: a clinicopathologic study of 31 cases of a rare neoplasm with new observations. am j surg pathol. 2012;36:1883-91. 5. alomari a, douglas s, galan a, narayan d, ko c. atypical presentation of digital papillary adenocarcinoma (abstract). j cutan pathol. 2014;41:221. 6. bakotic b, antonescu cr. aggressive digital papillary adenocarcinoma of the foot: the clinicopathologic features of two cases. j foot ankle surg. 2000;39:402-5. 7. jih dm, elenitsas r, vittorio cc, berkowitz ar, seykora jt. aggressive digital papillary adenocarcinoma: a case report and review of the literature. am j dermatopathol. 2001;23:154-7. 8. inaloz hs, patel gk, knight ag. an aggressive treatment for aggressive digital papillary adenocarcinoma. cutis. 2002;69:179-82. 9. bueno ra jr, neumeister mw, wilhelmi bj. aggressive digital papillary adenocarcinoma presenting as finger infection. ann plast surg. 2002;49:326-7. 10. mori o, nakama t, hashimoto t. aggressive digital papillary adenocarcinoma arising on the right great toe. eur j dermatol. 2002;12:491-4. 11. altman ce, hamill rl, elston dm. metastatic aggressive digital papillary adenocarcinoma. cutis. 2003;72:145-7. 12. gorva ad, mohil r, srinivasan ms. aggressive digital papillary adenocarcinoma presenting as a paronychia of the finger. j hand surg br. 2005;30:534. 13. gorva ad. digital papillary adenoma (adpa) and aggressive digital papillary adenocarcinoma (adpaca). am j dermatopathol. 2005;27:546-7. 14. keramidas eg, miller g, revelos k, kitsanta p, page re. aggressive digital papillary adenoma-adenocarcinoma. scand j plast reconstr surg hand surg. 2006;40:189-92. 15. bazil mk, henshaw rm, werner a, lowe ej. aggressive digital papillary adenocarcinoma in a 15-year-old female. j pediatr hematol oncol. 2006;28:529-30. 16. mangrulkar vh, gould es, miller f. digital papillary adenocarcinoma: a case report. hand surg. 2006;11:51-3. 17. rafee a, prasad g, phang s, ramesh p. aggressive digital papillary adenocarcinoma of the hand. j hand surg eur vol. 2007;32:275-6. 18. nishimoto j, amoh y, niiyama s, takasu h, katsuoka k. aggressive digital papillary adenocarcinoma on the palm with pulmonary metastases. j dermatol. 2008;35:468-70. 19. gole gn, tati sy, deshpande ak, gole sg. aggressive digital papillary adenocarcinoma in a young female—a rare presentation. j hand microsurg. 2011;3:31-3. 20. frey j, shimek c, woodmansee c, et al. aggressive digital papillary adenocarcinoma: a report of two diseases and review of the literature. j am acad dermatol. 2009;60:331-9. 21. crowson an, magro cm, mihm mc. malignant adnexal neoplasms. mod pathol. 2006; suppl 2:s93-126. 22. hsu hc, ho cy, chen ch, et al. aggressive digital papillary adenocarcinoma: a review. clin exp dermatol. 2010;35:113-9. 23. asgari m, chen s. papillary eccrine adenoma should not be mistaken for aggressive digital papillary adenocarcinoma. clin exp dermatol. 2014;39:223-4. 24. chen s. asgari m. papillary adenocarcinoma in situ of the skin: report of four cases. dermatol pract concept. 2014; 4:4. http:// dx.doi.org/10.5826/dpc.0402a04. 25. kao gf, graham jh, helwig eb. aggressive digital papillary adenoma and adenocarcinoma (abstract). arch dermatol. 1984;120:1612. 26. kao gf, helwig eb, graham jh. aggressive digital papillary adenoma and adenocarcinoma. a clinicopathological study of 57 patients, with histochemical, immunopathological, and ultrastructural observations. j cutan pathol. 1987;14:129-46. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020036 1 dermatology practical & conceptual introduction porocarcinoma (pc) is a malignant adnexal tumor that may develop “de novo” or from a poroid benign lesion. herein, we report a case of pc arising from a hidroacanthoma simplex (hs), describing its dermoscopic features to highlight the possible usefulness of dermoscopy in identifying malignant changes. case presentation a 75-year-old caucasian woman presented to our clinic for evaluation of an asymptomatic pinkish plaque on her left leg that had been biopsied several times and diagnosed as hs (figure 1). at subsequent follow-up visit, a keratotic lesion compatible with pc was found. no lymphadenopathy was present. dermoscopy of the nodule displayed crusts, whitish scales, and red oval areas of varying diameter surrounded by a white halo. inside these lobules, various types of faint/ blurred polymorphous vessels (chalice-shaped, dotted and linear) were present (figure 2). a skin biopsy of the nodule, performed for histopathological assessment, revealed neoplastic intraepidermal proliferation of enlarged cells with pale cytoplasm arranged in clusters and pleomorphic and hyperchromatic nuclei with mitoses; no evidence of dermal invasion was present (figure 3a). immunohistochemistry showed positivity for ck5/6, p16, ema , and cea markers porocarcinoma from preexisting hidroacanthoma simplex: dermoscopic findings vincenzo maione,1 martina perantoni,1 enzo errichetti,2 tiziana borra,3 piergiacomo calzavara pinton1,4 1 department of dermatology, asst spedali civili di brescia, brescia, italy 2 institute of dermatology, university of udine, department of experimental & clinical medicine, udine, italy 3 department of pathology, asst spedali civili di brescia, brescia, italy 4 university of brescia, faculty of medicine and surgery, brescia, italy key words: porocarcinoma, hidroacanthoma simplex, dermoscopy citation: maione v, perantoni m, errichetti e, borra t, calzavara pinton p. porocarcinoma from preexisting hidroacanthoma simplex: dermoscopic findings. dermatol pract concept. 2020;10(2):e2020036. doi: https://doi.org/10.5826/dpc.1002a36 accepted: december 10, 2019; published: april 20, 2020 copyright: ©2020 maione et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship:  all authors have contributed significantly to this publication. corresponding author: vincenzo maione, md, department of dermatology, spedali civili, piazzale spedali civili n 1, brescia, italy. email: maionevincenzo@gmail.com figure 1. clinical examination shows a well-demarcated plaque of 4.7 × 2.5 cm in size on the left leg, with a superimposed keratotic nodule at the periphery. https://doi.org/10.5826/dpc.1001a036 mailto:maionevincenzo@gmail.com 2 letter | dermatol pract concept 2020;10(2):e2020036 are typically uniform, while in pc they are inhomogeneous, probably because of irregular growth of cancer cell nests. dermoscopy may be a useful additional tool in detecting possible malignant changes in hs. references 1. suzaki r, shioda t, konohana i, ishizaki s, sawada m, tanaka m. dermoscopic features of eccrine porocarcinoma arising from hidroacanthoma simplex. dermatol res pract. 2010;2010:192371. 2. dong h, zhang h, liu n, soyer hp. dermoscopy of a pigmented apocrine porocarcinoma arising from a pigmented hidroacanthoma simplex. australas j dermatol. 2018;59(2):e151-e152. (figure 3b). based on the aforementioned histological and immunohistochemical findings, a diagnosis of pc in situ was made. a wide local excision of the lesion with histologically clear margins was carried out. conclusions to date, english literature offers only 9 histologically proven instances of pc arising from hs. in 2 of these cases, dermoscopic assessment was also performed and found to be useful to highlight possible malignant changes [1,2]. in particular, the polymorphism of vessels (including dotted, linear-irregular, glomerular, and hairpin vessels in one instance and glomerular and hairpin vessels in the other) was observed in the superimposed pc in both instances. irregularly shaped whitish negative network and hemorrhages along with crusts/ scales over pink-whitish or gray-whitish structureless areas were additional features in each case, respectively. it is important to note that the polymorphous vascular pattern and round-to-oval pink areas surrounded by a peripheral white halo (corresponding to clusters of cancer cells surrounded by stroma) are the main dermoscopic features of pc, yet such findings may also be seen less commonly in eccrine poroma. nevertheless, their presence may still be helpful in assisting possible malignant changes in hs as it typically shows different features, ie, brown globular areas surrounded by scaling collarette or white globular areas surrounded by regular brown lines. notably, in our case, vessels were quite faint and blurred owing to the intraepidermal localization of tumor with vessels arranged more deeply, yet they were still useful as they are not expected in hs. the same is valid for the presence of roundto-oval pink areas surrounded by peripheral white halos. it is interesting that, as mentioned above, these structures may also be seen in eccrine poroma but in this benign tumor they figure 2. polarized dermoscopy (×10) of the nodule reveals central crusting, faint/blurred polymorphous vessels (chalice-shaped [black arrow], dotted [white arrow], and linear [white circle]), and roundto-oval pink areas with different diameters surrounded by a peripheral white halo (box). figure 3. (a) histology displays enlarged tumor cells with pale cytoplasm along with pleomorphic and hyperchromatic nuclei with mitoses but no evidence of dermis invasion (h&e, ×10). (b) immunohistochemistry for p16 clearly marks the limits of porocarcinoma in relation to hidroacanthoma simplex (immunohistochemical stain for p16, ×10). dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020024 1 dermatology practical & conceptual introduction eruptive pseudoangiomatosis (ep) is a rare, benign, spontaneously regressing exanthema characterized by an eruption of distinctive erythematous angioma-like papules that are often surrounded by a pale halo, as in other cases with facial localization [1]. unlike an angioma, however, vascular ectasia without vascular proliferation is found at histology [2]. the etiopathological mechanism of ep remains unclear, but it seems to be correlated to viral infections such as echovirus, coxsackie, and adenovirus. ep can also appear a few minutes after insect bites, in particular mosquito or flea bites, and is also referred to as erythema punctatum higuchi or purpura pulicosa. mosquito bite reactions differ from one person to another, and this difference depends on the intensity of the immediate and delayed reactions in each individual. in this respect, repeated exposure to mosquito bites alters the bite reactions in humans. if the ep is a mosquito bite reaction, it should correspond to a stage v reaction (no immediate or delayed reaction) [1,3]. differential diagnosis includes multiple eruptive capillary hemangiomas, all drug eruptions, and adrenergic urticaria. in addition, dermoscopy could be a useful tool for differential diagnosis with other common vascular lesions. multiple eruptive capillary hemangiomas are characterized dermoscopically by reddish, well-demarcated, round or oval areas called lagoons or vascular lacunae. pigmented purpuric dermatosis is typically characterized by a coppery red background, round-to-oval dots, gray dots, and a network of brownishto-gray interconnected lines; 4 specific patterns of pigmented purpuric dermatosis have been reported in the literature. pyogenic granuloma, on the other hand, presents a reddish homogeneous area, white collarette, or white rail lines (even more so when associated together). moreover, the onset of pyogenic granuloma is usually preceded by traumas or infections [4]. case presentation a 2-month-old infant, during hospitalization for poor weight gain, was referred to our observation with a 1-day history of scattered bright red papular lesions on his right cheek, forehead, and eyelid, which disappeared at diascopy. the mother reported a mosquito bite a few minutes before the appearance eruptive pseudoangiomatosis induced by mosquito bites in an infant iria neri,1 valentina assirelli,2 marco a. chessa,1 carlotta gurioli,1 federica filippi,1 annalucia virdi1 1 dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy 2 division of pediatrics, department of medical and surgical sciences, university of bologna, bologna, italy key words: eruptive pseudoangiomatosis, insect bite reaction, infant, pediatric dermatology citation: neri i, assirelli v, chessa ma, gurioli c, filippi f, virdi a. eruptive pseudoangiomatosis induced by mosquito bites in an infant. dermatol pract concept. 2020;10(1):e2020024. doi: https://doi.org/10.5826/dpc.1001a24 accepted: october 23, 2019; published: december 31, 2019 copyright: ©2019 neri et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: i.n., f.f., and a.v. contributed equally to this work. all authors have contributed significantly to this publication. corresponding author: federica filippi, md, dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti 1, 40138 bologna, italy. email: federicafilippi8@gmail.com mailto:federicafilippi8@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020024 doangiomatosis induced by mosquito bites. j dermatol. 2012;39(3):301-305. 2. neri i, patrizi a, guerrini v, ricci g, cevenini r. eruptive pseudoangiomatosis. br j dermatol. 2000;143(2):435-438. 3. restano l, cavalli r, colonna c, cambiaghi s, alessi e, caputo r. eruptive pseudoangiomatosis caused by an insect bite. j am acad dermatol. 2005;52(1):174-175. 4. piccolo v, russo t, moscarella e, brancaccio g, alfano r, argenziano g. dermatoscopy of vascular lesions. dermatol clin. 2018;36(4):389-395. with a pale halo (or without on the face) during the summer season and in exposed areas, should suggest the diagnosis of ep caused by an insect bite. recognition of this entity is important, since it resolves spontaneously in about 3 weeks and does not require any further investigation or treatment [3]. references 1. oka k, ohtaki n, kasai s, takayama k, yokozeki h. two cases of eruptive pseuof the lesions (figure 1a). prodromal symptoms such as fever, cough, vomiting, and diarrhea, suggestive of viral infection, were absent. laboratory and instrumental findings excluded any infection or other diseases. dermoscopy (delta 20; heine, herrsching, germany) demonstrated an unspecific pattern characterized by an unfocused, enlarged vascular network on a reddish background but without a pale halo (figure 1b). the kind and distribution of the lesions in an exposed body area, the seasonality and the anamnestic data of an insect bite, suggested the diagnosis of ep, unusual for the absence of the typical anemic halo. because of this strong clinical suspicion, the patient’s young age, and the asymptomatic nature of the lesions, histopathological examination was not performed; at the follow-up visit 15 days later, the cutaneous lesions had spontaneously resolved. conclusions the sudden appearance of asymptomatic red papules in an infant or child, figure 1. (a) a few bright red papules spread on the face, which completely disappeared at diascopy. (b) dermoscopy shows diffuse telangiectasia and a few hemorrhages on a reddish background (×20). dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020022 1 dermatology practical & conceptual introduction the term white shiny structures groups 3 well-defined morphologies including white shiny lines, white shiny areas, and rosettes. they all can be observed exclusively with polarized light dermoscopy. rosettes are defined as 4 bright white circles arranged as a square resembling a 4-leaf clover, mainly localized in the follicular openings. despite being well-described dermoscopically, their exact histology correlation is uncertain. the presence of white rosettes is suggestive of a diagnosis of actinic keratosis or squamous cell carcinoma (scc), but they also can be seen in a range of skin conditions and in nonlesional photo-damaged skin [1]. scc of the lip represents 20% of all oral carcinomas; its dermoscopic criteria were recently described, with the main dermoscopic features being the presence of ulceration, scales, polymorphous vessels, and white structures such as white structureless areas, white shiny lines, white circles, and perivascular white halos [2]. herein we report a case showing multiple rosettes on an scc of the lower lip. case presentation a 65-year-old woman presented with an 8-month history of an enlarging asymptomatic lesion on her lower lip. physical examination showed a well-defined, indurated, reddish ulcerated plaque measuring 1.5 cm in diameter with multiple small, whitish dots and a brownish crust (figure 1). dermoscopy revealed a yellow-brown serohematic crust, ulceration, blood spots, polymorphous vessels, bright white circles, white structureless areas, and multiple rosettes of different sizes and a red background (figure 2, a and b). the histopathological examination revealed proliferation of atypical epithelial cells with eosinophilic cytoplasms, hyperchromatic and pleomorphic nuclei as well as focal formation of horny pearls (figure 3a). ulceration and superficial corneal material were also observed (figure 3b). no vascular or perineural invasion was noted. histopathology was consistent with well-differentiated scc. dermoscopy of a squamous cell carcinoma of the lower lip showing multiple rosettes rosario peralta,1 gabriel salerni,2 emilia cohen sabban,1,3 maría belén marin,1 horacio cabo1,3 1 dermatology department, instituto de investigaciones médicas a. lanari, university of buenos aires, argentina 2 hospital provincial del centenario de rosario, argentina, universidad nacional de rosario, argentina & diagnóstico médico oroño, rosario, argentina 3 school of medicine, university of buenos aires, argentina key words: dermoscopy, lip, squamous cell carcinoma, rosettes citation: peralta r, salerni g, cohen sabban e, marin mb, cabo h. dermoscopy of a squamous cell carcinoma of the lower lip showing multiple rosettes. dermatol pract concept. 2020;10(1):e2020022. doi: https://doi.org/10.5826/dpc.1001a22 accepted: september 19, 2019; published: december 31, 2019 copyright: ©2019 peralta et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rosario peralta, md, 3150 combatientes de malvinas, cp 1427, ciudad autónoma de buenos aires, argentina. email: rosarioperalta@yahoo.com mailto:rosarioperalta@yahoo.com 2 letter | dermatol pract concept 2020;10(1):e2020022 cell carcinoma: distribution, association to other dermoscopic signs and description of the rosette pattern. j eur acad dermatol venereol. 2018;32(1):48-52. 2. benati e, persechino s, piana s, et al. dermoscopic features of squamous cell carcinoma on the lips. br j dermatol. 2017;177(3):e41-e43. lar openings in mucous membrane, we consider that rosettes on the lip could be seen as due to an optical effect produced by the interaction of polarized light with the superficial corneal material; however, further studies are needed to confirm our preliminary observations. in addition, it has been reported that the presence of white and white-yellow color based in distinct dermoscopic structures is related to well or moderately differentiated variants of scc [2]; the present case shows an adequate histopathological grade differentiation correlation. references 1. lozano-masdemont b, polimón-olabarrieta i,  marinero-escobedo s,  gutiérrez-pecharromán a, rodríguez-lomba e. rosettes in actinic keratosis and squamous conclusions scc of the lip shares several dermoscopic features with cutaneous scc. in this report we describe the presence of rosettes on scc of the lip as a novel dermoscopic finding. in agreement with other reports, we noticed that the size of rosettes may vary and they may look more like targeted follicles or white circles, meaning that both signs could be a progression of the same feature [1]. although a definitive histopathological correlate has not yet been elucidated, it has been proposed that they are caused by the interaction of keratin-filled adnexal openings with the polarized light of the dermatoscope, or that they may correspond to changes induced by orthokeratosis and parakeratosis [1]. because of the absence of follicufigure 1. clinical presentation of a well-defined, firm, reddish ulcerated plaque, diameter 1.5 cm, in the center of the lower lip, with multiple small, whitish dots and a brownish crust on its lower portion. figure 2. polarized dermoscopy shows a yellow-brown serohematic crust, ulceration (black arrow), blood spots (asterisk), polymorphous vessels, multiple rosettes, and bright white circles on a red background (a). multiple rosettes of different sizes (b). figure 3. histopathological analysis shows (a) proliferation of atypical epithelial cells with eosinophilic cytoplasms and focal formation of horny pearls (h&e, ×10). (b) ulceration and superficial corneal material is also observed (h&e, ×10). dermatology: practical and conceptual letter | dermatol pract concept 2019;9(1):15 67 dermatology practical & conceptual introduction a 67-year-old-woman with a history of basal cell carcinoma (bcc) and actinic keratosis presented with an asymptomatic lesion on her central forehead for the preceding 3 months. there was no significant family history of cancer. case presentation cutaneous examination revealed a pearly white, domeshaped papule measuring 1 × 0.7 cm on the central forehead with telangiectatic vessels and yellow ovoid structures at dermoscopic examination (dermlite dl3 3gen llc, san juan capistrano, ca) (figure 1). the rest of the skin was otherwise unremarkable. reflectance confocal microscopy (vivascope 1500 multilaser, lucid, rochester, ny) showed a cystic lesion with hyporefractive content (figure 2) and some hyperrefractive cells in the periphery of the cyst (figure 2). surgical removal was performed and histopathological examination of the hematoxylin and eosin (h&e)–stained section revealed groups of peripheral basaloid cells in a lobular pattern. the tumor contained cystic spaces of mucin (figure 3) of different sizes, located peripherally to tumor nests. diagnosis of nodular cystic variant of bcc was given. nodular cystic variant of basal cell carcinoma: perfect correlation between histopathology and confocal microscopy cristina vico-alonso1, uxúa floristán-muruzábal2, reyes gamo-villegas2 1 department of dermatology and venereology, hospital universitario 12 de octubre, madrid, spain 2 department of dermatology and venereology, hospital universitario fundación alcorcón, madrid, spain key words: adenoid type basal cell carcinoma, reflectance confocal microscopy, dermoscopy citation: vico-alonso c, floristán-muruzábal u, gamo-villegas r. nodular cystic variant of basal cell carcinoma: perfect correlation between histopathology and confocal microscopy. dermatol pract concept. 2019;9(1):67-68. doi: https://doi.org/10.5826/dpc.0901a15 published: january 31, 2019 copyright: ©2019 vico-alonso et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: cristina vico-alonso, md, servicio de dermatología, hospital universitario 12 de octubre, avenida de córdoba s/n, 28041 madrid, spain. email: c.vicoalonso@gmail.com figure 1. dome-shaped papule, 1 × 0.7 cm in diameter on the central forehead. inset: telangiectatic vessels and yellow ovoid structures at dermoscopy. [copyright: ©2019 vico-alonso et al.] 68 letter | dermatol pract concept 2019;9(1):15 2. ruchita t, dilpreet k, gursheen k, et al. nodular cystic basal cell carcinoma of the trunk: a diagnostic dilemma in an unsuspecting youth. iran j pathol. 2017;12(4):410-412. conclusions clinical and morphological subtypes of bcc include solid, micronodular, cystic, multifocal, superficial, pigmented, adenoid, infiltrating, sclerosing, keratotic, infundibulocystic, metatypical, basosquamous, and fibroepitheliomatous [1]. the classic type is nodular, which usually appears as a pearly nodule with telangiectasias, located on sun-exposed areas. a relatively rare variant of nodular bcc is the cystic form, which shows cavities that may result from tumoral necrosis. it is a low-grade variant of conventional bcc with an estimated incidence of less than 3% [1]. this tumor has been reported few times in literature because of its low incidence. however, the importance of making a correct diagnosis lies in the necessity to differentiate this tumor from eccrine syringofibroadenoma [2]. this case highlights the presence of a rare nodular cystic variant of bcc with a pathological and confocal microscopy correlation that may help clinicians as well as pathologists to identify this form of bcc. the presence of isolated cystic hyporefractive lesions and surrounding hyperrefractive cells helps to perfectly identify this tumor by confocal microscopy. references 1. yoneta a, horimoto k, nakahashi k, mori s, maeda k, yamashita t. a case of cystic basal cell carcinoma which shows a homogenous blue/black area under dermatoscopy. j skin cancer. 2011;2011:450472. epub 2010 sep 23. figure 2. reflectance confocal microscopy: cystic lesion with hyporefractive content (yellow arrowhead) and some hyperrefractive cells (red arrowhead) in the periphery of the cyst. [copyright: ©2019 vico-alonso et al.] figure 3. groups of peripheral basaloid cells with hyporefractive content (yellow arrowhead) and mucin-filled cysts (asterisk; h&e, ×100). [copyright: ©2019 vico-alonso et al.] dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual & educational notes | dermatol pract concept 2013;3(4):7 33 introduction and discussion recently, dominique et al. reported that contamination of the dermoscopic lens by human papillomavirus (hpv) may be common [1]. results of their study revealed that wartspecific hpv dna is detected with a high frequency (43%) on a dermoscopic lens before examination and that the detection rate is increased to 82% after plantar wart examination. furthermore, cleaning dermoscope lenses with an antiseptic cleansing wipe containing bactericidal and virucidal agents was not effective in removing hpv dna, as 74% of samples were positive. although actual infectivity of the viruses was not investigated, their data indicate that dermoscopy could be a possible source of nosocomial infection. dermoscopy has proven its diagnostic capabilities in pigmented and non-pigmented skin tumors [2]. it is also useful in the diagnosis of cutaneous infectious and inflammatory diseases [3,4]. as a dermatologist’s stethoscope, the use of dermoscopy is increasing since it is a remarkable screening tool in daily routine practice [2]. in this regard, the study which demonstrated that dermoscopy is a possible source of infectious disease transmission raises medical, ethical, and legal concerns with dermatologists. it increases the need for effective disinfection methods for the equipment. proper sterilization or the use of preventive tools is crucial to prevent cross-contamination among patients. several previous studies have suggested methods to decrease possible nosocomial infection by dermoscopy. • kelly sc and purcell sm reported that alcohol-based gel inhibits bacterial colonization [5]. it can obviate the risk of nosocomial infection during dermoscopic examination. however, the risk of viral infection was not investigated in the study. • zampino et al suggested that polyvinyl chloride (pvc) food wrap can be used to prevent possible transmission of infections from mucosal lesions [6]. the pvc film is placed on the dermoscopic lens with mineral oil on both surfaces, which acts as a barrier for viral contamination. however, this method has its limitations, such as low availability of pvc film in dermatologic clinics, cumbersomeness of the technique, and unpredicted transmission of infections, which could occur if the film is damaged. • polarized noncontact dermoscopy (pnd) may be ideal in evaluating possible infectious lesions because it does not require direct contact with the lesions [7]. although direct contact can be theoretically avoided using pnd, unintentional contact could happen while focusing and observing the lesion because the space between pnd and skin is narrow. • disposable dermoscopic lens covers can be used. stauffer et al. used a disposable polyethylene lens cover that was selfprevention of possible cross-infection among patients by dermoscopy: a brief review of the literature and our suggestion je-ho mun1, sung-min park1, hyun-chang ko1, byung-soo kim2, moon-bum kim2 1 department of dermatology, pusan national university yangsan hospital, republic of korea 2 department of dermatology, pusan national university hospital, busan, republic of korea key words: dermoscopy, nosocomial infection, prevention, glass slide, warts citation: mun jh, park sm, ko hc, kim bs, kim mb. prevention of possible cross-infection among patients by dermoscopy: a brief review of the literature and our suggestion. dermatol pract conc. 2013;3(4):7. http://dx.doi.org/10.5826/dpc.0304a07. copyright: ©2013 mun et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. correspondence: je-ho mun, m.d., research institute for convergence of biomedical science and technology, pusan national university yangsan hospital, republic of korea. tel. +82 55 360 1674; fax. +82 55 360 1679. e-mail: jehomun@gmail.com 34 practical, conceptual & educational notes | dermatol pract concept 2013;3(4):7 method completely inhibits contact of the lens with the skin. the used glass slide can then be discarded. microscopic glass slides have several advantages as preventive covers because they are easily available at dermatologic clinics, as they are commonly used for koh examination and diascopy, they are inexpensive, have perfect transparency, and are effective as solid mechanical barriers against bacterial and viral infections. the disadvantages of using this tool are that putting hard pressure on the slide glass can cause obliteration of dermoscopic vascular structures and breakage of the glass. therefore, it should be noted that clinicians should put no or minimal pressure on the glass slide to preserve the vascular patterns of cutaneous lesions and to avoid unexpected injury to patients in breaking the slide. although several infection prevention measures have been suggested, further studies regarding actual risk of infection and preventive methods are required as dermoscopy is increasingly used. herein, we suggest a glass slide as a simple, low cost, and effective tool that can be used to prevent cross-contamination among patients during dermoscopic examination. references 1. penso-assathiany d, gheit t, pretet jl, et al. presence and persistence of human papillomavirus types 1, 2, 3, 4, 27, and 57 on dermoscope before and after examination of plantar warts and after cleaning. j am acad dermatol. 2013;68(1):185-6. 2. argenziano g, ferrara g, francione s, et al. dermoscopy—the ultimate tool for melanoma diagnosis. semin cutan med surg. 2009;28(3):142-8. 3. zalaudek i, giacomel j, cabo h, et al. entodermoscopy: a new tool for diagnosing skin infections and infestations. dermatology. 2008;216(1):14-23. 4. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198-205. 5. kelly sc, purcell sm. prevention of nosocomial infection during dermoscopy? dermatol surg. 2006;32(4):552-5. 6. zampino mr, borghi a, caselli e, et al. virologic safety of polyvinyl chloride film in dermoscopic analysis of mucosal areas. arch dermatol. 2007;143(7):945-6. 7. haliasos ec, kerner m, jaimes-lopez n, et al. dermoscopy for the pediatric dermatologist part i: dermoscopy of pediatric infectious and inflammatory skin lesions and hair disorders. pediatr dermatol. 2013;30(2):163-71. 8. stauffer f, kittler h, forstinger c, binder m. the dermatoscope: a potential source of nosocomial infection? melanoma res. 2001;11(2):153-6. made from standard household plastic wrap [8]. it can act as a mechanical barrier. however, the method has similar limitations as with pvc film described above. we believe that a commercial disposable lens can be developed in the future, but cost would be factor. our suggestion a glass microscope slide could be a possible practical tool to prevent cross-contamination among patients. as shown in figures 1 and 2, a glass slide is placed on the front of the dermoscopic lens to evaluate viral wart-like lesions. this figure 1. microscope glass slide used as a cover for dermoscopic lens to lesions suspected to be plantar warts. [copyright: ©2013 mun et al.] figure 2. thrombosed capillary loops are observed by dermoscopy. the transparent glass slide does not obscure observation of the lesion. as a mechanical barrier, it can prevent potential transmission of bacterial and viral infections. [copyright: ©2013 mun et al.] dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2012;2(2):2 3 a study assessing the feasibility and diagnostic accuracy of real-time teledermatopathology elisabeth riedl, m.d.1, 3, masoud asgari, m.d.2, diana alvarez, m.d.2, irina margaritescu, m.d.2, geoffrey j. gottlieb, m.d.2 1 department of dermatology, medical university of vienna, vienna, austria 2 ackerman academy of dermatopathology, new york, ny, usa 3 department of dermatology, mount sinai school of medicine, new york, ny, usa citation: riedl e, asgari m, alvarez d, margaritescu i, gottlieb gj. a study assessing the feasibility and diagnostic accuracy of real-time teledermatopathology. dermatol pract conc. 2012;2(2):2. http://dx.doi.org/10.5826/dpc.0202a02. received: january 3, 2012; accepted: february 25, 2012; published: april 30, 2012 copyright: ©2012 riedl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this study was supported by the oelzelt foundation of the austrian society of sciences. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: elisabeth riedl, m.d., department of dermatology, mount sinai school of medicine, one gustave l. levy place, new york, ny 10029. email: elisried@gmail.com. introduction dermatopathology is generally regarded as the gold standard for identification with specificity of those skin diseases that cannot be diagnosed on clinical grounds alone. in many instances those same skin diseases are diagnostically vexing when studied by conventional microscopy, and identification of them often requires expert consultation not readily available. this problem is most prominent in the diagnosis of melanocytic skin lesions. dermatopathologic diagnosis of melanoma represents a special circumstance because it is not based on a single criterion, but on a constellation of criteria that are not applied consistently by individual dermatopathologists [1-3]. that being so, a true gold standard is lackdermatopathology represents the gold standard for the diagnosis of skin diseases and neoplasms that cannot be diagnosed on clinical grounds alone. the aim of this study was to test the feasibility and to assess the accuracy of an internet-based real-time (live) teledermatopathology consultation. twenty teaching cases and 10 randomly selected routine cases were presented to four expert dermatopathologists, first by real-time teledermatopathology and, subsequently, in a blinded fashion, using light microscopy. throughout the study the overall diagnostic accuracy did not differ for the two methods. however, the mean level of confidence and the mean observation times differed significantly between real-time teledermatopathology and light microscopy (92.6±0.24% versus 99.5±0.02%, and 96.31±11.55 sec versus 25.47±3.85 sec, respectively). assessment of routine cases did not produce significant diagnostic differences between the two methods. these results prove that real-time teledermatopathology offers an affordable and technically simple technology that lends itself to training as well as to diagnosis of lesions from routine practice by experts situated at remote sites. abstract 4 research | dermatol pract concept 2012;2(2):2 ing and the availability of experts gains increasing importance to guarantee a specific diagnosis and the best available treatment according to the diagnosis for the patient. the introduction of teledermatopathology into the routine practice of dermatopathology offers several opportunities for monitoring and improving the quality of diagnosis of “difficult cases” not only in the realm of melanocytic neoplasms, but in every area of pathology in general [4,5]. the broad application of teledermatology in dermatopathology has been hampered by several obstacles, among them technical obstacles, that have prevented the use of it routinely [6]. methods of teledermatopathology include electronic transmission of still images [7], distant control of a motorized microscope, real-time transmission of digital images from the microscope (videoconferencing), and the assessment of digital images with a high resolution in combination with software that enables the user to load only the desired part of the huge image files (“virtual microscopy”) [8]. although “virtual microscopy“ represents the latest development in telepathology and is an attractive option for the diagnosis of selected cases, it is time consuming and technically challenging [9]. new internet-based software, like skype™, now permits establishment of real-time teledermatopathology, a dynamic method that offers an affordable and technically simple alternative to that what was employed before (ref: http://www.hl7.com.au/skype-video-conferencing.htm). in this study we tested the feasibility and accuracy of such a method. this objective was obtained in two phases, the first one designed to prove the principle of real-time teledermatopathology and the second one to set up a field experiment to verify its feasibility for routine histopathologic evaluation of skin lesions. materials and methods 1. study cases the ethics committee of the medical university of vienna approved this study. for the initial phase of the study, 20 specimens of skin lesions with clear-cut diagnoses were selected and designated as “teaching cases” after they had been reviewed and had been diagnosed without any ambiguity by at least two dermatopathologists at the department of dermatology, medical university of vienna, vienna, austria. these “teaching cases” included benign and malignant skin lesions and biopsies of inflammatory skin diseases (table 1). for the second phase of the study, a total number of 10 cases was randomly selected during routine consultation over a period of two weeks and designated as “routine cases.” for each set of cases, i.e., teaching cases and routine cases, a skype™ conference was initiated with the remote specialist at the ackerman academy of dermatopathology, new york, ny, usa, and cases were presented in real-time to each of the four participating dermatopathologists who made the diagnosis of the cases “on the screen“ over the internet. upon request, information regarding medical history, clinical setting and clinical diagnosis was provided. the diagnosis, differential diagnoses, level of confidence in the diagnosis, and the time needed to make a diagnosis, were recorded. after two weeks, the actual slides were reviewed by the same dermatopathologists in blinded fashion using conventional light microscopy. the same parameters that had been recorded during the teledermatopathology session were noted. the quality of diagnosis rendered remotely compared to the diagnosis “under the microscope“ was subjected to statistical analysis. 2. technical equipment skype™ is an internet-based communication software that offers free internet calls using a headset or free video calls over a web camera. teledermatopathology sessions were initiated by sending a request for teleconsultation to the remote study site. during the session, a corporate analysis of sections by video conferencing took place in real-time. the system consisted of a remotely controlled microscope (olympus microscope bx41-tf5; olympus, tokyo, japan) attached to a digital video camera equipped with live video stream transmitted at 800 x 600 pixels at 30 frames per second. an internet-connected personal computer with a window xp operating system (microsoft, redmond, va) was used for the study. lan connected the two study sites at a maximum transmission rate via internet of 54 mbit/sec. this system allowed remote operation of all the movable parts of the light microscope; the video signal was shared between the client at the center where the session was initiated and the expert center and was displayed on a viewing screen. in addition, an audio connection was established via skype™. 3. outcome, quality measurements, and statistical analysis the observer’s diagnosis “on the screen” was contrasted with the diagnosis “under the microscope” (looking at the same section of tissue in a blinded fashion). each time the observer was asked to provide the following information: a specific diagnosis, the level of confidence in that diagnosis, and one or more differential diagnoses. a comparison between the proportion of correct specific diagnoses by each mode of examination, the plausibility of the specific and differential diagnoses and the level of confidence in the specific diagnosis was performed. with regard to the specific diagnosis, the agreement between both modalities was calculated. in addition, the time needed for each case by teleconsultation was recorded and compared with the time needed for the diagnosis of the sections “under the microscope.” each parresearch | dermatol pract concept 2012;2(2):2 5 ticipant was asked to assess the quality of transmission and of the slides, respectively. finally, the request of the observer for additional clinical information was recorded. results characterization of study cases for study phases 1 and 2 according to the study protocol, cases differed between the two parts of the study in regard to diagnostic difficulty, types of diseases and unambiguity of diagnosis. since all specimens came from the same institution, the quality of the slides was comparable throughout the study. accordingly, study participants rated the technical quality of the slides as “good” or “excellent” (data not shown). moreover, all specimens were prepared from punch biopsies, biopsies or excisions. while the “teaching cases” included stereotypic presentations of common skin diseases (table 1), “routine cases” that were randomly collected during a two-week period also included cases without a clear-cut diagnosis (table 1). specifically, case 3 was diagnosed as pityriasis lichenoides chronica, but a drug eruption or skin lesion of lupus erythematosus could not be ruled out by the dermatopathologist on site. similarly, case 5 came with the provisional diagnosis “pityriasis rosea, rule out eczema or psoriasis.” finally, for case 10 no distinction between a primary melanoma and a melanoma metastasis was provided during initial diagnosis. all study participants were experienced dermatopathologists. two were board-certified dermatologists and two table 1. histopathologic diagnoses of slides used for teledermatopathology and microscopy including 20 “teaching cases” (left column) and 10 “routine cases” (right column) part a “teaching cases” part b “routine cases” 1 granuloma annulare 1 desmoplastic melanoma 2 reed’s nevus 2 basal cell carcinoma 3 invasive melanoma 3 pityriasis lichenoides chronica* 4 scabies 4 irritated seborrheic keratosis 5 squamous cell carcinoma 5 pityriasis rosea* 6 isthmus catagen cyst 6 basal cell carcinoma 7 basal cell carcinoma (bcc) 7 eczema/dermatitis 8 syringoma 8 lichen sclerosus et atrophicans 9 xanthogranuloma 9 neurofibroma 10 melanoma in situ 10 nodular melanoma* 11 blue nevus 12 chronic pigmented purpura 13 hidrocystoma 14 psoriasis 15 dermatofibroma 16 herpes simplex 17 leukocytoclastic vasculitis 18 lichen planus 19 congenital melanocytic nevus 20 keratoacanthoma * diagnosis of these cases included one ore more differential diagnosis as discussed in the text. 6 research | dermatol pract concept 2012;2(2):2 board-certified pathologists. furthermore, there was some heterogeneity in regard to duration of professional experience and places of dermatopathology training. however all participants shared at least a one-year period of dermatopathology training at the same institution. assessment of “teaching cases” proves the principle that real-time teledermatopathology compares to conventional light microscopy in regard to diagnostic accuracy the first phase of the study was set up as a proof of principle to test the method of real-time teledermatopathology. remote “teleconsultation” diagnoses of 20 teaching cases (table 1) were compared with diagnoses when assessing the same sections directly “under the microscope.” overall diagnostic accuracy, level of confidence and time needed to come to a diagnosis were evaluated. figure 1a illustrates that the overall diagnostic accuracy did not differ for the two methods. however, the overall mean level of confidence differed significantly between teleconsultation and direct slide assessment by light microscopy (92.6±0.24% versus 99.5±0.02%, p=0.008). as can be seen from figure 1b, teledermatopathology was also associated with a higher degree of interobserver variability in terms of confidence in the diagnosis. in line with this, observers relied more on additional clinical information (i.e., biopsy site, number of lesions, age of patient) when making the “on screen” diagnosis (data not shown). finally, as shown in figure 1c, the time that was needed to come to a diagnosis was significantly longer for teleconsultation sessions (96.31±11.55 sec versus 25.47±3.85 sec, p<0.001). real-time teledermatopathology and direct slide assessment by light microscope of routine cases yield a high degree of interobserver agreement randomly selected routine specimens were used to compare the accuracy of teleconsultation with direct slide assessment by light microscopy. this field experiment was designed to mirror the actual situation of routine dermatopathology consultation. of the 10 randomly selected cases, three specimens had been signed out originally without a final diagnosis (table 1). according to the “real-life” setting, rather than giving the number of correct diagnoses, interobserver agreement between teleconsultation and direct slide evaluation and the time needed to come to a diagnosis were assessed. figure 2a shows that the proportion of cases in which all observers agreed did not differ significantly between the two methods: observers agreed in six out of 10 cases with the “on screen” figure 1. proof of principle of live teledermatopathology evaluating diagnostic accuracy, level of confidence and time to diagnosis during assessment of “teaching cases.” a. bars represent the proportion of correct (corr) diagnoses during “online” (open bars) and “slide” (closed bars) assessment under the microscope by individual observers (a, b, c, d). b. bars represent the percentages of cases that yielded a confidence level of 100% by individual observers (a, b, c, d) during online” (open bars) and “slide” (closed bars) evaluation. c. bars represent time for diagnosis (sec) needed by individual observers (a, b, c, d) during teleconsultation (left panel) and direct slide assessment (right panel). p<0.001 between the two groups. a b c research | dermatol pract concept 2012;2(2):2 7 diagnosis compared to seven out of 10 cases of “under the microscope” diagnosis. comparable to the results obtained during phase 1, figure 2b shows that the duration to come to a diagnosis was significantly longer for the method of real-time teledermatopathology compared to direct slide evaluation by light microscopy (112.05±19.95 sec versus 35.43±7.47 sec, p<0.001). moreover, the time for diagnosis differed significantly between study observers (p=0.027, figure 2b). further analysis revealed that the time difference between teleconsultation and direct slide assessment is observer dependent and statistically significant (p= 0.001). this data show that teleconsultation compares to direct slide assessment under the microscope in terms of diagnostic accuracy. discussion real-time teledermatopathology represents a novel technique allowing for remote interactive teaching, expert consultation of difficult cases and second opinion consultation in sites where availability of pathologists is limited [10]. the live teledermatopathology sessions include the interactive control of a microscope by a remote presenter and a viewing pathologist. slides can be viewed in their entirety at different magnifigure 2. comparison of level of agreement and time needed for diagnosis in the evaluation of “routine cases.” a. bars represent percentage of cases with perfect agreement among observers during teleconsultation (left) and direct slide assessment (right). b. bars represent time needed for diagnosis (sec) by individual observers (a, b, c, d) during teleconsultation (left panel) and direct slide assessment (right panel). fication levels, and the images displayed on the video screen represent the actual slide. furthermore, the viewing pathologist can direct the remote operator to areas of specific interest within the sample. prerequisites for the successful implementation of such a method into daily teaching and dermatopathology consultation practice are high diagnostic accuracy and precision, cost and time effectiveness, and practicability. the results of this preliminary study prove that real-time (live) teledermatopathology offers an affordable and simple technology that lends itself to training as well as to diagnosis of difficult lesions by experts situated at remote sites. during the first study phase, the feasibility of teledermatopathology as a diagnostic tool was assessed. using teaching cases with common, clear-cut diagnoses we could demonstrate that the diagnostic accuracy was comparable between the two methods. this is the first and major requirement when searching for a method that could expand or, in some instances, replace direct slide assessment by light microscopy. furthermore, we found that although the confidence in the final diagnosis revealed some interobserver differences for the method of teleconsultation, the overall confidence levels did not differ for the two methods. another critical factor when it comes to practicability of a method is how time consuming it is likely to be. in this study we observed that in both settings, namely, evaluation of “teaching cases” and assessment of “routine cases” study participants needed significantly longer to reach a diagnosis when using teledermatopathology. still, on average it took less than two minutes to make a diagnosis “on screen.” the impressively short time for the “under the microscope” diagnosis that ranged between 25 and 35 seconds underlines the study participants’ high level of expertise. however, due to the relatively short interval between the teledermatopathology consultation and the direct microscopic evaluation, we cannot rule out that participants remembered some cases during the second evaluation and that this bias contributed to the unusually short time needed for “under the microscope” diagnosis. the fourth parameter that critically influences the practicability of a method of teledermatopathology is its cost effectiveness. we started out with the aim of finding a setup that includes a technically superior method that was at the same time affordable even for small-sized dermatopathology practices and hospital departments. the method of live teledermatopathology that we chose actually fulfills these requirements. the total cost was estimated at approximately €20,000, which included a camera-equipped light microscope, a personal computer (pc) and the necessary image software. the free internet communication software that was used during the study allowed top quality sound and image communication during teleconsultation. of course, a fast internet connection is a prerequisite for this setup. the main advantage of a b 8 research | dermatol pract concept 2012;2(2):2 this method over the more sophisticated method of “virtual microscopy” that uses digital image files that have to be generated and then uploaded on the computer or on a server [8] are the comparative low costs and time requirements associated with real-time teledermatopathology. a limitation is the dependency on the operator at the presenting site. on the other hand, this presumed limitation is advantageous if the presenting physician wants to consult with the remote expert. “virtual microscopy” allows assessing the uploaded specimen directly without being dependent on direct interaction with the remote site presenting the slide. additionally, this method allows storage of image files for future evaluation. however, in regard to its practical use for remote expert consultation, one has to bear in mind that this method is cost intensive especially for the site that seeks expert consultation. this might be one of the limiting factors for its integration into daily practice, especially in rural areas. the validity of real-time telepathology has been tested in a recent study in china [11]. in that study four pathologists evaluated 600 specimens from 16 organ systems first by telepathology and subsequently by light microscopy. comparable to our results, the investigators found a high level of diagnostic agreement between both methods. in line with our results, slide review by teleconsultation took three to four times longer compared to direct assessment under the microscope. in the case of virtual microscopy several studies have shown its value in regard to feasibility and diagnostic accuracy [12,13]. our study is the first to evaluate the use of real-time teledermatopathology for both teaching purposes and remote expert diagnosis. from our data we conclude that live teledermatopathology is a suitable method for histopathologic diagnosis of skin diseases. the differences seen in the time needed to make a diagnosis “on screen” was likely due to the variable degrees of experience in this method among participants. future studies will need to evaluate the effect of adequate training in live teledermatopathology and to assess its true potential in everyday dermatopathology practice. acknowledgments this study was supported by a grant from the oelzelt foundation of the austrian academy of sciences. the authors thank dr. harald kittler for expert statistical analysis of study data. references 1. ackerman ab. discordance among expert pathologists in diagnosis of melanocytic neoplasms. hum pathol. 1996;27(11):1115-6. 2. brochez l, verhaeghe e, grosshans e, et al. inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions. j pathol. 2002;196(4):459-66. 3. urso c, rongioletti f, innocenzi d, et al. interobserver reproducibility of histological features in cutaneous malignant melanoma. j clin pathol. 2005;58(11):1194-8. 4. leinweber b, massone c, kodama k, et al. teledermatopathology: a controlled study about diagnostic validity and technical requirements for digital transmission. am j dermatopathol. 2006;28(5):413-6. 5. deagustin d, sanmartin j, varela-centelles p, vidal s. seoane j. technological bases for teledermatopathology: state of the art. semin cutan med surg. 2008;27(1):25-31. 6. furness p. a randomized controlled trial of the diagnostic accuracy of internet-based telepathology compared with conventional microscopy. histopathology. 2007;50(2):266-73. 7. nordrum i, johansen m, amin a, isaksen v, ludvigsen ja. diagnostic accuracy of second-opinion diagnoses based on still images. hum pathol. 2004;35(1):129-35. 8. costello ss, johnston dj, dervan pa, o’shea dg. development and evaluation of the virtual pathology slide: a new tool in telepathology. j med internet res. 2003;5:e11. 9. massone c, soyer ph, lozzi gp, et al. feasibility and diagnostic agreement in teledermatopathology using a virtual slide system. hum pathol. 2007;38(4):546-54. 10. kaplan kj, burgess jr, sandberg gd, myers cp, bigott tr, greenspan rb. use of robotic telepathology for frozen-section diagnosis: a retrospective trial of a telepathology system for intraoperative consultation. mod pathol. 2002;15(11):1197-204. 11. li x, gong e, mcnutt ma, et al.. assessment of diagnostic accuracy and feasibility of dynamic telepathology in china. hum pathol. 2008;39(2):236-42. 12. koch lh, lampros jn, delong lk, chen sc, woosley jt, hood af. randomized comparison of virtual microscopy and traditional glass microscopy in diagnostic accuracy among dermatology and pathology residents. hum pathol. 2009;40(5):662-7. 13. nielsen ps, lindebjerg j, rasmussen j, starklint h, waldstrøm m, nielsen b. virtual microscopy: an evaluation of its validity and diagnostic performance in routine histologic diagnosis of skin tumors. hum pathol. 2010;41(12):1770-6. untitled research | dermatol pract concept 2015;5(2):2 21 dermatology practical & conceptual www.derm101.com infiltrating basal cell carcinoma: a stellate peri-tumor dermatoscopy pattern as a clue to diagnosis john h. pyne1, paul fishburn1, anthony dicker1, michael david1 1 the university of queensland, brisbane, australia key words: basal cell carcinoma; dermatoscopy; dermoscopy: infiltrating; skin cancer; vessels citation: pyne jh, fishburn p, dicker a, david m. infiltrating basal cell carcinoma: a stellate peri-tumor dermatoscopy pattern as a clue to diagnosis. dermatol pract concept 2015;5(2):2. doi: 10.5826/dpc.0502a02 received: may 17, 2014; accepted: january 8, 2015; published: april 30, 2015 copyright: ©2015 pyne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: john h. pyne, mbbs, boptom, mmed, phd, 131 ellesemere rd, gymea bay, nsw, australia . tel. 61.414.750625; fax. 61.2.95253193. email: j.pyne@uq.edu.au background: infiltrating basal cell carcinoma (bcc) has associated features that may be readily identified using dermatoscopy. objective: investigate a stellate dermatoscopy pattern extending from the peripheral margin of infiltrating bcc. methods: a total of 741 consecutive cases of bcc were assessed retrospectively using non-polarized dermatoscopy. following histopathologic examination, cases were categorized into six different bcc subtypes. infiltrating cases numbered 107. this stellate feature was defined as a geometric star shaped pattern extending outwards from the circumferential peripheral edge of the tumor, and identified by white lines, vessels or uneven skin surface morphology. the percentages of infiltrating subtype within the tumor mass and tumor depth were compared, with and without the stellate pattern. results: infiltrating bcc displayed the stellate pattern more than other bcc subtypes. concordance between the two observers was almost perfect for white lines: kappa coefficient of 0.87 (95% ci: 0.0.79-0.95) p<0.01 and substantial for vessels: kappa coefficient of 0.71 95% ci: 0.59-0.84) p<0.01. folds were only recorded in infiltrating cases (n=3). compared to other bcc subtypes the stellate pattern had a sensitivity of 31.7% and specificity of 94.1%. a higher mean fraction of the tumor mass containing infiltrating subtype was found when comparing stellate pattern observed to stellate pattern not observed (p<0.01). no statistically significant association was found between the tumor depth with and without the stellate pattern. conclusion: this study found a higher incidence of the stellate pattern within infiltrating bcc compared to the other bcc subtypes. as the percentage of the infiltrating subtype within the tumors increased the incidence of the stellate pattern also increased. abstract 22 research | dermatol pract concept 2015;5(2):2 collagen surrounding tumor islands to be more frequent in infiltrating (96%) compared to nodular (59%) and superficial (73%) bcc [14]. methods data collection occurred from 2010 to 2012 in a primary care skin cancer practice in sydney, australia. all cases were selected from the routine workflow. all cases were imaged using a non-polarized dermlite foto dermatoscope, coupled with a canon eos 550d camera. following imaging, full excision and histopathologic examination, all cases were allocated to various bcc subtypes. cases were not subjected to a preliminary partial biopsy by punch or shave to determine the histological diagnosis. cases were excised down to subcutaneous fat as a single surgical procedure, guided by a dermatoscopy tumor margin of at least 1 mm. the authors concede that this did not fully excise all cases due to poor clinical or dermatoscopy margin definition. however, the authors consider the residual tumor tissue volume in such cases as too small to adversely affect the relevant study results. data collection was prospective, while dermatoscopy image assessment was retrospective. each observer was blinded to the bcc subtype diagnosis and to the recordings of the other observer. none of the observers were treating clinicians for any of the study cases. inclusion criteria all consecutive cases excised within the study timeframe were considered for inclusion. after applying the exclusion criteria, all remaining cases were included in the study. exclusion criteria any diagnostic entity other than bcc was excluded. any collision situation with a bcc and another non-bcc diagnostic entity was excluded. these collisions were based on either clinical, dermatoscopic, or histopathologic assessments. any known previous surgical or medical intervention involving the bcc or site of excision also led to exclusion. sites juxtaposed to scars were excluded, as were cases occurring on sites unable to be imaged with dermatoscopy. stellate pattern: definition the stellate pattern is a geometrical pattern extending from the tumor margin out into the surrounding background skin. this geometrical pattern has a full circumferential distribution and is assessed using clinical examination or dermatoscopy. this pattern has a symmetrical star-like appearance and can be created by blood-filled vessels (see figure 1), surface morphology folds (see figure 2), or white linear structures (see figure 3). introduction basal cell carcinoma (bcc) is a common primary malignancy of the skin. different histopathologic subtypes have been recognized and associated with different tumor behaviors. tumors of the nodular and superficial subtype tend to have indolent behavior compared to those of the infiltrative subtype [1]. defining key histopathologic features of infiltrating bcc include collagen and fibroblasts in the tumor stroma, basaloid tumor cells in small spiky or angular nests [2] and poorly defined tumor margins. mixed subtypes are common, particularly infiltrating and nodular subtypes. examining bcc using dermatoscopy can identify the features associated with these different subtypes. various pigmented [3-6] and vascular [6,7] dermatoscopy features of bcc have been reported; however, previous studies tend to focus on superficial and/or nodular bcc subtypes. other bcc histological subtypes display more aggressive clinical behaviors [1], including micronodular, infiltrating and morphoeic bcc, and those bcc with squamous differentiation. the dermatoscopy features of these more aggressive bcc subtypes have not been extensively studied. when examined using non-polarized dermatoscopy [8], aggressive subtype bcc have been reported to have an absent or lower incidence of pink in the tumor and absent central tumor associated vessels. compared with more indolent bcc subtypes, infiltrative bcc have higher rates of incomplete surgical excision [9,10] and perineural invasion [1]. an increased incidence of infiltrating bcc has been reported following involvement, which leads to exenteration of the orbit [11]. identifying these lesions before surgery can assist planning and management. anecdotal observation led the authors of this study to investigate a geometrical feature surrounding some bcc observed using dermatoscopy. this feature radiates outwards from the peripheral tumor margin, in a star-like geometrical pattern. the authors propose the term “stellate pattern” to describe this feature. blood vessels in a radial distribution have been reported with ulcerated bcc [12]. these vessels are within the dermatoscopy-identified tumor “footprint” or margin. in contrast, the radial blood vessels featured in the stellate pattern extend from the tumor margin out into the surrounding background skin. recent studies [13,14] have found differences in dermatoscopy between infiltrating and other bcc subtypes. these differences include a lower frequency of arborizing vessels in infiltrating bcc compared to nodular bcc, reduced frequency of ulceration on infiltrative bcc compared to superficial bcc and a greater frequency of shiny white-red structureless areas within the tumor “footprint” of infiltrating bcc compared to both superficial and nodular bcc [13]. confocal reflectance microscopy has found compact research | dermatol pract concept 2015;5(2):2 23 pattern identified and not identified, for both observers. due to the presence of non-parametrical distributions, a mannwhitney u test #2s sentence 4) or an abridged version of it.eak, irrespective of stellate pattern or observer status, was used to detect the pattern and ob was used to test the equality of group medians. correlations were equated and assessed by spearman’s rank correlation coefficient, with p<0.05 constellate pattern: percentage of infiltrating subtype within the tumor when examining the hematoxylin and eosin stained case slides, a histopathologic assessment of the fraction or percentage of the tumor mass occupied by an infiltrating subtype was estimated to the nearest 10%. a comparison was made between the mean fraction of the infiltrating subtype present for stellate figure 1. (a) infiltrating basal cell carcinoma on the back, dermatoscopy image: blood-filled vessels displaying a radial stellate pattern. (b) histopathology of the same lesion, hematoxylin and eosin staining. [copyright: ©2015 pyne et al.] a b figure 2. (a) infiltrating and nodular basal cell carcinoma on the neck, dermatoscopy image: folds on the skin surface create a stellate pattern extending from the center of the tumor surface. (b) histopathology of the same lesion, hematoxylin and eosin staining. [copyright: ©2015 pyne et al.] a b figure 3. (a) infiltrating and nodular basal cell carcinoma on the leg, dermatoscopy image: circumferential white stellate areas emanating from the peripheral tumor margin. (b) histopathology of the same lesion, hematoxylin and eosin staining. [copyright: ©2015 pyne et al.] a b 24 research | dermatol pract concept 2015;5(2):2 entiation. infiltrating bcc cases ranged in age from 38 to 96, with 67% being male (n = 72). table 1 presents the numbers of bcc recorded by histopathologic diagnosed subtype. table 1 also shows the percentage of lesions identified as having a stellate pattern for both observers and the frequency of each stellate feature. concordance between the two observers to identify the stellate pattern overall by identifying either white lines, vessels or folds was substantial, with a kappa value of 0.66 (95% ci: 0.52 to 0.80). only three cases of folds creating a stellate pattern were recorded, all three cases were infiltrating bcc. the stellate pattern displayed by infiltrating bcc had a sensitivity of 31.7% and a specificity of 94.1%. as well as identifying the bcc subtypes present, the percentage of the tumor that displayed an infiltrative subtype on the histopathology slides was also assessed. this was graded in increments of 10%. as the percentage of infiltrating subtype increased within the tumor mass, the stellate pattern was recorded with a higher incidence (see table 2). an assessment was performed of any association between tumor depth and the percentage of infiltrating subtype present under stellate pattern (observed or not observed). only one correlation was found to be statistically significant at -0.25 (95% ci: -0.46 to -0.03) for the scenario involving no stellate pattern and observer two (see table 3). discussion the data from this study indicate that the stellate pattern has a higher incidence in bcc with the infiltrating or other sidered significant. statistical analyses were conducted using version 12.1 of the stata software package (statacorp, college station, texas). ethics approval was obtained from the university of queensland ethics committee. central ulceration on the stellate pattern: a comparison of different basal cell carcinoma subtypes based on central ulceration on the stellate pattern a cicatricial process from ulceration could be a confounding factor in the presentation of the stellate pattern. to investigate this possible confounding effect a sub-study was performed comparing stellate cases for central ulceration present or absent from the center of the stellate cases for different bcc subtypes. results following the application of the inclusion and exclusion criteria, a total of 741 cases remained. these 741 cases were identified on 523 patients who ranged in age from 27 to 98, with a mean age of 61. one of four different pathologists examined each specimen for histological assessment. the identified subtypes of bcc included superficial, nodular, superficial and nodular combined, nodulocystic, and the collective more aggressive subtypes. the more aggressive group was split into the infiltrative subtype and the other aggressive subtype bcc, see table 1. the aggressive bcc not of the infiltrative subtype were represented by micronodular and morphoeic bcc, as well as by bcc with squamous differtable 1. basal cell carcinoma subtypes confirmed by histopathology, frequency of stellate pattern observations. [copyright: ©2015 pyne et al.] bcc subtypes total cases n = 741 stellate pattern identified by both observers stellate white lines identified stellate vessels identified stellate surface folds identified superficial 194 (26.2%) 12 (6.2%) 9 (4.6%) 6 (3.1%) 0 superficial and nodular 216 (29.1%) 9 (4%) 9 (4.2%) 3 (1.4%) 0 nodular 190 (25.6%) 11 (5.8%) 9 (4.7%) 5 (2.6%) 0 nodulocystic 5 (0.7%) 0 0 0 0 infiltrating 107 (14.4%) 34 (31.8%) 28 (26.1%) 21 (19.6%) 3 (2.8%) aggressive noninfiltrating 29 (3.9%) 5 (17%) 4 (13.8%) 3 (1.0%) 0 table 2. basal cell carcinoma: variation in the percentage of tumor mass being infiltrating subtype and the presence of a stellate pattern. [copyright: ©2015 pyne et al.] percentage of tumor occupied by an infiltrating subtype < 30% 30% to < 70% 70% or more number of cases (total = 107) n = 67 n = 26 n = 14 stellate pattern identified by both observers 4/67 (6%) 19/26 (73%) 12/14 (86%) research | dermatol pract concept 2015;5(2):2 25 the presence of an infiltrating bcc subtype. combinations of the stellate features (white lines, vessels or folds) significantly increase the chance of a bcc being an infiltrating bcc. a chi-square test showed that bcc subtype and number of stellate pattern features was significantly related (p<0.01), with infiltrating bcc more likely in those with multiple stellate features, see table 4. to assess the potential for the stellate pattern to be confounded by ulcer induced cicatrization within infiltrating bcc we compared the presence or absence of central ulceration on stellate cases between different subtypes of bcc. table 5 sets out the recorded presence of central ulceration by bcc subtype. nodular bcc with a stellate pattern (n=11) had central ulceration on 5 cases (45%). stellate cases of infiltrating bcc (n=34) displayed central ulceration in 17 cases (50%). these very similar findings for the two different subtypes of bcc suggest that central ulceration is both not essential for the stellate pattern and not unique to infiltrating bcc. the typical histopathology of nodular bcc does not include cicatrization. future work could examine if there is any spatial correlation between prominent central ulceration on the stellate pattern and any associated histopathologic cicatrization. future investigation may assess the incidence and character of stellate patterns in diagnostic entities, as well as bcc. the stellate sign was not pathognomonic for the diagnosis of infiltrative bcc. however, identifying this dermatoscopy feature may help guide clinicians in their approach to managing the tumor. more aggressive subtypes, as shown in table 1. infiltrating and other more aggressive bcc subtypes typically display histopathology with increased collagen in the tumor stroma. the authors speculate that a contraction effect within the tumor stroma could be one explanation for the development of these stellate patterns. the proportion and location of infiltrating bcc within a bcc of mixed subtypes can vary. one limitation of this study was not assessing the effect of the location of infiltrating bcc within mixed subtype tumors on the incidence of the stellate pattern. another limitation of this study was using non-polarized dermatoscopy alone. using polarized dermatoscopy may produce different vessel and white structures results. tumors with a stellate pattern were found to contain a higher mean fraction of infiltrating bcc within the tumor mass compared to cases not displaying a stellate pattern. this mean fraction finding was significant and consistent for both observers. the relationship between tumor depth and percentage of infiltrating subtype present was found to be weak at best, irrespective of stellate pattern or observer status. we hypothesize the stellate pattern is dependent on sufficient infiltrating tumor occupying the papillary dermis. future investigation comparing infiltrating bcc involving predominantly the papillary dermis to infiltrating tumor predominately within the reticular dermis may produce different stellate pattern results rather than comparing depth alone. this study identified that these stellate patterns around a bcc provide an in vivo clue to the increased possibility of table 3. correlational analysis between observers. [copyright: ©2015 pyne et al.] observer 1 observer 2 n r 95% ci n r 95% ci stellate observed 43 -0.053 -0.348 to 0.251 33 0.084 -0.267 to 0.415 stellate not observed 64 -0.154 -0.386 to 0.095 74 -0.254 -0.456 to -0.028 r=spearman’s rank correlation coefficient table 4. number of stellate features present within a lesion. [copyright: ©2015 pyne et al.] bcc subtype all 3 stellate features present with any lesion any 2 features only 1 feature no stellate features present superficial n = 42 0 3 (7.1%) 9 (21%) 30 (71%) superficial and nodular n = 39 0 3 (7.7%) 6 (15%) 30 (77%) nodular n = 41 0 3 (7.3%) 8 (20%) 30 (73%) infiltrating n = 60 2 18 (30%) 10 (17%) 30 (50%) the three stellate pattern features are either: white lines, vessels or folds. the presence of a stellate pattern was defined as having one or more of any of the three stellate pattern features associated with any lesion. all the above cases were identified by both observers as either stellate present or absent. 26 research | dermatol pract concept 2015;5(2):2 3. menzies sw, westerhoff k, rabinovitz h, et al. surface microscopy of pigmented basal cell carcinoma. arch dermatol 2000;136(8):1012–16. 4. demirtasoglu m, ilknur t, lebe b, et al. evaluation of dermoscopic and histopathologic features and their correlations in pigmented basal cell carcinomas. j eur acad dermatol venereol 2006;20(8):916–20. 5. scalvenzi m, lembo s, francia mg, et al. dermoscopic patterns of superficial basal cell carcinoma. int j dermatol 2008;47(10):1015–18. 6. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol 2010;62(1):67–75. 7. micantonio t, gulia a, altobelli e, et al. vascular patterns in basal cell carcinoma. j eur acad dermatol venereol 2011;25:358–61. 8. pyne j, sapkota d, wong jc. aggressive basal cell carcinoma: dermatoscopy vascular features as clues to the diagnosis. dermatol prac conc 2012;2(3):2. 9. su sy, giorlando f, ek ew, et al. incomplete excision of basal cell carcinoma: a prospective trial. plast reconstr surg 2007;120(5):1240–8. 10. farhi d, dupin n, palangie a, et al. incomplete excision of basal cell carcinoma: rate and associated factors among 362 consecutive cases. dermatol surg 2007;33(10):1207–14. 11. iuliano a, strianese d, uccello g, et al. risk factors for orbital exenteration in periocular basal cell carcinoma. am j ophthmal 2012;153(2):238–41. 12. rosendahl c, cameron a, tschandl p, et al. prediction without pigment: a decision algorithm for non-pigmented skin malignancy. dermatol pract concept. 2014;4(1):9. 13. lallas a, tzellos t, kyrgidis a, et al. accuracy of dermoscopic criteria for discriminating superficial from other subtypes of basal cell carcinoma. j am acad dermatol 2013;70(2):303-11. 14. longo c, lallas a, kyrgidis a, et al classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy. j am acad dermatol 2014;71(4):716-24. conclusion bcc may display a stellate pattern extending from the periphery of the tumor when examined using dermatoscopy. these stellate patterns may be represented by white lines, blood vessels or surface folds in a circumferential radial pattern extending outwards beyond the tumor margin. when present, these stellate patterns may offer a clue to the presence of an infiltrating bcc subtype. references 1. crowson an. basal cell carcinoma: clinical features, histology, and biology. in: crowson an, magro c, mihm mc jr. biopsy interpretation of the skin: primary non-lymphoid cutaneous neoplasia. philadelphia, pa: lippincott williams wilkins, 2010:199-234. 2. sexton m, jones db, maloney me. histologic pattern analysis of basal cell carcinoma. j am acad dermatol 1990;23(6):1118–26. table 5. basal cell carcinoma with the stellate pattern identified by both observers: incidence of ulceration located at the centre of the stellate pattern. [copyright: ©2015 pyne et al.] basal cell carcinoma subtype with stellate pattern present ulceration at the centre of the stellate pattern superficial n = 12 3 (25%) superficial and nodular n = 9 1 (11%) nodular n = 11 5 (45%) infiltrating n = 34 17 (50%) dermatology: practical and conceptual research | dermatol pract concept 2020;10(2):e2020029 1 dermatology practical & conceptual immunohistochemical evaluation and clinicopathological correlation of mer and axl tyrosine kinase tam receptors in cutaneous melanoma andrea pontara,1 giovanni paolino,2,3 vanesa gregorc,4 santo raffaele mercuri,2 alessandra bulotta,4 pietro bearzi,2 claudio doglioni,5 nathalie rizzo5 1 internal medicine, irccs san raffaele scientific institute, milan, italy 2 unit of dermatology, irccs san raffaele scientific institute, milan, italy 3 department of internal medicine and medical specialties, dermatology clinic, la sapienza-university of rome, italy 4 department of medical oncology, irccs, san raffaele scientific institute, milan, italy 5 department of pathology, irccs san raffaele scientific institute, milan, italy key words: malignant melanoma, tyrosine kinase, mer, axl, receptors, therapy, tam citation: pontara a, paolino g, gregorc v, mercuri sr, bulotta a, bearzi p, doglioni c, rizzo n. immunohistochemical evaluation and clinicopathological correlation of mer and axl tyrosine kinase tam receptors in cutaneous melanoma. dermatol pract concept. 2020;10(2):e2020029. doi: https://doi.org/10.5826/dpc.1002a29 accepted: november 25, 2019; published: april 3, 2020 copyright: ©2020 pontara et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: andrea pontara, md, via pietro giardini, 1355, baggiovara (modena), italy. email: pontara.andrea@gmail.com background: malignant melanoma (mm) is potentially the most dangerous form of skin tumor. in the last few years, the so-called tam receptors, a unique family of tyrosine kinase (tk) receptors, have become increasingly important. objectives: to evaluate mer and axl tam receptor expression to find clinicopathological features that could explain the biological behavior of mm. patients and methods: clinicopathological data were obtained from an mm electronic database at our institute. we reviewed 24 cutaneous mm specimens. tam receptor expression was assayed using immunohistochemistry. combinative semiquantitative scoring was used for the evaluation of tam receptor expression (mertk and axltk). appropriate statistical methods were used to evaluate a possible correlation between tam receptor expression and the clinicopathological variables of the mm samples (univariate analysis and multivariate analysis). results: mertk and axltk were expressed differently in the mm samples, with a major expression of the first receptor. the cells of the tumor microenvironment contributed to the majority of the total score. a significant association was found between axlscore and the site of the tumor and between axlscore and the variable ulceration; another correlation was found between merscore and the folabstract https://doi.org/10.5826/dpc.1002a29 mailto:pontara.andrea@gmail.com 2 research | dermatol pract concept 2020;10(2):e2020029 ing lymphocytes (til), pigmentation, regression, peritumoral vascular invasion, nevus-associated mm, and according to tumor microenvironment expression. we considered as tumor microenvironment the expression of the receptors in nonmelanocytic cells in the dermal infiltrate, such as in macrophages; this was made possible by using a monoclonal antibody against cd163, marker of cells from the monocyte/ macrophage lineage. tam receptors were assayed using immunohistochemistry. standard formalin-fixed, paraffin-embedded 4-µm sections were stained using rabbit monoclonal immunoglobulin g (igg) against human mertk (catalog no. ab52968, clone no. y323, 1:50 dilution; abcam, uk) and a rabbit polyclonal igg against human axltk (catalog no. 8661s, clone no. c89e7, 1:600 dilution; cell signaling technology). a mouse monoclonal igg against cd163 (catalog no. 760 4437, clone name mrq-26; ventana) was used to identify histiocytes. horseradish peroxidase-labeled goat anti-rabbit igg (zhongshan golden bridge biotechnology, china) was used as secondary antibody. a widely accepted scoring system for immunochemistry does not exist yet. in this study we used a combinative semiquantitative scoring for both of the tam receptors analyzed (mertk and axltk), which considers the percentage of positive cells and the intensity of immunohistochemical staining in most of the examined fields. the percentage of positive cells was staged as follows: 0 (0%-10% of positive cells), 1 (11%-50% of positive cells), and 2 (51%-100% of positive cells). this score was calculated arbitrarily, taking a cue from the immunoreactivity score assessed by other reports [11]. the staining intensity was described using a simple qualitative scoring system: “−” score was given for lack of brown immunoreactivity, “+/−” score for very weak staining, “+” score for weak staining, “++” score for moderate staining, and “+++” score for high staining. after that the results were converted into grades: “−” score was assigned 0, “+/−” was 1, “+” was 2, “++” was 3, and “+++” was 4. the 2 scores were added together to obtain an intermediate score with 6 possible values (0 ÷ 6). the percentage of positive cells and the staining intensity were assessed for each of the following 3 components of the tumor: tumoral melanocytes of the dermoepidermal introduction malignant melanoma (mm) is potentially the most dangerous form of skin tumor, causing 90% of skin cancer mortality [1]. intermittent sun exposure and sunburns are strongly related to the development of mm; however, other factors may be involved in its pathogenesis [2]. mm has more mutations than any other cancer type, and genome aberrations are present in the majority of them. in this regard, oncogenic mutations in c-kit, nras, and braf components of the mapk pathway have been identified in nearly 90% of cutaneous mm [3]; in particular, braf and nras mutations are the most frequently observed [4]. regarding treatments, highly selective braf and mek inhibitors have demonstrated impressive clinical results [5]. however, the short duration of response, the acquired resistance in most cases, and the toxicity issues support the rationale for drug combination approaches to improve the outcome of mapk inhibitors, increasing their efficacy and preventing and/or overcoming resistance [6]. in the last few years, the so-called tam receptors (mer, axl, and tyro3), a unique family of tyrosine kinase (tk) receptors, have become increasingly important, with a potential role in the era of targeted therapy [7]. specifically, axl shows a role in the regulation of invasion and motility of tumoral cells; tyro3 promotes tumor proliferation and acts as a positive regulator of mitf in mm, while mer promotes cellular proliferation rather than migration [7-9]. however, their specific role in mm is still unknown, given the lack of scientific articles addressing the subject. for these reasons we aimed to conduct an exploratory evaluation of mer and axl tam receptor in primary mm and to find clinicopathological features that could be associated with their expression. materials and methods clinical and pathological data were obtained from an mm electronic database at our institute, selecting a period of research between january 1, 2010, and december 31, 2017. we reviewed 24 mm specimens, divided by sex (male or female), age (≤60 or >60 years), anatomical site (axial [head-neck, thorax-thoracic dorsum, abdomen] or peripheral [upper and lower limbs]), breslow thickness (≤0.8 or ≥0.81), mitotic rate (<1/mm2 or ≥1/mm2), ulceration, tumor-infiltratlowing characteristics: pathological stage of the tumor (pt), sex, ulceration, and tumor-infiltrating lymphocytes. conclusions: all correlations between the expression of mertk and axltk with the clinical and histological variables of mm should be validated in a large group of people in order to increase the validity and the impact of our observations, with subsequently therapeutic implications in the era of the “targeted therapy.” abstract research | dermatol pract concept 2020;10(2):e2020029 3 for each clinicopathological variable, stratified according to breslow depth. clinical and pathological features of the sample in the study were enrolled 6 patients with malignant melanoma pt1 (pathological stage of tumor 1), 6 patients with malignant melanoma pt2, 6 patients with malignant melanoma pt3, and 6 patients with malignant melanoma pt4. seventeen patients were men and 7 were women. mean age of the patients was 56 years (ranging between 29 and 78 years). regarding the anatomical site, 13 patients showed involvement of the trunk and 11 had an mm localized to the peripheral sites. a mitotic rate ≥1/mm2 was present in 20 patients, while ulceration was present in 11 patients. til, assessed only in mm with vertical growth, were present in 7 patients and absent in 10 samples. regression phenomenon was observed in 7 patients. four people had an mm with lymphovascular invasion, while in 6 cases mm was associated with a preexisting nevus (25% of the total). correlation of the expression of mer and axl in the analyzed specimens figure 1 shows the trend of merscore and axlscore for each patient. the expression of axl was lower than that of mer. the main reason for this finding is that mertk and axltk were expressed differently in the mm samples and in the 3 components of the tumor (tumoral melanocytes of the dermoepidermal junction, dermal tumoral melanocytes, tumor microenvironment [supplementary tables e2 and e3]). the cells of the tumor microenvironment contributed to the majority of the total score. the analysis of the cd163 junction immediately beneath the row of epidermal basal cells, dermal tumoral melanocytes, and the cells of the tumor microenvironment. finally, the final score for each patient was obtained summing the 3 intermediate scores with 18 possible values (0 ÷ 18). in each sample a tam immunohistochemical reactivity of more than 2 was defined as positive. data processing and statistical methods all histopathological and clinical data for each patient in the study were collected in an excel database. each patient was identified with a progressive number to protect his or her identity. the variables of interest were summarized according to an appropriate statistical description on the basis of their type. the score of the expression of the 2 tam receptors (mertk and axltk) was evaluated by 1 observer. statistical analysis was conducted using stata 9.1 software (statacorp, college station, tx, usa) by another person who had no initial knowledge of the detailed clinicopathological features of the lesions. a spearman rank correlation coefficient was used to evaluate the correlation between tam receptors’ staining intensity and the clinicopathological variables of the mm samples (univariate analysis). subsequently, assuming that the effects of the predictive variables were constant over time, a multiple logistic regression was performed (multivariate analysis). in all statistical methods, p ≤ 0.05 was considered significant. results a total of 24 patients were included in the analysis. the main clinicopathological features of the sample are reported in supplementary table e1, which shows the number of patients figure 1. graphical representation of merscore and axlscore for each patient. 4 research | dermatol pract concept 2020;10(2):e2020029 4.67 in pt4, showing an atypical distribution with a peak in the intermediate stages and lower values in the first and last stages (p = 0.04) (figure 2a). merscore was 6.82 in men and 11.57 in women (p = 0.01) (figure 2b). the average merscore was 10.25 in patients ≤60 years old and 6.17 in patients >60 years old (p = 0.06), 7.77 in mms of the head-neck, thorax-thoracic dorsum, and abdomen, and 8.73 in mms localized on the limbs (p = 0.8). regarding histology, we found that the mean values of merscore were 9.22 in superficial spreading melanoma, 5.33 in nodular melanoma, 6 in acral lentiginous melanoma, and 3 in lentigo maligna melanoma (p = 0.07) (figure 2c). the mean merscore was 6.6 in patients with a breslow thickness ≤0.80 mm and 8.63 in those with a thickness ≥0.81 staining revealed that the expression of mertk was given predominantly by these cells. mertk was expressed by tumoral melanocytes and the cells of the microenvironment; in particular, 13 patients expressed mertk in the dermoepidermal junction’s melanocytes (54% of the patients) and 12 in the dermal melanocytes (50% of the patients). only 1 patient did not express mertk in the cells of the tumor microenvironment. in contrast, axltk was expressed in all patients by the cells of the tumor microenvironment; only 1 patient exhibited the expression of this tam receptor also in tumoral melanocytes. expression of mertk evaluating merscore according to pt stage, we found that mean merscore was 6 in pt1, 13 in pt2, 9.17 in pt3, and figure 2. (a) box plot multiple comparison graph shows the distribution of merscore (mers) according to the different stages (pt) of melanoma samples. (b) box plot multiple comparison graph shows the distribution of merscore according to sex. (c) box plot comparison graph shows the variation of merscore according to the histology of melanoma: superficial spreading melanoma (ssm), nodular melanoma (nm), lentigo maligna (lm), and acral lentiginous melanoma (alm). (d) box plot multiple comparison graph shows the distribution of merscore according to the presence or absence of ulceration. research | dermatol pract concept 2020;10(2):e2020029 5 mm (p = 0.4), 4.75 in mms with mitoses <1/mm2, and 8.9 in those with mitoses ≥1/mm2 (p = 0.1). the average merscore was 10 in patients with ulceration (p = 0.01) (figure 2d), 8 in pigmented lesions (p = 0.7), and 6 in lesions with regression (p = 0.1). mean mer expression was 9.86 in lesions with til and 6.6 in lesions without til (p = 0.04) (figure 3). the mean merscore was 11.17 in nevus-associated mms (p = 0.1) and 4.67 in cases of microscopic satellites (p = 0.1). however, when we performed multiple logistic regression, only the variable ulceration maintained statistical significance (p = 0.03). all these data are summarized in table 1. subsequently, kaplan-meier curves were performed for the survival analysis, and the log-rank was used to evaluate the difference between the curves (supplementary table e4). figure 3. box plot multiple comparison graph shows the distribution of merscore according to tumor-infiltrating lymphocytes (til). merscore (mean±sd) pa pb sex 0.04 ns male 6.82±4.4 female 11.57±4.8 age 0.06 ns ≤60 years 10.25±4.6 >60 years 6.17±4.6 anatomical site 0.8 ns head-neck/ thorax-thoracic dorsum/abdomen 7.77±4.5 arms/legs 8.73±5.7 histology 0.07 ns ssm 9.22±5.1 nm 5.33±2.5 lmm 3 alm 6±5.7 pt 0.04 ns 1 6±4.5 2 13±3.5 3 9.17±4.9 4 4.67±2.8 breslow depth 0.4 ns ≤0.80 mm 6.6±4.8 >0.81 mm 8.63±5.1 mitoses 0.1 ns <1/mm2 4.75±2.8 ≥1/mm2 8.9±5.1 merscore (mean±sd) pa pb ulceration 0.01 0.03 presence 10±5.5 absence 6.69±4.1 til 0.04 ns presence 9.86±4.9 absence 6.6±4.6 pigmentation 0.7 ns presence 8±4.6 absence 10.5±10.6 regression 0.1 ns presence 6±4.4 absence 9.12±5.0 pvi 0.1 ns presence 4.5±2.1 absence 8.95±5.1 nevus-associated melanoma 0.1 ns presence 11.17±5.5 absence 7.22±4.5 microscopic satellites 0.1 ns presence 4.67±3.1 absence 8.71±5.0 aspearman test between the variables and mertk expression. bmultiple logistic regression between the variables and mertk expression. significant values are given in italic. alm = acral lentiginous melanoma; lmm = lentigo maligna melanoma; nm = nodular melanoma; ns = not significant; pvi = peritumoral vascular invasion; sd = standard deviation; ssm = superficial spreading melanoma; til = tumor-infiltrating lymphocytes. table 1. analysis of clinicopathological variables according to mertk expression (data continues next column) 6 research | dermatol pract concept 2020;10(2):e2020029 the mean axlscore was 4.33 in nevus-associated mms (p = 0.9) and 3.67 in the lesions with microscopic satellites (p = 0.3). in the multiple logistic regression only 2 variables maintained statistical significance: anatomical site (p = 0.01) and ulceration (p = 0.03). all these data are summarized in table 2. according to the expression of axltk in tumoral melanocytes, the patients were divided into 2 groups: axltk-negative (axltk−) lesions and axltk-positive (axltk+) lesions. the mean pfs was 76 months in axltk− mms and 94 months in the positive ones (p = 0.5), while the mean os was 79 months in axltk− lesions and 94 months in the positive ones (p = 0.5). in any case, statistical significance was not reached, also due to the low number of axltk+ lesions (n = 1) (supplementary table e5). subanalysis of mer and axl expression in microenvironment evaluating the expression of mer according to the microenvironment, we found that the expression was 4 in median breslow thickness of 2.2 mm (0.24-3.8), 3 in median breslow of 2.3 mm (0.49-4.1), 2 in median breslow of 2.4 mm (0.24.2), 1 in median breslow of 2.4 mm (0.9-4.1), and 0 in median breslow of 0.38 mm. the results did not reach statistical significance (spearman test) owing to the low number of patients and the high presence of variables (p = 0.7). performing the same analysis in axl we found that, regarding the microenvironment, the expression was 4 in median breslow of 0.2 mm (only 1 case), 3 in median breslow of 1.17 mm (0.24-4.2), 2 in median breslow of 2.7 mm (0.38-7), 1 in median breslow of 4.02 mm (only 1 case). also in this case significance was not reached (p = 0.1). discussion mertk and axltk receptors could play important roles in the development of mm: they act as direct drivers of the tumor progression and as inhibitory receptors in the cells of the tumor microenvironment that suppress host immunity. the few published scientific papers that have evaluated the expression of mertk and axltk in mm have been mainly conducted in vitro on samples of mm cell lines [7,9,11]. this study, on the contrary, assessed the expression of these tyrosine kinase receptors with immunohistochemical stains on biopsy of cutaneous mm specimens. as previously demonstrated [9], we confirmed the expression of mertk and axltk in mm samples with a prevalence of the first receptor (figure 5, a-d). our report also demonstrated that these 2 receptors are more expressed by the cells of the tumor microenvironment, basically by tumor macrophages, as also reported in a recent paper [12]. however, contrary to salmi et al [12], who evaluated mainly the according to the expression of mertk in tumoral melanocytes, the patients were divided into 2 groups: mertk-negative (mertk−) lesions and mertk-positive (mertk+) lesions. mean progression-free survival (pfs) was 55.22 months in mertk− lesions, while it was 93.58 in mertk+ lesions (p = 0.004); in the long term, we found that overall survival (os) was 62.9 in mertk− and 93.76 in mertk+ lesions (p = 0.02). expression of axltk the mean axlscore was 4.17 in pt1, 6.67 in pt2, 4.5 in pt3, and 3.83 in pt4, without reaching statistical significance with a p = 0.4. the statistical significance, in the univariate analysis, was not reached also for the variable sex (5.06 in men and 4.14 in women, p = 0.6). patients aged ≤60 showed a mean axlscore of 4.42, while in those aged >60 it was 5.17 (p = 0.5). the lesions localized on the head-neck, thorax-thoracic dorsum, or abdomen, in contrast to those localized to the limbs (arms, legs), showed a mean axlscore of 5.62 and 3.82, respectively (p = 0.01) (figure 4). regarding histology, we found that mean axlscore values were 5.11 in superficial spreading melanoma, 4.33 in nodular melanoma, 3 in acral lentiginous melanoma, and 3.5 in lentigo maligna (p = 0.2). the average axlscore was 4.4 in patients with breslow thickness ≤0.80 mm and 4.89 in patients with a thickness ≥0.81 mm (p = 0.4), 4.75 in mms with mitoses <1/mm2, and 4.8 in those with mitoses ≥1/mm2 (p = 0.3). the average axlscore was 4.27 in patients with ulceration (p = 0.9), 4.86 in pigmented lesions (p = 0.4), 4.14 in lesions with regression (p = 0.7), 6.75 in lesions with peritumoral vascular invasion (p = 0.5), and 3.83 in patients without perineural invasion. mean axl expression was 6.29 in lesions with til and 4.1 in lesions without til (p = 0.8). figure 4. box plot multiple comparison graph shows the distribution of axlscore according to the anatomical site (axial: head-neck, trunk; extremities: upper and lower limbs). research | dermatol pract concept 2020;10(2):e2020029 7 (p = 0.04). it is possible to assume a plausible role of the estrogen receptor in determining this difference between the sexes, since data have increasingly demonstrated a role of this receptor in the biology of mm [13,14]. moreover, it has been demonstrated that breast cancer, a hormone-sensitive tumor, expresses a high level of tam receptor [15]. the ulceration of the primary tumor also correlates with a more elevated expression of mertk (p = 0.01). more than half of the ulcerated mms (6/11) are pt2 and pt3 tumors, which are the stages with discrete proliferation rates and invasiveness. mertk induces upregulation of focal adhesion kinases, which promotes migration [16]. moreover, it has been found that merscore was higher in patients with the presence of til (p = 0.04). expression of tam receptors in cd68+ and cd163+ macrophages in benign and malignant melanocytic lesions, our study focused on the correlation between the expression of tam receptors and the histological main types of mm, with the relative clinicopathological correlations. we found a significant expression of mertk in pt2 and pt3 mm, with low levels in initial and advanced tumors; mertk surely has an important implication in the biological regulation of these 2 stages, and probably this is associated with different biological pathways between the initial tumorigenesis and more advanced primary tumors. the univariate correlation has also evidenced a significant association between mertk expression and sex: women have a more elevated expression of this receptor than men axlscore (mean±sd) pa pb sex 0.6 ns male 5.06±3.2 female 4.14±1.1 age 0.5 ns ≤60 years 4.42±1.2 >60 years 5.17±3.8 anatomical site 0.01 0.01 head-neck/ thorax-thoracic dorsum/abdomen 5.62±3.5 arms/legs 3.82±1.1 histology 0.2 ns ssm 5.11±3.1 nm 4.33±0.6 lmm 3 alm 3.5±2.1 pt 0.4 ns 1 4.17±2.9 2 6.67±4.2 3 4.50±3.1 4 3.83±2.1 breslow depth 0.4 ns ≤0.80 mm 4.4±1.3 >0.81 mm 4.89±3.0 mitoses 0.3 ns <1/mm2 4.75±1.3 ≥1/mm2 4.8±3.0 axlscore (mean±sd) pa pb ulceration 0.9 0.03 presence 4.27±1.00 absence 5.23±3.6 til 0.8 ns presence 6.29±4.7 absence 4.1±1.0 pigmentation 0.4 ns presence 4.86±2.9 absence 4±0 regression 0.7 ns presence 4.14±1.2 absence 5.06±3.2 pvi 0.5 ns presence 6.75±6.9 absence 4.4±0.9 nevus-associated melanoma 0.9 ns presence 4.33±0.8 absence 4.94±3.2 microscopic satellites 0.3 ns presence 3.67±1.5 absence 4.95±2.9 aspearman test between the variables and axltk expression. bmultiple logistic regression between the variables and axltk expression. significant values are given in italic. alm = acral lentiginous melanoma; lmm = lentigo maligna melanoma; nm = nodular melanoma; ns = not significant; pvi = peritumoral vascular invasion; sd = standard deviation; ssm = superficial spreading melanoma; til = tumor-infiltrating lymphocytes. table 2. analysis of clinicopathological variables according to axltk expression (data continues next column) 8 research | dermatol pract concept 2020;10(2):e2020029 the main limitation of our study is the small size of the sample. all the correlations between the expression of mertk and axltk with the clinical and histological variables of mm should be validated in a large group of people in order to increase the validity and the impact of the observations. therefore, a multivariate analysis and a proper sample size could demonstrate the actual role of these tk receptors. however, at the same time, the present findings could also be a consequence of the bias if the receptors show a different pattern of expression according to stage and other prognostic factors. another limitation of this study is that the cross-sectional analysis between the tam receptor scores (axlscore and merscore) and the clinicopathological variables of the tumor was done only at the time of its diagnosis. our analysis established a simple association between these scores and the different variables. an analysis of the expression of these receptors could also be evaluated during the patient’s follow-up, according to the tumor progression in order to hypothesize a pathogenetic correlation. the statistical analysis found an association between merscore of tumoral melanocytes and pfs/os (p = 0.004 and 0.02, respectively): the patients whose mertk expression in tumoral melanocytes is higher have a better prognosis; this evidence can be explained by the fact that the presence of til correlates with a favorable course [17]. this finding may have predictive clinical implications and could have a role in the organization of the follow-up of the patient with mm; for example, medical examinations could be closer in patients with a low tumoral melanocyte expression of mertk. the univariate statistical analysis regarding the expression of axltk revealed a significant association between the axlscore and the anatomical site of the tumor (p = 0.01); in particular, those mms that are localized to head-neck, thorax-thoracic dorsum, and abdomen have a higher axlscore than those on arms and legs. this reflects a different importance of this receptor in the mm pathogenesis according to the anatomical sites. it is well known that various genetic alterations differ with the anatomical site of mm, and probably this happens also for axltk expression [18]. figure 5. (a) cutaneous melanoma, pt3 (h&e, ×40). (b) cd163, in the same melanoma as depicted in panel a (×40). (c) mertk, in the melanoma depicted in panel a (×40). (d) axltk, in the melanoma depicted in panel a (×40). research | dermatol pract concept 2020;10(2):e2020029 9 8. zhu s, wurdak h, wang y, et al. a genomic screen identifies tyro3 as a mitf regulator in melanoma. proc natl acad sci u s a. 2009;106(40):17025-17030. 9. tworkoski ka, platt jt, bacchiocchi a, bosenberg m, boggon tj, stern df. mertk controls melanoma cell migration and survival and differentially regulates cell behavior relative to axl. pigment cell melanoma res. 2013;26(4):527-541. 10. fedchenko n, reifenrath j. different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—a review. diagn pathol. 2014;9:221. 11. sensi m, catani m, castellano g, et al. human cutaneous melanomas lacking mitf and melanocyte differentiation antigens express a functional axl receptor kinase. j invest dermatol. 2011;131(12):2448-2457. 12. salmi s, siiskonen h, sironen r, et al. the number and localization of cd68+ and cd163+ macrophages in different stages of cutaneous melanoma. melanoma res. 2019;29(3):237-247. 13. walker mj, ronan sg, han mc, beattie cw, das gupta tk. interrelationship between histopathologic characteristics of melanoma and estrogen receptor status. cancer. 1991;68(1):184-188. 14. de giorgi v, mavilia c, massi d, et al. estrogen receptor expression in cutaneous melanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. arch dermatol. 2009;145(1):30-36. 15. holland sj, pan a, franci c, et al. r428, a selective small molecule inhibitor of axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. cancer res. 2010;70(4):1544-1554. 16. wu y, singh s, georgescu mm, birge rb. a role for mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. j cell sci. 2005;118(pt 3):539-553. 17. haanen jb, baars a, gomez r, et al. melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific t cells may predict survival in resected advanced-stage melanoma patients. cancer immunol immunother. 2006;55(4):451-458. 18. monn kr, choi yd, kim jm, et al. genetic alterations in primary acral melanoma and acral melanocytic nevus in korea: common mutated genes show distinct cytomorphological features. j invest dermatol. 2018;138(4):933-945. conclusions this is a preliminary and exploratory study that correlates the clinicopathological characteristics of primary cutaneous mm with the levels of the immunohistochemical expression of mertk and axltk. moreover, it is a first attempt to evaluate a possible association between the expression of these 2 receptors and the prognosis of the patients. this study could be expanded with the evaluation of the expression of the tam receptor in metastatic melanomas and the screening of the mutation of the oncogenes nras, braf, and c-kit with subsequently therapeutic implications in the era of the “targeted therapy.” references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019;69(1):7-34. 2. paolino g, panetta c, cota c, et al. vitamin d receptor immunohistochemistry variability in sun-exposed and non-sun-exposed melanomas. melanoma res. 2017;27(1):17-23. 3. omholt k, platz a, kanter l, ringborg u, hansson j. nras and braf mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. clin cancer res. 2003;9(17):6483-6488. 4. hodis e, watson ir, kryukov gv, et al. a landscape of driver mutations in melanoma. cell. 2012;150(2):251-263. 5. chapman pb, hauschild a, robert c, et al. improved survival with vemurafenib in melanoma with braf v600e mutation. n engl j med. 2011;364(26):2507-2516. 6. prasad d, rothlin cv, burrola p, et al. tam receptor function in the retinal pigment epithelium. mol cell neurosci. 2006;33(1):96108. 7. schlegel j, sambade mj, sather s, et al. mertk receptor tyrosine kinase is a therapeutic target in melanoma. j clin invest. 2013;123(5):2257-2267. 10 research | dermatol pract concept 2020;10(2):e2020029 supplementary table e1. clinicopathological baselines of the sample pt1 pt2 pt3 pt4 sex male 3 3 5 6 female 3 3 1 0 age ≤60 years 3 4 2 3 >60 years 3 2 4 3 anatomical site head-neck 0 0 1 1 thorax-thoracic dorsum 2 3 1 2 abdomen 0 2 1 0 arms 2 0 0 2 legs 2 1 3 1 histology ssm 5 6 5 2 nm 0 0 1 2 lmm 1 0 0 0 alm 0 0 0 2 breslow depth (mean± sd, mm) 0.47±0.26 1.50±0.28 2.95±0.63 4.59±1.18 mitoses <1/mm2 4 0 0 0 ≥1/mm2 2 6 6 6 ulceration presence 1 3 3 4 absence 5 3 3 2 til presence 0 3 2 2 absence 1 1 4 4 pigmentation presence 6 6 5 5 absence 0 0 1 1 regression presence 3 1 0 3 absence 3 5 6 3 pvi presence 0 1 1 2 absence 6 5 5 4 pni presence 0 0 0 0 absence 6 6 6 6 nevus-associated melanoma presence 0 4 0 2 absence 6 2 6 4 microscopic satellites presence 0 0 1 2 absence 6 6 5 4 alm = acral lentiginous melanoma; lmm = lentigo maligna melanoma; nm = nodular melanoma; pni = perineural invasion; pt = pathological stage of tumor; pvi = peritumoral vascular invasion; sd = standard deviation; ssm = superficial spreading melanoma; til = tumor-infiltrating lymphocytes. research | dermatol pract concept 2020;10(2):e2020029 11 supplementary table e2. expression of mertk according to 3 different components of the tumor pt1 pt2 pt3 pt4 mertk dermoepidermal junction’s tumoral melanocytes 30.56% 30.77% 21.82% 10.71% dermal tumoral melanocytes 13.89% 30.77% 23.64% 10.71% tumor microenvironment 55.55% 38.46% 54.54% 78.58% supplementary table e3. expression of axltk according to 3 different components of the tumor pt1 pt2 pt3 pt4 axltk dermoepidermal junction’s melanocytes 0% 15% 0% 0% dermal melanocytes 0% 15% 0% 0% tumor microenvironment 25% 70% 100% 100% supplementary table e5. survival analysis according to axl expression pfs (months±sd) pa os (months±sd) pa axl− 76±31.2 0.5 79±29.6 0.5 axl+ 94 94 akaplan-meier product and log-rank test. os = overall survival; pfs = progression-free survival; sd = standard deviation. supplementary table e4. survival analysis according to mer expression pfs (months±sd) pa os (months±sd) pa mer− 55.22±36.3 0.004 62.9±35.4 0.02 mer+ 93.58±13.6 93.76±11.6 akaplan-meier product and log-rank test. significant values are given in italic. os = overall survival; pfs = progression-free survival; sd = standard deviation. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2013;3(4):2 7 the relevance of recognizing clinical and morphologic features of pityriasis lichenoides: clinicopathological study of 29 cases jandrei rogério markus1, vânia oliveira carvalho2, monica nunes lima3, kerstin taniguchi abagge2, alexandre nascimento4, betina werner4 1 division of pediatrics, itpac-porto nacional, tocantins, brazil 2 division of pediatric dermatology, clinical hospital of the federal university of paraná (ufpr), curitiba, brazil 3 division of statistics, department of pediatrics, clinical hospital of the federal university of paraná (ufpr), curitiba, brazil 4 division of medical pathology, federal university of paraná (ufpr), curitiba, brazil key words: pityriasis lichenoides, child, pityriasis lichenoides et varioliformis acuta, pityriasis lichenoides chronica citation: markus jr, carvalho vo, lima mn, abagge kt, nascimento a, werner b. the relevance of recognizing clinical and morphologic features of pityriasis lichenoides: clinicopathological study of 29 cases. dermatol pract conc. 2013;3(4):2. http://dx.doi.org/10.5826/ dpc.0304a02. received: march 11, 2013; accepted: july 9, 2013; published: october 31, 2013 copyright: ©2013 markus et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: vânia oliveira de carvalho, rua richard strauss 62, vista alegre. curitiba, cep: 80820-110, paraná, brazil. tel/ fax. +55 (41) 335-3477. email: rcarvalho50@hotmail.com background: pityriasis lichenoides (pl) is a lymphoproliferative disease of unknown origin; its diagnosis is based on clinical characteristics and confirmed by histology. objectives: to describe clinical and histological features of pl in 29 pediatric patients. materials and methods: retrospective descriptive study of children (patients less than 15 years old) diagnosed with pl between 1986 and 2010 at a reference service in pediatric dermatology from south brazil. results: twenty-nine pl cases were found by chart review in 24 years. mean age of diagnosis was 8 years (22 to 178 months) and a mean time of diagnosis was 13.8 months (1 to 120 months). twenty cases (69%) were male. seasonal correlation was found with colder months in 62% of cases (p<0.01). clinical diagnosis was pityriasis lichenoides chronica (plc) in 25 cases, and pityriasis lichenoides et varioliformis acuta (pleva) in four. itching was the main reported symptom occurring in 13 (45%). fourteen cases had been histologically evaluated. in six, microscopic findings were consistent with plc, in four consistent with pleva, and four biopsies exhibited mixed characteristics of both forms. concordance between clinical and histological diagnosis was seen in most cases. conclusion: pl occurs in children and young adults, more commonly in males, and during cold months. plc was the more frequent clinicohistologic form, and necrotic lesions characterized pleva. associating clinical and histological findings is important for differentiating between plc and pleva diagnosis. abstract 8 research | dermatol pract concept 2013;3(4):2 introduction pityriasis lichenoides (pl) is one group of inflammatory skin diseases which includes pityriasis lichenoides et varioliformis acuta (pleva), ulceronecrotic febrile mucha-habermann disease (a subtype of pleva which presents fever with ulcerated and necrotic lesions and other systemic symptoms), and pityriasis lichenoides chronica (plc) [1,2]. in pleva, lesions begin as redish-brown macules and papules which occur in successive crops and can be asymptomatic or itchy. they normally measure 2 to 3 mm and evolve quickly to crusted purpuric necrotic lesions. resolution can result in varioliform scarring. plc presents papules with characteristic signs of fine scaling, and resolution with postinflammatory hypopigmentation without scarring may occur [1]. in general, pl is more common in the first ten years of life, and it is believed that 19 to 38% of cases occur in the pediatric age group [1,3]. there are several hypotheses about its pathogenesis, including dermatitis mediated by immune complexes [3-7]. it has also been considered a lymphoproliferative disease triggered by antigen stimuli such as viruses or other infectious agents because clonality and prominent cd30 positivity has been demonstrated, especially in some histological variants [3,7-11]. the objective of this study is to describe the clinical and histological characteristics of pl in the pediatric age in a reference pediatric dermatology center in south brazil, with the aim of correlating history, clinical and microscopic findings with the classification of disease type (pleva or plc). method a retrospective descriptive observational study evaluated clinical and histological data from patients less than 15 years old diagnosed with pl seen at a specialized pediatric dermatology division of a public hospital in south brazil from 1986 to 2010. one pediatric dermatologist at this center evaluated all patients. the institution’s research ethics committee approved this study. medical records of pl patients were reviewed for the following variables: gender, age at start of signs or symptoms, history of infections in the six months before lesions, medication history, family history of similar lesions, disease duration, skin lesion distribution, treatments, associated symptoms, and pigment alterations and their duration after improvement. two researchers reviewed photographic documentation, when available, to confirm diagnosis and classify the disease into the two clinical forms—pleva or plc. those without photographic evidence were classified according to medical records. cases were classified as plc when there were residual hypochromic lesions, erythematous papules, and exfoliation with signs of fine scaling, and pleva when there was necrosis, hematic crusts, and the presence of atrophic scarring or associated fever. patients who had undergone skin biopsies had their slides reviewed and the following histological parameters evaluated. in the epidermis: acanthosis, spongiosis, lymphocyte exocytosis, parakeratosis, necrotic keratinocytes and scale crust. and in the dermis: papillary edema hemorrhage, perivascular lymphocytic infiltrate and atypical lymphocytes. these criteria were evaluated for the presence or absence in each case, and when present as discrete, moderate, or accentuated in an attempt to differentiate between plc and pleva. cases that presented a moderate or accentuated epidermal or dermal inflammatory component; and or frequent necrotic keratinocytes; and or scale crust were classified as the acute form (pleva). cases with more subtle histological alterations or with their absence were classified as the chronic form (plc). cases where parameters from both groups were found were classified as the mixed form. the summary measurements used in the descriptive statistics were mean, standard deviation, median, minimum and maximum values, and frequencies depending on type of variable studied. differences between ages were studied using the mann-whitney test considering a significance level of 5%. data were analyzed with the aid of software package statistica 7.1 (statsoft). results twenty-nine pl cases were evaluated; median age was 96 months (22 to 178 months). age at the start of symptoms had peaks at 8 years, followed by 12 and 14 years. mean time between start of symptoms and diagnosis was 1.15 years (1 month to 10 years). twenty patients were male (69%). in the comparison between gender and age at start of symptoms, median age at the start in males was 8.3 years (1 to 14.1 years) and in females 8.8 years (1.6 to 14.8 years; p=0.5). disease start predominated in winter and autumn months (figure 1). cutaneous alterations were present in all patients at examination. the most frequently observed lesions were papules (n=27), hypopigmentation and scaling (n=19) and figure 1. distribution of patients according to season of the year that symptoms started. [copyright: ©2013 markus et al.] research | dermatol pract concept 2013;3(4):2 9 mean evolution time to improvement in these 15 patients was seven months (1 to 96 months). three cases still had lesions at last evaluation and their mean follow-up time was 15 months. discussion pityriasis lichenoides is an uncommon skin disease with few studies on its clinical and histological presentation, especially in the pediatric age. mean age at the start was 8 years, with peaks at 8, 12, and 14 years. this varies depending on author between 5 and 9 years [8,12]. it predominated in males (69%), agreeing with literature where values range from 53% to 60% [8,12,13]. this dermatosis is believed to be seasonal, predominantly in autumn and winter, as seen in 62% of cases in this study; ersoy-evans et al. found this in 65% while wahie et al. did not observe seasonal variation [8,13]. despite the study having the limitation of being retrospective, the question exists whether there really are fewer cases in the warm months, or whether exposure to the sun could be an improvement factor for symptoms and consequently fewer patients seek for medical attention in these months. another possibility is that viral infections, which are prevalent during cold months, could be triggers [7,14]. most patients presented with papules in the first evaluation, followed by residual hypopigmentation and fine scaling. these clinical findings are compatible with plc. necrotic lesions, which are feature of pleva, were observed in 4 cases, which is less than in the literature [1,4]. in lesion distribution, the majority of lesions were located in the central body region. literature reports a predominance of the diffuse form (skin lesions spread in the entire body) in 70% of cases [8]. it must be stressed that classification by lesion distribution is observer dependent, considering the highest lesion concentration, allowing a patient with the central form to have some peripheral lesions. this brings into question the validity of using topographical classification for pl. the commonest symptom was itching, but most patients were asymptomatic, differently to ersoy-evans et al., who reported that most patients had pruritus. symptom evaluation could have been underestimated due to the nature of the retrofine scaling (n=13). there was also erythema (n=12), crusts (n=12), hyperpigmentation (n=5), necrosis (n=4), and purpuric lesions (n=3). classification by lesion distribution was of a central form, where lesions were found on the trunk and proximal limbs in 14 (48%), followed by diffuse (generalized lesions) in 13 (45%), and peripheral, where only the extremities presented lesions, in 2 (7%) cases. as for symptoms, 15 (52%) patients were asymptomatic, 13 (45%) had itching, and one fever. clinical classification revealed 4 pleva (figure 2a and 2b) and 25 plc (figure 2c and 2d). histological evaluation was possible in 14 patients; six (43%) presented histology consistent with the chronic form (plc), four (28.5%) with the acute form (pleva), and four (28.5%) presented histology with characteristics of both forms and were classified as mixed. comparing histology and clinical diagnoses showed that the six cases with plc histology also had the same clinical diagnosis. the four mixed histology cases clinically presented as plc. in the four acute histology (pleva) cases, one was clinically classified as plc (figure 3a and 3b). follow-up was lost in 11 cases. of the 18 followed up, improvement was seen in 15, of which 11 had recevied erythromycin or tetracycline and four were treated with moisturizing cream until returning after biopsy, when they presented disease remission without the need for specific treatment. figure 2. (a) pleva—2 to 3 mm reddish-brown purpuric papules. (b) varioliform scarring. (c) plc—erythematous papules with residual macules of postinflammatory hypopigmentation. (d) papule with a fine scaling that detaching from the periphery to the center (plc). [copyright: ©2013 markus et al.] figure 3. (a) erythematous papules with a fine scaling without necrosis. (b) hypochromic macules on the trunk. [copyright: ©2013 markus et al.] 10 research | dermatol pract concept 2013;3(4):2 references 1. paller as, mancini aj. hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence. 4th ed. philadelphia: elsevier saunders, 2011. 2. perrin bs, yan ac, treat jr. febrile ulceronecrotic muchahabermann disease in a 34-month-old boy: a case report and review of the literature. pediatr dermatol. 2012;29(1):53-8. 3. folster-holst r, kreth hw. viral exanthems in childhood. part 3: parainfectious exanthems and those associated with virus-drug interactions. j dtsch dermatol ges. 2009;7(6):506-10. 4. rook a, burns t. rook’s textbook of dermatology. 8th ed. west sussex: wiley-blackwell, 2010. 5. bowers s, warshaw em. pityriasis lichenoides and its subtypes. j am acad dermatol. 2006;55(4):557-72; quiz 573-556. 6. newell el, jain s, stephens c, martland g. infliximab-induced pityriasis lichenoides chronica in a patient with psoriasis. j eur acad dermatol venereol. 2009;23(2):230-1. 7. kim je, yun wj, mun sk, et al. pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica: comparison of lesional t-cell subsets and investigation of viral associations. j cutan pathol. 2011;38(8):649-56. 8. ersoy-evans s, greco mf, mancini aj, subasi n, paller as. pityriasis lichenoides in childhood: a retrospective review of 124 patients. j am acad dermatol. 2007;56(2):205-210. 9. kempf w, kazakov dv, palmedo g, et al. pityriasis lichenoides et varioliformis acuta with numerous cd30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. a clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. am j surg pathol. 2012;36(7):1021-9. 10. dereure o, levi e, kadin me. t-cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. arch dermatol. 2000;136(12):1483-6. 11. shieh s, mikkola dl, wood gs. differentiation and clonality of lesional lymphocytes in pityriasis lichenoides chronica. arch dermatol. 2001;137(3):305-8. 12. romani j, puig l, fernandez-figueras mt, de moragas jm. pityriasis lichenoides in children: clinicopathologic review of 22 patients. pediatr dermatol. 1998;15(1):1-6. 13. wahie s, hiscutt e, natarajan s, taylor a. pityriasis lichenoides: the differences between children and adults. br j dermatol. 2007;157(5):941-5. 14. mandell gl, bennett je, dolin r. mandell, douglas, and bennett’s principles and practice of infectious diseases. 7th ed. london: churchill livingstone, 2010. 15. carvalho vo, marinoni lp, tarastichuck av, giraldi s, abagge k. vitiligo: análise de 174 casos na população pediátrica. anais brasileiros de dermatologia. 1998;73:419-23. spective study; another possibility is the question of a subjective symptom, causing variations between different populations. fever was reported in one patient with pleva diagnosis [8]. follow-up is important to determine clinical improvement and adherence to prescribed treatment. follow-up was abandoned in 38% of patients; this also occurred in vitiligo patients in an earlier study at the same service [15], probably reflecting a characteristic peculiar to the type of population seen in this center. in most cases where evaluative follow-up was possible, there was clinical improvement and erythromycin or tetracycline treatment was effective, therefore this is the treatment of choice due to its anti-inflammatory effect and immunological control [8,12]. as in the clinical study, histology showed a predominance of parameters considered more characteristic of the chronic form. microscopic findings described in pl are controversial. some studies show a predominance of pleva, in 57.3% of patients [8], others show plc in 72% [12]. this probably reflects the diverse range of clinical presentations of the disease, which can characteristically exhibit lesions in different stages of evolution. there was one case where clinical and histological findings disagreed; this probably occurred due to the choice of lesion submitted for biopsy, which presented more accentuated erythema and scaling. the microscopic aspect actually showed the characteristics of the evolution phase of the lesion that was analyzed and not necessarily the disease of the patient as a whole. this reinforces the need to associate clinical and histological parameters in classifying the disease, it being advisable to not base pl classification just on microscopic aspects. conclusion pityriasis lichenoides in the pediatric age group begins around 8 years of age and is more frequent in boys. plc was prevalent and a delay in diagnosis was seen reinforcing the need for knowing the clinical characteristics of this dermatosis. disease seasonality could have implications in physiopathology, but needs evaluation with a larger number of cases for confirmation. cutaneous biopsy can be very valuable in definitive diagnosis, however morphological findings depend directly on the evolutionary phase of the lesion chosen for analysis. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020061 1 dermatology practical & conceptual introduction leishmaniasis is caused by an intracellular protozoon and is characterized by a broad spectrum of cutaneous, mucosal, and systemic presentations [1]. the clinical manifestations of leishmaniasis are determined by the subtype of the infectious agent and the immunocompetent profile of the patient [1]. the introduction of biologics is accompanied with impressive therapeutic outcomes, but also with an increase in the incidence of several infectious diseases [1]. we present the case of a patient who developed a disseminated cutaneous leishmaniasis infection during treatment with adalimumab. case presentation a 68-year-old man from southwestern greece presented in our dermatology department because of the appearance of 10 disseminated, centrally erosive, erythematous cutaneous nodules and plaques, approximately 1.5 to 2 cm in diameter, distributed in the trunk and the lower extremities, partially in a sporotrichoid pattern, which had been persistent over 7 months prior to the referral (figure 1). the patient was a farmer and had been receiving ongoing treatment with methotrexate (7.5 mg subcutaneously every week) and adalimumab (40 mg subcutaneously every other week) over a period of 9 a rare infectious complication of a treatment with biologics: disseminated cutaneous leishmaniasis associated with adalimumab kerasia-maria plachouri,1 maria gkermpesi,2 eleftheria vryzaki,1 pinelopi kollyrou,1 markos marangos,3 sophia georgiou1 1 department of dermatology, university general hospital of patras, greece 2 department of pathology, university general hospital of patras, greece 3 division of infectious diseases, university general hospital of patras, greece key words: adalimumab, leishmaniasis, immunosuppression, psoriasis, biologics citation: plachouri k-m, gkermpesi m, vryzaki e, kollyrou p, marangos m, georgiou s. a rare infectious complication of a treatment with biologics: disseminated cutaneous leishmaniasis associated with adalimumab. dermatol pract concept. 2020;10(3):e2020061. doi: https://doi.org/10.5826/dpc.1003a61 accepted: march 17, 2020; published: june 29, 2020 copyright: ©2020 plachouri et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: kerasia-maria plachouri, university general hospital of patras, rio 265 04, greece. email: kerasia.plachouri@ hotmail.com figure 1. cutaneous leishmaniasis lesions caused by l infantum on the left thigh of the patient. https://doi.org/10.5826/dpc.1003a61 mailto:kerasia.plachouri@hotmail.com mailto:kerasia.plachouri@hotmail.com 2 letter | dermatol pract concept 2020;10(3):e2020061 adhesion molecules such as e-selectin and intercellular adhesion molecule 1 [1]. the latter are necessary for the mononuclear cell recruitment and the formation of granulomas that enable the eradication of leishmania spp [1]. forty-nine cases of anti-tnf-α–associated leishmaniasis are published in the literature, 28 with cutaneous leishmaniasis, 16 with visceral leishmaniasis, and 5 with mucocutaneous leishmaniasis [1]. all patients with visceral leishmaniasis and mucocutaneous leishmaniasis received a systemic treatment; the therapy of choice was in most cases intravenous liposomal amphotericin b in various dosage regimens with a cumulative dose ranging from 15.4 mg/kg to 50 mg/kg, while less frequently parenteral pentavalent antimonials and miltefosine were also administered [1]. half of the patients with cutaneous leishmaniasis received a systemic treatment with liposomal amphotericin b as well, while the rest of the cases were treated with intralesional pentavalent antimonials, occasionally combined with surgical excision or cryotherapy [1]. it is interesting that the tnf-α inhibitor treatment had to be stopped in only 32 of the reported cases [1]. all patients showed a full recovery, but relapses were reported in 3 patients treated with intralesional pentavalent antimonials, 1 patient treated with surgery, and only 2 patients treated with systemic liposomal amphotericin b and miltefosine, respectively [1]. although these data seem relevant only for areas where these infectious diseases are endemic, such as south europe and south america, one cannot underestimate the fact that the massive human migration for socioeconomic reasons may gradually change the epidemiological and demographic aspects of infectious diseases [2]. it is necessary for physicians to gain familiarity with leishmaniasis and to maintain a high level of suspicion, especially in iatrogenically immunosuppressed patients, in order to reach an early diagnosis and thus prevent disease-related complications as well as disease transmission in nonendemic areas [2]. years for plaque psoriasis and psoriatic arthritis. at the time of presentation both diseases were in long-term remission, with no signs of cutaneous psoriatic lesions, lymphadenopathy, or arthritis during the physical examination. the histopathological examination of one of the skin lesions showed evidence of a leishmania spp infection (figure 2). the agent was identified as l infantum, using the polymerase chain reaction (pcr) technique in a skin biopsy sample. the screening for visceral leishmaniasis, which included the measurement of antibodies against the recombinant k39 antigen, the specific anti-leishmania antibody titers in blood serum, as well as pcr in a bone marrow aspirate sample, showed no leishmania-associated findings. an ultrasound examination showed no signs of hepatosplenomegaly and a chest x-ray revealed no abnormal findings. owing to the occurrence of 10 or more disseminated lesions in more than 2 noncontinuous anatomic locations, the condition was characterized as a disseminated cutaneous leishmaniasis. the treatment with adalimumab and methotrexate was interrupted and treatment with liposomal amphotericin b was initiated (3 mg/kg/day, administered intravenously on days 1-5, 10, 17, 24, 31, and 38). the therapy was well tolerated. in the 24-month follow-up the patient remained asymptomatic, with almost total clearance of the cutaneous lesions (figure 3). adalimumab was reinitiated 1.5 years after the successful eradication of leishmaniasis, with no signs of recurrence over the 48-month follow-up (figure 3). conclusions in the era of biologics, physicians often witness the reactivation of latent infections, such as tuberculosis or leishmaniasis [1]. when it comes to leishmaniasis in relation to tumor necrosis factor alpha (tnf-α) inhibitors, one of the suggested pathogenetic mechanisms of infection is believed to be a tnf-α inhibitor–mediated downregulation of endothelial figure 2. histopathological image of cutaneous leishmaniasis. dense dermal infiltrate of large histiocytes. leishman-donovan bodies are found in histiocytes, lining their internal membrane (arrow). an admixture of lymphocytes, neutrophils, and plasma cells are also present (arrow) (giemsa stain, ×400). figure 3. almost complete clearance of the leishmaniasis lesions on the left thigh of the patient (24-month follow-up). letter | dermatol pract concept 2020;10(3):e2020061 3 2019;13(8):e0007708. https://doi.org/10.1371/journal.pntd. 0007708 2. stamm lv. human migration and leishmaniasis—on the move. jama dermatol. 2016;152(4):373-374. https://doi.org/10.1001/ jamadermatol.2015.4765 references 1. bosch-nicolau p, ubals m, salvador f, et al. leishmaniasis and tumor necrosis factor alpha antagonists in the mediterranean basin: a switch in clinical expression. plos negl trop dis. https://doi.org/10.1371/journal.pntd.0007708 https://doi.org/10.1371/journal.pntd.0007708 https://doi.org/10.1001/jamadermatol.2015.4765 https://doi.org/10.1001/jamadermatol.2015.4765 dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020076 1 dermatology practical & conceptual introduction isolated lip lichen planus (lp) can mimic lip discoid lupus erythematosus, actinic cheilitis, pemphigus vulgaris, exfoliative cheilitis, and herpes simplex [1]. dermoscopic features of cutaneous lp have been well-described in the literature, with wickham striae (ws) as the distinctive feature of an active disease. however, the dermoscopic patterns of lip lp remain to be elucidated. only a few case reports have reported the dermoscopic patterns of lip lp that include ws: diffuse scaling and violaceous background [1,2]. herein, we aim to provide new insights into the dermoscopic profile of biopsy-proven cases of lip lp. case presentation a total of 12 biopsy-proven patients of lip lp who had not taken any treatment were included in the study (figure 1). clinical profiles of the patients are listed in table 1. nine cases (75%) had isolated lip involvement. one case (8.3%) had also involvement of buccal mucosa and 2 (16.6%) had additional buccal mucosal and cutaneous lp lesions. ten patients (83.3%) had a lower lip lp. dermoscopic images were captured using a dermlite dl4 dermatoscope attached to samsung galaxy note 10 mobile phone. the images were independently analyzed by 2 expert dermatologists. various dermoscopic features seen were ws (100%), scaling (100%), black/gray/brown/ pigmentation as dots or globules (100%), vascular pattern (91.7%), erosion with bleeding spots (50%), and rosettes (41.7%) over an erythematous-to-violaceous background in all 12 cases (table 2). a mixed pattern of ws and predominant radial pattern in 9/12 cases (75%) (figure 2) was noticed. these patients had a disease duration of >9 months. a “leaf venation-like pattern” was seen in 2 cases (16.7 %) with duration of lesions of <6 months (figure 3). linear ws were present in 4 cases (33.3%) (figure 4). all 6 cases (50%) with erosions had prominent hairpin and linear telangiectasia (figure 5). another vascular pattern seen in 9 (75%) cases was dotted (figure 4). black to gray-black pigmentation was highlighted in cases with disease duration of >12 months (figure 6). on polarized dermoscopy, rosettes are seen as 4 white dots arranged in a square resembling a 4-leaf clover, which corresponds to concentric horny material in follicular and dermoscopy of lip lichen planus—a descriptive study shekhar neema1, sunmeet sandhu1, a.w. kashif2, preema sinha1, rohit kothari1, s. radhakrishnan1 1 department of dermatology, armed forces medical college, pune, india 2 department of pathology, armed forces medical college, pune, india key words: dermoscopy, lip lichen planus, leaf venation-like, wickham striae citation: neema s, sandhu s, kashif aw, sinha p, kothari r, radhakrishnan s. dermoscopy of lip lichen planus—a descriptive study. dermatol pract concept. 2020;10(4):e2020076. doi: https://doi.org/10.5826/dpc.1004a76 accepted: april 21, 2020; published: october 26, 2020 copyright: ©2020 neema et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sunmeet sandhu, md, department of dermatology, armed forces medical college, southern command, solapur – pune hwy, wanowrie 411040, pune, india. email: sunmeet.sandhu@gmail.com 2 letter | dermatol pract concept 2020;10(4):2020076 conclusions our study provides new insights into dermoscopic features of lip lp. ws, pigmentation, scales, and telangiectasia are the hallmarks of lip lp. in contrast to the previously reported eccrine ducts at the infundibular level or peri-follicular concentric fibrosis. interestingly this pattern was seen in 4 patients (33.3%) with prominent scaling that might correspond to polarized keratin-filled eccrine duct narrowing at the lip margin (figure 5). the limitation of our study was a small number of patients and the lack of a control group; therefore, the accuracy of various diagnostic criteria could not be performed. table 1. demographic profile of patients with duration of disease number percentage gender male 8 66.7% female 4 33.3% age (years) <20 1 8.3% 21-40 2 16.7% 41-60 7 58.3% >60 2 16.7% duration (months) <6 2 16.7% 6-12 4 33.3% 12-24 4 33.3% >24 2 16.7% site of lesions lower lip 10 83.3% both lips 02 16.7% table 2. frequency of dermoscopic features in lip lichen planus (n=12) study dermoscopic feature number percentage 01 wickham striae 12 100% leaf venation-like 02 16.7% radial 09 75% linear 04 33.3% 02 scales 12 100% 03 pigmentation 12 100% gray-black granules, globules 10 83.3% brown 02 16.7% 04 vascular pattern 11 91.7% linear 10 83.3% hairpin 08 66.7% dotted 09 75% 05 background erythematous 07 58.3% violaceous 05 41.7% 06 erosion 06 50% 07 bleeding spots 04 33.3% 08 rosettes at lip margin 04 33.3% figure 2. radial pattern of wickham striae (blue circle), erosion and hairpin vessels (yellow arrow) (dermlite dl4; polarized, ×10). figure 1. biopsy from lip shows focal parakeratosis, hypergranulosis (blue arrow), interface dermatitis (yellow star), civatte bodies, and pigment incontinence, suggestive of lichen planus (h&e, ×100). letter | dermatol pract concept 2020;10(4):2020076 3 references 1. mathur m, acharya p, karki a, kc n, shah j, jha a. isolated lichen planus of lip: diagnosis and treatment monitoring using dermoscopy. clin case rep. 2019;7(1):146–148. doi: 10.1002/ccr3.1933. pmid: 30656029. 2. yeo ik, kim hk, kim dh, et al. oral lichen planus for whom dermoscopy was used as an adjuvant diagnostic tool. korean j dermatol. 2012;50(2):167-170. reticular pattern of cutaneous lp, radial ws are the characteristic feature seen in lip lp. leaf venation-like ws, hairpin vascular pattern, and rosettes are new dermoscopic features that we did not find described in lip lp. figure 3. leaf venation-like wickham striae (blue star), scaling, dotted vessels and pigmented granules over a violaceous background (yellow star) (dermlite dl4; polarized, ×10). figure 4. linear wickham striae (blue arrow), dotted, linear and hairpin vessels (yellow circle) (dermlite dl4; polarized, ×10). figure 5. erosion with bleeding spots and dotted vessels (blue circle), prominent hairpin and linear vessels (yellow rectangle). inset: rosettes (yellow star), bleeding spots and hairpin vessels (dermlite dl4; polarized, ×10). figure 6. prominent uniform-to-granular black pigmentation (yellow star) along with radial and linear wickham striae. gray dots and globules (blue star) (dermlite dl4; polarized, ×10). observation | dermatol pract concept 2011;1(1):7 25 cutaneous and uterine leiomyomatosis and ovarian cystadenoma associated with deficiency of fumarate hydratase cornelia hüller, m.d.1, norbert grunow, m.d.2, torsten nadler, m.d.3, michael bär, m.d.1* 1department of dermatology, görlitz municipal hospital, görlitz, germany 2department of pathology, görlitz municipal hospital, görlitz, germany 3department of gynecology, görlitz municipal hospital, görlitz, germany key words: uterine leiomyomatosis, ovarian cystadenoma, fumerate hydratase citation: hüller c, grunow n, nadler t, bär m. cutaneous and uterine leiomyomatosis and ovarian cystadenoma associated with deficiency of fumerate hydratase. dermatol pract concept 2011;1(1):7. http://dx.doi.org/10.5826/dpc.0101a07. editor: harald kittler, m.d. received: march 29, 2011; accepted: june 1, 2011; published: october 31, 2011 copyright: ©2011 hüller et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: michael bär, m.d., department of dermatology, görlitz municipal hospital, girbigsdorfer straße 1–3, 02828 görlitz, germany, tel. ++49.3581.371490, fax. ++49.3581.371499. email baer.michael@klinikum-goerlitz.de. we report on an exceedingly rare case of cutaneous and uterine leiomyomatosis in a 58-year-old caucasian woman associated with ovarian cystadenoma and complete deletion of the fumarate hydratase gene. all patients and their family members with verified mutation have to be regularly screened for associated neoplasms, in particular papillary renal cell carcinoma (hlrcc, hereditary leiomyomatosis and renal cell cancer). abstract case report we report on a 58-year-old caucasian woman that was hospitalized owing to a monstrous ovarian tumor on the right side with a three-month history of sudden abdominal growth and subsequent dyspnea. sonography and ct scan rendered an additional myomatous uterus with requirement of a bilateral hysterosalpingectomy. the last consultation with a gynecologist had been about eight years prior. the complete staging was without evidence of further neoplasms and the patient was otherwise healthy. the patient had eight deliveries and one abortion. she finally was referred to a dermatologist because of multiple agminated dense erythematous nodules restricted to the skin of the left shank and the right flank with a few aberrant lesions at the dorsal trunk only (figure 1). the patient reported occasionally associated painful sensations but did not request further treatment. the nodules obviously had rapidly appeared in the context of alvine tuberculosis at the age of 13. however, a relapse of the previous mycobacteriosis was excluded upon punctuation of the ovarian tumor. histopathologically, there was evidence of a severe fibroleiomyomatosis of the uterus with an associated dexter ovarian cystadenoma (diameter 25 cm) (figure 2). a biopsy of the dermatology practical & conceptual www.derm101.com 26 observation | dermatol pract concept 2011;1(1):7 a a a b b b c figure 3. piloleiomyoma consisting of a plaque-like confluent fascicular spindle cell proliferation obviously originating in the muscle of hair erection (a, he 40x). nuclei were cigar-shaped and in part exhibited vesicular pseudoinclusions (b, he 400x). there was no mitotic activity. however, some plump cells were seen and interpreted as a clue to ancient changes (c, he 400x). figure 2. an ovarian cystadenoma measuring 25 cm fixed by a standard formaldehyde solution (a); section across the uterine corpus revealing several intramural leiomyomas with obstruction of the uterine cavum (b). figure 1. agminated, in part, plaque-like confluent dense erythematous papules restricted to the skin of the left shank (a) and the right flank (b), with few aberrant lesions at the dorsal trunk only. there is no obvious relation to blaschko’s lines or dermatomes. observation | dermatol pract concept 2011;1(1):7 27 cutaneous lesions on the right flank revealed pilar leiomyomas consisting of a plaque-like confluent fascicular spindle cell proliferation obviously originating in the muscles of hair erection. nuclei were cigar-shaped and in part exhibited vesicular pseudoinclusions. there was no mitotic activity. however, some plump cells were seen and interpreted as a clue to ancient changes (figure 3). smooth muscular differentiation was confirmed immunohistochemically by coexpression of actin, desmin and smooth muscle actin. the proliferation index as detected by nuclear ki67 expression was less than 1%. blood samples with addition of edta were analyzed molecularpathologically and a complete deletion of the fumarate hydratase gene was detected. commentary in contrast to the frequent uterine leiomyomas, cutaneous leiomyomas are rare and benign, but occasionally painful tumors originating in the smooth muscles of the pilar apparatus, the vessels or the genital skin. in patients suffering from multiple cutaneous leiomyomas a germline mutation of the fumarate hydratase with incomplete penetrance may be frequently found. in females, this mutation may be frequently associated with uterine leiomyomatosis. our patient was not aware of a similar disease in other family members, however, had not been in contact with any of them for years; thus, a reliable statement about a given episodic versus familiar disease can not be given. fumarate hydratase is a constituent of the citric acid cycle and usually catalyzes the hydratation of fumarate to l-malate. however, the corresponding gene might be of additional impact as a tumor suppressor gene. leiomyomatosis cutis et uteri was first described in 1954 by blum and jean [1]. however, the eponymical denomination as reed’s syndrome was based on a corresponding case report published in 1973 [2]. the cutaneous lesions usually appear during adolescence, predominantly affecting the trunk and extremities in an agminated pattern [3]. a subset of patients is at relevant risk of early development of associated aggressive papillary renal cell cancer, a constellation then termed hereditary leiomyomatosis and renal cell cancer, hlrcc. further tumors associated with deficiency of the fumarate hydratase are cutaneous or uterine leiomyosarcomas, carcinomas of the bladder or prostate gland, breast cancer, gastrointestinal stroma tumors, but also benign tumors like adrenal adenomas, renal cysts or rarely, like in our patient, ovarian cystadenomas [4]. all patients and their family members with verified mutation have to be regularly screened for associated neoplasms, in particular, papillary renal cell carcinoma. females with cutaneous lesions only should be regularly screened for uterine disease, too, in order not to miss a relevant syndromal context. thus, eventually associated malignomas might be detected at an early stage with rather curative treatment options. among the reported, although experimental, treatment options of the cutaneous leiomyomas are excision or ablation by laser, but also analgetic approaches using botox, nifedipine, nitroglycerine, phenoxybenzamine, gabapentin, doxazosin or local anaesthetics [5]. references 1. blum p, jean l. leiomyome eruptif de besnier. bull soc f dermatol syph 1954;61(4):349-50. 2. reed wb, walker r, horowitz r. cutaneous leiomyomata with uterine leiomyomata. acta derm venereol 1973; 53(5):409-16. 3. alam na, barclay e, rowan aj, et al. clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. arch dermatol 2005;141(2):199-206. 4. ylisaukko-oja sk, cybulski c, lehtonen c, et al. germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma. eur j hum gen 2006;14(7):880-3. 5. kim g. multiple cutaneous and uterine leiomyomatosis (reed’s syndrome). dermatol online j 2005;11(4):21. dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;2(2):6 25 dermoscopy in the southern hemisphere: a success story h. peter soyer, m.d., facd1 1 dermatology research centre, the university of queensland, school of medicine, princess alexandra hospital, brisbane, australia. citation: soyer hp. dermoscopy in the southern hemisphere: a success story [editorial]. dermatol pract conc. 2012;2(2):6. http://dx.doi. org/10.5826/dpc.0202a06. copyright: ©2012 soyer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: h. peter soyer, m.d., facd. dermatology research centre, the university of queensland, school of medicine, princess alexandra hospital, brisbane, qld, 4102, australia. email: p.soyer@uq.edu.au. a success story when harald kittler asked me to write an editorial on dermoscopy (to be precise, he used the linguistically correct term dermatoscopy) for dermatology practical & conceptual, the journal founded by bernie ackerman and now under his editorship, i must admit i accepted his invitation with an element of uneasiness. perhaps because i recall that bernie never really embraced dermoscopy and not simply because of the linguistic misnomer [1]. as much as he was fascinated by the clinicopathologic correlation of inflammatory skin diseases, and to a lesser extent also of melanocytic proliferations, he seemed to ignore the equally fascinating universe of dermoscopic-pathologic correlation. in any case, all of my work in this arena in the last two decades was, and is, heavily influenced by bernie’s dogma of the significance of clinicopathologic correlation. therefore, i see this editorial is an excellent opportunity to pay respect to bernie as a mentor and a teacher and to cite the book of bernie’s that i have enjoyed reading most, namely, the lives of lesions [2]. in short, dermoscopic-pathologic correlation of melanocytic proliferations and study of the lives of naevi (and sometimes, by chance, melanomas) dermoscopically is based on his seminal work and influenced by his unique morphologic approach. and in this context i am very pleased indeed to write this editorial. given my current location in australia, brisbane, the capital of queensland to be precise, i wish to focus this editorial on dermoscopy down under, and i specifically draw attention to the following relevant points: i) dermoscopy is frequently adopted by a large proportion of australian dermatologists for detailed lesion examination. a nationwide dermoscopy survey investigating the prevalence, advantages and disadvantages of dermoscopy use among australian dermatologists gave evidence that a total of 98% of dermatologists (99 of the 283 [35%] dermatologists completed the survey eligibly) reported using dermoscopy, 95% of which had received formal training. further, 85% found it improved diagnosis compared to naked eye examination; and 57% of dermatologists used baseline dermoscopy to follow up changes in lesions over time [4]. ii) within australia, dermoscopy appears to be commonly utilised in the wider medical community, particularly in the non-dermatologist skin cancer medicine community (although no robust data are available), and an agenda for quality health outcomes has been recently proposed, including training and education in dermoscopy [3] to further improve this service that is in high demand. this agenda has been undertaken by several providers in colleges and universities in australia, who also provide education in dermoscopy at a high level. iii) evaluation of dermoscopic naevus patterns in the southern hemisphere. a recent study looking at baseline descriptions of naevus patterns in high and moderate/low melanoma risk groups of the population in queensland found that high melanoma risk does not influence dermoscopic naemailto:p.soyer@uq.edu.au 26 editorial | dermatol pract concept 2012;2(2):6 vus patterns. specifically, in both high and moderate/low risk groups, globular naevi predominated on the head/neck and abdomen/chest, reticular and non-specific naevi on the back, and non-specific patterns on the upper and lower limbs [5]. iv) the third world congress of dermoscopy to be held in brisbane in may 2012. this meeting, as the first international dermoscopy congress ever to be held south of the equator, promises dermatologists and general practitioners interested in skin cancer medicine an exciting and diverse scientific program addressing the current status of dermoscopy in addition to the research outcomes and future projections of its application in clinical practice (see http://www.dermoscopycongress2012.org/). therefore, it can be said that dermoscopy is generating the same clinical outcomes and research interest within the southern hemisphere, specifically here in australia, as it has throughout the world, and remains a vital component of expert lesion analysis. a final word needs to be said about harald kittler, the new editor of dermatology practical & conceptual. he is one of most assiduous fellows of bernie and although starting with dermatopathology a bit later in his professional life, he is living clinical dermatology and dermatopathology whole-heartedly and critically, both ingredients for a successful editorship. i wish him and dermatology practical & conceptual well, and i hope that readers will embrace this journal as they did with dermatopathology: practical & conceptual. acknowledgment: i am very grateful to ms. terri m. biscak, bbmedsc (hons) for her professional editing. references 1. ackerman ab. dermatoscopy, not dermoscopy! j am acad dermatol. 2006;55(4):728. 2. ackerman ab, ragaz a. the lives of lesions. chronology in dermatopathology. new york, ny: ardor scribendi, ltd.,1984. 3. wilkinson d, bourne p, dixon a, kitchener s. skin cancer medicine in primary care: towards an agenda for quality health outcomes. med j aust. 2006;184(1):11-2. 4. venugopal ss, soyer hp, menzies sw. results of a nationwide dermoscopy survey investigating the prevalence, advantages and disadvantages of dermoscopy use among australian dermatologists. australas j dermatol. 2011;52(1):14-8. 5. douglas nd, borgovan t, carroll mj, et al. dermoscopic naevus patterns in people at high versus moderate/low melanoma risk in queensland. australas j dermatol. 2011;52(4):248-53. http://www.dermoscopycongress2012.org/ http://www.dermoscopycongress2012.org/ http://www.ncbi.nlm.nih.gov/pubmed?term=%22ackerman ab%22%5bauthor%5d http://www.ncbi.nlm.nih.gov/pubmed?term=ackerman dermatoscopy http://www.ncbi.nlm.nih.gov/pubmed?term=ackerman dermatoscopy http://www.ncbi.nlm.nih.gov/pubmed/16398623 http://www.ncbi.nlm.nih.gov/pubmed/16398623 http://www.ncbi.nlm.nih.gov/pubmed/16398623 dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020070 1 dermatology practical & conceptual introduction pigmented epithelioid melanocytoma (pem) is an uncommon and recently described entity with unknown biologic behavior. it is a melanocytic tumor showing overlapping features of both an atypical epithelioid blue nevus and a lowgrade “animal-type melanoma.” pem occurs over a broad age range, with a predilection for children and young adults, and clinically appears as a macular, popular, or nodular lesion. dermoscopically, pem appears as a polymorphic lesion, characterized by homogeneous blue pigmentation and a combination of black, brown, and white colors. histopathologically, it is characterized by a dermal proliferation of heavily pigmented, both dendritic and spindle/epithelioid melanocytes, admixed with slightly larger, plumper, and less pigmented epithelioid cells [1]. involvement of the regional nodes has been reported but usually with no further spread of the disease. no histological criteria are predictive of metastatic behavior. case presentation we describe a case of vulvar mucosal pem, that occurred on the right small lip of a 50-year-old woman. clinically it appeared as an intensely pigmented, brown-black papule about 1 cm in size. on dermoscopy, we observed many irregular, black blotches surrounded by a whitish blue veil. no atypical vascular feature was detected. due to its globular structure and black-bluish color and considering the age of the patient and rapid onset, the lesion resembled a spitz nevus or an atypical spitz tumor (figure 1, a and b). however, spitzoid lesions do not show these dermoscopic features. therefore, an excisional biopsy was performed. the histological examination showed an acanthotic epidermis with a slightly warty profile overlying a large dermal nodular lesion with blurred borders consisting of hyperpigmented epithelioid and spindle dendritic melanocytes arranged in perivascular and periadnexal bundles, mixed with epithelioid nevoid cells and numerous melanophages. no significant atypia, mitosis, or necrosis was appreciated. a case of a pigmented epithelioid melanocytoma on a mucosal site alice ramondetta1, simone ribero1, luca conti1, pietro quaglino1, paolo broganelli1 1 dermatology clinic and surgical pathology section, department of medical sciences, university of turin, italy key words: melanocytoma, epithelioid cells, vulva, genital dermatopathology, melanocytic lesion citation: ramondetta a, ribero s, conti l, quaglino p, broganelli p. a case of a pigmented epithelioid melanocytoma on a mucosal site. dermatol pract concept. 2020;10(4):e2020070. doi: https://doi.org/10.5826/dpc.1004a70 accepted: april 21, 2020; published: october 26, 2020 copyright: ©2020 ramondetta et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: simone ribero, md, phd, dermatology clinic, department of medical sciences, university of turin, via cherasco 23, 10126, italy. email: simone.ribero@unito.it 2 letter | dermatol pract concept 2020;10(4):2020070 and malignant lesions, from which it must be distinguished, albeit with difficulty. references 1. moscarella e, ricci r, argenziano g, et al. pigmented epithelioid melanocytoma: clinical, dermoscopic and histopathological features. br j dermatol. 2016;174(5):1115-1117. https://doi. org/10.1111/bjd.14322. pmid:26614732. 2. uehara m, sato s, kato a, et al. a rare case of pigmented epithelioid melanocytoma on the penis as a divided nevus. eur j dermatol. 2014;24(2):248-249. https://doi.org/10.1684/ ejd.2014.2272. pmid:24723648. immunohistochemical staining was performed. while hmb45 and melan-a were positive, p16 was expressed on the entire lesion, and ki-67 showed low activity (1%) (figure 2, a and b). conclusions pigmented lesions of mucosal sites usually can be difficult to interpret. pem is a rare entity, and we report on a case of a female genital mucosal variant. uehara et al published a case of pem on the glans [2]. pem could mimic both benign figure 1. (a) clinical appearance: oval papule, brown-black in color, intensely pigmented, about 1 cm in size. (b) dermoscopy: many irregular, black blotches surrounded by a whitish blue veil. no atypical vascular feature was detected. figure 2. (a) histopathological specimen: acanthotic epidermis with a slightly warty profile overlying a large dermal nodular lesion with blurred limits consisting of hyperpigmented epithelioid and spindle dendritic melanocytes arranged in perivascular and periadnexal bundles, mixed with epithelioid nevoid cells and numerous melanophages. no significant atypia, mitosis, or necrosis was appreciated. immunohistochemical staining: hmb-45, melan-a (b) and p16 (all expressed), ki-67 (1%). a b a b dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;3(1):1 1 editorial in a recent two-part essay entitled “the dysplastic nevus: from historical perspective to management in the modern era” published in the journal of american academy of dermatology, duffy and grossman concluded, following comprehensive literature review, historically, histologically, clinically and molecularly, that the so-called dysplastic nevus is a type of melanocytic nevus and should be managed like other types of melanocytic nevi [1,2]. this reinforces the notion set forth by the late bernie ackerman, who asserted more than two decades ago that the so-called dysplastic nevus is the commonest melanocytic nevus in man [3]. duffy and grossman acknowledged that the term dysplastic nevus is inappropriate, however, they did not advocate change of the term in these words: “the term ‘dysplastic nevus,’ despite its problems, should not be abandoned—it has become entrenched in our dermatologic language and practice.” [1] we believe the authors underestimated the ramification of continuing the use of an inappropriate term. historically, the introduction of the term dysplastic nevus was based on an assumption, which has been found to be incorrect. clark and coworkers believed in the multistep carcinogenesis theory and thought that the lesion under discussion represented an intermediate step between nevus and melanoma. in an article by clark and coworkers, they expressed this view in these words: “[dysplastic nevi] fit nicely into the schema of progression from hyperplasia to dysplasia to neoplasia that is accepted in many epithelial tumor systems, both experimental and human” [4]. as one examines the literature, there is really no evidence in support of the multistep carcinogenesis theory and there is no intermediate entity between nevus and melanoma [5]. secondly, although the word “dysplasia” has never been lucidly defined in pathology, whenever the word dysplasia is used in tumor pathology, it generally refers to intraepithelial neoplasia with cytomorphologic features of malignancy, namely, carcinoma in situ lesions, by surgical pathologists. if one looks for an equivalent lesion to the so-called dysplastic (carcinoma in situ) lesions of epithelial tissue in melanocytic neoplasia, melanoma in situ would be the one, not the socalled dysplastic nevus. we have come to know the lesion under discussion is as a variant of melanocytic nevus and the commonest nevus in humans. in other words, it is totally benign and not dysplastic at all, namely, neither an intermediate step between nevus and melanoma nor a carcinoma in situ equivalent. there is no need to excise it surgically unless other than for cosmetic reasons or suspicion of melanoma. however, such a benign lesion has certainly been overtreated since 1980, when the term dysplastic nevus was first introduced [4], due to the continued wrong belief that it represented an intermediate step between nevus and melanoma or a carcinoma in situ equivalent. a survey by tripp et al found that 86% the so-called dysplastic nevus is not dysplastic at all raman madan1, sheng chen, m.d., ph.d.2 1 drexel university college of medicine, philadelphia, pa, usa 2 department of pathology and laboratory medicine, hofstra north shore-lij school of medicine, lake success, ny, usa citation: madan r, chen s. the so-called dysplastic nevus is not dysplastic at all. dermatol pract conc. 2013;3(1):1. http://dx.doi. org/10.5826/dpc.0301a01. copyright: ©2013 raman et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: sheng chen, m.d., ph.d., department of pathology and laboratory medicine, hofstra north shore-lij school of medicine, 6 ohio drive, suite 202, lake success, ny 11042, usa. tel. 516.304.7279; fax. 516.304.7270. email. schen@nshs.edu. 2 editorial | dermatol pract concept 2012;3(1):1 of dermatologists intend on biopsy to remove the so-called dysplastic nevus completely, 75% use margins of 2 mm or less, and 67% would re-excise the so-called dysplastic nevus with positive histologic margins [6]. continued use of the term dysplastic nevus will certainly prolong the confusion and controversy of more than 30 years for many more years to come and contribute to the over-treatment of innumerable patients. when a term does not reflect the true nature of a lesion and continues to cause confusion in the medical field and mismanagement of patients, then the term has to be changed. simply stating that a term “has become entrenched in our dermatologic language and practice” does not preclude that term from being changed. what should the lesion under discussion be called then? we propose to simply call it melanocytic nevus—that is what it truly is. alternatively, one can call it clark’s nevus, as the late ackerman proposed, if one desires to distinguish it from other types of nevi [7]. just do not call it dysplastic nevus any more, for the so-called dysplastic nevus is not dysplastic at all. references 1. duffy k, grossman d. the dysplastic nevus: from historical perspective to management in the modern era: part i. historical, histologic, and clinical aspects. j am acad dermatol. 2012;67(1):1. e1-16. 2. duffy k, grossman d. the dysplastic nevus: from historical perspective to management in the modern era: part ii. molecular aspects and clinical management. j am acad dermatol. 2012;67(1):19.e1-12. 3. ackerman ab. what nevus is dysplastic, a syndrome and the commonest precursor of malignant melanoma? a riddle and an answer. histopathology. 1988;13(3):241-56. 4. greene mh, clark wh jr, tucker ma, et al. precursor naevi in cutaneous malignant melanoma: a proposed nomenclature. lancet. 1980;2:1024. 5. chen s. the dysplastic nevus controversy: it is not about the nevus per se but one’s belief in the multistep tumorigenesis theory. am j dermatopathol. 2010;32(8):858. 6. tripp jm, kopf aw, marghoob aa, bart rs. management of dysplastic nevi: a survey of fellows of the american academy of dermatology. j am acad dermatol. 2002;46(5):674-82. 7. ackerman ab, magana-garcia m. naming acquired melanocytic nevi. unna’s, miescher’s, spitz’s clark’s. am j dermatopathol. 1990;12(2):193-209. dermatology: practical and conceptual commentary | dermatol pract concept 2020;10(1):e2020006 1 dermatology practical & conceptual introduction nevus comedonicus is a rare hamartoma of the pilosebaceous unit, first described by kofmann in 1895 [1]. in most cases it is present at birth but may also develop later, usually before the age of 10 years, without racial or sexual preponderance. when appearing in adults, although rare, it is frequently associated with irritation or trauma [2]. the lesions typically present a linear or zosteriform distribution, but extensive areas have already been described, including variant with bilateral involvement. the most frequently affected sites are the face, trunk, neck, and upper limbs. it may affect areas without hair follicles, such as the palms, soles, and the glans penis. scalp involvement is rare [3]. there may be associations with other skin lesions or abnormalities of the central nervous, musculoskeletal, and ocular system [4]. we present a case of nevus comedonicus in a woman suffering from obesity and acne vulgaris. case presentation a 40-year-old woman with a history of obesity and acne presented with an asymptomatic lesion that had appeared 20 years previously on the right thigh. the clinical aspect and extent of the lesion caused relevant psychosocial repercussions, interfering with her personal relationships. at dermatological examination, bundles of dilated hair follicles were observed, filled with dark-colored plugs, presenting a linear distribution in the right thigh with alteration of the skin pigmentation at the site of the lesion; at dermoscopy, well-defined homogeneous areas in dark brown shades were noted (figure 1, a and b). some cysts had been treated in the past with antibiotics, leaving some hyperchromic signs on the thigh. the patient also suffered from facial acne (figure 2) that was resistant to numerous treatments performed in previous years: topical and systemic antibiotics and topical and systemic retinoids. the histological examination performed with a 5-mm diameter punch showed a large group of dilated follicular ostia devoid of hair shafts but filled with keratin layers (figure 3). on the basis of the history and typical features of the lesion and histology, a nevus comedonicus in a patient with resistant acne and obesity was diagnosed. consultations with other specialists excluded the presence of extracutaneous signs or association with genetic syndromes and other diseases or nevus comedonicus syndrome. the patient refused genetic analysis. because of the extent of the lesion and the possibility of its turning into an unaesthetic scar, we treated nevus comedonicus with acne vulgaris and obesity caterina mazzella,1 gabriella fabbrocini,1 maria antonietta luciano,2 sara cacciapuoti1 1 dermatology unit, department of clinical medicine and surgery, federico ii university of naples, italy 2 dermatology unit, department of public health, federico ii university of naples, italy key words: nevus, acne, obesity, hamartoma, pilosebaceous unit citation: mazzella c, fabbrocini g, luciano ma, cacciapuoti s. nevus comedonicus with acne vulgaris and obesity. dermatol pract concept. 2020;10(1):e2020006. doi: https://doi.org/10.5826/dpc.1001a06 accepted: september 1, 2019; published: december 31, 2019 copyright: ©2019 mazzella et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: caterina mazzella, md, via s pansini, n. 5, 80131, naples, italy. email: caterinamazzella@libero.it https://doi.org/10.5826/dpc.1001a06 mailto:caterinamazzella@libero.it 2 commentary | dermatol pract concept 2019;10(1):id e2020006 in each case of nevus comedonicus, it is obligatory to rule out the comedonicus syndrome, which may include ocular lesions (cataract, corneal erosion), skeletal abnormalities (syndactyly, clinodactyly, the absence of hand bones on x-ray, scoliosis, vertebral defects), and neurological disturbances (microcephaly, mental deficiency, the dysgenesis of the corpus callosum) [7]. in some cases of nevus comedonicus, a somatic mutation in fibroblast growth factor-receptor gene 2 (fgfr2) has been identified, namely the ser252trp missense mutation. fgfr2 is expressed in keratinocytes, hair follicles, and sebaceous glands and has been implicated in induction of hypercornification and comedogenesis. germline fgfr2 mutations are also associated with acne, as seen in dominant apert syndrome. when occurring as a mosaic, the acne lesions follow the lines of blaschko, the pattern of embryological cell development and proliferation [8]. in a recent case, a postzygotic mosaicism was found in exon 4 of fgfr2 (c.758c>g, p.pro253arg) in low copy number. a similar mosaicism was also found in 2 other patients in p.ser252trp of exon 4 [9]. fgf signaling pathways lead to the interplay of the mtorc1 and foxo1 pathways; the same pathway is regulated by increased caloric intake, leading to the onset of acne and metabolic syndrome [10]. the 2 pathways could be strictly dependent, explaining our clinical case. the patient with 33% salicylic acid peeling and home-based topical retinoid therapy, obtaining only partial benefit. discussion the prevalence of nevus comedonicus has been estimated from 1 in 45,000 to 1 in 100,000. nevus comedonicus lesions might present with various patterns of distribution: unilateral, bilateral, linear, interrupted, segmental, or blaschkoid [5]. the major histopathological features are large-grouped, dilated follicular ostia devoid of hair shafts but filled with keratin layers. at some locations in the bases of the follicular invaginations one may observe singular rudimentary glands, which are not, however, obligatory as they may be absent. small cysts, cystic invaginations, and occasionally large cysts may be seen in histopathological investigation; the variable cystic structures are lined by keratinizing squamous epithelium. hyperkeratosis and acanthosis of the epidermis may be present but not paraor dyskeratosis [6]. nevus comedonicus syndrome (orpha:64754) belongs to the group of epidermal nevus syndromes including schimmelpenning syndrome, phacomatosis pigmentokeratotica, angora hair nevus syndrome, and becker nevus syndrome among others in which a genetic basis has not yet been identified [7]. figure 1. (a) clinical presentation: plaque-like lesion with wide-open follicles with blaschkoid distribution and alteration of the skin pigmentation. (b) dermoscopy (polarized ×10): well-defined homogeneous area in dark brown shade in the area of whitish skin of the right thigh. figure 2. papulopustular acne lesions of the face and erythematous acne scars due to past treatments. figure 3. histology presentation: dilated follicular ostia devoid of hair filled with keratin layers. commentary | dermatol pract concept 2020;10(1):e2020006 3 5. happle r. the group of epidermal nevus syndromes, part i: well defined phenotypes. j am acad dermatol. 2010;63:1-22. 6. jeong hs, lee hk, lee sh, kim hs, yi sy. multiple large cysts arising from nevus comedonicus. arch plast surg. 2012;39(1):6366. 7. vidaurri-de la cruz h,  tamayo-sánchez  l,  durán-mckinster c, de la luz orozco-covarrubias m, ruiz-maldonado r. epidermal nevus syndromes: clinical findings in 35 patients. pediatr dermatol. 2004;21(4):432-439. 8. munro cs, wilkie ao. epidermal mosaicism producing localised acne: somatic mutation in fgfr2. lancet. 1998;352(9129):704705. 9. melnik b, vakilzadeh f, aslanidis c, schmitz g. unilateral segmental acneiform naevus: a model disorder towards understanding fibroblast growth factor receptor 2 function in acne? br j dermatol. 2008;158(6):1397-1399. 10. clatici vg, voicu c, voaides c, roseanu a, icriverzi m, jurcoane s. diseases of civilization—cancer, diabetes, obesity and acne—the implication of milk, igf-1 and mtorc1. maedica (buchar). 2018;13(4):273-281. conclusions we suggest that the coexistence of comedonic nevus, acne, and obesity may not be a random association. future studies should investigate a screening of phenotypically similar patients for fgfr2 mutations and a possible therapeutic modulation of fgfr signaling. references 1. guldbakke kk, khachemoune a, deng a, sina b. naevus comedonicus: a spectrum of body involvement. clin exp dermatol. 2007;32(5):488-492. 2. tchernev g, ananiev j, semkova k, dourmishev la, schönlebe j, wollina u. nevus comedonicus: an updated review. dermatol ther (heidelb). 2013;3(1) :33-40. 3. garcia lc, cabeda lf, garcia r, borile g. nevus comedonicus: surgical treatment. rev bras cir plast são paulo. 2000;15:7-14. 4. yadav p, mendiratta v, rana s, chander r. nevus comedonicus syndrome. indian j dermatol. 2015;60(4):421. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2014;4(1):9 59 prediction without pigment: a decision algorithm for non-pigmented skin malignancy cliff rosendahl1, alan cameron1, philipp tschandl2, agata bulinska1, iris zalaudek3, harald kittler2 1 school of medicine, the university of queensland, australia 2 department of dermatology, division of general dermatology, medical university of vienna, austria 3 division of dermatology, medical university of graz, graz, austria; skin cancer unit, arcispedale santa maria nuova, irccs, reggio emilia, italy keywords: dermatoscopy, dermoscopy, non-pigmented, skin cancer, algorithm, white circles, keratin, vessels citation: rosendahl c, cameron a, tschandl p, bulinska a, zalaudek i, kittler h. prediction without pigment: a decision algorithm for non-pigmented skin malignancy. dermatol pract concept. 2014;4(1):9. http://dx.doi.org/10.5826/dpc.0401a09 received: july 14, 2013; accepted: september 4, 2013; published: january 31, 2014 copyright: ©2014 rosendahl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, ph.d., po box 734, capalaba, qld, australia. tel. +61.7.3245.3011; fax. +61.7.3245.3022. email: cliffrosendahl@bigpond.com. while there are several published comprehensive stepwise algorithmic methods for diagnosing pigmented skin malignancy, only limited material has been published for the stepwise assessment of nonpigmented lesions. we present a method based on pattern analysis, with a stepwise assessment, first, for ulceration, second, for white clues (defined as white lines, or in the case of a raised lesion any of the keratin clues: dermatoscopic white circles, dermatoscopic white structureless areas or surface keratin), and third, if no ulceration or white clues are present, proceed to vessel pattern analysis. this is a novel method, and apart from the assessment of white clues in raised lesions, it has not been formally tested. the priority of keratin clues in raised lesions over vessel pattern analysis has, however, been verified. it is conceded that this method is less specific than methods which have clues of pigmented structures, and accepting these limitations, prediction without pigment is a decision algorithm intended to guide the clinician in the decision as to whether to perform a biopsy rather than consistently leading to a specific diagnosis. reaching a more specific diagnosis at the end of our flowchart can be achieved by weighing of clues both clinical and dermatoscopic, and that ability can be expected to improve with both knowledge and experience, but no diagnostic method, including this one, can be 100% sensitive in diagnosing malignancy, in particular, melanoma. taking these limitations into account, any nonpigmented lesion, regardless of pattern analysis, which is raised and firm (nodular) and for which a confident, specific benign diagnosis cannot be made, should be excised to exclude the nodular variant of amelanotic melanoma. abstract 60 research | dermatol pract concept 2014;4(1):9 • arrangements (figure 2): random (non-specific), clustered, serpiginous (string of pearls), linear, centred, radial (starburst), reticular and branched (arborizing). prediction without pigment: a decision algorithm for non-pigmented skin malignancy in this context, “non-pigmented” means lesions with no melanin pigmentation (which may be black, brown, gray, or blue, depending on depth in the skin [18]). such lesions may still have pigment due to keratin (yellow or orange) or hemoglobin (red, purple, blue or black). both melanin and hemoglobin may produce blue and black pigmentation, and occasionally this can cause confusion. usually this can be resolved by considering the spectrum of colors present; when associated with brown or gray, black and blue are best interpreted as due to melanin, when associated with only red, they are best interpreted as due to hemoglobin [17]. only when there are no structures pigmented by melanin should other features be used to reach a decision about the need for biopsy and, second, to attempt to make a specific diagnosis [17]. in contrast to the dermatoscopic diagnosis introduction while limited material has been published for stepwise dermatoscopic assessment of non-pigmented skin lesions [1,2], dermatoscopy has mainly been proposed as an aid to the diagnosis of pigmented skin lesions, and it has been shown to increase diagnostic accuracy for all pigmented lesions, melanocytic and non-melanocytic [3-5]. pattern analysis was the original method of description and diagnosis for pigmented lesions [6] and, despite the development of many “simplified” algorithms, remains the method of experts. in 2007, kittler proposed a revision of pattern analysis [7], introducing an algorithm based on geometric, objective, well-defined descriptive terms that are applicable regardless of diagnosis. in 2008, kittler et al proposed a similar system for objective description of blood vessel patterns [8] to replace metaphoric descriptions of dermatoscopic features of non-pigmented skin lesions [1, 2, 9-16]. revised pattern analysis precisely defines eight types of vessel structures and eight vessel arrangements [17]. the types are as follows (closest metaphoric term italicized in brackets where available and different): • structures (figure 1): dots, clods (lacunes), linear straight, linear looped (hairpin), curved (comma), serpentine (linear irregular), helical (corkscrew) and coiled (glomerular). figure 1. schematic representation (left) and dermatoscopic image of examples (right) of the eight types of vessel structure defined in revised pattern analysis. the closest equivalent metaphoric term, when different, is italicized in brackets and the diagnosis of the lesion is in brackets at the end: (a) dots (melanoma); (b) clods (lacunes)(hemangioma); (c) lines straight (ulcerated bcc); (d) lines looped (hairpin vessels)(scc); (e) lines curved (comma vessels)(dermal nevus); (f) lines serpentine (linear irregular vessels) (bcc); (g) lines helical (corkscrew vessels)(iec); (h) lines coiled (glomerular vessels)(iec). [copyright: ©2014 rosendahl et al.] abbreviations used: bccbasal cell carcinoma; scc—squamous cell carcinoma; iec—intraepidermal squamous cell carcinoma. research | dermatol pract concept 2014;4(1):9 61 white clues: white lines and keratin clues in the absence of ulceration, the lesion is next assessed for presence of white clues, which are defined as white lines in any lesion, and in the case of a raised lesion, keratin clues: white circles, white structureless areas or surface keratin. the clue of white lines has only been formally evaluated in pigmented lesions [5], but the authors also consider it as an important clue in non-pigmented lesions, and have incorporated it into this algorithm [17]. the keratin clues which apply to raised lesions—white circles, white structureless areas and surface keratin—however, have been evaluated and have been found to be more robust than vessel analysis in differentiating squamous cell carcinoma (scc) and keratoacanthoma (ka) from other raised non-pigmented lesions [20]. a raised lesion is one that is significantly raised visibly or palpably and includes some papules and all nodules. white lines there are two types of white lines that can be present in both pigmented and non-pigmented lesions. first, there are white lines that may be seen with both polarizing and non-polarizof pigmented lesions, for non-pigmented lesions dermatoscopic features must be supplemented by clinical findings to achieve acceptable diagnostic accuracy [17]. in fact, with non-pigmented lesions it is often possible to make a confident specific benign diagnosis clinically; examples are cases of viral warts, seborrheic keratoses (sk) and dermal (unna or miescher) nevi. dermatoscopy can then be used simply to confirm this clinical diagnosis. if such a clinical diagnosis is not possible a lesion can be assessed in a stepwise pattern according to the “prediction without pigment” diagnostic flowchart (figure 3). ulceration the first assessment in the prediction without pigment algorithm is for the presence of ulceration. the presence of ulceration, either clinically or dermatoscopically, without a clear history of trauma should lead to a biopsy. ulceration is usually better appreciated clinically than by dermatoscopy. however, serum leaking from ulcerated areas may trap fibers of clothing or loose hair, so adherent fiber constitutes a dermatoscopic clue to ulceration [17]. ulceration is most commonly seen in basal cell carcinoma (bcc) and it is a published clue to bcc [19], but it can be seen in any malignancy. figure 2. schematic representation (left) and dermatoscopic image of examples (right) of the eight types of vessel arrangement defined in revised pattern analysis: (a) random (non-specific)(iec); (b) clustered (iec); (c) serpiginous (string of pearls) (cca); (d) linear (iec); (e) centered (seborrheic keratosis); (f) radial (starburst) (scc); (g) reticular (sun-damaged skin); (h) branched (arborizing) (bcc). [copyright: ©2014 rosendahl et al.] abbreviations used: bccbasal cell carcinoma; scc—squamous cell carcinoma; iec—intraepidermal squamous cell carcinoma; cca— clear cell acanthoma 62 research | dermatol pract concept 2014;4(1):9 lines seen with both polarizing and non-polarizing dermatoscopes are a clue to malignancy, they also occur in lichen planus as wickham’s striae. polarizing-specific white lines are a published clue to the benign conditions of scar tissue, spitz nevus, dermatofibroma (df), lichen planus like keratosis (lplk) [22] and pyogenic granuloma (termed “white rail lines” in the reference cited) [23], as well as the malignancies melanoma and bcc [22]. with respect to melanomas, they were more prominent in invasive (41%) than in-situ (17%) melanomas [22]. keratin clues if a non-pigmented lesion is not ulcerated and there are no white lines as a clue to malignancy, then there is one step to assess prior to the need to perform vessel pattern analysis. if the lesion is raised, then the three keratin clues of clinical or dermatoscopic surface keratin, dermatoscopic white structureless areas or dermatoscopic white circles are valuable clues to malignancy, specifically scc and ka. white circles have the highest specificity (87%) for scc/ka with a sensitivity of 44% for this diagnosis [20]. surface keratin is best appreciated clinically, as one of the purposes of dermatoscopy ing dermatoscopy (including reticular white lines originally called negative, white or inverse network or reticular depigmentation) and then there are polarizing-specific white lines (also known as chrysalis and as shiny or bright white lines [21]), which are only seen with polarizing dermatoscopes (see figure 4). both types of white lines are clues to malignancy [17], but they may also be seen in benign lesions, so the clinical context needs to be considered. for example, while white figure 3. flowchart for the prediction without pigment algorithm. end-points colored red are highly suspicious for malignancy, while those colored green should be benign. all other endpoints should be assessed by weighing all clues, both clinical and dermatoscopic, as there are malignant options in the differential diagnosis. the diagnoses listed are not exhaustive but are selected to guide the decision process. it may be useful to have this flowchart open when looking at the lesions depicted in figures 4-10. [copyright: ©2014 rosendahl et al.] abbreviations used: bcc—basal cell carcinoma; scc—squamous cell carcinoma; ka—keratoacanthoma; df—dermatofibroma; lplk— lichen-planus-like-keratosis (benign lichenoid keratosis); pg—pyogenic granuloma; iec—intraepidermal carcinoma (bowen’s disease or scc in-situ); sk—seborrheic keratosis; cca—clear cell acanthoma figure 4. polarized (a) and non-polarized (b) dermatoscopic image of a non-pigmented lesion reveals the dermatoscopic clue of polarizing-specific white lines. note the perpendicular orientation of these lines. this is a fibroepithelioma of pinkus—a variant of bcc. [copyright: ©2014 rosendahl et al.] research | dermatol pract concept 2014;4(1):9 63 at the right-hand side of the algorithmic flowchart to help reach a specific diagnosis. white clods and dots (also known as milia-like cysts) occur commonly in seborrheic keratosis but also in scc and melanoma. polarizing-specific white clods (referred to as white shiny areas and white shiny clods in the reference cited) are described as a published clue to bcc and melanoma [24]. areas of structureless pink and white are published as a clue to bcc [25]. four-dot-clods are frequently seen on actinic keratosis and intraepidermal squamous cell carcinoma (iec)—called rosettes in the reference cited [16]—but can be seen on any sun-damaged skin including on melanoma. vessel pattern analysis if a non-pigmented lesion cannot be confidently diagnosed clinically, is not ulcerated and there are no white clues, the final step in the algorithm is vessel pattern analysis [8,17]. one might also choose to perform vessel pattern analysis when the decision has already been made to perform a biopsy due to ulceration or white clues for the purpose of reaching a more specific diagnosis. first, the lesion is assessed to determine whether it is flat or raised, and the stepwise decision process proceeds differently in each case. if a lesion is flat then it is assessed as to whether the vessel pattern is polymorphous or monomorphous [8]. a pattern of vessels is termed polymorphous if there is more than one type of vessel without one predominating by far. a single dot, clod or line does not make a pattern polymorphous. a polymorphous pattern can be produced by either two distinct vessel patterns on different parts of a lesion or by more than one vessel type present in a speckled arrangement in significant numbers over the lesion. a pattern of vessels is termed monomorphous if one type of vessel predominates by far. a polymorphous pattern of vessels including a pattern of dot vessels requires biopsy on suspicion of melanoma [8] (figure 7) although the differential diagnosis also includes benign lesions. a polymorphous pattern of vessels without a pattern of dot vessels also requires consideration of biopsy because the differential diagnosis includes bcc and iec, as well as benign conditions including sk and lplk [17]. any monomorphous vessel pattern in a flat lesion other than clods-only should be considered for biopsy. flat lesions with a monomorphous pattern of dot vessels include iec (where tightly coiled vessels may sometimes appear as dots at standard dermatoscopic magnification), as well as the benign conditions of melanocytic nevus, viral wart, psoriasis and inflammatory conditions [17]. flat lesions with monomorphous serpentine vessels include bcc (figure 1f), as well as desmoplastic trichoepithelioma and scar tissue. flat lesions with monomorphous, coiled vessels include iec (referred to as glomerular vessels in the reference cited) [11] (figure 1h), is to render keratin invisible to better appreciate structures beneath the stratum corneum, but the other two keratin clues, white circles and white structureless areas, are dermatoscopic clues (figures 5 and 6). there are other clues provided by keratin not included in the flowchart because we regard them as of inadequate specificity for malignancy but which are useful when applied figure 5. surface keratin and a white structureless area are seen clearly on the close-up clinical image of a non-pigmented raised lesion on the ear of a 60-year-old man (left). they are also apparent in the dermatoscopic image (right) with the white structureless area indicated by an arrow. it is an scc. [copyright: ©2014 rosendahl et al.] figure 6. clinical and close-up images of a lesion on the hand of a 72-year-old-man which cannot be confidently diagnosed as benign clinically (upper images). dermatoscopically (lower image) there are intensely white circles (black arrows) and one of these in particular is projected obliquely (red arrow), showing a thin white cylinder from the center of which emerges a hair shaft. white circles are produced by highly keratinized malignant squamous cells invading hair follicles. [copyright: ©2014 rosendahl et al.] 64 research | dermatol pract concept 2014;4(1):9 as to whether the vessel arrangement is non-specific or alternatively one of four different specific vessel arrangements (radial, branched, serpiginous or centered) [17]. there are eight different vessel arrangements (figure 2), and of these the last seven are specific, but three of these arrangements (clustered, linear and reticular) are not expected in a raised lesion. if none of the four designated specific vessel arrangements are present the arrangement is described as “non-specific.” if the arrangement is non-specific and not clods-only, then a biopsy is indicated as melanoma, bcc and scc/ka are in the differential diagnosis as are benign lesions including sk and pyogenic granuloma (pg) [17] (figure 8). if the pattern is non-specific but clods-only the pattern is regarded as benign (hemangioma) [17]. as with the clods-only pattern in flat lesions, the clods must be red or purple and there must not be any vessels within any of the clods (see figure 9) [17]. if the vessel arrangement is specific, either radial, branched, serpiginous or centered, then the lesions are assessed according to each of these specific arrangements. lesions with a radial pattern of vessels include scc/ka (referred to as a starburst vessel pattern in the reference cited [16] (figure 2f—scc) and bcc with ulceration, as well as sebaceous gland hyperplasia (additional clue: several white or yellow clods in central location) and molluscum contagiosum (additional clue: single skin-colored or orange clod in central location). lesions with a branched vessel pattern include bcc, scc/ka, merkel cell carcinoma and any raised cyst or neoplasm, benign or malignant [17] (figure 2h—bcc). the serpiginous vessel pattern as well as the benign lesion sk, although sk will more commonly have polymorphous vessels and in most cases will have been diagnosed with confidence clinically [17]. if a flat lesion has a monomorphous pattern of vessels and the vessel pattern is (red/purple) clods-only, this is a benign pattern consistent with the diagnosis of hemangioma [17] (figure 1b). for this benign diagnosis to be made there must be no vessels within any of the clods and there must not be a history inconsistent with a benign diagnosis; the lesion must not be reported to be changing. if a lesion is raised assessment according to monomorphous versus polymorphous vessel pattern is not helpful for a decision algorithm. instead, raised lesions are first assessed figure 8. dermatoscopic image of a focally pigmented lesion. because focal pigment is present, this should be assessed as a pigmented lesion, and as it has chaos (asymmetry of structure or color) and the clue of an eccentric structureless area, it should be excised [5]. if the focal pigment is ignored and it is assessed as a non-pigmented lesion; it is raised, the vessel pattern is non-specific and is not clods-only, so it should be excised. this was an invasive melanoma (breslow thickness 2.5 mm). [copyright: ©2014 rosendahl et al.] figure 9. dermatoscopic image of a raised non-pigmented lesion. it does have the clue to malignancy of white lines (green arrows), which should lead to biopsy. if this was not noted and vessel pattern analysis was done it has a non-specific vessel arrangement. if this were interpreted as a structureless lesion (rather than clods-only), biopsy would therefore be indicated. if, however, it was interpreted as having a “clods-only” pattern, it can be seen on close inspection that there are vessels within some of the clods (black arrows). this by definition disqualifies this lesion from a benign “clods-only” categorization, which is important because this was a nodular melanoma (breslow thickness 1.2 mm). [copyright: ©2014 rosendahl et al.] figure 7. dermatoscopic image of a non-pigmented lesion. there is no ulceration and there are no “white clues” (as defined in the text). there are linear vessels covering the majority of the lesion with a pattern of dot vessels at the upper extremity. a polymorphous pattern of vessels, including a pattern of dot vessels, raises suspicion for melanoma. this was an invasive amelanotic melanoma (breslow thickness 0.3 mm). [copyright: ©2014 rosendahl et al.] research | dermatol pract concept 2014;4(1):9 65 2. zalaudek i, kreusch j, giacomel j, et al. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377–386; quiz 387–388. 3. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159–65. 4. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669–76. 5. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068–73. 6. pehamberger h, steiner a, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol. 1987;17(4):571-83. 7. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual. 2007;13(1):3. 8. kittler h, riedl e, rosendahl c, cameron a. dermatoscopy of unpigmented lesions of the skin: a new classification of vessel morphology based on pattern analysis. dermatopathology: practical & conceptual. 2008;14(4):4. 9. zalaudek i, argenziano g, leinweber b, et al. dermoscopy of bowen’s disease. br j dermatol. 2004;150(6):1112-6. 10. bugatti l, filosa g, de angelis r. the specific dermoscopical criteria of bowen’s disease. j eur acad dermatol venereol. 2007;21(5):700-1. 11. pan y, chamberlain aj, bailey m, et al. dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. j am acad dermatol. 2008;59(2):268-74. 12. felder s, rabinovitz h, oliviero m, kopf a. dermoscopic differentiation of a superficial basal cell carcinoma and squamous cell carcinoma in situ. dermatol surg. 2006;32(3):423-5. 13. zalaudek i, giacomel j, argenziano g, et al. dermoscopy of facial nonpigmented actinic keratosis. br j dermatol. 2006;155(5):951-6. 14. cuellar f, vilalta a, puig s, et al. new dermoscopic pattern in actinic keratosis and related conditions. arch dermatol. 2009;145(6):732. 15. kreusch j, koch f. incident light microscopic characterization of vascular patterns in skin tumors. hautarzt. 1996;47(4):264-72. 16. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2011;66(4):589-97. 17. kittler h, rosendahl c, cameron a, tschandl p. dermatoscopy. austria: facultas.wuv, 2011. 18. weismann k, lorentzen hf. dermoscopic color perspective. arch dermatol. 2006;142(9):1250. 19. altamura d, menzies sw, argenziano g, et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62(1):67–75. 20. rosendahl c, cameron a, argenziano g, et al. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. 2012;148(12):1386–92. 21. marghoob aa, cowel l, kopf aw, scope a. observation of chrysalis structures with polarized dermoscopy. arch dermatol. 2009;145(5):618. is specific to the benign lesion, clear cell acanthoma (cca) [2] (figure 2c). a centered pattern is also regarded as a benign pattern and is seen with papillomatous dermal nevi, seborrheic keratosis (figure 2e) and viral wart, but to qualify for this pattern the vessels must be in the center of skin-colored (not red or purple) clods (see figure 10) and the lesion must be truly non-pigmented [17]. conclusion an algorithmic flowchart for non-pigmented skin lesions is less specific than can be achieved for pigmented lesions. incorporating the clinical clues of ulceration and surface keratin with the dermatoscopic white line, keratin and vessel clues does, however, facilitate a stepwise process which can exclude some lesions from biopsy with confidence, while also predicting malignancy. prediction without pigment, analogous to the method for assessing pigmented skin lesions by revised pattern analysis, chaos and clues, provides a framework on which to build the learning that comes from accumulated experience. with non-pigmented lesions that cannot confidently be diagnosed clinically, the limitations of dermatoscopy must be acknowledged, and if there is any doubt following assessment a biopsy should be performed. references 1. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatology. 2006;212(1):7–18. figure 10. dermatoscopic image of a raised non-pigmented lesion, which does have vessels centered on non-pigmented clods but the clods are not skin-colored being markedly erythematous and in the upper part of the image there are purple clods. this lesion therefore, by definition, cannot be described as having a “centered” pattern. it was a nodular melanoma (breslow thickness 2.5 mm). [copyright: ©2014 rosendahl et al.] 66 research | dermatol pract concept 2014;4(1):9 24. liebman tn, rabinovitz hs, balagula y, jaimes-lopez n, marghoob aa. white shiny structures in melanoma and bcc. arch dermatol. 2012;148(1):146. 25. puig s, cecilia n, malvehy j. dermoscopic criteria and basal cell carcinoma. g ital dermatol venereol. 2012;147(2):135–40. 22. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67(2):194.e1–8. 23. zaballos p, llambrich a, cuéllar f, puig s, malvehy j. dermoscopic findings in pyogenic granuloma. br j dermatol. 2006;154(6):1108–11. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020051 1 dermatology practical & conceptual introduction oculocutaneous albinism (oca) is a group of autosomal recessive disorders characterized by defective melanin biosynthesis due to full or partial reduction in tyrosinase activity, which results in congenital depigmentation or hypopigmentation of the hair, skin, and eyes despite the normal number of melanocytes. in oca, reduced or absent protection of melanin leads to sensitivity to ultraviolet radiation and a predisposition to skin cancers. dermoscopic features of melanoma in patients with oca have been reported in a few case studies. here we report dermoscopic findings of an invasive melanoma arising from nevus in a patient with oca. case presentation a 32-year-old female patient with oca1 presented with a cutaneous lesion that had been enlarging for about a year. she stated that there was an asymptomatic pinkish plaque existing since childhood at the same location. the patient had hypomelanotic skin, blonde hair, blue-gray irides, and bilateral nystagmus. dermatological examination revealed multiple pinkish papules surrounding a main central tumoral lesion over the right forearm (figure 1). dermoscopy of the lesions showed central yellow to orange structureless areas, central hemorrhagic crust, a peripheral arrangement of large yellow to orange clods and structureless areas, and polymorphous vessels including linear, curved, and complex looped vessels (figure 2). an incisional biopsy was made with preliminary diagnoses of cutaneous sarcoidosis, leishmaniasis, and cutaneous lymphoma. histopathological examination of the incisional biopsy specimen revealed epidermal consumption, superficial dermal mononuclear inflammatory infiltration, a few bland-looking dermal nevus nests, and atypical melanocytic infiltration filling the lower half of the papillary dermis and reticular dermis with numerous mitoses, including atypical ones. no maturation was observed. breslow thickness was 2.3 mm. immunohistochemically, tumor cells were stained with hmb-45, melan-a, and s-100 (figure 3). a diagnosis of amelanotic nodular melanoma was made and a total excision with 2-cm margins was performed. no lymph node involvement and metastasis were detected. conclusions melanomas in patients with oca are rare and usually amelanotic. unfamiliar clinical and dermoscopic findings may cause diagnostic delay, which is usually associated with poor progdermoscopy of amelanotic melanoma in a patient with oculocutaneous albinism belkis uyar,1 ömer faruk elmas,1 asuman kilitçi,2 murat tad2 1 department of dermatology and venereology, ahi evran university, kirşehir, turkey 2 department of pathology, ahi evran university, kirşehir, turkey key words: oculocutaneous albinism, melanoma, dermoscopy citation: uyar b, elmas öf, kilitçi a, tad m. dermoscopy of amelanotic melanoma in a patient with oculocutaneous albinism. dermatol pract concept. 2020;10(3):e2020051. doi: https://doi.org/10.5826/dpc.1003a51 accepted: february 23, 2020; published: june 29, 2020 copyright: ©2020 uyar et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ömer faruk elmas, md, department of dermatology and venereology, faculty of medicine, ahi evran university, kirşehir 40000, turkey. email: omerfarukmd@gmail.com https://doi.org/10.5826/dpc.1003a51 mailto:omerfarukmd@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020051 references 1. peralta r, sabban ec, friedman p, et al. proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type ia. dermatol pract concept. 2017;7(1):39-42. https://doi.org/10.5826/dpc.0701a07 2. caldarola g, fania l, fossati b, et al. dermoscopy of melanocytic lesions in patients affected by oculocutaneous albinism: a case series. dermatology. 2013;226(4):358-361. https://doi.org/10. 1159/000351315 linear vascular structures should prompt to exclude melanoma and other malignancies. knowing the possible dermoscopic presentations of melanoma and the other tumors in patients with oca may lead to early diagnosis and favorable prognostic outcomes. age, location, ulceration, breslow thickness, mitosis rate, and vascular invasion are the indicators of prognosis of melanoma in oca as they are in any other type of melanoma. nosis. furthermore, nevi in patients with oca may have a similar dermoscopic pattern to that described for amelanotic melanoma [1]. only a few studies have reported dermoscopic findings of melanoma in patients with oca. irregular dots, globules, blue-white veil, peripheral arciform vessels, and milky red areas were the dermoscopic features reported in the study of caldarola et al [2]. the present case had a different dermoscopic presentation. a central core of orange structureless areas surrounded by large yellow to orange clods and polymorphous vessels including linear, curved, and complex looped ones composed the main picture. all previously described cases of amelanotic melanomas in patients with oca predominantly demonstrated a polymorphous vessel pattern. patients with oca may have numerous pinkish lesions, and it can be very difficult to differentiate melanoma from benign lesions. in this context, dermoscopic examination can be life-saving. dermoscopic analysis in patients with oca is mainly based on the vascular structures because of the lack of pigmentation [1]. pink nevi usually demonstrate only curved and comma vessels, while isolated lesions with dotted and figure 2. (a) handheld polarized dermoscopy shows central yellow to orange structureless areas, central hemorrhagic crust, peripheral arrangement of large yellow to orange clods and structureless areas, and (b,c) linear, curved, and complex looped vessels. figure 3. histopathological examination. (a) epidermal consumption, superficial dermal mononuclear inflammatory infiltration, and atypical melanocytic infiltration (h&e, ×200). (b) high power shows malignant melanocytes (black circles), atypical mitosis (white circle), and mononuclear inflammatory infiltration (blue circle) (h&e, ×400). (c) diffuse staining with melan-a (×200). (d) bland-looking dermal nests indicating underlying nevus (h&e, ×400). figure 1. multiple pinkish papules surrounding a main central tumoral lesion over the right forearm. https://doi.org/10.5826/dpc.0701a07 https://doi.org/10.1159/000351315 https://doi.org/10.1159/000351315 research | dermatol pract concept 2011;1(1):4 13 signature nevi: individuals with multiple melanocytic nevi commonly have similar clinical and histologic patterns robert m. hurwitz, m.d.1, larry j. buckel, m.d.1 1dermatopathology laboratory, inc., pc, indianapolis, indiana key words: signature nevi, patterns citation: hurwitz rm, buckel lj. signature nevi: individuals with multiple melanocytic nevi commonly have similar clinical and histologic patterns. dermatol pract concept 2011;(1):4. http://dx.doi.org/10:5826/dpc.0101a04. editor: harald kittler, m.d. received: december 17, 2010; accepted: april 27, 2011; published: october 31, 2011 copyright: ©2011 hurwitz et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. both authors have contributed significantly to this publication. corresponding author: robert m. hurwitz, md, dermatopathology laboratory, inc., pc, 9292 north meridian street, suite 210, indianapolis, in 46260, usa. tel. 317.403.7572. email: bobbyhur@aol.com. introduction individuals with multiple melanocytic nevi oftentimes have melanocytic nevi, usually two, with similar clinical and histopathologic patterns that may be typical or atypical. the melanocytic nevi are known in common parlance as signature nevi [1, 2]. in addition to being aware of these nevi, finding multiple unconventional melanocytic nevi with architectural pattern asymmetric and/or cellular pattern atypical helps to lend credence to the diagnosis of melanocytic nevus rather than melanoma. in order to evaluate the concept of the signature nevus we reviewed the histopathologic patterns of melanocytic nevi from patients having at least two nevi with similar histologic patterns. materials and methods melanocytic nevi from patients with multiple melanocytic nevi having at least two with similar histologic pattern were retrieved retrospectively from the files of dermatopathology laboratory inc., pc. melanocytic nevi were classified according to their pattern as previously described (figures 1-4) [3]. two dermatopathologists (rmh & ljb) reviewed the nevi over an eight-month period. results two hundred and eight melanocytic nevi from 77 patients, 59 females and 18 males, were included in the analysis. ages of the patients ranged from 13 to 82 years with a mean of 40 years and a median of 47 years. the signature melanocytic nevi were present on different anatomic sites (e.g., back, abdomen, face, scalp and extremity, etc.) in 51 of the patients, and on the same anatomic site in 26 patients. the 208 melanocytic nevi included 13 (17%) with three similar patterns and one (1.3%) with four similar patterns. the frequencies of melanocytic nevi according to histologic pattern are given in table 1. there were 14 variable histologic patterns, which included the most common “melanocytic nevus, compound, keratotic, lichenoid, perivascular & interstitial dermatology practical & conceptual www.derm101.com 14 research | dermatol pract concept 2011;1(1):4 figure 1. anatomic patterns of melanocytic nevi. a, junctional: single, nested melanocytes at the dermoepidermal junction and lower spinous layer. b, compound: single and nested melanocytes at the dermoepidermal junction, papillary dermis and/or reticular dermis. c, intradermal: single and nested melanocytes confined to the reticular dermis. figure 4. example of melanocytic nevus diagnosis based on anatomic, architectural and cellular patterns. a composite of single anatomic and cellular patterns with single or multiple architectural patterns. example: melanocytic nevus, compound, keratotic, lichenoid, perivascular and interstitial, typical cellular pattern. figure 2. architectural patterns of melanocytic nevi. a, epidermal: prominent epidermal rete and infundibula. b, keratotic: prominent surface and infundibular hyperkeratosis. c, interface: single and nested melanocytes at the dermoepidermal junction and lower spinous zone. d, lichenoid melanocytic: single and nested melanocytes at the dermoepidermal junction and lower spinous zone. e, lichenoid lymphocytic: single and nested melanocytes limited to the dermoepidermal junction and lower spinous zone associated with a patchy lymphocytic infiltration within a thickened papillary dermis. f, wedge-shaped: single and nested melanocytes in a “v” or wedgeshaped pattern in the reticular dermis. g, perivascular, periadnexal: single and small nested melanocytes around and associated with vascular and adnexal structures. h, interstitial: single and nested melanocytes splayed among collagen bundles in the reticular dermis. i, nodular: large round or oval collections of melanocytes in the dermis in the region of vascular and adnexal structures. j, diffuse: sheets of confluent melanocytes in the reticular dermis with little intervening stroma. k, fascicular: fascicles of melanocytes in the midst of collagen bundles in the reticular dermis. l, pigmented dendritic: melanin-laden, pigmented dendritic melanocytes and melanophages coupled with thickened collagen bundles. figure 3. cellular patterns of melanocytic nevi. a, typical (small and monomorphous): small, round, oval, polygonal, spindle or multinucleate melanocytes. b, atypical (large and pleomorphic). c, combined: both typical and atypical melanocytes. research | dermatol pract concept 2011;1(1):4 15 pattern” (n=52) and “melanocytic nevus, junctional, epidermal/interface pattern” (n=26), while “melanocytic nevus, nodular” was one of the least (n=2). discussion the article signature nevi [1] by suh and bolognia emphasized 10 clinical types or patterns of melanocytic nevi. these signature nevi predominate in patients with multiple melanocytic nevi and share a similar clinical appearance. ricotti presented the histopathologic phenomenon of “signature nevi” at the 12th joint meeting of the international society of dermatopathology [2]. likewise, we reviewed the histopathologic changes from biopsies of 208 melanocytic nevi taken from 77 patients over a period of eight months. biopsies were taken from two or more of their melanocytic nevi over four years that retrospectively had at least two similar histologic patterns, i.e., anatomic, architectural and cellular. interestingly, included in this total number of melanocytic nevi, 13 (17%) of the patients had similar histologic patterns in three of their melanocytic nevi, and one patient had 4 similar histologic patterns. thus, melanocytic nevi commonly have similar clinical as well as similar histologic patterns in patients with multiple melanocytic nevi, i.e., signature nevi. when one encounters a troublesome or atypical histologic pattern in one melanocytic nevus from an individual with many melanocytic nevi, e.g., architectural asymmetry and/or focal cellular atypia, it is common and expected to find other melanocytic nevi from that patient to have similar atypical histologic patterns. melanocytic nevi have been reported to have a variety of clinical phenotypic patterns [11], and a variety of histologic anatomic (figure 1), architectural (figure 2) and cellular patterns (figure 3) [3], not unlike that situation commonly found in apocrine neoplasia [4] and inflammatory skin diseases [5]. on occasion, an unusual melanocytic nevus will present with clinical and histologic changes that may be difficult to differentiate from a melanoma (figure 5a–c) and (figure 6a–c). a quandary often occurs when there are histologic changes in pattern architectural such as asymmetry or pattern combined cellular such as focal cellular atypia [6]. these variations may be found and are expected in melanomas as well as in some unusual melanocytic nevi, such as signature nevi [7], nevi with the “ugly duckling” sign [8, 9], acquired nevi [10], congenital nevi, spitz’s nevi [11, 12], dysplastic nevi [13], traumatized nevi, or those found on a “special site” such as the genitalia, perineum, thigh, umbilicus, palm, sole, scalp and ear, etc. in addition, some atypical patterns of melanocytic nevi are classified by acronyms such as min [14], sampus and meltump [15], and eponyms such as unna, clark, reed, miescher, zitelli, mark, seab and ackerman [16, 17], or too often with hazy descriptive monikers such as atypical nevus, dysplastic nevus with architectural disorder with moderate to severe cytologic atypia. the latter are often used to announce uncertainty and indecision by the pathologist as to whether the melanocytic proliferation is benign or malignant. those bewildering and evocative names unfortunately all too often bode ill for the patient and may lead to unwarranted surgical procedures, e.g. sentinel lymph node biopsy and lymphadenectomy [18]. regrettably, to date, there is no unanimity or litmus test to distinguish between those unusual and tricky clinical and histologic melanocytic nevi, or melanocytic proliferations from subtle melanomas. sorry to say, we must alas rely upon questionable subjective clinical and histologic morphologic criteria to arrive at a definitive diagnosis, nevus or melanoma [19, 20]. in summary, we agree that awareness and knowledge of the fact that an individual with multiple melanocytic nevi is prone to have several melanocytic nevi with similar and table 1. common histologic patterns and number of signature nevi in 77 patients with multiple melanocytic nevi 1. melanocytic nevus, compound, keratotic, lichenoid, perivascular & interstitial pattern (52) 2. melanocytic nevus, junctional, epidermal/interface pattern (34) 3. melanocytic nevus, compound, patchy lichenoid pattern (26) 4. melanocytic nevus, intradermal, nodular, perivascular & interstitial pattern (12) 5. melanocytic nevus, compound, keratotic pattern (8) 6. melanocytic nevus, intradermal, perivascular & interstitial pattern (7) 7. melanocytic nevus, compound, keratotic, perivascular-periadnexal, diffuse pattern (7) 8. melanocytic nevus, intradermal, wedge-shaped pattern (7) 9. melanocytic nevus, compound, lichenoid, perivascular & interstitial pattern (6) 10. melanocytic nevus, intradermal, keratotic, perivascular & interstitial pattern (6) 11. melanocytic nevus, compound, perivascular-interstitial & keratotic pattern (2) 12. melanocytic nevus, nodular pattern (2) 13. melanocytic nevus, nodular-diffuse pattern (2) 14. melanocytic nevus, compound, perivascular & interstitial pattern (2) 16 research | dermatol pract concept 2011;1(1):4 figure 5. melanocytic nevus, compound, lichenoid, combined cellular pattern from a 4x4 mm changing nevus on the back of a 29-yearold woman. melanocytic nevus, compound, lichenoid, combined cellular pattern from a 4x4 mm changing nevus on the back of a 29-year-old woman. there are predominately small round and oval pigmented melanocytes singly and in nests within the lower epidermis, structure of adnexa, and thickened papillary dermis where there are prominent, elongated rete ridges. there are a few melanocytes present above the dermoepidermal junction, several melanocytes with atypical nuclei in the midst of those with increased cytoplasm and prominent pigmented melanin granules, plus a variety of irregularly shaped nests of melanocytes. figure 6. melanocytic nevus, compound, lichenoid, combined cellular pattern from a 3x3 changing nevus on the abdomen of the same 29-year-old woman seen in figure 5. melanocytic nevus, compound, lichenoid, combined cellular pattern from a 3x3 mm changing nevus on the abdomen of the same 29-year-old women seen in figure 5. there are predominately small round and oval pigmented melanocytes within the lower epidermis and thickened papillary dermis where there are prominent, elongated rete ridges. there are a few melanocytes present above the dermoepidermal junction, several melanocytes with atypical nuclei, and a number of various melanocytes with abundant pale staining cytoplasm with melanin pigmented granules, in addition to several nests of melanocytes that vary in size and shape. research | dermatol pract concept 2011;1(1):4 17 13. ackerman ab, massi d, nielsen ta. dysplastic nevus: atypical mole or typical myth? philadelphia: ardor scribendi, ltd., 1999. 14. rosai j. rosai and ackerman’s surgical pathology. 9th ed. elsevier health sciences: philadelphia, 2004:172. 15. elder de, xu x. the approach to the patient with a difficult melanocytic lesion. pathol 2004; 36(5); 428-34. 16. ackerman ab, milde p. naming acquired melanocytic nevi. am j dermatopathol 1992:14(5):447-53. 17. ackerman ab. interactive quiz 781 and 783 (12/3/2008). zitelli’s nevus (superficial and “deep” congenital). web site. http://www. derm101.com/. accessed may 1, 2010. 18. leboit pe. slouching toward the lymphatic lumen. am j dermatopathol 2005;27(6):548-50. 19. hurwitz rm. letters to the editor. melanoma: experts disagree. dermatopathology: practical & conceptual1996;2(1):10. 20. farmer er, gonin r, hanna mp. discordance in the histopathologic diagnosis of melanoma and melanocytic neoplasms between expert pathologists. hum pathol 1996;27(6):528-31. 21. hurwitz rm, summerlin dj. malpractice: has the rage become an inquisition? j drugs dermatol 2007;6(10):977. sometimes unusual clinical patterns (signature nevi) as well as common and/or unconventional histologic patterns (anatomic, architectural and cellular). as a result, this concept of signature nevi supports unusual findings, clinical and histologic, to be customary and expected in melanocytic nevi for a particular individual with many melanocytic nevi. when a melanoma is in the differential diagnosis of a lesion pigmented, this valuable lesson may help to eliminate mistakes [21], avoid over diagnosing melanoma, and eliminate unnecessary surgery. thus, in the end, one will be more prone to arrive at an accurate, precise and definitive diagnosis of melanocytic nevus. acknowledgement we express our gratitude to prof. harald kittler and the reviewers of dermatology practical & conceptual for their time and effort in reviewing and analyzing our manuscript, and especially for their timely, critical and appropriate suggestions. references 1. suh ky, bolognia jl. signature nevi. j am acad dermatol 2009;60:508-14. 2. ricotti c. cockerell c, susa j, sinkre p, karai l. the histopathologic phenomenon of “signature nevi”. abstracts presented at the 46th annual meeting of the american society of dermatopathology, october 1-4, 2009. j cutan pathol 2010:37:107-92. 3. hurwitz rm, buckel lj, eads tj. histologic patterns of melanocytic nevi: a proposal for a new classification. j drugs dermatol 2007;6(5):487-92. 4. requena l, kiryu h, ackerman ab. neoplasms with apocrine differentiation. philadelphia: lippincott-raven, 1998. 5. ackerman ab. histologic diagnosis of inflammatory skin diseases. philadelphia: lea & febiger, 1978. 6. ackerman ab, cerroni l, kerl h. pitfalls in histopathologic diagnosis of malignant melanoma. philadelphia: lea & febiger, 1994. 7. bolognia jl. too many moles. arch derm 2006;142(2):508. 8. grob jj, bonerandi jj. the “ugly duckling”sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. arch dermatol 1998;134(1):103-4. 9. scope a, dusza sw, halpern ac, rabinowitz h, braun rp, zalaudek i, et al. the “ugly duckling”sign: agreement between observers. arch dermatol 2008;144(1):58-64. 10. saida t. histogenesis of congenital and acquired melanocytic nevi: a unifying concept. am j dermatopathol 2006; 28(4):377-9. 11. ackerman ab, elish d, shami s. “spitz’s nevus”: reassessment critical, revision radical. new york, ny: ardor scribendi, ltd., 2007. 12. cesinaro ma, foroni m, sighinolfi p, migaldi m, trentini gp. spitz nevus is relatively frequent in adults: a clinico-pathologic study of 247 cases related to patient’s age. am j dermatopathol 2005;27(6):469-75. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020055 1 dermatology practical & conceptual introduction lupus miliaris disseminatus faciei (lmdf) is an uncommon chronic inflammatory and granulomatous dermatosis, the exact etiology of which is hitherto unknown. lmdf typically manifests as yellowish red to brown papules on the face, particularly around the eyelids [1]. we present a case of lmdf and describe the dermoscopic findings of the case with histological correlation. case presentation a 32-year-old-man presented to the dermatology department with complaints of multiple raised reddish lesions over the face for the preceding 8 months. there was no history of redness of the face, photosensitivity, or other skin lesions. on mucocutaneous examination, multiple, discrete, reddish brown papules and plaques were seen over both cheeks, forehead, nose, and chin. there was clustering of lesions around the chin and periocular, perinasal, and perioral areas. no surface change, background erythema, or telangiectasia was seen. a few pitted scars were also present on both cheeks (figure 1, a-c). dermoscopic examination (dermlite ii hybrid m dermatoscope, magnification ×10 in polarized mode) revealed multiple, ill-defined, yellow to orangish brown, structureless areas present perifollicularly, few of which were filled with yellow or white keratotic follicular plugs (figure 2, a and b). histopathological examination of the patient revealed acanthotic epidermis with follicular plugging. dermis showed well-defined, predominantly perifollicular, epithelioid cell granulomas, focal caseous necrosis, and langhans and foreign body giant cells (figure 3, a-c). stains done for microorganisms (pas, zn) were negative. routine laboratory investigations including mantoux test, chest x-ray, and serum angiotensin-converting enzyme levels were all within normal limits. a diagnosis of lmdf was made after clinicopathological correlation and the patient was started on tablet doxycycline 100 mg twice a day for 6 weeks. although the patient did not follow up in person, upon telephonic inquiry he reported significant improvement and doxycycline was tapered to 100 mg once a day for another 4 weeks. dermoscopy of lupus miliaris disseminatus faciei: a step closer to diagnosis payal chauhan,1 rashmi jindal,1 nadia shirazi2 1 department of dermatology, himalayan institute of medical sciences, dehradun, india 2 department of pathology, himalayan institute of medical sciences, dehradun, india key words: lupus miliaris disseminatus faciei, dermoscopy, granulomatous disorders, doxycycline citation: chauhan p, jindal r, shirazi n. dermoscopy of lupus miliaris disseminatus faciei: a step closer to diagnosis. dermatol pract concept. 2020;10(3):e2020055. doi: https://doi.org/10.5826/dpc.1003a55 accepted: march 15, 2020; published: june 29, 2020 copyright: ©2020 chauhan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: payal chauhan, md, dnb, department of dermatology, himalayan institute of medical sciences, dehradun, india. email: chauhanpayal89@gmail.com https://doi.org/10.5826/dpc.1003a55 mailto:chauhanpayal89@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020055 conclusions the dermoscopic findings of follicular keratotic plugs and vessels over brownish yellow areas seen in our case are similar to those previously reported [1]. ayhan et al noted follicular keratotic plugs with vascular structures to be the predominant dermoscopic findings in cases described by them [1]. we believe that the reddish brown background seen in dermoscopy mirrors the dermal granulomas present in histology, with perifollicular structureless yellow to orangish brown areas representing the perifollicular localization of granulomas. keratotic follicular plugs on dermoscopy are believed to be secondary to the follicular hyperkeratosis and lateral pressure on follicles by the surrounding granulomas [1]. follicular plugs were seen under both the dermatoscope as well as microscope in the present case. lmdf needs to be differentiated from other disorders such as papular sarcoidosis, granulomatous rosacea, lupus vulgaris, and post kala-azar dermal leishmaniasis. perifollicular localization of figure 1. (a) multiple, discrete reddish brown papules over both cheeks, nose, eyelids, and forehead; (b) closer view showing clustering of papules over upper and lower eyelids, perinasal areas with a few pitted scars over the right cheek; and (c) grouped reddish brown papules over the chin, periocular and perinasal areas with scars seen over the left cheek, a few of the papules coalescing to form plaques over the left cheek. figure 2. (a,b) dermoscopic examination under polarized light (dermlite ii hybrid m, 3gen, san juan capistrano, ca, usa; magnification ×10, attached to dermlite iphone x adapter) of the papule revealed perifollicular structureless yellow to orangish brown areas (blue stars), with yellow (blue circles) or white (black circles) follicular keratotic plugs and perifollicular scales (black boxes). unfocused arborizing (white arrows) and (b) linear vessels (white box) present over reddish-brown background. letter | dermatol pract concept 2020;10(3):e2020055 3 lmdf, response can be variable [2,3]. other treatment modalities such as isotretinoin, dapsone, corticosteroids, and clofazimine have also been reported to be effective in some patients [3]. in the present case, doxycycline was preferred over minocycline because the former is more cost-effective. we present this case to describe dermoscopic findings in lmdf and their histological correlation. on a detailed where vascular polygons are characteristically seen. treatment of lmdf poses a challenge to physicians and is often unsatisfactory. the disease runs a protracted course, healing with unsightly scars over several months to years (1224 months usually). early treatment is warranted to prevent resolution of the disease with depressed scars [2]. although tetracyclines are considered first-line agents in the management of structureless yellow to orangish brown areas along with follicular keratotic plugs helps differentiate lmdf from its clinical mimickers such as sarcoidosis and lupus vulgaris, where—although yellowish orange areas are seen—they are not localized perifollicularly nor are keratotic plugs a prominent finding [1]. the absence of underlying vascular polygons would help in differentiating lmdf from granulomatous rosacea figure 3. (a) histopathological examination showing acanthosis and follicular plugging in epidermis. dermis shows well-defined granulomas with perifollicular localization predominantly (h&e, ×10). (b) perifollicular granulomas composed of predominantly epithelioid cells, a few lymphocytes, and giant cells in dermis (h&e, ×20). (c) higher power showing langhans (blue arrows) and foreign body giant cells (black arrow) with focal caseous necrosis (h&e, ×40). 4 letter | dermatol pract concept 2020;10(3):e2020055 literature search, we came across only one previous report focusing on the dermoscopic aspect of lmdf. dermoscopy can act as a valuable, real-time, bedside, auxiliary tool aiding the physician in reaching the diagnosis of this uncommon disorder. dermoscopy of differential diagnosis of lmdf is summarized in table 1. references 1. ayhan e, alabalik u, avci y. dermoscopic evaluation of two patients with lupus miliaris disseminatus faciei. clin exp dermatol. 2014;39(4):500-502. https://doi. org/10.1111/ced.12331 2. rocos d, kanitakis j. lupus miliaris disseminatus faciei: report of a new case and brief review of literature. dermatol online j. 2013;19(3):4. 3. toda-brito h, aranha jmp, tavares es. lupus miliaris disseminatus faciei. an bras dermatol. 2017;92(6):851-853. https://doi. org/10.1590/abd1806-4841.20174534 table 1. dermoscopic findings of differential diagnosis of lupus miliaris disseminatus faciei disorder dermoscopic findings sarcoidosis orangish areas with well-focused linear and branching vessels; white scar-like depigmented areas granulomatous rosacea linear reddish or purple vessels arranged in polygonal network (vascular polygons) with diffuse or localized orangish areas lupus vulgaris focal or diffuse orange areas with focused linear or branching vessels; milia-like cysts, pigmentation structures, whitish reticular streaks less commonly seen post kala-azar dermal leishmaniasis multiple yellow tears and erythema hansen disease diminished pigment network with yellowish orange areas in borderline tuberculoid spectrum; whitish yellow structureless areas with vessels in histoid leprosy; blanched erythema, follicular plugging, yellow-orange areas in type 1 reaction; increased erythema with dilated vessels in type 2 lepra reaction present case ill-defined, structureless, perifollicular, yellow to orangish brown areas with white or yellow keratotic follicular plugs; few linear and arborizing vessels over reddish brown background https://doi.org/10.1111/ced.12331 https://doi.org/10.1111/ced.12331 https://doi.org/10.1590/abd1806-4841.20174534 https://doi.org/10.1590/abd1806-4841.20174534 dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020112 1 dermatology practical & conceptual case presentation a 52-year-old man with no past medical history presented with an asymptomatic annular atrophic patch on the distal portion of the fourth toe of 2 years’ duration (figure 1b). the lesion began as a small keratotic papule that gradually enlarged centrifugally. he had received multiple treatments including cryotherapy, topical corticosteroids, antifungals, and antibiotics without improvement. dermoscopic examination revealed a scaly atrophic erythematous central area with a sharply demarcated peripheral hyperkeratotic structure (figure 1a). a skin biopsy of the edge of the lesion revealed a cornoid lamella with a column of parakeratotic cells extending from an invagination of the epidermis with absence of granular layer (figure 1c). the clinicopathologic correlation was consistent with porokeratosis of mibelli. porokeratosis of mibelli constanza riquelme-mc loughlin1, sebastian podlipnik1,2 1 department of dermatology, hospital clínic barcelona, universitat de barcelona, spain 2 institut d’investigacions biomediques august pi i sunyer (idibaps), barcelona, spain key words: porokeratosis, mibelli, dermoscopy, cornoid lamella citation: riquelme-mc loughlin c, podlipnik s. porokeratosis of mibelli. dermatol pract concept. 2020;10(4):e2020112. doi: https://doi.org/10.5826/dpc.1004a112 accepted: may 27, 2020; published: october 26, 2020 copyright: ©2020 riquele mcloughlin and podlipnik. this is an open-access article distributed under the terms of the creative commons attribution license (cc-by-nc-4.0), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sebastian podlipnik, md, department of dermatology, hospital clínic barcelona, universitat de barcelona, villarroel 170, 08036, barcelona, spain. email: spodlipnik@gmail.com figure 1. (a) polarized dermoscopy (dermlite ii prohr; magnification ×10) reveals a scaly atrophic erythematous central area, with a sharply demarcated peripheral hyperkeratotic structure (cornoid lamella). (b) unilateral annular patch on the distal portion of the fourth toe of the left foot. (c) punch biopsy of the edge of the lesion reveals a cornoid lamella with a column of parakeratotic cells extending from an invagination of the epidermis with absence of granular layer; h&e, magnification ×40. a b c 2 image letter | dermatol pract concept 2020;10(4):2020112 references 1. sousa herênio a, de morais cavalcanti sm, rodrigues de frança e, marques maranhão c, barbosa de alencar er. porokeratosis simulating bowen’s disease on dermoscopy. an bras dermatol. 2016;91(5 supplement 1):119-121. doi: 10.1590/abd18064841.20164479. pmid: 28300916. 2. navarrete-dechent c, uribe p, marghoob a. ink-enhanced dermoscopy is a useful tool to differentiate acquired solitary plaque porokeratosis from other scaly lesions. j am acad dermatol. 2019;80(6):e137-138. doi: 10.1016/j.jaad.2017.11.052. pmid: 29221722. teaching point porokeratosis can be mistaken with cutaneous squamous cell carcinoma in situ [1], tinea corporis, and circumscribed plantar hypokeratosis, among other annular lesions. dermoscopy is a useful tool that improves diagnostic accuracy and allows visualization of the cornoid lamella [2]. dp0204a11 dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):11 43 introduction the incidence rates of skin cancer in australia are the highest in the world. in 2002 the age-standardised incident rate for basal cell carcinoma (bcc) was estimated to be 884 per 100,000 of the population. this rate showed a threefold gradient between northern and southern australia [1]. bccs are the most common cutaneous tumours, accounting for approximately 70% of all malignant diseases of the skin. they are found predominantly on areas of skin exposed to the sun, particularly in fair skinned individuals. up to 80% of all bccs are found on the head and neck. they are more common in males, presumably related to occupational and recreational exposure to uv light. they tend to occur in older people [2]. in 2002 the age-standardised incidence of squamous cell carcinoma (scc) was estimated to be 387 per 100,000 of the population with a significant latitude gradient (similar to bccs). also, as for bccs, the incidence of sccs increases with increasing age. the head and neck are the most common sites of occurrence for scc in men, while upper limbs are the most common sites for women. when body surface area is taken into account the highest scc incidence in both men and women is found on the face, especially the lips nose cheek eyelids and ears [3]. in general the surgical management of scc is more radical than for bcc because sccs are potentially more aggressive, have a greater potential for local recurrence and may spread to regional lymph nodes and distant sites. over 70% of the bccs in australia were surgically excised [1]. the majority of sccs were surgically excised [1]. in australia about 400 people die from skin cancers other than melanoma each year. these are predominantly scc but some deaths are due to bcc [1]. the recommended surgical margin of excision for scc varies from 2 mm to 10 mm. histological margins of 1 mm or less mandates consideration of further therapy [3]. the diameter of scc correlates with risk of recurrence. lesions thicker than 4 mm or extending to at least the reticular dermis are associated with a higher rate of recurrence. a higher risk of local recurrence includes the ear. the majority of clinically favourable sccs of less than 2 cm can be excised with a margin of at least 4 mm [4]. v to y full thickness skin graft the majority of non-melanoma skin cancer (nmsc) occurs on the auricular helix and periauricular areas that are especially susceptible as they are exposed to the most uv light. defects of the upper third of the helical rim can be diffia novel treatment for nmsc of the ear: v to y full thickness skin graft graham sivyer, mbbs1 1 mermaid beach medical centre, queensland, australia key words: non melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, auricular helix, posterior ear, full thickness skin graft citation: sivyer g. a novel treatment for nmsc of the ear: v to y full thickness skin graft. dermatol pract conc. 2012;2(4):11. http:// dx.doi.org/10.5826/dpc.0204a11 received: january 29, 2012; accepted: august 15, 2012; published: october 31, 2012 copyright: ©2012 sivyer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: graham sivyer mbbs(hons) fsccanz, mermaid beach medical centre, 2506 gold coast highway, mermaid beach, queensland 4218 australia. tel. +61(0)755721668; fax .+61(0)755722866. email: graham.sivyer@ipnet.com.au. 44 observation | dermatol pract concept 2012;2(4):11 and hearing aids [5]. the objectives of surgical treatment of bccs and sccs are: (1) to cure by achieving histological confirmed complete excision of the tumour with a clear margin in width and depth, (2) to maintain normal function where possible, and (3) to achieve a good cosmetic result [6]. repair options of the middle and upper third of the ear include: side to side closure, wedge excision, bilobed transposition flap, banner transposition flap, helical crus rotation flap, helical rim advancement flap, and full thickness graft. the epidermis on the convex (posterior) aspect of the ear has a thicker subcutis of fat. this allows for a degree of laxity and movement as compared to the concave (anterior) aspect surface. the v to y full thickness graft (v2yftg) to repair defects on the helical rim makes use of this laxity (figure 1). once the ftg has been mobilised from the donor site on the convex aspect of the ear, it is advanced forward to cover the defect on the helical rim where the cancer has been excised (figure 2). the ftg is then sutured and if necessary a bolster tied over the area to minimise haematoma collection under the graft. sutures are removed after seven days. the principle of closure is similar to a v to y island flap without the attached pedicle. advantages of the v2y ftg include: (1) one wound only to manage, (2) good skin match and good cosmetic result, (3) less pain for the patient (particularly with wedge excisions), and (4) a relatively easy procedure to perform. cult to repair. the area is highly visible, making cosmetic results of utmost importance. it is also important to retain the supra-auricular sulcus to enable patients to wear glasses figure 1. (a) diagrammatic outline of circular lesion to be removed from the helical rim of the ear and the outline of the full thickness graft donor site on the posterior aspect of the ear. (b) diagram of completed v to y full thickness graft moved to cover the defect on the helical rim. [copyright: ©2012 sivyer.] a b a b e c fd figure 2. (a) cancer with margins on the helical rim and the full thickness graft donor area outlined. (b) cancer with margins on helical rim and full thickness graft donor on the posterior ear outlined. (c) full thickness graft after being moved forward to cover the defect being sutured into place. (d) bolster sutured over the full thickness graft. (e) posterior ear view after removal of sutures one week post surgery. (f) anterior ear view after removal of sutures one week post surgery. [copyright: ©2012 sivyer.] observation | dermatol pract concept 2012;2(4):11 45 4. basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in australia. cancer council australia and australian cancer network. sydney, 2008:53. 5. paver r, stanford d, storey l. dermatologic surgery: a manual of defect repair options. australia: mcgraw hill. 2011:243-95. 6. basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in australia. cancer council australia and australian cancer network. sydney, 2008:44. references 1. basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in australia. cancer council australia and australian cancer network. sydney, 2008:4. 2. weedon d. weedon’s skin pathology. 3rd ed. london, england: churchill livingstone elsevier 2010:682-3. 3. basal cell carcinoma, squamous cell carcinoma (and related lesions)—a guide to clinical management in australia. cancer council australia and australian cancer network. sydney, 2008,51. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020037 1 dermatology practical & conceptual introduction molluscum contagiosum (mc) is a viral infectious skin disease caused by molluscum contagiosum virus. direct contact with the infected skin and autoinoculation are the main ways of transmission. mc usually presents with pinkish to skin-colored and rounded umbilicated papules varying in size and shape. the diagnosis is usually based on the clinical features [1]. here we report a case of plantar mc that was initially misdiagnosed as viral wart. case presentation a 28-year-old man having a painless plantar lesion noticed 2 weeks previously was referred to our department with a preliminary diagnosis of plantar wart. physical examination revealed a 3-mm skin-colored lesion on the plantar surface of the right foot (figure 1). dermoscopic examination revealed a central yellowish structureless area surrounded by circumferential thick-branched vessel with bulbous ends (figure 2). hiv and vdrl (venereal disease research laboratory) tests were negative. a total shave excision was performed with preliminary diagnoses of mc and viral wart. histopathological examination showed numerous henderson-paterson bodies (intracytoplasmic hyaline eosinophilic inclusion bodies), confirming the diagnosis of mc (figure 3). the surgical intervention allowed a complete clearance of the lesion and no recurrence was observed after 2 months. conclusions mc is a common infectious condition that may affect both sexes and all age groups. it may present with single or multiple lesions. lower abdomen, thighs, genitals, and perianal areas are the common sites involved [1]. plantar mc is very rare. subungual, oral, and ocular regions are the other reported unusual localizations for mc. mc may have atypical presentations including giant and eczematous lesions. the atypical manifestations may imitate many conditions including warts, basal cell carcinoma, intradermal nevus, and amelanotic melanoma [2]. the clinical diagnosis may be difficult, especially in hiv-infected patients. plantar molluscum contagiosum with dermoscopic features ömer faruk elmas,1 asuman kilitçi2 1 department of dermatology and venereology, faculty of medicine, ahi evran university, kirsehir, turkey 2 department of pathology, faculty of medicine, ahi evran university, kirsehir, turkey key words: plantar, molluscum contagiosum, dermoscopy, dermatoscopy citation: elmas öf, kilitçi a. plantar molluscum contagiosum with dermoscopic features. dermatol pract concept. 2020;10(2):e2020037. doi: https://doi.org/10.5826/dpc.1002a37 accepted: november 20, 2019; published: april 3, 2020 copyright: ©2020 elmas and kilitçi. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: ömer faruk elmas, md, ahi evran university, faculty of medicine, kirsehir, 40000, turkey. email: omerfarukmd@ gmail.com https://doi.org/10.5826/dpc.1002a37 mailto:omerfarukmd@gmail.com mailto:omerfarukmd@gmail.com 2 letter | dermatol pract concept 2020;10(2):e2020037 references 1. meza-romero r, navarrete-dechent c, downey c. molluscum contagiosum: an update and review of new perspectives in etiology, diagnosis, and treatment. clin cosmet investig dermatol. 2019;12:373-381. 2. uzuncakmak tk, kuru bc, zemheri ei, zindanci i, turkoglu z, kavala m. isolated giant molluscum contagiosum mimicking epidermoid cyst. dermatol pract concept. 2016;6(3):71-73. other immunosuppressive conditions can also lead to atypical presentations. our patient had no history of systemic disease and immunosuppression. dermoscopy has recently become an indispensable diagnostic tool in daily dermatology practice. dermoscopic features of mc are well described. roundish white-to-yellow structures and peripheral crown vessels are the typical dermoscopic findings. radial and dotted vessels can also be seen. in our case, we observed a central yellowish structureless area surrounded by circumferential vessels. the main differential diagnosis was plantar verruca, in which dermoscopy usually reveals a lobulated surface with thrombosed capillaries giving a so-called “frogspawn appearance” in metaphorical language. to the best of our knowledge, dermoscopic features of plantar mc have not been described previously. figure 1. skin-colored papular lesion on the plantar surface (arrow). figure 2. central yellowish structureless area surrounded by a circumferential thick-branched vessel with bulbous ends. figure 3. histopathological examination showed numerous henderson-paterson bodies confirming the diagnosis of molluscum contagiosum. editorial | dermatol pract concept 2011;1(1):15 73 it is a great honour to be asked to establish and edit this new section of dermatology practical & conceptual. i have had the good fortune to study, work and practice in countries of widely varying socioeconomic status and to be able to concentrate for the last 10 years on delivering dermatology and skin cancer care in primary care practice. this has given me the opportunity to gain a perspective on medical practice internationally and the chance to engage in research, education and teaching in a primary care setting. having a strong interest in skin cancer management, it is with particular pleasure that i note that this journal is now the official journal of the international dermoscopy society and of the skin cancer college of australia and new zealand. it is often forgotten how great the burden of skin disease is in primary care around the world, yet there is so little research in the field and even less international teaching and communication on the subject. surveys of primary care in the netherlands [1,] australia [2] and the united kingdom [3] show the percentage of presentations relating to dermatological conditions are 12.4%, 10.4 % and 8.4 % respectively – about one in ten complaints dealt with in primary care are dermatologically related. there is also much variability between countries in the medical systems that deliver dermatological care and the interface between specialist dermatologists and primary care practitioners. these range from mainly hospital-centric models, such as in the united kingdom or saudi arabia; to relatively decentralized private practice, such as in australia; to areas where primary health care is delivered by non-physicians, such as by the health extension officers of papua new guinea; by teledermatology, as in remote areas of canada and australia; or self care, where there are no accessible health professionals as in so many parts of the world. training and education prospects vary just as widely. i recall the few hours a week of dermatology instruction over a one-month period that i was given in medical school and a textbook that had only twelve a5 pages of diagnostic images. fortunately, that deficit has been made up as a postgraduate, but not all graduates get that opportunity. added to this is the evident great geographic variation of the types of diseases and case mixes encountered, whether they are infectious conditions, such as cutaneous leishmaniasis, or more environmentally influenced conditions, such as skin cancer. over all of this is added the influence of socioeconomic development and ethnicity. “dermatology in primary care” will aim to take an international perspective, encouraging and highlighting research originating in primary care and offering teaching and review articles relevant to primary care. although the section will be necessarily brief in early journal editions, when fully developed, each edition will contain original research, review articles, opinion and editorial comment. in recognition of primary care practitioners being mainly morphologists, and in keeping with the focus of the journal, illustrated notable cases and educational case studies will be prominent. a particular feature of each edition will be a country-by-country perspective on primary care dermatological practice and how care is delivered. i look forward to a long relationship with the journal and its readers. dr. jeffrey keir mbbs mfammed(clin) dippracderm director, northern rivers skin cancer clinic, ballina, nsw, australia introduction to dermatology in primary care jeffrey keir, m.d. citation: keir j. introduction to dermatology in primary care [editorial]. dermatol pract concept 2011;1(1):15. http://dx.doi. org/10.5826/dpc.0101a15. copyright: ©2011 keir. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: dr. jeffrey keir, northern rivers skin cancer clinic, ballina, nsw, australia. email: tamarvillage@gmail.com. dermatology practical & conceptual www.derm101.com 74 editorial | dermatol pract concept 2011;1(1):15 references 1. verhoeven ew, kraaimaat fw, van weel c, et al. skin diseases in family medicine: prevalence and health care use. ann fam med 2008;6(4):349-54. 2. britt h, miller gc, knox s, et al. general practice activity in australia 2004–05. aihw cat. no. gep 18. canberra: australian institute of health and welfare, 2005. 3. kerr oa, tidman mj, walker jj, aldridge rd, benton ec. the profile of dermatological problems in primary care. clin exp dermatol 2010;35(4):380-3. epub 2009 oct 23. dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;2(4):1 1 editorial melanoma is a fascinating disease. it appears in a myriad of forms. no two melanomas look alike; every melanoma is unique morphologically. like other biologic phenomena it is highly complex and diverse in its forms of appearance. scientists attempt to bring order to the diversity of biologic phenomena by defining groups on the basis of shared characteristics and by giving names to these groups. what we call knowledge or, if one prefers a more elevated word, “truth,” is synonymous with being able to classify, name, and order phenomena correctly. in the 18th century the biologist carl linné established a universally accepted convention for the naming of organisms. according to linné, a tiger is a species (panthera tigris) that belongs to the genus “panther,” which is included in the family of felidae, which are part of the order carnivora, which belong to the class mammalia, which is included in the phylum chordata, which finally belongs to the kingdom animalia. it was not by accident that linné’s classification was hierarchic and based on morphologic (visible) criteria. in his influential book the order of things*, the great french historian and philosopher michel foucault advanced the hypothesis that all periods of history have possessed specific conditions of “truth” that constituted what was acceptable. scientific “truth” is nothing more than a mirror of mainstream thinking of an era and its power relations. the specific conditions of the 18th century presupposed a hierarchic classification and the sense of vision was so important for life sciences in those days that a biologist could be everything, but not blind (which is still true today for dermatologists and dermatopathologists). classifying diseases is not fundamentally different from classifying organisms. the classification of neoplasms as set forth by virchow in the 19th century is also hierarchic and based on morphologic (in this case histogenetic) characteristics. according to the who classification there are four major subtypes of melanoma: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. many arguments have been brought up against this classification. it was criticized for being inconsistent, illogical and practically useless. all these arguments fail to take into account that the validity and the spread of a given scientific point of view does not so much depend on constituency, logic, and practical value as on the prevailing (“mainstream”) thinking at a given time and on the power relations of individuals who support it in textbooks, journals, and scientific meetings. however, if we accept this classification, we can say that in analogy to the classification of organisms the subtype “superficial spreading melanoma” is included in the family of “melanoma,” which belongs to the class of “melanocytic neoplasms,” which are part of the kingdom of “neuroectodermal neoplasms,” which belong to the universe of “neoplasms.” as science progresses, the era of morphology is fading. the consequence is that organisms and diseases are being reclassified based on molecular findings. with regard to melanoma new mutations are discovered every other week and a new, molecular-based classification is emerging. in the near future we will be able to sequence entire genomes of tumor cells. it is very likely that we will discover that every melanoma is unique on a molecular level, in the same sense as every human being is unique. the consequence of such a scenario is that we will be facing innumerable subtypes because every melanoma is its own subtype. classifying phenomena into subgroups means highlighting the differences and disregarding the common; but if everything is different, isn’t it all the same? if, finally, everything turns out to be unique, then there is no hidden natural order; every order is imposed on the order of things and the classification of melanoma citation: kittler h. the order of things and the classification of melanoma. dermatol pract conc. 2012;2(4):1. http://dx.doi.org/10.5826/ dpc.0204a01. copyright: ©2012 kittler. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: harald kittler, md, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. e-mail: harald.kittler@meduniwien.ac.at. 2 editorial | dermatol pract concept 2012;2(4):1 the plethora of phenomena by human minds. in other words, there are innumerable ways to classify melanoma, or nevi, or every other phenomenon. every classification is convention, embedded in the scientific thinking of its time and dependent on power relations. not only did science make progress but power relations changed from the time linné introduced his system in the 18th century and when virchow introduced a pathologic classification of diseases in the 19th century. today power is not only played out in academic institutions, books and scientific journals but also in advisory boards, in national or international agencies that evaluate drugs or technical medical equipment, and in consensus conferences. it is not by chance that current suggestions for a new classification of melanoma are centered on gene products (for example b-raf) that are related to therapy. the growing influence of the pharmaceutical industry on scientific “truth” cannot be denied. there is another interesting consequence of the thinking that all melanomas are unique. note that we have said that the class of “melanocytic neoplasm” consists of two families: (1) benign melanocytic neoplasms (“nevi”) and (2) malignant melanocytic neoplasms. since all differences in the group of “malignant melanocytic neoplasms” finally will lead to innumerable groups, we may disregard all differences and look for the things in common. like all human beings are human, all melanomas are malignant! in other words there is only one type of malignant melanocytic neoplasm, which is melanoma. in this context the statement that, “there is only one type of melanoma,” sounds perfectly right from a logical point of view; at least, it cannot be refuted by enumerating differences, no matter if they are morphologic or molecular by nature. *foucault m. the order of things: an archeology of the human sciences. new york: pantheon books, 1970. editorial | dermatol pract concept 2012;2(1):10 53 dermatoscopy and skin imaging: the section to share your morphological observations and scientific insights alon scope, m.d.1 1 department of dermatology, sheba medical center, israel citation: scope a. dermatoscopy and skin imaging: the section to share your morphological observations and scientific insights. dermatol pract conc. 2012;2(1):10. http://dx.doi.org/10.5826/dpc.0201a10 copyright: ©2012 scope. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: alon scope, m.d., department of dermatology, sheba medical center, 52621, israel. tel. 972.35302419; fax. 972.35302375. email: scopea1@gmail.com. editorial dear colleagues, it is a great pleasure and honor to be the editor of the dermatoscopy and skin imaging section in dermatology practical and conceptual. we live in very exciting times in clinical dermatology. the use of primary morphology in diagnosis is natural for dermatologists and fundamental to our discipline; we are trained to diagnose skin disease based on the recognition of pathological patterns in the skin. thus, the use of non-invasive skin imaging enhances our morphological skills and adds depth to our view. with non-invasive imaging devices, such as dermatoscopy and confocal microscopy, we are able to see new structures and patterns under the skin’s surface that represent reproducible tissue pathology; this is dermatopathology at the bedside! the insights gained from recognitions of these new patterns have not only improved our diagnostic accuracy in the recognition of skin cancer [1,2], but have also opened new roads into the research of disease pathology, pathophysiology and treatment. as just one example, we are able, for the first time, to document and monitor change in pigmented lesions and better understand their rates and pattern of growth. the sonic study (study of nevi in children) has been documenting and following nevus evolution as children enter adolescence, using digital photography and dermatoscopy [3, 4]. we have shown that subsets of nevi that are recognized by their dermatoscopic pattern, namely, reticular and globular nevi, are distinct. globular-patterned nevi occur more frequently in the upper part of the body, tend to be larger in diameter and are more likely to occur in individuals with fair pigmentation phenotype and increased nevus counts; in contrast, reticular nevi are more frequent in the lower trunk and extremities, tend to be smaller in size, and constitute the main nevus pattern in individuals with dark skin phenotype and lower nevus counts [3]. moreover, nevi tend to retain their dermatoscopic pattern over time, so that cross-over between reticular and globular patterns is rare [4]. pellacani et al have followed the evolution of reticular and globular nevi using reflectance confocal microscopy and have shown that growth of nevi tends to occur within the same anatomic compartment-reticular nevi mostly grow along the basal layer of the epidermis, while in globular nevi, nests mostly grow in the superficial dermis-accounting for the retention of dermatoscopic pattern during evolution of nevi [5]. zalaudek et al have hypothesized that nevi with globular pattern and nevi with reticular pattern represent different pathways in nevus evolution and, furthermore, that melanomas with predominantly reticular pattern are fundamentally different from melanomas with predominantly globular pattern [6]. dermatology practical & conceptual www.derm101.com 54 editorial | dermatol pract concept 2012;2(1):10 importantly, in the first issue of dermatology practical and conceptual, beer, kittler and coworkers showed that melanomas that harbor a predominantly globular pattern (with large nests and aggregates on histopathology) grow faster than melanomas that show a predominantly reticular pattern (with lentiginous or small-nested pattern on histopathology) [7]. these findings are also in line with the previous observation of liu et al that melanomas can be divided into subsets of slow-growing or more rapidly growing melanomas [8]. thus, pattern of disease attests to biological behavior. as new biomarkers become available to better characterize subsets of diseases such as melanoma, we dermatologists can spearhead these efforts by pointing out the existence and characteristics of subsets of diseases via recognition of their unique morphology and then by correlating those morphological subsets with a unique molecular profile [9]. this is translational science at its best! and this is precisely the aim of the dermatoscopy and skin imaging section in dermatology practical and conceptual. this section offers an exciting opportunity for all of us to make new clinical and scientific observations at the bedside and to communicate their significance for diagnosis, prognosis or treatment. all that’s needed is a pair of eyes, in front of these eyes, an imaging device and of course patients, and behind these eyes, a curious and thoughtful mind. with this setup in place, scientific discoveries, clinical observations and new hypotheses will be inevitable! without a doubt, the members of the international dermoscopy society (ids) have been exemplary for precisely that. the abundance of bedside observations, interactive exchange of ideas and collegial spirit at the website of the ids is without peer. thus, the fact that dermatology practical and conceptual is the official journal of the ids is promising for great clinical and scientific merit. finally, please allow me introduce myself. i graduated from medical school at the tel aviv university. after completion of my dermatology residency at sheba medical center in israel, i decided to dedicate my career to the diagnosis and treatment of cancers of the skin. i was very fortunate to be trained by giants in the field, dedicated teachers and fruitful researchers. i completed a cutaneous oncology clinical and research fellowship at the dermatology service, memorial sloan-kettering cancer center in new york. my mentors, allan halpern and ashfaq marghoob, have been exceptional role models for clinician-scientists. i learned that every patient is a potential source for a new scientific observation, and every new scientific discovery can have implications and merit for better patient care. they have also taught me that the wealth of scientific insights needs to be clearly communicated to the scientific community and lay public by means of lectures and publications. they tirelessly practice and teach what they preach! subsequently, i was given the once in a lifetime opportunity by bernie ackerman to train as dermatopathology fellow at the ackerman academy of dermatopathology in new york, an institution dedicated to excellence in teaching. the year i spent at the academy under the phenomenal mentorship of bernie ackerman, geoff gottlieb and joan mones has ingrained in me the need for precision in language and diagnosis, clarity of thought and accountability in research. my mentor and friend harold rabinovitz from the university of miami has taught me the virtue of scientific sharing and has captivated me with his endless enthusiasm for research and technology. without a doubt, a highlight of my career as a physician-scientist has been the recognition of my efforts with the “paolo carli award for scientific excellence and contributions to dermoscopic research” given by the ids at the 2nd world congress of dermoscopy in barcelona (2009). at present, i am the director of the dermato-oncology clinic at the department of dermatology of sheba medical center, a large tertiary academic medical center in israel, and a research consultant at the dermatology service of memorial sloan-kettering cancer center, new york. in my practice, i integrate skin cancer surveillance and detection with skin imaging technologies, including dermatoscopy, total body photography, and reflectance confocal microscopy. i strongly believe dermatology practical and conceptual under the leadership of harald kittler will propagate the spirit of observational and scientific discoveries onto the younger generations. this spirit has been given thrust by no one like bernie ackerman. readers, please share your observations, discoveries and theories with the rest of us. we enthusiastically look forward to that. yours truly, alon scope, m.d. section editor dermatoscopy and skin imaging editorial | dermatol pract concept 2012;2(1):10 55 references kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159–65. pellacani g, guitera p, longo c, avramidis m, seidenari s, menzies s. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759–65. scope a, marghoob aa, dusza sw, et al. dermoscopic patterns of naevi in fifth grade children of the framingham school system. br j dermatol. 2008;158(5):1041–9. scope a, dusza sw, marghoob aa, et al. clinical and dermoscopic stability and volatility of melanocytic nevi in a population-based cohort of children in framingham school system. j invest dermatol. 2011;131(8):1615–21. pellacani g, scope a, ferrari b, et al. new insights into nevogenesis: in vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy. j am acad dermatol. 2009;61(6):1001–13. zalaudek i, leinweber b, hofmann-wellenhof r, et al. the epidermal and dermal origin of melanocytic tumors: theoretical considerations based on epidemiological, clinical and histopathological findings. am j dermatopathol. 2008;30(4):403–6. beer j, xu l, tschandl p, kittler h. growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings. dermatol pract conc. 2011;1(1):13. http://dx.doi. org/10.5826/dpc.0101a13. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol. 2006;142(12):1551–8. zalaudek i, guelly c, pellacani g, et al. the dermoscopical and histopathological patterns of nevi correlate with the frequency of braf mutations. j invest dermatol. 2011;131(2):542–5. dermatology: practical and conceptual review | dermatol pract concept 2019;9(4):3 265 dermatology practical & conceptual basal cell carcinoma originating in a tattoo: case report and review of an uncommon complication in tattoo recipients boya abudu1, christof p. erickson2, antoanella calame2, philip r. cohen3,4 1 university of california san diego school of medicine, la jolla, ca, usa 2 dermatology, compass dermatopathology, san diego, ca, usa 3 san diego family dermatology, national city, ca, usa 4 touro university california college of osteopathic medicine, vallejo, ca, usa key words: basal cell carcinoma, tattoo, immunocompromised district, pigment, skin cancer citation: abudu b, erickson cp, calame a, cohen pr. basal cell carcinoma originating in a tattoo: case report and review of an uncommon complication in tattoo recipients. dermatol pract concept. 2019;9(4):265-270. doi: https://doi.org/10.5826/dpc.0904a03 accepted: july 17, 2019; published: october 31, 2019 copyright: ©2019 abudu et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: boya abudu, mph, university of california san diego school of medicine, la jolla, ca 92093. email: boyaabudu30@gmail.com background: the placement of a tattoo is a common event. basal cell carcinoma arising from a tattoo is rare despite this neoplasm being the most common form of skin cancer. objective: we describe a 41-year-old man who developed a basal cell carcinoma in his tattoo and review the literature of basal cell carcinomas originating in a tattoo. methods: a literature search using pubmed was performed. the following terms were searched: “basal,” “carcinoma,” “cell,” and “tattoo.” the characteristics of individuals with a basal cell carcinoma originating in a tattoo were analyzed and summarized. results: a total of 13 patients (6 women and 7 men) with a basal cell carcinoma arising in a tattoo have been reported. the majority of the tumors were located on the head (6 cases, 46.2%) followed by either an upper extremity (4 cases, 30.7%) or the trunk (3 cases, 23.1%). most of the carcinomas were asymptomatic; however, 2 patients reported pruritus associated with their tumor. nodular basal cell carcinoma was the most common subtype diagnosed (5 tumors), followed by superficial basal cell carcinoma (2 tumors). one patient had either a pagetoid or a mixed (nodular and sclerosing) histology. the pathological variant was not described for 4 patients. conclusions: basal cell carcinoma arising in a tattoo is a rare occurrence. although this occurrence may be coincidental, emerging evidence of carcinogenesis associated with tattoo pigment may suggest a causal link. elucidating this important relationship warrants further investigation. abstract 266 review | dermatol pract concept 2019;9(4):3 clinical presentation and pathology findings established a diagnosis of a basal cell carcinoma arising in tattooed skin. the residual basal cell carcinoma was excised. the tumor was cleared after 2 stages of mohs micrographic surgery. the residual defect was repaired with a layered closure (figure 3). there was no recurrence at follow-up examination. review history the first report of a basal cell carcinoma originating at the site of a tattoo was described in 1976 [3]. bashir reported 2 patients: a 60-year-old woman and a 52-year-old man. both patients developed new lesions within tattoos that had been present for 15 to 20 years on the temporal scalp. since then, including our patient, only 11 individuals with a basal cell carcinoma arising in tattoos have been reported (table 1) [3-11]. we describe a man whose basal cell carcinoma appeared in his tattoo and also provide a comprehensive review of the features of the patients with basal cell carcinoma originating in a tattoo. epidemiology basal cell carcinoma originating in a tattoo has been described in 13 patients (tables 2 and 3). this includes 6 women ranging in age from 28 to 86 years (median, 62 years). it also includes 7 men ranging in age from 35 to 76 years (median, 52 years). the duration between application of the tattoo and discovery of the basal cell carcinoma among all patients ranged from 1 to 57.5 years (median, 14 years). in women, the duration ranged from 5 to 30 years (median, 13 years). in men, the duration ranged from 1 to 57.5 years (median, 15 years). the majority of patients in whom a basal cell carcinoma originated in a tattoo were caucasian (7 of 8 individuals, introduction basal cell carcinoma is the most common form of skin cancer [1]. tattooing has become a frequent occurrence; it is estimated that 25% of individuals aged 18 to 50 years have at least 1 tattoo [2]. the development of basal cell carcinoma in a tattoo is uncommon. we describe a man whose basal cell carcinoma developed within his tattoo. we also review the previously published individuals in whom this occurred. case report a 41-year-old caucasian man presented for evaluation of a new lesion on his left arm. he had a tattoo placed on his arm when he was 29 years old. ten months before presenting for evaluation, he noticed a red lesion appearing within his tattoo. the lesion was asymptomatic but continued to increase in size. cutaneous examination revealed a confluent tattoo occupying his left arm and forearm. within the green portion of the tattoo, there was an erythematous 15 × 7 mm red and brown plaque on his distal forearm (figure 1). there was no palpable axillary lymphadenopathy. a punch biopsy was performed. microscopic evaluation of the biopsy specimen showed nodular aggregates of basaloid tumor cells extending from the epidermis into the underlying dermis. there was palisading of the cells at the periphery of the tumor nodules. there was retraction of the dermal stroma from the periphery of the basal tumor cells. a large deposition of mucin was present within 1 of the tumor nodules. in addition, there were small black amorphous particles not only adjacent to the tumor, but also throughout the dermis (figure 2). the tumor was a nodular basal cell carcinoma. the black pigmented particles were the green tattoo. correlation of the figure 1. distant (a) and closer (b) views of a nodular basal cell carcinoma (within the white circle) presenting as a red plaque within the green tattoo on the left forearm of a 41-year-old man. [copyright: ©2019 abudu et al.] a b review | dermatol pract concept 2019;9(4):3 267 4 patients. the color of the tumor was not described for 9 of the patients. in 4 individuals, the basal cell carcinoma presented as an ulcer or an ulcerated lesion. the tumor presented as a nodule or a nodular plaque in 3 patients. two patients presented with a papule and 2 patients presented with a plaque. one woman presented with a cystic lesion on her eyelid [11]. the morphology was not described in 1 of the patients. the size of the basal cell carcinoma was described for 7 individuals. five women had a basal cell carcinoma that ranged in size from 6 to 20 mm (median, 10 mm). two men had a basal cell carcinoma that ranged in size from 7 to 15 mm (median, 11 mm). 87.5%). one woman was of east asian origin (1 of 8 individuals, 12.5%). the race was not described in 5 of the patients. symptoms most of the patients (11 of 13 individuals, 84.6%) were asymptomatic at presentation. however, 2 of the patients had pruritus localized to their tumor [6, 8]. one of the patients developed pruritus 5 years after tattoo placement on his back [8]. clinical presentation the color of the basal cell carcinoma ranged from red (2 patients) to brown (2 patients) to skin-colored (1 patient) in figure 3. appearance of the tattooed left forearm following the mohs micrographic surgery that removed the basal cell carcinoma. distant (a) and closer (b) views of the left forearm after a layered closure (between black arrows) was used to close the surgical defect following complete removal of the tumor. [copyright: ©2019 abudu et al.] a b figure 2. pathological features of a nodular basal cell carcinoma arising in a tattoo from the left forearm of a 41-year-old man. low (a), medium (b and c), and high (d) magnification views show nodular aggregates of basaloid tumor cells (asterisks) extending from the epidermis into the dermis. mucin is present in a tumor nodule (m) and there is retraction of the dermal stroma from the palisading cells at the periphery of the tumor nodules (red arrows). black, amorphous pigment (representing the green tattoo) is also present not only around the tumor but also in the dermis (black arrows). there is solar elastosis in the dermis (black circles) (h&e: a, ×4; b, ×10; c, ×20; d, ×40). [copyright: ©2019 abudu et al.] a c b d 268 review | dermatol pract concept 2019;9(4):3 dermoscopy dermoscopy was not reported in any of the individuals with basal cell carcinoma in a tattoo. we suspect that the dermoscopy of basal cell carcinoma originating from tattoos would have the same patterns as those occurring on tattoo-free skin: arborizing vessels, telangiectasias, blue-gray ovoid nests, globules, and ulceration [12]. in addition, dermoscopic features of a tattoo might be noted: a nonspecific homogenous pattern with nonsharp borders at the periphery [13]. the basal cell carcinoma within a tattoo often occurred in sun-exposed areas of the head or upper extremity (table 4). indeed, the most common location of tattoo-associated basal cell carcinoma was the head (6 patients, 46.2%) followed by an upper extremity (4 patients, 30.7%) and trunk (3 patients, 23.1%). in women, the most common location was the face (5 of 6 patients, 83.3%). in men, the most common location was an upper extremity (4 of 7 patients, 57.1%). table 1. publications describing the significance of basal cell carcinoma arising in a tattoo author, year [ref] contribution bashir, 1976 [3] the first reports of a bcc arising in a tattoo; on the temple of a woman and on the temple of a man. earley, 1983 [4] the first report of a bcc arising in a red tattoo on the shoulder of a man. they also reported a bcc arising on the hand of a man. wiener and scher, 1987 [5] the first report of a bcc arising in a blue and green tattoo on the forearm of a man. doumat et al, 2004 [6] the youngest man with a bcc arising in a tattoo. birnie et al, 2006 [7] the youngest patient with a bcc arising in a tattoo on the back of a woman. kluger et al, 2008 [8] a bcc arising in a tattoo on a man with a personal history of skin cancer (melanoma). the bcc was found on his back. lee et al, 2009 [9] a bcc arising in a tattoo of an individual of east asian origin whose lesion appeared on her eyebrow. omidian and emad-mostofi, 2009 [10] the largest bcc arising from a tattoo on the upper lip of a woman. a second woman with a crusted nodular bcc arising in a tattoo on her upper lip was also described. messmer et al, 2018 [11] the bcc on the lower eyelid of a woman was of mixed histology: nodular and sclerosing. she was also the oldest patient with a bcc originating in a tattoo. abudu et al, 2019 [current study] a nodular bcc arising in a green tattoo on the forearm of a man was described and a comprehensive review of all bccs originating in a tattoo was performed. bcc = basal cell carcinoma; ref = reference. table 2. clinical characteristics of 6 women with basal cell carcinoma arising in a tattoo c a, r dur site size; color morphology histology tattoo pigment tx ref 1 28, ca 6 central back 6 mm; pearly nodule nodular black ex [7] 2 60, ns 20 temple 7-8 mm; ns ulcer nos black ex [3], c1 3 60, ea 5 eyebrow 10 × 13 mm; skin-colored and translucent papule nodular black mms [9] 4 64, ca 30 upper lip 10 × 10 mm; ns crusting nodular plaque nodular blue ns [10], c2 5 72, ca ns upper lip 20 × 20 mm; brown and red pedunculated, umbrellashaped plaque nodular black, blue ns [10], c1 6 86, ca 13 l lower eyelid ns; ns cystic lesion nodular and sclerosing black, turquoise ex [11] a = age (years); c = case; ca = caucasian; dur = duration of tattoo (years); ea = east asian; ex = excision; l = left; mms = mohs micrographic surgery; nos = not otherwise specified (basal cell carcinoma); ns = not stated; r = race; ref = reference; tx = treatment. review | dermatol pract concept 2019;9(4):3 269 pathogenesis several adverse events have been documented to occur with tattoos, including reactive dermatoses, infections, and neoplasms [14]. in addition to basal cell carcinoma, other neoplasms that have appeared in tattoos include dermatofibrosarcoma protuberans, keratoacanthoma, leiomyosarcoma, melanoma, and squamous cell carcinoma. [15-17]. whether the appearance of these tumors is a serendipitous occurrence or related to tattoo-induced carcinogenesis remains to be definitively established. the possibility of the coincidental appearance of a basal cell carcinoma developing in a tattoo has been proposed. because the prevalence of tattoos is increasing, the likelihood of detecting a basal cell carcinoma at the site of a tattoo would also be expected to increase. however, the incidence of basal cell carcinoma originating in a tattoo is still rare relative to the increasing population of tattooed individuals [8]. an immunocompromised district describes an area of the skin that is more vulnerable to other dermatoses as compared with the rest of the body [18,19]. local immune dysregulation—of variable etiologies—results in an immunocompromised district; the immune aberration can be genetic or acquired. the etiology of an acquired immunocompromised pathology the most common pathological variant of basal cell carcinoma was nodular in 5 patients: 4 women and 1 man. superficial (2 men) and mixed (nodular and sclerosing, 1 woman) basal cell carcinomas were also observed, yet less frequently. one man’s tumor was described as pagetoid. the pathological variant was not described in 4 patients. in addition, all of the tissue specimens documented amorphous particles in the dermis. these particles represented the tattoo pigment. this pigment was most frequently observed perivascularly in the upper dermis. tattoo color basal cell carcinomas most commonly originated in black tattoos (7 patients, 53.8%). some of the basal cell carcinomas originated in blue (4 patients, 30.8%), turquoise (1 patient, 7.7%), or red (1 patient, 7.7%) tattoos. three of the patients’ tumors appeared within tattoos of 2 colors: black and blue (1 patient, 7.7%), black and turquoise (1 patient, 7.7%), and blue and green (1 patient, 7.7%). the color of the tattoo in which the basal cell carcinoma developed was not described for 3 patients. treatment the basal cell carcinoma was excised in 9 patients; 2 of these patients were treated with mohs micrographic surgery. the management was not described in the other 4 patients. the biological behavior of a basal cell carcinoma originating in a tattoo appears to be similar to that of basal cell carcinoma on tattoo-free skin. the prognosis for individuals with tattoo-associated basal cell carcinoma is excellent; all of the patients did well after removal of their tumor and experienced no recurrence. table 3. clinical characteristics of 7 men with basal cell carcinoma arising in a tattoo c a, r dur site size; color morphology histology tattoo pigment tx ref 1 35, ns 1 l scapula 7 mm; ns infiltrated papule pagetoid ns ex [6] 2 40, ca 7 back ns; ns ns superficial blue ex [8] 3 41, ca 12 l forearm 15 × 7 mm; red and brown plaque nodular ns mms cr 4 52, ns 15 temple ns; ns ulcerated lesion nos black ex [3], c2 5 64, ns 40 r hand ns; ns ulcer nos black ex [4], c2 6 64, ca 46 l arm ns; ns pearly nodule nos blue and green ns [5] 7 76, ns 57.5 shoulder ns; ns ulcerated lesion superficial red ex [4], c1 a = age (years); c = case; ca = caucasian; cr = current report; dur = duration of tattoo (years); ex = excision; l = left; mms = mohs micrographic surgery; nos = not otherwise specified (basal cell carcinoma); ns = not stated; r = race; ref = reference; r = right; tx = treatment. table 4. location of basal cell carcinoma in a tattoo women (n, %) men (n, %) total (n, %) head 5 (38.5%) 1 (7.7%) 6 (46.2%) upper extremity 0 (0%) 4 (30.7%) 4 (30.7%) trunk 1 (7.7%) 2 (15.4%) 3 (23.1%) total 6 (46.2%) 7 (53.8%) 13 (100%) 270 review | dermatol pract concept 2019;9(4):3 7. birnie aj, kulkarni k, varma s. basal cell carcinoma arising in a tattoo. clin exp dermatol. 2006;31(6):820-821. 8. kluger n, phan a, debarbieux s, balme b, thomas l. skin cancers arising in tattoos: coincidental or not? dermatology. 2008;217(3):219-221. 9. lee js, park j, kim sm, yun sk, kim hu. basal cell carcinoma arising in a tattooed eyebrow. ann dermatol. 2009;21(3):281284. 10. omidian m, emad-mostofi n. basal cell carcinoma arising from traditional tattoo. arch iran med. 2009;12(2):198. 11. messmer em, möhring-bengisu c, miller c. lidline tattoo associated with basal cell carcinoma of the lid margin—coincidence or association? [in german; abstract in english, german]. klin monbl augenheilkd. 2018;235(7):785-788. 12. lallas a, apalla z, ioannides d, et al. dermoscopy in the diagnosis and management of basal cell carcinoma. future oncol. 2015;11(22):2975-2984. 13. kendel m, toncic rj, bradamante m, et al. dermoscopy of a tattoo pseudolymphoma. dermatol pract concept. 2019;9(1):17-19. 14. kluger n. acute complications of tattooing presenting in the ed. am j emerg med. 2012;30(9):2055-2063. 15. basu p, erickson cp, calame a, cohen pr. osteoma cutis: an adverse event following tattoo placement. cureus. 2019;11(3):e4323. 16. paprottka fj, krezdorn n, narwan m, et al. trendy tattoos— maybe a serious health risk? aesthetic plast surg. 2018;42(1):310321. 17. kluger n, koljonen v. tattoos, inks, and cancer. lancet oncol. 2012;13(4):e161-e168. 18. ruocco v, ruocco e, piccolo v, brunetti g, guerrera lp, wolf r. the immunocompromised district in dermatology: a unifying pathogenic view of the regional immune dysregulation. clin dermatol. 2014;32(5):569-576. 19. cohen pr. zosteriform impetigo: wolf’s isotopic response in a cutaneous immunocompromised district. dermatol pract concept. 2015;5(3):35-39. 20. ruocco v, brunetti g, puca rv, ruocco e. the immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. j eur acad dermatol venereol. 2009;23(12):1364-1373. 21. engel e, ulrich h, vasold r, et al. azo pigments and a basal cell carcinoma at the thumb. dermatology. 2008;216(1):76-80. 22. regensburger j, lehner k, maisch t, et al. tattoo inks contain polycyclic aromatic hydrocarbons that additionally generate deleterious singlet oxygen. exp dermatol. 2010;19(8):e275-e281. 23. laux p, tralau t, tentschert j, et al. a medical-toxicological view of tattooing. lancet. 2016;387(10016):395-402. 24. engel e, spannberger a, vasold r, konig b, landthaler m, baumler w. photochemical cleavage of a tattoo pigment by uvb radiation or natural sunlight. j dtsch dermatol ges. 2007;5(7):583589. 25. engel e, vasold r, santarelli f, et al. tattooing of skin results in transportation and light-induced decomposition of tattoo pigments—a first quantification in vivo using a mouse model. exp dermatol. 2010;19(1):54-60. 26. cui y, churchwell mi, couch lh, doerge dr, howard pc. metabolism of pigment yellow 74 by rat and human microsomal proteins. drug metab dispos. 2005;33(10):1459-1465. 27. engel e, santarelli f, vasold r, et al. modern tattoos cause high concentrations of hazardous pigments in skin. contact dermatitis. 2008;58(4):228-233. district includes herpetic infections, ionizing or ultraviolet radiation, tattoos, and trauma. cutaneous exposure to these etiological factors increases the risk for immune destabilization at the affected site and subsequent development of another cutaneous disorder such as infection or neoplasm [20]. therefore, the appearance of a basal cell carcinoma in a tattoo may represent the development of the tumor in a tattoo-related immunocompromised district. many investigators consider the occurrence of skin cancer, particularly basal cell carcinoma, to be etiologically related to tattoos [21]. industrial compounds such as azo pigments and polycyclic compounds are common tattoo agents. these compounds are thought to have carcinogenic potential. azo pigments are a popular choice because of their durability, longevity, and color intensity; however, they have been associated with carcinogenesis in promoting basal cell carcinoma [21]. polycyclic aromatic hydrocarbons are frequently used with carbon in black tattoos. several in vitro studies of polycyclic aromatic hydrocarbons have supported the risk for carcinogenesis and mutagenesis when absorption of ultraviolet radiation results in the release of reactive oxygen species [22,23]. there is some evidence that ultraviolet radiation may lead to pigment decomposition; the byproducts may be toxic to the skin [24,25]. the extent to which skin metabolizes tattoo pigment remains unclear [26,27]. the appearance of most neoplasms in sun-exposed areas strengthens the evidence for this etiological relationship. conclusions the development of basal cell carcinoma in a tattoo is a rare occurrence that has been described in only 13 individuals. the majority of the tumors occurred in sun-exposed areas containing black pigment. the length of time between tattoo placement and tumor onset varied from 1 to 57.5 years. further studies are needed to investigate the role of pigment toxicology and skin metabolism for insight into the causal link between basal cell carcinoma and tattoos. references 1. lomas a, leonardi-bee j, bath-hextall f. a systematic review of worldwide incidence of nonmelanoma skin cancer. br j dermatol. 2012;166(5):1069-1080. 2. laumann ae, derick aj. tattoos and body piercings in the united states: a national data set. j am acad dermatol. 2006;55(3):413-421. 3. bashir ah. basal cell carcinoma in tattoos: report of two cases. br j plast surg. 1976;29(4):288-290. 4. earley mj. basal cell carcinoma arising in tattoos: a clinical report of two cases. br j plast surg. 1983;36(2):258-259. 5. wiener da, scher rk. basal cell carcinoma arising in a tattoo. cutis. 1987;39(2):125-126. 6. doumat f, kaise w, barbaud a, schmutz jl. basal cell carcinoma in a tattoo. dermatology. 2004;208(2):181-182. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020045 1 dermatology practical & conceptual introduction melanocytes may assume a variety of shapes: epithelioid, round, spindled, pagetoid, dendritic, and with clear cytoplasm, among others. a type of melanocyte with multivacuolated cytoplasm surrounding a dark-stained scalloped nucleus was initially described by eftychiadis et al as “sebocyte-like” [1]. these melanocytes are more commonly seen in benign congenital nevi, but also have been rarely reported in malignant melanoma, with only a few case reports in the literature [2]. the clear cell change is believed to result from intracellular enlargement of melanosomes with separation of their fibers. such neoplasms may mimic sebaceous neoplasms and clear cell carcinoma. we report a case of a metastatic melanoma with undifferentiated cells exhibiting sebaceous-like features. case presentation a 44-year-old woman with no significant medical history and no family history of melanoma presented with numerous firm subcutaneous nodules on her scalp, trunk, and extremities. the patient first noticed a nodule on her left upper arm 6 months prior, and then similar nodules arose diffusely. the patient endorsed fatigue, dyspnea, dysphagia, epigastric pain, right-sided weakness, and right leg pain. physical examination revealed numerous 1to 6-cm, firm, flesh-colored to red subcutaneous nodules diffusely on the scalp, neck, trunk, and extremities (figure 1). a total body skin examination did not identify lesions of concern for primary malignancy. brain mri and a whole-body ct scan revealed widespread soft tissue metastases, with innumerable lesions in the brain, chest wall, liver, spleen, and bone (figure 2). metastatic melanoma with sebocyte-like melanocytes and widespread visceral involvement li-wei chang,1 viktoryia kazlouskaya,1 jenna r. bordelon,1 marion a. hughes,2 yana g. najjar,3 yuri bunimovich,1 arivarasan karunamurthy,1 jonhan ho1 1 department of dermatology, university of pittsburgh medical center, pittsburgh, pa, usa 2 department of radiology, university of pittsburgh medical center, pittsburgh, pa, usa 3 department of medicine, university of pittsburgh medical center, pittsburgh, pa, usa key words: sebocyte-like melanocyte, metastatic melanoma, clear cell melanocyte, melanocyte, malignant melanoma citation: chang lw, kazlouskaya v, bordelon jr, hughes ma, najjar yg, bunimovich y, karunamurthy a, ho j. metastatic melanoma with sebocyte-like melanocytes and widespread visceral involvement. dermatol pract concept. 2020;10(2):e2020045. doi: https://doi. org/10.5826/dpc.1002a45 accepted: january 30, 2020; published: april 20, 2020 copyright: ©2020 chang et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: li-wei chang, md, dsc, department of dermatology, university of pittsburgh medical center, 3708 fifth avenue, 5th floor, suite 500.68, pittsburgh, pa 15213, usa. email: changl@upmc.edu https://doi.org/10.5826/dpc.1002a45 https://doi.org/10.5826/dpc.1002a45 mailto:changl@upmc.edu 2 letter | dermatol pract concept 2020;10(2):e2020045 skin biopsies taken from 2 nodules both revealed a deep dermal tumor composed of sheets of densely arranged atypical cells (figure 3). morphologically, many cells had scalloped nuclei and “bubbly” cytoplasm resembling sebaceous cells (figure 4). the cells expressed sox10 (figure 5) and were negative for pancytokeratin. ewsr1 fusion gene study, to rule out clear cell sarcoma, was negative. a diagnosis of metastatic melanoma was made; brafv600e mutation was identified. in addition, the patient had a pericardial effusion requiring a pericardial window and melanoma cells were found in the pericardial fluid. the patient was then started on encorafenib and binimetinib, and within 72 hours her cutaneous lesions were visibly regressing. a subsequent whole-body imaging after 2 months of treatment demonstrated marked reduction in the size and number of subcutaneous nodules in the thoracic and abdominal wall, as well as all visceral lesions. the majority of brain parenchymal lesions also decreased in size. at 4-month follow-up, the patient continued to do well clinically, but brain mri demonstrated progression of metastatic disease. conclusions the implication of sebocyte-like features on the prognosis of melanoma is not well established. few other cases have been reported, and none were as rapidly progressive as in this patient [2]. brafv600e mutation occurs in 50% of melanomas and has historically been associated with more aggressive disease. treatment with combined braf and mek inhibitors carries a high response rate and is therefore often first-line in those with high disease burden. we present a case of melanoma with sebocyte-like features that carries brafv600e mutation and significantly responded to combination targeted therapy. figure 1. multiple tender, firm, subcutaneous nodules on the trunk (a) with involvement of left axilla (b). figure 2. radiology findings. (a) axial t1 weighted image with contrast demonstrates multiple enhancing intracranial lesions (white arrows) within the right frontal and parietal lobe consistent with metastases. (b) axial fluid-attenuated inversion recovery (flair) images demonstrate varying degrees of vasogenic edema (white arrows) surrounding the brain metastases, most notably the right parietal lesion (black arrowhead). (c) axial ct image of the chest demonstrates multiple subcutaneous metastatic nodules (white arrowhead on a representative nodule). bilateral pleural effusions (white arrows) are also noted. (d) axial ct image of the abdomen with contrast demonstrates the large hypoenhancing left hepatic lobe lesion, compatible with a hepatic metastasis (black arrowheads). letter | dermatol pract concept 2020;10(2):e2020045 3 2. molina-ruiz am, ortiz-reina s, carranza c, kutzner h, requena l. sebocyte-like cell primary cutaneous melanoma: a rare cytologic variant of malignant melanoma. am j dermatopathol. 2015;37(11):862-865. references 1. eftychiadis as, iozzo rv, ackerman ab. sebocyte-like melanocytes in melanocytic nevi. dermatopathol pract concept. 1996;2:49-50. figure 3. dermal proliferation with sheets of undifferentiated cells. h&e staining. scanned slide, cropped image. figure 4. higher power shows undifferentiated cells with sebocyte-like morphology and melanin pigment. h&e staining. scanned slide, cropped image. figure 5. sebocyte-like cells in the dermal tumor express sox10. sox10 immunostaining, cropped image. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):17 81 dermatology practical & conceptual www.derm101.com “neglected nipples”: acanthosis nigricans-like plaques caused by avoidance of nipple cleansing grazyna kaminska-winciorek1, jerzy wydmanski1,2, alon scope,3,giuseppe argenziano4, iris zalaudek4,5 1 center for cancer prevention and treatment, katowice, poland 2 department of conventional and intraoperative radiotherapy maria skłodowska-curie memorial cancer center and institute of oncology gliwice branch, gliwice, poland 3 dermatology department, sheba medical center and sackler faculty of medicine, tel aviv university, tel-aviv, israel 4 skin cancer unit, arcispedale santa maria nuovairccs, reggio emilia, italy 5 department of dermatology, medical university of graz; graz, austria keywords: neglected nipples, acanthosis nigricans-like, hyperkeratosis, nipple hygiene, dermoscopy, dermatoscopy citation: kaminska-winciorek g, wydmanski j, scope a, argenziano g, zalaudek i. “neglected nipples”: acanthosis nigricans-like plaques caused by avoidance of nipple cleansing. dermatol pract concept. 2014;4(3):17. http://dx.doi.org/10.5826/dpc.0403a17 received: march 20, 2014; accepted: april 11, 2014; published: july 31, 2014 copyright: ©2014 kaminska-winciorek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: study supported in part by the italian ministry of health (rf-2010-2316524) competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: grazyna kaminska-winciorek md, phd, center for cancer prevention and treatment, 40-060 katowice, fliegera av. 16, poland. tel. + 48 698626208; fax. +48 322068113. email: dermatolog.pl@gmail.com background: acanthosis nigricans (an) develops sporadically or in association with obesity, insulinresistance and dark pigmentary phenotype. unusual clinical presentations of an may be diagnostically vexing. objectives: the aim of the report is to present unusual clinical and dermoscopic pictures of hyperkeratotic, brownish lesions of the nipples resembling acanthosis nigricans. patients/methods: data including clinical and dermoscopic features of two patients with the “neglected nipples”: acanthosis nigricans-like (an-like) hyperpigmented plaques caused by avoidance of nipple cleansing. results: beside the anamnestic clue, presentation of an-like plaques in the “neglected nipples” is limited to the breasts, in the absence of involvement of other flexural sites classically affected by an. dermoscopy aids the exclusion of a tumor, as it reveals exclusively structureless, brown-gray-black hyperkeratosis in the absence of criteria associated with melanocytic or non-melanocytic skin neoplasms of the nipple. the “neglected breasts” are easily treated by keratolytic creams and hygiene. conclusions: the “neglected nipples” condition, presenting as bilateral an-like papules and plaques of the nipples, is due to avoidance of cleansing of the nipple area, resulting in accumulation of keratotic cellular debris. abstract 82 observation | dermatol pract concept 2014;4(3):17 introduction acanthosis nigricans (an) is a skin condition that develops sporadically or in association with obesity, insulinresistance and dark pigmentary phenotype [1,2]. in rare cases, an represents a paraneoplastic syndrome associated with internal malignancies, mostly intrabdominal gastrointestinal cancers [1,3]. both benign and malignancy-associated an present initially as symmetrically dispersed darkened, slightly raised plaques that later progress to thick, keratotic, hyperpigmented, velvety plaques. an may occur at any anatomic site, but the flexural sites of the limbs, armpits and groins, as well as the neck folds are most commonly affected [1]. the workup associated with the diagnosis of an should exclude insulin resistance and internal malignancies; if an underlying malignancy is found, its treatment may lead to resolution of the an. in idiopathic cases, treatment aims to improve the cosmetic appearance and includes keratolytic creams or laser ablation. diet may be of benefit in obese patients [1,2]. although the clinical presentation of an usually points at the correct diagnosis, unusual clinical presentations of an may be diagnostically vexing. herein, we report on two patients presenting with similar hyperpigmented plaques affecting the nipples and discuss the common underlying cause and differential diagnosis. case presentation case 1 a 20-year-old woman was referred to dermato-oncological surgery because of gradually expanding keratotic plaques on both breasts. the patient presented a fair skin phototype and normal body mass index. her medical and family histories were unremarkable and she denied taking any medications. on clinical examination, symmetrically arranged, diffuse, yellowish to dark brown hyperkeratotic papules and plaques were bilaterally seen on the nipples, areolas and figure  1. clinical image of acanthosis nigricans-like lesions in a 20-year old woman. the lesions arose because she has avoided scrubbing the breasts. diffuse velvety, hyperkeratotic, yellow, brown to black papules and plaques are seen on both nipples, areolae and surrounding breast area are seen. insert: dermoscopy of the keratotic papules and plaques shows focally arranged, structureless gray-brown, angulated keratotic clods. [copyright: ©2014 kaminska-winciorek et al.] surrounding breast areas (figure 1). no other body sites were affected. dermoscopy revealed structureless black to yellowish keratotic clods (figure 1 insert). because the lesions were strictly limited to the breasts, the patient was interviewed in detail regarding her hygienic habits and in particular, whether she avoids scrubbing the breast area when taking a shower or drying with a towel; indeed, the patient confirmed that she avoids direct cleansing of the breasts due to fear and discomfort. subsequently, the patient was given teaching on adequate cleansing methods and was instructed to apply a topical keratolytic cream (5% salicylic acid) for one month. the patient was further offered psychological consultation but declined. at the one-month follow-up visit, the keratotic skin papules and plaques completely disappeared (figure 2). at subsequent follow-up visits 3 and 6 months later, no recurrence was detected. figure 2. clinical image of the breasts of the patient shown in figure, one month after topical treatment with keratolytic cream and hygienic teaching. complete clearance of the keratotic papules and plaques is seen. [copyright: ©2014 kaminska-winciorek et al.] observation | dermatol pract concept 2014;4(3):17 83 case 2 a 65-year-old man was referred to our skin cancer clinic because of keratotic plaque on the left nipple, tentatively diagnosed by the referring physician as seborrheic keratosis on the nipple. his medical history was unremarkable. at clinical examination, diffuse keratotic, brown to black papules coalescing to plaque were observed on the left areola, and to a lesser extent, also on the right areola (figure 3a, 3b and 3c). dermoscopically, the lesions presented as graybrown, angulated, keratotic clods (figure 3d). the rest of the skin examination was unremarkable. because of the symmetric arrangement of the keratotic plaques, the patient was asked about his washing routine and confirmed that he avoids washing or scrubbing the nipples because of a feeling of discomfort when touching them. the patient was further offered psychological consultation but declined. treatment with 5% salicylic acid cream for one month and instruction for methodical washing and scrubbing of the areola areas resulted in complete resolution of the keratotic lesions. at subsequent follow-up visits 3 and 6 months later, there was no recurrence of the keratotic lesions. conclusions hyperkeratosis of the nipple area has been reported in association with a range of diseases including benign and malignant forms of an, atopic dermatitis, darier disease, ichthyosis, hormonal disorders (diabetes mellitus, insulin resistance and thyroid disease), but also after pregnancy or in the context of nevoid hyperkeratosis of the nipple and areola or epidermal nevus [1,3,4,5]. however, the cases presented herein emphasize the importance of anamnestic interrogation, before proceeding to any laboratory workup to exclude conditions that could underlie recent onset an-like plaques. indeed, progressive accumulation of keratotic cellular debris around the nipple due to reluctance to cleanse this area can result in the clinical presentation of new-onset an-like plaques, a process that we refer to as the “neglected nipple.” the precise reason for neglecting the nipple hygiene remains to be elucidated, as both of our patients refused psychological consultation; the avoidance may simply stem from increased local sensitivity to scrubbing or a more complex, psychological process. besides the anamnestic clue, clinical clues to diagnosis of the “neglected nipple” include the presentation of symmetrically arranged hyperkeratotic papules and plaques strictly limited to nipple, areola and surrounding breast region, in the absence of involvement of any of the other body sites classically affected by an. the symmetrical and bilateral breast involvement differentiates the “neglected breast” from pigmented skin neoplasms of the nipple, including melanocytic nevi, melanoma, pigmented paget’s disease and seborfigure  3. (a) clinical overview of the thorax of a 65-year-old man presenting with acanthosis nigricans-like lesions of the areola. close up of the left (b) and right (c) areola reveals keratotic, polygonal brown-gray plaques at and around the nipple. d. dermoscopy of the plaques of the left nipple reveals keratotic, structureless, brown-gray angulated clods. [copyright: ©2014 kaminska-winciorek et al.] 84 observation | dermatol pract concept 2014;4(3):17 rheic keratosis; with few exceptions, the majority of these neoplasms will develop on only one nipple. dermoscopy further aids the exclusion of a tumor, as it reveals exclusively structureless brown-gray-black hyperkeratosis in the absence of criteria associated with melanocytic or non-melanocytic skin neoplasms of the nipple. in the differential diagnosis terra firma-forme dermatosis, wrongly considered a condition arising out of inadequate corporal hygiene, should also be taken into account. it is characterized by occurrence of dirty brown hyperkeratosis on the neck and ankles, suggesting negligence and affects both sexes equally [6]. in conclusion, the “neglected nipples” condition, presenting as bilateral an-like papules and plaques of the nipples, is due to avoidance of cleansing of the nipple area, resulting in accumulation of keratotic cellular debris. the diagnosis is confirmed by history and the condition resolved by simple teaching on hygienic methods and transient keratolytic topical treatment. it remains to be further elucidated whether the neglected nipples herald an underlying psychological problem. references 1. braun falco o, plewig g, wolff hh, et al. disorders of keratinization. in: braun falco o, plewig g, wolff hh, burgdorf whc (eds.). dermatology. 1st ed. berlin, heidelberg, new york: springerverlag, 2000:742-46. 2. boza jc, trindade en, peruzzo j, et al. skin manifestations of obesity: a comparative study. j eur acad dermatol venereol. 2012;26:1220-23. 3. lee hw, suh hs, choi jc, et al. hyperkeratosis of the nipple and areola as a sign of malignant acanthosis nigricans. clin exp dermatol. 2005;30:721-22. 4. schwartz ra. hyperkeratosis of nipple and areola. arch dermatol. 1978;114:1844-45. 5. higgins hw, jenkins j, horn td, et al. pregnancy-associated hyperkeratosis of the nipple: a report of 25 cases. jama dermatol. 2013;149:722-6. 6. pallure v, ameline m, plantin p, bessis d. terra firma-forme dermatosis. ann dermatol venereol. 2013;140:693-8. untitled cover art | dermatol pract concept 2011;1(1):1 1 moulage: “lupus erythematosus” beatrix patzak, m.d. 1 1director of the federal pathologic-anatomical museum, vienna, austria citation: patzak b. cover art: lupus erythematosus. dermatol pract concept 2011;1(1):1. http://dx.doi.org/10.5826/dpc.0101a01. copyright: ©2011 patzak. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: beatrix patzak, m.d., pathologic-anatomical museum, uni campus, spitalgasse 2, a-1090, vienna, austria. email: pat@narrenturm.at. figure 1. moulage. “lupus erythematosus”. federal pathologic-anatomical museum. vienna, austria, 1894. the first description of lupus erythematosus was given by pierre louis alphée cazenave, who was a coworker of laurent-théodore biett, in 1851. he used the french term “lupus erythemateux.” in 1856 ferdinand hebra translated this work into german and coined the term lupus erythematosus, which is the latin translation, and in 1863 isidor neumann propagated the greek term “lupus erythematodes.” in 1869 moritz kaposi published a comprehensive description of the cutaneous manifestations of lupus erythematosus. [1] the federal pathologic-anatomical museum in vienna houses 36 moulages with the diagnosis of lupus erythematosus, one of which is shown on the cover of the first issue of dermatology: practical and conceptual (figure 1). the oldest one dates back to 1894. most moulages originate from dermatology practical & conceptual www.derm101.com patients of moritz kaposi and gustav riehl, who succeeded his teacher kaposi as the professor of dermatologie und syphilis at the university of vienna in 1902. moulages are wax preparations (molds from real patients) made for teaching purposes. all moulages at the federal pathologic-anatomical museum in vienna were fabricated by the manufacturer karl henning and his son theodor. reference 1. scholz a, holubar k, burg g. geschichte der deutschsprachigen dermatologie. dresden: wiley-blackwell, 2009. dermatology: practical and conceptual research | dermatol pract concept 2019;9(4):7 283 dermatology practical & conceptual dermoscopic–histopathological correlation of eccrine poroma: an observational study marco a. chessa1, annalisa patrizi1, carlotta baraldi1, pier alessandro fanti1, alessia barisani1, sabina vaccari1 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: eccrine, poroma, dermoscopy, histopathology, diagnosis citation: chessa ma, patrizi a, baraldi c, fanti pa, barisani a, vaccari s. dermoscopic–histopathological correlation of eccrine poroma: an observational study. dermatol pract concept. 2019;9(4):283-291. doi: https://doi.org/10.5826/dpc.0904a07 accepted: july 15, 2019; published: october 31, 2019 copyright: ©2019 chessa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: annalisa patrizi, md, via massarenti 1, 40138 bologna, italy. email: alessiabarisani@gmail.com background: eccrine poroma (ep) is a benign adnexal neoplasm that can be pigmented in 17% of cases. four histopathological variants of ep exist. dermoscopically, ep can mimic many other skin neoplasms. objectives: to provide a dermoscopic–histopathological correlation of ep, classifying the clinical and dermoscopic features of eps on the basis of their histopathological subtype, in an attempt to better characterize these entities. patients and methods: a single-center retrospective study was conducted. clinical data were collected; patients were classified on the basis of the 4 histopathological variants of eps. dermoscopic images were reviewed. a dermoscopic–histopathological correlation was performed, and the results were compared with literature data. results: twenty-six lesions were included, both pigmented and nonpigmented. three of the 4 histopathological variants were identified. different dermoscopic features were observed for each distinct histopathological subtype of ep. the lesions mimicked different types of other skin neoplasms, in particular: nonpigmented hidroacanthoma simplex resembled nonmelanoma skin cancer; pigmented hidroacanthoma simplex appeared like a seborrheic keratosis or a solar lentigo; eps sensu stricto presented as pink nodules if nonpigmented and were similar to seborrheic keratosis if pigmented; dermal duct tumors appeared as pigmented nodular lesions. conclusions: distinct dermoscopic features appeared to be recurrent in each histopathological variant. dermoscopy can provide important clues for the diagnosis of ep; the final diagnosis is allowed by histopathology. to achieve a correct diagnosis of ep, because of its clinical and dermoscopic variability, surgical excision is recommended. abstract 284 research | dermatol pract concept 2019;9(4):7 polymorphous. finally, our results were compared with data from the literature. the study was approved by the local ethics committee. all patients gave their informed consent to the study. descriptive statistics were performed to analyze the clinical and demographic data. statistical analysis was performed using stata/se12.0 statistical software (stata, college station, tx). results twenty-six patients (14 men and 12 women) were included in this study; the mean age at diagnosis was 48.8 years (range 30-42 years). the lesions had been present for at least 1 year (range 1-20 years), without any significant changes in their clinical features over time. all lesions were asymptomatic and were detected incidentally during a routine dermatological visit. in our case series, 26 histopathologically diagnosed eps were included; 10 eps were nonpigmented and 16 were pigmented. clinically, all lesions were dome-shaped with well-defined borders and presented as a nodule in 11 cases and as a plaque in 15 cases. the main diameter of the eps ranged from 6 mm to 25 mm (mean 11 mm). different body areas were affected, in particular the trunk (9 cases), the face or scalp (7 cases), the feet or lower limbs (6 cases), and the abdomen (4 cases). all tumors were excised since a definitive diagnosis was not possible on the basis of clinical and dermoscopic features. a clinical/dermoscopic initial suspicion of ep was reported in only 5 cases. on histopathology, all lesions were characterized by the presence of small, dark, monomorphous, cuboidal poroid cells; pale and larger cuticular cells; and intracytoplasmatic or intercellular vacuolization. three of the 4 variants of eps were identified in our case series, considering the distribution of poroid cells through the epidermidis and the dermis (figure 1). the fourth variant (ph), as well as eps characterized by multiple histopathological variants in the context of the same lesion, was not detected in our case series. a dermoscopic–histopathological correlation was made in all cases. the 4 cases diagnosed as nonpigmented hidroacanthoma simplex (nphs) clinically resembled nonmelanoma skin cancers (nmscs), such as bowen disease (bd) (3 cases) or squamous cell carcinoma (scc) (1 case); on dermoscopy, polymorphous vessels were detected in all cases, consisting of glomerular, linear irregular, flower-like vessels and corkscrew vessels. milia-like cysts were also present (figure 2, a-c). the 5 cases of pigmented hidroacanthoma simplex (phs) appeared as a flat seborrheic keratosis (sk) or a solar lentigo (sl), respectively. on dermoscopy, network-like structures introduction eccrine poroma (ep) is a benign adnexal neoplasm that originates from the segment of the intradermal and intraepidermal eccrine duct. ep usually appears as an asymptomatic single lesion and could be pigmented in 17% of cases [1]. recently lallas et al presented 8 characteristic dermoscopic patterns of ep, each one resembling a common skin tumor [2]. because of its clinical and dermoscopic variability, ep is usually difficult to recognize and histopathology has a pivotal role in achieving the differential diagnosis. four histopathological variants depending on the localization of poroid cells have been reported: hidroacanthoma simplex (hs), ep sensu stricto, dermal duct tumor (ddt), poroid hidradenoma (ph). in addition, eps characterized by multiple histopathological variants, in the context of the same lesion, could be detected [3]. in the present study, we tried to provide a dermoscopic–histopathological correlation of eps. the clinical and dermoscopic features of eps were classified according to the histopathological subtype, in an attempt to assist the clinician who suspects this diagnosis. methods medical records and photographs were collected in a single-center retrospective study on eps histopathologically detected in our dermopathology laboratory, policlinico sant’orsola-malpighi, university of bologna, between january 2012 and december 2017. we recorded patients’ sex, age at diagnosis of eps, and morphology and distribution of the lesions. the cases were classified on the basis of the 4 possible histopathological variants of eps, and each form was classified as pigmented or nonpigmented depending on the presence or absence of melanin within the lesion. dermoscopic images were achieved using a digital video camera system (medicam 800; fotofinder systems gmbh, bad birnbach, germany; original magnifications ×20-×40). each dermoscopic image was then reviewed by 4 dermatologists. concordance between dermatologists was considered when 3 out of 4 agreed on the dermoscopic structure. a dermoscopic–histopathological correlation was performed for each lesion. on dermoscopy, the vascular patterns were described with the terms reported in the literature from inception to december 2017: glomerular or coiled vessels, linear irregular vessels, hairpin vessels, milky red areas, milky red globules, dotted vessels, helical vessels or corkscrew vessels, leaf-like vessels, flower-like vessels or cherry-blossom vessels or branched vessels with rounded endings, serpentine and chalice-form vessels [4-7]. the lesions with unique vessel morphology were considered monomorphous; those presenting any combination of ≥2 vessel types were considered research | dermatol pract concept 2019;9(4):7 285 dermoscopic features, whereas in the sixth case, an amelanotic melanoma was suspected. the 9 cases of pigmented eccrine poroma (pep) sensu stricto resembled an sk based on the clinical and dermoscopic features. comedo-like openings, milia-like cysts, and a cerebriform pattern were detected. the lesions were characterized by hairpin vessels in the central portion and linear irregular and serpentine vessels peripherally (figure 5, a-c). the 2 cases of pigmented dermal duct tumor (pddt) appeared as pigmented nodules of the scalp and the lower around follicles, comedo-like openings, and milia-like cysts were detected. in these cases a vascular pattern was not present (figure 3, a-c). all 6 cases of nonpigmented eccrine poroma (npep) sensu stricto clinically appeared as pink nodules. on dermoscopy, a polymorphous vascular pattern (including at least 2 types of vascular structures) was detected in all cases: glomerular vessels, milky red globules, milky red areas, flower-like vessels, and dotted vessels (figure 4, a-c). in 5 out of 6 cases, a diagnosis of ep was proposed by clinicians considering these figure 1. dermoscopic and histopathological findings of the 26 eccrine poromas included in the study. [copyright: ©2019 chessa et al.] 286 research | dermatol pract concept 2019;9(4):7 figure 3. (a) pigmented hidroacanthoma simplex appearing as a dark brown plaque located on the forehead. (b,c) on dermoscopy, a brown pseudonetwork with fingerprint-like structures around follicles (light blue arrow), milia-like cysts (dark blue triangle), and comedo-like openings (black arrow) were seen, mimicking a seborrheic keratosis (original magnifications ×20 and ×40, respectively). (d) on histopathology, sharply delineated aggregation of poroid, cuticular cells and tubular structures, and an increase of melanin pigment among the epidermis, were observed (h&e staining, original magnification ×10). (e) at higher magnification, small, dark, monomorphous, neoplastic poroid cells constitute most of the sharply circumscribed aggregations within the epidermis; these findings are diagnostic of hidroacanthoma simplex (h&e staining, original magnification ×40). [copyright: ©2019 chessa et al.] figure 2. (a) nonpigmented hidro acanthoma simplex (nphs) appearing as a pink plaque of the hip. (b,c) on dermoscopy, glomerular (black arrow), linear irregular (green bolt), flower-like (green arrow), and corkscrew vessels (yellow star) and milia-like cysts (dark blue triangle) were observed (original magnifications ×20 and ×40, respectively). (d) histopathological features of nphs were detected, consisting of well-circumscribed poroid cells arranged in an ovoid aggregation confined within the epidermis (h&e staining, original magnification ×4). (e) at higher magnification, sharply delineated aggregations of poroid cells that spare the basal layer of the epidermis and dark-staining pyknotic nuclei can be seen better (h&e staining, original magnification ×40). [copyright: ©2019 chessa et al.] research | dermatol pract concept 2019;9(4):7 287 hs is histopathologically characterized by nests of poroid cells confined to the epidermis, whereas clinically the lesions often appear as plaques [8]. nphs often resembles an nmsc, such as bd and scc [8]. in bd, scales are usually observed in the entire lesion, and glomerular vessels are a hallmark in 90% of cases [9]. in scc, atypical keratinization is typically prominent in the central part of the lesion, whereas in the periphery, polymorphous vessels, including linear irregular or serpentine vessels, could be detected on a white background [10,11]. however, the dermoscopic criteria useful to distinguish hs from bd [12] were not confirmed in our case series: in fact, glomerular vessels were detected also in nphs (figure 2, b and c); moreover, polymorphous vascular structures, such as linear irregular and glomerular vessels, were detected in nphs, similarly to scc (figure 2, b and c). instead, the presence of milia-like cysts in nphs (figure 2, b and c) might be a useful criterion for the differential diagnosis with bd and scc. phs could resemble a flat sk or an sl, as in our case series. however, sl is typically characterized by a structureless homogenous pigmentation and numerous openings of limb. in the first case, gray-yellow pigmented lobules separated by grayish septa with leaf-like and flower-like vessels were detected within the peripheral lobules (figure 6, a-c). the second pddt showed yellow pigmented lobules separated by grayish septa and monomorphous, flower-like vessels (figure 7, a-c). polymorphous vascular structures were found in 20 out of 26 eps. in 4 cases, a vascular pattern was not identifiable. the most frequently detected vascular patterns were linear irregular vessels in 11 cases and glomerular vessels in 10 cases. in 6 cases milky red globules and in 4 cases milky red areas were observed (figure 1). discussion in the literature, ep is often reported as a single entity, without any specification of the histopathological subtype [1,2]. the great clinical and dermoscopic variability within the category of eps is related to the distribution of the cells in the epidermis and the dermis. figure 4. (a) clinical presentation of a nonpigmented eccrine poroma sensu stricto as a pink nodule located on the foot. (b,c) dermoscopy shows milky red areas (light blue arrow), milky red globules (dark blue triangle), and dotted vessels (black arrow) (original magnifications ×20 and ×40, respectively). (d,e) histopathologically, the neoplasm consists of poroid and cuticular cells and tubular structures which are continuous with the epidermis (h&e staining, original magnifications ×10 and ×40, respectively). [copyright: ©2019 chessa et al.] 288 research | dermatol pract concept 2019;9(4):7 figure 5. (a) a pigmented eccrine poroma (pep) presenting as a well-defined, pigmented seborrheic keratosis-like lesion of the abdomen. (b,c) dermoscopy shows a gray-to-brown background with a uniform distribution of the vascular structures, consisting mainly of hairpin vessels (yellow star) in the central part and linear irregular (yellow arrow) and serpentine vessels (black arrow) at the periphery of the pep (original magnifications ×20 and ×40, respectively). (d) histopathologically, an increase of melanin pigment is present among the pep (h&e staining, original magnification ×10). (e) at higher magnification, the 2 cell types that constitute poromas are seen: cells with small dark-staining nuclei and scant cytoplasm are poroid cells, whereas cells with larger, paler nuclei and abundant cytoplasm are cuticular cells (h&e staining, original magnification ×20). [copyright: ©2019 chessa et al.] hair follicles [13]. in contrast, phs appeared to be characterized by an irregular pseudonetwork, some milia-like cysts, and comedo-like openings that could help rule out an sl (figure 3c). like in flat sks, also our case of phs (figure 3c) showed fingerprint-like structures around the hair follicles and comedo-like openings; however, the patient did not present any other similar lesions on the skin; therefore, an incisional biopsy was performed. in the literature, these dermoscopic and histopathological findings were reported when incisional biopsies were performed in the thinner part of the lesions [14,15]. the most common clinical presentation of npep is a firm nodule, from pink to red in color. these lesions are often characterized by polymorphous vessels [16]. on dermoscopy, many terms were used to describe the vascular patterns of npeps: structureless pink-white areas, milky red areas or red globular structures, lacuna-like areas, glomerular, chalice-form, cherry-blossom, flower-like, and leaf-like vessels [16-21]. the differential diagnosis includes several malignant lesions, such as bd, scc, and amelanotic melanoma. anamnestic data may be useful for the differential diagnosis, as npeps are generally reported as having been present for a long time, without any substantial variations. peps represent a small percentage of eps. these lesions may resemble an sk on dermoscopy, because comedo-like openings, milia-like cysts, and hairpin vessels are usually detected [1,22]. however, clinical and dermoscopic features may show some alarming features, such as blue-gray areas and polymorphous vessels [23], resembling a pigmented basal cell carcinoma (bcc) or a melanoma. ddt usually appears as papulonodules. dark brown roundish structures or dark bluish structureless areas may be observed [24]. a lobular overall appearance, histopathologically consisting of interlacing white cords, which separate gray-bluish structureless islands, has been reported, as well in our study, with or without vascular structures inside the islands [24,25]. we detected leaf-like and flower-like vessels in the peripheral lobules (figures 6c and 7c). histopathology is needed to rule out a nodular melanoma or a pigmented bcc. research | dermatol pract concept 2019;9(4):7 289 achieve a great number of cases and to find significant relationships from the data. despite these limitations, we were able to find 3 of the main histopathological variants and found that several dermoscopic features were recurrent in each histopathological variant (figure 1). to the best of our knowledge, no previous studies have investigated the dermoscopic–histopathological correlations of eps. further case series, and larger case numbers, may strengthen these associations. conclusions in the presence of a well-defined nodule or plaque, either pigmented or nonpigmented, with a low tendency to change over several years, the clinical suspicion of ep should be hypothesized. our data show that dermoscopy may provide important clues for this diagnosis; in particular, it can show the recurrence of distinct patterns in the different histopathological subtypes. nphs can often resemble an nmsc; phs may mimic an sk or an sl; ep sensu stricto may present as pink nodules, or like an sk if pigmented; ph may appear as a pigmented or a nonpigmented nodule, usually with a nonspecific, polymorphic vascular pattern; the differential diagnosis with amelanotic melanoma and ulcerated scc requires surgical excision [26]. eps characterized by multiple histopathological variants in the context of the same lesion usually show multiple colors, with thick vessels and large blue-gray ovoid nests, resembling a pigmented bcc [1,27]. these eps were scarcely reported in the literature, and their surgical excision is always suggested. polymorphous vessels (77% of cases in our study) are frequently associated with eps; this data was confirmed by marchetti et al in a recent cross-sectional, observational study on 113 eps [28]. according to the authors, milky red globules could be considered a dermoscopic feature specifically associated with eps [28]. ep has been named “the great dermoscopic imitator” owing to its clinical and, above all, dermoscopic variability. in the present work, we described their dermoscopic features on the basis of the histopathological subtype. limitations of this study are represented by the rarity of eps, which are often underestimated and make it difficult to figure 6. (a) a pigmented dermal duct tumor appearing as a pigmented nodule of the scalp. (b,c) dermoscopy reveals light brown, pigmented lobules separated by grayish septa, with some leaf-like (yellow star) and flower-like vessels (black arrow) in some peripheral lobules (original magnifications ×20 and ×40, respectively). (d) histopathological features consist of poroid cells and cuticular cells aggregated in small, discrete intradermal nodules (h&e staining, original magnification ×4). (e) at higher magnification, vacuoles are visible within cuticular cells and represent a stage en route to formation of ducts (h&e staining, original magnification ×40). [copyright: ©2019 chessa et al.] 290 research | dermatol pract concept 2019;9(4):7 5. ayhan e, ucmak d, akkurt z. vascular structures in dermoscopy. an bras dermatol. 2015;90(4):545-553. 6. togawa y. review of vasculature visualized on dermoscopy. j dermatol. 2017;44(5):525-532. 7. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol. 2014;170(3):514-526. 8. furlan kc, kakizaki p, chartuni jcn, sittart ja, valente nys. hidroacanthoma simplex: dermoscopy and cryosurgery treatment. an bras dermatol. 2017;92(2):253-255. 9. zalaudek i, argenziano g, leinweber b, et al. dermoscopy of bowen’s disease. br j dermatol. 2004;150(6):1112–1116. 10. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2012;66(4):589-597. 11. russo t, piccolo v, lallas a, et al. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. 12. shiiya c, hata h, inamura y, et al. dermoscopic features of hidroacanthoma simplex: usefulness in distinguishing it from bowen’s disease and seborrheic keratosis. j dermatol. 2015;42(10):10021005. ddt is often a pigmented nodule. however, a definitive diagnosis based on clinical and dermoscopic findings is generally challenging. because these benign neoplasms can often resemble other skin neoplasms, including bcc, scc, and malignant melanoma, and because their transformation into a porocarcinoma should be kept in mind [29], surgical excision is always recommended. references 1. minagawa a, koga h. dermoscopy of pigmented poromas. dermatology. 2010;221(1):78-83. 2. lallas a, chellini pr, guimarães mg, et al. eccrine poroma: the great dermoscopic imitator. j eur acad dermatol venereol. 2016;30(10):e61-e63. 3. battistella m, langbein l, peltre b, cribier b. from hidroacanthoma simplex to poroid hidradenoma: clinicopathologic and immunohistochemic study of poroid neoplasms and reappraisal of their histogenesis. am j dermatopathol. 2010;32(5):459-468. 4. martín jm, bella-navarro r, jordá e. vascular patterns in dermoscopy. actas dermosifiliogr. 2012;103(5):357-375. figure 7. (a) a pigmented dermal duct tumor presenting as a pigmented nodule of the lower limb. (b,c) dermoscopy shows yellow lobules separated by grayish septa, with flower-like vessels (yellow star) in some peripheral lobules (original magnifications ×20 and ×40, respectively). (d) histopathology shows poroid and cuticular cells aggregated in intradermal nodules with an increase of melanin pigment (h&e staining, original magnification ×10). (e) at higher magnification, the sequence of changes that leads to formation of ductal structures is visible; the earliest changes consist of tiny vacuoles within the cytoplasm of cuticular cells (h&e staining, original magnification ×40). [copyright: ©2019 chessa et al.] research | dermatol pract concept 2019;9(4):7 291 22. almeida fc, cavalcanti sm, medeiros ac, teixeira ma. pigmented eccrine poroma: report of an atypical case with the use of dermoscopy. an bras dermatol. 2013;88(5):803-806. 23. bombonato c, piana s, moscarella e, lallas a, argenziano g, longo c. pigmented eccrine poroma: dermoscopic and confocal features. dermatol pract concept. 2016;6(3):59-62. 24. oiso n, matsuda h, kawada a. biopsy-proven pigmented poroma with no vascular structure in dermoscopy. int j dermatol. 2014;53(6):e334-e335. 25. shalom a, schein o, landi c, marghoob a, carlos b, scope a. dermoscopic findings in biopsy-proven poromas. dermatol surg. 2012;38(7 pt 1):1091-1096. 26. robles-mendez jc, martınez-cabriales sa, villarreal-martinez a, et al. nodular hidradenoma: dermoscopic presentation. j am acad dermatol. 2017;76(2s1):s46-s48. 27. ichiyama s, hoashi t, funasaka y, et al. pigmented poroma on the temporal region dermoscopically mimicking basal cell carcinoma: a report of two cases. j dermatol. 2018;45(4):e94-e95. 28. marchetti ma, marino ml, virmani p, et al. dermoscopic features and patterns of poromas: a multicentre observational case-control study conducted by the international dermatoscopy society. j eur acad dermatol venereol. 2018;32(8):1263-1271. 29. shaw m, mckee ph, lowe d, black mm. malignant eccrine poroma: a study of twenty-seven cases. br j dermatol. 1982;107(6):675-680. 13. goncharova y, attia ea, souid k, vasilenko iv. dermoscopic features of facial pigmented skin lesions. isrn dermatol. 2013;2013:546813. epub 2013 feb 3. 14. dong h, zhang h, liu n, soyer hp. dermoscopy of a pigmented apocrine porocarcinoma arising from a pigmented hidroacanthoma simplex. australas j dermatol. 2018;59(2):e151-e152. 15. sato y, fujimura t, tamabuchi e, haga t, aiba s. dermoscopy findings of hidroacanthoma simplex. case rep dermatol. 2014;6(2):154-158. 16. espinosa ae, ortega bc, venegas rq, ramírez rg. dermoscopy of non-pigmented eccrine poromas: study of mexican cases. dermatol pract concept. 2013;3(1):25-28. 17. nicolino r, zalaudek i, ferrara g, et al. dermoscopy of eccrine poroma. dermatology. 2007;215(2):160-163. 18. ferrari a, buccini p, silipo v, et al. eccrine poroma: a clinical-dermoscopic study of seven cases. acta derm venereol. 2009;89(2):160-164. 19. sgouros d, piana s, argenziano g, et al. clinical, dermoscopic and histopathological features of eccrine poroid neoplasms. dermatology. 2013;227(2):175-179. 20. aydingoz ie. new dermoscopic vascular patterns in a case of eccrine poroma. j eur acad dermatol venereol. 2009;23(6):725726. 21. argenziano g, zalaudek i, corona r, et al. vascular structures in skin tumors: a dermoscopy study. arch dermatol. 2004;140(12):1485-1489. dermatology: practical and conceptual research | dermatol pract concept 2014;4(3):6 37 dermatology practical & conceptual www.derm101.com introduction: keratoacanthoma (ka) and invasive squamous cell carcinoma (scc) are keratinocytic tumors displaying vascular features, imaged using dermatoscopy. objective: compare the dermatoscopy vascular features of ka to scc. methods: this prospective study examined consecutive cases of 100 ka and 410 invasive scc in a single private practice in sydney, australia. vascular features were recorded in vivo direct from patients using a non-polarized delta 20 heine dermatoscope. these vascular features were: linear, branching, serpentine, hairpin, glomerular and dot vessels, the presence or absence of large diameter tumor vessels, vessel presence in central verses peripheral tumor areas and tumor pink areas in different proportions. following full excision, all cases were submitted for histopathologic diagnosis. results: branching vessels were the only vessel morphology that varied, with a significant incidence in ka (25.0%), compared to scc (10.7%), p < 0.01. large vessels were identified in 20.0% of ka, compared to 12.4% in scc, p = 0.05. no vessels were observed in the central tumor areas in 43.4 % of ka compared to 58.0% of scc, p = 0.01. other data comparing the central versus peripheral tumor areas for vessels present did not reveal any distinctive associations. there were no significant differences between ka and scc when reviewing the selected proportions of pink within the tumor. limitations: the vascular features may be confounded by tumor depth in ka. polarized dermatoscopy may not produce the same findings. conclusion: this study found branching vessels to have a higher incidence in ka compared to invasive scc. although not statistically significant, large diameter vessels were also more frequent in ka. proportions of pink within the tumor or central verses peripheral tumor vessel distribution were not useful diagnostic features separating ka from scc using dermatoscopy. abstract keratoacanthoma versus invasive squamous cell carcinoma: a comparison of dermatoscopic vascular features in 510 cases john h. pyne1, graham windrum1, devendra sapkota1, jian cheng wong2 1 school of medicine, university of queensland, brisbane, australia 2 school of mathematics and statistics, the university of new south wales, sydney australia keywords: keratoacanthoma, invasive squamous cell carcinoma, vessels, vascular, dermatoscopy citation: pyne jh, windrum g, sapkota d, wong jc. keratoacanthoma versus invasive squamous cell carcinoma: a comparison of dermatoscopic vascular features in 510 cases. dermatol pract concept. 2014;4(3):6. http://dx.doi.org/10.5826/dpc.0403a06 received: january 7, 2014; accepted: may 17, 2014; published: july 31, 2014 copyright: ©2014 pyne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: john pyne, mbbs, boptom, mmed, phd, 131 ellesemere rd, gymea bay, nsw australia. tel. 61.414.750625; fax. 61.2.95253193. email: j.pyne@uq.edu.au 38 research | dermatol pract concept 2014;4(3):6 introduction ka and invasive scc are both common keratinocytic tumors. ka can be thought of as a variant of well-differentiated scc, capable of spontaneous regression [1]. however, other authors have challenged this concept [2]; some consider ka a benign entity [3]. different histopathologic subtypes of ka have been proposed [4]. keratoacanthoma rarely metastasizes to lymph nodes [5]; and rarely undergoes perineural [6,7] or venous invasion [8]. the characteristic rapid growth, maturation, and involution of ka are not typical behaviors for well-differentiated invasive sccs. invasive scc is at risk of metastasizing with increasing tumor depth and a shift toward poor differentiation, among other factors. the various clinical, dermatoscopic [9,10], and histopathologic features of ka and scc overlap. dermatoscopy features of keratinization are more reliable than vascular features in diagnosing ka and scc [9]. pigmented scc [11] and pigmented keratoacanthoma [12] are rare; thus, pigmented dermatoscopy features are not useful for routine dermatoscopic guided diagnosis to confirm these tumors. there are no histologic findings proven to predict biologic behavior in ka [13]. acantholysis can occur in scc and when identified, has been stated to exclude keratoacanthoma [14]. various biochemical markers have not been found to provide a pathognomonic distinction between ka and scc. this study examined dermatoscopically identified vascular features comparing ka to scc. methods: the setting for the study was a single private practice in sydney, australia. data collection ran from 2009 until 2011. inclusion criteria: all patients examined within the study time window were considered for inclusion in the study. all cases required full excision down to fat, prior to submission for routine histopathologic assessment. all cases accepted into the study had histopathologic confirmation as either ka or invasive scc. exclusion criteria: any previous surgical or topical medical intervention on the site of the excision resulted in exclusion. medical intervention included field effect photodynamic therapy, or localized radiotherapy. sites juxtaposed to scars or tattoos were excluded. collision situations between either a ka or scc, and any other diagnostic entity based on clinical, dermatoscopy, or histopathology evidence were also excluded. cases of scc in situ without any invasion were excluded. tumors were collected from all presenting body sites. there were no exclusions based on body site. definition of vessel morphologies: the vessel morphologies chosen are all established and well known in the published literature on dermatoscopy. serpentine vessels are equivalent to linear-irregular vessels. however, the vast majority of this published work (on these vessel morphologies) is on entities that are neither ka nor invasive scc. definition of large “thick” vessels: a large vessel was defined as a dermatoscopically identified blood-filled vessel within the tumor “footprint”, with a diameter greater than the diameter of any visible vessels in the area, from the circumferential tumor margin out to a distance of 10mm. this assessment was qualitative, rather than done by actual physical measurement. thus, the method was chosen as it was rapid, easy to perform, reproducible, and may be relevant in practice. definition of central and peripheral tumor vessels: each tumor was divided into a central area (with a width of half the tumor diameter) and remaining peripheral area, adjusted for the tumor shape. the central and peripheral tumor areas were then divided into quadrants by horizontal and vertical axes. vessels were recorded as present in any quadrant when one or more vessels of any morphology were observed within that quadrant. definition of the proportion of pink in a tumor area: the presence of pink within a tumor was recorded as either: no pink within the tumor area, pink less than half the tumor area or pink equal to half or more of the tumor area. pink areas could be any shape or intensity within the tumor margin. collection of the dermatoscopy vascular data for each case was recorded direct from each patient, using a delta 20 heine dermatoscope, not photographs. to avoid compression on vessels, every case was examined with transparent ultrasound gel applied between the glass plate of the dermatoscope and the tumor. validation of the vascular features was assessed by comparing the recording of two observers (jp and ds). each observer was blinded to the other observer’s recording. concordance between the observers’ records was checked by calculating kappa values on 67 consecutive cases. histopathologic diagnosis of each case was performed by one of five pathologists, using routine hematoxylin and eosin staining. this study was approved by the ethics committee of the university of queensland. results: branching vessels were identified in 25.0% of ka (n=100), compared to 10.7% of scc (n=410), p < 0.01. figure 1 provides an example of branching large diameter vessels figure  1. ka: non-polarized dermatoscopy image taken with a dermfoto dermatoscope displaying large diameter branching vessels around a central keratin plug. [copyright: ©2014 pyne et al.] research | dermatol pract concept 2014;4(3):6 39 in a dermatoscopy image of a ka. large vessels occurred in 20.0% of ka, compared to 12.4% of scc (p= 0.05). figure 2 is a dermatoscopy image of an scc; branching and large diameter vessels are not seen. recorded vessel morphologies comparing scc with ka are set out in figure 3. see also figures 4 and 5. the inter observer kappa values for the vascular features are summarized in table 1. discussion data from this study found that only branching vessels were significantly different when comparing the two entities. this limited finding is consistent with the concept that vessels are not as useful as keratin features in the differential diagnosis process, supporting findings from earlier studies [9]. while branching vessels may be a feature of some ka, an increased incidence of branching vessels has also been reported as associated with well-differentiated scc of increasing tumor figure  2. scc: non-polarized dermatoscopy image taken with a dermfoto dermatoscope displaying peripheral hairpin or loop and dot vessels. vessels do not display large diameters or branching morphology. [copyright: ©2014 pyne et al.] figure 4. scc: distribution of vessels in the central and peripheral tumor areas compared with ka. no distinctive associations are seen. [copyright: ©2014 pyne et al.] figure 3. scc: vessel morphologies of scc compared with ka. [copyright: ©2014 pyne et al.] depth, and scc with a shift toward poor differentiation [15]. limitations of this study include the possibility of the confounding effect of including scc cases with increased tumor 40 research | dermatol pract concept 2014;4(3):6 scc. data from the central verses peripheral areas presence of vessels and the selected proportions of pink areas within the tumor did not show any highly significant differences between ka and scc. other vascular features such as vessel polymorphism, the spatial arrangement of vessels and vessel density (vessels per unit area) could be additional areas for future investigation. in practice, as well as keratin features, the symmetry and growth rate of a lesion may be other clues to resolving the differential diagnosis of ka versus scc. anecdotal observation by the authors during this study noted these large diameter vessels seemed more prevalent, with larger and thicker kas. future study may examine if there is a relationship between increasing tumor depth and variation in vascular features in ka. conclusion branching and large diameter vessels were found to have a higher incidence in ka, compared to invasive scc. in practice, facilitating this dermatoscopy differential diagnosis relies on additional clinical and dermatoscopic features, for example rapid growth and lesion circular symmetry favor ka. references 1. beham a, reqaure s, soyer hp, et al. keratoacanthoma: a clinically distinct variant of well differentiated squamous cell carcinoma. adv anat pathol. 1998;5(5):269–80. 2. weedon d, malo j, brooks d, et al. keratoacanthoma: is it really a variant of squamous cell carcinoma? anz j surg. 2010;80(3):129–30. 3. ko cj. keratoacanthoma: facts and controversies. clin dermatol. 2010;28(3):254–61. 4. misago n, inoue t, koba s, narisawa y. keratoacanthoma and other types of squamous cell carcinoma with crateriform depth, and or moderate, or poor differentiation. branching vessels were observed in 10.7% of the 410 scc cases in this study (well, moderate or poorly differentiated tumors combined), a subset of 294 consecutive cases were assessed for branching vessels in a separate study [15]. in this separate study [15] branching vessels were noted in 7.5% of welldifferentiated scc (n=255) and 28.2% of moderate or poorly differentiated scc (n=39). the significance of branching vessels in a radial pattern [9] combined with prominent keratin expression as clues to ka is worthy of more investigation. the irregular arrangement of branching vessels in poorly differentiated scc has yet to be quantified. although not highly statistically significant, vessels with large diameters were more frequent in ka, compared to figure 5. scc: proportions of pink area within the tumor compared with ka. pink areas were assessed using a pearson chi square test. no association was demonstrated, p > 0.1. [copyright: ©2014 pyne et al.] table 1. kappa values of the vascular features. agreement between two observers. [copyright: ©2014 pyne et al.] vessel feature kappa value confidence interval 95% linear 1.00 1.00 – 1.00 branching 0.87 0.81 – 0.94 serpentine 0.69 0.56 – 0.82 loop 0.71 0.61 – 0.81 coil 0.80 0.70 – 0.90 dot 0.60 0.47 – 0.74 large 0.94 0.87 – 1.00 central 0.95 0.90 – 1.00 peripheral 0.88 0.75 – 1.00 pink areas 0.83 0.71 – 0.95 research | dermatol pract concept 2014;4(3):6 41 architecture: classification and identification. j dermatol. 2013; 40(6):443-52. 5. piscioli f, boi s, zumiani g, et al. a gigantic metastasizing keratoacanthoma. am j dermatopathol. 1984;6:123–9. 6. petrie m, eliezri y, campanelli c. keratoacanthoma of the head and neck with perineural invasion: incidental finding or cause for concern? dermatol surg. 2010;36(7):1209–13. 7. godbolt am, sullivan jj, weedon d. keratoacanthoma with perineural invasion: a report of 40 cases. australas j dermatol. 2001;42(3):168–71. 8. tschandl p, rosendahl c, williamson r, weedon d. a keratoacanthoma with venous invasion. dermatol pract concept. 2012;2(4):3. http://dx.doi.org/10.5826/dpc.0204a03 9. rosendahl c, cameron a, argenziano g, et al. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. 2012;148(12):1386–92. 10. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2012;66(4):589–97. 11. rosendahl c, cameron a, bulinska a, et al. cutaneous pigmented invasive squamous cell carcinoma: a case report with dermatoscopy and histology. dermatol pract concept. 2011;1(1):14. http:// dx.doi.org/10.5826/dpc.0101a14 12. zalaudek i, giacomel j, leinweber b. squamous cell carcinoma including actinic keratosis, bowens disease, keratoacanthoma and its pigmented variants. in: soyer hp, argenziano g, hofmann wellenhof r, johr, rh (eds.). color atlas of melanocytic lesions of the skin. berlin: springer; 2007:295–302. 13. chartier m, rothe mj, grant-kels jm. keratoacanthoma. in: rigel d, friedman rj, dzubow lm, et al. (eds.). cancer of the skin. philadelphia: elsevier, 2005:395–409. 14. elston dm. malignant tumors of the epidermis. in: elston dm, ferringer t, ko cj, et al. (eds.). dermatopathology. 2nd ed. edinburgh: elsevier, 2014:56–70. 15. pyne jh, sapkota d, wong jc. squamous cell carcinoma: variation in dermatoscopic vascular features between well and nonwell differentiated tumors. dermatol pract concept. 2012;2(4):5. http://dx.doi.org/10.5826/dpc.0204a05 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2014;4(1):12 75 the patient a 56-year-old caucasian woman, with skin phototype iii, presented with an asymptomatic, slow-growing, gray-black plaque on her nose. the lesion had appeared almost 6 months prior, was 10 × 5 mm in size and presented with a paler, raised and scaly central area (figure 1). this area could be hardly differentiated from ulceration, however, that was excluded on histology. dermatoscopy with a non-contact polarizing dermatoscope revealed an unspecific pattern, structureless and asymmetric (figure 2), characterized by blue-gray radial lines, disposed centrifugally at the periphery of a structureless scaly center, with some blood spots. other dermatoscopic features were few peripheral ectatic linear vessels in the lower and less pigmented area, a few discrete blue-gray blotches and a pink-white halo around the lesion. no prior topical treatment was used before our consultation. the diagnoses proposed to the pathologist included basal cell carcinoma, adnexal tumor and melanoma, but the lesion was described as non-specific. surgical excision was performed with 2 mm margins. histopathologic examination revealed an aggregation of atypical epithelial cells in the dermis (figure 3), severe solar eosinophilic elastosis, squamous eddy, atypical and necrotic epithelial squamous cells and pigmented deposits of melanin (figure 4). an atypical pigmented lesion of the nose francesco savoia1, giuseppe gaddoni1, vincenzo albano1, vera tengattini2, lorenza ricci2, annalisa patrizi2, emilia crisanti3 1 unit of dermatology, ausl ravenna, italy 2 department of specialized, diagnostic and experimental medicine, division of dermatology, university of bologna, italy 3 unit of pathologic anatomy, ausl ravenna, italy keywords: pigmented squamous cell carcinoma, dermoscopy, pigmented lesion, melanoma, cutaneous carcinoma, dermatoscopy citation: savoia f, gaddoni g, albano v, tengattini v, ricci l, patrizi a, crisanti e. an atypical pigmented lesion on the nose. dermatol pract concept. 2014;4(1):12. http://dx.doi.org/10.5826/dpc.0401a12 received: august 20, 2013; accepted: november 1, 2013; published: january 31, 2014 copyright: ©2014 savoia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. vera tengattini, department of specialized, diagnostic and experimental medicine, division of dermatology, university of bologna, via massarenti, 1, 40138 bologna, italy. tel. +390516364198; fax. +390516363091. email: vera.tengattini@ hotmail.com figure 1. clinical picture: a gray-black plaque on the nose, with a paler, raised and scaly central area. [copyright: ©2014 savoia et al.] 76 quiz | dermatol pract concept 2014;4(1):12 what is your diagnosis? please send your answer to dpc@derm101.com. the first correct answer will receive a dl3n hand dermoscope [cordially sponsored by 3gen]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. october 2013 quiz answer the correct answer to the dermatoscopy quiz in the october 2013 issue is superficial basal cell carcinoma (http://dx.doi. org/10.5826/dpc.0304a10). congratulations to dr. john paoli, department of dermatology, sahlgrenska university hospital, gothenburg, sweden, who was the first to send us the correct answer! figure 3. aggregations of atypical epithelial cells in the dermis. (h&e 4x). [copyright: ©2014 savoia et al.] figure 4. histology: a closer view showing severe solar eosinophilic elastosis, squamous eddy, numerous atypical and necrotic epithelial squamous cells and pigmented deposits of melanin. (h&e 20x). [copyright: ©2014 savoia et al.] figure 2. non-contact polarized dermoscopy revealed an unspecific pattern, characterized by a rim of confluent blue-gray radial lines, with relatively ill-defined edges, ectasia of a few peripheral linear vessels, a few discrete blue-gray globules blotches (inferiorly), a central area with some whitish surface scale and blood spots, and a pink-white halo around the lesion. [copyright: ©2014 savoia et al.] http://dx.doi.org/10.5826/dpc.0304a10 http://dx.doi.org/10.5826/dpc.0304a10 dermatology: practical and conceptual observation | dermatol pract concept 2014;4(4):5 33 dermatology practical & conceptual www.derm101.com introduction gouty panniculitis is an unusual dermatologic manifestation of gout. the patient may present with subcutaneous nodules or indurated plaques, which may precede or appear subsequently to the joints involvement of chronic tophaceous gout. pathogenesis of gouty panniculitis is not fully understood but it has been postulated that overproduction and accumulation of uric acid are triggered by preexisting subcutaneous tissue damage with concomitant localized inflammation [1]. we report a case of gouty panniculitis presenting as extensive subcutaneous involvement with no significant history of gout. case report a 40-year-old man presented with a 2-year history of widespread nontender, firm, and white to yellow nodules and plaques over the trunk, arms, legs, and dorsum of both feet. the patient reported intermittent arthralgia and occasional swelling of both ankles over the past 4 years. the patient denied other concomitant medical conditions, including gouty arthritis or history of alcohol abuse. he reported a negative familial history of gout or renal diseases. physical examination revealed a body mass index (bmi) of 34 and blood pressure of 140/80 mmhg. other systemic evaluation was unremarkable except for the disseminated gouty panniculitis: an unusual presentation of extensive cutaneous tophi penvadee pattanaprichakul1, sumanas bunyaratavej1, philip m. mclain2, supenya varothai1 1 department of dermatology, faculty of medicine siriraj hospital, mahidol university, bangkok, thailand 2 university of texas health science center houston medical school, houston, texas, usa keywords: gouty panniculitis, disseminate, tophi citation: pattanaprichakul p, bunyaratavej s, mclain pm, vorothai s. disseminated gouty panniculitis: an unusual presentation of extensive cutaneous tophi. dermatol pract concept. 2014;4(4):5. http://dx.doi.org/10.5826/dpc.0404a05 received: august 15, 2014; accepted: september 19, 2014; published: october 31, 2014 copyright: ©2014 pattanaprichakul et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: penvadee pattanaprichakul, m.d., department of dermatology, faculty of medicine siriraj hospital, 2 prannok rd, siriraj, bangkoknoi, bangkok, thailand. tel. +662.419.7000, ext 4332-3; fax. +662.411.5031. email: penvadee.pat@mahidol.ac.th gouty panniculitis is a rare cutaneous illness characterized by the deposition of subcutaneous monosodium urate crystals with lobular panniculitis. only a small number of cases with gouty panniculitis have been reported in the literature with unclear pathogenesis. in this article, we present a case of disseminated gouty panniculitis in the patient who had never been diagnosed of gout but revealed significant hyperuricemia at the time of diagnosis. abstract 34 observation | dermatol pract concept 2014;4(4):5 presence of nodules and plaques with some ulceration covered with a chalk-like substance over all extremities, trunk, and dorsal feet (figure 1). clinical signs of arthritis and arthralgia were not appreciated at the time of examination. upon further investigation, the patient’s serum uric acid was elevated to 12.2 mg/dl (normal range 3.6-7.7 mg/dl). complete metabolic panel and complete blood cell count were within normal range except for the x-rays of the hands and feet which showed some osteophytes without significant bony destruction. a skin biopsy demonstrated basophilic, amorphous material surrounded by foreign body granulomas, located in the deep dermis and subcutaneous fat lobules with focal lymphohistiocytic infiltrate (figure 2a-d). these deposits were negatively birefringent under polarized microscopy. periodic acid-schiff (pas) and acid fast bacilli (afb) stain were negative for microorganisms. given the clinical and laboratory findings, the diagnosis of disseminated gouty panniculitis was made. discussion gouty panniculitis has been described as a rare cutaneous manifestation of gout characterized by the presence of monosodium urate crystal deposition in the subcutaneous tissue with predominantly lobular inflammation [1]. while an association with elevated serum uric acid levels is evident, our current knowledge of the pathogenesis is incomplete [1,2]. pre-existing tissue damage induced by venous stasis figure 1. extensive cutaneous nodules and plaques over trunk and extremities. (copyright: ©2014 pattanaprichakul et al.) and micro-trauma may play roles. literature review suggested that gouty panniculitis can occur before or after the development of classic tophaceous gout. gouty panniculitis clinically presents as indurated nodules or plaques with an irregular surface, found predominantly on the lower extremities with a tendency to ulcerate and drain a chalk-like substance [1,3-5]. unlike previous reports, our case demonstrated extensive skin lesions found not only on the lower extremities, but over the trunk and upper extremities. the condition has been reported to be related with the elevation of serum uric acid level in chronic tophaceous gout with a suboptimal treatment as a risk factor for the development and progression of gouty panniculitis [1]. in our case, the diagnosis of disseminated gouty panniculitis was made according to a combination of generalized cutaneous lesions and histopathological findings of deep dermal and subcutaneous deposits of amorphous material with needle-shaped spaces surrounded by granulomatous reaction with doubly refractile crystals and negative birefringence under polarized microscopy. however, in our case, we did not perform an alcohol-fixed skin biopsy to demonstrate the more prominent, brownish, negative-birefringent, needle-shaped crystals under polarization as another helpful diagnostic method to detect urate deposits. differential diagnosis of widespread gouty panniculitis includes other crystal deposition disease, such as pseudogout and oxalosis. for pseudogout, translucent, rhomboid and rod-shaped crystals with blunt ends showing positive birefringence under polarobservation | dermatol pract concept 2014;4(4):5 35 ization are characteristic findings [6]. cutaneous oxalosis demonstrates the yellow-brown crystals or blue birefringence under polarized light in the patients with chronic kidney disease with chronic dialysis and cutaneous involvement of oxalosis as the result of vascular complication such as livedo reticularis, acrocyanosis and peripheral gangrene in the setting of hyperoxaluria [7]. we believe the presentation of our patient, both clinical and histopathological, is similar to the previously proposed term “gout nodulosis” [8]. obesity, chronic venous insufficiency, long-term use of furosemide and glucocorticoids are considered to be the risk factors for cutaneous deposit of uric acid [4, 5]. therefore, obesity was considered to be the possible risk factor for the development of gouty panniculitis in our case. there is no specific therapy for gouty panniculitis. some reports noted improvement of skin lesions following systemic treatment for hyperuricemia. high-dose allopurinol 6001,200 mg/day and colchicine have been reported to improve the lesions of gouty panniculitis and prevent formation of new lesions [3]. our patient was treated with allopurinol 600 mg/day, which resulted in the gradual improvement of skin lesions over 3 months period. serum uric acid level decreased to 8.4 mg/dl over 6 months period and there were no episodes of arthritis or arthralgia at the latest follow-up visit. conclusion disseminated gouty panniculitis is an extremely unusual presentation of cutaneous tophi and may not be apparent to the physician in early stages of its development. clinical suspicion should be taken in patients with known history of gout or long-standing hyperuricemia with the onset of new cutaneous lesions as described. acknowledgment the authors would like to thank dr. punkae mahaisavariya for her valuable comments and suggestions upon the preparation of this case report. references 1. ochoa cd, valderrama v, mejia j, et al. panniculitis: another clinical expression of gout. rheumatol int. 2011; 31:831-5. 2. wernick r, winkler c, campbell s. tophi as the initial manifestation of gout. report of six cases and review of the literature. arch intern med. 1992; 152:873-6. 3. dahiya a, leach j, levy h. gouty panniculitis in a healthy male. j am acad dermatol. 2007; 57:s52-4. 4. leboit pe, schneider s. gout presenting as lobular panniculitis. am j dermatopathol. 1987; 9:334-8. 5. wang l, rose c, mellen p, branam g, picken mm. gouty panniculitis with ulcerations in a patient with multiple organ dysfunctions. case rep rheumatol. 2014; epub 2014 jun 15. 6. shidham v, chivukula m, basir z, shidham g. evaluation of crystals in formalin-fixed, paraffin-embedded tissue sections for the differential diagnosis of pseudogout, gout, and tumoral calcinosis. mod pathol. 2001; 14:806-10. 7. blackmon ja, jeffy bg, malone jc, knable jr al. oxalosis involving the skin: case report and literature review. arch dermatol. 2011; 11:1302-5. 8. iglesias a, londono jc, saaibi dl, pena m, lizarazo h, gonzalez eb. gout nodulosis: widespread subcutaneous deposits without gout. arthritis care res. 1996; 9:74-7. figure 2. (a) lobular panniculitis with amorphous material in deep dermis and subcutis (h&e, x40). (b-d) foreign-body granulomatous inflammation surrounding crystalline deposits [h&e; (b) x100, (c) x200, and (d) x400]. (copyright: ©2014 pattanaprichakul et al.) dermatology: practical and conceptual observation | dermatol pract concept 2016;6(1):6 19 dermatology practical & conceptual www.derm101.com introduction injections of botulinum toxin a (btx-a) targeting the facial muscles is widely used in the treatment of hyperdynamic facial lines, and it could be completely useful to correct the glabellar, forehead, temporal and crow’s feet lines [1]. as overall use of btx-a increases, it is not far from expectation to come across unusual complications of this product. a number of minor cutaneous complications might be observed after bta injection. local irritation and bruising at the site of injections are the most common side effects [2,3]. other rare adverse effects are necrotizing fasciitis and psoriasiform eruption [4,5]. unfortunately, the use of fake brands of btx-a has been reported mainly due to their lower cost. these unlicensed materials could probably cause more severe and bizarre side effects [6]. herein, we present a case of vasculitis with panniculitis after a patient underwent a cosmetic procedure that included injection of purported botulinum toxin a. case report a 45-year-old female presented to our dermatology clinic with the complaint of progressive periorbital edema and erythema since the night before. she could not open her eyes due to prominent edema. she mentioned btx-a injection for periorbital and glabellar rhytides for the first time in a private skin care office two weeks before that. she has been told to return after two weeks for further follow up and btx-a revasculitis with panniculitis following botulinum toxin a injection for cosmetic use nastaran namazi1, reza m. robati1, sahar dadkhahfar1, anoush shafiee1, farahnaz bidari-zerehpoush2 1 skin research center, shahid beheshti university of medical sciences, tehran, iran 2 department of pathology, loghman hakim hospital, shahid beheshti university of medical sciences, tehran, iran key words: botulinum, botulinum toxin a, vasculitis citation: namazi n, robati rm, dadkhahfar s, shafiee a, bidari-zerehpoush f. vasculitis with panniculitis following botulinum toxin a injection for cosmetic use. dermatol pract concept 2016;6(1):6. doi: 10.5826/dpc.0601a06 received: november 17, 2015; accepted: december 29, 20165; published: january 31, 2016 copyright: ©2016 namazi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: reza m. robati, md, skin research center, shahid beheshti university of medical sciences, shohada-e tajrish hospital, shahrdari st, 1989934148, tehran, iran. tel. +98-2122741507; fax; +98-21-22744393. email. rezarobati@sbmu.ac.ir botulinum toxin a injection is performed most frequently for facial rejuvenation all over the world. some bizarre and severe side effects have been reported after botulinum toxin a injection. herein, we present a case of vasculitis with panniculitis after a patient underwent a cosmetic procedure that included injection of purported botulinum toxin a. abstract 20 observation | dermatol pract concept 2016;6(1):6 discussion according to the previous reports, a variety of skin reactions, such as exanthematous reactions, edema, pruritus, alteration in skin color at the site of injection, psoriasiform eruption and anaphylactic reactions can occur after btx-a injection for both therapeutic and cosmetic purposes [5]. sarcoidal granuloma was also reported after btx-a injection [7]. sevinjection. two hours after the second injection, she noticed progressive swelling and redness in the injection sites as well as periorbital area. she neither suffered from any systemic disease or allergy to the specific drug or products. there are limited registered brands of btx-a in iran, including dysport (ipsen biopharmaceuticals ltd, uk) and neuronox (medytoxinc, south korea). the patient mentioned that the injected btx-a was not of these registered brands and that she had had this injection done at a very low cost. after calling the clinic where this procedure was performed, we found the injected product to be canitox, which is an unlicensed chinese brand of btx-a available in iran. on admission, her vital signs were stable. she did not have respiratory distress. the only abnormal finding in the physical examination was the prominent edema, purpuric papules and erythema in periorbital region and at the sites of btx-a injection in the forehead (figure 1). on the ophthalmological consult, her best corrected visual acuity, intraocular pressure and examination of anterior segment were normal. there were no signs of preseptal cellulitis. the routine laboratory findings were normal. the histopathological examination revealed transmural infiltration of neutrophils and eosinophils with endothelial swelling and fibriniod necrosis of the vessel walls. leukocytoklasia and extravasation of rbc were the other findings. moreover, there was infiltration of neutrophils and eosinophils in the subcutaneous fat. the infiltration consisted predominantly of neutrophils with scattered eosinophil aggregations. all these findings suggested the diagnosis of vasculitis with panniculitis (figure 2). treatment was initiated with oral prednisolone at the dose of 0.5 mg/kg and hydroxyzine 25 mg daily. the response to treatment was dramatic and she showed significant improvement within two days. the prednisolone was continued for three consecutive days and tapered over two weeks. the patient’s condition had not recurred at the two-month follow up. figure 1. prominent edema, purpuric papules and erythema in periorbital region and at the sites of btx-a injection in the forehead. [copyright: ©2016 namazi et al.] figure 2. (a and b). transmural infiltration of neutrophils and eosinophils with endothelial swelling and fibrinoid necrosis of the vessel walls and leukocytoclasia and extravasation of rbc. (c) infiltration of neutrophils and eosinophils in the subcutaneous fat [h&e (a)x10, (b)x40, (c)x40]. [copyright: ©2016 namazi et al.] observation | dermatol pract concept 2016;6(1):6 21 references 1. ghalamkarpour f, robati rm, aryanejad f, toossi p. supraciliary wrinkles and botulinum toxin a. clin exp dermatol. 2010;35:388-91. 2. ascher b, zakine b, kestemont p, et al. a multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of botulinum toxin a in the treatment of glabellar lines. j am acad dermatol. 2004;51:223-33. 3. fagien s, cox se, finn jc, et al. patient-reported outcomes with botulinum toxin type a treatment of glabellar rhytids: a doubleblind, randomized, placebo-controlled study. dermatol surg. 2007;33:s2-9. 4. latimer pr, hodgkins pr, vakalis an, et al. necrotising fasciitis as a complication of botulinum toxin injection. eye (lond). 1998;12:51-3. 9614517 5. bowden jb, rapini rp. psoriasiform eruption from intramuscular botulinum a toxin. cutis. 1992;50:415-6. 6. coleman k, zilinskas ra. fake botox, real threat. sci am. 2010; 302:84-9. 7. assmann t, krahl d, mang r. cutaneous sarcoidal granuloma after botulinum toxin type a injection. j am acad dermatol. 2013;69:e247-9. 8. pickett a, mewies m. serious issues relating to the clinical use of unlicensed botulinum toxin products. j am acad dermatol 2009;61:149-50. 9. careta mf, delgado l, patriota r. report of allergic reaction after application of botulinum toxin. aesthet surg j. 2015;35:np102-5. 10. schellekens h. factors influencing the immunogenicity of therapeutic proteins. nephrol dial transplant. 2005;20 suppl 6: vi3-9. eral brands of btx-a have been reported to cause bizarre reactions [6,8]. there is also a recent report of severe allergic reaction caused by chinese botulinum toxin a injection to treat facial wrinkles [9]. the mechanism by which btx-a induce the mentioned reaction is hardly understood. one explanation is the allergic potential of the toxin itself that may induce an immunologic reaction like any other protein. the other explanation is the effect of human serum albumin or gelatin added to the toxin in stimulating the immune reaction. the immune reactions toward biopharmaceutical products such as btx-a can be categorized in two main types: classical immune reactions to neo-antigens that mainly occur after injection of animal products and a breakdown of immune tolerance. several factors influence the immunogenic potential of btx-a including its biochemical structure (e.g., denaturation through oxidation), storage setting, impurities in the preparation, dose and frequency of injections, site of application, and genetic predisposition of patients themselves [10]. these mentioned mechanisms might also have taken part in the reaction in our patient. according to the injection of btx-a by a nonprofessional in this patient, the possibility of contamination or reactions to non-standard additive products, such as gelatin or sucrose, should also be considered [6,8]. in conclusion, it should be kept in mind that cosmetic procedures that involve injection of various agents may cause severe reactions, such as vasculitis that, although rare, are clinically significant to healthcare professionals. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020093 1 dermatology practical & conceptual case presentation a 57-year-old woman presented to consultation complaining of the progressive appearance of skin lesions predominantly distributed in the lower limbs. the spontaneous occurrence of lesions began during adolescence, with continuous appearance of new lesions to the present. the patient was otherwise healthy, and there was no previous history of trauma, autoimmune diseases, immunodeficiency or use of immunosuppressive drugs. cutaneous examination revealed firm brownish plaques and dome-shaped papules, ranging from 5 mm to 25 mm in diameter, with positive lateral dimple sign. the total number of lesions counted was greater than 180. dermoscopy was consistent with dermatofibroma in all lesions (figure 1). multiple dermatofibromas on the legs gabriel salerni1,2, carlos alonso2 1 dermatology department, hospital provincial del centenario de rosario, universidad nacional de rosario, argentina 2 diagnóstico médico oroño, rosario, argentina key words: dermatofibroma, fibrohistiocytoma, polarized light, imaging citation: salerni g, alonso g. multiple dermatofibromas on the legs. dermatol pract concept. 2020;10(4):e2020093. doi: https://doi. org/10.5826/dpc.1004a93 accepted: may 25, 2020; published: october 26, 2020 copyright: ©2020 salerni and alonso. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, bv. oroño 1441, cp 2000, rosario, argentina. email: gabrielsalerni@hotmail.com figure 1. dermoscopy was consistent with dermatofibroma in all lesions. 2 image letter | dermatol pract concept 2020;10(4):2020093 references 1. her y, hyeon ku s, ho kim k. a case of multiple eruptive dermatofibromas in a healthy adult. ann dermatol. 2014;26(4):539– 540. doi: 10.5021/ad.2014.26.4.539. pmid: 25143694. 2. an i, devran gevher o, esen m, ibiloğlu i, ecer n. multiple eruptive dermatofibromas in a patient with systemic lupus erythematosus treated with methylprednisolone. arch rheumatol. 2018;33(2):236–237. doi: 10.5606/archrheumatol.2018.6569. pmid: 30207570. teaching point while solitary dermatofibromas may be incidental findings, multiple dermatofibromas may be associated with systemic conditions, such as autoimmune diseases, cancer, chromosomal abnormalities, immunodeficiency, metabolic disorders; or previous therapies [1,2]. the presence of many dermatofibromas in a patient without relevant associations, as in this case, is an even less frequent situation. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2014;4(1):10 67 case report a 65-year-old man presented with an asymptomatic lesion on the left parietal scalp of 6 months’ duration. three years prior, a cylindroma on the same area was excised by a general surgeon. physical examination revealed a solitary 6 mm salmon-pink, firm, dome-shaped papule on the left parietal scalp (figure 1). dermatoscopic evaluation showed arborizing telangiectasia and several scattered white globules on a white to salmon pink background (figure 2). the lesion was excised for pathologic evaluation. histologic evaluation shows multiple irregular lobules in a jigsaw-mosaic pattern diagnostic of cylindroma (figures 3 and 4). discussion cylindromas are slowly growing benign adnexal tumors that occur most commonly on the head, neck, and scalp. they can occur as solitary or multiple tumors. while solitary cylindroma are sporadic and not inherited, multiple cylindromas occur in the autosomal dominant brook-spiegler syndrome (familial autosomal dominant cylindromatosis) [1,3]. there are currently only a few case reports of the dermatoscopic features of cylindroma in the medical literature. the reported patterns of cylindroma include arborizing vessels on a whitish-pinkish background, blue dots and globules, and ulceration [2,4,5]. our observations revealed arborizing telangiectasia and several scattered white globules on a white to salmon-pink background, which are similar to the previous reports. at this time, we are not certain if white globules dermatoscopic pattern of a cylindroma yoon k. cohen1, david j. elpern2 1 alta dermatology, mesa, arizona, usa 2 the skin clinic, williamstown, massachusetts, usa keywords: cylindroma, adnexal neoplasm, adnexal tumor, benign adnexal tumor, benign tumor, turban tumor, brooke-spiegler syndrome, dermatoscope, dermoscopy citation: cohen yk, elpern dj. dermatoscopic pattern of a cylindroma. dermatol pract concept. 2014;4(1):10. http://dx.doi.org/10.5826/ dpc.0401a10 received: july 8, 2013; accepted: september 23, 2013; published: january 31, 2014 copyright: ©2014 cohen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: yoon k. cohen, d.o., 12 meadow street, williamstown, ma 01267, usa. email: mail@yooncohen.com figure 1. clinical view of the cylindroma on the left parietal scalp. [copyright: ©2014 cohen et al.] the lesion. this feature may help differentiate cylindroma’s arborizing vessels from those of nodular basal cell carcinoma, which tend to be more pronounced at the center and do not have a particular pattern. more studies are essential to establish the definite dermatoscopic patterns of cylindroma. while most cylindromas are benign, there have been reports of solitary cylindromas undergoing malignant transformation, especially in tumors of the scalp present for long duration [3]. therefore, early diagnosis and management can offer patients the best possibility of cure. it is our hope that these observations may aid in the early diagnosis of cylindroma and help to differentiate them from malignant tumors. references 1. calonje e, brenn t, lazar a, et al. mckee’s pathology of the skin. 4th ed. new york: saunders, 2012. 2. lallas a, apalla z, tzellos t, lefaki i. dermoscopy of solitary cylindroma. eur j dermatol. 2011;21(4):645-6. 3. bansal c, batra m, lal n, srivastava an. cylindroma with malignant transformation. indian j dermatol. 2012;57(2):141-143. 4. cabo h, pedrini f, cohen sabban e. dermoscopy of cylindroma. dermatol res pract. 2010; 2010:285392. 5. jarrett r, walker l, bowling j. dermoscopy of brooke-spiegler syndrome. arch dermatol. 2009;145(7):854. 68 observation | dermatol pract concept 2014;4(1):10 are reproducible dermoscopic findings. further studies will be needed. however, an interesting observation of the vascular pattern of our patient’s cylindroma suggests that the vascular branches are more pronounced at the periphery [2] and that they extend from the periphery towards the center of figure 2. dermatoscopic view shows several scattered white globules and arborizing telangiectasia on a white to salmon pink background. the vascular branches are more pronounced at the periphery and they extend from the periphery towards the center of the lesion. [copyright: ©2014 cohen et al.] figure 3. well-circumscribed, non-encapsulated nodule in the dermis. there are multiple lobules arranged in a jigsaw-mosaic pattern. [copyright: ©2014 cohen et al.] figure 4. each lobule consists of two layers of cells; an outer layer of cells with small hyperchromatic nuclei and an inner section of cells with oval vesicular nuclei. each lobule is outlined by a dense pas-positive hyaline membrane. [copyright: ©2014 cohen et al.] dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual & educational notes | dermatol pract concept 2013;3(4):8 35 dermoscopy is helpful not only in the early differentiation of melanoma from nevus and other pigmented skin lesions, but also in the diagnosis of non-pigmented skin lesions. however, the dermoscopy device, or dermoscope (or dermatoscope), is usually viewed as either unnecessary or expensive by young dermatologists. in reality, there is no need to buy one to start learning/practicing dermoscopy because all the components of such device are already available in most dermatology clinics; all that is needed is the assembly of the different components to construct a dermoscope and use it to examine pigmented skin lesions. the assembly of a dermoscope requires four items: echo-gel, a glass slide, a penlight or electric torch, and an eyepiece lens of a microscope (or a 10-power magnifying lens). the assembly process is simple and includes placing an appropriate amount of echo-gel on the skin lesion, then mounting a glass slide, illumination of the lesion at an angle from above using a torch, and lastly, examination of the lesion using the eyepiece lens (figure  1). all dermatologists who do not have a commercial dermoscope are encouraged to try this and start dermoscopic examination in the outpatient clinic! self-assembly of a simple low-cost dermoscope for examination of skin lesions mizuki sawada1, masaru tanaka2 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of dermatology, tokyo women’s medical university, tokyo, japan citation: sawada m, tanaka m. self-assembly of a simple low-cost dermoscope for examination of skin lesions. dermatol pract conc. 2013;3(4):8. http://dx.doi.org/10.5826/dpc.0304a08 copyright: ©2013 sawada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: masaru tanaka, m.d., department of dermatology, tokyo women’s medical university medical center east, 2-110 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel: +81 3 3810 1111. fax: +81 3 3894 1441. e-mail: masarutanaka@1984.jukuin. keio.ac.jp figure 1. the assembly process includes placing echo-gel on the skin lesion, then mounting a glass slide, illumination of the lesion at an angle from above using a torch, and examination of the lesion using the eyepiece lens. [copyright: ©2013 sawada et al.] dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):17 313 dermatology practical & conceptual introduction papular epidermal nevus with “skyline” basal cell layer (pens) is an infrequent type of epidermal nevus, clinically characterized by hyperkeratotic papules or plaques. dermatological lesions have been described alone or associated with other symptoms as part of a syndrome. we describe a new case of this rare entity. case presentation a 5-year-old boy presented with multiple keratotic whitish plaques that were asymptomatic and randomly distributed on the buttocks, abdomen, and upper and lower limbs and had been increasing in number since birth (figure 1, a and b). dermoscopy of a lesion on the right leg revealed a homogeneous white pattern with well-defined borders. a lesion on the abdomen presented a homogeneous brown pigmentation, with hyperpigmented and well-defined borders, resembling leaf-like areas described in basal cell carcinoma (figure 1, c and d). the clinical differential diagnosis included mainly common keratinocytic nevi, viral warts, flat warts, and mosaicism of waxy keratosis of childhood, which differs clinically in shape, pattern of distribution, and number of lesions. biopsy taken from the lesion on the abdomen showed compact orthokeratotic hyperkeratosis, acanthosis with broad and rectangular rete ridges, and a basal cell layer with a striking palisaded arrangement of basal cell nuclei (figure 2). with these features, pens was diagnosed. neurological examination of the patient was normal, and the follow-up to date has not shown neurological disorders. there is no history of similar lesions in the patient’s family. discussion torrelo et al [1] first reported 5 cases with lesions clinically described as asymptomatic single or multiple keratotic papules or plaques with a rough, flat surface, whitish to brown color, and variable shape. none of the patients had a family history of similar lesions or other extracutaneous manifestations. histopathological features included compact orthokeratotic hyperkeratosis, acanthosis with broad and rectangular a pediatric case of papular epidermal nevus with “skyline” basal cell layer (pens) federico strambach1, vincenzo piccolo2, andrea ronchi3, teresa russo2, giuseppe argenziano2, elvira moscarella2 1 dermatology unit, hospital gral. de agudos carlos g. durand, buenos aires, argentina 2 dermatology unit, university of campania, luigi vanvitelli, naples, italy 3 pathology unit, university of campania, luigi vanvitelli, naples, italy key words: pens, dermoscopy, epidermal nevus, pediatric dermatology citation: strambach f, piccolo v, ronchi a, russo t, argenziano g, moscarella e. a pediatric case of papular epidermal nevus with “skyline” basal cell layer (pens). dermatol pract concept. 2019;9(4):313-314. doi: https://doi.org/10.5826/dpc.0904a17 accepted: may 14, 2019; published: october 31, 2019 copyright: ©2019 strambach et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, university of campania, luigi vanvitelli dermatology unit, via pansini 5, 80131 naples, italy. email: elvira.moscarella@gmail.com 314 letter | dermatol pract concept 2019;9(4):17 review of the literature. pediatr dermatol. 2016;33(3):296-300. 5. balestri r, rizzoli l, reach j, girardelli cr. dermoscopy of popular epidermal nevus with skyline basal cell layer. pediatr dermatol. 2017;34(2):e99-e101. 3. tadini g, restano l, happle r, itin p. pens syndrome: a new neurocutaneous phenotype. dermatology. 2012;224(1):24-30. 4. luna pc, pannizardi aa, martin ci, et al. papular epidermal nevus with skyline basal cell layer (pens): three new cases and rete ridges, and a basal cell layer with a striking palisaded arrangement of basal cell nuclei that resembled the “skyline” or “eyeliner” pattern described in bowen disease. although torrelo described randomly distributed lesions, a case of blaschkoid distribution has been reported [2]. tadini et al [3] reported neurological disorders in 5 of 6 patients described with pens, coining the term pens syndrome [3]. these neurological conditions can improve during childhood and adolescence. a positive relationship has been suggested between pens syndrome and the presence of more than 4 clinical lesions [4]. family cases have been reported. although different theories try to explain familial occurrence of pens, a paradominant inheritance seem to be the most likely inheritance pattern. regarding dermoscopy, 2 different patterns were present in our patient: a lesion with white homogeneous pattern and well-defined border, as already described by balestri et al [5], and a second one with hyperpigmented and well-defined borders, resembling leaflike areas as described in basal cell carcinoma. conclusions we describe a new case of pens showing 2 different dermoscopic patterns in the same patient. because reports of pens are scarce, we support the idea that more cases should be described in order to find a distinctive pattern of this keratinocytic nevus. references 1. torrelo a, colmenero i, kristal l, et al. papular epidermal nevus with ‘‘skyline’’ basal cell layer (pens). j am acad dermatol. 2011;64(5):888-892. 2. faure e, tadini g, brena m, cassulini lr. papular epidermal nevus with “skyline” basal cell layer (pens) following a blaschko linear pattern. pediatr dermatol. 2013;30(6):e270-e271. figure 2. histopathologically, (a) compact orthokeratotic hyperkeratosis, acanthosis with broad and rectangular rete ridges, and a basal cell layer with a striking palisaded arrangement of basal cell nuclei were seen. (b,c) higher magnification of palisade arrangement of the basal cell nuclei. [copyright: ©2019 strambach et al.] a cb figure 1. (a,b) multiple keratotic whitish plaques on the patient’s arms and abdomen, increasing in number since birth, asymptomatic. (c) dermoscopy of a lesion on the right leg revealed a homogeneous white pattern with well-defined borders. (d) one lesion on the abdomen presented a homogeneous brown pigmentation, with hyperpigmented and well-defined borders, resembling leaf-like areas described in basal cell carcinoma. [copyright: ©2019 strambach et al.] a c b d dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2021107 1 dermatology practical & conceptual clinicopathological and dermoscopic features in blashkoid angioma serpiginosum aditi dhanta1, gargi taneja1, neirita hazarika1, prashant joshi2 1 department of dermatology, all india institute of medical sciences, rishikesh, india 2 department of pathology, all india institute of medical sciences, rishikesh, india key words: punctate macules, angioma, lagoon, dermoscopy citation: dhanta a, taneja g, hazarika n, joshi p. clinicopathological and dermoscopic features in blashkoid angioma serpiginosum. dermatol pract concept. 2021;11(1):e2021107. doi: https://doi.org/10.5826/dpc.1101a107 accepted: june 20, 2020; published: january 29, 2021 copyright: ©2021 dhanta et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: aditi dhanta, md, department of dermatology, venereology and leprosy, all india institute of medical sciences, rishikesh, uttrakhand, india. email: draditidhanta@gmail.com introduction angioma serpiginosum (as) is an unusual vascular nevoid disorder that is more common in women. it begins in childhood and stabilizes in adulthood. dermoscopy of angioma serpiginosum reveals typical small, sharply demarcated, round-to-oval red lagoons, corresponding histopathologically to dilated, thin-walled capillaries found in the superficial dermis. clinical presentation a 29-year-old man presented with a 10-year history of asymptomatic red lesions over the left side of abdomen. there was no associated history of itching or trauma. general and systemic examination was normal. cutaneous examination revealed multiple minute, pinpoint, grouped, bright red, nonblanchable macules and irregular patches distributed in a patchy blaschkoid pattern over the left side of abdomen (figure 1). aq1 dermoscopy of the erythematous lesions using a 3gen dermlite ii hybrid m dermatoscope, polarized mode, ×10 magnification, revealed multiple oval-to-round, well-demarcated, red-colored lagoons on a slightly erythematous background (figure 2). lesions were nonblanchable on diascopy. a punch biopsy of 4 mm taken from erythematous lesions revealed the presence of mild hyalinization and increased proliferating small capillaries with a normal endothelial lining in the papillary and superficial reticular dermis (figure 3). there were neither epidermal changes nor extravasation of red blood cells. conclusions as is an uncommon benign, vascular nevoid disorder first described by hutchinson in 1889 [1]. the exact etiopathogenesis is unknown; however, a hyperestrogenic state is considered to play role in pathogenesis owing to its proliferative effects on vascular endothelial cells. a recently proposed etiology is an abnormal vascular response to cold that manifests aq2 2 letter | dermatol pract concept 2021;11(1):e2021107 figure 1. multiple pinpoint, grouped, bright red, nonblanchable macules and irregular patches distributed in a patchy blaschkoid pattern over the left side of abdomen. figure 2. dermoscopy of the erythematous lesions using a dermlite ii hybrid m dermatoscope, polarized mode, ×10 magnification, revealed multiple oval-to-round, well-demarcated, red-colored lagoons present on a slightly erythematous background. aq3 figure 3. (a) photomicrograph showing multiple dilated vessels present in a clover-leaf pattern in the upper dermis (h&e, ×10). (b) photomicrograph showing cluster of dilated thick-walled capillaries (due to deposition of pas-positive material) with flattened endothelial cells and red blood cells present in the center of the vessels (h&e, ×40). as formation and aggregation of newly formed capillaries that leads to large ecstatic vessels in the papillary dermis [2]. as typically begins in childhood and has preponderance in women. it is characterized by multiple small, asymptomatic, nonpalpable, deep red punctate macules organized in serpiginous and gyrate patterns. the lesions are predominantly distributed on the lower extremities and buttocks and usually appear unilateral, but bilateral asymmetric involvement or linear morphology has been reported, though rarely. segmental patterns of lesions, as seen in our case, may reflect cutaneous mosaicism. differential diagnosis includes pigmented purpuric dermatosis, unilateral nevoid telangiectasia, port-wine stain, and angiokeratoma corporis diffusum. apart from the clinical presentation, confirmation of diagnosis is made by histopathology. a characteristic histopathological feature of as is the vascular proliferation located at the papillary dermis, which is composed of dilated capillaries [2]. the lack of epidermal changes and extravasation of red blood cells distinguish as from angiokeratoma and pigmented purpuric dermatosis. clinical findings alone or a noncontributory biopsy report can be misleading, so dermoscopic features help to distinguish as from other vascular-related diseases. the letter | dermatol pract concept 2021;11(1):e2021107 3 characteristic dermoscopic findings reported in the literature include erythematous, well-demarcated, round-to-oval dots and lagoons [1,2]. the red lagoons represent dilated vascular spaces within the papillary or superficial reticular dermis. table 1 lists common differentials of as and their dermoscopic features. as is a benign disease and commonly asymptomatic requiring no treatment, although it raises cosmetic issues. there are several reports describing intense pulsed light or pulsed dye laser as treatment, with a clearance rate ranging from 25% to 75% [2]. references 1. sinha p, singh py, sood a, bharadwaj r. blaschkoid angioma serpiginosum: a dermoscopic diagnosis. indian dermatol online j. 2018;9:127-129. doi: 10.4103/idoj.idoj_122_17. pmid:29644203. 2. bhushan p, thatte ss, singh a. angioma serpiginosum: a case series of 4 patients. indian j dermatol venereol leprol. 2016;82(5):588. doi: 10.4103/0378-6323.182972. pmid:27241499. 3. piccolo v, russo t, moscarella e, brancaccio g, alfano r, argenziano g. dermatoscopy of vascular lesions. dermatol clin. 2018;36(4):389-395. doi: 10.1016/j.det.2018.05.006. pmid:30201148. table 1. dermoscopic findings of differential diagnosis of angioma serpiginosum differential diagnosis dermoscopic features angiokeratoma corporis diffusum • dark lacunae • blue-whitish veil • ulceration • rainbow pattern [3] pigmented purpuric dermatosis • coppery-red background • round-to-oval dots • gray dots • network [3] port-wine stain • deep form—red linear vessels and represent horizontally oriented capillaries • superficial form—red, rounded, globular vessels [3] unilateral nevoid telangiectasia • dense network of linear, tortuous. and branching telangiectasia [1] observation | dermatol pract concept 2011;1(1):5 19 an unclear, chronic nasal ulcer carolina talhari, m.d.1, josé antônio pedro mendes schettini, m.d.2, alexandra maria giovanna brunasso, m.d. 3,4 ,sinesio talhari, m.d.1, cesare massone, m.d.5 1department of dermatology, institute of tropical medicine, manaus, brazil 2foundation alfredo of matta, manaus, brazil 3division of environmental dermatology and venereology, medical university of graz, graz, austria 4department of dermatology, galliera hospital, genoa, italy 5division of general dermatology, medical university of graz, graz, austria key words: mucocutaneous leishmaniasis, nasal ulcer, gingival hyperplasia citation: talhari c, schettini ja, brunasso am, talhari s, massone c. an unclear, chronic ulcer. dermatol pract concept 2011;1(1):5. http://dx.doi.org/10.5826/dpc.0101a05. editor: harald kittler, m.d. received: june 5, 2011; accepted: july 1, 2011; published: october 31, 2011 copyright: ©2011 talhari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cesare massone, md, department of dermatology, medical university of graz, auenbruggerplatz 8, a-8036 graz, austria. tel. +43.316.385.3235, fax: +43.316.385.4957. email: cesare.massone@klinikum-graz.at. case report a 44-year-old brazilian man presented with an eight-month history of runny nose, hoarseness and progressive gingival swelling, which interfered greatly with nourishment and oral hygiene. the nasal lesion had appeared three years previous to his visit, while the gingival lesions had been present for a few months. the patient had been already seen by general practitioners and dentists and had received nonspecific therapy. he was not taking any drugs. physical examination showed a painless ulceration on the right nasal fossa (figure 1) and hyperplastic erythematous lesions on the upper gingival mucosa (figure 2). he had no fever and there was no lymphadenopathy nor hepatosplenomegaly. full blood count, liver and kidney function tests were within the normal range. hiv-serology was negative. cultures for bacteria, fungus and mycobacteria were negative. histological examination of a gingival lesion revealed a granulomatous inflammation without necrosis. fite, grocott methanamine silver and periodic acid schiff stains were negative. what is your diagnosis? figure 1. painless ulceration on the right nasal fossa. figure 2. hyperplastic erythematous lesions on the upper gingival mucosa. dermatology practical & conceptual www.derm101.com 20 observation | dermatol pract concept 2011;1(1):5 feature is a naso-oropharyngeal ulcer, which, if untreated for an extended period of time, can lead to perforation of the septum and even affecting the nose, palate and lips, causing palatal dysfunction, dysphagia, dysphonia, aspiration and severe disfigurement [3]. the differential diagnosis includes mainly deep mycotic infection, rhinoscleroma, wegener granulomatosis and extranodal nk-t cell lymphoma. pentavalent antimonials represent the first therapeutic choice; amphotericin b, pentamidine and miltefosine are the main alternatives [2, 3, 6]. while diagnosis of localized acl is easy (ulcerated lesions at the site of the bite), mcl may represent a diagnostic pitfall. delay in the diagnosis may lead to irreversible sequelae. it has recently been shown that the increase in travel to tropical countries has resulted in more cases of imported tropical infections [5]. the incidence of leishmaniasis among travelers returning from endemic areas is 38 per 1,000 patients with cutaneous disorders. this number increases to 143 per 1,000 travelers returning from south america with cutaneous disorders [5]. in the differential diagnosis of nasal ulcers in patients coming from endemic countries, mcl has to be ruled out. references 1. amato vs, tuon ff, bacha ha, neto va, nicodemo ac. mucosal leishmaniasis. current scenario and prospects for treatment. acta trop 2008;105(1):1-9. 2. schwartz e, hatz c, blum j. new world cutaneous leishmaniasis in travellers. lancet infect dis 2006;6(6):342-9. 3. silveira ft, lainson r, corbett ce. clinical and immunopathological spectrum of american cutaneous leishmaniasis with special reference to the disease in amazonian brazil: a review. mem inst oswaldo cruz 2004;99(3):239-51. 4. fischer m, gomespaes m, reinel d, talhari s. [diffuse infiltration of the external ear in a 59-year-old brazilian patient. “new world” cutaneous leishmaniasis (leishmaniasis tegumentar americana)]. hautarzt 2002;53(5):342-6. 5. freedman do, weld lh, kozarsky pe, et al. spectrum of disease and relation to place of exposure among ill returned travelers. n engl j med 2006;354(2):119–30. 6. chrusciak-talhari a, dietze r, chrusciak talhari c, et al. randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis caused by leishmania (viannia) guyanensis in manaus, brazil. am j trop med hyg 2011;84(2):255-60. answer mucocutaneous leishmaniasis discussion polymerase chain reaction disclosed leishmania spp. the diagnosis of mucocutaneous leishmaniasis (mcl) was made. intravenous glucantime (20 mg/kg/day) for 30 days and pentoxifyline 400 mg three times daily brought to the restitutio ad integrum. according to the world health organization, leishmaniasis is a parasitic protozoal disease transmitted to mammals by phlebotomine sand flies and remains a severe public health problem with 1.5 million new cases a year and a prevalence of 12 million cases worldwide [1-4]. even though it has long been endemic in developing countries, the economic globalization and the increased volume of international travel have extended its prevalence in developed countries [5]. the leishmania species are categorized into two groups: old world (southern europe, the middle east, africa and asia) and new world leishmaniasis (latin america; also called american cutaneous leishmaniasis). old world leishmaniasis is contracted in dry, desert-like climates, while new world leishmaniasis is contracted in jungles, forests, or rural areas. phlebotomine sand flies transmit the old world leishmaniasis, while lutzomyia transmits the new world leishmaniasis [2]. american cutaneous leishmaniasis (acl) is a zoonotic infection endemic to latin america. the causative agents include leishmania (l) (viannia) (v) braziliensis, l. mexicana, l. (v.) panamensis, and related species. the main reservoirs for l. (v.) braziliensis and other leishmania (vianna) spp. are small forest rodents [1-4]. the spectrum of acl includes single, localized, cutaneous ulcers, diffuse cutaneous leishmaniasis, and mucosal disease (mcl). acl is most common in persons working at the edge of the forest and among rural settlers. in brazil, the most frequent etiologic agent of mcl is l. braziliensis, and approximately half of the brazilian cases are diagnosed in the northern region of the country, including the brazilian amazon basin, a region visited by an increasing number of tourists [1-4]. infections by l. brasiliensis (but also other species) can “metastasize” to the mucous membranes in about 5% of the patients suffering from the cutaneous form of acl. mcl represents the hematogenous or lymphatic dissemination of parasites from the skin to the naso-oropharyngeal mucosa [1-4]. it may develop for months to years after the resolution of the original cutaneous lesion and may well worry tourists who travel to endemic areas [3]. the main clinical quiz | dermatol pract concept 2011;1(1):8 29 from the dermatologikum hamburg: quiz almut böer-auer, m.d.1, alexandra gust, m.d.1 1dermatologikum hamburg citation: böer-auer a, gust a. from the dermatologikum hamburg: quiz. dermatol pract concept 2001;1(1):8. http://dx.doi. org/10.5826/dpc.0101a08. copyright: ©2011 böer-auer et al. this is an an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: almut böer-auer, m.d., dermatologikum hamburg, drehbahn 1-3, 20354 hamburg, germany. email: boer@dermatologikum.de. the patient a 61-year-old woman presented herself with a chronic and widespread eruption of erythematous papules, pustules, ulcers, and hyperpigmented scars (figures 1a–e). she had a history of rheumatoid arthritis. a biopsy specimen was taken from a plaque on the leg (figures 2a–p). what is your diagnosis? answer and explanation rheumatoid neutrophilic dermatitis the section pictured in figures 2a–p shows irregular epidermal and infundibular acanthosis and dilation of infundibula filled with neutrophils. diffuse infiltrates are present in the dermis and are dominated by far by neutrophils. some nuclear dust of neutrophils is present but there is no deposition of fibrin in the vessel walls. fibrosis is seen in the deeper dermis. in the absence of clinical information, the best interpretation of the changes in this section is pyoderma gangrenosum. the clinical pictures (figures 1a–e), however, illustrate an extensive eruption that consists of erythematous papules, pustules, ulcers, and hyperpigmented scars. the clinical appearance taken together with the history of severe rheumatoid arthritis enables a diagnosis of rheumatoid neutrophilic dermatitis to be made based on clinicopathological correlation. rheumatoid neutrophilic dermatitis (rnd) was first described by ackerman in 1978 [1]. it appears in adults of both sexes with severe rheumatoid arthritis. lesions are typically distributed symmetrically over joints of the elbows and knees. individual lesions are papules, plaques and nodules, pustules, ulcerations, and scars. urticarial lesions also have been observed in some patients [1–3]. lesions come and go slowly over months or years [1]. rnd is associated invariably with severe rheumatoid arthritis. even though first described only in patients with high titers of rheumatoid factor, it was then shown to appear also in patients who are negative for a circulating rheumatoid factor [4]. histopathologic changes have been described as a heavy dermal infiltrate of neutrophils with variable degrees of leukocytoclasis but no vasculitis [1, 4]. fibrinoid degeneration of collagen, resembling the collagen changes present in rheumatoid nodules in a miniaturized form also has been reported [5]. the pattern of rheumatoid neutrophilic dermatitis bears many attributes in common with sweet’s syndrome, on one hand, and pyoderma gangrenosum, on the other. ackerman suggested that rheumatoid neutrophilic dermatitis could be a synonym for sweet’s syndrome in a patient with severe rheumatoid arthritis because one of the conditions known to be responsible for sweet’s syndrome is rheumatoid arthritis [6]. in contrast, association of rheumatoid neutrophilic dermatitis with pyoderma gangrenosum has been described [7]. in the patient presented here, some lesions were indistinguishable clinically from pyoderma gangrenosum, while typical lesions of sweet syndrome were lacking. in clinicopathologidermatology practical & conceptual www.derm101.com 30 quiz | dermatol pract concept 2011;1(1):8 figures 1a–e. clinical appearance of the widespread eruption of erythematous papules, pustules, ulcers, and hyperpigmented scars. a c d e b cal correlation, rnd seems to be distinct and different from both sweet’s syndrome and pyoderma gangrenosum. rheumatoid arthritis is a chronic inflammatory arthritis that relatively commonly shows extra-articular manifestations, especially in the skin. rheumatoid nodules, rheumatoid vasculitis, pyoderma gangrenosum, interstitial granulomatous dermatitis with arthritis, palisaded neutrophilic and granulomatous dermatitis, and rheumatoid neutrophilic dermatitis have been reported to be associated with the condition [8]. in comparison with other cutaneous manifestations of the disease, however, rheumatoid neutrophilic dermatitis is a very rare skin manifestation in patients with rheumatoid arthritis. in a relatively recent study of 215 patients with rheumatoid arthritis, only two were diagnosed with rheumatoid neutrophilic dermatitis [9]. treatment of rheumatoid neutrophilic dermatitis is often difficult. skin lesions do not respond necessarily to systemic treatment of the arthritis. usually, dramatic response to systemic corticosteroids is seen. however, lesions quickly reappear on withdrawal of that medication. references 1. ackerman ab. histologic diagnosis of inflammatory skin diseases. a method by pattern analysis. philadelphia: lea & febiger, 1978:437. 2. brown ts, fearneyhough pk, burruss jb, et al. rheumatoid neutrophilic dermatitis in a woman with seronegative rheumatoid arthritis. j am acad dermatol 2001;45(4):596–600. 3. ichikawa mm, murata y, higaki y, et al. rheumatoid neutrophilic dermatitis. eur j dermatol 1998;8(5):347–9. 4. bevin aa, steger j, mannino s. rheumatoid neutrophilic dermatitis. cutis 2006;78(2):133–6. 5. lazarov a, mor a, cordoba m, et al. rheumatoid neutrophilic dermatitis: an initial dermatological manifestation of seronegative rheumatoid arthritis. j eur acad dermatol venereol 2002;16(1):74–6. 6. ackerman ab, böer a, benin b, et al. histologic diagnosis of inflammatory skin diseases. an algorithmic method based on pattern analysis, 3rd edition. new york city: ardor scribendi, ltd., 2005. 7. macaya a, servitje o, jucglà a, et al. rheumatoid neutrophilic dermatitis associated with pyoderma gangrenosum. br j dermatol 2000;142(6):1246–8. 8. sayah a, english jc 3rd. rheumatoid arthritis: a review of the cutaneous manifestations. j am acad dermatol 2005;53(2):191– 209. 9. ergun t, inanc n, tuney d, et al. skin manifestations of rheumatoid arthritis: a study of 215 turkish patients. int j dermatol 2008;47(9):894–902. quiz | dermatol pract concept 2011;1(1):8 31 figures 2a–p. histopathology. a b e h j n m c f i k o d g l p dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020087 1 dermatology practical & conceptual introduction circumscribed acral hypokeratosis (cah) was recently described as a rare benign condition affecting the palms and soles of middle-aged patients that represents a possible localized abnormal keratinization [1]. case presentation a 68-year-old woman presented with an asymptomatic plantar lesion that had evolved over 10 years. on physical examination, a 1.5-cm erythematous patch on the plantar medial arch was seen with evident irregular and scaling edges (figure 1a). dermoscopy showed a stair-step desquamation at the periphery of the lesion and dotted vessels with a diffuse erythematous background scattered with white dots in linear arrangement on the ridges. in addition, several rosettes were observed on the ridges (figure 1b). histopathology showed stairlike thinning of the horny layer towards the center, protrusion of acrosyringeal corneocytes, and hypogranulosis under the hypokeratotic area. furthermore, dilated congestive capillaries were present in the papillary and reticular dermis (figure 1c). this lesion was successfully treated with surgical excision. the second patient, a man in his 70s, presented with a 15-year history of an asymptomatic erythematous, scaly, well-demarcated plaque on the plantar medial arch (figure 2a). dermoscopy showed a stair-step configuration of the border, a parallel white crista dotted pattern with some rosettes, and a homogeneous erythematous area with dotted vessels (figure 2b). histopathologic examination showed similar features as in the case above, and the patient received the same treatment. dermoscopic findings in our 2 cases are similar to those of topin et al [1]. we noted that the stair-step dermoscopic configuration at the periphery of the lesion correlates to stepped thinning of the stratum corneum towards the center. moreover, white dots correspond to acrosyringia that were accentuated as a result of the reduction in the horny layer. we used the term “parallel white crista dotted pattern” to describe the linear disposition of these structures on the ridges. this configuration is explained by the eccrine duct anatomy, which opens to the skin’s surface through the crista superficialis. dermoscopy of circumscribed acral hypokeratosis john j. dávila-rodríguez1, liliana garcía2, diana posso3, giuseppe argenziano4 1 department of dermatologic surgery, dermatologic institute of jalisco dr. josé barba rubio, guadalajara, mexico 2 department of dermatology, carlos andrade marín hospital, quito, ecuador 3 department of pathology, carlos andrade marín hospital, quito, ecuador 4 dermatology unit, university of campania, luigi vanvitelli, naples, italy key words: dermoscopy, circumscribed acral hypokeratosis, soles citation: dávila-rodríguez jj, garcía l, posso d, argenziano g. dermoscopy of circumscribed acral hypokeratosis. dermatol pract concept. 2021;11(1):e2020087. doi: https://doi.org/10.5826/dpc.1101a87 accepted: may 9, 2020; published: december 7, 2020 copyright: ©2020 dávila-rodríguez et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: john j. dávila rodríguez, md, department of dermatologic surgery, dermatologic institute of jalisco dr. josé barba rubio, gabriela mistral street, guadalajara, 44270, mexico. email: dr.davila.dermato@gmail.com 2 letter | dermatol pract concept 2021;11(1):e2020087 dermoscopy that is probably attributable to an optical effect. these structures are not specific and can be observed in a range of conditions from tumoral to inflammatory skin lesions. in table 1 the main dermoscopic differential diagnoses of cah are listed. conclusions dermoscopy can be useful in the diagnosis of cah and can help in differentiating this disease from other dermatoses affecting the palmoplantar areas. rosettes can be present and may correlate with a marked protrusion of acrosyrinwe suggest that the diffuse erythema may be the result of vessels becoming visible through the transparent and thin stratum corneum but also to the presence of dilated vessels at the papillary and upper reticular dermis. the congestive vessels correspond to dotted vessel pattern dermoscopically. we observed that this pattern tended to follow a linear configuration mainly on the furrows but occasionally on the ridges, too. the presence of rosettes in cah may be caused by the presence of concentric horny material in the acrosyringium. it could be that rosettes are more common in areas with marked protrusion of acrosyringeal corneocytes. it is currently known that rosettes are seen exclusively with polarized figure 1. (a) clinical presentation of circumscribed acral hypokeratosis. (b) dermoscopic description: stair-step desquamation at the periphery (star), dotted vessels (arrowhead), white dots (arrow) and rosettes (circles) in a linear distribution along the ridges. (c) stair-like thinning of the horny layer toward the center (arrow), protrusion of acrosyringeal corneocytes (stars) (h&e, × 10). the inset shows hypogranulosis under the hypokeratotic area and dilated congestive capillaries in the papillary and reticular dermis (h&e, × 40). a b c figure 2. (a) clinical and (b) dermoscopic description: stair-step desquamation (star), dotted vessels (arrowhead), white dots (arrow), and rosettes (circles). a b letter | dermatol pract concept 2021;11(1):e2020087 3 copy. ann dermatol venereol. 2017;144(3):197-202. doi: 10.1016/j.annder.2016.09.034. pmid: 27771123. 2. yang y, lin j, fang s, han s, song z. what’s new in dermoscopy of bowen’s disease: two new dermoscopic signs and its differential diagnosis. int j dermatol. 2017;56(10):1022-1025. doi: 10.1016/10.1111/ijd.13734. pmid: 28832993. geal corneocytes. we propose the term “parallel white crista dotted pattern” in order to describe the linear arrangement of white dots and rosettes on the ridges. references 1. topin-ruiz s, debarre jm, blanchard e, et al. circumscribed palmar hypokeratosis (cpm): the diagnostic value of dermostable 1. differential diagnoses of cah [1,2]. feature cah bowen disease mibelli porokeratosis scale peripheral stair-step scaly surface peripheral double rim central part erythematous and homogeneous erythematous with yellow crusts, focal hemorrhage, focal/multifocal hypopigmentation hypopigmented vessel pattern dotted in linear arrangement mainly on the furrows glomerular, arranged in clusters, linear, irregular or dotted dotted dots white in linear arrangement on the ridges gray, brown in patchy or linear arrangement red-brown rosettes yes yes no cah = circumscribed acral hypokeratosis dermatology: practical and conceptual review | dermatol pract concept 2020;10(1):e2020004 1 dermatology practical & conceptual introduction patients with chronic urticaria (cu) often consider diet modification and discuss potential trigger foods. in this review, we evaluate the evidence behind potential dietary triggers for cu including immunological triggers (eg, galactose-α-1,3-galactose [α-gal] in meat and anisakis simplex in uncooked fish) and nonimmunological triggers. nonimmunological triggers include compounds in tomatoes, food additives, herbs, wine, and other foods, as well as histamine in foods. the evidence diet and chronic urticaria: dietary modification as a treatment strategy joanna jaros,1 vivian y. shi,2 rajani katta3 1 university of illinois college of medicine, chicago, il, usa 2 department of medicine, dermatology division, university of arizona at tucson, az, usa 3 dermatology, mcgovern medical school at ut health, bellaire, tx, usa key words: chronic urticaria, diet, pseudoallergens, food additives, histamine citation: jaros j, shi vy, katta r. diet and chronic urticaria: dietary modification as a treatment strategy. dermatol pract concept. 2020;10(1):e2020004. doi: https://doi.org/10.5826/dpc.1001a04 accepted: september 25, 2019; published: december 31, 2019 copyright: ©2019 jaros et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta, md, mcgovern medical school at ut health, 6800 west loop south, ste 180, bellaire, tx 77401. email: info@kattamd.com patients with chronic urticaria (cu) often ask about dietary modification. research has indicated that specific dietary changes may be helpful in a subset of patients. immunological food reactions are rare, but potential triggers of cu include those seen in certain settings, as in patients with a history of tick bites, a history of raw or marinated fish ingestion, or those with celiac disease. nonimmunological food intolerances may also contribute, although mechanism of action is not well understood. trials of pseudoallergen-free diets and low-histamine diets have resulted in partial remission in a subset of patients, while oral provocation testing has confirmed that some patients experience worsening of symptoms after ingestion of food additives, tomatoes, herbs, seafood, alcohol, and other foods. an increased prevalence of vitamin d deficiency has also been noted in patients with cu compared with healthy controls. while oral antihistamines remain the mainstay of therapy in cu, education on potential dietary factors may be offered to a selection of the group of patients. for those at risk or reporting symptoms suggestive of celiac disease, vitamin d deficiency, delayed reactions to mammalian meat, or exposure to raw fish, further workup is recommended. while education on dietary modification may be offered to other patients, this approach may benefit only a subset, and no test is available to identify these patients. a minimum of 3 weeks may be needed to determine response, and only specific diets that have been systematically studied should be considered. any elimination diet should be used with caution because of the potential for nutritional deficiencies. abstract mailto:info@kattamd.com 2 review | dermatol pract concept 2020;10(1):e2020004 that are objectively reproducible but that do not involve an immunological mechanism. a n u m b e r o f f o o d s h a v e b e e n reported to worsen cu symptoms. these “trigger” foods include alcohol, food additives, seafood, certain vegetables and fruits, fermented foods, and others [6]. diagnostic and therapeutic strategies include food diaries, opt, or elimination diets. a review of 20 studies examined a total of 1,668 patients with cu who followed a systematic elimination diet approach. these consisted of pseudoallergen-free (paf) diet, low-histamine (lh) diet, or fish avoidance diet used in conjunction with their antihistamine therapy [9]. overall, these led to a combined complete remission in 4.9% and partial remission in 37.5% of subjects, with the highest rates reported for paf and lh diets followed for a median duration of 3 weeks [9]. partial remission rates in more than one-third of subjects are clearly worth further study, given the safety and low cost of these short-term dietary modifications. however, any study of cu must consider the significant spontaneous remission rate. antia et al summarized the research on the natural history of cu [3] and noted variability, with one study reporting 32% of patients symptom-free after 3 years [10] and other studies reporting about half of patients experiencing remission after 1 year [11,12]. lower remission rates are seen with more severe disease, while higher rates are seen with antihistamine treatment. it is noteworthy that no control group was used in any of the aforementioned dietary studies, and many patients were allowed to use antihistamines. therefore, it is difficult to compare these improvements with that expected via spontaneous remission. despite these caveats, results were promising. the median duration of dietary change was only 3 weeks, and approximately onethird of patients reported improvement. furthermore, several studies have doccells [7]. this results in vasodilation, sensory nerve activation, and plasma extravasation, ultimately resulting in dermal edema and wheals [2]. treatment with antihistamines significantly reduces these clinical findings [5]. a number of factors can cause mast cell activation, both immunological and nonimmunological. immunoglobulin e (ige)-mediated reactions are the primary immunological trigger [6]. nonimmunological mechanisms are less well understood, but include medications, infections, food, and alcohol, among others [2]. food allergies, which are due to defined immunological mechanisms, have been shown to be rare causes of cu. sánchez et al administered food challenge tests (utilizing 410 common foods) to 164 patients with cu and 38 controls. positive challenge tests occurred in only 1.2% of cu and 0.7% of control subjects [8]. food ige sensitization was similar in both groups (17.5% vs 16.5%, respectively) [8]. therefore, despite the high frequency of self-reported food sensitivities, single foods are unlikely cu triggers. however, a number of other studies have presented intriguing results demonstrating that groups of foods may worsen cu. specifically, elimination diets have improved symptoms in a subset of patients with cu, while oral provocation testing (opt) has resulted in flares. chronic urticaria and diet research has demonstrated that food allergies are extremely rare causes of cu. food allergies that may result in symptoms of cu include α-gal allergy (meat) and a simplex allergy (fish nematode). immunological reactions may occur due to gluten ingestion in celiac disease. f o o d i n t o l e r a n c e s i n c u a r e described more often than food allergies and are distinct from allergy [2]. these are defined as food-related symptoms and potential mechanisms behind these trigger foods is presented. finally, we explore the increased prevalence of vitamin d deficiency in cu. background urticaria is a relapsing-remitting condition with significant impact on quality of life (qol). clinically, half of patients present with only cutaneous wheals, 10% with angioedema, and 40% with both [1] and individual lesions classically last ≤24 hours. current guidelines classify urticaria as acute vs chronic, based on duration less than or greater than 6 weeks. cu is further subclassified as spontaneous (no specific eliciting factor involved) vs inducible [2]. the lifetime prevalence in the general population is estimated at 9% and has significant impact on patients’ qol [3]. cu is particularly challenging for patients, as it is frequently treatment-resistant, long-standing, and idiopathic. this review focuses on dietary modifications for cu, with an emphasis on chronic spontaneous urticaria. pathogenesis the etiology of cu is not well understood, and the majority of cases are considered idiopathic or due to autoreactivity [4]. at this time, neither european nor us guidelines recommend extensive laboratory testing or skin biopsy [2]. therapy is focused on symptom management, with h1 antihistamines as the mainstay [5]. on a cellular level, the primary inflammatory cells are mast cells and basophils [3]. activation of mast cells results in degranulation and release of preformed mediators, including vasoactive substances such as histamine and proinflammatory mediators such as tumor necrosis factor. mast cells also release newly synthesized leukotrienes, prostaglandins, cytokines, and platelet activating factor [6]. these mediators in turn activate and recruit other immune https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/urticaria https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/angioedema https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/laboratory-testing review | dermatol pract concept 2020;10(1):e2020004 3 well understood, as they do not act via ige and are negative on skin testing. a wide number of compounds and foods may act as pseudoallergens [2]. these include natural compounds (including certain fruits, spices, vegetables), artificial additives (dyes, preservatives, flavorings), and vasoactive compounds (acetyl salicylic acid, histamine, and nitric oxide) [10]. testing is typically with trial of elimination diet (ie, excluding compounds and foods reported as pseudoallergens) followed by opt [31]. despite the inherent difficulty, pseudoallergens have been studied in numerous trials. a systematic review summarized multiple paf diet trials, encompassing 1,555 patients [9]. overall, nearly 5% of patients showed complete remission, while 37% showed partial remission after median duration of 3 weeks. although none had a control group, several trials reported opt. overall, observational studies of paf diets have reported substantial reduction in medication usage [32], improved qol scores [32], and significant decrease in leukotriene e4 levels [33]. certain foods have been shown to trigger urticaria in diet-responsive patients during opt, including tomatoes, food additives, wine, and herbs. in one study, 73% of patients reported improvement after only 3 weeks of paf diet [34]. all responders later experienced symptoms after consuming a challenge meal rich in pseudoallergens [34]. opt with distillation extract from whole tomatoes resulted in positive urticarial reactions in more than 50% [34]. the culprit component remains unknown, as reactions were also common (32%) in those given a tomato fraction lacking salicylic acid or p-hydroxybenzoate [34]. of note, 46% of patients continuing dietary modification had full remission at 6 months [34]. in a similar study, 202 patients with cu underwent the same dietary modification for 3 months. among 62% of patients (126/202) who improved and later underwent opt with placebo controls, 37% reacted to food additives [35]. published reports from spain and italy. the antigen may be present in raw, marinated, or smoked fish [19], and larvae may be implicated [20]. a randomized controlled trial of 213 italian subjects with cu found that nearly 50% were sensitized to a simplex on skin prick testing [21]. a 6-month diet excluding marinated and raw fish led to resolution of cu in 77%, compared with 2% in controls [22]. other studies have not been as promising. a smaller trial found no improvement in either sensitized or nonsensitized patients after 3 months of avoidance [22,23]. additional studies have reported no change with fish-free diets, despite association between cu and a simplex positivity on skin prick testing [24]. it is theorized that mast cell activation in patients with cu and parasitic infections, such as a simplex, may involve the action of specific ige, th2 cytokine skewing, eosinophil recruitment to skin, and activation of the coagulation and complement systems [25]. with additional studies reporting benefit from fishfree diets [26], it is reasonable to either test at-risk patients or recommend trial avoidance. research has also demonstrated that those allergic to a simplex can consume frozen fish (−20°c for 48 hours) without risk of severe reaction [27]. smoked fish is not recommended owing to potential reactivity to heat-stable a simplex antigens [19]. gluten autoimmune diseases, including celiac disease, have been linked to cu [28]. case reports describe patients with celiac disease who develop cu following gluten ingestion [29,30]. therefore, for patients reporting symptoms suggestive of celiac disease, further workup is recommended. pseudoallergens pseudoallergic reactions are not considered true allergy. rather, they are a type of nonallergic hypersensitivity reaction. the mechanism of action is not umented positive blinded opt in a significant percentage of diet-responsive patients. therefore, despite the lack of controlled trials, it appears that some patients have dietary triggers that may be contributing to cu. galactose-α-1,3-galactose allergy galactose-α-1,3-galactose (α-gal) is an oligosaccharide expressed on glycoproteins and glycolipids of nonprimate mammals [13,14]. it can be transmitted to humans by ticks, including the lone star tick amblyomma americanum in the united states and other tick species in europe and australia [15]. injection of α-gal during a tick bite results in development of ige-mediated allergy to the α-gal antigen [16]. this antigen is then encountered when consuming mammalian meat (eg, beef, pork), as well as during infusions of the monoclonal antibody cetuximab [16]. in a study of 245 patients, symptoms included urticaria (93%), gastrointestinal distress (64%), and anaphylaxis (60%) [17]. symptom onset associated with α-gal hypersensitivity is typically delayed, occurring 2-6 hours after meat consumption [17]. given the atypical timing, patients are frequently misdiagnosed with idiopathic cu [14]. in one study, 20 of 29 patients with a diagnosis of cu had detectable serum α-gal antibodies, and of these, 95% reported tick bites [18]. avoidance of mammalian meat led to full remission in 9, and partial remission in 5 patients [18]. at this time, it is not known whether hypersensitivity will eventually improve. in summary, a food diary may identify delayed responses to meat, with confirmation via blood test for α-gal ige antibodies. in those with antibodies, recommended treatment is allergen avoidance. anisakis simplex hypersensitivity to a simplex, a sea fish nematode, may result in cu in coastal regions where uncooked fish is frequently consumed, with many of the 4 review | dermatol pract concept 2020;10(1):e2020004 lowing ingestion of foods containing lesser levels of histamine. this is thought to arise from a mismatch between accumulated histamine (from single foods and combinations of foods) and an individual’s capacity for histamine metabolism and clearance [42]. some individuals may be more susceptible to ingested histamine, such as those with impaired diamine oxidase activity [43]. intestinal diamine oxidase prevents dietary histamine uptake into the blood, and genetic factors, medical conditions, and alcohol may all reduce enzyme activity [44]. certain foods contain higher levels of histamine, especially those with higher microbial activity or deterioration [44]. seafood may contain higher levels depending on storage conditions and microbial exposure, as microbes convert amino acids such as histidine to biogenic amines [45]. fermented foods are therefore also likely to have higher levels, including aged cheeses, dry sausage, and fermented soy [46]. some plant foods have demonstrated higher levels as well, including tomatoes, eggplant, spinach, and avocado, although plant foods have demonstrated great variability in content [47]. some cu patients report improvement on lh diets. in one study of 56 patients with both cu and gastrointestinal symptoms, 61% noted improvement after 3 weeks, with the greatest reduction in the strongly affected subgroup [48]. another study also reported positive results, but indicated that response was unlikely due to decreased histamine ingestion [42]. in this study, 157 patients consumed a histamine-free, low pseudoallergen diet, with 46% reporting reduced cu activity [42]. all patients were then tested with oral histamine in a double-blind, placebo-controlled trial. while 17% reacted, no relationship was seen between response to diet and response to histamine. the researchers concluded that diets low in pseudoallergens may improve symptoms, but this response is not likely due to dietary hiscially to identify potential responders and elucidate mechanism of action, it may be offered as adjunct therapy. patients should be counseled that multiple foods should be excluded for up to 3 weeks before response may be seen. for responders, staged reintroduction of foods should then resume. food additives food additives, including dyes, preservatives, and artificial sweeteners [38], have been studied as components of paf diets, as well as independently. in one double-blind, placebo-controlled study of 838 patients, 31% experienced symptom improvement on a diet free of food additives [39]. one confounding factor is that such a diet may also be low in other pseudoallergens. food additives seem unlikely to be isolated triggers, given results of a challenge trial. in this study, 100 patients with cu were challenged with 11 food additives, including dyes, preservatives, and artificial sweeteners [40]. only 2 patients had an urticarial reaction on initial single-blind challenge, and neither reacted on second challenge. in conclusion, food additives alone do not appear to be a cu trigger, but a diet free of food additives (and presumably free of other potential triggers) may be helpful in a subset of patients. histamine the vasoactive amine histamine is released from mast cells and is an important cu mediator, and antihistamines are considered as mainstay therapy [3]. thus, researchers have evaluated lh diets as adjunct therapy for cu. ingestion of excess histamine may result in significant cutaneous as well as systemic symptoms, as in cases of histamine “poisoning” following ingestion of foods (such as certain fish) containing high levels of histamine. affected individuals have experienced pruritus, angioedema, wheals, and systemic symptoms [41]. histamine intolerance may occur as well, with symptoms folin another study evaluating 33 cu patients with known history of pseudoallergic reactions, 76% reacted to whole tomatoes, 50% to a panel of common food additives, 47% to herbal extracts in oil, and 44% to white wine [31]. researchers then tested steam distillates and residues of these foods. overall, patients reacted more strongly to tomato steam distillates (45%) than residue (15%) [31]. the tested residue was rich in histamine, salicylates, and proteins, and as only 15% of patients reacted to this residue, these are considered less likely triggers. when the tomato distillate was further analyzed by mass spectrometry, major ingredients included aldehydes, ketones, and alcohol, making these good targets for further study [31]. the exact mechanism of pseudoallergen activity is unknown, but one hypothesis centers on non-ige dependent histamine release from mast cells. in vitro analysis of skin biopsy specimens found that tomato extract enhances histamine release from mast cells through co-stimulation of substance p or c5a, but not ige [31]. food components may also act via mast cell-independent effects. for example, it has been proposed that foods rich in cinnamaldehyde (eg, tomatoes and spices such as cinnamon and cloves) may worsen rosacea by activating transient receptor potential channels to promote neurogenic vasodilation [36,37]. overall, paf diets have improved symptoms in a subset of patients. however, efficacy across studies has been highly variable and no trial has been placebo-controlled. regardless, many responders have demonstrated positive opt. in addition, zuberbier et al emphasize that pseudoallergic reactions are “known to be dose-dependent and frequently not restricted to just one agent” [31]. therefore, single food challenge tests may not be as useful as elimination of multiple potential trigger foods. in summary, while the value of paf diet requires further investigation, espereview | dermatol pract concept 2020;10(1):e2020004 5 tion on potential dietary factors may be offered to a selected group of patients. a food diary is recommended, and those with suspected delayed meat or a simplex allergy should be offered testing. in those at risk or reporting symptoms suggestive of celiac disease or vitamin d deficiency, further workup is recommended (table 1). for other patients, a 3-week elimination diet trial may be considered, excluding foods known to be pseudoallergens or those high in histamine (table 2). ingestion. nonimmunological reactions to foods are reported more frequently. trials of specific elimination diets have reported high rates of response after an average duration of only 3 weeks. in addition, opt has confirmed that some patients experience worsening of symptoms after ingestion of foods including food additives as well as natural foods such as tomatoes, herbs, seafood, alcohol, and others. the specific mechanism of action is not known. in conclusion, while oral antihistamines are first-line therapy, educatamine [42]. further clouding the issue is that oral histamine challenge tests may provoke responses even in those with no history of food intolerance; in one study, close to 50% of volunteers reacted [49]. in conclusion, lh diets may be helpful in a subset of patients with cu, but the reason remains unclear. lh diets tend to be low in pseudoallergens [48], which is one possible explanation [42]. at this time, no accurate testing is available to determine potential responders. the role of vitamin d the potential immunomodulatory role of vitamin d in urticaria has received increasing attention [50]. a recent meta-analysis of 14 studies and 1,655 patients found that prevalence of vitamin d deficiency is significantly higher in patients with cu than in healthy controls [51]. another meta-analysis confirmed these findings and proposed that cu is associated specifically with vitamin d deficiency, not insufficiency [52]. vitamin d deficiency is defined by serum 25-hydroxyvitamin d <20 ng/dl and insufficiency between 20 and 29 ng/dl [53]. early interventional studies reported t h a t v i t a m i n d s u p p l e m e n t a t i o n improved cu symptom severity, particularly in treatment-resistant patients with low baseline levels [54]. a later systematic review reported results of 7 studies describing cu improvement after highdose vitamin d supplementation, but doses and duration of use varied widely, indicating need for further study [55]. in summary, testing for vitamin d deficiency in those at risk, along with supplementation as appropriate, may be useful adjunctive therapy for patients with cu. conclusions i m m u n o l o g i c a l f o o d a l l e r g i e s are extremely rare but might be potential causes of cu in certain settings, as in patients with a history of tick bites or a history of raw, marinated, or smoked fish table 1. selected tests for suspected dietary factors in chronic urticaria patients reporting flares 2-6 hours following ingestion of lamb, pork, or beef, especially in those with history of tick bites i g e s e r u m a n t i b o d y t e s t for α-gal history of raw, marinated, or smoked fish ingestion, particularly in coastal european regions ige serum antibody test for anisakis simplex symptoms suggestive of celiac disease serum antibody testing for celiac disease and referral to gastroenterologist risk factors for vitamin d deficiency serum vitamin d levels α-gal = galactose-α-1,3-galactose; ige = immunoglobulin e. table 2. foods reported as nonimmunological chronic urticaria triggers food group reported triggers (suggest avoidance) seafood • avoid all except freshly caught and frozen fish, which is then cooked meat • aged sausages/smoked meats/processed meats dairy • fermented dairy (aged cheeses, yogurt, sour cream) vegetables • tomatoes • spinach, eggplant, avocado • fermented vegetables such as sauerkraut and kimchi • overripe vegetables fruits • all fruits • all fruit juices beverages • alcohol • herbal tea other • any fermented foods • food additives (dyes, preservatives, artificial sweeteners) • spices and herbs • chocolate • chewing gum/candy *consider trial of 3-week avoidance as adjunct to antihistamine therapy in treatment-resistant patients. *includes foods listed on the pseudoallergen-free diet and the low-histamine diet. 6 review | dermatol pract concept 2020;10(1):e2020004 16. qian j, liu t, yang l, daus a, crowley r, zhou q. structural characterization of n-linked oligosaccharides on monoclonal antibody cetuximab by the combination 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ventura mt, napolitano s, menga r, cecere r, asero r. anisakis simplex hypersensitivity is associated with chronic urticaria in endemic areas. int arch allergy immunol. 2013;160(3):297-300. 22. daschner a, de frutos c, valls a, et al. preliminary data of the effect of a temporary diet without fish in a randomised clinical trial of anisakis simplex sensitisation-associated chronic urticaria. allergy. 2011;66:33. 23. lópez-sáez mp, zubeldia jm, caloto m, et al. is anisakis simplex responsible for chronic urticaria? allergy asthma proc. 2003;24(5):339-345. 24. medina fernández a, barasona villarejo m, verdu benhamu m, moreno aguilar c, guerra pasadas f. anisakis allergy: clinical patterns and effectiveness of avoidance diet. allergy. 2010;65:407. 25. kolkhir p, balakirski g, merk hf, olisova o, maurer m. chronic spontaneous urticaria and internal parasites—a systematic review. allergy. 2016;71(3):308-322. 26. gracia-bara mt, matheu v, zubeldia jm, et al. anisakis simplex-sensitized patients: should fish be excluded from their diet? ann allergy asthma immunol. 2001;86(6):679-685. 27. trujillo mj, rodriguez a, gracia bara mt, et al. dietary recommendations for patients allergic to anisakis simplex. allergol immunopathol (madr). 2002;30(6):311-314. 28. kolkhir p, borzova e, grattan c, asero r, pogorelov d, maurer m. autoimmune comorbidity in chronic spontaneous urticaria: a systematic review. autoimmun rev. 2017;16(12):1196-1208. 29. haussmann j, sekar a. chronic urticaria: a cutaneous manifestation of celiac disease. can j gastroenterol. 2006;20(4):291-293. 30. peroni dg, paiola g, tenero l, et al. chronic urticaria and celiac disease: a case report. pediatr dermatol. 2010;27(1):108-109. 31. zuberbier t, pfrommer c, specht k, et al. aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria. j allergy clin immunol. 2002;109(2):343-348. 32. magerl m, pisarevskaja d, scheufele r, zuberbier t, maurer m. effects of a pseudoallergen-free diet on chronic spontaneous urticaria: a prospective trial. allergy. 2010;65(1):78-83. 33. akoglu g, atakan n, cakir b, kalayci o, hayran m. effects of low pseudoallergen diet on urticarial activity and leukotriene levels in chronic urticaria. arch dermatol res. 2012;304(4):257262. however, patients should be educated regarding several important caveats. this approach may benefit only a subset of patients, and at this time no test is commercially available to identify these patients. only specific diets that have been systematically studied should be considered, and a minimum of 3 weeks is needed to determine response. finally, any elimination diet has the potential to lead to nutritional deficiencies and should either be used only for short periods of time or with the aid of a nutritionist [2]. references 1. powell rj, leech sc, till s, huber paj, nasser sm, clark at. bsaci guideline for the management of chronic urticaria and angioedema. clin exp allergy. 2015;45(3):547-565. 2. zuberbier t, aberer w, asero r, et al. the eaaci/ga(2)len/ edf/wao guideline for the definition, classification, diagnosis and management of urticaria. allergy. 2018;73(7):1393-1414. 3. antia c, baquerizo k, korman a, alikhan a, bernstein ja. urticaria: a comprehensive review: treatment of chronic urticaria, special populations, and disease outcomes. j am acad dermatol. 2018;79(4):617-633. 4. sheikhi a, azarbeig m, karimi h. autohemotherapy in chronic urticaria: what could be the autoreactive factors and curative mechanisms? ann dermatol. 2014;26(4):526-527. 5. sharma m, bennett c, carter b, cohen sn. h1-antihistamines for chronic spontaneous urticaria: an abridged cochrane systematic review. j am acad dermatol. 2015;73(4):710-716.e4. 6. theoharides tc, valent p, akin c. mast cells, mastocytosis, and related disorders. n engl j med. 2015;373(2):163-172. 7. gonzalez-de-olano d, alvarez-twose i. mast cells as key players in allergy and inflammation. j investig allergol clin immunol. 2018;28(6):365-378. 8. sánchez j, sánchez a, cardona r. dietary habits in patients with chronic spontaneous urticaria: evaluation of food as trigger of symptoms exacerbation. dermatol res pract. 2018;2018:6703052. 9. cornillier h, giraudeau b, samimi m, et al. effect of diet in chronic spontaneous urticaria: a systematic review. acta derm venereol. 2019;99(2):127-132. 10. quaranta jh, rohr as, rachelefsky gs, et al. the natural history and response to therapy of chronic urticaria and angioedema. ann allergy. 1989;62(5):421-424. 11. kozel mm, mekkes jr, bossuyt pm, bos jd. natural course of physical and chronic urticaria and angioedema in 220 patients. j am acad dermatol. 2001;45(3):387-391. 12. champion rh, roberts so, carpenter rg, roger jh. urticaria and angio-oedema: a review of 554 patients. br j dermatol. 1969;81(8):588-597. 13. commins sp, click b, james h, borish l, platts-mills ta. delayed food allergy and anaphylaxis in patients with ige to alpha-gal: a carbohydrate antigen that produces ‘slowed’ mast cell histamine release. ann allergy asthma immunol. 2009;103(5):a3. 14. kennedy jl, stallings ap, platts-mills ta, et al. galactose-alpha-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. pediatrics. 2013;131(5):e1545-e1552. 15. steinke jw, platts-mills ta, commins sp. the alpha-gal story: lessons learned from connecting the dots. j allergy clin immunol. 2015;135(3):589-596; quiz 597. review | dermatol pract concept 2020;10(1):e2020004 7 46. stratton je, hutkins rw, taylor sl. biogenic amines in cheese and other fermented foods: a review. j food prot. 1991;54(6):460470. 47. sanchez-perez s, comas-baste o, rabell-gonzalez j, veciana-nogues mt, latorre-moratalla ml, vidal-carou mc. biogenic amines in plant-origin foods: are they frequently underestimated in low-histamine diets? foods. 2018;7(12). 48. wagner n, dirk d, peveling-oberhag a, et al. a popular myth— low-histamine diet improves chronic spontaneous urticaria—fact or fiction? j eur acad dermatol venereol. 2017;31(4):650-655. 49. wohrl s, hemmer w, focke m, rappersberger k, jarisch r. histamine intolerance-like symptoms in healthy volunteers after oral provocation with liquid histamine. allergy asthma proc. 2004;25(5):305-311. 50. straesser m, palacios t, kyin t, borish l, lawrence m. p55 seasonal correlations in chronic urticaria and allergic rhinitis. ann allergy asthma immunol. 2017;119(5):s39. 51. tsai ty, huang yc. vitamin d deficiency in patients with chronic and acute urticaria: a systematic review and meta-analysis. j am acad dermatol. 2018;79(3):573-575. 52. wang x, li x, shen y, wang x. the association between serum vitamin d levels and urticaria: a meta-analysis of observational studies. g ital dermatol venereol. 2018;153(3):389-395. 53. holick mf. the vitamin d deficiency pandemic: approaches for diagnosis, treatment and prevention. rev endocr metab disord. 2017;18(2):153-165. 54. boonpiyathad t, pradubpongsa p, sangasapaviriya a. vitamin d supplements improve urticaria symptoms and quality of life in chronic spontaneous urticaria patients: a prospective case-control study. dermatoendocrinol. 2014;6:e29727. 55. tuchinda p, kulthanan k, chularojanamontri l, arunkajohnsak s, sriussadaporn s. relationship between vitamin d and chronic spontaneous urticaria: a systematic review. clin transl allergy. 2018;8:51. 34. zuberbier t, chantraine-hess s, hartmann k, czarnetzki bm. pseudoallergen-free diet in the treatment of chronic urticaria: a prospective study. acta derm venereol. 1995;75(6):484-487. 35. pigatto pd, valsecchi rh. chronic urticaria: a mystery. allergy. 2000;55(3):306-308. 36. weiss e, katta r. diet and rosacea: the role of dietary change in the management of rosacea. dermatol pract concept. 2017;7(4):31-37. 37. pozsgai g, bodkin jv, graepel r, bevan s, andersson da, brain sd. evidence for the pathophysiological relevance of trpa1 receptors in the cardiovascular system in vivo. cardiovasc res. 2010;87(4):760-768. 38. sahu sc. food additives: a special issue of the journal food and chemical toxicology. food chem toxicol. 2017;107(pt b):529. 39. di lorenzo g, pacor ml, mansueto p, et al. food-additive-induced urticaria: a survey of 838 patients with recurrent chronic idiopathic urticaria. int arch allergy immunol. 2005;138(3):235-242. 40. rajan jp, simon ra, bosso jv. prevalence of sensitivity to food and drug additives in patients with chronic idiopathic urticaria. j allergy clin immunol pract. 2014;2(2):168-171. 41. colombo fm, cattaneo p, confalonieri e, bernardi c. histamine food poisonings: a systematic review and meta-analysis. crit rev food sci nutr. 2018;58(7):1131-1151. 42. siebenhaar f, melde a, magerl m, zuberbier t, church mk, maurer m. histamine intolerance in patients with chronic spontaneous urticaria. j eur acad dermatol venereol. 2016;30(10):1774-1777. 43. reese i, zuberbier t, bunselmeyer b, et al. diagnostic approach for suspected pseudoallergic reaction to food ingredients. j dtsch dermatol ges. 2009;7(1):70-77. 44. briguglio m, dell’osso b, panzica g, et al. dietary neurotransmitters: a narrative review on current knowledge. nutrients. 2018;10(5). pii: e591. 45. biji kb, ravishankar cn, venkateswarlu r, mohan co, gopal tk. biogenic amines in seafood: a review. j food sci technol. 2016;53(5):2210-2218. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020044 1 dermatology practical & conceptual introduction granulomatous slack skin (gss) is a very rare subtype of mycosis fungoides (mf), with fewer than 50 cases already reported. it is 1 of the 3 variants of mf, along with folliculotropic mf and pagetoid reticulosis (world health organization-european organization for research and treatment of cancer, 2018). there is a male predominance and an onset usually during adulthood. case presentation a 74-year-old man presented with a 4-year history of a lesion on his right axilla. during these years the patient had received various diagnoses, including intertrigo, dermatitis, and inverse psoriasis. based on his experience, minimal remission was observed only with the use of a medium-potency topical steroid, but the lesion relapsed after treatment discontinuation. clinical examination revealed a well-circumscribed erythematous plaque, consisting of pendulous, wrinkled, lax skin, unilaterally affecting the axillary fold (figure 1). dermoscopy showed pale orange areas on an erythematous background and fine linear vessels (figure 2a), which were suggestive of a granulomatous dermatosis. gss was our preferred diagnosis, owing to the striking clinical picture and the dermoscopic findings. histological examination following a biopsy revealed a dense granulomatous infiltrate in the dermis, composed of atypical lymphocytes, macrophages, and giant cells (figure 2b), along with a loss of elastic tissue. the epidermis was infiltrated by small, atypical lymphocytes with cerebriform nuclei. the atypical t cells had a cd3+, cd4+, cd7−, cd8− phenotype. the latter findings, as well as the monoclonal rearrangement of the t cell receptor genes, led to the diagnosis of gss. atypical lymphocytes were not present in the peripheral blood smear. full-body ct scan and the rest of the laboratory investigation results were unremarkable. the patient partially responded to re-puva treatment and then he was referred for radiotherapy. conclusions gss is clinically characterized by slow, progressive development of large areas of asymptomatic, pendulous, lax skin in the major skin folds, with a predilection for axillae and groins. clinically, differential diagnosis includes acquired cutis laxa, anetoderma, as well as other dermatoses involving granulomatous slack skin: a case report george balais,1 aimilios lallas,1 elizabeth lazaridou,2 linda kanatli,3 zoe apalla4 1 first dermatology department, aristotle university of thessaloniki, greece 2 second dermatology department, aristotle university of thessaloniki, greece 3 dermatology department, bozova national hospital, bozova sanliurfa, turkey 4 state dermatology department, hippokratio general hospital, thessaloniki, greece key words: granulomatous slack skin, mycosis fungoides, t cell, lymphoma, lymphocytes citation: balais g, lallas a, lazaridou e, kanatli l, apalla z. granulomatous slack skin: a case report. dermatol pract concept. 2020;10(2):e2020044. doi: https://doi.org/10.5826/dpc.1002a44 accepted: january 30, 2020; published: april 3, 2020 copyright: ©2020 balais et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: george balais, md, 83, kykladon str., 13231, petroupolis, athens, greece. e-mail: yorgosdmp95@gmail.com https://doi.org/10.5826/dpc.1002a44 mailto:yorgosdmp95@gmail.com 2 letter | dermatol pract concept 2020;10(2):e2020044 the skin folds [1]. to our knowledge, dermoscopic features of gss have never been described in the literature. as expected for a granulomatous process, the dermoscopic clues included orange areas and fine linear vessels. the latter pattern is not diagnostic, but it is suggestive of histological presence of granulomas in the dermis. the histological analysis reveals a dense, diffuse dermal infiltrate of atypical, irregular, convoluted lymphocytes (with a cd3+, cd4+, and cd8− phenotype) that may extend to the subcutaneous tissue, together with diffuse, multinucleated giant cells and histiocytes that display prominent elastophagocytosis and lymphophagocytosis. the granulomatous infiltrate is correlated with simultaneous loss of elastic fibers. molecular analysis reveals a monoclonal rearrangement of the t cell receptor genes. the diagnosis of gss, as in our case, is based on the typical clinical and histological features [2]. the disease follows an indolent course, with an excellent prognosis. the reported 5-year survival rate is almost 100%. however, since there is an association with other lymphoid neoplasias (mainly with hodgkin lymphoma), lifelong monitoring is recommended [2]. there is no standard of care for gss. common therapeutic strategies are puva, local or total skin electron beam radiotherapy, nitrogen mustard, interferons, corticosteroids, retinoids, azathioprine, methotrexate, or chemoimmunotherapy [2]. surgical excision can be considered, but it is only palliative, and recurrences usually occur [1]. references 1. cerroni l. granulomatous slack skin. june 2009. available at: https://www.orpha.net/consor/cgi-bin/oc_exp.php?lng=en& expert=33111. accessed january 10, 2020. 2. shah a, safaya a. granulomatous slack skin disease: a review, in comparison with mycosis fungoides. j eur acad dermatol venereol. 2012:26(12):1472-1478. figure 1. a well-circumscribed erythematous plaque, consisting of pendulous, wrinkled, lax skin, occupying the axilla is typical of granulomatous slack skin. figure 2. (a) the dermoscopic pattern consisting of pale orange areas on an erythematous background together with fine linear vessels is indicative of a granulomatous skin disease. (b) dermal infiltrate consisting of atypical, irregular, convoluted lymphocytes, together with multinucleated giant cells (h&e, ×40). https://www.orpha.net/consor/cgi-bin/oc_exp.php?lng=en&expert=33111 https://www.orpha.net/consor/cgi-bin/oc_exp.php?lng=en&expert=33111 dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(2):7 27 regression of nevi in a melanoma patient treated with interferon ayelet rishpon, m.d.1, nir nathanson, m.d.2 1 department of dermatology, tel aviv sourasky medical center, tel-aviv, israel 2 department of dermatology, sheba medical center, tel hashomer, israel key words: regression, nevi, interferon alpha2b citation: rishpon a, nathanson n. regression of nevi in a melanoma patient treated with interferon. dermatol pract conc. 2012;2(2):7. http://dx.doi.org/10.5826/dpc.0202a07. received: october 18, 2011; accepted: january 30, 2012; published: april 30, 2012 copyright: ©2012 rishpon et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ayelet rishpon, m.d., department of dermatology, tel aviv sourasky medical center, tel-aviv, israel. tel. 97236973356. email: arishpon@gmail.com. background high-risk melanoma patients are occasionally offered adjuvant treatment with interferon alpha 2b as a postsurgical treatment. this treatment is thought to improve disease-free survival by upgrading immunomodulatory functions, which cause an antitumor effect [1,2]. we describe a patient treated with adjuvant interferon therapy for stage iii melanoma, who presented multiple regressing nevi after the treatment. case report a 58-year-old male patient with a history of multiple basal cell carcinomas and a previous melanoma was diagnosed upon presentation with stage iii melanoma, consisting of a primary melanoma of the lower back with inguinal lymph node metastases. after excision of the primary tumor, the patient was treated with high-dose interferon alpha 2b for six months. four months after completing the interferon treatment, the patient sought treatment at the pigmented lesion clinic of sheba medical center, tel hashomer, israel. full body skin examination revealed multiple pigmented nevi of the trunk and extremities. of them, six nevi had a similar dermoscopic pattern, including a network and localized fine and coarse gray granularity which in general represent regression (figures 1, 2). in order to further analyze the lesions, confocal microscopy was performed (vivascope 1500, lucid inc, rochester, new york). instrumentation and acquisition procedures have been described previously [3,4]. confocal mosaic image (5 mm x 5 mm, compatible with low magnification microscopy) showed a ringed pattern correlating with the reticular dermoscopic pattern (figure 3). individual confocal images (0.5 mm x 0.5 mm, equivalent to high magnification microscopy) showed that in certain areas the ringed pattern is not visible and instead there are elongated refractile structures compatible with dendritic cells (figure 4). these dendritic cells could represent melanocytes, raising the possibility of pagetoid spread of a melanoma or http://dx.doi.org/10.5826/dpc.0202a 28 observation | dermatol pract concept 2012;2(2):7 langerhans cell, as part of the inflammation. histopathologic analysis of this lesion showed a dysplastic nevus with areas of melanosis, fibrosis and inflammation and no sign of pagetoid spread (figure 5a). in order to further identify the dendritic cells, cd1a and melan-a stains were performed. cd1a stain was positive throughout the epidermis (figure 5b) and melan-a stain was positive at the lower epidermis (figure 5c), suggesting that the dendritic cells represent langerhans cells as part of the inflammatory reaction. the five other lesions were biopsied as well, all showing histopathologically a dysplastic nevus with focal areas of regression. discussion regression of nevi in the setting of melanoma and interferon treatment might be induced by the melanoma, the interferon treatment, or both. examples of remote regression induced by melanoma include halo nevi and melanoma-associated leukoderma. these phenomena result from an immune reaction against shared antigens on benign and malignant melanocytes [5,6]. hu and colleagues described primary melanomas presenting as inflamed pigmented lesions during adjuvant interferon treatment for melanoma [7]. they suggest that the immunomodulatory effects of interferon targeting melanoma unmasked or “lit up” these subsequent primary melanomas. we hypothesize that this same effect might be responsible for causing inflammation, not only in melanomas, but also in nevi. it has been suggested that imiquimod, which stimulates interferon transcription, can cause regression or resolution of atypical nevi [8,9]. in a previous study, four of imiquimod treated nevi (compared to 0 non-treated nevi) showed partial regression on histopathology after 10 weeks of imiquimod treatment [8]. another study examined three patients, each with one atypical nevus treated with imiquimod for 12 weeks [9]. two lesions demonstrated inflammation on excisional biopsy. of note, since we saw the patient for the first time only after he had already completed the interferon treatment, the concept of the regression being caused by the interferon treatment is merely a hypothesis. as we do not have previous documentation of this patient’s nevi, we cannot rule out that this was the patient’s original nevi pattern. in fact there are figure 1. close-up clinical images of four of the patient’s nevi (arrows), showing pigmented maculae with a distinct gray focus. [copyright: ©2012 rishpon et al.] observation | dermatol pract concept 2012;2(2):7 29 three possible interpretations of this regression, its being, the original nevi pattern of this patient, caused by the melanoma, or caused by the adjuvant interferon treatment. understanding the pathogenesis of the findings described could have a role in improved melanoma diagnosis and treatment. for example, regression in nevi could be a surrogate for identifying patients in whom interferon mediates an inflammatory response against melanocytes. future studies regarding the pathogenesis of nevi regression in the setting of melanoma and interferon treatment are needed. figure 2. dermoscopic images of the four nevi showing network and localized gray granularity. [copyright: ©2012 rishpon et al.] figure 3. confocal microscopy mosaic (5 x 5 mm) at the level of the dermo-epidermal junction showing a ringed pattern on the right, and a disorganized pattern with disappearance of the ringed pattern in the center (red circle). inset: dermoscopic figure showing a network with localized gray granularity. [copyright: ©2012 rishpon et al.] figure 4. individual confocal image (500 x 500 microns) showing a close-up view of the ringed pattern (circle) and dendritic structures (arrows). [copyright: ©2012 rishpon et al.] 30 observation | dermatol pract concept 2012;2(2):7 references 1. kirkwood jm, ibrahim jg, sondak vk, ernstoff ms, ross m. interferon alfa-2a for melanoma metastases. lancet. 2002;359(9310):978-9. 2. wheatley k, hancock b, gore m, suciu s, eggermont a. interferon-alpha as adjuvant therapy for melanoma: a meta-analysis of the randomised trials. proc am soc clin oncol. 2001;20:1394. 3. rajadhyaksha m, grossman m, esterowitz d, webb rh, anderson rr. in vivo confocal scanning laser microscopy of human skin: melanin provides strongcontrast. j invest dermatol. 1995;104(6):946-52. 4. gonzalez s, gill m, halpern ac. reflectance confocal microscopy of cutaneous tumors: an atlas with clinical, dermoscopic and histological correlations. new york, ny: informa healthcare, 2008:30-75. 5. byrne kt, turk mj. new perspectives on the role of vitiligo in immune responses to melanoma. oncotarget. 2011;2(9):684-94. 6. zeff ra, freitag a, grin cm, grant-kels jm. the immune response in halo nevi. j am acad dermatol. 1997;37(4):620-4. 7. hu s, kim cc, jessup c, phung tl, curiel-lewandrowski c. primary cutaneous melanomas seen as inflamed pigmented lesions in patients undergoing adjuvant interferon treatment: a possible diagnostic clue for physicians. arch dermatol. 2009; 145(5):565-8. 8. dusza sw, delgado r, busam kj, marghoob aa, halpern ac. treatment of dysplastic nevi with 5% imiquimod cream, a pilot study. j drugs dermatol. 2006;5(1):56-62. 9. somani n, martinka m, crawford ri, dutz jp, rivers jk. treatment of atypical nevi with imiquimod 5% cream. arch dermatol. 2007;143(3):379-85. figure 5. (a) histopathology image showing a dysplastic nevus with dermal melanosis and fibrosis (hematoxylin & eosin [h&e], x20). (b) cd1a stain showing positively-stained cells throughout the epidermis (x40). (c) melan a stain showing positively staining cells only at lower part of epidermis (x40). [copyright: ©2012 rishpon et al.] a c b dermatology: practical and conceptual 318 letter | dermatol pract concept 2019;9(4):19 dermatology practical & conceptual introduction first defined in 1812 by wood, glomus tumors were known as “painful subcutaneous tubercles.” they commonly occur in middle-aged women and by the fifth decade in men. they are known as uncommon benign neuromyoarterial neoplasms that usually occur in the subungual region of the finger. extradigital location of glomus tumor is rare [1]: the forearm has been reported as the most common extradigital location. palm, wrist, and foot could also be affected. it generally appears as a solitary, small, pinkish tumor, or as multiple ones. we present a case of glomus tumor located on the buttock. case presentation a 65-year-old man with a history of myocardial infarction presented with a small, painful nodule of the left buttock of 15 years’ duration. the patient reported intense pain at pressure and movement that had recently worsened, triggered by the slightest touch. neither spontaneous pain nor cold sensitivity was reported. examination revealed a well-defined, 7× 7-mm, purple nodule on the upper external quadrant of the left buttock (figure 1). polarized noncontact dermoscopy (figure 2a) showed a central purple color surrounded by a whitish area and an external brown pigmentation. the diagnosis of extradigital glomus tumor was suspected, and it was confirmed by histopathological analysis, which showed a proliferation of blood vessels surrounded by small, uniform cells with round or oval nuclei (glomus cells) (figure 2b). the lesion was completely removed surgically. conclusion the classic triad of symptoms of glomus tumor—pain, pinpoint tenderness, and cold hypersensitivity—is very suggestive, but it may be incomplete as shown in our patient, leading to misdiagnosis. while described in a few cases, dermoscopic features may provide additional clues to the diagnosis: the central purple color corresponds to the enlarged vessels within the neuromyoarterial glomus body. the external whitish area is related to the fibrous capsule of the tumor, while the external brown pigmentation might be explained by its long course [2]. specific imaging techniques are recommended, even though mri could provide more details of the lesion and its association with the adjacent structures. confirmation relies always on histopathological glomus tumor of the buttock safa idoudi1, aycha arousse1, lobna boussofara1 1 dermatology department, farhat hached university hospital, sousse, tunisia key words: glomus tumor, dermoscopy, dermatology, tumor citation: idoudi s, arousse a, boussofara l. glomus tumor of the buttock. dermatol pract concept. 2019;9(4):318-319. doi: https://doi. org/10.5826/dpc.0904a19 accepted: july 16, 2019; published: october 31, 2019 copyright: ©2019 idoudi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: lobna boussofara, md, dermatology department, farhat hached university hospital, ibn jazzar avenue, 4000 sousse, tunisia. email: boussofara_l@yahoo.fr letter | dermatol pract concept 2019;9(4):19 319 references 1. lee dw, yang jh, chang s, et  al. clinical and pathological characteristics of extradigital and digital glomus tumours: a retrospective comparative study. j eur acad dermatol venereol. 2011;25(12):1392-1397. 2. oliveira a. dermoscopy in the diagnosis of extradigital glomus tumors. int j dermatol. 2016;55(9):e506-e508. findings showing an encapsulated fibrous tumor, with vascular spaces surrounded by glomus cells. surgical excision remains the only therapeutic option that provides immediate pain relief. it consists of wide excision of the tumor to avoid its recurrence. at the time of the present report, the patient continued dermatological follow-up and no recurrence was noted. figure 1. purple nodule of the upper external quadrant of the left buttock. [copyright: ©2019 idoudi et al.] figure 2. (a) polarized noncontact dermoscopy showed a central purple color surrounded by a whitish area and an external brown pigmentation. (b) histopathological analysis showed proliferation of blood vessels surrounded by small, uniform cells with round or oval nuclei (glomus cells). [copyright: ©2019 idoudi et al.] a b dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020069 1 dermatology practical & conceptual introduction syringotropic mycosis fungoides (stmf) is a rare variant of mycosis fungoides (mf) with prominent involvement of eccrine structures. it typically presents with red/skin colored/brown papules, patches, scaly plaques, nodules, and lichenification, along with pruritus, hair loss, and poor heat tolerance and sweating [1]. whether stmf is a subtype of folliculotropic mf (fmf) or a separate entity is still a matter of debate [1]. most stmf patients have a benign, indolent course and a better prognosis compared to patients with fmf [1]. histopathology is the gold standard for diagnosis of mf and stmf. case presentation we present 2 patients with a diagnosis of stmf, both with co-expression of cd4+/cd8+. patient 1, a 54-year-old man, presented with erythematous patches and plaques on the neck, face, arms, and back accompanied with pruritus. diagnosis was made using full-thickness skin biopsy; the sites were chosen upon dermoscopic examination of the most prominent lesions. few papules and milia-like cysts were seen. other lesions appeared as classical mf both clinically and dermoscopically (poorly elevated plaques and dry and lichenificated skin). no alopecia, follicular hyperkeratosis, or mucinorrhoea were noted; palms and soles were not affected. a diagnosis of folliculotropic and syringotropic mf was made. staging using the who/eortc classification indicated stage ib (t2n0m0b0) (figure 1). patient 2, a 64-year-old female, presented with erythematous papules, plaques, comedones, and milia localized on the neck and chest (that later progressed to the trunk and extremities), accompanied with pruritus. full-thickness skin biopsy was performed after the dermoscopic examination of the most prominent skin lesions, and a diagnosis of folliculotropic and syringotropic mf was established (stage iiib), phenotype cd4+/cd8+, cd30-. staging according to iscl/ eortc classification was t4n2m0b0 (figure 2). dermoscopy in both cases showed obliteration of the follicles, follicular accentuation, and follicular plugging (these observations for fmf have already been published), along dermoscopy of syringotropic and folliculotropic mycosis fungoides ružica jurakić tončić1, jaka radoš1, danijela ćurković, ivana ilić2, stefano caccavale3, mirna bradamante1 1 university department of dermatology and venereology, university hospital centre and school of medicine, zagreb, croatia 2 university hospital centre zagreb, department of pathology and cytology, university of applied health sciences, zagreb, croatia 3 department of dermatology, second university of naples, italy key words: dermoscopy, primary cutaneous lymphoma, mycosis fungoides, syringotropic mycosis fungoides, folliculotropic mycosis fungoides citation: jurakić tončić r, radoš j, ćurković d, ilić i, caccavale s, bradamante m. dermoscopy of syringotropic and folliculotropic mycosis fungoides. dermatol pract concept. 2020;10(4):e2020069. doi: https://doi.org/10.5826/dpc.1004a69 accepted: april 21, 2020; published: october 26, 2020 copyright: ©2020 jurakić tončić et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ružica jurakić tončić, md, university department of dermatology and venereology, university hospital center and school of medicine, kišpatićeva 12, zagreb, croatia. email: rjtoncic@gmail.com 2 letter | dermatol pract concept 2020;10(4):2020069 that this kind of bluish color is commonly observed with other eccrine type of tumors (such as eccrine hidrocystoma) [2]. accumulation of pigmented substances in eccrine glands was excluded by the pathologist; therefore, the bluish color is not a result of this kind of pigmentation. conclusions since currently there is no data on dermoscopic images of stmf, and these 2 patients differ in stage of the disease, we calculate that the differences observed are due to the stage of the disease and probably correspond to severity of the infiltration of eccrine ducts with atypical lymphocytes (staging of the patients). in order to understand this entity more, with loss of terminal follicles, comedo-like openings, and interconnected regular-appearing structureless patches [1] (figures 1 and2). orange color and follicular plugging were seen, corresponding to dense, diffuse, and perifollicular lymphocytic infiltrate. similar observations were made in both patients, with one major distinction. we have never observed the bluish structures with unsharp borders before in fmf patients, as in the case of patient 2, who presented with more advanced disease. these structures were not observed in pure fmf (figure 2). there are probably 2 explanations for this observation. in the patient 1, histology showed that follicles were more prominently affected and dermoscopic images correlated more with fmf, while in the patient 2 eccrine glands were predominantly affected. it is interesting to note figure 1. patient 1. clinical and dermoscopic presentation: dermoscopic images were taken from the lesion on which biopsy was done. the lesion was on the brachial region of the patient. along with typical dermoscopic presentation of mf on other parts of the body, on selected body parts, lesions presented with follicular accentuation and with follicular plugging. follicular accentuation and plugging were more visible when higher magnification was used. clinical staging of the patients at the time of evaluation was t2n0m0b0. (a) clinical presentation of lesion from where the biopsy was taken. (b-c) dermoscopy of the lesion from where the biopsy was taken. (d) dermoscopy of the skin from the presternal area. (e-h) histologic presentation of the lesion from where the biopsy was done. (e) follicular and ecrrine gland involvement by dense infiltrate of atypical lymphocytes (h&e, ×4). (f) marked folliculotropism, periand intrafolllicular lymphoid infiltration with mucin deposition (h&e, ×10). (g) syringometaplastic structures of eccrine glands surrounded and infiltrated by atypical lymphocytes (h&e, ×20). (h) immunohistochemical staining was positive for t lymphocytes (cd4; ×4) (i) lymphocytic infiltrate was composed of cd3+ lymphocytes (×4). clinical photography was taken with a canon powershot sx520 hs and the dermoscopic image with a nikon/dermlite photo. a b c d e f g h i letter | dermatol pract concept 2020;10(4):2020069 3 and pseudolymphomas presenting as solitary nodules and tumors: a case-control study with histopathologic correlation. int j dermatol. 2019;58: 1270-1276. doi: 10.1111/ijd.14590. pmid: 31347153. 2. duman n, duman d, sahin s. pale halo surrounding a homogeneous bluish-purplish central area: dermoscopic clue for eccrine hidrocystoma. dermatol pract concept. 2015;5:43-45. doi: 10.5826/dpc.0504a11. pmid: 26693090. we need dermoscopic studies with a larger number of the patients in different stages of the disease. references 1. navarrete-dechent c, del puerto c, abarzúa-araya á, et al. dermoscopy of primary cutaneous band t-cell lymphomas figure 2. patient no 2. clinical and dermoscopic presentation of the lesion on the face. in this patient follicular accentuation is less visible, follicular obliteration and plugging are more pronounced, and bluish, not well-defined areas are seen clinical staging of the patients at the time of evaluation was t4n2m0b0. (a) clinical presentation of the lesion from where biopsy was taken. (b-d) dermoscopic appearance of the lesion from where the biopsy was taken. dermoscopy shows obliteration of the follicles and in some parts bluish, not well -defined structures where eccrine involvment was found. (e-h) histology of the lesion from where biopsy was taken. (e) atypical lymphocytes surround and invade follicular epithelium (h&e, ×10). (f) atypical lymphocytes were positive for cd3+ on immunohistochemistry (×10). (g) cd3+ lymphocytes have a predilection for eccrine ducts (×20). (h) infiltration of eccrine ducts with atypical small to medium-sized lymphocytes (h&e, ×20). clinical photography was taken with a canon powershot sx520 hs and the dermoscopic image with a nikon/ dermlite photo. a b c d e f g h dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020058 1 dermatology practical & conceptual introduction rosacea is a chronic relapsing inflammatory skin disorder mainly affecting the central part of the face. clinically, it is characterized by facial redness and erythematous papules and pustules. due to overlapping features with other skin diseases, such as contact dermatitis, seborrheic dermatitis, acne vulgaris, cutaneous lupus, and carcinoid syndrome [1], the differential diagnosis is important. therefore, dermoscopy may provide additional features to improve the recognition of rosacea, including polygonal vessels with superficial scales and follicular plugs [2]. we report herein the dermoscopic pattern of a patient with rosacea and variations after systemic and intense pulsed light (ipl) therapy. case presentation a 22-year-old woman with fitzpatrick skin type iv presented to our clinic with a 3-month history of intense red lesions of the face. clinical examination revealed well-defined erythematous-edematous plaques covered with tiny papules, pustules, and a few nodules (figure 1a). the corresponding dermoscopic aspect was characterized by polygonal linear vessels, follicular plugs, brownish yellow areas, scales, follicular pustules, dilated follicles, and irregular and ill-formed rosettes (figure 2a). based on these clinical and dermoscopic features, a diagnosis of papulopustular rosacea was made. ivermectin 12 mg once a week and minocycline 100 mg once a day were given for 2 weeks. the patient was advised to apply broad-spectrum sunscreen. immediately after, the first session of ipl treatment was performed. ipl was then repeated every week for 6 weeks. the vascular probe, with a wavelength spectrum of 550-1,100 nm, was used and the patient received 6 passes in single pulse mode at a fluence of 12 j/cm2 followed by 6 passes in continuous mode of 7.1 j/cm2. clinical and dermoscopic improvement after treatment is reported in figures 1b and 2b. dermoscopic patterns of rosacea have been described in the current literature [2]. these dermoscopic patterns were observed in the case described herein. however, we detected an additional brownish hue in the context of yellowish areas, probably due to the dark skin color of the patient. furthermore, rosettes were ill-formed and ill-defined, resembling white shiny streaks in arcuate, short linear structures. dermoscopic monitoring of response to intense pulsed light in rosacea: a case report ajay deshapande,1 balachandra s. ankad2 1 dermatology, pune, maharashtra, india 2 department of dermatology, s. nijalingappa medical college, bagalkot, karnataka, india key words: rosacea, dermoscopy, intense pulsed light, monitoring citation: deshapande a, ankad bs. dermoscopic monitoring of response to intense pulsed light in rosacea: a case report. dermatol pract concept. 2020;10(3):e2020058. doi: https://doi.org/10.5826/dpc.1003a58 accepted: march 18, 2020; published: june 29, 2020 copyright: ©2020 deshapande and ankad. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: balachandra s. ankad, md, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587102, karnataka, india. email: drbsankad@gmail.com https://doi.org/10.5826/dpc.1003a58 mailto:drbsankad@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020058 sis of rosacea as well as for treatment monitoring. references 1. papageorgiou p, clayton w, norwood s, chopra s, rustin m. treatment of rosacea with intense pulsed light: significant improvement and long lasting results. br j dermatol. 2008;159(3):628632. https://doi.org/10.1111/j.13652133.2008.08702.x 2. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471507. https://doi.org/10.1007/s13555-0160141-6 conclusions systemic treatment and ipl therapy are good options in rosacea [1]. ipl ablates dilated dermal vessels and helps in collagen remodeling and improving skin texture [1]. demodex, which is commonly found in rosacea, is lightand heat-sensitive and known to aggravate rosacea during ipl treatment [1]. to prevent this reaction and to treat the papulopustular component, 2 doses of systemic ivermectin 12 mg weekly and minocycline 100 mg daily are advisable before initiating ipl therapy. monitoring the treatment response in rosacea is an important step in the management of the skin disease. in this case, the effectiveness of a combination of systemic and ipl treatments in rosacea was monitored by dermoscopy. we noticed significant improvement of vascular and follicular structures, scales, brownish yellow areas, and white streaks. hence, dermoscopy is useful in the assessment of treatment in rosacea. since dermoscopy is a rapid, easy, and noninvasive examination, it can be used in the clinical practice for the diagnofigure 1. (a) clinical image of a 22-year-old patient with a papulopustular rosacea before treatment. (b) clinical image of the same patient showing the improvement of rosacea after systemic and intense pulsed light treatment. boxes in both images represent the target areas where dermoscopy was performed. figure 2. (a) dermoscopy before treatment, showing brownish yellow areas (yellow arrows), linear vessels in polygonal pattern (black arrows), dilated follicles (blue arrows), follicular plugs (white arrows), ill-defined white rosettes (red arrows), and nonspecific scales (black circles). (b) dermoscopy after treatment, showing a reduction in vascular (black arrows) and follicular structures (white arrows), compared with pretreatment picture. brownish yellow areas (yellow star) and white streaks (red arrows) are also decreased. polarized mode, magnification ×10. https://doi.org/10.1111/j.1365-2133.2008.08702.x https://doi.org/10.1111/j.1365-2133.2008.08702.x https://doi.org/10.1007/s13555-016-0141-6 https://doi.org/10.1007/s13555-016-0141-6 observation | dermatol pract concept 2012;2(1):11 57 human papillomavirus-induced periungual pigmented bowen’s disease marigdalia k. ramirez-fort, m.d.1 1 department of surgery, university of pittsburgh medical center, pittsburgh, pa usa key words: human papillomavirus, pigmented bowen’s disease, periungual bowen’s disease citation: case report: human papillomavirus induced periungual pigmented bowen’s disease. dermatol pract conc. 2012;2(1):11. http://dx.doi.org/10.5826/dpc.0201a11. editor: alon scope, m.d. received: september 23, 2011; accepted: december 1, 2011; published: january 31, 2012 copyright: ©2012 ramirez-fort. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: marigdalia k. ramirez-fort, m.d., department of surgery, university of pittsburgh medical center, 200 lothrop st, pittsburgh, pa15213. tel. 908.285.8500. email: ramirezfortmk@upmc.edu. case report a 50-year-old male presented with an ill-defined hyperpigmented macule on the left pointer finger (figure 1). the lesion was reportedly first evident one year prior to presentation. clinically, the lesion was asymmetrical. notably, there was central hypopigmentation and obliteration of acral architecdermatology practical & conceptual www.derm101.com ture. differential diagnosis included acral nevus, tinea nigra, subcorneal bleeding, exogenous pigmentation, melanoma and pigmented bowen’s disease. dermatoscopically, the lesion was chaotic with regard to the distribution of color (figure 2). the lesion had different shades of brown and gray and its pattern was structureless. as noticed before by cameron et al, a structureless pattern is figure 1. clinical view. [copyright: ©2012 ramirez-fort.] figure 2. dermatoscopic view. [copyright: ©2012 ramirez-fort.] 58 observation | dermatol pract concept 2012;2(1):11 figure 3a–e. dermatopathologic view. [copyright: ©2012 ramirez-fort.] a b c d e observation | dermatol pract concept 2012;2(1):11 59 in keeping with the diagnosis of pigmented bowen’s disease [1]. histopathologic analysis of the lesion demonstrated a pigmented bowen’s disease (figure 3). there was acanthosis with focal hypergranulosis and parakeratosis. the epidermis was composed of atypical keratinocytes and a few scattered dyskeratotic cells. the superficial dermis had a light perivascular lymphocytic infiltrate. polymerase chain reaction sampling was positive for human papillomavirus (hpv), further confirming the diagnosis of an hpv-induced pigmented bowen’s disease. the lesion was excised completely and the surgical defect was closed primarily. discussion bowen’s disease may be induced by chronic exposure to forms of electromagnetic radiation, such as ultraviolet light (uv) or x-ray. bowen’s disease may also be induced by infection with hpv, as in the case presented above. bowen’s disease induced by hpv usually occurs on genital skin; multiple regional lesions are termed “bowenoid papulosis.” bowen’s disease is further categorized into pigmented or nonpigmented. it has been speculated that the source of pigment in bowen’s disease may represent a collision between a solar lentigo and bowen’s disease. although this explanation is reasonable for pigmented bowen’s disease on cutaneous sites chronically exposed to sunlight, it does not explain the pigmentation of “bowenoid papulosis” on genital skin or the case presented above. a more probable hypothesis considers neoplastic pigmentation as a direct reflection of the pigmentation present in the initial keratinocytes to proliferate. the hypothesis holds validity in the setting of a benign seborrheic keratosis or malignant lesion of bowen’s disease. some patients with bowenoid papulosis on genital skin develop subsequent periungual bowen’s disease. reported cases have found the same hpv strains in genital and periungual lesions, suggesting anogenital-digital spread of hpv as a possible etiology for hpv-positive periungual bowen’s disease [2]. the literature reports only one other case of a pigmented, periungual bowen’s disease by hu et al [3]. although the hpv status of the lesion is unknown, the group clearly demonstrated the utility of dermatoscopy in evaluation and further monitoring of disease progression. references 1. cameron a, rosendahl c, tschandl p, kittler h. dermatoscopy of pigmented bowen’s disease. j am acad dermatol. 2010;62(4):597–604. 2. hu sc, chiu hh, chen gs, et al. dermoscopy as a diagnostic and follow-up tool for pigmented bowen‘s disease on acral region. dermatol surg. 2008;34(9):1248–53. 3. shim wh, park hj, kim hs, et al. bowenoid papulosis of the vulva and subsequent periungual bowen‘s disease induced by the same mucosal hpvs. ann dermatol. 2011;23(4):493–6. dermatology: practical and conceptual book review | dermatol pract concept 2014;4(3):18 85 dermatology practical & conceptual www.derm101.com review by françois milette i heartily recommend this book to pathologists and dermatologists looking for a practical and easy to consult guide to differential diagnosis in dermatopathology. this book fulfills all the promises stated in its preface. this is rare! without any pretention, this guide is presented as a “supplement to existing textbooks of dermatopathology.” it does not pretend to cover every entity, it acknowledges its limitations to “classic” examples of each disease, and it stresses the fact that there is no substitute for experience in dealing with unusual cases and for a close collaboration between clinicians and pathologists in order to establish a reliable diagnosis. these may be statements of the obvious but they nevertheless are easy to forget, as any experienced dermatopathologist knows. indeed this practical guide is certainly not sufficient to acquire thorough practicing skill in dermatopathology. as the “supplement to existing textbooks” it intends to be, it certainly needs to be supplemented in return. nevertheless, from the very first pages to the last chapters, the reader senses that the author is an experienced practitioner effectively sharing his practical approach to skin biopsies. the book is constructed around its chapter 1c captioned “differential diagnosis lists.” in this chapter, the reader finds a list of various characteristics, some clinical (skin lesions with and without pruritus, the colors—white, red, green, yellow—of lesions, etc.); some physio-pathological (“kidney and the skin,” “gastrointestinal tract and the skin,” “pregnancy rashes,” “arthritis and skin diseases,” etc.); some topological (e.g., axilla, groin, head, elbow,. lesions); some histological review of practical dermatopathology, 2nd edition by ronald p. rapini françois milette1 1 centre hospitalier pierre-boucher, longueuil, canada citation: milette f. review of practical dermatopathology, 2nd edition by ronald p. rapini. dermatol pract concept. 2014;4(3):18. http:// dx.doi.org/10.5826/dpc.0403a18 published: july 31, 2014 copyright: ©2014 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: françois milette m.d., centre hospitalier pierre-boucher, longueuil, canada. email: francois.milette@cssspb.qc.ca figure  1. rapini rp. practical dermatopathology. 2nd ed. edinburgh  : elsevier, 2012. isbn: 978-0-323-06658-7. 460 pages. $189.00. (e.g., hemosiderin, horn cyst, interstitial inflammation, acantholysis), etc. for each of these nonspecific and rather arbitrary characteristics, a list of entities/diseases is given—151 lists! the most frequent entities on these lists are italicized identifying a first indication toward the final diagnosis. most entities listed are cross-referenced to one of the other chapters (chapters 2 to 29) of the book, on the first page of which they are included in a new differential diagnosis list. each element of this new list is then shortly discussed in a concise and very practical format, including a short definition with clinical and/ or physiopathological discussion, enumerations of histopathological characteristics and clinical variations and a new, more restricted list of differential diagnosis that can be the starting point of a new cycle of exploration through the book in the same or another chapter. high quality microphotographs are also presented of the classical aspect of most entities discussed. the whole book is thus structured around its chapter 1, which is, in fact, something like a crossroad in the labyrinth of dermatopathologic diagnoses, the book as a whole appearing therefore as a huge informal algorithm. 86 book review | dermatol pract concept 2014;4(3):18 certainly using this book/algorithm optimally requires experience and clinical knowledge, and this is admitted by the author in his preface. because of these need for experience and clinical knowledge, the book may not be a first choice for the beginner pathologist or dermatologist. or may it? for a beginner the problem would be where to start in his exploration of a given lesion. for example, is it to be approached as a violaceous lesion, a nodule, a knee lesion, a vasculitis? this may be of no consequence to the dermatologist who, in any case, will perform a biopsy, but the pathologist will have to select an entrance into the labyrinth. at first sight, therefore, this work may not be a good introductory book. on the other hand, though, one soon realizes that there is more than one way to exit the labyrinth and that gaining experience is precisely that: through repeated failures and successes, one finds the shortest way in various situations. if this book were considered a traveler’s guide in the world of dermatopathology, it may well be a very good introductory work after all! in any event, as this lengthy description suggests, this is not the kind of book to be read from cover to cover. it, rather, is a work through which to wander in search of the bestfitting diagnosis. and since this kind of wandering is precisely what the dematopathologist’s brain does all day long, going through it is like following in real-time the thought process of a practitioner. this is a remarkable achievement for the author and a very pleasurable experience for the reader, inducing reflection on the intellectual process called “making a diagnosis.” of course, this single author’s work, the synopsis of the thought process of an individual, is subjective, and the reader will here and there find some details he might have wished added, deleted or presented otherwise. but the approach adopted by dr. rapini is most pedagogical and everyone will be enriched by it. being a perpetual work in progress, this approach can never be definitive but continuously adapting it to one’s own thinking is a great source of professional growth. another very remarkable aspect of this arbeit that i would like to stress is that even if the author has tried to “distill [only] the most important facts into the text,” controversies are not overlooked and are stated in a remarkably concise and clear way, a powerful stimulus for looking farther into them. controversies are indeed “most important facts” never to be forgotten. consider, for example, how one of the most important controversies in dermatopathology—dysplasia in melanocytic lesions—is evoked: “the national institutes of health consensus conference published in the journal of the american medical associationin 1992 recommended that clinicians use the term “atypical mole” and that pathologists abandon the term dysplastic nevus in favor of the term nevus with architectural disorder, because these lesions usually have more architectural atypia (bridging, single melanocytes, shouldering, fibroplasia, lymphocytes, described below) than cytologic atypia. the consensus conference recommended grading the cytologic atypia (see below) as mild, moderate, or severe. because the architectural disorder is often more significant, some authorities grade both the architecture and the cytology. other pathologists refuse to grade these at all, citing papers showing irreproducibility. some pathologists use the term dysplastic nevus when the cytologic atypia is mainly within the epidermal melanocytes, using the term atypical nevus when it is in the dermis. others use the two terms as synonyms. unlike in gynecologic pathology, there is no uniform agreed-upon terminology for melanocytic neoplasms, and this is a big problem. since melanocytic terminology is more like the wild west, the clinician must know how a particular pathologist uses these terms. some authorities have complained that dysplastic nevus is overdiagnosed when there are only minimal architectural changes; ackerman sarcastically called it “the most common nevus in man”. the term clark nevus arose out of the aversion for calling these lesions truly ‘dysplastic.’” how could a beginner not question seriously the notion of dysplasia (and atypia) after its having been presented to him in such a way? the same is true concerning parapsoriasis: “parapsoriasis  is very  controversial. dermatologists use different terminology for various forms (many terms have historical significance only). some consider all examples of parapsoriasis to be mycosis fungoides, while others consider the small plaque type as benign and the large plaque (parapsoriasis en plaque) and variegate (retiform) types as representing early mycosis fungoides.” this admission of controversy is very appropriate, although i would have appreciated if dr. rapini had stated his practitioner’s point of view on these important subjects. in summary, this book is remarkable. it fulfills all its promises. it indeed is a valuable supplement to dermatopathology textbooks, serving as a guide into them, toward deeper knowledge on various entities. the book is particularly “user friendly” in its ebook version which is supplemented with online ressources, including a collection of clinical images and a pretest of 69 multiple choice questions. last and not least, the quality of the photomicropaphs included is outstanding, and if there is one suggestion i might dare make to the author, it would be to add more of them, perhaps as a new section of multimedia resources. dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2012;3(1):2 3 case report the 57-year-old woman pictured (figure 1) has had episodic pruritus of the mid-back for six years. she denied any apparent cause for the pruritus. at times there was an accompanying sensation of “pins and needles.” she also complained of heightened sensitivity in the area, which she noticed when putting on clothes or rubbing her back against the bed. she located the affected area medial to the left scapula. she could not identify anything that improved or worsened the symptoms. on examination, there was a hyperpigmented patch medial to the left scapula within the dermatomes of t2-t6. the patient had hyperesthesia to light touch in this area. there were no dermatitis, excoriations, or appreciable tissue texture changes, warmth, or edema. comment for centuries people have complained about an itch, just between the shoulder blades, that is out of reach to scratch. for some, the itch can become so persistent, so maddening that finding a way to scratch is all consuming. the backscratcher is such a primitive tool that even apes have been observed making them from tree branches. elaborate backscratchers have been fashioned from everything from whalenotalgia paresthetica: the unreachable itch carolyn ellis, d.o.1 1 largo medical center, largo, florida key words: notalgia paresthetica, pruritus, cutaneous neuropathy, neuropathic itch, backscratcher citation: ellis c. notalgia paresthetica: the unreachable itch. dermatol pract conc. 2013;3(1):2. http://dx.doi.org/10.5826/dpc.0301a02. received: september 5, 2012; accepted: december 3, 2012; published: january 31, 2013 copyright: ©2013 ellis. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to report. no sources of funding were used to assist in the preparation of this review. this literature review is an original contribution. corresponding author: carolyn ellis, d.o., 500 belcher rd s, #194, largo, fl 33771.tel. 207.542.9506. email: caroly.litty@gmail.com. background: notalgia paresthetica (np) is a very common, under-recognized condition characterized by pruritus in a unilateral, dermatomal distribution in the mid-back. chronic pruritus is sometimes accompanied by pain, paresthesias, or altered sensation to touch. objectives: to review the current literature with regards to the cause of np and its most appropriate treatment. methods: comprehensive literature review using pubmed to inspect the available data on np. results: the most likely cause of np is cutaneous nerve damage. many therapies have been tried in the treatment of np, mostly in small case studies. conclusions: the published cases and studies suggest symptoms of np are due to a cutaneous sensory neuropathy. treatments addressing the condition as such are more successful than traditional itch therapies. in many cases, a simple explanation for the persistent pruritus is satisfactory for patients. for very distressing cases, therapy should address the condition as a benign sensory neuropathy. further studies are needed to evaluate which treatments have the greatest potential for providing symptom relief. abstract bone to tortoiseshell and have been designed by diverse cultures throughout time. we postulate that notalgia paresthetica (np) was the stimulus leading to the invention of the backscratcher, perhaps by our primate ancestors. another possible explanation could be that the backscratcher or similar instrument is not the treatment of np but its cause. itch can lead to scratching and rubbing either with an instrument or against a wall, which leads to post-inflammatory hyperpigmentation and the findings that we call np. np is a common dermatologic complaint characterized by unilateral pruritus medial or inferior to the scapula. the condition was first described in 1934 by astwazaturow, though the complaint of a chronically itchy back has likely plagued people since the beginning of time. np is typically confined to the dermatomes of t2-t6 and may have accompanying pain, paresthesia, numbness, or hyperesthesia. a patch of lichenification or post-inflammatory hyperpigmentation is the result of chronic scratching [1-3]. it may be more prevalent in middle-age women and often lasts for years [4]. the cause of np is unclear. several possible etiologies have been proposed, but it is generally believed that np is a sensory neuropathy. a small study by springall and colleagues suggested a proliferation of cutaneous nerves in np 4 review | dermatol pract concept 2012;3(1):2 figure 1. (a) the symptomatic area medial to the patient’s left scapula is visible as a hyperpigmented patch. (b) the hyperpigmented patch is highlighted on the patient’s mid-back. [copyright: ©2013 ellis.] lesions [5]. this finding was not confirmed in any of the 14 patients savk et al biopsied; none of the tissue samples showed an increase in dermal innervation compared with controls [6]. most evidence suggests np is the result of damage to the cutaneous branches of the posterior divisions of the spinal nerves. this can occur either by impingement from degenerative changes in the spine or spasms in the paraspinal musculature. pain, paresthesia, and numbness are more commonly thought of as neurological findings, but pruritus is an often-unrecognized symptom of nerve damage. muscle spasms or fibrous bands may compress cutaneous nerves and cause symptoms. massey and pleet used electromyography to detect paraspinal denervation at t2-t6, corresponding to symptoms of np in 7 out of 9 patients. they suggest the sensory nerve branches at t2-t6 are susceptible to minor trauma because of how they pierce the multifidus spinae muscle [7]. the dorsal nerve roots exit the fascia of the multifidus spinae at a right angle en route to the epidermis; as a result they may be more exposed and prone to injury than in other areas of the back [7, 8]. these nerves can also be entrapped as they exit the spine through the vertebral foramen. a study by savk and savk of 43 patients with np showed over 60% had radiographic findings of degenerative vertebral changes or herniated discs in areas that corresponded to the dermatomal distribution of their symptoms [4]. several other studies have similarly shown an association between np and significant spinal pathology [2,3,9]. the diagnosis is made clinically on the basis of history. often, there are few if any signs of the disease; in some cases there may be localized hyperpigmentation or sensory findings in the infrascapular area. spinal imaging is not necessary unless the patient has other neurological or musculoskeletal symptoms. differential diagnosis should include tinea versicolor, contact dermatitis, parapsoriasis, neurodermatitis, and macular amyloidosis. biopsy of np may show signs of post-inflammatory hyperpigmentation, mild hyperkeratosis, and mild inflammatory infiltrate of the papillary dermis with dermal melanophages [2,3,6]. some studies show no evidence of amyloid deposition in np [2,6], while others do report sparse amyloid detected in dermal papillae [3,10]. this type of cutaneous amyloid is the result of damage to keratinocytes from chronic friction (scratching). it is therefore not surprising to see amyloid deposits in pruritic np lesions that have been present for years. however, the presence of amyloid can make the distinction from macular amyloidosis difficult, as there is considerable overlap of these two entities [10]. typical itch treatments such as antihistamines or topical steroids do not address the neuropathic itch of np [3]. other treatments that have been tried include topical capsaicin [11], cutaneous botulinum toxin type a injections [12], local review | dermatol pract concept 2012;3(1):2 5 nerve block [13], gabapentin [14], oxcarbazepine [15], and surgical decompression of the nerve [8]. these therapies have shown varied improvement of symptoms, may be expensive, invasive or require continued long-term use, and in some cases have undesirable side effects (table 1). recent studies have looked at several non-pharmacological, non-surgical therapies to address the neuro-musculoskeletal pathology presumed to cause np (table 1). savk and savk showed that transcutaneous electrical nerve stimulation yielded statistically significant improvement in the symptoms of 15 np patients with corresponding radiographic findings. from an initial pruritus of 10/10, there was a decrease in pruritus to a mean 6.8/10 after ten sessions over two weeks [9]. a case study using exercises to strengthen postural muscles and extend the spine, thereby reducing the angle of the cutaneous nerves as they pass through the muscles and the transverse processes, completely eliminated pruritus in two women with np [16]. acupuncture also appears promising for relief of np. a study of 16 patients with neurogenic pruritus, seven of which had presentations consistent with np, illustrated complete relief of pruritus in 75% after 2-6 treatments with deep intramuscular stimulation acupuncture. recurrence of symptoms did occur after 1-12 months without therapy in 37%, necessitating further treatment [17]. osteopathic manipulative treatment (omt) relieved pruritus in a middle-aged woman who developed np following a motor vehicle accident. soft tissue techniques applied to the affected upper thoracic and scapular regions improved the patient’s pain and itching [18]. this was only a single case study, but if proven effective it may be an easy way for osteopathic dermatologists comfortable with omt to treat these patients. table 1. treatment options for notalgia paresthetica treatments description efficacy capsaicin [11] 0.025% cream to affected areas 5 x day for 1 week, then 3 x day for 5 weeks 70% had improvement, but symptoms returned within a month of stopping treatment botulism toxin type a [12] 4 units per superficial injection, spaced 2 cm apart throughout affected area resolution of symptoms for over 18 months observed in one patient nerve block [13] 5 ml bupivacaine 0.75% with 40 mg methylprednisolone acetate resolution of symptoms for at least 12 months in one patient gabapentin [14] initial dose of 300 mg at bedtime, increased to 600 mg resolution in one patient while on medication. symptoms returned fully when medication stopped oxcarbazepine [15] initial dose of 300 mg twice daily. increased to 600 or 900 mg to achieve adequate relief improvement, no resolution, in four patients surgery [8] surgical decompression of cutaneous nerve resolution of symptoms observed in one patient transcutaneous electrical nerve stimulation [9] 5 20-minute sessions/week x 2 weeks, 50-100 hz with a 40-75 μs pulse width improvement of symptoms, no resolution, in 15 patients exercise [16] strengthening of rhomboid and latissimus dorsi muscles, stretching of pectoral muscles daily for one week resolution of symptoms in two patients acupuncture [17] deep intramuscular stimulation to paraspinal muscles in affected area every 1-2 weeks until relief partial to complete resolution after 2-6 treatments, but relapse of symptoms in 1-12 months, observed in 16 patients osteopathic manipulative treatment [18] muscle energy, soft tissue, inhibition, fascia release improvement of symptoms observed in one patient 6 review | dermatol pract concept 2012;3(1):2 all of these modalities warrant further investigation of their usefulness for the treatment of np and other types of neurogenic pruritus. patients often get some relief simply by learning the pruritus they are experiencing has a biological cause and a name. in persistent cases that interfere with quality of life, say if your patient owns multiple, strategically located back scratchers, some of these therapies may be worth trying. and while scratching to excess with a large salad fork is not recommended, for more mild symptoms, the timeless phrase, “i’ll scratch your back if you’ll scratch mine” is fitting. and the market for back scratchers is as strong as ever. conclusion take home messages about notalgia paresthetica: • np is a unilateral pruritus located medial or inferior to the scapula in the t2-t6 dermatomal region. • np is most often seen in middle-aged women and can last for months or years. • it may be accompanied by pain, paresthesias, numbness, or hypersensitivity. • symptoms are most likely caused by impingement of nerves as they exit the spinal column or traverse through muscles of the back. it is sometimes seen in association with herniated discs or degenerative disc disease. • traditional itch treatments (antihistamines, topical steroids) fail because they do not address the neuropathy. • many modalities have been used to treat np with varying success. the most important point to keep in mind is this is a harmless condition, which often does not warrant the potential side effects or risks of many treatments. • educating patients about the cause and course of the condition can be the most important aspect of treatment. acknowledgements: the author would like to acknowledge the invaluable contributions of david elpern, m.d. this paper was written during a dermatology clerkship in his office. his input and help with editing is greatly appreciated references 1. massey ew, pleet ab. localized pruritus–notalgia paresthetica. arch dermatol. 1979;115(8):982-3. 2. savk e, savk so, bolukbasi o, et al. notalgia paresthetica: a study on pathogenesis. int j dermatol. 2000:39(10):754-9. 3. raison-peyron n, meunier l, acevedo m, meynadier j. notalgia paresthetica: clinical, physiopathological and therapeutic aspects. a study of 12 cases. j eur acad dermatol venereol. 1999;12(3):215-21. 4. savk o, savk e. investigation of spinal pathology in notalgia paresthetica. j am acad dermatol. 2005;52(6):1085-7. 5. springall dr, karanth ss, kirkham n, darley cr, polak jm. symptoms of notalgia paresthetica may be explained by increased dermal innervation. j invest dermatol. 1991;97(3): 55561. 6. savk e, dikicioglu e, culhaci n, karaman g, sendur n. immunohistochemical findings in notalgia paresthetica. dermatology. 2002;204(2):88-93. 7. massey ew, pleet ab. electromyographic evaluation of notalgia paresthetica. neurology. 1981;31(5):642. 8. williams eh, rosson gd, elsamanoudi i, dellon al. surgical decompression for notalgia paresthetica: a case report. microsurgery. 2010;30(1):70-2. 9. savk e, savk o, sendur f. transcutaneous electric nerve stimulation offers partial relief in notalgia paresthetica patients with a relevant spinal pathology. j dermatol. 2007;34(5):315-9. 10. goulden v, highet as, shamy hk. notalgia paraesthetica—report of an association with macular amyloidosis. clin exp dermatol. 1994;19(4):346-9. 11. wallengren j, klinker m. successful treatment of notalgia paresthetica with topical capsaicin: vehicle-controlled, double-blind, crossover study. j am acad dermatol. 1995;32(2):287-9. 12. weinfeld pk. successful treatment of notalgia paresthetica with botulinum toxin type a. arch dermatol. 2007;143(8):980-2. 13. goulden v, toomey pj, highet as. successful treatment of notalgia paresthetica with a paravertebral local anesthetic block. j am acad dermatol. 1998;38(1):114-6. 14. loosemore mp, bordeaux js, bernhard jd. gabapentin treatment for notalgia paresthetica, a common isolated peripheral sensory neuropathy [letter]. j eur acad dermatol venereol. 2007;21(10):1440-1. 15. savk e, bolukbasi o, akyol a, karaman g. open pilot study on oxcarbazepine for the treatment of notalgia paresthetica. j am acad dermatol. 2001;45(4):630-2. 16. fleischer ab, meade tj, fleischer ab. notalgia paresthetica: successful treatment with exercises. acta derm venereol. 2011;91(1):356-7. 17. stellon a. neurogenic pruritus: an unrecognized problem? a retrospective case series of treatment by acupuncture. acupunct med. 2002;20(4):186-190. 18. richardson bs, way bv, speece aj. osteopathic manipulative treatment in the management of notalgia paresthetica. j am osteopath assoc. 2009;109(11):605-8. dermatology: practical and conceptual image letter | dermatol pract concept 2019;9(3):6 207 dermatology practical & conceptual a tiny melanoma: the beginning of a life aimilios lallas1, chryssoula papageorgiou1, christina nikolaidou2, zoe apalla3 1 first department of dermatology, aristotle university, thessaloniki, greece 2 department of histopathology, hippokration general hospital, thessaloniki, greece 3 state clinic of dermatology, hospital for skin and venereal diseases, thessaloniki, greece key words: melanoma in situ, dermoscopy, diagnosis citation: lallas a, papageorgiou c, nikolaidou c, apalla z. a tiny melanoma: the beginning of a life. dermatol pract concept. 2019;9(3):207-208. doi: https://doi.org/10.5826/dpc.0903a06 accepted: may 2, 2019; published: july 31, 2019 copyright: ©2019 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: aimilios lallas, md, phd, first department of dermatology, aristotle university, 124 delfon street, thessaloniki, greece. email: emlallas@gmail.com case presentation a 54-year-old man without personal or family history of melanoma was examined during a skin cancer screening campaign. the clinical examination revealed numerous nevi, angiomas, and seborrheic keratoses, all smaller than 5 mm and without morphological atypia (figure 1a). surprisingly, the dermoscopic examination of a 2-mmsized lesion (figure 1b) on his thorax revealed irregularly shaped hyperpigmented areas, a feature recently proposed to typify melanoma in situ (figure 1c) [1]. the lesion was excised with a 4-mm punch, and histopathology revealed an intraepidermal lentiginous and focally nested melanocytic proliferation with moderate to severe cytological atypia and pagetoid spread. the nests were variable in size and contained melanocytes with hyperchromatic cytoplasm. immunostaining revealed hyperplasia and asymmetric distribution of intraepidermal melanocytes and confirmed the pagetoid spread. a diagnosis of melanoma in situ was rendered. teaching point dermoscopy was introduced as a second-level method to further evaluate clinically preselected suspicious lesions. the size threshold for a lesion to be considered suspicious is 6 mm. our case suggests that no size threshold should be used for dermoscopic examination, since dermoscopy has the potential to uncover even smaller melanomas and help to eradicate a potentially life-threatening tumor with a minimally invasive intervention. reference 1. lallas a, longo c, manfredini m, et al. accuracy of dermoscopic criteria for the diagnosis of melanoma in situ. jama dermatol. 2018;154(4):414-419. 208 image letter | dermatol pract concept 2019;9(3):6 figure 1. a tiny pigmented skin lesion on the chest, barely seen macroscopically (a). close inspection reveals a 2-mm diameter brown macule (b). dermoscopy reveals irregularly shaped hyperpigmented areas, raising the suspicioun of an early melanoma, which was histopathologically confirmed (c). [copyright: ©2019 lallas et al.] a c b dermatology: practical and conceptual review | dermatol pract concept 2020;10(2):e2020031 1 dermatology practical & conceptual introduction yellow nail syndrome (yns) is a rare disorder characterized by typical nail alterations variably associated with lymphedema and respiratory disease. it mainly affects individuals over 50 years of age, although rare pediatric cases have been reported [1-14]. nail discoloration (chromonychia) varies from pale yellow to dark greenish, with enhanced transverse curvature and onycholysis. the nail plate is thickened, making the nails very nails: the window to the nose? update on yellow nail syndrome laura vollono,1 marco adriano chessa,2 antonio bruno,3 michela starace,2 aurora alessandrini,2 bianca maria piraccini2 1 dermatology unit, department of medicina dei sistemi, tor vergata university, rome, italy 2 dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, italy 3 radiology unit, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: yellow nail syndrome, lichen planus, arrested nail growth, respiratory disease citation: vollono l, chessa ma, bruno a, starace m, alessandrini a, piraccini bm. nails: the window to the nose? update on yellow nail syndrome. dermatol pract concept. 2020;10(2):e2020031. doi: https://doi.org/10.5826/dpc.1002a31 accepted: december 6, 2019; published: april 3, 2020 copyright: ©2020 vollono et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. marco adriano chessa, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti, 1-40138 bologna, italy. email: marco.adriano.chessa@gmail.com background: yellow nail syndrome is a rare condition characterized by typical nail alterations and variable presence of lymphedema and respiratory disease. the pathogenesis is still obscure, with most of the literature deriving from case reports and few investigations. the most reported respiratory conditions associated with yellow nail syndrome are pleural effusion and bronchiectasis, whereas association with rhinosinusitis is rarer. objectives: to describe a case of yellow nail syndrome and to provide a literature review regarding this disorder, discussing pathogenetic hypothesis, associated conditions, and therapeutic options. patients/methods: a 49-year-old man presented with arrested growth and alterations of his nails, without any history of previous trauma or inflammation but with a severe nasal septum deviation and a history of chronic rhinosinusitis. a diagnosis of yellow nail syndrome was made. results: six months after undergoing rhinoseptoplasty and treatment with oral vitamin e, the patient’s nails were cured. conclusions: this case emphasizes the role of the dermatologist in detecting systemic conditions. the correct diagnosis led to complete resolution of both nail alterations and associated respiratory disorders. abstract https://doi.org/10.5826/dpc.1001a30 mailto:marco.adriano.chessa@gmail.com 2 review | dermatol pract concept 2020;10(2):e2020031 hard and difficult to trim (scleronychia) and the lunula is obscured by nail hyperkeratosis. nail growth rate is half that of normal nails, with disappearing of cuticles. differential diagnosis includes onychomycosis, drug-induced nail discoloration, trauma, chronic paronychia, and acquired pachyonychia [15]. the pathogenesis is still obscure, with most of the literature deriving from case reports and few investigations. the most common lung conditions associated with yns are pleural effusion and bronchiectasis, although other respiratory disorders such as recurrent pneumonias, bronchitis, and chronic sinusitis have been included as diagnostic criteria [2,3]. the course of the nail disease does not necessarily parallel that of the associated conditions. we hereby report a case of yns with severe nasal septum deviation and chronic rhinosinusitis that completely resolved after surgical treatment of the respiratory disease and oral administration of vitamin e, together with a comprehensive review of the literature regarding this peculiar entity. case report a 49-year-old man presented to our nail clinic with arrested growth rate and alterations of his nails that started 6 months prior. his medical history was unremarkable, except for chronic rhinosinusitis. dermatological examination revealed increased transverse curvature, onycholysis, yellow-green discoloration, and nail fold swelling. notably, the cuticles were lacking (figure 1, a and b). he denied any previous trauma or manipulation of his nails. routine nail fungal culture was negative. neither swelling of the limbs nor facial edema was observed. based on the clinical picture and medical history, a head ct scan was performed, which detected a severe nasal septum deviation compromising the airway (figure 1c). chest x-ray was unrevealing. a diagnosis of yns with chronic rhinosinusitis was made. the patient underfigure 1. nail alterations characteristic of yellow nail syndrome. (a,b) absence of the cuticles and nail fold swelling are key to diagnosis. (c) head ct scan revealing type ii septal deviation (mladina classification) associated with unilateral spur compromising the airway (arrow, left) and secondary hypoplasia of the right middle nasal turbinate (arrow, right). (d,e) improved appearance of the nails 1 year after rhinoseptoplasty and oral vitamin e supplementation. review | dermatol pract concept 2020;10(2):e2020031 3 parietal pleura and subcutaneous tissue of yns patients. in the largest series published to date, maldonado et al hypothesized that yns pathogenesis might be due to microvasculopathy associated with protein leakage, rather than lymphatic functional impairment [2]. however, a recent case-control study on 17 yns patients with lower and/or upper limb lymphedema found a significantly higher rate of lymphatic morphological abnormality and reduced regional nodal uptake compared to healthy controls, concluding that yns should be considered as a lymphatic phenotype [23]. as suggested, it seems likely that one given unknown factor, genetic and/or extrinsic, determines a decline in lymph vessel function, leading to peripheral sclerosis of subcutaneous tissues and morphological abnormality of lymph vessels that worsen as the yns clinical manifestations become more evident. the role of titanium, especially titanium dioxide, has been recently evoked, although the mere exposure to the agent does not seem sufficient to develop the syndrome [43-45]. in any case, a detailed exposure history from patients with yns is indeed recommended. treatment a careful review of the literature points out that there is no consensus regarding yns treatment, owing to the lack of large-scale studies. treatment is typically based on anecdotal evidence, case reports, or small series. spontaneous resolution without any treatment has been observed. cancer treatment showed to lead to resolution of symptoms in patients affected by paraneoplastic yns [12]. topical treatments for nail changes such as triamcinolone injections and topical α-tocopherol (vitamin e) have been proposed, with inconsistent results [46-50]. management of lymphedema with manual lymphatic drainage and compression bandages is advisable in order to prevent irreversible hypertrophy of subcutaneous tissue [19]. yns has been also associated with several systemic conditions. hydrops fetalis, primary intestinal lymphangiectasis, and lymphedema-distichiasis syndrome has been reported in patients with yns, suggesting lymphatic impairment as a key factor in the development of the syndrome [24-26]. cases of iatrogenic yns following cardiac mitral valve replacement, implantation of permanent titanium cardiac pacemaker, and coronary artery bypass grafting have been recently published [27-29]. autoimmune diseases (primarily rheumatoid arthritis) and immune deficiency have been occasionally associated with yns, partially explaining the proneness to chronic infection of the respiratory system [30-33]. the hypothesis that yns may be a paraneoplastic syndrome derives from reports of malignant diseases diagnosed concurrently or closely thereafter in yns patients [2,3,17,3442]. the frequency of association between yns and various types of cancer is low and the matter remains controversial; however, a careful anamnesis of medical history and possible signs of systemic disease is recommended. pathogenesis the etiology of yns is obscure and investigations are few. most of the literature is from case reports, and the majority of case series include 3 or fewer patients, although large series of up to 41 cases have been published [1-3,21,23]. despite the paucity of evidence, a unifying lymphatic mechanism has been proposed to explain the development of lymphedema, pleural effusion, and nail alterations in yns. defective lymphatic drainage may be responsible for the sclerosis of the nail matrix tissue observed at light microscopy examination, with ectatic, endothelium-lined channels embedded in the fibrotic stroma, resulting in the clinically evident slow growth and thickening of the nails. the same mechanisms could be held responsible for the sclerosis and dilated lymphatic vessels also found in went rhinoseptoplasty and treatment with oral vitamin e (1,200 iu/day). one year later, his respiratory symptoms had resolved and his nails appeared completely cured (figure 1, d and e). discussion yns was first described in 1964 by samman and white, who reported the association between typical nail findings and lymphedema [16]. two years later, emerson added pleural effusion as a further diagnostic criterion [17]. later on, other chronic respiratory symptoms including sinusitis, bronchitis, recurrent pneumonias, pleuritis, and bronchiectasias have been included in the characteristic pulmonary manifestations of yns [16-20]. only 2 criteria out of 3 are required to diagnose yns, and the complete triad is reported to be present in only 27%-60% of cases [1-3,16,17,1922]. the possible interval between the first clinical sign (lymphedema, lung manifestations) and nail alterations hinders affirmation of the diagnosis; thus the condition may be underestimated. associated conditions the occurrence of lymphedema ranges between 29% and 80%, being the first sign of the syndrome in approximately one-third of cases [2,3,19]. clinical characteristics are the same as those of primary lymphedema, most commonly occurring on lower limbs, although facial edema and upper limb lymphedema have been rarely reported [16,23]. prevalence of pleural effusions is approximately 14%-16% in yns, with the prevalent clinical manifestation being chronic cough, and bronchiectasias are present in approximately 44% of patients [2]. acute or chronic sinusitis is frequently observed (14%83%), mainly affecting the maxillary and ethmoid sinus [1-3,19,21,22]. ct scans usually show mucosal thickening with enlargement of turbinates and fluid levels. 4 review | dermatol pract concept 2020;10(2):e2020031 underwent combined treatment with both rhinoseptoplasty and oral vitamin e supplementation, suggesting that a multidisciplinary therapeutic approach may be more likely to lead to a cure than a single medicine or treatment. further research is indeed required in order to investigate the potential of the above-mentioned therapeutic strategies and provide higher levels of evidence for the treatment of yns. this report aims to emphasize the role of the dermatologist in detecting systemic conditions, sometimes hidden behind what seems to be a mere aesthetic concern. we believe that our case is of special interest as the correct diagnosis led to appropriate therapeutic strategies, resulting in the complete resolution of both the nail alterations and associated respiratory condition. careful anamnesis regarding medical history and associated conditions should always be performed in order not to miss an opportunity to provide patients with proper care. references 1. hoque sr, mansour s, mortimer ps. yellow nail syndrome: not a genetic disorder? eleven new cases and a review of the literature. br j dermatol. 2007;156(6):1230-1234. 2. maldonado f, tazelaar hd, wang cw, ryu jh. yellow nail syndrome: analysis of 41 consecutive patients. chest. 2008;134(2):375-381. 3. piraccini bm, urciuoli b, starace m, tosti b, balestri r. yellow nail syndrome: clinical experience in a series of 21 patients. j dtsch dermatol ges. 2014;12(2):131-137. 4. magid m, esterly nb, prendiville j, fujisaki c. the yellow nail syndrome in an 8-year-old girl. pediatr dermatol. 1987;4(2):9093. 5. paradisis m, van asperen p. yellow nail syndrome in infancy. j paediatr child health. 1997;33(5):454-457. 6. göçmen a, küçükosmanoglu o, kiper n, karaduman a, ozçelik u. yellow nail syndrome in a 10-year-old girl. turk j pediatr. 1997;39(1):105-109. 7. yalçin e, dogru d, gönç en, cetinkaya a, kiper n. yellow nail syndrome in an infant presenting with lymphedema of the eyelids and pleural effusion. clin pediatr (phila). 2004;43(6):569-572. 8. douri t. yellow nails syndrome in two siblings. dermatol online j. 2008;14(9):7. 9. cebeci f, celebi m, onsun n. nonclassical yellow nail syndrome in six-year old girl: a case report. cases j. 2009;2:165. 10. nanda a, al-essa fh, el-shafei wm, alsaleh qa. congenital yellow nail syndrome: a case report and its relationship to nonimmune fetal hydrops. pediatr dermatol. 2010;27(5):533-534. 11. siddiq i, hughes dm. yellow nails, lymphedema and chronic cough: yellow nail syndrome in an eight-year-old girl. can respir j. 2012;19(1):35-36. 12. cecchini m, doumit j, kanigsberg n. atypical presentation of congenital yellow nail syndrome in a 2-year-old female. j cutan med surg. 2013;17(1):66-68. 13. dessart p, deries x, guérin-moreau m, troussier f, martin l. yellow nail syndrome: two pediatric case reports [article in french]. ann dermatol venereol. 2014;141(10):611-619. regarding systemic treatment, oral zinc sulfate supplementation (300 mg/day) resulted in improvement of lymphedema and nail alterations, but no effect on pulmonary manifestations was observed [51]. triazole antifungals such as itraconazole showed to exert limited effects on affected nails; however, combination treatment with pulsed oral fluconazole and oral α-tocopherol resulted in significant improvement of nail alterations [3,52-55]. the therapeutic effect may be exerted by a combination of the azole antifungals’ stimulation of linear nail growth and the vitamin e antioxidant properties that prevent colorless lipid precursor to be transformed into lipofuscin pigment responsible of nail yellowing [54,56,57]. oral vitamin e is traditionally prescribed also as monotherapy. because of its efficacy for chronic lower respiratory tract infections, clarithromycin (cam) theoretically makes a suitable candidate as therapeutic agent in yns. apart from a single case report in 2011, a recent observational study on 5 yns subjects with respiratory manifestations reported significant improvement of nail discoloration in parallel with improvement of respiratory symptoms after oral administration of cam [58,59]. the initial dosage was 200 mg/day, but therapeutic effects were not observed until the dosage was increased to 400 mg/day, suggesting that the activity of cam in yns may be dose-dependent. the therapeutic effect may be exerted by both antibacterial and anti-inflammatory activity of cam, improving both lymphatic drainage around nails with resolution of discoloration and reducing water and mucus secretion in the respiratory tract [60-62]. treatment for chronic rhinosinusitis is not specific for yns patients; however, global response to medications such as oral antibiotics or topical intranasal steroids or decongestants is poor, making surgical procedures often necessary. a few cases of yns with sinobronchial syndrome in which treatment with cam led to resolution of both nail and respiratory manifestations have been reported [58,59]. a case of a patient affected by yns with rhinosinusitis cured with combination treatment with triamcinolone injection, oral vitamin e, oral fluconazole, and robust medical regimen for rhinosinusitis has been reported, although the variety of treatment administered makes it is difficult to assess the relevance of each agent in the resolution of symptoms [50]. a single case of yns with rhinosinusitis whose nail manifestations were dramatically improved after endoscopic sinus surgery has been reported [63]. conclusions to our knowledge, this is the fourth report regarding successful treatment of yns manifestations in a patient with chronic rhinosinusitis, and the second one observing resolution of yns symptoms after sinus surgery. notably, our patient review | dermatol pract concept 2020;10(2):e2020031 5 36. iqbal m, rossoff lj, marzouk ka, steinberg hn. yellow nail syndrome: resolution of yellow nails after successful treatment of breast cancer. chest. 2000;117(5):1516-1518. 37. gupta ak, davies gm, haberman hf. yellow nail syndrome. cutis. 1986;37(5):371-374. 38. ginarte m, monteagudo b, toribio j. yellow nail syndrome and lung lymphoma. clin exp dermatol. 2004;29(4):432-433. 39. sève p, thieblemont c, dumontet c, et al. skin lesions in malignancy, case 3: yellow nail syndrome in non-hodgkin’s lymphoma. j clin oncol. 2001;19(7):2100-2101. 40. burrows np, jones rr. yellow nail syndrome in association with carcinoma of the gall bladder. clin exp dermatol. 1991;16(6):471-473. 41. guin jd, elleman jh. yellow nail syndrome: possible association with malignancy. arch dermatol. 1979;115(6):734-735. 42. mambretti-zumwalt j, seidman jm, higano n. yellow nail syndrome: complete triad with pleural protein turnover studies. south med j. 1980;73(8):995-997. 43. dos santos vm. titanium pigment and yellow nail syndrome. skin appendage disord. 2016;1(4):197. 44. itagaki h, katuhiko s. yellow nail syndrome following multiple orthopedic surgeries: a case report. j med case rep. 2019;13(1):200. 45. berglund f, carlmark b. titanium, sinusitis, and the yellow nail syndrome. biol trace elem res. 2011;143(1):1-7. 46. makrilakis k, pavlatos s, giannikopoulos g, toubanakis c, katsilambros n. successful octreotide treatment of chylous pleural effusion and lymphedema in the yellow nail syndrome. ann intern med. 2004;141(3): 246-247. 47. lambert em, dziura j, kauls l, mercurio m, antaya rj. yellow nail syndrome in three siblings: a randomized double-blind trial of topical vitamin e. pediatr dermatol. 2006;23(4):390-395. 48. abell e, samman pd. yellow nail syndrome treated by intralesional triamcinolone acetonide. br j dermatol. 1973;88(2):200-201. 49. williams hc, buffham r, du vivier a. successful use of topical vitamin e solution in the treatment of nail changes in yellow nail syndrome. arch dermatol. 1991;127(7):1023-1028. 50. imadojemu s, rubin a. dramatic improvement of yellow nail syndrome with a combination of intralesional triamcinolone, fluconazole, and sinusitis management. int j dermatol. 2015;54(11):e497-e499. 51. arroyo jf, cohen ml. improvement of yellow nail syndrome with oral zinc supplementation. clin exp dermatol. 1993;18(1):62-64. 52. tosti a, piraccini bm, iorizzo m. systemic itraconazole in the yellow nail syndrome. br j dermatol. 2002;146(6):1064-1067. 53. baran r, thomas l. combination of fluconazole and alpha-tocopherol in the treatment of yellow nail syndrome. j drugs dermatol. 2009;8(3):276-278. 54. luyten c, andré j, walraevens c, de doncker p. yellow nail syndrome and onychomycosis: experience with itraconazole pulse therapy combined with vitamin e. dermatology. 1996;192(4):406-408. 55. baran r. the new oral antifungal drugs in the treatment of the yellow nail syndrome. br j dermatol. 2002;147(1):189-191. 56. norton l. further observations on the yellow nail syndrome with therapeutic effects of oral alpha-tocopherol. cutis. 1985;36(6):457-462. 57. doncker pd, pierard ge. acquired nail beading in patients receiving itraconazole—an indicator of faster nail growth? a study 14. al hawsawi k, pope e. yellow nail syndrome. pediatr dermatol. 2010;27(6):675-676. 15. vignes s, baran r. yellow nail syndrome: a review. orphanet j rare dis. 2017;12(1):42. 16. samman pd, white wf. the “yellow nail” syndrome. br j dermatol. 1964;76:153-157. 17. emerson pa. yellow nails, lymphoedema, and pleural effusions. thorax. 1966;21(3):247-253. 18. maldonado f, ryu jh. yellow nail syndrome. curr opin pulm med. 2009;15(4):371-375. 19. nordkild p, kromann-andersen h, struve-christensen e. yellow nail syndrome—the triad of yellow nails, lymphedema and pleural effusions. acta med scand. 1986;219(2):221-227. 20. hiller e, rosenow ec, olsen am. pulmonary manifestations of the yellow nail syndrome. chest. 1972;61(5):452-458. 21. varney va, cumberworth v, sudderick r, durham sr, mackay is. rhinitis, sinusitis and the yellow nail syndrome: a review of symptoms and response to treatment in 17 patients. clin otolaryngol allied sci. 1994;19(3):237-240. 22. pavlidakey gp, hashimoto k, blum d. yellow nail syndrome. j am acad dermatol. 1984;11(3):509-512. 23. cousins e, cintolesi v, vass l, et al. a case-control study of the lymphatic phenotype of yellow nail syndrome. lymphat res biol. 2018;16(4):340-346. 24. slee j, nelson j, dickinson j, kendall p, halbert a. yellow nail syndrome presenting as non-immune hydrops: second case report. am j med genet. 2000;93(1):1-4. 25. govaert p, leroy jg, pauwels r, et al. perinatal manifestations of maternal yellow nail syndrome. pediatrics. 1992;89(6 pt 1):1016-1018. 26. desramé j, béchade d, patte jh, et al. yellow nail syndrome associated with intestinal lymphangiectasia [article in french]. gastroenterol clin biol. 2000;24(8-9):837-840. 27. sarmast h, takriti a. yellow nail syndrome resulting from cardiac mitral valve replacement. j cardiothorac surg. 2019;14(1):72. 28. suzuki t, tokuda y, kobayashi h. the development of yellow nail syndrome after the implantation of a permanent cardiac pacemaker. intern med. 2017;56(19):2667-2669. 29. waliany s, chandler j, hovsepian d, boyd j, lui n. yellow nail syndrome with chylothorax after coronary artery bypass grafting. j cardiothorac surg. 2018;13(1):93. 30. wells gc. yellow nail syndrome with familial primary hypoplasia of lymphatics, manifest late in life. proc r soc med. 1966;59(5):447. 31. gupta s, samra d, yel l, agrawal s. t and b cell deficiency associated with yellow nail syndrome. scand j immunol. 2012;75(3):329-335. 32. david-vaudey e, jamard b, hermant c, cantagrel a. yellow nail syndrome in rheumatoid arthritis: a drug-induced disease? clin rheumatol. 2004;23(4):376-378. 33. runyon ba, forker el, sopko ja. pleural-fluid kinetics in a patient with primary lymphedema, pleural effusions, and yellow nails. am rev respir dis. 1979;119(5):821-825. 34. thomas ps, sidhu b. yellow nail syndrome and bronchial carcinoma. chest. 1987;92(1):191. 35. carnassale g, margaritora s, vita ml, et al. lung cancer in association with yellow nail syndrome. j clin oncol. 2011;29(7):e156-e158. 6 review | dermatol pract concept 2020;10(2):e2020031 61. ianaro a, ialenti a, maffia p, et al. anti-inflammatory activity of macrolide antibiotics. j pharmacol exp ther. 2000;292(1):156163. 62. zarogoulidis p, papanas n, kloumis i, et al. macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. eur j clin. pharmacol. 2012;68(5):479-503. 63. hosokawa y, kuboki a, mori a, kanaya h, nakayama t, haruna s. yellow nail syndrome with dramatic improvement of nail manifestations after endoscopic sinus surgery. clin med insights ear nose throat. 2017;10:1179550617718184. using optical profilometry. clin exp dermatol. 1994;19(5):404406. 58. suzuki m, yoshizawa a, sugiyama h, et al. a case of yellow nail syndrome with dramatically improved nail discoloration by oral clarithromycin. case rep dermatol. 2011;3(3):251-258. 59. matsubayashi s, suzuki m, suzuki t, et al. effectiveness of clarithromycin in patients with yellow nail syndrome. bmc pulm med. 2018;18(1):138. 60. ikeda k, wu d, takasaka t. inhibition of acetylcholine-evoked clcurrents by 14-membered macrolide antibiotics in isolated acinar cells of the guinea pig nasal gland. am j respir cell mol biol. 1995;13(4):449-454. dermatology: practical and conceptual research | dermatol pract concept 2020;10(4):e2020094 1 dermatology practical & conceptual an open-label prospective study to compare the efficacy and safety of topical fluticasone versus tacrolimus in the proactive treatment of atopic dermatitis vinodhini r. mudaliyar1, asha pathak1, alok dixit1, sweta s. kumar2 1 department of pharmacology, uttar pradesh university of medical sciences, saifai, etawah, india 2 department of dermatology, uttar pradesh university of medical sciences, saifai, etawah, india key words: topical corticosteroids, topical calcineurin inhibitors, fluticasone propionate, tacrolimus, atopic dermatitis citation: mudaliyar vr, pathak a, dixit a, kumar ss. an open-label prospective study to compare the efficacy and safety of topical fluticasone versus tacrolimus in the proactive treatment of atopic dermatitis. dermatol pract concept. 2020;10(4):e2020094. doi: https:// doi.org/10.5826/dpc.1004a94 accepted: may 14, 2020; published: october 26, 2020 copyright: ©2020 mudaliyar et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. vinodhini r. mudaliyar, department of pharmacology, uttar pradesh university of medical sciences, saifai, etawah, 206130 india. email: drvinodhini14@gmail.com background: atopic dermatitis (ad), a chronic, recurrent inflammatory skin condition primarily affects children. topical treatment, systemic treatment, and phototherapy are mainstays of treatment. topical corticosteroids (tcs) are first-line therapy for ad but are associated with various adverse effects. topical calcineurin inhibitors (tci) can be used as an alternative to tcs. objective: the aim of the study is to compare the efficacy of topical preparations of fluticasone and tacrolimus in reducing the severity of disease and, to assess the quality of life (qol), and to estimate if any association exists between severity of disease and qol. methods: thirty-seven children with ad randomly received one of the 2 topical treatments, with daily application for the first 4 weeks in the acute phase and twice weekly for next 4 weeks in the maintenance phase. the severity of disease was assessed using scoring atopic dermatitis (scorad), and qol was assessed using the children’s dermatology life quality index (cdlqi). results: at the end of the acute phase, there was a reduction in scorad score of 69.29% in the fluticasone group and 64.2% in the tacrolimus group (p < 0.001). in the maintenance phase, the score had risen in the fluticasone group by a mean difference of 0.81, while in the tacrolimus group it decreased by 0.99. both fluticasone and tacrolimus groups improved in children’s qol (p < 0.001). positive correlation (r = 0.4668) exists between scorad and qol. the most common adverse skin reaction noted was skin burning with tacrolimus. conclusions: fluticasone and tacrolimus are equally efficacious in the treatment of ad and have similar benefits with children’s qol. tacrolimus is better than fluticasone at reducing the extent of lesions. abstract 2 research | dermatol pract concept 2020;10(4):e2020094 ad. the secondary objective was to assess the qol, to find the association between severity of disease and qol, and to assess the safety and tolerability of the medications. methods study design the present study was an 8-week, prospective, randomized, and an open-label study conducted on 37 children with ad in the department of pharmacology in collaboration with the department of dermatology, upums saifai, etawah. the study was approved by the institutional ethics committee (ec no. 39/2018), and written informed consent from the childrens’ parents was obtained after explaining the nature of the proposed medical intervention and reasonable consequences of their participation in the study. thirty-seven children who met the inclusion criteria (age 2-16 years of either gender, meeting the hanifin-rajka clinical criteria for the diagnosis of ad [12]) were recruited for the study period of 56 days (a 4-week acute flare-up phase followed by a 4-week maintenance phase). any form of dermatitis other than ad, untreated bacterial, fungal or viral skin lesion, or history of allergic reaction in the past to topical medications employed in this study were excluded. all 37 children were randomly assigned in 1:1 ratio to each group. group 1 (n = 19) received 0.005% fluticasone ointment twice daily and group 2 (n = 18) received 0.03% tacrolimus ointment once daily at night before sleep. in the maintenance phase (n=35), both groups continued the same topical medication twice weekly on 2 consequent nights at bedtime. medicines were applied using the fingertip unit (ftu) method [13]. the primary outcome comparing the efficacy of the 2 drugs was measured by the scoring atopic dermatitis (scorad) index [14]. the scorad index consisted of the description of the extent, intensity, and subjective symptoms. the formula applied for the scorad index was: a/5 + 7b/2 + c. we used a body diagram to analyze the area affected, and the most representative lesion was used for scoring. the intensity element of the scorad index consisted of 6 items: erythema, edema/papules, the effect of excoriations, lichenification, oozing/crust formation, and dryness, and each item had 4 grades: 0, 1, 2, and 3. dryness was assessed in non-inflamed skin. during the last 3 days, subjective items, that included daily pruritus and sleeplessness, were graded on a 10-cm visual analogue scale drawn on the scorad form. the secondary outcome determining the change in the qol after treatment was analyzed by the children’s dermatology life quality index (cdlqi). [15] both scorad and cdlqi scores were noted on the day of enrollment and at the end of weeks 2, 4, 6, and 8. introduction atopic dermatitis (ad) is a chronic, recurrent inflammatory skin condition, characterized by acute flare-ups of pruritic lesions, afflicting 15%-20% of children in developed countries [1]. it has no known cure and adversely affects the quality of life (qol) of patients and their families [2,3]. management of ad includes identifying and eliminating the triggering factors, restoring the skin barrier function, reducing inflammation, and treating secondary infection with antibiotics. among topical treatments there are bathing, emollients, topical corticosteroids (tcs), and topical calcineurin inhibitors (tci) [4]. proper bathing followed by the regular use of skin emollients for restoring hydration and identifying and eliminating trigger factors may be helpful in the treatment of acute flare-ups, but they do not sufficiently suppress the inflammation occurring deep at the molecular level to prevent future exacerbations. topical treatments like tcs [5,6] and tci [7,8] help to reduce inflammation by blocking various inflammatory cytokine productions at different levels of pathophysiology. both tcs and tci are first-line therapy for ad and are proven to be useful in both acute flare-ups and maintenance therapy. however, the major drawback encountered with tcs is the adverse effects associated with chronic use. tci are an excellent alternative with no steroid-related side effects, and they are safer to use on thinner skin [9]. they are either used alone or in combination with tcs and have proven to reduce frequency and severity of flare-ups. although tcs and tci are routinely prescribed topical treatments for ad in outpatient settings, tci are often selected for patients who do not respond to tcs and when the proactive approach is not a routinely followed strategy. available clinical studies neither reflect the common clinical practice nor the need for long-term treatment of ad in the indian population. a study by berth-jones et al [10] compared different formulations of fluticasone with placebo in a 16-week proactive regimen. after the amelioration in the acute phase, the risk of ad flare was 1.9 times lower with fluticasone ointment than under placebo. breneman et al [11] in a randomized study tested the proactive use of tacrolimus 0.03% ointment 3 times weekly in children that showed a longer median flare-free period in the proactive treatment group than in the control group. the differences in the study population, drug application schedule, and study duration make a direct comparison with various drugs a difficult task. we chose to study tcs and tci as first-line treatment both for reactive and proactive therapy. we divided our study into 2 phases in order to assess the efficacy and safety of topical treatment in the acute flare-up phase followed by a 4-week maintenance phase. the primary objective of the study was to compare the efficacy of topical preparations of 0.005% fluticasone versus 0.03% tacrolimus ointment in the treatment of research | dermatol pract concept 2020;10(4):e2020094 3 results table 1 shows the baseline demographic data pf gender details, age-wise distribution of cases, extent, intensity, subjective symptoms, scorad and qol scores. we screened a total of 37 children with moderately active ad. the mean ±sd age of all 37 children recruited for the study was 10.13 ±3.61 years. group wise (mean ± sd) age was 9.84 ± 3.78 years and 10.44 ± 3.50 years with no significant difference between groups. approximately 81% of children with ad had a personal or family history of atopy. at the end of statistics age and gender values of recruited children were analyzed with the chi-square test. data analysis for efficacy, as measured by scorad and qol of ad children using the cdlqi index, was performed by repeated measures anova. the association between scorad and cdlqi was conducted by pearson’s correlation and linear regression. the analysis was conducted on spss software, and a p value of <0.05 was considered statistically significant. table 1. demographic and disease characteristics in children with atopic dermatitis treatment groups fluticasone group (n=19) tacrolimus group (n=18) male:female 12:7 9:9 2-5 years (m/f) 2/2 1/1 6-10 years (m/f) 4/3 2/5 ≥11 years (m/f) 6/2 6/3 age years ± sd 9.84 ± 3.78 10.44 ± 3.50 affected sites—number of children that presented the body area involved in ad head and neck 8 3 extremities 15 14 trunk and back 13 15 genitals 3 3 total affected bsa bsa ± sd 37.57 ± 8.94 36.66 ± 10.35 0 to ≤25% 2 0 >25 to ≤50% 13 3 >50 to ≤75% 4 9 >75 to ≤100% 0 6 severity of ad scorad 38.75 ± 4.13 36.60 ± 4.45 mild (<25) 1 2 moderate (25 to ≤50) 16 14 severe (>51) 2 2 intensity erythema 1.78 ± 0.71 1.55 ± 0.70 edema/papules 0.89 ± 0.73 0.66 ± 0.59 oozing/crusting 0.78 ± 0.63 0.88 ± 0.67 excoriation 0.63 ± 0.76 0.55 ± 0.61 lichenification 0.52 ± 0.51 0.50 ± 0.70 dryness 1.84 ± 0.68 1.83 ± 0.51 subjective symptoms pruritus 6.10 ± 0.99 5.83 ± 0.70 sleeplessness 6.00 ± 0.94 6.05 ± 0.63 (table 1 continues) 4 research | dermatol pract concept 2020;10(4):e2020094 treatment groups fluticasone group (n=19) tacrolimus group (n=18) quality of life cdlqi 10.05 ± 4.27 10.77± 3.84 none or small 11 9 moderate 8 9 severe 0 0 domains of the cdlqi symptoms/feelings 3.10 ± 1.24 3.05 ± 1.25 leisure 2.05 ± 1.80 2.44 ± 1.58 school/holidays 0.84 ± 0.68 0.83 ± 0.78 relationships 2.00 ± 1.41 2.22 ± 1.00 sleep 1.73 ± 0.80 1.44 ± 0.61 treatment 0.31 ± 0.47 0.77 ± 0.64 medical history—number (%) of children with known trigger factors personal and family history of atopy 15 (78.94) 15 (83.33) seasonal variations (%) 11 (57.89) 12 (66.66) comparable. in the acute phase treatment, there was a reduction in the scorad by 42.60% and 69.29% at weeks 2 and 4 visits respectively when compared to baseline in the fluticasone group and by 42.34% and 64.20% in the tacrolimus group. significant reductions (p < 0.001) were observed in both scorad and cdlqi at week 2 and at end of the acute phase in both treatment groups. in the maintenance phase, no significant change in scorad was observed in either of the acute phase, 35 children entered into the 4-week maintenance phase; 2 children from group 1 discontinued the study, as they were satisfied with lesion improvements and did not show interest in continuing the treatment for one additional month. figures 1 and 2 show the changes in scorad and cdlqi in both groups. the intergroup comparison of scorad and cdlqi at respective baseline and all follow-up intervals were table 1. demographic and disease characteristics in children with atopic dermatitis (continued) ad = atopic dermatitis; bsa = body surface area; scorad = scoring atopic dermatitis; cdlqi = children’s dermatology life quality index. figure 1. changes in scorad in both treatment groups at week 0 (baseline), 2, 4 (end of acute phase), 6, and 8 (end of maintenance phase) [mean ± sem]. scorad = scoring atopic dermatitis. research | dermatol pract concept 2020;10(4):e2020094 5 subjective scores at all follow-up visits in both treatment groups. in the maintenance phase, a significant mean difference for subjective symptoms was observed within the tacrolimus group at week 6. figure 5 shows the association between the severity of the disease (scorad) and cdlqi. the analysis revealed statistical significance with p = 0.004, indicating the existence of a positive moderate correlation (r = 0.4668) between the 2 instruments. the most common adverse drug reaction (adr) was a sensation of skin burning. it was observed in 3 (8%) of all children receiving tacrolimus. no adr was found with the use of fluticasone. the treatment groups. however, the change in cdlqi was significant (p < 0.05) at week 8 when compared to baseline (week 4) within the fluticasone group, and in the tacrolimus group the change was significant at weeks 6 and 8 when compared to baseline (p < 0.05). figures 3 and 4 show changes in the body surface area (bsa) and subjective scores. the mean extent of lesions and subjective symptoms at the time of recruitment was comparable between both treatment groups. however, there was significant (p < 0.05) reduction in the tacrolimus group at week 8 than in the fluticasone group. at the end of the acute phase, there was significant reduction of mean extent and figure 2. changes in cdlqi in both treatment groups at week 0 (baseline), 2, 4 (end of acute phase), 6, and 8 (end of maintenance phase) [mean ± sem]. cdlqi = children’s dermatology life quality index. figure 3. changes in the extent of lesions (bsa) in both treatment groups at week 0 (baseline), 2, 4 (end of acute phase), 6, and 8 (end of maintenance phase) [mean ± sem]. bsa = body surface area. 6 research | dermatol pract concept 2020;10(4):e2020094 begin early in age. about 65% develop symptoms at 1 year of age, and 90% of affected individuals are younger than 5 years [17]. the disparity in the age of presentation in our study could be due to the inclusion criteria of recruiting children younger than 2 years of age. the present study found that both treatment groups had a significantly reduced scorad as early as week 2. at week 2 follow-up, only 1 child had moderate ad in the fluticasone group. in the rest of the children, scorad had decreased into the mild severity range. the results of this study show that both fluticasone and tacrolimus had similar efficacy in the acute treatment phase. in the maintenance phase, the scorad had risen in the fluticasone group by a mean difference of 0.8, while in tacrolimus it decreased by 0.99. due to the lack of head-to-head comparison of tcs and tci, it was difficult for us to compare our results with previous reports. however, our result is comparable to the longer median time to flare-up seen in 2 studies using fluticasone and tacrolimus separately [10,11] at approximately 16 weeks with use of fluticasone and 24 weeks with tacrolimus ointment. however, the disease severity in our study population was maintained in low range in both treatment groups, and there were no flare-up events observed within 8 weeks. clinically and statistically speaking, the difference in scorad was not significant in the present study, and it can be concluded that both treatments are efficacious during the intermittent maintenance phase to prevent acute exacerbations. a randomized, multicenter study determining the antipruritic efficacy of 0.03% topical tacrolimus (for children <16 years old) and 0.1% (for adults >16 years old) reported discussion this study evaluates the efficacy of an intermediate potent tcs, fluticasone 0.005% ointment and a tci, tacrolimus 0.03% ointment for treatment of moderate to severe ad in indian children. in this study, we included a total of 37 children with moderately active ad. the boy-to-girl ratio in the present study was 1.31:1, which is comparable to a clinico-epidemiological study of ad in north india, where male predominance was noted with 2.25:1 in infants and 1.3:1 in children [16]. the age distribution within 0-5 years, 6-10 years, and ≥11 years were 4, 7, 8 and 2, 7, 9 children in the 2 groups respectively. there was a greater proportion of children within the ≥ 11-years age group, although the disease is known to figure 4. changes in the subjective symptoms in both treatment groups at week 0 (baseline), 2, 4 (end of acute phase), 6, and 8 (end of maintenance phase) [mean ± sem]. figure 5. association between scoring atopic dermatitis (scorad) and children’s dermatology life quality index (cdlqi). research | dermatol pract concept 2020;10(4):e2020094 7 most episodes of a skin-burning sensation lasted less than 15 minutes. similarly, most episodes of pruritus lasted less than 2 hours. limitations our study has certain limitations, and the findings in this study should be interpreted with caution. first, the study had no wash-out period, and the drugs were initiated on the first visit to the outpatient department once the diagnosis was made. second, since the scoring system used for outcome measures included objective and subjective symptoms, the final score may have been influenced by parents, guardians, or by the children themselves. furthermore, we did not estimate cost effectiveness. the other shortcomings of the study are the small sample size and short study duration in the maintenance phase. thus, it is not possible to convincingly comment on time to flare-up and the long-term safety of both treatments. another demerit is that it was an open label study. a longer duration, single or double-blind study, and a larger sample size would be helpful in covering these shortcomings. conclusions both fluticasone and tacrolimus are equally efficacious in reducing severity of disease and preventing flare-ups in children suffering from moderate to severe ad. at week 8, tacrolimus is more efficacious than fluticasone in improving the extent of ad. however, in both groups the fluticasone and tacrolimus were equally efficacious in reducing subjective scores and improving qol in ad patients. positive correlation exists between the severity of the disease and children’s quality of life. references 1. williams h, robertson c, stewart a, et al. worldwide variations in the prevalence of symptoms of atopic dermatitis in the international study of asthma and allergies in childhood. j allergy clin immunol. 1999;103(1 pt 1):125-138. doi: 10.1016/ s0091-6749(99)70536-1. 2. su jc, kemp as, varigos ga, nolan tm. atopic eczema: its impact on the family and financial cost. arch dis child. 1997;76(2):159-162. doi: 10.1136/adc.76.2.159. 3. filanovsky mg, pootongkam s, tamburro je, smith mc, ganocy sj, nedorost st. the financial and emotional impact of atopic dermatitis on children and their families. j pediatr. 2016;169:285-290. doi: 10.1016/j.jpeds.2015.10.077. 4. rajagopalan m, de a, godse k, et al. guidelines on management of atopic dermatitis in india: an evidence-based review and an expert consensus. indian j dermatol. 2019;64(3):166181. doi: 10.4103/ijd.ijd_683_18. 5. ahluwalia a. topical glucocorticoids and the skin—mechaa mean scorad decrease from 29.1 to 17.3 with a mean difference of 11.8 (p < 0.0001) after 4 weeks [18]. in another study where 0.1% tacrolimus ointment was given twice a day, the drug showed 20.72% and 64.05% reduction in scorad at the end of weeks 2 and 4 respectively [19]. the efficacy in our study was approximately the same at week 4. however, at week 2, we had a greater scorad reduction by a difference of 21.62%. similarly, the scorad reduction was greater by a difference of 23.65% at week 4 compared to the earlier study. the disparity in the results could be due to the different concentrations of ointment used and the selection of the study population. in a study conducted by doss et al [20] on 479 children with ad who had responded insufficiently to conventional tcs treatment, fluticasone 0.005% ointment and tacrolimus 0.03% ointment were used as second-line treatment. the response rate was 86.3% in the tacrolimus group and 91.5% in the fluticasone group at day 21. this result was comparable to our study, as we had an approximately equal reduction in severity between both treatment groups. ad is known to affect the qol of patients and their family members. a majority of studies use scorad, but there are limited studies that try to find the association between severity of disease and qol. the present study tried to assess the qol of children and analyze the association between the severity of the disease and children’s qol. the association between the scorad and cdlqi indices showed reasonable positive moderate correlation (r = 0.4668) with p = 0.004. a similar study done by kim et al [21] showed positive correlation between the scorad index and cdlqi (r = 0.312, p = 0.039). another study by bezerra campos et al [22] found significant positive correlation (r = 0.68, p < 0.001) between severity of disease and qol of pediatric patients with ad. our study had similar comparable results and indicates the importance of including the assessment of qol as an objective to the clinical analysis. the result of the present study demonstrates that the qol is related to the severity of ad. the higher the scorad, the poorer the qol; therefore, early management of ad may help improve the qol of ad patients. in addition to medical management, psychological support may improve the longterm physical and emotional outcomes of all ad sufferers. the qol of children improved dramatically in both the treatment groups and continued to improve even through the maintenance phase. in our study, of all children with ad, 3 (8%) of those receiving tacrolimus treatment developed adr. the adr observed was a mild and transient application site reaction. in a 12-week study of both 0.03% and 0.1% tacrolimus by paller et al [23], the most common adrs observed were application site reactions, particularly skin burning and pruritus. they appeared during the first few days and then declined. 8 research | dermatol pract concept 2020;10(4):e2020094 15. lewis-jones ms, finlay ay. the children’s dermatology life quality index (cdlqi): initial validation and practical use. br j dermatol. 1995;132(6):942-949. doi: 10.1111/j.13652133.1995.tb16953.x. 16. sarkar r, kanwar aj. clinico-epidemiological profile and factors affecting severity of atopic dermatitis in north indian children. indian j dermatol. 2004;49(3):117-122. 17. sampson ha. atopic dermatitis. in: feigin rd, oski fa, deangelis c, eds. oski’s pediatrics principles & practice. 4th ed. lippincott williams & wilkins; 2006:2423-2424. 18. takeuchi s, saeki h, tokunaga s, et al. a randomized, open-label, multicenter trial of topical tacrolimus for the treatment of pruritus in patients with atopic dermatitis. ann dermatol. 2012;24(2):144-150. doi: 10.5021/ad.2012.24.2.144 19. pacor ml, di lorenzo g, martinelli n, mansueto p, rini gb, corrocher r. comparing tacrolimus ointment and oral cyclosporine in adult patients affected by atopic dermatitis: a randomized study. clin exp allergy. 2004;34(4):639-645. doi: 10.1111/j.1365-2222.2004.1907.x 20. doss n, kamoun mr, dubertret l, et al. efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized double-blind, non-inferiority trial vs. fluticasone 0.005% ointment. pediatr allergy immunol. 2010;21(2 pt 1):321-329. doi: 10.1111/j.1399-3038.2009.00895.x. 21. kim dh, li k, seo sj, et al. quality of life and disease severity are correlated in patients with atopic dermatitis. j korean med sci. 2012;27(11):1327-1332. doi: 10.3346/ jkms.2012.27.11.1327 22. bezerra campos al, moreira de araujo f, lopes dos santos ma, de assis santos dos santos a, avelar pires ca. impact of atopic dermatitis on the quality of life of pediatric patients and their guardians. rev paul pediatr. 2017;35(1):5-10. doi: 10.1590/1984-0462/;2017;35;1;00006. 23. paller a, eichenfield lf, leung dy, stewart d, appell m. a 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. j am acad dermatol. 2001;44(1 suppl):s47-s57. doi: 10.1067/mjd.2001.109813. nisms of action: an update. mediators inflamm. 1998;7(3):183193. doi: 10.1080/09629359891126. 6. altura bm. role of glucocorticoids in local regulation of blood flow. am j physiol. 1966;211(6):1393-1397. doi: 10.1152/ajplegacy.1966.211.6.1393. 7. eichenfield lf, tom wl, berger tg, et al. guidelines of care for the management of atopic dermatitis: section 2. management and treatment of atopic dermatitis with topical therapies. j am acad dermatol. 2014;71(1):116-132. doi: 10.1016/j. jaad.2014.03.023. 8. rico mj, lawrence i. tacrolimus ointment for the treatment of atopic dermatitis: clinical and pharmacological effects. allergy asthma proc. 2002;23(3):191-197. pmid: 12125507. 9. billiach a, aschauer h, aszodi a, steutz a. percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus. int j pharm. 2004;269(1):29-35. doi: 10.1016/j.ijpharm.2003.07.013. 10. berth-jones j, damstra rj, golsch s, et al. twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. bmj. 2003;326(7403):1367. doi: 10.1136/ bmj.326.7403.1367. doi: 10.1136/bmj.326.7403.1367. 11. breneman d, fleischer ab, abramovits w, et al. intermittent therapy for flare prevention and long-term disease controlled in stabilized atopic dermatitis: a randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle. j am acad dermatol. 2008;58(6):990-999. doi: 10.1016/j.jaad.2008.02.008. 12. hanifin jm, rajka g. diagnostic features of atopic dermatitis. acta dermatovener (stockholm). 1980;92:44-47. 13. finlay ay, williams ay, harding kg. “fingertip unit” in dermatology. lancet. 1989;2:155. doi: 10.1016/s01406736(89)90204-3. 14. kunz b, oranje ap, labreze l, stalder jf, ring j, taieb a. clinical validation and guidelines for the scorad index: consensus report of the european task force on atopic dermatitis. dermatology. 1997;195(1):10-19. doi: 10.1159/000245677. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):7 43 dermatology practical & conceptual www.derm101.com it has been observed that a patient’s “normal” moles resemble each other clinically. this concept also applies to dermoscopic observations, as shown by our previous demonstration that an individual’s nevi tend to have one to three predominant overall dermoscopic patterns [1]. a recent study investigated and compared the dermoscopic patterns of multiple primary melanomas (mpms) in a large series of patients [2]. the authors showed that mpms of elderly patients with sun-damaged skin were often dermoscopically similar in pigment network and regression structures. this observation is intriguing because it suggests that a rule valid for the nevi of an individual (all nevi have a similar dermoscopic pattern, typical or otherwise), may also be valid for melanomas: i.e., in a given individual, melanomas in similar anatomical sites have similar dermoscopic patterns [3]. however, the authors mainly assessed thin melanomas and admitted this as a limitation of their study: “thin and superficial spreading melanomas were predominant in our study population.” in the last five years we had the opportunity of observing five patients over 70 years of age with multiple melanomas (multifocal), thicker than 2 mm, located in photo-damaged areas (figure 1-4) (table 1). we evaluated the dermoscopic images of these pigmented skin lesions retrospectively. the images were taken using a photo camera equipped with a polarized contact dermoscope (dermlite® photo 3gen, san juan capistrano, ca, us). all images were analyzed by an expert dermoscopist (p.r.). lesions were evaluated for eight dermoscopic features, as reported in table 1. as suggested by moscarella et al. [2], similar appearance was defined as the same dermoscopically detected features with similar scores and/or with a difference in only one minor feature (a feature present in less than 10% of the lesion). different appearance was defined as different dermoscopically detected features with different scores in all melanomas of a given patient. features in a given lesion were quantified as present in < 10%, 10-50% and > 50% of the lesion. five patients (3 males) with a total of 12 melanomas were collected from the databases of three skin clinics. age ranged from 70 to 84 years (mean 76.6 years). three patients (60%) had two, and two patients (40%) had three primary melanomas. mean breslow thickness was 2.8 mm. as reported in table 2, in all our cases, the melanomas of a given patient shared very similar dermoscopic features and scores (table 2) (fig 1 a, b, c). we classified patients as having melanomas with similar or different dermoscopic features on multiple primary thick melanomas: similar dermoscopic pattern luca feci1, michele fimiani1, pietro rubegni1 1 department of clinical medicine and immunological sciences, dermatology section, university of siena, siena, italy keywords: dermoscopy, melanoma, multiple melanomas citation: feci l, fimiani, rubegni p. multiple primary thick melanomas: similar dermoscopic pattern. dermatol pract concept. 2014;4(3):7. http://dx.doi.org/10.5826/dpc.0403a07 received: october 3, 2013; accepted: march 18, 2014; published: july 31, 2014 copyright: ©2014 feci et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. pietro rubegni, dept. of clinical medicine and immunological science—dermatology section, policlinico “le scotte” viale bracci—53100 siena, italy. tel. +39 0577 40190. e-mail: rubegni@unisi.it 44 observation | dermatol pract concept 2014;4(3):7 dr. pietro rubegni provided substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data; dr. luca feci and dr. pietro rubegni drafted the article and revised it critically for intellectual content; prof. michele fimiani provided final approval of the version to be published. the basis of lesion scores. in particular, 4/5 patients (80%) showed melanomas that were dermoscopically similar, and 1/5 (20%) had melanomas that were dermoscopically different. in line with the experience described in moscarella et al., our results suggest that the principles valid for nevi of a given individual (all nevi have similar dermoscopic pattern, typical or otherwise) might also be valid for thick and thin melanomas [3]. however, thick melanomas may tend to be similar by nature. although our case series is too small for any statistical analysis, our preliminary results seem to corroborate the results of moscarella and colleagues. figure  1. (a) clinical appearance of two similar synchronous melanomas occurring on the back of a 77-year-old man; (b & c) dermoscopic images of the melanomas: breslow thickness 3.1 mm (b) and 2.2 mm (c). the lesions had the same dermoscopic features: atypical pigmented network, regression structures (chrysalis), eccentric globules, atypical vascular pattern and blue/white veil. [copyright: ©2014 feci et al.] figure 2. (a) clinical appearance of two similar synchronous melanomas occurring on the back of a 74-year-old man; (b & c) dermoscopic images of the melanomas: breslow thickness 3.8 mm (b) and 2.4 mm (c). the lesions had the same dermoscopic features characterized by blue/white veil, structureless areas and regression structures. [copyright: ©2014 feci et al.] figure  3. two similar melanomas occurring one on the back (a) and one on the left lower leg (b) of a 70-year-old woman; (a & b) dermoscopic images of the melanomas: breslow thickness 3.5 mm (a) and 2.7 mm (b). the lesions had the same dermoscopic features characterized by blue/white veil, structureless areas and regression structures. [copyright: ©2014 feci et al.] figure 4. three similar melanomas occurring two on the back (a, b) and one on the right lower leg (c) of a 78-year-old man; (a, b, c) dermoscopic images of the melanomas: breslow thickness 3.0 mm (a), 2.2 mm (b) and 2.4 mm (c). the lesions had the same dermoscopic features characterized by blue/white veil, structureless areas, streaks and peripheral globules more evident in figures b and c. [copyright: ©2014 feci et al. observation | dermatol pract concept 2014;4(3):7 45 table 1. dermographic data of the patients [copyright: ©2014 feci et al.] name sex age (years) location type of melanoma thickness of melanoma (mm) a.m. m 77 1) trunk 2) trunk 1) invasive superficial spreading melanoma 2) invasive superficial spreading melanoma 1) 3.1 2) 2.2 l.r. m 74 1) trunk 2) trunk 1) nodular melanoma 2) nodular melanoma 1) 3.8 2) 2.4 n.f. f 70 1) trunk 2) lower leg 1) invasive superficial spreading melanoma 2) invasive superficial spreading melanoma 1) 3.5 2) 2.7 m.m. f 84 1) trunk 2) trunk 3) upper harm 1) invasive superficial spreading melanoma 2) invasive superficial spreading melanoma 3) invasive superficial spreading melanoma 1) 3.1 2) 3.0 3) 2.2 c.r. m 78 1) trunk 2) trunk 1) lower leg 1) invasive superficial spreading melanoma 2) invasive superficial spreading melanoma 3) invasive superficial spreading melanoma 1) 3.0 2) 2.2 3) 2.4 table 2. evaluation and scores of the dermoscopic features [copyright: ©2014 feci et al.] % of the feature network (%) inverse network (%) regression structures (%) dots/ globules (%) structureless (%) vascular pattern (%) blue/ white veil (%) streaks (%) < 10% 6 (42.8) 2 (14. 2) 1 (8.3) 3 (21.4) 1 (8.3) 2 (14.2) 0 5 (35.7) 10-50% 4 (28.6) 0 6 (50) 1 (7.1) 5 (41.7) 6 (42.8) 3 (25) 2 (14.2) > 50% 0 0 5 (41.7) 0 6 (50) 5 (35.7) 9 (75) 0 total 10 (71.4) 2 (14.2) 12 (100) 4 (28.6) 12 (100) 13 (92.8) 12 (100) 7 (50) references 1. scope a, burroni m, agero al, et al. predominant dermoscopic patterns observed among nevi. j cutan med surg. 2006;10:170-4. 2. moscarella e, rabinovitz h, puig s, et al. multiple primary melanomas: do they look the same? br j dermatol. 2013;168:1267-72. 3. burroni m, dell’eva g, corona r, et al. interand intra-variability of pigmented skin lesions: could the abcd rule be influenced by host characteristics? skin res technol. 2004;10:193-9. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020097 1 dermatology practical & conceptual introduction penile cancer is an uncommon cancer in western countries, accounting for 0.4%0.6% of total malignancies. it is more common in asian countries and consists of 6% of total malignancies in india. it is more common in uncircumcised men, and the prevalence increases with age. phimosis, human papillomavirus, poor hygienic practice, uncircumcised state, lichen sclerosus et atrophicus (lsa), balanitis, penile trauma, and smoking are considered risk factors for penile cancer [1]. there is a delay in diagnosis, as it does not interfere with voiding and erectile function in its initial stage and the associated embarrassment due to its location. case presentation a 58-year-old male, who is a chronic tobacco chewer, presented with insidious onset of a gradually progressive painless ulceroproliferative growth over the glans penis of 1year’s duration. there was history of difficulty with voiding and sexual intercourse over the previous 2 months. there was no history suggestive of lsa. examination revealed phimosis and an ulceroproliferative growth measuring 2 × 2 cm over the glans penis. the growth was firm and displaced the urethral meatus (figure 1). bilateral inguinal lymphadenopathy was present. dermoscopy of the lesion showed polymorphic vessels (linear, coiled, hairpin, dotted, and corkscrew), white clods, and structureless white areas (figure 2.) a 54-year-old male, who is a chronic bidi smoker, presented with a painless ulceroproliferative growth over the glans penis of 6 months’ duration. the examination revealed an exophytic growth over the glans penis measuring 3 × 2 cm over the superior aspect of the glans and under the surface of the prepuce (figure 3). dermoscopy showed white structureless area, white clods, blood spots, erosion, and polymorphic vessels (figure 4). histopathology in both cases was consistent with moderately differentiated squamous cell carcinoma (scc) (figure 5). conclusions dermoscopy of invasive scc shows the presence of keratin and vascular features. keratin appears as white-to-yellow two cases of squamous cell carcinoma of the penis – a dermoscopic view shekhar neema1, s. radhakrishnan1, pratik kinra2, sunmeet sandhu1 1 department of dermatology, armed forces medical college, pune, india 2 department of pathology, armed forces medical college, pune, india key words: squamous cell carcinoma, penis, dermoscopy citation: neema s, radhakrishnan s, kinra p, sandhu s. two cases of squamous cell carcinoma of the penis—a dermoscopic view. dermatol pract concept. 2021;11(1):e2020097. doi: https://doi.org/10.5826/dpc.1101a97 accepted: june 7, 2020; published: december 10, 2020 copyright: ©2020 neema et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: shekhar neema, md, febdv, department of dermatology, armed forces medical college, wanowrie, pune, maharashtra 411040, india. email: shekhardvait@gmail.com 2 letter | dermatol pract concept 2021;11(1):e2020097 structureless areas, white circles (opaque center surrounded by a white halo), and white clods. the white circles correlate histopathologically with dilated infundibulum filled with keratin and the white clods to intraepidermal keratin pearls. the amount of keratin depends on the degree of differentiation. vascular features that can be seen are dotted vessels, glomerular vessels, linear irregular, hairpin, comma, or corkscrew vessels. in the event that one type of vessel morphology predominates, it is either monomorphic or polymorphic. the vessels can have specific arrangements, such as in the clustered arrangement in erythroplasia of queyrat, which is the genital counterpart of bowen disease [2]. the vessel morphology depends on tumor volume; dotted vessels are seen in intraepidermal carcinoma, while invasive scc shows linear vessels. other features are erosion, blood spots, and crust. the specificity of the white circle for diagnosis of cutaneous scc is 87%, but it may not be visible on sites where hair follicles are absent in patients with scc of the glans. though keratin and vascular features on dermoscopy are common in figure 1. ulceroproliferative growth measuring 2 × 2 cm over the right side of the glans penis. phimosis and edema of the prepuce can be appreciated. figure 2. dermoscopy shows dotted vessels (green arrow), linear vessels (blue arrow), hairpin vessels (orange arrow), corkscrew vessels (blue star), and serpentine vessels (orange star). white clods (blue circle) and white structureless areas (blue square) can be seen (dino-lite edge, polarized ×100). figure 3. ulceroproliferative growth measuring 3 × 2 cm over the glans penis. the surface shows purulent discharge and fine vessels. figure 4. dermoscopy shows a white structureless area (blue circle), linear vessels (blue arrow), hairpin vessels (yellow arrow), corkscrew vessels (blue star) and blood spots (green arrow) (dino-lite edge, polarized ×100). figure 5. histopathology shows nests and sheets of tumor cells showing nuclear pleomorphism, dilated vascular channels, and keratin pearl formation (h&e, ×10). letter | dermatol pract concept 2021;11(1):e2020097 3 destefano v. epidemiology and natural history of penile cancer. urology. 2010;76(2, suppl 1):s2–6. doi: 10.1016/j. urology.2010.03.003. pmid: 20691882 2. kamat d, vinay k. dermatoscopy of nonvenereal genital dermatoses: a brief review. indian j sex transm dis aids. 2019;40(1):13-19. doi: 10.4103/ijstd.ijstd_20_19. pmid: 31143854. all forms of scc, the specific dermoscopy features of white circles are not visible in scc of the glans, and diagnosis rests on the presence of vascular features and white clods. references 1. p o w s a n g m r , f e r r e i r a u , p o w s a n g j m , n a r d i a c , dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020080 1 dermatology practical & conceptual introduction genotrichoses are difficult to diagnose and pose a diagnostic and therapeutic challenge in most cases. accurate diagnosis of genotrichoses with hair shaft defects mandates utilization of polarized or electron microscopy. trichoscopy, the dermoscopy of hair and scalp diseases, is a well-established diagnostic technique for common hair disorders. recently its applications have been extended to genotrichoses [1]. trichoscopy is useful in genotrichoses presenting with hair shaft defects such as trichorrhexis nodosa, trichorrhexis invaginata, pili annulati, and monilethrix [2]. here we describe the importance of trichoscopy, which assisted in the diagnosis of a hair shaft disorder in a teenage girl. case presentation a 17-year-old girl, born out of a non-consanguineous marriage, presented with increased hair loss, frizzy rough hair, and an inability to grow hair beyond shoulder length since childhood (figure 1, a and b). she had received biotin supplements and 2% minoxidil topical solution in the past with no response. examination revealed short, lusterless, fragile hair with easy breakability. a hair pull test was negative; however, the hair broke easily along its shaft. skin, teeth and nails were normal. systemic examination was unremarkable. family history and past history were noncontributory. loose anagen hair syndrome and short anagen hair syndrome were considered as differentials. trichoscopic examination, with illuco ids-1000 with ×10 magnification, showed regular variations in the diameter of the hair shaft with elliptical nodes separated by internodes. hair casts and white scales in follicular and interfollicular areas were also noted (figure 2, a and b). trichoscopy of eyebrows was normal. microscopic examination was suggestive of monilethrix. conclusions monilethrix, a rare autosomal dominant disorder with variable expression, is characterized by fragility of hair and inability to grow in length. scalp, eyebrows, axillary, and pubic hairs are affected with associated follicular keratotic papules [2]. affected individuals have normal hair at birth with hair changes manifest in early childhood. clinically it hair shaft defect in a teenage girl: trichoscopy saves the day! balachandra s. ankad1, samipa s. mukherjee2 1 department of dermatology, s. nijalingappa medical college, bagalkot, karnataka, india 2 pediatric dermatology, cloudnine hospital, bengaluru, india key words: trichoscopy, monilethrix, diagnosis, genotrichoses citation: ankad bs, mukherjee ss. hair shaft defect in a teenage girl: trichoscopy saves the day! dermatol pract concept. 2021;11(1):e2020080. doi: https://doi.org/10.5826/dpc.1101a80 accepted: may 6, 2020; published: december 7, 2020 copyright: ©2020 ankad and mukherjee. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. balachandra s. ankad, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587102, karnataka, india. email: drbsankad@gmail.com 2 letter | dermatol pract concept 2021;11(1):e2020080 was made in this study. furthermore, prominent scales located in the perifollicular and interfollicular areas and hair casts were noted and were attributed to the lack of proper washing by the patient because of fear of losing hairs. it should be noted here that with no family history, absence of keratotic papules, late onset of symptoms, and the presence of frizzy, lusterless, and non-growing hairs, loose anagen hair syndrome, short anagen hair syndrome and weathering of hair nevertheless, trichoscopic examination clinched the diagnosis of monilethrix. presents with dull, lusterless, fragile short hairs. trichoscopy shows regularly placed nodes and internodes along the shaft that give the characteristic beaded appearance. elliptical nodes have normal hair diameter, medulla, and normal cortical cells, whereas internodes are narrower and are devoid of medulla with a lower number and wrinkling of cortical cells making them the site of fracture [1]. due to multiple fractures, hair shafts are bent regularly at multiple locations with a tendency to curve in different directions producing a “regularly bended ribbon sign” [1]. a similar observation figure 1. (a) clinical image of a teenage girl with dry, lusterless, and frizzy hair on the frontal area. (b) clinical image of the occipital area showing dry, lusterless, and frizzy hair. note that hairs are not growing beyond the neck and shoulders. a b figure 2. (a) trichoscopy of monilethrix shows regular distribution of nodes (yellow arrows) and internodes (red arrows). note that medulla is present in nodes and absent in internode segments. regrowing hair (pigtail hair; blue arrow), perifollicular scales (purple arrows), and interfollicular scales (red stars) are well appreciated. (b) trichoscopy of monilethrix shows regular distribution of nodes (yellow arrows) and internodes (red arrows). hair casts (blue arrows) and perifollicular casts (purple arrows) are well appreciated. a b letter | dermatol pract concept 2021;11(1):e2020080 3 references 1. rudnicka l, olszewska m, rakowska a, slowinska m. trichoscopy update 2011. j dermatol case rep. 2011;5(4):8288. doi: 10.3315/jdcr.2011.1083. pmid: 22408709. 2. holani ar, haridas ns, shah ng, chaudhari n. monilethrix: a rare case diagnosed by dermoscopy. indian j paediatr dermatol. 2019; 21(1):56-58. doi: 10.4103/ijpd.ijpd_78_19. pmid: 22408709. although the management of monilethrix remains challenging, the use of a trichoscope for the diagnosis of this rare and unsuspicious condition is noteworthy. it is not only diagnostic, but it also helps in differentiating monilethrix from other similar conditions such as monilethrix-like hair. dermatology: practical and conceptual review | dermatol pract concept 2020;10(3):e2020033 1 dermatology practical & conceptual introduction melanoma is a tumor with high impact through its rapidly growing incidence, high mortality, and increased complexity and costs of care in advanced stages. research efforts are fervently unfolding worldwide to shift its diagnosis toward earlier stages, to prevent its occurrence, and to develop breakthrough treatments. avid observation of the epidemiological data and trends is ongoing, to capture the first success signs of these initiatives through the changes in melanoma incidence or mortality, and to scour for clues for new risk factors or prognostic markers. epidemiological data are explosively accumulating through the continuous improvement and expansion of cancer registries. the digital age offers unprecedented facility of data collecting, sharing, and comparing across countries, regions, and centers. the picture of melanoma burden in europe melanoma epidemiology and early detection in europe: diversity and disparities ana-maria forsea1 1 oncologic dermatology department, elias university hospital; carol davila university of medicine and pharmacy, bucharest, romania key words: melanoma, epidemiology, early detection, disparities, europe citation: forsea am. melanoma epidemiology and early detection in europe: diversity and disparities. dermatol pract concept. 2020;10(3):e2020033. doi: https://doi.org/10.5826/dpc.1003a33 accepted: november 20, 2019; published: june 29, 2020 copyright: ©2020 forsea. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: ana-maria forsea, md, phd, oncologic dermatology department, elias university hospital; carol davila university of medicine and pharmacy, 17 marasti bvd. sector 1 bucharest, romania. email: aforsea@yahoo.com melanoma claims annually more than 20,000 lives in europe and is an important public health burden through its continuously increasing incidence and with its high mortality, costs, and complexity of care in advanced stages. epidemiological surveillance is indispensable for the research into its causes, new prognostic markers, and innovative therapies, as well as for the building of efficient cancer control plans. however, important differences in the sources and availability of accurate epidemiological data exist among european countries and regions, contributing to a heterogeneous picture with 20-fold differences in the reported national melanoma incidence rates, divergent mortality trends, and solid disparities in survival across the continent. countries in the eastern half of europe report the lowest incidence rates, but high case fatality, persisting and increasing mortality, a higher proportion of thicker tumors and late diagnosis, and lower survival rates. they are the least well equipped with quality cancer registration and reporting, and they lag behind in efficient cancer control plans implementation. this review highlights the main differences in melanoma epidemiology across europe, together with an insight into their underlying causes in the areas of melanoma registration, early diagnosis, and prevention. these differences should be acknowledged and understood by physicians, researchers, and all stakeholders involved in improving melanoma care and outcomes, as no one-size-fits-all solution can tackle the melanoma problem in europe. instead, there is a need for nuanced strategies, adapted to the heterogeneous national and regional contexts, that would build on european diversity to eliminate the outcome disparities. abstract https://doi.org/10.5826/dpc.1002a33 mailto:aforsea@yahoo.com 2 review | dermatol pract concept 2020;10(3):e2020033 the vast majority of pcrs report incidence and mortality data, but only 60% of them reportedly collect follow-up data for estimating cancer survival rates [8]. the see region has the lowest percentage of registries reporting on survival rates [8], while it estimates the lowest survival rates in europe, including for melanoma [4,18]. the see region has also the lowest proportion of pcrs producing more advanced data on stage at diagnosis, details and delay of first treatment, and compliance with treatment guidelines, while nordic pcrs score consistently at best across all these parameters [8,10]. reporting and publishing of european pcr data are also highly variable [4,5,8,14], and see countries are the least represented in general cancer and melanoma-focused studies [4,19-21]. centralized data at the european level, with an endeavor for standardization, were made available in the last decades through several platforms including the european network of cancer registries (encr) and the international agency for research on cancer (iarc) portals [9,22], as well as through high-resolution pan-european studies [4,22]. a major step forward in ensuring harmonized, centralized, and up-to-date reporting of european cancer data was the launching in 2018 of the european cancer information system (ecis) [17]. grounded in joint efforts of encr-joint research centre and iarc, the ecis reports national incidence and mortality estimates for the current year, historical recorded incidence and mortality indicators as available, and estimated 5-year survival rates for european union (eu) and european free trade association (efta) countries [21]. melanoma registration through pcrs faces additional specific challenges. while most pcrs reportedly collect data from pathology reports, hospital records, and death certificates [5], significantly fewer collect data from public or private outpatient clinics, hospices, or general practitioner records [9,10], where many localized melanomas are diagnosed and initially excised. different specialties involved in early melanoma diagnosis and treatment, from dermatologists to general practitioners and surgeons, have different patterns of cancer case reporting [4]. while stage at diagnosis is collected by most pcrs, fewer than 40% of them use the tumor-node-metastasis (tnm) classification for this purpose [15], and important parameters such as melanoma thickness or genetic profiling are often not recorded [23]. these concur with underreporting of melanoma cases and limitations in the analysis of cutaneous melanoma prognosis, early diagnosis, and care quality across europe. melanoma incidence and mortality in europe with the caveat of the variability of pcr output, as exposed above, the data available draw a highly heterogeneous epidemiological picture of melanoma in europe. we signaled becomes thus ever sharper, and so its heterogeneity becomes more apparent. the most visible, also to the public, are the glaring outcome disparities. melanoma survival exceeded 90% for 5-year relative rate for nordic or western countries, but is below 60% in eastern europe for people diagnosed as recently as this decade [1]. this is but the tip of the iceberg, whose base reaches deep into the disparities across the whole spectrum of melanoma care, from prevention and early diagnosis to access to treatment, and—not least important—to the availability and accuracy of the epidemiological data. this review aims to highlight the main differences in melanoma epidemiology across europe, bringing insight into their underlying causes in the areas of melanoma registration, early diagnosis, and prevention. it aims to offer a differentiated depiction of the challenges of melanoma epidemiological surveillance, in support of the concept that in order to tackle this tumor, no one-size-fits-all solution can work, but nuanced actions, adapted to the heterogeneous national and regional context in europe, are necessary. sources of epidemiological data for melanoma in europe epidemiological analyses, however complex, are only as good as their data sources. the foundation of cancer epidemiological surveillance consists of the population-based cancer registries (pcrs). pcrs are complex organizations destined to systematically collect, store, analyze, and report the data about all cancer cases occurring in a certain population, usually of a specific geographical area [2,3]. they are the fundamental source of objective information on cancer cases, but their function and performance is conditioned by the organization of the health systems in which they operate and by their legal, economic, social, and cultural context at the national or regional level. these are highly heterogeneous in europe, and so are pcrs’ quality, function, and output [4]. these differences have far-reaching consequences, as accurate and complete pcr data are indispensable for all aspects of epidemiological research and cancer control planning [2,4-7]. cutaneous melanoma is reported mostly to general pcrs, and these are so far the mainstay source of epidemiological data on melanoma in europe. close to 200 national or regional pcrs cover together approximately 60% of the population of europe, with increasing trend [8,9]. their coverage rate, data output, and quality differ largely, with the countries in south-eastern and eastern europe (see) lagging constantly behind [4,8,10-14]. twenty-two european countries have quality national pcrs, covering the entire population [4,8,15,16]. in contrast, 9 countries in see report only estimated incidence rates, calculated from partial registration data and neighboring countries’ quality registries [4,16,17]. review | dermatol pract concept 2020;10(3):e2020033 3 the incidence-mortality ratio increased sharply from east and south to north and west, ranging from 1.86 and 2 for albania and romania, to 8.35 in switzerland. as these dramatically low rates in eastern europe, both estimated and recorded, stem from the era before the widespread introduction of innovative therapies for advanced melanoma, they likely reflect disparities in early diagnosis and management of primary tumor across the continent. this is underlined by recent survival analyses stratified by tumor stage and thickness, showing that while the 5-year relative survival rate increased significantly from 2000 to 2013, this increase was no longer seen after adjustment for t stage [27]. increased survival appears thus due mostly to the increased earlier diagnosis of thinner tumors, with good prognosis. this finding emphasizes the urgent need to step up efforts in this direction in the eastern european countries. melanoma epidemiology trends in europe melanoma incidence has been constantly increasing in all european regions for the last few decades. during the 19952012 period, a statistically significant increase in the incidence of invasive melanoma was reported, with an average annual percent change (aapc) of 4.0% in men and 3.0% in women [20]. the increase tended to be higher in southern and eastern europe than in nordic countries [19,20]. in see countries, incidence rates increased over the period 20012010 across all age groups (25-49 years old, 50-69 years, and 70+ years) [28], although the steepest increases were noted in the older groups. incidence increased more rapidly in women than in men. in contrast, in nordic countries, a similar pcr-based analysis over the period 1990-2010 [19] showed a stabilization of incidence rates and even a decrease (in norway) in the youngest groups, with a marked increase persisting in over 70-year-olds. incidence increased more rapidly in women than in men under 70 years old, but the trend was reversed after this age. the marked increase in incidence noted in see countries is likely related at least partially to increased diagnosis and case registration in recent years, and as these improvements continue, the reported epidemiological data will come closer to reflecting the real melanoma burden in these countries. mortality has increased in europe, although at slower rates than incidence. in the period 1995-2013 mortality rates continued to increase in northern (aapc 1.6%-5.4%) and western europe (aapc 1.0%-2.1%) [20], while some countries (austria, switzerland) reported a flattening or even a slight decrease in overall mortality [20]. mortality trends were generally more favorable for women than men, and 19-fold differences in the estimated incidence rates across the continent [24], with a sharp north-to-south, west-to-east gradient. ten years later, the current ecis estimates maintain this trend, with the highest incidence rates in norway (29.6 age-standardized rate, world population [aswr]) and the lowest in romania (3.4 aswr), with 13.5 (aswr) european average [17]. looking closer, 3to 4-fold differences exist between neighboring countries’ rates, such as romania and hungary or poland and germany. as the population genotypic and phenotypic characteristics, sun exposure behavior, and uv index do not diverge much between these countries sharing borders, it is likely that these incidence disparities reflect inequalities in melanoma case diagnosis and registration, beyond the true burden of new melanoma. estimates of mortality rates vary less between countries, from the lowest of 1.1 aswr in malta, to 3.5 aswr in norway, with an average of 1.7 for the eu + efta countries [17]. norway is an outlier, at a distance from the next mortality rates in the neighboring nordic countries (ranging 1.7-2.7 aswr) [17]. comparable mortality rates between central and eastern european (cee) and western european countries, but with significantly lower incidence rates reported in cee countries, point to much higher case-fatality rates in eastern european countries [25]. mortality rates are uniformly higher in men than in women, ranging across europe from 0.9 to 2.8 in women, and from 1.3 to 4.2 aswr in men [17]. the nordic countries and switzerland show the highest gender difference in mortality rates, with the maximum in finland (1.1 in women vs 2.9 in men). melanoma continues to claim more than 20,000 lives annually in europe [17,24], with the highest proportion in cee countries [24]. melanoma survival in europe melanoma survival in europe has been constantly rising [26], but this encouraging news is far from uniform across the continent. the last eurocare-5 analysis of recorded data from 99 european pcrs shows that the 5-year relative survival rate for melanoma patients diagnosed between 2002 and 2007 is 86.58% for europe, with the highest rates reported in nordic countries (90%) and the lowest in eastern europe (69.78%) [26]. at the individual country level these rates go even lower, for example, in bulgaria to 40.73% and in poland to 55.35%. because of data missing from registries, not all european countries have survival data estimated by eurocare/ecis. in an attempt to fill this gap, our earlier study used the incidence-mortality ratio as proxy for estimating survival for all 40 european countries for which incidence and mortality data were available in iarc/globocan [25]. our estimation paralleled the hard data of eurocare, as 4 review | dermatol pract concept 2020;10(3):e2020033 [23]. in serbia between 2005 and 2010 the median breslow thickness reported was 3 mm [38]. in estonia the proportion of thin melanoma (t1 of tnm classification) increased from 7% in men and 14% in women in 1992 to 34% in men and 41% in women in 2010-2012, while the proportion of t4 tumors decreased slightly [39]. in croatia the mean breslow thickness reported in 2012 was 2 mm, with 75% of t4 tumors found in men and 60% of t1 tumors in women [40]. a regional reference center in romania reported a stage distribution of 18% t1 and 48.73% t4 [41]. an expert survey in 33 european countries estimated that melanomas thicker than 2 mm represented 46% of melanomas diagnosed in eastern europe, vs only 19% in western europe [42]. encouragingly, earlier diagnosis of thinner tumors appears also in the cee countries with longer-established pcrs, such as the czech republic, where between 1977 and 2008 the incidence rates increased at an estimated annual percentage change of 38%, for t1 tumors vs 5% for t4 tumors [43]. all available data suggest a general trend, albeit at different speeds, of a stronger increase in incidence of in situ and thin tumors, while thicker tumors continue to increase in incidence although at a significantly slower rate [29,33,3537,44]. this persistent proportion of thick tumors detected may explain the persisting and even increasing mortality rates across the continent, and it points to the necessity to intensify the efforts of primary and secondary prevention. melanoma prevention campaigns in europe the disparities in incidence and early diagnosis across the continent relate to significant differences in the level of population awareness and available primary and secondary prevention campaigns. nordic and western european countries have a several decades long tradition of public education campaigns for skin cancer prevention and early detection [34,37,42,45,46]. germany is the only country implementing a national skin cancer screening program [47-49], while diverse, high-risk-based selective screening programs are reported in western countries [50-52]. skin self-examination is promoted, pigment lesion clinics that fast-track patients with suspected melanoma [53-55] succeed in increased detection of thinner tumors, and various digital tools promoting public awareness, skin self-examination, or skin cancer risk estimation are developed [56-58]. this is in sharp contrast with the paucity of interventions reported in the eastern half of the continent. in an expert survey conducted in 32 european countries, fewer respondents in eastern europe compared with western europe reported the presence of governmental (12% vs 46%) or nongovernmental (35% vs 65%) initiatives for skin cancer prevention [42]. more favorable—even decreasing—in younger age groups, while elder men bore the highest burden of mortality increase [20,29]. in south-eastern and eastern europe the trends are more divergent. in the youngest age groups (25-49 years old) mortality nonsignificantly declined in most countries in the period 2000-2010 [28]. for the middle age group (50-69 years old), country reports are heterogeneous, with decreasing trends in a few countries such as czech republic and slovakia but increasing in the others, with a maximum for men in serbia (aapc 3.6%) and for women in slovenia (aapc 6.0%). the oldest groups show uniformly a marked mortality increase in both genders, up to 8% aapc in serbia. these highly heterogeneous data in close neighbors suggest differences in reporting besides disparities in melanoma diagnosis and treatment. the burden of melanoma is expected to continue to rise in the future across europe. the number of reported new cases is expected to rise as the population ages and as awareness and early detection increases, while sun-related behaviors do not seem to change significantly. the incidence rates are projected to rise until 2026 in northern europe and possibly stabilize afterward [30]. in south-eastern and eastern europe, the incidence rates are likely to continue to increase significantly also as a result of improving diagnosis, registration, and reporting [4,25]. it is difficult to speculate on future developments in mortality, as since the 2012-2015 innovative, efficient therapies have been introduced in european countries, yet access to them is highly uneven across the continent [31]. melanoma thickness in europe reported melanoma thickness has decreased markedly over the last decades. in germany the median breslow thickness decreased from 1.81 mm in 1980 to 0.53 mm in 2000 [32]. in switzerland the incidence rates of thin melanoma (<1 mm) increased approximately 4-fold between 1980 and 2010, while the incidence rates of thicker tumors remained relatively stable [33]. nordic and western countries report similar trends, leading to 60%-70% of melanomas being diagnosed under 1 mm in 2010-2015 [27,34-37]. a recent pcr-based study [20] found that since 1995 the incidence rates increased markedly both for in situ (aapc 7.7% in men; 6.2% in women) and thin melanoma (aapc 8.3% in women; 10% in men) in 12 countries situated, with one exception, in the western part of the continent. in contrast, thicker melanoma (>1 mm) incidence rates also increased, but much slower (apc 3.3%-2.2%) [20]. in the eastern part of europe the picture is different, as few reports on melanoma thickness exist, mostly from individual centers, whereas pcrs collect thickness data unevenly review | dermatol pract concept 2020;10(3):e2020033 5 across the continent in the collection and availability of accurate epidemiological data, in the capacity of early diagnosis, and in the prevalence 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https://doi.org/10.3109/13814788.2014.949669 https://doi.org/10.3109/13814788.2014.949669 8 review | dermatol pract concept 2020;10(3):e2020033 world society and european association of dermato-oncology survey in 34 countries. eur j cancer. 2018;104:201-209. https:// doi.org/10.1016/j.ejca.2018.09.013 70. wouters mw, michielin o, bastiaannet e, et al. ecco essential requirements for quality cancer care: melanoma. crit rev oncol hematol. 2018;122:164-178. https://doi.org/10.1016/j.critrevonc.2017.12.020 71. oecd. cancer care: assuring quality to improve survival. oecd health policy studies. paris: oecd publishing; 2013. available from: https://doi.org/10.1787/9789264181052-en 67. forsea am, tschandl p, zalaudek i, et al. the impact of dermoscopy on melanoma detection in the practice of dermatologists in europe: results of a pan-european survey. j eur acad dermatol venereol. 2017;31(7):1148-1156. https://doi.org/10.1111/ jdv.14129 68. forsea am, tschandl p, del marmol v, et al. factors driving the use of dermoscopy in europe: a pan-european survey. br j dermatol. 2016;175(6):1329-1337. https://doi.org/10.1111/ bjd.14895 69. kandolf sekulovic l, guo j, agarwala s, et al. access to innovative medicines for metastatic melanoma worldwide: melanoma https://doi.org/10.1016/j.ejca.2018.09.013 https://doi.org/10.1016/j.ejca.2018.09.013 https://doi.org/10.1016/j.critrevonc.2017.12.020 https://doi.org/10.1016/j.critrevonc.2017.12.020 https://doi.org/10.1787/9789264181052-en https://doi.org/10.1111/jdv.14129 https://doi.org/10.1111/jdv.14129 https://doi.org/10.1111/bjd.14895 https://doi.org/10.1111/bjd.14895 dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020015 1 dermatology practical & conceptual introduction dermatofibroma (df) is one of the most frequent skin tumors. several histopathological variants have been described, including fibrous histiocytoma (accounting for 80% of cases), aneurysmal, hemosiderotic, epithelioid, cellular, lipidized, atrophic, and clear cell variant. df has slight female predominance and is mostly localized on the limbs. eruptive dfs have been described in association with pregnancy and immunosuppression. in almost 80% of cases, the epidermis overlying df shows changes that range from simple hyperplasia to the proliferation of basaloid cells, morphologically indistinguishable from basal cell carcinoma (bcc) [1]. we report a case of collision tumor consisting of df and bcc. case presentation a 56-year-old woman presented with a papulonodular, erythematous, partially pigmented lesion, 18 × 8 mm in size, on her right thigh (figure 1a). the lesion was firm on palpation, revealing a pinch (dimple) sign. dermoscopy revealed 2 parts of the tumor, a pale pink amorphous area with white areas and blue-gray ovoid nests, specks of pigment, and spokewheel pigmentation (figure 1b). the tumor was surgically removed. histopathology confirmed 2 different parts of the lesion (figure 1, c and d), 1 encapsulated in the dermis consisting of mixture of fibroblasts and histiocytes arranged between collagen fibers (df) and the other, under the overlying acantholytic epidermis, a dermal tumor consisting of islets of atypical basaloid cells forming a palisading pattern at the periphery (bcc). conclusions only several cases of bcc overlying df have been reported in the literature [2]. we may assume, as have other authors, that basaloid proliferations (basal cell-like changes) and bccs (true neoplastic lesions) are a result of the inductive basal cell carcinoma overlying a dermatofibroma: a rare collision tumor sandra jerkovic gulin,1 davorin loncaric,2 jaka rados2 1 department of infectious diseases, dermatology, and venereology, general hospital sibenik, croatia 2 department of dermatology and venereology, university hospital centre zagreb, croatia key words: basal cell carcinoma, dermatofibroma, dermoscopy, collision tumors, histopathology citation: jerkovic gulin s, loncaric d, rados j. basal cell carcinoma overlying a dermatofibroma: a rare collision tumor. dermatol pract concept. 2020;10(1):e2020015. doi: https://doi.org/10.5826/dpc.1001a15 accepted: october 1, 2019; published: december 31, 2019 copyright: ©2019 jerkovic gulin et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sandra jerkovic gulin, md, department of infectious diseases, sibenik general hospital, stjepana radića 83, 22221 sibenik, croatia. email: sandrajerkovicgulin@gmail.com mailto:sandrajerkovicgulin@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020015 references 1. zaccaria e, rebora a, rongioletti f. multiple eruptive dermatofibromas and immunosuppression: report of two cases and review of the literature. int j dermatol. 2008;47(7):723-727. 2. córdoba s, hernández a, romero a, et al. basal cell carcinoma overlying a dermatofibroma. actas dermosifiliogr. 2005;96(9):612-615. effect of df and its fibrohistiocytic proliferation on the epithelial cells of the hair follicle [2]. this letter highlights the importance of dermoscopy and dermoscopic criteria in collision lesions in order not to miss skin cancer and gives a dermoscopic/histopathological description of a bcc and df in a collision lesion. figure 1. (a) clinical view: papulonodular, erythematous, partially pigmented lesion, 18 × 8 mm on the right thigh. (b) dermoscopic view: 2 parts of the tumor, a pale pink amorphous area with white areas and blue-gray ovoid nests, specks of pigment, and spoke-wheel pigmentation. (c,d) histopathology: 1 part of the lesion is encapsulated in the dermis consisting of a mixture of fibroblasts and histiocytes arranged between collagen fibers (dermatofibroma) and the other, under the overlying acantholytic epidermis, a dermal tumor consisting of islets of atypical basaloid cells in a palisading pattern at the periphery (basal cell carcinoma) (h&e, ×20). dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021008 1 dermatology practical & conceptual acne inversa-like lesions induced by a low dose of sorafenib javier aubán-pariente1, laura palacios-garcía1, cristina galache-osuna1, marc mir-bonafé1, patricia morales del burgo2, jorge santos-juanes1 1 department of dermatology, central university hospital of asturias, oviedo, spain 2 department of pathology, central university hospital of asturias, oviedo, spain key words: acne inversa, sorafenib, cutaneous adverse reactions, dermatopathology citation: aubán-pariente j, palacios-garcía l, galache-osuna c, mir-bonafé m. morales del burgo p, santos-juanes j. acne inversa-like lesions induced by a low dose of sorafenib. dermatol pract concept. 2021;11(2):e2021008. doi: https://doi.org/10.5826/dpc.1102a08 accepted: july 29, 2020; published: march 8, 2021 copyright: ©2021 aubán-pariente et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: javier aubán-pariente, md, central university hospital of asturias, dermatology department, av. roma, s/n, 33011 oviedo, spain. tel. 34-985108000. email: javiauban@gmail.com introduction sorafenib is an oral multikinase inhibitor approved for the treatment of unresectable hepatocellular carcinoma, differentiated thyroid cancer, and advanced renal-cell carcinoma. this drug blocks tumor cell proliferation and angiogenesis by inhibiting the raf serine/threonine kinases (raf1 and braf) as well as multiple receptor tyrosine kinases [1]. adverse skin reactions occur in up to 90% of patients. although acneiform eruptions have been widely reported in association with epidermal growth factor receptor (egfr) inhibition, ranging from 24%-91% of patients, those induced by sorafenib are rare. they usually appear in the first 6 weeks after drug onset and are located on the face. regarding clinical-pathological characteristics, acneiform eruptions induced by sorafenib are classified into 3 groups: papulopustular eruptions without associated retention lesions, nodular-cystic eruptions, and perforating folliculitis [2]. of these groups, papulopustular facial eruptions have been the most frequently observed. here we report a case of acne inversa-like lesions induced by a low dose of sorafenib in a 62-year-old man with hepatocellular carcinoma. case presentation a 62-year-old man was referred to us for evaluation of 2 exudative lesions on his lower extremities of 1-month duration. his medical history included sorafenib 400 mg/day for 4 months for diffuse hepatocellular carcinoma. the patient denied a history of similar lesions prior to the onset of sorafenib. physical examination revealed 2 indurated erythematous plaques on both thighs that were 2 to 6 cm in diameter (figure 1, a and b). the lesions had small oozing cavities, fistulous tracts, and depressed scar areas. no involvement of other locations was observed. skin swabs for viral and bacterial cultures were negative. a skin biopsy showed perifollicular and perivascular lymphohistiocytic infiltration (figure 2a). dilated follicular infundibula were filled with compact parakeratotic cornified cells and neutrophils (figure 2b). a diagnosis of acne inversa-like lesions induced by sorafenib was made, and topic 2 letter | dermatol pract concept 2021;11(2):e2021008 references 1. pichler m, carriere c, mazzoleni g, kluge r, eisendle k. acne inversa-like lesions associated with the multi-kinase inhibitor sorafenib. clin exp dermatol. 2014;39(2):232-233. doi: 10.1111/ ced.12257. pmid: 24330088. 2. borgia f, saitta c, vaccaro m, franzè ms, lentini m, cannavò sp. nodular-cystic eruption in course of sorafenib administration for hepatocarcinoma: an unconventional skin reaction requiring unconventional treatment. int j immunopathol pharmacol. 2017;30(3):327-331. doi: 10.1177/0394632017727618. pmid: 28825507. fusidic acid was prescribed twice a day. the oncologist temporarily discontinued treatment with sorafenib due to liver decompensation. after 1 month of sorafenib interruption, there was complete resolution of the eruption with mild scarring. conclusions five cases of acne inversa-like lesions associated with sorafenib have been reported, all of them in males [1,2]. clinical features of 4 of these patients were similar to the case presented here, and except for 1 case of classic hidradenitis suppurativa located in the bilateral axillae and inguinal region, the localization was atypical in affecting the legs, abdomen, or buttocks. histopathological analysis showed comedone-like follicular dilatation with perifollicular lymphohistiocytic infiltration. there appears to be a dose-dependent relationship between sorafenib and acneiform reaction. except in 1 case in which an acne inversa-like eruption resolved spontaneously, lesions only improved with dose reduction or treatment interruption in combination with topical retinoids, antibiotics, or benzoyl peroxide [1,2]. if we apply the naranjo drug reaction assessment tool to this case, the result would be “probable.” unlike previously reported cases, our patient developed acneiform lesions while on a low dose of 200 mg twice a day. further studies are needed to elucidate the pathogenic explanation and dose relationship between sorafenib and acne inversa-like lesions. figure 1. (a, b) two indurated erythematous plaques with fistulous tracts and depressed scar areas on both legs. figure 2. (a) perifollicular and perivascular lymphohistiocytic infiltration (h&e, ×20). (b) dilated follicular infundibula filled with compact parakeratotic cornified cells and neutrophils (h&e, ×100). dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;3(2):1 1 editorial i have great news for our readers, authors, reviewers and co-editors. we have finally succeeded in being included to pubmed central. this means that all articles published starting with the first issue of dermatology practical & conceptual will appear in full in the u.s. national institutes of health (nih) digital archive of biomedical and life sciences journal literature also known as pubmed central (pmc). this also means that pmc will submit a citation to pubmed as soon as the article is live in pmc. more than three years ago we decided to relaunch the journal formerly known as dermatopathology: practical & conceptual under a different name. when i took over the editorship from almut böer-auer who succeeded a. bernard ackerman, founder of the journal in 1995, i knew that i had big shoes to fill. chances were high that i would stumble. to step out of their shadows i elected to strike a new path: dermatopathology: practical & conceptual became dermatology practical & conceptual. as stated in my editorial in the first issue, the change of the journal’s title intended to express the change in the scope of the journal. based on the intention to broaden the scope, i decided to include sections dedicated to “dermatoscopy and skin imaging” and to “dermatology in primary care.” the other important change was that dermatology practical & conceptual became an open access journal in order to increase its visibility. we started with less than 500 unique visitors (readers) per month in late 2011 and increased the traffic to more than 1300 unique visitors per month in the last four months. our readers come from 87 different countries. the three most frequently assessed articles were (1) “nail matrix melanoma: consecutive cases in a general practice” by rosendahl et al with 2435 unique visitors and 2914 page views, (2) “histopathology of drug eruptions—general criteria, common patterns, and differential diagnosis” by weyers and metze with 1420 unique visitors and 1759 page views and (3) “pigmented tumor in the nostril” by jaada et al with 691 unique visitors and 891 page views. i would like to thank all authors who submitted their work to our journal. it demands a pinch of “grandeur” which not everybody can muster to send your excellent work to a journal that currently has no impact factor. i have read every single article and i have learned from each article. it made an impact on me and on our growing community of readers. i also want to thank the referees, the co-editors and the team at derm101. without their help the journal would not have succeeded. now, all this said, i have other important news for you. my mission is completed and it is time for me to move on. after three years of intensive work i think it is time that a new editor take over. my other duties and the expected workload related to the organization of the world congress of dermoscopy and skin imaging in vienna in 2015 do not allow me to fulfill my responsibilities as an editor of the journal. the new editor in chief will be appointed in may. the journal approaches exciting times and the tasks of the new editor in chief will be challenging. the next important step is to receive an impact factor for the journal. this needs persistence and quality. in this regard i would ask you to give the new editor the same kind of valuable support that i received from you during the last three years. these years were intensive and satisfying and i am happy that we have accomplished so much. mission completed citation: kittler h. mission completed. dermatol pract conc. 2012;3(2):1. http://dx.doi.org/10.5826/dpc.0302a01. copyright: ©2013 kittler. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: harald kittler, md, department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. e-mail: harald.kittler@meduniwien. ac.at. dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2012;2(4):2 3 introduction some issues are extremely simple if looked at without prejudice. this is also true for carcinomas. carcinomas are malignant neoplasms of epithelial cells. where are they going to arise? in the epithelium. therefore, at the outset, they must be confined to the epithelium. how are they going to look in the beginning? small and inconspicuous. how are they going to develop? they will grow and unfold the capacities with which they are endowed unless they are destroyed. this is nothing special but true for every living matter. but unprejudiced reflection is difficult because we all adopt conceptions of our time that channel our thinking. for many centuries, carcinomas were never treated before they had metastasized. recurrences were soon to occur, and most patients died shortly after seeking treatment. the incurability of cancer was so deeply rooted in the worldview of physicians that the diagnosis of cancer was always challenged when a patient survived. because carcinomas were excised only in stages far advanced, the bulk of the tumor was present in the dermis or deeper structures. that circumstance prompted rudolf virchow in 1855 to suggest derivation of carcinomas from cells of connective tissue, a concept to which he adhered for many years afterward. in 1865, carl thiersch proved the epithelial origin of cancer, but he believed that the true reason for the epithelial proliferation was a pathological weakness of the connective tissue that enabled sprouts of epithelium to grow in. as late as in 1894, hugo ribbert averred that carcinomas did not result from growth of epithelium into connective tissue but from growth of connective tissue into the overlying epithelium [1]. john templeton bowen this was the world of ideas that john templeton bowen absorbed before he described bowen’s disease 100 years ago. born in boston on july 8, 1857, bowen studied medicine at harvard medical school from which he graduated in 1884 (figure 1). afterwards he went to germany and spent the summer at the medical schools of berlin and munich. in 1885 he returned to europe and took graduate medical courses in vienna until september 1887. there he decided to specialize in dermatology. in 1889, bowen became physician to outpatients with diseases of the skin in the department of james the centennial of bowen’s disease— a critical review on the occasion of the 100th anniversary of its original description wolfgang weyers, m.d.1 1 center for dermatopathology, freiburg, germany citation: weyers w. the centennial of bowen’s disease—a critical review on the occasion of the 100th anniversy of its original description. dermatol pract conc. 2012;2(4):2. http://dx.doi.org/10.5826/dpc.0204a02. copyright: ©2012 weyers. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: wolfgang weyers, m.d., center for dermatopathology, engelbergerstr. 19, 79098 freiburg, germany. tel.: +49 761 31696; fax: +49 761 39772. e-mail: ww@zdpf.de. figure 1. john templeton bowen (1857-1940). clarke white at massachusetts general hospital. one year later, he was elected instructor in dermatology at the harvard medical school. following white’s retirement in 1902, bowen was promoted to assistant professor, and in 1907 he became the first wigglesworth professor of dermatology [2]. bowen devoted himself especially to dermatopathology. in cases that required histopathologic clarification, his expertise was sought. when white in 1889 gave the first precise description of dyskeratosis follicularis, bowen provided the histopathologic part, described a “keratosis of the epithelial lining of the mouths of the follicles” with “scattered bodies of a concentric arrangement” and came to the correct conclusion that he was dealing with a disorder of cornification [3]. a few months later, the disease was described independently by jean darier of paris who considered those “concentric bodies” to be parasites, so-called “psorosperms,” and referred to the disease as “psorospermose folliculaire végétante.“ bowen, however, after having studied additional biopsy specimens, insisted that the psorosperm-like bodies in the horny layer “undergo at least a partial keratosis, or, in other words, are subject to much the same changes that affect the tissue cells proper.” for those reasons, he did not accept the parasitic nature of the cells. eventually, darier 4 review | dermatol pract concept 2012;2(4):2 figure 2. figure from bowen’s original article. in the legend bowen noted that “the cicatricial portions mark the site of lesions previously removed.” figure 3. figure from bowen’s original article. the legend read as follows: “low power shows hyperkeratosis, proliferation and thickening of rete, vacuolization and abnormal cornification of cells; dilation of vessels of corium, with cell masses surrounding them.” figure 4. figure from bowen’s original article. in the legend bowen called attention to “abnormal transformation and cornification of rete cells.” figure 5. figure from bowen’s original article. in the legend bowen called attention to “peculiar ‘clumping’ of nuclei and karyokinesis.” in 1896 completely retracted his psorosperm theory and acknowledged that bowen was right [4,5]. most scientific contributions of bowen had a distinct histologic or histopathologic focus. some of them dealt exclusively with findings obtained by microscopy (figures 2-5), e.g., a study in 1889 about “the epitrichial layer of the skin” in which bowen proposed the existence of a distinct epithelial layer on the surface of the skin of human embryos review | dermatol pract concept 2012;2(4):2 5 between the third and sixth month of gestation [6]. others wedded clinical and histopathologic findings, including bowen’s study of the disease that came to bear his name. it was published in the journal of cutaneous diseases in 1912 under the title “precancerous dermatoses: a study of two cases of chronic atypical epithelial proliferation” [7]. bowen by far preferred the microscope to seeing patients. he was a member of several medical societies and in 1902 president of the american dermatological association, but he did not like public appearances. lectures were almost a torture to him. he loved children, but he never married. though very sociable in his youth, he withdrew more and more into himself as life went on. following his retirement in 1927, he read a lot and used to spend the summer months in europe, especially in france. in those years, he began to suffer from vertigo that became worse steadily. bowen died in boston on december 3, 1940 [2]. history of the description of bowen’s disease more than seventy years later, bowen’s name is still remembered by every student of medicine. that fact can be attributed chiefly to jean darier. the french pioneer of dermatopathology never met bowen personally, but he had great esteem for his american colleague and suggested in 1914 that the disease described by bowen be linked eponymically to his name [8]. two years earlier, bowen had detailed findings in two patients who presented with localized, irregular patches and plaques on the buttock and on the calf, respectively. the lesions measured about four inches in diameter. bowen described them as “only slightly elevated above the normal skin, of a moderately firm consistency, and dull red in color. the surface was in some places slightly crusted; in other places it had a papillomatous character. the lesions were in places confluent, forming areas of tumorlike masses; in other places, especially at the edge of the affected areas, they were discrete, or assumed annular or serpiginous figures. apparently, the lesions never disappeared spontaneously” [7]. histopathologic examination (figures 2-5) revealed “an extreme hyperplasia of the epidermis, especially of the rete, and an enlargement and engorgement of the vessels of the corium. . . . the stratum granulosum was nowhere apparent in its entirety. . . . a prominent feature of the rete appearances was the presence of very numerous mitoses of varying forms, extending from just above the basal cells to nearly the surface horny cells. these mitoses were not seen in the basal layer. a frequent change seen in the nuclei was that of clumping . . . the outline of from two to a dozen nuclei . . . could be seen huddled together in the remains of a much enlarged cellular space, with a clear space at the periphery. . . . there were also some epithelial pearls in the epidermis. . . . there was no sign of distinct carcinomatous formation however”[7]. cancer or not cancer, benign or malignant—bowen was torn in his interpretation of those findings. he was aware that many mitotic figures in all reaches of the epidermis, cells with large, clumped nuclei, close crowding of nuclei, and concentric masses of keratinizing epithelial cells known as “epithelial pearls” were strong indicators of cancer, but he was puzzled by the absence of detached aggregations of atypical cells in the dermis. in that regard he was not alone. other authors faced the same problems when confronted with incipient carcinomas; they recognized their malignant potential but shrank back from vocalizing it explicitly. the conception of cancer as a deeply infiltrating, destructive, rapidly fatal disease was anchored too deeply in their minds to appear compatible with early evolving stages of cancer devoid of dermal involvement. for example, when james paget in 1874 described a “disease of the mammary areola preceding cancer of the mammary gland” in fifteen female patients, he noted that all patients developed an obvious mammary carcinoma within at most two years. nonetheless, he considered the skin lesions to represent “long-persistent eczema, or psoriasis,” and suggested “that a superficial disease induces in the structures beneath it, in the course of many months, such degeneracy as makes them apt to become the seats of cancer” [9]. in the subsequent years, carcinomas developing on preexisting “eczematous” lesions were also described at other sites, such as the scrotum (crocker, 1888) or the glans penis (pick, 1891). at the international congress of dermatology in london in 1896, william dubreuilh of bordeaux introduced the term “precanceroses” for solar keratoses (“keratoma senile”), arsenical keratoses, “cornu cutaneum,” “leukokeratoses,” and other epithelial lesions that commonly gave rise to carcinoma. in contrast to paget, dubreuilh recognized that the “pre-existing” lesions were not benign. he emphasized that “this is not a malignant transformation, as we are used to call it; this is simply an aggravation or acceleration of the process because one finds in these precanceroses the essential characteristics of the malignant tumor.” nonetheless, dubreuilh refrained from calling the lesions malignant because they could “remain stationary indefinitely, they may also heal spontaneously” [10]. the fact that malignant neoplasms may grow extremely slowly, or apparently not at all, and that even widespread metastases may at times regress spontaneously, was beyond the horizon of physicians of that time. for decades to come, intraepithelial malignancies were referred to as “precanceroses.” one example was “erythroplasie du gland,” described in 1911 by louis queyrat of paris on the glans penis of four men. because three of those 6 review | dermatol pract concept 2012;2(4):2 patients also suffered from syphilis, queyrat was uncertain how to classify the disease. histologically, he found “epitheliomatous bulges, formed by polygonal cells which have lost their normal order.” he also described enlarged nuclei and mitotic figures. he did not refer to “erythroplasia” as an early stage of cancer but noted that this “chronic affection” was “able, in certain cases, to eventuate into an epithelioma” [11]. early stages of disease were also described for melanoma without being referred to as malignant. in 1892, jonathan hutchinson reported on “growth of epithelial cancer” in the vicinity of so-called “senile freckles,” irregular pigmented macules in the sun-exposed skin of elderly patients. hutchinson did not consider those freckles to be malignant but alluded to the “very remarkable fact, as seeming to imply some connection between the two conditions, that in each instance the epitheliomatous ulcer developed in close proximity to the black stain” [12] two years later, similar cases were described by dubreuilh under the designation “lentigo malin de vieillards” [13]. in 1912, dubreuilh returned to the subject and gave a precise description of melanoma in situ in all age groups and at all anatomic sites. meanwhile, he had observed some patients for years and had come to the conclusion that ”the appearance of a carcinoma in the melanosis is a possibility which has always to be feared, but this outcome is not fatal or rather may be postponed indefinitely. the malignant evolution may happen at the beginning, i.e., the carcinome d’emblée, with a delay of several months or several years, but sometimes it may not occur within a period of 20, 25, 30 years or more; it may also never happen.” in some cases, dubreuilh even observed partial regression of the lesions. in his view, those findings militated against malignancy. as a consequence, he dismissed his own previous designation “lentigo maligna” as “highly defective in every regard” and proposed the term “melanose circonscrite precancereuse” instead [14]. an additional twenty years had to pass until albert c. broders of the mayo clinic introduced the term “carcinoma in situ” for neoplasms “in which malignant epithelial cells . . . have not migrated beyond the juncture of the epithelium and connective tissue or the so-called basement membrane.” broders emphasized that “the entity called carcinoma or cancer, regardless of etiology, is a primary disease of epithelial cells, and . . . all other phases or sequelae, although of great importance, are in reality of secondary nature . . . the day has passed when epithelium can be considered noncarcinomatous or at the most only precarcinomatous because it is within the confines of the so-called basement membrane and, conversely, carcinomatous because it has penetrated beyond this barrier. it is therefore imperative that the microscopist take into consideration the character of the epithelial cells above everything else in order to arrive at a correct diagnosis” [15]. it may seem curious that such truisms needed to be emphasized at all. however, only after broders had coined the term “carcinoma in situ,” the obvious came to be accepted, namely, that a malignant neoplasm of epithelial cells begins in the epithelium. it took many more decades until the fact was appreciated that “lentigo maligna” is a synonym for melanoma in situ occurring in sun-damaged skin, and “bowen’s disease” a synonym for a particular type of carcinoma in situ characterized by scatter of markedly atypical epithelial cells in all reaches of the epidermis. the importance of referring to lesions by an unambiguous name that reflects their true biologic behavior could not be illustrated more emphatically than by reviewing the original articles of 1912. dubreuilh suggested refraining from treatment of the “circumscribed precancerous melanosis,” arguing that, “to me, the surgical operation does not seem to be justified in regard to the pure melanosis because its malignant transformation is uncertain” [14]. john templeton bowen treated lesions of his patients with various techniques but never strove for eradicating them completely. this was reflected by the outcome: “new lesions slowly grew at the periphery of the areas that had been treated by the curette or by freezing, and there were apparently some recurrences in the cicatrix or within its boundaries” [7]. had dubreuilh and bowen appreciated fully the malignant nature of the neoplasms they described, they would have been in a far better position to manage their patients. resurgence of bowen’s problems of interpretation in modern pathology it is deplorable, therefore, that the principle of unambiguous designations for intraepithelial malignancies has been challenged increasingly in recent years. for melanoma in situ, descriptive terms such as “atypical melanocytic hyperplasia” and “melanocytic intraepidermal neoplasia” have been introduced that are reminiscent fatally of bowen’s hapless designation “chronic atypical epithelial proliferation.” the consequences are the same: the malignancy of the process is obscured with the risk of inadequate treatment. the term “bowen’s disease” is acceptable as long as it is known to refer to one type of carcinoma in situ. however, the term was “deleted from the vocabulary of vulvar diseases” by gynecopathologists and was substituted in 1987 by the nonspecific designation “vulvar intraepithelial neoplasia” [16,17]. the latter designation came to be used indiscriminately for benign lesions, such as condyloma acuminatum, and for fully developed in-situ-carcinomas. in the case of problems in differential diagnosis, this proved to be very convenient because pathologists were relieved from the burden of decision, but the new terminology did not facilitate management review | dermatol pract concept 2012;2(4):2 7 of patients. what is an “intraepithelial neoplasia”? benign or malignant? does an epithelial tumor with markedly atypical nuclei and myriad mitoses really become malignant only after its first cells have traversed the basement membrane? and can early “invasion” be recognized consistently? is it not the “character of the epithelial cells” that must be taken into consideration “above every else in order to arrive at a correct diagnosis”? in recent years, the simple logic of albert c. broders has been suspended in some realms of medicine, and physicians once again find themselves in the same position as john templeton bowen 100 years ago. references 1. weyers w. the fallacy of the concept of invasion—critique in historical perspective with implications for diagnosis of early malignant neoplasms. am j dermatopathol. 2011;34:91-102. 2. white cj. john templeton bowen, m.d. 1857-1940. arch derm syph. 1941;43:386-8. 3. white jc. keratosis follicularis (psorospermose folliculaire végétante). j cutan genito-urinary dis. 1890; 8:13-20. 4. patterson jak. the tale of the psorosperm. am j dermatopathol. 1979;1:229-35. 5. king df. a footnote to “the tale of the psorosperm.” am j dermatopathol. 1982;4:313-4. 6. bowen jt. the epitrichial layer of the human epidermis. anat anzeiger. 1889;4:412-6, 441-50. 7. bowen jt. precancerous dermatosis: a study of two cases of chronic atypical epithelial proliferation. j cutan dis. 1912;30:241-55. 8. bernhard jd, elliot ad. a letter from darier to bowen on the naming of bowen’s disease. arch dermatol. 1983;119:261-2. 9. paget j. on disease of the mammary areola preceding cancer of the mammary gland. st. bartholomew’s hosp rep. 1874;10:879. 10. dubreuilh w. des hyperkératoses circonscrites. ann derm syph. 1896; sèr 3, 7:1158-1204. 11. queyrat l. erythroplasie du gland. bull soc fr derm syph. 1911;22:378-82. 12. hutchinson j. senile freckles. arch surg. 1892;3:319-22. 13. dubreuilh w. lentigo malin de vieillards. bull soc fr derm syph, séance du 4 aout 1894. 14. dubreuilh w. de la melanose circonscrite precancereuse. ann derm syph. 1912; sér. 5, 3:129-51. 15. broders ac. carcinoma in situ contrasted with benign penetrating epithelium. j am med assoc. 1932;90:1670-4. 16. kaufman rh, friedrich eg, jr., woodruff jd. new nomenclature for vulvar disease. obstet gynecol. 1976;147:122-4. 17. ridley cm, frankman o, jones isc, pincus sh, wilkinson ej, fox h, friedrich eg, jr., kaufman rh, lynch pj. new nomenclature for vulvar disease: international society for the study of vulvar disease. hum pathol. 1989;20:495-6. dermatology: practical and conceptual research | dermatol pract concept 2021;11(2):e2021035 1 dermatology practical & conceptual decreased serum levels of interleukin-4 and interleukin-21 in new pemphigus vulgaris patients, but not chronic patients with inactive disease compared to healthy controls pegah shahbazian1, maryam izad2,3, maryam daneshpazhooh1, hossein mortazavi3, zahra salehi2, shirin behruzifar1, soheil tavakolpour1,4, arghavan azizpour1 1 autoimmune bullous diseases research center, department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 2 department of immunology, school of medicine, tehran university of medical sciences, tehran, iran 3 ms research center, neuroscience institute, tehran university of medical sciences, tehran, iran 4 dana-farber cancer institute, harvard medical school, boston, usa key words: pemphigus vulgaris, elisa, cytokine, interleukin-4, interleukin-21 citation: shabazian p, izad m, daneshpazhooh m, mortazavi h, salehi z, behruzifar s, tavakolpour s, azizpour a. decreased serum levels of interleukin-4 and interleukin-21 in new pemphigus vulgaris patients, but not chronic patients with inactive disease compared to healthy controls. dermatol pract concept. 2021;11(2):e2021035. doi: https://doi.org/10.5826/dpc.1102a35 accepted: october 22, 2020; published: april 12, 2021 copyright: ©2021 shahbazian et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this study was funded and supported by tehran university of medical sciences (tums); grant no. 96-01-101-33881. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: arghavan azizpour, md, mph, tehran university of medical sciences, razi hospital, vahdat eslami avenue, tehran, iran. email: azizpour63@gmail.com background: pemphigus is a rare group of autoimmune blistering diseases with unknown etiology and unclear pathogenesis. pemphigus vulgaris (pv) is the most common subtype, and is characterized by ulcerations or flaccid blisters on mucous membranes and on the skin. it is accepted that cytokines have a critical role in the pathogenesis of pv, while their exact roles remain to be elucidated. objectives: this study assessed serum levels of interleukin (il)-4 and il-21 in different phases of the disease in comparison with healthy controls. methods: in a case-control cohort design, serum levels of il-4 and il-21 were determined by elisa in three groups: patients with newly diagnosed pv, patients with chronic, inactive pv (pv in remission), and healthy controls. results: the study included 88 individuals (58 women and 30 men), including 26 with newly diagnosed pv, 33 with pv in remission, and 29 healthy controls. a significant difference was found among the groups for il-21 (p = .044), but not for il-4 (p = .374). serum levels of il-4 and il-21 in newly diagnosed patients were significantly lower than in healthy controls (p = .005 for both), but these cytoabstract 2 research | dermatol pract concept 2021;11(2):e2021035 introduction pemphigus is a group of potentially fatal, chronic, autoimmune blistering diseases affecting the skin and mucous membranes. although the exact pathogenesis of this disease is not clearly understood, it is accepted that autoantibodies against desmoglein 1 (dsg1) and dsg3, produced by b cells, are the main cause of disease. in addition to b cells, autoreactive t cells seem to be required in the initial immunological steps for autoantibody induction [1]. indeed, the function of some t cells is required for the development, function, and antibody production of b cells and plasma cells during pemphigus [2]. in contrast, most regulatory t cells (tregs) can negatively influence b cell differentiation and function. t cells, which are sources of several cytokines and chemokines, not only affect other immune cells belonging to the innate and adaptive immune systems, but also can act in an autocrine manner. several cytokines have been studied in pemphigus patients so far [3,4]. some of these cytokines, such as interleukin (il)-4, are believed to be pathogenic [5] and some others, such as il-10, could be a double-edged sword [6]. regarding the roles of some other newly identified, less studied cytokines, such as il-21 and il-35, it is hard to judge, but they are probably pathogenic and protective, respectively [7,8]. in addition to indirect roles of t cells in the pathogenesis of pemphigus, direct recognition of anti-dsg3 by dsg3-specific cd4+ t helper cells has been suggested [9-11]. to date, several subsets of t helper (th) cells have been identified. these subsets, which include th1, th2, th9, th17, th22, follicular t helper (tfh), and treg subpopulations, could reciprocally regulate each other. previously, pemphigus used to be known as a th-2 dominant disease, while increasing pieces of evidence are suggesting a critical role of other subsets, such as th17 and tfh [12-14]. as already mentioned, cytokines do not only affect b cells, but could also affect other th cells. il-4 and il-21 are 2 critical cytokines involved in the differentiation of naïve th cells into th2 and th17, respectively. additionally, il-21 seems to be essential for tfh development [7]. to date, different studies have explored the role of il-4, and the majority of them are consistent with the suggested pathogenic role of this cytokine. il-4 is mainly produced by th2 cells and causes th2 cell differentiation in an autocrine manner. additionally, it induces isotype switching toward igg4, a well-recognized class of igg antibodies involved in pemphigus [15]. il-21 is another critical cytokine in the immune system that plays a role in the pathogenesis of immune-mediated diseases. it is mainly produced by natural killer t, th17, and tfh cells. it leads to the promotion of cd4+ t cells, including th2, th17, and tfh cells; cd8+ cytotoxic t lymphocytes are also affected by il-21 [7]. it also causes the production of igg in addition to negatively affecting tregs. in this study, we evaluated serum levels of il-4 and il-21 in 2 groups of patients with pemphigus vulgaris (pv), including newly diagnosed patients with active disease and patients with chronic, inactive disease, and compared them with healthy controls. materials and methods study design and inclusion criteria during a 2-year period (2016-2018), patients with newly diagnosed pv at the department of dermatology at razi hospital who met the inclusion criteria (see below) were included in the study (newly diagnosed pv group). additionally, patients with chronic but inactive pv (pv in remission group) as well as a similar number of matched healthy controls were included. before inclusion, all patients were examined by at least 1 dermatologist, and the diagnosis of pv was confirmed based on clinical features, detectable autoantibodies against dsg1 or dsg3, histopathology, and positive perilesional direct immunofluorescence studies. patient selection and cytokine assay the inclusion criteria for patients were: (1) confirmed diagnosis of pv, (2) treatment-naïve status for new cases and minimal or no therapy for patients with pv in remission (based on the 2008 consensus statement on definitions of pemphigus) [16], and (3) absence of biological therapies in the past 6 months. patients in the pv in remission group were either in complete remission, defined as having no new kine levels in patients with pv in remission were not different from those of controls (p = .343 and p = .221, respectively). also, no differences in cytokine levels were detected between the newly diagnosed patients and patients with pv in remission. regardless of disease phase, we detected significantly lower levels of il-21 in patients than controls (p = .027), but no differences for il-4 (p = .374). conclusions: il-4 and il-21 are involved in pv pathogenesis and disease severity. more studies are required to clarify the role of il-4 and il-21 in immunopathogenesis and immune response during pv. research | dermatol pract concept 2021;11(2):e2021035 3 or established lesions for at least 2 months, or partial remission, defined as the presence of transient new lesions that heal within 1 week without treatment. those in the control group were completely healthy and had no history of any skin disease, autoimmune disease, or malignancy. patients in remission who developed a new lesion within the past 2 months or who had old, persistent lesion(s) were excluded. also excluded were pregnant women, patients with other subtypes of pemphigus, and, during the study, any patient in the pv in remission group whose disease became active, defined as the development of new lesions that did not heal within 1 week without additional treatment. all study subjects provided written informed consent. after signing the consent letter, 6 ml of whole blood was taken from each contributor. serum was separated and then stored in -70°c for further experiments. serum levels of il-4 and il-21 were measured using elisa kits (thermo fisher scientific). study evaluation and statistical analysis demographic data, history of the disease, and type of therapy used were recorded and collected for each patient. results for serum concentrations of cytokines are presented as a mean ± standard deviation and median. to compare the mean concentrations in the groups of patients, an independent t test was used. to compare more than 2 samples separately, a one-way anova test was used. statistical analyses were performed using spss v.20.0 (ibm corp., armonk, ny, usa). p values <.05 were considered significant. data were graphed using the graphpad prism program (version 7.00, graphpad software inc.). ethical considerations the study was approved by the ethics committee of tehran university of medical sciences before initiating, and all persons who were enrolled provided written informed consent. the study was conducted in accordance with the declaration of helsinki. patients’ information was kept confidential and no patient/individual paid any charges. results a total of 88 patients was enrolled, including 26 (29.5%) newly diagnosed pv patients, 33 (37.5%) patients with pv in remission, and 29 (33%) healthy controls who were ageand sex-matched to the 59 pv patients. in total, 58 (65.9%) were females and 30 (34.1%) were males, with a mean age of 42.2 ± 10.5 years (range, 20-81). demographic data for each group are shown in table 1. table 2 reports the serum levels of il-4 and il-21 in the 3 groups, and figure 1 graphically shows the serum levels of (a) il-4 and (b) il-21. regarding il-4, no significant table 1. demographic data of the included patients and healthy participants newly diagnosed pv pv in remission healthy controls total gender male, n (%) 13 (43.3) 9 (30.0) 8 (26.7) 30 (100) female, n (%) 13 (22.4) 24 (41.4) 21 (36.2) 58 (100) age, mean ± sd (range), y 44.6 ± 9.0 (32-70) 43.6 ± 9.2 (28-59) 38.5 ± 12.4 (20-81) 42.2 ± 10.5 (20-81) pv = pemphigus vulgaris. table 2. il-4 and il-21 levels (pg/ml) in different phases of the disease group no. mean ± sd median range p il-4 newly diagnosed pv 26 8.63 ± 2.58 9.06 1.88-13.75 .374 pv in remission 33 15.92 ± 38.75 8.75 5.0-231.2 total 59 12.71 ± 29.06 8.75 1.88-231.2 healthy controls 29 17.89 ± 15.99 12.50 7.5-78.13 il-21 newly diagnosed pv 26 28.21 ± 23.81 21.94 7.1-122.7 .044 pv in remission 33 42.35 ± 54.19 28.03 10.84-269.9 total 59 36.13 ± 43.76 25.00 7.1-269.9 healthy controls 29 40.65 ± 49.37 43.97 13.3-269.9 il = interleukin; pv = pemphigus vulgaris. 4 research | dermatol pract concept 2021;11(2):e2021035 difference among the groups was found (p = .374, anova). however, new cases had significantly different serum levels of il-4 than healthy controls (p = .005). indeed, new patients with active disease had lower mean levels of il-4 than healthy individuals. in contrast, the mean of il-4 in patients with pv in remission was comparable to that of the control group (p = .810). we did not find any significant difference between the 2 groups of pv patients (p = .343). when the 2 groups of patients were combined and considered as a total patients group, no significant difference was noted with healthy controls (p = .374). regarding il-21, based on anova, serum levels of il-21 were significantly different among the 3 groups (p = .044). we observed a significantly lower mean serum level of il-21 in new patients (p = .005). however, there was no significant difference between patients with pv in remission and healthy controls (p = .202), as well as between the 2 groups of patients (p = .221). interestingly, we detected significantly lower levels of il-21 in total pv patients (both new and remission groups) than in the healthy controls group (p = .027). discussion this study shows that serum levels of il-4 and il-21 are significantly lower among pv patients than healthy controls. moreover, serum levels of il-21 could be different between newly diagnosed pv patients and patients with pv in remisfigure 1. serum levels of il-4 (a) and il-21 (b) in patients with newly diagnosed pv (“new” group), patients with chronic, inactive pv (“remission” group), and healthy controls. 300 200 100 il -4 (p g /m l) il-4 -100 new p-value = 0.810 p-value = 0.005 p-value = 0.374 p-value = 0.343 remission healthy controls 0 il-21 p-value= 0.202 p-value = 0.005 p-value = 0.027 p-value = 0.221300 200 100 il -2 1 (p g /m l) -100 new remission healthy controls 0 (a) (b) research | dermatol pract concept 2021;11(2):e2021035 5 sion. our results for il-4 imply a role of il-4 in the early phase of the disease, but not in a chronic, inactive phase of pv. previous studies have suggested both increased [17,18] and unchanged [19,20] serum levels of il-4 in pv patients compared to controls. in contrast with several pieces of evidence implying pathogenic roles of il-4 [5,21], we observed lower serum levels in new patients than in healthy controls. regarding il-21, we again found surprising results that were different from what we expected. although there is no study on serum levels of il-21 in pv patients, there is some evidence of the pathogenic role of il-21 in pv. yuan et al showed that most t lymphocytes infiltrating pv lesions were cd4+ t helper cells expressing il-21 [22]. moreover, not only elevated plasma il-21 concentrations have been reported in pv patients, but also dsg3-specific autoreactive t cells producing il-21 were detected upon ex vivo stimulation with dsg3 [11]. all this evidence led to suggesting a possible pathogenic role of il-21 in pemphigus [7]. additionally, in our recent study [23] on the evaluation of il21 gene expression at the transcription level, we did not find any difference between pemphigus patients and healthy controls. however, 3 months after rituximab administration, the expression of il21 had increased. these controversies between previous studies and the current study might be due to this study’s limitations or even suggest a high heterogeneity of pv, which could be managed with the view of personalized medicine [23]. although we did not find any significant differences in the cytokines between the 2 groups of pv patients, different cytokine profiles during the disease phases are plausible. in addition, treatment, previous exposure to certain biologics (eg, rituximab), and duration of disease could change the cytokine profiles of the patients. for example, in our recent study, we showed that, 3 months after rituximab administration, the expression of ebi3, pdcd1, il21 and il22 had increased (24]. additionally, in another study, we showed that the outcome of treatment with rituximab was different between patients treated early or late [25]. this finding might be explained by switching between the immune responses’ arms as time passes or might depend on the exposure to certain therapeutic agents. in this study, we tried to minimize the effects of treatment by including only patients who were off therapy or on minimal therapy. however, this study still has some limitations, which should be addressed. firstly, patients in the pv in remission group were not homogeneous. in fact, they were either in complete or incomplete remission. secondly, the majority of blood samples in the control group were taken from parents or siblings of the patients. therefore, because of their similar genetic backgrounds, these samples might have introduced some errors in the results and might not be representative of the healthy population. thirdly, the severity of patients’ disease was not considered. calculation of pdai scores, measurement of anti-dsg1 and anti-dsg3 levels, and evaluation of their associations with serum cytokines in a study with a larger number of patients are recommended for future studies. conclusions in conclusion, due to significantly different serum levels of il-4 and il-21 among the newly diagnosed pv patients and healthy controls, it can be speculated that these cytokines are involved in the development and pathogenesis of pv. however, according to the literature and due to the mentioned limitations of this study, especially the selection of controls, our results, especially the lower level of these cytokines in patients than in controls, might not be absolutely trustable. therefore, future studies without the mentioned limitations are required. acknowledgment this research was supported by tehran university of medical sciences (tums); grant no. 96-01-101-33881. references 1. amber kt, staropoli p, shiman mi, elgart gw, hertl m. autoreactive t cells in the immune pathogenesis of pemphigus vulgaris. exp dermatol. 2013;22(11):699-704. doi: 10.1111/exd.12229. pmid: 24433179. 2. fang h, li q, wang g. the role of t cells in pemphigus vulgaris and bullous pemphigoid. autoimm rev. 2020:102661. doi: 10.1016/j.autrev.2020.102661. pmid: 32942041. 3. tavakolpour s, mahmoudi h, mirzazadeh a, et al. pathogenic and protective roles of cytokines in pemphigus: a systematic review. cytokine. 2020;129:155026. doi: 10.1016/j.cyto.2020.155026. pmid: 32058276. 4. mahmoudi h, ebrahimi e, daneshpazhooh m, et al. single‐nucleotide polymorphisms associated with pemphigus vulgaris: potent markers for better treatment and personalized medicine. int j immunogenet. 2020;47(1):41-49. doi: 10.1111/iji.12451. pmid: 31342641. 5. tavakolpour s, tavakolpour v. interleukin 4 inhibition as a potential therapeutic in pemphigus. cytokine. 2016;77:1891-95. doi: 10.1016/j.cyto.2015.09.017. pmid: 26440137. 6. cho mj, ellebrecht ct, payne as. the dual nature of interleukin-10 in pemphigus vulgaris. cytokine. 2015;73(2):335-341. doi: 10.1016/j.cyto.2014.11.002. pmid: 25464924. 7. tavakolpour s. interleukin 21 as a new possible player in pemphigus: is it a suitable target? int immunopharmacol. 2016;34:139145. doi: 10.1016/j.intimp.2016.02.020. pmid: 26945832. 8. tavakolpour s, kheiry f, mirsafaei hs, akhlaghdoust m. the possible role of interleukin-35 and its therapeutic potential in pemphigus. int immunopharmacol. 2017;42:11-7. doi: 10.1016/j.intimp.2016.11.005. pmid: 27855302. 9. takahashi h, kouno m, nagao k, et al. desmoglein 3-specific cd4+ t cells induce pemphigus vulgaris and interface dermatitis 6 research | dermatol pract concept 2021;11(2):e2021035 in mice. j clin invest. 2011;121(9):3677-3688. doi: 10.1172/ jci57379. pmid: 21821914. 10. veldman cm, gebhard kl, uter w, et al. t cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. j immunol. 2004;172(6):3883. doi: 10.4049/jimmunol.172.6.3883. pmid: 15004196. 11. hennerici t, pollmann r, schmidt t, et al. increased frequency of t follicular helper cells and elevated interleukin-27 plasma levels in patients with pemphigus. plos one. 2016;11(2):e0148919. doi: 10.1371/journal.pone.0148919. pmid: 26872212. 12. zhu h, chen y, zhou y, wang y, zheng j, pan m. cognate th2-b cell interaction is essential for the autoantibody production in pemphigus vulgaris. j clin immunol. 2012;32(1):114-123. doi: 10.1007/s10875-011-9597-4. pmid: 22009001. 13. xu rc, zhu hq, li wp, zhao xq, yuan hj, zheng j, et al. the imbalance of th17 and regulatory t cells in pemphigus patients. eur j dermatol. 2013;23(6):795-802. doi: 10.1684/ ejd.2013.2177. pmid: 24192290. 14. kim ar, han d, choi jy, seok j, kim s-e, seo s-h, et al. targeting icos expressed on cxcr5+ pd-1+ t helper cells suppresses the progression of pemphigus vulgaris. j allergy clin immunol. 2020;146(5):1070-1079.e8. doi: 10.1016/j.jaci.2020.03.036. pmid: 32311391. 15. tavakolpour s, tavakolpour v. interleukin 4 inhibition as a potential therapeutic in pemphigus. cytokine. 2016;77:189-95. doi: 10.1016/j.cyto.2015.09.017. pmid: 26440137. 16. murrell df, dick s, ahmed a, et al. consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. j am acad dermatol. 2008;58(6):1043-1046. doi: 10.1016/j.jaad.2008.01.012. pmid: 18339444. 17. satyam a, khandpur s, sharma vk, sharma a. involvement of t(h)1/t(h)2 cytokines in the pathogenesis of autoimmune skin disease-pemphigus vulgaris. immunol invest. 2009;38(6):498509. doi: 10.1080/08820130902943097. pmid: 19811408. 18. el-darouti ma, hegazy ra, abdel hay rm, et al. study of t helper 1 and t helper 2 responses in pemphigus vulgaris patients receiving interferon alpha 2a injections in addition to a standard protocol therapy: a randomized controlled trial. arch dermatol res. 2015;307(4):299-307. doi: 10.1007/s00403-014-1522-2. pmid: 25450635. 19. lee sh, hong wj, kim s-c. analysis of serum cytokine profile in pemphigus. ann dermatol. 2017;29(4):438-445. doi: 10.5021/ ad.2017.29.4.438. pmid: 28761292. 20. timoteo rp, da silva mv, miguel cb, et al. th1/th17-related cytokines and chemokines and their implications in the pathogenesis of pemphigus vulgaris. mediators inflamm. 2017;2017:7151285. doi: 10.1155/2017/7151285. pmid: 28321152. 21. tavakolpour s. dupilumab: a revolutionary emerging drug in atopic dermatitis and its possible role in pemphigus. dermatol ther. 2016;29(5):299. doi: 10.1111/dth.12327. pmid: 26800435. 22. yuan h, zhou s, liu z, et al. pivotal role of lesional and perilesional t/b lymphocytes in pemphigus pathogenesis. j invest dermatol. 2017;137(11):2362-2370. doi: 10.1016/j. jid.2017.05.032. pmid: 28647348. 23. tavakolpour s. towards personalized medicine for patients with autoimmune diseases: opportunities and challenges. immunol letters. 2017;190:130-138. doi: 10.1016/j.imlet.2017.08.002. pmid: 28797806. 24. tavakolpour s, mahmoudi h, karami f, et al. investigating expression pattern of eight immune-related genes in pemphigus patients compared with the healthy controls and after rituximab therapy: potentials roles of ctla4 and fcgr3a genes expressio in outcomes of rituximab therapy. dermatol ther. 2020;33(6):e14380. doi: 10.111/dth.14380. pmid: 33090639. 25. balighi k, daneshpazhooh m, akbari z, tavakolpour s, azimi p, azizpour a. comparing the short-term therapeutic effects and safety profiles of rituximab therapy in pemphigus vulgaris patients either early treated or later than six months. j dermatolog treat. 2018:1-4. doi: 10.1080/09546634.2018.1509049. pmid: 30081690. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com background: the dermatoscopic features of facial lentigo maligna (lm), facial lentigo maligna melanoma (lmm) and acral lentiginous melanoma (alm) have been well described. this is the first description of the dermatoscopic appearance of a clinical series of cutaneous non-facial non-acral lentiginous growth pattern melanomas. objective: to describe the dermatoscopic features of a series of cutaneous non-facial non-acral lentiginous growth pattern melanomas in an australian skin cancer practice. method: single observer retrospective analysis of dermatoscopic images of a one-year series of cutaneous non-facial, non-acral melanomas reported as having a lentiginous growth pattern detected in an open access primary care skin cancer clinic in australia. lesions were scored for presence of classical criteria for facial lm; modified pattern analysis (“chaos and clues”) criteria; and the presence of two novel criteria: a lentigo-like pigment pattern lacking a lentigo-like border, and large polygons. results: 20 melanomas occurring in 14 female and 6 male patients were included. average patient age was 64 years (range: 44-83). lesion distribution was: trunk 35%; upper limb 40%; and lower limb 25%. the incidences of criteria identified were: asymmetry of color or pattern (100%); lentigolike pigment pattern lacking a lentigo-like border (90%); asymmetrically pigmented follicular openings (apfo’s) (70%); grey blue structures (70%); large polygons (45%); eccentric structureless area (15%); bright white lines (5%). 20% of the lesions had only the novel criteria and/or apfo’s. limitations: single observer, single center retrospective study. conclusions: cutaneous non-facial non-acral melanomas with a lentiginous growth pattern may have none or very few traditional criteria for the diagnosis of melanoma. criteria that are logically expected in lesions with a lentiginous growth pattern (lentigo-like pigment pattern lacking a lentigo-like border, apfo’s) and the novel criterion of large polygons may be useful in increasing sensitivity and specificity of diagnosis of these lesions. further study is required to establish the significance of these observations. abstract research | dermatol pract concept 2014;4(1):13 77 dermatoscopic features of cutaneous non-facial non-acral lentiginous growth pattern melanomas jeff keir1 1 department of dermatology, school of medicine, cardiff university, wales, uk; northern rivers skin cancer clinic, ballina, nsw, australia keywords: dermatoscopy, lentiginous melanoma, lentigo maligna, large polygons, asymmetrically pigmented follicular openings citation: keir j. dermatoscopic features of cutaneous non-facial and non-acral lentiginous growth pattern melanomas. dermatol pract concept. 2014;4(1):13. http://dx.doi.org/10.5826/dpc.0401a13 received: august 15, 2013; accepted: august 27, 2013; published: january 31, 2014 copyright: ©2014 keir. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: jeffrey keir mbbs fracgp fscca, northern rivers skin cancer clinic, ballina, nsw, australia. email: tamarvillage@gmail.com 78 research | dermatol pract concept 2014;4(1):13 been submitted for histology and were reported by any of six different pathologists, three each from two dermatopathology practices. all lesions had been photographed dermatoscopically with a nikon coolpix 4500 digital camera (nikon corporation, tokyo, japan) coupled to a dermlite ii pro hr dermatoscope (3gen llc, san juan capistrano, california). all facial and acral lesions were first excluded. histopathology reports of the remaining lesions were then reviewed. only those reported as having a lentiginous growth pattern were included and the following types of lesions were excluded: lesions with an ssm growth pattern (predominantly nested and pagetoid spread growth pattern; lesions with a mixed lentiginous and ssm growth pattern; lesions with rare growth patterns; and lesions with unspecified growth patterns. the following data was then extracted from the patient records of the included cases: patient age, patient sex, site of lesion, breslow thickness. dermatoscopic images of the lesions that met the inclusion criteria were reviewed by the author and scored for the presence or absence of: criteria used for facial lm [3]; criteria of chaos and clues [9]; presence or absence of a global appearance of lentigo-like pigment pattern lacking lentigolike border; and presence or absence of large polygons. a lentigo-like pigment pattern was defined as any combination of light brown structureless pattern, curved lines (“fingerprinting”) or fine lines reticular. a lack of lentigo-like border was defined as the lesion border not being sharply defined. large polygons have been previously defined informally by the author [10]. they are polygonal geometric shapes larger than the perifollicular rhomboidal structures previously described for facial lm and are formed by straight lines. the lines are grey or light brown (which on high magnification themselves may be formed by multiple fine dots) or are formed by the straight edge of a junction between lighter and darker areas of the lesion. these shapes may be complete (figure 1) or incomplete (figure 2) or may be formed by a coalescence of smaller geometric structures. they may be subtle and are best appreciated at lower magnification. results over the study period, a total of 66 cutaneous melanomas were detected in the practice. the inclusion criteria were met by 20 lesions on 20 patients. excluded from the study were acral or facial lesions (n=18) and non-facial non-acral lesions which lacked a lentiginous growth pattern (n=28). the histological growth patterns of the excluded non-facial non-acral lesions were: ssm pattern (n=13); mixed pattern (n=11); growth pattern not specified (n=3); and desmoplastic (n=1). there were 14 female and 6 male patients; average patient age was 64 years (range: 44-83). lesion distribution was: introduction cutaneous lentiginous growth pattern melanomas have been traditionally recognized in the literature as being either lentigo maligna/lentigo maligna melanoma (lm/lmm) of the head and neck, or acral lentiginous melanoma (alm) of the palmar and plantar skin. they are commonly quoted to comprise about 5% each of all melanomas. cutaneous lentiginous growth pattern melanomas may, however, occur more frequently than previously thought [1,2]; and in areas of warm climate, high ultraviolet light intensity (uvli) and predominantly outdoor lifestyles it is logical to expect that lentiginous growth pattern melanomas, particularly of the lm/ lmm type, may occur with increased frequency on non-facial and non-acral sites than in cooler and lower uvli climates. the dermatoscopic criteria for the detection of facial lm/ lmm and of alm are well established, and these features correlate with the unique histological structure of facial skin (absence of rete ridges and presence of numerous pilosebaceous units) [3] and plantar and palmar skin (ridge and furrow structures) [4,5]. some dermatoscopic features of non-acral, non-facial lentiginous growth pattern melanomas have recently been described in a report [6], and these and other features may be important in detecting these lesions in geographic regions where they may be expected to occur. as the traditional dermatoscopic criteria for detection of melanoma have been developed in temperate climates and weighted toward the detection of invasive lesions (mainly superficial spreading melanoma [ssm] growth pattern), they may miss detection of non-acral non-facial lentiginous growth pattern melanomas. additionally, a study of pigmented lesions in an australian primary care series demonstrated that the first-step criteria of the traditional two-step algorithms lacked specificity in identifying lesions as melanocytic, thus additional diagnostic criteria may be helpful to differentiate cutaneous non-facial non-acral lentiginous growth pattern melanomas from other lentigo-like lesions [7]. objective this study aims to describe the features of a series of cutaneous non-facial, non-acral lentiginous growth pattern melanomas seen in an open access primary care skin cancer clinic over a one-year period. method clinical data, histopathology records, clinical and dermatoscopic images and skin cancer audit and research database [8] records for all cutaneous melanomas detected over a oneyear period in an open access primary care skin cancer practice in coastal regional australia were reviewed. all lesions had research | dermatol pract concept 2014;4(1):13 79 involvement by the atypical melanocytes. nesting, bridging of rete ridges and pagetoid spread may be occasionally present but are not prominent features, although the latter has been described in some lentiginous melanomas [12,13,14]. they frequently occur on sundamaged skin where there may be varying degrees of epidermal and dermal atrophy as well as elastosis; lentigo maligna is the label used in this context. by their very nature they do not demonstrate many of the classical dermatoscopic features of melanoma: brown and black dots require pagetoid spread; thick lines reticular require preservation of rete ridges as well as bridging of rete ridges; pseudopods and radial lines require cords of cells to form [15, 16]. when in situ, they will not exhibit a large range of colors. the dermatoscopic features of cutaneous non-facial nonacral melanomas with a lentiginous growth pattern should trunk 35%; upper limb 40%; and lower limb 25%. there were two thin invasive melanomas with the remainder being in-situ. the incidence of dermatoscopic criteria identified in the series was: chaos 100% (n=20); lentigo-like pigment pattern lacking a lentigo-like border 90%; asymmetrically pigmented follicular openings (apfo’s) 70% (n=14); grey blue structures 70% (n=14); large polygons 45% (n=9); eccentric structureless area 15% (n=3); bright white lines 5% (n=1) (see table 1). twenty percent of all lesions had only the novel criteria and/or apfo’s. examples of lesions and key dermatoscopic features are illustrated in figures 1 to 5. discussion the coastal regions of northern australia have a high uv index, year round warm climate, a largely caucasian population and an outdoor sporting lifestyle. the local government region in which the clinic is located has the highest reported incidence of invasive melanoma in the world, with an age adjusted annual incidence of 100:100,000 per year for the 2004-2008 period [11]. chronic ultraviolet (uv) exposure occurs here not just on the head and neck but on the trunk and limbs. it is thus not surprising that there was a high incidence of cutaneous non-facial non-acral lentiginous growth pattern melanomas in this series, comprising 30% of all melanomas detected in the one-year period. if the facial lesions with a lentiginous growth pattern are included, cutaneous lentiginous growth pattern melanomas comprise 58% of melanomas seen in the practice over the study period, far higher than the traditionally quoted figures of 5%. histologically, cutaneous lentiginous growth pattern melanomas are comprised of a poorly circumscribed proliferation of atypical melanocytes at the dermoepidermal junction, usually with confluence and often showing follicular figure 1. an 8 x 11 mm diameter lentiginous growth pattern melanoma showing multiple complete large polygons. [copyright: ©2014 keir.] figure 2. a 13 mm diameter lentiginous growth pattern melanoma showing complete and incomplete large polygons. [copyright: ©2014 keir.] figure 3. dermatoscopy of case 13. this 6 mm diameter thin invasive melanoma shows a lentigo-like pigment pattern (light brown structureless and lines curved) and lacks a defined lentigo like border. arrows indicate multiple apfos as eccentrically pigmented light brown and/or grey circles. [copyright: ©2014 keir.] 80 research | dermatol pract concept 2014;4(1):13 the presence of geometric structures in melanoma has been previously described: rhomboidal structures in facial lentigo maligna [3,6], the geometric cutaneous sign [17], and a “zig-zag” pattern in facial lentigo maligna [18]. the presence of the large polygons defined by straight lines and often centred around follicles remains to be explained and verified, but may be due to regression phenomena. although cutaneous in-situ lentiginous growth pattern melanomas are said to have a low rate of progression to invasion of much less than 1% per year [19], 10% of the lesions seen in a one-year period in this practice were invasive. application of the criteria of lentigo-like lesion without lentigo-like border, apfo’s and large polygons to non-facial non-acral lesions may result in an increased detection of these melanomas before they become invasive. be able to be logically predicted from their histological description: the modest proliferation of melanocytes at the dej predicts a light brown color whose pattern will reflect preservation or otherwise of the rete ridges; the poor circumscription predicts that the lesion will not have a sharply defined edge; and follicular involvement predicts apfos. it is known that melanomas are immunogenic tumors, often provoking a host response: if there has been regression, there will be grey structures—usually grey dots and clods. in many respects these lesions may thus clinically resemble solar lentigines or lichen planus-like keratoses and often will occur on patients whose chronic uv exposure has resulted in a background assortment of many solar lentigines from which any lentiginous growth pattern melanoma must be distinguished. table 1. results showing demographics, site, breslow thickness and positive dermatoscopic criteria by case. [copyright: ©2014 keir] site breslow thickness dermatoscopic features* id sex age chaos lentigolike, lacking lentigo-like border apfos† polygons grey structures eccentric structureless area white lines 1 f 73 arm in situ x x x x 2 f 69 back in situ x x x x 3 f 54 back in situ x x x 4 f 54 chest in situ x x x 5 m 68 forearm in situ x x x x 6 f 55 back in situ x x x x 7 f 69 arm in situ x x x x 8 f 80 leg in situ x x x x 9 f 65 thigh in situ x x x x 10 f 46 back in situ x x x x 11 m 59 back 0.45 mm x x x 12 m 78 back in situ x x x x 13 f 44 forearm 0.29 mm x x x x x 14 m 70 thigh in situ x x x 15 f 59 back in situ x x x x 16 m 67 leg in situ x x x x x 17 m 65 arm in situ x x x x 18 f 57 arm in situ x x x 19 f 63 arm in situ x x x x x 20 f 83 forearm in situ x x x x x *note: the following dermatoscopic features were not seen in any lesion: classic lm features: rhomboidal structures. chaos and clues features: lines thick reticular, lines thick branched, pseudopods or lines radial segmental, black dots or clods peripheral, polymorphous vessels. †asymmetrically pigmented follicular openings research | dermatol pract concept 2014;4(1):13 81 with the criteria of apfo’s and large polygons detected the great majority of these lesions. one in five of the lentiginous melanomas in the study lacked any previously described dermatoscopic criteria for diagnosis of non-facial melanoma. in a warm high uv climate, cutaneous non-facial nonacral lentiginous growth pattern melanomas may be more common than previously reported and may possibly progress to invasion at a greater rate than previously reported. these additional dermatoscopic criteria may be helpful to increase early detection of these lesions. further multi-observer study with a larger series is required to verify these conclusions. references 1. swetter sm, boldrick jc, jung sy, egbert bm, harvell jd. increasing incidence of lentigo maligna melanoma subtypes: northern california and national trends 1990-2000. j invest dermatol. 2005;125(4):685-91. 2. forman sb, ferringer tc, peckham sj, et al. is superficial spreading melanoma still the most common form of malignant melanoma? j am acad dermatol. 2008;58(6):1013-20. 3. stolz w, schiffner r, burgdorf whc. dermatoscopy for facial pigmented skin lesions. clin dermatol. 2002:20(3):276-78. 4. oguchi s, saida t, koganehira y, et al. characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin: a videomicroscopic study. arch dermatol. 1998; 134(5):563-68. 5. ishihara y, saida t, miyazaki a, et al. early acral melanoma in situ: correlation between the parallel ridge pattern on dermoscopy and microscopic features. am j dermatopathol. 2006;28(1):21-27. 6. lau yn, affleck ag, fleming cj. dermatoscopic features of extrafacial lentigo maligna. clin exp derm. 2013; 38:612-616. 7. tschandl p, rosendahl c, kittler h. accuracy of the first step of the dermatoscopic 2-step algorithm for pigmented skin lesions. dermatol pract concept. 2012; 2(3):8. 8. rosendahl c, hansen c, cameron a, et al. measuring performance in skin cancer practice: the scard initiative. int j dermatol. 2011;50(1):44-51. 9. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—‘chaos and clues’. aust fam physician. 2012;41(7):482-7. 10. keir j. polygons in dermatoscopy—original presentation. july 9 2010. available at http://polygonsindermatoscopy.blogspot.com. au/. accessed 13th august 2013. 11. nsw cancer registry statistical reporting online statistics module [cancer institute nsw web site]. http://www.cancerinstitute.org.au/data-and-statistics/cancer-statistics/online-statisticsmodule. accessed 13th august 2013. 12. smoller b. histologic criteria for diagnosing primary cutaneous malignant melanoma. mod pathol. 2006;19:s34-s40. 13. reed ja, shea cr. lentigo maligna: melanoma in situ on chronically sun-damaged skin. arch pathol lab med. 2011;135(7): 838-41. 14. king r. lentiginous melanoma. arch pathol lab med. 2011; 135:337-41. limitations retrospective, single observer, single center study. conclusion cutaneous non-facial non-acral lentiginous growth pattern melanomas may lack traditional melanocytic criteria, or in the case of presence of network, the melanocytic criteria present may lack specificity. the global criterion of lentigolike pigment pattern lacking a lentigo-like border, combined figure 4. dermatoscopy of case 16. this 4.5 mm diameter melanoma in situ shows a lentigo-like pigment pattern (light brown structureless and lines curved) and lacks a defined lentigo like border. there are multiple complete and incomplete large polygonal shapes of varying sizes formed by lines composed of fine brown dots. arrows indicate multiple apfo’s as eccentrically pigmented light brown and/or grey circles. [copyright: ©2014 keir.] figure 5. dermatoscopy of case 19. this 4 x 7 mm diameter melanoma in situ shows a lentigo-like pigment pattern (light brown structureless and lines curved) and lacks a defined lentigo like border. in the center of the lesion, indicated by the circled area, there are multiple complete and incomplete large polygonal shapes of varying sizes formed by lines composed of fine brown dots. arrows indicate multiple apfo’s as eccentrically pigmented light brown and/or grey circles. [copyright: ©2014 keir.] http://polygonsindermatoscopy.blogspot.com.au/ http://polygonsindermatoscopy.blogspot.com.au/ http://www.cancerinstitute.org.au/data-and-statistics/cancer-statistics/online-statistics-module http://www.cancerinstitute.org.au/data-and-statistics/cancer-statistics/online-statistics-module http://www.cancerinstitute.org.au/data-and-statistics/cancer-statistics/online-statistics-module 82 research | dermatol pract concept 2014;4(1):13 17. morris ad, gee bc, millard lg. geometric cutaneous melanoma: a helpful clinical sign of malignancy? dermatol surg. 2003;29(8):827-8. 18. slutsky jb, marghoob aa. the zig-zag pattern of lentigo maligna. arch dermatol. 2010;146(12):1444. 19. weinstock ma, sober aj. the risk of progression of lentigo maligna to lentigo maligna melanoma. br j dermatol. 1987;116(3):303–10. 15. pellacani g, longo c, malvehy j, et al. in vivo confocal microscopic and histopathologic correlations of dermoscopic features in 202 melanocytic lesions. arch dermatol. 2008;144(12):1597-608. 16. braun rp, scope a, marghoob aa, kerl k, rabinovitz hr, malvehy j. histopathologic tissue correlations of dermoscopic structures. in: marghoob aa, malvehy j, braun r (eds.). atlas of dermoscopy. second edition. new york: informa healthcare, 2012:10-32. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com balloon cell melanoma is a rare melanoma subtype, with only one previous case with dermatoscopy published. it is often non-pigmented, leading to diagnostic difficulty, and there is a tendency for lesions to be thick at diagnosis. we report a case of balloon cell melanoma on the forearm of a 61-year-old man with both polarized and non-polarized dermatoscopy and dermatopathology. it presented as a firm pale nodule with focal eccentric pigmentation. the clinical images evoke a differential diagnosis of dermatofibroma, dermal nevus, spitz nevus and basal cell carcinoma as well as melanoma. this melanoma was partially pigmented due to a small, pigmented superficial spreading component on the edge of the non-pigmented balloon cell nodule, prompting further evaluation. in retrospect there was the clue to malignancy of polarizing-specific white lines (chrysalis structures) and polymorphous vessels, including a pattern of dot vessels. the reticular lines exclude basal cell carcinoma, polarizing-specific white lines are inconsistent with the diagnosis of dermal nevus and their eccentric location is inconsistent with both spitz nevus and dermatofibroma. excision biopsy was performed, revealing a superficial spreading melanoma with two distinct invasive components, one of atypical non-mature epithelioid cells and the other an amelanotic nodular component, comprising more than 50% of the lesion, characterized by markedly distended epithelioid melanocytes showing pseudo-xanthomatous cytoplasmic balloon cell morphology. a diagnosis of balloon cell melanoma, breslow thickness 1.9 mm, mitotic rate 3 per square millimeter was rendered. wide local excision was performed, as was sentinel lymph node biopsy, which was negative. abstract observation | dermatol pract concept 2014;4(1):11 69 balloon cell melanoma: a case report with polarized and non-polarized dermatoscopy and dermatopathology james maher1, alan cameron2, sharon wallace3, rafael acosta-rojas4, david weedon5, cliff rosendahl2 1 australian skin face body, ballarat, australia 2 school of medicine, the university of queensland, australia 3 st john of god pathology, ballarat, australia 4 deakin university, geelong, australia 5 sullivan nicolaides pathology, brisbane, australia keywords: dermatoscopy, dermoscopy, dermatopathology, balloon cell melanoma, balloon cells, chrysalis structures citation: maher j, cameron a, wallace s, acosta-rojas r, weedon d, rosendahl c. balloon cell melanoma: a case report with polarized and non-polarized dermatoscopy and dermatopathology. dermatol pract concept. 2014;4(1):11. http://dx.doi.org/10.5826/dpc.0401a11 received: august 12, 2013; accepted: september 9, 2013; published: january 31, 2014 copyright: ©2014 maher et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, ph.d., po box 734, capalaba, qld 4157, australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com mailto:cliffrosendahl@bigpond.com 70 observation | dermatol pract concept 2014;4(1):11 isolated lesion on the radial aspect of the left forearm. it was clearly nodular, with a smooth shiny surface, pale over most of its surface area with three discrete areas of brown pigmentation asymmetrically distributed at the periphery. three hair shafts were seen protruding from the surface of the nodule. a polarized dermatoscopy image (figure 2) taken with a dermlite dl3 dermatoscope (3gen, llc) coupled to a canon eos 450d camera showed a lesion 7 mm in maximum diameter. there was a central structureless white area with a rim of structureless brown at the superior border with very focal pigmented reticular lines. a small number of linear curved vessels were visible at the perimeter of the structureless white area and there was a pattern of dot vessels at the superior extremity of the image of the lesion (black arrow) and another at the lower left extremity (red arrow). the dot vessels seen at the top of the image were separated by a pattern of white perpendicular lines (black arrow) which were whiter than surrounding skin, that skin being characterized by confluent ephelides. a non-polarized dermatoscopic image (figure 3) (dermlite dl3 /canon eos case report a 61-year-old man attended a primary care skin cancer practitioner in ballarat, victoria, australia. there was no known family history of skin cancer. there was a past history of sunburn, and he had previously been treated for multiple non-melanoma skin cancers and one lentigo maligna. the only known comorbidity was hyperlipidemia for which the patient was taking a statin-class medication. the patient had no concern about any skin lesion and was not aware of a lesion on his left forearm in proximity to his wristwatch. on examination the patient was noted to have skin of fitzpatrick photo-type 2 and in addition to eight suspected bccs, a lesion was noticed on the left forearm (figure 1), which was firm and nodular to palpation. clinical and closeup images (figure 1a and b) taken with a canon eos 450d camera (canon usa, inc.) revealed a small, well-defined, figure 1. clinical (a) and close up (b) images of a pale nodule on the forearm of a 61-year-old man with skin of fitzpatrick photo-type 2. there are foci of eccentric pigmentation at the periphery. three hairs, similar to surrounding hairs, are seen to be emerging from the nodule. [copyright: ©2014 maher et al.] figure 2. polarized dermatoscopy image of the lesion shown in figure 1. there is a structureless white area with a rim of structureless brown containing focal reticular lines. a focal pattern of dot vessels coincides with a focal pattern of polarizing-specific perpendicular white lines (black arrow). there is another separate focal pattern of dot vessels (red arrow). elsewhere at the periphery of the structureless white area there are a several linear (curved) vessels. [copyright: ©2014 maher et al.] figure 3. non-polarized dermatoscopy image of the lesion shown in figure 2. no white lines are seen in this image. [copyright: ©2014 maher et al.] observation | dermatol pract concept 2014;4(1):11 71 of melanocytes, displaying nuclear atypia, including mitotic figures and balloon cell morphology, penetrating to the deep dermis (figures 4 and 7). staining with ki67 was positive in the balloon cell component. the lesion was signed out as a superficial spreading melanoma with an epidermal component, a dermal component of epithelioid cells and also a nodular component of balloon cells. breslow thickness was 1.9 mm with a mitotic rate 3 per square millimeter. no associated nevus was identified. the balloon cell component comprised over 50% of the lesion histologically, which categorized this lesion as a balloon cell melanoma as defined by kao et al [1]. wide deep excision was performed, as was sentinel lymph node biopsy, which was negative. at follow up 2 years posttreatment there is no reported recurrent disease. 450d) showed the same features as the polarized image with the exception that the focus of perpendicular white lines was no longer visible and these white lines could therefore be described as polarizing-specific white lines, also known as chrysalis structures. the patient was referred to a plastic surgeon who performed an excision biopsy. histopathology (figures 4-7) showed an atypical melanocytic lesion with an architecturally disorganized intraepidermal component composed of both nested and single atypical melanocytes with some areas of intraepidermal pagetoid spread (figures 5 and 6). in one area, non-maturing atypical melanocytes arranged in variably sized nests and cords extended to the base of the papillary dermis (figure 5, center). adjacent to this (figure 5, left side and figure 6) there was a relatively large nodule figure 4. low power dermatopathologic overview of the lesion shown in figures 1-3 with a dominant nodular component comprised exclusively of markedly distended epithelioid melanocytes showing pseudo-xanthomatous cytoplasmic balloon cell morphology. on the right side of the image (black-boxed area) there is a separate invasive component of non-balloon cell malignant melanocytes. the blackboxed area is shown at higher power in figure 5 and the red-boxed area in figure 6. [copyright: ©2014 maher et al.] figure 5. medium high power view of the black-boxed area in figure 4. atypical melanocytes are confluent at the dermoepidermal junction, and on the right side of the image they are seen as a nested proliferation in the deep papillary dermis including nests in proximity to an eccrine duct. on the left side of the image a separate population of atypical melanocytes with distended balloon cell morphology is apparent. melanin pigment can be seen at the dermoepidermal junction. [copyright: ©2014 maher et al.] figure 6. medium high power view of the red-boxed area in figure 4. the melanocytic proliferation at the dermoepidermal junction is only focally confluent and pagetoid spread is sparse and partial-thickness only. there is abundant melanin at the basal layer. large balloon cells are closely packed in the reticular dermis with an absence of intervening stroma in this part of the lesion. [copyright: ©2014 maher et al.] figure 7. high power view of distended, vacuolated balloon cells in the base of the nodule shown in figure 4. arrows point to a cell in mitosis. [copyright: ©2014 maher et al.] 72 observation | dermatol pract concept 2014;4(1):11 case reported here it was of concern to the patient who had traumatized it by scratching prior to presentation [9]. clinically and dermatoscopically the previously reported case was completely amelanotic. in the absence of pigment, the clinician had suspected melanocytic status due to the presence of terminal hairs and had proceeded to perform a biopsy, at least in part, because of that. the presence of terminal hairs was considered consistent with the presence of a pre-existing congenital type nevus, which was confirmed dermatopathologically [9]. in the case we report here, hairs can also be seen emanating from the lesion but they are seen to be vellus hairs, identical to those on surrounding skin. the case reported here had no associated nevus, and therefore we assume that the hairs protruding from it are incidental vellus hairs engulfed by the growing tumor. it has been reported that white globules correlate with balloon cell nests in balloon cell nevi [10]. in the only previously reported case of bcm with dermatoscopic images there were no white structures seen, only structureless yellow, presumed to be due to serous exudate consequent on ulceration [9]. in the case reported here the balloon cell component correlated with a white structureless area. bcm is reported to be challenging dermatopathologically, and it is accepted that immunohistochemical stains as well as clinico-pathologic correlation may be required to distinguish bcm from differential diagnoses including balloon cell change in benign nevi, clear cell sarcoma, clear cell metastatic renal cell carcinoma, bcc, squamous cell carcinoma, malignant clear cell acrospiroma, sebaceous carcinoma and clear cell dermatofibroma [11]. the melanocytic nature of balloon cells has been confirmed by immunohistochemical studies [12] and electron microscopy [13,14,15]. bcm differs from balloon cell nevus with respect to nuclear pleomorphism, atypia, mitoses, an absence of intervening stroma and a lack of maturation of melanocytes with descent into the dermis [1]. the case reported here exhibited all of these features and an increased ki-67 index in the balloon cell component. another difference between balloon cell nevus and bcm is that melanocytes in bcm generally lack melanin [1,16]. the melanoma presented here was not amelanotic (figures 5 and 6) but melanin was not detected in the balloon cell component (figures 4 and 7). bcm is regarded as a vertical growth phase melanoma [15] and as there are no reported cases of bcm with a junctional component of balloon cells it has been speculated that bcm may have a dermal origin [9]. bcm has previously been reported arising in the dermal component of superficial spreading melanoma [17], and it is possible that the melanoma reported here arose in that way. bcm is a rare subtype of melanoma, characterized by presentation as a thick tumor relative to lateral dimensions with a correspondingly adverse prognosis. the case reported here, conclusions balloon cell melanoma (bcm) was first described in 1970 [2] and it has actually been described as the rarest melanoma subtype [3]. the prognosis appears to be related to breslow thickness as with melanoma subtypes in general [1,4], but presumably because bcm tends to be thick at the time of presentation, the mortality rate is reported to be high. in the largest study, 19 of 33 (57.5%) patients with follow-up data died of disseminated disease 2 months to 12 years after initial treatment [1]. the lesion reported here presented as a pale nodule with asymmetric peripheral pigmentation in contrast to the more common presentation of bcm as non-pigmented [3]. there were similarities to the clinical appearance of dermatofibroma (df) which commonly presents as a nodule with a white center and reticular pigmentation peripherally [5]. the clinical appearance could also be interpreted as that of a dermal nevus, spitz nevus or basal cell carcinoma (bcc), although spitz nevus is rare at mature age. the various clinical appearances of bcm have been described in a review of the literature as nodular, as was the case with this one, as well as ulcerated, polypoid and papillomatous and the frequent absence of pigment has been noted [3]. dermatoscopic examination confirmed the presence of chaos (defined as dermatoscopic asymmetry of structure and/ or color) with the clue of an eccentric structureless (white) area, and this was seen as a clear indication for excisional biopsy according the algorithmic method for pigmented skin lesions, “chaos and clues” [6]. the asymmetric pigmentation was actually produced by the presence of a pigmented, non-balloon cell superficial spreading component beside the balloon-cell nodule, and it was this feature which made the clinician suspect melanoma both clinically and dermatoscopically. additional clues to malignancy are also evident in the dermatoscopic images. there are polymorphous vessels including linear curved vessels and vessels as a pattern of dots (figures 2 and 3), this pattern having been described as a clue to melanoma [7]. there is also a small focus of polarizingspecific white lines (also known as chrysalis structures) (figure 2, black arrow). this structure has been described as a clue to melanoma, as well as to bcc, df and spitz nevus [8] and it is suggested in the reference cited that these chrysalis structures correlate with dermal fibrosis, which is present in this case (figure 4). notably the dermatoscopic features were not consistent with the alternative diagnoses to melanoma based on clinical assessment because focal pigmented reticular lines excluded bcc, polarizing-specific white lines excluded dermal nevus and their eccentric location was not consistent with either spitz nevus or df. there is only one other reported case of bcm with dermatoscopy. it also presented as a nodule, but unlike the observation | dermatol pract concept 2014;4(1):11 73 morphology based on pattern analysis. dermatopathology: practical & conceptual. 2008;14(4):3. 8. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j. am. acad. dermatol. 2012;67(2):194. e1–8. 9. inskip m, magee j, barksdale s, weedon d, rosendahl c. balloon cell melanoma in primary care practice: a case report. dermatol pract concept. 2013;3(3):6. 10. jaimes n, braun rp, stolz w, busam kj, marghoob aa. white globules correlate with balloon cell nevi nests. j am acad dermatol. 2011;65(4):e119–120. 11. cagnano e, benharroch d, sion-vardy n. compound nevus with congenital features and balloon cell changes—an immunohistochemical study. ann diagn pathol. 2008;12(5):362–4. 12. ide f, obara k, enatsu k, mishima k, saito i. balloon cell nevus of the soft palate: an immunohistochemical and ultrastructural study. pathol int. 2004;54(11):872–6. 13. hashimoto k, bale gf. an electron microscopic study of balloon cell nevus. cancer. 1972;30(2):530–40. 14. okun mr, donnellan b, edelstein l. an ultrastructural study of balloon cell nevus. relationship of mast cells to nevus cells. cancer. 1974;34(3):615–25. 15. magro cm, crowson an, mihm mc. unusual variants of malignant melanoma. mod pathol. 2006;19suppl 2:s41–70. 16. baehner fl, ng b, sudilovsky d. metastatic balloon cell melanoma: a case report. acta cytol. 2005;49(5):543–8. 17. kiene p, petres-dunsche c, funke g, christophers e. nodular balloon cell component in a cutaneous melanoma of the superficial spreading type. dermatology. 1996;192(3):274–6. unlike the previous reported case with a dermatoscopic image, exhibited clinical clues to malignancy related to asymmetrical distribution of melanin, which was present in the non-balloon cell component. it also had the dermatoscopic clue of polarizing-specific white lines. as a superficial spreading melanoma with a nodule of bcm, this lesion was able to be recognized with suspicion for melanoma and treated promptly. references 1. kao gf, helwig eb, graham jh. balloon cell malignant melanoma of the skin. a clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations. cancer. 1992;15;69(12):2942–52. 2. gardner wa jr, vazquez md. balloon cell melanoma. arch pathol. 1970;89(5):470–2. 3. lee l, zhou f, simms a, et al. metastatic balloon cell malignant melanoma: a case report and literature review. int j clin exp pathol. 2011;4(3):315–21. 4. magro cm, crowson an, mihm mc. unusual variants of malignant melanoma. mod. pathol. 2006;19suppl 2:s41–70. 5. zaballos p, puig s, llambrich a, malvehy j. dermoscopy of dermatofibromas: a prospective morphological study of 412 cases. arch dermatol. 2008;144(1):75–83. 6. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—“chaos and clues.” aust fam physician. 2012;41(7):482–7. 7. kittler h, riedl e, rosendahl c, cameron a. dermatoscopy of unpigmented lesions of the skin: a new classification of vessel dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021114 1 dermatology practical & conceptual dermoscopic demonstration of darier sign sweta mukherjee1, shekhar neema2, preema sinha2, sunmeet sandhu2, a.w. kashif3, s. radhakrishnan2 1 department of pediatrics, command hospital, pune, india 2 department of dermatology, armed forces medical college, pune, india 3 department of pathology, armed forces medical college, pune, india key words: darier sign, mastocytosis, dermoscopy, dermatoscopy citation: mukherjee s, neema s, sinha p, sandhu s, kashif aw, radhakrishnan s. dermoscopic demonstration of darier sign. dermatol pract concept. 2021;11(1):e2021114. doi: https://doi.org/10.5826/dpc.1101a114 accepted: june 1, 2020; published: january 29, 2021 copyright: ©2021 mukherjee et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: shekhar neema, md, febdv, department of dermatology, armed forces medical college, pune, india. email: shekharadvait@gmail.com case presentation a 9-month-old child presented with a 3-month history of a solitary hyperpigmented plaque having a leathery surface and a peau d’orange appearance located on the inner aspect of left forearm (figure 1a), dermoscopically characterized by a pigment network on a yellow background (figure 1b). urtication of the lesion upon scratching (darier sign) was evident (figure 1c) and decreased pigment network density and yellow hue intensity on dermoscopy. (figure 1d). histopathology was consistent with mastocytoma (figures 1, e and f). teaching point darier sign is only seen in 50% of cases of mastocytomas on clinical grounds [1]. dermoscopic features of mastocytosis include light brown blots, pigment network, reticular vascular pattern and yellow-orange blots [2]. pigment network and yellow-orange blots histopathologically correspond to basal layer hyperpigmentation and dense mast cell infiltrate, respectively. eliciting darier sign points to degranulation of mast cells which leads to erythema and edema that in turn cause decrease in a yellowish hue and pigment network intensity along with appearance of peripheral erythema on dermoscopy. 2 image letter | dermatol pract concept 2021;11(1):e2021114 references 1. valent p, akin c, metcalfe dd. mastocytosis: 2016 updated who classification and novel emerging treatment concepts. blood. 2017;129(11):1420-1427. doi: 10.1182/blood-2016-09-731893. pmid:2803118.0 2. vano-galvan s, álvarez-twose i, de las heras e, et al. dermoscopic features of skin lesions in patients with mastocytosis. arch dermatol. 2011;147(8):932-940. doi: 10.1001/archdermatol .2011.190. pmid: 21844452. figure 1. (a) solitary plaque measuring 1 × 1 cm over the inner aspect of forearm. (b) polarized dermoscopy shows pigment network (blue arrow) on a yellow background (blue star) (dermlite dl4, ×10). (c) same plaque after eliciting darier sign: plaque has become more well-defined, surface appears like orange-peel, and surrounding skin is erythematous. (d) polarized dermoscopy after eliciting darier sign shows decrease in intensity of yellow hue (blue star), decreased density of pigment network (blue arrow), and surrounding erythema (orange erythema). the pigment network is broader compared to figure 1c due to edema in papillary dermis (dermlite dl4, ×10). (e) histopathology shows hyperpigmentation of basal layer (h&e, ×4) and (f) presence of mast cells in the papillary and reticular dermis (h&e, ×4; toluidine blue stain ×10). a b ed f c dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020025 1 dermatology practical & conceptual introduction fibroepithelioma of pinkus (fep) is an uncommon skin lesion considered to be a rare variant of basal cell carcinoma (bcc), even though some researchers have argued for its classification as a trichoblastoma. fep appears frequently as a solitary, flesh-colored, well-demarcated plaque, typically localized on the lumbosacral area of patients aged 40 to 60 years. it often develops in patients with a history of bcc, most commonly in women [1]. dermoscopy of fep is characterized by the presence of long, linear, irregularly distributed telangiectasia; whitish striations that sometimes cover larger areas or form a honeycomb pattern, indicating a highly collagenized or fibrotic stroma; brownish gray unstructured pigmentation; punctate vessels; milia-like cysts and follicular keratotic plugs. the differential diagnoses include dermal melanocytic nevus, pedunculated fibroma, acrochordon, and seborrheic keratosis. the recommended treatment of fep is complete excision. its clinical behavior is not aggressive and, because of its good prognosis, no special follow-up is recommended [1]. case presentation a 71-year-old white man presented to our outpatient dermatology clinic for a routine skin examination. he had a history of 2 completely excised bccs on the face. examination revealed diffuse actinic damage on sun-exposed skin areas. we noticed an atypical lesion on the lumbar back of irregular shape, approximately 0.8 cm in diameter and slightly raised (figure 1). the lesion presented a pigmented area and a distinct pink area. dermoscopic characteristics included, on the pigmented area, hyperpigmented blotches, blurred borders, and irregular peripheral network. nonpigmented area findings included pink color, dotted and polymorphous vessels, fine white scales, white septal streaks, and a focal ulceration area. histological examination revealed a proliferation of basaloid cells, with hyperchromatic nuclei and central mature keratinization, in part confined to the epidermis, in part composed of anastomosing strands emanating downward from the epidermis in the context of fibromyxoid stroma. adjacent to this area, a proliferation of mature melanocytes black and pink: single lesion or double diagnosis? ilaria proietti,1,2 marco di fraia,1,2 simone michelini,1,2 daniela colapietra,1,2 emma rullo,1,3 natale porta,1,3 vincenzo petrozza,1,3 nevena skroza,1,2 concetta potenza1,2 1 department of medico-surgical sciences and biotechnologies, sapienza university, rome, italy 2 dermatology unit daniele innocenzi, a. fiorini hospital, polo pontino, terracina, italy 3 pathology unit, i.c.o.t. hospital, latina, italy key words: pinkus, nevus, collision, dermoscopy citation: proietti i, di fraia m, michelini s, colapietra d, rullo e, porta n, petrozza v, skroza n, potenza c. black and pink: single lesion or double diagnosis? dermatol pract concept. 2020;10(1):e2020025. doi: https://doi.org/10.5826/dpc.1001a25 accepted: october 9, 2019; published: december 31, 2019 copyright: ©2019 proietti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ilaria proietti, md, dermatology unit daniele innocenzi, a. fiorini hospital, via firenze, 1, 04019, terracina (lt), italy. email: proiettilaria@gmail.com mailto:proiettilaria@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020025 dermoscopic look, the lesion could be misdiagnosed as a superficial spreading melanoma with a nodular component because the pink area could resemble melanoma regression and nodulation. we believe that our case is of particular interest also because, to our knowledge, the collision between fep and melanocytic proliferation has been previously described only once, by sunassee et al [2]. references 1. haddock es, cohen pr. fibroepithelioma of pinkus revisited. dermatol ther (heidelb). 2016;6(3):347-362. 2. sunassee a, kerkvliet am, jassim ad. combined melanocytic nevus, superficial congenital and deep penetrating types with fibroepithelioma of pinkus, collision tumor—a case report. s d med. 2017;70(8):363-365. distributed in single cells and rare nests was observed along the dermoepidermal junction, with dermal fibrosis and abundant lymphocytic infiltrate. the 2 proliferations were located less than 0.1 mm from one another (figure 2). histological diagnosis: “keratotic variant of superficial basal cell carcinoma with focal features of fibroepithelioma of pinkus. the lesion collides with a melanocytic junctional nevus with regression areas.” conclusions in this case, a bcc with focal fep aspects collided with a junctional melanocytic nevus with regression areas. dermoscopy of this lesion differed from the classic fep description, even though typical bcc patterns were not so evident. in our opinion, at a first figure 2. (a) low-power photomicrograph showing skin with a proliferation of basaloid cells and a melanocytic proliferation along the dermoepidermal junction, with dermal fibrosis and abundant lymphocytic infiltrate. the 2 proliferations were located less than 0.1 mm from one another (magnification ×2). (b) high-power photomicrograph showing the basaloid lesion composed of anastomosing basaloid strands emanating downward from the epidermis in the context of fibromyxoid stroma (magnification ×20). (c) high-power photomicrograph showing proliferation of melanocytes distributed in single cells and rare nests along the dermoepidermal junction (magnification ×20). figure 1. dermoscopic characteristics of the pigmented area: hyperpigmented blotches, blurred borders, and irregular peripheral network. nonpigmented area findings: pink color, dotted and polymorphous vessels, fine white scales, white septal streaks, and a focal ulceration area. essay | dermatol pract concept 2011;1(1):16 75 pathology in the former soviet union: scientific misconduct and related phenomena sergei v. jargin, m.d.1 1department of anatomical pathology, peoples’ friendship university of russia, moscow, russia key words: scientific misconduct, plagiarism citation: jargin sv. pathology in the former soviet union: scientific misonduct and related phenomena. dermatol pract concept 2011;1(1):16. http://dx.doi.org/10.5826/dpc.0101a16. editor: harald kittler, m.d. received: october 1, 2010; accepted: december 17, 2010; published: october 31, 2011 copyright: ©2011 jargin s. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: sergei v. jargin, m.d., clementovski per 6-82, 115184 moscow, russia. email: sjargin@.mail.ru. introduction in previous publications we presented several cases of plagiarism and manipulation with statistics in the former soviet union [1,2]. along with plagiarism, partial isolation from the rest of the world gave rise to another phenomenon: extensive criticism of foreign publications. this practice has been preserved until today. here we are presenting several quotations from english summaries of recent articles. the summaries are quoted verbatim, exactly as they are printed in the journal. „negative consequences of treatment are observed at least in 16% patients at multidisciplinary hospitals and may result from the causes that are independent of medical staff, but more frequently from errors and inadequate treatment standards due to human factors. systematic improvement of professionalism, which should be started from some educational reforms at medical institutes, is needed“ [3]. comment: this is a review of foreign literature with extensive criticism of the complications of therapy and professional misconduct in medicine in the u.s.a. and other countries. materials of the agency for healthcare research and quality, the national patient safety agency, the american iatrogenic association, and other sources are used. analogous phenomena in russia are not discussed. „the experience by pathologists and clinical physicians in using the classification of tubulointerstitial lesions of the kidney, which was developed in the 1980s, has shown that it adequately reflects the structure of this important section of renal pathology. at the same time the classification is proposed to be modified on the basis of the actual current spectrum of renal pathology“ [4]. comment: a critical review, written by one of the leading russian specialists in renal pathology, quotes only one foreign source, apart from two books translated into russian. this reference is given without authors’ or editors’ names: „renal disease. classification and atlas. vol. 2: tubulo-interstitial disease. new york: tokyo, 1982.“ furthermore, we would like to present some quotations (verbatim translation from russian) from textbooks and manuals bearing official recommendations of the ministry of health. in the textbook of general pathology [5], officially recommended for medical students, extensive discussions against unnamed foreign authors are led (verbatim translations from russian): “some authors declare that most important are local changes of organs and tissues, others advocate with the same persistence paramount importance of the general condition of the organism… both do not see the main thing” (p. 26). “they [unnamed foreign authors] erroneously think dermatology practical & conceptual www.derm101.com 76 essay | dermatol pract concept 2011;1(1):16 edition was noticed by students. we received no response to our letter to the dean of the medical faculty (figure 2) verbatim translations: “insufficient erythropoietic function of brain is a possible cause of anemia.” “a focus of extramedullary hemopoiesis is named leukemic infiltration.” “in exudative glomerulonephritis, serous, fibrinous or hemorrhagic exudate can accumulate within bowman’s capsule.” ”chronic pyelonephritis is a disease with predominant involvement of glomeruli (glomerulopathy).” “primarily contracted kidney is typical for arterial hypertension.” “reddish color of the liver in cirrhosis depends on the blood flow impediment in the portal vein.” “hepar lobatum belongs to infectious cirrhosis.” “abundance of mucus in the stomach is typical for atrophic gastritis.” “renal insufficiency (amyloidosis) is one of the main causes of death in chronic obstructive lung diseases.” “necrosis of tonsils and underlying tissues is typical for scarlet fever.” “necrosis of lymph nodes is typical for scarlet fever.” previously we reported on scientific misconduct with the example of the chancellor of moscow i.m. sechenov medical academy, mikhail a. paltsev, who simultaneously officiated as a head of the department of pathology (named pathological anatomy in russia) of the same academy [1, 2]. in the year 2009, paltsev abandoned both of his offices, but before doing so he provided employment for several functionaries (or their relatives) that did not have much experience in research or practice at the department of pathology. in fact, the department of pathology was regarded as a place where anyone (with permission from the nomenklatura could become a professor, a researcher, forge scientific papers, publish plagiarized textbooks, etc. some experienced specialists were dismissed to clear places for them, which was harmful to the quality of biopsy reporting. with time, the former functionaries accumulated some knowledge of pathology, and the system worked somehow. this phenomenon has been widespread since the late 1980s: many former functionaries were allowed into educational and scientific institutions, lowering the quality of academics there. among those employed by prof. paltsev at the department of pathology of moscow i.m. sechenov medical academyare the former komsomol activist andrei b. ponomarev (a relative of paltsev, according to some witnesses) and yuri a. kirillov, who has been manager at the ministry of health responsible for pharmacological research. in the past, kirillov used incisional renal biopsies (6–10 mm in size), taken during kidneythat the final diagnosis was, is, and will be morphological” (p. 224). “…many large modern foreign manuals of general pathology provide little if any information about etiology, pathogenesis and theory of disease. they elucidate exclusively factual achievements of ultrastructural and molecular pathology, not trying to make broad generalizations” (p. 35). another hallmark of this textbook is extensive criticism of generally accepted terminology from the international classification of diseases, for example, such terms as ischemic heart disease, cerebrovascular disease (pp. 261–270), or some terms with the ending -itis, e.g., gastritis, pancreatitis, hepatitis (p.154), which is a hardly suitable discussion in a textbook for medical students. at the same time, neologisms are invented: functiogenesis, morphofunctiogenesis, amiloidoblast, amiloidoclast etc. the new edition of this book [6] was enriched with plagiarism from robbins’ pathologic basis of disease [7] (pp. 53–55 vs. 20, 27–29) and renamed rukovodstvo (manual). former functionaries, promoted to high positions in science and education, do not always maintain a duly high level of educational publications. some quotations from the tests in pathological anatomy (figure 1), an edition that was used at the peoples’ friendship university of russia, are presented below [8]. outdated and erroneous information from this figure 1. tests in pathological anatomy. [8] the multiple-choice questions from this edition have been used for testing students at the peoples’ friendship university of russia. many tests are formulated incorrectly and contain outdated or wrong information. essay | dermatol pract concept 2011;1(1):16 77 figure 2. report to the dean of the medical faculty of peoples’ friendship university of russia. translation: upper left corner: registered 3.06.98; signature of the secretary at the dean’s office. to the dean of the medical faculty of peoples’ friendship university of russia professor v.a. frolov from the lecturer of the department of pathological anatomy jargin s.v. dear victor alekseevich, it was my duty to inform you about disagreement in our department in regard to computer testing of students. the multiple-choice questions for computer testing (enclosed) contain outdated information, numerous errors and inexactitudes. at least a half of the questions should be replaced or corrected. in the process of preparation of this edition, some questions that i have compiled were changed without informing me, which additionally enhanced the number of inexactitudes. a great part of outdated or wrong information originates from the last edition of the textbook by a.i. strukov and v.v. serov “pathological anatomy”. the students notice the errors and make remarks to me and other lecturers. at the same time, the head of the department insists on obligatory testing of students using these multiple-choice questions. during a lecture, he recommended to “learn the questions with the errors.” this issue i repeatedly discussed with the head of the department and the head of studies. herewith i ask for your permission to abolish obligatory computer testing of the students in pathological anatomy until the multiple choice questions will be prepared in accordance with modern know ledge. with gratitude, jargin s.v. 03.06.1998 enclosure: edition of the tests in pathological anatomy, special course. questions, containing errors, inexactitudes and incorrect formulations, are marked in the text. 78 essay | dermatol pract concept 2011;1(1):16 preserving operations (e.g., lithotomy) from patients with acute or chronic pyelonephritis, for research of questionable quality. for further details, see http://www.freewebs.com/ruspat1/reviewofliterature.htm. moreover, following the model of the head of the department, paltsev, some other lecturers and researchers of the department were involved in scientific misconduct (e.a. kogan, l.v. lysenko, p.v. yushkov, e.m. paltseva and others). we wrote about these facts to the present chancellor of moscow i.m. sechenov medical academy (recently renamed i.m. sechenov first moscow medical university), prof. p.v. glybochko, but received no response. extensive misquoting was demonstrated in the glybochko‘s doctoral dissertation (see http://www.freewebs.com/ruspat1/ apps/photos/album?albumid=3392303). the only person who criticized some of the forged scientific works and dismissals of the specialists experienced in diagnostic pathology was prof. tatiana n. hansen (t.n. ganzen according to the table 1: translation of the table pictured in fig 3. expression of bio-molecular tumor markers in thyroid diseases. note: 1 – number of positive cases; note 2 – mean percentage of positive cells (mean expression level of the bio-molecular markers) disease markers ki-67 p53 c-myc bcl-2 1 2 1 2 1 2 1 2 thyroid carcinoma (n=36) 36 from 36 14 36 from 36 45 36 from 36 5 36 from 36 6 thyroid adenoma (n=12) 12 from 12 < 1 0 from 12 0 12 from 12 4 12 from 12 4 autoimmune thyroiditis plus carcinoma (n=9) 9 from 9 < 1 0 from 9 0 9 from 9 4 9 from 9 4 thyroid tissue surrounding carcinoma (n=16) 16 from 16 < 1 16 from 16 < 1 16 from 16 5 16 from 16 4 thyroid tissue surrounding adenoma (n=5) 0 from 5 0 0 from 5 0 5 from 5 2 5 from 5 2 figure 4. fig. 711 from the manual [16]. translation of the legend: papillary carcinoma a – cystic clefts are formed between branching papillae (x90); b – papillae with strong fibrous stalks, covered by blast cells (x120); c – glandular and papillary structures within the blastic stroma (x120) comment: the illustrations are not characteristic for papillary thyroid carcinoma. ground-glass nuclei and other typical nuclear changes are not recognizable. the image in “c” can have originated from a regressively changed goiter. figure 3. table 1 from the article [10] essay | dermatol pract concept 2011;1(1):16 79 russian spelling). for that reason she was dismissed from the academy early in the 2000s. prof. hansen was one of the best specialists in biopsy and autopsy in the department and a good lecturer. her dismissal hurt the quality of biopsy reporting and even the caliber of teaching itself. some publications [9–11], obviously based on fabricated or modified data, are contradictory to generally accepted knowledge and can be misleading for practice. for example, immunohistochemical evidence of the gene p53 mutation was reported in all 36 studied cases of differentiated thyroid carcinoma, including 11 cases of follicular, 6 cases of papillary, 5 cases of medullary, and 14 cases of ‘papillary-follicular’ (absent in modern classifications) carcinoma; whereas in all cases of adenoma and other benign thyroid conditions (26 cases) no evidence of p53 mutation was found (figure 3) [10]. resulting statistical significance of the difference is extremely high (36/36 vs. 0/26, p<0.0001). in literature, p53 mutation is regarded to be a late event in thyroid carcinogenesis, associated with undifferentiated or anaplastic carcinomas, usually not occurring in differentiated tumors [12, 13]. therefore, the statement (verbatim translation): “high degree of expression of p53 in carcinomas and its absence in adenomas allows concluding that p53 can serve as a marker of thyroid carcinoma” [9] can lead one to overdiagnosis of malignancy, especially today, when the improved economy in russia enables the purchase of modern immunohistochemical kits and other new laboratory methods. the journal arkhiv patologii, where these materials were published, is the only russian journal intended for practical pathologists. our critical letter on this topic was rejected by arkhiv patologii. access to foreign professional literature remains limited in russia [14], which is harmful for practice and research. the widely used manual of tumor pathology [15] is outdated, imprecise, and in many fields (bone marrow, lymph nodes, thyroid, soft tissue tumors, and others is hardly suitable for diagnostics. some passages from the section on thyroid tumors [16] deserve to be quoted in verbatim translation: in the section “follicular carcinoma” on p. 356, it reads: “in highly differentiated form [of the follicular thyroid carcinoma], cancerous elements more or less resemble the follicles of mature thyroid. they have different form and size; the covering cells can have hyperchromic nuclei, crawling onto one another like ground watch glasses.” comment: the term “ground watch glasses” (yadra v vide pritertykh chasovykh stekol), a mistranslation of “groundglass nuclei,” can be found in many russian-language publications. it is a diagnostic criterion of the papillary thyroid carcinoma but not of follicular carcinoma. nuclear changes, characteristic of papillary carcinoma, are not visible in the figure 5. the whole section on follicular thyroid carcinoma is presented on this page from the manual [16]. the most important diagnostic criteria of follicular carcinoma – capsular and vascular invasions – are not mentioned at all. on the basis of this description no reliable differential diagnosis between follicular thyroid carcinoma and adenoma can be made. figure 6. text fragment from the section “thyroid carcinoma”, p. 402, from the atlas [19]. translation and comment are in the text. 80 essay | dermatol pract concept 2011;1(1):16 illustrations (figure 4). in the section about follicular thyroid carcinoma, the most significant diagnostic criteria, such as the capsular and vascular invasions, are not mentioned (figure 5). using this most authoritative manual of tumor pathology, issued by the n.n. blokhin cancer research center in moscow, it is not always possible to differentiate follicular thyroid carcinoma from adenoma. for many pathologists, especially outside moscow and st. petersburg, this two-volume edition has been the main source of information on many topics. another example from the same edition is found in the section on nasopharyngeal pathology [17], where no stromal atypia of nasal polyps [18] is described. we know of a case of a false-positive diagnosis of sarcoma as a consequence of it. in the new atlas of tumor pathology [19] the following is written in the section about thyroid carcinoma (p. 402) it reads (verbatim translation): “in severe dysplasia appear cell groups with clearly visible atypia. therefore, third grade dysplasia is considered as an obligate pre-cancer, which histologically is hardly distinguishable from carcinoma in situ. at the same time, it is believed that severe dysplasia differs from non-invasive cancer because it is reversible” (figure 6). nuclear atypia (enlargement, hyperchromatism, pleomorphism) is not considered in modern literature as a criterion of malignancy in follicular and papillary thyroid nodules, and the concepts of dysplasia and carcinoma in situ are not applied to them [20]. cases of false-positive diagnoses of thyroid carcinoma, caused by misinterpretation of nuclear pleomorphism as a criterion for malignancy, are known. overdiagnosis of malignancy (cases of false-positive diagnoses of thyroid carcinoma in children with corresponding overtreatment) has obviously been one of the overestimation mechanisms of the consequences of the chernobyl accident, in particular, thyroid cancer incidence [21, 22]. finally, thanks to the economic upturn in russia, some institutions started purchasing foreign literature, but it has not sufficed. on the other hand, acquisition of literature by medical libraries has decreased since the 1980s [14]. it comes as no surprise that foreign publications are, scarcely quoted in russian scientific articles; well-known phenomena, disease entities, morphological changes etc. are described without referring to foreign publications, which can be misunderstood as something new from soviet scientists [23, 24]. the following are two quotations from english summaries of articles recently published in arkhiv patologii. the summaries are available also on pubmed. „the structure, clinical manifestations, behavior of cavernous hemangioma of the skin of the face and neck, and the oral soft tissues were studied, by using biopsy specimens from 229 patients. three types of cavernous hemangioma of these areas were identified. their preferred treatments were defined and pathogenetically warranted“ [25]. comment: in describing such a well-known lesion as cutaneous hemangioma, the authors did not quote a single foreign source. the volume, pathological anatomy by paltsev and anichkov [26], largely plagiarized from robbins’ pathologic basis of disease [1, 27], is quoted instead. another example reads, „the authors present the incidence and specific features of specific bone marrow lesion and the state of normal hemopoiesis and stroma. the criteria for the differential diagnosis of reactive polyclonal lymphoid proliferation in the bone marrow that may accompany many haematological and non-haematological diseases with specific bone marrow lesion in lymphoproliferative diseases are outlined“ [28]/ the article continues, „according to our results, several histological types of bone marrow involvement in lymphoproliferative diseases can be distinguished: diffuse, interstitial and focal“ [28]. then follows the usual description of bone marrow involvement patterns by lymphoma that can be found in many textbooks, which are not referred to. the text can be misunderstood as an original description of bone marrow involvement patterns by lymphoproliferative disorders. in conclusion, in the russian-language handbook of immunohistochemistry [29] cannot substitute for internationally used manuals [30] because it contains references to dubious publications. scientific misconduct was proven also in a series of publications from the cardiology research centre in moscow [31]. further examples and illustrations can be found at http://www.freewebs.com/ruspat1/. in summary, there are many positive changes in russian pathology. there is a spirit of cooperation among russian pathologists. there are talented medical technologists producing thin slides using old sledge microtomes. the improved economy allows the purchase of modern equipment and the introduction of new methods into practice and research. hopefully, this article will be only of historical interest in the near future. summary there is a persisting interest in the topic of scientific misconduct. the following main forms of scientific misconduct are known: plagiarism, falsification or fabrication of data, manipulations with statistics, misquoting, false or gift authorship, as well as revenge on the whistleblowers revealing and exposing such cases. of particular concern is plagiarism, which is spreading today. former functionaries, promoted to high positions in academies and universities in the former soviet union, are often unable to maintain a duly high academic standards in publications. some textbooks, manuals and journal articles are imprecise, contain plagiaessay | dermatol pract concept 2011;1(1):16 81 rism or misleading information that lead to overdiagnosis of malignancy, and examples are provided in this article. in spite of remaining shortages and drawbacks, there are grounds for optimism. the upturn of the economy in russia is making possible the purchase of foreign literature and modern equipment, introducing new methods into research and practice. therefore, we hope that this article will be only of historical interest in the near future. references 1. jargin sv. history: examples of plagiarism from the former soviet union. dermatopathology: practical & conceptual 2008;14(2):19. 2. jargin sv. manipulation with statistics in medical research. dermatopathology: practical & conceptual 2009;15(1):21. 3. vovk ei, vertkin al, zairatyants ov, frolova yuv. foreign experience in registering and analyzing the poor outcomes of treatment (in russian with english summary). arkh patol 2007;69(5):16–24. 4. perov yl. tubular interstitial pathology of the kidney (on the 25th anniversary of the who expert committee classification). [russian with english summary]. arkhiv patologii (moscow) 2008;70(1):13–16. 5. sarkisov ds, paltsev ma, khitrov nk. obshaya patologiya cheloveka [human general pathology]. moscow: meditsina, 1995. 6. paltsev ma, khitrov nk. patologiya kletki. distrofiya, atrofiya i nekroz [dystrophy, atrophy and necrosis]. in: khitrov, nk, sarkisov ds, paltsev ma, editors. rukovodstvo po obshey patologii cheloveka [manual of human general pathology]. moscow: meditsina, 1999: 42–67. 7. cotran rs, kumar v, robbins sl. robbins’ pathologic basis of disease. philadelphia: w.b. saunders co, 1989. 8. babichenko ii, vladimirtseva al, gundorova lv, kharchenko nm, jargin sv. testy po patologicheskoy anatomii. chastniy kurs [tests in pathological anatomy. special course]. moscow: peoples’ friensdhip university of russia, 1997. 9. paltsev ma, kogan ea, tuntsova oi. immunohistochemistry of biomolecular markers of early thyroid cancer [russian with english summary]. arkh patol 1997;59(6):18–23. 10. paltsev ma. kogan ea, tuntsova oi, severin es, silaeva sa, golenchenko va. morphological and molecular-genetic characteristics of carcinoma, adenoma and surrounding tissue of the thyroid gland [russian with english summary]. arkh patol 1998;60(3):5–10. 11. paltsev ma, kogan, ea, tuntsova, ov. molecular markers of early thyroid cancer. path res pract 1997;193:390 (abstract p191). 12. soares p, sobrinho-simões m. recent advances in cytometry, cytogenetics and molecular genetics in thyroid tumors and tumorlike lesions. path res pract 1995;191:304–17. 13. suáres hg. genetic alterations in human epithelial thyroid tumours. clin endocrinol 1998;48:531–6. 14. jargin sv. the state of medical libraries in the former soviet union. health info libr j 2010;27(3):244–8. 15. krayevskiy na, smolyannikov av, sarkisov, ds, editors. patologo-anatomicheskaya diagnostika opucholey cheloveka. moskow: meditsina; 1993. 16. goldburt nn. opukholi shchitovidnoi zhelezy [thyroid tumors]. in: krayevskiy na, smolyannikov av, sarkisov, ds, editors. patologo-anatomicheskaya diagnostika opucholey cheloveka [pathologo-anatomic diagnostics of human tumors]. vol 2. moskow: meditsina; 1993:349– 62. 17. bykova vp. opukholi polosti nosa, okolonosovykh pazukh i nosoglotki [tumors of nasal cavity, paranasal sinuses, and nasopharynx]. in: krayevskiy na, smolyannikov av, sarkisov, ds, editors. patologo-anatomicheskaya diagnostika opucholey cheloveka [pathologo-anatomic diagnostics of human tumors]. vol 1. moskow: meditsina; 1993:409–36. 18. mills se, fechner re. the nose, paranasal sinuses, and nasopharynx. in: diagnostic surgical pathology. vol. 2. sternberg ss. (ed.), new york: raven press; 1989:663–4. 19. paltsev ma, anichkov nm. atlas patologii opukholei cheloveka [atlas of human tumor pathology]. moscow: meditsina; 2005:402. 20. rosai j. rosai and ackerman’s surgical pathology. vol. 1. edinburgh: mosby; 2004:515–94. 21. jargin sv. thyroid cancer after chernobyl: obfuscated truth. dose-response 2011. doi: 10.2203/dose-response.11-001.jargin. 22. jargin sv. chernobyl-related cancer: re-evaluation needed. turkish journal of pathology 2010;26(2):177-81. http://www.turkjpath.org/pdf/pdf_tpd_1440.pdf 23. ulanova vi, zinzerling va. clinical and morphological characteristics of infective endocarditis in hiv-infected drug addicts (in russian with english summary). arkhiv patologii. 2006;68(3):14–8. 24. zaitsev vs, zinzerling va, tsvetkov ea. clinicomorphological characteristics of laryngeal papillomatosis in children [russian with english summary]. arkhiv patologii 2005;67(2):27–9. 25. chumakova ma, chumakova tg, chumakov aa. cavernous hemangiomas of the skin of the face and neck and the oral soft tissues (in russian with english summary). arkhiv patologii 2007;69(5):41–4. 26. paltsev ma, anichkov nm. patologicheskaya anatomia [pathological anatomy]. moscow: medicina, 2001. 27. cotran rs, kumar v, robbins sl. robbins’ pathologic basis of disease. philadelphia: w.b. saunders co, 1994. 28. frank ga, kaplanskaia ib, glasko en, semenov ea, roshchina ls, korolev av. diagnosis of lymphoproliferative diseases by bone marrow trepanobiopsy specimens [russian with english summary]. arkhiv patologii 2007;69(3):15–8. 29. petrov sv, raikhlin nt (eds.). manual on immunohistochemical diagnosis of human tumors. 3rd edition (in russian). kazan: titul, 2004. 30. jargin sv. book review: dabbs dj. diagnostic immunohistochemistry, 3rd edition, elsevier [russian]. ukrainian med j 2010;78(4):96–98. 31. jargin sv. testing of serum atherogenicity on cell cultures: assessment of reliability gazzetta medica italiana 2011;170(2):159–63. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(2):4 17 sinus histiocytosis (rosai-dorfman disease) presenting with solitary cutaneous nodule: a very rare clinical entity emilia duarte-williamson, m.d.1, fiona antony, m.d.2, radu rotarescu, m.d.3 1 dermatology department, kent and canterbury hospital, canterbury, kent, uk 2 dermatology department, frimley park hospital, frimley, surrey, uk 3 dermatology department, stafford general hospital, stafford, staffordshire, uk key words: histiocytosis, sinus histiocytosis, rosai-dorfman, nodule citation: duarte-williamson e, antony f, rotarescu r. sinus histiocytosis (rosaidorfman disease) presenting with solitary cutaneous nodule: a very rare clinical entity. dermatol pract conc. 2012;2(2):4. http://dx.doi.org/10.5826/dpc.0202a04. received: january 22, 2012; accepted: february 25, 2012; published: april 30, 2012 copyright: ©2012 duarte-williamson et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: radu rotarescu, staff residences, block 1, flat/house 9, room 1, cowan drive, stafford, st16 3rs, united kingdom. tel. 07405137128; fax. 01543576134. email: radur30@gmail.com. introduction sinus histiocytosis with massive lymphadenopathy, also known as rosai-dorfman disease, is a very rare inflammatory entity. it is generally self-limited and confined mainly to the cervical lymph nodes. cutaneous manifestations are present in approximately 10% of patients [1]. it can be accompanied by fever, neutrophilia, polyclonal hypergammaglobulinemia and an elevated erythrocyte sedimentation rate. sinus histicytosis is part of the non-langerhans cell histiocytosis or cutaneous non-histiocytosis x, in which proliferation of macrophages always lack langherhans granules. this group of disorders is usually nonaggressive, self-healing and can affect both children and adults [2-7]. sinus histiocytosis is a rare inflammatory disease mainly affecting the cervical lymph nodes, presenting with skin lesions in 10% of cases. our patient had a solitary nodule on the trunk without any other clinical signs. the histology reported a dermal neoplasm composed mainly of macrophages and lymphocytes. macrophages were aggregated in clusters resembling lymph node sinuses. lymphophagocytosis or emperipolesis (the presence of an intact cell within the cytoplasm of another cell) was noted and the diagnosis of sinus histiocytosis established. abstract mailto:radur30@gmail.com mailto:radur30@gmail.com mailto:radur30@gmail.com mailto:radur30@gmail.com mailto:radur30@gmail.com 18 observation | dermatol pract concept 2012;2(2):4 report we report a very rare case of sinus histiocytosis, which presented with only a solitary cutaneous nodule and no other clinical manifestations or lymphadenopathy. a 75-year-old man was referred to the dermatology department with a six-month history of an asymptomatic solitary nodule on the trunk. his general practitioner had diagnosed a possible pyogenic granuloma, but could not exclude a malignant lesion. his medical history was unremarkable and he was otherwise well. examination revealed a 1.2 cm purple, soft, shiny nodule with a violaceous peripheral rim in the interscapular area (figure 1). dermoscopy was featureless. the lesion was excised immediately with the clinical suspicion of a probable amelanotic melanoma, squamous cell carcinoma, or merkel cell carcinoma in mind. the pathology reported a dermal lesion composed of an infiltrate of cells expanding and filling the papillary dermis and spreading into the deep reticular dermis (figure 2a). the infiltrate included prominent macrophages with pale, vacuolated cytoplasm, some multinucleate macrophages of similar staining characteristics, other small, untransformed macrophages and a large number of lymphoid cells. lymphocytes were predominant, but a modest number of plasma cells with a smaller number of other inflammatory cells were seen. the large pale staining macrophagic cells were positive for cd 68. they also expressed s100 protein, but hmb45 was negative. the large pale staining cells were pas negative. no microorganisms were seen in a section stained by the ziehl-neelsen method. macrophages were aggregated in clusters resembling lymph node sinuses. lymphophagocytosis or emperipolesis (the presence of an intact cell within the cytoplasm of another cell) was noticed and the diagnosis of sinus histiocytosis established (figure 2b). with this surprise diagnosis the patient was seen in clinic and a thorough physical examination was carried out. no lymphadenopathy or other clinical abnormality was found. the laboratory investigations (full blood count, c reactive protein, erythrocyte sedimentation rate, coagulation screen, electrolytes, renal and liver function tests) were all normal. levels of immunoglobulins g, a, m and serum protein electrophoresis were also normal. discussion approximately 365 cases of sinus histiocytosis with massive lymphadenopathy, also known as rosai-dorfman disease, have been described in the literature [2]. sometimes the cutafigure 1. purple, soft, shiny nodule with a violaceous peripheral rim in the interscapular area. [copyright: ©2012 duarte-williamson et al.] figure 2. (a) dermal tumor composed of an infiltrate of cells expanding and filling the papillary dermis and spreading into the superficial reticular dermis showing a diffuse dermal infiltrate. haematoxylin and eosin stain, original magnification x10. (b) the infiltrate included macrophages, large number of lymphoid cells, modest number of plasma cells and smaller number of other inflammatory cells. macrophages were aggregated in clusters resembling lymph node sinuses. lymphophagocytosis or emperipolesis (the presence of an intact cell within the cytoplasm of another cell) was noticed. haematoxylin and eosin stain, original magnification x40. [copyright: ©2012 duartewilliamson et al.] a b observation | dermatol pract concept 2012;2(2):4 19 neous manifestations may be the initial and sole presenting feature of this disease [2]. massive bilateral cervical lymphadenopathy is usually the hallmark of this condition; however, our patient presented with only a solitary cutaneous nodule with no lymph node enlargement, making the diagnosis more difficult. cutaneous lesions are reported to be polymorphic with yellowish patches and macules, reddish-brown papules, plaques and nodules that can become eroded or ulcerated [2]. the aetiology of the disease remains unclear, but a possible disturbance of cell-mediated immunity or a primary infection hypothesis with epstein-barr virus have been suspected [2]. the differential diagnosis is very broad and includes both proliferative and inflammatory diseases. in our case the initial suspicion was of a cutaneous malignancy. most of the sinus histiocytoses are self-healing with spontaneous regression over a period of months to years. very rarely when an internal organ is involved, for example, liver, spleen, upper respiratory tract, then glucocorticoids or other chemotherapeutic regimens may be required. solitary cutaneous lesions can be excised. widespread cutaneous disease has been treated successfully with dapsone or thalidomide [1]. our patient is undergoing close clinical follow-up, as it is possible that the solitary cutaneous nodule is the precursor to more extensive sinus histiocytosis (rosai-dorfman disease) [1]. however, even after a long follow-up of 12 months, there are no signs of disease progression. acknowledgement many thanks to dr. fiona antony for the histopathological diagnosis and for the assistance with the case. references 1. burgdorf whc, plewig g, wolff hh, et al. sinus histiocytosis with massive lymphadenopathy. in: burgdorf whc, plewig g, wolff hh, et al. braun-falco’s dermatology 3rd ed. heidelberg: springer medizin verlag, 2009:1528-9. 2. freedberg im, eisen az, wolff k, et al. sinus histiocytosis with massive lymphadenopathy. in: freedberg im, eisen az, wolff k, et al. fitzpatrick’s dermatology in general medicine. 6th ed., new york: mcgraw hill professional, 2003:1593-4. 3. weitzman, jaffe r. uncommon histiocytic disorders: the non-langherhans cell histiocytoses. pediatr blood cancer. 2005;45(3):256-64. 4. flater jl, maddox js, obadiah jm, hurley my. cutaneous rosai-dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. j cutan med surg. 2006;10(6):281-90. 5. foucar e, rosai j, dorfman r. sinus histiocytosis with massive lymphadenopathy (rosai-dorfman disease): review of the entity. semin diagn pathol. 1990;7(1):19-73. 6. kong yy, kong jc, shi dr, et al. cutaneous rosai-dorfman disease: a clinical and histopathologic study of 25 cases in china. am j surg pathol. 2007;31(3):341-50. 7. wang kh, chen wy, liu hn, huang cc, lee wr, hu ch. cutaneous rosai-dorfman disease: clinicopathological profiles, spectrum of evolution of 21 lesions in six patients. br j dermatol 2006;154(2):277-86. dermatology: practical and conceptual review | dermatol pract concept 2020;10(2):e2020048 1 dermatology practical & conceptual introduction a laser is a device that controls the way in which energized atoms release photons. “laser” is an acronym for “light amplification by stimulated emission of radiation,” which in itself describes the working of a laser. lasers do not provide permanent hair removal, but they are popular because of selective hair damage, less time consumption, longer hair-free interval, and fewer side effects. a single treatment can reduce hair by 10%-40% and repeated treatments by as much as 90%, and these results may persist for as long as 12 months [1,2]. laser hair removal is said to be permanent when there is a stable decrease in the number of terminal hair for a period longer than the complete hair growth cycle at a given site after treatment [2]. there are various factors related to technology and patient which could result in variable, unpredictable, or poor responses to laser hair removal in spite of ensuring appropriate indications and adequate parameters of laser use. laser physics parameters laser hair removal is a multifactorial process that involves complex photothermal reaction via the epidermis to the dermal matrix, aimed to cause hair follicle damage while sparing the epidermis. various laser parameters such as power, spot size, irradiation time, and repetition rate determine the final outcome in laser hair removal. tissue parameters such as absorption and scattering coefficients, density, heat capacity, and thermal conductivity are equally important. laser treatment in hirsutism: an update yasmeen jabeen bhat,1 safia bashir,1 nahida nabi,1 iffat hassan1 1 department of dermatology, std & leprosy, government medical college, srinagar, india key words: hirsutism, laser, photothermolysis, epilation citation: bhat yj, bashir s, nabi n, hassan i. laser treatment in hirsutism: an update. dermatol pract concept. 2020;10(2):e2020048. doi: https://doi.org/10.5826/dpc.1002a48 accepted: december 23, 2019; published: april 20, 2020 copyright: ©2020 bhat et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. yasmeen jabeen bhat, postgraduate department of dermatology, std & leprosy, government medical college, karan nagar srinagar, j&k 190010, india. email: yasmeenasif76@gmail.com unwanted hair growth, which is a common aesthetic problem, has traditionally been treated using various techniques such as shaving, waxing, and epilation, but most of these provide only a temporary solution. laser and light-based technology for hair removal has become one of the fastest growing procedures in modern cosmetic dermatology in the last decade. clinical experience suggests that in the ideal subject with fair skin and dark hair, laser treatment can reduce hair growth significantly. this article reviews the various laser and light-based devices used for hair removal along with the various laser and patient parameters that affect the outcome of laser treatment for hair removal. photoepilation, when properly used, offers clear advantages when compared with older, traditional techniques. abstract https://doi.org/10.5826/dpc.1002a48 mailto:yasmeenasif76@gmail.com 2 review | dermatol pract concept 2020;10(2):e2020048 should not be compromised during laser hair removal as this can decrease response to treatment. the following sections explain these factors in detail. skin type light skin (fitzpatrick skin type i-iv) and dark hair are an ideal combination for effective hair removal. since the chances of epidermal melanin absorption are less with higher fluence, short pulse duration can be used [9,10]. the absorption is more at the level of follicular melanin rather than epidermal melanin, thus reducing the chances of epidermal damage. the long-pulsed nd:yag laser remains the recommended choice in very dark individuals and tanned patients because of its longer wavelength [11]. the safety of patients with type v-vi skin is a challenge for laser hair removal because of the high density of competing chromophore in the epidermis. a wavelength that is less absorbed by melanin may be less effective clinically as the target chromophore for hair removal laser is melanin in the hair bulb and bulge. type of hair, color of hair, and stage of hair cycle the anagen hair is more prone to laser therapy since melanin is present only in anagen hair. at any given time, almost 10%-15% of hair may be catagen or telogen stage; hence treat ment has to be extended for many months to cover as many hair follicles in its anagen stage. terminal hair, being more pigmented, responds better than vellus hair. good response to laser hair removal occurs when the targeted hair has a high concentration of chromophores. thin, fine hairs have less pigment and hence are poor choices for laser hair removal, even with best fluences and multiple treatments, compared with thick terminal hairs [12,13]. this is true when treating areas such as the upper lip, where chromophore in vellus hairs is less for laser wavelength absorption. calculated thermal relaxation time is in the range of 100 milliseconds. the pulse duration thus used has to be in this range only. a subnormal therapeutic effect is usually caused by an inadequate pulse duration. principle of laser hair removal the technology used in hair removal by lasers is based on the principle of selective photothermolysis. according to this principle, selective thermal destruction of a target will occur if sufficient energy is delivered at a wavelength well absorbed by the target within a time period less than or equal to the thermal relaxation time of the target. the thermal relaxation time is the time it takes for the target to cool (half of its baseline temperature) and transfer the heat to surrounding structures [7]. under these conditions, it is possible to selectively target structures (eg, hair follicle) while sparing the surrounding structures or tissues. the target site for the selective destruction of hair follicles can either be endogenous melanin or exogenous chromophore. “thermal damage time” rather than the thermal relaxation time has also been introduced as a new concept in laser hair removal. ideal pulse duration for medium to coarse hair removal may be longer than the thermal relaxation time of the hair follicle as indicated by various studies. dark hair that contains large amounts of eumelanin readily absorbs these wavelengths and is most susceptible to laser-induced damage [8]. factors affecting outcomes of the laser therapy patient factors an ideal patient for conventional laser hair removal is one who has thick, dark terminal hairs, light skin, and normal hormonal status. patient selection fluence a proper fluence is of paramount importance in getting the required therapeutic effect in laser hair removal. while higher fluences can increase efficacy, they can also increase adverse effects. the right fluence is determined by the highest tolerable energy or a test patch that generates perifollicular erythema and edema [3]. with a diode laser, fluences in the range of 30-35 j/cm2 are adequate for type ii-iii skin. lower fluences in the range of 20-24 j/cm2 are used for darker skin types [4]. using suboptimal fluence is one of the most important causes of a poor response to laser hair removal. with lower fluences, temporary rather than permanent removal is achieved. roosen et al studied the effect of low-fluence photoepilation on hair follicles. their findings suggest that transition of anagen follicles to catagen phase happens with low fluences [5]. long-term effects of hair removal depend on a number of factors such as hair color, skin color, and the fluence tolerated by the patient. spot size spot size refers to the size of the laser probe or head that is used during a laser procedure. this in effect is the area over which the laser beam is delivered in a single shot of laser treatment. the importance of spot size lies in scattering of laser energy by collagen fibers outside the treatment zone. more photons are likely to be scattered if smaller spot sizes are used, while with larger spot sizes a higher percentage of photons are delivered to the skin and are likely to remain within the treatment area. one study showed a superior response to 18-mm spot size in comparison with 12-mm spot size in axillary hair removal [6]. pulse duration optimal pulse duration in hair removal is calculated based on thermal relaxation time. for terminal hairs, the review | dermatol pract concept 2020;10(2):e2020048 3 fair: 25%-50%; good: 50%-75%; excellent: >75%. figure 2 shows the side effects of laser hair removal. lasers used in hair removal more than 15 laser systems have been approved by the us food and drug administration for use in hair removal. these systems include ruby (694 nm), alexandrite (755 nm), diode (8001,000 nm), q-switched and long-pulsed neodymium: yttrium-aluminum-garnet (nd:yag; 1,064 nm), and intense pulsed light sources (550-1,200 nm). a summary of commercially available lasers is given below. normal-mode ruby laser (694 nm) the pulsed ruby laser was originally used to perform melanin-based selective photothermolysis of hair. the ruby laser delivers red light at a wavelength of 694 nm. ruby lasers are particularly useful for light-skinned (fitzpatrick skin types i-iii) individuals with dark hair because of high melanin absorpfollicle-stimulating hormone, leading to a decrease in ovarian androgen production and decrease in adrenal androgen. low-androgenic progestins are preferred as they cause antagonism of 5α-reductase and androgen receptor. insulin sensitizers such as metformin significantly decrease insulin resistance. untreated hormonal diseases can result in variable-to-poor responses to laser hair removal, and these patients usually require more sessions than patients with normal hormone levels [16,17]. site of hair removal since there are differences in anagen-telogen ratios in various anatomic sites, there may be differences in response rates. axillae and belt areas respond better than legs, arms, and chest. the procedure for laser hair removal is summarized in figure 1. grading of efficacy efficacy is graded according to a 4-point visual scale ranging from poor to excellent depending on the percentage of hair reduction from baseline: poor: <25%; hormonal profile patients should be evaluated for hirsutism by doing various hormonal assays, especially for testosterone levels, as these may influence the response to laser therapy. polycystic ovarian syndrome, thyroid dysfunctions, adrenal hyperplasias, and hyperprolactinemia are hormonal dysfunctions that influence hair regrowth following laser hair removal [14,15]. d u r i n g p r e g n a n c y t h e r e i s a n increase in the levels of prolactin. the hyperprolactin state has a melanocyte-stimulating effect. all light therapies are ineffective for hair reduction in cases of hyperprolactinemia due to pregnancy or amenorrhea galactorrhea syndrome, which upregulate melanocyte-stimulating hormone in stem cells of the hair. hyperprolactinemic states are often associated with polycystic ovarian syndrome. hirsutism that persists despite 6 or more months of monotherapy with an oral contraceptive demands additional pharmacological therapies. adding an antiandrogen is justified for women who choose hair removal therapy by laser/photoepilation, desiring a more rapid initial response. eflornithine cream can be added during treatment for women with known hyperandrogenemia who choose laser hair removal. a trial of at least 6 months before making changes in dose, changing medication, or adding pharmacological therapy to minimize hair regrowth with lasers is justified. concomitant hormone therapy in cases of cutaneous hyperandrogenism may overcome poor outcomes of a stand-alone laser hair removal procedure. it is important to establish the etiology and treat the underlying cause of hirsutism. peripheral androgen blockage can be achieved by suppression of underlying hormonal imbalance. this can further be combined with laser hair removal to optimize results. oral contraceptives cause suppression of production of luteinizing hormone and figure 1. the procedure for laser hair reduction. fg = ferriman-gallwey; usg = ultrasonography. 4 review | dermatol pract concept 2020;10(2):e2020048 demonstrated less hair reduction with the nd:yag laser compared with those results published with the ruby or alexandrite lasers [23]. a recent study by rogachefsky et al evaluated the efficacy of a long-pulsed nd:yag laser system. a cryogen spray-cooled long-pulsed nd:yag laser was used to treat 22 subjects. four adjacent sites were assigned to each subject and were treated with parameters of 50 j/cm2 with a 25-millisecond pulse duration, 60 j/cm2 with a 50-millisecond pulse duration, 80 j/ cm2 with a 50-millisecond pulse duration, and control. hair counts were obtained immediately and 1 week, 1 month, and 3 months after treatment, and multivariate regression analysis was used to determine the significance of hair reduction. at 3 months, the higher settings of 60 j/cm2 and 50 milliseconds and 80 j/cm2 and 50 milliseconds were statistically significant for reduced mean hair counts while the lowest setting at 50 j/cm2 and 25 milliseconds was not significant [24]. figures 3 and 4 show significant hair reduction in a patient after 6 sessions of nd:yag laser hair reduction. ing from 65% to 75% hair reduction at 3 months after 1 to 2 treatments with fluences of 10-40 j/cm2, to75% hair reduction in 91% of individuals 8 months after 3 to 4 treatments at 40 j/ cm2 have been reported with the diode laser system. sadick et al studied 24 female subjects (skin types ii-iv) treated 3 times at monthly intervals with a new 810-nm diode laser (spot size 12 mm, pulse width 50 milliseconds, fluence 25-35 j/cm2). it was noted that at 3 and 6 months of treatment, the mean hair removal efficiency was 74% and 79%, respectively [20]. nd:yag laser (1,064 nm) the q-switched 1,064-nm nd:yag laser with or without topical carbon suspension was one of the first laser systems used to remove hair. the poor absorption by melanin at this wavelength coupled with an epidermal cooling device makes the long-pulsed nd:yag laser a safe treatment option for patients with the darkest skin phototypes (iii-vi) and, therefore, for darker fitzpatrick skin types the long-pulsed nd:yag is preferred to the ruby laser [21,22]. overall, clinical studies have tion at 694 nm. allison et al studied the long-term hair regrowth in 3 patient groups: top lip (n = 25), axillae (n = 25), and legs (n = 9). two treatments were given on the right and left sides at monthly intervals followed by a third treatment given randomly to one side. hair counts of the experimental sites made at monthly intervals for 1 year indicated long-term hair reduction in all patients. a single treatment was seen to reduce hair counts by up to 75%. while 3 treatments had an impact for 2 additional months, no long-term effect was noted. spontaneous hair reduction was unexpectedly found at 5 months after treatment and lasted 2 months [18]. thus ruby laser produced a persistent two-thirds reduction in hair count over 8 months of follow-up and no significant regrowth follow-up to 12 months. studies with short-term follow-up have observed 37%-72% reduction at 3 months after 1 to 3 treatments, to a 38%-49% hair reduction 1 year after 3 treatment sessions. alexandrite laser (755 nm) the alexandrite laser allows greater depth of penetration, making it relatively safe in darker-skinned (fitzpatrick skin types i-iv) individuals. however, melanin absorption is somewhat less at the wavelength of alexandrite (755 nm) when compared with the ruby (694 nm). the reported success rate of hair removal using the alexandrite has ranged from 40% to 80% at 6 months after several treatments [19]. diode laser (800-1,000 nm) diode lasers for hair removal were cleared to market in the usa in 1997. individuals with darker skin can be treated more safely with this system because of the longer wavelength, the active cooling, and the longer pulse widths. the diode laser system has been found to be better tolerated by patients with darker skin types (v-vi) than the ruby laser. variable success rates rangfigure 2. side effects of laser hair removal. review | dermatol pract concept 2020;10(2):e2020048 5 clearance of 30%-50% is generally reported 6 months after the last treatment. patients with dark skin (fitzpatrick skin types iv and v) can be treated effectively with morbidity comparable with those with lighter skin. principle of selective photothermolysis with the melanin in the hair follicles as the chromophore. multiple treatments are necessary to achieve satisfactory results regardless of the type of laser used. after repeated treatments, hair intense pulsed light (5501,200 nm) this system delivers broad-spectrum, noncoherent radiation with wavelengths of 550-1,200 nm. one of 4 filters (590 nm, 615 nm, 645 nm, or 695 nm) is used to eliminate shorter wavelengths. in general, filters with higher cutoff values are used with darker skin types [25,26]. treatment with intense pulsed light may be useful for light-colored hair, although more treatment sessions are generally required. in one study, 60% hair reduction was reported 12 weeks after a single treatment with various cutoff filters (3444 j/cm2, 2-5 pulses, 1.5-3.5 milliseconds, 20-50 milliseconds delays) [27,28]. new combination trio is a single multiplex diode laser hand piece that offers the synergistic benefits of the 3 most effective wavelengths for hair removal. alex 755 nm wavelength the superficial penetration of 755 nm wavelength targets the bulge of the hair follicle and has thus been found to be more effective for superficially embedded hair in areas such as the eyebrows and upper lip. speed 810 nm wavelength it is especially helpful because of its deep penetration capabilities that target the bulge and bulb of the hair follicle. it is also ideal for treating the arms, legs, beard, and cheeks by moderate tissue depth penetration. yag 1,064 nm wavelength as this wavelength offers the deepest penetration of hair follicle, it targets the bulb and the papilla and also treats the deeply embedded hair in areas like the scalp, axillae, and pubic areas. in summary, the ruby laser (694 nm), alexandrite laser (755 nm), diode laser (800 nm), intense pulsed light source (550-1,200nm), and the nd:yag laser (1,064 nm), with or without the application of carbon suspension, work on the figure 3. hair reduction in a patient after 2 sessions of nd:yag laser hair removal. figure 4. significant hair reduction in the same patient after 4 and 6 sessions of nd:yag laser hair removal. 6 review | dermatol pract concept 2020;10(2):e2020048 transient erythema. histologically, the damage was shown to be limited to the target structures. clinical and histological acute phase changes associated with the use of traser have shown important observations; thus it can be used as a novel and effective method of hair removal [36]. vacuum-assisted laser hair removal in vacuum-assisted laser hair removal, a vacuum gently draws the skin into the hand piece; skin is stretched thin and thereby the target is pulled closer to the energy source. energy when applied to the target leads to spreading apart of the melanocytes and constriction of blood flow. target is damaged and skin is released [37]. large spot size vectus (palomar) is a hair removal system that uses a diode laser. it has a large spot size, which makes large areas such as back of legs easier to treat. the large spot size provides efficacious hair removal due to photon recycling and increased depth of penetration. in a study, 18-mm spot size was more effective than 12-mm spot size [37]. super hair removal the original concept of progressive photothermolysis is included in the operation of the diode laser super hair removal (shr) for photoepilation. during treatment, pulse repetition of the laser system shr is 10 hz. depilation is performed through the continuous movement of the hand piece over the skin surface while delivering laser pulses, which prevents energy from concentrating on a particular point and thus generating burns due to overheating. due to the relatively long-duration pulse of the laser shr and its high repetition frequency, the laser energy penetration is secondarily increased and reaches deeper into the skin through a thermal propagation mechanism [38]. future technology advances pneumatic skin flattening is a technique of reducing pain during the procedure. it works on gate theory of pain transmission wherein immediately prior to laser pulse it stimulates pressure receptors with the help of a vacuum chamber by generating a negative pressure and flattening the skin [34]. other than laser, alternative technologies such as electro-optical synergy technology have been used. electro optical synergy technology combines electrical and optical lights. first the hair shaft is heated by laser/light energy, which then is thought to concentrate the bipolar radiofrequency energy to the surrounding hair follicle. this has an advantage of the use of less fluence and hence less epidermal damage and can also be effective in poorly pigmented hair [35]. total reflection amplification of spontaneous emission of radiation a total reflection amplification of spontaneous emission of radiation (traser) is not a laser; it is fundamentally different, and, in many ways, much simpler in design. it utilizes the energy from, for example, a flash lamp to induce the spontaneous emission of photons from a fluorescent dye in solution, or ions impregnated in a crystal structure. the light generated can be tuned from uva to near infrared. response of hair follicles to this mode of energy delivery has been studied wherein the follicular structures were targeted with dye cell switched to sulforhodamine 640 chloride, producing a narrow peak of 654 nm. single 20-millisecond pulses with a 12-mm spot size and fluences from 14 to 20 j/cm2 were fired. chest hair was treated with contact cooling. clinical and histological punch biopsy at 30 minutes after hair treatment observations reflected a clinical end point of perifollicular edema and comparison of different laser and light-based devices the majority of studies have documented a superior efficacy of alexandrite and diode laser systems in hair removal in comparison with other lasers or light-based devices. in a study that compared the efficacy of 3 laser devices, a mean hair reduction of 59.5%, 70.3%, and 47.4% was reported after 3 sessions with diode, alexandrite, and nd:yag lasers, respectively [29,30]. in a randomized, split-face study, a mean reduction in hair count of 46% and 27% was reported after alexandrite and intense pulsed light systems, respectively [31]. in a comparative study on longpulsed nd:yag laser and intense pulsed light system in skin types iv-vi, the former device was found to be more effective than the latter for hair removal, with fewer side effects. in darker skin types, a superior efficacy of nd:yag laser over intense pulsed light system has been demonstrated [14]. for light, white, and gray hair laser hair removal is based on targeting melanin. absence of melanin or decreased melanin often results in failure of treatment. goldberg et al have used combined light/bipolar radiofrequency devices along with photosensitizers with some success, suggesting that photosensitizers augment the effects of combined radiofrequency devices in nonpigmented hair reduction [32]. a recent alternative approach has been external application of melanin to the hair through the use of liposomal technology. meladine, a topical melanin chromophore, has been studied in europe with interesting results. sand et al utilized melanin-encapsulated liposomes to improve performance of laser hair removal in nonpigmented hair [33]. review | dermatol pract concept 2020;10(2):e2020048 7 chromos for hair removal in various skin sites. lasers med sci. 2003;18(3):165170. 19. mustafa fh, jaafar ms, ismail ah, mutter kn. comparison of alexandrite and diode lasers for hair removal in dark and medium skin: which is better? j lasers med sci. 2014;5(4):188-193. 20. sadick ns, prieto vg. the use of a new diode laser for hair removal. dermatol surg. 2003;29(1):30-34. 21. shrimal a, sardar s, roychoudhury s, sarkar s. long-pulsed nd:yag laser and intense pulse light-755 nm for idiopathic facial hirsutism: a comparative study. j cutan aesthet surg. 2017;10(1):40-44. 22. chan cs, dover js. nd:yag laser hair removal in fitzpatrick skin types iv to vi. j drugs dermatol. 2013;12(3):366367. 23. giambrone d, ahn cs, rao b. laser hair removal using a650 microsecond pulsed nd:yag laser: a study of 298 patients. glob dermatol. 2014;1(1):9‐12. 24. rogachefsky as, becker k, weiss g, goldberg dj. evaluation of a long-pulsed nd:yag laser at different parameters: an analysis of both fluence and pulse duration. dermatol surg. 2002;28(10):932936. 25. trelles ma, ash c, town g. clinical and microscopic evaluation of long-term (6 months) epilation effects of the ipulse personal home-use intense pulsed light (ipl) device. j eur acad dermatol venereol. 2014;28(2):160-168. 26. mohanan s, basheerahmed p, priyavathani r, nellainayagam g. new intense pulse light device with square pulse technology for hirsutism in indian patients: a pilot study. j cosmet laser ther. 2012;14(1):14-17. 27. thacker p, kumar p. near infrared pulsed light for permanent hair reduction in fitzpatrick skin types iv and v. j cutan aesthet surg. 2016;9(4):249‐253. 28. schoenewolf nl, barysch mj, dummer r. intense pulsed light. curr probl dermatol. 2011;42:166-172. 29. ismail sa. long-pulsed nd:yag laser vs. intense pulsed light for hair removal in dark skin: a randomized controlled trial. br j dermatol. 2012;166(2):317-321. 30. puri n. comparative study of diode laser versus neodymium-yttrium aluminum: garnet laser versus intense pulsed light for the treatment of hirsutism. j cutan aesthet surg. 2015;8(2):97-101. 31. al-dhalimi ma, kadhum mj. a splitface comparison of facial hair removal 6. royo j, urdiales f, moreno j, al-zarouni m, cornejo p, trelles ma. six-month follow-up multicenter prospective study of 368 patients, phototypes iii to v, on epilation efficacy using an 810-nm diode laser at low fluence. lasers med sci. 2011;26(2):247-255. 7. altshuler gb, anderson rr, manstein d, zenzie hh, smirnov mz. extended theory of selective photothermolysis. lasers surg med. 2001;29(5):416-432. 8. sinclair rd, messenger ag, farrant p, berker da. acquired disorder of hair. in: griffiths c, barker j, bleiker t, chalmers r, creamer d, eds. rook’s textbook of dermatology. 9th ed. london: wiley-blackwell; 2016: 89.64-89.68. 9. vachiramon v, brown t, mcmichael aj. patient satisfaction and complications following laser hair removal in ethnic skin. j drugs dermatol. 2012;11(2):191-195. 10. richter al, barrera j, markus rf, brissett a. laser skin treatment in non-caucasian patients. facial plast surg clin north am. 2014;22(3):439-446. 11. rao k, sankar tk. long-pulsed nd:yag laser-assisted hair removal in fitzpatrick skin types iv-vi. lasers med sci. 2011;26(5):623-626. 12. vachiramon v, mcmichael aj. patient knowledge and attitudes on laser hair removal: a survey in people of color. j cosmet dermatol. 2011;10(3):197-201. 13. shirkavand a, ataie-fashtami l, sarkar s, et al. thermal damage patterns of diode hair-removal lasers according to various skin types and hair densities and colors: a simulation study. photomed laser surg. 2012;30(7):374-380. 14. karn d, krishna c, timalsina m, gyawali p. hormonal profile and efficacy of long pulse nd-yag laser in treatment of hirsutism. j nepal health res counc. 2014;12(26):59-62. 15. loriaux dl. an approach to the patient with hirsutism. j clin endocrinol metab. 2012;97(9):2959-2961. 16. nawrocka-rutkowska j, ciećwież s, marciniak a, et al. insulin resistance assessment in patients with polycystic ovary syndrome using different diagnostic criteria—impact of metformin treatment. ann agric environ med. 2013;20(3):528-532. 17. gacaferri lumezi b, goci a, lokaj v, et al. mixed form of hirsutism in an adolescent female and laser therapy. iran red crescent med j. 2014;16(6):e9410. 18. allison kp, kiernan mn, waters ra, clement rm. evaluation of the ruby 694 conclusions the use of lasers/light-based technology in the treatment of unwanted hair has become common. the acceptance of photoepilation by both physicians and patients is a direct reflection of the high degree of efficacy, few side effects, and few complications. the benefits of this technology, however, have largely been limited to individuals with dark hair and relatively fair skin. the major challenge in the field of photoepilation continues to be the development of technology that not only permanently and significantly reduces the number of hairs but also provides permanent and complete hair removal for all skin and hair types and colors. with current technology, the average clearance rate is 20%-75% after 1-6 months of follow-up. longterm studies with a follow-up of more than 1 year are needed to determine whether permanent hair removal can be accomplished. with the rapid pace of technological advancements and continued studies of hair biology, laser physics, skin optics, and cooling means, it is anticipated that permanent hair removal will be achieved in the near future. references 1. gan sd, graber em. laser hair removal: a review. dermatol surg. 2013;39(6):823838. 2. fernandez aa, frança k, chacon ah, nouri k. from flint razors to lasers: a timeline of hair removal methods. j cosmet dermatol. 2013;12(2):153-162. 3. barolet d. low fluence-high repetition rate diode laser hair removal 12-month evaluation: reducing pain and risks while keeping clinical efficacy. lasers surg med. 2012;44(4):277-281. 4. zhou zc, guo lf, gold mh. hair removal utilizing the lightsheer duet hs hand piece and the lightsheer et: a comparative study of two diode laser systems in chinese women. j cosmet laser ther. 2011;13(6):283-290. 5. roosen gf, westgate ge, philpott m, berretty pj, nuijs tam, bjerring p. temporary hair removal by low fluence photoepilation. lasers surg med. 2008;40(8):520-528. 8 review | dermatol pract concept 2020;10(2):e2020048 neous emission of radiation. plos one. 2012;7(4):e35899. 37. youssef nj, rizk ag, ibrahimi oa, tannous zs. long-term comparison of a large spot vacuum assisted handpiece vs the small spot size traditional handpiece of the 800 nm diode laser. j drugs dermatol. 2017;16(9):893-898. 38. semsettin k, seval dk, pinar o. comp a r i s o n o f s h r m o d e i p l s y s t e m with alexandrite and nd:yag lasers for leg hair reduction. balkan med j. 2012;29(4):401-405. chromophore for laser hair removal of blond, white, and gray hair. ann plast surg. 2007;58(5):551-554. 34.  yeung ck, shek sy, chan hh. hair removal with neodymium-doped yttrium aluminum garnet laser and pneumatic skin flattening in asians. dermatol surg. 2010;36(11):1664-1170. 35. sadick ns. electro-optical synergy in aesthetic medicine: novel technology, multiple applications. cosmetic dermatology. 2005;18(3):201-206. 36. zachary cb, gustavsson m. traser— total reflection amplification of spontawith the long-pulsed alexandrite laser and intense pulsed light system. j cosmet laser ther. 2015;17(5):267-272. 32. goldberg dj, marmur es, hussain m. treatment of terminal and vellus non-pigmented hairs with an optical/bipolar radiofrequency energy source with and without pre-treatment using topical aminolevulinic acid. j cosmet laser ther. 2005;7(1):25-28. 33. sand m, bechara fg, sand d, altmeyer p, hoffmann k. a randomized, controlled, double-blind study evaluating melanin-encapsulated liposomes as a dermatology: practical and conceptual practical, conceptual or educational notes | dermatol pract concept 2014;4(3):19 87 dermatology practical & conceptual www.derm101.com in dermoscopic examination, lighting of high quality and high intensity is needed to obtain accurate color reproducibility and correct microstructural identification of the target skin lesion. however, ordinary built-in illumination systems may be not sufficient to fulfill the requirement. to overcome this problem, we designed a dermoscope that allows the use of surgical light as illumination. even lighting of high quality and high intensity could be obtained using a large surgical light device such as a ceiling-suspended surgical light. our dermoscope is a modularly structured dermoscope composed of three parts: (1) a video or still digital camera with high-power zoom ability used for monitoring and recording images of the skin lesion; (2) a macro conversion lens used to enable macrophotography; and (3) a selfmade transparent spacer used to allow external light to pass through and to keep a precise distance between the tip of the macro conversion lens and the skin surface (figure 1). dermoscopic examination is performed with a gel applied to the skin surface under surgical light illumination from an oblique direction (figure 2). figure 3 shows the typical structure of the dermoscope composed of a digital camera (coolpix p7700; nikon, japan), a macro conversion lens (mns-202; raynox, japan), a dermoscope allowing the use of surgical light as illumination hiroshi sakai1, kyoko tonomura1, hirotsugu shirabe1, masaru tanaka2 1 department of dermatology, ntt west japan osaka hospital, osaka, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan citation: sakai h, tonomura k, shirabe h, tanaka m. a dermoscope allowing the use of surgical light as illumination. dermatol pract concept. 2014;4(3):19. http://dx.doi.org/10.5826/dpc.0403a19 received: march 29, 2014; accepted: march 29, 2014; published: july 31, 2014 copyright: ©2014 sakai et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: hiroshi sakai, md, department of dermatology, ntt west japan osaka hospital, 2-6-40 karasugatsuji, tennojiku, osaka-shi, osaka 543-8922, japan. tel: +81 6 6773 7111. fax: +81 6 6773 7747. e-mail: ihsorihiakasfds@gmail.com figure  1. our dermoscope is a modularly structured dermoscope composed of three parts: (1) a video or still digital camera with highpower zoom ability used for monitoring and recording images of the skin lesion; (2) a macro conversion lens used to enable macrophotography; and (3) a self-made transparent spacer used to allow external light to pass through and to keep a precise distance between the tip of the macro conversion lens and the skin surface. [copyright: ©2014 sakai et al.] and a self-made transparent spacer. the macro conversion lens is mounted on the camera through a 40.5-37 mm step down 88 practical, conceptual or educational notes | dermatol pract concept 2014;4(3):19 ability of the tip part is considered favorable from the viewpoint of hygiene. this study was presented at the 109th annual meeting of the japanese dermatological association (2010). the japanese version of this article was reported in hifu no kagaku, 2007; 6: 50-54. ring (c-b-405a; hassendo, japan). the transparent spacer is taped to the tip of the conversion lens. the transparent spacer consists of three acrylic parts: a larger tube, a smaller tube, a disk, bound together with adhesive. (figure 4a). the larger transparent acrylic tube has a 40 mm outer diameter, 30 mm inner diameter, and 10 mm length (figure 4b). the smaller transparent acrylic tube has a 32 mm outer diameter, 28 mm inner diameter, and 20 mm length (figure 4c) the transparent acrylic disk has a 30 mm diameter, and 2 mm thickness (figure 4d). this dermoscope has potential advantages. in practical use, surgical light illumination improves the visual recognition of the skin lesion, especially at high-power fields. in research use, this dermoscope provides high flexibility in the selection of the light source, camera, macro conversion lens, and the design of the transparent spacer. the easy exchangefigure 2. dermoscopic examination is performed with a gel applied to the skin surface under surgical light illumination from an oblique direction. [copyright: ©2014 sakai et al.] figure  3. the typical structure of the dermoscope composed of a digital camera (coolpix p7700; nikon, japan), a macro conversion lens (mns-202; raynox, japan), and a self-made transparent spacer. the macro conversion lens is mounted on the camera through a 40.5-37 mm step down ring (c-b-405a; hassendo, japan). the transparent spacer is taped to the tip of the conversion lens. [copyright: ©2014 sakai et al.] figure 4. the transparent spacer (a) consists of three acrylic parts: a larger tube (b), a smaller tube (c), a disk (d) bound together with adhesive. (b) the larger transparent acrylic tube has a 40 mm outer diameter, 30 mm inner diameter, and 10 mm length. (c) the smaller transparent acrylic tube has a 32 mm outer diameter, 28 mm inner diameter, and 20 mm length. (d) the transparent acrylic disk has a 30 mm diameter, and 2 mm thickness. [copyright: ©2014 sakai et al.] dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(1):e2020007 1 dermatology practical & conceptual zosteriform cutaneous distant metastases as onset of relapsing melanoma daniel morgado-carrasco,1 clara fernández-sartorio,1 cristina carrera1 1 melanoma unit, department of dermatology, hospital clínic de barcelona, universitat de barcelona, and centro de investigaciones en red de enfermedades raras (ciberer), instituto de salud carlos iii, spain key words: melanoma, zosteriform metastases, cutaneous metastases, melanoma metastases citation: morgado-carrasco d, fernández-sartorio c, carrera c. zosteriform cutaneous distant metastases as onset of relapsing melanoma. dermatol pract concept. 2020;10(1):e2020007. doi: https://doi.org/10.5826/dpc.1001a07 accepted: september 13, 2019; published: december 31, 2019 copyright: ©2019 morgado-carrasco et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: cristina carrera, md, phd, melanoma unit, department of dermatology, hospital clínic de barcelona, barcelona, spain. email: ccarrera@clinic.cat case presentation a 66-year-old man with a history of an ulcerated melanoma on the lumbar region, breslow index 2.9 mm, with regional lymph node involvement, presented with pinkish papules on his forehead 5 months after the initial surgery. the lesions rapidly evolved into multiple coalescent papulonodules forming a zosteriform plaque on his forehead (figure 1). skin biopsy confirmed the diagnosis of cutaneous melanoma metastases. teaching point zosteriform metastases are rare, with only about 60 cases reported, and melanoma is one of the most frequent neoplasms implicated [1,2]. physicians should suspect this infrequent form of skin metastases even when lesions are distant from the primary site. references 1. savoia p, fava p, deboli t, quaglino p, bernengo mg. zosteriform cutaneous metastases: a literature meta-analysis and a clinical report of three melanoma cases. dermatol surg. 2009;35(9):13551363. 2. chaudhary s, bansal c, husain a. literature meta-analysis of zosteriform cutaneous metastases from melanoma and a clinico-histopathological report from india. ecancermedicalscience. 2013;7:324. figure 1. metastatic melanoma. multiple coalescent papulonodules forming a zosteriform plaque on the forehead. mailto:ccarrera%40clinic.cat?subject= review | dermatol pract concept 2016;6(3):6 23 dermatology practical & conceptual www.derm101.com introduction atopic dermatitis (ad) is a chronic skin disorder that may result in multiple and notable effects on quality of life [1,2]. although the pathophysiology of ad has not been fully elucidated, it is currently believed to be due to a combination of epidermal barrier dysfunction, immune dysregulation, and environmental factors [2]. the spectrum of disease is wide, with many individuals requiring multiple topical medications, and some even requiring systemic immunosuppressive medications. given the chronicity of disease, and the potential side effects of even topical medications, many patients and parents are very interested in identifying alternative therapies for the treatment of ad, commonly referred to as eczema by patients and families[3]. in recent years, physicians have seen a growing cultural interest in “natural” eczema therapies or diet and eczema: a review of dietary supplements for the treatment of atopic dermatitis megan j. schlichte1, abbey vandersall2, rajani katta3 1 department of medicine, houston methodist hospital, houston, tx, usa 2 the ohio state university college of medicine, columbus, oh, usa 3 division of dermatology, houston methodist hospital, houston, tx, usa key words: atopic dermatitis, probiotics, prebiotics, vitamin d, fish oil, evening primrose oil, chinese herbal medicine citation: schlichte mj, vandersall a, katta r. diet and eczema: a review of dietary supplements for the treatment of atopic dermatitis. dermatol pract concept 2016;6(3):6. doi: 10.5826/dpc.0603a06 received: april 11, 2016; accepted: june 23, 2016; published: july 31, 2016 copyright: ©2016 schlichte et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajani katta, md, 6800 west loop south, suite 180, bellaire, tx 77401, usa. tel. 281-501-3150; fax. 832-8100072. in the context of increasing popularity of “natural” alternatives to conventional medicine, several dietary supplements have gained the attention of researchers and consumers alike in the treatment of atopic dermatitis (ad). readily available without a prescription and frequently perceived to have fewer side effects than traditional medications, these “natural” remedies may be featured in discussions with patients, and clinicians should therefore be familiar with their efficacy and safety. based on trials to date, no dietary supplements can be recommended for routine use in the treatment of ad. however, some promising results have been noted from the use of probiotics and prebiotics taken in combination. given significant differences in study design to date, however, further studies would be needed to clarify dose and strains of probiotics. studies of vitamin d have been limited and have produced conflicting results, although further trials in selected subsets of patients may be indicated. very limited data is available on fish oil supplements, while future studies on chinese herbal medicine would require evaluation of comparable herbs and formulations. finally, multiple trials of evening primrose oil and borage seed oil have shown improvement similar to placebo, and neither is currently recommended in eczema therapy. abstract 24 review | dermatol pract concept 2016;6(3):6 include increased incidence of wheezing bronchitis [13], infections, and bowel ischemia, although the source of infections has not been proven with certainty [14]. background—prebiotics in order to promote the healthy intestinal microflora that seems to be lacking in allergy-prone individuals, another novel treatment strategy involves the use of prebiotic supplementation. prebiotics are foods or supplements that contain non-digestible ingredients that selectively stimulate the growth and/or activity of non-pathogenic colonic bacteria [15]. prebiotics have the potential to create a nutrient-rich intestinal environment in which the microflora may thrive. alteration of the microflora may, in turn, convey allergyprotective effects by modulation of postnatal immune development [16]. prebiotics are often in the form of oligosaccharides. these may occur naturally in high quantities (as in human milk) or may be added as dietary supplements to foods, beverages, and infant formula [17]. dietary fiber and inulin, found in certain vegetables, may also be considered prebiotics [7]. prebiotics in the treatment of ad prebiotics have not been extensively studied in the treatment of ad. one small rct did find that prebiotics alone lowered the scorad index in children with ad [18]. overall, however, minimal evidence exists to support the use of prebiotics as a stand-alone therapy. synbiotics (combination therapy) a combination of prebiotics and probiotics, known as synbiotics, appears to hold promise in the treatment of ad. a recently published meta-analysis examined all published rcts of synbiotics for the treatment of ad, using the scorad index to evaluate efficacy [19]. the final analysis included 6 studies with 369 children. the authors concluded that the use of synbiotics for at least 8 weeks with mixedstrain bacterial species had a significant effect on improving the scorad index. this effect held only for children aged 1 year or older. probiotics containing single strains of bacteria did not show a significant effect. the studies included in the analysis used a variety of bacterial strains, some singlestrain and some mixed-strain, at differing doses and dosing regimens. the studies also used a variety of prebiotics, such as fructo-oligosaccharides, galacto-oligosaccharides, potato starch and lactose [19]. conclusion while further studies are needed to clarify strains, dosing, and targeted populations, the use of probiotics and prebiotics in combination appears to hold promise in the treatment of ad. based on the results of meta-analysis, the use of synbiotics dietary modifications that are perceived to be lower in risk than conventional therapies [4]. in this article, we review some of the alternative therapies that have received increasing interest from patients and researchers, including probiotics, prebiotics, vitamin d supplementation, fish oil supplements, evening primrose oil, and chinese herbal medicine. probiotics and prebiotics background—probiotics probiotics are defined as “live microorganisms (e.g., bacteria) that are either the same as or similar to microorganisms found naturally in the human body and may be beneficial to health” [5]. this microbiota not only promotes food digestion, but also influences local and global immunity. in healthy children, the gut flora is dominated by lactobacilli. in contrast, the gut flora of allergy-prone children has been noted to have higher numbers of gram-negative bacteria and staphylococcus aureus [6]. in the context of reduced colonic t-regulatory cells among individuals with a poorly developed microbiota, the potential for allergy protection is reduced, possibly predisposing an individual to ad. probiotic bacteria may naturally exist in certain foods, may be added to foods, or may be available as supplements. a number of different probiotic supplements, containing different strains and/or dosages of bacteria, are commercially available. the most studied probiotic bacteria include lactobacillus rhamnosus gg, bifidobacterium lactis, and streptococcus thermophiles [7]. probiotics in the treatment of ad a recent meta-analysis concluded that treatment with probiotics significantly decreased the scorad index in children over the age of 1 year. the analysis included 25 randomized controlled trials (rcts), with a total of 1599 subjects, and found that treatment with a mixture of different bacterial species or lactobacillus species showed greater benefit than those with bifidobacterium species alone [8]. previous metaanalyses, published in 2008, had found no significant reduction in eczema symptoms as compared with placebo overall [9,l0,11], but had noted that significant heterogeneity existed between studies and had called for further research. this heterogeneity continues to exist, which may be due to the use of different probiotic strains, the use of single probiotic strains versus multiple strains, and the use of differing placebos, with some studies utilizing prebiotic placebos. side effects limited side effects, in general, have been associated with the use of these bacteria. while most of the studies have reported no increased incidence of side effects as compared to placebo [12], there have been scattered reports of side effects. these review | dermatol pract concept 2016;6(3):6 25 lacking allergic sensitization. in the group with allergic sensitization, lower serum vitamin d levels were associated with higher scorad scores, while no correlation existed for the other group [28]. in another study, when looking at a subset of ad patients with food sensitization, mean serum levels of vitamin d were significantly higher in patients with mild disease as compared to those with moderate or severe ad [29]. trials of supplementation for the treatment of ad limited data is available regarding vitamin d supplementation in the therapy of ad, and conflicting results have been noted. a pilot study of 11 children with mild ad showed no significant difference between children given one month of vitamin d versus those given placebo [30]. similarly, in a trial of 45 patients, no significant difference in scorad was seen between the groups receiving vitamin d versus placebo [31]. one trial, however, did note benefit. a randomized, doubleblind, placebo-controlled (rdbpc) study of 60 ad patients found significant improvement in scorad in patients given vitamin d (1600 iu cholecalciferol) daily versus placebo [32]. supplementation may help those with frequent bacterial skin infections in another study, mean serum level of vitamin d in patients with ad was not statistically different from that of control patients. however, the subset of ad patients with low 25(oh)d3 had a greater frequency of bacterial skin infections than those with higher levels [33]. a subset of these patients with very low serum 25(oh) d3 concentrations (20 patients) underwent 3 months of supplementation with 2000 iu of oral cholecalciferol daily. following supplementation, mean scorad were significantly lower and fewer bacterial infections were seen. overall, marked improvement was seen in 90% of supplemented patients [33]. further support for screening those with frequent bacterial skin infections comes from another trial. in this study, 3 weeks of supplementation with 1000 iu/day of vitamin d resulted in increased expression of cathelicidin, an antimicrobial peptide [34]. conclusion at this time, vitamin d supplementation is not recommended for ad. however, several interesting studies have suggested that vitamin d supplementation should be investigated further in selected subsets of patients. these include ad patients with low or very low levels of vitamin d, those with food sensitization or aeroallergen sensitization, and those with frequent bacterial skin infections. further studies will need to focus on whether such patients may benefit from screening of serum levels as well as determination of correct screening tools and recommended dosage and duration of supplementation. appears most promising when given for at least 8 weeks to children over the age of 1 year, and with the use of probiotics that contain mixed strains of bacteria. given the mounting interest in their use, as reflected by their growing popularity in current food advertising, probiotics and prebiotics will likely become an increasingly common topic of conversation in clinical settings. vitamin d background a number of studies have evaluated a possible link between vitamin d deficiency and ad. from an epidemiologic standpoint, studies have shown a higher prevalence of ad in association with higher geographic latitude, which correlates to less sun exposure and therefore the possibility of less vitamin d production [20]. vitamin d has also been evaluated in the context of phototherapy. in one study of narrow-band uvb treatment, therapy was found to significantly increase serum calcidiol. at the same time, a significant increase was noted in antimicrobial peptide expression in healing skin lesions [21]. serum levels of vitamin d and correlation with ad prevalence and severity research utilizing serum levels of vitamin d is complex and controversial. some researchers have suggested that serum levels may not provide an accurate picture of vitamin d status, and some believe that low levels of vitamin d are a result of chronic inflammation, rather than the cause of chronic inflammation [22]. a few studies have examined the correlation between vitamin d levels in children and the prevalence and severity of ad, with conflicting findings. researchers in one study found high rates of vitamin d deficiency in children with ad, but no correlation between serum vitamin d concentration and ad severity [23]. other studies have found that mean serum levels of vitamin d are significantly higher in patients with mild ad as compared to those with moderate and severe disease [24,25,26]. not all studies have found this link though. one study, in fact, found the opposite. a study of 9838 children found a significantly decreased prevalence of ad in those in the lowest quartile for serum vitamin d levels [27]. the authors noted that because of the cross-sectional design of the study, causality cannot be determined, a point that applies to all studies evaluating serum levels at a single point in time. serum levels of vitamin d and correlation with subgroups of ad patients researchers have also examined serum levels of vitamin d in particular subgroups of ad patients. in one study, children were grouped into those with allergic sensitization to foods or common aeroallergens and those 26 review | dermatol pract concept 2016;6(3):6 counter. both are high in gamma-linolenic acid (gla), a substance which may play a role in eczema. a deficiency in essential fatty acids of the skin is one factor suspected of playing a role in eczema [39]. it has been hypothesized that a defect or deficiency in certain enzymes may result in a deficiency of gla in the skin [40]. gla is a type of ω-6 fatty acid. while some ω-6 fatty acids promote inflammation (such as linoleic acid and arachidonic acid), gla appears to reduce inflammation. a deficiency of gla in the skin may thus result in increased inflammation. therefore, there has been an interest in natural dietary sources of gla. epo, derived from a plant, contains 8% to 10% gla [15]. borage seed oil, another natural source, has been reported to contain at least 23% gla. trials of supplementation a number of studies have now evaluated patient use of these supplements. the results of this research indicate that epo and bo appear to have little or no place in current ad therapies. in a review of 27 studies (19 of epo and 8 of bo), it was found that treatment with either supplement failed to significantly improve global eczema symptoms as compared to placebo. the duration of treatment varied from 3 weeks to 24 weeks [41]. in terms of side effects, both supplements exhibited similar side effects, which were mild, transient, and mainly gastrointestinal. as these studies were short-term, the long-term adverse effects are not known. one case report has reported that epo taken for more than one year may increase risk of inflammation, thrombosis, and immunosuppression [42]. conclusion as improvement with both supplements was similar to that of placebo, neither is currently recommended for eczema treatment. it must be noted, though, that most studies in this review “failed to report on whether conventional treatment was continued or stopped during the study.” a 2006 analysis of 26 clinical studies found that epo had a beneficial effect on itching, crusting, and redness that became apparent between 4 and 8 weeks of treatment. however, the magnitude of the effect was reduced “in association with increasing frequency of potent steroid use” [43]. while epo and bo are therefore not recommended in patients with ad treated with topical steroids, their effects on patients not receiving any topical steroid therapy cannot be stated with certainty. chinese herbal medicine background many patients are drawn to chinese herbal medicine (chm), assuming that it is based on herbs and therefore should be safer. however, chm is not one specific supplement or medifish oil supplements background polyunsaturated fatty acids are divided into 2 families: ω-6 and ω-3. in the last several decades, dietary intake of ω-3 fatty acids has declined, while intake of ω-6 fatty acids has increased [15]. in fact, ω-6 fatty acids and ω-3 fatty acids are now consumed in a ratio of about 20-30:1 in the modern western diet, relative to 1-2:1 traditionally [35]. research has suggested that this imbalance may result in increased mediators of inflammation. arachidonic acid (aa), an ω-6 fatty acid, can increase immunoglobulin e (ige) antibodies and t helper 2 cytokines through inflammatory mediators such as prostaglandin e2, which ultimately results in sensitization to allergens. however, ω-3 long chain (lc) polyunsaturated fatty acids (pufa), which are found in high levels in fish oils, may displace aa and reduce the concentration of inflammatory mediators. this is one plausible mechanism by which diets high in ω-3 lcpufa may modulate the development of ige-mediated allergic disease [36]. trials of supplementation for the treatment of ad a cochrane database systematic review of fish oil supplements for the treatment of ad reviewed 3 rcts [37]. all 3 were small studies (31, 145, and 48 patients), and the review authors described these as being of poor methodological quality. in addition, one of the trials combined ω-3 and ω-6 fatty acid treatment with vitamins a and d, possibly introducing confounding factors [38]. despite the limitations of these trials, some encouraging results were noted. while several primary outcome measures were not significantly impacted by fish oil therapy, such as difference in topical steroid use between the 2 treatment groups, other benefits were seen. notably, pooled analysis of 2 of the studies found that fish oil significantly improved the effects on daily living as compared to placebo. a significant difference in area affected at the end of treatment, as assessed by the physician, was also noted. conclusion given some preliminary encouraging results, larger rcts of fish oil supplements should be pursued. given such limited data at this time, however, fish oil supplements would not be routinely recommended. evening primrose oil and borage seed oil background evening primrose oil (epo) and borage seed oil (bo) are two “natural” supplements that have been frequently touted as a treatment for eczema, and both are available over-thereview | dermatol pract concept 2016;6(3):6 27 been performed and therefore these cannot be recommended at this time. given some promising preliminary results, however, larger, controlled studies are warranted. studies on vitamin d supplementation have produced conflicting results as a whole, but additional studies in particular subsets of patients could be warranted. based on limited evidence of efficacy in clinical trials, chm is not recommended for ad at this time, although future well designed studies that evaluate standardized dosing and comparable herbs may be helpful. finally, neither epo nor bo has demonstrated significant improvement in ad (as compared to placebo) and neither is currently recommended for ad treatment. references 1. thestrup-pedersen k. clinical aspects of atopic dermatitis. clin exp dermatol 2000;25(7):535-43. pmid: 11122225. 10.1046/j.1365-2230.2000.00696.x. 2. bieber t. atopic dermatitis. new engl j med 2008;358:1483-94. pmid: 18385500. doi: 10.1056/nejmra074081. 3. goddard a, lio pa. alternative, complementary, and forgotten remedies for atopic dermatitis. evid based complement alternat med 2015;2015;676987. pmid: 26257817. doi: 10.1155/2015/676897. 4. johnston ga, bilboa rm, graham-brown ra. the use of dietary manipulation by parents of children with atopic dermatitis. br j dermatol 2004;150(6):1186-9. pmid: 15214908. doi: 10.1111/j.1365-2133.2004.05888.x. 5. national center for complementary and alternative medicine. oral probiotics: an introduction. http://nccam.nih.gov/health/ probiotics/introduction.htm. accessed on 26 aug 2014. 6. björkstén b, naaber p, sepp e, mikelsaar m. the intestinal microflora in allergic estonian and swedish 2-year-old children. clin exp allergy 1999;29:342-6. pmid: 10202341. doi: 10.1046/j.1365-2222.1999.00560.x. 7. thomas dw, greer fr; american academy of 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in the treatment of pediatric atopic dermatitis: a meta-analysis of randomized controlled trials. ann allergy asthma immunol 2008;101(5):508-16. pmid: 19055205. doi: 10.1016/s10811206(10)60290-6. cation; historically, chinese herbal preparations may contain many different plant extracts [44]. in fact, the authors of a recent review of chm note that these preparations may indeed be based on botanical substances (such as seeds and flowers) or may actually include animal or mineral substances [45]. they also specifically note that “chinese herbal medicines may be neither chinese nor herbal; the term chm in this review is used loosely to refer to any medicinal substances used within the paradigm of chinese medicine practice.” a cochrane systematic review of chm was published in 2013, and included a review of 28 rcts [45]. included in this review were studies that evaluated either oral or topical use of ”a single chinese medicinal herb or formula, manufactured or clinician self-designed chinese medicinal formulae.” they further state that, “a clinician self-designed formula is usually composed of different types of chinese herbs prescribed by a chinese medicine practitioner who determines the selection of herbs based on a person’s condition.” trials of supplementation after a systematic review of these trials, the authors reported that, “we could not find conclusive evidence that chm taken by mouth or applied to the skin was of benefit to children or adults with eczema” [45]. in drawing this conclusion, they noted that while individual studies had reported that chm was superior to conventional drugs, the conclusions were “based on very low quality evidence.” they assessed most of these studies as at high risk of bias, and also found substantial inconsistency between the studies. conclusion at this time, chm would not be recommended to ad patients. given some promising results, however, further well-designed and well-implemented studies that evaluate standardized dosing and comparable herbs, or standardized formulas, would be useful. it should be noted that such studies may not be possible with some forms of chm, as some practices require customizing formulas for individual patients. conclusion recently, dietary supplements—particularly those containing probiotics, prebiotics, vitamin d, fish oil, chinese herbal medicine (chm), evening primrose oil (epo) and borage seed oil (bo)—have garnered attention from researchers and patients as alternatives to conventional medicine for the treatment of ad. the use of probiotic and prebiotic supplements taken in combination has shown promise in rcts. however, significant variability was noted in studies, and further studies are required to determine target populations, strains and types of probiotics and prebiotics, and optimal dosing regimens. limited trials of fish oil supplements have 28 review | dermatol pract concept 2016;6(3):6 ity of childhood atopic dermatitis. pediatr allergy immunol 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10.1111/j.13652133.2008.08601.x. 31. javanbakht mh, keshavarz sa, djalali m, et al. randomized controlled trial using vitamins e and d supplementation in atopic dermatitis. j dermatolog treat 2011;22(3):144-50. pmid: 20653487. doi: 10.3109/09546630903578566. 32. amestejani m, salehi bs, vasigh m, et al. vitamin d supplementation in the treatment of atopic dermatitis: a clinical trial study. j drugs dermatol 2012;11(3):327-30. pmid: 22395583. 33. samochocki z, bogaczewicz j, jeziorkowska r, et al. vitamin d effects in atopic dermatitis. j am acad dermatol 2013;69(2):23844. pmid: 23643343. doi: 10.1016/j.jaad.2013.03.014. 34. hata tr, kotol p, jackson m, et al. administration of oral vitamin d induces cathelicidin production in atopic individuals. j allergy clin immunol 2008;122:829-31. pmid: 19014773. doi: 10.1016/j.jaci.2008.08.020. 35. dunstan ja, mori ta, barden a, et al. maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy. clin exp allergy 2002;33:442-8. pmid: 12680858. doi: 10.1046/j.1365-2222.2003.01590.x. 36. palmer dj, sullivan t, gold ms, et al. randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. allergy 2013;68(11):1370-6. pmid: 24111502. doi: 10.1111/ all.12233. 37. bath-hextall fj, jenkinson c, humphreys r, williams hc. dietary supplements for established atopic eczema. cochrane database syst rev 2012;5;2:cd005205. pmid: 22336810. doi: 10.1002/14651858.cd005205.pub3. 38. bjørneboe a, søyland e, bjørneboe ge, rajka g, drevon ca. effect of n-3 fatty acid supplement to patients with atopic dermatitis. j intern med suppl 1989;731:233-6. pmid: 2650695. 39. horrobin df. essential fatty acid metabolism and its modification in atopic eczema. am j clin nutr 2000;71(1 suppl):367s-72s. pmid: 10617999. 40. rackett sc, rothe mj, grant-kels jm. diet and dermatology. the role of dietary manipulation in the prevention and treatment of cutaneous disorders. j am acad dermatol 1993;29(3):447-61. pmid: 8349862. 41. bamford jt, ray s, musekiwa a, van gool c, humphreys r, ernst e. oral evening primrose oil and borage oil for eczema. cochrane database syst rev 2013 apr 30;4:cd004416. 42. phinney s. potential risk of prolonged gamma-linolenic acid use. ann intern med 1994;120(8):692. pmid: 8135457. 12. eigenmann pa. evidence of preventative effect of probiotics and prebiotics for infantile eczema. curr opin allergy clin immunol 2013;13(4):426-31. pmid: 23799337. doi: 10.1097/ aci.0b013e3283630bad. 13. kopp mv, hennemuth i, heinzmann a, urbanek r. randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of lactobacillus gg supplementation. pediatrics 2008;121(4):e850-6. pmid: 18332075. doi: 10.1542/peds.2007-1492. 14. boyle rj, bath-hextall fj, leonardi-bee j, murrell df, tang ml. probiotics for the treatment of eczema: a systematic review. clin exp allergy 2009;39(8):1117-27. pmid: 19573037 doi: 10.1111/j.1365-2222.2009.03305.x 15. finch j, munhutu mn, whitaker-worth dl. atopic dermatitis and nutrition. clin dermatol 2010;28(6):605-14. pmid: 21034985. doi: 10.1016/j.clindermatol.2010.03.032. 16. moro g, arslanoglu s, stahl b, jelinek j, wahn u, boehm g. a mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. arch dis child 2006;91(10):814-9. pmid: 16873437. doi: 10.1136/ adc.2006.098251. 17. roberfroid m. prebiotics: the concept revisited. j nutr 2007;137(3 suppl 2):830s–7s. pmid: 17311983. 18. shibata r, kimura m, takahashi h, et al. clinical effects of ketose, a prebiotic oligosaccharide, on the treatment of atopic dermatitis in infants. clin exp allergy 2009;39(9):1397-403. pmid: 19508323. doi: 10.1111/j.1365-2222.2009.03295.x. 19. chang ys, trivedi mk, jha a, lin yf, dimaano l, garciaromero mt. synbiotics for prevention and treatment of atopic dermatitis: a meta-analysis of randomized clinical trials. jama pediatr 2016;170(3):236-42. pmid: 26810481. doi: 10.1001/ jamapediatrics.2015.3943. 20. weiland sk, husing a, strachan dp, rzehak p, pearce n, isaac phase one study group. climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. occup environ med 2004;61(7):609-15. pmid: 15208377. doi: 10.1136/oem.2002.006809. 21. vähävihu k, ala-houhala m, peric m, et al. narrowband ultraviolet b treatment improves vitamin d balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. br j dermatol 2010;163(2):321-8. pmid: 20331450. doi: 10.1111/j.1365-2133.2010.09767.x. 22. mangin m, sinha r, fincher k. inflammation and vitamin d: the infection connection. inflamm res 2014;(63)10:803-19. pmid: 25048990. doi: 10.1007/s00011-014-0755-z. 23. chiu ye, havens pl, siegel dh, et al. serum 25-hydroxyvitamin d concentration does not correlate with atopic dermatitis severity. j am dermatol 2013;69(1):40-6. pmid: 23415685. doi: 10.1016/j.jaad.2013.01.010. 24. peroni dg, piacentini gl, cametti e, chinellato i, boner al. correlation between serum 25-hydroxyvitamin d levels and severity of atopic dermatitis in children. br j dermatol 2011;164(5):1078-82. pmid: 21087229. doi: 10.1111/j.1365-2133.2010.10147.x. 25. el taieb ma, fayed hm, aly ss, ibrahim ak. assessment of serum 25-hydroxyvitamin d levels in children with atopic dermatitis: correlation with scorad index. dermatitis 2013;24(6):296301. pmid: 24201460. doi: 10.1097/der.0000000000000010. 26. wang ss, hon kl, kong ap, pong hn, wong gw, leung tf. vitamin d deficiency is associated with diagnosis and severreview | dermatol pract concept 2016;6(3):6 29 to atopic eczema. dermatology 2000;201(3):191-5. pmid: 11096188. doi: 10.1159/000018487. 45. gu s, yang aw, xue cc, et al. chinese herbal medicine for atopic eczema. cochrane database syst rev 201310;9:cd008642. pmid: 24018636. doi: 10.1002/14651858.cd008642.pub2. 43. morse nl, clough pm. a meta-analysis of randomized, placebocontrolled clinical trials of efamol evening primrose oil in atopic eczema. where do we go from here in light of more recent discoveries? curr pharm biotechnol 2006 dec;7(6):503-24. 44. worm m, henz bm. novel unconventional therapeutic aproaches dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):18 315 dermatology practical & conceptual introduction dermatofibromas (dfs) can manifest as atrophic, depressed papules on the upper trunk and proximal upper extremities. histologically, dfs may demonstrate sebaceous induction in the upper dermis, particularly if they occur on the shoulder [1]. on dermoscopy, these glands are readily visible as discrete pale yellow clods, reminiscent of so-called “popcorn-like” structures present in sebaceous hyperplasia. however, this finding is rarely cited as a dermoscopic feature in dfs. here we detail a series of dfs presenting as atrophic papules with dermoscopic findings of yellow clods. case presentation we present 6 cases, descriptions of which follow: a 68-yearold woman with a 9× 8-mm atrophic df on the right upper back (case 1: figure 1, a-c); a 71-year-old man with an 8× 5-mm brown depressed df on the right proximal forearm (case 2: figure 2a); a 68-year-old man with a 1-cm pinkbrown atrophic df on the left upper arm (case 3: figure 2b); a 56-year-old man with an atrophic reddish df on the right upper extremity (case 4: figure 2c); an 82-year-old man with an atrophic reddish papule on the upper back (case 5: figure 2d); and a 55-year-old man with a pink plaque on the chest (case 6: figure 2e). discussion histologically, the presence of sebaceous glands and sebaceous induction overlying dfs has been well documented. this occurs in at least 15% of samples, particularly in dfs on the shoulder [1]. notably, the upper trunk is the most common site of clinically atrophic dfs. sebaceous hyperplasia in this setting likely represents epidermal induction and may be mediated by fibroblast-released growth mediators [1]. the dermoscopic findings present in dfs with sebaceous induction have been very rarely described in the literature [1]. however, widespread appreciation of this dermoscopic feature in dfs appears low, as evidenced in their exclusion in dermatofibroma with sebaceous induction: dermoscopic clues to improve recognition r. hal flowers1, darren guffey1, jonathan c. konopinski2, michael a. marchetti3, barbara b. wilson1 1 department of dermatology, university of virginia health system, charlottesville, va, usa 2 department of dermatopathology, university of virginia health system, charlottesville, va, usa 3 dermatology service, department of medicine, memorial sloan kettering, new york, ny, usa key words: dermoscopy, dermatofibroma, sebaceous induction citation: flowers rh, guffey d, konopinski jc, marchetti ma, wilson bb. dermatofibroma with sebaceous induction: dermoscopic clues to improve recognition. dermatol pract concept. 2019;9(4):315-317. doi: https://doi.org/10.5826/dpc.0904a18 accepted: may 25, 2019; published: october 31, 2019 copyright: ©2019 flowers et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: m.a.m. has support from a national institutes of health support grant to memorial sloan kettering cancer center (p30 ca008748). competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: r. hal flowers, md, 1221 lee st., p.o. box 800718, uva health system, charlottesville, va 22908-0718. email: rf9rj@virginia.edu 316 letter | dermatol pract concept 2019;9(4):18 figure 1. (a) case 1 had a 9× 8-mm atrophic violaceous papule with several foci of dark brown pigmentation and inferiorly located whitish structures. (b) dermoscopy of case 1 shows round white-yellow clods admixed with central scar-like patch and a peripheral pigment network. (c) histological examination of case 1 shows a cellular dermal infiltrate composed of bland fibrohistiocytic cells. the epidermis is acanthotic, exhibiting a broadening and anastomosis of pale-staining rete ridges parallel to the skin surface. notably, there is induction of sebaceous glands (h&e, ×4). [copyright: ©2019 flowers et al.] reported classifications of df patterns. in these reports, yellowish globular structures on dermoscopy were histopathologically correlated with a prominent sebaceous component. review of the literature reveals that previous dermoscopic descriptions of these structures exist, but that the correlation with sebaceous glands is not always made. for example, karaarslan et al show a dermoscopic image of an atrophic df and describe “multiple, small scar-like areas”; they include a histological image with prominent sebaceous glands, which appear to correspond to these “scar-like areas” [2]. figure 2. (a) dermoscopy of case 2 shows a patchy peripheral pigment network and central white structureless area with multiple white-yellow clods. (b) dermoscopy of case 3 shows a prominent vascularity with numerous yellow clods of varying sizes. (c) dermoscopy of case 4 shows faint peripheral pigment network, central red patch, and a few admixed yellow clods. (d) dermoscopy of case 5 shows background brownish homogeneous pigmentation with broad telangiectasias and scattered yellow clods with prominent follicular orifices. (e) dermoscopy of case 6 shows background erythema with a few overlying central yellow clods. [copyright: ©2019 flowers et al.] a b d c e letter | dermatol pract concept 2019;9(4):18 317 references 1. monteagudo b, figueroa-silva o, suárez-amor o, álvarez jc. hallazgos clínicos, dermatoscópicos e histopatologicos de un dermatofibroma con inducción sebácea [in english, spanish]. actas dermosifiliogr. 2017;108(9):874-876. 2. karaarslan ik, gencoglan g, akalin t, ozdemir f. different dermoscopic faces of dermatofibromas. j am acad dermatol. 2007;57(3):401-406. conclusions we have observed that highly characteristic yellowish white discrete round clods are often present on dermoscopy of dfs which are clinically depressed or inverted (clinically atrophic dfs) on the upper torso, shoulder, and upper extremities. these yellow to yellow-white clods on dermoscopy correlate with sebaceous glands found in dfs. this dermoscopic finding may help the clinical recognition of a subset of atrophic dfs, which often lack the characteristic dimpling and palpability of typical dfs. dermatology: practical and conceptual review | dermatol pract concept 2015;6(2):7 37 dermatology practical & conceptual www.derm101.com introduction the term “spitz lesion” was first introduced in 1948 by sophie spitz referring to “melanomas of childhood” [1]. these lesions were later reclassified as benign melanocytic and considered likely to occur also in older patients. usually presenting as a pink-red papule on the face or lower extremities, spitz nevus displays a benign clinical behavior. in 1975, reed et al [2] spitz/reed nevi: a review of clinical-dermatoscopic and histological correlation ana f. pedrosa1,2, jose m. lopes2,3, filomena azevedo1, alberto mota1,2 1 department of dermatology and venereology, centro hospitalar são joão epe, porto, portugal 2 faculty of medicine, university of porto, porto, portugal 3 department of pathology, centro hospitalar são joão epe, porto, portugal key words: dermatoscopy; reed nevus; spindle and/ or epithelioid cell nevus; spitz nevus citation: pedrosa af, lopes mm, azevedo f, mota a. spitz/reed nevi: a review of clinical-dermatoscopic and histological correlation. dermatol pract concept 2016;6(2):7. doi: 10.5826/dpc.0602a07 received: november 27, 2015; accepted: february 19, 2016; published: april 30, 2016 copyright: ©2016 pedrosa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ana filipa bastos pedrosa, md, department of dermatology and venereology, centro hospitalar são joão epe, alameda prof. hernani monteiro, 4200-319 porto, portugal. tel. +351 225512193. email: anabastospedrosa@gmail.com background: spitz/reed nevi are melanocytic lesions that may mimic melanoma at clinical, dermatoscopic and histopathological levels. management strategies of these lesions remain controversial. objectives: we aim a correlation among clinical-dermatoscopic and histological features of a series of spitz/reed nevi diagnosed during 7 years at the department of dermatology. methods: clinical, dermatoscopic and histological features of spitz/reed nevi diagnosed at our tertiary hospital from 2008 to 2014 were reviewed in order to seek correlation. results: all described dermatoscopic patterns for spitz/reed nevi were found among the 47 enrolled patients; starburst and atypical/multicomponent patterns prevailed (57.4%). reticular pattern predominated among children younger than 12 years, whereas homogeneous pattern was more frequent in patients older than 12 years, although these differences were not statistically significant (p=0.785). among histological atypical lesions, all dermatoscopic patterns were represented, but the atypical/ multicomponent predominated (56.3%). two out of 11 dermatoscopically atypical lesions did not show histopathological counterpart. conclusions: the excision of spitz/reed nevi in adults is supported, given the inability to accurately predict those with histopathological atypia, based on clinical and dermatoscopic features, which may raise concern about malignancy. abstract 38 review | dermatol pract concept 2016;6(2):7 inc, bad birnbach, germany). the histological classification of excisional biopsies was based on hematoxylin-eosin (he) stained slides, which were considered representative of the lesion. whenever necessary, new slides were prepared from the stored paraffin blocks. the research was focused on the correlation of clinical-dermoscopic and histological features, using image examples, whenever possible. statistical analysis was performed using software (spss v22.0, ibm corp, armonk, ny). descriptive frequencies were calculated to characterize the study population. kruskal-wallis test was performed to determine whether dermoscopic patterns differed among age groups. p values below 0.05 were considered statistically significant. results of the 47 enrolled patients, 80.9% (38/47) were females, and the overall median age was of 15 years (range 3-72 years), including 59.6% (28/47) under 18 years of age (3-17 years) and 40.4% (19/47) adults (19-72 years). the most common lesion sites were the lower extremities (24/47, 51.1%), followed by the upper extremities (11/47, 23.4%), the trunk (7/47, 14.9%) and the face (5/47, 10.6%). most frequently described were black (20/47, 42.6%) and brown lesions (17/47, 36.2%). only 5 out of 47 (10.6%) lesions were pink-red. table 1 details the clinical and histological features according to the main dermatoscopic patterns. the prevailing dermatoscopic patterns were the starburst and the atypical/ multicomponent, which accounted for 57.4% (27/47) of the cases. reticular pattern predominated among young children under 12 years of age (3/5, 60%), whereas homogeneous pattern was more frequently found among patients over 12 years old (6/8, 75%), although these differences were not statistically significant (p=0.785, kruskal-wallis test). the reticular pattern encompassed the inverse white (n=3) and the superficial black network (n=2). the clinical-dermatoscopic-histological correlation of excised spitz/reed nevi revealed overlapping histopathological features among lesions displaying distinct dermatoscopic patterns (figures 1-3). among lesions with histopathological atypia (16/47, 34.0%), all dermatoscopic patterns were represented, although the atypical/multicomponent predominated (9/16, 56.3%). conversely, in 2 out of 11 cases (18.2%) exhibiting dermatoscopic atypia, particularly asymmetry and atypical network, the histopathological sections did not confirm the presence of criteria of atypia. so far, none of the cases developed local recurrence or distant spread after excision (median follow-up time of 14 months). in the pediatric patients (aged under 18 years) with suspected spitz/reed nevus by dermoscopy who had submitted described a benign pigmented melanocytic lesion, predominantly found on the lower extremities and thereafter named reed nevus, which is currently regarded as the pigmented counterpart of spitz nevus [3,4]. the main concern with these lesions remains their propensity to mimic melanoma at clinical, dermatoscopic and histopathological levels [5]. dermoscopy improves diagnostic accuracy in many cutaneous lesions, including spitz/reed nevi, for which the following patterns were identified: globular, reticular (inverse white and superficial black network), starburst, homogeneous and atypical/multicomponent [4,6]. despite the attempts, there is no consensus in the histopathological classification of these lesions [7,8]. although considered by some authors [3] an exclusively spindle-cell nevus, reed nevus may display a mixed pattern with epithelioid and spindle cells. in classical spitz nevus, melanocytes are characteristically epithelioid but often also spindle-shaped [3]. spitz/reed nevi with atypia include a subset of lesions not fulfilling the histopathological criteria for melanoma, but displaying at least one of the following: a) asymmetry; b) poor lateral circumscription; c) predominance of single melanocytes over nests; d) ulceration; e) extensive involvement of the dermis and subcutis; f) impaired maturation; g) excessive mitotic activity; and h) deep dermal mitoses [3]. this manuscript aims to correlate the clinical-dermatoscopic and histological findings in a series of spitz/reed nevi in adults and children followed at the department of dermatology of an university hospital, reviewing and discussing the latest available data on this particular issue. methods we conducted a cross-sectional and retrospective study at the department of dermatology of a tertiary university hospital over a 76-month period, from january 2008 until april 2014. in this department, adult patients with a suspicion of spitz/reed nevi on clinical and dermatoscopic grounds were submitted to excision of these lesions. all patients with a histologically confirmed diagnosis of spitz/reed nevi were enrolled. demographic and clinical data were collected from comprehensive databases including patient age, gender, lesion color and location on the body, as well as any relevant medical history. dermoscopic images were reviewed and classified in terms of the abovementioned respective patterns. histopathological features, such as the presence of a junctional component, spindle cells and atypia, based on abovementioned criteria, were further analyzed by two independent double-blinded pathologists. there were no specific requirements regarding the technical equipment for image acquisition and both polarized and nonpolarized dermoscopic images were included, although the most common system used was fotofinder® dermoscope (fotofinder systems, review | dermatol pract concept 2015;6(2):7 39 table 1. clinical and histological features of the cases according to the dermatoscopic pattern. [copyright: ©2016 pedrosa et al.] clinicopathological data dermatoscopic pattern homogeneous n (%) 8 (17.0) globular n (%) 7 (14.9) reticular n (%) 5 (10.7) starburst n (%) 16 (34.0) atypical n (%) 11 (23.4) age in years (median/range) 22/69 16/25 11/32 16/46 12/60 female gender (n/%) 5/62.5 6/85.7 3/60 14/87.5 10/90.9 color, n (%) black 5 (62.5) 2 (28.6) 1 (20) 10 (62.5) 2 (18.2) brown 1 (12.5) 4 (57.1) 1 (20) 4 (25) 7 (63.6) grayish 1 (20) 2 (12.5) 2 (18.2) pink-red 2 (25) 1 (14.3) 2 (40) location, n (%) face and neck 2 (25.0) 1 (14.3) 2 (18.2) upper extremities 3 (37.5) 1 (14.3) 1 (20) 5 (31.3) 1 (9.1) lower extremity 2 (25.0) 5 (71.4) 1 (20) 5 (31.3) 8 (72.7) buttocks 1 (20) 2 (12.5) trunk 1 (12.5) 2 (40) 4 (25.0) histology, n (%) junctional component 6 (75.0) 1 (14.3) 2 (40.0) 6 (37.5) 2 (18.2) spindle cells 7 (87.5) 6 (85.7) 4 (80.0) 12 (75.0) 8 (72.7) atypical features 1 (12.5) 1 (14.3) 2 (40.0) 3 (18.8) 9 (81.8) figure 1. black-colored, flat lesion on the right thigh of an 11-year-old female child. (a) a superficial black network emerges under the dermatoscopic examination, overlying a diffuse bluish pigmentation. (b) histopathology shows a junctional melanocytic lesion with focal areas of pigmented parakeratosis (black arrow) which explains the superficial black network seen in (a). the dense band of superficial dermal melanophages is thought to be responsible for the bluish background (he, x20). pigmented spindle-shaped melanocytes predominate in well-demarcated junctional nests (insets, x100 and x200). [copyright: ©2016 pedrosa et al.] figure 2. brown-colored lesion on the left arm of a 33-year-old female. (a) this atypical/multicomponent patterned lesion is dermatoscopically asymmetric typified by pseudopods irregularly distributed at the periphery and an atypical network attenuated at the right side. (b) histopathology unveils a junctional asymmetric lesion with epidermal hyperplasia, hyperkeratosis and hypergranulosis exhibiting a focal infiltration of dermal melanophages responsible for the blue-whitish veil seen under dermoscopy (he, x40). confluent epithelioid and spindle-shaped melanocyte nests are observed in insets (he, x100 and x200). [copyright: ©2016 pedrosa et al.] 40 review | dermatol pract concept 2016;6(2):7 cal architecture, cellular maturation in the deep dermis, and absence or scant mitotic activity. however, the histological differential diagnosis of spitzoid tumors often represents a difficult challenge, with several lesions uncovered in a “gray zone” raising interobserver disagreement [3,10]. the presented results support that spitz/reed nevi should be excised in adults and children older than 12 years old, in agreement with lallas et al [10], given the inability to predict with accuracy those with histopathological atypia that may raise concern about aggressive behavior and hinder the differential diagnosis with spitzoid melanoma. clinical and dermatoscopic follow-up was the first choice in 6 pediatric patients under 12 years of age with lesions classified as typical spitz/reed nevi on clinical and dermatoscopic grounds, and an involution pattern was observed in more than half of the cases along 6 to 24 months, supporting an observational initial approach with clinical and dermatoscopic follow-up of spitz/reed nevi in young children, in accordance with other authors [7,8]. references 1. spitz s. melanomas of childhood. am j pathol 1948; 24:591-609. pmid: 18859360 2. reed rj, ichinose h, clark wh, jr., mihm mc, jr. common and uncommon melanocytic nevi and borderline melanomas. semin oncol 1975; 2:119-47. pmid: 1234372 3. ferrara g, argenziano g, soyer hp, et al. the spectrum of spitz nevi: a clinicopathologic study of 83 cases. arch dermatol 2005; 141:1381-7. pmid: 16301385. doi: 10.1001/archderm.141.11.1381 4. argenziano g, soyer hp, ferrara g, et al. superficial black network: an additional dermoscopic clue for the diagnosis of pigmented spindle and/or epithelioid cell nevus. dermatology 2001; 203:333-5. pmid: 11752824 5. ferrara g, gianotti r, cavicchini s, et al. spitz nevus, spitz tumor, and spitzoid melanoma: a comprehensive clinicopathologic overview. dermatol clin 2013; 31:589-98, viii. pmid: 24075547. doi: 10.1016/j.det.2013.06.012 to excision (n=28), histopathology confirmed the diagnosis without any prepubertal melanoma diagnosed, although 8 cases (8/28, 28.6%) exhibited at least one histopathological criteria of atypia. six additional pediatric patients under 12 years of age and displaying lesions clinical and dermatoscopically very suggestive of spitz/reed nevi were initially monitored with follow-up visits: 4 lesions showed an involution pattern and 2 showed a growing or stable pattern along 6 to 24 months. discussion similarly to ferrara et al [3], we found overlapping histopathological features between lesions categorized as epithelioid and/or spindle-cell nevi supporting the unifying denomination of spitz/reed nevi. additionally, as in the abovementioned study [3], an association between dermatoscopic and histopathological atypia was not always found, especially referring to dermatoscopic asymmetry, raising the possibility that histological sections may not always be representative of the whole lesion. a blue-whitish central veil or a diffuse bluish pigmentation found in lesions with distinct dermatoscopic patterns (figures 1, 2) usually results from dermal accumulation of melanophages and does not imply regression and therefore should not be considered as an atypical dermatoscopic finding in this setting. we report a prevalence of an atypical/multicomponent dermatoscopic pattern of 23.4%, which is in accordance with other studies [9]. the reticular pattern predominated in children under 12 years old, although without statistical significance, this finding may support the importance of this pattern in early stages of development of these nevi [9]. conversely, the homogeneous pattern was more frequent among older patients, as expected by the presumed natural evolution of these lesions [8]. histopathological features that favor the diagnosis of spitz/reed nevus over spitzoid melanoma are the symmetrifigure 3. a pink pale papule on the face of a 5-year-old female child. (a) a homogeneous pink-red pattern exhibiting dermatoscopically dotted and linear vessels and sparse pigmented globules not apparent at naked eye examination. (b) histopathology shows a compound, symmetrical lesion with shallow depth, well-demarcated borders and a marked dermal inflammatory cell infiltrate in lower magnification (he, x40). epithelioid and spindle-cell nests of melanocytes and sparse melanophages are observed, as well as scant pigment deposition (inset, x200). [copyright: ©2016 pedrosa et al.] review | dermatol pract concept 2015;6(2):7 41 ment. dermatology 2009; 218:48-51. pmid: 18832809. doi: 10.1159/000161120 9. de giorgi v, savarese i, rossari s, et al. clinical and dermoscopic features of small reed nevus (<6 mm). j eur acad dermatol venereol 2013; 27:919-21. pmid: 22324638. doi: 10.1111/j.14683083.2012.04457.x 10. lallas a, moscarella e, longo c, et al. likelihood of finding melanoma when removing a spitzoid-looking lesion in patients aged 12 years or older. j am acad dermatol 2015; 72:47-53. pmid: 25440960. doi: 10.1016/j.jaad.2014.09.037 6. zalaudek i, kittler h, hofmann-wellenhof r, et al. “white” network in spitz nevi and early melanomas lacking significant pigmentation. j am acad dermatol 2013; 69:56-60. pmid: 23415462. doi: 10.1016/j.jaad.2012.12.974 7. tlougan be, orlow sj , schaffer jv. spitz nevi: beliefs, behaviors, and experiences of pediatric dermatologists. jama dermatol 2013; 149:283-91. pmid: 23553063. doi: 10.1001/jamadermatol.2013.1124 8. nino m, brunetti b, delfino s, et al. spitz nevus: follow-up study of 8 cases of childhood starburst type and proposal for manageobservation | dermatol pract concept 2012;2(1):12 61 pre-emptive diagnosis of a case of scabies by dermatopathology cliff rosendahl mbbs1, alan cameron mbbs2, david weedon m.d.3 1 capalaba general practice, brisbane, australia 2 beenleigh family practice, brisbane, australia 3 sullivan nicolaides pathology, brisbane, australia key words: scabies, dermatopathology, dermatoscopy, dermoscopy citation: rosendahl c, cameron a, weedon d. pre-emptive diagnosis of a case of scabies by dermatopathology. dermatol pract conc. 2012;2(1):12. http://dx.doi.org/10.5826/dpc.0201a12. editor: jeffrey keir, mbbs received: november 8, 2011; accepted: december 6, 2011; published: january 31, 2012 copyright: ©2012 rosendahl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: cliff rosendahl, mbbs, po box 734, capalaba, queensland, 4157, australia. tel. +61419769970; fax. +61732453022 . email: cliffrosendahl@bigpond.com. case presentation a 39-year-old woman reported to her general practitioner with a new pigmented skin lesion on her right pectoral region. dermatoscopically there were no suspicious features and the decision was made to monitor it over a three-month period. at follow-up imaging there was some minor change, possibly related to technical factors (the original camera/ dermatoscope combination was not available), and after discussion with the patient a decision was made to perform an excisional biopsy. the pathologist reported the lesion as a: “… dysplastic naevus of the compound type” with “… mild atypia and active lymphocytic regression.” he made the additional comment: “two apparent scabies mites are present.” this was not expected, as the patient had complained of no symptoms of scabies and no skin eruption had been observed to suggest that diagnosis. the patient returned for her routine postoperative review one week after the excision. she now complained of an intensely itchy skin eruption and wondered if she was having an allergic reaction to the local anaesthetic or antiseptic skin preparation solution used at the time of surgery. examination dermatology practical & conceptual www.derm101.com figure 1. clinical and close-up image of a pigmented skin lesion taken four months prior to biopsy. [copyright: ©2012 rosendahl et al.] 62 observation | dermatol pract concept 2012;2(1):12 revealed a skin eruption consistent with scabies. appropriate topical treatment was prescribed and the symptoms and signs of scabies resolved over a period of weeks. the source of infestation was not identified and no household member or other personal contact was reported to have developed symptoms prior, or subsequent to, this case. discussion scabies infestation is caused by sarcoptes scabiei var hominis, an obligatory human parasite, which spreads from person to person by transmission of fertilised female mites by direct skin contact [1]. a typical infestation involves a stable population of 15–20 adult female mites, which burrow in the stratum corneum where they deposit eggs and faeces [2]. the clinical symptoms of an intensely itchy eruption occur typically after a delay of two to six weeks in the case of an initial infestation and are caused by a host immune response to the mite and its faeces [3]. the diagnosis of scabies can be made either empirically on clinical grounds or with confirmation using skin scraping, the adhesive tape test or dermatoscopy [1]. because there are other conditions that can cause similar symptoms, the diagnosis of scabies may be delayed, and not only can this occur in general practice but it has been reported in a tertiary facility with access to specialist dermatologist services [4], in a hospital emergency department [5] and in an aged care facility with resulting widespread transmission and extreme economic cost [6]. to avoid transmission and the associated morbidity and cost, accurate prompt cost-effective diagnosis is desirable. conclusion the case reported here occurred in a general practice setting with a patient base of around 5,000, where scabies is diagnosed infrequently, approximately three to four times per year. this low incidence increases the risk of missed diagnosis of scabies, but as long as it is suspected, it can be diagnosed very cost-effectively by the preferred method of author cr, dermatoscopy. this permits an unequivocal diagnosis when the mouthparts of the female mite are seen at the end of a burrow in the skin giving the “jet and contrail” dermatoscopic sign [7]. examination for this sign can take some time and effort and in this case the need for this was averted by a pre-emptive histological diagnosis. the biopsy for collateral reasons occurred prior to any clinical manifestation of scabies infestation and recognition by the pathologist delivered a firm diagnosis so that the condition was promptly recognised on presentation, diagnosed and treated, minimising the risk of further transmission. figure 3. dermatopathology image of the pigmented skin lesion shown in the previous images showing two apparent scabies mites at the level of the stratum corneum. [copyright: ©2012 rosendahl et al.] figure 2. dermatoscopy image of the pigmented skin lesion taken six days prior to biopsy, [copyright: ©2012 rosendahl et al.] figure 4. clinical composite of images taken one week after biopsy showing a skin eruption consistent with scabies. [copyright: ©2012 rosendahl et al.] observation | dermatol pract concept 2012;2(1):12 63 references walter b, heukelbach j, fengler g, worth c, hengge u, feldmeier h. comparison of dermoscopy, skin scraping, and the adhesive tape test for the diagnosis of scabies in a resource-poor setting. arch dermatol. 2011;147(4):468–73. scabies. web site. http://medent.usyd.edu.au/fact/scabies.html. accessed december 9, 2011. buehlmann m, beltraminelli h, strub c, et al. scabies outbreak in an intensive care unit with 1,659 exposed individuals – key factors for controlling the outbreak. infect control hosp epidemiol. 2009;30(4):354–60. obasanjo oo, wu p, conlon m, et al. an outbreak of scabies in a teaching hospital: lessons learned. infect control hosp epidemiol. 2001;22(1):13–8. hong m-y, lee c-c, chuang m-c, chao s-c, tsai m-c, chi c-h. factors related to missed diagnosis of incidental scabies infestations in patients admitted through the emergency department to inpatient services. acad emerg med. 2010;17(9):958–64. de beer g, miller ma, tremblay l, monette j. an outbreak of scabies in a long-term care facility: the role of misdiagnosis and the costs associated with control. infect control hosp epidemiol. 2006;27(5):517–8. tschandl p, argenziano g, bakos r, et al. dermoscopy and entomology (entomodermoscopy). j dtsch dermatol ges. 2009;7(7):589–96. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):8 47 dermatology practical & conceptual www.derm101.com case presentation a 29-year-old japanese man presented with a reddish nodule, of approximately 15 mm in diameter, on the nose (figure 1). the lesion had gradually grown in size since childhood. the patient had no associated symptoms or family history. dermatoscopic examination of the nodule revealed a yellowishwhite network, yellowish-orange globules at its center, and a pinkish structureless peripheral area (figure 2a). we initially suspected that the lesion was an adnexal tumor or a sebaceous neoplasm. the tumor was excised completely. on histopathological examination, we observed an exophytic lesion composed of dilated, follicular infundibular structures connected with multiple sebaceous lobules and surrounded by fibrous connective tissue with thick collagen bundles (figure 3a). cleft formation between fibroepithelial units and intervening stroma was evident (figure 3c). moreover, the surrounding stroma was fibrotic, with a high number of small vessels (figure 3c). no hair shafts were present in the cystic cavity. these findings were consistent with a diagnosis of folliculosebaceous cystic hamartoma (fsch). discussion fsch, first described by kimura et al. in 1991, is characterized by a relatively rare cutaneous hamartoma composed dermatoscopy of folliculosebaceous cystic hamartoma emiko watanabe-okada1, yuichi kurihara1, shunichi miyakawa1, masaru tanaka2 1 division of dermatology, kawasaki municipal hospital, kawasaki, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan keywords: folliculosebaceous cystic hamartoma, sebaceous trichofolliculoma, yellowish-white network, yellowish-orange dots/globules, dermatoscopy citation: watanabe-okada e, kurihara y, miyakawa s, tanaka m. dermatoscopy of folliculosebaceous cystic hamartoma. dermatol pract concept. 2014;4(3):8. http://dx.doi.org/10.5826/dpc.0403a08 received: february 4, 2014; accepted: march 18, 2014; published: july 31, 2014 copyright: ©2014 watanabe-okada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: emiko watanabe-okada, m.d. tel. +81-44-233-5521; fax. +81-44-245-9600. email: emicat720@yahoo.co.jp a 29-year-old japanese man presented to our institution with a nodule on his nose that had increased in size since childhood. physical examination indicated the presence of an elastic, firm, pedunculated red nodule measuring 15 mm in size. dermatoscopic examination of the nodule indicated a yellowishwhite network, yellowish-orange dots/globules at its center, and a pinkish-white structureless peripheral area. histopathological examination of an excisional biopsy specimen showed a dilated infundibulocystic structure with sebaceous lobules proliferating radially, surrounded by fibrous stroma. moreover, mature adipocytes and small vessels were noted in the stroma. based on these histopathologic findings, the patient was diagnosed with folliculosebaceous cystic hamartoma. abstract 48 observation | dermatol pract concept 2014;4(3):8 of follicular, sebaceous, and mesenchymal components [1]. fsch clinically manifests as a solitary skin-colored sessile or pedunculated nodule that is most commonly located on the central part of face, particularly on the nose or the paranasal area. the lesion is usually < 3 cm in size [2]. fsch shares several similar histopathological features with sebaceous trichofolliculoma (stf) and may be considered a variant of stf with a marked sebaceous component figure  1. clinical photograph showing a pedunculated reddish nodule on the nose. [copyright: ©2014 watanabe-okada et al.] figure 2. (a) a pinkish-white structureless peripheral area. (b) dermatoscopy of the nodule shows white structureless areas, a yellowishwhite network and (c) yellowish-orange dots/globules at its center. [copyright: ©2014 watanabe-okada et al.] [3]. however, certain histopathologic features of fsch are believed to be distinct, and thus, this condition can be differentiated from stf. ansai et al. described that the prominent mesenchymal component and double cleft formation between fibroepithelial units and the altered stroma are distinguishing features of fsch. in contrast, stf has rudimentary hair follicles and hair shafts connecting to the infundibular cyst wall, and lacks the distinctive mesenchymal component observed in fsch [2]. on dermatoscopy, we detected a yellowish-white network and yellowish-orange dots/globules at its center, with a pinkish structureless peripheral area (figure 2a). the whitishyellow network observed on histopathological examination represented the elongation of the rete ridges in addition to dermal sebaceous components (figures 2b and 3b). moreover, whitish-yellow clods were identified at the center of the nodule, indicating the presence of exophytic lesions consisting of sebaceous lobules connected to the dilated infundibular cystic structures via sebaceous ducts (figure 2b). furthermore, at the center of the nodule, the yellowish-orange globules represented conglomerations of sebaceous glands located in the superficial dermis (figure 2c). the color of the pinkish structureless peripheral area appeared similar to that of dermal dilated blood vessels. based on the clinical findings, the differential diagnoses would include melanocytic nevus, poroma, and sebaceoma. however, additional features observed via dermatoscopy could help exclude these disorders, including the lack of residual pigmentation around the hair follicles suggesting melanocytic nevus, the absence of glomerular or hairpin vessels and a whitish-pink network suggesting poroma, and the presence of a yellowish structureless area and arborizing vessels suggesting sebaceoma. observation | dermatol pract concept 2014;4(3):8 49 to our knowledge, only one case presenting with the dermatoscopic features of fsch has been reported in japan [4]. in that report, the dermatoscopic features of fsch included a yellowish-orange area and whitish-yellow globules. although fsch can only be diagnosed based on the microscopic features, certain characteristic dermatoscopic features observed in the present case may also be useful to distinguish among several differential diagnoses. moreover, we believe that the awareness of this entity and the use of dermatoscopy can facilitate the diagnosis of fsch. in conclusion, we described the dermatoscopic features of fsch, such as a whitish-yellow network, yellowish-orange dots/globules, and whitish-yellow clods. however, additional dermatoscopic findings are needed to elucidate whether the features described here are characteristic findings in fsch. references 1. kimura t, miyazawa h, aoyagi t, et al. folliculosebaceous cystic hamartoma: a distinctive malformation of the skin. am j dermatopathol. 1991;13:213-20. 2. ansai s, kimura t, kawana s. a clinicopathologic study of folliculosebaceous cystic hamartoma. am j dermatopathol 2010;32:815-20. 3. plewig g. sebaceous trichofoliculoma. j cutan pathol. 1980;7: 394-403. 4. oishi k, ohara k. a yellow-red colored nodule on an infant’s cheek. j jpn dermatohistopathol soc. 2009:25:9-12 (in japanese). figure 3. (a) histopathologic examination reveals an exophytic lesion consisting of a dilated infundibular cystic structure with sebaceous lobules connected via sebaceous ducts. (h&e x5). (b) numerous mature sebaceous lobules along with the elongation of the rete ridges in the epidermis are seen. (h&e x20). (c) a cleft is noted between the fibroepithelial units and the surrounding stroma; the stroma is prominent, with fibrillar bundles of collagen and a high number of small blood vessels. (h&e x40). [copyright: ©2014 watanabe-okada et al.] dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(2):8 31 extensive regression in pigmented skin lesions: a dangerous confounding feature aimilios lallas, m.d.1, zoe apalla, m.d.1, elvira moscarella, m.d.2, iris zalaudek, m.d.3,4, thrasivoulos tzellos, m.d.1, ioanna lefaki, m.d.1, carlo cota, m.d.2, giuseppe argenziano, m.d.4 1 state clinic of dermatology, hospital of skin and venereal diseases of thessaloniki, greece 2 department of dermatologic oncology, santa maria and san gallicano dermatologic institute, ifo of rome, rome, italy 3 department of dermatology, medical university of graz, graz, austria 4 dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, italy key words: pigmented lesion, regression, melanoma, lichen planus-like keratosis citation: lallas a, apalla z, moscarella e, et al. extensive regression in pigmented skin lesions: a dangerous confounding feature. dermatol pract conc. 2012;2(2):8. http://dx.doi.org/10.5826/dpc.0202a08. received: december 13, 2011; accepted: february 20, 2012; published: april 30, 2012 copyright: ©2012 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aimilios lallas, m.d., state clinic of dermatology, hospital of skin and venereal diseases of thessaloniki, delfon 124, 54643, thessaloniki, greece. tel. 00306932368102; fax. 00302310850762. email: emlallas@gmail.com. spontaneous regression in melanomas is not an uncommon phenomenon, as it has been described in 10-35% of primary cutaneous lesions [1]. regression does not appear to predict a more favorable course, since even fully regressed melanomas may progress into metastatic disease [2]. several dermoscopic features have been correlated with the regression process, including white scar-like depigmented areas and gray-blue, pepper-like granules, which correspond to dermal scarring, pigment incontinence and presence of melanophages [3,4]. regression may occur not only in melanomas, but also in melanocytic nevi, which similarly may exhibit white areas and gray-blue granules or areas under dermoscopy [5]. overall, white areas have been proposed to be associated with the fibrosis type of regression and gray-blue areas to the melanosis type of regression of melanocytic tumors [3]. lichen planus like keratosis (lplk) is considered to represent a regressed solar lentigo or seborrheic keratosis. dermoscopy of lplk at the late stage of the regression process reveals a diffuse gray-blue granular pattern, similar to that observed in regressed melanocytic lesions [6]. in this context, when evaluating skin lesions that exhibit high degree of regression, interpretation of dermoscopic findings may be problematic, especially when no other dermoscopic clues can be recognized. abstract mailto:emlallas@gmail.com 32 observation | dermatol pract concept 2012;2(2):8 case presentation the fully regressed melanoma in figure 1 was found on the arm of a 50-year-old man, who was recently diagnosed with metastatic melanoma of the ipsilateral axillary lymph nodes (figure 1a). dermoscopic examination revealed a diffuse blue-gray granular pattern, scar-like, depigmented areas, and a roundish ulceration in the absence of any specific features of melanoma (figure 1b). histopathologic examination showed hyperplasia of the epidermis, prominent scar-like fibrosis of the dermis (corresponding dermoscopically to scar-like depigmented areas), vascular hyperplasia, moderately dense inflammation, pigment incontinence and accumulation of melanophages (observed as blue-gray granularity under dermoscopy) (figures 1c,d). the latter resulted in a fuzzy appearance of the dermis, obstructing the recognition of residual melanocytes, which were finally highlighted by immunohistochemistry, as slight positivity in s100 and hmb45 stains. in addition, we present a melanocytic nevus (figure 2) and a lplk (figure 3), both typified by features of diffuse regression, namely blue-gray granules and whitish areas. similar to the melanoma case, no other dermoscopic clues allowing a confident diagnosis could be identified. histopathologic features of the nevus were very similar to those observed in the melanoma case, including prominent fibrosis, mild inflammation, telangiectasias and scattered melanophages (figures 2c,d). on the other hand, the lplk was histopathologically characterized by mild acanthosis, a bandlike lymphocytic infiltrate, focal vacuolar degeneration of the basal cell layer, dermal fibrosis, and abundant melanophages in the upper dermis (figure 3c,d). conclusions zalaudek et al proposed that the management of melanocytic lesions exhibiting dermoscopic features of regression may be figure 1. (a) clinical image showing a suspicious pigmented lesion on the arm of a 50-year-old man, who was recently diagnosed with metastatic melanoma of the ipsilateral axillary lymph nodes. (b) diffuse granular pattern in the absence of melanoma-specific criteria in dermoscopy. scar-like depigmented areas (black arrows) and a roundish ulceration (white arrow) can also be identified. (c, d) histopathologic images showing prominent dermal fibrosis, increased vascularity and accumulation of melanophages (hematoxylin & eosin [h&e] x10 magnification (c), h&e x20 magnification (d)). [copyright: ©2012 lallas et al.] observation | dermatol pract concept 2012;2(2):8 33 facilitated by the use of an algorithm based on the degree and combination of regression features [3]. in particular, the authors suggest that risk of melanoma is higher for lesions showing either moderate or high degree of regression features along with the presence of combined blue and white areas. the dermoscopic diagnosis of a lplk may be assisted by the identification of areas reminiscent of a solar lentigo or a seborrheic keratosis within the lesion [7]. however, at the end-stage of the regression process, when such features have disappeared and the lesion is characterized only by the presence of blue-gray granules, lplk may strikingly mimic regressive melanoma [6]. in the three lesions reported here, the presence of prominent regression features did not allow a confident differential diagnosis. under this scenario, an otherwise benign lesion, as a melanocytic nevus, or even a lplk, may be virtually indistinguishable on clinical and dermoscopic examination from a melanoma and vice versa. in such cases, even histopathologic examination may fail to establish a definite diagnosis. thus, in lesions exhibiting high degree of regression under dermoscopy, complete excision and careful clinicopathologic evaluation is mandatory to reach a reliable final diagnosis. references 1. blessing k, mclaren km. histological regression in primary cutaneous melanoma: recognition, prevalence and significance. histopathology. 1992;20(4):315–22. 2. bories n,  dalle s,  debarbieux s, balme b, ronger-savié s, thomas l. dermoscopy of fully regressed cutaneous melanoma. br j dermatol. 2008;158(6):1224-9. 3. zalaudek i, argenziano g, ferrara g, et al. clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study. br j dermatol. 2004;150(1):64–71. 4. massi d, de giorgi v, carli p, santucci m. diagnostic significance of the blue hue in dermoscopy of melanocytic lesions: a dermoscopic–pathologic study. am j dermatopathol. 2001;23(5): 463–9. figure 2. (a) clinical image showing a fully regressed melanocytic nevus (arrow). (b) dermoscopy reveals diffuse blue-gray granules, white areas and some telangiectatic vessels. remnants of pigmented network can be observed at the upper right part of the lesion. (c, d) scattered melanophages, prominent fibrosis and telangiectasias can be seen on histopathology, corresponding to the above-mentioned dermoscopic features (h&e x20 magnification). [copyright: ©2012 lallas et al.] http://www.ncbi.nlm.nih.gov/pubmed?term=%22bories n%22%5bauthor%5d http://www.ncbi.nlm.nih.gov/pubmed?term=%22dalle s%22%5bauthor%5d http://www.ncbi.nlm.nih.gov/pubmed?term=%22debarbieux s%22%5bauthor%5d 34 observation | dermatol pract concept 2012;2(2):8 5. menzies sw, gutenev a, avramidis m, baltrac a, mccarthy wh. short-term digital surface microscopic monitoring of atypical or changing melanocytic lesions. arch dermatol. 2001;137(12):1583–9. 6. raptoulis g, spencer r, einstein b, oliviero m, braun r, rabinovitz h. lichen planus-like keratosis of the face: a simulator of melanoma in situ. dermatol surg. 2007;33(7):854-6. 7. oliviero m, rabinovitz h. lichen planus-like keratosis. in: malvehy j, puig s (eds). principles of dermoscopy. barcelona, spain: self-published, 2002:145–54. figure 3: (a, b) clinical and dermoscopic aspect of a lichen planus-like keratosis exhibiting blue-gray granules, white areas and telangiectasias. no areas reminiscent of a solar lentigo or a seborrheic keratosis could be observed. (c, d) histopathologically, the lesion is characterized by a band-like lymphocytic infiltrate, dermal fibrosis and abundant melanophages in the upper dermis (h&e x10 magnification (c), h&e x20 magnification (d)). [copyright: ©2012 lallas et al.] dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2021109 1 dermatology practical & conceptual circumscribed palmar hypokeratosis: case report of an underdiagnosed disease judit algarra-sahuquillo1, maría-del-mar pestana-eliche1, eva fagundo-gonzález1, josé-maría ramírez-conchas1, rosa-nieves rodríguez-rodríguez2 1 dermatology department, hospital universitario de canarias, la laguna, tenerife, spain 2 pathology department, hospital universitario de canarias, la laguna, tenerife, spain key words: hypokeratosis, stratum corneum, palms, keratinocyte citation: algarra-sahuquillo j, pestana-eliche mm, fagundo-gonzález e, ramírez-conchas jm, rodríguez-rodríguez rn. circumscribed palmar hypokeratosis: case report of an underdiagnosed disease. dermatol pract concept. 2021;11(1):e2021109. doi: https://doi. org/10.5826/dpc.1101a109 accepted: june 19, 2020; published: january 29, 2021 copyright: ©2021 algarra-sahuquillo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: judit algarra-sahuquillo, md, dermatology department, hospital universitario de canarias, carretera ofra s/n, 38320, la cuesta, santa cruz de tenerife, spain. email: judalg13.10@gmail.com introduction circumscribed palmar hypokeratosis is a rare asymptomatic condition consisting of focal thinning of the stratum corneum. little is known about this entity, and only a few cases have been described. case presentation a 63-year-old woman, with a history of high blood pressure and waldenström macroglobulinemia, presented to our department for the evaluation of a solitary well-demarcated depressed plaque in the thenar eminence of the left hand that had been present for 10 years (figure 1). the patient denied any associated symptoms or previous trauma. dermoscopy showed a stepped-scaly border and punctate vessels on an erythematous base, with regularly distributed white dots (figure 2). a biopsy was performed that revealed a thinning of the stratum corneum and a slightly diminished stratum figure 1. clinical image of a single well-demarcated, erythematous plaque in the thenar eminence of a 63-year-old woman. 2 letter | dermatol pract concept 2021;11(1):e2021109 conclusions circumscribed palmar hypokeratosis is a little-known disease first described in 2002 by urbina et al. it consists of an asymptomatic, erythematous, round-shaped, atrophic lesion, usually solitary, generally located in the thenar or hypothenar eminence of palms among middle-aged women [1]. the pathogenesis of this entity remains uncertain, but genetic abnormalities in keratin expression seem to be the main hypothesis, as a congenital case is described. typical findings of dermoscopy correlate with histopathology, showing a peripheral stepped-scaly border delimiting an erythematous base due to the transparency of the stratum corneum with white spots probably representing acrosyringium. histopathological findings are practically invariable, revealing an abrupt decrease of the stratum corneum compared with normal skin as the only particular characteristic in the histology. a subtly decreased granular layer is also frequent. parakeratosis and cornoid lamella are usually absent. an unspecific inflammatory infiltrate in the dermis can be observed, though rarely [2]. differential diagnosis of circumscribed palmar hypokeratosis should include porokeratosis of mibelli, bowen disease or traumatic erosions; however, the dermoscopy and histopathological findings are keys to reaching a correct diagnosis. we report a new case of this entity, that is infrequently seen but should be considered in the differential diagnoses of palm lesions. references 1. urbina f, pérez a, requena l, rütten a. circumscribed palmar or plantar hypokeratosis 10 years after the first description: what is known and the issues under discussion. actas dermosifiliogr. 2014;105(6):574-582. doi: 10.1016/j.adengl.2014.05.015. 2. ishiko a, dekio i, fujimoto a, kameyama k, sakamoto m, benno y, et al. abnormal keratin expression in circumscribed palmar hypokeratosis. j am acad dermatol. 2007;57(2):285-291. doi: 10.1016/j.jaad.2007.02.035. pmid:17553594. figure 2. dermoscopic image: erythematous plaque with punctate vessels and regularly distributed white dots, delimited by a stepped-scaly border. figure 3. skin structure formed by epidermis and dermis. thinning of the epidermis with diminished stratum corneum and stratum granulosum and scattered mononuclear inflammatory elements in the dermis. granulosum compared with the surrounding normal skin. parakeratosis was not present, and only scattered mononuclear inflammatory elements were found in the dermis (figure 3). the diagnosis of circumscribed palmar hypokeratosis was reached, and due to its benign nature, no treatment was carried out. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020016 1 dermatology practical & conceptual introduction nodular melanoma (nm) constitutes 9% to 15% of invasive melanoma and represents a potentially lethal skin tumor. it is the most frequent subtype of thick, rapidly growing melanomas and is often diagnosed at a locally advanced stage, conferring a worse prognosis [1]. in many countries, patients seek their first consultation with a general practitioner and then they are referred to a dermatologist. other times, patients seek their first consultation with a dermatologist. since it has been reported that nm can grow at a rate of 0.5 mm per month, time is crucial and even slight delays in the management of these lesions could affect the patient’s prognosis. case presentation a 53-year-old woman with no history of melanoma presented with a lesion on her left lumbar region that had appeared 5 months previously. physical examination revealed an erythematous, elevated, ulcerated nodular neoformation that was 10 × 10 mm in diameter. dermoscopy showed an asymmetric, achromic lesion with no specific criteria for melanocytic lesion; pink structureless central area, irregular blue blotches, and linear irregular vessels were observed (figure 1a). excision was scheduled for 10 days after the first consultation. before the procedure, dermoscopy revealed significant changes: the lesion showed a prominent central crust, augmentation of blue-gray blotches, and significant increase in the irregular blood vessels at the periphery (figure 1b). histopathology reported an ulcerated nm, breslow thickness 3.7 mm, clark iv with a mitotic rate of 5/mm2. conclusions nm lesions may clinically present as symmetrical, firm papules or nodules with light color (amelanotic) and with regular border and therefore do not meet the “abcd” rule (a for asymmetry, b for border irregularity, c for color variability, and d for diameter >6 mm). for this reason, the alternative “efg” rule (e for elevation, f for firm consistency, and g for progressive growth) is more suitable for nm [1]. nm lesions grow rapidly (0.5 mm/month), develop depth of invasion faster than other radial growth melanomas, and account for 66% of tumors thicker than 3 mm; for these reasons, nm causes a high percentage of deaths due to melanoma [2]. in the present case, within a 10-day interval between first rapid dermoscopic changes in nodular melanoma josé alberto garcía-lozano,1 gabriel salerni,2 adrian cuellar-barboza,1 jesús alberto cárdenas-de la garza,1 jorge ocampo-candiani1 1 universidad autónoma de nuevo león, servicio de dermatología, hospital universitario dr. josé e. gonzález, monterrey, méxico 2 hospital provincial del centenario de rosario, argentina, & facultad de medicina, universidad nacional de rosario, argentina key words: dermoscopy, skin cancer, nodular melanoma, noninvasive imaging tools, dermato-oncology citation: garcía-lozano ja, salerni g, cuellar-barboza a, cárdenas-de la garza ja, ocampo-candiani j. rapid dermoscopic changes in nodular melanoma. dermatol pract concept. 2020;10(1):e2020016. doi: https://doi.org/10.5826/dpc.1001a16 accepted: august 29, 2019; published: december 31, 2019 copyright: ©2019 garcía-lozano et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gabriel salerni, md, phd, bv. oroño 1515, cp 2000, rosario, argentina. email: gabrielsalerni@hotmail.com mailto:gabrielsalerni@hotmail.com 2 letter | dermatol pract concept 2020;10(1):e2020016 consultation and surgical procedure, we observed by dermoscopic examination that the lesion underwent significant changes, especially an increase in vascularization. taking this case into consideration, we encourage dermatologists to take urgent action when nm cannot be ruled out to avoid unnecessary delay that could affect the patient’s prognosis. more population-based strategies to increase awareness about risk factors and clinical features are needed to detect nm at an early stage since classic skin cancer screening campaigns are unlikely to improve early diagnosis of this melanoma subtype. references 1. menzies sw, moloney fj, byth k, et al. dermoscopic evaluation of nodular melanoma. jama dermatol. 2013;149(6):699709. 2. kelly jw, chamberlain aj, staples mp, mcavoy b. nodular melanoma: no longer as simple as abc. aust fam physician. 2003;32(9):706-709. figure 1. clinical and dermoscopic image of the ulcerated nodular melanoma on the first consultation (a) and before surgical procedure (b). note the significant changes in the lesion within 10 days. dermatology: practical and conceptual research | dermatol pract concept 2020;10(4):e2020088 1 dermatology practical & conceptual validation of a novel cutaneous neoplasm diagnostic self-efficacy instrument (cndsei) for evaluating user-perceived confidence with dermoscopy kelly c. nelson1, ashley e. brown2, amanda herrmann3, chloe dorsey4, julie m. simon4, janice m. wilson5, stephanie a. savory6, lauren e. haydu4 1 department of dermatology, the university of texas md anderson cancer center, houston, tx, usa 2 mcgovern medical school, the university of texas health science center at houston, houston, tx, usa 3 department of pathology, the university of texas health science center at houston, houston, tx, usa 4 department of surgical oncology, the university of texas md anderson cancer center, houston, tx, usa 5 department of dermatology, the university of texas medical branch, galveston, tx, usa 6 department of dermatology, the university of texas southwestern medical center, dallas, tx, usa key words: dermoscopy, construct validation, early detection, melanoma, dermatology education, self-efficacy, validation study, medical image interpretation citation: nelson kc, brown ae, herrmann a, dorsey c, simon jm, wilson jm, savory, sa, haydu le. validation of a novel cutaneous neoplasm diagnostic self-efficacy instrument (cndsei) for evaluating user-perceived confidence with dermoscopy. dermatol pract concept. 2020;10(4):e2020088. doi: https://doi.org/10.5826/dpc.1004a88 accepted: may 12, 2020; published: october 26, 2020 copyright: ©2020 nelson et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this project is supported by the generous philanthropic contributions of the lyda hill foundation to the university of texas md anderson cancer center moon shots program™. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: kelly c. nelson, md, the university of texas md anderson cancer center, department of dermatology, 1400 pressler street, unit 1452, houston tx 77030, usa. email: kcnelson1@mdanderson.org background: accurate medical image interpretation is an essential proficiency for multiple medical specialties, including dermatologists and primary care providers. a dermatoscope, a ×10-×20 magnifying lens paired with a light source, enables enhanced visualization of skin cancer structures beyond standard visual inspection. skilled interpretation of dermoscopic images improves diagnostic accuracy for skin cancer. objective: design and validation of cutaneous neoplasm diagnostic self-efficacy instrument (cndsei)—a new tool to assess dermatology residents’ confidence in dermoscopic diagnosis of skin tumors. methods: in the 2018-2019 academic year, the authors administered the cndsei and the long dermoscopy assessment (lda), to measure dermoscopic image interpretation accuracy, to residents in 9 dermatology residency programs prior to dermoscopy educational intervention exposure. the authors conducted cndsei item analysis with inspection of response distribution histograms, assessed internal reliability using cronbach’s coefficient alpha (α) and construct validity by comparing baseline cndsei and lda results for corresponding lesions with one-way analysis of variance (anova). abstract 2 research | dermatol pract concept 2020;10(4):e2020088 methods as a quality improvement initiative, per policy, the curriculum and instrument development efforts did not require formal supervision by our institutional review board, but did receive quality improvement advisory board oversight. we delivered our educational intervention and instruments in the 2018-2019 academic year to 9 academic dermatology residency programs participating in the derm:emd program: university of texas health science center at houston/md anderson cancer center houston, texas; baylor college of medicine houston, texas; baylor scott & white health dallas, texas; university of north texas health dallas, texas; university of texas southwestern medical center dallas, texas; university of texas at austin dell medical school austin, texas; university of texas medical branch health galveston, texas; university of missouri school of medicine columbia, missouri; and texas tech university health sciences center, lubbock, texas. the cndsei, developed by our team (figure s1), included 52 total questions divided into 4 distinct types: (1) how comfortable are you with diagnosing the following conditions with naked eye examination (n=15 different lesion types); (2) how comfortable are you with diagnosing the following conditions with dermoscopic examination (n=15); (3) how comfortable are you with distinguishing between the following (two) diagnoses with naked eye examination (n=11); and (4) how comfortable are you with distinguishing between the following (two) diagnoses with dermoscopic examination (n=11). answer options included a likert scale ranging from 1 to 10 with 1 labeled as “low comfort” and 10 labeled as “high comfort.” the lda included 30 dermoscopic images that residents were asked to classify in 3 ways: (1) whether the lesion is malignant or benign, (2) whether the lesion is melanocytic or non-melanocytic, and (3) the corresponding exact lesion type from options presented based on the logic of responses to #1 and #2 (figure s2). twenty-nine of the images corresponded exactly to lesion types that were interrogated on introduction accurate medical image interpretation is a diagnostic proficiency in almost every area of medical education. the validation of metrics that quantify confidence and skill in image interpretation is necessary to measure the impact of educational efforts. a dermatoscope is a medical device that pairs a 10× magnifier with polarized light, facilitating a more complete visualization of skin structures not readily visible to typical clinical examination. skilled interpretation of dermoscopic images has been shown to reduce both false positives and false negatives during melanoma screening examinations when compared to clinical (naked-eye) examination alone [1,2]. nevertheless, dermoscopy education in dermatology residency programs offers opportunity for improvement: 38% of us dermatology residents receive no dermoscopy training, and those residents who do receive training average only 2 hours of educational exposure [3,4]. our group leveraged project echo (extension for community healthcare outcomes), a telementoring framework, to deliver the dermatology early melanoma diagnosis (derm:end) educational intervention [5]. to evaluate our educational intervention, we developed, tested, and validated 2 precisely aligned and complimentary instruments: the long dermoscopy assessment (lda) and the cutaneous neoplasm diagnostic self-efficacy instrument (cndsei). a panel of pigmented lesion and dermoscopy experts developed both instruments in accordance with the association for medical education in europe guidelines for a successful questionnaire [6]. next, we utilized pilot versions of the lda and cndsei in the first year of the telementoring education intervention. based on participant feedback, we revised the instrument questions and responses for clarity and administered the revised instruments in year 2 of the program. to validate the cndsei, we demonstrate the feasibility and internal consistency reliability of the instrument as well as construct validity, or the degree to which the instrument measures what it intends to measure. results: at baseline, residents respectively demonstrated significantly higher and lower cndsei scores for correctly and incorrectly diagnosed lesions on the lda (p = 0.001). the internal consistency reliability of cndsei responses for the majority (13/15) of the lesion types was excellent (α ≥ 0.9) or good (0.8≥ α <0.9). conclusions: the cndsei pilot established that the tool reliably measures user dermoscopic image interpretation confidence and that self-efficacy correlates with diagnostic accuracy. precise alignment of medical image diagnostic performance and the self-efficacy instrument content offers opportunity for construct validation of novel medical image interpretation self-efficacy instruments. abstract research | dermatol pract concept 2020;10(4):e2020088 3 results forty-seven dermatology residents completed the cndsei and lda prior to receiving the 2018-2019 dermoscopy educational intervention. generally, respondents accessed the survey without issues, understood what the questions asked, and finished the questionnaire in a timely manner, confirming instrument feasibility. respondents utilized all response options on the 10-point likert scale (1-10) (figures 1 and 2). eight of the 47 residents did not respond to the final 2 cndsei questions, and these are recorded as “0” on the histogram (n = 16). the internal consistency reliability of 47 participant responses to 15 baseline cndsei items (diagnosing lesion types with dermoscopy) was excellent (α = 0.971), however, the mean inter-item correlation was high (0.712; range=0.335-0.961). to assess construct validity of the cndsei instrument, we examined the distribution of participant baseline cndsei responses (confidence) according to their lda responses the cndsei. both the cndsei and the lda were administered prior to dermoscopy educational intervention exposure via the online survey tool, qualtrics (qualtrics international inc., provo, ut, usa). we constructed pre-curriculum cndsei histograms for all responses, per question, and per lesion types (benign, malignant, melanocytic, and non-melanocytic), and visually inspected the response distributions. we assessed the internal consistency reliability of baseline cndsei to 15 items (question type 2 above), responses with cronbach’s coefficient alpha, including assessment of inter-item mean correlations. the construct validity of the cndsei was assessed with the one-way analysis of variance (anova) between cndsei responses (reflecting participant dermoscopic interpretation confidence) and lda responses (reflecting participant dermoscopic interpretation performance) for each of the 29 specific lesion types queried on both assessments. we utilized ibm spss statistics version 24 (spss; chicago, il) and sas version 9.4 (sas; cary, nc) to conduct our analyses. figure 1. distribution of baseline cndsei responses to 26 questions on the use of dermoscopy by 47 dermatology residents (n = 1,222 total responses): (a) overall, (b) by benign versus malignant lesion type, and (c) by melanocytic versus non-melanocytic lesion type. the likert scale (1-10) was utilized with 1 defined as “low comfort,” 10 defined as “high comfort,” and 0 for a question not answered by a resident (no response). a b c d) 4 research | dermatol pract concept 2020;10(4):e2020088 for the lesion-types classified by participants on lda correctly versus incorrectly (f = 6.91, p = 0.001). discussion the growing emphasis on competency-based medical education necessitates the validation of metrics that can quan(accuracy) for corresponding lesion types (figure 3). at baseline, residents demonstrated higher confidence (median 6.3, average 5.9 cndsei) for corresponding lesion types that they correctly identified on the lda and lower confidence (median 6, average 5.4 cndsei) for corresponding lesions that were incorrectly identified on the lda. there was a statistically significant difference in baseline cndsei scores figure 2. distribution of baseline cndsei responses from 47 dermatology residents by question/lesion type. the likert scale (1-10) was utilized with 1 defined as “low comfort,” 10 defined as “high comfort,” and 0 for a question not answered by a resident (no response). figure 3. distribution of cndsei responses to 15 “diagnosing with dermoscopy” questions according to the lda result (correct or incorrect) for the corresponding lesion type (n = 1303). the likert scale (1-10) was utilized with 1 defined as “low comfort,” 10 defined as “high comfort,” and 0 for a question not answered by a resident (no response). research | dermatol pract concept 2020;10(4):e2020088 5 subjects are less likely to answer questions that do not seem relevant. content validity addresses whether the instrument covers most or all dimensions of the concept to be measured [10]. the analysis establishing content validity is theoretical and based on expert opinion, systematic review of the literature review, and factor analysis. factor analysis is the grouping of questions into subtypes to meet each desired domain. in our tool, questions were grouped by lesion type and more broadly by benign and malignant types. finally, construct validity, classically inferred by the term validity, is the degree to which an instrument measures what it intends to measure. construct validity is evaluated by exploring the relation of the instrument with the behavior it measures [10]. our study offers proof of concept that close alignment of the medical image interpretation accuracy instrument and the self-efficacy instrument content facilitates construct validation of the self-efficacy instrument, a concept that is applicable to other educational settings, including pathology and radiology. in our tool, confidence in dermoscopy skill with specific lesion types was directly and significantly related to the ability to correctly diagnose those same lesion types on the lda. limitations eight of the 47 residents did not reach the final 2 questions; participant feedback on this limitation included both timing and patchy internet signaling at their testing sites. in future versions more time will be allotted for use if needed. questionable inter-observer reliability for compound nevus can be attributed to the low number of questions. additionally, this instrument is limited by being validated against 1 specific dermoscopy assessment, the lda. the lda was designed with questions specific to the didactic content in the author’s (k.c.n.) dermoscopy curriculum, which emphasized distinguishing between specific pairings of lesions with similar clinical but distinct dermoscopic features, an educational approach that may not be shared by other curricula. this could alter the validity of the self efficacy instrument when compared to another dermoscopy assessments, especially in regard to the “distinguishing between” questions. finally, inter-rater and test-retest reliability were not assessed. test-retest reliability was not feasible to assess, as we only tested at baseline and after intervention with the intention of seeing a variance. inter-rater reliability is not applicable to the construct in this context, as we are measuring self-perceived confidence that cannot be quantified by a separate rater. tify skill acquisition. medical image interpretation skills are critical proficiencies in almost all fields of medical practice. in radiology there have been efforts to develop and validate simulation-based assessments that mirror real-life clinical decision-making [7] and to quantify radiographic image interpretation skills of non-radiologists [8]. both tools relied on comparison of non-experts (medical students/interns) to more experienced users (senior residents) for construct validation of medical image interpretation accuracy [7,8]. while medical image interpretation accuracy is important, one’s perceived ability to achieve certain attainments [9], or self-efficacy, is an important determinant of practice change. instruments addressing self-efficacy must be carefully validated to demonstrate the ability to appropriately capture user confidence in the construct it intends to measure [10]. we present a unique model for construct validation of medical image interpretation self-efficacy instruments by precisely aligning medical image interpretation accuracy and self-efficacy instrument content. in validating an educational metric, it is important to meet 3 criteria: feasibility, reliability, and validity. feasibility is the extent to which an instrument is simple, easy to understand, and brief. the best instruments are useless if they are incomprehensible, lengthy, and expensive. pilot studies are used to test feasibility. based on participant feedback from the initial cndsei pilot study, the authors reworded and reorganized questions for clarity. with the updated cndsei version, as validated herein, participants completed the instrument in a timely fashion, and demonstrated normal distribution of responses. reliability reflects the degree an instrument measures its endpoint accurately and is evaluated by examining the proportion of total variance that can be attributed to true differences between subjects. this is accomplished by the use of cronbach’s coefficient alpha for intra-subject (one resident’s internal consistency between each question) and inter-subject (variability of residents’ responses per single question) reliability [10]. our tool demonstrated excellent internal consistency reliability for intra-resident responses. thus, we demonstrated that the overall confidence with dermoscopy was consistent for each resident. however, inter-item correlation was high, indicating that there is a limited aspect of the confidence construct being measured by each item. in addition, high levels of the cronbach’s coefficient alpha can be a result of a large number of items, as required in our study to appropriately represent the range of cutaneous neoplasms encountered in dermatology practice. there are many aspects of validity: face validity, content validity, and construct validity. the validation of an instrument should address all aspects of validity if possible. face validity refers to the degree that an instrument appears to measure what it wants to measure, an important feature as 6 research | dermatol pract concept 2020;10(4):e2020088 2. dinnes j, deeks jj, grainge mj, et al. visual inspection for diagnosing cutaneous melanoma in adults. cochrane database syst rev. 2018;12:cd013194. doi: 10.1002/14651858. cd013194. pmid: 30521684. 3. patel p, khanna s, mclellan b, krishnamurthy k. the need for improved dermoscopy training in residency: a survey of us dermatology residents and program directors. dermatol pract concept. 2017;7(2):17-22. doi: 10.5826/dpc.0702a03. pmid: 28515987. 4. chen ya, rill j, seiverling ev. analysis of dermoscopy teaching modalities in united states dermatology residency programs. dermatol pract concept. 2017;7(3):38-43. doi: 10.5826/ dpc.070308. pmid: 29085718. 5. project echo: early melanoma diagnosis. accessed august 14, 2019. https://www.mdanderson.org/education-training/globaloutreach/project-echo/programs/early-melanoma-diagnosis.html 6. artino ar jr, la rochelle js, dezee kj, gehlbach h. developing questionnaires for educational research: amee guide no. 87. med teach. 2014;36(6):463-74. doi: 10.3109/0142159x.2014.889814. pmid: 24661014. 7. gondim teixeira pa, cendre r, hossu g, et al. radiology resident mr and ct image analysis skill assessment using an interactive volumetric simulation tool—the radiolog project. eur radiol. 2017;27(2):878-887. doi: 10.1007/s00330-016-43845. pmid: 27165134. 8. seagull fj, bailey je, trout a, cohan rh, lypson ml. residents’ ability to interpret radiology images: development and improvement of an assessment tool. acad radiol. 2014;21(7):909-15. doi: 10.1016/j.acra.2014.03.010. pmid:24928160. 9. burrell amg, allan jl, williams dm, johnston m. what do self-efficacy items measure? examining the discriminant content validity of self-efficacy items. br j health psychol. 2018;23(3):597-611. doi: 10.1111/bjhp.12306. pmid:29520897. 10. bandura a. guide for constructing self-efficacy scales. in: pajares f, urdan t, eds. self-efficacy beliefs of adolescents. information age publishing, inc.; 2006:307-337. conclusions skillful interpretation of dermoscopic images offers an opportunity to reduce false negatives and positives in the detection of melanoma. validation of instruments to quantify dermoscopic skill and confidence is essential for the development and iterative improvement of sound dermoscopy educational programs. the cndsei instrument can accurately measure confidence in dermoscopic skill and has predictive value for the ability to diagnose lesions correctly with dermoscopy. the validation of this tool will be useful in measuring change in dermoscopy education interventions for both dermatology and primary care residents. supporting performance of full-skin examinations and skillful dermoscopic evaluation of lesions of concern by primary care providers in low dermatology access areas offers the opportunity to reduce diagnostic barriers in broader patient populations. additionally, the concept of aligning medical image interpretation and self-efficacy instrument content can be broadly applied to medical image interpretation fields beyond dermatology, including radiology, pathology, gynecology, and others. the ability to accurately quantify medical image interpretation skill acquisition has practical application across many fields in patient care. references 1. ferrante di ruffano l, takwoingi y, dinnes j, et al. computer-assisted diagnosis techniques (dermoscopy and spectroscopy-based) for diagnosing skin cancer in adults. cochrane database syst rev. 2018;12:cd013186. doi: 10.1002/14651858. cd013186. pmid: 30521691. research | dermatol pract concept 2020;10(4):e2020088 7 figure s1. the cutaneous neoplasm dermoscopy self-efficacy instrument (cndsei). figure s2. the long dermoscopy assessment (lda) question format and branching logic dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020081 1 dermatology practical & conceptual introduction bubble hair abnormality describes hair damage characterized by the formation of air cavities within the cortex of the hair, due to the high temperature of water inside the shaft, that induces keratin hydrolysis and local air expansion. it is linked to excessive cosmetic treatments, in particular, prolonged exposure of damp hair to the high temperatures (> 125 c°) of blow dryers or electric curlers, and is typically encountered in women. we describe the trichoscopic features of 3 cases of bubble hair abnormality highlighting the utility of trichoscopy. case presentation a 51-year-old caucasian woman complained of a 6-month history of hair breakage that started with frequent at-home hair dyeing. physical examination revealed a circumscribed area of short and broken hairs localized to her vertex. invivo trichoscopy revealed numerous hair shafts containing irregularly spaced bubbles and broken hairs. we made a diagnosis of bubble hair abnormality and advised her to discontinue all dye and heat-related practices. a 42-year-old caucasian woman complained of increased hair shedding. trichoscopy showed signs of telogen effluvium, and upon careful observation of the anterior region of the fringe, some bubble hairs were discovered (figure 1). the patient admitted to wrapping the hair of the frontal hairline over a round metal brush for several minutes while blow drying it. a 35-year-old caucasian woman complained of diffuse hair loss and the presence of damaged strands of hair that resulted after hot-combing the hair while it was still wet. a tuft of short broken hairs, paler than the surrounding hair, was evident in the affected area. trichoscopy showed the presence of broken and bubble hair in the site of the thermal trauma. conclusions cosmetic hair treatments, such as hair straighteners and relaxers, cleave disulfide bonds and can cause hair damage to the superficial cuticles. the loss of lipids on the hair surface during chemical hair treatments may lead to loss of cohesiveness between cuticle cells, and the reduction in the hair shaft cysteine levels correlates to a greater susceptibility to hair weathering and hair fragility. for a correct diagnosis in cases of hair fragility, direct examination of hair shafts with trichoscopy is recommended. in the literature, previous reports have underlined the utility of trichoscopy for bubble hair abnormality and describe white oval spaces with swiss-cheese structure and dysmorphia of the distal hair shaft [1,2]. bubble hair and the usefulness of trichoscopy aurora alessandrini1, michela starace1, francesca bruni1, bianca maria piraccini1 1 department of experimental, diagnostic and specialty medicine, division of dermatology, university of bologna, italy key words: bubble hair, hair ironing, hair shaft, hair fragility, hair disorders citation: alessandrini a, starace m, bruni f, piraccini bm. bubble hair and the usefulness of trichoscopy. dermatol pract concept. 2020;10(4):e2020081. doi: https://doi.org/10.5826/dpc.1004a81 accepted: april 30, 2020; published: october 26, 2020 copyright: ©2020 alessandrini et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: aurora alessandrini, md, department of experimental, diagnostic and specialty medicine, division of dermatology, university of bologna, via massarenti, 1, 40138 bologna, italy. email: aurora.alessandrini3@unibo.it 2 letter | dermatol pract concept 2020;10(4):2020081 in conclusion, bubble hair abnormality is an acquired hair shaft disorder that can present as a circumscribed area of broken hairs that do not grow, especially when there is a history of frequent cosmetic or thermal hair practices. references 1. wallace mp, de berker da. hair diagnoses and signs: the use of dermatoscopy. clin exp dermatol. 2010;35(1):41-46. doi: 10.1111/j.1365-2230.2009.03383.x. pmid: 19549236. 2. albers ln, maley am, mackelfresh jb. blowing bubbles: dermoscopy of bubble hair. int j trichology. 2017;9(3):122-123. doi: 10.1111/10.4103/ijt.ijt_11_17. pmid: 28932065. in 2 of our patients, there was a history of blow drying wet hair, while 1 patient had only bleached it with an athome procedure. when wet, the hair fiber can expand up to 30% in diameter and it retains water within its structure, resulting in the formation of expanding and destructive bubbles within the fiber. as reported in case 1, chemical treatments and previous hair damage may also precipitate the onset of bubble hair abnormality and lower the threshold for bubble formation [2]. all our patients improved after discontinuation of hot blow drying or avoiding the application of chemicals, confirming the acquired nature of the disease. figure 1. (a) clinical picture of a female patient affected by bubble hair abnormality in the anterior region of the fringe. (b) clear evidence of bubble hair with trichoscopy at ×20 magnification, blue circle. (c) a broken hair and a bubble hair at ×70 magnification; fotofinder systems. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020092 1 dermatology practical & conceptual case presentation an otherwise healthy 9-year-old boy presented with itching and painful lesions on both thumbs of 5 months’ evolution. he had received treatment with high-potency topical corticosteroids with partial improvement. physical examination showed erythema, lichenification and fissures on the tips of both thumbs (figure 1). patch testing was performed, with negative results. after exhaustive questioning, the parents stated that the child usually spent several hours per day playing video games. the boy also admitted to being “addicted to playstation games.” a diagnosis of frictional dermatitis was made. the lesions completely resolved following 2 weeks of forced abstinence from video gaming. teaching point among the cutaneous manifestations of excessive video gaming, video gamer thumb or “playstation thumb” refers to the presence of hyperkeratosis, blisters, and petechiae on the tips of the thumbs [1]. multiple cutaneous disorders can arise from excessive use of electronic devices [2], and a high index of suspicion is necessary to allow an early diagnosis. references 1. wolf r, wolf d. playstation thumb. int j dermatol. 2014;53(5):617-618. doi: 10.1111/ijd.12368. pmid: 24602007. 2. jalink mb, heineman e, pierie jp, ten cate hoedemaker ho. nintendo related injuries and other problems: review. bmj. 2014 16;349:g7267. doi: 10.1136/bmj.g7267. pmid: 25515525. playstation thumb: frictional dermatitis caused by excessive video game playing jaime piquero-casals1, daniel morgado-carrasco2, juan francisco mir-bonafé3, eduardo rozas-muñoz4 1 department of dermatology, dermik, clínica dermatológica multidisciplinar, barcelona, spain 2 department of dermatology, hospital clínic de barcelona, universitat de barcelona, spain 3 department of dermatology, hospital son llàtzer, palma de mallorca, spain 4 department of dermatology, hospital de san pablo, coquimbo, chile key words: playstation thumb, texting thumb, video game; nintendinitis, frictional dermatitis, tech thumb citation: piquero-casals j, morgado-carrasco d, mir.bonafé jf, rozas-muñoz e. playstation thumb: frictional dermatitis caused by excessive video game playing. dermatol pract concept. 2020;10(4):e2020092. doi: https://doi.org/10.5826/dpc.1004a92 accepted: june 1, 2020; published: october 26, 2020 copyright: ©2020 piquero-casals et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author:jaime piquero-casals, md, phd, dermik, clínica dermatológica multidisciplinar, carrer de les escoles pies, 7, 08017, barcelona, spain. email: j.piquero@dermik.es 2 image letter | dermatol pract concept 2020;10(4):2020092 figure 1. erythema, lichenification and fissures on the tips of both thumbs. observation | dermatol pract concept 2016;6(3):10 51 dermatology practical & conceptual www.derm101.com introduction trichoepitheliomas are uncommon, benign, adnexal neoplasms that originate from the hair follicles. they usually present as solitary lesions but in the familial setting they appear as multiple lesions. multiple familial trichoepithelioma constitute an autosomal dominant disease characterized by the appearance of multiple flesh-colored, symmetrical papules, tumors and/or nodules located in the central face and occasionally on the scalp [1]. herein we present an interesting case of a female with multiple facial papules easily diagnosed as trichoepitheliomas with the use of dermoscopy. case report a 29-year-old otherwise healthy female presented to our clinic for evaluation of multiple firm, flesh-colored, domeshaped papules distributed primarily along the nasolabial folds and forehead. she first noticed their appearance during multiple familial trichoepithelioma: confirmation via dermoscopy cristián navarrete-dechent1,2, shirin bajaj3, ashfaq a. marghoob3, sergio gonzález2,4, daniel muñoz5 1 department of dermatology, facultad de medicina, pontificia universidad católica de chile, santiago, chile 2 melanoma and skin cancer unit, facultad de medicina, pontificia universidad católica de chile, santiago, chile 3 dermatology service, memorial sloan kettering cancer center, hauppauge, ny, usa 4 department of pathology, facultad de medicina, pontificia universidad católica de chile, santiago, chile 5 department of dermatology, complejo asistencial hospital sótero del río, santiago, chile key words: trichoepithelioma, diagnosis, dermoscopy, dermatoscopy, cyld citation: navarrete-dechent c, bajaj s, marghoob aa, gonzález s, muñoz d. multiple familial trichoepithelioma: confirmation via dermoscopy. dermatol pract concept 2016;6(3):10. doi: 10.5826/dpc.0603a10 received: march 20, 2016; accepted: may 1, 2016; published: july 31, 2016 copyright: ©2016 navarrete-dechent et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cristián navarrete-dechent, md, department of dermatology, facultad de medicina, pontificia universidad católica de chile, 4686 vicuña mackenna, macul, santiago, 7820436, chile. tel. (56 2) 2354 8454; fax. (56 2) 2552 9974. e-mail: ctnavarr@gmail.com trichoepitheliomas are uncommon benign adnexal neoplasms that originate from the hair follicles. multiple familial trichoepithelioma constitute an autosomal dominant disease characterized by the appearance of multiple flesh-colored, symmetrical papules, tumors and/or nodules in the central face and occasionally on the scalp. although clinical diagnosis is usually straightforward in light of the family history and naked-eye examination, dermoscopy may aid in its confirmation. dermoscopy of each papule revealed in-focus arborizing vessels, multiple milia-like cysts and rosettes amidst a whitish background. in a patient with multiple facial papules revealing a dermoscopic appearance described above, the diagnosis of sporadic or familial multiple trichoepithelioma should be considered. abstract 52 observation | dermatol pract concept 2016;6(3):10 monly present as solitary papules, but in the familial setting they appear in clusters characteristically involving the central face and/or the scalp [2]. they present with variable size from small papules that are of minor cosmetic relevance to multiple tumors that can lead to functional impairment such as visual obstruction. the incidence of multiple familial trichoepithelioma (omim #601606) in the us has been reported to be between 2.14—2.7 cases per year, with a female predilection [2,3]. they frequently first appear during childhood or adolescence. adolescence, after which they progressively increased in number (figure 1). scalp examination was unremarkable. of note, she reported multiple relatives from her maternal lineage that developed similar lesions during youth. dermoscopy of each papule revealed a similar appearance: in-focus arborizing vessels, multiple milia-like cysts and rosettes amidst a whitish background (figure 2). histologic examination revealed a small, well-circumscribed, dermal tumor with branched nests of basaloid cells, small keratin cysts, and a rather dense collagenous stroma with visible fibrocytes, consistent with trichoepithelioma (figure 3). discussion trichoepitheliomas are rare benign hamartomatous tumors originating from the pilosebaceous follicle. they most comfigure 1. multiple familial trichoepithelioma. clinical presentation. (a) overview image view. (b) close-up. [copyright: ©2016 navarrete-dechent et al.] a b figure 2. dermoscopic features. (a) image taken with contact polarized light. (b) contact non-polarized light view. (original magnification 10x). [copyright: ©2016 navarrete-dechent et al.] a b observation | dermatol pract concept 2016;6(3):10 53 when evaluating a solitary papule with the aforementioned dermoscopic findings, a biopsy may be necessary for definitive diagnosis. if a biopsy is contemplated, then it is important to underscore that small partial biopsies may lead the pathologist to misinterpreted the specimen as basal cell carcinomas [12]. histopathology findings suggesting the diagnosis of trichoepithelioma over basal cell carcinoma include the fibrocytic loss of the stroma, aggregations of cells with smooth borders, the presence of granulomatous inflammation, monomorphic nuclei and papillary mesenchymal bodies [1]. finally, treatment options for multiple trichoepithelioma include destructive/ablative techniques such as cryotherapy, dermabrasion, electrodissection and radiation therapy, all with variable to poor outcomes [2]. interestingly, our patient chose not to undergo any treatment, which is also a valid option. conclusion a patient evaluated with multiple facial papules that on dermoscopy reveal in-focus arborizing vessels, multiple milia-like cysts and rosettes amidst a whitish background should lead the clinician to consider the diagnosis of sporadic or familial multiple trichoepithelioma. references 1. mapar ma, ranjbari n, afshar n, karimzadeh i, karimzadeh a. severely disfiguring multiple familial trichoepitheliomas with basal cell carcinoma. indian j dermatol venereol leprol 2014;80(4):349-52. pmid: 25035368. doi: 10.4103/03786323.136924. 2. kataria u, agarwal d, chhillar d. familial facial disfigurement in multiple familial trichoepithelioma. j clin diagn res 2013;7(12):3008-9. pmid: 24551711. doi: 10.7860/ jcdr/2013/6218.3830. 3. yiltok sj, echejoh go, mohammad am, et al. multiple familial trichoepithelioma: a case report and review of literature. niger j clin pract. 2010;13(2):230-2. pmid: 20499764. 4. harada h, hashimoto k, ko ms. the gene for multiple familial trichoepithelioma maps to chromosome 9p21. j invest dermatol 1996;107(1):41-3. pmid: 8752837. doi: 10.1111/1523-1747. ep12297860 5. young al, kellermayer r, szigeti r, et al. cyld mutations underlie brooke-spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. clin genet 2006;70(3):2469. pmid: 16922728. doi: 10.1111/j.1399-0004.2006.00667.x. 6. nagy n, farkas k, kemény l, széll m. phenotype-genotype correlations for clinical variants caused by cyld mutations. eur j med genet 2015;58(5):271-8. pmid: 25782638. doi: 10.1016/j. ejmg.2015.02.010. 7. kazakov dv, vanecek t, zelger b, et al. multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including cyld and ptch gene analysis, of a series of 16 patients. am j dermatopathol 2011;33(3):251-65. pmid: 21389835. doi: 10.1097/dad.0b013e3181f7d373. initially this disease was believed to be linked to loss in the heterozygosity of the 9p21 gene [4], however, recent studies have reported a mutation in the cylindromatosis tumor suppressor gene (cyld) located in the chromosome 16q12-q13 in roughly 40% of cases [5]. this gene is a tumor suppressor gene altered in both multiple familial trichoepithelioma, familial cylindromatosis and in the brooke-spiegler syndrome [5]. in fact, those three conditions appear to be a spectrum of genodermatoses with a common molecular origin—cyld mutation spectrum [6]—but with differing clinical manifestations [5,7-9]. missense mutations of the cyld gene appears to be more frequent in familial trichoepitheliomas than in brooke-spiegler syndrome or familial cylindromatosis and this may, in part, explain the phenotypic differences in these conditions [6]. while the ptch gene was also thought to be linked to the etiopathogenesis of multiple familial trichoepithelioma, recent evidence suggests that it is rarely, if ever, mutated in this disease [7]. dermoscopy allows for the noninvasive visualization of structures not visible to the naked eye, and when correctly interpreted improves the clinicians’ diagnostic accuracy. although a facial papule displaying arborizing vessels and shiny white structures under dermoscopy is highly suggestive of basal cell carcinoma, the patient’s clinical history and the presence of numerous identical lesions raised the clinician’s suspicion for multiple familial trichoepithelioma. importantly, each lesion had a similar dermoscopic morphology that was consistent with features that have previously been described for desmoplastic trichoepithelioma and solitary trichoepitheliomas, namely, arborizing vessels and milia-like cysts [10,11]. the presence of milia-like cysts in dermoscopy was correlated with the presence of keratin cysts in the histopathology (figure 3). figure 3. photomicrograph showing a small, well-circumscribed, dermal tumor, with branched nests of basaloid cells, keratin cysts, and a dense collagenous stroma (h&e, 40x). [copyright: ©2016 navarrete-dechent et al. 54 observation | dermatol pract concept 2016;6(3):10 confocal microscope findings of trichoepithelioma. dermatology 2007;215(4):354-8. pmid: 17911996. doi: 10.1159/000107631. 11. lazaridou e, fotiadou c, patsatsi a, et al. solitary trichoepithelioma in an 8-year-old child: clinical, dermoscopic and histopathologic findings. dermatol pract concept 2014;4(2):55-58. pmid: 24855576. doi: 10.5826/dpc.0402a11. 12. poniecka aw, alexis jb. an immunohistochemical study of basal cell carcinoma and trichoepithelioma. am j dermatopathol. 1999;21(4):332-6. pmid: 10446773. 8. zheng g, hu l, huang w, et al. cyld mutation causes multiple familial trichoepithelioma in three chinese families. hum mutat 2004;23(4):400. pmid: 15024746 doi: 10.1002/humu.9231 9. farkas k, deák bk, sánchez lc, et al. the cyld p.r758x worldwide recurrent nonsense mutation detected in patients with multiple familial trichoepithelioma type 1, brooke-spiegler syndrome and familial cylindromatosis represents a mutational hotspot in the gene. bmc genet 2016;17(1):36. pmid: 26861065. doi: 10.1186/s12863-016-0346-9. 10. ardigo m, zieff j, scope a, et al. dermoscopic and reflectance dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(1):3 7 case presentation a 17-year-old girl presented with a six-month history of multiple asymptomatic brownish atrophic plaques in a zosteriform distribution on the left side of her trunk (figure 1). there was no family history of a similar skin disease. laboratory studies were unremarkable for any chronic or autoimmune disorder. biopsy of a lesion showed a normal epidermis with increased pigmentation of the basal layer and a broad dermis with thickened collagen fibers and diminished periadnexal and subcutaneous fat tissue (figures 2, 3, 4). clinical and dermatopathologic findings were compatible with atrophoderma of moulin. the use of topical steroids and tacrolimus as a second-line regimen did not result in any improvement of lesions. discussion linear atrophoderma is a rare, acquired, linear dermatosis. it is named after moulin, who, in 1992, reported on five patients with pigmented and more or less atrophic bands along blaschko’s lines [1]. the age of onset in the first described cases ranged from 6 to 20 years. lesions were unilateral, forming a recumbent “s” pattern, and the intensity of pigmentation and atrophy was variable. they remained stable throughout an observation period of 2 to 30 years. of the skin biopsies performed on three patients, there was only irregular and moderate hyperpigmentation of the basal layer. in the dermis, there was no distinct pigment incontinence, no inflammation or alteration of connective tissue texture, and the clinical linear atrophoderma of moulin: a case report and review of the literature aikaterini patsatsi, m.d.1, aikaterini kyriakou, m.d. msc1, george chaidemenos, m.d.2, dimitrios sotiriadis, m.d.1 1 second dermatology department, aristotle university school of medicine, papageorgiou hospital, thessaloniki, greece 2 dermatology practice, thessaloniki, greece key words: linear, atrophoderma, moulin, linear scleroderma citation: patsatsi a, kyriakou a, chaidemenos g, sotiriadis d. linear atrophoderma of moulin: a case report and review of the literature. dermatol pract conc. 2013;3(1):3. http://dx.doi.org/10.5826/dpc.0301a03. received: june 14, 2012; accepted: november 25, 2012; published: january 31, 2013 copyright: ©2013 patsatsi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aikaterini patsatsi, m.d., plagiari po box 461, 57500 thessaloniki, greece. tel. +306944500285; fax. +302310991583. email: katerinapatsatsi@gmail.com linear atrophoderma of moulin is a rare, acquired, linear dermatosis. we present a 17-year-old girl with multiple asymptomatic brownish atrophic plaques in a zosteriform distribution on the left side of the trunk. clinical presentation and dermatopathology was compatible with the diagnosis of linear atrophoderma. twenty years after its initial description by moulin, there are yet a limited number of case reports and unanswered questions regarding this entity. abstract 8 observation | dermatol pract concept 2012;3(1):3 tion of the basement membrane [2,7]. few reports suggest an inflammatory early stage is suggested. the question of a transient inflammatory early stage that is no longer present by the time of clinical evaluation and biopsy remains. although the alteration of the connective tissue is not described in the original paper, most of the reviewed papers describe an increase of collagen. unaltered, fragmented or decreased collagen fibers have been also reported in isolated cases, as well as edema of the dermis (table 1). another issue that has not been addressed is the cause of the clinical presentation of atrophic plaques. does the loss of subcutaneous fat result in atrophy? in conclusion, even now, 20 years after the first description of atrophoderma of moulin this rare disease is puzzling. it seems to occur at any age. it is characterized clinically by the presence of atrophic patches distributed along blaschko lines and dermatopathologically by a normal epidermis with a hyperpigmented basal layer, a dermis with thickened collagen fibers and loss of subcutaneous fat. etiology and pathogenesis of this disease remains still unclear. impression of skin atrophy was attributed to atrophy of the subcutaneous tissue [1]. up to now there have been 30 reported cases of linear atrophoderma of moulin [2-22]. in 2005, ang et al mentioned that many cases of linear dermatoses were grouped under the umbrella of linear atrophoderma [23]. in table 1, 30 reported cases that resemble the initial description of linear atrophoderma of moulin are listed. now, twenty years after the initial description of this entity, there are still some unresolved issues. the differential diagnosis of zosteriform or linear scleroderma is not clear clinically nor dermatopathologically. it may well be that linear atrophoderma of moulin and zosteriform or linear scleroderma belong to the spectrum of a single disease. with the growing literature it has been demonstrated that age of onset is not limited to childhood or adolescence. the disease may also present later in life. lesions are not always unilateral. they may be bilateral but in a linear distribution along blaschko’s lines (table 1). distribution mainly along the blaschko lines reflects mosaicism. dermatopathologic findings of linear atrophoderma of moulin vary. the epidermis is normal in the majority of cases. however, in two reports there was vacuolar degenerafigure 1. atrophic plaques on the left side of the trunk. [copyright: ©2013 patsatsi et al.] figure 2. normal epidermis and broad dermis. [copyright: ©2013 patsatsi et al.] figure 3. normal epidermis with hyperpigmented basal layer. [copyright: ©2013 patsatsi et al.] figure 4. thickened collagen fibers in the dermis. [copyright: ©2013 patsatsi et al.] observation | dermatol pract concept 2012;3(1):3 9 table 1. reported cases of linear atrophoderma of moulin cases case no. age at presen tation/ sex area of involvement disease duration when reported histological findings moulin 1992, 1st of 5 cases [1] 1 8/m left side of trunk moulin 1992, 2nd of 5 cases [1] 2 7/f right side of trunk moulin 1992, 3rd of 5 cases [1] 3 15/m right side of trunk moulin 1992, 4th of 5 cases [1] 4 20/m left side of trunk moulin 1992, 5th of 5 cases [1] 5 6/m left arm and trunk baumann et al 1994 [2] 6 22/m right arm and trunk ballooning in basal epidermis (?), increased collagen in dermis braun rp, saurat jh, 1996 [3] 7 16/m left side of back, left side of abdominal area wollenberg a et al, 1996 [4] 8 5/f right arm/ trunk 17 epidermal atrophy, increased collagen in dermis artola igarza jl et al, 1996 [5] 9 16/f left part of the trunk increased collagen in the dermis cecchi and giomi, 1997 [6] 10 12/f right arm and back hyperpigmentation in the basal layer of the epidermis rompel r et al, 2000 [7] 11 17/f right side of the trunk, right buttock focal vacuolar degeneration of the basal layer, increased collagen in dermis browne c et al, 2000 [8] 12 10/m trunk and limbs, bilateral 6 slightly thinned epidermis with prominent blood vessels, slight increase in the amount of collagen martin et al 2002 [9] 13 9/m left side of trunk increased collagen miteva l et al, 2002 [10] 14 20/f right arm, buttock and leg 4 years increased collagen utikal et al, 2003 [11] 15 29/m limbs and trunk, bilateral 6 years slight edema of the dermis utikal et al, 2003 [11] 16 15 /f limbs and trunk, bilateral 13 years slight edema of the dermis danarti et al, 2003 (1st of 4 cases) [12] 17 14/f left side of the body 1 year perivascular lymphocytic infiltrate danarti et al, 2003 (2nd of 4 cases) [12] 18 24/f left side of her abdomen and her back, left arm biopsy not performed danarti et al, (3rd of 4 cases) [12] 19 38 /f left medial thigh 1.6 year unremarkable epidermis and dermis (continued next page) 10 observation | dermatol pract concept 2012;3(1):3 cases case no. age at presen tation/ sex area of involvement disease duration when reported histological findings danarti et al, 2003, (4th of 4 cases) [12] 20 15/f left side on the buttock and on her lateral iliac crest along blaschko’s lines 1 year biopsy not performed miteva l et al 2005 [13] 21 9/m left side of the trunk, left upper limb 5 years increased collagen atasoy m et al, 2006 [14] 22 16/m right side of the trunk, right arm 2 years epidermal atrophy, fragmented collagen fibers zampetti a et al, 2008 [15] 23 37/f left arm and trunk 5 years hyperpigmentation of epidermal basal cells, slight thickening of the collagen fibers in the mid-deep dermis gecchi et al, 2008 [16] 24 9/m exclusive involvement of the neck 1 year a normal epidermis with moderate, diffuse hyperpigmentation of the basal layer a perivascular lymphocytic infiltrate was noted in the dermis, without any other pathologic feature lopez n et al, 2008 [17] 25 17 /m right upper arm 1 year localized hyperpigmentation in the basal layer of the epidermis ozkaya e et al, 2010 [18] 26 18/f legs, arms and trunk including the axillary regions 1 year slight epidermal acanthosis, a slightly hyperpigmented basal layer, and a slight decrease in elastic fibers in papillary dermis ripert c et al, 2010 [19] 27 14/f left side of trunk 15 months dermal atrophy with pigmentation of the basal layer and a perivascular lymphocytic infiltrate schepis c et al, 2010 [20] 28 14/m left side of trunk a few months a hyperpigmented basal layer in the upper dermis, dilated superficial vessels were visible the mid and deep dermis were mildly edematous table 1. (continued) (continued next page) observation | dermatol pract concept 2012;3(1):3 11 references 1. moulin g, hill mp, guillaud v, barrut d, chevallier j, thomas l. acquired atrophic pigmented band-like lesions following blaschko’s lines. ann dermatol venereol. 1992;119(10):729-36. 2. baumann l, happle r, plewig g, schirren cg. [atrophodermia linearis moulin. a new disease picture, following the blaschko lines.] [article in german] hautarzt. 1994;45(4):231-6. 3. braun rp, saurat jh. a case of linear atrophoderma of moulin. j dermatol. 1996;23(9):660. 4. wollenberg a, baumann l, plewig g. linear atrophoderma of moulin: a disease which follows blaschko’s lines. br j dermatol. 1996;135(2):277-9. 5. artola igarza jl, sánchez conejo-mir j, corbí llopis mr, et al. linear atrophoderma of moulin: treatment with potaba. dermatology. 1996;193(4):345-7. 6. cecchi r, giomi a. linear atrophoderma of moulin. acta derm venereol. 1997;77(6):485. 7. rompel r, mischke al, langner c, happle r. linear atrophoderma of moulin. eur j dermatol. 2000;10(8):611-3. 8. browne c, fisher bk. atrophoderma of moulin with preceding inflammation. int j dermatol. 2000;39(11):850-2. 9. martin l, georgescu v, nizard s, happle r, estève e. [unilateral atrophoderma following blaschko’s lines: blaschkolinear morphoea or moulin’s linear atrophoderma?] [article in french]. ann dermatol venereol. 2002;129(4 pt 1):431-2. 10. miteva l, obreshkova e. an unusual manifestation of linear atrophoderma of moulin. acta derm venereol. 2002;82(6):479-80. 11. utikal j, keil d, klemke cd, bayerl c, goerdt s. predominant telangiectatic erythema in linear atrophoderma of moulin: novel variant or separate entity? dermatology. 2003;207(3):310-5. 12. danarti r, bittar m, happle r, kōnig a. linear atrophoderma of moulin: postulation of mosaicism for a predisposing gene. j am acad dermatol. 2003; 49(3):492-8. 13. miteva l, nikolova k, obreshkova e. linear atrophoderma of moulin. int j dermatol. 2005;44(10):867-9. 14. atasoy m, aliagaoglu c, sahin o, ikbal m, gursan n. linear atrophoderma of moulin together with leuconychia: a case report. j eur acad dermatol venereol. 2006;20(3):337-40. 15. zampetti a, antuzzi d, caldarola g, caldarola g, celleno l, amerio p, feliciani c. linear atrophoderma of moulin. eur j dermatol. 2008;18(1):79-80. 16. cecchi r, bartoli l, brunetti l, pavesi m. linear atrophoderma of moulin localized to the neck. dermatol online j. 2008;14(6):12. 17. lópez n, gallardo ma, mendiola m, bosch r, herrera e. [a case of linear atrophoderma of moulin]. article in spanish. actas dermosifiliogr. 2008;99(2):165-7. 18. özkaya e, yazganoōlu kd. lentiginosis within plaques of linear atrophoderma of moulin: a twin-spotting phenomenon? br j dermatol. 2010;163(5):1138-40. 19. ripert c, vabres p. linear atrophoderma of moulin associated with antinuclear antibodies. j eur acad dermatol venereol. 2010;24(1):108-9. 20. schepis c, palazzo r, lentini m. a teen-ager with linear atrophoderma of moulin. dermatol online j. 2010;16(2):7. 21. tukenmez demirci g, altunay ik, mertoglu e, kucukunal a, sakiz d. linear atrophoderma of moulin on the neck. j dermatol case rep. 2011;5(3):47-9. 22. norisugi o, makino t, hara h, matsui k, furuichi m, shimizu t. evaluation of skin atrophy associated with linear atrophoderma of moulin by ultrasound imaging. j am acad dermatol. 2011;65(1):232-3. 23. ang gc, lee jb. linear atrophoderma of moulin: is it a single disease? j am acad dermatol. 2005;52(5):923-4. cases case no. age at presen tation/ sex area of involvement disease duration when reported histological findings tukenmez demirci g et al, 2011 [21] 29 39/f left half of the neck 22 years a normal epidermis outlined by a hyperpigmentedbasal layer in the papillary dermis proliferation of superficial vessels with mild lymphocytic infiltrate and melanin-laden macrophages were present collagen fibers and elastic fibers were normal norisugi o et al, 2011 [22] 30 26/m right side of trunk, posterior right leg 1 year thickness of the subcutaneous tissue was reduced in lesional skin compared to normal skin by ultrasound examination our case 31 17/f left side of trunk 6 months thin epidermis, hyperpigmentation of the basal layer, increased collagen fibers, rather thin subcutis table 1. (continued) dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021148 1 dermatology practical & conceptual sebaceous filaments yuvrah singh1, shekhar neema1, amit bahuguna1, disha dabbas1 1 department of dermatology, armed forces medical college, pune, india key words: sebaceous filaments, demodex, mites, dermoscopy citation: singh y, neema s, bahuguna a, dabbas d. sebaceous filaments. dermatol pract concept. 2021;11(1):e2021148. doi: https://doi.org/10.5826/dpc.1101a148 accepted: august 17, 2021; published: january 29, 2021 copyright: ©2021 singh et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: shekhar neema, md, department of dermatology, armed forces medical college, pune, maharashtra, india. email: shekharadvait@gmail.com case presentation a 16-year-old boy with a known case of autism spectrum disorder presented with complaints of multiple yellowish white deposits over hair-bearing areas of his face for the previous 3 years. on examination, there were multiple filamentous, off-white to yellowish, follicular growths in his perioral region, eyelashes, eyebrows, nose, and cheeks (figure 1a). dermoscopy revealed uniform cylindrical, solid, off-white colored deposits encircling normal hair follicles (figure 1b). the gram stain and potassium hydroxide preparations were negative. the growths were clinically diagnosed to be sebaceous filaments. figure 1. (a) filamentous, off-white to yellowish follicular growths in the perioral region, eyelashes, eyebrows, nose, and cheeks. (b) uniform, cylindrical, solid, off-white colored deposits encircling normal hair follicles seen on non-polarized dermoscopy. dermatology: practical and conceptual review | dermatol pract concept 2020;10(3):e2020066 1 dermatology practical & conceptual introduction squamous cell carcinoma (scc) is the second most common cutaneous malignancy after basal cell carcinoma, with an increasing incidence worldwide [1]. although many factors can increase the risk for scc, cumulative sun exposure, especially in childhood and youth, is of greatest importance. moreover, in recent years, immunosuppression, including that associated with organ transplantation, has emerged as an increasingly important contributor to tumorigenesis [2,3], and the arousal of scc in areas of chronic inflammation must also be kept in mind. scc accounts for most nonmelanoma skin cancer–related metastatic disease; therefore, recognition and treatment of early scc is important for the prevention of neoplastic progression. although histopathology and surgical excision remain the gold standard for the diagnosis and treatment of scc, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy (rcm) are increasing the diagnostic accuracy of these keratinizing neoplasms, squamous cell carcinoma: an update on diagnosis and treatment andrea combalia,1 cristina carrera1,2 1 dermatology department, university of barcelona, hospital clínic de barcelona, spain 2 centro de investigación biomédica en red de enfermedades raras (ciberer), instituto carlos iii, barcelona, spain key words: bowen disease, squamous cell carcinoma, actinic keratosis, cancerization field, dermoscopy, confocal microscopy, staging, treatment citation: combalia a, carrera c. squamous cell carcinoma: an update on diagnosis and treatment. dermatol pract concept. 2020;10(3):e2020066. doi: https://doi.org/10.5826/dpc.1003a66 accepted: april 20, 2020; published: june 29, 2020 copyright: ©2020 combalia and carrera. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: cristina carrera, md, phd, university of barcelona, dermatology department, melanoma group idibaps, hospital clínic barcelona, villarroel 170, esc 1-4, despatx 1, 08036 barcelona, spain. email: ccarrera@clinic.cat squamous cell carcinoma (scc) accounts for most nonmelanoma skin cancer–related metastatic disease and deaths. histopathology and correct surgical excision remain the gold standard for the diagnosis and treatment of scc; however, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy have increased the diagnostic accuracy in terms of early recognition, better differential diagnosis, more precise selection of areas to biopsy, and noninvasive monitoring of treatments. the therapeutic intervention in patients with severe actinic damage and multiple in situ/ low-risk scc, and the development of innovative treatments such as epidermal growth factor receptor inhibitors and immune checkpoint inhibitors for locally advanced and metastatic scc, are improving considerably the approach to the disease. this review summarizes the up-to-date knowledge in the field of detection, treatment, and monitoring of cutaneous scc. abstract https://doi.org/10.5826/dpc.1003a66 mailto:ccarrera@clinic.cat 2 review | dermatol pract concept 2020;10(3):e2020066 unaided eye [5]. although there is some overlap between dermoscopic features of actinic keratosis (ak), in situ scc (bowen disease), and microinvasive scc, there are also some important indicators that can assist in the diagnosis of scc and its subsequent management [6]. table 1 and figure 6 summarize the main dermoscopic findings of the spectrum of ak and scc [7]. in situ scc (bowen disease) is characterized by yellowish white opaque scales and clusters of 2 types of roundish vascular pattern: small dotted vessels and glomerular or coiled vessels. both patterns often appear within the same lesion and are distributed in small, densely packed clusters or allowing better recognition and a more precise selection of suspicious areas to biopsy, and provide a noninvasive, accurate way to monitor treatments. moreover, the therapeutic intervention on the cancerization field in patients with severe actinic damage and multiple in situ/low-risk scc, and the development of innovative treatments such as epidermal growth factor receptor inhibitors and immune checkpoint inhibitors for locally advanced and metastatic scc, are improving considerably the approach to the disease. update on the diagnosis clinical and dermoscopic presentation a presumptive diagnosis of scc is based on the physician’s interpretation of clinical information, including appearance and morphology, anatomic location, and patient-reported history. while the most frequent clinical presentation of scc in situ is an erythematous scaly patch or slightly elevated plaque, which is barely noticed by the patients, invasive scc is often ulcerated and can be patchy, papulonodular, papillomatous, or exophytic (figures 1-5). although histopathology remains the gold standard for the diagnosis of scc, some noninvasive optical technologies such as dermoscopy and rcm have recently been applied in an attempt to enhance clinical diagnosis accuracy and to obtain an in vivo characterization of the tumor [4]. dermoscopy is a noninvasive diagnostic technique that allows in vivo evaluation of colors and microstructures of the epidermis, the dermoepidermal junction, and the papillary dermis at 10-fold magnification [1], which improves diagnostic accuracy for scc compared to inspection by the figure 1. advanced and recurrent squamous cell carcinoma with nodal involvement in an elderly woman with dementia and chronic myeloid leukemia. large ulcerative and keratotic tumor with numerous actinic keratosis and satellite nodular lesions on the surrounding skin. she presented with locoregional lymph node involvement on parotid homolateral region. figure 2. multiple skin cancers, mainly squamous cell carcinomas, in a solid organ transplant patient. figure 3. example of cancerization field. multiple actinic keratoses in a patient with marked sun-damaged skin. review | dermatol pract concept 2020;10(3):e2020066 3 figure 4. (a) clinical image of bowen disease. (b) dermoscopic image of bowen disease where clusters of glomerular and dotted vessels and whitish scales can be identified. figure 5. (a) clinical image of a well-differentiated squamous cell carcinoma (keratoacanthoma-like) on the nose of a patient with sun-damaged skin. (b) dermoscopy shows a symmetric lesion with a central ulceration, surrounded by hairpin vessels with a whitish halo in a crown distribution. table 1. dermoscopic features of actinic keratosis and squamous cell carcinoma spectrum dermoscopic criteria description red color: vessels erythema structureless pale red areas without any recognizable areas red pseudonetwork structureless red areas intermingled with small roundish white areas that correspond to follicular infundibulum red starburst radial arranged structureless red lines or hairpin vessels that surround a yellow to white structureless scaly center and that have an overall starburst appearance dotted vessels tiny red dots densely aligned next to each other glomerular vessels variation on theme of dotted vessels, they are larger than dotted vessels, have convoluted morphology, and are often distributed in clusters hairpin vessels vascular loops sometimes twisted and bent, usually surrounded by a whitish halo when seen in keratinizing tumors linear irregular vessels linear or slightly curved; irregularly shaped, sized, and distributed red structures whitish yellow structures white circles (targetoid hair follicle) roundish structures of varying size composed of a white yellowish to light brown structureless center and a white outer structureless rim; this pattern corresponds to keratotic plugs within follicular openings of skin rosettes four closely aggregated white, small dots corresponding to follicular opening and resembling a 4-leaf clover; if one imagines connecting 4 dots with one line, the geometric figure of a rhombus can be formed white structureless areas the absence of any structure; they may cover large areas of the tumor and may be associated with large targetoid hair follicles yellow to light brown opaque scales yellow to light brown opaque structureless areas with a scaly or keratotic aspect which do not cover large areas of the tumor surface keratin mass centrally located, amorphous, yellow-white to light brown areas without any recognizable structure red-brown structures erosions small and irregularly distributed orange to red to red-brown structureless areas; they correspond to superficial hemorrhages and are usually associated with yellow opaque structures ulceration large irregularly shaped or roundish areas of dull red or red-brown structureless color 4 review | dermatol pract concept 2020;10(3):e2020066 described for in situ scc can be found in eczematous lesions, showing the necessity of integrating clinical examination with dermoscopic features and other imaging techniques. other in vivo imaging techniques reflectance confocal microscopy rcm is a noninvasive technique for in vivo imaging of the skin with a cellular-level resolution (0.5-1.0 mm in the lateral dimension and 4-5 mm the axial) [8] that uses near-infrared laser light at 830 nm. the imaging depth is in relation to the wavelength of the laser light used, but limited to 200-300 mm, which corresponds to the papillary dermis in normal skin [8]. this technique reproduces horizontal images of the skin in shades of gray, with a resolution comparable with that of conventional histology. it is painless and harmless; it allows the evaluation of a larger area of skin, the mapping of a whole tumor and margins, and the imaging of exactly the same location over time; and it does not induce any kind of skin damage or inflammatory response [9]. in the context of keratinizing tumors, if rcm is available in referral centers, it can be used routinely for several purposes: diagnosing the wide spectrum of nonmelanoma skin cancer-aks, demarcation of surgical margins of tumors, differential diagnosis from other tumors on sun-damaged skin, and monitoring both invasive and noninvasive therapies such as topical imiquimod, 5-fluorouracil, photodynamic therapy, laser therapy, or groups [1]. in pigmented bowen disease, other dermoscopic features are represented by small brown globules, which are regularly packed or aligned in a patchy distribution, and by gray to brown homogeneous pigmentation. white circles are a specific feature of early scc and actinic keratosis. they are white structures within the hair follicle that might present a ring-like or targetoid appearance due to the white yellowish keratotic plug in the center of the follicular opening and white halo surrounding it. when in situ scc progresses to microinvasive scc, the lesion thickens clinically, and hairpin and/or linear-irregular vessels appear in dermoscopy examination, occasionally giving a red starburst-like image on dermoscopy. in addition to typical vessel morphology, a keratotic center and ulceration might be seen. invasive scc presents more polymorphic vessels such as linear irregular, hairpin and grouped glomerular/ dotted vessels over a whitish background with a central mass of keratin or ulceration [1]. such dermoscopic features reflect a “vertical” growth phase (dermal invasion) [6]. the combination of clustered dotted/glomerular vascular patterns and hyperkeratosis, seen as discrete yellow scales, has previously been shown to achieve 98% diagnostic probability for scc [7]. however, the adherent surface scale often obscures the underlying morphological features, meaning that vessels may be better visualized at the periphery of the lesion. moreover, the absence of these vessels will not exclude the presence of an in situ scc. furthermore, the same pattern figure 6. dermoscopic features found in the progression model of actinic keratosis into squamous cell carcinoma (scc) in situ and invasive based on the article of zalaudek et al [6]. review | dermatol pract concept 2020;10(3):e2020066 5 stratum granulosum in combination with architectural disarray in the spinous layer and/or tumor nests in the dermis (aggregates of atypical keratinocytes) has been reported as the main rcm features to distinguish scc from ak [14]. moreover, the presence of round nucleated cells at the spinous-granular layers (which means parakeratosis and dyskeratotic cells) and round blood vessels traversing through the dermal papilla are the key features of scc on rcm [10,15]. the roundish vessels, which correspond to the “glomerular vessels” typically seen by dermoscopy, can be found in scc by rcm even when they are not clearly visible with other imaging technologies. table 2 summarizes the features of ak and scc by rcm [9]. high-frequency ultrasonography and doppler mode high-frequency ultrasonography (hfus) is a fast and accessible, noninvasive, convenient, practical, and safe dermatological diagnostic imaging examination that is now widely cryotherapy. however, there is a clear limitation to the ability of the microscope to evaluate the thickest components of the tumors, as occurs in some cases of scc in which hyperkeratosis predominates. the presence of hyperkeratotic surface on the lesion can make the rcm examination challenging, as the epidermal layers might be poorly visualized due to limited rcm laser penetration [9,10]. moreover, early recognition of scc by rcm is difficult, and clear differentiation between ak and in situ scc or between in situ and invasive scc remains a challenge, as keratinocyte atypia is considered in both the most relevant parameter [11,12]. aks on rcm are characterized by individual, highly refractile, round nucleated cells in the stratum corneum (which indicates parakeratosis) and an increase of thickness of stratum corneum seen as refractile amorphous material (hyperkeratosis) [13]. however, the presence of architectural disarray (severe disarranged epidermal pattern in which the honeycomb pattern is no longer visible) in the table 2. reflectance confocal microscopy (rcm) findings in actinic keratosis and squamous cell carcinoma and their histopathological correlations [9,15] level/features description histopathological correlation stratum corneum scale white refractile amorphous material increase of thickness of stratum corneum parakeratosis individual highly refractile round cells with a hyporefractile visible nucleus parakeratotic cells epidermis spinous stratum atypical honeycomb pattern irregular size and shape of cells with variable thickness and brightness of the lines abnormal pattern of the spinous layers targetoid cells cells with a refractile nucleus, hyporefractile periphery, and refractile membrane (target-like) apoptotic large cells epidermis spinous-granular layers disarranged and disrupted epidermal pattern severe architectural disarray in which the honeycomb pattern is no longer visible epidermis spinous-granular layers epidermis (full thickness) atypical honeycomb pattern irregular honeycomb also affecting the stratum granulosum cellular atypia affecting the complete epidermal layers dermoepidermal junction thickened papillae enhanced honeycomb surrounding the dermal papillae atypical hyperplasia of the basal epidermal layer surrounding the dermal papilla dermis dermal elastosis curled and clumped fibers in upper dermis and slightly small dilated vessels dermal elastosis round blood vessels dilated blood vessels within the dermal papillae that run perpendicular to the horizontal rcm plane of imaging (s-shaped vessels) neovascularization irregular and hairpin vessels atypical and marked dilated loop vessels surrounding refractile tumor nests neovascularization 6 review | dermatol pract concept 2020;10(3):e2020066 light. used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, oct may offer additional diagnostic information. as occurs in hfus, the method is useful for preoperative evaluation of the tumor size in patients with scc, as it provides a real-time imaging of nonmelanoma skin cancer to a depth of approximately 1.5 mm [18]. however, its specificity is low and there are no pathognomonic features of scc under oct examination. diagnosis confirmation, staging, and follow-up diagnosis is routinely confirmed by biopsy, and histological examination will differentiate between in situ and invasive scc and detect aggressive histopathological growth patterns. however, conventional histopathological examination is also undergoing some changes, as new imaging techniques are emerging and beginning to replace the typical fixation, processing, and staining methods. this is the case of ex vivo fluorescence and rcm, which allows a rapid microscopic examination of freshly excised unfixed tissue directly in the surgery room during mohs surgery after a few seconds of immersion in a fluorescence media [19]. this optical imaging modality uses the inherent light-scattering properties of the different components of the tissue and generates optical images similar to h&e-stained tissue sections obtained by cutting frozen or fixed tissues [20]. under conventional histopathology or ex vivo rcm, features such as the degree of differentiation, aggressive histological subtypes (acantholytic, adenosquamous, and carcinosarcomatous), depth greater than 2 mm (measured from the granular layer of the adjacent intact epidermis), clark level iv or greater, and presence of perineural and/or angiolymphatic invasion classify the lesion as high risk [2]. the differential diagnosis between scc subtypes is mandatory, as it will further determine the therapeutic approach and follow-up of the tumor. once an invasive/aggressive scc is diagnosed, it must be staged as the risk for metastasis is reported to be approximately 4% [21], and even 2 to 3 times higher in immunosuppressed individuals [22]. locoregional invasion can be assessed by hfus or oct in some cases as mentioned above. however, additional imaging techniques such as computed tomography (ct) or magnetic resonance imaging (mri) are frequently required to assess the depth of invasion in critical areas such as the face or the scalp, as scc is more likely to invade soft tissues, cartilage, and adjacent bone than other nonmelanoma skin cancer. cutaneous in-transit regional lymph node metastases are the most common metastatic presentation; therefore, clinical assessment of regional lymph nodes must be always included in the physical examination and supported by complementary imaging techniques such as ultrasonography and positron emission computed tomography (pet/ct). used in skin cancer. it allows real-time visual information with high diagnostic value and provides the physician with an extra hand in everyday practice. hfus uses frequencies of approximately 20 mhz, which are dedicated to depicting the skin and allow scanning of the whole skin (epidermis, papillary, reticular dermis, blood vessels, and upper parts of subcutaneous tissue—depending on the localization). as the ultrasound probe increases in frequency, its resolution increases but penetration decreases. used in conjunction with clinical and/or dermoscopic examination of suspected skin cancer, hfus may offer additional diagnostic information compared to other technologies. in fact, wortsman et al, in a large retrospective study of 4,338 ultrasonographic skin examinations, showed that the addition of hfus increased the correctness of clinical diagnosis from 73% to 97% [16]. in hfus, tumor depth is ascertained with b-mode, and doppler blood flow technologies permit the measurement of tumor neovascularity and the mapping of vascular structures. scc is usually seen as a hypoechogenic mass in relation to the surrounding tissue, without clear specific features that allow the differential diagnosis from other nonmelanoma skin cancer or other skin lesions. sometimes the inflammation and the scar tissue beneath or surrounding the lesion can be isoechoic to the tumor and lead to misjudgment of borders. moreover, the hyperkeratotic scale characteristic of some scc might also interfere in the image of the tumor. in fact, to study the lesions that have severe crusting or keratinization such as some scc, it is recommended to remove the scale or crust, since they cause attenuation of the sound beam, reducing the accuracy of the test. accordingly, marmur et al pointed out that, owing to the scc characteristic of generally presenting hyperkeratosis and to the higher inflammatory process associated, the tumor area could be overestimated in some cases when evaluated by ultrasound [17]. for this reason, hfus must always be considered a complementary diagnostic technique in scc. however, hfus is useful for determining the local aggressiveness of the tumor. scc is more likely to invade soft tissues, cartilage, and adjacent bone than other nonmelanoma skin cancer, and this can be assessed with ultrasonography. in fact, currently, the main clinical use of hfus in scc regards preoperative assessment of the invasion in critical areas such as the face or the scalp, as hfus gives a clear picture of the size and depth of the tumor, which is particularly important in planning the extent of the surgery. optical coherence tomography optical coherence tomography (oct) is an emerging technology that uses infrared light for performing high-resolution, cross-sectional imaging. oct is analogous to ultrasound imaging, except that it uses light instead of sound [1] and it magnifies the surface of a skin lesion using near‐infrared review | dermatol pract concept 2020;10(3):e2020066 7 surgery was recently updated by a combined task force of the american academy of dermatology, the american college of mohs surgery, the american society for dermatologic surgery association, and the american society for mohs surgery [27]. nonsurgical treatment low-risk scc if surgical therapy is not feasible or elected, nonsurgical local approaches may be considered [2]. for in situ or low-risk scc, the physician can choose photodynamic therapy (a 2-step method consisting of topical application of a photosensitizer, either 5-aminolevulinic acid or methylaminolevulinate, followed by 1 to several hours of incubation by light irradiation, typically with a blue, red, or broadband light source), or topical therapy with imiquimod (3.75%-5%), or 5-fluorouracil. these modalities not only treat the tumor, but also have an effect on the cancerization field if applied in a larger area. nonsurgical ablative modalities are also accepted in some cases in which surgery is not feasible, contraindicated, or not preferred by the patient. these include laser ablation (co2, erbium), electrocoagulation, and cryosurgery. however, given the lack of histological margin control with these approaches, the recurrence rate of scc is higher [28]. primary local radiation can also be used in special situations when other therapies are contraindicated or impractical [2,29]. high-risk scc and metastatic disease high-risk scc should always be surgically excised, preferably by mohs technique; however, adjuvant radiation therapy to the local tumor site following surgical treatment may be considered in primary scc concerning perineural invasion or at high risk for regional or distant metastasis. regarding locally advanced and metastatic scc, treatment is based on the extent of disease. if lymph nodes are involved, dissection must be performed whenever possible, and adjuvant radiation with or without concurrent systemic therapy must be considered [2]. systemic therapies such as capecitabine or epidermal growth factor receptor inhibitors (cetuximab, panitumumab) [30,31] have demonstrated efficacy in patients with advanced, unresectable scc. based on the high mutational loads of scc, the well-known infiltration with lymphocytes, and programmed death ligand 1 (pd-l1) expression, there is a promising utility in treating scc with the immune checkpoint inhibitors such as pembrolizumab [32]. recently the first anti-pd1 drug cemiplimab was approved by the us food and drug administration (september 2018) and by the european medicines agency (july 2019) after having demonstrated responses in about 50% of advanced or metastatic scc [33]. staging of the tumor is classically performed according to the tnm (tumor, node, and metastasis) american joint committee on cancer (ajcc) criteria [23]. however, the latest guidelines of care for the management of scc suggest that the staging of localized scc in clinical practice might be done using the current national comprehensive cancer center (nccn) risk stratification, as they include both clinical and pathological parameters, and suggest therapeutic approaches for each stage of the tumor [24], and that the brigham and women’s hospital (bwh) tumor classification system [25] might be chosen to evaluate the prognosis and clinical outcome of the patients diagnosed with scc, as it provides a more accurate method of prognostication. in all the staging scales there are several clinical-pathological markers of high-risk scc such as tumor size (which can vary depending on the location), breslow or tumor depth, perineural and lymph/vascular invasion, histological differentiation of the tumor (despite not being included in the latest ajcc classification), and the immune status of the patient (worse prognosis is seen in immunocompromised patients). when the patient fulfills 2 or more high-risk markers, further staging by sentinel lymph node biopsy (slnb) is recommended, as about 20% of these patients will present positive slnb. however, the impact on the overall survival or disease-free survival has still not been established [25,26]. follow-up of patients must be individualized and determined both by the clinical history of the individual and the subtype of the scc; however, screening for new primary skin cancers should be performed at least once per year, adjusting frequency on the basis of individual patient risk. update on the treatment the recently published guidelines for scc [2] resume the evidence-based recommendations for clinical treatment and management of patients with scc. surgical treatment surgical excision is still the gold standard and includes conventional and mohs surgery [26]. conventional excision must ensure complete removal and therefore include a margin of clinically normal-appearing skin around the tumor and surrounding erythema. clinical margins can be assessed prior to surgery by imaging techniques such as dermoscopy, rcm, hfus, or oct, which decrease the rates of incomplete excision and affected margins. nccn guidelines recommend 4to 6-mm clinical margins for standard excision of low-risk scc [24], whereas mohs surgery is recommended in high-risk scc, scc in immunocompromised patients, or “special-site scc” such as head and neck, where tissue conservation is important [27]. the criteria for appropriate use of mohs 8 review | dermatol pract concept 2020;10(3):e2020066 8. carrera c, puig s, malvehy j. in vivo confocal reflectance microscopy in melanoma. dermatol ther. 2012;25(5):410-422. https:// doi.org/10.1111/j.1529-8019.2012.01495.x 9. pellacani g, scope a, ferrari b, et al. new insights into nevogenesis: in vivo characterization and follow-up of melanocytic nevi by reflectance confocal microscopy.  j am acad dermatol. 2009;61(6):1001-1013. https://doi.org/10.1016/j. jaad.2009.04.018 10. malvehy j, hanke-martinez m, costa j, salerni g, carrera c, puig s. semiology and pattern analysis in nonmelanocytic lesions. in: hofmann-wellenhof r, pellacani g, malvehy j, soyer hp, eds. reflectance confocal microscopy for skin diseases. berlin, heidelberg: springer-verlag; 2012:237-252. https://doi. org/10.1007/978-3-642-21997-9_18 11. pellacani g, ulrich m, casari a, et al. grading keratinocyte atypia in actinic keratosis: a correlation of reflectance confocal microscopy and histopathology. j eur acad dermatol venereol. 2015;29(11):2216-2221. https://doi.org/10.1111/jdv.13215 12. seyed jafari sm, timchik t, hunger re. in vivo confocal microscopy efficacy assessment of daylight photodynamic therapy in actinic keratosis patients. br j dermatol. 2016;175(2):375-381. https://doi.org/10.1111/bjd.14517 13. moscarella e, rabinovitz h, zalaudek i, et al. dermoscopy and reflectance confocal microscopy of pigmented actinic keratoses: a morphological study. j eur acad dermatol venereol. 2015;29(2):307-314. https://doi.org/10.1111/jdv.1253 14. peppelman m, nguyen kp, hoogedoorn l, van erp pe, gerritsen mj. reflectance confocal microscopy: non-invasive distinction between actinic keratosis and squamous cell carcinoma. j eur acad dermatol venereol. 2015;29(7):1302-1309. https://doi. org/10.1111/jdv.12806 15. rishpon a, kim n, scope a, et al. reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. arch dermatol. 2009;145(7):766-772. https://doi.org/10.1001/ archdermatol.2009.134 16. wortsman x, wortsman j. clinical usefulness of variable-frequency ultrasound in localized lesions of the skin. j am acad dermatol. 2010;62(2):247-256. https://doi.org/10.1016/j.jaad.2009.06.016 17. marmur es, berkowitz ez, fuchs bs, singer gk, yoo jy. use of high-frequency, high-resolution ultrasound before mohs surgery. dermatol surg. 2010;36(6):841-847. https://doi.org/10.1111/ j.1524-4725.2010.01558.x 18. fujimoto jg, pitris c, boppart sa, brezinski me. optical coherence tomography: an emerging technology for biomedical imaging and optical biopsy. neoplasia. 2000;2(1-2):9-25. 19. longo c, ragazzi m, rajadhyaksha m, et al. in vivo and ex vivo confocal microscopy for dermatologic and mohs surgeons. dermatol clin. 2016;34(4):497-504. https://doi.org/10.1016/j. det.2016.05.012 20. pérez-anker j, ribero s, yélamos o, et al. basal cell carcinoma characterization using fusion ex vivo confocal microscopy: a promising change in conventional skin histopathology. br j dermatol. 2020;182(2):468-476. https://doi.org/10.1111/bjd.18239 21. brantsch kd, meisner c, schönfisch b, et al. analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. lancet oncol. 2008;9(8):713-720. https://doi.org/10.1016/s1470-2045(08)70178-5 22. cooper jz, brown md. special concern about squamous cell carcinoma of the scalp in organ transplant recipients. arch derconclusions the main advances in scc diagnosis are in the field of noninvasive imaging techniques. while histopathology remains the gold standard, noninvasive imaging techniques such as dermoscopy and rcm have recently been applied not only to enhance clinical diagnostic accuracy, but also to achieve an in vivo microscopic characterization of the tumors and margins previous to biopsy and surgery. the role of doppler ultrasonography in evaluating the deep invasive components and lymph node involvement is unquestionable. as a result, the staging, management decisions, and treatment monitoring of the scc is continuously improving thanks to the development of skin imaging techniques. moreover, the current concept of cancerization field and the development of several nonsurgical treatment modalities (imiquimod, 5-fluorouracil, ablative laser plus photodynamic therapy) have provided a wider range of therapies for 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dermatol pract concept 2020;10(2):e2020039 1 dermatology practical & conceptual efficacy of topical finasteride 0.5% vs 17α-estradiol 0.05% in the treatment of postmenopausal female pattern hair loss: a retrospective, single-blind study of 119 patients alfredo rossi,1 francesca magri,1 andrea d’arino,1 flavia pigliacelli,1 marta muscianese,1 pierpaolo leoncini,2 gemma caro,1 alessandro federico,1 maria caterina fortuna,1 marta carlesimo1 1 division of dermatology, department of internal medicine and medical specialties, sapienza university, rome, italy 2 department of pediatric hematology and oncology, istituto di ricovero e cura a carattere scientifico (irccs), bambino gesù children’s hospital, rome, italy key words: female pattern hair loss, topical finasteride, 17α-estriadol, minoxidil citation: rossi a, magri f, d’arino a, pigliacelli f, muscianese m, leoncini p, caro g, federico a, fortuna mc, carlesimo m. efficacy of topical finasteride 0.5% vs 17α-estradiol 0.05% in the treatment of postmenopausal female pattern hair loss: a retrospective, single-blind study of 119 patients. dermatol pract concept. 2020;10(2):e2020039. doi: https://doi.org/10.5826/dpc.1002a39 accepted: november 3, 2019; published: april 20, 2020 copyright: ©2020 rossi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alfredo rossi, md, division of dermatology, department of internal medicine and medical specialties, sapienza university, viale del policlinico 155, 00100, rome, italy. email: alfredo.rossi@uniroma1.it background and objectives: female pattern hair loss (fphl) is a common form of scalp hair loss that occurs in 38% of females. currently, minoxidil solution is the only therapy approved by the us food and drug administration, but many other treatments are used, including cyproterone acetate, spironolactone, topical 17α-estradiol, and prostaglandin analogs. systemic finasteride has been considered a treatment option in women even though its teratogenic effects tend to limit its prescription. recently, topical finasteride has been evaluated to limit the side effect profile of the drug. the objective of the present study is to compare retrospectively the efficacy of topical 0.05% 17α-estradiol solution and a 0.5% finasteride lotion in the treatment of fphl. patients and methods: we enrolled 119 postmenopausal female patients. the first group comprised 69 women treated with finasteride 0.5% and minoxidil 2%. the second group included 50 women treated with 17α-estradiol 0.05% and minoxidil 2%. at baseline and at 6and 12to 18-month follow-up, global photographs were systematically taken. three operators blind to the prescribed treatment evaluated photographs using a 7-point scale. one-way analysis of variance and unpaired student t tests were performed to analyze 7-point scale scores. results: the improvement was statistically significant from 6 months to 12-18 months, both for finasteride (p < 0.005) and 17α-estradiol (p < 0.05). the efficacy of topical finasteride was significantly abstract https://doi.org/10.5826/dpc.1002a39 mailto:alfredo.rossi@uniroma1.it 2 research | dermatol pract concept 2020;10(2):e2020039 the sample included 119 female patients affected by fphl (i-ii-iii type of ludwig classification) followed in our department of dermatology. inclusion criteria and exclusion criteria for the study are summarized in table 1. patients undergoing treatment 1 comprised 50 female patients, topically treated with a galenic 100-ml solution containing finasteride 0.5%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.4%. patients were between 46 and 74 years old and were observed between 2016 and 2019. patients undergoing treatment 2 comprised 69 female patients who were prescribed a 100-ml galenic formulation containing 17α-estradiol 0.05%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.87%. patients were observed within a 10-year time range, from 2009 to 2019. the patients’ ages ranged from 45 to 79 years. all patients were instructed to apply 1 ml of the assigned topical solution every night, on the vertex and frontal mineral supplements, and prostaglandin analogs, as well as surgical therapy and light therapy [10]. the weak estrogen 17α-estradiol has been used for many years as a 0.25-mg/ml topical alternative for the treatment of both male androgenetic alopecia and fphl given the absence of feminizing estrogenic activity [11] and its ability to weakly inhibit 5α-reductase. the objective of the present study was to compare retrospectively the efficacy of a topical 0.05% 17α-estradiol solution and a 0.5% finasteride lotion in the treatment of fphl. methods we performed an observational retrospective single-blind study of 119 female postmenopausal patients affected by fphl. the purpose of this study was to evaluate and compare the efficacy of 2 different fphl treatments: topical finasteride 0.5% and minoxidil 2% lotion (treatment 1) vs 17α-estradiol 0.05% and minoxidil 2% formulation (treatment 2). introduction female pattern hair loss (fphl), once known as female androgenetic alopecia, is a common form of nonscarring scalp hair loss in women occurring in 38% of women between the ages of 50 and 70 years [1,2]. it is characterized by a progressive miniaturization of hair follicles especially localized in the frontal, central, and parietal regions of the scalp [3]. the pathophysiology of fphl is still not completely clear. even though genetic and hormonal factors are considered involved as in the more common male form [4], its link to androgen hormones is less clear as it has been shown to appear in females affected by complete androgen insensitivity syndrome [5]. the 2 drugs approved by the us food and drug administration (fda) and european medicines agency for the treatment of male androgenetic alopecia are topical 2% and 5% minoxidil and oral finasteride (1 mg/day) [6]. currently, minoxidil solution is the only fda-approved therapeutic option for fphl. finasteride is a selective type ii 5α-reductase inhibitor, the enzyme responsible for the conversion of testosterone (t) to its more active form dihydrotestosterone (dht). it has been considered a treatment option also in women even though its teratogenic effects tend to limit its prescription. reports of its efficacy in women are contradictory, with less consistent results than in men [7,8]. recently, topical formulations have been evaluated to limit the side effect profile of the drug [9]. other commonly used therapies in fphl are cyproterone acetate, spironolactone, flutamide, topical 17α-estradiol, greater than that of 17α-estradiol solution, both at the 6-month (p < 0.05) and at the 12to 18-month follow-up (p < 0.005). in general, the highest improvement was observed after 12-18 months of treatment with topical finasteride therapy. conclusions: topical finasteride 0.5% in combination with minoxidil 2% could represent a valid therapeutic option for the treatment of postmenopausal fphl, showing higher efficacy than topical 17α-estradiol with minoxidil 2% both at 6-month and 12to 18-month follow-up. abstract table 1. inclusion and exclusion criteria for the study inclusion criteria: • postmenopausal patients • female pattern hair loss • type i-ii-iii of ludwig classification • no other concomitant treatments, including hormonal replacement therapy exclusion criteria: • concomitant treatments of the scalp • associated systemic diseases and/or systemic therapies which could influence hair growth (such as oncological patients undergoing chemotherapy) • concomitant scalp diseases (such as lichen planopilaris, alopecia areata, frontal fibrosing alopecia, telogen effluvium) research | dermatol pract concept 2020;10(2):e2020039 3 excluded these patients from further analyses. the following results apply only to patients who showed improvement following treatment (n = 112). we tested whether the 2 treatments led to improvements of different entity by comparing the mean ratings on the 7-point scale. the improvement was statistically significant from 6 months to 12-18 months, both for finasteride (p < 0.005) and 17α-estradiol (p < 0.05) galenic −1 on the 7-point scale). in the group to which treatment 2 (17α-estradiol) was prescribed, 64 out of 69 patients (92.7%) showed improvement. four out of 69 patients worsened after 12-18 months (average rating of −1 in all cases), while 1 patient had worse scores already at 6 months (rated −2 after 6 months and −1 after 12-18 months). given the small number of patients who showed a worsening of their condition following either treatment, we region. follow-up visits occurred after 6 and 12-18 months. at the time of the diagnosis, and at each of the follow-up visits, pictures of the frontal and vertex scalp regions were systematically taken using a fotofinder video dermatoscope (medicam 800). the instrument was placed on the rotating arm of a head-positioning device (canfield scientific), permitting a standardized photograph collection. to assess the improvement at different time intervals, 3 operators blind to the prescribed treatment evaluated photographs of the affected areas for each patient at baseline, at 6 months, and at 12-18 months from diagnosis. for the evaluation, a 7-point improvement scale was used. this is a standardized quantitative score for measuring the hair growth and clinical response: −3 = greatly decreased, −2 = moderately decreased, −1 = slightly decreased, 0 = no change, +1 = slightly increased, +2 = moderately increased, and +3 = greatly increased. all operators rated photographs for all participants at all time points, and the score was then averaged. statistical analyses one-way analysis of variance and unpaired student t tests were performed using spss software v19 (ibm, armonk, ny, usa) and graphpad prism v6 (graphpad software, san diego, ca, usa). confidence interval was set to 95% assuming statistically significant p values ≤ 0.05. results in our sample of 119 patients, hair loss improvement was observed in 112 women, while worsening was noticed in 7 patients. specifically, in the group to which treatment 1 (topical finasteride) was prescribed, 48 out of 50 patients (96%) showed improvement, while 2 out of 50 showed an increase of hair loss after 6 months (both of these patients’ photographs had an average rating of figure 1. scalp photographs and trichoscopy of a patient undergoing topical treatment with finasteride lotion, at baseline (a,c) and after 6 months of therapy (b,d). figure 2. macroscopic and trichoscopy pictures of a patient under treatment with 17α-estradiol topical lotion, at baseline (a,c) and after 6 months of therapy (b,d). 4 research | dermatol pract concept 2020;10(2):e2020039 formulations (figures 1-3). more important, the efficacy of topical finasteride (treatment 1) was significantly greater than that of the 17α-estradiol solution (treatment 2), both at the 6-month (p < 0.05) and at the 12to 18-month follow-up (p < 0.005) (figure 4). in general, the highest improvement was observed after 12-18 months of treatment with topical finasteride and minoxidil therapy (figure 5). discussion in our work, we compared 2 galenic formulations for the treatment of fphl. the first 100-ml solution contained 17α-estradiol 0.05%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.87%. the second 100-ml formulation was composed of finasteride 0.5%, minoxidil 2%, hydrocortisone butyrate 0.08%, and cyclosilicone pentamer 16% in alcohol 96° 81.4%. hydrocortisone butyrate is a class ii steroid that blocks the inflammatory process induced by lymphocytic peri-infundibular and peristhmic infiltrate [12,13]. minoxidil is a piperidinopyrimidine derivative and its action is believed to be due to its vasodilator properties. this is realized through the opening of potassium channels localized on the smooth muscular cells of the peripheral artery [14]. approved in 1979 for hypertension, it is largely used as a topical product for alopecia owing to its common adverse effect of inducing hair growth. minoxidil modifies the hair cycle, shortening the telogen phase or prolonging the anagen phase [12]. it directly stimulates the dermal papilla or the follicular hair matrix cells, causing an increase of vascular endothelial growth factor and consequently angiogenesis [12,15]. furthermore, it has been hypothesized that it activates the prostaglandin endoperoxide synthetase enzyme type i, which induces hair growth [16]. figure 3. using the 7-point scale, the improvement was statistically significant from 6 months to 12-18 months, both for finasteride (p < 0.0027) and 17α-estradiol (p < 0.0205). est = 17α-estradiol; fin = finasteride; fphl = female pattern hair loss; 0 = no change; 1 = slightly increased; 2 = moderately increased; 3 = greatly increased. figure 4. greater efficacy of topical finasteride than 17α-estradiol solution, both at 6 months (p < 0.0368) and at 12-18 months follow-up (p < 0.0042). est = 17α-estradiol; fin = finasteride; 0 = no change; 1 = slightly increased; 2 = moderately increased; 3 = greatly increased. figure 5. the highest improvement is observed after 12 to 18 months of treatment with topical finasteride and minoxidil therapy. currently, minoxidil is the only fda-approved therapeutic option for fphl [17]. the 2% concentration was approved in 1991, and 5% minoxidil was approved in 2014 [18]. systemic finasteride inhibits the type ii 5α-reductase, which normally catalyzes the conversion of testosterone (t) to dihydrotestosterone (dht), the more active form of t. finasteride is research | dermatol pract concept 2020;10(2):e2020039 5 pausal fphl, showing higher efficacy than topical formulation containing 17α-estradiol 0.05% in combination with minoxidil 2% and hydrocortisone butyrate 0.08%, both at 6-month and 12to 18-month follow-up. references 1. birch mp, messenger jf, messenger ag. hair density, hair diameter and the prevalence of female pattern hair loss. br j dermatol. 2001;144(2):297-304. 2. price vh. androgenetic alopecia in women. j investig dermatol symp proc. 2003;8(1):24-27. 3. olsen ea. female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective. j investig dermatol symp proc. 2005;10(3);217221. 4. messenger ag. hair through the female life cycle. br j dermatol. 2011;165( suppl 3):2-6. 5. cousen p, messenger a. female pattern hair loss in complete androgen insensitivity syndrome. br j dermatol. 2010;162(5):1135-1137. 6. rossi a, anzalone a, fortuna mc, et al. multi-therapies in androgenetic alopecia: review and clinical experiences. dermatol ther. 2016;29(6):424-432. 7. iorizzo m, vincenzi c, voudouris s, piraccini bm, tosti a. finasteride treatment of female pattern hair loss. arch dermatol. 2006;142(3):298-302. 8. olszewska m, rudnicka l. effective treatment of female androgenic alopecia with dutasteride. j drugs dermatol. 2005;4(5):637-640. 9. lee sw, juhasz m, mobasher p, ekelem c, mesinkovska na. a systematic review of topical finasteride in the treatment of androgenetic alopecia in men and women. j drugs dermatol. 2018;17(4):457463. 10. choe sj, lee s, choi j, lee ws. therapeutic efficacy of a combination therapy of topical 17alpha-estradiol and topical minoxidil on female pattern hair loss: a noncomparative, retrospective evaluation. ann dermatol. 2017;29(3):276282. 11. moos wh, dykens ja, howell n. 17α-estradiol: a less-feminizing estrogen. drug dev res. 2008;69(4):177-184. 12. rossi a, iorio a, scarnò m, et al. use of topical minoxidil, 17α-estradiol and hydrocortisone butyrate in frontal fibrosing parable with the improvement of 17α-estradiol-treated patients at 12-18 months. indeed, topical 17α-estradiol therapy required more time to achieve the same results of finasteride. the greater rapidity and higher efficacy of finasteride could be explained with 2 observations. first, finasteride induces a stronger block of type ii 5α-reductase, if compared with the weak inhibition of 17α-estradiol. moreover, the inhibition of type ii 5α-reductase induced by finasteride could cause a t escape, which in turn stimulates the aromatases, increasing estradiol conversion and guaranteeing an adjunctive activity similar to that of 17α-estradiol. as we have shown, both therapies produced an improvement that was already visible at 6 months and especially after 12-18 months. indeed, the treatment should be always continued for long periods to achieve better results. concerning topical finasteride’s side effects, a systemic absorption is possible, as described by caserini et al [22]. also, suchonwanit et al demonstrated a lower serum level of dth in postmenopausal women treated with it. indeed, topical finasteride should be used only in postmenopausal women. a limit of our study was the absence of a control group. another limit was the lack of hair analysis besides global photographs. we did not perform a computerized quantitative measure (trichoscale) because most of our female patients refused to realize a circumscribed shaved area on the scalp with tattoos. another limit was the subjective assessment of patients, even though all observers were blind to the therapies. regardless, the use of the 7-point scale allowed us to perform a valid statistical analysis. conclusions based on our results, topical finasteride 0.5% in combination with minoxidil 2% and hydrocortisone butyrate 0.08% could represent a valid therapeutic option for the treatment of postmenonot fda-approved for the female population. studies are limited and variable dosages of oral finasteride have been tested in female patients (1-5 mg/day) with conflicting results [19]. therefore, further randomized studies are still necessary to determine the efficacy and optimal dosage of this drug. moreover, systemic finasteride is associated with several side effects, especially sexual alterations, and its assumption is contraindicated during pregnancy and breast-feeding because of the risk of feminization of the male fetus [18]. with the aim of reducing oral finasteride side effects, a topical formulation of this drug was introduced years ago, with promising results in male patients. recently, suchonwanit et al [20] studied and compared for the first time the efficacy of topical 0.25% finasteride combined with 3% minoxidil solution and 3% minoxidil solution as monotherapy in 30 fphl postmenopausal patients. in their work, the finasteride/ minoxidil solution was significantly superior to minoxidil in improvement of hair diameter. 17α-estradiol solutions represent another therapeutic option for fphl. this is a stereoisomer of the female hormone 17β-estradiol, which weakly inhibits 5α-reductase. furthermore, it suppresses the 17β-dehydrogenase, causing a reductive conversion of androstenedione to t, and it stimulates the aromatase, which induces the conversion of t to estradiol [21]. in our work, through global photographs and using the 7-point rating scale, we observed that both galenic formulations determined a statistically significant improvement of hair loss from 6-month follow-up to 12to 18-month follow-up. more important, 0.5% finasteride showed higher efficacy than 0.05% 17α-estradiol lotion, both at 6 and 12-18 months. this outcome was statistically significant. i t i s i n t e r e s t i n g t h a t f i n a s teride-treated patients had an improvement at 6 months, which was com6 research | dermatol pract concept 2020;10(2):e2020039 of 0.25% finasteride and 3% minoxidil versus 3% minoxidil solution in female pattern hair loss: a randomized, double-blind, controlled study. am j clin dermatol. 2019;20(1):147-153. 21. kim jh, lee sy, lee hj, yoon ny, lee ws. the efficacy and safety of 17α-estradiol (ell-cranell® alpha 0.025%) solution on female pattern hair loss: single center, open-label, non-comparative, phase iv study. ann dermatol. 2012;24(3):295-305. 22. caserini m, radicioni m, leuratti c, annoni o, palmieri r. a novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers. int j clin pharmacol ther. 2014;52(10):842-849. mechanism affecting hair growth both in vitro and in vivo. j invest dermatol. 1992;98(3):315-319. 17. r o g e r s n e , av r a m m r . m e d i c a l treatments for male and female pattern hair loss. j am acad dermatol. 2008;59(4):547-566. 18. fabbrocini g, cantelli m, masara a, annunziata mc, marasca c, cacciapuoti s. female pattern hair loss: a clinical, pathophysiologic, and therapeutic review. int j womens dermatol. 2018;4(4): 203-211. 19. hu ac, chapman lw, mesinkovska na. the efficacy and use of finasteride in women: a systematic review. int j dermatol. 2019;58(7):759-776. 20. suchonwanit p, iamsumang w, rojhirunsakool s. efficacy of topical combination alopecia. eur j inflamm. 2014;12(2):399404. 13. whiting da. diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. j am acad dermatol. 1993;28(5 pt 1):755-763. 14. rossi a, cantisani c, melis l, iorio a, scali e, calvieri s. minoxidil use in dermatology, side effects and recent patents. recent pat inflamm allergy drug discov. 2012;6(2):130-136. 15. walsh ds, dunn cl, james wd. improvement in androgenetic alopecia (stage v) using topical minoxidil in a retinoid vehicle and oral finasteride. arch dermatol. 1995;131(12):1373-1375. 16. buhl ae, waldon dj, conrad sj, et al. potassium channel conductance: a dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(1):e2020020 1 dermatology practical & conceptual case presentation an otherwise healthy 20-year-old man presented to the emergency department with a 5-day history of low-grade fever and malaise, followed by the appearance of painful lesions on his tongue. physical examination revealed marked alterations of the tongue (figure 1), including hyperplasia of fungiform papillae on the tip, white hairy tongue on the dorsum, fissured tongue on the lateral borders, and multiple small, coalescing ulcerations with scalloped borders and erythematous rim. only 1 similar erosion was found on the lower lip and 1 on the hard palate, and gingivae were spared. polymerase chain reaction of an ulcer swab was positive for herpes simplex virus, type 1, allowing the diagnosis of an atypical form of herpetic gingivostomatitis. teaching point herpesvirus family has a broad spectrum of mucocutaneous manifestations. multiple oral ulcerations with scalloped borders should raise the suspicion of herpetic gingivostomatitis, even if typical involvement of keratinized mucosa is absent. catastrophic tongue juan jimenez-cauhe,1 sandra dominguez-carames,2 daniel ortega-quijano,1 diego fernandez-nieto1 1 servicio de dermatología, hospital universitario ramon y cajal, irycis, madrid, spain 2 servicio de otorrinolaringología, hospital universitario ramon y cajal, irycis, madrid, spain key words: herpesvirus, oral ulcers, gingivostomatitis, tongue citation: jimenez-cauhe j, dominguez-carames s, ortega-quijano d, fernandez-nieto d. catastrophic tongue. dermatol pract concept. 2020;10(1):e2020020. doi: https://doi.org/10.5826/dpc.1001a20 accepted: august 22, 2019; published: december 31, 2019 copyright: ©2019 jimenez-cauhe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: juan jimenez-cauhe, md, dermatology department, ramon y cajal university hospital. carretera colmenar viejo km 9.100, 28034 madrid, spain. email: jjimenezc92@gmail.com figure 1. clinical image showing hyperplasia of fungiform papillae on the tip, white hairy tongue on the dorsum, fissured tongue on the lateral borders, and multiple small, coalescing ulcerations with scalloped borders and erythematous rim. a b mailto:jjimenezc92@gmail.com letter | dermatol pract concept 2011;1(1):17 83 letter to the editor ricardo e. achenbach, m.d.1 1department of dermatology, pirovano hospital, buenos aires, argentina key words: mitotic index, melanoma staging, sentinel lymph node biopsy, melanoma citation: achenbach re. letter to the editor [letter]. dermatol pract concept 2011;1(1):17. http://dx.doi.org/10.5826/dpc.0101a17. editor: harald kittler, m.d. received: october 1, 2010; accepted: december 17, 2010; published: october 31, 2011 copyright: ©2011 achenbach. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. the author has contributed significantly to this publication. corresponding author: ricardo e. achenbach, m.d., hospital pirovano, avenida monroe 3555, buenos aires, argentina. email: rachenbach@hotmail.com. in reply to “to count or not to count – that is the question” dear editor, i would like to comment on the editorial by almut böer-auer entitled, “to count or not to count – that is the question!” [1] and the subsequent survey about the mitotic index (mi) as a result of the seventh edition of the melanoma staging and classification of the ajcc, published by balch et al [2]. the staging and classification of melanoma by the so-called experts changes every two to four years and not precisely due to consistent and useful scientific progress in the diagnosis, etiopathogenic or therapeutic issues, but according to the objectives and interests preset by these same “experts.” during my 30 years of clinical diagnosis, and especially since the year 2000, at which time i started reading and diagnosing the biopsies of each and every case at my hospital in which melanoma is suspected, the mi has had no importance for me at the moment of making a therapeutic decision, even though the dermatopathologists on my team have reported the mi as “low, medium or high.” i would never dream of phoning a pathologist to be informed of the mi in any case of melanoma. the mi given by the dermatopathologist in his report is irrelevant to me. on the other hand, if the melanoma has hemolymphatic invasion or neurotrophic differentiation, i would be more worried. only a few histopathological features – whether it is in situ or not, if there is vascular embolus or neural compromise, its thickness with all its flaws – and almost nothing else will make me change my course of action after confirming a diagnosis. in my point of view, the importance given to the mi has only one and shameful purpose: to have more slnbs (sentinel lymph node biopsy) made and therefore earn more money. the slnb as it has been proven (mslt-1) – and as foretold by ackerman – is a procedure which does not offer any benefit to the patient with melanoma, no matter what its thickness is [3-7]. as it has frequently been written in this journal, i have been able to follow numerous cases of thin melanomas which have had dreadful endings in a short time and many other cases where melanomas were thick, ulcerated and with a lot of mitosis that after years remain alive. the consensus guidelines of staging and treatment for melanoma have reached the point that only papers and lectures which are in favor of slnb are accepted and those that are against this procedure are censored [8]. most of these “experts” are surgeons or oncologists who practice slnb as a routine even in melanomas which are less than 1 mm thick or thicker than 4 mm. as i see it, the dermatologists that face this neoplasia day after day are scarce. dermatology practical & conceptual www.derm101.com 84 letter | dermatol pract concept 2011;1(1):17 there is no doubt that the dermatologist is the best physician to address melanoma and, coupled with the dermatopathologist, is the one who will be responsible for the final diagnosis and treatment. due to the narrow surgical margin with which we operate on the melanomas in our department of dermatology, we rarely refer any cases to a surgeon. we operate on them ourselves, and in our experience, we have had no cases of recurrence/persistence. lymph node surgery is only carried out if some node is palpable at the moment of the diagnosis or in the follow-up. slnb is not done in our department. we do inform the patient of the risk/benefit aspects of the procedure, and if the patient decides to have it performed, we refer him/her to another center. it would be interesting to conduct another survey in the last issue of dermatopathology: practical & conceptual in which well-known clinical dermatologists could be asked what importance he/she gives to the mi reports from the pathologist and if in a melanoma of 1 mm or less thick finding mitotic features would induce him/her to have a slnb performed by a surgeon. it is my belief that such a survey would give us an idea of the number of dermatologists who think for themselves and those who just do what everybody does. references 1. böer a. to count or not to count – that is the question. editorial. dermatopathology: practical & conceptual 2010;16(3):4. 2. balch cm, gershenwald je, soong sj, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol 2009;20; 27(36):6199-206. epub 2009 nov 16. 3. brett mc, scott d, howard wr. sentinel lymph node biopsy and completion lymph node dissection for malignant melanoma are not standard of care. clin dermatol 2009; 27:350-4. 4. gonzález u. cloud over sentinel node biopsy: unlikely survival benefit in melanoma. arch dermatol 2007;143(6):775-6. 5. kanzler mh. the current status of evaluation and treatment of high-risk cutaneous melanoma: therapeutic breakthroughs remain elusive. arch dermatol 2007;143(6):785-87. 6. zitelli ja. sentinel lymph node biopsy: an alternate view. dermatol surg 2008;34(4):544-9. 7. medalie n, ackerman ab. sentinel node biopsy has not benefit for patients whose primary cutaneous melanoma has metastasized to lymph node and therefore should be abandoned now. br j dermatol 2004:151(2):298-307. 8. thomas jm. freedom of expression or protectionism in the debate on sentinel node biopsy in melanoma. j am acad dermatol 2009;61(6):1079. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(2):3 9 introduction differentiation of a melanocytic nevus and melanoma is often a dilemma clinically as well as histologically. this dilemma involves inexperienced as well as knowledgeable pathologists. the provoking question turns out to be: why is this differential diagnosis often a quandary? the answer lies in the fact that there are overlapping cytological and architectural criteria used interchangeably for a melanoma and melanocytic nevus. the criteria emphasized often vary from institution to institution and pathologist to pathologist. regrettably, similar criteria attributed to both benign and malignant melanocytic proliferations, melanocytic nevus and melanoma, are used interchangeably: thus the quandary. discussion melanocytes in the skin situated at the dermoepidermal junction are relatively monomorphic, with clefting of their small dark nuclei from their paltry cytoplasms [1]. melanocytic nevi are hamartomas composed of melanocytes with relatively monomorphic basophilic nuclei with paltry, clefted cytoplasm in nests, fascicles, columns, cords, and aggregates, as well as solitary units that may involve the epidermis, dermis, and structures of adnexal. cytologically, the monomorphous melanocytes of melanocytic nevi are in an erratic, unpredictable assortment of small and minimally larger sizes and shapes, e.g., round, oval, spindle-shaped, polygonal, plasmacytoid, ballooned, fusiform, dendritic, pagetoid and multinucleate. not uncommonly, they are associated with pseudoacantholysis. melanocytes of melanocytic nevi in the skin are usually small, monomorphous and routinely are located at the dermoepidermal junction and not above it, as solitary units as well as in nests at the dermoepidermal junction and dermis. nuclei may be diverse, as well, ranging from typical small and uniform small round/oval with small nucleoli, to atypical large, pleomorphic, hyperchromatic, heterochromatic, with prominent nucleoli, necrosis, mitosis, and above the dermoepidermal junction as seen in a genital melanocytic nevus, melanocytic nevus of the palm/sole, and in the so-called spitz’s nevus [2]. the amount of cytoplasm within an individual melanocyte of a melanocytic nevus is routinely paltry and insignificant, but may be variable, inconsistent and unpredictable. architecturally, criteria for melanocytic nevi usually include symmetry, sharp circumscription, wedge-shaped, maturation with progressive decent into the dermis, and lack of scatter of melanocytes above the dermoepidermal junction (pagetoid pattern) across a broad front. to the contrary, criteria for melanoma cytologically and architecturally are usually the reverse to those of melanocytic nevus, but not always. shapes of melanocytes of a melanoma are similar to a melanocytic nevus, e.g., round/ oval, spindle-shaped, fusiform, polygonal, with pseudoacatypical or typical pagetoid cell: a subtle clue to differentiate a melanoma from a melanocytic nevus robert m. hurwitz, m.d. key words: melanoma, melanocytic nevus, pagetoid cell citation: hurwitz r. atypical or typical pagetoid cell: a subtle clue to differentiate a melanoma from a melanocytic nevus. dermatol pract conc. 2013;3(2):3. http://dx.doi.org/10.5826/dpc.0302a03. received: december 28, 2012; accepted: march 1, 2013; published: april 30, 2013 copyright: ©2013 hurwitz. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: robert m. hurwitz, m.d., cutaneous and maxillofacial pathology laboratory, pc, 9292 north meridian street, suite 210, indianapolis in 46260, usa. email: bobbyhur@aol.com. antholysis, etc., but time and again with large round pleomorphic nuclei, often with some frequency large vesicular nuclei with prominent large red centrally located nucleoli. on the other hand, for example, some melanomas may have an increased number of solitary small melanocytes at the dermoepidermal junction, with solitary melanocytes outnumbering those in aggregations and nests, especially early in its evolution. in addition, periodically, a melanoma early in its evolution may exhibit a number of melanocytes with riveting, elongated, pigmented dendrites that extend into the upper spinous layer. interestingly, as well as fascinatingly, and to the contrary, some melanocytic nevi may also have a number of similar criteria of melanoma, e.g., small melanocytes and small nests of melanocytes. in addition, an early or evolving melanoma may have increased elongated dendritic melanocytes, while to the contrary a spitz’s nevus with elongated dendritic melanocytes commonly are seen in asians and african americans [3]. congenital melanocytic nevus shortly after birth, and nevi involving “special sites” such as the genitalia, perianal, breast/nipple/areola, palms/soles, scalp, ear and umbilicus, as well as in the often perplexing persistent (recurrent) nevus, regularly have criteria common to melanoma, e.g., scatter of melanocytes above the dermoepidermal junction. noticeably, if not outright stunning, some melanocytic nevi with criteria of a melanoma have been added to a bewildering and confusing register of melanocytic nevi which supposedly have a propensity to evolve into a melanoma, i.e., the so-called pre-melanoma. some monikers include an atypical mole, dysplastic nevus, nevus with architectural disorder and cytologic atypia, atypical spitz nevus/tumor, as well as neoplasms of indeterminate 10 observation | dermatol pract concept 2012;3(2):3 figure 1. melanocytic nevus with typical pagetoid melanocytes. typical pagetoid melanocytes are round with abundant pale cytoplasm with uniform staining small, and slightly large round/oval basophilic nuclei. numerous routine appearing small round/oval melanocytic nevus cells are present in number with their usual paltry, clefted cytoplasm with periodic patchy melanin, in association with variable size and shaped aggregates of routine appearing basophilic small and large round/oval nucleated melanocytic nevus cells. malignant potential with evasive monikers (nimp, sampus, meltump) [4,5,6,7]. noteworthy, the so-called pagetoid cell [7] is the quintessential example of uncertainty and misunderstanding as to whether the melanocyte with abundant pale cytoplasm is truly an atypical pagetoid cell of melanoma, or a typical pagetoid cell of a melanocytic nevus. the typical pagetoid cell is located commonly at the dermoepidermal junction or dermis in customary, routine traditional junctional or compound melanocytic nevi, spitz’s nevus, or genital melanocytic nevus (figure 1). on the other hand, the atypical pagetoid cell of melanoma is considered a cell that simulates those cells seen in extramammary paget’s disease, which have large nuclei with abundant pale staining cytoplasm. in a melanoma, there may be many melanocytes with large, basophilic round/oval, fusiform or polygonal shaped melanocytes with riveting large pleomorphic nuclei, large nucleoli, abundant pale staining cytoplasm, and frequently in pagetoid pattern (figure 2). in addition to melanoma and some spitz’s nevi, atypical pagetoid cells are common to squamous cell carcinomas, e.g., bowen’s disease, paget’s disease of the breast, and apocrine carcinomas. therefore, when a melanocyte has abundant pale cytoplasm and is associated with a large round/oval pleomorphic nucleus, it is acknowledged and known as an atypical pagetoid cell. this is contrasted to a typical pagetoid cell, which has a small or slightly large round/oval nucleus with abundant pale cytoplasm but without significant nuclear atypia and pleomorphism. to boot, a mitotic figure, typical or atypical may be observed on occasion in either a typical or atypical pagetoid melanocyte. figure 2. melanoma in situ with numerous atypical pagetoid melanocytes in pagetoid pattern. the atypical pagetoid melanocytes are large round and polygonal-shaped with abundant pale staining cytoplasm with large round, pleomorphic, hyperchromatic, heterochromatic basophilic nuclei. the scatter of notorious, atypical pagetoid melanocytes involving the basal, spinous and granular layers of the epidermis, i.e., pagetoid pattern. observation | dermatol pract concept 2012;3(2):3 11 conclusion in summary, the dilemma of whether a pigmented melanocytic proliferation is a melanoma or melanocytic nevus perhaps rests on the recognition of overlapping criteria, and the detection of the typical or atypical pagetoid melanocyte. references 1. ackerman ab, elish d, shami s. spitz’s nevus: reassessment critical, revision radical. new york: ardor scribendi, ltd., 2007:16-7. 2. ackerman ab, elish d, shami s. spitz’s nevus: reassessment critical, revision radical. new york: ardor scribendi, ltd., 2007:155. 3. ackerman ab. clues to diagnosis in dermatopathology. clue 137. http://www.derm101.com 4. elder de, xu x. the approach to the patient with a difficult melanocytic lesion. pathol. 2004;36(5):428-34. 5. rosai j. rosai and ackerman’s surgical pathology. 9th ed. elsevier health sciences: philadelphia, 2004:172. 6. ackerman ab, massi d, nielsen ta. dysplastic nevus: atypical mole or typical myth? new york: ardor scribendi ltd., 1999. 7. ackerman ab. clues to diagnosis in dermatopathology. clue 140 http://www.derm101.com. dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021111 1 dermatology practical & conceptual acquired brachial cutaneous dyschromatosis: a rarely recognized condition jorge román-sainz1, sergio samer tabbara-carrascosa1, marta martínez-garcía1, adrián imbernón-moya1 1 dermatology unit, hospital universitario severo ochoa, leganés, spain key words: dyschromatosis, poikiloderma, sun damage, hyperpigmentation, pigmentary disorders citation: román-sainz j, tabbara-carrascosa st, martínez-garcía m, imbernón-moya a. acquired brachial cutaneous dyschromatosis: a rarely recognized condition. dermatol pract concept. 2021;11(1):e2021111. doi: https://doi.org/10.5826/dpc.1101a111 accepted: june 22, 2020; published: january 29, 2021 copyright: ©2021 román-sainz et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: jorge román-sainz, md, travesía de téllez, 8, 7º r, 28007, madrid, spain. email: jorgesheldon@gmail.com introduction acquired brachial cutaneous dyschromatosis (abcd) is a pigmentary disorder located on the forearms, especially affecting middle-aged women aged 50-70 with fitzpatrick’s phototype iii-iv [1]. there are only 23 cases reported in the literature, although it is likely underreported by patients due to its lack of symptoms [2]. case presentation a 71-year-old woman, with skin type iii was referred to the dermatology unit for a 6-month history of asymptomatic skin lesions on her forearms. she reported intense, chronic sun exposure. she was being treated with lisinopril, an angiotensin converting enzyme (ace) inhibitor, due to hypertension. dermatological exploration showed confluent, symmetrical, light brown hyperpigmented and hypopigmented macules with linear and oval morphology and cutaneous atrophy (figure 1). skin biopsy revealed a preserved epidermis with slight hyperpigmentation of the basal layer, and a few telangiectases at the dermal level with marked actinic elastosis. the patient was diagnosed with acquired brachial cutaneous dyschromatosis (abcd). photoprotection was prescribed, and she had partial improvement of the lesions after 6 months. conclusions abcd was first reported by rongioletti and rebora in the year 2000 [1]. it is an acquired pigmentary disorder that presents as asymptomatic light brown patches interspersed with hypopigmented macules [1]. histology shows poikilodermatous tissue with hyperpigmentation of the basal layer, solar elastosis, and superficial telangectases [1,2]. most of the reported cases present bilaterally on the distal aspect of the forearms [1]. twenty cases were reported (85%) in females, with only 3 cases in males [1,2]. the age of onset ranged from 50-70, and 91% of cases have been reported in patients with skin phototype iii-iv, with only 2 cases being a type ii [1,2]. an 2 image letter | dermatol pract concept 2021;11(1):e2021111 association with civatte poikiloderma was found in 9 (39%) patients [1]. the incidence and prevalence of this disorder are unknown. abcd is thought to be an underdiagnosed disease, likely due to lack of consultation by the patients. there are currently 2 hypotheses about the etiopathogenesis of abcd. the first one states that abcd is related to chronic treatment with ace inhibitors; 14 (60%) patients were reported to have been in treatment with such drugs for years [1]. the other theory claims that abcd is more related to cumulative sun damage, as most of the patients had evidence of chronic sun exposure [2]. both hypotheses could explain the cause of abcd in a majority of these cases, and this is likely due to an interaction between ace inhibitors and sun exposure in predisposed patients. differential diagnosis must include civatte poikiloderma, melasma, postinflammatory hyperpigmentation, pigmented contact dermatitis (berloque dermatitis), macular amyloidosis, prurigo pigmentosa, and drug-induced hyperpigmentation. although these disorders may be clinically similar, they can be easily differentiated with histopathogical examination. there is no standard treatment for abcd. strict photoprotection is the most widely recommended, but a combination of topical depigmenting agents, chemical peels, and laser treatments can be considered [2]. references 1. rongioletti f, rebora a. acquired brachial cutaneous dyschromatosis: a common pigmentary disorder of the arm in middle-aged women. j am acad dermatol. 2000;42(4):680-684. doi: 10.1067/ mjd.2000.103273. pmid:10727320. 2. choi mj, byun jy, choi hy, choi yw. acquired brachial cutaneous dyschromatosis in a middle aged male. ann dermatol. 2018;30(3):342-344. doi: 10.5021/ad.2018.30.3.342. pmid:29853750. figure 1. (a) clinical image showing linear hyperpigmented macules with atrophic and poikilodermal skin. (b) histopathological image showing epidermal atrophy, as well as hyperpigmentation of the basal layer, solar elastosis, and telangiectases at the superficial dermis. a b dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):3 9 introduction different forms of squamous cell carcinoma (scc) exist, keratoacanthoma (ka) variously being regarded as a variant of scc or as a benign and self-limiting lesion [1]. though invasion of adnexal, vascular or nervous structures usually precludes the presence of a benign tumour, a series of ka with perineural invasion has been published before [2], as has a case with venous invasion [3]. in this report we present the case of a non-pigmented raised skin tumour, with clinical and histologic features of ka, showing venous invasion. case report a 79-year-old man with a past history of both non-melanoma skin cancer and melanoma presented with a new lesion on his left forehead. the lesion had not been noticed at a previous visit four weeks earlier, and he believed it had appeared and grown over the preceding three weeks. the lesion (figure 1) was raised and symmetrical with central keratin surrounded by a white area, which merged to a pink area peripherally. it was not tender to palpation and some surface scale was evident. dermatoscopy (figure 2) revealed a non-pigmented lesion with a central structureless orange area (consistent with keratin) surrounded by a large structureless white area merging into a structureless pink area at the periphery. there was a pattern of branched serpentine vessels visible over most of the surface area outside of the keratin. blood-spots were seen on the keratin. on histologic examination of the excision specimen there was a well-differentiated squamoproliferative lesion with the characteristic pattern of keratinisation seen in a ka [4]. in each of the two transverse sections taken there was a nest of keratinising squamous cells within the lumen of a vein in the deep dermis. the wall of the vein was highlighted using a a keratoacanthoma with venous invasion philipp tschandl, m.d.1, cliff rosendahl, mbbs2, richard williamson, m.d.3, david weedon, m.d.3 1 department of dermatology, medical university of vienna, austria 2 school of medicine, university of queensland, brisbane, australia 3 sullivan nicolaides pathology, brisbane, australia key words: keratoacanthoma, squamous cell carcinoma, dermatoscopy, dermoscopy dermatopathology, venous invasion citation: tschandl p, rosendahl c, williamson r, weedon d. a keratoacanthoma with venous invasion. dermatol pract conc. 2012;2(4):3. http://dx.doi.org/10.5826/dpc.0204a03. received: may 23, 2012; accepted: august 28, 2012; published: october 31, 2012 copyright: ©2012 tschandl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, school of medicine, university of queensland, 5 larbonya cres, capalaba, qld 4156, australia. email: cliffrosendahl@bigpond.com. keratoacanthomas are variously regarded as a self-limiting variant of squamous cell carcinoma or as a distinct benign lesion and they very seldom show attributes normally associated with malignant behaviour, such as perineural invasion. herein we report the case of a keratoacanthoma with venous invasion proven by immunoperoxidase and elastic tissue stains. abstract 10 observation | dermatol pract concept 2012;2(4):3 1. they are each morphologically distinctive. 2. the behaviour of ka with perineural and/or intravenous invasion is quite different to that of scc showing the same phenomenon. 3. there are possible alternative interpretations for purported cases of ka that metastasised [7]. richard reed, a noted dermatopathologist, at the time of this controversy about ka being scc, went as far as to say: “those of us who compliantly acquiesce to the authors’ dogmatic position will have relinquished both soul and conscience” [8]. while not all of the authors hold that extreme view, we do agree that over diagnosis is as culpable as under diagnosis [1]. although the presence of venous invasion would be consistent with an scc, in the view of the authors, this lesion still represents a ka. this is also consistent with the clinical history of a new and rapidly growing lesion, though sccs can also occur rapidly. dermatoscopically it is not possible to distinguish scc and ka with confidence [9]. dermatoscopic central keratin with blood spots, white structureless areas and branched serpentine vessels are consistent with both diagnoses. histopathologically the present tumour was classified as a ka on the basis of a squamoproliferative lesion with the characteristic pattern of keratinization, unique to ka [4]. the cells in a ka have a distinctive hue to their cytoplasm, which is paler than seen in a scc and this is best seen in the large central cells that may be up to double the size of peripheral cells. these central pale cells are also much larger than the cells of an scc [4]. venous invasion of keratinocytes was confirmed by immunoperoxidase as well as verhoeff-van gieson stains (figure 3). conclusion ka is a commonly encountered lesion on sun-damaged skin and it is characterised by benign behaviour without metastaverhoeff-van gieson stain (vvg), immunoperoxidase stains for desmin, and a stain for smooth muscle actin (figure 3). findings and treatment options were discussed with the patient, and the decision was made to perform a deep and wide surgical excision with an additional 5 mm clinical margin. discussion ka is variously regarded as a benign keratinising tumour and an scc variant characterised by benign (non-metastasising) behaviour. [1] although invasion of peripheral nerves has been reported [2,5] this has not been associated with an adverse prognosis. one of the authors (dw, data not shown) has now seen 122 cases of ka with perineural invasion without a single case of adverse outcome. venous invasion has been reported [3] and observed previously [6]. we suggest that ka is not a variant of scc on the following grounds [1]: figure 1. (a) a new raised lesion is present on the left forehead. (b) close-up imaging reveals central keratin surrounded by a white area, which merges into a pink area peripherally. there is also some surface scale. a b figure 2. dermatoscopy reveals a non-pigmented lesion with a central structureless orange area (consistent with keratin) surrounded by a large structureless white area merging into a structureless pink area at the periphery. there is a pattern of branched serpentine vessels visible over most of the surface area outside of the keratin. blood-spots are seen on the keratin. observation | dermatol pract concept 2012;2(4):3 11 a b c d e figure 3. histopathology of reported tumour. (a) overview h&e-stain. (b) close-up of venous invasion. (c) immunohistochemistry smooth muscle actin (sma). (d) immunohistochemistry desmin. (e) verhoeff-van gieson stain revealing elastic fibres within the venous wall. an alarming but benign phenomenon. am j dermatopathol. 1992;14(5):414-7. 4. weedon d. weedon’s skin pathology. 3rd ed. london, england: churchill livingstone, 2009:702-8. 5. janecka ip, wolff m, crikelair gf, cosman b. aggressive histological features of keratoacanthoma. j cutan pathol. 1977;4(6):342-8. 6. weedon dd, malo j, brooks d, williamson r. squamous cell carcinoma arising in keratoacanthoma: a neglected phenomenon in the elderly. am j dermatopathol. 2010;32(5):423-6. 7. hodak e, jones re, ackerman ab. solitary keratoacanthoma is a squamous-cell carcinoma: three examples with metastases. am j dermatopathol. 1993;15(4):332–42; discussion 343–52. 8. reed rj. response. am j dermatopathol. 1993;15(4):347-51. 9. rosendahl c, cameron a, argenziano g, zalaudek i, tschandl p, kittler h. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. in press 2012. sis and with ultimate complete regression expected. we have reported a case with venous invasion, a feature normally indicative of malignant behaviour and guarded prognosis. this case has been managed by wide surgical excision and scheduled follow-up. references 1. weedon d, malo j, brooks d, williamson r. keratoacanthoma: is it really a variant of squamous cell carcinoma? anz j surg. 2010;80(3):129-30. 2. godbolt am, sullivan jj, weedon d. keratoacanthoma with perineural invasion: a report of 40 cases. australas j dermatol. 2001;42(3):168-71. 3. calonje e, jones ew. intravascular spread of keratoacanthoma. dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(3):3 7 dermatology practical & conceptual www.derm101.com the patient a 65-year-old woman presented in our department with a threeyear history of a new, slowly growing asymptomatic lesion on her vulva. the physical examination revealed a 10 mm sized, an unusual lesion in the right place grigorios theodosiou1, valeria zafeiriadou2, marina papageorgiou3, ioanna mandekou-lefaki3 1 department of dermatology, skåne university hospital, malmö, sweden 2 first department of dermatology-venereology, aristotle university medical school, hospital for skin and venereal diseases, thessaloniki, greece 3 state clinic of dermatology, hospital for skin and venereal diseases, thessaloniki, greece citation: theodosiou g, zafeiriadou v, papageorgiou m, mandekou-lefaki i. an unusual lesion in the right place dermatol pract concept 2016;6(3):3. doi: 10.5826/dpc.0603a03 copyright: ©2016 theodosiou et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: grigorios theodosiou, md, department of dermatology, skåne university hospital, jan waldenströms gata 16, 20502 malmö, sweden. tel. + 0046 040-33 65 16. email: gregtheodosiou@yahoo.com. figure 1. a well-circumscribed, flesh-colored, domeshaped nodule on the left labia majora of the vulva. [copyright: ©2016 theodosiou et al.] figure 2. cystic tumor with papillary and glandular areas. [copyright: ©2016 theodosiou et al.] well-circumscribed white to skin-colored elevated firm nodule with a smooth surface on the left labia majora of her vulva (figure 1). there was no family history of similar lesions. the lesion was excised. histopathologic examination revealed a well-circumscribed tumor located in the dermis with no connection with the overlying epidermis. within the tumor a complex network with anastomosing papillary structures and tubules as well as glandular areas was observed. the epithelial lining consisted of an inner layer of monomorphic, columnar cells with eosinophilic cytoplasm and nipple-like projections on the surface surrounded by a layer of myoepithelial cells (figure 2). mailto:gregtheodosiou@yahoo.com 8 quiz | dermatol pract concept 2016;6(3):3 tory epithelium [17]. from its histopathologic similarities to intraductal papilloma of the breast, an accessory mammarylike gland has also been speculated as another candidate source [1,18,19]. the location of the anogenital hp is thought to mirror the distribution of anogenital mammary-like glands [1,18,19]. from this point of view, cases of ectopic hp involving the eyelid and the external auditory canal are viewed as examples of adenomas with papillary architecture arising in moll’s glands and ceruminous glands, respectively [9,20]. konstantinova et al have recently conducted a clinicopathological study of 264 tumors detailing various changes in the tumor and adjacent anogenital mammary-like glands (agmlg) with emphasis on mammary-type alterations. the study showed that the histopathological changes in hp run a broad spectrum comparable with that in the mammary counterpart and benign breast disease [21]. the presence of hpv dna in the lesion tissue has been identified in a few cases. however hpv does not appear to play a causative role to the pathogenesis of hp [16,22]. the differential diagnosis of hp includes apocrine hidrocystoma, bartholin gland cyst and syringocystadenoma papilliferum. malignant transformation is extremely rare. there are five documented cases of ductal carcinoma in situ (dcis) arising within a pre-existing hidradenoma papilliferum in the peerreviewed literature [23-25]. another two cases of invasive carcinomas arising from hp (malignant perianal papillary hidradenoma, vulvar adenosquamous carcinoma) have been reported [26,27]. the treatment of choice is total excision. recurrence is unusual and commonly attributed to incomplete excision of the primary tumor. in conclusion, we present a case of hp, which is a rare tumor of the anogenital region. diagnosis is based on histopathology due to the lack of specific clinical features. surgical excision is therefore required for definite diagnosis and cure. references 1. kazakov dv. site-specific adnexal neoplasms, mimics thereof and related conditions. in: kazakov dv, mckee p, michal m, kacerovska d. cutaneous adnexal tumors. philadelphia: lippincott williams and wilkins 2012: 463-9. 2. patterson j. sweat gland tumors. in: weedon d. weedon´s skin pathology. 4th ed. london: churchill livingstone elsevier, 2016; 947-8. 3. rutten a. adnexal tumors. in: braun-falco o. braun-falco’s dermatology. 3rd ed. berlin: springer-verlag, 2009:1378. 4. taylor rs, perone jb, kaddu s, kerl h. appendage tumors and hamartomas of the skin. in: wolff k, goldsmith l, katz s, et al. fitzpatrick’s dermatology in general medicine. 7th ed. new york: mcgraw hill, 2007:1071. what is your diagnosis? diagnosis hidradenoma papilliferum clinical course as hp is considered a benign appendageal tumor and was totally excised, no further diagnostic or therapeutic procedures were performed. answer and explanation hidradenoma papilliferum (hp) is a rare benign appendageal tumor occurring mainly in the anogenital region of adult women [1,2]. since werth first described hidradenoma papilliferum (hp) in 1878, numerous cases have been described, including more than 30 cases of ectopic localization [3]. the most common appearance is that of a solitary, asymptomatic, well-circumscribed, skin-colored or pinkish nodule or nodulocystic lesion measuring, in most cases, from 0.5—1 cm. larger lesions, measuring up to 10 cm, are rare. the tumor is slowly growing. however, rapid growth, possibly accelerated by trauma, has been occasionally described. rare symptoms include pain and drainage [1-4]. the tumor primarily affects almost exclusively the vulvar and anogenital region of middle-aged women [5]. the labia majora and labia minora are almost equally affected, together accounting for almost 90% of the cases. the rest involve the fourchette, clitoris, perianal area and perineum [1-5]. ectopic lesions developing on the eyelids, orbit, auditory canal, nose, breast, chest and abdomen have been reported [6-14]. cases in men have been described [12]. hp can only be diagnosed by histological examination, because the right diagnosis is almost never made clinically. hp is usually partly cystic and has both papillary and glandular areas. within the tumor, a complex network with anastomosing papillary and tubules as well as glandular structures is observed. the epithelial lining consists of an inner layer of secretory cells and an outer layer of myoepithelial cells. the inner layer consists of monomorphic, cuboidal or columnar cells with clear or eosinophilic cytoplasm demonstrating focal “decapitation secretion” [1-6]. in some cases, remnants of anogenital mammary-like glands may be seen adjacent to the hp [1]. the mitotic index is variable, but even high mitotic index does not predict a more aggressive behavior [15]. oxyphilic metaplasia, though rare, can lead to a misdiagnosis of malignancy [16]. the histogenesis of hp remains unclear. histopathologic and ultrastructural findings have demonstrated that the differentiation of hp is more closely related to apocrine secrequiz | dermatol pract concept 2016;6(3):3 9 17. hashimoto k. hidradenoma papilliferum: an electron microscopic study. acta derm venereol 1973; 53:22-30. pmid: 4120803. 18. van der putte sc. mammary-like glands of the vulva and their disorders. int j gynecol pathol 1994;13:150-60. pmid: 8005737. 19. nishie w, sawamura d, mayuzumi m, takahashi s, shimizu h. hidradenoma papilliferum with mixed histopathologic features of syringocystadenoma papilliferum and anogenital mammary-like glands. j cutan pathol 2004;31:561-4. pmid: 15268713. doi: 10.1111/j.0303-6987.2004.00176.x. 20. netland pa, townsend dj, albert dm, jakobiec fa. hidradenoma papilliferum of the upper eyelid arising from the apocrine gland of moll. ophthalmology 1990;97:1593-8. pmid: 1965020. doi: 10.1016/s0161-6420(90)32373-4. 21. konstantinova am, michal m, kacerovska d et al. hidradenoma papilliferum: a clinicopathological study of 264 tumors from 261 patients, with emphasis on mammary-type alterations. am j dermatopathol 2016. in press. 22. kazakov dv, nemcova j, mikyskova i, et al. human papillomavirus in lesions of anogenital mammary-like glands. int j gynecol pathol. 2007;26:475-80. pmid: 17885501. doi: 10.1097/ pgp.0b013e31803104af. 23. castro cy, deavers m. ductal carcinoma in-situ arising in mammary-like glands of the vulva. int j gynecol pathol 2001;20:27783. pmid: 11447997. 24. vazmitel m, spagnolo dv, nemcova j, michal m, kazakov dv. hidradenoma papilliferum with a ductal carcinoma in situ component: case report and review of the literature. am j dermatopathol 2008;30:392-4. pmid: 18645314. doi: 10.1097/ dad.0b013e31817c6a7d. 25. shah ss, adelson m, mazur mt. adenocarcinoma in situ arising in vulvar papillary hidradenoma: report of 2 cases. int j gynecol pathol 2008;27:453-6. pmid: 18580327. doi: 10.1097/ pgp.0b013e31815b8eee. 26. shenoy ymv. malignant perianal papillary hidradenoma. arch dermatol 1961;83:965-7. 27. bannatyne p, elliott p, russell p. vulvar adenosquamous carcinoma arising in a hidradenoma papilliferum, with rapidly fatal outcome: case report. gynecol oncol 1989;35:395–8. pmid: 2557272. 5. woodworth h, dockerty mb, wilson rb, et al. papillary hidradenoma of the vulva: a clinicopathologic study of 69 cases. am j obstet gynecol 1971;110:501-8. pmid: 4325819. doi: 10.1016/0002-9378(71)90691-0. 6. vang r, cohen pr. ectopic hidradenoma papilliferum: a case report and review of the literature. j am acad dermatol. 1999; 41:115-8. pmid: 10411423. doi: 10.1016/s0190-9622(99) 70418-4. 7. santa cruz dj, prioleau pg, smith me. hidradenoma papilliferum of the eyelid. arch dermatol 1981;117:55-6. pmid: 6257184. doi: 10.1001/archderm.1981.01650010061028. 8. katz se, collins ab, peters sb. hidradenoma papilliferum of the orbit. orbit. 2013;32:49-50. pmid: 23387456. doi: 10.3109/01676830.2012.739673. 9. nissim f, czemobilsky b, ostfeld e. hidradenoma papilliferum of the external auditory canal. j laryngol otol 1981;95:843-8. pmid: 6267150. 10. lee ej, shin mk, haw cr, et al. two cases of hidradenoma papilliferum of the nose. acta derm venereol. 2010;90:322-3. pmid: 20526565. doi: 10.2340/00015555-0845. 11. kim yj, lee jw, choi sj, et al. ectopic hidradenoma papilliferum of the breast: ultrasound finding. j breast cancer 2011;14:153-5. pmid: 21847412. doi: 10.4048/jbc.2011.14.2.153. 12. tanaka m, shimizu s. hidradenoma papilliferum occurring on the chest of a man. j am acad dermatol 2003;48:s20-1. pmid: 12582377. doi: 10.1067/mjd.2003.125. 13. morimura s, kadono t, sugaya m, et al. ectopic hidradenoma papilliferum on the abdomen. eur j dermatol. 2011;21:278-9. pmid: 21411413. doi: 10.1684/ejd.2010.1236. 14. abudu ek, umanah in, ekpo md, et al. a giant ectopic hidradenoma papilliferum in a niger delta region of nigeria. rare tumors 2011;3(4):e50. pmid: 22355505. doi: 10.4081/ rt.2011.e50. 15. sington j, chandrapala r, manek s, hollowood k. mitotic count is not predictive of clinical behavior in hidradenoma papilliferum of the vulva: a clinicopathologic study of 19 cases. am j dermatopathol 2006;28:322-6. 16. kazakov dv, mikyskova i, kutzner h, et al. hidradenoma papilliferum with oxyphilic metaplasia: a clinicopathological study of 18 cases, including detection of human papillomavirus. am j dermatopathol 2005; 27:102-10. pmid: 16871035. http://dx.doi.org/10.1016/0002-9378(71)90691-0 dermatology: practical and conceptual letter | dermatol pract concept 2019;9(4):22 325 dermatology practical & conceptual introduction some cutaneous manifestations can hide systemic symptoms of dermatomyositis (dm). the wong-type dermatomyositis (w-dm) should be considered in the differential diagnosis in children with overlapping symptoms of dm and pityriasis rubra pilaris (prp). this rare form of dm is reported in only 27 cases in the literature: 6 cases of pediatric age and only 3 with associated cutaneous features of prp (2 females aged 1 and 18 years and a 12-year-old boy) [1]. our patient was the fourth case of w-dm with associated cutaneous features of prp and the first under the age of 10 years. punch biopsy and knowledge of rare diseases improve the diagnostic ability and therapy. differential diagnosis includes lupus erythematosus, prp, and psoriasis. we wish to draw attention to an extremely rare condition in children and, through the clinical images, we highlight the peculiarity of this rare form of dm. case presentation a 7-year-old boy was hospitalized because of asthenia, bilateral palpebral edema, and rash. follicular and nonfollicular erythematous and hyperkeratotic papules were detected on his limbs, merging into red hyperkeratotic patches/plaques on the outer side of the legs (figure 1, a and b). purple plaques on the knees (figure 1c), erythematous desquamating patches on the elbows (figure 1d), and gottron papules (figure 2a) on metacarpophalangeal articulations were present. blood tests showed increasing muscle enzyme levels. elbow punch biopsy showed ortho/parakeratosis with perivascular lymphocytic infiltrate, necrotic keratinocytes, and vacuolar interface dermatitis; a dilated follicular infundibulum with keratotic plug was also found (figure 2, b and c) [1,2]. w-dm was diagnosed and an mri scan of his legs was compatible with dm. we decided to treat the patient with a combination of a high-dose short course of intravenous methylprednisolone at a dose of 30 mg/kg/day (maximum dose 1 g) for 3 wong-type dermatomyositis: an extremely rare disease in childhood mario diplomatico1, orsola ametrano2, maria elena errico3, angela mauro4, roberto rega5, rita sottile4 1 department of woman, child and of general and specialized surgery, university of campania, naples, italy 2 dermatology unit, aorn santobono-pausilipon, naples, italy 3 pathology unit, aorn santobono-pausilipon, naples, italy 4 rheumatology unit, aorn santobono-pausilipon, naples, italy 5 university of naples federico ii, italy key words: dermatomyositis, pediatric rheumatology, dermatology citation: diplomatico m, ametrano o, errico me, mauro a, rega r, sottile r. wong-type dermatomyositis: an extremely rare disease in childhood. dermatol pract concept. 2019;9(4):325-326. doi: https://doi.org/10.5826/dpc.0904a22 accepted: july 3, 2019; published: october 31, 2019 copyright: ©2019 diplomatico et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: mario diplomatico, department of woman, child and of general and specialized surgery, university of campania, via luigi de crecchio 2, 80138, napoli, italy. email: mario.diplomatico@gmail.com 326 letter | dermatol pract concept 2019;9(4):22 references 1. mutasim df, egesi a, spicknall ke. wong-type dermatomyositis: a mimic of many dermatoses. j cutan pathol. 2016;43(9):781-786. 2. umanoff n, fisher a, carlson ja. wong-type dermatomyositis showing porokeratosis-like changes (columnar dyskeratosis): a case report and review of the literature. dermatopathology (basel). 2015;2(1):1-8. 3. canavan t, sidorsky t, doan lt, et al. a case of wong-type dermatomyositis with concomitant anti-mda5 features. j am acad dermatol. 2014;70(3):e62-e64. consecutive days and methotrexate 15 mg/m2 (maximum 25 mg/dose once weekly, with associated folic acid 1 mg/day), obtaining a dramatic improvement in his clinical condition. conclusions w-dm should be considered in the differential diagnosis also in younger children with overlapping symptoms of dm and prp [3]. figure 1. (a,b) follicular and nonfollicular erythematous and hyperkeratotic papules merging into red hyperkeratotic patches/ plaques on the outer side of the legs. (c) purple plaques with hyperkeratotic papules on the knees. (d) erythematous desquamating patches on the elbows. [copyright: ©2019 diplomatico et al.] figure 2. (a) gottron papules. (b,c) ortho/parakeratosis with perivascular lymphocytic infiltrate, necrotic keratinocytes, and vacuolar interface dermatitis; there is also a dilated follicular infundibulum with keratotic plug. [copyright: ©2019 diplomatico et al.] dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;2(2):5 21 the patient a 48-year-old woman presented herself with an erythematous macule on the extensor surface of the right thigh. the lesion had been present for years, but recently the patient noticed some increase in size and changes in the coloration. this had prompted her to see a dermatologist (figure 1). a biopsy was taken and photomicrographs are presented in figures 2a-i. what is your diagnosis? answer and explanation hobnail lymphatic malformation (so-called hobnail hemangioma or targetoid hemosiderotic hemangioma) dilated and bizarre-shaped vessels are seen in the upper reticular dermis and extend into the papillary dermis. at the periphery of the lesion vessels are smaller in diameter and assume slit-like configurations between collagen bundles reminiscent of the macular stage of kaposi’s disease. at from the dermatologikum hamburg: quiz almut böer-auer, m.d.1 1 dermatologikum hamburg, hamburg, germany citation: böer-auer a. from the dermatologikum hamburg: quiz. dermatol pract conc. 2012;2(2):5. http://dx.doi.org/10.5826/ dpc.0202a05. copyright: ©2011 böer-auer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: almut böer-auer, m.d., dermatologikum hamburg, drehbahn 1-3, 20354 hamburg, germany. tel. +49. 40. 3510750. email: boer@dermatologikum.de. figure 1. clinical appearance. [copyright: ©2011 böer-auer.] mailto: 22 quiz | dermatol pract concept 2012;2(2):5 a b c figure 2a-i (left and above). histopathology. [copyright: ©2011 böer-auer.] d g e h f i higher magnification, the vessels are seen to be lined by a single layer of endothelial cells with plump nuclei. nuclei have a typical hobnail appearance in some vessels, whereas others show what has been described as a matchstick morphology. in some foci, papillary projections protrude into the lumen of a vessel. the lesion is covered by a broad zone of parakeratosis. numerous extravasated erythrocytes are present between collagen bundles. a sparse infiltrate of lymphocytes, histiocytes, and few plasma cells is also present. iron stain highlights numerous hemosiderophages (figure 3). in clinicopathological correlation, the findings seen in this patient are stereotypical of a fully developed lesion of so-called hobnail lymphatic malformation (hlm) (formerly called hobnail hemangioma or targetoid hemosiderotic hemangioma). the targetoid appearance seen clinically is explained by the hemorrhage and the hemosiderin deposits that form a halo around the angioma. hlm arises commonly on the extremities and trunk and lesions are usually less than 1 cm in diameter. the clinical presentation is not always as characteristic as seen here. studies on larger series of patients have shown that often lesions present as angiomatous macule or papule without any halo [1-3]. this variation has been interpreted as different stages in the process of evolution and devolution of the lesion, as result of hormonal influences, or as a result of previous trauma to a preexisting angioma. in the case shown here, the broad zone of parakeratosis indicates that the lesion has, in fact, been irritated from the outside. the clinical variation of the lesion is reflected in the number of different diseases that have been considered as clinical differential diagnoses of patients reported in the literature [1-3]. it includes such conditions as disparate as melanocytic lesions, infantile hemangioma, tufted angioma, kaposi sarcoma, insect bites, erythema multiforme, and dermatofibroma. not only clinically but also histopathologically hlm shows some variation. mentzel et al studied 62 cases and described a biphasic growth pattern of dilated vessels lined by hobnail endothelial cells in superficial parts of the lesion and collagen dissecting narrow vessels in deeper parts of the lesion. some lesions resembled cavernous lymphangioma or lymphangioma circumscriptum, others had features reminiscent of retiform hemangioendothelioma, progressive lymphangioma and so-called dabska’s tumor [3]. late lesions have been described as showing collapsed vascular lumina, fibrosis, and abundant hemosiderin [3]. quiz | dermatol pract concept 2012;2(2):5 23 it is important to note that hobnail endothelial cells are not unique to hobnail angioma but may also be seen in retiform hemangioendothelioma, progressive lymphangioma, and papillary intralymphatic angioendothelioma. but the most important differential diagnosis of hlm is the macular stage of kaposi’s disease. the promontorium sign, slit-like proliferations of capillaries, hemorrhage, hemosiderophages, and infiltrates containing plasma cells can be seen in both conditions [2-5]. however, intraluminal papillary projections and hobnail appearance of endothelial cells is usually not seen in kaposi’s disease and vessel proliferations of a macular stage of kaposi’s disease almost always spare the papillary dermis, whereas hobnail angioma typically involves the papillary dermis. moreover, lesions of kaposi’s disease are usually positive for human herpesvirus type 8. the condition presented here was first described in 1988 by santa cruz and aronberg. they recognized it as a distinctive entity and characterized it clinically and histopathologically [1]. they were impressed by the clinical appearance, which was targetoid in all of their cases and termed it “targetoid hemosiderotic hemangioma.” the term “hobnail hemangioma” was introduced in 1999 by guillou et al, who attempted to emphasize the histopathological hallmark of the condition, namely, endothelial cells shaped like hobnails and matchsticks [2]. hlm is conventionally classified as a benign vascular tumor, but it has been a matter of controversy whether it can be differentiated from blood vessels or lymphatics and whether it is a true neoplasm or a malformation. franke et al, in 2004, showed that endothelia of hobnail hemangiomas exhibit an antigenic profile similar to normal lymphatics, the majority of neoplastic vascular channels expressing cd31 but not cd34 and lacking pericytes [4]. moreover, the lymphatic endothelial cell marker d2-40 (podoplanin) was strongly positive in all lesions studied by them. therefore, they suggested that what had been called hobnail hemangifigure 3. iron staining. [copyright: ©2011 böer-auer.] oma really was a lymphangioma and that naming it “hemosiderotic angioma” or “hemosiderotic cutaneous lymphangioma“ would be more appropriate [4]. very recently, in january 2012, immunostaining with the endothelial marker wilms tumor 1 (wt1) has been investigated in larger series of the tumor and has illuminated the nature of it. wt1 is considered to be expressed by vascular neoplasms but not by malformations. trindade and coworkers studied 52 cases of hlm and none of them expressed wt1. in 10 of their cases, the authors also performed other stainings and found lesions to be positive with d2-40 and negative with ki-67 and human herpesvirus 8 latent nuclear antigen. the authors concluded that these results supported a lymphatic line of differentiation, but because of wt1 negativity it should be classified as a lymphatic malformation. they suggested the term “superficial hemosiderotic lymphatic malformation’’ for the condition [5]. at the same time, al dhaybi et al investigated 12 pediatric cases of hlm with almost the same set of immunohistochemical markers. they found d2-40 immunostaining to be positive in all cases, while wt1 was largely negative. the authors also concluded that hobnail hemangioma should be classified as lymphatic vascular malformation and proposed the name “targetoid hemosiderotic lymphatic malformation” [6]. in short, what has been described as hobnail hemangioma (or targetoid hemosiderotic hemangioma) has recently been shown to be a lymphatic malformation based on immunohistochemical staining characteristics. that is why, here, we replaced the former term hobnail hemangioma with the term hobnail lymphatic malformation. references 1. santa cruz dj, aronberg j. targetoid hemosiderotic hemangioma. j am acad dermatol. 1988;19(3):550-8. 2. guillou l, calonje e, speight p, rosai j, fletcher cd. hobnail hemangioma: a pseudomalignant vascular lesion with a reappraisal of targetoid hemosiderotic hemangioma. am j surg pathol. 1999;23(1):97-105. 3. mentzel t, partanen ta, kutzner h. hobnail hemangioma (“targetoid hemosiderotic hemangioma”): clinicopathologic and immunohistochemical analysis of 62 cases. j cutan pathol. 1999;26(6):279-86. 4. franke fe, steger k, marks a, kutzner h, mentzel t. hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. j cutan pathol. 2004;31(5):362-7. 5. trindade f, kutzner h, tellechea o, requena l, colmenero i. hobnail hemangioma reclassified as superficial lymphatic malformation: a study of 52 cases. j am acad dermatol. 2012;66(1):112-5. epub 2011 aug 6. 6. al dhaybi r, lam c, hatami a, powell j, mccuaig c, kokta v. targetoid hemosiderotic hemangiomas (hobnail hemangiomas) are vascular lymphatic malformations: a study of 12 pediatric cases. j am acad dermatol. 2012;66(1):116-20. epub 2011 jul 27. dermatology: practical and conceptual review | dermatol pract concept 2015;5(1):1 1 dermatology practical & conceptual www.derm101.com – m – macromelanosome: syn. for giant melanosome. macrophages: are phagocytic cells that have round, oval, or angular shapes and a nucleus that typically is pale blue, situated eccentrically, and shaped somewhat like a kidney. when viewed through a conventional microscope, the features of relatively inactive macrophages are similar to those of fibrocytes or endothelial cells. upon activation, however, a macrophage becomes larger, its nucleolus more prominent, and its cytoplasm filled with granules and vacuoles. by electron microscopy, macrophages are seen to contain phagosomes together with an assortment of secondary lysosomes replete with indigestible remains. macrophages are derived from cells in the bone marrow that differentiate into monocytes and that in the tissues become fully differentiated as macrophages. at that stage, they no longer are capable of dividing. macrophages are widely distributed in the body and are considered to be connective tissue cells because they derive from mesenchyme and represent a normal component of loose connective tissue. they constitute an essential component of other tissues and organs, especially the hematopoietic, liver, lung, and skin. macule: a small, flat, non-palpable spot on the skin, up to 1.0 cm in size (this is the size that historically has been used) and of a color different from that of the surrounding normal skin, i.e., depigmented lesion as in the residuum of a “halo nevus” or hyperpigmented as in a freckle or a lesion of melanoma in situ. a larger analogue of a macule is called a patch. a macule can result from pigmentary abnormalities, such as increased melanin in the epidermis, as in a freckle, or decreased melanin in the epidermis, as in confetti-sized lesions of vitiligo. pinpoint purple macules (petechiae) are caused by erythrocytes extravasated in the papillary dermis, and larger spots marked by hemorrhage can be produced by trauma as in “senile” purpura and in a “hickey.” reddish macules, such as those of viral exanthemas, result from erythrocytes that fill capillaries and venules, both of which are dilated widely. magnification: is the act of enlarging the size of something, particularly an optical image. in optics, it refers to the ratio of size of an image to size of an object. in histopathologic skin examinations, scanning, low, medium, and high magnification refer roughly to enlargements of 1.0-2.5, (scanning); 4x (low), 10x-20x (medium), 40x (high), “other powers” are rarely necessary. scanning magnification is requisite for using a method for diagnosis based on pattern analysis of inflammatory cells and the silhouette of neoplasms. in a broader sense the “first lowest” magnification is the clinical lesion which then progresses to the specimen grossly (little help in dermatopathology) and then to the microscope. malformation: denotes an abnormal structure that resulted from aberration in embryologic development, (i.e., in dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 7 (m-o) bruce j. hookerman1 1 dermatology specialists, bridgeton, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. part 7 (m-o). dermatol pract concept 2015;5(1):1. doi: 10.5826/dpc.0501a01 copyright: ©2015 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce j. hookerman, md, 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@aol.com mailto:bjhookerman@aol.com 2 review | dermatol pract concept 2015;5(1):1 the embryologic anlage) for example, an arteriovenous shunt. although, the term “malformation” is used as a synonym for hamartoma, the two are different. the latter is a potpourri of tissue elements normally present at a particular site, e.g. nevus sebaceous, where as a malformation, as it name denotes represents a fundamental error in embryologic development, e.g., nevus comedonicus. malignant: refers to a proliferation that has the capability to kill by either destruction locally or metastasis. the term should not be used to describe attributes cytopathologic, i.e., “malignant-looking cells,” or to characterize certain inflammatory diseases of the skin, such as malignant atrophic papulosis (degos’ disease), malignant syphilis, and malignant pyoderma. as stated above the term malignant should not be used as a synonym for abnormalities nuclear, no matter how riveting; no correlation necessary exists between “nuclear atypia” and behavior biologic, as is apparent in the process inflammatory known as “dermatofibroma with monster cells” and at times in the benign proliferation named “classic” spitz’s nevus. (see silhouette) mantle: refers to the cloak like appearance of cords of epithelial cells, as visualized in two-dimensional sections cut routinely from specimens in preparation for viewing by conventional microscopy, that emanate from both sides of follicles at the junction of infundibular epidermis and isthmus, and that hang like sleeveless outer garments along the sides of an inferior segment of a follicle for a short distance. in actuality, when viewed in three dimensions, mantles are like skirts; they encircle follicles. they are affiliated with both vellus and terminal follicles, but are much more striking in association with vellus ones. their raison d’être at puberty in response to the flow of androgens is to give rise to sebaceous units (i.e., glands and ducts). at first, mantles are composed of wholly undifferentiated epithelial cells that, in time, exhibit one or two cells with vacuolated cytoplasm, then vacuolated cells, then vacuolated cells whose nuclei are scalloped like those of mature sebocytes, and then what seems to be efflorescence, initially as blossoms of sebocytes and eventually as blooming forth of a bounty of flowers in the form of fully formed sebaceous lobules. at menopause and andropause, in response to marked decline in the flow of androgens, sebaceous glands and ducts wither slowly to once again become mantles. those undifferentiated structures, when injured as by the effects of mohs’ micrographic surgery, proliferate and show some signs of sebaceous differentiation, a condition known imprecisely as “folliculocentric basaloid proliferation.” this was thought originally to represent hyperplasia of bulge epithelium, but it is appreciated now to be hyperplasia of mantle epithelium. fibrofolliculoma is a hamartoma with differentiation towards mantles and trichodiscoma is the same hamartoma at a stage later when sebaceous lobules and ducts have become evident. margination of nucleoplasm: describes the appearance of nuclei in infections by herpes viruses that are characterized by accentuation of their rims and pallor of their centers. matrical cells: are situated in the bulb of follicles and histopathologically are seen to differentiate into epithelium with seven appearances singular, namely, the outer sheath, the three components of the inner sheath (henley, huxley, and cuticle), and the three components of hair (cuticle, cortex, and medulla). matrical cells of a follicle are different fundamentally from “follicular” germinative cells, the latter arising from surface ectoderm in an embryo and giving rise to an entire infundibular-apocrine-sebaceous-follicular unit, including matrical cells of a follicle. in contrast to matrical cells that are housed always in the bulb, germinative cells in life post natal are situated at the base of the isthmus of a follicle, where, at the end of telogen, they are responsible for reconstituting the stem and the bulb of a follicle in anagen, a process that has nothing to do with “bulge activation.” matrical cells differ cytologically from germinative cells by being larger, having a nucleus paler, displaying a nucleolus prominent, and being in mitosis often. abnormal matrical cells constitute the benign proliferations pilomatricoma and matricoma, and the malignant matrical carcinoma. matrix: is a term employed in three ways different as follows: (1) connective tissue that gives support to structures epithelial and is composed of ground substance, glycoproteins, and water; (2) a part of the follicular bulb whose cells differentiate into seven types of epithelia distinctive of the outer sheath, inner sheath, and the hair shaft; (3) the generative squamous epithelium of the nail unit located beneath and proximal to the lunula and that eventuates in formation of the nail plate. (see matrical cells) maturation: is a process of differentiation whereby cells evolve toward completion of their expected course biological and, in the process, exhibit distinctive changes morphologic. during maturation, cells lose capability for mitosis and, therefore, multiply no longer. their cytoplasm becomes filled with products of synthesis of protein in the case of keratin (the result being cells cornified) and of lipid in that of sebaceous secretion (the result being sebocytes formed fully), their nuclei become smaller progressively and more chromatic and, in some instances, e.g., corneocytes of the stratum corneum invariably, but sebocytes contiguous with sebaceous ducts episodically, nuclei disappear completely. these alterations physiological are accompanied by changes cytologic. for example, cornified cells of an epidermis represent maturation complete of epidermal basal cells, cornified cells of a hair review | dermatol pract concept 2015;5(1):1 3 shaft are signs of maturation complete of matrical cells in a follicular bulb, and mature sebocytes in the center of lobules signify maturation complete of immature sebaceous cells at the periphery of lobules. mature sebocyte: denotes a sebaceous cell typified by cytoplasm copious replete with vacuoles that house lipid and a nucleus scalloped as a consequence of pressure on it by an ever-increasing number of vacuoles. mature sebocytes represent development chronologic of immature sebocytes positioned at the periphery of a sebaceous lobule. in time, those cells generative move progressively toward the center of the lobule in order to come near a sebaceous duct into which their secretion holocrine will be poured, they en route becoming transformed from a cell with a round nucleus and hardly any cytoplasm to a cell with a scalloped nucleus and abundant vacuolated cytoplasm. medulla: is the innermost part of a terminal hair, but it is not present at all in a vellus hair. contiguous with a perforated medulla is the thicker solid cortex of a hair that, in turn, is surrounded by the thick cuticle of a hair. meirowsky pheonomenon: is a darkening of already existing epidermal melanin beginning within seconds and completed within minutes to a few hours after exposure to long-wave ultraviolet radiation. it was observed originally in cadavers, thereby excluding active synthesis of melanin as a cause of the pigmentation. melanin: a high-molecular weight biochrome that results from the oxidation of tyrosine by tyrosinase within melanosomes. there are two varieties: 1. eumelanin, a brownish-black melanin present in ellipsoidal melanosomes. 2. phaeomelanin, a brownish-yellow melanin present in spherical melanosomes. eumelanin and phaeomelanin initially have a common biosynthetic pathway; under appropriate physiologic conditions dopaquinone reacts with cysteine to produce intermediate metabolites that form phaeomelanin. phaeomelanin is found only in red or blond hair and feathers. melanocyte: a cell capable of synthesizing melanin and thought to be derived during development embryologic from a cell in the neural crest. in normal skin, melanocytes are disposed as solitary units positioned relatively equidistant from one another at the junction between dermis and epidermis (both surface and infundibular), in the bulb of hair follicles, and in the matrix of nails, melanocytes situated at the dermoepidermal junction are seen in sections prepared conventionally and stained by hematoxylin and eosin to possess a small dark nucleus and scant, often stellate shaped cytoplasm that is separated from keratocytes adjacent by a space, the latter finding being a consequence of shrinkage during processing of tissue and the reason that for nearly half a century melanocytes were referred to, erroneously, as “clear cells of masson.” melanocytes also are found in the normal eye (retina, choroid, and iris) and brain (arachnoid). melanocytic nevi and melanomas originate from abnormal melanocytes at the dermal epidermal junction. when a melanoma is found in conjunction with a nevus it develops from the same abnormal melanocytes at the dermal epidermal junction also (except in rare cases). melanocytic nevi do not “transform” into melanoma. melanocyte-keratocyte unit: a structural and functional unit that is made up of a melanocyte and an associated numerically relatively constant population of keratocytes, the number of which may vary in different body regions. the melanocyte and its associated keratocytes seem to function symbiotically, the melanocyte synthesizing melanosomes and transferring them to the keratocytes. this process is known as apocopation (the tip of the dendrite are snipped off and engulfed by the keratocytes. parenthetically, it is imprecise to say “epidermal melanin unit.” the unit really consists of keratocytes and the melanocyte supplying it. furthermore, melanocytes are cells that synthesize melanin, a substance that scatters and absorbs light and that thereby protects the skin from the damaging effects of ultraviolet light. melanocytes are found chiefly in the basal layer of the epidermis, but also at sites such as the iris and the retina of the eyes. the amount of melanin in the epidermis determines the degree of color of the normal skin. melanocytic nevus: a hamartoma (i.e., a congenital nevus, such as “giant hairy nevus”) or a benign neoplasm (e.g., an acquired nevus such as “classic” spitz’s nevus and reed’s nevus) made up of abnormal melanocytes, some of which are arranged in nests and/or fascicles, i.e., reed’s nevus, as well at times in columns, cords, and strands, and even as solitary units. in most kinds of nevi, melanocytes constituent have small, monomorphic nuclei. in “classic” spitz’s nevus, however, nuclei of melanocytes may be large and pleomorphic. melanocytic tumor of uncertain malignant potential (meltump): a phrase coined by david elder and used by him, his co-workers, and followers of them for diagnosis of a “category that is comprised of melanocytic proliferations that form tumors in the dermis, and are therefore potentially capable of metastasis.” for elder et al., “examples of such lesions may include “atypical” “classic” spitz’s nevi, deep penetrating nevi, possible nevoid melanomas, or cellular blue nevi, where because of increased mitotic activity or cytologic “atypia,” a diagnosis of invasive or tumorigenic melanoma cannot be ruled out.” because meltump is as unfathomable and as unuseful as sampus 4 review | dermatol pract concept 2015;5(1):1 (superficial atypical melanocytic proliferation of uncertain significance), another acronym spawned by elder et al., it is best discarded now before a foothold is gained by it in the lexicon of general pathology and of dermatopathology. melanogenesis: the biosynthesis of melanin and its deposition on the protein matrix of the melanosome. melanoma: a malignant proliferation of melanocytes. melanoma in-situ: a proliferation of abnormal melanocytes with atypical nuclei confined to the epidermis, surface and infundibular, and at times also to epithelial structures of adnexa (i.e., hair follicles, and sebaceous, apocrine, and eccrine units) that fulfills all of the criteria for melanoma in an epithelium. virtually all primary cutaneous melanomas begin in the epidermis, i.e., in situ. (see in-situ) melanoma of childhood: a synonym used by spitz for juvenile melanoma, which she asserted repeatedly was “applied only as an abbreviation for malignant melanoma.” it has been shown that sophie spitz was dealing with at least three different kinds of proliferations, not a single kind. one was a “classic” spitz’s nevus; the second was a combined congenital nevus with “spitz’s” cells and the third was what she termed a “spindle cell tumor.” (see juvenile melanoma) melanophage: a macrophage that has ingested melanin; an analogue of a lipophage and siderophage. melanophore: a type of melanocyte that participates with other chromatophores in the rapid color changes of animals by intracellular rearrangement (aggregation and dispersion) of melanosomes. melanophores are not present in human or other primates. melanosis: a term with several meanings. clinically, a “condition” of blackening; in this sense, the term has been applied in dermatology to melanosis of the genitalia (melanotic macule and patch), a wholly benign condition, and to what has formerly been called circumscribed precancerous melanosis, a melanoma in situ usually situated on sun-damaged skin of a face: histopathologically, a band like infiltrate of melanophages in a thickened papillary dermis of lesions of primary cutaneous melanoma that have undergone partial or complete regression. in ophthalmologic pathology, acquired melanosis is a euphemism for melanoma in situ of the conjunctiva. melanosis coli is a darkening of the colonic lamina propria secondary to the accumulation of pigment in macrophages, the exact nature of which is unknown but is thought to be related to the use of laxatives that contain anthracene. melanosome: an organelle within the cytoplasm of melanocytes that has the function of initiating the biosynthesis of melanin. melanosomes have a highly organized internal structure that may appear as either parallel strands or concentric lamellae depending upon the plane of their section. the lamellae have a regular pattern of dense particles with characteristic periodicity. eumelanosomes are ellipsoidal; phaeomelanosomes are spherical. they develop in stages as follows: stage i. the melanosome is a dopa-positive vesicle without recognizable internal structure. stage ii. the melanosome has developed its characteristic internal structure (vide supra). stage iii. some deposition of melanin appears on the lamellae. stage iv. the melanosome is so completely melanized that its internal structure is obliterated. melanosome complex (compound melanosome): an intracytoplasmic, membrane-limited vesicle that contains two or more melanosomes. these vesicles also contain lysosomal enzymes and are, presumably, secondary phagolysosomes. melanosome complexes have been found in keratocytes, melanocytes, langerhans cells, and melanophages. merocrine: designates a gland or a secretion produced by that gland in which cells responsible for producing it remain intact during the manufacture and release of the substance chemical, the eccrine gland being the only merocrine gland in the skin. mesenchyme: is embryonic connective tissue derived from mesoderm. mesenchyme, the source of all types of adult connective tissue, acts as packing between developing parenchymal structures. mesenchymal cells have numerous potentialities, i.e., they may differentiate along several lines to become various kinds of connective tissue cells such as fibrocytes, adipocytes, and chondrocytes. some multi-potential mesenchymal cells persist in adults and then, as a consequence of certain stimuli, differentiate into other types of cells, a process known as metaplasia. mesoderm: all constituents of human skin are derived from either ectoderm or mesoderm. the elements in skin, i.e., langerhans’ cells, macrophages, mast cells, fibrocytes, blood vessels, lymph vessels, muscles, and adipocytes originate from mesoderm. metaplasia: refers to conversion of one type of cell to another in response to a stimulus. there are epithelial metaplasias, such as squamous metaplasia of the bronchial epithelium secondary to the effects of smoking cigarettes, and connective tissue metaplasias, such as the appearance of cartilage in mixed tumors of the skin as a result of fibrocytes becoming chondrocytes. fibrocytes also are thought to be responsible for metaplastic formation of bone in pilomatricoma and of adipose tissue in various benign epithelial proliferations with adnexal differentiation. review | dermatol pract concept 2015;5(1):1 5 metastasis: literally, means “out of place.” metastasis is the spread of cells by blood vessels or lymph vessels (or across serosal surfaces) from a primary neoplasm to distant sites; often the cause of death. however, in the field of melanocytic proliferations of the skin some patients may live with their metastases as in metastatic melanoma of the skin. micaceous: bearing scales (particularly those of psoriasis) that peel off like sheets of mica. microabscess, microvesiculation, microcyst: these three terms are used for changes seen histopathologically, namely, a small collection of neutrophils within an epithelium or nonepithelium, a tiny vesicle caused by spongiosis, ballooning, or acantholysis, and a little cyst, usually an epidermal (infundibular) one, known also as a milium. each of the terms in this title is unnecessary, because, through a microscope, everything is “micro”; it suffices, therefore, to refer simply to abscess, vesicle, or cyst. minimual deviation melanoma: a term introduced, along with “borderline melanoma,” by richard j. reed that lacks meaning because no melanoma qualifies truly as “minimal deviation” (deviation from what?) or “borderline” (border between what?). minimal deviation melanoma,” like “borderline melanoma,” is an evasion from acknowledging one really does not know. it should be pointed out that the evasions in the realm of melanocytic proliferations have increased rapidly. this can be seen most easily by reading “pathology reports” of melanocytic proliferations by dermatopathologists in our country (or world for that matter). this is the reason that every dermatologist should know what their dermatopathologist is conveying by the “language” they use. they may be using a different “language” than you. you must understand what is being said so that you can properly treat the patient. on “the other side” hopefully, the pathologist will try to “know” the dermatologist or the other person who has removed the specimen. mitotic figures: is the appearance morphologic as visualized by microscopy conventional of chromosomes during mitosis. chromosomes are identified as thread-like or filamentous structures and mitosis consists of stages known as prophase, anaphase, metaphase, and telophase. mitotic figures are present in normal skin, especially in zones generative, i.e., the basal layer of the epidermis and the matrix of follicles and nail units. an increase in the number of mitotic figures is expected in some inflammations, e.g., psoriasis and in a lesion evolving as in pilomatricoma. abnormal mitotic figures, such as forms tripolar and ring, occur more commonly in malignant proliferations such as melanoma, but may be noted uncommonly in such proliferations benign as “classic” spitz’s nevus, other melanocytic nevi and poromas for instance. mixed infiltrate of inflammatory cells: an infiltrate composed of different types of inflammatory cells, i.e., not only lymphocytes but also neutrophils, eosinophils, or plasma cells. monomorphous infiltrate: an infiltrate composed of only one type of cell, i.e., mast cells in urticaria pigmentosa or abnormal lymphocytes in some lymphomas. mucin: is an acid mucosubstance that consists mostly of hyaluronic acid. in the skin, mucin is of two kinds, epithelial and connective tissue. epithelial mucin is hardly detectable in normal skin, but connective tissue mucin is copious in follicular papillae, especially of terminal follicles in anagen, and around eccrine glands and proximal ducts. in states pathologic, so called follicular mucinosis, better termed “epithelial mucinosis” because it affects infundibular epidermis and sebaceous glands more often than it does follicles, is the stereotype for epithelial mucin and focal mucinosis for connective tissue mucin. mucopolysaccharides: are high molecular-weight compounds that, on hydrolysis, yield mixtures of monosaccharides and products derived from them. there are two general classes of mucopolysaccharides, neutral and acid. the neutral ones contain a n-acetylhexosamine and some neutral groups; acid mucopolysaccharides contain a n-acetylhexosamine and an acid moiety, usually an uronic acid. in more precise biochemical terms, most mucopolysaccharides are proteoglycans, i.e., molecules that consist of proteins to which chains of oligosaccharides or polysaccharides are attached covalently. each polysaccharide consists of repeating disaccharide units in which d-glucosamine or d-galactosamine always is present. each disaccharide unit contains an uronic acid, glucuronic acid, or l-iduronic acid. common examples of proteoglycans are chondroitin sulfate (a prominent component of cartilage), keratin sulfate (abundant in the cornea), heparin (plentiful in mast cells), heparan sulfate, and dermatan sulfate. the most common acid mucopolysaccharide in normal skin is hyaluronic acid. mucosubstance: is a generic term that refers to a group of proteins conjugated with carbohydrates. the main types of mucosubstances are mucopolysaccharides, mucoproteins, and mucoids. in biochemical terms, most mucosubstances belong to the group of glycoproteins (i.e., most mucous secretions) or proteoglycans (i.e., chondroitin sulfate, hyaluronic acid, keratin sulfate, and heparan sulfate). munro’s microabscess: a discrete collection of neutrophils within mid spinous zone of psoriasis are termed “microabcesses.” (see pustule for clarification of this word.) myoepithelial cells: surround glandular secretory cells and have features of both epithelial and smooth muscle 6 review | dermatol pract concept 2015;5(1):1 cells. they lie just above the basal lamina and, by conventional microscopy, are slender, with small, dark nuclei and scant cytoplasm. by electron microscopy, myoepithelial cells are seen to possess bundles of tonofilaments, desmosomes, and well-developed basal lamina, focal linear densities associated with basal lamina, occasional pinocytotic vesicles, and microfilaments. myoepithelial cells have distinctive immunocytochemical characteristics such as a high content of alkaline phosphatase, and presence of smooth muscle actin and s-100 protein. these cells serve to cause peristaltic contractions of glands, particularly apocrine ones, and thereby to force secretions from glands into ducts. myotropism: an attraction to muscle, especially ones smooth of hair erection, as in the case sometimes for melanocytes in desmoplastic melanoma, in superficial and “deep” congenital nevi, and, at times, in “classic” spitz’s nevi. the usage of this term might be better replaced by intramuscular: present within the muscles and perimuscular: present around the muscles. (see neutrotropism for similar discussion.) myxoid: denotes resemblance to mucin and appears as basophilic granular, stringy, and feathery material in sections stained by hematoxylin and eosin and viewed by conventional microscopy. even though the terms myxoid and mucoid often are used synonymously, in histopathologic jargon mucoid refers to a substance produced by or related to epithelia, whereas myxoid indicates a similar-appearing substance produced by or related to connective tissue cells. (i.e., fibrocytes). this distinction may be justified in view of the different composition of mucosubstances produced by epithelial and connective tissue cells. – n – necrobiosis: in times past, palisaded granulomas were termed “necrobiotic granulomas.” the meaning of the word “necrobiosis” is opaque because it is an oxymoron, implying as it does a condition (-osis) of life (-bio) and death (necro-) together. dermatopathologists of yore used the term to describe the death of tissue simultaneous with replacement of it by what they considered to be viable tissue. we eschew the term “necrobiosis” because it is so imprecise and thereby impedes communication. moreover, it is completely unnecessary. the findings that characterize the palisaded granulomas are distinctive, namely, a pattern exemplified by epithelioid histiocytes aligned in the manner of stakes around a central focus, usually one of altered connective tissue. when that focus is mucin mostly, the inflammatory process is granuloma annulare; when it is fibrin overwhelmingly, the diagnosis is rheumatoid nodule; when it consists of bundles of degenerated collagen, the diagnosis is necrobiosis lipoidica; and when it is degenerated collagen along with deposits of lipid in conjunction with cholesterol clefts, the diagnosis is necrobiotic xanthogranuloma. how the changes in the locus in the center of the palisade of histiocytes come to occur is not known, but vasculitis of a small vessel may initiate it, and lysosomal enzymes released by histiocytes may sustain it. it is easy to conceive of the macrophages coming to be aligned in a palisade subsequent to mini-infarctions that cause alteration of connective tissue focally, the granulomatous inflammation being an attempt to contain the effects of the injury. in some instances of granuloma annulare, histiocytes in addition to being arranged in a palisade in foci in the dermis are distributed interstitially, in strands, cords, or columns in other foci, i.e., between bundles of collagen. necrosis: refers to changes morphologic that occurs after death of cells or of tissues as evidenced by three crucial signs nuclear: pyknosis, karyorrhexis, and karyolysis. because necrosis pertains only to cells that once were living, the term cannot be applied properly to collagen bundles or to elastic fibers; alteration injurious of those tissues is designated “degeneration.” neither is the term necrosis applied to cells that have cornified by either a mechanism physiological (i.e., corneocytes of a normal stratum corneum) or pathologic (i.e., corneocytes in a squamous cell carcinoma). the causes responsible most often for necrosis in the skin and other organs are supply insufficient of blood (i.e., infarction), trauma (i.e., excoriation), and infection (i.e., by pseudomonas aeruginosa in ecthyma gangrenosum). in the teaching classic of general pathology, several different types of necrosis have been recognized, among them being caseous, colliquative, liquefactive, mixed, septic, and aseptic. that classification of necrosis is neither illuminating nor useful, and, therefore, is not employed in this work. apoptosis, in our judgment, simply is one type of necrosis because it fulfills criteria nuclear for necrosis, namely, pyknosis and karyorrhexis. necrosis en masse: refers to morphologic changes that result from death of a large number of neoplastic cells. it tends to be demarcated sharply from adjacent, seemingly viable cells. one supposed mechanism for this type of necrosis is ischemia, the vascular supply being insufficient to maintain the viability of all of the neoplastic cells. necrosis en masse usually is present in proliferations that are malignant, but some benign neoplasms, i.e., the poromas (hidroacanthoma simplex, poroma, dermal duct tumor, and poroid hidradenoma) are often associated with necrosis en masse, and many examples of malignant neoplasms are devoid of any sign of necrosis en masse. as a rule, no infiltrate of inflammatory cells is seen either within or around zones of necrosis en masse. (see necrosis) necrosis of individual cells: in contrast to necrosis en masse, designates morphologic changes that result review | dermatol pract concept 2015;5(1):1 7 from death of discrete cells arranged as solitary units. these changes are pyknosis, karyorrhexis, or karyolysis. the cytoplasm of the necrotic cells tends to be brightly eosinophilic. in general, necrosis of individual cells is a consequence of direct effects on them such as those of lymphocytes on the epidermis of erythema multiforme or graft-versus-host reaction, neutrophils and eosinophils on the epidermis of fixed drug eruption, or of ultraviolet light on the epidermis in sunburn or in phototoxic dermatitides. a dyskeratotic cell is a slowly dying cell with a pyknotic nucleus and eosinophilic cytoplasm that cannot be differentiated from a rapidly dying cell on the basis of cytologic findings alone. this differentiation requires visualization of the cornified layer to see if it is normal (as is the case when keratocytes have died rapidly) or parakeratotic (when they are dying more slowly). necrotizing vasculitis: is a synonym for leukocytoclastic vasculitis. it is a misleading term because endothelial cells of affected venules are not necrotic. for that reason, the term should be eschewed. neoplasm: refers to a proliferation of cells whose growth both exceeds and is uncoordinated with that of normal tissues, and which persists in the same excessive manner thereafter. a neoplasm (i.e., a seborrheic keratosis) differs from a hyperplasia (i.e., a verruca vulgaris) because a hyperplasia regresses after the stimulus that evoked it (papillomavirus in this example) has been withdrawn. neoplasms may be benign (i.e., they neither kill by local destruction nor by metastasis, for example, a trichoblastoma) or malignant (i.e., they have the capability to kill by destruction locally or by metastases, for example, matrical carcinoma). each of the definitions of neoplasm, hyperplasia, benign, and malignant are flawed, as is true for all definitions that attempt to capture biological phenomena. for example, nearly all keratoacanthomas of the solitary type regress without any treatment, yet that proliferation is a squamous-cell carcinoma, not a hyperplasia. furthermore, classic definitions of benign and malignant do not yet permit ready categorization of diseases like kaposi’s sarcoma and histiocytosis x. because no satisfactory definition of neoplasm has been yet set forth, including the one just given, the term “proliferation” may better serve. the kind of proliferation can be stated (i.e., benign, malignant, epithelial, and non-epithelial), then based on the type(s) of cells or signs of differentiation a specific diagnosis may be achieved. in this work sometimes “proliferation” is used and sometimes the more traditional word is used, e.g. neoplasm, hyperplasia, hamartoma, malformation, etc. neoplasm of indeterminate malignant potential (nimp): a phrase introduced by w.h. clark, jr., as a diagnosis for those neoplasms of melanocytes that he could not classify as being benign (a nevus) or malignant (a melanoma). but those five words do not convey anything of meaning to a clinician except that the histopathologist is unable to make a diagnosis with specificity, i.e., “classic” spitz’s nevus or “spitzoid melanoma.“ that being the case, it would be better by far for the histopathologist to acknowledge his/her inability to come to a diagnosis with specificity, rather than to imply that the neoplasm itself is indeterminate, i.e., uncertain about its own potential for malignancy; (the proliferation is certain but the pathologist is not.) in short, nimp (neoplasm of indeterminate malignant potential) is as great an impediment to diagnosis with precision and to comprehension with profundity in the sphere of melanocytic neoplasia as are meltump (melanocytic tumor of uncertain malignant potential) and sampus (superficial atypical melanocytic proliferation of uncertain significance and others). nest: a roundish collection of cells, either epithelial, as in syringoma, or non-epithelial, as in a nevus or a melanoma. nest of melanocytes: a circumscribed roundish aggregation of melanocytes. neurodermatitis: a term meant to describe changes in the skin that were thought to be related in some way to “nerves,” either organically or psychologically. two types of neurodermatitis have been described, namely, circumscribed (lichen simplex chronicus) and disseminated (atopic dermatitis). there is little agreement among dermatologists about what, in actuality, constitutes neurodermatitis clinically, histopathologically, pathogenically, or etiologically. therefore, the term should not be used at all. instead, a diagnosis with specificity should be issued, one that identifies exactly the results of scratching, such as erosions and ulcerations, and of prolonged rubbing, such as lichen simplex chronicus. all the lesions that make up the disease known as atopic dermatitis result from scratching wildly and rubbing hard skin that is exquisitely itchy. neurotropism: a biological phenomenon that indicates growth or turning movement of a cell or a collection of cells toward a nerve. in a strictly morphologic sense, it is not definable. adj. neurotropic. the following terms are suggested: (1) intraneural—present within any part of a nerve (epineurium, perineurium, or endoneurium) and (2) perineural: situated around a nerve, outside the epineurium. strictly speaking, the suffix tropism implies movement, the best example being the turning or bending phenomenon plants suffer in response to light as the environment stimulus, called phototropism. literally, neurotropism means a “turning towards a nerve or having an affinity for a nerve.” neurotropism and neurotropic are almost universally defined as “having an affinity to nerves or neural tissue” that implying a specific biologic behavior. rarely, definitions include morphologic findings and, in those few instances, they define neurotropism as “localizing selec8 review | dermatol pract concept 2015;5(1):1 tively in nerve.” never, however, is neurotropism defined as “localizing selectively around nerves.” the terms neurotropism and neurotropic are employed inconsistently in a variety of different circumstances. in the setting of viral infections and intoxication, neurotropism is used to refer to viruses or drugs that selectively affect neural tissue. when it comes to neoplastic diseases, some authors consider neurotropic to be synonymous with neuroinvasive, i.e., tumor cells being present within nerves, others use the same term to designate cancer cells around the nerves but not within them. by some authors, neurotropism is applied to tumor cells within either perineurium or intraneurium, and the others apply the term neurotropism only when the medial perineurium is involved. last, “neurotropism” is used as the tendency for cut nerve ends to join others to restore the lost function. these are only some examples of the variety of meanings the literature offers. with the exceptions of viruses like varicella-zoster, toxins like tetanus toxin, and the regenerative processes of nerves after injury, most usages of neurotropism and neurotropic in the literature of dermatopathology refer to malignant neoplasms that grow either along or within nerves. when cells are seen to be disposed around or within nerves and the disease are thought to be benign, as it typically occurs in leprosy that pattern is usually not called neurotropic, but referred to as perineural. it seems that dermatopathologists use the word neurotropism only after they have come to the conclusion that a lesion is a malignant neoplasm, as expecting a certain behavior of cells. in fact, in some cases the finding of “neurotropism” is used to define a specific subtype of tumor such as in squamous cell carcinoma and “neurotropic” melanoma that morphologic feature then implying a certain biologic behavior. interestingly, and more correctly, the term “neurotropic” is almost never applied to microcystic adnexal carcinoma, which typically grows along nerves so that often proliferations of the neoplasm are found around and occasionally within the nerves. in that setting, the term “perineural invasion” is used instead by most authors even though the appearance morphologically is the same as with squamous cell carcinoma and melanoma that grow along and within nerves. in actuality, the suffix tropism designates a movement, but a movement cannot be seen in the static tissues of a slide. pathologists should limit themselves to describing the changes and their location with regard to normal structures, and should avoid interpretations in regard to “movement” and “behavior.” in sum, definitions and usages of neurotropism and neurotropic refer to neurotropism as a physiologic or pathophysiologic process on one hand and as a variety of morphologic findings on the other. for that reason, the words neurotropism and neurotropic are best avoided in description of microscopic findings in sections of tissue. the terms perineural and intraneural are purely descriptive and therefore more accurate. neural differentiation: the morphologic development within the proliferation of structures that simulate nerves. some nests of nevus cells in intra-dermal components of melanocytic nevi may undergo morphologic changes during maturation that result in structures (viz. lame foliates) that resemble fascicles of nerves. this type of morphogenesis occurs less commonly in melanomas and blue nevi than in melanocytic nevi. nevoid: resembling a nevus; a term that we eschew because it lacks specificity, i.e., the kind of nevus, i.e., epidermal, connective tissue, melanocytic, etc., is not stipulated. nevoid melanoma: a term meant to designate a particular type of melanoma, i.e., one that mimics a nevus histopathologically. in fact, there is no agreed on “nevoid melanoma,” any more than there is consensus about what constitutes “borderline melanoma and “minimal deviation melanoma”; all are melanomas and should be diagnosed, unmodified, as what they are. every melanoma misdiagnosed histopathologically is nevoid, and there are many thousands of those in the united states every year, which would be absurd, were it not so serious. evasions like “borderline,” “minimal deviation,” and “nevoid” profit neither histopathologists nor patients and, that being so, should be abandoned. nevus: in dermatology, when unmodified, pertaining to a birthmark, a hamartoma that may be composed of melanocytes, e.g., giant hairy congenital nevus, nevus spilus, and agminated spitz’s nevus, of keratocytes, e.g., verrucous epidermal nevus, ichthyosis hystrix, and segmental porokeratosis, of connective tissue elements mostly, e.g., collagenous nevus, elastic tissue nevus, and nevus lipomatosus, or of a mix of epithelial and non-epithelial elements, e.g., trichofolliculoma, fibrous papule of the face, and fibrofolliculoma/ trichodiscoma. it is applied also to a proliferation of melanocytes that becomes manifest long after birth, e.g., an acquired nevus, e.g., clark’s nevus, “classic” spitz’s nevus, and reed’s nevus. the word “nevus” should not be used unmodified. nevus cell (nevocyte): a misnomer; a so-called nevus cell, nevocyte, or nevomelanocyte is a melanocyte of a melanocytic nevus. melanocytes of nevi of all kinds differ cytopathologically from melanocytes found at the dermoepidermal junction of normal skin by virtue of their larger nucleus and their cytoplasm that does not retract during processing with formation of a cleft, their tendency to lack dendrites prominent, to aggregate (in nests and/or fascicles), and, often, to review | dermatol pract concept 2015;5(1):1 9 possess no melanin discernible. despite all the differences, they are melanocytes nonetheless, albeit abnormal ones; prior to “maturation,” they are capable of synthesizing melanin, which certifies them as melanocytes. the use of the terms nevus cell, nevocyte, and nevomelanocyte are eschewed. melanocytes should be described for what they are. nodule: clinically, a dome-shaped solid lesion between 1.0 cm and 2.0 cm in diameter formed by cells, deposits, or elements of connective tissue and, histopathologically, a dense, discrete collection of inflammatory cells (i.e., lymphocytes in lymphocytoma cutis), neoplastic cells (i.e., abnormal melanocytes in melanomas), deposits (i.e., urates in gouty tophi), or elements of connective tissue (i.e., collagen in neurofibroma) in the skin, in the subcutaneous fat, or in both of them together. nodules may evolve from macules through papules in melanoma, mycosis fungoides, and kaposi’s sarcoma (which is not a sarcoma, but a true hyperplasia, in the original sense of the word, of endothelial cells), and they themselves may eventuate in tumors that sometimes ulcerate. sarcoidal and tuberculoid granulomas, lymphoid follicles, cutaneous lymphoid hyperplasia, and metastases to skin are but three other examples of nodules that are visualizable histopathologically. non-epithelial structures of adnexa: in the skin, smooth muscles of hair erection, nerves, and blood vessels. nuclear ‘dust’: results from karyorrhexis, which is synonymous with leukocytoclasis, i.e., a sign of necrosis, along with pyknosis and karyolysis. the dust like particles consists of fragments of leukocytic nuclei, usually those of polymorphs. there also may be lymphocytic “nuclear dust.” (i.e., lupus erythematous). nucleoplasm: refers to the protoplasm of the nucleus of a cell. – o – oblique sections: not at right angles to a specified or implied line. often, dermatopathologists speak of “tangential sections” of tissue to describe grossing which deviates from the perpendicular. the more correct word is “oblique.” organoid: means resembling an organ and is used to describe certain hamartomas, malformations, and neoplasms whose components simulate the general structure of an organ. trichofolliculoma and nevus sebaceous are hamartomas known as organoid nevi because each consists of individual components that resemble those in normal skin, but that are arrayed haphazardly. teratomas, such as dermoids, some neuromas, and melanocytic nevi with neurotization, exhibit features that qualify them as organoid. this term is rarely used now because each proliferation can be named for what it is. orthokeratosis: hyperkeratosis in which nuclei are absent from cornified cells. (see hyperkeratosis) outer sheath or outer root sheath: of a follicle is the distinctive outermost epithelial layer that extends from the base of a bulb to the base of the infundibulum. at the base of a bulb it is exceedingly thin, consisting of a single layer of cells, and until the level of the b-fringe (below the adamson’s fringe) it is only two cells wide. above the b-fringe, the outer sheath is multilayered. the outer sheath can be divided into three parts, at the bulb, the stem, and the isthmus. cells of the outer sheath at the bulb possess abundant pale or clear cytoplasm that, beyond adamson’s fringe, becomes less clear and more pink. a prominent basement membrane, known also as a glassy membrane, is present along the entire length of the outer sheath. the lower two parts of the outer sheath (i.e., at the bulb and the stem) retract and disappear during the catagen phase of a follicular cycle. the isthmus is unaffected by the follicular cycle. for many years, speculation has abounded concerning the origin of cells responsible for formation of a new follicle at the end of telogen. it long was an article of faith that matrical cells were primordial in that regard. during the last decade of the 20th century, the “bulge-activation hypothesis” gained acceptance, the supposition being that the bulge of the follicle, which serves as a site for attachment of a muscle of hair erection, serves also as a reservoir for stem cells that, at the outset of anagen, give rise to a new inferior segment of a follicle. our studies of sections of tissue of normal follicles, cut in both vertical and horizontal directions, have led us to a different conclusion. for one the bulge is very different structurally from that pictured and described by proponents of the “bulge-activation hypothesis,” i.e., it is not a single knobby protuberance that emanated from a discrete locus on one side of a follicle, but rather numerous finger-like projections that emerge along more than half the circumference of it. for another, bulges are irrelevant to the follicular cycle; the cells that become germinative, form a follicular germ, and soon transform into matrical cells en route to producing a new lower segment in anagen. they derive from cells left behind at the base of the isthmus at the end of catagen, those cells lying dormant throughout telogen, only to be reawakened by a call from mesenchymal cells that reside immediately below and that come together to form a new follicular papilla. each of the bulges is attached to a fascicle of smooth muscle whose sole purpose is to enable hairs to become erect. oval melanocyte: a cell that is longer than it is wide, but does not have tapering ends like those of a spindle cell. oval melanocytes may be large or small. large oval cells are sometimes found in melanomas and in “classic” spitz’s nevi. small oval cells are seen in melanocytic nevi. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com practical, conceptual, educational notes | dermatol pract concept 2014;4(1):14 83 case report a 27-year-old woman presented to a dermatology practice in williamstown, massachusetts with a pigmented skin lesion on her left anterior shoulder. she was originally seen four months earlier, and as the lesion was noted to be “somewhat atypical,” she had been given a follow-up appointment to be reviewed in six months. she made the decision to present earlier because “the lesion had changed in color.” on examination a 4-5 mm diameter tan papule with an irregularity of pigment was observed and the notation was made in the patient’s notes that “ . . . clinically this does not look very worrisome but the change is concerning . . .” and for that reason excision biopsy was performed. the preferred algorithmic method of the treating dermatologist (dje) is a novel method known as ‘blinck’ [1]. this method combines both clinical and dermatoscopic clues to guide the decision to biopsy. the fact that the lesion was glowing in the dark: case report of a clue-poor melanoma unmasked by polarized dermatoscopy yoon k. cohen1, david j. elpern1, deon wolpowitz2, cliff rosendahl3 1 the skin clinic, williamstown, massachusetts, usa 2 department of dermatology and section of dermatopathology, boston university school of medicine, boston, massachusetts, usa 3 school of medicine, university of queensland, brisbane, australia keywords: melanoma, nevus, congenital-type nevus, polarized dermoscopy, polarized dermatoscopy, dermatopathology, polarizing-specific white lines, chrysalis, blinck algorithm, chaos and clues algorithm citation: cohen yk, elpern dj, wolpowitz d, rosendahl c. glowing in the dark: case report of a clue-poor melanoma unmasked by polarized dermatoscopy. dermatol pract concept. 2014;4(1):14. http://dx.doi.org/10.5826/dpc.0401a14 received: september 15, 2013; accepted: october 9, 2013; published: january 31, 2014 copyright: ©2014 cohen et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, mbbs, ph.d., po box 734, capalaba, qld 4157, australia. tel. +61 7 3245 3011; fax. +61 7 3245 3022. email: cliffrosendahl@bigpond.com we report a case of a melanoma arising in a congenital-type compound nevus, which was excised because it was observed by both the patient and the treating dermatologist to have changed. because the lesion was routinely photo-documented with both polarized and non-polarized dermatoscopy images prior to excision, these images were available for subsequent examination. matched images are presented in what appears to be unique in the published literature: polarizing-specific white lines are identified as a compelling clue to the diagnosis of melanoma in a lesion that contains no clues apparent in the non-polarized image. dermatopathology images reveal that the melanoma is arising in conjunction with a congenital type nevus. as expected, dermatoscopic polarizing-specific white lines are evident on the melanoma but not the nevus, and while a possible explanation is discussed, this remains speculative. abstract mailto:cliffrosendahl@bigpond.com 84 practical, conceptual, educational notes | dermatol pract concept 2014;4(1):14 were taken routinely as part of the clinical record of a lesion scheduled for excision biopsy to exclude melanoma, and this was done in spite of a low level of suspicion, which was based on the history of change rather than on the clinician’s assessment of the dermatoscopic appearance. “lonely” (the only one of its kind in that location) and that the patient was “nervous” gave a score of two and that score leads to excision biopsy according to ‘blinck’. prior to excision biopsy, dermatoscopic images were obtained in both polarizing and non-polarizing mode (figures 1-3) with a canfield dermscope (canfield scientific inc. usa) coupled to an iphone (apple inc. usa). the images figure 1. non-polarized dermatoscopic image of a lesion on the anterior left shoulder of a 27-year-old woman. there is a pattern of apparently exophytic brown clods centrally, surrounded by a zone of structureless brown with a pattern of small brown clods peripherally. there are some eccentric foci of darker brown pigment on the right side of and to the right of the larger clods. [copyright: ©2014 cohen et al.] figure 2. polarized dermatoscopic image of the same lesion as displayed in figure 1. in this image a millimeter scale reveals that the dimensions of the dark brown lesion are 5 x 4 mm. white lines that are clearly whiter than the patient’s skin color are present over the center of the lesion and demarcate the clods seen with non-polarizing dermatoscopy (figure 1). a pattern of small brown clods surrounds the lesion in some parts, extending to the borders of the image. hairs are seen on the lesion peripheral to, but not over, the pattern of white lines. [copyright: ©2014 cohen et al.] figure 3. a couplet of (a) non-polarizing dermatoscopy and (b) polarizing dermatoscopy of the lesion displayed in figures 1 and 2 revealing the correlation between the polarizing-specific white lines in b and the large brown clods in a. the smaller brown clods surrounding the lesion are not separated by white lines, but by skin-colored lines. hairs are seen in image b, but they are not present on the central part of the lesion where the polarizing-specific white lines are seen. [copyright: ©2014 cohen et al.] practical, conceptual, educational notes | dermatol pract concept 2014;4(1):14 85 fascia, and a sentinel lymph node biopsy was performed, which was negative. conclusions dermatoscopy relies on either fluid immersion or cross-polarization to reduce light scatter at the air-skin interface, and it is known that these different methods have an impact on the colors and structures which are displayed [2]. non-polarized dermatoscopy has been said to provide superior rendition of dermatopathologically (figures 4-7) this lesion displayed both architectural and cytological criteria consistent with melanoma arising in conjunction with a compound melanocytic nevus with congenital nevus features, and benign nevus cells were reported as being present in the dermis at a deeper level than the deepest observed melanoma cell. the breslow thickness was 1.01 mm and the mitotic rate was reported as 1 per square millimeter. the lesion was re-excised with one a centimeter peripheral clearance margin, deep to but not including muscle figure 4. low power hematoxylin and eosin image (40x) of the central exophytic portion of the lesion shown on figures 1-3. a neoplastic proliferation of melanocytes is present in the epidermis as single cells and discohesive nests with clefting and in the dermis predominantly as nests. the boxed area is shown at higher power in figure 5. scale bar, 100 µm. [copyright: ©2014 cohen et al.] figure 5. hematoxylin and eosin image (100x) of the boxed area in figure 4 showing severely atypical and epithelioid melanocytes distributed both in the epidermis as markedly discohesive and irregular junctional nests, as a near confluent proliferation of single cells along the dermoepidermal junction lining a hair follicle, and in the subjacent papillary dermis (black arrows). fibrotic bands of collagen, many orientated vertically, are seen separating nests of neoplastic melanocytes. scale bar, 100 µm. [copyright: ©2014 cohen et al.] figure 6. hematoxylin and eosin image (40x) of part of the lesion shown in figures 1-3 adjacent to the area shown in figure 4. in addition to a neoplastic epidermal proliferation of melanocytes (boxed area upper left) there is a broad junctional and deep dermal melanocytic proliferation present with congenital nevus architecture. arrowheads point to the dermal component. the boxed area is shown at higher power in figure 7. scale bar, 100 µm. [copyright: ©2014 cohen et al.] figure 7. hematoxylin and eosin image (200x) of the boxed area in figure 6. irregular junctional nests (black arrows) comprised of severely atypical epithelioid melanocytes overlie dermal nests of banal and nevic appearing melanocytes (asterisks). scale bar, 100 µm. [copyright: ©2014 cohen et al.] 86 practical, conceptual, educational notes | dermatol pract concept 2014;4(1):14 here is the so-called “cobblestone” pattern (pattern of clods) described as the pattern of a congenital type nevus and this lesion had none of the specific criteria of melanoma according to that method. likewise this lesion did not score as a melanoma according to the abcd dermatoscopic algorithm [9], the 3-point checklist [10], the 7-point checklist [11], the menzies method [12] or the cash algorithm [13]. the “chaos & clues” algorithm [14,15] identifies suspicion for malignancy based on the presence of chaos (defined as asymmetry of structure and/or color) plus the presence of at least one of eight clues, including the clue of “white lines,” and therefore that method would identify this lesion as suspicious but only if polarized dermatoscopy was employed. pswl, which were the critical diagnostic feature in this case, have been attributed to the presence of collagen in the context of dermal fibrosis, which has birefringent properties causing rapid randomization of polarized light thus making the collagen more conspicuous [5]. dermatopathologic collagen bands are in fact evident in this case (figures 4 and 5). in attempting to explain the presence of pswl in melanoma but not nevi, it has been proposed that basic fibroblast growth factor (bfgf), maximally expressed at the advancing front of the neoplasm adjacent to fibrotic changes in the dermis may be associated with tightly woven collagen bundles encircling microinvasive melanoma nests [5] and that these structures may correlate with pswl. in melanomas, melanocyte-induced de novo collagen 1 type synthesis can be identified with sirius red staining [5], which has not been demonstrated in nevi [16]. while these factors may play a role in the differential presence of pswl in melanoma, but not in the associated nevus, the actual dermatopathological correlation remains speculative. this case illustrates the critical role that polarized dermatoscopy can play and argues strongly for its inclusion in the clinical routine. we also suggest that the observation of polarizing-specific white lines should lead to consideration of excision biopsy in any lesion when either nevus or melanoma is in the differential diagnosis. if polarizing-specific white lines are subtle, they may be best appreciated by comparing the polarized and non-polarized view. for this reason we suggest that both polarizing and non-polarizing modes of dermatoscopy should be employed routinely, this practice being facilitated by dermatoscopes that can be conveniently switched between modes. references 1. bourne p, rosendahl c, keir j, cameron a. blinck—a diagnostic algorithm for skin cancer diagnosis combining clinical features with dermatoscopy findings. dermatol pract conc. 2012;2(2):12. 2. benvenuto-andrade c, dusza sw, agero alc, et al. differences between polarized light dermoscopy and immersion contact dermoscopy for the evaluation of skin lesions. arch dermatol. 2007;143(3):329–38. superficial structures while polarized dermatoscopy reveals a clearer rendition of deeper structures as well as of structures not seen with non-polarized dermatoscopy, including four-dot clods (also known as rosettes) and polarizing-specific white lines (also known as chrysalis, crystalline structures and shiny white streaks) [3]. the most widely utilized and publicized method for recognizing melanomas based on their clinical appearance is the abcd method [4]. this method relies on the lesion exhibiting asymmetry, an irregular border, color irregularity and a minimum diameter of 6 mm. no clinical image was taken of the lesion reported here, but the dermatoscopy images reveal that it had asymmetry of color with two shades of brown, a regular border and dimensions of 5 x 4 mm, and therefore it would not have met the criteria for melanoma on the basis of the abcd clinical algorithm. the non-polarized dermatoscopic image of the lesion reported here (figures 1 and 3a) shows a pattern of brown clods centrally surrounded by a zone of structureless brown, and further peripherally there is a pattern of small brown clods. there is some minor irregularity of pigment distribution, evident as several eccentric foci of dark brown color over the lighter brown clods. the polarized image (figures 2 and 3b) shows the same basic pattern as the non-polarized image, but in addition there is a pattern of white lines, whiter than surrounding skin color, and predominantly oriented in a perpendicular arrangement. because these white lines are not present in the non-polarized dermatoscopy image, they can be described with certainty as dermatoscopic polarizing-specific white lines (pswl). in the polarized images hairs are visible peripherally but they are absent over the central area where the polarizing-specific white lines are present (figures 2 and 3b). pswl are a published clue to melanoma, spitz nevus, basal cell carcinoma, dermatofibroma, scar tissue and benign lichenoid keratosis [5]. although there is a large list of differential diagnoses for lesions with this clue, it is notable that if this clue is seen in a melanocytic lesion that is not a spitz nevus, then the diagnosis of melanoma can be expected. it is also known that polarizing specific white lines are more frequently seen in melanomas, which are invasive [5]. the likelihood of spitz nevus decreases with increasing age [6], and some authors recommend the excision of all spitz nevi at any age due the fact that the distinction from melanoma can be challenging dermatopathologically [7]. in the largest study evaluating pswl, of the non-biopsied lesions, none of 9750 clark nevi, 90 congenital melanocytic nevi (cmn), 168 intradermal nevi (idn) and 15 blue nevi displayed this structure, while of the biopsied lesions one of 20 clark nevi, two of 10 idn and none of one cmn displayed pswl [5]. according to the original dermatoscopic method of classic pattern analysis [8], the global pattern of the lesion presented practical, conceptual, educational notes | dermatol pract concept 2014;4(1):14 87 11. argenziano g, fabbrocini g, carli p, et al. epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. comparison of the abcd rule of dermatoscopy and a new 7-point checklist based on pattern analysis. arch dermatol. 1998;134(12):1563–70. 12. menzies sw, ingvar c, crotty ka, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):1178–82. 13. henning js, dusza sw, wang sq, et al. the cash (color, architecture, symmetry, and homogeneity) algorithm for dermoscopy. j am acad dermatol. 2007;56(1):45–52. 14. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068–73. 15. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—“chaos and clues.” aust fam physician. 2012;41(7):482–7. 16. van kempen lclt, rijntjes j, mamor-cornelissen i, et al. type i collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma. int j cancer. 2008;122(5):1019–29. 3. pan y, gareau ds, scope a, et al. polarized and nonpolarized dermoscopy: the explanation for the observed differences. arch dermatol. 2008;144(6):828–9. 4. friedman rj, rigel ds, kopf aw. early detection of malignant melanoma: the role of physician examination and self-examination of the skin. ca cancer j clin. 1985;35(3):130–51. 5. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol. 2012;67(2):194.e1–8. 6. vollmer rt. patient age in spitz nevus and malignant melanoma: implication of bayes rule for differential diagnosis. am j clin pathol. 2004;121(6):872–7. 7. weedon d. weedon’s skin pathology, 3rd edition. edinburgh: churchill livingstone, elsevier, 2010:4. 8. pehamberger h, steiner a, wolff k. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol. 1987;17(4):571–83. 9. nachbar f, stolz w, merkle t, et al. the abcd rule of dermatoscopy. high prospective value in the diagnosis of doubtful melanocytic skin lesions. j am acad dermatol. 1994;30(4):551–9. 10. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679–93. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021024 1 dermatology practical & conceptual little patients, big issues: something about rapidly growing nodular spitzoid lesions in childhood ilenia marafioti1, maria lentini1, carmelo romeo2, serafinella p. cannavò1, mario vaccaro1 1 department of clinical and experimental medicine, dermatology, university of messina, italy 2 department of human pathology of adult and childhood gaetano barresi, university of messina, italy key words: spitz nevus, spitzoid neoplasms, children, dermoscopy, surgery citation: marafioti i, lentini m, romeo c, cannavò sp, vaccaro m. little patients, big issues: something about rapidly growing nodular spitzoid lesions in childhood. dermatol pract concept. 2021;11(2):e2021024. doi: https://doi.org/10.5826/dpc.1102a24 accepted: september 14, 2020; published: march 8, 2021 copyright: ©2021 marafioti et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: mario vaccaro, md, phd, department of clinical and experimental medicine, dermatology, university of messina, via c. valeria, gazzi, 98125 messina, italy. email: mario.vaccaro@unime.it introduction management of melanocytic lesions during childhood is often difficult. this is due to the rarity of melanoma during the first years of life and to rapid growth of lesions in younger patients regardless of their benign or malignant nature. spitzoid lesions are very common in dermatological practice. this group of neoplasms includes spitz nevi and spitzoid melanomas. between these extremes there are atypical spitz tumors of uncertain histological definition and malignant potential. diagnosis is often controversial since they show clinical and biological variability, and no specific guidelines are available. case presentation a 3-year-old healthy girl, with a family history positive for melanoma, presented with a roundish, unevenly pigmented, symptomless papule of recent onset on the lateral surface of her left leg (figure 1a). dermoscopy showed a central hypopigmented area with dotted vessels surrounded by inverse network associated with regularly distributed peripheral globules (figure 1b). clinical diagnosis was spitz nevus, and the patient was scheduled for follow-up. after 3 months, the lesion appeared nodular, asymmetrically enlarged and intensely pigmented (figure 1c). dermoscopy showed striking dermoscopic changes, namely, pseudopods with irregular distribution (peripheral and central), asymmetrically distributed globules of different size and color, and blue-white veil (figure 1d). despite the patient’s age, we had to remove the lesion. histopathology revealed epidermal hyperplasia, lengthening of epidermal ridges, transepidermal elimination of moderately pigmented epithelioid melanocytic nests, and a lot of melanophages in the papillary dermis (figure 2, a and b). a diagnosis of spitz nevus without cytological atypia was made. letter | dermatol pract concept 2021;11(2):e2021024 figure 1. (a, b) clinical and dermoscopic features of spitz nevus at the beginning and (c, d) after 3 months: (a) a 6 × 6 mm roundish, unevenly brownish papule; (b) a central hypopigmented area with dotted vessels surrounded by inverse network associated with regularly distributed peripheral globules; (c) an 8 × 7 mm asymmetrical papule characterized by brown to dark intense pigmentation; and (d) a central blue-white veil and peripheral hyperpigmented network with pseudopods. figure 2. histopathological examination revealed epidermal hyperplasia, lengthening of epidermal ridges, transepidermal elimination of moderately pigmented epithelioid melanocytic nests, and a lot of melanophages in the papillary dermis (h&e, original magnification [a] ×4 and [b] ×20x). letter | dermatol pract concept 2021;11(2):e2021024 3 conclusions spitz/reed nevi are acquired benign melanocytic lesions. they are mostly found on the face and lower limbs of children and young women [1]. they can be flat or nodular, hyperor hypopigmented, and characterized by several dermoscopic patterns such as the starburst pattern (51%), regularly distributed dotted vessels (19%), and globular with reticular depigmentation (17%). multicomponent, homogeneous, and reticular patterns can also be observed [2]. histopathological examination may show epithelioid melanocytes (in childhood), spindle cells (in adolescence and adulthood), or both. spitz nevus is characterized by rapid growth, and sometimes both clinical history and dermoscopy may suggest spitzoid melanoma. from the data in literature we know that, though rare, pediatric melanoma has to be considered. according to stefanaki et al. pediatric melanoma represents 1%-4% of all melanomas and 1%-3% of all pediatric malignancies, being the most frequent skin tumor in children. they distinguished 3 melanoma age groups, namely, neonatal (extremely rare), prepubescent children, and adolescents (having the same risk factors than adults). they also emphasized the importance of family history in children of all ages, because familial cases represent 5%-10% of melanomas [3]. our excision could be considered an overtreatment, but this is very common in everyday dermatological practice. there are no standardized criteria or specific guidelines for management of spitzoid lesions, and their behavior can be tricky and unpredictable. in 2017, the international dermoscopy society proposed management guidelines in order to reduce unnecessary excisions without increasing the risk of underestimating misleading lesions. on the basis of the scheme, asymmetric spitzoid tumors should always be excised, symmetrical nodular lesions should be excised or scheduled for close follow-up, while symmetrical flat lesions can be monitored until stabilization on the basis of patient’s age [2]. according to this algorithm, excision was unavoidable in our case. nevertheless, dermoscopy is extremely important to select lesions that can be followed over time, such as our nevus at its onset. reports and in depth analysis of ambiguous lesions like this are essential to improve diagnostic accuracy and reduce surgery to bare minimum, especially when a little courage from dermatologists is required. references 1. dika e, ravaioli gm, fanti pa, neri i, patrizi a. spitz nevi and other spitzoid neoplasms in children: overview of incidence data and diagnostic criteria. pediatr dermatol. 2017;34(1):25-32. doi: 10.1111/pde.13025. pmid: 27874206. 2. lallas a, apalla z, ioannides d,, et al. update on dermoscopy of spitz/reed naevi and management guidelines by the international dermoscopy society. br j dermatol. 2017;177(3):645-655. doi: 10.1111/bjd.15339. pmid: 28118479. 3. stefanaki c, chardalias l, soura e, katsarou a, stratigos a. paediatric melanoma. j eur acad dermatol venereol. 2017;31(10):16041615. doi: 10.1111/jdv.14299. pmid: 28449284. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):20 89 dermatology practical & conceptual www.derm101.com introduction cutis marmorata telangiectatica congenita (cmtc) was first described by a dutch pediatrician, von lohuizen, in 1922, in the netherlands, and since in his description of cmtc, less than 250 cases had been reported. cmtc is not very commonly reported disorder and is sporadic in nature. it is a congenital vascular anomaly characterized by persistent cutis marmorata, telangiectasia, phlebectasia, and sometimes, cutaneous atrophy and skin ulceration is present. a variety of associated defects have been described in up to 50% of cases [1]. it is usually a benign congenital skin lesion that is present at birth but may develop later on in life. case report a 20-year-old unmarried female presented with persistent reticulated purplish erythematous to hyperpigmented lesions mainly over both breasts since childhood. the patient also had ulcerations and atrophy over both breasts where a reticulated pattern and dilated veins were prominent (figures 1 and 2). there was no abnormality in limbs, asymmetry of the cutis marmorata telangiectatica congenita restricted to both breasts in a young female snehal balvant lunge1, pradeep mahajan2 1 department of dermatology, jawaharlal nehru medical college, belgaum, india 2 bhingare laboratories, pune, india keywords: cutis marmorata, breast, ulceration, von lohuizen citation: cutis marmorata telangiectatica congenital restricted to both breasts in a young female. dermatol pract concept. 2014;4(3):20. http://dx.doi.org/10.5826/dpc.0403a20 received: april 1, 2014; accepted: may 17, 2014; published: july 31, 2014 copyright: ©2014 lunge et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. snehal balvant lunge, department of dermatology, jawaharlal nehru medical college, belgaum, india. email: drsnehallunge@gmail.com cutis marmorata telangiectatica congenita (cmtc) is a very rarely occurring congenital disorder with persistent cutis marmorata, telangiectasia, and phlebectasia. this disorder may be associated with cutaneous atrophy and ulceration of the involved skin. we herewith report a 20-year-old female patient with cmtc since childhood along with ulcerations on both breasts. cmtc is a benign vascular anomaly presenting with dilatation of capillaries and veins of dermis and is apparent at birth. the patient had reticulated bluish-purple skin changes over both breasts. although it resembled physiological cutis marmorata, it was more pronounced and definitely was unvarying and permanent in pattern. a variety of vascular malformations have been described along with this disorder. etiology is not very clear; it may be multifactorial in origin. prognosis in uncomplicated cases is good. abstract 90 observation | dermatol pract concept 2014;4(3):20 in 1970 petrozzi et al. [2] reported the first case of cmtc in united states. the frequency of this disorder is not known. in most cases reported, patients have associated malformations, hypoplasia of the limbs [3], or hyperplasia of the limbs. the condition closely resembles cutis marmorata, a relatively common disorder. the benign reticular mottling of the skin seen in small children due to physiologic dilatation of capillaries and small venules in response to cold environment is the most significant difference that exists between the congenital cutis marmorata (cmtc) and physiologic cutis marmorata, a clue that can help to distinguish between these lesions. although physiological cutis marmorata disappears with local warming, the congenital condition (cmtc) will persist despite increases in ambient temperature [4]. in our case cmtc was diagnosed on a clinical basis initially because skin lesions did not disappear with local warming [5]. the pattern of the lesions in cutis marmorata telangiectatica congenita may include prominent veins, telangiectasias, cutaneous atrophy, ulceration and hyperkeratosis of affected skin. the presence of cutaneous atrophy or skin ulceration could be useful in distinguishing between the congenital and physiologic types. cutaneous atrophy and skin ulceration body, other vascular anomalies, neurological complications, ocular changes, or syndactyly. general examination and systemic examination was within normal limits. similar, but less pronounced, types of skin lesions were present in the patient’s father and aunt, mainly over the extremities. we considered the differential diagnoses of cutis marmorata telangiectatica congenita, physiological cutis marmorata, erythema ab agne, livedoid vasculitis, connective tissue disorders, and antiphospholipid syndrome. complete blood count and all routine investigations were normal. antiphospholipid antibody and ana tests were negative. skin biopsy from the affected area showed classic dilated capillaries and veins in the dermis (figure 3). similar dilated capillaries and veins were seen in the subcutaneous tissue along with proliferation of vascular channels (figure 4). the clinical and histopathological findings led to a final diagnosis of cutis marmorata telangiectatica congenita. discussion cmtc is a very rarely reported congenital cutaneous disorder and is usually present at birth but may also appear up to two years after birth. however, since the first description of cmtc in 1922 by von lohuizen, less than 250 cases worldwide have been published to date. figure  1. reticulate erythema over both breasts with ulceration and atrophy. [copyright: ©2014 lunge et al.] figure  2. right side of breast showing reticulate erythema with atrophy. [copyright: ©2014 lunge et al.] figure 3. dilatations of veins and capillaries in dermis. [copyright: ©2014 lunge et al.] figure 4. proliferation of vascular channels in subcutaneous tissue. [copyright: ©2014 lunge et al.] observation | dermatol pract concept 2014;4(3):20 91 evaluations, including ophthalmological examination, were normal. she had no asymmetry of the limbs or limb growth abnormality. the incidence of abnormalities associated with cmtc varies from 18.8 to 89% [8,9]. the association of macrocephaly with cmtc is a subgroup of distinct disorders and it may be associated with overgrowth syndrome [10]. rare reports include atypical cmtc with retinoblastoma [11]. interestingly, cmtc associated with meningioma or leukemia has also been reported and is very rarely associated with mental retardation, aplasia cutis congenita, multicystic renal disease, glaucoma, and mongolian spot [12]. a review of the literature reveals existing controversies regarding gender-related prevalence of cmtc. several series reveal that the disorder affects girls more than boys, however, statistical evaluation showed no significant difference between both. a report also suggests that boys tend to have localized disease. our case was a young female patient with localized reticulated lesions on both breasts, uncommon and hitherto unreported. the differential diagnosis includes capillary malformations [13], ktw syndrome, neonatal lupus erythematosus, nevus anemicus, physiological cutis marmorata, livedo reticularis associated with collagen vascular disorders, antiphospholipid antibody syndrome, nevus flammeus, and diffuse phlebectasia. the disorder was diagnosed clinically and histopathologically. in the dermis, dilatation of capillaries and venules with a proliferation of vascular channels is an atypical histopathological finding [14]. the imaging studies were indicated only for the evaluation of any suspected congenital anomalies associated with cmtc. the disorder is self-limiting and treatment is not necessary unless complicated with other associated anomalies, such as glaucoma, multicystic kidney disease, asymmetry of limbs, and cardiac malformations. different approaches of treatment for cmtc include cold avoidance, vasodilators, aspirin, pentoxifylline, puva, and ipl [15]. in some cases consultations with orthopedics, neurosurgery, ophthalmology, and vascular cosmetic surgery may be necessary. conclusion our female patient had unique findings with restricted cmtc over both breasts, which is very uncommon. references 1. way bh, herrmann j, gilbert ef, johnson sa, opitz jm. cutis marmorata telangiectatica congenita. j cutan pathol. 1974;1:10– 25. are common features of cutis marmorata telangiectatica congenita, but they are not present with physiological cutis marmorata [4]. in addition, the presence of sharp demarcation of localized lesions favors a diagnosis of the congenital type over physiological cutis marmorata, which appears more mottled and has ill-defined borders of skin lesions. our patient had prominent veins, telangiectasias, cutaneous atrophy and ulceration along with reticulate erythema, favoring a diagnosis of cmtc. diagnostic criteria for cmtc helped to clearly distinguish cmtc from other vascular anomalies. a case series published in the literature by kienast and hoeger in 2009 [5] suggested the diagnostic criteria for cmtc that includes (1) three major criteria: congenital reticulate (marmorated) erythema, absence of venectasia, and unresponsiveness to local warming); and (2) two of the five minor criteria: fading of erythema within two years, telangiectasia, port-wine stain outside the area affected by cmtc, ulceration, and atrophy. these criteria are sufficient for the diagnosis of cmtc. reticular erythema present at birth is a common finding in all reported cases, so it has been considered major criteria for cmtc. physiological cutis marmorata occurs in otherwise healthy people in a cold environment; cmtc does not respond to local warming. the absence of venectasia in the affected region of skin is a very important finding and differentiates cmtc from klippel–trenaunay–weber (ktw) syndrome. the presence of telangiectasia and ulcerations found in a few cases can be classified as minor criteria, but if present, strongly favor a diagnosis of cmtc [5]. our patient meets two major criteria (congenital reticulate erythema, unresponsiveness to local warming) and three minor criteria (telangiectasia, ulceration, atrophy) and, therefore, we believe that it is a crystal clear case of cmtc. the pathogenesis of these disorders is not very clear and the cause may be multifactorial in origin. most cases occur sporadically, although very rare cases have suggested a possible genetic link [4]. our case favors familial origin because the patient’s father and aunt had similar lesions, though less pronounced, that were situated over both extremities. teratogens [6] and autosomal dominant mode of inheritance with incomplete penetrance have been considered as etiologies. some authors suggest that the lethal gene hypothesis might explain the patchy distribution of the skin lesion that occurs sporadically in cases of cmtc. this case reports on a 20-year-old female, who had persistent cutis marmorata, telangiectasia, and phlebectasia with ulcerations over both breasts where the reticulated pattern and dilated veins are seen. vascular anomalies, for example, sturge-weber syndrome [7], klippel–trenaunay–weber syndrome have been associated with cmtc. the female patient reported in this article had a normal facies with no other vascular abnormality elsewhere in body, and systemic 92 observation | dermatol pract concept 2014;4(3):20 10. moore ca, toriello hv, abuelo dn, et al. macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. am j med genet. 1997;70:67–73. 11. schwartz iv, felix tm, riegel m, schüler-faccini l. atypical macrocephaly-cutis marmorata telangiectatica congenita with retinoblastoma. clin dysmorphol. 2002;11:199�202. 12. torrelo a, zambrano a, happle r. large aberrant mongolian spots coexisting with cutis marmorata telangiectatica congenita (phacomatosis pigmentovascularis type v or phacomatosis cesiomarmorata) j eur acad dermatol venereol. 2006;20:308–10. 13. cohen pr, zalar gl. cmtc: clinicopathological characteristics and differential diagnosis. cutis. 1998;42:418. 14. fujita m, darmstadt gl, dinulos jg. cutis marmorata telangiectatica congenita with hemangiomatous histopathologic features. j am acad dermatol. 2003;48:950–4. 15. srinivas cr, kumaresan m. lasers for vascular lesions: standard guidelines for care. ijdvl. 2011;77(3):349-68. 2. petrozzi jw, rahn ek, mofenson h, greensher j. cutis marmorata telangiectatica congenita. arch dermatol. 1970;101:74–7. 3. avci s, calikoglu e, sayli u. cutis marmorata telangiectatica congenita: an unusual cause of lower extremity hypoplasia. turk j pediatr. 2001;43:159–61. 4. garzon mc, schweiger e. cutis marmorata telangiectatica congenita. semin cutan med surg. 2004;23:99–106. 5. kienast ak, hoeger ph. cutis marmorata telangiectatica congenita: a prospective study of 27 cases and review of the literature with proposal of diagnostic criteria. clin exp dermatol. 2009;34:319–23. 6. bhargava p, kuldeep cm, mathur nk. cutis marmorata telangiectatica congenita with multiple congenital anomalies: further clues for a teratogenic cause. dermatology. 1998;196:368–70. 7. powell st, su wp. cutis marmorata telangiectatica congenita: report of nine case and review of literature. cutis. 1984;34:305. 8. picascia dd, esterly nb. cutis marmorata telangiectatica congenita: report of 22 cases. j am acad dermatol. 1989;20:1098–1104. 9. south da, jacobs ah. cutis marmorata telangiectatica congenita (congenital generalized phlebectasia). j pediatr. 1978;93:944–9. dermatology: practical and conceptual research | dermatol pract concept 2020;10(3):e2020071 1 dermatology practical & conceptual diagnostic concordance in tertiary (dermatologists-to-experts) teledermoscopy: a final diagnosis-based study on 290 cases anne marchetti,1 stephane dalle,1,4,5,6 delphine maucort-boulch,2,3,4,5 mona amini-adl,1 sébastien debarbieux,1 nicolas poulalhon,1 marie perier-muzet,1 alice phan,1 luc thomas1,4,5,6 1 service de dermatologie, centre hospitalier lyon sud, france 2 service de biostatistique-bioinformatique, pôle santé publique, hospices civils de lyon, france 3 laboratoire de biométrie et biologie évolutive, équipe biostatistique-santé, villeurbanne, france 4 université de lyon, lyon, france 5 université claude bernard, lyon, france 6 centre de recherche en cancérologie de lyon, france key words: teledermoscopy, tertiary teledermatology, nail, pediatric, dermoscopy citation: marchetti a, dalle s, maucort-boulch d, amini-adl m, debarbieux s, poulalhon n, perier-muzet m, phan a, thomas l. diagnostic concordance in tertiary (dermatologists-to-experts) teledermoscopy: a final diagnosis-based study on 290 cases. dermatol pract concept. 2020;10(3):e2020071. doi: https://doi.org/10.5826/dpc.1003a71 accepted: april 14, 2020; published: june 29, 2020 copyright: ©2020 marchetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this work is supported in part by grants from lyon 1 university and the hospices civils de lyon. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication in acquisition of data and critical revision of the manuscript and important intellectual input. a.m., s.d., and l.t. are responsible for study concept and design. a.m. and l.t. are responsible for the analysis and interpretation of data and drafting of the manuscript. statistical analysis was performed by d.m.b. corresponding author: prof. luc thomas, department of dermatology, centre hospitalier lyon sud, 69495 pierre bénite, france. email: luc.thomas@chu-lyon.fr background: teledermoscopy (tds) improves diagnostic accuracy and decreases the number of unnecessary consultations. objectives: to determine the diagnostic concordance in tertiary (dermatologist-to-experts) tds with histopathology/follow-up–based diagnosis. methods: a descriptive retrospective cohort study including 290 requests. results: perfect diagnostic concordance was found in 202 (69.7%) cases and partial agreement in 29 (10%). disagreement was found in 59 (20.3%) cases. perfect concordance on the benign/malignant nature of the lesion was found in 227 (78.3%) cases and disagreement in 63 (21.7%). in onychology, diagnostic concordance was perfect in 43 (76.8%) cases, partial in 7 (12.5%), and there was disagreement in 6 (10.7%). final concordance on the benign/malignant nature of the lesion was perfect in 48 (85.7%) and there was disagreement in 8 (14.3%) nail cases. for pediatric requests, diagnostic concordance was perfect in 29 (65.9%) cases, partial in 5 (11.4%), and there was disagreement in 10 (22.7%). final concordance on the benign/malignant nature of the lesion was observed in 34 (77.3%) cases, disagreement in 10 (22.7%). abstract https://doi.org/10.5826/dpc.1003a71 mailto:luc.thomas@chu-lyon.fr 2 research | dermatol pract concept 2020;10(3):e2020071 management. we restricted this study to dermoscopy containing pictures requests made by dermatologists or skin cancer hyperspecialized gps. in cases of multiple td consultations for the same lesion, only the first was considered, whereas in requests for multiple lesions, each lesion was analyzed as a single statistical event. in this “real-life” study, no standardization of picturing mode was used. these pictures were analyzed by 1 among the 7 experts (at least 10 years of practice of dermoscopy and 10 publications on the field of dermoscopy) in tds in the department; response was sent to the referring clinician and saved for analysis. experts responded about diagnosis, possible differential diagnoses, the benign/malignant nature of the lesion, and management (excision, follow-up, biopsy, confocal microscopy, or picturing). case revisions all pictures and answers have been retrospectively analyzed by a dermatology resident (a.m.) and a senior expert (s.d., l.t.). lesions were subclassified into pigmented skin lesions (psl), amelanotic tumors (at), nail pigmentation (np), and other nail lesions (nl). picture quality was assessed. the gold standard was either histopathology or reasonable-delay (at least 1 year) benign evolution in all cases. indeed, the level of evidence is weaker in the second case. however, systematic surgical excision of all cases would have been unethical. moreover, surgical recommendation for benign conditions to an expert’s eyes would have resulted in greater bias since our series could not then be considered a “real-life” one. cases with neither histopathological nor follow-up information were excluded. the large number of pediatric and onychology cases allowed us to perform a subgroup analysis. definitions of concordance/disagreement the definitions of concordance and disagreement are indicated in table 1. statistical analysis analyzes were done with r software (version 3.4.4, r development core team. r: a language environment for statistical computing. vienna, austria. isbn 3-900051-07-0. url: http: //www.r-project.org, 2018) by an independent statistics expert (d.m.b.). we used average, standard deviation, median, first and third quartile, range for continuous introduction diagnosis of skin cancer is challenging for solitary practicing dermatologists. teledermatology (td) exists in 2 modes: store-and-forward and live interactive [1]; in store-andforward, the most used, information is sent to an electronic platform for delayed analysis. in 2 systematic reviews, td was found inferior to face-to-face (ftf) dermatology but the accuracy was deemed acceptable by the authors [2,3]. however, coates et al pointed out some limitations of td such as the lack of total-body skin examinations [4]. teledermatology is classified as primary, secondary, and tertiary td. primary td involves communication between patients and a general practitioner (gp). in secondary td, gps communicate with dermatologists. in tertiary td, dermatologists receive an expert opinion [1]. according to finnane et al, the main limitation of all td studies published since 2009 was that tele-expert diagnosis was compared to that of a primary physician, not to the final histopathology/follow-up–based diagnosis [2]. teledermoscopy (tds) is based on transmission of a dermoscopy picture. tds is known to improve diagnostic accuracy and decrease the rate of unnecessary consultations in dermatology compared with td alone [5-7], yet most of the published studies were performed in a secondary telemedicine setting. by contrast, the aim of this study, performed in our unit dedicated to private practice dermatologists with special extra-competence in difficult-to-diagnose skin lesions encompassing many digital dermoscopy follow-ups, nail tumors, and pediatric lesions, was to (1) determine the final diagnostic concordance between the diagnosis made by the tele-expert and the final diagnosis and (2) evaluate the efficiency of tertiary tds. methods patients we conducted an unselected consecutive cohort study between january 1, 2016, and december 31, 2016. referring clinicians sent td requests on an encrypted, firewall-protected storeand-forward server of the hospices civils de lyon (https:// myhclpro.sante-ra.fr/). clinicians provided age, sex, location, personal and family medical history, and macroscopic and dermoscopic pictures to experts and questions on diagnosis and conclusions: this study confirms that tertiary tds improves diagnostic accuracy of pigmented skin lesions. moreover, it shows encouraging results in unusual conditions such as ungual and pediatric skin tumors. the main limitation was the retrospective nature and the “real-life” setting of our study that could have created a selection bias toward inclusion of the most difficult cases. abstract http://www.r-project.org https://myhclpro.sante-ra.fr/ https://myhclpro.sante-ra.fr/ research | dermatol pract concept 2020;10(3):e2020071 3 (39%) male; median age was 45 years and there were 44 (15.2%) children (aged ≤15 years). referring clinicians referring clinicians were 78 (93.9%) dermatologists and 6 (7.1 %) skin cancer hyperspecialized gps. referring clinicians of our geographic region (rhône alpes auvergne) accounted for 152 (53.9%); 2 (0.7%) requests were international. requests requests included a median number of 2 (range 1-6) dermoscopy pictures in a total number of 3 (range 1-24). in 32 cases (11%) we did not receive accompanying close-up or wide-angle standard pictures. these standard images were variables; and percentages and effectives for discontinuous variables. variables were compared with chi-square or fischer exact test when necessary. the ethical committee of lyons university hospital approved the study protocol on may 17, 2018. results populations figure 1 represents the flow chart of the study. two hundred ninety teledermoscopic requests with known final diagnosis were included on a total of 2,528 tertiary td requests sent between january 1, 2016, and december 31, 2016. one hundred seventy-seven (61%) patients were female and 113 table 1. definitions of study outcomes study outcome reference standard index test final diagnostic concordance histopathological result (excised or biopsied lesions) or follow-up (nonexcised lesions) teledermatologist expert diagnosis perfect final diagnostic concordance teledermatologists and final diagnosis is identical partial concordance final diagnosis is included in the differential diagnosis list by the expert but not in first position disagreement on final diagnosis final diagnosis not suggested by the expert in his differential diagnosis list prediagnostic concordance teledermatologist diagnosis referring clinician proposed diagnosis perfect prediagnostic concordance teledermatologists and referring clinical initial proposition for diagnosis are the identical partial prediagnostic concordance diagnosis given by the expert is included in the differential diagnoses list by the referring clinician but not in first position disagreement on prediagnosis diagnosis given by the expert is different from the initially proposed one(s) by the referring clinician management concordance teledermatologist management referring clinician proposed management perfect management concordance teledermatologists and referring clinical initial proposition for management are identical partial concordance on management final management suggested by the expert is proposed by the referring clinician but not in first position disagreement on management the final management proposed by the expert is different from the initially proposed one by the referring clinician benign/malignant concordance histopathological result or followup (nonexcised lesions) teledermatologist expert diagnosis on benign/malignant nature perfect final concordance on the benign/ malignant nature of the lesion teledermatologists and final diagnosis on the benign/malignant nature of the lesion is identical disagreement on the nature of the lesion teledermatologists and final diagnosis on the benign/malignant nature of the lesion is different prediagnostic benign/malignant concordance teledermatologist diagnosis on benign/malignant nature referring clinician proposed diagnosis on benign/malignant nature perfect prediagnostic concordance on the benign/malignant nature of the lesion teledermatologists and referring clinical initial proposition for the benign/ malignant nature of the lesion is identical disagreement on prediagnosis on the nature of the lesion teledermatologists and referring clinical initial proposition for the benign/ malignant nature of the lesion is different 4 research | dermatol pract concept 2020;10(3):e2020071 (43.2%) and by another expert in 18 (40.9 %). onychology represented 7 (15.9%) pediatric cases. main diagnoses all diagnoses are reported in table 2. the most common diagnoses for psl were benign melanocytic lesion in 134 (67.3%) cases, ungual squamous cell carcinoma in 10 (35.7%) for nl (np excluded), focal melanocytic activation in 10 (35.7%) cases of np, and basal cell carcinoma for at in 8 (22.9%) cases. management of skin tumors and psl excision was recommended in 65/290 (22.4%) of all skin tumors and in 44/199 (21.1%) of psl; 3-month follow-up was recommended in 50 (17.4%); nail biopsy was recommended in 26 (46.4%) nail cases. when recommended, biopsies and excisions were performed in all cases. experts recommended a hyperspecialized university hospital consultation in 65 (22.6%) cases; they considered it unnecessary in 2 among 32 cases for whom it was requested (6.3%). diagnostic correlation histopathological diagnosis was available in 167 (57.6%) cases and reasonable-delay benign follow-up in the remaining 123 (42.4%). perfect final diagnostic concordance between teledermatologists and histopathology or follow-up was present in 258 (89%) cases. dermoscopy pictures were of good quality in 260 (89.7%) cases. in 170 (58.6%) cases, a report on medical history of the patient was lacking. a personal history of melanoma was mentioned in 25 (8.6%) cases. family history of melanoma was reported in 14 (4.8%) cases. the most common purpose for tds consultation was evaluation of psl in 199 (68.6%) cases, followed by nail diseases in 56 (19.3%) cases, then by at in 35 (12.1%). referring forms reported history of an enlarging lesion in 33 (11.4%) cases, change in a preexisting lesion in 11 (3.8%) and onset of a new lesion in 56 (19.3%). the evolution time before teleconsultation was 6 to 12 months in 55 (19%) cases; only 14 (4.8%) lesions were present for less than 3 months. diagnosis was the principal question in 42 (14.5%) cases, then management in 183 (63.1%) and both in 48 (16.5%). in 32 (11%) cases, motivation was to obtain a university hospital appointment (e-referral). expert answers experts submitted their answers in a mean time of 2.21 days (median 1 day; range 1-14 days). in 11 (3.8%) cases, no diagnosis was made by an expert. one expert answered to 177 (61%) requests and to 41 (73.2%) nail requests. pediatric cases were managed by one expert with acknowledged hyperspecialization in pediatric dermatology (a.p.) in 19 figure 1. flow chart of the study. research | dermatol pract concept 2020;10(3):e2020071 5 among the remaining cases, 2 were melanomas: 1 was left undiagnosed because of a poor-quality picture (and reported as such to the referring clinician and finally excised) and the other was a 0.2-mm melanoma diagnosed as an atypical found in 202 (69.7%) cases (figure 2). partial concordance was found in an additional 29 (10%) cases. disagreement was found in 59 (20.3%) cases; in 51 (86.4%), a benign lesion for which management was not compromised was found. table 2. summary of all teledermoscopy final (histopathology or evolution) diagnoses lesion type main diagnoses final diagnoses (n = 290) (100%) final pediatric diagnoses (n = 44) (15.2%) pigmented skin lesions n = 199 (68.6%) n = 30 (15.1%) pediatric benign melanocytic lesions (nevi, blue nevi, hallo nevi, congenital nevi) melanoma spitz tumors (spitz nevi and malignant spitzoid tumors) malignant epithelial tumors (bcc, bowen disease, scc) benign epithelial tumors (seborrheic keratoses, lentigos) other diagnoses • collision tumors • dermatofibroma • postinflammatory pigmentation • exogenous pigmentation • mastocytosis 134 (67.3%) 17 (8.5%) 3 (1.5%) 7 (3.5%) 31 (15.7%) 1 (0.5%) 3 (1.5%) 1 (0.5%) 1 (0.5%) 1 (0.5%) 25 (83.3%) 2 (6.7%) 2 (6.7%) 1 (3.3%) amelanotic tumors n = 35 (12%) n = 7 (20%) pediatric malignant epithelial tumors (bcc, bowen disease, scc) benign epithelial tumors (seborrheic keratoses, epidermoid cysts, warts) benign melanocytic lesions spitz tumors (spitz nevi and malignant spitzoid tumors) melanoma vascular lesions (angioma, pyogenic granuloma) other diagnoses • dermatofibroma • juvenile xanthogranuloma • adnexal tumors (trichoblastoma, pilomatricoma) • inflammatory diseases 11 (31.5%) 4 (11.4%) 4 (11.4%) 2 (5.7%) 1 (2.9%) 4 (11.4%) 3 (8.6%) 2 (5.7%) 2 (5.7%) 2 (5.7%) 1 (14.3%) 2 (28.6%) 1 (14.3%) 2 (28.6%) 1 (14.2%) nail pathology (longitudinal np excluded) n = 28 (9.7%) n = 1 (3.6%) pediatric subungual scc epithelial benign tumors (warts, onychopapilloma) subungual exostosis melanoma other diagnoses • onychotillomania • glomus tumor • hamartoma • trauma-induced nail changes • onychomycosis • pyogenic granuloma • fibromyxoma • myxoid pseudocyst 10 (35.7%) 4 (14.2%) 3 (10.7%) 1 (3.6%) 1 (3.6%) 1 (3.6%) 1 (3.6%) 1 (3.6%) 2 (7.1%) 2 (7.1%) 1 (3.6%) 1 (3.6%) 1 (100%) longitudinal np n = 28 (9.7%) n = 6 (21.4%) pediatric focal melanocytic activation including drug-induced np, trauma-induced np, ethnic-type np acquired benign melanocytic lesions congenital nevi of the nail unit melanoma other diagnoses • subungual hemorrhage • onychopapilloma • scc 10 (35.7%) 7 (25%) 3 (10.7%) 4 (14.3%) 1 (3.6%) 1 (3.6%) 2 (7.1%) 1 (16.7%) 2 (33.3%) 3 (50%) bcc = basal cell carcinoma; np = nail pigmentation; scc = squamous cell carcinoma. 6 research | dermatol pract concept 2020;10(3):e2020071 nevus for which a 6-month follow-up was suggested, which then led to the correct diagnosis. other misdiagnosed tumors were 5 basal cell carcinomas (in 3 cases histopathology was, however, recommended; in 1 case a 3-month follow-up was recommended; no treatment was recommended in the fifth case) and 1 squamous cell carcinoma (no response because of poor-quality picture). prediagnostic concordance is presented in table 3. for example, the referring clinician and expert totally agreed on the diagnosis of the histopathology-confirmed melanoma shown in figure 3. however, the referring clinician and expert disagreed on diagnosis and management of the lesion shown in figure 4 but histopathology confirmed a dermatofibroma, as proposed by the expert. benign/malignant concordance was found in 227 (78.3%) cases, discordance in 63 (21.7%) cases (figure 5). prediagnostic benign/malignant concordance and management concordance results are presented in tables 4 and 5, respectively. figure 2. perfect final diagnostic concordance between teledermoscopy expert and final diagnoses (histopathology or reasonable-delay benign follow-up). table 3. prediagnostic concordance between teledermoscopy expert and referring clinician all requests (n = 290) (100%) nail requests (n = 56) (19.3%) pediatric requests (n = 44) (15.2%) perfect prediagnostic concordance 116 (40%) 16 (28.6%) 21 (47.7%) partial prediagnostic concordance 44 (15.2%) 12 (21.4%) 4 (9.1%) disagreement on prediagnosis no hypothesis from referring clinician no hypothesis from teledermoscopy expert 130 (44.8%) 76 (26.2%) 11 (3.8%) 28 (50%) 21 (37.5%) 0 19 (43.2%) 9 (20.5%) 3 (6.8%) results in the nail and pediatric subgroups are presented in figures 2 and 5 and tables 3, 4, and 5. the experts’ diagnostic concordance with final diagnosis was statistically lower for at: total disagreement on 18/35 (51.4%) when compared to 57/199 (28.6%); 6/28 (21.4%) and 7/28 (25%) for psl, np, and nl (p = 0.028), respectively. discussion we report herein the first robust, final diagnosis-based, reallife concordance study in tertiary (specialists-to-experts) store-and-forward tds. tertiary td is used in order to seek expert opinion/second opinion, but also to obtain an expert ftf consultation (e-referral). it may also be used for resident training and continuous medical education of specialists [8]. tds is a specialized research | dermatol pract concept 2020;10(3):e2020071 7 figure 4. a 70-year-old woman presented with a pigmented atypical lesion on the leg. the referring clinician suggested excision for a possible melanoma. the diagnosis of dermatofibroma, suggested by the expert, was confirmed by histopathology.  figure 3. a 72-year-old man presented with a pigmented atypical lesion on the abdomen for 6 months. expert and clinicians both diagnosed a melanoma and suggested excision of the lesion. histology found a superficial spreading melanoma 0.35 mm thick. figure 5. perfect final concordance on the benign/malignant nature of the lesion between teledermoscopy expert and final diagnoses (histopathology or reasonable-delay benign follow-up). 8 research | dermatol pract concept 2020;10(3):e2020071 lesion is also suggested by a 45.2% prediagnostic benign/ malignant disagreement. moreover, analysis of diagnostic disagreements between expert and referring clinician showed that the expert was correct in the majority of cases (72.7%). our results in tertiary tds are similar to previously published results in secondary settings (51%-94% for diagnostic accuracy between td and histopathology [excised lesion]) and ftf diagnosis (nonexcised lesions) when dermoscopy is performed [2,9-17]. literature data combined with ours suggest an interesting improvement of diagnosis by transmission of dermoscopy pictures in cases of doubtful psl. however, one author reported that the addition of tds did not significantly improve diagnostic accuracy compared to transmission of standard pictures alone for malignant psl [18] and suggested that tds was useful only for malignant amelanotic skin tumors (aggregated accuracy, p = 0.0017; primary accuracy, p = 0.0382) [19]. this discrepancy might be explained by the tertiary setting of our study, referred cases being found difficult-to-diagnose by dermatology specialists concerned less with basal cell carcinomas and more with unusual (acral, pediatric) pigmented skin tumors. the only available report on histopathology-based tertiary td, including 33 cases, was centered on inflammatory skin diseases; it also demonstrated a high (78.8%) level of concordance [20]. van der heijden et al showed that in 81% of cases, dermatologists would have referred the patient to a tertiary center without the help of td [21]. our study also approach within td known to improve diagnostic accuracy and to decrease the rate of unnecessary consultations in dermatology compared with td without dermoscopy [5-7], yet all published studies to date were performed in a secondary telemedicine setting. in most published td studies, the main methodological limitation was the absence of correlation study with final diagnosis established either on histopathology or follow-up [2]. moreover, no secondary-setting tds published studies included follow-up information for nonexcised lesions [2]. in our study, the gold standard was histopathology in 57.6% of the cases or follow-up in 42.4%. we report a high (79.7%) diagnostic concordance between tds experts and final diagnosis except for diagnosis of at, for which the diagnostic discordance was significantly higher (51%) than for psl (28.6%), nl (25%), and np (21.4%). we also report a high (78.3%) concordance level about the diagnosis of malignant/benign nature of the lesion. our results suggest that tds improved diagnosis and management because of an observed high level of discordance between diagnosis proposed by the referring clinician and the expert (44.8%) and a high frequency of alternative management proposed by the expert (46.5%). interestingly enough, analysis of our misdiagnosed cases showed only 1/23 (4.3%) undiagnosed melanoma and concerned an early case (0.2 mm) for which digital follow-up was suggested. improvement on the diagnosis regarding the malignant/benign nature of the referred table 4. management concordance between teledermoscopy expert and referring clinician all requests (n = 290) (100%) nail requests (n = 56) (19.3%) pediatric requests (n = 44) (15.2%) perfect management concordance 75 (25.9%) 19 (33.9%) 13 (29.5%) partial concordance on management 80 (27.6%) 13 (23.2%) 13 (29.5%) disagreement on management no management proposed by the referring clinician no management proposed by expert in teledermoscopy 135 (46.5%) 75 (25.9%) 11 (3.8%) 24 (42.9%) 15 (26.8%) 0 18 (41%) 5 (11.4%) 0 table 5. prediagnostic benign/malignant concordance between teledermoscopy expert and referring clinician all requests (n = 290) (100%) nail requests (n = 56) (19.3%) pediatric requests (n = 44) (15.2%) perfect prediagnostic concordance on benign/ malignant nature of the lesion 159 (54.8%) 26 (46.4%) 29 (65.9%) disagreement on prediagnosis on the nature of the lesion no hypothesis from the referring clinicians no hypothesis from teledermoscopy expert 131 (45.2%) 76 (26.2%) 11 (3.8%) 30 (53.6%) 21 (37.5%) 0 15 (34.1%) 9 (20.5%) 3 (6.8%) research | dermatol pract concept 2020;10(3):e2020071 9 compared with solitary nonexpert assessment and offers additional support for the management of unusual conditions such as ungual and pediatric skin tumors with easier access to regional, national, and international expert opinion. acknowledgments referring clinicians: mme. delphine anuset; mme. sylvie arvieu; mme. laure baudoux; mr. antoine claeys; mme. dominique charleux; mme. geneviève choquet; mme. claire dubas-coudert; mr. jean-yves forestier; mme. florence hoareau; mme. fanny humbert; mme. marion gabillot; mme. céline graveriau; mme. celine langella; mme. annelaure liegon; mme. noemie litrowski; mme. marie-cécile marcilly luaute; mme. laurence barrie; mme. susanne evanno-meertz; mr. remi lombard; mme. marion loppin; mme. catherine maisonneuve; mme. cristina mangas; mme. aurore meyer; mme. juliette miquel; mme. stefana-nicoleta balica; mr. jean paroissien; mme. anne sarazin; mme. anne-laure rival-tringali; mme. barbara haettich-pialoux; mme. celina duchemin; mme. fabienne pousset-léger; mme. benedicte courtois; mme. aline montet; mme. ghislaine de cambourg; mme. françoise wolf; mme. caroline dumortier; mme. isabelle mironneau; mme. isabelle guillot pouget; mme. elodie archer; mme. mounia naji; mr. davide sali; mr. thomas delaporte; mme. nancy arpin; mme. sophie brunet-coupelon; mme. nathalie gunera saad; mme. fanny locatelli; mme. pauline chappuis; mme. aude alquier bouffard; mme. anne-lise vincent; mme. fabienne martin; mme. astrid baeke; mme. françoise truchot; mme. elise arbona vidal; mr. yvan ali cherif; dominique segault; mme. mathilde tardieu; mme. nadia ruffion; mme. marie charlotte deroo-berger; mme. isabelle mironneau; mme. sandy leger; mme. carine merlen-djafri; mme. emmanuelle besson; mme. pascale perrin; mme. elodie couderc; mme. nadege thieulent; mme. cecile ludmann; mr. cliff rosendahl; mme. marie-emilie deschamps; mme. janique gremion; mme. laure cellarier; mme. daphné dumon; mr. stephane bosonnet; mme. blandine pincemaille; mme. marie-laure batard; mme. valerie doffoel-hantz; mme. marie-france bouthenet; mme. marie-france brun; mme. christine dissard; mme. claire lonuveille; mme. deborah salik; mme. helene flacher; mme. marion gabillot; mme. claire demongeot; mme. karen talour; mr. philipe castets; mme. cécile dolla; mr. marc lopvet, department of medical information, hospices civils de lyon. references 1. tensen e, van der heijden jp, jaspers mwm, witkamp l. two decades of teledermatology: current status and integration in demonstrates that, in “real life,” the delay to obtain an expert opinion is short (2.21 days, median 1 day). in our study, 65 (22.6%) cases were referred to our hospital after tds. although almost half of our tds recruitment is generated outside our region, this high number is explained by the high proportion of nail conditions for which biopsy is difficult to conduct in home offices. cheung et al also demonstrated that td avoided ftf consultation in 68% of cases with good-quality pictures [22]. dermoscopy picture quality was good in 89.7% of cases in our study, similar to massone et al (88%) [14]. in another secondary-setting tds study, the quality of transmitted pictures was relatively lower, with only 36% good and 28% fair [12] and a lower accuracy and reliability compared with ftf consultation ( 0.66 on diagnosis and 0.42 on management), supporting the concept that tds is highly dependent on picture quality [12]. our study assessed the concordance between tds and final diagnosis in pediatric skin tumors. consultation offers in pediatric dermatology are scarce and are by far exceeded by the demand. td is used to facilitate access to highly specialized pediatric dermatology opinion and to select cases for whom an ftf consultation is needed [23]. in the literature, diagnostic concordance between pediatricians and teledermatologists ranges from 16.7% to 82% [23-26]. these studies concern inflammatory skin diseases and do not include dermoscopy pictures. diagnostic concordance was reasonably high (77.3%). management concordance level between pediatricians and teledermatologists ranged from 25% to 44% vs 55% to 76% in adult patients. our study concerned exclusively pediatric skin tumors, including dermoscopy pictures, and our results (59%) are very similar. our study encompassed a large number (19.3%) of nail teleconsultations. we found a high diagnostic concordance between tds expert and final diagnosis in 50 (89.3%) and a high number of diagnostic (50%) and management (42.9%) changes after tds, suggesting a high impact on patient’s outcome. the main limitation of our work was its cohort nature and the “real-life” setting evaluating our routine telemedicine platform with no previously agreed-upon way to report on outcome. many cases (89.5%) were excluded because of unavailable histopathology/outcome information. this could have created a selection bias toward inclusion of the most difficult cases, the referring clinicians being less willing to retrieve patient information in case of indolent conditions or unchanged diagnosis and management after tds. conclusions in addition to previously published reports, this study confirms that tertiary tds improves diagnostic accuracy of psl 10 research | dermatol pract concept 2020;10(3):e2020071 14. massone c, maak d, hofmann-wellenhof r, soyer hp, frühauf j. teledermatology for skin cancer prevention: an experience on 690 austrian patients. j eur acad dermatol venereol. 2014;28(8):1103-1108. https://doi.org/10.1111/jdv.12351. 15. tan e, yung a, jameson m, oakley a, rademaker m. successful triage of patients referred to a skin lesion clinic using teledermoscopy (image it trial). br j dermatol. 2010;162(4):803-811. https://doi.org/10.1111/j.1365-2133.2010.09673.x. 16. warshaw em, gravely aa, nelson db. reliability of store and forward teledermatology for skin neoplasms. j am acad dermatol. 2015;72(3):426-435. https://doi.org/10.1016/j. jaad.2014.11.001. 17. börve a, dahlén gyllencreutz j, terstappen k, et al. smartphone teledermoscopy referrals: a novel process for improved triage of skin cancer patients. acta derm venereol. 2015;95(2):186-190. https://doi.org/10.2340/00015555-1906. 18. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for pigmented neoplasms. j am acad dermatol. 2009;61(5):753-765. https://doi.org/10.1016/j.jaad.2009.04.032. 19. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for nonpigmented neoplasms. j am acad dermatol. 2009;60(4):579-588. https://doi.org/10.1016/j.jaad.2008.11.892. 20. lozzi gp, soyer hp, massone c, et al. the additive value of second opinion teleconsulting in the management of patients with challenging inflammatory, neoplastic skin diseases: a best practice model in dermatology? j eur acad dermatol venereol. 2007;21(1):3034. https://doi.org/10.1111/j.1468-3083.2006.01846.x. 21. van der heijden jp, de keizer nf, witkamp l, spuls pi. evaluation of a tertiary teledermatology service between peripheral and academic dermatologists in the netherlands. telemed e-health. 2014;20(4):332-337. https://doi.org/10.1089/tmj.2013.0197. 22. cheung cm, muttardi k, 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2010;62(1):61-66. https://doi.org/10.1016/ j.jaad.2009.05.039. national healthcare systems. curr dermatol rep. 2016;5:96-104. https://doi.org/10.1007/s13671-016-0136-7. 2. finnane a, dallest k, janda m, soyer hp. teledermatology for the diagnosis and management of skin cancer: a systematic review. jama dermatol. 2017;153(3):319-327. https://doi.org/10.1001/ jamadermatol.2016.4361. 3. warshaw em, hillman yj, greer nl, et al. teledermatology for diagnosis and management of skin conditions: a systematic review. j am acad dermatol. 2011;64(4):759-772. https://doi. org/10.1016/j.jaad.2010.08.026. 4. coates sj, kvedar j, granstein rd. teledermatology: from historical perspective to emerging techniques of the modern era, part ii: emerging technologies in teledermatology, limitations and future directions. j am acad dermatol. 2015;72(4):577-586. https://doi. org/10.1016/j.jaad.2014.08.014. 5. ferrándiz l, ojeda-vila t, corrales a, et al. impact of dermoscopy on an internet-based skin cancer triage system: interim results of a randomized study. j am acad dermatol. 2017;76(2):342-343. https://doi.org/10.1016/j.jaad.2016.02.1165. 6. moreno-ramirez d, ferrandiz l, galdeano r, camacho fm. teledermatoscopy as a triage system for pigmented lesions: a pilot study. clin exp dermatol. 2006;31(1):13-18. https://doi. org/10.1111/j.1365-2230.2005.02000.x. 7. de giorgi v, gori a, savarese i, et al. teledermoscopy in doubtful melanocytic lesions: is it really useful? int j dermatol. 2016;55(10):1119-1123. https://doi.org/10.1111/ijd.13281. 8. van der heijden jp, spuls pi, voorbraak fp, et al. tertiary teledermatology: a systematic review. telemed e-health. 2010;16(1):5662. https://doi.org/10.1089/tmj.2009.0020. 9. congalton at, oakley am, rademaker m, bramley d, martin rcw. successful melanoma triage by a virtual lesion clinic (teledermatoscopy). j eur acad dermatol venereol. 2015;29(12):24232428. https://doi.org/10.1111/jdv.13309. 10. kroemer s, frühauf j, campbell tm, et al. mobile teledermatology for skin tumour screening: diagnostic accuracy of clinical and dermoscopic image tele-evaluation using cellular phones. br j dermatol. 2011 may;164(5):973-979. https://doi.org/10.1111/ j.1365-2133.2011.10208.x. 11. tan e, oakley a, soyer hp, et  al. interobserver variability of teledermoscopy: an international study. br j dermatol. 2010;163(6):1276-1281. https://doi.org/10.1111/j.13652133.2010.10010.x. 12. van der heijden jp, thijssing l, witkamp l, spuls pi, de keizer nf. accuracy and reliability of teledermatoscopy with images taken by general practitioners during everyday practice. j telemed telecare. 2013;19(6):320-325. https://doi. org/10.1177/1357633x13503437. 13. senel e, sabancılar e, mansuroğlu c, demir e. a preliminary study of the contribution of telemicroscopy to the diagnosis and management of skin tumours in teledermatology. j telemed telecare. 2014;20(4):178-183. https://doi. org/10.1177/1357633x14533885. https://doi.org/10.1111/jdv.12351 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https://doi.org/10.1016/j.jaad.2014.08.014 https://doi.org/10.1016/j.jaad.2016.02.1165 https://doi.org/10.1111/j.1365-2230.2005.02000.x https://doi.org/10.1111/j.1365-2230.2005.02000.x https://doi.org/10.1111/ijd.13281 https://doi.org/10.1089/tmj.2009.0020 https://doi.org/10.1111/jdv.13309 https://doi.org/10.1111/j.1365-2133.2011.10208.x https://doi.org/10.1111/j.1365-2133.2011.10208.x https://doi.org/10.1111/j.1365-2133.2010.10010.x https://doi.org/10.1111/j.1365-2133.2010.10010.x https://doi.org/10.1177/1357633x13503437 https://doi.org/10.1177/1357633x13503437 https://doi.org/10.1177/1357633x14533885 https://doi.org/10.1177/1357633x14533885 review | dermatol pract concept 2011;1(1):9 33 histopathology of drug eruptions – general criteria, common patterns, and differential diagnosis wolfgang weyers, m.d.1, dieter metze, m.d.2 1center for dermatopathology, freiburg, germany 2department of dermatology, university of münster, münster, germany key words: drug eruptions, histopathology, skin citation: weyers w, metze d. histopathology of drug eruptions – general criteria, common patterns, and differential diagnosis. dermatol pract concept 2011;1(1):9. http://dx.doi.org/10.5826/dpc.0101a09. editor: harald kittler, m.d. received: april 11, 2011; accepted: may 18, 2011; published: october 31, 2011 copyright: ©2011 weyers et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. both authors have contributed significantly to this publication. corresponding author: wolfgang weyers, m.d., center for dermatopathology, engelbergerstr. 19, 79106 freiburg, germany. tel.: +49.761.31696. fax: +49.761.39772. e-mail: ww@zdpf.de. drug eruptions are among the most common inflammatory diseases of the skin and also among those biopsied most often. yet, the value of histopathologic examination of drug eruptions has often been disputed. one reason is that the spectrum of histopathologic changes in drug eruptions is broad. nevertheless, each histopathologic pattern assumed by drug eruptions has a limited number of differential diagnoses, and numerous criteria and clues are available to distinguish drug eruptions from other diseases associated with those patterns. by recognition of common patterns, consideration of differential diagnoses, and attention to distinct clues, a histopathologic diagnosis of drug eruption can usually be made with confidence. abstract introduction drug eruptions are among the most common diseases of the skin. in most instances, they are diagnosed readily on the basis of clinical picture and clinical history, namely, a symmetrical, widespread maculopapular eruption following recent intake of a newly prescribed drug. in many cases, however, diagnosis is not so apparent because the patient does not give a reliable clinical history, because the patient takes several drugs since a long time, because the eruption is caused by food additives rather than a medication, or because the eruption mimicks other skin diseases. the latter may range from psoriasis to pityriasis rosea, from lichen planus to mycosis fungoides, from urticaria to the urticarial stage of autoimmune bullous diseases, from post-herpetic erythema multiforme to lupus erythematosus, and from porphyria to scleroderma. because of their frequency and the wide spectrum of clinical presentations, drug eruptions are biopsied often and are among the most common inflammatory skin diseases encountered by histopathologists. the spectrum of histopathologic presentations of drug eruptions, however, is not smaller than that of clinical ones. dermatology practical & conceptual www.derm101.com 34 review | dermatol pract concept 2011;1(1):9 mimicking other diseases, but may elicit those diseases, e.g., drug-induced psoriasis, pemphigus, lupus erythematosus, or linear iga dermatosis. in those instances, naturally, biopsy specimens reveal changes of the authentic disease. some drug eruptions are thought to be caused by activation of a latent infection by viruses, such as human herpesvirus 6, cytomegalovirus, and epstein barr virus, which may explain why viral exanthemata and drug eruptions may be indistinguishable clinically and histopathologically [7-9]. viral exanthemata are biopsied rarely, and the spectrum of histopathologic changes induced by them is not well known. this is another factor hampering distinction between viral exanthemata and drug eruptions. viral diseases have been claimed to be associated commonly with a lymphocytic vasculitis, a finding that, in our experience, is rare in drug eruptions [10]. some viral exanthemata can be recognized by distinctive changes, such as ballooning and multinucleated keratocytes in measles and keratocytes with steel-grey nuclei with margination of nucleoplasm in infections by herpesviruses [11–12]. often, however, there are no such distinguishing features. common patterns of viral exanthemata include a superficial perivascular infiltrate of lymphocytes without associated epidermal changes, a superficial vacuolar interface dermatitis, sometimes associated with eosinophils and neutrophils, a lichenoid dermatitis, and a mild spongiotic dermatitis. all those patterns may also be encountered in drug eruptions [10]. despite those limitations, drug eruptions can usually be diagnosed with confidence on the basis of histopathologic changes alone. it is common practice in laboratories of dermatopathology to examine sections of biopsy specimens before obtaining any clinical information. if this is done, and the presumptive diagnosis of a drug eruption is rendered, it is our experience that the latter is usually corroborated by the clinical diagnosis of the referring physician. all histopathologic diagnoses must be submitted to critical review in the context of additional information, such as clinical findings, clinical history, and laboratory data. this does not distinguish drug eruptions from any other skin disease, and the reliability of histopathologic diagnosis of a drug eruption is not smaller than that of diseases for which biopsy is recommended without reservation, be it lichen planus, lupus erythematosus, or granuloma annulare. in the following, we wish to discuss criteria that aid in recognition of drug eruptions in general, describe common patterns of drug eruptions, and discuss the differential diagnosis of those patterns. the statements made are based on personal experience of many years, on a review of the literature, and on systematic analysis of histopathologic findings in 60 cases of maculopapular drug eruption in which the eliciting drugs were known and the eruption cleared following cessation of them. in that study, cases diagnosed clinically in 1997, ackerman emphasized that “drugs can elicit any of the nine basic patterns of inflammatory diseases in the skin, and none of those patterns is specific for a drug eruption. there is but one exception, to date, to the precept that drug eruptions cannot be diagnosed with specificity through the microscope, namely, fixed drug eruption” [1]. in more than a decade following that sobering assessment of the import of histopathological analysis for the diagnosis of drug eruptions, only little progress has been made. for some differential diagnoses, criteria have been set forth to facilitate distinction of drug eruptions from other inflammatory skin diseases, e.g., lichenoid drug eruption from lichen planus, psoriasiform drug eruption from psoriasis vulgaris, and granulomatous drug eruption from granuloma annulare. in a recent review of histopathologic patterns of cutaneous drug eruptions, one finding indicative of drug eruptions in general has been noted, namely, combination of different patterns in a single specimen. another finding mentioned as “a diagnostic clue” to drug eruptions was presence of eosinophils, but the authors emphasized that “one must be cautious not to consider them the panacea of histologic diagnosis for a drug reaction as their presence does not make a drug reaction the correct diagnosis. conversely, the absence of eosinophils does not rule out a drug eruption. in other words, they may or may not be present in these reactions” [2]. the vagueness of histopathologic descriptions of drug eruptions, and the caution exercised in interpretation of them, has created the impression that biopsy of drug eruptions has little value. current textbooks of dermatology emphasize that, in reactions to drugs, “the histological changes are no more distinctive than are the clinical features,” the only exceptions being “vegetating iododermas and bromodermas, certain lichenoid eruptions and fixed drug eruptions,” in which “the histological changes … are not pathognomonic, but are sufficiently characteristic to be of importance in differential diagnosis” [3]. no such importance is attributed to histopathologic study of morbilliform drug eruptions, which have been estimated to account for 95% of all drug eruptions [4]. the latter are said to show only “non-specific lymphohistiocytic infiltrates in perivascular arrangement. for that reason, histopathologic examination can contribute only little to diagnosis and differential diagnosis” [5]. as a consequence, it has been stated unequivocally that “biopsy of morbilliform eruptions is not recommended” [6]. in our view, those conclusions are wrong and potentially harmful, as they may lead to incorrect diagnoses and mismanagement of patients. it is true that histopathologic diagnosis of drug eruptions may be difficult, may remain equivocal, and require clinico-pathologic correlation, but this is true for all diseases. compared to other inflammatory diseases of the skin, histopathologic diagnosis of drug eruptions is impeded by the fact that drugs may not only cause eruptions review | dermatol pract concept 2011;1(1):9 35 as drug-induced erythema multiforme, stevens-johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, as well as lichenoid and bullous drug eruptions were excluded. results of that study are being published separately [13]. for this review, we re-examined biopsy specimens of 300 consecutive cases seen in our laboratory in which the diagnosis of a drug eruption of any kind was given both, histopathologically and clinically, but in which data concerning the eliciting drug and follow-up were available for only a minority of patients. the purpose of that endeavor was to assess the relative frequency of different histopathologic patterns of drug eruptions in the routine material of a laboratory of dermatopathology. findings of that survey are summarized in table 1. general criteria several findings are typical of drug eruptions in general. some of them may appear banal. nevertheless, when encountered in association with a particular pattern, they may help to rule out other diseases associated with that pattern. these findings include: 1. signs of acuteness drug eruptions, as their name indicates, are usually acute, eruptive diseases that appear suddenly and progress rapidly in both, extension and intensity. as a consequence, they are usually biopsied early in their course. histopathologic evidence of an eruptive disease biopsied early in its course includes • a normal basket-woven cornified layer despite spongiosis or hydrops of keratocytes in the basal or spinous zone (the reason being that the interval of time between onset of the eruption and biopsy of it is too small to permit alterations in the lower epidermis to affect to stratum corneum), • edema of the papillary dermis, • angiectases of capillaries and venules in the superficial dermis, • many neutrophils in the lumina of dilated venules, • extravasation of erythrocytes. by contrast, signs of chronicity militate against a drug eruption, namely, • marked epithelial hyperplasia, • marked hyperkeratosis, • coarse collagen bundles in elongated dermal papillae, • fibrosis of the papillary and superficial reticular dermis, • numerous melanophages or siderophages in the superficial dermis. table 1: histopathologic findings in 300 cases with the clinical and histopathologic diagnosis of drug eruption pattern lymphocytic dermal without epidermal changes (n=12) superficial and deep dermal with eosinophils and neutrophils (n=12) severe vacuolar interface dermatitis (n=38) mild vacuolar interface dermatitis (n=83) lichenoid dermatitis (n=36) lichenoid psoriasiform dermatitis (n=18) spongiotic dermatitis (n=62) pustular dermatitis (n=19) subepidermal bullous dermatitis (n=6) granulomatous dermatitis (n=12) leukocytoklastic vasculitis (n=2) superficial 10 0 28 55 26 11 54 18 4 0 0 superficial and deep 2 12 10 28 10 7 8 1 2 12 2 perivascular 11 0 5 12 0 0 6 0 0 0 0 interstitial 1 12 33 71 36 18 56 19 6 12 2 vacuolar + 0 0 0 83 28 17 41 11 3 6 1 ++ 0 0 38 0 8 1 0 2 3 0 0 spongiosis + 0 0 38 44 16 18 56 12 2 3 0 ++ 0 0 0 0 0 0 6 7 0 0 0 necrotic keratinocytes + 0 0 4 62 22 11 10 7 5 0 0 ++ 0 0 34 0 13 4 0 1 1 0 0 eosinophils + 0 8 20 51 17 13 45 13 6 10 0 ++ 0 4 12 18 2 4 13 6 0 0 2 neutrophils + 0 10 18 40 4 6 33 0 4 2 0 ++ 0 2 8 0 0 1 3 19 0 0 2 neutrophils in vessels 1 10 19 29 9 7 26 16 3 6 2 36 review | dermatol pract concept 2011;1(1):9 of course, drug eruptions may also be chronic and may be biopsied after many months. signs of chronicity, therefore, do not rule out a drug eruption. for example, anticonvulsant drugs such as phenytoin and carbamazepin may elicit chronic drug eruptions that, because of a lichenoid infiltrate of lymphocytes with largish nuclei, epidermotropism, epidermal hyperplasia, and fibrosis of the papillary dermis, may mimick mycosis fungoides [14–17]. fixed drug eruptions that have recurred several times at the same site are also associated with signs of chronicity, namely, marked fibrosis of the papillary dermis and many melanophages. nevertheless, most drug eruptions show signs of acuteness rather than chronicity, and those signs are among the most important clues to histopathologic diagnosis of a drug eruption (figure 1 a, b). 2. vacuolar interface dermatitis the most common histopathologic pattern of drug eruptions is a vacuolar interface dermatitis. the extent of interface changes varies greatly, from extensive vacuolar alteration at the dermo-epidermal junction and many necrotic keratocytes at all levels of the epidermis, as in most cases of fixed drug eruption and toxic epidermal necrolysis, to focal and very subtle changes. the latter may not be apparent immediately. when a drug eruption is suspected, it is worthwhile to screen all sections of the biopsy specimen for evidence of a subtle vacuolar interface dermatitis. 3. presence of neutrophils and eosinophils drug eruptions, like many other inflammatory diseases, are often associated with an infiltrate of eosinophils and/or neutrophils. in a recent study of morbilliform drug eruptions, eosinophils were found in 50% and neutrophils in 36% of cases [18]. in our study of maculopapular drug eruptions in which the eliciting agents were known, the numbers were higher, namely, 60% for eosinophils and 50% for neutrophils. in brief, eosinophils and/or neutrophils are present in the majority of drug eruptions. eosinophils are more common, but because they are seen in such a wide variety of diseases, they are less distinctive for drug eruptions. an infiltrate of neutrophils is rarer but of greater diagnostic import. the combination of both, eosinophils and neutrophils, is seen in only a limited number of diseases, including urticaria, autoimmune bullous diseases, sweet’s syndrome, reactions to arthropod assaults, some folliculitides, and, most commonly, drug eruptions. most of those differential diagnoses are characterized by findings not usually seen in drug eruptions, such as a very dense infiltrate of neutrophils in sweet’s syndrome, a wedge-shaped infiltrate in responses to arthropod assaults, or a florid suppurative folliculitis. drug eruptions also have additional features that often allow a specific diagnosis to be made. a sparse perivascular and interstitial infiltrate of neutrophils and eosinophils in concert with subtle vacuolar changes at the dermo-epidermal junction is virtually diagnostic of a drug eruption. 4. several histopathologic patterns in a biopsy specimen drug eruptions may present themselves with different histopathologic patterns. each of those patterns may be caused by a variety of inflammatory skin diseases. a combination of two or more patterns in a single biopsy specimen, however, favors a drug eruption. as mentioned above, the most common pattern of drug eruptions is an interface dermatitis which is usually also seen when patterns are combined. regardless of the pattern of inflammation, ranging from superficial perivascular to superficial and deep perivascular and interstitial, from spongiotic to granulomatous, and from subcorneal pustular to subepidermal bullous, presence of tiny foci of vacuolar changes at the junction, sometimes associated with but a few necrotic keratocytes, should raise suspicion of a drug eruption (figure 2 a, b). figure 1. a) spongiotic drug eruption with mild spongiosis in the lower half of the epidermis and a basket-woven cornified layer. b) umina of dilated venules in the upper dermis are filled with clusters of neutrophils. review | dermatol pract concept 2011;1(1):9 37 5. several discrete foci of inflammation in a biopsy specimen most maculopapular drug eruptions are generalized eruptions in which the degree of inflammation varies. individual lesions tend to be circumscribed poorly and blend into one another. accordingly, there may be two or more discrete foci of inflammation in a punch biopsy specimen, separated from one another by areas in which the inflammation is less pronounced. this may help to distinguish drug eruptions from diseases with distinct papules, such as lichen planus and pityriasis lichenoides. 6. constellation of findings not corresponding to any well-defined disease drug eruptions may mimic many other skin diseases. sometimes, histopathologic findings of a drug eruption are indistinguishable from those of another disease, but in most instances, the histopathologic presentation of the latter is modified, e.g., by parakeratosis and a diminished granular zone in what seems to be lichen planus, by numerous eosinophils in what seems to be pustular psoriasis, or by deep extension of the infiltrate in what seems to be bullous pemphigoid. a constellation of findings that does not correspond to any well-defined disease should raise suspicion of a drug eruption [2]. 7. other clues to diagnosis of a drug eruption drug eruptions usually affect trunk and extremities. palms and soles are involved only rarely, and if they are, there are usually also lesions at other sites that are selected for biopsy. as a consequence, drug eruptions, with the exception of fixed drug eruption, are biopsied rarely on palms and soles. the same is true for the face and scalp. hence, when one sees a biopsy specimen from face, scalp, or palmar and plantar surfaces, a drug eruption is unlikely. drug eruptions are most common in elderly patients. consideration of the age of patients, including histopathologic indicators of it, such as pronounced solar elastosis, may facilitate especially distinction between drug eruptions and viral exanthemata. drug eruptions may be associated with atypia of keratocytes. the affected cells are swollen, have large nuclei, and either large, prominent nucleoli or irregularly dispersed chromatin. nuclei may also be hyperchromatic. in contrast to epithelial neoplasms, atypical keratocytes are usually confined to discrete foci and are not crowded together closely. they have been described especially in reactions to chemotherapeutic drugs [19–20]. however, they may be seen in response to a wide variety of drugs and seem to be related to interface changes, since they are also encountered episodically in other interface dermatitides, such as lichen sclerosus and lupus erythematosus. in brief, atypical keratocytes are neither a sensitive nor a specific finding. nevertheless, because they are more common in drug eruptions than in other inflammatory skin diseases, they may serve as a clue to histopathologic diagnosis of a drug eruption (figure 3 a, b). common patterns and differential diagnoses lymphocytic dermatitis without epidermal changes this is the least distinctive pattern of a drug eruption. it is not very common, accounting for only 12 of 300 (4%) consecutive cases examined. often subtle vacuolar changes at the junction or slight spongiosis in the lower half of the spinous zone can be detected in sections of what, at first blush, seems to be a perivascular lymphocytic dermatitis without epidermal changes. in other cases, scrutiny reveals eosinophils and/or neutrophils in addition to lymphocytes. when neither subtle vacuolar changes at the junction, spongiosis, nor eosinophils and neutrophils are present, the differential diagnosis includes a wide variety of diseases. a figure 2. a) combination of patterns in a granulomatous drug eruption: vacuolar changes at the dermo-epidermal junction are associated with focal spongiosis and a small granuloma in the upper dermis. b) small granuloma interspersed with many lymphocytes in the upper dermis. 38 review | dermatol pract concept 2011;1(1):9 sparse superficial perivascular infiltrate of lymphocytes is physiologic and may be seen in clinically normal skin as well as in the earliest stage of diseases that, at a later stage, are associated with distinctive histopathologic findings. hence, if the infiltrate is very sparse, a specific diagnosis, and even a meaningful differential diagnosis, cannot be rendered. a relatively dense perivascular infiltrate of lymphocytes without associated epidermal changes, however, is not physiologic and excludes diseases that, given the degree of inflammation, should also sport additional findings. in that instance, the differential diagnosis includes schamberg’s disease, secondary syphilis, erythema chronicum migrans, polymorphous light eruption, pernio, lupus erythematosus tumidus (including jessner’s lymphocytic infiltration and reticular erythematous mucinosis), viral exanthemata, and drug eruptions. drug eruptions with a wholly lymphocytic infiltrate usually affect only the superficial dermis. in the 300 consecutive cases diagnosed clinically as a drug eruption, we encountered only two with a superficial and deep wholly lymphocytic infiltrate. by contrast, the infiltrates in infections by borrelia, polymorphous light eruption, pernio, and tumid lupus erythematosus usually affect the entire dermis. other findings may also be helpful to rule out differential diagnoses, such as mucin in the interstitial dermis in tumid lupus erythematosus, some plasma cells in secondary syphilis, and erythrocytes in dermal papillae and epidermis in schamberg’s disease. drug eruptions are also associated commonly with extravasation of erythrocytes and may be indistinguishable from schamberg’s disease [2]. in hemorrhagic drug eruptions, however, erythrocytes are mostly seen around venules of the superficial plexus rather than in discrete collections in dermal papillae. when consisting of lymphocytes only, the infiltrate in drug eruptions tends to be restricted to perivascular areas with only little involvement of the interstitium. this helps to distinguish drug eruptions from infections by borrelia which are usually associated with many lymphocytes in the interstitial dermis. superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils this pattern, in the absence of significant epidermal changes, was found in 12 of 300 consecutive cases of drug eruptions (4%). if the infiltrate is sparse, the most important differential diagnosis is urticaria. in such cases, the epidermis and papillary dermis should be screened for subtle alterations that may be visible only in step sections, such as slight focal spongiosis or interface changes, slight subepidermal fibrosis or some melanophages. any of those findings militates against urticaria. the same is true for perivascular accentuation of the infiltrate. other clues to an urticarial drug eruption are pronounced edema of the papillary dermis and more neutrophils than normally seen in urticaria [2]. however, even in cases in which none of those clues to a drug eruption are encountered, causation of urticaria by a drug cannot be ruled out. if the infiltrate is denser, the most important differential diagnosis is a response to an arthropod assault. features in favor of the latter include focal accentuation of the infiltrate or confinement of it to one area of the biopsy specimen, wedge-shaped configuration of the infiltrate, marked edema of the reticular dermis with smudging of collagen fibers, and a single focus of spongiosis, especially if located above the deepest extension of the infiltrate. by contrast, features favoring a drug eruption include a relatively homogeneous distribution of the infiltrate and several foci of subtle epidermal changes. vacuolar interface dermatitis vacuolar interface dermatitis is the most common pattern of drug eruptions. in a recent study of morbilliform drug eruptions, interface changes were described in 53% of cases [18]. in our study of maculopapular drug eruptions, subtle vacuolar changes at the dermo-epidermal junction were noticed in 58 of 60 cases (97%), and of the 300 consecutive cases, figure 3. a) superficial vacuolar interface dermatitis with atypical keratocytes caused by an angiotensin-converting enzyme antagonist. b) nuclei of keratocytes are large; some are hyperchromatic, others have prominent nucleoli. review | dermatol pract concept 2011;1(1):9 39 141 (47%) were classified as vacuolar interface dermatitis, although subtle vacuolar changes at the junction were also present in cases in which another pattern predominated. the degree of interface changes is highly variable, ranging from slight vacuolar alteration at the junction with few, if any, necrotic keratocytes to severe vacuolar changes with myriad necrotic keratocytes at the junction and in the upper reaches of the epidermis and, sometimes, confluent epidermal necrosis. cases with severe interface changes correspond, at least in part, to drug-induced erythema multiforme, stevensjohnson syndrome, and toxic epidermal necrolysis. the diseases entering into differential diagnosis of that pattern are different from those that must be considered in drug eruptions with only mild interface changes. for that reason, we made a distinction between severe and mild vacuolar interface dermatitides. a) severe vacuolar interface dermatitis this pattern was encountered in 38 of 300 cases (13%), 13 of which were diagnosed clinically as fixed drug eruption. the latter did not differ substantially from other cases of this group. in 26 cases, numerous eosinophils and neutrophils were present in the infiltrate, and in 10 cases, at least some eosinophils and/or neutrophils could be detected. only four cases were associated with a wholly lymphocytic infiltrate. areas of confluent epidermal necrosis were observed in nine cases, including four cases of fixed drug eruption. in 10 cases (including five of fixed drug eruption), the infiltrate extended into the lower half of the dermis. the differential diagnosis of these cases includes postherpetic erythema multiforme. the epidermal changes are indistinguishable. in general, the infiltrate in post-herpetic erythema multiforme is more perivascular and restricted to the superficial dermis, but involvement of the interstitium and the lower dermis may occur. in the vast majority of cases of post-herpetic erythema multiforme, the infiltrate is wholly lymphocytic. in the literature, eosinophils have been reported in erythema multiforme but, with rare exceptions [21], no clear distinction was made between post-herpetic and druginduced cases [22–23]. when those cases were distinguished, eosinophils were found to be more common in drug-induced erythema multiforme [24–25]. this corresponds to our own experience. for the purpose of this study, we re-examined biopsy specimens of five patients with recurrent post-herpetic erythema multiforme and four patients with erythema multiforme who were younger than 20 years. in three cases of post-herpetic erythema multiforme, few neutrophils were spotted in the papillary dermis, and in one case, a single eosinophil was found. this differs markedly from the high frequency and often high number of eosinophils and neutrophils in drug eruptions with severe vacuolar interface changes (figure 4 a, b). another clue to drug etiology that has been reported in erythema multiforme is acrosyringeal concentration of necrotic keratocytes, a phenomenon that may be related to concentration of drugs in sweat and to direct toxic effects on eccrine ductal epithelium [25]. we found an accumulation of necrotic keratocytes around acrosyringia in nine of the 40 drug eruptions with severe vacuolar interface changes, whereas it was not encountered in post-herpetic erythema multiforme. hence, although present in only a minority of cases, concentration of necrotic keratocytes around acrosyringia may help to distinguish drug eruptions from postherpetic erythema multiforme. other diseases entering into the differential diagnosis of drug eruptions with severe vacuolar interface changes are acute cases of pityriasis lichenoides and lupus erythematosus. in the latter conditions, the infiltrate is usually superficial and deep, whereas it is only superficial in the majority of des with severe interface changes. in pityriasis lichenoides, the infiltrate is often wedge-shaped, a pattern not observed in drug eruptions, and usually consists of lymphocytes only, whereas most drug eruptions are associated with neutrophils figure 4. a) superficial vacuolar interface dermatitis with a relatively sparse perivascular and interstitial infiltrate, dilated venules in the upper dermis, many necrotic keratocytes, and a basket-woven cornified layer. b) the infiltrate consists of lymphocytes, eosinophils, and neutrophils. the constellation of findings is typical of a drug eruption. 40 review | dermatol pract concept 2011;1(1):9 and/or eosinophils. other findings encountered commonly in pityriasis lichenoides, but not in drug eruptions, are mounts of parakeratosis and/or scale-crusts housing neutrophils. lupus erythematosus is typified by a superficial and deep perivascular vacuolar interface dermatitis composed of lymphocytes only. drug eruptions may also show a wholly lymphocytic infiltrate, but in those cases, the infiltrate is usually confined to the superficial dermis, which is rare in lupus erythematosus. cases of lupus erythematosus confined to the superficial dermis usually show a perivascular arrangement of the infiltrate. by contrast, it has been emphasized that presence of interface changes in drug eruptions is “strongly associated with an interstitial infiltrate” [18]. this corresponds to our own experience. in acute cases of lupus erythematosus, the infiltrate tends to be perivascular and interstitial and is associated with neutrophils and, sometimes, eosinophils. these cases may be very similar to drug eruptions. however, eosinophils, if present at all, are rare and outnumbered vastly by neutrophils. the infiltrate, while often extending to the interstitium, tends to show a stronger perivascular accentuation than in most drug eruptions. moreover, some cases of acute lupus erythematosus show smudging of the dermo-epidermal interface and increased amounts of mucin in the reticular dermis. together, those criteria usually allow acute lupus erythematosus to be distinguished from drug eruptions. yet another differential diagnosis is acute graft-versushost disease. the latter typically presents itself as a superficial vacuolar interface dermatitis with a relatively sparse, wholly lymphocytic infiltrate and numerous necrotic keratocytes. sometimes, however, the infiltrate may be relatively dense and associated with eosinophils. irrespective of whether or not eosinophils are present, a drug eruption can never be excluded. because eosinophils have been reported to occur in only 5 to 15% of cases of acute graft-versushost disease [26–28], their presence has led repeatedly to misdiagnosis as a drug eruption, thereby delaying treatment of graft-versus-host disease [29]. as a consequence, it has been recommended not to perform skin biopsies in settings with high probability of acute graft-versus-host disease, such as following allogenic stem cell transplantation [30]. however, in addition to eosinophils that are of limited diagnostic value, other findings may serve to distinguish a drug eruption from acute graft-versus-host disease, including deep extension of the infiltrate and presence of neutrophils. extension of the infiltrate into the deep dermis is observed in only a minority of drug eruptions, but neutrophils are commonly found and were numerous in more than half of our drug eruptions associated with severe interface changes, sometimes exceeding eosinophils in number. by contrast, in one study of acute graft-versus-host disease, not a single neutrophil was observed in 98 biopsy specimens [26]. b) mild vacuolar interface dermatitis a mild vacuolar interface dermatitis with only subtle vacuolar changes at the dermo-epidermal junction and few, if any, necrotic keratocytes is the most common pattern of drug eruptions. in our study of 300 consecutive drug eruptions, it was observed in 83 cases (28%). as mentioned previously, the constellation of mild vacuolar interface changes and a sparse superficial perivascular and interstitial infiltrate of lymphocytes, eosinophils, and neutrophils is virtually diagnostic of a drug eruption (figure 5 a, b). the differential diagnosis of drug eruptions with mild vacuolar interface changes includes diseases normally associated with a more pronounced interface dermatitis, such as lupus erythematosus and acute graft-versus-host disease, but also diseases that are never associated with severe interface changes, including viral exanthemata and some autoimmune bullous diseases, especially the urticarial stage of bullous pemphigoid. because the latter may also be associated with a superficial perivascular and interstitial infiltrate of eosinophils and neutrophils, distinction of it from a drug eruption may be particularly challenging. a clue to diagnosis of bullous pemphigoid is presence, and sometimes clusterfigure 5. a) superficial perivascular and interstitial dermatitis with focal, very subtle vacuolar changes at the junction. b) the infiltrate consists of lymphocytes, eosinophils, and neutrophils. the constellation of findings is typical of a drug eruption. review | dermatol pract concept 2011;1(1):9 41 ing, of eosinophils at the dermo-epidermal junction to which they are attracted following binding of autoantibodies to hemidesmosomes. accumulation of eosinophils at the junction is not a feature of drug eruptions. likewise, eosinophils in the epidermis are commonly seen in the urticarial stage of bullous pemphigoid but are rare in drug eruptions. in our study of maculopapular drug eruptions, neutrophils in the epidermis were found in 19 of 60 cases (17%), but eosinophils in only two cases (3%). features favoring a drug eruption are necrotic keratocytes that are exceedingly rare in bullous pemphigoid, predominance of neutrophils that are sparse or absent in bullous pemphigoid, perivascular accentuation of the infiltrate, and subepidermal fibrosis. the latter may be observed in drug eruptions but does not occur in the urticarial stage of bullous pemphigoid whose lesions are either evanescent or, if persisting at the local site, eventuate into a subepidermal blister. lichenoid dermatitis this pattern was found in 36 of 300 consecutive cases of drug eruptions (12%). it was nearly always associated with lichenplanus-like epidermal changes, namely, irregular acanthosis, an at least focal saw-tooth pattern of rete ridges, wedgeshaped zones of hypergranulosis, and compact orthokeratosis. in general, the lichenoid pattern seems to correspond to a later stage of drug eruption. neutrophils in the epidermis, dermis, or lumina of venules are exceptional. eosinophils were found in only about half of our cases and, with few exceptions, were not abundant. by contrast, most cases showed some fibrosis of the papillary dermis and numerous melanophages, indicating a lesion of longer standing. the most important differential diagnosis is lichen planus. some lichenoid drug eruptions are indistinguishable histopathologically from lichen planus. in those cases, a specific diagnosis can only be made on the basis of clinical history and subtle clinical differences, such as larger, domed and slightly scaly papules and preferential involvement of trunk and extensor surfaces of extremities in lichenoid drug eruptions, rather than small, flat-topped, monomorphous papules on the flexor aspects of forearms, skins, ankles, genitalia, and oral mucous membranes in lichen planus [31]. often, however, there are histopathologic differences that allow lichenoid drug eruptions to be distinguished from authentic lichen planus, including focal thinning of the epidermis, a diminished granular zone, foci of parakeratosis, abundance of necrotic keratocytes that may form clusters and may be seen in all layers of the epidermis, extravasation of erythrocytes, deep extension of the infiltrate, and presence of eosinophils in the infiltrate [31–34]. because lichen planus usually affects middle-aged patients, whereas drug eruptions are more common in the elderly, high age and signs thereof, especially abundant solar elastosis, favor a drug eruption. yet another distinguishing feature noted in 16 of our 36 cases of lichenoid drug eruption is slight spongiosis. in 10 cases, clusters of neutrophils were present in dilated venules of the papillary dermis (figure 6 a, b). none of those findings excludes lichen planus, but a combination of several of them is a strong indicator of a lichenoid drug eruption. at least two of the aforementioned distinguishing feaures were observed in 31 of 36 lichenoid drug eruptions (86%). another clue to diagnosis of a lichenoid drug eruption noted in the literature, but not observed in any of our cases, is presence of multinucleated histiocytic giant cells at the dermo-epidermal junction or within epidermal or adnexal epithelium [36–36]. lichenoid psoriasiform dermatitis a lichenoid psoriasiform dermatitis was observed in 18 of 300 consecutive drug eruptions (6%). in addition to a patchy lichenoid infiltrate of lymphocytes and uneven psoriasiform epidermal hyperplasia, those cases were associated with very scant spongiosis, some lymphocytes in the epidermis, and subtle fibrosis with coarse collagen fibers in the papillary dermis. figure 6. a) lichenoid drug eruption that resembles lichen planus because of irregular epithelial hyperplasia, focal hypergranulosis, orthokeratosis, and a “saw-tooth” pattern of rete ridges. b) some eosinophils within the infiltrate and numerous neutrophils in the lumina of dilated venules militate against lichen planus and favour a drug eruption. 42 review | dermatol pract concept 2011;1(1):9 all those features are also seen in the patch stage of mycosis fungoides. moreover, subtle vacuolar changes at the dermo-epidermal junction, lymphocytes with largish nuclei, and eosinophils may be seen in both diseases. in the literature, drug eruptions mimicking mycosis fungoides have been reported especially following intake of carbamazepin and phenytoin [14-17], but other compounds have also been implicated [37-41]. because drug eruptions may also simulate mycosis fungoides clinically, differentiation of those diseases is all the more challenging. it has been claimed that drug-induced pseudolymphomas “cannot be differentiated from true lymphomas through clinical, pathological or molecular findings,” the only way of differentiation being “resolution of the lesions after the medication involved is suspended” [17]. although this is true for individual cases, there are several histopathologic clues that help to distinguish mycosis fungoides from mycosis fungoides-like drug eruptions. in the patch stage of mycosis fungoides, one may see lymphocytes aligned in the basal layer, dense infiltrates of lymphocytes in dermal papillae, lymphocytes in the epidermis that are larger than those in the dermis, and intra-epidermal collections of largish lymphocytes, findings hardly ever encountered in drug eruptions. drug eruptions that present themselves as a lichenoid psoriasiform dermatitis with fibrosis in the papillary dermis are chronic lesions, following prolonged intake of the eliciting drug. nevertheless, they tend to retain signs of acute inflammation not normally seen in mycosis fungoides, including a wholly basket-woven cornified layer, edema of the papillary dermis, sometimes presence of neutrophils in the infiltrate, markedly dilated venules in the papillary dermis, and, not uncommonly, many neutrophils in the lumina of dilated venules (figure 7 a, b). early patches of mycosis fungoides usually do not show a striking predominance of cd4-positive lymphocytes, but if such predominance is found, it militates against a drug eruption in which cd4 and cd8-positive lymphocytes are present in roughly equal numbers [41]. another differential diagnosis of lichenoid psoriasiform drug eruptions is secondary syphilis. in both diseases the infiltrate may be composed of lymphocytes, histiocytes, eosinophils, neutrophils, and plasma cells. however, in syphilis, epithelioid histiocytes and plasma cells are common and may outnumber lymphocytes, whereas eosinophils are exceptional. the opposite is true for drug eruptions. another finding commonly seen in secondary syphilis, but not in drug eruptions, is pallor of keratocytes in the upper part of the epidermis. spongiotic dermatitis drug eruptions commonly present themselves as a spongiotic dermatitis. we found a spongiotic dermatitis in 62 of 300 consecutive drug eruptions (21%), and some spongiosis was also present in many other cases in which it was not the predominant pattern. in our study of maculopapular drug eruptions in which the eliciting agents were known, 58 of 60 cases (97%) were associated with at least subtle spongiosis [11]. most commonly, spongiosis is mild and confined to the lower half of the epidermis. spongiotic vesicles were seen in less than half of the cases classified as spongiotic dermatitis. those vesicles were usually small and confined to one or two foci, a pattern observed in 20 of 62 cases (32%). marked spongiosis across a broad front with large confluent vesicles was seen in only 6 cases (10%), all of which were associated with at least some eosinophils and neutrophils in the epidermis. spongiotic drug eruptions must be distinguished from other spongiotic dermatitides, especially pityriasis rosea, erythema annulare centrifugum, and contact and nummular dermatitis. unlike drug eruptions, those diseases are rarely figure 7. a) lichenoid psoriasiform drug eruption mimicking the patch stage of mycosis fungoides because of a patchy lichenoid infiltrate, focal presence of lymphocytes in the epidermis in concert with scant spongiosis, focal alignment of lymphocytes in the basal layer of the epidermis, and wiry bundles of collagen in the papillary dermis. b) features militating against mycosis fungoides are scattered eosinophils, widely dilated venules in the upper dermis, and, especially, numerous neutrophils in the lumina of venules. review | dermatol pract concept 2011;1(1):9 43 associated with neutrophils, and although eosinophils are common, they tend to be less abundant than in spongiotic drug eruptions, the latter sometimes showing clusters of eosinophils in the upper dermis. another common finding in drug eruptions that is rare, or less pronounced, in other spongiotic dermatitides, is many neutrophils in dilated venules. the most common pattern of spongiosis in drug eruptions, namely, mild spongiosis without vesiculation across a broad front in the lower half of the epidermis, is relatively distinctive (figure 8). cases with tiny isolated spongiotic vesicles resemble pityriasis rosea and erythema annulare centrifugum (figure 9). the latter diseases are often associated with focal scale-crusts, which are rare in spongiotic drug eruptions, and they hardly ever show extension of the infiltrate into the deep dermis, a finding encountered in nearly one third of our cases of spongiotic drug eruptions. in acute cases of contact and nummular dermatitis, there is more spongiosis in relationship to the density of the infiltrate. in drug eruptions associated with marked spongiosis and confluent spongiotic vesicles, the infiltrate is usually very dense, and eosinophils in the epidermis are more common than in contact and nummular dermatitis. the latter diseases usually show broad zones of parakeratosis. by contrast, a spongiotic dermatitis in which the cornified layer is mostly basketwoven should raise suspicion of a drug eruption. chronic lesions of contact and nummular dermatitis usually show epidermal hyperplasia, which is rare or minimal, in spongiotic drug eruptions. pustular dermatitis neutrophils in the epidermis are commonly observed in drug eruptions. in our study of maculopapular drug eruptions in which the eliciting agents were known, 19 of 60 cases (32%) were associated with at least some neutrophils in the epidermis. the latter were mostly seen in or immediately beneath the cornified layer. large aggregations of neutrophils with formation of spongiform pustules, however, are relatively rare. we observed that pattern in 19 of 300 consecutive drug eruptions (6%). three of those cases were diagnosed clinically as acute generalized exanthematous pustulosis. the latter cases were among those in which pustules were aggregated most closely but, otherwise, they were indistiguishable from other pustular drug eruptions. all cases were associated with eosinophils and edema of the papillary dermis, which sometimes was prominent. in eight of 19 cases, necrotic keratocytes were scattered in the epidermis. two cases not diagnosed clinically as acute generalized exanthematous pustulosis were associated with subtle signs of leukocytoclastic vasculitis, namely, fibrin in the wall of at least one venule and some nuclear dust. the differential diagnosis of pustular drug eruptions includes pustular psoriasis, deficiency disorders such as necrolytic migratory erythema and acrodermatitis enteropathica, and pemphigus, especially iga pemphigus. in pemphigus, the infiltrate tends to be relatively evenly distributed. in the dermis, it is usually restricted to the upper half and does not show significant perivascular accentuation. in the epidermis, neutrophils may be dispersed evenly across a broad front in concert with scant spongiosis [42]. by contrast, the infiltrate in drug eruptions is often accentuated around blood vessels and may be deep as well as superficial. in the epidermis, neutrophils are not scattered broadly but usually aggregated in discrete foci. evidently, signs of acantholysis favor pemphigus and militate against a drug eruption, although some acantholytic cells may also be found in pustules of drug eruptions. in cases of doubt, this differential diagnoses can be resolved easily by immunofluorescence studies. intraor subcorneal abscesses in deficiency disorders are usually elongated rather than discrete, as in most cases of pustular drug eruptions. when drug eruptions are associated with elongated abscesses, the infiltrate is usually very dense figure 8. maculopapular drug eruption with mild spongiosis in the lower half of the epidermis and a basket-woven cornified layer. figure 9. spongiotic drug eruption with isolated spongiotic vesicles. the cornified layer is mostly basket-woven. typical of a drug eruption are widely dilated vessels in the upper dermis. 44 review | dermatol pract concept 2011;1(1):9 and associated with many eosinophils, whereas disorders of deficiency, as a rule, show a mild or moderately dense infiltrate and few or no eosinophils. in pustular drug eruptions, the cornified layer is mostly basket-woven, whereas disorders of deficiency usually show confluent parakeratosis. a clue to diagnosis of disorders of deficiency is pallor of the upper half of the epidermis. by contrast, in drug eruptions, the lower half of the epidermis may appear pale due to mild spongiosis there. prurigo pigmentosa is a rare disease of unknown etiology characterized by sudden onset of papules and papulovesicles in a reticular pattern on the back, neck, and chest that tends to resolve within days, leaving behind net-like hyperpigmentation. histopathologically, early stages are characterized by a superficial infiltrate predominated by neutrophils that are scattered in the epidermis where they may form subcorneal pustules. because lesions may also show prominent edema in the papillary dermis, subtle vacuolar changes at the junction, necrotic keratocytes, and some eosinophils in the infiltrate, a distinction from pustular drug eruptions may be impossible. however, eosinophils tend to be sparse in number, whereas there are often abundant eosinophils in drug eruptions. moreover, unlike pustular drug eruptions, lesions of prurigo pigmentosa commonly exhibit nuclear dust [43]. the most important differential diagnosis of pustular drug eruptions is pustular psoriasis. pustular psoriasis is more difficult to distinguish from drug eruptions than other types of psoriasis because of lack of epidermal hyperplasia and common presence of some eosinophils. in drug eruptions, however, eosinophils are more numerous and may be seen in clusters, a finding militating strongly against psoriasis. in a recent comparison of acute generalized exanthematous pustulosis and pustular psoriasis, criteria with the highest distinguishing value in favor of the former diagnosis were eosinophils, especially when present within pustules, necrotic keratocytes, focal leukocytoclasia, and deep extension of the infiltrate [44]. moreover, spongiosis in pustular drug eruptions has been claimed to be “usually mild, in contrast to that seen in pustular psoriasis.” [2] subepidermal bullous dermatitis autoimmune subepidermal bullous diseases may be induced by drugs, a phenomenon especially common in linear iga dermatosis. subepidermal blisters in drug eruptions, however, may also result from an interface dermatitis and, rarely, from massive edema in the papillary dermis. we observed subepidermal blisters in six of 300 consecutive drug eruptions (2%), all of which showed signs of interface dermatitis (figure 10 a, b). in four of those cases, a clinical differential diagnosis of drug eruption versus bullous pemphigoid was given, and the latter diagnosis was excluded by failure to detect autoantibodies in elisa and/or immunofluorescence studies. histopathologic differentiation between bullous pemphigoid and bullous drug eruptions may be difficult because both diseases, in addition to subepidermal blisters, may show a perivascular and interstitial infiltrate with many eosinophils and some neutrophils in the superficial and mid dermis. necrotic keratocytes may also be seen in both diseases. in bullous pemphigoid, however, the latter are restricted to the roof of the blister. necrotic keratocytes at the edge of the blister, where the epidermis has not yet detached from the dermis, strongly favor a drug eruption. the same is true for other signs of interface dermatitis, including prominent vacuolar alteration at the junction and melanophages in the papillary dermis. neutrophils are less common in bullous pemphigoid and, when present, usually sparse (figure 8 a, b). granulomatous dermatitis drug eruptions may be associated with granulomatous inflammation. we observed granulomas in 12 of 300 consecutive drug eruptions (4%). two patterns of granulomatous inflammation could be distinguished. in five cases, there were figure 10. a) bullous drug eruption with a large subepidermal blister caused by simvastatin. b) the edge of the blister reveals signs of an interface dermatitis with vacuolar changes at the dermo-epidermal junction and numerous necrotic keratocytes. there are no eosinophils at the junction. review | dermatol pract concept 2011;1(1):9 45 one or few small, round to oval, sharply circumscribed granulomas in the upper dermis. in three of those cases, at least one granuloma was situated in close proximity to an eccrine duct, suggesting damage to the duct and leakage of sweat as a possible cause of granulomas. all five cases were associated with epidermal changes, either focal spongiosis (two cases), or foci of interface dermatitis (two cases), or both (one case). the associated epidermal changes distinguished those drug eruptions from the most important differential diagnosis, sarcoidosis (figures 2 a, b). another clue to diagnosis of a drug eruption observed in two cases were neutrophils in the lumina of venules, a finding hardly ever observed in sarcoidosis. the second pattern of granulomatous dermatitis was scatter of histiocytes among collagen bundles in one or more poorly circumscribed areas in the superficial and/or deep dermis. there also was a perivascular lymphocytic infiltrate. those changes resembled the interstitial type of granuloma annulare. of seven cases with that pattern, two were indistinguishable from granuloma annulare. in both, a drug eruption could be diagnosed with confidence because of onset of lesions following administration of a new drug (captopril and allopurinol, respectively) and gradual resolution after cessation of it. in those two cases, numerous eosinophils were present, but the latter may also be seen in granuloma annulare. the five other cases could be distinguished from granuloma annulare because of associated epidermal changes, namely, interface changes in four and spongiosis in one of them. subtle signs of an interface dermatitis have been described as a histopathologic clue to diagnosis of a granuloma annularelike drug eruption [45]. in five of our seven cases of granuloma annulare-like drug eruption, eosinophils and neutrophils were sparse or absent. a clue to diagnosis of a drug eruption present in four of seven granuloma annulare-like lesions was presence of neutrophils in the lumina of venules. leukocytoclastic vasculitis in our study of 300 consecutive drug eruptions, two cases showed signs of leukocytoclastic vasculitis. in both, a clinical diagnosis of drug eruption had been given because of onset of lesions shortly after administration of a new drug. in one of those cases, the same type of eruption had occurred once before following administration of the same drug (azithromycin). both cases showed stereotypic features of leukocytoclastic vasculitis, namely, fibrin in the walls of venules, extravasation of erythrocytes, and an inflammatory infiltrate composed of lymphocytes, neutrophils, and eosinophils in concert with nuclear dust. in both cases, there were more eosinophils than normally seen in leukocytoclastic vasculitis, including focal clusters of eosinophils. this is in concurrence with a recent study in which a significantly higher number of eosinophils was found in drug-induced than in non-druginduced cases of leukocytoclastic vasculitis. in that study, the course of drug-induced cases was found to be less severe, with lower incidence of extra-cutaneous involvement and faster resolution [46]. although presence of many eosinophils does not exclude other causes of leukocytoclastic vasculitis, it may serve as a clue to causation by a drug. discussion adverse cutaneous reactions to drugs may occur in many different forms. so divergent are the patterns of drug eruptions that they cannot be considered variants of a single pathologic process. evidently, the cytokines involved in eruptions presenting as a pustular, spongiotic, or severe interface dermatitis must be very different from one another. when several biopsies are taken from the same patient, they usually show the same predominant pattern, although associated findings, such as focal spongiosis in a vacuolar interface dermatitis, may be seen in only one of two biopsy specimens. moreover, patients with recurrent drug eruptions usually show always the same type of response. and yet, there is some overlap. signs of interface dermatitis, for example, are extremely common in drug eruptions. they are mostly mild and most often seen in maculopapular drug eruptions, but even in the latter, they may be pronounced, reaching the degree expected in erythema multiforme and stevens-johnson syndrome. by contrast, the two latter conditions may be associated with only mild interface changes. likewise, histopathologic changes typical of fixed drug eruption, i.e., a pronounced superficial and deep vacuolar interface dermatitis with many necrotic keratocytes and eosinophils and neutrophils in the infiltrate, may be seen in widespread maculopapular drug eruptions, whereas cases diagnosed clinically as fixed drug eruption may be nearly devoid of interface changes. in fact, two of our cases with the clinical diagnosis of fixed drug eruption and associated with many eosinophils and neutrophils showed focal spongiosis as the only epidermal alteration. maculopapular drug eruptions may be associated with suband intracorneal pustules indistinguishable from those of acute generalized exanthematous pustulosis, the latter possibly being an exaggerated form of the same process. not uncommonly, pustular drug eruptions are associated with focal signs of an interface dermatitis. the same is true for spongiotic and granulomatous eruptions. in brief, although clinical entities, such as stevens-johnson syndrome, fixed drug eruption, and acute generalized exanthematous pustulosis are associated with distinctive histopathologic changes, and may be recognized by them, the spectrum of those changes is broader than often suggested in the literature, and it is not always possible to distinguish them from other types of drug eruptions. 46 review | dermatol pract concept 2011;1(1):9 because of overlap of presentations, it was often difficult to attach individual cases to one of the categories of patterns. this, however, is not only unavoidable, but irrelevant for the purpose of distinguishing drug-induced cutaneous eruptions from those not induced by a drug. for that purpose, it is helpful to consider the differential diagnosis of a given pattern and findings that allow drug eruptions to be recognized in that particular context. the categories of patterns discussed above do not encompass the entire spectrum of drug eruptions. for example, there were no examples of nodular dermatitis and panniculitis among our cases. nevertheless, the vast majority of drug eruptions can be assigned to one of the aforementioned categories, and if general criteria for recognition of drug eruptions are observed, and the particular differential diagnoses considered, histopathologic diagnosis of a drug eruption can usually be made with confidence. as in all other inflammatory diseases, the histopathologic diagnosis must be substantiated by clinicopathologic correlation. references 1. ackerman ab, chongchitnant n, sanchez j, et al. histologic diagnosis of inflammatory skin diseases. 2nd ed. baltimore: williams & wilkins, 1997:317. 2. justiniano h, 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pn, goodfield mj, maclennan ka, stevens a, millard lg. severe cutaneous reactions to captopril and enalapril: histological study and comparison with early mycosis fungoides. j clin pathol 1986;39(8):902-7. 38. kardaun sh, scheffer e, vermeer bj. drug-induced pseudolymphomatous skin reactions. br j dermatol 1988;118(4):845-52. 39. magro cm, crowson an. drugs with antihistaminic properties as a cause of atypical cutaneous lymphoid hyperplasia. j am acad dermatol 1995;32(3):419-28. 40. gordon kb, guitart j, kuzel t, et al. pseudo-mycosis fungoides in a patient taking clonazepam and fluoxetine. j am acad dermatol 1996;34(2):304-6. 41. clark sh, duvic m, prieto vg. mycosis fungoides-like reaction in a patient treated with gleevec. j cutan pathol 2003;30(4):27981. 42. ackerman ab, guo y. vitale p, vossaert k. clues to diagnosis in dermatopathology iii. chicago: ascp press, 1998:53-56. 43. boer a, misago n, wolter m, kiryu h, wang xd, ackerman ab. prurigo pigmentosa: new observations and comprehensive review. dermatopathology: practical & conceptual 2002;8(3). 44. kardaun sh, kuiper h, fidler v, jonkman mf. the histopathological spectrum of acute generalized exanthematous pustulosis (agep) and its differentiation from generalized pustular psoriasis. j cutan pathol 2010;37(12):1220-29. 45. magro cm, crowson an, schapiro bl. the interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. j cutan pathol 1998;25(2):72-8. 46. bahrami s, malone jc, webb kg, callen jp. tissue eosinophilia as an indicator of drug-induced cutaneous small-vessel vasculitis. arch dermatol 2006;142(2):155-61. dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(2):e2021007 1 dermatology practical & conceptual cutaneous ulcers in an untreated hiv patient xavier bosch-amate1, xavier fustà-novell1, daniel morgado-carrasco1 1 department of dermatology, hospital clínic de barcelona, universitat de barcelona, spain key words: cutaneous ulcers, syphilis, malignant syphilis, men who have sex with men citation: bosch-amate x, fustà-novell x, morgado-carrasco d. cutaneous ulcers in an untreated hiv patient. dermatol pract concept. 2021;11(2):e2021007. doi: https://doi.org/10.5826/dpc.1102a07 accepted: august 5, 2020; published: march 8, 2021 copyright: ©2021 bosch-amate et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: daniel morgado-carrasco, md, dermatology department, hospital clínic, university of barcelona, spain. email: morgadodaniel8@gmail.com case presentation a 22-year-old man presented with a 6-month history of asthenia, anorexia, severe weight loss of 20 kg, low-grade fever, and cutaneous lesions that had occurred within 1 month. more importantly, this patient presented with untreated hiv infection. physical examination revealed a few erythematous and ulcerated plaques (some with necrotic crusts) on his trunk and extremities (figure 1) and absence of lesions on mucous membranes, palms and soles. blood tests showed 284 cd4/μl and hiv viral load 243,000 copies/ml. nontreponemal tests showed elevated vdrl titers (1/32). lumbar puncture ruled out neurosyphilis. with a diagnosis of malignant syphilis, benzathine penicillin 2.4 mu was administered intramuscularly with complete resolution of symptoms. figure 1. (a, b) malignant syphilis. erythematous and ulcerated plaques with well-demarcated borders on the left arm. 2 image letter | dermatol pract concept 2021;11(2):e2021007 teaching point syphilis has a broad spectrum of mucocutaneous manifestations. malignant syphilis is a rare form of secondary syphilis, associated in most cases with hiv infection, that could present with a few cutaneous lesions. in our case histopathology was not done; however, it usually shows the presence of a dense inflammatory infiltrate, sometimes with a lichenoid pattern, with lymphocytes, plasma cells, and occasional presence of granulomas. early detection of the coexistence of secondary syphilis and hiv infection is essential for correct management and the avoidance of serious complications [1,2]. references 1. tucker jd, shah s, jarell ad, tsai ky, zembowicz a, kroshinsky d. lues maligna in early hiv infection case report and review of the literature. sex transm dis. 2009;36(8):512-514. doi: 10.1097/ olq.0b013e3181a2a946. pmid 19455078. 2. fustà-novell x, morgado-carrasco d, barreiro-capurro a, et al; miembros del grupo de trabajo de infecciones de transmisón sexual del hospital clínic de barcelona. syphilis maligna: a presentation to bear in mind. actas dermosifiliogr. 2019;110(3):232-237. doi: 10.1016/j.ad.2018.02.024. pmid 30098705. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com atypical fibroxanthoma of the cheek—case report with dermatoscopy and dermatopathology mike inskip1, jill magee2, david weedon3, cliff rosendahl4 1 sun patrol skin cancer clinic, berwick, australia 2 dorevitch pathology, heidelberg, australia 3 sullivan nicolaides pathology, brisbane, australia 4 school of medicine, the university of queensland, brisbane, australia keywords: dermatoscopy, dermoscopy, atypical fibroxanthoma, pleomorphic dermal sarcoma citation: inskip m, magee j, weedon d, rosendahl c. atypical fibroxanthoma of the cheek—case report with dermatoscopy and dermatopathology. dermatol pract concept. 2014;4(2):16. http://dx.doi.org/10.5826/dpc.0402a16 received: november 7, 2013; accepted: november 25, 2013; published: april 30, 2014 copyright: ©2014 inskip et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: mike inskip, sun patrol skin cancer clinic, 48 van der haar avenue, berwick vic 3806, australia. email: sunpatrol.scc@bigpond.com introduction atypical fibroxanthoma is an uncommon tumor of fibrous tissue, a spindle cell neoplasm. it has locally aggressive behavior and a tendency to recur after surgery. however its metastatic potential is low [1]. it is most often found on the head and neck on sun damaged skin in elderly patients. clinically it presents as a solitary nodule often with ulceration which can grow rapidly [2,3]. case report a 73-year-old man presented to a primary care skin cancer clinic in melbourne, australia for a routine skin cancer examination. he was concerned about a deep red, slightly domed lesion on his right cheek. this appeared some six weeks earlier. there was a long history of recreational sun exposure. there was a past history of multiple non-melanoma skin cancers, both basal cell carcinoma and squamous cell carcinoma. he had received several courses of 5-fluorouracil cream field therapy to multiple actinic keratoses of the forehead, temples and nose in the last 10 years. a whole body skin examination was undertaken with the aid of a heine delta 20 nonpolarizing dermatoscope (heine optotechnik, herrshing, germany). digital clinical and dermatoscopic images were taken with a medicam 800 fotofinder non-polarizing camera (fotofinder systems gmbh, aichner, birnbach, germany) the dermatoscopy images being at 20x magnification. there was severe actinic damage of the scalp, temples and nose plus less severe actinic damage to the upper trunk and distal limbs with multiple actinic keratoses and solar lentigines. the lesion of concern was located on the right mid cheek and measured 15 mm x 10 mm in diameter (figure 1). observation | dermatol pract concept 2014;4(2):16 77 we present a case report of an atypical fibroxanthoma on the cheek of a 73-year-old man. clinical, dermatoscopic and dermatopathologic images are presented. abstract 78 observation | dermatol pract concept 2014;4(2):16 it was non-pigmented and was composed of two separate parts, a larger deep red nodule inferiorly continuous with a white nodule superiorly. dermatoscopically (figure 2) there was a red structureless area inferiorly and a well demarcated white area superiorly. there were a few erosions and a polymorphous vascular pattern comprising dot and linear vessels. based on the polymorphous vascular pattern, a preoperative diagnosis of a malignant skin tumor including amelanotic melanoma, undifferentiated squamous cell carcinoma, merkel cell carcinoma or other malignant uncommon adnexal tumor was suspected. an excisional biopsy was performed and the specimen was submitted for assessment by a specialist dermatopathologist. examination of the histological sections (figures 3-6) revealed sun damaged skin with a hypercellular proliferation of atypical spindle cells in the dermis. this proliferation abutted the undersurface of the epidermis but did not appear to be continuous with it. the cells were arranged in whorled nests as well as in sheets. prominent mitotic activity was seen with a mitotic rate of approximately 2 per square millimeter. figure 1. clinical image of a non-pigmented skin lesion on the right cheek of a 73-year-old man. [copyright: ©2014 inskip et al.] figure 2. dermatoscopy: red structureless area inferiorly and a large well demarcated white clod superiorly plus a polymorphous vascular pattern comprising dot and linear vessels. [copyright: ©2014 inskip et al.] figure 3. low power photomicrograph showing an ulcerated hypercellular  proliferation of atypical spindle cells forming irregular fascicles and sheets, extending down to the subcutis. [copyright: ©2014 inskip et al.] figure 4. medium power photomicrograph demonstrating nuclear pleomorphism. [copyright: ©2014 inskip et al.] figure 5. high power photomicrograph demonstrating an area of necrosis and foreign body reaction. [copyright: ©2014 inskip et al.] observation | dermatol pract concept 2014;4(2):16 79 on sun damaged skin in older patients should be completely excised and submitted for specialist dermatopathological examination especially when a benign lesion cannot be confidently excluded on dermatoscopy. dermal nevus and sebaceous hyperplasia would be the most common benign raised lesions on the face in older patients. the lesion we present did not have the typical yellow clods and crown pattern blood vessels of sebaceous hyperplasia. neither did it have the typical brown clods and curvilinear blood vessel patterns of dermal nevus. application of the “efg rule,” which recommends excision of any skin lesion with the clinical features of elevation, firmness and growth would have also ensured this lesion was removed and subjected to histopathological examination [6,7]. atypical fibroxanthoma is currently considered an uncommon tumor. however, such uncommon tumors will present more often as the world population increases in age and has increased access to modern medicine. dermatoscopy is a relatively new diagnostic tool. the authors feel it is important to publish such dermatoscopic images as ours to as wide an audience as possible to aid clinical diagnosis in future. references 1. mirza, weedon d. atypical fibroxanthoma: a clinicopathological study of 89 cases. australas j dermatol. 2005;46(4):235-8. 2. fretzin df, helwig eb. atypical fibroxanthoma of the skin. a clinicopathologic study of 140 cases. cancer. 1973;31(6):1541–52. 3. bugatti l, filosa g. dermatoscopic features of cutaneous atypical fibroxanthoma: three cases. clin exp dermatol. 2009;34(8): 898–e900. 4. miller k, goodlad jr, brenn t. pleomorphic dermal sarcoma: adverse histologic features predict aggressive behavior and allow distinction from atypical fibroxanthoma. am j surg pathol. 2012;36(9):1317–26. bizarre multinucleated giant cells were present. the lesion extended through the full thickness of the dermis into the subcutis to a depth of approximately 2.5 mm (approximate due to fragmentation). immunohistochemical stains were performed. these were negative for s100, and cytokeratin ae1/ae3 and high molecular weight keratin, and positive for the histiocytic marker cd68 (kp-1), favoring the diagnosis of atypical fibroxanthoma. it was initially thought this lesion might be a pleomorphic dermal sarcoma, a rare and more aggressive variant of atypical fibroxanthoma [4]. however, the criteria of perineural and lymphovascular invasion were absent. in the end it was felt the lesion was more in keeping with an atypical fibroxanthoma with inflammation. conclusion until recent years there has been little published literature about the dermatoscopy of atypical fibroxanthoma. in 2009 bugatti et al described the dermatoscopic patterns of three cases of atypical fibroxanthoma and concluded that “atypical fibroxanthoma may be added to the list of slightly pigmented, reddish, malignant cutaneous tumors such as squamous cell carcinoma, merkel cell carcinoma, amelanotic⁄hypomelanotic melanoma and eccrine porocarcinoma, displaying prominent and chaotic dermatoscopic neoangiogenetic features in more advanced stages of proliferation” [3]. in 2013 lallas et al reported on the dermoscopic patterns of five atypical fibroxanthomas which were “typified by reddish and whitish areas in combination with a polymorphous vascular pattern consisting of various combinations of linear, dotted, hairpin and highly tortuous vessel irregularly distributed over the surface of the lesion” [5]. these descriptions fit in with the dermatoscopic appearance of the lesion we present. any growing nodular lesion figure 6. immunohistochemistry showed positive staining for cd68, (a) a histiocytic marker and (b) cd 10, consistent with atypical fibroxanthoma. cytokeratin and s100 stains were negative. [copyright: ©2014 inskip et al.] a b 80 observation | dermatol pract concept 2014;4(2):16 7. chamberlain aj, fritschi l, kelly jw. nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection j am acad dermatol. 2003;48(5):694–701. 5. lallas a, moscarella e, argenziano g, et al. dermoscopy of uncommon skin tumors. australas j dermatol. epub 2013 jul 19. 6. giacomel j, zalaudek i, mordente i, nicolino r, argenziano g. never perform laser treatment of skin tumors with clinical “efg” criteria. j dtsch dermatol ges. 2008;6(5):386-8. http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed?term=giacomel j%5bauthor%5d&cauthor=true&cauthor_uid=18042248 http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed?term=zalaudek i%5bauthor%5d&cauthor=true&cauthor_uid=18042248 http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed?term=mordente i%5bauthor%5d&cauthor=true&cauthor_uid=18042248 http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed?term=nicolino r%5bauthor%5d&cauthor=true&cauthor_uid=18042248 http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed?term=argenziano g%5bauthor%5d&cauthor=true&cauthor_uid=18042248 http://www.ncbi.nlm.nih.gov.ezproxy.library.uq.edu.au/pubmed/18042248 dermatology: practical and conceptual review | dermatol pract concept 2020;10(4):e2020095 1 dermatology practical & conceptual from skin to kidneys: cutaneous clues of renal disease in children mario diplomatico1, pierluigi marzuillo1, angela la manna1, andrea apicella2, stefano guarino1, vincenzo piccolo3 1 general and specialized surgery for women and children, university of campania luigi vanvitelli, naples, italy 2 emergency and icu departments, aorn santobono-pausilipon, naples, italy 3 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: pediatrics, dermatology, nephrology, vasculitides, syndromes citation: diplomatico m, marzuillo p, la manna a, apicella a, guarino s, piccolo v. from skin to kidneys: cutaneous clues of renal disease in children. dermatol pract concept. 2020;10(4):e2020095. doi: https://doi.org/10.5826/dpc.1004a95 accepted: june 1, 2020; published: october 26, 2020 copyright: ©2020 diplomatico et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: mario diplomatico, md, general and specialized surgery for women and children, university of campania luigi vanvitelli, via luigi de crecchio 2, 80138, napoli, italy. email: mario.diplomatico@gmail.com background: the skin is often seen as a world apart, but not rarely do cutaneous manifestations reveal signs of systemic disease. objectives: the aim of this review is to include in one paper all the possible correlations between nephrological and dermatological manifestations of the same disease in pediatric patients while also keeping in mind that in apparent exclusively dermatological diseases there can be nephrological manifestations as part of the same disorder and vice versa. methods: we searched on pubmed for a possible link between skin and kidney matching the following terms and correlated mesh terms: dermatology, skin, kidney, renal disease, nephrology, pediatrics, child, childhood, vasculitis, and cancer. we selected only articles reporting a link between nephrology and dermatology in pediatrics, and they are all included in this comprehensive review. results: kawasaki disease, henoch-schönlein purpura, systemic lupus erythematosus, dent disease, subcutaneous fat necrosis, langerhans cell histiocytosis, renal cell carcinoma, non-hodgkin lymphoma, tuberous sclerosis complex and syndromes with increased risk for wilms tumor, fabry disease, nail-patella syndrome, neurofibromatosis type 1, beckwith-wiedemann syndrome, adams-oliver syndrome 1, apert syndrome, fanconi pancytopenia syndrome, pallister-hall syndrome, and fanconi pancytopenia syndrome are all conditions in which there can be both nephrological and dermatological manifestations in children. conclusions: we could not find any reports that focused attention on the link between nephrological and dermatological manifestations of the same disease in children. it is also important for clinicians to keep in mind that in what may appear to be an exclusively dermatological disease, there can be nephrological manifestations as part of the same disorder and vice versa. abstract 2 review | dermatol pract concept 2020;10(4):e2020095 ated with the risk of cardiac damage. as recently reported by chuang et al, renal involvement is underestimated, and they found it in 52% of the cases with a significant association between acute kidney injury (aki) and age and alanine transaminase (alt) level: the younger the age and/or the higher the alt value, the more important it is to check renal function during both acute and convalescent phases. they also found that sterile pyuria was more prevalent in kd patients with aki than in the non-aki group (p < 0.01). although they did not find a significant correlation at the multivariate logistic regression (p = 0.72), recent studies are frequently supporting the involvement of kidney, bladder, and urethra in its formation [1,2]. henoch-schönlein purpura is an iga vasculitis characterized by lower extremity purpura that is variably associated with abdominal, joint and renal involvement. in contrast to kd, the risk of renal involvement (hematuria and proteinuria within or beyond nephrotic range) in patients affected by hsp increases with age: children older than 8 years have a 2.7-fold higher risk of nephritis [3]. the most common primary large vessel vasculitis in childhood is takayasu arteritis, even though it is predominantly reported in the second and third decades of life, most likely due to its subtle onset that contributes to a delayed diagnosis. it is mainly characterized by constitutional symptoms, alteration of peripheral pulses, hypertension (due to the narrowing of one or both renal arteries, often overlooked in children), and arthralgias, but it may also present with skin involvement, such as rashes or nodules resembling pyoderma gangrenosum or erythema nodosum [4]. as a key point, we suggest checking renal involvement in almost every vasculitis. systemic lupus erythematosus systemic lupus erythematosus (sle) is a chronic autoimmune inflammatory disease affecting many organs. the manifestations in children are the same as in adults, but children are more often affected by a severe organ involvement as a presenting manifestation, primarily nephropathy and hematological involvement [5]. cutaneous manifestations (some of which are included in the diagnostic criteria) are extremely common in sle, as they present as the first sign in up to 25% of cases and are classified into specific and non-specific lupus manifestations. lupus-specific manifestations are acute (malar rash and photosensitive lupus rash), subacute (maculopapular rash), chronic (discoid rash), whereas nonspecific ones are mucosal ulcers, non-scarring alopecia, and vascular abnormalities (periungual erythema, livedo reticularis, raynaud phenomenon, vasculitis) [6]. variable degrees of renal involvement are present in up to 70% of children introduction the skin is primarily involved in many diseases, and some cutaneous manifestations can also reveal signs of an internal disease. renal disease is revealed by the changing amount, concentration, elements, and color of the urine, but sometimes it can be suspected based on cutaneous manifestations. what about the possibility of recognizing or suspecting renal diseases by skin manifestations in pediatric patients? the aim of the present review is to examine cutaneous involvement with nephrological diseases, to explore the importance of the cutaneous manifestations as a clue to kidney disease, and to put the attention on their possible link. search strategy we searched pubmed for a possible link between skin and kidney using these search strategies: (“kidney”[mesh] and “dermatology”[mesh] and “pediatrics”[mesh]), (“kidney”[mesh] and “dermatology”[mesh] and “child”[mesh]), (“kidney”[mesh] and “dermatology”[mesh] and “childhood”), (“nephrology”[mesh] and “dermatology”[mesh] and “child”[mesh]), (“nephrology”[mesh] and “child”[mesh] and “skin”[mesh]), (“kidney diseases”[mesh] and “dermatology”[mesh] and “child”[mesh]), (“kidney diseases”[mesh] and “dermatology”[mesh] and “pediatrics”[mesh]), (“vasculitis”[mesh] and “dermatology”[mesh] and “pediatrics”[mesh]), (“vasculitis”[mesh] and “kidney”[mesh] and “pediatrics”[mesh]), (“neoplasms”[mesh] and “dermatology”[mesh] and “pediatrics”[mesh]), (“neoplasms”[mesh] and “kidney”[mesh] and “pediatrics”[mesh]). we selected only articles that reported a link between nephrology and dermatology in pediatrics, and they are all included in this comprehensive review. vasculitis vasculitis is different from systemic lupus erythematosus (sle) in that inflammation of blood vessels may occur as a primary process, and because of multisystemic involvement, many subspecialties are involved in its diagnosis. in pediatrics, the most common primary medium to small vessel vasculitides in childhood are kawasaki disease (kd) and henoch-schönlein purpura (hsp). kd is a febrile disease associated with polymorphous exanthema, changes in extremities (erythema of the palms and soles, indurative edema of the hands and feet, swelling, and fissuring between the nails and the tips of the fingers), bilateral bulbar conjunctivitis without exudate, lip and oral cavity involvement, and cervical lymphadenopathy. notably, it is always associreview | dermatol pract concept 2020;10(4):e2020095 3 fabry disease fabry disease is an x-linked metabolic disorder due to a deficiency of lysosomal α-galactosidase a. this deficiency leads to accumulation of glycosphingolipids in the whole body, including the heart and peripheral and autonomic nervous systems later in life. onset of symptoms seems to occur earlier in males than in females (mean age 10.9 vs 22.6 years). children diagnosed with fabry disease can develop proteinuria, anhidrosis, and angiokeratoma. early recognition is important because increasing evidence suggests that enzyme replacement treatment is most beneficial in terms of clinical outcome when initiated early in the disease process [16]. subcutaneous fat necrosis until the establishment of protocols for therapeutic neonatal hypothermia, a documented complication was subcutaneous fat necrosis (sfn). sfn is a granulomatous disorder associated with perinatal asphyxia, trauma, or prolonged exposure to cold, that presents with subcutaneous indurated purplecolored nodules associated with hypercalcemia (probably because of the damage to the fat tissue). although not clearly understood, the mechanism of hypercalcemia in sfn may be due to the damage to fat tissue that causes necrosis, increased production of 1.25-dihydroxyvitamin d by macrophages, increased calcium absorption from the gastrointestinal tract, and osteoclast activation by prostaglandins. severe hypercalcemia (calcium level >3 mmol/l) is a life-threatening condition at any age, has a mortality rate of up to 15% in sfn, and it is associated with kidney injury, with or without nephrocalcinosis, as well as with cardiac complications [17]. in the case of severe hypercalcemia a urinalysis and kidney ultrasounds are suggested. langerhans cell histiocytosis langerhans cell histiocytosis (lch) is a rare disease characterized with various presentations. the most commonly involved sites are bones, skin, lymph nodes, pituitary gland, liver, lung, and spleen, and the dissemination affects the prognosis and treatment. histopathology shows monoclonal langerhans cells together with lymphocytes, eosinophilic granulocytes and non-dendritic histiocytes. this disease usually presents on the skin with brown or purplish papules and an eczematous rash (often misdiagnosed as “cradle cap” on the scalp). renal involvement is rarely reported in the literature but is characterized by a variable infiltration of glomeruli or interstitium, and presents as nephrotic syndrome or interstitial nephritis [18]. more frequently, polyuria and polydipsia can be the nephrological signs of pituitary gland involvement causing central diabetes insipidus [19]. affected by sle. lupus nephritis is defined by kidney biopsy in 6 classes and can be present without any other sign of sle [7]. lupus nephritis is not the only way in which sle can involve the kidney. other forms of renal involvement are: tubulointerstitial nephritis (strong correlation with the prognosis for hypertension, elevation of plasma creatinine concentration, and progressive clinical course); vascular disease (with deposition of immune deposits in the glomeruli, thrombotic microangiopathy, and atherosclerosis); glomerular podocytopathy (independent of immune complex deposition); and collapsing glomerulosclerosis (similar to hiv-associated nephropathy) [8–11]. if sle is suspected, screening for renal involvement is suggested, ie, a urinalysis to rule out the presence of hematuria and proteinuria. dent disease dent disease is a heterogeneous x-linked recessive disorder that, similarly to fanconi syndrome, presents with low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, and progressive renal failure. up until now, due to its heterogeneity, only 2 genes have been identified: clcn5 (dent disease type 1-60% of cases) and ocrl1 (dent disease type 2-15% of cases). the remaining percentage of disease remains genetically unexplained, as there have been reported cases of patients with dent disease phenotype without mutations in these 2 genes [12,13]. no association between skin and dent disease type 2 (dd-2) before 2018 was reported, although it has been reported with lowe syndrome, namely, oculocerebrorenal syndrome; secondary to a mutation in the same ocrl1 gene; and sometimes presents with eruptive hair vellus hair cysts, tricho epithelioma, and excessive skin folds [14]. marzuillo et al reported the possible association between dd-2 and hidradenitis suppurativa. hidradenitis suppurativa has a prevalence of 1% in the general population with an average age onset in the second to third decade of life but a prevalence of 80% in patients affected by dd-2: all males, with mean age of onset of 13 years. as postulated, a possible explanation could be an increased susceptibility to staphylococcal cutaneous infections and a stimulation of cutaneous inflammation associated with impairment of the junctional components due to mutations in ocrl1 gene that drastically reduce (<10%) inositol polyphosphate 5-phosphatase (ocrl1) activity [15]. therefore, dent disease should be taken into consideration when evaluating a male child or a young boy with hidradenitis suppurativa and proximal tubule dysfunction with low molecular weight proteinuria and hypercalciuria, nephrolithiasis, nephrocalcinosis, progressive renal failure, and intellectual disability. 4 review | dermatol pract concept 2020;10(4):e2020095 neurofibromatosis type i (nf1) is a genetic disorder due to a mutation in or deletion of the nf1 gene that produces neurofibromin, a tumor suppressor protein. nf1 is usually recognized by axillary freckling, café-au-lait spots, and neurofibromas, but the kidney may also be involved in developing wt or angiomyolipomas. this disease also affects the bones, eyes, and nervous system [25]. beckwith-wiedemann syndrome is an overgrowth disorder due to abnormalities involving genes on chromosome 11. beckwith-widemann syndrome is characterized by large kidneys with medullary dysplasia, renal cysts, and urinary tract anomalies, neuroblastoma or wt (approximately 7.5% of cases), hemihypertrophy, and facial nevus flammeus in skin [26]. adams-oliver syndrome 1 is a genetic disorder that manifests with occasional urinary tract anomalies associated with a more common aplasia cutis congenita of the parietal region, trunk or limbs, cutis marmorata, telangiectasia congenita, and hypopigmented skin [26]. apert syndrome is an autosomal dominant disease, with onset in infancy, that presents with craniofacial anomalies, syndactyly, hyperhidrosis, and pronounced acne at adolescence. in 10% of cases, it is associated with polycystic kidneys and hydronephrosis [26]. fanconi pancytopenia syndrome commonly affects the skin, producing brownish pigmentation, and the kidneys by developing different renal anomalies such as hypoplasia or malformation [26]. pallister-hall syndrome usually affects both kidneys with renal ectopia or dysplasia and the skin with midline facial hemangioma [26]. conclusions we could not find any reports that focused attention on the link between nephrological and dermatological manifestations of the same disease in children. it is also important for clinicians to keep in mind that in what may appear to be an exclusively dermatological disease, there can be nephrological manifestations as part of the same disorder and vice versa. whenever a kidney disease is suspected, the following tests must always be performed: urinalysis and quantification of proteinuria, serum creatinine, and urea and an ultrasound of kidneys. acknowledgments the authors thank anna carella for reviewing the english language of this manuscript. renal cell carcinoma renal cell carcinoma is extremely rare in children, but is more common in adolescents older than 15 years of age. the classic triad of hematuria, flank pain, and palpable abdominal mass is present in less than 10% of adult cases; the diagnosis is often incidental. the skin may be involved by flushing because of prostaglandins production [20]. non-hodgkin lymphoma non-hodgkin lymphoma is a tumor originating from lymphoid tissues, mainly lymph nodes, that in about 30% of cases presents with extranodal involvement at the diagnosis. the most commonly involved sites are skin, bone marrow, central nervous system, gastrointestinal and genitourinary tract, thyroid, and sinuses. the skin is the second most common extranodal localization of disease presenting with rashes or lesions that should always be biopsied. the possible renal involvement (up to 14% of cases) includes enlarged kidneys, ureteral obstruction (due to retroperitoneal disease), tubular dysfunction (due to acute uric acid nephropathy), and renal failure [21]. other syndromes, malformations and genetic disorders wilms tumor (wt) is rarely diagnosed in the neonate, but it is the most common renal cancer in childhood (95% of cases). in approximately 10% of cases, it is part of syndromes such as wagr, beckwith-weidemann, and denys-drash. certain overgrowth conditions associated with capillary malformation and hemihypertrophy or macrocephaly-capillary malformation also have an increased risk for wt; in these cases, a ultrasonographic screening for wt is necessary [22]. tuberous sclerosis complex is an autosomal dominant genetic disorder (tsc1 or tsc2 genes) with an incidence of 1:5000-10000 that involves many organ systems. reported skin lesions are hypopigmented macules, angiofibromas, shagreen patches, fibrous plaque, and ungual fibromas, whereas renal lesions include angiomyolipomas, cysts, lymphangiomas, and renal cell carcinoma that can interfere with renal function causing hypertension and hemorrhage. since the prevalence of renal manifestations increases with age, ultrasonographic follow-up is required every 1-3 years [23]. nail-patella syndrome is an autosomal dominant condition affecting the nails, skeletal system, kidneys, and eyes, and while renal failure can appear later in life, the most common sign is having missing or underdeveloped fingernails and toenails [24]. review | dermatol pract concept 2020;10(4):e2020095 5 ture. 1996;379(6564):445-449. doi: 10.1038/379445a0. pmid:8559248. 14. erdoğan f, ismailoğullari s, soyuer i, ferahbaş a, poyrazoğlu h. different seizure types and skin lesions in oculocerebrorenal syndrome of lowe. j child neurol. 2007;22(4):427-431. doi: 10.1177/0883073807301928. pmid:17621522. 15. marzuillo p, piccolo v, mascolo m, et al. patients affected by dent disease 2 could be predisposed to hidradenitis suppurativa. j eur acad dermatology venereol. 2018;32(8):e309-e311. doi: 10.1111/jdv.14860. pmid:29430722. 16. eng cm, germain dp, banikazemi m, et al. fabry disease: guidelines for the evaluation and management of multi-organ system involvement. genet med. 2006;8(9):539-548. doi: 10.1097/01.gim.0000237866.70357.c6. pmid:16980809. 17. arango ml, shah an. visual diagnosis: an infant with rash and hypercalcemia. pediatr rev. 2019;40(3):e11-e13. doi: 10.1542/pir.2017-0058. pmid:30824504. 18. materne c, porubsky s, gerth j, grone h-j, wolf g. histiocytosis x and renal insufficiency. nephrol dial transplant. 2007;22(12):3664-3667. doi: 10.1093/ndt/gfm299. pmid:17890248. 19. marzuillo p, grandone a, guarino s, et al. a 23-month-old girl with chronic ‘seborrhoeic’ dermatitis, dehydration and failure to thrive. arch dis child educ pract ed. april 2018:edpract-2018-314828. doi: 10.1136/archdischild-2018-314828. pmid:29703813. 20. sadeghian a, rouhana h, oswald-stumpf b, boh e. etiologies and management of cutaneous flushing. j am acad dermatol. 2017;77(3):405-414. doi: 10.1016/j.jaad.2016.12.032. pmid:28807108. 21. hunter s, samir a, eisner b, et al. diagnosis of renal lymphoma by percutaneous image guided biopsy: experience with 11 cases. j urol. 2006;176(5):1952-1956; discussion 1956. doi: 10.1016/j.juro.2006.07.032. pmid:17070216. 22. peterman cm, vadeboncoeur s, mulliken jb, fishman sj, liang mg. wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly–capillary malformation: a retrospective study. j am acad dermatol. 2017;77(5):874-878. doi: 10.1016/j.jaad.2017.06.014. pmid:28822558. 23. curatolo p, bombardieri r, jozwiak s. tuberouse sclerosis. lancet. 2008;372:657-668. doi: 10.1016/s0140-6736(08)612799. 24. sweeney e, hoover-fong je, mcintosh i. nail-patella syndrome. in: gene reviews. university of washington, seattle; 1993-2020. http://www.ncbi.nlm.nih.gov/pubmed/20301311. 25. has c, he y. renal-skin syndromes. cell tissue res. 2017;369(1):63-73. doi: 10.1007/s00441-017-2623-y. pmid: 28432467. 26. reimer a, he y, has c. update on genetic conditions affecting the skin and the kidneys. front pediatr. 2018;6(march). doi: 10.3389/fped.2018.00043. pmid:29552546. references 1. chuang gt, tsai ij, lin mt, chang ly. acute kidney injury in 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(oxford). 2009;48(12):16161618. doi: 10.1093/rheumatology/kep256. pmid:19713441. 11. salvatore sp, barisoni lmc, herzenberg am, chander pn, nickeleit v, seshan s v. collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease. clin j am soc nephrol. 2012;7(6):914-925. doi: 10.2215/ cjn.11751111. pmid:22461531. 12. hoopes rr, shrimpton ae, knohl sj, et al. dent disease with mutations in ocrl1. am j hum genet. 2005;76(2):260-267. doi: 10.1086/427887. pmid:15627218. 13. lloyd se, pearce sh, fisher se, et al. a common molecular basis for three inherited kidney stone diseases. nauntitled observation | dermatol pract concept 2015;5(2):24 121 dermatology practical & conceptual www.derm101.com nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses bryce d. beutler1, philip r. cohen2 1 university of nevada, las vegas, school of allied health sciences, las vegas, nv, usa 2 department of dermatology, university of california san diego, san diego, ca, usa key words: abraxane, albumin, cremophor, docetaxel, kolliphor, nab-paclitaxel, paclitaxel, photodermatoses, photosensitvity, taxane citation: beutler bd, cohen pr. nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses. dermatol pract concept 2015;5(2):24. doi: 10.5826/dpc.0502a24 received: january 12, 2015; accepted: march 16, 2015; published: april 30, 2015 copyright: ©2015 beutler et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: taxanes [paclitaxel, nab-paclitaxel (abraxane, celgene corp, usa), and docetaxel]— used in the treatment of lung, breast, and head and neck cancers—have been associated with cutaneous adverse effects, including photodermatoses. purpose: we describe a woman with non-small cell lung cancer who developed a photodistributed dermatitis associated with her nab-paclitaxel therapy and review photodermatoses in patients receiving taxanes. materials and methods: the features of a woman with a nab-paclitaxel-associated photodistributed dermatitis are presented and the literature on nab-paclitaxel-associated photosensitivity is reviewed. results: our patient developed nab-paclitaxel-associated photodistributed dermatitis on the sun-exposed surfaces of her upper extremities, which was exacerbated with each course of nab-paclitaxel. biopsies revealed an interface dermatitis and laboratory studies were negative for lupus erythematosus and dermatomyositis. her condition improved following topical corticosteroid cream application and strict avoidance of sunlight. conclusion: chemotherapy can be associated with adverse mucocutaneous events, including dermatoses on sun-exposed areas of the skin. paclitaxel and nab-paclitaxel have both been associated with photodermatoses, including dermatitis, erythema multiforme, onycholysis, and subacute cutaneous lupus erythematosus. strict avoidance of sun exposure, topical or oral corticosteroids, and/or discontinuation of the drug results in improvement with progressive resolution of symptoms and skin lesions. development of photodermatoses is not an absolute contraindication to continuing chemotherapy, provided that the cutaneous condition resolves with dermatosis-directed treatment and the patient avoids sun exposure. abstract 122 observation | dermatol pract concept 2015;5(2):24 including: carboplatin and pemetrexed, gemcitabine, and vinorelbine. treatment with nab-paclitaxel [185 milligrams (100 mg/m2) each week] had been initiated two months prior to the development of the rash. cutaneous examination revealed individual and confluent, erythematous and scaly, plaques on the sun-exposed areas of her neck and arms (figure 1). hyperpigmentation was observed on her face, neck, and upper chest (figures 1 and 2). punch biopsies from the extensor distal left and right arms both show mild spongiosis with hyperkeratosis; scattered dyskeratotic cells are present in the epidermis. there is a sparse interface dermatitis; mild incontinence of pigment is present in the dermis (figure 3). colloidal iron stained sections demonstrate a mild increase of mucin (figure 4). laboratory studies revealed a positive ana at a low titer of 1:160 with a nucleolar pattern. negative studies included antibody to: dsdna, ro, la, smith, rnp, scl-70, jo-1, and histone igg. normal studies included: creatine kinase, aldolase, ldh, ast, and alt. after correlating the clinical, pathology, and laboratory findings, a diagnosis of nab-paclitaxel-associated photosenintroduction taxane-associated cutaneous adverse reactions include photodermatoses [1-3]. we describe a woman with non-small cell lung cancer who developed a dermatitis on sun-exposed areas that progressively worsened with each dose of nab-paclitaxel. we also review other photodermatoses in patients receiving paclitaxel or nab-paclitaxel and address the treatment options for individuals affected by these drug-associated conditions. case report a 69-year-old woman presented for evaluation with a photodistributed rash on the extensor surfaces of her upper extremities. her past medical history was significant for stage iv non-small cell lung cancer. she had progressive disease after sequentially receiving prior antineoplastic therapies, figure 1. erythematous plaques on the sun-exposed extensor surfaces of the patient’s arms with focal sparing of the dermatosis on her left extensor arm corresponding to the area of her skin that had been covered by a wrist watch; there is also hyperpigmentation on her posterior neck. [copyright: ©2015 beutler et al.] figure 2. hyperpigmentation of sun-exposed locations: the face, anterior neck, and “v” area of the upper chest. [copyright: ©2015 beutler et al.] figure 3. hematoxylin and eosin stained sections of nab-paclitaxelassociated photodermatitis show hyperkeratosis, mild acanthosis, and spongiosis with effacement of the rete ridges. there is a sparse interface dermatitis with subtle alteration of the epidermal basal layer and incontinence of pigment in the papillary dermis (hematoxylin and eosin; x40). [copyright: ©2015 beutler et al.] figure 4. colloidal iron stained sections of nab-paclitaxel-associated photodermatitis show a mild increase of mucin in the upper dermis. there are scattered dyskeratotic cells in the epidermis and incontinence of pigment in the papillary dermis (colloidal iron; x20). [copyright: ©2015 beutler et al.] observation | dermatol pract concept 2015;5(2):24 123 the face, upper central chest, and extensor forearms. the condition was successfully treated with topical corticosteroids and strict photoprotection. the patient was able to continue to receive paclitaxel therapy with no recurrence of erythema multiforme or onycholysis [1]. photo recall phenomenon [3] and subacute cutaneous lupus erythematosus [8-10] have been associated with paclitaxel therapy in female patients. one woman developed a lupus erythematosus-like reaction one day after her first dose of paclitaxel. she presented with edema and erythema spreading bilaterally from her nose to her cheeks. a positive ana titer of 1:40 in a nucleolar pattern was observed. topical and systemic corticosteroids were administered and the lesions began to clear. interestingly, the patient was subsequently able to tolerate nab-paclitaxel therapy; the authors attributed her eruption to the kolliphor el solvent rather than the paclitaxel [10]. however, a recent report has linked subacute cutaneous lupus erythematosus to kolliphor el-free nab-paclitaxel. a 62-year-old woman developed erythematous papules and plaques of subacute lupus erythematosus on her sun-exposed arms and chest that appeared after her third infusion with nab-paclitaxel. the lesions completely disappeared after the nab-paclitaxel was withdrawn [7]. reports of photosensitivity dermatitis in patients receiving paclitaxel or nab-paclitaxel therapy are uncommon. however, it is possible that the incidence of these cases is higher than reflected in the literature. we hypothesize that additional affected individuals may not have been recognized or reported since the treatment duration is limited and the dermatoses resolve spontaneously once the agent has been discontinued. drug-induced photosensitivity can be phototoxic or photoallergic. phototoxic dermatoses are common and typically present as a sunburn that appears immediately after moderate exposure to ultraviolet radiation. conversely, photoallergic reactions are rare and are often characterized by pruritic or eczematous lesions that appear on sun exposed areas of the skin 24-72 hours after minimal sun exposure (table 1) [11]. the clinical presentation of our patient’s nab-paclitaxelinduced photodermatosis is most consistent with a photoallergic reaction. the mechanism of pathogenesis for taxane-associated photosensitivity remains to be determined. in some of the patients treated with paclitaxel, aberrations in the biosynthesis of porphyrins have been demonstrated [10,12]. whether elevated porphyrins are an essential feature or an epiphenomenon for the development of paclitaxel-related photosensitivity remains to be determined. our patient declined additional blood and urine studies to evaluate porphyrins after her dermatosis resolved. sitive dermatitis was established. clobetasol 0.05% cream was applied twice daily and she avoided exposure to the sun. most of the erythematous plaques resolved within two weeks. triamcinolone 0.1% cream was substituted — initially, twice and then once daily — until the dermatitis completely resolved. the patient was able to continue receiving nabpaclitaxel therapy without recurrence of her symptoms. discussion taxanes are used in the treatment of lung, breast, ovarian, pancreatic, and head and neck cancers. the first taxane, paclitaxel, was isolated from the bark of the pacific yew tree (taxus brevifolin) by monroe e. wall and mansukh c. wani in 1967. its structure was subsequently elucidated in 1971. however, due to the cost and difficulty of the extraction process and the limited supply of the pacific yew tree, commercial development of paclitaxel did not begin until 1991 [4,5]. paclitaxel is poorly soluble in water and thus most commercially available preparations once contained the non-ionic solvent kolliphor el (basf, usa, formerly cremophor el). nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed in order to reduce or eliminate the risk of hypersensitivity reactions associated with kolliphor el-based paclitaxel. nab-paclitaxel, marketed under the trade name “abraxane,” is an injectable formulation of albumin-linked paclitaxel that can be administered without steroid or antihistamine prophylaxis for hypersensitivity reactions [6]. paclitaxel-induced photodermatoses include erythema multiforme, onycholysis, photo recall phenomenon, and subacute cutaneous lupus erythematosus [1]. it is possible that the photodermatosis in some of these patients was associated with kolliphor el rather than paclitaxel. to the best of our knowledge, subacute cutaneous lupus erythematosus is the only photosensitivity disorder that has been linked specifically to nab-paclitaxel therapy [7]. paclitaxel-induced erythema multiforme on sun-exposed skin has previously been observed. a 40-year-old woman with metastatic breast cancer presented with photodistributed erythema multiforme and onycholysis following treatment with paclitaxel and trastuzumab. elevated urinary and erythrocyte porphyrins were also observed. the severity of the reaction necessitated withdrawal of paclitaxel therapy. the lesions gradually resolved and the porphyrins normalized following withdrawal of the drug [2]. another patient—a 56-year-old woman who was receiving adjuvant weekly paclitaxel for the treatment of intraductal breast carcinoma—developed photodistributed erythema multiforme and onycholysis shortly after brief exposure to sunlight. she developed pruritic and erythematous skin lesions that spread only to sites that were exposed to sunlight: 124 observation | dermatol pract concept 2015;5(2):24 related, photosensitive conditions in patients with cancer. j drugs dermatol 2009;8(1):61-64. pmid: 19180897. 2. cohen ad, mermershtain w, geffen db, et al. cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins. j dermatolog treat 2005;16(1):19-21. pmid: 15897162. 3. ee hl, yosipovitch g. photo recall phenomenon: an adverse reaction to taxanes. dermatology 2003;207(2):196-198. pmid: 12920374. 4. pazdur r, kudelka ap, kavanagh jj, cohen pr, raber mn. the taxoids: paclitaxel (taxol) and docetaxel (taxotere). cancer treat rev 1993;19(4):351-386. pmid: 8106152. 5. wall me, wani mc. camptothecin and taxol: discovery to clinic—thirteenth bruce f. cain memorial award lecture. cancer res 1995;55(4):753-760. pmid: 7850785. 6. yardley da. nab-paclitaxel mechanisms of action and delivery. j control release. 2013;170(3):365-372. pmid: 23770008. 7. lamond nw, younis t, purdy k, dorreen ms. drug-induced subacute cutaneous lupus erythematosus associated with nabpaclitaxel therapy. curr oncol 2013;20(5):e484-487. pmid: 24155645. 8. chen m, crowson an, woofter m, luca mb, magro cm. docetaxel (taxotere) induced subacute cutaneous lupus erythematosus: report of 4 cases. j rheumatol 2004;31(4):818-820. pmid: 15088316. 9. adachi a, horikawa t. paclitaxel-induced cutaneous lupus erythematosus in patients with derum anti-ssa/ro antibody. j dermatol 2007;34(7):473-476. pmid: 17584326. 10. pham aq, berz d, karwan p, colvin ga. cremophor-induced lupus erythematosus-like reaction with taxol administration: a case report and review of the literature. case rep oncol 2011;4(3):526-530. pmid: 22125524. 11. dawe rs, ibbotson sh. drug-induced photosensitivity. dermatol clin 2014;32(3):363-368. pmid: 24891058. 12. tokunaga m, iga n, endo y, et al. elevated protoporphyrin in patients with skin cancer receiving taxane chemotherapy. eur j dermatol 2013;23(6):826-829. pmid: 24480579. 13. vihinen p, paija o, kivisaari a, koulu l, aho h. cutaneous lupus erythematosus after treatment with paclitaxel and bevacizumab for metastatic breast cancer: a case report. j med case rep 2011;5:243. pmid: 21707979. treatment of taxane-induced photodermatoses typically involves topical or systemic corticosteroids and photoprotection. oral antihistamines may also be helpful for some patients [3,13]. the presence of a photodermatosis is not an absolute contraindication to continuing chemotherapy, especially with strict avoidance of sun exposure. however, withdrawal of the drug may be required if the cutaneous reaction is severe or if the lesions fail to resolve with conservative treatment. conclusion taxanes are chemotherapeutic agents used in the management of various neoplasms. paclitaxel and nab-paclitaxel are taxanes that have been associated with photodermatoses, including erythema multiforme, onycholysis, photo recall phenomenon, and subacute cutaneous lupus erythematosus. the incidence of photodermatoses secondary to paclitaxel or nab-paclitaxel may be higher than the published literature reflects. the development of symptoms and/or skin lesions on sun-exposed areas in patients receiving these agents should prompt the clinician to evaluate the patient for a drug-related photodermatosis. evaluation could include serologic tests (to evaluate for lupus erythematosus and porphyria) and tissue biopsy for microscopic examination. strict adherence to avoiding exposure to sunlight should be initiated. symptomatic treatments with topical or, if necessary, systemic corticosteroids should also be considered. the development of a taxane-associated photodermatosis is not an absolute contraindication to continuing treatment with the drug. however, limited exposure to ultraviolet radiation is recommended. references 1. cohen pr. photodistributed erythema multiforme: paclitaxeltable 1. drug-induced photosensitivity: phototoxicity versus photoallergy phototoxicity photoallergy incidence common rare appearance sunburn-like appearance with erythema and/or edema dermatitis onset immediately after exposure to sunlight 24-72 hours after exposure to sunlight required dose of uv radiation moderate-high low required dose of drug moderate-high low areas affected sun-exposed areas only initially sun-exposed areas and may spread to photoprotected areas pathophysiology tissue injury cell-mediated immune response dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(2):e2021002 1 dermatology practical & conceptual peas out of the pod theocharis n. kirtsios1, zoe apalla1, aimilios lallas2 1 second department of dermatology, aristotle university, thessaloniki, greece 2 first department of dermatology, aristotle university, thessaloniki, greece key words: melanoma in situ, dermoscopy, diagnosis congenital nevus, acral nevus, acral melanoma citation: kirtsios tn, apalla z, lallas a. peas out of the pod. dermatol pract concept. 2021;11(2):e2021002. doi: https://doi .org/10.5826/dpc.1102a02 accepted: july 22, 2020; published: march 8, 2021 copyright: ©2021 kirtsios et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: theocharis nektarios kirtsios, md, second department of dermatology, aristotle university, thessaloniki, greece. email: theocharisk@hotmail.com case presentation a 43-year old woman presented to our department for a total-body mole check. on clinical examination, a pigmented macule was noted on her right palm (figure 1a). the patient reported that the lesion appeared approximately 3 years earlier. based on dermoscopic examination (figure 1b), the lesion was assessed as suspicious for melanoma and an excision was performed. the histopathological diagnosis was melanoma in situ. teaching point the anatomical features of acral skin produce unique and distinctive dermoscopic patterns when it comes to discriminating between acral nevi and melanoma. the diagnosis is guided by inspection of the furrows and ridges. nevi usually display a parallel furrow pattern, consisting of parallel brown lines occupying the furrows, while the ridges are not pigmented [1]. a subtype of this pattern includes brown dots in the eccrine ducts located on the ridges (“peas in the pod”). no other distribution of brown dots is expected in a nevus [2]. when “the peas are out of the pod,” the suspicion of melanoma should be raised, as in our case. references 1. saida t, koga h. dermoscopic patterns of acral melanocytic nevi: their variations, changes, and significance. arch dermatol. 2007;143(11):1423-1426. doi: 10.1001/archderm.143.11.1423. pmid: 18025367. 2. lallas a, kyrgidis a, koga h, et al. the braaff checklist: a new dermoscopic algorithm for diagnosing acral melanoma. br j dermatol. 2015;173(4):1041-1049. doi: 10.1111/bjd.14045. pmid: 26211689. 2 image letter | dermatol pract concept 2021;11(2):e2021002 figure 1. (a) a brown macule noticed on the palm of a 43-year-old woman. (b) dermoscopy (captured with polarized dermoscopy, magnification ×10) revealed pigmentation occupying mainly the ridges and brown dots scattered all over the lesion. they were heterogeneous in size and randomly distributed, not restricted to the eccrine duct openings. the lesion was excised with the suspicion of melanoma and histopathologically diagnosed as melanoma in situ. (c, d) examples of acral nevi, from different patients, displaying a “peas in a pod” pattern, with the brown dots distributed in parallel lines and equal distance between each other (polarized dermoscopy, magnification ×10). dermatology: practical and conceptual 320 letter | dermatol pract concept 2019;9(4):20 dermatology practical & conceptual introduction pemphigus consists of a group of rare autoimmune blistering diseases that are typically characterized by the appearance of intraepithelial blisters on the skin and/or mucosa. pemphigus vulgaris (pv) and pemphigus foliaceus (pf) are 2 well-known forms of pemphigus. although they have distinct clinicopathological features, each of these conditions could switch to the other. the köbner phenomenon (kp) is described as the appearance of new lesions in the uninvolved skin as a consequence of different kinds of trauma. it has been described in several skin disorders, including psoriasis, vitiligo, lichen planus, and rarely pemphigus [1]. here we report a patient with previously diagnosed mucocutaneous pv who developed pf after rituximab (rtx) therapy and developed crusted lesions some weeks after surgery for femoral avascular necrosis at the surgical site. case presentation a 55-year-old man with an 8-year history of mucocutaneous pv (confirmed with pathological findings and direct immunofluorescence) was treated with rtx in february 2017, after his disease had flared. both anti-desmoglein (anti-dsg) 1 and anti-dsg3 were positive (>200 u/ml) at the time of infusion. his disease went into remission within 3 months after the last dose of rtx and remained on minimal therapy (5 mg prednisolone daily and 7.5 mg methotrexate weekly) for more than a year. in may 2018 he complained of the development of dry lesions on the chest, consistent with pf. after checking anti-dsg1/3 titers, we found that anti-dsg1 was 63 u/ml, while anti-dsg3 was negative. in june 2018 a surgical procedure was performed in an attempt to treat femoral avascular necrosis. despite the successful surgery, after 6 weeks new lesions appeared on the surgery site, which seemed to be related to kp (figure 1, a and b). at the last follow-up in may 2019, the lesions were about to disappear via low-dose steroid treatment (figure 2, a and b). conclusions in addition to several suggested triggers for pemphigus, trauma can trigger the onset of new lesions in patients with pemphigus. a variety of procedures from minor skin surköbner phenomenon in a rituximab-treated pemphigus patient: beware disease activity soheil tavakolpour1, hamidreza mahmoudi1, nika kianfar1, shayan dasdar1, maryam daneshpazhooh1 1 autoimmune bullous diseases research center, tehran university of medical sciences, tehran, iran key words: pemphigus vulgaris, pemphigus foliaceus, köbner phenomenon, rituximab, surgery citation: tavakolpour s, mahmoudi h, kianfar n, dasdar s, daneshpazhooh m. köbner phenomenon in a rituximab-treated pemphigus patient: beware disease activity. dermatol pract concept. 2019;9(4):320-321. doi: https://doi.org/10.5826/dpc.0904a20 accepted: june 26, 2019; published: october 31, 2019 copyright: ©2019 tavakolpour et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: hamidreza mahmoudi, md, autoimmune bullous diseases research center, razi hospital, vahdate-eslami square, 11996, tehran, iran. email: hr_mahmoody@yahoo.com letter | dermatol pract concept 2019;9(4):20 321 ever, if the surgery is urgent and patient is not in remission, increasing the dose of corticosteroid could probably prevent kp or at least mitigate its risk. however, further studies are needed to better understand approaches for preventing kp in patients with pemphigus. references 1. balighi k, daneshpazhooh m, azizpour a, et al. koebner phenomenon in pemphigus vulgaris patients. jaad case rep. 2016;2(5):419-421. 2. daneshpazhooh m, fatehnejad m, rahbar z, et al. trauma-induced pemphigus: a case series of 36 patients. j dtsch dermatol ges. 2016;14(2):166-171. geries to major abdominal and thoracic surgeries have been reported as triggers of kp in pemphigus. however, the number of reported cases is too small to draw any conclusion about the pathogenesis of kp. the reported mean interval between trauma and the development of lesions was approximately 5 weeks [2]. in our patient, the disease was both clinically and serologically active at the time of surgery, which might be a risk factor for kp. in general, unnecessary surgery and blunt trauma should be avoided in patients with pemphigus [2]. necessary procedures should be postponed if possible to a time when the patient is both clinically and serologically in remission, to minimize the risk of kp. this could be achieved 1-3 months after rtx therapy and usually lasts for 6-12 months. howfigure 1. (a) pemphigus foliaceus lesions on the chest, representing disease activity. (b) new lesions that developed approximately 6 weeks after hip surgery suggest köbner phenomenon. [copyright: ©2019 tavakolpour et al.] figure 2. disappearance of all skin lesions on the chest (a) and hip (b), 7 months after treatment with low-dose prednisolone (<10 mg/d). [copyright: ©2019 tavakolpour et al.] dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020057 1 dermatology practical & conceptual introduction generalized eruptive histiocytosis (histiocytoma) (geh) is a very rare cutaneous non-langerhans cell histiocytosis, characterized by recurrent crops of small red to brown papules. case presentation a 58-year-old woman with an 8-month history of hundreds of symmetric yellow-brown flat-topped papules (figure 1, a and b) came for dermatologist consultation. the lesions appeared in crops localized on the trunk and extremities. it was believed that the skin lesions were caused by trazodone and lithium, which were being used in the treatment of bipolar disorder. the medications were stopped, but the lesions continued to develop. routine blood and urine analyses were unremarkable. dermoscopy was performed on one representative lesion on the lower leg. the histology was consistent with the diagnosis of geh (figure 1, c-g). after geh diagnostics, additional investigations were done. hyperprolactinemia, hypercorticism, and hypofunction of the thyroid gland were detected. abdominal ultrasonography and mri of the sella turcica and hematological studies with biopsy of the bone marrow were without pathological findings. three years from the first onset, the skin lesions mostly resolved, leaving hyperpigmented macules. literature review seventy-four cases (58.1% males) of geh have been published, including 24 (32.4%) children (table 1 and supplementary references, which are appended to the pdf). the average age was 30.5 years. in adults and children the average age was 43.2 years and 4.2 years, respectively. the most frequent body site was the trunk (86%), followed by the extremities (79%). the lesions resolved spontaneously from 2 weeks onward, but in rare cases persisted for 20 years. in 4 children the lesions evolved into xanthoma disseminatum; in 1 child the lesions coexisted with juvenile xanthogranuloma. dermoscopy of generalized eruptive histiocytosis: case report and brief review of the literature danijela dobrosavljevic,1,2 jovana majstorovic,1 martina bosic2,3 1 clinic of dermatovenereology, clinical centre of serbia, belgrade, serbia 2 faculty of medicine, university of belgrade, serbia 3 institute of pathology, university of belgrade, serbia key words: generalized eruptive histiocytosis, non-langerhans cell histiocytosis, histiocytic disorders, dermoscopy, dermatoscopy citation: dobrosavljevic d, majstorovic j, bosic m. dermoscopy of generalized eruptive histiocytosis: case report and brief review of the literature. dermatol pract concept. 2020;10(3):e2020057. doi: https://doi.org/10.5826/dpc.1003a57 accepted: february 27, 2020; published: june 29, 2020 copyright: ©2020 dobrosavljevic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: danijela dobrosavljevic, md, phd, clinic of dermatovenereology, pasterova 2 st, clinical centre of serbia and faculty of medicine, university of belgrade, belgrade, serbia. email: danijela_dobrosavljevic@yahoo.co.uk https://doi.org/10.5826/dpc.1003a57 mailto:danijela_dobrosavljevic@yahoo.co.uk 2 letter | dermatol pract concept 2020;10(3):e2020057 (table 1). in preschool children, diabetes insipidus should be suspected if geh evolves into xanthoma. in adults, hematological follow-up is suggested. clinical differential diagnosis of geh includes other histiocytic disorders such as letterer-siwe disease, juvenile xanthogranuloma (multiple), papular xanthoma, and progressive nodular histiocytosis. exanthema due to medications and viruses, with separate entity gianotti-crosti syndrome and early eruption of guttate psoriasis, are main differentials as well. although geh is a benign, self-healing eruption of non-langerhans cell lineage, follow-up is necessary. two age groups of geh patients are reported: up to 14 years and adults. brain infiltrations and diabetes insipidus are reported in 3 (12.5%) children up to age 4 years with xanthomatous evolvement. in 5 (10.0%) of the published adult cases, hematological disorders of myeloid lineage such as acute monocytic/monoblastic leukemia (2 cases) or chronic myelomonocytic/eosinophilic leukemia (3 cases) are reported figure 1. (a,b) symmetric yellow-brown, flat-topped papules localized on the trunk (a) and extremities (b). (c) dermoscopic finding: orange-yellow homogeneous pigmentation, delicate linear branching, and serpentine vessels. solitary, red clods are present in some lesions. (d) dermoscopic finding after 3 months: partially regressed lesions reveal yellow background and linear serpentine vessels. (e) focally dispersed small dermal granulomas composed of histiocytes and multinuclear giant cells with peripheral arrangement of nuclei (e,f) (h&e, ×100). (f) focal emperipolesis is noted in giant cells (arrows) (h&e, ×400). (g) positive immunohistochemical staining of cd68 in granulomas (magnification ×200). immunohistochemically, granulomas presented with profile cd68+ cd163+/−, and cd1a−. letter | dermatol pract concept 2020;10(3):e2020057 3 table 1. clinical characteristics of the published cases with generalized eruptive histiocytosis (histiocytoma) (geh) referencea age at onset (yrs)b sex location course associated finding wise (1919)c 22 m trunk, proximal part of extremities lasted 20 years none glauberzon and lebedeff (1952)c 34 f disseminated not defined none calas et al (1959)c 52 m face, trunk, extremities not defined none baccaredda-boy (1960)c 33 m trunk, extremities, face, mouth no data, died after 19 years mutilating polyarthritis herzberg (1961)c 30 f trunk, extremities spontaneous regression after 13 years amenorrhea winkelmann and muller (1963) 51 f trunk, extremities number of lesions increased within 15 months osteoarthritis winkelmann and muller (1963) 58 m trunk, axillae, pubic area and penis, buccal mucosa increasing in number within 4 years none winkelmann and muller (1963) 38 f face, trunk, extremities cleared gradually after 12 years none cramer (1963) 25 m disseminated resistant to steroids none pegum (1973) 42 m trunk, extremities no regression after 2.5 years high cholesterol sohi et al (1979) 49 m generalized regressed in a few months, then recurred 2 years later none winkelmann (1980) 3 months f extensor limbs, buttocks persisted until at least 9 years old glaucoma and uveitis caputo et al (1981) 25 m thorax, abdomen, inguinal fold, proximal extremities resolved spontaneously in 4 years none aso et al (1982) 4 m disseminated spontaneous regression of 80% lesions after 2 years none arnold et al (1982) 32 m disseminated persisted for 20 years none bobin et al (1983) 22 m trunk, extremities partial regression within 1 year none idikio and hogan (1983) 57 f abdomen, pubic area, breasts, back, axillae, face unchanged in 9 years hyperlipidemia type iv statham et al (1984) 66 f trunk, extremities, nasal mucosa death 18 months after the diagnosis from acute leukemia acute leukemia of monoblastic/histiocytic origin caputo et al (1987) 11 months m trunk, neck, head, extremities disappeared in 5 years none caputo et al (1987) 11 months f face, trunk mostly regressed in 6 years none caputo et al (1987) 10 months m trunk, scrotum mostly regressed in 2 years none caputo et al (1987) 44 months f trunk, axillae, face mostly regressed in 3 years none (table 1 continues) 4 letter | dermatol pract concept 2020;10(3):e2020057 table 1. clinical characteristics of the published cases with generalized eruptive histiocytosis (histiocytoma) (geh) (continued) referencea age at onset (yrs)b sex location course associated finding shimizu et al (1987) 24 m cheeks, later generalized regressed in 1 year none sigal-nahum et al (1987) 7 f face, buttocks, extremities spontaneous regression and new crops within few months none braun-falco et al (1988) 19 m trunk, axillary, face, throat evolved into xanthoma disseminatum none grob et al (1988) 25 m face, axillary eruption persisted 2 years none umbert and winkelmann (1989) 67 f face, trunk, arms slow progression within 9 years hypothyroidism, normolipemic xanthelasma, polyclonal gammopathy ashworth et al (1990) 21 m disseminated, sparing mucosa 8 years continual progression of the disease atopic dermatitis, asthma saijo et al (1991) 14 f trunk within 14 months: partial regression with new lesions none stables and mackie (1992) 55 f arms, trunk, upper thighs, face present for at least 24 months none izaki et al (1993) 1 m face, neck, upper arms persisted for next 5 years until spontaneous resolution none goerdt et al (1994) 69 m trunk, extremities persisted for at least 5 years high cholesterol repiso et al (1995) 4 m face, trunk, proximal extremities evolved into xanthoma disseminatum developed diabetes insipidus and brain infiltrations gibbs and o’grady (1996) 41 m face, arms, torso lesions persisted for 9 years diabetes mellitus type ii jang et al (1999) 3 months m face, trunk, groin, upper and lower limbs spontaneous regression within 2 months; no new lesions within 2 years none matsushima et al (1999) 5 f generalized spontaneous regression within 8 months rheumatic fever wee et al (2000) 9 m trunk, proximal extremities spontaneous regression of some lesions with new crops none marzano et al (2002) 33 f trunk, extremities resolved within 6 months none wollenberg et al (2002) 13 f abdomen, trunk persisted for 3 years coexistence with skin lesions proven to be indeterminate cell histiocytosis klemke et al (2003) 59 m trunk, neck, face, and thighs improved under aplasiogenic regimen acute monocytic leukemia seward et al (2004) 55 m trunk, extremities several lesions resolved after cryotherapy none deng et al (2004) 39 m face, trunk, limbs spontaneously resolved within 6 months increased eosinophilia mehravaran (2004) 53 f trunk, upper extremities no follow-up none tamiya et al (2005) 14 months f trunk, extremities spontaneously resolved within 1 month immunoglobulin g, human herpesvirus 6 (table 1 continues) letter | dermatol pract concept 2020;10(3):e2020057 5 table 1. clinical characteristics of the published cases with generalized eruptive histiocytosis (histiocytoma) (geh) (continued) referencea age at onset (yrs)b sex location course associated finding vázquez-blanco et al (2006) 64 m trunk, extremities, mucous membranes subsided after photochemotherapy, but reappeared none kiliç et al (2006) 1 m face, trunk, extremities stable for 12 months, partial regression after 41 months none lan ma et al (2007) 32 f trunk, extremities, face in 3 months resolved with puva eosinophilia in peripheral blood and in bone marrow cytology tang et al (2007) 36 f trunk, abdomen, extremities after 8 years, spontaneous regression of some lesions observed none fernández-jorge et al (2007) 41 f trunk and arms spontaneously resolved in 11 months hypercholesterolemia bajaj and iqbal (2008) 28 m face, chest, axillae resolved after 1 week with liquid nitrogen none kwinter and dekoven (2009) 53 f face, neck, arms resolved after 8 months with isotretinoin, then recurred none chern et al (2010) 5 months f face, trunk, arms, legs spontaneously resolved in 6 months mild leukocytosis aggarwal et al (2010) 61 m trunk, arms, legs spontaneously resolved with relapses within 4 years none sharath kumar et al (2011) 23 f face, trunk, arms, legs minimal resolution, persisted 5 years none attia et al (2011) 48 f upper limbs and trunk spontaneously resolved none montero et al (2012) 80 m trunk, abdomen resolved after 6 months chronic myelomonocytic leukemia verma (2012) 10 m hands, feet, trunk coexistence with juvenile xanthogranuloma lesions none cardoso et al (2013) 79 m trunk, eyelids spontaneously resolved in 2 months none zamudio vega et al (2013) 8 m face, upper extremities 8 months unchanged none shon et al (2013) 84 m face, neck, arms died after 4 months chronic myelomonocytic leukemia kazi et al (2014) 23 m lower extremities no follow-up none ghandi et al (2015) 28 f face, trunk, extremities spreading within 2 years none ziegler et al (2015) 20 m trunk, extremities complete remission with imatinib fip1l1-pdgfrapositive chronic eosinophilic leukemia hansel et al (2015) 60 m trunk, extremities remission with puva and topical corticosteroids none mahajan et al (2015) 60 m extremities no follow-up none wilk et al (2016) 64 m trunk, extremities unchanged for several years none (table 1 continues) 6 letter | dermatol pract concept 2020;10(3):e2020057 conclusions our case emphasizes the importance of dermoscopic examination in the everyday practice of dermatologists. further studies of skin histiocytic disorders are required in order to establish all dermoscopic criteria. acknowledgment the authors thank mrs. ana ivkovic from the institute of oncology and radiology of serbia, belgrade, serbia, and mr. william russell-edu from the european institute of oncology, milan, italy, for providing scientific literature. references 1. kaçar n, demirkan n, duygulu ş. generalized eruptive histiocytosis diagnosed in light of dermoscopic findings. int j dermatol. 2018;57(3):355-357. https://doi.org/10.1111/ijd.13867 2. erricheti e, stinco e. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. https:// doi.org/10.1007/s13555-016-0141-6 a case describing dermoscopy of geh lesions resembling molluscum contagiosum in an infant has been published [1]. a homogeneous orange-yellow pattern with an erythematous border described as “setting-sun” was recognized. histology revealed histiocytic cells with foamy xanthomatous cytoplasm [1]. the dermoscopic finding in our case presented with orange-yellow homogeneous pigmentation, delicate linear branching, serpentine vessels, and solitary, red clods. histology revealed histiocytic cells forming granulomas. the dermoscopic differential diagnosis of geh is broad and encompasses juvenile xanthogranuloma, cutaneous sarcoidosis, necrobiosis lipoidica, granuloma annulare (palisading granuloma histological subtype), elastosis perforans serpiginosa, granulomatous rosacea, annular elastolytic giant cell granuloma, and rheumatoid nodules. among infective diseases, lupus vulgaris, cutaneous leishmaniasis, borderline tuberculoid leprosy, and majocchi granuloma are the most important differentials [2]. combining clinical, dermoscopic, and histological findings is of greatest importance in any of the diseases mentioned. table 1. clinical characteristics of the published cases with generalized eruptive histiocytosis (histiocytoma) (geh) (continued) referencea age at onset (yrs)b sex location course associated finding piney et al (2016) 28 m face, trunk, extremities resistant to imatinib, interferon alpha, anakinra; resolved after puva therapy arthralgia alperovich et al (2017) 3 f trunk, face 6-month follow-up: cns lesions-xanthomata diabetes insipidus arif et al (2017) 26 f face, trunk, arms persisted and coalesced within 3 months none kar et al (2018) 6 f face, axillae, trunk spontaneously resolved none kaçar et al (2018) 19 months f diaper area, extremities, trunk spontaneously resolved none costin et al (2019) 24 f trunk, neck and proximal upper extremities unchanged after 1 year none takahashi et al (2019) 1 m trunk after 1 year partially regressed none kobayashi et al (2019) 7 months m neck, trunk, extremities 2-year follow-up; lesion evolved into xanthoma disseminatum; resistance to chemotherapy diabetes insipidus afull references are provided in the supplementary content, which is appended to the pdf. bage is given in years except where indicated as months. cin 1963 winkelmann and muller reported 3 cases of geh, but some cases with cutaneous and histological abnormalities consistent with geh were reported before their report, under different names (sohi et al, dermatologica. 1979;159(6):71-75; bobin et al, ann dermatol venereol. 1983;110(10):817-824). https://doi.org/10.1111/ijd.13867 https://doi.org/10.1007/s13555-016-0141-6 https://doi.org/10.1007/s13555-016-0141-6 letter | dermatol pract concept 2020;10(3):e2020057 7 supplementary material: table 1 references 1. wise f. multiple endothelioma of the skin. am j med sci. 1919;157:236-253. 2. glauberzon sa, lebedeff ya. multiple plane dermato-fibrome (fibroma simplex, derma-fibroma lenticulare). vesternick venerologie dermatologie. 1952;35. excerpta med (section 13)6:68. 3. calas e, tramier g, coulier l. reticulose benigne (histiocytomes multiples dissemines). bull soc fr derm syph. 1959;66:120-121. 4. baccaredda-boy a. paraxathomatose (thesaurotische) system histiocytose. hautarzt. 1960;11:58-63. 5. herzberg jj. eruptive symmetrisch angeordnete eosinophile granulome der haut. arch klin exp dermatol. 1961;212:282-297. 6. winkelmann rk, muller sa. generalized eruptive histiocytoma: a benign papular histiocytic reticulosis. arch dermatol. 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https://doi.org/10.1590/s0365-05962013000100015 https://doi.org/10.1590/s0365-05962013000100015 dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020072 1 dermatology practical & conceptual case presentation a 34-year old female with an unremarkable medical history presented with a 3-month history of scalp pruritus. physical examination revealed small whitish lesions resembling nits, abundant on one dreadlock. trichoscopy showed many whitish, tubular and non-adherent structures on the hair shafts (figure 1). there was no evidence of nits or lice on the rest of the scalp. teaching point pseudonits, hair casts, or keratin cysts are white objects that easily move along the hair. there are 2 types: (1) parakeratotic, associated with seborrheic dermatitis, psoriatic or excessive traction, and (2) peripilar, the pathogenesis of which is not clear but is more frequent in young women. trichoscopy findings include whitish cylindrical structures around the hair shaft. nits (main differential) present brown ovoid structure with a curved end (vital) or translucent structure with a planar end (empty). pseudonits are frequently misdiagnosed as pediculosis capitis; trichoscopy, then, is essential for differentiation, avoiding patient anxiety and unnecessary treatments. pseudonits or hair casts vania lukoviek1,2, josep malvehy1, susana puig1, sebastian podlipnik1 1 department of dermatology, university of barcelona, spain 2 department of dermatology, university hospital of canarias, tenerife, spain key words: pseudonits, nits, dermoscopy, polarized light dermoscopy citation: lukoviek v, malvehy j, puig s, podlipnik s. pseudonits or hair casts. dermatol pract concept. 2020;10(4):e2020072. doi: https://doi.org/10.5826/dpc.1004a72 accepted: april 16, 2020; published: october 26, 2020 copyright: ©2020 lukoviek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sebastian podlipnik, md, phd, melanoma unit, dermatology department, hospital clinic barcelona, villarroel 170, 08036, barcelona, spain. email: podlipnik@clinic.cat figure 1. trichoscopy reveals pseudonits. 2 image letter | dermatol pract concept 2020;10(4):2020072 2. lokhande aj, sutaria a. adult onset hair casts: nits which do not itch! int j trichology. 2017;9(2):70-72. doi: 10.4103/ijt. ijt_30_17. pmid: 28839391. 3. frança k, tadeu villa r, rezende silva i, almedia carvalho c, bedin v. hair casts or pseudonits. int j trichology. 2011;3(2):121122. doi: 10.4103/0974-7753.90834. pmid: 22223977. acknowledgments thanks to our patients and their families who are the main reason for our studies; to paul hetherington for helping with english editing and correction of the manuscript. references 1. lacarrubba f, verzì ae, micali g. trichoscopy in the differential diagnosis of pseudonits. skin appendage disord. 2019;5(3):142145. doi: 10.1159/000493741. pmid: 31049334. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020077 1 dermatology practical & conceptual introduction glomus tumors (gt) are uncommon, usually benign, slow-growing, painful lesions [1]. they are frequently solitary and located on the extremities, mostly in the subungual areas of the digits [1]. extradigital gt are rare, and little is known of their clinical and dermoscopic features, which explains frequent diagnostic delays. we present a case of an extradigital solitary glomus tumor located on the back, and we describe its dermoscopic features in such an exceptional location. case presentation a 64-year-old woman presented with a 1-year history of a slow-growing painful nodular lesion on the back. the pain worsened with movement or mild touch, including simple contact with clothing. physical examination revealed a well-defined, smooth, purple papule 8 mm in diameter (figure 1). polarized, non-contact dermoscopy showed a structureless purple area (figure 2). an excisional biopsy was performed. histopathology confirmed the diagnosis, showing a clinical and dermoscopic features of an extradigital glomus tumor of the back maha lahouel1, ines lahouel1, yosra soua1, mouna ben hamouda1, manel njima2, monia youssef1, jameleddine zili1 1 department of dermatology, chu fattouma bourguiba, monastir, tunisia 2 department of pathology, chu fattouma bourguiba, monastir, tunisia key words: glomus tumor, back, extradigital, dermoscopy citation: lahouel m, lahouel i, soua y, ben hamouda m, nijma m, youssef m, zili j. clinical and dermoscopic features of an extradigital glomus tumor of the back. dermatol pract concept. 2020;10(4):e2020077. doi: https://doi.org/10.5826/dpc.1004a77 accepted: april 21, 2020; published: october 26, 2020 copyright: ©2020 lahouel et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maha lahouel, md, dermatology department, fattouma bourguiba hospital, monastir, tunisia. email: mahalahouel@gmail.com figure 1. clinical aspect: a purple well-defined papule on the back. 2 letter | dermatol pract concept 2020;10(4):2020077 mented in 5 previous cases [2]. dermoscopic presentation revealed homogeneous, structureless, patternless lesions in all cases; a multicolored background, including a central purple area and a peripheral whitish homogeneous area in 1 case; yellow-to-white background in 3 cases; and multiple peripheral telangiectasias on the surface (2 cases). a structureless purple area, as seen in this observation, was described in 1 case. the central purplish structureless area correlates to enlarged vessels within the neuromyoarterial glomus body, while the surrounding white homogeneous area most likely corresponds to its fibrous capsule. conclusions extradigital locations of gt may represent a diagnostic challenge. while not specific, dermoscopy provides additional clues to complement the differential diagnosis of gt in less common locations. however, confirmation requires histopathological study after surgical biopsy. references 1. chou t, pan sc, shieh sj, lee jw, chiu hy, ho cl. glomus tumor: twenty-year experience and literature review. ann plast surg. 2016;76:s35–40. doi: 10.1097/ sap.0000000000000684. pmid: 26808758. 2. oliveira a. dermoscopy in the diagnosis of extradigital glomus tumors. int j dermatol. 2016;55(9):e506–e508. doi: 10.1111/ ijd.13289. pmid: 27126571. tumor enveloped by a fibrous capsule with vascular spaces surrounded by glomus cells (figure 3). the excision was followed by immediate disappearance of the pain without recurrence to this day. glomus tumors are uncommon neoplasms of the glomus body [1]. gt account for less than 2% of all soft tissue tumors [1]. they usually present as a blue-to-pink soft nodule associated with a classic triad of symptoms: pain, pinpoint tenderness, and cold sensitivity [2]. these tumors tend to be small (<2 cm), frequently solitary, and located on the extremities, mostly in the subungual areas of the digits [2]. however, they can be found anywhere on the body. extradigital cases reported in the literature correspond to 26.7% of all gt [2]. extradigital localizations are (in decreasing order of frequency): the upper extremities, lower extremities, trunk, and face [1]. nevertheless, to the best of our knowledge, the occurrence on the back, as the case of our patient, is extremely rare. extradigital gt differ in some clinical features from digital gt. patients with extradigital gt are older than those with digital gt [1]. while there is an equal incidence of all gt in both men and women, extradigital gt are found more commonly in men [2]. symptoms such as pain and hypersensitivity to cold are less frequently observed in patients with extradigital gt, leading to misdiagnosis [1]. the most common misdiagnoses were hemangioma, neuroma, and neurofibroma [1]. dermoscopic features of extradigital gt have been docufigure 2. polarized, non-contact dermoscopy showed a structureless purple area. figure 3. (a) dermal solid sheet of blue cells with a thin fibrous capsule (h&e, ×40). (b) the cells are uniform with indistinct borders, eosinophilic cytoplasm, round nuclei and bland chromatin (h&e, ×400). a b dermatology practical & conceptual www.derm101.com essay | dermatol pract concept 2012;2(4):12 47 introduction the process of making a diagnosis is a process of problemsolving during which the diagnostician notices various attributes of a patient, recognizes associations between the attributes, and applies a classification—the disease process that can then be treated, hopefully to good result for the patient. but at the heart of it, “making a diagnosis” is a very human endeavor; “to classify is human.” our training helps us to be systematic in applying the label that we call a diagnosis to a patient, but the process of classification is something that we are born to do. problem-solving necessarily involves a sense of uncertainty. if one knew the answer ahead of time, one would not have “a problem” to begin with. as we all know, there is a very large amount of potential data out there and it can be difficult, especially with the time constraints we face, to figure out which attributes of the patient we should look for (what data we will need to consider). also, although we do not like to admit it, we know our cognitive abilities are somehow limited, throwing yet another chink into the process. basically, this essay is an inquiry into how a finite mind can work efficiently and with purpose in what is for practical purposes a world with infinite data. we will examine various types of uncertainty and consider the implications of each type with respect to the task at hand. we will look at the various elements that make up the problem-solving process of arriving at a diagnosis and see how those elements can interact with each other, sometimes with surprising results. inherent in the concept of diagnosis is that illness is involved. somehow, whatever state we are in, if we can be better, we must be ill now. so to consider the problem of making a diagnosis, we should consider the concept of health—can we identify readily “health” and “illness” and differentiate between the two? recognizing health and illness all of us physicians likely think we have a pretty good idea of “health.” webster defines “health” as “the condition of an organism or one of its parts in which it performs its vital functions normally or properly”; also “flourishing condition.” before i go too much further, please recall the discussions in earlier essays in this series about the nature of definition, both ostensive (definition by showing) and verbal, (interpretation) [1] and the (unavoidable) ambiguity of language (language) [2]. most attributes, especially attributes of disease, are not readily observed by us. parenthetically, there is a discussion about problems of taxonomy later in this essay. imagine you are in the waiting room of a clinic. you notice men and women, girls and boys, some sit alone, others seem to be in small groups. you notice an older gentleman sitting and talking to a middle-aged gentleman. you imagine a (healthy) son has accompanied his father to the appointment. surely the older man is ill, since the likelihood of illness increases with age. then a name is called. the younger man stands and follows the office staff in to see the doctor. in fact, the younger on the nature of thought processes and their relationship to the accumulation of knowledge, part xvi—the process of making a diagnosis cris anderson, m.d.1 1 southern illinois university school of medicine, springfield, il, usa citation: anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xvi—the process of making a diagnosis. dermatol pract conc. 2012;2(4):12. http://dx.doi.org/10.5826/dpc.0204a12. copyright: ©2012 anderson this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: cris anderson, m.d. email: crisj@me.com. 48 essay | dermatol pract concept 2012;2(4):12 man is ill and his father has accompanied him, providing moral support. now imagine you are downtown shopping. many people are on the street, going into and coming out of stores. who has a kidney transplant? who takes medication to treat high blood pressure? who has high cholesterol? most of the attributes we use to identify illness are not directly visible. even people who have diseases of the skin generally wear clothing that prevents others from noticing a lesion. basically, we must decide which attribute is important to notice and how we might best notice the attribute. in medicine, the vast majority of attributes are noticed by indirect means. we order a blood test or we do a biopsy and stain the fixed tissue to highlight a potential attribute to best advantage. in addition to the fact that attributes associated with disease may not be readily visible, members of the population, including providers of health care, do not agree on whether an attribute identified is actually within the spectrum of “health” or “disease.” consider the following scenarios. first, when i was in medical school on a rheumatology rotation my mentor described a situation in which a patient of his, a young man, presented complaining of back pain when he lifted heavy weights as part of his exercise program. my mentor worked him up and found he had a spondylolisthesis of l4-l5. my mentor explained the situation to him, that it was a congenital condition that would require back surgery to “fix,” but that if the patient would not lift such heavy weights he would not have the back pain to begin with and would not require surgery. in fact, if the patient had not been lifting such heavy weights, he may have gotten through his life without ever knowing about his condition. the patient, however, insisted that the surgery be performed because he wanted to pursue a career in government service that required an extraordinary degree of physical conditioning. the surgery was performed and, as far as my mentor knew, the patient did well and gained employment in the job of his dreams. but was the patient ill? how many of us can perform extraordinary physical feats, say on a par with an olympic athlete? are we unhealthy? and what about latisse, the glaucoma drug bimatoprost marketed as promotion for its side effect of causing longer thicker eyelashes? are people with puny eyelashes necessarily ill? should every human being on the face of planet earth take a statin drug to lower cholesterol—this seems to be what “big pharma,” large pharmaceutical companies, would like us to believe. consider the other end of the spectrum. ross upshur, in “looking for rules in a world of exceptions” [3], writes the following about one of his patients, “consider the following patient. mrs g. is 82 years old. when i assumed her care six years ago, she was given a prognosis of six months to live from severe congestive heart failure. mrs. g has lived beyond her original six-month prognosis. would one consider her in good health? i don’t know. to consider her healthy is not in any way correct. to call her unhealthy is also seemingly inappropriate. i believe she is in equilibrium. [upshur catalogs mrs. g’s experiences with (both the diseases themselves and the reaction to her by healthcare providers) endometrial adenocarcinoma, flash pulmonary edema, aortic valve replacement, and type 2 diabetes mellitus] . . . she now requires a complex regimen of medications [including] diuretics, antihypertensives, cardiac medications, cholesterol-lowering medications, and diabetic medications . . . the critical determinant of why mrs. g is still alive today . . . [has less to do with evidence-based therapy and more] to do with the fact that she has an adult son who is developmentally delayed and is absolutely dependent on her for emotional and psychological survival.” is a person who has never had a complaint of ill health and who feels well an hour before s/he drops dead from a heart attack healthy? the point i wish to make is that the same definition of health does not apply in every situation. a determination of health depends very much on context and perspective. the context and perspective of the patient, practitioner, and society all interweave to decide who is healthy and who is ill. before we proceed to the process of making a diagnosis, we will start with an ideal situation to which we can compare our reality. the ideal—by which we are able to make a correct diagnosis every time basically, we require three things to be able to make a diagnosis: 1) a knowledge base, 2) a set of reasoning skills, and 3) the ability to obtain specific data in the case of an individual patient. ideally, every disease would be fully understood and specific criteria would be defined to allow diagnosis of that, and only that disease. additionally, no diseases would share identical criteria—there would always be at least one attribute that would differentiate between similar diseases (that is to say, there would not be two or more names for the same disease). second, the criteria used to define the disease would be unambiguous. that is to say, the same observer would make the same assessment of each attribute every time (intra-observer consistency) and different observers would all make the same assessment of the same attribute (inter-observer consistency). furthermore, every diagnostician would have access to the entire knowledge base and the knowledge base itself essay | dermatol pract concept 2012;2(4):12 49 would be internally consistent (all “facts” would be satisfiable with all other “facts”—there would be no contradictions or paradoxes arising in head-to-head consideration of different “facts”). also, in conjunction with the two previous paragraphs, specific and parsimonious criteria would be defined for each disease and these criteria would be agreed upon by all to be sufficient to make a specific diagnosis such that disease a, and only disease a, is defined by the chosen subset of data selected from all of the data known about disease a. this item addresses the topic in information theory of “data compression” and relates to the desirability of making a diagnosis with a minimum of ancillary testing (in order to save time and money within the health care system). additionally, the inner workings of each diagnostician would be logically consistent. each diagnostician could assume confidently that, as each attribute of the patient is learned, all relevant data from memory would “pop” into mind and allow him/her to follow the algorithm of the process of diagnosis to the diagnosis, which would be correct in every case. obviously, in the system as a whole, we are nowhere near to our ideal and, in fact, we never can be since the universe, as discussed in earlier essays in this series, is non-deterministic. types of uncertainty there are multiple types of uncertainty and each type has different implications for us in our task of making a diagnosis. two types of uncertainty are trivial. first, we might have known some fact and forgotten it. second, perhaps we have not learned a fact yet, but some one else knows. for these two types of uncertainty, all we must do is look up the answer. a third type of uncertainty is real and unresolvable. it arises from the necessity of learning about populations by sampling. as we all know, when a new ancillary test comes out to aid in the diagnosis of a disease, it is assigned a “sensitivity” and “specificity” based on the performance of the test in the original study population. as we will discuss later in this essay, the attributes of the patient sitting before us do not match exactly the attributes of the study population. in fact, no two people share identical attributes (not even identical twins). to confound the issue even further, the new test is compared to a “gold standard” test—ideally a test the results of which differentiate perfectly all people who have the disease in question from all people who do not have the disease. of course, we realize that no existing “gold standard” is ideal. our entire system of making diagnoses and utilizing ancillary testing is rooted in the concept that someone knows, somehow, who really has a disease and who does not. this is simply not true. all we have is a group of people; each person of the group has numerous attributes (some of which they share in common with other members of the group and some of which they do not share). we hope we have understood causally the disease in question well enough that a core subset of attributes is shared by group members with the disease and that a similar, but not identical, core subset of attributes is shared by the group members without the disease. we then ask the question, “does this new test differentiate reliably between the two groups?” can we use this new test to diagnose reliably a new patient who is not a member of the original study group? since, by definition, we will use the new test on a patient outside the original test group, uncertainty related to the incomplete overlap of attributes necessarily introduces uncertainty into the diagnosis of every patient we see. this type of uncertainty can be lessened somewhat by ensuring that relevant attributes of the study population are well-known and that the patient on whom we are using the test actually shares the relevant attributes. a fourth type of uncertainty is related to the philosophical concept of “vagueness.” just where do we draw the line? in an earlier essay in this series we discussed the work of bart kosko, in fuzzy thinking [4], about assigning in a dichotomous manner attributes that actually occur on a continuum. in his example of apples, if we have a hundred apples and try to put them into two groups, one of red apples and one of green apples, the color of some apples will be clearly overwhelmingly red or green, but many apples will have both colors and will be more difficult to assign. examples of this “vagueness” type of uncertainty are encountered in the practice of medicine on a daily basis. for patients with shortness of breath, one must consider whether the problem is more likely to be cardiac or pulmonary in origin. we have available in our diagnostic armamentarium b-type natriuretic peptide (bnp), which is released when the heart muscle is stretched during heart failure. using bnp as a diagnostic aid works great, doesn’t it? if the patient is short of breath and his bnp is less than 100 units, the patient can be safely classified as a pulmonary patient. if the patient is short of breath and her bnp is more than 500 units, the patient can be safely classified as a cardiac patient. pretty nifty! but what about the patient who is short of breath and has a bnp of 300 units (half way between 100 and 500)? in this case we simply cannot use this test to make our decision—we must search for other attributes that will help us. and similar examples abound in our daily practice. the uncertainty of “vagueness,” however, can be tamed somewhat by defining more carefully the context of the patient. all we must do is identify other attributes that alter the context of the patient and make some of the attributes we have identified more helpful—more dichotomous towards making a decision. in the new context, attribute a 50 essay | dermatol pract concept 2012;2(4):12 now argues unequivocally either for or against a diagnostic possibility. more about context later. another type of uncertainty is that which arises in the context of experience (or lack thereof) and is the result of making decisions based on “explicit” or “implicit” knowledge. luchins [5] avers that “explicit” knowledge is analogous to reading written directions to perform some action, while “implicit” knowledge is analogous to how the experience of actually performing the written instructions changes how one performs the action over time (with practice). an expert (one who has performed many times the action described in the written directions), for example, executes the written directions differently from someone who is following the instructions for the first time. the expert, via feedback gleaned while watching interim events during his/her multiple attempts performing the task, alters slightly his/her interpretation of the instructions and performs the task differently, paying particular attention to one facet or another along the way. importantly, the results of this feedback are not usually written into a new version of the instructions. in fact, because of the ambiguity of language (as discussed in the essay in this series on language), it is probably not even possible to write reliably implicit knowledge into written instructions. each performer of the task learns nuances from repeated performance and over time, his/her performance improves with continued iterations (the so-called “learning curve”). this fifth type of uncertainty, then is the difference between the written instructions themselves and the unwritten “value added” to the performance resulting from experience. see below the discussion of heuristics. yet another source of uncertainty arises from the the fact that all testing is indirect. we often know what we want to know, but we cannot look for it directly. we perform a test and from the results of that test we make inferences about what we really want to know. for example, we often want to know how well the tissues of a patient are oxygenating. tests that are used to assess this include a hemoglobin or hematocrit to assess oxygen carrying capacity and the partial pressure of oxygen in the blood. when a patient is relatively healthy, that is to say when most of the patient’s physiologic systems are working well, inferences made from indirect evidence work admirably. suppose a patient comes to the doctor’s office complaining of shortness of breath on exertion. if we find that the patient has a lower than normal hemoglobin/hematocrit, we likely assume that is the reason for the symptoms, prescribe an appropriate hematinic agent, and have the patient return in a few weeks to see if the symptoms have improved and the hemoglobin/hematocrit have returned to the normal range. but many of us have likely stood at the bedside of a gravely ill patient with advanced sepsis syndrome. the skin appears dusky or pasty or gray and the hemoglobin is a little low (not low enough to explain the clinical appearance) and the pressure of oxygen is likely adequate. we have obtained our tests to try and see how well the patient is oxygenating, but his appearance itself tells us—he is not doing well. in fact, there is no ancillary test that truly assesses directly how oxygen is being utilized at the cellular level. and this problem is repeated throughout our practices, day in and day out. radiology sees “shadows,” not tumors; levels of any analyte obtained from a blood sample test the level on a “well-mixed” sample (from a fairly large peripheral vein or artery), making it more difficult to assess a focal process. additionally, a sample is analyzed in such a way that the analyte usually reacts in a “test system,” making the analyte more visible (perhaps with a monoclonal antibody and/or a chromogen). even when we look histologically at structure, we see artifact induced by us—the process of biopsy wrenches the tissue from the rest of the body thereby severing its ability to receive messages that direct its function, furthermore we place it in fixative to ensure it does not deteriorate, and then we slice it thinly and stain it in a variety of ways, using chemical properties to view indirectly one facet or another. eosinophils, for example are named after their staining properties, not after any sort of function they may have. even our own senses “process” raw data and present it to our brains in a different format than received at the receptors of the energy we sense. then we “recognize” the data after our brain has processed it and sent a conclusion to our consciousness somewhere. we can “work around” the uncertainty arising as a result of vagaries associated with the “indirectness” of testing by performing an additional (indirect) test that examines a different aspect of the problem, thereby obtaining “convergent” evidence. convergent evidence comes about when results of tests looking at a problem from different perspectives all support the same hypothesis. another type of uncertainty is a type we can only know in hindsight—the so-called “unknown unknowns.” for this type of uncertainty we may not even know what questions to ask or how to ask a question. an example of this type of uncertainty occurred relative to subclassifying types of leukemia. circa 1970 or so, acute lymphoblastic leukemia (all) was known and treatable; most children fared pretty well, but a small percentage did not respond as expected to therapy. at the time, the diagnosis was made by observing cells from bone marrow or peripheral blood smeared on a glass slide stained with wright-giemsa stain. shortly thereafter histochemical staining techniques were developed that could differentiate b lymphocytes from t lymphocytes. it turned out that the patients with b cell all responded to therapy much better than the patients with t cell all. pre 1970, differences existed between b cells and t cells, but we essay | dermatol pract concept 2012;2(4):12 51 could not tell the difference. today we have flow cytometry and cluster designator markers and many subsets of lymphocytes can be detected; therapies for each subtype of leukemia or lymphoma have been developed. yet another type of uncertainty arises as a result of the ambiguity of language. this topic is addressed more fully in earlier essays in this series on “interpretation” and “language.” this type of uncertainty can be minimized by paying careful attention to the context of the situation in which words are used and by using standard definitions of the words, appropriate to the context. context will be discussed in more detail later in this essay. can we draw any valid conclusions at all? good heavens! if everything we “know” is a derivation of something else, and an inexact datum to boot, how can we make any progress? an important point to make here is that uncertainty is not the same as randomness. while we may not be able to pinpoint exactly, and while we therefore feel uncertain, about some aspect of our work, we can be confident that the “true” answer lies somewhere between a set of limits; thus, the result is not random and completely unpredictable. the most important thing we can do is to make careful observations, check the validity of those observations with others (test inter-observer agreement), consider possible patterns and/or develop hypotheses of “causation” about the set of observations, and then test the competing hypotheses. that is to say, to evaluate observations via the process we know as science. important factors in reasoning are context and perspective. a scientifically-minded human will construct carefully a context and consider different perspectives, reasoning through the data from each of the perspectives, trying to find a “truth.” it is also important that multiple people evaluate the same data. the importance of collective efforts is that different people will likely have different perspectives. even if two people are considering what they think is the same perspective, the differing prior experiences of the two “thinkers” will likely lead them to a slightly different view of, and conclusion from, the data, and ensuing discussion will likely further expand the joint thinking process. if different people can confirm data or reaffirm proofs of conclusions drawn, it is more likely that the data and conclusions are “true,” that is to say conform with principles of universal law. it is most important that we take pains to ensure that we are describing a consistent system. bronowski [6] relates that kurt godel and bertrand russell have reminded us, in a consistent system there are true things that cannot be proved (godel’s incompleteness theorem), but (russell) in an inconsistent system one can “prove” anything! the root of much of the uncertainty we face arises from the situation that we are faced, as a direct result of the nature of the universe in which we find ourselves, with infinite variation around a number of common themes. human beings are very much alike (each of us shares a large number of the attributes of “humanness”), but additionally, each of us is different in some ways from all others of the set of human beings (the entire set of attributes that describes each of us is different from the entire set of attributes that describes each and every other member of the set “human beings”). psoriasis, for example, has multiple presentations and features, but all features and presentations share commonalities that, when present, allow us to make the diagnosis and to have certain expectations about treatments that will be efficacious. the task we face is to recognize which subset of attributes represent the commonalities required to make a specific diagnosis among the entire set of attributes that comprise the “infinite variation.” human senses (sight, hearing, touch, etc) work by synthesizing many bits of data almost instantaneously; in fact, we are not even sure as individuals how we accomplish this feat and are not even aware consciously of many of the bits of energy impinging on our senses. consider the problem of recognition of human faces by computers. computers have not done very well, especially in the earliest attempts at programming computers to recognize faces, although progress toward recognition has been made. we humans, on the other hand, usually have little trouble recognizing faces that we have seen previously, even if the face belongs to someone we do not know well. also, we usually have little trouble recognizing a high school classmate 20 years later at a reunion, even thought many features have changed (such as sagging jowls, wrinkles, gray hair, and the like). parenthetically, sacks [7] relates that a small percentage of people have prosopagnosia, the inability to recognize faces. the ability to recognize faces has been very important to humans throughout our evolution because we need to remember who has treated us fairly or unfairly so we can behave appropriately at a future encounter. good face recognition skills serve a survival advantage. when computers proved miserable in their first attempts, the human programmers began considering just which features humans consider important. programs started with photographs, but it turned out that computers could not recognize a recently photographed person who was now tired, for example, because eyelids were puffier or darker than the original photo for comparison. over time, and with adjustments to programming made possible by careful study by humans of which features are more important than others, computer face recognition has become better. 52 essay | dermatol pract concept 2012;2(4):12 for another example that “important” features can be discerned, forensic anthropologists can draw pictures of what people may have looked like from the bone structure of a skull. drawings of proposed current appearance of a missing adult are made from photographs of those same people as children who have been abducted. using “important” features in the photograph of the child and enhancing those features using changes expected with growth and development and aging, a drawing is created to see if anyone has seen recently a teenager or adult who may have been the abductee. we seem to “know” inherently what features of human faces are important, but we may not be able to articulate what those features are. our ability to recognize faces represents a heuristic—a “short cut” we use to make decisions. much study has been done about heuristics. are they intuition that can never be defined? if someone says they have a “gut feeling” or instinct, should we trust them? i think it likely that what we call instincts or heuristics can be ultimately defined, if we deem them important enough to study and solve. an elegant example is given by gerd gigerenzer in gut feelings [8]. he describes the “gaze heuristic.” a friend of his played baseball and was very good at catching fly balls. the player’s coach thought he was lazy because he would sometimes just trot slowly to catch the ball, and the coach thought he should run as fast as he could to where he had calculated the ball would land. when the player did this, he missed more balls than if he used his usual technique. an assumption, prior to discovering the heuristic, was that players made complex calculations about trajectories. gigerenzer quotes richard dawkins from the selfish gene, “when a man throws a ball high in the air and catches it again, he behaves as if he had solved a set of differential equations in predicting the trajectory of the ball. he may neither know nor care what a differential equation is, but this does not affect his skill with the ball. at some subconscious level, something functionally equivalent to the mathematical calculations is going on.” gigerenzer then describes the difficult of computing a ball’s trajectory. one must consider a parabolic curve and consider air resistance and wind and initial velocity and projection angle . . . parenthetically, i remember when taking physics courses it took me several minutes to do my calculations, even with a slide rule. gigerenzer describes that studies were performed to see what ball players actually do when they position themselves to catch a ball and discovered a technique called the “gaze heuristic.” the “gaze heuristic” works when the ball is high in the air. the player looks at the moving ball and decides if the angle of gaze is constant or changing. the heuristic states, “fix your gaze on the ball, start running, and adjust your running speed so that the angle of gaze remains constant.” if players do this, they do not need to consider wind speed or spin of the ball or any other variables. gigerenzer mentions that most ball players are unaware of how they actually catch balls, and their lack of awareness does not matter if the player is successful. but importantly, gigerenzer avers that once the mechanism of a heuristic is known, it can be taught to people less successful and improve their performance. he describes another and similar heuristic used by airplane pilots. “if another airplane approaches and you fear collision, look for a scratch on the windshield and observe whether the plane moves relative to the scratch. if it does not, dive away immediately.” obviously, one does not want to “catch” an airplane, as one does want to catch a fly ball. gigerenzer further avers that “a simple rule is less prone to estimation and calculation error and is intuitively transparent.” that is to say, it is preferable to use heuristics in many situations. however, one should recognize the heuristic as a heuristic and know the mechanism by which it works. daniel kahneman, in thinking fast and slow [9], quotes herbert simon, a long-time researcher in the psychology of accurate intuition. speaking of simon’s studies of chess masters, kahneman observes, “the psychology of accurate intuition involves no magic . . . you can feel simon’s impatience with the mythologizing of expert intuition when he writes: ‘the situation has provided a cue; this cue has given the expert access to information stored in memory, and the information provides the answer. intuition is nothing more and nothing less than recognition.’ . . . valid intuitions develop when experts have learned to recognize familiar elements in a new situation and to act in a manner that is appropriate to it.” thus, expert and accurate intuition is the ability to recognize common themes in the new situation arising in an instance of (infinite) variation. and we must study the behaviors of experts to learn the mechanisms of their heuristics so that they can be shared, thereby, in keeping with the topic of this essay, improving the overall performance of diagnosticians in the healthcare system. if we want to understand how experts think, we must understand how the human mind works. the workings of the human mind basically, we can only think about what pops into our minds. furthermore, there is a limit to how many items we can ponder simultaneously. what pops into our minds depends on association—that is to say, when we try to recall something, we try to draw an association with something else that helps us remember that item. items that pop into our minds are likely to arrive there by “similarity matching” (“it looks like . . .”), “frequency gambling” (“i have seen that often lately”), and “recency” (“i just saw that”). that item we are consideressay | dermatol pract concept 2012;2(4):12 53 ing reminds us of something else, so we consider whether the new item belongs to the same class that we are reminded of. we have seen a number of one class in particular, so if we see something that shares (reminds us of) an attribute with something we see often, surely this new item is also of the frequently noted class. gary marcus, in kluge, [10] reminds us that we have evolved the processes of thought that we now possess, so those processes must be good enough to enable us to survive long enough to reproduce others of our kind. we can learn and memorize various facts, but we must be able to recall items when we need to. whether we recall what we need often depends on the context of the situation in which we are trying to think and how closely that context relates to the one in which we learned the fact we now need to recall. kahneman describes the large amount of work he and many other students of human cognitive neuroscience have performed over the past few decades and relates the conclusions they have drawn. we have covered some of the work in earlier essays in this series. kahneman uses the metaphor of two systems of thought, which he calls system one and system two. kahneman observes “system 1 operates automatically and quickly, with little or no effort and no sense of voluntary control [while] system 2 allocates attention to the effortful mental activities that demand it, including complex computations. the operations of system 2 are often associated with the subjective experience of agency, choice, and concentration.” system one is actually the prime mover and is responsible for letting thoughts arrive in our conscious awareness. kahneman points out that we, ourselves, identify with system 2, “the conscious reasoning self that has beliefs, makes choices, and decides what to think about and what to do. although system 2 believes itself to be where the action is, the automatic system 1 is the hero . . . the automatic operations of system 1 generate surprisingly complex patterns of ideas, but only the slower system 2 can construct thoughts in an orderly series of steps.” kahneman lists, in order of complexity, some examples of activities thought to performed by system 1: • detect that an object is more distant than another • orient to the source of a sudden sound • complete a common phrase, such as “bread and . . .” • respond to a horrible picture by making a “disgust face” • detect hostility in a voice • answer 2 + 2 =? • read words on large billboards • drive a car on an empty road • find a strong move in chess, if you are a chess master • understand simple sentences • recognize that a “meek and tidy soul with a passion for detail” [discussed earlier in kahneman’s book as a stereotype for a librarian] resembles an occupational stereotype. says kahneman “we are born to perceive the world around us, recognize objects, orient attention, avoid losses, and fear spiders. other mental activities become fast and automatic through prolonged practice.” kahneman describes further system two, “the highly diverse operations of system 2 have one feature in common: they require attention and are disrupted when attention is drawn away. here are some examples: • brace for the starter gun in a race • focus attention on the clowns in the circus • focus on the voice of a particular person in a crowded and noisy room • look for a woman with white hair • search memory to identify a surprising sound • maintain a faster walking speed than is natural for you • monitor the appropriateness of your behavior in a social situation • count the occurrences of the letter a in a page of text • tell someone your phone number • park in a narrow space (for most people except the garage attendant [who can use system one for this]) • compare two washing machines for overall value • fill out a tax form • check the validity of a complex logical argument kahneman observes that everyone has a degree of awareness that his/her capacity to pay attention is limited. he describes the study from the book by chabris and simons, the invisible gorilla, in which students, directed to count passes on a basketball court were concentrating so hard that they failed to see a gorilla walk onto the court. kahneman notes that “intense focussing on a task can make people effectively blind, even to stimuli that normally attract attention.” kahneman concludes that system one generates suggestions to system two. these suggestions are impressions, intuitions, intentions, and feelings. but once endorsed by system two, “impressions and intuitions turn into beliefs, and impulses turn into voluntary actions . . . [most of the time, and when life runs smoothly] system 2 adopts the suggestions of system 1 with little or no modification . . . [but] when system 1 runs into difficulty [for example when asked to multiply 17 × 24], it calls on system 2 to support more detailed and specific processing that may solve the problem of the moment . . . system 2 is [also] activated when an event is detected that violates the model of the world that system 1 maintains.” kahneman continues, “the division of labor between system 1 and system 2 is highly efficient: it minimizes effort and optimizes performance. the arrangement works well most of the time because system 1 is generally very good 54 essay | dermatol pract concept 2012;2(4):12 at what it does: its models of familiar situations are often accurate, its short-term predictions are usually accurate as well, and its initial reactions to challenges are swift and generally appropriate. system 1 has biases, however, systematic errors that it is prone to make in specified circumstances . . . it sometimes answers easier questions than the one it was asked, and it has little understanding of logic and statistics . . . [also] it cannot be turned off.” another facet of our minds is that we see what we want or expect to see. in the essay in this series on patterns, we discussed the work of erich harth [11]. he described what occurs in one’s brain as one is walking along a beach. one’s eye catches sight of a round, shiny object. one’s brain tries to make it into a coin, but one’s senses can save the day by imposing reality on the situation. if one concentrates one’s visual apparatus on the object and compares it to one’s expectation of the appearance of a coin, one can see if the edge of the coin is oriented at right angles to the circular surface (no), or if the surface is truly round (no), or whether there is some sort of etching—the head of a former president, perhaps—on the surface of it (no); by using one’s senses to compare what one sees to one’s expectation of what one thinks or hopes it might be, one concludes that what one really sees is a piece of shell. of course, one must engage system two in order to make the determination. a frequent occurrence of a failure in comparing what one sees with what one expects is when one tries to proofread one’s own work, especially shortly after one has written it. if one lays the work down for a day or two before proofreading, one is much more likely to detect the errors that are present. another thing that kahneman points out is that humans have a strong desire for everything to fit together into a logical story. if fact, whenever we have available a few data items, we invent a story to make all the facts fit together. it is important to us that what ever occurs has a cause. when we learn a few data, even if those data prove later to be unrelated in a causal manner, our system one tries to relate them in a causal way. kahneman gives an example “‘fred’s parents arrived late. the caterers were expected soon. fred was angry.’ you know why fred was angry, and it is not because the caterers were expected soon. in your network of associations, anger and lack of punctuality are linked as an effect and its possible cause, but there is no link between anger and the idea of expecting caterers. a coherent story was instantly constructed as you read; you immediately knew the cause of fred’s anger. finding such causal connections is part of understanding a story and is an automatic operation of system 1. system 2, your conscious self, was offered the causal interpretation and accepted it.” kahneman also points out that system 2 can only work on one problem at a time. recall from above that maintaining a higher than usual walking speed is a system 2 activity. kahneman performed some studies in which, while walking at a fast pace with a test subject, the test subject would be asked to perform a complex multiplication task, such as multiply 17 by 24. each time, the test subject would slow down to complete the multiplication task. the implication of this is that humans really cannot multitask two system 2 activities at the same time. we might be able to perform a system 1 activity concurrently with a system 2 activity, but not two activities that each require our attention (a defining aspect of a system 2 activity) another thing about the way humans think—we tend to think automatically somebody must know the answer to any question that arises. we may admit, reluctantly, that perhaps we ourselves do not know the answer to some question, but we assume that somebody knows. this is natural in a way. when we are children, our parents or guardians teach us about the world around us. whenever we do not know something, we ask them and almost always an answer is forthcoming. if they do not know, we are referred to references (dictionaries, encyclopedias and the like) and the answer is there. even when we have difficulty finding an answer, we assume the answer must be out there somewhere. it takes a long time, but eventually, especially when we get to graduate school, we begin to learn that some questions do not have satisfactory answers. we detect inconsistencies between the “answer” to this question and the “answer” to another question. we recognize that both answers cannot be true at the same time, and we can find no ready resolution to the dilemma. thinking recursively another thing about how humans think—we think recursively. when ever we have a thought, we tend to modify that thought by something else that pops into our minds. james reason, in human error [12], posits that people solve problems in three basic ways: skill-based, rule-based, and knowledge-based. skill-based is used most often and relies almost entirely on the automaticity of “system 1.” examples include tying one’s shoes, answering a telephone, brushing one’s teeth, or riding a bicycle. once we learn the activity, we hardly think about it. the action just seems to occur without much conscious thought, once we decide to initiate the action. rule-based refers to following specific rules to an end. algorithms are a good example of rule-based actions, and we are encouraged often to use algorithms when we practice medicine. for both skill-based and rule-based activities we are familiar with the situation and we know what to expect. the only problems with execution of these activities arise when we are distracted during skill-based actions or essay | dermatol pract concept 2012;2(4):12 55 when we misidentify the problem and choose an inappropriate rule to execute for a rule-based problem. we use knowledge-based techniques when we face problems that are new. we have never seen anything quite like the situation we find ourselves faced with. as a result we have to figure out what to do as we go along. at each stage, as we are trying to solve the problem, we ask ourselves, “are we any closer to the answer?” interestingly, we solve these problems by imagining a desired result and then trying to get to that result. we say to ourselves, “it looks a little like that other problem i had, so i’ll try this maneuver that worked back then.” after that step, we reassess and decide whether we seem to be closer to our imagined goal. if so, we continue. if not, we take a step back and try another tack. it is the process of assessment and reassessment, using the feedback we receive from observing the status of events at each step of our progress and then deciding on the next maneuver based on the information gleaned, that is the recursive process. interestingly, this process that we have evolved to use is modeled in manufacturing endeavors as “good manufacturing processes,” or gmp. by following gmp and checking the interim product after each step, the firm has an opportunity to make alterations and save a batch of product that, if not manufactured according to gmp, might otherwise be lost. the point i am trying to make about thinking recursively is that even though thoughts occur to us in succession, we do not really think in a linear fashion. algorithms, however, do tend to encourage us to think linearly. consider driving through territory new to you in an area of town that has many signs and many potential turn offs. you have a set of directions, and you know the name of the place to which you are traveling. assume you have a fairly good sense of direction and can tell north, south, east, and west. you know you are traveling in a northerly direction. while turning here at this street and driving through two lights, then turning at a service station, etc, you become aware that you are moving in a southeasterly direction. what do you do? you still have ten steps to follow on your set directions. do you travel in a “linear fashion,” continuing with the set of directions until you are at the last one (analogous to linear thinking)? or do you pull over and stop, reexamine your directions to see if you might have made an error, and possibly turn around and go back to the last site where you felt you were still traveling in a northerly direction—the sense that you were meeting your expectation (analogous to recursive thinking)? melanie mitchell, in complexity: a guided tour [13], describes her experience of writing a computer program that solves problems by making analogies. mitchell quotes marvin minsky, a founder of the field of artificial intelligence, who said, “easy things are hard,” referring to attempts to understand some of a human’s most basic thought processes and to replicate those processes by computer programming. mitchell says of analogy-making, “ . . . analogy-making is the ability to perceive abstract similarity between two things in the face of superficial differences. this ability pervades almost every aspect of what we call intelligence.” mitchell quotes henry david thoreau, “all perception of truth is the detection of analogy.” a basic premise underlying the project was that the strategy used in solving new problems is one of “explore and exploit.” one thing mitchell realized was that all possibilities must be potentially available, but they cannot be equally available. for example, counterintuitive possibilities must be potentially available, but must require a cogent reason to be considered strongly enough to warrant committing significant resources for adequate exploration of that possibility. she also realized the importance of keeping a balance between exploration and exploitation. “when promising possibilities are identified, they should be exploited at a rate and intensity related to their estimated promise, which is continually being updated. [recursive evaluation] but at all times exploration for new possibilities should continue. the problem is how to allocate limited resources—. . . be they lymphocytes, enzymes, or thoughts—to different possibilities in a dynamic way that takes new information into account as it is obtained.” mitchell’s goal was to write a computer program called “copycat” (because a premise of the project was that “analogy-making is a subtle form of imitation”). the goal of the program was to start with the example of two given strings of letters, similar but with an alteration, and then to give the problem of a “test” string of letters for the computer to come up with an altered string that was analogous to the example. one given alteration was “abc morphs to abd.” the test was “mrrjjj morphs to ?” the goal was to use concepts possessed by the program (concepts thought to underlie human ability to form analogy) to build perceptual structures. “ . . . descriptions of objects, links between objects in the same string, and correspondences between objects in different strings . . . the structures the program builds represent its understanding of the problem and allow it to formulate a solution . . . the concepts [must] be adaptable to different situations . . .” mitchell continues, “ . . . a scheme [was proposed] for exploring uncertain environments: the ‘parallel terraced scan,’ . . . in this scheme many possibilities are explored in parallel, each being allocated resources according to feedback about its current promise, whose estimation is updated continually as new information is obtained. . . . all possibilities have the potential to be explored, but at any given time only some are actively explored, and not with equal resources. when a person ( . . . or an immune system) has little information about the situation facing it, the exploration of possibilities starts out being very random, highly parallel (many possibilities 56 essay | dermatol pract concept 2012;2(4):12 being considered at once) and unfocused: there is no pressure to explore any particular possibility more strongly than any other. as more and more information is obtained, exploration gradually becomes more focused (increasing resources are concentrated on a smaller number of possibilities) and less random: possibilities that have already been identified as promising are exploited.” mitchell’s program has subroutines such as “slipnet” that is a ‘network of concepts, each of which consists of a central node surrounded by potential associations and slippages’; “workspace,” ‘in which letters composing the analogy problem reside and in which perceptual structures are built on top of letters’; “codelets,” ‘agents that continually explore possibilities for perceptual structures to build in workspace . . . [and working in teams] . . . [using a parallel terrace scan] . . . [teams of codelets] “via competition and cooperation, gradually build up a hierarchy of structures that defines the program’s ‘understanding’ of the situation with which it is faced’; and “temperature,” “which measures the amount of perceptual organization in the system . . . high temperature corresponds to disorganization and low temperature corresponds to a high degree of organization.” observes mitchell, “via the mechanisms [of the program], copycat avoids the catch-22 of perception: you can’t explore everything, but you don’t know which possibilities are worth exploring without first exploring them. you have to be open-minded, but the territory is too vast to explore everything; you need to use probabilities in order for exploration to be fair. in copycat’s biologically inspired strategy, early on there is little information, resulting in high temperature and a high degree of randomness, with lots of parallel explorations. as more and more information is obtained and fitting concepts are found, the temperature falls, and exploration becomes more deterministic and more serial as certain concepts come to dominate. the overall result is that the system gradually changes from a mostly random, parallel, bottom-up mode of processing to a deterministic, serial, focused mode in which a coherent perception of the situation at hand is gradually discovered and gradually ‘frozen in.’” it seems to me that mitchell’s program serves as a good analogy for the process we use for making a diagnosis, or for that matter for any problem-solving activity. and because we face infinite variation around a number of common themes, we must use a “knowledge-based” approach to problemsolving more often than we would like to, even if we narrow somewhat early in the process our exploration by recognizing an attribute, or group of attributes, that seem to suggest to us a specific common theme. however, as admonished by mitchell and her program we must still “explore” to a small degree less likely probabilities. after all, if we do not consider, however briefly, a diagnosis, we will never make that diagnosis. dealing with large amounts of data how do we humans deal with large amounts of data? is more data always better? we have already learned from kahneman’s work that our minds are lazy. we know there is no way we can learn and use efficiently vast amounts of data. we need shortcuts of some sort. a common thing that we humans seem to want is some sort of “unifying theory.” we think in our heart of hearts that if we have the rule, or a small and easily remembered set of rules, we can figure out anything and we will not have to memorize so much and work so hard to make progress. surely, it is preferable to have as much data as possible— or is it? if we consider the example of sudoku, one strategy to solving a puzzle is to start by writing all the possible candidate numbers in the top of each empty square, then look at the puzzle, including the possibilities, and try to figure out which number goes in each square. as an avid fan of sudoku, i actually used this technique when i first started working the puzzles. but it ended up being very confusing— there was simply too much data to consider at one time and i had more difficulty solving puzzles than i now do. i learned a few strategic “tricks” and now i only write possibilities at the top of the square when i have the square down to two or three candidates. when we make a diagnosis, i posit that it is also possible to have too much data. it is much easier to figure out a diagnosis by performing a little strategic “legwork” first (by considering the clinical definitions of the diseases on our list of differential diagnoses for the patient) and to then order judiciously a few ancillary studies to further “flesh out” the data (determined by the clinical definitions) missing from our earlier “legwork.” is all data “information”? it seems that data can only be considered “information” in the context of the problem as a whole. data that distracts us does not help us solve the problem. that extraneous data only takes up space in our working memory and we waste time trying, as kahneman warns us, to make a coherent story of all the data residing in working memory. as reason would say, extraneous and distracting data serve as “nonsigns” (as opposed to “signs,” which argue in favor of an hypothesis, or “countersigns,” which argue against an hypothesis) and, therefore, nonsigns do not serve as “information.” the importance of context i mentioned earlier that context is vitally important to making correctly inferences about data. i recall an incident that occurred early in my pathology residency; i had been on my first surgical pathology rotation for only a couple of weeks. one case i had was a keratotic skin lesion from a middle-aged essay | dermatol pract concept 2012;2(4):12 57 person. i was still at the stage of looking through pathology textbooks and matching pictures to make a diagnosis. paging through lever’s histopathology of the skin, i happened upon a picture that looked very like the material on my glass slide. the caption of the picture read “acrokeratosis verruciformis of hopf.” i carefully made a note of that and went on to the next case. when i went to sign out my cases with my attending and told him my diagnosis, he said, “have you ever made a diagnosis of acrokeratosis verruciformis of hopf before?” i looked quizzically at him—surely he knew this was my second week ever of surgical pathology, and on autopsy rotations we never paid much attention (rightly or wrongly) to the deceased’s skin. i said, “no.” he responded, “well you better make the diagnosis now because you will likely never make the diagnosis again in you entire career.” i had read that the disease was rare, but the picture did look “exactly” like what was on the glass slide representing the patient’s skin lesion. at that point in my career i had very little understanding of what sorts of information could be learned from looking at tissue through a microscope. i had no concept of how much context was necessary to make a correct diagnosis. i still burn with shame whenever i think of my early diagnostic faux pas. but at least i learned a lesson from that experience. yair newman, in “meaning-making in language and biology” [14], points out that both language and biological systems operate in recursive-hierarchical and semantically open systems. for example, he points out that a word, by itself, can have any number of meanings. but when a word is in a sentence, the meaning of that word becomes more restricted. the meaning is further restricted when the sentence is in the additional context of a paragraph. meaning can be further restricted by the chapter and book in which the word finds itself. in this way, a finite number of symbols (for example an alphabet) can be used to make an infinite number of messages. additionally, while one cannot understand a word without seeing the sentence it is in, neither can one understand the sentence without understanding the words. this serves as “interaction-in-context” and exhibits hermeneutic circularity (which means that there is recursive feedback between the levels of interaction). newman discusses further the example of protein conformation. in the context of the cellular machinery proteins fold to a certain conformation even though some of the intermediate steps might have a higher, rather than lower, energy state (which would be unexpected to occur under the hypothesis that the protein will conform only to a lower state of energy). of course, in the context of enzymes and catalysts, the protein is able to be temporarily in less stable intermediate conformations on the way to the final conformation. using the example of the immune system, newman mentions that an agent may only serve as an antigen if the immune agents (macrophages, t cells, b cells, and cytokines) act in concert to recognize the agent as an antigen. some people are allergic to ragweed or peanuts and other people are not, for example. furthermore, even second messengers such as cyclic adenosine monophosphate (camp), although technically freely diffusible within a cell and potentially able to interact with different subsystems (having potentially different meanings), are generated and utilized focally, near the membrane-bound proteins with which they form a cellular subsystem of action and regulation. in making a diagnosis, context is created by looking for multiple attributes that make up the set of a specific disease. a chief complaint can mean many conditions, but by adding attributes, gradually other conditions on the list of differential diagnoses are eliminated. a context is created such that the chief complaint comes to mean only one disease. for the example of substernal chest pain, if we add the attributes of “pressure,” radiation to the left arm, no change with breathing cycle, lasts about 20 minutes and goes away, relieved by sublingual nitroglycerin, and aggravated by exercise and exposure to cold, we can exclude the possibilities of musculoskeletal pain, pleurisy, and dissecting aortic aneurysm, but we are still left with the possibilities of cardiac angina, hypertrophic cardiomyopathy, aortic stenosis, and esophageal spasm. if we then add to the context the item of systolic ejection murmur, we narrow the problem down to aortic stenosis. data and information; context and perspective i have used frequently the terms “data,” “information,” “context,” and “perspective.” how are the meanings of these terms related? a “datum” is a fact that has not yet registered in a human brain. once a datum registers in a human brain (once a person is actually paying attention to a datum), it becomes “information.” james gleich, in the information [15], mentions the lamentation of heinz von foerster during an early cybernetics conference, who complained “ . . . that information theory was merely about ‘beep beeps,’ saying that only when understanding begins, in the human brain, ‘then information is born—it’s not the beeps.’” thus, a datum becomes information when the human mind, using system 1, begins to associate the datum with other information/data stored in the human brain. “context” is the “system” of interacting data/information, being considered recursively by the thinking human. 58 essay | dermatol pract concept 2012;2(4):12 “perspective” is a sort of “lens” through which a thinking human considers the data/information and context. perspective can be purposely altered to a certain extent, although as mentioned in the earlier essay in this series on interpretation some of our bedrock beliefs are so ingrained in our worldview that we are not consciously aware of how we came to believe them and we may not be able to consider some perspectives that would require considering those beliefs to be false. an example of a datum not registering in the brain of a diagnostician, and thus not becoming information, might be examining the results of a complete blood count. the diagnostician glances at the entire sheet of data, but perhaps only registers the hemoglobin, hematocrit, total white blood cell count, and platelet count, paying no attention to the mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, or mean platelet volume. all those data values are reported by the lab on the report, but diagnosticians may not pay attention to them in a specific patient case. making a diagnosis so, if we cannot make a diagnosis under ideal conditions, how do we do it? the ground rules still apply. that is to say we still require a knowledge base, a set of reasoning skills, and the ability to acquire necessary data in the case of an individual patient. considering how the human mind works, we must wait until some possible disease state pops into our minds. we know from the work of kahneman and reason, that common diseases (frequency-matching) are likely to pop up, recently thought-about (recency-matching) diseases are likely to pop up, and diseases that we are familiar with that have similar features (similarity-matching) are likely to pop up. since the human mind works by association, as soon as the mind of a diagnostician is stimulated by hearing a chief complaint (the usual stimulus in the healthcare setting) or by noticing something amiss (seeing what could only be a melanoma on the neck of the person standing in front of us in a check-out line at the grocery store or seeing an unresponsive person, having witnessed his recent collapse in the park) or even a combination of the two (a suspected malingerer with a complaint that seems improbable in the context of additional data), that diagnostician begins using system 1 and starts to make associations and draw data from stored memory into working memory. in addition to the fact that we must wait for some idea to pop into our mind based on what we see is that “we notice what we notice” and nothing more. ian stewart, in the mathematics of life [16], discusses the work of taxonomists. states stewart, “taxonomists quickly learned that the most important features for classification were seldom those that immediately attracted the attention of the human observer. . . . which characters are best suited for classifying organisms? tigers and zebras are both striped, but that doesn’t imply that they are closely related. in fact, tigers and zebras do not belong to the same genus, to the same family or even to the same order. tigers are in the order carnivora (carnivores), but zebras are in the order perissodactyla (oddtoed hoofed animals). the two species come together only on the level of their class: both are mammals. so characters that strike the eye, like the tiger’s stripes, are often less significant than subtler ones, such as how many toes the creature possesses.” still explaining taxonomy, stewart also reminds us, “one of the first steps in the development of any branch of science is to find a way to organize the wealth of observations that nature presents to us, and this is especially necessary in biology, because of the vast diversity of life.” stewart describes the use by taxonomists of cladograms, diagrams that relate branch points and their timing and that describe shared attributes and the time during evolution that the attributes split or diverged (were no longer shared by subsequent [new] groups). each “clade” represents an ancestral organism with all of its evolutionary descendants. stewart mentions that constructing a clade “involves three steps: collect data on the organisms concerned, think about suitable cladograms, and choose the best of these.” from the collected data, a set of characters are selected and the candidate organisms are assigned a value for having (1) or not having (0) the attribute. then the data is assessed as to how many organisms have the highest percentage of attributes, how many a smaller percentage and so on. organisms more closely related share more attributes and those sharing fewer attributes are less closely related. the data is then fed into a computer and the computer generates possible cladograms. the computer then analyzes statistically the data to see which cladogram is the best fit. then starting with the values generated, the computer re-runs the data multiple times until there is no significant difference between the previously run cladogram and the subsequent one. the process is re-run, using different attributes. the goal says, stewart, is to find convergent evidence, “we can be very confident if different data, analyzed by different methods, lead to similar results.” i believe this is similar to the process of figuring out which attributes associate to define a disease. if we consider the example above of substernal chest pain, we can see that a certain number of attributes are shared by the different disease entities that make up our differential diagnosis, but as the problem is considered in the context of different data (new attributes added to the mix), some possibilities become less likely (less closely related to the definition of the disessay | dermatol pract concept 2012;2(4):12 59 ease). also, consider over time how the understanding has evolved of various disease processes and how new attributes are added to the armamentarium in order to better classify a disease. we have iterated the process of defining a disease over decades, each new study helping to find a better definition of disease, a definition that will hopefully differentiate that disease from all others. of course contrary to the ideal conditions for making a diagnosis, the knowledge base of each of us is limited, the knowledge base itself has items lacking because many diseases are not fully understood, and some of our current “knowledge” will prove incorrect, perhaps because data is missing or because we have made incorrect inferences about the data we have. the best we can do, really, is to consider a differential diagnosis based on the presenting situation, either chief complaint or observation of some aspect of the patient. the practice of medicine is a “team sport” (not necessarily a team working at the same time and on the same patient, but collectively and over time we physicians share knowledge about a population of patients), so we had best consider a differential diagnosis that is listed by an authority for the presenting situation. an authority might be a text or consensus statement from a professional society, for example. then, in order to figure out the most important additional data to obtain, we must understand the clinical definitions of the disease entities on our list of differential diagnoses. this is in a way analogous to using a stratagem in solving a sudoku puzzle—instead of obtaining a large number of data, some of which might be merely distracting and not helpful, we obtain the more helpful data. the clinical definitions include the clinical features, including items of history, information obtained from physical exam maneuvers, and ancillary testing necessary to make a diagnosis of disease “a.” parenthetically a clinical definition of a disease differs from a pathophysiologic definition of the disease. the clinical definition depends on the pathophysiologic definition, but consists of items readily discernible in a clinical setting. for example, the pathophysiologic definition of myocardial infarction might be “death of myocardial fibers due to occlusion of a coronary artery by a blood clot caused by the rupture of an atherosclerotic plaque, leading to segmental loss of contractility of the heart muscle in the area supplied by the occluded artery and leading to decreased cardiac output and possibly arrhythmia, etc. evidence of myocardial death includes features histologically of, first, contraction band necrosis and, subsequently infiltration of the necrotic area by neutrophils . . .” the clinical definition is as follows: at least two of 1) chest pain consistent with ischemic chest pain (substernal, squeezing, pressure, radiation to jaw or arm, may be accompanied by diaphoresis), 2) localized ischemic changes on electrocardiogram, consistent with blockage of a coronary artery, and 3) elevated cardiac marker (troponin and/or creatine kinase (ck)-mb. the clinical definitions are developed over time, after many studies, including postmortem examinations on prior patients, have been performed elucidating the pathophysiologic definitions. clinical definitions emphasize sets composed of clinical features and routine diagnostic tests, each set ideally unique to the disease in question; pathophysiologic definitions often rely on specialized testing that has not yet been approved for patient testing outside the research setting. when considering the items on our list of differential diagnoses and when looking for data that answers the question, “does this patient have the features required to diagnose clinically disease ‘a,’ disease ‘b,’ or disease ‘c’?” we must ask the question from the perspective of each disease on the list of differential diagnoses. we must say to ourselves, “feature one is a sign (favors the diagnosis) for disease ‘a,’ but a countersign (argues against the diagnosis) for disease ‘b,’” and so forth, going through each of the data from the perspective of each disease. then the disease that has the fewest countersigns is the most likely diagnosis. of course, any very important countersigns may cause us to broaden our list of differential diagnoses, considering a less common disease as the cause. with the data we have, we engage in an episode of recursive thinking, going back and forth in our minds between possibilities until we finally decide on one—the diagnosis. there are two very important points to keep in the back of our minds when we are making a diagnosis. first, disease entities do not have differential diagnoses. disease entities share attributes and groups of attributes. only the attributes and groups of attributes themselves have differential diagnoses. this may seem like a nit-picking distinction, but it is crucial. think about times you have read an article about one disease or another in the context of thinking about a particular patient. what happens when you get to the list of supposed differential diagnoses for that disease? you probably think to yourself, “i would never have considered that disease in this patient.” and then what? if you believe that diseases have differential diagnoses, just because that disease was on the list of differential diagnoses you might order another test or two to rule out the disease that you were not even considering for that patient. but if you look at it from the perspective of the previous paragraph and think about which attribute or attributes the patient has that led you to read the article to begin with, you can then decide rationally whether the disease on the list you were not considering initially should be considered (shares the attribute(s) with the disease described in the article and with your patient) or whether the disease described in the article shares other attri60 essay | dermatol pract concept 2012;2(4):12 butes with the disease listed as a differential diagnosis, but other attributes that your patient does not exhibit; that is to say, you should not consider that disease on the differential list as a possibility for your patient. for example, if a child presents with limb pain, one possibility is sickle cell crisis. if one reads an article about sickle cell disease in all its manifestations, the list of differential diagnoses might include carotid-cavernous sinus fistula. if the patient does not have the attribute of a swollen proptotic eye, one need not consider carotid-cavernous sinus fistula as a diagnostic possibility. on the other hand, if acute leukemia is on the list of differential diagnoses, sickle cell crisis can share the attribute of limb pain with a presentation of acute leukemia and leukemia should be considered in the differential because both conditions share the attribute exhibited by the patient—limb pain. disease states can be considered sets of attributes. each disease-set has many attributes and only a subset (of the disease-set as a whole) of the attributes serve to define the disease for diagnostic purposes. for example, fever is a common symptom and is an attribute shared by many diseases, but usually we recognize that fever means “the patient is ill” and we look for other attributes that define more closely the nature of the disease. periodicity of the patient’s fever may suggest malaria, for example, or presence of a rash accompanying the fever may suggest measles as another example; and usually we order an ancillary test, perhaps a wright-giemsa stained smear of peripheral blood to look for malarial parasites. when considering the concept of disease-sets when making a diagnosis, it can be useful to consider venn diagrams, whereby one looks for areas of overlap between sets. looking for attributes in the area of overlap, that is to say looking for shared attributes, does not help us differentiate between disease-sets. we must look for attributes outside the area of overlap to differentiate between two (or more) diseases. the second very important point is that there is one inviolable rule that applies to the process of making a diagnosis. that rule is baye’s rule. for a population in which there are members of different classifications, but with each member of the population sharing a given attribute or group of attributes, the likelihood that a specific classification should be applied to a member of that population is directly proportional to the prevalence of the classifications in the population. for example, if the population consists of 1110 items and if 1000 items are class a, 100 items are class b, and 10 items are class c, if one pulls one item “out of the hat (the hat representing the attribute or group of attributes in question)” at random, the likelihood is much higher that the item will be of class a than of any other class. items of class a are ten times more likely than class b and 100 times more likely than class c. as we add attributes to the set that represents the attributes of our patient, some differential diagnostic possibilities drop out of contention because those deleted diseases have attributes that exclude them from consideration or because they do not have an attribute or attributes required to make a diagnosis, leaving fewer and fewer possibilities. for a disease entity defined precisely, when the attributes of the patient match the set of attributes that make up that disease, the prevalence of the disease in a population of patients sharing all the attributes of our patient approaches 100 percent (of course there will always be some disease not yet discovered that cannot be excluded or some disease we failed to consider; thus the prevalence cannot reach 100%). the problem, of course, in using this inviolable rule arises from trying to assign the attribute to begin with, particularly if that attribute is “a matter of degrees,” like the red and green apples or patients with shortness of breath with a measurement of b-type natriuretic peptide level. attributes that lie on a continuum can only be assigned as “yes/no” in context, and by a process of recursive analysis. we must continuously “shuffle” or “juggle” the data, considering slightly new perspectives with each additional datum thrown into the mix until any change in the “apparent answer” becomes insignificant. when the degree of change has become insignificant, then we have “homed in” on a “common theme,” the insignificant change representing part of the infinite variation that is an integral part of the system in which we live and work. failure in making a diagnosis using the analogy of explore and exploit, we can fail at a number of places on the road to making a correct diagnosis. we can fail to recognize an attribute and not even realize a diagnosis should be made. we can “home in” on an attribute that is not important, or fail to follow up by looking for more important attributes (from the standpoint of accurate classification) and end up making a wrong diagnosis. we can look for “confirmatory” attributes only (from the perspective of only one potential diagnosis on our list of differential diagnoses), failing to rule out other items on the list of differential diagnoses. we must remember that we diagnosticians are human beings first and diagnosticians second. we think just like all other human beings. we must remember to engage system 2 to ensure we are not making a careless mistake. in the end, every human being classifies items many times a day, but as diagnosticians, our classifications affect another human life and we must take care when we perform our task that we have taken reasonable precaution to avoid the errors common to the process of classification, errors that are most often due to “signing off” too soon on the work of system 1. essay | dermatol pract concept 2012;2(4):12 61 conclusion the process of making a diagnosis is analogous to a complex adaptive system and, therefore, principles that apply to complex adaptive systems apply to the process of making a diagnosis. complex adaptive systems are composed of interacting elements, each part doing a different job, but each part integral to the outcome. while we can observe and study elements, we can not observe and study interactions in the same way. we can only observe outcomes, that is to say changes to an element, that result from the interaction(s). furthermore, no one element controls the system; however, any one element can affect all other elements. some of the elements that make up the system that is the process of making a diagnosis include the subsystems of the human mind (perception, interpretation, imagination, classification, attempts to construct coherence between items of information, knowledge base, ability to recall stored items into working memory, and in general all the items attributed by kahneman to system 1 and system 2) and the relationship of each human’s mind to culture and society (including our ability collectively to study disease processes and our collective understanding of the concepts of health and disease). any one of these elements can, and does, influence the ultimate diagnosis of a given patient at a given time. complex systems, by definition are not completely predictable. to review from edelman and tononi [17] “only something that appears to be both orderly and disorderly, regular and irregular, variant and invariant, constant and changing, stable and unstable deserves to be called complex.” that interactions themselves are not observable directly explains in large part the unpredictability that occurs in complex systems. systematic errors occur in all systems and these errors are predictable but the timing of these errors is not predictable (although systematic errors do not necessarily occur frequently—errors occur secondary to interactions that stress the system in some way). if the process of thinking is a system, there are predictable systematic errors that occur during processes of human thought, such as confirmation bias, failure to consider viable potential diagnoses (premature closure), and the like. life itself is a complex adaptive system of which each of us is a member, and as a result we must expect rules to change. some rules, basic rules, do not change—the mechanism of the hydrogen bond, for example. but strategic rules can change and we must be on our guard, continually looking and assessing “outcomes” to see if we expect them or whether we ourselves should change a strategic rule. it has been said we live in the age of information. we all think we know what that means—that there is “data, data everywhere.” we think that too much information is a relatively new occurrence. however, gleich describes the observations of oxford scholar robert burton who wrote in the year 1621 (that is to say about 390 years ago, and before isaac newton, david hume, pierre laplace, bertrand russell and the many others who have tried to make sense of our world and to understand it), “i hear news every day, and those ordinary rumors of war, plagues . . . thefts . . . comets . . . of towns taken, cites besieged in france . . . persia . . . daily musters and preparations . . . which these tempestuous times afford . . . so many men slain . . . stratagems and fresh alarms. a vast confusion of vows . . . edicts . . . lawsuits . . . grievances are daily brought to our ears. new books every day . . . whole catalogs of volumes of all sorts . . . controversies in philosophy, religion . . . now come tidings of weddings . . . jubilees . . . sports . . . then again, as in a new shifted scene, treasons . . . enormous villanies of all kinds . . . new discoveries, expeditions; now comical then tragical matters . . . today . . . officers created, to-morrow of some great men deposed, and then again of fresh honors conferred . . . one purchaseth another breaketh: he thrives, his neighbor turns bankrupt; now plenty, then again dearth and famine . . . thus i daily hear, and such like.” gleich continues, “another way to speak of anxiety is in terms of the gap between information and knowledge. a barrage of data so often fails to tell us what we need to know. knowledge, in turn, does not guarantee enlightenment or wisdom . . . it is an ancient observation, but one that seemed to bear restating when information became plentiful—particularly in a world where all bits are created equal and information is divorced from meaning.” it seems that the only way left to us to make progress and to diminish the anxiety (felt by all diagnosticians) associated with the glut of information is to leave the age of information behind us and to enter the age of context and perspective. by entering the age of context and perspective, “all bits” will no longer be equal and “information” will no longer be “divorced from meaning.” each of the ages of mankind have formed the foundation of the next age. principles learned in the stone age persisted in the iron age and on up through the ages of agriculture and industry. information will not disappear if we leave the age of information. on the contrary, “information” can only gain meaning and actually inform us if we use that information “in context” and look at the information “from a variety of perspectives.” by doing so, we can make a decision that makes the most sense in the context of what proves to be the best perspective. 62 essay | dermatol pract concept 2012;2(4):12 as minsky has reminded us, things that are easy for humans to do are sometimes difficult to study because they are so easy and it is not clear to us what we actually do, but by perseverance, we can make progress. a computer program (copycat), can make an analogy, one of the most basic cognitive tasks humans do. scientists have figured out the mechanisms of some heuristics, reliable short cuts to making correct decisions quickly. although we may not know how or why we know something, simon avers that a mechanism exists, if only we look for it, and the technique can be taught. we can put our minds to the problem of using context and perspective more often and more appropriately, thereby improving our efforts at diagnosis. while uncertainty cannot be banished from our existence, we can ease the anxiety resulting from the gap between information and knowledge. summary the process of making a diagnosis is a problem-solving activity carried out in the human brain by thinking recursively using a strategy of “explore and exploit” under the condition of uncertainty that arises from multiple sources. required for success are a knowledge base, a set of reasoning skills, and the ability to obtain the appropriate data in the case of a specific patient. context and the use judiciously of perspective are the keys to minimizing the anxiety that can overcome us in the cognitive gap between information and knowledge. failures at diagnosis are due to systematic error and are both predictable in nature, if not in time, and avoidable potentially if one understands the process. references 1. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part viii: interpretation. dermatopathology: practical and conceptual. 2006;12(4):23. 2. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xiv: language—can it be used unambiguously? dermatopathology: practical and conceptual. 2010;16(2):18. 3. upshur r. looking for rules in a world of exceptions, reflections on evidence-based practice. perspect biol med. 2005;48(4):47789. 4. kosko b. fuzzy thinking: the new science of fuzzy logic. new york: hyperion, 1993. 5. luchins d. clinical expertise and the limits of explicit knowledge. perspect biol med. 2012;55(2):283-290. 6. bronowski j. the origins of knowledge and imagination. new haven: yale university press, 1978. 7. sacks o. the mind’s eye. new york: vintage books, 2010. 8. gigerenzer g. gut feelings. new york: penguin books, 2007. 9. kahneman d. thinking, fast and slow. new york: farrar, straus and giroux, 2011. 10. marcus g. kluge: the haphazard evolution of the human mind. boston: mariner books, 2009. 11. harth e. the creative loop: how the brain makes a mind. reading, massachusetts: addison-wesley publishing company, 1993. 12. reason j. human error. new york: cambridge university press, 1990. 13. mitchell m. complexity: a guided tour. new york: oxford university press, 2009. 14. newman y. “meaning-making” in language and biology. perspect biol med. 2005;48(3):317-27. 15. gleich j. the information. new york: pantheon books, 2011. 16. stewart i. the mathematics of life. new york: basic books, 2011. 17. edelman g, tononi g. a universe of consciousness: how matter becomes imagination. new york: basic books, 2000. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(3):12 59 dermatology practical & conceptual www.derm101.com pigmented eccrine poroma: dermoscopic and confocal features caterina bombonato1, simonetta piana2, elvira moscarella3, aimillios lallas4, giuseppe argenziano5, caterina longo3 1 dermatology unit, university of modena and reggio emilia, italy 2 pathology unit, arcispedale s. maria nuova, irccs, reggio emilia, italy 3 dermatology and skin cancer unit, arcispedale s. maria nuova, irccs, reggio emilia, italy 4 first department of dermatology, aristotle university, thessaloniki, greece 5 dermatology unit, second university of naples, naples, italy citation: bombonato c, piana s, moscarella e, lallas a, argenziano g, longo c. pigmented eccrine poroma: dermoscopic and confocal features. dermatol pract concept 2016;6(3):12. doi: 10.5826/dpc.0603a12 received: april 23, 2016; accepted: may 27, 2016; published: july 31, 2016 copyright: ©2016 bombonato et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: caterina longo, md, phd, dermatology and skin cancer unit, arcispedale santa maria nuova-irccs, viale risorgimento, 80, 42100 reggio emilia, italy. tel. +390522295612; fax. +390594224271. email: longo.caterina@gmail.com eccrine poroma is a rare benign adnexal tumor of epithelial cells originating from the terminal ductal portion of the sweat glands that is typically located on palms and soles, although other cutaneous sites can be affected [1]. it is usually nonpigmented even if there is a pigmented variant that corresponds to 17% of cases and it is usually underdiagnosed, since it is mistakenly confused with other pigmented tumors [2,3]. dermoscopy and reflectance confocal microscopy (rcm) may assist in the correct diagnosis of this tumor. herein, we report one case of pigmented eccrine poroma (pep) that simulated clinically a cutaneous melanoma or a basal cell carcinoma. dermoscopy and rcm excluded the possibilities of those two diagnoses; the overall confocal findings were suggestive for a benign epithelial tumor. histology was fundamental to diagnose this lesion as a pigmented eccrine poroma. even if the diagnosis of eccrine poroma remains histopathological still, as in this case report, noninvasive tools such as dermoscopy and rcm examinations can be of help to rule out the diagnosis of melanoma. larger studies on this rare pigmented variant of eccrine poroma could shed new light on the identification of specific diagnostic dermoscopic and confocal features. abstract 60 observation | dermatol pract concept 2016;6(3):12 melanocytic proliferation was detected upon rcm and thus a diagnosis of melanoma was excluded. histologic examination, at scanning view, showed a well-circumscribed lesion with a pattern of growth in broad anastomosing bands (figure 3a). the overlying epidermis was hyperkeratotic (figure 3b). at higher magnification, it was composed of monomorphous cuboidal cells with features of poroid maturation into small ductal lumina (blue arrows) and containing variably sized melanin granules (arrows) (figure 3c-d). atypical mitoses, cytologic atypia or other features suggestive of malignant transformation were not seen. a diagnosis of pigmented eccrine poroma was rendered. discussion pinkus first described eccrine poroma in 1956 [4]. this benign adnexal neoplasm often appears as a firm, flesh-colored to reddish nodule, papule or plaque, at the acral sites, which are the sites with higher concentration of eccrine sweat glands. it is more frequent between the fourth and sixth decades of life [5] without sex predilection. its pathogenesis is unknown, but may be related to trauma, radiation or scars [2]. they are usually nonpigmented even if the pigmented variant can be occasionally found [6]. this variant seems to be more frequent in non-white people and on non-acral sites. frequently it is confused clinically with seborrheic keratosis, epithelialized pyogenic granuloma, basal cell carcinoma (bcc), squamous cell carcinoma (scc), angiofibroma, and cutaneous melanoma. for these reasons it can be regarded as “big simulator,” and thus diagnostic tools can be of help in differentiating eccrine poroma from other entities. dermoscopy of this tumor has been partially depicted. ferrari et al. [7] summarized dermoscopic structures in a series of non-pigmented poroma in which the main dermoscopic clues were: a white-to-pink halo surrounding the vessels, pink-white structureless areas, vascular structures of case presentation a 74-year-old woman, with a firm, slow-growing, variably pigmented nodule on her thigh was referred to our unit. the lesion was elevated at the periphery and partially ulcerated, well delimited and asymptomatic (figure 1a). dermoscopy showed asymmetry, white-blue color at the periphery and polymorphous vessels in the center associated with crystalline structures and multiple erosions (figure 1b). differential diagnosis included pigmented basal cell carcinoma, melanoma and benign epithelial neoplasms. analysis of rcm images revealed a well-demarcated tumor (figure 2a) composed of dark homogeneous islands surrounded by bright stroma (figure 2b). tumor cells were small and uniform in size and shape and vessels were well represented (figure 2c). the rcm features were not indicative of basal cell carcinoma because of the lack of palisading, clefting and typical shape of tumor nests. furthermore, no figure 1. clinical presentation of the nodule on the posterior part of the tight (a); dermoscopy reveals blue-white structures at the periphery, erosions and polymorphous vessels in the center (polarized dermoscopy 10x)(b). [copyright: ©2016 bombonato et al.] figure 2. confocal microscopy shows a well-demarcated tumor (a) characterized by dark homogeneous island (red arrows) surrounded by a bright stroma (yellow asterisk) (b); small cells (arrows) and vessels (red asterisk) (c). [copyright: ©2016 bombonato et al.] observation | dermatol pract concept 2016;6(3):12 61 arising from the eccrine ducts often are difficult to differentiate from an eccrine poroma [12]. even if the diagnosis of eccrine poroma remains histopathological still, as in this case report, noninvasive tools such as dermoscopy and rcm examinations can be of help to rule out the diagnosis of melanoma and non-melanoma skin cancers. larger studies on this rare pigmented variant of eccrine poroma could shed new light on the identification of specific diagnostic dermoscopic and confocal features. references 1. betti r, bombonato c, cerri a, et al. clinically and/or histologically pigmented poromas in caucasian patients. g ital dermatol venereol 2014;149:341-6. pmid: 24819762. 2. avilés-izquierdo ja, velàzquez-tarjuelo d, lecona-echevarria m et al. dermoscopic features of eccrine poroma. acta dermosifiliogr 2009;100(2):133-6. pmid: 19445878. 3. minagawa a, koga h. dermoscopy of pigmented poromas. dermatology. 2010;221:78-83. pmid: 20516657. doi: 10.1159/000305435. 4. goldman p, pinkus h, rogin jr. eccrine poroma, tumors exhibiting features of the epidermal sweat duct unit. ama arch derm 1956;74(5):511-21. pmid: 13361538. 5. abenoza p, ackerman ab. ackerman’s histologic diagnosis of neoplastic skin diseases. philadelphia: lea and febiger, 1990;113-85. 6. hu sc, chen gs, wu gs et al. pigmented eccrine poromas: expression of melanocyte stimulating cytokines by tumor cells glomerular and linear irregular vessels, hairpin vessels, and linear irregular vessels. minagawa et al. [3] valuated pep, describing 12 cases in which vascular structures, globule-like structures and comedo-like openings were the hallmarks. more recently, it has been shown that eccrine poroma might mimic several benign and malignant tumors also from a dermoscopic aspect [8]. additional to the use of dermoscopy, reflectance confocal microscopy is currently used to increase diagnostic accuracy of skin tumors [9,10,11] since it provides skin imaging in vivo at cellular level resolution close to conventional histology. in the current case, rcm highlighted the presence of tumor nests with clearly visible outline, small sized tumor cells and overall symmetric silhouette. although the diagnosis of pigmented eccrine poroma was not possible since diagnostic rcm criteria have been not previously identified, the findings were not suggestive of bcc or melanoma: furthermore, the overall analysis of the architecture and cytology suggested the diagnosis of an epithelial benign lesion. routinely the diagnosis of eccrine poroma is made by histopathology. on histology basaloid cells growing in nests and solid nodules are, by definition, characterized by more or less evident poroid differentiation, that is, small ductal lumina bordered by an eosinophilic cuticle. poroid differentiation occurs also in other entities such as hydroacanthoma simplex, dermal ductal tumor and poroid hidradenoma. benign tumors figure 3. histology reveals a well-demarcated tumor growing in large nests and covered by hyperkeratotic epidermis (a-b, he 40x). it is composed of monomorphous cuboidal cells with features of poroid maturation into small ductal lumina (blue arrows) and containing variably sized melanin granules (black arrows) (c-d, he 200x). [copyright: ©2016 bombonato et al.] 62 observation | dermatol pract concept 2016;6(3):12 10. longo c, lallas a, kyrgidis a, et al. classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy. j am acad dermatol 2014;71(4):716-24. 11. pellacani g, pepe p, casari a et al. reflectance confocal microscopy as a second-level examination in skin oncology improves diagnostic accuracy and saves unnecessary excisions: a longitudinal prospective study. br j dermatol 2014;171(5)1044-51. pmid: 24928707. doi: 10.1016/j.jaad.2014.04.067. 12. battistella m, langbein l, peltre band cribier b. from hidroacanthoma simplex to poroid hidroadenoma: clinicopathologic and immunohistochemic study of poroid neoplasm and reappraisal of their histogenesis. am j dermatopathol 2010;32:459-68. pmid: 20571345. doi: 10.1097/dad.0b013e3181bc91ff. does not always result in melanocytic colonization. j eur acad dermatol venereol 2008;22:303-10. pmid: 18269598. doi: 10.1111/j.1468-3083.2007.02406.x. 7. ferrari a, buccini p, silipo v, et al. eccrine poroma: a clinical-dermoscopic study of seven cases. acta derm venereol 2009;89:1604. pmid: 19326001. doi: 10.2340/00015555-0608. 8. lallas a, chellini pr, guimaraes mg, et al. eccrine poroma: the great dermoscopic imitator. j eur acad dermatol venereol 2015 aug 31. epub ahead of print. pmid: 26333195. doi: 10.1111/ jdv.13302. 9. scope a, selinger l, oliviero m, et al. precise longitudinal tracking of microscopic structures in melanocytic nevi using reflectance confocal microscopy: a feasibility study. jama dermatol 2016;152(3):299-304. pmid: 26746569. doi: 10.1001/jamadermatol.2015.4993. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020034 1 dermatology practical & conceptual introduction kindler syndrome is a rare autosomal recessive genodermatosis characterized by acral bullae in infancy followed by photosensitivity and progressive poikiloderma. the gene involved in kindler syndrome is fermt1, which encodes ferritin family homolog 1 protein linking actin to the underlying extracellular matrix. case presentation a 16-year-old boy with a history of second-degree consanguinity and similar complaints in a younger sibling presented with complaints of acral bullae in childhood, photosensitivity, thinning of skin involving dorsum of hands and feet, and redness of eyes. on examination, the patient was of average build and had normal physical and mental development. dermatological examination revealed poikiloderma involving the neck, cigarette paper scarring of skin of dorsum of hands and feet, oral leukokeratosis, conjunctivitis, gingivitis, and palmar keratoderma (figures 1-6). we performed dermoscopy of involved skin. dermoscopy of skin of dorsum of hands shows absence of eccrine gland opening and reticular pigment network and presence of white structureless areas suggesdermoscopy of kindler syndrome shekhar neema,1 preema sinha,1 sunmeet sandhu,1 sweta mukherjee,2 s. radhakrishnan1 1 department of dermatology, armed forces medical college, pune, india 2 department of pediatrics, command hospital, pune, india key words: kindler syndrome, dermoscopy, genodermatoses citation: neema s, sinha p, sandhu s, mukherjee s, radhakrishnan s. dermoscopy of kindler syndrome. dermatol pract concept. 2020;10(2):e2020034. doi: https://doi.org/10.5826/dpc.1002a34 accepted: november 11, 2019; published: april 3, 2020 copyright: ©2020 neema et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: shekhar neema, md, febdv, department of dermatology, armed forces medical college, pune-411040, india. email: shkharadvait@gmail.com figure 1. atrophy of skin of dorsum of both hands (cigarette paper scarring). https://doi.org/10.5826/dpc.1002a34 mailto:shkharadvait@gmail.com 2 letter | dermatol pract concept 2020;10(2):e2020034 classic clinical features, kindler syndrome was diagnosed. genetic testing was advised for confirmation, but the patient refused as he could not afford the test. conclusions kindler syndrome is a rare disorder with acral bullae in infancy, poikiloderma, and photosensitivity as predominant tive of atrophy and scarring; tips of fingers show absence of dermatoglyphic pattern; neck skin shows background erythema, dotted vessels, and pigmented dots suggestive of poikiloderma. dermoscopy of neck skin also shows the island of normal skin with a reticulate pigmentary pattern in between affected skin, suggestive of revertant mosaicism (figures 7-10). the rest of the dermatological and systemic examination was within normal limits. based on history and figure 2. poikiloderma (atrophy, telangiectasia, and hyperpigmentation) involving the neck. figure 4. conjunctivitis. figure 3. waxy keratoderma involving both palms. figure 5. periodontitis. figure 6. oral leukokeratosis involving gingival mucosa. figure 7. dermoscopy of skin of dorsum of hand shows lack of eccrine gland openings, structureless white areas (blue star) suggestive of atrophy, and scarring (dermlite dl4, polarized view). letter | dermatol pract concept 2020;10(2):e2020034 3 references 1. lai-cheong je, mcgrath ja. kindler syndrome. dermatol clin. 2010;28(1):119-124. 2. lai-cheong je, moss c, parsons m, almaani n, mcgrath ja. revertant mosaicism in kindler syndrome. j invest dermatol. 2012;132(3 pt 1):730-732. features. other features are eye involvement in the form of conjunctivitis, conjunctival scarring, corneal erosion, and ectropion of lower lids; oral involvement in the form of gingivitis, periodontitis, premature loss of teeth, and leukokeratosis; urethral meatal stenosis and urethral stricture, labial synechiae and vaginal stenosis, and esophageal or rectal mucosal stenosis. waxy hyperkeratosis of palms and soles with loss of dermatoglyphics, pseudosyndactyly, and axillary freckling are other features. patients with kindler syndrome have a higher risk of development of squamous cell carcinoma [1]. revertant mosaicism is a genetic phenomenon that results in spontaneous partial or complete correction of affected phenotype, characterized by the presence of a healthy patch of skin in the affected skin and can be confirmed by immunostaining of normal skin [2]. light microscopy of kindler syndrome shows hyperkeratosis, epidermal atrophy, and focal vacuolization of basal keratinocytes, melanophages, and colloid bodies. electron microscopy shows the reduplication of lamina densa. the identification of the loss-of-function mutation in the fermt1 gene confirms the diagnosis. our patient had classic clinical features and revertant mosaicism. dermoscopy helped in the identification of features such as adermatoglyphia and revertant mosaicism and in documenting poikiloderma and cigarette paper scarring. dermoscopy may not be required for confirmation of diagnosis of this rare disorder, but it may help us in delineating some subtle clinical features. to our knowledge, this is the first time dermoscopy of kindler syndrome has been described. figure 8. dermoscopy of skin of fingers shows absence of dermatoglyphics. figure 9. dermoscopy of neck skin shows background erythema, white polygonal areas (blue circles), dotted vessels (yellow arrow), and uneven pigmented dots (green arrow). figure 10. dermoscopy of neck skin shows white polygonal areas (blue circle), pigmented dots (yellow arrow), and presence of normal skin with reticular pigment pattern (red star). dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021105 1 dermatology practical & conceptual myopericytoma as a differential diagnosis of pyogenic granuloma camila scharf1, giuseppe argenziano1 1 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: myopericytoma, pyogenic granuloma, dermoscopy, soft-tissue tumor, myofibroma citation: scharf c, argenziano g. myopericytoma as a differential diagnosis of pyogenic granuloma. dermatol pract concept. 2021;11(1):e2021105. doi: https://doi.org/10.5826/dpc.1101a105 accepted: june 24, 2020; published: january 29, 2021 copyright: ©2021 scharf and argenziano. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: camila scharf, md, msc, via sergio pasini, 5, 80131 naples, italy. email: camila.scharf@unicampania.it case presentation a 46-year-old male first visited the dermatology unit complaining of a fast-growing lesion on the ankle (figure 1a). dermoscopy initially revealed typical findings pointing to pyogenic granuloma with homogeneous white-red areas surrounded by a whitish collarette (figure 1b). since the lesion was painful and friable, it was excised, and histopathology reported a myopericytoma. teaching point myopericytoma is a rare, benign, slow-growing soft-tissue tumor of perivascular cells. the most common location is on the distal extremities, and though the etiology is unknown, it has been associated with local trauma. histologically, it is characterized by a well-circumscribed, nonencapsulated proliferation of spindle-shaped cells arranged in perivascular concentric rings. therefore, it can be a differential diagnosis for hemangiopericytomas, myofibromas, and glomus tumors. dermoscopy has been previously disclosed unfocused arborizing vessels, structureless light brown areas, and shiny white streaks [1,2]. in our case, dermoscopy presented homogeneous white-red areas surrounded by a whitish collarette and classic features of pyogenic granuloma, which was our first clinical suspicion. dermoscopy training is essential for all practitioners and with experience we might banalize a few cases, but we must keep in mind that some dermoscopic features may be shared by different lesions. figure 1. (a) well-defined lesion, clinically consistent with pyogenic granuloma. (b) dermoscopy showing homogeneous white-red areas surrounded by a whitish collarette. a b 2 image letter | dermatol pract concept 2021;11(1):e2021105 references 1. boix-vilanova j, del pozo hernando lj, rodrigo lara h, corral-magaña o. [distal digital myopericytoma: a dermoscopy case study]. actas dermosifiliogr. 2020;111(4):338-341. doi: 10.1016/j.ad.2018.09.015. pmid: 31627853. 2. ruiz-arriaga lf, ramirez teran al, ortiz-hidalgo c, et al. myopericytoma in an unusual location. dermatol online j. 2018;24(4):13030/qt5z02t0dk. pmid: 29906007. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(1):4 13 case report a 56-year-old caucasian male with a history of uncontrolled diabetes mellitus and multiple other comorbidities was evaluated for slowly expanding plaques of his right lower leg, left forearm and left dorsal hand that had been present for the past six years. the patient denied any associated pruritus or pain. there was no history of previous trauma, immunosuppression, recent travel or prior treatment of the areas. his most recent laboratory values were significant for a hemoglobin a1c (hba1c) of 8.9%. physical examination revealed annular waxy brown plaques with central atrophy and a lilac colored advancing edge located on the left posteriorlateral calf measuring 5 x 4 cm, left dorsal hand 5 x 3.5 cm, and left forearm 11 x 9 cm (figure 1). interestingly, a 5.5 x 4.5 cm plaque on the right anterior lower leg exhibited central hyperkeratosis as opposed to atrophy (figure 2). a punch biopsy of the atrophic plaque on the left forearm was performed, which revealed granulomatous inflammation with epithelioid granulomas and plasma cells. periodic acid-schiff, gomori’s methenamine silver, acid-fast bacteria and fite stains were negative for organisms. a subsequent biopsy of an adjacent area demonstrated an attenuated epidermis with diffuse and palisaded granulomatous inflammation within the deeper levels of the dermis (figure 3). the inflammatory infiltrate was composed of lymphocytes and histiocytes, admixed with scattered perivascular plasma cells (figure 4). there was minimal increase in interstitial mucin. bacterial, fungal and acid-fast bacteria cultures for the second biopsy remained negative. the diagnosis is that of necrobiosis lipoidica (nl). the lesions were treated with topical emollients and clobetasol ointment once daily. after one month of treatment the patient reported improved appearhyperkeratotic necrobiosis lipoidica farhan khan, m.d.1, marigdalia k. ramirez-fort, m.d.1, c. stanley chan, m.d.2, theodore rosen, m.d.2 1 center for clinical studies, houston, tx, usa 2 department of dermatology, baylor college of medicine, houston, tx, usa keywords: necrobiosis lipoidica, granulomatous inflammation citation: khan f, ramirez-fort mk, chan s, rosen t. hyperkeratotic necrobiosis lipoidica. dermatol pract conc. 2013;3(1):4. http:// dx.doi.org/10.5826/dpc.0301a04. received: july 31, 2012; accepted: december 1, 2012; published: january 31, 2013 copyright: ©2013 khan et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: farhan khan, m.d., center for clinical studies, 6655 travis, suite 120, houston, texas 77030, usa. tel. 713.528.8818. fax. 713.528.8848 e-mail: fkhan@ccstexas.com. figure 1. two of the reddish-brown plaques on the leg. note the difference in their clinical appearance. [copyright: ©2013 khan et al.] 14 observation | dermatol pract concept 2012;3(1):4 otic pattern is usually present in patients with diabetes and the granulomatous pattern is more common in non-diabetic patients [2]. in both types, the epidermis is usually normal with the dermis being affected. there have been a few cases of unusual presentations of necrobiosis lipoidica in the literature. parra, in 1977, first reported three cases of perforating necrobiosis lipoidica in which transfollicular elimination of degenerated collagen appeared clinically as hyperkeratotic papules on the surface ance of all lesions including the hyperkeratotic one, with no increase in size of the plaques. discussion necrobiosis lipoidica was first described by oppenheim in 1929, and he named it dermatitis atrophicans diabetica [1]. today however, the preferred name is necrobiosis lipoidica due to its prevalence in a significant number of non-diabetic patients [2]. necrobiosis lipoidica is a rare degenerative connective tissue disease of unclear etiology [3]. this disease is more common in females with a female-to-male ratio of approximately 3 to 1 [3]. it has been estimated that up to 65% of patients with necrobiosis lipoidica have underlying diabetes mellitus [2]. however, only 0.3% of patients with diabetes mellitus have necrobiosis lipoidica [7]. diabetic patients with necrobiosis lipoidica do appear to have a higher rate of diabetes-related complications [6]. necrobiosis lipoidica classically presents as a red-brown papule that slowly progresses into yellow–brown, telangiectatic plaques surrounded by raised, violaceous rims [2,3]. the plaques often develop central epidermal atrophy [4]. oftentimes, scattered hyperkeratotic plugs and superficial telangiectasia are noted [2]. it is usually seen with bilateral symmetry of the pretibial region and less commonly it may affect the upper extremities, face, and scalp [6]. ulceration is the most common complication and may occur in up to 35% of patients [4]. there are two distinct histological patterns in necrobiosis lipoidica, both with isolated dermal pathology. the necrobifigure 2. hyperkeratotic scaling of the plaque on the right anterior shin. [copyright: ©2013 khan et al.] figure 4. a mixed perivascular infiltrate composed of lymphocytes and histiocytes with plasma cells (h&e, original magnification 400x). [copyright: ©2013 khan et al.] figure 3. an interstitial granulomatous dermatitis aligned parallel to the skin surface (h&e, original magnification 100x). [copyright: ©2013 khan et al.] observation | dermatol pract concept 2012;3(1):4 15 3. peyrí j, moreno a, marcoval j. necrobiosis lipoidica. semin cutan med surg. 2007 jun;26(2):87-9. review. pubmed pmid: 17544959. 4. wee sa, possick p. necrobiosis lipoidica. dermatol online j. 2004;10(3):18. pubmed pmid: 15748588. 5. gottrup f, karlsmark t. leg ulcers: uncommon presentations. clin dermatol. 2005;23(6):601-11. review. pubmed pmid: 16325069. 6. izikson l, english jc. noninfectious granulomatous diseases: an update. adv dermatol. 2006;22:31-53. review. pubmed pmid: 17249294. 7. boulton aj, cutfield rg, abouganem d, angus e, flynn hw jr, skyler js, penneys ns. necrobiosis lipoidica diabeticorum: a clinicopathologic study. j am acad dermatol. 1988;18(3):530-7. pubmed pmid: 3351015. 8. parra ca. transepithelial elimination in necrobiosis lipoidica. br j dermatol. 1977;96(1):83-6. pubmed pmid: 843440. 9. hammami h, youssef s, jaber k, dhaoui mr, doss n. perforating necrobiosis lipoidica in a girl with type 1 diabetes mellitus: a new case reported. dermatol online j. 2008;14(7):11. review. pubmed pmid: 18718195. 10. abdulla fr, sheth pb. a case of perforating necrobiosis lipoidica in an african american female. dermatol online j. 2008;14(7):10. pubmed pmid: 18718194. 11. de la torre c, losada a, cruces mj. necrobiosis lipoidica: a case with prominent cholesterol clefting and transepithelial elimination. am j dermatopathol. 1999;21(6):575-7. pubmed pmid: 10608254. 12. pestoni c, ferreirós mm, de la torre c, toribio j. two girls with necrobiosis lipoidica and type i diabetes mellitus with transfollicular elimination in one girl. pediatr dermatol. 2003;20(3):211-4. pubmed pmid: 12787268. 13. mcdonald l, zanolli md, boyd as. perforating elastosis in necrobiosis lipoidica diabeticorum. cutis. 1996;57(5):336-8. review. pubmed pmid: 8726715. 14. michaels bd, mullinax ka, wells mj, stetson cl. tuberous necrobiosis lipoidica. arch dermatol. 2007;143(4):546-8. pubmed pmid: 17438196. 15. joshi a, rathi sk, khanna n. necrobiosis lipoidica mimicking cellulitis. indian j dermatol venereol leprol. 1997;63(3):191-2. pubmed pmid: 20944321. 16. liapon ao, mashkilleison al, mkhitarian ag. [non-diabetic necrobiosis lipoidica clinically resembling degos’ papulosis]. vestn dermatol venerol. 1985;(8):38-9. russian. pubmed pmid: 4072386. 17. alonso ml, rios jc, gonzalez-beato mj, et al. necrobiosis lipoidica of the glans penis. acta derm venereol. 2011;91(1):1056. pubmed pmid: 21103831. 18. lynch m, callagy g, mahon s, murphy la. arcuate plaques of the face and scalp. atypical necrobiosis lipoidica (anl) of the face and scalp. clin exp dermatol. 2010;35(7):799-800. doi: 10.1111/j.1365-2230.2010.03831.x. pubmed pmid:20831607. of the plaques [8]. perforating necrobiosis lipoidica is rare and only a few cases have been described in the literature [9-13]. michaels and mullinax et al reported a case of tuberous necrobiosis lipoidica in which they observed yellow nodules, reminiscent of tuberous xanthomas, superimposed on patches of necrobiosis lipoidica [14]. these nodules eventually coalesced and grew more nodular and verrucous over time. joshi and rathi et al described a patient with necrobiosis lipoidica that had erythematous, indurated and tender plaques with superficial ulceration that clinically mimicked cellulitis [15]. the lesions were not yellow or waxy and no telangiectasia was seen. liapon and mashkilleison et al reported a case of necrobiosis lipoidica in a non-diabetic patient that clinically resembled degos’ papulosis [16]. alonso et al described a case of ulcerated necrobiosis lipoidica on the glans penis that was initially suspicious for squamous cell carcinoma [17]. the ulcer had red borders, a base that was erythematous, and a center that was necrotic. nl has also been reported in other unusual locations. lynch et al described a case of atypical necrobiosis lipoidica as arcuate plaques that appeared on the face and scalp [18]. no cases of hyperkeratotic necrobiosis lipoidica, though, have been reported previously. there are numerous treatments available for necrobiosis lipoidica, however, no modality is consistently effective and leads to complete resolution [6]. it is widely agreed upon that good diabetic glycemic control does not relate to control of nl [2]. conclusion this case illustrates a unique presentation of necrobiosis lipoidica. not only were the plaques in unique locations, but one plaque clinically exhibited significant central hyperkeratosis as opposed to epidermal atrophy, which to the best of our knowledge has never been reported in the literature. references 1. oppenheim m. eigentumlich disseminierte degeneration des bindegewebes der haut bie einem diabetiker. z hautkr. 19291930;32:179. 2. lowitt mh, dover js. necrobiosis lipoidica. j am acad dermatol. 1991 nov;25(5 pt 1):735-48. review. pubmed pmid: 1802895. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):11 59 dermatology practical & conceptual www.derm101.com a 34-year-old woman presented with an 8-month standing eruption disseminated on the trunk and anterior upper limbs. following their initial appearance, the skin lesions were described to occur in crops. on clinical examination, lesions of recent onset were small, dome-shaped, pale-red papules surrounded by an erythematous halo (figure 1a), while papules of longer duration displayed a central ulceration covered by a yellowish crust and were surrounded by a whitish rim (figure 2a). finally, porcelain-white scars with a reddish or hyperpigmented halo were noted on the site of healed lesions. a 44-year-old man presented with widespread, bilateral and symmetrical skin lesions with a 6-month history. similarly to the previous patient, the eruption consisted of lesions in three different evolution stages: reddish papules of recent onset, measuring 5 to 10 mm in diameter and not disappearing with pressure; reddish papules with a purple or necrotic center with or without central crust; and porcelain-white scars surrounded by an erythematous halo (figure 3a). dermoscopic examination in both patients revealed three different patterns, each one corresponding to a different evolution stage. specifically, papules of recent onset were dermoscopically characterized by the combination of a reddish-to-purple background and purpuric dots (figure 1b). at an intermediate progression stage, the papules displayed a targetoid pattern with yellowish, purple or necrotic center surrounded by an erythematous halo (figure 2b). finally, the dermoscopic variability of degos disease at different stages of progression javiera pérez anker1, grazyna kaminska-winciorek2, aimillios lallas3, sofia nicoletti1, krzysztof januszewski4, maria eugenia mazzei5, jerzy wydmanski6, alejandra larre borges,1 iris zalaudek7 1 unidad de lesiones pigmentadas pigmentadas, cátedra de dermatología, hospital de clínicas, universidad de la república, montevideo, uruguay 2 the center for cancer prevention and treatment, katowice, poland 3 skin cancer unit, arcispedale santa maria nuova irccs, reggio emilia, italy 4 department of pathology, silesian medical center, silesian medical university, katowice, poland 5 unidad de dermatopatología, cátedra de dermatología, hospital de clínicas, universidad de la república, montevideo, uruguay 6 department of conventional and intraoperative radiotherapy maria skłodowska-curie memorial cancer center and institute of oncology gliwice branch, gliwice, poland 7 department of dermatology, medical university of graz, graz, austria keywords: degos disease, dermoscopy, dermatoscopy, vessels citation: pérez anker j, kaminska-winciorek g, lallas a, nicoletti s, januszewski k, mazzei me, wydmanski j, larre bores a, zalaudek i. the dermoscopic variability of degos disease at different stages of progression. dermatol pract concept. 2014;4(3):11. http://dx.doi. org/10.5826/dpc.0403a11. received: march 9, 2014; accepted: may 5, 2014; published: july 31, 2014 copyright: ©2014 pérez anker et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. dr. pérez anker and dr. kaminska-winciorek contributed equally to this study. all authors have contributed significantly to this publication. corresponding author: grazyna kamińska-winciorek, the center for cancer prevention and treatment, fliegera av. 16, 40-060 katowice, poland. e-mail: dermatolog.pl@gmail.com 60 observation | dermatol pract concept 2014;4(3):11 dermoscopy of healed lesions revealed a whitish structureless center surrounded by a rim of short, thin and slightly curved vessels (figure 3b, c). a biopsy was taken from three lesions, one of each progression stage. the histopathologic findings corresponded well to the dermoscopic criteria (figures 1c & d, 2c & d, 3d). the histopathologic examination in both patients was overall suggestive of degos disease (dd). the clinical recognition of dd is often troublesome, since the disease is characterized by polymorphic and rather unspecific cutaneous manifestations [1,2]. as highlighted by our cases, clinical examination usually reveals lesions at different progression stages, ranging from light pink papules that do not fade with pressure to necrotic papules surrounded by erythema and whitish scars [1-3]. a delayed diagnosis might significantly deteriorate the patient’s prognosis, since dd is a potentially fatal obliterative arteritis syndrome with an unpredictable physical course. specifically, in some affected patients the disease remains restricted to the skin and follows a long benign course, while others die due to fulminating peritonitis or cerebral infractions within the first few years [3,4]. effectively, the diagnosis of dd should always be followed by figure 1. dome-shaped reddish papules of recent onset (white arrows) on the thigh of a 34-year-old woman (a). dermoscopic examination revealed a reddish-to-purple background and purpuric dots (b). histopathologically, the lesions were characterized by focal basal vacuolization, necrotic keratinocytes and moderate superficial perivascular lymphocytic infiltration in the dermis (c-h&e x100). a higher magnification revealed intravascular thrombi without fibrinoid necrosis of the wall and some extravasated red blood cells (d-h&e x200). [copyright: ©2014 pérez anker et al.] figure  2. longer standing papules in the same patient with central ulceration or necrosis (a), dermoscopically typified by a necrotic center surrounded by an erythematous halo (b). histopathology showed extensive epidermal necrosis with foci of re-epithelialization and superficial and deep perivascular inflammatory infiltrate in the dermis (c-h&e x100). at a higher magnification, numerous extravasated red cells, some intraluminal thrombi and capillary congestion without leukocytoclasia was seen (d-h&e x200). [copyright: ©2014 pérez anker et al.] observation | dermatol pract concept 2014;4(3):11 61 monitoring for systemic involvement, and treatment should be adjusted accordingly [3,4]. in our patients, laboratory, imaging and endoscopic examinations did not reveal any signs of systemic involvement. in the first patient, a treatment with 100 mg of aspirin daily was initiated, followed by remission of the lesions and no relapse during a 4-year follow up. the second patient was already under anticoagulant medication because of heart failure, and no additional treatment was initiated. dermoscopy has been shown to enhance the recognition of several inflammatory skin diseases, especially when the macroscopic morphology is not typical enough to allow a clinical diagnosis [5-7]. a dermoscopic “crown of thorns,” consisting of linear and hairpin vessels surrounding a central scar, has been previously described in dd [8-10]. our cases highlight that the latter pattern can be seen in late-stage lesions of dd, while early and intermediate lesions exhibit different dermoscopic findings, as shown in figures 1 to 3. our findings provide an indication that dermoscopy might enhance the clinical recognition of dd, by revealing three different patterns which correspond to lesions at different evolution stages and mirror the underlying histopathologic alterations. references 1. degos r. papulose atrophiante maligne. in: degos r (ed). dermatologie. 1st ed. paris: flammarion medecine-sciences; 1953:295-6. 2. farrell am, moss j, costello c, et al. benign cutaneous degos disease. br j dermatol. 1998;139:708-12. 3. scheinfeld n. degos´ disease is probably a distinct entity: a review of clinical and laboratory evidence. j am acad dermatol. 2005;52:375-8. 4. theodoridis a, makrantonaki e, zouboulis cc. malignant atrophic papulosis (kohlmeier-degos disease). a review. orphanet j rare dis. 2013;8:10. 5. lallas a, zalaudek i, argenziano g, et al. dermoscopy in general dermatology. dermatol clin. 2013;31:679-94. 6. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol. 2013 nov 22. doi: 10.1111/bjd.12685. [epub ahead of print] 7. zalaudek i, lallas a, moscarella e, et al. the dermatologist’s stethoscope-traditional and new applications of dermoscopy. dermatol pract concept 2013;3:67-71. 8. wobser m, burger m, trautmann a. the red flag. am j med. 2010;123:31-3. 9. darwich e, guilabert a, mascaro jm, et al. dermoscopic description of a patient with thrombocythemia and factor v leiden mutation-associated degos’ disease. int j dermatol. 2011;50:604–6. 10. cavalié m, tsilika k, sillard l, et al. reflectance confocal microscopy features of degos disease. jama dermatol. 2013; e1-2. figure 3. porcelain-white scars with a reddish or hyperpigmented halo on the forearm of a 44-year-old man (a). dermoscopic examination showed a central whitish structureless area (b), sometimes surrounded by a rim of short, thin, slightly curved vessels (c). histopathology revealed an atrophic epidermis and dermal fibrosis with absence of pilosebaceous units. [copyright: ©2014 pérez anker et al.] dermatology: practical and conceptual review | dermatol pract concept 2016;6(3):7 31 dermatology practical & conceptual www.derm101.com solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment philip r. cohen1 1 department of dermatology, university of california san diego, san diego, california key words: adult, cd2, cd25, cell, cutaneous, disease, kit, kit d816v, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, urticaria citation: cohen pr. solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment. dermatol pract concept 2016;6(3):7. doi: 10.5826/dpc.0603a07 received: march 31, 2016; accepted: june 18, 2016; published: july 31, 2016 copyright: ©2016 cohen. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: mastocytosis is either cutaneous (with skin-limited proliferation of mast cells) or systemic (with mast cells in extracutaneous sites). the onset of solitary mastocytoma in an adult is rare. purpose: a woman with the new onset of solitary mastocytoma is described. the clinical features of patients with adult-onset solitary mastocytoma are summarized. recommendations for the evaluation and treatment of individuals with adult-onset solitary mastocytoma are proposed. methods: pubmed was searched with the key words: adult, cd2, cd25, cell, cutaneous, disease, kit, kit d816v, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, and urticarial. the papers generated by the search, and their references, were reviewed. results: a 38-year-old taiwanese woman presented with an asymptomatic brown patch, which morphologically mimicked a dysplastic nevus, on her right abdomen; biopsy demonstrated a solitary mastocytoma. comprehensive evaluation (including serologic and bone marrow examination) excluded systemic mastocytosis and her residual mastocytoma is being monitored. adult-onset solitary mastocytoma has been described in 16 patients. lesions were either on the head and neck (5/14), torso (5/14) or extremities (4/14). urtication following lesion rubbing was noted in 79% (11/14) of patients. excision of the mastocytoma [75% (9/12)] was the most common treatment. other management approaches included corticosteroids (topical or intralesional), antihistamines (systemic) or observation. systemic symptoms were noted in 5 patients: flushing (3 women) and pruritus (3 women); gastrointestinal symptoms and headaches, flushing and/or anaphylaxis were each noted in one woman. none of the patients with adult-onset solitary mastocytoma had systemic mastocytosis; however, only 3 women were evaluated for systemic mastocytosis. conclusions: systemic mastocytosis is common in adults with new onset cutaneous mastocytosis. therefore, a conservative work up for new onset solitary mastocytosis in adults is proposed to include complete blood cell counts, serum chemistries (including liver function tests), and serum tryptase level and bone marrow biopsy to evaluate for mast cell clusters, morphology and immunophenotype and kit gene mutation in codon 816. similar serologic testing should be considered annually for adultonset solitary mastocytosis patients without systemic disease. abstract 32 review | dermatol pract concept 2016;6(3):7 fevers, fatigue, night sweats, weight loss or skin rashes. she had experienced diarrhea whenever she ate wheat, several years earlier, but this subsided once she eliminated gluten from her diet. her bowel movements are normal and she has no abdominal cramping or reflux. cutaneous examination of her right abdomen showed an 8 x 4 mm brown patch with irregular borders (figure 1). her left breast showed a 9 x 5 mm, 2-toned brown patch with irregular borders (figure 2). dark brown 2 x 2 mm macules were noted superiorly and inferiorly on the deltoid area of her right arm (figure 3). microscopic examination of a biopsy from the right abdomen lesion showed an infiltrate of monomorphous mononuclear cells in the upper dermis (figure 4). tryptase highlights the cells comprising the infiltrate, consistent with cutaneous mastocytosis (figure 5). correlation of the clinical presentation and the pathologic findings establishes the diagnosis of an adult-onset solitary mastocytoma. the biopsy specimens from the left breast, superior right arm and inferior right arm showed dermatofibroma, compound nevus and junctional dysplastic nevus with mild atypia. introduction cutaneous mastocytosis can present as either urticarial pigmentosa (also referred to as maculopapular cutaneous mastocytosis), diffuse cutaneous mastocytosis, telangiectasia macularis perstans, and mastocytoma [1-5]. mastocytomas are most commonly seen in infants (under 2 years of age) and children (ranging in age from 2 year to less than 16 years); many of these lesions improve spontaneously over several years duration [2,3,5,6]. the adult-onset of a solitary mastocytoma has seldom been reported [2]. a woman who developed a solitary mastocytoma is described and the characteristics of other men and women with adult-onset mastocytoma are reviewed. evaluation of these individuals for systemic mastocytosis and treatment options for the solitary mast cell skin lesion are discussed. case report a healthy 38-year-old taiwanese woman noticed four new asymptomatic pigmented lesions that had appeared during the prior year. she has no prior history of itching, flushing, figure 1. distant (a) and closer (b) views of the right abdomen show a solitary mastocytoma presenting as a brown patch with irregular borders. [copyright: ©2016 cohen.] a b figure 2. distant (a) and closer (b) views of the left breast show a dermatofibroma presenting as a two-toned brown patch with irregular borders. [copyright: ©2016 cohen.] a b review | dermatol pract concept 2016;6(3):7 33 15 mast cells, abnormal morphology of the mast cells, nor expression of cd2 and/or cd25 by the bone marrow mast cells. in addition, the bone marrow specimen did not demonstrate a kit mutation at codon 816. therefore, she did not fulfill the any of the criteria for systemic mastocytosis. subsequent examination of her skin did not reveal any similar appearing lesions. the biopsy site at her left abdomen had healed. there was urtication of the residual lesion after rubbing, demonstrating a positive darier’s sign. since the mastocytoma was otherwise asymptomatic and she had no mastocytosis-associated general symptoms, she elected to monitor the residual lesion. discussion mastocytosis, a disease in which there is an accumulation of mast cells in tissues, has two variants: cutaneous mastocytolaboratory studies demonstrated normal complete blood counts (including eosinophils) and platelet count, normal serum chemistries (including liver function tests), and normal serum tryptase level of 2.2 ug/l (normal, < 10.9 ug/l). kit (d816v) mutation by polymerase chain reaction was not detected in her peripheral blood. a bone marrow biopsy examination did not show foci of greater than or equal to figure 3. distant (a) and closer (b and c) views of the right deltoid area show a compound nevus (superior) (a and b) and a junctional dysplastic nevus with mild atypia (inferior) (a and c); both presented as dark brown macules. [copyright: ©2016 cohen.] a b c figure 4. distant (a) and closer (b and c) views of the skin biopsy of the mastocytoma on the right abdomen, stained with hematoxylin and eosin, show a monomorphous mononuclear cell infiltrate in the upper dermis (hematoxylin and eosin, a = x4; b = x20; c= x 40). [copyright: ©2016 cohen.] a b c 34 review | dermatol pract concept 2016;6(3):7 referred to as a ‘solitary mastocytoma’; this designation shall be used in this paper. however, in a recent consensus report on the cutaneous manifestations in patients with mastocytosis, the investigators recommended that the term ‘cutaneous mastocytoma’ be used to describe mastocytosis of the skin in individuals with 3 or less isolated mast cell skin lesions. if 4 or more lesions are noted, the patient was classified as having urticaria pigmentosa [4]. the occurrence of a mastocytoma in an adult—a person 16 years of age or older—is rare [2]. it was originally described in 2 of the 14 patients reported by johnson and helwig in 1961 [8]. to the best of my knowledge, including the currently reported woman, adult-onset solitary mastocytoma has only been described in 16 individuals (table 2) [2,7-16]. adult onset solitary mastocytoma has occurred in 8 men and 6 women. two additional adults are included in a report that provided a comparison of mastocytosis with onset in children and adults; however, no additional epidemiologic features were provided. the adults ranged from 16 to 46 years of age (median, 22 years). the age at which the mastocytoma was discovered in men ranged from 16 to 46 years (median, 20 years). in women, the onset of discovery ranged from 18 to 37 years (median, 24 years). six of the patients were indian and four were caucasian; one woman was taiwanese. sis and systemic mastocytosis [1-5]. cutaneous mastocytosis occurs when the mast cell proliferation is limited to the skin; evaluation for systemic mast cell disease is negative [3,4]. adult-onset cutaneous mast cell disease is usually associated with systemic mastocytosis [1,3,4]. systemic mastocytosis is characterized by increased mast cells in extracutaneous sites, such as the bone marrow, gastrointestinal tract, lymph nodes, liver or spleen [1,3] skin involvement may also be present [1]. the world health organization has established major and minor diagnostic criteria for systemic mastocytosis (table 1) [1,3] a mastocytoma is a localized dermal accumulation of mast cells that clinically presents as a reddish-brown macule or slightly raised papule; the lesion can be as large as 8 cm, thereby developing into a patch or nodule [7]. it usually presents as a single lesion; therefore, it has previously been figure 5. distant (a) and closer (b and c) views of the right abdomen mastocytoma skin biopsy, stained with tryptase, show that the cells in the upper dermis are highlighted by the immunoperoxidase stain [tryptase, a = x4; b = x20; c=x40). [copyright: ©2016 cohen.] a b c table 1. diagnostic criteria for systemic mastocytosis [a] [copyright: ©2016 cohen.] major criteria the presence of multifocal dense infiltrates of mast cells in the bone marrow or other extracutaneous organs, confirmed by special stains such as mast cell tryptase (greater than15 mast cells aggregating) minor criteria atypical mast cell morphology: in mast cell infiltrates in the bone marrow or other extracutaneous organs, greater than 25% of the mast cells are spindle-shaped or otherwise atypical; or in bone marrow smears, greater than 25% of the mast cells are spindle-shaped or otherwise atypical aberrant mast cell immunophenotype: mast cells in extracutaneous organs (cd117) co-express either cd2 or cd25 or both, as determined by flow cytometry activating point mutation of kit in codon 816 is present in extracutaneous organs baseline serum tryptase level is persistently elevated (greater than 20 ng/ml); this does not count in patients who have an associated clonal hematologic non-mast cell disease (ahnmd) [a] the diagnosis of systemic mastocytosis is fulfilled either by: (1) the presence of the major criterion plus one minor criterion or (2) the presence of at least three minor criterion. review | dermatol pract concept 2016;6(3):7 35 table 2. characteristics of individuals with adult-onset solitary mastocytoma [a,b] [copyright: ©2016 cohen.] case age on dx ra s size (mm) color site symptoms lesion general treatment ref 1 16 18 ca m 5 x 5 pink l thigh i,u excision 15 2 17 21 ns m 15 x 15 brown-red r cheek b,t,u excision 8c14 3 19 24 in m 25 x 25 hypopigmented nape of neck i,u excison 14c1 4 20 30 in m 30 x 25 hypopigmented nape of neck i,u ils [c] 14c2 5 20 50 in m 78 x 82 brown-red l back b,i,u ns 13 6 27 27 ns m 6 x 6 brown-red r thigh b,u excision 8c12 7 [d] 39 39 ca m 10 x 7 red l forearm ns 9 8 [e] 46 46 ca m 5 x 4 nonpigmented r medial canthus excison 12 9 18 19 in w 125 x 125 red-purple r chest b,i,t,u + [f] excison 16c2 10 20 22 in w 25 x 25 yellow, red-purple l shoulder b,i,t,u + [g] poa, topical steroid, ils 16c1 11 23 33 ca w 50 x 30 brown-red l supraclavicular i,u +[h] excision 11 12 24 24 in w 15 x 15 red l forearm i,t,u +[i] poa, topical steroid, then excision [i] 10 13 [j] 30 30 ns w 33 x 15 flesh-colored scalp +[j] excision 7 14 37 38 tw w 8 x 4 brown r abdomen u none cr [a] abbreviations: b, blister; c; case; ca, caucasian; dx, diagnosis age when lesion was biopsied or excised (years); i, itch (after rubbing); ils, intralesional corticosteroid; in, indian, l, left; m, man; mm, millimeters; ns, not stated; t, tender; tw, taiwanese; u, urtication (positive darier’s sign) after rubbing lesion; on, onset age when lesion initially was noted by patient (years); poa, oral antihistamine; r, right; ra, race; ref, references; s, sex; w, woman; +, present; -, absent [b] cases 15 and 16 were cited in a manuscript that provided a comparison of mastocytosis with onset in children and adults. adult onset solitary mastocytoma was listed in 2 of the individuals; neither had systemic symptoms (pruritus, flushing, abdominal pain, diarrhea or headache). complete resolution of the skin lesion was observed in one of the individuals; the other person was not followed for at least 10 years [2]. [c] he received 20 mg/ml of kenalog into the lesion every 3 weeks for 2 injections; there was decreased itching of the lesion, but no change in its size. also, the positive urtication (darier’s sign) of the lesion persisted. [d] the pathology report read: “the h. and e. stain is not diagnostic. with toluidine blue the upper cutis shows about 10 mast cells per high power field, somewhat concentrated around the blood vessels.” the patient was presented by dr. jesse a. tolmach as “urticaria pigmentosa (solitary lesion in adult) at the newyork academy of medicine, section of dermatology and syphilology meeting on march 6, 1962 . the unopposed comments of dr. arthur bernard hyman were: “ . . . where no other pathology is found and there are 10 mast cells per high-power field, it is considered, according to our present arbitrary standards, as more than sufficient to make a diagnosis and confirms a diagnosis of urticarial pigmentosa. [e] the patient also had severe prolidase deficiency. he had 2 adjacent solitary mastocytomas; the larger (inferior) measured 5 x 4 mm and the superior lesion was smaller. [f ] the patient had facial flushing and generalized itching. [g] the patient had facial flushing and generalized itching every 2-3 months; the “itching was suppressed only with continuous use of systemic antihistaminics and topical steroids, later intralesional steroids relieved pruritus for 6 months.” [h] the patient had one episode of gastrointestinal distress with severe nausea and vomiting, diarrhea, and abdominal pain. complete blood cell counts, platelet counts and liver function tests were normal and stool guiac was negative. [i] she had intense bouts of pruritus every 3-4 weeks. she was initially treated symptomatically with systemic antihistamines and topical corticosteroids with a partial response. subsequently, an excisional biopsy was performed. [j] she had a 10-year history of headaches, flushing, and anaphylaxis triggered by exercise, stress, heat or scalp friction. the patient experienced no flushing or anaphylaxis while pregnant, but her symptoms returned after delivery. the subcutaneous scalp mass was excised; postoperatively, she had no further symptoms at 27 months follow-up. 36 review | dermatol pract concept 2016;6(3):7 women) [10,16]. one of the women had experienced only one episode of gastrointestinal distress characterized by severe nausea and vomiting, diarrhea and abdominal pain [11]. another woman had generalized symptoms of 10 years duration consisting of headaches, flushing and anaphylaxis that were triggered by exercise, stress, heat or scalp friction; her mastocytoma presented as a subcutaneous scalp nodule [7]. all patients had hematoxylin and eosin stained tissue biopsy confirmation of their mastocytoma. the mast cells were typically present in the upper dermis—in either nodular or interstitial or sheet-like infiltrates and/or around blood vessels. they presented as monomorphic mononuclear cells with abundant pale basophilic staining, granule containing, cytoplasm. special histopathologic and/or immunohistochemical stains were used to confirm the suspected diagnosis of mast cells: azure a [15], cd25 (inerleukin-2 receptor alpha chain) [12], giemsa [7,8], kit (cd117, the receptor for stem cell factor) [12], toluidine blue [8,9,14] and tryptase [7,12,current report]; the granules in the cytoplasm were clearly demonstrated using either giemsa and toluidine blue stain [8]. in some of the patients lymphocytes [7] or eosinophils [14,15] were also present in the dermal infiltrate. the management of the solitary mastocytoma was described for 12 patients. excision (9/12, 75%) was the most common treatment. this was either performed as an excisional biopsy during the initial evaluation [8,10-12,15,16] or subsequently [7,14]. two individuals were initially treated with oral antihistamines and topical corticosteroids [10,16]; the lesions were subsequently treated with either excision [10] or an intralesional corticosteroid injection [16]. the woman in the current report received no additional treatment following her biopsy; her lesion was asymptomatic and she remains free of symptoms. intralesional corticosteroids have been used to successfully treat solitary mastocytomas in infants [22]. the mastocytoma was treated with intralesional corticosteroids in two patients [14,16]. a 30-year-old indian man had two injections—three weeks apart—of 20 mg/ml of kenalog®, that resulted in decreased itching but neither size change nor ceasing of urtication of the lesion [14]. also, a 22-year-old indian woman whose itching was relieved for six months following intralesional corticosteroids; her pruritus previously has only been suppressed with continuous use of systemic antihistamines and topical corticosteroids [16]. in addition to the reported patient, evaluation for systemic mastocytosis was only preformed in 2 patients [7,11]. one patient was a 33-year-old caucasian woman who had experienced one episode of gastrointestinal distress (associated with severe nausea and vomiting, diarrhea, and abdominal pain) two years earlier. she had a complete blood cell count, platelet count and liver function tests that were normal and a stool guaiac examination that was negative [11]. the onset age of the mastocytoma was the same age as the diagnosis of the lesion in five individuals: three men and two women. a delay from 1 year to 30 years (median, 4 years) occurred between the age when the other nine patients initially recognized the skin lesion and the diagnosis was established. for the five men, between 2 to 30 years (median, 5 years) passed between the onset age and diagnosis age of their mastocytoma. for the four women, between 1 to 10 years (median, 2 years) passed between the onset age and diagnosis age of their mastocytoma. the clinical appearance of the mastocytoma varied from a patch to a plaque to a nodule. the color varied from brown to brown-red to red or pink; part of one woman’s lesion was yellow. three of the men had lesions that were either hypopigmented or non-pigmented. the women in this report had a brown patch that was clinically suspected to be a dysplastic nevus; solitary [11] and multiple [17,18] mastocytomas have previously been misinterpreted as a melanocytic nevus. the hyperpigmentation associated with mastocytomas has been postulated to be secondary to induction of melanocytes by increased local concentrations of soluble mast cell growth factors from the mast cell lesions of cutaneous mastocytosis [13,19-21]. in addition to a melanocytic nevus (or a dysplastic nevus [current report] or spitz nevus [11], the clinical differential diagnosis of solitary mastocytoma includes chronic arthropod bite reaction [15], cyst [8], granuloma [8], hidrocystoma [15], leukemia cutis [11], and xanthogranuloma [11]. the solitary mastocytomas ranged in size from 5 x 4 mm to 12.5 x 12.5 cm. one man, who had severe prolidase deficiency, had two adjacent cutaneous mastocytomas located on his right medial canthus; the inferior lesion was 5 x 4 mm and the superior lesion was smaller. all of the other adults only had a single lesion. a positive darier’s sign (observed as urtication of the lesion after rubbing) was noted in 79% (11/14) of the patients. therefore, the absence of urtication after stimulation of the lesion does not exclude the possibility of a mastocytoma. other lesional symptoms included blistering (36%, 5/14), pruritus (64%, 9/14), and tenderness (29%, 4/14). the mastocytomas were located on the head and neck (36%, 5/14), the torso (36%, 5/14) and the extremities (29%, 4/14). the most common locations—each with two individuals—were the arms, legs, and posterior neck. all other sites only had one person: abdomen, back, cheek, chest, medial canthus, scalp, shoulder, and supraclavicular area. generalized symptoms associated with the solitary mastocytoma were observed in 31% (5/16) of the individuals [7,10,11,16]. all of the patients were women: three indian [10,16], one caucasian [11], and one whose race was not reported [7]. the symptoms most commonly occurring included flushing (three women) [7,16] and pruritus (three review | dermatol pract concept 2016;6(3):7 37 row should be evaluated for c-kit mutation at codon 816; in addition the bone marrow aspirate and biopsy should be examined for foci of greater than or equal to 15 mast cells, morphology of the mast cells, and expression of cd2 and/or cd25 by bone marrow mast cells [3,4]. if the initial evaluation for systemic mastocytosis is negative, annual testing for complete blood cell and platelet counts, serum chemistries including liver function tests, and a serum tryptase level should be considered. conclusions a mastocytoma presents as a reddish-brown papule that consists of an accumulation of mast cells in the dermis. a solitary mastocytoma can be a single lesion of cutaneous mastocytosis or represent the cutaneous stigmata of systemic mastocytosis. solitary mastocytomas typically appear in infants or children, are not associated with systemic disease, and occasionally resolve spontaneously. albeit less common, solitary mastocytomas have been described in 16 adults: 8 men and 6 women; 2 individuals did not have any epidemiologic features reported. the onset age for appearance of adult-onset solitary mastocytoma ranged from 16 to 46 years (median, 22 years). however, confirmation of the mastocytoma diagnosis was the same as the lesion onset age in five patients; there was a delay between 1 to 30 years (median, 4 years) between recognizing the skin lesion and establishing the diagnosis in the other nine patients. routine and special stains of a lesional biopsy confirmed the diagnosis. the head and neck (5/14), the torso (5/14) and the extremities (4/14) were the sites of the mastocytomas. they ranged in size from 5 x 4 mm to 12.5 x 12.5 cm. their color varied from brown to brown-red to red or pink; yet three lesions were either hypopigmented or non-pigmented. post-rubbing urtication (signifying a positive darier’s sign) was noted in 79% (11/14) of the mastocytomas. none of the patients had systemic mastocytosis. however, five patients (31%of 16 individuals) had generalized symptoms. flushing (3 women) and pruritus (3 women) were the most common symptoms. gastrointestinal symptoms (one episode in one woman) and a 10-year duration of headaches, flushing and anaphylaxis were symptoms in other women. treatment of solitary mastocytoma was excision of the lesion in 75% (9/12) of the patients either as past of the diagnosis evaluation or subsequently. other modalities, with varying success, included topical or intralesional corticosteroids and systemic antihistamines. observation of the residual lesion was also conducted for one patient who had no general or lesion symptoms. evaluation for systemic mastocytosis was only performed in three individuals. diagnostic tests were limited to routine systemic mastocytosis was suspected in a 30-year-old woman with a 10-year history of anaphylaxis, headaches and flushing triggered by exercise, heat, scalp friction or stress [7]. she had a major criterion for the diagnosis of systemic mastocytosis (a few clusters of greater than 15 mast cells were present on the bone marrow biopsy specimen), but did not fulfill any of the diagnostic minor criteria (table 1) [1,3]. although her serum tryptase level was elevated (ranging from 11 to 14 ng/ml), it was below the 20 ng/ml threshold established by the world health organization. in addition, there was neither d816v mutation in the kit gene nor evidence of the fep1l1pdgfra fusion transcript on her molecular studies [7]. the reported patient, a 38-year-old taiwanese woman, had no local or systemic symptoms of mastocytosis. however, since adult onset cutaneous mastocytosis is commonly associated with systemic mastocytosis [1,3,4], she received an evaluation for systemic disease. her complete blood cell and platelet counts, serum chemistries (including liver function tests), and tryptase level were normal. in addition, c-kit d816v mutation was not detected in her peripheral blood. her bone marrow aspirate and biopsy were negative for clusters of mast cells, c-kit mutation at codon 816, and mast cell expression of cd2 and/or cd25 by flow cytometry or immunohistochemistry. hence, she did not fulfill either the major or any of the minor criteria for diagnosis of systemic mastocytosis. recommendations for the treatment and evaluation of patients with adult onset solitary mastocytoma remain to be established. similar to the successful treatment of infantonset solitary mastocytoma [23], an excisional biopsy or subsequent excision of a biopsy-confirmed cutaneous mastocytoma was performed in 75% (9/12) of the patients with adult onset solitary mastocytomas. some symptomatic relief was provided with oral antihistamines, topical corticosteroids or intralesional corticosteroids; however, these interventions were only performed in a small number of patients. it is not unreasonable to observe the residual, biopsy-confirmed, mastocytoma in patients whose skin lesion is asymptomatic and who does not have systemic disease, similar to the patient in this report. to date, none of the patients with adult onset solitary mastocytoma have systemic mastocytosis. however, the number of patients in the literature is small and comprehensive evaluation for systemic disease was only performed in two women. since adult onset mastocytosis has such a high correlation with systemic disease (albeit indolent systemic mastocytosis in some of these individuals), a conservative recommendation to evaluate adults with the new onset of a solitary mastocytoma for systemic mastocytosis is reasonable. this should include a complete blood cell and platelet count, serum chemistries that include liver function tests, and a serum tryptase. peripheral blood and/or the bone mar38 review | dermatol pract concept 2016;6(3):7 5. lange m, lugowska-umer h, niedoszytko m, et al. diagnosis of mastocytosis in children and adults in daily clinical practice. acta derm venereol 2015 aug 13. doi:10.2340/00015555-2210. [epub ahead of print] 6. caplan rm. the natural course of urticaria pigmentosa: analysis an followup of 112 cases. arch dermatol 1963;87:146-57. pmid: 14018418. doi: 10.1001/archderm.1963.01590140008002. 7. khan k, kupferman me, gardner jm, ivan d. solitary mastocytoma in an adult with an unusual clinical presentation [letter]. j am acad dermatol 2011;65:683-4. pmid: 21839341. doi: 10.1016/j.jaad.2010.08.013. 8. johnson wc, helwig eb. solitary mastocytosis (urticaria pigmentosa). arch dermatol 1961;84:806-15. pmid: 14452118. doi:10.1001/archderm.1961.01580170100014. 9. tolmach ja. urticaria pigmentosa. arch derm syphilol 1946;54:479. pmid: 21000217. 10. jain vk, dayal s. solitary mastocytoma in an adult. j dermatol venereol leprol 1997;63:310-311. pmid: 20944363. 11. ashinoff r, soter na, freedberg im. solitary mastocytoma in an adult: treatment by excision. j dermatol surg oncol 1993;19:4878. pmid: 8496494. 12. ma sp, hardy tg. solitary mastocytoma of the eyelid in an adult patient with prolidase deficiency. ophthal plast reconstr surg 2015;20:e1-e3. pmid: 25603535. doi: 10.1097/ iop.0000000000000376. 13. harman m, akdeniz s, balci g, uzunlar ak. a brownishred plaque in an adult. indian j dermatol venereol leprol 2009;75:101. pmid: 19180694. 14. pandhi d, singal a, aggarwal s. adult onset, hypopigmented solitary mastocytoma: report of two cases. indian j dermatol venereol leprol 2008;74:41-3. pmid: 18187823. 15. baraf cs, shapiro l. solitary mastocytoma: case report in an adult. arch dermatol 1969;99:589-90. pmid: 4976401. 16. mittal rr, goyal dk. solitary mastocytoma in adults. indian j dermatol venereol leprol 1990;56:315-6. 17. novy fg jr. single lesion of urticaria pigmentosa (nevus?). arch dermatol syphilol 1950;61:514-5. 18. jacobs ph. urticaria pigmentosa; solitary lesions occurring in a mother and her daughter. ama arch dermatol 1958;77:112-4. pmid: 13486943. 19. okun mr. mast cells and melanocytes. int j dermatol 1976;15:71122. pmid: 825478. doi: 10.1111/j.1365-4362.1976.tb00167.x. 20. okun mr. mast cells, melanocytes, balloon cells [letter]. am j dermatopathol 1982;4(5):478-9. pmid: 7149204. 21. okun mr, bhawan j. combined melanocytoma-mastocytoma in a case of nodular mastocytosis. j am acad dermatol 1979;1;33847. pmid: 117029. 22. kang n-g, kim t-h. solitary mastocytoma improved by intralesional injections of steroid. j dermatol 2002;29:536-8. pmid: 12227491. doi: 10.1111/j.1346-8138.2002.tb00323.x. 23. birt ar, nickerson m. generalized flushing of the skin with urticarial pigmentosa. arch dermatol 1959;80:311-7. pmid: 13800941. serologic laboratory tests in one woman. the other women had a more comprehensive evaluation including serum tryptase level and bone marrow biopsy searching for clusters of mast cells, aberrant mast cell morphology or immunophenotype, and kit gene mutation in codon 816. although none of the patients with adult-onset solitary mastocytoma had systemic mastocytosis, only a small number of these individuals have been described. yet, the new onset of cutaneous mastocytosis in adults is commonly associated with systemic disease—albeit the incidence of indolent systemic mastocytosis remains to be established in this group of patients. therefore, until further data is accumulated, conservative recommendations with regards to the work up of adults with new onset solitary mastocytosis are reasonable. in summary, it is proposed that the initial work up for adult-onset solitary mastocytoma would include a complete blood cell count, serum chemistries (including liver function tests), and serum tryptase level; serologic evaluation for d816v mutation in the kit gene should also be considered. in addition, a bone marrow biopsy to assess, not only mast cell clusters, morphology and immunophenotype, but also kit gene mutation in codon 816, should be performed. in patients with adult-onset solitary mastocytoma without systemic mastocytosis, yearly blood tests to evaluate complete blood cell counts, chemistries (including liver function tests), and tryptase level should be considered. references 1. berezowska s, flaig mj, rueff f, et al. adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. mod pathol 2014;27:19-29. pmid: 23807778. doi: 10.1038/modpathol.2013.117. 2. middelkamp hup ma, heide r, tank b, mulder pg, orate ap. comparison of mastocytosis with onset in children and adults. j eur acad dermatol venereol 2002;16:115-20. pmid: 12046810. doi: 10.1046/j.1468-3083.2002.00370.x. 3. lange m, nedoszytko b, gorska a, et al. mastocytosis in children and adults: clinical disease heterogeneity. arch med sci 2012;8:533-41. pmid: 22852012. doi: 10.5114/ aoms.2012.29409. 4. hartmann k, escribano l, grattan c, et al. cutaneous manifestations in patients with mastocytosis: consensus report of the european competence network on mastocytosis; the american academy of allergy, asthma & immunology; and the european academy of allergology and clinical immunology. j allergy clin immunol 2016;137:35-45. pmid: 26476479. doi: 10.1016/j. jaci.2015.08.034. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020082 1 dermatology practical & conceptual case presentation a caucasian woman in her 40s, without relevant medical history, consulted the dermatology department for multiple bluish soft nodules on her tongue, lips, oral mucosa and perioral skin (figure 1). the lesions had appeared during childhood and had grown progressively. she noted that her father had very similar lesions. an ultrasound showed venous malformation, and a diagnosis of familial cutaneomucosal venous malformations was made. familial cutaneomucosal venous malformations juan francisco mir-bonafé1, marc mir-bonafé2, jaime piquero-casals3, eduardo rozas-muñoz4 1 department of dermatology, hospital son llàtzer, palma de mallorca, spain 2 department of dermatology, hospital universitario central de asturias, oviedo, spain 3 department of dermatology, clínica dermatológica multidisciplinar dermik, barcelona, spain 4 department of dermatology, hospital de san pablo, coquimbo, chile key words: venous malformations, tie2, cutaneomucosal venous malformations citation: mir-bonafé jf, mir-bonafé m, piquero-casals j, rozas-muñoz e. familial cutaneomucosal venous malformations. dermatol pract concept. 2020;10(4):e2020082. doi: https://doi.org/10.5826/dpc.1004a82 accepted: may 1, 2020; published: october 26, 2020 copyright: ©2020 mir-bonafé et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: juan francisco mir-bonafé, md, department of dermatology, hospital son llátzer, carretera manacor, pk4, palma de mallorca, spain. email: joanmirbonafe@gmail.com figure 1. multiple bluish soft nodules on the tongue, lips, oral mucosa, and perioral skin. 2 image letter | dermatol pract concept 2020;10(4):2020082 der, osler-weber-rendu syndrome, which is characterized by telangiectases resulting from arteriovenous malformations [2]. in doubtful cases, ultrasonography, mri, a histopathological study, and genetic assays may be needed. references 1. shu w, lin y, hua r, et al. cutaneomucosal venous malformations are linked to the tie2 mutation in a large chinese family. exp dermatol. 2012;21(6):456457. doi: 10.1111/10.1111/j.1600-0625.2012.01492.x. pmid: 22621187. 2. orizaga-y-quiroga tl, villarreal-martínez a, jaramillo-moreno g, ocampo-candiani j. osler-weber-rendu syndrome in relation to dermatology. actas dermosifiliogr. 2019;110(7):526-532. doi: 10.1111/10.1016/j. ad.2018.11.007. teaching point familial cutaneomucosal venous malformations are the result of a germline mutation in the tie2 receptor, with an autosomal dominant pattern of inheritance [1]. they usually present as multiple lesions that often appear from birth or during childhood and tend to grow throughout life. even though they can be present in any location, they are more frequent on the face, with special predilection for the oral mucosa, lips and tongue. rarely, they affect intestinal or anal mucosa. venous malformations affecting the lips, tongue, or oral mucosa are rare. a diagnosis is based primarily on clinical findings. the differential diagnosis includes vascular tumors such as infantile hemangioma and pyogenic granuloma, venous lake, and other vascular malformations such as arteriovenous or lymphatic ones. the lips, tongue, buccal mucosa may be involved in another rare autosomal dominant disordermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020019 1 dermatology practical & conceptual introduction tocilizumab (tcz) is a humanized monoclonal antibody directed against the interleukin 6 receptor, which has a main use in the treatment of several rheumatological diseases but also giant cell arteritis and polymyalgia rheumatica. despite the undoubted efficacy of this target therapy, immuno-mediated adverse events have increasingly been reported, including cutaneous sarcoidosis, psoriasis, acute generalized exanthematous pustulosis, leukocytoclastic vasculitis, drug reaction with eosinophilia and systemic symptoms (dress) syndrome, and granuloma annulare. case presentation a 75-year-old man was referred to our clinic 5 days after the onset of diffuse multiple painful targetoid plaques asymmetrically distributed on the lower extremities, trunk, neck, and nucha. the lesions were starting to coalesce to form irregular, sharply bordered plaques. he also presented with a marked periocular swelling (figure 1, a-d). the patient had a history of polymyalgia rheumatica and had been treated with oral steroids for 10 years, which were then suspended because of the onset of severe osteoporosis, with recurrence of symptoms. hence, subcutaneous tcz was started at the dosage of 162 mg/week. four days after the first administration of tcz, the patient reported sporadic painful annular plaques on his neck; the day after the second injection, the lesions were spreading to the rest of the body. moreover, the patient reported arthralgias, general malaise, headache, and fever (38.3°c). clinical observations and laboratory values were evaluated to rule out other drug-induced conditions with cutaneous involvement. investigations yielded a peripheral leukocytosis with neutrophilia and elevation of erythrocyte sedimentation rate and c-reactive protein. in erythema multiforme the lesions are itchy and typically start on the extremities symmetrically, with centripetal spreading [1]. a key characteristic of urticaria-angioedema is the evanescence of skin lesions (wheals last less than 24 hours), whereas our patient presented with persistent plaques. autoimmune screen was negative and sun-exposed areas were spared, so drug-induced tocilizumab-induced sweet syndrome in a patient with polymyalgia rheumatica federica filippi,1 marco a. chessa,1 annalisa patrizi,1 carlotta baraldi,1 francesca ferrara,1 federico bardazzi1 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: tocilizumab, tocilizumab-induced sweet syndrome, drug-induced sweet syndrome, neutrophilic dermatosis citation: filippi f, chessa ma, patrizi a, baraldi c, ferrara f, bardazzi f. tocilizumab-induced sweet syndrome in a patient with polymyalgia rheumatica. dermatol pract concept. 2020;10(1):e2020019. doi: https://doi.org/10.5826/dpc.1001a19 accepted: july 23, 2019; published: december 31, 2019 copyright: ©2019 filippi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: f.f., m.a.c., and f.b. contributed equally to this work. all authors have contributed significantly to this publication. corresponding author: marco a. chessa, md, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, via massarenti, 1-40138 bologna, italy. email: marcoadriano.chessa@gmail.com mailto:marcoadriano.chessa@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020019 (0.05% clobetasol propionate cream) once daily were prescribed. the systemic steroid was tapered to 10 mg/day within consequently, tcz was discontinued and oral prednisone at a dosage of 0.6 mg/kg/day and a topical steroid subacute cutaneous lupus erythematosus (antinuclear antibody positive in 60%-80% of cases) was excluded. finally, wells syndrome is characterized by itchy and indurated plaques with erythema and edema, and systemic symptoms may be present, so histopathology is mandatory for differential diagnosis. histopathological examination showed a dense perivascular infiltrate composed largely of neutrophils throughout the papillary dermis (figure 1, e and f). sweet syndrome is the most representative entity of febrile neutrophilic dermatoses. it can present as 1 of 3 clinical types: classic or idiopathic, malignancy-associated, or drug-induced. in drug-induced sweet syndrome, all of the following criteria should be present to achieve the diagnosis: (1) abrupt onset of painful erythematous plaques or nodules; (2) histopathological findings of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (3) fever >38°c; (4) temporal relation between use of medication and clinical presentation or relapse with readministration; and (5) disappearance of lesions after drug discontinuation or treatment with systemic corticosteroids [2]. our case fulfilled all of these criteria and thus the diagnosis of tcz-induced sweet syndrome was made. figure 1. clinical and histopathological findings. (a-d) multiple painful targetoid plaques characterized by irregular sharp border, central desquamative rim in some lesions and asymmetrically distributed on lower extremities, trunk, neck, and nucha. periocular swelling, left side worse than right. (e) dense infiltrate composed largely of neutrophils in the upper dermis (h&e, ×4). (f) higher magnification of the neutrophilic infiltrate with some nuclear fragmentation; vasodilation and swelling of endothelium with moderate extravasation of erythrocytes and prominent edema were also present (h&e, ×10). (g,h) clinical remission within 3 months, after tocilizumab interruption and systemic and topical steroid administration. letter | dermatol pract concept 2020;10(1):e2020019 3 duced subacute cutaneous lupus with erythema multiforme-like lesions: the enigma of the rowell syndrome. j dtsch dermatol ges. 2014;12(11):1039-1042. 2. walker dc, cohen pr. trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced sweet’s syndrome. j am acad dermatol. 1996;34(5 pt 2):918-923. conclusions in conclusion, clinicians should be aware of this possible reaction even though the causality has not been proven yet in the literature. references 1. baroni a, piccolo v, russo t, cozzolino d, mascolo m, chessa ma. norfloxacin-in6 weeks. the patient improved significantly after 4 weeks and had a complete remission in 3 months (figure 1, g and h). successively, to reduce the corticosteroid intake, in cooperation with his rheumatologist, an off-label treatment with adalimumab (40 mg every 2 weeks subcutaneously) was started. after a 3-month follow-up, no relapse was observed. dermatology: practical and conceptual research | dermatol pract concept 2020;10(2):e2020043 1 dermatology practical & conceptual prevalence and associations of general practice registrars’ management of impetigo: a crosssectional analysis from the registrar clinical encounters in training (recent) study hilary gorges,1 clare heal,1 mieke van driel,2 amanda tapley,3 joshua davis,4 andrew davey,3 elizabeth holliday,5 jean ball,6 nashwa najib,3 neil spike,7 kristen fitzgerald,8 parker magin3 1 mackay clinical school, college of medicine and dentistry, james cook university, mackay, australia 2 primary care & general practice, faculty of medicine, university of queensland, australia 3 gp synergy, australia 4 global and tropical health division, menzies school of health research school of medicine, darwin, australia 5 biostatistics, school of medicine and public health, university of newcastle, callaghan, australia 6 clinical research design and statistics, hunter medical research institute, new lambston heights, australia 7 department of general practice, the university of melbourne, notting hill, australia 8 general practice training tasmania key words: impetigo, prevalence, bacterial, primary care, skin infection citation: gorges h, heal c, van driel m, tapley a, davis j, davey a, holliday e, ball j, najib n, spike n, fitzgerald k, magin p. prevalence and associations of general practice registrars’ management of impetigo: a cross-sectional analysis from the registrar clinical encounters in training (recent) study. dermatol pract concept. 2020;10(2):e2020043. doi: https://doi.org/10.5826/dpc.1002a43 accepted: january 29, 2020; published: april 3, 2020 copyright: ©2020 gorges et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: during the data collection period 2010 to 2015, funding of the recent study was by the participating educational organizations: general practice training valley to coast, the victorian metropolitan alliance, general practice training tasmania, tropical medicine training, and adelaide to outback gp training program. these organizations were funded by the australian government. from 20162019, the recent study was funded by an australian government commissioned research grant, and supported by gp synergy, the general practice regional training organization for new south wales and the australian capital territory. gp synergy is funded by the australian government. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. hilary gorges, mackay clinical school, college of medicine and dentistry, james cook university, mackay base hospital, bridge rd., mackay qld 4740 australia. email: hilary.gorges@jcu.edu.au background: impetigo is a mild bacterial skin infection of childhood that is usually managed empirically in primary care. objective: to establish the prevalence and associations of impetigo in general practice (gp) registrars’ consultations. methods: cross-sectional analysis of the registrar clinical encounters in training (recent) study data. abstract https://doi.org/10.5826/dpc.1002a43 mailto:hilary.gorges@jcu.edu.au 2 research | dermatol pract concept 2020;10(2):e2020043 of 44.5% (interquartile range [iqr] 34%-49.2%), there is a lack of data for non-aboriginal and torres strait islander australian populations [2]. the prevalence of impetigo presenting in the general population in australia is unknown, and its associations are unexplored. the aim of this study is to investigate the prevalence of impetigo presenting to australian gp registrars, and the associations and outcomes of these consultations. methods recent project data were analyzed from the multisite cohort study of australian gp registrars’ clinical practice, detailed methodology of which is described elsewhere [10]. outcome factor the outcome factor was a problem/diagnosis being “impetigo,” defined by the international classification of primary care, second edition classification system [11] as code s84. independent variables were related to registrar, patient, practice, and consultation. registrar variables registrar variables were age, sex, training term, place of medical qualification (australia/international), full-time/part-time, and worked at the practice previously. patient variables patient variables were age, sex, aboriginal/torres strait islander, non–english-speaking background (nesb), problem/diagnosis was new, new to the practice, and new to the registrar. practice variables practice variables were training “region,” rurality/urbanity, practice size (number of gps), socioeconomic status of area, and routine bulk-billing. postal codes defined rurality of location using australian standard geographical classification-remoteness area classification [12] and the location’s socioeconomic index for area relative index of disadvantage [13]. what is known about the topic? impetigo is a bacterial skin infection, most prevalent in remote aboriginal communities, with implications for antimicrobial stewardship. what does this paper add? prevalence of impetigo and associated characteristics in the australian population, outside of remote aboriginal communities. introduction impetigo is a common skin infection [1,2] caused by staphylococcus aureus or streptococcus pyogenes [2,3]. it is often seen in childhood and is associated with poverty and tropical environments [2] and is most prevalent in remote indigenous australian children [2]. as a mild disease with good prognosis and potential for self-resolution [3], impetigo is managed in primary care [3,4], but because of its significant disease burden and highly contagious nature [2,3], empirical antibiotic treatment is recommended. skin swabs for bacterial culture are reserved for severe/recurrent disease or empirical treatment failure [5,6]. thus the management of impetigo has considerable implications for antibiotic stewardship. previous analysis from the registrar clinical encounters in training (recent) study [7] raised questions regarding interpretation of australian guidelines for impetigo management and the subsequent implications for antibiotic stewardship. characterizing the prevalence of impetigo and its associations is important to optimize and explore management that promotes antimicrobial stewardship. skin conditions are among the most common problems in australian general practice (gp), managed in 17.4 per 100 encounters, and they account for 11.3% of problems [8]. despite this frequency, studies have shown that registrars find skin conditions challenging and are not adequately prepared for the dermatology burden in the community [9]. impetigo prevalence in global communities has been measured extensively, and while it is highest in remote aboriginal and torres strait islander populations, with a median prevalence results: impetigo was managed in 0.24% of problems and 0.43% of consultations. patient variables associated with impetigo presentations were younger age and impetigo as a new problem, while patients with non–english-speaking backgrounds were less likely to present with impetigo. associated registrar variables were being new to the registrar and practicing in outer regional/remote locations. compared with all other problems/diagnoses, impetigo more often involved information seeking, ordering pathology, and prescription of medication, but less often involved follow-up or referral. conclusions: impetigo accounts for 0.43 per 100 gp registrar consultations in australia. association with outer regional/remote areas may reflect climate and socioeconomic factors that predispose to impetigo. associated pathology requests may reflect a lack of confidence in gp registrars’ management of impetigo. cultural differences may exist regarding health-seeking behavior relating to impetigo. abstract research | dermatol pract concept 2020;10(2):e2020043 3 results a total of 1,741 registrars (response rate 96%) contributed 377,980 patient problems over 214,888 consultations. impetigo was diagnosed in 915 consultations, accounting for 0.24% of all problems and managed in 0.43 per 100 consultations. characteristics associated with an impetigo diagnosis on multivariable analysis, younger patients (age 0-14, compared to 15-34: odds ratio [or] 7.14, 95% ci 5.75-8.86, p < 0.001) and patients new to the registrar (or 1.33, 95% ci 1.11-1.60, p = 0.002) were more likely to present with impetigo (table 1). nesb patients were less likely to present with impetigo (or 0.57, 95% ci 0.36-0.89, p = 0.015). registrars working in outer regional/remote/very remote areas (or 1.66, compared to major cities: 95% ci 1.11-2.48, p = 0.014) and male registrars (or 1.20, 95% ci 1.45-1.01, p = 0.038) were more likely to see patients with impetigo. what happens differently during impetigo consultations? impetigo consultations were significantly shorter in duration (14 vs 19 minutes on unadjusted analysis and or 0.94 per additional minute, 95% ci 0.93-0.96, p < 0.001 on multivariable analysis) and the registrars were more likely to seek help (or 2.53, 95% ci 2.13-3.02, p < 0.001) (table 1). of those who sought help from supervisors, the highest proportion were first-term registrars (70.7%) (table 2). the most frequent resource type used was electronic; the most common was therapeutic guidelines (61.65%) (tables 2 and 3). impetigo was more likely to present as a new, rather than existing, problem (or 2.19, 95% ci 1.74-2.76, p < 0.001). what outcomes are different in impetigo consultations? impetigo consultations were significantly more likely to involve pathology being ordered (or 2.43, 95% ci 1.933.06, p < 0.001) (table 1), the majority being skin swabs for bacterial culture (47%) (table 4). impetigo consultations were more likely to involve medication prescription (or 12.8, 95% ci 9.34-17.5, p < 0.001) but less likely to result in follow-up (or 0.71, 95% ci 0.59-0.86, p = 0.001) or referral (or 0.11, 95% ci 0.04-0.29, p < 0.0001). of impetigo consultations, 83% did not result in generation of a learning goal. discussion prevalence impetigo accounted for 0.24% of problems seen by australian gp registrars and was managed in 0.43 per 100 consulconsultation and educational variables consultation variables included duration, number of diagnoses/problems, pathology/imaging ordered, specialist referral made, follow-up organized, and medication prescribed. educational variables included seeking information or assistance and generating learning goals. statistical analysis we conducted cross-sectional analysis of data from the recent cohort study performed on 16 rounds of 6-monthly collected data from 2010-2017, with analysis at the individual problem/diagnosis level. the proportion of registrars’ impetigo problems/diagnoses and the proportion of impetigo consultations were calculated, with 95% confidence intervals (cis). impetigo vs other problems/diagnoses to test associations of a problem/diagnosis being impetigo, simple and multiple logistic regression analyses were used within the generalized estimating equations framework, accounting for clustering of patients within registrars. all variables with a p value <0.20 in univariate analysis were included in the multiple regression model. covariates with p > 0.2 in the multivariable model were tested for removal. covariates were removed if this did not substantively change the remaining coefficients in the model. to examine 3 separate issues within our research question, 3 models were built, each with the dependent variable “impetigo problem/diagnosis”: 1. to examine associations of a problem/diagnosis being impetigo (compared with other problems/diagnoses), patient, practice and registrar independent variables were entered in a regression model. 2. to examine in-consultation differences of an impetigo problem/diagnosis compared with other problems/diagnoses, the above variables were entered in a model along with consultation duration, information/assistance accessed by registrar, and number of problems/diagnoses dealt with in consultation. 3. to examine whether actions from managing impetigo differ from those managing other problems/diagnoses, all variables entered in the previous 2 models were entered in a model along with learning goals generated, follow-up organized, specialist referrals made, and pathology and imaging ordered. statistical analyses were programmed using stata 14.0 and sas v9.4. p values <0.05 were considered statistically significant. ethics approval the university of newcastle human research ethics committee approved the study (reference h-2009-0323). 4 research | dermatol pract concept 2020;10(2):e2020043 table 2. resource type used for impetigo consultations presented by training term resource type used in impetigo consultation term 1 frequency (%) term 2 frequency (%) term 3 frequency (%) total electronic 113 (52.6) 54 (25.1) 48 (22.3) 215 supervisor 65 (70.7) 21 (22.8) 6 (6.5) 92 book 13 (72.2) 3 (16.7) 2 (11.1) 18 specialist 0 (0) 2 (66.7) 1 (3.3) 3 other 5 (55.6) 2 (22.2) 2 (22.2) 9 table 1. patient, registrar, and consultation characteristics associated with impetigo variable class univariate adjusted or (95% ci) p or (95% ci) p patient variables patient age group 0-14 years 7.97 (6.64, 9.57) <0.0001 7.14 (5.75, 8.86) <0.0001 35-64 years 0.38 (0.29, 0.50) <0.0001 0.38 (0.28, 0.52) <0.0001 65+ years 0.12 (0.07, 0.20) <0.0001 0.12 (0.07, 0.24) <0.0001 patient sex female 0.66 (0.57, 0.76) <0.0001 0.87 (0.74, 1.02) 0.0795 aboriginal or torres strait islander yes 2.66 (1.78, 3.98) <0.0001 1.48 (0.96, 2.28) 0.0758 non–english-speaking background yes 0.40 (0.27, 0.58) <0.0001 0.57 (0.36, 0.89) 0.0145 patient/practice status new to practice 1.90 (1.44, 2.50) <0.0001 0.93 (0.67, 1.29) 0.6588 new to registrar 2.11 (1.80, 2.48) <0.0001 1.33 (1.11, 1.60) 0.0018 registrar variables registrar sex female 0.75 (0.64, 0.87) 0.0003 0.83 (0.69, 0.99) 0.0382 worked at practice previously yes 0.85 (0.70, 1.03) 0.0992 0.82 (0.66, 1.02) 0.0758 registrar age 1.01 (1.00, 1.02) 0.1100 1.00 (0.98, 1.01) 0.7376 practice variables practice routinely bulk bills yes 0.66 (0.53, 0.81) <0.0001 0.78 (0.60, 1.01) 0.0622 rurality inner regional 1.32 (1.10, 1.58) 0.0024 1.14 (0.91, 1.43) 0.2516 outer regional remote 1.41 (1.13, 1.77) 0.0029 1.66 (1.11, 2.48) 0.0139 socioeconomic index for area 1.03 (1.00, 1.05) 0.0587 1.02 (0.98, 1.06) 0.2831 region region 2 0.40 (0.28, 0.57) <0.0001 0.37 (0.24, 0.56) <0.0001 region 3 0.84 (0.66, 1.07) 0.1525 0.66 (0.48, 0.90) 0.0080 region 4 0.65 (0.54, 0.77) <0.0001 0.54 (0.42, 0.68) <0.0001 region 5 1.47 (1.00, 2.16) 0.0475 0.79 (0.45, 1.39) 0.4087 region 6 0.49 (0.34, 0.72) 0.0002 0.47 (0.29, 0.78) 0.0032 consultation variables new problem seen yes 4.14 (3.36, 5.11) <0.0001 2.19 (1.74, 2.76) <0.0001 sought help any source yes 2.68 (2.32, 3.11) <0.0001 2.53 (2.13, 3.02) <0.0001 consultation duration 0.93 (0.92, 0.94) <0.0001 0.94 (0.93, 0.96) <0.0001 no. of problems 0.44 (0.40, 0.49) <0.0001 0.95 (0.84, 1.07) 0.4079 consultation outcome variables pathology ordered yes 1.13 (0.95, 1.35) 0.1705 2.43 (1.93, 3.06) <0.0001 follow-up ordered yes 0.83 (0.72, 0.96) 0.0137 0.71 (0.59, 0.86) 0.0004 referral ordered yes 0.03 (0.01, 0.08) <0.0001 0.11 (0.04, 0.29) <0.0001 medication prescribed yes 15.7 (12.1, 20.3) <0.0001 12.8 (9.34, 17.5) <0.0001 ci = confidence interval; or = odds ratio. research | dermatol pract concept 2020;10(2):e2020043 5 impetigo consultations in our study compared with mainstream gps. patients being more likely to present to the registrar with impetigo as a new problem or for the first time reflects impetigo’s acute nature. patients may be more willing to see registrars for acute issues or perceived minor problems [22]. consultations for acute conditions are also booked on shorter notice, with the first doctor available, who is usually the registrar [9]. nesb patients were less likely to present with impetigo. one-tenth of gp patients are from nesb [8] and 21% of australians speak a language other than english at home [23]. our finding may reflect cultural practices that predispose patients to impetigo; also as impetigo is a mild condition with the potential for self-resolution, this may reflect different cultural approaches to health-seeking behavior regarding impetigo. differences in impetigo consultations impetigo consultations were shorter; this is expected as impetigo is a common condition with a clinical diagnosis, systemically well patients [3,4], and clear guidelines available [6]. registrars are more likely to seek information/assistance for impetigo despite its being a mild disease. first-term registrars were more likely to seek help from their supervisor than those in advanced terms, which may reflect initial inadequate preparation for the dermatological disease burden in the community [9], with confidence improving with experience. the most commonly used resources were electronic (table 2); the therapeutic guidelines [6] were most often used (table 3). in impetigo consultations the majority of registrars (83%) did not generate learning goals, patients were mostly children, and medication was usually prescribed; therefore, registrars may have used this reference for dose checking rather than guidance on diagnosis/management. tations. finding comparable data regarding the prevalence of impetigo is difficult. the beach study grouped impetigo with other “skin problems,” which were seen in 17.4 per 100 consultations [8]. in aboriginal and torres strait islander communities, impetigo encounters have been recorded as high as 7.5 per 100 consultations [14]. in a dutch study, yearly impetigo incidence was 4 per 100 patients aged <18 years; however, the proportion of consultations was not measured [15]. impetigo prevalence in global communities has been measured more extensively, although the majority of data was collected before 2010, with only 3 studies from 2010-2015 (3%) [2]. impetigo prevalence is highest in remote aboriginal and torres strait islander populations with a median prevalence of 44.5% (iqr 34%-49.2%) [2]. a canadian study of 2 first nation communities found impetigo prevalence between 1% and 4.2% [16]; in comparison, the median prevalence of impetigo in africa is 7% (iqr 4.1%-12.3%) [2] and 0.75% in japan [17]. there is a paucity of prevalence data for north america, china, most european countries and non-aboriginal australian populations [2,18]. impetigo diagnosis characteristics registrars working in outer regional/remote areas were more likely to see patients with impetigo. impetigo is most prevalent in poorly resourced areas and tropical/arid climates [2]; the regional differences seen in our study may reflect lower income level and more tropical/arid climates [12,19] in australian outer regional/remote areas. most patients with impetigo were <14 years, consistent with impetigo being a childhood disease [1,3]. registrars see younger patients than do established gps [8,20]; of registrar consultations, 17% involve patients <14 years [20,21] compared with 12% for established gps [8]. registrars are also more likely to see new patients, new problems, and acute illnesses [8], which may result in an elevated proportion of table 3. electronic resources used for impetigo consultations resource frequency (%) therapeutic guidelines 127 (61.65) royal children’s hospital guidelines 22 (10.68) dermnet nz 17 (8.25) australian medicines handbook 11 (5.34) monthly index of medical specialties (mims online) 6 (2.91) murtagh's general practice 4 (1.94) other 19 (9.2) total 206 table 4. pathology ordered for impetigo pathology request frequency (%) skin swab mc&s 96 (47) swab mc&s 57 (28) nose swab mc&s 16 (7.9) herpes simplex culture 11 (5.4) viral swab mc&s 4 (2) mc&s 3 (1.5) other 16 (7.9) total 203 mc&s = microscopy, culture and sensitivity. 6 research | dermatol pract concept 2020;10(2):e2020043 6. etg. electronic therapeutic guidelines complete: impetigo. https://tgldcdp.tg.org.au/viewtopic?topicfile=impetigo&guide linename=antibiotic&topicnavigation=navigatetopic#toc_ d1e108. published 2018. accessed august 2, 2018. 7. heal c, gorges h, van driel ml, et al. antibiotic stewardship in skin infections: a cross-sectional analysis of early-career gp’s management of impetigo. bmj open. 2019;9(10):e031527. 8. britt h, miller gc, henderson j, et al. general practice activity in australia 2015-16. http://purl.library.usyd.edu.au/sup/9781743 325131. published 2015-2016. accessed october 24, 2018. 9. whiting g, magin p, morgan s, et al. general practice trainees’ clinical experience of dermatology indicates a need for improved education: a cross-sectional analysis from the registrar clinical encounters in training study. australas j dermatol. 2017;58(4):e199-e206. 10. morgan s, magin pj, henderson km, et al. study protocol: the registrar clinical encounters in training (recent) study. bmc fam pract. 2012;13:50. 11. britt h. a new coding tool for computerised clinical systems in primary care—icpc plus. aust fam physician. 1997;26(suppl 2): s79-s82. 12. australian bureau of statistics. 1216.0—australian standard geographical classification (asgc), 2006. http://www.abs.gov. au/ausstats/abs@.nsf/latestproducts/1ae106c101420508ca 2571a900170741. published july 2006. accessed august 2, 2018. 13. australian bureau of statistics. 2039.0—information paper: an introduction to socio-economic indexes of areas (seifa), 2006. http://www.abs.gov.au/ausstats/abs@.nsf/mf/2039.0/. published 2006. accessed august 2, 2018. 14. thomas dp, heller rf, hunt jm. clinical consultations in an aboriginal community-controlled health service: a comparison with general practice. aust n z j public health. 1998;22(1):86-91. 15. loadsman men, verheij tj, van der velden aw. impetigo incidence and treatment: a retrospective study of dutch routine primary care data. fam pract. 2019;36(4):410-416. 16. nicolle le, postl b, urias b, law b, ling n. group a streptococcal pharyngeal carriage, pharyngitis, and impetigo in two northern canadian native communities. clin invest med. 1990;13(3):99-106. 17. furue m, yamazaki s, jimbow k, et al. prevalence of dermatological disorders in japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study. j dermatol. 2011;38(4):310-320. 18. romani l, steer ac, whitfeld mj, kaldor jm. prevalence of scabies and impetigo worldwide: a systematic review. lancet infect dis. 2015;15(8):960-967. 19. peel mc, finlayson bl, mcmahon ta. updated world map of the köppen-geiger climate classification. hydrol earth syst sci. 2007;11(5):1633-1644. 20. simon m, henderson k, tapley a, et al. problems managed by australian general practice trainees: results from the recent (registrar clinical encounters in training) study. educ prim care. 2014;25(3):140-148. 21. freed gl, spike n, magin p, morgan s, fitzgerald m, brooks p. the paediatric clinical experiences of general practice registrars. aust fam physician. 2012;41(7):529-533. 22. bonney a, phillipson l, reis s, jones sc, iverson d. patients’ attitudes to general practice registrars: a review of the literature. educ prim care. 2009;20(5):371-378. 23. australian bureau of statistics. 2016 census: multicultural. http:// www.abs.gov.au/ausstats/abs@.nsf/lookup/media%20release3. published 2016. accessed october 31, 2018. different outcomes in impetigo consultations impetigo consultations were more likely to involve pathology being ordered, the majority being skin swabs for bacterial culture (table 4), and medication prescription. as guidelines advise empirical treatment for impetigo, reserving skin swabs for severe, resistant, or recurrent disease [6], this may demonstrate lack of confidence with treating dermatological conditions. follow-up and referrals were less likely in impetigo consultations, reflecting the mild nature of the disease and preferred management in primary care [3,4]. strengths and limitations the strengths of this study are a large sample size of gp registrars with a high response rate from across australia, including major cities and remote areas. a limitation of the analysis and interpretation of the data is the absence of information regarding the severity of impetigo. we are unable to account for this variable in our interpretation, and low numbers of aboriginal and torres strait islander patients (4%) means we were underpowered to analyze this variable. conclusions impetigo accounts for 0.43 per 100 consultations seen by australian gp registrars. it is more common in outer regional/ remote/very remote areas and usually presents as a new problem. nesb patients are less likely to present with impetigo, which may reflect different cultural approaches to the management of a mild, potentially self-limiting condition. impetigo was associated with pathology being ordered, which may reflect a lack of confidence in australian gp registrars when dealing with this presentation. references 1. sladden mj, johnston ga. common skin infections in children. bmj. 2004;329(7457):95-99. 2. bowen ac, mahe a, hay rj, et al. the global epidemiology of impetigo: a systematic review of the population prevalence of impetigo and pyoderma. plos one. 2015;10(8):e0136789. 3. who. epidemiology and management of common skin diseases in children in developing countries. http://www.who.int/maternal_ child_adolescent/documents/fch_cah_05_12/en/. published 2005. accessed august 2, 2018. 4. shallcross lj, petersen i, rosenthal j, johnson am, freemantle n, hayward ac. use of primary care data for detecting impetigo trends, united kingdom, 1995-2010. emerg infect dis. 2013;19(10):1646-1648. 5. bowen a. the australian healthy skin consortium. national healthy skin guideline: for the prevention, treatment and public health control of impetigo, scabies, crusted scabies and tinea for indigenous populations and communities in australia. https://rhdaction.org/resources/national-healthy-skin-guideline prevention-treatment-and-public-health-control-impetigo. published 2018. accessed august 2, 2018. https://tgldcdp.tg.org.au/viewtopic?topicfile=impetigo&guidelinename=antibiotic&topicnavigation=navigatetopic#toc_d1e108 https://tgldcdp.tg.org.au/viewtopic?topicfile=impetigo&guidelinename=antibiotic&topicnavigation=navigatetopic#toc_d1e108 https://tgldcdp.tg.org.au/viewtopic?topicfile=impetigo&guidelinename=antibiotic&topicnavigation=navigatetopic#toc_d1e108 http://purl.library.usyd.edu.au/sup/9781743325131 http://purl.library.usyd.edu.au/sup/9781743325131 http://www.abs.gov.au/ausstats/abs http://www.abs.gov.au/ausstats/abs http://www.abs.gov.au/ausstats/abs http://www.abs.gov.au/ausstats/abs http://www.abs.gov.au/ausstats/abs http://www.who.int/maternal_child_adolescent/documents/fch_cah_05_12/en/ http://www.who.int/maternal_child_adolescent/documents/fch_cah_05_12/en/ https://rhdaction.org/resources/national-healthy-skin-guideline-prevention-treatment-and-public-health-control-impetigo https://rhdaction.org/resources/national-healthy-skin-guideline-prevention-treatment-and-public-health-control-impetigo editorial | dermatol pract concept 2012;2(1):1 1 dermatology practical & conceptual www.derm101.com dermatopathology comes to life! harald kittler, m.d. 1 1 department of dermatology, division of general dermatology, medical university of vienna, austria citation: kittler h. dermatopathology comes to life! [editorial]. dermatol pract conc. 2012;2(1):1. http://dx.doi.org/10.5826/dpc.0201a01. copyright: ©2012 kittler. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: harald kittler, m.d., department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18–20, 1090 vienna, austria. tel. +43.1.40400.7700; fax. +43.1.25330.331137. email: harald.kittler@meduniwien.ac.at. dermatopathology comes to life! dermatopathology has lost its momentum in science. nowadays it is mainly a diagnostic aid but has little impact on the way we generate concepts about a disease. in the old days many innovative concepts that advanced dermatology in particular and medicine in general started by observing a piece of tissue by light microscopy. the optical microscope was a central instrument to medicine like galileo’s telescope was to astronomy. galileo’s telescope revealed unexpected phenomena that challenged traditional geocentric astronomy, and light microscopy challenged traditional views of biology and medicine. those days are over and will never come back. when we think about innovation in medical science today we think about molecular biology and experimental medicine. it is hoped that, one day, molecular biology will reveal the hidden code of life in a way that every biologic state, physiologic or pathologic, becomes predictable. these hopes are similar to the deterministic view of physicists in the 19th century who thought that for everything that happens there are conditions such that, given them, nothing else could happen. this deterministic view was heavily influenced by the enormous success of newtonian physics. today it is generally accepted that this view was too optimistic. it seems that the world we live in is undetermined. what we call “law of nature” seems to express the limits of what might happen but does not determine what exactly will happen under certain conditions. if we are unable to predict exactly what will happen, we can only observe it in real life or simulate it in an experiment. an experiment is simply a specific type of observation under controlled conditions. according to karl popper, the main role of experiment and observation in science is not to prove but to disprove (“falsify”) concepts. however, there is no justification for the belief that performing experiments is more “scientific” or “better” science than performing direct observations. who needs a foucault pendulum (a typical experiment) to demonstrate the rotation of the earth if it can be observed directly by an astronaut in a space capsule? what does this all have to do with dermatology and dermatopathology? dermatopathology is mainly an observational and not an experimental discipline. every new and unexpected observation may, in the same way as experimental data, enrich our knowledge by important details, which are not consistent with previous interpretations of phenomena. an accumulation of such inconsistencies usually leads to scientific crisis that is finally resolved by a novel conceptual framework or paradigm that replaces the old one. this is how science progresses. paradigm shifts are often accompanied by novel technical developments that change our point of view. the good news is that such novel technical developments are about to revive our discipline’s impact on science. the recent developments in vivo microscopy imaging techniques, such as confocal laser scanning microscopy, optical coherence tomography, multiphoton microscopy, or optical sonography have the potential to bring dermatopathology back to life. the study by skvara et al [1] in this issue of dermatology practical and conceptual is a good example of how in vivo imaging techniques are about to change our point of view. they combined in vivo reflectance with fluorescence confocal microscopy and provided exciting insights on human skin in vivo. it would be completely wrong to think that the major purpose of such a device is the diagnosis of skin diseases. 2 editorial | dermatol pract concept 2012;2(1):1 these modern devices are equivalent to galileo’s telescope of the 17th century, and it is only a matter of time until in vivo microscopy imaging devices will reveal unexpected phenomena that will challenge traditional views of dermatology and dermatopathology. traditionally dermatopathologists examine a dead piece of tissue under the microscope, but at some point in time one has to break with one’s tradition or one becomes extinct. although unrecognized by those who think that “real” science is restricted solely to experimental medicine and molecular biology, the molecular revolution is not the only revolution going on in medicine. in vivo microscopy imaging techniques are about to change medicine practically and conceptually. from a conceptual point of view these techniques will enable us for the first time to observe the evolution of skin diseases in vivo on a microscopic level. from a practical point of view they will help us to target therapeutics more efficiently. dermatopathologists are most competent to examine a piece of skin through a microscope, whether ex vivo or in vivo. they only have to change their point of view from static to dynamic. by means of in vivo techniques dermatopathology has the potential to regain momentum in science and to become essential with regard to modern individualized therapy; an opportunity that should not be missed. reference 1. skvara h, plut u, schmid ja, jonak c. combining in vivo reflectance with fluorescence confocal microscopy provides additive information on skin morphology. dermatol pract conc. 2012;2(1):2. http://dx.doi.org/10.5826/dpc.0201a02. book review | dermatol pract concept 2011;1(1):18 85 book review: rongioletti f, smoller br (eds.). clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease. new york: springer; 2010. reviews by christine ko, m.d. and françois milette, m.d. with response from the authors editorial comment by mark a. hurt, m.d., book review editor citation: book review: clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease. new york: springer, 2010. dermatol pract concept 2011;1(1):18. http://dx.doi.org/10.5826/dpc.0101a18. copyright: ©2011 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, md., 226 millpark dr., maryland heights, mo, 63043. tel. 314.991.4470. email: markhurt@aol.com. review by christine ko, m.d. this is an ambitious undertaking, as suggested by the lengthy title, and the authors successfully cover endocrine, metabolic, nutritional, and deposition disorders. the book is all the more thorough as there is seamless assimilation of clinical, histologic, and radiologic information for these diseases. the aims are fulfilled with 1) concise text, 2) atlas-like inclusion of over 174 clinical photos and 116 histopathologic photomicrographs, 3) insight into the clinical appearance and course of disease, 4) detailed histopathologic descriptions, 5) therapeutic options, and 6) bulleted key points. this book should appeal to all dermatopathologists, as it is compact, richly illustrated, and easy to read. some minor criticisms include a need for white balancing many of the histopathologic photomicrographs and for improvement of brightness and color of the clinical photographs. despite this, the figures more than adequately depict the numerous diseases summarized in this book. in particular, some of the images not to be missed include beautiful clinical examples of necrobiosis lipoidica (fig. 2.1), pretibial myxedema (plaque-type) (fig. 3.2), acromegaly (fig. 4.1), eruptive xanthoma (fig. 6.4), fixed drug (fig. 14.6), and primary systemic amyloidosis (fig. 17.4). this atlas further delves into variants of granuloma annulare (chapter 2), pretibial myxedema (chapter 3), xanthomas (chapter 6), and mucinoses (chapter 18). while this is a strength, it also is a minor weakness, as the appetite is whetted to see even more images of rare variants like discrete papular lichen myxedematosus and pure nodular lichen myxedematosus. the authors are recognized experts in the subjects covered in this book, and even while achieving their broad aims, the authors include valuable pearls throughout the text. rongioletti f, smoller br (eds.). clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease. new york: springer; 2010. 195 pp with index. isbn 978-1-60761-180-6. dermatology practical & conceptual www.derm101.com 86 book review | dermatol pract concept 2011;1(1):18 review by françois milette, md this book is presented to its reader as “a concise atlas and text for the practicing dermatologist, pathologist, dermatopathologist, endocrinologist, and internist.” in this context, what should we expect from it? certainly an atlas should be complete and well-illustrated, whereas a text (or textbook) should be clearly and logically written. if it meets those requirements, it has a chance of being practically useful. last – and this is related to completeness of covering of the subject – to be worth its price, it should add to what is available in other textbooks already published. therefore, i have retained three criteria to evaluate in my review of this book: completeness, image quality, and logic and clarity of the approach presented. concerning completeness, suffice it to say that an atlas pertaining to, among other things, metabolic diseases with cutaneous manifestations should include lysosomal diseases (mucolipidoses, glycogenoses, sphingolipidoses, cystinosis, etc.) that do not appear in this book but can be found in other textbooks [1], therefore more complete at least on this point. those diseases are extremely rare, of course, but this is no excuse to neglect them, as lipoid proteinosis, which is discussed at length in a chapter devoted to it alone in this book, can hardly be considered frequent. as for the quality of the images, great efforts have been made to include numerous clinical photographs and histological microphotographs. the quality of these images, however, is very unequal. some are crystal clear but, unfortunately, others are suboptimal and look as if they had been taken through filters of various colors: blue, green, yellow, pink, etc. with the technology available today, it should have been relatively easy to standardize the quality of the images. one wonders, by the way, why the photograph on page 185 occupies the whole page and is the only photograph in the whole book to do so. concerning the logic of the approach, things start badly, as no introduction is offered to define the various categories of diseases discussed in the book. one may argue that everybody knows what endocrine, metabolic, nutritional, and deposition diseases are, but the authors themselves admit rightly that the categories as they use it are not exclusive, therefore questioning the pertinence of their enterprise. moreover, the warning placed in the preface that some diseases will appear in more than one category made this reader uneasy and suggests that some confusion exists in the organization of this book. for me, this was confirmed by the reading of it, which i found very hard to complete. the authors suggest that that hormones and nutrition influence metabolism profoundly and any “deposition” is the result of faulty metabolism, the incapacity to catabolize the material some involve differentiating certain disorders: for example, acne secondary to hypercorticism lacks comedones and cysts (unlike acne vulgaris), siderosis around eccrine glands may be specific for idiopathic hemochromatosis, and the linear array of papules is a clue for scleromyxedema as opposed to scleredema or scleroderma. a treatment pearl is using the hyperpigmentation of addison disease to monitor disease activity. as the authors’ expertise shines through with comprehensive coverage of the myriad diseases, it would be of value to know their opinion on issues like: a) lichen myxedematosus – how frequently is it associated with paraproteinemia or other systemic findings [1]? should all cases be screened and, if so, just once? b) reticular erythematous mucinosis – the literature suggests many cases are associated with autoimmune disorders [2]. is the author’s experience different? c) calciphylaxis – how often is it not in the setting of renal failure [3, 4]? is there a better prognosis if not truncal? overall, this book succinctly achieves a wide-ranging look at endocrine, metabolic, nutritional, and deposition disease. concise text accompanies numerous photographs and photomicrographs, enabling the reader to get a handle on these diseases clinically and histopathologically. this is a worthy read for anyone interested in these disorders. dr. ko is an associate professor of dermatology at yale university dermatopathology, new haven, ct, usa. contact her at christine.ko@yale.edu. references 1. wang p, yang h, ran y. localized papular mucinosis with iga nephropathy: a case report. arch dermatol 2011;147(5):599-602. pubmed pmid: 21576580. 2. kreuter a, scola n, tigges c, altmeyer p, gambichler t. clinical features and efficacy of antimalarial treatment for reticular erythematous mucinosis: a case series of 11 patients. arch dermatol 2011;147(6):710-5. epub 2011 feb 21. pubmed pmid: 21339419. 3. harris rj, cropley tg. possible role of hypercoagulability in calciphylaxis: review of the literature. j am acad dermatol 2011;64(2):405-12. epub 2010 aug 12. review. pubmed pmid: 20708299. 4. swanson am, desai sr, jackson jd, andea aa, hughey lc. calciphylaxis associated with chronic inflammatory conditions, immunosuppression therapy, and normal renal function: a report of 2 cases. arch dermatol 2009;145(6):723-5. pubmed pmid: 19528437. book review | dermatol pract concept 2011;1(1):18 87 deposited. therefore, the inclusion of the entities discussed in one or another category can only be arbitrary, and it is. one of the consequences that results from classifying into undefined and overlapping categories is that some diseases are classified in a manner that appears simply nonsensical to a naïve reader. if hyperlipidemia is easily understood as a metabolic disease resulting from inherited or toxic faulty metabolism of lipids, it is hard to understand how obesity can be included in the same group of diseases and not considered nutritional! isn’t obesity the stereotypical example of nutritional disease, or does it result, as in the mind of the authors, from a faulty metabolism? and what about glucagonoma syndrome (gs) and necrolytic migratory erythema (nme)? glucagonoma is a neoplasm and, therefore, logically, gs and nme, the physiopathology of which is unknown, are classical paraneoplastic syndromes as the authors themselves admit in the very first sentence of their chapter 16. so why do they discuss it as a nutritional disease? and why isn’t glucagonoma discussed in the chapter on endocrine or pancreatic diseases or, if need be, as a “metabolic” disease? this book raises more problems than it offers solutions, and many, many other questions could be enumerated here, but this is only a book review and no place for such lengthy development. in this work, the authors place the latin phrase, repetita iuvant, repetition is useful. by this, they want to justify the presence of some entities in more than one chapter as intended to offer “different perspectives.” it is not, however, repetition to which the reader is exposed; it is to redundancy and to arbitrary, incomplete and fairly illogical classification of rare diseases. after going through this book, my comprehension of the subjects addressed by it was not made clearer, and in response to the use of the latin phrase repetita iuvant, i would say that if it is true that repeating the same phone number three times helps in remembering it, three different numbers told in a row are certainly not easier to learn. lastly, the very title of this book sounds bizarre: clinical and pathological aspects of skin diseases [sic] in endocrine, metabolic, nutritional and deposition disease [sic]. in short: diseases in disease. one immediately feels uneasy. if some entities described, for instance, necrobiosis lipoidica, are indeed diseases of their own that may occur alone or in association with another disease (in this case diabetes), others can simply not be described as diseases. mucinosis and calcinosis, for example, are not diseases but histopathologic patterns occurring in many different contexts, e.g., neoplastic, endocrine, inflammatory, etc. it is no surprise; therefore, that confusion arises from the reading of this book confounding diseases and patterns. a more adequate title could have read cutaneous manifestations of endocrine, metabolic, nutritional and deposition diseases: clinical and pathological aspects and perhaps would have helped the work to be more coherent. dr. milette is a pathologist at the centre hospitalier pierre-boucher longueuil, qc, canada. contact him at francois.milette@cssspb.qc.ca. reference 1. weedon d. skin pathology. 3rd edition. churchill livingstone: elsevier, 2010. drs. rongioletti & smoller respond to dr. milette’s review our main goal was not to write a complete and exhaustive compendium. rather, it was to write just a concise atlastext to transfer to the practicing dermatologist, pathologist, endocrinologist, and internist all of our experience and our photographic and graphic materials on some topics that are often covered scantily, receive little emphasis, or are found scattered in different sections of the general textbooks of dermatology or dermatopathology. this is a first edition where, of course, there is ample room for improvement and all criticisms are welcome and really appreciated. milette’s criticisms are best divided into constructive and irrelevant. constructive criticism the criticism for not including lysosomal disorders is valid. however, these diseases belong largely to the pediatric sphere that is not a strict part of our expertise. we understand that all this does not necessarily follow from the title of the volume, and actually may leave some readers unsatisfied. in fact, we have discussed adding “in adults” to the title (which is already perceived as long). if a next edition is taken into consideration, it will be our first concern to add a chapter devoted to lysosomal storage diseases. we agree that some pictures are not of outstanding quality. it is not always easy to get good clinical and histological photographs from uncommon diseases. some pictures were old, difficult to reproduce, and supplied from the archives of the departments; the individuals who wrote the chapters supplied some others. of course, we know that is editor’s task to ensure that the image quality is optimal. we will take heed of this suggestion for the future. irrelevant criticisms for improvement classification: there is no perfect classification on which all can agree. classification, however, is a fundamental process and a necessary starting point in the study of the natural history of disease. we think that there is nothing wrong to 88 book review | dermatol pract concept 2011;1(1):18 classify obesity as a metabolic disease, and we are not alone in this position [1]. moreover, isn’t it true that the association of obesity with hypertension, glucose intolerance, and lipid metabolism disorder is diagnosed as metabolic syndrome [2]? the same holds for diabetes, which is classified both as a metabolic or a nutritional disease in various textbooks and articles. necrolytic migratory erythema has been included in the chapter of “nutritional” for two reasons: it is considered pathogenetically due to a relative deficiency of zinc and essential fatty acids because the tumor reduces the amount of albumin that normally carries it around the body, and its histological features are similar to acrodermatitis enteropathica and pellagra, which are clearly nutritional disorders. necrolytic migratory erythema has also been seen in the absence of a glucagon-producing tumor and may be associated with various systemic diseases, such as celiac disease, ulcerative colitis, etc. thus, its inclusion in the chapter of pancreatic disease or paraneoplastic disorders could also have been questioned. concerning the repetition of just a few disease in different chapters, this is not a matter of redundancy or arbitrary and incomplete classification of rare diseases, but, on the contrary, it reflects how metabolic, endocrinologic, nutritional, and deposition diseases may have overlapping features presenting with the same skin manifestation. for instance, pretibial myxedema can be considered both as a skin manifestation of thyroid disease and also classified among the primary cutaneous mucinoses; the same is true for macular or lichen amyloidosis that can be considered both as a skin manifestation of men 2a and also classified among the primary cutaneous amyloidoses. we think that there is nothing obscure or confusing to discuss a disease that is always the same but occurs in different backgrounds and eventually from distinct perspectives. of course, the more the reader is familiar with this field, the higher and clearer is the perception and the understanding of the different diseases. this book, in fact, is not for absolute beginner. the criticism of the words “skin diseases” in the title and the suggestion that they should be replaced by “cutaneous manifestations” is an example of an irrelevant criticism without any practical consequence. “disease” as paraphrased according to the merriam-webster dictionary is a condition of the living animal or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms. thus, we don’t understand why the term cannot be applied in our setting. many of the illustrated skin conditions are “disease” per se and not only skin manifestations of systemic conditions. incidentally, we consider cutaneous mucinoses and cutaneous calcifying disorders not as simple histological patterns but as a group of different deposition disorders that are heterogeneous. an accurate knowledge of their clinicopathologic features is essential in order not to miss some important underlying association (scleromyxedema and monoclonal gammopathy, calciphylaxis in renal disease, etc). in conclusion, we believe constructive criticism is welcome and worth voicing and may contribute to the improvement of our book. spurious criticism goes nowhere and sometimes may mask an underlying lack of robust arguments. franco rongioletti bruce r. smoller dr. rongioletti is professor of dermatology in the section of dermatology and department of pathology, university of genova, genova, italy. contact him at franco.rongioletti@ unige.it. dr. smoller is professor of pathology and dermatology in the department of pathology, university of arkansas for medical sciences, little rock, ar, usa. contact him at smollerbrucer@uams.edu. references 1. bray ga. the metabolic syndrome and obesity. totowa nj: humana press inc. 2007. isbn 1588298027. 2. eckel rh, grundy sm, zimmet pz. the metabolic syndrome. lancet 200516-22;365(9468):1415-28. review. pubmed pmid: 15836891. final comment by mark a. hurt, md i thank drs. ko and milette for their reviews of this book, and i thank also drs. rongioletti and smoller for considering and responding to dr. milette’s review. as drs. rongioletti and smoller are both editors and authors, they are not the only authors of the book. there is a total of 23 authors, including the editors, and they are positioned principally in europe and the united states, the exception being two authors from mexico. of the 23 chapters in the book, all but nine are written by authors other than the editors. in their preface, drs. smoller and rongioletti lay out the reason and purpose of their book: “dr. rongioletti has been studying, diagnosing, treating, and researching mucinoses and deposition disorders for years and this work represents his dream of consolidating his amassed experiences into a concise atlas and text for the practicing dermatologist, pathologist, dermatopathologist, endocrinologist, and internist.” furthermore “dr. smoller has also been actively interested in cutaneous pathology as a window for systemic diseases and his written extensively on this topic.” finally book review | dermatol pract concept 2011;1(1):18 89 “it is the hope of the authors that each chapter will provide insights into the clinical appearance and course of the diseases presented, followed by a review of the pathogenesis for each disease, and a close inspection of the histopathologic changes and any accompanying special studies that might be required to establish a diagnosis.” this is a book that is of standard journal size, is relatively thin considering the subject matter, at 194 pages including the index, and the paper is of reasonably good quality. the editors divide the book into four major parts, as follows: i. cutaneous endocrine disease (classified by the diseased organ) ii. cutaneous metabolic disease (classified by the product of the abnormal metabolism) iii. cutaneous nutritional disease (classified by the product of deficiency or excess without respect, necessarily, to cause) iv. cutaneous deposition disease (classified by the product of deposition) the authors present the chapters within each part as if they were separate small reviews as though in a journal. each begins with a section of “key points” similar to an abstract, except organized by bullet points, which i find to be a useful feature. the organization of subject matter within each chapter is by a number outline, adding additional sub-points as needed; there is no strict separation into labeled sections of “clinical presentation,” “histopathological findings,” etc., even though those descriptions are found in the paragraphs of the text. furthermore, the authors augment the text with ample photographs of somewhat uneven quality that refer back to the text thus allowing one to find where the authors discuss the histopathological findings. the text flows easily from well-constructed sentences within concise paragraphs. although most of the abbreviations are relatively easy to grasp from the text, a key to abbreviations in the front of each chapter might be a consideration for any future editions. although one can criticize the authors for some of the photographs in this book, i am amazed at how many very good to excellent photographs are included, especially given the rarity of some of the conditions. minor improvements of standardization of photographic hue and contrast will serve to make the second edition better. i offer one consideration for any future edition of this book, and it is a difficult addition: a diagnostic algorithm linked to the text. although this is a difficult task, and it perhaps is unfair to ask so much of the authors, it is enormously beneficial to have an algorithm when confronted with specific, concrete histopathologic findings in the daily work of developing a differential diagnosis for the purpose of rendering a specific diagnosis. thus, a three-pronged approach – an algorithm, a text (with atlas), and a well-developed index – should serve well the second edition of this book. until then, i will become a serious student of this version. mark a. hurt, md book review editor dr. hurt practices dermatopathology in maryland heights, mo, usa. contact him at markhurt@aol.com. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021014 1 dermatology practical & conceptual entodermoscopy: a useful tool for the diagnosis of cutaneous larva migrans claudio conforti1, arianna dri1, ludovica toffoli1, enrico zelin1, iris zalaudek1, nicola di meo1 1 dermatology clinic, hospital maggiore, university of trieste, italy key words: entodermoscopy, dermoscopy, larva migrans, tropical disease citation: conforti c, dri a, toffoli l, zelin e, zalaudek i, di meo n. entodermoscopy: a useful tool for the diagnosis of cutaneous larva migrans. dermatol pract concept. 2021;11(2):e2021014. doi: https://doi.org/10.5826/dpc.1102a14 accepted: august 3, 2020; published: march 8, 2021 copyright: ©2021 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: arianna dri, md, dermatology clinic, hospital maggiore, piazza ospitale 1, trieste, italy. email address: arianna. dri@gmail.com introduction cutaneous larva migrans (clm) is a zoonotic skin infestation caused by different species of helminths of the hookworm family, clinically characterized by a cutaneous erythematous serpiginous track. it is endemic in tropical countries; however, cases in western europe are increasing and usually affect returning travelers. clm is typically acquired through contact with feces of infected animals, especially when walking barefoot on contaminated soil. feet are the typical site of infestation, since the parasite penetrates through the skin digging a burrow. the diagnosis of clm is usually based on morphology of skin lesions. herein we report 2 cases in which dermoscopy helped the interpretation of cutaneous signs, confirming the clinical diagnosis of clm. case presentation the first case concerns a 26-year-old man who came in for consultation for a creeping eruption located on the sole of the left foot. he was a homeless, of south asian origin, and had immigrated in italy 2 months prior. he described walking barefoot during the journey. the eruption consisted of a winding lesion of about 5 cm, over slightly erythematous skin (figure 1a). the patient complained of an itch that had been persisting for many weeks. dermoscopy (dermlite; ×10) revealed a well-defined yellowish serpiginous course with whitish scales extending across the metatarsal plantar surface of the foot. it represented the path of the parasite within the skin. a small cluster of brown dots was visible at one end of the track, that probably was the correlate of the body of the parasite (figure 1b). these findings pointed towards the diagnosis of clm. a second case, an otherwise healthy 34-year-old woman, presented with an erythematous and pruritic eruption beside the mammary areola (figure 1c). no other body areas were involved. the disorder developed 1 week after returning from a trip to the caribbean, during which time she was topless and came into contact with sand. dermoscopic evaluation showed a reddish serpiginous track and yellow areas on the background (figure 1d). integration of clinical and anamnestic data led to a diagnosis of clm. the body of letter | dermatol pract concept 2021;11(2):e2021014 figure 1. (a) clinical presentation of cutaneous larva migrans (clm) of the foot. it presents as a serpiginous white scaly lesion (circle), over slightly erythematous skin. (b) the main dermoscopic features of clm of the foot are small brown dots (arrow), corresponding to the body of the helminth, and white segmental scales outlining the parasite’s burrow within the skin (dermlite; ×10). (c) clm of the nipple presenting as a creeping erythematous eruption. (d) dermoscopy of clm of the nipple shows a reddish serpiginous track and yellow areas on the background (dermlite; ×10). the parasite was not visible, likely because it was digging the burrow at deeper layers of the skin. alternatively, it could have been masked by the intense phlogistic reaction of the delicate breast area. few reports concerning dermoscopic presentation of clm are available in literature so far. the body of the helminth has been described as composed of translucent yellow-brownish structureless oval spots in a segmental arrangement, sometimes associated to red dotted vessels in the empty burrow [1,2]. in clinical practice scabies could also be included in the differential diagnosis of an itchy eruption. upon dermoscopy its lesions are characterized by a typical dark brown triangle, corresponding to the anterior pigmented part of the mite, in contiguity with a whitish curved line representing the burrow. the global appearance is addressed as the jet with contrail sign. moreover, scabies usually involves multiple peculiar body locations and often affects cohabiting partners. both our patients were treated with albendazole 400 mg orally for 3 days. betamethasone plus fusidic acid ointment was prescribed 2 times per day, in order to reduce local skin inflammation. favorable clinical response was obtained within 2 weeks. conclusions the diagnosis of clm infestation is often based on anamnesis and clinical presentation since it is characterized by the distinctive pruritic serpiginous track involving a single body area. nevertheless, dermoscopy can be a useful tool when uncertain, as it allows a clearer view of the curvilinear burrow and occasionally the direct visualization of the parasite’s body. skin infestations are becoming increasingly common due to climate change towards milder temperatures, the frequent trips to tropical countries, and the migration phenomenon, so dermoscopy helps clinicians deal with these emergent pathologies. references 1. zalaudek i, giacomel j, cabo h, et al. entodermoscopy: a new tool for diagnosing skin infections and infestations. dermatology. 2007;216(1):14-23. doi: 10.1159/000109353. pmid:18032894. 2. lacarrubba f, verzì ae, dinotta f, scavo s, micali g. dermatoscopy in inflammatory and infectious skin disorders. g ital dermatol venereol. 2015;150(5):521-531. 3. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol. 2014;170(3):514-526. doi: 10.1111/bjd.12685. pmid: 24266695. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021060 1 back to the basics: response of alopecia areata universalis to intravenous high-dose pulse corticosteroid therapy kerasia-maria plachouri1, chrysa oikonomou1, eleftheria vryzaki1, sophia georgiou1 1 department of dermatology, university general hospital of patras, patras, greece key words: alopecia areata universalis, intravenous, pulse corticosteroids, remission citation: plachouri km, oikonomu c, vryzaki e, georgiou s. back to the basics: response of alopecia areata universalis to intravenous high-dose pulse corticosteroid therapy. dermatol pract concept. 2021;11(4):e2021060. doi: https://doi.org/10.5826/dpc.1104a60 accepted: december 10, 2020; published: october, 2021 copyright: ©2021 plachouri et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: kerasia-maria plachouri, university general hospital of patras, patras, greece. email: kerasia.plachouri@hotmail.com introduction alopecia areata is an autoimmune disorder of the hair follicles, with various subtypes, such as alopecia focalis, alopecia totalis, alopecia universalis (au) and alopecia with ophiasis pattern [1]. au refers to a complete loss of scalp and body hair, and it is considered to be associated with an unfavorable prognosis, both in terms of poor response to most treatments, as well as in terms of discouraging spontaneous remission rates, documented to be lower than 10% [1]. despite numerous therapeutic attempts including with modern agents, such as biologics and jak-inhibitors, everyday practice continues to rely frequently on the use of topical or systemic corticosteroids, with varying treatment outcomes [1-2]. here we present the case of a patient with au that showed an almost complete response to pulse treatment with intravenous methylprednisolone. case presentation a 34-year-old male patient presented to our dermatology department due to multiple hair loss patches on the scalp, eyebrows, and beard. hair loss patches first appeared approximately 7 months prior to the referral. other than elevated serum iges (1650 iu/ml), no other blood abnormalities could be detected. due to progressive hair loss, despite a topical combination therapy with clobetasol propionate ointment 0.05% and minoxidil solution 5%, we opted for an intravenous corticosteroid pulse therapy (750 mg methylprednisolone in 250 ml dextrose over 3 consecutive days, every 4 weeks, for a period of 6 months), overlapped with the aforementioned ongoing topical regimen. five months after therapy initiation the patient gradually lost almost all scalp and body hair (figure 1, a and b). however, evidence of substantial hair regrowth was documented during 2 letter | dermatol pract concept. 2021;11(4):e2021060 the last methylprednisolone cycle, firstly on the scalp region and then, on the rest of face and body areas. after the cessation of the intravenous pulse therapy, the patient continued to use irregularly mometasone furoate solution 0.1%, as well as minoxidile solution 5% on the scalp region, in order to maintain hair regrowth. in the 10-month follow-up, significant hair regrowth was sustained in all previously affected areas of the head and body (figure 1, c and d). interestingly, the patient reported an alteration of the shape and texture of the newly regrown hair on the scalp region following the intravenous steroid treatment, from straight to curly. conclusions au constitutes a therapeutic challenge for the physician and a significant psychological burden for the affected individual [1-2], due to the lack of established on-label treatments. in our case, hair regrowth during the course of the pulse therapy suggests a treatment response, rather than a spontaneous remission. the intravenous corticosteroid pulse therapy not only offers the advantage of minimizing steroid-associated side effects, but it is also linked with lower relapse rates for the patients who actually showed a response to treatment [2]. references 1. kassira s, korta dz, chapman lw, dann f. review of treatment for alopecia totalis and alopecia universalis. int j dermatol. 2017;56(8):801-810. doi: 10.1111/ijd.13612. pmid: 28378336. 2. shreberk-hassidim r, ramot y, gilula z et al. a systematic review of pulse steroid therapy for alopecia areata. j am acad dermatol. 2016;74(2):372-4.e1-5. doi: 10.1016/j.jaad.2015.09.045. pmid: 26775777. figure 1. (a) almost complete scalp hair loss. (b) complete loss of facial hair. (c) sustained hair regrowth in the scalp region during the 10-month follow-up visit after the cessation of the pulse methylprednisolone therapy. (d) sustained hair regrowth on face area during the 10-month follow-up visit after the cessation of pulse methylprednisolone therapy. essay | dermatol pract concept 2012;2(1):13 65 on the nature of thought processes and their relationship to the accumulation of knowledge, part xv – limits to cognition: epistemic, random, or both? cris anderson, m.d.1 1 southern illinois university school of medicine, springfield, il, usa citation: anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xv – limits to cognition: epistemic, random, or both? dermatol pract conc. 2012;2(1):13. http://dx.doi.org/10.5826/dpc.0201a13. copyright: ©2012 anderson. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: cris anderson, m.d., 88 artists place, carbondale, il 62903, usa. email: crisj@me.com. dermatology practical & conceptual www.derm101.com introduction the purpose of this essay is to explore the nature of limits to cognition. are the limits epistemic, are they irreducible, or both? for the purposes of this essay, “epistemic” refers to issues related to our thought processes and “irreducible” refers to randomness. many of the essays in this series have addressed limits to cognition, focusing primarily on limits epistemic. in this essay i want to introduce the possibility that at least some of the limits we face are inherent in the universe as a result of the complexity of the universe and not merely the result of limits of our brains, individually and/or collectively. first we will consider some aspects of our understanding of the concept of limits. then we will review a little about how our brains evolved. we will then discuss epistemic limits. we will then review evidence that our brains are actually “hard-wired” to think probabilistically and review some precepts from complexity theory. how do we understand the concept of limits? as we learned in the previous essay on language, words are ambiguous and meaning becomes more restricted in context. the word “limits” is no exception and can also refer to many ideas. encarta world english dictionary defines “limit” as “the farthest point, degree, or boundary, especially one that cannot or should not be passed or exceeded; the boundary or edge of an area, or something that marks a boundary or edge; a feature or circumstance that restricts what can be done.” another point about language is that emotion is often attached to the meaning of a word. for example, in the essay in this series on “evidence” [1], it was pointed out that, although most of us assume, when we hear the word “evidence,” that the bit of evidence must be true and unassailable, we apply that attribute – true unassailable – to the word, but in actuality, “evidence” is merely a term that can be applied to anything we want to persuade others to believe. i believe that one attribute that we have a strong tendency to apply to the word “limit” is that of “not enough.” we hear often about “limited resources.” according to economists, an unlimited resource is one for which everyone could have as much as s/he wants if the item is free. parenthetically, an important concept here is “wants,” as opposed to “needs.” clearly economists consider many everyday items to be “limited resources,” since many people will say something like “i’ll take ten – no i’ll take a hundred – let’s make it a thousand, why don’t we.” but “limit,” per se, does not necessarily imply that there “is not enough to go around.” for example, mathematically, 66 essay | dermatol pract concept 2012;2(1):13 “limit” means a value that will not be exceeded by a mathematical formula. for example, if we divide 1 by 2 and then divide that answer by 2 again and continue n times where n is a positive integer that approaches infinity, the answer approaches zero. but the answer never actually is zero and a mathematician can perform the operation an unlimited number of times because of the concept of “infinity.” any person can have as many as s/he wants of the numbers in that infinite series; but the ultimate answer does have a limit – zero. i bring this last point up because, when we look more closely into cognitive limits, i do not want us to think automatically that there is some sort of limit to the number of “facts” that can ever exist – that some day someone will say, “gee, everything that is to be known in the universe is known.” i think there is ample evidence that that day will not dawn. what does occur is that each time we think about some idea, we must define the problem, thus drawing a set of limits within which to consider that idea. but the number of ideas out there is infinite – without limit. so what exactly is limited? as jacob bronowski has pointed out in the origins of knowledge and imagination [2] and as lawrence slobokin has pointed out in simplicity and complexity in games of the intellect [3], it is necessary to “limit,” that is to say, draw a set of boundaries, or describe a “frame of reference” from which to consider our problem. without rules, we cannot draw any valid conclusions at all. we are reminded by godel that, in any consistent system, there are true things that we cannot prove and that, in an inconsistent system, we can “prove” anything. every time we frame a problem, we do so in order to make that system consistent so that any conclusions we can draw will be valid. what we are not limited in is our ability to reframe a problem; we can reframe a problem in innumerable ways. then we are free to make new connections and gain new knowledge (as per bronowski). for decades, neuroscientists shared the problem “frame” of determinism. but when that frame was finally exited and the new frame, described by glimcher and discussed later in this essay, of game theory or neuroeconomics, it became possible to draw new conclusions about mechanisms of human thought. we must be mindful of the problem, discussed in earlier essays in this series, of “authority.” we must learn from authority, but we must not be bound by authority. as feyerabend has pointed out in against method [4] much can be gained and learned by considering new data in the context of multiple possible theories in order to avoid being bound by a charismatic or dogmatic authority. glimcher [5] has referred us to the work of david marr, who has insisted that the best way to work through neurophysiologic problems is to consider the goal of a behavior. epistemic limits in this series of essays we have discussed that our ability to think is limited in a number of ways. for one thing, we can only consider a certain number of items at any one time – those items we can “juggle” in working memory. for another thing, we must define each problem before we can think about it – we draw boundaries that define the problem, excluding necessarily items that we deem “irrelevant” to the problem at hand. also, we define certain rules that pertain to the problem, and must hold to those rules while considering the problem, since those rules constitute part of the boundary of the problem. as jacob bronowski has pointed out in the origins of knowledge and imagination, it simply is not possible to consider the entire universe as “the problem”; we must carve out a small part of it at any one time. we think if we can frame a problem just right – that is, if we ask the right question in the right way, all will become clear and all puzzlement will dissolve into a universal truth – like the buddha’s enlightenment. but this feeling of “surety” is merely a trick of the brain. david gamez, in what we can never know [6], posits that many of our attempts to explain and make sense of the world are in essence hermeneutic circles. encarta world english dictionary defines “hermeneutic” as “serving to interpret or explain something.” “hermeneutics,” then, is the “science and methodology of interpreting texts [or bodies of thought, or theories].” a key point brought out by gamez is that the interpreter or explainer cannot interpret or explain without him/herself being part of the world or theory being described. all stable hermeneutic circles, as gamez calls them, are necessarily self-reflexive and must be able to explain how the person could create the theory in the first place. this sets us up for paradox that might arise from using self-reference unwisely, as discussed in more detail in the essay in this series on language. additionally, a concept that is pretty much accepted is that none of us really “knows” what our world is like. everything we sense is interpreted by our brain, and our brain has no mechanism for experiencing the world directly. the theory is usually referred to as the “brain-in-a-vat” theory. the theory asserts that our reality is merely a “virtual reality” constructed by our brain. gamez describes a “dream” about being in a blue room. writes gamez, “i close my eyes and cross the room to the table. on the table lies a large piece of meat. with my left arm i reach out and feel the meat. it is warm, textured, rubessay | dermatol pract concept 2012;2(1):13 67 bery and slightly sticky with blood. i pick the meat up. it is heavy and pulls my arm towards the ground. with my eyes still closed i reach out with my right arm. i can feel nothing there: the piece of meat has vanished and so has the table. my right hand moves about freely in empty space where the table and meat were present only a moment before. i allow my right arm to fall by my side and reach out again with my left arm. now the meat and table have returned. once again i palpate textured flesh between my fingers; once again i encounter an area in the world that resists my grasp. i open my eyes. a piece of meat oozes gently onto the white table in front of me. i look at my left hand. it is pink and opaque; it obscures the objects behind it. within the visual form of my left hand i experience the sensations of my left hand. these are initially very diffuse, but by concentrating i can focus on the feeling in each finger. when i wiggle the fingers of my left hand i see a pink form wiggling in space in front of me. now i gaze at might right hand. my right hand is transparent; it does not obscure the objects behind it. i experience my right hand within a diffuse hand-shaped zone in front of me. by concentrating, i can feel the sensations in each finger. when i wiggle the fingers of my right hand i do not see anything happening in the world in front of me, but i can still feel my fingers wiggling. my left arm is visible between my shoulder and my left hand. my right arm becomes invisible about ten centimeters from my shoulder. the visible part of my right arm emerges from my shoulder and terminates in a stump. the transparent part of my right arm extends from the stump to my transparent hand.” gamez’s “dream” is that of one’s experience with a phantom limb following amputation. gamez goes on to point out that amputees often experience a vivid phantom. the brain “expects” certain events and fills them in. the brain itself is intact and all the “hardware” of the sensory and motor cortex assigned to the now absent limb is still present and operating. in the essay in this series on patterns, we looked at the work of erich harth, who discussed how the brain can “augment” certain “perceived” features, but that our experience with our actual senses usually allows us to determine “reality” from the construct. harth points out that we rarely hallucinate when we are awake, alert, and observant. jeffrey schwartz, in the mind and the brain [7], discusses that the brain exhibits “neuroplasticity.” pathways that are used often, such as practicing a musical instrument or sport, are reinforced, adding new neurons to the pathway, while pathways not used atrophy, such as after a stroke. i think there may be no way around understanding our world as a sort of “virtual reality.” the question, i think, is whether we should allow ourselves to become paralyzed by this very realistic view of our existence. as gigerenzer has pointed out in adaptive thinking [8] and some of his other works, we humans have co-evolved with the world and, whatever “reality” is out there as viewed from the nonexistent “ultimate frame of reference,” we perceive the wave-lengths of light we need to perceive to survive and can solve problems well enough to survive in the world as it “exists.” what matters then is, given our starting point (our “virtual reality”), where can we go from here? and an important part of the plan is to ensure that we define whatever frame of reference we are using at the time in a consistent way and that we strive to ensure interand intraobserver agreement. background – evolution gary marcus, in kluge: the haphazard evolution of the human mind [9], points out that evolution works with what is available at the time and “experiments” through mutation, seeing what ends up fitter than others, the fitter thus producing more progeny and continuing the process through time. parenthetically, “kluge” is a “clumsy or inelegant – yet surprisingly effective – solution to a problem.” marcus avers that biology is loaded with kluges. he mentions that the human spine is not the most efficient way to support load in an upright two-legged creature; yes, our hands are free, which aids survival, but we are prone to develop back pain. we evolved from quadripeds, so we are stuck with having one column to support our upper bodies instead of the more efficient (from an engineering point of view) four equal cross-braced columns. he continues with another anatomical kluge – the human eye. the retina “is installed backward … leaving us with a pair of blind spots.” says marcus, “nature is prone to making kluges because it doesn’t ‘care’ whether its products are perfect or inelegant. if something works, it spreads. if it doesn’t work, it dies out. genes that lead to successful outcomes tend to propagate; genes that produce creatures that can’t cut it tend to fade away; all else is metaphor. adequacy, not beauty, is the name of the game.” marcus mentions instances of the sublime in evolution. “the human retina can detect a single photon in a darkened room…spider silk is stronger than steel and more elastic than rubber… hemoglobin is exquisitely adapted to the task of transporting oxygen …” he points out that “sometimes elegance and kluginess coexist, side by side. highly efficient neurons…are connected to their neighbors by puzzlingly inefficient synaptic gaps, which transform efficient electrical activity into less efficient diffusing chemicals, and these in turn waste heat and lose information.” he mentions, using the analogy of hill-climbing mentioned in the essay in this series on reasoning, that the vertebrate eye is elegant in its capacity to focus and adjust to varying amounts of light and “operates with more sophistication than most digital cam68 essay | dermatol pract concept 2012;2(1):13 eras,” but it is hobbled by the construction of the retina with its blind spot. “on the highest peak of evolution, our eyes would work much as they do now, but the retina would face forward (as it does in the octopus), eliminating those blind spots. the human eye is about as good as it could be, given the backward retina, but it could be better – a perfect illustration of how nature occasionally winds up notably short of the highest possible summit.” marcus also mentions that there exists a sort of “‘evolutionary inertia’ since new genes must work in concert with old genes and because evolution is driven by the immediate... natural selection tends to favor genes that have immediate advantages, discarding options that might function better in the long term.” marcus quotes francois jacob, who noted that evolution is like a tinkerer “who...often without knowing what he is going to produce...uses whatever he finds around him, old cardboards, pieces of strings, fragments of wood or metal, to make some kind of workable object...[the result is] a patchwork of odd sets pieced together with and where opportunity arose.” of jacob’s words, quips marcus, “if necessity is the mother of invention, tinkering is the geeky grandfather of the kluge.” marcus opines that kluges give us both insight into our evolutionary history and clues to how we can improve ourselves. marcus states of human memory, “memory is, i believe, the mother of all kluges, the single factor most responsible for human idiosyncrasy. our memory is both spectacular and a constant source of disappointment … our memory is prone to distortion, conflation, and simple failure.” he compares human memory to that of the computer, finding our human memory to be “fragile,” yet that of the computer “robust.” he points out that computer programmers have constructed a computer’s memory to be “postalcode”; each bit of information is assigned a specific location in the databank. our memory is “contextual.” says marcus “…we pull things out of our memory by using context, or clues, that hints at what we are looking for. it’s as if we say to ourselves, every time we need a particular fact, ‘um, hello, brain, sorry to bother you, but i need a memory that’s about the war of 1812. got anything for me?’ often our brain obliges, quickly and accurately yielding precisely the information we want…even though [we] might not have the foggiest idea where in [our] brain that information was stored.” he points out that contextual memory has a very long evolutionary history, existing not only in vertebrates, but also in arachnids and mollusks. an advantage to contextual memory is that it prioritizes by bringing to mind common and recent items. recall from the essay in this series on error and expectation that james reason explained his model in which we recall items by “frequency gambling” and “similarity matching,” with a small compartment adjacent to working memory that holds recent items for rapid retrieval. marcus also points out that context-dependent memories can search in parallel and do not have the need to “keep track of [their own] internal hardware (like computers do), thereby making up for slowness of neurons compared to computer memory chips. marcus adds that search engines even mimic the human brain by choosing cues to eliminate some possibilities instead of marching steadfastly through each location in the hard drive and listing all possible “matches.” marcus admits that no one knows for sure how the human brain recalls items into current thought; he opines that the process is autonomous. in the first essay in this series we noted that karl lashley had observed that one is never conscious of the process of thinking; one is only conscious of the product that one has thought. a knowledge products audio-course i once listened to about complexity points out that complex systems must have a way of getting rid of waste as a means of adapting to change. perhaps, therefore, it is a good thing that we do not remember everything. useful things are likely to occur commonly and we are likely to remember items that will be utilized. as marcus points out, we have evolved to have context-dependent memory, thus it must have served us fairly well to date. besides, we have constructed computers and developed libraries to hold “memories” for us and to document our history. because our memories are inexact at times, and because we do not know everything, our brains do not have access in a timely manner to all answers; therefore, we must have some sort of game plan for solving problems under the condition of uncertainty. probability theory was developed, beginning in the mid 1600s. but is that theory just a “frame of reference” constructed by humans to deal with uncertainty? or could a method for dealing with “probability” actually be built into our brains? we have discussed in earlier essays in this series, including evidence, the work of gerd gigerenzer, who has concluded that “logic” is not the natural thought pattern of humans. humans have, rather, developed “fast and frugal heuristics” to deal with most day-to-day problems. however, it turns out that, although we do not naturally think “logically” according to the formal rules of logic developed by mathematicians over the ages, our brains do have a mechanism for considering and dealing with probability. it is clear to us, from an evolutionary standpoint, and by this i mean including nonhuman animals, that an individual organism cannot have complete knowledge and must be able to function successfully under the condition of uncertainty. essay | dermatol pract concept 2012;2(1):13 69 glimcher’s work paul glimcher, in decisions, uncertainty, and the brain [5], outlines the history of man’s quest to understand how the brain “thinks,” describing developments beginning from the renaissance and bringing us through the time of publication of his book in 2003. glimcher posits that limitations to thought are unavoidable because randomness is an inherent property of the universe. he opines that from the earliest study of the mechanisms of human thought, the underlying, often not explicitly stated, concept was that of determinism. furthermore, he suggests that the very method of study actually requires that the world be deterministic. he points out that during the period of history known as the enlightenment, it was recognized that there were limitations to existing knowledge. in order to eliminate the gaps in knowledge, a method of describing the world and for testing the accuracy of descriptions was developed, which we know as the “scientific method.” the scientific method was rooted in the most logically rigorous system of thought available at the time – analytic geometry, developed by rene descartes. the whole premise underlying the scientific method is that the world is deterministic and that it is possible to develop models/descriptions of the physical world that are predictive – that correct models will predict the future. analytic geometry is a determinate mathematical system; thus, states glimcher, “…[there was] a significant bias in the way that scientists thought about the world. believing that the future state of the world could be predicted with analytic geometry not only implied that the world was deterministic, it also rested on the assumption that the world must be deterministic.” so, from the time of the enlightenment, we have been caught up in a paradox related to self-reference. slowly, over time, various scientists and mathematicians have chipped away at the assumption to end all assumptions – that the world is deterministic. probability theory was developed. godel’s theorem proved that in a consistent, closed system (and all systems we define to study are closed) items that were true in that system could not be proved in the system as defined. game theory was developed. furthermore, as jacob bronowski has pointed out in origins of knowledge and imagination, as new connections are made when thinking about the world, new knowledge is gained. scientists began to approach the problem of learning about how thought processes actually work by looking at the problem from different perspectives. when neuroscientists began their studies, opines glimcher, they adopted the assumption of determinism. charles sherrington in the early 1900s studied the flex arc of the bicep contraction in decerebrate cats, in whom the spinal cord had been completely transected from the brain cephalad to the reflex studied. he demonstrated in his model the deep tendon stretch reflex with which we physicians are all familiar. however, glimcher points out that “reflexes are a theory and not a fact.” he does not argue that the reflex demonstrated by sherrington does not exist, rather he disputes that “reflexes” are the way problems are solved by humans as they go about their daily lives. glimcher points out that people have argued that it has been proved beyond reasonable doubt that the “stretch response [that we actually demonstrate] and the stretch reflex [the theory to explain the stretch response] are physiologically equivalent.” however, glimcher avers, “over the last hundred years many intelligent and respected physiologists have suggested that the reflex is not an adequate model for explaining any determinate behavior. many of the physiologists have argued that there simply are no such things as reflexes in the real world.” a problem arises when one begins to consider just exactly what the reflex is. if one holds an arm at different angles relative to gravity, the arm moves differently when stimulated to respond by the supposed reflex, depending on the angle at which it is held. one would have to propose that a number of separate reflexes exist, one for each possible angle relative to gravity. glimcher hypothesizes that portions of the brain integrate bits of information before initiating an appropriate response. many experiments, of which sherrington’s is one, have been designed and carried out starting with the “hardware” and trying to see what that hardware could do. glimcher refers us to the work of david marr, a computer scientist working in the field of cognitive neuroscience, who suggested that a better approach might be to consider the goal of a behavior. the goal of any behavior is, of course, to improve the fitness of the organism exhibiting said behavior. glimcher describes some of the experiments performed. economics, especially classical economics, assumes that humans, but also other organisms, choose to maximize their “take.” however, taking into account the constraints of evolution – that the organism is fittest that has the best apparatus at the time for dealing with the environment as it is at the time and that, referring to the hill-climbing analogy described in the essay in this series on patterns, many “peaks” climbed may be local peaks and not the highest peak – “no actual neural system could ever achieve any computational goal with 100 percent efficiency.” additionally, as we will see, it behooves an organism to “test” the system periodically to ensure that a new paradigm is, or is not, preferable to the current favored choice. as an example, foraging theorists have tried to figure out how animals decide what to eat. animals may encounter, but decide not to eat, a prey item (be that item an animal in the case of carnivores, or plants in the case of herbivores). it is hypothesized that the forager might consider the size of the 70 essay | dermatol pract concept 2012;2(1):13 potential food item, the time required to obtain it, and the scarcity of that type of prey. once an animal has begun to eat an item, it must decide when to stop eating it. theorists hypothesize that there must be a theory of predation. “optimal predation is the process of achieving a maximum rate of energy intake with a minimal expenditure of effort in a random and unpredictable world.” attempts have been made to determine the most efficient predation strategy for any animal, using mathematical tools to formalize such strategies. glimcher describes an experiment performed by krebs and colleagues in the mid 1970s, testing the foraging efficiency of titmice (a type of bird). titmice like to eat mealworms. the test system was such that a hungry titmouse was placed in a one cubic meter cage, beneath which a conveyor belt was running, carrying mealworms. there was a hole cut in the bottom of the cage and the titmouse would sit on a perch conveniently placed so that the titmouse could see anything passing by on the conveyor belt. the investigators made “standardized” mealworms by cutting up mealworms. “large” mealworms consisted of eight body segments from the mid portion of a mealworm and “small” mealworms consisted of four segments. five foraging situations were devised to test the titmice. in condition a, large and small mealworms were placed independently on the conveyor belt, but each appeared once every 40 seconds such that large and small meal worms were encountered at a rate of about once every 1.5 minutes. in condition b, the worms were encountered with equal frequency, as in a, but the rate doubled to one encounter every 20 seconds. in conditions c, d, and e, the large worms appeared every 6.5 seconds, but the small prey rate was varied to between once every 3.5 seconds to once every 20 seconds. an underlying hypothesis held by the investigators was that the large mealworms held for the titmice twice the value of the small mealworms. the scientists considered it likely that birds that handled small prey the fastest, would always take all prey because the highest rate of energy intake would be achieved by taking all prey, large and small – the birds were fast enough to not miss any worms going by on the conveyor belt. slower birds, on the other hand were predicted to take only large prey once the large prey was available more often than every 7-8 seconds. it was thought that the slow birds would ignore the small mealworms in conditions c, d, and e. when the experiment was run, the fast birds were unselective, as predicted. also, the slow birds did show a preference for the large worms once they were available every 6.5 seconds, and this included the condition in which the small worms were available more often. another hypothesis krebs wanted to test was the socalled “zero-one” rule. this rule stated that, if the prey is worth eating, it is worth eating all the time, and if the prey is not worth eating, it would never be eaten. in conditions c, d, and e, it was observed that the slow birds, although selective, took the large worms only about 85% of the time; they took the smaller worms occasionally. krebs hypothesized that the birds would occasionally take small worms to update for themselves an internal estimate of the relative profitability of the two prey types, the rationale being that the birds recognize that situations change in “the real world,” and it is prudent to “keep up with the times” so to speak. alternatively, it may be, considering the process of evolution as described by marcus, the birds may be unable to behave “optimally.” glimcher describes his own work using the visual system of rhesus monkeys. visual information is received by right and left retinas, which process the information somewhat and send the information via the optic nerve to the neurons of the lateral geniculate nucleus (lgn). the structure of the lgn is such that each location in the nucleus is specialized to monitor a specific position in the visual world. the geniculate maps then project to specific areas of the visual cortex, these areas also being topographically organized. within each topographic area, some neurons respond to vertical information, some to tilted information, some to colors, and so on. the retinotopic map projects to area v1 in the visual cortex, and sends information to other areas such as v2, v3, v4 and mt; there are more than 30 mapped areas that each contribute to our perception visually of the world. glimcher studied visual saccades in monkeys. visual saccades (the quick component of eye movements) are controlled by a number of neural circuits that control the six muscles within the orbit that move the eye so that gaze can be stabilized and aligned to compensate for the animal’s selfmotion and the like. information to control saccadic movement goes through centers in the brain, the superior colliculus (sc) and frontal eye field (fef); the sc and fef are also constructed in topographic fashion. the actual studies consisted of rewarding monkeys with berry berry fruit juice whenever they learned specific visual saccade tasks. electrodes were placed in specific neurons in the monkeys’ brains to see when these neurons were active relative to the portion of the task they were performing. the monkeys would stare at an oscilloscope screen and look for the appearance of a stimulus/point. the tasks would vary. sometimes the monkey was supposed to stare at stimulus, but move his/her focus to a second point on the screen when it appeared. sometimes the monkey was to ignore the appearance of the second point (continuing to stare at the first point). sometimes the monkey was to move his/her gaze to point two after point one disappeared from the screen. sometimes the monkey would have to remember where the extinguished point was and return his/her gaze there after a delay of a second or two. and so forth. in each study, the monkey had to figure out what s/he was supposed to do by finding out whether his/her behavior was rewarded by juice. essay | dermatol pract concept 2012;2(1):13 71 each study was constructed as a series of, say, a hundred or so trials while the monkey learned what s/he was supposed to do, followed by multiple iterations of a slight alteration of the first trial and so forth. an important part of the brain glimcher and others studied is the lateral intraparietal area (lip), which seemed to be related to holding attention or having an intention to perform another action. glimcher devised a complex experiment (says glimcher, “amazing though it may seem, the monkeys readily learned this task”). “each cued saccade trial began with the illumination of a central yellow light at which the monkey had to look. after a brief delay, the secondary and tertiary targets were illuminated, one at the best location and one at the null location. after a further delay, the central yellow light changed color. on a randomly selected 50% of trials it turned green. on the other trials it turned red. the monkey had been taught in advance that on trials in which the central fixation stimulus turned red, the left light served as the secondary target (the saccadic goal) and the right light served as the tertiary target (a completely irrelevant distractor). on trials in which the fixation stimulus turned green, the converse was true; the right light served as the target and the left light was irrelevant. the monkey was, however, not allowed to look at the secondary target until we turned off the central fixation stimulus. if, after that point, the monkey looked at the correct target, she received the juice reward.” glimcher had thought to prove conclusively that either the lip carries sensory-attentional signals, or the lip carries motor intention plans. the hypothesis was that “if the lip were motor-intentional, the neurons should respond strongly when the stimulus within the response field was a target, but not at all when it was an irrelevant distractor.” the results showed that the lip neurons discriminated between the two conditions, but the neurons were not silent – only less active – when the stimulus was the distractor. after additional studies, at least as complex for the monkeys to learn, glimcher concluded that the lip neurons in fact more likely track both prior and posterior probabilities throughout the trials. further studies showed, “in our freechoice task, both monkeys and posterior parietal neurons behaved as if they had knowledge of gains associated with different actions. these findings support the hypothesis that variables that have been identified by economists, psychologists and ecologists as important in decision-making are represented in the nervous system.” glimcher then moves to the subject of game theory. “game” in “game theory” refers to all interactions between intelligent competitors. von neumann and morgenstern developed the concept, trying to develop a mathematical system that would describe how an actor in a “game” would make choices to obtain the best possible outcome for himself “given that his opponent or opponents were also attempting to obtain the best possible outcome for themselves.” john nash developed the mathematical formulas that describe the “nash equilibrium” point, for which either choice has the same value to the chooser. glimcher concludes, reviewing the work of maynard smith on the concept of evolutionary stable strategies (ess), what is important is that at the level of individual acts behavior must be unpredictable, but for the whole population, behavior must be “lawful and predictable at a probabilistic level.” as an example, glimcher describes the work of harper who studied foraging of ducks. there was a population of 33 ducks on a lake at cambridge university. harper devised an experiment whereby two people, harper and an assistant, would throw 2-gram or 4-gram bread balls from positions about 20 meters apart at the edge of the lake. the person throwing the 2-gram balls would throw one bread ball every 5 seconds. the other person would throw the 4-gram balls either every 5 seconds (one experiment) or 10 seconds (second experiment). the experiment was considered from the standpoint that one duck was playing against the rest of the flock so that the mathematics to determine the prediction would be simplified. the hypothesis was that the duck-ofinterest would join the line to maximize his intake of bread. for the experiment where the two sizes are thrown at the same interval, twice as much actual bread is in the 4-gram area, so that it is more likely that a duck would join that line. if all 33 ducks rush to the 4-gram line, however, only 2/3 of the possible bread is being eaten, so some ducks should notice this and go to the other line. when the time interval between the 4-gram bread balls was doubled, equal amounts of bread are available from each line and the prediction is that there would be an equal number of ducks in each line. when harper actually performed the experiment, he found that the ducks figured out the situation in about 60 seconds, before even half of the ducks had actually received a bread ball. glimcher advises us that, although game theory can provide an accurate way to predict equilibrium situations, “...the great limitation of contemporary game theory is that it fails to provide tools for describing the dynamic process by which equilibriums are reached.” glimcher describes the “inspection” game of “work or shirk.” in one iteration of the game, humans play against a computer. a worker is expected by his boss to work every day to earn his wage. the boss, however, does not work at the same location and either trusts the worker to be working or goes to inspect to see if the worker actually shows up. if the boss finds out the worker did not show up, the worker does not get paid. the variables of the game include e (the effort the worker expends at work), w (the wage the boss pays the worker), p (the value to the boss of the product produced by the worker), and i (the cost to the boss of inspecting). if the 72 essay | dermatol pract concept 2012;2(1):13 worker works and the boss inspects, the worker earns {w e}; the boss earns {p w i}. if the worker works and the boss does not inspect, the worker earns the same as before, but the boss earns more by not having to pay for the inspection {p w}. if the worker does not work and the boss inspects, the worker earns nothing {no wage, but no effort expended} and the boss has only the cost of the inspection {i; no product, but no wage paid}. if the worker does not work and the boss does not inspect, the worker gets his wage {w; no effort expended} and the boss pays only the wage {w; no product received and no cost of inspection}. the actual mathematical numbers vary according to how the numerical values of e, w, p and i are set, but it comes down to the formulae as the outcome for the equilibrium of i/w as the probability of the worker shirking and e/w for the probability of the boss inspecting. this was the actual outcome in the contest between the human (worker) and the computer (boss). glimcher carried out this experiment with his monkeys since he wanted to know if the lateral intraparietal (lip) area was at work. he reasoned that if the monkeys were somehow computing and behaving so as to maintain the nash equilibrium, “… across all of the different conditions we studied there should never have been a change in lip firing rates if the lip firing rates encode relative expected utility.” and that is just what glimcher found. throughout various values of e, w (more or less milliliters of juice for the monkeys), p, and i, the firing rate of the lip neurons “was pretty stable throughout the day, even though the animal’s behavior varied significantly from one block of trials to the next.” glimcher concluded that “these computations [performed by the lip neurons] seemed be the same regardless of whether the monkey was in a deterministic task [such as the experiment with the complex saccadic task described earlier] … or an irreducibly uncertain task [such as work/shirk] … neurons in lip did seem to see all of behaviour as a single continuum governed by a single set of goal directed rules and computations.” precepts from complexity theory in his teaching company course, understanding complexity [10], scott page makes important points about complex systems. first, biologic systems are adaptive. that is to say, as mentioned earlier in reference to game theory, when elements of a system interact, those elements influence each other and change their behavior in response to what the other element does. second, in any complex system, no single element controls the system, but any element can influence any or all other elements. page refers to adaptability in systems as “nonstationarity.” returning to the “hill-climbing” analogy referred to earlier, in a stationary system, a landscape might be referred to as “rugged.” some hills are higher than others, but the height of them does not change – they remain stationary. page introduces the concept of “dancing” landscapes. in dancing landscapes, the hills actually change heights. those hills are not stationary. the heights of the hills in a dancing landscape adapt according to influences. conclusion i think it is clear from the discussion above that there are epistemic limits to cognition. i think it is equally clear that there are limits to cognition that are due to randomness – randomness generated in the complex adaptive system in which we live. from the work of glimcher, marcus, and page we can see that intelligence, including human intelligence, has evolved in an adaptive/dancing landscape and that we have developed a hard-wired capability to assess issues of probability and to deal with uncertainty, coping as we must with intelligent adapting beings. as glimcher pointed out, until fairly recently humans have assumed the existence of determinism, relegating all feelings of uncertainty to the realm epistemic. determinism, however, assumes stationarity. i think there is ample evidence, via complexity theory, that our world exhibits features of nonstationarity. our task, then, is to embrace the concept of nonstationarity and to reconsider as much as possible what we think we have already learned from this new perspective. harth, as discussed in more detail in the essay in this series on patterns [11], has described that when we look for something, our brains are likely to “see” the item, enhancing some features of what we are looking at to meet our expectations. he also points out that we use our senses to evaluate the object and to “rein in” our imaginations, informing our brain that what we really see is not the “coin in the sand at the beach” we are looking for, but merely a piece of shell. we rarely hallucinate. our senses serve as a sort of “tether” to reality. when we learn to evaluate patients in medical school and residency and to use various instruments to extend our native human abilities and to interpret histologic sections during our pathology training, we rely on our mentors to say “yes, that is the rash of dermatitis herpetiformis” or “no that is not invasive cancer because...” each of us needs some sort of tether to reality, just as we need our senses to keep our brains from hallucinating. i think our next task is to improve the way we as individuals interact so that we, collectively, can define new frames of reference from which we can gain new knowledge. we essay | dermatol pract concept 2012;2(1):13 73 must learn about and understand how our brains work as well as how complex systems work and use this knowledge to further our understanding of the world. while we will never escape the epistemic limit to cognition imposed by the “brain-as-virtual-reality-only” or “brain-in-a-vat” point of view, i do not think this should limit our progress very much. after all, we have co-evolved with our environment to sense the items we can sense and we are surviving. summary evidence exists that there are limits to cognition. some limits are the result of our embodiment whereby our brains have no direct experience with the world; all experience is via the senses and all input is processed in some way by the brain before we become conscious of a thought. other limits are due to the nature of the world itself; the world being a complex adaptive system. however, although limits exist, there are still an infinite number of thoughts and hypotheses about the world we can entertain by viewing each body of data from multiple points of view and by helping each other to discern a collective reality, about which can draw conclusions, and from which, we can progress as a species, understanding more fully how we exist and evolve in the complex adaptive system in which we live. references 1. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xiii: the nature of evidence. dermatopathology: practical and conceptual. 2009;15(4):20. http://www.derm101.com/content/57644. 2. bronowski j. the origins of knowledge and imagination. new haven: yale university press, 1978. 3. slobodkin l. simplicity & complexity in games of the intellect. cambridge, massachusetts: harvard university press, 1992. 4. feyerabend p. against method. 4th ed. london: verso, 2010. 5. glimcher p. decisions, uncertainty, and the brain. cambridge, massachusetts: mit press, 2003. 6. gamez d. what we can never know. london: continuum, 2007. 7. schwartz j. the mind and the brain. new york: regan books, 2002. 8. gigerenzer g. adaptive thinking. new york: oxford university press, 2000. 9. kluge g. the haphazard evolution of the human mind. boston: mariner books, 2009. 10. page s. understanding complexity [dvd]. chantilly, va: the teaching company, 2009. 11. anderson c. on the nature of thought processes and their relationship to the accumulation of knowledge, part xii: detecting and using patterns. dermatopathology: practical and conceptual. 2009;15(2):16. http://www.derm101.com/content/32781. dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;2(4):4 13 the patient a 44-year-old man presented to the clinic with complaints of “sun allergy” following a weekend of photo-exposure without use of any sunscreens. he said that the lesions started as blisters, became reddish and progressed to hemorrhagic lesions with crusting (figure 1a). they healed in a week with scars. on examination, the patient had lesions on photoexposed surfaces with patchy erythema and hemorrhagic crusts. no blisters were noted. the skin over the knuckles and digits appeared thickened (figure 1b). there were multiple, small hypopigmented scars on the chest, dorsa of hands, and cheeks (figure 1c). from the dermatologikum hamburg: quiz wendemagegn e. yeshanehe, m.d.1, rajalakshmi tirumalae, m.d., dnb2, almut böer-auer, m.d.3 1 assistant professor of dermatovenereology, bahir dar university, bahir dar, ethiopia 2 associate professor of pathology, st. john’s medical college, bangalore, india 3 dermatologikum hamburg, hamburg, germany citation: yeshanehe we, tirumalae r, böer-auer a. from the dermatologikum hamburg: quiz. dermatol pract conc. 2012;2(4):4. http:// dx.doi.org/10.5826/dpc.0204a04. copyright: ©2012 yeshanehe et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: rajalakshmi tirumalae, m.d., department of pathology, st. john’s medical college, bangalore 560034, india. email: rajnav@gmail.com. figure 1a. erythematous lesions on the forearm, some with crusts. a b figure 1b. thickening of skin over knuckles and fingers. c figure 1c. hypopigmented scars over the chest. 14 quiz | dermatol pract concept 2012;2(4):4 a biopsy was taken and photomicrographs are presented in figures 2a-h. what is your diagnosis? a b c d e g f h figure 2a-h. what is your diagnosis? quiz | dermatol pract concept 2012;2(4):4 15 with the features mentioned above the differential diagnoses considered were amyloidosis, erythropoietic protoporphyria, and lipoid proteinosis. congo red did not stain the deposits, making amyloidosis unlikely. in lipoid proteinosis, the deposits usually surround the eccrine secretory coils also, a feature absent in this case. moreover, lipoid proteinosis has an onset in infancy with a characteristic cry of the child due to deposits in the larynx and oral cavity. in erythropoietic protoporphyria, pas-positive, brightly eosinophilic, concentric deposits are seen around the blood vessels without involvement of the eccrine coils, similar to the present case. in clinicopathological correlation, the thickening of the skin is a consequence of deposition of protoporphyrins, commonly due to a rare genetic deficiency of the enzyme ferrochelatase [1,2]. it manifests during early childhood in the form of burning, erythema, and edema following photoexposure. the lesions heal with residual “icepick” scars over the face and knuckles. scleroderma-like thickening may also be encountered later in the course of the disease. when a diagnosis of epp is suspected, blood, stool, and urine should be examined for porphyrins. usually, blood answer and explanation erythropoietic protoporphyria (epp), late onset. in this patient, the history of photosensitivity combined with red and painful skin lesions should raise the suspicion of epp. however, the clinical differential diagnoses include polymorphous light eruption, phototoxic and photoallergic dermatitis, lupus erythematosus, solar urticaria, and other porphyrias. the indurated skin seen in chronic lesions of epp must be differentiated from sclerodermas, lichen amyloidosis, and lipoid proteinosis. histopathologically, the biopsy showed a normal epidermis. the papillary dermis demonstrated extensive, circumscribed deposits of eosinophilic, homogenous material (figures 2a-h). on higher magnification, these deposits were seen to be surrounding markedly thickened walls of upper dermal capillaries and stained bright red with pas (figures 3a, b). there were no deposits around the eccrine units. immunostains for collagen type iv ratified these findings, showing a markedly thickened basement membrane around blood vessels but sparing eccrine units (figures 4a, b). figure 3a and b. the deposits are brightly pas positive (periodic acid-schiff, x20). the eccrine units, however, are spared and only the vessel walls are thickened (periodic acid-schiff, x200). a b figure 4a and b. immunostain for type iv collagen highlights the deposits in the papillary dermis (collagen iv, x20). eccrine coils show no deposits, in contrast to the thickened vessel walls (collagen iv, x400). a b 16 quiz | dermatol pract concept 2012;2(4):4 al reported on a patient with late onset epp in 1985 and, since then, around 12 additional patients with adult onset epp have been described in the literature [11-19]. eight of these cases were associated with hematological malignancies such as myelodysplastic syndrome (mds) (often the sideroblastic anemia subtype) or myeloproliferative diseases [2,12,14,15,17,20-22]. two of these patients developed liver dysfunction [2,18] in the course of their disease. the histopathologic finding of rimming of vessel walls by eosinophilic material is by no means exclusive to epp. it may be seen in other forms of porphyria, such as porphyria cutanea tarda (pct). however, subepidermal blistering is common in pct but not in epp. the blister is cell-poor and is underlined by a zone of solar elastosis. pseudoporphyria in patients on hemodialysis or with chronic renal insufficiency shares a similar histology, but not the biochemical abnormalities. lipoid proteinosis (hyalinosis cutis et mucosae) is the next differential diagnosis to be considered. lipoid proteinosis has an infantile onset characterized clinically by a hoarse cry, oral nodules, and waxy papules along the lid margins. there is deposit of a similar pas positive material around blood vessels as well as around eccrine coils, which are generally spared in epp. the material also contains some lipid. finally, amyloidosis may mimic the eosinophilic deposits of epp but amyloid can be identified by immunohistochemical staining with either cytokeratin or immunoglobulin light chain antibodies. [2,6]. in summary, the finding of pas-positive deposits around dermal vessels has different consequences in adults and children, with porphyrias straddling both the age groups, especially if associated with photosensitivity. it is important to evaluate serum and urine porphyrin profiles in such cases to nail the specific diagnosis because the histologic features, although characteristic, are not entirely specific. references 1. richard e, robert-richard e, ged c, moreau-gaudry f, de verneuil h. erythropoietic porphyrias: animal models and update in gene-based therapies. curr gene ther. 2008;8(3):176-86. 2. goodwin rg, kell wj, laidler p, et al. photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells. blood. 2006;107(1):60-2. 3. todd dj. erythropoietic protoporphyria. br j dermatol. 1994;131(6):751-6. 4. cox tm. erythropoietic protoporphyria.  j inherit metab dis. jun 1997;20(2):258-69. 5. parker m, corrigall av, hift rj, meissner pn. molecular characterization of erythropoietic protoporphyria in south africa. br j dermatol. 2008;159(1):182-91. 6. poh-fitzpatrick mb, wang x, anderson ke, bloomer jr, bolwell b, lichtin ae. erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in and stool porphyrin levels are elevated while urine examination is normal, since protoporphyrins are water-insoluble. elevated levels of porphyrins in urine signify the onset of hepatic involvement and are very useful in monitoring the disease, together with porphyrin isomer ratios [3]. in this patient, the free protoporphyrin in blood was 18630 nmol/l (normal: 9-89 nmol/l), which was markedly elevated. zinc protoporphyrin was 68.1 μmol/l and total protophyrin was 19192 nmol/l, both being clearly higher than normal. these findings are consistent with a diagnosis of erythropoietic protoporphyria. urine examination revealed normal coproporphyrin levels, but an elevated coproporphyrin isomer i (43.8%) and a depressed coproporphyrin isomer ii (56.2%). even without porphyrinuria, this alteration in isomer ratio is an early sign of hepatic involvement and such patients derive benefit from prophylactic therapy. porphyrias are a group of metabolic diseases that result from aberration in the heme biosynthesis pathways [4,5]. porphyria cutanea tarda (pct) is the commonest manifestation in the skin, followed by epp. epp most often results from hereditary mutation of a gene on chromosome 18q21.3. epp exhibits both recessive and dominant patterns of inheritance. rarely, an acquired somatic mutation or deletion of a ferrochelatase (fech) gene leads to an adult-onset protoporphyria disorder. the mutation results in impaired activity of fech, the enzyme that catalyzes the final step in the formation of heme, resulting in increasing deposits of protoporphyrin in plasma, skin and liver [1,2,6]. in 2008, whatley et al identified eight families with a protoporphyria indistinguishable clinically from the predominant form of the disease, but without ferrochelatase mutations, that is now called x-linked dominant protoporphyria [7]. deposits of protoporphyrin in skin leads to acute photosensitivity. ultraviolet light absorption by protoporphyrin in plasma and erythrocytes when blood circulates through the dermal vessels results in formation of free radicals. erythrocytes become unstable and injury to the skin is induced [8]. a significant increase in the hepatobiliary excretion of protoporphyrin can damage the liver through both cholestatic phenomena and oxidative stress predisposing the individual to hepatobiliary disease of varying severity [9,10]. when the onset of disease is in adulthood, as it was the case in this patient, it is important to note that it may be associated with myelodysplastic syndromes and other hematologic malignancies [3,4]. an acquired somatic mutation or deletion of the ferrochelatase gene is the purported causation. it is imperative to check the hematologic parameters of the patient. however, no such association was identified in the patient presented here and his blood counts were normal. even though late onset epp is very rare and usually associated with hematological malignancy, cases without such association have also been observed. murphy et quiz | dermatol pract concept 2012;2(4):4 17 15. berroeta l, man i, goudie dr, whatley sd, elder gh, ibbotson sh. late presentation of erythropoietic protoporphyria: case report and genetic analysis of family members. br j dermatol. 2007;157(5):1030-1. 16. goodwin rg, kell wj, laidler p, et al. photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells. blood. 2006;107(1):60-2. 17. lim hw, cooper d, sassa s, dosik h, buchness mr, soter na. photosensitivity, abnormal porphyrin profile, and sideroblastic anemia. j am acad dermatol. 1992;27(2 pt 2):287-92. 18. shirota t, yamamoto h, hayashi s, fujimoto h, harada y, hayashi t. myelodysplastic syndrome terminating in erythropoietic protoporphyria after 15 years of aplastic anemia. int j hematol. 2000;72(1):44-7. 19. aplin c, whatley sd, thompson p, et al. late onset erythropoietic porphyria caused by a chromosome 18q deletion in erythroid cells. j invest dermatol. 2001;117(6):1647-9. 20. sarkany rp, ross g, willis f. acquired erythropoietic protoporphyria as a result of myelodysplasia causing loss of chromosome 18. br j dermatol. 2006;155(2):464–6. 21. rothstein g, lee r, cartwright ge. sideroblastic anemia with dermal photosensitivity and greatly increased erythrocyte protoporphyrin. n engl j med. 1969;280(11):587–90. 22. sato y, motoji t, yamada o, ito y, et al. [a case of sideroblastic anemia with dermal photosensitivity and increased erythrocyte protoporphyrin (in japanese)]. rinsho ketsueki.1981;22(12):1971–6. a patient heteroallelic for ferrochelatase gene mutations.  j am acad dermatol. 2002;46(6):861-6. 7. tsuboi h, yonemoto k, katsuoka k. erythropoietic protoporphyria with eye complications. j dermatol. 2007;34(11):790-4. 8. whatley sd, ducamp s, gouya l, et al. c-terminal deletions in the alas2 gene lead to gain of function and cause x-linked dominant protoporphyria without anemia or iron overload. am j hum genet. 2008;83(3):408-14. 9. lecha m, puy h, deybach jc. erythropoietic protoporphyria. orphanet j rare dis. 2009;4:19. 10. anstey av, hift rj. liver disease in erythropoietic protoporphyria: insights and implications for management. gut. 2007;56(7):1009-18. 11. murphy gm, hawk jl, magnus ia. late onset erythropoietic protoporphyria with unusual cutaneous features. arch dermatol 1985;121(10):1309–12. 12. spann ct, tok j, nimer s, zug k, deleo v. adult onset erythropoietic protoporphyria in association with myelodysplastic syndrome [abstract]. american academy of dermatology annual meeting, new orleans, la, february 22-27, 2002. 13. murphy gm, hawk jl, magnus ia. late onset erythropoietic protoporphyria with unusual cutaneous features. arch dermatol 1985;121(10):1309–12. 14. bharati a, badminton mn, whatley sd, o’brien dv, bell hk. late onset erythropoietic protoporphyria in association with haematological malignancy. clin exper dermatol 2006;31(5):668-70. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020086 1 dermatology practical & conceptual introduction rosai-dorfman disease (rdd) is a reactive and histioproliferative disorder of unknown cause. it predominantly affects the cervical lymph nodes, with extranodal lesions in 40% of cases (skin lesions comprise 16%). the presence of characteristic rdd symptoms (fever, night sweats, and weight loss), termed b symptoms, is considered systemic rdd. primary cutaneous rdd (crdd) comprises 3% of all rdds. it is localized to the skin with no systemic symptoms or abnormal blood examination findings. although it often occurs on the face, there are very few reports of primary crdd of the scalp. we report a case of primary crdd of the scalp that needed to be distinguished from angiosarcoma. case presentation a 51-year-old man noticed a mass on his head 6 months before his first visit, and 2 months prior, biopsy had been performed at a nearby hospital owing to gradual mass enlargement. histopathological findings indicated angiosarcoma. pet/ct detected a skin lesion with accumulation in the right temporal region and no metastasis (figure 1a). therefore, he was referred to our hospital. clinical examination revealed a smooth, soft, and mobile red mass measuring 2.5 × 2 cm in the right temporal region (figure 1b), and the pathological diagnosis was reconsidered because he was younger than the typical angiosarcoma patient and had no purpura around the mass. numerous inflammatory cells (plasma cells) were seen in the dermis (figure 2a). many large histiocytes formed a nodular/diffuse pattern (figure 2b). normal lymphocytes and neutrophils were detected in the cytoplasm of large histiocytes, termed emperipolesis. tumor cells were positive for s100 and cd68 and negative for cd1a, cd34, and erg. (figure 2c). thus, crdd was diagnosed. at follow-up 10 months after the patient’s first visit, with no treatment, the tumor reduced in size. conclusions five cases of crdd of the scalp have been reported (4 primary skull rdd with subcutaneous infiltration and 1 primary crdd of the scalp) [1]. accumulation of rdd on pet/ct has been reported [2]. therefore, it must be differentiated from other malignant diseases. primary cutaneous rosai-dorfman disease of the scalp haruki mizuta1,2, eiji nakano3, naoya yamazaki1 1 department of dermatologic oncology, national cancer center hospital, tokyo, japan 2 department of plastic and reconstructive surgery, graduate school of medicine, osaka city university, osaka, japan 3 division of dermatology, department of internal medicine, kobe university graduate school of medicine, hyogo, japan key words: rosai-dorfman disease, cutaneous rosai-dorfman disease, scalp, angiosarcoma citation: mizuta h, nakano e, yamazaki n. primary cutaneous rosai-dorfman disease of the scalp. dermatol pract concept. 2021;11(1):e2020086. doi: https://doi.org/10.5826/dpc.1101a86 accepted: may 14, 2020; published: december 7, 2020 copyright: ©2020 mizuta et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this work was supported in part by the national cancer center research and development fund (29-a-3). competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: eiji nakano, md, phd, division of dermatology, department of internal medicine, kobe university graduate school of medicine, hyogo, 7-5-1 kusunoki-cho, chuo-ku, kobe 650-0017, japan. email: einakano@med.kobe-u.ac.jp 2 letter | dermatol pract concept 2021;11(1):e2020086 regression and has a good prognosis. minimally invasive modalities, such as excision and topical, local injection of, and internal use of steroids, are options for treatment; however, a benign or malignant diagnosis greatly influences the treatment strategy. thus, it is crucial to consider crdd in the diagnosis of atypical skin cancers. references 1. kaskas nm, kern m, johnson a, et al. a case of cutaneous rosai-dorfman disease with underlying calvarial involvement and absence of braf v600e mutation. jaad case rep. 2015;1(6):408-411. doi: 10.1016/j.jdcr.2015.10.003. pmid: 26858984. 2. hadchiti j, kamar fg, ghosn ja, et al. 18f-fluoro-2deoxyglucose positron emission-computed tomography in a rare cutaneous form of rosai-dorfman disease: a case report. mol clin oncol. 2018;8(2):236-241. doi: 10.1016/10.3892/ mco.2017.1507. pmid: 29435284. our case mimicked an atypical angiosarcoma that presented as classical angiosarcoma found on sun-damaged skin of the head and neck of elderly patients, lymphedema associated angiosarcoma in postmastectomy or lymphatic malformations, and post-radiation angiosarcoma in radiation fields. histopathological crdd findings revealed large histiocytes, which form nodular/diffuse patterns with skin infiltration and are positive for s100 and cd68 but negative for cd1a. these histological features indicate rdd as a non langerhans cell histiocytosis. further, immunohistochemical staining of cd34 and erg, markers of vascular endothelium, distinguishes crdd from angiosarcoma. emperipolesis, in which normal lymphocytes and neutrophils are recognized in the cytoplasm of histiocytes, is a characteristic feature of crdd. these 3 features must be present to suspect angiosarcoma. crdd undergoes spontaneous figure 1. clinical findings: (a) pet/ct taken at the nearby hospital. a skin lesion with an accumulation is seen in the right temporal region away from the skull. (b) clinical findings at the first visit: a smooth, soft, and mobile red mass measuring 2.5 × 2 cm with no surrounding purpura. a b figure 2. histopathological features: (a) there are many large histiocytes forming a nodular/diffuse pattern (h&e, ×200). (b) normal lymphocytes and neutrophils are detected in the cytoplasm of the large histiocytes, which is called emperipolesis (h&e, ×400). (c) the large histiocytes are positive for s100 (immunohistochemical staining, ×200). a b c observation | dermatol pract concept 2011;1(1):10 49 background: basal cell carcinoma usually occurs in sun exposed areas of older male individuals. objectives: to emphasize the importance of histological step sections in the pursuit of the correct diagnosis when microscopic findings do not correspond to clinical hypothesis. patient: 21-year-old female with a superficial basal cell carcinoma in pubic region diagnosed after histological step sections and treated with topical imiquimod. conclusions: although very rare, basal cell carcinomas do occur in young patients and, at times, on areas of the body where they are not conventionally seen. step sections are an important tool that dermatopathologists should use on a regular basis to enhance diagnostic accuracy. abstract saved by step sections: an unusual presentation of basal cell carcinoma betina werner, m.d.1, fabiane mulinari-brenner, m.d.2 1dermatopathologist, curitiba, parana, brazil 2dermatologist, curitiba, parana, brazil key words: basal cell carcinoma, step sections, pubic region, differential diagnosis, biopsy citation: werner b, mulinari-brenner f. saved by step sections: an unusual presentation of basal cell carcinoma. dermatol pract concept 2011;1(1):10. http://dx.doi.org/10.5826/dpc.0101a10. editor: harald kittler, m.d. received: october 1, 2010; accepted: december 17, 2011; published: october 31, 2011 copyright: ©2011 werner et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: betina werner, m.d., rua dr. nelson de souza pinto, 759, 82200-060 curitiba, parana, brazil. tel. 55 41 9116 0525. email: betina.werner@gmail.com. introduction basal cell carcinomas are usually found in sun exposed areas of older individuals, especially the head and neck [1, 2, 3]. the incidence of basal cell carcinoma in patients younger than 50 years old, was 5% in one brazilian study [4], and these were mainly in regions exposed to sunlight. although several cases of basal cell carcinoma in the vulva can be found in the literature [5–8], only one case reported it to occur in the pubic region [9]. we describe a young female patient with an enlarging erythematous macule on the pubic region that was diagnosed as superficial basal cell carcinoma. there was no clinical suspicion of malignant neoplasia, however, that diagnosis was possible by performing histological step sections. case report a 21-year-old female presented a 2 cm erythematous macule on the pubis that had been slowly enlarging over a period of 18 months (figure 1). her main complain, actually, was diffuse hair thinning and scalp scaling, which was interpreted as androgenetic alopecia associated with seborrheic dermadermatology practical & conceptual www.derm101.com 50 observation | dermatol pract concept 2011;1(1):10 titis. she was otherwise healthy with no other significant skin abnormalities. mycologic tests (direct examination with potassium hydroxide and culture) done on the pubic lesion were negative. no improvement was seen after topical corticosteroid for 10 days. a skin biopsy (3 mm punch) was performed with the following clinical hypothesis: seborrheic dermatitis, eczema, psoriasis, tinea incognita. histological sections (figures 2a, 2b, 2c) showed a well-demarcated area of ulceration with crust. adjacent epidermis depicted irregular acanthosis and prominent spongiosis with inflammatory cells in exocytosis; superficial and mid-dermis presented a dense inflammatory infiltrate composed mainly of lymphocytes. step sections were ordered because skin ulceration is unusual in those clinical differential diagnoses listed. new sections (figures 3a, 3b and 3c) surprisingly showed neoplastic blocks attached to the epidermis demonstrating slitlike retraction of the palisaded basaloid cells from the adjacent stroma. the diagnosis of superficial basal cell carcinoma was yielded. the patient started topical imiquimod cream (figure 4a), five days a week for six weeks. severe inflammation was noticed in week three (figure 4b), followed by crusting in week six (figure 4c), and complete healing. no signs of recurrence was seen at a six-month follow-up (figure 4d). discussion to the best of our knowledge, this is the first case report of superficial basal cell carcinoma in the pubic region of a young adult female. the only case we found in the literature occurring in the pubic region was a polypoid basal cell carcinoma (fibroepithelioma of pinkus) measuring 7.1 × 5.0 × 2.2 cm in a 61-year-old woman – a totally different clinical and histological setting from the case reported herein. figure 1. clinical appearance: 2 cm erythematous patch with focal crusting and scaling. figure 2. a: panoramic view of first section showing well demarcated area of ulceration of the epidermis with crust. original magnification (objective) x20; b: epidermis with ulceration and irregular acanthosis; dense inflammatory infiltrate composed mainly of lymphocytes in superficial and mid-dermis. original magnification (objective) x100; c: detail of epidermis with scale crust and prominent spongiosis with inflammatory cells in exocytosis. original magnification (objective) x200. a b c observation | dermatol pract concept 2011;1(1):10 51 another feature that contributes to the peculiarity of this case is that the diagnosis of basal cell carcinoma was possible because step sections were ordered. the order was based on the odd aspect of the first hematoxylin and eosin slide where an area of ulceration could be seen. a pas stain with diastase was already performed and had not given any enlightenment on the matter. the intention of ordering deeper sections was to find the explanation for that ulceration and to rule out the remote possibility of a bullous disease or of herpes simplex virus infection. actually, in the author’s (bw) own experience, herpes simplex virus infection is the “champion” among the diagnoses made by deeper/step sections, especially when follicular herpes infection is present. resnik and dileonardo [10] reported three such cases, a setting they called “herpes incognito.” some studies have approached the matter of step sectioning in dermatopathology [11–14] and its usefulness in enhancing diagnostic accuracy and cost-benefit issues are the major concerns. these authors were all convinced that 30–37% of their cases benefitted from that practice [11–14]. the higher rate of ordering step sections was obtained in a retrospective study by maingi and helm [11], where the dermatopathologist felt compelled to order deeper sections based on histological aspects. this study best reflects what in reality occurs in a dermatopathology service – 63% of the step sectioned cases could be signed out without ordering them, with no change in diagnosis. on the other hand, if no step sectioning were performed, 37% of the patients would not benefit maximally from the diagnostic power of skin biopsy. step sectioning can be crucial to diagnosis, like what happened in the case reported by us. figure 3. a: panoramic view after step sectioning. ulcerated area was associated to a superficial neoplasia demonstrating slit-like retraction from the subjacent dermis. original magnification (objective) x20; b: closer view of superficial basal cell carcinoma. original magnification (objective) x100; c: detail of neoplastic blocks with palisaded basaloid cells and characteristic separation from papillary dermis. original magnification (objective) x200. figure 4. a: clinical aspect before treatment; b: three weeks after imiquimod cream with severe inflammation; c: six weeks after imiquimod cream with partial healing and focal crusting; d: six months after treatment. complete healing and no signs of recurrence. a b c 52 observation | dermatol pract concept 2011;1(1):10 references 1. roewert-huber j, lange-asschenfeldt b, stockfleth e, kerl h. epidemiology and aetiology of basal cell carcinoma. br j dermatol 2007;157(suppl 2):47–51. 2. lear w, dahlke e, murray ca. basal cell carcinoma: review of epidemiology, pathogenesis, and associated risk factors. j cut med surg 2007;11(1):19–30. 3. carucci ja, leffell dj. basal cell carcinoma. in: wolff k, goldsmith la, katz si, gilchrest ba, paller as, leffell dj (eds.). fitzpatrick’s dermatology in general medicine. 7th ed. new york: the mcgraw-hill companies, inc., 2008:1036-42. 4. almeida ac, yamashita t, conte b, mattos ac, veríssimo rp, ferreira mc. [frequency of basal cell carcinoma in a population younger than 50 years of age: clinical study and literature review]. an bras dermatol 2009;84(6):692-4. 5. thomas rh, mcgibbon dh, munro dd. basal cell carcinoma of the vulva in association with vulval lichen sclerosus et atrophicus. j royal soc med 1985;78(suppl 11):16-18. 6. mateus c, fortier-beaulieu m, lhomme c, et al. basal cell carcinoma of the vulva: 21 cases. ann dermatol venereol 2001;128(1):11-5. 7. pisani c, poggiali s, la de padova l, andreassi a, bilenchi r. basal cell carcinoma of the vulva. j eur acad dermatol venereol 2006;20(4):446–8. 8. suda t, kakinuma h. erosive velvety lesion on the vulva – vulvar basal cell carcinoma. arch dermatol 2006;142(3):385-90. 9. misago n, suzuki y, miura y, narisawa y. giant polypoid basal cell carcinoma with features of fibroepithelioma of pinkus and extensive cornification. eur j dermatol 2004;14(4):272-5. 10. resnik ks, dileonardo m. herpes incognito. am j dermatopathol.2000; 22(2):144-50. 11. maingi cp, helm kf. utility of deeper sections and special stains for dermatopathology specimens. j cutan pathol 1998;25(3):1715. 12. carag hr, prieto vg, yballe ls, shea rs. utility of step sections: demonstration of additional pathological findings in biopsy samples initially diagnosed as actinic keratosis. arch dermatol 2000;136(4):471-5. 13. guille dr. accurate diagnosis of cutaneous keratinocytic neoplasms: the importance of histological step sections (and other factors). arch dermatol 2000;136(4):535-7. 14. bruecks ak, shupe lm, trotter mj. prospective step sections for small skin biopsies. arch pathol lab med 2007;131(1):107–11. dermatology: practical and conceptual review | dermatol pract concept 2020;10(2):e2020032 1 dermatology practical & conceptual introduction reflectance confocal microscopy (rcm) is a high-resolution, noninvasive imaging technique being increasingly used as an aid to diagnosis in the dermatology setting. rcm is applied in the diagnosis of both melanoma and nonmelanoma skin tumors, but also in the interpretation and management of inflammatory and infectious skin diseases [1-7]. when can rcm be used in the clinical setting? • to increase the specificity and sensitivity of diagnosis in most of the skin cancers. • to increase diagnostic accuracy in other diagnoses. • to guide biopsy in a suspicious lesion. • to map the limits of some large tumors, defining margins for a correct surgical excision. • to follow clinical and therapeutic evolution of a skin disease. which is the correct rcm instrument version to be applied according to the clinical presentation and anatomical site? the basic principle of rcm is a point source of light, which is tightly focused on a specific point in the tissue. the light is backscattered by certain tissue structures because of variations of refractive indices within the skin; specifically, melin vivo reflectance confocal microscopy in general dermatology: how to choose the right indication chiara franceschini,1 flavia persechino,1,2 marco ardigò1 1 clinical dermatology department, san gallicano dermatological institute (irccs), rome, italy 2 department of clinical and molecular medicine, sapienza university of rome, italy keywords: reflectance confocal microscopy, static and handled probe, melanoma, nonmelanoma skin cancer, inflammatory skin diseases, limits citation: franceschini c, persechino f, ardigò m. in vivo reflectance confocal microscopy in general dermatology: how to choose the right indication. dermatol pract concept. 2020;10(2):e2020032. doi: https://doi.org/10.5826/dpc.1002a32 accepted: november 20, 2019; published: april 3, 2020 copyright: ©2020 franceschini et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. c. f. and f. p. made equal contributions to the manuscript. corresponding author: marco ardigò, md, phd, u.o.c. clinical dermatology, san gallicano dermatological institute, ifo, rome, via elio chianesi n. 53, 00144 rome, italy. email: marco.ardigo@ifo.gov.it reflectance confocal microscopy (rcm) is a high-resolution, noninvasive imaging technique being increasingly used as an aid to diagnosis in the dermatology setting. rcm is applied in the diagnosis of both melanoma and nonmelanoma skin tumors, but also in the interpretation and management of inflammatory skin diseases. two different devices with different designs for specific indications are available in the market: a static and a handheld probe. several clinical presentations of the lesion could affect the examination, such as the presence of ulceration or hyperkeratosis; moreover, the anatomical site can drive the probe selection as well as the effective indication to rcm examination. in this review article, indications for the use of rcm are described in detail with a schematic approach for practical purposes. abstract https://doi.org/10.5826/dpc.1002a32 mailto:marco.ardigo@ifo.gov.it 2 review | dermatol pract concept 2020;10(2):e2020032 in order to permit an acceptable examination of the target lesion. the typical limits are represented by hyperkeratotic and ulcerated lesions. in acral sites, rcm can be used only in a limited number of cases (figure 4) [15]. in table 1, possible solutions to overcome some of the limitations of rcm are explained. which are the clinical characterizations of the lesions that affect the rcm examination? even if the existing probes allow the examination of the majority of lesions in the majority of anatomical sites, there are limits of rcm application described in the literature [13,14]. if several limits are effectively unsolvable, in clinical practice specific solutions can be applied anin, hydrated collagen, and keratin are highly reflective skin components, which appear brighter on rcm images than the surrounding structures [8-10]. only light reflected back from the tissue focus point is allowed to enter the rcm detector through a pinhole-sized spatial filter and to be processed by the dedicated software. currently, 2 different rcm probes are available in the market, showing different designs for different indications: a static rcm (vivascope 1500, caliber i.d. inc., rochester, ny, usa) and a handheld rcm device (vivascope 3000, caliber i.d. inc.). • the traditional wide probe rcm uses a near-infrared, low-power laser beam (830-nm diode laser, power up to 35 mw) for imaging. the laser beam is scanned in a 2-dimensional grid over the skin to obtain a thin horizontal optical section, which is displayed as a grayscale image (“single rcm image”: 500 × 500 μm fieldof-view). an automated stepper can be used to obtain up to 64 sequential images, making a mosaic grid of 16 × 16 contiguous images in the horizontal plane (8 × 8 mm2 field-of-view; named “vivablock”). by adjusting the focal length of the laser beam, a series of consecutive single rcm images can be stacked vertically (named “vivastack”), from the skin surface to superficial dermis, at the same point in the tissue. rcm allows dermoscopy–rcm direct correlation by clicking on a specific area of the dermoscopy image and consequently the rcm optic moves automatically to the selected site of the lesion. • the handheld rcm has the same technical characteristics as the traditional rcm. it allows one to investigate curved anatomical sites, such as the nose or eyelids and mucous membranes, and it does not require fixation of the probe to the skin; the field-of-view is, however, limited to 1 × 1 mm2 and the handheld device does not use a dermoscopic picture to guide rcm imaging [11,12]. table 1. limitations of reflectance confocal microscopy (rcm) and their possible solutions green = possible to overcome; yellow = not always easy to overcome; red = never overcome (figures 1-4). review | dermatol pract concept 2020;10(2):e2020032 3 3 months of digital dermoscopy monitoring. the excision of those lesions with rcm-positive features and/or presenting major changes on digital dermoscopic follow-up could reduce the number of biopsied nevi by about 47% [17]. in the case of suspicious melanorcm has been demonstrated to be particularly efficient in the study of flat pigmented lesions, with good performance in the differential diagnosis of atypical nevi and with significant reduction of unnecessary excision [2,4,16]. stanganelli et al proposed rcm after discussion melanoma and nevi rcm criteria for melanoma have been extensively described in the literature and are routinely used for the management of suspicious melanocytic lesions. figure 2. nodular lesions. (a) clinical image of a crusted nodular lesion. (b) dermoscopic image of the crusted basal cell carcinoma (bcc). (c) reflectance confocal microscopy (rcm) examination does not allow the evaluation of the crusted portion. (d) rcm evaluation of peri-crusted tissue allows the identification of basaloid nest of nodular bcc. (e) clinical image of the nodular pigmented lesion. (f) dermoscopic image of the nodular pigmented lesion. (g) rcm examination shows roundish pagetoid cells up-located into the epidermal layer. (h) at the rcm examination in the peri-nodular portion of the lesion, we observe the rings and atypical cells to identify the atypical nodular melanocytic lesion. figure 1. hyperkeratotic lesions. (a) clinical presentation of hyperkeratotic lesion on the scalp. (b) dermoscopic image of the hyperkeratotic portion. (c) reflectance confocal microscopy (rcm) examination does not allow the evaluation of the hyperkeratotic portion because of high backscattering of the light due to keratin. (d) dermoscopic image of the same area after 2 weeks of keratolytic ointment application. (e) rcm examination allows identification of basaloid nests of basal cell carcinoma. 4 review | dermatol pract concept 2020;10(2):e2020032 component, the detection of superficial rcm features characterizing melanocytic proliferations could support lesion management, assisting in the presurgical definition of the nature of the lesion. cytic lesions, to avoid sample errors, the use of static rcm for a total lesion mapping has to be preferred, when possible, to the handheld version. in the case of nodular lesions, even if rcm does not allow the evaluation of the deep cellular figure 3. ulcerated lesions. (a) clinical presentation of oral squamous cell carcinoma (scc). (b) high magnification image of the scc located on the labial commissure. (c) reflectance confocal microscopy (rcm) examination does not allow the evaluation of the ulcerated portion. (d) rcm shows severe cellular atypia of the epithelium in the peri-ulcerated portion. (e) clinical examination of vegetative ulcerated lesion of the glans. (f) dermoscopic image shows white concentric structures as scc. (g) rcm examination does not allow the evaluation of the peripheral portion. (h) rcm of the central portion is characterized by architectural disarray and cellular pleomorphism at spinous and granular layers as sign of the cellular severe dysplasia of scc. figure 4. acral pigmented lesions. (a) clinical examination of pigmented melanocytic lesion on the sole. (b) dermoscopic image of an atypical melanocytic lesion. (c,d) reflectance confocal microscopy (rcm) examination does not allow the evaluation of the melanocytic proliferation due to the hyperkeratosis and acanthosis of the epidermis characterizing the acral skin. (e) clinical examination of pigmented lesion located at the interdigital space. (f) dermoscopic image of an atypical melanocytic lesion. (g,h) rcm allows the detection of atypical nests. review | dermatol pract concept 2020;10(2):e2020032 5 diagnosis of pigmented macules of the face remains challenging in some cases when lesions share several dermoscopic features, such as brown pseudonetwork and annular granular structures. in the case of spreading lm cases, handheld rcm supports both diagnoses as well as permits the mapping of the extension of the lesion identifying the margins [28,29]. several specific features characterizing lm have been reported in the literature (ie, medusa head-like structures, folliculotropism of atypical cells, dendrites in the epidermis, etc) making lm one of the most clear diagnoses on rcm. differential diagnosis between lm and pigmented actinic keratosis is supported on rcm by distribution around adnexal structures of dendritic, atypical melanocytes [22] (figure 5). superficial and multifocal bcc tumor islands can be difficult to detect on the face because they can be misinterpreted as adnexal structures. in the case of squamous proliferations, especially in sun-damaged skin, atypical keratinocytes are the key for a correct diagnosis. hair follicles can be differentiated from tumor islands because they are also visible at the skin surface (as hair follicle openings [20,23]). acral skin normal acral skin is characterized by the presence of ridges and furrows, with the openings of sweat ducts in the center of the ridges, and lack of hair follicles. epidermal ridges appear as broad parallel bands with a regular honeycomb pattern; epidermal furrows are visible as parallel dark areas disrupting the honeycomb pattern. the openings of sweat ducts appear as bright roundish circles plugged in lines inside the honeycomb pattern. rcm shows meissner corpuscles as medium reflective ovoid structures in the upper part of dermal papillae, the main touch-pressure sensation receptors in skin without hairs. the dermoepidermal junction (dej) and the dermis are not always visible in the acral region, depending on the thickness of the epidermis. in the area around the proximal nail fold near the cuticle and in the fingertips, stellate bright bodies are often visible, corresponding to keratinocyte membranes in a plane not parallel to the microscope tip (figure 4) [15,30]. oral and genital mucosa oral cavity and genitalia can be analyzed by rcm to evaluate benign, malignant, and precancerous lesions, identifying specific descriptors for inflammatory or neoplastic diseases [31,32]. mucosa is particularly suitable for rcm: the absence of cornified superficial layer and the thickness of this epithelium allows for higher definition and deeper penetration of the laser, with no consequent light backscattering and the possibility of a better-detailed visualization of cellular morphology and dermal structures in comparison with the skin tissue. the normal mucosa differs from normal skin in the absence of the stratum corneum and the pigmentation of the nonmelanoma skin cancer also in the case of nonmelanoma skin cancer, rcm devices have to be selected according to the anatomical sites. rcm findings of basal cell carcinoma (bcc) have been widely described in the literature: dark silhouettes, bright tumor islands with peripheral palisading, cleft-like dark spaces, dendritic cells, plump-bright cells, and dilated canalicular vessels [18-22]. bcc is classified in different histological subtypes: nodular, superficial, morpheaform, infundibulocystic, fibroepithelioma of pinkus. the most common type is the nodular; it can be easily diagnosed using a handheld rcm device when detection of a single tumor island can be sufficient for a conclusive diagnosis. bcc, when pigmented, shows clearly detectable, bright tumor islands. superficial bcc is characterized mainly by “streaming” of keratinocytes: ie, the orientation of keratinocytes in the same direction. dark silhouettes are found mainly in infiltrating bcc. superficial bcc is characterized mainly by “streaming” of keratinocytes: ie, the orientation of keratinocytes in the same direction. dark silhouettes are found mainly in infiltrating bcc. a major limit of rcm examination of bcc is represented by the ulceration, bleeding, and crusts, which when present obscure the laser penetration into the tumoral lesion (figure 2). detection of atypical keratinocytes in the context of erythematous-scaling lesions on sun-exposed areas is characteristic of squamous cell proliferations. the histological spectrum from actinic keratosis to squamous cell carcinoma can be studied using rcm with the limit related to the evaluation of the tumoral infiltration into the dermis due to the virtual horizontal sectioning of the tissue and an efficient determination of the grading of atypia of the keratinocytes [23]. anatomical sites face the most effective application of the rcm handheld version is in the evaluation of pigmented macules and patches located on the sun-damaged skin of the face [23-25]. the handheld version allows one to reach difficult anatomical sites such as the periocular area, ears, and nose. moreover, the handheld rcm permits the evaluation of lesions larger than 8 mm in diameter, representing the limit of mosaicking of the static probe. finally, the handheld device allows, in real time, collection of microscopic data useful for dermoscopy correlation for a quick diagnosis. differential diagnosis of pigmented flat lesions of exposed areas comprehends melanocytic skin neoplasm, lentigo maligna (lm), and lentigo maligna melanoma vs nonmelanocytic neoplasms as pigmented actinic keratosis, solar lentigo, and lichen planus-like keratosis [24,26,27]. dermoscopy 6 review | dermatol pract concept 2020;10(2):e2020032 agement. in detail, a study from the international confocal working group demonstrated the role of rcm for the identification of the major groups of superficial inflammatory skin diseases: psoriasiform, spongiotic, and interface dermatitis [5,35,36]. deep inflammatory processes cannot be examined by rcm because of limits of penetration of laser into the skin. psoriasiform dermatitis prototypic diseases: plaque psoriasis and seborrheic dermatitis. on rcm, psoriasiform dermatitis is characterized by the presence of thickened epidermis (>60-80 μm) and hyperkeratosis (20-40 μm), often in association on rcm with the presence of high refractive round to polygonal structures inside the stratum corneum, corresponding to parakeratosis. on rcm, papillomatosis is seen as “up-located,” enlarged dermal papillae with thin interpapillary epidermal spaces in plaque psoriasis. prominent dark canalicular structures filling the dermal papillae are detectable, representing dilated vessels in a vertical orientation. the progressive normalization of the aspects can be used for the therapeutic response assessment [37] (figure 6). differently in seborrheic dermatitis, dilated vessels are detectable as horizontally oriented and located mainly around adnexal structures; demodex folliculorum located in the ostium of the sebaceous glands represents a specific aspect of seborrheic dermatitis [38]. dej and the difference in keratinocytes details identification: much more detailed in the mucosa with nuclei easily visible in many areas of the upper layers as bright, large, round structures in the center of the cells. in normal conditions, in both oral and genital mucosa epithelial cells are regular in shape and size, differently from malignant tumors, in which the normal architecture is not preserved and cells are not homogeneous [33,34]. the examination of mucosa is limited by the design of the rcm microscopes available in the market, with only possible evaluation of the tissue using the handheld rcm; this device is directly applied through a smaller tip (1.5 cm in diameter) on the genital mucosa or on the dorsal and lateral surface of the tongue, on the inner part of the lips, and in some parts of gingiva. however, for the examination of oral mucosa, characterized by presence of concavity and convexity and mucosal sites not supported by bones and rigid structures, a dedicated handheld device is needed. to reach deeper oral sites with limited accessibility as the floor of the mouth, ventral tongue, gingiva, and inner part of the cheeks, the handheld rcm has been redesigned with a longer optic (approximately 10 cm long and 1 cm in diameter) (figure 8a). inflammatory diseases rcm in the evaluation of inflammatory diseases has been described in the literature to support the clinical-microscopic correlation for diagnosis confirmation and therapeutic manfigure 5. pigmented macules of the face. (a) clinical image of a large lentigo maligna (lm). (b) dermoscopic image of lm showing black rhomboidal structure and obliteration of the hair follicles. (c,d) reflectance confocal microscopy (rcm) image at the level of the epidermis shows irregular honeycombed pattern and abundant hyperreflective dendritic cells in relation to an ill-defined hair follicle. (e) clinical image of pigmented actinic keratosis. (f) dermoscopic image of pigmented actinic keratosis: light brown pseudonetwork and irregular follicular pigmentation. (g,h) rcm image in the epidermal layer shows irregular honeycombed pattern and few fine tangled lines displayed around a well-defined hair follicle without the invasion of the hair follicle. review | dermatol pract concept 2020;10(2):e2020032 7 ferent body sites; for these reasons, it is more useful than the static version for the examination of inflammatory diseases. scalp diseases prototypic diseases: scarring alopecia (sa) and nonscarring alopecia (nsa). clinical management of alopecia represents one of the major issues in dermatology. scalp biopsies are not easily accepted, because of the high bleeding and sensitive anatomical area, and are not repeatable during therapy. however, a prompt diagnosis is highly recommended for an early onset of adequate treatment to avoid irreversible hair loss. in many cases, rcm offers to clinicians the possibility of a real-time, noninvasive distinction between sa and nsa [35,40]. nsa, in particular androgenic alopecia, is characterized by the presence of miniaturization of hair shaft and follicular keratosis. conversely, the absence of these 2 rcm criteria and the presence of inflammatory cells in the epidermis or around adnexal structures are suggestive of sa (lichen planopilaris, dle, other). sa is classified as interface dermatitis, characterized by involvement of the dej, with consequent obscuration and disappearing of the dermal papillae and absence of the normal rimming at the rcm examination. infiltration of adnexal structures represents the main expression of the interface change, and in lichen planopilaris it can be the prevalent location of the inflammatory cells’ infiltration [41]. with rcm, dermatologists involved spongiotic dermatitis prototypic diseases: irritant contact dermatitis and allergic contact dermatitis. spongiotic dermatitis is characterized by dark areas at the level of the epidermis with broadband intercellular spaces and round to oval bright cellular structures between keratinocyte spaces corresponding to intraepidermal spongiosis associated with the inflammatory cells. in acute phases, intraepidermal vesicles are detected as well-demarcated dark spaces between keratinocytes, filled by “floating” inflammatory cells. the absence of papillomatosis or lichenoid infiltrate, typically observed in psoriasiform dermatitis and interface dermatitis, helps to confirm the clinical suspect of spongiotic dermatitis [35] (figure 7). interface dermatitis prototypic diseases: lichen planus and discoid lupus erythematosus (dle). interface dermatitis is characterized by the inflammatory process involving the dej. on rcm, the papillary rims are obscured by the presence of the inflammatory cells with an obliteration of the ring-like structures around dermal papillae that are not detectable and not surrounded by the bright rims usually seen in normal skin. inflammatory cells can be also detected at the level of the epidermis as well as in the upper dermis around vessels and especially around adnexal structures in dle [38,39]. the handheld version can be moved freely on the skin and allows analysis of large surfaces and of several lesions at diffigure 6. psoriasiform dermatitis. (a) clinical image of erythematosus plaque on the leg. (b) dermoscopic image shows scale and dotted vessel. (c) reflectance confocal microscopy (rcm) reveals hyperkeratosis and high refractive round to polygonal structures inside the stratum corneum, corresponding to parakeratosis. (d) rcm examination shows enlarged dermal papillae with thin interpapillary epidermal spaces, associated with dilated vessels in a vertical orientation. (e) clinical image after treatment with local steroid for 3 months. (f) on dermoscopy disappearance of the scale. (g) rcm reveals regular honeycombed of the epidermal layer. (h) rcm shows a decrease of papillomatosis. 8 review | dermatol pract concept 2020;10(2):e2020032 moreover, in specific diseases (mycosis fungoides or scalp alopecias), or in patients with multiple lesions (lichen planus, lupus), rcm imaging can be used as a real-time guide for optimal biopsy site selection to reduce the number of unsuccessful histopathological examinations or to avoid late-stage lesion sampling [35,40]. conclusions rcm is a high-resolution, noninvasive imaging technique used in the diagnosis of both melanoma and nonmelanoma skin tumors and in the interpretation and management of inflammatory skin diseases. two different devices with different designs for specific indications are available in the market: a static and a handheld probe. the typical limits are represented by hyperkeratotic and ulcerated lesions. in acral sites, rcm can be used only in a limited number of cases. we describe the indications for the use of rcm for a schematic approach for practical purposes. references 1. guitera p, pellacani g, longo c, et al. in vivo reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. j invest dermatol. 2009;129(1):131-138. 2. pellacani g, guitera p, longo c, et al. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759-2765. in the management of scalp disease can assess the amount of inflammatory cells and evaluate the effective status of the disease’s activity. infectious diseases several descriptions of rcm features of cutaneous parasites, such as demodex folliculorum and sarcoptes scabiei, and infectious skin diseases have been reported in the literature, and there have been sporadic reports of detection of dermatophytes using rcm [7]. however, probably the most effective application of rcm in infectious diseases is in viral diseases. even if rcm cannot directly observe virus, cytopathic effect associated with herpes viruses such as varicella zoster and herpes simplex has been described, underlining the possibility of a prevesicular stage detection [42]. compared to blood tests and cytological direct tests, rcm has the advantages of being noninvasive, quick, and able to image the entire affected cutaneous surface. therapeutic follow-up and biopsy site selection once rcm descriptive parameters of a specific neoplastic or inflammatory entity are defined, the normalization of the features during medical treatments can be used for the therapeutic response assessment (figure 6). therapeutic follow-up has been reported in the literature for psoriasis, cutaneous lymphomas, noninvasive therapies for nonmelanoma skin cancer, and scalp diseases [43-46] (figure 8). figure 7. spongiotic dermatitis and herpes simplex. (a) clinical image of eczema of the nipple. (b) dermoscopic examination shows scale and erythema. (c) reflectance confocal microscopy (rcm) shows intercellular edema and inflammatory cells at the level of epidermis. (d) vesicles are detected as dark areas at the level of the epidermis, associated with inflammatory cells. (e,f) dermoscopic evaluation or erythematous tissue of the lip. (g,h) rcm shows atypical keratinocytes with viral cytopathy and intraepidermal vesicles. review | dermatol pract concept 2020;10(2):e2020032 9 12. cinotti e, labeille b, cambazard f, perrot jl. confocal microscopy for special sites and special uses. dermatol clin. 2016;34(4):477-485. 13. levine a, markowitz o. in vivo reflectance confocal microscopy. cutis. 2017;99(6):399-402. 14. longo c, pellacani g. melanomas. dermatol clin. 2016;34(4):411419. 15. cinotti e, debarbieux s, perrot jl, et al. reflectance confocal microscopy features of acral lentiginous melanoma: a comparative study with acral nevi. j eur acad dermatol venereol. 2016;30(7):1125-1128. 16. carrera c, puig s, malvehy j. in vivo confocal reflectance microscopy in melanoma. dermatol ther. 2012;25(5):410-422. 17. stanganelli i, longo c, mazzoni l, et al. integration of reflectance confocal microscopy in sequential dermoscopy follow-up improves melanoma detection accuracy. br j dermatol. 2015;172(2):365-371. 18. peccerillo f, mandel vd, di tullio f, et al. lesions mimicking melanoma at dermoscopy confirmed basal cell carcinoma: evaluation with reflectance confocal microscopy. dermatology. 2019; 235(1):35-44. 19. agero al, busam kj, benvenuto-andrade c, et al. reflectance confocal microscopy of pigmented basal cell carcinoma. j am acad dermatol. 2006;54(4):638-643. 20. cinotti e, jaffelin c, charriere v, et al. sensitivity of handheld reflectance confocal microscopy for the diagnosis of basal cell carcinoma: a series of 344 histologically proven lesions. j am acad dermatol. 2015;73(2):319-320. 21. ulrich m, roewert-huber j, gonzález s, rius-diaz f, stockfleth e, kanitakis j. peritumoral clefting in basal cell carcinoma: correlation of in vivo reflectance confocal microscopy and routine histology. j cutan pathol. 2011;38(2):190-195. 3. goldgeier m, fox ca, zavislan jm, et al. noninvasive imaging, treatment, and microscopic confirmation of clearance of basal cell carcinoma. dermatol surg. 2003;29(3):205-210. 4. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy of pigmented skin lesions—improvement in melanoma diagnostic specificity. j am acad dermatol. 2005;53(6):979-985. 5. ardigo m, longo c, gonzalez s, the international confocal working group inflammatory diseases project. multicentre study on inflammatory skin diseases from the international confocal working group: specific confocal microscopy features and an algorithmic method of diagnosis. br j dermatol. 2016;175(2):364-374. 6. cinotti e, labeille b, cambazard f, perrot jl. reflectance confocal microscopy in infectious diseases. g ital dermatol venereol. 2015;150(5):575-583. 7. cinotti e, perrot jl, labeille b, cambazard f. reflectance confocal microscopy for cutaneous infections and infestations. j eur acad dermatol venereol. 2016;30(5):754-763. 8. kose k, cordova m, duffy m, flores es, brooks dh, rajadhyaksha m. video-mosaicing of reflectance confocal images for examination of extended areas of skin in vivo. br j dermatol. 2014;171(5):1239-1241. 9. rajadhyaksha m, anderson rr, webb rh. video-rate confocal scanning laser microscope for imaging human tissues in vivo. appl opt. 1999;38(10):2105-2115. 10. rajadhyaksha m, gonzález s, zavislan jm, anderson rr, webb rh. in vivo confocal scanning laser microscopy of human skin ii: advances in instrumentation and comparison with histology. j invest dermatol. 1999;113(3):293-303. 11. cinotti e, labeille b, cambazard f, thuret g, gain p, perrot jl. reflectance confocal microscopy for mucosal diseases. g ital dermatol venereol. 2015; 150(5):558-593. figure 8. interface dermatitis. (a) clinical image of the use of the new probe, specific for the oral cavity. (b) clinical examination of lichen in the inner part of the cheek. (c,d) reflectance confocal microscopy (rcm) examination. in oral lichen, inflammatory cells in the epidermal layer are detectable. (e) clinical examination of scarring alopecia (lichen planopilaris). (f) dermoscopic image shows white areas and follicular hyperkeratosis. (g,h) rcm shows the absence of miniaturization of hair shaft and follicular keratosis and the presence of inflammatory cells in the epidermis or around adnexal structures and the consequent disappearing of the normal rimming. 10 review | dermatol pract concept 2020;10(2):e2020032 including 10 macular melanomas. br j dermatol. 2014;170(6): 1276-1284. 35. ardigo m, agozzino m, franceschini c, lacarrubba f. reflectance confocal microscopy algorithms for inflammatory and hair diseases. dermatol clin. 2016;34(4):487-496. 36. agozzino m, gonzales s, ardigò m. reflectance confocal microscopy for inflammatory skin diseases. actas dermosifiliogr. 2016;107(8):631-639. 37. lacarrubba f, ardigò m, di stefani a, verzì ae, micali g. dermatoscopy and reflectance confocal microscopy correlations in nonmelanocytic disorders. dermatol clin. 2018;36(4):487-501. 38. agozzino m, berardesca e, donadio c, et al. reflectance confocal microscopy features of seborrheic dermatitis for plaque psoriasis differentiation. dermatology. 2014;229(3):215-221. 39. lacarrubba f, verzì ae, caltabiano r, broggi g, di natale a, micali g. discoid lupus erythematous: reflectance confocal microscopy features correlate with horizontal histopathological sections. skin res technol. 2019;25(2):242-244. 40. ardigò m, agozzino m, franceschini c, et al. reflectance confocal microscopy for scarring and non-scarring alopecia realtime assessment. arch dermatol res. 2016;308(5):309-318. 41. agozzino m, tosti a, barbieri l, et al. confocal microscopic features of scarring alopecia: preliminary report. br j dermatol. 2011;165(3):534-540. 42. lacarrubba f, verzi ae, musumeci ml, micali g. early diagnosis of herpes zoster by handheld reflectance confocal microscopy. j am acad dermatol. 2015;73(6):e201-e203. 43. agozzino m, donadio c, franceschini c, ardigò m. therapeutic follow-up of lichen planopilaris using in vivo reflectance confocal microscopy: a case report. skin res technol. 2015;21(3):380-383. 44. ardigò m, el shabrawi-caelen l, tosti a. in vivo reflectance confocal microscopy assessment of therapeutic follow-up of cutaneous t-cell lymphomas causing scalp alopecia. dermatol ther. 2014;27(4):248-251. 45. agozzino m, noal c, lacarrubba f, ardigò m. monitoring treatment response in psoriasis: current perspectives on the clinical utility of reflectance confocal microscopy. psoriasis (auckl). 2017;7:27-34. 46. agozzino m, russo t, franceschini c, et al. effects of topical piroxicam and sun filters in actinic keratosis evolution and field cancerization: a two-center, assessor-blinded, clinical, confocal microscopy and dermoscopy evaluation trial. curr med res opin. 2019;35(10):1785-1792. 22. segura s, puig s, carrera c, palou j, malvehy j. development of a two-step method for the diagnosis of melanoma by reflectance confocal microscopy. j am acad dermatol. 2009;61(2):216-229. 23. ulrich m, maltusch a, rius-diaz f, et al. clinical applicability of in vivo reflectance confocal microscopy for the diagnosis of actinic keratoses. dermatol surg. 2008;34(5):610-619. 24. cinotti e, labeille b, debarbieux s, et al. dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2018;32(8):1284-1291. 25. guitera p, pellacani g, crotty ka, et al. the impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. j invest dermatol. 2010;130(8):2080-2091. 26. persechino f, de carvalho n, ciardo s, et al. folliculotropism in pigmented facial macules: differential diagnosis with reflectance confocal microscopy. exp dermatol. 2018;27(3):227-232. 27. de carvalho n, farnetani f, ciardo s, et al. reflectance confocal microscopy correlates of dermoscopic patterns of facial lesions help to discriminate lentigo maligna from pigmented nonmelanocytic macules. br j dermatol. 2015;173(1):128-133. 28. couty e, tognetti l, labeille b, et al. in vivo reflectance confocal microscopy combined with the ‘spaghetti technique’ for the identification of surgical margins of lentigo maligna: experience in 70 patients. j eur acad dermatol venereol. 2018;32(9):e366-e368. 29. pellacani g, de carvalho n, ciardo s, et al. the smart approach: feasibility of lentigo maligna superficial margin assessment with hand-held reflectance confocal microscopy technology. j eur acad dermatol venereol. 2018;32(10):1687-1694. 30. cinotti e, fouilloux b, perrot jl, labeille b, douchet c, cambazard f. confocal microscopy for healthy and pathological nail. j eur acad dermatol venereol. 2014;28(7):853-858. 31. agozzino m, buccini p, catricalà c, et al. noninvasive assessment of benign pigmented genital lesions using reflectance confocal microscopy. br j dermatol. 2015;173(5):1312-1315. 32. ardigo m, donadio c, franceschini c, catricalà c, agozzino m. interest of reflectance confocal microscopy for inflammatory oral mucosal diseases. j eur acad dermatol venereol. 2015;29(9):1850-1853. 33. agozzino m, bhasne p, franceschini c, vincenza g, catricalà c, ardigò m. noninvasive, in vivo assessment of oral squamous cell carcinoma. br j dermatol. 2014;170(3):754-756. 34. debarbieux s, perrot jl, erfan n, et al. reflectance confocal microscopy of mucosal pigmented macules: a review of 56 cases dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021059 1 dermoscopic predictors of tumor thickness in cutaneous melanoma: a retrospective analysis of 245 melanomas enrique rodríguez-lomba1, belén lozano-masdemont2, lula maría nieto-benito1, elisa hernández de la torre1, ricardo suárez-fernández1, josé antonio avilés-izquierdo1 1 department of dermatology, hospital general universitario gregorio marañón, madrid, spain 2 department of dermatology, hospital universitario de móstoles, madrid, spain key words: melanoma, breslow index, tumor thickness, dermoscopy, dermatoscopy, epiluminescence microscopy citation: rodríguez-lomba e, lozano-masdemont b, nieto-benito lm, hernández de la torre e, suárez-fernández r, avilés-izquierdo ja. dermoscopic predictors of tumor thickness in cutaneous melanoma: a retrospective analysis of 245 melanomas. dermatol pract concept. 2021;11(3):e2021059. doi: https://doi.org/10.5826/dpc.1103a59 accepted: december 23, 2020; published: may 20, 2021 copyright: ©2021 rodríguez-lomba et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: enrique rodríguez-lomba, md, department of dermatology, hospital general universitario gregorio marañón, c/ dr. esquerdo, 46 – 28007 madrid, spain. email: enriquerlomba@outlook.com introduction: the literature regarding the association of dermoscopic structures with breslow thickness in melanoma is scarce, limited to small case series, and mostly outdated. objective: this study determined the dermoscopic patterns, colors and structures that are associated with melanoma in situ, thin melanomas (<0.8 mm) and thick melanomas potentially requiring sentinel lymph node biopsy according to current guidelines (≥0.8 mm). methods: a retrospective evaluation of 245 dermoscopic images of primary cutaneous melanoma located on the trunk or limbs was performed by consensus of 2 dermoscopists. results: red-pink, blue-gray and white color, blue-white veil, shiny white streaks, irregular vessels, blue-black pigmentation, milky red areas, pseudolacunae, ulceration and rainbow pattern were associated with thickness ≥0.8 mm, whereas atypical pigmented network, regression and hypopigmented areas were significantly associated with early melanomas. limitations: this is a retrospective study performed in a single institution. melanomas of special sites were excluded from our evaluation. dermoscopy is based on subjective evaluations that depend largely on the observers’ experience. conclusions: the identification of certain dermoscopic structures and colors might help in the discrimination between thin and thick melanomas. abstract 2 research | dermatol pract concept. 2021;11(3):e2021059 introduction the literature regarding the association of patterns, colors and dermoscopic structures with breslow thickness in melanoma is scarce, limited to small case series, and mostly based on outdated nomenclature [1-5]. certain specific dermoscopic structures could help in the early identification of melanomas with tumor thickness ≥0.8 mm, potentially eligible for sentinel lymph node biopsy according to current guidelines. on the other hand, one author [6] recently criticized the established recommendation of re-excision of clinical safety margins in thin melanomas that have already been completely excised. according to them, a “personalized excision” approach would be preferable and should be included in future guidelines [6]. dermoscopy could be useful in the identification of sharply confined melanomas with a high probability of tumor thickness <0.8 mm, allowing us to excise them in a single surgical procedure with adjusted margins. the aim of this study was to determine the dermoscopic colors and structures that are associated with both early melanomas (<0.8 mm) and thick melanomas (≥0.8 mm). materials and methods a retrospective evaluation of 245 dermoscopic images of primary cutaneous melanoma was performed. all the dermoscopic images were collected from the database of the melanoma unit in our department. these were obtained using a digital microscopy system comprising a dermlite photo ii pro hr dermoscopy lens [3gen] on an e-420 camera (olympus). the lesion diameter had to be small enough to fit in the whole picture in order to qualify for inclusion. we excluded cases without histopathological confirmation, cases with melanoma metastases, as well as primary melanomas of special sites (facial, acral, nail, genital or mucosal melanoma). images with thick hair density, blood or scales that impeded an adequate dermoscopic evaluation were also excluded. clinical and histopathological data was obtained from patients’ records and included age at diagnosis, sex, anatomical location of the tumor, and tumor diameter, palpability, and breslow thickness. a list of the dermoscopic criteria established by previous publications was evaluated by consensus of 2 blinded expert dermoscopists (j.a.a.i., e.r.l). the following dermoscopic features were analyzed: colors (light brown, dark brown, black, blue-gray, red-pink, white), asymmetry of color and structures, atypical pigmented network, irregular globules, streaks, irregular blotches, shiny white streaks, negative pigment network, blue-white veil, hypopigmented areas, prominent skin markings, structureless brown areas, blue-black pigmentation, milky red areas, rainbow pattern, pseudolacunae, ulceration, and irregular vessels. data were analyzed using spss version 22.0 (32-bits edition). univariate analysis for qualitative variables was performed using pearson’s chi-square test and fisher’s exact test. a p value less than .05 was considered statistically significant. sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were calculated using 2×2 contingency tables. the odds ratio (or) was calculated for all variables with a confidence interval of 95% (95% ci). results a total of 245 melanomas were analyzed. three subtypes were initially defined: melanoma in situ (intraepidermal), thin melanomas (breslow thickness <0.8 mm), and thick melanomas (breslow thickness ≥0.8 mm). the number of cases in each of these groups was 52 (21.2%), 98 (40.0%), and 95 (38.7%), respectively. the mean breslow thickness was 0.98 mm (range, 0-9.00 mm). the median breslow thickness was 0.60 mm, and only 23 melanomas (9.3%) had a breslow thickness larger than 1.5 mm. clinical and epidemiological features are presented in table 1. tumor diameter and palpability were the only clinical variables that showed statistically significant differences (p = .001 for both). all in situ melanomas were non-palpable. less than half of the <0.8 mm melanomas were clinically raised (n = 46; 46.9%), while most of the ≥0.8 mm melanomas were palpable (n = 86; 90.5%). thick melanomas were more frequently larger than 10 mm (73.6%) than were thin melanomas (50.0%) and melanoma in situ (48.1%). there were no significant differences in age at diagnosis (mean ages, 59.13, 57.55 and 59.19 years, respectively) or sex distribution among the groups. melanoma in situ and thin melanomas were slightly more frequent in women (53.8% and 53.1%, respectively), while thick melanomas were more prevalent in men (53.7%). most of the melanomas were located in areas of intermittent sun exposure (n = 225; 91.8%) due to the exclusion criteria in our study design. table 2 summarizes the frequencies of colors and dermoscopic structures within each group. light brown color was more frequent in early melanomas (melanoma in situ and thin melanoma), while blue-gray, red-pink or white color was more commonly observed in thick melanomas (p ˂.05). the presence of three or more colors showed no significant difference between groups. early melanomas presented a higher frequency of atypical pigmented network, regression and hypopigmented areas. shiny white streaks, blue-white veil, blue-black pigmentation, milky red areas, rainbow pattern, pseudolacunae, ulceration, irregular vessels and polymorphous vascular pattern were more frequent in thick melanomas (p ˂ .05). no significant differences were observed in color or structure asymmetry between the three groups. research | dermatol pract concept. 2021;11(3):e2021059 3 table 1. clinical and epidemiological features, by tumor thickness feature melanoma in situ (n = 52) melanoma ˂0.8 mm (n = 98) melanoma ≥0.8 mm (n = 95) p mean age, y 59.13 57.55 59.19 ns ≥65 y, n (%) 23 (44.2) 43 (43.9) 43 (45.3) ns male:female, n (%) 24:28 (46.2:53.8) 46:52 (46.9:53.1) 51:44 (53.7:46.3) ns palpability, n (%) 0 (0) 46 (46.9) 86 (90.5) .001 tumor diameter ≥10 mm, n (%) 25 (48.1) 49 (50.0) 70 (73.6) .001 tumor location, n (%) ns chronic exposure 5 (9.6) 7 (7.1) 2 (2.1) intermittent exposure 45 (86.5) 89 (90.8) 91 (95.8) non-exposed areas 2 (3.8) 2 (2.0) 2 (2.1) ns = not significant. table 2. frequencies of colors and dermoscopic structures, by tumor thickness feature melanoma in situ (n = 52) melanoma ˂0.8 mm (n =98) melanoma ≥0.8 mm (n = 95) p color light brown 50 (96.2) 93 (94.9) 78 (82.1) .003 dark brown 49 (94.2) 92 (93.9) 79 (83.2) .240 black 34 (65.4) 47 (48.0) 55 (57.9) .104 blue-gray 22 (42.3) 58 (59.2) 77 (81.1) .000 red-pink 6 (11.5) 22 (22.4) 49 (51.6) .000 white three or more colors 6 (11.5) 42 (80.8) 23 (23.5) 81 (82.7) 41 (43.2) 84 (88.4) .000 .383 atypical pigmented network 36 (69.2) 41 (41.8) 33 (34.7) .000 irregular globules 22 (42.3) 51 (52.0) 37 (38.9) .172 irregular blotches 22 (42.3) 54 (55.1) 40 (42.1) .139 regression 21 (40.4) 47 (48.0) 24 (25.3) .004 shiny white streaks 9 (17.3) 35 (35.7) 52 (54.7) .000 hypopigmented areas 8 (15.4) 15 (15.3) 6 (6.3) .104 streaks 7 (13.5) 23 (23.5) 18 (18.9) .333 prominent skin markings 6 (11.5) 7 (7.1) 5 (5.3) .376 structureless brown areas 5 (9.6) 13 (13.3) 15 (15.8) .576 blue-white veil 4 (7.7) 17 (17.3) 55 (57.9) .000 negative pigment network 4 (7.7) 7 (7.1) 7 (7.4) .992 irregular vessels 4 (7.7) 21 (21.4) 41 (43.2) .000 blue-black pigmentation 3 (5.8) 5 (5.1) 18 (18.9) .003 milky red areas 2 (3.8) 14 (14.3) 34 (35.8) .000 ulceration 0 (0) 4 (4.1) 35 (36.8) .000 rainbow pattern 0 (0) 6 (6.1) 25 (26.3) .000 pseudolacunae 0 (0) 3 (3.1) 23 (24.2) .000 two cohorts were grouped for the calculation of sensitivity, specificity, ppv, npv and or: early melanomas (n = 150) and thick melanomas (n = 95). results are presented in table 3. the presence of three or more colors presented the highest sensitivity (88.4%) for a thickness ≥0.8 mm, although most of the criteria showed sensitivity values lower than 50%. most of the criteria showed higher than 80% specificity for ≥0.8 mm tumor thickness. the highest specificity was obtained for pseudolacunae (98.0%), ulceration (96.7%) and rainbow pattern (95.3%). ppv was highest for 4 research | dermatol pract concept. 2021;11(3):e2021059 ulceration (87.5%) and pseudolacunae (88.5%), whereas the other features showed low values. npv was lower than 80% for all dermoscopic features. the following colors and structures were associated with melanoma thickness ≥0.8 mm: red-pink (or = 4.641), blue-gray (or = 3.743), white (or = 3.168), blue-white veil (or = 8.446), shiny white streaks (or = 2.913), irregular vessels (or = 3.796), blue-black pigmentation (or = 4.149), milky red areas (or = 4.668), pseudolacunae (or = 15.653), ulceration (or = 16.917) and rainbow pattern (or = 7.296). on the other hand, atypical pigmented network (or = 5.505), regression (or = 0.408) and hypopigmented areas (or = 0.372) were significantly associated with early melanomas. discussion argenziano et al [1] reported for the first time in 1997 the differences of colors and dermoscopic structures in a case series of 72 melanomas (41 thin melanomas <0.75 mm, 31 thick melanomas ≥0.75 mm). the authors reported a higher frequency of pigment network, radial streaming and white scar-like areas in thin melanomas, whereas gray-blue areas, structural asymmetry and a vascular pattern were more frequent in thick melanomas. a significant association between the presence of a pigment network and thin melanomas was noted, as well as gray-blue areas and a vascular pattern in thick melanomas. these findings were confirmed in a study of 84 melanomas by stante et al [2]. a few attempts have been made to reliably predict tumor thickness by dermoscopy, such as the clinical-dermoscopic algorithm published in 1999 by argenziano et al [3]. the authors reported that the combination of palpability, tumor diameter ≥15 mm, pigment network, gray-blue areas, and atypical vascular pattern increased the prediction accuracy by 14% compared to palpability alone and 9% compared to dermoscopy alone. others have tried to apply well-known table 3. diagnostic accuracy of colors and dermoscopic structures for tumor thickness ≥0.8 mm feature sens. spec. ppv npv or (95% ci) color red-pink 51.6 81.3 63.6 72.6 4.641 (2.611-8.242) blue-gray 46.7 81.1 49.0 79.5 3.743 (2.044-6.853) white 43.2 80.7 58.6 69.1 3.168 (1.785-5.626) black 57.9 46.0 40.4 63.3 1.123 (0.632-1.965) dark brown 83.2 6.0 35.9 36.0 0.315 (0.133-0.740) light brown three or more colors 82.1 88.4 4.7 18.0 35.3 40.6 29.2 71.1 0.225 (0.081-0.562) 1.676 (0.789-3.563) asymmetry of colors 78.9 22.7 39.3 63.0 1.099 (0.589-2.051) asymmetry of structures 78.9 16.0 37.3 54.5 0.714 (0.370-1.380) ulceration 36.8 96.7 87.5 70.7 16.917 (6.326-45.265) pseudolacunae 24.2 98.0 88.5 67.1 15.653 (4.549-53.854) blue-white veil 57.9 86.0 72.4 76.3 8.446 (4.568-15.67) rainbow pattern 26.3 95.3 78.1 67.1 7.296 (3.018-17.687) milky red areas 35.8 89.3 68.0 68.7 4.668 (2.395-9.096) blue-black pigmentation 18.9 94.7 69.2 64.8 4.149 (1.724-9.983) irregular vessels 43.2 83.3 62.1 69.8 3.796 (2.102-6.855) shiny white streaks 54.7 70.7 54.2 71.1 2.913 (1.702-4.973) structureless brown areas 15.8 88.0 45.5 62.3 1.375 (0.656-2.880) negative pigment network 7.4 92.7 38.9 61.2 1.005 (0.376-2.690) streaks 18.9 80.0 37.5 60.9 0.935 (0.488-1.792) irregular blotches 42.1 49.3 34.5 57.4 0.708 (0.422-1.189) irregular globules 38.9 51.3 33.6 57.0 0.673 (0.399-1.134) prominent skin markings 5.3 91.3 27.8 60.4 0.585 (0.202-1.699) atypical pigmented network 34.7 48.7 30.0 54.1 0.505 (0.295-0.856) regression 25.3 54.7 26.1 53.6 0.408 (0.238-0.717) hypopigmented areas 6.3 84.7 20.7 58.8 0.372 (0.149-0.950) sens. = sensitivity; spec. = specificity; ppv = positive predictive value; npv = negative predictive value; or = odds ratio; ci = confidence interval. research | dermatol pract concept. 2021;11(3):e2021059 5 table 4. significant associations between specific dermoscopic features and breslow thickness melanoma ˂0.8 mm melanoma ≥0.8 mm colors light brown red-pink blue-gray white dermoscopic features atypical pigmented network regression hypopigmented areas blue-white veil shiny white streaks irregular vessels blue-black pigmentation milky red areas rainbow pattern pseudolacunae ulceration dermoscopic algorithms to predict tumor thickness. the abcd rule had an adequate performance in predicting tumor thickness in a series of 84 cutaneous melanomas when a total dermatoscopy score (tds) cut-off of 6.80 was applied [4]. despite the initially promising results of the preoperative assessment of melanoma thickness by dermoscopy, few studies of this approach have been published since then. nomenclature in dermoscopy has expanded over the past decade, and the impact of some dermoscopic structures has not yet been studied. melanoma guidelines have been updated, and 0.8 mm is now considered the cut-off between t1a and t1b melanomas [7]. the present study expands on this literature and updates it with updated nomenclature. in addition, our study had a bigger sample than previous studies, and we investigated a larger variety of dermoscopic structures. the only clinical features that reached statistical significance were tumor size ≥10 mm, a slightly lower cut-off than 15 mm as previously reported [3], and palpability. although in situ melanomas were all non-palpable and more than 90% of the >0.8 mm thick melanomas were clearly palpable, 46.9% of the early invasive melanomas (<0.8 mm) were also palpable. the analysis of this single parameter would have classified these thin melanomas as thick when they were not, and on the contrary, 9.5% of thick melanomas would have been wrongly classified as thin. table 4 presents the colors and structures associated with melanomas <0.8 mm and ≥0.8 mm. thin melanomas were associated with light brown color whereas thick melanomas were associated not only with blue-gray color, but also red-pink and white. however, the clinical and dermoscopic evaluation of colors must take into account the area of examination, both histologically and dermoscopically. it is not uncommon for melanomas, especially superficial-spreading subtypes, to present areas of different thickness throughout their width. thick melanomas may show light brown areas in their periphery, and blue areas in the thicker center that must always be considered. no statistically significant differences were observed regarding asymmetry of color or structures, unlike a previous study based on digital analysis [8]. this discrepancy might be related to a more rigid interpretation of asymmetry by computerized algorithms than the human eye. atypical pigmented network, regression and hypopigmented areas were associated with early melanomas here (figure 1) as in previous reports [1, 2]. ulceration, pseudolacunae, blue-white veil, milky red areas, irregular vessels, blue-black pigmentation and shiny white streaks were associated with a melanoma tumor thickness ≥0.8 mm (figure 2). the latter has already been reported to be associated with thicker melanomas in a case series of 144 melanomas [9]. the evaluation of figure 1. dermoscopic predictors of thin melanoma (<0.8 mm tumor thickness). (a) atypical pigmented network. (b) regression. (c) hypopigmented areas. 6 research | dermatol pract concept. 2021;11(3):e2021059 dermoscopic structures should consider the same principles mentioned previously in color evaluation. mun et al [10] recently reported the dermoscopic differences between thin and thick acral melanomas (<2 vs. >2 mm) in a cohort of 75 cases. the authors concluded that blue (or = 7.09), white (or = 5.04), atypical vessels (or = 34.58), blue-white veil (or = 9.60) and ulceration (or = 5.08) were associated with thick acral melanomas. while our study specifically excluded acral melanomas, most of our results are consistent with theirs. the combination of dermoscopy and other imaging techniques such as optical coherence tomography, multispectral imaging and high-frequency ultrasonography could further enhance the preoperative assessment of melanoma patients towards “personalized medicine”. together with palpability and these specific dermoscopic findings, they could allow a fairly precise tumor thickness prediction. however, caution is recommended before the excision of early melanomas in a single surgical procedure. to date, clinical guidelines do not have a recommendation for this approach, and further evidence is required before standardization. it should be limited to cases with a high malignancy suspicion, and not done in doubtful cases, in order to minimize the risk of causing unnecessary, large scars in benign lesions. the benefits and risks of performing a single-step surgery on a patient need to be adequately addressed before proceeding. limitations of our study are its retrospective nature and single-institution design. melanomas of special sites were excluded from our evaluation. dermoscopy is based on subjective evaluations that depend largely on the observers’ experience. larger prospective studies focusing on the reliability of the combination of certain colors and structures are required to confirm and validate our findings. conclusions certain dermoscopic structures and colors might help in the discrimination between thin and thick melanomas. although none of them are entirely specific to either group, the combination of more than one of them in a single lesion increases the probability of an adequate tumor thickness prediction. for example, pigmented lesions presenting palpable blue-white veil, milky red areas and ulceration are unlikely to be early melanomas. on the other hand, lesions presenting an atypical pigmented network and small foci of regression without any other dermoscopic features are very unlikely to be >0.8 mm thickness. the reliability of the combination of certain dermoscopic colors and structures is to be determined, and should be the subject of future studies. references 1. argenziano g, fabbrocini g, carli p, de giorgi v, delfino m. epiluminescence microscopy: criteria of cutaneous melanoma progression. j am acad dermatol. 1997;37(1):68-74. doi: 10.1016/s0190-9622(97)70213-5. 2. stante m, de giorgi v, cappugi p, gianotti b, carli p. non-invasive analysis of melanoma thickness by means of dermoscopy: a retrospective study. melanoma res. 2001;11(2):147-152. doi: 10.1097/00008390-200104000-00009. pmid: 11333124. 3. argenziano g, fabbrocini g, carli p, de giorgi v, delfino m. clinical and dermatoscopic criteria for the preoperative evaluation of cutaneous melanoma thickness. j am acad dermatol. 1999;40(1):61-68. doi: 10.1016/s0190-9622(99)70528-1. 4. carli p, de giorgi v, palli d, giannotti v, giannotti b. preoperative assessment of melanoma thickness by abcd score of dermatoscopy. j am acad dermatol. 2000;43(3):459-466. doi: 10.1067/mjd.2000.106518. pmid: 10954657. figure 2. dermoscopic predictors of thick melanoma (≥0.8 mm tumor thickness). (a) blue-black pigmentation. (b) blue-white veil. (c) shiny white streaks. (d) irregular vessels. (e) rainbow pattern. (f) milky red areas. (g) ulceration. (f) pseudolacunae. research | dermatol pract concept. 2021;11(3):e2021059 7 5. de giorgi v, carli p. dermoscopy and preoperative evaluation of melanoma thickness. clin dermatol. 2002;20(3):305-308. doi: 10.1016/s0738-081x(02)00224-9. 6. weyers w. “personalized excision” of malignant melanoma-need for a paradigm shift in the beginning era of personalized medicine. am j dermatopathol. 2019;41(12):884-896. doi: 10.1097/ dad.0000000000001450. pmid: 31490196. 7. balch cm, gershenwald je, soong s, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199-6206. doi: 10.1200/jco.2009.23.4799. pmid: 19917835. 8. rubegni p, cevenini g, sbano p, et al. evaluation of cutaneous melanoma thickness by digital dermoscopy analysis: a retrospective study. melanoma res. 2010;20(3):212-217. doi: 10.1097/ cmr.0b013e328335a8ff. pmid: 20375922. 9. verzi ae, quan vl, walton ke, et al. the diagnostic value and histologic correlate of distinct patterns of shiny white streaks for the diagnosis of melanoma: a retrospective, case-control study. j am acad dermatol. 2018;78(5):913-919. doi: 10.1016/j. jaad.2017.11.021. pmid: 29138058. 10. mun jh, jo g, darmawan cc, et al. association between breslow thickness and dermoscopic findings in acral melanoma. j am acad dermatol. 2018;79(5):831-835. doi: 10.1016/j. jaad.2018.06.004. pmid: 29906546. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020040 1 dermatology practical & conceptual introduction trichotillomania is a self-induced hair loss originating from pulling of one’s own hair repetitively in a compulsive manner, leading to significant hair loss. although scalp hair is the most common site of involvement, it is also reported in other hair-bearing areas of the body such as eyelashes, eyebrows, and beard. trichoscopic criteria have been well described for scalp trichotillomania including mainly broken hairs at different lengths, short hairs with trichoptilosis, coiled hairs, hook hairs, tulip hairs, flame hairs, and v-sign [1]. yet, to our knowledge there are no data regarding the trichoscopic features of this alopecia on eyebrows. case presentation a 40-year-old man presented with a years-long history of numerous nevi. while he was being examined by a computerized polarized light videodermatoscope (fotofinder dermoscope; teachscreen software gmbh, bad birnbach, germany), almost complete loss of his eyebrows was noticed. dermatological examination showed a few hairs on the lateral sides, while there were just black dots and some broken hairs on the remaining part of the eyebrows (figure 1). trichoscopic examination revealed various findings, namely broken hairs at different lengths, coiled hairs, hook hairs, short hairs with trichoptilosis, v-sign, flame hairs, tulip hairs, black dots, and a few yellow dots (figure 2, a and b). after we took a careful history, he reported that he had been pulling out his eyebrow hairs during stressful times for the past 4 years. conclusions the main clinical differential diagnosis of trichotillomania is patchy alopecia areata. however, it creates a diagnostic chaltrichoscopic features of eyebrow trichotillomania: it looks similar to scalp trichotillomania a. tülin güleç1 1 department of dermatology and venereology, başkent university faculty of medicine, ankara, turkey key words: eyebrow, trichoscopy, trichotillomania, dermoscopy citation: güleç at. trichoscopic features of eyebrow trichotillomania: it looks similar to scalp trichotillomania. dermatol pract concept. 2020;10(2):e2020040. doi: https://doi.org/10.5826/dpc.1002a40 accepted: december 11, 2019; published: april 3, 2020 copyright: ©2020 güleç. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: prof. dr. a. tülin güleç, başkent university faculty of medicine, department of dermatology and venereology, mareşal fevzi çakmak cad., 53. sokak, no:48, kat: 4, bahçelievler, ankara, turkey. email: tulinogulec@hotmail.com figure 1. eyebrow trichotillomania. almost complete loss of eyebrows with a few hairs on the lateral sides, and black dots with some broken hairs on the remaining main part. https://doi.org/10.5826/dpc.1002a40 mailto:tulinogulec@hotmail.com 2 letter | dermatol pract concept 2020;10(2):e2020040 trichoscopic features of scalp trichotillomania and confirmed it by the appropriate history. consequently, we suggest that trichoscopy is also beneficial for the clinical diagnosis of eyebrow trichotillomania. references 1. martin jm, montesinos e, cordero p, gonzalez v, ramon d. trichoscopic features of trichotillomania. pediatr dermatol. 2019;36(2):265-267. 2. velez n, khera p, english jc 3rd. eyebrow loss: clinical review. am j clin dermatol. 2007;8(6):337-346. lenge in particular when it occurs on a body site other than the scalp, and/or if the patient denies the habit of hair pulling. besides, eyebrow alopecia may be secondary to numerous causes such as hypothyroidism, chemotherapy, secondary syphilis, leprosy, and frontal fibrosing alopecia in addition to alopecia areata [2]. furthermore, trichoscopic findings are not necessarily identical in alopecias that can involve both scalp and eyebrow hairs, as in frontal fibrosing alopecia. it presents red or gray dots on the eyebrow area, while loss of follicular openings, perifollicular erythema, and scaling are the main features on the frontal scalp. yet, in the present case, we could easily diagnose trichotillomania when we observed identical figure 2. trichoscopic features of eyebrow trichotillomania. (a) black dots (red arrows), broken hairs at different lengths (green arrows), yellow dot (orange arrow), hook hair (blue arrow), tulip hairs (yellow arrow), v-sign (purple arrow). (b) broken hairs at different lengths (green arrows), hook hair (blue arrow), flame hair (red star), tulip hair (yellow arrow), v-sign (purple arrow), yellow dot (orange arrow), short hairs with trichoptilosis (blue stars), black dot (red arrow) (original magnifications: a,b, ×20). dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020056 1 dermatology practical & conceptual introduction urticarial vasculitis presents with urticarial wheals and/or angioedema, often with purpura and ecchymotic stain. it can be associated with physical urticaria and appears more frequently in the pressure sites [1]. urticarial vasculitis is most often idiopathic, although it has been described in association with connective tissue diseases (systemic lupus erythematosus and sjögren syndrome), neoplasia (monoclonal gammopathy and lymphoma), chronic viral infection, drugs, and serum sickness‐like diseases [1]. herein we report a case of gravitational urticarial vasculitis induced by standing and sitting more than 15 minutes. case presentation a 31-year-old man presented with painful and/or pruritic erythematous wheals on his legs after about 30 minutes standing, since childhood (6-7 years old). the wheals resolved within 3 to 4 days of rest. he did not complain of fever, arthritis, or malaise. his medical history was not significant. his father, aunt, and 2 cousins had similar symptoms and history, which improved after several years. as a provocation test, the patient was asked to hang one of his legs over the site of a chair and to bend the other leg. after 15 minutes, painful erythematous edematous plaques appeared on the hanging leg (figure 1). a skin lesion punch biopsy revealed perivascular lymphocytic and neutrophilic infiltration extending to deep dermis and subcutaneous tissue and vasculitis involving small to medium-sized blood vessels (figure 2). further evaluations including antinuclear antibody, antineutrophil cytoplasmic antibody, antiphospholipid, viral markers, serum complement, and cryoglobulin level were normal. the patient had received hydroxyzine, fexofenadine, and cetirizine, but they were ineffective, so we prescribed colchicine 1 mg/day, which was effective; the patient was lesion-free when he was on treatment. after 1 month’s treatment the patient discontinued colchicine and did not return for follow-up. a young man with gravitational urticarial vasculitis ali sadeghinia,1 jafar taghizade,2 nooshin dolatyabi,1 amir-hooshang ehsani,1 pedram noormohmadpour,1 anahita rostami1 1 department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran 2 department of dermatopathology, razi hospital, tehran university of medical sciences, tehran, iran key words: gravitational urticarial vasculitis, physical urticaria citation: sadeghinia a, taghizade j, dolatyabi n, ehsani a, noormohmadpour p, rostami a. a young man with gravitational urticarial vasculitis. dermatol pract concept. 2020;10(3):e2020056. doi: https://doi.org/10.5826/dpc.1003a56 accepted: february 27, 2020; published: june 29, 2020 copyright: ©2020 sadeghinia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: anahita rostami, md, department of dermatology, razi hospital, tehran university of medical sciences, vahdat islami square, tehran 1199663911, iran. email: annahitarostami@gmail.com https://doi.org/10.5826/dpc.1003a56 mailto:annahitarostami@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020056 references 1. monroe ew. urticarial vasculitis: an updated review. j am acad dermatol. 1981;5(1):88-95. https://doi.org/10.1016/ s0190-9622(81)70080-x 2. hirohata a, yamaoka t, hayashi m, tani m, katayama i. unique case of postural cholinergic urticaria induced by a standing position. clin exp dermatol. 2016;41(4):439-440. https://doi. org/10.1111/ced.12796 by antineutrophil agents. we speculate that increasing intravascular pressure leads to microvascular endothelial damage and triggers extravasation of immune cells (including neutrophils and lymphocytes) and vascular damage in susceptible cases. examination of further cases and recognition of clinical aspects will afford a better understanding of the underlying mechanisms. conclusions it is known that urticarial vasculitis more frequently develops at pressure sites, but it is unusual to develop after standing or changing position [1]. hirohata et al reported a case of postural cholinergic urticaria induced by a standing position, the same as our patient. histopathological evaluation revealed mild perivascular lymphocytic infiltration, but there was no evidence of vasculitis [2]. this is a case of urticarial vasculitis induced by gravity with an unusual clinical presentation, which was managed figure 2. (a) soft tissue edema within the deep dermis and around eccrine coil (h&e, ×4). (b) lymphocytic and neutrophilic perivascular infiltration (h&e, ×10). (c) fibrin deposition and extravasation of red blood cells in favor of small vessel vasculitis (h&e, ×40). figure 1. development of urticarial plaques on the right leg after 15 minutes of the leg hanging. https://doi.org/10.1016/s0190-9622(81)70080-x https://doi.org/10.1016/s0190-9622(81)70080-x https://doi.org/10.1111/ced.12796 https://doi.org/10.1111/ced.12796 dermatology: practical and conceptual 322 letter | dermatol pract concept 2019;9(4):21 dermatology practical & conceptual introduction pink lesions can be clinically challenging to diagnose, and dermoscopy can be useful to better characterize them. we describe clinical and dermoscopic features of 3 neurothekeomas, rare pink tumors of which only 2 dermoscopic descriptions are available. case presentation the first case concerned a 45-year-old woman affected by multiple sclerosis, who came to our observation for an asymptomatic nodule on her left forearm, slow-growing for 10 months. clinical examination showed a pinkish nodule of approximately 1 cm in size, fixed and soft at palpation, with a macroscopically detectable arborizing vessel (figure 1a). dermoscopy revealed pink ovoid areas in the center surrounded by a whitish halo on a yellowish background (figure 1b). histological examination showed a dermal multilobular unencapsulated mass, extending to subcutis, composed of spindle cells dispersed in a large amount of myxoid stroma, a description that allowed the diagnosis of mixed neurothekeoma (cellular and myxoid) (figure 1c). the second and third case corresponded to slow-growing asymptomatic nodular pinkish lesions, located on the right shoulder of a 58-year-old man (figure 1d) and on the ala nasi of a 14-year-old girl (figure 1g). dermoscopy showed 2 flesh-colored lesions with irregular linear and arborizing thin and thick vessels (figure 1, e and h). in both cases, histological examination was essential for the diagnosis of mixed neurothekeoma (figure 1, f, i, and j). discussion the term neurothekeoma was coined in 1980 by gallagher and helwig with reference to a rare dermal benign tumor originating from the sheath of peripheral nerves. until now, histogenesis remains a tough question: neuroectodermal, fibrohistiocytic, and myofibroblastic derivation have been neurothekeomas: dermoscopic features of 3 cases irene campana1, elisa cinotti1, paolo broganelli2, alessandro di stefani3, emanuele trovato1, luca provvidenziale1, roberto perotti1, arianna lamberti1, pietro rubegni1 1 dermatology section, department of medical science, surgery and neurological sciences, university of siena, siena, italy 2 a.o.u., città della salute e della scienza di torino, turin, italy 3 institute of dermatology, fondazione policlinico universitario a. gemelli irccs, rome, italy key words: neurothekeomas, dermoscopy, dermatopathology, skin tumors citation: campana i, cinotti e, broganelli p, di stefani a, trovato e, provvidenziale l, perotti r, lamberti a, rubegni p. neurothekeomas: dermoscopic features of 3 cases. dermatol pract concept. 2019;9(4):322-324. doi: https://doi.org/10.5826/dpc.0904a21 accepted: july 3, 2019; published: october 31, 2019 copyright: ©2019 campana et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: irene campana, md, department of medical, surgical and neurological science, dermatology section, university of siena, s. maria alle scotte hospital, viale bracci 16, 53100 siena, italy. email: irenecamp89@gmail.com letter | dermatol pract concept 2019;9(4):21 323 among nodular basal cell carcinoma mimickers because it can show arborizing vessels that are notoriously a hallmark of this tumor [2]. moreover arborizing vessels can also be found in other amelanotic nodular skin tumors, such as merkel cell carcinoma and adnexal tumors, which should also be considered among the differential diagnosis on dermoscopy. our observation adds new dermoscopic findings to neurothekeoma that could represent integrating clues for its diagnosis: pinkish areas surrounded by a whitish halo and a yellowish background. the latter could be related to the amount of myxoid component; pinkish areas, instead, could reflect the peculiar lobular morphology of our tumor encircled by fibrosis. proposed. on the basis of the amount of myxoid matrix and the immunohistochemical pattern, 3 histopathological variants are recognized: cellular, myxoid, and mixed. clinical diagnosis is challenging and neurothekeoma is often mistaken for basal cell carcinoma, achromic melanoma, spitz nevus, or adnexal tumor (mainly pilomatricoma). dermoscopic features of neurothekeoma have been previously reported in only 2 cases of myxoid [1] and cellular [2] variant. both tumors were characterized by well-focused arborizing vessels, and one [1] was also connoted by a whitish area and white clods that were related to fibrotic septa and peripheral fibrosis of the tumor. our cases confirmed that neurothekeoma should be included figure 1. clinical, dermoscopic, and histological features of 3 neurothekeomas. case 1: (a) pink nodule. (b) dermoscopy shows pink ovoid areas in the center surrounded by a whitish halo and a yellowish background. (c) histological examination (h&e stain ×100) shows a mixed neurothekeoma: plexiform architecture in which each single nodule appears variable in size, separated from the others by fibrous septa and composed of areas of myxoid substance with proliferation of spindle cells at the periphery. case 2: (d) pink nodule. (e) dermoscopy shows irregular linear and arborizing vessels on a homogeneous pink-whitish background. (f) histological examination (h&e ×50) shows a mixed type neurothekeoma: a poorly circumscribed lobular mass involving reticular dermis and subcutis, with small nests and fascicles of short spindle cells in a variable myxomatous stroma separated by thin fibrous septa which correspond to sclerotic collagen bundles. case 3: (g) pink nodule. (h) dermoscopy reveals thick, well-focused arborizing vessels, irregular linear vessels, and some white areas on a dull pink background. (i) histological examination (h&e ×100) shows a mixed type neurothekeoma with nests and fascicles of spindle and epithelioid cells that sometimes have a concentric or whirling arrangement and a myxoid stroma; neoplastic cells (j) (h&e ×400) are recognized for their pale eosinophilic cytoplasm, their vesicular nuclei, and their indistinct cell membranes. [copyright: ©2019 campana et al.] 324 letter | dermatol pract concept 2019;9(4):21 references 1. cavicchini s, guanziroli e, del gobbo a, scaparro m, gianotti r. neurothekeoma, a hard to diagnose neoplasm among red nodules. australas j dermatol. 2018;59(4):e280-e282. 2. aydingoz ie, mansur at, dikicioglu-cetin e. arborizing vessels under dermoscopy: a case of cellular neurothekeoma instead of basal cell carcinoma. dermatology online j. 2013;19(3):5. conclusions neurothekeoma should be included in the maze of differential diagnoses of pink lesions and in particular among mimickers of basal cell carcinoma on dermoscopy. nevertheless, further cases are needed to establish the diagnostic value of white areas and pinkish areas surrounded by a whitish halo and yellowish background. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(3): e2021021 1 clear cell acanthoma with melanophages simulating a spitz nevus thaís andrade de oliveira1, gabriella brancaccio2, ilenia d’ambra2, andrea ronchi3, francesca pagliuca3, giuseppe argenziano2 1 department of dermatology, faculdade de medicina de jundiaí, são paulo, brazil. 2 dermatology unit, university of campania “l. vanvitelli”, naples, italy 3 pathology unit, department of mental and physical health and preventive medicine, university of campania “l. vanvitelli”, naples, italy. key words: dermoscopy, skin neoplasm, pigmented clear cell acanthoma, pathology citation: de oliveira ta, brancaccio g, d’ambra i, ronchi a, pagliuca f, argenziano g. clear cell acanthoma with melanophages simulating a spitz nevus. dermatol pract concept. 2021; 11(3): e2021089. doi: https://doi.org/10.5826/dpc.1103a89 accepted: february 14, 2021; published: july 8, 2021 copyright: ©2021 de oliveira et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none authorship: all authors have contributed significantly to this publication corresponding author: thaís andrade de oliveira, department of dermatology, faculdade de medicina de jundiaí, são paulo, brazil. e-mail: thaisandrade8@gmail.com introduction clear cell acanthoma (cca) is an unusual and benign epidermal tumor that is usually found on the limbs as a solitary reddish papule. other variants include polypoid, giant, multiple, eruptive, and pigmented clear cell acanthoma. the typical dermoscopic pattern, known as “string of pearls”, is characterized by dotted and glomerular vessels in a mesh-like or serpiginous arrangement [1]. here, we describe a clear cell acanthoma with melanophages, dermoscopically mimicking a spitzoid melanocytic tumor. case presentation a 22-year-old woman presented a slightly elevated, brownish, oval papule measuring 3 x 4 mm located on her right shoulder (figure 1a). the dermoscopic findings were equivocal, revealing brown globules with regular distribution and a brown blotch at the periphery (figure 1b). the first hypothesis was that of a spitz nevus, and excision was indicated. histological examination (h&e stain) revealed an epithelial tumor characterized by psoriasiform hyperplasia, parakeratosis, and large keratinocytes with pale cytoplasm. some melanophages were evident at the level of the superficial dermis (figure 2). thus, a clear cell acanthoma (cca) with melanophages was diagnosed. discussion pigmented cca was first described by langer et al [2], who reported 5 cases of macroscopically pigmented forms. microscopically, the authors found pale glycogen-containing keratinocytes, increased number of melanocytes containing melanin granules among the tumoral keratinocytes and, most importantly, large melanophages clumps between tumor nests in papillary dermis, characteristic of the pigmented variant. in 2 image letter | dermatol pract concept. 2021;11(3): e2021021 figure 1. (a) a slightly elevated, brownish, oval papule measuring about 3 x 4 mm located on the right shoulder. (b) on dermoscopy, the lesion showed brown globules with regular distribution, and a kind of a blotch at 6 hours. figure 2. (a) epithelial tumor showing psoriasiform hyperplasia, parakeratosis, and pale cytoplasm of keratinocytes (h&e, x40). (b) some melanophages were present in the superficial dermis (h&e, x100). table 1. pigmented cca: dermoscopic descriptors authors dermoscopy descriptors saeki et al, 2014 homogeneous brown-to-black pigmentation with peripheral regular network. kiyohara et al, 2019 homogeneous brown pigmentation with a peripheral dark red area, that corresponds to a string of pearls pattern. oliveira et al, 2020 brown globules with regular distribution over homogeneous brown pigmentation. the present case, the lesion appeared clinically pigmented due to the presence of melanophages in papillary dermis, rather than the presence of melanocytes in the context of the lesion. overall, 12 cases of pigmented cca have been described in the literature. scheinfeld [1], reported a glistening brown nodule which was diagnosed as a pigmented cca, and jacyk et al [2], reported a case of a man with multiple pigmented cca, 4 in total. both reports lacked a dermoscopic appearance description. later, saeki et al [1], described a pigmented cca located on the finger. this was dermoscopically characterized by a homogeneous brown-to-black pigmentation with peripheral regular network, simulating a pigmented nevus. finally, kiyohara et al [1], published the first case of a pigmented cca with a string of pearls pattern visible on dermoscopy. table 1 shows the dermoscopic descriptors that have already been reported in the literature, including ours. in conclusion, pigmented cca is a rare variant of an uncommon benign tumor with unspecific dermoscopic features, whose diagnosis is usually done relying on histological findings. image letter | dermatol pract concept. 2021;11(3): e2021021 3 references 1. kiyohara t, shijimaya t, miyamoto m et al. pigmented clear cell acanthoma with a string of pearls pattern on dermoscopy: the first case demonstrating visualization. j dermatol. 2019; 46 (7): e258-e259. doi: 10.1111/1346-8138.14773. 2. jacyk wk, baran w, essop a. multiple pigmented clear cell acanthoma in an african patient. j eur acad dermatol venereol. 2016; 30(3):494-6. doi: 10.1111/jdv.12882. dermatology: practical and conceptual research | dermatol pract concept 2015;5(1):2 11 dermatology practical & conceptual www.derm101.com dermatoscopic imaging of skin lesions by high school students: a cross-sectional pilot study michael a. marchetti1, maira fonseca1, stephen w. dusza1, alon scope1,2, alan c. geller3, marilyn bishop4, ashfaq a. marghoob1, susan a. oliveria1, allan c. halpern1 1 dermatology service, memorial sloan kettering cancer center, new york, new york, usa 2 department of dermatology, sheba medical center and sackler school of medicine, tel aviv university, tel aviv, israel 3 harvard school of public health, social and behavioral sciences, boston, massachusetts, usa 4 school health services, framingham public schools, framingham, massachusetts, usa key words: dermoscopy, dermatoscopy, dermoscopy, education; dermoscopy, methods, photography, photography, education, teledermatology, teledermoscopy, teledermatoscopy citation: marchetti ma, fonseca m, dusza sw, scope a. geller ac, bishop m, marghoob aa, oliveria sa, halpern ac. dermatoscopic imaging of skin lesions by high school students: a cross-sectional pilot study. dermatol pract concept 2015;5(1):2. doi: 10.5826/ dpc.0501a02 received: may 16, 2014; accepted: august 29, 2014; published: january 30, 2015 copyright: ©2015 marchetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: research reported in this publication was supported by the national institute of arthritis and musculoskeletal and skin diseases of the national institutes of health under award number r01-ar049342. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. competing interests: the authors have no conflicts of interest to disclose. all persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication. corresponding author: michael a. marchetti, md, dermatology service, memorial sloan kettering cancer center, 160 east 53rd street, 2nd floor, new york, ny 10022, usa tel. 212-610-0770; fax. 212-308-0739. email: marchetm@mskcc.org background: the ability of novices to perform imaging of skin lesions is not well studied. objectives: to determine the ability of 12th grade high school students without formal training to take clinical and dermatoscopic images of skin lesions on patient-actors. patients/methods: nineteen participants were divided into 11 gender-specific groups of 1-2 students. groups were provided written instructions and assessed in their ability to (a) identify 8 pre-specified skin lesions, (b) take overview clinical images, and (c) take contact, polarized dermatoscopic images. groups captured the same images twice using two different cameras [nikon tm 1 j1 / veos hd1 and a veos ds3 (canfield scientific, inc.)]. the sequence of camera use was determined using block randomization. if students made visibly poor skin contact during dermatoscopic imaging using their first camera, study investigators provided verbal instructions to place the second camera directly onto the skin. students completed anonymous surveys before and after the imaging activity. results: students were proficient at identifying the correct pre-specified skin lesions (86/88, 98%), capturing sufficient quality overview clinical images of the back and legs (41/42, 98%), and taking dermatoscopic images of the entire skin lesion (174/176, 99%). regarding dermatoscopic image quality, 116 of 175 (66%) images were in focus. out of focus images were attributed to poor skin contact. groups that received feedback (n=4) were able to obtain a significantly higher proportion of in focus dermatoscopic images using their second camera compared to their first camera (16% to 72%, p<0.001). conclusions: we identified several barriers that exist for participant-acquired dermatoscopic imaging. instructions emphasizing the importance of skin contact are useful. our results may help guide future patient-acquired teledermatoscopy efforts. abstract mailto:marchetm@mskcc.org 12 research | dermatol pract concept 2015;5(1):2 introduction the incidence of melanoma continues to increase in many countries [1-3]. dermatoscopy has been shown to significantly improve the diagnostic accuracy of physicians for primary cutaneous melanoma [4,5]. patient-acquired dermatoscopy has been suggested as a possible means to improve the ability of patients to detect melanoma during skin self-examination (sse) [6]. a majority of melanomas are self-detected and laypersons’ sensitivity for melanoma detection has been found to be higher with dermatoscopic images than with clinical photographs [7,8]. more recently, patient-acquired teledermatoscopy has been studied among adult patients at high risk for melanoma as a means to improve and complement sse [9]. in two pilot studies, janda et al found that patientacquired teledermatoscopy is a feasible and potentially useful clinical tool but that significant barriers exist [9,10]. of note, these studies were limited to highly motivated adults and did not directly monitor or assess participants performing dermatoscopic imaging in a supervised setting, precluding the identification of the technical challenges encountered during the imaging process as well as the contributing factors leading to poorer quality images. as part of an ongoing longitudinal study of individual nevi in children and adolescents, we have serially imaged participants during middle and high schools with clinical and dermatoscopic imaging [11-19]. our observations have documented the relative stability of nevus dermatoscopic patterns during early adolescence and have preliminarily identified differences in the anatomic site distribution and size changes among dermatoscopically defined nevus subsets [11,20,21]. we plan to validate our findings into early adulthood by continuing to prospectively monitor individual nevi after high school graduation via participant-acquired dermatoscopic imaging. to accomplish this aim, we will ship an imaging packet to study participants containing explicit instructions for acquiring overview clinical and dermatoscopic images along with a camera. with the assistance of a person of their choice, participants will be asked to take clinical and dermatoscopic images of specific skin lesions on their backs and legs and upload them to a study website. to plan our methods and identify potential technical and logistical barriers for dermatoscopic imaging, we performed a small pilot study using current participants that included direct observation by study investigators of participant-acquired dermatoscopic imaging. our rationale included applicability to patient-acquired teledermatoscopy efforts through identification of some of the intrinsic difficulties that may exist for novices performing dermatoscopic imaging, as well as measuring receptivity to this evolving imaging technology. in this study, our primary objective was to determine the ability of 12th grade high school students to capture overview clinical and dermatoscopic images of specific skin lesions on patient-actors without prior formal instruction or demonstration. methods study overview institutional review board approval for this study was obtained from the harvard school of public health in accordance with the helsinki declaration. participants were 12th grade high school students, recruited from the sonic graduating class of 2014 (n=130) at framingham high school, who previously underwent clinical and dermatoscopic imaging of back and leg nevi while in the 8th and 11th grades. students from this class were recruited through e-mail correspondence or personal contact by a study nurse (m.b.). students and/or parents provided written informed consent and/or assent for participation. a monetary incentive was offered to students upon study completion. the study was conducted in april 2014. sample size was determined based on logistical constraints of time required to perform the pilot intervention. the imaging had to be completed during one school day, within the confines of the participants’ non-academic time and the limited physical space available for the study. procedures in advance of the study, students were informed that they would be taking photographs of skin lesions on patientactors but received no specific details regarding the types of images or the specific cameras to be used. a study investigator (m.m.) provided a 5-minute introduction at the beginning of each imaging activity that explained the purpose and overview of the study but included no imaging or camera instructions or demonstrations. participants completed a pre-imaging survey and data were obtained on receptivity, confidence, and ability as they related to the imaging process, before being divided into gender-specific groups of 2 students (supplementary materials). if scheduled participants were unavailable to take part on the day of the study, groups of 1 student were created as scheduling constraints permitted. each group was assigned a gender-matched patient-actor. one male and one female patient-actor, ages 33 and 28 years respectively, were used in the study. both the male and female patient-actors had 18 or more skin lesions on the back and 5 or more skin lesions on the anterior legs (male) or posterior legs (female). the baseline overview back and leg images of the patient-actors were taken the week of the study and annotated with both arrows and numberand color-coded icons to mark specific skin lesions. the clinical diagnoses of skin lesions used included 7 melanocytic nevi and 1 lentigo on the male and 7 melanocytic nevi and 1 dermatofibroma on the female. a range of dermatoscopic patterns (e.g., globular, reticular, homogenous, and multicomponent) was present in the nevi. research | dermatol pract concept 2015;5(1):2 13 explicit written instructions, annotated baseline overview photographs (both color print and digital formats, permitting zoom-in) of the patient-actors’ backs and legs, numberand color-coded stickers, and two sets of cameras were provided to each group. camera a was the veos ds3 (canfield scientific, inc., fairfield, nj, usa), which is a handheld camera integrated within an ipod touch (apple inc.) that permits both clinical and dermatoscopic imaging. camera b was a customized nikon tm 1 j1 with fixed-focus, and a magnetically attached veos hd1 (canfield scientific, inc.). camera order was randomized for each group using block randomization procedures and students were allowed a maximum of 35 minutes to complete the imaging activity. written instructions prompted students to identify prespecified skin lesions on the back (n=5) and legs (n=3) of the patient-actor using the annotated baseline overview back and leg images as a reference. upon lesion identification, students placed the corresponding numberand color-coded sticker immediately adjacent to the lesion on the patient-actor’s skin. then, groups were instructed to use their first camera to take overview (n=2) and dermatoscopic images (n=8). instructions explained that overview images should match the baseline overview images and include all skin lesions marked with stickers. students were next instructed to take contact, polarized dermatoscopic images of all skin lesions they had marked with stickers. students were informed not to delete any photos and to take as many photos as needed. before capturing each dermatoscopic image, students were asked to gently wipe skin lesions with 70% isopropyl alcohol swabs. if after finishing use of the first camera, groups were noted to make visibly poor or no skin contact during dermatoscopic imaging, study staff verbally informed students of the need to place the camera firmly onto the skin. instructions informed groups to repeat all imaging with their second camera. all skin lesions were small enough to be captured within the field of view of a single dermatoscopic image. at completion, students completed a post-imaging survey (supplementary materials). survey responses for both the pre-imaging and post-imaging surveys were anonymous. imaging and image assessment time was recorded for each group for the following components: (a) nevus identification / sticker placement—defined as pick-up of stickers until placement of last sticker, (b) camera 1 use—defined as pick-up of first camera until put-down of first camera, (c) camera 2 use—defined as pick-up of second camera until put-down of second camera, and (d) total duration—defined as start of imaging activity to put-down of camera 2. during the imaging session, study staff recorded the ability of each group to correctly identify and mark prespecified skin lesions with stickers and to wipe each skin lesion with a 70% isopropyl alcohol swab immediately prior to dermatoscopic imaging. the application of 70% isopropyl alcohol prior to dermatoscopic imaging was recommended to optimize image quality [22]. image quality was assessed by two study investigators (m.m. and m.f.). overview images were assessed for focus (yes, no) and quality (sufficient, insufficient). overview images were rated in focus if no blurriness was present in the image and of sufficient quality if they permitted accurate identification of the skin lesions marked with stickers for dermatoscopic imaging. dermatoscopic images were assessed for: (a) presence of the sticker (yes, no), (b) inclusion of the entire skin lesion (yes, no), and (c) focus (yes, no). a dermatoscopic image was considered in focus if there was no blurriness of the skin lesion, permitting the accurate identification of colors, structures, and patterns present in the skin lesion. if multiple overview or dermatoscopic images were taken of the same anatomic site or skin lesion, analysis was restricted to the best image as determined by the study investigators. statistical analysis descriptive statistics was used to assess the study variables. fisher’s exact test and mcnemar’s chi-square were used for comparisons of categorical data. all tests were two-sided and a p value <.05 was considered statistically significant. results participants twenty-four high school seniors (12 males, 12 females) consented for the study but 5 were ineligible to participate [exam (n=1), field trip (n=1), absent (n=3)]. nineteen participants (9 males, 10 females; mean age (sd) 18.1 (± 0.29) years) completed the study and were divided into 11 groups (8 groups of 2 participants and 3 groups of 1 participant). imaging activity groups required a mean of 15 minutes 10 seconds to complete the imaging activity. participants were able to correctly identify preselected lesions on the patient-actors 86 out of 88 times (98%) (8 lesions per 11 groups). participants were successful in taking overview clinical images of sufficient quality (41/42, 98%), wiping lesions with isopropyl alcohol swabs before dermatoscopy (160/176, 91%), and capturing dermatoscopic images that included the sticker (174/176, 99%) and the entire lesion (174/176, 99%) (table 1). regarding dermatoscopic image quality, 116 of 176 (66%) images were in focus. a higher percentage of back images were in focus than leg images, although the difference was not statistically significant (70% v. 59%, p = 0.144). based on direct observation, 4 of the 11 groups made poor or no skin contact during dermatoscopic imaging with their first camera. for these groups, study staff verbally informed 14 research | dermatol pract concept 2015;5(1):2 participants to firmly place the camera onto the skin before using their second camera. four of the 6 groups that started with the veos ds3, but none of the groups that started with the nikon tm 1 j1 / veos hd1, required assistance. the 4 groups that received verbal feedback performed significantly better in obtaining in-focus dermatoscopic images with use of their second camera compared to their first camera (72% v. 16%, respectively, p < 0.001). groups not requiring help captured a significantly higher percentage of in focus dermatoscopic images than groups receiving assistance (79% v. 44%, p < 0.001). among groups not requiring help, a non-statistically significant higher percentage of back and leg images were in focus using the nikon tm 1 j1 / veos hd1 than the veos ds3 (82% v. 73%, p = 0.364). survey data—participant receptivity, confidence, and ability overall, a majority of students (15/19, 79%) rated the imaging activity as either “very easy” or “easy” (table 2). no significant differences were observed between camera types for difficulty of use with 84% of participants rating both the nikon tm 1 j1 and the veos hd1 “very easy” or “easy” to use (p = 1.0). participants reported high levels of comfort and confidence in finding and having a person of their choice take dermatoscopic images of their moles in both preand postimaging surveys. the percentage of “very comfortable” students increased from 42% in the pre-imaging survey to 68% in the post-imaging survey (p = 0.06). complete survey data is provided in the supplementary materials (see pages 19-28). discussion we found that 12th grade high school students are capable of capturing sufficient quality clinical and dermatoscopic images of specific skin lesions without formal training. participants also reported feeling comfortable and confident with taking dermatoscopic images of their skin lesions. as participants will not be able to capture images of lesions on all body sites (e.g., back), it is important to note that they identified multable 1. imaging activity results. (copyright: ©2015 marchetti et al.) imaging variables overall (n=11) veos† nikon° camera order 1 camera order 2 (n=6) (n=5) veos† first nikon° second nikon° first veos† second total duration 15:10 — — — — — — lesion identification and sticker placement 2:26 — — 2:33 2:19 imaging 6:16 6:54 5:37 7:39 5:37 5:36 6:01 overview clinical images* in focus 35/42 (83%) 16/22 (73%) 19/20 (86%) 8/12 (67%) 9/10 (90%) 10/10 (100%) 8/10 (80%) back 18/21 (82%) 8/11 (73%) 10/10 (91%) 4/6 (67%) 5/5 (83%) 5/5 (100%) 4/5 (80%) legs 17/21 (77%) 8/11 (73%) 9/10 (82%) 4/6 (67%) 4/5 (67%) 5/5 (100%) 4/5 (80%) sufficient quality 41/42 (98%) 21/22 (95%) 20/20 (100%) 11/12 (92%) 10/10 (100%) 10/10 (100%) 10/10 (100%) back 20/21 (95%) 10/11 (90%) 10/10 (100%) 5/6 (83%) 5/5 (100%) 5/5 (100%) 5/5 (100%) legs 21/21 (100%) 11/11 (100%) 10/10 (100%) 6/6 (100%) 5/5 (100%) 5/5 (100%) 5/5 (100%) dermatoscopic images sticker visible 174/176 (99%) — — — — — — entire nevus present 174/176 (99%) — — — — — — nevus in focus all nevi 116/176 (66%) 46/88 (52%) 70/88 (80%) 20/48 (42%) 37/48 (77%) 33/40 (83%) 26/40 (65%) back nevi 77/110 (70%) 30/55 (55%) 47/55 (85%) 11/30 (37%) 25/30 (83%) 22/25 (88%) 19/25 (76%) leg nevi 39/66 (59%) 16/33 (48%) 23/33 (70%) 9/18 (50%) 12/18 (67%) 11/15 (73%) 7/15 (47%) † veos ds3 (canfield scientific, inc.) ° nikon tm 1 j1 and veos hd1 (canfield scientific, inc.) *two overview images were not taken by 1 group. research | dermatol pract concept 2015;5(1):2 15 table 2. participant reported receptivity, confidence, and ability related to imaging process (copyright: ©2015 marchetti et al.) no./total no. (%) pre-imaging survey (n=19) post-imaging survey (n=19) today, how comfortable are you having a person of your choice take photos of moles on your back and legs? very comfortable 8 (42%) 13 (68%) comfortable 9 (47%) 4 (21%) neither comfortable nor uncomfortable 2 (11%) 1 (5%) uncomfortable 0 0 very uncomfortable 0 0 no response 0 1 (5%) today, how confident are you, with the aid of a person of your choice, in your ability to take photos of moles on your back and legs using a provided camera? very confident 11 (58%) 12 (63%) confident 6 (32%) 6 (32%) neither confident nor unconfident 2 (11%) 0 unconfident 0 0 very unconfident 0 0 no response 0 1 (5%) answer the following questions as if it is 3 years from today. how confident are you in your ability to find a person of your choice to help you take photos of moles on your back and legs? very confident 13 (68%) 11 (58%) confident 6 (32%) 8 (42%) neither confident nor unconfident 0 0 unconfident 0 0 very unconfident 0 0 who would you ask to help you take photos of the moles on your back and legs 3 years from today? (select all that apply) parent 17 (89%) 16 (84%) sibling 12 (63%) 12 (63%) another family member 9 (47%) 9 (47%) boyfriend/girlfriend 12 (63%) 12 (63%) friend 19 (100%) 19 (100%) not sure 0 0 other:___________________________________________________ 0 0 don’t think i can find somebody to help take photos 0 0 the following questions relate to today’s imaging session. in general, how difficult did you find today’s imaging session? very easy —6 (32%) easy —9 (47%) (continued next page) 16 research | dermatol pract concept 2015;5(1):2 tiple people with whom they would feel comfortable asking to help them with imaging. no students reported difficulty with the imaging activity. our data complements and builds upon a previous study performed by janda et al that examined the feasibility of patient-acquired teledermatoscopy as a tool to enhance skin self-examinations [9]. eight of the 10 participants in that study reported that taking dermatoscopic images was ‘easy’ and 88% (58/66) of dermatoscopic images were rated as ‘good quality’ by the study investigators. the contributing factors leading to poorer quality images were not reported, but were likely difficult to quantify as dermatoscopic imaging technique was not directly observed by study investigators. it is also important to note the differences in their study population, which was restricted to highly motivated adult patients with a personal or family history of melanoma, atypical moles, or multiple moles, limiting the generalizability of their results to other less-motivated patient populations. as the participants in our study are drawn from a populationbased study sample, our results may be more representative of the general population. the need to place cameras directly on the skin for contact, polarized dermatoscopic imaging was not always intuitive to participants. although printed instructions informed students to place cameras directly onto skin lesions and included representative images demonstrating this particular step for each camera, we did not provide a live or recorded demonstration of dermatoscopic imaging. four of 11 groups (36.4%) required feedback regarding dermatoscopic technique from study investigators. importantly, after receiving verbal instructions, the dermatoscopic image quality of these students improved significantly, suggesting a rapid learning curve. a potential limitation of our printed instructions may have been the terminology used to refer to dermatoscopic imaging. we used the term “close-up images” for “dermatoscopic images.” a more practical layperson term for “dermatoscopic images” may be “contact images” in situations when contact, polarized dermatoscopy is desired. future studies may benefit from instructions that emphasize the need for firm and flat contact of the camera surface with the skin. despite no statistical difference in the percentage of in focus back and leg dermatoscopic images, we observed that students had more difficulty imaging leg lesions. we suggest that anatomic differences between the legs (cylindrical shape and location close to the ground) and back (flat and easy to access while standing) may have been contributing factors. of note, all 4 groups that initially had difficulty with skin contact started with the veos ds3, although we found that the student responses for camera difficulty did not differ by camera type. the additional mass of the nikon tm 1 j1 / veos hd1 compared to the veos ds3 (0.57 kg v. 0.53 kg, respectively) may have unintentionally assisted users in achieving better skin contact. in the future, we plan to provide a short video with an explicit demonstration of the technique required for contact, polarized dermatoscopic imaging. we will also consider recommendations for lower neither easy nor difficult —4 (21%) difficult —0 very difficult —0 how easy was it to use the veos ds3? very easy —9 (47%) easy —7 (37%) neither easy nor difficult —2 (11%) difficult —1 (5%) very difficult —0 how easy was it to use the nikon tm 1 j1 / veos hd1? very easy —7 (37%) easy —9 (47%) neither easy nor difficult —3 (16%) difficult —0 very difficult —0 percentages may not add to 100% due to rounding. table 2. (continued from previous page) no./total no. (%) pre-imaging survey (n=19) post-imaging survey (n=19) research | dermatol pract concept 2015;5(1):2 17 extremity lesions to be imaged with the subject lying down (e.g., on a bed) to facilitate skin contact. as the participants of this pilot study originated from a larger skin imaging study and have previously, albeit briefly, been exposed to dermatoscopic imaging by professional photographers, our results may not be applicable to other populations. the number of anatomic sites imaged, diversity and size of skin lesions included, and modalities of dermatoscopic imaging examined were also restricted and limit the generalizability of our findings. our results may not be representative of dermatoscopic imaging on acral, intertriginous, or hairy sites, as well as the face, scalp, and nails. furthermore, our methodology did not include skin lesions of a size requiring multiple dermatoscopic images or with dermatoscopic structures that may be technically challenging to image, including blood vessels, vascular blush, and shiny white structures (e.g., crystalline, chrysalis, shiny white lines/ areas/strands, and rosettes). we also did not assess other modalities of dermatoscopic imaging including non-contact, polarized dermatoscopy and contact, non-polarized dermatoscopy. due to time, space, and logistical constraints, our sample size was limited, precluding a meaningful analysis or comparison between sample subgroups. patient-acquired dermatoscopy is expected to become more common with the commercial availability of inexpensive attachments that facilitate mobile phone dermatoscopic imaging. certain patient populations, including high-risk melanoma patients, may find this technology useful when performing skin self-examinations and monitoring individual melanocytic nevi for change. patient-acquired dermatoscopy may also be useful for physician-initiated sequential digital dermatoscopic imaging, allowing repeat follow-up images to be taken by patients and potentially eliminating the need for a return office visit. clinical studies examining skin lesions over time may similarly benefit from participant-acquired dermatoscopic imaging by reducing study expenditures and the number of required protocol visits. our preliminary study identified several barriers to participant-acquired dermatoscopic imaging. we believe that by modifying the imaging protocol based on the lessons learned herein, participantacquired dermatoscopic imaging will become feasible for clinical and research purposes. in summary, we found that inadequate skin contact during contact, polarized dermatoscopic imaging, particularly on the lower extremities, was the most common contributing factor to out of focus images. future studies of patient-acquired teledermatoscopy may benefit from the use of video instructions and recommendations for imaging to be performed with participants lying down. acknowledgements: the authors thank the students who participated in the study, giada marchetti and jedediah smith (canfield scientific, inc.), for their service as patient-actors, and tom bialoglow (canfield scientific, inc.), jedediah smith (canfield scientific, inc.), and dennis dasilva (canfield scientific, inc.) for providing the cameras used in the study and assisting with study logistics. references 1. ferlay j, shin hr, bray f, et al. estimates of worldwide burden of cancer in 2008: globocan 2008. int j cancer 2010;127(12):2893-917. 2. parkin dm, pisani p, ferlay j. estimates of the worldwide incidence of 25 major cancers in 1990. int j cancer 1999;80(6):82741. 3. garbe c, leiter u. melanoma epidemiology and trends. clin dermatol 2009;27(1):3-9. 4. kittler h, pehamberger h, wolff k, et al. diagnostic accuracy of dermoscopy. lancet oncol 2002;3(3):159-65. 5. vestergaard me, macaskill p, holt pe, et al. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol 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framingham school system. j invest dermatol 2011;131(8):1615-21. 12. scope a, marghoob aa, dusza sw, et al. dermoscopic patterns of naevi in fifth grade children of the framingham school system. br j dermatol 2008;158(5):1041-49. 13. lavigne ea, oliveria sa, dusza sw, et al. clinical and dermoscopic changes in common melanocytic nevi in school children: the framingham school nevus study. dermatology 2005;211(3):23439. 14. dusza sw, halpern ac, satagopan jm, et al. prospective study of sunburn and sun behavior patterns during adolescence. pediatrics 2012;129(2):309-17. 15. dusza sw, oliveria sa, geller ac, et al. student-parent agreement in self-reported sun behaviors. j am acad dermatol 2005;52(5):896-900. 16. geller ac, oliveria sa, bishop m, et al. study of health outcomes in school children: key challenges and lessons learned from the framingham schools’ natural history of nevi study. j sch health 2007;77(6):312-18. 17. oliveria sa, geller ac, dusza sw, et al. the framingham school nevus study: a pilot study. arch dermatol 2004;140(5):545-51. 18. oliveria sa, satagopan jm, geller ac, et al. study of nevi in children (sonic): baseline findings and predictors of nevus count. am j epidemiol 2009;169(1):41-53. 18 research | dermatol pract concept 2015;5(1):2 19. oliveria sa, scope a, satagopan jm, et al. factors associated with nevus volatility in early adolescence. j invest dermatol 2014;134(9):2469-471. 20. wu x, fonseca m, marchetti ma, et al. longitudinally followed nevi in children and adolescents show significant size changes. abstract #300 presented at the 2014 society of investigative dermatology in albuquerque, new mexico. j invest dermatol 2014;134 suppl 1:s49-60. 21. fonseca m, burnett m, dusza s, et al. dermoscopic patterns of nevi have a distinct anatomical distribution in adolescents. abstract #315 presented at the 2014 society for investigative dermatology meeting in albuquerque, new mexico. j invest dermatol 2014;134 suppl 1:s49-60. 22. gewirtzman aj, saurat jh, braun rp. an evaluation of dermoscopy fluids and application techniques. br j dermatol 2003;149(1):59-63. see pages 19-28 for supplementary materials. research | dermatol pract concept 2015;5(1):2 19 20 research | dermatol pract concept 2015;5(1):2 research | dermatol pract concept 2015;5(1):2 21 22 research | dermatol pract concept 2015;5(1):2 research | dermatol pract concept 2015;5(1):2 23 24 research | dermatol pract concept 2015;5(1):2 research | dermatol pract concept 2015;5(1):2 25 26 research | dermatol pract concept 2015;5(1):2 research | dermatol pract concept 2015;5(1):2 27 28 research | dermatol pract concept 2015;5(1):2 dermatology: practical and conceptual research | dermatol pract concept 2020;10(4):e2020106 1 dermatology practical & conceptual diminished expression of galectin-3 around blisters in bullous pemphigoid: an immunohistochemistry study maryam aghighi1, bruce r. smoller2 1 department of pathology, robert wood johnson barnabas health, livingston, nj, usa 2 department of pathology, university of rochester school of medicine and dentistry, rochester, ny, usa key words: bullous pemphigoid, galectin-3, blister formation citation: aghighi m, smoller br. diminished expression of galectin-3 around blisters in bullous pemphigoid: an immunohistochemistry study. dermatol pract concept. 2020;10(4):e2020106. doi: https://doi.org/10.5826/dpc.1004a106 accepted: june 12, 2020; published: october 26, 2020 copyright: ©2020 aghighi and smoller. this is an open-access article distributed under the terms of the creative commons attribution license (cc-by-nc-4.0), which permits unrestricted noncommercial, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: m.a. and b.s. contributed significantly to the manuscript. b.s. designed the study. m.a. and b.s. analyzed and interpreted the data. m.a. wrote the initial draft of the manuscript. m.a. and b.s. edited and finalized the manuscript. corresponding author: maryam aghighi, md, department of pathology, robert wood johnson barnabas health, 94 old short hills road, livingston, nj 07039, usa. email: maryam.aghighi@rwjbh.org background: bullous pemphigoid (bp) is a subepidermal blistering disorder caused by autoantibodies directed against hemidesmosomal proteins. many patients with bp demonstrate circulating ige autoantibodies. although the role of ige in the pathogenesis of bp is unknown, a correlation between ige antibodies and eosinophilia has been observed. soluble cd23 and galectin-3 are the main elements of the ige group. the roles for cd23 in bp as a potential biomarker and ige production regulator have been characterized, but no studies have evaluated any roles for galectin-3 in this disease. objective: in this study, we evaluated galectin-3 expression in bp as a first step in assessing its role in the pathogenesis of this autoimmune blistering process. patients and methods: sixty specimens diagnosed as bp were stained with antibodies to galectin-3. the percentages of nuclear and cytoplasmic galectin-3 expression and staining intensity were evaluated. results: there was a significant difference in galectin-3 cytoplasmic and nuclear expression within keratinocytes immediately surrounding and above the blisters: (1) cytoplasmic (mean = 17.2% ± 2.4%) vs adjacent unaffected skin (mean = 66.7% ± 2.0%, p < 0.0001) and (2) nuclear (mean = 1.9% ± 0.4%) vs adjacent unaffected skin (mean = 13.2% ± 1.2%, p < 0.0001). conclusions: lower expression of galectin-3 around blisters in bp may suggest a role as an adhesion molecule. loss of galectin-3 may add to the extension of blister formation by initiating cell-extracellular matrix disassembly and may be involved with the associated dermal inflammation and the eosinophil chemotaxis. further studies will be necessary to elucidate the result of this observed loss on disease pathogenesis. abstract 2 research | dermatol pract concept 2020;10(4):e2020106 showed the highest intensity with very dark brown-colored stain. interobserver concordance was high, as staining differences were prominent. all statistical calculations were performed using microsoft excel software. an alpha level of p < 0.05 was used to indicate significant differences. results all included specimens had been previously diagnosed as bp based upon the patients’ clinical findings, histologic findings of a subepidermal blister that contained eosinophils in the blister cavity, and the demonstration of linear staining with igg and c3 along the dermal-epidermal junction on contemporaneously received biopsies analyzed with direct immunofluorescence. galectin-3 showed lower expression above and lateral to the blisters compared to adjacent unaffected skin. we observed these changes in galectin-3 expression in both cytoplasmic and nuclear patterns around the blisters and adjacent unaffected skin. the galectin-3 expression was diffuse in adjacent unaffected skin with high intensity in both the cytoplasm and nucleus of keratinocytes. however, expression was diminished and irregular, with lower intensity above and lateral to the blisters. we observed a strong expression of galectin-3 in the inflammatory infiltrate and the surrounding vessels underlying the blisters, as well as the sebaceous glands near the blisters. out of 60 biopsies analyzed, this difference was noted in galectin-3 cytoplasmic expression of 56 biopsies (93.3%) and failed to demonstrate the difference in only 4 biopsies (6.7%). similarly, galectin-3 nuclear expression of 59 biopsies (98.3%) demonstrated this difference, while only 1 biopsy (1.7%) did not show the difference. figure 1, a-d illustrates an example in which 10% galectin-3 positivity is noted in a cytoplasmic pattern with the intensity of 1+ and 1% nuclear expression with an intensity of 1+ above (figure 1 b) and lateral (figure 1 d) to the blister. these were significantly lower than adjacent unaffected skin (figure 1c), demonstrating 70% galectin-3 positivity in a cytoplasmic pattern with an intensity of 2+ and 10% nuclear expression with the intensity of 2+. figure 2, a-d demonstrates that galectin-3 was expressed in 5% and 1% in cytoplasmic and nuclear patterns respectively with the intensity of 1+ above (figure 2b) and lateral (figure 2d) to the blister, which were significantly lower than adjacent unaffected skin (figure 2c) with 70% and 20% galectin-3 positivity in cytoplasmic and nuclear patterns respectively with the intensity of 3. similarly, figure 3, a-d shows 10% cytoplasmic and 1% nuclear galectin-3 positivity with the intensity of 1+ above (figure 3b) and lateral (figure 3d) to the blister in cytointroduction bullous pemphigoid (bp) is a subepidermal disorder described by autoantibodies against hemidesmosomes in the dermal and epidermal junction, usually in elderly patients. bp usually starts with pruritis and urticaria and subsequently progresses to the development of blisters on the skin caused by subepidermal separation through the basement membrane at the level of the lamina lucida [1]. in addition to the igg deposition seen along the dermal-epidermal junction (variably with depositions of igm, iga and c3, as well), most patients with bp present an autoimmune response by generating ige autoantibody. although the role of ige in the pathogenesis of bp is unknown, a correlation between ige antibodies and eosinophilia has been observed [2]. soluble cd23 and galectin-3 are 2 main elements of the ige group. while the role of soluble cd23 in bp as a potential biomarker, ige production regulator and disease severity predictor has been characterized [3], no studies about putative roles for galectin-3 in bp have been performed [4]. galectin-3 is a beta galactoside binding protein that is essential in the cell-to-cell or matrix adhesion. it broadly exists in the nucleus and cytoplasm of various cell types or may be found extracellularly on the cell surface [5]. as no studies have been reported on the role of galectin-3 immunohistochemical profile in pemphigoid disease, we attempted to evaluate the galectin-3 expression in patients with bp in the current study. materials and methods this retrospective study was approved by the institutional review board of our institution. we included 60 specimens from 55 patients diagnosed with bp between 2017 and 2020. five patients had 2 such biopsies. the biopsy specimens were processed in formalin, dehydrated through graded alcohol washes, embedded in paraffin and sliced on a microtome. tissue slices on glass slides were stained with cell marque mouse monoclonal galectin-3 (milliporesigma, inc.) using an autostainer link 48 (agilent technologies, inc) with low ph antigen retrieval and envision flex detection kit. the antibody was used in a dilution of 1:25. the immunohistochemical analysis was performed under a light microscope (olympus bx40f). the percentage of galectin-3 nuclear and cytoplasmic expression around blister and adjacent unaffected skin were evaluated both qualitatively and semi-quantitatively by the authors and compared using a t-test. the intensity of galectin-3 around the blister and adjacent unaffected skin was evaluated semi-quantitatively using the range of 1+ to 4+ and compared using a t-test. the value of 1+ showed the lowest intensity with very light brown-colored stain, and 4+ research | dermatol pract concept 2020;10(4):e2020106 3 to differentiation and maturation of the keratinocytes [6,7]. galectin-3 has an important function in cancer development and in inflammatory and immune responses. it has intracellular and extracellular functions, such as playing a crucial role in cell-to-cell interactions. galectin-3 is expressed in keratinocytes, which is believed to have an impact on the functionality of immune cells in response to inflammatory skin conditions. the role of galectin-3 in wound healing and various inflammatory skin diseases, such as atopic dermatitis and psoriasis, has been characterized previously. it has been reported that intracellular galectin-3 has an impact on the expression of cell surface and extracellular matrix receptors, which subsequently affects cell-matrix interactions and cell migration. this process has a significant contribution to the healing of wounds [8]. galectin-3 is a pro-inflammatory mediator in atopic dermatitis, needed for the inflammatory response to epicutaneous antigens via its impact on t cells [9]. galectin-3 expression in dermal capillaries has a role in the reorganization of the capillary system and the involvement of inflammatory cells in psoriasis [10]. additionally, it has been shown that plasmic and nuclear patterns, which were significantly lower than adjacent unaffected skin (figure 3c) with 60% and 10% galectin-3 positivity with the intensity of 3+ in cytoplasmic and nuclear patterns. statistically, there was a significant difference in galectin-3 cytoplasmic expression within keratinocytes immediately surrounding and above the blisters (mean = 17.2% ± 2.4%) compared to those in the adjacent unaffected skin (mean = 66.7% ± 2.0%, p < 0.0001, figure 4a). similarly, galectin-3 keratinocyte nuclear expression around blisters (mean = 1.9% ± 0.4%) was significantly lower than in adjacent unaffected skin (mean = 13.2% ± 1.2%, p < 0.0001; figure 4b). in addition, the cytoplasmic intensity of galectin-3 around blisters (mean = 1.42 ± 0.08) was significantly lower than adjacent unaffected skin (mean = 2.6 ± 0.06, p < 0.0001; figure 4c). discussion galectin-3 is a β-galactoside binding lectin that is found in epithelial cells, including keratinocytes. it is expressed in the nucleus and cytoplasm of normal keratinocytes and related figure 1. lower expression of galectin-3 around the blister compared to adjacent unaffected skin. (a) galectin-3 stain of a subepidermal blister of bullous pemphigoid (×20), (b) lower expression of galectin-3 above the blister (×200), (c) adjacent unaffected skin (×200), (d) lower expression of galectin-3 lateral to the blister (×200). a b c d 4 research | dermatol pract concept 2020;10(4):e2020106 α6β4, wherein integrin α6β4 functions as a laminin-332 receptor. galectin-3 stimulates the relationship of laminin-332 and integrin α6β4 [14]. galectin-3 also promotes epidermal growth factor receptor causing genesis of cell surface proteins. this process is essential to control the cell signal pathway and migration [15]. blister formation in bp happens as a result of the loss of epithelial cell-extracellular matrix adhesion at the hemidesmosomal junction. since galectin-3 in keratinocytes regulates cell-extracellular matrix adhesion, its lower expression around blisters in bp may disrupt the hemidesmosomal adhesion complex, resulting in blister formation. while autoantibodies directed against bp1 and 2 antigens trigger the blister formation, loss of galectin-3 may play a role in the extension of blister formation by initiating cell-extracellular matrix disassembly at the level of the lamina lucida of the basement membrane zone and may also be involved with the inflammatory response and eosinophil chemotaxis underlying the blisters, further accentuating the extent of blister formation. galectin-3 has a role in melanocytic and non-melanocytic skin cancers [11]. galectin-3 promotes cell adhesion, progression and metastasis in melanoma, and its expression is higher in abnormal melanocytes, in contrast to benign, banal melanocytes [12]. higher expression of galectin-3 in basal cell carcinoma (bcc) and squamous cell carcinoma (scc) has been observed [11]. it may interact with regulatory genes and influence the development and progression of bcc and scc. the cytoplasmic expression of galectin-3 is correlated with tumor size in scc [6]. there has been no report regarding the role of galectin-3 in blister-forming skin disorders such as bp. urticarial lesions may be one of the first presentations in bp and progress to recurrent chronic blisters. eosinophils are involved in the pathogenesis of bp and essential for anti-bp2 ige-mediated blistering. since galectin-3 is the main element of the ige group, galectin-3 may have a role in the formation of blisters in this disorder. hemidesmosomes are essential structures in keratinocytes for epithelial cell-extracellular matrix connections [13]. hemidesmosomes are composed of plectin 1a and integrin figure 2. lower expression of galectin-3 around the blister compared to adjacent unaffected skin. (a) galectin-3 stain of a subepidermal blister of bullous pemphigoid (×20), (b) lower expression of galectin-3 above the blister (×200), (c) adjacent unaffected skin (×200), (d) lower expression of galectin-3 lateral to the blister (×200). a b c d research | dermatol pract concept 2020;10(4):e2020106 5 figure 3. lower expression of galectin-3 around the blister compared to adjacent unaffected skin. (a) galectin-3 stain of a subepidermal blister of bullous pemphigoid (×20), (b) lower expression of galectin-3 lateral to the blister (×200), (c) adjacent unaffected skin (×200), (d) lower expression of galectin-3 above the blister (×200). figure 4. comparison of galectin-3 expression in blister and adjacent unaffected skin. (a) cytoplasmic expression (p < 0.0001), (b) nuclear expression (p < 0.0001), (c) intensity (p < 0.0001). gal-3 = galectin-3. a c d b a b c 6 research | dermatol pract concept 2020;10(4):e2020106 skin. j dermatol sci. 2011;64(2):85-91. doi: 10.1016/j.jdermsci.2011.07.008. pmid: 21889881. 7. chen h-y, lo c-h, li c-s, hsu dk, liu f-t. galectins and cutaneous immunity. dermatol sin. 2012;30(4):121-127. doi: 10.1016/j.dsi.2012.10.002. 8. cao z, said n, amin s, et al. galectins-3 and-7, but not galectin-1, play a role in re-epithelialization of wounds. j biol chem. 2002;277(44):42299-42305. doi: 10.1074/jbc.m200981200. pmid: 12194966 9. saegusa j, hsu dk, chen h-y, yu l, fermin a, fung ma, liu f-t. galectin-3 is critical for the development of the allergic inflammatory response in a mouse model of atopic dermatitis. am j clin pathol. 2009;174(3):922-931. doi: 10.2353/ ajpath.2009.080500. pmid: 19179612. 10. lacina l, plzakova z, smetana k, stork j, kaltner h, andre s. glycophenotype of psoriatic skin. folia biol (praha). 2006;52(1-2):10-15. pmid: 17007105. 11. kapucuoglu n, basak py, bircan s, sert s, akkaya vb. immunohistochemical galectin-3 expression in non-melanoma skin cancers. pathol res pract. 2009;205(2):97-103. doi: 10.1016/j.prp.2008.09.001. pmid: 18951731. 12. prieto vg, mourad-zeidan aa, melnikova v, et al. galectin-3 expression is associated with tumor progression and pattern of sun exposure in melanoma. clin cancer res. 2006;12(22):67096715. doi: 10.1158/1078-0432.ccr-06-0758. pmid: 17121890. 13. koster j, geerts d, favre b, borradori l, sonnenberg a. analysis of the interactions between bp180, bp230, plectin and the integrin α6β4 important for hemidesmosome assembly. j cell sci. 2003;116(2):387-399. doi: 10.1242/jcs.00241. pmid: 12482924. 14. walko g, castañón mj, wiche g. molecular architecture and function of the hemidesmosome. cell tissue res. 2015;360(2):363-378. doi: 10.1007/s00441-014-2061-z. pmid: 25487405. 15. kariya y, kawamura c, tabei t, gu j. bisecting glcnac residues on laminin-332 down-regulate galectin-3-dependent keratinocyte motility. j biol chem. 2010;285(5):3330-3340. doi: 10.1074/jbc.m109.038836. pmid: 19940114. conclusions we demonstrated lower expression of galectin-3 around the blisters in bp specimens. the pathogenesis of the blister formation may be associated, at least in part, with altered expression of galectin-3. further studies are required to elucidate the result of this loss on the pathogenesis of the observed histologic findings and determine the exact pathogenesis of blister formation. acknowledgments we would like to express our special thanks of gratitude to ms. sierra kovar who helped us in collecting the cases and preparing and staining the slides. references 1. schmidt e, della torre r, borradori l. clinical features and practical diagnosis of bullous pemphigoid. immunol allergy clin. 2012;32(2):217-232. doi: 10.1016/j.iac.2012.04.002. pmid: 22560135. 2. platzer b, ruiter f, van der mee j, fiebiger e. soluble ige receptors—elements of the ige network. immunol lett. 2011;141(1):36-44. doi: 10.1016/j.imlet.2011.08.004. pmid: 21920387. 3. messingham kn, holahan hm, frydman as, fullenkamp c, srikantha r, fairley ja. human eosinophils express the high affinity ige receptor, fcεri, in bullous pemphigoid. plos one. 2014;9(9). doi: 10.1371/journal.pone.0107725. pmid: 25255430. 4. messingham kn, crowe tp, fairley ja. the intersection of ige autoantibodies and eosinophilia in the pathogenesis of bullous pemphigoid. front immunol. 2019;10:2331. doi: 10.3389/ fimmu.2019.02331. pmid: 31636640. 5. dumic j, dabelic s, flögel m. galectin-3: an open-ended story. biochim biophys acta. 2006;1760(4):616-635. doi: 10.1016/j. bbagen.2005.12.020. pmid: 16478649. 6. larsen l, chen h-y, saegusa j, liu f-t. galectin-3 and the dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021129 1 dermatology practical & conceptual scalp basal cell carcinoma presenting as alopecia alexandra c. goetze1, giovana liz marioto de campos2,3, felipe bochnia cerci3,4, betina werner5 1 clínica newestetic, curitiba, brazil 2 department of dermatology, hospital universitário evangélico mackenzie, curitiba, brazil 3 clínica cepelle, curitiba, brazil 4 department of dermatology, hospital de clínicas da universidade federal do paraná, curitiba, brazil 5 department of pathology, hospital de clínicas da universidade federal do paraná, curitiba, brazil key words: basal cell carcinoma, alopecic plaque, arborizing vessels, mohs micrographic surgery, skin cancer citation: goetze a, marioto de campos gl, cerci fb, werner b. scalp basal cell carcinoma presenting as alopecia. dermatol pract concept. 2021;11(1):e2021129. doi: https://doi.org/10.5826/dpc.1101a129 accepted: august 6, 2020; published: january 29, 2021 copyright: ©2021 goetze et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alexandra c. goetze, md, clínica newestetic, rua pedro viriato parigot de souza, 318, curitiba, brazil. email: alexandracgoetze@gmail.com case presentation a healthy 32-year-old woman presented with a 7-year history of a slowly growing asymptomatic alopecia plaque on the scalp. physical examination revealed a 4.7 × 2.4 cm erythematous indurated alopecic plaque on the left parieto-occipital scalp (figure 1a). a 3 mm papule could be noticed on the inferior area of the plaque. dermoscopy showed multiple arborizing vessels in the plaque with no follicular openings (figure 1b). histopathologic examination revealed an infiltrative basal cell carcinoma (bcc) with no evidence of sebaceous nevus (figure 1c). the patient was treated with mohs micrographic surgery followed by primary closure. at a 3-year follow-up, no recurrence was noted. figure 1. (a) indurated alopecic plaque on the left parieto-occipital scalp. trichotomy was performed around the plaque prior to the surgery. (b) dermoscopy demonstrated multiple arboriform vessels. (c) histopathology revealed infiltrative chords and irregular small nests of basaloid cells with palisading and clefting in some areas surrounded by a desmoplastic dermis. there was no sign of follicular germ or papilla formation throughout the neoplasia (h&e, original magnification ×10). 2 image letter | dermatol pract concept 2021;11(1):e2021129 teaching point alopecia of the scalp caused by bcc can manifest without pearly borders and ulceration and can be mistaken for other conditions such as discoid lupus erythematosus or alopecia areata [1]. an indurated plaque of alopecia with arborizing vessels on dermoscopy should raise the suspicion for bcc. reference 1. scheinfeld, n. review of scalp alopecia due to a clinically unapparent or minimally apparent neoplasm (sacuman). acta derm venereol. 2006;86(5):387-392. doi: 10.2340/00015555-0160. dermatology: practical and conceptual review | dermatol pract concept 2020;10(3):e2020074 1 dermatology practical & conceptual introduction chemotherapy-induced alopecia (cia), one of the most dramatic side effects of chemotherapy [1], occurs in about 65% of patients receiving cytotoxic drugs [2]. the hair-shaft shedding can occur from a few days to weeks after the beginning of chemotherapy, with different shedding patterns depending on the severity of the insult. specifically, telogen effluvium is associated with mild to moderate damage, while dystrophic anagen effluvium follows severe damage. no guidelines are available for the prevention and treatment of cia. several devices and drugs are used, but the results are often disappointing and the scientific rationale for their use is unclear [3]. to undertake successful management, it is important to distinguish among cia induced by cytotoxic drugs, cia prevention and treatment of chemotherapyinduced alopecia alfredo rossi,1 gemma caro,1 maria caterina fortuna,1 flavia pigliacelli,1 andrea d’arino,1 marta carlesimo1 1 department of hematology, oncology and dermatology, sapienza university of rome, italy key words: hair loss, chemotherapy, treatment, alopecia citation: rossi a, caro g, fortuna mc, pigliacelli f, d’arino a, carlesimo m. prevention and treatment of chemotherapy-induced alopecia. dermatol pract concept. 2020;10(3):e2020074. doi: https://doi.org/10.5826/dpc.1003a74 accepted: april 14, 2020; published: june 29, 2020 copyright: ©2020 rossi et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gemma caro, md, section of dermatology, department of clinical, internal, anesthesiological and cardiovascular sciences, sapienza university of rome, viale del policlinico, 155, 00161, rome, italy. email: gemmacaro90@gmail.com background: chemotherapy-induced alopecia (cia) is one of the most dramatic side effects of chemotherapy. currently no guidelines are available for its prevention and treatment. several devices and drugs are used, but results are often disappointing. aims: our aim is to analyze drugs and devices proposed in the literature for prevention and treatment of cia induced by cytotoxic drugs and to discuss the evidenced-based opinion. methods and results: scalp cooling is the only agent that has been approved by the us food and drug administration for cia prevention. minoxidil and bimatoprost should not be used during chemotherapy administration, but they can be used after chemotherapy discontinuation to obtain greater regrowth. conclusions: therapy should always be modulated for the patient and no fixed protocol should be used. trichoscopy and trichogram could be useful tools in supporting this treatment. abstract https://doi.org/10.5826/dpc.1003a74 mailto:gemmacaro90@gmail.com 2 review | dermatol pract concept 2020;10(3):e2020074 of hematological tumors [12]. finally, this device is contraindicated in cold agglutinin disease, cryoglobulinemia, and posttraumatic cold injury because of the risk of triggering local or generalized attack [13,14]. soref and fahl evaluated the efficacy of topical vasoconstrictors epinephrine and norepinephrine in preventing chemotherapyand radiotherapy-induced alopecia in rats [15]. induction of hypoxia signal by local vasoconstriction preserves hair follicle cells and reduces the amount of drug reaching hair follicle [16]. the use of vasoconstrictors 3 times a day leads to effective and long-lasting vasoconstriction. in humans, when applied applied on nasal mucosae for a long time, topical vasoconstrictors could induce rhinitis medicamentosa that may present with inflamed, dry mucosa prone to bleeding, edema, and associated insomnia [17,18]. it is reasonable to hypothesize that no risk of thinning and bleeding exists in cases of scalp application, since scalp is thicker than mucosa and has a different vascularization. the limitation of scalp cooling is that its action is confined to the application time, which usually coincides with the drug infusion. we know that the half-life of chemotherapeutic drugs is longer than their infusion time; for this reason toxic effects are prolonged too. scalp refrigerating and consequent vasoconstriction limited to infusion time could not prevent toxic effects occurring during the weeks from one infusion to another. meanwhile, daily topical application of vasoconstrictors could overcome this problem to ensure better results in preventing cia. moreover, these drugs could be used also in patients who develop severe peripheral neuropathies after receiving platinum derivatives and who do not tolerate scalp cooling. topical minoxidil topical minoxidil 2% and 5% is widely used, but clinical studies have reported disappointing results. in particular, rodriguez et al reported severe alopecia in 88% and 92% of the patients treated with, respectively, topical minoxidil 2% and 5% [19]. it was effective in shortening the period of baldness, as reported by duvic et al [20], and safety and tolerability were good. duvic et al reported scalp pruritus in 60% and scalp folliculitis in 25% of the patients, and new hair growth on the face in 8 women [20]. we would not recommend minoxidil for cia prevention, not only because of its clinical inefficacy, but in particular because of the lack of a scientific rationale for its use. even if minoxidil’s mechanism of action is still not completely clear, it is well known that it induces vasodilation by opening potassium channel localized on smooth muscular cells of peripheral arteries, with consequent slowing of circulation. this leads to a greater permanence of the anticancer induced by targeted therapy, and cia induced by hormonal therapy. each of these types is different in clinical aspect and pathogenetic mechanism, so treatment should be different too. in this review we focus only on cia induced by cytotoxic drugs. these agents are still largely used, and they are associated with the most extreme type of alopecia, which occurs in a high percentage of the cases. moreover, all these drugs, although with different mechanisms, work by inducing apoptosis of rapidly proliferating cells [2,4]. this allows us to use therapeutic strategies that can be common to all of them. this approach is not possible with cia induced by targeted therapies or hormonal treatments. separate works should address those treatments. as already stated, cytotoxic drugs all have as their main targets rapidly proliferating cells. keratinocytes of the hair follicle matrix are highly proliferative during the anagen phase, and together with the pigmentary system they are very sensitive to toxins and drugs [2,4]. instead, catagen and telogen phases are mitotically less active, so they are protected from chemotherapy toxicity [2,4]. normally up to 90% of scalp hairs are in the anagen phase; for this reason hair loss is usually massive. even if this kind of alopecia is generally reversible in 3 to 6 months, and permanent alopecia is rare, this side effect has a considerable psychological effect [2,4,5]. our aim is to analyze drugs and devices proposed in the literature for the prevention and treatment of cia induced by cytotoxic drugs and to discuss the evidenced-based opinion. it is important to distinguish between drugs and devices aimed to prevent alopecia (such as scalp cooling) and drugs and devices that sustain hair regrowth. scalp cooling and topical vasoconstrictors scalp-cooling devices refrigerate the scalp with consequent local vasoconstriction and reduction of drug inflow to the hair follicles. it is largely used, and alopecia prevention rates are reported to be between 50% and 80% [6-8]. recently, this device was approved by the us food and drug administration as the only efficient agent preventing cia [9]. patient compliance is high, even though headache, discomfort, nausea, and xerosis may occur [10]. this device is recommended in patients affected by solid tumors undergoing chemotherapeutic protocols associated with a high risk of developing cia. meanwhile, patients receiving platinum derivatives have severe peripheral neuropathies which limit their tolerance to cold [11]; for this reason scalp cooling should be avoided in these patients. moreover, the risk of scalp metastasis prohibits the use of scalp cooling in cases review | dermatol pract concept 2020;10(3):e2020074 3 blood levels, weight, and height, ensuring blood concentration between 40 and 60 ng/ml, which is considered the optimal range [28-30]. miscellaneous several other molecules have been proposed and studied for cia prevention and treatment. some of them did not give the expected results and thus were abandoned. some others were studied only in vitro or in animal models, so further investigations are needed. these studies are summarized in table 1 [31-40]. discussion with the exception of scalp cooling, we actually have no effective drugs for cia prevention. we emphasize that therapy should always be modulated for the patient and no fixed protocol should be used. trichoscopy and trichogram could help in understanding the type and grade of hair damage and what kind of treatment is the best option in a given moment [22]. moreover, the treatment should consider the oncological therapy and course (which and how many cycles of chemotherapy the patient will face), because the intervention acts longer than instantly. we outline these concepts in table 2. ideally, there should be sufficient time (from 2 to 4 weeks) before starting chemotherapy for administering a drug capable of inducing the telogen phase, in order to bring the hair follicle to a protected state during chemotherapy. if this is possible, after chemotherapy discontinuation molecules such as minoxidil and prostaglandin analogues could be used to accelerate the regrowth in anagen. in this way we would avoid the dramatic hair shedding that occurs 14 days after the first chemotherapy dose, and hair would be maintained for about 3 months when a telogen effluvium would occur, followed by a normal anagen without dystrophy. obviously, this is a hypothesis, and more studies should be conducted. conclusions with this work we seek to clarify the mechanisms of action of drugs usually used in cia prevention and treatment, indicating the positive and negative aspects of each (table 3). a better understanding of the pathogenetic mechanism of cia should lead to more successful treatment, and we hope that in the near future more efficacious, personalized, and targeted treatment options will be developed. drug around the hair follicle. minoxidil, in addition, is able to induce angiogenesis by upregulating vascular endothelial growth factor expression, and to activate prostaglandin endoperoxide synthase 1, which is able to stimulate hair growth [21]. this effect is exactly opposite to the scalp-cooling effect. moreover, the final effects of minoxidil are the shortening of the telogen phase and extension of the anagen phase. since the anagen phase is the most susceptible to drug insult, it is clear that this molecule cannot be used during chemotherapy administration. we suggest using minoxidil after chemotherapy discontinuation in order to obtain a greater regrowth. the best moment for introducing minoxidil should be evaluated considering chemotherapeutic drug half-life and monitoring scalp with trichoscopy and trichogram [22]. topical hydrocortisone could be associated with minoxidil topical application, acting as an anti-inflammatory agent but also helping follicular growth. prostaglandin analogue another proposed molecule is the topical bimatoprost 0.03%, which is a prostaglandin analogue. its efficacy was demonstrated with a randomized trial on 130 patients affected by chemotherapy-induced or idiopathic alopecia of eyelashes, which reported a clinical improvement in 37.5% of patients vs 18.5% of controls [23]. bimatoprost works by protecting follicles in the anagen phase and improving follicular growth in anagen i. for these reasons it should be used with the same indications of minoxidil. 1,25-dihydroxyvitamin d3 calcitriol (1,25-dihydroxyvitamin d3) has also been proposed as a cia preventive agent. this molecule has several actions on keratinocytes, including dna synthesis inhibition by blocking cellular cycle in g0/g1 phase, promoting cellular differentiation, and inhibiting ki67 expression and cell growth [24,25]. initially calcitriol appeared effective in preventing cia induced by cytosine [26], but further studies conducted on patients in treatment with anthracyclines and cyclophosphamide showed no efficacy [27]. moreover, contact dermatitis was reported after prolonged topical application of calcitriol. topical application could be replaced by systemic administration of vitamin d3 in the postchemotherapy phase in order to take advantage of its effects on the hair follicle morphogenesis, enhancing the effects of simultaneous topical application of minoxidil and/or prostaglandin analogues. dosage should be evaluated on the basis of vitamin d basal 4 review | dermatol pract concept 2020;10(3):e2020074 table 2. how trichoscopy could guide alopecia treatment trichoscopic features meaning suggested therapeutic conduct black dots and flame hairs acute and severe insult in anagen phase intensify therapies such as scalp cooling or topical vasoconstrictors with the aim of protecting hair follicles as much as possible. pohl-pinkus hairs damage occurred, but it was not difficult to completely interrupt the mitotic activity; the insult just reduced mitotic activity (hair shaft constrictions) the exact identification of timing could enable us to intensify the use of scalp cooling or topical vasoconstrictors when the insult is more aggressive. numerous yellow dots follicles are protected by acute damage (kenogen phase) use scalp cooling or topical vasoconstrictors with caution (for example, reducing the time or the number of applications). it has been hypothesized that a delayed hypoxic insult could induce neogenesis of hair follicle stem cells [15]. indiscriminate use of scalp cooling and vasoconstrictors could be harmful if other chemotherapy cycles are expected. table 1. molecules proposed and studied for cia prevention and treatment molecule supposed activity evidence model reference α-tocopherol preventing doxorubicininduced alopecia clinical efficacy not demonstrated (systemic administration) human studies • wood [31] • martin-jimenez et al [32] • perez et al [33] cyclin-dependent kinase 2 (cdk-2) inhibitors cia prevention cia reduction in the 33%50% (topical application) rat model • davis et al [34] palbociclib (cdk4/6 inhibitor) prevention of alopecia induced by taxanes protection of transit amplifying and stem/ progenitor cells through g1 arrest ex vivo organ culture model • purba et al [35] interleukin 1 protection from cytosine arabinoside and cytarabine-induced alopecia cia reduction rat model • jimenez et al [36] • jimenez et al [37] cyclosporin recovery from cyclophosphamideinduced alopecia induction of thick and long hairs after 21 days of cyclophosphamide administration mice model • shirai et al [38] epidermal growth factor protection from 1-β-darabinofuranosylcytosine (ara-c)-induced alopecia protection from alopecia limited to the treated area rat model • jimenez et al [36] fibroblast growth factor protection from 1-β-darabinofuranosylcytosine (ara-c)-induced alopecia protection from alopecia limited to the treated area rat model • jimenez & yunis [39] local pharmacological inhibitors of p53 prevention from alopecia induced by cytotoxic drugs just theoretical use real use unlikely because of possible carcinogenesis risk • botchkarev et al [40] in this table we summarize molecules that have been proposed and studied for chemotherapy-induced alopecia (cia) prevention and treatment, but which are not currently used in humans and for which further investigations are needed. review | dermatol pract concept 2020;10(3):e2020074 5 ta b le 3 . st u d ie s, p o si ti ve a n d n eg at iv e a sp ec ts , p ro b ab le m ec h an is m s o f a ct io n , a n d r ec o m m en d at io n s o f a va il ab le d ru gs a n d d ev ic es i n c ia p re ve n ti o n a n d t re at m en t a v a il a b le d ru g s a n d d e v ic e s s tu d ie s p o si ti v e a sp e ct s n e g a ti v e a sp e ct s p ro b a b le m e ch a n is m o f a ct io n r e co m m e n d a ti o n s sc al p c o o li n g • b re ed e t al [1 2 ] • m ac d u ff e t al [ 7 ] • sh in e t al [ 9 ] • p ro ch il o e t al [ 8 ] • h ig h p at ie n t co m p li an ce • h ea d ac h e, d is co m fo rt , n au se a, a n d x er o si s m ay o cc u r • a ct io n l im it ed t o th e ap p li ca ti o n ti m e • l o ca l va so co n st ri ct io n a n d r ed u ct io n o f d ru g in fl o w t o t h e h ai r fo ll ic le s • r ec o m m en d ed f o r p at ie n ts a ff ec te d b y so li d t u m o rs u n d er go in g ch em o th er ap eu ti c p ro to co ls a ss o ci at ed w it h h ig h r is k o f d ev el o p in g c ia • n o t re co m m en d ed f o r p at ie n ts a ff ec te d b y h em at o lo gi ca l tu m o rs , c o ld a gg lu ti n in d is ea se , cr yo gl o b u li n em ia , a n d p o st tr au m at ic c o ld i n ju ry o r re ce iv in g p la ti n u m d er iv at iv es t o p ic al ep in ep h ri n e an d n o re p in ep h ri n e • so re f & f ah l [1 5 ] • r at h m an jo ss er an d e t al [ 1 6 • a ct io n a ls o d u ri n g th e w ee k s fr o m o n e in fu si o n t o a n o th er • p o ss ib le u se a ls o i n p at ie n ts r ec ei vi n g p la ti n u m d er iv at iv es • a p p li ca ti o n m o re ti m es p er d ay • in d u ct io n o f h yp o x ia s ig n al b y lo ca l va so co n st ri ct io n p re se rv es h ai r fo ll ic le ce ll s an d r ed u ce s th e am o u n t o f d ru g re ac h in g h ai r fo ll ic le • r ec o m m en d ed f o r p at ie n ts a ff ec te d b y so li d t u m o rs u n d er go in g ch em o th er ap eu ti c p ro to co ls a ss o ci at ed w it h h ig h r is k o f d ev el o p in g c ia ( in cl u d in g p la ti n u m d er iv at iv es ), i n cl u d in g p at ie n ts a ff ec te d b y co ld a gg lu ti n in d is ea se , c ry o gl o b u li n em ia , a n d p o st tr au m at ic c o ld i n ju ry • n o t re co m m en d ed f o r p at ie n ts a ff ec te d b y h em at o lo gi ca l tu m o rs t o p ic al m in o x id il 2 % an d 5 % • r o d ri gu ez e t al [ 1 9 ] • d u vi c et a l [2 0 ] • g o o d s af et y an d to le ra b il it y • h ai r re gr o w th ac ce le ra ti o n • n o r es u lt s re ga rd in g h ai r lo ss p re ve n ti o n • v as o d il at io n a n d a n gi o ge n es is i n d u ct io n (g re at er p er m an en ce o f th e an ti ca n ce r d ru g ar o u n d t h e h ai r fo ll ic le ) • h ai r gr o w th s ti m u la ti o n b y ac ti va ti n g p ro st ag la n d in e n d o p er o x id e sy n th as e 1 • sh o rt en t el o ge n p h as e an d e x te n d an ag en p h as e (h ai r fo ll ic le m o st su sc ep ti b le t o d ru g in su lt ) • n o t re co m m en d ed f o r c ia p re ve n ti o n • r ec o m m en d ed a ft er c h em o th er ap y d is co n ti n u at io n in o rd er t o o b ta in a g re at er r eg ro w th ( in p ar ti cu la r in p at ie n ts w it h p re vi o u s m al e an d f em al e p at te rn h ai r lo ss ) t o p ic al b im at o p ro st 0 .0 3 % • g la se r et a l [2 3 ] • g o o d s af et y an d to le ra b il it y • h ai r re gr o w th ac ce le ra ti o n • n o r es u lt s re ga rd in g h ai r lo ss p re ve n ti o n • p ro te ct io n o f fo ll ic le s in a n ag en p h as e an d i m p ro vi n g fo ll ic u la r gr o w th i n an ag en i ( h ai r fo ll ic le m o st s u sc ep ti b le to d ru g in su lt ) • n o t re co m m en d ed f o r c ia p re ve n ti o n • r ec o m m en d ed a ft er c h em o th er ap y d is co n ti n u at io n i n o rd er t o o b ta in a g re at er r eg ro w th t o p ic al c al ci tr io l (1 ,2 5 -d ih yd ro x yvi ta m in d 3 ) • ji m en ez e t al [2 6 ] • h id al go e t al [2 7 ] • n o n e w it h t o p ic al ap p li ca ti o n • c o n ta ct d er m at it is • a ct io n o n k er at in o cy te s • n o t re co m m en d ed • e va lu at e sy st em ic c al ci tr io l (1 ,2 5 -d ih yd ro x yv it am in d 3 ) ad m in is tr at io n i n p o st ch em o th er ap y p h as e c ia = c h em o th er ap yin d u ce d a lo p ec ia . 6 review | dermatol pract concept 2020;10(3):e2020074 16. rathman-josserand m, genty g, lecardonnel j, et al. human hair follicle stem/progenitor cells express hypoxia markers. j invest dermatol. 2013;133(8):2094-2097. https://doi.org/10.1038/ jid.2013.113 17. patel a, levi jr, brook cd. should excess topical decongestant use raise a red flag? rhinitis medicamentosa and opioid use disorder. ann otol rhinol laryngol. 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melanoma, skin cancer, diagnostic algorithm, blinck, primary care citation: bourne p, rosendahl c, keir j, cameron a. blinck—a diagnostic algorithm for skin cancer diagnosis combining clinical features with dermatoscopy findings. dermatol pract conc. 2012;2(2):12. http://dx.doi.org/10.5826/dpc.0202a12. received: october 30, 2011; accepted: february 20, 2012; published: april 30, 2012 copyright: ©2012 bourne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: all authors declare no conflict of interest with regards the preparation or writing of this paper. they have not accepted from a sponsor, pharmaceutical company or other organization any funds for research, consultancy fees, fellowship/research/ education grants, nor hold any stock or shares in any entity that may gain financial benefit or detriment as a result of the deliberations set out in or the conclusions of the study. all authors have contributed significantly to this publication. corresponding author: peter bourne, skin cancer clinic of toowoomba, suite 10, 9 scott st, toowoomba, queensland 4350, australia. tel. 07 46 130333; fax. 07 46 130055.email: peter_bourne@bigpond.com. background: deciding whether a skin lesion requires biopsy to exclude skin cancer is often challenging for primary care clinicians in australia. there are several published algorithms designed to assist with the diagnosis of skin cancer but apart from the clinical abcd rule, these algorithms only evaluate the dermatoscopic features of a lesion. objectives: the blinck algorithm explores the effect of combining clinical history and examination with fundamental dermatoscopic assessment in primary care skin cancer practice. patients/methods: clinical and dermatoscopic images of 50 skin lesions were collected and shown to four primary care practitioners. the cases were assessed by each participant and lesions requiring biopsy were determined on separate occasions using the 3-point checklist, the menzies method, clinical assessment alone and the blinck algorithm. results: the blinck algorithm had the highest sensitivity and found more melanomas than any of the other methods. however, blinck required more biopsies than the other methods. when comparing diagnostic accuracy, there was no difference between blinck, menzies method and clinical assessment but all were better than the 3-point checklist. conclusions: these results suggest that the blink algorithm may be a useful skin cancer screening tool for australian primary care practice. abstract 56 research | dermatol pract concept 2012;2(2):12 introduction most gp skin cancer training courses in australia encourage beginners to use dermatoscopy algorithms when deciding if a lesion requires biopsy to exclude skin cancer. indeed, the ability to recognise dermatoscopic criteria correctly and apply a dermatoscopic algorithm is often seen as the sine qua non of excellence in primary care skin cancer practice. the benefits of using a scored “dermatoscopy-only” algorithm are well documented [1,2]. however, this approach does not score often useful clinical information such as history of lesion change, the “ugly duckling” sign [3,4] and even the patient’s own instinct regarding the lesion. the authors feel that a more “holistic” diagnostic approach, where these clinical aspects are also scored, may reduce the chances of the student missing less obvious skin cancers. methods we performed a retrospective analytical trial to see if a new algorithm, incorporating clinical as well as dermatoscopic criteria, was any different to the three methods commonly used in australia primary care practice to diagnose skin cancer. the new algorithm, blinck, was developed and compared to two “dermatoscopy-only” algorithms, (the 3-point checklist and the menzies method), and clinical assessment alone. the blinck algorithm was designed as an assessment tool for primary care skin cancer clinicians and does not require the user to be an “expert” in dermatoscopy. in contrast to most existing algorithms, the distinction between melanocytic and non-melanocytic [5] lesions is not necessary and both pigmented and non-pigmented lesions may be assessed. the acronym, blinck, refers to six questions that should be asked when assessing a skin lesion and includes both clinical and dermatoscopic features. b – benign: is the lesion immediately recognisable as a common benign tumour, on clinical and dermatoscopic examination, with other similar lesions being present on that part of the body, e.g., typical solar lentigo, seborrheic keratosis, haemangioma or dermatofibroma? if ‘yes’, no further action is required. if ‘no’, then proceed to the following four questions. l – lonely: is this lesion, clinically and dermatoscopically, the only one of its type on that region of the body, i.e., an “outlier” or “ugly duckling”? ‘yes’ scores 1. i – irregular: for pigmented lesions, is the lesion dermatoscopically irregular, that is, does it have an asymmetrical pigmentation pattern and more than one colour? for non-pigmented lesions, is there an irregular vascular pattern? ‘yes’ scores 1. n – nervous: is the patient nervous or concerned that this particular lesion may be a skin cancer? (this excludes the “generally anxious” patient or patients with hypochondriasis). c – change: does the patient, or another observer, feel that the lesion is changing? (note that only a total score of 1 can be given if either or both of these last two questions are answered ‘yes’.) k – known clues: does the lesion definitely have any one of the following dermatoscopic “clues” to malignancy? • atypical network—unmistakable variation in thickness of network line • pseudopods or streaks—segmental • black dots, globules or clods—irregular and peripheral • eccentric structureless zone • blue or grey colour—irregular distribution • vessels—1. polymorphous; 2. finely focused and arborizing; 3. glomerular (coiled) shaped • acral lesions—1. parallel ridge pattern; 2. diffuse irregular brown/black pigmentation ‘yes’ to any one of these scores 1 (maximum score of 1). a total score of 2 or more out of 4 requires biopsy. to compare blinck with the other diagnostic methods a pilot trial was conducted using images of skin lesions typically seen in australian primary care skin cancer practice. from june 1 to july 6, 2009, all skin lesions consecutively excised to exclude skin cancer were recorded by an experienced skin cancer doctor, (a.c.), working in a dedicated skin cancer practice in brisbane, australia. clinically obvious basal cell carcinomas which could be easily diagnosed without dermoscopy were not included in the collection set. high quality clinical and dermatoscopic photographs of 50 skin lesions were obtained, (non-polarised dermatoscopic images taken with a non-polarised dermlite foto attachment, or dermlite fluid dermatoscope, (3gen, llc), and canon d40 digital camera, (tokyo, japan). written patient consent was obtained in every case and any history of lesion change or patient concern was documented, as well as whether the lesion was thought to be an “ugly duckling” by the original examiner. as common lesions such as the dermatofibroma, seborrhoeic keratosis and congenital naevus sometimes pose a diagnostic challenge for inexperienced clinicians, an example of each, seen during the collection period, was included in the set of 50. these three cases were assessed as being obviously benign by a.c. and not biopsied. as well, a flat naevus that was unchanged on sequential digital monitoring was included in the set without biopsy. histopathological examination of the other 46 lesions revealed 19 to be skin cancers with nine being melanomas (eight in situ and one invasive). figures 1 and 2 show an example of a melanoma case from the trial. four primary care clinicians, (three gps and a clinical nurse), with varying levels of dermatoscopic experience, were asked to review the photographs and select which lesions were suspicious for malignancy, hence requiring biopsy. this assessment was done on four occasions, each time using a different diagnostic approach. the following methods were used in this order. 1. 3-point checklist—only dermatoscopic images were shown. research | dermatol pract concept 2012;2(2):12 57 figure 1. despite being dermatoscopically bland, this lesion had changed and was “lonely,” scoring 2 in the blinck method and mandating biopsy. histopathology is shown demonstrating melanoma in situ. a: clinical view. b: macro view. c: dermatoscopic view. [copyright: ©2012 bourne et al.] figure 2. dermatoscopic view. a: histology slide 1. b: histology slide 2. c: histology slide 3. [copyright: ©2012 bourne et al.] a c b 58 research | dermatol pract concept 2012;2(2):12 2. menzies method—only dermatoscopic images were shown. 3. clinical assessment alone—only clinical images were shown. 4. blinck—dermatoscopic and clinical images were supplied as well as information regarding reported lesion change, “ugly duckling” sign or patient concern as recorded by original examiner. the clinicians received prior instruction on the use of the three algorithms, and excel answer sheets for each method listed the various criteria used in that algorithm. the clinicians were asked to decide if these criteria were present or not and the spreadsheet was used to calculate the results. the clinician’s response for each case was compared to the correct diagnosis and graded as true positive, false negative, false positive or true negative. the number of cancers and melanomas correctly detected and the number of biopsies indicated for each clinician and each method were also recorded (table 1). four clinicians using four methods resulted in 16 contingency tables for sensitivity and specificity. as two of the methods related only to pigmented lesions, (3-point and menzies), the five non-pigmented specimens in the set of 50 were excluded from the contingency tables for these methods. specificity, sensitivity and diagnostic accuracy were calculated according to standard formula. analysis of variance (anova) was used with the lsd test, (least significant difference test), to detect differences between clinicians and methods. a p-value of <0.05 indicated statistical significance. the means for specificity, sensitivity and diagnostic accuracy are shown with their 95% confidence interval, (95% ci). we used the statistica software package for statistical analysis. results there were no differences between the clinicians regarding sensitivity, specificity, diagnostic accuracy, number of cantable 1. true and false positives and negatives for the four methods by the four clinicians with sensitivity, specificity, melanomas found and biopsies indicated. clinician method true pos false neg false pos true neg sens. spec. number melanomas found number biopsies indicated p.b. 3point 11 23 5 6 68.8 20.7 6 34 menzies 6 8 10 21 37.5 72.4 2 14 clinical 9 5 10 26 47.3 83.9 2 14 blinck 19 13 0 18 100 58.1 9 32 c.r. 3point 11 18 5 11 68.7 37.9 6 29 menzies 10 6 6 23 62.5 79.3 5 16 clinical 13 14 6 17 68.4 54.8 3 27 blinck 19 23 0 8 100 25.8 9 42 d.b. 3point 11 18 5 11 68.8 37.9 5 29 menzies 11 14 5 15 68.8 51.7 6 25 clinical 9 6 10 25 47.4 80.6 2 15 blinck 16 15 3 16 84.2 51.6 8 31 h.c.   3point 5 8 11 21 31.3 72.4 2 13 menzies 8 8 8 21 50 72.4 3 16 clinical 9 9 10 22 47.4 80 2 18 blinck 15 11 4 20 78.9 64.5 7 26 research | dermatol pract concept 2012;2(2):12 59 cers detected, number of melanomas found or biopsies indicated, however, there were significant differences between the four methods (table 2). blinck had higher sensitivity and found significantly more melanomas than the other three methods. however, the menzies method and clinical only approach had higher specificity and resulted in fewer biopsies than blinck. diagnostic accuracy was the same for blinck, menzies and clinical only, and all were better than the 3-point checklist. blinck had higher sensitivity, diagnostic accuracy, number of cancers found and number of melanomas found than the 3-point checklist, but had similar specificity and number of biopsies required. the 50 lesions used in the trial were sourced from 46 patients, 22 male and 24 female, with ages varying between 30 and 60 years (average 58 years). anatomical sites of lesions are shown in table 3. four clinically benign lesions were included in the set without a histological diagnosis, (dermatofibroma, seborrhoeic keratosis, congenital naevus and monitored flat naevus), and the remainder were subjected to histological examination (table 4). discussion australia has the highest rate of melanoma in the world [6]. it is the third most common cancer in australia in both men and in women [7]. approximately two out of every three australians will be diagnosed with skin cancer before the age of 70 [8] and roughly a million gp visits are made annually for skin cancer. this makes skin cancer the most expensive of all cancers for the australian health system [9, 10]. more skin cancers are diagnosed and treated in australia by primary care doctors than by medical specialists [11]. these generalists require a simple yet accurate screening tool that will allow the detection of melanoma and other skin cancers at an early stage when complete cure is possible. currently, most introductory skin cancer courses in australia endorse dermatoscopic evaluation of suspicious skin lesions as the preferred screening method, commonly using the 3-point checklist or the menzies method [12,13]. other clinical features that may assist with the diagnosis of skin cancer have been previously studied. the “ugly ducktable 2. mean values of sensitivity, specificity and diagnostic accuracy with 95% confidence intervals (ci) are shown, as well as numbers of melanomas and cancers found and biopsies required. means followed by the same letter in each column were not significantly different.   sensitivity (95% ci) specificity (95% ci) diagnostic accuracy (95% ci) melanomas found (9 total) total cancers found (19 total) number biopsies (50 total) 3-point 59.4a (52.2-66.5) 42.2a (35.0-49.4) 48.3a (44.7-52.0) 5b 9a 26ab menzies 54.7a (47.4-62.0) 69ab (62.2-75.7) 63.9b (60.4-67.3) 4ab 9a 18a clinical 52.6a (40.1-54.7) 74.8b (74.0-85.7) 65.0b (61.5-68.5) 2a 10a 18a blinck 90.8b (86.5-95.0) 50ab (42.7-57.3) 65.5b (62.1-69.8) 8c 17b 33b table 3. anatomical location of lesions location number face 8 neck 1 chest 3 back 21 shoulder 2 arm 3 thigh 4 leg 7 foot plantar 1 60 research | dermatol pract concept 2012;2(2):12 ling” sign has been shown to be of possible use in melanoma screening [4]. importantly, the ability to assess whether a lesion is “different” from surrounding lesions does not appear to require advanced training. hence, it would seem sensible that primary care clinicians seek out “ugly duckling” lesions when performing a skin examination, (“lonely” in the blinck algorithm). lesion change is also known to be associated with malignancy, particularly in patients over 50 years of age [14], and consideration of this clinical feature would also seem prudent. a disproportionate amount of concern for a lesion by the patient, (“nervous”), may have significance for two reasons. firstly, patients may be uncertain if their lesion has changed or perhaps they may simply fail to volunteer the history of change, bleeding, itch or soreness. they suspect that it is a cancer but assume the doctor is able to make the diagnosis by mere inspection without needing any clinical history. however, this history may be the only clue to malignancy in dermatoscopically bland lesions, and a false negative diagnosis may be made using dermatoscopic assessment alone. secondly, dismissing a lesion about which the patient is quite concerned may have medico-legal consequences should it prove later to be malignant. in this small trial, the blinck algorithm, which scored these extra clinical features along with basic dermatoscopic assessment, found more skin cancers and melanomas than the commonly endorsed methods in australia. however, more excisions were required to achieve this result. this raises the question as to what is the best measure of “accuracy” in melanoma diagnosis. argenziano has suggested that nne, (number of melanocytic lesions needed to be excised in order to find one melanoma), may be useful for measuring accuracy in melanoma detection and compared the nne in specialised and non-specialised clinical settings [15]. in his study the nne reduced over time from 12.8 to 6.8 with specialised clinics but remained unchanged at 29.4 in nonspecialised centres. this would seem to suggest that a level around 6.8 may be an appropriate goal for skin cancer clinicians. in our study, the overall nne for melanoma by all clinicians using the blinck algorithm was 6, with the 3-point checklist 11, the menzies method 13 and clinical assessment only 22, suggesting that blinck may have value as a skin cancer screening tool. as this trial was limited by the small number of skin cancers and melanomas, and by the fact that it was a virtual study without direct assessment of patients’ lesions, it is difficult to draw definite conclusions regarding the benefits of combining clinical with dermatoscopic features in one diagnostic algorithm. indeed, it could be said that clinicians using dermatoscopic-only algorithms implicitly incorporate relevant clinical aspects of the case in their decision making process. however, knowing how much weight to give these clinical aspects is often difficult for novices. being forced to score the clinical with the dermatoscopic findings may help develop a more structured and holistic approach when deciding if a lesion requires biopsy. references 1. zalaudek i, argenziano g, soyer hp, et al., three-point checklist of dermoscopy: an open internet study. br j dermatol. 2006;154(3):431-7. 2. menzies sw, ingvar c, crotty ka, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):1178-82. 3. grob jj, bonerandi jj, the ‘ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. arch dermatol. 1998;134(1):103-4. 4. scope a, dusza sw, halpern ac et al. the “ugly duckling” sign: agreement between observers. arch dermatol. 2008;144(1): 58-64. 5. kittler h. why the first step should be abandoned! arch dermatol. 2010;146(10):1182-3. table 4. breakdown of correct lesion diagnosis of the 50 cases. correct diagnosis number banal naevus 10 blue naevus 1 naevus and seborrhoeic keratosis/ solar lentigo collision 3 seborrhoeic keratosis 5 solar lentigo 4 lichen planus-like keratosis (lplk) 4 dermatofibroma 1 psoriasis 1 solar keratosis 2 intraepidermal carcinoma 3 regressed keratoacanthoma 1 basal cell carcinoma 6 lentigo maligna 1 melanoma in situ 7 melanomainvasive (0.52 mm breslow) 1 research | dermatol pract concept 2012;2(2):12 61 6. australian institute of health and welfare and australasian association of cancer registries. cancer in australia 2001. aihw cat. no. can 23. aihw: canberra, 2004. 7. australian institute of health and welfare (aihw) and australasian association of cancer registries (aacr). cancer in australia: an overview. cancer series no 46. aihw: canberra, 2008. 8. staples m, elwwod m, non-melanoma skin cancer in australia: the 2002 national survey and trends since 1985. med j aust. 2006;184(1):6-10. 9. australian institute of health and welfare (aihw). non-melanoma skin cancer: general practice consultations, hospitalisation and mortality. cancer series no. 43 catalogue no. 49. aihw: canberra, 2008. 10. 10. australian institute of health and welfare (aihw). health system expenditures on cancer and other neoplasms in australia, 2000–01. health and welfare expenditure series number 22. aihw: canberra, 2005. 11. 11. askew da and wilkinson d. skin cancer surgery in australia 2001–2005:the changing role of the general practitioner. med j aust. . 2007;187(4):210-4. 12. sccanz. certificate in skin cancer medicine. sccanz web site, http://www.sccanz.com.au. accessed october 30, 2011. 13. uq. certificate in primary care skin cancer medicine. skin cancer courses web site; http://www.skincancercourses.com.au/ skc/index.htm. accessed october 30, 2011. 14. banky p, kelly jw, english dr et al. incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma. arch dermatol. 2005;141(8):998-1006. 15. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10year survey. [published online ahead of print 2011 oct 6]. j am acad dermatol. 2011. http://dx.doi. org/10.1016/j.jaad.2011.07.019. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(2):e2021031 1 drug intake and actinic keratosis: a case-control study andrea sechi1, ambra di altobrando1, eugenio cerciello1, elisa maietti2, annalisa patrizi1, francesco savoia1 1 dermatology, irccs policlinico di sant’orsola. department of experimental, diagnostic and specialty medicine, alma mater studiorum university of bologna, italy 2 department of biomedical and neuromotor sciences, university of bologna, italy key words: drug reaction, photosensitivity, actinic keratosis, angiotensin receptor blockers, antiplatelet drug citation: sechi a, di altobrando a, cerciello e, maietti e, patrizi a, savoia f. drug intake and actinic keratosis: a case-control study. dermatol pract concept. 2021;11(2):e2021031. doi: https://doi.org/10.5826/dpc.1102a31 accepted: february 3, 2021; published: april 12, 2021 copyright: ©2021 sechi et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: a.s and a.d. contributed equally to this work. all authors have contributed significantly to this publication. corresponding author: andrea sechi, md, dermatology -irccs policlinico di sant’orsola. department of experimental, diagnostic and specialty medicine, alma mater studiorum university of bologna, italy, via massarenti 9, 40138 bologna, italy. email: andrea.sechi@ hotmail.com background: actinic keratosis (ak) is a form of premalignant keratinocyte dysplasia. recently, the role of photosensitizing drugs in the development of ak has been postulated. objective: this study evaluated a possible association between the use of photosensitizing drugs and the development of ak. a secondary aim was to identify a possible association between any medication other than those primarily examined and ak. methods: a single-center, case-control study assessed the cumulative drug exposure of 90 patients with ak and 90 controls visiting a dermatology service for other skin ailments. before the visit, patients were interviewed to collect data on daily therapy and the lag-time of discontinued drugs within the last 2 years, and to record the drug’s active ingredient, dosage, and duration of therapy. in addition, sociodemographic characteristics including age, sex, educational level, skin phototype, and cumulative sun exposure habits were gathered. results: by logistic regression, exposures to angiotensin ii receptor blockers (arbs) and antiplatelet agents were identified as independent risk factors for the development of ak. arb intake was associated with ak only at high exposure (or = 13.6; 95% ci, 2.0-93.8). the use of antiplatelet drugs was borderline, yet not significant, at low exposure (or = 3.31; 95% ci, 0.86-12.7), but increased in a dose-dependent manner. the strongest correlation was found at the highest cumulative dose (>1100 dose unit-years (or = 4.38; 95% ci, 1.16-16.6). conclusions: high exposure to arbs and antiplatelet agents may promote ak carcinogenesis in atrisk patients. abstract 2 research | dermatol pract concept. 2021;11(2):e2021031 introduction actinic keratosis (ak) is a common skin lesion caused by the proliferation of atypical keratinocytes. in the literature, ak is considered as a form of either premalignant dysplasia or in situ squamous cell carcinoma (scc). the finding that 60% of sccs arise at the site of a previous ak supports the pathogenetic model of a continuous progression between ak and scc [1]. aks may evolve following 1 of 3 paths: spontaneous regression, stable existence, or malignant progression. natural remission positively correlates with working outdoors due to decreased sun sensitivity, and has been observed in more than 50% of aks. however, regressed lesions easily reappear over time [2]. the risk of malignant transformation of ak into an invasive scc has been investigated in many studies. a 0.6% progression rate for a single ak was reported over 1 year, and 2.6% in 4 years [1]; in a 20-year period, this rate ranges from 0.025% to 20% [2]. the reason for such a wide difference is mainly the lack of a consensus definition of ak, with no risk stratification according to ak features. ak clinical presentation is highly polymorphic, with a variable combination of erythema, hyperkeratosis, and telangiectasia. in this scenario, aks with rapid growth, bleeding, ulceration, induration and inflammation, and those >1 cm in size are at increased risk of progression to invasive scc [3]. there is extensive evidence regarding ak risk factors. for instance, uv irradiation promotes carcinogenesis through the induction of p53 mutations, which elude cell-cycle checkpoints and promote the uncontrolled proliferation of dysplastic keratinocytes [2]. recent advances confirm the influential role of uvb rays in the formation of thymidine dimers in the dna and rna of keratinocytes [2]. as a consequence, cumulative sun exposure is closely related to the onset of ak and scc in the photo-exposed areas [4]. both a history of sunburns, mainly those occurring in childhood [5], and chronic sun exposure (due to outdoor occupations or hobbies) increase the risk of developing ak, with an increasing trend towards older ages [4]. moreover, the most susceptible subjects have fair skin phototypes [4] or are immunosuppressed (eg, transplant recipients and people with genetic disorders affecting dna-repair mechanisms) [2]. additional risk factors are male sex, a smoking habit, and the assumption of photosensitizing drugs [6,7]. the assumption of drugs that target the skin by any mechanism (eg, dermal deposit, skin thinning), such as oral retinoids, topical retinoids, tetracycline, macrolides, aminoquinolines, amiodarone, and methoxypsoralen, make the skin more vulnerable to sun damage [7]. in 2018, the european medicines agency (ema) released a warning concerning the risk of developing non-melanoma skin cancer (nmsc) from the use of thiazide diuretics [8]. the ema pharmacovigilance risk assessment committee based this warning on the results of a danish case-control study that found dose-response relationships between the long-term intake of hydrochlorothiazide and the risk of developing basal cell carcinoma and scc [9]. therefore, patients assuming hydrochlorothiazide alone or in combination with other diuretics, or nondiuretic antihypertensives, especially those with prior nmsc, are recommended to apply sunscreen daily and to attend regular dermatological check-ups. prompted by this warning, we performed a prospective, single-center case-control study to evaluate a possible association between the use of photosensitizing drugs and the development of ak. a secondary aim of the study was to identify a possible association between any medication other than those primarily examined and ak. materials and methods over a 6-month period, 90 ak cases were recruited consecutively from the dedicated nmsc outpatient service and 90 controls were recruited from several services of general dermatology at the sant’orsola-malpighi hospital. the study was approved by central emilia wide area ethical committee; it started on january 1, 2020, and ended on may 31, 2020. a cut-off age higher than 60 years was set as an inclusion criterion for both groups. a medical history of ak or nmsc was an exclusion criterion for controls. all patients provided written informed consent for enrollment in the study. to collect information on sociodemographic characteristics, skin phototype, cumulative sun exposure, and drug intake, patients were interviewed on a standardized questionnaire and then examined by an experienced dermatologist. sun exposure was considered high in the case of more than a 5-year outdoor occupation or more than 10 years of outdoor recreational exposure. the survey also inquired about the long-term use of any class of medications, including drugs taken for at least 2 consecutive years and withdrawn within 3 months of the index date. data recorded included the drug’s active ingredient, daily dosage, duration of therapy and, in case of dosage variation, the new dosage and year of variation. for each patient, cumulative exposure was calculated as the product of the duration of treatment multiplied by the daily dosage (dose unit-years). statistical analysis continuous data were described by means and standard deviations (sd) or by median and interquartile ranges in case of a strongly asymmetric distribution (eg, exposure to drugs). for each categorical variable, we reported the absolute and relative frequencies expressed as percentages. the comparison between cases and controls was performed using the t-test for continuous variables with a normal research | dermatol pract concept. 2021;11(2):e2021031 3 distribution (eg, age) and the mann-whitney test for continuous variables with a skewed distribution (eg, drug exposure). pearson’s chi-square test and fisher’s exact test were used for comparisons of categorical variables. to assess an association between drug exposure and ak development, we used a multiple logistic regression model adjusted for the possible confounding effects of sociodemographic characteristics. the results of logistic regression were expressed as odds ratios (ors) and confidence intervals (95% ci). statistical significance was set at p = .05. the analyses were conducted using the statistical software stata version 15 (statacorp, college station, tx, usa). results overall, 180 patients were assessed, 90 cases and 90 controls (table 1). the 2 groups differed significantly in age, sex, skin type, and recreational sun exposure (p < .001). compared with controls, cases were older (mean, 79.4 vs. 73.3 years), more frequently male (73.3% vs. 38.9%), and more likely to have skin phototype i-ii (52.2% vs. 14.4%). combined sun exposure was lacking in 11.1% of cases and 46.6% of controls, mild-moderate in 4.4% and 18.9%, and high in 84.4% and 34.4%, respectively. no difference in terms of educational level was observed between the groups. drug exposure differed between groups for 2 classes of medications: angiotensin receptor blockers (arbs) and antiplatelet drugs (table 2). similar proportions of patients took arbs in the case and control groups (22.2% vs. 18.9%); however, the cumulative exposure was significantly higher in cases (p < .015). on the other hand, more than twice as many cases than controls took antiplatelet drugs (48.9% vs. 22.2%). no association was found between ak and other drugs, including thiazides and other diuretics, statins, ß-blockers, calcium channel blockers, ace inhibitors, anticoagulants (warfarin and novel oral anticoagulants) and the antiarrhythmic drug amiodarone (data not shown). the exposure to arbs and antiplatelet agents was categorized into 3 classes: high, low, and no exposure. cut-off values of 750 and 1100 unit-years, respectively for arbs and antiplatelet drugs, were used to distinguish high vs. low exposure. these new variables were included in a logistic regression model, adjusted for age, sex, skin type, and sun exposure (table 3). even after adjusting for sociodemographic features, the exposure to arbs and antiplatelet agents was significantly associated with the presence of ak. an increase in the probability of ak was found only with high exposure to arbs (or = 13.6; 95% ci, 2.0-93.8). the low exposure to antiplatelet agents was not significant at the statistical analysis (or = 3.31; 95% ci, 0.86-12.7), but the high exposure was significant (or = 4.38; 95% ci, 1.16–16.60), showing a dose-dependent association. table 1. sociodemographic features of cases and controls factor cases (n = 90) controls (n = 90) p age, mean ± sd 79.4 ± 7.2 73.3 ± 8.6 <.001 sex, no. (%) male female 66 (73.3) 24 (26.7) 35 (38.9) 55(61.1) <.001 education, no. (%) primary school middle school high school university degree 37 (41.1) 19 (21.1) 23 (25.6) 11 (12.2) 26 (28.9) 18 (20.0) 23 (25.6) 23 (25.6) .103 skin phototype, no. (%) i-ii iii-iv 47 (52.2) 43 (47.8) 13 (14.4) 77 (85.6) <.001 sun exposure at work, no. (%) 12 (13.3) 5 (5.6) .07 recreational sun exposure, no. (%) absent mild-moderate high 16 (17.8) 4 (4.4) 70 (77.8) 45 (50.0) 17 (18.9) 28 (31.1) <.001 combined sun exposure, no. (%) absent mild-moderate high 10 (11.1) 4 (4.4) 76 (84.4) 42 (46.7) 17 (18.9) 31 (34.4) <0.001 4 research | dermatol pract concept. 2021;11(2):e2021031 table 2. frequency and duration of exposurea to the examined drugs drug class statistical parameter cases (n = 90) controls (n = 90) p angiotensin receptor blockers n (%) 20 (22.2) 17 (18.9) .580 exposure 960 [469-2360] 300 [90-750] .015 antiplatelet drugs n (%) 44 (48.9) 20 (22.2) <.001 exposure 1100 [750-1780] 750[300-1215] .037 statins n (%) 29 (32.2) 30 (33.3) .874 exposure 110 [80–180] 100 [60 – 190] .382 calcium channel blockers n (%) 15 (16.7) 18 (20.0) .563 exposure 60 [35-100] 80 [40-240] .638 beta-blockers n (%) 29 (32.2) 24 (26.7) .414 exposure 400 [60-1100] 97.5 [20-860] .133 ace inhibitors n (%) 29 (32.2) 29 (32.2) 1.0 exposure 52.5 [45-120] 55 [27.5-180] .870 warfarin n (%) 7 (7.8) 8 (8.9) .787 exposure 45 [20-115] 50 [22.5-97.5] 1.0 novel oral anticoagulants n (%) 2 (2.2) 5 (5.6) .444 exposure 10 [5-15] 75 [40-110] .171 thiazides n (%) 20 (22.2) 12 (13.3) .119 exposure 225 [87.5-412.5] 137.5 [56.25-387.5] .402 loop diuretics n (%) 17 (18.9) 15 (16.7) .697 exposure 165 [50-250] 150 [50-400] .406 drug exposure was calculated as the daily dose multiplied by the years of therapy (dosage unit-years) and is reported as the median (interquartile range). ace = angiotensin-converting enzyme. table 3. multiple logistic regression model predicting actinic keratosis variables no. or (95% ci) arbs • no exposure • low exposure • high exposure (>750 dose unit-years) 143 18 19 1.00 0.25 (0.05 1.32) 13.6 (2.0 – 93.8) antiplatelet agents • no exposure • low exposure • high exposure (>1100 dose unit-years) 116 31 33 1.00 3.31 (0.86 – 12.69) 4.38 (1.16 – 16.60) note: the model is adjusted for age, sex, skin type, and sun exposure. arbs = angiotensin receptor blockers; ci = confidence interval; or = odds ratio. table 4. concomitant exposure to arbs and antiplatelet drugs cases controls exposure to antiplatelet drugs, n (%) exposure to antiplatelet drugs, n (%) low moderate high absent low high exposure to arbs low 38 (42.2) 16 (17.8) 16 (17.8) absent 58 (64.4) 8 (8.9) 7 (7.8) moderate 3 (3.3) 1 (1.1) 2 (2.2) low 8 (8.9) 4 (4.4) 0 (0) high 5 (5.6) 1 (1.1) 8 (8.9) high 4 (4.4) 1 (1.1) 0 (0) arbs = angiotensin receptor blockers. research | dermatol pract concept. 2021;11(2):e2021031 5 eight cases were concomitantly exposed to arbs and antiplatelet drugs, whereas no double exposure was found in controls (table 4). discussion two studies based on danish national data showed a dose-dependent, cumulative association between the photosensitizing activity of hydrochlorothiazide and nmsc, including basal cell carcinoma and scc [9,10]. one of these studies highlighted a 7-fold increased risk of scc lip cancer in exposed subjects [10]. the other study found the strongest associations with: a cumulative hydrochlorothiazide dose >200 mg, female sex, upper or lower limbs, and age <50 years [9]. the postulated pathogenetic mechanism is photosensitivity due to hydrochlorothiazide, which is well documented and could enhance photocarcinogenesis [1-14]. subsequently, further papers on the association between photosensitizing agents and nmsc were published and yielded conflicting results. indeed, some studies showed no association between hydrochlorothiazide and nmsc, and some authors raised concerns about the methodological limitations of the 2 danish studies [15-24]. in contrast to the danish studies, our study did not find any evidence of an association between thiazide diuretics and actinic keratosis, probably due to the limited use of thiazides in our sample. instead, our study showed that high exposure to arbs and even low exposure to antiplatelet drugs, in a dose-dependent pattern, represent significant risk factors for the development of ak. in the literature, a similar study conducted in 1999 assessed the impact of photosensitizing drugs on the development of ak. however, the number of patients was small (34 cases and 34 controls), and the use of cardiovascular drugs was also considerably low [7]. other recent studies demonstrated the induction of photosensitivity in patients taking arbs, and hypothesized drug-driven carcinogenesis favored by sun exposure [25-29]. however, as for hydrochlorothiazide, the results of different studies are contradictory. conflicting evidence regarding the use of antiplatelet agents comes from a brazilian case-control study, which demonstrated a protective effect of acetylsalicylic acid on the development of ak [30]. this study enrolled 74 cases and 216 controls, and the median duration of therapy was 36 months. the use of acetylsalicylic acid was an independent protective factor for ak onset since it was associated with a lower ak count on the face and upper extremities, regardless of concomitant risk factors. in our study, ticlopidine and clopidogrel were used by only 3 cases and 1 control: for this reason, we included all antiplatelet agents within a single group. the main limitation of our study is that it is inadequately powered to detected mild differences in drug exposures between cases and controls. for instance, the differential percentage in the use of oral diuretic thiazides (22.2% vs. 13.3%) would require a sample size of 288 cases and 288 controls to be significant at p < .05, with 80% power. furthermore, cases were not closely matched to controls in terms of age, sex, or skin phototype. consecutive recruitment of patients was pursued to avoid selection bias but implied a significant inhomogeneity in the 2 groups. the study design foresaw these results, and aimed to adjust all possible confounding factors by multivariate analysis. in southern europe, the high prevalence of ak made the recruitment of controls extremely difficult in older age groups. besides, the case group had significantly more men and fairskin individuals. the sex difference between the groups may have affected their use of sun-protective measures, as women are more inclined to apply sunscreen. however, sun-protective behaviors were not recorded in our survey. they could have affected the quality of our data due to the dose-dependent ability of sun-blockers to increase the ak remission rate and prevent the development of new lesions [2]. another limitation of our study is the inclusion of patients using multidrug therapies, which, however, reflects real practices and the disease burden of elderly patients. the current study was underpowered to identify potential synergic or antagonistic effects of the simultaneous use of multiple drugs. supplementary analyses adjusted for the concomitant use of antihypertensive/diuretic drugs should be performed in a larger series. a possible synergistic effect of taking two photosensitizing drugs favoring ak genesis could not be excluded. in our study, the number of patients on both antiplatelet and arb therapy was very low. table 4 shows that none of the controls with high exposure to antiplatelet agents was exposed to arbs at the same time. in contrast, the 8 patients on dual therapy with high exposure to antiplatelet drugs and arbs were in the case group. therefore, a more extensive study with a larger population size is warranted to characterize patients taking both drugs, and to define the attributable risk of developing ak for each medication. conclusions our study was designed to investigate a possible association of photosensitizing drugs and ak. our results suggest a correlation between the use of arbs or antiplatelet agents and the onset of ak. arbs possess a known photosensitizing effect, which could be the missing link between their use and the development of ak. antiplatelet agents do not induce photosensitivity, and their association with ak remains unknown. further studies are needed to assess the pro-car6 research | dermatol pract concept. 2021;11(2):e2021031 cinogenic potentials of these 2 classes of drugs, in order to prompt adequate dermatological screening and sun protection, mainly in patients with a medical history of nmsc. references 1. criscione vd, weinstock ma, naylor mf, et al; department of veteran affairs topical tretinoin chemoprevention trial group. actinic keratoses: natural history and risk of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. cancer. 2009;115(11):2523. doi: 10.1002/cncr.24284. pmid: 19382202. 2. siegel ja, korgavkar k, weinstock ma. current perspective on actinic keratosis: a review. br j dermatol. 2017;177(2):350-358. doi: 10.1111/bjd.14852. pmid: 27500794. 3. quaedvlieg pj, tirsi e, thissen mr, et al. actinic keratosis: how to differentiate the good from the bad ones? eur j dermatol. 2006;16(4):335–339. pmid: 16935787. 4. hensen p, müller ml, haschemi r, et al. predisposing factors of actinic keratosis in a north-west german population. eur j dermatol. 2009;19(4):345. doi: 10.1684/ejd.2009.0706. pmid: 19470418. 5. frost ca, green ac, williams gm. the prevalence and determinants of solar keratoses at a subtropical latitude (queensland, australia). br j dermatol. 1998;139(6):1033-1039.  doi: 10.1046/j.1365-2133.1998.02560.x. pmid: 9990367. 6. de berker d, mcgregor jm, mohd mustapa mf, exton ls, hughes br. british association of dermatologists’ guidelines for the care of patients with actinic keratosis 2017. br j dermatol 2017;176(1):20-43. doi: 10.1111/bjd.15107. pmid: 28098380. 7. placzek m, eberlein-könig b, przybilla b. association between actinic keratoses and potentially photosensitizing drugs. n engl j med 1999;341(19):1474-1475. doi: 10.1056/ nejm199911043411915. pmid: 10577103. 8. european medicines agency—pharmacovigilance risk assessment committee (prac). prac recommendations on signals. 1 october 2018. accessed: february 14, 2021. available at: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-3-6-september-2018-prac-meeting_en-0.pdf. 9. pedersen sa, gaist d, schmidt saj, hölmich lr, friis s, pottegård a. hydrochlorothiazide use and risk of nonmelanoma skin cancer: a nationwide case-control study from denmark. j am acad dermatol 2018;78(4):673-681.e9. doi: 10.1016/j. jaad.2017.11.042. pmid: 29217346. 10. pottegård a, hallas j, olesen m, et al. hydrochlorothiazide use is strongly associated with risk of lip cancer. j intern med 2017;282(4):322–331.  doi: 10.1111/joim.12629. pmid: 28480532. 11. friedman gd, asgari mm, warton em, chan j, habel la. antihypertensive drugs and lip cancer in non-hispanic whites. arch intern med. 2012;172(16):1246-1251. doi: 10.1001/ archinternmed.2012.2754. pmid: 22869299. 12. o’gorman sm, murphy gm. photosensitizing medications and photocarcinogenesis. photodermatol photoimmunol photomed. 2014;30(1):8-14. doi: 10.1111/phpp.12085. pmid: 24393207. 13. jensen aø, thomsen hf, engebjerg mc, olesen ab, sørensen ht, karagas mr. use of photosensitising diuretics and risk of skin cancer: a population-based case-control study. br j cancer. 2008;99(9):1522-1528. doi: 10.1038/sj.bjc.6604686. pmid: 18813314. 14. schmidt saj, schmidt m, mehnert f, et al. use of antihypertensive drugs and risk of skin cancer. j eur acad dermatol venereol. 2015;29(8):1545–1554. doi: 10.1111/jdv.12921. pmid: 25640031. 15. pottegård a, pedersen sa, schmidt saj, et al. use of hydrochlorothiazide and risk of skin cancer: a nationwide taiwanese case-control study. br j cancer. 2019;121(11):973-978. doi: 10.1038/s41416-019-0613-4. pmid: 31673105. 16. han s, wolfe cm, angnardo l, et al. hydrochlorothiazide use and increased squamous cell carcinoma burden in a highrisk mohs population: a cross-sectional study. dermatol surg. 2020;46(5):704-708. doi: 10.1097/dss.0000000000001875.  17. park e, lee y, jue ms. hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: a nationwide retrospective cohort study from korea. korean j intern med. 2019;35(4):917-928. doi: 10.3904/kjim.2019.218.  18. olde engberink rhg, van der hoeven nv, zwinderman ah, van den born bh. hydrochloorthiazide en huidkanker [hydrochlorothiazide and skin cancer]. ned tijdschr geneeskd. 2019;163:d3755. 19. mhra drug safety update: hydrochlorothiazide and non-melanoma skin cancer. drug ther bull. 2019;57(5):70. doi: 10.1136/ dtb.2019.000023. pmid: 31018928. 20. morales dr, pacurariu a, slattery j, kurz x. association between hydrochlorothiazide exposure and different incident skin, lip and oral cavity cancers: a series of population-based nested case-control studies. br j clin pharmacol. 2020; 86(7):1336-1345. doi: 10.1111/bcp.14245. pmid: 32068906. 21. kreutz r, algharably eah, douros a. reviewing the effects of thiazide and thiazide-like diuretics as photosensitizing drugs on the risk of skin cancer. j hypertens. 2019;37(10):1950-1958. doi: 10.1097/hjh.0000000000002136. pmid: 31145177. 22. becquart o, guillot b, bourrain j-l, duflos c, du-thanh a. risque de cancers cutanés sous hydrochlorothiazide: revue systématique [hydrochlorothiazide use and risk of skin cancers: a systematic review]. rev med interne. 2019;40(9):617-622. doi: 10.1016/j.revmed.2019.04.008. pmid: 31101331. 23. shin d, lee es, kim j, guerra l, naik d, prida x. association between the use of thiazide diuretics and the risk of skin cancers: a meta-analysis of observational studies. j clin med res. 2019;11(4):247-255. doi: 10.14740/jocmr3744. pmid: 30937114. 24. faconti l, ferro a, webb aj, cruickshank jk, chowienczyk pj; british and irish hypertension society. hydrochlorothiazide and the risk of skin cancer. a scientific statement of the british and irish hypertension society. j hum hypertens. 2019;33(4):257258. doi: 10.1038/s41371-019-0190-2. pmid: 30842544. 25. viola e, coggiola pittoni a, drahos a, moretti u, conforti a. photosensitivity with angiotensin ii receptor blockers: a retrospective study using data from vigibase®. drug saf. 2015;38 (10):889-894. doi: 10.1007/s40264-015-0323-7. pmid: 26187686. 26. nardone b, orrell ka, vakharia pp, west dp. skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (tnf-αis), angiotensin-receptor blockers (arbs), phosphodiesterase type 5 inhibitors (pde5is) and statins—weighing the evidence. expert opin drug saf. 2018;17(2):139-147. doi: 10.1080/14740338.2018.1400530. pmid: 29103328. research | dermatol pract concept. 2021;11(2):e2021031 7 27. nardone b, majewski s, kim as, et al. melanoma and non-melanoma skin cancer associated with angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers and thiazides: a matched cohort study. drug saf. 2017;40(3):249–255. doi: 10.1007/ s40264-016-0487-9. pmid: 27943160. 28. moscarelli l, zanazzi m, mancini g, et al. keratinocyte cancer prevention with ace inhibitors, angiotensin receptor blockers or their combination in renal transplant recipients. clin nephrol. 2010;73:439-445. doi: 10.5414/cnp73439. pmid: 20497756 29. christian jb, lapane kl, hume al, eaton cb, weinstock ma; vattc trial. association of ace inhibitors and angiotensin receptor blockers with keratinocyte cancer prevention in the randomized vattc trial. j natl cancer inst. 2008;100:1223-1232. doi: 10.1093/jnci/djn262. pmid: 18728281 30. schmitt j, miot h. oral acetylsalicylic acid and prevalence of actinic keratosis. rev assoc médica bras. 2014;60(2):131-138. doi: 10.1590/1806-9282.60.02.010. pmid: 24919000. dermatology practical & conceptual www.derm101.com review by lynn a. cornelius, m.d. targeted therapeutics in melanoma, gajewski and hodi (eds.), is one of a series of publications from current clinical oncology that provides up-to-date information regarding new developments in cancer diagnosis and treatment provided by experts in the respective specialty fields. this volume, with a focus on melanoma, delivers just that, with an impressive list of international contributors. the title may be somewhat misleading, as the book covers mutation-, antiangiogenesisand immune-targeted therapies equally well. it serves as an excellent resource for physicians who, in any specialty, diagnose and treat melanoma patients. for anyone familiar with melanoma, it is clear that the landscape is rapidly evolving. melanoma has been long recognized as a disease that, once widely metastatic, is nearly uniformly fatal. conventional chemotherapy has been disappointing, and despite the recognition that melanoma is one of the more immunogenic of tumors, the effectiveness of previous treatments targeting immune modulation has been meager, at best. in a few short years, however, we have gone from discovery in the laboratory to more effective, although not yet universally curative, treatments. furthermore, with the application of each new therapy in tandem with on-going basic science investigations, we are gaining more insight into the biology and the mutational drivers of this disease. overall, the book is organized in a very logical manner, although it is also formatted such that the reader can easily locate information that is specific and stand-alone in a particular area of interest. the contents are segregated into three parts: part i, advances in melanoma biology, serves as an introduction into melanoma genomics, molecular targets and predictive biomarkers in the disease. part ii, signaling molecules as molecular targets, includes background information on molecular pathways that are relevant to melanoma biology, the rationale for targeting specific molecules, and a relatively current synopsis of clinical trials to date. part iii, rational immunotherapy approaches in melanoma, similarly addresses the known immunobiology of melanoma to date, and the underlying principles for specific immunemodulating treatments—those in current use in the clinic and others in clinical trial. a few of the chapters in parts ii and iii are somewhat dense (in the authors’ attempts to describe complex tumor and system biology), but this does not detract from the take-away message. the corollary to this point is that any reader familiar with the subject matter will, most likely, still glean additional insight into the topic. many of the chapters have informative illustrations and tables. one note is that the book has more typographical and formatting errors than would be expected in a formal pubbook review | dermatol pract concept 2012;2(4):13 63 gajewski tf, hodi fs. targeted therapeutics in melanoma. new york: springer, 2012 reviews by lynn a. cornelius, m.d., mark a. hurt, m.d. citation: gajewski tf, hodi fs. targeted therapeutics in melanoma. dermatol pract conc. 2012;2(4):13. http://dx.doi.org/10.5826/ dpc.0204a13. copyright: ©2012 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr., maryland heights, mo 63043, usa. tel. 314.991.4470. email: markhurt@aol.com. gajewski tf, hodi fs. targeted therapeutics in melanoma. new york: springer, 2012. 337 pp.; isbn 978-161779-406-3; upc 9781617794063; $219. 64 book review | dermatol pract concept 2012;2(4):13 lication. this can be slightly distracting, but may reflect the current content and timeliness of the publication. as someone who is familiar with the field, i feel this is an excellent resource and reference for physicians and scientists who want a comprehensive overview of current advances in melanoma therapy. i truly appreciate the opportunity to provide this review. lynn a. cornelius, m.d. is winfred a. & emma r. showman professor of dermatology and chief of the division of dermatology at washington university school of medicine st. louis, mo, usa. contact dr. cornelius at: lcorneli@dom.wustl.edu. comments by mark a. hurt, m.d. i thank dr. cornelius for her constructive review. i contacted the book’s editors, but neither replied to my enquiry. i extend the opportunity for them to respond to dr. cornelius or to me. this book is 377 pages, including the index. as the title states, it is a tome targeted toward the targeted therapy of melanoma, not the diagnosis as such. this fact alone serves to remove it from the daily experience, currently, of many, if not most, dermatopathologists. this is a book for physicians who treat patients with an established diagnosis of melanoma. the editors begin in their preface with the depressing fact that the fda, from 1976 until 2011, approved only two forms of non-surgical therapy—these include dacarbizine, approved in 1976, and il-2, approved by the fda in 1998. they continue, however, that genomic technologies have been the source of newer information on oncogene mutations that have led to the knowledge of kinases present in some melanomas. this reviewer wonders what advances might have been made on this front without the heavy-hand of fda approval that has violated the rights of patients and physicians in attempting heroic advancements in the treatment of melanoma. the editors divide this book into three parts: the first addresses advances in the understanding of the biology of melanoma; the second explores signaling molecules as molecular targets; the third grapples with immunotherapeutic approaches in the treatment of melanoma. all of the chapters are written as though they were stand-alone articles, each with an abstract, body, and conclusion. of note to dermatopathologists, there has been difficulty in finding correlation with the model of so-called melanoma “progression” as advocated by clark et al (1984) [1] to the genomics of melanoma. kashini-sabet, in chapter 2 (melanoma genomics), rightly states that “while this model of melanoma progression was described several years ago and is well understood, prior to the advent of microarray analysis, one would be hard pressed to identify genes whose differential expression corresponded to any of these phases of melanoma progression.” this is not at all surprising given that the “progression” hypothesis was dubious from the very beginning, and i take issue that anyone ever understood it. there is no credible evidence that melanocytic nevi “transform” into melanomas; cells transform, but lesions do not. what is readily observable is that there are nevi, nevi in conjunction with melanomas, and melanomas. how a melanocyte eventually becomes a melanoma is as much an enigma today as it was when clark et al wrote their article in 1984. it is true that much new information about certain genes associated with melanomas, but this is not the same as knowing the cause(s) of melanoma. the editors, in part ii, organize the discussion of signaling molecules as molecular targets for the treatment of melanoma. these articles center on kit, b-raf inhibition, the notch and β-catenin pathways, stat3 and src signaling, tor, p13k & akt pathways, antiapoptotic pathways, and antiangiogenesis therapy. immunotherapeutics, discussed in part iii, include melanoma antigens recognized by t lymphocytes, melanoma vaccines, adoptive cell therapy for treatment of metastatic melanoma, anti-ctla-4 monoclonal antibodies, anti pd-1 and anti b7-h1/pd-l1 monoclonal antibodies, agonist immune costimulatory agents, novel cytokines, and modulation of the tumor environment. ultimately, this technical work requires a considerable base of knowledge to understand and apply. i think the appeal of it is for those melanoma oncologists and dermatologists with a strong focus on the medical treatment of advanced melanoma. this is particularly true for patients with melanomas that have evolved beyond the surgical stages. i suspect, in the next few years, dermatopathologists will find a role in the assistance of dermatologic oncologists who use these therapies to treat patients with advanced melanoma. in the meantime, dermatopathologists might want to purchase this book as a point of reference, as these foci of research and treatment are only the beginning of what promises to be an explosion of possible treatments for patients with melanoma. reference 1. clark wh jr, elder de, guerry d 4th, epstein mn, greene mh, van horn m. a study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. hum pathol 1984 dec;15(12):1147-65. pubmed pmid: 6500548. dr. hurt is the book review editor of dermatology practical and conceptual, and he practices dermatopathology in maryland heights, mo, usa. contact him at markhurt@aol.com. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021010 1 dermatology practical & conceptual new dermoscopic keys for circumscribed acral hypokeratosis: report of four cases paula majluf-cáceres1, cristián vera-kellet1, sergio gonzález-bombardiere2 1 department of dermatology, pontificia universidad católica de chile 2 department of dermatopathology, pontificia universidad católica de chile key words: acral hypokeratosis, image enhancement, dermatopathology, dermoscopy citation: majluf-cáceres p, vera-kellet c, gonzález-bombardiere s. new dermoscopic keyes for circumscribed acral hypokeratosis: report of four cases. dermatol pract concept. 2021;11(2):e2021010. doi: https://doi.org/10.5826/dpc.1102a10 accepted: august 9, 2020; published: march 8, 2021 copyright: ©2021 majluf-cáceres et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: paula majluf-cáceres, md, centro médico san joaquin, vicuña mackenna 4686, macul, chile. email: pamajluf@ uc.cl introduction descriptions of the dermoscopic features of acral hypokeratosis (ah) are few. clinically it can resemble other entities, such as bowen disease or porokeratosis of mibelli. although ah is considered a benign pathology, in 2010 a case with actinic keratosis in the hypokeratosic epidermis and underlying elastosis was reported [1], hence the importance of knowing the dermoscopic findings for an early diagnosis and to rule out other differential or coexisting diagnoses. case presentation our case series was comprised of 4 patients with ah confirmed by biopsy in the hypothenar eminence. figure 1a shows ah in a 61-year-old and figure 1b a 78-year-old woman with a 10-year history of ah. dermoscopy revealed pink areas on a red milky blush with scattered red dots, steplike scales at the periphery, and elongated whitish structures in a fibrillar raindrop pattern (figure 1, c and d). the third case corresponded to asymptomatic ah (figure 1e) that had developed 2 weeks after a cutting wound in a 30-year-old woman. dermoscopy showed a red dot pattern over a homogeneous red-yellow area (figure 1f). the fourth case was a 54-year-old woman affected by ah for 8 years (figure 1g). dermoscopy revealed a fine white pseudonetwork, pink stiff areas on a red milky blush with red dots, step-like scales at the periphery, and elongated whitish structures in a fibrillar raindrop pattern. (figure 1h). microscopy revealed an area of hypokeratosis demarcated by a sharp and frayed cut-off from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis (figure 2). 2 letter | dermatol pract concept 2021;11(2):e2021010 figure 1. clinical and dermoscopic features. (a and b) cases 1 and 2: atrophic erythematous plaque with an irregular hyperkeratotic border. (c) dermoscopy shows pink areas on a red milky blush with scattered red dots, step-like scales at the periphery and elongated whitish structures in a raindrop pattern. (d) dermoscopy shows red milky blush, pink islets with dotted vessels, elongated whitish structures in raindrop pattern and staircase sign. (e) case 3: depressed erythematous plaque, surrounded by an hyperkeratotic border. (f) dermoscopy showed a red dot pattern over a homogeneous red-yellow area. letter | dermatol pract concept 2021;11(2):e2021010 3 figure 2. histology displays an area of hypokeratosis demarcated by a sharp and frayed cut-off from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis and slightly thickened collagen fibers in the reticular dermis (h&e, ×10). conclusions previous case series reported star-like desquamation at the periphery,and a well-demarcated erythema with reddish dots. these structures correlate with histopathological studies showing a sharply demarcated area of hypokeratosis, dilated capillaries in the papillary dermis and vessels in the upper reticular dermis [2]. a recent case report of congenital plantar ah showed a white thin scale and a reticulated surface with no visible acrosyringia opposing the typical dermoscopic acral pattern [3]. our study revealed different dermoscopic findings than previously published: a fine white pseudonetwork and elongated whitish structures in a “raindrop pattern” found in those patients with longstanding ah and could be correlated with the increasing collagen proliferation and thickening. thus in our case of 2-weeks’ onset ah, only a yellowish-red blush and red dots with peripheral step-like scales were distinguishing. references 1. kanitakis j, lora v, balme b, roby j. premalignant circumscribedpalmar hypokeratosis: a new form of circumscribed palmar hypokeratosis? case report and literature review. dermatology. 2010;220(2):143-146. doi: 10.1159/000264607. pmid:19955702. 2. nishimura m, nishie w, nakazato s, nemoto-hasabe i, fujita y, simizu h. circumscribed palmar hypokeratosis: correlation between histopathological patterns and dermoscopic findings. br j dermatol. 2012;167:221-222. doi: 10.1111/j.13652133.2012.10855.x. pmid:22283364. 3. bassi a, oranges t, massi d, piccolo v, mazzatenta c, neri i. congenital circumscribed plantar hypokeratosis. int j dermatol. 202059(10):e367-e369. doi: 10.1111/ijd.14967. pmid: 32516442. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021005 1 dermatology practical & conceptual unusual presentation of cutaneous b-cell lymphoma atop an arteriovenous fistula made for renal dialysis ahmed abdelbary1, hadir shakshouk1 1 department of dermatology, andrology and venerology, alexandria university, egypt key words: cutaneous b cell lymphoma, skin malignancy, dermatopathology, lymphoma citation: abdelbary a, shakshouk h. unusual presentation of cutaneous b-cell lymphoma atop an arteriovenous fistula made for renal dialysis. dermatol pract concept. 2021;11(2):e2021005. doi: https://doi.org/10.5826/dpc.1102a05 accepted: july 15, 2020; published: march 8, 2021 copyright: ©2021 abdelbary and shakshouk. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: hadir shakshouk, msc, department of dermatology, andrology and venerology, alexandria university, egypt. email: drhadir58@gmail.com introduction primary cutaneous b-cell lymphomas (pcbcls) are uncommon diseases with heterogeneous clinical pictures and prognoses. pcbcls are classified into 3 main subtypes: cutaneous marginal zone lymphoma (pcmzl), cutaneous follicle center lymphoma (pcfcl), and cutaneous diffuse large b-cell lymphoma, leg-type (dlbcl-lt). each subtype has a distinct clinical presentation and histopathological, molecular and immunologic profiles. they also differ considerably in prognosis and treatment [1]. we report an atypical case of pcbcl, leg type (lt) arising atop an arteriovenous (av) fistula made for renal dialysis in a young woman. case presentation a 32-year-old woman presented with multiple tender erythematous papules of 1 month’s duration on her right forearm on top of an av fistula that was made for renal dialysis. she was a known renal failure patient since her early twenties and had been on renal dialysis since then. she reported that lesions on her forearm were increasing in number and size and becoming more painful. physical examination revealed multiple erythematous papules and nodules on the forearm. they were firm in consistency and tender on palpation. one of the nodules showed superficial ulceration (figure 1). given figure 1. multiple erythematous papules and nodules on the forearm, one showing superficial ulceration. 2 letter | dermatol pract concept 2021;11(2):e2021005 the nodule arose on top of an av fistula, our clinical differential diagnosis included a wide range of vascular tumors. histopathological examination revealed grenz zone and diffuse infiltration of large pleomorphic cells occupying the whole dermis (figure 2). some mitotic figures were noted. cd20 was found to be diffusely positive for all these atypical cells and cd4 was negative. this highlighted the possibility of cutaneous b-cell lymphoma. further immunohistochemical analysis showed diffuse bcl-2 positive staining and few scattered bcl-6 positive staining (figure 3). cd10 and mum1 were negative. a battery of laboratory investigations and radiological imaging were unremarkable. given these histopathological and immunohistochemical findings, a diagnosis of primary cutaneous b-cell lymphoma, leg type was made. the patient received one cycle of r-chop (rituximab, doxorubicin, vincristine, cyclophosamide and prednisone), but she unfortunately died. conclusion pcbcl-lt is considered an aggressive type of cutaneous b-cell lymphoma. it presents clinically as nodules of violaceous color with frequent ulceration. it is predominant in elderly females. secondary involvement of other organs can occur shortly after diagnosis that leads to a poor prognosis. distinction for systemic lymphoma can be difficult [1]. typical histopathological features include a dense diffuse infiltrate composed of centroblasts and immunoblasts occupying the dermis and extending to the hypofigure 2. histopathological examination of the lesion showed: (a) grenz zone, dense diffuse infiltrate with pleomorphic cells in the dermis (h&e, ×10 original magnification) and (b) centroblasts and immunoblasts, (h&e, ×40 original magnification). figure 3. immnunohistochemical staining showed: (a) diffuse positive staining for cd20 and (b) diffuse positive staining for bcl-2 (×10 original magnification). letter | dermatol pract concept 2021;11(2):e2021005 3 dermis. immunohistochemical staining shows positivity for the usual b cell markers, cd20 and cd-79a, and characteristically diffuse positivity for bcl-2 and mum1. bcl-2 positivity has been linked to poor prognosis in some studies [2]. mum1 has been shown to be negative in pcbcl-lt in some reports. given its poor prognosis, pcbcl-lt requires aggressive treatment. chemotherapy with r-chop is considered the first line [2]. primary cutaneous b-cell lymphomas are rare tumors and often represent a diagnostic challenge. extensive immunohistochemical studies are crucial to determining the type in addition to laboratory and radiological workups to exclude extracutaneous involvement. references 1. suárez al, pulitzer m, horwitz s, moskowitz a, querfeld c, myskowski pl. primary cutaneous b-cell lymphomas: part i. clinical features, diagnosis, and classification. j am acad dermatol. 2013, 69(3):329.e321-329.e313. doi: 10.1016/j.jaad.2013.06.012. pmid: 23957984. 2. malachowski sj, sun j, chen pl, seminario-vidal l. diagnosis and management of cutaneous b-cell lymphomas. dermatol clin. 2019, 37(4):443-454. doi: 10.1016/j.det.2019.05.004. pmid: 31466585. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020101 1 dermatology practical & conceptual introduction spitz tumors are a heterogenous group of melanocytic neoplasms, which on histology demonstrate enlarged oval, epithelioid or spindled melanocytes, often in association with epidermal hyperplasia. the degree of pigmentation and presence or absence of maturation is variable. the molecular genetic basis for these variations in histomorphology is increasingly being recognized. spitz tumors typically harbor hras activating mutations, inactivation or deletion of bap1 or gene fusions involving the kinases ros1, alk, ntrk1, braf, ret, met or ntrk3 [1]. some of these aberrations have been associated with progression to melanoma, while others have not [2]. there is little in the literature regarding the impact of particular molecular subtypes of spitz on clinical dermoscopic appearance. most publications describe the clinical-dermoscopic features common to spitz tumors as an entire category. we deduce that, as many of these neoplasms have characteristic histomorphology, clinical-dermoscopic features may be relatively consistent for a particular molecular genetic aberration. herein, we describe the clinical dermoscopic features of a spitz tumor with an lmnantrk1 fusion presenting in an adult. case presentation a 51-year-old man with a history of numerous clinically atypical pigmented lesions, multiple biopsy-confirmed dysplastic nevi, and a first-degree relative with metastatic melanoma presented for a follow-up comprehensive skin examination. due to the patient’s high risk, his skin surface was being surveyed longitudinally with digital whole-body photography and high-resolution dermoscopy. a new lesion was identified on his left calf, which was not present on exam 6 months prior. clinical examination revealed a smooth, red, domeshaped 5 × 5 mm papule with little surface change (figure 1a). on dermoscopy, the lesion was symmetric and demonstrated a regular array of coiled-glomerular vessels admixed with crystalline structures (figure 1b). on histopathology, there was a broad compound proliferation of enlarged spindled and epithelioid (amelanotic) melanocytes with associated epidermal hyperplasia (figures 2 and 3). many junctional melanocytic nests demonstrating peripheral clefting and occasional kamino bodies were observed. thin and elongated “filigree-like” rete ridges were seen, occasionally extending into the superficial tumor aggregates. in the dermis, there were “lobulated nests” along with conspicuous melanocytic matdermoscopic features of spitz tumor with lmna-ntrk1 fusion ben j. friedman1,2, gabrielle robinson1, laurie kohen1 1 department of dermatology, henry ford health system, detroit, mi, usa 2 department of pathology and laboratory medicine, henry ford health system, detroit, mi, usa key words: dermoscopy, spitz tumor, ntrk1 fusion, spitz nevus citation: friedman bj, robinson g, kohen l. dermoscopic features of spitz tumor with lmna-ntrk1 fusion. dermatol pract concept. 2021;11(1):e2020101. doi: https://doi.org/10.5826/dpc.1101a101 accepted: june 16, 2020; published: december 10, 2020 copyright: ©2020 friedman et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ben j. friedman, md, 3031 w. grand blvd ste. 800, detroit, mi 48202, usa. email: bfriedm1@hfhs.org 2 letter | dermatol pract concept 2021;11(1):e2020101 uration. given more than the occasional pagetoid scatter of individual melanocytes in the epidermis as well as proliferation between the rete ridges in some foci, the lesion was felt to represent a spitz nevus with atypical features. complete excision was recommended given margin involvement. from the above-mentioned histological features [2], the tumor was suspected to harbor an ntrk1 fusion, and this was confirmed through an rna-based next generation sequencing assay, which detected a 5’ partner of lmna. although rare melanomas harboring ntrk1 fusions exist, spitz lineage more commonly portends indolent biologic behavior. in the unlikely event of disease progression, our patient would be a candidate for targeted therapy with trk inhibitors. conclusions the presence of a dome-shaped red papule with a regular array of glomeruloid vessels admixed with crystalline structures should prompt clinical suspicion of a spitz tumor with a ntrk1 fusion. although some variants of bowen disease contain similar vessel morphology, the coexistence of crystalline structures and lack of scale would be unusual. furthermore, the diffuse (as opposed to grouped) arrangement of the vessels is not typical for bowen disease. additional larger series are needed to replicate these findings and inform on the clinical-dermoscopic features of particular molecularly defined spitz tumor subtypes. references 1. quan, vl, panah, e, zhang, b, shi, k, mohan, ls, gerami, p. the role of gene fusions in melanocytic neoplasms. j cutan pathol. 2019;46:878-887. doi: 10.1111/ cup.13521. pmid: 31152596. 2. yeh i, busam kj, mccalmont th, et al. filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize spitz tumors with ntrk1 fusion. am j surg p a t h o l . 2 0 1 9 ; 4 3 ( 6 ) : 7 3 7 7 4 6 . d o i : 10.1097/pas.0000000000001235. pmid: 30844834. figure 1. (a) clinical: red dome-shaped papule on left calf. (b) dermoscopic: regular array of glomeruloid vessels admixed with crystalline structures. a b figure 2. histopathology, low power. compound proliferation of enlarged spindled and epithelioid melanocytes with nests containing peripheral clefts. there are “filagree-like” rete ridges with lobulated nesting pattern (h&e, original magnification ×100). figure 3. histopathology, high power. hypervascular papillary dermis is seen in between the altered rete pegs containing coils of dilated capillaries, which correlates to the dermoscopic vascular morphology (h&e, original magnification ×300). dermatology: practical and conceptual observation | dermatol pract concept 2016;6(2):9 49 dermatology practical & conceptual www.derm101.com introduction syphilis is an infectious disease caused by treponema pallidum. secondary syphilis presents with generalized lesions on the skin and mucous membranes, primarily macules and then progressing to papules. when the papules become hypertrophic and coalesced on macerated skin or mucous membranes, they are called condyloma lata, which more commonly occur around the anus and vulva. we report a case of condylomata lata occurring on the ankle, an unusual site. condylomata lata on the ankle: an unusual location eri ikeda1, akane goto1, reiko suzaki1, mizuki sawada1, itaru dekio1, sumiko ishizaki1, mariko fujibayashi2, hayato takahashi3, masaru tanaka1 1 department of dermatology, tokyo woman’s medical university medical center east, tokyo, japan 2 department of pathology, tokyo woman’s medical university medical center east, tokyo, japan 3 department of dermatology, keio university school of medicine, tokyo, japan key words: condyloma lata, syphilis, dermoscopy, unusual location, ankle citation: ikeda e, goto a, suzaki r, sawada m, dekio i, ishizaki s, fujibayashi m, takahashi h, tanaka m. condyloma lata on the ankle: an unusual location. dermatol pract concept 2016;6(2):9. doi: 10.5826/dpc.0602a09 received: november 10, 2015; accepted: march 19, 2016; published: april 30, 2016 copyright: ©2016 ikeda et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: eri ikeda, md, department of dermatology, tokyo women’s medical university medical center east, 2-1-10 nishi-ogu, arakawa-ku, tokyo 116-8567, japan. tel. +81 3 3810 1111; fax. +81 3 3894 1441. email. eriikeda-tjo@umin.net a 43-year-old japanese man presented with reddish nodules on the ankle. the nodules had a yellowish crust and eroded surface. dermoscopy revealed red to milky-red globules at the periphery and some glomerular vessels in the center and a whitish-pink network, which corresponded to capillary dilatation in the papillary dermis and prominent acanthosis, respectively. these structures were surrounded by a yellowish peripheral structureless area and multiple white, small, round structures in the center, corresponding to the macerated horny layer and keratin plugs. blood samples were positive for rapid plasma reagin (1:64), treponema pallidum hemagglutination assay (1:20480), and fluorescent treponemal antibody-absorption (1:1280). a lesional skin biopsy specimen showed irregular acanthosis and papillomatosis. the warthin-starry and anti-treponema pallidum antibody stains on the biopsy specimen revealed many spirochetes in the lower epidermis and the papillary dermis. a diagnosis of secondary syphilis with condylomata lata was made. after one week of treatment with oral benzylpenicillin benzathine hydrate (bicillin® g granules 400,000 units; banyu pharmaceutical co., ltd, tokyo, japan), 1.6 million units (u) daily, the ankle lesions had resolved with a small ulcer and pigmentation. although syphilis is a relatively common disease, this case study reports an unusual presentation as well as dermoscopy findings. abstract 50 observation | dermatol pract concept 2016;6(2):9 with the following titers: blood rapid plasma reagin (serological test for syphilis) at 1:64 (normal, 1:<1), t. pallidum hemagglutination assay at 1:20480 (normal, 1:<80) and fluorescent treponemal antibody-absorption test at 1:1280 (normal, 1:<20). the anti-hiv antibody test was negative. a biopsy sample was obtained from the larger nodule. the histopathological findings included irregular acanthosis and papillomatosis, a parakeratotic horny layer, and dense lymphocytic and plasma cell infiltration in the papillary and upper dermis (figure 3a). warthin-starry (figure 3b) and case presentation a 43-year-old japanese man presented at a dermatology clinic with multiple erythema on the legs, which had been noticed for three months. because treatment with a topical glucocorticosteroid, betamethasone butyrate propionate ointment (antebate, torii pharmaceutical, tokyo), was not effective and several nodules were also present on the left ankle the patient was referred to our university hospital. the family history and patient’s past medical history were not remarkable. when asked, the patient denied contracting syphilis by a non-sexual route. his work history indicated he was a field superintendent and wore protective shoes throughout the workday. physical examination showed an indurated reddish nodule measuring 30 x 25 mm with an “8”-shaped raised border and partly covered by yellowish crust (figure 1a). there was another yellowish, crusted nodule measuring 15 x 5 mm near the heel. multiple scaly reddish macules measuring up to 5 mm were noted on the palms and soles (figure 1b). dermoscopy of the largest nodule demonstrated red to milky red globules and some glomerular vessels and a whitish pink network on the raised border (figure 2). a yellowish structureless area was noted at the periphery and multiple white, small, round structures were noted in the center. laboratory data showed a white blood cell count of 10400/ml (normal, 3900 to 9800). the assays were positive figure 1. clinical photographs. (a) an indurated reddish nodule of 30 x 25 mm with an “8”-shaped raised border partly covered by yellowish crust. (b, c) multiple scaly erythematous plaques up to 5 mm on the palms and soles. [copyright: ©2016 ikeda et al.] figure 2. dermoscopy of condyloma lata. red to milkyred globules, glomerular vessels and a whitish-pink network on the raised border. there is a yellowish structureless area at the periphery and multiple white, small, round structures in the center. [copyright: ©2016 ikeda et al.] a b c observation | dermatol pract concept 2016;6(2):9 51 was not seen during the treatment. the patient discontinued hospital visits after four weeks of oral treatment. conclusions condylomata lata consist of flat-topped eroded weeping papules occurring mainly on the perianal area and the vulva [1]. unusual sites of occurrence include the axilla, palms, face, umbilicus, and toe webs [2-7]. the reason for the unusual or widespread lesions could be attributed to mechanical friction and local hyperhidrosis [2, 3]. the present case showed an extremely rare site for the occurrence of condylomata lata. this rare occurrence of condylomata lata on the ankle could be explained by the patient’s work history of wearing protective shoes that cause a hyperhidrotic environment coupled with the physical friction associated with walking. we hypothesize that the cause for condyloma lata in this case might be due to the patient’s work history of wearing protective shoes that provide an ideal environment for the proliferation of the treponemal spirochetes. the route of transmission of infection is unknown because the patient denied any route. dermoscopy of condyloma lata has not been previously reported in the literature. the pathological features of prominent acanthosis seemed to correspond to the whitish-pink network on dermoscopy. the capillary dilatation in the papillary dermis appeared to be corresponding to red to milky-red globules. the yellowish structureless area at the periphery and multiple whitish clods in the center could be explained by the macerated horny layer and keratin plugs. this study was presented at the 113th annual meeting of the japanese dermatological association. references 1. kinghorn gr. syphilis and bacterial sexually transmitted infections. in: da burns, sm breathnach, nh cox et al, ed. rook’s textbook of dermatology. 8th ed. southern gate: blackwell, 2010: 34.1-14. 2. fiumara nj. unusual location of condyloma lata. a case report. br j vener dis 1977;53:391-3. pmid: 606337 3. el-saad el-rifaie m. condylomata lata of the palms: an unusual site. br j vener dis 1980;56:267-8. pmid: 7427699 4. sundararaj as, williams j, gopinathan r, deivam s. unusual manifestations of early syphilis in a married male. florid manifestations of condylomata lata on the face. int j std aids 1995;6:52-3. pmid: 7727585 5. hayashi m, ito k, ishiji t, et al. secondary-stage syphilis with unusual clinical features. pract dermatol 2012;34:1189-92. 6. tham sn, lee ct. condyloma latum mimicking keratoacanthoma in patient with secondary syphilis. genitourin med 1987;63:33940. pmid: 3679220 7. rosen t, hwong h. pedal interdigital condylomata lata: a rare sign of secondary syphilis. sex transm dis 2001;28:184-6. pmid: 11289202 anti-t. pallidum antibody (figure 3c) stains revealed many spirochetes in the lower epidermis and the papillary dermis. based on the above clinical, serological, and histopathological findings, the diagnosis of secondary syphilis (condylomata lata on the ankle and syphilitic psoriasis on the palms and soles) was made. one week after treatment with oral benzylpenicillin benzathine hydrate (bicillin® g granules 400,000 units; banyu pharmaceutical co., ltd, tokyo, japan) 1.6 million u daily, the ankle lesions had almost resolved with a small ulcer and pigmentation remaining. the jarisch-herxheimer reaction figure 3. histopathology from condyloma lata. hematoxylin-eosin staining (a) showing irregular acanthosis and papillomatosis, a parakeratotic horny layer, and dense lymphocytic and plasma cell infiltration in the papillary and upper dermis. warthin-starry (b) and anti-treponema pallidum antibody (c) stains revealing many spirochetes in the lower epidermis and the papillary dermis. [copyright: ©2016 ikeda et al.] a b c dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(2):e2020046 1 dermatology practical & conceptual case presentation a 62-year-old indian man with a strong family history of metabolic syndrome (mets) presented with asymptomatic, granular-surfaced, dark brown pigmentation on the cheeks (figure 1, a and b). nuchal/axillary acanthosis nigricans (an) were conspicuously absent. dermoscopy showed exaggerated light brown pseudoreticular network and scattered brown globules and structureless areas. at higher magnification (×150), oval dark brown annular “ring”-like structures centered around hair follicles were observed (figure 1c). the dermoscopic image was conspicuously devoid of sulci/cristae (which are considered typical of an). examination and biochemical evaluation revealed blood pressure = 160/102 mm hg, waist circumference = 92 cm, fasting blood glucose = 126 mg/dl, and fasting serum triglycerides = 438 mg/dl, confirming central obesity with mets. histopathology revealed hypermelanized epidermis and dermis, and basal melanocytosis (figure 1d). clinicodermoscopicopathological correlation diagnosis was maturational hyperpigmentation (mh) with mets. teaching point although facial an and mh may actually represent evolutionary standpoints on the morphological spectrum of cutaneous markers of mets (cmm) [1], labeling them as synonymous [2] without dermoscopy/supportive evidence seems inappropriate at present. maturational hyperpigmentation is a newly described facial melanosis. it is a cmm akin to facial an with which it does share some morphological features as well; however, specific features such as relatively softer surface with conspicuous but finer granularity and indistinct margins on gross morphology, and distinctive dermoscopy and histopathology [1], warrant identification of mh as a separate nosological entity. thus, every physician’s awareness of this relatively less evident and lesser-known asymptomatic entity is paramount to facilitate prompt workup for mets. maturational hyperpigmentation: cutaneous marker of metabolic syndrome sidharth sonthalia,1 mahima agrawal,2 poonam sharma,3 amarendra pandey4 1 skinnocence: the skin clinic & research center, gurugram, india 2 lhmc & associated hospitals, new delhi, india 3 skin institute & school of dermatology (sisd), new delhi, india 4 cosmasure skin hair, fat management and laser clinic, jabalpur, india key words: maturational hyperpigmentation, facial melanosis, metabolic syndrome, facial acanthosis nigricans, dermoscopy citation: sonthalia s, agrawal m, sharma p, pandey a. maturational hyperpigmentation: cutaneous marker of metabolic syndrome. dermatol pract concept. 2020;10(2):e2020046. doi: https://doi.org/10.5826/dpc.1002a46 accepted: february 9, 2020; published: april 20, 2020 copyright: ©2020 sonthalia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sidharth sonthalia, md, dnnb, mnams, skinnocence: the skin clinic & research center, c-2246, sushant lok-1, block-c, gurugram-122009, india. email: sidharth.sonthalia@gmail.com https://doi.org/10.5826/dpc.1002a46 mailto:sidharth.sonthalia@gmail.com 2 image letter | dermatol pract concept 2020;10(2):e2020046 references 1. sonthalia s, sarkar r, neema s. maturational hyperpigmentation: clinico-dermoscopic and histopathological profile of a new cutaneous marker of metabolic syndrome. pigment int. 2018;5(1):54-56. 2. verma s, vasani r, joshi r, phiske m, punjabi p, toprani t. a descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using homa2 ir. indian dermatol online j. 2016;7(6):498-503. figure 1. maturational hyperpigmentation. (a) patch of dark brown pigmentation with ill-defined margins and conspicuous granular surface over the right cheek (white arrow) extending from the angle of the eye to nearly the angle of the mouth. (b) similar but much lighter pigmentation over the left cheek suggestive of an evolving lesion. (c) videodermoscopic image of the hyperpigmentation on the right side revealing exaggerated light brown pseudoreticular network with scattered brown globules and structureless areas, perifollicular oval dark brown “rings” (blue arrows), and absence of sulci and cristae, the dermoscopic features that are pathognomonic of cutaneous acanthosis nigricans. the perifollicular rings can be appreciated better at higher magnification (blue arrows) in the figure inset (polarized, ×35 and ×150; escope videodermoscope, timpac healthcare pvt. ltd., new delhi, india). (d) histopathology showing basal cell layer melanocytosis, hypermelanization of basal and squamous layers of epidermis, and the dermis. hyperkeratosis and papillomatosis are minimal-to-absent. h&e, ×400. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com review | dermatol pract concept 2012;3(2):4 13 introduction a bernard ackerman always had a “dream” that a dictionary would be created for dermatopathology (and dermatology) so that these fields could better communicate with one another, in one “language.” he felt that until a real dictionary came into being neither would be authentic branches of knowledge. he also felt that this dictionary would serve pathology as well. many tried to complete this “project” (in philadelphia, new york, and elsewhere) but none succeeded. bernie considered morris leider’s 1976 dermatology dictionary a very limited one for many reasons. bernie’s own efforts with almut böer, m.d. in the journal, dermatopathology: practical & conceptual used an “extended discussion of each word.” they managed to get through the “a’s” (over a two year period) and attempted to show others how a dictionary should be completed. they encouraged others (using their model) to continue this work. this compendium of words is not meant to be “original” nor is, it a “dictionary” as defined. the oxford dictionary, second edition revised, says “dictionary: a reference book containing an alphabetical list of words with information given for each word, usually including meaning, pronunciation, and etymology.” this work is essentially based on bernie’s opinions about words. my task has been to “pluck” the words, ideas, and concepts out, organize them, rewrite some and add some of my own. discussions of words have been taken from: • all his glossaries from 1978-2010—the glossaries have been the most useful • all his books from 1978-2010 (the material “outside” the glossaries) • the journal, dermatopathology practical & conceptual (with almut böer, m.d. and other authors) and bernie’s material from other places, (i.e., indianapolis meetings, palm springs meetings, aad meetings, isdp, asdp, as well as the material from the institute of dermatopathology at jefferson in philadelphia and the ackerman academy in new york, etc.) the journal has been extremely useful. its use accounts for why there are so many words in the “a’s” compared to other letters since this was the only letter for which definitions were done. in summary, the glossaries and “the journal” were the most useful. in addition the reader should keep in mind the following: whenever i say bernie’s works i am including his coauthors, if any. a portion of the material is copied verbatim from bernie’s material. i fully acknowledge that. (however, this is a tribute to bernie.) its essence and beyond is “ackermanian.” much of the material has been paraphrased from bernie’s works. a small amount of material comes from “others” and has been paraphrased or rewritten. (i.e., epidermotropism, neurotropism). some of bernie’s “words” have been rewritten by me in order to update the material as old ideas were discarded and new ones came to fruition (i.e., the infundibulum is epidermal). one change in a concept usually leads to many changes in the meanings of a word or many words. i hope my updates of bernie’s “definitions” which i decided to do have stayed true to bernie’s ideas and opinions (mine are very similar). some of the discussions of words are long and dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. introduction and part 1 bruce j. hookerman, m.d.1 1 dermatology, st. louis, missouri, usa citation: hookerman bj. dermatopathology: an abridged compendium of words. a discussion of them and opinions about them. introduction and part 1. dermatol pract conc. 2013;3(2):4. http://dx.doi.org/10.5826/dpc.0302a04. copyright: ©2013 hookerman. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: bruce hookerman, m.d., 12105 bridgeton square drive, st. louis, mo 63044, usa. email: bjhookerman@att.net. 14 review | dermatol pract concept 2012;3(2):4 rambling and repetitious (i.e., in-situ). the reason for this is that in many cases (especially in the “a’s”) they follow bernie and almut’s method and definitions. also, some discussions are pieced together from multiple sources. i hope this piecing together of a discussion of a word from various ackerman sources has not lead to confusion. the oxford, webster, and other well known dictionaries are accepted as “definers of the english language.” they do not differ very much. however, among the different “schools of dermatopathology” there are large differences in the usage, understanding, and the meaning of words (much less so for dermatology.) i feel this is driven by differences in concepts, criteria, plus intangibles that really make one “dictionary” which is accepted by all an impossibility! additionally on this subject there is something even more fascinating to me. each school feels that what they say (or think) regarding certain subjects (i.e., melanocytic neoplasia) makes perfect sense (to them) and the other “school” is “wrong.” each feels just as strongly about their own concepts, criteria, etc. and cannot “believe” the other school. (in many instances, one school may only marginally read what another school writes.) many are in between, some ideas from one group and also another. (i feel that before you can disagree with another’s concepts you must first be “clear” about your own and be able to state why “something is what it is.”) it is challenging to translate one language into another and thus know what the other side is “talking about” (unless the writing is unintelligible.) from this imperfect work i hope you will “take what you want and leave the rest.” the compendium (part 1) – a – abnormal melanocyte: any melanocyte, particularly one of a melanocytic nevus or of a melanoma, that differs cytopathologically from that of a melanocyte situated at the dermoepidermal junction of normal skin. by definition, a melanocyte positioned at that junction is normal and a melanocyte of a nevus or of a melanoma is abnormal. nuclei of melanocytes at the junction are small, round or oval, monomorphic, and monochromatic, and do not exhibit a nucleolus. as a rule, nuclei of abnormal melanocytes of a nevus and of a melanoma are larger than those of normal melanocytes, sometimes, as in the case of some “classic” spitz’s nevi and of some melanomas, being much larger. in nevi other than “classic” spitz’s nevi, nuclei of abnormal melanocytes tend to be monomorphic and monochromatic; in “classic” spitz’s nevi, they may be pleomorphic and, at times, heterochromatic. in melanomas, nuclei of abnormal melanocytes often are pleomorphic and heterochromatic. in both “classic” spitz’s nevi and melanomas, nuclei may sport a prominent nucleolus, but only in some melanomas is that nucleolus dead center in a vesicular nucleus of virtually every abnormal melanocyte constituent. in nevi other than “classic” spitz’s nevi, nuclei of abnormal melanocytes organized in aggregations are equidistant from one another; in “classic” spitz’s nevi and in melanomas; they often are not equidistant, that being a consequence of variability of the size and shape of nuclei, but also of the amount varied of cytoplasm. abnormal mitotic figure: a mitotic figure that is aberrant, such as being tripolar or tetrapolar, or of the configuration of a ring, in contrast with a normal appearance bipolar. abnormal mitotic figures are seen episodically in melanomas and, rarely, but surely, in “classic” spitz’s nevi. abortive: premature, prematurely, cut short. abortive has been defined in a variety of ways despite the fact that the meaning of it originally was “born prematurely.” in medicine in general, abortive refers to arrest in development, meaning that, biologically, a structure does not mature completely. in regard to a particular disease, the term also has the meaning of being “incomplete” clinically and histopathologically. concerning matters morphologic, however, the word abortive, as it is applied in the language of dermatology and dermatopathology, has yet to be defined in a cogent manner. in every instance in which the word “abortive” is employed for findings morphologic, the word is used wrongly. small plaque parapsoriasis is a manifestation of mycosis fungoides (not an abortive lymphoma), and psoriasis that spreads centrifugally is very much psoriasis (not abortive pustular psoriasis). immature structures in sections of tissue should be designated immature, not abortive. an adnexal anlage is an immature adnexal structure, the word anlage being german for an aggregation of cells in an embryo that represents the first evidence of a future structure. what is meant by an abortive anlage is just as opaque as what is intended by abortive melanosomes; melanosomes may be less than fully melanized, but that does not make them abortive. abscess: clinically a circumscribed collection of pus and histopathologically a localized collection of neutrophils. an abscess may come into being without any cause infectious, and in the skin most abscesses are not a result of infection. the most common abscesses recognizable clinically results from rupture of an infundibular cyst, and the most common circumstance in which that occurs is “cystic” acne vulgaris. abscesses of noninfectious nature are encountered histopathologically in eruptive lesions of psoriasis, “pustular” psoriasis being a caricature of the process, they having been given designations like munro’s microabscess and spongiform pustule of kogoj. strictly speaking, an abscess review | dermatol pract concept 2012;3(2):4 15 consists of neutrophils and both parts and products of them; “necrotic tissue” and “fluid products of tissue breakdown” are irrelevant to the composition of an abscess. although signs of inflammation, i.e., redness, may be observable around some abscesses, that surely is not always the case; for example, pustules widespread of von zumbusch psoriasis sometimes develop in skin devoid of redness. at other times, however, these pustules are situated on erythematous skin. the pus of an abscess need not be flowing and may never flow. in contrast, suppuration refers to the formation or discharge of pus. an exudate is fluid that has exuded from tissues and it need not be pus (purulence); it may be serous or hemorrhagic. a furuncle is an abscess situated around the base of a hair follicle, the process having begun as a suppurative infundibulitis that extended along the follicle to the base of it. the same may be said for hidradenitis suppurativa and its analogues, namely, acne conglobata, acne keloidalis, and dissecting cellulitis of the scalp (perifolliculitis abscedens and suffodiens). pathologenetically, hidradenitis suppurativa has nothing whatever to do with eccrine or apocrine glands. although the term “abscess cavity” is employed so often it has become cliché, it is a contradiction in terms because a cavity is an empty space. the same is true for “chronic abscess”; it is a non-sequitur because an abscess, consisting as it does of neutrophils, always is acute in terms of sequence chronologic of the inflammatory process, it being followed by granulomatous and fibrosing inflammation, the latter truly being “chronic.” last, pautrier’s microabscess is wrong on both counts: the phenomenon was described by darier, not pautrier, and the cells that make up the collection are lymphocytes, not neutrophils. a cluster of lymphocytes does not qualify as an abscess. acantho-: a prefix meaning spinous or prickle and in dermatology/ dermatopathology applied to spinous (prickle) cells of an epithelium acantholysis: a process whereby epithelial cells, as a consequence of loss of connections (desmosomes) between them, separate from one another, becoming round and eventually dying, the process ending in formation of either a cleft or a blister. acantholysis refers to a process and, that being the case cannot properly be said to be a “disruption” or “dissolution.” moreover, cells of the spinous, granular, and cornified layers may become acantholytic, for example, in focal acantholytic dyskeratosis as it presents itself in darier’s disease, grover’s disease, a particular kind of epidermal nevus, and a distinctive benign keratosis (acantholytic dyskeratotic acanthoma). not only cells of the epidermis (both surface and infundibular) are affected, but those of cutaneous ducts and even glands, namely, the sebaceous, apocrine, and eccrine. when epithelial cells separate completely from one another, they are doomed to become necrotic, which, in classic pathology is a particular type of degenerative phenomenon typified by pyknosis, karyorrhexis, and karyolysis, not by hyalin, which is a generic, antiquated designation for any substance, ranging from fibrin to amyloid, that resembles glass, and, because of its utter nonspecificity, should be eschewed because it is uninstructive. as stated earlier acantholysis pertains to a process pathologic that leads to formation of round epithelial cells that are separate distinctly from their neighbors, those cells being called acantholytic ones. acantholytic cells are observed in different kinds of processes pathologic, among those being inflammatory ones, such as pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, infection by herpes virus (herpes simplex, zoster, and varicella), and grover’s disease; neoplastic ones, such as squamous-cell carcinoma of the solar keratotic type (so-called pseudoglandular squamous-cell carcinoma); cystic ones, such as warty dyskeratoma; hamartomatous ones, such as an epidermal nevus punctuated by foci of acantholytic dyskeratosis, and one that escapes categorization readily in the classification of classic pathology, namely, darier’s disease. moreover, acantholytic cells may be brought into being by different mechanisms, the two most common being immunologic, as in pemphigus vulgaris and pemphigus foliaceus, and secondary to the effects of products of neutrophils as occurs in bullous impetigo and dermatitis herpetiformis. by virtue of these different mechanisms, acantholytic cells may appear above the basal layer, as in hailey-hailey disease, in the spinous zone mostly, as in infection by herpes virus, in the granular zone, as in pemphigus foliaceus, and in the cornified layer, as in darier’s disease. whenever neutrophils enter the epidermis in large numbers, the effects of enzymes released by them may induce formation of acantholytic cells in the spinous and granular zones, as occurs in inflammatory diseases as disparate from one another as pustular psoriasis and a pustular expression of dermatophytosis. and whenever neutrophils in subepidermal spaces and in subepidermal blisters are extraordinarily numerous, as is expected in lesions developed fully of dermatitis herpetiformis and bullous lupus erythematosus, acantholytic keratocytes may come into being at the base of the epidermis. when acantholysis occurs rapidly in an inflammatory disease, such as in pemphigus vulgaris, acantholytic cells die soon and become necrotic. when, however, acantholysis develops more slowly in an inflammatory disease, such as is the reality in hailey-hailey disease, acantholytic cells die more slowly, permitting time for cornification to occur as evidenced by the presence of acantholytic cells that are dyskeratotic. acantholytic cells in squamous cell carcinoma, warty dyskeratoma, the epidermal nevus typified by foci of acantholytic dyskeratosis, and in darier’s disease all cornify abnormally. 16 review | dermatol pract concept 2012;3(2):4 the notion of “villi” appearing in any disease of the skin characterized by acantholysis is misguided; what are said to be villi are merely prominent, but normal, dermal papillae crowned by an epidermal basal layer above which a cleft or blister has formed secondary to acantholysis. last, it should be noted that there are no truly subcorneal blisters, either as a consequence of substances immunologic or of effects enzymatic. the blisters actually develop in the uppermost part of the spinous zone or in the granular zone and by extension upward soon result in what seems to be a subcorneal blister. in reality, acantholytic cells may come into being above the basal layer (which is viable), as well as in the spinous and granular layer (which also are viable), but they cannot come into existence immediately beneath the cornified layer (which is nonviable). (see acantholytic dyskeratosis) acantholytic: pertaining to acantholysis acantholytic cell: an epithelial cell that has separated from other epithelial cells and in the process becomes round. acantholytic dyskeratosis: a condition marked histopathologically by changes in foci or in confluence of surface and/or infundibular epidermis marked by a suprabasal cleft above which cells in the spinous and granular layers have cornified prematurely (dyskeratosis) and become separated from one another (acantholysis), in conjunction often with parakeratotic cells that also have become acantholytic. acantholytic dyskeratosis is a distinctive pattern of changes identifiable with specificity histopathologically, it being a “reaction” only in the sense that all patterns histopathologic observed in skin and in other organs are a reaction to something; what exactly is not known with surety except for those patterns that result unquestionably from an infections agent, such as infection by papillomavirus, the virus of molluscum contagiosum, and herpes virus. although the denominators in common for acantholytic dyskeratosis are a suprabasal cleft and above it the presence of cells that are acantholytic and dyskeratotic, concurrently, the findings may be met with not only in foci of surface epidermis, such as in darier’s disease, grover’s disease, and one type of epidermal nevus, but also in a manner confluent dramatically in infundibular epidermis as occurs in the lining of a cyst known colloquially as warty dyskeratoma. acantholytic dyskeratotic cells in epidermal epithelium are not, in themselves, sufficient to qualify as “acantholytic dyskeratosis.” for example, once a blister forms, no matter whether as a papulovesicle of grover’s disease or as a bulla of hailey-hailey disease, both of those conditions being typified by the presence of acantholytic dyskeratotic cells, the findings no longer are considered to be mere “acantholytic dyskeratosis.” once serum has entered such a space, a cleft in an epidermis that houses acantholytic dyskeratotic cells is transformed into a blister, no matter how subtle or tiny, such as in a papulovesicle of grover’s disease. when a lesion is a papulovesicle and no longer a papule, the term “acantholytic dyskeratosis” is not appropriate because the acantholytic dyskeratotic cells are joined by serum. “foci of acantholytic dyskeratosis” (focal acantholytic dyskeratosis) occur in surface epidermis of darier’s disease and grover’s disease, both of which are typified by lesions widespread. parenthetically, in most patients with grover’s disease, called originally by grover “transient acantholytic dermatosis,” the condition is not evanescent, but persistent. darier’s disease always consists of keratotic papules, that is, rough surfaced ones, and that is the case, too, for that expression of grover’s disease in which each focus of acantholytic dyskeratosis is topped by a short column of parakeratosis; often, however, papules of grover’s disease have a smooth surface because no zone of parakeratosis sits atop a focus in the epidermis in which acantholytic cells are accompanied by a tad of serum and/or a hint of spongiosis. both the systematized and palmoplantar expressions of focal acantholytic dyskeratosis are representative of a type of epidermal nevus. in contradistinction to focal acantholytic dyskeratosis is confluent acantholytic dyskeratosis, which manifests itself usually in so-called warty dyskeratoma, which is not a neoplasm (tumor) but a particular type of infundibular cyst, the lining of which shows acantholytic dyskeratosis in confluence. because parakeratotic contents of the cyst are housed wholly within the lining enveloping of it, the papule or small nodule neither is seen nor felt to be keratotic clinically. much more common than warty dyskeratoma, which usually presents itself as a solitary lesion, is a keratotic papule typified histopathologically by foci of acantholytic dyskeratosis, to wit, acantholytic dyskeratotic acanthoma. although that keratotic papule tends to appear as a solitary lesion on a trunk, it may present itself rarely as several lesions. the acantholytic dyskeratotic changes that occur in a solar keratosis are those of very superficial expression of pseudoglandular squamous-cell carcinoma and are not those of acantholytic dyskeratosis. the two processes are different clinically, histopathologically, cytopathologically, biologically, and conceptually, although both have in common acantholytic dyskeratotic cells. in focal and in confluent acantholytic dyskeratosis, nuclei are not crowded and atypical, and acantholytic dyskeratotic cells are present in the spinous and granular zones (so-called corps rounds) and acantholytic parakeratotic cells (so-called grains) are present, too. in contrast, nuclei of cells in “pseudoglandular” solar keratosis are crowded and atypical, and acantholytic dyskeratotic cells are confined to the spinous zone; never are they found review | dermatol pract concept 2012;3(2):4 17 in the granular zone or in the cornified layer. the term “pseudoglandular” derives from the gland-like appearance, at least to the eye of some histopathologists of days gone by, created by suprabasal clefts that form consequent to acantholysis in aggregations of squamous-cell carcinoma; acantholytic dyskeratotic cells with an atypical nucleus reside in those clefts. (see acantholysis) acanthoma: a benign proliferation characterized by a circumscribed increase in thickness of the epidermis consequent to an increase in thickness of the spinous (prickle, malpighian) zone secondary usually to an increase in number of cells, but episodically, to an increase in size of cells or, rarely, both of them together. in practice the designation has been given to such disparate conditions as pale-cell acanthoma, in which the morphologic findings are of pale-cell acanthosis, and to acantholytic dyskeratotic acanthoma, in which they are of focal acantholytic dyskeratosis. in short, the term “acanthoma” is not specific and has been applied to various conditions characterized by proliferation of spinous cells. an “acanthoma” is a tumor only in the sense of a benign proliferation, not in the sense of a swelling; most true acanthomas are but slightly elevated above the surface of the skin, e.g., pale-cell acanthoma (degos-civatte) and acantholytic dyskeratotic acanthoma. a so-called pilar sheath acanthoma is a proliferation with follicular differentiation, to wit, toward the isthmus, and to a much lesser extent with sebaceous ductal differentiation. the term acanthoma should not be used for tumor, unmodified, not only because no acanthoma is a tumor in the sense of a mass greater than 2.0 cm in greatest diameter, but also because no acanthoma is malignant. in the jargon of general pathology, tumor usually denotes a malignant proliferation. neither should the term acanthoma be used for a benign proliferation with follicular differentiation nor for a hyperplasia. “acanthoma” is used for such disparate processes pathologic as hypertrophy (increase in size of cells) and hyperplasia (increase in number of cells) that comes into being by way of persistent mechanical trauma, as in acanthoma fissuratum, for a benign neoplasm such as large-cell acanthoma (a solar lentigo in which nuclei of keratocytes are larger than usual for that incipient reticulated seborrheic keratosis), melanoacanthoma (a pigmented seborrheic keratosis peppered by melanocytes with striking dendrites), and clear (pale)-cell acanthoma (a benign neoplasm of epidermal keratocytes that spares acrosyringia), and for lesions that are malignant, such as keratoacanthoma which is a type (keratoacanthomatous) of squamous-cell carcinoma, irrespective of whether that neoplasm arises in skin that bears hair follicles or that does not subungual). keratoacanthoma does not qualify as a true acanthoma, because it is a malignant proliferation. (see tumor) acanthotic: pertaining to acanthosis. acanthosis: an increase in thickness of the epidermis consequent to an increase in thickness of the spinous (prickle, malpighian) zone secondary usually to an increase in number of cells (hyperplasia), but, episodically, to an increase in size of cells (hypertrophy) or, rarely, both of them together. there is a difference between hyperplasia and hypertrophy of cells of the spinous zone; hyperplasia pertains to an increase in number of cells, whereas hypertrophy refers to increase in size of cells. both hyperplasia and hypertrophy of spinous cells result in a thickened epidermis. hyperplasia of spinous cells occurs, for example, in psoriasis, whereas hypertrophy of spinous cells appears in lichen planus. both hyperplasia and hypertrophy of spinous cells are seen in some examples of lichen simplex chronicus. because the term acanthosis nearly always is employed conventionally as a synonym for thickening of the epidermis as a result of an increased number of spinous cells, it is incorrect to use it for proliferations, whether benign, such as seborrheic keratosis, or malignant, such as bowen’s disease. the word acanthosis also is applied aptly to hyperplasias like those of psoriasis, long-standing lesions of allergic contact dermatitis and of nummular dermatitis, and pityriasis rubra pilaris. it is imprecise to refer to acanthosis as “irregular” and “regular”; neither of those modifiers ever has been defined in a crisp, lucid way. it is proper, however, to describe epidermal rete ridges as being of even or uneven length, having a smooth or jagged outline, and being thin or thick. each of those descriptors is definable in fashion comprehensible. in sum, although acanthosis may come into being as a consequence of hypertrophy of spinous cells, when the word acanthosis is employed in dermatopathology, it is usually meant to designate hyperplasia, not hypertrophy. achromia: state of being devoid of color. syn. achromatosis. achromia means a state of complete absence of color of the skin, but no cutaneous condition ever is devoid wholly of color, and that is why the term has no place in the language of dermatology. the phrase so popular today among dermatologists, namely, “skin of color,” which is meant to apply only to the integument of africans (and especially african-americans), asians (and especially asian-americans), and hispanics (and especially hispanic-americans) has no basis scientific whatsoever; all peoples, including caucasians, have “skin of color.” it is dangerous to mix political agendas suffused with financial incentives and the profession of medicine. often the word achromia is defined as absence of natural pigmentation, which means pigmentation by melanin, but, in fact, the skin is colored not only by melanin but by effects of the organization of corneocytes of the stratum corneum 18 review | dermatol pract concept 2012;3(2):4 and of the thickness of that cornified layer (i.e., it may have a slightly yellow cast when corneocytes are arranged compactly in a markedly thickened stratum corneum), degree of perfusion by blood (i.e., it may be red or livid), or by deposits of various kinds, i.e., of hemosiderin (which may cause the skin to assume a brown hue). a reduction in pigmentation by virtue of a decrease in melanin in the epidermis may be designated specifically hypomelanosis, which is manifested clinically as hypopigmentation, and amelanosis, which is expressed clinically as depigmentation. hypomelanosis is seen in post inflammatory hypopigmentation, and amelanosis is observed in the depigmentation of vitiligo. changes in color of skin may be indicative of a specific disease, for example, absence of perfusion of blood in vessels of nevus anemicus resulting in whiteness of that flat lesion. in short, a term that has applicability clinically, such as depigmentation, is preferable to one that does not, such as achromia. what is called “achromia” in the common parlance of dermatology is not really characterized by absence of color. achromia parasitica, achromic nevus, and incontinentia pigmenti achromians of lto, as well as lesions in yaws or onchocercosis, are typified by hypopigmentation, not by depigmentation; the latter being a condition that results from absence total of melanin from the epidermis. a distinction must be made in this regard, therefore, between hypopigmentation in which the amount of melanin from the epidermis is reduced considerably, as is the case in one expression morphologic of the patch stage of mycosis fungoides (hypopigmented mycosis fungoides), and absence entirely of melanin from the epidermis, as is the situation in lesions developed fully of vitiligo. achromic: pertaining to achromia, not colored. acid mucosubstance: is a histochemical term for a polymer of glucose and amino groups (mucopolysaccharides, glycosaminoglycans) that takes a stain in an acid medium. acinar: pertaining to an acinus. acinous: resembling an acinus acinus: a group of berry-shaped secretory parts (alveoli) of a gland that are continuous with a single duct; the smallest lobule of a lobulated gland. the term acinus, fundamentally, has denotations morphologic, but it is defined differently in regard to different organs, such as the liver, pancreas, lung, and skin. the situation is even more confusing in regard to the relationship between acinus and alveolus. in latin, acinus means a berry or a grape, whereas alveolus refers to a small sac. it is not correct, therefore, to define acinus as a small saclike dilatation; that is the correct definition for alveolus. in the lung, acinus and alveolus clearly are different from one another, alveolus being a tiny air containing sac, in contrast to acinus which is made up of numerous alveoli that enter the same terminal bronchiole. in regard to the pancreas and the parotid gland, the term acinus designates the terminal part of the gland that consists of secretory cells positioned around a minute hollow opening to a duct. in dermatopathology, the words alveolus and acinus pertain to structures glandular, and they often are used interchangeably in the sense of denoting the smallest part of a gland. it would be more precise, however, to define those words in a manner terminologic analogous to that for structures anatomic in the lung, employing the term alveolus for the smallest portion of a gland and acinus for the terminal lobule of a gland that consists of a group of alveoli continuous with a single duct. (see alveolus) the sebaceous gland is characterized by holocrine secretion, meaning that individual cells of the gland rupture with material released from those cells becoming the secretion itself. it is not correct to state, however that the acini degenerate. the situation is just the reverse of “degeneration”; cells of an acinus mature and the product of that maturation is sebaceous secretion. in dermatopathology, the word acinus is used either to designate the terminal part of a gland (including the eccrine and apocrine glands) or to describe the lobulated architecture of a gland like a sebaceous one. terms like uniacinar and multiacinar derive from the second use of the word acinus. the eccrine gland and the apocrine gland are both tubular and have no lobules. use of acinus in regard to an eccrine gland or an apocrine gland refers to the definition of that word as the terminal part of a gland. acneiform: resembling clinically different expressions morphologic of acne vulgaris. syn. acneform, acneiforme, acneforme. the statement “resembling acne” does not convey a sense for how, precisely, a particular condition actually resembles acne. in reality, there are many manifestations morphologic of acne vulgaris, among them comedones, papules, papulopustules, pustules, cysts, rounded masses (conglobate), draining sinuses, and scars. each of those lesions has an appearance distinctive, clinically and histopathologically. acneiform lesions as they present themselves clinically, in the sense of resembling grossly those of acne vulgaris, may be encountered in conditions as disparate as halogenoderma, secondary syphilis, rosacea, tropical acne, and steroid acne, each of which is a process pathologic different from acne vulgaris. acneiform lesions as they express themselves histopathologically, in the sense of resembling those of acne vulgaris, may be met with in conditions as unrelated as occupational acne (in which insoluble cutting oils, to wit, machine oils, induce formation of comedones), pomade acne (in which a perfumed ointment, particularly in a scented dressing for hair, review | dermatol pract concept 2012;3(2):4 19 causes comedones to come into being), and favre-racouchot syndrome (in which extensive exposure long standing to sunlight, as evidenced by an extraordinary amount of solar elastosis brings about comedones). the word “acne” never should be used unmodified, any more than should the words “lupus” and “nevus.” each of them must be employed always with a modifier, for example, acne vulgaris, acne keloidalis, and acne cosmetica, lupus vulgaris, lupus pernio, and lupus profundus, and melanocytic nevus, nevus sebaceous, and nevus unius lateris. just as a reader is confounded by the definition of “acneiform eruptions resembling acne lesions” because the statement does not make clear whether by “acne lesions” is meant lesions of acne vulgaris and, if that is what is intended which of the many kinds of lesions of acne vulgaris is meant. in times past rosacea was referred to by dermatologists, universally, as acne rosacea, but that practice, confusing as it was, is much less in evidence today. rosacea is a disease different from acne vulgaris, even though both conditions have a predilection for the face, tendency to consist mostly of papules and pustules, and inclination to infundibulocentricity. it also must be emphasized that by acneiform is meant resemblance, clinically and/or histopathologically, to individual lesions of acne vulgaris, and not the disease acne vulgaris per se. acneiform lesions in diseases other than acne vulgaris may be found at sites anatomic very different from those favored by lesions of acne vulgaris. acral: pertaining to the parts most distal of the body, referring particularly to the extremities, that is, the hands and feet, and especially the parts most distal of them, namely, fingers and toes, but also, conceptually, to other distal parts, such as the nose, the ears, and penis. the word acral is used in the language of dermatology as a synonym for hand(s) and/or foot (feet), and especially, the fingers and toes, that is, the parts most distal of the limbs. in theory, however, acral pertains to all parts distal, such as the nose and the ears and even to the penis, but, in practice that is not the way the term is used. and that is why all the conditions whose name is prefixed by acro-, such as acrodermatitis continua (hallopeau), acrodermatitis chronica atrophicans, and acrosclerosis, nearly always affect hands and/or feet especially and sometimes, but not always, the extremities proximal to those parts most distal. the use of the word “acral” for hands and feet in general and for fingers and toes in particular is proper, but what is confusing is not the application of the term acral to certain sites anatomic, but the use of it to modify terms like “fibrokeratoma,” “nevi,” and “microlivedo,” instead of referring specifically to fibrokeratoma on a site acral, melanocytic nevi on a site acral, and to microlivedo (whatever that means) on a site acral. acral parts of the body: the distal parts, such as hands, feet, and even the penis but especially the fingers and toes, nose, and ears. acral parts of the skin: refers to the distal parts, especially the skin of the fingers and toes, but also the nose, ears, and even the penis. acro-: a prefix meaning the furthest point and in dermatology referring to the part most distal of the extremities, especially to hands and feet, and, more particularly, to fingers and toes. the prefix acrousually is not employed by dermatologists as a synonym for the extremities per se, but for the distal part of the extremities, to wit, hands and feet, and, in particular, fingers and toes. although acro-, like acral, often pertains to the part of extremities most distal, as in the terms acrodermatitis continua (which is but one of many manifestations clinical of pustular psoriasis), acrokeratosis verruciformis (which are keratotic warty papules of darier’s disease that occur on the dorsa of hands), and acrodermatitis chronica atrophicans (a particular manifestation of borreliosis that affects especially the legs and feet, and culminates in broad patches of atrophy), it also is applied to conditions that affect the face as well as the distal part of extremities, for example, acrogeria (which conveys an impression of severe premature aging), acromegaly (which gives the appearance of progressive enlargement of parts affected), and acrosclerosis (which causes the forearms and hands, legs and feet, and face to look and feel tight severely) as well as to conditions characterized by considerable length or height, such as acrochordon (which is a long, cordlike polyp or papilloma known colloquially as a skin tag). acrospiroma: refers to a benign proliferation composed of cells thought to resemble those of the distal segment of eccrine ducts, i.e., acrosyringia. the term encompasses conditions of histopathologic characteristics very different from one another, among them being eccrine poroma, dermal duct tumor, poroid hidradenoma, and apocrine hidradenoma. because the term acrospiroma is not indicative of a specific proliferation, it is best avoided in favor of a designation that actually conveys specificity. acrosyringeal: pertaining to an acrosyringium, especially of an eccrine duct. acrosyringium: in general, the distal intraepithelial end portion of a duct of an adnexal gland (sebaceous, apocrine, and eccrine), but in particular and in parlance common of an eccrine duct. acrosyringium designates the distal intraepithelial end portion of a duct of an adnexal gland and, therefore, is not limited to the eccrine gland, the duct of which spirals 20 review | dermatol pract concept 2012;3(2):4 through surface epidermis. the apocrine duct, too, has a distal intraepithelial part, namely, that portion of the duct which spirals through infundibular epidermis at about midway through the course of it. the sebaceous duct also enters the infundibulum at the junction of it and the isthmus of a hair follicle. acrosyringia of eccrine glands and of apocrine glands spiral in the same manner as they pass through surface epidermis and infundibular epidermis respectively. the sebaceous duct passes through the junction of infundibulum and isthmus in a straight line. for purposes practical, the term acrosyringium is used as a synonym for the part of the eccrine duct that spirals through surface epidermis, but the apocrine duct also spirals through epidermis, albeit the infundibular component of it. that being so, a distinction clear should be made between eccrine acrosyringia and apocrine acrosyringia. none of those who employ the word “acrosyringium” in articles and texts make that distinction. it is sufficient to refer to the duct of the sebaceous gland as the sebaceous duct. when authors write of a neoplasm being derived from an acrosyringium, they mean to say that it differentiates toward cells of an eccrine duct. it cannot be stated with surety from whence cells of hidroacanthoma simplex, so-called eccrine poromas, dermal duct tumor, and syringoma originate truly, and that being the case, it is best to speak and write of “differentiation toward” rather than “origin from.” in the case of syringoma, differentiation seems to be apocrine, rather than eccrine, in character, whereas for poromas, it can be eccrine or apocrine. the cells of acrosyringia not only are different from epidermal keratocytes biologically (“separate symbionts in the epidermis”), but morphologically, too. the two, types of cells, acrosyringeal and epidermal keratocytic, can be identified for what they are by microscopy conventional especially in the cornified layer of normal volar skin, where corneocytes of acrosyringia assume the appearance of a corkscrew as the duct spirals through that nonviable portion of surface epidermis. moreover, acrosyringia of eccrine ducts largely are spared in the benign proliferations of epidermal keratocytes known as pale-cell acanthoma and in the malignant proliferation of epidermal keratocytes (a squamous-cell carcinoma) called solar (actinic) keratosis. last, an acrosyringium does not “extend deep into the upper dermis”; by definition it is the intraepithelial part of the duct of an adnexal gland. acrotrichial: pertaining to an acrotrichium. acrotrichium: the distal segment of infundibular epidermis that traverses surface epidermis. the definition of acrotrichium was coined by h. pinkus as the analogue follicular of the acrosyringium, by which terms he meant to identify the distal intraepidermal segment of the follicle for the former and the distal intraepidermal segment of the eccrine duct for the latter. pinkus considered the funnel-shaped infundibulum to be the distal part of a follicle and he thought the acrotrichium was synonymous with infundibulum, it being the part that passes through the epidermis. in reality, however, the infundibulum is epidermis, it being infundibular epidermis in contrast to surface epidermis, and not at all a component of the follicle (the latter consisting of bulb, stem, and isthmus). it should be noted that being the case, the concept of acrotrichium is flawed irreparably, not the least of those limitations being that the word “acrotrichium,” from two greek elements, means the distal part of the hair, whereas what pinkus intended by it was the distal part of the follicle which, in actuality, is the isthmus, not the infundibulum as he supposed, that structure actually being epidermis. although pinkus seems to have been the only one to define the term acrotrichium,” it nonetheless is used widely by authors of textbooks of dermatology and dermatopathology, although none of them states precisely what they mean by it. the confusion about the use of “acrotrichium” and “acrotrichial” derives from the notion erroneous that they are analogues of acrosyringium and acrosyringeal; they are not. the acrosyringium refers specifically to the intraepidermal part of the eccrine duct, but there is no intraepidermal part of a hair follicle. the follicle ends at the infundibulum, which is a part of the epidermis, the major component of which is surface epidermis. the proximal part of a follicle is the bulb, the distal part of the isthmus, and what lies between is the stem. in brief, there is no place right for the term “acrotrichium” in the lexicon of cutaneous histology or of dermatopathology. actinic: meaning caused by radiant energy, especially by ultraviolet light. in dermatology and dermatopathology, the adjective “actinic” designates conditions in general and changes morphologic in particular that are caused by exposure to radiant energy and especially by ultraviolet light. the term is not restricted to effects chemical of those rays, but in most instances refers to changes pathophysiological induced by them. actinic, in the original meaning of it, refers to any kind of ray, not only to rays of ultraviolet light. therefore changes induced by x-rays, like those responsible for radiation dermatitis, may be called properly “actinic,” but not “solar,” which refers specifically to rays from the sun. in short, actinic is a generic term that applies equally to radiation keratosis and to solar keratosis, whereas solar is more specific and is applicable, in particular, to that alteration of dermal connective tissue (solar elastosis) and to superficial squamous cell carcinoma of one type (solar keratosis) brought into being by rays of the sun. review | dermatol pract concept 2012;3(2):4 21 the word “actinic” often is used synonymously with “solar” to designate changes morphologic that come into being after exposure longstanding to sunlight, i.e., solar (actinic) keratosis, which is a very superficial expression of the most common type of squamous-cell carcinoma. whereas solar pertains only to exposure to sunlight, actinic designates any kind of ray that causes changes in tissue. actinic (solar) keratoses and actinic (solar) elastosis nearly always are caused by ultraviolet light and, therefore, it is more precise to designate them solar keratosis and solar elastosis. the changes histopathologic in a keratosis induced by longstanding exposure to x-rays are indistinguishable from those in a keratosis brought about by chronic exposure to sunlight. solar elastosis, however, is very different morphologically from radiation sclerosis, the former being fibrillar and the latter not at all fibrillary (being termed badly “homogenization” of collagen). the type of porokeratosis named “disseminated superficial actinic” is a consequence of exposure for many years to rays of the sun in a patient susceptible, presumably genetically. actinic granuloma: a term that should not be used, because it is a misnomer as a consequence of the misperception that the condition being referred to is something other than granuloma annulare on skin damaged severely by sunlight with resultant elastophagocytosis. actino-: prefix meaning related to or caused by radiant energy, especially by ultraviolet light activated: not definable morphologically. the word “activated” usually is not defined in dictionaries or in textbooks of dermatology and dermatopathology. only the verb “to activate” is defined in general dictionaries and in some medical dictionaries, and “activated” is mentioned as the past tense of that verb. “activate” is defined in collins concise dictionary, 2001 as “to make active or capable of action,” in merriamwebster’s collegiate dictionary, 2001 as “to make active or more active,” in taber’s cyclopedic medical dictionary, 2001 as “to make active,” and in dorland’s illustrated medical dictionary, 2000 and stedman’s medical dictionary, 2000 as “to render active.” even were “activated” understood as “being made more active,” it is not clear what is meant by “active” in regard to findings in sections of tissue in which no action is apparent in the sense of anything being in motion. lesions as they are observed histopathologically are static and, therefore, cannot be described rightly as active. because the term “activated” is not defined in any dictionary or: textbook of dermatology or dermatopathology, it is not clear what is meant by “activated” lesions of mycosis fungoides, and “activated” lymphocytes or t cells. it is clear, however, that none of these “activations” can be identified morphologically, either by inspection gross (clinically) or by microscopy (histopathologically). even if the term “activated” could be defined meaningfully, for one example, as “being stimulated by cytokines,” changes induced by cytokines may not be visualizable through a microscope conventional and those changes that are visualizable may not be caused necessarily by effects of cytokines. moreover, if lesions clinical or changes in sections of tissue are designated “activated,” the implication is that a stage of the same process properly should be considered “inactivated.” but no such definition is to be found in any textbook of dermatology or dermatopathology, the reason being that no such concept has yet to be set forth. therefore, there is no place in either dermatology or pathology, including dermatopathology, for the terms “active” or “activated.” testimony to the assertion just made is the fate of what was called in the late 1940s by arthur allen “junctional activity” and “active” or activated “junctional nevus.” those terms were as beloved by general pathologists and dermatologists interested in neoplasms of melanocytes as is the word “dysplasia” by them today. but, whereas “melanocytic dysplasia” (and derivatives of the concept, namely “dysplastic nevus” and “dysplastic nevus syndrome”) has had a relatively long run, i.e., nearly 30 years with the promise of several decades more, “junctional activity” and “activated junctional nevus” became passé after but 20 years, now being employed never-and with good reason. what allen pictured in every one of many photomicrographs published was melanoma in situ. active: i.e., tending to act. not definable morphologically. in the realm of assessment morphologic in pathology, gross and microscopic, no action is observable in the sense of anything being in motion. lesions as they are perused, clinically and histopathologically, are static. that being the case, they cannot be described rightly as being “active.” because no movement is discernible in lesions as they are viewed clinically and by conventional microscopy in sections of tissue, it is inaccurate to describe changes noted in them as being active. of course there is activity, in vivo, in all lesions in the skin throughout the entire course chronologic of them, both in evolution and devolution; even a scar is associated invariably with subtle changes of remodeling, a type of activity. the rim erythematous of lesions annular, such as those of erythema multiforme, erythema annulare centrifugum, dermatophytosis, lichen planus, sarcoidosis, and syphilis, often is referred to by clinicians as the “active border.” the proper designation simply is the “border,” which can be modified by words descriptive such as erythematous, violaceous, and scaly. the periphery of lesions of all inflammatory diseases of the skin, not only those that are arcuate, annular, and polycyclic, is the zone that, in vivo, is associated with changes that are especially dynamic, and where histopathologically the infiltrate of inflammatory cells is seen to be most dense. 22 review | dermatol pract concept 2012;3(2):4 what allen in the 1940s, ’50s, and ’60s called “active junctional nevus” was, in actuality, melanoma in situ, that being evident in photomicrograph after photomicrograph published by him. in brief, “active junction nevus” was wrong on all three counts: the proliferations were not active as judged morphologically, the melanocytes were not confined to the dermoepidermal junction, and the “nevus” was a melanoma. it was allen who also introduced the flawed notion of “junctional activity” of melanocytes. not only was activity of melanocytes not discernible by microscopy conventional, but allen never defined the term itself in crisp, comprehensible, lucid fashion; in fact, for nearly 50 years allen insisted stubbornly that melanocytes sprung directly from epidermal histiocytes. both “active junctional nevus” and “junctional activity” are now relics historical, just as will be the case one day for dysplasia, including melanocytic dysplasia, dysplastic nevus, and the dysplastic nevus syndrome. active junctional nevus: is a term that should not be employed because it has never been defined in a comprehensible way. arthur allen, in the late 1940’s, introduced that phrase, but what he pictured in numerous photomicrographs published as stereotypical of the condition was indubitable melanoma in situ, he not acknowledging the reality of malignancy of it. moreover, “active” indicates a dynamic that cannot be identified by microscopy; everything seen in sections of tissue is static. accuminate: pointed. in dermatology, the word “accuminate” usually is applied to a papule whose surface is gently, rather than sharply, pointed. never is a papule characterized by a slender point; and that being the case the term acuminate is inaccurate as a description for any papules. accuminate in regard to a papule pertains to a lesion whose shape is domed to a variable degree. an examining finger can feel the hint of the gently pointed surface of the papule better than the naked eye can visualize it. nearly always a papule comes to be pointed subtly because of spongiosis in a discrete focus of the epidermis, as is the case for an id reaction and for miliaria rubra. a keratotic plug is not pointed and, therefore does not qualify as being accuminate. so called condyloma acuminatum, an infection of mucocutaneous regions by papillomavirus, is not at all pointed, clinically or histopathologically, but is characterized by gentle papillations. neither is so called giant condyloma acuminatum of buschke and lowenstein pointed, the surface of that verrucous expression of squamous cell carcinoma usually is papillated, i.e., like nipples, rather than pointed. adamantinoid: resembling morphologically adamantinoma (ameloblastoma) of the bone or oral cavity; designating aggregations of cells in a neoplasm, which are columnar and arranged in a palisade at the periphery and separated from one another by prominent spaces in the center. this pattern is known as stellate reticulum. the adjective adamantinoid is not defined in any dictionary in use commonly or in any textbook of dermatology or dermatopathology. the etymologic basis of it is misleading, the reason being that adamantinoid in histopathology does not pertain to resembling the hardest metal or diamond. it refers to adamantine; the designation for enamel of teeth, which indeed is very hard. proliferations derived from cells of the enamel organ (ameloblasts) are called ameloblastomas or adamantinomas. “adamantinoid” is used in dermatopathology and in dermatology, for both a benign and malignant neoplasm of trichoblasts, each of which bears similarities histopathologically to adamantinoma (ameloblastoma) found in bones of the jaw. the benign proliferation is known as adamantinoid trichoblastoma and to the malignant one as adamantinoid trichoblastic (basal cell) carcinoma. the word adamantinoid as a modifier in both instances refers to the appearance histopathologically of abnormal trichoblasts in aggregations whose cells at the periphery are columnar and arranged in a palisaded, and whose cells in the rest of them are separated from another by prominent spaces that are transversed by elongated intercellular bridges. the pattern just described, known as stellate reticulum, is found stereotypically in adamantinoma, but in cutaneous pathology it is encountered in adamantinoid trichoblastoma and adamantinoid trichoblastic carcinoma. the neoplastic cells in adamantinoma are ameloblasts, not trichoblasts. adamson’s fringe (a-fringe): marks the boundary between a follicular bulb and stem, and is the site at which cells of huxley’s layer of the inner sheath lose their trichohyalin granules and becomes compactly arranged blue-gray corneocytes. above adamson’s fringe, cornification of the inner sheath and of the hair itself is complete (i.e., orthokeratotic). nuclei are present in cells of the inner sheath and hair in the bulb below adamson’s fringe, but no nuclei are detectable in cells in the stem above it. dermatophytes that infect hair are able to descend to the level of adamson’s fringe, but not below it, because those fungi are able to live only in cells that have cornified completely, such as those in the stratum corneum and nail plate. adeno-: prefix meaning pertaining to a gland adenocarcinoma: is a malignant proliferation of epithelial cells that shows tubular (glandular and/or ductal) differentiation or consists of glandular or ductal cells. when adenocarcinoma is primary in skin, the neoplastic cells differentiate toward sebaceous glands, apocrine glands, or eccrine glands (or the ducts of those glands), or tubules of review | dermatol pract concept 2012;3(2):4 23 it are lined by neoplastic cells like those glands or ducts. in a well-differentiated adenocarcinoma, some cells resemble those of normal glands, i.e., vacuolated cells of sebaceous glands or cells with secretion typical of apocrine glands. in a poorly differentiated adenocarcinoma few cells are identifiable with exactness as being sebaceous or apocrine, as two examples. of course, any hint of “differentiation” can be helpful in the diagnosis. some adenocarcinomas in skin are not primary there; they are metastases. adenoid: having the appearance of a gland or duct of a gland. in dermatopathology, adenoid pertains to looking like a cutaneous gland or the duct of a gland as evidenced usually by formation of tubules, those structures being apocrine glands or ducts of them, and eccrine glands and the ducts of them. the term “adenoid” is not applied to an appearance like that of the third gland in the skin, to wit, the sebaceous gland, which consists of lobules rather than of tubules, or to the duct of it which, although it is tubular, cornifies, and, as a consequence, has an appearance entirely different histologically from that of the duct of an apocrine or an eccrine gland. at times, cells with glandular differentiation can be identified in a proliferation even in the absence of a single tubular structure, such as the clear cells of apocrine hidradenoma, known also as solid-cystic hidradenoma, clear-cell hidradenoma, and pale-cell hidradenoma. neoplastic epithelial cells in an apocrine mixed tumor can be recognized for what they are by their shapes polygonal and plasmacytoid. in cutaneous pathology, unlike pathology in general, the word adenoid never is applicable to lymphoid tissue. the designation “adenoid” for a type of seborrheic keratosis is inaccurate because the cords of pigmented epidermal cells in no way resemble glands themselves or ducts of glands, the synonym for the adenoid type of seborrheic keratosis being “reticulated,” which means netlike, as truly is the situation in time for that benign keratosis. the acantholytic type of solar (actinic) keratosis is but a stage in the evolution of what later is termed, conventionally, pseudoglandular squamous-cell carcinoma, the gland like structures coming into being as a consequence of the formation of acantholytic, dyskeratotic spinous cells above suprabasal spaces of aggregations that make up the malignant proliferation. in actuality, the suprabasal clefts bear no resemblance truly to any gland. the term adenoid cystic carcinoma is correct only partly, that particular expression of apocrine carcinoma being adenoid in the sense that those aggregations are punctuated by round spaces that house mucin, thereby conveying the impression vaguely of gland like structures in cribriform pattern. those spaces, however, are not truly glandular and, moreover, are small, which disqualifies them as being cystic. adenoid cystic: refers to a distinctive sieve like pattern in an epithelial neoplasm in which discrete aggregations of cells house spaces that are relatively equidistant from one another, are relatively uniform in size and shape, and contain mucin. the term is derived from the appearance of a type of carcinoma of salivary glands, but it has come to designate other malignant proliferations with a similar pattern in other sites, such as types of apocrine carcinoma and trichoblastic (basal-cell carcinoma). the designations adenoid cystic carcinoma, adenocystic carcinoma, adenocystic basal cell carcinoma, and adenoid basal cell carcinoma are confusing. in brief, adenoid cystic carcinoma is a specific type of carcinoma that may develop in skin, where it shows signs of apocrine differentiation, in salivary glands, and in the breast, an organ whose mammary glands exhibit apocrine secretion. adenocystic carcinoma is also a specific neoplasm that, in the skin, is better known as mucinous carcinoma, and in the breast, as colloid carcinoma. like adenoid cystic carcinoma, adenocystic carcinoma sometimes shows evidence of apocrine secretion. in contrast, the so called adenocystic and adenoid types of trichoblastic (basal cell carcinoma), although devoid of signs of follicular differentiation (i.e., germs and papillae, bulbs and papillae, trichohyalin granules, and blue-grey corneocytes arranged compactly), are composed of follicular germinative cells and are all nodular trichoblastic (basal cell carcinomas). they do not show evidence of apocrine differentiation. it would be preferable to call these three neoplasms adenoid cystic carcinoma, mucinous carcinoma, and trichoblastic (basal cell carcinoma), because their morphologic variations are so numerous and, with rare exceptions those variations do not influence biologic behavior. adenoid cystic carcinoma and mucinous carcinoma may arise in the skin and in the breast where their morphologic features are maintained. adenoma: a benign proliferation made up of glandular or ductal cells that often assume the forms of tubules, an indication of glandular or ductal differentiation. an adenoma is a tumor only in the sense that it is a proliferation; it may present itself clinically as a papule, nodule, tumor, or plaque. the malignant counterpart of adenoma is adenocarcinoma. an adenoma consists of cells of glandular or ductal character, and although it usually shows signs of glandular or ductal differentiation, it may not necessarily do that, i.e., some apocrine mixed tumors are entirely solid, being composed wholly of polygonal and plasmacytoid myoepithelial cells and most examples of clear-cell syringoma are devoid entirely of tubules, as are numerous examples of the poromas. origin is irrelevant to characterization of adenoma; it matters not from whence an adenoma derives (i.e., there is no clue to the origin of adenomas known as in cylindroma, spiradenoma, apocrine hidradenoma, and poroid hidrad24 review | dermatol pract concept 2012;3(2):4 enoma, no connection being apparent to preexisting normal glandular or ductal epithelium), only that the cells that make it up are glandular or ductal in nature and they are given to glandular or ductal differentiation as evidenced by formation of structures that resemble glands or ducts. what is termed, conventionally, sebaceous adenoma, really is a superficial sebaceous carcinoma (this is a matter of debate) analogous to superficial basal cell carcinoma and to solar keratosis, the latter being a superficial squamous-cell carcinoma of one type. so-called cystic sebaceous adenoma is a histopathologic variant of sebaceous carcinoma and, nearly always, indicates that the patient who bears it has muir-torre syndrome. adenoma sebaceum is a misnomer on both counts, namely, it is not a benign neoplasm of glandular or ductal cells and it is unrelated to sebaceous epithelium. in actuality, it is a type of follicular hamartoma joined by angiofibromatous elements and often by an increase in number of melanocytes at the dermo-epidermal junction. the findings morphologically of adenoma sebaceum are identical to those of fibrous papule of the face. trichoadenoma is also incorrectly used. it is basically infundibular and is therefore, epidermal not glandular. apocrine papillary cystoadenoma and tubular adenoma are correct uses. adenomatoid: resembling an adenoma. adenomatous: relating to an adenoma. adipo-: prefix meaning relating to fat. adipoblasts: known also as lipoblasts, are mesenchymederived presumptive fat cells that are present normally only in embryonal and fetal fat. adipocyte: a non-epithelial cell that manufactures lipid and, when mature, sports cytoplasm consisting entirely of a large vacuole of fat. syn. lipocyte, adipose cell. an adipocyte is not “a fat cell,” the cell is not fat, it is filled with fat! moreover, the definition “fat cell” does not distinguish an adipocyte from a lipophage, which is a macrophage that houses fat or an adipocyte from a mature sebocyte, which is an epithelial cell that produces fat. an adipocyte makes fat which then is stored in its cytoplasm. an immature adipocyte does not display a large vacuole of fat within its cytoplasm; it may exhibit only a tiny vacuole, if one at all. adipocytes in the subcutaneous fat, each one of which is encircled by a capillary, are arranged in lobules intersected by fibrous septa that by virtue of the intersections create an appearance of a fenestrated pattern. an adipocyte has a cell membrane, not a cell wall. mature fat is designated white because of the cast of it grossly, whereas immature fat in an embryo is termed brown because of its hue macroscopically. in contrast to white fat, brown fat contains many small vacuoles in its cytoplasm, thereby earning its nickname mulberry cell. adipose: pertaining to or consisting of adipose tissue. adipose tissue: connective tissue made up of adipocytes and arranged usually in lobules separated from one another by fibrous septa. adipose tissue is not simply fat, like triglycerides and cholesterol, and it is not just fatty tissue because sebaceous lobules also could be said to be fatty tissue. adipose tissue is that kind of connective tissue which consists mainly of adipocytes, i.e., nonepithelial cells that manufacture lipid and, when mature, consists almost entirely of a large vacuole of fat, the nucleus being so inconspicuous at the very periphery of the cell that it often is bypassed by the knife of a microtome. a definition of adipocytes being a cell distended by droplets of fat is not precise because that definition applies equally to mature sebocytes and to lipophages. adipose tissue not only consists of adipocytes, but of those cells arrayed characteristically in lobules that come into being by virtue of struts in the form of fibrous septa that house blood vessels and nerves. the subcutaneous fat consists of adipose tissue arranged in lobules that are created by intersections of fibrous septa. there are two kinds of adipose tissue in the human body, namely, brown and white, the latter being the constituent of the subcutaneous fat. some neoplasms, such as lipomas and variations on the theme of them, such as angiolipomas and fibrolipomas, are made up of adipocytes arranged in lobules, but that does not qualify as adipose tissue because the arrangement of cells in conjunction with fibrous septa does not approximate that which is characteristic of normal adipose tissue, such as is met with in the panniculus adiposus. distinction between mature and immature adipose tissue turns on the presence or absence of immature adipocytes (adipoblasts). subcutaneous tissue does not always consist of mature adipose tissue, e.g., that in an embryo. adnexa: sing. adnexus; in general, structures that are adjacent or subordinate to more major anatomic parts and in dermatology in particular, structures accessory to the two major components of the skin, namely, the epidermis and the dermis, including both ones that are epithelial (the folliculosebaceous-apocrine unit, the eccrine unit, and the nail unit) and ones that are nonepithelial (the nerves, smooth muscles, and blood and lymphatic vessels.) in general the term “adnexa” refers to parts that are in continuity with or in close proximity to a more major organ, such as the ovaries and fallopian tubes in regard to the uterus. in the skin, however, the word “adnexa” does not designate adjunctive parts, but rather authentic components of it, namely, those that are epithelial, such as the folliculoreview | dermatol pract concept 2012;3(2):4 25 sebaceous-apocrine and eccrine units and the nail unit, and those that are nonepithelial, like nerves, smooth muscles, and vessels. in contradistinction to the adnexal (accessory) epithelial and non-epithelial components of the skin, the appendages, that is hair shaft and nail plate, are structures produced by epithelial components of the skin, to wit, cells in the matrix of a hair follicle and cells in the matrix of a nail unit, respectively. in sum, adnexa and appendages of the skin are not synonyms; appendages represent the products generative of adnexa. the term “adnexa” is employed by most authors only for certain epithelial structures in the skin, namely, folliculosebaceous-apocrine and eccrine ones, but it is not used by them for the nail unit. moreover, the term “adnexa” refers rightly not only to epithelial structures, but to nonepithelial ones like nerves, smooth muscles, and vessels. a part of an adnexal epithelial structure may be rooted in the subcutaneous fat, not simply in the dermis. for example, glands of apocrine and eccrine units and the bulb of follicles situated on the scalp are lodged in the subcutaneous fat. the same statement can be made about some nonepithelial adnexal structures, such as blood vessels and nerves in the subcutaneous fat that are in continuity with those same structures in the dermis. philosophically and practically, nonepithelial structures in contiguity with epithelial structures of adnexa, for example, a follicular papilla and a perifollicular sheath juxtaposed to a follicle, are, in actuality, adnexal structures, too. adnexal: pertaining or relating to adnexa adnexocentric: describes the orientation of cells particularly melanocytes of a congenital nevus around epithelial and nonepithelial structures of adnexa. these are some similar uses with “angiocentric.” however this arrangement is an expected finding in this type of nevus and therefore is redundant (as is angiocentric). (see angiocentric) adventitia: the outermost connective tissue of an organ, vessel, or structure, but, not applied usually to organs covered by a serosa. often “adventitia” is said to be a synonym for “tunica externa” of the arteries and venules, which consists of connective tissue. more correctly, the term adventitia is defined as the outermost layer of any organ, except for those covered by serosa. the term “adventitia” is employed rarely in regard to the skin and then usually in reference to the combination of papillary dermis and periadnexal dermis, those two parts of similar composition being termed the “adventitial dermis.” the word adventitial is applied, too, to the outermost part of arteries and veins, the adventitia of arteries being made up of collagen and elastic fibers, and containing tiny nerves and capillaries, the “vasa vasorum.” sometimes, elastic fibers form an “external elastic membrane” in vessels muscular, but it is always less prominent than the internal elastic membrane, which typically is present in arteries and not in veins. adventitial: pertaining to adventitia and in the skin to the combination of papillary dermis and periadnexal dermis, the two, together being designated the adventitial dermis. aggregation: collection of discrete units of the same kind of cells or fibers. an aggregation is not a clumped mass of material, but a collection or a cluster of units of the same kind of cells or of fibers that remain discrete and separate from one another. the word derives from the latin grex meaning collection or herd. in the realm of histopathology, aggregations may consist of cells or of fibers. in the sphere of clinical dermatology, when lesions of the same kind are aggregated, the phenomenon is referred to as agminated. aggregation and aggregate are used synonymously to designate collections of structures of the same kind, such as epithelioid cells, smooth muscle cells, blood or lymph vessels, or filaments of amyloid. aggregated: characterized by aggregation. agminated: lesions in a cluster, each of which is discrete and of a single kind. the term agminated refers to lesions that are clustered, aggregated, or grouped, but it implies, too, that individual lesions in the group are discrete and of the same kind, like sheep in a herd. an agminated spitz nevus would be an example of this. the word aggregated, which sometimes is employed as a synonym for agminated, conveys the sense that the lesions are similar to one another, but it does not communicate that those lesions are discrete, i.e., not given to confluence, as is the case for ones that are agminated. lesions in the skin may be grouped in a fashion other than agminated, among those being herpetiform, zosteriform, corymbiform, segmental, linear, and annular. agminated is the proper designation for discrete lesions of a single kind that are grouped together at a particular site, but that are not arranged in special distribution, such as along a dermatome, in a line, or in a ring. for that reason, lesions that are segmental and confluent are not truly agminated. moreover, the designation “agminate folliculitis” is incorrect; the pustules, by themselves, could be considered correctly to be agminated because they are similar to one another and are present in a cluster, but the fact that they are present within “erythematous plaques” excludes them from being designated rightly agminated. alopecia: loss of hair, either physiologically or pathologically, or absence of hair from birth on. alopecia should refer not only to absence of hair, but also to loss of hair, in fashion either diffuse or localized. the 26 review | dermatol pract concept 2012;3(2):4 term alopecia conveys nothing about either the extent of loss of hair in terms of geographic range or amount of actual loss at a particular site, nor does the word communicate anything about the anatomic site or sites at which the loss of hair occurs. loss of hair can appear only at sites where hair is present normally, i.e., the scalp as opposed to palms and soles, no hair being present normally at those latter sites. neither is the cause of a particular loss of hair transmitted by the term alopecia, which in the vast majority of instances is not a result of an inflammatory process but of one wholly physiologic, namely, the effect of androgens on common (androgenetic) baldness. in short, alopecia is a general designation for all kinds of hair loss and for absence of hair irrespective of cause, site, or kind of follicles (terminal or vellus) affected. it may be consequent to destruction of follicles themselves, but also to inability of terminal follicles to maintain their structure, they, in the course of time, becoming vellus (as is the situation in androgenetic [common] baldness) or to severing of hair shafts of follicles whose viable epithelium remains intact (as is the situation in trichotillomania). the term alopecia is generic for loss or absence of hair and conveys nothing about the specific kind of hair loss. no pattern typical for alopecia exists, the range being extraordinary, from a macule of alopecia areata to alopecia universalis (these two being different extents of a single pathologic process mediated by lymphocytes) and from a subtle retraction of the hair line anteriorly to near total baldness in androgenetic alopecia (those two being different extents of a single pathologic process devoid of infiltrates of inflammatory cells and mediated by the effects of hormones). loss of hair can be caused also by factors as diverse as congenital absence of follicles (aplasia cutis), follicles rendered defective because of the effects of a drug administered systemically (i.e., cyclosporin), an inflammatory process that sends follicles in anagen into telogen (i.e., “moth-eaten” alopecia of secondary syphilis), destruction of hair shafts by an infectious agent (i.e., a dermatophyte), and a congenital abnormality of hair shafts (i.e., monilethrix). it is not correct that alopecias are inflammatory in most instances; “common baldness” is so designated because it is the most common type of alopecia far and away, being entirely physiologic and unassociated with an infiltrate of inflammatory cells. it is wrong equally to use aberrant hair growth as a synonym for alopecia, because hypertrichosis as it occurs in hirsutism also could be deemed properly a kind of abnormal hair growth. congenital alopecia can result from absence of follicles or lack of growth of hair and, therefore, alopecia cannot be defined only as loss of hair, because it may be a consequence of absence of hair from birth. alopecic: pertaining to total loss of hair physiologically or pathologically, or to have an absence of hair from birth. alveolus: in dermatopathology, the words alveolus and acinus pertain to structures glandular, and they often are used interchangeably in the sense of denoting the smallest part of a gland. it would be more precise, however, to define those words in a manner terminologic analogous to that for structures anatomic in the lung, employing the term alveolus for the smallest portion of a gland and acinus for the terminal lobule of a gland that consists of a group of alveoli continuous with a single duct. amelanotic: pertaining to absence of melanin. the adjective amelanotic designates the complete absence of melanin in tissue in general and in melanocytes in particular. absence of melanin does not mean that a tissue is necessarily nonpigmented because other pigments may be deposited in the skin, among them, hemosiderin, hematoidin, and exogenous pigments, such as those of tattoos. the adjective amelanotic is not restricted to findings in the skin because an amelanotic metastasis of melanoma may be present in any organ. amelanotic is used most often to designate a type of melanoma, i.e., one that is red or skin-colored clinically devoid of melanin histopathologically. when studied by electron microscopy, the neoplastic melanocytes in an amelanotic melanoma house melanosomes, some of which may be melanized partially. a condition termed amelanosis is typified not only by absence of melanin from melanocytes, but from keratocytes, too, consequent to a defect determined genetically in the metabolism of melanin. (see achromia) amiantacea: like asbestos. syn. amiantaceous. in general, amiantaceous or amiantacea means like asbestos an in particular in dermatology those adjectives designate a lesion that clinically is covered by a scale so thick and hard that it resembles asbestos. tinea (pityriasis) amiantacea is not a disease per se, but a description of scales so thick and hard that they are reminiscent of the structure of asbestos. some authors employ the term tinea amiantacea for a manifestation of psoriasis on the scalp, others for seborrheic dermatitis complicated by infection with bacteria, still others for an expression on the scalp of nonbullous congenital ichthyosiform erythroderma, and some as a disease unto itself. in actuality, amiantaceous as a descriptive term is analogous to ostraceous, furfuraceous, and rupial. these latter terms and amiantaceous are not used often in dermatology anymore. amorphous: having no distinctive shape; without characteristic shape. the adjective amorphous describes something that has no readily recognizable characteristic shape however, all structures in the skin (and in every other organ) have an identifiable shape; none are amorphous. the word “amorreview | dermatol pract concept 2012;3(2):4 27 phous,” therefore, has no place in description of gross or microscopic attributes of any organ. in every instance in dermatology and dermatopathology in which the word “amorphous” is employed, the structure in point is not shapeless; it has a definite shape. for example, amyloid in the papillary dermis in macular and papular (lichenoid) expressions of amyloidosis is globular, as is the secretion “pinched off’” by cells of an apocrine gland. mucin is finely granular, crystals of gout are spicular, and colloid is homogeneous. never, therefore, can the term “amorphous” be applied properly to any component of the skin. amphophilic: stained with both acid and basic stains, (i.e., with hematoxylin and eosin), as is expressed in a color that combines pink and blue. syn. amphophil, amphophile, amphophilous. amphophilic refers to capability to stain with both acid and basic dyes as is the case for the abundant cytoplasm of abnormal melanocytes of polygonal shape in “classic” spitz’s nevi that with hematoxylin and eosin are colored pink and blue together. the word “amphophilic” is used correctly in current text books of dermatology and dermatopathology. amyloid: homogeneous, amphophilic, often globular material (consisting of glycoproteins) that may be deposited in a variety of tissues, among them being those of the skin and subcutaneous fat, when stained by crystal violet appears red, and when examined through an electron microscope is seen to be composed of straight fibrils 7.5-10mm in diameter. amyloid, in the original meaning of the word, designates substances that when stained with iodine respond in a manner similar to that of starch. in the skin, however, amyloid is not a complex of mucopolysaccharides, but consists of various substances that have in common a similar appearance in sections of tissue stained with hematoxylin and eosin and with crystal violet (congo red is ineffective for demonstrating amyloid with repeatability in the skin), as well as a consistent appearance in sections of tissue examined by electron microscopy. biochemically, the various substances known as amyloid share the basic structure of glycoproteins, but they are very different from one another in origin and in other details. in the skin, amyloid derived from necrotic epidermal keratocytes as a consequence of animated scratching is present in the papillary dermis (at first as macular amyloidosis and, if that condition is then rubbed persistently for long, as papular [lichenoid] amyloidosis), whereas amyloid that comes into being from a systemic disease, e.g., a dyscrasia of plasma cells, may be deposited in the wall of vessels, leading thereby to leakage of erythrocytes and even to hemorrhage. under no circumstance should amyloid be characterized as being “hyaline in appearance” because “hyaline” is a term generic that lacks specificity. in short, the definition of amyloid as a substance morphologic does not turn at all on the origin of it or on the biochemical character of it, but on the appearance of it as assessed by conventional microscopy and electron microscopy. the term amyloid lacks specificity because there are so many different kinds of amyloid. where as amyloid derived from necrotic epidermal keratocytes may contain melanin and be stained by anticytokeratin antibody, amyloid that comes from immunoglobulins secreted by plasma cells lacks those characteristics. not only does some material designated amyloid come from sources other than immunocytes, but, as a rule, amyloid in the skin is made up mostly of necrotic keratocytes. different kinds of amyloid deserve to be given different appellations. were that practice employed, the term “amyloid,” unmodified, would become as passé as lentigo, unmodified, nevus, unmodified, and parapsoriasis, unmodified. anagen: that part of a follicular cycle during which a hair grows because the bulb is formed fully and matrical cells in the center of it mature to become the hair shaft. anagen is not the “growing phase of a hair follicle” and not the “growth stage of hair development,” but that part of the follicular cycle during which a hair grows. it is not the follicle that is growing, but the hair shaft that is growing as a consequence of maturation of matrical cells, just as is the case also for the inner sheath and the outer sheath, both of which represent maturation of matrical cells situated off center in the bulb. moreover, it is not necessary to designate that part of the follicular cycle as “active” because growth of hair is never passive. last, it is the follicle that cycles, not the hair, the stages in that cycle being known as anagen (during which the bulb of a fully formed follicle produces a growing hair), catagen (during which the bulb and stem of a follicle involutes), and telogen (during which only the isthmus of the follicle and, continuous with it, a tiny remnant of the inferior segment, i.e., bulb and stem remain, “resting” prior to the onset of anagen anew). vellus hair follicles proceed through the same cycle as do terminal follicles, but the former are situated more superficially, always rooted in the upper part of the reticular dermis, in contrast to terminal follicles that are based in the lower part of the reticular dermis and, sometimes, in the subcutaneous fat, such as is invariable on a normal scalp with pelage prominent. every time reference is made to “hair cycle,” it is “follicular cycle” that is meant; the follicle cycles, not the hair. analysis: denotes separation of elements into component parts, such as the act of assessing the components of histopathology patterns in order to come to a specific diagnosis, as of an inflammatory or neoplastic skin disease. pattern analysis is part of the method by which the diagnoses of inflammatory and proliferative skin diseases are made. using 28 review | dermatol pract concept 2012;3(2):4 pattern analysis, silhouette, algorithms, and other tools the diagnoses of such diseases can be made in an orderly way. anaplasia: a characteristic particular of a neoplasm, usually a malignant one, in which all of the cells constituent are immature, that is, nuclei of them are crowded, pleomorphic, and heterochromatic, and cytoplasm is scant, thereby precluding identification with specificity either of the cells themselves or of the proliferation itself; immaturity of cells of a neoplasm. reversion pertains to characteristics biologic, not to attributes morphologic; one cannot observe reversion through a microscope. for that reason, anaplasia, if it is to be employed at all, should refer to findings morphologic and not to function. although the changes seen in anaplasia doubtlessly reflect abnormal growth of cells and possibly even reversion in growth of them, growth in any form is irrelevant to definition of the term. “primitive” implies primary or original, and the abnormal cells of anaplasia surely cannot be judged to qualify as that. individual cells of a proliferation may be described as immature, partially mature, or mature, but not as undifferentiated, poorly differentiated, or well differentiated; only numerous cells in proximity to one another can differentiate, that is, form structures that resemble those in normal tissues or organs of an embryo, a fetus, or an individual postnatal. if by dedifferentiation is meant “regression of a specialized cell or a tissue to simpler unspecialized form (stedman’s 2001), then despite the inadequacies of that definition, dedifferentiation is a synonym for anaplasia and should be defined, as we have proposed, in the same way, namely, morphologically, not biologically. phrases like “loss of orientation [of cells] to one another and to their axial framework and blood vessels” and “nuclear contour angulation” are uninformative and, therefore, are unhelpful in defining “anaplasia.” the problems inherent in the definition by others of the term “anaplasia” become manifested in usage of the word. in short, there is no unanimity in regard to how anaplasia should be employed. some authors utilize it to describe abnormalities cytopathologic that conventionally are designated “nuclear atypia,” others for lack of features histopathologic they deem to be specific, and still others as a synonym for dysplasia, a term that is often invoked but has yet to be defined in a comprehensible, lucid, repeatable manner. in brief, failure to define anaplasia in a manner meaningful renders the word useless in the parlance of pathology in general and of dermatopathology in particular. anastomose: to connect or join structures by a union of parts in a fashion intercommunicating. the verb to anastomose does not mean to connect structures that formerly were separated, but rather to link two structures, usually ones of the same kind. those structures not only can be vessels, but ones tubular such as those in apocrine cribriform carcinoma and those solid such as abnormal trichoblasts in cords and columns of fibroepitheliomatous trichoblastic (basal-cell) carcinoma. those structures linked surely need not have been separated previously. the verb “anastomose” is used rarely in dermatology and dermatopathology, whereas the word anastomosing, which is derived from it, is employed commonly as an adjective for a pattern, usually of a neoplasm, in which numerous communications are established among structures of similar composition. the term is not restricted to angiomatous or vascular structures as, for example, in sinusoidal hemangioma. “anastomosing” also is employed as a synonym for a pattern of epithelium in which cords and columns are linked in a manner fenestrated. anastomosed: characterized by anastomosis. anastomosing: describes a pattern in which numerous communications are established among structures of similar composition, it being created by structures tubular housed in proliferations of epithelial cells that exhibit adnexal differentiation, such as apocrine mixed tumors and apocrine fibroadenomas. fibroepithelial trichoblastic (basal cell) carcinoma (pinkus) also is marked by anastomosis striking of cords and columns of neoplastic cells, the arrangement of elements epithelial and nonepithelial in that condition resembling windows separated by panes, i.e., fenestrated. anastomosis: the union of parts in a manner intercommunicating. the word “connection” is not quite right to characterize anastomosis because it does not convey the sense that the two structures joined actually communicate with each other. a connection exists, too, between structures linked but without any communication of them. the word “union” describes better the continuity between structures in an anastomosis. in dermatology, the word anastomosis is employed nearly exclusively to refer to communication between blood vessels. in general, the term also designates communications between structures tubular, such as between the gastrointestinal and the urogenital tracts, consequent to a union produced artifactually. in principal, the term anastomosis could be used for communication between solid structures of the same kind, i.e., trabeculae of neuroendocrine carcinoma, as well as between tubular structures of the same kind. anatomy: is a science that pertains to the structure of the body of an animal (or plant) and to the relationship of the parts of the body to one another. it is predicated mostly on what is learned from dissection of a body. gross (macroscopic) anatomy deals with structures that can be identified by a naked eye. in contrast, histologic (microscopic) anatreview | dermatol pract concept 2012;3(2):4 29 omy deals with structures so minute that they can be seen only through a microscope. anemicus: anemic, bloodless. in dermatology, the english word anemia hardly ever is encountered, where as the latin word anemicus is used to designate pallor of lesions clinical, it’s pertaining solely and specifically to reduction or absence of perfusion with blood of a tissue in a locus discrete. the adjective anemicus, which is synonymous with anemic, appears in the term “nevus anemicus,” a site of skin localized that lack the usual perfusion of blood. when erythema is induced in the skin adjacent to nevus anemicus, as is done conventionally by applying ice to the region, the lesion of nevus anemicus itself remains white, in contrast stark to the redness of the skin around it. no relationship exists between the appearance anemic of those nevi and anemia systemically. a reference to “anemic infarcts” is incorrect because the infarct is not anemic; the infarct causes pallor of tissue because the lumen of vessels that supply the site is obstructed. moreover, in medicine in general, the word anemic is used principally to convey a relationship direct to anemia. in that sense, an anemic infarction would be an infarct caused by anemia, which certainly is not the case. in dermatology, anemic should be used only as a designation of lesions that lack perfusion with normal blood, the example consummate of that being nevus anemicus. anetoderma: a kind of atrophy of the skin characterized clinically by a protrusion (colloquially referred to as an outpouching) in the form of a papule or a nodule that is so compressible it can be herniated readily and histopathologically by loss of elastic fibers especially, but also of collagen in the reticular dermis, usually in the upper half of it. anetoderma is a term generic for one type of cutaneous atrophy, namely, that characterized by slackness in the form of a pouch, an appearance that result from loss of elastic fibers especially, but also of collagen, in the upper half of the reticular dermis. atrophy results from loss of substance, and in the skin there are two basic types of it, to wit, that which involves loss of dermal papillae (with subsequent loss of epidermal rete ridges) and the other that involves loss of a rather circumscribed zone of reticular dermis. almost always, those two expressions of atrophy are secondary to the effects of products of inflammatory cells, although the first type also may be consequent to the effects of neoplastic lymphocytes in mycosis fungoides (i.e., poikiloderma vasculare atrophicans). loss of dermal papillae leads to atrophy clinical typified by skin that displays a shiny surface, loss of normal skin markings, and capability to wrinkle easily when it is compressed between the thumb and the forefinger. sometimes wrinkling is apparent without intervention by the fingers of an examiner. when there also are changes associated of hyperand hypopigmentation, as well as telangiectases, the constellation of findings is known as poikiloderma. all forms of poikiloderma, irrespective of character fundamental, of which there are many, result from loss of dermal papillae and of epidermal rete ridges. in contrast to attributes clinical of atrophy that develops consequent to loss of dermal papillae, atrophy clinical secondary to loss of reticular dermis is typified by a pouch that can be herniated with ease, a condition termed anetoderma. when anetoderma presents itself as papules, as occurs often on the back of young men with severe acne vulgaris, the condition is referred to wrongly as macular atrophy (it is papular, not macular). when anetoderma presents itself as a nodule (and, rarely, a tumor) of cause unknown, it was termed in times past “anetoderma of schwenninger and buzzi.” atrophy may involve subcutaneous fat, as well as the skin. when huge numbers of adipocytes are lost, as they are in lipodystrophy, lupus profundus, and pancreatic panniculitis, a gully forms, which is just the opposite of what happens in anetoderma. anetoderma is a term generic for atrophy of the skin of one particular type. so called macular atrophy is one kind of anetoderma, but it is not a synonym for anetoderma. there are no “anetoderma-like skin changes”; there is either anetoderma or there is not. neither is a distinction between “primary” and “secondary” anetoderma instructive; everything is secondary to something and that applies, too, to anetoderma. so-called primary anetoderma is merely anetoderma whose cause could not be determined (idiopathic). all anetodermas, therefore, are “secondary” and, that being so; stating “secondary” is redundant. although loss of elastic tissue surely is responsible largely for the appearance of anetoderma (destruction of elastic fibers doubtlessly occurs by a process other than “elastolysis,” whatever that may mean), collagen, to an extent much less, is lost along with it, as might be expected in a condition that usually comes into being as a result of the effect of large numbers of inflammatory cells whose products do not make a distinction in influence destructive between kinds of connective tissue, i.e., elastic and collagenous, although elastic tissue undergoes degeneration far more readily than does collagen. aneurysm: saclike dilation of a vessel. an aneurysm is a saclike widening of a vessel, but the word does not tell anything about the kind of vessel affected or the extent of the widening, either in terms of length or breadth of it. it may be an artery, a vein, an arteriole, a venule, a capillary or a lymphatic. the extent of dilation may be very long and broad, as in an aneurysm of the aorta, or short and rather narrow, as in a “thrombosed capillary aneurysm,” which actually is a markedly ectatic venule. the aneurysm may be pulsatile if the vessel affected is one of the larger 30 review | dermatol pract concept 2012;3(2):4 arteries of the body, it can be filled with clotted blood if the vessel is a vein or an artery or arteriole in a person whose blood pressure is low, or it may be filled with lymph if the vessel affected is a lymphatic. the dilation may be the result of weakness acquired in the wall of the vessel, as is the case with aortic aneurysm in cardiovascular syphilis, but it also may be a consequence of an error in development embryologically, as in marfan syndrome. in brief, the term aneurysm itself communicates nothing about the kind of vessel affected, the extent of the effect, or the cause of it. when the term aneurysm is used without qualification further, authors who employ it usually intend it to mean a saclike dilation of arteries. nevertheless, aneurysm also is used to designate widening of other kinds of vessels, such as veins or capillaries. it is a contradiction in terms to refer to a cirsoid aneurysm because that proliferation of small blood vessels approximated closely is a hemangioma, which is not a saclike dilation of a single vessel. the term cutaneous aneurysm is imprecise because it is not the cutis which is aneurysmal, but an artery positioned in the skin. dilation extraordinary of lymphatics in a type of “deep” lymphangioma is called, rightly, caverns and not aneurysms. aneurysmal: pertaining to an aneurysm angio-: prefix pertaining to a lymphatic or blood vessel angiocentric: centered around a vessel, usually a venule, but sometimes around a larger vessel. the word “angiocentric” is not defined in most dictionaries devoted to medical terms. moreover, in major textbooks of dermatology and dermatopathology, no definition of “angiocentric” is provided. despite the fact that the word “angiocentric” is not defined in most medical dictionaries and not in any textbook of dermatology or dermatopathology, it is employed widely by authors of those textbooks. they use it to characterize lymphomas, inflammations, infiltrates, and “features” various. the term also is found in the name itself of diseases, like “angiocentric t-cell lymphoma.” curiously, the meaning of all these designations is unclear, but that should not be surprising, given the reality that a definition of “angiocentric” never is provided. the word, literally, means “in the center of a vessel,” but that is not how the term is used by histopathologists, they seeking to describe a pattern of distribution of cells, usually of nature inflammatory, or various proliferations around vessels, those cells sometimes also being present in the wall and in the lumen of the vessels. furthermore, it is truistic to speak of angiocentricity of cells of an inflammatory disease because in every instance the cells of such a process appear first in tissue in the vicinity adjacent immediately to venules. in regard to malignant neoplasms, angiocentric t-cell lymphoma surely is not the only lymphoma in which t-lymphocytes are arrayed in fashion angiocentric; so, too, it is for mycosis fungoides, lymphomatoid papulosis, and adult t-cell lymphoma/leukemia, as but three examples. the arrangement of abnormal melanocytes of a congenital nevus in distribution angiocentric and adnexocentric is expected in that type of it referred to by us as “superficial and deep” the cliché “angioinvasion and angiodestruction” has become synonymous with changes reputed to be characteristic histopathologically of angiocentric t-cell lymphoma, but, as can be understood readily, that has no legitimacy because “angioinvasive” and “angiodestructive” are phenomena that can not be discerned morphologically; neither “invasion” nor “destruction” are identifiable in sections of tissue scrutinized through a microscope conventional. angioid: resembling a lymphatic or blood vessel angioma: an increase in number of blood vessels or lymphatics, usually ones that are dilated, but not otherwise abnormal morphologically, in a lesion circumscribed. angioma is not necessarily a swelling or tumor; witness the tiny papule known as cherry hemangioma. neither is it correct to designate an angioma; a tumor in the sense of neoplasm, because what is called an angioma by dermatologist and pathologists may be a hamartoma, a choristoma, or a malformation, not only a benign neoplasm, of course all are generically “proliferations” and this may be an easier term. for example, a pyogenic granuloma is a hyperplasia (it involutes in time in the absence of any treatment), a port wine stain is a malformation, a glomangioma is a hamartoma (it is composed of elements, namely, venules, glomus cells, and fascicles of smooth muscle, that are present normally in skin), and strawberry hemangioma is a benign neoplasm. neither is a definition for angioma such as “an abnormal growth produced by the dilatation or new formation of blood vessels” precise, it being applicable equally to angiosarcoma. the term “angioma,” either with or without the prefix lymphor hem-, is employed usually for lesions benign of character vascular, including malformations vascular like nevus flammeus and hemangiomas like cherry angioma. when authors speak of angioma without specification further, they usually mean hemangioma, not lymphangioma. nevus flammeus is a deformity of vessels that comes about during embryogenesis and qualifies, therefore, as a vascular malformation and not as a hemangioma. the same obtains for angioma serpiginosum; it, too, is a vascular malformation, not a hemangioma. angiomatous: pertaining to an angioma. angiotropism: not definable for purposes practical. adj. angiotropic review | dermatol pract concept 2012;3(2):4 31 a biological phenomenon that indicates growth or the turning movement of a cell or a collection of cells toward a vessel. in strictly morphologic sense, not definable. the following terms should be used instead: 1. intravascular: within the lumen of a vessel. 2. perivascular: around a vessel. 3. intramural: in the wall of a vessel. in general, the suffix–tropism implies a movement. in biology, tropism designates the movement of an organism in response to an external source of stimulus, usually toward or away from it. in medicine, tropism is used to refer, i.e., to viruses and other pathogens that affect only a certain host (host tropism) or only one specific type of cell (cell tropism). neither the adjective “angiotropic” nor the noun “angiotropism” is defined in any of standard medical dictionary or in any textbook of dermatology or dermatopathology. strictly speaking, the suffix–tropism implies a movement, the best example being the turning or bending phenomenon plants suffer in response to light as the environmental stimulus, called phototropism. literally, angiotropism means a “turning towards a vessel or having an affinity for a vessel.” even though a term should not be used before it is defined properly, angiotropism and angiotropic are used in a variety of different circumstances. they demonstrate that angiotropic and angiotropism are not employed consistently: when referring to melanoma, they are used for cells that “occupy a pericytic location,” and authors specifically emphasize that there should be no evidence of intravasation in that circumstance. when referring to a specific type of lymphoma, so called intravascular lymphoma or angiotropic lymphoma signals exactly the opposite, namely, confinement of the neoplastic cells of lymphoma to a vascular lumina. some authors use angiotropic synonymously with the term “angioinvasive,” and they designate it by the presence of neoplastic cells within vessel walls. yet other authors employ angiotropic for inflammatory cells being present around vessels, that being synonymous with “perivascular,” or for inflammatory cells being present within vessel walls, that being a normal finding in any kind of perivascular dermatitis when small vessels are concerned, whereas it is a sign of vasculitis when large vessels are concerned, such as is the case, i.e., in periarteritis nodosa. meaningful definition of a term, however, should not be dependent on the diseases entity to which it is applied, but it should be clear and independent of the disease for which it is disposed. many questions remain unanswered, i.e., why is angiotropism not used for distribution of melanocytes in a congenital nevus? why not for neutrophils in nodular vasculitis? why not for proliferations of endothelial cells of kaposi’s sarcoma, which usually surround a preexisting vessel in the “promontorium sign”? why not fat deposits around vessels such as amyloid in systemic amyloidosis? and why not for presence of melanoma cells within a vessel? it appears that authors make no clear distinctions between angiotropic and angiocentric; between angiotropic and angiodestructive; between angiocentric and perivascular, or between angiotropic and intravascular. interestingly, the majority of usages of angiotropism in literature of dermatopathology refer to malignant conditions, such as melanoma and lymphoma, which are known to be capable of spreading through sanguineous or lymphatic vessels. that journey of malignant cells, however, can not be seen through the microscope. a pathologist can only identify the precise location of cells in relation to preexisting vascular structures. in fact, intravascular as well as perivascular and angiocentric location of cells is much more commonly encountered in benign lesions than in malignant ones. but in benign lesions, we usually do not attribute any prognostic meaning to these cells, whereas neoplastic cells in and around blood vessels are often considered to be synonymous with metastasis. dermatopathologists seem to use the word angiotropism only after they have come to the conclusion that a lesion is a malignant proliferation. application of the term angiotropism implies invariably that a dermatopathologist expects a certain behavior of the cells. but dermatopathologists should limit themselves to describing accurately what they really see. for this reason, the word angiotropism should not be used in a description of microscopic findings in sections of tissue. the terms intravascular, perivascular, and intramural are purely descriptive and therefore more accurate as stated earlier. anlage: in an embryo, an aggregation of cells that represent progenitors of tissue or an organ. an anlage is an aggregation of cells in an embryo that signifies a stage incipient in the development of a tissue or an organ. anlage is synonymous with primordium. it is imprecise to define anlage as “foundation of a subsequent development” because it is not a foundation, but an initial stage in development (which is subsequent) and because development does not necessarily mean formation of a tissue or an organ. an anlage refers specifically to that aggregation of cells visualizable as representing the very first stage in development of a tissue or an organ. at about 10 weeks in the life of an embryo, two anlagen appear on the undersurface of surface ectoderm, namely, that which gives rise to the infundibulo-apocrine-sebaceous follicular unit on one hand and that which eventuates in the eccrine unit on the other. the word anlage is employed mostly by authors european, and especially ones german-speaking. americans tend to use the word primordium in its stead, but, in actuality, that is not done very often. in fact, most textbooks of dermatology and dermatopathology do not provide much informa32 review | dermatol pract concept 2012;3(2):4 tion about embryology of the skin in general or structures adnexal (epithelia and non-epithelial) in particular. annular: in the shape of a ring, syn, annulare. the term anulus or annulus is latin for little ring or finger ring, the latin word for ring being anus. an annulus is circular, but the word is not synonymous with a circle; in terms geometric, an annulus is the region between two concentric circles, whereas a circle is solid. a lesion is round but the center is different from the border. thus, a round lesion is not necessarily annular. in dermatology, the word annular applies to a lesion that is circular in the shape of a ring, and the term nummular to one that is circular and solid. the word annular is used to describe the shape of lesions clinical. it is true that annular and round are different from one another and, therefore, should not be used interchangeably; in a lesion annular, the center is different from the periphery, whereas in a round lesion the center and the periphery are more or less the same. nevertheless, an annular lesion is round, which means that any part at the circumference of it is equidistant from the center of it. most lesions that are said to be annular clinically are not truly annular geometrically. the term annular is employed widely and incorrectly to designate lesions whose contour is closed and that may be round, oval, or polycyclic. annular is used, therefore, interchangeably and wrongly with circular, circinate, arcuate, and polycyclic, none of which are shaped like a ring. for this reason among others, the appellation “annular erythemas” is a misnomer; most lesions of diseases grouped under that title have configurations arcuate and polycyclic, as well as annular. the term “granuloma annulare” derives from but a single manifestation clinical of that disease, namely, a papule or plaque ring like because of an elevated border and a depressed center. other presentations clinical of granuloma annulare are discrete papules, plaques, and nodules devoid of a shape like that of a ring, and papules and plaques whose configuration is arcuate or oval, but not annular. anonychia: absence of nail, i.e., nail plate. anonychia is defined correctly in dictionaries of medicine as well as in textbooks of dermatology as absence of nails, meaning absence of nail plates. the term tells nothing about the cause of that absence, which includes diseases of character as different as lichen planus, pemphigus vulgaris, erythema multiform, epidermolysis bullosa dystrophica, infection by fungi, or effects adverse of trauma and drugs and even aberrations in utero that result in congenital absence of nails. the term anonychia is analogous to atrichia which designates absence of hair. the word anonychia alone however does not allow any conclusion to be drawn about the nature of the defect, i.e., injury to the nail matrix, any more than the word atrichia communicates anything about the nature of the defect responsible for it, i.e., injury to cells in the follicular matrix. anonychia is employed correctly when it designates conditions in which nail plates are absent. that applies to congenital absence of nails, as well as to absence of nails that follows on inflammatory diseases (or neoplastic ones like mycosis fungoides) that affect the nail matrix. when the nail is absent or destroyed, anonychia is likely to be permanent. if, however, matrical cells remain visible after injury to them, such as occurs after episodes febrile in the extreme, then anonychia is likely to be transient; the nail matrix begins to manufacture a nail plate anew. aphtha: small ulcer on a mucous membrane. an aphtha is a small ulcer that occurs on a mucous membrane. it is not restricted to the oral mucosa. when aphthae appear concurrently in the mouth and on the genitalia the possibility of behcet’s disease should come to mind. an aphtha is a term for a clinical feature morphologic and is not synonymous with a disease, namely, aphthosis. an ulcer may be situated on skin or on mucous membrane, whereas an aphtha, by definition, is confined to a mucous membrane. an ulcer on a mucous membrane and on skin may be surrounded by a rim of redness and may be covered by a grayish or yellowish, exudate. defects in aphthosis, in primary infection by herpes simplex, as well as in lesions on mucous membranes of behcet’s disease, are called aphthae. the term aphthous ulcer is used interchangeably with aphtha, but that is redundant because an aphtha is an ulcer, i.e., one situated on a mucous membrane. the macule, vesicle, or pustule that precedes the aphtha in behcet’s disease or aphthosis is not called an aphtha, because an aphtha is a small ulcer, that is, a defect in both mucosal epithelium and lamina propria. the appearance clinical and histopathological of an aphtha does not allow differentiation between behcet’s disease and recurrent aphthosis, but the course clinical does, i.e., oral and genital manifestation of aphtha and/or associated symptoms of the eyes and of the brain signifies behcet’s disease. aphthoid: similar to aphthae aphthous: relating to or characterized by aphthae aplasia: lack of development of a tissue or an organ. although “aplasia” designates lack of development of a tissue or an organ, it is not just a failure to develop normally; hypoplasia also fulfills that definition. as far as development in an embryo is concerned, aplasia of a tissue or an organ may be present at birth, but aplasia of tissue that may develop during the course of a lifetime, like of the bone marrow, may manifest itself at any time, i.e., after chemotherapy for leukemia, aplasia of bone marrow may result. even in hematology it is not correct to define aplasia as “incomplete, retarded, or review | dermatol pract concept 2012;3(2):4 33 defective development, or cessation of the usual regenerative process,” because that definition includes hypoplasia. “aplasia” appears almost exclusively in dermatology and dermatopathology in the term aplasia cutis congenita, a group of rare diseases congenital characterized by either lack in a locus discrete of skin and/or subcutaneous tissue. lesions of aplasia cutis congenita may present themselves clinically as an ulcer at birth, but usually by that time they have healed with a scar that comes to be covered by a thin epidermis. aplasia also may be employed for lack of development of any kind, like that of a limb or of red blood cells. aplastic: pertaining to aplasia. apo-: prefix meaning off, away from. apocrine: denoting a method of secretion whereby the product of a gland accumulates in the apical part of cells, which then detaches in a manner that has been likened to “decapitation,” “pinching off,” and “snouts.” the notion of “losing cellular tissue in the process of secreting” is inadequate for definition of the term apocrine because that is what happens, too, in holocrine secretion, such as that of sebaceous glands in which the cell in its entirety becomes the product of secretion. apocrine secretion is not simply a “pinching off” of the free end of the secretory cell, but is separation complete of the apical part from the rest of the cell. that part apical of the cell is different from the rest of it because products secretory accumulate there prior to the separation taking place. the apical portion of the cell is not incorporated in the secretion, but rather itself consists largely of the product secretory. parenthetically, it is illogical to say that apocrine secretion occurs in apocrine glands and mammary glands, because mammary glands are apocrine glands. the purpose of apocrine glands is to produce a secretion, known colloquially as “decapitation secretion,” the exact role of which is not understood. the function appreciated best is the secretion of cells of the mammary gland, which is an apocrine gland, specialized to produce colostrum. apocrine glands are identifiable morphologically by the apical part of cytoplasm giving the appearance of being “pinched off” or “decapitated.” an “apocrine system” per se does not exist; apocrine glands at different sites anatomic are specialized to produce secretion as different from another as “mother-milk” and cerumen. the adjective apocrine is used not only to denote a component of the gemisch known as a type of secretion, but to convey a sense for “pertaining to or derived from apocrine glands.” apocrine glands are situated normally in the axillae, perineum, periumbilical region, and eyelids, and to an extent lesser, on the face and scalp. other clues to apocrine glands or differentiation towards them although not as specific as decapitation secretion include fringe, vacuoles in a ring at the periphery of a lumen, mucinous cells, signet ring cells, polygonal cells, plasmacytoid cells, large round granules in cytoplasm, lipofuscin, elongated tubules, papillations, continuity of tubules (other than sebaceous ductal ones) and infundibula, and the presence, in sections from the same biopsy specimen, of a hamartoma or neoplasm that shows follicular and/or sebaceous differentiation. however, as noted earlier, the finding of unquestionable decapitation secretion in a proliferation, primary in the skin is virtually specific for apocrine differentiation. apoptosis: a type of necrosis in which cells characterized by pyknosis and karyorrhexis are removed by phagocytosis. if apoptosis means “the death of cells which occurs as a normal part of an organism’s development,” then every keratocyte that matures to become a cornified cell of the stratum corneum of epidermis, of the hair shaft, in the process of dying, which is the case for every cell, and of the nail plate should rightly be considered apoptotic. the “death” of any keratocyte could be deemed “programmed,” that is, to end as a dead cell, a corneocyte in the stratum corneum, in the hair shaft, or in the nail plate. the life span of every cell in the body is limited genetically, but surely not all cells are designated apoptotic. it makes no sense to invoke “requirement of energy of the process” as a criterion for differentiating apoptosis from necrosis; that requirement cannot be identified morphologically. a “deletion of selected cells in both physiologic and pathologic processes” also cannot be the basis for criteria morphologic. characterizing apoptotic cells as “single homogenous eosinophilic necrotic cells (civatte or colloid-bodies),” “fragmentation into membrane bound particles,” or “marked by the shrinkage of the cell, condensation of chromatin, formation of cytoplasmatic blebs, fragmentation of the cell into membrane-bound apoptotic bodies” hardly justifies the concept; each of those findings are possessed by cells that in classic pathology virchowian qualify as necrotic. controversies should rage (but do not) about definition of the terms “apoptosis” and “apoptotic.” the fact that definition, at times, is constructed solely on the basis of findings morphologic at other times on the basis of a process physiological, and on the basis at other times pathologic, indicates how flawed irreparably is the concept of apoptosis. morphologically, cells said to be apoptotic are typified by pyknosis and karyorrhexis, those criteria for more than 150 years having been signs agreed on for necrosis. in the short space of 30 years, the concept of apoptosis has become accepted universally; despite the fact that it has never been defined comprehensibly. “programmed cell death” is not a definition, but a phrase that conveys ignorance of principles fundamental of physiology and of pathology. curiously, the concept derived initially from observation of changes affiliated with a process physiologic (i.e., necrosis of individual cells of the 34 review | dermatol pract concept 2012;3(2):4 bulb and the stem of a hair follicle as it involutes in catagen), but soon was extended to findings associated with nearly every process pathologic in every organ, even being invoked as the key to pathogenesis of cancer. moreover, apoptosis sometimes is used in regard to differentiation of a process and at other times to refer to loss of differentiation of a process. some authors claim that irradiation causes apoptosis and that the “sunburn cell” is the example stereotypical of an apoptotic cell, whereas others acknowledge that irradiation and ultraviolet light may cause necrosis. no one has yet refuted the assertion that the attributes cytologic claimed to be identifying of so-called apoptosis, to wit, pyknosis and karyorrhexis are the very same ones requisite for recognition of necrosis. all of this renders it impossible to employ the term apoptosis in a fashion rational and meaningful, but apologists for the term make no effort whatsoever to respond to criticism of it but they proceed to expand the number of conditions claimed by them to be characterized by it! apoptotic: pertaining to or characterized by apoptosis. appendages: structures produced in the skin, emerge from the skin, and extend beyond the surface of the skin, namely, hairs and nails. matrical cells of mature hairs are seated in a follicular bulb and matrical cells of nails are positioned in the matrix of a nail unit. in general, appendage is a part attached to a main structure. the term does not convey anything, however, about the function of the part appended, i.e., whether it is subordinate or not. in dermatology, the term appendage designates structures that are manufactured in the skin and that extend beyond it, to wit, hair and nails. in contradistinction, the term adnexa designates epithelial (follicular-sebaceous-apocrine units, eccrine units, and matrix and bed of nail units) and nonepithelial (smooth muscles, nerves, vessels) structures that are housed entirely in the skin (and subcutaneous fat). as is apparent readily, the term appendage often is employed when adnexal structures really are meant. the only true skin appendages are hair and nails, and those structures, per se, are not associated with any neoplasm; so-called skin appendage tumors are actually adnexal proliferations of the adnexa of skin (and/or subcutaneous fat); benign and malignant proliferations may differentiate toward epithelial and nonepithelial structures of adnexa. arborization: describes a tree-like shape that is a result of inward turning of epithelial structures of adnexa at the periphery of a structure such as a common wart, a seborrheic keratosis, or a pyogenic granuloma around which the change sometimes is called, inaccurately, an “epidermal collarette.” in truth, the elongated collars of epithelium are eccrine ducts and hair follicles, not epidermal rete ridges. architectural: pertaining to architecture. architectural atypia and architectural disorder: clichés that are meaningless and, therefore, to be eschewed. for the term “architectural atypia” and “architectural disorder” to have meaning repeatable, there must be a definition agreed-on of “architectural typia” and “architectural order,” but none exists. in fact, the standard for architectural typia and architectural order of skin is normal skin itself and, therefore, any deviation from normal skin by any neoplasm, benign or malignant, nevus or melanoma, qualifies as architectural atypia and architectural disorder, both of which fail to inform in general and about diagnosis specific in particular. architecture: in general, the design, in its entirety, of the structure of a thing; in dermatopathology, the design of an abnormal condition of the skin as assessed by visualization of the structure in its entirety and of its constituent parts. interestingly, neither the noun architecture nor the adjective architectural is defined in standard dictionaries devoted to medicine general or in any textbook of dermatology and dermatopathology. in the most recent edition of dorland’s illustrated medical dictionary, architecture is defined tautologically as pertaining to architectural pattern; no definition of architectural pattern is provided there. in dermatopathology, architecture pertains to the overall structure of an abnormal condition as it is assessed at scanning magnification of a conventional microscope, with particular reference to each of the components, including distribution and arrangement of cells, as well as of noncellular constituents, such as fibers and deposits. it is apparent from the quotations above that the words architecture and architectural are employed commonly in textbooks of dermatology and dermatopathology, although a precise definition of those terms cannot be found in any of them. what truly is meant by intrinsic epidermal architecture, architectural atypia, or architectural disorder is impossible to fathom; the terms are opaque. if such designations are meaningless, how can they possibly be helpful to those charged with responsibility for determining whether a particular neoplasm is benign or malignant? ackerman never referred, ever, to “architectural atypia,” except to decry the use of it. he did introduce the concept of silhouette (architectural pattern) of a proliferation as being the representation morphologic of the behavior biologic of that particular neoplasm and, therefore, the surest route to deciding whether that neoplasm is benign or malignant. he also ridiculed repeatedly the concept of “architectural disorder,” asking rhetorically how that purported phenomenon could possibly be identified when no one had ever supplied a definition of “architectural order.” for ackerman, the word atypia never should be used for architecture (i.e., “dysplastic nevus”) of a proliferation or for an unconventional presentation of a review | dermatol pract concept 2012;3(2):4 35 common disease (i.e., “atypical pityriasis rosea”), but only for nuclear characteristics of cells, especially pleomorphism and heterochromasia (and much less so for large size and hyperchromasia). arcuate: shaped like an arc or a bow. syn. arciform. in dermatology, the adjectives arcuate and arciform are used synonymously to describe lesions that clinically are shaped like either a bow or an arc. a lesion arcuate may come into being over time, like papules of granuloma annulare become confluent, or by growth continous, such as a plaque of melanoma. it is imprecise to define the arcuate as being arranged in arches because that criterion is satisfied equally by the term polycyclic. in textbooks and in articles given to dermatology and dermatopathology, the adjectives annular, gyrate, figurate, circinate, arcuate, and polycyclic often are used interchangeably or in conjunction with each other. in most instances, no definition is provided for any of them. an annulus is a ring or ring like structure, a gyrate lesion is circular, round, or spiraled, and a figurate lesion may assume any number of geometric shapes. circinate means rounded, arcuate means formed like an arc, and polycyclic refers to a group of bowshaped lesions that have become confluent to form a special design. annular or gyrate lesions may evolve from ones arcuate or circinate (circular) or they may resolve asymmetrically, so that an arc or bow actually comes into existence as the lesion resolves. a single disease, such as urticaria, bullous pemphigoid in the urticarial stage of it, and mycosis fungoides in the plaque stage, may express itself in the form of all of the shapes of lesions just mentioned. arrector: the muscle of hair erection. syn. arrector muscle, arrector pili muscle. arrector has only one meaning in dermatology and dermatopathology, namely, erection of the smooth muscle affiliated with a hair follicle. a designation more correct than muscle of hair erection is muscle of follicular erection, but arrector pili muscle, arrector muscle, arrector pili, or simply arrector are synonyms for it. the arrector pili muscle is smooth muscle that originates from bulges of the isthmus of hair follicles and seems to insert at the base of epidermal rete ridges. when the muscle contracts, a papule ever so-subtle of normal skin comes into being in the form of what clinically is called “cutis anserine” by physicians and “goose bumps” by laypersons. some hamartomas and neoplasms may consist of smooth muscle of follicular erection, for example, leiomyoma of one type (the other type being composed of smooth muscle affiliated with blood vessels rather than with hair follicles). the so-called bulge is not single a structure but rather several bulges of isthmic epithelium. although the exact site of insertion of the arrector pili muscle has to this day not been demonstrated beyond doubt, almost certainly it is the base of epidermal rete ridges and not the dermal papillae. that is true in general for origin and insertion of muscles, to wit, from one type of structure to another of the same type. arteriole: smallest of arteries that end as capillaries. arterioles sometimes are referred to as precapillary arteries, that is, the smallest arteries of the body which terminate in a network of capillaries. in contrast to capillaries themselves, the wall of arterioles contains smooth muscle. arterioles are differentiated histologically from venules by possession of an internal elastic membrane. under normal circumstances, arterioles end in a network of capillaries, i.e., the superficial and deep plexuses of the reticular dermis, as well as in conditions pathologic, such as the hyperplasia known as pyogenic granuloma; the vascular malformation designated spider angioma and the benign neoplasm, referred to as cirsoid aneurysm. the number of layers of smooth muscle is not relevant to establishing a vessel as an arteriole; what matters is that it contains some smooth muscle. artery: a vessel that conveys blood away from the heart and that consists of three layers termed intima (endothelium, connective tissue, internal elastic membrane), media (smooth muscle, and elastin), and externa (connective tissue). syn. arteria. artery is a vessel that conveys blood away from the heart. most arteries, therefore, carry oxygenated blood except for pulmonary and umbilical arteries in an embryo. the wall of arteries usually is thicker than those of corresponding veins and the lumen of them is smaller and rounder. the wall of an artery consists of three layers, namely, intima, media, and externa, the latter also named adventitia. the intima is made up of endothelium that covers connective tissue as well as a more or less prominent layer of smooth muscle that is surrounded by an internal elastic membrane. the media is fashioned entirely of smooth muscle in arteries of the so-called muscular type, but it also contains elastic fibers in those that are found close to the heart, e.g., the aorta. the adventitia consists of connective tissue (collagen and elastin), and contains nerves and, occasionally, blood vessels, the so called vasa vasorum. sometimes, elastic fibers form an external elastic membrane, but that structure always is less prominent than the internal elastic membrane. artery is used correctly to designate vessels that convey oxygenated blood from the heart to the rest of the body. arteries branch and become arterioles, which, in turn, become capillaries. a vascular plexus consists of arteries, capillaries, and veins, not of capillaries only. in the skin, the two plexuses in the dermis, the superficial one in the upper part of the reticular dermis and the deep one in the lower part of the reticular dermis, are connected to one another through 36 review | dermatol pract concept 2012;3(2):4 “intercommunicating” vessels. arteritis means inflammation of an artery, so-called arteritis temporalis being associated commonly with arteries that may no longer be pulsating, because the lumen of the vessel has been obliterated consequent to the effects of the inflammatory process. arteries in the skin and subcutaneous tissue always are of the muscular type, arteries of the elastic type being found only in the immediate vicinity of the heart. it is not necessary, therefore, to designate arteries in the skin “muscular.” artifact: something that is not natural but made by human beings deliberately or by instruments technologic. artifactual: not natural, made by human beings or by technology. syn. artefactual, artificial, artifactitious, factitious, facticial. the adjective artifactual is derived from the latin word arte, meaning art, and the verb facere, meaning to make, it designating something that comes into being by manipulation of humans or by the effects of instruments of technology. that which is present in nature never is artifactual, whereas findings that are pathologic may come about as a consequence of a “natural” process, such as one infectious, immunologic, or metabolic, or as a result of manipulation external. that being the case, as far as changes in viable tissue are concerned, that which is artifactual also is pathologic, i.e., trichotillomania or factitious panniculitis. artifactual is used in dermatopathology in two different circumstances. first, it designates findings, clinically and histopathologically, that are caused by trauma inflicted by the person himself/herself or by another person. trichotillomania and traction alopecia are examples of those phenomena. second, all changes in sections of tissue that is introduced by defective technique of a physician in the course of biopsy, or of a machine, or of a histotech in a laboratory during the process of preparation of tissue are designated artifactual, i.e., crushing of cells during manual extraction of a specimen from the skin. both usages are correct. the words artifactual, artificial, artifactious, artifactitious, facticious, and facticial are used interchangeably. contrary to popular belief facticial changes in the skin may be diagnosed for what they are by paying attention to the criteria for them. asteatosis: condition of slight scaliness purported to be “dryness” secondary to decrease in normal quantity of lipids in the skin. “asteatosis” literally means a condition in which fat is lacking, but that is not what dermatologists intend when they use it. they mean fine scaling, usually on the extremities and particularly on the extensor aspect of the legs, a condition they call “dry skin,” which they deem to be common, and which they ascribe often to “bathing too frequently” or to “using harsh soaps.” some european authors use “asteatosis” synonymously with “sebostasis,” although there is no evidence at all that the fine scaling is attributable to a decrease in secretion sebaceous or in sebum. combining the adjective “asteatotic” with the term “eczema” or “dermatitis” implies that an inflammatory disease of the skin is either caused by asteatosis (which is merely the presence of fine scales) or that the asteatosis results from the dermatitis, neither of those theses being compelling. in brief, there is no true asteatotic dermatitis or asteatotic eczema (see definition [actually absence of it] of “eczema”); asteatotic has to do only with subtle scaling and nothing at all to do with inflammation. the confusion is compounded by linking asteatotic eczema to eczema craquele, which has never been shown to be spongiotic dermatitis, and to nummular dermatitis, which is an authentic spongiotic dermatitis that may eventuate in spongiotic vesicles. in sum, if asteatotic is to be employed at all, it should refer only to paltry scaling that probably is physiologic rather than pathologic. asteatotic: pertaining to asteatosis. asteroid: in the shape of a star, in the shape of the flower aster. “asteroid” is derived from the greek word aster (star) and designates structures that have the shape or appearance slightly of a star. in regard to appearance histopathologic, asteroid refers to a structure somewhat circular associated with elements linear oriented centrifugally, thereby simulating the points of a star. in reality, what is termed “asteroid,” conventionally, by histopathologists resembles only vaguely a star. in dermatopathology, “asteroid” is used mostly for bodies found in macrophages, ones both mononuclear and multinucleate (histiocytic giant cell). the structures once were considered to be specific for sarcoidosis, but, in time, it became apparent that they were found in cells of granulomatous inflammation of all kinds. moreover, “asteroid” is employed also for blastospores in sporotrichosis. in each of those instances, the term is utilized more or less correctly because “asteroid bodies,” as well as “sporothrix asteroid,” are reminiscent somewhat of a star. asymmetry: lack of symmetry; in dermatopathology, marked variation in structure of two halves of a lesion as it is assessed at scanning magnification of a microscope conventional and in dermatology uneven distribution and shape of lesions on halves of the body. symmetry and asymmetry in dermatopathology and dermatology usually refer to silhouette architectural of lesions histopathologically and distribution and shape of lesions clinically, the symmetry and asymmetry being assessed bilaterally. bilateral symmetry means that a lesion can be divided review | dermatol pract concept 2012;3(2):4 37 by a longitudinal plane into halves that are mirror images of one another. never in biology, however, is a lesion as it is assessed clinically or histopathologically absolutely symmetrical. the terms symmetry and asymmetry, therefore, are relative, asymmetry usually referring to differences marked in the “halves” of a lesion than to true “absence of symmetry.” interestingly, no definition of asymmetry can be found in any textbook of dermatopathology or of dermatology. the terms asymmetry and symmetric are used to characterize distribution and shape of lesions clinically and silhouette of lesions histopathologically. asymmetry is mentioned often as a criterion for malignancy, i.e., in the so-called abcd rule (asymmetry, border irregularity, color variability, diameter> 6.00 mm) for diagnosis clinical of melanoma. unfortunately, that simplistic mnemonic alone does not work for many “pigmented lesions” of the skin, no small number of benign conditions, such as many congenital nevi and clark’s nevi, fulfilling the criteria, and of melanoma failing to fulfill them, chief among those melanomas being those that develop in prepubescent children, hardly any of those ever being diagnosed clinically as melanoma. considering the fact that asymmetry is used as a criterion histopathologic for malignancy, it is surprising that no attempt has been made to define that word in any textbook of dermatopathology. in sections of tissue, only two dimensions of a lesion can be assessed. therefore, a lesion that seems to be symmetrical in two dimensions may be asymmetrical in the third dimension, which may not be visualizable in a particular section of tissue, that reality not being uncommon in circumstance of melanoma arising in association with a melanocytic nevus and when the blade of a microtome cuts only through that part of the lesion consisting of nevus, the melanoma in conjunction with it not having been sampled. it should be noted that symmetry or lack there of is only one criteria (but a major one) for the diagnosis of melanoma. a constellation of criteria must be used for melanoma and for all proliferations to determine benignancy verses malignancy. most feel there is a higherarchy of criteria. some being more important then others. (e.g., ackerman feels that symmetry is more important then circumsciption, etc.) atopy: a genetic disposition toward development of allergic rhinitis, allergic asthma, and allergic urticaria. pruritus is a common symptom, and response to it by furious rubbing and scratching produces the skin disease known as atopic dermatitis. atrichia: means absence of hair. syn. atrichiosis, atrichosis. atrichia is defined correctly as absence of hair, but the term itself does not tell anything about the reason for that absence, which may be congenital or acquired and may occur in the presence of hair follicles or in the absence of them. the adjective atrichial, therefore, refers to absence of hair, and not to absence of follicles. although the word alopecia usually is used in common parlance of dermatology to identify a condition characterized by absence of hair, rarely does a definition of atrichia make clear the distinction between alopecia (loss of hair) and atrichia (absence of hair), the terms not being synonymous. “atrichia can be understood well in the context of its derivation from a(absence of) and trichos (hair), in contrast to alopecia, which comes from the greek alopex (fox), the reference being to loss of the mange of a fox. not all conditions that are termed alopecia are reminiscent of a fox’s mange clinically, but all of them are characterized by loss of hair to extent various. rarely is the word “atrichia” employed in textbooks of dermatology and dermatopathology. some authors use it only to designate absence congenital of hair. others mention atrichia in regard to absence of hair shafts in the presence of follicles, in contradistinction to aplasia in which follicles are lacking entirely. in fact, the word atrichia conveys nothing other than absence of hair, the cause of that absence not being communicated, it hardly ever being identifiable clinically. alopecia areata, traction alopecia, and alopecia mucinosa (the latter being one of many manifestations of mycosis fungoides) may present themselves as atrichia. atrophic: pertaining to atrophy. syn. atrophied atrophoderma: atrophy of skin, that is, reduction in amount of tissue in the dermis, especially elastic tissue but also often of collagen. syn. atrophia cutis, atrophodermia. atrophoderma is atrophy of skin, but the loss essential to what is seen clinically as atrophy pertains to loss of dermis, not of epidermis. if, however, there is loss of dermal papillae, it is inevitable that that will be followed by loss of epidermal rete ridges. the loss of epidermis in that circumstance is paltry in comparison to loss of volume of dermis, and it is the latter which is responsible for the signs clinical of atrophy. an atrophoderma can be localized or widespread, as is the case, too, for many other processes pathologic of skin. although the term has been employed for conditions like atrophodermia ulerythematosa or atrophoderma of pierini and pasini, the word atrophoderma does not refer to any specific condition per se. atrophy has different causes and assumes different appearances clinically. in the majority vast of instances, atrophy is not a result of “improper” development of the skin, but a consequence of the effects of products released from inflammatory cells, lymphocytes in particular, fibrocytes, which then manufacture connective tissue altered markedly. that is what happens in conditions like atrophic lichen planus and lichen sclerosus et atrophicus. but products of inflammatory cells, in particular neutrophils, can destroy fibers and hereby induce changes of atrophy in a condition such as cutis laxa. anetoderma is not a synonym for atrophoderma, but rather is one kind of atrophoderma, characterized 38 review | dermatol pract concept 2012;3(2):4 by loss of both elastic fibers, and to a lesser extent collagen, in the upper half of the reticular dermis with resultant slackness in the form of a pouch. in contrast, atrophy of dermal papillae leads to skin that displays a shiny surface, loss of normal skin markings, and facility for wrinkling easily. atrophoderma is used most often in dermatology for the atrophoderma of pasisni and pierini, which in actuality, is nothing other than a late stage of morphea. the term follicular atrophoderma is a contradiction in the sense that it is infundibular epidermis that withers, not the dermis per se. because the term “atrophoderma” is generic and does not refer specifically to anyone condition, and because it encompasses so many different manifestations morphologic of loss of dermis, it has little utility for parlance of dermatology and dermatopathology. atrophy: loss of substance consequent to reduction in amount of tissue. syn. atrophia atrophy is neither a condition in which there is failure to develop fully nor an alteration regressive, but one that results from a loss of substance. it is a term that refers to reduction, morphologically, in amount of tissue. the term implies nothing about cause, mechanism, or type of tissue lost. it can occur during embryogenesis, i.e., in incontinentia pigmenti, or after birth, in poikiloderma vasculare atrophicans (mycosis fungoides) and it can follow on a process inflammatory or one neoplastic. atrophy can affect the epidermis, the dermis, or the subcutaneous tissue, or a combination of them. when there is loss of dermal papillae and, subsequently, of epidermal rete ridges, the skin appears shiny and crinkled (superficial atrophy); when there is loss of a rather discrete zone in the upper half of the reticular dermis, the skin pouches out (midatrophy); when there is loss of adipocytes in the subcutaneous fat, a gully forms (deep atrophy). so-called macular atrophy is actually papular; it is a type of anetoderma that comes into being by virtue of loss of elastic tissue and also of collagen in the reticular dermis. anetoderma is but one type of atrophy; it is not a synonym for atrophy. atrophie blanche, the end stage of livedo vasculitis, may be atrophic, but it may be characterized only by postinflammatory pigmentary changes without any signs overt of atrophy. the best example of superficial atrophy is lichen sclerosus et atrophicus, of midatrophy anetoderma, and of deep atrophy lipodystrophy. atypia: deviation from the normal; not conforming to type. in histopathology, nuclei of cells that are crowded, pleomorphic, and heterochromatic in comparison with the usual appearance of nuclei of that particular type of cell. syn. atypism. the definition of “atypia” as a state of being not typical or the condition of being irregular or not conforming to type is based on derivation of the word from the greek a(not) and typos (type), but it does not inform much to a student of the subject. in pathology in general, the term atypia is used specifically to designate characteristics nuclear that are different from the appearance of nuclei of normal cells in regard to size, shape, and/or color, the cliché for that being nuclei that are “large, hyperchromatic, and pleomorphic.” curiously, a definition of atypia is found but rarely in textbooks of dermatology, dermatopathology, and general pathology, although the identification of atypia is said to be of importance crucial for identification of proliferations as being malignant. pleomorphic nuclei, hyperchromasia of nuclei, coarse nuclear membranes, clumping of chromatin, large nucleoli, an increase in ratio of nucleus/cytoplasm, and abnormal mitotic figures often are mentioned as attributes ancillary in definitions of the term atypia. hardly ever cited, however, is crowding of nuclei, which is much more helpful in assisting a histopathologist in regard to coming to diagnosis of malignant proliferations than are large size and hyperchromasia of nuclei. as a matter of fact, large size alone is of no importance in the distinction of a benign from a malignant proliferation; large monomorphic nuclei are not regarded as being atypical. hyperchromasia of nuclei in itself is of no benefit in the differentiation of a benign from a malignant process. for example, normal lymphocytes are so deeply blue when stained by hematoxylin and eosin that they seem sometimes to be black, and, therefore, lymphocytes never can be judged to be hyperchromatic. in brief, the three signs most important of atypia in order descending are crowding of nuclei, pleomorphism (variation markedly in size and shape), and heterochromasia (variation markedly in the intensity of staining). there is no correlation direct between atypia nuclear and malignancy biological witness for example, the “monster” nuclei in some dermatofibromas and xanthogranulomas, inflammatory conditions both and in some benign neoplasms like “classic” spitz’s nevus and ancient schwannoma. in reverse, some malignant neoplasms are devoid of cells that exhibit nuclear atypia, chief among them being lymphocytes in the patch stage of mycosis fungoides, mesenchymal cells at any stage of dermatofibrosarcoma protuberans, and neoplastic cells of a metastasis to skin of renal-cell carcinoma. “atypia” is not used exclusively to designate attributes pathologic of nuclei. some authors employ the term “cytologic atypia” (linguistically, it would be more correct to speak of “atypia of nuclei” or nuclear atypia), others “architectural atypia” which is meaningless utterly because no definition has been proffered ever of “architectural typia.” equally opaque are designations like atypical “classic” spitz’s nevus, atypical blue nevus, and atypical fibrous histiocytoma. clinicians also have gotten into the act of “atypia” and, in the process, have muddled matters further. for example, dermatologists not only refer to “atypical pityriasis rosea” and review | dermatol pract concept 2012;3(2):4 39 “atypical psoriasis” but to atypical (dysplastic) moles, better designated clark’s nevi, (which are the most common by far of all types of melanocytic nevi), to atypical (dysplastic) mole syndrome (which is not a syndrome because it does not consist of a group of signs (and sometimes of symptoms) that together constitute a particular .condition, but rather a single finding, namely a number of clark’s nevi, and to atypical mycobacteria (which are atypical only because mycobacterium tuberculosis was judged arbitrarily to be typical). it becomes apparent that recognition of atypia is reputed to be helpful for diagnosis of malignant neoplasms such as melanoma, yet a benign neoplasm of melanocytes, namely, “classic” spitz’s nevus, may sport nuclei more strikingly atypical than in most melanomas. it is incorrect to use terms like “endothelial atypia,” because it is not the endothelium itself of angiosarcoma that is atypical but the cells that make it up. a term like atypicality is unsatisfactory because the noun pertaining to the adjective is atypia, not atypicality, and usage of the latter term for features of malignancy of a neoplasm adds nothing noteworthy. what is meant by “reactive atypia” is mere speculation, although it is used often to convey a sense for atypia of cells of an inflammatory process (when general pathologists invoke the word “reactive,” as they often do, they mean “inflammatory process”), and a big nucleolus is not in itself a sign of atypia, it being but one attribute of an atypical nucleus. in dermatopathology, atypia should be used only to designate nuclei of cells that possess certain characteristics repeatable that pertain to size, shape, and/or color in contrast with the appearance normal of cells of the same particular type and for nothing else. in conclusion, some noted dermatopathologists believe there really is no need to use the word atypia or atypical in dermatology or pathology including dermatopathology. even in regard to nuclei; those can be described simply as being “large,” “pleomorphic,” or “heterochromatic” without any reference at all to atypia or atypical. the point here is to “say what you see.” atypical melanocytic hyperplasia: a phrase that is wrong conceptually and linguistically. literally, it denotes an increase in fashion abnormal of melanocytes, but those who use the term really mean an increase in number of abnormal melanocytes; the “hyperplasia” is not, what they mean to be atypical, but rather the melanocytes themselves. furthermore, what is designated “hyperplasia” actually is neoplasia; (although this word is also poorly defined) the proliferation of melanocytes does not involute, an attribute essential to hyperplasia authentic. the phrase “atypical melanocytic hyperplasia” superseded “active junctional nevus” and preceded “pagetoid melanocytic proliferation” in the lexicon of evasions by histopathologists from a diagnosis of “nevus” or “melanoma,” it having been in parlance common from the mid 1960s to about 1980. those three terms unconstructive were replaced in the early 1980s by mild, moderate, and severe “dysplasia,” that hedge being the one utilized most often to this day for the purpose of avoiding issuance of a diagnosis direct of “nevus,” “melanoma” or “melanoma arising in an existing nevus” or “i do not know” and therefore the lesion must be removed completely. of course, why one “does not know” is discussed. autoeczematization: not definable. not surprisingly the term “autoeczematization” rarely is defined in dictionaries or textbooks of dermatology and dermatopathology. leider and rosenblum assert that the word is synonymous with autosensitization, and that is the position largely of dorland’s illustrated medical dictionary in 2000. its definition also is not helpful because “spread of lesions from a circumscribed focus of eczema” requires a definition lucid of eczema for the phrase to have meaning and no such definition exists. criteria morphological for recognition of autosensitization are not provided in any of the definitions just quoted. in short, the word has no place in dermatology or dermatopathology. autoeczematization” is a synonym for “autosensitization” and for “id reaction,” and is claimed by some authors to be characterized by a “widespread vesicular eruption” typified histopathologically by “spongiotic dermatitis.” other authors emphasize that the condition comes into being secondary to an existing “localized infectious focus,” (“focus of infection”) a concept that was rife in the 1930s and 1940s when such a focus of infection in the teeth, tonsils, or gall bladder was sought for any patient who had what was designated “autosensitization,” “autoeczematization,” or for “pustular bacterial of andrew” (which was simply pustular psoriasis on palms and soles). needless to say, dermatologists today are loathe to recall that once a “focus of infection” was suspected, it was not unusual for the patient to be relieved of all teeth, the tonsils, and the gallbladder. there are no criteria histopathologic for distinguishing “autoeczematization” from allergic contact dermatitis, nummular dermatitis, or dyshidrotic dermatitis, which may manifest itself first as a localized eruption and later as one widespread that is determined by microscopy conventional to be spongiotic dermatitis. autosensitization: not definable. rarely is the term “autosensitization” ever defined and when it has been, the definition provided is unenlightening, i.e., sensitization towards one’s own tissues” and “sensitivity to one’s own cells fluids, or tissues.” those phrases are reminiscent vaguely of the concept current of so-called autoimmune diseases, but what is called “autosensitization” or “autoeczematization” has nothing whatsoever to do with lupus erythematosus and rheumatoid arthritis. moreover, the term “auto-immunization” itself is opaque. that being 40 review | dermatol pract concept 2012;3(2):4 true, those “auto-” words are best eschewed. see also autoeczematization. the word “autosensitization” is used as a synonym for “autoeczematization” and “id” reaction. but no author makes any effort, let alone one serious, to define or explain any of those terms. some authors contradict others in regard to description of features clinical of what they call autosensitization. equally unclear is what is meant by “dissemination often widespread and quick, of a previous localized eczematous’ process” on one hand and presentation as “vesicular and on the palms” on the other. no author of a textbook of dermatology or dermatopathology provides criteria based on findings repeatable for identification morphologic, i.e., (clinically or histopathologically) of the condition they refer to as autosensitization, and no attempt is made to distinguish histopathologically that condition reported from allergic contact dermatitis, nummular dermatitis, and dyshidrotic dermatitis. in actuality, on grounds histopathologic alone, the four “entities” cannot be differentiated one from another. it is not an overstatement that the phenomenon autosensitization is “poorly understood and somewhat difficult to describe.” it may be that the phenomenon itself is ill-conceived. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3): e2021061 1 cutaneous metastasis presenting as vesicular-like lesions ravikumar mudugal1, anupama bains1, anil budania1, meenakshi rao2 1 department of dermatology, all india institute of medical sciences, jodhpur, rajasthan, india 2 department of pathology, all india institute of medical sciences, jodhpur, rajasthan, india key words: cutaneous metastasis, vesicular-like citation: mudugal r, bains a, budania a, rao m. cutaneous metastasis presenting as vesicular-like lesions. dermatol pract concept. 2021;11(3): e2021061. doi: https://doi.org/10.5826/dpc.1103a61 accepted: december 1, 2020; published: july 8, 2021 copyright: ©2021 mudugal et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: anupama bains, dermatology opd, opd building, aiims jodhpur, basni phase 2, jodhpur, rajasthan, india. email: whiteangel2387@gmail.com. case presentation a 76-year-old man presented with vesicular-like lesions covering the submandibular area and the sides of the neck (figure 1). the patient was a known case of squamous cell carcinoma affecting the floor of the mouth. histopathology of the lesions showed a tumor in the dermis with squamoid morphology, polygonal cells, abundant eosinophilic cytoplasm, and vesicular nucleus (figure 2). on immunohistochemistry, cells were positive for p63 and p40 markers. final diagnosis of cutaneous metastasis, secondary to squamous cell carcinoma, was made. teaching point cutaneous metastases generally present as solitary or multiple hard nodules. other atypical presentations such as morphea-like, erysipelas-like, alopecia neoplastica, zosteriform metastases, etc., are rarely seen [1]. vesicobullous metastasis is rare and has been previously described in breast cancers and melanomas. in our case, because of the vesicular-like lesions, figure 1. multiples vesicular-like lesions over the anterior and lateral side of the neck. the disease mimicked disseminated herpes zoster, radiotherapy induced bullous pemphigoid, hence awareness regarding such presentation is important. 2 image letter | dermatol pract concept. 2021;11(3): e2021061 references 1. mordenti c, peris k, fargnoli mc, cerroni l, chimenti s. cutaneous metastatic breast carcinoma: a study of 164 patients. acta dermatovenerol 2000;9:143-8. figure 2. histopathological examination (h&e, x40) showed tumor in dermis with squamoid morphology, polygonal cells, abundant eosinophilic cytoplasm, and vesicular nucleus. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021001 1 dermatology practical & conceptual in situ melanoma of the nipple and areola: a dermoscopic report in two new cases giulio tosti1, camilla salvini2, alessia barisani3, sabina vaccari3 1 divisione di chirurgia del melanoma, sarcoma e tumori rari, irccs, istituto europeo di oncologia, milan, italy 2 unit of dermatology, usl toscana centro-prato hospital, prato, italy 3 dermatology, department of experimental, diagnostic and specialty medicine, policlinico sant’orsola-malpighi, university of bologna, italy key words: nipple, areola, melanoma, dermoscopy citation: tosti g, salvini c, barisani a, vaccari s. in situ melanoma of the nipple and areola: a dermoscopic report in two new cases. dermatol pract concept. 2021;11(2):e2021001. doi: https://doi.org/10.5826/dpc.1102a01 accepted: july 10, 2020; published: march 8, 2021 copyright: ©2021 tosti et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: alessia barisani, md, via massarenti 1, 40138 bologna, italy. email address: alessiabarisani@gmail.com introduction the diagnosis of nipple and areola complex (nac) lesions can be challenging even for expert dermatologists, since several differential diagnoses, including neoplastic and inflammatory conditions, should be acknowledged. nac melanoma is rare; dermoscopy may aid in its correct evaluation. we report here 2 new cases of in situ nac melanoma. case presentations case 1. a 60-year-old caucasian woman presented with a 4 mm pigmented lesion on the areola at the edge of the nipple (figure 1a). during the previous 4 months, the lesion had progressively darkened. dermoscopy showed a dark symmetrical macule with a thickened atypical pigment network and irregular blotches (figure 1b). the lesion was flat, with no signs of infiltration or discharge. histopathology revealed an in situ melanoma. case 2. a 48-year-old caucasian man presented with a 7 mm irregularly shaped macule affecting his left areola (figure 1c). he was asymptomatic and had a 100+ nevi body count. dermoscopy showed light to darker brown pigmentation with a multi-component pattern and an atypical pigment network (figure 1d). also in this case histopathology revealed an in situ melanoma. b o t h p a t i e n t s u n d e r w e n t w i d e e x c i s i o n w i t h a 5-mm margin. conclusions nac melanoma represents an uncommon diagnosis, and until now only a few cases have been reported in the literature. the first dermoscopic observation was reported by shiga et al [1], who described a well-circumscribed, blackish macule (10 mm in size) on the left nac; dermoscopy displayed pigment network, irregular blotches and bluewhite veil on the normal-colored nac; and histopathology revealed a 0.3-mm melanoma. later, cinotti et al [2] reported another case of melanoma of the areola showing, on dermoscopy, irregular pigmented network with blotches and blue-white veil. letter | dermatol pract concept 2021;11(2):e2021001 the dermoscopic features of our 2 cases are concordant with those previously described. the differential diagnosis includes: melanocytic nevi, melanosis, and pigmented mammary paget disease (mpd). melanocytic nevi in this site often represent a challenging diagnosis, partly because of the irregular surface of the nac, with duct orifices modifying the distribution of the pigment, thus favoring false-positive diagnoses. in a multicentric study, 16 out of the 66 nevi evaluated on dermoscopy (24%) were classified as melanoma using the 7-point checklist [2]. moreover, the normal areola can display a brown pigment network and might sometimes be a site of friction and repetitive trauma. melanosis of the nac can share some clinical features with melanoma, representing a possible cause of diagnostic concern. melanosis may reveal a network and a cobblestone pattern which may be difficult to differentiate from melanocytic lesions. figure 1. (a) case 1. a 60-year-old caucasian woman presenting an atypical dark pigmented lesion 4 mm in diameter located at the areola. (b) dermoscopy showed a dark symmetrical macule characterized by a thickened atypical pigment network and irregular blotches (b, original magnification ×20). (c) case 2. a 48-year-old man affected by an irregularly shaped macular lesion 7 mm in diameter at the left areola. (d) dermoscopy shows light to darker brown pigmentation with a multi-component pattern and atypical pigment network (d, original magnification ×40). dermoscopic features of pigmented mpd include structureless brown and red areas, pinkish background, irregular vessels and irregular blue and brown dots. only a few cases of nac melanoma with dermoscopic findings were reported in the literature. the cases presented here represent a clinico-dermoscopic report of in situ nac melanoma. references 1. shiga k, oiso n, narita t, kimura m, kawada a. dermoscopy for malignant melanoma of the nipple and the areola. j dermatol. 2015;42:339–341. doi: 10.1111/1346-8138.12759. pmid: 25639330. 2. cinotti e, galluccio d, ardigò m, et al. nipple and areola lesions: dermoscopy and reflectance confocal microscopy features. j am acad dermatol. 2019;81(2):610-613. doi: 10.1016/j. jaad.2018.11.017. pmid: 30458212. dermatology: practical and conceptual observation | dermatol pract concept 2014;4(3):12 63 dermatology practical & conceptual www.derm101.com case presentation an 89-year-old caucasian man presented to our clinic with a 3-year history of an asymptomatic, slow-growing, hyperpigmented skin lesion located on the distal third of the dorsal aspect of the right arm. the patient had no personal or family history of skin cancer. the physical examination revealed an asymmetrical, ill-defined brown patch with 21 mm of maximum diameter (figure 1). dermoscopy examination of the lesion disclosed an atypical network, irregularly distributed brown and black globules, pigmented internal melanoma and satellite blue papule andré oliveira1, edith arzberger2, cesare massone2, iris zalaudek2, regina fink-puches2, rainer hofmann-wellenhof2 1 department of dermatology, hospital de curry cabral—centro hospitalar de lisboa central, lisboa, portugal 2 department of dermatology, medical university of graz, graz, austria keywords: blue nevus, cutaneous melanoma metastasis, dermoscopy, foreign body reaction, malignant melanoma, optical coherence tomography, reflectance confocal microscopy citation: oliveira a, arzberger e, massone c, zalaudek i, fink-puches r, hofmann-wellenhof r. melanoma and satellite blue papule. dermatol pract concept. 2014;4(3):12. http://dx.doi.org/10.5826/dpc.0403a12 received: april 27, 2014; accepted: may 3, 2014; published: july 31, 2014 copyright: ©2014 oliveira et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: andré oliveira, m.d., department of dermatology–hospital de curry cabral centro hospitalar de lisboa central, rua da beneficência nº8, 1069-166, lisboa, portugal. tel. +351912561666; fax. +351217924392. email: andre.oliveira@sapo.pt the colors that are seen in dermoscopy depend on the anatomic level of the skin at which the chromophores are seen. blue color can be found in a variety of melanocytic and nonmelanocytic lesions. an 89-year-old man presented with a 3-year history of a slow-growing, hyperpigmented patch located on the distal third of the right arm. dermoscopy showed an atypical network, irregularly distributed globules, pigmented internal streaks and a milky-red area. based on these findings a diagnosis of slow-growing malignant melanoma was made. simultaneously, a well-defined blue papule was seen on the proximal third of the same arm. dermoscopy disclosed a homogeneous blue pattern. after clinical and dermoscopic correlation our differential diagnosis for this blue lesion included cutaneous melanoma metastasis, blue nevus and foreign body reaction. the patient recalled its onset 75 years ago after a grenade explosion. we also discuss the blue lesion appearance under reflectance confocal microscopy and high-definition optical coherence tomography. histopathological examination after excision of the hyperpigmented patch and blue papule revealed a melanoma in situ and a foreign body reaction, respectively. the diagnostic evaluation of a blue lesion should always rely on the integration of all data, especially clinical and dermoscopic features. other non-invasive techniques, like reflectance confocal microscopy and high-definition optical coherence tomography can also be important aids for its differential diagnosis. abstract 64 observation | dermatol pract concept 2014;4(3):12 streaks and a milky-red area (figure 2). based on clinical and dermoscopic findings a diagnosis of slow-growing malignant melanoma was made. lymph node inspection was unremarkable. simultaneously, a well-defined blue papule with 4 mm figure  1. simultaneously observed irregular brown patch (distal third) and blue papule (proximal third) on the dorsal aspect of the right arm. [copyright: ©2014 oliveira et al.] figure 2. dermoscopy observation (brown patch): atypical network, irregular brown and black globules, pigmented internal streaks and milky-red area. [copyright: ©2014 oliveira et al.] figure  3. dermoscopy observation (blue papule): homogeneous blue pattern. [copyright: ©2014 oliveira et al.] figure  4. reflectance confocal microscopy examination (mosaic 2 x 2 mm): normal honeycomb pattern, edged-papillae, absence of atypical cells and dendritic melanocytes in the dermis; elongated cords and bulbous projections (yellow circle), flattened junction and moderately refractive lace-like material adjacent to collagen bundles (blue circle) were also seen at the upper dermis. [copyright: ©2014 oliveira et al.] of maximum diameter was seen on the proximal third of the dorsal aspect of the same arm (figure 1). dermoscopy showed a homogeneous blue pattern (figure 3). the diagnosis of cutaneous melanoma metastasis was immediately suspected. the patient was then asked for its onset and evolution. he remembered this blue lesion for 75 years. the diagnosis of common blue nevus was also considered. the patient added that the papule followed local skin injuries from a grenade explosion during the ii world war. therefore, foreign body reaction and traumatic pigmentation were also included in the differential diagnosis. observation | dermatol pract concept 2014;4(3):12 65 the blue papule was further examined by reflectance confocal microscopy (rcm) and high-definition optical coherence tomography (hd-oct). rcm (vivascope1500®; lucid inc., rochester, n.y., usa) evaluation was unremarkable, with normal honeycomb pattern, edged-papillae in the dermal-epidermal junction, and absence of atypical cells and dendritic melanocytes in the superficial dermis. some changes attributed to chronic sun exposure were seen, including elonfigure 5. high-definition optical coherence tomography (slice and en face mode): scattered highly refractile inflammatory cells (yellow arrows) and aggregates of brightly refractile particles (red square) in the deeper dermis. [copyright: ©2014 oliveira et al.] figure 6. high-definition optical coherence tomography features of aggregates of highly refractile particles in the deeper dermis were better represented under histogram “image splitter,” possibly corresponding to foreign body. [copyright: ©2014 oliveira et al.] figure 7. histopathological examination of the blue papule showed a foreign body with fibrosis and sparse inflammatory infiltrate (hematoxylin-eosin, x100). [copyright: ©2014 oliveira et al.] gated cords, flattened junction and moderately refractive lace-like material adjacent to collagen bundles, correlating to solar elastosis at the upper dermis (figure 4). hd-oct (skintell®, agfahealthcare, belgium) en face mode enabled the observation of scattered bright inflammatory cells in the dermis and clusters of bright coarse particles in the deeper dermis (figure 5). these particles were better represented using oct histogram “image splitter” in which the number of pixels with specific values is isolated in an image (figure 6). both lesions were excised. subsequent histopathological examination of the hyperpigmented patch confirmed the diagnosis of melanoma in situ, while the examination of the blue papule revealed a foreign body with fibrosis and sparse inflammatory infiltrate (figure 7). conclusions several non-invasive imaging techniques have emerged in recent years aiming for higher accuracy of in vivo diagnosis. these include dermoscopy, reflectance confocal microscopy (rcm) and high-definition optical coherence tomography (hd-oct). the colors that are seen in dermoscopy depend on the anatomic level of the skin at which the chromophores (melanin, hemoglobin, collagen) are seen. blue color can be found in a variety of melanocytic and nonmelanocytic lesions. its diagnosis can be challenging especially if a diffuse bluish pigmentation is found under dermoscopy. the differential diagnosis of melanocytic lesions with blue color should include blue nevus, spitz nevus, malignant melanoma and cutaneous melanoma metastasis. blue hue can also be seen in nonmelanocytic lesions like seborrheic keratosis, including lichen planus-like keratosis, hemangioma, pigmented basal cell carcinoma, hemosiderotic dermatofibroma, kaposi sarcoma and 66 observation | dermatol pract concept 2014;4(3):12 angiosarcoma. finally, exogenous dermal blue pigmentation, such as ink tattoo, radiation tattoo, and traumatic penetration of foreign pigmented materials. our differential diagnosis for this blue lesion included cmm, common blue nevus and foreign body reaction/exogenous pigmentation. cutaneous melanoma metastasis was our first and immediate diagnosis because of the simultaneous observation of a suspected melanoma and a blue lesion with homogeneous blue color under dermoscopy, and located in proximity to the primary melanoma. however, the suspected melanoma lesion had a slow-growing progression, and dermoscopy revealed asymmetrical network, irregular globules and internal streaks, which were a clue for a thin melanoma. the diagnosis of cmm is usually suspected based on a history of primary invasive, thick melanomas [2]. the lesion history with a 75-year duration of onset also allowed for the clinical exclusion of cmm. the clinical and dermoscopic diagnosis of common blue nevus was then considered relying on the dermoscopic observation of diffuse, homogeneous bluish pigmentation, in absence of specific melanoma criteria, on a long-standing, stable lesion [3]. the possible post-traumatic relation to the onset of the lesion made us include the diagnosis of exogenous traumatic pigmentation, usually also associated with a blue structureless pattern in dermoscopy. since dermoscopy was not conclusive rcm examination of the blue papule was performed. rcm allows for the visualization of microscopic features in vivo with a nearly histological resolution. increasing knowledge on the rcm appearance of a wide range of skin lesions may help us to improve our bedside diagnostic accuracy [4]. the findings of normal honeycomb pattern and lack of atypical cells and dendritic melanocytes in the superficial dermis allowed the exclusion of cmm and blue nevus in the examined skin levels. however, limited laser depth penetration (250 mm) hampers visualization of the deep dermis representing a limitation of rcm in the assessment of both cmm and common blue nevus [5,6]. hd-oct is a recently introduced technique based on the same principles of conventional oct but differing on its ability to give optical imaging up to 570 mm deep within the skin with high resolution of 3 mm both in axial and lateral directions. this technique is capable of capturing not only slice but also en face images in real time and fast threedimensional acquisition. therefore, hd-oct allows in vivo examination of the skin enabling visualization of individual cells with a greater depth than rcm. en face mode imaging and histogram representation showed scattered highly refractile inflammatory cells and aggregates of brightly refractile particles in the deeper dermis [7,8]. it was also possible to exclude cmm and blue nevus, in a greater depth penetration using hd-oct. en face and histogram changes possibly corresponded to foreign body material and inflammation associated to the skin trauma reported by the patient that took place 75 years ago. the definite diagnosis in our case was made with the histopathological examination that revealed a foreign body in the deeper dermis, a possible consequence of the grenade explosion, showing good correlation with the hd-oct findings of large bright refractile particles in the same location. the deeper location of foreign material in our case caused a bluish appearance, both in clinical and dermoscopic presentation. it can be explained by a similar phenomenon as seen with dermal melanin: the tyndall effect of the physical light scattering effect of blue pigmentation in the dermis. in conclusion, the diagnostic evaluation of a blue lesion should always rely on the integration of all data, including patient’s age, duration of onset and rate of growth of the lesion, palpability and dermoscopic features [1]. other noninvasive techniques, like rcm and hd-oct can also be important aids in the differential diagnosis of a blue lesion. hd-oct showed good correlation to the histopathological features of foreign body reaction. as a rule all blue lesions that not fulfil clinical and dermoscopic criteria for a specific benign lesion should be excised. that was particularly true in our case due to the puzzling simultaneous clinical appearance of a melanoma and blue lesion. even with a very long history of “blue.” references 1. longo c, scope a, lallas, a, et al. blue lesions. dermatol clin. 2013;31:637-47. 2. pellacani g, bassoli s, longo c, cesinaro am, seidenari s. diving into the blue: in vivo microscopic characterization of the dermoscopic blue hue. j am acad dermatol. 2007;57:96-104. 3. ferrara g, soyer hp, malvehy j, et al. the many faces of blue nevus: a clinicopathologic study. j cutan pathol. 2007;34:543-51. 4. pellacani g, cesinaro am, longo c, grana c, seidenari s. microscopic in vivo description of cellular architecture of dermoscopic pigment network in nevi and melanomas. arch dermatol 2005;141:147-54. 5. longo c, farnetani f, ciardo s, et al. is confocal microscopy a valuable tool in diagnosing nodular lesions? a study of 140 cases. br j dermatol. 2013;169:58-67. 6. longo c, casari a, beretti f, cesinaro am, pellacani g. skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy. j am acad dermatol. 2014;68:e73-82. 7. boone malm, norrenberg s, jemec gbe, del marmol v. imaging of basal cell carcinoma by high-definition optical coherence tomography: histomorphological correlation. a pilot study. br j dermatol. 2012;167: 856-864. 8. boone malm, norrenberg s, jemec gbe, del marmol v. highdefinition optical coherence tomography imaging of melanocytic lesions: a pilot study. arch dermatol res. 2014;306:11-26. supplement | dermatol pract concept 2011;1(1):19 91 supplement: abstracts from the sccanz skin cancer conference, june 3–5, 2011, gold coast, australia citation: abstracts from the sccanz skin cancer conference, june 3-5, 2011, gold coast, australia. dermatol pract concept 2011;1(suppl ):19. http://dx.doi.org/10.5826/dpc.0101a19. copyright: ©2011 this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. sccanz skin cancer conference abstracts 2011 serial dermatoscopic monitoring and melanoma breslow thickness in a primary care skin cancer clinic – a pilot study jeffrey g. keir, mbbs, mfammed(clin), dippracderm northern rivers skin cancer clinic ballina, new south wales, australia introduction: serial dermatoscopic monitoring of pigmented skin lesions may introduce a delay in diagnosis of melanoma. conversely it is argued that feature-poor melanomas may not otherwise be diagnosed without a large increase in biopsy rates. this study compared average breslow thickness of melanomas that have been serially monitored with those that have not. method: a retrospective analysis of a clinical audit of all histopathologically confirmed melanomas detected over a two-year period in a primary care skin cancer clinic was performed. data collected included patient age and sex, date of first monitoring, date of decision to biopsy, breslow thickness, and histopathologic diagnosis. lesions judged to be dermatoscopically borderline for melanoma were serially imaged using a molemax i (derma instruments, austria). monitored lesions were reviewed at three months and then on subsequent patient review throughout the normal course of their care. incidences of in-situ lesions and averages of breslow thickness of monitored and unmonitored lesions were calculated and compared. results: a total of 90 melanomas were detected. 26% were invasive, with an average breslow thickness of 0.9 millimetres. 33 melanomas had been monitored and 27% of these were invasive with an average breslow thickness of 0.33 millimetres. 57 melanomas were not monitored and 26% of these were invasive with an average breslow thickness of 1.2 millimetres. there was no significant difference in the proportion of in-situ lesions detected. monitored lesions which were invasive were significantly thinner (p <0.04; z=-1.743; two independent sample wilcoxon rank sum test). only 7/33 (21%) of monitored melanomas showed change at three months. conclusion: in a small single centre study, the use of monitoring to detect melanomas resulted in a similar proportion of in-situ melanomas and did not result in an increase in breslow thickness of invasive melanomas at time of excision, compared with unmonitored lesions. this may be because borderline lesions are detected earlier in their evolution, or may be inherently slower growing. a monitoring interval of 3 months may not be sufficient to detect change in borderline lesions. a further larger study is required to confirm these findings. malignant zo benign ratio of skin biopsies: a retrospective study of an australian public hospital dermatology department heidi rolfe, mbbs introduction: accurate identification of malignant lesions is important for patient safety as well as reducing the number of benign lesions removed and thus reducing costs and workdermatology practical & conceptual www.derm101.com 92 supplement | dermatol pract concept 2011;1(1):19 intravenous sedation for skin cancer surgery donald guadagni, beng, msc, fracs guadagni surgical, ltd. whakatane, new zealand introduction: skin cancer surgery is usually performed under either local or general anaesthetic. in our hands the use of intravenous sedation combined with local anaesthetic has both greatly increased the acceptability of local anaesthetic as well as decreased the need for general anaesthetic. this paper describes the accreditation requirements for the use of sedation and local anaesthetic in skin cancer surgery, our set up, technique, and monitoring for nurse sedation as well as staff training and approximate set up costs. method: 10-year retrospective audit of skin cancer surgery intravenous sedation cases in a private clinic. all sedation cases had a ‘sedation audit form’ completed results: during the last 10 years we have performed over 3000 operations for skin cancer with 28% done under local, 68% sedation & local and only 2.6% under general anaesthetic. sedation is usually used for multiple and more complex procedures with 80% of our flaps and 85% of skin grafts being done under sedation. there were no deaths, no respiratory arrests, no cardiac arrests, no patients needing transfer to an overnight facility and a minor complication rate of less than 0.5%. most patients were recovered and discharged within an hour of their procedure’s completion with less than 0.1% requiring more than two hours of recovery for sedation reasons. adding sedation to local increases the cost of surgery with us by approximately $275 but is $1100– 1500 less expensive than the same procedure under ga. conclusion: properly carried out, intravenous sedation is a safe and cost effective procedure in the ambulatory surgical management of skin cancer. load. by quantifying malignant to benign biopsy ratios at this point in time we can see if current methods have improved the accuracy of diagnosis. this also helps effectively assess the impact of new vectors in skin cancer diagnosis when they are introduced. methods: 6546 biopsies/excisions were performed in an 18-month period from july 2010 until december 2011 in the dermatology opd at a tertiary teaching hospital. dermatology registrars and consultants were involved in assessing lesions for biopsy. results: the biopsy to treatment ratio (btr) was calculated as the total number of biopsies divided by the number of non-melanoma skin cancers identified. the btr of 1.97 indicated about one in two biopsies identified a skin cancer. the ratio of melanoma to nevi was 1:6.4 (55 melanomas were diagnosed). the ratio of melanoma to benign pigmented lesion was 1:14.7 giving a number needed to treat (nnt) of 15. discussion/conclusion: a previous study1 of skin cancer clinics in australia reported nnt as 29 and btr of 3. nnt in this study may be lower because benign lesions referred only to pigmented, not non-pigmented lesions. biopsies in this study were for many different conditions not just suspected skin cancers and thus the btr would be lower if only suspected skin cancers were included. the melanoma to nevi ratio in this study is better than 1:15.5 reported previously in a small study using digital dermoscopy to monitor high risk patients2. in a study3 of fully qualified dermatologist who all used dermoscopy, melanoma to nevi ratios were 1:4.3. this suggests more experience and stringent use of dermoscopy could improve biopsy accuracy. references 1. wilkinson d, askew ad, dixon a. skin cancer clinics in australia: workload profile and performance indicators from an analysis of billing data. med j australia 2006;184:4;162-4. 2. bauer j, blum a, strohhäcker u, garbe c. surveillance of patients at high risk for cutaneous malignant melanoma using digital dermoscopy. br j dermatol 2005;152:87-92. 3. carli p, de giorgi v, crocett e, mannone f, massi d, chiarugi a, giannotti b. clinical and laboratory investigations. improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol 2004:150:687-92. supplement | dermatol pract concept 2011;1(1):19 93 photoprotective effects of carrageenan against uvbirradiation in human keratinocytes hacat cells s.m. mohamed, s.k. ho, s.m.i aboo-sufee, v.k. vangeta, w.l. chu international medical university kuala lumpur, malaysia introduction: kappa (k), lambda (l), and iota (i) carrageenans, are sulphated polysaccharides inthe cell wall of red seaweeds mostly of genera chondrus, eucheuma, gigartina and iridae. they are widely used as an excipient of skincare products but their biological activity has not been investigated extensively. our previous findings indicated that carrageenans were non-toxic tomurine normal fibroblasts (3t3) and were able to reduce uvb-induced cell killing while interestingly reverting necrotic death to apoptosis. in this study, we aim to elucidate the protective mechanism exerted by carrageenans in human keratinocytes cells, hacat. methods: cytotoxicity of i(ii), i(iv), l, k-carrageenans was determined against hacat cells using the colorimetric mtt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. photoprotection by the carrageenans was monitored 24and 72-hours after uvb irradiation by the reduction of cell killing in carrageenan-pretreated hacat cells. dpph [1,1-diphenyl-2-picrylhydrazyl] radical scavenging assay was performed to deduce if its photoprotective activity was mediated by the presence of sulphur moieties in carrageenans. results: carrageenans were relatively non-toxic to hacat cells as the cd50 values were not apparent at <10μg/ml. photoprotection was significant especially by i(ii) against 50mj uvb up to 72 hours after irradiation. however, there was no correlation between the number of sulphate groups present in different types of carrageenan with its photoprotective potential. conclusions: carrageenan showed photoprotective potential against uvb as seen in with i(ii) indicated the highest potency. results of radical scavenging activities suggest that the photoprotective mechanism was not dependent upon the presence of sulphur moities. we believe that the insights in this study have the potential of refining and adding new knowledge on the mechanism of action of the photoprotective effect of carrageenan. photoprotective role by carrageenans offers an enhanced value of skincare products when they work synergistically with the other active constituents. dermatology: practical and conceptual review | dermatol pract concept 2020;10(3):e2020050 1 dermatology practical & conceptual introduction autoimmune bullous disorders (abds) encompass a number of heterogeneous conditions linked by the loss of tolerance to structural proteins of the skin. as a consequence of breakdown of tolerance, autoantibodies targeting epidermal or subepidermal adhesion proteins are produced. the loss of adhesion between keratinocytes or between basal keratinocytes and the underlying epidermal basement membrane leads to an impaired resilience of the epidermis resulting in intraepithelial or subepithelial blisters and erosions of the skin and mucous membranes. abds pemphigus vulgaris and bullous pemphigoid: update on diagnosis and treatment vito di lernia,1 dahiana m. casanova,1 mohamad goldust,2 cinzia ricci1 1 dermatology unit, arcispedale santa maria nuova, azienda usl-irccs di reggio emilia, italy 2 university guglielmo marconi, rome, italy & department of dermatology, university hospital, basel, switzerland key words: pemphigus, pemphigoid, autoimmune, bullous, disorder citation: di lernia v, casanova dm, goldust m, ricci c. pemphigus vulgaris and bullous pemphigoid: update on diagnosis and treatment. dermatol pract concept. 2020;10(3):e2020050. doi: https://doi.org/10.5826/dpc.1003a50 accepted: march 5, 2020; published: june 29, 2020 copyright: ©2020 di lernia et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: vito di lernia, md, dermatology unit, arcispedale santa maria nuova, viale risorgimento 80, 42123 reggio emilia, italy. email: vito.dilernia@ausl.re.it autoimmune bullous disorders are a heterogeneous spectrum of skin disorders characterized by the production of autoantibodies against adhesion molecules of the skin. the 2 major groups of diseases are “pemphigus diseases” and “autoimmune bullous diseases of the pemphigoid type.” pemphigus diseases are a group of autoimmune blistering diseases of the skin and mucous membranes characterized by intraepithelial cleft and acantholysis. the main subtypes of pemphigus include pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. diagnosis is based on clinical manifestations and confirmed with histological, immunofluorescence, and serological testing. recently multivariant enzyme‐linked immunosorbent assay systems have been developed as practical screening tools for patients with suspected autoimmune bullous dermatoses. the current first-line treatment of pemphigus is based on systemic corticosteroids that are often combined with immunosuppressive adjuvants, such as azathioprine, mycophenolate mofetil, and the anti-cd20 monoclonal antibody rituximab, usually at initiation of treatment. rituximab efficacy is higher when it is administered early in the course of the disease. therefore, it should be used as first-line treatment to improve efficacy and reduce cumulative doses of corticosteroids and their side effects. treatment of bullous pemphigoid is based on disease extension. localized and mild forms can be treated with superpotent topical corticosteroids or with nonimmunosuppressive agents. in patients with generalized disease or whose disease is resistant to the treatments described above, systemic corticosteroids are preferred and effective. adjuvant immunosuppressants are often combined with steroids for their steroid-sparing effect.  abstract https://doi.org/10.5826/dpc.1003a50 mailto:vito.dilernia@ausl.re.it 2 review | dermatol pract concept 2020;10(3):e2020050 tic pemphigus (table 1). pemphigus is driven by pathogenic antibodies to both desmoglein (dsg) 1 and 3 (pv, mucocutaneous type), or dsg3 (pv, mucosal dominant-type), or dsg1 (pf). numerous antigens are involved in paraneoplastic pemphigus (table 2). abds of the pemphigoid type or autoimmune subepidermal blistering diseases of the skin and mucosae constitute a large group of diseases characterized by the production of circulating autoantibodies against several structural proteins of the basement membrane zone, leading histologically to subepidermal blistering. the main disorders include bp, pemphigoid gestationis, mucous membrane pemphigoid, epidermolysis bullosa acquisita, and anti-p200 pemphigoid [2] (table 3). bp is characterized by the generation of autoantibodies directed in particular against bp180/collagen xvii and bp230/dystonin. epidemiology prospective studies suggest the incidence rates of abds are in the range of 14.5-20.4/million [3-5]. most of the available epidemiological data derive from pv, the most frequently reported disorder among the pds, and bp [3]. pv incidence appears to be highly variable according to geographic regions and ethnic groups. the incidence rates reported in european prospective studies range between 0.5 and 4.0/million [5,6]. higher rates, up to 16.1/million/year, have been observed in subjects from israel and iran [7,8]. in fact, the disease is more common among individuals of ashkenazi origin, but also in ethnic groups from iraq and iran. therefore, ethnic differences should be taken into account when comparing incidence rates in countries with populations of jewish heritage [3,9]. pemphigus is most frequently diagnosed between ages 50 and 60 in european countries, but it can be seen earlier outside of europe. are a major cause of severe morbidity and considerable mortality [1]. based on the available literature data, this paper aims to provide an up-to-date overview on diagnosis and therapy of pemphigus vulgaris (pv) and bullous pemphigoid (bp), which represent the 2 major diseases in the heterogeneous clinical spectrum of abds. classification the classification of an abd relies on the level of blistering and considers 2 major groups of diseases, namely “pemphigus diseases”(pds) and “abds of the pemphigoid type.” pds are characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepithelial blistering. there are several variants of pemphigus, but the 3 major forms include pv, pemphigus foliaceus (pf), and paraneoplastable 2. classification and autoantigens in pemphigus group diseases diseases ig antigen pemphigus vulgaris, mucosal dominant type pemphigus vulgaris, mucocutaneous type igg igg dsg3 dsg3 + dsg1 pemphigus vegetans igg dsg3, dsg1, dsc3 pemphigus herpetiformis igg dsg1, (dsg3), dscs pemphigus foliaceus igg dsg1 pemphigus erythematosus igg dsg1 paraneoplastic pemphigus igg plectin, epiplakin, desmoplakin i/ii, bp230, envoplakin, periplakin, dsg3, dsg1, dscs, α-2-macroglobulin-like-1 iga pemphigus, subcorneal pustular dermatosis type iga pemphigus, intraepidermal neutrophilic type iga dermatosis iga iga dsc1 unknown bp = bullous pemphigoid; dsc = desmocollin; dsg = desmoglein; ig = immunoglobulin. table 1. classification of pemphigus type variants pemphigus vulgaris pemphigus vegetans pemphigus herpetiformis pemphigus foliaceus fogo selvagem (pemphigus brasiliensis) pemphigus erythematosus paraneoplastic pemphigus atypical pemphigus “drug-induced” pemphigus iga pemphigus ig = immunoglobulin. review | dermatol pract concept 2020;10(3):e2020050 3 cadherins dsg1 and dsg3, causes loss of epidermal keratinocyte adhesion. dsg3-specific autoreactive t cells are deleted in periphery, and regulatory t cells (tregs) play an important role in such peripheral tolerance [17]. environmental factors, in particular pathogens, have been hypothesized as causes of reverting immunological tolerance with resulting autoantibody production [18]. a possible link with rotavirus infection has been suggested because of cross-reactive vh1-46 antibodies, which are able both to disrupt keratinocyte adhesion and inhibit rotavirus replication [19]. an additional relationship between the exposure to a noninfectious environmental antigen and the development of an autoimmune response to self-antigen has been documented in fogo selvagem, the endemic form of pf. in this condition, cross-reactive epitopes on dsg1 and ljm11 sand fly salivary gland antigen could drive the production of pathogenic igg4 autoantibodies anti-dsg1 [20]. although antibody-mediated disease mechanisms in pv are widely characterized, the t cell implication has to be better clarified. autoreactive cd4+ t lymphocytes have been implicated in the regulation of the production of pathogenic anti-dsg3 autoantibodies by b cells [21]. there is a strong association between pv and distinct major histocompatibility complex class ii haplotypes, which are considered essential for the presentation of specific dsg3 peptides to autoreactive cd4+ helper t cells [18,22]. the causes of loss of tolerance leading to the production of antibodies anti-bp180/collagen xvii and bp230/dystonin, and less frequently also against other antigens in bp, are not known. bp has been linked to environmental factors as physical agents, such as radiation therapy, ultraviolet radiation [23] trauma, neurodegeneration or neuroinflammation [24] and drugs, in particular gliptins [25]. muramatsu et al demonstrated that tregs are essential in preventing the spontaneous production of bp autoantibodies as well [26]. an imbalance between autoreactive helper t cells and tregs and a t cell-independent activation of a toll-like receptor the yearly incidence of bp reported in european prospective studies varies between 2.5 and 13/million [5,6]. the largest series of patients (n = 869) collected in a retrospective historical cohort from the uk showed higher incidence rates of 42.8/million [10]. rising incidence rates of bp in europe have been linked to risk factors, including population aging; drugs, in particular antidiabetics; diuretics; phenothiazines; major cognitive impairment; and disabling neurological disorders [3,11]. bp affects mostly the elderly: it is generally seen in individuals older than 70 years. overall incidence is higher in females [3]. genetics there is evidence that genetics plays a critical role in pv development, severity, and prognosis. an increased frequency of hla-drb1*04:02 haplotypes in ashkenazi jewish patients [12] and dqb1*05:03 in non-jewish caucasian populations [13] has been observed. the coexistence of alleles of drb1*14/dqb1*05 and a*11/dqb1*05 would be strongly influential for the predisposition to the disease, while that of hla-b*50/dqb1*02 could play a protective role [14]. in addition, multiple single nucleotide polymorphisms within different genes may confer susceptibility to the diseases, probably in a population‐specific way [15]. serological typing for hla class ii antigens in patients with abd of the pemphigoid type revealed a highly significant association with hla-dqβ1*0301 [16]. pathophysiology pv and bp are characterized by the loss of tolerance to autoantigens expressed primarily in the skin, in particular desmosomal proteins in pv and components of the hemidesmosomes in bp. in pds, the production of pathogenic immunoglobulin g (igg) autoantibodies, mainly igg4, against the desmosomal table 3. classification and autoantigens in autoimmune bullous disorders of the pemphigoid type diseases ig antigen bullous pemphigoid ig bp180, bp230 pemphigoid gestationis ig bp180, bp230 linear iga dermatosis iga bp180 mucous membrane pemphigoid igg/iga bp180, bp230, laminin 332, α6β4 integrin anti-laminin γ-1 pemphigoid igg laminin γ-1(p200) lichen planus pemphigoid igg bp180, bp230 epidermolysis bullosa acquisita igg type vii collagen dermatitis herpetiformis iga (igg) epidermal transglutaminase, tissue transglutaminase, deamidated gliadin bp = bullous pemphigoid; ig = immunoglobulin. 4 review | dermatol pract concept 2020;10(3):e2020050 (figures 4 and 5). pruritus is common and often severe. after rupture, bullae leave moist erosions and crusts that resolve without scarring. mucosal involvement may be observed in 10% to 30% of the cases with oral, esophageal, and genital involvement. two disease scores, the bp disease area index and the autoimmune bullous skin disorder intensity score, have shown significant reliability, validity, and responsiveness [29-31]. bp shows a different clinical course in infants and system could underlie a b cell stimulation, with resulting bp autoantibody production [24]. clinical presentation pv, the most frequent and severe form of pemphigus, affects both skin and mucosal surfaces. the disease often begins in the oral mucosa with superficial, flaccid blisters that rapidly rupture, leaving slow-healing, painful, moist erosions that may make oral intake difficult and cause pain and fetor as well. accompanying symptoms are sialorrhea and bloody saliva. involvement of other skin areas may occur from weeks to months later. in addition to the cutaneous and mucosal surfaces of the mouth (figure 1), the pharynx, vocal folds, and anogenital mucosa may also be affected. scalp involvement is observed in up to 60% of patients (figure 2). clinical variants include mucosal-only disease (which correlates with circulating anti-dsg3 autoantibodies), cutaneous-only disease (anti-dsg1 antibody predominant), or more frequently, mucocutaneous involvement (presence of both anti-dsg1 and anti-dsg3 antibodies). recently, clinical scores of disease severity have been implemented. the pemphigus disease area index and autoimmune bullous skin disorder intensity score have been recognized as robust tools to correctly assess disease activity [27]. classic bp affects elderly individuals, usually above age 70 years. the spectrum of clinical presentation is highly variable. in a consistent proportion of patients, the blistering eruption is preceded by a prodromal nonbullous phase, usually lasting weeks to months and even, in rare cases, remaining the only manifestation of the disease [28]. during the nonbullous phase, pruritic, erythematous, or urticarial patches and plaques occur. also eczematous, polycyclic, targetoid, nodular, or lichenoid lesions may be observed (figure 3). the bullous phase is characterized by tense bullae on an erythematous, urticarial base, localized or widespread figure 1. solitary lip ulcerations as highly unusual manifestations of pemphigus. figure 2. erosions, crusted and scaly plaques in a case of pemphigus of the scalp. the scalp shows an abundance of desmogleins in hair follicles and may be the first location of the disease. figure 3. numerous polycyclic and targetoid lesions during the nonbullous phase of bullous pemphigoid. review | dermatol pract concept 2020;10(3):e2020050 5 intraepidermal blister caused by acantholysis, which consists of the separation of keratinocytes just above the basal cell layer due to a loss of the normal cell attachment. in the cavity of the blister, a few inflammatory cells, in particular eosinophils, may be observed. the surrounding inflammation is minimal [22]. eosinophilic spongiosis may be the only histological feature of pemphigus in the initial stages. in such cases eosinophils invade a spongiotic epidermis without evidence of acantholysis. single or grouped acantholytic cells can be quickly documented by cytological examination (tzanck cytodiagnostic test). after opening of an intact roof of a blister, material has to be scraped from the base of a vesicle or blister and smeared onto a microscopic slide. after air-drying, samples are commonly stained with may-grünwald-giemsa and evaluated. this test does not replace histological examination, since acantholytic keratinocytes may also be observed in other dermatoses as a secondary phenomenon to inflammation or ballooning degeneration. bullous pemphigoid the histopathological assessment of an early bulla shows a subepidermal blister containing a net of fibrin with a variable number of eosinophils and/or neutrophils accompanied by a dermal inflammatory infiltrate mainly consisting of eosinophils and neutrophils [3,33]. in the nonbullous phase, histopathological findings may be nonspecific, since only subepidermal clefts and eosinophilic spongiosis may be observed [34]. direct immunofluorescence dif is the most reliable and sensitive diagnostic test for abds for the most part. however, nonspecific staining may occasionally be seen in other cutaneous disorders with occasional false-positive findings [35,36]. dif investigates the skin or children. acral involvement is common, especially on the face (62%), palms and soles (79%); localized lesions on the genital area may be observed in 17% of cases [32]. diagnosis clinical presentations of abds often overlap, and diagnosis may not be easily made on the basis of clinical features alone. therefore, abds are usually diagnosed using 3 criteria: (1) the overall clinical picture, including patient history and physical examination; (2) histopathology; and (3) a positive direct immunofluorescence (dif) microscopy, usually performed on perilesional skin, or serological detection of autoantibodies against the involved epithelial antigens [22]. immunodiagnostic tests are particularly useful to differentiate the various diseases. histopathology pemphigus vulgaris biopsy should be taken in an early intact blister. when only erosions are present, as usually happens in the oral area, a biopsy should be obtained from the active border of a denuded area. the characteristic histological finding is an figure 4. urticarial and polycyclic lesions of the nonbullous phase of bullous pemphigoid associated with a tense bulla on the flexor surface of a forearm. figure 5. typical tense bullae on an erythematous base in a patient with bullous pemphigoid. 6 review | dermatol pract concept 2020;10(3):e2020050 dsg1 and dsg3 generally correlate with the extent and clinical activity of disease, and high levels of anti-dsg1 by elisa has a positive predictive value for skin relapses [37]. therefore, elisa may represent a good serological marker of disease activity, although evidence about its predictive value from large prospective cohort studies is lacking [37]. one must keep in mind that anti‐dsg antibodies have been occasionally discovered in sera of normal patients and those affected with other bullous diseases [41]. in addition, a small number of pemphigus patients may not show the pv phenotype expected by their dsg autoantibody serum profile [42]. bullous pemphigoid iif may demonstrate circulating igg antibodies binding to the basal membrane. the most specific test substrate for bp is salt-split skin, which is healthy human skin in which subepidermal splitting was induced by 1 mol/l sodium chloride solution [43]. other substrates include monkey or rabbit esophagus, with possible lower sensitivity [38]. elisa test may show anti-bp180 and anti-bp230 igg antibodies. the serum level of anti-bp180 antibodies may be monitored during the course of the disease. high titers of anti-bp180 nc16a igg after therapy cessation are considered a predictor of risk of relapse. even then, the test result may be positive in healthy individuals or in individuals with other pruritic, inflammatory skin disorders [38]. therapeutic management because of their chronic nature, abds may last for a lifetime or for several years with a high tendency to relapse. pv is a potentially life-threatening skin disorder that requires early recognition and prompt treatment. bp is highly associated with old age, distinct drugs, and neurological and psychiatric diseases. treatment depends on the extent and severity of disease. in both conditions the primary objective is to promote healing of the bullous and erosive cutaneous and/or mucous lesions. additional goals are to reduce itch, prevent or reduce the recurrences of the blistering eruptions, improve the quality of life of patients, and minimize and identify as quickly as possible serious side effects associated with long-term treatment, particularly in the elderly [37,38]. a complete medical history focusing on drug history and comorbid diseases that may affect treatment decisions is mandatory. a complete biochemistry screening should be conducted and should include liver and renal function tests. treatment pemphigus vulgaris the morbidity and mortality of pv have remained high owing to complications of therapy, such as pneumonia, septicemia, mucous membrane and shows antibody deposition on the keratinocyte cell surface (in pds) or along the basement cell membrane (in bp). pemphigus vulgaris biopsy of perilesional skin or mucosa shows deposits of igg at the keratinocyte cell membrane [22,37]. igg deposition is seen in up to 100% of patients with active disease. complement (c3) deposition may not be observed, since igg4, the dominant subclass of igg involved in pv, does not fix complement. bullous pemphigoid it is best to biopsy perilesional skin from a recent blister. the diagnostic hallmark consists of fine, linear, continuous deposits of igg and/or c3 along the dermal-epidermal junction. occasionally iga and ige may be observed showing a similar pattern [33,38]. salt-split technique is a useful tool in the differential diagnosis of other abds, such as epidermolysis bullosa acquisita, which shows a similar dif pattern. in bp, immune deposits are found in the epidermal side or mixed at both the epidermal and dermal sites of the split (n-serration pattern), while in epidermolysis bullosa acquisita, deposits are typically localized on the dermal side of the cleavage (u-serration pattern). serological studies the method of serological detection of the autoantibodies largely relies on indirect immunofluorescence (iif) and enzyme‐linked immunosorbent assay (elisa) tests. recently, novel diagnostic multivariant assays were developed as practical screening tools for patients with suspected abd with the aim of processing the most common autoantibodies simultaneously [39,40]. pemphigus vulgaris iif allows for the detection of circulating autoantibodies against proteins or epithelial keratinocytes by incubating patient serum with appropriate commercially available substrates containing the target antigen. the testing study is conducted on monkey esophagus or epithelial substrates. pv sera produces a characteristic smooth and reticular pattern on most epithelial layer, referred as “fishnet-like,” “chicken wire,” or “honeycomb” pattern [37,38]. cloning of the gene coding for the major pemphigus antigens, dsg1 and dsg3, has enabled the production of recombinant proteins, which are used to detect igg autoantibodies by elisa [41]. the dsg3/dsg1 autoantibody profile defines the clinical outcome, since pv with exclusive involvement of the mucous membranes is associated with igg against dsg3, while the mucocutaneous variant of pv is associated with both anti-dsg1 and anti-dsg3 igg. the detection of igg autoantibodies by elisa is positive in more than 90% of cases [37]. the titers of serum igg autoantibodies against review | dermatol pract concept 2020;10(3):e2020050 7 nosuppressive adjuvant drug is continued, while the prednisone is gradually tapered. no particular advantage has been found with intravenous corticosteroid pulse treatment over treatment with oral corticosteroids [46]. rituximab, a chimeric monoclonal antibody targeting the cd20 antigen of b lymphocytes, has recently emerged as a highly promising therapeutic option for pv. rituximab causes b-cell depletion and a subsequent reduction in pathogenic autoantibodies. pretreatment investigations, contraindications, and treatment schedules are summarized in table 4. rituximab is one of the only drugs to gain european medicine agency and us food and drug administration approval for the treatment of pv. previous clinical experiences showed its dramatic efficacy as secondor third-line treatment in severe recalcitrant or relapsing cases of pv [47,48]. in particular, a meta-analysis including 578 patients with pemphigus showed a remission rate of 76% following a single cycle of rituximab, with a relapse rate of 20% (2 years) to 60% (5 years) [49]. more robust evidence showed a higher efficacy when it was administered early in the course of the disease [50]. ritux 3, a prospective, open-label, randomized clinical trial investigated rituximab as first-line treatment in combination with short-term prednisone vs prednisone alone for the treatment of pemphigus. results showed that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events [50]. at month 24, 89% of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off therapy vs 34% of 44 assigned to prednisone alone. a post hoc analysis of the enrolled patients in the ritux 3 study showed a steroid-sparing effect of rituximab, with rituximab-treated patients having lower cumulative and cardiovascular disease. therefore, correct management of the comorbidities of pemphigus is crucial to decrease disease‐associated morbidity and mortality. the traditional treatment paradigm of pv relies on systemic corticosteroid immunosuppression. prednisone is usually given at 0.5-1.5 mg/kg/day as a typical initial dosage. the therapeutic effect is evaluated by the number of new blisters per day and the ability to stop the blistering eruption. in refractory cases, the initial dose may be increased to 2 mg/kg/day. on the other hand, if clinical remission is obtained and no new blisters occur, glucocorticoids may be gradually tapered. appropriate steroid‐tapering strategies may prevent relapses, although an optimal treatment regimen remains indeterminable because of the lack of evidence. a decrease in the titers of circulating autoantibodies may drive tapering decisions. recommendations by an international expert panel are to check serum autoantibodies at the initiation of treatment, after 3 months and every 3-6 months, or in case of relapse [44]. control of disease activity is usually achieved within several weeks, whereas complete remission of quiescent disease on minimal treatment (≤10 mg/day prednisone) more often requires several months. long-term, complete remission off treatment may require years of therapy [45]. additional immunosuppressive adjuvants, such as azathioprine (1-3 mg/kg/day) or mycophenolate mofetil (2 g/ day), are often administered at initiation of treatment or in refractory cases in order to achieve faster or better control of the disease and spare corticosteroids, respectively. second-line adjuvants include cyclophosphamide, methotrexate, intravenous immunoglobulins, and immunoadsorption. the latter treatment consists of the passive removal of igg from the patient’s systemic circulation. when complete remission is obtained with combined therapy, the dosage of the immutable 4. dosage and pretreatment investigations for rituximab in pemphigus vulgaris rituximab dosage pretreatment investigations contraindications adverse events two 1,000-mg intravenous infusions separated by 2 weeks [1]; lower doses (500 mg) may be used for retreatment (at month 12 and every 6 months thereafter); methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion complete blood cell count, liver and renal function tests, creatinine, interferon gamma release assay, hepatitis b and hepatitis c markers, hiv antibodies, chest x-ray, ecg, cardiological examination active, severe infections, severely immunocompromised state, severe heart failure (new york heart association class iv) or severe, uncontrolled cardiac disease, cardiomyopathy, ischemic heart disease, severe arrhythmias such as rapid atrial fibrillation, frequent premature ventricular contractions infusion reactions, depression, infections, cardiac disorders, rare cases of fatal progressive multifocal leukoencephalopathy the dosing protocol corresponds to that of the european medicine agency’s “summary of product characteristics” and us food and drug administration’s highlights of prescribing information. different dosing protocols are reported in expert recommendations and therapeutic guidelines [42,50]. 8 review | dermatol pract concept 2020;10(3):e2020050 bullous pemphigoid although there is no generally accepted classification of disease severity, a classification of bp into mild (<10% affected body surface area), moderate, and severe forms has been suggested [57]. the effectiveness of topical therapy with superpotent topical corticosteroids in localized and moderate forms of bp is supported by a cochrane review [38,58]. be aware that the dose of 40 g every day or 10 to 30 g every day [59,60], which has proven equally effective as systemic prednisolone, is equivalent to about a tube per day. practicability and limitations of this drug regimen are that for some patients with bp, a twice-daily topical application [57] on widespread areas or the daily purchase of an ointment tube may not be manageable. in the localized, nonsevere forms, immunomodulatory, nonimmunosuppressant drugs such as doxycycline may be considered a viable option [61]. although its exact mechanism of action is not well understood, doxycycline proved to be not inferior to oral prednisolone for short-term blister control and is safer in the long term [61,62]. systemic corticosteroid therapy (prednisone 0.5 mg/kg/day) represents the treatment of choice for severe forms [38]. for maintenance treatment, doses may be tapered gradually within 4 to 6 months of initiation of treatment. adjunctive therapy includes combination with azathioprine, mycophenolate mofetil, tetracyclines plus nicotinamide, methotrexate, and dapsone [63] (figure 7). bacterial superinfection of erosions should be treated with local antiseptics. wound dressings should be considered for large wounds. sterile puncture of large blisters is recommended [57]. available data suggest that rituximab may provide clinical benefits for patients with refractory bp [64], although with less effectiveness. a complex interplay of complement activation of igg autoantibodies deposited doses of corticosteroids and experiencing less severe or life-threatening corticosteroid-related adverse events [51]. therefore, intravenous rituximab is now recommended as first-line option for new-onset moderate to severe pemphigus, but also for previously treated patients who do not achieve clinical remission with systemic corticosteroids and/ or immunosuppressive adjuvants [44,52]. the introduction of rituximab presents an opportunity to change the traditional therapeutic approach to pv. a complete remission off therapy may represent a realistic expectation for many patients. many aspects remain to be deepened. b-cell repopulation, low cd41 t-cell count, persistence of anti-dsg1 (>20 iu) and dsg3 (>120 iu) at month 3, and severe pemphigus disease area index score at baseline (>45) were identified as predictors of relapse in patients treated with rituximab [53,54]. additional areas that deserve further studies are the combination protocols with corticosteroids, the possibility of using cd20 inhibitors alone, prevention of relapses, the role of anti-dsg elisa values as biomarkers to drive further infusions, and the benefit from combining other adjuvants in patient management. consequently, the therapeutic algorithm of pv could be redefined in the future (figure 6). topical therapy of pv is essentially symptomatic and is practiced to alleviate inflammation and prevent secondary infections. usually corticosteroids, calcineurin inhibitors or corticosteroids and antibiotics in combination are administered on the cutaneous and mucous lesions. cutaneous erosive lesions should be covered using low-adhesive wound dressings. supportive care for oral lesions includes gel-containing local anesthetics and proper dental care. limited experience proved rituximab useful in refractory pf as well [55,56]. figure 6. treatment options for pemphigus. review | dermatol pract concept 2020;10(3):e2020050 9 immune suppression in pv by therapeutic immunoadsorption of pathogenic autoantibodies [68,69]. a promising approach is the use of reengineering chimeric autoantibody receptor t cells. patient-derived t cells are modified ex vivo to express a chimeric antibody receptor, which allows selective recognition and consequent killing of anti-dsg3 autoreactive b lymphocytes [70,71]. also in bp, new therapeutic targets aim to provide new treatment strategies that may go beyond nonspecific immunosuppression. in addition to omalizumab, monoclonal antibodies to il-5 such as mepolizumab and bertilimumab, an anti-eotaxin-1 antibody, are currently being investigated in bp [65]. in the context of immunomodulatory drugs, dimethyl fumarate, which is a prodrug utilized in psoriasis and multiple sclerosis, is also under investigation for bp because of its pleotropic anti-inflammatory effects [72]. references 1. kridin k. pemphigus group: overview, epidemiology, mortality, and comorbidities. immunol res. 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j dermatol venereol leprol. 2020;86(1):39-44. https://doi.org/10.4103/ijdvl.ijdvl_848_17 49. wang hh, liu cw, li yc, huang yc. efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. acta derm venereol. 2015;95(8):928-932. https://doi. org/10.2340/00015555-2116 50. joly p, maho-vaillant m, prost-squarcioni c, et al. first-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. lancet. 2017;389(10083):2031-2040. https://doi.org/10.1016/s01406736(17)30070-3 51. chen dm, odueyungbo a, csinady e, et al. rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect. br j dermatol. 2020;182(5):11111119. https://doi.org/10.1111/bjd.18482 52. daneshpazhooh m, balighi k, mahmoudi h, et al. iranian guideline for rituximab therapy in pemphigus patients. dermatol ther. 2019;32(5):e13016. https://doi.org/10.1111/dth.13016 53. albers ln, liu y, bo n, swerlick ra, feldman rj. developing biomarkers for predicting clinical relapse in pemphigus patients treated with rituximab. j am acad dermatol. 2017;77(6):10741082. https://doi.org/10.1016/j.jaad.2017.07.012 54. saleh ma. a prospective study comparing patients with early and late relapsing pemphigus treated with rituximab. j am acad dermatol. 2018;79(1):97-103. https://doi.org/10.1016/ j.jaad.2018.01.029 55. sharma vk, bhari n, gupta s, et al. clinical efficacy of rituximab in the treatment of pemphigus: a retrospective study. indian j dermatol venereol leprol. 2016;82(4):389-394. https://doi. org/10.4103/0378-6323.174379 56. de sena nogueira maehara l, huizinga j, jonkman mf. rituximab therapy in pemphigus foliaceus: report of 12 cases and review of recent literature. br j dermatol. 2015;172(5):1420-1423. https://doi.org/10.1111/bjd.13586 57. eming r, sticherling m, hofmann sc, et al. s2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid. j dtsch dermatol ges. 2015;13(8):833-844. https://doi. org/10.1111/ddg.12606 58. kirtschig g, middleton p, bennett c, murrell df, wojnarowska f, khumalo np. interventions for bullous pemphigoid: a summarised cochrane review. clin exp dermatol. 2011;36(4):449450. https://doi.org/10.1111/j.1365-2230.2011.04104.x 59. joly p, roujeau jc, benichou j, et al. a comparison of oral and topical corticosteroids in patients with bullous pemphigoid. n engl j med. 2002;346(5):321-327. https://doi.org/10.1056/ nejmoa011592 60. joly p, roujeau jc, benichou j, et al. a comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. j invest dermatol. 2009;129(1):1681-1687. https://doi.org/10.1038/ jid.2008.412 pemphigoid: italian guidelines adapted from the edf/eadv guidelines. g ital dermatol venereol. 2018;153(3):305-315. 34. machado-pinto j, mccalmont th, golitz le. eosinophilic and neutrophilic spongiosis: clues to the diagnosis of immunobullous diseases and other inflammatory disorders. semin cutan med surg. 1996;15(4):308-316. https://doi.org/10.1016/s10855629(96)80044-7 35. schmidt e, goebeler m, hertl m, et al. s2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. j dtsch dermatol ges. 2015;13(7):713-727. https://doi. org/10.1111/ddg.12612 36. miller dd, bhawan j. bullous tinea pedis with direct immunofluorescence positivity: when is a positive result not autoimmune bullous disease? am j dermatopathol. 2013;35(5):587-594. https://doi.org/10.1097/dad.0b013e3182604854 37. feliciani c, cozzani e, marzano av, et al. italian guidelines in pemphigus—adapted from the european dermatology forum (edf) and european academy of dermatology and venerology (eadv). g ital dermatol venereol. 2018;153(5):599-608. https:// doi.org/10.23736/s0392-0488.18.06073-x 38. feliciani c, joly p, jonkman mf, et al. management of bullous pemphigoid: the european dermatology forum consensus in collaboration with the european academy of dermatology and venereology. br j dermatol. 2015;172(4):867-877. https://doi. org/10.1111/bjd.13717 39. van beek n, dähnrich c, johannsen n, et al. prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases. j am acad dermatol. 2017;76(5):889-894. https://doi. org/10.1016/j.jaad.2016.11.002 40. yang a, xuan r, melbourne w, tran k, murrell df. validation of the biochip test for the diagnosis of bullous pemphigoid, pemphigus vulgaris and pemphigus foliaceus. j eur acad dermatol venereol. 2020;34(1):153-160. https://doi.org/10.1111/jdv.15770 41. amagai m, komai a, hashimoto t, et al. usefulness of enzyme‐linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. br j dermatol. 1999;140(2):351-357. https://doi.org/10.1046/j.13652133.1999.02752.x 42. jamora mj, jiao d, bystryn jc. antibodies to desmoglein 1 and 3, and the clinical phenotype of pemphigus vulgaris. j am acad dermatol. 2003;48(6):976-977. https://doi.org/10.1067/ mjd.2003.438 43. bağcı is, horváth on, ruzicka t, sárdy m. bullous pemphigoid. autoimmun rev. 2017;16(5):445-455. https://doi.org/10.1016/ j.autrev.2017.03.010 44. murrell df, peña s, joly p, et al. diagnosis and management of pemphigus: recommendations of an international panel of experts. j am acad dermatol. 2020;82(3):575-585.e1. https://doi. org/10.1016/j.jaad.2018.02.021 45. almugairen n, hospital v, bedane c, et al. assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including mediumand high-dose corticosteroids. j am acad dermatol. 2013;69(4):583588. https://doi.org/10.1016/j.jaad.2013.05.016 46. mentink lf, mackenzie mw, tóth gg, et al. randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: 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2019;10:1919. https://doi.org/10.3389/fimmu.2019.01919 67. bilgic a, murrell df. what is novel in the clinical management of pemphigus. expert rev clin pharmacol. 2019;12(10):973-980. https://doi.org/10.1080/17512433.2019.1670059 68. langenhan j, dworschak j, saschenbrecker s, et al. specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. exp dermatol. 2014;23(4):253-259. https://doi.org/10.1111/exd.12355 69. hofrichter m, dworschak j, emtenani s, et al. immunoadsorption of desmoglein-3-specific igg abolishes the blister-inducing capacity of pemphigus vulgaris igg in neonatal mice. front immunol. 2018;9:1935. https://doi.org/10.3389/fimmu.2018.01935 70. ellebrecht ct, bhoj vg, nace a, et al. reengineering chimeric antigen receptor t cells for targeted therapy of autoimmune disease. science. 2016;353(6295):179-184. https://doi.org/10.1126/ science.aaf6756 71. didona d, maglie r, eming r, hertl m. pemphigus: current and future therapeutic strategies. front immunol. 2019;10:1418. https://doi.org/10.3389/fimmu.2019.01418 72. wannick m, assmann jc, vielhauer jf, et al. the immunometabolomic interface receptor hydroxycarboxylic acid receptor 2 mediates the therapeutic effects of dimethyl fumarate in autoantibody-induced skin inflammation. front immunol. 2018;9:1890. https://doi.org/10.3389/fimmu.2018.01890 61. williams hc, wojnarowska f, kirtschig g, et al. doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. lancet. 2017;389(10079):1630-1638. https://doi.org/10.1016/ s0140-6736(17)30560-3 62. yamagami j. recent advances in the understanding and treatment of pemphigus and pemphigoid. f1000res. 2018;7:f1000 faculty rev-1360. published 2018 aug 30. https://doi.org/10.12688/ f1000research.14474.1 63. sticherling m, franke a, aberer e, et al. an open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone. br j dermatol. 2017;177(5):12991305. https://doi.org/10.1111/bjd.15649 64. kremer n, snast i, cohen es, et al. rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature. am j clin dermatol. 2019;20(2):209-216. https:// doi.org/10.1007/s40257-018-0401-6 65. amber kt, maglie r, solimani f, eming r, hertl m. targeted therapies for autoimmune bullous diseases: current status. drugs. 2018;78(15):1527-1548. https://doi.org/10.1007/s40265-0180976-5 66. seyed jafari sm, gadaldi k, feldmeyer l, yawalkar n, borradori l, schlapbach c. effects of omalizumab on fcεri and ige exhttps://doi.org/10.3389/fimmu.2019.01919 https://doi.org/10.1080/17512433.2019.1670059 https://doi.org/10.1111/exd.12355 https://doi.org/10.3389/fimmu.2018.01935 https://doi.org/10.1126/science.aaf6756 https://doi.org/10.1126/science.aaf6756 https://doi.org/10.3389/fimmu.2019.01418 https://doi.org/10.3389/fimmu.2018.01890 https://doi.org/10.1016/s0140-6736(17)30560-3 https://doi.org/10.1016/s0140-6736(17)30560-3 https://doi.org/10.12688/f1000research.14474.1 https://doi.org/10.12688/f1000research.14474.1 https://doi.org/10.1111/bjd.15649 https://doi.org/10.1007/s40257-018-0401-6 https://doi.org/10.1007/s40257-018-0401-6 https://doi.org/10.1007/s40265-018-0976-5 https://doi.org/10.1007/s40265-018-0976-5 supplement | dermatol pract concept 2012;2(2):16 83 dermatology practical & conceptual www.derm101.com dermoscopy in non-pigmented eccrine poromas. study of mexican cases b. carlos-ortega1, a. domínguez-espinosa2, r. quiñones-venegas3, r. gonzalez ramírez4 1 dermatologist and dermato-oncologist, hospital de especialidades centro médico la raza, instituto mexicano del seguro social, méxico city, mexico 2 dermatologist and dermatopathologist, hospital general de zona 8 “gilberto flores izquierdo” instituto mexicano del seguro social, méxico city, mexico 3 dermatologist and dermatology surgeon. instituto dermatológico de jalisco, guadalajara, méxico 4 dermatologist. servicios médicos u.a.n.l., monterrey, méxico background: non pigmented eccrine poroma is a benign tumor that can have dermoscopic features mimicking malign neoplasias. the characteristic vascular pattern of this tumor hasn’t been established. we found a scarcely reported vascular pattern, which can be useful to distinguish this tumor from malignant ones and propose a new nomenclature to these vessels due their similarity with the common calla flower and cherry blossoms tree. observations: we study 10 proven mexican cases of eccrine poroma and nearly half of them presented irregular linear and branched vessels with semi-elliptical, circular or semicircular endings, we called them “chalice-form” and “cherry-blossoms” vessels. the structureless pink-white areas were the most common finding and some vascular patterns reported in other studies were barely found. conclusions: due to the variability in the dermoscopic patterns found in non pigmented eccrine poroma, further studies are required to establish the specificity of these vessels, however they hasn’t been reported in other benign or malign neoplasias so, if seen, they can be an useful key leading to the diagnostic of eccrine poroma. basal cell carcinoma: dermoscopy vascular features of different subtypes john pyne1, devendra sapkota1, jian cheng wong2 1 school of medicine, the university of queensland, brisbane, australia 2 school of mathematics and statistics, the university of new south wales, sydney, australia background: basal cell carcinoma is a common tumour, which presents with various subtypes. these subtypes usually display vascular features, which are readily identified using dermoscopy. objective: dermoscopy vascular features of superficial, superficial and nodular, nodular and combined aggressive subtypes were compared for diagnostic discrimination. method: dermoscopy vascular features were recorded in vivo for 1098 consecutive bcc. cases with potential confounding from previous intervention were excluded. these vascular features included branching, serpentine, dot, glomerular, loop and linear vessels, the proportions of pink, central verses peripheral vessel distribution and the presence of large vessels. kappa values were calculated for each defined vascular feature. results: different subtypes of bcc have distinctive vascular features. superficial bcc (n=284) have more than half the tumour area pink (85%) and absent large vessels (93%), ci 85%—95%. nodular bcc (n=230) are characterized by large vessels (46%, ci 39%-52%, p<0.001) compared to other subtypes, as well as less dot, coil and loop vessels. aggressive bcc (n=213) display a tumour area with no pink (12%) or less than half the area pink (27%) and absent vessels in the central tumour area (22%, p<0.001) compared to other subtypes. abstracts from the 3rd world congress of dermoscopy, may 17 to 19, 2012, brisbane australia citation: abstracts from the 3rd world congress of dermoscopy, may 17 to 19, 2012, brisbane australia. dermatol pract conc. 2012;2(2 suppl):16. http://dx.doi.org/10.5826/dpc.0202a16. copyright: ©2012. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 84 supplement | dermatol pract concept 2012;2(2):16 kappa values for all recorded features ranged from 0.48 to 1.0. limitations: aggressive subtypes within the combined aggressive group were not assessed separately. all data was recorded using non polarized dermoscopy. conclusions: diagnostic discrimination between different subtypes of bcc is facilitated by vascular feature assessment. the lower limb has different variation in bcc vessel features, compared to other anatomic sites. dots/globules on dermoscopy in nail-apparatus melanoma yuji inoue1, scott w menzies2, satoshi fukushima1, hazuki nishi-kogushi1, azusa miyashita1, shinichi masukuchi1, faith muchemwa1,3, toshiro kageshita4, hironobu ihn1 1 department of dermatology and plastic surgery, faculty of life sciences, kumamoto university, kumamoto, japan 2 melanoma diagnostic centre, sydney cancer centre, royal prince alfred hospital, sydney, australia 3 department of immunology, university of zimbabwe college of health sciences, harare, zimbabwe 4 kageshita dermatological clinic, kumamoto japan introduction: dermoscopic features of nail apparatus melanoma are different from those of other sites. ronger et al. described seven dermoscopic features of melanonychia. methods: features of dermoscopic examination of 31 patients with nail apparatus melanomas were reviewed retrospectively. results: a brownish discoloration of the background and irregular lines were the most common feature, followed by and (micro-) huchinson’s sign. dots/globules were seen in 8 of 31 cases (25.8%). conclusions: dermoscopy was very useful in the diagnosis of nail-apparatus melanoma, and dots/globules might be the one of features of nail apparatus melanoma. reference 1. ronger s, touzet s, ligeron c, et al. dermoscopic examination of nail pigmentation. arch dermatol. 2002; 38:1327-33. complex dermatoscopy diagnostics of melanoma d. sokolov1, i. boulytcheva1, g. vorozhtsov2, s. kuzmin2, a. makhson1, v. sokolov2 1 moscow city oncological hospital n62, moscow, russian federation 2 sue “iscc “intermedbiophyschem,” moscow, russian federation introduction: in spite of the fact that frequency of melanoma makes 3-5 % of all primary malignant tumors of skin, it is the main reason of death of patients in oncodermatology. over the last 6 years complex dermatoscopy examination has been intensively used in clinical practice of moscow oncological hospital no 62 for the detection and characterization of melanoma and other pigmented skin lesions. method: complex dermatoscopy diagnostics include digital photo, zoom-photo, standard and microdermatoscopy, fluorescent dermatoscopy. at the first stage, we take digital photos and perform computer mapping of the patient’s skin. at the second stage, zoom-photo with a 10-fold enlargement is taken for each suspicious lesion. at the third stage, we perform a standard dermatoscopy with a 10-fold enlargement, microdermoscopy with a 120-fold enlargement and a fluorescent dermatoscopy with 5-ala (alasens). applying the complex method of dermatoscopy diagnostics we studied the reliability of characteristics describing malignant and benign pigmented skin lesions in 497 patients with 1735 pigmented skin lesions (280 non-melanocytic, 1271 melanocytic lesions (65 melanoma, 259 dysplastic nevi)). the data of the complex dermatoscopic investigation were compared to the results of morphological investigation of surgery samples. results: sensitivity and specificity dermatoscopy diagnostics of melanoma has made 92 % and 72 % accordingly. consider high efficiency, non-invasive character of method of complex dermatoscopy diagnostics of melanoma of skin it should be used first of all for examination in groups of high risk of melanoma. this scientific trial is supported by moscow. circumscribed palmar hypokeratosis: correlation between histopathological patterns and dermoscopic findings machiko nishimura, wataru nishie, shinichi nakazato, ikue nemoto-hasebe, yasuyuki fujita, hiroshi shimizu department of dermatology, hokkaido university graduate school of medicine, sapporo, hokkaido circumscribed palmar hypokeratosis (cph) is a rare skin disorder that typically develops on the palms of middle-aged women. cph is clinically characterized by well-demarcated, slightly scaling erythema that is sometimes difficult to differentiate from bowen’s disease and porokeratosis of mibelli. cph is usually diagnosed by its clinical and histopathological features. we present a 61-year-old japanese female presented with a 10-year history of a well-demarcated, 6x6mm asymptomatic erythema on the right palm. we show an apparent correspondence between the dermoscopic findings and histopathological features of the lesional skin, which indicates that the pathogenesis of cph is associated not only with abnormal keratinization but also with hyper vascular formation. supplement | dermatol pract concept 2012;2(2):16 85 effect of narrowband uvb phototherapy on melanocytic naevi c. y. lin, a. oakley, m. rademaker, s. hill, a. yung department of dermatology, waikato hospital, hamilton, new zealand introduction: melanocytic naevi have been observed to undergo morphological changes following exposure to narrowband ultraviolet b (nbuvb). we aimed to analyse changes occurring in naevi exposed to nbuvb in a large cohort. method: 51 subjects referred for phototherapy had macro and dermoscopic images of prominent melanocytic naevi taken immediately prior to nbuvb treatment; after 10 exposures; after 30 exposures or at the end of the treatment course if earlier; and 3 months after discontinuing treatment. four dermatologists, by consensus, examined each naevi for specific clinical and dermoscopic features, at each time point. the size (area) of each naevus was determined by plenimetry. preliminary results: 36 of 51 patients had complete sets of images. the most common global dermoscopic pattern in the 440 naevi examined, were reticular (50%) and globular (32%). following nbuvb exposure, 45% of reticular naevi displayed changes in local features with blurring or merging of lines. increase in colour intensity and in the number of dots/ globules was observed in 63% of globular naevi. 167 naevi (40%) underwent change in size following uv exposure. of these, 54% (91/167) decreased in size, with median area reduction of 8% (0.9%-42%); whilst 46% (76/167) increased in size, with median area increase of 9% (1%-76%). the trend was for these naevi to return to their pre-treatment size after phototherapy. of the 440 naevi reviewed, none displayed changes suspicious of malignancy. conclusion: around half of exposed naevi undergo size/ morphological changes following a course of nbuvb. size changes tended to revert to pre-treatment values 3 months after discontinuing phototherapy. dermoscopy and reflectance confocal microscopy to aid in the detection of lentigo maligna recurrence after treatment s. segura1, f. gallardo1, a. toll1, c. barranco2, i. membrive3, r. m. pujol1 1 department of dermatology, hospital del mar, barcelona, spain 2 department of pathology, hospital del mar, barcelona, spain 3 department of radiotherapy, hospital del mar, barcelona, spain introduction: distinguishing between recurrence of lentigo maligna (lm) and postinflammatory hyperpigmentation after treatment may be challenging. reflectance confocal microscopy (rcm) and dermoscopy might be of help in this clinical setting. methods: we performed dermoscopy and rcm in 7 patients that showed pigmentation in areas previously treated for lm. previous treatments were radiotherapy (4), cryotherapy (2) and surgical excision (1). correlation between rcm findings and histological/immunohistochemical features was evaluated. results: two cases treated with radiotherapy exhibited blue-gray granules around hair follicle openings under dermoscopy. rcm exam correlated these structures with widespread plump cells in the upper dermis without other features suggesting recurrence of lm, definitely excluded in the biopsy. in 3 cases (2 radiotherapy, 1 surgery) dermoscopy showed irregular brown pigmentation, areas with fingerprint-like structures and focal grayish dots. in these cases rcm demonstrated widespread dendritic bright cells at basal and suprabasal layers. no evidence of lm was detected on histology, but immunohistochemistry showed positive langerhans’ cells at suprabasal layers and dendritic hmb-45-positive melanocytes at the basal layer. the two cases that had been treated with cryotherapy did not show clear-cut dermoscopic criteria for lm. however, rcm was highly suggestive of melanoma that was histologically confirmed. conclusion: rcm can be useful in the monitoring of lm after treatment. in photodamaged skin, the visualization of widespread dendritic cells in basal and suprabasal layers by rcm may mimic a recurrence of lm. these structures correlate with activated nonmalignant hmb45-positive melanocytes and langerhans’ cells and may represent a pitfall in the confocal evaluation of these lesions. dermatoscopy of patients with radiationinduced pigmented basal cell carcinoma f. moeineddin, h. ghaninejad, h. moslehi, a. h. rajaee department of dermatology, razi hospital, tehran university of medical sciences, tehran, iran introduction: dermatoscopy is one of several non-invasive approaches that use to improve the diagnostic accuracy. it has been applied in the diagnosis of skin tumors such as basal cell carcinoma (bcc). method: one hundred lesions from 39 patients (28 men and 11 women) were included in this study. all patients had a past history of childhood radiation therapy, primarily for treatment of tinea capitis. they presented with lesions that were morphologically highly suspicious to be pigmented bcc. using a digital dermatoscope, all lesions were photographed and evaluated for the presence of menzies bcc criteria and other features. all lesions were subsequently, underwent biopsy. 86 supplement | dermatol pract concept 2012;2(2):16 results: when combined with clinical diagnosis, menzies dermatoscopic criteria for bcc diagnosis have 100% sensitivity and 90.9% specificity. tree like vessels, maple leaf-like structures and spoke wheel patterns were only seen in bcc lesions. large gray-blue globules were seen in 76.4%, blue gray ovoid nest in 66.3%, arborizing vessels in 63%, maple leaf like pattern in 45%, ulceration in 43.8% and spoke wheel pattern in 28% of bcc lesions. the results confirmed the usefulness of dermatoscopy for better decision-making in the clinically suspected bcc lesions after radiation. references 1. soyer hp, kerl h. surface microscopy of pigmented cutaneous tumors. ann dermatol venereol. 1993;120:15-20. 2. menzies sw, westerhoff k, et al. surface microscopy of pigmented basal cell carcinoma. arch dermatol. 2000;136:1012-6. a blueprint for staging of murine melanocytic lesions in genetically modified mice lynlee l. lin1,2, elizabeth m.t. wurm1, blake ferguson2, duncan lambie 3, tarl w. prow1, graeme j. walker2, h. peter soyer 1 1 dermatology research centre, the university of queensland, school of medicine, brisbane, queensland, australia 2 skin carcinogenesis laboratory, queensland institute of medical research, brisbane, queensland, australia 3 anatomical pathology, princess alexandra hospital, brisbane, queensland, australia it is well known that when mice are engineered with mutations in molecular pathways that drive human malignant melanoma (mm) development, they too develop the disease. little attention has been paid, however, to the natural history of naevi and melanomas developing in mouse models, and how this relates to the particular mutation the animal carries. gaining the knowledge of the behaviour of each individual mouse lesion provides a relevant link for translation of information obtained from the mouse model to the corresponding clinical condition. the ultimate goal of the mouse mm model is to gain understanding of how certain mutations influence lesion dynamics, and to provide appropriate models for preclinical evaluation of melanoma therapies. we recently reported the development melanocytic lesions, along the spectrum of naevus to mm, in cdk4r24c/ r24c::tyr-nrasq61k mice. we followed the development of lesions over time using digital photography and dermoscopy to correlate the clinical appearance with histopathologic features of melanocytic lesions developing in this model. we have identified essentially two types of lesions and studied their respective growth patterns. we developed a staging system, based on the level of extension in to the dermis, which offers a practical linkage between murine mm models and standard clinical diagnosis. we will discuss how we have used these methods to help us understand the development of melanomas in mice carrying other mutations (e.g., in the p53 and arf genes) that result in a very different mode of tumour progression than we see in the original model. refining mole phenotype with anatomic distribution and dermoscopic patterns of clinically dysplastic nevi: a pilot study l. smith, d. polsky the ronald o. perelman department of dermatology, new york university langone medical center, new york, new york, usa introduction: individuals with increased quantities of clinically dysplastic nevi (dn), such as those with the atypical mole syndrome (ams), have an elevated melanoma risk. little is known, however, about the influence of qualitative mole phenotypic factors on melanoma risk, such as anatomic distribution and dermoscopic appearance of dn. objective: to compare the anatomic distribution and dermoscopic appearance of dn among ams patients with or without a personal history of melanoma. method: we conducted a retrospective case-control study of clinical and dermoscopic images from 22 ams patients with or without a personal history of melanoma (11 cases and 11 controls, respectively) using molemap software. the anatomic location and dermoscopic pattern for each dn was analyzed. results: 676 of 1822 lesions met criteria for dn. 391of 676 (58%) dn were located on cases compared to 285/676 (42%) located on controls. cases had more dn on the legs than controls (29% vs. 15%, p = 0.009), and fewer dn on the chest (7% vs. 14%, p = 0.009). disorganized globular dn and homogeneous dn, were more common among cases than controls (18% vs. 11%, p = 0.0126; 18% vs. 6%, p = 0.001, respectively). dn exhibiting peripheral network with central globules were more frequent in controls (20% vs. 3%, p = 0.002). conclusion: these data suggest that dn exhibit significantly different anatomic distributions and dermoscopic patterns among ams patients with or without a melanoma history. these differences may be helpful in improving melanoma risk prediction among high-risk individuals with increased quantities of dn. dermatoscopy of genital warts h. dong1, d. shu1, t. m. campbell2, j. frühauf3, h. p. soyer2, r. hofmann-wellenhof3 1 department of dermatology, the first teaching hospital, university of zhengzhou, zhengzhou, china supplement | dermatol pract concept 2012;2(2):16 87 2 dermatology research center, the university of queensland, school of medicine, brisbane, australia 3 department of dermatology, medical university of graz, graz, austria background: genital warts may mimic a variety of conditions, thus complicating their diagnosis and treatment. the recognition of early flat lesions presents a diagnostic challenge. objective: we sought to describe the dermatoscopic features of genital warts, unveiling the possibility of their diagnosis by dermatoscopy. methods: dermatoscopic patterns of 61 genital warts from 48 consecutively enrolled male patients were identified with their frequencies being used as main outcome measures. results: the lesions were examined dermatoscopically and further classified according to their dermatoscopic pattern. the most frequent finding was an unspecific pattern, which was found in 15/61 (24.6%) lesions; a fingerlike pattern was observed in 7 (11.5%), a mosaic pattern in 6 (9.8%), and a knoblike pattern in 3 (4.9%) cases. in almost half of the lesions, pattern combinations were seen, of which a fingerlike/knoblike pattern was the most common, observed in 11/61 (18.0%) cases. among the vascular features, glomerular, hairpin/dotted, and glomerular/dotted vessels were the most frequent finding seen in 22 (36.0%), 15 (24.6%), and 10 (16.4%) of the 61 cases, respectively. in 10 (16.4%) lesions no vessels were detected. hairpin vessels were more often seen in fingerlike (x2 = 39.31, p = .000) and glomerular/dotted vessels in knoblike/mosaic (x2 = 9.97, p = .008) pattern zones; vessels were frequently missing in unspecified (x2 = 8.54, p = .014) areas. conclusions: there is a correlation between dermatoscopic patterns and vascular features reflecting the life stages of genital warts; dermatoscopy may be useful in the diagnosis of early-stage lesions. comparison of the sensitivity and specificity of the dermoscopic findings of alopecia areata, androgenetic alopecia, and cicatricial alopecia u. gunay1, m. t. sahin1, g. dinc-horasan2, s. ozturkcan1 1 department of dermatology, celal bayar university, medical faculty, manisa, turkey 2 departments of public health, celal bayar university, medical faculty, manisa, turkey introduction: the aim of this study was to compare the specificity and sensitivity of the dermoscopic findings of alopecia areata (aa), androgenetic alopecia (aga) and cicatricial alopecia. method: a total of 99 patients with alopecia (37 aa, 39 aga, 23 cicatricial alopecia) were admitted to our study. an informed consent form was signed by the patients and volunteers, followed by dermoscopic examination and photography. results: yellow dots, exclamation mark, broken hairs, black dots were more specific for aa; reduced follicular ostia, white patches, white dots, blue-grey dots, red dots, keratin plugs, branching capillaries, tufted follicle and perifollicular scales were more frequently observed in cicatricial alopecia. hair diameter diversity, perifollicular pigmentation and peripilar erythema were mostly observed in aga. yellow dots with short vellus hairs were observed both in aa and aga. reduced hair diameter was observed in significant ratio both in aa and cicatricial alopecia. unlike previous studies, “yellow dots” were observed nearly equally both in aa and aga. “short vellus hair” was observed frequently both in aga and aa. moreover, we revealed “reduced hair diameter” in aa and “honeycomb-like erythema” in cicatricial alopecia, which have never been reported before in previous dermoscopic and trichoscopic studies that were carried in different alopecia types. conclusion: we think that our study is unique and important not only because it is the first study in literature to compare the clinical and dermoscopic findings of aa, aga, and cicatricial alopecia, but also evaluating the specificity and sensitivity of these findings. dermoscopic analysis of synchronous melanoma: 5 years’ experience at a tertiary skin cancer clinic in the united kingdom s. j. arnold, j. c. r. bowling department of dermatology, churchill hospital, oxford, united kingdom the incidence of multiple primary melanoma ranges from 2-12% in various studies, with the majority of second primary melanomas detected within the first three years. in particular, many patients in this group have more than one melanoma at presentation (synchronous melanoma). clinicopathological studies of patients with multiple primary melanomas have found that most subsequent melanomas are less invasive than the initial melanoma, however many do not have the typical clinical or dermoscopic appearances of melanoma. patients with multiple benign naevi frequently show a predilection for certain dermoscopic patterns across all of their naevi (the concept of ‘moles breed true’). furthermore, dysplastic naevi or melanomas are frequently first detected due to their difference from surrounding benign naevi: the ‘ugly duckling sign.’ we sought to determine whether synchronous melanomas in individual patients had similar dermoscopic profiles. therefore, the dermoscopic appearances of synchronous 88 supplement | dermatol pract concept 2012;2(2):16 melanomas arising in patients attending a tertiary skin cancer clinic in the united kingdom from 2005-2010 were reviewed. we found that patients with synchronous melanomas may not show a predilection for any particular dermoscopic pattern. therefore, unlike benign naevi, multiple primary melanomas do not ‘breed true’; these ‘ugly ducklings’ need to be assessed, clinically and dermoscopically, on an individual basis. usefulness of dermoscopy during laser or ipl treatments domenico piccolo department of dermatology, university of l’aquila, l’aquila, italy dermoscopy is a non-invasive instrumental method for the in-vivo study of pigmented skin lesions. this technique allows for viewing the parameters that would otherwise be invisible to the naked eye. over recent years dermoscopy has proved to be extremely useful even on dermatological pathologies of an inflammatory origin and skin parasitosis. the introduction of the new laser and intense pulsed light systems has made it possible to cure pathologies difficult to treat with the instruments available to doctors ten years ago. the use of dermoscopy has proved to be particularly important immediately after treatment for observing positive or negative results, any side effects, or early signs of relapses. in this way the patient and the doctor know with good approximation what they can expect from a specific treatment. the constant application of dermoscopy to laser and ipl treatment can also be useful for educational purposes in order to better understand how to interpret the dynamics of specific pathologies and the results which the different types of lesions and skin may have when crossed by a laser beam or luminous energy. the use of dermoscopy before surgical excision of a given melanocytic lesion with co2 laser is also indispensable for medical—legal purposes. the dermoscopic image of the lesion immediately after treatment is important for demonstrating the absence or residual presence of pigment as well as the depth reached and the absence of any thermal damages. dermoscopy is a particularly useful method for predicting the therapeutic success of the vascular treatments. the dermoscopic exam performed before treatment makes it possible to quantify the number and gauge of the vessels to be treated and the presence of any photodamage. the reaction of the vessel immediately after ipl or nd-yag laser treatment can be of two types: coagulation of the vessel with colour change from red to blue or contraction of the vessel with disappearance or reduction in size. these epiphenomena are clearly visible with the help of dermoscopy. in our experience, dermoscopy has demonstrated to be an extraordinary instrument for determining any possible adverse events immediately after laser or ipl treatment. this allows physicians to provide suitable therapy in advance and inform the patient about any possible undesirable effects. our results demonstrated that dermoscopy can definitely be considered a first choice exam of great validity, above all due to the exactness and extreme accuracy in identifying the target to be hit. in most cases this has made it possible to immediately predict the treatment results. the dermoscopic exam performed some time after treatment demonstrated that it is indispensable for verifying the final results, especially in the cases of epithelial tumours treated with pdt. on concluding this study we suggest that the dermoscopic exam should be an integral part of all laser and ipl treatments. visual language in dermoscopy: a tool for novices and experts t. o’brien, z. assarian geelong dermatology, geelong, australia visual language refers to the integration of shapes (symbols or signals), images (codes or objects) and words (text and speech) into a single communication unit. the broad concept of shape can be subdivided into the basic elements of visual language: dot, line, shape and colour. these are the raw materials of all visual information. dermoscopic images are made up of these basic elements. reading these elements abstractly can help both the learner and expert in dermoscopic diagnosis. does it look like melanoma? the effect of sunless tanning on dermoscopy of pigmented skin lesions—a pilot study j. dahlén gyllencreutz1, k. bengtsson boström2, k. terstappen1 1department of dermatology, skaraborg hospital, skövde, sweden 2r&d centre skaraborg primary care background: the use of dermoscopy has led to an improvement in diagnosing malignant melanoma (mm), which is important for the prognosis of the patient. sunless tanning agents containing dihydroxyacetone (dha) could lead to a decrease in uv exposure decreasing the risk for mm. importantly, dha has been reported to change the dermoscopic image and could thus endanger the diagnostic improvement of dermoscopy. objective: to investigate if the use of dha can lead to changes that simulate a real, clinically relevant dermoscopic change suggesting malignant transformation in facial solar supplement | dermatol pract concept 2012;2(2):16 89 lentigo/ initial seborrheic keratosis (sl/isk) or in nevi on the body. method: seven patients with 25 pigmented skin lesions (pls) were photographed resulting in 38 dermoscopic images. photographs were taken before, one week after and 1-2 months after the use of dha. two dermatologists separately evaluated the dermoscopic features according to menzies’ method (lesions on the body) or pattern analysis (facial lesions). results: in facial psls unclear dermoscopic lesions were registered by both evaluators significantly more often after dha use than before (42 vs.12 %, p=0,021 and 69 vs.19 %, p=0.001). furthermore, follicular pigmentation that partly mimics that of lentigo maligna was also seen significantly more often after dha use than before (80 vs.12%, p<0.001 and 69 vs. 15%, p<0.001) and in these instances the evaluators recommended a biopsy. unclear lesions in nevi on the body were not significantly increased after dha use. conclusion: dermatologists that come across unclear dermoscopic findings, especially in facial pls, should ask about the use of dha. a survey of us dermatology chief residents with regard to the nature, significance, and management of dysplastic nevi t. p. wu, l. smith, t. newlove, c. hwa, j. a. stein, d. polsky ronald o. perelman department of dermatology, new york university langone medical center, new york, usa introduction: a 2002 survey of fellows of the american academy of dermatology found substantial variation in the management of dysplastic nevi and attitudes toward their biological significance. objective: to assess the attitudes and practices of newly graduated us dermatologists with respect to dysplastic nevi and compare these findings with those from the 2002 survey. methods: an online survey was sent to 139 chief residents of us dermatology training programs. results: a 59% response rate was achieved. all residents accept the dysplastic nevus as a clinical entity, and all report access to a dermatoscope in clinic. 98% agree that dysplastic nevi mark persons at increased risk for melanoma, compared to 59% of aad fellows in 2002. 94% of chief residents use dermoscopy to manage pigmented lesions, compared to 23% of aad fellows in 2002. although 92% of chief residents report receiving dermoscopy training, only 48% train with a pigmented lesion specialist. among those training without a specialist, less than half receive classroom or bedside teaching compared to 77% of those who train with a specialist. of those who train with a specialist, 77% agree that dermoscopy can help differentiate melanoma from benign lesions, compared to 46.5% of those who train without a specialist (p=0.0067). conclusion: residents are receiving a more unified message regarding the biological significance of dysplastic nevi and nearly all use dermoscopy as a diagnostic tool. additionally, specialists can provide dedicated instruction to trainees fostering greater confidence in the utility of dermoscopy for the management of pigmented lesions. reference 1. tripp jm, kopf aw, marghoob aa, bart rs. management of dysplastic nevi: a survey of fellows of the american academy of dermatology. j am acad dermatol. 2002;46:674-82. dermoscopy in dark-skinned people: the experience of the national institute for health, migration and poverty (nihmp) in rome (italy) v. padovese, m. valenzano, g. franco, r. fazio, r. testa, g. costanzo, c. mirisola national institute for health, migration and poverty (nihmp), rome (italy) little is known about dermoscopy in dark-skinned people and whether it can influence diagnostic performance. conditions as diverse as inflammatory and infective dermatoses, tumours and pigmented and non-pigmented skin lesions have been documented in white population but few studies report dermoscopic features in dark skin. moreover, clinical diagnosis in skin of darker color is made difficult by unusual presentations, annular patterns and absence of erythema. the aim of this study is to assess whether dermoscopy can be a useful diagnostic tool in dark skinned population and compare dermoscopic features in the different phototypes. migrants of ethnic skin attending the dermatology department of nihmp in rome affected by inflammatory and infective dermatoses, tumours and pigmented skin lesions underwent dermoscopic examination after clinical evaluation. we present a case series and document how the routine use of dermoscopy can guide the dermatologist in diagnosing skin lesions of difficult interpretation and accurately classify pigmented lesions. references 1. bowling j, argenziano g, azenha a, bandic j, bergman r et al. dermoscopy key points: recommendations from the international dermoscopy society. dermatology. 2007;214:3-5. 2. de giorgi v, trez e, salvini c, et al. dermoscopy in black people. br j dermatol. 2006;155:695-9. 90 supplement | dermatol pract concept 2012;2(2):16 apoptosis in seborrheic keratoses: an open door to a new dermoscopic score olga simionescu1, bogdan o. popescu1,.2, mariana costache1,2, emilia manole2, stefan spulber3, mihaela gherghiceanu2, andreas blum4 1 carol davila’ university of medicine and pharmacy, bucharest, romania 2 victor babes’ national institute of pathology, bucharest, romania 3 karolinska institutet, stockholm, sweden 4 private and teaching practice of dermatology, konstanz, germany background: the aetiology of seborrheic keratoses (sk), the most common benign epithelial tumours, and any relationship with malignancy are not yet known. as a protective anti-cancer mechanism, apoptosis reflects cellular loss as a reaction to proliferative activity. objectives: the objective of this study was to quantify apoptosis in different sk types (acanthotic, hyperkeratotic, reticulated, irritated, and clonal) and correlate the dermoscopic picture with apoptosis rate. methods: after a qualitative and quantitative analysis of dermoscopic images, we defined a new quantitative dermoscopic score (c3v2f, crypts, millia cysts, colours, hairpin vessels, irregular vessels, fissures) from 0 to 22, which enabled us to establish cut-offs correlating with apoptosis rates. results: all five sk forms were associated with lower apoptosis rates compared to normal skin. a c3v2f score >10 and greater number of crypts and colours reflected a higher apoptosis rate, which implies a benign character of evolution. in contrast, the presence of irregular vessels on more than 50% of the lesion surface implied a lower rate of apoptosis and probably associated with a risk of malignant transformation. based on the dermoscopic information, we used multiple regression to establish a model for estimating the rate of apoptosis with a 0.7 prediction interval (approximately 1 standard deviation). conclusions: the new c3v2f score could be valuable for the clinical evaluation of possible sk prognosis and decisions regarding excision. evaluating the first step of the dermatoscopic 2-step method in non-sun damaged and chronically sun damaged patients p. tschandl1, c. rosendahl2, h. kittler1 1 department of dermatology, medical university of vienna, vienna, austria 2 school of medicine, university of queensland, brisbane, australia usage of the diagnostic two-step method in teaching dermatoscopy is widely accepted and was approved in a consensus meeting in 2003. the differentiation of melanocytic and non-melanocytic lesions (“the first step”) contains the risk of misclassification and can therefore lead to wrong diagnoses. this risk is inherent especially when applied by dermatoscopists at a beginning level, the most frequent users of published algorithms. the present study aimed to evaluate the frequency of misclassifications according to the first step. we included 707 consecutive cases from 553 patients (mean age: 54.7 years, sd: ±18.1 years) with (n=331) and without (n=222) chronically sun-damaged skin. the cases were collected from a tertiary referral center at a university hospital in europe and from a primary care skin cancer clinic in brisbane (australia). dermatoscopic images were evaluated in a blinded fashion for the presence of features described in the 2-step algorithm to determine their melanocytic or nonmelanocytic origin. mucosal, genital and non-pigmented lesions were excluded. the sensitivity of the first step was 97.1% for patients with chronic sun-damage and 96.8% for patients without or moderate sun damaged skin. the specificity was 33.6% for patients with chronic sun-damage and 67.9% for patients without or moderate sun-damaged skin. the most common reasons for misclassification were a pigmented network in 69 cases and an absence of any given features in 74 cases. references 1. argenziano g et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-93. 2. marghoob aa, braun r. proposal for a revised 2-step algorithm for the classification of lesions of the skin using dermoscopy. arch dermatol. 2010;146(4):426-8. pigmented actinic keratosis: brazilian cases mauricio nascimento pigmented actinic keratoses play a difficult role in the differential diagnosis of lentigo maligna on the face. however some helpful hints as neighborhood sign, rough appearance, abrupt interruption of pigment pseudo network could help in such diagnosis. the authors present a visual set of lesions illustrating this concept. references 1. schiffner r, schiffner-rohe j, vogt t, et al. improvement of early recognition of lentigo maligna using dermatoscopy. j am acad dermatol. 2000;42:25-32. 2. cognetta ab, stolz w, katz b, tullos j, gossain s. dermatoscopy of lentigo maligna. dermatol clin. 2001;19:307-18. 3. katz b, rao b. pigmented actinic keratosis. in: marghoob aa, braun rp, kopf aw. atlas of dermoscopy. london: taylor & francis, 2005: 86-90. supplement | dermatol pract concept 2012;2(2):16 91 4. zalaudek i; ferrara g, leinweber b, mercogliano a, d´ambrosio a, argenziano g. pitfalls in the clinical diagnosis of pigmented actinic keratosis. j am acad dermatol. 2005;53:1071-4. observation of a five year high risk clinic for primary melanoma fj moloney1,2,3, p. guitera1.3, e. coates1, 2,3, n. haass1.2,,3, k. ho1, r. khoury, g. mann3,4, sw menzies1,3 1 sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, new south wales, australia 2 department of dermatology, royal prince alfred hospital, sydney, new south wales, australia 3 university of sydney, sydney, new south wales, australia 4 westmead millennium institute, westmead hospital, sydney, new south wales, australia introduction: while australia has the highest worldwide melanoma incidence, certain subpopulations are at extreme risk and early melanoma diagnosis is crucial. knowledge of the role of clinical imaging techniques in this group is somewhat limited. objective: to determine for high risk patients the natural history and role of total body photography (tbp) and sequential digital dermoscopy imaging (sddi) in early primary melanoma detection. method: 312 patients at extreme melanoma risk were monitored six monthly after baseline tbp over a 5 year period. inclusion criteria were ≥1 of: (1) cdkn2a or cdk4 mutation; (2) ≥3 1st/2nd degree relatives with prior melanoma and a personal history; (3) dysplastic naevus syndrome and a melanoma history; (4) history of ≥2 primary melanomas. all patients were screened against tbp at each visit with sddi short term (3 months) and long term (≥6 months) monitoring employed following established criteria and atypical lesions excised. results: the median follow-up time was 3.5 years (iqr: 2.4-4.2 years). 77 primary melanomas were detected, 16 at baseline visit and 61 subsequently. median breslow thickness was in situ melanoma (iqr: in situ-0.60mm). 39.3% were detected using tbp and 39.3% with sddi. six melanomas were ≥1mm breslow thickness (including three desmoplastic and one scalp melanoma). 142 bccs and 64 sccs were excised and the overall benign/malignant excision ratio was 1.4:1 and 4.2:1 for melanocytic lesions. conclusion: monitoring extreme risk patients with tbp and sddi assisted with the effective early diagnosis of primary melanoma. hyper-vigilance for difficult to detect thick melanoma subtypes is crucial. automated detection and analysis of pigment networks, streaks and scale for melanoma diagnosis on dermoscopic images maryam sadeghi1,2,3, tim k. lee1,2,3, david i. mclean3, harvey lui2,3, m. stella atkins1,3 1 school of computing science, simon fraser university, vancouver, canada 2 cancer control research and integrative oncology, bc cancer agency, vancouver, canada 3 photomedicine institute, department of dermatology and skin science, ubc, vancouver, canada introduction: with recent advances in skin imaging technologies there has been an increasing demand for image processing techniques in computer aided-diagnosis of pigmented skin lesions using dermoscopy images. our work follows a relatively new trend in clinical dermatology to identify specific ‘dermoscopic structures’ such as streaks, scale, and pigment network, which are used to aid the diagnosis of malig nant melanoma. method: irregular pigment network and streaks are two important positive features of melanoma and scale seems to be a negative feature based on our studies on the dry polarized contact dermoscopy. we present a novel approach to detect, segment, analyze and visualize pigment network, streaks, and scale in dermoscopic images, according to their clinical definitions. three important dermoscopic structures (pigment network, streaks, and scale) are modeled based on the structural (shape), geometric (spatial arrangement), chromatic and textural features defined by experts in dermoscopy. our approach has several steps; pre-processing that includes image enhancement and automatic skin lesion segmentation, object detection using morphologic techniques, and feature extraction and classification into irregular or regular structures. the presence and absence of these structures can be used for malignancy detection in skin lesions. results: our results over 945 images show an accuracy of 92% on pigment network detection, 82% on typicalatypical pigment network classification, 78.5% on streaks detection, 83.5% on regular-irregular streaks classification and 84% on scale detection. melanoma invasiveness depends on preventive behavior and total number of nevi. a retrospective study in 176 patients a. kardynal 1 , m. slowinska1, j. sicinska 1, m. maj1, a. rakowska1, j. czuwara1, e. kowalska-oledzka1, e. piekarczyk1, b. goralska-zaleska1, m. lukomska1, o. warszawik1, m. kurzeja1, a. wiergowska1, a. nasierowska-guttmejer2, l. rudnicka1,3 1 dept. dermatology csk mswia, warsaw, poland 92 supplement | dermatol pract concept 2012;2(2):16 2 dept. pathology csk mswia, warsaw, poland 3 faculty of health sciences, warsaw medical university, warsaw, poland introduction: high melanoma-related mortality rates remain a problem in poland. the aim of the study was to evaluate melanoma invasiveness depending on dermoscopy screenings, preventive behavior and clinical findings. method: a retrospective study based on revised medical records between years 2004-2011 and completed questionnaires of patients diagnosed with melanoma. results: in the analyzed timeframe 176 patients were diagnosed in our department with melanoma (57%-f, 43%m). a total of 38,4% were diagnosed as melanomas in situ. among invasive melanomas mean breslow thickness was 1.03 mm. about 80% of melanoma patients were phototype i-ii, what corresponds to usual numbers in polish population. a history of sun burns recorded 83,6% of patients with melanoma and 69,3% of healthy control. about 60% of patients had more than 50 nevi. in this group mean breslow thickness was 1,32 mm and 46,6% of melanomas were in situ. in patients with less than 50 nevi mean breslow thickness was 2,25 mm and 32,7% of melanomas were in situ. about 60% of patients were never screened for melanoma. in this group 35% of melanoma were in situ, and mean breslow thickness was 1,77mm (1,35 mm—f, 2,77 mm—m). within patients screened for melanoma at least once 49% of melanomas were in situ and mean breslow thickness was 0,89 mm -f and 1,18 mm—m patients. conclusions: thickness of melanoma (in breslow scale) is significantly lower in patients who had a history of at least one dermoscopy screening prior to diagnosis and in patients who have multiple nevi. dermoscopy use in the next generation: a survey of dermatology trainees p. piliouras1,2, p. buettner3, h.p. soyer4 1 department of dermatology, royal brisbane and women’s hospital, brisbane, queensland, australia 2 school of medicine, james cook university, townsville, queensland, australia 3 skin cancer research group, school of public health, townsville, queensland, australia 4 dermatology research centre, school of medicine, the university of queensland, brisbane, queensland, australia introduction: the use of dermoscopy is rapidly expanding. the dermatoscope is now used in everyday practice. we sought to investigate the use of dermoscopy in australian dermatology trainees. method: an invitation to complete a web-based survey was sent via e-mail. the survey was composed of a combination of questions from a standardized survey of the international dermoscopy society, a previous published dermoscopy survey of australian consultant dermatologists and questions posed by us. two-sided fisher’s exact tests, chi-square tests and exact chi-square tests for trend were used to assess differences between australian consultant dermatologists (n=99) and trainee dermatologists (n=44). a significance level of 0.05 was assumed. the statistical analysis was conducted using spss release 18 (ibm spss inc, chicago, il). results: the response rate was 55% (44 out of 88 trainees). there were  31.8% (n=14) male and 68.2%  (n=30) female respondents. the mean age was 33 years (sd=5.41). all respondents used dermoscopy with the majority (54.5%, n=24) using a dermatoscope for 3-5 years. when asked whether a dermatoscope was an essential tool for a trainee dermatologist, 95.5% (n=42) responded yes. when comparing consultants and trainees, there was a significant difference in their answers when questions concerning identifying melanoma early in the curable stage, use in non-pigmented tumours, helping to improve record keeping, documentation for medical liability and anticipation for future use of dermoscopy were asked (p<0.05). an index of diagnostic difficulty for malignant melanoma j. f. kre usch dermatological practice, luebeck, germany introduction: comparing diagnostic skills for identifying malignant melanoma strongly depends on characteristics of the tumors analyzed. for benchmarking diagnostic studies on melanoma the average tumor thickness is neither representing clinical nor dermoscopic difficulty of diagnosis. it is evident that an investigator encountering only large, dark and asymmetric lesions has to face less diagnostic problems as compared to another one excising small, symmetric and possibly hypopigmented melanoma, too. most important for cost efficiency in health care systems is the benign-malignant ratio of excisions with suspect of melanoma. comparing the ratios of different investigators cannot be made without taking diagnostic difficulty of the lesions into account. methods: a two-step procedure is presented including clinical as well as dermoscopic features contributing to the diagnostic difficulty of a given lesion. first, a lesion must be considered worthy of examination by dermoscopy. an index of clinical diagnostic difficulty characterizes these lesions. in a second step, certain dermoscopic criteria must be present to raise suspicion of malignancy. a score of features is presented to define diagnostic difficulty of melanoma for both steps. the index of diagnostic difficulty ranges from zero to infinite and thus comprises easy-to-diagnose classical supplement | dermatol pract concept 2012;2(2):16 93 melanoma as well as so-called featureless melanoma, fairly impossible to spot in the skin. examples are demonstrated. conclusion: in future studies, the average index of difficulty of melanoma with the study population should be calculated in order to compare benchmark results of various centres. is reflectance confocal microscopy a useful aid in diagnosis of regressive lesions? elisabeth m.t. wurm, edith arzberger, rainer hofmann-wellenhof department of dermatology, medical university of graz, austria regressive cutaneous lesions are a significant diagnostic challenge as they lack distinct clinical and dermoscopic features. reflectance confocal microscopy (rcm) is a tool for non-invasive diagnosis of melanocytic skin lesions that has been shown to be useful in diagnosis of non-pigmented skin lesions. little is known, however, about the value of rcm in diagnosis of regressive lesions. we will present a case series of regressive lesions including clinical, dermoscopic and rcm images as well as histopathological diagnoses, and discuss specific features that, in our view, might be of use in diagnosis of these challenging lesions. clinical and dermatoscopic characteristics of melanocytic nevi in turkish young people with 18-25 years old a. öztürk, e. arca, g. açıkgöz, z. kurumlu gülhane military medical academy, school of medicine, department of dermatology, ankara, turkey background and aim: melanoma is a malign tumor of the skin. malign transformation in the already existing nevus is the most seen etiological factor for melanoma. this study was done to determine the clinical and dermatoscopic characteristics of melanocytic nevi in turkish young people with 18-25 years old. material and methods: a total of 688 young people from the patients and students of gülhane military medical academy, school of medicine, and department of dermatology were included in the study. a questionnaire was applied including age, sex, sunblock use, and sunburn history. on clinical examination, we evaluated number of nevi, location of nevi and skin type. nevi that are equal or greater than 3mm were examined dermatoscopically, recorded and scored by using pattern analysis, abcd total dermoscopic score, 7 point checklist, menzies algorithm, 3 point checklist and cash algorithm. results: totally 668 young people were physically examined in this study (268 of which were women and 400 of which were men). the most common skin phototype in both sexes was type 3 (91.6% of women, 85.25% of men). a total of 453 nevi were examined dermatoscopically. the most common localization of nevi was on the head and neck region (n=144; 31.8%), followed by anterior trunk and abdomen (n=128; 28.3%), back (n=122; 26.9%) and extremities (n=45; 9.9%). the most common dermatoscopic global feature was the globular pattern (n=135; 29.8%), followed by reticular pattern (n=88; 19.4%), and cobblestone pattern (n=64; 8.8%). conclusion: this is the first study about the characteristics of melanocytic nevi at this age group and lays the foundation for future studies that will elucidate the relationship between nevi, dermatoscopic pattern and the other factors in a population-based cohort. dermoscopy of alopecia neoplastica r. m. bakos, t. s. souza, r. heck department of dermatology, hospital de clínicas de porto alegre, universidade federal do rio grande do sul, porto alegre, brazil introduction: alopecia neoplastica is a rare disorder that in most cases represents metastatic breast cancer. dermoscopy might be a useful tool in clinical evaluation. case report: a 72 year-old woman reported asymptomatic localized hair loss with a progressive course during the past 4 months. she presented a past history of breast adenocarcinoma diagnosed 5 years ago. on physical examination there was a mildly indurated, slightly erythematous plaque of alopecia on parietal scalp. dermoscopy reveals only overlying telangiectasias diffusely distributed. biopsy proved a metastatic carcinoma compatible with a mammary origin. discussion: in woman, breast cancer is the most common malignancy that metastasizes to the skin. alopecia neoplastica is a rare asymptomatic manifestation of cutaneous metastases and it might present as single or multiple slightly erythematous round plaques of alopecia, usually with peripheral telangiectasias. the clinical picture may mimic several dermatoses and therefore the diagnosis might be delayed. dermoscopy might be an important diagnostic tool, mainly on the exclusion of other dermatoses with already described dermoscopy patterns such as alopecia areata, which presents for example short “exclamation mark” hairs and yellow dots, discoid lupus erythematous, that shows follicular plugs and red dots, and tinea capitis, which exhibits broken and comma hairs. in conclusion, alopecia neoplastica is an uncommon cutaneous disease. although it lacks a characteristic dermoscopic pattern, dermoscopy might be helpful in its evaluation especially when dermoscopic features of other common dermatoses are not present and should lead dermatologists to perform histologic examination in such cases. 94 supplement | dermatol pract concept 2012;2(2):16 acral melanoma in spain; retrospective study of 275 cases in a referral center cristina carrera1,3, adrià gual1, alba díaz2, susanna nogués1, adriana p. garcía2, llùcia alós2, antoni vilalta1, josep palou1, susana puig1, 3, josep malvehy1, 3 1 melanoma unit, department of dermatology, hospital clínic de barcelona, idibaps, barcelona, spain 2 department of pathology2, hospital clínic de barcelona, idibaps, barcelona, spain 3 ciber enfermedades raras, instituto de salud carlos iii, barcelona, spain introduction: acral melanomas (am) can be misdiagnosed in early stages and it has postulated that the delay in the detection could be the main cause of a poor prognosis. methods: retrospective clinical-prognostic, dermoscopic and histopathologic review of am in a referral unit from 1986 to 2010. results: 275 am were included (61% women; mean age of 56y, range 12-96). the most frequent location was on feet (83%), 60% were ulcerated 20% achromic. dermoscopically (68 cases) multicomponent global pattern was the most frequent (35%), parallel ridge pattern could be identified in up to 50% of cases. more than 40% presented blue whitish veil and streaks. 60% of achromic tumours showed milky red areas and/or atypical vessels, and were correlated to higher breslow index. at the time of consultation in our unit all showed dermoscopic clues of malignancy. histopathologically they consisted in acral lentiginous melanoma (alm) 57%, superficial spreading (ssm) 30% (75% women), and nodular (nm) 6%. 24% were in situ melanomas whereas the mean breslow thickness of invasive cases was 3.02mm. in a mean follow-up of 55.16 months 27% died due to melanoma. prognostic factors by multivariate analysis were age at diagnosis, breslow, and histopathologic subtype. alm and nm presented a poorer outcome than ssm (or 10.95, p0.02). conclusions: diagnosis of am in our population is delayed and dermoscopy could help to identify difficult lesions, especially achromic tumours. in addition to misdiagnosis, subtypes of alm and nm presented a poorer prognosis after been adjusted by age and breslow. dermoscopy of common inflammatory skin diseases of the face m. maj1, m. kurzeja1, a. rakowska1, m.slowinska1, m. olszewska2, l. rudnicka1,3 1 department of dermatology, central clinical hospital mswia, warsaw, poland 2 department of dermatology, warsaw medical university, poland 3 faculty of health sciences, warsaw medical university, poland introduction: skin inflammation of the face can be caused by different factors such as infections, allergies, physical and chemical agents and reactions due to medications. skin inflammatory diseases are often accompanied by patches, blisters, dryness of the skin, burning and itching, which affect the appearance and texture of the skin. differential diagnosis may be difficult. we investigated, whether dermoscopy may aid differential diagnosis of inflammatory skin diseases of the face. method: a total of 50 patients with nummular lesions on the face were included into the study (pemphigus vulgaris, pemphigus foliaceous, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, atopic dermatitis, psoriasis, seborrheic dermatitis, rosacea, tinea, pityrosporum folliculitis, sycosis). videodermoscopy was performed with fotofinder 2. results: in dermoscopy of pemphigus vulgaris and pemphigus foliaceous we observed: bloody-red, sharply demarcated, polygonal areas, glomerular vessels and peripherally attached linear scales. in discoid lupus erythematosus most characteristic dermoscopy features were: thick arborizing vessels, fine scaling and large, keratotic plugs. in seborrheic dermatitis fine arborizing vessels and yellowish scaling were most prominent. dermoscopy of psoriasis showed regularly distributed globular vessels. uv-enhanced dermoscopy (uved) may be beneficial in differential diagnosis of microsporum canis infections and pityrosporum folliculitis. in conclusion, dermoscopy may be applied in differential diagnosis of inflammatory diseases of the face. cutaneous malignant melanoma metastases (cmmm): dermoscopic features and differential diagnosis karem ortiz, joanne costa, gabriel salerni,valeria borges, cristina carrera, susana puig, josep malvehy melanoma unit, department of dermatology, hospital clinic, barcelona, spain cutaneous metastases of melanoma can be confused with other skin lesions. dermoscopy could be helpful in the differential diagnosis. we described the distinctive dermoscopic patterns of cmmm assessing their sensitivity and specificity performing a retrospective study of 146 dermoscopic images of cmmm from 42 patients attended in our institution since 2002 to 2009. first, two investigators established six dermoscopic patterns of cmmm. the correlation of 75 dermoscopic images with their distinctive patterns was assessed by 4 independent dermatologists. finally, a pool of 163 dermoscopic images including cmmm and non-metastatic lesions were evaluated by the same four dermatologists in order to assess supplement | dermatol pract concept 2012;2(2):16 95 the diagnostic utility of the dermoscopic patterns to recognize cmmms. the six dermoscopic patterns of cmmm were blue nevus-like, nevus-like globular and non-globular, angiomalike, vascular and unspecific. when cmmm were classified accordingly to these patterns, agreement between the investigators and the four dermatologists ranged from κ = 0.56 to 0.7. the interobserver agreement was good (> 80% for angioma-like, nevus-like and blue nevus-like patterns). 71 cmmm, 16 angiomas, 22 blue nevus, 15 malignant melanoma (unspecific or globular pattern), 11 seborrheic keratosis, 15 melanocytic nevus with globular pattern and 13 pink lesions with vascular pattern were evaluated by 4 dermatologists showing an overall sensitivity of 68% (between 54.9-76%) and specificity of 80% (between 68.593.5) for the diagnosis of cmmm that varies according to the experience of the observer and point out the difficulty in the identification of some metastases. nevertheless, the majority of the lesions were correctly identified as cmmms. references 1. bono r, giampetruzzi ar, concolino f, et al. dermoscopic patterns of cutaneous melanoma metastases. melanoma res. 2004;14(5):367-73. 2. minagawa a, koga h, sakaizawa k, et al. dermoscopic and histopathological findings of polymorphous vessels in amelanotic cutaneous metastasis of pigmented cutaneous melanoma. br j dermatol. 2009;160:1134-6. an innovative primary care physician training program in dermoscopy in underserved and rural communities in pennsylvania r. i. neves1, l. kanzleiter-keister2 1 penn state hershey melanoma center, pennsylvania state university, department of surgery, division of plastic surgery. hershey, pennsylvania, usa 2 department of family and community medicine, pennsylvania state university, college of medicine. hershey, pennsylvania, usa pennsylvania is a very rural state within the united states with many health care concerns. of the 67 counties within the commonwealth, 52 are designated as primary care shortage areas with significant concerns of access to primary health care services. the economic backbone of this state is agriculture, lumbering and mining, which require long hours of exposure to the environment. health indices of the commonwealth demonstrate an increase in skin cancer and melanoma incidence. with a minimum of six months or greater to schedule an appointment with a dermatologist, the department of family medicine and the penn state hershey melanoma center developed an education and training program for primary care physicians in dermoscopy to: develop an educated primary care physician workforce in rural and underserved areas skilled in the use of dermoscopy increase access to screening and early detection interventions for skin lesions through primary care to prevent progression of the disease decrease cost to health care interventions through early detection and better diagnosis accuracy this workshop describes the educational content, instructional methods and evaluative processes used to train primary care physicians to become competent and skilled in the use of dermoscopy and confident in the delivery of primary and secondary interventions. the facilitator also explore the lessons learned in the pilot dermoscopy training session implemented in the department of family and community medicine at penn state college of medicine which served to frame the changes in curriculum and instructional media applied in the first training series. references 1. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24:1877-82. 2. carli p, de giorgi v, crocetti e, et al. improvement of malignant/ benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150:68792. teledermoscopy using handheld dermoscope coupled with smartphone john paoli1, alex börve2, carin sandberg1, karin terstappen3 1 department of dermatology, sahlgrenska university hospital, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 department of orthopaedics, sahlgrenska university hospital, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, gothenburg, sweden 3 department of dermatology, kärnsjukhuset, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, skövde, sweden new mobile phones, so-called smartphones, with builtin digital cameras used in combination with customized dermoscopes can hopefully be used to carry out teledermoscopic evaluations of suspicious skin lesions. in this study, we included 69 melanocytic and non-melanocytic lesions in which malignancy was suspected upon clinical and dermoscopic examination by a dermatologist during a face-to-face visit. prior to biopsy or excision, clinical and dermoscopic digital photographs were taken with a smartphone and a dermoscope that could be fitted directly onto the smartphone. the suspected diagnosis, the level of diagnostic difficulty and the management decision was provided and later 96 supplement | dermatol pract concept 2012;2(2):16 compared to the histopathological report. furthermore, the image quality was assessed. these same parameters were also provided by two experienced dermoscopists who independently reviewed the clinical and dermoscopic photographs together with relevant clinical information but without seeing the patient and without knowledge of the histopathological report. we will report on the diagnostic accuracy of the dermatologist meeting the patient face-to-face compared to histopathology, the diagnostic accuracy of the two teledermatologists, the interobserver agreement between the two teledermatologists and between the teledermatologists and the dermatologist meeting the patient face-to-face. we will also present the image quality of this innovative dermoscopic technology and discuss the potential of using this method for teledermoscopy between primary care physicians and dermatologists. teledermoscopy in serbia: more than two years of experience in five centers j. bandic1, d. dobrosavljevic2, b. spasic3, s. cvetkovic3, s. dimitrijevic3, m. davidovic3, lj. stanisic3, s. kovacevic4, s. jesic5, d. nikolic6, s. rogozarski7, t. reza7, z. manasijević7, z. ceranic3, s. vjetrov7, m. bandic1, m. strbac1, m. surla1 and m. vasilevski1 1 ors hospital belgrade, belgrade, serbia 2 klinicki centar srbije, belgrade, serbia 3 opsta bolnica leskovac, leskovac, serbia 4 s-medica loznica, loznica, serbia 5 dermatolog, uzice, serbia 6 kbc bezanijska kosa, belgrade, serbia 7 dom zdravlja pancevo, pancevo, serbia introduction: teledermoscopy is a rapidly developing field of dermatology and teledermatology. many studies have described its advantages and disadvantages with special emphasis to shorten waiting lists, make dermatologist consultation easy accessible and in reducing the costs of examination of pigmented skin lesions (psl). a non-commercial teledermatology network based on store-and-forward operation was established in serbia in 2009. method: six dermatologists, two surgeons and three general practitioners trained in dermoscopy from five towns in serbia equipped with teleskin teledermoscopy system® obtained clinical and dermoscopic images of the suspicious psl. the images were sent using store-and-forward system in order to obtain expert second opinion and recommendation concerning excision of the psl. results: total of 2528 patients with 3153 psl was enrolled into the study from july 1st 2009.—december 1st 2011. dermoscopical diagnoses were: 1800 melanocytic nevi, 84 melanomas, 697 seborrheic keratoses, 122 angiomas, 87 dermatofibromas and 341 basocellular carcinomas. interobserver agreement between dermatologists and experts was a perfect agreement (first and second opinion) for melanoma k value > 0.89 (0,79—0,92), for melanocytic nevus k value > 0,92 (0,85—0,94), for seborrheic keratosis k value > 0,89 (0,75—0,92), for angioma k value > 0,93 (0,78— 0,96), for dermatofibroma k value > 0,86 (0,49—0,94) and for basal cell carcinoma k value > 0,95 (0,84—0,98 ). between general practitioners and experts, moderate to perfect (0,60—0,92) agreement was obtained for most of the lesions. and at the end, between surgeons and experts, k value was substantial to perfect (0,67—0,83) for all lesions. conclusion: in our experience, this large teledermoscopy study provided data that teledermoscopy is more reliable concerning melanocytic lesions vs. non-melanocytic lesions. apart from its teaching potential, the use of teledermoscopy as a triage tool offers the potential to improve the healthcare access and delivery, both in general practice and on specialist level. references 1. tan e, oakley a, soyer hp, haskett m, marghoob a, jameson m and rademaker m. interobserver variability of teledermoscopy: an international study. br j dermatol. 2010;163: 1276-81. 2. fabbrocini g, balato a, rescigno o, mariano m, scalvenzi m, brunetti b. telediagnosis and face-to-face diagnosis reliability for melanocytic and non-melanocytic ‘pink’ lesions. j eur acad dermatol venereol. 2008;22:229-34. dermoscopic findings in biopsyproven poromas: a case series a. shalom1, o. schien1, c. landi2, a. marghoob3, b. carlos4, a. scope3,5 1 department of plastic surgery, assaf harofeh medical center, zerifin, israel 2 dermatologic unit, surgical department “infermi” hospital, rimini, italy 3 dermatology service, memorial sloan-kettering cancer center, new york, ny, usa 4 dermatology service, hospital de especialidades, mexico city, mexico 5 dermatology department, sheba medical center, ramat gan, israel background: poromas are often misdiagnosed as skin cancers. objectives: to describe clinical and dermoscopic features of biopsy-proven poromas. methods and materials: biopsy-proven poromas were retrospectively collected from image-database of four hospitals. data collected included patient’s demographics and anatomic location of lesions. clinical and dermoscopic images were analyzed. supplement | dermatol pract concept 2012;2(2):16 97 results: in all, 19 patients (10 males, mean age 64, range 35-90 years) contributed 19 biopsy-proven poromas. nine lesions (47%) were on the foot and 10 (53%) on leg, thigh, trunk or face. mean size was 7.8 mm; plantar poromas were larger than poromas elsewhere on the body (10 versus 5 mm, p<0.01). on dermoscopy, common vascular patterns were glomerular vessels in 10 cases (53%), looped in 9 (47%) and leaf and flower-like vessels in 8 (42%). additional dermoscopic features included structureless areas in 15 cases (79%) and interlacing white cords in 9 (47%). in retrospective search through image-database of 5200 excised lesions, interlacing white cords were found in 2of 201 melanomas (2%). conclusions: among biopsied poromas, about half arose on non-acral skin. leaf and flower-like vessels may be a unique dermoscopic feature of poromas. while interlacing white cords are commonly seen in poromas, they are rarely seen in melanoma. grey-blue areas in the melanocytic lesions: how important are they? rodica cosgarea, loredana ungureanu department of dermatology, university of medicine “iuliu hatieganu” cluj-napoca, romania introduction: the dermatoscopic structures, which are suggestive for melanoma, are in general well defined and some of them have a stronger diagnostic value. the blue or grey-blue colour can be found in some melanomas but also in some melanocytic nevi. method: we evaluated the dermoscopies of 152 melanomas and 123 atypical nevi recommended for excision. the melanoma group was divided in four subgroups in accordance with the thickness of melanoma: in situ, under 1 mm, between 1-2 mm and more than 2 mm. we registered the following dermatoscopic structures: grey-blue areas with different patterns (globules, net with lines and holes, structureless, grey dots with peppering aspect), blue-whitish veil and white areas. we analyzed the frequency of every structure in each group of lesions. results: we found that grey-blue areas are high suggestive for melanoma in all the four types of patterns: the reticular ones are most frequently encountered in thin melanomas and the structureless blue areas in thicker melanomas. the whitish-blue veil was most frequently found in the thicker melanomas. the blue areas were also found in dysplastic nevi but in a lower degree in comparison with melanomas. conclusions: the grey-blue structures are relevant for melanoma in high degree, even for very thin melanomas. references 1. bassoli s, borsari s, ferrari c, et al. grey-blue regression in melanoma in situ-evaluation on 111 cases. j skin cancer. 2011; 2011:180980. 2. massi d, de giorgi v, et al. diagnostic significance of the blue hue in dermoscopy of melanocytic lesions. am j dermatopathol. 2001;23(5):463-9. is it necessary to perform eye examination for patients with cutaneous dysplastic nevi? i. kilinc karaarslan a. yagcı 2, a. tuna t. ozkapu m. palamar2, f. ozdemir1 1 ege university, medical faculty, department of dermatology, izmir, turkey 2 ege university, medical faculty, department of ophthalmology, izmir, turkey introduction: regular dermatological examination for patients with dysplastic nevi is indicated. however, the literature on whether those patients should also be examined by ophthalmologists or not regarding a relation between ocular melanoma and cutaneous dysplastic nevi is limited. in this study we aimed to screen the eyes of our patients who had been followed-up with the diagnosis of cutaneous dysplastic nevi. method: we examined the eyes of 110 patients with dysplastic nevi (47 had the diagnosis of dysplastic nevus syndrome type a, b, c, d1 or d2) for any lesion and compared the results with a control group consisted of 110 sex, age and skin-type matched patients without a diagnosis of dysplastic nevi or melanoma. results: no ocular melanoma was detected in any of the groups. the frequency of the conjunctival nevi, iris nevi, choroidal nevi and conjunctival acquired melanosis were similar in both groups. iris freckles were detected more frequently in the study group. conjunctival racial hyperpigmentation was detected more frequently in the control group (p<0.05). references 1. toth-molnar e, olah j, dobozy a, hammer h. ocular pigmented findings in patients with dysplastic naevus syndrome. melanoma res. 2004;14(1):43-7. 2. hurst ea, harbour jw, cornelius la. ocular melanoma: a review and the relationship to cutaneous melanoma. arch dermatol. 2003;139(8):1067-73. dermatoscopic features of a series of non-facial non-acral lentiginous growth pattern melanomas jeffrey keir northern rivers skin cancer clinic, ballina, new south wales, australia introduction: dermatoscopic features of facial lentigo maligna (lm) and acral lentiginous melanoma are well described. lentiginous growth pattern (lgp) melanoma, including lm, is increasing in diagnostic incidence but the 98 supplement | dermatol pract concept 2012;2(2):16 dermatoscopic features of non-acral non-facial lgp melanomas are not yet described. early recognition of lgp melanomas is important, as these tend to lack braf mutations that are a target of therapies for metastatic melanoma. method: a 12-month case series of melanomas detected in a primary care skin cancer clinic was imaged clinically and dermatoscopically before biopsy. dermatoscopic images were assessed for proposed clues to lgp melanoma, including: lentigo-like pigment patterns associated with a lack of lentigo-like border; atypical follicular pigmentation patterns; geometric/polygonal pigment patterns and grey structures. the results of this were compared for statistical significance between groups of non-facial non-acral melanomas categorised by the following histologically reported growth patterns: lgp, mixed lentiginous and nested growth pattern, and superficial spreading melanoma (ssm). results: 66 melanomas (12 invasive) were diagnosed in 59 patients: 11 facial, 1 acral, 54 non-facial/non-acral (23 lgp, 13 mixed pattern, 14 ssm, 1 desmoplastic, 3 not specified). the following were associated with non-facial nonacral lgp and mixed pattern melanomas over ssm: a disorganized lentigo-like pigment pattern lacking a lentigo-like border (p<0.001); atypical follicular pigmentation patterns (p<0.05); and rhomboidal shapes (p<0.05). mixed pattern melanomas and ssm were more likely to have structureless pink areas than were lgp melanomas (p<0.05). ssm were more likely to be invasive at diagnosis (p<0.05). conclusion: lgp melanomas may have a specific pattern of dermatoscopic features. further multicentre study is required. dermoscopic features of clear-cell acanthoma g. lyons1, a. j. chamberlain2, j. w. kelly2 1 occupational dermatology research and education centre (odrec), skin and cancer foundation, melbourne, australia 2 the victorian melanoma service, the alfred hospital, melbourne, australia background: clear-cell acanthoma is a rare benign epidermal tumour. the dermoscopic features appear fairly unique. objectives: to delineate the key features of clear-cell acanthoma on dermoscopy. methods: we reviewed the dermoscopic features of all published cases of clear-cell acanthoma in the literature to date and report 4 new cases of our own. results: all cases featured scattered pinpoint dotted or larger red globules. the majority of cases showed the typical ‘string of pearls’ or linear arrangement. this characteristic linear arrangement of red globules is ultimately reticular and strikingly symmetric when fully developed. in some cases, the pattern is incomplete or partly developed but still recognisable. other features such as crusting, hyperkeratosis or a peripheral collarette may be present. conclusion: clear cell acanthoma has distinctive dermoscopic features that help in reaching a confident clinical diagnosis and minimizing the need for biopsy. reference 1. degos r, civatte j. clear-cell acanthoma. experience of 8 years. br j dermatol. 1970;83:248-54. dermoscopic characteristics of merkel cell carcinoma c. jalilian, a. j. chamberlain, m. haskett, c. rosendahl, j. keir, h. beck, p. varghese, m. goh, a. mar, s. hosking, i. hussain, c. mclean, j. w. kelly victorian melanoma service, the alfred hospital, melbourne, australia merkel cell carcinoma (mcc) is an aggressive cutaneous malignancy with a high mortality rate. diagnosis is often delayed. no case series analysing the dermoscopic features of mcc have been published. clinical and dermoscopic images of biopsy proven mccs were analysed in a retrospective manner with existing dermoscopic criteria being scored independently by three dermatologist. the most frequent clinical features were cherry red colour, shiny and wellcircumscribed nodules. significant dermoscopic features include linear irregular and poorly focused vessels, milky pink areas, white areas and architectural disorder. pigmented structures were absent for all lesions. the dermoscopic features described here should help achieve earlier diagnosis of mcc, which facilitates timely treatment. dermoscopic aspects of cutaneous gastric carcinoma metastases r. m. bakos, g. f. escobar, j. ribar, m. q. tubone department of dermatology, hospital de clínicas de porto alegre, porto alegre, brazil cutaneous metastases might be the initial presentation of internal malignancies in 22% of patients. 1 up to 10% of all visceral malignant tumors develop cutaneous metastases, which represent 2% of all skin tumors. however, skin metastases from signet ring cell gastric carcinoma are uncommon. we present the dermoscopic aspects of a patient with gastric adenocarcinoma and multiple skin nodules. case report: a 55-year-old man presented with a progressive generalized cutaneous eruption. examination revealed asymptomatic small erythematous firm nodules. dermoscopy showed a polymorphous vascular pattern. one supplement | dermatol pract concept 2012;2(2):16 99 year prior to this event, this patient had been submitted to a partial gastrectomy due to a poorly differentiated, diffuse type, signet-ring cell gastric adenocarcinoma. histologic and immunohistochemical studies of the lesions confirmed progression of the neoplasia to the skin. discussion: few reports have described the dermoscopic features of non-melanoma cutaneous metastases. an atypical vascular pattern was observed in one report of skin metastases of thyroid carcinoma and this feature was considered pathognomonic for neoplastic neovascularization, both benign and malign, concluding that such lesions should be biopsied. to our knowledge, no reports analyzed the dermoscopic features of gastric carcinoma metastases. we observed a prominent atypical vascular pattern, demonstrating that this feature might also be observed in nodular lesions of cutaneous metastases of gastric carcinoma. this report emphasizes that cutaneous metastases of internal malignancies might have its initial presentation on the skin and that dermoscopy is an important diagnostic tool in evaluating such lesions. references 1. nashan d, müller ml, braun-falco m, reichenberger s, szeimies rm, bruckner-tuderman l. cutaneous metastases of visceral tumours: a review. j cancer res clin oncol. 2009;135:1-14. 2. de giorgi v, alfaioli b, massi d, et al. solitary cutaneous metastasis as the first sign of relapse of thyroid carcinoma: a clinical, dermoscopic-pathologic case study. dermatol surg. 2009;35:523-6. 3. aneiros-fernandez j, husein-elahmed h, arias-santiago s, et al. cutaneous metastasis as first clinical manifestation of signet ring cell gastric carcinoma. dermatol online j. 2010;16:9. dermoscopic aspects of extragenital lichen sclerosus r. m. bakos, g. f. escobar, a. c. fischer, a. cartel department of dermatology, hospital de clínicas de porto alegre, porto alegre, brazil lichen sclerosus (ls) is an unusual chronic inflammatory skin disease. although it may affect all areas of the body, only 15% compromises the extragenital area. initial lesions are porcelain white papules, plaques or atrophic patches. we present the dermoscopy aspects of two patients with extragenital le. case report: patient 1: a 19-year-old woman, presented with a 2-year history of two pruritic whitish plaques on her left upper back. dermoscopy showed a whitish-pink background, surrounded by linear vascular structures and hairpin-like vessels. yellowish areas were also visualized. patient 2: a 59-year-old woman, presented with a 5-month history of asymptomatic hyperchromic plaques on her axillas. dermoscopy showed irregularly distributed black granules, predominantly over whitish areas. discrete follicular plugging was also observed. discussion: dermoscopy of extragenital lichen sclerosus has been described in previous reports. garrido-ríos et al studied four women with extragenital ls and described, as major dermoscopic findings, whitish areas with comedo-like openings in the center of the lesions, which corresponded to follicular plugging and atrophy of the epidermis. moreover, kimura et al reported one case, with comedo-like openings, telangiectasias on a whitish-pink background and red-violet to brown-red perifollicular ovoid structures, corresponding to follicular plugging. in our patients, we observed linear vascular structures, hairpin-like vessels and irregularly distributed black granules, predominantly over whitish areas. contrasting with the prior descriptions, follicular plugging was discrete. in conclusion, we present a different dermoscopic pattern of extragenital le, which may aid the clinical diagnosis of this unusual skin disorder. references 1. monsálvez v, rivera r, vanaclocha f. lichen sclerosus. actas dermosifiliogr. 2010;101:31-8. 2. kimura a, kambe n, satoh t, togawa y, suehiro k, matsue h. follicular keratosis and bullous formation are typical signs of extragenital lichen sclerosus. j dermatol. 2010;38:834-6. 3. farris dr, hardy d, kagen mh, don pc, weinberg jm. extragenital pigmented lichen sclerosus. j eur acad dermatol venereol. 2000;14:322-4. 4. garrido-ríos aa, alvarez-garrido h, sanz-muñoz c, aragonesesfraile h, manchado-lópez p, miranda-romero a. dermoscopy of extragenital lichen sclerosus. arch dermatol. 2009;145:1468. double comparison of teledermoscopy: interobserver variability and relation to histopathology j. bandic¹, d. dobrosavljevic², i. drljevic³, n. pesic4, s. kamberova4, d. nikolic,1 m. strbac1, n. vuckovic5, z. janjic5, m. bandic¹ 1 ors hospital belgrade, belgrade, serbia 2 klinicki centar srbije, beograd, serbia 3 klinicki centar univerziteta u sarajevu. bosnia and herzegovina 4 klinicki centar skopje, skopje, macedonia 5 klinicki centar vojvodine, novi sad, serbia introduction: teledermoscopy, with all its pros and cons, allows for a grand entrance of new perspectives, and not only for pigmented skin lesions (psl). regardless of good interobserver concordance, literature still lacks the data about the comparison of teledermoscopic diagnoses to histopathologic (hp) ones. method: 5 experts from different centers in serbia, bosnia and herzegovina, and macedonia are included in the study. during a two-month period, they will establish clinical and dermoscopic diagnoses on 1000 patients with 1000 histologically verified pigmented skin lesions, through use of the 100 supplement | dermatol pract concept 2012;2(2):16 teledermoscopy network. 1000 psl contain: 130 melanomas, 230 basal cell carcinomas, 450 melanocytic lesions, 150 seborrheic keratoses, 20 angiomas and 20 dermatofibromas. each patient has, other than personal, the following data: age, sex, skin phototype and melanoma risk factors. each lesion has: a clinical image, anatomic localization, abcde clinical information and a dermoscopic image. design of the study: in the course of 2011 jadran bandic has selected the material for the study from the ors hospital database in belgrade. during the period spanning february 1 to april 1 2012, marijana bandic will include 20 new cases daily (100 per week, over the course of 10 weeks with week 11 reserved for cases that get left behind for any reason) into the teledermoscopy network. clinical diagnosis will be the one to be established first, with the dermoscopic image being made available for review and diagnosis after the clinical diagnosis has been made. clinical diagnosis will not be made available for correction. results: the study will show results of accordance amongst experts in relation to hp diagnosis, for every psl type and not only the relation between dermoscopic vs. hp diagnosis, but also relation between clinical and hp diagnosis. discussion: we believe that the right path for teledermoscopy is to be directed towards primary healthcare. in order for that path to be realised it is necessary for experts to provide background education and quick an efficient control, until the arrival of an automated process. the validity of this opinion will be pointed out by the expected results. references 1. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for pigmented neoplasms. j am acad dermatol. 2009;61:753– 65. 2. tan e, yung a, jameson m, et al. successful triage of patients referred to a skin lesion clinic using teledermoscopy (image it). br j dermatol. 2010; 162:803–11. early melanoma with halo eczema (meyerson’s phenomenon) lisa byrom1, karl rodins2, and jim muir3 1 m.b.b.s, b. physio., intern, mackay base hospital, mackay australia. 2 m.b.ch.b., f.r.c.p.a., dermatology registrar, greenslopes hospital, brisbane australia. 3 m.b.b.s., f.a.c.d., dermatologist, mater hospital and private practice, brisbane australia. we present a case of a 49-year-old man who presented with a solitary atypical pigmented lesion with a surrounding halo of dermatitis. dermoscopy showed a pigment network at the periphery with areas of scar-like depigmentation, negative pigment network and erythema. the lesion was treated preoperatively with a potent topical corticosteroid resulting in a reduction of inflammation. histology showed an early clark level 1 melanoma arising within a severely dysplastic compound melanocytic naevus. there was an adjacent perivascular chronic inflammatory cell infiltrate with occasional eosinophils. minimal, though definite spongiosis with parakeratosis was also present. the scar was subsequently re-excised achieving appropriate excision margins for melanoma in situ. six months later, there was recurrence of dermatitis at the scar with no evidence of recurrent melanoma. to our knowledge, melanoma with meyerson phenomenon has not been reported in the literature. this case highlights that all lesions should be evaluated on clinical and dermoscopic grounds regardless of the presence or absence of eczema. our case adds yet another entity that may display meyerson phenomenon and consequently a halo of eczema cannot be considered a reassuring sign when evaluating melanocytic lesions. analysis of cdkn2a alelic variants in mexican patients with malignant melanoma: preliminary study b. carlos-ortega1, j. lópez-valdez2,3, g. gómez1, h. urueta-cuellar4, j. toral-lópez5, l. marques-valdemar6, s. cuevas-covarrubias4, l. gonzález-huerta4 1 centro médico nacional “la raza” imss,1 méxico 2 d.f. hospital centenario miguel hidalgo, aguascalientes, méxico 3 universidad cuauhtémoc aguascalientes, aguascalientes, mexico 4 hospital general de méxico, méxico 5 d.f. centro médico ecatepec, cuernavaca, méxico 6i ssemym, instituto de biología, unam, méxico, d.f. background: cdkn2a and ck4 are high penetrance genes associated to high risk of melanoma. cdkn2a is a tumor suppressor gene located in 9p21, it is composed by 4 exons, which code for p14 and p16. isoform p16 acts as a tumour suppressor gene, which binds to cdk4 and cdk6, inhibiting linking with cycline d1, thus avoiding both formation of cdk/cycline d1 complex and cell cycle. cdkn2a is inactivated by some different ways: intragenic mutations, homocygotic deletion and cpg islands hypermetilation on its promoter causing some different neoplasms such as pancreatic adenocarcinoma and malignant melanoma. aim: to identify alelic variants which could (or could not) influence risk (predisposition) of mm in mexican patients. materials and methods: genomic dna was obtained from peripheral blood samples. alpha isoform codifying region of cdkn2a was amplified, after that automatized sequenciation in a abi310 sequencer was performed. results: twenty-eight patients with mm analysis of codifying and intronic regions of p16 showed 2 polymorphous supplement | dermatol pract concept 2012;2(2):16 101 heterocygotic variants: c.-2g>a in 4 patients with mm and p.i49t in 11 patients with mm. both variants were also identified in healthy controls. conclusions: our study found 2 different variants in melanoma patients: c.-2g>a which-–to our knowledge—has not been reported and p.i49t which partially influences in the binding to cyclin d1-cdk4/6 complex, and inhibition of cellular growth and proliferation. as well as presence of other alelic variants in genes involved in melanoma development, considering also studying influencing environmental factors. shiny white streaks in malignant melanoma: a sign of thick tumours cristina carrera, priscilla ishioka, danielle shitara, yarel alonso-pinedo, leyla palacios-bejarano, susana puig, josep malvehy melanoma unit, department of dermatology, hospital clínic de barcelona, idibaps, barcelona, spain ciber enfermedades raras, instituto de salud carlos iii, barcelona, spain introduction: in the context of melanocytic tumours white shiny streaks (sws) or chrysalides have been related to malignant melanoma. it still remains unclear the biological significance of this dermoscopic criterion. methods: systematic study of sws in 125 melanomas (56% in situ; 44% invasive with mean breslow 1.7 mm (48%<1mm)) and 305 melanocytic nevi consecutively excised in a melanoma unit of a referral hospital in barcelona. results: sws were present in 5 nevi (4.67%) compared to 41 melanomas (38,32%) (24 ssmm (58,5%), 11 lmm (26.8%), 3 nm (7.4%), 3 others (7.3%)). the presence of sws correlated with a 10.33 fold risk of harboring a diagnosis of invasive melanomas when compared to in situ melanomas (or: 10.33, ic 95% 3.812-28.014, p<0.005). among invasive melanoma, sws had 4.46 fold risk to be thick melanomas (breslow>1mm) (or 4.46, ic95% 1.444-13.792 p=0.009). sws were also observed more frequently in mm with black (p<0.05), gray, white or red colours (p<0.001); structureless area, blue whitish veil, regression, atypical blotch, multicomponent (all p<0.001) or unspecific pattern (p<0,05), polymorphic vessels and milky red globules (both p<0.001) but not with dotted vessels (p =0.792). the mean tds score for melanomas with sws was 6.61 and without sws 5.62 (p<0.05). sws were also observed in 3 cases with tds <4.75 (3.8%). conclusions: sws in the context of a melanocytic tumour is associated to malignancy, and to invasive melanoma, with a higher breslow thickness and higher tds. in some few cases the presence of sws was seen in mm with tds of benignity. use of dermoscopy as aid for the diagnosis of extramammary paget disease (empd), and clinical assessment after brachytherapy a. m. carrozzo1, p. donati2, l. muscardin2, a. distefani1,3, c. cipriani4, f. a. sedda5, 1 department of dermatology, university of tor vergata, rome, italy 2 department of dermatopathology, ircss san gallicano rome, italy 3 department of anatomic pathology, university of tor vergata, rome, italy 4 department of nuclear medicine, s. eugenio hospital, rome, italy 5 department of uttmat, enea, casaccia, italy extramammary paget’s disease (empd) is a rare, usually non-invasive intraepithelial adenocarcinoma, preferentially localized on genitals in postmenopausal women in their sixth-seventh decade of life. empd may or may not be associated with an underlying malignancy. the diagnosis is obtained by histopathology and immunohistochemistry. in the last few years, dermoscopy, besides pigmented lesions, has been increasingly employed also for the evaluation of non-pigmented skin tumours and inflammatory diseases, such as for assessment after therapies. we report five cases of empd: 4 women and 1 man, aged from 65 to 79 years old, with lesions localized on the vulva, perianal region and glans penis, which we evaluated by dermoscopy. in 5/5 cases, dermoscopic examination revealed a repetitive pattern characterized by a diffuse pinkish background mottled with crimson and bright white irregular structures, grossly mixed together, occasionally forming a sort of thick reticulation; this picture was reminiscent for us of a raspberry slush. in all 5 cases histopathology subsequently confirmed the diagnosis of empd. whereas there is no standard treatment, as alternative to surgery, we treated our patients by superficial brachytherapy. this new therapy, successfully utilized for non-melanocytic skin tumors, basically consists in a superficial high dose brachytherapy, characterized by the use of a radioactive betaemitting isotope, rhenium188, incorporated in a specially formulated inert synthetic resin. an histological examination confirmed the clinical-dermoscopic healing of our patient’s lesions. thanks to dermoscopy, we could better identify the extent of the tumor and follow up our patient after therapy. imaging of an atypical naevus spilus with in vivo confocal microscopy e. coates1,2,3, m. laing1, p. guitera1,3 1 sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, new south wales, australia 102 supplement | dermatol pract concept 2012;2(2):16 2 department of dermatology, royal prince alfred hospital, sydney, new south wales, australia 3 university of sydney, sydney, new south wales, australia introduction: naevus spilus, or speckled lentiginous naevus (sln), is characterised by darkly pigmented macules or papules on a background of light-brown pigmentation. it is usually present at birth as a “café-au-lait” macule, with often widespread darker pigmented macules developing years to decades later. the importance of close follow-up is underlined by case reports of melanoma developing within naevus spilus. case summary: a 54-year-old lady with no prior melanoma history presented with a pigmented lesion on her lateral thigh present since birth. clinical examination revealed a 4x5cm café-au-lait macule with superimposed maculopapular speckles, consistent with naevus spilus. dermoscopy showed a darker focus within the lesion though no classic features of melanoma. in-vivo reflectance confocal microscopy demonstrated multiple atypical bright large cells with upward migration consistent with melanoma-in-situ. the remainder of the lesion contained only monomorphous small bright cells organised around a very regular papillae ring. histopathology of a biopsy taken from the atypical area noted could not exclude a melanoma-in-situ. conclusion: malignant melanoma arising in a naevus spilus is a rare event. the café-au-lait macule is often present at birth and the darker pigmented speckles that develop subsequently in number and size over many years are challenging to monitor. in-vivo confocal microscopy is a well proven laser imaging technique for pigmented lesions, allowing non-invasive examination of the epidermis. we propose its use in identification of areas of dynamic change in clinically and dermoscopically equivocal lesions, thereby assisting in the early detection of melanoma arising in naevus spilus. melanoma detection in high risk patients: a case series e. coates1,2,3, f.j. moloney1,2,3, p. guitera1,3, n. haass1,2,3, k. ho1, r. khoury1, g. mann3,4, s.w. menzies1,3 1 sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, new south wales, australia 2 department of dermatology, royal prince alfred hospital, sydney, new south wales, australia 3 university of sydney, sydney, new south wales, australia 4 westmead millennium institute, westmead hospital, sydney, new south wales, australia introduction: australia has the highest worldwide incidence of cutaneous melanoma. certain subpopulations are at extreme risk and early detection in this group is critical to reducing disease mortality. clinical imaging techniques permit early melanoma diagnosis and improved patient prognosis. regular patient and doctor examination of total body photography (tbp) baseline images enables identification of changing or new skin lesions. sequential digital dermoscopy imaging (sddi) additionally permits the capture and assessment of successive dermoscopic images over short term (average 3 months) or long-term (≥6 months) intervals to assess for morphological change and permits detection of still featureless incipient melanomas. case series: a melanoma case series of high risk patients diagnosed with melanoma through sddi monitoring is presented from a 312 patient cohort managed in the sydney melanoma diagnostic centre high risk melanoma clinic since 2006. no classic dermoscopic features were present initially and only minimal changes were noted on sddi monitoring. these included subtle lesion enlargement, regression and focal change, with the cases representing key diagnostic lessons from this extreme risk patient group. conclusion: early melanoma diagnosis, particularly in extreme risk patients, is crucial though challenged by the absence of classic diagnostic criteria. this case series reinforces the importance of the role of tbp and sddi in monitoring patients at extreme risk of melanoma. reference 1. kittler h, guitera p, riedl e, et al. identification of clinically featureless incipient melanoma using sequential dermoscopy imaging. arch dermatol. 2005;142(9):1113-9. thick melanoma detection in a five-year high risk clinic for primary melanoma e. coates1,2,3, f. j. moloney1,2,3, p. guitera1,3, n. haass1,2,3, k. ho1, r. khoury1, g. mann3,4, s. w. menzies1,3 1 sydney melanoma diagnostic centre, royal prince alfred hospital, sydney, new south wales, australia 2 department of dermatology, royal prince alfred hospital, sydney, new south wales, australia 3 university of sydney, sydney, new south wales, australia 4 westmead millennium institute, westmead hospital, sydney, new south wales, australia introduction: melanoma thickness is a key determinant in long-term prognosis. thick melanomas (≥1mm breslow thickness) confer a significantly poorer prognosis, especially in patients already at extreme melanoma risk. supplement | dermatol pract concept 2012;2(2):16 103 increased knowledge regarding the characteristics of thick melanomas diagnosed in this subgroup is crucial to enable earlier detection and increased survival. objective: to evaluate ≥1mm melanomas detected during a five-year study for patients at extreme melanoma risk. method: 312 patients at extreme melanoma risk were examined six monthly using baseline total body photography for 5 years. inclusion criteria were ≥1 of: (1) cdkn2a or cdk4 mutation; (2) ≥3 1st/2nd degree relatives with a melanoma history and a personal history; (3) dysplastic naevus syndrome (dns) and a melanoma history; (4) history of ≥2 primary melanomas. short term (3 months) and long term (≥6 months) sequential digital dermoscopic imaging were employed following established protocols. atypical lesions were excised. all ≥1mm melanomas were analysed. results: 77 primary melanomas were detected, 16 at baseline visit and 61 subsequently. 6 melanomas had a breslow thickness of ≥1mm. these included three desmoplastic melanomas (1.6mm, 8.5mm and 21mm) and a 1.0mm superficial spreading melanoma (ssm) with clinically light/tan amelanotic morphology, a 1.0mm unclassified scalp melanoma on a lady and a 1.0mm ssm with nodular component. conclusion: early diagnosis of desmoplastic melanoma is especially challenging in extreme risk melanoma patients. a high vigilance for light or tan coloured amelanotic lesions and formal scalp examination will assist in reducing the thick melanoma incidence in patients at extreme melanoma risk. how difficult is the dermatoscopic diagnosis in early melanoma? rodica cosgarea1, loredana ungureanu1, liliana rogojanu2 1 department of dermatology, university of medicine “iuliu hatieganu” cluj-napoca, romania 2 department of pathology, county emergency clinical hospital cluj-napoca, romania introduction: the first clinical signs of melanoma are sometimes difficult to be diagnosed. due to dermoscopy we can make very often an early diagnosis. the general wish is to make an in situ melanoma diagnosis as often as possible in the patients with melanoma. method: we analyzed 26 dermoscopies of 12 cases with in situ melanoma and 14 cases with melanoma thickness under 1 mm. we registered for each dermoscopy the following structures: irregular pigmented network, irregular brown globules, irregular distributed black or grey dots, pseudopods and radial streaming, grey-blue areas with different patterns, atypical vascular pattern, white scar-like areas and regression of the structures which were fading. results: we found that irregular pigment network and radial streaming are of great help for diagnosis of thin melanomas. regression of dermatoscopic structures, grey-blue areas and irregular grey or black dots are often found in the in situ melanomas. in the followed up lesions, the changes in the pigment network, a small white or pinkish structure, new minimal vessel structures and few uniform grey, black dots or globules in the periphery indicate the change to malignant state. conclusion: from our few cases we can conclude that the grey-blue structures and the fading of the structures could be important dermatoscopic changes that could announce the onset of melanoma. dermatoscopic findings  in jellyfish stings l. j. del pozo hernando, n. izquierdo herce, a. martín santiago, j. escalas taberner, a. bauzá alonso dermatology department, hospital universitari son espases, palma de mallorca, spain introduction: jellyfish are free-life members of the phylum cnidaria, who share the presence of a type of venomous stinging cell (cnidocyte, cnidoblast, or nematocyte) mostly located in the tentacles and around the mouth. diagnosis of jellyfish stings is mainly made on clinical grounds, but the finding of cnidioblasts in skin scraping or biopsy may be helpful in some cases. we evaluated the usefulness of dermoscopy in the diagnosis of jellyfish stings. method: we reviewed  retrospectively the  clinical and dermoscopic pictures of 8 patients (6 females and two males) diagnosed of jellyfish stings in the last 5 years at mallorca, a spanish island in the mediterranean sea. results: depending on the clinical stage of the lesions, there were dotted and telangiectatic vessels and reticular pigmentation. however, the most conspicuous image on the acute stage was the presence of brown pinpoint crusts, 0.1mm in diameter on average, almost evenly spaced following a lineal distribution. this feature corresponds to the entry points of the harpoon-like structures contained in the nematocysts that are responsible for injecting the toxin into the skin. to the best of our knowledge, these findings have not been previously reported in the literature. references 1. williamson ja, fenner pj, burnett jw, rifkin jf. venomous and poisonous marine animals: a medical and biological handbook, 1996. 2. zalaudek i, giacomel j, cabo h, et al. entodermoscopy: a new tool for diagnosing skin infections and infestations. dermatology. 2008;216:14-23. 104 supplement | dermatol pract concept 2012;2(2):16 pyoderma gangrenosum versus basal cell carcinoma: is dermoscopy helpful? d. a. dreval, u. s. globina department of dermatology, international clinic and hospital medem, saint-petersburg, russia pyoderma gangrenosum (pg) is a chronic skin disease, characterized by neutrophilic infiltration and destruction of tissue. it occurs most commonly in association with a systemic disease, especially chronic colitis. the main clinical finding is ulcer. differential diagnosis includes infectious ulceration and skin cancer. we tried to use dermoscopy for make precise diagnosis. a 24-year-old white man presented with a 3-month history of a quickly growing painful ulcer on his left groin. the patient had a history of crohn disease for 18 years. he took oral glucocorticoids or sulfasalazine from time to time. clinically, the lesion had irregular shape 4-6 cm with dusky-red or purple sharply borders. the base of the ulcer was purulent with hemorrhagic exudate, partially covered by necrotic eschar with granulation tissue and scars areas. on dermoscopy diffuse white to red shiny areas with ulceration, arborizing vessels and short fine telangiectasia, multiple structures like blue-gray ovoid nests was found in the lesion. it’s a typical dermoscopic picture of basal cell carcinoma (bcc). biopsy excluded any skin cancer. serology, cultural investigation tests helped rule out infectious etiology of the ulcer. histopathological findings were non-specific and corresponded to pg. the lesion healed during some weeks after treatment by oral sulfasalazine and topical corticosteroids. pg may simulate bcc clinically and dermoscopically. diagnosis of pg, just as any other lesions, should base on the integrated assessment of the detailed history, physical examination, dermoscopy and skin biopsy. photographic artifact simulating regressing melanocytic lesion—a potential pitfall of total body photography s. p. edwards, a. j. chamberlain victorian melanoma service, the alfred, prahran, victoria, australia clinical photography is a useful tool for dermatologists particularly when monitoring skin lesions. clinicians using photography should be aware of potential image artifacts that may blur the clinical picture. dust contamination for instance can mimic a regressing melanocytic lesion as exemplified by our recent experience. regular cleaning of photographic hardware, ideally by professionals, will help to minimise this problem. argyria mimicking a blue nevus: dermoscopy features m. l. enei1, f. m. paschoal2 1 private office, centro dermatológico dra. leonor enei, iquique, chile 2 instituto de dermatología. faculdade de medicina do abc – são paulo, brasil skin staining as a result of exposure to silver is known as localized argyria. this is a rare phenomenon caused by the direct application of silver and is clinically manifested by blue-grey discoloration. we report the case of a 30-year old patient, bearer of a clinical condition of localized argyria in the ear lobes, caused by an earring screw, who had remained asymptomatic for over 20 years. clinically, the patient manifested a welldemarcated, dark blue grey a papule of 1 cm in diameter similar to a blue nevus. in the dermoscopy we observed blue gray, granular and annular structures around the eccrine ostium, and little linear structures. these structures are not observed in blue nevis. we also observed a scar, not visible clinically. the histopathology showed the presence of fine, brownish to blackish particles throughout the upper and deep dermis prone to concentrating around the elastic collagenic, vascular vessels and eccrine glands. to our knowledge, dermoscopy features have not reported in argyria. references 1. takeishi e, hirose r, hamasaki y, katayama i. localized argyria 20 years after embedding of acupuncture needles. eur j dermatol. 2002;12(6):609-11. 2. sugden p, azad s, erdmann m. argyria caused by an earring. br j plastic surg. 2001;54(3):252-3. dermoscopy of melanocytic lesions of the vulva a. ferrari1, i. zalaudek2, g. argenziano2, p. buccini1, p. de simone1, v. silipo1, l. eibenschutz1, r. covello3, i. sperduti4, c. catricalà1 1 department of oncologic dermatology, san gallicano dermatological institute, rome, italy 2 dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, italy 3 department of pathology, regina elena national cancer institute, rome, italy 4 unit of biostatistics, regina elena national cancer institute, rome, italy clinical and epidemiological characteristics of melanocytic vulvar lesions are different from those of other body sites. vulvar melanoma typically occurs in postmenopausal supplement | dermatol pract concept 2012;2(2):16 105 women as solitary or multifocal disease; a small subset of vulvar nevi, known as atypical melanocytic nevi of the genital type (amngt), are commonly associated with a younger age compared with melanoma and common nevi and show histological features that may overlap with melanoma. we report the dermoscopic features of 42 melanocytic lesions that include 29 common nevi, 8 amngt and 5 melanomas collected at the melanoma unit of san gallicano dermatological institute in rome. all nevi appeared as solitary flat or palpable tumors. on dermoscopy, a globular pattern, a mixed pattern and homogeneous brown-gray pigmentation were the most prevalent patterns among nevi. the mixed pattern, defined as the combination of 2 or more dermoscopic patterns in the absence of melanoma-specific features, and characterized by the combination of parallel structures with globules or a homogeneous brown-gray pigmentation, was the most frequently pattern observed in amngt. all melanomas showed a multicomponent pattern, and, in most cases, reticular depigmentation and blue-white veil as dermoscopic local features. based on our results, we propose to perform a dermoscopic follow-up for solitary flat or palpable lesions showing a mixed pattern in child to teenager. surgical excision or a punch biopsy are recommended when a multicomponent pattern, reticular depigmentation or bluewhite veil are seen, independent of the clinical features of the lesion, to rule out a melanoma. references 1. ronger-savle s, julien v, duru g, raudrant d, dalle s, thomas l. features of pigmented vulval lesions on dermoscopy. br j dermatol. 2011;164:54-61. 2. ferrari a, zalaudek i, argenziano g, et al. dermoscopy of pigmented lesions of the vulva: a retrospective morphological study. dermatology. 2011;222(2):157-66. unusual dermoscopic presentations of dermatofibroma a. ferrari1, p. buccini1, p. de simone1, l. eibenschutz1, v. silipo1, c. cota2, g. argenziano3, i. zalaudek3, c. catricalà1 1 department of oncologic dermatology, san gallicano dermatological institute, rome, italy 2 laboratory of pathology, san gallicano dermatological institute, rome, italy 3 dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, italy dermatofibroma is a skin neoplasm that is usually easy to be diagnosed clinically and dermoscopically, but in some cases its differentiation from other tumors may be difficult. different morphologic faces of dermatofibromas may be dependent to various evolutive stages, but also to special histopathologic variants or special locations of these tumors. we report the results of a dermoscopic study of 130 cases of dermatofibromas that were consecutively collected at the melanoma unit of san gallicano dermatological institute in rome. “central white scar-like patch and peripheral thin pigment network” was the most frequently observed pattern. in particular we described additional patterns defined by us, namely, the nondermatofibroma-like patterns that were found in 17.7% of cases. these patterns were characterized by a combination of features reminiscent of melanoma (melanoma-like pattern) in 7.7% of cases or other neoplasms (such as a melanocytic nevus, a vascular tumor, or a basal cell carcinoma) in 10% of cases. although we were not allowed to define a specific dermoscopic profile for each histopathologic variant of dermatofibroma for the low number of these variants, we found a significant association with locations, global dermoscopic patterns and local features. the knowledge of all these variables could represent a further aid for the diagnosis. however, a full surgical removal is always recommended in all doubtful cases, especially in high-risk patients and/or with a history of recent onset or changes. references 1. karaarslan ik, gencoglan g, akalin t, ozdemir f. different dermoscopic faces of dermatofibromas. j am acad dermatol. 2007;57:401-406. 2. zaballos p, puig s, llambrich á, malvehy j. dermoscopy of dermatofibromas. a prospective morphologic study of 412 cases. arch dermatol. 2008;144(1):75-83. acquired dermal melanocytosis of the face and extremities in a young japanese woman yuki hashimoto, atsushi shimizu, akira ishiko the first department of dermatology, school of medicine, toho university, tokyo, japan a 25-year-old woman presented with non-palpable pigmented reticulated pigmentation with discrete brown macules on her dorsal surface of hands and feet. she had noted those hyperpigmentation from a childhood. the pigmented macules gradually increased in intensity and extent and, slight pigmentation also appeared on her nasal wings five years ago. physical examination revealed multiple, discrete, coalescing faint brown macules and small brown spots distributed symmetrically on the dorsa of the hands and feet, the bilateral extensor surfaces of the forearms and the lower legs, and the nasal wings. the patient was otherwise healthy and taking no medication. her older sister has also deeplypigmented macules of her extremities. dermoscopy showed coarse reticular pigmentation pattern with color heterogeneity and blurred margin. skin biopsy from the left lower leg showed discontinuous basal melanosis in the epidermis and melanin-laden cells in the upper dermis. immunohistochemical analysis revealed the presence of s-100 positive dermal 106 supplement | dermatol pract concept 2012;2(2):16 melanocytes and cd68 positive melanophages. these clinicopathological features were consistent with acquired dermal melanocytosis of the face and extremities (admfe), which was proposed by hidano in 1991. admfe is characterized by the development of multiple coalescing brown spots of the extremities and the nasal wings. differentiation from dyschromatosis symmetrica hereditaria (dsh) is necessary. unlike dsh, there was no psuedopigment network in admfe suggesting that brown pigmentation may be due to dermal melanocytes and melanophages, but not basal melanosis. we report here the first dermoscopic description of a japanese patient with admfe. freely designable acrylic dermoscopy modules h. hinogami1 , y. shimizu1 , h. sakai1 , h. shirabe1 , m. tanaka2 1 department of dermatology, ntt west japan osaka hospital, osaka, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan introduction: we elaborated dermoscopy modules with acrylic tubes and plates that can be combined with a highvision video camera and a macro lens. aims: to design a narrow tipped module that can fit onto interdigital or periorbital concave skin surfaces and to design a tilting module for oblique view dermoscopy. method: we examined melanocytic skin lesions on the concave skin areas such as interdigital and periorbital skin using a narrow dermoscopy module and soles of the feet using a tilting dermoscopy module. results: all the dermoscopy images taken with these dermoscopy modules were clear with high resolution. a narrow dermoscopy module allowed clear dermoscopy images of melanocytic nevi on the interdigital or periorbital areas. a tilting dermoscopy module enabled fibrillar pattern to be observed as original parallel furrow pattern. dermoscopic features of subungual melanoma in situ: our experiences of three japanese cases taiki isei subungual melanoma in situ (early melanoma of nail apparatus) is a relatively rare subtype of malignant melanoma. the clinical resemblance of this type to benign melanonichia striata makes it difficult to differentiate between these nail disorders. detection of early lesions of subungual melanoma is beneficial for the improvement of prognosis. in this paper, we examined 3 patients with subungual melanoma in situ and analysed the characteristics of their pigmentation of the nail apparatus with the use of a dermatoscope. case 1 is a 33 year-old woman with melanonychia of her right thumb. case 2 is a 44 year-old woman with narrow pigment line on her right little fingernail with 2 years of evolution. case 3 is a 61 year-old man showing pigment striae on his index finger nail. excisional biopsy was performed, and pathological examination revealed all 3 cases as melanoma in situ. two of 3 cases had multiple pigment lines of nail plate. only one presented irregular lines with variegation in colours. though all the cases showed no hutchinson’s sign, only one case showed pseudo-hutchinson’s sign. micro-hutchinson’s sign was detected in 2 of 3 cases. our results suggest that precise dermoscopic examination can be an easier and more reliable procedure for the detection of early subungual malignant melanoma. dermoscopy of fungal melanonychia i. kilinc karaarslan1, a. erbas1, d. aytimur1, t. akalın2, f. ozdemir1 1 ege university, medical faculty, department of dermatology, izmir, turkey 2 ege university medical faculty, department of pathology, izmir, turkey introduction: differential diagnosis of pigmented lesions of the nail has special importance. dermoscopic features of various melanocytic and nonmelanocytic pigmented lesions of the nail are available in the literature, however the data on dermoscopy of fungal melanonychia is lacking. in this study, we aimed to define dermoscopic features observed in cases of fungal melanonychia. method: we reviewed the cases of fungal melanonychia that had been seen at our dermoscopy unit within the past year. specimen for mycologic examination was obtained by the curettage of the pigmented portion of the nail. the pigmented part was totally removed by curettage in order to see the nail bed to exclude any melanocytic lesion. results: twenty lesions in 13 cases (10 male, age ranged 34-80 years) were observed. all were located on toes and all were gray-black in color. clinically, 2 of them were difficult to differentiate from a melanocytic lesion. on dermoscopy, melanonychia was mostly observed as multicolored (brown, gray, black, and in some cases red indicating hemorrhage) pigmentation (19/20). the multicolored pigmentation was homogeneous in 9 of the cases and, gray-black pigment aggregates, which may be called as pigmented clusters, accompanied the multicolored homogeneous pigmentation in 10 lesions. in 1 of the cases, the pigmentation was homosupplement | dermatol pract concept 2012;2(2):16 107 geneous and was observed only in gray-black color. trichophyton rubrum and candida albicans were causative agents. references 1. tosti a, piraccini bm, de farias dc. dealing with melanonychia. semin cutan med surg. 2009;28:49-54. 2. micali g, lacarrubba f, massimino d, schwartz ra. dermatoscopy: alternative uses in daily clinical practice. j am acad dermatol. 2011;64:1135-46. dermoscopic features of basal cell carcinoma according to histopathologic subtypes park jungmin, mun jeho, jwa seungwook, song margaret, kim hoonsoo, ko hyunchang, kim byungsoo, kim moonbum department of dermatology, school of medicine, pusan national university, busan, korea basal cell carcinoma (bcc) is a slowly growing malignant epithelial tumor and world’s most common cancer. clinicopathologic appearances of bccs are classified as non-aggressive types, which include nodular, superficial, and adenoid variants, and aggressive types, which consist of morpheaform, micronodular, and infiltrative variants. dermoscopy is a noninvasive diagnostic tool, which is helpful in differential diagnosis between benign and malignant pigmented skin lesions. though numerous studies have reported dermoscopic patterns of bccs, there was a lack of study for dermoscopic features of bcc according to their histopathologic subtypes. in this study, we conducted retrospective histopathologic and dermoscopic analysis of 128 bccs (91 with non-aggressive type and 37 with aggressive type) and compared dermoscopic differences according to histopathologic subtypes. punctum in epidermal cyst and punctum-like structures in other dermatoses: the probability of presence and dermoscopic findings kim taewook, mun jeho, jwa seungwook, song margaret, kim hoonsoo, ko hyunchang, kim byungsoo, kim moonbum department of dermatology, school of medicine, pusan national university, busan, korea epidermal cysts are one of the most common types of benign skin tumors. although they are frequently encountered in the daily dermatological practice, the differential diagnosis of epidermal cysts is very broad. therefore, they often become a complex diagnostic challenge for the clinicians. an epidermal cyst exhibits as a well-defined dermal nodule and is characterized by a central punctum that represents the plugged pilosebaceous unit. though observation of a punctum can be used as a clue for the diagnosis of an epidermal cyst, a study regarding it was hardly reported. to our knowledge, there was only a single study conducted in 1980, had reported that a punctum was visible to the naked eye in 15 out of 34 epidermal cysts (42.1%). therefore, we evaluated the presence or not of punctum and punctum-like structure of the skin lesion of which the first clinical diagnosis was epidermal cyst. and, we examined dermoscopic features of punctum and punctum-like structure, because dermoscopy provides clinicians with magnified in vivo observation of the morphologic features of the skin that are often imperceptible to the naked eye. we thought it could be used as an adjuvant tool in the diagnosis of epidermal cysts. herein, we report the probability to find punctum in epidermal cyst and punctum-like structures in other dermatoses. in addition, other various skin tumors or cysts such as pilomatricoma, lipoma, pilar cyst, neurofibroma, and so on were examined to compare the dermoscopic differences of punctum in epidermal cyst and punctum-like structures in other dermatoses. irregular fibrillar pattern is an artifactual expression of parallel ridge pattern t. kiyohara, s. satoh, m. yasuta, m. kumakiri department of dermatology, university of fukui, fukui, japan introduction: miyazaki et al. reported that regular fibrillar pattern of an acral nevus was changed into parallel furrow pattern by horizontally moving the cornified layer with the probe of a dermoscope. maumi et al also reported that regular fibrillar pattern changed into parallel furrow pattern by oblique view dermoscopy. method: we observed an irregular fibrillar pattern in acral melanoma in situ of a 54-year-old japanese woman by oblique view dermoscopy. the slanting angle of the melanin columns in the cornified layer was confirmed by use of dermlite dl-100 (3gen, dana point, calif., usa). after the direction of viewing was fixed so that the parallel ridge pattern was observed, pictures were taken with the derma9500 (derma medical, yokohama, japan) and k-y jelly (johnson and johnson, new brunswick, n.j., usa). results: while a picture taken by ordinary dermoscopy showed an irregular fibrillar pattern, a picture by oblique view dermoscopy demonstrated a parallel ridge pattern. references 1. miyazaki a, saida t, koga h, oguchi s, suzuki t, tsuchida t. anatomical and histopathological correlates of the dermoscopic patterns seen in melanocytic nevi on the sole: a retrospective study. j am acad dermatol. 2005;53:230-6. 108 supplement | dermatol pract concept 2012;2(2):16 2. maumi y, kimoto m, kobayashi k, ito n, saida t, tanaka m. oblique view dermoscopy changes regular fibrillar pattern into parallel furrow pattern. dermatology. 2008;218:385-6. dermoscopic features from two cases of reticulated acanthoma with sebaceous differentiation ken kobayashi1, masaru tanaka1, takayuki inoue1, fuyuki oryu2 1 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 2 department of dermatology, tachikawa sogo hospital, tokyo, japan case 1: a 75-year-old japanese woman was referred with a 17-year history of a solitary brown macule on the right elbow. physical examination revealed a 6-mm smooth light brown macule. dermoscopic examination demonstrated central hypopigmentation area surrounding homogeneous yellowish light brown structureless area and radially arranged light brown leaf-like areas at the periphery. dark brown pigment network and spoke-wheel areas were also seen in the leaf-like areas. clinical and dermoscopic findings suggested superficial basal cell carcinoma with a differential diagnosis of early seborrheic keratosis. histopathological diagnosis was reticulated acanthoma with sebaceous differentiation (rasd). case 2: an 89-year-old japanese man was referred with a 1-year history of a solitary brown nodule on the left neck. physical examination revealed a 9.2 x 6.7 mm multilobulated brown nodule. dermoscopic examination demonstrated numerous grayish to blue-gray blotches with a non-pigmented area containing multiple linear and hairpin vessels. peripheral radially arranged light brown leaf-like areas and comedo-like openings were also noted. clinical and dermoscopic findings suggested seborrheic keratosis with a differential diagnosis of pigmented eccrine poroma. histopathological diagnosis was rasd. temporal changes of the objective discrimination index permit identification of early nail apparatus melanoma h. koga1, a. sekiguchi2, t. saida1, t. sota2 1 department of dermatology, shinshu university school of medicine, matsumoto, nagano 390-8621, japan 2 department of electrical engineering and bioscience, waseda university, shinjuku, tokyo169-8555, japan background: it is well known that follow-up observation is important to detect melanoma at an early stage. however, to our best knowledge, such capabilities have been beyond the scope of specifications for automated melanoma detection systems. aim: to investigate whether temporal changes of the objective discrimination index previously proposed by our group help us to detect early nail apparatus melanoma. patients and method: dermoscopic images of five lesions of longitudinal melanonychia seen in japanese adult patients were used. two lesions were clinically and dermoscopically diagnosed as benign longitudinal melanonychia and 3 lesions showed equivocal dermoscopic features, suspected to be evolving lesions of melanoma in situ. the size of each image was adequately reduced to ensure that the spatial resolution of each image was the same. nail plate pigmentation excluding artifact bubbles was analyzed. the index representing variegation in color was automatically calculated from rgb values contained in each pixel according to the previously proposed method. temporal changes were evaluated at most for 31.6 months. results and discussion: in the 2 benign longitudinal melanonychia, the indices were always below the threshold value, mostly constant or decreasing monotonically. the suspicious 3 lesions were finally biopsied. histopathologically, one lesion was diagnosed as benign melanonychia since no proliferation of atypical melanocytes was detected. in this lesion, the indices were always below the threshold and decreased monotonically during the course. the remaining2 lesions were histopathologically diagnosed as melanoma in situ. in one lesion, the index remained above the threshold, though it slightly decreased with time. the other lesion was characterized by a rapidly increasing index, though the value remained under the threshold. in conclusion, temporal changes of the index, which reflects activity of melanocytes, surely help us to identify early evolving lesions of nail apparatus melanoma. morphometric analysis of arborizing vessels in skin tumors j.f. kreusch, f. koch dermatological practice, luebeck, germany introduction: vascular structures are a most important tool for dermoscopic diagnosis of (hypo)-pigmented lesions. especially basal cell carcinoma (bcc) displays a distinctive pattern, so-called arborizing vessels. however, similar vascular structures can be found in various other tumors. as the descriptive term “arborizing vessels” is somewhat subjective and there is a considerable interobserver variability in perception we felt it was desirable to achieve a precise and quantitative characterization of morphological details. methods: images of 18 basal cell carcinoma, 4 malignant melanoma, 3 hyperplastic sebaceous glands and 3 blue supplement | dermatol pract concept 2012;2(2):16 109 nevi showing vascular structures resembling “arborizing vessels” were used for morphometric analysis. vascular patterns in facial skin were analyzed as well, serving as a pattern of reference. analysis was performed with established methods used in geography for characterization of fluvial systems. the following parameters were recorded: branching of the vessels, determining the number (“order”) of bifurcating vessels from the stem vessel. diameter of vessels in all subbranches and distances between each fork was measured. the angle within each fork and the curve radius of winding vessels were determined. further analysis of the data permitted calculation of parameters such as number of bifurcations and number of curves along the course of a winding vessel. analysis was performed using standard statistical procedures. results: arborizing vessels in non-bcc-tumors can be clearly distinguished from bcc vessels using these parameters. the data may be helpful for developing imaging systems diagnosing bcc by means of the vascular pattern or for follow-up of alterations of the vascular supply under therapy. videodermoscopy in the evaluation of pemphigus vulgaris and pemphigus foliaceus. m. kurzeja1, a. rakowska1, l. rudnicka1, m. olszewska2 1 department of dermatology csk mswia, warsaw, poland 2 department of dermatology warsaw medical university, warsaw, poland introduction: pemphigus is an autoimmune bullous disease affecting the skin and mucous membranes. there are two main types of pemphigus: pemphigus vulgaris (pv) and pemphigus foliaceus (pf). the aim of the study was to evaluate the characteristic features of pv and pf in videodermoscopy. methods: twenty-four lesions of 15 patients with pv and twenty six lesions of 11 patients with pf were examined using fotofinder 2 videodermoscope. results: pink-red areas were present in 58% (14/24) of pv and in 61% (16/26) of pf lesions. glomerular vessels were observed in 50% (12/24) of pv and in 69% (18/24) of pf lesions. in the proximity of skin lesions multiple, irregular elongated blood vessels were visible in 67% (16/24)of pv and in 54% (14/26) of pf cases. videodermoscopy of skin lesions also showed yellowish areas in 25% (6/24) of pv and in 23% (6/26) of pf lesions. moreover yellow dots with whitish halo were visible in 42% (10/24) of pv and 46% (12/26) pf lesions. videodermoscopy also revealed the presence of two type of scaling: scaling like broken ice floe visible in 12% (3/24) of pv and in 8% (2/26) of pf lesions and scaling like a wave hitting the shore visible in 25% (6/24) of pv and in 38% (10/26) of pf lesions. conclusions: these data show the most characteristic feature of pemphigus in videodermoscopy are pink-red areas and glomerular vessels within the lesions and multiple, irregular elongated blood vessels in the proximity of skin lesions. a survey about the use of dermoscopy in greece e. lazaridou, e. kyrmanidou, c. fotiadou, c. giannopoulou, a. trigoni, d. ioannides first department of dermatology-venereology, aristotle university medical school, thessaloniki, greece introduction: we conducted a survey to evaluate the prevalence of dermoscopy use among greek dermatologists, the method by which they learned to use it, how often they use it and whether they believe it is effective. method: a questionnaire was handed over to all participants attending an annual dermoscopy seminar in thessaloniki, greece, in november 2011. four hundred thirty nine attendants completed the survey. results: three hundred participants (68.5%) had been previously trained in dermoscopy. the majority (73.6%) first learned how to use dermoscopy by attending a seminar. two hundred and forty-six (56.1%) dermatologists claimed to use dermoscopy more than once daily and 20 (5%) never had used dermoscopy. the most popular algorithm used for the evaluation of pigmented skin lesions was the abcd algorithm (70.8%) followed by pattern analysis. the most common response (33.8%) as to why dermoscopy is effective was that it detects melanoma earlier. one third of those who found dermoscopy ineffective thought so, because it needs excessive training. about a minute was the time most attendants (53%) needed to evaluate a skin lesion by dermoscopy; less than a minute was reported by 33.8%. most dermatologists (76.8%) used dermoscopy not only for evaluating pigmented skin lesions. for 25.8% of the participants it was the first time they attended a dermoscopy seminar and 98.7% would like to attend more such seminars. nearly half of the attendants (41.7%) were dermatologists with less than 10 years of clinical experience and 23.8% were residents. dermoscopic features of melanocytic skin lesions in greek children and adolescents. association with environmental factors and skin types. preliminary data e. lazaridou, a. papakonstandinou, c. fotiadou, c, giannopoulou, c. savvoulidis, i. papagaryfallou, d. ioannides first department of dermatology-venereology, aristotle university medical school, thessaloniki, greece 110 supplement | dermatol pract concept 2012;2(2):16 introduction: acquired nevi often present in childhood and increase in number and size during early and middle life. as they represent important risk factors for melanoma, the knowledge of their epidemiology, especially in young age, is essential. in our study, that is currently ongoing, we intend to determine the dermoscopic features and prevalence of dermoscopic patterns of nevi and their association with environmental factors and skin types, using cross-sectional data from a population-based cohort of children and adolescents. method: the study population is going to include all students, aged 6-18 years, from 6 different schools in thessaloniki, greece, whose parents are going to consent to a total body clinical and dermoscopic examination of their nevi. for each participant a questionnaire is completed, which includes data on age, sex, pigment phenotype, sun sensitivity, sun exposure, sunblock use, previous sunburn history and family history of skin cancer. the total number of nevi is recorded, distributed on head and neck, anterior trunk, back, upper and lower extremities, palms and soles. dermoscopic patterns of all nevi are recorded as globular, reticular, homogeneous, mixed and unspecified. results: to date, only 388 adolescents, aged 15-18 years, and no children have been examined. a total of 17759 nevi have been recorded with a reticular predominant dermoscopic pattern (74.25%). globular pattern was seen in 16.08% of nevi, homogeneous pattern in 3.77% and mixed pattern in 5.9% of nevi. this is the first, still ongoing, population-based study evaluating clinical and dermoscopic features of nevi in greek children and adolescents. clinical, videodermoscopic, ultrasonographic and histopathological features of fordyce angiokeratoma m. maj1, a. nasierowska-guttmejer2, l. rudnicka1 1 department of dermatology, central clinical hospital mswia, warsaw, poland 2 department of pathology, central clinical hospital mswia, warsaw, poland introduction: angiokeratomas are benign vascular lesions that histopathologically consist of dilated subepidermal vessels and in most cases are associated with acanthosis or hyperkeratosis. the prevalence of angiokeratomas is estimated to be approximately 0,16% among the general population. five clinical types are recognized: angiokeratoma of mibelli, angiokeratoma of fordyce (angiokeratoma scroti), angiokeratoma corporis diffusum, angiokeratoma circumscriptum neviforme and solitary angiokeratoma. angiokeratomas of fordyce are typically asymptomatic, soft, solitary or multiple blue-to-red papules, plaques or nodule with a diameter of 2 to 10 mm located on the scrotum, shaft of penis, labia majora, inner thigh or lower abdomen. the pathophysiology of angiokeratoma remains unknown, although increased venous pressure may contribute to their formation. other causative factors include acute or chronic trauma and nevoid or vascular malformations. the precise incidence of angiokeratomas of fordyce is unknown, but they are considered common, especially with increasing age and male gender. usually, they do not require treatment. method: we performed clinical, videodermoscopic, ultrasound and histopathological examination of fordyce angiokeratoma. ultrasound examination was performed with 30mhz ultrasound transducer with 0,1mm resolution and 7mm penetration. fotofinder 2 system was used for videodermoscopy. results: we present a 36-year-old man with asymptomatic red-violaceous papules, 2-5 mm in diameter on the scrotum. videodermoscopy revealed red-blue lacunae and whitish veil that corresponded to hyperkeratosis and acanthosis. ultrasound scan showed hypoechogenic and mixed echogenicity lesions with indistinct margins. histopathology was characteristic of angiokeratoma. in conclusion, fordyce angiokeratoma shows red-blue lacunae and whitish veil in videodermoscopy. in ultrasonography the lesions are hypoechogenic or show mixed echogenicity. meyerson phenomenon in a becker nevus. clinical features and videodermoscopy m. maj, e. kowalska-oledzka, m. olszewska, l. rudnicka specjalisci dermatolodzy, warsaw, poland introduction: becker nevus is a late-onset of epidermal nevus or birthmark, occurring mostly in males, due to an overgrowth of the epidermis, melanocytes and hair follicles. it develops during childhood or adolescence on the shoulders or upper trunk. a becker nevus is a large one-sided brown patch. after puberty it often becomes darker and hairy. meyerson nevus (halo dermatitis, halo eczema, meyerson’s phenomenon) occurs when a focal and transitory eczematous eruption arises around melanocytic lesions. it appears to occur more commonly in young males (average age 30 years). it most often occurs in healthy individuals but also observed in patients with eczema or other atopic conditions. it usually develops as a single itchy patch. method: videodermoscopy was performed with a fotofinder 2 system at magnifications 20x and 70x. results: we present a 4-year-old boy with becker nevus localized on right arm and a 1-week history of a pruriginous and erythematous halo with blistered yellowish rash which partially surrounded proximal part of hairy, symmetrical becker nevus of 3x5cm in diameter. videodermoscopy supplement | dermatol pract concept 2012;2(2):16 111 revealed regular melanocytic pattern with yellowish vesicles in the proximal pole. after one week of topical anti-inflammatory and antibacterial treatment meyerson nevus disappear and control videodermoscopy revealed only pigment network. conclusions: meyerson phenomenon does not seem to alter significantly dermoscopic features of becker nevus. the role of ultrasonography in in vivo evaluation of melanoma thickness. ultrasonography, videodermoscopy and histopathology in selected cases of melanoma m. maj1, e. szymanska1, j. czuwara1, o. warszawik1, m. majsterek1, e. piekarczyk1, j. sicinska1, m. slowinska1, a. nasierowska-guttmejer2, a. nowicki3, l. rudnicka1,4 1 department of dermatology, central clinical hospital mswia, warsaw, poland 2 department of pathology, central clinical hospital mswia, warsaw, poland 3 polish science academy, warsaw, poland 4 faculty of health sciences, warsaw medical university, warsaw, poland introduction: essential for increasing the chance of detecting melanoma are: the health education, regular skin examination by the patient and by the dermatologists and improving diagnostic methods in medicine. dermoscopy has developed into a standard method in diagnosing melanoma. this method may provide some insight into the tumor thickness, but no precise measurement is possible. the aim of our study was to evaluate whether ultrasonography may provide important pre-excision information about the tumor and its thickness. method: a total of 40 common nevi and 25 cases of cutaneous melanoma were evaluated clinically, by videodermoscopy, and 30 mhz ultrasonography. in ultrasonography assessment of echogenicity, depth of the lesion and vascularity were performed. all images were analyzed in the context of histopathology results. results: in ultrasonography melanoma has been visible as hypoechogenic area clearly separated from the environment, usually with uneven borders. dimensions of lesions were adequate to those seen in histopatology. we found that ultrasound evaluation involved a risk of mistake in evaluation of lesion size related to various causes: presence of hair follicles, sweat glands and sebaceous glands or the inflammatory infiltrates. in 24/25 cases videodermoscopy showed features characteristic of melanoma. in conclusion, we believe that skin ultrasonography allows evaluation of melanoma thickness prior to surgery and is an important accessory tool to dermoscopy or videodermoscopy, which serve as diagnostic aids to establish the diagnosis. videodermoscopy and confocal reflectance microscopy (rcm) features of beard folliculitis m. maj, o. warszawik, i.walecka, l. rudnicka 1 department of dermatology, central clinical hospital mswia, warsaw, poland beard folliculitis (folliculitis simplex barbae, sycosis barbae) is characterized by pustules penetrated by hairs, with inflammation of the hair follicles localized in the bearded area and on the upper lip. infection can be spread through contaminated shaving tools. laboratory examinations are typically not obtained because diagnosis is usually made based on history and clinical examination alone. in cases resistant to standard therapy, cultures, gram stain, potassium chloride preparation and biopsy are the diagnostic tests of choice. histologically sycosis barbae is defined as the presence of inflammatory cells within the wall and ostia of the hair follicle, creating a follicular-based pustule. videodermoscopy was performed with fotofinder 2. rcm was performed with vivascope 1500 we report the case of a 43-year-old man with an acute onset of small pustules surrounded by erythema that were pierced by a central hair easily extracted from the follicle localized on the upper lip and chin. pustules ruptured and leaved a yellow crust. deeper changes manifest as erythematous, fluctuant nodules. skin lesions were associated with discomfort and suppurative drainage. in videodermoscopy we observed: dilated linear vessels around hair follicle, in some areas absence of follicular units with yellow dots and in some dystrophy of hair shaft (hair contraction), scaling and white-yellowish lacunas correspond to pustules. rcm images revealed the presence of groups of inflammatory cells inside hair follicles, inflammatory cell infiltration at the level of the spinous and granular layers and increased vascularity. in conclusion, dermoscopy and rcm may be helpful tools in diagnosing beard folliculitis of atypical clinical presentation. combined tumor: atypical spitz naevus associated with deep penetrating naevus: case report g. mazzocchetti 1, f. de francesco1, a. d’orazio2 1 department of dermatology, civil hospital “renzetti” of lanciano, asl lanciano-vasto-chieti 2 department of pathology, civil hospital “renzetti” of lanciano, asl lanciano-vasto-chieti 112 supplement | dermatol pract concept 2012;2(2):16 the association of spitz nevus with deep penetrating nevus is a tumor of rare cancers combined, especially in puberty. the authors report a case of a 11-year-old girl with a pigmented lesion of about 1x08 cm, centered by a bluish papule on the skin of 0.7x06 detected with sharp margins. the appearance was characterized by a composite pattern with all the features of melanoma. the authors discuss the complexity of the case. furthermore, the authors discuss aspects dermoscopy and histological features of the tumor combined. dermoscopy features of macular amyloidosis n. merino de paz, m. rodriguez-martin, p. contrerasferrer, m. pestana-eliche, m. garcia-bustinduy, m. saezrodriguez, a. noda-cabrera, f. guimera martin-neda dermatology derparment, hospital universitario de canarias, la laguna, spain macular amyloidosis (ma) is a common variant of primary localized cutaneous amyloidosis. it is secondary to amyloid deposits on dermis, but the etiopathogenic mechanism is still unknown. clinical presentation consists of grayish-brown pigmented and pruritic macules located on the upper back or arms. nowadays, a cutaneous biopsy may be performed for a final diagnosis. the amyloid deposits are within the dermal papillae and they are usually globular, resembling colloid bodies, but sometimes they are too small and escape to detection. congo red stain shows apple-green birefringence under polarizing light. differential diagnoses of poikiloderma of civatte and postinflammatory hyperpigmentation could be established. so, the description of dermoscopy patterns for ma could be useful to diagnose and to differentiate it from other entities. we present a series of 15 cases of ma with histological confirmation. first, we describe the main dermoscopic findings in ma. we analyze the results and compare ma dermoscopic features with dermoscopic findings in other entities as postinflammatory hyperpigmentation. references 1. lambert wc. cutaneous deposition disorders. in: farmer er, hood af, eds. pathology of the skin. norwalk, conn: appleton & lange; 1990:432-50. 2. rados j, marinovic kulisic s, lipozencic j, budimcic d, loncaric d. macular amyloidosis: a case report. acta dermatovenerol croat. 2008;16(3):138-41. 3. röcken c. differential diagnosis of amyloidosis. verh dtsch ges pathol. 2002;86:107-15. clinical, histological and dermoscopic changes over time in urticarial vasculitis m. s. jang, j. b. park, d. y. kang, j. s. kang, s. t. kim, k. s. suh department of dermatology, kosin university college of medicine, busan, south korea urticarial vasculitis (uv) is a subset of vasculitis characterized clinically by urticarial skin lesions and histologically by leukocytoclastic vasculitis. the cutaneous lesions are urticarial in appearance, but usually last 24-72 hours and may have residual changes of purpura, scaling and hyperpigmentation. however, it is difficult to find out clinical differentiation between common urticaria and early urticarial lesions of urticarial vasculitis. polarized dermoscopes (pd) use the properties of crosspolarized light to view deeper skin structures, not visible to the unaided eye, and they allow better visualization of blood vessels and reddish hue associated with some lesions. in this respect, through pd, clinical, histological and dermoscopic changes over time in urticarial vasculitis were observed. although clinically hard to distinguish early urticarial lesions in urticarial vasculitis from common urticaria, but histological diagnosis was available to show the early phase of leukocytoclastic vasculitis characterized by prominent dermal edema, focal fibrinoid vascular change and a sparse infiltrate composed of lymphocytes and eosinophils. although not prominent, dermoscopically purpuric red dots and globules were seen in early lesions. urticarial lesions faded, made it easier to distinguish between common urticaria and urticarial vasculitis. purpura or hyperpigmentation lesions showed dermoscopically purpuric dots or globules in a patchy orange-brown background. these structures were associated with fibrin deposits, nuclear dust, and extravasation and degradation of red blood cells, demonstrating fully developed lcv. in conclusion, pd faithfully reflect clinicohistopathologic transition from early to late stages in uv and appear to be helpful in differentiating early lesions of uv from common urticaria. references 1. vázquez-lópez f, maldonado-seral c, soler-sánchez t, perez-oliva n, marghoob aa. surface microscopy for discriminating between common urticaria and urticarial vasculitis. rheumatology. 2003;42:1079-82. 2. benvenuto-andrade c, dusza sw, agero al, scope a, rajadhyaksha m, halpern ac, marghoob aa. differences between polarized light dermoscopy and immersion contact dermoscopy for the evaluation of skin lesions. arch dermatol. 2007;45:329-38. 3. calonje e, brenn t, lazar a, mckee ph (eds). mckee’s pathology of the skin with clinical correlations, 4th ed. boston: saunders, 2011:259-80. supplement | dermatol pract concept 2012;2(2):16 113 characteristic dermoscopic features of pseudoxanthoma elasticum: dots in the yellow net r. moriuchi, w. nishie, s. shinkuma, y. fujita, h. shimizu department of dermatology, hokkaido university graduate school of medicine, sapporo, japan we describe novel dermoscopic features observed on the pebbly surface of pseudoxanthoma elasticum (pxe) in two adult cases. clinically, a 45-year-old and a 60-year-old woman showed typical ‘chicken skin’ appearance on the neck and axillary regions. the lesional skin showed hypotrichosis and concomitant comedones. histopathologically the affected areas showed degenerated collagen fibers and calcium deposits in the dermis. notably, dermoscopy clearly revealed that the hypotrichosis was associated with remnant or broken hairs whose follicles were accentuated as brownish dots. in addition, remnant hair follicles were distributed around the yellow pebbly surface, probably corresponding to dermal calcium deposits. furthermore, abnormal hair follicles were located in gaps in the yellow net. consistent with these dermoscopic findings, histopathology showed immature hair follicles that were displaced by degenerated collagen fibers and keratotic plugging. dots in the yellow net pattern would be characteristic dermoscopic feature observed in ‘chicken skin’ regions of pxe. learning process and practice transformation for primary care physicians in the use of dermoscopy r. i. neves1, l. kanzleiter-keister2 1 penn state hershey melanoma center, pennsylvania state university, department of surgery, division of plastic surgery. hershey, pennsylvania, usa 2 department of family and community medicine, pennsylvania state university, college of medicine. hershey, pennsylvania, usa access to health care services takes on a new definition when scheduling visits with specialists in urban areas is a six-month wait listing. this is the case for dermatology consults in pennsylvania. with the rural nature of pennsylvania and exposure to the environment through farming, lumbering and mining, the departments of family medicine and the melanoma center developed a pilot training program for primary care physicians in the use of dermoscopy. physicians were required to complete workshops in real time as well as extensive self-directed activities that developed the knowledge and skills in dermoscopy and the self-confidence and self-efficacy in its application to patient care. this study looked at the learning process as well as the implication to practice transformation, increasing patient access, early diagnosis and avoidance of unnecessary biopsies. references 1. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24:1877-82. 2. carli p, de giorgi v, crocetti e, et al. improvement of malignant/ benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150:68792. dermatoscopic features of basal cell carcinoma a. hlebnikova, n. novoselova department of skin diseases, faculty of post-gradual professional training of physicians, first moscow medical state university i.m. setchenov, russia introduction: basal cell carcinoma is the most frequent cutaneous neoplasm. today all known treatments are effective on the primary stages of bcc, hence it is very important early detection of the tumor. dermatoscopy has proven to be a helpful tool in diagnosing of bcc. methods: dermatoscopic characteristics were analyzed in 57 patients at 42-90 years of age. we observed 73 bccs. multiple bccs were included. all diagnoses were confirmed by the cytologic or pathologic examination. results: among numerous variations in clinical presentation of bcc, such as superficial bcc, nodular bcc, ulcerating bcc, pigmented bcc, sclerosing bcc most common dermatoscopic features were ulceration in 49 bccs (67%); shiny white to red structureless areas in 27 (36%); blue/gray ovoid nests in 13 bccs (17%); leaflike areas in 12 bccs (16%). the vessels were presented by arborizing telangiectasia in 33 bccs (45%), which were more frequent in nodular bccs; hairpin vessels in 33 bccs (45%), short fine telangiectasia in 18 bccs (24%) that was more frequent in superficial bccs. less frequent we observed glomerular vessels, dotted, comma vessels, linear irregular vessels. the large amount of the dermatoscopic features observed proves that the dermatoscope increases our chances of detecting bcc in early stages. the importance of dermoscopy in differential diagnosis of trombosed solitary angiokeratoma mimicking malignant melanoma s. ozturkcan1, m. t. sahin1, c. bilac1, o. tosun2, p. temiz3 1 department of dermatology, celal bayar university medical faculty, manisa, turkey 2 dermatology clinic, manisa state hospital, manisa, turkey 114 supplement | dermatol pract concept 2012;2(2):16 3 department of pathology, celal bayar university medical faculty, manisa, turkey mibelli’s angiokeratoma is a rare benign condition. the lesion is a 2to 8-mm hyperkeratotic or verrucoid nodule that is blue-red or grey and may have a central haemorrhagic crust. it is most often seen on the dorsa of the toes and fingers, knees, elbows, feet, and lateral lower quadrants of the breasts. when extensive thromboses develop in an angiokeratoma, this nodular bluish-black lesion may clinically simulate a nodular melanoma. a 13-year-old girl presented to our outpatient clinic with a one-year history of a dark red-black lesion 0.6x0.8 cm in size on the medial side of her right femoral region. she had a history of bleeding of the lesion following traumas that most of its surface was covered by firm haemorrhagic crusts. dermoscopic examination revealed dark red-black, sharply demarcated haemorrhagic crusts in different sizes, under which red-blue lagoons could be distinguished. moreover, some hairpin vessels supporting malignant melanoma were detected at the periphery of the lesion. finally the lesion was totally extirpated, and based on dermoscopic and histopathologic findings, it was diagnosed as trombosed solitary angiokeratoma of mibelli. in conclusion, dermoscopy seems to represent an effective and reliable method in differential diagnosis between pigmented non-melanocytic (angiokeratoma mibelli) and melanocytic lesions (malignant melanoma). shiny white streaks: a sign of malignancy in skin tumors susana puig, priscila ishioka, danielle shitara, yarel alonso-pinedo, leyla palacios-bejarano, cristina carrera, josep malvehy melanoma unit, department of dermatology.hospital clínic de barcelona, idibaps, barcelona, spain ciber enfermedades raras, instituto de salud carlos iii, barcelona, spain introduction: shiny white streaks (sws) are a new dermoscopic criteria detected under polarized light that have been associated to melanoma and other skin tumours. methods: analysis of 800 dermoscopic images for the evaluation of the presence of sws in the diagnosis of malignant skin tumors. the data set comprised 125 melanomas, 133 basal cell carcinomas (bcc), 305 melanocytic nevi, 49 seborrheic keratosis, 36 actinic keratosis, 21 squamous cell carcinomas (scc), 19 solar lentigos, 11 dermatofibromas, 9 lichenoid keratosis, 1 neuroendocrine carcinoma, and 44 benign tumors (hemangiomas, benign keratomas). results: sws were observed in 107 tumors (13.37%); 41 melanomas (38,32%), 41 bcc (38.32%), 5 nevi (4.67%), 6 dermatofibromas (56,1%), 4 actinic keratosis (3.74%), 3 scc (2.80%), 2 lichenoid keratosis (1.87%), 2 solar lentigos (1.87%), 2 seborrhreic keratosis (1.87%), 1 neuroendocrine carcinoma (0.93%). only 1,6% of all nevi presented sws. the presence of sws suggested a 10-fold risk of malignancy (melanomas, bcc, scc, neuroendocrine carcinoma) (or: 10.534 ic 95% 6.35717.455 p<0.0005). concerning the subtype of bcc data set (133 lesions) they were; 65 superficial (48.87%), 20 infiltrating (15.03%), 35 nodular (26.31%), 9 tricholemmal (6.76%), 3unspecified (2.25%), 1 pigmented bcc (0.75%). among all bcc 30.8% presented sws and there was no significant difference regarding histopathological subtype. interestingly, sws were observed more frequently in ulcerated bccs (p<0.005). conclusions: the presence of sws in a skin tumor is associated to malignancy. except in the case of dermatofibromas, this criterion is rarely seen in benign cutaneous tumours. basal cell carcinoma: the correlations between dermoscopy identified large tumour vessels with tumour thickness and subtype histopathology john pyne1, devendra sapkota1, jian cheng wong2 1,2 from the school of medicine, university of queensland, brisbane, australia 3 school of statistics and mathematics, university of new south wales, sydney, australia background: basal cell carcinoma (bcc) presents with variable thickness in a variety of histopathological subtypes. dermoscopy features of bcc include large diameter blood vessels. objective: to investigate if dermoscopy identified large diameter blood vessels correlate with: (1) thicker tumours and (2) bcc subtype histopathology. method: consecutive bcc cases (n=1098) were assessed in vivo for large diameter blood vessels within the tumour “footprint” prior to full excision. the histopathological identified subtype categories of (1) superficial plus nodular, (2) nodular and (3) aggressive subtypes were compared for the presence of large blood vessels. large vessels were defined as any vessel with a diameter larger than the largest background vessel out to 10mm from the tumour margin. tumours with known previous intervention were excluded. ultrasound gel was applied between the tumour surface and glass plate of the dermatoscopes to avoid vessel compression. data validation was assessed by two observers (n=108) by a cohen kappa value of 0.96 for agreement on the presence of large vessels. results: all 3 bcc categories recorded a higher incidence of thicker tumours with large diameter blood vessels. nodusupplement | dermatol pract concept 2012;2(2):16 115 lar bcc consistently has the highest incidence of large diameter vessels compared to the other subtypes (p<0.005). limitations: cases were not categorized by tumour horizontal size. recurrent tumours were excluded from the study. conclusion: thicker tumours do tend to display larger vessels, although the difference in thickness is relatively small. large diameter vessels add the features used to discriminate bcc subtypes. squamous cell carcinoma: dermoscopy guided assessment of the grade of tumour differentiation john pyne1, devendra sapkota2 and jian wong3 1,2 from the school of medicine, university of queensland, brisbane, australia 3 school of statistics and mathematics, university of new south wales, sydney, australia background: squamous cell carcinoma management and prognosis is influenced by the grade of tumour differentiation. dermoscopy features associated with different grades of differentiation in scc have not been previously reported. objective: compare well differentiated (n=255) to combined moderate and poorly differentiated scc (n=39) with an emphasis on dermoscopy features. method: a prospective study of 294 consecutive cases of histopathology confirmed invasive scc was conducted to compare the dermoscopy features of well with moderate or poorly differentiated scc. dermoscopy vascular features were recorded in vivo and included: branching, serpentine, dot, hairpin, glomerular and linear vessels, the proportion of pink in the tumour and the number of distinct vessel types. these features were identified using a heine delta 20 dermatoscope. photographic images were recorded by a dermlite foto dermatoscope coupled to a canon eos 550d camera. vascular feature validation was assessed for interobserver agreement using kappa values, which ranged from 0.66 to 1.00. results: moderate and poorly differentiated scc, display branching (28%, p<0.001) and serpentine (62%, p<0.005) blood vessels are more frequent than well differentiated tumours. the proportion of pink areas in the tumour varies between differentiation grades. moderate and poorly differentiated tumours display larger numbers of vessel types. increasing tumour depth from 1 to greater than 4mm was found to be associated with an increased proportion of moderate or poorly differentiated scc. limitations: all data was generated using non-polarized light dermoscopy. data was not categorized by anatomic site or tumour horizontal diameter. conclusions: dermoscopy enhances the identification of the grade of tumour differentiation in scc. a novel acquisition device for total body photography j. quintana1, r. campos1, r. garcia1, j. freixenet1, n. gracias1, s. puig2, j. malvehy2 1 computer vision and robotics group, university of girona, girona, spain 2 melanoma unit, dermatology department, clínic hospital of barcelona, barcelona, spain detecting changes in lesions is the most sensitive clinical sign for the early detection of melanoma. thus, some diagnostic procedures incorporated some years ago the ‘evolving’ factor on their methods. this ‘evolving’ parameter measures changes in colour, shape and/or size of pigmented lesions as an early sign of melanoma. total body photography (tbp) has been reported in the literature describing its advantages on diagnosing skin diseases, combining images acquired with high-resolution digital cameras and baseline photography. these images are referenced by patient and date of acquisition and then compared over time with other explorations using specific software to automatically detect changes or by a physician that visually compares them. tbp systems acquire nowadays around 20 images in standardized patient positions covering the face, neck, area behind the ears, scalp (in bald individuals), anterior and posterior trunk, and the extremities (including palms and soles). our proposed method acquires 800 images covering the full body with a much higher resolution (in the order of 25 pixels per millimetre). also the system incorporates a cross-polarized lighting in order to both reduce the reflexions on the images and also to see deeper pigmentation. such volume of images will be mapped to a standard reference system, which encodes a 3d representation of the body of the patient. this allows the registering of the spatial position of each lesion, automatically managing duplicated views of the same lesion from different perspective points. further works will allow lesion segmentation, characterization and automatic comparison. pigmented basal cell carcinoma mimicking cutaneous melanoma in two patients: the diagnostic aid of dermoscopy rejane reginaldi, fernanda tolstoy, juliana marques, dolival lobão, gabriella campos-do-carmo national cancer institute, inca—rio de janeirobrazil introduction: pigmented basal cell carcinoma (bcc) can be clinically confused with melanoma, dermoscopy being 116 supplement | dermatol pract concept 2012;2(2):16 a useful tool in differential diagnosis by identifying criteria that favor one or the other. we present two cutaneous melanoma-simulating lesions to the naked-eye, but with significant bcc dermoscopic features, emphasizing the usefulness of this diagnostic method in the approach of pigmented lesions. case 1: ccpl, white, 19-year-old, male, student, presenting a dark, papular lesion with irregular pigmentation and asymmetric borders on his left arm deltoid region, four years of progress, and a “change-in-aspect” in the last 12 months. dermoscopy revealed ovoid nests, spokewheel-like pigmented structures, and maple leaf-like pigmentation, typical of pigmented bcc. histopathology: bcc case 2: ffa, white, 43-year-old, female, doctor, presenting a 1cm pigmented lesion on her right paravertebral region, crusted surface with a pearly, pigmented edge. dermoscopy revealed arborizing vessels, ovoid nests, specific for pigmented basal cell carcinoma, and a greyish blue veil, more common in melanoma, directing us to a dermoscopic high score, characteristic of lesions at high risk of malignancy. lesion excised. histopathology: bcc. conclusion: dermoscopy can assist in directing the conduct in cases of cutaneous melanoma simulating lesions, and is an essential semiological method for these lesions, once it allows the identification of several criteria for melanocytic and non-melanocytic lesions. in inca, dermoscopy is used as a screening exam for dermathological surgery, allowing faster surgery of melanocytic lesions suggesting melanoma and elective resection of bcc. chaos and clues: an algorithm for the diagnosis of malignancy (any type) in pigmented skin lesions by dermatoscopy cliff rosendahl1, alan cameron1, philipp tschandl2, agata bulinska1, jean-yves gourhant3, harald kittler2 1 school of medicine. the university of queensland, brisbane, australia 2 department of dermatology and venereology, medical university of vienna, austria 3 centre de dermatologie, nemours, france there are a number of published algorithms developed to assist in the diagnosis of malignancy in pigmented skin lesions. many of these algorithms require mathematical calculations making application to routine practice laborious. we present an algorithm based on ‘revised pattern analysis’ known as ‘chaos and clues.’ structures are clearly defined and named with simple geometric, rather than metaphoric, terminology. there is no need to make a presumptuous decision about melanocytic status as a first step. there are no mathematical calculations and the method is designed to integrate seamlessly into routine skin examination. ‘chaos and clues’ was evaluated in a study on 463 consecutively treated pigmented skin lesions, including 29 melanomas, in a primary care practice in australia and was shown to diagnose pigmented skin malignancy (including melanoma, pigmented basal cell carcinoma and pigmented squamous cell carcinoma in situ) with a sensitivity of 90.6% and a specificity of 62.7%. the algorithm is presented on a poster complete with an algorithmic flowchart, a step-by-step explanation of the method illustrated with high resolution dermatoscopy images, and a summary of validation studies. references 1. kittler h. dermatoscopy: introduction of a new algorithmic method based on pattern analysis for diagnosis of pigmented skin lesions. dermatopathology: practical & conceptual. 2007;13(1):3. 2. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad. dermatol 2011;64:1068-73. recovering intrinsic skin reflectance under arbitrary illumination from dermoscopy images maryam sadeghi1,2,3, tim k. lee1,2,3, david i. mclean3, harvey lui2,3, m. stella atkins1,3 1 school of computing science, simon fraser university, vancouver, canada 2 cancer control research and integrative oncology, bc cancer agency, vancouver, canada 3 photomedicine institute, department of dermatology and skin science, ubc, vancouver, canada introduction: new dermoscopes come with a polarization feature that allows the user to reduce the effect of reflections and glare. however, the built-in white leds used for polarization cause a special redial lighting artifact resulting in separate areas of over and under-exposure that must be removed before any image analysis. for example, the consistent lighting is an extremely important feature in segmenting lesions from normal skin. method: we have proposed a new approach that finds intrinsic images by a fast entropy minimization and subtraction. first, two images with different lightings (polarized and non-polarized) are captured from the same skin surface. pixels are transformed from 3d rgb triples into a 2d colour space g/r, b/r, and then logarithms are taken. the values across different lightings tend to fall on straight lines in 2d and change of illumination simply amounts to movement along such lines. therefore, it is straightforward to devise a 1d illumination-invariant image by projecting the 2d chromaticity points into a direction perpendicular to all such supplement | dermatol pract concept 2012;2(2):16 117 lines. we find the projection angle such that minimizes the entropy. this intrinsic images plus a calibration image of the normal skin is used to find the artifact pattern to be subtracted from dermoscopy images to recover the image that portrays only the inherent reflectance properties of skin. results: the qualitative results of our experiments show that the proposed method can significantly improve the quality of images and our quantitative results show 11.5% improvement in skin lesion segmentation accuracy in illumination corrected data sets. dermoscopic and histopathologic diagnosis of inverted follicular keratosis clinically mimicking basocellular carcinoma and lentigo maligna m. t. sahin1, c. bilac1, p. temiz2, s. ozturkcan1 1 department of dermatology, celal bayar university, medical faculty, manisa, turkey 2 department of pathology, celal bayar university, medical faculty, manisa, turkey inverted follicular keratosis is almost always a solitary lesion, occurring mainly in adult life. about 85 % of these lesions are found on the face. the duration of the lesion, when known, has varied between six weeks and three years. most of the lesions are between 3 and 8 mm in maximum diameter. they are generally asymptomatic, firm, pinkish papules. clinically they are often considered to be viral warts, basal cell carcinoma or a variety of benign lesions. they are thought to originate specifically from the infundibulum of the hair follicle. differential diagnosis includes “irritated” seborrheic keratosis, keratoacanthoma, viral warts, and squamous carcinoma, an 85-year-old female patient admitted our out-patient clinics with a complaint of itchy papular lesion on her right cheek for 2 months. dermatologic examination revealed centrally located grey-blue papular lesion 0.5 cm in size, with a peripheral hyperpigmented macular component 1.5 cm in size. dermoscopically, macular part of the lesion was consisting of pseudo-pigment network. central papular lesion was white-grey in colour, where hairpin vessels, linear and glomerular vessels in radial distribution could be seen. on the papular part of the lesion 3 crypt-like structures brown in colour with different sizes were seen. histopathologic examination revealed multilobulated cells with narrow cytoplasm, and slight pleomorphism; focal keratinizations and squamous nests inside the lesion. there was a chronic inflammatory response at the periphery of the lesion consisting of foreign body type giant cells. pas stain was negative. where some immunohistochemical stainings including hmb-45, cytokeratin-7, and s-100 were negative, ema and hmwck were found to be positive. according to these histopathologic and dermoscopic findings our case was diagnosed as inverted follicular keratosis. we present this case to draw attention to the importance of dermoscopy and histopathology in the diagnosis of inverted follicular keratosis. dermoscopic, trichoscopic, and histopathologic findings of a rare case of tufted hair folliculitis m. t. sahin1, c. bilac1, p. temiz2, s. ozturkcan1 1 department of dermatology, celal bayar university medical faculty, manisa, turkey 2 department of pathology, celal bayar university medical faculty, manisa, turkey tufted hair folliculitis which affects the scalp, is a rare, progressive pattern of scarring alopecia. the presence of groups of 10-15 hairs emerging from a single follicular opening in adults is its characteristic feature. tufts of hair associated with scars have been described in association with several other forms of alopecia. staphylococcal organisms frequently are cultured from lesions of tufted hair folliculitis, but their role in pathogenesis is unclear. patients with tufted hair folliculitis report slowly developing hair loss. pain or swelling of the affected scalp frequently accompanies the hair loss. crust and scales adherent to the scalp and hair are frequently seen. the ability to express pus from the follicular orifice is a constant finding. this process usually is limited to a single area of the scalp that enlarges gradually. the most prominent feature of this disorder is the presence of tufts of 8-15 hairs that appear to emerge from a single follicular orifice in a “doll’s hair” pattern. adjacent to and intermingled with the tufts are areas of scarring alopecia, with complete loss of follicles. the area of tufts and scarring is somewhat well circumscribed and may be accompanied by varying degrees of edema, erythema, and tenderness. tufts of hair amid areas of scarring, giving the classic appearance of tufted hair folliculitis, have been described in patients with a number of different disorders, including scars from surgery or trauma, acne keloidalis, folliculitis decalvans, dissecting cellulitis of the scalp, lichen planus, and pemphigus vulgaris. a 37-year-old male patient admitted to our outpatient clinics with complaint of itchy areas on his scalp for 8 years. clinical examination revealed scattered cicatricial alopecia areas and tufted hairs limited to his parietal region. there were crusts and scales around hairs and scalp in trichoscopy. tufts of 8-15 hairs that appear to emerge from a single follicular orifice were seen. perifollicular teleangiectasic erythema was detected in cicatricial areas. we present this rare case to demonstrate and discuss the trichoscopic, dermoscopic, and histopathologic findings of tufted hair folliculitis. 118 supplement | dermatol pract concept 2012;2(2):16 longitudinal melanonychia in children m. sawada, t. matsumoto, k. yokota, m. akiyama department of dermatology, nagoya university graduate school of medicine, nagoya, japan background: dermatologists often come up against a problem of treatment for longitudinal melanonychia in children. clinical, dermatoscopic and pathological criteria that permit clear differentiation between benign melanocytic activation and proliferation from nail matrix melanoma have not been established for children. the clinical and dermatoscopic features that are considered to be possible indicators of nail unit melanoma in adults are sometimes observed in benign melanocytic activation and hyperplasia in children. nail melanoma in children is very rare. thus, there is still a controversy whether a single band of lm with clinical and dermoscopic features that suggest melanocyte hyperplasia in a child should be excised or not. objectives: we aim to provide more insight into the diagnosis of longitudinal melanonychia in children. methods: in the present study, we examined the characteristics of longitudinal melanonychia in children, which have been followed in our institute. results: in some lm lesions in children, color irregularity, irregular lines and triangular pigmentation were seen at first sight. in addition, pigmentation of the periungual skin was sometimes observed. these features were suggestive of malignant melanoma in situ. however, further dermoscopic examinations often revealed features indicating benign nature of the lesions, including regular lines in the lm and parallel furrow, fibrillar, lattice-like and globular patterns in pigmentation on the periungual skin (pseudo-hutchinson’s sign). conclusions: we often encounter embarrassing lm cases in children. however, even in such cases, thorough dermoscopic examinations might give us clues to deny malignant melanoma. references 1. tosti a, piraccini bm, de farias dc. dealing with melanonychia. semin cutan med surg. 2009;28(1):49-54. 2. tosti a, piraccini bm, cagalli a, haneke e. in situ melanoma of the nail unit in children: report of two cases in fair-skinned caucasian children. pediatr dermatol. 2012;29(1):79-83. how many malignant melanomas might we miss when not using the dermoscopy? a. shalom1, s. sandbank1, a. scope2 1 department of plastic surgery, assaf harofeh medical center, zerifin, israel 2 dermatology department, sheba medical center, ramat gan, israel introduction: dermoscopy is a portable tool for the diagnosis of pigmented skin lesions. the aim of this prospective study was to evaluate how many malignant melanomas might not be excised based on clinical examination alone, but would be removed if dermoscopy were used. the secondary aim was to describe the morphologic characteristics of these misdiagnosed (false negative) mms. material and methods: all patients coming for a routine check-up underwent a total body clinical examination, followed by dermoscopic evaluation. lesions found to be suspicious on either clinical or dermoscopic evaluation were excised for histopathologic examination. prior to surgical removal, the clinical and the dermoscopic index of suspicion was scored, categorized on a scale of: 0not suspicious for mm, 0.5low index of suspicion 1high index of suspicion for mm, and clinical and dermoscopic imaging was performed. for all biopsy-proven mms, the clinical and dermoscopic scores were retrospectively evaluated and proportions of true positive mms (clinical and dermoscopic scores >0) and false negative mms (clinical or dermoscopic scores =0) were compared using chi square test. images of those that received a clinical or dermoscopic score of 0 were evaluated and the morphologic characteristics of those false negative mms were described. results: between august 2008 and august 2010, 5700 patients came for routine examination. fifty-nine biopsyproven mms (1%) were identified. the proportion of mms receiving a clinical score of 0 was 27%, 0.5 was 33% and 1 was 40%; dermoscopy was more accurate in identifying true positive mms, the proportion of mms receiving a dermoscopic score being 0 was 15%, 0.5 was 3% and 1 was 82% (p< 0.01). among these 59 mms, 16 (27%) of mm received a clinical score of 0 (false negative mms); 3 of them (18.7%), would still have been excised because of clinical suspicion for bcc, but other 12 lesions (81.3%), would not have been excised on clinical grounds alone. the false negative mms were morphologically characterized as being significantly smaller in size and having a light color or being amelanotic higher than true positive mms. conclusions: dermoscopy enable the clinician to correctly diagnose a subset of mms that would be false negative mms on clinical examination alone. especially, dermoscopy is helpful above and beyond clinical examination for smaller and lightly pigmented mms. proportion of malignant to benign skin lesion excision at the era of dermoscopy a. shalom, n. zmora department of plastic surgery, assaf harofeh medical center, zerifin, israel supplement | dermatol pract concept 2012;2(2):16 119 introduction: since dermoscopy had been introduced and popularized many authors quote the ration of 4 to 1 (benign to malignant pigmented lesion rationevus to mm) at the highly skilled pigmented lesion clinics, to be a magic number reflecting the efficiency of dermoscopy in reducing unnecessary skin lesion excision. but in true life plastic surgeons and dermatologist are excising a great variety of other skin lesion. in this prospective study we are evaluating the work of one plastic surgeon and calculating the ratios between the different types of excised skin tumors with and without dermoscopy. material and methods: from august of 2008 until july 2010 all cutaneous lesions that were excised by a single plastic surgeon were first examined by dermoscopy and then the lesions were photographed with the dermoscope. all excised cutaneous lesions were recorded in the surgeon logbook and in a computerized database according to the pathology report in a standardized manner; this was defined as the study group. the control group compared of all patients that were treated by the same surgeon between october 2001 to december of 2003 in which the entire log book with the clinical evaluation and pathology reports was available, and at that time patients had only clinical evaluation without dermoscopy examination. once the data was gathered, analysis using excel program was used in order to evaluate the exact ratios of each type of lesion excised as part of the total excised skin lesion, the total malignant to benign ratio was determined and the ratio of benign to malignant ratio of the pigmented lesion was calculated as well (malignant melanoma to nevus). the proportion of the different types of malignant tumors within the total malignant lesions, and the proportion of the different types of benign lesions within the benign lesions group was calculated as well results: in the study group 1817 lesions were excised, there were 1491 (82%) benign lesions and 329 (18%) malignant lesions. in the dermoscopy group 2162 lesion were excised, there were significantly less benign lesions excised 1278 (59%), and significantly more malignant lesions 884 (41%) excised. the ratio of nevus to melanoma was 1:34 and it has been decreased significantly to 1:12 on the dermoscopy group. the ratios between the different malignant lesions had an increase in the bcc and mm excision in the dermoscopy group. the overall mm excision has doubled from 1:90 to 1:44 from all excisions. discussions: dermoscopy has proved to be an efficient tool to prevent unnecessary skin biopsies. it has increasing significantly the proportion of malignant lesions excised, and doubled the amount of mm excision. it has a significant impact on morbidity reduction (reducing the amount of unnecessary surgeries), and great economic saving impact by the same manner. clinical behaviour of the desmoplastic melanoma subtype sarah shen, benny zhang, john spillane peter maccallum cancer centre, melbourne, australia introduction: desmoplastic melanoma (dm) has been shown to have adverse features including deeper invasion, propensity for perineural spread, and higher rates of local recurrence and distant metastasis. current literature has focused on the subclassification of dm into pure (pdm) and mixed (mdm) subtypes and their differing capacity for nodal spread and recurrence. we report a single institution’s experience of dm, examining the clinical behavior of the two histologic subtypes and implications for management. methods: a 10-year review of all patients diagnosed with dm at the peter maccallum cancer centre was undertaken. cases were divided into 2 groups based on histologic classification: pdm and mdm. results: sixty-five patients were reviewed (42 pdm and 23 mdm patients). the majority of both subtypes arose in the head and neck with presentation as a pigmented lesion more frequent for mdm (60.9% vs 38.1%). breslow thickness was greater in the pdm than in the mdm group (mean 7.0 vs 3.5mm). one of 11 pdm and none of 5 mixed dm patients had positive sentinel lymph node bopsy (slnb). disease recurrence occurred in 26 of 61 patients (43%) overall (14 mdm and 12 pdm patients). regional ln metastasis was seen in 18% of patients with a higher rate seen in the mdm group. conclusion: clinicopathologic features of pdm and mdm subtypes differ. despite a low rate of positive slnb, a significant number of both pdm and mdm patients developed regional nodal disease. these factors should be taken into account when managing the different subtypes of dm. references 1. george e, mccain se, slingluff cl, polissar nl, patterson jw. subclassification of desmoplastic melanoma: pure and mixed variants have significantly different capacities for lymph node metastasis. j cutan pathol. 2009;36:425-32. 2. busam kj. cutaneous desmoplastic melanoma. adv anat pathol. 2005;12:92. 3. pawlik tm, ross mi, prieto vg, et al. assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma. cancer. 2006;106:900. dermatoscopy follow-up examination of clinically atypical nevi d. sokolov1, i. boulytcheva1, a. makhson1, g. vorozhtsov2, s. kuzmin2, v. sokolov2 1 moscow city oncological hospital n62, moscow, russian federation 2 sue “iscc “intermedbiophyschem,” moscow, russian federation 120 supplement | dermatol pract concept 2012;2(2):16 introduction: dysplastic nevus has got a definite set of clinical, dermatoscopy and morphological features and shows a high risk of skin melanoma occurrence. statistical research data reveal that from 7 to 18% of the total population are patients with dysplastic nevus. however, despite the revealed clear correlation between a dysplastic nevus and high risk of skin melanoma occurrence, the referential data demonstrate that the majority of the dysplastic nevi never developed into a melanoma. method: in moscow oncological hospital κ 62, the dermatoscopy follow-up examination was carried out from 2004 through 2008 to monitor the dynamics in structure of melanocytic nevi in 44 patients with high risk of melanoma. the total number of investigated clinically atypical nevi was 223. the final diagnosis was based on histopathological examination. results: a definitely clear change in the dermatoscopy structure was recorded in 10.3% of the total clinically atypical melanocytic nevi. all the changed nevi had the features of the melanocytic dysplasia of different categories. in 75% of clinically diagnosed atypical nevi, there was no evidence of the melanocytic dysplasia and there was no change in the nevi dimension or structure for the follow-up period of 6 to 24 months. the obtained data of dynamic dermatoscopy examination demonstrate that the noninvasive method in question should be applied to detect the skin melanoma at its early stages, dysplastic nevus and to reduce the number of excisions of clinically atypical benign melanocytic skin lesions. subclinical extension of morphea-like basal cell carcinoma: hyperspectral evaluation t. nagaoka1, y. kiyohara2, a. nakamura1, a. yamaguchi3, and t. sota1,3 1 waseda research institute for science and engineering, waseda university, shinjuku, tokyo, japan 2 department of dermatology, shizuoka cancer center hospital, nagaizumi, shizuoka, japan 3 department of electrical engineering and bioscience, waseda university, shinjuku, tokyo, japan background: it is important to evaluate subclinical extension of morphea-like basal cell carcinoma (bcc) before planning surgery because recurrence may be caused by incomplete tumor excision. dermoscopy and/or ultrasonography sometimes fails to identify the extent of subcutaneous involvement. aim: to verify the usefulness of hyperspectral images of bcc in identifying the extent of subcutaneous involvement and setting the margin required for complete tumor excision. patient and method: the patient was a 64-year-old japanese female. the pigmented tumor was located on the nose. dermoscopic and ultrasonographic images were taken and hyperspectral data were measured using a hyperspectral imager (msi-03: mitaka kohki, japan). the hyperspectral data were analyzed and converted into several images using an original spectral analysis algorithm. the resultant images were compared with the dermoscopic and ultrasonographic images and, furthermore, with histopathological findings. results and discussion: an image constructed from the hyperspectral data satisfactorily represented subclinical extension of morphea-like bcc, while dermoscopic images could not. the radial size was consistent with the tumor size estimated based on the histopathological examination. with respect to the ability to predict tumor size, hyperspectral images are superior or at least comparable to ultrasonographic images. the hyperspectral imaging technique presented here is considered to have considerable promise in setting the margin required for complete tumor excision. trichoscopy of adult alopecia areata—a pattern study alin tatu private practice and)faculty of medicine and pharmacy, dunarea de jos university, galati, romania dermoscopy of hair-trichoscopy allows exploration of the hair at 10 to 800x and to observe precisely the types of hair, follicular openings, the peripilar signs and to follow up the evolution of the disease or the treatment efficacy prior to naked eye clinical observation. i studied 84 adults with 143 plaques of alopecia areata by trichoscopy before and after 3 months of treatment. 71,3% of plaques had regularly distributed yellow dots, corresponding to hyperkeratotic plugs in hair follicle. 51,7% had exclamation mark hair. 46,1% had dystrophic–broken hair; 27,9% had cadaverised hairs, black dots in the hair follicles. 8,8% had short pseudo regrowing hairs that are apparently regrowing but they are atrophic hairs and are a sign of activity of alopecia areata. they mostly disappear at 3 months trichoscopic follow up. 13,2 % had corkscrew hairs; 4,8% had circle hairs; 4,1% had vellus hairs-0,03 mm or less in thickness; 3,5% had white dots-feature of fibrosis; they have extensive persistent alopecia areata. i did not find any pseudo moniletrix hairs. the most frequent pattern is the presence of regular yellow dots (71,3 %), the second the presence of exclamation mark hairs (51,7%), and the third is the presence of dystrophicbroken hairs (46,1 %). the presence of pseudo regrowing hairs is a sign of the activity of alopecia areata. they are thin hairs that differ from normal thick, real regrowing hairs, sign of treatment efficacy. supplement | dermatol pract concept 2012;2(2):16 121 references 1. rudinicka l, olszewska m, rakowska a, et al. trichoscopy: a new method for diagnosing hair loss. j drugs dermatol. 2008;7(7):6514. 2. tosti a. dermoscopy of hair and scalp disorders: pathological and clinical correlations. informa healthcare. 2008:1-168. blue-white variant of pigmented basal cell carcinoma m. turkmen1, b. gerceker turk1, i. kilinc karaarslan1, b. yaman2, f. ozdemir1 1 ege university medical faculty, department of dermatology, izmir, turkey 2 ege university medical faculty, department of pathology, izmir, turkey introduction: the typical dermoscopic features of basal cell carcinomas have been well known. besides them, some other dermoscopic features such as multiple brown to black dots and globules, blue/white veil-like structures, and nonarborizing vessels have also been described. recently, “diffuse blue-white areas” has been reported as a dermoscopic pattern in some pigmented bccs, namely “blue-white variant.” method: we aimed to evaluate our cases with blue-white variant of basal cell carcinoma seen at the dermoscopy unit between 2003 and 2011. we reviewed the patient files; and for the cases with blue-white variant of basal cell carcinoma, the clinical and dermoscopic images and histopathological sections were re-evaluated. results: eleven cases were detected. three of them were excluded because of poor image quality. eight cases (2 females, age ranged 45-66 years) were included. on dermoscopy, diffuse blue-white areas were observed together with arborizing telangiectasia, non-arborising vessels, focal areas of ulceration, milia-like cysts or thin scales. in all of them, melanoma was considered in the differential diagnosis. histopathologically all of the lesions were compatible with nodular or nodulo-ulcerative type of pigmented bcc. diffuse blue–white areas corresponded to aggregates of basaloid cells together with the diffusely distributed pigmented melanophages in the stroma. although this type of pigmented bcc is rare, it needs a special attention mimicking a melanoma. references 1. altamura d, menzies sw, argenziano g et al. dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. j am acad dermatol. 2010;62(1):67-75. 2. scalvenzi m, lembo s, francia mg et al. dermoscopic patterns of superficial basal cell carcinoma. int j dermatol. 2008;47 (10):1015-8. dermoscopic features of linear porokeratosis: different aspects in its development m. turkmen1, b. gerceker turk1, i. kilinc karaarslan1, g. kandiloglu2, f. ozdemir1 1 ege university medical faculty, department of dermatology, izmir, turkey 2 ege university medical faculty, department of pathology, izmir, turkey linear porokeratosis (lp) is a rare form of porokeratosis characterized by linear hyperkeratotic papules and annular plaques arranged along the blaschko lines. here, we report a case and describe the dermoscopic features of lp for the first time. a twenty-two-year-old-woman had red-brown hyperkeratotic linear and annular plaques with elevated borders extending from the right mammary to the right axilla along the blaschko lines. the dermoscopic features observed in the case were varying according to the age of the lesions. the “early” papular lesions exhibited peripheral, thin whitish-yellow “thread-like structure” together with brown-black dots at the inner side. the early plaques revealed the same peripheral thread-like structure, however the dots were at the outer side and the ones in the inner part coalesced to form a gray-brown “network-like appearance.” the early larger plaques showed linear arrangement of these dots both in the inner and the outer side of this thread-like peripheral structure, thus appeared as a “whitish-yellow track” together with a network-like appearance at the center again. the “mature” plaques showed the peripheral whitish-yellow track together with a central “reddish vascular network” instead of gray-brown network-like structure. finally in the oldest lesions central “pinkishwhite scar like area” accompanied the features of the mature plaques. dermoscopic features of other types of porokeratoses have been defined in a few case reports in the literature. however, to our knowledge, the dermoscopic features of lp are described for the first time. in addition, we point out “the variation of the dermoscopic findings in relevance to the age” and a new dermoscopic feature, “the gray-brown pigment network-like appearance,” which may help improve the clinical and differential diagnosis. references 1. pizzichetta ma, canzonieri v, massone c, soyer hp. clinical and dermoscopic features of porokeratosis of mibelli. arch dermatol. 2009;145(1):91-2. 2. panasiti v, rossi m, curzio m, bruni f, calvieri s. disseminated superficial actinic porokeratosis diagnosed by dermoscopy. int j dermatol. 2008;47(3):308-10. 122 supplement | dermatol pract concept 2012;2(2):16 the open pores with plugs in porokeratosis clearly visualized with the dermoscopic furrow ink test h. uhara1, a. miyazaki2, h. koga1, k. matsumoto1, r. okuyama1, t. saida1 1 department of dermatology, shinshu university school of medicine, matsumoto, japan 2 department of dermatology, suwa red cross hospital, suwa, japan porokeratosis was named based on mibelli’s concept that the column of parakeratosis, the cornoid lamella, emerges only from ostia of eccrine ducts. however, in 1970, reed et al. proposed the cornoid lamella was not originated from the ostia of eccrine duct. although this hypothesis has been generally accepted, some researchers have reported that cornoid lamella is sometimes seen in infundibular and eccrine ductal epithelium as well as epidermis. several dermoscopic findings of porokeratosis have been reported, including the whitish peripheral rim, the brown globules and/or dots, red dots/red lines and scar like structures in the center of the lesions. we studied 5 cases of porokeratosis of mibelli dermoscopically. in all cases, dermoscopic findings showed the small shining white or brown spots inside the lesions. the staining of the skin surface by white board marker (furrow ink test) visualized more clearly multiple open pores with plugs and some of which corresponded to hair. pathological findings showed that keratotic column was seen in the part corresponding to hair and sweat pore. open pores might be an important sign suggesting porokeratosis. the staining method by white board marker, furrow ink test, could allow us to better visualize the texture of skin. dermoscopic findings in bowen’s disease on the lip tomoaki yokoyama1, takeru funakoshi1, akiko tanikawa1, masayuki amagai1, keisuke okabe2, kazuo kishi2 1 department of dermatology, keio university school of medicine, tokyo, japan. 2 department of plastic and reconstructive surgery, keio university school of medicine, tokyo, japan a 37-year-old japanese male presented with a 4-month history of a solitary dark brown plaque located on the right angle of the mouth. there was no significant medical history, and he was otherwise healthy. on the physical examination, there was a well-demarcated, solitary dark brown plaque that measured 7.8 x 5.6 mm in size. dermoscopic examination demonstrated slate-blue dots/ globules and irregular blue-white network in the center of the lesion. atypical vascular pattern and multiple gray to brown dots in lines were observed at the periphery. glomerular vessels were not observed. we suspected a pigmented skin lesion and performed the excisional biopsy. the histopathology showed the psoriasiform pattern with regular acanthosis with thickening of the rete ridges and overlying hyperkeratosis. epidermis showed full-thickness involvement with an atypical keratinocytes. atypical mitoses were also observed. basal hyperpigmentation was observed. dermal papillae are elongated upward and filled with melanin pigment. there was no evidence of dermal invasion. inflammation was not observed in the dermis. in the papillary and reticular dermis, numbers of dilated vessels were increased. considering these findings, the diagnosis of pigmented bowen’s disease was made and the local wide resection was performed by the plastic surgeon. bowen’s disease on the lip is exceedingly rare and this is the first reported case featuring the dermoscopic findings as far as we know. we discuss the dermoscopic/dermatopathologic correlation and conclude that bowen’s disease should be considered in the differential diagnoses of mucosal pigmented lesions. the impact of sub-specialization and dermatoscopy use, on accuracy of melanoma diagnosis among primary care doctors in australia cliff rosendahl1, gail williams1, diann eley1, tobias wilson2, greg canning2, jeffrey keir2, ian mccoll3, david wilkinson1 [j am acad dermatol10.1016/j.jaad.2011.12.030] 1 school of medicine, the university of queensland, australia 2 the skin cancer college of australia and new zealand, brisbane, australia 3 australian institute of dermatology, john flynn hospital, tugun, qld, australia introduction: dermatoscopy improves accuracy of melanoma diagnosis but the impact of sub-specialization in skin cancer practice among general practitioners on melanoma diagnostic accuracy is not known. objective: to assess the impact of dermatoscopy use and sub specialization on the accuracy of melanoma diagnosis by general practitioners. methods: we did a prospective study on the skin cancer audit research database and measured melanoma ‘number needed to treat’ (nnt), with 21,900 lesions excised to diagnose 2,367 melanomas. results: melanoma nnt fell from a high of 17.0 (95% confidence interval [ci] 14.5-20.7) among general practitioners with a generalist practice to 9.4 (8.9-10.1), among supplement | dermatol pract concept 2012;2(2):16 123 those with a specific interest in skin cancer, and 8.5 (8.19.0) among those practising only skin cancer medicine (p<0.0001). melanoma nnt fell from a high of 14.6 (12.018.6) among dermatoscopy low / non-users, to 10.9 (9.812.4) among medium users, and 8.9 (8.6-9.3) among high users (p<0.0001). the association between nnt and practice type remained (p<0.0001) when adjusted for dermatoscopy use and other variables. the association between nnt and dermatoscopy use disappeared (p=0.41) when adjusted for practice type and other variables. limitations: there is selection bias with respect to participating doctors and completeness and accuracy of data are not independently verified in scard. conclusions: general practitioners who subspecialize in skin cancer have a higher use of dermatoscopy and diagnose melanoma with greater accuracy than their generalist counterparts. references 1. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159:669–76. 2. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3:159–65. 3. rosendahl c, hansen c, cameron, et al. measuring performance in skin cancer practice: the scard initiative. int j dermatol. 2011 jan;50(1):44–51. dermatology: practical and conceptual commentary | dermatol pract concept 2020;10(3):e2020091 1 dermatology practical & conceptual with the sudden onset of the covid-19 pandemic crippling the world, dermatologists are using teledermatology to care for their patients remotely. diagnosing skin cancer with only clinical photos alone is difficult, and as patients do not have access to a dermatoscope and are isolated at home, a simple technique using a disinfection spray, cooking oil, or water and a camera has shown promising results. the patient applies the immersion fluid on the lesion of concern and takes 1-3 focused images with a camera distance of ~20-30 cm using ambient indoor or outdoor light for illumination (figure 1). to obtain better image quality, hairs should be removed and air bubbles should be avoided. the diagnosing dermatologist will enlarge the focused images on the computer screen, analyze the visible morphologic features and colors of the upper layers of the epidermis, and make further recommendations. home dermoscopy during the covid-19 pandemic andreas blum1, michelle menzies2 1 public, private and teaching practice of dermatology, konstanz, germany 2 skintography, sydney, australia key words: home dermoscopy, pandemic, covid-19 citation: blum a, menzies m. home dermoscopy during the covid-19 pandemic. dermatol pract concept. 2020;10(4):e2020091. doi: https://doi.org/10.5826/dpc.1004a91 accepted: may 27, 2020; published: october 26, 2020 copyright: ©2020 blum and menzies. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: andreas blum, md, msc, augustinerplatz 7, 78462 konstanz, germany. email: a.blum@derma.de figure 1. dermatoscope-less recording of a skin lesion of interest with visible morphologic features. 2 commentary | dermatol pract concept 2020;10(3):e2020091 eccentric streaks (arrows) and an eccentric hyperpigmentation (asterisk) with dark brown and black colors, and histopathology confirmed the diagnosis of an early invasive melanoma (tumor thickness 0.4 mm). it must be mentioned that this simple approach of “home dermoscopy” does not replace medical examination with a real dermatoscope. two cases demonstrate this simple technique: (1) a 20-year-old male with a new nodular lesion on his shoulder (figure 2). the enlarged image showed dotted vessels (arrows) and pink color. urgent surgery with histopathology was recommended to exclude the spitzoid melanoma or to confirm the benign spitz nevus (as in this case). (2) a 24-year-old female with a growing lesion on her leg (figure 3). the enlarged image revealed figure 2. enlarged image on screen revealed morphologic features of dotted vessels (arrows) and pink color; histologically a benign spitz nevus was confirmed. figure 3. enlarged image on screen revealed morphologic features of eccentric streaks (arrows) and an eccentric hyperpigmentation (*) with dark brown and black colors; histologically an early invasive melanoma (tumor thickness 0.4 mm) was confirmed. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(1):e2020008 1 dermatology practical & conceptual case presentation a 54-year-old-man diagnosed with a deficiency of interleukin-36 receptor antagonist (ditra) under anti-interleukin-1 therapy with anakinra (described elsewhere [1]) presented with an erythrodermic pustular psoriasis 5 months after suspension of his biological treatment (figure 1a). anakinra and topical corticoids were then initiated. three days later, a halo of nonreddened skin circumscribing an erythematous pustular plaque was observed on his right side (figure 1b). the patient showed a complete clinical response in the following weeks. teaching point ditra is an autoinflammatory disorder caused by mutations in the ilrn36 gene, characterized by abrupt-onset episodes of generalized pustular psoriasis, fever, and systemic woronoff ring in deficiency of interleukin-36 receptor antagonist (ditra) daniel morgado-carrasco,1 sebastian podlipnik,1 josé m. mascaró, jr1 1 department of dermatology, hospital clínic de barcelona, universitat de barcelona, spain keywords: woronoff ring, psoriasis, ditra, deficiency of interleukin-36 receptor antagonist, anakinra citation: morgado-carrasco d, podlipnik s, mascaró jm jr. woronoff ring in deficiency of interleukin-36 receptor antagonist (ditra). dermatol pract concept. 2020;10(1):e2020008. doi: https://doi.org/10.5826/dpc.1001a08 accepted: september 5, 2020; published: december 31, 2019 copyright: ©2019 morgado-carrasco et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: josé m. mascaró, jr, md, department of dermatology, hospital clínic de barcelona, barcelona, spain. email: josemanuel.mascaro@gmail.com figure 1. woronoff ring in deficiency of interleukin-36 receptor antagonist (ditra). (a) widespread erythematous and pustular rash on the trunk. (b) halo of nonreddened skin circumscribing an erythematous pustular plaque on the right side (3 days after initiating anakinra and topical corticosteroids). mailto:josemanuel.mascaro@gmail.com 2 image letter | dermatol pract concept 2020;10(1):e2020008 references 1. podlipnik s, morgado-carrasco d, fustà-novell x, et al. dynamics of plasma cytokines in a patient with deficiency of interleukin-36 receptor antagonist successfully treated with anakinra. br j dermatol. 2018;178(4):e258-e260. 2. park kk, swan jw, eilers d, tung r, koo j. woronoff ring associated with adalimumab therapy for psoriasis. cutis. 2014;93(2):e1-e2. involvement. the woronoff ring is an underrecognized sign of psoriasis, a halo of nonerythematous skin surrounding psoriatic plaques. its pathogenesis is not fully understood; a relative deficiency of prostaglandins and endoglin has been reported. the woronoff ring can occur after topical corticoid or tar treatment, fumaric acid esters, phototherapy, biological therapy [2], or even in untreated psoriasis. observation | dermatol pract concept 2012;2(1):4 25 langerhans cell histiocytosis – a case report thiago jeunon, m.d.1, maria auxiliadora jeunon sousa, m.d.2, nilton santos-rodrigues, m.d.2, raquel lopes, m.d.3 1 departments of dermatology and pathology, hospital federal de bonsucesso and id-investigação em dermatologia, rio de janeiro, brazil 2 id-investigação em dermatologia, rio de janeiro, brazil 3 department of dermatology, hospital federal de bonsucesso, rio de janeiro, brazil key words: langerhans cell histiocytosis, langerhans cell, dermatology, histopathology, diabetes insipidus, hypogonadotropic hypogonadism citation: jeunon t, jeunon sousa ma, santos-rodrigues n, lopes r. langerhans cell histiocytosis – a case report. dermatol pract conc. 2012;2(1):4. http://dx.doi.org/10.5826/dpc.0201a04. editor: harald kittler, m.d. received: april 15, 2011; accepted: august 1, 2011; published: january 31, 2012 copyright: ©2012 jeunon et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: thiago jeunon, m.d., rua barão de mesquita 200/901 tijuca, rio de janeiro – rj, brasil cep:20540-003. tel/fax. +55 21 22340722. email: thiago.jeunon@gmail.com. dermatology practical & conceptual www.derm101.com a 17-year-old male presented for dermatologic consultation with slightly elevated reddish papules covered by yellowish scales in the scalp for the last two years and reddish and indurated ulcers in the perineum lasting six months. additional complaints included polyuria, polydipsia, delay in the development of secondary sexual characteristics and hearing loss of the right ear secondary to a medium otitis. lesions from scalp and perineum were sampled for histopathologic examination and revealed a dense cellular infiltrate made up of mononuclear cells with conspicuous eosinophilic cytoplasm and large cleaved vesicular nucleus, some of them with shapes resembling the format of a kidney and others reminiscent of coffee beans. numerous intermingling eosinophils were present. the diagnosis of langerhans cell histiocytosis was then rendered and confirmed by positive immunostaining of neoplastic cells for anti-cd1a and anti-s100 protein antibodies. the work-up revealed diabetes insipidus, hypogonadotropic hypogonadism, hiperprolactenemia, growing-hormone deficiency and thickness of the pituitary stalk. the patient was treated with prednisone and vinblastin based chemotherapy regimen for six months with complete remission, but presented recurrence of some lesions in the scalp, which were handled with topical mustard and corticosteroids. after chemotherapy, the endocrinologic disturbances were corrected with hormonal replacement therapy. the patient is currently in good health with a follow-up of five years. abstract 26 observation | dermatol pract concept 2012;2(1):4 case presentation a 17-year-old white male presented to dermatological consultation with some asymptomatic, slightly elevated, erythematous papules covered by yellowish scales in the scalp vertex and temporal regions of two years’ duration and small indurated ulcers with elevated borders at the perineum for six months (figure 1). he complained of urinary frequency (up to 20 times/day) and excessive thirst (up to five liters of water/day) which were previously diagnosed as manifestations of primary polydipsia. there was a delay in the development of secondary sexual characteristics and a hearing loss in the right ear secondary to a medium otitis five years before the present consultation. he also complained of low stature in comparison to his high school peers. actually, his height was 1.70 m, being at the 25th percentile according to the cdc 2000 growth chart (height versus age percentile graphic). in addition to the skin lesions, physical exam showed slight bilateral gynecomastia, absence of terminal hairs in the beard area, axillae and pubis, as well as underdevelopment of testicles and penis (figure 2). there were no lymph node or visceral enlargements. one scalp lesion and another one from the perineum were biopsied and both revealed a dense cellular infiltrate made up of mononuclear cells with conspicuous eosinophilic cytoplasm and large cleaved vesicular nucleus, some of them with shapes resembling the form of a kidney or of a coffee bean. the infiltrate was disposed in the superficial and middle dermis, assumed a band-like array and formed a sheet of cells in some areas. in other foci, in which neoplastic cells were sparser, numerous intermingling eosinophils were present (figure 3). the surface of the perineal lesion was ulcerated, while in the lesion of the scalp some neoplastic cells were present between the keratocytes of an otherwise preserved epidermis. the diagnosis of langerhans cell histiocytosis (lch) was made based on morphologic criteria and confirmed by positivity of abnormal langerhans cells by anti-cd1a and anti-s100 immunostains and negativity for anti-cd68. the patient was admitted to the adolescent ward for additional investigation. he had mild anemia, normal basic biochemistry tests, negative serologic tests for syphilis and negative mycological tests of the lesions (direct exam and culture). total skeleton radiograph and scintigraphy failed to show any bone lesion. thorax radiography, abdominal ultrasonography and computerized tomography of the abdomen were normal. the setting of hypogonadotropic hypogonadism was defined by blood dosage of lh (0.10 mui/ml, normal range of 0.8 – 7,6), fsh (0.53 mui/ml, normal range of 0.7-11.1), total testosterone (27.0 ng/dl, normal range: 241-827) and free testosterone (0.50 pg/dl, normal range of 120–550) and hyperprolactenemia by the high blood level of prolactin (32.6 ng/ml, normal range of 4.6–21.4). diabetes insipidus was confirmed by water restriction test, in which the patient was unable to concentrate the urine, in spite of an increase of concentration of blood sodium from 139-149 meq/l and development of arterial hypotension. all these parameters were reversed after administration of figure 1. (a) slightly elevated erythematous papules covered by yellowish scales in the vertex of the scalp. (b) reddish scaly papules at the temporal region. (c) three ulcers at the perineum, one with elevation of the borders. [copyright: ©2012 jeunon et al.] a b c observation | dermatol pract concept 2012;2(1):4 27 anti-diuretic hormone analog, which the patient continues to take. an insulin-induced hypoglycemia provocative test demonstrated gh deficiency, but cortisol secretion was preserved. blood tsh and free t4 were within the normal range. magnetic resonance imaging of the sella turcica showed thickening of the pituitary stalk and size reduction of the pituitary, suggesting infiltration of the neurohypophysis by the abnormal langerhans cells. there was no indication at the mri of other pathologic process that could explain the endocrinologic disturbances. the final diagnosis was of lch with involvement of the skin, the pituitary stalk (diabetes insipidus and hyperprolactenemia), and the anterior pituitary (hypogonadotropic hypogonadism and gh deficiency). the patient was treated with a chemotherapy regimen consisting of an induction phase with prednisone 40 mg/m2/day every day for four weeks with withdrawal for two additional weeks and vinblastin 6mg/m2 iv bolus once a week in the first six weeks. the consolidation phase lasted six months with five days of prednisone 40 mg/m2/day and one application of vinblastin 6 mg/m2 iv bolus every three weeks. the patient experienced complete remission (figure 13), and after the end of chemotherapy his puberty was induced by hormonal replacement therapy. some months later, there was recurrence of lesions in the scalp confirmed on histopathologic grounds, which were successfully treated with topical corticosteroid and nitrogen mustard. the patient is currently in good health with a follow up of six years. conclusion lch is a considerably rare disease with 4.1-4.6 cases for each million children and is regarded as an idiopathic monoclonal proliferation of abnormal langerhans cells [1]. whether it is an inflammatory condition or a true neoplasm has been a matter of debate [2,3]. those cells may infiltrate and affect any organ, such as skin, pituitary, bones, lungs, brain and lymph nodes, liver, spleen, or hematopoietic system. lch presents with a broad spectrum of manifestations, varying from solitary lesions to disseminated, multisystem, life-threatening disease. previous to the unifying concept advanced by jaffe and lichtenstein in 1944, some clinical syndromes had been independently described and later named eponymously [4]. letterer-siwe disease usually occurs in children under one year of age, has a poor prognosis and manifests itself as fever and skin rash, hepatomegaly, splenomegaly, pulmonary symptoms and anemia [5]. hand-schuller-christian disease usually affects children older than three years old and is defined by the triad of exophthalmos, diabetes insipidus and skull defect. eosinophilic granuloma refers to a single bone lesion in older children, teenagers or adults with symptoms of pain, swelling and, eventually, pathologic fracture, but with a very good prognosis [1,5,6]. however, many cases do not fit exactly in any of these late descriptions, which have more historical importance than clinical usage and, currently, cases have been classified into two major categories: (1) “single-system” lch, subdivided further into unifocal (single lesion on bone, skin or lymph node) or multifocal (multiple lesions on bone or multiple lymph nodes) and (2) “multi-system” lch, when disease affects two or more different organs, with subdivision into low-risk or highrisk groups depending on the absence or presence of involvement of liver, lungs, spleen or hematopoietic system [2]. lch affects the skin in about 40% of cases. typically, the cutaneous lesions consist of small translucent, skin-colored, yellowish, red, or even purpuric scaly papules, usually located on the trunk and scalp. vesicles and pustules may also come into being. nodular lesions are particularly presfigure 2. (a) slight bilateral gynecomastia and absence of terminal hairs in beard area and axillae. (b) underdevelopment of genitalia in relation to age. [copyright: ©2012 jeunon et al.] a b 28 observation | dermatol pract concept 2012;2(1):4 figure 3. (a) langerhans cell histiocytosis, perineal lesion, scanning magnification. note the dense band-like cellular infiltrate in the dermis and ulceration at the right side of the section (h&e, x20). (b) band-like cellular infiltrate in the superficial and middle dermis. the intense pink areas correspond to clusters of eosinophils and the paler pink areas correspond to groups of abnormal langerhans cells (h&e, x100). (c) abnormal langerhans cells with vesicular cleaved nucleus and numerous intermingling eosinophils (h&e, x400). (d) cytological details of abnormal langerhans cells. note the amphophilic abundant cytoplasm and the large cleaved vesicular nucleus. the cell in the center of the photomicrograph has the appearance of a kidney (h&e, x1000). (e) dense infiltrate of langerhans cells forming a sheet in the dermis and blurring the dermoepidermal junction (h&e, x100x). (f) a sheet of abnormal langerhans cells (h&e, x400). (g) cytological details of abnormal langerhans cells. note the coffee bean and kidney shapes of the large cleaved nucleus (h&e, x1000). [copyright: ©2012 jeunon et al.] a b c d e g f observation | dermatol pract concept 2012;2(1):4 29 ent in mucous membranes and may become crusted and ulcerated [7]. a presumptive diagnosis is based mainly on the recognition of the abnormal langerhans cells in the dermis and, eventually, permeating the epidermis and epithelial structure of the anexa [3,5]. these cells are morphologically distinctive by virtue of their single large, vesicular, opened-chromatin, cleaved nucleus, with shapes resembling the silhouette of a kidney or a coffee bean and their abundant eosinophilic to amphophilic cytoplasm. the infiltrate composed of langerhans cells may vary from dense to sparse and might have many intermingling inflammatory cells, particularly eosinophils. a definitive unequivocal diagnosis requires demonstration through electron microscopy of intracytoplasmatic birbeck bodies or immunostaining of the cells by anti-cd1a and anti-s100 antibodies, with negativity for anti-cd68 [5, 8]. langerin is another useful highly specific langerhans cell marker. the evaluation of the extent of the disease and the therapy of choice in each case involves a multidisciplinary team of clinicians/pediatricians, dermatologists, pathologists, hematologists, endocrinologists, radiologists and orthopedists. the therapeutic approach to lch depends upon the number and extent of the lesions, number of organs affected, age of the patient, presence of involvement of liver, lungs, spleen or hematopoietic system and of any organ dysfunction. in most patients with limited cutaneous disease, an expectant management usually is enough, but topical steroids can be used too in selected cases [9,10]. isolated skin lesions may be surgically excised, while more extensive skin disease might be managed with psoralen-uva phototherapy, photodynamic therapy or topical nitrogen mustard [6,1114]. localized bone lesions are managed with curettage, for diagnostic and therapeutic proposes, intralesional steroids, or low-dose radiation [15]. for “multi-organ” disease, especially the high-risk group, prednisone alone or prednisone plus chemotherapeutic drugs, vincristine or etoposide being the most widely used, have been advocated by histiocytosis society protocols [1,13]. there is still much controversy about the ideal approach in these cases, and study groups around the world are being conducted to clarify it [10]. references 1. crooks b, grenier d. langerhans cell histiocytosis: a complex recurrent disease. paediatr child health. 2010;15(2): 69–70. 2. abla o, egeler rm, weitzman s. langerhans cell histiocytosis: current concepts and treatments. cancer treat rev. 2010;36(4):354–9. 3. ackerman ab, bennin b, gotllieb gj. histopathologic diagnosis of inflammatory skin diseases. an algorithmic method based on pattern analysis. 3rd ed. new york: ardor scribendi ltd, 2005. 4. ackerman ab, mones jm. langerhans’ cell granulomatosis. in: ackerman ab, mones jm (eds.). resolving quandaries in dermatology, pathology & dermatopathology, vol 2. new york: ardor scribendi ltd, 2001:222–7. 5. li z, yanqiu l, yan w, et al. two case report studies of langerhans cell histiocytosis with an analysis of 918 patients of langerhans cell histiocytosis in literatures published in china. int j dermatol. 2010; 49(10): 1169–74. 6. failla v, wauters o, caucanas m, nikkels-tassoudji n, nikkels af. photodynamic therapy for multi-resistant cutaneous langerhans cell histiocytosis. rare tumors. 2010; 2(2): e34. 7. foley s, panting k, bell h, leonard n, franks a. rapid resolution of primary vulval adult langerhans cell histiocytosis with very potent topical corticosteroids. australas j dermatol. 2011;52(1): e8–e14. 8. egeler rm, van halteren ag, hogendoorn pc, laman jd, leenen pj. langerhans cell histiocytosis: fascinating dynamics of the dentritic cell-macrophage lineage. immunol rev. 2010;234(1):213– 32. 9. minkov m, prosch h, steiner m. langerhans cell histiocytosis in neonates. pediatr blood cancer. 2005;45(6): 802–7. 10. satter ek, high wa. langerhans cell histiocytosis: a review of the current recommendations of the histiocyte society. pediatr dermatol. 2008;25(3): 291–5. 11. ng-cheng-hin b, o’hanlon-brown c, alifrangis c, waxman j. langerhans cell histiocytosis: old disease new treatment. q j med. 2011;104(2): 89–96. 12. hoeger ph, nanduri vr, harper ji, atherton da, pritchard j. long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis. arch dis child. 2000;82(6):483–7. 13. arceci rj, brenner mk, pritchard j. controversies and new approaches to treatment of langerhans cell histiocytosis. hematol oncol clin north am. 1998;12(2):339–57. 14. aihara m, hasegawa t, okuyama y, hiruma m, ikeda s. langerhans cell histiocytosis treated with narrow-band ultraviolet b. j dermatol, 2011; 38(2):151–4. 15. margo ce, goldman dr. langerhans cell histiocytosis. surv ophthalmol. 2008;53(4):332–58. figure 4. complete healing of the perineal lesions after chemotherapy. [copyright: ©2012 jeunon et al.] dermatology: practical and conceptual review | dermatol pract concept 2020;10(1):e2020003 1 dermatology practical & conceptual update on dermoscopy and infectious skin diseases vincenzo piccolo1 1 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: dermatoscopy, dermoscopy, infections, infectious, entomodermoscopy citation: piccolo v. update on dermoscopy and infectious skin diseases. dermatol pract concept. 2020;10(1):e2020003. doi: https://doi. org/10.5826/dpc.1001a03 accepted: september 7, 2019; published: december 31, 2019 copyright: ©2019 piccolo. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: vincenzo piccolo, md, ii policlinico, edificio 9c, primo piano, via pansini 5 80131 napoli, italy. email: piccolo. vincenzo@gmail.com introduction nowadays, dermoscopy is a global worldwide diffuse diagnostic tool supporting clinicians in their daily hard task of correct orientation among dermatological diseases [1]. born to be an instrument for early diagnosis of skin cancer, the dermatoscope is now considered the dermatologist’s stethoscope [2], as it can be routinely used to support diagnosis in general dermatology, so spreading its utility in cutaneous inflammatory and infectious diseases. as concerns the latter, plenty of papers have been published since the first description of dermoscopic findings of scabies [3]. a galloping enthusiasm toward dermoscopy in recent years induced dermatologists all over the world to describe everyday novel dermoscopic signs in almost every dermatological disease, thus sometimes generating confusion in terminology. a recent consensus by the international dermoscopy society tried to put order in that confusion by redefining the most accepted dermoscopic criteria and terminology in inflammatory and infectious diseases of skin [4]. as a general consideration, when approaching cutaneous infectious diseases (entomodermoscopy), a risk of spreading the infection through the dermatoscope does exist [5,6], but a few recommendations can limit or avoid the issue. first, noncontact dermoscopy should be preferred as the diagnostic approach and nowadays it is easier because of growing diffusion of polarized handled dermatoscopes, which avoid skin contact. second, the use of antiseptics and instrument disinfection after each use is mandatory. the use of disposable transparent devices has been abandoned because of interference with the correct visualization of the skin. nowadays, dermoscopy is a global worldwide diffuse diagnostic tool supporting clinicians in their daily hard task of correct orientation among dermatological diseases. born to be an instrument for early diagnosis of skin cancer, the dermatoscope is now considered the dermatologist’s stethoscope, as it can be routinely used to support diagnosis in general dermatology, so spreading its utility in cutaneous inflammatory and infectious diseases, as adjuvant and not substitute to histology and potassium hydroxide examination. as concerns the latter, plenty of papers have been published since the first description of dermoscopic findings of scabies. the aim of this review is to give the clinician a practical approach to dermoscopic parameters of cutaneous infectious diseases with a focus on the latest updates in this topic. abstract 2 review | dermatol pract concept 2020;10(1):e2020003 often surrounded by a whitish halo (figure 1), assuming a “frogspawn appearance” [7]. filiform warts. filiform warts often appear in periorificial areas, mostly in children or in the beard area of men. dermoscopy shows the same features as common warts, with more prevalent papillae [7] (figure 2). flat warts. flat warts present as plane-topped papules, often spread on the face or dorsa of hands. dermoscopy observation may be difficult because of lack of striking findings, although small dotted vessels on a yellowish background may be seen (figure 3). these features may be helpful to distinguish flat warts from folliculitis or acne, usually showing follicular findings [7]. plantar warts. among the most common type of warts, plantar warts show at dermoscopy as small dotted hemorrhagic structures corresponding to thrombosed vessels, visible in the context of whitish or yellowish papillae which interrupt cutaneous dermatoglyphics (figure 4). easy to recognize, plantar warts are sometimes misdiagnosed as tylomas the aim of this review is to give the clinician a practical approach to dermoscopic parameters of cutaneous infectious diseases with a focus on the latest updates in this topic. human papillomavirus infections human papillomavirus infections are among the most common cutaneous infections in human beings, as the human papillomavirus is ubiquitous and its clinical expression can be extremely variable. from this clinical variability, a variegate presentation of dermoscopic findings derives. there is a constant feature that can often be observed in warts, ie, dotted vessels and/or hemorrhagic points that can be variably found in different kinds of viral warts. common warts. common warts are the most frequent type of warts. they can appear on any part of the body, although hands represent the most affected area. common warts usually show at dermoscopy as grouped papillae, with dotted or loop vessels, and/or hemorrhagic points and lines figure 1. typical papillae in a common wart centered by hemorrhagic dots in turn surrounded by whitish halos. figure 2. projected papillae in a filiform wart of beard area. dotted vessels are detectable at the extremities of each papilla. figure 3. dotted vessels on a whitish background found in flat warts of the scalp. figure 4. plantar wart showing hemorrhagic dots corresponding to thrombosed vessels. interruption of dermatoglyphics is clearly evident. review | dermatol pract concept 2020;10(1):e2020003 3 presence of a central pore on a white-yellowish amorphous area, often surrounded by thin crown vessels [7] (figure 6). a large variation in dermoscopic findings of mc has been reported [9], regarding both central structures and vessels. central pore may be absent (figure 7), with the only central amorphous area detectable at dermoscopic examination. on the other hand, vessels may be visible or not and, when present, they can show different patterns, such as crown, radial, or dotted [9]. what’s new? with handled dermatoscope, the correct detection of vessels is not always easy because of pressure induced by the dermatoscope itself on the lesion. an interesting paper by ku et al [10] has correlated features of white structures in mc to histopathology. the authors have recognized 3 types of central white structures in relation to the size, duration, and histopathology of mc. classic mc presents with a central roundish white (hyperkeratosis without interruption of dermatoglyphics) and must be distinguished from acral melanoma, sometimes unfortunately misinterpreted as wart [7]. genital warts. the sexually transmitted disease of our century, genital warts or condylomata, are quite easy to diagnose, although in early stages dermoscopy could be very useful to avoid overdiagnosis and distinction from noninfectious genital lesions often misdiagnosed as warts, ie, hirsuties penis, vestibular papillomatosis, fordyce granules, and genital angiokeratomas. the most common dermoscopic finding is the so-called mosaic pattern, ie, the presence of grouped dotted or glomerular vessels at center surrounded by a whitish network (figure 5). the papillae can sometimes project outward. pigmented genital warts can be occasionally observed, and they usually show at dermoscopy a cerebriform or seborrheic keratosis-like appearance [7]. what’s new? a recent study has investigated dermoscopic features of urethral condylomata [8], showing as expected a predominance of vessels that can vary in morphology from more common dotted to polymorphous vessels, but the authors recommend biopsy to confirm the diagnosis. molluscum contagiosum molluscum contagiosum (mc) is a very common infection caused by poxvirus, potentially occurring at any age and body location, more frequent in atopic children or in adults as sexually transmitted disease. it typically appears with single or multiple variably-sized translucent papules, sometimes umbilicated. clinical diagnosis is quite easy, mostly in multiple lesions. in mc presenting as a single lesion, differential diagnosis may be challenging. dermoscopy usually shows the figure 5. mosaic pattern in anogenital warts of a child. figure 6. typical dermoscopic appearance of molluscum contagiosum, showing a central pore on whitish amorphous structure surrounded by linear vessels. figure 7. the presence of central orifice is not mandatory in molluscum contagiosum as in this case. 4 review | dermatol pract concept 2020;10(1):e2020003 other common causes of hair loss, especially in children, such as alopecia areata and trichotillomania. the most common and first described trichoscopic finding in tc is the so called “comma hair,” ie, a shortened, curved hair resulting from the fungal invasion of the shaft [11] (figure 9). other nonspecific dermoscopic findings have been reported in tc, namely black dots, dystrophic hairs, and hair casts [11] (figure 10). what’s new? tinea capitis. recently, plenty of novel dermoscopic findings have been detected in tc, in particular zig-zag hair [12] (ie, hair with multiple breakage bands provoking bending of the hair shaft in different areas), corkscrew hair [12] (the equivalent finding of comma hair in patients with curly hair) (figure 11), and the highly specific morse code-like or barcode hairs [13], visible at high magnification with multiple horizontal transparent bands along the hair shaft. another piece of news comes from the potential correlation between etiology and dermoscopy in tc. indeed, a preliminary observation area. on the other hand, small and “young” lesions usually show a 4-leaf-clover-like appearance, whereas large and “old” mc is characterized by a polylobular appearance (figure 8). dermatophytic infections among dermatophytic infections, tinea capitis (tc) is the one that took most diagnostic advantage from the use of dermoscopy over time. tc is a common dermatophytosis of the scalp of children and rarely adults. several agents have been isolated in patients with tc, with microsporum canis being the most common in europe, accounting for 80% of cases, followed by trichophyton spp, progressively increasing as etiological agent of tc. single or multiple alopecic scaly patches of the scalp are the usual clinical presentation of tc, whose diagnosis should be confirmed by potassium hydroxide examination and microbiological culture [11]. although it can be easily recognized on the basis of clinical findings, dermoscopy may find a great role in differential diagnosis with figure 8. polylobular appearance of an “old” molluscum of the dorsum. figure 9. diffuse comma hair in a patients affected by tinea capitis. figure 11. corkscrew and barcode-like hair in tinea capitis.figure 10. tinea capitis showing different findings including comma hair, hair casts, dystrophic hairs, and zig-zag hair. review | dermatol pract concept 2020;10(1):e2020003 5 for most fungal nail infections. in recent years several studies have shown the utility of onychoscopy in the diagnosis of onychomycosis. in a recent clinical overview in the journal of the american academy of dermatology, onychoscopy was recognized as a supportive tool for the diagnosis of onychomycosis [19,20] and its differential diagnosis [21]. the most common dermoscopic finding is the fringed proximal onycholytic border, associated with longitudinal striae with fading resembling “aurora borealis” (figure 14), and ruinlike appearance of the subungual hyperkeratosis and debris (figure 15). recently, onychoscopy of fungal melanonychia has been described with different colors in nail discoloration including black, white, yellow, and orange, allowing a differential diagnosis with malignant melanonychia [20,22,23]. pediculosis head lice. pediculosis capitis (or head lice) is a worldwide diffuse infestation due to pediculus humanus capitis that indicated that morse code-like hair could be secondary to ectothrix-type hair parasitization secondary to microsporum infection, whereas black dots and dystrophic hair mostly associated to trichophyton infection, even if these data should be confirmed by larger studies. tinea corporis. numerous papers have been published about dermoscopic findings in tinea capitis, but only a limited amount of novel information is now available about dermoscopy of tinea corporis. in particular, the presence of black dots surrounded by a pale whitish halo could indicate the involvement of vellus hair (figure 12) and the need for systemic antifungal treatment [14]. similar findings have been recently reported in tinea incognito (figure 13) and majocchi granuloma in association with small pustules [15,16]. tinea manuum. lately, dermoscopy of tinea manuum has been reported, showing predominant scaling associated with dotted vessels detectable in the furrows [17,18]. onychomycosis. onychomycosis is listed in the group of dermatophytic infections, as dermatophytes are responsible figure 13. a challenging diagnosis of tinea incognito could be favored by dermoscopy showing vellus hair involvement and pustules. figure 15. ruin-like appearance of distal border of nail seen at dermoscopy. figure 14. onychomycosis showing fringed proximal onycholytic border associated with longitudinal striae. figure 12. newly described vellus hair involvement in tinea corporis, identified by black dystrophic hair. 6 review | dermatol pract concept 2020;10(1):e2020003 pthirus pubis. unlike head lice, pthirus pubis is predominantly a sexually transmitted disease among adults that usually appears with itch in the pubic and genital area. dermoscopy confirms the clinical suspicion by direct detection of the pthirus, whose body is more flattened and larger than pediculus capitis, adherent to pubic hairs and blood-feeding. the blood-filled intestine of pthirus resembles the body of a scorpion (personal observation) (figure 18). nits can be detected in pthirus pubis as well. pthirus could potentially affect children as well, whose infection is transmitted by adults. pediatric pthirus usually occurs on the eyelashes, and less frequently eyebrows, and hair with dermoscopy playing a key role for the detection of the parasite (figure 19), its prompt treatment and follow-up [7]. what’s new? no great news is available about dermoscopy of pediculosis, except a paper about the use of the dermatoscope for the diagnosis of pediculosis corporis [24]. is usually quite easy to diagnose. diagnostic delay may be provoked by low socioeconomic level and by the interval between the infestation and the appearance of the main symptom of pediculosis, namely the itch occurring a few weeks later. the diagnosis is immediate when the parasites are seen at the inspection of scalp hair, but it is not always so easy, especially in patients with scaling conditions of the scalp (psoriasis, seborrheic dermatitis) and when panic is diffuse among communities where pediculosis is spreading. the detection of lice (figure 16) is difficult through the dermatoscope [7]. conversely, nits are well recognizable through trichoscopic examination as ovoid structures anchored to the hair shaft, which appear brown when still vital and translucent with a sharp free end when empty (figure 17). through dermoscopy nits can be distinguished from pseudonits, such as hair casts appearing as cylindrical whitish structures surrounding the hair shaft and easy to remove [7]. figure 17. nits adherent to hair shafts highly diagnostic in pediculosis capitis. figure 16. rare picture of pediculus capitis seen at dermoscopy. figure 18. a couple of pthirus found on the pubis of young man. note the scorpion-like appearance of blood-filled intestine. figure 19. nits and lice adherent to eyelashes in a child affected by pthiriasis palpebrarum. review | dermatol pract concept 2020;10(1):e2020003 7 tinea nigra tinea nigra is a relatively uncommon dematiaceous fungal infection, usually caused by phaeoannellomyces werneckii. tinea nigra is diffuse in the tropical and subtropical areas of central and south america, africa, and asia. it often occurs as occasional infection after traveling in these areas of the world. it usually affects young people and presents as an irregular acral pigmentation that may mimic a melanocytic lesion. dermoscopy typically shows a weak pigmentation composed of thin bundles of spicules, arranged in parallel lines mainly in some peripheral areas (figure 23) [28-31]. the pigmentation usually does not follow the dermatoglyphic furrow and ridges, although in some cases the parallel ridge pattern could be hard to distinguish from acral melanoma [28-31]. tungiasis tungiasis is a parasitic infection due to tunga penetrans, which is endemic in africa, central america, asia, and caribscabies scabies is undoubtedly in general dermatology the skin disease whose diagnosis has gained most advantage by the use of the dermatoscope. indeed, dermoscopy has revolutionized the approach to the diagnosis of scabies in the last decade. scabies lacks clinical specific and diagnostic features and, traditionally, diagnosis is based on the severe itch and cutaneous lesions appearing in preferential body areas, such as wrists, finger web spaces, axillae, and genitals. the burrow produced by the female mite is highly diagnostic, but hard to detect by the naked eye. before dermoscopy, diagnostic confirmation of scabies was given by the direct observation of mite, feces, and eggs after casual skin scraping, but the sensitivity of this test is low and its reliability is operator-sensitive. the so called delta-wing jet with contrail sign is probably the most notorious dermoscopic picture ever and represents the irregular burrow excavated by the mite, whose anterior part of the body is visible at dermoscopy as a small black arrowhead area at the end of the whitish wavy line [25] (figure 20). nowadays, this finding is considered pathognomonic for scabies, regardless of the patient’s age, the location of the lesion, and type and duration of the infection. what’s new? recently, a novel dermoscopic sign was described in norwegian scabies, namely the “noodle sign” [26] (figure 21), ie, an accumulation of hundreds of burrows in the same dermoscopic field, given the patient’s immunosuppression and the consequent disease severity. another quite recent finding is related to neonatal scabies [27], whose dermoscopy has lately been described as similar to that found in adults but with a different, more precocious and non-itchy occurrence of cutaneous nodules in these very young patients (figure 22). figure 21. grouped mite burrows configuring the “noodle sign” in crusted scabies. figure 20. delta-wing jet with contrail sign in scabies. figure 22. nodular scabies of newborn detected at dermoscopy. 8 review | dermatol pract concept 2020;10(1):e2020003 hyperkeratosis, central erosion or ulceration, and “white starburst-like pattern” may be observed. vascular structures are often detectable with variable morphology (dotted, linear, polymorphous, hairpin, mixed) [33]. a recent larger study published in dermatology: practical and conceptual has confirmed these findings [34]. cutaneous larva migrans cutaneous larva migrans is a tropical infection due to ancylostoma, whose reservoir is dogs’ and cats’ intestine. the most common nematode provoking the so-called creeping eruption is the ancylostoma braziliense, diffuse in north, central, and south america and caribbean. it usually presents as a quite typical serpiginous, linear, slightly elevated, itchy erythema occurring on the feet, web spaces, arms, or buttocks [35]. dermoscopy shows multiple translucent yellow-brown structureless areas arranged in a segmental fashion (figure 26), bean and is occasionally seen in europe and north america in travelers. barefoot walking on sand contaminated by pigs’ and cows’ feces favors contact with the impregnated parasite, which penetrates through the skin and feeds on the host’s blood. as a consequence, tungiasis clinically presents as a small whitish plantar hyperkeratosis with a central black area, often misdiagnosed as plantar wart. dermoscopy plays an important role in differential diagnosis and typically shows a homogeneous white area centered by a black pore (figure 24), which represents the pigmented chitin around the exoskeleton of tunga [32]. eggs enclosed in the jelly-bag can be detected as ovoid gray-blue structures in proximity to the central pore and disposed in a chain-like fashion. expelled eggs can rarely be seen. ex vivo dermoscopy may be useful for the confirmation of the diagnosis, allowing direct visualization of the parasite. leishmaniasis leishmaniasis is an infection provoked by the protozoa leishmania whose reservoirs are dogs and rodents, that occasionally affects humans through the vectors sandflies. leishmaniasis is diffuse worldwide, with different species predominating in each part of the world. cutaneous leishmaniasis (cl) usually occurs as single or multiple nodules or plaque appearing in the area of protozoan inoculation. lesions often present a serous crust covering an ulceration. although clinical appearance could be enough to suspect cl, diagnosis could be challenging in most cases, above all in nonendemic areas [33,34]. dermoscopy of cl was described for the first time in 2009. the most common finding was generalized erythema, followed by a very characteristic feature, namely “yellow tears” (figure 25). the latter are yellowish white round-to-oval structures. moreover, figure 23. typical findings of tinea nigra showing weak pigmentation composed of thin bundles of spicules, arranged in parallel lines mainly in some peripheral areas. figure 24. dermoscopy of tungiasis showing a homogeneous white area centered by a black pore. figure 25. a child affected by cutaneous leishmaniasis showing at dermoscopy yellow tears on a reddish orange background. review | dermatol pract concept 2020;10(1):e2020003 9 references 1. russo t, piccolo v, lallas a, argenziano g. recent advances in dermoscopy. f1000res. 2016 feb 17;5. pii: f1000 faculty rev184. doi:10.12688/f1000research.7597.1. 2. zalaudek i, lallas a, moscarella e, longo c, soyer hp, argenziano g. the dermatologist’s stethoscope—traditional and new applications of dermoscopy. dermatol pract concept. 2013;3(2):67-71. 3. argenziano g, fabbrocini g, delfino m. epiluminescence microscopy: a new approach to in vivo detection of sarcoptes scabiei. arch dermatol. 1997;133(6):751-753. 4. errichetti e, zalaudek i, kittler h, et al. standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (non-neoplastic dermatoses): an expert consensus on behalf of the international dermoscopy society. br j dermatol. 2019 may 11. doi: 10.1111/bjd.18125. epub ahead of print. 5. kelly sc, purcell sm. prevention of nosocomial infection during dermoscopy? dermatol surg. 2006;32(4):552-555. 6. penso-assathiany d, gheit t, prétet jl, et al. presence and persistence of human papillomavirus types 1, 2, 3, 4, 27, and 57 on which represent the body of the worm, with dotted vessels detectable where the burrow is empty [35]. other diseases with the spread of dermoscopy in dermatology, numerous novel findings in different infectious diseases have been described. what’s new? pseudomonas onychopathy may be quickly detected through dermoscopy for the green nail discoloration provoked by the production of the pigment pyocyanin [36] (figure 27). trichomycosis axillaris has been found to show at dermoscopy yellowish hair casts around axillary hairs [37] (figure 28). differential diagnosis through dermoscopy of different types of folliculitis has been proposed [38]. conclusions and future perspectives one of the most fascinating aspects of dermoscopy is that it looks like a never-ending science, with news published frequently. diagnostic approach to infectious diseases is different nowadays also thanks to the dermatoscope, which has progressively increased diagnostic confidence with rarer diseases, such as leishmaniasis, tungiasis, and larva migrans. it is important to state that dermoscopy is not the unique diagnostic tool for most infectious diseases of the skin and should be considered supportive and not a substitute for the other well-known diagnostic techniques, such as potassium hydroxide examination and histology. the low cost of the handheld instrument and the spread of the technique among dermatologists all over the world will probably provide more details about less common tropical infectious diseases whose diagnosis is still challenging for most dermatologists. figure 26. segmented serpiginous appearance of larva migrans at dermoscopy. figure 27. yellow-to-green discoloration of the nail at dermoscopic examination of nail plate. figure 28. dermoscopic appearance of trichomycosis axillaris showing yellowish hair casts around axillary hairs. 10 review | dermatol pract concept 2020;10(1):e2020003 23. russo t, piccolo v, panarese i, alfano r, argenziano g. a challenging toenail melanonychia. j dtsch dermatol ges. 2019;17(1):85-86. 24. martins lg, bernardes filho f, quaresma mv, bellott tr, botelho ln, prata ac. dermoscopy applied to pediculosis corporis diagnosis. an bras dermatol. 2014;89(3):513-514. 25. argenziano g, fabbrocini g, delfino m. epiluminescence microscopy: a new approach to in vivo detection of sarcoptes scabiei. arch dermatol. 1997;133(6):751-753. 26. chavez-alvarez s, villarreal-martinez a, argenziano g, ancer-arellano j, ocampo-candiani j. noodle pattern: a new dermoscopic pattern for crusted scabies (norwegian scabies). j eur acad dermatol venereol. 2018;32(2):e46-e47. 27. neri i, chessa ma, virdi a, patrizi a. nodular scabies in infants: dermoscopic examination may avoid a diagnostic pitfall. j eur acad dermatol venereol. 2017;31(12):e530-e531. 28. smith sb, beals sl, elston dm, meffert jj. dermoscopy in the diagnosis of tinea nigra plantaris. cutis. 2001;68(6):377-380. 29. piliouras p, allison s, rosendahl c, buettner pg, weedon d. dermoscopy improves diagnosis of tinea nigra: a study of 50 cases. australas j dermatol. 2011;52(3):191-194. 30. noguchi h, hiruma m, inoue y, miyata k, tanaka m, ihn h. tinea nigra showing a parallel ridge pattern on dermoscopy. j dermatol. 2015;42(5):518-520. 31. nazzaro g, ponziani a, cavicchini s. tinea nigra: a diagnostic pitfall. j am acad dermatol. 2016;75(6):e219-e220. 32. bauer j, forschner a, garbe c, röcken m. dermoscopy of tungiasis. arch dermatol. 2004;140(6):761-763. 33. llambrich a, zaballos p, terrasa f, torne i, puig s, malvehy j. dermoscopy of cutaneous leishmaniasis. br j dermatol. 2009;160(4):756-761. 34. serarslan g, ekiz ö, özer c, sarıkaya g. dermoscopy in the diagnosis of cutaneous leishmaniasis. dermatol pract concept. 2019;9(2):111-118. 35. aljasser mi, lui h, zeng h, zhou y. dermoscopy and near-infrared fluorescence imaging of cutaneous larva migrans. photodermatol photoimmunol photomed. 2013;29(6):337-338. 36. romaszkiewicz a, sławińska m, sobjanek m, nowicki rj. nail dermoscopy (onychoscopy) is useful in diagnosis and treatment follow-up of the nail mixed infection caused by pseudomonas aeruginosa and candida albicans. postepy dermatol alergol. 2018;35(3):327-329. 37. rojas mora e, freites martínez a, hernández-núñez a, borbujo martínez j. trichomycosis axillaris: clinical, wood lamp, and dermoscopic diagnostic images. actas dermosifiliogr. 2017;108(3):264-266. 38. durdu m, errichetti e, eskiocak ah, ilkit m. high accuracy of recognition of common forms of folliculitis by dermoscopy: an observational study. j am acad dermatol. 2019;81(2):463-471. dermoscope before and after examination of plantar warts and after cleaning. j am acad dermatol. 2013;68(1):185-186. 7. tschandl p, argenziano g, bakos r, et al. dermoscopy and entomology (entomodermoscopy). j dtsch dermatol ges. 2009;7(7):589-596. 8. zhang y, jiang s, lin h, guo x, zou x. application of dermoscopy image analysis technique in diagnosing urethral condylomata acuminata. an bras dermatol. 2018;93(1):67-71. 9. ianhez m, cestari sda c, enokihara my, seize mb. dermoscopic patterns of molluscum contagiosum: a study of 211 lesions confirmed by histopathology. an bras dermatol. 2011;86(1):74-79. 10. ku sh, cho eb, park ej, kim kh, kim kj. dermoscopic features of molluscum contagiosum based on white structures and their correlation with histopathological findings. clin exp dermatol. 2015;40(2):208-210. 11. slowinska m, rudnicka l, schwartz ra, et al. comma hairs: a dermatoscopic marker for tinea capitis: a rapid diagnostic method. j am acad dermatol. 2008;59(5 suppl):s77-s79. 12. lacarrubba f, verzì ae, micali g. newly described features resulting from high-magnification dermoscopy of tinea capitis. jama dermatol. 2015;151(3):308-310. 13. wang hh, lin yt. bar code-like hair: dermoscopic marker of tinea capitis and tinea of the eyebrow. j am acad dermatol. 2015;72(1 suppl):s41-s42. 14. knöpfel n, del pozo lj, escudero mdel m, martín-santiago a. dermoscopic visualization of vellus hair involvement in tinea corporis: a criterion for systemic antifungal therapy? pediatr dermatol. 2015;32(5):e226-e227. 15. piccolo v, corneli p, russo t, zalaudek i, alfano r, argenziano g. dermoscopy as a useful tool in diagnosis of tinea incognito. int j dermatol. 2019;58(2):e32-e34. 16. piccolo v, di brizzi ev, russo t, et al. majocchi’s granuloma on the face: dermoscopy and reflectance confocal microscopy. int j dermatol. 2019;58(9):e180-e182. 17. errichetti e, stinco g. dermoscopy in tinea manuum. an bras dermatol. 2018;93(3):447-448. 18. jakhar d, kaur i, sonthalia s. dermoscopy of tinea manuum. indian dermatol online j. 2019;10(2):210-211. 19. piraccini bm, balestri r, starace m, rech g. nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. j eur acad dermatol venereol. 2013;27(4):509-513. 20. lipner sr, scher rk. onychomycosis: clinical overview and diagnosis. j am acad dermatol. 2019;80(4):835-851. 21. piccolo v, argenziano g, alessandrini am, russo t, starace m, piraccini bm. dermoscopy of subungual exostosis: a retrospective study of 10 patients. dermatology. 2017;233(1):80-85. 22. russo t, piccolo v, lallas a, et al. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. dermatology: practical and conceptual research | dermatol pract concept 2020;10(3):e2020059 1 dermatology practical & conceptual early squamous cell carcinoma with perineural invasion: a prospective study examining anatomic site, tumor surface diameter, invasion depth, and grade of differentiation in 1,772 consecutive cases john h. pyne,1 esther myint,1 simon p. clark,1 maddie gorji,1 ruihang hou1 1 prince of wales clinical school, university of new south wales, sydney, australia key words: squamous cell carcinoma, perineural invasion, grade of differentiation, invasion depth, anatomic site citation: pyne jh, myint e, clark sp, gorji m, hou r. early squamous cell carcinoma with perineural invasion: a prospective study examining anatomic site, tumor surface diameter, invasion depth, and grade of differentiation in 1,772 consecutive cases. dermatol pract concept. 2020;10(3):e2020059. doi: https://doi.org/10.5826/dpc.1003a59 accepted: march 13, 2020; published: june 29, 2020 copyright: ©2020 pyne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: associate professor john pyne, 131 ellesmere rd, gymea bay, new south wales 2227 australia. email: j.pyne@ uq.edu.au background: squamous cell carcinoma (scc) may present with perineural invasion (pni). objective: to investigate the characteristics of early invasive scc with or without pni. methods: consecutive scc excisions were prospectively reviewed from a single australian community-based practice for 2016-2018. tumor characteristics recorded were anatomic site, maximum microscopic tumor surface diameter, invasion depth, grade of differentiation, and diameter of nerves with pni. results: in total, 1,772 cases were collected. no pni cases were found on female patients. seven of the total 10 pni cases were on facial sites. maximum average microscopic tumor surface diameters ranged from 10.1 mm (well differentiated) up to 11.0 mm (moderately differentiated). maximum average invasion depths by differentiation ranged from 1.7 (well differentiated) up to 2.6 mm (poorly differentiated). the pni cases were as follows: well differentiated (n = 0), moderately differentiated (n = 4), or poorly differentiated (n = 6). minimum average histopathological margins for well, moderately, and poorly differentiated scc, respectively, were 1.4, 1.1, and 1.3 mm. minimum microscopic tumor surface diameters for pni cases were 7 mm for moderately and 5 mm for poorly differentiated scc. minimum microscopic invasion depths for pni cases were 2.2 mm for moderate and 0.9 mm for poor differentiation. conclusions: we found early scc with pni displayed nerve diameters of 0.1 mm or less and were exclusively on male patients aged 60 or older, on chronically sun-exposed sites of the head and upper midline anterior chest. histopathological features associated with pni were moderate and poor differentiation, tumor invasion beyond 0.9 mm, and adjacent lymphocytosis. abstract https://doi.org/10.5826/dpc.1003a59 mailto:j.pyne@uq.edu.au mailto:j.pyne@uq.edu.au 2 research | dermatol pract concept 2020;10(3):e2020059 ethics approval (project no. 2016001221). full excision was attempted on all cases by typically using a fusiform ellipse cut down to the subcutis. cases with prior partial biopsies and known recurrent scc cases as well as scc receiving prior pharmaceutical or ablative treatments were excluded. all cases excised during the study were marked on a body map. this map was checked prior to subsequent excisions to exclude recurrent cases. there were no exclusions based on age, anatomic site, or nerve diameters with pni. prior to excision, every case was examined using a delta 20 t heine dermatoscope to identify the surface margin of the tumor. excisions were marked out with an in vivo surface margin of 1 to 2 mm. excised tissue was sectioned by transverse bread loafing at 3-mm intervals along the entire specimen. following h&e staining, all cases underwent histopathological examination. all cases of keratoacanthoma, scc in situ, and any diagnosis other than invasive scc were excluded. depth of invasion was measured from the granular layer in the epidermis down to the deepest tumor cells to the nearest 0.1 mm. this invasion depth measurement was consistently performed independent from the adjacent skin surface. assessing the grade of differentiation was based on the original description by broders [16]. where the grade of differentiation varied within a tumor mass, the grade present closest to poor differentiation was recorded for that case. we defined pni as malignant squamous cells identified within the perineural space that must be located outside the tumor mass. cases with malignant cells in the perineural space where the involved nerve was only found inside the tumor mass were excluded. two board-certified dermatohistopathologists blind to each other’s findings had to agree pni was present within a case for pni classification. cases in which only 1 of the 2 histopathologists identified pni were excluded from pni allocation. mimics of pni were well known to the reporting histopathologists. to assess whether localized lymphocytosis is a clue to pni, the co-location of lymphocytes with pni or juxtaposed to the pni was recorded when seen. the qualitative density of lymphocytes per unit area juxtaposed to the pni was compared with the lymphocyte density in the background tissue well away from the involved nerve. results after initial exclusion criteria were applied, a total of 1,772 scc cases were collected. male patients numbered 740 (63.4%) and females 427 (36.6%). patients had predominantly northern european ancestry with fair skin. the characteristics of the study cases are shown in table 1. intratumor pni was reported in 18 cases (11 cases with moderate differentiation and 7 cases with poor differentiation). the cases introduction over recent decades the prevalence of cutaneous squamous cell carcinoma (scc) has increased [1]. a recent review [2] found multiple studies demonstrating perineural invasion (pni) is significantly associated with a higher risk of recurrence following surgery, metastasis, and disease-specific death. reported presentations of scc with pni vary from 2.5% to 6% [3]. most studies on pni tend to focus on advanced disease treated in tertiary facilities. pni has been referred to as either “incidental” when asymptomatic and involving small-diameter nerves compared with “clinical” when symptomatic and involving larger nerve diameters [4]. this small nerve diameter has been defined as equal to or less than 0.1 mm [5]. little is known of the characteristics of early-stage, smaller-dimension scc with early-onset pni. over the past 2 decades, publications [2,5] have consistently stated that an increase in nerve diameters beyond 0.1 mm is associated with a poorer prognosis including disease-specific death. both the clinical and dermoscopic features of scc vary with the grade of differentiation [6]. pain and numbness have been reported as clues to pni [7,8]. poorly differentiated scc tends to have a higher prevalence of pni [9,10] compared with welland moderately differentiated tumors. an increase in pni has also been recorded in scc with a desmoplastic stroma [11]. increasing scc tumor diameter correlates with increased depth of pni [12]. a minimum biopsy depth of 3 to 4 mm has been recommended to optimize not missing pni [12]. some scc without pni may display features mimicking pni [13]. peritumoral fibrosis is a known mimic of pni [14]. combining epithelial membrane antigen with cytokeratin mnf116 has been stated to facilitate diagnosing pni when both of these immunohistochemical stains are positive [15]. as pni develops, it is not clear whether advanced pni correlates with an increase in affected nerve diameters alone and/or with an increase in the spatial distribution of smaller affected nerve diameters. the intention of our study was to identify clinical and histopathological characteristics of early-stage scc associated with early-appearance pni. identifying clinical characteristics of scc associated with the threshold onset of early pni may facilitate the bedside earlier detection of pni, thus improving patient outcomes. furthermore, an awareness of a higher chance for pni being present based on the histopathological characteristics of an scc case may also assist histopathologists in the early detection of pni. materials and methods consecutive invasive scc cases were prospectively collected from routine workflow in a community-based private practice in sydney, australia, from 2016 to 2018. the university of queensland (brisbane, australia) authorized research | dermatol pract concept 2020;10(3):e2020059 3 differentiation n=65/83 (78%) (table 2). table 2 illustrates the shift from well to poor differentiation was also associated with increasing rates of peripheral only, deep only, and combined peripheral and deep margin involvement. nine of the 10 pni cases recorded a nerve diameter of less than 0.1 mm (table 3). the largest nerve diameter recorded was 0.1 mm (1 case), indicating all the study cases represent incidental pni. the minimum ages for moderately and poorly differentiated cases, respectively, were 64 and 60 years. all 8 pni cases not invading the subcutis displayed tumor-associated lymphocytes. only 2 cases recorded both tumor invasion and pni involving the subcutis. in both cases, no tumor-associated lymphocytes were found (table 3). table 3 also shows the anatomic sites for all pni cases. during the study the number of cases of scc excised per patient was recorded and is shown in table 4. a trend is noted where an increase in the number of scc cases per patient with only intratumor pni were excluded from the study. only cases with pni outside the tumor mass (n = 10) entered the final study results. of these 10 pni cases, 2 cases were noted to have both intratumor pni and pni outside the tumor mass. poorly differentiated scc cases presented with deeper average invasion (2.3 mm) and a higher prevalence of pni cases (n = 6/10). all cases without pni combined had an average invasion depth of 1.8 mm (95% confidence interval [1.7-1.9] p < 0.001) compared with 3.0 mm average invasion depth for all cases with pni (95% confidence interval [1.54.4] p < 0.001). a minimum depth of invasion for all pni cases by grade of differentiation was 2.2 mm for moderately and 0.9 mm for poorly differentiated cases. moderately differentiated cases with pni had an average invasion depth of 3.7 mm. in comparison, the average invasion depth for poorly differentiated pni cases was 2.4 mm. an example of an invasive scc displaying moderate differentiation and pni is shown in figures 1 and 2. although the intention was to fully excise all cases, histopathologically identified margin involvement with invasive scc did occur in some cases. by grade of differentiation, clear histopathological margins were as follows: well n = 1,178/1,253 (94%), moderate n = 392/436 (90%), and poor figure 1. moderately differentiated squamous cell carcinoma: h&e staining demonstrating perineural invasion displayed with magnification ×10. figure 2. perineural invasion below an invasive squamous cell carcinoma: same case and staining as figure 1 at magnification ×40. table 1. squamous cell carcinoma: characteristics of study cases by grade of differentiation well (n = 1,253) moderate (n = 436) poor (n = 83) age (male n = 1,319) mean 73 74 73 iqr 66-81 67-82 64-83 n 897 358 65 age (female n = 452) mean 72 74 81 iqr 65-80 67-83 70-91 n 356 78 18 maximum microscopic average surface diameter (mm) diameter 10.1 11.0 10.7 p <0.0001 <0.0001 0.048 iqr 7-13 8-14 7-14 maximum average invasion depth (mm) depth 1.7 2.1 2.6 p <0.0001 <0.0001 <0.0001 iqr 1-2.1 1.3-2.5 1.1-3.0 perineural invasion present (all male) n 0 4 (0.92%) 6 (7.2%) iqr = interquartile range. 4 research | dermatol pract concept 2020;10(3):e2020059 host immunosuppression may be a confounding factor in the study findings. one of the moderately differentiated scc cases had background rheumatoid arthritis of 11 years’ duration. one patient with a poorly differentiated case had chronic lymphatic leukemia known for 3 years. discussion with only 10 pni cases in a total cohort of 1,772 cases, the overall pni presentation was approximately 0.56%. compared with other studies, this percentage of cases with pni is during the study was associated with a higher prevalence of pni (table 4). most of the pni cases (6/10) were found on patients with 4 or more scc cases. limitations poorly differentiated cases had a higher rate of involved microscopic margins. as pni was defined as being outside the tumor mass, some pni may have be missed with involved tumor margins. thus pni may be underrepresented within the total poorly differentiated cases. table 4. squamous cell carcinoma (scc) with perineural invasion (pni): patients by number of scc cases n patients with only 1 scc case patients with 2 scc cases patients with 3 scc cases patients with >3 scc cases no. of patients (no pni) 1,157 745 (64.4%) 229 (19.8%) 67 (5.8%) 116 (10.0%) no. of patients (with pni) 10 3 1 0 6 the number “n” lists the number of patients with squamous cell carcinoma, not the number of scc cases. table 3. squamous cell carcinoma with perineural invasion (pni): characteristics of all cases found in the study patient all male age (yrs) site grade of differen­ tiation tumor surface diameter (mm) tumor invasion depth (mm) pni nerve diameter (mm) tumor in subcutis (yes/no) pni in subcutis (yes/no) tumor associated lymphocytes (yes/no) 1 60 forehead poor 11 2.2 0.04 n n y 2 64 shoulder mod 23 7.7 0.04 y y n 3 69 chest poor 8 2.3 0.03 y n y 4 71 chest mod 12 2.5 0.05 n n y 5 75 cheek poor 8 0.9 0.07 n n y 6 80 forehead poor 10 3.0 0.03 n n y 7 85 cheek mod 15 2.2 0.03 n n y 8 87 cheek mod 7 2.2 0.05 n n y 9 80 eyelid poor 5 2.4 0.1 y y n 10 81 cheek poor 11 3.6 0.07 n n y table 2. squamous cell carcinoma: recorded margin involvement by grade of differentiation grade of differentiation well (n = 1,253) moderate (n = 436) poor (n = 83) clear margins n = 1,178 (94%) n = 392 (90%) n = 65 (78%) peripheral margin only involved n = 38 (3%) n = 22 (5%) n = 5 (6%) deep margin only involved peripheral and deep margin both involved n = 12 (1%) n = 25 (2%) n = 9 (2%) n = 13 (3%) n = 7 (9%) n = 6 (7%) peripheral only involved margin, deep only involved margin, and both peripheral and deep margins involved are separately listed. research | dermatol pract concept 2020;10(3):e2020059 5 a single case of acantholytic scc was noted in 1 of the 10 cases with pni. this case occurred on the cheek of a man aged 75 years with an invasion depth of only 0.9 mm. this case sounds a warning that early scc with poor differentiation and an invasion depth of only 1 mm may present with pni. for moderately differentiated scc we found the threshold for increased vigilance for pni was an invasion depth of 2.2 mm. the relatively uncommon prevalence of both acantholysis and pni limits investigation of their potential association. lymphovascular invasion was also found in another single pni case. this case occurred on the eyelid of a man aged 80 years with an scc displaying infiltrative architecture, multifocal pni, and an invasion depth of just 2.4 mm. whether there is an association between infiltrative architecture or desmoplasia and early multifocal pni may be worth further study. metastatic behavior from a primary scc with an invasion depth of less than 2 mm and desmoplastic histology has been reported [18]. however, overall metastatic potential in scc requires an invasion depth to exceed 2 mm [18]. as invasion depth increases beyond 2 mm so does the increase in metastatic potential. we found deeper tumor invasion of 2.2 mm or greater was also associated with increasing prevalence of pni. histologically identified solar elastosis was an anecdotal observation with most pni cases in our study. the extent to which solar elastosis is a marker for pni risk also invites future investigation. conclusions our study found early incidental pni on men aged 60 years or older with a high prevalence on facial sites and patients with four or more scc cases. threshold histopathological features associated with early pni included increased surface microscopic diameters greater than 5.0 mm, tumor invasion depth beyond 0.9 mm, either moderate or poor differentiation, and adjacent lymphocytosis. references 1. green ac, olsen cm. cutaneous squamous cell carcinoma: an epidemiological review. br j dermatol. 2017;177(2):373-381. https://doi.org/10.1111/bjd.15324 2. thompson ak, kelley bf, prokop lj, murad mh, baum cl. risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease specific death: a systematic review and meta-analysis. jama dermatol. 2016;152(4): 419-428. https:// doi.org/10.1001/jamadermatol.2015.4994 3. leibovitch i, huilgol sc, selva d, hill d, richards s, paver r. cutaneous squamous cell carcinoma treated with mohs micrographic surgery in australia i. experience over 10 years. j am acad dermatol. 2005;53(2):253-260. https://doi.org/10.1016/j. jaad.2005.02.059 very low. previous pni studies have typically been on cohorts based in tertiary facilities. there are at least 2 factors that may account for low pni percentage in our study. first, the study deliberately selected a community-based cohort with early disease and smaller-size cases. the intention 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https://doi.org/10.1001/jama dermatol.2017.1680 6. lallas a, pyne j, kyrgidis a, et al. the clinical and dermoscopic features of invasive squamous cell carcinoma depend on the grade of differentiation. br j dermatol. 2015;172(5):1308-1315. https://doi.org/10.1111/bjd.13510 7. okholm c, frendø m, kiss k, von buchwald c. cheek numbness caused by perineural tumor invasion of the infraorbital nerve: a review of 3 diagnostically challenging cases. am j case rep. 2018;19:296-300. https://doi.org/10.12659/ajcr.907034 8. pyne jh, myint e, clark sp, et al. squamous cell carcinoma: pain as a clue to increased tumour diameter, increased invasion depth, the grade of differentiation, acantholysis and perineural invasion. j clin exp dermatol. 2020;45(2):180-186. https://doi. org/10.1111/ced.14066 9. verburg m, lang m, mühlstädt m, et al. cutaneous squamous cell carcinoma with perineural invasion: report on eight cases and review of the literature. dermatology. 2015;230(2):135-142. https://doi.org/10.1159/000368771 10. campoli m, brodland dg, zitelli j. a prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma. j am acad dermatol. 2014;70(4):630-636. https:// doi.org/10.1016/j.jaad.2013.11.034 11. salmon pj, hussain w, geisse jk, grekin rc, mortimer nj. sclerosing squamous cell carcinoma of the skin, an underemphahttps://doi.org/10.1111/j.1524-4725.2010.01850.x https://doi.org/10.1111/j.1524-4725.2010.01850.x https://doi.org/10.1097/dss.0000000000001581 https://doi.org/10.1097/dss.0000000000001581 https://doi.org/10.1016/j.jdcr.2018.09.002 https://doi.org/10.1016/j.jdcr.2018.09.002 https://doi.org/10.1111/j.1524-4725.2008.34412.x https://doi.org/10.1111/j.1524-4725.2008.34412.x https://doi.org/10.1111/ced.13222 https://doi.org/10.1001/jamadermatol.2013.746 https://doi.org/10.1001/jamadermatol.2013.746 https://doi.org/10.1016/s1470-2045(08)70178-5 https://doi.org/10.1002/hed.10025 https://doi.org/10.1001/jamadermatol.2017.1680 https://doi.org/10.1001/jamadermatol.2017.1680 https://doi.org/10.1111/bjd.13510 https://doi.org/10.12659/ajcr.907034 https://doi.org/10.1111/ced.14066 https://doi.org/10.1111/ced.14066 https://doi.org/10.1159/000368771 https://doi.org/10.1016/j.jaad.2013.11.034 https://doi.org/10.1016/j.jaad.2013.11.034 dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021013 1 dermatology practical & conceptual dermoscopic appearance of an annular subacute cutaneous lupus erythematosus biswanath behera1, rashmi kumari2, debasis gochhait3, pavithra ayyanar4 1 department of dermatology and venereology, aiims, bhubaneswar, india 2 department of dermatology, venereology and leprology, jipmer, puducherry, india 3 department of pathology, jipmer, puducherry, india 4 department of pathology, aiims, bhubaneswar, india key words: annular scle, subacute cutaneous lupus erythematosus, scle, dermoscopy citation: behera b, kumari r, gochhait d, ayyanar p. dermoscopic appearance of an annular subacute cutaneous lupus erythematosus. dermatol pract concept. 2021;11(2):e2021013. doi: https://doi.org/10.5826/dpc.1102a13 accepted: august 14, 2020; published: march 8, 2021 copyright: ©2021 behera et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rashmi kumari, md, department of dermatology, venereology and leprology, jipmer, puducherry, pin-605006. email:rashmi.sreerag@gmail.com introduction subacute cutaneous lupus erythematosus (scle) is characterized mainly by cutaneous disease and usually has a good prognosis. the presence of nonscarring papulosquamous and annular polycyclic lesions are the hallmark of the disease. although the diagnosis is a straightforward task, at times, it can be confused with other inflammatory dermatoses. there are limited dermoscopic features described for scle [1]. case presentation a 40-year-old man with skin phototype iv presented with a 1-month history of multiple reddish skin lesions over the anterior chest, neck, and upper back. it was associated with a history of photosensitivity and on-and-off joint pain. he denied any history of prior drug intake. cutaneous examination revealed multiple erythematous, scaly papules and annular plaques. a few of the plaques showed a peripheral rim of white scales (figure 1). the differential diagnoses of scle, psoriasis, and petaloid seborrheic dermatitis were considered. figure 1. multiple erythematous scaly annular plaques over the chest. inset shows peripheral rim of scaling. 2 letter | dermatol pract concept 2021;11(2):e2021013 dermoscopic examination showed a white to reddish-white homogenous area, patchy clustered brown to blue-gray dots and peppering (dots without circumscription), scales, and a mixed vascular pattern comprised of linear, hairpin, dotted, and glomerular vessels. the white homogenous area surrounded, or become prominent, around the blood vessels and hair follicles (figure 2). there was no follicular plugging or dilatation, and the hair follicles within the lesions appeared to be normal. laboratory investigations revealed mild anemia (hemoglobin 11.2gm/dl) and positive antinuclear and anti-ro antibodies. histopathology showed hyperkeratosis, a focal atrophic epidermis, basal vacuolar degeneration, pigmentary incontinence, and upper dermal telangiectatic blood vessels (figure 3). immunohistochemistry showed a linear deposition of immunoreactant igg and c3 along the dermoepidermal junction. the diagnosis of scle was made. the patient was advised in strict sun protection and started with tablet hydroxychloroquine 200 mg (4 mg/kg per day) once daily, topical mometasone ointment, and sunscreen. two constant dermoscopic features, whitish scales and a mixed vascular pattern over a pinkish, or reddish background, were reported in a case series of scle. the scales were located either diffusely or at the periphery. the vessels included linear, linear irregular, branching, and sparsely distributed dotted vessels [1]. a similar pattern was observed in the index case, except for the presence of a prominent white homogenous area and brown to blue-gray dots/peppering. dermoscopy can be a useful tool to differentiate annular scle from its main differential diagnoses that include psoriasis, that is characterized by the presence of regularly figure 2. (a, b) dermoscopy (heine delta20 dermatoscope; magnification ×10)) shows a white to reddish-white homogenous area, patchy clustered brown to blue-gray dots (blue asterisk), blue-gray peppering (red asterisk), scales, and a mixed vascular pattern, comprised of linear, hairpin (black arrow) and glomerular (blue arrows) vessels. prominent white homogenous area around blood vessels (purple arrow) and normal looking hair follicles (red arrow). figure 3. histology shows hyperkeratotic atrophic epidermis, basal vacuolar degeneration, cytoid body, melanin incontinence, and upper dermal dilated blood vessels (h&e, ×400). distributed dotted vessels and white scales on a light to dull red background; pityriasis rosea, that usually shows peripheral white scales (collarette sign) and patchy dotted vessels; and granuloma annulare, that demonstrates a whitish to yellow-orange area along with varying morphology vessels. in contrast to scle, discoid lupus erythematosus is dominated by follicular plugging, dilated follicles, a perifollicular whitish halo, and a monomorphic vascular pattern, a feature that can be helpful to distinguish extrafacial discoid lupus erythematosus from scle [2]. letter | dermatol pract concept 2021;11(2):e2021013 3 conclusion in conclusion, a dermoscopy pattern, white to reddish-white homogenous area with brown to blue-gray dots/peppering and mixed vascular pattern, can be useful to diagnose and differentiate annular scle from its clinical mimics. references 1. errichetti e, piccirillo a, viola l, stinco g. dermoscopy of subacute cutaneous lupus erythematosus. int j dermatol. 2016;55(11):e605-e607. doi: 10.1111/ijd.13331. pmid: 27260752. 2. lallas a, argenziano g, apalla z, et al. dermoscopic patterns of common facial inflammatory skin diseases. j eur acad dermatol venereol. 2014;28(5):609-614. doi: 10.1111/jdv.12146. pmid: 23489377. letter | dermatol pract concept 2012;2(1):14 75 medical dramas – the pros and the cons khalid al aboud, m.d.1 1 department of pathology, wake forest university school of medicine, winston-salem, nc, usa citation: al aboud k. medical dramas – the pros and the cons. dermatol pract conc. 2012;2(1):14. http://dx.doi.org/10.5826/dpc.0201a14. copyright: ©2012 al aboud. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: khalid al aboud, m.d., wake forest university school of medicine, department of pathology, medical center boulevard, winston-salem, nc 27157-1072, usa. tel. 336. 713.5933; fax. 336.716.-7595. email: amoa61@hotmail.com. opinion there has been increasing interest in the field of medicine and in the social life of patients as well as health care providers in the realm of the media, namely, films and television shows. table 1 lists some popular television series that are based on events germane to the medical field [1–7]. these shows constitute a genre in television, the ‘’medical drama.” a medical drama can be defined as a television drama in which events center on a hospital, an ambulance staff, or other medical environment [8]. dr. kildare, which first aired in 1961, is generally considered to be the first medical drama on american television. the show was a success and, soon thereafter, the medical drama became a popular television genre. in the united states, most medical dramas run one hour long and, more often than not, are set in a hospital. most current medical dramas go beyond the events pertaining to the characters’ jobs and portray some aspects of their personal lives. for example, a typical medical drama might have a storyline in which two doctors fall in love [8]. communications theorist marshall mcluhan, in his 1964 work on the nature of media, predicted a big success of this particular genre on television because such a medium “creates an obsession with bodily welfare” [8]. these shows have high viewership ratings. for example, the television series house was among the top ten rated shows in the united states from its second through its fourth season; in the 2008–9 season, it fell to nineteenth overall. distributed to 66 countries, house was the most watched television program in the world in 2008 [5]. health care providers, in particular, have become more interested in this type of drama and are not only watching the television shows, but are also keenly observing their medical content. there are even websites dedicated to physician reviews on these television series. they review them for medical accuracy [9] and give medical opinions, breakdowns, and expert commentaries on each episode [10]. these television programs have received many awards and critical acclaim. however, they are often controversial in their frank depictions of violence, sexuality, recreational drug use, and surgical procedures [11–16]. this type of drama originated in the united states, but many other countries are developing their own versions of medical dramas [8]. there are some who contend that these television shows can be useful in reinforcing the principles of medical ethics, professionalism (i.e., communications skills, patient confidentiality, and bedside manner, including sensitivity and empathy), history taking, and clinical examination especially for medical students and junior doctors and that they could even replace lecture-based modules [13]. some even argue that the medical drama is a narrative genre that may foster better emotional engagement with a patient, and moral imagination resulting in a more ethically sensitive student of medicine [11-13]. some authors think that they may have an impact on the public in that they might be disseminating fundamental principles of medicine in the context of entertainment [14]. in some episodes of these shows, ordinary people are seen saving lives by performing cardiopulmonary resuscitation and other first aid procedures. it might be that these dramas are putting medical professionals and the medical field in general in a less than flatterdermatology practical & conceptual www.derm101.com 76 letter | dermatol pract concept 2012;2(1):14 ing light to the public, possibly affecting the confidence they may have in doctors. for example, the doctor in the show house does not wear a lab coat. in my opinion, this can be viewed as non-professional. the social lives and personal behaviors of doctors in a given show from one country might not be viewed well by viewers in another country with a different cultural background. is the target audience for these shows the health care provider or the public in general? is the medical content of these shows accurate? only the future will tell what impact this type of drama will continue to have on the public. in this author’s opinion, doctors and filmmakers should come together to produce what is of benefit as well as of entertainment to public. the show remarks emergency! emergency! is an american television series that combines the medical drama and action-adventure genres. it was produced by mark vii limited (jack webb’s company) and distributed by universal studios. it debuted as a midseason replacement on january 15, 1972, on nbc, replacing the shortlived series the good life, and ran until september 3, 1977. emergency! was created and produced by jack webb and robert cinader, both of whom were also responsible for the police drama adam12. the show focuses on paramedics john gage and roy desoto (played by randolph mantooth and kevin tighe) of the los angeles county fire department’s station 51 (actually station 127 in carson, california), and the hospital emergency room staff (played by robert fuller, julie london and bobby troup) with whom the paramedics work to save lives. it was also the first show to feature paramedics who help rescue victimized or hurt patients. emergency! and adam-12 were similar in that they featured dedicated civil servants handling two or three varied and unrelated incidents during a typical shift. despite not being a top 30 series for six seasons, emergency! was still an audience favorite show, and despite good ratings, it was canceled in 1977. however, the show returned as a series of six “movie of the week” specials between late 1977 and the spring of 1979. years after the cancellation of the series, it was sold into syndication, tv land, and rtv [1]. er er is an american medical drama television series created by novelist michael crichton that aired on nbc from september 1994 to april 2009. it was produced by constant c productions and amblin entertainment, in association with warner bros. television. it is set primarily in the emergency room (er) of fictional county general hospital in chicago, illinois. the show ran for 15 seasons, becoming the longest-running primetime medical drama in american television history. it won 23 emmy awards [2]. grey’s anatomy grey’s anatomy is an american medical drama television series. it follows the lives of interns, residents and their mentors in the fictional seattle grace-mercy west hospital in seattle, washington. the pilot episode, “a hard day’s night” premiered in march 2005 on abc. the first episode watched by 16.25 million viewers, and the first season finale attracting 22.22 million viewers. the show is one of the most watched prime time television series [3]. house house, also known as house, m.d., is an innovative take on the medical drama in which the villain is a medical malady and the hero is an irreverent, controversial doctor who trusts no one, least of all his patients. [4] it is debuted on the fox network on november 2004. the show’s central character is dr. gregory house (hugh laurie), an unconventional medical genius who heads a team of diagnosticians at the fictional princetonplainsboro teaching hospital (ppth) in new jersey [5]. dr. gregory house (hugh laurie), devoid of bedside manner and dealing with his own constant physical pain, uses a cane that punctuates his acerbic, brutally honest demeanor. his behavior often borders on antisocial, but house is a brilliant diagnostician whose unconventional thinking and flawless instincts afford him a great deal of respect. an infectious disease specialist, he thrives on the challenge of solving medical puzzles in order to save lives [4]. house celebrated its 100th episode milestone in february 2009. the finale of the show’s sixth season aired in may 2010 [5]. table 1. select medical dramas listed alphabetically. [copyright: ©2012 al aboud.] letter | dermatol pract concept 2012;2(1):14 77 references 1. emergency! wikipedia.org. web site. http://en.wikipedia.org/ wiki/emergency! 2010 july 16. accessed july 16, 2010. 2. er (tv series). wikipedia.org. web site. http://en.wikipedia.org/ wiki/er_(tv_series). 2010 july 15. accessed july 18, 2010. 3. grey’s anatomy. wikipedia.org. web site. http://en.wikipedia.org/ wiki/grey’s_anatomy. 2010 july 18. accessed july 18, 2010. 4. house. fox.com. web site. http://www.fox.com/house/about/. accessed july 18, 2010. 5. house (tv series). wikipedia.org. web site. http://en.wikipedia. org/wiki/house_(tv_series). 2010 july 16. accessed july 16, 2010. 6. nip/tuck. wikipedia.org. web site. http://en.wikipedia.org/wiki/ nip/tuck. 2010 july 14. accessed july 18, 2010. 7. scrubs (tv series). wikipedia.org. web site. http://en.wikipedia. org/wiki/scrubs_(tv_series). 2010 july 19. accessed july 19, 2010. 8. medical drama. wikipedia.org. web site. http://en.wikipedia.org/ wiki/medical_ 2010 june 18. accessed july 18, 2010. 9. house medical reviews. polite dissent. web site. http://www. politedissent.com/house_pd.html. accessed july 18, 2010. 10. house m.d. a disease a day. web site. http://www.diseaseaday. com/tv-shows/house-m-d. accessed july 18, 2010. 11. arawi t. using medical drama to teach biomedical ethics to medical students. med teach. 2010; 32(5):e205–10. 12. rich le, simmons j, adams d, thorp s, mink m. the afterbirth of the clinic: a foucauldian perspective on “house m.d.” and american medicine in the 21st century. perspect biol med. 2008;51(2):220–37. 13. lim ec, seet rc. in-house medical education: redefining teleeducation. teach learn med. 2008;20(2):193–5. 14. elkamel f. the use of television series in health education. health educ res. 1995;10(2):225–32. 15. wicclair mr. the pedagogical value of house, m.d. – can a fictional unethical physician be used to teach ethics? am j bioeth. 2008; 8(12):16–7. 16. strauman e, goodier bc. not your grandmother’s doctor show: a review of grey’s anatomy, house, and nip/tuck. j med humanit. 2008;29(2):127–31. the show remarks nip/tuck nip/tuck is an american drama series created by ryan murphy, which aired on fx in the united states. the series focuses on mcnamara/troy, a plastic surgery practice, and follows its founders, sean mcnamara and christian troy. each episode typically involves the cosmetic procedures of one or more patients, and also features the personal and professional lives of its main cast. the show began in 2003, and the sixth and final season started airing october 2009, and concluded the series in march 2010, with the 100th episode [6]. scrubs scrubs is an american comedy-drama television series created in 2001 by bill lawrence and produced by abc studios. the show follows the lives of several employees of sacred heart, a teaching hospital. it features fast-paced screenplay, slapstick, and surreal vignettes presented mostly as the daydreams of the central character, dr. john “j.d.” dorian, who is played by zach braff. the show’s title is a play on surgical scrubs and a term for a low-ranking or insignificant person (at the beginning of the show, most of the main characters were medical interns, one of the lowest ranks in the medical hierarchy). scrubs premiered in october 2001 on nbc. during the seventh season, nbc announced that it would not renew the show. shortly after the seventh season finale, abc announced that it had picked up the series for a new season and in january 2009, the eighth season of scrubs premiered on abc. the ninth season, which premiered on december 2009 on abc, features several new cast members and is set at a new facility. on may 14, 2010, it was announced that scrubs was officially canceled by abc [7]. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020053 1 dermatology practical & conceptual introduction delayed tattoo reactions include a wide range of clinical presentations and overlapping forms; thus diagnosis can be challenging. we present a case of a delayed tattoo reaction from red dye. case presentation an otherwise healthy 40-year-old man presented with firm elevated plaques that arose 4 months previously, within a multicolored tattoo on the right forearm, 8 months after the execution of the tattoo (figure 1a). the patient claimed minimal and only occasional itching. polarized dermoscopy (luminis visiomed, caliber) highlighted multiple keratotic plugs within the lesion, limited to the red-dyed areas (figure 1). examination with line-field confocal optical coherence tomography (lc-oct) [1] of both the transitional lesionalto-healthy part (figure 1c) and the central part of the lesion (figure 2a) showed a hyperkeratotic flattened epidermis and a blurred basal membrane due to the presence of inflammatory infiltrate, suggesting a lichenoid/interface dermatitis pattern. comparative examination with high-frequency ultrasound 70 mhz (hfus) (vevo md, visualsonics) up to a depth of 5.5 mm performed at the same location revealed multiple anechoic holes and posterior shadowing due to dilated vessels, and inflammation in the superficial and deep dermis (figure 1d). punch biopsy taken at the same location for histopathological examination revealed hyperkeratosis, flattened epidermis with hyperkeratosis and blurring of the basal membrane; lymphocytic lichenoid inflammatory infiltrate in the superficial dermis (figure 2b); and clustered infiltrate around red pigment deposits in reticular dermis, focally periadnexal and perivascular (figure 2c). immunohistochemical study revealed a mixed inflammatory chronic infiltrate composed of b and t lymphocytes. red dye deposdelayed tattoo reaction from red dye with overlapping clinicopathological features: examination with high-frequency ultrasound and line-field optical coherence tomography linda tognetti,1 sean ekinde,1 cyril habougit,2 elisa cinotti,2 pietro rubegni,1 jean luc perrot3 1 department of dermatology, division of medical, surgical and neurosciences, university of siena, italy 2 anatomopathology service, university hospital of saint-etienne, saint-etienne, france 3 department of dermatology, university hospital of saint-etienne, saint-etienne, france keywords: tattoo reaction, high-frequency ultrasound, line-field optical coherence tomography citation: tognetti l, ekinde s, habougit c, cinotti e, rubegni p, perrot jl. delayed tattoo reaction from red dye with overlapping clinicopathological features: examination with high-frequency ultrasound and line-field optical coherence tomography. dermatol pract concept. 2020;10(3):e2020053. doi: https://doi.org/10.5826/dpc.1003a53 accepted: february 21, 2020; published: june 29, 2020 copyright: ©2020 tognetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: linda tognetti, md, dermatology unit, division of medical, surgical and neurosciences, university hospital of siena, viale bracci, 53100 siena, italy. email: l.tognetti@stuent.unisi.it https://doi.org/10.5826/dpc.1003a53 mailto:l.tognetti@stuent.unisi.it 2 letter | dermatol pract concept 2020;10(3):e2020053 figure 1. (a) severe persistent tattoo reaction from red dye. (b) dermoscopic examination (×20) of a swelling elevated area (white circle in a) highlights the presence of yellowish circles within the stained skin corresponding to perifollicular openings filled with keratin, dyed by exogenous pigment. examination of transition healthy-to-lesional zone (white square) with (c) line-field confocal optical coherence tomography and (d) high-frequency ultrasound 70 mhz: inflammatory infiltrates (asterisks) and dilated vessels are visible in papillary and reticular dermis of lesional skin, generating diffuse anechoic holes in the papillary and reticular dermis, respectively. dej = dermoepidermal junction; e = epidermis; mf = muscularis fascia; pd = papillary dermis; rd = reticular dermis; sc = stratum corneum; sg = stratum granulosum; v = vessels. figure 2. (a) line-field confocal optical coherence tomography image (0.5 mm in depth, axial and lateral resolution of 1 µm) of lesional skin. (b) histological correlation: pas om200× shows thickened and hyperreflective stratum corneum (sc) due to hyperorthokeratosis; narrowed stratum granulosum (sg) and stratum spinosum (ss); blurred dermoepidermal junction (dej) due to infiltrating lymphocytes; dilated vessels (v) and chronic inflammatory infiltrate (asterisks) in the papillary (pd) and reticular dermis (rd) appearing as  hyporeflective  areas surrounding red pigment deposits. (figure continues next page) letter | dermatol pract concept 2020;10(3):e2020053 3 egorized into a rigid classification, the present case should be interpreted as a severe delayed tattoo reaction from red dye with overlapping features of the pseudolymphomatous, lichenoid, and hyperkeratotic pattern. getting closer to an in vivo histology and providing higher resolution than conventional oct, the new lc-oct [1] can be proposed to better characterize the superficial part of a tattoo reaction of uncertain pattern and/or with clinical overlapping features, in combination with hfus, which is able to reveal the inflammation in the deep dermis [1]. moreover, the 2 techniques can be used to monitor treatment response to laser or intralesional therapy. references 1. dubois a, levecq o, azimani h, et al. line-field confocal optical coherence tomography for high-resolution noninvasive imaging of skin tumors. j biomed opt. 2018;10(23):1-9. https://doi. org/10.1117/1.jbo.23.10.106007. 2. forbat e, al-niaimi f. patterns of reactions to red pigment tattoo and treatment methods. dermatol ther (heidelb). 2016;6(1):1323. https://doi.org/10.1007/s13555-016-0104-y. its were distributed in the deep dermis only and spared the superficial dermis (figure 2d). conclusions in the last decade, delayed tattoo reactions have been on the increase due to the popularity of tattoos [2]. metal components of the red dye (eg, nickel, mercury, and cadmium) have been addressed as the chronic antigenic stimulating agent causing a polyclonal proliferation of lymphoid cells. traditionally, 4 histological patterns were described for delayed tattoo reactions, ie, hyperkeratotic pattern, lichenoid dermatitis, pseudolymphomatous pattern, and granulomatous pattern. however, this classification often fails to correlate significantly with clinical appearance of the lesions and has limited utility in daily practice, especially when multiple or overlapping clinicopathological features can be detected inside the same lesion [2]. indeed, in this case we can observe keratotic cysts on dermoscopy, in favor of the hyperkeratotic pattern; histological features of lichenoid dermatitis; and evolution and clustered deep dermal infiltrate typical of the pseudolymphomatous pattern. thus, rather than being catfigure 2. (continued) (c) h&e staining (om25×) demonstrates a lymphocytic infiltrate exhibiting both a lichenoid and a cluster distribution, focally periadnexal and perivascular. red pigment deposits are distributed in the whole thickness of rd and reach the upper part of the hypodermis (hd). (d) no staining (om25×). https://doi.org/10.1117/1.jbo.23.10.106007 https://doi.org/10.1117/1.jbo.23.10.106007 https://doi.org/10.1007/s13555-016-0104-y dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020073 1 dermatology practical & conceptual case presentation infantile hemangioma is a common benign vascular proliferation seen in the pediatric age group. dermoscopy of hemangioma shows lacunae of variable sizes and dilated vessels against a red to reddish blue background [1]. we report the dermoscopic evaluation of regression of infantile hemangioma on topical timolol. a 3-month old infant presented with complaints of a red raised proliferative lesion of 5 × 5 cm over the abdomen since 8-10 days of life. a clinical diagnosis of infantile hemangioma was made. the infant was started on topical timolol 0.5% drops twice a day. dermoscopic evaluation follow-up (dl 3n, polarized, × 20) was done at 0, 1, 3, 5, and 7 months. the erythema was first to respond, followed by decrease in the depth of the lesion. black dots (black arrow) represent thrombosed capillaries that disappeared in the initial phase of treatment (figure 1a). white dots (white arrow) represent the eccrine openings that were uninvolved during the entire course of regression (figure 1b). the classical features, lacunae (yellow arrow) and vascular structures/red dots (green arrow) (figure 1b), appeared later on at the 3-month follow-up visit once the lesion had flattened, and subsequently lacunae became empty (white asterisk) and the entire erythema was replaced by brown diffuse pigmentation (red arrow) and dots representing residual pigmentation (figure 1d). teaching point dermoscopic evaluation of hemangioma may help to assess the response of treatment. references 1. piccolo v, russo t, moscarella e, et al. dermatoscopy of vascular lesions. dermatol clin. doi: 10.1016/j.det.2018.05.006. pmid: 30201148. dermoscopic evaluation of infantile hemangioma treated with topical timolol rubina jassi1, sarita sanke1, ram chander1 1 department of dermatology, lady hardinge medical college & associated hospitals, new delhi, india key words: hemangioma, infantile hemangioma, timolol, dermoscopy citation: jassi r, sanke s, chander r. dermoscopic evaluation of infantile hemangioma treated with topical timolol. dermatol pract concept. 2020;10(4):e2020073. doi: https://doi.org/10.5826/dpc.1004a73 accepted: march 25, 2020; published: october 26, 2020 copyright: ©2020 jassi et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sarita sanke, md, dnb, department of dermatology, lady hardinge medical college & associated hospitals, shivaji stadium bus terminal, shaheed bhagat singh marg, connaught place, new delhi, 110001, india. email: sankesarita@gmail.com 2 image letter | dermatol pract concept 2020;10(4):2020073 figure 1. (a) baseline: diffuse red background with multiple eccrine openings, enhanced skin markings, fine white surface, scaling, and thrombosed capillaries (black arrow). (b) 3-month follow-up: lesion flattened, eccrine openings (white arrow), vascular dots (green arrow), and lacunae (yellow arrow) seen more clearly. scaling and skin markings disappeared. (c) 5-month follow-up: erythema decreased, lacunae and red dots disappeared, brown pigmentation replacing the erythema. (d) 7-month follow-up: diffuse brown residual pigmentation (red arrow) and empty lacunae (white asterisk). a b c d dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021004 1 dermatology practical & conceptual stewart-treves syndrome as a rare and fatal complication of post-traumatic lymphedema on the lower extremity leandro linhares leite1, valeria rossato1 1 hospital são lucas da pucrs, porto alegre, brazil key words: stewart-treves syndrome, lymphedema, lymphangiosarcoma, hemangiosarcoma, lower extremity citation: leite ll, rossato v. stewart-treves syndrome as a rare and fatal complication of post-traumatic lymphedema on the lower extremity. dermatol pract concept. 2021;11(2):e2021004. doi: https://doi.org/10.5826/dpc.1102a04 accepted: july 1, 2020; published: march 8, 2021 copyright: ©2021 leite and rossato. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: leandro linhares leite, md, msc, rua dr freire alemão, 660, 90450-060 porto alegre, brazil. email: leitelll@ gmail.com introduction stewart-treves syndrome (sts) is a rare disorder characterized by the development of angiosarcoma in an area of chronic lymphedema [1]. it was classically described in the upper limb after radical mastectomy with axillary lymph node resection, but there are reports related to idiopathic, congenital, post-surgical, traumatic or infectious lymphedema [1]. only 10% of cases are reported in places other than upper limbs [1]. case presentation a 70-year-old man presented with a 2-year history of a vegetating friable mass with progressive growth on his left leg and mild local pain (figure 1a and b). he had a history of a car accident with trauma to the left thigh 21 years before that complicated with chronic lymphedema in the affected limb. incisional biopsy showed dermal vascular proliferation with positive immunohistochemistry (ihc) for cd31, cd34 and factor viii, a condition compatible with angiosarcoma. the patient was referred for surgical excision, and the histopathological analysis of the specimen revealed high-grade undifferentiated malignancy, fusocellular and epithelioid cells with significant nuclear atypia, areas of necrosis, and fibromyxoid stroma (figure 2a). ihc was positive for cd31, fli-1, and factor viii and negative for human herpesvirus-8. computed tomography revealed lung metastases (figure 2b), and the patient died of complications from pulmonary hemorrhage 3 weeks after surgery. conclusions cutaneous angiosarcomas are aggressive tumors that emerge from the vascular endothelium, usually related to predisposing factors such as chronic lymphedema and radiation exposure [1]. sst was first described in 1948 as a cutaneous lymphangiosarcoma in a series of 6 cases associated with chronic lymphedema after radical mastectomy 2 letter | dermatol pract concept 2021;11(2):e2021004 figure 2. images of complementary studies of the case. (a) spindle cells with nuclear atypia and prominent nucleoli varying in size and shape. h&e, original magnification ×100. (b) multiple pulmonary nodules with the compatible appearance of metastatic implants. figure 1. clinical presentation of the lesion. (a) a vegetating and friable mass on the lateral aspect of the left leg. (b) the notable asymmetry between the legs caused by lymphedema in the left leg. note that there is also edema due to chronic venous insufficiency in both legs. for breast cancer. angiosarcomas usually take 5 to 15 years to arise after mastectomy [1]. it is postulated that lymphedema creates an environment of local immunosuppression and impairs immune surveillance mechanisms, predisposing one to the emergence of atypical angiogenesis and malignancy [2]. immunohistochemistry is often necessary to confirm the diagnosis and tissue origin and stain positive for factor viii, cd34, cd31, and vimentin. the main differential diagnosis is kaposi sarcoma, which is usually identified by immunohistochemistry analysis for human herpesvirus 8 [1]. the prognosis is poor, given the high rate of local recurrence and tendency for early metastases, mainly to the lungs [1]. this extremely rare case presented as a growing mass located on the lower limb with no previous history of lymphatic surgery, radiation, or malignancy. the late diagnosis contributed to the bad outcome, as the best management for sts is early diagnosis and surgical removal with amputation or wide local excision [1]. adjuvant treatment with chemotherapy and radiotherapy is usually recommended, but their contributions remain uncertain [1]. despite treatment, the prognosis is still poor with a mean survival time of 19 to 34 months, and the majority of the patients die from metastatic disease within 2 years [1]. notwithstanding the aggressiveness, this tumor develops in a predictable and specific clinical context with well-established predisposing factors. thus, physicians should be alert of new or growing lesions in lymphedema sites, regardless of location, to provide early diagnosis and increase the chances for successful treatment. furthermore, letter | dermatol pract concept 2021;11(2):e2021004 3 preventive methods to treat lymphedema, such as weight loss, physiotherapy, and compressive measures, should be encouraged [1]. references 1. sharma a, schwartz ra. stewart-treves syndrome: pathogenesis and management. j am acad dermatol. 2012;67(6):1342-1348. doi: 10.1016/j.jaad.2012.04.028. pmid: 22682884. 2. ruocco v, brunetti g, puca r v, ruocco e. the immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. j eur acad dermatol venereol. 2009;23(12):1364–1373. doi: 10.1111/j.14683083.2009.03345.x. pmid: 19548975. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021.11(3): e2021043 1 bevacizumab-induced geographic tongue marta martinez-garcia, jorge roman-sainz, nicolás silvestre-torner, sergio tabbara carrascosa dermatology service. severo ochoa university hospital, leganés, madrid key words: bevacizumab, geographic tongue, self-solving, infiltrating ductal carcinoma, vascular endothelial growth factor protein citation: martinez-garcia m, roman-sainz j, silvestre-torner n, tabbara carrascosa s. bevacizumab-induced geographic tongue. dermatol pract concept. 2021.11(3): e2021043. doi: https://doi.org/10.5826/dpc.1103a43 accepted: november 23, 2020; published: july 8, 2021 copyright: ©2021 martinez-garcia et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: marta martínez garcía, dermatology service. severo ochoa university hospital, leganés, madrid. e-mail: martamgml@yahoo.es introduction geographic tongue condition, or benign migratory glossitis, is a self-limited and often recurrent process, which occurs in around 2.5%. of the general population. the diagnosis is clinical and is characterized by the presence of atrophic areas located on the back and lateral edges of the tongue, caused by the absence of filiform papillae. its cause is unknown, it is associated with multiple systemic diseases and occasionally with drug use. case presentation here we present a case of a 43-year-old patient diagnosed with infiltrating ductal carcinoma. 1 year later, he presented tumor recurrence and treatment was started with capecitavin (1500 mg/m2 for 14 days) and bevacizumab (15 mg/m2 every 21 days), obtaining complete remission. in the last 12 months he underwent maintenance therapy with bevacizumab (15 mg/m2/21 days). in the last quarter of the last 12 months the patient reported the appearance of migratory lesions located on the back of the tongue, which evolved in outbreaks and were accompanied by pain and stinging with the ingestion of certain foods. the patient reported no clear relationship with the administration of bevacizumab. on the first examination, several atrophic plaques were observed, surrounded by a slightly elevated, white, keratotic border, arranged in a concentric fashion (figure 1). following 2 follow-up months, an additional examination was performed. a notable spontaneous improvement of the lesions was observed (figure 2). conclusions the association of the geographic tongue condition with the use of bevacizumab, whose target is the vascular endothelial growth factor protein a (vegf-a), has recently been described [1]. vegf-a activity blockade could impede the normal reparative capacity of the epithelium at the level of the lingual mucosa, which could explain the development of these lesions. the increasing use of this type of drug as a treatment for multiple tumors might facilitate the appearance of new cases of geographic tongue. an in-depth knowledge of the recently described association of the geographic tongue condition following bevacizumab use will prevent misdiagnosis and unnecessary treatment in these patients, who are often immunosuppressed. 2 letter | dermatol pract concept. 2021.11(3): e2021043 references 1. sundar s, burge f. geographical tongue induced by axitinib. bmj case rep. 2015; 2015:bcr2015211318. 2015 oct 16. doi:10.1136/bcr-2015-211318. pmid:26475876 figure 1. atrophic plaques surrounded by a keratotic border figure 2. improvement of lesions dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021022 1 dermatology practical & conceptual eruptive syringomas on the neck: clinicopathological and dermoscopic features gargi taneja1, neirita hazarika1, riti bhatia1 1 department of dermatology and venereology, all india institute of medical sciences, rishikesh, india key words: syringomas, eccrine gland neoplasms, neck, eruptive citation: taneja g, hazarika n, bhatia r. eruptive syringomas on the neck: clinicopathological and dermoscopic features. dermatol pract concept. 2021;11(2):e2021022. doi: https://doi.org/10.5826/dpc.1102a22 accepted: september 8, 2020; published: march 8, 2021 copyright: ©2021 taneja et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: riti bhatia, md, department of dermatology and venereology, all india institute of medical sciences, rishikesh, india. email: ritibhatia_aiims@yahoo.com  introduction syringoma is a benign adnexal tumor that originates from the acrosyringium. eruptive syringoma is a rare variant that manifests in the form of skin-colored or brownish, shiny, angulated papules that occur in successive crops. dermoscopic evaluation reveals brownish regular pigment network and tiny whitish dots between adjacent papules that correspond histologically to multiple eccrine ducts lined by a double-layered epithelium, giving a paisley tie appearance. this case of eruptive syringomas presenting with brownish papules on the neck highlights the importance of histopathological and dermoscopic evaluation.      case presentation a woman in her late twenties presented with a 7to 8-year history of asymptomatic papules on the neck. the papules developed episodically, in clusters (figure 1). she had no history of chronic disease and no family history of a similar condition. physical examination revealed multiple monomorphic brownish papules on the anterior part of the neck and chest. routine laboratory tests, including lipid profile and serum thyroid hormone levels, were all normal. figure 1. multiple monomorphic brownish papules on the neck and upper chest. a 4-mm punch biopsy was obtained from one of the papules. histopathologic analysis revealed multiple eccrine ducts and solid nests of epithelial proliferation within the letter | dermatol pract concept 2021;11(2):e2021022 dermis. the ducts were lined by a double-layered epithelium. amorphous eosinophilic material could be appreciated in some ductal lumina. some ducts showed small, comma-like extension of epithelial cells. the stroma was collagenous (figure 2). dermoscopic evaluation (polarized mode, dermlite) of a papule revealed brownish regular pigment network and tiny whitish dots between adjacent papules (figure 3). based on clinical, histopathogical, and dermoscopic features, a diagnosis of eruptive syringomas was made. conclusions syringoma is a benign adnexal tumor that originates from the acrosyringium [1]. the commonest type of syringoma is the localized variant that usually involves the periorbital area. eruptive syringoma is a rare variant that manifests around puberty in the form of skin-colored or brownish, shiny, angulated papules that occur in successive crops. other variants include the familial type and trisomy 21-associated syringoma. eruptive syringoma usually involves the anterior chest, upper abdomen, axillae, and periumbilical region [1]. it has been reported in association with down syndrome, prurigo nodularis, sarcoidosis, psychiatric disorders, and ehlers–danlos syndrome. clinical differential diagnoses include steatocystoma multiplex, disseminated xanthoma, multiple trichoepitheliomas, urticaria pigmentosa, and disseminated granuloma annulare. histopathological findings include eccrine ductal proliferation in a dense fibrous stroma. there is formation of nests and cords of double-layered epithelial cells. the outer epithelium is often elongated into comma-like structures, resembling a paisley tie pattern. dermoscopic features include a delicate pigment network and multifocal whitish areas [2]. the pigment network has been attributed to overlying basal hyperpigmentation, more so in the eruptive variant. whitish dots in between the pigment network corresponds to the opening of eccrine glands, which are larger than those of uninvolved skin [2]. however, dermoscopic features of syringoma are described somewhat variably in the literature. the reticular brown pigmentation may not to be present in all cases, especially in isolated syringoma [3]. most cases of eruptive syringomas show a fine pigment network with whitish areas, but data is limited due to the sparse literature on this topic [4]. the rosette pattern of whitish dots has also been described in 1 case report [4]. the lesions are benign and usually remain static. treatment modalities include dermabrasion, excision, electrodesiccation, chemical peeling, and oral and topical retinoids. the outcome is usually unsatisfactory. this case of eruptive syringomas presenting with brownish papules on the neck highlights the importance of histopathological and dermoscopic evaluation.      references 1. pruzan dl, esterly nb, prose ns. eruptive syringoma. arch dermatol. 1989;125(8):1119-1120. doi: 10.1001/archderm .1989.01670200095017. pmid: 2547344. 2. ankad bs, sakhare ps, prabhu mh. dermoscopy of non-melanocytic and pink tumors in brown skin: a descriptive study. indian j dermatopathol diagn dermatol. 2017;4(2):41-51. doi: 10.4103/ijdpdd. ijdpdd_10_17. 3. corazza m, borghi a, minghetti s, ferron p, virgili a. dermoscopy of isolated syringoma of the vulva. j am acad dermatol. 2017;76(2s1): s37-s39. doi: 10.1016/j.jaad.2016.06.009. pmid: 28087025. 4. zhong p, tan c. dermoscopic features of eruptive milium-like syringoma. eur j dermatol. 2015;25(2):203-204. doi: 10.1684/ ejd.2014.2506. pmid: 25961748.  figure 2. lesional biopsy shows multiple eccrine ducts and solid nests of epithelial proliferation with comma-like structures, resembling a paisley tie pattern (h&e, ×400). figure 3. dermoscopic image (polarized mode, dermlite) of the papule shows regular brownish pigmented network (circle) and multiple tiny white dots (black arrow). observation | dermatol pract concept 2011;1(1):11 53 a 64-year-old man was noted to have a single pigmented lesion in the nostril of his nose. clinical examination revealed a 5 mm nodular growth and brown lesion. with a presumed clinical diagnosis of malignant skin tumor, a biopsy was performed. the histological examination revealed the unexpected diagnosis of pigmented inverted follicular keratosis. the inverted follicular keratosis is an uncommon benign lesion that is usually diagnosed histologically rather than clinically. it commonly simulates other proliferative skin lesions. abstract pigmented tumor in the nostril nawel jaada, m.d.1, ines zaraa, m.d.1, ines chelly, m.d.2, rym cheikhrouhou, m.d.1, sondes trojjet, m.d.1, dalenda el euch, m.d.1, mourad mokni, m.d.1, slim haouet, m.d.2, amel ben osman, m.d.1 1dermatology department, la rabta hospital, tunis, tunisia 2pathology department, la rabta hospital, tunis, tunisia key words: inverted follicular keratosis, seborrheic keratosis citation: jaada n, zaraa i, chelly i, et al. pigmented tumor in the nostril. dermatol pract concept 2011;1(1):11. http://dx.doi.org/10.5826/ dpc.0101a11. editor: harald kittler, m.d. received: october 1, 2010; accepted: january 27, 2011; published: october 31, 2011 copyright: ©2011 jaada et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ines zaraa, m.d., assistant professor, dermatology department, la rabta hospital, jabbari, bab saadoun, tunis, 1007 tunisia. tel: +21698307425, fax: +21671569449. e-mail: inesrania@myway.com. introduction the inverted follicular keratosis is an uncommon benign lesion that is usually diagnosed histologically rather than clinically. we report on a singular case of a pigmented skin lesion, which was revealed on histological examination to be a pigmented inverted follicular keratosis. observation we present a case of a white 64-year-old man, with no significant co-morbidities, who had a remote history of a profigure 1. exophytic, corneal brown lesion located in the left nostril. dermatology practical & conceptual www.derm101.com 54 observation | dermatol pract concept 2011;1(1):11 figure 2. a: epithelial proliferation both above and below the level of residual epidermis (hematoxylin and eosin (h&e) stain); b: keratin crypt formation at the surface of the lesion with hyperkeratotic epithelium and acanthosis (h&e stain); c: epithelial proliferation containing a squamous eddy formation (h&e stain); d: high-power photomicrograph depicting base of inverted follicular keratosis with peripheral palisading of basaloid cells at the periphery of the tumor lobules and intercellular edema; e: squamous eddy formation. a b d c e observation | dermatol pract concept 2011;1(1):11 55 longed sun exposure. the patient presented with an asymptomatic nodular growth and brown lesion measuring 5 mm in diameter and located in the left nostril of the nose (figure 1); the patient had noticed the appearance of the lesion a few months previous to his visit to us. clinically, the tumor appeared to be limited to the skin with no evidence of deep infiltration. basal cell carcinoma, squamous cell carcinoma, melanoma and seborrheic keratosis were considered as possible diagnoses. the patient had a skin quarter biopsy. the histopathologic findings, illustrated in figures 2a–e show downward growth of the epithelium with intralesional corneal cystic inclusions, surrounded by nonspecific chronic inflammatory infiltration, with no evidence of cellular atypia. the epidermis revealed hyperkeratosis, acanthosis, and papillomatosis with a sharp dermarcation line. polymerase chain reaction (pcr) for human papillomavirus (hpv) was negative. four months later, the patient reported a spontaneous regression of the remaining tumor (figure 3). comment histologic examination of this lesion revealed features consistent with inverted follicular keratosis (ifk). a mild controversy currently exists in the literature concerning the origin of ifk. helwig and others [1, 2] support the hair follicle as the origin of this lesion, while some authors believe that this lesion is best characterized as a variant of seborrheic keratosis (sk) that has been irritated, [3] and others consider it as distinct entity [4]. it is characterized by a squamous epithelial expansion of the infundibular portion of the hair follicle in an exophytic and endophytic pattern. ifk is a benign skin lesion reported initially by helwig [1] that occurs in middle aged or older patients (>50 years), with median age at presentation of 69 years. men are affected about twice as often as women. in ifk the lesions are generally asymptomatic, firm, and pinkish papules, but it can present chromatic variants, typically from yellow to brown, in relation to the content of melanin [5]. the lesion most often arises as a solitary skin nodule on the face (85%) [4]; however, multiple ifk have been described in cowden’s syndrome [6]. the cheek and the upper lip are the sites of predilection; other sites affected are the chin, forehead, eyebrow, nose, and eyelid [7]. most of the lesions are between 3 and 8 mm in maximum diameter, but a few reach a size of 10 mm. the duration of the lesion varies between six weeks and three years in most cases, and in some cases as long as 15 years has been reported [7]. ifk can be misdiagnosed clinically as different skin cancers. indeed, in our observation the lesion mimicked the clinical appearance of basal cell carcinoma, or pigmented sk, or benign adnexal tumor. the diagnosis was based on histological examination, therefore, and a skin biopsy should always be performed in order to exclude its malignant nature. in fact, ifk can also be mistaken clinically as melanoma because of the heavily pigmented nature of the lesion [8]. in our observation, the histological appearance of the tumor fits perfectly with the description in the literature. histopathological examination showed epithelial proliferation above and below the level of the epidermis with hyperkeratosis, parakeratosis and papillomatosis of the epidermis. in addition, we note a broad fingerlike downward epithelial proliferation containing occasional horn cysts, which consists of two cell types, basal cells located in the periphery and malpighian cells in the center. these structures are named “squamous eddies.” generally, the base of the lesion is sharply delineated from the underlying corium and contains intercellular edema and a minimal inflammatory infiltrate with no evidence of cellular atypia. all these morphological findings are suggestive of ifk. irritated seborrheic keratosis is the first histopathological differential diagnosis. acceptance of the “irritation theory” implies that a lesion of seborrheic keratosis must be present before the irritation can occur. since a primary characteristic of seborrheic keratosis is its lack of penetration into the dermis, the presence of a prominent downward growth pattern in ifk suggests a different theory of origin. the presence of surface crypts, horn cysts, a downward growth pattern, and frequent association with the hair follicle in ifk favors a follicular origin. some authors considered ifk as distinct from sk [4]. in addition to exophytic and endophytic patterns, a few koilocytes may occur in ifk and never in sk. appearance of eosinophilic cytoplasm in ifk contrast with the appearance of basaloid cell cytoplasm in sk. lastly, the squamous eddies are not pathognomonic of the ifk, but they are particularly numerous [9]. in our case the only close differential diagnosis is trichilemmoma. ifk shares some histologic features with trichilfigure 3. spontaneous regression of the inverted follicular keratosis 56 observation | dermatol pract concept 2011;1(1):11 emmona. there is a proliferation of pale-staining outer root sheath-type epithelium that is well circumscribed and surrounded by a fibrotic stroma. both lesions show peripheral palisading of basaloid cells at the periphery of the tumor lobules. however in ifk, there are concentric layers of squamous cells with evidence of keratinization forming squamous eddies. in addition, some authors postulate that hpv is associated to trichilemmona lesions [10]. the pcr for hpv performed in our case was negative. the histopathological diagnosis of ifk can mimic also verruca vulgaris, viral warts, and squamous cell carcinoma. ifks can contain cellular atypia, and squamous eddies bear some resemblance to those of squamous cell carcinoma [11,12]. the well-delineated base, broad acanthotic epithelial downgrowth, squamous eddy formation, and lack of epithelial dysplasia support a diagnosis of ifk here [2]. the pathologist should be most attentive whenever histopathologic features suggestive of ifk are present. indeed, more than half of these lesions have been mistaken for squamous cell carcinoma on initial evaluation, and this can result in unnecessarily drastic treatment of a benign lesion. references 1. helwig eb. inverted follicular keratosis. in: seminar on the skin: neoplasms and dermatosis. washington, dc, american society of clinical pathologists, international congress of clinical pathology, 1954. 2. adrian j. inverted follicular keratosis of the lip. oral surg oral med oral pathol 1984;57(6):625-30. 3. lever wf. inverted follicular keratosis is an irritated seborrheic keratosis. am j dermatopathol 1983;5(5):474. 4. azzopardi jg, laurini r. inverted follicular keratosis. j clin pathol 1975;28(6):465-71. 5. villaret ab, gily b, aga a. inverted follicular keratosis of the nasal vestibule. otolaryngol head neck surg 2009;141(2):288-9. 6. ruhoy sm, thomas d, nuovo gj. multiple inverted follicular keratoses as a presenting sign of cowden’s syndrome: case report with human papillomavirus studies. j am acad dermatol 2004;51(3):411–5. 7. soylu l, akcali c, aydogan lb, ozsahinoglu c, tuncer i. inverted follicular keratosis. am j otolaryngol 1993;14(4):247-8. 8. thom ga, quirk cj, heenan pj. inverted follicular keratosis simulating malignant melanoma. australas j dermatol 2004;45(1):55-7. 9. choi hj, yun sk, kim hu, ihm cw. squamous eddies in irritated seborrheic keratosis. am j dermatopathol 2007;29(1):28-31. 10. stierman s, chen s, nuovo g, thomas j. detection of human papillomavirus infection in trichilemmomas and verrucae using in situ hybridization. j cutan pathol 2010;37(1):75-80. 11. shih cc, yu hs, tung yc, tsai kb, cheng st. inverted follicular keratosis. kaohsiung j med sci 2001;17(1): 50-4. 12. roth lm, look ky. inverted follicular keratosis of the vulvar skin: a lesion that can be confused with squamous cell carcinoma. int j gynecol pathol 2000;19(4):369-73. dp0204a5 dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2012;2(4):5 19 squamous cell carcinoma: variation in dermatoscopic vascular features between well and non-well differentiated tumors john pyne mbbs boptom (hons) mmed1, devendra sapkota bsc m.d.1, jian cheng wong bsc (hons) mstat2 1 school of medicine, the university of queensland, brisbane, australia. 2 school of mathematics and statistics, the university of new south wales, sydney, australia. key words: squamous cell carcinoma, well, moderate, poor, differentiation, vascular citation: pyne j, sapkota d, wong jc. squamous cell carcinoma: variation on dermatoscopy vascular features between well and non-well differentiated tumors. dermatol pract conc. 2012;2(4):5. http://dx.doi.org/10.5826/dpc.0204a05. received: april 6, 2012; accepted: july 21, 2012; published: october 31, 2012 copyright: ©2012 pyne et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. drs. john pyne, devendra sapkota and mr. jian cheng wong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. corresponding author: dr john pyne, 131 ellesmere rd, gymea bay nsw 2227, australia. tel. 61+414 750 625; fax. 61+2+9525 3193. email: j.pyne@uq.edu.au. objective: compare the dermatoscopy vascular features of well differentiated with non-well differentiated squamous cell carcinoma (scc). design: a prospective study of 294 consecutive cases of histopathologically confirmed invasive scc compared the dermatoscopic vascular features of well to combined moderate and poorly differentiated tumors. these features were recorded live directly from the patients and included: the percentage of pink in the tumor, the presence of branching, serpentine, dot, hairpin, glomerular and linear vessels, and the number of these vessel types present within each tumor. vessel types were also reviewed by tumor depth in 1 mm increments. setting: two medical practices in sydney, australia. patients: eighty-six female and 208 male patients (29–95 years old). main outcome measure: dermatoscopic vascular feature variation between grades of tumor differentiation and tumor depth. results: of 294 invasive sccs, 255 (87%) were well differentiated, 32 (11%) were moderately differentiated and 7 (2%) were poorly differentiated. the percentage of pink areas within tumors varied between differentiation grades. the combined group of moderate and poorly differentiated tumors displayed more branching (28%, p<0.001) and serpentine (62%, p<0.005) blood vessels compared to well differentiated tumors (8% and 38%, respectively). moderate and poorly differentiated tumors displayed larger numbers of vessel types (3.3) compared to well differentiated tumors (2.6, p < 0.01). branching and serpentine vessels both increased in incidence with increasing tumor depth (p<0.05). conclusion: grades of tumor differentiation in scc display varying dermatoscopic vascular features. the incidence of branching and serpentine vessels increases with increasing tumor depth and the shift towards poor differentiation. abstract 20 research | dermatol pract concept 2012;2(4):5 study time window, all cases for excision where invasive scc was the obvious diagnosis, or in the differential, were assessed for inclusion. vascular features were recorded live directly from a patient by observer 1, who then left the room. observer 2 then immediately entered the same room to record data live directly from the same patient with the same dermatoscope. exclusion criteria exclusion criteria were applied with the intention of preventing cases entering the study with dermatoscopic features confounded by a range of external factors not due to the tumor alone. these exclusion criteria were: residual or recurrent tumors at sites of previous surgical intervention (including partial biopsies); tumors with any part involving mucosal surfaces, tattoos or juxtaposed to scars; sites of previous radiotherapy, photodynamic therapy, cryotherapy, laser ablation, or topical pharmacological therapy (either patient or clinician initiated); and collision situations between invasive scc and any non-scc related entity evident from clinical, dermoscopic or histopathological examination and all cases of keratoacanthoma diagnosed by histopathology. keratoacanthomas have been observed with a higher incidence of branching vessels (25%, n = 100) compared to invasive scc (11%, n = 410, unpublished data). vascular features assessed the tumor vascular features examined included: the percentage of pink area within a tumor, recorded as either no pink, less than 50% pink, or greater than 50% pink within the tumor boundary and the presence of tumor vessels with dot, hairpin (loop), glomerular (coil), branching (arborizing), serpentine (curvilinear) and linear (no branches or curves) morphology. the number of these different vessel morphologies within the tumor boundary was also recorded. after the application of exclusion criteria, the defined vascular features of the remaining cases were recorded with a heine delta 20® nonpolarized dermatoscope (heine, optotechnic gmbh, herrsching, germany). recording was performed prior to anesthetic injection, excision and submission for routine histopathological examination. to avoid vessel compression and enhance image resolution, all data was recorded after transparent ultrasound gel was applied between the glass plate of the dermatoscope and the skin surface. all excised tissue was submitted for routine histopathological confirmation using hematoxylin and eosin staining. histopathology reports were used to exclude all entities other than invasive scc from the study. tumor thickness was measured in all cases to the nearest 0.1 mm and tabulated with the grade of either well, moderate or poor differentiation. due to the low number of cases, moderate and poorly differentiated tumors were assessed combined. introduction compared to well differentiated squamous cell carcinoma (scc), moderate and poorly differentiated scc behave in a more aggressive manner and portend a worse prognosis [1]. tumor differentiation has recently been incorporated into the new american joint committee on cancer staging system for cutaneous scc [2]. non-well differentiated sccs have been reported as deeper tumors [3] with greater recurrence rates [3,4]. poorly differentiated scc on the ear or mucosal lip has an increased risk of metastasis [4,5]. differentiation grade in scc has been stated as an independent adjusted predictor for overall survival [6]. tumor differentiation in scc presents along a spectrum from well to moderate to poor differentiation, which is determined using histopathologic criteria originally described by broders [7]. broders’ original grading system correlates biological behaviour with differentiation in four grades. grade 1 is characterized by abundant keratinization, little nuclear anaplasia and less than 25% undifferentiated cells. these features extend on spectra through to grade 4 where there is little or no keratinization, extensive nuclear anaplasia and greater than 75% undifferentiated cells. concordance in the histopathological assessment of scc may lack consistency, even between experienced observers [8,9]. routine histopathology reporting, as used in this study, categorizes scc into three grades: well, moderate and poorly differentiated. dermatoscopic assessment of invasive scc is a relatively neglected area of published investigation. cutaneous horn formation and prominent surface scale are clinical features of keratinization that commonly develop on keratinocytic tumors. dermatoscopically identified white circles (which represent targetoid infilling of the follicular infundibulum by keratinocytic hyperplasia), can be observed as part of in situ and invasive scc [10]. vessels associated with invasive scc are often surrounded by a white halo, which is characteristic of keratinocytic tumors [11]. although pigmented blood breakdown products are frequently seen with invasive cutaneous scc, the presence of dermatoscopically identifiable melanin pigment is rare [12,13]. we speculated that grade of differentiation in scc may have characteristic dermatoscopic appearances determined more by vascular and keratinization features rather than pigmented structures. vascular features were the focus of this study. methods data was collected from july 2009 to december 2010 from two medical practices in sydney, australia. the study was approved by the ethics committee from the university of queensland, brisbane, australia. throughout the research | dermatol pract concept 2012;2(4):5 21 entiated tumors, moderate and poorly differentiated tumors tend to have a higher proportional incidence as tumor depth increases (table 1). maximum recorded tumor depth for each grade of differentiation was well (7.5 mm), moderate (6.0 mm) and poor differentiated (6.3 mm); the range of tumor depth and mean depth by grade of tumor differentiation are displayed in table 2. pink areas examination of the data on the percentage of pink areas does not reveal any highly distinctive association between the grade of differentiation and the proportion of pink within the tumor (figure 1). when reviewing the poorly differentiated tumor data alone, 5 out of these 7 cases had greater than 50% pink within the tumor boundary. vessel morphology moderate and poorly differentiated scc displayed branching in 28.2% (11/39) ci 16.5–43.8 and serpentine vessels in 61.5 % (24/39) ci 45.9–75.1 compared to well differentiated scc with 7.5% (19/255) ci 4.8–11.3 and 37.6% (96/255) ci 31.9–43.7 respectively (figure 2). in poorly differentiated tumors, 4 out of the 7 cases had branching vessels. hairstatistical assessment interobserver agreement between two of the authors (jp and ds) was assessed. kappa values from 0.41 to 0.60 indicate moderate agreement between observers, 0.61 to 0.80 are regarded as substantial agreement, and from 0.81 to 1.00 almost perfect. confidence intervals were set at 95%. logistic regression was carried out to test for significance of trends. logistic regression was used to model binary response variables (i.e., vessel morphology observed or not observed) in terms of explanatory variables (tumor depth). results a total of 294 cases entered the study based on histopathological confirmation of invasive scc. these 294 cases were comprised of well differentiated 86.7% (255/294), moderately differentiated 10.9% (32/294), or poorly differentiated 2.4% (7/294) tumors. the age of patients ranged from 29 to 95 years, the median age was 72 years, the mean age 70.8 years, and 70.7% (208/294) were males. well differentiated tumors tend to present in higher proportions with less depth (table 1). compared to well differtable 1. squamous cell carcinoma: tumor cases by depth (mm) and grade of differentiation tumor depth (mm) < 1.0 1.0–1.9 2.0–2.9 3.0–3.9 4.0 or > well differentiated scc total cases n = 255 percentage n = 124 49.4% n = 66 26.3% n = 46 18.3% n = 10 3.98% n = 5 1.99% moderately differentiated scc total cases n = 32 percentage n = 5 16% n = 12 38% n = 9 28% n = 2 6.1% n = 4 13% poorly differentiated scc total cases n = 7 nil 0% n = 2 2% n = 1 1% n = 2 2% n = 2 2% table 2. squamous cell carcinoma: tumor depth—range and mean by grade of differentiation tumor differentiation grade range of tumor depth mean tumor depth well differentiated n = 255 0.1–7.5 mm 1.3 mm moderate differentiated n = 32 0.7–6.0 mm 2.3 mm poorly differentiated n = 7 1.5–6.3 mm 3.6 mm 22 research | dermatol pract concept 2012;2(4):5 figure 3. vessel polymorphism by grade of tumor differentiation. a right shift for the probability density curves of moderate and poorly differentiated scc compared to well differentiated scc indicate that moderate and poorly differentiated tumors are more likely to display numerous vessel morphologies. the area under curve when number of vessel morphologies were larger or equal than 3 represents the total probability for 3 or more vessel morphologies being observed within the tumors. the moderate and poorly differentiated scc had a larger area under curve (i.e., higher probability) compared to well differentiated scc. the point at maximal probability represents the number of vessel morphologies being observed most frequently within the tumors. this number is also higher (a right shift) for moderate and poorly differentiated scc compared to well differentiated scc. [copyright: ©2012 pyne et al.] pin vessels were also significantly more frequent in moderate and poorly differentiated tumors. however, this has limited practical diagnostic value as the majority of well differentiated tumors also display hairpin vessels. vessel polymorphism: number of vessel morphologies the number of different vessel morphologies present within the tumor mass as a function of tumor grade is displayed in figure 3. for the study vessel morphologies selected, there is a significant increase in the average number of these vessel types in moderate and poorly differentiated tumors: 3.3 compared to 2.6 in well differentiated tumors, p < 0.01. examples of vessel morphology and polymorphism among scc with well, moderate and poor differentiation are shown (figures 4-6). of note, while well differentiated tumors commonly show a white halo (figure 4), poorly differentiated tumors typically displayed vessels without a white halo (figure 6). vessel morphology variation with tumor differentiation and depth branching, serpentine and linear vessel morphology records were each separately reviewed comparing well and non-well differentiated tumors by depth, as displayed in figures 7, 8 and 9 respectively. while both branching and serpentine vessels show an increase in incidence with depth, this trend is more pronounced in non-well differentiated tumors. for non-well differentiated scc, branching and serpentine vessel incidence significantly increases with increasing tumor depth, p < 0.05. well differentiated scc also shows a trend of increasing branching and serpentine vessel incidence, however the significance of the trend is statistically weak. the trends in linear vessel are not statistically significant for both well and non-well differentiated scc. figure 1. the percentage of pink in the tumor mass. [copyright: ©2012 pyne et al.] figure 2. comparison of different vessel morphologies with differentiation. [copyright: ©2012 pyne et al.] research | dermatol pract concept 2012;2(4):5 23 and hairpin vessels and fewer numbers of vessel types. vessels commonly showed a white halo. moderate and poorly differentiated tumors displayed a larger number of vessel types and frequently had irregular, bizarre vessel forms in irregular arrangements. bizarre vessel forms can contribute to vessel areas were frequently central and in irregular spatial arrangements. vessel types and polymorphism well differentiated tumors had a relatively reduced incidence of branching and serpentine vessel forms. they were also characterized by dot, glomerular interobserver agreement on classification by vessel morphology kappa values for branching vessels (0.81) and pink areas (0.80) were almost perfect. serpentine (0.78) and hairpin (0.74) vessels were in substantial agreement (table 3). discussion increased tumor depth was associated with a higher proportion of non-well differentiated scc. this result is consistent with earlier work [3). thicker non-well differentiated tumors often appeared endophytic and usually displayed a relatively low profile surface, and this was quite characteristic of poorly differentiated tumors. in practice, poorly differentiated scc a deeper tumor depth may not be apparent from both clinical and dermatoscopy observation. pink areas the study records of the crude percentage of pink in the tumor mass did not demonstrate convincingly obvious differences between the different differentiation grades. pink areas in well differentiated tumors were often observed distributed relatively even around the periphery of the lesion. in non-well differentiated scc, the associated pink figure 4. dermatoscopy of a well differentiated scc on the shoulder, orderly peripheral dot vessels merging into more central hairpin or loop vessels. the central tumor area has an elevated surface with white structureless areas. vessels displaying a while halo are easily identified. [copyright: ©2012 pyne et al.] figure 5. dermatoscopy of a moderately differentiated scc on the temple; flat pink central area with peripheral pink and white areas displaying asymmetric spatial distribution, bizarre vessel forms, numerous branching and serpentine vessels. [copyright: ©2012 pyne et al.] figure 6. dermatoscopy of a poorly differentiated scc on the ear; the tumor surface follows the cartilage contours; pink areas cover the whole tumor surface; branching vessels without a white halo are common. [copyright: ©2012 pyne et al.] figure 7. branching vessels by tumor depth: well differentiated scc verses non-well differentiated scc . [copyright: ©2012 pyne et al.] figure 8. serpentine vessels by tumor depth: well differentiated scc verses non-well differentiated scc. [copyright: ©2012 pyne et al.] 24 research | dermatol pract concept 2012;2(4):5 major limitations of this study include a small number of poorly differentiated sccs (n = 7), moderately differentiated scc (n = 32), and the reviewing and analysis of moderately and poorly differentiated tumors combined together. the use of polarized dermatoscopy may not produce the same findings as the study non-polarized dermatoscopy. the presence or absence of ulceration was not recorded in the study data. tumor ulceration may alter the vessel features. future investigation of non-well differentiated scc exploring the spatial distribution of vessel types and the spapolymorphism; however, this aspect of vessel form variation was not incorporated into the data records. in addition, poorly differentiated tumors typically displayed vessels without a white halo. vessel morphology variation with tumor differentiation and depth branching and serpentine vessel incidences increased with increasing tumor depth for both well and non-well differentiated tumors; this trend was more pronounced for moderate and poorly differentiated tumors compared to well differentiated tumors. linear vessels did not display this trend. table 3. squamous cell carcinoma: vascular feature kappa values vascular feature cohen’s kappa value con!dence interval lower bound con!dence interval upper bound branching vessels 0.83 0.67 0.99 serpentine vessels 0.78 0.49 1.00 hairpin vessels 0.74 0.57 0.91 glomerular vessels 0.87 0.75 0.99 dot vessels 0.66 0.45 0.87 linear vessels 1.00 1.00 1.00 pink areas 0.80 0.58 1.00 figure 9. linear vessels by tumor depth: well differentiated scc verses non-well differentiated scc. [copyright: ©2012 pyne et al.] tial variation in pink within the tumor boundary correlated to the immediate histopathology may reveal useful information relevant to practice. the incidence of perivascular white halos in well differentiated compared to poorly differentiated tumors also deserves further investigation. conclusions dermatoscopy features correlating with the grade of differentiation in scc will be expected to vary depending on the proportion and spatial location of areas of specific differentiation within a tumor mass. however, various vascular features may serve as indicators to the grade of differentiation in scc. this study found that the shift from well towards poor differentiation in scc is represented by an increase in the incidence of branching and serpentine vessels that increased with tumor depth and an increase in vascular polymorphism. acknowledgement the statistical analysis in this study was made by mr. wong and dr. pyne. drs. pyne, sapkota and mr. wong contributed to the analysis and interpretation of data. research | dermatol pract concept 2012;2(4):5 25 8. davis da, donahue jp, bost je, horn td. the diagnostic concordance of actinic keratosis and squamous cell carcinoma. j cutan pathol. 2005;32(8):546-51. 9. jagdeo j, weinstock ma, piepkorn m, bingham sf; department of veteran affairs topical tretinoin chemoprevention trial group. reliability of the histopathology diagnosis of keratinocyte carcinomas. j am acad dermatol. 2007;57(2):279-84. 10. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of actinic keratosis, intraepidermal carcinoma and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2012;66(4):589-97. 11. zalaudek i, giacomel j, leinweber b. squamous cell carcinoma including actinic keratosis, bowen’s disease, keratoacanthoma, and its pigmented variants. in: soyer hp, argenziano g, hofmann-wellenhof r, johr r (eds.). color atlas of melanocytic lesions of the skin. berlin heidelberg: springer, 2007:295-302. 12. sattler ek. pigmented squamous cell carcinoma. am j dermatopathol. 2007;29(5): 486-9. 13. de giorgi v, alfaioli b, papi f, et al. dermoscopy in pigmented squamous cell carcinoma. j cutan med surg. 2009; 13(6): 326-9. references 1. cassarino ds, derienzo dp, barr rj. cutaneous squamous cell carcinoma: a comprehensive clinicopathological classification. part one. j cutan pathol. 2006;33(3):191-206. 2. farasat s, yu ss, neel va, et al. a new american joint committee on cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (t) characteristics. j am acad dermatol. 2011;64(6):1051-9. 3. jensen v, prasad ar, smith a, et al. prognostic criteria for squamous cell cancer of the skin. j surg res. 2010:159(1): 509-16. 4. eroglu a, berberoglu u, berreroglu s. risk factors related to locoregional recurrence in squamous cell carcinoma of the skin. j surg oncol 1996;61(2):124-30. 5. samarasinghe v, madan v, lear jt. management of high-risk squamous cell carcinoma of the skin. expert rev anticancer ther. 2001;11(5): 763-9. 6. kyrgidis a, tzellos tg, kechagias n, et al. cutaneous squamous cell carcinoma (scc) of the head and neck: risk factors of overall and recurrence-free survival. eur j cancer. 2010:46(9):1563-72. 7. broders ac. practical points on the microscopic grading of carcinoma. ny state j med. 1932;32:667-71. dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(2):e2021015 1 dermatology practical & conceptual is it possible to improve scabies diagnosis performance? vincenzo greco1, massimiliano scalvenzi1, gabriella fabbrocini1, matteo megna1 1 dermatology unit, department of clinical medicine and surgery, university of naples federico ii, italy key words: scabies, mite, feces, eggs, jetliner, jet trail, polarized light, dermoscopy citation: greco v, scalvenzi m, fabbrocini g, megna m. is it possible to improve scabies diagnosis performance? dermatol pract concept. 2021;11(2):e2021015. doi: https://doi.org/10.5826/dpc.1102a15 accepted: august 31, 2020; published: april 12, 2021 copyright: ©2021 greco et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo greco, md, department of dermatology, university of naples federico ii, via pansini 5, 80131 naples, italy. email: vingreco@live.com case presentation we present the same case of scabies (figure 1a) photographed with a new polarized light dermoscope (figure 1b) and with an older immersion contact dermoscope (figure 1c). teaching point dermoscopy allows a high sensitivity and specificity for scabies diagnosis [1]. although modern dermoscopes with polarized light can better analyze pigmented lesions figure 1. (a) scabies: clinical aspects. (b) polarized light dermoscopy. (c) immersion contact dermoscopy. 2 image letter | dermatol pract concept 2021;11(2):e2021015 without necessitating a liquid interface or direct skin contact with the instrument, they do not perform as well when interpreting superficial epidermal lesions of scabies. note that, with new polarized light dermoscopes, the “jet trail” (the burrow) is easily visible, but a clear differentiation of artefacts induced by scratching or small dirt particles is not easy to obtain [2]. paradoxically, scabies was more easily detected in the past with older dermoscopes because immersion contact dermoscopy reduces the reflection capacity of keratinocytes of the burrow so that the “jetliner,” feces, and eggs that are usually covered by the shiny keratinocytes of the jet trail, are better detected. in conclusion, we suggest using older dermoscopes or the immersion technique for mite search. references 1. marghoob aa, swindle ld, moricz cz, et al. instruments and new technologies for the in vivo diagnosis of melanoma. j am acad dermatol. 2003;49(5):777–799. doi: 10.1016/s01909622(03)02470-8. pmid: 14576657 2. micali g, lacarrubba f, verzì ae, chosidow o, schwartz ra. scabies: advances in noninvasive diagnosis. plos negl trop dis. 2016;10(6):e0004691. doi: 10.1371/journal.pntd.0004691. pmid: 27311065. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021009 1 dermatology practical & conceptual sea urchin skin lesions: a case report maría florencia suarez-conde1, maría gabriela vallone1, virginia mariana gonzález1, margarita larralde1 1 dermatology department, hospital alemán, buenos aires, argentina key words: aquatic dermatoses, echinoderm, sea urchin, dermoscopy, dermatoscopy, foreign body citation: suarez-conde mf, vallone mg, gonzález vm, larralde m. sea urchin skin lesions: a case report. dermatol pract concept. 2021;11(2):e2021009. doi: https://doi.org/10.5826/dpc.1102a09 accepted: august 16, 2020; published: march 8, 2021 copyright: ©2021 suarez-conde et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maría florencia suarez-conde, md, dermatology department, hospital alemán, buenos aires, argentina. av. pueyrredón 1460, ciudad de buenos aires. argentina. email: fsuarezconde@gmail.com introduction sea urchins are invertebrates and members of the echinoderm family that are found on the rocky seabeds and corals in tropical and temperate waters. there are over 700 known species of sea urchins, 80 of which contain toxic substances to humans. as a result, they are responsible for a wide range of conditions, including simple penetrating wounds, granulomatous processes, and systemic complications [1]. we present the case of a patient who was affected by a penetrating injury caused by sea urchin spines. the diagnosis was established based on the epidemiological characteristics, clinical presentation, and dermoscopic features. case presentation a 20-year-old man presented with puncture wounds on his right sole after having stepped on a rock in the sea on the coast of italy. the patient was referred with localized pain during the first 48 hours. physical examination revealed several cylindrical foreign bodies exhibiting blackish pigmentation in the right sole and ankle (figure 1). polarized dermoscopy revealed figure 1. cylindrical foreign bodies in the sole and ankle of the right foot. 2 letter | dermatol pract concept 2021;11(2):e2021009 remarkable resemblance, although with less magnification and resolution, to scanning electron microscopy images of sea urchin spines [2]. clinical and dermoscopic findings and epidemiological features established the diagnosis. the spines were then mechanically removed. conclusions skin disorders caused by sea urchin contact most commonly compromise feet and ankles. the spines can penetrate the skin and easily break into several fragments, and the most common initial manifestation is acute localized pain that resolves within hours or days, as was the case of our patient [1]. diagnosis is usually based on clinical findings and history. differential diagnoses include other types of foreign bodies such as wood fragments and puncture wounds from sharp objects, among others. histopathological examination may also prove helpful in cases of late granulomatous reactions [1]. according to our findings, dermoscopy may also serve as a valuable tool. indeed, dermoscopic images of sea urchin spines were remarkably similar to electron microscopy images published in the literature. references 1. rossetto al, de macedo mora j, haddad junior v. sea urchin granuloma. rev inst med trop sao paulo. 2006;48(5):303-306. doi: 10.1590/s0036-46652006000500013. pmid 17086323. 2. merino m, vicente e, gonzález kn, torres fg. ageing and degradation determines failure mode on sea urchin spines. mater sci eng c mater biol appl. 2017;78:1086-1092. doi: 10.1016/j. msec.2017.04.155. pmid: 28575943. figure 2. lateral view of one of the spines with a violaceous-black pigmentation and a striated external surface that correlates with the white lines seen on dermoscopy. figure 3. frontal view of one of the fragments, with circular shape and regular whitish and violaceous lines, radiating towards the periphery. foreign bodies, some of them placed in an oblique angle within the stratum corneum and showing a conical shape, a violaceous-black pigmentation, and a striated external surface. others, placed transversely to the skin, exhibited a circular shape with concentric whitish lines, regularly radiating towards the periphery and matching the external striae or septa (figures 2 and 3). these dermoscopic images bear a dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2020085 1 dermatology practical & conceptual introduction acquired perforating dermatosis (apd) is a cutaneous disorder characterized by transepidermal elimination of dermal connective tissue. acquired reactive perforating collagenosis (arpc), the most common form of apd, is usually associated with underlying diabetes mellitus and chronic renal failure. here we aimed to demonstrate dermoscopic patterns of arpc in a series of 7 patients. case presentation a total of 60 lesions from 7 patients with a histopathological diagnosis of arpc were evaluated. the mean age of the patients was 56 years and the majority was male (n=6). the most common clinical manifestations were itchy, crusted papules (figure 1a) followed by excoriated papules (figure 1b) and white-to-brown macules (figure 1c). the mean disease duration was 10 months. the most common localization of the lesions was on the lower extremities (n=7). four patients had generalized lesions involving the lower extremities and trunk. all recruited patients had diabetes mellitus. diabetes mellitus was accompanied by renal failure in one of the patients. a total of 5 different dermoscopic patterns were identified (figure 2) and illustrated (figure 3). pattern 1 (n=14, 23%) showed a white rim surrounding a central yellow-to-brown structureless area. the most common pattern was pattern 2 (n=21, 35%), which was composed of a central yellow–to-brown structureless area and blood spots surrounded by a collarette of scale, a peripheral pinkish structureless area, and dotted vessels. pattern 3 (central white structureless area surrounded by curved lines and brown reticular lines; n=10, 17%) and pattern 5 (central multicolor structureless areas including red, brown and white areas, surrounded by brown reticular lines; n=7, 12%) were characteristic of the late and healed lesions. pattern 4 (n=8, 13%) was characterized by central blood spots and concentric white-to-brown rims possibly associated with scratching of the lesions. four patients showed more than 1 pattern. histopathological examination of all samples revealed an invaginating epidermal process composed of hyperkeratosis overlying a cup-shaped depression and transepidermal elimination of eosinophilic altered collagen fibers (figures 4 and 5). dermoscopic patterns of acquired reactive perforating collagenosis ömer faruk elmas1, asuman kilitci2, belkiz uyar1 1 department of dermatology, faculty of medicine, kirşehir ahi evran university, kirşehir, turkey 2 department of pathology, faculty of medicine, kirşehir ahi evran university, kirşehir, turkey key words: dermoscopy, perforating dermatosis, perforating collagenosis, transepidermal elimination citation: elmas öf, kilitci a, uyar b. dermoscopic patterns of acquired reactive perforating collagenosis. dermatol pract concept. 2021;11(1):e2020085. doi: https://doi.org/10.5826/dpc.1101a85 accepted: may 6, 2020; published: december 7, 2020 copyright: ©2020 elmas et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ömer faruk elmas, md, department of dermatology, faculty of medicine, kirşehir ahi evran university, kirşehir, 40000, turkey. email: omerfarukmd@gmail.com 2 letter | dermatol pract concept 2021;11(1):e2020085 reported in previous studies [1,2]. patterns 4 and 5 have apparently not been identified in previous studies. in this study, only well-established lesions (patterns 1 and 2) were biopsied to achieve a definitive diagnosis, and all specimens showed typical histopathological features of the entity. the histopathological counterpart of the central yellow-to-brown structureless area is central keratin debris. the peripheral conclusions there are very few reports on the dermoscopic features of arpc [1,2]. in this case study, we identified a total of 5 different dermoscopic patterns. pattern 1 and pattern 2 possibly indicate well-established lesions, and the dermoscopic findings represented by these patterns were similar to those figure 1. acquired reactive perforating collagenosis with different stages of lesions. (a) crusted and (b) excoriated papules and (c) white-to-brown macules. a b c figure 2. different dermoscopic patterns of acquired reactive perforating collagenosis: (a) pattern 1; (b) pattern 2; (c) pattern 3; (d) pattern 4; and (e) pattern 5. a b c d e letter | dermatol pract concept 2021;11(1):e2020085 3 white rim and collarette of scale probably reflect invaginating epidermal hyperplasia. the possible histopathological counterpart of the central white structureless area is fibrotic collagen formation in the dermis. the peripheral pinkish structureless area and dotted vessels may represent dermal inflammatory reaction with superficial dilated vessels. peripheral brown reticular lines may correspond to hyperpigmented basal keratinocytes. to conclude, dermoscopy may be a useful diagnostic tool in suspected cases of arpc. the peculiar dermoscopic patterns we identified may lead the way to more comprehensive studies. figure 3. illustration of the dermoscopic patterns identified for acquired reactive perforating collagenosis. figure 4. acquired reactive perforating collagenosis. (a) a cupshaped epidermal invagination with keratin and inflammatory debris (h&e, ×50) and (b, c) transepidermal elimination of vertically oriented altered collagen (h&e, ×200; ×400). a b c pattern 1 central yellow-to-brown structureless and blood spots surrounded by a whithe rim, peripheral pinkish structureless, dotted vessels pattern 2 central yellow-to-brown structureless and blood spots surrounded by a collarette of scale, peripheral pinkish structureless pattern 3 central white structureless surrounded by curved lines and brown reticular lines pattern 4 central yellow-to-brown hemorrhagic crust, surrounded by concentric brown and white rims pattern 5 central multicolor structureless areas including red, brown and white surrounded by brown reticular lines 4 letter | dermatol pract concept 2021;11(1):e2020085 dermatol pract concept. 2018;8(4):303-305. doi: 10.5826/ dpc.0804a11. pmid: 30479861. 2. kittisak p, tanaka m. dermoscopic findings in a case of reactive perforating collagenosis. dermatol pract concept. 2015;5(2):75-77. doi: 10.5826/dpc.0502a13. pmid: pmid: 26114057. acknowledgement we would like to thank beyza nur elmas for illustrating the dermoscopic patterns. references 1. ormerod e, atwan a, intzedy l, stone n. dermoscopy features of acquired reactive perforating collagenosis: a case series. figure 5. acquired reactive perforating collagenosis. hyperkeratosis overlying the cup-shaped depression in the epidermis may correspond to central yellow-to-brown structureless area observed on dermoscopic examination. epidermal hyperplasia adjacent to the cup-shaped depression with overlying hyperkeratosis may reflect (a) dermoscopic peripheral white rim and collarette scale (h&e, ×50). (b) transepidermal elimination of altered collagen (h&e, ×400) and (c) superficial dermal fibrotic collagen bundles (h&e, ×200) may correspond to dermoscopic white structureless areas. (c) superficial dermal vessels and perivascular inflammatory infiltration may represent dermoscopic peripheral pinkish structureless areas and dotted vessels. a b c dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020030 1 dermatology practical & conceptual introduction kimura disease was reported for the first time as “hyperplastic lymphogranuloma with eosinophilia” [1]. the cause of kimura disease remains unknown, and reasons such as an allergic or unusual reaction to an unknown antigen or clonal aspecific lymphocyte proliferation have been considered. some have hypothesized on the role of interleukins (il-4, il-5) and mast cells, regulating immunoglobulin e (ige) synthesis and eosinophil infiltration. case presentation a 34-year-old caucasian woman presented with erythematous lightly hard nodules of 1-2 cm of maximum diameter, at the level of the auricle (figure 1, a and b). physical examination revealed an asymptomatic lymphadenomegaly of the left cervical region. the only value of interest was the elevated ige concentration (total ige 3,775 iu/ml vs normal value 260 iu/ml). ultrasonography of the thyroid and lymph nodes of the neck revealed the presence of multiple swollen, hypoechoic, and hyperplastic lymph nodes at the submandibular, parotid, and left ear region, where the largest was 3 cm with a hypervascular hilum. the histological findings from a biopsy of a lesion at the level of the left retroauricular region showed spongiosis of the epidermis and a remarkable proliferation of vascular structures of the derma with hypertrophic endothelium protruding into the lumen and a remarkable perivascular inflammatory infiltrate with the presence of numerous eosinophil cells (figure 1, c-e). ultrastructural analysis shows at the level of the papillary and reticular dermis many vascular structures lined by endothelial cells in massive columnar shape that protrude into the lumen (figure 1, f and g). we performed an arteriogram of the left carotid, which showed a pathological hypervascularity with at least 1 main remission of kimura disease with carotid hypervascularization after cyclosporine treatment severino persechino,1 armando bartolazzi,2 flavia persechino,3 antonella tammaro,1 sabatino valente,3 salvatore raffa,3,4 vincenzo visco,3,4 maria rosaria torrisi3,4 1 dermatology unit, sant’andrea hospital, sapienza university of rome, italy 2 histopathology unit, sant’andrea hospital, sapienza university of rome, italy 3 department of clinical and molecular medicine, sant’andrea hospital, sapienza university of rome, italy 4 ultrastructural pathology laboratory, sant’andrea hospital, sapienza university of rome, italy key words: kimura disease, cyclosporine, carotid hypervascularity, eosinophilia citation: persechino s, bartolazzi a, persechino f, tammaro a, valente s, raffa s, visco v, torrisi mr. remission of kimura disease with carotid hypervascularization after cyclosporine treatment. dermatol pract concept. 2020;10(2):e2020030. doi: https://doi.org/10.5826/ dpc.1002a30 accepted: december 6, 2019; published: april 3, 2020 copyright: ©2020 persechino et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: severino persechino, md, dermatology unit, sant’andrea hospital, sapienza university of rome, italy. email: severino.persechino@uniroma1.it https://doi.org/10.5826/dpc.1001a30 https://doi.org/10.5826/dpc.1001a30 mailto:severino.persechino@uniroma1.it 2 letter | dermatol pract concept 2020;10(2):e2020030 figure 1. (a,b) physical examination revealed an asymptomatic lymphadenomegaly of the left cervical region. the cutaneous lesions were nodules of 1-2 cm of maximum diameter, with a slightly hard consistency, with the upper layer slightly erythematous at the level of the auricle. (c-e) the histological findings from a biopsy of a lesion at the level of the left retroauricular region showed spongiosis of the epidermis and a remarkable proliferation of vascular structures of the derma (see black arrows in e) with hypertrophic endothelium protruding into the lumen and a strong perivascular inflammatory infiltrate with the presence of numerous eosinophil cells. (c,d) h&e staining. (e) toluidine blue semithin section. (f,g) ultrastructural analysis shows at the level of the papillary and reticular dermis many vascular structures lined by endothelial cells that protrude into the lumen. (f,g) transmission electron microscopy, uranyl acetate/lead citrate. morgagni 268d electron microscopy, fei company, hillsboro, or. en = endothelial cell; eo = eosinophil; l = lumen. letter | dermatol pract concept 2020;10(2):e2020030 3 the patient was treated for 2 years, resulting in the regression of the cutaneous lesions (figure 2, a and b) at physical examination and reduction of the vascularization with eosinophilia at histological examination (figure 2, c and d). ultrastructural examination shows the persistence of eosinophilic infiltrate mostly localized around branch and 2 secondary branches of the carotid tree that supplied the angiomatous lesion of the upper two-thirds of the ear and at least 3 veins that drained quickly the contrast medium to the external jugular vein. clinical and histological data and elevated concentration of ige allow us to confirm a case of kimura disease. considering that the location of the disease did not allow a surgical approach as it would put at serious risk the anatomical and functional integrity of the left ear, and the failure of local and systemic interferon and corticosteroid therapy, we chose immunosuppressant therapy with cyclosporine (3.5 mg/kg/day). figure 2. the patient was treated for 2 years without interruption, causing the regression of the cutaneous lesions at physical examination (see a and b) and reduction of the vascularization with eosinophilia at histological examination (see c and d). (c) toluidine blue semithin section. (d) h&e staining. (e) ultrastructural examination shows the persistence of eosinophilic infiltrate mostly localized around vascular structures. transmission electron microscopy, uranyl acetate/lead citrate. morgagni 268d electron microscopy, fei company, hillsboro, or. en = endothelial cell; eo = eosinophil; l = lumen. 4 letter | dermatol pract concept 2020;10(2):e2020030 left carotid tree. this evidence could endorse the immunological mechanism for the pathogenesis of kimura disease. references 1. kim ht, szeto c. eosinophilic hyperplastic lymphogranuloma, comparison with mikulicz’s disease. chin med j. 1937;23(69):700. 2. kung it, gibson jb, bannatyne pm. kimura’s disease: a clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia. pathology. 1984;16(1):39-44. hyperplasia was the only side effect in our patient. nowadays the patient is followed every 6 months; 2 years after onset he had no recurrences. conclusions it seems relevant to highlight the unexpected effect of cyclosporine therapy, found by the arteriogram and never highlighted in current literature, namely the reduction of the neoangiogenesis and hypervascularization of the lesions as shown by the arteriography of the vascular structures (figure 2e). the most important differential diagnosis is angiolymphoid hyperplasia with eosinophilia (iale). one of the differences between these two entities is the ige concentration, which is high for kimura disease and normal for iale [2]. the total ige amount was 875 ui/ ml, with a reduction of vascularization at the arteriogram of the left carotid. despite the risk of kidney disease associated with both kimura disease and the use of cyclosporine, gingival dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020084 1 dermatology practical & conceptual introduction cutaneous angiosarcoma (cas) is an aggressive mesenchymal neoplasm of vascular endothelial cells that typically presents in middle-aged to elderly individuals as an expanding ecchymotic patch on the head or neck region [1]. as more dermoscopic features of uncommon skin tumors are described in the literature, the importance of establishing specific criteria for the diagnosis of high-risk lesions is paramount. in this article, we delineate the dermoscopic features of cas and their correlation to its histopathologic findings. case presentation our patient is a 74-year-old man who presented to the clinic with a 2-month history of a red-purple and yellow-black patch on his left periorbital skin expanding to involve his left forehead, frontal, temporal, and parietal scalp (figure 1). palpable edema was appreciated periorbitally. a punch biopsy was performed and demonstrated a high-grade inpurpuric plaques—dermoscopic and histopathological correlation of cutaneous angiosarcoma daniel w. cole1, tomas huerta2, aleodor andea2,3, trilokraj tejasvi2 1 wayne state university school of medicine, detroit, mi, usa 2 department of dermatology, university of michigan, ann arbor, mi, usa 3 department of pathology, university of michigan, ann arbor, mi, usa key words: cutaneous angiosarcoma, dermoscopy, nonmelanocytic skin cancer, histopathology citation: cole dw, huerta t, andea a, tejasvi t. purpuric plaques—dermoscopic and histopathological correlation of cutaneous angiosarcoma. dermatol pract concept. 2020;10(4):e2020084. doi: https://doi.org/10.5826/dpc.1004a84 accepted: may 16, 2020; published: october 26, 2020 copyright: ©2020 cole et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: daniel w. cole, bs, wayne state university school of medicine, 540 e canfield st, detroit, mi 48201, usa. email: dcole@med.wayne.edu figure 1. exam showed a red-purple and yellow-black patch on the left periorbital skin that expanded to involve the left forehead, frontal, temporal, and parietal scalp. 2 letter | dermatol pract concept 2020;10(4):2020084 filtrative vascular neoplasm involving the dermis consistent with a diagnosis of angiosarcoma (figure 2). cd31 and erg immunohistochemical stains highlighted the atypical endothelial cells confirming the diagnosis. the dermoscopy image from our patient demonstrated dark red and purple structureless zones on a light red background. a violaceous hue was also observed in more densely covered areas (figure 3). there were thick white, perpendicular, and polygonal lines scattered throughout. centrally we noted many dark red and purple dots and clods clustered around follicular openings, which appeared as white and yellow circles. this observation is a unique pattern in cas. interpreted in conjunction with the histopathologic images (figure 2), the perifollicular clods represent vascular channels that remarkably spare pilosebaceous units despite the infiltrative, aggressive nature of these tumors. the varying color gradations correlate with the position of the vascular structures in the dermis, with superficial dermal vascular structures appearing red to dark red, and deeper dermal involvement (nearly to the level of the subcutis) imparting a violaceous hue to the lesion. figure 2. punch biopsy. (a) lower power view of tumor architecture sparing pilosebaceous units. (b) infiltrative vascular neoplasm involving the dermis and extending to the peripheral margin. (c) irregular interanastomosing vascular channels lined by atypical endothelial cells. (d) immunohistochemical stain for erg highlights the atypical endothelial cells. (e) immunohistochemical stain for cd31 highlights the atypical endothelial cells. a b c d e figure 3. dermoscopy demonstrating dark red and purple structureless zones on a light red background with a violaceous hue seen in more densely covered areas. dark red and purple clods are clustered around follicular openings that appear as yellow and white circles. thick, polygonal and perpendicular white lines are scattered throughout. letter | dermatol pract concept 2020;10(4):2020084 3 of many dark red and purple clods surrounding follicular openings, along with previously described features and a suggestive history, should prompt high clinical suspicion of cas and histopathologic evaluation. references 1. oiso n, matsuda h, kawada a. various colour gradations as a dermatoscopic feature of cutaneous angiosarcoma of the scalp. australas j dermatol. 2013;54(1):36-38. doi: 10.1111/j.14400960.2012.00885.x. pmid: 22458422. 2. deinlein t, richtig g, schwab c, et al. the use of dermatoscopy in diagnosis and therapy of nonmelanocytic skin cancer. j dtsch dermatol ges. 2016;14(2): 144-151. doi: 10.1111/ ddg.12903. pmid: 26819109. conclusions in previous reports, cas is dermoscopically characterized by structureless, patchy pink, red, and purple-blue areas with yellowish round clods corresponding to follicular openings [2]. these color gradations represent various tumor components: pink areas are highly cellular, red polymorphic areas consist of telangiectasias or vascular channels, and dark red to purple areas may be organizing thrombus, hemorrhage, or dilated vascular structures [1]. additionally, white lines may be present within these areas or at the periphery of nodular foci and are histopathologically correlated to fibrous septa between neoplastic vascular spaces [2]. the perifollicular clods observed in our patient represent tumor vascular channels. although rare, the aggressive nature of this malignancy underscores the importance of early diagnosis. the presence dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(2):e2021006 1 confluent and reticulated papillomatosis associated with obesity: case series of three patients successfully treated with oral doxycycline maha lahouel1, amina aounallah1, sana mokni1, colandane belajouza1, mohamed denguezli1 1 department of dermatology, farhat hached university hospital, sousse, tunisia key words: confluent and reticulated papillomatosis, obesity, treatment, doxycycline citation: lahouel m, aounallah a, mokni s, belajouza c, denguezli m. confluent and reticulated papillomatosis associated with obesity: case series of three patients successfully treated with oral doxycycline. dermatol pract concept. 2021;11(2):e2021006. doi: https://doi. org/10.5826/dpc.1102a06 accepted: july 29, 2020; published: april 12, 2021 copyright: ©2021 lahouel et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maha lahouel, md, dermatology department, fattouma bourguiba university hospital, sousse, tunisia. email: mahalahouel@gmail.com introduction confluent and reticulated papillomatosis (crp) of gougerot and carteaud is a rare skin disorder [1,2]. its pathogenesis remains unclear, which explains the multiplicity of therapy options with variable results [1]. herein, we describe 3 cases of crp, discuss its association with obesity, and report the effectiveness of doxycycline in its treatment. case presentations case 1: a 20-year-old woman presented with hypertrophic squamous lesions mainly localized on the trunk that had been evolving for the previous 2 years. at presentation, the patient had a body mass index (bmi) of 35.9 (obesity class ii). examination revealed brownish, hyperkeratotic, confluent papules with a reticulated pattern in the periphery affecting mainly the trunk (figure 1a), the neck and the back. a biopsy demonstrated compact hyperkeratosis, acanthosis, papillomatosis, and hyperpigmentation of the basal layer. the diagnosis of crp was made. doxycycline was initiated (100 mg daily). two months later, the patient was free of cutaneous lesions (figure 1b). the patient’s skin condition was stable after 1 year of follow-up. case 2: a 21-year-old overweight man (bmi >25) presented with a 5-month history of asymptomatic lesions on the trunk. on dermatologic examination, there was a reticular network of hyperpigmented papules and plaques on the anterior region of the trunk (figure 2a). a biopsy specimen revealed hyperkeratosis, papillomatosis, and a perivascular inflammatory infiltrate in the dermis with no signs of fungal infection, confirming the diagnosis of crp. within 1 month of doxycycline treatment (100 mg daily), lesions disappeared completely, with no relapse during 18 month-follow-up period (figure 2b). case 3: a 16-year-old obese adolescent (bmi >35) presented with a 6-year history of asymptomatic, pigmented, 2 letter | dermatol pract concept. 2021;11(2):e2021006 hyperkeratotic papules and plaques around the neck and on the trunk (figure 3a). histological examination revealed orthohyperkeratosis, acanthosis, and papillomatosis associated with a normal dermis. a diagnosis of crp was made and the patient was started on doxycycline (100 mg/day), with complete clearance of lesions in 2 months (figure 3b). however, the patient was lost to follow-up. conclusions crp is a rare dermatosis that affects young adults. clinically, the eruption is characterized by the presence of pigmented hyperkeratotic papules and plaques generally asymptomatic and confluent in the center with reticular pattern at the periphery [1]. the lesions are typically localized to the trunk. the pathogenesis of crp remains uncertain [1,2]. some theories have suggested a disorder of keratinization, an involvement of bacterial pathogens via an alteration of sebum, or an abnormal response to host bacteria. another hypothesis is endocrine disturbance based on an association of crp with obesity, insulin resistance, diabetes mellitus, and other disorders of the thyroid and pituitary glands. to date, only 10 cases of crp associated with obesity (including the presented cases) have been reported in the literature [2]. figure 1. (a) brownish, confluent papules with a slightly hyperkeratotic surface that affected mainly the trunk. (b) complete clearance of the eruption after 2 months of treatment with doxycycline. figure 2. (a) asymptomatic hyperpigmented papules and plaques with a reticulated pattern. (b) complete resolution of lesions within 1 month of doxycycline treatment. letter | dermatol pract concept. 2021;11(2):e2021006 3 a pathogenic link between these 2 conditions is suggested by the insulin resistance and the resulting hyperinsulinemia in obese patients. high circulating insulin levels have mitogenic and anti-apoptotic activities on keratinocytes [2]. these activities may provide an explanation for the epidermal overgrowth and papillomatosis seen in our patients. concerning treatment, various modalities, mostly antibiotics, have been proposed with variable responses [1]. complete resolution with doxycycline in our cases further support cyclins, safe and effective agents, as the treatment of choice for crp. their effectiveness is mainly attributed to their anti-inflammatory properties, most probably attributed to inhibiting neutrophil migration and subsequent reactive oxygen species release that inhibit matrix metalloproteinases, rather than antimicrobial effects alone. references 1. lim jhl, tey hl, chong ws. confluent and reticulated papillomatosis: diagnostic and treatment challenges. clin cosmet investig dermatol. 2016;9:217-223. doi: 10.2147/ccid.s92051. pmid: 27601929. 2. fukumoto t, kozaru t, sakaguchi m, oka m. concomitant confluent and reticulated papillomatosis and acanthosis nigricans in an obese girl with insulin resistance successfully treated with oral minocycline: case report and published work review. j dermatol. 2017;44(8):954-958. doi: 10.1111/1346-8138.13819. pmid: 28295566. figure 3. (a) pigmented hyperkeratotic skin eruption on the trunk particularly on the intermammary region. (b) complete clearance of lesions after 2 months of doxycycline. dermatology practical & conceptual www.derm101.com essay | dermatol pract concept 2012;2(2):14 71 essay definitions diagnosis: a judgment about what a particular illness or problem is, made after making an examination. [cambridge dictionaries online. diagnosis. cambridge university press 2011. accessed february 17, 2012. http:// dictionary.cambridge.org.] diagnose (to): to recognize and name the exact character of a disease or a problem, by making an examination. [cambridge dictionaries online. diagnose. cambridge university press 2011. accessed february 17, 2012. http://dictionary.cambridge.org.] prognosis: (1) a doctor’s judgment of the likely or expected development of a disease or of the chances of getting better; (2) a statement of what is judged likely to happen in the future, especially in connection with a particular situation. prognose (to): to make a prognosis. [cambridge dictionaries online. prognosis. cambridge university press 2011. accessed february 17, 2012. http://dictionary.cambridge. org.] according to the definitions above, a diagnosis is an affirmation based on an examination, recognition and naming of the exact character of a present disease. for example the identification of mycobacterium tuberculosis in sputum implies a certainty: the patient has tuberculosis. all to the contrary, prognosis is a statistical computation of what might occur in the future. by its very nature, statistical evaluation is uncertain. statistics is nothing but a precise quantification of uncertainty. diagnosis is certain; prognosis is uncertain. a patient with tuberculosis may die from his disease or he may not. nobody will try to “adjust therapy to prognosis” for a tuberculous patient; antituberculous drugs will be prescribed. during the last few decades, and for reasons not entirely clear (some even suspect such as the redefinition of diseases according to the medications available in the market), in cases of cancer pathologists have been asked more frequently to evaluate the prognosis of (to “grade”) neoplasms on the basis of the histological characteristics of tumors. the “grading systems” are more and more elaborate, proliferate everywhere, occupying an ever-growing part of textbooks. this even goes to the point where diseases tend to be defined by their prognosis. it is not rare to find in the literature statements such as: “the evolution of dermatopathology, along with the development and introduction of new molecular biology techniques with the identification of new biomarkers, has opened a new field that may [emphasis ours] allow the classification of lesions in function of their prognoses in a completely objective and reproducible manner, putting an end to the eternal debates regarding the subjectivity of the currently utilized grading criteria.” [arumi-uria m. dysplastic nevus: the eye of the hurricane. j cutan pathol. 2008;35 suppl 2:16-9.] and even: “a diagnosis is a clinical tool that assists in the process of codifying patients into disease groups that share a common outcome and a common set of predicting outcome: a fourfold delusion! françois milette, md1 1 centre hospitalier pierre-boucher, longueuil, canada citation: milette f. predicting outcome: a fourfold delusion! dermatol pract conc. 2012;2(2):14. http://dx.doi.org/10.5826/dpc.0202a14. copyright: ©2012 milette. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: françois milette, m.d., centre hospitalier pierre-boucher, longueuil, canada. email: francois.milette@rrsss16. gouv.qc.ca. http://dictionary.cambridge.org http://dictionary.cambridge.org http://dictionary.cambridge.org http://dictionary.cambridge.org http://dictionary.cambridge.org 72 essay | dermatol pract concept 2012;2(2):14 prognosis. for instance, it is worse to suffer from small-cell carcinoma of the lung than from basal-cell carcinoma of the skin. one is therefore justified in communicating to a patient the prognosis associated with his disease. it is even correct to specify the prognosis by specifying the diagnosis in terms cogent, for instance, by typing and sub-typing tumors according to solid morphological basis, but prognosis nevertheless remains a (more or less) likely statement concerning the future of a population of patients, whereas diagnosis must remain a sure fact concerning the present of an individual patient. the patient dying from metastatic basal-cell carcinoma does not care for a minute that he had a 99.99% chance of survival when the rare patient surviving 10 years with small-cell carcinoma of the lung has had these years spoiled by the constant threat implied that he had a 90% chance of dying as a result of his disease. and to all other patients, that information is useless. the only conceivable usefulness of prognosis is to calibre the aggressiveness of therapy: “bad” cancers are worth being treated more aggressively than “good” cancers. to this end the prognosis implied by a precise diagnosis should suffice. other aspects of the misunderstanding of prognosis by clinicians are illustrated well by the two following examples: (1) we have seen a patient surviving 30 years with metastatic melanoma or small-cell carcinoma of the lung, who refuses to believe the diagnosis even after the slides had been reviewed and the diagnosis confirmed. outcome was inconsistent with the diagnosis according to them and therefore the diagnosis must have been wrong. this is nonsense. delusion. no individual outcome is inconsistent. the chance of winning a lottery may be very low, but can you imagine a winner being told that the fact that he won meant that it was not a lottery to which he participated? (2) we have seen patients who thought they were cured and told by their doctor that “one never is cured from cancer” with devastating consequences. delusion once again! some patients are cured from even the worst cancers. in every case, moreover, the fundamental diktat of medicine, primum non nocere, must be respected; “information” such as “one never is cured from cancer” simply violates it. the third delusion afflicts the pathologist, and it is enough to make one paranoid. it is not sufficient anymore for him to make a correct diagnosis. he must now also report thickness in hundredths of millimetre, grades histological and/or cytological on scales of 3, 5 and even 10, distances of margins in fractions of a millimetre, mitotic activity, percentages of tissue affected by cancer in a biopsy, presence of ulceration, necrosis, apoptotic rates, etc. and with all these “prognostic factors” added to it, his “diagnosis” soon fills two pages! afraid of missing some “important prognostic factor” he response to therapy.” [elder d, elenitsas r, johnson jr bl, murphy gf, xu x (eds.) lever’s histopathology of the skin. 10th ed. philadelphia, pa: lippincott williams & wilkins, 2009.] how far we are with this definition from the classic definition quoted earlier that has been the cornerstone of the practice of medicine for centuries! at least such a redefinition should be the subject of a debate among pathologists but no objection, no reaction is raised in the community of pathologists against those assertions and against new entities defined on the basis of them. they are even received with enthusiasm! such profession of faith meets consensus if not unanimity. according to this textbook definition, penicillin sensitive pneumonia, pyelonephritis and meningitis would be one single diagnosis: each entity being able to cause death if untreated (“common outcome”) and all of them responding favourably to penicillin (“common set of response to therapy”)! in fact even if the promise of “objective” classification of lesions according to their prognoses were met (and this is far from certain even in the mind of the author of the article quoted, as implied by his use of the word “may”), prognosis would still remain what it is: an approximation of the likely outcome; never a certainty. with time this leads to a devaluation of diagnosis and to confusion in the understanding of diseases, to a degradation of pathology itself. examples are numerous of the noxious consequences that result from confounding diagnosis and prognosis: it is the favorable prognosis of melanoma in situ that for years has impaired the recognition of its being melanoma; it is the “indolent clinical behavior” of small plaque parapsoriasis that continues to impair the recognition of its being mycosis fungoides; it is “outcome” of spitzoid melanoma metastatic to lymph node that purportedly justifies the flawed concept of “metastatic spitz nevus”; it is purported indolent biologic behavior that constitutes the raison d’être of “small and medium cell cutaneous t-cell lymphoma” as an entity different from mycosis fungoides, etc. in short, defining disease according to prognosis is a delusion. no clinician is satisfied by a “likely diagnosis” and no pathologist should accept entities defined by prognosis, a “judgment of the likely or expected development of a disease.” this is the first of four delusions hidden behind “prediction of outcome.” it concerns the very understanding of diseases and affects the students of them. the second delusion concerns the clinician and can be stated thus: informing a patient of his “individual prognosis” reveals a total misunderstanding of the nature of a prognosis—it being a statistical value and therefore applicable only to a population of patients. it is perfectly true that various tumors have various prognoses and that any diagnosis comes with its associated essay | dermatol pract concept 2012;2(2):14 73 after all, if it is legitimate for a suffering person to ask “what will happen to me?” it is just as legitimate for a healthy person to ask, “what are my chances of getting sick?” and when experts pretend to have answered the first question, it is only a matter of time before they become tempted to answer the second, acquiring the power to cure diseases even before they occur! ultimately this transforms risks into diseases and makes everybody sick! after all, isn’t life the ultimate risk in itself, the ultimate “disease” from which everybody shall die? without entirely discrediting “evaluation and treatment of risks,” we wish to stress here the dark sides of it that can take delusional proportions. first, the apparent benefits of such an approach may appear as positive as to hinder any critic of it. second, these same benefits apparently may induce, in a very delusional manner, denial of the side effects of “treating risks.” third, economical interests generated by treating a huge number of healthy persons may create massive incentive in favour of possibly useless or even harmful “risk therapy.” fourth, patients refusing to have their risks evaluated may be refused insurability or, worse, be brought to feel guilty for their insouciance [1]. in short, a diagnosis certain must remain the cornerstone of therapy; prognosis in individual case is of little, if any, utility to a clinician and may, in many ways, be harmful to patients. pathologists therefore should concentrate exclusively on the diagnosis and forget about the prognosis if they want to avoid, as modern haruspices, being the laughing stock of future generations. reference 1. marcotte j, milette f. cancer screening: i go . . . yes . . . no . . . perhaps later . . . dermatopathology: practical and conceptual. 2008;15(1):20. http://www.derm101.com/indexdpc?issueid=57. forgets to concentrate on diagnosis. after a while it becomes necessary for him to take refuge in the no man’s land of “dysplasia” and other “entities of unknown or indeterminate significance” and, compiling data for “predicting outcome,” he becomes something like a haruspex, this diviner of antiquity whose function was to predict, for the benefit of the emperor (the clinician), the issue of a battle by reading in the viscerae of a sacrificed animal (the patient) (figure 1). poor pathologist caught in such a cruel trap of being mocked! the fourth delusion is induced in patients when, as a result of the first three delusions already described, they are informed of “their” prognosis. it may take various forms. for instance, a “good” prognosis may induce reassurance, perhaps even euphoria, only to be deceived later by facts whereas a “bad” prognosis if not inducing depression or despair, may spoil the duration of survival. more importantly perhaps, a subtle form of delusion is created in the mind of patients through a drift from “prediction of outcome” for diseased individuals to “evaluation of risks” for healthy persons. figure 1. the bronze sheep’s liver of piacenza, with etruscan inscriptions, intended as a guide to the haruspex of roman antiquity for “predicting outcome” of battles. [wikipedia. haruspex. 18 february 2012. accessed february 18, 2012. http://en.wikipedia.org/wiki/ haruspex.] dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021025 1 dermoscopic features of foreign body cutaneous granuloma: a case series claudio conforti1 arianna dri1, enzo errichetti2, enrico zelin1, iris zalaudek1, nicola di meo1 1dermatology clinic, maggiore hospital, university of trieste, piazza ospitale 1, trieste, 34125, italy. 2 dermatology clinic, santa maria della misericordia hospital, udine, 33100, italy. key words: dermoscopy, granuloma, foreign bodies, diagnosis, dermatology citation: conforti c, dri a, errichetti e, zelin e, zalaudek i, di meo n. dermoscopic features of foreign body cutaneous granuloma: a case series. dermatol pract concept. 2021; 11(3): e2021025. doi: https://doi.org/10.5826/dpc.1103a25 accepted: september 9, 2020; published: july 8, 2021 copyright: ©2021 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none authorship: all authors have contributed significantly to this publication corresponding author: dri arianna, md. dermatology clinic, hospital maggiore, trieste, italy. email: arianna.dri@gmail.com introduction foreign body cutaneous granuloma (fbcg) is a form of chronic inflammatory response of the body to various agents. from a histological perspective, it consists of a necrotic center surrounded by macrophages, epithelioid cells, and fibrous tissue. it clinically presents as a solitary infiltrated pink-reddish nodule. cases presentation case i a 62-year-old woman came in consultation for a pink-reddish 5 mm nodule located on the sole of the right foot, at the periphery of a skin graft for an excision of a melanoma (breslow 1.35 mm) performed 3 months earlier. dermoscopy showed a structureless homogeneous milky-red area with vessels, a clinical diagnosis of loco-regional melanoma metastasis was hypothesized (figure 1a). case ii a 70-year-old man presented with a newly arisen red painless nodule about 5 mm in diameter located in right hypochondrium, close to a surgical scar. the patient underwent cholecystectomy 20 years ago. dermoscopic examination highlighted a homogenous bright red, roundish central area, surrounded by a scaly collarette and a violaceous halo (figure 1b). case iii a 57-year-old woman sought consultation for a 4 mm pinkish painful nodule on the dorsal region of her left wrist. the nodule appeared 6 months ago, following a gardening session. dermoscopy showed a structureless homogeneous reddish background and a central umbilication, surrounded by fine whitish scales (figure 1c). case iv a 30-year-old man presented with a newly-onset, irritated, itching papule on the medial surface of left leg. he denied surgical procedures or traumas. upon dermoscopy the lesion 2 letter | dermatol pract concept. 2021; 11(3): e2021025 showed a central whitish scar-like area surrounded by a structureless pinkish ring with linear vessels (figure 1d). excision and subsequent histological examination of the lesions led to fbcg diagnosis including a suture stitch (case i and ii), the thorn of a rose (case iii) and an ingrowing hair (case iv) respectively. conclusions to the best of our knowledge, very few reports in the literature illustrated the dermoscopic fbcg pattern, so far. our case series highlights fbcg’s heterogeneous presentation, since it revealed reddish or bluish structureless areas, rainbow pattern, polymorphic vessels, scar-like areas, erosions, and scales. fbcg differential diagnosis basically encompasses all entities presenting as solitary pink-reddish nodules. the appearance of new lesions on a surgical scar deriving from a previous excision should immediately raise suspicion of local recurrences and a biopsy should be performed. similarly, a biopsy procedure must be performed if cutaneous lymphomas, kaposi’s sarcoma, merkel cell carcinoma, or amelanotic figure 1. cases’ dermoscopic examination. (a) dermoscopic examination (dermlite 3gen, x10) of fbcg developed around a suture stitch and clinically configuring as a pink-reddish nodule located at the periphery of a skin graft for a previous excision of a melanoma. it configures as a structureless homogeneous milky-red area, with foci of vessels (arrows) and peripheral scales (case i). (b) dermoscopic examination (dermlite 3gen, x10) of the fbcg triggered by a suture stitch, clinically presenting as a nodule on the scar of a previous cholecystectomy. it displays a homogenous bright red roundish central area, surrounded by a scaly collarette and a violaceous halo (case ii). (c) dermoscopic evaluation (dermlite 3gen, x10) of the fbcg including the torn of a rose, which clinically configured as a pinkish painful nodule on the wrist of the women. it is characterized by a structureless homogeneous reddish background and a central umbilication surrounded by scales (case iii). (d) dermoscopic examination (dermlite 3gen, x10) of the irritated papule on the leg of the young man (case iv), showing a central scar-like white area surrounded by a concentric structureless pinkish ring with linear vessels (arrows). letter | dermatol pract concept. 2021; 11(3): e2021025 3 melanoma are suspected. conversely, dermoscopic evaluation is usually specific enough to make diagnosis of spinal and basal cell carcinoma, dermal nevus, angioma, and dermatofibroma. in conclusion, dermatologists should include fbcg in the differential diagnosis of pink-reddish elevated lesions in body sites that are compatible with their presence. fbcg lacks pathognomonic dermoscopic features. still, dermoscopy represents a useful tool that can help clinicians when making an exclusion diagnosis, by ruling out conditions characterized by more specific patterns. nevertheless, it is crucial to manage uncertain nodular lesions with excision and follow-up, these should never be considered as an option when dealing with fast growing or nodular lesions [1,2]. references 1. zaballos p, carulla m, ozdemir f, et al. dermoscopy of pyogenic granuloma: a morphological study. br j dermatol. 2010;163(6):1229-37. doi: 10.1111/j.1365-2133.2010.10040.x. 2. moscarella e, zalaudek i, agozzino m, et al. reflectance confocal microscopy for the evaluation of solitary red nodules. dermatology. 2012;224(4):295–300. doi: 10.1159/000339339. dermatology: practical and conceptual review | dermatol pract concept 2015;5(1):3 29 dermatology practical & conceptual www.derm101.com introduction granuloma annulare (ga) is a common idiopathic disorder affecting the dermis and subcutaneous tissues [1]. this benign dermatosis generally presents with generalized or localized lesions; macular, patch, perforating, and subcutaneous ga have also been described [1,2]. the localized form consists of one or more annular lesions composed of dermal papules. the generalized form is less frequently seen, presenting as a generalized papular eruption. ulceration, while not a typical feature associated with ga, has been seen in the less common perforating variant [2]. necrobiosis lipoidica (nl) is a rare chronic granulomatous disease characterized by erythematous papules or plaques that grow centrifugally, becoming brownish-yellow with central atrophy [3]. the lesions are typically seen in the pretibial region, but can also appear on the face, penis, scalp, and trunk. ulceration has been demonstrated to occur in up to 35% of patients with nl [4]. ga and nl differ in their clinical appearance, course, and prognosis. both dermatoses remain unclear in their pathogenesis. delayed-type hypersensitivity has been postulated to cause ga [5-8]; other authors mention vasculitis as a potential mechanism [3,9,10]. microangiopathy has been granuloma annulare and necrobiosis lipoidica with sequential occurrence in a patient: report and review of literature katherine a. rupley1, ryan r. riahi2, deirdre o’boyle hooper3 1 department of internal medicine, louisiana state university, baton rouge, louisiana, usa 2 department of dermatology, louisiana state university, new orleans, louisiana, usa 3 audubon dermatology, new orleans, louisiana, usa key words: concomitant, diabetes, granuloma, granuloma annulare, necrobiosis lipoidica, occurrence, review, same, sequential, simultaneous citation: rupley ka, riahi rr, o’boyle hooper d. granuloma annulare and necrobiosis lipoidica with sequential occurrence in a patient: report and review of literature. dermatol pract concept 2015;5(1):3. doi: 10.5826/dpc.0501a03 received: september 15, 2014; accepted: october 5, 2014; published: january 30, 2015 copyright: ©2015 rupley et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: katherine a. rupley, md, department of internal medicine, lsu health sciences center baton rouge, 5246 brittany drive, baton rouge, la, 70808, usa. tel. 225 803 1419. email: kruple@lsuhsc.edu granuloma annulare (ga) and necrobiosis lipoidica (nl) are granulomatous diseases of undetermined etiology. rarely, both dermatoses have been reported to occur concomitantly in patients. ga and nl are characterized histologically by areas of necrobiosis of collagen. the two diseases share some common characteristics, which may suggest that these dermatoses could occur as a spectrum in some patients or possibly share a similar pathogenesis. we report on a 67-year-old caucasian woman with a history of nl on the anterior shins that later developed lesions of ga on the breasts, trunk, and wrist. we also review the literature and discuss the characteristics of patients with concomitant ga and nl. abstract 30 review | dermatol pract concept 2015;5(1):3 suggested to play a role in the etiology and pathogenesis of nl [4,11,12]. while differences exist, both dermatoses share similarities including an association with diabetes, similar histological patterns, and they more commonly affecting women [1,2,9]. rarely, patients may present with or subsequently develop both ga and nl [2,3,9,13-18]. to our knowledge, there are ten previously documented cases of ga and nl occurring in the same patient [2,3,9,1318]. we report on a 67-year-old caucasian female with a history of nl on the lower legs who presented with erythematous papules and plaques over her breasts, trunk, and wrists; subsequent biopsy of a lesion on the trunk was consistent with ga. we describe the characteristics of patients with concomitant ga and nl and discuss similarities and differences between the two dermatoses. figure 1. lower legs with irregular, annular plaques with erythematous rim and yellow, atrophic centers. (copyright: ©2015 rupley et al.) case report a 67-year-old caucasian woman with a past medical history of diabetes mellitus type 2 and hypertension presented to clinic with a 15-year history of a progressively enlarging, asymptomatic plaques on her lower shins. the patient states the lesions initially began as red bumps that spread out and enlarged. she was seen by an outside dermatologist who had biopsied the area and was told she had necrobiosis lipoidica diabeticorum. she had tried superpotent topical steroids and intralesional kenalog with moderate improvement. physical examination demonstrated erythematous annular plaques with an erythematous rim and atrophic center with yellow discoloration over the lower extremities bilaterally (figure 1). the patient was treated with intralesional kenalog with significant improvement. the patient was seen for follow-up and stated she began developing new lesions on her thighs, trunk upper arm, and wrists (figure 2a, b, c, d). the lesions appeared as erythematous papules brown plaques, some with a central clearing. punch biopsy of the chest was performed and revealed discrete areas of palisading histiocytes surrounding collections of mucin with perivascular lymphocytes, suggestive of interstitial granuloma annulare (figure 3a, b, c). discussion granuloma annulare is characterized by grouped papules coalescing into annular plaques occurring most commonly on the back of hands and feet. nl typically presents with erythematous papules and plaques that expand centrifugally and tend to occur on the lower extremities. both dermatoses are more common in women [3]. a pubmed search was performed to find cases of ga and nl occurring in the same patient. the keywords concomitant, granuloma annulare, necrobiosis l i p o i d i c a , p a t i e n t , s a m e , se quential, and simultaneous were used. to the best of our knowledge, there have been 10 reported cases with ga and nl occurring in the same patient. these patients as well as our patient are described (table 1) [2,3,9,1318]. nine of the 11 patients were women (82%) with an average age of 30 years at the time of having both ga and nl. men (2 of the 11 figure 2a. left thigh with numerous erythematous papules and plaques. (copyright: ©2015 rupley et al.) figure 2b. lower chest and abdomen with erythematous, indurated papules. (copyright: ©2015 rupley et al.) review | dermatol pract concept 2015;5(1):3 31 patients, 18%) were of an average age of 25 years when concomitant ga and nl was discovered. duration of the lesions ranged from 6 months to 20 years. the lesions of nl were all found on the lower extremities [4]. the lesions of ga were found on the ankles, feet, legs, trunk, and upper extremities. of the 11 patients, 7 patients (7 of the 11, 64%) had diabetes or were pre-diabetic [2,3,9,13-18]. ga and nl share similarities and differences (table 2) [1-11,13-24]. both diseases can present with annular lesions and rarely involve the face. both also occur more frequently in women. histologic examination of both ga and nl can demonstrate central areas of necrobiosis with an infiltrate of histiocytes and lymphocytes [13]. the infiltrate may also contain epithelioid cells and giant cells [13]. granuloma annulare has increased mucin in the centers of the granulomas, while nl shows increased extracellular lipids [3]. ga has been figure 2c. right upper extremity with erythematous plaques and annular plaques. (copyright: ©2015 rupley et al.) figure 2d. right wrist with erythematous and brown indurated papules. (copyright: ©2015 rupley et al.) figure 3a. scanning view reveals necrobiotic collagen and dermal inflammation. (copyright: ©2015 rupley et al.) figure 3b. individual collagen fibers are swollen and intensely eosinophilic. histiocytic infiltrate around collagen fibers and a circumferential lymphocytic infiltrate are apparent (40x). (copyright: ©2015 rupley et al.) figure 3c. there is a heavy histiocytic infiltrate surrounding and separating collagen fibers (100x). (copyright: ©2015 rupley et al.) 32 review | dermatol pract concept 2015;5(1):3 associated with hiv and paraneoplastic syndromes while nl does not share these associations [20-22]. in 1934, ketron suggested that nl might be a variant of ga based on histologic findings [25]. in a publication in 1941, francis ellis suggested that the lesions of ga and nl could be the same entity [26]. dr. ellis mentions the first patient with both ga and nl in a manuscript by wood and beerman [19]. in 1968, the topic was readdressed by fred feldman, who presented the first case report primarily focusing on ga and nl in the same patient [13]. in this paper, paul hirsch mentions the presence of ga and nl in the same patient could possibly yield credence to a unifocal pathogenesis [13]. treatment of ga and nl can include intralesional triamcinolone, short courses of systemic steroids, and topical steroids [3,4,11]. other therapies used for ga have included dapsone, imiquimod, topical nitrogen mustard, topical retitable 1. cases of concomitant granuloma annulare and necrobiosis lipoidica in the same patient [2,3,9,13-18]. (copyright: ©2015 rupley et al.) case age / race sex / dm status duration of having both ga and nl clinical appearance ref 1 25/c/f/nd 5 years nl: firm, yellow shiny plaque with telangiectasias on pretibial region of the right leg ga: irregularly shaped annular lesions on volar right wrist [13] 2 30/nr/f/dm2 nr nl: large superficial oval lesion on shins ga: skin colored papules in an annular pattern on dorsal left foot [15] 3 31/nr/f/dm2 nr nl: bilateral pretibial plaques with atrophy ga: red-brown papules on the dorsal feet [14] 4 23/nr/f/nd nr nl: discreet reddish-brown patches with a yellow hue on the left pretibial surface ga: well-defined erythematous annular lesion with central clearing on right lower leg [16] 5 57/c/f/nd 20 year nl: irregular oval plaques on bilateral pretibial regions ga: annular erythematous nodules on feet, thighs, back, arms, hands [9] 6 70/c/f/dm2 6 months nl: ulceration of bilateral lower extremity including the pretibial region ga: widespread papular and annular eruption [2] 7 10/c/f/mody 2 years nl: erythematous plaques with waxy central clearing on left pretibial region ga: dyschromic red-brown plaques on the bilateral ankles [17] 8 39/nr/m/nd 3 years nl: brownish yellow confluent plaques with atrophic centers on ankles ga: violaceous annular plaques on upper limbs, thighs and abdomen, with infiltrated and defined borders [3] 9 11/c/m/dm1 1.5 years nl: large brown plaque with an atrophic center on pretibial region ga: pinkish-brown circular patch on the dorsum of the foot [18] 10 15/c/f/pd 3 years nl: yellowish-brown plaque with ulceration on right pretibial region ga: diffuse brown patch with small papules on left upper leg [18] 11 67/c/f/dm2 15 years nl: erythematous annular plaques with atrophic center on bilateral lower extremities ga: erythematous papules and plaques with central clearing on trunk and wrists [cr] aa = african american; c = caucasian; cr = current report; dm1 = diabetes mellitus type 1; dm2 = diabetes mellitus type 2; f = female; m = male; mody = maturity onset diabetes of the young; nd = no diabetes nr = not reported; pd = pre-diabetic; ref = references; sa = south asian american. review | dermatol pract concept 2015;5(1):3 33 noids, and ultraviolet light [1,3]. our patient’s nl lesions were treated with intralesional kenalog® with improvement; anecdotally, the patient reports her nl had significant improvement after she began a diet and exercise regimen and subsequently lost 15 pounds. intralesional kenalog, pentoxifylline, and plaquenil® have been utilized in the treatment of the patient’s ga lesions without benefit. conclusion nl and ga are two disease entities that have many similarities and differences. rarely, both diseases have been found to occur in the same patient. the two diseases share some common characteristics, which may suggest these dermatoses could occur as a spectrum in some patients. we report the eleventh example of a patient with both ga and nl and describe the characteristics of patients with concomitant ga and nl. further studies and evaluation needs to be performed to further elucidate the mechanisms and to discover if these disease entities are related. references 1. thornsberry la, english jc 3rd. etiology, diagnosis, and therapeutic management of granuloma annulare: an update. am j clin dermatol 2013;14(4):279-90. 2. berkson mh, bondi ee, margolis dj. ulcerated necrobiosis lipoidica diabeticorum in a patient with a history of generalized granuloma annulare. cutis 1994;53(2):85-86. table 2. similarities and differences of granuloma annulare and necrobiosis lipoidica [1-11,13-14]. (copyright: ©2015 rupley et al.) granuloma annulare necrobiosis lipoidica both dermatoses clinical features • grouped papules • more common on hands and arms • without ulceration • plaques with violaceous rim and yellowbrown atrophic centers • telangiectasias • more common on lower leg • ulceration can occur • decreased sensation • annular lesions • rarely involving the face epidemiology • more common in women histology • increased mucin deposition in areas of granulomatous inflammation • can have infiltrative pattern , palisading granuloma pattern, and/or epithelioid nodule (sarcoidal granuloma) pattern • diffuse inflammation involving dermis and subcutaneous fat • plasma cells • vessel changes including deposition of paspositive material • endothelial proliferation • telangiectatic vessels • ulceration • early lesions with leukocytoclasia • necrobiosis with an infiltrate of histiocytes and lymphocytes • epithelioid cells disease associations • thyroid disease • systemic sarcoidosis • hiv infection • malignancy • paraneoplastic with lymphoma • lipid abnormalities • diabetes mellitus treatment • isotretinoin • dapsone • antibiotics (minocycline, ofloxacin, rifampin) • stanozolol • nicofuranose • ticlopidine • tnf alpha inhibitors • tretinoin • thalidomide • mycophenolate mofetil • topical and intralesional steroids • uv therapy • antimalarials • pentoxifylline • niacinamide postulated pathogenesis • delayed type hypersensitivity • trauma • insect bite reaction • immune mediated vascular disease • microangiopathic vessel changes 34 review | dermatol pract concept 2015;5(1):3 3. souza fh, ribeiro cf, pereira ma, mesquita l, fabrício l. simultaneous occurrence of ulcerated necrobiosis lipoidica and granuloma annulare in a patient: case report. an bras dermatol 2011;86(5):1007-10. 4. reid sd, ladizinski b, lee k, baibergenova a, alavi a. update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. j am acad dermatol 2013;69(5):783-91. 5. muhlbauer je. granuloma annulare. j am acad dermatol 1980;3:217-30. 6. smith md, downie jb, dicostanzo d. granuloma annulare. int j dermatol 1997;36:326-33. 7. dabski k, winkelmann rk. generalized granuloma annulare: clinical and laboratory findings in 100 patients. j am acad dermatol 1989;20:39-47. 8. cohen pr, carlos ca. granuloma annulare mimicking sarcoidosis: report of patient with localized granuloma annulare whose skin lesions show three clinical morphologies and two histology patterns. am j dermatophatol. in press. 9. crosby dl, woodley dt, leonard dd. concomitant granuloma annulare and necrobiosis lipoidica. report of a case and review of the literature. dermatologica 1991;183(3):225-29. 10. dahl mv, ullman s, goltz rw. vasculitis in granuloma annulare: histopathology and direct immunofluorescence. arch dermatol 1977;113(4):463-67. 11. kota sk, jammula s, kota sk, meher lk, modi kd. necrobiosis lipoidica diabeticorum: a case-based review of literature. indian j endocrinol metab 2012;16(4):614-20. 12. ngo bt, hayes kd, dimiao dj, et al. manifestations of cutaneous diabetic microangiopathy. am j clin dermatol 2005;6(4):225-37. 13. feldman ff. granuloma annulare and necrobiosis lipoidica in the same patient. arch dermatol 1968;98(6):677-78. 14. schwartz me. necrobiosis lipoidica and granuloma annulare. simultaneous occurrence in a patient. arch dermatol 1982;118 (3):192-93. 15. burton jl. granuloma annulare, rheumatoid nodules and necrobiosis lipoidica. br j dermatol 1977;97 suppl 15:52-54. 16. cohen ij. necrobiosis lipoidica and granuloma annulare. j am acad dermatol 1984;10(1):123-24. 17. marchetti f, gerarduzzi t, longo f, et al. maturity-onset diabetes of the young with necrobiosis lipoidica and granuloma annulare. pediatr dermatol 2006;23(3):247-50. 18. davison je, davies a, moss c, et al. links between granuloma annulare, necrobiosis lipoidica diabeticorum and childhood diabetes: a matter of time? pediatr dermatol 2010;27(2):178-81. 19. wood mg, beerman h. necrobiosis lipoidica, granuloma annulare, and rheumatoid nodule. j invest dermatol 1960;34:139-47. 20. cohen pr. granuloma annulare, relapsing polychondritis, sarcoidosis, and systemic lupus erythematosus: conditions whose dermatologic manifestations may occur as hematologic malignancy-associated mucocutaneous paraneoplastic syndromes. int j dermatol 2006;45(1):79-80. 21. cohen pr. granuloma annulare associated with malignancy. south med j 1997;90(1):1056-19. 22. cohen pr, grossman me, silvers dn, deleo va. human immunodeficiency virus-associated granuloma annulare. int j std aids 1991;2(3):168-171. 23. gross pr, shelley wb. the association of generalized granuloma annulare with antihyroid antibodies. acta derm venereol (stockh) 1971;51(1):59-62. 24. umbert p, winkelmann rk. granuloma annulare and sarcoidosis. br j dermatol 1977;97(5):481-86. 25. traub ef. morphea, with histologic picture of tuberculoid. arch derm syphilol 1935:32(6): 953-54. 26. ellis fa. necrobiosis lipoidica: a form of granuloma annulare? arch derm syphilol 1941;43(5):822-28. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021; 11(3): e2021041. 1 the atomizer sign: a diagnostic clue to fragrance allergic contact dermatitis eduardo rozas-muñoz1, jaime piquero-casals2, juan-francisco mir-bonafé3 1 department of dermatology, hospital san pablo, coquimbo, chile 2 department of dermatology, clínica dermatológica multidisciplinar dermik, barcelona 3 department of dermatology, hospital son llàtzer, palma de mallorca, spain key words: allergic contact dermatitis, fragrances, neck citation: rozas-muñoz e, piquero-casals j, mir-bonafé jf. the atomizer sign: a diagnostic clue to fragrance allergic contact dermatitis. dermatol pract concept. 2021; 11(3): e2021041. doi: https://doi.org/10.5826/dpc.1103a41 accepted: november 12, 2020; published: july 8, 2021 copyright: ©2021 rozas-muñoz et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none authorship: all authors have contributed significantly to this publication corresponding author: eduardo rozas-muñoz, md. department of dermatology, hospital san pablo, avenida videla s/n, 1780000 -coquimbo. chile. email: docrozas@yahoo.com case report a 63-year-old man presented with pruritic and well-defined erythematous and vesicular eczematous plaques involving the anterior aspect of the neck and chest, present for the last 3 months (figure 1). the rest of the physical examination was unremarkable, and there was no past or family history of seborrhea or psoriasis. the patient was treated with topical corticosteroids showing some improvements, but with frequent relapses. patch test with thin-layer rapid use (t.r.u.e.) epicutaneous patch test™ revealed a positive (+++) reaction to fragrance mix i. the patient was therefore instructed to avoid fragrance-containing products showing complete improvement of his dermatitis. teaching point the presence of an eczematous dermatitis on the anterior neck in the adam’s apple region has been referred to as the atomizer sign, being a common area of application of aerosol figure 1. eczematous plaques involving the anterior aspect of the neck (adam’s apple region) and “v” of the anterior chest. 2 image letter | dermatol pract concept. 2021; 11(3): e2021041. perfumes or cologne [1]. patients with this peculiar presentation should be patch tested to rule-out any allergic contact dermatitis to fragrances. references: 1. sharon e jacob, mari paz castanedo-tardan. a diagnostic pearl in allergic contact dermatitis to fragrances: the atomizer sign. cutis. 2008;82(5):317-318. pmid: 19090333. dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(2):e2021012 1 dermatology practical & conceptual bullous aplasia cutis congenita—description of a novel dermoscopic feature aradhana rout1, sandeep arora1, rajeshwari dabas1, debatraya paul1 1 department of dermatology, command hospital air force bangalore, india key words: bullous aplasia cutis congenita, cobblestone pattern, developmental abnormality, congenital anomalies, dermoscopy citation: rout a, arora s, dabas r, paul d. bullous aplasia cutis congenita—description of a novel dermoscopic feature. dermatol pract concept. 2021;11(2):e2021012. doi: https://doi.org/10.5826/dpc.1102a12 accepted: july 30, 2020; published: march 8, 2021 copyright: ©2021 rout et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sandeep arora, md, department of dermatology, command hospital air force, bangalore 560007, india. email: aroraderma@gmail.com case presentation a 1-year-old boy presented with a solitary alopecic atrophic area on the scalp and a history of a fluid-filled lesion at the site that had presented a few days after birth and healed with thinning of skin (figure 1a). examination revealed a 2 × 2 cm solitary, well-defined alopecic patch with atrophy on the scalp vertex without any underlying bone defect. dermoscopy revealed (figure 1b) absent follicular openings, a few distended blood vessels, a few visible hair bulbs, and a branching network of reticulated white-colored streaks on atrophic skin resembling cobblestones. figure 1. (a) solitary alopecic patch with atrophic translucent skin and the (b) dermoscopic image with absent follicular openings, a few distended blood vessels (red arrow), a few visible pigmented hair bulbs (blue arrow), and cobblestoning (black arrows). 2 image letter | dermatol pract concept 2021;11(2):e2021012 teaching point although all signs may not be present in a case, the classic dermoscopic findings described are [1]: absence of follicular openings, thick, distended blood vessels, a hair collar sign with hair shafts arranged radially and forming a ring of hypertrichosis, and bulbs of anagen hair seen through the translucent epidermis resembling a golf stick [2]. however, recently a new pseudomembranous pattern has been identified, which can be included within a clinical and dermoscopic spectrum ranging from the classic to the pure membranous form of aplasia cutis congenita [3]. of these findings, our case had only a few distended vessels but was absent hair collar and golf stick signs. however, the atrophic skin in our case presented as cobblestoning visible on dermoscopy, which is a unique feature of bullous aplasia cutis congenita. references 1. costa pinheiro am, silva mauad eb, amarante fernandes lf, bruno drumond r. aplasia cutis congenita: trichoscopy findings. int j trichology. 2016;8(4):184-185. doi: 10.4103/ijt.ijt_90_15. pmid: 28442877. 2. cutrone m, grimalt r. the trichoscopic “golf club set” sign for bullous aplasia cutis congenita. skin appendage disord. 2018;4(4):320322. doi: 10.1159/000486463. pmid: 30410906. 3. chessa ma, filippi f, patrizi a, et al. aplasia cutis: clinical, dermoscopic findings and management in 45 children. j eur acad dermatol venereol. 2020;34(11):e724-e726. doi: 10.1111/ jdv.16542. doi:10.1111/jdv.16542. pmid: 32346876. dermatology: practical and conceptual commentary | dermatol pract concept 2021;11(1):e2021141 1 dermatology practical & conceptual utility of blue light in dermoscopy for diagnosing stable lesions in vitiligo balakrishnan nirmal1 1 department of dermatology, christian medical college, vellore, india key words: vitiligo, amelanotic vitiligo, blue light, dermoscopy citation: nirmal b. utility of blue light in dermoscopy for diagnosing stable lesions in vitiligo. dermatol pract concept. 2021;11(1):e2021141. doi: https://doi.org/10.5826/dpc.1101a141 accepted: september 19, 2020; published: january 29, 2021 copyright: ©2021 nirmal. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: balakrishnan nirmal, md, department of dermatology, christian medical college, vellore, india. email: nimu2swash@yahoo.co.in it is important to identify the nature of the border of a vitiligo lesion to ascertain the activity of the disease. ascertaining disease stability is an important prerequisite before subjecting the patient to surgical management. detection of an amelanotic lesion with a sharply demarcated border (asdb) under wood lamp is considered stable. unstable, active vitiligo lesions are associated with hypomelanotic appearance with poorly defined borders (hpdb) [1]. however, wood’s lamp requires a dark room and is difficult to use in busy outpatient practice. loss of melanin in vitiligo is seen clearly with a 470-nm blue light source from a multispectral dermoscope (dermlite dlii, multispectral; 3gen, san juan capistrano, ca). melanin absorption is highest in the ultraviolet spectrum and decreases toward a higher wavelength. blue light from the dermoscope has a wavelength closer to the absorption peak of melanin [2] and is useful in delineating asdb in stable vitiligo better than white-light dermoscopy (figure 1). hpdb seen in unstable vitiligo does not show this sharp delineation (figure 2). blue light increases the contrast between lesions retaining melanin and areas of melanin loss, thus is useful for differentiating stable from unstable vitiligo. figure 1. vitiligo; stable lesion. (a) white-light and (b) blue-light dermoscopy (×10). blue light (470 nm) delineates amelanotic vitiligo with the sharply demarcated border better than white-light dermoscopy. 2 commentary | dermatol pract concept 2021;11(1):e2021141 references 1. benzekri l, gauthier y, hamada s, hassam b. clinical features and histological findings are potential indicators of activity in lesions of common vitiligo. br j dermatol. 2013;168(2):265-271. doi: 10.1111/bjd.12034. pmid:.22963656. 2. kaliyadan f, jayasree p, kuruvilla j, errichetti e, lallas a. the use of blue light, multispectral dermoscopy in vitiligo: a pilot study [published online ahead of print, 2020;26(4):612-614. skin res technol. 2020;10.1111/srt.12837. doi: 10.1111/srt.12837. pmid: 31904163. figure 2. vitiligo; unstable lesion. (a) white-light and (b) blue-light dermoscopy (×10). blue light (470 nm) does not delineate hypomelanotic vitiligo with the poorly defined border. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(1):e2020021 1 dermatology practical & conceptual introduction primary mammary carcinomas involving the nipple rarely may exhibit features such as pigmented skin lesions mimicking melanoma clinically, histopathologically, and dermoscopically because of the presence of melanin pigment and melanophages. we describe a rare case of invasive ductal carcinoma that presented as a pigmented tumoral lesion involving the nipple of a man. case presentation a 61-year-old man presented with a pigmented itchy skin lesion on his right nipple that had been growing slowly for 7 months; in recent months the lesion had been bleeding easily. a physical examination revealed a well-demarcated, 15× 10-mm, grayish black ulcerated plaque with induration on the right nipple (figure 1a). dermoscopic findings are shown in figure 1, b and c. histopathological and immunohistochemical examination of the skin biopsy showed a diagnosis of grade ii infiltrative ductal carcinoma infiltrating the areola and nipple (figure 2). the patient had modified radical mastectomy and axillary lymph node dissection. conclusions male breast cancer is a rare neoplasm that accounts for 1.2% to 2% of all cancers among men and 1% of the total cases of breast cancer. unlike more reported cutaneous metastatic pigmented carcinoma of the breast, primary pigmented carcinoma of the breast is extremely rare. in the present case, dermoscopy showed a chaotic pattern including central white structureless area, white lines, ulceration, circumferential blue-gray structureless areas, peppering, and polymorphic vessels. these dermoscopic features confirm the difficulty of making a correct presurgical diagnosis with dermoscopy since differential diagnoses included mainly melanoma and basal cell carcinoma but also pigmented paget disease and metastatic breast carcinoma. in the reported cases of primary pigmented breast carcinoma, it has been hypothesized that the proliferation of melanocytes might be stimulated by a carcinoma located in close proxpigmented primary carcinoma of the breast in a man: a dermoscopic challenge bengu nisa akay,1 incilay kalay yildizhan,1 ayca kirmizi,2 hilal ozakinci,2 seher bostanci1 1 ankara university school of medicine, department of dermatology, ankara, turkey 2 ankara university school of medicine, department of pathology, ankara, turkey key words: male breast cancer, nipple, dermatoscopy, dermoscopy, melanoma citation: akay bn, kalay yildizhan i, kirmizi a, ozakinci h, bostanci s. pigmented primary carcinoma of the breast in a man: a dermoscopic challenge. dermatol pract concept. 2020;10(1):e2020021. doi: https://doi.org/10.5826/dpc.1001a21 accepted: october 23, 2019; published: december 31, 2019 copyright: ©2019 akay et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: incilay kalay yıldızhan, md, ankara universitesi tıp fakültesi i̇bni sina hastanesi, akademik yerleske m1 blok dermatoloji anabilim dalı, 06100 altindag, ankara, türkiye. email: incilaykalay@gmail.com mailto:incilaykalay@gmail.com 2 letter | dermatol pract concept 2020;10(1):e2020021 imity to the epidermis or alternatively melanocytes in the epidermis might have migrated to the tumor nest as a result of a chemoattractant released by the tumor cells [1]. another hypothesis was figure 1. (a) physical examination revealed a well-demarcated, 15× 10-mm, grayish black ulcerated plaque with induration on the right nipple. (b,c) dermoscopy shows a chaotic pattern including central white structureless area and white lines (purple star), ulceration with hemorrhage (black star), circumferential blue-gray structureless areas (blue star), peppering (red star), collarette scale (green star), and polymorphic vascular structures composed of dotted, clod, serpentine, and curved vessels (black circle, red arrow, green arrow, black arrow, respectively). that the disturbance of the basal layer could cause melanocyte migration into tumor nests and transfer melanin to tumor cells, leading to the dermoscopic large brown clods and blue-white clods that arranged randomly, similar to basal cell carcinoma in a case of pigmented invasive ductal carcinoma [2]. the dermoscopic circumferential blue-gray structureless areas in our case could be figure 2. (a,b) histopathological examination shows the atypical epithelioid cells ulcerating the epidermis and diffusely infiltrating all the dermis forming a nodular mass, and there was no pagetoid spread in the epidermis (h&e, original magnification ×10, ×30). (c) a large number of melanophages are seen in the papillary dermis secondary to ulceration (h&e, original magnification ×40). tumor cells were (d) diffusely stained with estrogen receptor (original magnification ×10), (e) diffusely stained with cytokeratin 7 (original magnification ×10), and (f) negative with melan-a stain, which emphasized the melanophages in the papillary dermis (original magnification ×40). letter | dermatol pract concept 2020;10(1):e2020021 3 cells may phagocytose the terminal parts of dendritic processes of melanocytes with subsequent dispersal of the melanin granules contained therein. in summary, pigmented lesions on special sites can be challenging and dermatoscopy has limitations in discrimination of melanoma from nonmelanocytic neoplasms. clinical, dermoscopic, and histopathological examination including immunohistochemical analyses are necessary to achieve the correct diagnosis for suspicious cases. the result of ulceration and basal vacuolar degeneration leading to melanin incontinence with numerous melanophages and melanin in the papillary dermis. in contrast to some reported cases of pigmented breast cancer, there was no melanin inside carcinoma cells but it was dispersed along the papillary dermis. in those cases, one hypothesis for the presence of melanin inside carcinoma cells was that melanocytes may inject melanin into carcinoma cells through their dendrites and neoplastic references 1. konomi k, imayama s, nagae s, terasaka r, chijiiwa k, yashima y. melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. j surg oncol. 1992;50(1):62-66. 2. horikawa h, umegaki-arao n, funakoshi t, amagai m, tanaka m. dermoscopy of pigmented invasive ductal carcinoma mimicking basal cell carcinoma. australas j dermatol. 2017;58(4):326-327. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(2):e2020041 1 dermatology practical & conceptual introduction sudden change in a pigmented lesion accompanied by the appearance of new lesions is a cause for concern for potential melanoma development. here we present such a case, diagnosed as eruptive blue nevi in a young woman. this case highlights the importance of dermoscopy for the diagnosis of this rare phenomenon. case presentation a 24-year-old woman with no significant medical history presented with a blue lesion on her right shin. the patient reported that the lesion had been present on her leg for many years but had started growing in the preceding 2 months. in addition, she had noticed 2 additional similar, albeit smaller, blue lesions that had appeared on her right thigh and her buttocks 2 weeks before. the lesions were asymptomatic, and the patient denied any additional complaints at the time of examination. clinical examination revealed a well-circumscribed, 6 mm in diameter, blue-gray nodule on the distal lateral aspect of the right shin (figure 1a). smaller macules, 4 mm in diameter, with a lighter blue color, were present on her right thigh and buttocks (figure 1b). dermoscopic examination revealed structureless, blue, symmetrical lesions, with a homogenous pattern (figure 2). histopathological examination confirmed the clinical suspicion of a cellular blue nevus, with a ki-67 proliferation index of less than 1%, and negative hmb45 and mart-1 stainings. conclusions blue nevus is a benign neoplasm composed of aberrant melanocytes located in the dermis, which can be found in 0.5%4% of the white population. it is usually acquired during the second decade of life, presenting as a macule, papule, nodule, or plaque on the buttocks, face, scalp, hands, or feet. several types of blue nevi exist, including common, cellular, or combined blue nevus; atypical or malignant blue nevus; and large patch/plaque lesions [1]. when a blue nevus develops, it usually remains stable and does not change with time. furthermore, the presence of multiple blue nevi is a rare phenomenon and usually presents as aggregated or plaque-type lesions. so far, there have been only 13 reports of eruptive blue nevi, where the number of eruptive blue nevi: a rare phenomenon diagnosed with the aid of dermoscopy laurent klapholz,1 yuval ramot1 1 department of dermatology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, israel key words: blue nevus, melanoma, dermoscopy, dermatology, skin citation: klapholz l, ramot y. eruptive blue nevi: a rare phenomenon diagnosed with the aid of dermoscopy. dermatol pract concept. 2020;10(2):e2020041. doi: https://doi.org/10.5826/dpc.1002a41 accepted: december 4, 2019; published: april 3, 2020 copyright: ©2020 klapholz and ramot. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: yuval ramot, department of dermatology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, 9112001, israel. email: yramot@gmail.com https://doi.org/10.5826/dpc.1002a41 mailto:yramot@gmail.com 2 letter | dermatol pract concept 2020;10(2):e2020041 2. kesty k, zargari o. eruptive blue nevi. indian j dermatol venereol leprol. 2015;81(2):198-201. k, eds. fitzpatrick’s dermatology in general medicine. 8th ed. new york: mcgraw-hill; 2012. nevi varied from 3 to hundreds [2]. in general, but also in the case of eruptive blue nevi, the sudden eruption of multiple nevi is observed following physiological conditions such as pregnancy or pathological disorders such as sunburn or trauma. although the clinical and dermoscopic features of the lesions in the patient described here were typical for a blue nevus, the sudden change and the appearance of new lesions in a short period of time were suspicious, especially when considering the importance of the blue hue as part of the dermoscopic features of malignancy. this, together with the lack of any triggering factor, warranted histopathological examination of the lesion to rule out malignancy. here we presented a rare case of eruptive blue nevi in a patient with no known triggering factors. it highlights the need for careful inspection of these lesions to rule out melanoma or malignant blue nevus, especially since melanoma has been reported to mimic benign blue nevus. references 1. grichnik jm, rhodes ar, sober aj. benign neoplasias and hyperplasias of melanocytes. in: goldsmith la, katz si, gilchrest ba, paller as, leffell dj, wolff figure 1. (a) a well-circumscribed, blue-gray macule on the distal lateral aspect of the right shin. (b) a smaller blue lesion on the right thigh. figure 2. dermoscopic examination of the lesions on the shin (a) and thigh (b) showing structureless, blue, symmetrical lesions, with a homogenous pattern. dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2012;3(1):7 25 background eccrine poroma (ep) is a relatively common benign adnexal neoplasm that is of eccrine origin. ep commonly occurs on the soles and lateral aspects of the feet, but it can also be found on other anatomic sites. it appears more frequently in adults. the most common clinical presentation is a firm nodule, from pink to red in color, sometimes slightly pedunculated, measuring up to 2 cm in diameter. sometimes ep presents as a small papule or as a verrucous plaque. occadermoscopy of non-pigmented eccrine poromas: study of mexican cases ana elena domínguez espinosa1, blanca carlos ortega2, ricardo quiñones venegas3, roger gonzález ramírez4 1 hospital general de zona 8, gilberto flores izquierdo, instituto mexicano del seguro social, mexico city, mexico 2 hospital de especialidades, centro médico la raza, instituto mexicano del seguro social, mexico city, mexico 3 instituto dermatológico de jalisco, guadalajara, mexico 4 servicios médicos, u.a.n.l., monterrey, mexico key words: dermoscopy, eccrine poroma, polymorphous vascular pattern citation: domínguez espinosa ae, carlos ortega b, quiñones venegas r, gonzález ramírez r. dermoscopy of non-pigmented eccrine poromas: study of mexican cases. dermatol pract conc. 2013;3(1):7. http://dx.doi.org/10.5826/dpc.0301a07. received: september 5, 2012; accepted: november 8, 2012; published: january 31, 2013 copyright: ©2013 domínguez espinosa et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: ana elena domínguez espinosa, calzada general anaya 338, col del carmen coyoacán cp. 04100, mexico city, mexico. tel. +52 (55) 56328385; fax. +52(55) 24583961. email: anaelenad@yahoo.com.mx. background: eccrine poroma is a benign neoplasm that can mimick a malignant neoplasm dermoscopically. the characteristic vascular pattern of this tumor has not been established. objective: to evaluate dermoscopic features of non-pigmented eccrine poroma in mexican patients. method: we retrospectively studied histologically proven cases of eccrine poroma from three mexican hospitals analyzed by four dermoscopists. results: thirteen cases were studied. a polymorphous vascular pattern was found in most cases. four presented with irregular linear and branched vessels with semi-elliptical, or semicircular endings (“chalice-form” and “cherry-blossoms” vessels). structureless pink-white areas were the most common other dermoscopic finding. conclusions: “chalice-form” and “cherry-blossom” vessels have not been reported in other benign or malignant neoplasms and can be a useful clue to the diagnosis of non-pigmented eccrine poroma. due to the variability of dermoscopic patterns of eccrine poroma further studies are required to establish the specificity of our findings. abstract 26 research | dermatol pract concept 2012;3(1):7 cific clues or patterns of non-pigmented ep have not been established. the aim of this study was to evaluate dermoscopic features of non-pigmented ep in mexican patients and to compare our findings with those already published. material and methods this is a retrospective study, including histologically verified cases of non-pigmented ep examined by dermoscopy, in three different mexican hospitals with polarized and nonpolarized dermoscopy (dermlite pro hr and dermlite hybrid m; 3 gen, dana point, ca, usa). the photographs were taken with a nikon coolpix p5100. all cases were analyzed with polarized light with and without immersion; for contact dermoscopy we used common cleansing gel alcohol. all cases were photographed with and without immersion with minimum pressure on the tumor. each dermoscopic image was evaluated independently by four dermoscopists for the presence of vascular pattern and additional clues. sionally ep can be pigmented. usually it is a solitary tumor. when multiple lesions appear on palms and soles the condition has been termed eccrine poromatosis [1,2]. dermatopathologically it is a proliferation arising from the lower portion of the epidermis from where it extends into the dermis forming a mass or broad anastomosing bands, composed of epithelial cells with uniform cuboidal appearance with round basophilic nuclei, connected by intercellular bridges. in the majority of cases, small ducts and occasionally cystic spaces are found within the aggregations of tumor cells [3]. dermoscopy is a non-invasive technique that is useful for the diagnosis of benign and malignant melanocytic and non-melanocytic lesions. in general the presence of a polymorphous vascular pattern is considered to be a useful clue to differentiate between benign and malignant neoplasms. vascular patterns, including morphology and distribution of vessels, can be useful to make a specific diagnosis, especially in combination with other structures. however, only a few articles describe the dermoscopic features of non-pigmented ep [4-7]. since the number of published articles is small, spetable 1. dermoscopic structures patient sex/age anatomic site hair pin vessels linear irregu lar vessels chaliceform/cherry blossoms structureless pink-white areas milky-red/ lacu na-like areas ulceration glomerular vessels 1 f/63 thigh +/+ + 2 f/82 upper arm + +/+ + 3 m/49 foot +/+ + 4 m/44 back + + 5 f/35 foot + + + 6 m/41 foot + +/+ + + 7 m/36 foot + + +* + 8 m/78 abdomen + + 9 f/46 foot + + + + 10 m/63 foot -/+ +* + 11 m/57 foot +* 12 f/48 foot +* 13 f/46 trunk + + + +* number 5 3 4/4 9 9 3 2 percentage 38% 23% 30% 70% 70% 23% 15% research | dermatol pract concept 2012;3(1):7 27 the dermoscopic features are presented in table 1. we found no differences with regard to dermoscopic structures seen with polarized light with immersion and polarized light without immersion. nine cases (70%) showed a polymorphous vascular pattern, including at least two types of vascular structures; four of them (30%) showed irregular linear vessels with a semi-elliptical ending giving the appearance of a chalice (“chalice-form”). in addition to “the chalice-form” vessels, three cases (23%) also showed structures combining thin branching vessels with circular and semicircular tips, very similar to the structure of the cherry blossom tree; and, in addition, one of these displayed a small ulceration (figures 1, 2, 3). one more case showed “cherry-blossom” vessels in the center of the lesion and milky-red globule/ lacuna-like areas surrounded by pink-to-white halo (“frogegg” aggregations) in the periphery. four more cases (in total results we included 13 cases of 4 women and 7 men. the mean age was 53 years (range 35—82). all patients were mexican with fitzpatrick’s phototype skin iii and iv. none of them had medical histories of importance for the present illness. only two patients reported pruritus and two reported pain during walking. eight cases were located on the feet. the remaining cases were located on the arm, thigh, abdomen, back and lateral aspect of the trunk. clinically the lesions presented as pink-to-red nodules, as nodules with a keratotic plug, and as a warty, papillated plaque. the average diameter was of 12 mm (range 5-20 mm). the lesions developed to their current size within 1 to 15 years. the clinical differential diagnoses included keratoacanthoma, clear cell acanthoma, larva migrans, amelanotic melanoma and squamous cell carcinoma. figure 1. case 1. immersion polarized dermoscopy shows the chalice-form and cherry blossom vessels (arrows) and small ulceration (cross). [copyright: ©2013 domínguez espinosa et al.] figure 2. case 3. polarized dermoscopy without immersion showing cherry-blossom, chalice-form vessels (arrows), and structureless pinkwhite areas (cross). [copyright: ©2013 domínguez espinosa et al.] figure 3. case 6. immersion polarized dermoscopy. cherry-blossom, chalice-form (thin arrows) hairpin vessels (thick arrows), structureless pink-to-white areas (cross). [copyright: ©2013 domínguez espinosa et al.] figure 4. case 11. polarized dermoscopy without immersion. frogegg aggregations (arrows) and central lacuna-like area (cross). [copyright: ©2013 domínguez espinosa et al.] 28 research | dermatol pract concept 2012;3(1):7 characteristic of non-pigmented ep in of our series, were also found in most cases in the study of ferrari et al [6]. the well-circumscribed milky-red lacunas separated by whitepink bands, the “frog-egg” appearance, which were seen in five (38%) of our patients, were also found in 30% of cases studied by minagawa et al [9]. conclusion the “chalice-form” and “cherry-blossom” vessels are a good clue for the diagnosis of non-pigmented ep, although, for unknown reasons, the pattern of non-pigmented ep is not uniform, and further studies are required to establish the specificity of our findings. references 1. taylor s, perone j, kaddu s. appendage tumors and hamartomas of the skin. in: wolff k, ed. fitzpatrick’s dermatology in general medicine. 7th ed. usa: mcgraw hill, 2008: 1069-87. 2. calonje e. tumours of the skin appendages. in: burns t, ed. rook’s textbook of dermatology. 8th ed. oxford, uk: wiley blackwell, 2010:53.1-53.44. 3. elder d, elenitsas r, bernett j, et al. tumors with eccrine differentiation. in: elder d, ed. lever’s histopathology of the skin. 9th ed. philadelphia, usa: lippincot williams & wilkins, 2005:898910. 4. avilés-izquierdo ja, velázquez-tarjuelo d, lecona-echevarria m, lázaro-ochaita p. [dermoscopic features of eccrine poroma.] article in spanish. actas dermosifilogr 2009;100(2):133-6. 5. blum a, metzler g, juergen b. polymorphous vascular patterns in dermoscopy as a sign of malignant skin tumors. a case of an amelanotic melanoma and a porocarcinoma. dermatology. 2005;210(1):58-9. 6. ferrari a, buccini p, silipo v, et al. eccrine poroma: a clinical-dermoscopic study of seven cases. acta derm venereol. 2009;89(2):160-4. 7. nicolino r, zalaudek i, ferrara g, et al. dermoscopy of eccrine poroma. dermatology. 2007;215(2):160-3. 8. aydingoz ie. new dermoscopic vascular patterns in a case of eccine poroma. j eur acad dermatol venereol. 2009;23(6):725-6. 9. minagawa a, koga h, takahashi m, sano k, okuyama r. dermoscopic features of nonpigmented eccrine poromas in association with their histopathological features. br j dermatol. 2010;163(6):1264-68. 10. suzaki r, shioda t, konohana i, ishizaki s, sawada m, tanaka m. dermoscopic features of eccrine porocarcinoma arising from hidroacanthoma simplex. dermatol res pract. 2010:192371. 30%) show these “frog-egg” aggregations (figure 4) and the rest of the cases combined linear irregular, hairpin vessels in addition to milky–red globules-like areas. in nine cases (70%) a structureless pink-to-white area was found, the most frequently found non-vascular structure. the dermatopathologic findings were typical for eccrine poroma. all lesions were formed of cuboidal basophilic cells arranged in anastomosing broad bands with small ductal spaces in contact with the epidermis and extending onto the dermis. some cases show pseudocystic spaces with mucous stroma. the capillaries were dilated and filled with erythrocytes. since all the samples were cut vertically, we could not carry out any other histological analysis of the vascular morphology. discussion eccrine poroma can mimic malignant tumors, including amelanotic melanoma, which emphasizes the importance of characterizing the dermoscopic patterns of non-melanocytic lesions. altamura et al were the first to publish dermoscopic characteristics of a case of non-pigmented ep. since then 22 additional cases have been reported. all reported cases had a polymorphous vascular pattern [4,6-9]. this pattern is characterized by the presence of irregular vessels that vary in size and shape and by the combination of different types of vessels. the vascular pattern of cases reported by aydingoz [8] was described as “floral and leaf-like.” we propose to call these vessels “chalice-form” and “cherry-blossom vessels” because of their similarity with a chalice and because the branches resemble the flowers of cherry trees. we consider these terms easy to remember. these vascular patterns seem to combine hairpin and branched vessels and have not been reported as part of the vascular pattern of melanoma or other malignant tumors [5,10]. therefore, the presence of this vascular pattern could be a helpful clue in differentiating ep from other benign or malignant non-pigmented neoplasms. however, given the small number of cases in our study, it would be premature to consider these vessels specific for eccrine poroma. although in other studies glomerular, arborizing and linear irregular vessels were dominant, we barely found them in our series. structureless pink-to-white areas, a dominant dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;2(3):9 51 quiz a 19-year-old male patient presented with a yellow nodular lesion on the scalp with dark eccentric pigmentation (figure 1). dermatoscopy reveals a structureless yellow area combined with serpentine branched vessels and a large blue clod (figure 2). what is your diagnosis? dermatoscopy: what is your diagnosis? philipp tschandl, m.d.1 1 department of dermatology, division of general dermatology, medical university of vienna, austria citation: tschandl p. dermatoscopy: what is your diagnosis? dermatol pract conc. 2012;2(3):9. http://dx.doi.org/10.5826/dpc.0203a09. copyright: ©2012 tschandl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: philipp tschandl, m.d., department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. +43.1.40400.7700; fax: +43. 1.408.19.28. e-mail: philipp.tschandl@ meduniwien.ac.at. figure 1. a—clinical picture of a papular lesion on the scalp. b—clinical closeup. [copyright: ©2012 tschandl.] a b figure 2. dermatoscopy: a structureless yellow to orange area, a single blue clod, and serpentine branched vessels can be seen. [copyright: ©2012 tschandl.] 52 quiz | dermatol pract concept 2012;2(3):9 please send your answer to dpc@derm101.com. the first to respond with the correct answer will receive a complimentary copy of the book, dermatoscopy: an algorithmic method based on pattern analysis [facultas verlag, 2011]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. answer to april 2012 quiz the correct answer to the quiz in the april 2012 issue is xanthogranuloma. please see article 3 of this issue of dermatology practical and conceptual for a detailed description of xanthogranuloma with dermatoscopic/dermatopathologic correlation [http://dx.doi.org/10.5826/dpc.0203a03]. congratulations to iara trocoli drakensjö, who was the first to send us the correct answer to this quiz! dermatology: practical and conceptual review | dermatol pract concept 2021;11(1):e2021126 1 dermatology practical & conceptual reappraising elements of the aseptic technique in dermatology: a review samiya khan1, terri shih2, shawn shih3, amor khachemoune4,5 1 long school of medicine, university of texas health science center at san antonio, tx, usa 2 david geffen school of medicine at university of california, los angeles, ca, usa 3 university of central florida college of medicine, orlando, fl, usa 4 veterans affairs medical center, brooklyn, ny, usa 5 department of dermatology, suny downstate, brooklyn, ny, usa key words: gloves, sterilization, wound infection, mohs surgery, skin neoplasms citation: khan s, shih t, shih s, khachemoune a. reappraising elements of the aseptic technique in dermatology: a review. dermatol pract concept. 2021;11(1):e2021126. doi: https://doi.org/10.5826/dpc.1101a126 accepted: august 7, 2020; published: january 29, 2021 copyright: ©2021 khan et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: amor khachemoune md, faad, facms, 800 poly place, dermatology service, brooklyn, ny, 11209 usa. email: amorkh@gmail.com dermatologic procedures are performed under varying degrees of antisepsis, and no clear guidelines exist regarding the role of the aseptic technique in dermatology. this review aims to clarify the terminology surrounding surgical asepsis and examines the importance of various components of the aseptic technique in cutaneous surgery. included are studies examining optimal glove type, surgical instruments, skin antisepsis, and cost-reducing protocols. our review highlights that most dermatology procedures are not performed under completely sterile conditions due to the lack of environmental and foot traffic controls in dermatology offices. in addition, for some outpatient procedures, such as for minor excisions and mohs surgery before reconstruction, elements of the clean technique can be used without increasing infection rates. however, data on the feasibility of a clean protocol for mohs reconstruction is conflicting. future prospective, randomized trials analyzing various components of the aseptic technique in dermatology are greatly needed so that guidelines can be established for practicing dermatologists. abstract introduction over the years, dermatologic surgical procedures have increased. those performed in outpatient settings allow the dermatologist to provide more cost-effective treatment options for patients than procedures performed in hospital settings [1]. in fact, a survey performed by the american society for dermatologic surgery showed that dermatologists 2 review | dermatol pract concept 2021;11(1):e2021126 performed 12.5 million procedures in 2018, a 60% increase since 2012 [2]. despite the high volume of procedures performed by dermatologists, no standard guidelines exist regarding the extent of antisepsis required for these procedures. we aim to conduct a comprehensive literature review to elucidate our understanding of the role and necessity of the aseptic technique in dermatology practice. discussion reviewing the terminology multiple terms that describe varying degrees of sterility during medical procedures exist. terms such as “aseptic” and “sterile” are often used interchangeably, and multiple definitions are available. the following definitions are based on the descriptions provided by the aseptic non-touch technique framework, a clinical practice standard developed by rowley in the united kingdom in the 1990s and currently implemented in more than 25 countries [3]. clean: free from visible marks and stains. aseptic: free from pathogenic organisms in numbers needed to cause infection. sterile: free from all microorganisms. in addition, according to the joint commission, the clean and aseptic techniques are differentiated based on 4 primary factors (table 1) [4]. clean technique: • barrier: appropriate hand hygiene, clean gloves. • patient and environmental preparation: efforts to prevent direct contamination. • environmental controls: routine cleaning of patient’s environment. • contact: sterile to sterile contact is not a consideration. aseptic technique: • barrier: sterile gloves, sterile drapes, and sterile masks to prevent the transfer of microorganisms from the environment to the patient. • patient and equipment preparation: antiseptic skin preparation of patient at time of procedure, sterile instruments, sterile equipment, sterile devices. • environmental controls: close doors during procedures, minimize traffic into and out of operating rooms, exclude unnecessary personnel during procedures. • contact: only sterile-to-sterile contact is allowed. historically the term sterile technique has been used interchangeably with aseptic technique. however, a true sterile technique is impossible to achieve in most healthcare settings due to the presence of airborne organisms [3]. the dermatology office environment the practice of antisepsis in the surgical operating room involves the adoption of strict sterile techniques. multiple, extensive guidelines have been published regarding proper sterile technique during surgery. while exact practices may vary at each institution, sterile technique in an operating room generally includes environmental cleaning, hand hygiene, preoperative skin preparation, sterile surgical attire, and maintaining a sterile surgical field. in addition, the operating room must also have high-efficiency particulate air filters and directional airflow to minimize airborne infection [5]. in contrast to the traditional operating room, dermatology offices do not have strict requirements on the use of sterile technique during dermatologic surgeries, and without ventilatory systems, achieving a truly sterile environment is impossible in dermatology offices. with a shortage of scientific data, dermatologists must personally decide for themselves the degree of sterility they would like to practice during procedures. as a result, aseptic techniques vary. a survey regarding perioperative antiseptic practices among members of the american college of mohs surgery showed that many traditional aseptic techniques are not used among dermatologists. for example, only 35% of respondents reported utilizing a preoperative hand scrub before mohs surgery [6]. when aseptic techniques are employed, they are generally used for excisional surgeries, flaps, grafts, and mohs repairs [7]. asepsis for these procedures is different than general table 1. definition of terms term definition current use in dermatology clean technique • maintaining an environment that is free from marks and stains • includes hand hygiene, clean gloves, efforts to prevent contamination, and routine cleaning • punch biopsy • shave biopsy • mohs surgery aseptic technique • maintaining an environment that prevents infection • includes the use of sterile attire, sterile equipment, antiseptic skin preparations, and environmental controls. only sterile to sterile contact is allowed. • excisions • flaps and grafts • mohs repairs review | dermatol pract concept 2021;11(1):e2021126 3 surgery, however, because while sterile materials and gloves are used, there is no regulation in regard to foot traffic, airflow, or surgical scrub. smaller procedures, such as shave or punch biopsies and curettage, use the clean technique. in addition, mohs micrographic surgery (mms) is typically considered a clean procedure rather than a sterile procedure because patients move between procedure and waiting rooms, covering their wound with a nonsterile bandage [8]. despite the low incidence of strict aseptic technique use among dermatologists, the rate of surgical site infections in dermatologic surgery remain incredibly low (0.07% to 5%) [8]. surgical gloves a major area of investigation regarding aseptic practices in dermatology has been centered on the use of sterile vs clean gloves during dermatologic procedures (table 2). in 2006, rhinehart et al. published the first study examining this issue, conducting a retrospective chart review of 1,239 patients who underwent mms by one of 2 surgeons. rhinehart and his colleagues observed no statistically significant difference in surgical site infection (ssi) rates between sterile and clean gloves for mms before reconstruction when controlling for the surgeon who performed the surgery and other components of the perioperative aseptic technique. for example, both the clean and sterile glove groups utilized identical antiseptic skin preparations, handwashing protocols, and sterile linens. in addition, if a surgical assistant was present, he or she utilized the same type of gloves as the primary surgeon [9]. other prospective studies have similarly found clean gloves to be noninferior to sterile gloves in preventing infections [10-13]. a recently conducted systematic review of ssi rates with sterile vs clean gloves in both cutaneous and dental procedures found the same finding even when controlling for only dermatologic procedures through a subgroup of patients undergoing mohs surgery [14]. another study, a prospective trial examining 3,491 dermatologic surgical procedures conducted by rogues et al in 2007, found a lower rate of surgical site infections with sterile glove use than when sterile gloves were not used (14.7% vs 3.7%) [15]. however, this pattern was only found for reconstructive procedures such as flaps and grafts and not simple excisions. moreover, the high rate of infection seen in this study is atypical for most dermatologic procedures and may be due to the inclusion of both hospital and outpatient procedures in this study. based on rogue’s analysis, it is also difficult to discern whether no gloves or nonsterile gloves were used as a control in the investigation. taken together, most studies show no significant difference in infection rates between sterile and clean gloves for simple outpatient dermatologic procedures. in fact, the bacterial load found on clean gloves has been found to be inadequate to cause infection [16]. on the other hand, more complex excisions and reconstructions may benefit from the use of sterile gloves; although, more prospective studies examining sterile vs clean-glove use in more complex excisions is needed. surgical instruments and materials the sterilization of surgical instruments is another component of the perioperative aseptic technique that helps reduce the potential of spreading infection. a few studies have been conducted regarding surgical instrument sterilization in dermatology offices. nasseri and colleagues, for example, found that among 338 patients undergoing mms, using a single table 2. summary of studies comparing sterile vs nonsterile glove use in dermatology author study type findings rhinehart et al [9] (2006) retrospective • no difference in ssi rate between nonsterile or sterile gloves rogues et al [15] (2007) prospective observational • lower rate of ssi with the use of sterile gloves compared to nonsterile gloves during reconstructive procedures • no difference in ssi rate between nonsterile and sterile gloves for simple excisions xia et al [10] (2011) prospective randomized • no difference in ssi rate between nonsterile or sterile gloves mehta et al [11] (2014) prospective • no difference in ssi rate between nonsterile and sterile gloves brewer et al [14] (2016) systematic review/ meta-analysis • no difference in ssi rate between nonsterile and sterile gloves (including when looking at mohs micrographic surgery subtype) michener et al [12] (2019) prospective randomized • no difference in ssi rate between nonsterile and sterile gloves kemp et al [13] (2019) retrospective • ssi rate was 3.02% with sterile glove and 4.17% with nsg 4 review | dermatol pract concept 2021;11(1):e2021126 set of sterile instruments for both the tumor extirpation and repair stages of mms resulted in an acceptably low incidence of surgical site infections and increased cost savings [8]. findings by liu and colleagues further elucidate the role of the aseptic technique in dermatology by showing that new non-evidence-based guidelines proposed by the joint commission on the accreditation of health care organizations on the sterilization of instruments in outpatient procedures did not reduce the incidence of infection after dermatologic surgery [17]. the guidelines mandated that each item be sorted and sterilized individually but only when producer instructions were available. this increased the average time to set up a tray for each stage of the procedure, but provided no overall benefit, highlighting that evidence-based recommendations are still needed in this realm [17]. some studies have looked at ssi rates after the use of multiple sterile instruments and materials rather than gloves in isolation. a prospective study by rogers and colleagues in 2010 found that the use of a clean surgical technique (consisting of clean gloves, clean draping, and a reusable sterile set of instruments) in 1,000 patients for all stages of mohs surgery (including reconstruction) led to a low rate of infection of 0.91% [18]. however, no control group was used in the study. a study published by martin and colleagues, also in 2010, reported that heightened infection control practices reduced the rate of ssi in a statistically significant manner from 2.5% to 0.9% for 950 mohs surgeries. the heightened aseptic regimen included jewelry restriction, alcohol hand scrub before each stage, and sterile gloves, gowns, towels, and dressings, which correspond to parts of the aseptic technique [19]. a follow-up study published in 2012 compared the ssi rates between 2 lowand high-cost infection control practices and found that the less expensive measures that omitted sterile gloves, sterile gowns, and sterile drapes did not change infection risk in mohs surgery [20]. based on these studies it is possible that lower cost, less sterile protocols could be implemented without compromising safety, but more specific recommendations and conclusive evidence is needed. skin antiseptics antiseptic scrubs are used in the aseptic technique to prepare the skin before surgery to remove transient bacteria while minimizing the remaining resident flora. currently, no definitive guideline exists for antiseptic use in dermatologic surgery, although multiple options such as isopropyl alcohol, povidone, and chlorhexidine exist. studies on antiseptic use in dermatology are limited, although a study by alam and colleagues found that preoperative chlorhexidine use correlates with a lower postoperative infection risk in mms [21]. however, the estimated absolute risk reduction was shown to between 0.45% and 0.53% and therefore exceptionally small [21]. among studies outside the field of dermatology, a recent systematic review and meta-analysis of 19 studies concluded that chlorhexidine is associated with fewer positive skin infections compared to iodophors, such as povidone iodine and iodine povacrylex [22]. with limited data, dermatologists must use specific attributes relating to the various antiseptics to guide product usage. for example, povidone iodine is not recommended in those with an allergy to iodine, and alcohols should be avoided in wet areas of the skin due to flammability [23]. moreover, solutions containing chlorhexidine and alcohol-containing agents should not be used on the face due to the potential for serious eye injury. for example, chlorhexidine use has been associated with irreversible keratitis leading to blindness and ototoxicity. therefore, for head and neck procedures, one should consider povidone iodine or chloroxylenol for surgical site prep and chlorohexidine for more distant sites due to its superior length of activity [24]. surgical face masks, caps, gowns, and shoes studies specific to the importance of surgical face masks, caps, gowns, and shoe covers—key components of the aseptic technique—are lacking. a review examining attire published by eisen in 2011 concludes that no evidence exists to prefer one form of attire over another in dermatologic surgery and that the use of masks, head coverings, operating room shoes, and shoe covers have not been shown to avert surgical site infections [25]. for example, cochrane systematic review from 2016 found no evidence that face masks reduced the rate of ssis during clean surgery, but the limited number of studies in the review makes it unsafe to draw any definite conclusions [26]. in addition, evidence on the utility of gowns seems to be conflicting, and earlier studies analyzing bacterial load in gowns may be irrelevant due to the vastly improved gown materials of today [27]. regarding more commonly worn outpatient attire, a systematic review by goyal and colleagues, which included 22 studies pertaining to microbial contamination, found providers’ white coats and scrubs associated with multidrug resistant organisms, with white coats having a higher degree of contamination due to less frequent laundering [28]. therefore, the authors suggest that white coats should be laundered at least weekly and scrubs should be changed daily. while these are general suggestions, appropriate guidelines should be established within dermatology based on the type of patient-physician encounter. handwashing handwashing is an important component of both the clean and aseptic technique and, in the mid 1970s, was recognized as “the most important procedure in preventing nosocomial infections” by the us center for disease control and prevention (cdc) and was included in the cdc guidelines by the 1980s [29]. in the field of dermatology, the practice of review | dermatol pract concept 2021;11(1):e2021126 5 proper hand hygiene is of particular concern because patientdepressed barrier function, associated with a variety of skin diseases, makes them more susceptible to infectious disease. in addition, the skin of dermatologists or their assistants can be easily contaminated. a study sampling 13 dermatologists found all physicians’ hands to be contaminated with microbial pathogens, with one hand contaminated by mrsa [30]. in the same study, compliance with handwashing was found to be only 31.4%. presently, the cdc recommends alcohol-based sanitation to be used predominantly, although handwashing with soap and water is preferred before eating, after using the restroom, when hands are visibly soiled, and when clostridium difficile exposure is suspected [31,32]. a strict surgical hand scrub that generally includes cleaning one’s hands up to the forearm with a brush has not been tested in dermatology, and such a protocol is likely unnecessary in the dermatology practice. nevertheless, hand antisepsis should be performed before and after patient contact. conclusions reappraisal of sterile procedures in dermatology the aseptic technique involves the creation of a sterile field and preservation of this sterility throughout the procedure. due to a lack of guidelines, the degree of asepsis practiced by dermatologist varies by procedure. more complex and invasive procedures, such as mohs reconstruction or liposuction, increase the necessity for surgical asepsis. in reality, dermatologists employ a “modified aseptic” technique when performing these procedures, as complete sterility is impossible to achieve in most dermatology offices. for example, using a single pair of sterile gloves or even a new, sterilized tray does not ensure complete asepsis because the surgical staff may not be wearing sterile attire while interacting with the patient or surgical materials. in addition, most dermatology offices see frequent foot traffic from patients and family members without regulations for when procedure room doors should be closed, and this further reduces the sterility of the environment. taken together, aseptic practices in dermatology vary. there is moderate evidence to show that the use of clean gloves may be justified in the setting of simple dermatologic procedures. however, this justification may not apply to more advanced dermatologic surgeries. a few studies have also shown that various cost-reducing practices, such as using a single set of sterile instruments or a clean surgical technique does not harm surgical site infection rates in dermatology. more studies are needed regarding the utility of surgical attire such as face masks, caps, and gowns in dermatology. proper hand hygiene should, in general, always be used for both clean and aseptic procedures. while it is difficult to isolate one variable due to many possible factors leading to post-surgical infections, rigorous, well-designed randomized controlled trials are needed to help establish guidelines for the scope of asepsis required for various types of dermatologic surgery. references 1. chen jt, kempton sj, rao vk. the economics of skin cancer: an analysis of medicare payment data. plast reconstr surg glob open. 2016;4(9):e868. doi: 10.1097/gox.0000000000000826. pmid: 27757333. 2. asds members performed nearly 12 million treatments in 2017. accessed december 3, 2019. https://www.asds.net/skin -experts/news-room/press-releases/asds-members-performed -nearly-12-million-treatments-in-2017. 3. rowley s, clare s. right asepsis with antt® for infection prevention. in: moureau nl, ed. vessel health and preservation: the right approach for vascular access. springer international publishing; 2019:147-162. doi: 10.1007/978-3-030-03149-7_11. 4. clabsi_toolkit_tool_3-8_aseptic_versus_clean_technique. pdf. accessed december 3, 2019. https://www.jointcommission. org/assets/1/6/clabsi_toolkit_tool_3-8_aseptic_versus_clean_ technique.pdf. 5. gaines s, luo jn, gilbert j, zaborina o, alverdy jc. optimum operating room environment for the prevention of surgical site infections. surg infect (larchmt). 2017;18(4):503-507. doi: 10.1089/sur.2017.020. pmid: 28402706. 6. eisen db, warshawski l, zloty d, azari r. results of a survey regarding perioperative antiseptic practices. j cutan med surg. 2009;13(3):134-139. doi: 10.2310/7750.2008.08019. pmid: 19426621. 7. elliott tg, thom ga, litterick ka. office based dermatological surgery and mohs surgery: a prospective audit of surgical procedures and complications in a procedural dermatology practice. australas j dermatol. 2012;53(4):264-271. doi: 10.1111/j.14400960.2012.00951.x. pmid: 23043516. 8. nasseri e. prospective study of wound infections in mohs micrographic surgery using a single set of instruments. dermatol surg. 2015;41(9):1008-1012. doi: 10.1097/dss.0000000000000458. pmid: 26230327. 9. rhinehart mbm, murphy mme, farley mf, albertini jg. sterile versus nonsterile gloves during mohs micrographic surgery: infection rate is not affected. dermatol surg. 2006;32(2):170-176. doi: 10.1111/j.1524-4725.2006.32031.x. pmid: 16442035. 10. xia y, cho s, greenway ht, zelac de, kelley b. infection rates of wound repairs during mohs micrographic surgery using sterile versus nonsterile gloves: a prospective randomized pilot study. dermatol surg. 2011;37(5):651-656. doi: 10.1111/j.15244725.2011.01949.x. pmid: 21457390. 11. mehta d, chambers n, adams b, gloster h. comparison of the prevalence of surgical site infection with use of sterile versus nonsterile gloves for resection and reconstruction during mohs surgery. dermatol surg. 2014;40(3):234-239. doi: 10.1111/ dsu.12438. pmid: 24446695. 12. michener m, xia y, larrymore d, mcgraw t, mccarthy s. a comparison of infection rates during skin cancer excisions using nonsterile vs sterile gloves: a prospective randomized pilot study. 6 review | dermatol pract concept 2021;11(1):e2021126 j cosmet dermatol. 2019;18(5):1475-1478. doi: 10.1111/ jocd.12860. pmid: 30661299. 13. kemp dm, weingarten s, chervoneva i, marley w. can nonsterile gloves for dermatologic procedures be cost-effective without compromising infection rates? skinmed. 2019;17(3):155-159. 14. brewer jd, gonzalez ab, baum cl, et al. comparison of sterile vs nonsterile gloves in cutaneous surgery and common outpatient dental procedures: a systematic review and meta-analysis. jama dermatol. 2016;152(9):1008-1014. doi: 10.1001/jamadermatol.2016.1965. pmid: 27487033. 15. rogues am, lasheras a, amici jm, et al. infection control practices and infectious complications in dermatological surgery. j hosp infect. 2007;65(3):258-263. doi: 10.1016/j. jhin.2006.09.030. pmid: 17244515. 16. creamer j, davis k, rice w. sterile gloves: do they make a difference? am j surg. 2012;204(6):976-979; discussion 979-980. doi: 10.1016/j.amjsurg.2012.06.003. pmid: 23231936. 17. liu a, lawrence n. incidence of infection after mohs micrographic and dermatologic surgery before and after implementation of new sterilization guidelines. j am acad dermatol. 2014;70(6):1088-1091. doi: 10.1016/j.jaad.2014.02.014. pmid: 24680104. 18. rogers hd, desciak eb, marcus rp, wang s, mackay-wiggan j, eliezri yd. prospective study of wound infections in mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. j am acad dermatol. 2010;63(5):842851. doi: 10.1016/j.jaad.2010.07.029. pmid: 20800320. 19. martin je, speyer l-a, schmults cd. heightened infection control practices are associated with significantly lower inf e c t i o n r a t e s i n o f f i c e b a s e d m o h s s u r g e r y. d e r m a t o l s u r g . 2 0 1 0 ; 3 6 ( 1 0 ) : 1 5 2 9 1 5 3 6 . d o i : 1 0 . 1 1 1 1 / j . 1 5 2 4 4725.2010.01677.x. pmid: 20698870. 20. lilly e, schmults cd. a comparison of highand low-cost infection-control practices in dermatologic surgery. arch dermatol. 2012;148(7):859-861. doi: 10.1001/archdermatol.2012.602. pmid: 22801633. 21. alam m, ibrahim o, nodzenski m, et al. adverse events associated with mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers. jama dermatol. 2013;149(12):1378-1385. doi: 10.1001/jamadermatol.2013.6255. pmid: 24080866. 22. privitera gp, costa al, brusaferro s, et al. skin antisepsis with chlorhexidine versus iodine for the prevention of surgical site infection: a systematic review and meta-analysis. am j infect control. 2017;45(2):180-189. doi: 10.1016/j.ajic.2016.09.017. pmid: 27838164. 23. echols k, graves m, leblanc kg, marzolf s, yount a. role of antiseptics in the prevention of surgical site infections. dermatol surg. 2015;41(6):667-676. doi: 10.1097/dss.0000000000000375. pmid: 25984901. 24. ammirati ct. chapter 2 aseptic technique. in: robinson jk, sengelmann rd, hanke cw, siegel dm, bhatia ac, rohrer te, eds. surgery of the skin. mosby; 2005:25-37. doi: 10.1016/ b978-0-323-02752-6.50007-9. 25. eisen db. surgeon’s garb and infection control: what’s the evidence? j am acad dermatol. 2011;64(5):960.e1-20. doi: 10.1016/j.jaad.2010.04.037. pmid: 20850894. 26. vincent m, edwards p. disposable surgical face masks for preventing surgical wound infection in clean surgery. cochrane database syst rev. 2016;4:cd002929. doi: 10.1002/14651858. cd002929.pub3. pmid: 27115326. 27. saleh k, schmidtchen a. surgical site infections in dermatologic surgery: etiology, pathogenesis, and current preventative measures. dermatol surg. 2015;41(5):537-549. doi: 10.1097/ dss.0000000000000364. pmid: 25888316. 28. goyal s, khot sc, ramachandran v, shah kp, musher dm. bacterial contamination of medical providers’ white coats and surgical scrubs: a systematic review. am j infect control. 2019;47(8):9941001. doi: 10.1016/j.ajic.2019.01.012. pmid: 30850250. 29. vermeil t, peters a, kilpatrick c, pires d, allegranzi b, pittet d. hand hygiene in hospitals: anatomy of a revolution. j hosp infect. 2019;101(4):383-392. doi: 10.1016/j.jhin.2018.09.003. pmid: 30237118. 30. cohen ha, kitai e, levy i, ben-amitai d. handwashing patterns in two dermatology clinics. dermatology (basel). 2002;205(4):358361. doi: 10.1159/000066421. pmid: 12444331. 31. smith c, srivastava d, nijhawan ri. optimizing patient safety in dermatologic surgery. dermatol clin. 2019;37(3):319-328. doi: 10.1016/j.det.2019.02.006. pmid: 31084726. 32. messina mj, brodell la, brodell rt, mostow en. hand hygiene in the dermatologist’s office: to wash or to rub? j am acad dermatol. 2008;59(6):1043-1049. doi: 10.1016/j.jaad.2008.07.033. pmid: 18848734. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021137 1 clinical, dermoscopic, and histopathologic aspects of amelanotic lentigo maligna melanoma catalin mihai popescu¹, corina barna², alexandru metea³, razvan theodor andrei4, mona taroi2 1 carol davila university of medicine and pharmacy bucharest, dermatology department, bucharest, romania 2 military emergency hospital sibiu, dermatology department, sibiu, romania 3 military emergency hospital sibiu, head and neck surgery department, sibiu, romania 4 synevo laboratory bucharest, pathology department, bucharest, romania key words: amelanotic, lentigo maligna melanoma, dermoscopy citation: popescu cm, barna c, metea a, andrei rt, taroi m. clinical, dermoscopic, and histopathologic aspects of amelanotic lentigo maligna melanoma. dermatol pract concept. 2021;11(4):e2021137. doi: https://doi.org/10.5826/dpc.1104a137. accepted: march 22, 2021; published: october, 2021 copyright: ©2021 popescu et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: corina barna, “alexandru augustin” military emergency hospital sibiu, sibiu, romania. email: corinabarna83@gmail.com introduction amelanotic melanomas represent 2% of all melanoma subtypes. amelanotic lentigo maligna and amelanotic lentigo maligna melanoma are rare entities. clinical suspicion is very low and the clinical differential diagnosis includes a variety of benign and malignant lesions such as basal cell carcinoma, squamous cell carcinoma, or dermatitis [1]. case presentation a 73-year-old woman presented with a 4-month history of a pink plaque with a white halo on the right cheek (figure 1). dermoscopic examination showed polymorphous vessels, milky red areas, and polarizing specific perpendicular white lines (figure 1, a-d). punch biopsy revealed a predominantly lentiginous proliferation within the basal layer of epidermis, with forming nests, consisting of epithelioid atypical cells, including areas of thinning of epidermis with loss of rete ridges, and indefinite borders. severe solar elastosis was present within the dermis. no melanin pigmentation was identified. tumor was excised and upon complete removal immunohistochemical analysis was carried out. the specimen shows a junctional amelanotic proliferation with a lentiginous pattern of growth (figure 2a), irregular nests formation with bridging of rete ridges (figure 2e), intraepidermal ascending cells, deep follicular extension and small foci of papillary dermal invasion (figure 2e). these features were confirmed by sox10 stains and melana (figure 2, b and c). diagnosis of amelanotic lentigo maligna melanoma was made with breslow thickness 0.7 mm. conclusion amelanotic lentigo maligna and amelanotic lentigo maligna melanoma are very rare with very low clinical suspicion and 2 letter | dermatol pract concept. 2021;11(4):e2021137 performing dermoscopy on pink lesions can help raise the suspicion of this diagnosis. to our knowledge, even if dermoscopic features of amelanotic melanoma have been described in several articles, there is no evidence reporting on dermoscopic findings of amelanotic lentigo maligna or amelanotic lentigo maligna melanoma. polarized dermoscopy allows better appreciation of deeper structures such as collagen and vessels. perpendicular white lines or shiny white streaks are shiny, bright, often orthogonal, linear streaks seen only with polarized light in dermatofibromas, scars, melanomas, basal cell carcinoma (bcc), and melanocytic naevi, especially spitz naevi [2]. dermoscopy is therefore a tool that helps distinguish between inflammatory pink lesions and tumoral pink lesions. even if they may be present in benign tumors, perpendicular white lines are also a clue to malignancy, although these were more commonly observed in invasive melanomas rather than thin melanomas [2]. nevertheless, the presence of perpendicular white lines could also represent a guide in the diagnosis of thin melanomas, especially those with few diagnostic criteria, as reported in this situation [2]. in conclusion, the presence of perpendicular white lines should lead to biopsy. in this particular case, the absence of clear-cut clinical and dermoscopic features for an alternative diagnosis was an additional reason for performing biopsy. diagnosis of amelanotic lentigo maligna melanoma can only be made by histopathology and immunohistochemical stains are very helpful in these cases. figure 1. (a) clinical aspect. pink plaque with white halo on the right cheek. (b) polarized dermoscopy of the entire lesion showing milky red areas, perpendicular white lines and polymorphous vessels. (c, d) polarized dermoscopy (detail) showing perpendicular white lines and polymorphous vessels. letter | dermatol pract concept. 2021;11(4):e2021137 3 references 1. perera e, mellick n, teng p, beardmore g. a clinically invisible melanoma. australas j dermatol. 2014;55(3):e58–e59. doi: 10.1111/ajd.12022. pmid: 23425084. figure 2. (a) junctional amelanotic proliferation with a lentiginous pattern of growth, intraepidermal ascending cells, and deep follicular extension (h&e). (b) sox10 stain. junctional amelanotic proliferation with a lentiginous pattern of growth, intraepidermal ascending cells, and deep follicular extension. (c) melana stain. junctional amelanotic proliferation with a lentiginous pattern of growth, intraepidermal ascending cells, and deep follicular extension. (d) junctional amelanotic proliferation with a lentiginous pattern of growth (h&e). (e) irregular nests formation with bridging of rete ridges and small foci of papillary dermal invasion (h&e). 2. shitara d, ishioka p, alonso-pinedo y, et al. shiny white streaks: a sign of malignancy at dermoscopy of pigmented skin lesions. acta derm venereol. 2014; 94: 132–137. doi: 10.2340/000155551683. pmid: 24002051. editorial | dermatol pract concept 2011;1(1):12 57 dermoscopy: a new perspective giuseppe argenziano, m.d.1, iris zalaudek, m.d.2 1 dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, italy 2 department of dermatology, medical university of graz, graz, austria citation: argenziano g, zalaudek i. dermoscopy: a new perspective. [editorial]. dermatol pract concept 2011;1(1):12. http://dx.doi. org/10.5826/dpc.0101a12. copyright: ©2011 argenziano et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: giuseppe argenziano, m.d., dermatology unit, medical department, arcispedale santa maria nuova, reggio emilia, via g. fiorelli 5, 80121 naples, italy. tel. +39.336.415.093. email: g.argenziano@gmail.com. editorial it is our great pleasure to accept the invitation of the editor-in-chief of dermatology practical & conceptual, our friend, harald kittler, to write some remarks regarding the aims and scopes of the new collaboration between the international dermoscopy society (ids) and dermatology practical & conceptual (dpc). the international dermoscopy society the ids was founded in 2003 to promote clinical research in dermoscopy and to represent a clinically oriented international organization with a thrust towards helping and improving education in dermoscopy. our membership is worldwide and currently more than 100 countries are represented, with individuals joining by direct application for free membership. our organization conducts a world congress every three years and sister society meetings every year during the aad congress in the usa and the eadv congress in europe. the dermatologist’s stethoscope by enabling visualization of anatomic structures below the epidermis, dermoscopy serves as a bridge between clinical observation and histopathology and offers clinicians an invaluable tool to detect early-stage skin cancers and resolve the diagnosis of clinically equivocal lesions. dermoscopy first began to gain widespread acceptance and use among dermatologists in the early 1990’s. the dermatoscopes that were commercially available then were large instruments that required an oil or alcohol interface to reduce light reflection. the market has expanded greatly since that time, and instruments that are now available range from inexpensive, handheld, cross-polarized, direct contact devices (requiring no immersion oil) to complex systems with video recording. the dermatoscope is increasingly used as the dermatologist’s stethoscope, not only because it reveals a new and fascinating morphologic dimension of pigmented and nonpigmented skin tumors but also because it improves the recognition of a growing number of skin symptoms in general dermatology. because of the growing number of dermoscopy indications, it is not a surprise that the use of this noninvasive diagnostic tool is spreading worldwide. as the number of dermoscopy users grows, the number of scientific publications on dermoscopy has also increased significantly. more than 1000 articles have been published between 2003 and 2007, three times the number of the previous five years, and about 1100 dermoscopy articles have been referenced in pubmed just in the last 3 1/2 years. the joint venture between the ids and dpc multiple resources are available to assist clinicians who decide to incorporate dermoscopy into their practice. the recently redesigned website of the ids (http://www.dermoscopy-ids.org/) is an educational resource in itself, with monthly cases, tutorials, podcasts, discussion forums, recent publications, and dermoscopy-related links, including links dermatology practical & conceptual www.derm101.com 58 editorial | dermatol pract concept 2011;1(1):12 to free tutorials. the recent collaboration with the editor-inchief of dpc brings to each of the 2500+ ids members the advantage of complimentary access to derm101.com (http:// www.derm101.com/), the largest online library of resources for the diagnosis and treatment of skin diseases. moreover, dpc has become the new official organ of the ids. the vision behind this was to give to the ids members and to researchers the possibility to read and publish articles in the field of dermoscopy that are of higher quality. dpc has opened, in fact, a new section on dermoscopy, edited by alon scope, ensuring more visibility for peer-reviewed and high quality papers in the field of this useful technique. the open-access format of dpc will ensure wider readership of its scientific, including those in the dermoscopy section. we are very confident that the collaboration between the ids and dpc will be a success and will contribute to the continued and widespread use of dermoscopy by clinicians throughout the globe. quiz | dermatol pract concept 2012;2(1):6 35 from the dermatologikum hamburg: quiz almut böer-auer, m.d.1 1 dermatologikum hamburg, germanya citation: böer-auer a. from the dermatologikum hamburg: quiz. dermatol pract conc. 2012;2(1):6. http://dx.doi.org/10.5826/dpc.0201a06. copyright: ©2011 böer-auer. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: almut böer-auer, m.d., dermatologikum hamburg, drehbahn 1–3, 20354 hamburg, germany. tel. +49. 40. 3510750. email: boer@dermatologikum.de. the patient a 78-year-old man presented with a keratotic and crusted plaque on the scalp (figure 1). he had a history of multiple actinic keratoses with various attempts at treatment. the lesion was excised under the clinical diagnosis of squamous cell carcinoma. photomicrographs of a section are presented in figures 2a–s. what is your diagnosis? answer and explanation erosive pustular dermatosis of the scalp the section pictured in figure 2a–s shows an eroded and partly ulcerated epidermis (figure 2g) covered by extensive scale crust housing numerous neutrophils (figure 2s). some dermatology practical & conceptual www.derm101.com neutrophils are scattered within the epidermis (figures 2d and 2h). a diffuse infiltrate of neutrophils, lymphocytes, plasma cells, and histiocytes is present in the dermis (figures 2i, 2a, 2q). fibrosis can be seen around infundibula of terminal hair follicles (figures 2m, 2o). out of the clinical context, these findings are not unequivocally diagnostic and bacterial infection, deep mycosis, or dissecting cellulitis of the scalp may be considered in the differential diagnosis. in correlation with the clinical picture of a large crusted lesion on the scalp, however, the changes have to be interpreted as erosive pustular dermatosis of the scalp. in this patient, the lesions worsened after the surgical procedure (figure 3a) and improved only with treatment with oral corticosteroids (figure 3b). erosive pustular dermatosis of the scalp (epds) was first described by pye and colleagues in 1979. they had observed six patients, all elderly women, who presented themselves with pustules and erosions on the scalp [1]. lesions were not responsive to antibiotics but resolved on topical treatment with potent corticosteroids. since 1979, a number of case reports and a few studies on patients with similar findings appeared in the literature of dermatology and have recently been reviewed [2]. clinical descriptions of patients diagnosed with erosive pustular dermatosis of the scalp are very similar. most patients were women presenting with crusts, pustules, and erosions on the scalp. in some patients, alopecia was said to have been accompanying. while many reports state that patients were elderly, a few reports told of patients less than 50 years of age. lesions were said to have been present for months or years in most patients.figure 1. clinical appearance. [copyright: ©2012 böer-auer.] 36 quiz | dermatol pract concept 2012;2(1):6 f ig u re 2 a –s . h is to p at h o lo gy . w h at i s yo u r d ia gn o si s? [c o p yr ig h t: © 2 0 1 2 b ö er -a u er .] s a b e h j n mc f i k o d g l p q r quiz | dermatol pract concept 2012;2(1):6 37 clinically, there are similarities between lesions of erosive pustular dermatosis of the scalp and folliculitis decalvans, but in the latter condition erosion is not a typical feature. moreover, male patients have been described with erosive pustular dermatosis of the scalp on sites affected also by androgenetic alopecia. in contrast, folliculitis decalvans is seen only on sites baring terminal hair follicles. histopathologic findings of erosive pustular dermatosis of the scalp are not presented in detail in most of the articles [2]. features mentioned included “atrophy of the epidermis,” “chronic inflammation,” “plasma cells,” and, occasionally, “polymorphous infiltration” and “spongiform pustules” [3]. even though clinical descriptions of the condition include alopecia as a common clinical feature, involvement of follicles is mentioned rarely in descriptions of histopathologic findings. pye et al, however, had emphasized destruction of follicles as a histopathologic finding [1]. just as in the case presented here, patients described in the literature often presented with a quite advanced stage of the disease, and it is not clear to date what early lesions looked like, i.e., whether pustulation started as an infundibulitis or within surface epidermis. a broad variety of events have been documented to evoke erosive pustular dermatosis of the scalp, among them being local trauma, synthetic fiber implantation, craniotomy for removal of a suprasellar meningioma, surgical excision and grafts for squamous cell carcinoma and basal cell carcinoma, cochlear implant surgery, co2 laser vaporization, radiation therapy, cryotherapy, photodynamic therapy, topical tretinoin, topical imiquimod, topical 5-fluorouracile to treat multiple actinic keratosis, gefitinib and radiotherapy for brain metastases, and zoster ophthalmicus [2,4–6]. in the patient presented here, one or more of the various attempts to treat actinic keratoses, such as photodynamic therapy and repeated shave excisions, might have been among the initiating events. the denominator all the possible cases mentioned is that they all represent damage to the tissue followed by local inflammation. the initiation of pustular dermatosis of the scalp by trauma, no matter of what kind, seems to suggest that the condition is mediated by a pathergic phenomenon, similar to the situation in pyoderma gangrenosum. the connection of erosive pustular dermatosis of the scalp to local trauma is a feature that differentiates it from folliculitis decalvans, a disease that develops without any previous tissue damage. in many patients diagnosed with erosive pustular dermatosis of the scalp, response to potent topical corticosteroids was favorable [2]. other medications that proved to be effective were other immunosuppressive agents such as acitretin, tacrolimus and calcipotriol [2,7,8]. failure to respond to antibiotic treatment militates strongly against a bacterial cause of the condition and against similarities in pathogenesis to folliculitis decalvans and its analogues. in patients diagnosed with erosive pustular dermatosis of the scalp who responded to oral administration of zinc, a possible differential diagnosis could be zinc deficiency, which may manifest itself also with pustules and erosions on the scalp. even though erosive pustular dermatitis of the scalp seems to be distinctive clinically and pathogenetically, histopathologic findings of the condition are still poorly characterized. the patient presented here illustrates, however, that a sure diagnosis can be made based on clinicopathological correlation.  figure 3. (a) exacerbation after excision and transplantation; (b) improvement on corticosteroids. [copyright: ©2012 böer-auer.] a b 38 quiz | dermatol pract concept 2012;2(1):6 references pye rj, peachey rd, burton jl. erosive pustular dermatosis of the scalp. br j dermatol. 1979;100(5):559–66. böer-auer a. new quandary: erosive pustular dermatosis of the scalp? dermatopathology: practical & conceptual. 2010;16(2):8. http://www.derm101.com/content/66982. noé c, grob jj, choux r, bonerandi jj. [erosive pustulosis of the scalp. a spongiform pustular dermatosis?] ann dermatol venereol. 1993;120(10):693–5. grattan ce, peachey rd, boon a. evidence for a role of local trauma in the pathogenesis of erosive pustular dermatosis of the scalp. clin exp dermatol. 1988;13(1):7–10. ena p, lissia m, doneddu gm, campus gv. erosive pustular dermatosis of the scalp in skin grafts: report of three cases. dermatology. 1997;194(1):80–4. rongioletti f, delmonte s, rossi me, strani gf, rebora a. erosive pustular dermatosis of the scalp following cryotherapy and topical tretinoin for actinic keratoses. clin exp dermatol. 1999;24(6):499–500. darwich e, muñoz-santos c, mascaró jm jr. erosive pustular dermatosis of the scalp responding to acitretin. arch dermatol. 2011;147(2):252–3. kim kr, lee jy, kim mk, yoon ty. erosive pustular dermatosis of the scalp following herpes zoster: successful treatment with topical tacrolimus. ann dermatol. 2010;22(2):232–4. observation | dermatol pract concept 2012;2(1):5 31 nodules on the right ear carolina talhari, m.d.1, alexandra maria giovanna brunasso, m.d.2,3, sinesio talhari, m.d.1, cesare massone, m.d.4 1 department of dermatology, institute of tropical medicine, manaus, brazil 2 division of environmental dermatology and venereology, medical university of graz, graz, austria 3 department of dermatology, galliera hospital, genoa, italy 4 division of general dermatology, medical university of graz, graz, austria key words: nodule, ear, mycosis, lobomycosis citation: talhari c, brunasso amg, talhari s, massone c. nodules on the right ear. dermatol pract conc. 2012;2(1):5. http://dx.doi.org/10.5826/dpc.0201a05. editor: harald kittler, m.d. received: june 2, 2011; accepted: july 20, 2011; published: january 31, 2012 copyright: ©2012 talhari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cesare massone, m.d., department of dermatology, medical university of graz, auenbruggerplatz 8, a-8036 graz, austria. tel. +43.316.385.3235; fax. +43.316.385.4957. email: cesare.massone@klinikum-graz.at. case report a healthy 17-year-old boy with a one-year history of asymptomatic, slowly enlarging nodules affecting his right ear was seen. the patient’s past medical history was unremarkable, he was not immunosuppressed, he was not taking any drugs, and he was employed as a rubber worker in the amazon region. physical examination revealed ill-defined, smooth, shiny, hard nodules on his right ear (figure 1). the consistency of the skin lesions was hard, and pain was absent. regional lymph nodes were not enlarged. laboratory examination showed unremarkable complete blood count, urinalysis, hepatic and renal function tests, serum glucose, elisahiv and erythrocyte sedimentation rate. chest x-rays were normal. histopathologic examination showed a diffuse granulomatous infiltrate involving the entire dermis, constituted by histiocytes and multinucleated giant cells (figures 2, 3). the histiocyte’s cytoplasm contained rounded yeast-like hyaline cells with a thick double birefringent membrane. these cells were forming chains of multiple organisms. the grocottdermatology practical & conceptual www.derm101.com figure 1. multiple, non-ulcerated nodules and plaques on the right ear. [copyright: ©2012 talhari et al.] 32 observation | dermatol pract concept 2012;2(1):5 gomori methenamine-silver nitrate stain allowed better visualization of chains of darkly pigmented, spheroidal, yeastlike organisms (figure 4). what is your diagnosis? answer localized lobomycosis discussion lobomycosis, described by jorge lobo, is a deep chronic cutaneous, non-life threatening mycosis restricted to areas of the amazon, a region characterized by tropical rainy weather [1-3]. the agent of lobomycosis is lacazia loboi, an intracellular spherical yeast of 8-12 nm of diameter that resides in macrophage vacuoles [4]. the fungus is easily found in lobomycotic skin lesions but it has never been cultivated [4]. the precise natural reservoir of l. loboi is unknown, but soil and vegetation seem to be probable sources of infection [1-3]. the disease can be found in dolphins and is more prevalent in human beings that live near aquatic environments, suggesting that l. loboi is an hydrophilic fungus [1,2,5]. the disease affects mostly young, non–immune suppressed, male patients between 21-40 years of age [1-3]. the direct inoculation into the dermis is probably the way of transmission [4]. the incubation period is long and the infection often goes through a quiescent period (months to years) [3]. the lesions often begin as small papules or pustules associated with a burning sensation or mild pruritus [6]. the lack of other systemic involvement is characteristic [1,6]. the typical keloid-like skin lesions appear only after several months and the typical appearance is ‘‘keloids over keloids’’ [1-3,6]. lesions have well defined margins, are not attached to deeper structures, and can disseminate by contiguity or by auto-inoculation [1]. the process of dissemination lasts several decades. clinical differential diagnosis of lobomycosis includes lepromatous leprosy, chromoblastomycosis, keloids, xanthomas, fibromas, kaposi’s sarcoma, neurofibromas and dermatofibrosarcoma protuberans [1]. moreover, in our specific case, the differential diagnosis includes leprosy, relapsing polychondritis, indolent cd8+ lymphoid proliferation of the ear, and borrelia lymphocytoma (noted only from an academically point of view; the amazon is not endemic for borrelia infection). the fungus load on skin smears is usually very large with a high number of rounded cells that do not need to be stained. skin sections are characterized by a diffuse granulomatous dermatitis involving the entire dermis and extending to the figure 2. diffuse granulomatous infiltrate involving the entire dermis (haematoxilin and eosin [h&e], original magnification: 20x). [copyright: ©2012 talhari et al.] figure 3. the histiocyte’s cytoplasm contains rounded yeast-like hyaline cells with a thick double birefringent membrane. these cells are forming chains of multiple organisms. (h&e, original magnification: 400x). [copyright: ©2012 talhari et al.] figure 4. the grocott-gomori methenamine-silver nitrate stain shows chains of darkly pigmented, spheroidal, yeast-like organisms (original magnification: 200x). [copyright: ©2012 talhari et al.] observation | dermatol pract concept 2012;2(1):5 33 subcutaneous fat [7]. the grocott’s stain allows the visualization of chains of darkly pigmented, spheroidal, yeast-like organisms with thick (double) birefringent walls [7]. treatment is very problematic in heavily infected patients with many large lesions [3]. prompt diagnosis and treatment are mandatory in order to obtained a high cure rate [1,3]. the most successful treatment option is a wide surgical excision, but relapses are common [1]. systemic therapy with clofazimine has been successfully used [8]. other reported therapies are ketoconazole, itraconazole, amphotericin b, and 5-fluorocytosine [1,8]. in our patient the nodules were partially excised, he was given itraconazole 200 mg for 8 months, and is still undergoing therapy. references 1. talhari s. doenca de jorge lobo. in: talhari s, garrido neves r, eds. dermatologia tropical. rio de janeiro: ed medsi, 1997:237– 53. 2. talhari s, cunha mg, schettini ap, talhari ac. deep mycoses in amazon region. int j dermatol. 1988;27(7):481–4. 3. lupi o, madkan v, tyring sk. tropical dermatology: bacterial tropical diseases. j am acad dermatol. 2006;54(4):559–78. 4. taborda pr, taborda va, mcginnis mr. lacazia loboi gen. nov., comb. nov., the etiologic agent of lobomycosis. j clin microbiol. 1999;37(6):2031–3. 5. haubold em, aronson jf, cowan df, mcginnis mr, cooper cr jr. isolation of fungal rdna from bottlenose dolphin skin infected with loboa loboi. med mycol. 1998;36(5):263–7. 6. silva d. estudo experimental da micose de lobo. an bras dermatol. 1994;69:88–91. 7. opromolla dva, belone aff, taborda pro, taborda vba. [clinico-pathological correlation in 40 cases of lobomycosis]. an bras dermatol. 2000;75:425–34. 8. fischer m, chrusciak talhari a, reinel d, talhari s. successful treatment with clofazimine and itraconazole in a 46 year old patient after 32 years duration of disease. hautarzt. 2002;53(10):677–81. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):10 43 dermatology practical & conceptual www.derm101.com early diagnosis of genital mucosal melanoma: how good are our dermoscopic criteria? tova rogers, mfa1, melissa pulitzer, md2, maria l. marino, md1, ashfaq a. marghoob, md1, oliver zivanovic, md3, michael a. marchetti, md1 1 dermatology service, memorial sloan kettering cancer center, new york, ny, usa 2 pathology service, memorial sloan kettering cancer center, new york, ny, usa 3 gynecology service, department of surgery, memorial sloan kettering cancer center, new york, ny, usa key words: melanoma, genital, mucosal melanoma, dermoscopy citation: rogers t, pulitzer m, marino m, marghoob a, zivanovic o, marchetti m. early diagnosis of genital mucosal melanoma: how good are our dermoscopic criteria? dermatol pract concept 2016;6(4):10. doi: 10.5826/dpc.0604a10 received: april 28, 2016; accepted: july 25, 2016; published: october 31, 2016 copyright: ©2016 rogers. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: michael a. marchetti, md, dermatology service, department of medicine, memorial sloan kettering cancer center, 16 e 60th street, new york 10065, usa. tel. 646-888-6016; fax: 646-888-6478. email: marchetm@mskcc.org background: there are limited studies on the dermoscopic features of mucosal melanoma, particularly early-stage lesions. described criteria include the presence of blue, gray, or white colors, with a reported sensitivity of 100%. it is unclear if these features will aid in the detection of early mucosal melanoma or improve diagnostic accuracy compared to naked-eye examination alone. case: an asian female in her fifties was referred for evaluation of an asymptomatic, irregularly pigmented patch of the clitoral hood and labia minora of unknown duration. her past medical history was notable for stage iv non-small cell lung cancer. she denied a personal or family history of skin cancer. dermoscopic evaluation of the vulvar lesion revealed heterogeneous brown and black pigmentation mostly composed of thick lines. there were no other colors or structures present. as the differential diagnosis included vulvar melanosis and mucosal melanoma, the patient was recommended to undergo biopsy, which was delayed due to complications from her underlying lung cancer. repeat dermoscopic imaging performed three months later revealed significant changes concerning for melanoma, including increase in size, asymmetric darkening, and the appearance of structureless areas and central blue and pink colors. histopathological examination of a biopsy and subsequent resection confirmed the diagnosis of melanoma in situ. conclusion: previously described dermoscopic features for mucosal melanoma may not have high sensitivity for early melanomas. additional studies are needed to define the dermoscopic characteristics of mucosal melanomas that aid in early detection. health care providers should have a low threshold for biopsy of mucosal lesions that show any clinical or dermoscopic features of melanoma, especially in older women. abstract mailto:marchetm@mskcc.org 44 observation | dermatol pract concept 2016;6(4):10 on examination, a 12 x 13 mm, irregular, dark brownblack patch was noted on her clitoral hood and labia minora (figure 1). ill-defined, patchy, light brown pigmentation on bilateral labia minora was also observed. there was no lymphadenopathy on palpation of the inguinal and femoral nodal basins. dermoscopic evaluation of the lesion was performed using polarized contact dermoscopy with ultrasound gel and a polyvinyl chloride barrier. it revealed heterogeneous brown and black pigmentation composed of thick lines without other structures (figure 2a). there was no evidence of blue, gray, or white colors or other dermoscopic features reported to be specific for the diagnosis of melanoma. the differential included mucosal melanosis and melanoma. given the atypical clinical appearance of a large, asymmetric, pigmented macule with color variegation, a biopsy was recommended but was delayed due to complications from the patient’s underlying malignancy. on follow-up examination three months later, repeat dermoscopic imaging with polarized contact dermoscopy using ultrasound gel and a polyvinyl chloride barrier revealed significant changes concerning for melanoma, including increase in size, asymmetric darkening, and the appearance of structureless areas and central blue and pink colors (figure 2b). histopathological examination of an incisional biopsy and subsequent excision revealed melanoma in situ with a characteristic proliferation of enlarged, poorly nested and confluent, severely atypical melanocytes. other notable histopathologic findings included skipping foci of heavily pigmented dermal melanophages, variable lichenoid inflammatory infiltrate, and marked vascular ectasia and congestion (figure 3). case report an asian female in her fifties was referred for evaluation of an asymptomatic, pigmented vulvar lesion of unknown duration. she denied a personal or family history of skin cancer. her past medical history was notable for stage iv non-small cell lung cancer diagnosed nine months prior and managed with surgery and oral erlotinib. figure 2. polarized contact dermoscopic images of vulvar melanoma in situ. (a) baseline dermoscopic image showed heterogeneous and asymmetric brown and black pigmentation composed of thick lines. (b) repeat dermoscopic imaging three months later showed increase in size, asymmetric and multifocal darkening, and the appearance of structureless areas and central blue and pink colors. [copyright: ©2016 rogers.] figure 1. clinical appearance of vulvar melanoma in situ showed 12 x 13 mm asymmetric patch with color variegation on the clitoral hood and labia minora. [copyright: ©2016 rogers.] observation | dermatol pract concept 2016;6(4):10 45 clinically, vm can present as flat or raised lesions with irregular borders and are often greater than 7 mm in size [7]. a majority of vm are pigmented, however, amelanotic vm accounts for 4% to 27% of cases [2,4]. late symptoms include bleeding and pruritus, while many lesions, especially early lesions, can be asymptomatic [2]. most vm are diagnosed at locally advanced stages. a 2015 study that included 63 cases of vm demonstrated a median breslow thickness at presentation of 3.3 mm (range: 0-20mm) [1]. regional nodal disease is not uncommon at presentation [4]. the most common histological subtypes of vm are superficial spreading and nodular [1,8]. compared to cutaneous melanoma, vm show distinct genetic mutations. a 2014 study evaluating the genetic profiles of vm found kit mutations in 18% of cases (7/39) and nras mutations in 12% of cases (5/42). no mutations in braf (0/39) or egfr (0/30) were found [9]. the overall prognosis of vm is worse than that for cutaneous melanoma, with 61% versus 91% fiveyear melanoma-specific survival rates, respectively [8]. it is conclusion vulvar melanoma (vm) accounts for 1% to 3% of all melanomas arising in women [1]. it most frequently occurs in the fifth or sixth decade of life, suggesting that clinicians should have a heighted suspicion for melanoma when evaluating pigmented mucosal lesions in older women [2-4]. the incidence is slightly higher in caucasians compared to hispanics, asians, blacks, and american-indians [5]. risk factors include chronic inflammation, such as that associated with lichen sclerosis [6]. the differential diagnosis of pigmented vulvar lesions includes vulvar nevi and vulvar melanosis (also referred to as vulvar lentiginosis or vulvar melanotic macule), particularly in younger individuals. vulvar nevi tend to present clinically as evenly pigmented papules or macules with regular borders. their colors range from red to dark brown-black and they typically measure less than 1 cm. vulvar melanosis is characterized by single or multiple, irregularly pigmented, tan to black macules or patches with uneven borders [6]. figure 3. histopathology of vulvar melanoma in situ. (a) photomicrograph of initial biopsy specimen showing a broad, asymmetric, junctional melanocytic proliferation with variable epidermal acanthosis and dermal clusters of heavily pigmented melanophages (hematoxylineosin stain, original magnification x100). (b, c, d) images of excised specimen showing confluent, severely atypical melanocytes with pagetoid spread (b), hematoxylin-eosin stain, original magnification x400), areas with lichenoid lymphoid infiltrates and melanophages (c), hematoxylin-eosin stain, original magnification x200), and the intersection of congested and ectatic vasculature with dermal melanophages and junctional melanoma (d), hematoxylin-eosin stain, original magnification x200). [copyright: ©2016 rogers.] 46 observation | dermatol pract concept 2016;6(4):10 4. dematos p, tyler d, seigler hf. mucosal melanoma of the female genitalia: a clinicopathologic study of forty-three cases at duke university medical center. surgery. 1998;124(1):38-48. pmid: 9663250. 5. hu dn, yu gp, mccormick sa. population-based incidence of vulvar and vaginal melanoma in various races and ethnic groups with comparisons to other site-specific melanomas. melanoma res 2010;20(2):153-8. pmid: 20147857. doi: 10.1097/ cmr.0b013e32833684e8. 6. murzaku ec, penn la, hale cs, pomeranz mk, polsky d. vulvar nevi, melanosis, and melanoma: an epidemiologic, clinical, and histopathologic review. j am acad dermatol 2014;71(6):1241-9. pmid: 25267379. doi: 10.1016/j.jaad.2014.08.019. 7. murzaku ec, hayan s, rao bk. methods and rates of dermoscopy usage: a cross-sectional survey of us dermatologists stratified by years in practice. j am acad dermatol 2014;71(2):393-5. pmid: 25037790. doi: 10.1016/j.jaad.2014.03.048. 8. tcheung wj, selim ma, herndon je 2nd, abernethy ap, nelson kc. clinicopathologic study of 85 cases of melanoma of the female genitalia. j am acad dermatol 2012;67(4):598-605. pmid: 22243767. doi: 10.1016/j.jaad.2011.11.921. 9. aulmann s, sinn hp, penzel r, et al. comparison of molecular abnormalities in vulvar and vaginal melanomas. mod pathol 2014;27(10):1386-93. pmid: 24603591. doi: 10.1038/modpathol.2013.211. 10. ragnarsson-olding bk. primary malignant melanoma of the vulva—an aggressive tumor for modeling the genesis of non-uv light-associated melanomas. acta oncol 2004;43(5):421-35. pmid: 15360046. 11. blum a, simionescu o, argenziano g, et al. dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the international dermoscopy society (ids). arch dermatol 2011;147(10):1181-7. pmid: 21680757. doi: 10.1001/archdermatol.2011.155. 12. de giorgi v, massi d, salvini c, mannone f, cattaneo a, carli p. thin melanoma of the vulva: a clinical, dermoscopic-pathologic case study. arch dermatol 2005;141(8):1046-7. pmid: 16103344. doi: 10.1001/archderm.141.8.1046. 13. lin j, koga h, takata m, saida t. dermoscopy of pigmented lesions on mucocutaneous junction and mucous membrane. br j dermatol 2009;161(6):1255-61. pmid: 19673880. doi: 10.1111/j.1365-2133.2009.09251.x. 14. ferrari a, buccini p, covello r, et al. the ringlike pattern in vulvar melanosis: a new dermoscopic clue for diagnosis. arch dermatol 2008;144(8):1030-4. pmid: 18711077. doi: 10.1001/ archderm.144.8.1030. 15. mannone f, de giorgi v, cattaneo a, massi d, de magnis a, carli p. dermoscopic features of mucosal melanosis. dermatol surg 2004;30(8):1118-23. pmid: 15274702. doi: 10.1111/j.15244725.2004.30337.x. 16. ronger-savle s, julien v, duru g, raudrant d, dalle s, thomas l. features of pigmented vulval lesions on dermoscopy. br j dermatol 2011;164(1):54-61. pmid: 20846309. doi: 10.1111/j.13652133.2010.10043.x. 17. betti r, menni s, crosti c. melanoma of the glans penis. euro j dermatol 2005;15(2):113-5. pmid: 15757826. unclear if the poorer prognosis associated with vm is due to later detection or more aggressive biological behavior [10]. dermoscopic features of vm have been described. blum et al evaluated 11 cases of vm, 10 of which were invasive, and found that the presence of blue, gray, or white colors with or without structureless areas had 100% sensitivity for melanoma [11]. de giorgio et al described a case of superficial spreading melanoma of the vulva with a breslow depth of 0.5 mm that presented with a blue-gray area and whitish veil [12]. lin et al evaluated the dermoscopic features of 40 pigmented mucosal lesions in japanese patients, including 8 melanomas, 2 of which were vulvar. they found that 6 of the 8 melanomas (75%), including both vulvar lesions, had multicomponent patterns. the vulvar lesions also had multiple colors and blue-white veils [13]. these findings are in contrast to the described dermoscopic features of vulvar melanosis, which include a ring-like pattern, a homogeneous or structureless pattern, a reticular pattern, and a globular pattern [14-16]. a limitation of the studies evaluating the dermoscopic morphologies of mucosal melanoma is that the studied lesions were clinically detected and often of an advanced stage; it is therefore unknown if the application of these criteria will aid in the detection of early mucosal melanomas. consistent with this limitation, betti et al described a case of melanoma in situ on the glans penis with an irregular pigment network but no other worrisome features [17]. in order to not miss an opportunity for early detection of mucosal melanoma, health care providers should have a low threshold for biopsy of lesions that demonstrate any clinical or dermoscopic features concerning for melanoma. this is especially true for older patients. larger studies are needed to more rigorously define clinical and dermoscopic criteria that accurately distinguish early mucosal melanomas from benign skin lesions. references 1. seifried s, haydu le, quinn mj, scolyer ra, stretch jr, thompson jf. melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases. ann surg oncol 2015;22(6):1959-66. pmid: 25384702. doi: 10.1245/s10434-014-4215-3. 2. dunton cj, berd d. vulvar melanoma, biologically different from other cutaneous melanomas. lancet 1999;354(9195):2013-4. pmid: 10636360. doi: 10.1016/s0140-6736(99)00390-6. 3. sanchez a, rodriguez d, allard cb, et al. primary genitourinary melanoma: epidemiology and disease-specific survival in a large population-based cohort. urol oncol 2016;34(4):166.e7-14. pmid: 26739672. doi: 10.1016/j.urolonc.2015.11.009. https://www.ncbi.nlm.nih.gov/pubmed/15274702 https://www.ncbi.nlm.nih.gov/pubmed/20846309 dermatology: practical and conceptual observation | dermatol pract concept 2016;6(3):11 55 dermatology practical & conceptual www.derm101.com case presentation a 72-year-old male with a recent diagnosis of acute myeloid leukemia (aml) had been commenced on chemotherapy— daunorubicin and cytarabine. he was also on ciprofloxacin, posaconazole and acyclovir for antimicrobial prophylaxis. within forty-eight hours of starting chemotherapy, he developed fever of 40oc and was commenced on piperacillin-tazobactam. on day 4 of chemotherapy a rash was noted. he was pancytopenic with an absolute neutrophil count of 0.34x109/l and a platelet count of 20x109/l. c-reactive protein was raised at 322mg/l and a septic screen two neutrophilic dermatoses captured simultaneously on histology christina wlodek1, nidhi bhatt2, cameron kennedy1 1 department of dermatology, bristol royal infirmary, bristol, uk 2 department of pathology, bristol royal infirmary, bristol, uk key words: neuturopilic dermatosis, neutrophilic eccrine hidradenitis, sweet’s syndrome citation: wlodek c, bhatt n, kennedy c. two neutrophilic dermatoses captured simultaneously on histology. dermatol pract concept 2016;6(3):11. doi: 10.5826/dpc.0603a11 received: december 14, 2015; accepted: may 27, 2016; published: july 31, 2016 copyright: ©2016 wlodek et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: christina wlodek, bsc, mbbs, bristol royal infirmary, department of dermatology, upper maudlin street, bristol bs2 8hw, united kingdom. tel. 0117 923 000; fax. 0117 342 2845. email: christina.wlodek@gmail.com a number of neutrophilic dermatoses are associated with malignancies and their treatment. these rarely occur together in the same patient. a caucasian 72-year-old male was treated for acute myeloid leukemia (aml) with chemotherapy including daunorubicin and cytarabine. within 48 hours of commencing treatment, he developed pyrexia and, two days later, disseminated non-tender pink plaques on the limbs and trunk. a skin biopsy showed a dermal interstitial infiltrate of lymphocytes, histiocytoid cells and predominantly neutrophils. this extended into the subcutis, where a neutrophilic lobular panniculitis was seen. these findings are consistent with sweet’s syndrome. in addition, a neutrophilic and lymphocytic infiltrate was also present around eccrine coils and lower ducts. the eccrine epithelium showed squamous metaplasia with dyskeratosis and sloughing into the lumen. these latter findings are consistent with neutrophilic eccrine hidradenitis (neh). these two histologically distinct entities form part of the neutrophilic dermatoses that have been described in oncology patients with reports of concurrent or sequential occurrence of various neutrophilic dermatoses in the same patient. ours, however, is only the second reported case of simultaneously captured sweet’s and neh in the setting of aml. the most likely explanation is that of an epiphenomenon, whereby the neutrophilic infiltrate extended around the sweat glands in the context of the neutrophilic dermatosis. abstract 56 observation | dermatol pract concept 2016;6(3):11 (figure 2b) with dyskeratosis and sloughing into the lumen. surrounding these changes there was a neutrophilic and lymphocytic infiltrate. fungal, bacterial and mycobacterial cultures were negative. to our knowledge this is only the second reported case of concomitant sweet-like neutrophilic dermatosis and neutrophilic eccrine hidradenitis (neh) in the setting of aml. since the original description by r. d. sweet in 1964, acute febrile neutrophilic dermatosis (sweet’s syndrome) is known to be associated with leukemia and in particular the acute myelomonocytic type [1]. histology typically demonstrates a dense infiltrate of mature neutrophils in the upper half of the dermis but the location of the infiltrate can vary. less commonly the neutrophils are perivascular. neutrophils can also migrate into the epidermis or underlying adipose tissue [2]. to the best of our knowledge there are no literature reports of the neutrophilic infiltrate involving the eccrine glands. was negative. granulocyte-colony stimulating factor was not administered. at the time of dermatology review, the patient had been pyrexial for four days. he had disseminated non-tender pink plaques on the limbs and trunk. some lesions were imminently vesicular while others hemorrhagic. since the rash was asymptomatic no treatment was felt necessary. an incisional biopsy was performed. within 7 days the eruption resolved. the skin biopsy showed subepidermal edema (figure 1a), with no interface damage. there was extensive red cell extravasation in the dermis and an interstitial infiltrate of lymphocytes, histiocytoid cells and predominantly neutrophils. this extended into the subcutis, where a neutrophilic lobular panniculitis was seen. there was no evidence of vasculitis (figure 1b). a second striking abnormality was centered around the eccrine coils and lower ducts (figure 2a). the eccrine epithelium showed squamous metaplasia figure 1. (a) a scanning power view showing subepidermal edema and a diffuse infiltrate throughout the dermis and subcutis. (b) high power view of neutrophils within the dermis. note the absence of vasculitis. hematoxylin and eosin, original magnification (a) x40 (b) x100. [copyright: ©2016 wlodek et al.] figure 2. (a) high power view of neutrophilic infiltration of eccrine sweat glands (arrows) and epithelial necrosis (circled) together with intraluminal necrotic eosinophilic debris (*). (b) upper part of eccrine duct showing squamous metaplasia (circled). hematoxylin and eosin, original magnification (a) x200 (b) x300. [copyright: ©2016 wlodek et al.] observation | dermatol pract concept 2016;6(3):11 57 of pathological changes described has expanded. there can be variability in the composition of the infiltrate as well as its depth. we could hypothesize that this case describes yet a further expansion of the pathological description. however, the occurrence of these two entities concurrently, in this same patient, is not entirely unexpected. the patient had a hematological malignancy well known to be associated with sweet’s syndrome and at the same time was receiving an agent, cytarabine, that has a well-established association with neh. thus we feel the most likely explanation is that of an epiphenomenon, where by the neutrophilic infiltrate has extended around the sweat glands in the context of the neutrophilic dermatosis. references 1. cohen pr. sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. orphanet j rare dis 2007;2(1):34. pmid: 17655751. doi: 10.1186/1750-1172-2-34. 2. cohen pr, kurzrock r. sweet’s syndrome revisited: a review of disease concepts. int j dermatol 2003;42(10):761-78. pmid: 14521689. doi: 10.1046/j.1365-4362.2003.01891.x. 3. greer ke, cooper ph. sweet’s syndrome (acute febrile neutrophilic dermatosis). clin rheum dis 1982;8(2):427-41. pmid: 6754235. 4. harrist tj, fine jd, berman rs, murphy gf, mihm mc, jr. neutrophilic eccrine hidradenitis. a distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. arch dermatol 1982;118(4):263-6. pmid: 6950689. doi: 10.1001/archderm.1982.01650160053024. 5. allegue f, soria c, rocamora a, munoz e, et al. neutrophilic eccrine hidradenitis in two neutropenic patients. j am acad dermatol 1990;23(6 pt 1):1110-3. pmid: 2273110. 6. kuttner bj, kurban rs. neutrophilic eccrine hidradenitis in the absence of an underlying malignancy. cutis 1988;41(6):403-5. pmid: 3391045. 7. cohen pr. neutrophilic dermatoses occurring in oncology patients. int j dermatol 2007;46(1):106-11. pmid: 17214733. doi: 10.1111/j.1365-4632.2006.02605.x. 8. gross pr, margolis d. neutrophilic dermatosis versus neutrophilic eccrine hidradenitis. n engl j med 1999;340(17):1371. pmid: 10223880. doi: 10.1056/nejm199904293401718. 9. zehani a, chelly i, abdelmalek r, et al. [adult idiopathic neutrophilic eccrine hidradenitis mimicking sweet’s syndrome]. tunis med 2013;91(5):366-7 pmid: 23716340. a few lymphocytes are typically present in older lesions, in a perivascular pattern. vasculitis is usually absent [3], although a secondary leukocytoclastic vasculitis has been described in several cases [2]. neh is a more recently characterized entity—first reported in a patient treated with cytarabine for aml [4]. since then, other malignancies and chemotherapeutic agents have been implicated. the histological hallmark is a neutrophilic infiltrate around and within eccrine secretory coils often associated with vacuolar degeneration and even necrosis of the secretory epithelium. the neh literature does not report any neutrophilic infiltrates away from the eccrine sweat glands. in the setting of neutropenia the infiltrate may be sparse [5]. squamous metaplasia is occasionally seen. the pathologic mechanism of neh remains unclear. it was postulated to be linked to the high concentrations of chemotherapy drugs secreted into eccrine glands, however cases of neh have been seen in the absence of chemotherapy and aml [6]. these two histologically distinct entities form part of the neutrophilic dermatoses that have been described in oncology patients. there are reports of concurrent or sequential occurrence of various neutrophilic dermatoses in the same patient [7]. however, ours is the second reported case of simultaneous sweet-like neutrophilic dermatosis and neh. there is a case similar to ours where there was a background of aml treated with chemotherapy, including cytarabine, in a patient with both sweet’s and neh. the patient suffered a recurrence of the eruption when a relapse of the aml was treated with chemotherapy, but did not have a recurrence when consolidation chemotherapy was given during remission [8]. our patient did have a recurrence of aml 8 weeks after completing his second cycle of chemotherapy. since then he has been on azacitidine (an antimetabolite) to control disease progression. to date he has not experienced a recurrence of the cutaneous eruption. another case of concomitant sweet’s plus neh reported in the tunisian literature appeared to be idiopathic [9]. conclusion since sweet’s syndrome was initially recognized, the spectrum dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020063 1 dermatology practical & conceptual introduction langerhans cell histiocytosis (lch) is a dysfunction and proliferation of langerhans cells that cause a polymorphic disease depending on the affected organs [1]. we present the dermoscopic appearance of congenital lch. case presentation a healthy-appearing preterm newborn presented with multiple erythematous and violaceous maculopapular and nodular skin lesions scattered over trunk, face, scalp, nails, palms, and soles. the lesions were purplish-brownish, elastic, and not ulcerated. no other abnormalities were found. the lesions presented with variable clinical and dermoscopic appearance depending on the stage. the most striking finding was the presence of reddish lilac pigmentation of nodular lesions with the presence of peripheral violaceous vessels resembling a solar eclipse (figure 1). the majority of small papules showed multiple violaceous lacunae and clods over a light brown background; others presented a central scar-like area surrounded by whitish streaks (figure 2). histopathology confirmed the diagnosis of lch, presenting diffuse proliferation of histiocytes in the reticular dermis surrounded by ectatic vessels (figure 3). immunohistochemical staining results for s100, cd1a, and langerin were dermoscopy of congenital langerhans cell histiocytosis ramon pigem,1 ariann dyer,1 sebastian podlipnik,1 cristina carrera,1 susana puig,1 juan ferrando1 1 department of dermatology, hospital clínic, universitat de barcelona, barcelona, spain key words: langerhans cell, histiocytosis, solar eclipse, dermoscopy citation: pigem r, dyer a, podlipnik s, carrera c, puig s, ferrando j. dermoscopy of congenital langerhans cell histiocytosis. dermatol pract concept. 2020;10(3):e2020063. doi: https://doi.org/10.5826/dpc.1003a63 accepted: march 28, 2020; published: june 29, 2020 copyright: ©2020 pigem et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ramon pigem, md, department of dermatology, hospital clínic of barcelona, villarroel, 170 (08036) barcelona, spain. email: rpigem@clinic.cat figure 1. dermoscopic examination of a lesion in the fully developed stage. the dark pigmentation in the center and the violaceous vessels on the periphery resemble a solar eclipse over a starry sky. note the burgundy color of the vessels. https://doi.org/10.5826/dpc.1003a63 mailto:rpigem@clinic.cat 2 letter | dermatol pract concept 2020;10(3):e2020063 2. song m, kim sh, jung ds, ko hc, kwon ks, kim mb. structural correlations between dermoscopic and histopathological features of juvenile xanthogranuloma. j eur acad dermatol venereol. 2011;25(3):259-263. https://doi.org/10.1111/j.14683083.2010.03819.x positive. electron microscopy showed large histiocytes with reniform nuclei and birbeck and vermiform bodies (figure 4). conclusions dermoscopically characteristic lilac pigmentation and multiple burgundy round lacunae on the periphery were seen in our case. especially when the lesions are in the fully developed stage, the dermoscopic image resembles a solar eclipse. there could be a parallel between this sign and the “setting sun” appearance described in early evolutionary and fully developed stages of juvenile xanthogranuloma (non-langerhans cell histiocytosis) [2]. references 1. shaffer mp, walling hw, stone ms. langerhans cell histiocytosis presenting as blueberry muffin baby. j am acad dermatol. 2005;53(2 suppl 1):s143-s146. https://doi.org/10.1016/j. jaad.2005.01.015 figure 2. dermoscopic examination of 2 different lesions. (a) lesion in the early evolutionary stage with multiple violaceous lacunae and mild brown pigmentation. (b) different lesion in the late regressive stage with central scar surrounded by whitish streaks and an eccentric focus of residual pigmentation. figure 3. h&e-stained biopsy showing a dense dermal infiltrate of large histiocytes with pale cytoplasm and ectatic vessels in the dermis. original magnification ×40. figure 4. (a) electron microscopy shows birbeck and vermiform bodies. (b) large histiocytes with reniform nuclei were also observed. https://doi.org/10.1111/j.1468-3083.2010.03819.x https://doi.org/10.1111/j.1468-3083.2010.03819.x https://doi.org/10.1016/j.jaad.2005.01.015 https://doi.org/10.1016/j.jaad.2005.01.015 dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021011 1 dermatology practical & conceptual usefulness of topical imiquimod 3.75% in cytokeratin 7 positive extramammary paget disease of the vulva: towards personalized therapy sara mazzilli1, annunziata dattola1, anna angela criscuolo2, terenzio cosio1, luca bianchi1, elena campione1, monia di prete3, elisabetta botti2  1 dermatology unit, department of systems medicine, university of rome tor vergata, italy  2 department of gynecology, university of rome tor vergata, italy  3 anatomical pathology, university of rome tor vergata, italy  key words: imiquimod, extramammary paget disease, vulva, cytokeratin 7 citation: usefulness of topical imiquimod 3.75% in cytokeratin 7 positive extramammary paget disease of the vulva: towards personalized therapy. dermatol pract concept. 2021;11(2):e2021011. doi: https://doi.org/10.5826/dpc.1102a11 accepted: august 8, 2020; published: march 8, 2021 copyright: ©2021 mazzilli et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sara mazzilli, md, dermatologic unit, department of systems medicine, university of rome tor vergata, 00133 rome, italy. email: saramazzilli2@gmail.com introduction extramammary paget disease (empd) of the vulva, a rare adenocarcinoma in situ, is often resected with involved margins. the clinical presentation presents with erythematous plaques of sluggish growth, well-defined edges, fine scaling, excoriations, ulcerations, and lichenification. empd can manifest as a single whitish or confluent, sometimes ulcerated lesion. candidiasis, psoriasis and chronic lichen simplex should be considered in the differential diagnoses [1]. immunohistochemistry studies became the gold standard for pathologic prognosis, and the data for empd includes cytokeratin 7 (ck7) that appears to be related to slow pathologic progression [2]. the histogenesis of empd is complex; paget cells could originate from the underlying intraductal cancer and migrate through the basement membrane to the nipple or genital areas. histopathology represents the gold standard for diagnosis of empd and immunohistochemical staining differentiates between this skin disorder and intraductal cancer. it is postulated that mammary paget disease as an in-situ carcinoma with paget cells undergoing malignant transformation. surgical excision and micrographic surgery are generally the best treatment options, although recurrences are frequent because it is difficult to obtain optimal surgical margins. local recurrence rates after surgery vary from 34% to 56%, and patients often experience a real “surgical calvary.” in cases of very extensive lesions or difficult locations, such as the genital localization, second-line therapy such as topical therapy could be proposed. case presentation we performed 2 surgeries on a 60-year-old woman to remove a lesion on the left vulva. a biopsy was performed and was in line with the clinical picture (figure 1). histopathological letter | dermatol pract concept 2021;11(2):e2021011 figure 1. (a) clinical image of extramammary paget disease before treatment: scaly lichenified lesion on the left vulva. (b) clinical image after treatment with 3.75% imiquimod: clinical resolution with slight inflammation due to the therapy. (c) dermoscopy shows the presence of structureless whitish areas. (d) dermoscopy shows conspicuous reduction in whitish areas. (e) histopathology of extramammary paget disease (h&e). (f)  cytokeratin 7 immunostaining shows positivity at the basalar level, a positive index of paget disease. (g) histopathology after treatment shows a mild perivascular inflammatory infiltrate associated with telangiectasias in the superficial chorion as per imiquimod response (h&e). letter | dermatol pract concept 2021;11(2):e2021011 3 examination and immunohistochemical profile corroborated a diagnosis of empd (figure 1, e and f). we prescribed imiquimod 3.75% following the dosage guidelines: once daily for 15 days, subsequently interrupting therapy for 15 days, and again once a day for other 15 days. after about 5 months she repeated another therapy session and achieved good clearance of the lesions without obvious side effects or post-surgical sequelae. there was clinical and dermoscopic improvement of the lesion after treatment (figure 1d). after treatment, a biopsy was performed to confirm empd absence (figure 1g). we used the topical disease approach for this case of ck7+ low progression empd to avoid another surgery and the high psychological and physical impact it might have, reclaim the previously excised region, and minimize the use of drugs in order to reduce local adverse events. conclusions topical imiquimod 3.75% is an excellent therapeutic tool for ck7+ empd in cases when surgery is not recommended. imiquimod could also be used in cases of recurrence or in a post-adjuvant therapy regime to avoid the risk of disease relapse, or to avoid permanent anogenital mutilation and functional impairment after surgery. more studies are required to evaluate tailor-made therapies based on the empd histopathological phenotype, stains and molecular markers.  references 1. st claire k, hoover a, ashack k, khachemoune a. extramammary paget disease. dermatol online j. 2019;25(4):13030/qt7qg8g292. pmid: 31046904. 2. damavandy aa, terushkin v, zitelli ja, et al. intraoperative immunostaining for cytokeratin-7 during mohs micrographic surgery demonstrates low local recurrence rates in extramammary paget’s disease. dermatol surg. 2018;44(3):354-364. doi: 10.1097/ dss.0000000000001355. pmid: 29517496.  dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020064 1 dermatology practical & conceptual introduction meyerson phenomenon (mp) is an uncommon condition consisting of a symmetric area of eczema encircling a preexisting central cutaneous lesion such as a melanocytic nevus, a nonmelanocytic skin neoplasia, or a melanoma. mp has been reported to occur both in acquired melanocytic nevi in adults and congenital melanocytic nevi (cmni) in the pediatric population [1]. case presentations case 1 a 2.5-year-old boy was referred to us for a small cmn of the back encircled by an eczematous patch (figure 1a). the patient, who had been suffering from atopic dermatitis since birth, complained of itching. dermoscopy revealed a multicomponent pattern, with atypical globules and blotches of pigment, a central blue veil, along with perilesional erythema (figure 1b). therapy with a topical mometasone furoate led only to transient improvement, with recurrence after discontinuation and with persistence of the alarming dermoscopic features. surgical excision of the lesion was performed and histology was suggestive of a cmn with mp. the excision of the lesion led to complete healing. case 2 a 6-year-old boy was referred to us for a medium-sized cmn of the right thigh that had progressively changed over the previous 12 months. on physical examination, a brown patch with ill-defined margins, 6 cm in maximum diameter, surmounted by yellow crusts and fissures, was observed (figure 2a). the patient complained of itching and pain. he had suffered from atopic dermatitis during the first years of life, in remission at the time of consultation. dermoscopic congenital melanocytic nevi with meyerson phenomenon: two case reports and review of the literature ambra di altobrando,1 iria neri,1 annalisa patrizi,1 michela tabanelli,2 cosimo misciali,1 carlotta baraldi,1 francesco savoia1 1 department of experimental, diagnostic and specialty medicine, dermatology, university of bologna, italy 2 dermatology unit, ausl della romagna, ravenna, italy key words: congenital melanocytic nevus, meyerson phenomenon, dermoscopy, dermatopathology, topical steroids citation: di altobrando a, neri i, patrizi a, tabanelli m, misciali c, baraldi c, savoia f. congenital melanocytic nevi with meyerson phenomenon: two case reports and review of the literature. dermatol pract concept. 2020;10(3):e2020064. doi: https://doi.org/10.5826/ dpc.1003a64 accepted: march 31, 2020; published: june 29, 2020 copyright: ©2020 di altobrando et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. francesco savoia and ambra di altobrando equally contributed to the paper. corresponding author: ambra di altobrando, md, via massarenti 1, 40138 bologna, italy. email: ambra.dialtobrando@studio.unibo.it https://doi.org/10.5826/dpc.1003a64 https://doi.org/10.5826/dpc.1003a64 mailto:ambra.dialtobrando@studio.unibo.it 2 letter | dermatol pract concept 2020;10(3):e2020064 examination revealed areas characterized by pigment network and areas with a homogeneous pigmentation, in association with scales and glomerular and dotted vessels (figure 2, b and c). moreover, short, linear black fibers of clothing entrapped in the irregular eczematous surface of the lesion were detected. the use of clobetasol propionate 0.05% cream led to a reduction of the inflammation, without complete healing of the eczema, which recurred immediately after treatment discontinuation. a punch biopsy was performed and histopathology showed the features of a normal cmn associated with a chronic dermatitis, allowing the diagnosis of cmn with mp (figure 2d). because of the severe pruritus and the chronic course despite therapy, seriate excisions were planned and performed, in order to achieve complete healing. discussion mp involving cmni in the pediatric population is rare (table 1). the most important differential diagnosis is melanoma, because the halo of eczema may cause clinical and worrisome dermoscopic features, including ‘‘blue-white structures’’ and ‘‘blue areas” [1]. although mp can have a spontaneous complete resolution when associated with cmn, some authors have reported a chronic course with complete healing achieved only after excision of the cmn [2]. the use of potent topical steroids is associated with faster healing, even though recurrence of mp can occur within the same nevus or in different lesions [2]. figure 2. (a) a medium-sized congenital melanocytic nevus surmounted by yellow crusts and fissures. (b) dermoscopy showed scales, glomerular/dotted vessels, and short linear black fibers stuck to the eczematous surface. (c) areas with a homogeneous pigmentation were observed on dermoscopy. (d) histopathology showed the features of a normal congenital melanocytic nevus associated with a chronic dermatitis. figure 1. (a) a small congenital melanocytic nevus with meyerson phenomenon. (b) dermoscopy revealed a multicomponent pattern, with atypical globules and blotches of pigment, a central blue veil, along with perilesional erythema. letter | dermatol pract concept 2020;10(3):e2020064 3 conclusions our cases highlight the fact that in children mp in cmni can have a chronic course, with severe eczema, itch, and pain, and can be responsible for alarming dermoscopic features, simulating a melanoma. references 1. richey p, radfar a, kirkorian ay. blue areas on dermoscopy of a congenital nevus with meyerson phenomenon. j am acad dermatol. 2015;73(5):e161-e163. https:// doi.dx.org/10.1016/j.jaad.2015.07.004. 2. rolland s, kokta v, marcoux d. meyerson phenomenon in children: observation in five cases of congenital melanocytic nevi. pediatr dermatol. 2009;26(3):292297. https://doi.dx.org/10.1111/j.15251470.2009.00931.x. 3. weijns me, houtappel m. an infant with a nevus on the upper leg [in dutch]. ned tijdschr geneeskd. 2017;161:d1532. pmid: 28880143. 4. tauscher a, burch jm. picture of the month—quiz case. diagnosis: meyerson phenomenon within a congenital melanocytic nevus. arch pediatr adolesc med. 2007;161(5):471‐472. https://doi. dx.org/10.1001/archpedi.161.5.471 5. pižem j, stojanovič l, luzar b. melanocytic lesions with eczematous reaction (meyerson’s phenomenon)—a histopathologic analysis of 64 cases. j cutan pathol. 2012;39(10):901‐910. https://doi.dx. org/10.1111/j.1600-0560.2012.01960.x. ta b le 1 . c as es o f c o n ge n it al m el an o cy ti c n ev i w it h m ey er so n p h en o m en o n i n t h e pe d ia tr ic p o p u la ti o n r e f. n o . o f p a ti e n ts a g e g e n d e r lo ca ti o n ty p e o f le si o n a to p ic d e rm a ti ti s t h e ra p y t h e ra p e u ti c r e sp o n se e v o lu ti o n r ic h ey [ 1 ] 1 4 y ea rs f b ac k c o n ge n it al m el an o cy ti c n ev u s n o — — — r o ll an d [ 2 ] 5 m ea n a ge 3 .6 y ea rs (2 w ee k s8 ye ar s) 3 m , 2 f u p p er ex tr em it y, an k le , t ru n k , ar m a n d l eg , th ig h c o n ge n it al m el an o cy ti c n ev u s 2 o u t o f 5 p at ie n ts t o p ic al s te ro id s im p ro ve m en t in 3 ca se s, n o i m p ro ve m en t in 1 c as e; i m p ro ve m en t w it h r ec u rr en ce a ft er su sp en si o n o f tr ea tm en t in 1 c as e, n o t re at m en t in 1 c as e d ec re as e in p ig m en ta ti o n o f n ev i in 1 c as e, n o fo ll o w -u p i n 1 c as e, n o im p ro ve m en t o ve r ti m e in 1 c as e, 1 c as e lo st a t fo ll o w -u p , i m p ro ve m en t o ve r ti m e in 1 c as e w ei jn s [3 ] 1 4 m o n th s m u p p er l eg c o n ge n it al m el an o cy ti c n ev u s — — — — t au sc h er [ 4 ] 1 7 m o n th s m a rm c o n ge n it al m el an o cy ti c n ev u s — — — — p iž em [ 5 ] 5 7 m ea n a ge 3 9 y ea rs (1 4 -8 1 ) 5 3 % f , 4 7 % m b ac k , a b d o m en , u p p er ex tr em it ie s, lo w er ex tr em it ie s, b re as t 1 6 a cq u ir ed n ev i, 3 c o n ge n it al n ev i, 2 s p it z n ev i, 2 9 d ys p la st ic n ev i, 1 4 m el an o m as 1 5 % o f re ca ll ed p at ie n ts re p o rt ed a h is to ry o f at o p y — — — o u r ca se s 2 2 y ea rs , 6 ye ar s 2 m b ac k a n d t h ig h 2 c o n ge n it al m el an o cy ti c n ev i y es t o p ic al s te ro id s; su rg ic al e x ci si o n im p ro ve m en t w it h to p ic al s te ro id s b u t re cu rr en ce a ft er su sp en si o n o f tr ea tm en t c o m p le te h ea li n g o f ec ze m a w it h s u rg ic al ex ci si o n https://doi.dx.org/10.1016/j.jaad.2015.07.004 https://doi.dx.org/10.1016/j.jaad.2015.07.004 https://doi.dx.org/10.1111/j.1525-1470.2009.00931.x https://doi.dx.org/10.1111/j.1525-1470.2009.00931.x https://doi.dx.org/10.1111/j.1600-0560.2012.01960.x https://doi.dx.org/10.1111/j.1600-0560.2012.01960.x dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(4):e2021070 1 vulvar hidradenoma papilliferum dermoscopically mimicking basal cell carcinoma andrija jovic 1, danijela popovic1, sladjana cekic1, natasa vidovic2, nikola zivkovic2,3, zorana zlatanovic1, danica tiodorovic1,3 1 clinic of dermatovenereology, clinical center of nis, serbia 2 center for pathology and pathological anatomy, clinical center of nis, serbia 3 faculty of medicine, university of nis, nis, serbia key words: hidradenoma papilliferum, dermoscopy, vulvar basal cell carcinoma, differential diagnosis, adnexal tumor citation: jovic a, popovic d, cekic s, vidovic n, zivkovic n, zlatanovic z, tiodorovic d. vulvar hidradenoma papilliferum dermoscopically mimicking basal cell carcinoma. dermatol pract concept. 2021;11(4):e2021070. doi: https://doi.org/10.5826/dpc.1104a70 accepted: february 2, 2021; published: october, 2021 copyright: ©2021 jovic et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: andrija jovic, clinic of dermatovenereology, clinical center of nis, serbia. andrijajovic@rocketmail.com introduction hidradenoma papilliferum (hp), otherwise known as papillary hidradenoma, is a benign adnexal neoplasm that almost exclusively occurs in the adult female affecting the anogenital area. hp can infrequently appear in ectopic extragenital sites including the head, chest, and abdomen, affecting both females and males equally. although it represents the most common vulvar adnexal neoplasm, dermoscopic features of vulvar hp have been sparsely reported, being limited to only one small case series [1]. herein, we present a case of hp with peculiar dermoscopic features resembling non-pigmented basal cell carcinoma. case presentation a 68-year-old female patient presented with a 9-month history of an asymptomatic, slow-growing nodule on the right inner side of the labia majora. her past medical history was unremarkable. clinical examination revealed a firm, reddish, non-ulcerated nodular lesion measuring 25x10 mm in diameter (figure 1a). upon dermoscopy, the lesion showed a prominent vascular pattern consisting of the well-focused arborizing vessels over the pinkish background with whitish areas (figure 1b). the lesion was completely excised, and histopathological examination was consistent with the diagnosis of hidradenoma papilliferum revealing a characteristic, well-circumscribed dermal lesion with prominent elongated tubular and papillary structures lined by columnar cells without cellular atypia and mitoses (figure 2, a and b). the patient was reassured about the benign nature of the lesion. conclusion vulvar hp are rare benign adnexal lesions that may appear with different clinical presentations, with the most common 2 letter | dermatol pract concept. 2021; 11(4):e2021070 one being unilobular, a small nodule ranging from 10 mm to 20 mm, while other clinical forms including the giant one, multilobular or plaque type are considered as rare. with respect to color, vulvar hp are predominantly red or skin-colored, usually revealing a smooth and non-ulcerated surface. furthermore, the lesions with blue coloration have also been reported. a differential diagnosis based on a clinical presentation is broad and often involves both benign and malignant figure 1. clinical and dermoscopic aspects of vulvar hidradenoma papilliferum (hp). (a) hp involving the right inner site of the labia majora in a form of a red nodule with non-ulcerated surface. (b) dermoscopy revealed prominent and well-focused arborizing vessels over the pinkish and whitish background. (*) artifacts. figure 2. (a) histopathological examination revealed a well-circumscribed dermal tumor without connection with the overlying non-ulcerated epidermis (h&e, x4). (b) tubular and papillary structures lined by epithelium consisted of the layers of two cell types: cuboidal and luminal columnar cells (h&e, x10). lesions, including epidermal cyst, blue nevus, squamous cell carcinoma, melanoma, or basal cell carcinoma, particularly in the presence of ulceration [1]. currently, there is a lack of published data regarding the dermoscopic features seen in vulvar hp and to the best of our knowledge, only one case series study reported dermoscopy findings of this rare neoplasm [1]. tosti et al [1] presented a series of histopathologically proven vulvar hps, describing letter | dermatol pract concept. 2021; 11(4):e2021070 3 the dermoscopic features in 5 out of 7 cases. according to them, vulvar hps are typified by a dermoscopic variability, whereas the presence of the polymorphous vascular pattern was the most prevalent dermoscopic feature. namely, 4 out of 5 lesions exhibited a polymorphous vascular pattern comprising lacunae (red globular structures), glomerular, linear, serpentine and telangiectatic vessels. however, in this case, we observed a monomorphous vascular pattern composed of well-focused arborizing vessels similar to those found in the vulvar non-pigmented basal cell carcinoma (bcc) described by cinotti et al [2]. furthermore, we observed homogenous whitish areas in which there is another dermoscopically overlapping finding of genital bcc [2]. in conclusion, we report a peculiar case of vulvar hp revealing overlapping dermoscopic features with non-pigmented bcc features. additional studies, including a larger number of vulvar hps, may better characterize the dermoscopic features and provide potential dermoscopic clues for this rare benign lesion. references 1. tosti g, salvini c, barisani a, et al. vulvar hidradenoma papilliferum. a clinical and dermoscopic study in a case series. clin exp dermatol. 2020;45(8):1036-1039. doi: 10.1111/ced.14254. pmid: 32356582. 2. cinotti e, tonini g, perrot jl, et al. dermoscopic and reflectance confocal microscopy features of two cases of vulvar basal cell carcinoma. dermatol pract concept. 2018;8(1):6871. doi: 10.5826/dpc.0801a17. pmid: 29445582. pmcid: pmc5808379. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(2):e2021018 1 granuloma annulare located on striae distensae tal goldberger1, s. sheffer levi1, gil armoni1, stephanie ben-shushan2, alexander maly2, yuval ramot1 1 department of dermatology, hadassah medical center and the faculty of medicine, hebrew university of jerusalem, jerusalem, israel; 2 department of pathology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, israel key words: granuloma annulare, dermatopathology, striae distensae, scar citation: goldberger t, sheffer-levi s, armoni g, ben-shushan s, maly a, ramot y. granuloma annulare located on striae distensae. dermatol pract concept. 2021;11(2):e2021018. doi: https://doi.org/10.5826/dpc.1102a18 accepted: september 3, 2020; published: april 12, 2021 copyright: ©2021 goldberger et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: yuval ramot, md, msc, department of dermatology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, pob 12000, jerusalem, 9112001, israel. email: yramot@gmail.com introduction granuloma annulare (ga) is a noninfectious granulomatous dermatitis that is more common in children and young adults. it manifests clinically as localized or generalized rash in micropapular, nodular, perforating, patch, or subcutaneous forms. insect bites, trauma, tuberculin skin testing, ultraviolet radiation exposure, and bacterial and viral infections have been proposed as inciting factors; however, the exact pathophysiology of ga remains elusive [1]. case presentation a 36-year-old male with a history of diabetes mellitus, hypertension, hyperlipidemia, fatty liver, gout, nephrolithiasis, benign thyroid nodules, and glaucoma presented to our outpatient dermatology clinic with nontender papulonodular lesions of 1 year’s duration. skin examination revealed purple-brown papules and nodules distributed symmetrically on the abdomen with accentuation and accumulation of the lesions mostly over areas of striae distensae (sd), and to a lesser degree on the thighs (figure 1, a and b). punch biopsies taken from the abdominal lesions demonstrated a diffuse inflammatory infiltrate, composed mainly of cd68+ histiocytes and lymphocytes (figure 2, a and b). these findings were consistent with incomplete ga. conclusions granuloma annulare is known to be diverse in morphology, distribution, and histology. yet, the unique distribution pattern of the lesions in our case, localized mainly to the sd, was intriguing. lesions of ga were reported to occur at sites of previous skin conditions, such as herpes zoster, and at sites of trauma and inflammation, such as following vaccinations, tattoos and surgical incisions [2]. striae distensae have been previously associated with several skin lesions, including leukemia cutis, keloid, linear focal elastosis, urticarial vasculitis, lupus erythematosus, chronic graft-versus-host disease, and a granulomatous reaction following microneedling. the formation of striae alba (sa), the mature scar-like form of sd, is accompanied 2 letter | dermatol pract concept. 2021;11(2):e2021018 by several immune events that include mast cell degranulation, macrophage activation, perivascular lymphocytic cuffing, and dermal edema. these immune events eventually allow the maturation (healing) of the primary erythematous striae rubra into the pale, atrophic, scar-like sa. the various immune processes involved in the formation of sd may, in susceptible patients, recruit t-helper and other immune cells to promote the formation of ga in the context of aberrant wound healing [2]. our case suggests a possible connection between ga and sd. previous reports have associated the formation of ga with scarred or irritated skin. therefore, the development of ga in the distribution of sd, which is a phenomenon of dermal scarring, is biologically plausible. references 1. bolognia jl, schaffer jv, cerroni l. dermatology. 4th ed. china: elsevier ltd; 2018. 2. borgia f, cannavo sp, guarneri f, manfre c, vaccaro m. isomorphic response after saphenectomy in a patient with granuloma annulare. j am acad dermatol. 2004;50(2suppl): s31-33. doi: 10.1016/s0190-9622(03)01578-0. pmid: 14726862. figure 1. (a) multiple erythematous, violaceous papules and nodules located on the abdomen of a man, distributed mostly along striae distensae. (b) a closer perspective of the lesions on the abdomen. figure 2. histopathologic image of a skin biopsy taken from a lesion on the abdomen, demonstrating (a) diffusely infiltrated dermis with histiocytes and lymphocytes (h&e, original magnification ×40). (b) cd68+ histiocytes diffusely infiltrating the dermis (original magnification ×100). dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021003 1 dermatology practical & conceptual dermoscopic features of two cases of angiolymphoid hyperplasia with eosinophilia and review of the literature bengu nisa akay1, mehmet fatih atak1, banu farabi1,2 1 dermatology department, ankara university school of medicine, turkey 2 dermatology department, rutgers university, robert wood johnson medical center, new jersey, usa key words: angiolymphoid hyperplasia with eosinophilia, red clods, dermoscopy citation: akay bn, fatih atak m, farabi b. dermoscopic features of two cases of angiolymphoid hyperplasia with eosinophilia and review of the literature. dermatol pract concept. 2021;11(2):e2021003. doi: https://doi.org/10.5826/dpc.1102a03 accepted: july 26, 2020; published: march 8, 2021 copyright: ©2021 akay et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: banu farabi, md, rutgers university, robert wood johnson medical center, new brunswick, nj, usa. email: banufarabi91@gmail.com introduction angiolymphoid hyperplasia with eosinophilia (alhe) is a rare benign vascular tumor that typically presents as papules or nodules that are pink or dull red in color and are located predominantly in the head and neck region. mural damage or rupture of large intralesional vessels suggest that trauma or arteriovenous shunting may play a etiological role, and a history of trauma can be elicited in some patients. the lesions may be asymptomatic or may be painful, pruritic, bleeding or pulsatile. some patients have regional lymph node enlargement and peripheral eosinophilia. clinical diagnosis of this entity can be challenging especially in atypical presentations and dermoscopy might be helpful when considring alhe as a differential diagnosis. to date, dermoscopic features of alhe have been described in 3 cases [1,2]. herein, we present 2 cases of alhe with their dermoscopic features. case presentations the reported characteristics and dermoscopic findings of our patients are presented in table 1. clinical and dermoscopic images are shown in figure 1. both of our patients’ diagnoses have been confirmed by histopathological examination. discussion alhe is a rare benign vasoproliferative disorder of unknown origin. various hypotheses have been described including prior trauma, reactive hyperplasia, benign neoplasia, hyperestrogenemia, infectious agents, and atopy. although alhe is a benign entity, it can be confused with many conditions including sarcoidosis, lymphocytoma cutis, kaposi sarcoma, angiosarcoma and metastatic tumors clinically. therefore, biopsy is often required for diagnosis. 2 letter | dermatol pract concept 2021;11(2):e2021003   a g e (y e a rs ) s e x lo ca ti o n d u ra ti o n c li n ic a l fe a tu re s p re ce d in g t ra u m a d e rm a to sc o p y c b c a n d u s g f in d in g s c as e 1 4 6 f em al e r ig h t p o st er io r au ri cu la r ar ea 3 m o n th s a sy m p to m at ic , m u lt in o d u la r, re d d is h l es io n n o h is to ry o f tr au m a l ar ge s iz ed r ed c lo d s w it h ra n d o m ly a rr an ge d s h o rt w h it e li n es a n d r eg u la r d o tt ed ve ss el s o ve r ea ch c lo d n o rm al c as e 2 3 5 m al e l ef t p re au ri cu la r ar ea 8 m o n th s p ru ri ti c, m u lt ip le p in k -c o lo re d p ap u le s n o h is to ry o f tr au m a a f o ca l ar ea c o m p o se d o f re d c lo d s, p in k -b ro w n st ru ct u re le ss a re as w it h se rp en ti n e an d l o o p ed v es se ls , su b tl e w h it e li n es n o rm al r o d ri gu ez -l o m b a et a l. c as e 1 4 5 m al e in n er a sp ec t o f th e le ft th ig h 6 m o n th s a sy m p to m at ic , en la rg in g, p in k co lo re d n o d u le n o t m en ti o n ed p o ly m o rp h o u s va sc u la r p at te rn c o m p o se d o f d o tt ed , co rk sc re w , a n d i rr eg u la rli n ea r ve ss el s ar ra n ge d ra d ia ll y o ve r a d if fu se p al e re d d is h b ac k gr o u n d n o t m en ti o n ed r o d ri gu ez -l o m b a et a l. c as e 2 1 7 f em al e f ro n t o f th e n ec k r ec en t o n se t a sy m p to m at ic , p in k -c o lo re d m u lt in o d u la r p ro li fe ra ti o n n o t m en ti o n ed d o tt ed a n d i rr eg u la r ve ss el s re gu la rl y d is tr ib u te d w it h in ea ch n o d u le o ve r a d if fu se li gh t p in k b ac k gr o u n d n o t m en ti o n ed sa n to sa e t al . 5 5 m al e n o se 7 m o n th s b le ed in g, 5 -m m d ia m et er l es io n w it h s o li ta ry u lc er e le ct ro ca u te ry p er fo rm ed t o t h e le si o n c o n si d er ed k er at o ac an th o m a, 1 ye ar p re vi o u sl y m u lt ip le d o tt ed v es se ls an d c en tr al u lc er at io n w it h ad ja ce n t w h it e ar ea n o t m en ti o n ed c b c = c o m p le te b lo o d c o u n t; u sg = u lt ra so n o gr ap h y. ta b le 1 . c o m p ar is o n o f c as e 1 a n d c as e 2 w it h c u rr en t c as es r ep o rt ed i n t h e l it er at u re letter | dermatol pract concept 2021;11(2):e2021003 3 figure 1. clinical and dermoscopic pictures of angiolymphoid hyperplasia with eosinophilia. (a) a 46-year-old woman with a multinodular reddish lesion on the right posterior auricular area. (b) dermoscopic image shows red clods with dotted vessels, subtle white lines and pink structureless areas. (c) a 34-year-old man with multiple pink-colored papules in the left preauricular area. (d, e) dermoscopic images show a focal area of red clods and subtle white lines and a peripheral brown structureless area. dermoscopic features of alhe are described in 2 case reports [1,2]. rodriquez et al. observed a polymorphous vascular pattern consisting of dotted and linear vessels on a pale reddish to pinkish background [1]. santosa et al. described a clinical mimicker of keratoacanthoma, showing a central keratin mass and ulceration surrounded by dotted, globular and linear irregular vessels on dermoscopy [2]. in our first case case we observed large red clods with dotted vessels, subtle white lines and pink structureless areas. in the previous reports of alhe red clods were not observed. our second case also presented with a focal area of red clods and subtle white lines and serpentine-looped vessels arranged on a pale pink-brown structureless area. conclusions pink lesions represent a challenge for dermatologists and dermoscopy has proven to be a valuable tool in improving the diagnosis of cutaneous neoplasms in comparison with examination with the naked eye. although pink structureless areas, polymorphic vessels and white lines observed in our 2 cases can be observed in other pink nodular lesions, namely, amelanotic melanoma, spitz nevus, and dermatofibroma, the presence of red clods is helpful in differentiating a vascular lesion from the aforementioned entities. other vascular tumors such as angiosarcoma and kaposi sarcoma are the major differential diagnoses for alhe. in kaposi sarcoma 4 letter | dermatol pract concept 2021;11(2):e2021003 the presence of large red clods is not expected as observed in our cases. also, red clods are not reported in angiosarcoma. in conclusion, considering the typical location and clinical findings, alhe should be kept in mind as a differential diagnosis in the presence of dermoscopic red clods. references 1. rodriguez-lomba e, avilés-izquierdo ja, molina-lópez i, parra-blanco v, lázaro-ochaita p, suárez-fernández r. dermoscopic features in 2 cases of angiolymphoid hyperplasia with eosinophilia. j am acad dermatol. 2016; 75(1):e19-21. doi: 10.1016/ j.jaad.2016.02.1145. pmid: 27317536. 2. santosa c, wardhana m, saputra h. angiolymphoid hyperplasia with eosinophilia with clinical pictures of keratoacanthoma: a rare case report. clin case rep. 2019;7(1):189-192. doi: 10.1002/ ccr3.1949. pmid: 30656039. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(4):e2021122 1 congenital melanotic macule of the tongue: a five-year follow-up natália maira resende1, flávia vasques bittencourt1 bernardo gontijo1 1 federal university of minas gerais medical school, belo horizonte, mg, brazil keywords: nevus, pigmented, melanoma, dermoscopy citation: resende nm,vasques bittencourt f, gontijo b. congenital melanocytic macule of the tongue: a five-year follow-up. dermatol pract concept. 2021; 11(4):e2021122. doi: https://doi.org/10.5826/dpc.1104a122 accepted: march 10, 2021; published: october, 2021 copyright: ©2021 resende et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: natália maira resende, md, federal university of minas gerais medical school, belo horizonte, mg, brazil. email: nataliamresende@yahoo.com.br introduction congenital melanotic macule of the tongue (cmmt) is a rare and underestimated benign entity with few cases reported in the literature [1]. clinical characteristics include solitary or multiple asymptomatic congenital melanotic lesions on the tongue with subsequent proportional growth; diameter ranging from 0.3 to 3 cm; homogeneous or heterogeneous color, often very dark and worrisome; and a negative family history of systemic conditions associated with mucosal pigmentation. cmmt can occur in all skin phototypes, but it tends to be more frequent in dark-skinned patients. histologic findings show increased deposits of melanin in the basal cell layer, with a normal number of melanocytes and various degrees of hyperkeratosis. other diseases presenting oral mucous hyperpigmentation, such as pigmented fungiform papillae, lingua nigra villosa, laugier hunziker syndrome, and peutz–jeghers syndrome, can easily be excluded based on clinical grounds alone. oral congenital melanocytic nevi are exceptionally rare, with only 6cases reported in the literature, in all cases the tongue was not involved [2]. although cmmt clinical features can be worrisome and mimic melanoma, this malignancy is exceptionally rare in childhood and has never been reported in the oral cavity in this age group [1]. the cause of cmmt is unclear. congenital lesions might represent a hamartoma of melanocytes with localized functional change in melanin production. no predisposing or causative factors occurring during gestation have been linked to cmmt. to exclude malignancy, some authors suggest performing a tongue biopsy. others argue that follow-up alone is justified, since cmmt clinical features are distinctive, congenital melanocytic nevus of the tongue is an extremely rare disorder, and congenital melanoma has never been reported in the oral cavity. if significant changes occur, a biopsy should be considered. case presentation a 5-month-old boy, born at term, skin phototype iii, was referred for evaluation of congenital, asymptomatic pigmented lesions on the tongue that had enlarged proportionally 2 letter | dermatol pract concept. 2021; 11(4):e2021122 to the infant’s growth. figures 1 a-c show clinical presentations upon the patient’s first visit, and at the age of 2 and 5 years, respectively. his medical history was unremarkable and there was no family history of melanoma or pigmented oral lesions. physical examination revealed asymmetrical brown-gray macules located on the right side of the dorsal surface of the tongue. no palpable cervical nodes were found. due to the child’s compliance, dermoscopy was only carried out at 2 years of age. oral dermoscopy descriptions are rare, and most focus on labial lesions. as for the tongue, the few existing reports describe the patterns of pigmented fungiform papillae. we identified a homogeneous light brown area and projections with vessels (figure 2). mucous melanoma shows a great heterogeneity of colors and a multicomponent pattern, both of which were absent in our patient. conclusions our patient’s follow-up, with photographic documentation from the first medical evaluation at 5 months until 5 years of age, is one of the longest reported in the literature. additionally, this is the first dermoscopy report in a case of cmmt. although this entity is more common in people with dark phototypes (iv, v e vi), our case reports cmmt in a phototype iii child. it is important to raise awareness on this underreported entity to avoid unnecessary aggressive surgical approaches in children. clinical follow-up alone is warranted due to the extremely rare occurrence of oral congenital melanocytic nevi and the unreported childhood congenital melanoma of the oral cavity. references 1. savoia f, ricci l, patrizi a, gaddoni g. congenital melanotic macules of the tongue. a case report and brief review of the literature. pediatr dermatol.2015; 32:109-12. 2. marangon júnior h, souza pea, soares rv, andrade bab, almeida op, horta mcr. oral congenital melanocytic nevus: a rare case report and review of the literature. head and neck pathol 2015; 9:481–487. figure 1. clinical presentations. (a) five months old. (b) two years old. (c) five years old. figure 2. dermoscopy dermatology: practical and conceptual letter | dermatol pract concept 2020;10(4):2020113 1 dermatology practical & conceptual introduction there is increasing interest in procedures to improve skin quality with short downtime. specifically, topical carbon suspension combined with q-switched nd:yag laser treatment (carbon peel laser technique) has gained popularity in the last few years. the aim of this case report is to present the use of the carbon peel laser in the treatment of a patient with enlarged skin pores and comedones. case presentation we present herein the case of a 42-year-old woman who complained of oily skin, dilated pores, and noninflammatory comedones. the patient was treated with the carbon peel laser technique after acquiring the informed consent. before treatment, the patient’s face was washed, and the carbon lotion (carbon pigments; renlive cosmeceuticals, dueville, vi, italy) was applied evenly over the face, except for the upper eyelids, eyebrows, and lips, and allowed to penetrate the skin and hair follicles for 10 minutes. the excess of carbon was removed and then the q-switched 1064-nm nd:yag laser was employed to vaporize the skin surface. the q-switched nd:yag laser (xlase plus, biotec italia srl, dueville, vi, italy) energy was delivered with a 7-mm diameter spot-sized handpiece at a repetition rate of 6 hz. a single pass was carried out on face with the laser. the pulse width was of 9 nanoseconds and fluence was 2.6 j/cm2. three sessions of treatment were performed at monthly intervals. clinical pictures were taken before the laser sessions and 1 month after the last laser session. figure 1 shows clinical pictures before and after treatment, showing the improvement in the skin, mainly with a reduction of skin pore size. no severe adverse events were reported. only a mild erythema after treatment was observed. conclusions the carbon peel laser technique was originally described in 1997 by goldberg et al for laser hair removal. after providing carbon peel laser technique to improve skin quality: back to science! stefania guida1, elisabetta fulgione2, ilaria d’ambra2, graziella babino2, giovanni pellacani1, francesca farnetani1 1 dermatology unit, department of surgical, medical, dental and morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, modena, italy 2 department of dermatology, university of campania luigi vanvitelli, naples, italy key words: carbon peel laser, q-switched laser, carbon suspension, enlarged pores citation: guida s, fulgione e, d’ambra i, babino g, pellacani g, farnetani f. carbon peel laser technique to improve skin quality: back to science! dermatol pract concept. 2020;10(4):e2020113. doi: https://doi.org/10.5826/dpc.1004a113 accepted: may 16, 2020; published: october 26, 2020 copyright: ©2020 guida et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: guida stefania, md, phd, dermatology unit, department of surgical, medical, dental and morphological science with interest related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, via del pozzo 71, 41124 modena, italy. email: drstefaniaguida@gmail.com 2 letter | dermatol pract concept 2020;10(4):2020113 data are available on the literature. the last publication was reported in 2012. our case report showed that treatment with carbon peel laser was effective for acne prone skin and had an excellent safety profile. further studies are needed in order to find adequate protocols of treatment. references 1. chung h, goo b, lee h, roh m, chung k. enlarged pores treated with a combination of q-switched and micropulsed 1064 nm nd:yag laser with and without topical carbon suspension: a simultaneous split-face trial. laser ther. 2011;20(3):181-188. doi: 10.5978/islsm.20.181. pmid: 24155527. 2. jung jy, hong js, ahn ch, yoon jy, kwon hh, suh dh. prospective randomized controlled clinical and histopathological study of acne vulgaris treated with dual mode of quasi-long pulse and q-switched 1064-nm nd:yag laser assisted with a topically applied carbon suspension. j am acad dermatol. 2012;66(4):626-633. doi: 10.1016/j.jaad.2011.08.031. pmid: 22033354. the evidence for the effect on the hair follicle, the technique has been extended to treat acne vulgaris and pores [1,2]. in one study, different laser protocols were employed involving a small number of patients, and only a single experience for each indication was reported. nevertheless, common mechanisms of action were hypothesized related to the peeling effect of the procedure, such as the reduction of microbial colonization of p. acnes, sebaceous gland function, together with the histologically proven thinning of the stratum corneum of the epidermis. taken together, all these mechanisms might contribute to reduced inflammation [2]. interestingly, the carbon peel laser technique has been proven to provide a peeling effect, cleaning off the skin surface and the plugged pores, thereby correcting the hypercornification of follicular epithelium that might block the physiologic outflow of sebum to the skin surface and reducing skin inflammation [2]. however, despite the popularity of this technique and much information accessible on the internet, little scientific figure 1. clinical pictures of a 42-year-old woman (a) before and (b) after treatment with carbon peel laser. a b dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021049 1 prevalence of metabolic syndrome and its parameters and their correlations with psoriasis duration, severity, and sleep quality in psoriasis patients: a cross-sectional study betul tas1, vasfiye kabeloglu2 1 department of dermatology and venereology, university of health sciences, istanbul bagcilar research and training hospital, istanbul, turkey 2 department of neurology, university of health sciences, bakirkoy prof. dr. mazhar osman research and training hospital, istanbul, turkey key words: psoriasis, metabolic syndrome, sleep quality, comorbidity citation: tas b, kabeloglu v. prevalence of metabolic syndrome and its parameters and their correlations with psoriasis duration, severity, and sleep quality in psoriasis patients: a cross-sectional study. dermatol pract concept. 2021;11(3):e2021049.doi: https://doi. org/10.5826/dpc.1103a49 accepted: december 14, 2020; published: may 20, 2021 copyright: ©2021 tas and kabeloglu. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: betul tas, md, department of dermatology and venereology, university of health sciences, istanbul bagcilar research and training hospital, atakoy 7-8, kısım, martı 14/105, bakirkoy, istanbul, turkey. email: betulavc@yahoo.com background: psoriasis is an inflammatory skin disease that may lead to comorbidities, including metabolic syndrome (ms). objective: we determined the prevalence of ms and its correlation with psoriasis duration, severity, and sleep quality in psoriasis patients. methods: a total of 112 subjects with chronic plaque psoriasis were studied. demographics, ms parameters, disease duration, severity, and sleep quality were examined. the psoriasis area and severity index (pasi) and the pittsburgh sleep quality index (psqi) were used to assess psoriasis severity and sleep quality, respectively. presence of ms and its correlations with psoriasis duration, severity and sleep quality were investigated. results: of 112 patients, 76 (67.8%) were diagnosed with ms. of all patients, 74.1% had a high pasi, and 84.8% had a high psqi. the mean values of psoriasis duration, body mass index, waist circumference, fasting glucose, homa-ir, triglyceride levels, blood pressure, psqi, sleep latency, and daytime sleep dysfunction were significantly higher in the ms group than non-ms group, whereas the mean hdl level was lower. the prevalences of ms, high fasting glucose, and low hdl were significantly higher among female, but not male, patients with severe psoriasis (pasi >10) than those without severe psoriasis. disease duration, high body mass index, waist circumference, blood pressure, fasting abstract 2 research | dermatol pract concept. 2021;11(3):e2021049 introduction psoriasis is an immune-mediated, inflammatory skin disease. because of the increasing rate of coexistence with many co morbidities, psoriasis is starting to be considered a multisystem disease. many comorbidities have been described, such as arthritis, obesity, hypertension, dyslipidemia, diabetes mellitus, cardiovascular diseases (cvds), and sleep disorders [1,2]. various factors play roles in the sharing of pathogenetic mechanisms between psoriasis and these comorbidities. common pathways and cytokine profiles are used to explain this interaction. thanks to these relationships, psoriasis is beginning to be associated with metabolic syndrome (ms) [3]. on the other hand, ms itself is a multisystem disease that is associated with disorders such as hypertension, dyslipidemia, high blood glucose, and cvds. psoriasis and obesity are chronic inflammatory diseases, and a strong correlation has been reported between these two disorders. abdominal obesity is considered the most important parameter in the development of ms in psoriasis patients [4]. adipose tissue secretes cytokines like tumor necrosis factor alpha (tnf-alpha), which induces the production of free fatty acids, decreases adiponectin synthesis, disrupts insulin signaling, and ultimately leads to insulin resistance [5].levels of tnf-alpha has been found to be significantly higher in the skin of psoriasis patients than unaffected people [6,7]. thus, it is suggested that obesity plays an important role in increasing the risk of development of ms, diabetes mellitus and cvds in psoriasis patients [8,9].psoriasis may also lead to poor sleep quality, because it causes itchiness and sleep disturbances [10,11].thus, we investigated the presence of ms and ms parameters and their correlations with psoriasis duration, severity, and sleep quality, and also detected predictive factors in the development of ms in psoriasis patients. patients and methods this was a cross-sectional, observational study. the study protocol was approved by the ethics committee of university of health sciences, istanbul bagcilar research and training hospital (approval code, 2018.11.1.08.108), and written informed consent was obtained from all study subjects. study participants were recruited from patients who attended our dermatology clinics between january and july 2019.the study was conducted in accordance with the world medical association’s declaration of helsinki, 2013. inclusion criteria were: ≥18 years of age, clinical and histopathological diagnosis of psoriasis, proficiency in communication, enough understanding of questionnaires, having no other dermatological disorders, and absence of a previous ms-diagnosis. exclusion criteria were: cognitive impairment, having other dermatological, neurological, ear-nose-throat disorders, or having an acute upper-respiratory-tract infection that could cause poor sleep quality. patients were recruited until the number enrolled reached a previously determined sample size (it was detected using a sample calculation with a single group proportional data size). referencing the average number of patients who were admitted to our clinics in the determined period, the sample size was determined to be 99with a 95% level of confidence and a 5% of margin of error. however, approximately 10% more subjects were enrolled, in case any of the enrolled subjects dropped out of the study. data collection and analyses the study subjects’ age, gender, disease duration, smoking habit, alcohol consumption habit were recorded, as were previously diagnosed coexistent chronic diseases, namely diabetes mellitus, hypertension, lung disease, chronic kidney disease, cerebrovascular disease, and thyroid disease. psoriasis severity was evaluated using the psoriasis area and severity index (pasi) [12]. this index combines a score for severity (erythema, induration and desquamation, grades of 0-4) and the percentage of affected areas (head, arms, trunk and legs, from 0% to 100%). minimum and maximum scores are 0 and 72, respectively. values higher than 10 indicate moderate-severe psoriasis. sleep quality was evaluated with the pittsburgh sleep quality index (psqi), which measures sleep quality over the previous month, and includes 19 questions to be answered by patients and 5questions rated by their bed or room partner (if one exists). the questions form the component scores, each of which has a range of 0-3 points. a score of 0 indicates no glucose, homa-ir, triglyceride levels, low hdl, and poor sleep quality were significantly correlated with the presence of ms. however, only waist circumference, fasting glucose, blood pressure, and low hdl were predictive of the development of ms. conclusions: ms is common among psoriasis patients, and especially in females with advanced psoriasis, high fasting glucose, and low hdl levels. besides diagnostic criteria of ms, a long duration of psoriasis, poor sleep quality and high-homa-ir correlate with the development of ms. high fasting glucose and low hdl levels may facilitate ms development in association with psoriasis severity in females. research | dermatol pract concept. 2021;11(3):e2021049 3 difficulty in sleep, while a score of 3 indicates severe difficulty. the 7sub-component scores, which indicate subjective sleep quality (pssq), sleep latency (psl), sleep duration (psdu), habitual sleep efficiency (phse), sleep disturbances (psdi), use of sleeping medication (pusm), and daytime sleep dysfunction (pdsd), add up to a total score (0-21 points). a total score ≥5 indicates poor sleep quality [13]. the psqi was adapted to the turkish population by agargun et al [14]. the national cholesterol education program adult treatment panel iii (atp iii) criteria were used to investigate ms parameters [15]. first, the anthropometric parameters of weight, body mass index (bmi), and waist circumference, and systolic and diastolic blood pressures (sbp, dbp) were measured [14]. subjects who had ≥3 of the following parameters were diagnosed with ms: fasting glucose ≥110 mg/dl; fasting triglyceride ≥150 mg/dl; hdl<50 mg/dl for women and<40 mg/dl for men; waist circumference>88cm for women and >102 cm for men; and sbp ≥130 mmhg or dbp ≥85 mmhg [15]. bmi was calculated as weight (kilograms) divided by height (square meters), and was evaluated as non-obese (<30) and obese (≥30) [16]. waist circumference was measured at the midpoint between the twelfth rib and the iliac crest [17]. sbp and dbp were measured following the jnc-7 guidelines [18]. plasma fasting glucose, hdl and triglyceride levels were analyzed by automated enzyme immunoassay and serum insulin levels were measured using an electrochemiluminescence immunoassay (cobras 6000-601 automated analyzer, roche diagnostics). insulin resistance was detected by calculating the homeostatic model assessment-insulin resistance (homa-ir) index as follows: homa-ir=fasting insulin (miu/l)×fasting glucose (mg/dl)/405 [19]. values of homa-ir were considered normal if <2.5 and high if ≥2.5 [20]. statistical analyses ncss (number cruncher statistical system, 2007) software was used. standard descriptive statistics were expressed as mean and standard deviation (sd) or number and percentage. the normality assumptions were checked using the kolmogorov-smirnov test. independent-samples t-test was used to compare quantitative data when their distribution was normal, whereas the mann‐whitney u test was used to compare means when the distribution was not normal. qualitative data was compared with pearson’s chi-square test. spearman’s rho test was used for the correlation of dependent and independent variables which were distributed asymmetrically, a p value <.05 was considered significant. strength of correlations was determined according to rho (r) values, as follows: r< 0.2 (very weak, no correlation), r=0.2-0.4 (weak), r=0.4-0.6 (moderate), r=0.6-0.8 (strong), and r> 0.8 (very strong). predictivity of determinant factors was detected with logistic regression analysis. results were determined with 95% confidence. results a total of 112 patients with psoriasis (53 men and 59 women) were included in the study (table 1). their mean age was 46.5 years (sd = 13.2years; range, 21-73 years). overall, 50% of them was obese and 78.6% had high waist circumference;42.0% had high fasting glucose, 83.0% had high triglyceride, and 61.6% had low hdl levels. hypertension and high homa-ir were detected in 23.2% and 63.4% of cases, respectively. pasi values were high in 74.1% of subjects, whereas 84.8% had high psqi values. the most detected comorbidity was hypertension (23.2%). alcohol consumption was reported by 15.2%, whereas 38.4% were smokers. ms was diagnosed in 76 (67.8%) of the 112 patients. proportionately more women had ms, but this association was not significant (table 2). more patients in the ms group than non-the ms group had high values of waist circumference, bmi, triglyceride levels, fasting glucose, blood pressure (each p = .0001) and homa-ir (p= .014), and low values of hdl (p= .0001). more patients in the ms group had psqi scores ≥5(p = .046), while similar percentages of patients in both groups had pasi scores >10. mean values of age, disease duration, ms parameters, pasi, psqi and its subgroups are compared in table 3. the means of disease duration, bmi, waist circumference, fasting glucose, homa-ir, triglyceride levels, psqi, psl, and pdsd were significantly higher, and hdl values were significantly lower in the ms group. then, for all 112 patients, ms parameters were compared in subgroups according to pasi (≤10 vs. >10) and gender (table 4). high fasting glucose, low hdl levels, and a diagnosis of ms were significantly more frequent only in females with high pasi (p =.003, p = .027, p = .031, respectively). correlations between diagnosis of ms and clinical characteristics such as psoriasis duration, pasi and psqi are shown in table 5. positive correlations were detected between ms and disease duration, bmi, waist circumference, high blood pressure, fasting glucose, homa-ir, triglyceride levels and psqi, whereas hdl values were negatively correlated with it. the impacts of the correlative parameters on ms development are shown in table 6. only waist circumference, fasting glucose, high blood pressure, and low hdl had predictive effects. discussion psoriasis is a chronic inflammatory skin disease that affects 2%-4% of the general population [21,22]. the prevalence of ms has been reported to be35% in the united states [21]. in the turkish population, it has been reported to be34.9% (25.2% in men and 40.1% in women) by gündo4 research | dermatol pract concept. 2021;11(3):e2021049 gan et al [23] and 33.9% by gemalmaz et al [24]. although there was a female predominance (52.7%) in our study, the prevalence of ms in men and women was similar (p =.230). although the exact relationship is not fully understood, it is well known that psoriasis patients have a higher prevalence of ms, which changes with a person’s genetic susceptibility, aging, dietary habits, and sedentary behaviors [25]. in a comprehensive meta-analysis, the prevalence of ms among people with psoriasis was in the range of 20%-50%, in which adjusted ors were reported as 1.22, 1.56, and 1.98 for mild, moderate and severe psoriasis, respectively [26]. another meta-analysis of 12studies found that the prevalence of ms was 2.2-times higher in psoriasis patients than in the general population. it was reported as 49.4% by ferdinando et al [25], which was 1.8-times higher (35.0%) than in the control group. in another meta-analysis of 35 studies from 20 countries, the pooled or for ms in psoriasis patients was 2.14 compared to the general population [21]. additionally, ors have been reported to be2.94 and 3.65 in different provinces of turkey, by zindanci et al [27] and tasliyurt et al [28]. adisen et al found that the prevalence was 12.6% in 563 psoriasis patients [29], whereas baeta et al showed that it was 44.9% in 190 psoriasis patients [30]. in our study, 67.8% of patients had ms (72.8% in females and 62.2% in males). although the age range, mean age, and gender distribution of our study were similar to those in the aforementioned studies, they were still higher than in those studies. however, another study from turkey indicated that ms prevalence was 43.5% in females and 41.4% in males in 2010; this study predicted that the table 1. clinical characteristics of 112 psoriasis patients characteristic patients, no. (%) gender m 53 (47.3) f 59 (52.7) bmi (kg/m2) <30 56 (50.0) ≥30 56 (50.0) waist circumference (cm) m<102, f<88 24 (21.4) m>102, f>88 88 (78.6) alcohol consumption 17 (15.2) smoking habit 43 (38.4) triglyceride (mg/dl) <150 19 (17.0) ≥150 93 (83.0) hdl (mg/dl) m<40, f<50 69 (61.6) m>40, f>50 43 (38.4) blood pressure(mmhg) sbp<130, dbp<85 86 (76.8) sbp≥130, dbp≥85 26 (23.2) fasting glucose(mg/dl) <110 65 (58.0) ≥110 47 (42.0) homa-ir <2.5 41 (36.6) ≥2.5 71 (63.4) pasi ≤10 29 (25.9) >10 83 (74.1) psqi <5 17 (15.2) ≥5 95 (84.8) comorbidities chronic lung disease 1 (0.9) chronic kidney disease 0 (0) cerebrovascular disease 0 (0) thyroid disease 5 (4.5) hypertension 26(23.2) diabetes mellitus 23 (20.5) bmi = body mass index; dbp = diastolic blood pressure; f = female; hdl = high-density lipoprotein; homa-ir = homeostatic model assessment insulin resistance; m = male; pasi=psoriasis area and severity index; psqi = pittsburg sleep quality index; sbp = systolic blood pressure. research | dermatol pract concept. 2021;11(3):e2021049 5 prevalence of ms will increase in the coming years [29]. considering this information [21,23,31] and due to the fact that ms is more common in psoriasis patients [25, 26, 29, 30, 31], our results are in line with the expectations mentioned. the role of age and gender on ms development in psoriasis patients varied in different studies. kim et al [32] and altunay et al [3] showed that the presence of ms was significantly higher in older psoriasis patients, and the prevalence was insignificantly higher in males. adisen et al [29] also stated that it did not vary by gender but was higher in older people [29]. we did not find a significant difference according to either age or gender. the exact mechanism for the link between psoriasis and ms is uncertain. however, common pathways through th1/th17 cells, and common effects of pro-inflammatory cytokines on adipocytes, glucose regulation, lipid status, and endothelial function are used to try to explain it [21, 25]. psoriasis and ms can develop in a person independently of each other. however, it is suggested that the existence of one of them can facilitate the development of the other, because of a shared immunopathogenesis involving chronic inflammation mediated by cytokines such as ifn-gamma, il-17, il-23, and tnf-alpha. similarly, insulin-like growth factor is a shared mediator for the development of diabetes mellitus, hyperlipidemia and keratinocyte proliferation in psoriatic skin [21]. it is also suggested that obesity in psoriasis patients plays a key role in the increased risk for ms development [8,9]. common outcomes of both psoriasis and ms are abdominal obesity, hypertension, dyslipidemia, and insulin resistance [21]. although the relationship between psoriasis severity and ms has been reported differently in the literature [33], ms prevalence usually increases with psoriasis severity, when ms components are considered individually [21]. however, adisen et al [29]and altunay et al [3] found that mean scores of pasi were not different between patients with and without ms, whereas itani et al [33] reported that the mean pasi score was greater in psoriasis patients with than without ms. we did not find any difference between groups according to pasi. however, although the prevalences of ms were not different by gender, the presence of ms was significantly higher in females with high pasi than in males. moreover, when considering different pasi groups, only fasting glucose and hdl levels table 2. clinical characteristics of psoriasis patients without (n = 36) and with (n = 76) metabolic syndrome: analysis of frequencies characteristic   non-ms group1 ms group1 p2 gender m 20 (55.6) 33 (43.4) .230 f 16 (44.4) 43 (56.6) waist circumference (cm) m<102, f<88 19 (52.8) 5 (6.6) .0001 m>102, f>88 17 (47.2) 71 (93.4) bmi (kg/m2) triglyceride (mg/dl) ≥30 11 (30.6) 45 (59.2) .0001 <150 14 (38.9) 5 (6.6) .0001 ≥150 22 (61.1) 71 (93.4) hdl (mg/dl) m<40, f<50 28 (22.2) 15 (80.3) .0001 m>40, f>50 8 (77.8) 61 (19.7) fasting glucose (mg/dl) <110 33 (91.7) 32 (42.1) .0001 ≥110 3 (8.3) 44 (57.9) blood pressure (mmhg) sbp<130, dbp<85 35 (97.2) 51 (67.1) .0001 sbp≥130, dbp≥85 1 (2.8) 25 (32.9) pasi ≤10 12 (33.3) 17 (22.4) .216 >10 24 (66.7) 59 (77.6) psqi <5 9 (25.0) 8 (10.5) .046 ≥5 27 (75.0) 68 (89.5) homa-ir <2.5 19 (52.8) 22 (29.0) .014 ≥2.5 17 (47.2) 54 (71.1) smoking habit 14 (38.9) 29 (38.2) .941 alcohol consumption 5 (13.9) 12 (15.8) .793 1values are no. (%) of patients. 2 pearson’s chi-square test. bmi = body mass index; dbp = diastolic blood pressure;f = female; hdl = high-density lipoprotein; homa-ir = homeostatic model assessment insulin resistance;m = male; pasi = psoriasis area and severity index; psqi = pittsburg sleep quality index;sbp = systolic blood pressure. 6 research | dermatol pract concept. 2021;11(3):e2021049 significantly differed between the genders. thus, higher rates of ms in women with severe psoriasis might be related to their high fasting glucose and low hdl values. on the other hand, it has been stated that ms development may be affected by psoriasis duration. altunay et al’s study showed that there was no relationship between disease duration and the presence of ms [3], whereas itani et al [33]and adisen et al [29] reported that ms was significantly higher in psoriasis patients with longer than shorter duration, as in our study. considering the different ms parameters, we found that the means of bmi, waist circumference, fasting glucose, triglyceride, and blood pressure were significantly higher in the ms group, whereas hdl levels were significantly lower. so, our results support the understanding that psoriasis patients are at risk of having all ms parameters. additionally, we assessed the prevalence of insulin resistance in our-study subjects. polic et al [34] found a correlation between high homa-ir levels and a diagnosis of ms in psoriasis patients, and homa-ir was significantly higher in patients with severe psoriasis. similarly, we detected significantly higher homa-ir levels in the ms group, but homa-ir was not related to psoriasis severity. moreover, because of the stronger correlation of ms with fasting glucose than with homa-ir, the former may have more importance on the development of ms. alcohol use and a smoking habit may trigger or worsen psoriasis [29] and cardiovascular, metabolic and hepatic complications in ms [31]. smoking may affect clinical variability or course of psoriasis because of causes or increases in oxidative stress, functional morphological changes in polymorphonuclear leukocytes, and release of chemotactic factors and cytokines like interleukins, tnf-alpha, and transforming growth factor beta. it is also suggested that alcohol makes psoriasis worse by affecting lymphocyte transformation. rates of smoking and alcohol use have been reported as 20%-65% and 3.3%-24% in psoriasis patients, respectively [29]. this study found that these prevalences were 38.39% and 15.8%, which are consistent with the literature. however, both habits did not show any correlation with the presence of ms. on the other hand, sleep disturbances have been reported in approximately 50%-60% of psoriasis patients [35]. hawro et al reported that 39% of psoriasis patients had overall poor sleep quality, especially daytime sleepiness and awakenings during sleep [36]. disturbances in sleep quality have usually been associated with itchiness and low quality of life in psoriasis patients [37, 38]. melikoğlu [39]and jensen et al [40] reported that psoriasis patients had significantly poorer overall sleep quality than controls, at the rates of 60% and 53.9%, respectively, whereas shutty et al [41] reported table 3. clinical characteristics of psoriasis patients without (n = 36) and with (n = 76) metabolic syndrome: analysis of means characteristic no-ms group1 ms group1 p age (years) 44.17±13.24 47.58±13.1 .202* bmi (kg/m2) 28.33±4.08 31.15±4.88 .003* waist circumference(cm) 97.47±13.3 112.54±12.14 .0001* triglyceride (mg/dl) 163.81±62.47 203.68±80.24 .01* hdl (mg/dl) 48.13±10.07 39.75±5.21 .0001* fasting glucose (mg/dl) 97.82±12.41 115.92±21.98 .0001* homa-ir 2.39±1.06 3.48±3.19 .048ǂ pasi 22.59±18.69 23.97±15.83 .684* disease duration (years) 8.76±5.78 13.09±8.99 .01ǂ psqi (total) 7.94±4.72 10.01±4.78 .034* pssq 1.75±0.87 1.79±0.79 .812ǂ psl 1.25±1.00 1.74±1.00 .018ǂ psdu 1.17±1.13 1.43±1.20 .266ǂ phse 0.61±0.99 0.92±1.12 .159ǂ psdi 1.36±0.64 1.62±0.65 .052ǂ pusm 0.58±0.81 0.71±0.92 .480ǂ pdsd 1.22±0.96 1.79±0.88 .003ǂ 1values are mean (sd). *independent-samples t test.ǂmann-whitney u non-parametric test bmi = body mass index; homa-ir = homeostatic model assessment insulin resistance; pasi = psoriasis severity index; pdsd = pittsburg daytime sleep dysfunction; phsenm = pittsburg habitual sleep efficiency; psdi = pittsburg sleep disturbance; psdu = pittsburg sleep duration; psl = pittsburg sleep latency; psqi = pittsburg sleep quality index;pssq = pittsburg subjective sleep quality; pusm = pittsburg use of sleeping medication. research | dermatol pract concept. 2021;11(3):e2021049 7 table 4. comparison of metabolic syndromeparameters, by pasi and gender1 parameter gender   pasi p2 ≤10 (n = 29) >10 (n = 83) waist circumference(cm) m <102 3 20.00% 13 34.21% .310 >102 12 80.00% 25 65.79% f <88 3 21.43% 5 11.11% .325 >88 11 78.57% 40 88.89% bmi (kg/m2) m ≥30 14 26.41% 39 73.58% f ≥30 15 25.42% 44 74.57% .052 blood pressure(mmhg) m sbp<130, dbp<85 12 80.00% 29 76.32% .773 sbp>130, dbp>85 3 20.00% 9 23.68% f sbp<130, dbp<85 12 85.71% 33 73.33% .342 sbp>130, dbp>85 2 14.29% 12 26.67% fasting glucose(mg/dl) m <110 11 73.33% 19 50.00% .123 ≥110 4 26.67% 19 50.00% f <110 13 92.86% 22 48.89% .003 ≥110 1 7.14% 23 51.11% homa-ir m <2.5 7 46.67% 13 34.21% .399 ≥2.5 8 53.33% 25 65.79% f <2.5 7 50.00% 14 31.11% .197 ≥2.5 7 50.00% 31 68.89% triglyceride (mg/dl) m <150 1 6.67% 3 7.89% .879 >150 14 93.33% 35 92.11% f <150 6 42.86% 9 20.00% .086 >150 8 57.14% 36 80.00% hdl (mg/dl) m <40 7 46.67% 23 60.53% .359 >40 8 53.33% 15 39.47% f <50 8 57.14% 38 84.44% .031 >50 6 42.86% 7 15.56% metabolic syndrome diagnosis m ms (-) 5 33.33% 15 39.47% .678 ms (+) 10 66.67% 23 60.53% f ms (-) 7 50.00% 9 20.00% .027 ms (+) 7 50.00% 36 80.00% total ms (-) 12 41.38% 24 28.92% .216 ms (+) 17 58.62% 59 71.08% 1values are no. (%) of patients. 2 pearson’s chi-square test bmi = body mass index; homa-ir = homeostatic model assessment insulin resistance; ms = metabolic syndrome; pasi = psoriasis area and severity index. that poor sleep quality in psoriasis patients was 4.3-times higher than in healthy controls. however, stinco et al [42] did not find any difference in sleep quality between psoriasis patients and healthy controls. in our study, 84.8% of patients had psqi values ≥5, indicating poor sleep quality. this result agrees with the literature, but the rate is higher. additionally, the psqi mean was significantly higher in the ms group than non-ms group. sleep latency and daytime sleep dysfunction were significantly higher in the ms group; these results are similar to those of hawro et al [36]. moreover, it is a wellknown fact that the prevalence of respiratory difficulties such as obstructive sleep apnea is higher in obese patients, which lead to sleep disorders, and there is high prevalence of obesity in patients with psoriasis [11]. because most of our ms subjects were obese, and there was no relation between the presence of ms and psoriasis severity in the whole group, their poor sleep quality might be more related to their obesity than their psoriasis severity. however, ms prevalence was significantly higher in females with severe psoriasis, compared to males. because the significantly higher fasting glucose and lower hdl were also detected only in females with severe psoriasis, these abnormalities might be more related to the 8 research | dermatol pract concept. 2021;11(3):e2021049 ta b le 5 . p ea rs o n ’s r h o ( an d p v al u e) b et w ee n a d ia gn o si s o f m et ab o li c sy n d ro m e (m s) a n d c li n ic al c h ar ac te ri st ic s fo r 1 1 2 p so ri as is p at ie n ts m s d is e a se d u ra ti o n b m i w a is t ci rc u m fe re n ce tr ig ly ce ri d e h d l b lo o d p re ss u re fa st in g g lu co se h o m a -i r pa s i p s q i s m o k in g h a b it a lc o h o l co n su m p ti o n 1 0 .2 4 4 0 .2 7 5 0 .5 2 6 0 .2 4 3 -0 .2 7 9 0 .3 3 3 0 .4 6 9 0 .1 8 7 0 .0 3 9 0 .2 -0 .0 0 7 0 .0 2 5 m s (0 .0 1 ) (0 .0 0 3 ) (0 .0 0 0 1 ) (0 .0 1 ) (0 .0 0 3 ) (0 .0 0 0 1 ) (0 .0 0 0 1 ) (0 .0 4 8 ) (0 .6 8 4 ) 0 .0 3 4 ) (0 .9 4 1 ) (0 .7 9 6 ) 1 0 .2 1 3 0 .0 8 5 0 .0 6 -0 .1 3 9 0 .1 2 7 0 .2 1 2 -0 .0 8 1 0 .0 4 2 0 .1 8 0 .0 0 2 0 .1 0 5 d is ea se (0 .0 2 4 ) (0 .3 7 3 ) (0 .5 3 ) (0 .1 4 4 ) (0 .1 8 2 ) (0 .0 2 5 ) (0 .3 9 5 ) (0 .6 6 ) (0 .0 5 7 ) (0 .9 8 4 ) (0 .2 6 9 ) d u ra ti o n 1 0 .4 4 7 0 .0 9 6 0 .0 3 1 0 .2 1 9 0 .0 4 0 .1 0 3 0 .0 1 2 0 .0 5 3 0 .0 4 2 -0 .0 5 7 b m i (0 .0 0 0 1 ) (0 .3 1 4 ) (0 .7 4 3 ) (0 .0 2 1 ) (0 .6 7 5 ) (0 .2 8 1 ) (0 .9 0 2 ) (0 .5 7 6 ) (0 .6 5 9 ) (0 .5 5 4 ) 1 0 .0 8 5 -0 .0 2 2 0 .1 8 4 0 .1 3 5 0 .0 5 2 -0 .0 1 7 0 .2 -0 .0 3 5 -0 .0 8 2 w ai st (0 .3 7 3 ) (0 .8 1 4 ) (0 .0 5 2 ) (0 .1 5 5 ) (0 .5 8 9 ) (0 .8 6 ) (0 .0 3 4 ) (0 .7 1 3 ) (0 .3 8 8 ) ci rc u m fe re n ce 1 -0 .0 6 3 0 .1 5 2 0 .1 8 0 .2 3 5 0 .1 5 8 0 .1 5 2 0 .0 4 3 0 .0 4 6 t ri gl yc er id e (0 .5 1 2 ) (0 .1 0 9 ) (0 .0 5 8 ) (0 .0 1 3 ) (0 .0 9 6 ) (0 .1 1 ) (0 .6 5 1 ) (0 .6 2 8 ) 1 -0 .1 1 8 -0 .1 5 4 0 .0 3 1 0 .2 0 4 0 .1 2 2 0 .0 8 6 -0 .0 6 9 h d l (0 .2 1 6 ) (0 .1 0 6 ) (0 .7 4 6 ) (0 .0 3 1 ) (0 .2 0 2 ) (0 .3 6 9 ) (0 .4 6 8 ) 1 0 .0 0 4 0 .2 0 6 0 .1 5 -0 .0 3 1 0 .0 4 4 0 .0 6 2 b lo o d (0 .9 6 8 ) (0 .0 3 ) (0 .1 1 5 ) (0 .7 4 6 ) (0 .6 4 3 ) (0 .5 1 5 ) p re ss u re 1 0 .1 9 9 0 .1 8 7 0 .2 6 5 -0 .0 0 2 -0 .0 5 7 f as ti n g (0 .0 3 5 ) 0 .0 4 8 ) (0 .0 0 5 ) (0 .9 8 6 ) (0 .5 4 9 ) gl u co se 1 -0 .0 0 9 0 .0 1 3 0 .1 8 0 .0 4 1 h o m a -i r (0 .9 2 6 ) (0 .8 9 3 ) (0 .0 5 7 ) (0 .6 7 1 ) 1 0 .2 9 8 -0 .0 4 6 0 .0 7 3 pa si (0 .0 0 1 ) (0 .6 3 2 ) (0 .4 4 3 ) 1 0 .0 0 4 0 .0 4 2 p sq i (0 .9 6 7 ) (0 .6 6 2 ) 1 0 .4 3 4 sm o k in g (0 .0 0 0 1 ) h ab it 1 a lc o h o l co n su m p ti o n b m i = b o d y m as s in d ex ; h o m a -i r = h o m eo st at ic m o d el a ss es sm en t in su li n r es is ta n ce ; m s = m et ab o li c sy n d ro m e; p a si = p so ri as is a re a an d s ev er it y in d ex ; p sq i = p it ts b u rg h s le ep q u al it y in d ex . research | dermatol pract concept. 2021;11(3):e2021049 9 development of ms in females than in males. considering the correlations between the presence of ms and study parameters, significant positives were detected between the presence of ms and waist circumference, fasting glucose, high blood pressure, bmi, psoriasis duration, high triglyceride, poor sleep quality, and high homa-ir, whereas high hdl levels were negatively correlated. when the effects of correlative factors were evaluated with a logistic regression analysis, only high fasting glucose, low hdl, hypertension, and waist circumference had predictive effects on the development of ms. the present study is not without limitations. the study population is relatively small, and the study was done at only a single research center. moreover, a relationship between the presence of ms and psoriasis severity was not established, which may seem contradictory to some literature [11,21,29]. lastly, a relative inequality in the gender of study subjects can raise concerns regarding the validity of our findings. however, we believe that this inequality may in some sense be valuable in indicating real predominance of ms in females with severe psoriasis, although there was no significant difference in the presence of ms according to gender. our results are still striking enough to reach significant conclusions as follows: detection of higher ms prevalence than previously reported in turkey [23, 24, 31], confirmation of previous predictions that the prevalence of ms will gradually increase over time, agreement with the literature that ms development increases with psoriasis duration, and significantly higher values of psqi and homa-ir only in the ms group (apart from diagnostic parameters of ms) despite the absence of significant differences between the groups by age, gender or psoriasis severity. finally, and perhaps most importantly, an inference of the present study is detection of significantly high fasting glucose and low hdl values only in females with severe psoriasis, compared to males, which may be the reason why ms was detected at a higher rate in females with psoriasis. to the best of our knowledge, this association has not been reported previously. however, controlled, broad-based and prospective studies are needed to confirm our results. acknowledgement we thank jessica eri motai from bogazici university department of foreign languages for editing the english of the paper. references 1. kim n, thrash b, menter a. comorbidities in psoriasis patients. semin cutan med surg. 2010;29(1):10-15. doi: 10.1016/j. sder.2010.01.002. pmid: 20430302. 2. lotti t, hercogova j, prignano f. the concept of psoriatic disease: can cutaneous psoriasis any longer be separated by the systemic comorbidities? dermatol ther. 2010;23(2):119-122. doi: 10.1111/j.1529-8019.2010.01305.x. pmid: 20415818. 3. altunay i, tukenmezdemirci g, ates b, et al. do eating disorders accompany metabolic syndrome in psoriasis patients? results of a preliminary study. clin cosmetinvestig dermatol.2011;4:139-143. doi: 10.2147/ccid.s24165. pmid: 21931499. 4. herron md, hincley m, hoffman ms, et al. impact of obesity and smoking on psoriasis presentation and management. arch dermatol. 2005;141(12):1527-1533. doi:10.1001/archderm.141.12.1527. pmid: 16365253. 5. sterry w, strober be, menter a; 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syndrome in the world and turkey.turkiyeklinikleri j int med sci.2006;2:18-24. 24. gemalmaz a, aydin s, basak o, discigil g, kurul a. prevalence of metabolic syndrome in a rural turkish population: comparison and concordance of two diagnostic criteria. turk j med sci.2008;38(2):159-165.https://app.trdizin.gov.tr/publication/ paper/detail/tnpnne5uvte= 25. ferdinando lb, fukumoto pk, sanches s, fabricio lhz, skare tl. metabolic syndrome and psoriasis: a study in 97 patients. rev assoc med bras. 2018;64(4):368-373. doi: 10.1590/18069282.64.04.368. pmid: 30133617. 26. gisondi p, fostini ac, fossà i, girolomoni g, targher g. psoriasisandthemetabolicsyndrome. clindermatol. 2018;36(1):21-28. doi:10.1016/j.clindermatol.2017.09.005. pmid: 29241748. 27. zindanci i, albayrak o, kavala m, et al. prevalence of metabolic syndrome in patients with psoriasis. the scientific world journal. 2012;2012:312463. doi:10.1100/2012/312463. pmid:22654590. 28. tasliyurt t, bilir y, sahin s, et al. erectile dysfunction in patients with psoriasis: potential impact of the metabolic syndrome. eur rev med pharmacol sci. 2014;18(4):581–586. pmid: 24610625 29. adişen e, uzun s, erduran f, gürer ma. prevalence of smoking, alcohol consumption and metabolic syndrome in patients with psoriasis. an bras dermatol. 2018;93(2):205-211. doi: 10.1590/ abd1806-4841.20186168. pmid: 29723384. 30. baeta ig, bittencourt fv, gontijo b, marcos e, goulart a. comorbidities and cardiovascular risk factors in patients with psoriasis. an bras dermatol. 2014;89(5):735-744. doi:10.1590/abd18064841.20142874. pmid: 25184912. 31. balkan f. metabolic syndrome.article in turkish. ankara med j.2013;13:85-90. https://dergipark.org.tr/tr/pub/amj/issue/1739/21396 32. kim gw, park hj, kim hs, et al. analysis of cardiovascular risk factors and metabolic syndrome in korean patients with psoriasis. ann dermatol.2012;24(1):11-15. doi: 10.5021/ ad.2012.24.1.11. pmid: 22363149. 33. itani s, arabi a, harb d, hamzeh d, kıbbi ag. high prevalence of metabolic syndrome in patients with psoriasis in lebanon: a prospective study. int j dermatol.2016;55(4):390-395. doi: 10.1111/ijd.12811. pmid: 26748974. 34. polic mv, miskulin m, smolic m, et al. psoriasis severity-a risk factor of insulin resistance independent of metabolic syndrome. int j environ res public health. 2018 13;15(7):1486. doi: 10.3390/ijerph15071486. pmid: 3001841. 35. henry al, kyle sd, bhandari s, chisholm a, griffiths cem, bundy c. measurement, classification and evaluation of sleep disturbance in psoriasis: a systematic review. plos one. 2016;21;11(6):e0157843. doi: 10.1371/journal.pone.0157843. pmid: 27327082. 36. hawro t, hawro m, zalewska-janowska a, weller k, metz m, maurer m. pruritus and sleep disturbances in patients with psoresearch | dermatol pract concept. 2021;11(3):e2021049 11 riasis. arch dermatol res.2019;312(2):103-111. doi: 10.1007/ s00403-019-01998-7.pmid: 3131671. 37. biçici f, hayta sb, akyol m, özçelik s, çınar z. evaluation of sleep quality in patients with psoriasis. turkderm. 2015;49(3):208-212. doi: 10.4274/turkderm.70707 38. gowda s, goldblum om, mccall wv, feldman sr. factors affecting sleep quality in patients with psoriasis. j am acad dermatol. 2010;63(1):114-123. doi: 10.1016/j.jaad.2009.07.003. pmid: 19944485. 39. melikoglu m. sleep quality and its association with disease severity in psoriasis. eurasian j med.2017;49:124-127. doi: 10.5152/ eurasianjmed.2017.17132. pmid: 28638255. 40. jensen p, zachariae c, skov l, zachariae r. sleep disturbance in psoriasis—a case-controlled study. br j dermatol. 2018;179(6):1376-1384. doi: 10.1111/bjd.16702. pmid: 29704428. 41. shutty bg, west c, huang ke, et al. sleep disturbances in psoriasis. dermatol online j. 2013;19(1)1. pmid: 23374943. 42. stinco g, trevisan g, piccirillo f, et al. psoriasis vulgaris does not adversely influence the quality of sleep. g ital dermatol venerol. 2013;148(6):655-659. pmid: 24442047. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021042 1 what’s under the veil? michela starace, miriam anna carpanese, francesca bruni, iria neri, bianca maria piraccini, aurora alessandrini dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: phthirus pubis, parasite infestation, scalp involvement, sexually transmitted disease citation: starace m, carpanese ma, bruni f, neri i, piraccini bm, alessandrini a. what’s under the veil? dermatol pract concept. 2021; 11(3): e2021042. doi: https://doi.org/10.5826/dpc.1103a42 accepted: november 12, 2020; published: july 8, 2021 copyright: ©2021 starace et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none declared. authorship: all authors have contributed significantly to this publication. corresponding author: miriam anna carpanese md, department of experimental, diagnostic and specialty medicine division of dermatology, university of bologna, bologna, italy, via massarenti, 1, 40138 bologna, italy. email: miriam.carpanese@gmail.com introduction phthirus pubis is an ectoparasite, whose only host are humans. phthirus pubis is responsible for the corresponding parasitic infestation that is sexually transmitted and usually affects the genital areas. despite being rare, scalp involvement is becoming increasingly frequent because of the increasing habit of pubic hair removal. we present the case of a pregnant woman with isolated scalp involvement and a diffuse cutaneous rash of the body. case presentation a 21 year old woman from pakistan, 22 weeks pregnant, presented with a widespread intensely pruritic cutaneous rash of the body that persisted in the last 1 month. she had been previously examined at the maternity department and at the emergency room without a diagnosis. dermatological examination revealed reddish and itchy papules surrounded by erythema and scratching lesions over the trunk, the arms, and the back. (figure 1, a and b). the patient was asked to remove the veil from her head to facilitate the physical examination. with some resistance and difficulty, the patient finally removed the veil. this was the first time her scalp was examined as no one had ever asked her to do so in the previous examinations. the scalp was completely covered in both live lice and nits. a video of walking lice was also taken (supplementary material). (figure 1c). the presence of crusty and scaly plaques over the patient’s ear and the neck indicated a secondary impetiginisation, due to scratching. no lice were found upon body inspection. when asked about her clinical history the patient confirmed that her husband also presented the same symptoms, especially at the level of the genital area, on pubic hairs. this anamnestic data and the identification of the lice allowed to diagnose a phthirus pubis infestation that was exclusively located on the scalp. treatment included total hair shaving and successive application of a malathion solution. conclusion phthirus pubis is an obligate ectoparasite, it is usually sexually transmitted and spreads via the direct contact whit an affected person. phthirus pubis classically affects pubic, axillary and body hair, but also beard, scalp and eyelash infestation have been described. the scalp involvement is very 2 letter | dermatol pract concept. 2021; 11(3): e2021042 rare, in these cases it might be the only location affected, as experienced by our patient. the increasing diffusion of pubic hair removal’s habit, destroying the lice’s natural habitat is an effective preventive procedure against phthirus pubis [1]. phthirus pubis showed the ability to change its tropism, leading to increasingly frequent atypical infestations in other parts of the body such as scalp, eyebrows, axillae, and trunk. as the atypical patterns of pubic lice infestation are becoming more frequent compared to the past, it is important to recognise phthirus pubis in cases of resistant pruritus and dermatitis [2]. this reported case highlights the importance of considering an eventual phthirus pubis infestation in patients presenting a lice infestation, exclusively affecting the scalp. this consideration allows for a correct diagnosis and treatment, including the treatment of sexual partners. finally, another important take-home message is to always perform a full body examination, also in parts where the patient denies the disease. supplementary materials the video showing reported live lice on the patient’s head is available at: https://youtu.be/uplfzrc8nrm references 1. veraldi s, schianchi r, ramoni s, nazzaro g. pubic hair removal and phthirus pubis infestation. int j std aids. 2018; 29(1):103104. doi: 10.1177/0956462417740292. pmid: 29130406 2. jimenez-cauhe j, fernandez-nieto d, ortega-quijano d, ramos-rodriguez d. characterization of phthirus pubis with ex vivo dermoscopy. sex transm dis. 2020;47(4):280-281. doi: 10.1097/olq.0000000000001126. pmid: 32004257 figure 1. (a) reddish and itchy papules surrounded by erythema and scratching lesions over the trunk, the legs and the arms. (b) over the back. (c) live lice and nits covering the scalp of the patient. dermatology practical & conceptual www.derm101.com editorial | dermatol pract concept 2012;2(3):1 1 european dermatology: great past— no future? the title of this article is not my own creation. it was suggested by the editor of the journal, but i eagerly agreed to use it because i strongly disagree with it. not all the past of european dermatology was great (i am focusing mainly on central europe). there were our giants: founding fathers who established the foundation of our discipline, established schools and created an aura of excellence nonpareil around themselves. but there were also mediocre epigones during whose times the progress of dermatology froze or came to a standstill. we recently overcame a lengthy period of stagnation one generation ago. and why no future? dermatology has probably never experienced a better time than it has had in the past years, and the luster of our specialty shows no sign of fading; there are still many research problems to explore, many interesting diagnoses to be made, there is a constant influx of new highly effective therapies, and most dermatologists both in hospital and private practice are doing well economically. i believe that the future of dermatology may be bright. we cannot afford to sit back and expect this to simply happen; it will take considerable efforts on the part of all of us to insure this rosy future. besides its greatness, the history of dermatology also shows some degree of faintheartedness and a staunch and slightly paranoid preparedness to keep intruders from its premises. we never have given up territory voluntarily, even if we felt that our overstretched forces could not hold it any longer. one of my first impressions in dermatology, around 1966 on the occasion of a meeting of the austrian dermatological society, was of a universal sense of cassandra-like doom, which broke out because the “lupus-station” of a large peripheral hospital in vienna was closed down by the hospital authorities. the lupus-station was a ward of several dozen beds exclusively allotted (at least theoretically) to patients with skin tuberculosis—most beds being empty, of course, because the incidence of tuberculosis had dropped dramatically after world war ii. skin doctors may suffer somewhat from a freudian trauma: however smart they may be in research or in clinical performance, they feel that the fellow physicians and the general public hold them in mild disregard because dermatology is not perceived as “real” medicine. this attitude is not so much sensed in large cities with a long tradition in dermatology, but more clearly in small towns. this is probably one of the reasons why the dermatology department is usually among the first victims in hospitals when it comes to the reduction of beds or the cutting of funds. it is not surprising that in the 1930s in vienna, two-thirds of dermatologists were jewish—they were simply not welcome in “real” medicine, like internal medicine or surgery. we still bear some of this basic mistrust, and we bare our teeth when we see our dominance over melanoma, lymphoma, autoimmune diseases and many other disorders threatened. interestingly, the rise of dermatology began when the skin was finally perceived as an organ of its own; now, when it is clear that this organ obeys the same rules as most others, alarmists fear that competition from other specialties may lead to its fall. but there is a counter-trend. in our part of the world, dermatology has swallowed a large european dermatology: great past—no future? peter fritsch, m.d.1 1 chairman emeritus, department of dermatology and venereology, medical university of innsbruck, austria citation: european dermatology: great past—no future? [editorial]. dermatol pract conc. 2012;2(3):1. http://dx.doi.org/10.5826/ dpc.0203a01. copyright: ©2012 fritsch. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: email: esther.fritsch@chello.at. 2 chapter | dermatol pract concept 2012;2(3):1 number of “subspecialties” like allergy, histopathology, phlebology, and (in some places) proctology and andrology, not to mention cosmetic dermatology. this umbrella approach has functioned well for some decades, but now we are at a crossroads; we do not have the manpower to handle all these ample fields properly, nor to provide adequate teaching for our juniors. an experienced university dermatologist specializing in allergy has calculated that all the dermatology centers in austria together could not possibly handle the testing of drug allergy patients, even if freed from all other clinical work, if the guidelines for drug testing were strictly followed. equally disquieting is the threat to dermatohistopathology. due to the rigid training rules imposed by regulatory authorities, it will be very difficult to maintain continuing education in the field of dermatopathology. its disappearance from smaller dermatology departments in austria is a realistic possibility. medicine in austria, and probably in most of europe, is threatened by the current financial crisis. in austria, the problem began a number of years ago with the ever-increasing savings plans, which impoverished the wissenschaftsfonds (the central austrian agency for funding research) and bled the universities and hospitals financially, which then led to a shortage of personnel and funds. in dermatology, the problem is compounded by a vicious circle of hyperactivity: still too many beds, too many wards, too many outpatients, and too many subspecialties—all making it hard to provide adequate care and still nurture an intellectual discipline. there is no easy way out. we have to reconsider our overall position in the medical system: we will probably have to jettison some of our pet clinical and laboratory activities, adjust and focus on our patient care, downsize our facilities and try to cooperate (as difficult as it may be) with the hospital authorities. most crucially, we must then redirect our energies into rewarding research and clinical activities. this is not easy and may provoke resistance from politicians and patients. there is also a serious flaw in the idea of trying to get rid of “simple” cases in order to get leeway for more important things; routine cases are the indispensable training ground for excellent clinical performance. i have seen quite a number of outstanding academic dermatologists who have had difficulties in making simple diagnoses. in the present time of shortage of personnel and funds, we have to reject the outdated tenet that the dermatologist must master the laboratory work himself. when i was a resident, it was the residents who worked in histochemistry, electron microscopy, cell culture and other fields. this was appropriate many years ago and served a good purpose, but now the doctors are needed in clinical work, and laboratory work has become much too difficult to be mastered by non-professionals. today, we must cooperate with phds, but the goal and direction of research must be defined by the physician. in the old times, the research questions were directly generated from clinical problems. i remember when my teacher, klaus wolff, told us during a laboratory meeting: “sitting in the refrigerator is a piece of pemphigus skin in which we will hopefully find intercellular immunoglobulin deposits at the ultrastructural level.” and so it was. today, research questions sometimes seem to be derived from an alternative universe. dermatologists should not forget that their research should primarily serve dermatological purposes. when i was a resident, we did not really feel that the function of langerhans cells would ever be unraveled, that melanoma could ever be defeated, and that the cause of genodermatoses would ever be pinpointed. today, we are very close to all these answers and many other goals. i am very curious as to what dermatology has in store for us in future. until then, we must try to adapt to the economic, organizational and structural conditions of today. this is a darwinian process like several others before which dermatology has successfully mastered. dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2020096 1 dermatology practical & conceptual case presentation an otherwise healthy 49-year-old man presented to the emergency department with complaint of a 3-day history of abdominal bulging (figure 1a) in the same location of a previous herpes zoster infection. the bulge increased with valsalva maneuver. skin examination still revealed residual lesions of herpes zoster (figure 1b). the final diagnosis was postherpetic pseudohernia, and at the 3-month follow-up visit, it had disappeared. teaching point herpes zoster is characterized by clustered maculopapular and vesicular lesions along a dermatome as a result of reactivation of varicella zoster virus in the dorsal root ganglia of abdominal wall postherpetic pseudohernia gerald selda-enriquez1, ana laura melian-olivera1, patricia burgos-blasco1, daniel ortega-quijano1 1 servicio de dermatología, hospital universitario ramón y cajal, irycis, madrid, spain key words: postherpetic pseudohernia, herpes zoster, infectious disease, dermatology citation: selda-enriquez g, melian-olivera al, burgos-blasco p, ortega-quijano d. abdominal wall postherpetic pseudohernia. dermatol pract concept. 2021;11(1):e2020096. doi: https://doi.org/10.5826/dpc.1101a96 accepted: june 8, 2020; published: december 10, 2020 copyright: ©2020 selda enriquez et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gerald selda-enriquez, md, servicio de dermatología, hospital universitario ramón y cajal, carretera colmenar viejo km 9.100, 28034 madrid, spain. email: geraldselda@gmail.com figure 1. (a) bulging is seen in the right abdomen. (b) erythematous maculopapular lesions due to herpes zoster are observed along the right t9-10 dermatome, consistent with the area where bulging is seen. a b 2 image letter | dermatol pract concept 2021;11(1):e2020096 references 1. healy c, mcgreal g, lenehan b, mcdermott ew, murphy jj. self-limiting abdominal wall herniation and constipation following herpes zoster infection. qjm. 1998;91(11):788‐789. doi: 10.1093/qjmed/91.11.788. pmid: 10024942. 2. yoo j, koo t, park e, et al. abdominal pseudohernia caused by herpes zoster: 3 case reports and a review of the literature. jaad case rep. 2019;5(8):729–732. doi: 10.1016/j.jdcr.2019.06.019. pmid: 31440570. peripheral nerves. an infrequent complication is postherpetic pseudohernia which arises when the anterior root ganglia is involved, thus provoking muscular paralysis [1]. differential diagnosis with true hernia by means of clinical and radiological exams is critical, as it does not require surgery and tends to disappear spontaneously in the majority of cases after less than a year [2]. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(1):e2021154 1 dermatology practical & conceptual dermoscopy of aplasia cutis congenita: a case report and review of the literature rasna neelam1, mio nakamura2, trilokraj tejasvi2 1 university of michigan medical school, ann arbor, mi, usa 2 department of dermatology, university of michigan, ann arbor, mi, usa key words: aplasia cutis congenita, alopecia, dermoscopy, trichoscopy citation: neelam r, nakamura m, tejasvi t. dermoscopy of aplasia cutis congenita: a case report and review of the literature. dermatol pract concept. 2021;11(1):e2021154. doi: https://doi.org/10.5826/dpc.1101a154 accepted: september 28, 2020; published: january 29, 2021 copyright: ©2021 neelam et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: trilokraj tejasvi, md, department of dermatology, university of michigan, 1910 taubman center, 1500 e. medical center dr, ann arbor, mi 48109, usa email: ttejasvi@med.umich.edu introduction aplasia cutis congenita (acc) is a rare heterogeneous congenital disorder characterized by focal or widespread absence of the skin. its estimated incidence is 1-3 in 10,000 live births and about 70% to 90% of cases present as isolated scalp lesions [1]. the condition can present variably depending on the tissue layers involved and the extent of healing in utero. commonly, acc presents as a small, solitary hairless skin defect covered with atrophic tissue, eschar, granulation tissue, or ulcerations. it can be classified into membranous and nonmembranous clinical subtypes and has also been categorized into 9 groups based on location and associated congenital anomalies [1]. herein, we describe a case of acc diagnosed by using dermoscopy as a helpful diagnostic tool. case presentation a woman in her early twenties with a history of alopecia since birth presented with 2-3 months of waxing and waning, dull, throbbing, and point tenderness in one of the patches of alopecia. the alopecic patch had been present on the right parietal-occipital scalp since birth and has been stable in size and appearance for years. three other round patches of alopecia had also been present since birth and remained asymptomatic. on clinical examination of the scalp, an atrophic white patch of alopecia was noted (figure 1). ill-defined bogginess was noted surrounding the lesion, extending to the central and posterior occipital scalp. the differential diagnosis included acc, alopecia areata, tinea capitis, and trichotillomania. on dermoscopic examination, the alopecic patch showed a translucent epidermis with multiple branched blood vessels and hair bulbs at the edge of the patch (figure 2). based on the clinical and dermoscopic findings, the diagnosis of acc was favored. a non-contrast head ct showed no evidence of osseous, vascular, neural, or soft tissue defects. the patient was counseled to avoid trauma to the lesion and was instructed to follow up with her primary care physician for management of scalp tenderness and pain, likely representing headache or migraine, rather than a symptom of the lesion. 1452_dp1101a154.indd 11452_dp1101a154.indd 1 22/01/21 11:45 am22/01/21 11:45 am 2 letter | dermatol pract concept 2021;11(1):e2021154 described as starburst-like [4] or “golf club set-like” [5] and are clearly visible from the bulbs to the follicular ostia under a thin epidermis. as noted above, on our dermoscopic evaluation, we noted a translucent epidermis, visible vascular network, and radially arranged hair bulbs. these specific findings are consistent with acc. dermoscopy is useful in distinguishing acc from other similar appearing disorders in its differential such as alopecia, tinea capitis, and trichotillomania. acc can be differentiated from other types of congenital or acquired alopecia, such as triangular temporal alopecia, which shows presence of vellus hairs only in affected sites; alopecia areata, which shows black dots, yellow dots, and exclamation hairs; tinea capitis, which shows coiled or comma shaped hairs; and trichotillomania, which shows broken hairs and flame hairs [3]. membranous acc can also be distinguished from nevus sebaceous by visualizing a lack of skin appendages and a translucent appearance [2]. while biopsy for histopathologic evaluation can be performed to diagnose acc, showing a thin layer of dermal collagen without epidermis or adnexal structures, biopsies can be avoided if the diagnosis can be made clinically. currently, there is no consensus on the management of acc. conservative therapy is generally suggested for small lesions, whereas the risks and benefits of surgical intervention are often weighed for treatment of larger lesions in consultation with pediatric plastic surgeons. in conclusion, dermoscopy/trichoscopy is a valuable diagnostic tool for acc and can help distinguish acc from other types of congenital or acquired alopecias. dermatologists should familiarize themselves with the dermoscopic findings of acc—a translucent epidermis, a visible vascular network, lack of appendages, and hair bulbs arranged radially along or sometimes within the margins of alopecia. references 1. martinez-regueir brackenrich j, brown a. aplasia cutis congenita. in: statpearls. treasure island (fl): statpearls publishing; 2020. 2. damiani l, aguiar fm, da silva mv, miteva mi, pinto gm. dermoscopic findings of scalp aplasia cutis congenita. skin appendage disord. 2017;2(3-4):177-179. doi:10.1159/000453041. doi: 10.1159/000453041. pmid:28232928. 3. rakowska a, małgorzata m, małgorzata z, et al. trichoscopy of focal alopecia in children-new trichoscopic findings: hair bulbs arranged radially along hair-bearing margins in aplasia cutis congenita. skin appendage dis. 2016;2(1-2):1-6.doi: 10.1159/000445721. pmid:27843914. 4. verzì ae, lacarrubba f, micali g. starburst hair follicles: a dermoscopic clue for aplasia cutis congenita. j am acad dermatol. 2016;75(4):e141-e142. doi: 10.1016/j.jaad.2016.02.1216. pmid:27646756. 5. cutrone m, grimalt r. the trichoscopic “golf club set” sign for bullous aplasia cutis congenita. skin appendage disord. 2018;4(4):320-322. doi: 10.1159/000486463. pmid:30410906. figure 1. an atrophic white patch of alopecia on the scalp figure 2. dermoscopy of the alopecic patch shows a translucent epidermis with multiple branched blood vessels and hair bulbs at the edge of the patch. conclusions recent published reports demonstrate the emerging use of dermoscopy and trichoscopy as a valuable tool for diagnosing acc [2-5]. dermoscopic images at hair-bearing margins reveal a translucent epidermis, a visible vascular network, and hair bulbs arranged radially along the margins of alopecia [2,3]. additional dermoscopic findings have included absent follicular openings, thicker vessels, and distinct collar hypertrichosis [2]. hair bulbs have been shown on trichoscopy, visible through a semi-translucent epidermis [3]. radially oriented, horizontally extending hair follicles have been 1452_dp1101a154.indd 21452_dp1101a154.indd 2 22/01/21 11:45 am22/01/21 11:45 am dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2020098 1 dermatology practical & conceptualdermatology practical & conceptual case presentation two infants aged 11 and 5 months consulted for eczematous plaques on the nape. their parents reported that the lesions had developed over previous erythematous stains. both cases corresponded to eczematous changes over nevus simplex, known as meyerson phenomenon (figure 1). meyerson phenomenon over nuchal nevus simplex ada claret-de castro1, marc mir-bonafé2, josé maría mir-bonafé3, juan francisco mir-bonafé4 1 department of pediatrics, hospital general de granollers, barcelona, spain 2 department of dermatology, hospital universitario central de asturias, oviedo, spain 3 department of dermatology, clínica juaneda, palma de mallorca, spain 4 department of dermatology, hospital son llàtzer, palma de mallorca, spain key words: meyerson phenomenon, nevus simplex, salmon patch, capillary malformation, eczematous changes citation: claret-de castro a, mir-bonafé m, mir-bonafé jm, mir-bonafé jf. meyerson phenomenon over nuchal nevus simplex. dermatol pract concept. 2021;11(1):e2020098. doi: https://doi.org/10.5826/dpc.1101a98 accepted: june 16, 2020; published: december 7, 2020 copyright: ©2020 claret-de castro et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. corresponding author: juan francisco mir-bonafé, md, department of dermatology, hospital son llàtzer, carretera manacor, pk4, palma de mallorca, spain. email: joanmirbonafe@gmail.com figure 1. two cases of meyerson phenomenon over nuchal nevus simplex. 1325-dp1101a98.indd 1 18/12/20 15:22 2 image letter | dermatol pract concept 2021;11(1):e2020098 treatment discontinuation, and pulsed dye laser therapy sometimes may be needed [2,5]. references 1. loh j, kenny p. meyerson phenomenon. j cutan med surg. 2010;14(1):30-32. doi: 10.2310/7750.2009.08065. pmid: 20128988. 2. tay yk, morelli j, weston wl. inflammatory nuchal-occipital port-wine stains. j am acad dermatol. 1996;35(5 pt 2):811-813. doi: 10.1016/s0190-9622(96)90090-0. pmid: 8912592. 3. rozas-muñoz e, frieden ij, roé e, puig l, baselga e. vascular stains: proposal for a clinical classification to improve diagnosis and management. pediatr dermatol. 2016;33(6):570-584. doi: 10.1111/pde.12939. pmid: 27456075. 4. pavlovic md, adamic m. eczema within port wine stain: spontaneous and laser-induced meyerson phenomenon. acta dermatovenerol alp pannonica adriat. 2014;23(4):81-83. doi: 10.15570/actaapa.2014.20. pmid: 25527042. 5. kim sj, kim yc. eczema within a capillary malformation: a case of meyerson phenomenon. ann dermatol. 2016:28(6):781-782. doi: 10.5021/ad.2016.28.6.781. pmid: 27904286. teaching point meyerson phenomenon is defined as a spontaneous eczematous reaction within an overlying skin lesion. this phenomenon was first reported in melanocytic lesions [1]; however, it has also been related to seborrheic keratosis, dermatofibroma, molluscum contagiosum, and many other lesions. although many hypotheses have been proposed, its origin is still unknown, and its relationship with atopic dermatitis remains controversial. even though meyerson phenomenon over capillary malformations is not frequent, it has been associated with nevus simplex [2,3], port-wine stains [4], and trunk and limb capillary malformations [5]. exceptionally, it has been reported after laser treatment [4]. although its diagnosis is clinical, in doubtful cases we may perform histopathological study. histopathological findings include characteristic features of eczema such as spongiosis, acanthosis, parakeratosis, and superficial dermal lymphocytic infiltrate overlying capillary ectasias [1,5]. prognosis is good, and topical corticosteroids are usually successfully used to treat the eczema. nevertheless, some lesions may recur after 1325-dp1101a98.indd 2 18/12/20 15:22 dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com research | dermatol pract concept 2012;3(2):5 41 mobile teledermoscopy—there’s an app for that! alexander börve, m.d.1, karin terstappen, m.d., ph.d.2, carin sandberg, m.d., ph.d.3, john paoli, m.d. 3 1 department of orthopaedics, sahlgrenska university hospital, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 department of dermatology and venereology, skaraborgs sjukhus, skövde, sweden 3 associate professor, department of dermatology and venereology, sahlgrenska university hospital, institute of clinical sciences at the sahlgrenska academy, university of gothenburg, gothenburg, sweden key words: mobile teledermoscopy, smartphone application, teledermatology, malignant melanoma, non-melanoma skin cancer citation: börve a, terstappen k, sandberg c, paoli p. mobile teledermoscopy—there’s an app for that! dermatol pract conc. 2013;3(2):5. http://dx.doi.org/10.5826/dpc.0302a05. received: october 23, 2012; accepted: january 15, 2013; published: april 30, 2013 copyright: ©2013 börve et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: the study was financed by grants from the federal government under the alf agreement and a grant from signe och olof wallenius stiftelse. competing interests: alexander börve is the owner of idoc24® ab. all authors have contributed significantly to this publication. corresponding author: john paoli, m.d., associate professor, department of dermatology and venereology, sahlgrenska university hospital, 413 45 gothenburg, sweden. tel. 46 730 40 40 44; fax. 46 31 821 871. email: john.paoli@vgregion.se. background: the introduction of the smartphone with high-quality, built-in digital cameras and easyto-install software may make it more convenient to perform teledermatology. in this study we looked at the feasibility of using a smartphone (iphone 4®) with an installed application especially developed for teledermatology (idoc24®) and a dermoscope (fotofinder handyscope®) that is customized to attach to the smartphone to be able to carry out mobile teledermoscopy. objectives: to study the diagnostic accuracy of this mobile teledermoscopy solution, to determine the interobserver concordance between teledermoscopists (tds) and a dermatologist meeting the patient face-to-face (ftf), and to assess the adequacy of the tds’ management decisions and to evaluate the image quality obtained. patients/methods: during a 16-week period, patients with one or more suspicious skin lesions deemed to need a biopsy or excision were included. the smartphone app was used to send a clinical image, a dermoscopy image and relevant clinical information to a secure internet platform (tele-dermis®). two tds assessed the incoming cases, providing a specific primary diagnosis and a management decision. they also graded the image quality. the histopathological diagnosis was used as the gold standard. results: sixty-nine lesions were included. the ftf dermatologist’s diagnostic accuracy was 66.7%, which was statistically higher than td 1 (50.7%, p=0.04) but similar to td 2 (60.9%, p=0.52). the interobserver concordances between the ftf dermatologist and the two tds and between the respective tds showed moderate to substantial agreement. the tds provided adequate management decisions for 68 (98.6%) and 69 (100%) lesions, respectively. the image quality was rated as excellent or sufficient in 94% and 84% of the cases by the respective tds. conclusion: this novel mobile teledermoscopy solution may be useful as a triage tool for patients referred to dermatologists for suspicious skin lesions. abstract 42 research | dermatol pract concept 2012;3(2):5 introduction the incidence of skin cancer is increasing among fair-skinned individuals worldwide due to excessive sun exposure, an older population, and an increase in the number of immunosuppressed patients [1,2]. in 2010, melanoma and squamous cell carcinoma represented 14% of all cancers diagnosed in sweden [3]. furthermore, 15% of male and female swedes will develop at least one basal cell carcinoma before the age of 74 years [4]. meanwhile, national health budgets in the western world are strained with limited resources to handle an aging population [5]. in sweden, referrals from general practitioners (gps) are paper-based, are sent by post, and contain no photographic documentation. in addition, they often lack important descriptive clinical details. with written paper referrals, there is a theoretical risk that patients with malignant lesions can be incorrectly triaged as having a low level of suspicion with subsequent long waiting times and vice versa. therefore, novel and more effective approaches to how skin cancer patients are referred to dermatologists are warranted. sending digital images of skin lesions with relevant clinical information to a dermatologist for his/her opinion is known as teledermatology [6]. when dermoscopic images of the lesions are included, the consultation is called teledermoscopy [7]. teledermatology and teledermoscopy have shown promising results with high concordance in diagnostic accuracy in comparison with face-to-face (ftf) visits [8-16]. clinical and dermoscopic images and relevant clinical information can be sent by email [8,14], through specialized telemedicine software and virtual private networks for online consultation [9,10,12,13,15] or via multimedia messaging system (mms) [17]. today, with the introduction of smartphones with built-in digital cameras and internet connectivity, one could also use a so-called mobile application or “app” for teledermatology. moreover, several companies have also started producing dermoscopes that can be coupled with smartphones. in other words, mobile teledermoscopy referrals could become a reality if gps were provided with a smartphone with a pre-installed teledermoscopy referral app and a customized dermoscope. the primary objective of this study was to determine the diagnostic accuracy of a digital referral process using a novel mobile teledermoscopy app. the secondary objectives were to analyze the interobserver concordances between two teledermoscopists (tds) and a ftf dermatologist, the adequacy of the management decisions provided by the tds, as well as the quality of the acquired images. materials and methods during a 16-week period, consecutive patients with one or more suspicious skin lesions were included in the study if a biopsy or excision was deemed to be necessary after clinical and dermoscopic examination during a ftf visit with a single dermatologist. all patients had previously been referred to the department of dermatology at sahlgrenska university hospital by a gp. the exclusion criteria were: patients under 18 years, patients with no knowledge of the swedish language, skin lesions located on a part of the skin that did not allow for digital photography with the smartphone and customised dermoscope used in the study and skin lesions in which histopathological examination was not performed. the local ethics committee approved the study and all patients gave written informed consent prior to inclusion. the study was carried out using a smartphone (iphone® 4, apple, cupertino, california, usa), a dermoscope customised to be attached to the smartphone (fotofinder handyscope®, fotofinder systems gmbh, bad birnbach, germany), a secure web-based teledermoscopy platform (tele-dermis®, idoc24® ab, gothenburg, sweden) and an iphone app (idoc24® ab, gothenburg, sweden) installed on the smartphone. this equipment is shown in figure 1. a dermatologist with several years of experience in the fields of skin cancer and dermoscopy first evaluated the skin lesions clinically and with manual dermoscopy during a ftf visit. before performing a biopsy or an excision, a case was created in the smartphone app for each skin lesion simulating a teledermoscopy referral. the app first prompted the user to take one clinical overview image of the skin lesion with the smartphone’s 5-megapixel digital camera using the autofocus function. in order to standardize photography as much as possible, the user was advised to acquire the images in a well-illuminated room, using a neutral background, no flash, autofocus and an appropriate distance from the patient to include the detail as well as important surrounding skin structures. then, a single dermoscopic image was taken with the same camera after attaching the smartphone to the customised dermoscope. the contact dermoscope used polarized light from lightemitting diodes and provided up to 20x magnification. the resulting digital photographs had a size of 1024 × 766 pixels. finally, all relevant clinical information about the patient and lesion were added to a standardized query form in the app including: age, sex, a lesion description, size (mm), localization, duration, symptoms, previous treatments and other relevant medical information. the referral was then sent to the tele-dermis® platform using the smartphone’s 3g internet connection. the whole referral process required approximately two minutes to carry out per case. all information sent through the app was anonymous. upon sending the referral, the app automatically created a unique 8-digit identification code that was saved in the referring physician’s smartphone and on the tele-dermis® platform. the system simultaneously sent email notifications research | dermatol pract concept 2012;3(2):5 43 to the two tds for assessment. the participating tds were two specialists in dermatology who also had several years of experience within the fields of skin cancer and dermoscopy. the email received by the tds contained a direct link to the tele-dermis® platform. after logging in, the cases were assessed and triaged independently by both tds on a computer screen (19-inch liquid crystal display monitor). they were asked to assess if the lesion was benign or malignant and if it was melanocytic or non-melanocytic. they were also asked to choose one of the following specific primary diagnoses: melanoma, melanoma in situ, dysplastic nevus, benign nevus, basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma in situ, actinic keratosis, seborrhoeic keratosis, dermatofibroma, angioma or other. potential differential diagnoses were not taken into consideration. furthermore, they provided a management decision figure 1. technologic equipment used in the mobile teledermoscopy solution: (a) the smartphone (iphone 4®) with the idoc24® app showing on the display; (b) the dermoscope (fotofinder handyscope®) with its six light-emitting diodes lit; (c) the dermoscope attached to the smartphone displaying a dermoscopic image of a reticular nevus; and (d) a dermatologist viewing a case on the internet platform (tele-dermis®). [copyright: ©2013 börve et al.] 44 research | dermatol pract concept 2012;3(2):5 (excision, biopsy, follow-up with digital dermoscopy or no treatment), they evaluated the image quality (excellent, sufficient or poor) and they judged the level of diagnostic difficulty (high or low). the same assessment was also carried out separately by the ftf-dermatologist. the assessments regarding the nature of the lesion (benign vs. malignant, melanocytic vs. non-melanocytic and the specific primary diagnosis) were compared to the histopathological diagnosis (gold standard) in order to analyse the diagnostic accuracy of the ftf-dermatologist and both tds. in order to study any differences between the ftf-dermatologist and the respective tds or between td 1 and td 2, exact mcnemar tests were carried out. the interobserver concordances for these parameters were also calculated using raw rate and cohen’s kappa () analyses. furthermore, interobserver concordances were analysed using the same statistical methods in regards to the management decision, the image quality and the level of diagnostic difficulty. statistical significance was taken as p <0.05. results sixty-two consecutive patients (24 female and 38 male) with a mean age of 64 years (range 25-94 years) were included in the study. six patients had multiple lesions. four of them had two lesions and two patients had three, which were initially included. however, one of the patients with three lesions ended up only having two excised during surgery. thus, one lesion was excluded, giving a total of 69 included lesions. the histopathological diagnoses and the nature of these 69 lesions are shown in table 1. in total, there were 40 malignant lesions (58%, 12 melanocytic and 28 non-melanocytic) and 29 benign lesions (42%, 18 melanocytic and 11 non-melanocytic). the number of melanocytic and nonmelanocytic lesions was thus 30 (43.5%) and 39 (56.5%), respectively. table 1. number of benign or malignant and melanocytic or non-melanocytic lesions included in the study. [copyright: ©2013 börve et al.] histopathological diagnosis number of lesions (%) malignant melanocytic lesions melanoma 5 (7.2%) melanoma in situ 7 (10.1%) benign melanocytic lesions dysplastic nevus 12 (17.4%) benign nevus 6 (8.7%) malignant non-melanocytic lesions basal cell carcinoma 25 (36.2%) squamous cell carcinoma 1 (1.4%) squamous cell carcinoma in situ 1 (1.4%) cutaneous metastasis 1 (1.4%) benign non-melanocytic lesions seborrhoeic keratosis 6 (8.7%) angioma 2 (2.9%) other 3 (4.3%) total 69 (100%) the diagnostic accuracy of the ftf dermatologists and the two tds is shown in table 2. the specific primary diagnosis given by the ftf dermatologist was correct for 46 lesions (66.7%), showing statisti table 2. diagnostic accuracy of the face-to-face dermatologist and the two teledermoscopists in relation to the specific primary diagnosis and the classification of the lesion in different diagnostic categories. [copyright: ©2013 börve et al.] diagnostic level ftf (95% ci)* td 1 (95% ci)* td 2* (95% ci)* primary diagnosis 66.7% (54.9–76.6%) 50.7% (39.2–62.2%) 60.9% (49.1–71.5%) benign vs malignant 87.0% (77.0–93.0%) 75.4% (64.0–84.0%) 79.7% (68.8–87.5%) melanocytic vs non-melanocytic 89.9% (80.5–95.0%) 84.1% (73.7–90.9%) 92.8% (84.1–96.9%) combination** 79.7% (68.8–87.5%) 68.1% (56.4–77.9%) 76.8% (65.6–85.2%) *ftf, face-to-face dermatologist; td 1, teledermoscopist 1; td 2, teledermoscopist 2; ci, confidence interval. **combination of correct classification as benign or malignant and melanocytic or non-melanocytic. research | dermatol pract concept 2012;3(2):5 45 cally higher accuracy than td 1 who diagnosed 35 lesions correctly (50.7%, p=0.04) but similar accuracy compared to td 2 who had 42 correct diagnoses (60.9%, p=0.52). no statistical differences were observed between the two tds for the specific primary diagnosis (p=0.19). accuracy increased for all three dermatologists when it came to classifying the lesions as benign or malignant and/or melanocytic or nonmelanocytic. as shown in table 2, the diagnostic accuracy was highest for all three dermatologists when differentiating between melanocytic and non-melanocytic lesions but dropped slightly when classifying the lesions as benign or malignant. consequently, the diagnostic accuracy in regards to lesion classification combining the diagnostic categories was also lower. for the classification of the lesions as benign or malignant, melanocytic or non-melanocytic and the combination of both criteria, no statistical differences were observed between the ftf dermatologist and the respective tds or between td 1 and td 2. as shown in table 3, the interobserver concordance (raw rate) for the specific primary diagnosis was 55% between the ftf dermatologist and td 1, 57% between the ftf dermatologist and td 2, and 58% between td 1 and td 2. the resulting cohen’s  values were 0.47, 0.48 and 0.51, respectively. the interobserver concordances for lesion classification in the different diagnostic categories ranged from 71-91% with  values of 0.49-0.82. the interobserver concordances observed between the ftf dermatologist and the two tds and between the respective tds were practically identical for all levels of diagnosis. management decisions were only considered to be adequate for malignant melanocytic lesions if the dermatologist chose to excise them. biopsy or excision was considered adequate management for malignant non-melanocytic lesions, whereas any alternative was considered adequate for all benign lesions. the tds were not completely blinded table 4. management decisions. [copyright: ©2013 börve et al.] management ftf * td 1* td 2* excision 53 46 51 biopsy 16 9 9 fu digital dermoscopy* 0 2 5 no treatment 0 12 4 *ftf, face-to-face dermatologist; td 1, teledermoscopist 1; td 2, teledermoscopist 2; fu, follow-up table 3. interobserver concordance. [copyright: ©2013 börve et al.] ftf vs td 1* ftf vs td 2* td 1 vs td 2* diagnostic level ioc (95% ci)* κ* ioc (95% ci)* κ* ioc (95% ci)* κ* primary diagnosis 55% (43–67%) 0.47 57% (44–68%) 0.48 58% (45–70%) 0.51 benign vs malignant 77% (65–86%) 0.50 78% (67–87%) 0.50 78% (67–87%) 0.49 melanocytic vs non-melanocytic 88% (78–95%) 0.77 91% (82–97%) 0.82 88% (78–95%) 0.77 combination** 71% (59–81%) 0.60 72% (60–83%) 0.61 71% (59–81%) 0.59 *ftf, face-to-face dermatologist; td 1, teledermoscopist 1; td 2, teledermoscopist 2; ioc, interobserver concordance; ci, confidence interval; κ, kappa value. **combination of correct classification as benign or malignant and melanocytic or non-melanocytic. from the ftf dermatologist’s management decision since they knew that all lesions were going to be either biopsied or excised, but they still elected follow-up with digital dermoscopy or no treatment for some cases as shown in table 4. subsequently, td 1 provided adequate management decisions in 68 cases (98.6%). in one case, ‘no treatment’ would have been chosen for a melanoma in situ that was given a primary specific diagnosis of benign nevus. td 2 would have managed all 69 cases (100%) adequately. the interobserver concordance in regards to the management decisions between the tds was 68% (95% ci, 56-79%) with a  value of 0.34. regarding the diagnostic difficulty of the 69 lesions, the ftf dermatologist considered that 37 lesions had a high diagnostic difficulty (53.6%). however, td 1 and td 2 scored 60 (87.0%) and 42 lesions (60.9%) respectively as having a high diagnostic difficulty. the image quality was deemed to be excellent in 61 cases (88.4%) and sufficient in 8 cases (11.6%) by the ftf dermatologist. td 1’s ratings were clearly worse with 65 cases (94.2%) rated as having sufficient quality and 4 cases (5.8%) as having poor quality. td 2’s scores were in between, resulting in 15 cases (21.7%) 46 research | dermatol pract concept 2012;3(2):5 with excellent quality, 43 cases (62.3%) with sufficient quality and 11 cases (15.9%) with poor quality. there was poor agreement between all three dermatologists regarding the image quality ( values around 0). three examples of the image quality obtained are shown in figure 2. discussion the diagnostic accuracy of the tds using this novel mobile teledermoscopy app was comparable to that of the ftf dermatologist in regards to the primary diagnosis and in regards to the classification of the lesions in the various diagnostic categories. the only statistically significant difference was the lower diagnostic accuracy of td1 in regards to the primary diagnosis (50.7%), when compared to the ftf dermatologist (66.7%). overall, the diagnostic accuracy in regards to the primary diagnosis in our study was within the ranges observed in two teledermoscopy studies designed similarly to ours. in these studies, the diagnostic accuracy for the primary diagnosis was 46.8 % for nonpigmented neoplasms and 51.6%-56.9% for pigmented neoplasms depending on the type of dermoscope used [9,10]. in comparison with other teledermoscopy studies, however, the diagnostic accuracy of the tds in our study was slightly lower, which in most cases may be due to differences in study design. tan et al obtained a diagnostic accuracy of 72.3% using teledermoscopy, but included evidently benign lesions and did not use histopathology as their gold standard [15]. in a swiss study including 55 histopathologically verified lesions, the diagnostic accuracy was 74.5 % when classifying the lesions in diagnostic categories [12]. in a study by blum et al, three tds with varying experience in dermoscopy reviewed 157 lesions and were able to recognize the correct diagnostic category in 87.0%-90.7% of the cases [11]. a recent study using dermoscopic images taken with a mobile phone camera manually applied onto a pocket dermoscope showed a diagnostic accuracy of 75%. however, this study included differential diagnoses, 8% of the lesions were excluded due to poor image quality and not all lesions were confirmed histopathologically [13]. a study by piccolo et al on 66 lesions resulted in a diagnostic accuracy of 86%, but 97% of the lesions were benign [16]. similarly, a spanish study including 61 cases rendered an accuracy of 94%, but only two lesions were malignant [14]. interestingly though, another study by piccolo et al. showed a very high diagnostic accuracy, varying from 77% to 95%, with greater accuracy among tds with more experience in dermoscopy. in this study, lesions with a high diagnostic difficulty were included and histopathology was used as their gold standard [8]. figure 2. image quality of four different lesions included in the study. clinical and dermoscopic images of: (a,b) a spitzoid nodular melanoma; (c,d) a seborrheic keratosis (note: this was the only case in which both teledermoscopists rated the images as having poor quality); (e,f)) a basal cell carcinoma; and (g,h) a dysplastic nevus. [copyright: ©2013 börve et al.] research | dermatol pract concept 2012;3(2):5 47 in our study, a relatively high interobserver concordance with moderate to substantial agreement between the ftf dermatologist and the tds and between the two tds was observed. the interobserver concordance was highest when distinguishing between melanocytic and non-melanocytic lesions. the tds would have recommended ‘no treatment’ for a few lesions. this could have resulted in inadequate management of a patient with mm in situ. it is therefore important to remember that such a risk exists if teledermoscopy is to be used to avoid ftf visits. melanomas have been underdiagnosed as benign melanocytic nevi or seborrheic keratoses in other teledermoscopy studies as well [8,9,11,15,18]. the rating of the image quality varied greatly between the three dermatologists. the ftf dermatologist found all images to have a satisfactory image quality, whereas the tds rated 4 and 11 cases (14 different cases), respectively, as having poor quality. this may be due to a grading bias since the ftf dermatologist acquired the images himself, whereas the tds were perhaps influenced negatively by the high diagnostic difficulty of these 14 cases. in fact, both tds graded all of these cases as having a high diagnostic difficulty and the ftf dermatologist graded 12 of these 14 cases in the same way. nevertheless, no images needed to be excluded due to poor quality. as seen in other teledermoscopy studies, poor image quality did not correlate with lower diagnostic accuracy for any of the three dermatologists [8,9,16]. in images with suboptimal quality, the inclusion of relevant clinical information about the patient and the lesion may act as a complement to the images and help the dermatologist with his/her assessment [11]. goulart et al recently identified a possible use for dermoscopy in skin self-examination [19]. although this mobile teledermoscopy app could be used by patients directly, our initial intention is to use it in triaging patients with suspicious skin lesions that are referred to dermatologists from gps. in this sense, there are several limitations to this study. first of all, there was a selection bias since only lesions requiring biopsy or excision were included. the tds were aware of this fact, which may have influenced their management decisions. this selection bias also means that the assessed lesions do not reflect the wider spectrum of diagnoses seen among all the patients referred to us in routine clinical practice. if the app were used for referral triage, the proportion of benign lesions would certainly increase and histopathological confirmation would not always be ethically possible. also, differential diagnoses would have to be taken into account in such a scenario since these could affect patient prioritization. furthermore, all images in this study were taken by the ftf dermatologist, who had experience in using the imaging equipment. the image quality may be affected negatively when the smartphones are put in the hands of gps. in order to assess how this app would perform as a triage tool, our group has initiated a larger prospective, multicenter, teledermoscopy trial in which gps from multiple primary health care centers will refer patients with suspicious lesions to tds at two hospitals in western sweden using this app. potentially, this could lead to more accurate patient prioritization and the possibility of planning for surgery on the patient’s first visit to the dermatologist when necessary. also, the referring gp could receive faster feedback regarding the suspected diagnosis and the dermoscopic findings, adding educational value. furthermore, patients with evidently benign lesions could receive reassuring news almost directly, thereby avoiding the nervous wait of weeks or months before finally meeting with a specialist. using teledermatology and teledermoscopy for triaging patients with a suspicion of skin cancer has already been shown to be both feasible and economically viable [20-22]. like other teledermoscopy solutions, the app provides a digital referral system that can transfer all relevant clinical information in combination with high-quality digital clinical and dermoscopic images to a dermatologist within seconds. contrary to other teledermoscopy solutions, the whole teledermoscopy solution fits in your pocket and does not require any cables or the need to transfer images from a camera to a computer prior to sending the case. furthermore, the standardized query form minimizes the risk of the gp forgetting to include relevant clinical information in the referral. lastly, and as we have shown here, this mobile teledermoscopy solution allows tds to achieve a diagnostic accuracy comparable that of a ftf dermatologist. the introduction of smartphones with easy-to-install “apps” can potentially revolutionize the way gps communicate with dermatologists. in 2009, massone et al envisioned “one click” skin cancer diagnosis through mobile teledermoscopy, and this app takes us a step closer to this goal [7]. references 1. van der leest rj, de vries e, bulliard jl, et al. the euromelanoma skin cancer prevention campaign in europe: characteristics and results of 2009 and 2010. j eur acad dermatol venereol. 2011;25:1455-65. 2. sullivan an, bryant ea, mark la. malignant melanoma in transplant patients: a case report and review of the literature. cutis. 2012;89:133-6. 3. welfare tscrnboha. cancer incidence in sweden 2010, 2011. 4. welfare tscrnboha. basal cell carcinoma in sweden 20042008, 2010. 5. welfare nboha. the status and development in health care and social services in sweden 2011, 2012. 6. whited jd. teledermatology research review. int j dermatol. 2006;45:220-9. 48 research | dermatol pract concept 2012;3(2):5 7. massone c, brunasso am, campbell tm, soyer hp. mobile teledermoscopy—melanoma diagnosis by one click? semin cutan med surg. 2009;28:203-5. 8. piccolo d, smolle j, argenziano g, et al. teledermoscopy—results of a multicentre study on 43 pigmented skin lesions. j telemed telecare. 2000;6:132-7. 9. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for pigmented neoplasms. j am acad dermatol. 2009;61:753-65. 10. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for nonpigmented neoplasms. j am acad dermatol. 2009;60:579-88. 11. blum a, hofmann-wellenhof r, luedtke h, et al. value of the clinical history for different users of dermoscopy compared with results of digital image analysis. j eur acad dermatol venereol. 2004;18:665-9. 12. braun rp, meier m, pelloni f, et al. teledermatoscopy in switzerland: a preliminary evaluation. j am acad dermatol. 2000;42:770-5. 13. kroemer s, fruhauf j, campbell tm, et al. mobile teledermatology for skin tumour screening: diagnostic accuracy of clinical and dermoscopic image tele-evaluation using cellular phones. br j dermatol. 2011;164:973-9. 14. moreno-ramirez d, ferrandiz l, bernal ap, duran rc, martin jj, camacho f. teledermatology as a filtering system in pigmented lesion clinics. j telemed telecare. 2005;11:298-303. 15. tan e, yung a, jameson m, oakley a, rademaker m. successful triage of patients referred to a skin lesion clinic using teledermoscopy (image it trial). br j dermatol. 2010;162:803-11. 16. piccolo d, smolle j, wolf ih, et al. face-to-face diagnosis vs telediagnosis of pigmented skin tumors: a teledermoscopic study. arch dermatol. 1999;135:1467-71. 17. borve a, holst a, gente-lidholm a, molina-martinez r, paoli j. use of the mobile phone multimedia messaging service for teledermatology. j telemed telecare. 2012;18:292-6. 18. ferrara g, argenziano g, cerroni l, et al. a pilot study of a combined dermoscopic-pathological approach to the telediagnosis of melanocytic skin neoplasms. j telemed telecare. 2004;10:34-8. 19. goulart jm, malvehy j, puig s, et al. dermoscopy in skin selfexamination: a useful tool for select patients. arch dermatol. 2011;147:53-8. 20. lim d, oakley am, rademaker m. better, sooner, more convenient: a successful teledermoscopy service. australas j dermatol. 2012;53:22-5. 21. moreno-ramirez d, ferrandiz l, nieto-garcia a, et al. storeand-forward teledermatology in skin cancer triage: experience and evaluation of 2009 teleconsultations. arch dermatol. 2007;143:479-84. 22. moreno-ramirez d, ferrandiz l, ruiz-de-casas a, et al. economic evaluation of a store-and-forward teledermatology system for skin cancer patients. j telemed telecare. 2009;15:40-5. book review | dermatol pract concept 2012;2(1):15 79 the cover figure 1. weedon d. weedon’s skin pathology. 3rd ed. london: churchill livingstone elsevier, 2010. two volumes with index and separate references. isbn 978-0-70203941-6; $499 msrp. review by mark a. hurt, m.d. why should one review weedon’s third edition of skin pathology? after all, it has been available for over a year, and most dermatopathologists, surgical pathologists, and dermatologists interested in dermatopathology have a copy of it or have access to it. how will a review of this book help them? my tripartite answer is simple. it deserves a review because of its near 20-year history; it deserves a hearing because of its author – and it is primarily the work of a single author; and it is grand in scope as it attempts to cover aspects of every major area of dermatopathology. dr. weedon’s preface is a must read. he tells us explicitly that “... this is likely to be the last edition of this book by the current author...” and so it is the end of an era no different in magnitude, if not in intellectual outreach, as the passing of dr. ackerman in 2008. fortunately, dr. weedon is still alive at this writing, and he will continue, hopefully, to shower us with his integrations of dermatopathologic knowledge for some time to come. this is an exhaustive text with 1041 pages in the main text and 881 pages of references. both volumes together weigh 18½ pounds, so this is not a set for any backpack. it resides in my office on a shelf with easy access to my desk. the cover is a deep blue with pleasing gray lettering; i would have preferred cloth for durability, but the cover supplied is adequate if one does not move the book around too much. on the inside cover are instructions for access to the website that allows internet access to the full content of the text and references for those who have purchased it. this is a colorful book made of very nice, sturdy, nonglare paper. all of the photographs are in color, and there is color-coding of the chapters for relatively easy access. there is repeated use of the colors but with enough separation that it is not confusing to find the needed chapter just by matching the colors. an added bonus in this addition is the presence of uniform, well-photographed examples of lesions – and lots of them! – which is a big plus. in the case of many of the rare conditions he describes, he provides at least one reference  – usually a list of key references – so that the reader can find photographs of the rare examples. another fantastic weedon d. weedon’s skin pathology. 3rd ed. london: churchill livingstone elsevier, 2010 review by mark a. hurt, m.d. and response by david weedon, m.d. citation: book review: weedon d. weedon’s skin pathology. 3rd ed. london: churchill livingstone elsevier, 2010. dermatol pract conc. 2012;2(1):15. http://dx.doi.org/10.5826/dpc.0201a15. copyright: ©2012 hurt. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 226 millpark dr, maryland heights, mo, 63043, usa. tel. 314.991.4470; email: markhurt@aol.com. dermatology practical & conceptual www.derm101.com 80 book review | dermatol pract concept 2012;2(1):15 resource is the presence of tables highlighting the differential diagnosis, histopathological features, and other items related to clinicopathologic correlation. there are seven sections. the first two address broad issues in the discipline, such as an approach to and the identification of patterns of inflammatory skin diseases. sections 3 and 4 address specific diseases of the two compartments of the skin: the epidermis and dermis, respectively. sections 5 and 6 address the skin in systemic disease and infections and infestations, respectively. finally, section 7 addresses “tumors,” where dr. weedon cuts a swath through malformations, hyperplasias, hamartomas, and neoplasms. dr. geoffrey strutton provides the text for the section on “cutaneous infiltrates – lymphomatous and leukemic.” dermatopathologists spend much of their time identifying criteria that they must integrate to formulate a diagnosis. this applies to any diagnosis. i cannot claim to speak for all dermatopathologists, but my practice is similar to many and consists of a wide spectrum of conditions, principally of melanocytic lesions (approximately 30%), other kinds of hamartomas and neoplasms (another 30-40%), with the remainder being composed of inflammatory diseases of the skin and miscellaneous conditions. although i can produce a differential diagnosis usually from memory today, it was not always so, and often i need help still. it is thus of great importance to find methods that allow one to have an algorithmic window into the diagnostic process. dr. ackerman did this famously with his “pattern” method. dr. weedon accomplishes this by providing, in his chapter 1, “an approach to the interpretation of skin biopsies.” in this approach, he divides inflammatory conditions into “major tissue reaction patterns” and “minor tissue reaction patterns.” the “major patterns” are lichenoid, psoriasiform, spongiotic, vesiculobullous, granulomatous, and vasculopathic. the “minor patterns” are epidermolytic hyperkeratosis, acantholytic dyskeratosis, cornoid lamellation, papillomatosis, acral angiofibromas, eosinophilic cellulitis with “flame figures,” and transepithelial elimination. finally, the “patterns of inflammation” are similar, in principle, to those of ackerman’s “pattern method,” albeit somewhat abbreviated and with slightly different emphasis. they are: superficial perivascular inflammation, superficial and deep dermal inflammation, folliculitis and perifolliculitis, and panniculitis. sections 3-6 are the expansions of these tissue reaction patterns and patterns of inflammation. chapter 2, “diagnostic clues” provides dr. weedon’s pearls of wisdom from his many years of experience as a dermatopathologist. although many of these clues may not enhance readily the diagnostic ability of the novice, those with a few years of practice will recognize immediately how useful they are. in essence, these “clues” are specific findings that allow one to develop a differential diagnosis or a specific diagnosis in some instances. as a rule, these “clues” open the door of one’s mind, but a diagnosis usually requires three to five criteria (sometimes more), all occurring together in a reproducible and repeatable manner, to establish a diagnosis. one should use this chapter as a boilerplate on which to underline and add one’s own experience to that which dr. weedon has started. in the following sections, concerned primarily with inflammatory diseases, the sections follow the basic outline above, exploding the conditions into their minutest detail, including references. i challenge anyone to provide a text with the kind of detail that dr. weedon provides, especially from a single-authored text. in fact, i suspect it is because of a single author that everything in it seems so seamless. dr. weedon’s treatment of “tumors” is comprehensive, and despite my disagreement with how he approaches some of the conditions, notably keratoacanthoma and clark’s (socalled dysplastic or atypical) nevi, he is better than many writers are in that he provides considerable context on all sides of the issues. i, for instance, have come to regard keratoacanthoma as a form of hyperplasia, which is in sharp contrast with dr. ackerman’s view of them as malignant neoplasia (squamous cell carcinoma). i also think, somewhat ironically, that keratoacanthoma (as a form of hyperplasia) is uncommon; most lesions that have a pattern similar to keratoacanthomas are neoplastic: squamous cell carcinomas, as dr. ackerman advocated. dr. weedon is one of few authors who still regard keratoacanthomas as benign squamous cell proliferations. he does not state its nosological position as hyperplasia or neoplasia, but he does state, “terms such as ‘squamous cell carcinoma’ and ‘squamous cell carcinoma (keratoacanthomatous type)’ are frequently used. their use cannot be justified on morphological or biological grounds.” this book review is not a forum to settle such matters, but the readers should be aware of dr. weedon’s position not only because it runs counter to commonly held views, at least in the united states, but also because he devotes considerable space to it in the text. as for clark’s nevus (lentiginous melanocytic nevus), i have a long-standing objection to the continued usage of the terms “dysplastic” and “atypical” to describe such lesions. this is because they are indeed benign, and even its proponents admit it today, even though the admission is couched in unintelligible terminology, such as “lentiginous hyperplasia” and “random cytologic atypia,” implying that these lesions both are and are not malignant at the same time and in the same respect. the proponents of these terms have never laid a proper foundation for such usage, and i do not think they can or will because those terms are undefined and indefinable, especially as concrete findings in specific lesions. that said, dr. weedon gives respect to all viewpoints in his text, which is more than i can say for the proponents of those book review | dermatol pract concept 2012;2(1):15 81 viewpoints. again, one cannot resolve this problem in a book review except to point out lines of disagreement. dr. weedon is somewhat refreshing in his treatment of melanoma. it is an objective account of the different viewpoints in the literature, including his. there is considerable effort to report on traditional views of classification as well as challenges to those viewpoints. in a general textbook, this is both important and laudable. ajcc reporting of melanoma has recently included a mitotic index for all melanomas with a dermal component 1mm thick or less. the text does not state this explicitly, likely owing to publication timing. there is, more or less, a traditional approach to adnexal proliferations. again, dr. weedon provides a well-rounded, objective approach to these lesions, and he acknowledges his disagreement with dr. ackerman on the nosologic position of most sebaceous neoplasms commonly thought of as adenomas, but which dr. ackerman regarded as carcinomas. this is an important and yet not fully resolved controversy that needs more research to settle definitively, in my opinion. at the very least, dr. weedon opens the door on the subject so that readers can walk through to consider the problem for themselves. finally, i have found it very useful to access the internet website for this book at www.expertconsult.com. after plugging in the pass code and assigning a name a password, one can access the full text, photographs, and references. this is a real time saver, considering the size of the book and the ability to search on specific words using the search engine. who should own this book? – everyone who makes dermatopathology his or her profession. in 1992, with the publication of the very first edition of dr. weedon’s book under the banner of the symmers series of pathology texts, i was relatively young in the field of dermatopathology, then 36 years old, and i still had a lot to learn. when i now compare that seminal text with dr. weedon’s 2010 version of it, really a fourth edition, even though it is labeled as the third, i am astounded at how far he has come in his own education, thus enhancing mine, now a student 55 years old. dr. weedon reminds me why i became a physician and that i still have a lot to learn about dermatopathology – as do we all who practice it. it is the end of an era. i cannot speak for my profession, but i can speak for myself, and i hope others will agree with me. thank you, dr. weedon, for an excellent textbook and for your years-long efforts to produce it. mark a. hurt, m.d. book review editor response and comments by david weedon it is not my usual practice to comment on reviews of my book, but as this will be the last edition that i author, i wanted to make a few comments for the younger generation of dermatopathologists and pathologists, particularly on the approach taken to the classification of diseases and the influences that shaped it. i have been privileged to see many interesting cases during my professional career and i should report my millionth patient early next year. pathologists who practised dermatopathology in the 1960s and 1970s were heavily influenced by the writings of walter lever and to a lesser extent by hamilton montgomery (mayo clinic), hermann pinkus and amir mehregan. lever’s approach was partly clinical with, for example, the “erythemato-squamous” diseases lumped together. this chapter included such histologically disparate entities as psoriasis and lichen planus. lever was an excellent book if one knew the diagnosis. in the late 1970s and early 1980s, the approach changed with ackerman’s landmark “gold” edition in 1978 and the onset of courses at grossingers, run by martin brownstein, with the assistance of a large faculty. loren e. golitz was also a director of the courses. it moved to london in 1985, with martin black as the course director, along with martin brownstein. independently, bernard ackerman ran his own courses, including the famous sherlockian-inspired course in london in july 1981. as brownstein and ackerman both practised in new york, there was a degree of professional rivalry between the two, although ackerman was on the faculty of brownstein’s course at grossingers in august/ september, 1981. ackerman, as the founder of the international society of dermatopathology in 1980, also organised/ inspired conferences under its auspices with a very enjoyable conference in liege, belgium in august 1984. at the brownstein course at grossingers, a week later, i spoke on “eczematous dermatitis” (in defiance of ackerman’s views that it should be “spongiotic dermatitis”—i subsequently saw the “light”), “psoriasiform dermatitis,” and “lichenoid dermatitis.” i had given similar lectures at the skin pathology course run by the victorian faculty of the australasian college of dermatologists in melbourne in the late 1970s and early 1980s. similar themes had been expressed at earlier brownstein courses before i joined the faculty. this approach differed from the earlier writings of lever. as one of the few dermatopathologists on the faculty of both the brownsteinand ackerman-inspired courses, i remember, vividly, feeling a little nervous about being in both “camps” simultaneously, but i survived and enjoyed the camaraderie and intellectual exchanges with such people as martin black, edward wilson jones, loren golitz, ronald barr, amir mehregan, ken hashimoto, john maize, neil 82 book review | dermatol pract concept 2012;2(1):15 smith, richard reed, robert freeman, helmut kerl, robert jones, rona mackie, martin mihm, geoff gottlieb, clay cockerell, david elder, wallace clark, jim graham, and numerous others. i was influenced by them all, and i refined my approach as a consequence of their lectures and discussions with them. it took five years to write the first edition (in the symmer’s series). finally, since the publication of my book, we have published further papers on the abortive variant of keratoacanthoma and the development of squamous cell carcinoma in keratoacanthoma (probably missed in many superficial shaves). i am convinced, beyond a reasonable standard of doubt, that keratoacanthomas and squamous cell carcinomas are as different as “chalk and cheese.” readers should await an interesting study in the pipeline that will add further weight in supporting my views (the work is not from me, but i am prevented by confidentiality agreements from saying any more). david weedon david weedon, ao, md, frcpa, fcap(hon), is honorary professor of pathology, bond university, gold coast, australia; senior visiting pathologist, royal brisbane & women’s hospital, brisbane, australia; and dermatopathologist, sullivan nicolaides pathology (a division of sonic healthcare), austrialia. contact him at d_weedon@snp.com.au. dermatology: practical and conceptual review | dermatol pract concept 2016;6(2):8 43 dermatology practical & conceptual www.derm101.com “the difficulty lies, not in the new ideas, but escaping from the old ones, which ramify . . . into every corner of our minds.” jm keynes the general theory of employment, interest and money (1936; palgrave macmillan) problems in the diagnosis of spitzoid neoplasms and possible causes spitzoid neoplasms may pose significant diagnostic problems, because in a fraction of them it is quite difficult or impossible to establish if they are benign or malignant lesions. an time to reconsider spitzoid neoplasms? carmelo urso1 1 department of anatomic pathology, dermatopathology section, sm annunziata hospital, ausl toscana centro, florence, italy key words: spitz tumors, spitz nevus, atypical spitz tumor, spitzoid melanoma, melanoma citation: urso c. time to reconsider spitzoid neoplasms? dermatol pract concept 2016; 6(2):8. doi: 10.5826/dpc.0602a08 received: december 6, 2015; accepted: march 12, 2016; published: april 30, 2016 copyright: ©2016 urso. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: carmelo urso, md, department of anatomic pathology, dermatopathology section, sm annunziata hospital, ausl toscana centro, antella, florence, i-50012 italy. tel. +39 055 6936416; fax. +39 055 6936294. email: cylaur@libero.it background: spitzoid neoplasms may pose significant diagnostic problems because in a fraction of them it is quite difficult or impossible to establish if they are benign or malignant lesions. an extraordinarily large number of studies have been made in attempts to solve this problem; regrettably, the histological criteria proposed and the various special sophisticated techniques employed have proven to be ineffective in making this distinction with confidence. objectives: to explore the possible causes for this diagnostic failure and an attempt to identify the source of this problem. method: a historical and technical analysis of the specialized literature is performed, critically evaluating the main points of this controversial topic. results: the reasons for the diagnostic failure in spitzoid neoplasms are not clear but could be the result of inappropriate conceptual representation. the analysis of available data and a rational review of old and new assumptions and concepts may suggest a different representation for spitzoid neoplasms: spitz nevus, atypical spitz tumor and spitzoid melanoma, rather than being three different tumors that are difficult or impossible to distinguish with assurance, could be viewed as one unique entity, spitz tumor (st). this tumor is a low-grade malignant neoplasm, in which the amount of intrinsic risk is variable, ranging from very low to high (st1, st2, st3), and malignant potential could be estimated. conclusions: the proposed alternative representation of spitzoid neoplasms as a unique tumor may help in overcoming the difficulty in diagnosis of these tumors. summary 44 review | dermatol pract concept 2016;6(2):8 and of malignant melanoma. between these two diagnostic categories, it is admitted to exist an ill-defined gray area encompassing lesions variously termed “tumors of difficult or uncertain diagnosis or potential,” “meltumps,” or “i don’t know” [13,15–19]. this representation appears to be essentially based on two old postulates, frequently repeated, but never properly demonstrated: 1) malignant melanoma is a unique neoplasm and 2) sn is a nevus. the first postulate was enunciated by ackerman in the 1980s [20]; however, increasing data coming from mutational and genetic studies show that what is currently called “melanoma” is an assemblage of different tumors [21]. the second dates back to 1949, when allen established the “juvenile melanoma” to be a nevus [22]. in subsequent years, the a priori assumption that juvenile melanoma, renamed as sn, was a nevus and therefore fully benign, was largely accepted. although not scientifically demonstrated, this statement significantly influenced the evaluation of spitzoid neoplasms. in fact, although local recurrences, cutaneous satellitosis, cells in lymphatics and nodal metastases/deposits—features traditionally associated with a malignant behavior—were occasionally observed, sn was considered benign because the outcome was favorable or more favorable than expected [23–26]. on the other hand, cases with the same clinical and histological features but with visceral metastases and unfavorable outcome were regarded as melanomas, erroneously diagnosed as sn [27]. the following syllogism seems to be the basis for the current representation: 1) sn is a nevus; 2) a nevus is invariably benign; 3) sn is invariably benign. this syllogism is formally correct, but the first premise (“sn is a nevus”) is not demonstrated; it is an a priori enunciation that might be not true. in subsequent years, in an attempt to explore a possibly different perspective, it was proposed to set spitzoid neoplasms apart from the other melanocytic lesions. they were defined as an autonomous class of benign and malignant tumors with a peculiar features. the immediate consequence of this representation was that, if spitzoid neoplasms were a separate group of lesions, diagnostic histological criteria to differentiate benign form malignant forms might not be the same used to differentiate conventional nevi from conventional melanoma; so, new criteria, or a new use of existing criteria, appeared to be opportune [28]. this class of lesions included poorly understood cases labeled as atypical spitz tumor (ast). there is more than one reason to think that understanding ast may be the key to the problem. understanding atypical spitz tumors in a recent review, the clinicopathological characteristics of 541 asts were tabulated [29]. in this study, it was reported that ast has a relevant rate of positive sentinel nodes (39%), extraordinarily large number of studies have been made in attempts to solve the problem of the differential diagnosis of spitzoid neoplasms, i.e., distinguishing spitz nevus (sn) from spitzoid melanoma (sm) [1–2]. regrettably, the proposed histological criteria have often proven to be ineffective in making this distinction with confidence, and the concordance of dermatopathologists is excessively low [1,3]. moreover, immunohistochemistry and other special techniques, including polymerase chain reaction (pcr) and in situ hybridization (ish), have proven to be either totally ineffective for the diagnosis or useful just as ancillary tools [4]. finally, molecular genetic studies, including analysis of gene mutations, fluorescence in situ hybridization (fish) analysis and comparative genomic hybridization (cgh) [5-10], have also failed to achieve a consistent distinction between malignant from benign forms [11-12]. in this disappointing context, the vexing question remains as to why the diagnosis of spitzoid neoplasms appears to be so exceedingly difficult and, therefore, so dramatically exposed to error. many possible causes may be at the source of this problem. years ago, ackerman wrote that this problem was due to the failure of the human brain [13]; however, this opinion does not appear fully convincing, because it is very difficult to explain why it does not generally fail in the diagnosis of basal cell carcinoma, actinic keratosis, or dermatofibroma, and so frequently fails in spitzoid neoplasms. a second possibility may be that, despite the numerous studies, a special technique capable of producing a reliable distinction between sn and melanoma has not been yet found. it is possible that such a technique will be available in the future; however, after more than 60 years, the large number and the great variety of very sophisticated special techniques employed with relatively disappointing results [4] may suggest that the achievement of this technique is not probable. a third possibility may lie in the fact that the histological criteria currently used to segregate benign from malignant forms do not work properly because they are inadequately studied or poorly reproducible. actually, an examination of the pertinent literature shows that histological differential criteria between sn and melanoma have been very accurately studied and globally have a good reproducibility [2]. in sum, not one of analyzed causes seems be convincingly identifiable as the source of the problematic histologic diagnosis of spitzoid neoplasms. looking for a new perspective in 2004, cerroni hypothesized that the perspective from which spitzoid neoplasms were regarded might be wrong [14] and, therefore, a possible cause of diagnostic failure might be an inadequate conceptual representation of these tumors. in the current representation, sn and sm are considered mere morphologic variants, respectively, of melanocytic nevus review | dermatol pract concept 2016;6(2):8 45 are malignant tumors, albeit with a relatively favorable prognosis. they possess a low malignant potential. it has been underscored that considering the malignant potential of tumors as an all-or-none phenomenon is an oversimplification. the paradigm “benign-versus-malignant,” based on the clinical course of the disease, seems to be a rather rough approach to a biologic property (the malignant potential) of tumors, which in reality could have a different expressivity [31]. it is not possible to precisely estimate the malignant potential of a given lesion, but that is certainly not the same in all tumors and can be approximately defined as low, moderate or high. available data show that asts are malignant but seem to have a relatively low malignant potential [29]. a tumor with low malignant potential is not necessarily a tumor having an invariably limited metastatic capability (for example, a tumor capable of regional but not distant metastases) [32]. it can be a tumor with a metastatic rate statistically lower than expected. in effect, asts have metastatic and mortality rates statistically lower than “conventional melanomas” [29]; they could be properly considered low-grade melanomas, as sophie spitz did in 1948 [33]. the notion that asts constitute a unique clinicopathologic entity and therefore are melanomas, albeit of low-grade, may explain many, if not all, issues, including why they are so similar to sm, why ast and sm may be histologically indistinguishable, why they are not separable by any special technique, why more than occasionally the attempts to differentiate them fail, and finally why the diagnostic concordance among pathologists is so low [1,3,4]. spitzoid neoplasms as a unique entity: the spitz tumor moreover, as we extend our analysis from asts to the entire category of spitzoid neoplasms, it is interesting to examine the tables concerning the differential features between sn, ast and sm, for example, that published by barnhill in 2004 [34]. in this table, and in similar ones, no one single criterion or groups of criteria appear to be really distinctive of ast in respect to sm. all parameters listed are shared by both the lesions. there is no substantial difference in their histologic appearance or in their structure but only a modulation of the histological features, being less pronounced in ast and more prominent in sm [34]. ast and sm seem to have the same histological characteristics and no special technique is capable to distinguish them confidently. morphologically and structurally, they appear as a unique tumor. in addition, in the same table, the same circumstances can be noted comparing ast to sn. again, no one single criterion or groups of criteria appear to be distinctive of ast in respect to sn. all parameters listed are shared by both the lesions. there is no substantial difference in their histologic appearance or a relatively high rate of non-sentinel node involvement (19%), a very low incidence of local recurrences (<1%), a small but definite rate of regional metastases (3%), a very small rate of distant metastases (1%), and a very low mortality (1%). discussing their results, the authors posed the question of the nature of asts, recalling two hypotheses: 1) asts are a confused assemblage of morphologically ambiguous benign nevi with associated benign cells in lymph nodes and of morphologically ambiguous malignant melanomas; and 2) asts are a group of biologically intermediate tumors, i.e., melanomas with a relatively good prognosis. unfortunately, in their paper, the authors did not discuss the problem any further. actually, these two hypotheses deserve to be deeply analyzed. the first implies that asts—belonging to the same cellular lineage, with the same clinicopathologic characteristics, not distinguishable on clinical and/or histological grounds, nor with the available special techniques—may be different tumors with totally different biology, some asts being benign and some malignant. this is to say that these tumors cannot be appropriately diagnosed on the basis of their morphology or structure but only a posteriori on the basis of follow-up data and of the final outcome. if a principle like this were extensively applied, a lesion presently diagnosed as “superficial spreading melanoma” should be a posteriori classified as a “melanoma” only if the patient developed metastases or died, but regarded as “nevus” or as “atypical nevus” if the patients survived. this is illogical. this hypothesis produces an insurmountable diagnostic impasse, due to the fact that the same histologic appearance may not imply the same diagnosis. the second hypothesis implies that asts—belonging to the same cellular lineage, with the same clinicopathologic characteristics, not distinguishable on clinical and/or histological grounds, nor with the available special techniques— cannot be biologically different tumors, but are to be regarded as a unique group of neoplasms. the existence of a reliable correspondence between the histologic appearance and the diagnosis permits these tumors to be diagnosed on the basis of their morphology and overcomes the diagnostic impasse. at least pragmatically, the first hypothesis should be rejected because it inhibits the diagnosis; the second should be accepted because it makes the diagnosis possible and could solve many problems. in fact, if asts are a unique group of tumors that are diagnosable clinically and histopathologically and that represent a unique clinicopathologic entity, the nature of such tumors ceases to be nebulous. they are not nevi and are not benign, because they are capable of metastases and, albeit rarely, of killing patients [29]. however, the low rates of distant metastases and of deaths (in part due to the fact that the tumors with the characteristics of ast and unfavorable outcome are currently separated a posteriori under the label of sms [30]) demonstrate that they properly 46 review | dermatol pract concept 2016;6(2):8 9) epidermal ulceration 10) cells in lymphatic vessels this 10-feature list is different from the lists commonly employed in the differential diagnosis between sn and sm, and it is used in a different way. in fact, these latter lists generally contain a higher number of parameters to assess any given lesion; the diagnosis emerges from a quantitative and qualitative evaluation of the considered parameters. unfortunately, however, it is not specified how many parameters are requested for the diagnosis, and if it is requested the presence of the majority of them, if all parameters have the same weight, if there exist major and minor parameters and, in this case, how many major and how many minor parameters are necessary. moreover, there are no indications for a qualitative evaluation of any single parameter. this is certainly at the source or, at least, substantially contributes to producing the disappointingly low diagnostic concordance [3]. the proposed use of the 10-feature list is different and suggested by the analysis of previously published cases [28]. in 2001, fabrizi and massi stated that a combination of just three features (nuclear/nucleolar pleomorphism, mitoses and growth in solid sheets) should suggest the diagnosis of malignancy (melanoma) “without hesitation” [37]. similarly, in 2014, massi and leboit recently wrote that “even a single mitotic figure favors melanoma” in an appropriate context (cellular atypia and growth in solid sheets) [38]. moreover, case 21 published by walsh et al in 1998, a woman aged 24, who died 73 months after excision, presented a small 3 mm papular lesion “simulating spitz nevus” without evident mitotic figures; from the microphotograph the lesion seemed to show just an extension to the reticular dermis and an incomplete maturation [2]. in addition, case 19 published in the same study, a woman aged 32 with regional lymph node metastasis 11 months after excision, presented a small 5 mm, clinically symmetrical, papular dome-shaped lesion with “spindled melanocytes resembling those of a spitz nevus” and just an asymmetric shoulder in half of the lesion [2]. therefore, the study of previously published cases demonstrates that spitzoid neoplasms with metastases and/ or fatal outcome might present only a few or just one parameter that would indicate malignancy. consequently, to avoid under-diagnosing spitzoid neoplasms [39], it was suggested that the very presence of at least one of the features of the 10-feature list be considered as sufficient for a diagnosis of potential malignancy [28]. therefore, in a spitzoid neoplasm, if even a single feature included in the list, evaluated as present/absent, is identified, the diagnosis should not be sn, but at least ast [28]. on the other hand, data collected showed that asts are tumors with a low malignant potential and with a risk of an adverse event estimable as low or moderate [29]. consequently, an st showing at least one of the features of in their structure but only a modulation of the histological features, being less pronounced in sn and more prominent in ast [34]. ast and sn seem to have the same histological characteristics, and no special technique is capable to distinguish them confidently. morphologically and structurally, they appear as a unique tumor. in sum, all spitzoid neoplasms, including forms currently labeled as sn, ast and sm, share the same histological characteristics, and no special technique is capable to distinguish them confidently; morphologically and structurally, they appear as being a unique tumor. spitzoid neoplasms, rather an autonomous class of tumors, including benign, borderline and malignant forms [28], more properly seem to be a unique entity, showing a modulation of the histologic features, of the risk and, consequently, of the prognosis [18]. this unique entity, which may be termed as spitz tumor (st), appears to be characterized histologically by the presence of atypical large spindle and/or epithelioid cells, as noted in early papers [35], and genetically by chromosome rearrangements involving kinase fusion [36]. st is malignant, but seems to possess a low malignant potential. the malignant potential of st is globally lower that expected in conventional melanoma of the same thickness, but variable, as it does not seem to be the same in all cases. it is impossible to obtain a precise quantitative estimation of the malignant potential of a single st, but it is possible to have an approximate estimation of it, evaluating the amount of risk. in st, this risk may range from very low to high and may be expressible as statistical probability that an adverse event (nodal or visceral metastasis, death) occurs or is detected; in each single case, however, the prognosis is unpredictable. the representation of spitzoid neoplasms as a unique tumor (st) makes the diagnosis possible and relatively easy, relying only on the recognition of the peculiar cell type. proposal for risk assessment in spitz tumor the challenging subsequent steps concern the assessment of risk in st. in previous studies, some features associated with a potential risk have been pointed out. in 2005, in a review of 100 cases reported in 24 studies published between 1948 and 2003, a list of histologic features associated with metastases and/or a potentially adverse prognosis was compiled [28]. the following revised list includes 10 histologic parameters: 1) solid sheets and nodular growth 2) deep dermis and/or subcutaneous fat extension 3) dermal mitoses (>2 per section) 4) marked nuclear pleomorphism 5) abundant melanin in deep cells 6) marked asymmetry 7) cellular necrosis 8) high number of suprabasal melanocytes review | dermatol pract concept 2016;6(2):8 47 of spitz nevus and spitzoid melanoma. am j surg pathol 2005; 29(9):1145-51. pmid: 16096402 7. gerami p, jewell s, morrison l, et al. fluorescence in situ hybridization (fish) as an ancillary tool in the diagnosis of melanoma. am j surg pathol 2009; 33(8):1146-56. pmid: 19561450 8. bastian bc, olshen ab, leboit pe, pinkel d. classifying melanocytic tumors based on dna copy number changes. am j pathol 2003; (5)163:1765-70. pmid: 14578177. doi: 10.1016/s00029440(10)63536-5 9. bauer j, bastian bc. distinguishing melanocytic nevi from melanoma by dna copy number changes: comparative genomic hybridization as a research and diagnostic tool. dermatol ther 2006; 19(1):40-9. pmid: 16405569. doi: 10.1111/j.15298019.2005.00055.x 10. raskin l, ludgate m, iyer r, et al. copy number variations and clinical outcome in atypical spitz tumors. am j surg pathol 2011; 35(2):243-52. pmid: 21263245. doi: 10.1097/ pas.0b013e31820393ee 11. gaiser t, kutzner h, palmedo g et al. classifying ambiguous melanocytic lesions with fish and correlation with clinical long term follow up. mod. pathol 2010; 23(3):413–9. pmid: 20081813. doi: 10.1038/modpathol.2009.177 12. massi d, cesinaro am, tomasini c, et al. atypical spitzoid melanocytic tumors: a morphological, mutational, and fish analysis. j am acad dermatol 2011; 64(5):919-35. pmid: 21496703; doi: 10.1016/j.jaad.2010.05.043 13. mones jm, ackerman ab. “atypical” spitz’s nevus, “malignant” spitz’s nevus, and “metastasizing” spitz’s nevus: a critique in historical perspective of three concepts flawed fatally. am j dermatopathol 2004; 26(4):310-33. pmid: 15249862 14. cerroni l. spitzoid tumors. a matter of perspective? am j dermatopathol 2004; 26(1):1-3. pmid: 14726816 15. barnhill rl. the spitzoid lesion: rethinking spitz tumors, atypical variants, ‘spitzoid melanoma’ and risk assessment. mod pathol 2006; 19 suppl. 2:s21-s33. pmid: 16446713 16. ludgate mw, fullen dr, lee j, et al. the atypical spitz tumor of uncertain biologic potential. a series of 67 patients from a single institution. cancer 2009; 115(3):631-41. pmid: 19123453. doi: 10.1002/cncr.24047 17. da forno pd, pringle jh, fletcher a, et al. braf, nras and hras mutations in spitzoid tumours and their possible pathogenetic significance. br j dermatol 2009; 161(2):364-72. pmid: 19438459. doi: 10.1111/j.1365-2133.2009.09181.x 18. cerroni l, barnhill r, elder d, et al. melanocytic tumors of uncertain malignant potential: results of a tutorial held at the xxix symposium of international society of dermatopathology in graz, october 2008. am j surg pathol 2010; 34(3):314-26. pmid: 20118771. doi: 10.1097/pas.0b013e3181cf7fa0 19. ferrara g, cavicchini s, corradin mt. hypopigmented atypical spitzoid neoplasms (atypical spitz nevi, atypical spitz tumors, spitzoid melanoma): a clinicopathologic update. dermatol pract concept 2015; 5(1):45-52. pmid: 25692081. doi: 10.5826/ dpc.050106 20. ackerman ab. malignant melanoma: a unifying concept. hum pathol 1980; 11(6):591-5. pmid: 7450735 21. curtin ja, fiedlyand j, kageshita t, et al. distinct sets of genetic alterations in melanoma. n eng j med 2005; 353(20):2135–47. pmid: 16291983. doi: 10.1056/nejmoa050092 22. allen ac. a reorientation of the histogenesis and clinical significance of cutaneous nevi and melanomas. cancer 1949; 2(1):2856. pmid: 18108903 the 10-feature list (although often, more than one feature is detected) should be considered “spitz tumor with lowmoderate risk” (st2). moreover, in 2010, three features were found to be statistically associated with a high risk and an unfavorable outcome: dermal mitoses (>4 per section), deep or marginal mitoses, and heavy inflammatory infiltrate [18]. therefore, the presence of one or more of these three features in an st that also shows a variable number of the 10 abovementioned features, evaluated as present/absent, may confer a high risk of an adverse event, and these cases should be diagnosed as “spitz tumor with high risk” (st3). conversely, lesions showing none of the 10 features, nor one of the three features and that are small, symmetric, with a horizontal silhouette, with uniform cells and evident maturation can be assumed to have a very low malignant potential and diagnosed as “spitz tumor with very low risk” (st1). the re-definition of lesions currently labeled sn that are considered fully benign as st1, and considered as very low risk, takes into account the objective impossibility of excluding the minimal risk implicit in the diagnosis of sn, as sagaciously noted by piepkorn [40]. results of genetic analyses may be used for a further evaluation of risk. provisionally, fish analysis, if positive, should prevent the diagnosis of st1; if negative it should not impede the diagnoses of st2 and st3. chromosomal alterations, as homozygous 9p21 deletion and 6p25 and/or 11q13 gains, indicating a high risk, prevent the diagnoses of st1 and st2 [41]. in comparing this diagnostic approach to the current system of diagnosis, part of sn could probably be diagnosed as st2 and part of ast as st3. on the basis of the class of risk (st1, st2, st3) an appropriate gradable management of patients with st can be established [19]. references 1. barnhill rl, argenyi zb, from l, et al. atypical spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. hum pathol 1999; 30(5):513–20. pmid: 10333219 2. walsh n, crotty k, palmer a, mccarthy s. spitz nevus versus spitzoid malignant melanoma; an evaluation of the current distinguishing histopathologic criteria. hum pathol 1998; 29(10):110512. pmid: 9781649. doi: 10.1016/s0046-8177(98)90421-x 3. farmer er, gonin r, hanna rp. discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. hum pathol 1996; 27(6):528-31. pmid: 8666360 4. hosler ga, patterson jw. lentigines, nevi and melanomas. in: weedon d. weedon’s skin pathology, 4th ed. philadelphia: churchill livingstone, 2016: 854. 5. takata m, lin j, takayanagi s, et al. genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid lesion. br j dermatol 2007; 156(6):1287-94. pmid: 17535228. doi: 10.1111/j.1365-2133.2007.07924.x 6. van dijk mc, bernsen mr, ruiter dj. analysis of mutations in braf, n-ras, and h-ras genes in the differential diagnosis http://dx.doi.org/10.1016/s0002-9440(10)63536-5 http://dx.doi.org/10.1016/s0002-9440(10)63536-5 48 review | dermatol pract concept 2016;6(2):8 33. spitz s. melanoma of childhood. am j pathol 1948; 24(3):591609. pmid: 18859360 34. barnhill rl, busam k. spitz nevus and variants. in: barnhill rl, piepkorn m, busam k (eds.). pathology of melanocytic nevi and malignant melanoma, 2nd ed. new york: springer-verlag, 2004: 162. 35. mcwhorter he, woolner lb. pigmented nevi, juvenile melanomas, and malignant melanomas in children. cancer 1954: 7(3):564-85. pmid: 13160941 36. wiesner t, he j, yelensky r, et al. kinase fusions are frequent in spitz tumors and spitzoid melanomas. nat commun 2014;5:3116. pmid: 24445538. doi: 10.1038/ncomms4116 37. fabrizi g, massi g. spitzoid malignant melanoma in teenagers: an entity with no better prognosis than that of other forms of melanoma. histopathology 2001; 38(5):448-53. pmid: 11422482. doi: 10.1046/j.1365-2559.2001.01102.x 38. massi g, leboit pe (eds.). spitzoid melanoma. in: massi g, leboit pe. histological diagnosis of nevi and melanoma. heidelberg: springer-verlag, 2014: 842. 39. leboit pe. “safe” spitz and its alternative. ped dermatol 2002; 19(2):163-5. pmid: 11994185. doi: 1046/j.15251470.2002.00032.x 40. piepkorn m. spitz nevus is melanoma. am j dermatopathol 2005; 27(4):367-69. pmid: 16121067 41. gerami p, scolyer ra, xu x, et al. risk assessment for atypical spitzoid melanocytic neoplasms using fish to identify chromosomal copy number aberrations. am j surg pathol 2013; 37(5):67684. pmid: 23388126. doi: 10.1097/pas.0b013e3182753de6 23. harvell jd, bastian bc, leboit pe. persistent (recurrent) spitz nevi. am j surg pathol 2002; 26(5):654-61. pmid: 11979096 24. song jy, kwon ja, park cj. a case of spitz nevus with multiple satellite lesions. j am acad dermatol 2005; 52(2 suppl 1):s48-50. pmid: 15692514. doi: 10.1016/j.jaad.2004.07.026 25. howat aj, variend s. lymphatic invasion in spitz nevi. am j surg pathol 1985; 9(2):125-8. pmid: 3919599 26. zatterstrom u, thor a, nordgran h. cervical metastasis from spitz nevus of the buccal mucosa. melanoma res 2008; 18(1); 36-9. pmid: 18227706. doi: 10.1097/cmr.0b013e3282f356e4 27. kernen ja, ackerman lv. spindle cell nevi and epithelioid cell nevi (so-called juvenile melanomas) in children and adults: a clinicopathologic study of 27 cases. cancer 1960; 13:612-25. pmid: 14408617 28. urso c. a new perspective for spitz tumors? am j dermatopathol 2005; 27(4):364-6. pmid: 16121065 29. lallas a, kyrgidis a, ferrara g, et al. atypical spitz tumours and sentinel lymph node biopsy: a systematic review. lancet oncol 2014; 15(4):e178-83. pmid: 24694641. doi: 10.1016/s14702045(13)70608-9 30. paradela s, fonseca e, pita s, et al. spitzoid melanoma in children: clinicopathologic study and application of immunohistochemistry as an adjunct diagnostic tool. j cutan pathol 2009; 36(7);740-52. pmid: 19032380. doi: 10.1111/j.1600-0560.2008.01153.x 31. rosai j. the benign versus malignant paradigm in oncologic pathology: a critique. sem diagn pathol 2008; 25(3):147-53. pmid: 19007100 32. smith kj, barrett tl, skelton hg iii, lupton gp, graham jh. spindle cell and epithelioid cell nevi with atypia and metastasis (malignant spitz nevus). am j surg pathol 1989; 13(11):931-9. pmid: 2802011 http://dx.doi.org/10.1016/j.jaad.2004.07.026 dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020090 1 dermatology practical & conceptual case presentation a 57-year old man with known multiple atypical nevi presented for his regular yearly follow-up visit. he had no history of personal or familial melanoma. during the visit, we observed a roundish, well-demarcated, nodular lesion with a diameter of 8 mm on his right flank. a shiny surface, some scales at the periphery and clinically visible vessels were observed. the lesion was firm on palpation. on dermoscopy, the lesion presented a polymorphic vascular pattern (linear-irregular, glomerular, and hairpin vessels), blue-reddish lacunae randomly distributed over the lesion as well as some hemorrhagic crusts (figure 1, a and b). the nodule was excised, and histopathology showed an irritated seborrheic keratosis with reactive atypia. teaching point seborrheic keratoses, especially irritated lesions, present in a huge morphological variety clinically and dermoscopically. these lesions can exhibit features suggestive of amelanotic melanoma, merkel cell carcinoma (eg, polymorphic vessels), or basal cell carcinoma and require histological examination [1,2]. references 1. carrera c. the many faces of seborrheic keratosis. actas dermosifiliogr. 2019;110(5):338. doi: 10.1016/10.1016/j. ad.2018.12.005. 2. carrera c, segura s, aguilera p, et al. dermoscopic clues for diagnosing melanomas that resemble seborrheic keratosis. jama dermatol. 2017;153(6):544-551. doi: 10.1016/10.1001/jamadermatol.2017.0129. pmid: 28355453. polymorphic vessels–think about seborrheic keratosis teresa deinlein1, elena eber1, regina fink-puches1, rainer hofmann-wellenhof1 1 department of dermatology and venereology, medical university of graz, austria key words: seborrheic keratosis, melanoma, dermoscopy, polymorphic vessels citation: deinlein t, eber e, fink-puches, hofmann-wellenhof r. polymorphic vessels—think about seborrheic keratosis. dermatol pract concept. 2020;10(4):e2020090. doi: https://doi.org/10.5826/dpc.1004a90 accepted: may 25, 2020; published: october 26, 2020 copyright: ©2020 deinlein et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rainer hofmann-wellenhof, md, department of dermatology and venereology, medical university of graz, auenbruggerplatz 8, 8036 graz, austria. email: rainer.hofmann@medunigraz.at 2 image letter | dermatol pract concept 2020;10(4):2020090 figure 1. (a) clinical image showing a roundish, well demarcated red nodule with a maximum diameter of 8 mm. additionally, a shiny surface, some peripheral scales, and different types of vessels are observable. (b) on dermoscopy, a polymorphic vascular pattern composed of linear-irregular, glomerular, and hairpin vessels is evident. moreover, blue reddish lacunae and hemorrhagic crusts are seen. a b dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(3):1 1 dermatology practical & conceptual www.derm101.com clinical presentation an 82-year-old man with fitzpatrick skin type iii presented for the evaluation of a lesion on the left upper back. a scaly pink papule was observed (figure 1). the differential diagnosis included squamous cell carcinoma (scc), actinic keratosis, basal cell carcinoma, and amelanotic melanoma. dermoscopic appearance on dermoscopy, multiple coiled blood vessels (also termed glomerular vessels) were scattered across the papule (figure 2) [1]. a pink papule on the back of an 82-year-old man: an example of the buttonhole sign on reflectance confocal microscopy syril keena t. que1, naiara fraga-braghiroli2, jane m. grant-kels1, harold s. rabinovitz2, margaret oliviero2, alon scope3 1 department of dermatology, university of connecticut health center, farmington, ct, usa 2 department of dermatology, university of miami miller school of medicine, miami, fl, usa 3 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel citation: que skt, fraga-braghiroli n, grant-kels jm, rabinovitz hs, oliviero m, scope a. a pink papule on the back of an 82-year-old man: an example of the buttonhole sign on reflectance confocal microscopy dermatol pract concept 2016;6(3): doi: 10.5826/dpc.0603a01 received: december 2, 2015; accepted: april 25, 2016; published: july 31, 2016 copyright: ©2016 que et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: dr. scope’s confocal microscopy research is supported by the european commission marie curie fp7 reintegration grant (pirg07-ga-2010-268359). dr. rabinovitz has received equipment and funding for a fellowship program from lucid inc. competing interests: dr. rabinovitz is an investigator in a study coordinated by lucid inc, manufacturer of a commercial confocal microscope. the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: syril keena que, md, university of connecticut health center department of dermatology, 21 south rd, farmington, ct 06030, usa. tel. 860. 679.4600. email: keenaq@gmail.com figure 1. squamous cell carcinoma in situ. scaly pink papule on the left upper back. [copyright: ©2016 que et al.] figure 2. squamous cell carcinoma in situ. dermatoscopic image showing dotted and round blood vessels (black arrows) appearing centrally and around the periphery. [copyright: ©2016 que et al.] mailto:keenaq@gmail.com 2 quiz | dermatol pract concept 2016;6(3):1 discussion a buttonhole sign in the presence of an atypical honeycomb pattern is an rcm clue for scc. previous articles have correlated dotted vessels on dermoscopy with sparsely distributed round vessels on rcm [2]. here we report a new rcm diagnostic clue not previously reported—the presence of numerous round vessels in an scc in situ with coiled vessels. the uniformity, clustered nature, and multitude of these round vessels reflect the way these vessels repeatedly loop through the dermal papillae. this finding is not specific for scc and can be observed in conditions like psoriasis or clear cell acanthoma, when there are coiled or glomerular vessels seen under dermoscopy. however, in scc the increased vascularity is seen under rcm in conjunction with irregularity of the honeycomb pattern of the spinous and granular layers of the epidermis. references 1. rishpon a, kim n, scope a, et al. reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. arch dermatol 2009 jul;145(7):766-72. pmid: 19620557. doi: 10.1001/archdermatol.2009.134. 2. ahlgrimm-siess v, cao t, oliviero m, et al. the vasculature of nonmelanocytic skin tumors on reflectance confocal microscopy: vascular features of squamous cell carcinoma in situ. arch dermatol 2011 feb;147(2):264. pmid: 21339468. doi: 10.1001/ archdermatol.2010.416. reflectance confocal microscopy appearance reflectance confocal microscopy (rcm) at the level of the dermo-epidermal junction shows dermal papillae appearing in cross-section as perfect circles, resembling “buttons.” round blood vessels traverse through the dermal papillae, appearing centrally and around the periphery as “buttonholes” (figure 3). the surrounding epidermis is characterized by an atypical honeycomb pattern consisting of cells with variability in brightness and in the size of nuclei. what is your diagnosis? diagnosis histopathology revealed scc in situ (figure 4). the “buttonholes” seen on rcm correlate with numerous tortuous blood vessels at the dermal papillae of the scc in situ (figure 5). figure 3. squamous cell carcinoma in situ. at the level of the dermoepidermal junction, reflectance confocal microscopy reveals round blood vessels (“buttonholes”) traversing the dermal papillae (“buttons,” red arrows). [copyright: ©2016 que et al.] figure 4. histopathology reveals full-thickness cytological atypia with mitoses and acantholysis, consistent with squamous cell carcinoma in situ. [copyright: ©2016 que et al.] figure 5. psoriasis. at the level of the dermo-epidermal junction, reflectance confocal microscopy reveals round blood vessels (“buttonholes”) traversing the dermal papillae (“”buttons”, red arrows). [copyright: ©2016 que et al.] dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(4):e2021065 1 classic and simultaneous clinical findings of an exuberant case of netherton syndrome: a clinical report ademar schultz junior 1, karina demoner de abreu sarmenghi¹, ingrid zon sassine¹, camila pedruzze machado¹, priscila pinto barroso1 , victor catrinque nascimento² 1 dermatology unit, hospital santa casa de misericórdia de vitória, vila rubim, vitória, es, brasil. 2 escola superior de ciências da santa casa de misericórdia de vitória, bela vista, vitória, es, brasil. keywords: netherton syndrome, dermoscopy, eyebrows, congenital ichthyosiform erythroderma. citation: schultz junior a, de abreu sarmenghi kd, zon sassine i, pedruzze machado c, pinto barroso p, catrinque nascimento v. classic and simultaneous clinical findings of an exuberant case of netherton syndrome: a clinical report. dermatol pract concept. 2021; 11(4):e2021065. doi: https://doi.org/10.5826/dpc.1104a65. accepted: january 21, 2021; published: october, 2021 copyright: ©2021 schultz junior et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ademar schultz junior, md, dermatology unit, hospital santa casa de misericórdia de vitória, vitoria, espirito santo, brasil. e-mail: asjunior16@hotmail.com introduction netherton syndrome (ns) is a rare autosomal recessive genodermatosis, characterized by of ichthyosis linearis circumflexa (ilc), bamboo hair (trichorrhexis invaginata), and atopic dermatitis [1]. ns has no definitive cure. it is a rare dermatosis, which is difficult to diagnose, as the components of the syndrome may not be detected at the same time. it is therefore essential to deepen our understanding of this disease. in this article we present an exuberant case of ns with classic clinical findings, simultaneously to the diagnosis. case report a 20-year-old dark-skinned woman attended her first dermatology visit due to erythema, flaking, and hair loss. at 3 months old, she had diffuse erythema and itchy scaling skin. at 3 years old, she had opaque and brittle hair, developing areas of alopecia in the temporal and occipital regions. physical examination showed alopecia in the temporal and occipital regions, eyelid eczema, and eyelashes and distal third of eyebrows thinning (figures 1, a and b). the patient had generalized erythroderma, lichenification of flexures and erythematous lesions with double-edge scaling, and serpiginous and polycyclic lesions at the level of the abdomen, upper, and lower limbs (figures 1, c and d). at trichoscopy, golf tee hair was seen on the eyebrows and trichorrhexis invaginata at the optical microscopy of the hair (figure 2, a and b). the patient maintained supportive treatment with skin hydration and a therapeutic plan to initiate systemic retinoids. 2 letter | dermatol pract concept. 2021; 11(4):e2021065 conclusion ns comprises the alterations in the cornification of the skin due to mutations in the serine protease inhibitor kazal type-5 (spink5), which encodes the serine protease inhibitor lekti (lympho-epithelial kazal-type-related inhibitor) expressed on epithelial surfaces [1]. diagnosis is difficult due to the multiple variables of the clinical presentation. eventually, patients with ns manifest ichthyosis linearis circumflexa (ilc). the latter appears after 2 years of age, being characterized by erythematous-serpiginous lesions, which are polycyclic and show a double-edged scale. in some individuals with spink5 mutations, ilc is the only clinical manifestation of ns [1]. figure 1. (a) an important xeroderma can be seen in the entire area of the face, extending to the neck and shoulders. there is erythema, edema and peeling of the eyelids, characterizing eczema. the lateral portion of the eyebrows stands out. (b) alopecia in the occipital and temporal region. (c) generalized involvement of the body by erythematous, scaly, and polycyclic lesions. (d) erythematous, polycyclic, serpiginous, and annular lesion. it has a double scaling edge. this set characterizes the circumflex linear ichthyosis, which is a particular phenotype of the disease figure 2. (a) optical microscopy of the scalp hair (magnification x40). visualization of bamboo hair or invaginated trichorexis, a more specific alteration of the disease. (b) detail of the trichoscopy of the right eyebrow revealing hair alteration “golf tee hair”. letter | dermatol pract concept. 2021; 11(4):e2021065 3 the basis for diagnosis is the trichorrhexis invaginata (ti) or bamboo hair, characterized by the invagination of the distal part over the proximal part of the hair shaft. however, it is not uncommon that hundreds of hair samples are examined for ti to be found. thus, the diagnosis is often only established after several years of monitoring [1]. in some cases, there is a history of consanguineous parents, eosinophilia and increased ige in peripheral blood. atopy associated with ns can lead to an incorrect diagnosis of atopic dermatitis or severe eczema. therefore, ns must be considered in children with atopic eczema who do not respond to standard treatment. up to 75% of patients develop other atopic manifestations such as asthma, allergic rhinitis, angioedema, prutitus, and urticaria [1]. there is no specific treatment for ns. throughout life, the treatment is symptomatic and individualized. therapeutic options that can be used are phototherapy, systemic retinoids, and immunosuppressants. new studies are being carried out with anti-tnf treatment showing good perspectives. recently, an exploratory study has shown good results with topic pimecrolimus 1% cream, revealing low systemic absorption and favorable safety and efficacy profile [2]. concisely, skin lesions presenting simultaneously with hair changes are not widely common, which makes diagnosis difficult. thus, we highlight the role of the dermatologist in the surmise of rare diseases based on the finding of specific skin and hair lesions, making it possible to perform an early diagnosis. references: 1. sun jd, linden kg. netherton syndrome: a case report and review of the literature. int j dermatol. 2006;45:693-7. doi: 10.1111/j.1365-4632.2005.02637.x. pmid: 16796630. 2. yan ac, honig pj, ming me, weber j, shah kn. the safety and efficacy of pimecrolimus, 1%, cream for the treatment of netherton syndrome: results from an exploratory study. arch dermatol. 2010;146:57–62. doi: 10.1001/archdermatol.2009.326. pmid: 20083693. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021076 1 a cross-sectional survey of knowledge of skin cancer in saudi arabia hend m. al-atif1 1 department of internal medicine, college of medicine, king khalid university, abha, saudi arabia key words: skin cancer, sunscreen, sunburn, sun exposure, questionnaire, sun-protective behavior citation: al-atif hm. a cross-sectional survey of knowledge of skin cancer in saudi arabia. dermatol pract concept. 2021;11(3):e2021076. doi: https://doi.org/10.5826/dpc.1103a76 accepted: february 7, 2020; published: may 20, 2021 copyright: ©2021 al-atif. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. corresponding author: hend m. al-atif, md, assistant professor and consultant of dermatology, department of internal medicine, college of medicine, king khalid university, po box 9060, abha 61431, saudi arabia. email: hmsalatif@yahoo.com background: skin cancer has become one of the world’s leading health problems, and incidence rates are on the rise. the leading causes of skin cancer are sun exposure, family history and sunburn, and the most agreed-upon preventative behaviors are sunscreen application and sun avoidance. objectives: this study assessed the knowledge of the causes of skin cancer and awareness of preventative measures in saudi arabia. methods: a cross-sectional study was conducted among 529 participants in a whatsapp group over 3 months. consenting participants completed a validated, 18-item questionnaire. results: of 529 total participants, nearly 55% of participants reported an awareness of skin cancer, 35% understood its metastasis and 55.1% knew about its spread. however, 44% of participants were unaware of the different types of the disease. social media was reported to be the most common source of information. the majority of participants were able to identify symptoms of skin cancer and had knowledge of risk factors. most participants understood proper preventative measures, and reported that they use sunscreen regularly. conclusions: the general knowledge of skin cancer in saudi arabia is not high but is increasing. however, sun-protective behaviors are lacking, despite the population’s knowledge of the benefits. awareness campaigns and incentive programs may encourage better preventative behavior. future studies should explore participants’ awareness of more specific aspects of skin cancer using a more diverse and extensive population sample. abstract 2 research | dermatol pract concept. 2021;11(3):e2021076 introduction skin cancer is a group of diseases characterized by the abnormal mutation and multiplication of cells in the epidermal layer of the skin [1]. it is a major health problem worldwide, and has a great economic burden in both developed and developing nations [2]. there are two main types of skin cancer: melanoma, which is more likely to result in death, and non-melanoma skin cancer, which includes basal cell carcinoma and squamous cell carcinoma [3]. skin cancer is much more common among white populations than among people of color [4], although fewer data are available on skin cancer in non-white populations [5]. the worldwide prevalence of skin cancer is 197.9 per 100,000 [6], with the highest rates occurring in australia and new zealand [6,7]. the global incidence of skin cancer is increasing [8]. however, this finding may be due to an increase in screenings and biopsies, as opposed to an increase in actual disease prevalence [9]. the most-cited cause of skin cancer is exposure to sunlight, specifically uv irradiation [10], which has been exacerbated by depletion of the ozone layer. therefore, living in sunny climates is a risk factor [11]. other risk factors include a family history of skin cancer, a history of severe sunburn and the age at which sunburns occur [12], as well as having fair skin [13]. a survey by al-dawsari and shahab [14], conducted in 2016 in the eastern part of saudi arabia, found that 60% of subjects described their skin as being of the fitzpatrick type iii or v while the rest described their skin as types i or ii. a cross-sectional study by alliali et al in makkah, saudi arabia, in 2014 found that almost two-thirds of saudi women had a naturally light type of skin (types iii or iv) [15]. the main appearance of basal cell carcinoma on the skin is a pigmented lesion, which can be pink, brown or black-blue, while squamous cell carcinoma appears as a rough or scaly, red-brown papule [16]. the most commonly used approach for diagnosing irregular moles and pigmented lesions as melanoma is the abcde method, which stands for “asymmetry, border irregularity, color variation, diameter and evolving” [11]. symptoms of advanced melanoma include anorexia, bleeding, pain, and fatigue, among others [17]. skin cancer awareness increases with the incidence rate in a population. several studies have shown a high level of general awareness of skin cancer globally, including in the united kingdom and pakistan [18,19]. one systematic review of north american studies found that skin cancer knowledge had a positive association with sun-protective behavior [20]. one study found that women have a greater awareness of skin cancer than men [21]. furthermore, one us study showed higher levels of awareness among white americans than hispanic or african-american participants [22]. a study conducted in riyadh, saudi arabia, showed that the population had a good general awareness of skin cancer but little awareness of specific details of the disease, with 83% stating they were unaware that sun exposure causes skin cancer [23]. however, a later study in jeddah, saudi arabia, showed that 73% of participants were aware of the association between skin cancer and exposure to sunlight, although 58% did not know that moderate tanning also poses a risk [24]. this study assessed the knowledge of skin cancer in the saudi arabia population through a questionnaire designed to measure this knowledge more accurately than in previous studies. methods study design a population-based, cross-sectional survey was conducted over a period of 3 months, beginning in january 2020. people from the general population of saudi arabia were eligible to participate if they were ≥18 years old. they were informed that the data were to be collected anonymously, and were asked to provide consent before responding. anonymous reporting and confidentiality protocols were maintained at all levels. ethical approval was obtained from king khalid university review board. a whatsapp group was created for distributing the study form, which consisted of an 18-item questionnaire, designed on google forms. data collection this study used a validated questionnaire that was developed on the basis of an in-depth literature search for surveys of skin cancer awareness conducted in different countries. questions from previously published [25,26] studies were adapted on the basis of feedback from 3 experts in skin disease research. these previously published studies included one by al robaee [25] and one by agarwal et al [26]. the questionnaire was piloted with a separate random sample of 30 participants, who provided feedback on the clarity of questions. the questionnaire collected sociodemographic data, including age, gender and education level. questions were designed to assess participants’ general knowledge of skin cancer, hazards of excessive sunlight exposure, protection methods and sunscreen use. general knowledge of skin cancer was measured by asking about the participants’ history of skin cancer, the sources of their information, and the appearance of, risk factors for and prevention of skin cancer. questions were asked about the participants’ knowledge of the pros and cons of using sunscreen, on what basis they select a sunscreen, the site and frequency of usage, and any complications after sunscreen application. statistical analysis data entry and statistical analysis were performed using statistical package for social sciences software v25 (spss). research | dermatol pract concept. 2021;11(3):e2021076 3 continuous variables are presented as mean and standard deviation (sd), and categorical variables are presented as numbers and percentages. results data were collected from 529 participants with a mean age of 36 years (sd = 10 years). the majority of participants were women and university educated (table 1). about 55.1% of participants knew about skin cancer (n=285), primarily from social media. knowledge of specific types of skin cancer was lower. knowledge of the appearance of skin cancer was more common, with 92% (n=402, the number of respondents=437) of participants correctly reporting a change in skin color, while 62% (n=218, the number of respondents=352) correctly reported skin elevation, and 77% (n=308, the number of respondents=400) correctly reported wounds and ulcers. only 35% (n=179, the number of respondents=511) of participants reported knowledge of metastasis, while 57% (n=295) reported no knowledge about skin cancer spread. the majority of participants correctly identified the most important risk factors for skin cancer (figure 1). most participants had some knowledge of the indicators of cancer growth. of 453 respondents, 93% reported change in size as an indication of cancer growth, while 88% reported change in color and 91% reported bleeding as important indicators. however, appearance of the hair was considered an important indication by only 36% of participants. more than half (54%) reported that wearing clothes to cover the skin was important for skin cancer prevention, while sunscreen use and periodic examination were considered significant by, respectively, 445 (90.4%, respondents=492) and 417 (85.8%, respondents=486) participants. the majority of participants also correctly identified risk factors for skin cancer linked to sun exposure (figure 2) and reported the benefits of sunscreen (figure 3). less than half of participants reported some harmful effect of using sunscreen (table 2). most participants correctly reported that sunscreens differ from each other, and most reported at least some sunscreen use (table 2). participants reported that price (62%), density (66%), ingredients (75%), sun protection factor (spf) (81%), doctor recommendation (82%) and country of the manufacturer (53%) were important factors behind their selection of a sunscreen. the primary reason that most participants reported as being behind a decision not to use sunscreen was time (56%). a minority (16%) reported complications of sunscreen use. discussion the findings of the study show varying awareness among people in saudi arabia on the subject of skin cancer. while the large majority of study participants correctly identified risk factors and preventative measures, most reported using sunscreen daily. this study has multiple methodological issues. first, the large majority of participants were women, so data on the knowledge and behavior of saudi men may be less reflective of the population. second, although the study included participants from multiple geographic locations, the sample size was relatively small. similar studies in other geographic areas and other countries may have different findings and limiting generalizability of the results. last, in a cross-sectional study, causality cannot be ascertained. all data were self-reported, introducing a chance of recall bias. this manuscript reports on a convenience sample, representing the population of the saudi arabia to the extent possible. however, this study also has several strengths. the use of a validated tool for measuring awareness provided a wider range of more specific results. moreover, pairing assessment of a population’s knowledge with behavior provided information on what specific areas of information should be addressed. table 1. sociodemographic characteristics of the study participants (n=529) sociodemographic characteristic no. (%) sex male 58 (11.2) female 459 (88.8) missing data 12 education secondary or below 67 (13.0) university 449 (87.0) missing data 13 information about skin cancer yes 285 (55.1) no 213 (41.2) don’t know 19 (3.7) missing data 12 source of information audiovisual 110 (24.7) print media 90 (20.2) social media 189 (42.4) relatives 57 (12.8) missing data 83 types of skin cancer yes 285 (55.4) no 3 (0.6) don’t know 226 (44.0) missing data 15 4 research | dermatol pract concept. 2021;11(3):e2021076 92 62 77 35 93 91 36 0 10 20 30 40 50 60 70 80 90 100 change in skin color skin elevation wounds and ulcers metastasis change in size of a mole bleeding appearance of hair k n o w le d g e o f v a r io u s c a te g o r ie s in p er c en ta g e risk factors for skin cancer s u r v e y p a r t i c i p a n t s ’ k n o w l e d g e o f t h e r i s k fa c t o r s f o r s k i n c a n c e r survey participants figure 1. clustered column showing survey participants’ knowledge of the risk factors for skin cancer. 91% 71% 77% 90% 80% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% darkening of skin appearance of wrinkles skin cancer skin burns melasma p er c en ta g e risk factors for skin cancer linked to sun exposure r i s k fa c t o r s f o r s k i n c a n c e r l i n k e d t o s u n e x p o s u r e risk factors for skin cancer linked to sun exposure figure 2. clustered column showing participants’ understanding of the harmful effects of sunlight. the results show a much greater awareness of skin cancer in the general population of saudi arabia than a 2016 study conducted in riyadh, in which 83% of participants did not know that sun exposure causes skin cancer [23], as well as a 2010 study in the qassim province, in which only 56% of participants had knowledge of the association [25]. the level of awareness reported in this study is similar to the results of a 2020 study in jeddah, in which 73% of participants reported awareness of the association between skin cancer and sun exposure [24]. sunscreen usage was inadequate in that study, with only 36% of participants using it regularly; this rate is slightly higher than that of other saudi studies, in which only 24% of respondents reported regularly using sunscreen [26,27]. one possible reason for the relatively higher levels of awareness among participants in the present study is that 89% were women, and a previous study indicated research | dermatol pract concept. 2021;11(3):e2021076 5 table 2. knowledge of sunscreen among study participants (n=529) information on sunscreen no. (%) harm of using sunscreen pimples missing data 212 (47.7) 85 skin irritation 186 (42.2) missing data 88 difference in sunscreen yes missing data 391 (75.) 12 usage of sunscreen yes missing data 418 (82) 19 use of sunscreen/day once 329 (78.7) twice 67 (16.0) thrice 22 (5.3) application of sunscreen face missing data 462 (96.9) 52 hands missing data 345 (77.7) 85 arms missing data 103 (27.9) 160 other parts missing data 57 (15.7) 166 97 82 73 66 35 86 13 0 20 40 60 80 100 120 protects the skin from ultraviolet sunlight prevents darkening of the skin protects the skin from agiing prevents skin cancer skin colour opens prevents skin burns useless p er c en ta g e benefits of sunscreen pa r t i c i p a n t s u n d e r s t a n d i n g o f t h e b e n e f i t s o f s u n s c r e e n figure 3. clustered column showing participants’ understanding of the benefits of sunscreen. that women are more likely to be knowledgeable about skin cancer than men [23]. however, the higher level of education in this study may also have made the awareness of skin cancer somewhat higher. one important implication of this study is that, while knowledge about skin cancer and its risk factors may have increased, the practice of sun-protective behaviors continues to be alarmingly low. this finding indicates that the saudi population may benefit from an increase in awareness campaigns targeting sunscreen usage as well as increased recommendations from medical professionals. additionally, regular and affordable testing for skin cancer should be made available nationally, to increase both awareness of skin cancer as well as opportunities for early detection. conclusions general skin cancer knowledge appears to be higher among the saudi population than in previous years, with social media being the most common source of information. however, sun-preventative behaviors, especially sunscreen use, continue to be inadequate, despite the high levels of awareness. future studies should address 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and actinic keratosis among the general population of western saudi arabia. j fam med prim care. 2020;9(1):374-378. doi: 10.4103/jfmpc.jfmpc_874_19. pmid: 32110621. 25. al robaee aa. awareness to sun exposure and use of sunscreen by the general population. bosn j basic med sci. 2010;10(4):314318. doi: 10.17305/bjbms.2010.2678. pmid: 21108614. 26. agarwal sb, godse k, patil s, nadkarni n. knowledge and attitude of general population toward effects of sun exposure and use of sunscreens. indian j dermatol. 2018;63(4):285-291. doi: 10.4103/ijd.ijd_609_17. pmid: 30078870.. 27. alghamdi km, alaklabi as, alqahtani az. knowledge, attitudes and practices of the general public toward sun exposure and protection: a national survey in saudi arabia. saudi pharm j. 2016;24(6):652-657. doi: 10.1016/j.jsps.2015.04.002. pmid: 27829807. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021100 1 risankizumab for plaque and guttate psoriasis in a patient with iga-related glomerulonephritis annunziata dattola1, arianna zangrilli1, luca bianchi1 1 department of dermatology university of rome “tor vergata”, rome, italy key words: guttate psoriasis, risankizumab, multi-failure, renal disease citation: dattola a, zangrilli a, bianchi l. risankizumab for plaque and guttate psoriasis in a patient with iga -related glomerulonephritis. dermatol pract concept. 2021;11(4):e2021100. doi: https://doi.org/10.5826/dpc.1104a100 accepted: march 8, 2021; published: october, 2021 copyright: ©2021 dattola et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: annunziata dattola, department of dermatology, policlinico tor vergata, rome, italy. email: nancydattola@gmail.com introduction guttate psoriasis is a subtype of psoriasis characterized by acute eruption of numerous small, erythematous papules and plaques. it usually occurs in children and adolescents, but it can occur in other age groups. streptococcus infection is an important risk factor which can usually precede its development by 2-3 weeks [1]. risankizumab is a novel anti-interleukin 23 humanized antibody developed for severe plaque psoriasis. it is a humanized immunoglobulin monoclonal antibody (ig) g1 selectively binding to and inhibiting p19 subunit of il-23. no clinical cases are reported in literature regarding the use of risankizumab for guttate psoriasis’ treatment, but there is evidence reporting resolution of guttate psoriasis after 1 guselkumab injection, another novel anti-il-23 [2]. phase 3 trials evaluating the effectiveness and safety of risankizumab in patients with moderate-to-severe plaque psoriasis were: ultimma-1 (n = 506), ultimma-2 (n = 491), immhance (n = 507), and immvent (n = 605). in ultimma-1 and ultimma-2, randomized, double-blind, placebocontrolled, and active comparator-controlled trials, patients were randomized for risankizumab 150 mg, ustekinumab (45 mg or 90 mg), or placebo. results showed a higher efficacy of risankizumab compared to ustekinumab and placebo; at week 16, psoriasis area and severity index 90 (pasi 90) was achieved by 75.3% and 74.8% of patients receiving risankizumab versus 42.0% and 47.5% receiving ustekinumab, respectively in ultimma-1 and ultimma-2 [3]. case presentation we describe a case of a 32-year-old female patient affected by plaque psoriasis at the level of the trunk and the extremities, covering approximately 30% of the patient’s body surface area (pasi score 18). she is also affected by “early stages” of glomerulonephritis iga-related for 10 years, now under control without treatment. the patient was treated with several topical treatments, phototherapy, systemic corticosteroids, and methotrexate for 6 months with no clinical efficacy. cyclosporine was administered for glomerulonephritis. in 2016, after screening for 2 letter | dermatol pract concept. 2021;11(4):e2021100 biological treatment, she started treatment with etanercept 50 mg subcutaneous injection every week. after 24 weeks of treatment, following the loss of efficacy with etanercept, we began adalimumab 40 mg subcutaneous injection therapy. while the patient was undergoing adalimumab treatment, we observed a good control of cutaneous psoriasis (pasi residual 3) for 12 months. after 12 months with adalimumab the patient developed psoriatic lesions at the limbs and trunk; we decided to continue the treatment evaluating the patient at the next visit. at follow-up we noticed an important flair of the skin lesions, psoriatic plaques on the arms, and guttate psoriasis on the trunk. adalimumab treatment was therefore discontinued. laboratory test did not detect abnormalities, streptozyme test was performed because of the appearance of guttate psoriasis and result was negative. treatment with secukinumab was excluded because of recurrent genital candidiasis medical history. ixekizumab was also excluded due to eczematous episodes localized on the patient’s face. in january 2019 risankizumab therapy was started (150 mg subcutaneous injection) (figure 1a). after 1 month of treatment followed by an episode of sore throat with positive streptozyme test treated only with streptococcus salivarius probiotics, the patient’s clinical manifestations worsened, shifting from a pasi 12 to pasi 20 (figure 1b). the patient was followed up to the next visit, and after 12 weeks of treatment, there was a reduction of pasi (pasi score 5) and good clinical improvement, with complete resolution of plaque psoriasis and guttate lesions after 16 weeks of treatment (pasi 0) (figure 1c). complete resolution of cutaneous plaque and guttate psoriasis was achieved after 12 months of treatment (figure 1d). conclusions psoriasis is a complex disease, caused by an inflammatory cascade involving cytokines as tnfα, and the il-17/il-23 axis. there are currently different treatment options to control the disease. according to new evidence, it is important to build personalized therapy considering the characteristics of psoriasis and the presence of co-morbidities that may affect the clinical response. here we reported the effectiveness of risankizumab for both psoriatic plaque and guttate psoriasis. references 1. fang r, sun q. guttate psoriasis. indian pediatr. 2020;57(6):596597. doi: 10.1007/s13312-020-1880-0. pmid: 32562412. 2. shalanda l. hall, wasim haidari, steven r. feldman. resolution of guttate psoriasis plaques after one-time administration of guselkumab. j drugs dermatol. 2019;18(8):822-823. 3. dattola a, silvestri m, tamburi f, amoruso gf, bennardo l, nisticò sp. emerging role of anti-il23 in the treatment of psoriasis: when humanized is very promising. dermatol ther. 2020:e14504. doi: 10.1111/dth.14504. figure 1. (a) start of risankizumab treatment. (b) clinical situation after 1 month of treatment following an episode of sore throat with positive streptozyme test. (c) complete resolution of plaque psoriasis and guttate lesions after 16 weeks of treatment. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022002 1 crusted umbilicated papules in a child hitaishi mehta1, sheetanshu kumar1, divya aggarwal2, debajyoti chatterjee2, keshavamurthy vinay1 1 department of dermatology, venereology and leprology, postgraduate institute of medical education and research, chandigarh, india 2 department of histopathology, postgraduate institute of medical education and research, chandigarh, india key words: reactive perforating collagenosis, rpc, perforating disorders citation: mehta h, kumar s, aggarwal d, chatterjee d, vinay k. crusted umbilicated papules in a child. dermatol pract concept. 2022;12(1):e2022002. doi: https://doi.org/10.5826/dpc.1201a02 accepted: april 14, 2021; published: january 2022 copyright: ©2022 mehta et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: keshavamurthy vinay, md, dnb, mnams, department of dermatology, venereology and leprology, postgraduate institute of medical education and research, chandigarh, india. e-mail: vinay.keshavmurthy@gmail.com. introduction reactive perforating collagenosis (rpc) is a rare benign perforating disorder characterized by transepidermal elimination of collagen fibers. both familial and acquired forms of rpc exist, the latter in association with end-stage chronic kidney disease and diabetes mellitus. the very rare childhood form has slight male predilection and is commonly familial [1]. case presentation dermatology consultation was sought for a school-age child with multiple mildly itchy, red, raised lesions on his face and dorsum of hands, which were first noticed by the parents at 2 years of age. the parents also reported spontaneous healing of a few of the lesions with residual hypopigmented scars. preceding history of insect bites or trauma was denied. he was born out of a non-consanguineous marriage, and no one in family had a history of similar lesions. examination revealed multiple skin-colored to erythematous discrete papules on both cheeks (figure 1a) and dorsum of hands (figure 1b) with central adherent keratotic plugs along with few well-circumscribed areas of atrophic scars. dermoscopy of an individual lesion is presented in figure 2a. routine laboratory parameters including renal function tests, fasting blood sugar, and urinalysis were within normal limits. histopathological examination of a facial papular lesion revealed compact orthoand parakeratotic epidermis with a cup-shaped lesion lined by acanthotic epidermis on both sides along with mild perivascular and periadnexal lymphomononuclear cell infiltrate mixed with collagen bundles in the dermis (figure 2b). altered collagen could be seen extruding trans epidermally through the cup-shaped depression. a diagnosis of rpc was reached. the child was treated with topical tretinoin 0.025% ointment with satisfactory improvement after 1 month. conclusions familial rpc commonly presents as erythematous papules with central adherent scale-crust over the extensor aspect of 2 research letter | dermatol pract concept. 2022;12(1):e2022002 extremities. superficial trauma precedes most lesions. individual lesions heal within 6-10 weeks, but recurrences are common. although the familial and acquired forms appear similar in morphology and on histopathology, the acquired form tends to be more persistent and shows transepidermal elimination of both collagen and elastin. the central homogeneous yellowish area observed on dermoscopy corresponds to the central scale or crust, and the white rim of varying thickness corresponds to the epidermal invagination, along with an erythematous halo which arises due to small blood vessels around the lesion [2]. histopathology reveals a plug of keratotic debris with vertically oriented collagen fibers extending into the plug, along with parakeratosis, epithelial hyperplasia, and dyskeratotic keratinocytes [1]. the diagnosis is mostly clinical and requires histopathology for confirmation. investigations other than punch figure 1. (a) multiple skin-colored to erythematous discrete papules on left cheek with central adherent keratotic plugs along with few well circumscribed areas of atrophic scars on cheek. (b) crusted umbilicated papules over dorsum of both hands. figure 2. (a) dermoscopy reveals a yellowish central homogenous area along with a white rim surrounded by erythematous halo at the periphery (dermlite ii, hybrid m, ×10, polarized). (b) histopathological examination (h&e, ×40) of the punch biopsy taken from one of the papular lesions on the face showing orthokeratotic epidermis with a cup shaped lesion lined by acanthotic epidermis on both sides along with mild perivascular and periadnexal lymphomononuclear cell infiltrate mixed with collagen bundles in the dermis. the cup-shaped lesion was densely packed with degenerated basophilic collagen bundles. research letter | dermatol pract concept. 2022;12(1):e2022002 3 biopsy are neither necessary nor contributory. differential diagnosis includes papular urticaria, prurigo nodularis, perforating folliculitis, and elastosis perforans serpiginosa. along with avoidance of trauma, topical therapies reported to be successful include retinoids, corticosteroids, and salicylic acid. other therapies are systemic antihistamines, retinoids, methotrexate, photochemotherapy, nb-uvb, and cryotherapy. most of the patients have a relapsing-remitting course throughout their lifetimes. childhood rpc is a rare entity with an obscure etiopathogenesis and usually self-limiting course. awareness among clinicians regarding this entity is imperative in order to avoid misdiagnosis, anxiety among parents, and over-aggressive management. informed consent: informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. millard pr, young e, harrison de, wojnarowska f. reactive perforating collagenosis: light, ultrastructural and immunohistological studies. histopathology. 1986;10(10):1047-1056. doi:10.1111/j.1365-2559.1986.tb02541.x. pmid: 2430879. 2. kittisak p, tanaka m. dermoscopic findings in a case of reactive perforating collagenosis. dermatol pract concept. 2015;5(2): 75-77. doi: 10.5826/dpc.0502a13. pmid: 26114057. pmcid: pmc4462904. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021028 1 congenital melanocytic nevus regression lacking the halo phenomenon: the influence of the body site maristela garcia bassotto de andrade 1, giuseppe argenziano2, vincenzo piccolo2, eugenia veronica di brizzi2, elvira moscarella2 1dermoscopy fellow, university of campania “l. vanvitelli”, naples, italy 2dermatology unit, university of campania “l. vanvitelli”, naples, italy key words: congenital melanocytic nevus, spontaneous regression, children, involution of nevus, pediatric dermatology, dermoscopy. citation: de andrade mgb, argenziano g, piccolo v, di brizzi ev, moscarella e. congenital melanocytic nevus regression lacking the halo phenomenon: the influence of the body site. dermatol pract concept. 2021; 11(3): e2021028. doi: https://doi.org/10.5826/dpc.1103a28 accepted: september 29, 2020; published: july 8, 2021 copyright: ©2021 de andrade al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maristela garcia bassotto de andrade, dermoscopy fellow at “l. vanvitelli” university of campania, italy. email:marisgba@hotmail.com introduction regression of congenital melanocytic nevus (cms) has been reported, mainly associated with an immunological mechanism and with the occurring halo phenomenon (a depigmentation zone appearing around the nevus). according to tokura et.al (as cited in kageshita, 2003) cd8 t-cell mediated immunity and igm antibodies may be involved in immunological mechanism of regression [1]. the spontaneous or idiopathic regression of a congenital nevus is uncommon and seems to be most frequent when localized at the level of the palmoplantar region [1,2]. case presentation here we report a case of a 6-year-old male, presenting a lesion on the second finger of the right foot that appeared at birth. clinically, it presented as a 1cm diameter nodule, characterized by a heterogeneous brownish color, a hypo-pigmented raised area at the center, and well-defined borders (figure 1a). when analyzed through dermoscopy, the lesion showed a peripheric reticular pattern with parallel furrows pattern visible on 1 side of the lesion. in the central-nodular area, the presence of multiple grayish dots and globules over a pinkwhite background was detected (figure 1b). the lesion was monitored over 3 years. it did not vary in size, but underwent dramatic pigmentation changes (figure 1c), turning color to light brown, both at the periphery and in the center (figure 1d). conclusion cmn may regress in a variety of ways. ciampo et al. [2] described several distinct mechanisms including trauma, the presence of the depigmentation halo, desmoplasia or even regression without any of the mentioned modalities, which was called idiopathic. although idiopathic regression is uncommon, kageshita (2003) [1], reported on 2 cases of complete cmn spontaneous regression, in the palmar region of 2 japanese girls. 2 letter | dermatol pract concept. 2021; 11(3): e2021028 despite the absence of a histopathological confirmation, the author concluded that there might be a regression mechanism unrelated to autoimmune issues. according to the statistical analysis carried out by ciampo et al [2], it was observed that the probability of regression in a congenital nevus located in the palmar and plantar region is 4.95 times greater than in other locations. our patient presented a clearing of the lesion color with no evidence of other mechanisms, suggesting a stop in pigment production by the nevus as a regression mechanism, as it occurred in the above-mentioned cases. moreover, the location of the lesion supports the hypothesis that the palmoplantar location is relevant in the spontaneous regression process. our report lacks histopathologic examination results, therefore larger case series supported by histopathologic examination are necessary. references 1. kageshita, toshiro & inoue, yuji & ono, tomomichi. spontaneous regression of congenital melanocytic nevi without evidence of the halo phenomenon. dermatology (basel, switzerland). 2003; 207:193-5. doi: 10.1159/000071794. pmid: 12920373 2. ciampo l, milano a, colonna v, bonifazi e. prevalence of spontaneous regression in congenital melanocytic nevus. eur. j. pediat. dermatol. 2008; 18 (3): 164-173.retrieved from https:// www. ejpd.com/journal/index.php/ejpd/article/view/492. figure 1. (a) brownish papule with a heterogeneous color measuring about 1 cm located on the second toe of the right foot. (b) on dermoscopy, the lesion showed a reticular and a parallel furrows pattern at the periphery. in the central-nodular region, multiple grayish dots and globules over a pink-white background were visible. (c) clinical lightening of the lesion after 3 years. (d) the lesion appeared cleared in color, both peripherally and in the center. dermatology: practical and conceptual image letter | dermatol pract concept 2020;10(4):2020079 1 dermatology practical & conceptual case presentation a 53-year-old man presented with a 5-year history of a slowly increasing black macule on the palmar side of the ring finger (figure 1a). dermoscopic examination showed a “chaos” pattern composed of scaly surface, whitish clods, eccentric blackish brown structureless areas, parallel lines on both furrow and ridge, and peripheral segmental radial lines (figure 1b). total excision was performed, and histopathologic features were characteristic of bowen disease (figure 1, c and d). teaching point pigmented bowen disease of the palm and sole is a rare subtype of bowen disease that mimics melanoma [1,2]. two previous reports described a multicomponent pattern with regularly distributed dotted vessels and peripheral parallel furrow/lattice-like pattern and/or parallel ridge pattern [1,2]. in our case, we found the following dermoscopic signs suggesting a melanoma diagnosis: atypical parallel pattern along both the furrow and ridges in the left part of the lesion and a more chaotic pattern with segmental radial lines on the right. other dermoscopic features were instead suggestive of bowen disease, such as a scaly surface and linear arrangement of dotted vessels. references 1. cavicchini s, tourlaki a, ghislanzoni m, alberizzi p, alessi e. pigmented bowen disease of the palm: an atypical case diagnosed by dermoscopy. j am acad dermatol. 2010;62(2):356-357. doi: 10.1016/j.jaad.2009.01.035. pmid: 20115962. 2. nako t, hoashi t, mayumi n, et al. case of pigmented bowen’s disease on the volar aspect of the finger dermoscopically mimicking melanoma in situ. j dermatol. 2017;44(5):545-546. doi: 10.1111/1346-8138.13643. pmid: 27790749. a case of pigmented bowen disease on the finger mimicking melanoma showing a chaos pattern on dermoscopy ryoji kurita1, yaei togawa1, keisuke suehiro1, hiroyuki matsue1 1 department of dermatology, graduate school of medicine, chiba university, japan key words: pigmented bowen’s disease, melanoma, parallel furrow pattern, parallel ridge pattern, dotted vessels citation: kurita r, togawa y, suehiro k, matsue h. a case of pigmented bowen disease on the finger mimicking melanoma showing a chaos pattern on dermoscopy. dermatol pract concept. 2020;10(4):e2020079. doi: https://doi.org/10.5826/dpc.1004a79 accepted: may 6, 2020; published: october 26, 2020 copyright: ©2020 kurita et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: yaei togawa, md, department of dermatology, graduate school of medicine, chiba university, 1-8-1 inohana, chuo-ku, chiba-shi, chiba, 260-8670 japan. email: togawa-yk@faculty.chiba-u.jp 2 image letter | dermatol pract concept 2020;10(4):2020079 figure 1. (a) a black macule was seen on the right ring finger, measuring 8 × 6 mm. (b) dermoscopy shows multicomponent chaos pattern composed of eccentric blackish brown structureless areas from the center to right side of the lesion, some scattered whitish clods, parallel lines on both the furrow and ridge on the left side (blue arrowheads), segmental radial lines from the upper to right rim of the lesion (white arrowheads), and linear arrangement of dotted vessels in the lower right rim of the lesion (black dotted circle). (c) histopathology revealed hyperkeratosis and acanthosis with elongation and thickening of the rete ridges in the epidermis (h&e stain, lower magnification). (d) in higher magnification (h&e, ×200), atypical epidermal cells with loss of cell polarity and some atypical individual cell dyskeratosis in the epidermis and melanin deposition in the basal layer were seen. hmb45, s-100, and melan-a stains were negative (data not shown). a b c d dermatology: practical and conceptual editorial | dermatol pract concept 2021;11(1):e2021084 1 dermatology practical & conceptual it is not easy to precisely define when dermoscopy was “invented.” the first description of the idea of in-vivo direct skin microscopy goes back to 1950 when leon goldman applied it to detect cutaneous filariae [1]. as he extended his research to the in-vivo microscopic examination of nevi, he provided the first pieces of evidence on the potential of this method to uncover clinically invisible morphologic structures of skin tumors [2]. twenty years later, in 1970, rona mackie provided the first description of the microscopic surface patterns of nevi, melanoma, basal cell carcinoma, and angioma [3]. in 1980, fritsch and pechlaner improved the technique and suggested that it had the potential of improving the clinical discrimination between benign and malignant skin neoplasms [4]. in the late 1980s the first efforts of systematically categorizing the observed features of lesions and assessing their diagnostic significance were published. parameters to be evaluated would include patterns, colors, intensity of pigmentation, configuration, regularity, and other characteristics of the surface and the margin of the lesion [5]. this was, in fact, the introduction of pattern analysis in dermoscopy. a deluge of publications by several research groups followed in the last decade of the twentieth century. today, most of what is considered basic dermoscopy knowledge sprang from a plethora of publications within that short period. the modified pattern analysis, the abcd rule of dermoscopy, the menzies method, and the 7-point checklist were published between 1994 and 1998 [6-9]. almost simultaneously, large studies on basal cell carcinoma and melanoma on specific locations (eg, acral, face) came to light [10-12]. at the beginning of the new millennium, when the first consensus meeting among dermoscopy experts was held, it seemed that all dermoscopy knowledge had been discovered [13]. it is true that most of the information included in the publication that summarized the consensus meeting of 2000 is still considered valid; but what followed in the increased amount of research, was totally unpredictable. we used the scopus database to retrieve data on publications on dermoscopy, using the following search terms: “dermoscopy” or “dermatoscopy” or “epiluminescence microscopy.” our search revealed a total of 17,213 items. of them, 392 items had been published in the years leading up to and including 2000 and 16,821 items have been published since 2001. of the latter group, 3,426 were published between 2001 and 2010 and 13,395 between 2011 and 2020. the graphs below illustrate the number of publications per year, highlighting the almost exponential increase (figures 1, 2, 3). research in dermoscopy: the best is yet to come! aimilios lallas1, giuseppe argenziano2 1 first department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece 2 dermatology unit, university of campania, naples, italy citation: lallas a, argenziano g. research in dermoscopy: the best is yet to come! dermatol pract concept. 2021;11(1):e2021084. doi: https://doi.org/10.5826/dpc.1101a84 published: january 29, 2021 copyright: ©2021 lallas and argenziano. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: aimilios lallas, md, first department of dermatology, school of medicine, faculty of health sciences, aristotle university, thessaloniki, greece. email: emlallas@gmail.com 2 editorial | dermatol pract concept 2021;11(1):e2021084 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 62 2253 documents by yeardocuments d o c u m e n t s year 1955 1961 1967 1973 1979 1985 1991 1997 2003 2009 2015 2021 2500 2000 1500 1000 500 0 1920 1615 1469 1275 1271 1038 921 859 year figure 1. 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2253 documents by yeardocuments d o c u m e n t s 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2500 2250 2000 1750 1500 1250 1000 750 500 1920 1615 1469 1275 1271 1038 921 859 712 year year figure 3. 2020 2019 2018 2017 2016 2015 2014 2013 2011 2253 1920 documents by yeardocuments d o c u m e n t s year 2001 2003 2005 2007 2009 2011 2013 2015 2017 2019 2021 2500 2000 1500 1000 500 0 1615 1469 1275 1271 1038 921 859 712 2012 year figure 2. editorial | dermatol pract concept 2021;11(1):e2021084 3 several factors might be driving this impressive trend. improved understanding of dermoscopic morphology generated the need for more profound investigations. the expansion of the use of dermoscopy in the field of inflammatory and infectious dermatoses opened a new horizon for scientific research. above all, a new generation of young passionate researchers in the field has surfaced. up to the year 2000, argenziano, g. zalaudek, i. longo, c. pellacani, g. lallas, a. moscarella, e. malvehy, j. marghoob, a.a. puig, s. 0 100 200 300 400 hofmann-wellenhof, r. figure 4. table 1 ranking author number of papers 1 argenziano, g. 345 2 zalaudek, i. 280 3 longo, c. 263 4 pellacani, g. 235 5 lallas, a. 200 6 moscarella, e. 180 7 malvehy, j. 165 8 marghoob, a. a. 161 9 puig, s. 158 10 hofmannwellenhof, r. 130 11 tosti, a. 120 12 soyer, h. p. 116 13 thomas, l. 111 14 micali, g. 103 15 cinotti, e. 102 16 lacarrubba, f. 100 17 carrera, c. 98 18 piana, s. 88 19 perrot, j. l. 85 20 rubegni, p. 85 21 kittler, h. 80 22 apalla, z. 79 23 scope, a. 79 24 patrizi, a. 77 25 errichetti, e. 76 ranking author number of papers 26 piraccini, b. m. 68 27 rudnicka, l. 68 28 dika, e. 64 29 haenssle, h. a. 61 30 stinco, g. 61 31 tanaka, m. 60 32 farnetani, f. 59 33 peris, k. 59 34 dalle, s. 58 35 bonifazi, e. 56 36 dusza, s. w. 55 37 labeille, b. 52 38 halpern, a. c. 51 39 mun, j.h. 50 40 blum, a. 49 41 tschandl, p. 49 42 stanganelli, i. 48 43 starace, m. 48 44 verzì, a. e. 48 45 braun, r.p. 47 46 cambazard, f. 47 47 piccolo, v. 47 48 marchetti, m. a. 46 49 kyrgidis, a. 44 50 miteva, m. 44 worldwide only 14 authors had published 10 or more papers on dermoscopy. today, 145 authors have published more than 30 articles each. the annual rate of published dermoscopy articles continued to increase steadily during the last decade. the 10 top authors of dermoscopy papers from 2011 to date are listed in figure 4 and a list of the top 50 authors in table 1. 4 editorial | dermatol pract concept 2021;11(1):e2021084 in the year 2020, which was dominated by the covid pandemic, the number of published dermoscopy papers reached a historic high of 2,253 items, with 118 different authors publishing more than 5 papers each. the top 10 are listed in figure 5. several journals have published dermoscopy articles throughout the last decades, including all the top-ranking dermatology journals. the largest number has been published in the journal of the american academy of dermatology (788), followed by the journal of the european academy of dermatology and venereology (571) (figure 6). the fact that the official journals of the 2 largest dermatologic societies in the world published so many papers on the topic highlights their popularity among reader-clinicians. dermatology practical and conceptual is not included in this list because it is a new journal that only recently has been indexed by scopus. being the official journal of the international dermoscopy society and given us the considerable space we need to devote to dermoscopy papers, and we are confident that our journal will one day appear high up in this list. predicting the future is a difficult task, and we cannot know if this trend will continue in the forthcoming years or if it will stabilize. what we believe to be true of the future is that dermoscopy will continue to be an invaluable tool for clinicians, inspire research, and unite the medical community. these are the ideals to which we aspire. aimilios lallas, md deputy editor giuseppe argenziano, md editor-in-chief zalaudek, i. longo, c. pellacani, g. lallas, a. apalla, z. malvehy, j. rubegni, p. cinotti, e. argenziano, g. errichetti, e. 0 10 20 30 40 figure 5. figure 6. documents documents per year by source d o c u m e n t s journal of the american academy of dermatology journal of the european academy of dermatology and venereology british journal of dermatology international journal of dermatology skin research and technology journal of dermatology australasian journal of dermatology european journal of dermatology anais brasileiros de dermatologia 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 year 586 480 339 308 287 284 278 228 198 125 100 75 50 25 0 skin research and technology international journal of dermatology british journal of dermatology journal of the european academy of dermatology and venereology journal of the american academy of dermatology source editorial | dermatol pract concept 2021;11(1):e2021084 5 references 1. goldman l, ortiz lf. types of dermatitis in american onchocerciasis. arch derm syphilol. 1946;53:79. doi: 10.1001/archderm.1946.01510310003001. 2. goldman l. some investigative studies of pigmented nevi with cutaneous microscopy. j invest dermatol. 1951;16:407-426. doi: 10.1038/jid.1951.48. 3. mackie r. an aid to the preoperative assessment of pigmented lesions of the skin. br j dermatol 1971;85:232-238. doi: 10.1111/ j.1365-2133.1971.tb07221.x. 4. fritsch p, pechlaner r. the pigment network: a new tool for the diagnosis of pigmented lesions. j invest dermatol. 1974;74:458-459. 5. pehamberger h, steiner a, wolff c. in vivo epiluminescence microscopy of pigmented skin lesions. i. pattern analysis of pigmented skin lesions. j am acad dermatol. 1987;17(4):571-583. doi: 10.1016/s0190-9622(87)70239-4. 6. argenziano g, soyer hp, de giorgi v, et al. interactive atlas of dermoscopy. milan: edra medical publishing and new media; 2000. 7. argenziano g, fabbrocini g, carli p, de giorgi v, sammarco e, delfino m. epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions: comparison of the abcd rule of dermatoscopy and a new 7-point checklist based on pattern analysis. arch dermatol. 1998;134(12):1563-1570. doi: 10.1001/archderm.134.12.1563. 8. menzies sw, ingvar c, crotty ka, mccarthy wh. frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):11781182. doi: 10.1001/archderm.1996.03890340038007. 9. stolz w, riemann a, cognetta ab, et al. abcd rule of dermatoscopy: a new practical method for early recognition of malignant melanoma. eur j dermatol. 1994;4:521-527. 10. schiffner r, schiffner-rohe j, vogt t, et al. improvement of early recognition of lentigo maligna using dermatoscopy. j am acad dermatol. 2000;42(1 pt 1):25-32. doi: 10.1016/s01909622(00)90005-7. 11. oguchi s, saida t, koganehira y, ohkubo s, ishihara y, kawachi s. characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin: a videomicroscopic analysis. arch dermatol. 1998;134(5):563-568. doi: 10.1001/ archderm.134.5.563. 12. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-693. doi: 10.1067/ mjd.2003.281. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(1):9 33 reflectance confocal microscopy: a useful and non-invasive tool in the in vivo differentiation of benign pigmented skin lesions from malignant melanoma. report of a case ramin mofarrah, m.d.1, verena ahlgrimm-siess, m.d.2, cesare massone, m.d.1, rainer hofmann-wellenhof, m.d.1 1 department of dermatology, medical university of graz, austria 2 department of dermatology, paracelsus private medical university of salzburg, austria key words: reflectance confocal microscopy, seborrheic keratosis, melanoma, histopathology, dermoscopy citation: mofarrah r, ahlgrimm-siess v, massone c, hofmann-wellenhof r. reflectance confocal microscopy: a useful and non-invasive tool in the in vivo differentiation of benign pigmented skin lesions from malignant melanoma. report of a case. dermatol pract conc. 2013;3(1):9. http://dx.doi.org/10.5826/dpc.0301a09. received: may 7, 2012; accepted: july 31, 2012; published: january 31, 2013 copyright: ©2013 hofmann-wellenhof et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rainer hofmann-wellenhof, m.d., department of dermatology, medical university of graz, auenbruggerplatz 8, 8036 graz, austria. tel. +43.316.385.2371; fax. +43.316.385 2466. email: rainer.hofmann@medunigraz.at. report of case a 67-year-old man was referred to our department because of a pigmented skin lesion that was clinically suspicious for melanoma. the patient presented with several pigmented skin lesions on the back. he reported that they had been present for a few years and that he had noticed a change in color and slow enlargement in one pigmented skin lesion on his right shoulder. clinically, there was a light-to-dark brown patch approximately 1.5 cm in diameter. dermoscopy showed a light-todark brown homogenous-reticular pattern with focal graybrown to gray-white areas (figure 1a). the clinical and dermoscopic features were most suggestive of a solar lentigo / early seborrheic keratosis (sk) with regression, but a melanoma on sun-damaged skin or a collision of a melanoma with an sk were considered in the differential diagnosis. with reflectance confocal microscopy (rcm), a slightly atypical honeycomb pattern was seen at the superficial epidermal layers. at the basal layer, multiple densely packed edged papillae of different sizes and shapes were observed (figure 1b). the diagnosis of seborrheic keratoses (sk) undergoing regression can be challenging clinically and dermoscopically. we report a case of a sk with a history of change and equivocal dermoscopic features, thereby showing confocal features suggestive of solar lentigo/early sk. the present case emphasizes the potential value of reflectance confocal microscopy (rcm) in the differentiation of malignant from benign pigmented skin lesions. abstract 34 observation | dermatol pract concept 2012;3(1):9 figure 1. (a) dermoscopy showed a light to dark brown homogenous-reticular pattern (insert; area within the dashed square at higher magnification) with focal gray-brown to gray-white areas. (b) on rcm, dense edged papillae (arrows) are observed at the basal layer at low magnification (1.5 x 1.5 mm). (c) at high magnification (0.5 x 0.5 mm), small bright, monomorphous cells are seen outlining dermal papillae of different sizes and shapes (arrows). (d) cord-like structures (arrows) are displayed at the dej at low magnification (1.5 x 1.5 mm). (e) bright, branching tubular structures (“cords,” arrows) are observed at the dej at high magnification (0.5 x 0.5 mm). plump, bright cells are found within the upper dermis (arrowhead). (f) histology showed epidermal hyperplasia characterized by thin strands of basaloid cells and basal hyperpigmentation without increase of melanocytes. in the superficial dermis, few melanophages and solar elastosis were present. [copyright: ©2013 hofmann-wellenhof et al.] observation | dermatol pract concept 2012;3(1):9 35 in addition, we observed multiple bright, round to triangular, non-nucleated cells, suggestive of aggregates of melanophages due to partial regression. confocal criteria suggestive of a melanoma, such as bright, pagetoid nucleated cells, cerebriform cell clusters, or a disarrangement of the dej with non-edged papillae were not seen. these findings were in line with the rcm criteria of lichen planus-like keratosis reported by bassoli et al [11]. in our opinion, the present case demonstrates the potential value of rcm in the diagnosis and differentiation of benign and malignant pigmented skin lesions. rcm may improve the diagnostic accuracy and spare unnecessary excisions of benign pigmented skin lesions with equivocal clinical and dermoscopic features. references 1. elgart gw. seborrheic keratoses, solar lentigines, and lichenoid keratoses. dermatoscopic features and correlation to histology and clinical signs. dermatol clin. 2001;19(2):347-57. 2. pastar z, lipozencić j, rados j, stajminger g. regressing seborrheic keratosis—clinically and dermoscopically mimick ing a regressing melanoma. acta dermatovenerol croat. 2007;15(1): 24-6. 3. braga jc, scope a, klaz i, mecca p, spencer p, marghoob aa. melanoma mimicking seborrheic keratosis: an error of perception precluding correct dermoscopic diagnosis. j am acad dermatol. 2008;58(5):875-80. 4. argenziano g, rossiello l, scalvenzi m, et al. melanoma simulating seborrheic keratosis: a major dermoscopy pitfall. arch dermatol. 2003;139(3):389-91. 5. rajadhyaksha m, grossman m, esterowitz d, webb rh, anderson rr. in vivo confocal scanning laser microscopy of human skin melanin provides strong contrast. j invest dermatol. 1995;104(6):946–52. 6. langley rgb, rajadhyaksha m, dwyer pj, et al. confocal scanning laser microscopy of benign and malignant melanocytic lesions in vivo. j am acad dermatol. 2001;45(3):365-76. 7. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy of pigmented skin lesions—improvement in melanoma diagnostic specificity. j am acad dermatol. 2005;53(6):979-85. 8. gonzález s, gill m, halpern ac. reflectance confocal microscopy of cutaneous tumors. an atlas with clinical, dermoscopic and histological correlations. 2nd ed. london: informa healthcare, 2011. 9. langley rg, burton e, walsh n, propperova i, murray sj. in vivo confocal scanning laser microscopy of benign lentigines: comparison to conventional histology and in vivo characteristics of lentigo maligna. j am acad dermatol. 2006;55(1):88-97. 10. hofmann-wellenhof r, pellacani g, malvehy j, soyer hp (eds). reflectance confocal microscopy for skin diseases. berlin: springer-verlag, 2012. 11. bassoli s, rabinovitz hs, pellacani g, et al. reflectance confocal microscopy criteria of lichen planus-like keratosis. j eur acad dermatol venereol. 2012;26(5):578-90. the bright cells surrounding the dermal papillae were monomorphous in size and shape (figure 1c). in addition, bright branching tubular structures “cords” and bulbous projections were seen at the dermo-epidermal junction (dej) (figure 1d). the superficial dermis displayed aggregated bright, round to triangular, non-nucleated cells, suggestive of melanophages (figure 1e). the overall rcm impression was of a seborrheic keratosis undergoing regression. the lesion was surgically removed by shave biopsy due to the history of change and the presence of regression structures together with a pigment network in dermoscopy. histology showed epidermal hyperplasia characterized by thin strands of basaloid cells, horn cysts and basal hyperpigmentation without increase of melanocytes. in the superficial dermis, a few melanophages and solar elastosis were present (figure 1b). the diagnosis of a reticulated seborrheic keratosis was made. discussion seborrheic keratoses are benign skin neoplasms that can usually be recognized either clinically or dermoscopically [1]. however, seborrheic keratoses displaying regression structures in dermoscopy can occasionally mimic melanomas. in addition, melanomas arising in association with seborrheic keratoses have been described in the literature [2-4]. rcm is a novel, non-invasive imaging technique that allows for examination of the epidermis and superficial dermis at a cellular resolution [5]. confocal criteria for the diagnosis of benign and malignant melanocytic skin lesions have been extensively described in the literature [6-7]; however, there are only a few reports in the literature dealing with confocal features of solar lentigines/seborrheic keratoses [8-10]. the main rcm features of solar lentigo/seborrheic keratosis undergoing regression (lichen planus-like keratosis) and their relative frequencies found in the study by bassoli et al were: (i) typical honeycomb pattern of the spinous layer (78.6%); (ii) elongated cords and/or bulbous projections at the dermalepidermal junction (75%); and (iii) numerous plump-bright cells and/or bright stellate spots in the superficial dermis (92.9%) [11]. these rcm features correlated with the following histopathological findings: (i) spinous-granular layers without significant atypia of keratinocytes; (ii) elongated, bulbous rete ridges; and (iii) dense infiltration of melanophages and lymphocytes in superficial dermis. with the use of these diagnostic criteria 71.4% of lplk could be classified correctly, while misclassification of any of the skin cancers as lichen planus-like keratosis was avoided. in our patient, we observed characteristic rcm features of sk, such as densely packed edged papillae, bright branching tubular structures, and bulbous projections at the dej. dermatology: practical and conceptual review | dermatol pract concept 2016;6(3):8 39 dermatology practical & conceptual www.derm101.com pityriasis rosea in pregnancy: report of a spousal occurrence and craniosynostosis in the healthy newborn tiffany y. loh1, philip r cohen2 1 school of medicine, university of california san diego, la jolla, ca, usa 2 department of dermatology, university of california san diego, la jolla, ca, usa key words: conjugal, craniosynostosis, newborn, pityriasis, pregnancy, rosea, sagittal, spouse citation: loh ty, cohen pr. pityriasis rosea in pregnancy: report of a spousal occurrence and craniosynostosis in the healthy newborn. dermatol pract concept 2016;6(3):8. doi: 10.5826/dpc.0603a08 received: january 11, 2016; accepted: may 1, 2016; published: july 31, 2016 copyright: ©2016 loh et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: philip r. cohen, md. email: mitehead@gmail.com background: pityriasis rosea is a papulosquamous disease. it may occur during pregnancy; in this setting, it has occasionally been associated with adverse outcomes. purpose: a woman who developed pityriasis rosea at the beginning of her eighth week of gestation is described. the outcomes in newborns delivered by pregnant women who developed pityriasis rosea during gestation are summarized. method: a 28-year-old woman developed pityriasis rosea during her eighth week of pregnancy. her husband had pityriasis rosea two months earlier. pubmed was searched for the following terms: conjugal, craniosynostosis, newborn, pityriasis, pregnancy, rosea, sagittal, spouse. the papers were reviewed and the references cited were evaluated. results: our patient delivered a healthy male infant after 41 weeks of gestation. he had normal weight, height, and apgar scores. isolated sagittal craniosynostosis was diagnosed and was successfully treated at nine weeks after birth without complications. conclusion: several retrospective studies have investigated the possibility of adverse outcomes in infants born to women who developed pityriasis rosea during pregnancy, such as stillbirth, low gestational weight, hypotonia, and premature delivery. however, there are also reports of healthy newborns in women who have had pityriasis rosea during gestation. our patient carried the fetus one week postterm and delivered a healthy boy via c-section; isolated sagittal craniosynostosis was later diagnosed and successfully repaired. the occurrence of craniosynostosis in a woman who developed pityriasis rosea during her first trimester of pregnancy may be two coincidental events. abstract 40 review | dermatol pract concept 2016;6(3):8 introduction pityriasis rosea is considered to be a benign cutaneous condition [1-4]. however, in the setting of pregnancy, adverse effects on the newborn may be observed [5,6]. craniosynostosis is a congenital abnormality, which can occur as an isolated finding or as part of a syndrome with other associated features [7,8]. a woman who developed pityriasis rosea during her first trimester of pregnancy and who subsequently delivered a healthy baby with craniosynostosis is described, and a b c d e figure 1. distant view of abdomen (a), back (b), and left flank (c) of a 28-year old woman at 10 weeks gestation who developed annular lesions of pityriasis rosea 2 weeks earlier. closer views show the herald patch on her right abdomen (d) and additional plaques with peripheral scaling on her left flank (e). observations of infants born to women who are diagnosed with pityriasis rosea during their gestation are summarized. case report a 28-year-old healthy woman presented at 10 weeks gestation with a skin rash. two weeks earlier, at eight weeks gestation, she had noticed an initial skin lesion on her abdomen (figure 1). shortly thereafter, she began to develop new lesions on her abdomen and back. her husband, a 29-year-old man, had presented two months earlier with similar-appearing annular lesions on his neck (figure 2). a larger lesion had initially appeared on his left neck. within the next five days, additional lesions appeared on the remainder of his neck and subsequently, a few lesions appeared on his distal upper extremities. a diagnosis of inverse pityriasis rosea was established based on the clinical history and lesion morphology. his lesions resolved review | dermatol pract concept 2016;6(3):8 41 consultation confirmed the diagnosis; at 9 weeks postpartum, endoscopic repair was performed successfully with no adverse sequelae. discussion pityriasis rosea classically presents as annular plaques with peripheral scale, typically located between the neck and the groin, and may be seasonal in occurrence [2,3,9]. less commonly, it can present with lesions on the neck and extremities (inverse pityriasis rosea) [10-11] or during pregnancy [5,6,12,13]. the pathogenesis of pityriasis rosea remains to be definitively established. however, associations with human herpes virus (hsv)-6 and hsv-7 have been observed [14-18]. several studies have found that patients with pityriasis rosea have higher levels of hsv-6 and hsv-7 detected in their skin, suggesting that infection by these viruses may have a causal effect on the development of pityriasis rosea. occasionally, pityriasis rosea has been documented in siblings or in spouses (table 1) [19-21]. in these circumstances, over the next two weeks after treatment with triamcinolone 0.1% cream twice daily. cutaneous examination of the patient’s lesions showed multiple annular plaques with peripheral scaling on the abdomen and back (figure 1). her lesions were similar in morphology to those of her husband. she declined skin biopsy. a diagnosis of pityriasis rosea was established based on the appearance of the lesions and history. cetaphil® cream was applied twice daily to the patient’s lesions; the lesions resolved during the next eight weeks. her obstetrician was contacted. she was classified as a high-risk pregnancy and was followed closely for the remainder of her gestation. the patient went into labor at 40 weeks and 6 days. after 15 hours of labor, the baby had not descended into the pelvis; there was no fetal distress, and a decision for c-section was made. his apgar scores at one and five minutes were 9/9, weight 3827.1 g, and height 50.8 cm. prior to discharge from the hospital, it was noted that the infant had a curved head. x-ray revealed a sagittal craniosynostosis. neurosurgery a b c d figure 2. anterior (a), posterior (b), and lateral (c and d) views of the neck of a 29-year old man, who is the husband of the woman in figure 1, show annular plaques with peripheral scaling of pityriasis rosea that had developed 2 months prior to those of his wife. the right (c) and left (d) neck show pityriasis rosea lesions, including the herald patch on his left neck (d). 42 review | dermatol pract concept 2016;6(3):8 several retrospective studies have observed adverse events affecting the newborn in women who develop pityriasis rosea during pregnancy (table 2) [6,14,22]. in these individuals, the dermatosis lasted 3 to 13 weeks. the adverse events predominantly included stillbirth at 11 to 28 weeks (median 16 weeks), premature delivery (<37 weeks), hypotonia, weak motion, and low birth weight. less common adverse effects were hydramnios and foramen ovale. apgar scores ranged from 6 to 9. some investigators have discovered that pityriasis rosea occurring earlier in pregnancy, such as in the first trimester, have been more often associated with a poorer prognosis, compared to women who developed the dermatosis during the second or third trimesters [6]. however, our review of the literature showed that the majority of women (16/25, 64%) who experienced adverse events had the onset of pityriasis rosea that occurred during the second trimester. the onset of pityriasis rosea occurred during the first trimester in 9 women (36%) and none in the third trimester. additional studies looking at the association between hsv-6 and hsv-7 dna and the occurrence of pityriasis rosea in pregnancy have also been performed [13,14,17,18]. some of the studies found reactivation of hsv-6 during pregnancy. however, a positive correlation between viral infection and clinical features of pityriasis rosea was not established [17,18]. individual case reports, including the patient in this report, have described 29 women who developed pityriasis the skin eruption may occur sequentially. our patient’s husband developed and cleared inverse pityriasis rosea two months prior to his wife developing classic pityriasis rosea. similar to our patient, in the majority of cases of pityriasis rosea occurring in couples, the lesions appeared in the husband prior to the wife (table 1). the interval between onset of pityriasis rosea in the wife after occurrence in the husband ranged from seven days to one year (median: 2 months). one woman had recurrence of pityriasis rosea each sequential year in the spring [21]. our review of the literature, including the patient in this report, discovered 54 women who developed pityriasis rosea during their pregnancy (table 2 [6,14,22] and table 3 [6,12-14,23,24]). the onset of pityriasis rosea ranged from week 8 of gestation (3 patients: cases 7 and 8 in table 2 and case 14 in table 3) to week 32 (1 patient: case 7 in table 3). the median number of weeks of pregnancy at the onset of pityriasis rosea was 19. an equal number of women were either uniparous or multiparous. twenty-five women—ages 24 to 34 (median age 29)—had no prior pregnancies. however, pityriasis rosea occurred during either the second (20 women) or the third pregnancy (6 women) for the other women. most of the women (66%, n=35) developed pityriasis rosea during the second trimester of gestation (13-28 weeks). nineteen percent (10 women) had the onset of their dermatosis during the first trimester (0-12 weeks). only 10% (5 women) experienced it in the third trimester (29-40 weeks). table 1. pityriasis rosea in spouses: summary of patient features. [copyright: ©2016 loh et al.] ca foi ois ha hl hdur wa wl wdur recur ref 1 h 7 d 40 4x2 cm oval patch on rlq abdomen 10 d; tx nd 36 • 30x10 cm patch r flank • bilateral axilla • 2x1 cm oval lesion l arm extensor surface 3 wk; tx nd no 20 2 nd nd nd neck, upper limbs 4 wk, no tx 28 neck, chest, thighs, upper limbs 4 wk, no tx no 19 3 h 1 y nd trunk nd 34 upper trunk, ribs [a] maximum 6 wk per episode yes [b] 21 4 h 2 mo 29 neck, distal upper limbs 2 wk, tac bid 28 abdomen, back 10 wk, cetaphil cream no cr bid=twice daily; c=couples; ca=case; cr=current report; d=days; foi=first occurred in; h=husband; ha= husband’s age in years at onset of pityriasis rosea; hdur=duration in husband; hl=husband’s location of lesion(s); mo=months; nd=not described; ois=onset in spouse; recur=recurrence of pityriasis rosea; rlq=right lower quadrant; tac=triamcinolone cream 0.1%; tx=treatment; wa=wife’s age in years at onset of pitryiasis rosea; wl=wife’s location of pityriasis rosea lesion(s); wdur=duration in wife; wk=weeks; y=years [a] distribution of the lesions was only described for the last recurrence [b] the woman had 4 recurrences, one per year; each recurrence occurred in the spring review | dermatol pract concept 2016;6(3):8 43 table 2. adverse outcomes in infants born to women who developed gestational pityriasis rosea during pregnancy [copyright: ©2016 loh et al.] case a #pp o dur symptoms* loc del* newborn weight (g)# apgar score oae ref 1 24 1 6 3 nd thorax, scattered over body 28 stillbirth, 2325 at autopsy nd 22 2 25 0 18 5 no lower l, t(<50%) 36 3000 7 weak motion 14 3 25 0 19 6 no l, t (<50%) 35 2700 7 hypotonia 14 4 26 0 25 5 yes t (<50%) 36 2950 8 6 5 27 0 19 8 yes l, t (>70%) 32 1900 8 hypotonia 14 6 27 0 19 5 no lower l, t (<50%) 34 2600 6 hypotonia, weak motion 14 7 28 0 8 9 yes l, t 11 abortion na 6 8 28 0 8 11 yes l, t 11 stillborn na 14 9 28 0 9 10 yes l, t 17 stillborn na 14 10 28 1 10 6 yes l, t 12 stillborn na 14 11 29 1 12 11 yes l, t 16 stillborn na 14 12 29 1 16 4 no t (<50%) 36 2950 7 hypotonia 14 13 29 0 15 9 no l, t 34 2100 8 weak motion 14 14 30 1 11 10 yes l, t (>70%) 18 stillborn na 14 15 30 1 11 13 yes l, t 12 stillborn na 14 16 30 0 16 9 yes l, t 38 3100 9 hydramnios 14 17 31 1 15 6 no t (<50%) 38 2800 8 hypotonia, foramen ovale 14 18 31 2 19 4 no lower l, t (<50%) 36 3100 8 foramen ovale 14 19 31 1 20 5 no lower l, t (<50%) 35 2900 6 hypotonia 14 20 32 0 10 11 yes l, t (>70%) 16 stillborn na 14 21 32 2 15 8 yes l, t (>80%) 17 stillborn na 14 22 32 2 18 8 yes l, t 39 2900 9 hydramnios 14 23 33 1 14 9 no l, t 33 2100 7 hypotonia 14 24 34 1 14 9 no t 38 3000 8 hypotonia, hydramnios 14 25 34 1 18 8 no upper l, t (<50%) 34 2650 8 6 *constitutional symptoms (i.e., other than cutaneous symptoms) including fatigue, headache, insomnia, gastrointestinal disturbance, inability to concentrate. c=case; a=mother’s age at onset of pityriasis rosea; #pp=number of previous pregnancies; loc=location; l=limbs; t=trunk; nd=not described; o=onset of pityriasis (weeks in pregnancy); dur=duration of pityriasis rosea (weeks); l=location of lesions; del=delivery (weeks in pregnancy); oae=other adverse events * premature <37 weeks [a] # low birth weight <2500g [b] [a] “preterm birth.” world health organization. http://www.who.int/mediacentre/factsheets/fs363/en/ date of access: 13 dec. 2015. [b] “pediatric and pregnancy nutrition surveillance system: pednss health indicators.” center of disease and control. http://www. cdc.gov/pednss/what_is/pednss_health_indicators.htm. date of access: 13 dec. 2015. http://www.who.int/mediacentre/factsheets/fs363/en/ http://www.cdc.gov/pednss/what_is/pednss_health_indicators.htm http://www.cdc.gov/pednss/what_is/pednss_health_indicators.htm 44 review | dermatol pract concept 2016;6(3):8 table 3. healthy infants born to mothers who developed pityriasis rosea during pregnancy. [copyright: ©2016 loh et al.] case a #pp o dur symptoms* loc del newborn weight (g)# apgar score ref 1 24 1 21 6 no t (<50%) 38 3900 10 6 2 25 0 24 6 no lower l, t (<50%) 38 3250 9 6 3 26 0 24 4 no (<50%) 40 3850 9 6 4 26 0 26 5 yes lower l, t (<50%() 39 3700 9 6 5 26 0 30 6 no t (<50%) 41 3800 8 6 6 27 0 24 5 no t (<50%) 39 3400 10 6 7 27 0 32 5 no l, t (<50%) 38 3900 10 6 8 28 1 13 5 yes t (<50%) 39 3650 9 6 9 28 2 21 5 no t (<50%) 39 3000 9 6 10 28 0 21 10 no t, proximal aspects of four extremities nd, uneventful nd nd 12 11 28 0 23 5 no t (<50%) 38 3100 8 6 12 28 0 26 4 no t (<50%) 38 3800 10 6 13 28 nd nd, last trimester nd nd r hip, bilateral thighs nd, uneventful nd nd 13 14 28 0 8 10 no t 41 3827 9 cr 15 29 0 26 6 yes t (<50%) 37 3200 8 6 16 29 1 28 5 no t (<50%) 41 3600 9 6 17 30 1 26 4 no l, t 50% 38 3600 9 6 18 30 1 26 4 no t (<50%) 39 3500 10 6 19 30 1 29 5 no t (<50%) 37 3000 8 6 20 30 0 29 6 no upper l, t (<50%) 37 3100 8 6 21 30 1 30 4 no lower l, t (<50%) 38 3400 9 6 22 31 2 14 4 no t (<50%) 38 3300 10 6 23 31 1 24 5 yes lower l, t (<50%) 38 2750 7 14 24 31 1 26 5 no lower l, t (<50%) 38 3300 8 6 25 32 0 26 5 no t (<50%) 38 3250 8 6 26 33 0 11 8 no t, proximal aspects of four extremities nd, full-term 2640 nd 12 27 33 2 23 4 no t (<50%) 39 3200 9 6 28 nd nd nd nd nd nd nd nd nd 23 29 nd nd nd nd nd nd nd nd nd 24 *constitutional symptoms (i.e., other than cutaneous symptoms) including fatigue, headache, insomnia, gastrointestinal disturbance, inability to concentrate. c=case; a=mother’s age at onset of pityriasis rosea; #pp=number of previous pregnancies; loc=location; l=limbs; t=trunk; nd=not described; o=onset of pityriasis (weeks in pregnancy); dur=duration of pityriasis rosea (weeks); loc=location of lesions; del=delivery (weeks in pregnancy) premature <37 weeks [a] # low birth weight <2500g [b] [a] “preterm birth.” world health organization. http://www.who.int/mediacentre/factsheets/fs363/en/ date of access: 13 dec. 2015. [b] “pediatric and pregnancy nutrition surveillance system: pednss health indicators.” center of disease and control. http://www. cdc.gov/pednss/what_is/pednss_health_indicators.htm. date of access: 13 dec. 2015. http://www.who.int/mediacentre/factsheets/fs363/en/ http://www.cdc.gov/pednss/what_is/pednss_health_indicators.htm http://www.cdc.gov/pednss/what_is/pednss_health_indicators.htm review | dermatol pract concept 2016;6(3):8 45 pityriasis rosea also occasionally occurs in women during pregnancy. however, the true incidence is not known, since gestational pityriasis rosea is not frequently reported. some researchers noted that pityriasis rosea occurring earlier in pregnancy had a greater probability of resulting in adverse events for the fetus, including stillbirth, low gestational weight, hypotonia, and/or premature delivery. however, there are a similar number of reports of women who developed pityriasis rosea during their gestation and delivered normal newborns. indeed, the ratio of normal to abnormal newborns was found to be 29:25. our patient developed pityriasis rosea during her first trimester beginning at 8 weeks gestation and lasting through 18 weeks. her son was carried to term and delivered at 40 weeks and 6 days with apgar scores, weight, and height in normal range. isolated craniosynostosis was discovered and subsequently repaired. whether the presence of craniosynostosis was associated with our patient’s development of pityriasis rosea during her pregnancy remains to be determined. references 1. wollenberg a, eames t. skin diseases following a christmas tree pattern. clin dermatol 2011;39:189-94. pmid 21396559. doi: 10.1016/j.clindermatol.2010.09.011. 2. neoh cy, tan aw, mohamed k, sun yj, tan sh. characterization of the inflammatory cell infiltrate in herald patches and fully developed eruptions of pityriasis rosea. clin exp dermatol 2010;35:300-4. pmid: 19663842. doi: 10.1111/j.13652230.2009.03469.x. 3. sharma l, srivastava k. clinicoepidemiological study of pityriasis rosea. indian j dermatol venereol leprol 2008;74:647-9. pmid: 19171994. rosea during pregnancy and have delivered healthy newborns (table 3) [6,12-14,23,24]. indeed, the literature shows a ratio of 6:5 with regards to healthy newborns versus newborns with adverse events being delivered to women with gestational pityriasis rosea. however, the number of publications regarding gestational pityriasis rosea on the outcome of the newborn may not accurately reflect the incidence of normal newborns whose mothers had gestational pityriasis rosea, since clinicians may not report these women or journals may elect not to publish the papers. craniosynostosis is a premature fusion of one or more sutures of the skull. it can occur as an isolated incidental event or as part of syndrome (table 4) [25,26]. as an isolated incidental finding, sagittal craniosynostosis, as observed in our patient’s newborn, is the most common form. if left unrepaired, craniosynostosis may lead to a deformed skull, elevation of intracranial pressure, and cognitive impairment [27]. our patient’s infant was evaluated shortly after delivery and had repair of the sagittal craniosynostosis at 9 weeks, with no complications and subsequent normal development. the incidence of sagittal craniosynostosis is about 1 in 5,000 live births [28]. to the best of our knowledge, isolated craniosynostosis has not been observed in newborns of women who developed pityriasis rosea during their gestation. indeed, the occurrence in our patient’s child may merely be a coincidence and not associated with her episode of pityriasis rosea during her first trimester. conclusion pityriasis rosea usually occurs as an isolated skin condition. less commonly, it may be observed in spouses or in siblings. table 4. syndromes associated with carniosynostosis [25,26] syndrome [a] features/comment apert syndrome brachycephaly, flat nasal bridge, syndactyly of fingers (“mitten fingers”), syndatyly of toes crouzon syndrome long face with proptosis, maxillary hypoplasia, mandibular prognathism, conductive hearing loss. associated with increased paternal age. synostosis may involve the coronal, sagittal, and lambdoid sutures. can also present with acanthosis nigricans. pfeiffer syndrome hypertelorism, maxillary hypoplasia, mandibular prognathism, turribrachycephaly. partial syndactyly of fingers and toes. may have choanal atresia or stenosis or radiohumeral synostosis at elbows saethre-chotzen syndrome short stature, brachycephaly, acrocephayly, plagiocephaly, facial asymmetry, hypertelorism, beaked nose, deafness, cardiac defect. carpenter syndrome brachycephaly with synostosis of coronal, lambdoid, and sagittal sutures. midface hypoplasia, low-set ears, high arched palate, coxa valgu, genu valgum, polydactyly/ syndactly/clinodactyly/camptodactyly. [a] these are the syndromes most frequently associated with craniosynostosis. other less common associated syndromes associated with craniosynostosis include: antley-bixler, craniofrontonasal dysplasia, craniosynostosis mental retardation syndrome of lin and gettig, cutis gyrate syndrome of beare and stevenson, cytochrome p450 oxidoreductase deficiency with antley-bixler phenotype, hunter-mcalpine craniosynostosis, jackson-weiss, muenke, and baller-gerold, opitz trigonocephaly, and shprintzen-goldberg craniosynostosis. 46 review | dermatol pract concept 2016;6(3):8 sociated with systemic active infection with both human herpesvirus-7 and human herpesvirus-6. j invest dermatol 2002;119:7937. pmid: 12406322. doi: 10.1046/j.1523-1747.2002.00200.x. 17. ohashi m, yoshikawa t, ihira m, et al. reactivation of human herpesvirus 6 and 7 in pregnant women. j med virol 2002;67:3548. pmid: 12116027. doi: 10.1002/jmv.10083 18. dahl h, fjaertoft g, norsted t, wang fz, mousavi-jazi m, linde a. reactivation of human herpesvirus 6 during pregnancy. j infect dis 1999;180:2035-8. pmid: 10558965. doi: 10.1086/315115. 19. lemster n, neumark m, arieh i. pityriasis rosea in a woman and her husband—case report and review of the literature. case rep dermatol 2010;2:135-9. pmid: 21399750. doi: 10.1159/ 000319759. 20. miller th. pityriasis rosea: report of three cases in one family, with clinical variations in two of them. ama arch derm syphilol 1941;44:66-8. 21. halkier-søresnsen l. recurrent pityriasis rosea. new episodes every year for five years. a case report. acta derm venereol 1990;70:179-80. pmid: 1969211. 22. overton rw. pityriasis rosea in pregnancy: a case report. j iowa med soc 1969;58:1239-40. pmid: 5705310. 23. salin rw, curtis ac, wheeler a. the treatment of pityriasis rosea with convalescent plasma, gamma globulin, and pooled plasma. ama arch dermatol 1957;76:659-62. pmid: 13468800. 24. zeligman i. cortisone therapy for pruritic pityriasis rosea. bull school of medicine, university of maryland. 1955;40:76-7. pmid: 1438900. 25. genereviews: fgfr-related craniosynostosis syndromes http:// www.ncbi.nlm.nih.gov/books/nbk1455/. accessed on 10 jan. 2016. 26. panigrahi i. craniosynostosis genetics: the mystery unfolds. indian j hum genet 2011;17:48-53. pmid: 22090712. doi: 10.4103/0971-6866.86171. 27. massimi l, caldarelli m, tamburrini g, paternoster g, di rocco c. isolated sagittal craniosynostosis: definition, classification, and surgical indications. childs nerv syst 2012;28:1311-7. pmid: 22872242. doi: 10.1007/s00381-012-1834-5. 28. epidemiology of nonsyndromic craniosynostosis in children: incidence and prevalence. (updated 2015). retrieved 10 jan. 2016, from http://ispn.guide/book/the%20ispn%20guide%20to%20 pediatric%20neurosurgery/congenital%20disorders%20 of%20the%20nervous%20system/non%20syndromic%20 craniosynostosis/epidemio 4. gonzález lm, allen r, janniger ck, schwartz ra. pityriasis rosea: an important papulosquamous disorder. int j dermatol 2005;44:757-64. pmid: 16135147. doi: 10.1111/j.13654632.2005.02635.x. 5. bianca s, ingegnosi c, ciancio b, gullotta g, randazzo l, ettore g. pityriasis rosea in pregnancy. reprod toxicol 2007;24:277-8. pmid: 17604600. doi: 10.1016/j.reprotox.2007.05.005. 6. drago f, broccol f, zaccaria e, et al. pregnancy outcome in patients with pityriasis rosea. j am acad dermatol 2008;58:s78-83. pmid:18489054. doi: 10.1016/j.jaad.2007.05.030. 7. governale ls. craniosynostosis. pediatr neurol 2015;pii:s0887 8994. pmid: 26371995. doi: 10.1016/j.pediatrneurol.2015.07. 006. 8. heuzé y, holmes g, peter i, richtsmeier jt, jabs ew. closing the gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. cur genet med rep 2014;2:135-45. pmid: 26146596. doi: 10.1007/s40142-014-0042-x. 9. stulberg dl, wolfrey j. pityriasis rosea. am fam physician 2004;69:87-91. pmid: 14727822. doi: 10.1016/j. jpag.2006.12.005. 10. trager jd. what’s your diagnosis? scaly pubic plauqes in a 2-year-old girl—or an “inverse” rash. j pediatr adolesc gynecol 2007;20:109-11. pmid: 17418397. 11. chuh a, zawar v, lee a. atypical presentations of pityriasis rosea: case presentations. j eur acad dermatol venerol 2005;19:120-6. pmid: 15649208. doi: 10.1111/j.1468-3083.2004.01105.x. 12. chuh aa, lee a, chan pk. pityriasis rosea in pregnancy—specific diagnostic implications and management considerations. aust n z j obstet gynaecol 2005;45:252-3. pmid: 15904457. doi: 10.1111/j.1479-828x.2005.00399.x. 13. cruz mj, baudrier t, azevedo f. atypical pityriasis rosea in a pregnant woman: first report associating local herpes simplex virus 2 reactivation. j dermatol 2012;39:490-2. pmid: 21958020. doi: 10.1111/j.1346-8138.2011.01349.x. 14. drago f, broccolo f, javor s, drago f, rebora a, parodi a. evidence of human herpesvirus-6 and -7 reactivation in miscarrying women with pityriasis rosea. j am acad dermatol 2014;71:1989. pmid: 24927696. doi: 10.1016/j.chemosphere.2014.04.107. 15. broccolo f, drago f, careddu am, et al. additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. j invest dermatol 2005;124:1234-40. pmid: 15955099. doi: 10.1111/j.0022-202x.2005.23719.x. 16. watanabe t, kawamura t, jacob se, et al. pityriasis rosea is asobservation | dermatol pract concept 2012;2(1):7 39 extraocular sebaceous carcinoma: a series of three cases with varied presentation poonam k. panjwani, m.d.1, rajalakshmi tirumalae, m.d.1, julian a. crasta, m.d.1, suraj manjunath, ms, mch2, pritilata rout, m.d.1 1 department of pathology, st. john’s medical college, bangalore, india 2 department of surgical oncology, st. john’s medical college, bangalore, india key words: sebaceous carcinoma, extraocular citation: panjwani pk, tirumalae r, crasta ja, manjunath s, rout p. extraocular sebaceous carcinoma: a series of three cases with varied presentation. dermatol pract conc. 2012;2(1):7. http://dx.doi.org/10.5826/dpc.0201a07. received: april 12, 2011; accepted: june 12, 2011; published: january 31, 2012 copyright: ©2012 panjwani et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: rajalakshmi tirumalae, m.d., dnb, associate professor, department of pathology, st. john’s medical college, bangalore – 560034, india. tel. +91.80.22065053. email: rajnav@gmail.com. background: extraocular sebaceous carcinomas are rare cutaneous malignancies that account for only about 25% of all sebaceous carcinomas. the most common site of occurrence is the head/neck region. they are aggressive neoplasms that possess metastatic potential to regional or distant sites. wide local excision of the lesion with removal of regional lymph nodes is the usual mode of therapy. methods: we present a series of three cases of sebaceous carcinomas occurring in extraocular sites outside the head and neck areas, like the axilla, chest wall, arm and thigh. one of these cases had an associated colonic carcinoma and constituted muir-torre syndrome (mts). another case presented with a skin nodule and regional nodal metastasis. the third case had a history of recurrent similar lesions at the same site. conclusion: although rare, extraocular sebaceous carcinomas are seen at varied sites and frequently pose problems in diagnosis. a longterm follow-up of these cases is warranted due to their aggressive behaviour, risks of recurrence, metastasis and the possibility of development of visceral malignancies. abstract dermatology practical & conceptual www.derm101.com 40 observation | dermatol pract concept 2012;2(1):7 introduction sebaceous carcinomas are most commonly encountered in the ocular region. extraocular sites for these tumours account for only about a quarter of the cases and usually include the skin of the head and neck region. they can also occur on the trunk, extremities, genitalia and rare sites like lungs, salivary glands, breast [1]. the morphologic diversity of these tumours, especially in unusual sites, makes their distinction from more common primary tumours of those organs a difficult task. it is important to identify them accurately, as they have a high incidence of recurrence and association with regional nodal metastasis. we report a series of sebaceous carcinomas occurring at extraocular, extra-head and neck sites. these cases are presented for their rarity, histopathologic spectrum and difficulty encountered in diagnosis. case reports case 1 a 44-year-old man presented with skin nodules on the arm and anterior chest wall three years ago. the lesions ranged in size from 1 to 2.5 cm in diameter. on excision, the lesions were cystic and filled with purulent material, justifying the clinical impression of epidermal cyst. histology revealed a cystic-solid tumour in the dermis (figure 1a). the tumour cells were arranged in nests within the cyst wall. necrosis was present (figure 1a). the cells were crowded with scant cytoplasm and admixed with cells showing multivacuolated appearance and scalloped nuclei, characteristic of sebocytic differentiation (figure 2b). a diagnosis of sebaceous carcinoma was made on both lesions. the patient had multiple recurrences of similar lesions on the thigh and back during a two-year follow-up. there was no regional node involvement. the patient gave a history of surgery for adenocarcinoma of the colon. thus, it constituted muir-torre syndrome(mts). the patient is currently asymptomatic. case 2 a 48-year-old man presented to the fnac (fine needle aspiration cytology) clinic of our hospital one year ago with a nodular axillary mass measuring around 5 x 4 cm. the patient had no palpable or radiologically detected breast lesions. the axillary skin was puckered and the mass was palpable (figures 2a, 2b). fine needle aspiration of the mass showed a neoplasm with plasmacytoid morphology (figure 2c). biopsy revealed poorly differentiated tumour cells with a nodular architecture in the dermis. a few cells showed cytoplasmic vacuoles (figure 2d). immunohistochemistry was done for cytokeratin (ck) 7, ck 20, hmb-45, s-100, psa (prostate specific antigen) and ttf-1 (thyroid transcription factor), all of which were negative. the tumour cells were positive for ck, ema (epithelial membrane antigen) and focally for cd 15. ema staining showed a bubbly, vacuolated cytoplasm in many cells, highlighting their sebocytic nature (figure 3d). a final diagnosis of sebaceous carcinoma was made. this was followed by a wide excision of the axillary mass with regional lymph node dissection. there were varying architectural patterns, such as solid nests (figure 3a), areas with comedo-necrosis (figure 3b), and thick cords with hyalinisation (figure 3c). plasmacytoid appearance, which dominated the fnac smears, was seen only in foci. sebocytic differentiation was also focal. regional axillary nodal metastasis was present. the postoperative period was uneventful and the patient is currently free of disease. case 3 a 78-year-old lady presented to the fnac clinic of our hospital with history of erythematous nodular and plaque-like lesions measuring 6 x 4 cm on the right anterior chest wall figure 1. cystic-solid tumour in dermis with areas of necrosis (a) (h&e, x100). vacuolated bubbly cytoplasm of tumour cells (b) (h&e, x400). [copyright: ©2012 panjwani et al.] a b observation | dermatol pract concept 2012;2(1):7 41 (figure 4a). she was operated on 10 years ago for similar lesions at this site. there were no palpable lesions in both breasts and mammography was negative. fine needle aspiration from the nodule showed a poorly differentiated carcinoma (figure 4b). a wide local excision was performed. no breast or axillary lesions were detected per operatively. a tumour was seen in the dermis with the characteristic morphology of sebaceous carcinoma (figure 4c) and a prominent pagetoid spread (figure 4d). sebocytic vacuolated cells were highlighted by the ema stain (figure 4e). discussion extraocular sebaceous carcinomas are rare. they are common in the elderly with a slight female preponderance. they carry a high risk for local recurrence. wide local excision with removal of regional nodes is the mode of treatment. around 20–25% of cases show distant metastasis. the tumour mortality is around 20% [1]. the hallmark of sebocytic differentiation is the presence of multivesicular and vacuolated cytoplasm [1,2]. these variably atypical polygonal tumour cells are usually arranged as dermal nodules with a fibrovascular stroma that doesn’t exhibit much desmoplasia. however, these classical features may be subtle or even absent in a few cases. a varied morphologic spectrum has been described for these tumours, like basaloid, squamoid, organoid, pseudo-neuroendocrine, etc [3,4]. this diversity may be explained by the common embryologic origin of the folliculo-sebaceous-apocrine unit being recapitulated in their neoplasms, as well. these tumours are known to be great mimics of different types of neoplasms, which often makes the right diagnosis a challenge [5]. this was demonstrated in our second case in which the tumour showed a range of cytoarchitectural features and rendered the diagnosis difficult. immunohistochemistry confirmed the diagnosis. the vacuolated cytoplasm accentuated by the ema stain is a typical feature of sebaceous carcinomas, along with positivity for pancytokeratin, cd 15 and ca 15.3 [1]. figure 2. nodular mass in the axilla with puckering of the skin (a+b). fnac showing tumour cells with plasmacytoid morphology (c) (h&e, x400). nests of vacuolated cells separated by fibrous septae (d) (h&e, x200). [copyright: ©2012 panjwani et al.] a c b d 42 observation | dermatol pract concept 2012;2(1):7 the site of the tumour in the second case was also more in favour of a breast primary than other neoplasms. breast carcinoma needs to be ruled out in axillary masses. ductal carcinoma of the breast shows a positive stain for ck-7, unlike our case. it should be noted that primary sebaceous carcinoma of the breast is extremely rare in comparison to an extraocular sebaceous carcinoma arising from the skin. a few cases of a sebaceous carcinoma of the breast have been reported in patients having mts [6,7]. very rarely, a myoepithelial neoplasm of the breast may also show varied patterns like clear cells and a plasmacytoid morphology. however, one needs to consider the overall morphology, presence of spindle cells, mitotic activity and myoepithelial markers, if necessary, to make the distinction [8]. a metastatic tumour from other sites also needs to be ruled out in such cases, for which immunostains are very useful. our first case was a prototype of mts. this is a rare autosomal dominant genodermatosis. it is characterised by the occurrence of sebaceous gland neoplasms and/or kerafigures 3. varied morphology and patterns of the tumour cells: solid nests (a), comedonecrosis (b) and cords with hyalinisation (c) (h&e x10). ihc for ema showing characteristic vacuolated cytoplasm in tumour cells (d) (ema, x400). [copyright: ©2012 panjwani et al.] a c b d toacanthomas in association with a visceral malignancy, commonly of the gastrointestinal or the genitourinary tract [9–12]. genetically, these tumours are characteristed by mutations in the mismatch repair gene products, especially msh-2 [13]. cystic differentiation is an important histologic clue to its association with mts, as seen in our case. this cystic appearance is very rare in sebaceous tumours not associated with the mts [14]. such patients need to be screened for a concomitant gi malignancy and followed up closely. screening of family members is desirable. the third case that we encountered showed a pagetoid spread of the tumour. this is considered to be a “field effect” rather than being direct precursor of or extensions from an underlying sebaceous carcinoma [1]. it is particularly common in eyelid tumours. an exclusively in-situ component may rarely occur and differentiating this from an in-situ squamous carcinoma may be extremely difficult, especially if sebocytic differentiation is sparse. a thorough histologic examination is crucial. observation | dermatol pract concept 2012;2(1):7 43 a c e b d figure 4. nodular, plaque-like lesions on anterior chest wall (a). fnac showing a poorly differentiated carcinoma (b) (h&e, x200). nested tumour cells in dermis (c) (h&e, x40). pagetoid spread of cells showing sebocytic differentiation (d) (h&e, x100). ihc for ema highlighting the vacuolated, bubbly cytoplasm. (e) (ema, x400). [copyright: ©2012 panjwani et al.] 44 observation | dermatol pract concept 2012;2(1):7 conclusion the morphologic variations that can be encountered along with occurrence at unusual sites can render extraocular sebaceous carcinomas elusive to the pathologist. a high index of suspicion and a careful search for sebocytic differentiation are the key features. ema immunostain is a useful adjunct in doubtful cases, as it highlights the multivacuolated cytoplasm. the pathologist needs to be cognisant of the histopathologic gamut of sebaceous carcinomas to avoid misdiagnosis. references 1. rutten a, wick mr, sangueza op, wallace c. tumours with sebaceous differentiation. in who classification of tumours. lyon: iarc press, 2006:160–3. 2. misago n, mihara i, ansai s, narisawa y. sebaceoma and related neoplasms with sebaceous differentiation: a clinicohistopathological study of 30 cases. am j dermatopathol. 2002;24(4):294–304. 3. kazakov dv, spagnolo dv, kacerovska d, michal m. unusual patterns of cutaneous sebaceous neoplasms. diag histopathol. 2010;16(9):425–31. 4. kazakov dv, kutzner h, rütten a, mukensnabl p, michal m. carcinoid-like pattern in sebaceous neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. am j dermatopathol. 2005;27(3):195– 203. 5. buitrago w, joseph ak. sebaceous carcinoma: the great masquerader: emerging concepts in diagnosis and treatment. dermatol ther. 2008;21(6):459–66. 6. alzaraa a, ghafoor i, yates a, dhebri a. sebaceous carcinoma of the skin of the breast: a case report. j med case reports. 2008;2:276. 7. propeck pa, warner t, scanlan ka. sebaceous carcinoma of the breast in a patient with muir-torre syndrome. am j roentolgenol. 2000;174(2):541–2. http://www.ajronline.org/content/174/2/541.long. 8. rosen pp. myoepithelial neoplasms. in: rosens’ breast pathology. philadelphia, pa: lippincott williams & wilkins, 2001:121–38. 9. abbas o, mahalingam m. cutaneous sebaceous neoplasms as markers of muir-torre syndrome: a diagnostic algorithm. j cutan pathol. 2009;36(6):613–9. 10. tsalis k, blouhos k, vasiliadis k, tsachalis t, angelopoulos s, betsis d. sebaceous gland tumours and internal malignancy in the context of muir-torre syndrome. a case report and review of the literature. world j surg oncol. 2006;4:8. 11. cohen pr, kohn sr, kurzrock r. association of sebaceous gland tumours and internal malignancy: the muir-torre syndrome. am j med. 1991;90(5):606-13. 12. lachiewicz am, wilkinson tm, groben p, ollila dw, thomas ne. muir-torre syndrome. am j clin dermatol. 2007;8(5):315-9. 13. popnikolov nk, gatalica z, colome-grimmer mi,sanchez rl. loss of mismatch repair proteins in sebaceous gland tumours. j cutan pathol. 2003;30(3):178–84. 14. al-shobaili ha, al-ghamdi km, al-ghamdi wa. cystic sebaceous carcinoma: is it a constant pathognomic marker for muirtorre syndrome? j drugs dermatol. 2007;6(5):540–3. dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2012;2(2):15 75 review by heinz h. kutzner, m.d. this book definitely fills a gap. among the plethora of outstanding molecular pathology textbooks (e.g., molecular genetic pathology by liang cheng and david y. zhang, humana press, 2008; and molecular pathology by william b. coleman and gregory j. tsongalis, academic press, 2009), murphy’s book is a glittering diamond that should be read from cover to cover by every dermatologist and dermatopathologist. it is worth every dollar—and even more. michael murphy and his multi-author team have achieved the difficult task of putting together a concise and highly readable text that covers all molecular biology topics relevant to murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. citation: book review: murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. dermatol pract conc. 2012;2(2):15. http://dx.doi.org/10.5826/dpc.0202a15. copyright: ©2012 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr, maryland heights, mo, 63043, usa. tel. 314.991.4470; email: markhurt@aol.com. figure 1. murphy mj (ed). molecular diagnostics in dermatology and dermatopathology. new york: springer science + business media (humana press), 2011. 478 pp with index. isbn 978-1-60761-170-7; upc 9781607611707; $239. dermatologists and dermatopathologists. each topic was researched in depth and is up to date. both neophytes and experienced dermatologists with a sound molecular background will profit equally from this book, which is full of details, surprises, new developments in the field, and data relevant to the daily professional lives of dermatologists and dermatopathologists. murphy’s 478-page book contains 23 chapters and 1 addendum (written by 32 authors): 1. introduction to molecular diagnostic testing in dermatology and dermatopathology 2. principles in molecular biology 3. technologies in the molecular diagnostics laboratory 4. cytogenetics of primary skin tumors 5. melanocytic neoplasms i: molecular diagnosis 6. melanocytic neoplasms ii: molecular staging 7. non-melanoma skin cancers and hereditary cancer syndromes 8. cutaneous sarcomas and soft tissue proliferations 9. molecular determination of soft tissue margins, clonal origin, and histogenesis of skin cancers 10. mycosis fungoides and related lesions 11. cutaneous non-mf t-cell and nk-cell lymphoproliferative disorders 12. cutaneous b-cell lymphomas 13. leukemia cutis 14. inflammatory disorders of the skin 15. infectious diseases of the skin i: dermatophytosis/ onychomycosis mailto: 76 book review | dermatol pract concept 2012;2(2):15 a beautiful chapter! encyclopedic definitely is a hyperbolic term, but in the context of molecular biology in conjunction with dermatology/dermatopathology, murphy’s book comes quite close to it. “primer” and “encyclopaedic manual” aside, is there something left for the experienced dermatologist and dermatopathologist with a profound background in molecular biology, or is this just another book for the shelf? not at all! this book is full of hidden surprises (which might be a euphemism for one’s many blind spots, i hate to admit); i loved to read about chronic wounds and biofilms, about the cytogenetic alterations associated with the leukemias (a very detailed a precise account), and many others. and what about the figures, tables, and photomicrographs? just the right dosage—and some of it is even in color. personally, i am more visually oriented and cannot get enough of long and detailed tables, figures, color photomicrographs, which help me to understand the written material much faster, particularly in a complicated field like this one. in general, the authors did a very good job here. the printed pictorial material is always a compromise: publishers hate it (costs and space!), while readers love it (particularly the visually oriented ones). a nice table and picture are always welcome. any serious criticism? none! any suggestions and wishes? yes, i sincerely hope dr. murphy will sell a million copies of it, or even more! and, needless to add, these copies should be read also! repeatedly! did i already mention the price? forget about money! this is a must-have! would this be “the book” for the lonely island? definitely yes! if you already read tolstoy’s war and peace, this would be the perfect time to grab the blue murphy! a word of caution? true story: at the recent asdp meeting in seattle, i overheard an enthusiastic young colleague approaching david weedon with the words, “dr. weedon, we love your book. we always use it as a prop!” never say this to dr. murphy! his book is “un-prop-able.” this book was made exclusively for reading. besides, you can carry it everywhere. dr. kutzner practices dermatology and dermatopathology at dermatopathologie friedrichshafen in germany. contact him at kutzner@ dermpath.de. review by wolfgang weyers, m.d. molecular dermatopathology is an evolving field of medicine that acquires rapidly increasing importance in the diagnosis and management of patients with skin diseases. there is a need, therefore, for a reference that imparts knowledge 16. infectious diseases of the skin ii: non-dermatophytic infections 17. wound healing disorders: chronic wounds and keloids 18. alopecias 19. genodermatoses: inherited diseases of the skin 20. molecular aspects of skin aging 21. pharmagogenetics and pharmacogenomics i: linking diagnostic classification to therapeutic decisions 22. pharmagogenetics and pharmacogenomics ii: genetic determinants of drug response and adverse drug reactions 23. regulatory, legal, coding, billing, reimbursement, and ethical considerations for molecular diagnostic testing in dermatology and dermatopathology 24. additional resources who can benefit from this book? everybody in the field of dermatology and dermatopathology in particular! molecular techniques and principles have been invading the field of dermatology and dermatopathology for many years with few doctors keeping pace with the deluge of new and exciting developments and findings in the world of molecular biology, molecular medicine, and pathology. one can use murphy’s molecular diagnostics both as an easy-to-follow textbook and as an encyclopedic reference manual (where, within a second, you can look up that particular important fact that you are looking for so desperately in a conference, or at the microscope, or at the computer writing a paper). can the neophyte really use this book as a “primer”? not exactly. it will definitely take some endeavor and stamina—but it is feasible, particularly for those who have been avoiding the field whenever and wherever possible and are now trying to catch up. besides, one does not have to read and know everything in molecular biology. some topics may slumber for a while and then suddenly become “hot” for informational value. there are three very well written introductory chapters on general molecular biology; they cover about everything one should know on basic molecular biology in medicine. additionally, each special chapter begins with a concise introduction that allows one to put facts and data into perspective, providing a perfect overview. can murphy’s book also be used as a reference manual? definitely yes! many chapters contain a remarkable wealth of information, e.g., the chapter on dermatophytosis (among many others), which would take hours or days to compile from other sources. the chapters on melanoma, soft tissue tumors, and lymphomas/leukemia are outstanding and make great reading, particularly for oncologists and dermatopathologists. if you are interested in the intricacies of targeted medicine of malignant melanoma, go to chapters 5 and 6. problems with genodermatoses? go to chapter 19: 31 pages and 14 detailed tables, as well as 97 references tell you all you need and want to know and may want to recheck later. mailto:kutzner@dermpath.de mailto:kutzner@dermpath.de book review | dermatol pract concept 2012;2(2):15 77 melanoma skin cancers and hereditary cancer syndromes,” the authors claim simplistically that keratoacanthoma “does not exhibit distinct histopathological features nor specific protein biomarkers that allow a definite discrimination from scc,” as if there were no histopathologic criteria for differentiation between keratoacanthoma and conventional squamous-cell carcinoma that work in the majority of cases. they go on to explain that, “a lower degree of chromosomal instability in ka compared to scc . . . provides a potential approach to genetically differentiate ka from scc,” but do not allude to the vagueness of those findings in ambiguous cases. in regard to melanoma, the authors allude correctly to the subjectivity entering into histopathologic diagnosis, e.g., in differentiation of spitz’s nevus from spitzoid melanoma, but do not acknowledge that in molecular methods, such as fish, evaluation is also subjective and that the establishment of certain cut-off points for fish signals, even if backed by profound studies, is by its very nature arbitrary. in many chapters, a word of caution vis-á-vis results of molecular studies is missing entirely. this impairs seriously the practical utility of the book. for example, in lymphomas, clonality is often detectable in one biopsy but not the other. nevertheless, the reproducibility of molecular studies is not addressed. in patients with leukemia who develop unrelated skin diseases, non-neoplastic inflammatory cells entering the skin are often accompanied by some leukemic cells that can be demonstrated immunohistochemically, a finding that has no prognostic significance. obviously, those cells can also be detected by molecular studies, and at even lower numbers. nevertheless, the editor of the book and author of the chapter about “leukemia cutis” adheres to the traditional separation between “(a) ‘leukemids’ . . . in which inflammatory lesions contain no neoplastic cells; and (b) leukemia cutis (lc) . . . in which leukemic cells (myeloid or lymphoid) infiltrate the skin,“ and avers that “prognosis for patients with acute lc is generally very poor” (pp. 263f). the problem of the great sensitivity of molecular studies, allowing for identification of infinitesimal numbers of neoplastic cells with no prognostic import at all, is not discussed. in regard to infectious diseases such as tuberculosis or borreliosis, no word is uttered concerning sensitivity and specificity of pcr studies. what does failure to detect dna of borrelia in formalinfixed tissue imply? should patients be treated nonetheless? and how dependable is a positive test? how common are false positive results? is it better to rely on molecular studies or other findings, such as histopathologic pattern? what is known about sensitivity of molecular tests in different manifestations of infection, such as erythema migrans and acrodermatitis chronica atrophicans in the case of borreliosis and lupus vulgaris and erythema induratum in the case of tuberculosis? obviously, these are questions of great importance for the management of patients, but physicians will not find about the pros and cons, possibilities and limitations of molecular techniques to physicians who are not experts in the field. michael murphy must be commended for having recognized this need and for having assembled a broad array of co-authors in order to create the first textbook of molecular diagnostics in dermatology and dermatopathology, a book that, according to its preface, is aimed at “any physician,” particularly dermatologists and dermatopathologists, and has been designed to be used “as a reference guide in their daily practice of medicine.” first attempts are always difficult, and hardly any pioneering effort is a complete success. this also applies to the book under discussion. however, first attempts are essential to create a platform from which to proceed. considering the rapid progress in molecular diagnosis, there soon will be need for a second edition, and the purpose of a review resides not only in representing the finished product but also, and especially, in indicating ways of improving it. the finished product is a multi-author book that covers many aspects of molecular dermatopathology, ranging from “principles of molecular biology” to “technologies in the molecular diagnostics laboratory” and from molecular aspects of specific inflammatory and neoplastic skin diseases to “pharmacogenetics and pharmacogenomics.” if physicians turn to this “reference guide in their daily practice of medicine,” they will find almost anything, and the knowledge conveyed will enable them to understand reports concerning molecular findings. as in all multi-author books, however, the emphasis varies from chapter to chapter. of 15 chapters dealing with specific diseases, some focus on diagnosis, others on prognosis, and still others on molecular techniques. some chapters are very practical, e.g., the one on “cutaneous non-mf t-cell and nk-cell lymphoproliferative disorders” in which clinical, histopathological, immunohistochemical, and molecular findings are presented and assessed in regard to their diagnostic value. this enables physicians to integrate different aspects into a meaningful diagnostic procedure that may differ from disease to disease. for example, demonstration of monocloncal integration of htlv-i proviral dna in tumor cells is important for diagnosis of adult t-cell leukemia/ lymphoma, whereas in regard to lymphomatoid papulosis, the authors acknowledge that “molecular studies add little value.” likewise, the chapter about “cutaneous sarcomas and soft tissue proliferations” considers molecular testing as one of several diagnostic avenues, alludes to new immunohistochemical markers based on the knowledge of specific molecular alterations, and discusses sensitivity and specificity of the respective methods. this is noteworthy because other chapters tend to trivialize or neglect the value of diagnostic methods other than molecular ones. for example, in the chapter about “non78 book review | dermatol pract concept 2012;2(2):15 genetically altered cells are “pre-neoplastic” rather than neoplastic, and what they mean by the terms “pre-neoplastic” and “overt malignancy.” those deficiencies are relevant because they are related to one of the most important challenges for molecular pathology, namely, reconsideration of current concepts of disease. for example, the question whether molecular alterations in normal-appearing cells in the vicinity of squamous-cell carcinomas are non-neoplastic consequences of chronic solar damage or part and parcel of the neoplastic process might be resolved by comparing molecular alterations in those cells with alterations in cells of normal-appearing, sun-damaged skin further away from the neoplasm. if one adheres to opaque concepts such as “pre-neoplastic” and “overtly malignant” lesions, however, one does not ask the question and cannot give the answer. studies concerning molecular differences between solar keratoses and squamous-cell carcinomas have demonstrated more similarities than differences, but in keeping with predominant wisdom the authors of the chapter about “cytogenetics of primary skin tumors” emphasize differences such as “higher frequency of loh in ak compared to scc” (p. 63), rather than considering the obvious conclusion that solar keratoses are early manifestations of squamous-cell carcinoma. the notion that recurrences of basal-cell carcinomas are evidence of greater “aggressiveness” has prompted molecular studies “to distinguish between aggressive and nonaggressive bcc” (p. 61). recurrences, however, are chiefly a result of the pattern of growth. recurrences are caused by incomplete excisions, and the latter are more common in poorly circumscribed lesions. although the pattern of growth may be linked to distinctive molecular alterations, recognition of the pattern suffices to predict the probability of recurrences. in this chapter, as in several others, data of studies are presented that are often equivocal and have little import. by contrast, many important issues are not being addressed. for example, it is a notorious problem to distinguish irritated seborrheic keratoses and irritated warts from squamous-cell carcinoma, especially in small biopsy specimens. there can be no doubt that worldwide thousands of re-excisions are performed daily for ostensible squamous-cell carcinomas that, in reality, are irritated examples of benign epithelial lesions. this is one of many examples in which molecular tests might have greater importance than for distinction between aggressive and nonaggressive basal-cell carcinoma or different stages of development of squamous-cell carcinoma. yet, they are not considered in this textbook. the utility of the book is compromised further by its lack of focus on a particular readership. although, according to the preface, the book has been written for “any physician,” some chapters are replete with technical details, such as precise amino acid sequences of primers that are interesting only an answer in this “reference guide in their daily practice of medicine.” in the daily practice of medicine, molecular techniques are employed most commonly for the detection of infectious agents. it is noteworthy that, in this textbook, the chapter concerning “non-dermatophytic infections” is one of the shortest, deals mostly with methodology, is replete with general statements concerning the current and potential importance of molecular diagnostic techniques, and has practically nothing to say about the reliability of specific methods for specific infections. in fact, common diseases such as tuberculosis and borreliosis, are hardly mentioned at all and, consequently, are not listed in the index. neither are other infectious diseases, such as orf, bartonellosis, and leprosy. parenthetically, fungal infections are covered in a separate chapter that is substantially longer than the chapter dealing with all other infectious diseases. this lack of balance, a common problem of multi-author textbooks, is also evident in other respects. for example, opaque concepts are presented without being defined consistently, in various chapters. in the chapter on “mycosis fungoides and related lesions,” the authors refer to so-called “cutaneous t-cell lymphoid dyscrasia” as “a group of idiopathic chronic dermatoses, with persistent cutaneous infiltrates of monoclonal or restricted oligoclonal t cells” that have “a potential, albeit low, for progression to ctcl,” whereas, in the chapter on “inflammatory disorders of the skin,” they note that “cutaneous t-cell dyscrasias (i.e., lymphomas) can occasionally masquerade . . . as inflammatory dermatoses.” in other words, according to one chapter, “t cell lymphoid dyscrasias” are distinguished from lymphoma, whereas, in another chapter, they are referred to as lymphomas. interestingly, the editor of the book, michael murphy, was the senior author of both chapters, indicating that he has no clear concept of what he is writing about. just as “cutaneous t-cell dyscrasias,” many other vague concepts and clichés are adopted wholesale and are presented without an attempt at integration. for example, in keeping with leaflets for the uninitiated laity, melanoma is said to be “the most deadly form of skin cancer” (p. 59), although other neoplasms of the skin, such as cutaneous angiosarcoma, are clearly more malignant. basal-cell carcinoma is said to account “for ~80% of all skin cancers” and squamous-cell carcinoma “for almost 20% of all skin cancers” (p. 60), although those numbers are invalid, based as they are on studies that include superficial basal-cell carcinomas but exclude superficial squamous-cell carcinomas, such as bowen’s disease and solar keratoses. field cancerization is said to be characterized by “a clonal proliferation of preneoplastic genetically altered, but morphologically normalappearing cells . . . prior to the development of overt malignancy” (p. 191), but the authors fail to explain why those book review | dermatol pract concept 2012;2(2):15 79 dr. weyers practices dermatopathology at the center for dermatopathology, freiburg, germany. contact him at ww@zdpf.de. comment by mark a. hurt, m.d. i thank my colleagues, drs. kutzner and weyers, for their insightful reviews of this book. i contacted dr. murphy to obtain his response to the reviewers; he read the reviews, but he declined to comment. i extend the offer for a reply should dr. murphy wish to respond in a later issue of the journal. when approaching such a weighty topic as molecular diagnostics in dermatology and dermatopathology, i am reminded of the difficulty in establishing a diagnosis based on the classical techniques of clinicopathological correlation. the process is from clinical to histopathological to correlation to diagnosis—with prognosis coming much later epistemologically. this method has been an enormous achievement for mankind, and it cannot be reversed in any meaningful way. with the introduction of molecular information, the process does not change, but it becomes more complex . . . because there is more data to correlate and more variables that introduce the possibility of error into the process of diagnosis. as with any multi-authored work, one expects some degree of uneven writing and presentation; that is the case in this arbeit. including the editor, there are 32 authors involved in the writing of 23 chapters. most authors write from institutions within the united states. a few other countries are represented; these include australia, taiwan, germany, the united kingdom, italy, canada, and france. there is one page of “additional resources” highlighting a number of websites to organizations involved in the molecular genetics of varying conditions. this is followed by an index of 12 pages. this book is rather small—not the usual journal size— and it is a throwback to the days of small monographs in pathology. such monographs, as azzopardi’s problems in breast pathology, were, as a rule, filled with photographs and relatively large type—often 12 point—usually in times roman. in contrast, the type font in this book is times roman, but it is very small, probably 8 or 9 point, which is considerably smaller than historical works, and this fact alone makes for difficult reading. the book is at its best when the text is combined with tables and photographs of the techniques and some of the relevant lesions in question. chapter 3 on molecular techniques by drs. elaba, murphy, and mnayer is a concise introduction to the applied technology that comprises the field of molecular testing in dermatology and dermatopathology (table 3.1); it is a solid overview. the tables are especially helpful for focusing in on the disease, the molecufor a limited audience and that are not provided in other chapters. some passages seem to have been written for politicians or health-care managers. an entire chapter is devoted to coding, billing, and reimbursement, and statements concerning financial aspects also pepper other chapters. in the first chapter, the editor claims that, “in view of the unsustainable health care expenditures in the usa (17% gdp), . . . potential savings . . . can come as a result of preventative and/or more accurate testing.” there can be little doubt that molecular diagnostics will raise, rather than curtail, costs in the health care sector because many tests do not substitute but supplement other methods of diagnosis. seductive statements such as these may serve to increase the acceptance of molecular diagnostics by credulous laymen but can hardly appeal to physicians “in their daily practice of medicine.” for the sake of the average physician, as the official target audience, “principles of molecular biology” and “technologies in the molecular diagnostics laboratory” are discussed in the introductory chapters. in those chapters, the structure of dna and rna, the composition of the human genome, and nearly all techniques of molecular diagnosis are discussed in brief sections. however, the impression is created that this discussion is a compulsory exercise. for somebody not particularly knowledgeable in molecular biology, many explanations are opaque. for example, why is there “need for dna from peri-lesional non-tumor cells” in tests for loss of heterozygosity? and how do primers work? when dna is polymerized following binding of the primer to one strand, why not the entire strand? why is the pcr product restricted to a short target sequence? the authors do not mention the fact that a pair of primers is required, binding to different loci adjacent to the two ends of the target sequence. these, and many other issues, are not explained in a way that an average physician with only rudimentary knowledge in molecular biology might have a chance to understand. another factor that impairs seriously the utility of the book for the average physician is the constant use of acronyms that are not being explained. here and there, one can find an explanation of acronyms, such as cep6, etbr, rflp, or rreb1, at the beginning of a section or chapter, but some acronyms are not explained at all or are at a place impossible to find. the book would profit greatly from a table in which acronyms are listed and explained in alphabetical order, possibly in different colors for acronyms referring to genes, proteins, diagnostic methods, and diseases. in sum, the book by murphy and co-workers is a premiere, the first textbook about molecular diagnosis in dermatopathology. as such, it is a worthwhile endeavor, but flaws are substantial, and there are two good reasons to look forward to a second edition, namely, (1) increasing knowledge in molecular dermatopathology and (2) improvement of many weaknesses that characterize the first edition. mailto:ww@zdpf.de 80 book review | dermatol pract concept 2012;2(2):15 pregnancy, respectively. this said, it is, indeed, exciting to consider that cells of a melanoma away from the obvious neoplasm (principally in situ lesions for practical purposes) might be detected in fields that look as though they are in a control field but are, in fact, areas of melanoma that mimic the control field (i.e., “field cells”). i believe that the identification of these kinds of cells will have impact in the future on how to plan for staged excisions of melanoma, provided that the costs of mapping are feasible. in my practice of evaluating staged excisions of melanomas and melanomas in situ for mohs surgeons, i have found that standard techniques are very useful, those using melan-a and comparing the peripheral margins to the prior biopsies and to the debulk specimens. perhaps only 1 to 2% of patients ever have persistence and regrowth (so-called “true local recurrence”) after using this technique; if molecular techniques for the evaluation of peripheral margins ever become realistic in practice, they might eliminate this 1 to 2% after the lesions are found to persist. the good news seems to be that even when this happens, the patient outcomes are usually not worsened [1]. i agree wholeheartedly with dr. murphy that differentiation between primary and metastatic neoplasms would be of great benefit diagnostically and prognostically for patients (page 196). he reviews the status of techniques, such as the detection of fusion genes for “signature” genetic abnormalities and reverse transcription sequencing identification, which seem promising. in sum, i recommend this book principally as a reference work that many will not be able to read easily unless they are involved in the daily work of the molecular evaluation of patients’ various conditions, especially genodermatoses and some neoplasms. it fills a niche in the arsenal of tools for dermatopathologists, and it is well worth the price. reference 1. brown cd, zitelli ja. the prognosis and treatment of true local cutaneous recurrent malignant melanoma. dermatol surg. 1995 apr;21(4):285-90. pubmed pmid: 7728476. dr. hurt is the book review editor for dermatology practical and conceptual, and he practices dermatopathology in maryland heights, mo, usa. contact him at markhurt@aol.com. lar technique necessary, the molecular findings in the skin or other organs (or both), and relevant literature related to the findings. a good example of this is dr. murphy’s chapter 13 on “leukemia cutis,” specifically table 13.2. this is the kind of tool that draws the reader into the problems encountered in practice and allows for differentiation and integration of the techniques and findings. another excellent example of the integration of diseases is that of drs. smith & mclean in chapter 19 on “genodermatoses: inherited diseases of the skin.” this chapter is rich in the explanation of patterns of inheritance, gene(s) involved, omim numbers, and clinical nomenclature. these kinds of presentations alone justify purchasing the book if nothing more than just to have all of this information in one relatively small, concise text. chapters relevant to the day-to-day problems confronting dermatopathologists are chapters 5 through 8, which address melanocytic neoplasia, non-melanocytic neoplasia, and soft tissue neoplasia. these are the core of the book, and the various authors address techniques relevant to diagnosis and, to some extent, prognosis. of note, there is the fact that the genetic testing in a given neoplasm centers on identifying abnormal genetic patterns in the lesions in question compared to known controls of abnormal patterns found in malignancy. as a rule, the problem in melanocytic neoplasia, at least in my experience, is whether the lesion in question is melanoma or not. in other kinds of lesions, whether carcinoma or sarcoma, it seems that the diagnosis of malignancy is often already established by other techniques before genetic analysis adds additional information for subclassification of those malignancies. one problem i encountered when reading this work was the concept of “pre-neoplasia,” which dr. murphy addressed in chapter 9 (“molecular determination of tissue margins, clonal origin, and histogenesis of skin cancers”). i reject this concept. one cannot find a meaningful use for it. it is similar to being a “little pregnant.” one is or is not pregnant—and a lesion is or is not neoplastic. molecular genetics will not “solve” this issue because it is philosophical in nature, and there is no gene for philosophy. it is true that one can identify the conditions in which a neoplasm arises, just as one can identify the conditions in which a pregnancy occurs, but the conditions are not the same as the actual neoplasm or the mailto:markhurt@aol.com dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(3): e2021023 1 early dermoscopic signs leading to primary systemic amyloidosis’ diagnosis: a case report trashita hassanandani, bhabani s.t.p. singh, bikash ranjan kar department of dvl, ims & sum hospital, bhubaneswar, odisha, india key words: dermoscopy, primary systemic amyloidosis, cutaneous citation: hassanandani t, singh bstp, kar br. early dermoscopic signs leading to primary systemic amyloidosis’ diagnosis: a case report. dermatol pract concept. 2021;11(3): e2021023. doi: https://doi.org/10.5826/dpc.1103a23 accepted: september 7, 2020; published: july 8, 2021 copyright: ©2021 hassanandani et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. corresponding author: bhabani s.t.p. singh, mbbs md, associate professor, department of dvl, ims & sum hospital, bhubaneswar, odisha, india. email: drbstp@gmail.com introduction amyloidosis is characterised by an extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. skin and mucosae can be involved either as a part of primary cutaneous amyloidosis or secondary to systemic amyloidosis. cutaneous changes are seen in about 25% of patients with primary systemic amyloidosis. here we present unique dermoscopic features of cutaneous lesions in a case of primary systemic amyloidosis (psa). case presentation a 26-year-old male presented closely set skin-coloured papules over the eyelids, around the nose, mouth, and over the scalp. few papules had turned red over the past 6 months (figure 1). the patient reported a history of generalized weakness, hoarseness of voice, and an increase in the size of his tongue (figure 2). dermoscopic analysis revealed lesions characterized by white to yellowish clods. many lesions showed vascular proliferation with a glomerular pattern against a red to pink background (figures 3 and 4). histopathology showed clumps of pale acellular eosinophilic material (figure 5), positive for congo red stain in the papillary dermis (figure 6). further investigations revealed renal impairment with proteinuria. 24-hour urine protein was 1879.8 mg/day. urine electrophoresis showed monoclonal spikes in the gamma region. a final diagnosis of myeloma associated systemic amyloidosis was made. the patient started bortezomib-cyclophosphamide-dexamethasone treatment cycles every 28 days and is currently under follow up. the most common clinical cutaneous presentations of systemic amyloidosis are haemorrhagic lesions (petechiae, purpura, and ecchymoses), which are caused by amyloid deposition within dermal blood vessel walls, leading to vessel fragility. when there is a greater amount of amyloid deposition in the skin, the patient may develop papules, plaques, and even nodules, which may exhibit a haemorrhagic appearance. in our case, the lesions were mainly translucent to skin coloured. dermoscopic findings showed white to yellowish clods. vascular proliferation was distinctly seen in a glomer2 letter | dermatol pract concept. 2021;11(3): e2021023 figure 1. skin to reddish coloured papules around the eyes, nose, and lips. figure 2. macroglossia with teeth indentation marks on the sides of the tongue figure 3. white to yellowish background with few lesions showing glomerular vessels (dermlite dl3, polarized view). figure 4. red to pinkish background with vessels. (dermlite dl3, polarized view). classically evident haemorrhagic papules of systemic amyloidosis. in literature, these glomerular vessels are commonly encountered in non-pigmented bowen’s disease and superficial basal cell carcinoma. nevertheless, there are no reports of these vascular patterns in amyloidosis. in a report by hu et al (2019), dermoscopy of facial papules in a case of systemic amyloidosis revealed a diffusely yellowish surface with pinpoint petechiae [1]. a high degree of suspicion and early ular pattern with a red to pink background. the yellowish appearance of skin lesions on dermoscopic examination may correspond histologically to amyloid deposition in the upper dermis. the glomerular vessels appearing as clustered or coiled vessels located on one side of the lesion resembling renal glomeruli, correspond possibly histologically to small dermal blood vessels. a dermoscopic examination can detect early vascular changes, prior to the clinical appearance of letter | dermatol pract concept. 2021;11(3): e2021023 3 figure 5. histopathological features showing clumps of pale acellular eosinophilic material in the papillary dermis. (h&e, x10). dermoscopic evaluation can help prompting systemic amyloidosis’ diagnosis with cutaneous involvement [2]. conclusion glomeruloid vessels found in a yellowish background can represent a clinical feature of cutaneous lesions of primary systemic amyloidosis. these cutaneous findings can serve as an early dermoscopic sign to suspect cutaneous changes before the classic haemorrhagic appearance of systemic amyloidosis. references 1. stephen chu-sung hu, chi-ling lin, hsin-su yu. dermoscopic assessment of xerosis severity, pigmentation pattern and vascular morphology in subjects with physiological aging and photoaging. european journal of dermatology. 2019;29(3):274-280. 2. ankad bs, sakhare ps, prabhu mh. dermoscopy of non-melanocytic and pink tumors in brown skin: a descriptive study. indian j dermatopathol diagn dermatol. 2017;4:41-51. doi: 10.4103/ ijdpdd.ijdpdd_10_17 figure 6. congo red stain shows brick-red coloured amyloid deposits in the dermis and around blood vessels. dermatology: practical and conceptual research | dermatol pract concept 2017;7(2):2 7 dermatology practical & conceptual www.derm101.com use of and intentions to use dermoscopy among physicians in the united states jeffrey b. morris1, sara v. alfonso1, nilda hernandez1, m. isabel fernández1 1 college of osteopathic medicine, nova southeastern university, ft. lauderdale, fl, usa key words: dermoscopy, dermatoscopy, epiluminescence microscopy, use, intentions citation: morris jb, alfonso sv, hernandez n, fernández mi. use of and intentions to use dermoscopy among physicians in the united states. dermatol pract concept. 2017;7(2):2. doi: https://doi.org/10.5826/dpc.0702a02 received: april 5, 2016; accepted: december 9, 2016; published: april 30, 2017 copyright: ©2017 morris et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. author contributions: morris, alfonso, hernandez and fernández participated in all aspects of study development, implementation, analyses, interpretation of findings and manuscript development. morris and fernández have full access to the study data and assume full responsibility for the integrity of the data and the accuracy of the data analyses. ethical committee approval: nova southeastern university institutional review board, approved on august 27, 2015 corresponding author: m. isabel fernández, phd, 2000 s. dixie hwy suite 108 miami, fl 33133, usa. tel. 305-860-8710; fax. 305-8608742. e-mail: mariafer@nova.edu background: dermatologists routinely use dermoscopy to improve diagnostic accuracy of skin cancers. much less is known about its use among other physicians who routinely examine the skin, such as family physicians, internists and plastic surgeons. objectives: to document the use of dermoscopy in a sample of us physicians and to examine physician and practice characteristics associated with ever having used a dermascope and having some intentions to incorporate dermoscopy into clinical practice during the next 12 months. methods: from september 2015 to february 2016, we recruited 1,466 practicing physicians in person and online to complete an anonymous survey that assessed: demographic factors; physicians and practice characteristics; confidence differentiating skin lesions; knowledge and use of dermoscopy; and intentions and barriers to use dermoscopy. we conducted bivariate analysis to examine the relationship between key factors and the outcomes and entered the significant predictors into two separate logistic regressions. results: fifteen percent of participants had ever used a dermascope and 6% were currently using it. factors significantly associated with ever having used a dermascope (model 1) and having intentions to use (model 2) at the multivariate level were: recent graduation from medical school (strongest predictor in both models), identifying as a family physician, seeing a higher number of patients with skin cancer and having a higher level of confidence differentiating skin lesions. both models were highly significant. conclusion: use of dermoscopy was low. promotional efforts to increase dermoscopy use in the us are needed. abstract 8 research | dermatol pract concept 2017;7(2):2 indicating that pcps can effectively use the dermascope to increase their sensitivity of diagnosing malignant skin lesion with little or no decrease in specificity [17-19]. for instance, argenziano et al reported statistically significant differences in sensitivity between dermoscopy and visual examination (79.2% vs 54.1% respectively); 23 malignant skin tumors were missed using visual examination and only 6 using dermoscopy [17]. in another study, dermoscopy significantly increased the pcp’s ability to detect melanoma from dermoscopic images; sensitivity increased from 54.6% to 75.9% [18]. using within-lesion controls, menzies et al asked participants to rate suspicious lesions and provide management options (e.g., referral, biopsy, etc.) using visual inspection and then to repeat the rating with the aid of a dermascope [19]. there was a 63.5% reduction in the number of benign lesions requiring excision or referral from use of the dermoscopic intervention and sensitivity of diagnosis almost doubled. a recent study of french pcps provides additional evidence supporting use of the dermascope for melanoma screening [20]. these studies suggest dermoscopy can improve the pcp’s diagnostic accuracy for skin cancer. another group that may benefit from using the dermascope is plastic surgeons. interest among this group of physicians is increasing as demonstrated by a recent study conducted among plastic surgeons attending the first dermoscopy for plastic surgeons conference [21]. participants were asked to mark skin lesions as certainly benign (leave), probably benign (excise) and malignant (excise) based on a clinical picture before and after a one-day dermoscopy training course [21]. after the training course, and with the addition of the dermoscopic images, the sensitivity of accurately diagnosing a malignant lesion increased from 56% to 64% and specificity increased from 44% to 64%. dermoscopy also resulted in a near doubling in the number of correctly diagnosed benign lesions. expanding use of the dermascope among plastic surgeons may yield additional benefits in the diagnosis and treatment of skin cancer and may also lead to additional uses for the dermascope. in spite of this strong evidence supporting the dermascope as an important diagnostic tool, little is known about use of the dermascope among us based physicians. in response to this need, we conducted a study to: (1) document the use of dermoscopy in a sample of us physicians; (2) examine physician and practice characteristics associated with ever having used a dermascope and intentions to use a dermascope; and (3) examine possible barriers that might hamper its use. methods from september 2015 to february 2016, we recruited 1,466 physicians representing 49 states in person (e.g., conferences, offices, houses, etc.) and online (professional associations, introduction skin cancer is the most common cancer in the united states (us) [1]. over the past three decades, there have been more cases of skin cancer reported than all other cancers combined [2,3]. skin cancer poses a substantial and increasing economic burden on the us health care system [4]. between 2007 and 2011, the average annual cost for treating skin cancer increased by 126.2% compared to a 25.1% increase for all other cancers [4]. although non-melanoma skin cancers are more prevalent, melanoma is far more deadly [5]. during the past three decades, there has been 20% to 60% decrease in mortality rates for cancers of the cervix, colon, prostate and breast while mortality from melanoma has increased [6,7]. early detection is key to achieving more positive treatment outcomes [8]. because many patients are seen first by primary care physicians (pcps), these doctors are poised to play a critical role in early detection of skin cancers. the most common way that many pcps screen for skin cancer is through visual inspection, which is not highly sensitive [9]. among pcps the sensitivity of visual inspection ranges from 37.5% to 60.9% [9]. thus, reliance on visual inspection alone may not be the optimal strategy for early detection of skin cancers. adding relatively inexpensive, but highly sensitive and specific non-invasive technology, such as the dermascope, may enhance the effectiveness of visual exams for detecting early stage skin cancers. dermoscopy is a non-invasive in vivo technique that allows visualization of subsurface structures of the skin that are not visible with the naked eye. several meta-analyses provide strong evidence indicating that dermoscopy improves accuracy in diagnosing skin cancer [10-12]. in a 2008 metaanalysis, the odds of melanoma detection by dermoscopy was 15.6 times higher than by naked-eye examination (ci = 2.9-83.7, p = .016), and the sensitivity rate was 90% compared to 71% for naked-eye examination with no significant changes in specificity [10]. in a more recent study, dermoscopy resulted in 42% fewer excisions compared to naked-eye examination and had a 21% increase in specificity [13]. despite the benefits, the diagnostic accuracy of the dermascope is contingent on the skill of the user and the cancerous lesions having typical features [14]. notwithstanding, dermoscopy is routinely used among dermatologists in many countries. for instance, approximately 95% of dermatologist in france, 98% of those in australia, and 98.5% of those in the uk use dermoscopy in their clinical practice [15]. in contrast, use of dermoscopy among us dermatologists is much lower. in 2009, 48% of the 3,238 us dermatologists surveyed reported using dermoscopy in their practice [16]. efforts to promote the use of the dermascope among us dermatologists are warranted. because dermascopes are relatively inexpensive and easy to use with minimal training, they can be readily integrated into routine primary care [17]. there is emerging evidence research | dermatol pract concept 2017;7(2):2 9 confidence in differentiating skin lesions: participants reported their degree of confidence differentiating between cancerous and non-cancerous skin lesions using a 5-point likert scale ranging from “not confident at all” to “very confident”. knowledge and use of dermoscopy: using four dichotomous items, participants reported whether or not they had heard of, read about, ever used and currently use a dermascope. intentions to use a dermascope in the next 12 months: using a 5-point likert scale, where 1 is “not at all likely” and 5 is “very likely”, participants reported how likely they are to incorporate the dermascope into their clinical practice within the following 12 months. to create the dichotomous outcome variable, intentions to use the dermascope in the following 12 months, all scores of 1 were recoded as no intentions and scores of 2 and greater were collapsed and recoded as some intentions. barriers: for each of 10 potential barriers (e.g., insufficient reimbursement, increased patient anxiety, etc.), participants reported the degree to which the item was a barrier to incorporating dermoscopy in their clinical practice. response options ranged from 1 “no barrier” to 5 “a very big barrier”. for each item, we calculated mean scores and used these scores to identify the top three barriers. analysis plan: we used measures of central tendency (mean, mode) and descriptive statistics (frequencies, etc.) to examine sample characteristics and conducted bivariate analysis (chi square) to examine the relationship between key factors and our two dependent variables: (1) ever used the dermascope; (2) intentions to incorporate use of the dermascope into their clinical practice in the following 12 months. in accordance with hosmer and lemeshow, we entered the variables whose p values were statistically significant or approaching significance (p < .20) in the bivariate analysis in the logistic regressions [22]. the sample size for the logistic regression on “ever used a dermascope” (which we refer to as model 1) was 1,332 and the sample size for the logistic regression on “intentions to use a dermascope” (which we refer to as model 2) was 1,168. the reduced sample size for model 2 was due to missing data on the dependent variable, which occurred at the early stages of data collection. as soon as we realized that some participants were skipping the intention item because it was partially hidden by the clipboard, we remedied the situation. results sample characteristics are described in table 1. our sample was primarily white (77.1%), males (65.3%), trained as do’s (62%), and identified as family physicians (48.4%). fifty-four e-mail, etc.) to complete a brief cross-sectional survey. we recruited at nine national and international conferences that primarily targeted pcps and others most likely to use dermoscopy. we purposefully excluded recruiting at conferences targeting dermatologists. to reduce cost, we focused on conferences held in cities (e.g., tampa, orlando, miami, fort lauderdale, atlanta, boca raton, weston) geographically more proximal to the investigators, such as the 2015 conference for the american college of osteopathic internists and the 2016 southeastern society of plastic and reconstructive surgeons. to be eligible, physicians had to be: (1) 18 years of age or older; (2) currently practicing in the us; and (3) able to understand english. the study was approved by the nova southeastern university (nsu) institutional review board as exempt on august 27, 2015. we approached potential participants, briefly described the study and ascertained whether or not they were eligible. to those eligible and willing to participate, we gave a clipboard with the survey and an explanatory cover letter stating that participation is voluntary, that they would not receive an incentive, and that by completing the survey they were consenting to be in the study. eighty-six percent of participants were recruited face-to-face and the majority of those eligible agreed to participate. we used surveymonkey® to create an electronic version of the cover letter and questionnaire which we distributed via personal e-mails and professional list servers. eligible and willing participants clicked on the link provided and were redirected to a secure website to complete the survey. we entered paper surveys into spss® and merged the file with the data collected online. because we found no standardized instrument to measure dermoscopy use in the published literature, we selected specific items from past surveys directly relevant to our study and developed new items to assess domains of interest. we pilot tested the newly developed survey on ten respondents to assess comprehension and readability. we revised select items to improve comprehension and omitted items that were redundant or unclear. the final instrument consisted of 46 items measuring the following areas: demographic factors: participants reported their age, gender and race/ethnicity. physician characteristics: participants reported their type of medical degree (doctor of osteopathic medicine [do] or medical doctor [md]), year of graduation from medical school, percentage of time spent in direct patient care, number of patients seen per month and number of patients presenting with lesions suspicious for skin cancer in a typical month. practice characteristics: participants reported their type of medical practice (e.g., solo, group, academic, etc.), the state in which they practiced, and location of practice (urban, suburban or rural). 10 research | dermatol pract concept 2017;7(2):2 percent of participants had heard of the dermascope and 26% had read about it in the medical literature. fifteen percent of our sample had ever used the dermascope and 6% were currently using it in their clinical practice. the most frequently cited barriers to incorporating the dermascope in routine care were: (1) the cost of the equipment (m = 3.72, sd = 1.29); (2) time and training requirements to become proficient in its use (m = 3.46, sd = 1.24); and (3) insufficient reimbursement (m = 3.32, sd = 1.49). table 2 summarizes factors significantly associated with ever having used a dermascope and with having some intentions to use the dermascope in the following 12 months at the bivariate level. at the bivariate level, ever having used a dermascope was significantly associated with year of graduation, gender, degree, specialty, practice type, percentage of time spent in direct patient care, number of patients seen per month who present with suspicious skin lesions that may be cancerous, and level of confidence differentiating benign and malignant skin lesions. having intentions to use in 12 months was significantly associated with year of graduation, gender, variable n valid % year of graduation (n1 = 1,391) before 1980 182 13.1 1980-1989 316 22.7 1990-1999 305 21.9 2000-2009 352 25.3 2010-2015 236 17.0 ethnicity (n1 = 1,452) white 1,119 77.1 black 103 7.1 hispanic/latino 96 6.6 asian/pacific islander 92 6.3 other 42 2.9 gender (n1 = 1,456) male 951 65.3 female 505 34.7 degree (n1 = 1,455) d.o. 900 61.7 m.d. 558 38.3 practice location (n1 = 1,450) urban 532 36.7 suburban 609 42.0 rural 296 20.4 other 13 .9 specialty (n1 = 1,458) family medicine 705 48.4 internal medicine 298 20.4 plastic surgery 231 15.8 other2 224 15.4 practice type (n1 = 1,455) solo 402 27.6 group 495 34.0 hospital-based 254 17.5 academic medicine 158 10.9 community health 94 6.5 other 52 3.6 time in direct patient care (n1 = 1,457) 0-25% 54 3.7 26%-50% 55 3.8 51%-75% 167 11.5 76%-100% 1181 81.1 # of patients/month (n1 = 1,437) ≤100 327 22.8 101-200 330 23.0 201-300 295 20.5 301-400 257 17.9 ≥ 401 228 15.9 variable n valid % # of patients/month with suspicious lesions (n1 = 1,424) ≤ 1.5 298 20.9 1.51-4.99 248 17.4 5-9.99 250 17.6 10-19.99 278 19.5 ≥ 20 350 24.6 level of confidence (n1 = 1,451) not confident at all 59 4.1 a little confident 311 21.4 neither confident nor unconfident 310 21.4 confident 616 42.5 very confident 155 10.7 heard of a dermascope (n1 = 1,451) yes 787 54.2 read about a dermascope (n1 = 1,426) yes 377 26.4 used a dermascope (n1 = 1,445) yes 211 14.6 currently use a dermascope (n1 = 1,445) yes 87 6.02 intentions to incorporate dermoscopy into clinical practice in 12 months (n1 = 1,267) yes 656 51.8 1n varies due to missing data 2 other category includes specialties with less than 25 participants that included pediatricians, geriatricians, obstetricians etc. table 1. sample characteristics. [copyright: ©2017 morris et al.] research | dermatol pract concept 2017;7(2):2 11 us physicians. thus, the low rates of dermoscopy use in our study may be partially explained by the absence of practice guidelines. reimbursement rates may also be a limiting factor to its use in the us since no additional reimbursement is provided, as is true for otoscopy or stethoscopy [25]. this is in direct contrast to practices in other countries such as australia, where dermoscopy has been reimbursable since 1987 [26]. given skin cancer’s burden on the health care system and the benefits of early detection, promoting the use of dermoscopy to us physicians, who routinely examine pigmented skin lesions, is warranted. it is interesting to note that cost and reimbursement were two of the three most frequently cited barriers to incorporating the dermascope into routine practice. although not specifically stated, the other barrier, time and training requirements, also has fiscal elements. in the current managed care environment with its increased competition for health care dollars, negotiated payment structures, shrinking reimbursements and patient quotas, physicians are concerned about introducing procedures which may impact their productivity and bottom line. given that dermoscopy significantly improves the diagnosis of melanoma and the cost of treating melanoma is reduced when detected early, routine dermoscopic screening for individuals at high risk should be adequately reimbursed and incorporated into the preventive care services mandated through the patient protection and affordable care act [27]. another important contribution of our study was examining the factors associated with use of the dermascope and having some intention to use the dermascope in the next 12 months. it was noteworthy that for both regression models, the same set of factors emerged as significant predictors, degree, practice location, specialty, practice type, number of patients seen per month, number of patients seen per month who present with suspicious skin lesions that may be cancerous, and level of confidence differentiating benign and malignant skin lesions. the results of the two logistic regressions are reported in table 3. graduating medical school more recently, being a family physician, seeing a higher number of cancer patients and having a higher level of confidence differentiating benign and malignant skin lesions were significantly associated with ever having used a dermascope and having intentions to use a dermascope. recent graduation from medical school was the strongest predictor in both logistic regression models; participants who graduated between 2010 and 2015 were 8.10 times more likely to have used the dermascope and 2.86 times more likely to report intentions to use it than physicians who graduated before 1980. participants with a higher level of confidence differentiating skin lesions were 2.18 times more likely to have used a dermascope and 1.16 times more likely to report intentions to use than those with a lower level of confidence. model 1 correctly classified 86.6% of participants (p < .001) and model 2 correctly classified 66.2% of participants (p < .001). discussion although there is widespread use of dermoscopy among physicians in other countries, our study indicates low use among us physicians. treatment guidelines from other countries recommend use of dermoscopy to improve diagnostic accuracy [23,24]. similar recommendations have yet to be issued for table 2. bivariate analysis of factors associated with ever having used a dermascope and having some intentions to use a dermascope in the next 12 months. [copyright: ©2017 morris et al.] ever used a dermascope some intentions to use in 12 months 2 ρ 2 ρ year of graduation 49.61 4 .000* 19.86 4 .001* ethnicity 2.12 4 .833 7.47 4 .188 gender 7.12 1 .008* 7.57 1 .006* degree 4.17 1 .041* 14.79 1 .000* practice location 3.72 3 .294 24.04 3 .000* specialty 32.11 3 .000* 106.51 3 .000* practice type 34.18 5 .000* 15.48 5 .009* % of time spent in direct patient care 7.91 3 .048* 4.61 3 .203 # of patients/month 6.82 4 .146 29.77 4 .000* # of patients/month with suspicious lesions 17.41 4 .002* 46.69 4 .000* level of confidence 49.01 4 .000* 24.71 4 .000* *statistically significant 12 research | dermatol pract concept 2017;7(2):2 months [30]. media attention, editorials in the medical literature and additional promotional efforts by experts and professional organizations may persuade those with intentions to incorporate the dermascope into their practice to actually do so. studies with representative samples of physicians who graduated within the last 15 years would yield additional data to further elucidate the factors associated with use and intentions to use dermoscopy. type of medical specialty was another important predictor in both models. in contrast to other subspecialties, family physicians had the highest odds of ever having used a dermascope and intentions to incorporate its use in their clinical practice. in some ways this is not surprising because family physicians conduct more skin cancer screenings than other pcps, and the dermascope has been shown to increase diagnostic accuracy for melanoma [31]. additionally, since the intention item was placed near the end of the survey and many of the prior items highlighted the characteristics and benefits of the dermascope, participants who regularly screen for skin cancer may have been primed to express more favorable intentions regarding future use of the dermascope. notwithstanding the significance of our findings, our sample may not be representative of the population of us based physicians due to convenience sampling. although we recruited physicians practicing in all states but nebraska, a suggesting that these are robust predictors. however, the magnitude of the associations differed. for instance, recent graduates, those who graduated after 2009 and those who graduated between 2000 and 2009, were 8.1 times and 2.73 times more likely, respectively, to have ever used the dermascope compared to those graduating before 1980. since use of the dermascope in the us has been slowly gaining acceptance during the last decade, it could be that more training programs have been acquiring the device [28,29]. thus, more recent graduates could have been exposed or have had experience using the dermascope during medical school or residency. furthermore, since 41.2% of participants who had ever used the dermascope were currently using it, exposure during medical training could have promoted current use. similarly, those who graduated after 2009 and those who graduated between 2000 and 2009, were 2.86 times and 2 times more likely, respectively, to report having some intentions to incorporate the dermascope into their practice in the following 12 months. it could be that recent graduates, who are likely to be younger, may be more open to trying new technology compared to participants graduating prior to 1980 who may be nearing retirement age. although intentions do not always predict future behaviors, it was encouraging to note that 52% of participants expressed some intention to incorporate dermoscopy into their practice within the next 12 table 3. logistic regression models. [copyright: ©2017 morris et al.] model 1ever used a dermascope model 2some intentions to use in 12 months beta or 95% ci ρ beta or 95% ci ρ year of graduation before 1980 (referent) 1980-1989 -.13 .88 .42-1.76 .721 .64 1.90 1.22-2.99 .005* 1990-1999 -.01 .99 .49-2.01 .986 .46 1.59 1.00-2.53 .051 2000-2009 1.01 2.73 1.39-5.37 .004* .70 2.00 1.25-3.19 .004* 2010-2015 2.09 8.10 3.83-17.12 .000* 1.05 2.86 1.66-4.93 .000* specialty family med. (referent) internal medicine -.95 .39 .23-.66 .000* -.26 .78 .55-1.10 .156 plastic surgery -1.81 .16 .08-.36 .000* 2.04 .13 .08-.22 .000* other .06 1.06 .64-1.73 .828 -.52 .60 .41-.87 .008* # of patients/month with suspicious lesions ≥ 20 (referent) 10-19.99 -4.27 .65 .40-1.06 .087 -.18 .84 .57-1.23 .367 5-9.99 -.681 .51 .30-.86 .011* -.42 .66 .44-.98 .041* 1.51-4.99 -.303 .74 .43-1.30 .266 -.40 .67 .44-1.00 .052 ≤ 1.5 -1.30 .27 .14-.52 .000* -1.05 .35 .23-.53 .000* level of confidence .78 2.18 1.77-2.68 .000* .15 1.16 1.02-1.32 .020* *statistically significant research | dermatol pract concept 2017;7(2):2 13 2. stern, rs. prevalence of a history of skin cancer in 2007: results of an incidence-based model. arch dermatol. 2010;146(3):279–282. 3. wehner m, chren mm, nameth d, et al. international prevalence of indoor tanning: a systematic review and meta-analysis. jama dermatol. 2014;150(4):390–400. 4. guy gp, machlin sr, ekwueme du, yabroff kr. prevalence and costs of skin cancer treatment in the u.s., 2002-2006 and 20072011. am j prev med. 2014;48(2):183–187. 5. seer cancer statistics factsheets. bethesda, md: national cancer institute. accessed september 15, 2015. melanoma of the skin. available at http://seer.cancer.gov/statfacts/html/melan.html. accessed september 15, 2015. 6. geller ac, swetter sm, weinstock ma. focus on early detection to reduce melanoma deaths. j invest dermatol. 2015;135(4):947– 949. 7. geller ac, swetter sm, brooks k, demierre mf, yaroch al. screening, early detection, and trends for melanoma: current status (2000-2006) and future directions. j am acad dermatol. 2007;57(4):555–572. 8. balch cm, gershenwald je. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199– 6206. 9. herschorn a. dermoscopy for melanoma detection in family practice. can fam physician. 2012;58(7):740–745. 10. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669–676. 11. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159–165. 12. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? arch dermatol. 2001;137(10):1343–1350. 13. van der rhee ji, bergman w, kukutsch na. impact of dermoscopy on the management of high-risk patients from melanoma families: a prospective study. acta derm venereol. 2011;91(4):428–431. 14. skvara h, teban l, fiebiger m, binder m, kittler h. limitations in dermoscopy in the recognition of melanoma. arch dermatol. 2005;141(2):155–160. 15. butler td, matin rn, affleck ag, fleming cj, bowling jc. trends in dermoscopy use in the uk: results from surveys in 2003 and 2012. dermatol pract concept. 2015; 5(2):29–38. 16. h.c. engasser, e.m. warshaw. dermatoscopy use by us dermatologists: a cross-sectional survey. j am acad dermatol. 2010;63(3):412–419. 17. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877–1882. 18. westerhoff k, mccarthy wh, menzies sw. increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy. br j dermatol. 2000;143(5):1016–1020. 19. menzies sw, emery j, staples m, et al. impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. br j dermatol. 2009;161(6):1270–1277. 20. chappuis p, duru g, marchal o, girier p, dalle s, thomas l. dermoscopy: a useful tool for general practitioners in melanoma screening: a nationwide survey. br j dermatol. 2016; 175(4):744750. large proportion of participants practiced in the southeast since we primarily recruited at conferences located in this region of the country. our findings can only be generalized to physicians attending these conferences. our data collection method was self-report, which has some limitations [32]. however given that we were not collecting sensitive data, the tendency towards providing socially desirable responses in self-report data was minimized. because we expected that many participants would have little knowledge of the dermascope, we provided a brief description of its properties (that it was relatively inexpensive, easy to use and more effective for screening than naked-eye examinations) as a preamble to the intention items. although this positive description might have prompted some participants to respond more favorably, almost half did not suggesting that the effect was attenuated. last, because participants completed the survey without direct oversight from the researchers, there were some skip pattern errors and missed responses. in summary, our study represents an initial step in understanding use of dermoscopy among us based physicians. despite the strong evidence supporting use of dermoscopy to enhance diagnostic accuracy primarily for melanoma, the low levels of use among us-based physicians is concerning, particularly in light of the morbidity, mortality and health care cost of melanomas, especially those detected later in their disease course. although the evidence supporting routine population-based screening for skin cancer is equivocal, promoting routine dermoscopic screening of patients at high risk may be beneficial [33]. efforts to increase dermoscopy use among physicians routinely examining high-risk patients are needed. acknowledgments we would like to thank the dean of nsu com and the nsu research fellowship program for the opportunity to conduct this research. this manuscript represents valid work and has not been published or under consideration for publication in any other journal. all data created during this research is available in hard copy at our office and in an spss® database. the study was supported by internal university funds and the authors do not have conflicts of interest. furthermore, all of the authors contributed significantly to the design and conduct of the study and participated in the development of the manuscript. references 1. cancer facts & figures 2014. atlanta, ga: american cancer society: 2014. accessed january 2, 2016. basic cancer facts. available at http://www.cancer.org/acs/groups/content/@research/ documents/webcontent/acspc-042151.pdf. published 2014. accessed january 2, 2016. http://seer.cancer.gov/statfacts/html/melan.html 14 research | dermatol pract concept 2017;7(2):2 28. charles ca, yee vs, dusza sw, et al. variation in the diagnosis, treatment, and management of melanoma in situ: a survey of us dermatologists. arch dermatol. 2005;141(6):723–729. 29. terushkin v, oliveria sa, marghoob aa, halpern ac. use of and beliefs about total body photography and dermatoscopy among us dermatology training programs: an update. j am acad dermatol. 2010;62(5):794–803. 30. danner un, aarts h, de vries nk. habit vs. intention in the prediction of future behaviour: the role of frequency, context stability and mental accessibility of past behaviour. br j soc psychol. 2008;47(2):245–265. 31. oliveria sa, heneghan mk, cushman lf, ughetta ea, halpern ac. skin cancer screening by dermatologists, family practitioners, and internists: barriers and facilitating factors. arch dermatol. 2011;147(1):39–44. 32. paulhus dl, vazire s. the self-report method. in: robins rw, fraley ac, krueger rf. handbook of research methods in personality psychology. new york: the guilford press; 2009:224–239. 33. kaiser permanente research affiliates evidence-based practice center. rockville, md: agency for healthcare research and quality. accessed february 11, 2016. screening for skin cancer in adults: an updated systematic evidence review for the u.s. preventative service task force. available at http://www.uspreventiveservicestaskforce.org/home/getfile/1/4334/skincandraftes/ pdf. published december 2015. accessed february 11, 2016. 21. townley wa, cassell oc, bowling j. dermoscopy-time for plastic surgeons to embrace a new diagnostic tool? j plast reconstr aesthet surg. 2011;64(10):1386–1387. 22. hosmer dw, lemeshow s. applied logistic regression. 3rd ed. new york: john wiley & sons, inc; 2000. 23. australian cancer network melanoma guidelines revision working party. clinical practice guidelines for the management of melanoma in australia and new zealand. cancer council australia and australian cancer network, sydney and new zealand guidelines group. approved october 2008. available at http:// www.cancer.org.au/content/pdf/healthprofessionals/clinicalguidelines/clinicalpracticeguidelines-managementofmelanoma. pdf. accessed january 28, 2016. accessed on november 25, 2015. 24. castro lg, messina mc, loureiro w, et al. guidelines of the brazilian dermatology society for diagnosis, treatment and follow up of primary cutaneous melanoma—part 1. an bras dermatol. 2015;90(6):851–861. 25. fox gn. dermoscopy: an invaluable tool for evaluating skin lesions. am fam physician. 2008;78(6):704–706. pmid: 18819235. 26. soyer hp, argenziano g, talamini r, chimenti s. is dermoscopy useful for the diagnosis of melanoma? arch dermatol. 2001;137(10):1361–1363. 27. rosenbaum s. the patient protection and affordable care act: implications for public health policy and practice. public health rep. 2011;126(1):130–135. http://www.uspreventiveservicestaskforce.org/home/getfile/1/4334/skincandraftes/pdf http://www.uspreventiveservicestaskforce.org/home/getfile/1/4334/skincandraftes/pdf http://www.uspreventiveservicestaskforce.org/home/getfile/1/4334/skincandraftes/pdf http://www.cancer.org.au/content/pdf/healthprofessionals/clinicalguidelines/clinicalpracticeguidelines-managementofmelanoma.pdf http://www.cancer.org.au/content/pdf/healthprofessionals/clinicalguidelines/clinicalpracticeguidelines-managementofmelanoma.pdf http://www.cancer.org.au/content/pdf/healthprofessionals/clinicalguidelines/clinicalpracticeguidelines-managementofmelanoma.pdf http://www.cancer.org.au/content/pdf/healthprofessionals/clinicalguidelines/clinicalpracticeguidelines-managementofmelanoma.pdf research | dermatol pract concept 2017;7(2):2 15 1. how old are you?____________________ 2. what is your gender? 1. male 2. female 3. which of the following most closely describes your ethnic background? 1. white, non-hispanic origin 2. black, non-hispanic origin 3. hispanic/latino/latina 4. asian/pacific islander 5. native american 6. other, please specify____________________ 4. in which state do you spend the majority of your time practicing medicine? ____________________ 5. what type of medical degree do you have? 1. d.o. 2. m.d. 6. what year did you graduate from medical school?____________________ 7. how would you best describe your primary specialty area? 1. family practice 2. internal medicine 3. obstetrics/gynecology 4. pediatrics 5. adolescent medicine 6. surgery 7. geriatrics 8. other, please specify____________________ 8. what percentage of your time is spent in direct patient care? 1. 0 to 25% 2. 26% to 50% 3. 51% to 75% 4. 76% to 100% 9. which of the following best describes your type of medical practice? 1. solo practice 2. single specialty group practice 3. multispecialty group practice 4. hospital-based practice 5. academic medicine 6. community health center or community clinics 7. other, please specify¬____________________ 10. which of the following best describes the location of your primary practice? 1. urban 2. suburban 3. rural 4. other, please specify____________________ 11. in a typical month, approximately how many patients do you see?____________________ 12. in a typical month, approximately how many of the patients you see present with suspicious skin lesions that might be cancerous?____________________ 13. how confident are you in your ability to differentiate between cancerous and non-cancerous skin lesions? 1. not confident at all 2. a little confident 3. neither confident nor unconfident 4. confident 5. very confident 14. when a patient presents with a suspicious skin lesion, which of the following most closely describes what you typically do? 1. conduct a naked eye examination of the lesion 2. examine lesion with the aid of a magnifying device 3. refer patient to a dermatologist 4. other, please specify____________________ 15. physicians use different strategies to get up to date medical information. which of the following are your 2 top sources for obtaining information on skin cancer screening and prevention? 1. medical journals 2. internet sources other than medical journals 3. conferences 4. discussions with colleagues 5. media coverage 6. other, please specify____________________ 16. have you ever heard of a dermascope, a device that helps physicians screen for skin cancers? 1. no (skip to q17) 2. yes if yes, in what context did you hear about it? 1. a conversation with a colleague 2. at a conference 3. at a ground rounds 4. at a class 5. other, please specify____________________ 17. have you ever read about dermoscopy in the medical literature? 1. no (skip to q18) 2. yes if yes, how much have you read? 1. 1 article 2. 2 to 4 articles 3. 5 or more articles 18. have you ever used a dermascope? 1. no 2. yes if yes, do you currently use it in your clinical practice? 1. no 2. yes please read each question carefully and provide your answers by circling the number that reflects your answer or writing the response on the line provided. please remember that this survey is completely anonymous and there are no right or wrong answers. thank you once again for your participation in this study. 16 research | dermatol pract concept 2017;7(2):2 intention to use the following questions address different properties of skin cancer screening tools that make them more or less acceptable to physicians. using a scale from 1 to 5, where 1 is not at all likely and 5 is very likely, please tell us how likely you are to use a dermascope in your clinical practice if it . . . not at all likely very likely 1. was easy to use 1 2 3 4 5 2. costs less than $500 1 2 3 4 5 3. could be attached to a smartphone 1 2 3 4 5 4. was handheld 1 2 3 4 5 5. training could be done in 1 day 1 2 3 4 5 6. is more sensitive than a naked eye exam 1 2 3 4 5 7. costs more than $1500 1 2 3 4 5 8. requires little maintenance 1 2 3 4 5 9. requires a lot of practice 1 2 3 4 5 10. does not record digital images 1 2 3 4 5 11. reduces the need for biopsies 1 2 3 4 5 12. can help identify suspect skin lesions quickly 1 2 3 4 5 13. decreases cost of care 1 2 3 4 5 14. increases your confidence in screening for skin cancer 1 2 3 4 5 15. could increase revenue 1 2 3 4 5 16. adds a few minutes to the patient encounter 1 2 3 4 5 the prevalence of skin cancer is increasing and primary care providers are well poised to assist in its early detection. dermascopes are relatively inexpensive, easy to use, and there is strong evidence indicating that they are more effective at screening for skin cancer than naked eye examinations. 19. using a scale from 1 to 5, where 1 is not at all likely and 5 is very likely, how likely are you to incorporate use of a dermascope as part of your clinical practice within the next 6 months?____________________ 20. using a scale from 1 to 5, where 1 is not at all likely and 5 is very likely, how likely are you to incorporate use of a dermascope as part of your clinical practice within the next 12 months?____________________ barriers to use there are a number of issues that may keep physicians from incorporating dermoscopy into their clinical practice. on a scale from 1 to 5, where 1 is no barrier and 5 is a very big barrier, please tell us the degree to which each of the following items represents a barrier to incorporating dermoscopy into your clinical practice. no barrier very big barrier 1. insufficient reimbursement 1 2 3 4 5 2. added time to the patient encounter 1 2 3 4 5 3. cost of the equipment 1 2 3 4 5 4. time and training requirements to become proficient in its use 1 2 3 4 5 5. skin cancer screening is a low priority for non-dermatologists 1 2 3 4 5 6. increased patient anxiety 1 2 3 4 5 7. increased risk of lawsuits 1 2 3 4 5 8. patients may not accept it 1 2 3 4 5 9. dermatologic concerns may be secondary to chief complaint if there are multiple comorbidities 1 2 3 4 5 10. no available training 1 2 3 4 5 11. dermatologic concerns may be secondary to chief complaint if there are multiple comorbidities 1 2 3 4 5 12. no available training 1 2 3 4 5 dermatology practical & conceptual www.derm101.com essay | dermatol pract concept 2012;2(3):11 57 comedy of melanoma management in his “essay on comedy” in 1877, george meredith noted, “the test of true comedy is that it shall awaken thoughtful laughter.” [1] this does not necessarily mean that a comedy must be funny. laughter can also be provoked by matters serious or sad. most psychologists agree that the predominant characteristics connected with the phenomenon of laughter are incongruity or contrast in the object creating it and shock or emotional seizure on the part of the subject. freud pointed out that laughter is a sign of relief from tension. rené descartes emphasized the suddenness of laughter evoked by circumstances that “cause the lungs suddenly to inflate” so that “the air they contain is forced out through the windpipe with impetuosity,” whereas thomas hobbes related laughter to feelings of superiority, to a “sudden glory arising from sudden conception of some eminency in ourselves by comparison with the infirmity of others, or with our own formerly.” [2] all those feelings can be provoked if one starts to think about concepts in the management of melanoma. sad in many ways because misconceptions may come to bear severely on patients, the history of melanoma management is also rivetingly funny because it possesses all ingredients of a good comedy. first, many concepts pertaining to melanoma are replete with incongruities that truly are breathtaking. as a novice, one may neglect them and adhere obediently to established standards of care, but if one’s intellectual faculties are not benumbed completely, the question will sooner or later arise, “what’s wrong with my brain that i simply cannot get it?” that is the moment of shock or despair, an important element of good comedy, and then comes the moment of relief, to wit, the sudden awareness that nothing is wrong with one’s brain but only with the premises of melanoma management, a moment of alleviation and laughter that leads to what hobbes called “sudden glory,” a feeling of superiority in comparison with acolytes of such concepts, including one’s former self. examples are legion. a particularly striking one is recommendations concerning margins of excision. for decades, huge excisions necessitating free transplants of skin were required for melanomas that already had been removed completely. the fable was spread, and believed throughout the world, that excision of a scar and a chunk of healthy skin could prevent death from melanoma. when in the 1970s margins of excision were reduced for thin melanomas, basic principles of logic were violated even more flagrantly. margins of excision were adjusted to the risk of nodal and visceral metastases, rather than the risk of persistence of the neoplasm at the primary site, as if excision of some skin around the site of a primary cutaneous melanoma of the leg or trunk could have any effect on metastases in the groin, lung, or liver. moreover, the horizontal margin of excision “mitogenicity”—the latest and most hilarious episode in the slapstick comedy of melanoma management wolfgang weyers, m.d.1 1 center for dermatopathology, freiburg, germany citation: weyers w. “mitogenicity”—the latest and most hilarious episode in the slapstick comedy of melanoma management. dermatol pract conc. 2012;2(3):11. http://dx.doi.org/10.5826/dpc.0203a11. copyright: ©2012 weyers. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: wolfgang weyers, m.d., center for dermatopathology, engelbergerstr. 19, 79098 freiburg, germany. tel. +01149.761.31696; fax. +01149.761.39772. e-mail: ww@zdpf.de. 58 essay | dermatol pract concept 2012;2(3):11 was not adjusted to the horizontal extent of the melanoma but to the vertical one. if one told a kindergarten child that, when searching for a hidden treasure, one needs to dig a wider hole the deeper the treasure is buried, the child would probably pause briefly and then burst out in laughter. the same reaction would be very healthy for surgeons required by current standards of care to perform wider excisions for thicker melanomas. [3] ready for another joke? since clark advanced the current classification of malignant melanoma in 1969, nodular melanoma was considered to be the most dangerous type. whenever the nodular type came into play, extra centimetres of skin were added to the already generous margins of excision, elective lymph node dissections were performed, and hyperthermic perfusions of the limbs with cytostatics were considered. but what is nodular melanoma? clark defined it by “dermal invasion throughout the lesion, wherever there is intraepidermal growth. . . . if this growth extends beyond the width of 3 rete ridges in any section, the tumor is classified as a superficial spreading melanoma.“ [4] according to this definition, one can never be sure that one is dealing with a nodular melanoma. if the definition of nodular melanoma seems to be fulfilled because the intraepidermal component does not extend beyond the dermal one for more than 3 rete ridges in 10 or 20 step sections, this could easily be the case in the 21st section. moreover, those who attach prognostic significance to the nodular type claim, in effect, that prognosis of an advanced melanoma is not determined by its thickness of 3 or 4 mm, but by demonstration of an increased number of intraepidermal melanocytes for only 3, rather than 4, rete ridges beyond the peripheral margins of the dermal nodule, i.e., a difference of maybe 0.1 mm. and those who contend that a few melanoma cells confined to the epidermis have an independent effect on prognosis are the same who aver that a wholly intraepidermal proliferation of melanoma cells carries no risk at all, who even claim that there is “no biologic evidence that in situ melanoma is a malignant disease.” [5] how about that for an incongruity? it must be acknowledged that, after many years of steadfast adherence to the concept of an especially grave prognosis of nodular melanoma, most statistics revealed no independent effect on prognosis, and the type of melanoma is no longer considered in staging systems. but whenever a statistical study suggests some prognostic effect, it keeps popping up. for example, in a recent analysis of patients with melanoma in whom sentinel lymph node biopsies (slnb) had been performed, the authors found that “significant parameters upon sln positivity were tumor thickness and nodular type of melanoma” and suggested that “in case of a nodular melanoma subtype slnb should also be considered at a tumor thickness below 1 mm.” [6] sad to say, and at the same time hilariously funny, that lack of a few additional melanoma cells confined to the epidermis continues to determine management of melanoma in the 21st century. once one gets into telling jokes, one can go on and on because one joke reminds of another. that’s also what makes a good comedy—one gag is not sufficient. let me share with you another one: every histopathologist and nearly all dermatologists and surgeons are fully aware of the fact that specimens shrink considerably following excision. shrinkage by 30 to 40% of the original size is the rule, so that a neoplasm originally measuring 20 mm in diameter will have a diameter of only 12 or 13 mm when measured under the microscope. the degree of shrinkage varies greatly in dependence from factors such as anatomic site, age of patient, and time of fixation in formalin. [7,8] measurement of size in histopathologic sections is also influenced by the way sections are cut. if they are not cut strictly perpendicularly to the surface of the skin but slightly obliquely, lesions will appear thicker than they actually are. because of those foibles, measurements are necessarily imprecise. factors related to the handling of specimens may easily influence the measured thickness of melanomas in the range of several tenths of millimeters. nevertheless, when breslow in 1970 introduced thickness of melanomas as a gauge for prognosis of them, he distinguished prognostic groups on the basis of one hundredth of a millimetre, and failure to mention the second decimal was regarded as imprecise for decades to come [9]. breslow’s exaggerated pursuit of precision was incorporated in all staging systems, and patients were often managed differently depending on whether their melanoma measured 0.75 or 0.76 mm in thickness. when those fraction numbers were finally substituted by whole numbers, namely, 1, 2, and 4 mm, in the staging system of the american joint committee on cancer in 2001, that change was not caused by a sudden eruption of common sense but because the new categories were “more clinically convenient and widely used” and were no worse, in statistical analyses, than the fraction numbers used before. inherent limitations in the accuracy of measurements were never considered. [10] as if this were not risible enough, some authors even claimed that mother nature revealed itself in the second place after the decimal point. based on statistical evaluation of survival rates, dermatologists of harvard university and new york university calculated “natural break points for primary-tumor thickness in clinical stage 1 melanoma” that were said to be located between 0.84 and 0.85 mm, 1.69 and 1.70 mm, and 3.59 and 3.60 mm, respectively. they claimed, in earnest, that the risk of metastasis did not increase gradually, but “in quantum jumps” that were clearly defined by nature and signified “decisive events in the natural history of primary melanoma growth at these thickness values.” [11] and these esoteric assumptions were not made by moony mystics but by renowned professors of medicine, including essay | dermatol pract concept 2012;2(3):11 59 martin mihm, alfred kopf, arthur j. sober, and thomas b. fitzpatrick. in a comparison of the magnitude of madness and the magnitude of earthquakes, the 1906 san francisco earthquake with values between 7.7 and 7.9 on the moment magnitude scale would be outnumbered easily by this article that deserves an 8.5 on the madness scale. like the moment magnitude scale for earthquakes, the magnitude scale for madness has no defined upper limit. the advantage of such a scale is its openness for new, unexpected events. indeed, the “natural break points” for melanoma thickness have been topped by a new invention, “mitogenicity.” although this term is new, it has a relatively long history that needs to be told in order to convey a full sense for the comic. there was a time, not too long ago, when melanomas were said to begin as blue-black nodules usually resulting from malignant transformation of a nevus or “precancerous melanosis.” this misconception was caused, in part, by a phenomenon found in many types of malignancies, but especially commonly in malignant melanoma, to wit, genetic instability that causes new populations of cells to develop. in the mid 20th century, melanomas were hardly ever excised in the absence of exophytic nodules. the latter were often composed of sheets of large, strikingly atypical cells with many mitotic figures that differed markedly from the adjacent flat portion of the melanoma where cells were smaller, less atypical, and mitotic figures hard to find. those cytological differences furthered misinterpretation of the flat stage of melanoma as a benign precursor. in the 1950s and 60s, criteria began to be established that allowed the flat stage of melanoma to be recognized for what it was. [12] this, however, implied that melanoma growth was not a wholly quantitative process but also involved qualitative alterations reflected in the development of circumscribed nodules composed of different types of cells. those obvious qualitative changes were interpreted by clark and coworkers as evidence for the relatively new hypothesis of multistep carcinogenesis. the conviction that melanoma was a model for multistep carcinogenesis was the foundation on which all later concepts were built, ranging from dysplastic nevi to the radial and vertical growth phase. when clark in 1969 described the types of melanoma currently recognized, he noted that origin of melanoma from a nevus was “the exception rather than the rule.” [4] fifteen years later, in order to satisfy the concept of multistep carcinogenesis, he returned to the position that melanomas resulted from transformation of melanocytic nevi in what he called “six evident lesional steps of tumor progression,” namely, “1) the common acquired melanocytic nevus; 2) a melanocytic nevus with lentiginous melanocytic hyperplasia, i.e., aberrant differentiation; 3) a melanocytic nevus with aberrant differentiation and nuclear atypia, i.e., melanocytic dysplasia; 4) the radial growth phase of primary melanoma; 5) the vertical growth phase of primary melanoma; and 6) metastatic melanoma.” in regard to melanoma, he contended that “the radial growth phase is . . . not associated with metastasis, and it is hypothesized that such tumors do not have competence for metastasis. for a melanoma to acquire competence for metastasis it must progress to the next step of tumor progression—the vertical growth phase. this lesional step is characterized by the appearance of a new population of cells within the melanoma, not an expansion of the cells forming the pre-existing radial growth phase.” [13] in these words, clark described accurately the qualitative change that can be noted in the growth of many advanced melanomas. however, circumscribed nodules arising in the midst of a larger melanoma are not always formed by a different population of cells. in many melanomas, cells of the exophytic nodule and of the adjacent flat component look just the same. because those melanomas are also thick and associated commonly with metastases, clark had to change his definitions in order to adhere to the concept of growth phases as distinct biologic steps of tumor progression; the definition of the vertical growth phase had to be expanded and that of the radial growth phase constricted. clark still emphasized that “the vertical-growth phase may . . . give rise to cell populations commonly associated with metastatic disease, a phenomenon referred to as intralesional transformation,” but evidence of “intralesional transformation” was no longer required for the vertical growth phase. instead, clark made the pronouncement: “invasion to levels iii, iv, and v is, by definition, the vertical-growth phase.” [5] in other words, nature was no longer observed but defined, but that change in attitude allowed clark and co-workers to adhere to the concept of radial growth phase as a stage of “invasive melanoma lacking competence for metastasis.” [14] unfortunately, it turned out that level ii melanomas may also metastasize, and the definitions had to be changed again. david elder defined the vertical growth phase of melanoma by either “at least one cluster (nest) in the dermis that is larger than the largest intraepidermal cluster” or “presence of any mitoses in the dermal component of the melanoma.” [15] it was a long way from the point of origin of the concept of growth phases, namely, the authentic observation of a qualitative change in the growth of melanoma caused by development of a new population of cells, to the single mitotic figure in the dermis, and the desperate attempts to save the concept of “invasive melanoma lacking competence for metastasis” are a comedy in itself. the new definition of growth phases, however, caused the spotlight of attention to focus on mitotic figures. the value of mitotic figures as a gauge for prognosis of melanoma had been assessed before. for example, schmoeckel reported in 1983 that, in an “evaluation of clinical and histological prognosticators” of melanoma, “the most 60 essay | dermatol pract concept 2012;2(3):11 effective proved to be tumor thickness and mitotic activity.” [16] by contrast, mcgovern claimed that, “high mitotic activity . . . exerted only an indirect effect upon survival, tumour thickness being the most important prognostic determinant.” [17] in the 2001 version of the staging system for melanoma of the american joint committee on cancer (ajcc), mitotic figures were not mentioned at all [10]. then came the renaissance. in 2003, a group from the university of sydney reported results of an “analysis of 3661 patients from a single center,” according to which “tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma.” the influence of mitoses on the 10-year survival rate was most pronounced in thick melanomas but also significant in melanomas measuring ≤1 mm. most importantly, the authors noted “that patients with tumors recorded as having 0 mitoses/mm2 had significantly better survival than those with 1 mitosis/mm2.” [18] these findings, of course, were like wind for the mills of proponents of the new definition of growth phases. stimulated by the new data, they did not hesitate to reassess their own material in regard to mitoses and soon announced that, “a new prognostic factor, vgp mitogenicity, was identified.” the new term, “mitogenicity,” referred to melanomas “with a mitotic rate greater than zero.” of course, that term made no sense. one may refer to mitoses as being “tumorigenic,” because mitoses may be regarded as formative elements of the tumor, but to refer to a tumor as being “mitogenic,” implying that the tumor is the formative element of mitoses, is obviously absurd. yet, introduction of the new term may be regarded as a stroke of genius because “mitogenicity” sounds much more scientific than the paltry word, “mitosis.” the authors concluded that “mitogenicity, a feature of the vgp, is important beyond those factors that are used at present to stage thin melanomas. . . . our data support the incorporation of mitogenicity into the next version of ajcc staging for melanoma.” [19] that recommendation was heeded, one explanation probably being that applicants and decision-makers were more or less identical. as a consequence, “mitogenicity” found its way into in the “final version of 2009 ajcc melanoma staging and classification” that announced, “mitotic rate replaces level of invasion as a primary criterion defining t1b melanomas.” t1b melanomas were defined as melanomas measuring up to 1 mm in thickness that were either ulcerated or had a mitotic rate of ≥1/mm2. in regard to prognosis, the ajcc stated that, “the 10-year-survival rate was 95% for non-ulcerated t1 melanomas with a mitotic rate of less than 1/mm2 and dropped to 88% if the mitotic rate was at least 1/mm2.” based on those assumed differences in prognosis, the committee concluded that “sentinel lymph node biopsy . . . should be recommended selectively for patients with t1b melanomas.” [20] but how to assess mitotic rate? the ajcc requires the “hot spot approach” that was explained in a separate “protocol for the examination of specimens from patients with melanoma of the skin” in these words: “the recommended approach to enumeration of mitoses is to, first, find the area in the vertical growth phase containing most mitotic figures, the so-called hot spot. after counting the mitoses in the hot spot, the count is extended to adjacent fields until an area corresponding to 1 mm2 is assessed. if no hot spot can be found and mitoses are randomly scattered throughout the lesion, then several different, randomly chosen areas should be counted, summed, and the average listed as the mitotic rate. in tumors where the invasive component is less than 1 mm in area, an attempt may be made to extrapolate a rate per square millimeter.” [21] so far, so good—but you might now ask, “where is the comic?” when going to a comedy in your local theatre, you expect to be entertained, and the same can be expected from an article that promises, in its title, to reveal a new climax in the slapstick comedy of melanoma management. a little patience, please. . . . one comical aspect is that, in a classification advanced with the pretension to guide management of melanoma worldwide, factors influencing mitotic counts were not considered. the ajcc did not even specify whether counts should only include mitoses in the dermis, in keeping with the concept of “mitogenicity” as a “feature of the vertical growth phase,” or those in the epidermis as well. it did not specify whether only routine sections stained with hematoxylin and eosin were approved for assessment of mitotic rate, or whether other techniques were also permitted. immunohistochemical stains for mitotic figures (mf) are far more sensitive. for example, a recent study using “an antibody to phosphohistone h3 (phh3, ser10) that labels mfs in all stages of mitosis” revealed marked differences to the count of mitoses in h&e sections. “the mean mr was 1.63 by anti-phh3, and 0.67 for h&e, representing a mean increase of 243%.” [22] most importantly, the ajcc did not declare how many sections should be screened for presence of mitotic figures. it is evident that results may differ considerably if 10, rather than 5 or 2, sections are examined. there are many other factors that influence mitotic rate. one is time. mitoses usually take between 30 and 120 minutes, and the metaphase is much shorter. mitotic rate may, therefore, depend on whether or not a surgeon decides to make a coffee break before the next biopsy. in high-ploidy cells, metaphases have been found to be prolonged in time [23]. hence, the increased number of mitoses commonly found in nodules of melanoma composed of markedly atypical cells may be caused not only by enhanced proliferation but also by prolongation of the metaphase. once a melanoma has been excised, mitotic rate is influenced by fixaessay | dermatol pract concept 2012;2(3):11 61 tion. poor or delayed fixation results in a reduced mitotic rate. the decrease in counts of mitotic figures was said to be “largely due to their decreased identifiability, and only partly attributable to a completion of the cell cycle.” [24] identification of mitotic figures is often difficult and unreliable, especially in the case of thick sections or shrinkage artifacts caused by poor fixation or processing. it may be rendered impossible by crush artifacts. when a melanocyte in mitosis is discovered, it may be difficult to decide whether that cell is located at the junction or in the uppermost portion of papillary dermis. moreover, not every mitotic figure in a melanoma is produced by a neoplastic melanocyte. fibrocytes, endothelial cells, and inflammatory cells may also undergo mitosis, and when this happens in the substance of a melanoma, distinction from mitosis of a neoplastic melanocyte may be impossible; if additional sections are cut for immunohistochemistry, the mitotic figure in question is usually no longer visible. if there are many mitotic figures, all those problems are of little consequence because one can neglect a doubtful finding. the american joint committee on cancer, however, blinded by statistical computations, defined t1b melanomas by a mitotic rate of 1/mm2, and with that threshold, each doubtful finding can make a difference. in nearly all studies that evaluated reproducibility of histopathologic parameters, the interobserver reliability for mitotic rate was poor [25-27]. after having re-discovered the prognostic significance of mitotic figures, the melanoma group of the university of sydney also re-assessed interobserver reproducibility and came to a very different result. although reproducibility for mitotic rate was worse than for tumor thickness and ulceration, it was judged as being “excellent.” the authors attributed that deviation from results of previous studies to the advantages of the “hot spot approach.” they argued that, in most previous studies, “the number of mitoses in at least 10 hpfs over the entire lesion was determined and then expressed as the average number of mitoses/5 hpf. . . . as the number of mitotic figures often varies greatly between different parts of a tumor, . . . there is likely to be significant measurement error between observers.” [28] the authors were right: by focusing on the “hot spot” and then counting the total number of mitoses in the “hot spot” and adjacent fields corresponding to an area of 1 mm2, reproducibility of mitotic rate can be enhanced. however, they neglected a pitfall that they dug themselves and into which the entire melanoma group of the american joint committee on cancer fell in a slapstick comedy manner, namely, the consequences of combining the “hot spot approach” with a threshold of 1 mitotic figure. with the original approach, counting mitoses in a broad area and then giving an average number per 5 high power microscopic fields, a threshold of 1 mitotic figure might be meaningful because the average mitotic rate is usually lower in thin melanomas. with the “hot spot approach,” a threshold of 2 or more mitotic figures might also be meaningful because more than one mitotic figure in a circumscribed area implies enhanced proliferation. detection of a single mitosis, however, implies nothing. one mitotic figure can be found in any melanoma if one looks hard enough. it can be found in any nevus. in a recent study of banal melanocytic nevi, at least one mitotic figure was found in between 19.5 and 42.8% of cases, depending on whether sections were stained with hematoxylin and eosin or immunohistochemical markers for mitoses [29]. those numbers could have been raised to nearly 100% if lesions had been examined entirely. the high priests of melanoma prognostication love complex computations, but one easy computation has never been made by them: if a melanoma has a diameter of 1 cm, and the thickness of a histopathologic section is 5 μm, then one needs 10,000 through 5, equal 2000, sections to assess that lesion completely. of course, no pathologist can study 2000 sections thoroughly for presence of mitotic figures. instead, a few sections are studied, and if one mitosis is found, it could be the only one in the entire melanoma. if none is found in 10 or 20 sections, it could be found in section 1850. parenthetically, it has been known, since the 1850s, that the mode of propagation of cells in animals and plants is division. since more than a century, this is what one learns in the basic biology class in school. how can anybody, let alone professors of medicine, expect that a melanoma, i.e., a growing neoplasm, could be devoid of mitoses? how can anybody attach prognostic significance to a single mitotic figure? and yet, if a pathologist finds a single mitotic figure in a melanoma and then assesses mitotic rate by use of the “hot spot approach,” that mitotic figure is the hot spot. if, in accordance with the guidelines of the american joint committee on cancer, “the count is extended to adjacent fields until an area corresponding to 1 mm2 is assessed” and no more mitoses are found, the mitotic rate will automatically be ≥1/mm2 and will thus fulfill criteria for stage t1b. and what are t1a melanomas? there is a synonym for them, namely, “t1b melanomas in which mitoses have not been searched for long enough.” in other words, the new classification of thin melanomas is based entirely on chance, and lots of sweat, computations, and research dollars have been spent for nothing but a joke. isn’t that hilarious? with the new melanoma classification, the american joint committee on cancer has proved itself as a genuine joint comedy on cancer. but the best is still to come: proponents of that comedy on cancer had not the slightest idea what they were doing when setting the threshold for mitoses at ≥1/mm2. they were unaware of the circumstance that, by following the recommended “hot spot approach,” their own definition for t1b 62 essay | dermatol pract concept 2012;2(3):11 melanomas would be fulfilled by demonstration of a single mitotic figure. this is evidenced by the fact that they continued to speak of “mitotic rate” and “hot spot approach,” although there is no need to follow that approach in order to classify a melanoma as t1a or t1b [20]. once a single mitotic figure is found, the work is done. that this was never considered qualifies “mitogenicity” for a straight 9 on the limitless madness scale (which is much more than the 8.5 for “natural break points for primary-tumor thickness” because that scale is logarithmic). earthquakes of similar magnitude have been recorded only rarely. the latest one of the very few in history that reached a magnitude of 9 on the moment magnitude scale was the sendai earthquake in japan. the devastation that followed was terrible, but it was not caused chiefly by the original quake but subsequent events, such as a tsunami, an explosion in a nuclear power plant, and several aftershocks. likewise, “mitogenicity,” the latest eruption on the limitless madness scale for melanoma, has been followed by comical aftershocks of lower magnitude that may have serious consequences. despite its limitations, the new ajcc classification, including “mitogenicity,” might have some limited value for statistical evaluations. as a finding based principally on chance, however, “mitogenicity” can never be used for decision-making in individual cases. curiously, that obvious fact was not appreciated by the ajcc, according to which “sentinel lymph node biopsy . . . should be recommended selectively for patients with t1b melanomas.” [20] the story of sentinel lymph node biopsy is yet another comical episode in melanoma management; although it has import only for staging and has not been shown to have any therapeutic effect, it is “offered” to patients as if it would do them any good [30]. for an individual patient with a thin melanoma, however, demonstration of a single mitotic figure, possibly the only one in hundreds of sections, may have drastic consequences. according to the new classification, that melanoma must be classified as stage t1b and may result in a sentinel lymph node biopsy. if that biopsy is assessed in accordance with the new ajcc staging system that “considers it acceptable to classify nodal metastases solely on the basis of ihc staining,” a few cells stained with “at least one melanomaassociated marker” qualify as stage n1, and all too often result in prophylactic lymph node dissections [20]. the latter are associated with significant morbidity but do not reduce mortality because, even in the case of nodal metastases, removal of lymph nodes does not affect metastases in internal organs from which patients eventually die [31]. in brief, detection of a single mitotic figure may cause harm and distress, and if one such figure is present in the few sections of a thin melanoma that are being examined, patients can only hope that it is overlooked by the pathologist. one may now ask whether that new climax in the comedy of melanoma management is truly comical, whether it is ridiculous or sad, whether it should make us laugh or cry. those opposites, however, do not exclude one another. already aristotle pointed out that “comedy deals in the risible, and the risible is an aspect of the shameful, the ugly, or the base.” [2] in the middle ages, french physician laurent joubert noted that we laugh at “something that strikes us as ugly, deformed, dishonest, indecent, malicious and scarcely decorous,” especially at deeds or sayings “which have the appearance of ugliness without being pitiable.” in joubert’s view, laughter was always related to joy but could never be joy unalloyed because some measure of scorn or dislike for baseness and ugliness could not be avoided. “given that everything which is ridiculous arises from ugliness and dishonesty,” joubert argued, it follows that “anything ridiculous gives us pleasure and sadness combined.” [32] although laughter is not only caused by the ridiculous but may also be an expression of pure joy, those observations had substance and exerted a profound influence on the perception of comic and laughter. laughter was thought of chiefly as “a subdivision of the base,” an expression of scorn for certain vices. although aristotle had insisted that the vices deserve to be reproved and laughter, therefore, had a moral role to play in our lives, laughter came to be perceived with distaste [2]. thomas hobbes criticized those who “think the infirmities of another sufficient matter for his triumph” [33] and referred to laughter as an expression of weakness, “a sign of pusillanimity“ that was “incident most to them, that are conscious of the fewest abilities in themselves; who are forced to keep themselves in their own favour, by observing the imperfections of other men.” [34] in his view, laughter was a form of incivility and needed to be eliminated or at least controlled [2] is it a form of incivility to speak of a “slapstick comedy of melanoma management” and of an “american joint comedy on cancer”? as a matter of fact, the comedians and their comedy fulfil all requirements for the ridiculous, but is it not impolite to ridicule them? after all, they are colleagues who intend to accomplish their tasks in serious fashion and who, in many fields, may be smarter than the one mocking them. laughter at the expense of others has always aroused mixed feelings and has often been reproached. for example, when the prime father of physicians, hippocrates, was once called to democritus, the “laughing philosopher,” he found the latter laughing in the face of citizens weeping for him. hippocrates first took democritus to task for his insensitivity, but democritus explained that, “i am laughing only at mankind, full of folly,” and at a world in which men occupy themselves “with matters of no value, and consume their lives with ridiculous things.” when hippocrates left him, he was deeply impressed by “the very wise democritus, essay | dermatol pract concept 2012;2(3):11 63 who alone is capable of giving wisdom to everyone in the world.” [2] that’s what laughter about the ridiculous is about. it is not personal but laughter at the folly of mankind. and it fulfils a function, namely, imparting wisdom, if only a little grain of it. for that purpose, mock is often better suited than serious debate. george meredith noted that “the laughter of satire is a blow in the back or the face,” whereas “the laughter of comedy is impersonal and of unrivalled politeness, nearer a smile; often no more than a smile.” the comedy of melanoma management would not have been to the taste of meredith because it is a slapstick comedy. its jokes are far too obvious for the refined senses of an english gentleman of the 19th century, and the laughter created by them lingers between that of satire and comedy. nevertheless, presentation of melanoma management as the comedy that it is may stand meredith’s “test of true comedy,” namely, “that it shall awaken thoughtful laughter.” [1] some thoughts arising from that laughter might have a salutary effect on melanoma management. references 1. meredith g. an essay on comedy and the uses of the comic spirit. westminster: archibald constable and company, 1897:25. 2. skinner q. hobbes and the classical theory of laughter. in: sorell t, foisneau l (eds.). leviathan after 350 years. oxford: oxford university press, 2004:139-66. 3. weyers w. excision of melanoma in historical perspective—triumph of irrationality for nearly a century. dermatopathology & conceptual. 1997;3(3):238-46. 4. clark wh jr, from l, bernardino ea, mihm mc. the histogenesis and biologic behavior of primary human malignant melanoma of the skin. cancer res. 1969; 29(3):705-27. 5. clark wh jr, ainsworth am, bernardino ea, yang ch, mihm mc jr, reed rj. the developmental biology of primary human malignant melanomas. sem oncol. 1975;2(2):83-103. 6. kunte c, geimer t, baumert j, et al. prognostic factors associated with sentinel lymph node positivity and effect of sentinel status on survival: an analysis of 1049 patients with cutaneous melanoma. melanoma res. 2010;20(4):330-7. 7. kerns mjj, darst ma, olsen tg, fenster m, hall p, grevey s. shrinkage of cutaneous specimens: formalin or other factors involved? j cutan pathol. 2008;35(12):1093-6. 8. hudson-peacock mj, matthews jns, lawrence cm. relation between size of skin excision, wound, and specimen. j am acad dermatol. 1995;32(6):1010-15. 9. breslow a. thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. ann surg. 1970;172(5):902-8. 10. balch cm, buzaid ac, soong sj, et al. final version of the american joint committee on cancer staging system for cutaneous melanoma. j clin oncol. 2001; 19(16):3635-48. 11. day cl, lew ra, mihm mc jr,. the natural break points for primary-tumor thickness in clinical stage 1 melanoma. new engl j med. 1981;305(19):1155. 12. weyers w. criteria for diagnosis of melanoma histopathologically in historical perspective. dermatopathology: practical & conceptual. 2002;8(4):8. 13. clark wh jr, elder de, guerry d iv, epstein mn, greene mh, van horn m. a study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. hum pathol. 1984;15(12):1147-65. 14. elder de, guerry d iv, epstein mn, et al. invasive malignant melanomas lacking competence for metastasis. am j dermatopathol. 1984;6 suppl 55-61. 15. elder d, elenitsas r. benign pigmented lesions and malignant melanoma. in: elder d, elenitsas r, jaworsky c, johnson b jr (eds.). lever’s histopathology of the skin. 8th ed. philadelphia, new york: lippincott-raven, 1997:656. 16. schmoeckel c, bockelbrink a, bockelbrink h, koutsis j, braunfalco o. lowand high-risk malignant melanoma—i. evaluation of clinical and histological prognosticators in 585 cases. eur j cancer clin oncol. 1983;19(2):227-35. 17. mcgovern vj, shaw hm, milton gw, farago ga. prognostic significance of the histological features of malignant melanoma. histopathology. 1979;3(5):385-93. 18. azzola mf, shaw hm, thompson jf, et al. tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma. an analysis of 3661 patients from a single center. cancer. 2003;97(6): 1488-98. 19. gimotty pa, elder de, fraker dl, et al. identification of highrisk patients among those diagnosed with thin cutaneous melanomas. j clin oncol. 2007;25(9):1129-34. 20. balch cm, gershenwald je, soong sj, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199-206. 21. frishberg dp, balch c, balzer bl, et al. protocol for the examination of specimens from patients with melanoma of the skin. arch pathol lab med. 2009;133(10):1560-7. 22. casper dj, ross ki, messina jl, et al. use of anti-phosphohistone h3 immunohistochemistry to determine mitotic rate in thin melanoma. am j dermatopathol. 2010;32(7):650-4. 23. de la hoz c, baroja a. proliferative behaviour of high-ploidy cells in two murine tumour lines. j cell sci. 1993;104 (pt 1):31-6. 24. donhuijsen k, schmidt u, hirche h, van beuningen d, budach v. changes in mitotic rate and cell cycle fractions caused by delayed fixation. hum pathol. 1990;21(7):709-14. 25. larsen te, little jh, orell sr, prade m. international pathologists congruence survey on quantitation of malignant melanoma. pathology. 1980;12(2):245-53. 26. heenan pj, matz lr, blackwell jb, et al. inter-observer variation between pathologists in the classification of cutaneous malignant melanoma in western australia. histopathology. 1984;8(5): 717-29. 27. cook mg, clarke tj, humphreys s, et al. the evaluation of diagnostic and prognostic criteria and the terminology oft hin cutaneous malignant melanoma by the crc melanoma pathology panel. histopathology. 1996;28(6):497-512. 28. scolyer ra, shaw hm, thompson jf, et al. interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas. am j surg pathol. 2003;27(12):1571-6. 29. glatz k, hartmann c, antic m, kutzner h. frequent mitotic activity in banal melanocytic nevi uncovered by immunohistochemical analysis. am j dermatopathol. 2010;32(7):643-9. 30. gimotty pa, yoon f, hammond r, rosenbaum p, guerry d iv. therapeutic effect of sentinel lymph node biopsy in melanoma remains an open question. j clin oncol. 2009;27(26):4236-8. 64 essay | dermatol pract concept 2012;2(3):11 31. meier f, will s, ellwanger u, et al. metastatic pathways and time course in the orderly progression of cutaneous melanoma. br j dermatol. 2002;147(1):62-70. 32. joubert l. traité du ris, contenant son essance, ses causes, et mervelheus essais, curieusemant recherchés, raisonnés & observés. paris, 1579:16ff. 33. hobbes t. the elements of law natural and politic. edited by ferdinand tönnies, 2nd ed. london: m.m. goldsmith, 1969: 42. 34. hobbes t. leviathan. revised student edition edited by richard tuck. cambridge: cambridge university press, 1996:43. dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(1):e2022018 1 collagen supplements for aging and wrinkles: a paradigm shift in the fields of dermatology and cosmetics hend al-atif1 1 college of medicine, king khalid university, saudi arabia key words: aging, oral collagen, topical collagen, collagen supplements, wrinkling citation: al-atif h. collagen supplements for aging and wrinkles: a paradigm shift in the fields of dermatology and cosmetics. dermatol pract concept. 2022;12(1):e2022018. doi: https://doi.org/10.5826/dpc.1201a18 accepted: may 26, 2021; published: january 2022 copyright: ©2022 hend al-atif. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. corresponding author: hend al-atif, college of medicine, king khalid university, saudi arabia. e-mail: hmsalatif@yahoo.com introduction: slowing the aging process by use of collagen supplements has become a driving force in the field of dermatology and cosmetics. generally, oral and topical collagen are used in anti-aging products, as reported in the literature. objectives: the overarching goal of this research is to collate the consequences of oral collagen with those of topical collagen in reducing or delaying the aging process. methods: we executed an electronic search in google scholar and pubmed. we considered a study eligible if it was original research, published in english between 2010 and 2020, and if it provided information on the topic of collagen and aging. we retrieved 12 full-text articles, and these were assessed by reviewers independently. results: all human studies included in the review were randomized controlled trials mainly conducted in highto middle-income countries which highlighted that both oral and topical collagen supplements help to delay the aging process, with no differences arising between the two types of collagen. the evidence from the reviewed studies suggested that both collagen supplements improve skin moisture, elasticity, and hydration when orally administered. additionally, collagen reduces the wrinkling and roughness of the skin, and existing studies have not found any side effects of its oral supplements. conclusions: both oral and topical collagen can contribute to reducing or delaying skin aging. future epidemiological studies with large sample sizes and thorough follow-up measures would be required to comprehensively understand the potential effects of these two types of collagen on the aging process. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022018 introduction aging of the skin is a continuous process related to a depletion in the physiological function of the skin [1]. both natural and unnatural factors cause human beings and animals to experience physiological alterations in different organs as time passes [2]. cutaneous aging is a multifactorial activity dependent on both inherent (genetic, hormonal, and metabolic), and extrinsic factors (perennial exposure to uv rays, smoking, air pollution, chemicals and poor nutrition) [3,4]. aging has a detrimental effect on connective tissue in the skin, leading to declines in elastin and collagen fibers and thus resulting in fine lines and wrinkles [3]. furthermore, aging reduces the production of proteoglycans and glycosaminoglycan (such as hyaluronic acid) in the skin, as well as cartilage [4]. as a result, skin tissue weakens, losing its integrity, and the skin becomes dry, unable to retain enough moisture. although multiple intrinsic processes can affect the aging process, factors such as exposure to sun, liquid intake, lifestyle, and pollution can exacerbate the aging process [1]. moreover, skin wrinkling also progresses as dermal thickness is reduced over time due to decreased collagen [5,6].  most of the collagen supplements recommended by experts are enriched with peptides containing amino acids including proline, glycine, and hydroxyproline considered to be essential components of collagen [7-9]. beyond this, researchers have claimed that increasing peptide production of hyaluronic acid in skin fibroblasts induces fibroblast migration and strengthens collagen, thus raising the amount of moisture in the stratum corneum [10]. hence, the existing data suggest that the presence of these proteins in the body helps to maintain the amount of collagen in the skin [10]. furthermore, collagen is considered crucial for skin health because both photo-aging and intrinsic aging decrease its presence in the body [11]. this in turn causes a decrease in the skin thickness, as well as a loss of elasticity and flexibility [12]. in recent years, collagen supplements have been increasingly used, as they are advertised as a potential remedy against the aging process [13]. it has been found that marine fish collagen has homology with human collagen and therefore it has been widely utilized as nutritional addendum along with collagen peptides [14]: they have a very good safety profile, biocompatibility, high bioavailability in the human gastrointestinal barrier, safety, and high bioactivity [15]. objectives current research reveals that collagen use could result in a reduction of wrinkles, rejuvenation of skin, and reversal of skin aging [16], which may improve skin hydration and elasticity [17]. however, the available evidence regarding types of collagen or its mechanism of action, duration to produce desired results and side effects have not been rigorously reviewed or synthesized. this could create controversy in using collagen to reverse the aging process. moreover, it is yet unclear which type of collagen (topical or oral) needs to be used to produce these coveted effects. therefore, we undertook this research to collate the consequences of oral collagen with those of topical collagen in reducing or delaying the aging process. methods the researcher conducted this research to appraise, synthesize, and aggregate the available evidence to measure how both oral and topical collagen are used to reduce or delay the aging process. inclusion and exclusion criteria the researcher carried out an electronic search on different attributes of collagen, such as the benefits of collagen supplements, types, mechanisms of action, and side effects, as well as how long it takes to produce results. study inclusion eligibility was contingent on whether the research had focused the effects of collagen supplements on aging reversal and whether it was an original study published in english from 2010 to 2020 across both developed and developing countries. the researcher excluded secondary data, letters to the editor, case reports, and gray literature from this review. information sources and search strategy  the research was conducted by the researcher who completed a search of published articles in 2020, scanning databases such as pubmed and google scholar. an independent search was carried out by the author, who examined the results for potentially appropriate studies, retrieving any needed full-text articles. the researcher grouped search terms into 4 major categories by picos (population, intervention, comparison, outcomes and study) design as a framework to formulate eligibility criteria. the researcher identified a combination of medical subject heading (mesh) keywords and text words. the most prevalent search terms found in abstracts and titles included the following: “collagen supplement and aging,” “collagen supplement and wrinkles,” “role of collagen supplement in skin rejuvenation, “collagen supplement and aging reversal,” “benefits of collagen supplements in reducing aging,” “types of collagen in reducing aging,” “mechanism of collagen supplements in reducing aging” and “side effects of collagen supplements used for anti-aging”. data extraction  all appropriate research studies were imported into the reference manager software (endnote, clarivate analytics) file, where each study was reviewed, and titles were also screened for duplicates. the abstracts were not considered for further original article | dermatol pract concept. 2022;12(1):e2022018 3 review, which did not explicitly explore the study objective. finally, the full-text articles of the remaining germane articles were obtained and examined. this action was followed by abstracting and summarizing the articles that met the eligibility criteria using a proforma standard. aside from this, the bibliography of the remaining studies was scrutinized to avoid missing any useful studies. this process of searching the articles was carried out independently by the author, and their judgments and extracted summaries were matched to identify the differences and to resolve them accordingly. independent reviewers filled out a standardized data extraction sheet for the eligible research articles. the reviewers compared the data extraction tables to ensure including the imperative findings of the eligible studies and pilot tested these sheets before beginning the extraction process. besides, prevailing research articles on the chosen topic were reviewed to describe the data extraction proforma objectives. any discrepancies between the independent reviewers were resolved by consensus between two other reviewers.  results decisions reached regarding the search strategy  the researcher screened the identified articles initially by titles, then by abstracts, and finally, a full-text article assessment was carried out, discarding any articles not meeting the pre-defined eligibility criteria. as a result, the initial search identified 820 citations in pubmed and google scholar; however, 150 articles were duplicates. of the remaining 670 unique studies, the researcher reviewed titles and abstracts, finding 150 relevant abstracts. upon reviewing the latters, 135 articles did not meet the eligibility criteria. hence, the researcher was able to retrieve the complete texts of 15 articles, though more than 12 articles met the necessary criteria and were included in the review, as shown in figure 1. usage of oral collagen supplements: evidence from human studies a study was conducted in japan in which authors gave collagen peptides to patients with aging, wrinkled skin (table 1). these patients included 66 women from japan who were more than 40 years old, about whom researchers recorded any improvements in skin parameters. these patients were given either 10 g of collagen for 56 continuous days or no treatment at all (placebo) [18]. the authors observed a statistically noteworthy dissimilarity in the moisture of the skin throughout the experiment, accompanied by a substantial increase in the moisture for the group under treatment when compared with the placebo group. skin moisture analyzers were utilized to test skin moisture; they are portable devices that test different skin factors utilizing records identified through data base searching n=820 after removal of duplicate studies n=150 number of unique studies n=670 number of relevant abstracts n=150 number of full texts n=15 number of articles included in the review n=12 in c lu d ed el ig ib il it y sc r ee n in g id en ti fi c a ti o n eligibility criteria not met n=3 eligibility criteria not met n=135 number of irrelevant titles and abstracts n=520 figure 1. flow chart summarizing the identification and selection of papers. 4 original article | dermatol pract concept. 2022;12(1):e2022018 bioelectric impedance analysis. the level of skin moisture is ascertained by the time it takes for the current to travel across the skin. additionally, the same study enrolled french women of more than 40 years old and followed a similar protocol for collagen treatment for about 3 continuous months. at the completion of treatment, the author found a noteworthy moisture elevation in the collagen treatment group compared with the placebo group [18]. moving forward, researchers undertook a randomized controlled trial (rct) in order to evaluate the potency of collagen peptides [19]. recruited participants were randomly assigned to ingest either oral liquid supplements containing collagen peptides (50 ml) or placebo daily for 12 weeks [19]. no noteworthy dissimilarity in skin elasticity was noticed between the 2 arms (table 1). however, in the subgroup analysis, the authors noticed that study participants who underwent cosmetic surgeries in the treatment group showed improvement in skin elasticity, as opposed to their counterparts, who showed no improvement. at the completion of the study, participants in the therapeutic arm achieved higher marks in some skin parameters like hydration and elasticity [19]. in another rct, women were allocated to 4 different arms [20]. the first arm received 2.5 grams of collagen hydrolysate, the second arm was given 5.0 grams of collagen hydrolysate, the third arm received 2.5 grams of a placebo, and the fourth arm was given 5.0 grams of placebo [20]. participants were followed for around 60 days, and it was found that each treatment arm with a different dose of collagen hydrolysate showed a statistically noteworthy rise in the elasticity of the skin when juxtaposed with their counterparts in 2 placebo groups. improvement in elasticity was noticed among elderly women relatively earlier (ie, at 1-month follow-up) [20]. furthermore, a positive correlation was observed between treatment with collagen hydrolysate and skin moisture and evaporation, with statistically insignificant results [20]. another double-blinded rct was undertaken to assess the collagen (with low molecular weight) effects on the elasticity of the skin elasticity, hydration, and finally wrinkling [21]. this study was conducted with korean women at least 40 years old (n = 64) who were randomized to 1000 mg of collagen or to placebo every day for 3 months [21]. the authors found noteworthy elevations in skin hydration in the treatment arm even at 6 weeks of follow-up when compared to the placebo group. furthermore, different parameters of skin wrinkling (all 3 parameters) and skin elasticity (1/3 parameters) were notably elevated in the treatment arm when compared with the placebo group, as shown in table 1 [21]. in the same vein, 1 more rct was conducted to find out the effects of collagen hydrolysate constituted of the bioactive dipeptides, prolylhydroxyproline, and hydroxypropylglycine on chinese women (n = 85) of at least 35 years of age [22]. the study was comprised of 3 main groups: 1 was randomized to receive collagen peptides (higher content), 1 was randomized to collagen peptides (lower content), and the last group received placebo [22]. the total duration of the study was roughly 2 months, and participants took their respective treatments daily. both intervention arms demonstrated substantial improvement in skin moisture, especially around the cheek and canthus, as opposed to the placebo group, which displayed no such improvements. moreover, the findings also showed a substantial increase in the moisture and elasticity of the skin, as well as a reduction in wrinkling and roughness in the first treatment group, unlike either the second or the placebo groups, as shown in table 1 [22]. usage of oral collagen supplements: evidence from animal studies apart from studies conducted on human beings, animals have been examined as well to assess the effect of collagen [23]. in animal models, the authors have used clinical and histological appearance, along with gene expression, to study the necessary outcomes. one research was carried out to assess the consequences of collagen hydrolysates on 9-month-old mice for 24 weeks. the results of the study revealed a significant increase in both distribution and density of said collagen and ratio between type i and type iii collagen, with a particular dose-response relationship [23]. in another study, collagen peptides were given to mice for one and a half months [24]. the authors found a higher expression of genes, along with their upregulation in the skin [24]. one more study was conducted on mice, in which they were fed a diet containing collagen hydrolysate for roughly 3 months. the study revealed improvements in the water content of their skin and an increase in elasticity, as opposed to the mice in the control group, who experienced no such benefits [25]. lastly, mice were observed on a diet rich in prolylhydroxyproline and hydroxypropylglycine for around 5 weeks in one more study. the mice that received collagen hydrolysates showed increased skin hydration [26].  usage of topical collagen application on delaying the aging process generally, there have been fewer studies assessing the effect of topical collagen on the aging process when compared with the studies conducted for oral collagen supplements. for instance, one conducted by sanz et al in 2015 revealed that those women who were asked to apply a product containing collagen performed better than those in the control group [27]. more specifically, around three quarters of the treated women showed anti-wrinkling effects and substantial increases in the dermal density and elasticity of their skin after 7 days of treatment [27]. similarly, matthias et al conducted a retrospective study in germany and south africa on 480 original article | dermatol pract concept. 2022;12(1):e2022018 5 ta b le 1 . p re vi o u s u sa ge o f o ra l c o ll ag en s u p p le m en ts : e vi d en ce f ro m h u m an s tu d ie s s tu d y a u th o r s tu d y y e a r c o u n tr y s tu d y d e si g n s a m p le s iz e p a rt ic ip a n ts a g e ( y e a rs ) in te rv e n ti o n c o n tr o l a rm s tu d y r e su lt s a d v e rs e e ff e ct s sa n gs u w an et a l [4 0 ] 2 0 2 0 t h ai la n d r c t 3 6 p o st m en o p au sa l w o m en 5 0 -6 0 5 g ra m s o f o ra l co ll ag en h yd ro ly sa te p la ce b o ‐ s k in e la st ic it y w a s fo u n d t o b e si g n if ica n tl y d if fe re n t b et w ee n i n te rv en ti o n a n d co n tr o l gr o u p s. n o n e ž m it ek et a l [3 9 ] 2 0 2 0 g er m an y r c t 3 4 c au ca si an h ea lt h y fe m al es 4 0 –6 5 1 0 m l o f a sy ru p h av in g fi sh c o ll ag en an d o th er a ct iv e in gr ed ie n ts 1 0 m l o f co lo re d p la ce b o h av in g fl av o rs w it h o u t ac ti ve in gr ed ie n ts ‐ d er m is d en si ty w as i m p ro ve d . ‐ p er io rb it al w ri n k le a re a w as r ed u ce d ‐ im p ro ve m en t in s k in s m o o th n es s. ‐ sk in h yd ra ti o n i m p ro ve d . ‐ d er m is t h ic k n es s, t ra n sep id er m al w at er lo ss a n d v is co el as ti ci ty d id n o t im p ro ve . n o n e c am p o s et a l [2 9 ] 2 0 1 9 r c t 6 0 h ea lt h y st u d y p ar ti ci p an ts 4 0 -5 0 t o p ic al a n d h yd ro ly ze d co ll ag en p la ce b o i n o ra l fo rm ‐ t o p ic al c o ll ag en i m p ro ve d s k in e la st ic it y an d v is co el as ti ci ty p ar am et er s. ‐ sk in e la st ic it y, h yd ra ti o n a n d e ch o ge n ic it y o f d er m is w er e im p ro ve d a ft er 1 m o n th o f to p ic al c o ll ag en a p p li ca ti o n , as w el l as o ra l co ll ag en . n o n e b o lk e et a l [4 1 ] 2 0 1 9 g er m an y r c t 7 2 h ea lt h y fe m al es ≥ 3 5 2 .5 g ra m s o f co ll ag en a n d o th er a ct iv e in gr ed ie n ts p la ce b o ‐ h yd ra ti o n o f sk in , el as ti ci ty a n d d en si ty w er e im p ro ve d . ‐ t h er e w as r ed u ct io n i n s k in r o u gh n es s. ‐ a ll t es t p ar am et er s w er e d if fe re n t b et w ee n in te rv en ti o n a n d p la ce b o g ro u p s, w h ic h al so r em ai n ed a t th e ti m e o f fo ll o w -u p . n o n e k im e t al [2 1 ] 2 0 1 8 k o re a r c t 6 4 k o re an w o m en 4 0 –6 0   c o ll ag en w it h lo w m o le cu la r w ei gh t p la ce b o   ‐ t h e in te rv en ti o n g ro u p s h o w ed i m p ro ve m en t in t h e h yd ra ti o n v al u es o f sk in a t 6 an d 1 2 w ee k s. ‐ t h re e p a ra m et er s o f sk in w ri n k li n g im p ro ve d d ra st ic al ly i n t h e in te rv en ti o n , a s o p p o se d t o t h e p la ce b o . ‐ 1 /3 p ar am et er s im p ro ve d s u b st an ti al ly i n th e in te rv en ti o n g ro u p a ft er 1 2 w ee k s as o p p o se d t o p la ce b o g ro u p . ‐ 2 /3 p a ra m et er s in t h e in te rv en ti o n a rm im p ro ve d a ft er 1 2 w ee k s. n o n e t ab le 1 c o n ti n u es 6 original article | dermatol pract concept. 2022;12(1):e2022018 s tu d y a u th o r s tu d y y e a r c o u n tr y s tu d y d e si g n s a m p le s iz e p a rt ic ip a n ts a g e ( y e a rs ) in te rv e n ti o n c o n tr o l a rm s tu d y r e su lt s a d v e rs e e ff e ct s in o u e et a l [2 2 ] 2 0 1 7 c h in a r c t 8 5 c h in es e w o m en 3 5 –5 5   c o ll ag en h yd ro ly sa te h av in g a h ig h er c o n te n t o f b io ac ti ve co ll ag en c o ll ag en h yd ro ly sa te h av in g a lo w er c o n te n t o f b io ac ti ve co ll ag en p la ce b o ‐ t h e in te rv en ti o n a rm d em o n st ra te d a s ig n if ic a n t im p ro v em en t o v er t h e p la ce b o ar m i n m o is tu re , el as ti ci ty , w ri n k le s, a n d ro u gh n es s. n o n e g en o ve se et a l [1 9 ] 2 0 1 7 r o m e (i ta ly ) r c t 1 2 0 f :1 1 1 m : 9 v o lu n te er su b je ct s 4 7 .7 2 ( 6 .5 ) 4 9 .6 5 ( 6 .5 ) 5 0  m l o f co ll ag en p la ce b o ‐ -n o d if fe re n ce w as s ee n b et w ee n t h e in te rve n ti o n a n d p la ce b o a rm s fo r sk in e la st ic it y. -s u b je ct s w h o h a d c o sm et ic s u rg er ie s d em o n st ra te d i n cr ea se d s k in e la st ic it y. n o ad ve rs e ev en ts sa n z et a l [2 7 ] 2 0 1 5 sp ai n o p en a n d in tr a‐ in d iv id u al st u d y cl in ic al st u d y 3 2 w o m en w o m en w it h se n si ti ve sk in b ea ri n g w ri n k le s 4 5 -5 5 (m ed ia n : 4 9 ) se ru m c o n ta in in g an a m al ga m at io n o f p ro ‐c o ll ag en li p o p ep ti d e, ex tr ac t o f ap p le , cr ea ti n e, a n d u re a se lf -c o n tr o l ‐ 7 1 % o f th e w o m en i n t h e in te rv en ti o n gr o u p e x p er ie n ce d a n ti -w ri n k le e ff ec ts . ‐ d e rm a l d e n si ty i m p ro v e d b y 1 1 % af te r 1 w ee k . ‐ si gn if ic an t im p ro ve m en t w as s ee n in c u ta n eo u s h yd ra ti o n a n d c u ta n eo u s el as ti ci ty (c h ee k b o n e) a ft er 1 w ee k w h en c o m p ar ed w it h b as el in e. n o t re p o rt ed a ss er in et a l [4 2 ] 2 0 1 5 ja p an an d f ra n ce r c t 6 6 ja p an es e an d 1 0 6 f re n ch w o m en ja p an es e an d f re n ch w o m en 4 0 ‐5 9   4 0 ‐6 5 1 0 g o f co ll ag en p la ce b o ‐ si gn if ic an t im p ro ve m en t in s k in h yd ra ti o n an d d er m is d en si ty a ft er 8 w ee k s o f in ta k e ‐ a s ig n if ic a n t re d u ct io n w a s se en i n t h e fr a g m en ta ti o n o f th e d er m a l co ll a g en n et w o rk . n o n e p ro k sc h et a l [2 0 ] 2 0 1 3 n o t re p o rt ed r c t  6 9 w o m en 3 5 ‐5 5  y ea rs o ld 2 .5  g o f c h , a n d 5 .0  g o f c h 2 .5  g o f p la ce b o , an d 5 .0  g o f p la ce b o ‐ a s ig n if ic a n t im p ro v em en t w a s se en i n el as ti ci ty o f sk in in b o th in te rv en ti o n a rm s, as c o m p ar ed t o t h e p la ce b o a rm . ‐ e ld er ly w o m en s h o w ed a s ta ti st ic al ly s ig n if ic an tl y h ig h er s k in e la st ic it y le ve l. ‐ n o e ff ec t o f c h w as s ee n o n s k in h yd ra ti o n a n d e va p o ra ti o n . n o n e ta b le 1 . p re vi o u s u sa ge o f o ra l c o ll ag en s u p p le m en ts : e vi d en ce f ro m h u m an s tu d ie s (c o n ti n u ed ) t ab le 1 c o n ti n u es original article | dermatol pract concept. 2022;12(1):e2022018 7 s tu d y a u th o r s tu d y y e a r c o u n tr y s tu d y d e si g n s a m p le s iz e p a rt ic ip a n ts a g e ( y e a rs ) in te rv e n ti o n c o n tr o l a rm s tu d y r e su lt s a d v e rs e e ff e ct s b yr n e et a l [3 0 ] 2 0 1 0 ir el an d r c t 2 2 c au ca si an fe m al e su b je ct s 3 9 t o 6 0 t ri p le p ep ti d e co m p le x ( 3 % ) p la ce b o ‐ t h er e w a s su b st a n ti a l re d u ct io n i n t h e fr eq u en cy o f w ri n k le s, t o ta l w ri n k le s u rfa ce a ve ra ge , w ri n k le l en gt h a n d a ve ra ge w ri n k le d ep th i n t h e in te rv en ti o n g ro u p , as o p p o se d t o p la ce b o g ro u p . ‐ t h er e w a s im p ro v em en t in t h e w ri n k le p ar am et er s b y 1 0 –1 9 % c o m p ar ed w it h th e u n tr ea te d b as el in e, a n d t h is i m p ro ve m en t w as 1 3 –2 8 % w h en c o m p ar ed t o t h e p la ce b o g ro u p . n o n e a u st e t al [2 8 ] 2 0 0 8 g er m an y r et ro sp ec ti ve an al ys is 4 8 0 f : 4 0 0 m : 8 0 p at ie n ts t h e m ea n (s d ) w as 4 9 ± 1 5 .5 y ea rs p er cu ta n eo u s co ll ag en se lf -c o n tr o l ‐ t h er e w as i m p ro ve m en t in t h e sk in b y 6 0 to 8 0 % . ‐ a s u b st an ti al u p su rg e in c o ll ag en a n d e la sti n d ep o si ti o n o n h is to lo gi ca l e x am in at io n w as o b se rv ed i n t h e su b se t o f p at ie n ts . ‐ t h er e w as a r o u gh ly 4 0 % t h ic k en in g o f th e ep id er m is m ai n ly s tr at u m s p in o su m af te r 1 y ea r o f tr ea tm en t. n o t re p o rt ed c h = c o ll ag en h yd ro ly sa te ; sd = s ta n d ar d d ev ia ti o n ; r c t = r an d o m iz ed c o n tr o l tr ia l. ta b le 1 . p re vi o u s u sa ge o f o ra l c o ll ag en s u p p le m en ts : e vi d en ce f ro m h u m an s tu d ie s (c o n ti n u ed ) 8 original article | dermatol pract concept. 2022;12(1):e2022018 patients with wrinkles, lax skin, scarring, and stretch marks [28]. these patients were administered percutaneous collagen after preparing their skin with necessary vitamins and creams for at least 1 month [28]. the findings demonstrated that patients were found to have skin 60% to 80% improved from before the treatment. furthermore, researchers carried out a histologic examination on a subset of patients that demonstrated a substantial upsurge in collagen and elastin deposition. there was around 40% thickening of the epidermis, mainly stratum spinosum, 1 year after treatment [28]. similarly, campos et al evaluated the consequences of topical and oral collagen additions in the skin enhancement of 60 healthy female subjects. the findings showed that females who were given a topical product demonstrated a substantial rise in skin hydration and elasticity at the end of 1 month. on the other hand, the group with oral supplementation showed more noticeable results in dermal echogenicity and decreasing pore size at the end of 3 months without any adverse effects [29]. another study demonstrated that those patients who received topical treatment showed a noteworthy depletion in the total wrinkle surface, number of wrinkles, and average wrinkle length and depth were observed in comparison with those who underwent placebo.  in addition, the anti-wrinkle activity of the topical triple peptide complex (3%) has been reported by a clinical research conducted by byrne et al in 2010. their findings suggested that topical application significantly improves the photo-damaged skin by the end of 1 month when compared with the placebo group [30]. these studies revealed noteworthy relative depletions in the number of wrinkles and total wrinkle surface in conjunction with increase in their mean depth and length at the end of 1 month, ranging from 10% to 28% [30]. mechanism of action of collagen supplements one of the proteins found in abundance in human beings is collagen, and it helps to maintain the structure, stability, and strength of the dermal layers [31]. the studies have shown antioxidant and established reparative actions of collagen in wrinkled or damaged skin. skin experiences the double action of collagen: first, it provides the skin essential components for both elastin and collagen, and second, it is attached to the fibroblast receptors in the dermis to initiate the production of elastin and hyaluronic acid [32]. so far, oral collagen has been studied to a greater extent than topical collagen. the available literature suggests that the topical application of collagen improves both skin elasticity and texture. however, topical collagen does not infiltrate the skin completely owning to its high molecular weight [33]. in contrast, oral collagen ingestion has been found to improve mechanical properties by increasing both the density and the diameter of collagen fibrils [34]. orally consumed collagen bioactive peptides are absorbed relatively quickly because such collagen products have lower molecular weights, distributing these peptides easily across several tissues [35]. additionally, evidence from the animal models suggested that oral administration of collagen reduces the intensity of skin hydration caused by uv radiation and also reduces hyperplasia of the epidermis caused by uv rays [36]. furthermore, oral intake of collagen enhances the moisture content of the skin, especially the stratum corneum, as well as the elasticity of the skin, reducing wrinkling and roughness [37]. overall, collagen causes an increase in fibroblasts and extracellular matrix proteins and a decrease in metalloproteinase. these rising fibroblasts found in the various layers of the human dermis produce a plethora of extracellular matrix proteins that enhance skin health and thus slow skin aging [38]. side effects of collagen supplements reported in human studies  generally, no adverse effects of oral and topical collagen have been observed in any of these studies [39]. there have been no side effects such as vomiting, diarrhea, nausea, or constipation reported in the treatment or control groups of any of the studies [40]. for example, trials conducted in 2019 and 2020 found no adverse effects of collagen until they observed their participants [39,41]. these findings were also confirmed by a research by inoue et al in 2017, where they conducted a rct to assess the effect of high versus low doses of collagen and placebo [22]. likewise, genovese et al had shown analogous findings concerning the side effects during the period of study while comparing the effect of supplements on skin elasticity, wrinkling, and roughness with the placebo [19]. besides, these findings were further endorsed by a study conducted in 2013 by proksch et al: the authors found no side effects in any of the 4 groups that were assigned to high-dose collagen, low-dose collagen, a high-dose placebo, or a lowdose placebo [20]. one more double-blinded rct conducted on korean women showed no adverse events related to the treatment or intervention throughout the study period [21]. similarly, there were no adverse effects of topical collagen in various studies [28-30]. conclusions based on the existing literature from both animal and human studies, it seems that oral collagen supplements improve skin elasticity, turgor, and hydration and reduce skin wrinkling and roughness. the existing premise reveals that neither oral nor topical collagen is superior to the other; rather, both types reduce or delay skin aging. thus, products of collagen peptides can be considered to be anti-aging remedies by dermatologists, especially in cosmetics. however, the existing evidence has not provided enough robust evidence for collagen original article | dermatol pract concept. 2022;12(1):e2022018 9 supplements due to differences in the weights of collagen being topically and systemically absorbed. hence, more epidemiological and interventional studies with large sample sizes and required follow-up appointments are requested to assess the effectiveness of the topical compounds containing collagen on wrinkled and aging skin while comparing the same to the oral collagen supplement instead of the placebo. as the trend of both forms of collagen supplement use might continue to rise, more thorough research is required to validate their potential positive effects before they are widely used. one of the strengths of the included studies was research design, as all the studies on human beings were rcts that provided solid evidence due to the balance of known and unknown confounders between the treatment and control groups. however, the types and doses of collagen were not similar across the studies; therefore, further studies with consistent doses in different settings may be required before making any judgments about the use of oral collagen. this is crucial because some of the proponents of collagen might try to apply the results of animal models to human beings, but animal studies cannot be generalized to humans due to differences in physiological and biological mechanisms. in the same way, these collagen products have usually been tested in the developed or high-income sectors of different age groups. thus, there is no evidence about whether these products could produce analogous results in the various populations residing in lowto middle-income countries with limited resources. hence, this warrants the replication of similar studies in developing countries by using a similar study design. lastly, the review found no side effects of either topical or oral collagen treatment during the study period, and most of the studies had followed their participants for 12-24 weeks. thus, there is no clear evidence about how these collagen products 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2019;11(10):2494. doi: 10.3390/nu11102494. pmid: 31627309. pmcid: pmc6835901. 42. asserin j, lati e, shioya t, prawitt j. the effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials. j cosmet dermatol. 2015;14(4):291301. doi: 10.1111/jocd.12174. pmid: 26362110. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021; 11(4): e202173 1 congenital fibrous hamartoma of the tip of the tongue: a benign entity ambra di altobrando1, luca casadio2, iria neri3 1 ausl della romagna, dermatology unit, ravenna, italy. 2 department of pediatrics, santa maria delle croci hospital, ravenna, italy. 3 department of experimental, diagnostic and specialty medicine, dermatology, university of bologna, italy. citation: di altobrando a, casadio l, neri i. congenital fibrous hamartoma of the tip of the tongue: a beningn entity. dermatol pract concept. 2021; 11(4): e202173. doi: https://doi.org/10.5826/dpc.1104a73 accepted: january 26, 2021; published: october 2021 copyright: ©2021 di altobrando et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ambra di altobrando, md, ausl della romagna, dermatology unit, ravenna, italy. email: ambra.dialtobrando@auslromagna.it case presentation a 1-month-old second-born girl was referred to our clinic due to congenital lesions affecting the tongue. the baby, born at full term, following an uncomplicated pregnancy, was otherwise healthy and breastfeeding, and her family members reported no medical history of note. clinical examination showed 2 dome-shaped pearly nodules of 0.1 cm in maximum diameter on the dorsal aspect of the tip of her tongue (figure 1a). dermoscopy revealed subtle, radial, linear, and comma vessels over a pearly background (figure 1b). diagnosis of congenital fibrous hamartomas of the tip of the tongue was made. teaching point congenital fibrous hamartoma of the tip of the tongue consists of 1 or 2 asymptomatic pearly or yellowish nodules, not exceeding 0.5 cm in maximum diameter, located ventrally or dorsally at the tip of the tongue. it is not associated with cleft lip or palate, or with feeding problems. dermoscopy, even if not diagnostic in this case, can be useful to highlight its benign features. management includes regular follow-up, whereas surgical excision should be avoided, since the clinical picture is classic and stable over time [1]. 2 image letter | dermatol pract concept. 2021; 11(4): e202173 references 1. di altobrando et al. congenital fibrous hamartoma of the tip of the tongue: a novel peculiar entity. pediatr dermatol. 2021; 38(1):287-289. doi: 10.1111/pde.14363. pmid: 33174210. figure 1. (a) two dome-shaped pearly nodules on the dorsal surface of the tip of the tongue. (b) dermoscopy showed subtle, radial, linear, and comma vessels over a pearly background. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022057 1 dermoscopy to the rescue in an annular enigma: a rare case of annular pityriasis versicolor presenting in an unusual location farida kapadia1, vidya kharkar1, tejas vishwanath1 1 dermatology department, kem hospital, mumbai, india citation: kapadia f, kharkar v, vishwanath t. dermoscopy to the rescue in an annular enigma: a rare case of annular pityriasis versicolor presenting in an unusual location. dermatol pract concept. 2022;12(2):e2022057. doi: https://doi.org/10.5826/dpc.1202a57 accepted: august 22, 2021; published: april 2022 copyright: ©2022 rejeb et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: dr. tejas vishwanath, md dermatology, fellow at kem hospital, mumbai, acharya dhonde marg, parel east, mumbai, india. e-mail: tejasvishwanath.igs@gmail.com case presentation a 29-year-old female presented with asymptomatic annular plaques solely over the medial thighs since 1 month (figure 1a, inset, 1b). considering annular lichen planus and porokeratosis, dermoscopy (polarized, otiez dermoscope) was performed. it revealed attenuated central pigmentary network and white scales and peripheral brown peripheral scales with accentuation in skin creases (figure 1c). scales disappeared after wiping with spirit swab (figure 1d). on woods lamp examinationyellowish fluorescence was seen (figure 1e). on potassium hydroxide mount with chicago sky blue, hyphae and spores were evident (figure 1f). thus, a diagnosis of pityriasis versicolor was made. teaching point pityriasis versicolor presents with varied color tones and morphologies.1,2 the annular variant noted in the present case has not yet been described. therefore, the diagnosis was not clinically suspected. dermoscopy was the game changer since it gave telltale clues: scales in skin creases along with pigment dilution. peripheral brown scales without accentuation in the creases constitute an unusual feature probably due to retention parakeratosis since it disappeared on swabbing. 2 image letter | dermatol pract concept. 2022;12(2):e2022057 figure 1. (a,b) multiple discrete scaly annular patches with peripheral rim of hyperpigmentation and central hypopigmentation over bilateral thighs. (c) dermoscopy (captured with polarized dermoscopy, magnification x 10) revealed brown scales at the periphery of the lesion with white fine scales at the center within the skin creases. (d) on wiping the lesion with an alcohol swab, dermoscopic analysis showed complete disappearance of brown scales in the periphery with pigment dilution in the center. (e) yellowish green fluorescence seen at woods lamp examination (f) koh mount shows fungal spores and hyphae (spaghetti and meatball appearance). image letter | dermatol pract concept. 2022;12(2):e2022057 3 references 1. acharya r, gyawalee m. uncommon presentation of pityriasis versicolor; hyper and hypopigmentation in a same patient with variable treatment response. our dermatol online. 2017;8(1):43-45. doi:10.7241/ourd.20171.11 2. varada s, dabade t, loo ds. uncommon presentations of tinea versicolor.  dermatol pract concept. 2014;4(3):93-96. doi: 10.5826/dpc.0403a21. pmid: 25126470. pmcid: pmc4132011. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2022;12(1):e2022008 1 a newborn with a blasckoid-like distribution rash: never forget to use the dermoscope federica filippi1, marco adriano chessa1, federico bardazzi1, iria neri1 1 dermatology unit, ircss policlinico di s. orsola, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy citation: filippi f, chessa ma, bardazzi f, neri i. a newborn with a blasckoid-like distribution rash: never forget to use the dermoscope. dermatol pract concept. 2022;12(1):e2022008. doi: https://doi.org/10.5826/dpc.1201a08 accepted: april 25, 2021; published: january 2022 copyright: ©2022 filippi et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: marco adriano chessa, md, dermatology unit, department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy. e-mail: marco.adriano.chessa@gmail.com case presentation a 30-day-old newborn presented with a 7-day history of an erythematous-crusted rash with a blasckoid-like distribution on his arm and lower limb (figure 1, a and b). the baby was sleeping well, and systemic symptoms were absent. a complete blood exam showed no abnormalities except for a mild eosinophilia. dermoscopy revealed crusted scabies (figure 1c). the patient was treated with permethrin 5% cream, applied and left on the skin for 4 hours for 2 consecutive nights and then again for 2 consecutive nights after 7 days. other family members were given the same treatment regimen, permethrin 5% cream, applied and left on the skin for 8 hours. teaching point norwegian or crusted scabies is a variant of scabies with a massive infestation of sarcoptes scabiei. most cases are reported in immunocompromised patients; however, in an immature immune system, overcrowded living conditions can lead to the appearance of the disease in newborns. our case is peculiar because of the absence of symptoms and the papulo-erythematous blasckoid-like presentation [1]. in these cases, dermoscopy has a central role in quickly arriving at a diagnosis and avoiding unnecessary investigation [2]. 2 image letter | dermatol pract concept. 2022;12(1):e2022008 references 1. neri i, chessa ma, virdi a, patrizi a. nodular scabies in infants: dermoscopic examination may avoid a diagnostic pitfall. j eur acad dermatol venereol. 2017;31(12):e530-e531. doi: 10.1111/jdv.14401. pmid: 28609546. 2. engelman d, yoshizumi j, hay rj, et al. the 2020 international alliance for the control of scabies consensus criteria for the diagnosis of scabies. br j dermatol. 2020;183(5):808820. doi: 10.1111/bjd.18943. pmid: 32034956. pmcid: pmc7687112. figure 1. detail of the erythematous-crusted rash.and. (a) right lower limb. (b) left arm with a blasckoid-like distribution. (c) the dermoscopic examination at a magnification of ×10 revealed the clue for diagnosis: typical small brown pigmented triangular structures, the so-called hang-glider sign, in addition to s-shaped white burrows or jet-liner sign were detected, leading to the diagnosis of crusted scabies. dermatology: practical and conceptual letter | dermatol pract concept 2020;10(3):e2020067 1 dermatology practical & conceptual introduction pigmented epithelioid melanocytoma (pem) is a very uncommon type of the tumor and, because of its cellularity and atypia, may be mistaken for conventional melanoma [1,2]. pem clinically presents as a darkly pigmented, slowly growing nodule in young patients [2]. owing to the dermal infiltrates, it clinically presents with a blue-gray color. typical localizations are face, trunk, extremities, and genitalia. the term pigmented epithelioid melanocytoma was proposed by zembowicz et al in 2004, who renamed epithelioid blue nevus, previously described by carney [1]. histologically pem is characterized by heavily pigmented epithelioid/dendritic cells with prominent nucleoli and pigment located at the periphery of the cytoplasm. interspersed melanophages are in some lesions prominent and in others rare. cells show no signs of maturation. mitoses are infrequent. the biological behavior is not well known, but generally pem is considered a low-grade neoplasm [1,2]. although reports are limited, evidence supports the notion that the tumor follows an indolent clinical course. of patients who underwent sentinel lymph node biopsies, 60% of patients in the current series and 46% of patients in the series of zembowicz et al exhibited lymph node metastases, supporting a high rate of regional spread [1]. only 1 documented case of a distant metastasis of pem to the liver has been documented. however, the overall survival is excellent, with no reported cases of death. case presentation we present 2 cases of pem, each of which presented as a newly occurring lesion that was part of a medium-sized congenital nevus. the first child, 3 years of age, presented with rapidly growing nodular changes over 4 months. urgent excision was made to rule out melanoma in medium-sized congenital nevus. the nevus was excised completely. histopathological diagnosis of a combined tumor composed of 2 components, pem and junctional melanocytic nevus, was made in 2 independent expert centers (figure 1, a-c). pigmented epithelioid melanocytoma in congenital nevus of medium size in children ružica jurakić tončić,1 slobodna murat susic,1 danijela curkovic,1 mikela petkovic,1 bostjan luzar,² ivana ilic³ 1 university hospital centre zagreb, department of dermatology and venereology, school of medicine, university of zagreb, croatia 2 institute of pathology, medical faculty, university of ljubljana, slovenia 3 university hospital centre zagreb, department of pathology and cytology, university of applied health sciences, zagreb, croatia key words: melanocytoma, epithelioid pigmented melanocytoma, medium-sized congenital nevus, children citation: jurakić tončić, murat susic s, curkovic d, petkovic m, luzar b, ilic i. pigmented epithelioid melanocytoma in congenital nevus of medium size in children. dermatol pract concept. 2020;10(3):e2020067. doi: https://doi.org/10.5826/dpc.1003a67 accepted: april 20, 2020; published: june 29, 2020 copyright: ©2020 jurakic toncic et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ružica jurakić tončić, md, university of zagreb, school of medicine, department of dermatology and venereology, salata 4, 10000, zagreb, croatia. email: rjtoncic@gmail.com https://doi.org/10.5826/dpc.1003a67 mailto:rjtoncic@gmail.com 2 letter | dermatol pract concept 2020;10(3):e2020067 the second child, 6 months old, was sent for examination of a medium-sized plantar congenital nevus. the child’s parents noticed that parts of the nevus got darker in comparison with the rest of the nevus. the child was sent for partial excision of the darkest parts of the lesion. the samples were sent for a histopathological analysis and diagnosis of composite melanocytic tumor, made of a congenital type of melanocytic nevus and pem, was established in 2 independent expert centers (figure 2, a-c). figure 1. clinical, dermoscopic, and histological images of the lesion in the first child. (a) nodular black-blue lesion inside of medium-sized congenital nevus. camera: canon powershot sx520 hs. (b) dermoscopy shows metal-blue nodular part and black dots (peppering) around nodular part in surrounding congenital nevus. photo taken by 3gen dermlite foto. (c) in histopathological slides an asymmetrical melanocytic lesion is seen in the epidermis and in a dermis. the epidermal component is made of melanocytic nests of a different size. most melanocytes in the nests are round and have small nuclei, indistinctive nucleoli, and average-size cytoplasm with some pigment. in a few nests larger melanocytes with larger nuclei and larger nucleoli are seen. the same type of nevoid melanocytes is seen in a dermis admixed with epithelioid and dendritic melanocytes and a large amount of melanophages (h&e, ×4). dendritic melanocytes show plexiform growth pattern (h&e, ×10; h&e, ×40). only a few mitoses are seen in epithelioid melanocytes. on the periphery of the lesion is lymphocytic infiltrate. figure 2. clinical, dermoscopic, and histological images of the lesion in the second child. (a) blue-black macule inside the congenital plantar medium-sized nevus. camera: canon powershot sx520 hs. (b) dermoscopy shows metal-blue part in congenital nevus, with black dots, but less sharply demarcated. photo taken by 3gen dermlite foto. (c) histologically, the lesion was composed of epidermal and dermal melanocytic nests with the dermal component being partly composed of small oval melanocytes and partly of epithelioid and dendritic melanocytes that grow in a plexiform pattern. there were no mitoses (h&e, ×4; h&e, ×10). there is large amount of melanophages among the melanocytes. the dermal component is partly composed of epithelioid and dendritic melanocytes that grow in a plexiform pattern surrounding the adnexa (h&e, ×40). letter | dermatol pract concept 2020;10(3):e2020067 3 low-grade melanocytic tumor with limited metastatic potential, but further studies including follow-up of the patients are needed. references 1. zembowicz a, carney ja, mihm mc. pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. am j surg pathol. 2004;28(1):31-40. https:// doi.org/10.1097/00000478-200401000-00002 2. moscarella e, ricci r, argenziano g, et al. pigmented epithelioid melanocytoma: clinical, dermoscopic and histopathological features. br j dermatol. 2016;174(5):1115-1117. https://doi. org/10.1111/bjd.14322 in both cases, deep penetrating nevus was excluded due to immunohistochemistry. conclusions melanocytoma is extremely rare. it was described in another report as a part of the congenital nevus. the size of the nevus was not mentioned, and lesions had been observed since the child’s birth. our report describes two unusual cases of melanocytoma in medium-sized congenital nevi of children occurring after birth. the dermoscopic features of pem were described in a small case series, but no correlation between dermoscopy and histopathology was found [2]. pem should be considered as https://doi.org/10.1097/00000478-200401000-00002 https://doi.org/10.1097/00000478-200401000-00002 https://doi.org/10.1111/bjd.14322 https://doi.org/10.1111/bjd.14322 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022058 1 recurrent acute generalized exanthematous pustulosis to two different drugs: oxacillin and dextromethorphan confirmed by patch test zied kenani1, rima gammoudi1, neila fathallah2, amina aounallah1, sana mokni1, lobna boussofara1, nejet ghariani1, colandane belajouza1, chaker ben salem2, mohamed denguezli1 1 department of dermatology, farhat hached hospital, sousse, tunisia 2 department of pharmacovigilance, reference center for cutaneous adverse reactions, faculty of medicine, university of sousse, sousse, tunisia. key words: acute generalized exanthematous pustulosis, oxacillin, dextromethorphan, recurrence, patch test citation: kenani z, gammoudi r, fathallah n et al. recurrent acute generalized exanthematous pustulosis to two different drugs: oxacillin and dextromethorphan confirmed by patch test. dermatol pract concept. 2022;12(2):e2022058. doi: https://doi.org/10.5826/dpc.1202a58 accepted: august 24, 2021; published: april 2022 copyright: ©2022 kenani et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: zied kenani, md, department of dermatology, farhat hached hospital, avenue ibn jazzar, 4002, sousse, tunisia. e-mail: zieedken@gmail.com introduction acute generalized exanthematous pustulosis (agep) is a potentially severe skin condition, mainly drug induced [1]. recurrences are rare and generally induced by related drugs. dextromethorphan is an antitussive agent which is unusually reported as culprit in agep. herein we report a rare case of relapsing agep to dextromethorphan and oxacillin. case presentation a 32-year-old woman, with a history of a controlled generalized pustular psoriasis, presented to our department with a 4 day history of fever with predominately flexural eruption of non-follicular pustules on a erythematous background, which had started 2 days after the intake of oxacillin and tiaprofenic acid. investigations found an elevated absolute neutrophil count and skin biopsy demonstrated histologic features consistent with agep. skin lesions totally resolved within 10 days after oxacillin discontinuation. a patch test with oxacillin and tiaprofenic acid (the commercialized form used by the patient diluted to 30% pet.) was performed and showed a +++ skin reaction to oxacillin on day 4 but no reaction to tiaprofenic acid. all penicillins were prohibited. two years later the patient presented with a similar eruption and fever 4 days after taking 2 multi-compound medications named goldix day (dextromethorphan, doxylamine, paracetamol) and goldix night (dextromethorphan, paracetamol, phenylephrine) for a cold (figure 1). she denied taking any other drug. complete blood count showed 2 research letter | dermatol pract concept. 2022;12(2):e2022058 paracetamol. we performed a genetic analysis to determine whether there was mutation of the il36rn gene, as it may be a predisposing factor, but we did not find such mutation in our patient. conclusions recurrences in agep are rare and often induced by related drugs, mainly b-lactams. our case suggests that it may be induced by chemically different medications in potentially predisposed patients possibly having pattern of cytokine dysregulation. indeed, it seems that psoriasis might be a risk factor of relapsing agep. we have also shown that il36rn gene mutation does not fully explain the pathogenesis of pustular generalized eruptions. moreover, our observation is notable for the implication of dextromethorphan, a widely used opioid antitussive agent, as a culprit drug. to the best of our knowledge, only 1 case of agep induced by dextromethorphan and confirmed by patch testing has been previously reported [2]. references 1. sidoroff a, dunant a, viboud c, et al. risk factors for acute generalized exanthematous pustulosis (agep)—results of a multinational case-control study (euroscar). br j dermatol. 2007;157(5):989–996. doi: 10.1111/j.13652133.2007.08156.x. pmid: 17854366. 2. rashid, rs,  ahmed, i,  shim, tn.  acute generalized exanthematous pustulosis due to dextromethorphan.  contact dermatitis.  2020;83(5):424–425. doi: 10.1111/cod.13633. pmid: 32506524. marked neutrophilia and skin biopsy was consistent with agep. diagnosis was defined following euroscar criteria. patch testing with the component of the commercialized package of goldix day (30 % pet.), goldix night (30 % pet.) and paracetamol (50% pet.) was performed. the patch test preparations were applied in iq ultra (chemotechnique diagnostics). the patch tests were occluded for 48 hours, and readings were performed according to icdrg/escd criteria on day 2 and day 4. patch testing showed a ++ skin reaction to goldix day and goldix night, but was negative to paracetamol (figure 2). the oral provocation test to paracetamol was also negative. the constituent dextromethorphan was not available for testing, but was suspected as the cause of the reaction as it was the only compound in common besides figure 1. diffuse erythema with multiple small pustules. figure 2. (a) positive patch test reaction to goldix day on day 4. (b) positive patch test reaction to goldix night on day 4. (c) no reactions to paracetamol were seen on day 4. dermatology: practical and conceptual correction | dermatol pract concept 2020;10(1):e2020026 1 dermatology practical & conceptual dermatol pract concept. 2019;10(1):e2020026. november 4, 2019. doi: https://doi.org/10.5826/dpc.1001a26 disseminate recurrent folliculitis and hidradenitis suppurativa are associated conditions: results from a retrospective study of 131 patients with down syndrome and a cohort of 12,351 pediatric controls in the article titled “disseminate recurrent folliculitis and hidradenitis suppurativa are associated conditions: results from a retrospective study of 131 patients with down syndrome and a cohort of 12,351 pediatric controls” by sechi et al [1] (https:// dpcj.org/index.php/dpc/article/view/dermatol-pract-concept articleid-dp0903a03), published on july 31, 2019, the last 2 authors were omitted in error. these authors should have been listed as annalucia virdi and iria neri. these authors have no conflicts of interest to disclose, and they contributed significantly to this publication. this article was corrected online on november 4, 2019. the editors regret the error. reference 1. sechi a, guglielmo a, patrizi a, savoia f, cocchi g, leuzzi m, chessa ma, virdi a, neri i. disseminate recurrent folliculitis and hidradenitis suppurativa are associated conditions: results from a retrospective study of 131 patients with down syndrome and a cohort of 12,351 pediatric controls. dermatol pract concept. 2019;9(3):187-194. doi: https://doi.org/10.5826/ dpc.0903a03  correction https://doi.org/10.5826/dpc https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0903a03 https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0903a03 https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0903a03 _goback dermatology: practical and conceptual research | dermatol pract concept 2020;10(4):e2020122 1 dermatology practical & conceptual introduction congenital triangular alopecia (cta) is a benign, asymptomatic, nonprogressive, localized and noncicatricial type of alopecia that is usually first noted during infancy or childhood. previously other names have been used to describe this condition, such as brauer nevus or temporal triangular alopecia. cta most commonly affects the frontotemporal region of the scalp in a unilateral pattern, more frequently involving the left side. in a minority of cases a bilateral involvement has been reported [1]. the pattern of hair loss is traditionally described as triangular, oval, or lancet-shaped with the apex toward the vertex [2]. the diagnosis is mainly based on its clinical appearance, and usually pathology is not atypical presentation of congenital triangular alopecia: a case series in italy michela starace1, miriam anna carpanese1, diego abbenante1, francesca bruni1, bianca maria piraccini1, aurora alessandrini1 1 department of experimental, diagnostic and specialty medicine, division of dermatology, university of bologna, italy key words: congenital triangular alopecia, scalp, trichoscopy, atypical citation: starace m, carpanese ma, abbenante d, bruni f, piraccini bm, alessandrini a. atypical presentation of congenital triangular alopecia: a case series in italy. dermatol pract concept. 2020;10(4):e2020122. doi: https://doi.org/10.5826/dpc.1004a122 accepted: july 3, 2020; published: october 26, 2020 copyright: ©2020 starace et al. this is an open-access article distributed under the terms of the creative commons attribution license (cc-by-nc-4.0), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: miriam anna carpanese, md, department of experimental, diagnostic and specialty medicine—division of dermatology, university of bologna, via massarenti, 1, 40138 bologna, italy. email: miriam.carpanese@gmail.com background: congenital triangular alopecia (cta) is a benign, asymptomatic, nonprogressive, localized and noncicatricial type of alopecia that is usually first noted during infancy or childhood. the pattern of hair loss is traditionally described as triangular, oval or lancet shaped with apex toward the vertex. objective: we present a case series of cta located in unusual sites. patients and methods: we performed trichoscopy in 78 patients with cta. from this group, we selected 10 individuals (4 males and 6 females) whose disease was not localized on the typical scalp area. results: the alopecic area was located on the occipital region in 5 patients, the parietal region in 4 patients, at the vertex in 1. with trichoscopy, vellus hairs were detected in all patients, and evidence of empty follicles was noticed only in 3 patients. conclusions: in contrast with the preconceived notion that all ctas are frontotemporal, our case series points out that this disease could be localized in other scalp sites abstract 2 research | dermatol pract concept 2020;10(4):e2020122 reported worldwide. it usually appears in a sporadic form, but familial cases have been described [6,7]. in a smaller percentage of cases, about 15%, cta can be associated with other disorders or syndromes, such as phacomatosis pigmentovascularis [8,9]. to date, the etiology is unknown, and no specific treatments are available for this benign condition. despite the typical presentation of cta as a triangular or oval patch of circumscribed alopecia localized in the frontotemporal area, some authors reported atypical locations of cta in the mid-frontal region of the scalp [10], the occipital area [11], the left temporo-parietal-vertex region of the scalp [12], and the eyebrows [13]. the diagnosis of cta is mainly based on its clinical appearance and location. pathology shows miniaturized follicles that replace terminal hairs, with an increased proportion of vellus or indeterminate hairs. the total number of follicle units is in the normal range [1], but it is not usually performed. the differential diagnoses of the disease include alopecia areata, trichotillomania, traction alopecia, and congenital aplasia cutis. several cases reported in literature show that cta could be misdiagnosed and incorrectly treated as other forms of focal alopecia, principally alopecia areata [11,14]. for this reason, trichoscopy can be useful, avoiding scalp biopsy or useless treatments. typical trichoscopic findings include normal follicular openings with vellus hairs covering the alopecic area and terminal hairs on the outskirt of the lesion [15]. classic signs of alopecia areata, black or yellow dots or exclamation marks, are absent in cta. inui et al [16] proposed 4 diagnostic criteria for cta: triangular or spearshaped area of alopecia involving the frontotemporal region of the scalp; trichoscopic features of normal follicular openings with vellus hair surrounded by normal terminal hair and absence of yellow and black spots, dystrophic hairs and needed to confirm the diagnosis. trichoscopy can be useful in excluding other diseases characterized by localized alopecia [3], such as alopecia areata. herein, we present a case series of cta located in unusual sites. methods during the period from 2012 to 2020, at outpatient hair consultation of the department of experimental, diagnostic and specialty medicine at the university of bologna, we diagnosed 78 patients with cta. in all patients we performed trichoscopy using a fotofinder dermatoscope. from this group, we selected 10 individuals (12.8%) whose disease was not localized in the typical scalp area. all the patient’s data are summarized in table 1. results in this group there were 6 males and 4 females with a mean age of 3.5 years. regarding the location on the site, the alopecic area was located on the occipital region in 5 patients, the parietal region in 4 patients, and at the vertex in 1 patient (figure 1, a and b). with trichoscopy, vellus hairs were detected in all patients, and evidence of empty follicles was noticed only in 3 patients (figure 1, c and d). discussion cta is a non-scarring type of alopecia. its exact incidence is not known, but some studies reported an estimated rate of 0.11% [4]. most ctas present in children between 3 and 6 years old, but it can also occur in adult patients. according to kumar dey et al [5], as of 2016, only 127 cases had been table 1. clinical data from patients with cta localized on atypical scalp area case number age sex site vds 1 3 m occipital vellus hair 2 5 m parietal vellus hair 3 1 f occipital vellus hair and empty follicles 4 4 f parietal vellus hair 5 5 f occipital vellus hair 6 4 m occipital vellus hair and empty follicles 7 2 f parietal vellus hair and empty follicles 8 3 m parietal vellus hair 9 4 m occipital vellus hair 10 3 f vertex vellus hair cta = congenital triangular alopecia; vds = videodermoscopy research | dermatol pract concept 2020;10(4):e2020122 3 references 1. trakimas c, sperling lc, skelton hg 3rd, smith kj, buker jl. clinical and histologic findings in temporal triangular alopecia. j am acad dermatol.1994;31(2 pt 1):205-209. doi: 10.1016/ s0190-9622(94)70147-4. 2. trakimas ca, sperling lc. temporal triangular alopecia acquired in adulthood. j am acad dermatol. 1999;40(5 pt 2):842844. doi: 10.1053/jd.1999.v40.a97651. pmid: 10321631. 3. yin li vc, yesudian pd. congenital triangular alopecia. int j trichology. 2015;7(2):48-53. doi: 10.4103/09747753.160089. pmid: 26180448. 4. garcía-hernández mj, rodríguez-pichardo a, camacho f. congenital triangular alopecia (brauer nevus). pediatr dermatol. 1995;12(4):301-303. doi: 10.1111/j.1525-1470.1995. tb00187.x. pmid: 8747572. decreased follicular openings; and persistence of no significant hair growth after dermoscopic and clinical confirmation of the existence of vellus hairs. our cases fulfill all the criteria for cta except the site of involvement. conclusions in contrast with the preconceived notion that all ctas are frontotemporal, our case series points out that this disease could be localized in other scalp sites. this focus is important because cta is an underdiagnosed condition, and in order to avoid redundant therapies, it should be included in differential diagnosis when evaluating a circumscribed hairless patch on the scalp. figure 1. two cases of our series: (a) occipital cta; (b) vertex cta. with trichoscopy, vellus hairs are evident (c, d), but also empty follicles (d). cta = congenital triangular alopecia. a b c d 4 research | dermatol pract concept 2020;10(4):e2020122 cia, redundancy in therapy without improvement. dermatol ther. 2018;31(6):e12698. doi: 10.1111/dth.12698. pmid: 30284356. 11. jamwal a, sharma sd. congenital triangular alopecia. indian pediatr. 2014;51(6):511. 12. singh n, goyal a, thappa dm, rajesh ng. congenital triangular alopecia: is it always confined to fronto-temporal region? indian j dermatol venereol leprol. 2016;82(1):112. doi: 10.4103/0378-6323.157456. pmid: 26728834. 13. yadav d, khandpur s, subhadarshani s, sahni k. congenital symmetrical circumscribed patterned non-scarring alopecia of eyebrows: a variant of congenital triangular alopecia or an anatomical variation? bmj case rep. 2019 ;12(5): e227472. doi: 10.1136/bcr-2018-227472. pmid: 31129634. 14. yamazaki m, irisawa r, tsuboi r. temporal triangular alopecia and a review of 52 past cases. j dermatol. 2010;37(4):360-362. doi: 10.1111/j.1346-8138.2010.00817.x. pmid: 20507407. 15. iorizzo m, pazzaglia m, starace m, militello g, tosti a. videodermoscopy: a useful tool for diagnosing congenital triangular alopecia. pediatr dermatol. 2008;25(6):652-654. doi: 10.1111/j.1525-1470.2008.00811.x. pmid: 19067883. 16. inui s, nakajima t, itami s. temporal triangular alopecia: trichoscopic diagnosis. j dermatol. 2012;39(6):572-574. doi: 10.1111/j.1346-8138.2011.01348.x. pmid: 21906133. 5. dey vk, bhadoria ts, saxena a, jaisinghani ak, patil ay, dubey n. congenital triangular alopecia: the 127(th) case. int j trichology. 2016;8(1):50-51. doi: 10.4103/09747753.179399. pmid: 27127384 6. patrizi a, morrone p, fiorentini c, bianchi t. an additional familial case of temporal triangular alopecia. pediatr dermatol. 2001;18(3):263-264. doi: 10.1111/j.1525-1470.2001.19144.x. 7. ruggieri m, rizzo r, pavone p, baieli s, sorge g, happle r. temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. arch dermatol. 2000;136(3):426-427. doi: 10.1001/archderm.136.3.426. pmid: 10724218. 8. oliveira lc, miranda ar, pinto sa, ianhez m. case for diagnosis. alopecia areata and congenital triangular alopecia. an bras dermatol. 2014;89(2):353-355. doi: 10.1590/abd18064841.20142740. pmid: 24770522. 9. león-muiños e, monteagudo b, labandeira j, cabanillas m. [bilateral congenital triangular alopecia associated with congenital heart disease and renal and genital abnormalities]. actas dermosifiliogr. 2008;99(7):578-579. doi: 10.1016/s15782190(08)70322-6. 10. goldust m, rahmatpour rokni g, sadr s, mirabi a, rezaee e, goren a, lotti t. anterior, frontal congenital triangular alopedermatology: practical and conceptual dermatology practical & conceptual commentary | dermatol pract concept. 2021;11(3):e2021080 1 solidarity and voluntarism amid the covid-19 pandemic: skin cancer screening for blood donors katerina grafanaki1, sophia georgiou1, alexander j. stratigos2 1 department of dermatology, university hospital of patras, school of medicine, university of patras, greece 2 department of dermatology-venereology, andreas syggros hospital, national and kapodestrian university of athens, greece key words: skin cancer screening, volunteer blood donors, teledermatology, red cross, public health, solidarity citation: grafanaki k, georgiou s, stratigos aj. solidarity and voluntarism amid the covid-19 pandemic: skin cancer screening for volunteer blood donors. dermatol pract concept. 2021;11(3):e2021080. doi: https://doi.org/10.5826/dpc.1103a80 accepted: february 5, 2021 published: may 20, 2021 copyright: ©2021 grafanaki et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: katerina grafanaki msc, md, phd, department of dermatology, university hospital of patras, school of medicine, university of patras, 26504 patras, greece. email: grafanaki@med.upatras.gr melanoma is the deadliest skin cancer, and its incidence is increasing globally. it is preventable, and indeed increased sun awareness campaigns and early diagnoses through skin cancer screening programs for the general population have contributed to decreasing mortality from melanoma. many of the volunteer activities involved in raising public awareness about melanoma are provided by dermatological societies and volunteer dermatologists who are often not sufficiently credited for their contributions. the recipients of these free services include blood donors and emergency service providers (eg, hellenic red cross samaritans). although efforts over the past decade have led to a significant reduction in skin cancer, activities have been suspended and, in many cases, disrupted since the outbreak of coronavirus disease 2019 (covid-19) created a public health emergency of international concern. national health systems are overburdened, and patients are avoiding specialist visits due to fears of becoming infected with the sars-cov-2 virus while attending a medical clinic. as a result, a 68.61% reduction in skin cancer diagnoses has been reported in the uk [1]. during the strict government measures to contain the spread of sars-cov-2 and minimized the number of covid-19 cases, dermatologists have limited their activities to dermatological emergencies and have opted to practice teledermatology for less urgent issues. concurrently, another major disruption due to the covid-19 pandemic is a shortage of blood for transfusions. every 2 seconds, a patient in the united states needs a red blood cell transfusion; almost 5,000 platelet units and 6,500 units of plasma are required daily. plasma containing antibodies against sars-cov-2 could be transfused into severely ill patients with covid-19 [2]. importantly, lack of ethnic diversity within the donor pool and rare blood types should be acknowledged [3]. during the pandemic, 86,000 american red cross (arc) blood drives were cancelled, whereas in europe and asia blood banks continue to play a vital role in ensuring an uninterrupted supply of blood and blood components [3]. an opportunity to donate is an opportunity to save a life. the arc is offering free sars-cov-2 antibody testing to blood donors [2]. the international federation of the red 2 commentary | dermatol pract concept. 2021;11(3):e2021080 cross is an impartial, neutral, and independent organization whose mission is to assist in the response to humanitarian emergencies such as epidemics [3]. since 1985, the american academy of dermatology has been offering free skin cancer screening. volunteer dermatologists have performed more than 2.8 million screenings and detected more than 31,500 suspected melanomas and 278,000 suspicious lesions, saving countless lives [4]. skin cancer awareness month (united states), euromelanoma (europe), and similar campaigns on other continents, which have a significant impact on early diagnosis of melanoma, were either mostly realized via internet and were mass media-based or were cancelled, depending on the country’s restrictions. while the pandemic may represent a threat to many aspects of our existence, dermatologists can show a humanitarian face through voluntary skin cancer screening of life-saving volunteer blood donors. early detection of melanoma is facilitated by teledermatology using smartphones [5] and teledermoscopy [6]. these tools increase dermatological access in rural regions and contribute to gender, racial and ethnic equity [7], especially in heterogeneous socioeconomic groups such as blood donors who would otherwise not seek a dermatologist during these times. virtual melanoma checks, with 94% diagnostic accuracy [8], could eliminate the risk of contracting covid-19. patients with potentially malignant lesions can be diagnosed and biopsied. the limitation due to the number of high-risk blood donors to be screened could be overcome through careful selection by a pre-screening questionnaire considering their age, phototype, and familial, personal and sun exposure histories. for example, people who volunteer as lifeguards, a profession with high sun exposure, could be prioritized. teledermatology could be delivered using either store-andforward or real-time video technology, or a hybrid of both [9]. “in the presence of epidemics or other danger, i will not allow fear of personal harm to turn me from my duty,” says the hippocratic oath. most of us have not worked through pandemics before, but it is time to embrace humanity and solidarity. volunteering motivation is important in forming a person’s decision to contribute their time and effort without expecting financial rewards. in a time of deep economic crisis, unemployment and social exclusion, solidarity and non-profit assistance to fellow human beings is an urgent need of both the state and society. amid the ongoing pandemic, blood donations and skin cancer screening must not be disrupted; they can be continued as long as attention is foremost paid to patient safety. supporting volunteer blood donors through voluntary skin cancer screening could be an excellent initiative, bringing people together, giving us the opportunity to abandon the illusion of power and admit our weakness to the ongoing pandemic. only with humility, solidarity, and insight can we accomplish sustainability despite the challenges. skin cancer screening of volunteer blood donors could be a high-impact skin cancer prevention initiative, rewarding and motivating for volunteers. the volunteer dermatologist may feel fulfillment from wiping out preventable skin cancer. the blood donor will be motivated and encouraged to continue with their life-saving donations. in light of a change in dermatology practice, investing in prevention strategies in public health and social protection is the mark of a responsible action policy. the covid-19 pandemic is probably here to stay and is delaying preventive skin cancer diagnosis and treatment that our health system will struggle to cover. perhaps this is the impetus to mobilize and do something useful and lifesaving during this public health emergency. references 1. andrew tw, alrawi m, lovat p. reduction in skin cancer diagnoses in the uk during the covid-19 pandemic. clin exp dermatol. 2020;46(1):145-146. doi: 10.1111/ced.14411. pmid: 32754962. 2. sen-crowe b, mckenney k, mckenney m, elkbuli a. challenges associated with blood banks and blood donations during the covid-19 pandemic. am j emerg med. 2020;20: 30546-5. doi: 10.1016/j.cll.2020.08.013. pmid: 32674923. 3. international federation of the red cross (ifrc) voluntary blood donation. accessed november 28, 2020. https://media.ifrc.org/ ifrc/what-we-do/health/voluntary-blood-donation/ 4. american academy of dermatology association. free skin cancer screenings. accessed november 28, 2020. https://www.aad.org/ public/public-health/skin-cancer-screenings 5. malhi is, yiu zzn. algorithm-based smartphone apps to assess risk of skin cancer in adults: critical appraisal of a systematic review. br j dermatol. 2020 aug 31. doi: 10.1111/bjd.19502. pmid: 32866990. 6. tognetti l, cevenini g, moscarella e, et al. validation of an integrated dermoscopic scoring method in a european teledermoscopy web platform: the idscore project for early detection of melanoma. j eur acad dermatol venereol. 2020;34(3):640-647. doi: 10.1111/jdv.15923. pmid: 31465600. 7. hadeler ek, beer j nouri k. teledermatology: improving access or widening healthcare disparities? 2020;19(12):1248. doi: 10.36849/jdd.2020.5693. pmid: 33346507. 8. massone c, maak d, hofmann-wellenhof r, soyer hp, frühauf j. teledermatology for skin cancer prevention: an experience on 690 austrian patients. j eur acad dermatol venereol. 2014;28(8):1103-1108. doi: doi: 10.1111/jdv.12351. pmid: 24372877. 9. kazi r, evankovich mr, liu r, et al. utilization of asynchronous and synchronous teledermatology in a large health care system during the covid-19 pandemic. telemed j e health. 2020 oct 19. doi: 10.1089/tmj.2020.0299. pmid: 33074786. dermatology: practical and conceptual dermatology practical & conceptual commentary | dermatol pract concept. 2021;11(2):e2021034 1 well-differentiated squamous cell carcinoma: is histological differentiation a relevant prognostic parameter? iago gonçalves ferreira1,2, ana letícia boff 1, laura luzzato1, paulo r. martins souza1,2, mariele bevilaqua1 1 dermatology service, santa casa de misericórdia de porto alegre, brazil 2 federal university of health sciences of porto alegre, brazil key words: squamous cell carcinoma, head and neck squamous cell carcinoma, skin neoplasms, prognosis citation: gonçalves ferreira i, boff al, luzzato l, martins souza pr, bevilaqua m. well-differentiated squamous cell carcinoma: is histological differentiation a relevant prognostic parameter? dermatol pract concept. 2021;11(2):e2021034. doi: https://doi.org/10.5826/ dpc.1102a34 accepted: october 21, 2020; published: april 12, 2021 copyright: ©2021 gonçalves ferreira et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: iago gonçalves ferreira, md, dermatology service, santa casa de misericórdia de porto alegre, av. independência, 75, porto alegre rs, brazil. email: iago_goncalves14@hotmail.com introduction squamous cell carcinoma (scc) represents about 20% of non-melanoma skin cancers, being the second most prevalent type after basal cell carcinoma [1,2]. most sccs have good prognosis after surgical excision. however, about 5% of cases progress to locally advanced or metastatic lesions with unfavorable prognosis [3,4]. the degree of histological differentiation has been considered an independent predictor of recurrence, metastasis, and survival rates. lower recurrence and metastasis rates are attributed to well-differentiated sccs as compared to poorly differentiated sccs [1]. we present the case of a patient with well-differentiated scc of the head, with an exuberant clinical presentation. discussion a 78-year-old female patient from a rural town in southern brazil was referred to the dermatology service for a tumoral lesion in the right upper face. the patient was a farmer and smoker, had diabetes and a history of breast cancer, and had skin phototype iii. the tumor had progressively grown for about 2 years, with intensive expansion in the past 6 months. the patient reported previous secondary bacterial infections, which were treated with systemic antibiotics, and myiasis in the lesion. she had previously refused tumor biopsy. the physical exam showed an extensive, friable tumor with necrotic areas, bloody drainage and myiasis larvae on the lesion surface (figure 1). due to the advanced condition, the patient was referred to the emergency service for hospital admission. cranial computed tomography showed a tumor mass in right upper face with invasion of the subcutaneous tissue and skullcap (figure 2). the patient underwent surgical resection of the tumor and of the frontal process of zygomatic bone, followed by skin grafting from an abdominal donor site. the surgical sample was submitted to histological analysis, which showed 2 commentary | dermatol pract concept. 2021;11(2):e2021034 a well-differentiated scc with an infiltrative, ulcerated pattern, invasion of the dermis, hypodermis, periocular soft tissues, bone, and fibrous tissue, as well as perineural invasion (figure 3). clinical staging did not demonstrate metastasis, and the patient evolved with bleeding at the surgical site and secondary anemia. after clinical stabilization, she was discharged from the hospital with outpatient follow-up. due to her comorbidities (chronic kidney failure, smoking and type 2 diabetes) as well as her difficulty adhering to treatment, the oncology team opted for palliative management of the case. the prognosis of sccs depends on factors intrinsic to each patient and cancer, which will determine the aggressive potential of a lesion. the risk factors for poor prognosis are related to size and depth, extension to subcutaneous tissue, poor histological differentiation and perineural invasion. regarding the individual, characteristics such as immunosuppression and previous sccs are also considered [5,6]. regarding histology, sccs are classified according to their degree of keratinization, nuclear atypia and histological architecture. they are therefore classified into 4 degrees of differentiation: well differentiated (g1), moderately differentiated (g2), poorly differentiated (g3), and undifferentiated (g4) [1,7,8]. however, according to the national comprehensive cancer network (nccn), there is currently a tendency to classify sccs into 2 degrees of differentiation: well to moderately differentiated, and poorly differentiated [9]. figure 1. (a, b) macroscopic clinical images showing the tumor on the patient’s face and the presence of myiasis larvae (white arrows). figure 2. (a) a 3d tomographic image reconstruction showing an expansive lesion in the right frontal area with periorbital involvement. (b) contrasted computed tomographic image showing an expansive lesion in the right frontal area, in the axial slideplane. commentary | dermatol pract concept. 2021;11(2):e2021034 3 the nccn’s clinical practice guidelines in oncology indicate that well-differentiated sccs have better prognosis than poorly differentiated carcinomas, as well as lower rates of recurrence and metastasis (based on retrospective studies) [9]. furthermore, the guidelines consider, as factors for poor scc prognosis: neoplasms originating from chronic skin ulcers and scars; perineural involvement and poor histological differentiation; immunosuppressive status; adenoid, desmoplastic and adenosquamous histological subtypes; and size, with risk depending on tumor extension and the affected region [10]. nevertheless, the prognostic parameters for sccs are not always well-defined in the literature, which makes it difficult to elucidate which combinations of factors predict better or worse prognosis [5]. some authors have pointed to poor histological differentiation as an important definer of metastasis and recurrence, and to tumor diameter and depth as parameters inversely proportional to differentiation grade in sccs [1,7,11,12]. a french cohort study about advanced scc (stage iv) showed that about 78% were well differentiated (g1) [13]. a cohort study with 195 german patients with stage iii or iv sccs demonstrated that about 80% did not have desmoplasia and 92% did not have neural invasion, diverging from factors for poor scc prognosis [14]. we reinforce the understanding that the degree of differentiation should not be analyzed in isolation to express the impact of sccs [6], as the patient had a lesion expansion of about 15 cm in diameter, with perineural invasion of dermis and hypodermis, facial disfigurement, and rapid, progressive growth, despite the well-differentiated degree of the tumor. advanced head and neck sccs may have an intense negative impact on the social interactions and functionality of individuals due to the facial disfigurement caused, and therefore are a risk factor for depression and suicide [6]. however, non-melanoma skin cancers have high cure rates, especially when diagnosed and treated early. late diagnosis has been attributed to characteristics such as low social status, lack of personal hygiene, fear of diagnosis, and potential consequences [15]. such situations were identified in this patient’s history: she was from a rural town and had bad memories from her previous breast cancer treatment. thus, she refused to seek medical attention, which aggravated her condition. this study draws attention to the fact that we must evaluate the prognostic histological parameters of cutaneous sccs together with each patient’s unique factors. in isolation, histological differentiation should not be taken as a predictor of neoplastic behavior. references 1. parekh v, seykora jt. cutaneous squamous cell carcinoma. clin lab med. 2017;37(3):503-525. doi: 10.1016/j.cll.2017.06.003. pmid: 28802498. 2. hall et, fernandez-lopez e, silk aw, dummer r, bhatia s. immunologic characteristics of nonmelanoma skin cancers: implications for immunotherapy. am soc clin oncol educ b. 2020;(40):398-407. doi: 10.1200/edbk_278953. pmid: 32207669. 3. que skt, zwald fo, schmults cd. cutaneous squamous cell carcinoma: incidence, risk factors, diagnosis, and staging. j figure 3. (a) squamous cell proliferation infiltrating the dermis (h&e, ×40). (b) keratin production in the center of the squamous proliferation (h&e, ×400). (c) perineural infiltration by neoplastic cells (h&e, ×400). 4 commentary | dermatol pract concept. 2021;11(2):e2021034 am acad dermatol. 2018;78(2):237-247. doi: 10.1016/j. jaad.2017.08.059. mid: 29332704. 4. ascierto pa, garbe c. updates and new perspectives in nonmelanoma skin cancer therapy: highlights from “immunotherapy bridge”. immunotherapy. 2020;12(3):167-174. doi: 10.2217/ imt-2020-0042. pmid: 32208790. 5. jennings l, schmults cd. management of high-risk cutaneous squamous cell carcinoma. j clin aesthet dermatol. 2010;3(4): 39-48. 6. kim rh, armstrong aw. nonmelanoma skin cancer. dermatol clin. 2012;30(1):125-139. doi: 10.1016/j.det.2011.08.008. pmid: 22117874. 7. waldman a, schmults c. cutaneous squamous cell carcinoma. hematol oncol clin north am. 2019;33(1):1-12. doi: 10.1016/j.hoc.2018.08.001. pmid: 30497667. 8. amin mb, edge s, greene f, et al. eds. ajcc cancer staging manual. 8th ed. springer international publishing; 2017. 9. nccn clinical practice guidelines in oncology—squamous cell skin cancer, version 1.2021. 2021. national comprehensive cancer network. accessed: 01 april 2021 https://www.nccn.org/ professionals/physician_gls/pdf/squamous.pdf. 10. miller sj, alam m, andersen j, et al. basal cell and squamous cell skin cancers. j natl compr cancer netw. 2010;8(8):836-864. doi: 10.6004/jnccn.2010.0062. pmid: 20870631. 11. thompson ak, kelley bf, prokop lj, murad mh, baum cl. risk factors for cutaneous squamous cell carcinoma recurrence,metastasis, and disease-specific death: a systematic review and meta-analysis. jama dermatol. 2016;152(4):419-428. doi: 10.1001/jamadermatol.2015.4994. pmid: 26762219. 12. pyne jh, barr e, myint e, clark sp, david m, na r. invasive squamous cell carcinoma: comparison of differentiation grade and tumour depth by anatomical site in 1666 tumours. clin exp dermatol. 2018;43(1):3-10. doi: 10.1111/ced.13222. pmid: 29064114. 13. chapalain m, baroudjian b, dupont a, et al. stage iv cutaneous squamous cell carcinoma: treatment outcomes in a series of 42 patients. j eur acad dermatol venereol. 2020;34(6):1202-1209. doi: 10.1111/jdv.16007. pmid: 31587382. 14. amaral t, osewold m, presser d, meiwes a, garbe c, leiter u. advanced cutaneous squamous cell carcinoma: real world data of patient profiles and treatment patterns. j eur acad dermatol venereol. 2019;33(s8):44-51. doi: 10.1111/jdv.15845. pmid: 31658392. 15. misiakos ep, damaskou v, koumarianou a, et al. a giant squamous cell carcinoma of the skin of the thoracic wall: a case report and review of the literature. j med case rep. 2017;11(1):10-13. doi: 10.1186/s13256-017-1281-8. pmid: 28494816. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3):e2021047 1 unilateral pompholyx in a patient of anterior horn disease: an unusual presentation biswanath behera1, rashmi kumari2, debasis gochhait3 , pavithra ayyanar4 1 department of dermatology, and venereology, aiims, bhubaneswar, india. 2 department of dermatology, venereology and leprology, jawaharlal institute of postgraduate medical education and research (jipmer), puducherry, india 3 department of pathology, jawaharlal institute of postgraduate medical education and research (jipmer), puducherry, india 4 department of pathology, aiims, bhubaneswar, india. key words: dermoscopy, eczema, dyshidrotic, pompholyx citation: behera b, kumari r, gochhait d, ayyanar p. unilateral pompholyx in a patient of anterior horn disease: an unusual presentation. dermatol pract concept. 2021; 11(3):e2021047. doi: https://doi.org/10.5826/dpc.1103a47 accepted: january 3, 2021; published: july 8, 2021 copyright: ©2021 behera et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none. competing interests: the authors have no conflict of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. rashmi kumari, m.d., associate professor, dept. of dermatology, venereology and leprology, jipmer, puducherry, pin-605006. phone no09489692199, emailrashmi.sreerag@gmail.com introduction pompholyx is a type of eczematous dermatitis, presenting deep-seated vesicles and bullae (blisters) over the bilateral acral skin. isolated palmar involvement is the most common (70%), followed by palmoplantar (20%), and isolated plantar involvement (10%). diagnosis is rarely difficult when it presents in the classical form, although, at times, dermatoses such as dyshidrosiform bullous pemphigoid, epidermolysis bullosa aquisita, and in the pediatric population, scabies and acropustulosis need to be ruled out. the unilateral localization of pompholyx is an unusual presentation [1]. case presentation a 25-year-old male had a 2-months history of itchy lesions over the right hand, associated with increased sweating. the patient was a known case of anterior horn disease and had right upper limb paresis. he denied any personal or family history of atopy, prior history of contact dermatitis, or adverse drug reaction. cutaneous examination showed multiple deep-seated vesicles over the palmar, lateral, and dorsal areas of the right medial 4 digits, with areas showing desquamation (figure 1). the contralateral hand was within normal limits. upon nonpolarized dermoscopy only featureless areas (figure 2) were evident. therefore, a differential diagnosis of pompholyx and tinea manuum was considered. histological analysis showed acanthotic epidermis, spongiosis, spongiotic vesicles, and upper perivascular mild lymphocytic infiltration (figure 3). staining for fungus and bacteria detection was negative. the diagnosis of pompholyx was made, and the patient was treated with topical clobetasol 0.05% cream twice daily, for 15 days. pompholyx can be associated with or present manifestations of various dermatoses such as atopic dermatitis, contact dermatitis, adverse drug eruption, id reactions, and hiv infection [1]. unilateral pompholyx can be challenging to diagnose and needs to be distinguished from tinea pedis, 2 letter | dermatol pract concept. 2021; 11(3):e2021047 bullous impetigo, herpes zoster, fixed drug eruption, and friction blister as all of them can produce itchy vesiculobullous lesions [1].pompholyx is known to be associated with hyperhidrosis and factors that promote an increase in sweating. it is exacerbated by hot and humid environments, stress, smoking, and the use of occlusive gloves. the association of pompholyx with increased sweating is further supported by the acral location of pompholyx, which has the highest concentration of sweat glands, increased perspiration volume in patients with pompholyx, and iontophoresis as a modality of therapy [1].in our case, the unilateral localization of pompholyx was associated with an ipsilateral upper limb paresis and anterior horn disease. a similar case of unilateral pompholyx has been reported in association with amyotrophic lateral sclerosis (als). the authors attributed the disease-associated sympathetic overactivity to be responsible for the increased sweating and development of pompholyx [2]. various cutafigure 1. (a) and (b) multiple deep-seated vesicles (arrows) over the palmar, lateral, and dorsal aspect of right medial four digits, along with areas of desquamation. the contralateral hand is within normal limits. figure 2. dermoscopy under nonpolarized mode showing featureless areas. figure 3. histology showing the acanthotic epidermis, spongiosis, spongiotic vesicles, and upper perivascular mild lymphocytic infiltration (h&e, x100). letter | dermatol pract concept. 2021; 11(3):e2021047 3 neous changes have been described in the paralytic limb, such as edema, reduced minimum erythema dose, increased tanning, and reduced sebum secretion. in the index case, the altered autonomic nervous function is possibly responsible for the unilateral localization of the pompholyx, as evidenced by increased sweating [3]. the sympathetic system’s role is further backed up by the resolution of the right-sided eczema and hyperhidrosis with the persistence of contralateral hyperhidrosis and eczema, following right-sided sympathectomy [4]. it is postulated that the high concentration of cytokines and proteases detected in the sweat stimulate inflammation and spongiosis, leading to the development of pompholyx [4]. conclusion in conclusion, we reported a rare case of unilateral pompholyx in a patient with anterior horn disease that was localized to the ipsilateral side of the upper limb paresis. references 1. guillet mh, wierzbicka e, guillet s, dagregorio g, guillet g. a 3-year causative study of pompholyx in 120 patients. arch dermatol. 2007;143(12):1504-1508. doi: 10.1001/archderm.143.12.1504 2. nakai k, yoneda k, moriue t, hosokawa y, yokoi i, kubota y. unilateral palm pompholyx in a patient with amyotrophic lateral sclerosis. eur j dermatol. 2011;21(3):445-446. doi: 10.1684/ ejd.2011.1349 3. long cc, lever lr, marks r. unilateral bullous pemphigoid in a hemiplegic patient. br j dermatol. 1992 ;126(6):614-616. doi: 10.1111/j.1365-2133.1992.tb00110.x 4. chowdhury mm, hedges r, lanigan sw. unilateral resolution of palmar eczema and hyperhidrosis complicated by horner’s syndrome following ipsilateral endoscopic cervical sympathectomy. br j dermatol. 2000; 143(3):653-654. doi: 10.1111/j.13652133.2000.03733.x dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022063 1 dermoscopic keys in extragenital bullous hemorrhagic lichen sclerosus siddharth mani, bhavni oberoi department of dermatology, inhs asvini, near rc church, colaba, mumbai, india key words: lichen sclerosus, hemorrhagic, dermoscopy, follicular plugs citation: mani s, oberoi b. dermoscopic keys in extragenital bullous hemorrhagic lichen sclerosus. dermatol pract concept. 2022;12(2):e2022063. doi: https://doi.org/10.5826/dpc.1202a63 accepted: september 22, 2021; published: april 2022 copyright: ©2022 mani et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication corresponding author: bhavni oberoi, department of dermatology, inhs asvini, near rc church, colaba, mumbai400005 india. e-mail: bhavni.oberoi@gmail.com introduction lichen sclerosus (ls) is a chronic inflammatory dermatosis characterized by leukoderma and scarring, predominantly affecting the genital skin. it may sometimes involveextragenital areas. the suffix atrophicans is no longer used as a few cases are associated with hypertrophy rather than atrophy. few atypical variants include bullous, hemorrhagic, pigmented, verrucous, and keratotic forms. herein, we report a case of extragenital bullous hemorrhagic lichen sclerosus with its dermoscopic features. case presentation a 40-year-old male presented with a nine-month history of a slow-growing asymptomatic raised lesion on his back associated with occasional bleeding episodes after casual trauma. there was no history of similar lesions in the past or elsewhere on the body. physical examination revealed a solitary, well-defined, 2.5 cm × 2.0 cm, non-tender, hemorrhagic bulla with crusting in the center and atrophy in the surrounding area (figure 1 a). dermoscopy revealed superficial yellowish white and hemorrhagic crusts, follicular plugs, and multicolored diffuse hemorrhagic area with varying shades ranging from black to red, with black color representing old hemorrhage and red color representing recent hemorrhage (figure 1b). surrounding skin revealed atrophy with follicular plugs (figure 1c). based on the clinical and dermoscopic examination, we considered hemorrhagic lichen sclerosus, irritated seborrheic keratosis, bowen disease, and discoid lupus erythematosus as our differential diagnoses. histopathology revealed follicular plugs, epidermal atrophy, subepidermal blister, and hyalinized compact collagen, which confirmed the case to be ls (figure 1d). discussion the extragenital form of ls is less common, and the bullous hemorrhagic form is very rare, with only a handful of cases in the literature. this form is generally associated with less pruritus and the absence of any malignancy, as seen in our patient as well. in our case, the lesion was present on the back, a site that has not been reported for this particular variant. the formation of bullous lesions has been described 2 research letter | dermatol pract concept. 2022;12(2):e2022063 in ls. a possible explanation for the formation of bulla and hemorrhage could be the pronounced edema within the skin that disrupts the capillaries collagen support, predisposing them to rupture with minimal trauma or damage [1]. conclusions dermoscopy of extragenital ls has been described as white structureless areas, follicular plugs, white chrysalis-like structures, and variable vascular patterns being the essential components [2]. our case had superficial yellowish white and hemorrhagic crusts, a multicolored (black to red) hemorrhagic area, and a peripheral atrophic area with follicular plugs. there was no vascular pattern which commensurates with the chronicity of the lesion. the patient was managed with topical corticosteroids with a good response. this case report helps establish the fact that follicular plugs which have been reported in ls are seen in this rare variant also. in addition, the dermoscopic features of the hemorrhagic area of ls, which have not been previously described, have been figure 1. a. a solitary, well defined, 2.5 cm × 2.0 cm, non-tender, hemorrhagic bulla with crusting in the centre and atrophy in the surrounding area. b. dermoscopic examination of lesion shows superficial yellowish white and hemorrhagic crusts, follicular plugs and multicolored diffuse hemorrhagic area with varying shades ranging from black to red (black color representing old hemorrhage and red color indicating recent hemorrhage). blue color indicates marking for biopsy site. c. dermoscopic examination of surrounding skin shows atrophy with follicular plugs. d. skin biopsy showing presence of follicular plugs, epidermal atrophy, subepidermal blister and hyalinized compact collagen (h&e x 40). research letter | dermatol pract concept. 2022;12(2):e2022063 3 brought out. this report will enhance the existing repertoire of knowledge of dermoscopic features of ls which may aid diagnosis in future and avoid invasive procedures. references 1. gómez-calcerrada, del cerro heredero m, sanchez mh, fernandez rs, de eusebio murillo e, yus es. bullous and hemorrhagic lesions. arch dermatol. 1999;135(1):81-86. doi: 10.1001/archderm.135.1.81. pmid: 9935386. 2. ankad bs, beergouder sl. dermoscopic patterns in lichen sclerosus: a report of three cases. ind dermatol online j. 2015;6(3):237-240. doi:10.4103/2229-5178.156450. pmid: 26009734. pmcid: pmc4439768. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 11(3): e2021044 1 dermoscopy and histopathology of darier diseaseassociated nevoid hyperkeratosis of nipple and areola siddhartha dash, biswanath behera, aparna palit, madhusmita sethy department of dermatology, and venereology, and pathology, all india institute of medical sciences (aiims), bhubaneswar, india key words: darier disease, dermoscopy, nevoid hyperkeratosis, nipple citation: dash s, behera b, palit a, sethy m. dermoscopy and histopathology of darier disease-associated nevoid hyperkeratosis of nipple and areola. dermatol pract concept. 2021; 11(3): e2021044. doi: https://doi.org/10.5826/dpc.1103a44 accepted: october 6, 2020; published: july 8, 2021 copyright: ©2021 dash et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none declared. authorship: all authors have contributed significantly to this publication. corresponding author: dr. biswanath behera, assistant professor, department of dermatology, and venereology, all india institute of medical sciences (aiims), bhubaneswar. odisha, india. email: biswanathbehera61@gmail.com. introduction nevoid hyperkeratosis of nipple and areola (nhna) has been classified into 3 types: type 1 is associated with an epidermal nevus; type 2 with various dermatoses such as the darier disease (dd), chronic eczema, and cutaneous t-cell lymphoma; type 3 is of unknown etiology. despite the multifactorial association, a consistent morphological feature of nhna is the presence of brown verrucous plaques involving the nipple and areola area, making the clinical distinction difficult [1]. case presentation a 25-year-old male with skin type v presented with multiple variably pigmented lesions all over the body since the age of 5. he reported a history of swelling affecting the bilateral nipple-areola complex (nac) for 1 year. lesions were foul-smelling and exacerbating during summer. he did not report a similar family history. on cutaneous examination, the bilateral nac showed erythematous to gray verrucous plaques that hindered the visibility of the nipples (figure 1a). dermoscopic examination (dermlite, dl4, 10x magnification) of the nac revealed a central crater filled with a yellow to yellowish-brown keratotic plug surrounded by white radial streaks, and outermost brown homogenous area and pigment network (figure 1b). the shape of the craters was variable with an angulated border. histological examination of the plaque over the nac, revealed a suprabasal acantholysis along with corp ronds and grains (figure 1c). a diagnosis of nevoid hyperkeratosis of nipple and areola (nhna) secondary to darier disease (dd) was made. besides, there were multiple erythematous to gray-brown verrucous papules scattered all over the body, more so in the seborrheic distribution (figure 2a), which revealed a similar dermoscopic pattern irrespective of the size or duration of the lesions (figure 2, b and c). the patient was treated with 30 mg isotretinoin capsules once a day. 2 months post-therapy, nhna dermoscopic features and cutaneous lesions showed a significant improvement (figure 3). 2 letter | dermatol pract concept. 11(3): e2021044 dermoscopic features of nhna are sparsely reported. mazzella et al. reported multiple blue-gray globules and leaflike areas in the case of type 3 nhna [1]. in the index case, a similar dermoscopic pattern comprising of a central varying shaped crater surrounded by white radial streaks, and an outermost brown homogenous area to pigment network, was observed for nhna and verrucous papules. this suggests the replication of dd dermoscopic features despite the varying morphological presentation, size, and location of the lesions. lacarrubba et al. described a similar dermoscopic pattern for dd, consisting of polygonal, star-like, or roundish-ovalshaped yellowish/brownish areas of various sizes surrounded by a thin whitish halo, as reported by us [2].in addition to differentiating other causes of nhna, the observed dermofigure 1. (a) erythematous to gray-coloured verrucous plaque hindering the visibility of the nipple. (b) dermoscopic examination showing varying shape central crater filled with yellow to yellowish-brown keratotic plug surrounded by white radial streaks, and outermost brown homogenous area and pigment network. the craters have an angulated border. (c) histopathology from nipple-areola complex showing suprabasal acantholysis, along with corps ronds and grains at the base of a surface crater (h&e, x50). letter | dermatol pract concept. 11(3): e2021044 3 figure 2. (a) multiple erythematous to gray-brown verrucous papules over the back. (b) and (c) early and advanced papules showing varying shaped central crater filled with yellow to yellowish-brown keratotic plug surrounded by white radial streaks, and outermost brown homogenous area and pigment network. figure 3. (a)subsidence of dermoscopic features of nevoid hyperkeratosis of nipple and areola. (b) improvement of the verrucous papules is evident by the disappearance of central crater, keratotic plugs, and white streaks. scopic pattern can be extremely helpful, especially for dd patients presenting with isolated hyperkeratosis of the nipple. in concurrence with clinical improvement, the disappearance of dermoscopic features, the central crater, and radial streaks, suggest the response to therapy. conclusion here we reported a characteristic dermoscopic pattern found in a case of dd associated nhna, which can be valuable for future diagnosis and for differentiating it from other nhna causes. 4 letter | dermatol pract concept. 11(3): e2021044 references 1. lacarrubba f, verzì ae, errichetti e, stinco g, micali g. darier disease: dermoscopy, confocal microscopy, and histologic correlations. j am acad dermatol. 2015;73(3):e97-e99. doi: 10.1016/j. jaad.2015.04.066 2. mazzella c, costa c, fabbrocini g, et al. nevoid hyperkeratosis of the nipple mimicking a pigmented basal cell carcinoma. jaad case rep. 2016;2(6):500-501. doi: 10.1016/j.jdcr.2016.09.007 dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021046 1 sodium hypochlorite 0.005% versus placebo in the treatment of mild to moderate acne: a double-blind randomized controlled trial azadeh dorostkar1, mehdi ghahartars1, mohammad reza namazi1, nafiseh todarbary2, maryam hadibarhaghtalab1, maryam rezaee1 1 dermatology department, shahid faghihi hospital, shiraz university of medical sciences, shiraz, iran 2 student research committee, shiraz university of medical sciences, shiraz, iran key words: topical, sodium hypochlorite, acne vulgaris, treatment citation: dorostkar a, ghahartars m, namazi mr, todarbary n, hadibarhaghtalab m, rezaee m. sodium hypochlorite 0.005% versus placebo in the treatment of mild to moderate acne: a double-blind randomized controlled trial. dermatol pract concept. 2021;11(3):e2021046. doi: https://doi.org/10.5826/dpc.1103a46 accepted: december 9, 2020; published: may 20, 2021 copyright: ©2021 dorostkar et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. competing interests: the authors have no conflicts of interest to declare. funding: none corresponding author: maryam hadibarhaghtalab, department of dermatology, faghihi hospital, zand street, shiraz, iran. email: maryam_hadibarhaghtalab@yahoo.com background: acne vulgaris is a common inflammatory disease of the pilosebaceous follicle that affects many teenagers and young people. there is an obvious need for topical treatments with good tolerability and efficacy for the management of acne lesions. objective: this study determined the therapeutic efficacy of topical sodium hypochlorite solution (0.005%) in the treatment of mild to moderate acne lesions. methods: this placebo-controlled randomized controlled trial compared 0.005% sodium hypochlorite to placebo administered topically on each side of the patients’ faces 3 times a day for 1 month. the numbers of papules and pustules were recorded at baseline, 1, 2 and 4 weeks after initiation. results: the total number of papules and pustules decreased after topical application of sodium hypochlorite 0.005% for 1 month. conclusions: topical sodium hypochlorite solution (0.005%) can be effective in the treatment of mild to moderate acne, and its clinical efficacy was evaluated between the male and female groups and between the hormonal and non-hormonal ones. trial registration: our study was registered in the iranian registry of clinical trials (irct) with the code number irct20200701047976n1. abstract 2 research | dermatol pract concept. 2021;11(3):e2021046 introduction acne vulgaris, the most common dermatological disease, affects 35%-90% of adolescents [1]. acne is inflammation of the pilosebaceous units of the skin, and it presents as lesions such as scars and hyperpigmentation [2]. although the ideal treatment for acne is still under investigation, an effective regimen to reduce lesions can be found for most patients. however, there is a lack of high-quality evidence on the comparative effectiveness of common topical and systemic acne treatments [3]. additionally, the complex combination treatment regimens that affect different aspects of acne pathophysiology can lead to poor treatment adherence and may decrease the effectiveness of the treatment [4]. sodium hypochlorite is a common antiseptic agent with a broad application in medicine, including use in bladder and urethra irrigation, control of some topical mycoses, prophylaxis against burn infections, and as an irrigant in dental root canal procedures [5]. in 2017, eriksson and colleagues revealed that sodium hypochlorite 0.004% considerably decreased the s. aureus load in atopic dermatitis lesions [6]. additionally, hunter revealed that sodium hypochlorite accelerated the remission of herpes simplex lesions [5]. we hypothesized that sodium hypochlorite 0.005% is possibly effective in treating mild to moderate acne. therefore, this placebo-controlled, randomized controlled trial investigated the therapeutic efficacy of sodium hypochlorite 0.005% in the treatment of mild to moderate acne. methods this randomized controlled trial was conducted on 40 consecutive acne patients seen at the dermatology clinic of shahid faghihi hospital, from november 2017 to april 2018. patients with secondary acne caused by lactation, dermatology conditions, or allergy to sodium hypochlorite as well as those who had taken isotretinoin or systemic or topical antibiotics within the past 2 months were excluded from the study. the review board of shiraz university of medical sciences approved the study, and all recruited patients filled the informed consent form. the study was registered in the iranian registry of clinical trials (irct) with the code number irct20200701047976n1. the patients were randomly assigned to receive sodium hypochlorite 0.005% or placebo, to be administered topically on each side of their face 3 times a day for 1 month. the patients were not aware of the type of solution (placebo or sodium hypochlorite) applied to their faces. moreover, the dermatologist and the observer were blinded to the identity of the solution applied to each patient. we used the modified global acne grading scale (mgags) to assess the severity of acne during the study. statistical package for social science for windows was used for data analysis. because the data were non-parametric, we used the wilcoxon test to compare the numbers of lesions between the two groups. additionally, we used the friedman test to evaluate changes in the number of papules and pustules during the study. a p-value <0.05 was considered statistically significant. results the study enrolled 40 patients with mild to moderate acne, including 32 (80%) women and 8 (20%) men. the mean age of the patients was 21.3 years (range, 15–28 years). after one month, the total number of papules and pustules decreased significantly, from 759 to 476, in the patients (p < 0.0001). moreover, the number of papules decreased significantly after one month (p < 0.0001), while the number of pustules did not change significantly (p = 0.692). table 1 shows the statistical analysis of papules and pustules over 1 month. table 2 shows the statistical analysis in hormonal and non-hormonal groups. the number of papules and pustules did not change significantly in these groups over 1 month (in both groups; p > 0.05). the number of pustules decreased in the female group (p = 0.005) but the number of papules did not change remarkably (p >0.05). table 3 shows the statistical analysis for males vs females. topical application of sodium hypochlorite caused more acne remission in the female group than in the male group (p > 0.05). table 1. mean rank of papules and pustules in 40 acne patients who received either hypochlorite sodium or placebo over one month hypochlorite group placebo group p value papules week 1 9.83 9.33 0.319 week 2 6.99 7.78 0.266 week 4 5.85 7.66 0.015 pustules week 1 7.99 5.28 0.003 week 2 4.14 5.25 0.029 week 4 2.93 5.00 0.002 research | dermatol pract concept. 2021;11(3):e2021046 3 discussion our study shows that the total number of acne lesions decreased significantly after applying sodium hypochlorite 0.005% topically 3 times a day for 1 month. consequently, topical application of sodium hypochlorite 0.005% can be effective in the treatment of mild to moderate acne. a reduction in the total number of papules and pustules highlights the antimicrobial properties of sodium hypochlorite. del rosso and colleagues reported that sodium hypochlorite was an effective antimicrobial agent to decrease the load of s. aureus in atopic dermatitis lesions [8]. coetzee and colleagues indicated that an un-buffered solution of sodium hypochlorite 0.006% was effective in the management of infected burn wounds caused by pseudomonas aeruginosa, s. aureus and streptococcus pyogenes [9]. consequently, sodium hypochlorite can possibly be helpful to decrease the load of propionibacterium acnes in acne lesions. a reduction of pustules in the female group was associated with the topical application of sodium hypochlorite 0.005%. consequently, we can use it as a treatment for female acne similar to other topical products [10]. preneau and dreno showed that female acne is a common female disease (40%-50%) that should be treated differently from adolescent acne because of differences in the clinical scale and therapeutic algorithm [11]. acne therapy comprises several options, but the efficacy and adverse events of each treatment are under investigation. by way of illustration, treatment with oral antibiotics is long-lasting because of bacterial resistance, adverse effects table 2. ranking of papules and pustules in the patients with hormonal and non-hormonal acne who received hypochlorite sodium or placebo over 1 month. hypochlorite group placebo group p value hormonal papules week 1 3.00 7.00 0.673 week 2 5.33 5.75 0.645 week 4 5.75 5.13 0.473 hormonal pustules week 1 3.67 5.67 0.170 week 2 5.81 4.25 0.051 week 4 5.13 4.00 0.028 non-hormonal papules week 1 10.15 16.08 0.410 week 2 11.47 13.00 0.299 week 4 14.53 12.50 0.014 non-hormonal pustules week 1 8.75 13.15 0.009 week 2 14.88 9.68 0.206 week 4 13.53 11.64 0.028 table 3. mean rank of papules and pustules in the male and female patients who received hypochlorite sodium or placebo over 1 month. hypochlorite group placebo group p value male papules week 1 4.14 7.00 0.107 week 2 4.92 5.17 0.399 week 4 5.21 4.25 0.095 male pustules week 1 3.25 4.30 0.201 week 2 5.33 4.33 0.252 week 4 4.67 4.00 0.158 female papules week 1 9.59 15.68 0.124 week 2 11.50 14.17 0.518 week 4 14.97 13.50 0.062 female pustules week 1 9.21 14.47 0.008 week 2 15.47 9.30 0.058 week 4 14.25 11.00 0.005 4 research | dermatol pract concept. 2021;11(3):e2021046 and low efficacy during short-term application. additionally, acne therapy with isotretinoin is teratogenic with noticeable side effects; thus, it needs close follow-up. hormonal therapy is limited to female patients and its side effects include abnormal menstruation, nausea and vomiting, weight gain, breast tenderness, and higher risk of thromboembolism [12]. furthermore, costs and availability are considerable factors of treatment, especially in developing countries. therefore, sodium hypochlorite 0.005% can be a suitable option for acne treatment due to its low cost, high availability and few side effects. sodium hypochlorite 0.005% was safe and well-tolerated by patients of our study, but skin-related adverse events such as skin irritation or itching, and acne reoccurrence have been our concerns after discontinuation of sodium hypochlorite 0.005%. studies have revealed that combination therapy is more successful in acne treatment. as a result, the combination of sodium hypochlorite 0.005% with retinoids or antibiotics can improve the anti-inflammatory effects of the treatment regimen or reduce the resistance to antibiotics, respectively [2]. additionally, the combination with compounds such as azelaic acid, salicylic acid and tazarotene can be effective in acne therapy. as hidalgo et al.’s study showed, the bactericidal effect of sodium hypochlorite increases by reducing the ph [5]. because our study group was small, more studies with more patients are needed to determine the clinical efficacy of sodium hypochlorite 0.005% in acne therapy. in conclusion, our randomized controlled trial demonstrates that sodium hypochlorite 0.005% is an effective and safe treatment for acne, and that the therapeutic outcomes were different between hormonal and non-hormonal acne and between male and female groups. references 1. tan jk and bhate k. a global perspective on the epidemiology of acne. br j dermatol. 2015. 172 suppl 1: 3-12. doi: 10.1111/ bjd.13462. pmid: 25597339 2. fox l, et al. treatment modalities for acne. molecules. 2016. 21(8). doi: 10.3390/molecules21081063. pmid: 27529209 3. williams hc, dellavalle rp, and garner s. acne vulgaris. lancet. 2012. 379(9813): 361-72. doi: 10.1016/s0140-6736(11)60321-8 4. moradi tuchayi s, et al. acne vulgaris. nat rev dis primers. 2015. 1: 15029. doi. 10.1038/nrdp.2015.29. pmid: 27189872 5. hidalgo e, bartolome r, dominguez c. cytotoxicity mechanisms of sodium hypochlorite in cultured human dermal fibroblasts and its bactericidal effectiveness. chemico-biological interactions. 2002. 139(3): 265-282. doi: 10.1016/s0009-2797(02)00003-0. 6. eriksson s, et al. antibacterial and antibiofilm effects of sodium hypochlorite against staphylococcus aureus isolates derived from patients with atopic dermatitis. br j dermatol. 2017. 177(2): 513521. doi: 10.1111/bjd.15410. pmid: 28238217 7. hunter dt. sodium hypochlorite in the treatment of herpes simplex virus infections. cutis. 1983. 31(3): 328-32. 8. del rosso jq and bhatia n. status report on topical hypochlorous acid: clinical relevance of specific formulations, potential modes of action, and study outcomes. j clin aesthet dermatol. 2018. 11(11): 36-39. 9. coetzee e, et al. the use of topical, un-buffered sodium hypochlorite in the management of burn wound infection. burns. 2012. 38(4): 529-33. doi: 10.1016/j.burns.2011.10.008. pmid: 22100425 10. bagatin e, et al. adult female acne: a guide to clinical practice. anais brasileiros de dermatologia. 2019. 94(1): 62-75. doi. 10.1590/abd1806-4841.20198203. pmid: 30726466 11. preneau s. and dreno b. female acne a different subtype of teenager acne? j eur acad dermatol venereol. 2012. 26(3): 27782. doi: 10.1111/j.1468-3083.2011.04214.x pmid: 21848892 12. hilerowicz y, et al. thermomechanical ablation-assisted photodynamic therapy for the treatment of acne vulgaris. a retrospective chart review of 30 patients. lasers in surgery and medicine. n/a(n/a). dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022060 1 dermoscopic features of amelanotic and hypomelanotic melanomas: a review of 49 cases sarah dawood1, alla altayeb1, ausama atwan1, caroline mills1 1 st woolos hospital, dermatology department, newport, united kingdom. key words: hypomelanotic melanoma, amelanotic melanoma, dermatoscopy, dermoscopy, skin cancer citation: dawood s, altayeb a, atwan a, mills c. dermoscopic features of amelanotic and hypomelanotic melanomas: a review of 49 cases. dermatol pract concept. 2022;12(2):e2022060. doi: https://doi.org/10.5826/dpc.1202a60 accepted: october 21, 2021; published: april 2022 copyright: ©2022 dawood et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr sarah dawood, st woolos hospital dermatology 131 stow hill, newport np20 4sz, united kingdom. e-mail: sarahamrd@live.co.uk introduction amelanotic and hypomelanotic melanomas (ahm) represent 2-8% of all melanomas. they are often diagnosed late due to the lack of a distinctive clinical appearance. as a result, ahm is associated with higher mortality compared with pigmented melanomas. it is, therefore, crucial to be aware of the dermoscopic features of such lesions to aid early diagnosis. case presentation during a 6-year period (2014-2019), a total of 165 melanoma cases were diagnosed via our teledermoscopy service, using nikon d300s camera and heine® delta 20t dermatoscope. of those, 49 cases (29.7%) were ahm, including 27 males and 22 females with a median age of 68 years (range 16-87 years). most amh were on the upper limbs (20 patients) and the trunk (13 patients). the rest were on the lower limbs (9 patients), and head and neck (7 patients). most lesions (n = 46, 83.8%) were invasive ahm ( superficial spreading = 27; nodular = 14; desmoplastic melanoma = 3; lentigomaligna melanoma = 2). the remaining 3 lesions were in situ ahm. the median breslow thickness of ahm was higher than pigmented mm (ahm = 1.7 mm interquartile range [iqr] = 3.50) versus 0.98 mm (iqr = 1.23) for pigmented mm). short white lines (figure 1b) and milky-red areas ( figure 2b) were the most common dermoscopic findings in our cohort of ahm, observed in 39 lesions (79.6%) and 33 lesions (67.3%), respectively. milky-red areas were present in similar frequencies in lesions ≤ 1 mm in thickness (70%) and lesions > 1 mm in thickness (63.9%) (table 1). in our study, 63.3% of ahm had more than one vascular pattern (table 1). dotted, linear, and looped vessels were present in 57.1%, 63.2%, and 63.3% of lesions, respectively. dotted vessels were seen in 90% of ahm of < 1mm, compared with 44.4% of ahm of > 1mm.  remnant pigment was present in 27 lesions (55.1%), and present in 70% of lesions ≤ 1mm in thickness and 50% of lesions > 1 mm in thickness. gray granular structures and lacunae were less frequently seen, found in 44.9% and 26.5% of lesions, respectively.  2 research letter | dermatol pract concept. 2022;12(2):e2022060 discussion short white lines were the most common finding in our cohort, seen in 79.6% of cases. this is higher than reported observations at 30.8% [1]. we assume reviewing magnified images on the monitor contributed to better visualization of these subtle features. the incidence of milky-red areas in our study (67.3%) was close to the incidence reported in the literature at 54.5% [2,3]. also, polymorphic vessels, an important distinguishing feature in ahm, were present in over 50% of our ahm cases. dotted vessels were present in nearly half of our cases. this was similar to the incident reported in the literature [1]). zalaudeket al reported a strong association between figure 2. (a) lesion on the lower leg of a 57-year-old woman. a confirmed melanoma with breslow thickness of 3 mm. (b) dermoscopy shows irregularly distributed dotted vessels (arrows), a milky red area (star), and a subtle remnant of pigment at the periphery. figure 1. (a) lesion on the forearm of a 46-year-old woman. a confirmed melanoma with breslow thickness of 1.1 mm. (b) dermoscopy shows dotted (black arrows) and looped (white arrows) vessels, milky red areas (stars), and white structures (long arrows). research letter | dermatol pract concept. 2022;12(2):e2022060 3 dotted vessels and ahm with breslow thickness less than 1 mm [4]. our study supports this observation. conclusions our study reinforces the findings that polymorphic vessels and milky-red areas are common features of ahm. in addition, our study indicates that short white lines are also common and helpful predictive feature. clinicians should be aware of these dermoscopic findings when non-specific lesions are encountered. acknowledgement we thank the medical illustration department at aneurin bevan university health board for providing the teledermatology service. references 1. paolino g, bearzi p, pampena r, et al. clinicopathological and dermoscopic features of amelanotic and hypomelanotic melanoma: a retrospective multicentric study. int j dermatol. 2020;59(11):1371-1380. doi: 10.1111/ijd.15064. pmid: 32726478. 2. pizzichetta ma, talamini r, stanganelli i, et al. amelanotic/ hypomelanotic melanoma: clinical and dermoscopic features. br j dermatol. 2004;150(6):1117-1124. doi: 10.1111/j.13652133.2004.05928.x. pmid: 15214897. 3. lin mj, xie c, pan y, jalilian c, kelly jw. dermoscopy improves diagnostic accuracy for clinically amelanotic nodules. australas j dermatol. 2019;60(1):45-49. doi: 10.1111/ajd.12902. pmid: 30123971. 4. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part i. melanocytic skin tumors j am acad dermatol. 2010;63(3):361-374. doi: 10.1016/j.jaad.2009.11.698. pmid: 20708469. table 1. dermoscopic features of amelanotic and hypomelanotic melanoma in our study dermoscopic criteria ahm ≤ 1mm in thickness (n = 10) ahm > 1 mm in thickness (n = 36) ahm in situ (n = 3) total ahm (n = 49) n % n % n % n % dotted vessels 9 90.0 16 44.4 3 100 28 57.1 linear vessels 5 50.0 23 63.9 3 100 31 63.2 looped vessels 3 30.0 26 72.2 2 66.7 31 63.3 granular structures 5 50.0 16 44.4 1 33.3 22 44.9 short white lines 8 80.0 28 77.8 3 100 39 79.6 lacuna structures 3 30.0 10 27.8 0 0 13 26.5 milky-red areas 7 70.0 23 63.9 3 100 33 67.3 remnant pigment 7 70.0 18 50.0 2 66.7 27 55.1 polymorphous vessels 6 60.0 22 61.1 3 100 31 63.2 ahm = amelanotic and hypomelanotic melanomas. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022121 1 dermatology practical & conceptual dermoscopy of pseudoepitheliomatous hyperplasia tattoo reaction pattern biswanath behera1, rashmi kumari2, debasis gochhait3, pavithra ayyanar4 1 department of dermatology and venereology, aiims, bhubaneswar, india 2 department of dermatology, venereology and leprology, jawaharlal institute of postgraduate medical education and research (jipmer), puducherry, india 3 department of pathology, jawaharlal institute of postgraduate medical education and research (jipmer), puducherry, india 4 department of pathology, aiims, bhubaneswar, india keywords: dermoscopy, pseudoepitheliomatous hyperplasia, squamous cell carcinoma, tattoo citation: behera b, kumari r, gochhait d, ayyanar p. dermoscopy of pseudoepitheliomatous hyperplasia tattoo reaction pattern. dermatol pract concept. 2022;12(3):e2022121. doi: https://doi.org/10.5826/dpc.1203a121 accepted: november 29, 2021; published: july 2022 copyright: ©2022 behera et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: rashmi kumari, m.d., associate professor, dept. of dermatology, venereology and leprology, jipmer, puducherry, pin-605006. phone no09489692199, email: rashmi.sreerag@gmail.com introduction delayed cutaneous tattoo reactions are a relatively rare occurrence and include, lichenoid, granulomatous, allergic, pseudoepitheliomatous (peh), and pseudolymphoma. dermoscopic features of delayed tattoo reaction patterns are rarely reported [1]. case presentation a 21-year-old male had a one-year history of a slow-growing, asymptomatic lesion over a blue tattoo. it started six months after the tattooing. cutaneous examination showed solitary erythematous to bluish verrucous plaque over the tattoo (figure 1a). dermoscopic examination under nonpolarized mode revealed two distinct zones. the central area had white scales, white to pinkish-white structureless area, comedo-like opening with keratotic plugging, white circles, red globules, hemorrhage, hairpin, and linear irregular vessels. the peripheral zone showed a gray-white to bluish-white structureless area (figure 1, b and c). the differential diagnoses included were lupus vulgaris, tuberculosis verrucosa cutis (tbvc), chromoblastomycosis, and granulomatous tattoo reaction pattern. histology showed hyperkeratosis, parakeratosis, pseudoepitheliomatous hyperplasia, spongiosis, and lymphocytic exocytosis. in addition to tattoo pigment, the dermis had a subepidermal band-like, perivascular and peri-adnexal predominant lymphocytic infiltration and occasional plasma cells. also, the epidermis showed focal keratinocyte swelling, dyskeratotic cells, and the dermis showed an increased number and dilated dermal blood vessels. (figure 2, a and b). other investigations were within normal limits. the diagnosis of peh tattoo reaction pattern was made, and the patient was treated with intralesional triamcinolone acetonide 40 mg/ml. peh is the result of benign hyperplasia of the epidermal and adnexal epithelium. tattoo-induced peh is a rare 2 research letter | dermatol pract concept. 2022;12(3):e2022121 figure 1. (a) solitary erythematous to bluish verrucous plaque over the tattoo. (b) dermoscopic examination under nonpolarized mode (heine delta20®, 10x magnification) shows white scales, white to pinkish-white structureless area, comedo-like opening with keratotic plugging, white circles (blue arrow), red globules, hemorrhage, and linear irregular vessels (red arrow). (c) the peripheral zone shows a gray-white to bluish-white structureless area and hairpin vessels (blue arrow). red arrow points white circle. figure 2. (a) histology shows pseudoepitheliomatous epidermal hyperplasia (h & e, x100). (b) a subepidermal band-like, perivascular and periadnexal, predominant lymphocytic infiltration, along with tattoo pigments (h&e, x100). benign reaction pattern commonly to red or purple pigment. differentiating peh from squamous cell carcinoma (scc) is vital to reduce patient morbidity and cosmetic disfigurement, as the latter can occur independently over tattoo or arise from the peh. the early onset and lesions confinement to the tattoo margins favors peh, while a late onset and involvement beyond the tattoo border suggest scc. research letter | dermatol pract concept. 2022;12(3):e2022121 3 a homogenous violaceous pattern with follicular white-yellow halo was reported in a case of tattoo pseudolymphoma [1]. the dermoscopic features described for scc are scales, keratin, white circles around a dilated and plugged follicular infundibulum, white structureless area, blood spots, and hairpin, linear, linear irregular, glomerular, or polymorphic vascular pattern [2]. in the index case, the following dermoscopic features overlapped with scc: white homogenous area, keratotic follicular plugging surrounded by white circles, and polymorphous vascular structures. however, the patient age, temporal correlation, and circumscription of the plaque, along with dermoscopic findings, were suggestive of peh. the dermoscopic features described for other differential diagnoses are the following: lupus vulgaris shows a diffuse or localized yellow-orange structureless area and linear branching vessels; tbvc displays a yellowish-red to yellowish brown areas, scales, and out-of-focus vascular structures; chromoblastomycosis is reported to have scale, crust, and yellow structureless and pink-white areas; and granulomatous tattoo reaction shows crystalline structures and orange structureless area [3-5]. conclusions we are reporting the clinico-dermoscopic-pathologic features of a case of peh tattoo reaction pattern. dermoscopy may help distinguish peh from other differential diagnoses described above, but not from scc, in which case only clinical and anamnestic data may help in their differentiation. references 1. kendel m, toncic rj, bradamante m, et al. dermoscopy of a tattoo pseudolymphoma. dermatol pract concept. 2019;9(1): 17-19. doi: 10.5826/dpc.0901a04. pmid: 30775141; pmcid: pmc6368077. 2. rosendahl c, cameron a, argenziano g, zalaudek i, tschandl p, kittler h. dermoscopy of squamous cell carcinoma and keratoacanthoma. arch dermatol. 2012;148(12):1386-1392. doi: 10.1001/archdermatol.2012.2974. pmid: 22986634. 3. jakhar d, gupta rk, sarin n. dermoscopy of tuberculosis verrucosa cutis. indian dermatol online j. 2020;12(1):206-207. doi: 10.4103/idoj.idoj_292_19. pmid: 33768061; pmcid: pmc7982051. 4. jayasree p, malakar s, raja h, gopinathan nair n. dermoscopic features in nodular chromoblastomycosis. int j dermatol. 2019 ; 58(5):e107-e109. doi: 10.1111/ijd.14344. epub 2018 dec 18. pmid: 30565211. 5. bombonato c, argenziano g, lallas a, moscarella e, ragazzi m, longo c. orange color: a dermoscopic clue for the diagnosis of granulomatous skin diseases. j am acad dermatol. 2015;72 (1 suppl):s60-s63. doi: 10.1016/j.jaad.2014.07.059. pmid: 25500047. dermatology: practical and conceptual editorial | dermatol pract concept 2020;10(2):e2020049 1 dermatology practical & conceptual the outbreak of the novel coronavirus infection (covid-19) in china in december 2019 and the rapid subsequent spread of the infection worldwide have created awareness among patients and doctors. to date (march 20, 2020) 250,856 confirmed cases and 10,389 deaths have been reported [1]. beyond the important health issue, effects on economy, education, social life, and tourism have arisen. most hospitals in the affected countries are full of real and suspected cases, therefore overloading health professionals as has rarely happened before. the emergency mostly involves internal medicine departments, including infectious diseases, respiratory medicine, and emergency and intensive care units. to a lesser extent, other specialties have been hit by the problem as well. what happened to dermatology? in a couple of weeks we have thoroughly changed our way of doing things, and frightened patients have contributed to these changes, producing some effects that are without precedent: 1. consultations in outpatient clinics have considerably declined in number for two main reasons: patients are afraid and dermatologists recommend avoiding non-urgent visits. 2. governments (as happened in italy, for instance) have stopped all visits to outpatient clinics except for oncology. 3. dermatological consultation requires close contact with patients, thus producing fear among doctors of being infected, consequently reducing the quality of performance. 4. although authorities recommend the use of protective masks for health practitioners, most of them have not been provided because of the high demand of these disposables. 5. surgery for skin cancer is often postponed according to the patient’s will. 6. patients stop taking medications independently, in particular, immunosuppressants and biological drugs, thinking their use leads to a higher risk of developing coronavirus infection. the list of consequences for our practice could be endless, and the same is likely in other medical specialties as well. the virus, along with the fear of the virus, has undoubtedly changed our lives. it is not easy to establish what the right thing to do is and, although isolation is mandatory to control the infection, postponing some medical procedures could be lethal to some patients. specialty-specific recommendations should be urgently available for each branch of medicine to avoid self-management and confusion among clinicians and subsequent serious consequences to patients. reference 1. coronavirus covid-19 global cases by the center for systems science and engineering (csse) at johns hopkins university (jhu). available at: https://coronavirus.jhu.edu/map.html. accessed march 20, 2020. the impact of novel coronavirus on dermatology vincenzo piccolo,1 giuseppe argenziano1 1 dermatology unit, university of campania, naples, italy citation: piccolo v, argenziano g. the impact of novel coronavirus on dermatology. dermatol pract concept. 2020;10(2):e2020049. doi: https://doi.org/10.5826/dpc.1002a49 accepted: march 10, 2020; published: march 24, 2020. copyright: ©2020 piccolo and argenziano. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, md, dermatology unit, university of campania, via pansini 5, ii policlinico-edificio 9c, naples, italy. email: piccolo.vincenzo@gmail.com https://coronavirus.jhu.edu/map.html https://doi.org/10.5826/dpc.1002a49 mailto:piccolo.vincenzo@gmail.com dermatology: practical and conceptual research | dermatol pract concept 2021;11(1):e2021139 1 dermatology practical & conceptual scale and pustule on dermoscopy of rosacea: a diagnostic clue for demodex species gamze serarslan1, özlem makbule kaya2, emre dirican3 1 department of dermatology, mustafa kemal university, hatay, turkey 2 department of parasitology, mustafa kemal university hatay, turkey 3 department of biostatistics, mustafa kemal university hatay, turkey key words: demodex folliculorum, demodex brevis, rosacea, dermoscopy citation: serarslan g, makbule ö, dirican e. scale and pustule on dermoscopy of rosacea: a diagnostic clue for demodex species. dermatol pract concept. 2021;11(1):e2021139. doi: https://doi.org/10.5826/dpc.1101a139 accepted: september 8, 2020; published: january 29, 2021 copyright: ©2021 serarslan et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: gamze serarslan, md, mustafa kemal university, faculty of medicine, department of dermatology, 31100 hatay, turkey. email: gserarslan@hotmail.com background: demodex mites are highly found in the skin of patients with rosacea.the diagnosis of demodex can be made by standardized skin surface biopsy. dermoscopy is a tool used in the noninvasive diagnosis of various dermatological diseases. objectives: to determine whether dermoscopic features of demodicosis are associated with the result of standardized skin surface biopsy in patients with rosacea and to compare dermoscopic features of rosacea in demodex-positive and negative samples and demodex type. methods: a total of 30 patients (7 male, 23 female) were included in the study. dermoscopic examination was performed on both the clinically most severely affected areas and adjacent healthy skin. the skin surface biopsy sample was taken from the same place from where the dermoscopic image was taken. results: a total of 83 (lesion n = 60, non-lesion n = 23) areas were evaluated. demodex was detected in 60.2% (n = 50) of the samples. half of these samples revealed only demodex folliculorum, and the remaining half revealed d folliculorum and demodex brevis. of thedemodex-positive samples, 88% had demodex tails (p =0.001) and68% demodex follicular openings (p = 0.002) on dermoscopy. in d folliculorum+d brevis-positive samples, the rate of scale and pustule was higher than d folliculorum-positive samples (p = 0.017 and p = 0032,respectively). conclusions: the sensitivity and specificity of demodex tail are higher than demodex follicular opening and scale and pustule detection with dermoscopy and may indicate the coexistence of both d folliculorum and d brevis. abstract 2 research | dermatol pract concept 2021;11(1):e2021139 dermoscopic evaluation the dermoscopic evaluation was performed by the same clinician (g.s.) by using a handheld dermoscope (dermlite dl4; 3gen, inc., san juan capistrano, usa) at ×10 magnification (cross-polarized light). images were recorded directly by the smartphones attached magnetically to the dermoscope. dermoscopic examination was performed on both the clinically most severely affected areas and adjacent healthy skin. dermoscopic definitions • demodex tail; a gelatinous, whitish creamy thread, 1-3 mm in length [7]. • demodex follicular opening; containing round, amorphic, grayish/light brown plugs surrounded by an erythematous halo [7]. • dermoscopic features of rosacea; vascular structures, follicular plug, white or yellowish scale, orange yellowish areas, dilated follicles, and follicular pustules [6,9]. standardized skin surface biopsy an sssb sample was taken from the same place from which the dermoscopic image was taken. an area of 1 cm2 was marked on a microscope slide. a drop of cyanoacrylate was placed on the other side of the slide in the middle of this area. the sample was gently pressed onto the surface and removed slowly after about 30-45 seconds. a few drops of glycerin were dropped onto the biopsy specimens and covered with coverslip. the samples were examined with a light microscope (leica dm750, switzerland) at ×4, ×10, and ×40 magnifications by an expert parasitologist. the diagnosis of 5 or more demodex mites in 1 cm2 was evaluated as positive. species identification of mites was made in accordance with the relevant literature [2]. statistical analysis data was analyzed with 95% confidence using the spss for windows (version 21; ibm corp, armonk, new york, usa). frequency percent was used in the expression of clinical data and mean ± standard deviation was used in continuous variables. chi-square test and kappa coefficient were used to analyze the relationship of categorical variables. in addition, sensitivity and specificity values, which are among the basic measures, were included to evaluate the diagnostic performance of the developed tests. results demographic and clinical data a total of 83 lesion areas and non-lesion areas from 30 (7 male, 23 female) patients were evaluated. the mean age of the patients was 42.50 ± 12.74 years (range, 18-72 years), and the duration of the disease was 5.41 ± 6.90 years (range, 0.125-30 years). the patients had erythematotelangiectatic introduction rosacea is a chronic inflammatory disease that affects the face, including cheeks, chin, nose, and forehead. there is no diagnostic laboratory test for rosacea. the diagnosis and classification of rosacea are based on the clinical characteristics of the patient. although the pathogenesis of rosacea is not fully understood, genetics, immune factors, neurovascular dysregulation, microorganisms, and environmental factors are thought to play a role. there are differences in skin flora composition, such as increased commensal organisms of skin in rosacea patients. demodex species (d folliculorum and d brevis) are known commensals of facial skin. d folliculorum is mostly located in the hair follicle, and d brevis is frequently found in sebaceous and meiboman glands [1]. d folliculorum is the largest member of its genus and can reach a length of 0.3-0.4 mm. d brevis is shorter and is 0.2-0.3mm long. the opisthosomal tip of d folliculorum is round, and in d brevis is pointed. in addition, d folliculorum has spurs on the legs, but d brevis does not. the mouthparts of d folliculorum are more developed than those of d brevis [2-4]. the number of demodex mites is higher on the skin in patients with rosacea  [1]. the diagnosis of demodex can be made by a method called standardized skin surface biopsy (sssb), by which it is possible to collect the superficial part of the horny layer and the complete follicle contents [5]. dermoscopy is a tool used in the noninvasive diagnosis of various dermatological diseases such as scalp and hair diseases, nail and nail fold anomalies, and cutaneous infections (infestations and inflammatory dermatoses) [6]. demodex tails (dt) and demodex follicular openings (dfo) have been reported to be demodicosis-specific dermoscopic features [7]. in this study, we aimed to determine whether dermoscopic features specific to demodicosis are associated with the results of sssb obtained from the same localization in patients with rosacea. we aimed to compare dermoscopic features of rosacea in demodex-positive and negative samples and demodex type. methods patients this prospective study was conducted in a tertiary hospital. it was accepted by the local ethics committee. a total of 30 patients (7 male, 23 female), who were seen in the dermatology outpatient clinic and were diagnosed with rosacea, were included in the study. the diagnosis of rosacea was made according to national rosacea society criteria [8]. individuals who had received any topical or systemic rosacea treatment within the previous 2 months of enrollment were excluded from the study. information such as age, gender, duration of disease, and clinical subtype of the disease, was recorded. research | dermatol pract concept 2021;11(1):e2021139 3 (et) (n = 17) and papulopustular (pp) (n = 13) rosacea subtypes. sssb and dermoscopy of 83 samples were evaluated. sixty of these samples were from the lesion area [cheek (n = 38), chin (n = 11), forehead (n = 7), nose (n = 4)] and 23 were from the normal skin area. thirty-three of the samples taken from the lesion sites were from patients with et rosacea, and 27 were from patients with pp rosacea. fourteen of the samples taken from normal skin areas were from patients with et rosacea, and 9 were from patients with pp rosacea (table 1). sssb findings demodex was detected by sssb in 60.2% (n = 50) of the samples. half of these samples revealed only d folliculorum, and the remaining half d folliculorum and d brevis (figure 1). all but 2 of the samples detected in demodex belonged to the lesion areas. dermoscopic findings dermoscopy revealed that dt was present in 88% (n = 44) of the samples that were positive with sssb (p = 0.001). dfo was present in 68% (n = 34) of sssb-positive samples (p = 0,002) on dermoscopy. examples of dt and dfo are shown in figure 2. kappa value, sensitivity, and specificity of dt and dfo are shown in table 2. there were no statistically significant differences between the d folliculorum-positive and d folliculorum + d brevis-positive samples in terms of dt (p = 1.00) and dfo (p = 0.363). dermoscopic features of the d folliculorum-positive lesion samples and d folliculorum + d brevis-positive lesion samples were compared. in the d folliculorum + d brevis-positive samples, the rate of scale and pustule was higher, compared to thed folliculorum-positive samples (p = 0.017 and p = 0.032, respectively). the details of dermoscopic features of the lesion areas according to the demodex type are table 1. clinical and demographic characteristics of the patients and lesions characteristics n (%) sex female 23 (76.6) male 7 (23.4) age (years); mean ± sd 42.50 ± 12.74 duration of disease(years); mean ± sd 5.41 ± 6.90 rosacea subytpe erythematotelangiectatic 17 (56.6) papulopustular 13 (43.4) total number of samples lesions 60 (72.2) controls 23 (27.8) location of lesions   cheek 38 (63.3) chin 11 (18.3) forehead 7 (11.6) nose 4 (6.8) figure 2. examples of (a) demodex follicular openings (stars) and (b) demodex tails. figure 1. (a) demodex folliculorum. (b) demodex brevis (original magnification ×400). 4 research | dermatol pract concept 2021;11(1):e2021139 shown in table 3. as reported by lallas et al. some pustules that were not clinically noticeable could be detected in the dermoscope [8]. dilated follicles were not included in the statistical analysis because of low rate. lesion areas were analyzed according to the rosacea subtype. the most common dermoscopic features in both et rosacea and pp rosacea were vascular structure (59.6% and 40.4%, respectively) and scale (54.1% and 45.9%, respectively). the dermoscopic features of demodex-positive and negative lesion samples were compared and the results were as follows: follicular plugging (87.5%), vascular structures (71.4%), and orange-yellow areas (70.6%) were common in demodex-positive samples of et rosacea. although dilated follicles were present in 100% of these samples, the number of this dermoscopic feature was low (n=3). scale (100%), orange-yellow areas (87.5%), and follicular plugging (84.6%) were frequently detected dermoscopic findings in the demodex-positive samples of pp rosacea (figure 3). conclusions we found that the dermoscopic findings of dt and dfo were statistically significant in terms of the presence of demodex (p = 0.001 and p = 0.002, respectively). the sensitivity and specificity of dt and dfo were 0.88/0.73 and 0.68/0.67, respectively. there are a few studies on the relationship between dt and dfo findings and demodex in dermoscopy. segal et al. were the first to describe these 2dermoscopic features associated with demodex. the authors reported that the dermoscopy findings showed excellent agreement with the microscopic findings [7]. it was also reported that the tails are less abundant in the inflammatory forms of demodicosis including rosacea-like demodicosis [7]. in a study conducted in patients with demodicosis including rosacea, it was reported that dt was the only specific and sensitive criterion in the diagnosis [11]. in another study, the sensitivity and specificity of the dt were reported as 66.7% and 100%; the sensitivity and specificity of the dfo were reported as 54.8% and 97%, respectively, in patients with demodex-associated folliculitis [12]. in the studies mentioned above, some of the results are not compatible with each other—including our study. the reason for this may be the difference in the patient groups studied. the superficial layer of the horn layer and the pilosebaceous follicle content can be collected by sssb. however, not all biotopes of d folliculorum can be collected with sssb, table 2. p value, kappa value, sensitivity and specifity of demodex tail and demodex follicular opening   demodex (–) demodex (+) p value kappa sensitivity specifity demodex tail (–) 24 (72.7) 6 (12.0) 0.001* 0.617 0.88 0.73 (+) 9 (27.3) 44 (88.0) dilated follicular opening (–) 22 (66.7) 16 (32.0) 0.002* 0.338 0.68 0.67 (+) 11 (33.3) 34 (68.0) table 3. dermoscopic features of lesion areas according to the demodex type demodex type total p value d folliculorum n (%) d folliculorum + d brevis n (%) scale (–) 13 (54.2) 5 (20.8) 18 0.017 (+) 11 (45.8) 19 (79.2) 30 pustule (–) 20 (83.3) 12 (50.0) 32 0.032 (+) 4 (16.7) 12 (50.0) 16 follicular plug (–) 17 (70.8) 13 (54.2) 30 0.371 (+) 7 (29.2) 11 (45.8) 18 vascular structures (–) 4 (16.7) 8 (33.3) 12 0.317 (+) 20 (83.3) 16 (66.7) 36 orangeyellowish area (–) 13 (54.2) 16 (66.7) 29 0.555 (+) 11 (45.8) 8 (33.3) 19 research | dermatol pract concept 2021;11(1):e2021139 5 and it can cause false-negative results. forton et al. offered to perform a second sssb at the same place [13]. although dt was detected on dermoscopy, sssb was negative in 9 of 83 samples in our study. this may be because no sample was taken from the same place more than once. in addition, the number of samples taken from the control area was less than the number of samples taken from the lesion area. this is the limitation of our study. in the d folliculorum + d brevis-positive samples, the rate of scale and pustule was higher compared to the d folliculorum-positive samples. karadağ köse et al. reported similarly that demodicosis might be suspected in the presence of epidermal scale [11]. the results of our study can generally be evaluated as follows: (1) although dt and dfo indicate demodex on dermoscopy, the sensitivity and specificity of dt are higher than the dfo. (2) scale and pustule detection on dermoscopy may indicate the coexistence of both d folliculorum and d brevis. references 1. ahn cs, huang ww. rosacea pathogenesis. dermatol clin. 2018;36(2):81-86. doi: 10.1016/j.det.2017.11.001.pmid: 29499802. 2. desch c, nutting wb. demodex folliculorum (simon) and d. brevis akbulatova of man: redescription and reevaluation. j parasitol. 1972;58(1):169-177. doi: 10.2307/3278267. pmid: 5062457. 3. rufli t, mumcuoglu y. the hair follicle mites d. folliculorum and d. brevis: biology and medical importance. a review. dermatologica. 1981;162(1):1-11. doi: 10.1159/000250228. pmid: 6453029. 4. jing x, shuling g, ying l. environmental scanning electron microscopy observation of the ultrastructure of demaodex. microsc res tech. 2005;68(5):284-289. doi: 10.1002/ jemt.20253. pmid: 16315233. 5. forton f, seys b. density of demodex folliculorum in rosacea: a case-control study using standardized skin-surface biposy. br j dermatol. 1993;128(6):650-659. doi: 10.1111/j.13652133.1993.tb00261.x. pmid: 8338749. 6. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther (heidelb). 2016;6(4):471-507. doi: 10.1007/s13555-016-0141-6.pmid: 27613297. 7. segal r, mimouni d, feuerman h, pagovitz o, david m. dermoscopy as a diagnostic tool in demodicidosis. int j dermatol. 2010;49(9):1018-1023. doi: 10.1111/j.13654632.2010.04495.x. pmid: 20931672. 8. tan j, almeida lmc, bewley a, et al. updating the diagnosis, classification and assessment of rosacea: recommendations from the global rosacea consensus (rosco) panel. br j dermatol. 2017;176(2):431-438. doi: 10.1111/bjd.15122.pmid: 27718519. 9. lallas a, argenziano g, apalla z, et al. dermoscopic patterns of common facial inflammatory skin diseases. j eur acad dermatol venereol. 2014;28(5):609-614. doi: 10.1111/jdv.12146. pmid: 23489377. 10. lallas a, argenziano g, longo c, et al. polygonal vessels of rosacea are highlighted by dermoscopy. int j dermatol. 2014;53(5):e325327. doi: 10.1111/ijd.12270.pmid: 23879349. 11. karadağ köse ö, borlu m. definition of videodermoscopic features of demodicosis. int j dermatol. 2019;58(10):1153-1159. doi: 10.1111/ijd.14547. pmid: 31198996. 12. durdu m, errichetti e, eskiocak ah, ilkit m. high accuracy of recognition of common forms of folliculitis by dermoscopy: an observational study. j am acad dermatol. 2019;81(2):463-471. doi: 10.1016/j.jaad.2019.03.054.pmid: 30914342. 13. forton f, song m. limitations of standardized skin surface biopsy in measurement of the density of demodex folliculorum. a case report. br j dermatol. 1998;139(4):697-700. doi: 10.1046/j.1365-2133.1998.02471.x.pmid: 9892917. dilated follicles follicular plugs vascular structures white/yellowish scales pustules orange-yellowish areas et d( –) et d( +) pp d( –) pp d( +) 20 15 10 0 5 20 15 10 0 value 5 figure 3. the frequency of dermoscopic features of the lesion samples with and without demodex. dermatology: practical and conceptual editorial | dermatol pract concept 2020;10(1):e2020001 1 dermatology practical & conceptual the definition of a spectrum of melanocytic tumors, with superficial atypical proliferations (high-grade dysplastic nevus and melanoma in situ) and mass-forming (tumorigenic) neoplasms (melanocytomas) considered as an intermediate molecular progression stage in melanomagenesis, has been recently set forth by the who working group [1]. the existence of a molecular spectrum involves progressive accumulation of genetic abnormalities which, in turn, implies an increasing risk of unfavorable biological behavior. it is thus supposed that: 1. benign nevi harbor a single driver mutation (involving nras in congenital nevi, braf in acquired nevi, hras in a few spitz nevi, gnaq or gna11 in blue nevi) or translocation (kinase fusion of alk, braf, ros1, ntrk1, ntrk3, met, ret, map3k3, or map3k8 in several spitz nevi) [2]. 2. intermediate melanocytic tumors may develop from benign nevi by acquiring an additional pathogenic mutation (bap1 mutation in bap1-inactivated nevus [3], ctnnb1 or apc in deep penetrating nevus [dpn] [4], prkar1a or prkca in pigmented epithelioid melanocytoma [pem] [5]). 3. malignant melanoma develops after additional promoting mutations involving mapk pathway genes (eg, nf1, kit, ccnd1), g1/s checkpoint regulation genes (eg, cdkn2a, cdk4, p53), chromatin modifier genes (swi/ snf, bap1), and/or telomere regulation genes (tert, sf3b1, eif1ax) [6]. according to the who working group, intermediate melanocytic tumors are histopathologically defined as having increased cellularity and/or atypia if compared with a common nevus [1]. thus, the molecular intermediate progression stage corresponds to a morphological intermediate and both are also mirrored by the intermediate biological behavior of melanocytomas, with their characteristically high incidence of nodal metastases coupled with a very low incidence of distant metastases [7]. in the progression model described above, nevi can be melanoma precursors because they are composed by partially transformed melanocytes. if so, common nevi do not melanocytic skin tumors: does the molecular progression model fit with the routine clinicopathological practice? gerardo ferrara,1 mirna bradamante2 1 anatomic pathology unit, macerata general hospital, macerata, italy 2 department of dermatology and venereology, university hospital centre zagreb, croatia key words: nevus, melanocytoma, melanoma, histopathology, molecular genetics citation: ferrara g, bradamante m. melanocytic skin tumors: does the molecular progression model fit with the routine clinicopathological practice? dermatol pract concept. 2020;10(1):e2020001. doi: https://doi.org/10.5826/ dpc.1001a01 accepted: september 9, 2019; published: december 31, 2019 copyright: ©2019 ferrara and bradamante. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: gerardo ferrara, md, anatomic pathology unit, macerata general hospital, via santa lucia 2, i-62100 macerata, italy. email: gerardo.ferrara@libero.it https://doi.org/10.5826/ mailto:gerardo.ferrara@libero.it 2 editorial | dermatol pract concept 2020;10(1):e2020001 sent a unique broad category (with some morphomolecular subgroups) of tumors completely different from conventional melanocytic tumors, because they might not be morphobiologically intermediate, but morphobiologically peculiar. in fact, their rate of nodal metastases is much higher than that of conventional melanoma and their entiating benign from malignant tumors with the use of different kinds of surrogate gold standard (interobserver agreement, nodal metastases, distant metastases, disease-related death [11,12]). however, the attempt at differentiating benign and malignant tumors within the intermediate category might be wrong: melanocytomas might repreexist at all because all of them harbor 1 potentially dangerous mutation; thus, a dichotomic histopathological approach (nevus vs melanoma) can no longer be applied as being too simplistic a view. however, the paradox according to which completely innocent nevi do not exist at all (because all of them harbor a potentially dangerous mutation) is obviously misleading because the estimated risk of malignant transformation of a nevus is roughly 1:33,000 [8]. thus, the progression model from nevus to melanoma applies to a percentage of melanocytic tumors that is indeed minimal (even negligible, if one does not consider the potentially dramatic clinical consequences of such an unlikely event). likewise, with distant metastases as the surrogate gold standard for malignancy, a progression of melanocytoma to conventional melanoma is highly unlikely. in addition, the correlation between molecular and histopathological features is clearly imperfect to date, because melanocytomas themselves can show various degrees of histopathological atypia, and this “morphological spectrum within the spectrum” is incompletely mirrored by the molecular data available so far [9]. the consequence is that the mutations listed above for both benign and intermediate melanocytic tumors have no diagnostic or prognostic significance; they simply allow one to ascribe a given melanocytic tumor to a given subgroup (conventional, spitzoid, bap1-deficient, dendritic cell [cellular blue nevus-like], dpn-like, pem) [10]. e v e n t h e c o r r e l a t i o n b e t w e e n morphology and biological behavior of melanocytoma can be questioned, because several studies carried out on melanocytomas (all based on a low number of cases because of the relative rarity of such tumors and the need for long-term follow up [11]) have disclosed no clear-cut relationship between the qualitative and quantitative histopathological features of atypia and the clinical outcome. notably, these studies were conceived with the goal of differtable 1. proposed list of histopathological criteria of atypia for prognostic assessment of melanocytomas entity proposed criteria of histopathological atypia melanocyoma (applicable to all entities listed below) • large diameter (>4 mm) • asymmetry/asymmetric involvement of the epidermis • necrosis (single cell or en masse) • ulceration • mitoses >2/mm2 • cells within the lymph vessels atypical spitz tumor • deep or marginal mitoses • solid sheets/nodular growth • brisk or heavy inflammatory infiltrate • deep extension (>2 mm in thickness) • (abundant) melanin in deep cells • confluent (nonrandom) nuclear pleomorphism bap1-inactivated nevus/ melanocytoma (bap1inactivated melanocytic atypical intradermal tumor) • deep or marginal mitoses • confluent (not loose) sheets of cells • expansile growth • melanocytes with increased nucleocytoplasmic ratio atypical cellular blue nevus/ melanocytoma (atypical dendritic cell tumor) • irregularly oriented fascicles • areas of predominance of melanophages over melanocytes • brisk or heavy inflammatory infiltrate • cytological atypia (prominent nucleoli; dendritic cells with thick and irregular processes) atypical deep penetrating nevus/melanocytoma (atypical deep penetrating nevus-like tumor) • quadrangular/nodular silhouette • lack of the context of a combined nevus • brisk or heavy inflammatory infiltrate pigmented epithelioid melanocytoma • deep or marginal mitoses • quadrangular/nodular silhouette • deep extension (>2 mm in thickness) • confluent (nonrandom) nuclear pleomorphism of the epithelioid cell component • brisk or heavy inflammatory infiltrate • dendritic cells with thick and irregular processes editorial | dermatol pract concept 2020;10(1):e2020001 3 5. c o h e n j n , j o s e p h n m , n o r t h j p, et al. genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in prkar1a, and prkca genes. am j surg pathol. 2017;41(10):1333-1346. 6. papadodima o, kontogianni g, piroti g, maglogianni i, chatziioannou a. genomics of cutaneous melanoma: focus on next-generation sequencing approaches and bioinformatics. j transl genet genom. 2019;3:7. available at: https:// jtggjournal.com/article/view/3027. 7. zembovicz a, scolyer ra. nevus/melanocytoma/melanoma: an emerging paradigm for classification of melanocytic neoplasms? arch pathol lab med. 2011;135(3):300-306. 8. tsao h, bevona c, goggins w, quinn t. the transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population-based estimate. arch dermatol. 2003;139(3):282-288. 9. de la fouchardière a, caillot c, jacquemus j, et al. β-catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors. virchows arch. 2019;474(5):539-550. 10. ferrara g, improta g. molecular diagnostics in melanocytic tumors: the pathologist’s perspective. adv mol diag. 2016;1(1). available at: https://pdfs. semanticscholar.org/f146/4c81a8b8f 5922ef6dd699f4d0adc95bf7b06.pdf. 11. ferrara g, de vanna ac. fluorescence in-situ hybridization for melanoma diagnosis: a review and a reappraisal. am j dermatopathol. 2016;38(4):253-269. 12. cerroni l, barnhill r, elder d, et al. melanocytic tumors of uncertain malignant potential: results of a tutorial held at the xxix symposium of the international society of dermatopathology in graz, october 2008. am j surg pathol. 2010;34(3):314-326. 13. lallas a, krygidis a, ferrara g, et al. atypical spitz tumours and sentinel lymph node biopsy: a systematic review. lancet oncol. 2014;15(4):e178-e183. conclusions the correlation between molecular and histopathological features of melanocytic tumors is still largely incomplete. from a practical point of view, however, only a very limited number of cases seen in clinical practice run the entire spectrum of molecular and biological progression of melanomagenesis; thus, the molecular progression model has a very limited clinical impact. rather than intermediate stages in an unlikely path toward melanoma, melanocytomas are probably best regarded as morphobiologically peculiar melanocytic tumors, namely, strongly lymphotropic (lowgrade) melanocytic malignancies; their clinical management should be thus discussed case by case in a multidisciplinary setting by integrating the histopathological findings with the clinical data. references 1. bastian bc, de la fouchardiere a, elder de, et al. genomic landscape of melanoma. in: elder de, massi d, scolyer ra, willemze r, eds. who classification of skin tumours. 4th ed. lyon, france: iarc; 2018:72-75. 2. dimonitsas e, liakea a, sakellariou s, et al. an update on molecular alterations in melanocytic tumors with emphasis on spitzoid lesions. ann transl med. 2018;6(12):249-265. 3. wiesner t, murali r, fried i, et al. a distinct subset of atypical spitz tumors is characterized by braf mutation and loss of bap1 expression. am j surg pathol. 2012;36(6):818-830. 4. yeh i, lang ue, durieux e, et al. combined activation of map kinase pathway and β-catenin signaling cause deep penetrating nevi. nat commun. 2017;8(1):644. rate of distant metastases is extremely low (and not simply lower than that of melanoma of the same thickness); thus, they are peculiar because they probably stand as strongly lymphotropic (lowgrade) melanocytic malignancies [13]. if we consider melanocytomas as a unique broad category (with its subgroups), then it is not surprising that morphology alone cannot be predictive of the clinical outcome, because even in a cohort of conventional thick melanomas morphology alone cannot allow one to discriminate cases that will metastasize from cases that will not. in conventional melanoma, after making the diagnosis, there are some prognostic parameters (the most important being breslow thickness and ulceration) that can help assess the risk of a melanoma to give metastasis; likewise, after making a diagnosis of melanocytoma, the histopathological assessment might be aimed at a prognostic evaluation. thus, the best strategy might be listing the morphological features of atypia observed in any melanocytoma, thereby considering these features as prognostic factors and not as histopathological differential features between benign and malignant tumors. a list of these putative histopathological prognostic criteria for any category of melanocytoma is given in table 1; and not secondary to these histopathological criteria, the clinical features of any melanocytoma—the patient’s age; the location and the clinical features of the tumor—should be fully considered in order to assess the best management strategy. https://jtggjournal.com/article/view/3027 https://jtggjournal.com/article/view/3027 https://pdfs.semanticscholar.org/f146/4c81a8b8f5922ef6dd699f4d0adc95bf7b06.pdf https://pdfs.semanticscholar.org/f146/4c81a8b8f5922ef6dd699f4d0adc95bf7b06.pdf https://pdfs.semanticscholar.org/f146/4c81a8b8f5922ef6dd699f4d0adc95bf7b06.pdf dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(2):6 49 introduction the diagnosis of melanomas smaller than 4 mm presents difficulties because the clinical and dermatoscopic features of small melanomas have been reported infrequently. case report a 38-year-old australian-born woman of italian descent, with fitzpatrick type 4 skin, presented for a routine yearly skin examination. she was examined with a heine delta 20 dermatoscope (heine, optotechnic gmbh, herrsching, germany) and had been having total body photography with a molemax dermdoc video monitoring system (derma medical systems, austria). in previous years some pigmented lesions (psls) had been observed to change with symmetrical growth of peripheral clods. these were deemed to be maturing nevi and had not been excised. one pigmented skin lesion had been excised in 2007 and was reported by the pathologist to be an irritated dysplastic nevus. at this visit in may 2012, a new lesion was detected on the left arm (figure 1a). clinically it was noted to be darker than surrounding psls and dermatoscopically pseudopods and radial lines were arranged circumferentially around a a tiny invasive melanoma: a case report with dermatoscopy and dermatopathology gary pellizzari, mbbs1, jill magee m.d.2, david weedon, m.d.3, cliff rosendahl, mbbs4 1 nepean family medical centre and skin detective, victoria, australia 2 dorevitch pathology, heidelberg, australia 3 sullivan nicolaides pathology, brisbane, australia 4 school of medicine, the university of queensland, brisbane, australia key words: melanoma, small melanoma, dermatoscopy, dermoscopy, dermatopathology citation: pellizzari g, magee j, weedon d, rosendahl c. a tiny invasive melanoma: a case report with dermatoscopy and dermatopathology. dermatol pract conc. 2013;3(2):6. http://dx.doi.org/10.5826/dpc.0302a06. received: november 2, 2012; accepted: january 31, 2013; published: april 30, 2013 copyright: ©2013 pellizzari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, po box 734, capalaba, queensland, 4157, australia. tel. 61 7 3245 3011; fax. 61 7 3245 3022. email: cliffrosendahl@bigpond.com. we present a case of an early invasive melanoma (breslow thickness 0.25 mm), 1.6 mm in diameter on the arm of a 38-year-old woman. she was under surveillance due to having multiple (>100) nevi, and the melanoma was assessed as a new lesion by the examining doctor. clinically the lesion was hyperpigmented compared with surrounding nevi and dermatoscopically it had a clue of pseudopods/lines radial, but they were arranged in an arguably symmetrical circumferential pattern around a structureless blue-gray center. generally melanomas are expected to be dermatoscopically asymmetrical, but we believe that this case illustrates the fact that small melanomas may be recognized by clues such as pseudopods/lines radial and dermatoscopic gray even when they have not yet developed unequivocal asymmetry. abstract 50 observation | dermatol pract concept 2012;3(2):6 structureless blue-gray center (figure 1b); the radial lines were arguably symmetrically distributed, appearing in all quadrants of the perimeter while being less clearly defined and sparser in one quadrant. this lesion was new at mature age (evolving), which raised suspicion for malignancy despite the lesion’s small size and equivocal symmetry [1]. the lesion was subjected to excision biopsy and dermatopathologic assessment (figure 2 composite) showed a small, but asymmetric, nested and single cell proliferation of atypical melafigure 1. (a) clinical image and (b) dermatoscopic image of a new pigmented skin lesion on the arm of a 38-year-old woman. radial lines/pseudopods are arranged circumferentially around a structureless blue-gray centre. although radial lines/pseudopods are present in all quadrants of the periphery they are less numerous in the upper-left quadrant. asymmetry is assessed as equivocal. [copyright: ©2013 pellizzari et al.] nocytes along the dermoepidermal junction with scattered single cell intraepithelial upward spread. there was limited extension into the papillary dermis to a depth of 0.25 mm. superficial dermal melanosis and inflammation were present along with mild fibroplasia, suggesting a component of regression to a depth of 0.35 mm. in spite of the dermatoscopic appearance of lines radial circumferential, there were no spitzoid features dermatopathologically. the diagnosis of early level 2 malignant melanoma of superficial spreading type was rendered. physical examination revealed no evidence of lymphatic or systemic metastasis and the patient will have routine clinical and dermatoscopic surveillance in accordance with current guidelines [2]. discussion a proportion of melanomas have been found not to fit the d criterion of the abcd acronym, where d stands for a diameter of 6 mm or greater. such small melanomas have a reported frequency of 11.4-38.2% of all melanomas [3-6]. one review in particular, published in 2004, found that small melanomas include less than 1 to 38% of all invasive melanomas [1] and it recommended that the abcd acronym be modified to abcde with “e” to stand for “evolving.” previously the dermatoscopic features of an in-situ melanoma with a diameter of 1.6 mm were reported [7]. published dermatoscopy images revealed that even at this minute size there was unequivocal asymmetry of structure and the presence of the dermatoscopic clue to melanoma of gray dots. it satisfied the criteria for malignancy of the 3-point checklist [8], the menzies method [9] and chaos and clues [10]. teng et al reported the dermatoscopic features of an in-situ melanoma with a diameter of 2 mm [11]. a published dermatoscopy image revealed unequivocal asymmetry of both color and structure with some lines radial segmental and blue-gray structures. in the case that we report, the lesion was noted to be hyperpigmented compared to surrounding psls. one previous study reported that intensity of dark pigmentation was the defining clinical characteristic in each of 13 (including 5 invasive) small melanomas (<4 mm diameter) in a series of 95 melanomas [5], although this may in fact be due to selection bias as minute dark melanomas are more likely to be noticed and assessed in comparifigure 2. (a) low power and (b, c) high power dermatopathologic images of the lesion shown in figure 1. [copyright: ©2013 pellizzari et al.] observation | dermatol pract concept 2012;3(2):6 51 son to small pale melanomas which may be present but not detected. the case reported here, unlike the two previously reported smallest in-situ melanomas [7,11] did not exhibit unequivocal dermatoscopic asymmetry, and this is significant because dermatoscopic asymmetry is a generally accepted criterion for all of the published clinical and dermatoscopic algorithms. however in one study of consecutive pigmented skin lesions with a maximum diameter of 6mm (range 3-6 mm) excised in a specialized university dermatology department over four years, 34 out of a total of 103 melanocytic lesions were melanomas [12], and of those 34 melanomas only 11 (32.4%) were asymmetrical. this supports the need to assess small psls without the required algorithmic criterion of asymmetry. in one pilot study of 28 diagnosed melanomas less than or equal to 4 mm in diameter, there were only 14 (50%) that were unanimously diagnosed as melanomas by each of three dermatopathologists [13]. the dermatopathologic criteria of these were evaluated. the criteria regarded as most significant included pagetoid spread (n=9/14), irregular nesting (n=9/14), predominance of individual junctional melanocytes (n=6/14) and cytological atypia (n=13/14). the very small melanoma we present in this case report exhibited all of these features as well as poor maturation in the invasive portion with pigmentation and nesting to the base of the lesion. conclusion the melanoma reported here had the same diameter, of 1.6 mm, as the previously smallest reported melanoma with dermatoscopic images, but it differed in that it was invasive. as has been previously reported with small melanomas, it was darker than surrounding nevi but this may be due to selection bias. we regard it as very significant that this melanoma did not have unequivocal asymmetry, although it did have recognized clues to malignancy, including the presence of gray color and radial lines/pseudopods, albeit arranged in a circumferential pattern. we believe that very small pigmented lesions which have any recognized clues to melanoma should be assessed for biopsy whether or not unequivocal asymmetry is present. references 1. abbasi nr, shaw hm, rigel ds, et al. early diagnosis of cutaneous melanoma: revisiting the abcd criteria. jama. 2004; 292(22):2771–6. 2. australian cancer network melanoma guidelines revision working party. clinical practice guidelines for the management of melanoma in australia and new zealand. the cancer council australia and australian cancer network, sydney and new zealand guidelines group. wellington, 2008:xxxii. 3. fernandez em, helm kf. the diameter of melanomas. dermatol surg. 2004;30(9):1219–22. 4. abbasi nr, yancovitz m, gutkowicz-krusin d, et al. utility of lesion diameter in the clinical diagnosis of cutaneous melanoma. arch dermatol. 2008;144(4):469–74. 5. goldsmith sm, solomon ar. a series of melanomas smaller than 4 mm and implications for the abcde rule. j eur acad dermatol venereol. 2007;21(7):929–34. 6. helsing p, loeb m. small diameter melanoma: a followup of the norwegian melanoma project. br j dermatol. 2004;151(5):1081–3. 7. rosendahl c, cameron a, bulinska a, williamson r, kittler h. dermatoscopy of a minute melanoma. australas j dermatol. 2011; 52(1):76–8. 8. argenziano g, soyer hp, chimenti s, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679–93. 9. menzies sw, ingvar c, crotty ka, mccarthy wh. . frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. arch dermatol. 1996;132(10):1178–82. 10. rosendahl c, cameron a, mccoll i, wilkinson d. dermatoscopy in routine practice—‘chaos and clues’ aust fam physician. 2012;41(7):482–7. 11. teng pp, hofmann-wellenhof r, campbell tm, soyer hp. dermoscopic presentation of a 2-mm melanoma in situ. australas j dermatol. 2010;51(2):152–3. 12. de giorgi v, savarese i, rossari s, et al. features of small melanocytic lesions: does small mean benign? a clinical-dermoscopic study. melanoma res. 2012;22(3):252–6. 13. ferrara g, tomasini c, argenziano g, zalaudek i, stefanato cm. small-diameter melanoma: toward a conceptual and practical reappraisal. j cutan pathol. 2012;39(7):721–3. dermatology: practical and conceptual correction | dermatol pract concept 2021;11(1):e2021102 1 dermatology practical & conceptual dermatol pract concept. 2021;11(1):e2021102. december 15, 2020. doi: 10.5826/dpc.1101a102 meyerson phenomenon over nuchal nevus simplex in the image letter article titled “meyerson phenomenon over nuchal nevus simplex” by claret-de-castro et al [1] (https:// dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp1a01a98), published on december 9, 2020, the figure callout was missing. the text, figure 1, was inserted in the article. this article was corrected online on december 15, 2020. the editors regret the error. reference 1. claret-de castro a, mir-bonafé m, mir-bonafé jm, mir-bonafé jf. meyerson phenomenon over nuchal nevus simplex. dermatol pract concept. 2021;11(1):e2020098. doi: https://10.5826/ dpc.1101a98. correction dermatology: practical and conceptual correction | dermatol pract concept 2020;10(1):e2020027 1 dermatology practical & conceptual dermatol pract concept. 2019;10(1):e2020027. november 10, 2019. doi: https://doi.org/10.5826/dpc.1001a27 alopecia areata incognita and diffuse alopecia areata: clinical, trichoscopic, histopathological, and therapeutic features of a 5-year study in the article titled “alopecia areata incognita and diffuse alopecia areata: clinical, trichoscopic, histopathological, and therapeutic features of a 5-year study” by alessandrini et al [1] (https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0904a05), published on october 31, 2019, table 2 included an error. the last row should have read clobetasol 0.05% foam. these authors have no conflicts of interest to disclose, and they contributed significantly to this publication. this article was corrected online on december 31, 2019. the editors regret the error. reference 1. alessandrini a, starace m, bruni f, brandi n, baraldi c, misciali c, fanti pa, piraccini bm. alopecia areata incognita and diffuse alopecia areata: clinical, trichoscopic, histopathological, and therapeutic features of a 5-year study. dermatol pract concept. 2019;9(4):272-277 . doi: https://doi.org/10.5826/dpc.0904a05. correction https://doi.org/10.5826/dpc https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0904a05 https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp0904a05 _goback dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022019 1research letter | dermatol pract concept. 2022;12(1):e202201 1 gorlin syndrome: sequential digital dermoscopy of palpebral basal cell carcinomas in a patient treated with vismodegib luis mena-vergara1, mariana silva-astorga1, carolina carrasco-cancino1, leoncio muñoz-uslar2 1 department of dermatology, faculty of medicine, university of chile, santiago, chile 2 dermatology service, hospital del salvador, santiago, chile key words: gorlin syndrome, digital dermoscopy, palpebral basal cell carcinoma, vismodegib citation: mena-vergara l, silva-astorga m, carrasco-cancino c, muñoz-uslar l. gorlin syndrome: sequential digital dermoscopy of palpebral basal cell carcinomas in a patient treated with vismodegib. dermatol pract concept. 2022;12(1):e2022019. doi: https://doi.org/10.5826/dpc.1201a19 accepted: may 26, 2021; published: january 2022 copyright: ©2022 mena-vergara et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: mariana silva astorga, department of dermatology, university of chile, santiago, chile. e-mail: valesilva.astorga@gmail.com introduction gorlin-goltz syndrome (gs) is a multi-system genetic disorder, characterized by the development of jaw keratocystic odontogenic tumors (kot) and multiple basal cell carcinoma (bcc) at young ages. patients inherit a defective copy of ptch1, a tumor suppressor gene, responsible for hedgehog pathway signaling (hps) inhibition.  ptch1 mutations and loss of the remaining wild-type allele are also exhibited in >90% of sporadic bccs [1].  while most cases are amenable to surgery, locally advanced bccs and unresectable tumors represent a complex scenario, in which hps inhibitors may be a feasible treatment option with better clinical outcomes [1]. digital images can be useful in following up bcc response to treatment [2]. we describe the involution of bccs dermoscopic criteria recorded with sequential digital dermoscopy (sdd), in a patient with gs during treatment with vismodegib. case presentation a 58-year-old man with gs diagnosed at age of 7 years, presented with over 50 tumoral lesions and the presence of multiple bccs in both eyelids was noted (figure 1a). he had history of several surgical interventions to remove kots and bccs with torpid evolution and development of retractile scars that in turn required advanced plastic surgical treatment to maintain functionality, resulting in aesthetic alterations (figure 1a). due to the high risk of causing severe ocular morbidity with a new surgery, vismodegib was initiated, resulting in a significant clinical response after 2 months. ssd was performed before and during treatment, and it revealed shrinking of palpebral tumors and regression of dermoscopic structures (figures 1 and 2). 2 research letter | dermatol pract concept. 2022;12(1):e2022019 figure 1. (a) retractile scars due to several surgical interventions with secondary bilateral ectropion and ptosis. multiple bccs involving the scalp and periocular area (white arrows). (b) pigmented bcc in superior left eyelid before vismodegib: typical dermoscopic structures, blue-gray globules, ovoid nest and arborizing vessels (blue arrow). (c) week 2: disappearance of some globules (white circle) and less notorious telangiectasia (blue arrows). (d) week 7: arborizing vessels are no longer visible (blue circle). (e) week 8: notable regression of bcc structures; only a few blue-gray globules persist. figure 2. nonpigmented basal cell carcinoma (bcc) in superior left eyelid. (a) before vismodegib. dermoscopic structures of a nonpigmented bcc: multiple fine telangiectasia (red circle), crusting (blue arrows), whitish unstructured zones (green arrows). (b) week 2: notable less crusting and shrinking of whitish unstructured areas (green stars). (c) week 7: a few fine telangiectasias persist, whitish areas are no longer visible, and some white shiny lines can be identified (black arrows). (d) week 8: almost no white lines and vessels remain. research letter | dermatol pract concept. 2022;12(1):e2022019 3 conclusions the presence of multiple bccs is a hallmark finding in gs [1]. bcc accounts for 90% of malignant periocular tumors and represents 4.4%-18.0% of all bccs [1]. most periocular bccs are curable with surgery; however, in patients with more extensive involvement, a surgical resection with curative intent may lead to substantial morbidity or deformity because of the need to remove periocular or orbital tissues that results in reduced functionality and quality of life [1]. other therapeutic modalities such as photodynamic therapy and topical medications have been used as treatments for small or superficial bccs. radiotherapy should be avoided in gs [1]. vismodegib is a first-in-class inhibitor of the hps, and it reduces bcc tumor burden and blocks the growth of new bccs in patients with gs [1]. vismodegib has shown superior outcomes compared to other therapies; however, complete histologic clearance is not always achieved, and risk of progression or recurrence has been described after treatment cessation [1]. sdd is used for monitoring bccs response to topical chemotherapy [2]. the presence or disappearance of bcc dermoscopic criteria correlates with tumor persistence or histopathologic clearance respectively [2]. blue-gray globules and ovoid nests can be detected for a longer period of time, whereas other typical structures decrease in size and number after chemotherapy initiation [2]. there is lack of evidence about sdd of bccs in patients with gs treated with vismodegib. sdd may help in detecting subtle changes and in facilitating the diagnosis of recurrence or progression of bccs in patients treated with vismodegib or alternative treatments other than surgery. references 1. herms f, lambert j, grob jj, et al. follow-up of patients with complete remission of locally advanced basal cell carcinoma after vismodegib discontinuation: a multicenter french study of 116 patients. j clin oncol. 2019;37(34):3275-3282. doi: 10.1200/jco.18.00794. pmid: 31609670. grajdeanu ia, vata d, statescu l, et al. use of imaging techniques for melanocytic naevi and basal cell carcinoma in integrative analysis (review). exp ther med. 2020;20(1):78-86. doi: 10.3892/ etm.2020.8620. pmid: 32508998; pmcid: pmc7271701. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021063 1 efficacy and safety of 25% trichloroacetic acid peel versus 30% salicylic acid peel in mild-to-moderate acne vulgaris: a comparative study surabhi dayal1, satbir singh, priyadarshini sahu1 1 department of dermatology, venereology and leprology, pt b d sharma university of health sciences, rohtak, haryana, india key words: acne vulgaris, trichloroacetic acid, salicylic acid, michaelsson acne score citation: dayal s, singh s, sahu p. efficacy and safety of 25% trichloroacetic acid versus 30% salicylic acid peel in mild-to-moderate acne vulgaris: a comparative study. dayal dermatol pract concept. 2021;11(3):e2021063. doi: https://doi.org/10.5826/dpc.1103a63 accepted: january 11, 2021; published: may 20, 2021 copyright: ©2021 dayal et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: surabhi dayal, md, department of dermatology, venereology and leprology, pt b d sharma university of health sciences, 18, vikas nagar, rohtak, haryana, 124001, india. email: surabhidayal7@gmail.com background: both salicylic acid (sa) and trichloroacetic acid (tca) have proven efficacy with good safety profiles in the treatment of acne vulgaris. objectives: this study compared the clinical efficacy and safety of 25% tca and 30% sa peels in the treatment of mild and moderate acne vulgaris. methods: patients with mild or moderate acne vulgaris were randomized into 2 groups of 25 persons each, and treated with either the tca peel or the sa peel at 2-week intervals for 12 weeks. evaluation of active acne was done by individual lesion counts (comedones, papules and pustules) and calculation of the michaelsson acne score (mas). results: both peels led to significant decrease in individual lesion counts and mas compared to baseline values, without significant differences between the treatment groups. thus, the peels had equivalent efficacy against acne vulgaris. the tca peel was better in treating non-inflammatory lesions, while the sa peel was better for inflammatory lesions, but the differences were not significant. no serious adverse effects were recorded, but more patients in the tca peel group experienced burning and stinging sensations. conclusion: the efficacy of 25% tca is comparable to that of 30% sa in mild-to-moderate acne vulgaris, but safety and tolerability were better with the sa peel than tca peel. abstract 2 research | dermatol pract concept. 2021;11(3):e2021063 introduction acne vulgaris is an inflammatory disorder of the pilosebaceous unit, characterized by noninflammatory lesions (ie, comedones) and inflammatory lesions such as papules, pustules, nodules, cysts and abscesses [1]. a variety of therapeutic modalities are available, including systemic, topical and physical therapies. topical retinoids, benzoyl peroxide and antibiotics have been the cornerstone of topical treatment of acne [2]. combination formulations of these topical agents are also commonly prescribed for acne. recently, topical dapsone, azelaic acid 5%, topical delta-aminolevulinic acid and α-hydroxy acids have been used to treat acne vulgaris [3,4]. acne vulgaris may be associated with residual pigmentation and scar formation, leading to anxiety, stress and depression. there are various treatment modalities available for acne scars, including chemical peeling, chemical reconstruction using tca cross, dermabrasion, laser treatments, punch techniques, subcision and dermal fillers [5]. different types of ablative and non-ablative lasers can be used for scar treatment. ablative lasers include the carbon dioxide laser and erbium-yag laser [6]. non-ablative lasers stimulate dermal fibroblasts to produce new collagen. nd-yag, diode and recently a new 675-nm red touch laser are various types of non-ablative lasers used to treat acne scars [7]. chemical peel is a well-documented treatment in the management of acne vulgaris and its sequelae, such as post-inflammatory hyperpigmentation (pih) and scarring [1,8]. in acne vulgaris, both salicylic acid (sa) and trichloroacetic acid (tca) have proven efficacy as peeling agents with good safety profiles [9-12]. however, there is paucity of studies comparing the therapeutic effect of tca peel with the more commonly used sa peel, especially in dark-skinned patients [9,10]. therefore, the present study was undertaken to compare the efficacy and safety of 25% tca peel versus 30% sa peel for mild-to-moderate facial acne vulgaris in indian patients. material and methods this was a 12-week, prospective, randomized interindividual study. the study was approved by the ethics committee of pt. b. d. sharma, university of health sciences, rohtak (approval letter no. iec/th/18/svd/01). patients with acne vulgaris presenting to the outpatient clinic of the department of dermatology were consecutively included in the study. written informed consent was obtained from all patients aged ≥ 18 years and guardians of the patients age less than 18 years in the study. patient selection patients with mild or moderate facial acne vulgaris (grade i, comedones, occasional papules; and grade ii, comedones, many papules, few pustules), as defined by vaishampayan et al. [3], were eligible for inclusion in the study. patients were excluded if they had grade iii or iv acne vulgaris (ie, with infiltrates, abscesses and nodulocystic lesions); if they were taking any acne medications or had taken oral or topical medications in the past 4 weeks; if they were pregnant or nursing a baby; if they had known hypersensitivity to the formulations used in the study or a history of photosensitivity, hypertrophic scars, keloidal tendency, active or recurrent herpes simplex infection, or any kind of active dermatosis; and if they had unrealistic expectations. a detailed history was taken to rule out all exclusion criteria. a history of all precipitating or initiating factors was taken. treatment included patients were randomized into 2 equal groups using a chit-based lottery method. patients of group 1 were treated with 25% tca peel and patients of group 2 were given 30% sa peels, at 2-week intervals for a total of 12 weeks. clinical evaluation was done every 2 weeks throughout the study period. to detect hypersensitivity to the peeling agents, a test peel was done by applying the treatment to the postauricular area. peeling was done according to the standard guidelines for chemical peeling [13]. in the tca peel group, development of uniform erythema as diffuse redness with light cloudy white frosting was considered the desired endpoint. in the sa peel group, immediate whitening, (ie, pseudofrost) within 30 seconds was the end point. after achieving the endpoint, the peel was removed by rinsing with cold water followed by gentle drying with gauze. any acute minor side effects related to the therapy were treated with appropriate medication by an investigator. clinical assessment of efficacy clinical photographs of each patient were taken at 2-week intervals, with front, right and left views of the face. michaelson acne scores (mas) [14] were calculated at baseline and at each visit. acne improvement was graded according to the reduction in mean mas between baseline and 12 weeks, and evaluated as good when greater than 50%, fair when 21%50%, and poor when less than 20%. statistical analysis the statistical package for social sciences (spss) for microsoft windows 20th version was used for statistical analysis. for the comparison of nominal or continuous data such as age distribution, duration of disease, individual lesion count and mas within the group and between the groups, paired and unpaired student’s t tests were used, respectively. categorical data, ie, sex of the patients and improvement in acne in each group, were compared using the chi-squared test. research | dermatol pract concept. 2021;11(3):e2021063 3 the tests were performed at a 5% level of significance and an association was found to be significant if the p value was <.05. results a total of 50 patients with mild or moderate acne vulgaris were included in the study and randomized to treatment with either a 25% tca peel or 30% sa peel. the groups were comparable with respect to age distribution, sex, duration of disease and mean mas at baseline (table 1). there were no statistically significant differences between the groups with respect to mean comedo, papule and pustule counts before starting the therapy. before-after clinical photographs for one patient in each group are shown in figures 1 and 2. evaluation of clinical efficacy the mean comedo counts at the end of therapy were significantly lower than the baseline values in both groups (figure 3). the decrease started after 2 weeks of therapy and remained statistically significant throughout the therapy. however, there was no difference between the two groups in terms of the change in comedo counts at the end of therapy (p = .89). the mean percentage decrease in comedo counts from baseline in group 1 was 53.91% (sd = 9.43%) and in group 2 53.71% (sd = 13.66%), without a significant difference (p = .95). there was significant decrease in mean papule count from the baseline values in both groups at the end of 12 weeks of therapy (figure 4). the decrease started at 2 weeks and remained significant throughout the therapy. however, the difference between the groups was not significant at the end of therapy (p = .34). the percentage decrease in mean papule count in group 1 was 56.68% (sd = 13.12%) and in group 2 59.93% (sd = 13.94%), without a significant difference (p = .4) after 12 weeks of therapy. there was significant decrease in mean pustule count from the baseline values in both groups at the end of 12 weeks of treatment (figure 5). a significant decrease in mean pustule count from baseline was observed in group 1 at the end of 4 weeks, while the decrease in mean pustule count started earlier, ie, at the end of 2 weeks in group 2. however, the difference between the groups in terms of pustule count was not significant at the end of therapy (p = .28). the percentage decreases in mean pustule count in groups 1 and 2 were 51.98% (sd = 19.32%) and 55.15% (sd = 18.01%), respectively, but the difference was not significant (p = .55). there was significant decrease in mean mas in both groups from baseline to the end of therapy (figure 6). the significant decrease in mean mas was observed at the end of 2 weeks in both groups. however, the difference in mean mas between the groups was not significant at the end of therapy (p = .74). on comparing the groups in terms of percentage decrease in mean mas at the end of 12 weeks with respect to baseline, group 2 showed slightly better results with a percentage decrease of 55.97% (sd = 11.32%) as compared to 54.64% (sd = 9.32%) in group 1. however, the difference between the groups was not significant (p = .65). on analyzing the change in mas between the start and end of therapy, we found that all patients had good or fair improvement and none had poor improvement. good improvement (>50% decrease in mas) was seen in 15 of the 25 patients in group 1 (tca peel) and in 17 patients of group 2 (sa peel), without a significant difference (p = .54). fair improvement (20%-50% decrease in mas) was present in 10 patients in group 1 and 8 patients in group 2 (p = .52). adverse effects as far as side effects are concerned, burning and stinging sensations were more common in group 1 (20 of 25 patients) than in group 2 (10 of 25 patients); this difference was statistically significant (p = .004). post-peel erythema was also more common in group 1 (10 of 25 patients) than in group 2 (4 of 25 patients), but this difference was not significant (p = table 1. baseline characteristics of the 50 patients with acne vulgaris tca peel group (n = 25) sa peel group (n = 25) p age (years), mean (sd) 17.9 (2.4) 17.8 (1.9) .95 sex, n .56 male 9 11 female 16 14 disease duration (months), mean (sd) 18.24 (17.92) 24.24 (21.56) .075 comedone count, mean (sd) 157.08 (83.49) 164.04 (70.96) .75 papule count, mean (sd) 38.8 (18.06) 37.72 (20.46) .84 pustule count, mean (sd) 14.44 (5.8) 13.96 (7.88) .8 mas, mean (sd) 146.2 (59.62) 146.78 (51.27) .97 mas = michaelsson acne score; sa = salicylic acid; sd = standard deviation; tca = trichloroacetic acid. 4 research | dermatol pract concept. 2021;11(3):e2021063 .05). pih was observed in 5 patients in group 1 and 2 patients in group 2 (not significant). it resolved on its own in group 2, while in group 1 it resolved after treatment with topical application of mild desonide cream and strict sun protection for 1 week. no patient in the study had blistering, crusting, scaling, hypertrophic scarring or keloid formation. discussion chemical peeling is a well-known treatment for acne. peeling agents that have been used in the treatment of acne vulgaris include alpha hydroxy acids (eg, glycolic acid, lactic acid, mandelic acid), beta hydroxy acids (eg, salicylic acid, lipohydroxy acid), tretinoin peels, tca peels and jessner’s solution [1,9-12,15-17]. tca peel is effective for histologically and clinically improving the skin in a variety of dermatological conditions [18,19]. it has been used to treat acne, either alone or in combination with other drugs. sa peel (20%-30%) is a well-established superficial peeling agent for the treatment of acne vulgaris [3], and its efficacy has been documented by several studies [3, 8-12]. sa is effective against both acne and pih, which are common in people with skin of dark color. its whitening effect is an important factor in its choice as a superficial peeling agent for asian patients with acne vulgaris [20]. we found only 2 studies that compared the efficacy and safety of sa and tca peels [9,10]. in a recent study by abdel hay et al [10], a combination solution of 20% azelaic acid and 20% sa was compared with 25% tca peel in 34 patients with mild or moderate acne vulgaris. at the end of 8 weeks, significant improvements were seen in both treatment groups. however, the difference between the 2 treatments was not significant. according to the authors, the combination of azelaic acid and sa is recommended in the early stage of the disease, ie, when patients have inflammatory lesions, while tca is preferred for patients with non-inflammatory lesions. in a comparative, split-face study by abdel meguid et al [9], 25% tca peels and 30% sa peels were compared in 20 patients of fitzpatrick skin types iii to v with facial acne. at the end of the figure 1. improvement in lesions of acne vulgaris before and after tca peel. before treatment after treatment research | dermatol pract concept. 2021;11(3):e2021063 5 figure 2. improvement in lesions of acne vulgaris before and after sa peel. study, total improvement was more frequent with the sa than tca peel, but the difference was not statistically significant. total improvement in comedones was more frequent with tca peeling, while improvement of inflammatory lesions was more frequent on the side treated with the sa peel. however, the results did not reach the level of statistical significance. our study enrolled 50 patients with mild or moderate acne vulgaris. objective evaluation of active acne was done by individual lesion counts (comedones, papules and pustules) and calculation of mas. in terms of improvement in non-inflammatory lesions (ie, comedones), both peels brought a significant decrease in mean comedo counts from their respective baseline values. the percentage decrease in non-inflammatory lesions was slightly more with 25% tca peel than 30% sa peel; however, the difference was not significant at the end of therapy. this finding is in agreement with the study by abdel meguid et al [10], and may be due to fact that both tca peel and sa peel have comedolytic action. the mechanism of action of tca peel in the treatment of acne vulgaris is due to its ability to diminish corneocyte cohesion and keratinocyte plugging, thus helping in comedolytic action. in addition, application of tca to the skin causes precipitation of proteins and coagulative necrosis of epidermal cells, leading to removal of damaged skin and its replacement by normal tissue [19]. the effect of sa is mainly due to the lipophilic activity and comedolytic effect. the initial event in comedo formation is excessive keratinization in the mid-portion of the follicular canal; due to its lipophilic nature, sa preferentially acts on the sebaceous unit which is required and important for comedolysis [9]. since both tca and sa facilitate comedolysis, the effectiveness of both peels with respect to comedolytic action may be comparable. in our study, a significant decrease in mean papule count was observed after 2 weeks of therapy, but there was no significant difference between the groups at the end of therapy. the overall percentage decrease in mean papule count was better in group 2 (sa peel group) than in group 1 (tca peel before treatment after treatment 6 research | dermatol pract concept. 2021;11(3):e2021063 group), but the difference was not significant. similarly, a significant decrease in mean pustule count started earlier (ie, at 2 weeks) in the sa peel group than tca peel group in which it was seen at 4 weeks of therapy. furthermore, the overall percentage decrease in mean pustule count was better in the sa peel group than the tca peel group, but the difference was not significant. thus, there was statistically significant decrease in mean pustule count after completion of therapy in the 2 groups, but the difference was not significant at the end of therapy. the study by abdel meguid et al [9] found that 30% sa peels are superior to 25% tca peels for treating inflammatory lesions in dark-skinned patients. thus, the results of our study regarding the improvement in inflammatory acne lesions are in agreement with that study. the better effects in terms of improvement of papules and pustules (inflammatory lesions) with the sa peel than tca peel may be due to the anti-inflammatory action of sa through inhibition of the arachidonic acid cascade [21,22]. on analyzing the improvement in mas, there was a statistically significant difference from baseline values to the figure 3. mean comedo counts in group 1 (tca peel) and group 2 (sa peel) throughout the treatment period. m ea n c o m r d o n e c o u n t 164.04 157.08 147.76 145.8 133.48 129.04 121.2 116.32 p–value duration of therapy 108.56 104.56 94.28 92.76 79.64 group 1 group 2 77.6 160 180 140 120 100 80 60 40 20 0.75 0 0.890.92 0.920.82 0.820.8 baseline 2nd week 4th week 6th week 8th week 10th week 12th week figure 4. mean papule counts in group 1 (tca peel) and group 2 (sa peel) throughout the treatment period. m ea n p a p u le c o u n t 38.8 37.72 34.44 33.36 29 26.8 25.16 23.68 p–value duration of therapy 21.56 20.16 18.52 17.12 16.2 group 1 group 2 14.08 45 40 35 30 25 20 15 10 0.84 0 5 0.340.83 0.580.61 0.640.68 baseline 2nd week 4th week 6th week 8th week 10th week 12th week research | dermatol pract concept. 2021;11(3):e2021063 7 end of therapy in both groups, but the difference between groups was not significant. thus, our result is in agreement with those of abdel meguid et al [9], who also found that the efficacy of 25% tca peels and 30% sa peels are comparable in the treatment of mild-to-moderate acne vulgaris. as far as side effects are concerned, patients of both groups tolerated the peels very well. however, the sa peel was found to be safer in terms of side effects like erythema and pih, and was superior as far as burning and stinging sensations were concerned. no patient experienced any serious adverse effect requiring cessation of therapy. however, as skin of color is more prone to developing pih, the sa peel seems to be the better choice for dark skin owing to the additional advantage of its whitening effects [15,20]. the anti-inflammatory action of sa further adds to its beneficial effects as compared to tca peel [21,22]. furthermore, our patients also demonstrated better tolerability to the sa peel than the tca peel in the form of less burning and stinging, which enhances the compliance of patients with skin of color. figure 5. mean pustule counts in group 1 (tca peel) and group 2 (sa peel) throughout the treatment period. m ea n p u st u le c o u n t 14.44 13.96 13.76 12.04 12 10.8 10.6 9.4 p–value duration of therapy 9.16 8.36 7.68 7.56 7.16 group 1 group 2 5.92 16 14 12 10 8 6 4 2 0.8 0 0.280.43 0.920.54 0.570.43 baseline 2nd week 4th week 6th week 8th week 10th week 12th week figure 6. mean michaelsson acne scores (mas) in group 1 (tca peel) and group 2 (sa peel group) throughout the treatment period. m ea n m a s c o u n t 146.78 146.2 135.48 131.62 119.86 113.06 106.76 100.62 p–value duration of therapy 96.88 89.26 81.18 78.98 69.12 group 1 group 2 65.96 160 140 120 100 80 60 40 20 0.97 0 0.740.8 0.840.65 0.540.65 baseline 2nd week 4th week 6th week 8th week 10th week 12th week 8 research | dermatol pract concept. 2021;11(3):e2021063 our study has strengths related to the relatively larger study group and the use of an objective method to analyze the improvement of acne, ie, calculation of mas. however, there are also a few limitations to our study. firstly, follow-up was not done to determine the recurrence rate among the patients. secondly, we did not evaluate the patients’ satisfaction with the treatments. conclusions our study demonstrated that the efficacy of 25% tca peel is comparable to that of the 30% sa peel in the treatment of mild or moderate facial acne vulgaris in indian patients. furthermore, the 30% sa peel is marginally better than the 25% tca peel for inflammatory lesions, while for non-inflammatory lesions 25% tca seems better. in terms of safety and tolerability, the 30% sa peel was better than the 25% tca peel, as a greater number of patients in the 25% tca peel group developed adverse effects such as burning, stinging, pih and post-peel erythema than in the 30% sa peel group. hence, this study infers that although the therapeutic efficacies of the 25% tca and 30% sa peels are comparable in indian acne vulgaris patients, the 30% sa peel seems to be the treatment of choice for indian patients due to its lightening effects and the lesser chance of causing pih. references 1. layton am, eady ea, zouboulis cc. acne. in: griffiths cem, barker j, bleiker t, chalmers r, creamer d, eds. rook’s textbook of dermatology. 9th ed. oxford: blackwell publishing; 2016:90.1-65. 2. arshdeep, de d. what’s new in the management of acne? indian j dermatol venereol leprol. 2013;79(3):279-287. doi: 10.4103/0378-6323.110748. pmid: 23619432. 3. vaishampayan s, baveja s, garg s. acne, rosacea and perioral dermatitis. in: valia rg, valia ar, eds. iadvl textbook of dermatology. 4th ed. mumbai: bhalani publishing house; 2016:1400-1447. 4. del duca e, manfredini m, petrini n, et al. daylight photodynamic therapy with 5-aminolevulinic acid 5% gel for the treatment of mild-to-moderate inflammatory acne. g ital dermatol venereol. 2019 sep 12. doi: 10.23736/s0392-0488.19.06392-2. pmid: 31525842. 5. fabbrocini g, fardella n, monfrecola a, proietti i, innocenzi d. acne scarring treatment using skin needling. clin exp dermatol. 2009;34(8):874-879. doi: 10.1111/j.1365-2230.2009.03291.x. pmid: 19486041. 6. you hj, kim dw, yoon es, park sh. comparison of four different lasers for acne scars: resurfacing and fractional lasers. j plast reconstr aesthet surg. 2016;69(4):e87-95. doi: 10.1016/j. bjps.2015.12.012. pmid: 26880620. 7. cannarozzo g, silvestri m, tamburi f, et al. a new 675-nm laser device in the treatment of acne scars: an observational study. lasers med sci. 2021;36(1):227-231. doi: 10.1007/s10103-02003063-6. pmid: 32533470. 8. thiboutot d, gollnick h, bettoli v, et al; global alliance to improve outcomes in acne. new insights into the management of acne: an update from the global alliance to improve outcomes in acne group. j am acad dermatol. 2009;60(5suppl):s1-s50. doi: 10.1016/j.jaad.2009.01.019. pmid: 19376456. 9. abdel meguid am, elaziz ahmed attallah da, omar h. trichloroacetic acid versus salicylic acid in the treatment of acne vulgaris in dark-skinned patients. dermatol surg. 2015; 41(12):13981404. doi: 10.1097/dss.0000000000000522. pmid: 26551771. 10. abdel hay r, hegazy r, abdel hady m, saleh n. clinical and dermoscopic evaluation of combined (salicylic acid 20% and azelaic acid 20%) versus trichloroacetic acid 25% chemical peel in acne: an rct. j dermatolog treat. 2019;30(6):572-577. doi: 10.1080/09546634.2018.1484876. pmid: 29862871. 11. dayal s, amrani a, sahu p, jain vk, jessner’s solution vs. 30% salicylic acid peels: a comparative study of the efficacy and safety in mild-to-moderate acne vulgaris. j cosmet dermatol. 2017;16(1):43-51. doi: 10.1111/jocd.12266. pmid: 27557589. 12. dayal s, kalra kd, sahu p. comparative study of efficacy and safety of 45% mandelic acid versus 30% salicylic acid peels in mild-to-moderate acne vulgaris. j cosmet dermatol. 2020;19(2):393-399. doi: 10.1111/jocd.13168. pmid: 31553119. 13. khunger n; iadvl task force. standard guidelines of care for chemical peels. indian j dermatol venereol leprol. 2008;74 suppl:5-12. pmid: 18688104. 14. michaelsson g, juhlin l, vahlquist a. oral zinc sulphate therapy for acne vulgaris. acta derm venereol. 1977;57(4):372. pmid: 70937. 15. keri j, shiman m. an update on the management of acne vulgaris. clin cosmet investig dermatol. 2009;2:105-111. doi: 10.2147/ ccid.s3630. pmid: 214369 16. khunger n, vedamuthy m, arsiwala s, vedamurthy a. tretinoin peels. in: khunger n, ed. step by step chemical peels. new delhi: jaypee brothers medical publishers (p) ltd; 2009:159-178. 17. levesque a, hamzavi i, seite s, rougier a, bissonnette r. randomized trial comparing a chemical peel containing a lipophilic hydroxy acid derivative of salicylic acid with a salicylic acid peel in subjects with comedonal acne. j cosmet dermatol. 2011;10(3):174-178. doi: 10.1111/j.1473-2165.2011.00566.x. pmid: 21896127. 18. khunger n. trichloroacetic acid peels. in: khunger n, ed. step by step chemical peels. 2nd ed. new delhi: jaypee brothers medical publishers ltd; 2014:79-110. 19. chun ey, lee jb, lee kh. focal trichloroacetic acid peel method for benign pigmented lesions in dark-skinned patients. dermatol surg. 2004;30(4 pt 1):512-516. doi: 10.1111/j.15244725.2004.30166.x. pmid: 15056140. 20. ahn hh, kim ih. whitening effect of salicylic acid peels in asian patients. dermatol surg. 2006;32(3):372-375. 21. zaenglein al, pathy al, schlosser bj, et al. guidelines of care for the management of acne vulgaris.  j am acad dermatol. 2016; 74(5):945-973. doi: 10.1016/j.jaad.2015.12.037. pmid: 26897386. 22. zakopoulou n, kontochristopoulos g. superficial chemical peels.  j cosmet dermatol. 2006;5(3):246-253. doi: 10.1111/j.1473-2165.2006.00254.x. pmid: 17177748. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021; 11(4):e2021124 1 clinical and dermoscopic features of melanocytic lesions on the face versus the external ear teresa deinlein1, andreas blum2, günter schulter3, holger a. haenssle4, ralph braun5, roberta giuffrida6, rainer hofmann-wellenhof1 1 department of dermatology, medical university of graz, graz, austria 2 public, private, and teaching practice, konstanz, germany 3 department of psychology, biological psychology unit, karl-franzens-university graz, graz, austria 4 department of dermatology, university of heidelberg, heidelberg, germany 5 department of dermatology, university of zürich, zürich, switzerland 6 department of clinical and experimental medicine, dermatology, university of messina, messina, italy key words: nevi, melanoma, dermoscopy, face, ear citation: clinical and dermoscopic features of melanocytic lesions on the face versus the external ear. deinlein t, blum a, schulter g, haenssle ha, braun r, giuffrida r, hofmann-wellenhof r. dermatol pract concept. 2021; 11(4):e2021124. doi: https://doi.org/10.5826/dpc.1104a124 accepted: april 6, 2021; published: september 2021 copyright: ©2021 deinlein et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: prof. rainer hofmann-wellenhof, md. department of dermatology, medical university of graz, auenbruggerplatz 8, graz, austria. email: rainer.hofmann@medunigraz.at introduction: melanoma of the external ear is a rare condition accounting for 7-20% of all melanomas of the head and neck region. they present classical features of extra-facial melanomas clinically and dermoscopically. in contrast, facial melanomas show peculiar patterns in dermoscopy. objectives: to evaluate whether there are clinical and/or dermoscopic differences in melanocytic lesions located either at the external ear or on the face. methods: in this retrospective study we reviewed an image database for clinical and dermoscopic images of melanomas and nevi located either on the face or at the level of the external ear. results: 65 patients (37 men; 63.8%) with 65 lesions were included. we found no significant differences in comparing face melanomas with melanomas at the level of the external ear, neither clinically nor dermoscopically. however, we provided evidence for differences in some clinical and dermoscopic features of melanomas and nevi of the external ear. conclusions: in this study, we reported no significant differences in comparing melanomas on the face with melanomas of the external ear, both clinically and dermoscopically. furthermore, we provided data on clinical and dermoscopic differences comparing nevi and melanoma of the external ear. abstract 2 research | dermatol pract concept. 2021; 11(4):e2021124 introduction melanoma of the external ear (mee) is a rare condition, and its prognosis is still a matter of debate as long-term data are lacking. the external ear is considered as a special location as the skin is thin and lymphatic drainage is unpredictable. about 25% of all cutaneous melanomas are located at the head and neck region and among those, 7-20% are located on the external ear [1-4]. querying the surveillance, epidemiology, and end results registry (seer-registry) reveals 76,380 new diagnosed cases of mee in 2016 in the united states. 2 population-based analyses suggest surgical removal as the treatment of choice; however, following recent data, wider surgical margins for melanomas of the external ear do not affect the overall survival [3,4]. reviewing current literature shows, that melanomas of the external ear exhibit classical features of extra-facial melanomas, both clinically and dermoscopically (eg atypical pigment network, irregular dots and/ or globules, and peripheral streaks) (figure 1, a and b) [5]. in contrast, melanomas of the face are known to be associated with chronic sun-damaged skin and considered as slow-growing tumours. their incidence increases mostly due to the higher cumulative exposure to ultraviolet radiation [5-7]. stolz et al [6], first described a progression model from in-situ melanomas of the face (lentigo maligna) to dermoscopically invasive ones. at initial stages asymmetric pigmented follicles and grey dots around the follicles are observable. as the tumour progresses rhomboidal structures key messages • melanomas of the external ear and face melanomas differ in terms of their prevalence, clinical, dermoscopic appearance, and biological behaviour. prognosis of ear melanomas is still a matter of debate. it is common knowledge that ear melanomas usually exhibit the classical features of extra-facial melanoma. • to date, no study formally investigated possible clinical and/or dermoscopic differences in melanocytic lesions on the face versus the external ear. the results of this study show no significant differences when comparing melanocytic lesions on the face versus the external ear, thus indicating that face-specific criteria for melanomas are also valid for melanomas of the external ear and vice versa. furthermore, data on clinical and dermoscopic differences comparing nevi and melanoma of the external ear are here reported for the first time. figure 1. (a) clinical and (b) dermoscopic image of a melanoma of the external ear. one can observe a dark brownish to black-coloured, well demarcated lesion clinically. it exhibits an irregular pigment network and shinywhite streaks in dermoscopy. histopathology reported a malignant melanoma with a tumor thickness of 0.4 mm. research | dermatol pract concept. 2021; 11(4):e2021124 3 and finally homogenous pigmented areas and obliteration of the follicles are seen (figure 2, a and b). sensitivity and specificity of these features are reported to be 89% and 93% respectively [5-7]. the aim of this study was to evaluate whether there are clinical and/or dermoscopic differences in melanocytic lesions located either at the external ear or on the face. methods this was a retrospective observational single-centre study conducted at the department of dermatology in graz to evaluate whether there are clinical and/or dermoscopic differences in melanocytic lesions located either at the ear or in the face. the study was conducted over a 1-year period. ethics’ committee approval was waived since we did not affect the standard care of patients and data were anonymized. research was performed following the principles of the declaration of helsinki. we retrospectively reviewed the image database from the department of dermatology in graz for all clinical and dermoscopic images of melanomas (histopathologically proven) and nevi (histopathologically proven or unchanged in a follow-up over 6 months) located either on the face or at the level of the external ear. for 7 cases, there were no clinical images as follow-ups with sequential dermoscopy alone were performed. clinical images were obtained using a 10.2-megapixel digital camera (d200, nikon corporation tokyo, japan) and dermoscopic images were acquired with a 4-megapixel digital camera (nion coolpix 4500, nikon, new york, usa) equipped with a contact polarized dermoscope (dermlite photo 3gen, california, usa). due to comparison reasons, we matched each group of melanomas to contain almost the same number of patients. patients’ demographics (sex and age at diagnosis) and tumor information (anatomic site and histological diagnosis) were summarized in an excel file. all clinical and dermoscopic images were subsequently uploaded in the web-based database of the international skin imaging collaboration (isic archive). this upload was necessary as 5 experts evaluated the images from different departments over europe. experts had full access to the images and were blinded for tumor data. lesions were reviewed and analyzed following the clinical and dermoscopic criteria based on the third consensus conference of the international dermoscopy society from 2016 [11]: i. colour clinically: black, brown, grey-blue, light-brown, red, and white. ii. face-specific dermoscopic features: asymmetric pigmented follicular openings, pseudonetwork, annular-granular pattern/grey dots, circle within a circle/concentric circles. iii. melanoma criteria in general: irregular globules, scar-like depigmentation, tan peripheral structureless area, atypical pigment network, blue-white veil, milky-red areas, pseudopods, regular globules. statistical analyses were performed calculating 2 unifactorial analyses of variance (one-way anova) with the clinical and dermoscopic criteria as independent variables and the mean ratings of the 5 experts as the dependent variables using the latest spss software (version 23; ibm, armonk, ny, u.s.a). expert ratings varied from 0 (none of the five experts diagfigure 2. (a) clinical (a) and (b) dermoscopic features of a melanoma on the left cheek. clinically, a lightto dark brown, poorly demarcated macule is evident. the lesion shows different shades of brown, asymmetric pigmented follicular openings, and some concentric circles. histopathological report revealed an in-situ melanoma. 4 research | dermatol pract concept. 2021; 11(4):e2021124 nosed a specific feature) to 5 (all 5 experts observed a single feature) in a specific patient. comparison of means of these expert ratings across all patients was then done by analyses of variance. moreover, we also estimated the reliability of clinical and dermoscopic judgements, ie, the inter-rater repeatability using intraclass correlations (spss: two-way mixed model testing absolute agreement of single raters). these correlation measures are reported in table 1 and reflect the variation between the raters evaluating the same criterion in the same group of 65 patients examined in our study. the higher the coefficients, the higher was the consistency of ratings concerning a certain clinical or dermoscopic feature. values lower than 0.5 are indicative of a poor reliability, ie, experts substantially differ in their ratings of that feature. results demographics and lesions’ characteristics a total of 65 patients (37 men; 63.8%) with 65 lesions were included. the mean age at presentation was 48 years (range 8-92 years). 43 lesions (66.2%) were located at the ear and 22 on the face (33.8%). the localisation of the lesions in the face scattered as follows: 12 lesions were located on the cheek, 4 lesions on the nose, 3 pre-auricular lesions, 2 lesions at the level of the temple, and 1 lesion on the chin. the distribution of the lesions affecting the different parts of the ear showed the following: 26 lesions were located at the helix, 6 lesions on the earlobe and the back of the auricle respectively, 4 lesions on the antihelix, and 1 lesion on the antitragus. 47 lesions (72.3%) were histopathologically diagnosed as melanomas (8 in-situ melanomas and 39 invasive melanomas) with a mean tumour thickness of 1.21mm (range 0.13mm-6.0mm). among those, 25 lesions (53.2%) were located on the ear, showing a mean tumour thickness of 1.47mm and 22 (46.8%), on the face with a mean tumour thickness of 0.87mm. 18 lesions were due to not observable changes during follow-up diagnosed as nevi; all of these were located at the level of the ear. co-occurrences of clinical features irrespectively of tumors’ localization a total of 58 clinical images was evaluated based on the abovementioned criteria and revealed the following significant co-occurrences of clinical colours: i. black colour and grey-blue colour (r=0.54, p < 0,001); ii. brown colour and light-brown colour (r=0.64, p <0,001); iii. grey-blue colour with white and red colour (r=0.34, p <0,01 and r=0.43, p < 0,001 respectively); iv. red colour with white colour (r=0.41, p <0,001). table 1. intra-class correlations of expert ratings of clinical and dermoscopic features. the left column shows the evaluated clinical (c) and dermoscopic (d) features. in the right column the intra-class correlations of the respective features are shown; values lower than 0.5 indicate a poor reliability. feature (c=clinical; d=dermoscopic) intra-class correlation colour black (c) 0.800 colour brown (c) 0.350 colour grey-blue (c) 0.638 colour light-brown (c) 0.426 colour red (c) 0.728 colour white (c) 0.606 asymmetric pigmented follicular openings (d) 0.547 irregular globules (d) 0.412 regression/scar-like depigmentation (d) 0.241 annular-granular pattern/grey dots (d) 0.642 tan peripheral structureless areas (d) 0.115 concentric circles (d) 0.681 atypical pigment network 0.500 blue-white veil (d) 0.710 shiny-white structures (d) 0.777 milky-red areas (d) 0.654 peripheral streaks (d) 0.110 pseudonetwork (d) 0.250 regular globules (d) 0.655 research | dermatol pract concept. 2021; 11(4):e2021124 5 comparison of clinical features in melanomas on the ear vs. nevi on the ear a significant difference concerning clinical features when comparing these groups could be established. diagnoses of the clinical feature “colour gray-blue” were more than twice frequent in melanomas than in nevi (mean expert ratings: 0.45 vs. 0.21; f (1/34) =4.11; p=0.05). comparison of clinical features of melanomas on the face vs. melanomas of the ear no significant differences could be recognized concerning clinical features in these groups. co-occurrences of dermoscopic patterns irrespectively of tumors’ location a total of 65 dermoscopic images was evaluated concerning face-specific and general criteria of melanomas. the following significant co-occurences of patterns were observed: i. asymmetric pigmented follicles with scar-like depigmentation, annular-granular structures, tan peripheral structureless areas and concentric circles (r=0.52, p <0.001; r=0.56, p <0.001; r=0.36, p <0.003 and r=0.38, p <0.004 respectively). ii. scar-like depigmentation with annular-granular structures, tan peripheral structureless areas, concentric circles, bluewhite veil and milky-red areas (r=0.34, p <0.006; r=0.45, p <0,001; r=0.32, p <0.009; r=0.27, p <0.027 and r=0.27, p <0.032 respectively). iii. annular-granular structures with concentric-circles (r=0.3, p <0.016) and negative correlation of annular-granular patterns with regular globules (r=-0.015, p <0.015) iv. tan peripheral structureless areas with concentric circles and atypical pigment network (r=0.32, p <0.008 and r=0.25, p <0.04). v. atypical pigment network with a blue-white veil (r=0.32, p <0.009). vi. blue-white veil with shiny-white structures and milky-red areas (r=0.28, p <0.022 and r=0.42, p <0.001). vii. negative correlation of regular globules with asymmetric pigmented follicles and tan peripheral structures (r=-0.28, p <0.021 and r=-0.27, p <0.027). comparison of dermoscopic features of ear melanomas versus nevi on the ear we found some dermoscopic patterns to be significantly different between melanomas and nevi at the ear: asymmetric pigmented follicles, scar-like depigmentation, annular-granular patterns, tan peripheral structureless areas and regular globules; detailed results are provided below (table 2). comparison of dermoscopic features of face melanomas versus ear melanomas no significant differences could be proven concerning dermoscopic features in comparing these groups. discussion in this retrospective study including 65 patients we did not find any significant clinical or dermoscopic differences when comparing melanomas on the face and melanomas of the external ear. to the best of our knowledge, this is the first study providing data on this topic. these results somewhat contradict previous knowledge as skin’ s structure and texture at the external ear and on the face seem to be very similar. consequently, face-specific criteria for melanomas should be valid and be used also for melanomas of the external ear. of note, the limitation of this study relies on the fact that most of the included melanomas were invasive while just 8 tumors table 2. comparison of dermoscopic features in melanomas at the ear versus nevi at the ear. feature melanomas mean (n=25) nevi mean (n=18) f (1/34) p≤ asymmetric pigmented follicles 0.40 0.11 10.93 0.002 irregular globules 0.14 0.15 0.04 n.s. scar-like depigmentation 0.20 0.04 7.03 0.011 annular-granular structures 0.40 0.07 16.45 0.000 tan peripheral structureless areas 0.16 0.01 11.54 0.002 concentric circles 0.17 0.04 4.05 n.s. atypical pigment network 0.20 0.11 1.41 n.s. blue-white veil 0.24 0.14 1.27 n.s. shiny-white structures 0.29 0.12 2.67 n.s. milky-red areas 0.07 0.08 0.53 n.s. peripheral streaks 0.08 0.04 0.84 n.s. pseudonetwork 0.20 0.24 0.26 n.s. regular globules 0.03 0.22 9.60 0.004 n.s. not significant 6 research | dermatol pract concept. 2021; 11(4):e2021124 were in-situ melanomas. it is well known that – as melanomas progress – one can find similar clinical and dermoscopic features irrespectively of the tumor’s localization [5,9,11-13]. moreover, we found significant differences in clinical and dermoscopic patterns when comparing melanomas and nevi on the external ear. melanomas of the external ear exhibited the clinical feature “colour gray-blue” more than twice frequent when compared to nevi on the ear (figure 3, a-d). this is in line with data from the literature, as gray-blue colour is considered as a strong clue for melanoma [5,9,11,12]. moreover, we presented a number of dermoscopic features differing between melanomas and nevi of the ear respectively (table 2). these results are again in line with current data as asymmetric pigmented follicles, scar-like depigmentation, annular-granular structures and tan peripheral structureless areas were significantly more frequent observed in melanomas, whereas regular globules typically indicate nevi [9,11,12]. the early differentiation of figure 3 a-d. two clinical images comparing a nevus (a) and a melanoma (b) of the external ear. the nevus presents as roundish, well-demarcated, dark-brown plaque, whereas the melanoma presents as oval-shaped lesion showing different shades of brown, black and whitish-blue areas. histopathology reported a tumour thickness of 0.6mm. respective dermoscopic images are shown in the lower line. the nevus (c) exhibits regular distributed brownish and black globules. the melanoma (d) shows different shades of brown colour and black as well as whitish-blue areas. research | dermatol pract concept. 2021; 11(4):e2021124 7 melanocytic lesions at the external ear is of clinical relevance. a large study [14] comparing melanomas of the external ear and the head-/neck-region in over 130,000 patients proved that ear melanomas were an independent factor for tumor stage i and invasive behaviour. furthermore, the authors found that men had a higher likelihood to develop mee when compared to women. furthermore, significant co-occurrences among different dermoscopic patterns regardless of tumors’ localization were observed. notably, all positive correlations were found between face-specific and extra-facial criteria for melanoma. in addition, we found a number of negative correlations in this group. regular globules were negative correlated with asymmetric pigmented follicles and tan peripheral structures (p <0,021 and p <0,027, respectively); furthermore, a negative correlation between annular-granular patterns and regular globules could be proven (p <0,015). these results are well-established knowledge as regular globules in dermoscopy indicate a benign nevus whereas asymmetric pigmented follicles, tan peripheral structures, and the annular-granular pattern are strong indicators for melanomas [9,11-13]. from this one can infer that the presence of dermoscopic patterns considered as “benign” excludes a melanoma and the other way round. our study has several limitations. first, due to the retrospective setting of our study, the interpretation of results is limited. second, we did not include nevi of the face and can therefore not provide data about this entity in comparison to investigated entities. however, there is evidence that nevi of the face are mainly congenital and, especially in older individuals (>51 years), mostly present as raised, palpable, and hypopigmented lesions [13]. third, the mean tumor thickness of melanomas on the face versus the external ear differed substantially (0,87 mm versus 1,47 mm). therefore, comparison of these melanoma-types is limited. fourth, we did not include information about the total number of nevi, personal or family history of melanoma or degree of photo damage. to conclude, our study for the first time described that there are no significant differences when comparing melanomas of the face and melanomas of the external ear, clinically and dermoscopically. these results indicate that face-specific criteria for melanomas are also valid for melanomas of the external ear and vice versa. furthermore, our study for the first time provided data on clinical and dermoscopic differences in comparing nevi and melanoma of the external ear. references 1. frost j, dunne da, powell bw. external ear melanoma: a 10year assessment of management and outcomes. j plast reconstr aesthet surg. 2017;70(4):551-552. 2. surveillance, epidemiology, and end results (seer) program . research data (1973-2013), national cancer institute, dccps, surveillance research program, surveillance systems branch. updated: april 2016. accessed january 2021. http://www.seer. cancer.gov/. 3. deep nl, glasgow ae, habermann eb, et al. melanoma of the external ear: a population-based study. am j otolaryngol. 2017;38(3):309-315. doi: 10.1016/j.amjoto.2017.01.032. pmid: 28258767. 4. patel td, chin oy, baredes s et al. a population-based analysis of melanoma of the external ear. otol neurotol. 2018;39(2):e137-e142. doi: 10.1097/mao.0000000000001645. pmid: 29194224. 5. kaminska-winciorek g, calik j, 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dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2022;12(1): e2022037 1 pemphigus vulgaris: present and future therapeutic strategies dario didona1, giovanni paolino2, giovanni di zenzo3, biagio didona3, riccardo pampena4, matteo riccardo di nicola2, santo raffaele mercuri2 1 department of dermatology and allergology, philipps university, marburg, germany 2 unit of dermatology, irccs san raffaele hospital, milan, italy 3 idi-irccs, rome, italy 4 centro oncologico ad alta tecnologia diagnostica-dermatologica, azienda unità sanitaria locale-irccs di reggio emilia, italy key words: anti-cd20 antibodies, neonatal fc receptor (fcrn), pemphigus, rituximab, treatment citation: didona d, paolino g, di zenzo g, didona b, pampena r, di nicola mr, mercuri sr. pemphigus vulgaris: present and future therapeutic strategies. dermatol pract concept. 2022;12(1): e2022037. doi: https://doi.org/10.5826/dpc.1201a37 accepted: august 18, 2021; published: january 2022 copyright: ©2022 didona et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. dd and gp have equally contributed to the article and share co-first authorship. corresponding author: matteo riccardo di nicola, unit of dermatology, irccs san raffaele hospital, milan, italy. e-mail: dinicola.matteo@hsr.it pemphigus vulgaris (pv) belongs to the group of autoimmune blistering diseases. pv can affect not only mucous membranes, but also the skin and it is characterized by serum igg autoantibodies against desmoglein 1 and 3, two major components of desmosomes. the introduction of glucocorticoids improved dramatically the prognosis of patients affected by pv. however, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. rituximab, a chimeric anti-cd20 monoclonal antibody, has been recently approved as in-label therapy for pv, leading to an improvement of the prognosis and higher remission rate. furthermore, other anti b-cell therapies and several anti-cd20 biosimilars have been introduced in the clinical practice. we focused on present and future therapeutic approaches in pv. abstract introduction pemphigus vulgaris (pv) belongs to autoimmune blistering diseases and it is characterized by flaccid blisters and erosions, that can involve not only the skin, but also mucous membranes [1]. three main forms of pemphigus are described: pv, pemphigus foliaceus (pf), and paraneoplastic pemphigus [1–6]. 2 review | dermatol pract concept. 2022;12(1): e2022037 methods we conducted a review to identify studies that documented the current therapeutic strategies for pemphigus vulgaris, as well as the future ones. all type of study, in english language, was considered eligible for this review, including case reports and case series. the main search was conducted in the electronic databases of medline, embase and cochrane central register of controlled trials (central) from inception to january 2021 using different combinations of the following terms: “pemphigus”, “pemphigus vulgaris”, “treatment” and “therapy”. additionally, we concluded the manual search by reviewing all relevant citations within the selected and identified articles. epidemiology pv is the most frequent type of pemphigus [1]. it usually affects people between 50–60 years of age [7]. a female to male ratio of 5.0 was reported in the usa [7]. in the american general population, an annual incidence of 4.2/ 1,000,000 inhabitants was reported, but it was much higher in the jewish-american population [7]. this is due to the most prominent expression of specific hla class ii genes in pv patients with jewish background, such as hla-drb1*0402 and hla-dqb1*0503 [7]. clinical features of pv pv usually arises with painful and refractory oral erosions (figure 1) [1]. furthermore, other mucous membranes can be affected [1]. most of patients also develop flaccid skin blisters that rapidly evolve into oozing erosions (figure 2) [1]. rarely, pemphigus patients show a clinical and serological transition from pv to pf or conversely. this phenomenon could be due to the epitope spreading, a process of diversification of bor t-cell responses from the initial dominant epitope to a second one [8]. pathogenesis cutaneous desmoglein-1 (dsg1) can be expressed in the whole epidermis, cutaneous dsg3 is typically found in the lower epidermis, while in the mucosa dsg1 and dsg3 are located in the whole squamous layer, with a higher expression of dsg3 [9]. therefore, pv patients who show only anti-dsg1 immunoglobulin g (igg) serum antibodies develop only skin blisters, and, in the case of detectable anti-dsg3 igg serum antibodies, the clinical phenotype is characterized by erosions or ulcerations of mucosal membranes [10]. furthermore, the production of both anti-dsg1 and anti-dsg3 igg serum autoantibodies provokes skin and mucosal lesions [10]. evidence suggests that anti-dsg1 and anti-dsg3 autoantibodies are responsible for a loss of cell-cell adhesion between keratinocytes [11,12]. the most important targets for autoantibodies in pv are represented by the extracellular domains of dsg [13,14]. further mechanisms can also lead to acantholysis in pv, such as dsg endocytosis and desmosome disassembly [15,16], and intercellular stretch at non-acantholytic cell layers caused by pathogenic autoantibodies [17,18]. in addition, non-dsg igg serum autoantibodies have been reported as important in pv pathogenesis, including those directed against desmocollins, mitochondria, pemphaxin, and alpha-9 acetylcholine receptor [13,19]. diagnosis of pv the diagnosis of pv requires not only compatible clinical features, but evidence of pathological features of involved skin and the presence of autoantibodies by direct immunofluorescence microscopy of non-affected skin. indirect immunofluorescence microscopy, enzyme-linked immunosorbent assay and other techniques have a confirmatory role [5]. the most important pathological feature is the intraepidermal acantholysis [20]. direct immunofluorescence of non-affected skin detects igg and proteins of complement c3 (c3) on epidermal keratinocytes (figure 3) [20,21]. indirect figure 1. large erosions of the oral mucosa. figure 2. multiple erosions on the back of this male patient. review | dermatol pract concept. 2022;12(1): e2022037 3 immunofluorescence on monkey esophagus detects a fishnet pattern due to igg antibodies reactivity to cell membrane of epithelial or epidermal cells [20]. current therapies corticosteroids prednisolone is usually administered as initial therapy in pv in association with immunosuppressive agents, such as azathioprine (aza) and mycophenolate mofetil (mmf), or anti-cd20 monoclonal antibodies [1]. in patients with several comorbidities and in those who cannot undergo a therapy with anti-cd20 monoclonal antibodies or immunosuppressive agents, prednisolone as monotherapy is still recommended as first-line therapy [1]. nevertheless, plenty of side effects have been described after prolonged corticosteroid (cs) therapy, including severe infections, secondary impairment of adrenal glands, osteoporosis, hyperglycemia, and hypertension [1]. aza aza downregulates purine metabolism, and blocks the synthesis of dna, rna, and proteins. in addition, aza causes a reduction of langerhans cells and monocytes, and reduces the activity of tand b-lymphocytes [1]. furthermore, aza blocks t-helper-cell dependent responses of b-cells [1]. aza dosage should be adapted to thiopurine-methyltransferase activity, the enzyme responsible for aza metabolism. adverse events (aes) are reported in up to 30% of patients, including nausea, pancreatitis, diarrhea, aphthous stomatitis, and maculopapular rash [1]. pancytopenia and hepatotoxicity are reported as severe aes [1]. mmf mmf leads to a suppression of the immune system by a selective blockade of inosine monophosphate dehydrogenase, that produces a downregulation of the pathway of purine synthesis in tand b-cells [1]. because of its mode of action, mmf represents a safer cs-sparing drug compared to other immunosuppressive drugs [1]. moderate gastrointestinal aes are frequently reported [1]. in addition, mmf can increase the risk of hematologic malignancies, skin basal cell, and squamous cell carcinoma [1]. cyclophosphamide cyclophosphamide (cyp) is an alkylating prodrug [1]. it is converted in the liver into 2 active metabolites, which cause cell death through the downregulation of dna replication. cyp blocks the release of cytokines and reduces the lymphocytic inflammation [1]. it is recommended as a rescue drug, since its administration is characterized by several aes, such as nausea, fatigue, pancytopenia, and alopecia [1]. a severe complication of cyp treatment is hemorrhagic cystitis, which can be avoided with the administration of adequate fluid intake and sodium 2-mercaptoethane sulfonate [1]. cyp administration can cause transitional cell carcinoma of the bladder [1]. in addition, transient or lasting impairment of gonadal function has been reported [1]. rituximab rituximab (rtx) is a chimeric monoclonal anti-cd20 antibody, that targets cd20, a transmembrane receptor, expressed at several stages of the b-cell maturation [22]. rtx causes b-cell depletion through different mechanisms: 1) direct induction of apoptosis; 2) complement-dependent cytotoxicity; 3) antibody-dependent cytotoxicity; 4) antibody-dependent phagocytosis; and 5) trogocytosis [23,24]. the last mechanism is characterized by the elimination of rtx-cd20 complexes by macrophages, that causes cell death by a still unknown mechanism [25]. pv patients on rtx can develop opportunistic infections, such as pneumocystis jirovecii pneumonia [23], but it is still unclear whether pv on rtx may receive a pneumocystisjirovecii prophylaxis [26]. furthermore, reactivation of hepatitis b and c and tuberculosis could be possible [23]. side effects related to rtx administration are represented mostly by type i allergic reaction and cytokine release syndrome [23]. furthermore, late aes include serum sickness and toxic epidermal necrolysis [23,27]. the optimal rtx dose in pv is still under debate. two main protocols have been proposed: 2 intravenous infusions of 1000 mg each 2 weeks apart (rheumatoid arthritis protocol) and 4 infusions of 500-mg each weekly [23,28]. in 2017, a prospective randomized controlled trial that compared rtx combined with cs versus cs alone in patients with newly diagnosed pv showed a significantly higher remission rate off-therapy in the rtx cohort [29]. furthermore, re-treatment with a single rtx dose of 500 mg after 12 and figure 3. deposition of igg and/or c3 on the surface of epidermal keratinocytes detected by direct immunofluorescence. c3 = proteins of complement c3; igg = immunoglobulin g. 4 review | dermatol pract concept. 2022;12(1): e2022037 18 months was highly effective in achieving a long-term clinical remission [29]. ofatumumab ofatumumab is a fully human anti-cd20 monoclonal antibody used as therapy in chronic lymphocytic leukemia. its target is represented by another cd20 epitope compared to the one targeted by rtx [30]. ofatumumab has been used for pv patients who developed side effects or loss of response to rtx [31]. intravenous immunoglobulin intravenous immunoglobulin (ivig) is used for immunomodulatory therapy of several inflammatory disorders [32]. the mechanism of action of ivig is still not completely known, but several modes of action have been proposed [33,34]. however, the main mechanism of action is considered the implementation of degradation of immunoglobulins by binding the neonatal of fc receptor (fcrn) [33,34]. the standard administration schedule is 2 g/kg in 5 days (400 mg/kg per day in 5 days) must be kept in mind that ivig does not show an immunosuppressive activity [32,34]. it can be administered in combination with systemic cs and other immunosuppressants in recalcitrant pv [35]. side effects were not frequently described [36,37]. early aes include headache, nausea, fever, tachycardia, malaise, arthralgia, and dyspnea [36,37]. late-onset aes include, aseptic meningitis, acute renal failure, thromboembolic events, and pseudohyponatremia [36,37]. immunoadsorption through immunoadsorption (ia) igg were passively removed from systemic circulation [1]. the combination of ia with immunosuppressive therapies is considered an effective treatment for pemphigus patients with severe activity, because ia allows an immediate removal of pathogenic autoantibodies. infections are still the most frequently complications [1]. ia is considered an effective treatment in patients with severe disease (> 30% of the body surface or >25% of genital or oral mucosa) or with involvement of the conjunctiva or esophagus [1]. future therapeutic approaches car-t cell therapies chimeric antigen receptor (car)-t-cell therapy has been described as promising therapy in hematology [1]. car-t cell therapy is a paradigmatic example of adoptive cell transfer therapy. indeed, autologous t-cells are modified ex-vivo to express a car, which leads to a specific targeting of a particular antigen and elimination of the antigen-expressing cells [38,39]. the cars are composed of 3 domains: 1) the extracellular domain, which represents the antigen recognition domain; 2) the transmembrane and hinge domain; 3) the one or more intracellular t-cell signaling domains [39]. in 2016, t-cells were modified to express a chimeric autoantibody receptor (caar), which was composed by dsg 3 fused to a cd137cd3-zeta signaling domains [39]. desmoglein-3 caar-t-cells show a selective cytotoxicity directed to cells with anti-dsg3 b cell receptors in vitro and destroy dsg3-specific b-cells in vivo. in a pv mouse model, caar-t cells reduced pathogenic igg antibodies and improved the clinical picture [40]. anti-neonatal fc receptor (fcrn) the fcrn is formed by the mhc class i-like heavy chain and the β 2 -microglobulin light chain [41]. it has played a central role in the homeostasis of igg. indeed, the igg-fcrn complex avoids the degradation of igg, leading to a recycle and release of igg [42,43]. in a knockout mouse for fcrn, loss of cell-cell adhesion by passive transfer of antibodies against dsg was not evident [44]. furthermore, it was reported that blocking fcrn impaired the capability of pv to determine acantholysis [45]. a randomized, double-blind, placebo-controlled study with efgartigimod, a human igg1-derived fc fragments bound to fcrn, reported the efficacy of the drug in 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dermatol pract concept. 2022;12(1):e2022010 1 study of nail psoriasis and dermoscopic correlation with dermoscopic and modified dermoscopic nail psoriasis severity indexes (dnapsi and dmnapsi) sandeep arora1, debatraya paul2, richa kumar3, anuj bhatnagar2, gulhima arora4, sunita mech2, devinder kumar suhag2 1 department of dermatology, army college of medical sciences & base hospital delhi cantt, india 2 command hospital air force bangalore, india 3 command hospital eastern command kolkota, india 4 mehektagul dermaclinic, new delhi, india key words: nail psoriasis, nail psoriasis severity index, psoriasis area severity index, dermoscopy, onychoscopy citation: arora s, debatraya p, richa k et al. study of nail psoriasis and dermoscopic correlation with dermoscopic and modified dermoscopic nail psoriasis severity indexes (dnapsi and dmnapsi). dermatol pract concept. 2022;12(1):e2022010. doi: https://doi .org/10.5826/dpc.1201a10 accepted: may 4, 2021; published: january 2022 copyright: ©2022 arora et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: sandeep arora, army college of medical sciences & base hospital delhi cantt, india. e-mail: aroraderma@gmail.com background: nail involvement in psoriasis may be assessed clinically, ultrasonologically, and dermoscopically. the aim of this study was to assess the dermoscopic features of nails in psoriasis, to compare them with the clinical findings, and to correlate them with the nail psoriasis severity index (napsi) score. methods: we recruited 120 patients with psoriatic nail changes for the study. the psoriasis area severity index (pasi) was used to assess the severity of disease. clinical and dermoscopic (dermlite dl4, ×10, polarized and non-polarized) nail examination determined napsi, modified napsi (mnapsi), and napsi determined with dermoscopic findings (dermoscopic napsi [dnapsi] and dermoscopic modified napsi [dmnapsi]) were used to assess severity of nail involvement. results: subungual hyperkeratosis (50.8%) and nail plate thickening (56.7%) were the commonest clinical nail changes found, and dermoscopically, they were subungual hyperkeratosis and pitting (68.3% each). the average median with interquartile range of pasi and napsi scores were 7.5 [5.7-10.8] and 8.0 [6-12], respectively. napsi scores increased significantly with the increase in pasi scores (p < 0.001). a comparison of napsi and mnapsi with dnapsi and dmnapsi revealed that napsi, mnapsi, and dnapsi increased significantly with an increase in pasi scores. the dnapsi scores increased significantly with increased mnapsi and dmnapsi, and mnapsi and dmnapsi were significantly good predictors of joint involvement in psoriasis. conclusions: dermoscopy allows for better visualization of nail findings. evaluating napsi and mnapsi scores in conjunction with dnapsi and dmnapsi increases their helps detect early psoriasis, detection of worsening moderate-to-severe psoriasis (pasi >10) and predict joint involvement and their severity. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022010 introduction nail changes in psoriasis are significant findings and associated with a significant psychological impact [1]. nail lesions are observed in about one-half of patients with psoriasis, with an estimated lifetime incidence of 80-90% [2]. most psoriasis cases present with nail changes, while isolated nail psoriasis is rare, occurring in 1-5% of patients [3]. these changes are most common in older patients, in severe forms of psoriasis, in cases with longer duration of disease, and in the presence of psoriatic arthritis, in which case the incidence of nails changes is over 80% [4]. more severe nail psoriasis is associated with a more severe cases of psoriatic arthritis [5]. the clinical presentation of nail psoriasis varies according to the severity and localization of the lesion: the nail matrix, the nail bed, and in severe forms, the entire nail structure [6,7]. the most common nail lesion reported is pitting, followed by nail bed discoloration, onycholysis, subungual hyperkeratosis, abnormalities of the nail plate, and splinter hemorrhages [8]. they lead to significant functional impairment, pain, and psychosocial distress, and patients report significantly worse values in satisfaction with their treatment due to the stress and time involved in treatment [2,9]. dermoscopy with polarized and non-polarized modes is useful in the evaluation of superficial nail plate/matrix changes, such as pitting and crumbling, and deeper nail bed psoriatic nail involvement in the form of onycholysis, oil spots, subungual hyperkeratosis and splinter hemorrhages, especially when there are no typical clinical features [10,11]. objectives the focus of our study was to determine the frequency of dermoscopic findings in psoriatic nails and to compare the dermoscopic examination with the clinical examination to investigate the relationships between the indicators of disease severity. methods this was a prospective observational study conducted from october 2018 to october 2019 in the department of dermatology in a tertiary care teaching hospital. approval from the institutional ethics committee of command hospital air force bangalore was obtained vide ec/chaf bangalore/2018/27 dated 14 may 2018. clinically diagnosed psoriasis patients who visited the dermatology outpatient clinic were screened, and 120 patients aged 14-75 years with nail psoriasis were examined clinically and with dermoscope (dermlite dl4, ×10; polarized and non-polarized modes). onychomycosis was ruled out after performing koh mount on nails and fungal cultures from all the suspected cases. patients with coexisting onychomycosis, erythrodermic psoriasis, patients in remission following systemic treatment for psoriasis, pregnant women, patients not consenting to the study, and patients with systemic disorders that may have influenced nail changes were excluded from the study. the clinical-demographic profile of the participants was documented. clinical images of the hands and feet and radiographs were taken, and the classification criteria for psoriatic arthritis (caspar) scores were calculated. disease severity was assessed using psoriasis area severity index (pasi) as a clinical assessment tool for each patient. all nails were examined clinically followed by a dermoscopic examination. dermoscopic images were captured with dermlite dl4, ×10, polarized and non-polarized modes. the nail psoriasis severity index (napsi) and modified napsi (mnapsi) scores were calculated for both fingernails and toenails. with dermoscopic findings we recalculated napsi and labeled it dermoscopic napsi (dnapsi) and dermoscopic modified napsi (dmnapsi). statistical analysis all characteristics were summarized. for continuous variables, the summary statistics of mean ± standard deviation (sd) were used. for categorical data, the number and percentage were used in the data summaries and diagrammatic presentation. if the pvalue/ zvalue was < 0.05, then the results were statistically significant; otherwise, they were considered as not statistically significant. a receiver operating characteristic (roc) curve was plotted for napsi, d napsi, dmnapsi, and mnapsi to compare their predictive ability for clinical joint involvement. the odds ratio of napsi and dmnapsi to their correlation with caspar was also analysed. data were analyzed using spss software v.23.0. results a total of 120 patients with psoriatic nail involvement were included in the study. the mean age of the patients was 47.3 ± 13.1 years (range 14-74 years). fifty-five percent of patients had the disease for more than 5 years, and the duration of treatment ranged from 0.2 to 11 years (4.9 ± 2.6 years). the mean body mass index (bmi) of the study population was 26.3 ± 3.2 kg/m2. hypertension was the commonest comorbidity (table 1). chronic plaque psoriasis was the commonest clinical presentation (79.2%) and 72.5% of the patients had a pasi score <10; 51.7% of study subjects had a napsi score bewteen 6 and10. arthritis was noted in 11.7% of cases (n = 14), 90% (n = 108) had a caspar score of 3 or more. the mean numbers of fingernails and toenails affected were 3.5 ± 1.2 and 3.6 ± 1.5 with a mean napsi score of 10.1 ± 6.1. a larger number of nail changes were detected with dermoscopy. nail original article | dermatol pract concept. 2022;12(1):e2022010 3 table 1. socio-demographic details of patients (n=120) demographic details n (%) age-group, years ≤ 30 31-40 41-50 51-60 >60 16 (13.3) 18 (15.0) 33 (27.5) 35 (29.2) 18 (15.0) gender males females 99 (82.5) 21 (17.5) bmi (kg/m2) (asia-pacific guidelines)[17] underweight (<18.5) normal (18.5 22.9) overweight (23.0 24.9) obese class i (25.0 29.9) obese class ii (> 30.0) 01 (0.8) 16 (13.3) 28 (23.3) 56 (46.7) 19 (15.8) disease duration 1 – 6 months 6 – 12 months 1 – 5 years > 5years 07 (05.8) 12 (10.0) 35 (29.2) 66 (55.0) comorbidities hypertension diabetes arthritis others 29 (24.2) 19 (15.8) 14 (11.7) 02 (01.7) bmi = body mass index. matrix signs were noted in 95.8 % of cases and nail bed signs were noted in 85.0% of cases. clinically, nail plate thickening (56.7%) and subungual hyperkeratosis (50.8%) were the most common presentations and, on dermoscopic examination, pitting (72.5%) and subungual hyperkeratosis (68.3%) the most frequent ones (figure 1) (table 2). the mean (range) of pasi, napsi, mnapsi, dnapsi and dmnapsi scores were 7.5 (1.8-36.0), 8.5 (3-39), 7.0 (0-34), 11.0 (3-45) and 11.0 (0-44), respectively. napsi, mnapsi and dnapsi scores increased significantly with the rise in pasi scores (r = 0.56, p < 0.001), (r = 0.57, p < 0.001) and (r = 0.54, p < 0.001), respectively (figures 2 and 3). the scores of dnapsi also increased significantly with the increase of mnapsi and dmnapsi scores (r = 0.84 with p < 0.001 and r = 0.87 with p < 0.001, respectively) (figure 4). keeping the variables like age, gender, bmi, napsi scores, presence of comorbidities, duration of onset of disease, and duration of treatment constant in for analysis the increase in dnapsi scores by 1 unit is likely to detect pasi scores <10 by 1.08 times and pasi scores between 10 and 20 by 1.01 times compared to pasi scores >20. the increase in napsi scores by 1 unit is less likely to detect pasi scores <10 and between 10 and 20 by 0.69 times compared to pasi scores >20. similarly, the increase in dmnapsi scores by 1 unit is less likely to detect pasi scores <10 by 0.59 times and pasi scores between 10 and 20 by 0.69 times compared to pasi scores >20. the adjusted odds values showed that dnapsi scores were more likely to detect psoriasis at an early stage compared to napsi and dmnapsi. although the scores were not significant predictors in detecting psoriasis at an early stage (p > 0.05) (table 3), dnapsi was likely to detect a rise in pasi in moderate-to-severe psoriasis better than napsi. hence, follow-up of cases with this index can alert an impending worsening of the condition. the receiver operating characteristic (roc) curve plotted for napsi, d napsi, dmnapsi, and mnapsi to compare their predictive ability for clinical joint involvement revealed that mnapsi and dmnapsi were significantly better predictors of joint involvement compared to other nail psoriasis severity indices (napsi, dnapsi) (p < 0.05) (figure 5). though none of the severity measure scores (napsi, dnapsi, mnapsi and dmnapsi) were statistically significant (p > 0.05) for joint involvement, dmnapsi scores showed higher odds ratio values, indicating that unitary increase in dmnapsi scores increased the odds of being in the caspar scores of 2, 3 and 4 by 2.10 times, 2.19 times, and 2.13 times compared to a caspar score of 5. similarly, napsi scores showed higher odds ratio values, indicating that unit increase in napsi scores increased the odds of being in the caspar scores of 2, 3 and 4 by 1.58 times, 1.85 times and 2.03 times compared to a caspar score of 5. the odds of napsi scores increased with increase in the grades of severity of joint involvement based on caspar criteria, and odds of dmnapsi remained almost the same, with no statistical difference between these two (p > 0.05) (table 4). the mean ranks of mnapsi increased significantly with the duration of the disease (1-6 months = 47.57; 12-60 months = 60.00; >60 months = 67.34, with p < 0.05), except at 6-12 months (31.88, p > 0.05). the mean ranks of other scores, ie dnapsi, dmnapsi and napsi, did not vary significantly in relation to the durations of the disease (p > 0.05) (table 5). conclusions dermoscopy allows for better visualization of the nail bed and nail matrix abnormalities, and detects early or mild, as well as late changes in the disease, as was also seen in the present study [12]. with its routine use in clinical practice, early and late descriptions of skin, nail and hair diseases are being elaborated in literature increasingly. however, their relevance and importance to standard clinical findings need 4 original article | dermatol pract concept. 2022;12(1):e2022010 table 2. frequency distribution of clinical and dermoscopic nail bed and nail matrix findings among patients findings clinical examination dermoscopic examination number (n) percentage (%) number (n) percentage (%) nail bed signs splinter hemorrhages 06 05.0 31 25.8 subungual hyperkeratosis 61 50.8 82 68.3 distal onycholysis 54 45.0 62 51.7 oil drop sign 37 30.8 47 39.2 dilated hyponychial capillaries 18 15.0 18 15.0 nail matrix signs nail plate thickening 68 56.7 71 59.2 pitting 60 50.0 87 72.5 leukonychia 13 10.8 26 21.7 transverse grooves 14 11.7 24 20.0 trachyonychia 01 0.8 14 11.7 red spots on lunula 04 03.3 05 04.2 crumbling 23 19.2 23 19.2 figure 1. dermoscopic image. (a) subungual hyperkeratosis. (b) pitting. (c) distal onycholysis. (d) splinter hemorrhages (dermlite dl4, ×10, polarized). original article | dermatol pract concept. 2022;12(1):e2022010 5 figure 2. (a) correlation of pasi and napsi scores. (b) correlation of pasi and mnapsi scores. mnapsi = modified nail psoriasis severity index; pasi = psoriasis area severity index. figure 3. correlation of pasi and dnapsi (dermoscopically assessed napsi) scores. dnapsi = dermoscopic nail psoriasis severity index; pasi = psoriasis area severity index. 40 r sq linear = 0.321* pasi score n a p si s c o r e 30 20 10 0 0 10 20 30 40 40 r sq linear = 0.334* pasi score m o d if ie d n a p si 30 20 10 0 0 10 20 30 40 50 r sq linear = 0.293* 40 30 d er m o sc o p ic n a p si 20 10 0 0 10 20 pasi score 30 40 to be validated. in this study we compared nail changes observed in both dermoscopic and clinical examinations and determined their association using napsi score and their correlation between the indicators of disease severity, ie pasi and napsi scores. chronic plaque psoriasis is known to be the commonest pattern of psoriasis, as evidenced in our study. the mean age of our cohort (47.3 ± 13.1 years) with psoriasis was similar to those reported literature [13]. in our study, we had 55% males and a duration of disease of 4.9 years, which is higher than other studies reporting nail findings [14,15]. elobeid et al found a mean bmi of 25.3 kg/m2, similar to our findings if not for a marginally higher bmi (26.3 kg/m2) which may have been due to different study populations and study settings [16][17]. in psoriasis, nail lesions usually manifest 10 years later than skin lesions, and nail involvement is present in 20%-50% of psoriatic patients [18-21]. according to polat and kapicioglu, the most common clinical and dermoscopic findings were pitting and leukonychia [12], and wanniang et al noted salmon patch (oil drop sign) and splinter hemorrhages significantly better with the dermoscope [22]. in addition to pitting, yorulmaz and artuz found salmon patch (oil drop sign) to be associated with higher napsi scores [13]. however, in our study, pitting, subungual hyperkeratosis, nail plate thickening, and distal onycholysis were present in the majority of patients, and all nail changes were noted significantly better on dermoscopy. the difference in our observations from the reported literature may be due to different disease duration and severity with an average napsi score of 8 in our study versus 23, indicating higher disease severity among their patients [22]. dermoscopic nail findings of subungual hyperkeratosis and oil drop signs were significantly associated with a higher median napsi score >8 in our study. the scores of napsi, mnapsi and dnapsi increased significantly with the rise in pasi scores, which partially corroborates the findings of studies by hallaji et al and prevezas et al [23,24]. the dnapsi helped detect early psoriasis but did not perform well in detecting changes in severity in early psoriasis. however, dnapsi was better than napsi at detecting worsening pasi in moderate-to-severe psoriasis. cassell et al formulated mnapsi as a gold standard with good correlation with other disease severity measures [25]. the scores of dmnapsi along with mnapsi were found to be significantly better predictors of joint involvement compared to other nail psoriasis severity indices. both mnapsi and dmnapsi increased with severe joint involvement, based on the caspar criteria, with no statistically significant difference between these two scores. hence, dmnapsi is consistent as mnapsi in correlation with joint severity. 6 original article | dermatol pract concept. 2022;12(1):e2022010 50.00 r sq linear = 0.763* 40.00 30.00 20.00 10.00 0.00 0 10 20 dermoscopic napsi d er m o sc o p ic m n a p si 30 40 50 r sq linear = 0.71*40 30 20 10 0 0 10 20 dermoscopic napsi m o d if ie d n a p si 30 40 50 figure 4. (a) correlation between dmnapsi and dnapsi scores. (b) correlation between mnapsi and dnapsi scores. dnapsi = dermoscopic nail psoriasis severity index; dmnapsi = dermoscopic modified nail psoriasis severity index; mnapsi = modified nail psoriasis severity index. table 3. predictors of severity of nail psoriasis based on pasi scores pasi severity scores measures of nail psoriasis severity index unadjusted odds ratio (or) adjusted odds ratio (or) 95% confidence interval (ci) p-value <10 dnapsi§ 0.08 1.08 0.31 – 3.79 0.90 napsi 0.36 0.69 0.25 – 1.99 0.50 dmnapsi¥ 0.52 0.59 0.34 – 1.06 0.08 10-20 dnapsi§ 0.02 1.01 0.29 – 3.52 0.98 napsi 0.36 0.69 0.25 – 1.95 0.49 dmnapsi¥ 0.38 0.69 0.39 – 1.20 0.19 reference category: pasi score more than 20; §-dermoscopic napsi; ¥ dermoscopic modified napsi dnapsi = dermoscopic napsi; dmnapsi = dermoscopic modified napsi; napsi = nail psoriasis severity index; pasi = psoriasis area and severity index 1.0 d napsi napsi m napsi dm napsi reference line 0.8 0.6 se n si ti v it y 0.4 0.2 0.0 0.0 0.2 1 specificity 0.4 0.6 0.8 1.0 figure 5. predictive ability of napsi, mnapsi, dmnapsi, and dnapsi in detecting joint involvement. dnapsi = dermoscopic nail psoriasis severity index; dmnapsi = dermoscopic modified nail psoriasis severity index; mnapsi = modified nail psoriasis severity index; napsi = nail psoriasis severity index. original article | dermatol pract concept. 2022;12(1):e2022010 7 table 4. comparison of measures of nail psoriasis severity indices as predictors of psoriatic arthritis based on caspar criteria caspar criteria measures of nail psoriasis severity index unadjusted odds ratio (or) adjusted odds ratio (or) 95% confidence interval (ci) p-value 2 dnapsi§ 0.02 0.99 0.48 -2.02 0.97 mnapsi 0.79 0.46 0.15 – 1.35 0.16 napsi 0.46 1.58 0.54 – 4.62 0.40 dmnapsi¥ 0.74 2.10 0.69 – 6.45 0.19 3 dnapsi§ 0.25 0.78 0.39 – 1.55 0.47 mnapsi -0.87 0.42 0.15 – 1.22 0.11 napsi 0.62 1.85 0.85 – 5.28 0.25 dmnapsi¥ 0.79 2.19 0.73 – 6.61 0.16 4 dnapsi§ 0.31 0.74 0.35 – 1.54 0.42 mnapsi 0.75 0.48 0.16 – 1.40 0.18 napsi 0.71 2.03 0.68 – 6.02 0.20 dmnapsi¥ 0.76 2.13 0.69 – 6.52 0.19 reference category: caspar criteria of 5; §-dermoscopic napsi; ¥ dermoscopic modified napsi caspar = classification criteria for psoriatic arthritis; dnapsi = dermoscopic napsi; dmnapsi = dermoscopic modified napsi; napsi = nail psoriasis severity index; pasi = psoriasis area and severity index. table 5. comparison of mean ranks of nail psoriasis severity index among different durations of onset of disease in months measures of nail psoriasis severity index duration of onset in months z value (p value)1-6 (n=7) 6-12 (n=12) 12-60 (n=35) >60 (n=66) mean ranks of dnapsi§ 53.07 69.38 69.74 54.77 5.39 (0.15) mean ranks of mnapsi¥ 47.57 31.88 60.00 67.34 11.74 (0.008)* mean ranks of napsi 59.86 63.13 68.60 55.80 3.19 (0.36) mean ranks of dmnapsi 43.79 45.12 58.99 65.87 5.63 (0.13) ¥-modified napsi; §-dermoscopic napsi; *statistically significant difference at p < 0.05 dnapsi = dermoscopic napsi; dmnapsi = dermoscopic modified napsi; napsi = nail psoriasis severity index. the mean ranks of mnapsi increased significantly with duration of onset of disease, except at 6-12 months. the mean ranks of other scores, ie dnapsi, dmnapsi and napsi, did not vary significantly across the durations of onset of disease. our aim in this study was to utilize the dermoscope to detect nail changes in psoriasis, and it revealed that nail changes are better visualized and detected earlier. nail scoring for psoriasis utilizing dnapsi helps in the early diagnosis and assessment and detection of worsening moderate-to-severe psoriasis (pasi >10) as compared to napsi. the use of dermoscopy for detecting joint severity as per caspar criteria was consistent with naked-eye assessment of nail findings. however, as none of these indices proved to be statistically significant by themselves, their true significance may be revealed with larger studies using dnapsi and dmnapsi. we do recommend the use of a dermoscope as a routine tool in assessing nail psoriasis. 8 original article | dermatol pract concept. 2022;12(1):e2022010 references 1. de jong em, seegers ba, gulinck mk, boezeman jb, van de kerkhof pc. psoriasis of the nails associated with disability in a large number of patients: results of a recent interview with 1,728 patients. dermatology. 1996;193(4):300-303. doi: 10.1159/000246274. pmid: 8993953. 2. reich a, szepietowski jc. health-related quality of life in patients with nail disorders. am j clin dermatol. 2011;12(5):313320. doi: 10.2165/11592120-000000000-00000. pmid: 21834596. 3. dogra a, arora ak. nail psoriasis: the journey so far. indian j dermatol. 2014;59(4):319-333. doi: 10.4103/00195154.135470. pmid: 25071247; 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[dermoscopy in nail psoriasis]. an bras dermatol. 2010;85(1):101-103. doi: 10.1590/s0365-05962010000100017. pmid: 20464097. 12. polat a, kapıcıoğlu y. dermoscopic findings of psoriatic nail and their relationship with disease severity. turkderm. 2017;51:119–23. doi: 10.4274/turkderm.54289. 13. yorulmaz a, artuz f. a study of dermoscopic features of nail psoriasis. postepy dermatol alergol. 2017;34(1):28-35. doi: 10.5114/ada.2017.65618. pmid: 28286468; pmcid: pmc5340855. 14. yadav ta, khopkar us. dermoscopy to detect signs of subclinical nail involvement in chronic plaque psoriasis: a study of 68 patients. indian j dermatol. 2015;60(3):272-275. doi: 10.4103/00195154.156377. pmid: 26120154; pmcid: pmc4458939. 15. prabhakar v, joy b, thyvalappil a, sridharan r, sreenivasan a, mathew p. prevalence, clinical profile, and severity of nail involvement in psoriasis – a hospital-based cross-sectional study from a tertiary care center in north kerala. j skin sex transm dis 2019;1(2):72-6. 16. elobeid he, alfarouk ko, ahmed n. aljarbou an, et al. correlation between the body mass index and psoriasis in dermatology and venereology teaching hospital in khartoum. ajdv. 2017;6:30–39. doi:10.5923/j.ajdv.20170602.03 17. misra a. ethnic-specific criteria for classification of body mass index: a perspective for asian indians and american diabetes association position statement. diabetes technol ther. 2015;17(9):667-671. doi:10.1089/dia.2015.0007 18. the etiology, pathophysiology,differential diagnosis, clinical findings, and treatment of nail psoriasis | intechopen [internet]. 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[nail psoriasis in individuals with psoriasis vulgaris: a study of 661 patients]. actas dermosifiliogr. 2011;102(5):365-72. doi: 10.1016/j. ad.2011.02.007. pmid: 21514549. 21. baran r. the burden of nail psoriasis: an introduction. dermatology. 2010;221 suppl 1:1-5. doi: 10.1159/000316169. pmid: 20733309. 22. wanniang n, navya a, pai v, ghodge r. comparative study of clinical and dermoscopic features in nail psoriasis. indian dermatol online j. 2020;11(1):35-40. doi: 10.4103/idoj.idoj_51_19. pmid: 32055506; pmcid: pmc7001394. 23. hallaji z, babaeijandaghi f, akbarzadeh m, et al. a significant association exists between the severity of nail and skin involvement in psoriasis. j am acad dermatol. 2012;66(1):e12-13. doi: 10.1016/j.jaad.2010.10.021. pmid: 22177647. 24. prevezas c, katoulis ac, papadavid e, panagakis p, rigopoulos d. short-term correlation of the psoriasis area severity index, the nail psoriasis area severity index, and the dermatology life quality index , before and after treatment, in patients with skin and nail psoriasis. skin appendage disord. 2019;5(6):344349. doi: 10.1159/000499348.. pmid: 31799260; pmcid: pmc6883452. 25. cassell s, bieber j, rich p, et al. the modified nail psoriasis severity index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis. j rheumatol. 2007;34(1):123-129. pmid: 17216680. dermatology: practical and conceptual review | dermatol pract concept 2020;10(4):e2020121 1 dermatology practical & conceptual introduction actinic keratosis (ak) is a cutaneous neoplasm that arises on chronically sun-exposed skin. for years, ak was considered to be a separate entity from squamous cell carcinoma (scc) [1], a premalignant lesion; however, in recent years this concept has been challenged, and now most authors consider ak the continuum of scc [2-4]. the rate of progression to scc differs greatly among the studies, ranging from 0.025%-20% per year [5,6]; however, it has been documented that 60%-80% of sccs arise from ak. correct diagnosis is important for prompt treatment [5]. dermoscopy is a tool that aids in the clinical diagnosis of multiple melanocytic and non-melanocytic lesions. several dermoscopic patterns for the detection of ak have been described: gray structures, scale, and rhomboidal lines, among others, for pigmented ak [7-9], and linear wavy vessels, follicular plugs surrounded by a pink-red pseudonetwork, and scaling have been described in nonpigmented ak [10]. despite the widespread use of dermoscopy, there are no recent diagnostic accuracy of dermoscopy of actinic keratosis: a systematic review karla l. valdés-morales1, maría luisa peralta-pedrero1, fermín jurado-santa cruz1, martha alejandra morales-sánchez1 1 centro dermatológico dr. ladislao de la pascua, mexico city, mexico key words: actinic keratosis, dermoscopy, dermatoscopy, diagnostic accuracy citation: valdés-morales kl, peralta-pedrero ml, jurado-santa cruz f, morales-sánchez ma. diagnostic accuracy of dermoscopy of actinic keratosis: a systematic review. dermatol pract concept. 2020;10(4):e2020121. doi: https://doi.org/10.5826/dpc.1004a121 accepted: may 25, 2020; published: october 26, 2020 copyright: ©2020 valdés-morales et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: martha alejandra morales-sánchez, md, vértiz 464, esq. eje 3 sur, col. buenos aires, alcaldía cuauhtémoc, 06780, d.f., méxico. email: marthamoralessanchez@gmail.com introduction: dermoscopy is a tool that aids clinicians in the diagnosis of actinic keratosis; however, few diagnostic accuracy studies have determined its sensitivity and specificity for this diagnosis. objective: determine the diagnostic accuracy of dermoscopy on actinic keratosis. methods: a systematic review was conducted on embase, pubmed, scopus and the cochrane central registry of controlled trials from inception to august 2019. results: we screened 485 titles and abstracts. two studies comprising 219 actinic keratoses were eligible for qualitative analysis. the number and heterogeneity of included studies limited a quantitative analysis. conclusions: studies that focus specifically on the diagnostic accuracy of dermoscopy for actinic keratosis are lacking. abstract 2 review | dermatol pract concept 2020;10(4):e2020121 were “actinic keratosis” and “dermoscopy,” as well as its synonyms “dermatoscopy” and “epiluminescence microscopy.” studies that met the criteria were retrieved and reviewed by 2 researchers, and discrepancies were settled by a third researcher. the extracted information included study type, number of patients in each study, patient characteristics, type of test, and reference standard. two authors independently extracted these data, and discrepancies were identified and resolved by discussion with a third reviewer. applicability and risk of bias was assessed using the quadas-2 instrument [13], including every checkpoint except the appropriate interval between index test and reference standard test, which was not applicable to this clinical scenario. the reference standard test was the histopathologic study. results the search yielded a total of 1,165 studies; duplicates were removed, and a total of 485 titles and abstracts were reviewed (figure 1). seventeen studies were read in full text, and 2 of them fulfilled eligibility criteria, with a total of 219 actinic keratoses in 210 patients (table 1). both studies showed a male predominance, as well as a mean age that ranged between 67 and 69 years. the studies were held in australia, italy, usa [14], and spain [15]. of the 15 excluded studies, exclusions were mainly due to study flow and to different study objectives, for example, determining correlation between histopathology and dermoscopy [16,17], aiming to distinguish between pigmented ak and lentigo maligna [7,18], determining dermoscopic pattern frequency [19], or evaluation of a different diagnostic tool [20,21], among others. excluded studies and reasons for exclusion are presented on supplementary table 1. the quadas-2 risk of bias and applicability assessment is shown in table 2. the reference standard and index test systematic reviews that report the sensitivity and specificity of this tool in the diagnosis of ak. methods we conducted a systematic review of the literature in accordance with the preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies (prisma-dta statement) [11] and the cochrane handbook for systematic reviews of diagnostic test accuracy [12]. this protocol was registered on the international prospective register of systematic reviews (crd42019116000). the main purpose of this study was to determine the sensitivity and specificity of dermoscopy for the diagnosis of ak. inclusion/exclusion criteria we included studies in which participants were adults (>18 years old) and studies that followed a diagnostic accuracy study flow, ie, patients with suspicion of ak underwent a dermoscopic examination (index test) then a histopathological study (reference standard test). published articles written in the english or spanish language that followed this study flow were included in the systematic review. studies in which participants had the histopathological diagnosis of ak prior to examination of dermoscopic images by an evaluator, studies in which the clinical and dermoscopic diagnosis was not blinded from a dermatopathologist, and case reports were excluded. data extraction and analysis a literature search was conducted on embase, medline, scopus, and the cochrane central registry of controlled trials from inception to august 2019. the key words used figure 1. prisma flow diagram (ak = actinic keratosis; pak = pigmented actinic keratosis; lm = lentigo maligna). review | dermatol pract concept 2020;10(4):e2020121 3 discussion in this review, 2 studies fulfilled inclusion criteria with a low risk of applicability; huerta-brogeras et al had a low risk of bias, whereas zalaudek et al had high risk of bias, mainly due to study flow and timing, not clearly specifying eligibility and exclusion criteria, as well as timing of the histopathological diagnosis within the study flow. the most common dermoscopic finding in both studies was the presence of a red pseudonetwork surrounding follicular openings comprising the “strawberry pattern” [14]. despite the widespread use of dermoscopy for ak, few studies that prospectively evaluate its sensitivity and specificity have been published. descriptive studies have been completed, wherein the frequency of each dermoscopic sign [19] or its correlation with histopathological findings are reported [17,22]. of 70 aks studied by zalaudek et al in 2012, the red pseudonetwork was the most frequent finding (67.1%), followed by scales and targetoid hair follicles [23]. kelati et al described dermoscopic findings in 232 cases of facial pigmented ak, and the most frequent findings were: rhomboidal appearance (82.8%), inner gray halo (58.6%), scales (39.2%), jelly sign and superficial pigmentation (37.5%), among others [19]. lee et al examined the correlation between dermoscopic and histopathological findings had a low risk of bias in both studies [14,15], however, the flow and timing as well as patient selection had a high risk of bias in the zalaudek et al [14] study, as the study design was not clearly stated. on the other hand, both studies show a low concern regarding applicability. both studies evaluated the characteristics of dermoscopic photographs, including erythematous pseudonetwork, surface scale, linear wavy vessels, and follicular plugs. zalaudek et al added coiled and dotted vessels to the dermoscopic features being evaluated. sensitivity and specificity of dermoscopy for the diagnosis of aks were calculated by huerta-brogeras et al [15] with a sensitivity of 98.7% and specificity of 95%. in the second study [14], all but one dermoscopist suspected ak as the initial diagnosis with an overall sensitivity of 97.5%; however, in 19 of those lesions, the initial diagnosis also included bowen disease or superficial basal cell carcinoma. if we consider these cases as negative tests, the calculated sensitivity would decrease to 51.2%. overall, the most common dermoscopic finding was surface scale (86.7%), followed by follicular openings (83.1%) and erythematous pseudonetwork (79.9%), both comprising the “strawberry pattern,” and lastly, linear wavy vessels (71.2%). important clinical and methodological heterogeneity between the studies was considered, so a pooled sensitivity and specificity was not calculated. table 1. study characteristics of included studies study characteristics zalaudek, 2006 [14] huerta-brogeras, 2012 [15] dermatoscope heine delta 20 hand-held dermatoscope or a dermlite foto lens attached to a nikon coolpix 4500 digital camera dermlite foto lens attached to canon 400d camera included lesions nonpigmented ak nonpigmented and pigmented ak number of patients 32 178 number of ak 41 178 age (mean) 69 years 67 years clinical examination (naked eye vs. photography? photograph naked-eye dermoscopic examination (real time vs. photography) photograph photograph hp study of all lesions yes yes ak = actinic keratosis; hp = histopathological study table 2. risk of bias assessment and applicability using quadas-2 tool study (first author and year) risk of bias applicability patient selection index test reference standard test flow and timing patient selection index test reference standard test huerta-brogeras, 2012 [15] low low low low low low low zalaudek, 2006 [14] high low low high low low low 4 review | dermatol pract concept 2020;10(4):e2020121 on non-facial topographies, as well as of different types of aks, are needed. huerta-brogeras et al [15] excluded lesions that upon clinical examination were suspected to be malignant. in future diagnostic accuracy studies, malignant and equivocal lesions should be included because the clinical differential diagnosis of ak includes bowen disease, invasive scc, superficial basal cell carcinoma, and even granulomatous and inflammatory conditions [28-30]. lesions that may resemble ak clinically should be included in diagnostic accuracy studies and subjected to the dermoscopic and histopathological examinations to objectively measure precision of dermoscopy. guidelines for reporting diagnostic accuracy studies (stard) were updated on 2015, recommending key points for the elaboration and publication of these types of studies [31]; this allows for more homogeneous study designs to be accomplished in diagnostic accuracy studies. throughout the literature review, we noted different dermoscopic terms for similar dermoscopic structures and patterns among studies. for more uniform language, dermatologists should adhere to the standardized dermoscopic terminology published by the international dermoscopy society [32,33] both for academic and clinical studies. having uniform dermoscopic terminology will enable more homogenous and comparable studies and will facilitate dermoscopic training. conclusions dermoscopy is a practical tool to aid in the diagnosis of ak; however, studies that focus specifically on the diagnostic accuracy of dermoscopy for actinic keratosis are lacking. references 1. siegel ja, korgavkar k, weinstock ma. current perspective on actinic keratosis: a review. br j dermatol. 2017;177(2):350-358. doi: 10.1111/bjd.14852. pmid:27500794 2. berman b, cockerell cj. pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. j am acad dermatol. 2013;68(1):s10-s19. doi: 10.1016/j.jaad.2012.09.053. pmid:23228301. 3. rosen t, lebwohl mg. prevalence and awareness of actinic keratosis: barriers and opportunitiesj am acad dermatol. 2013;68(1):s2-s9. doi: 10.1016/j. jaad.2012.09.052. pmid:23228302. 4. conforti c, beninati e, dianzani c. are actinic keratoses really squamous cell cancer? how do we know if they would become malignant? clin dermatol. 2018;36(3):430-432. doi: 10.1016/j.clindermatol.2017.08.013. pmid:29908585. 5. rigel ds, stein gold lf. the importance of early diagnosis and treatment of actinic keratosis. j am acad dermatol. 2013;68(1):s20-s27. doi: 10.1016/j. jaad.2012.10.001. pmid:23228303. 6. de oliveira ecv, da motta vrv, pantoja pc, et al. actinic keratosis review for clinical practice. int j derin korean patients. among the results was the frequency of dermoscopic findings in 61 aks from 47 patients: white yellow scale (73.1%), targetoid sign (65.4%), white structureless area (50%), red background (50%), red pseudonetwork (46.2%), and rosettes (7.7%) [17]. studies comparing dermoscopic features to distinguish between lentigo maligna and pigmented ak have been published [7,9,18]. akay et al evaluated dermoscopic parameters of lentigo maligna in facial pigmented skin lesions; 67 pigmented aks were included in the study, and the frequency of dermoscopic findings was reported: slate gray dots (70%), annular-granular pattern (39%), brown-to-gray pseudonetwork (36%), and rhomboidal structures (36%) were the most frequent. in their study, the presence of pseudonetwork was found to be specific for pigmented ak [18]. in 2012, rosendahl et al [24] conducted a diagnostic accuracy study of dermoscopy on melanocytic and non-melanocytic pigmented lesions, and a few years later, gomez-martin et al [25] published a diagnostic accuracy study of dermoscopy and reflectance confocal microscopy on pink flat lesions of the legs. both studies followed an adequate diagnostic accuracy flow design and performed a quantitative analysis of data, including sensitivity and specificity; however, even though aks were included in both studies, gomez-martin et al grouped aks with scc and bowen disease, while rosendahl et al considered ak a superficial variant of scc and grouped them with malignant lesions in the study. bowen disease and scc are the main differential diagnoses of ak, and the lack of specific results for ak was the reason for exclusion of these studies from the present review. the most significant limitation of this study is the inclusion of only 2 studies in our analysis. the aim of this study was to perform a diagnostic accuracy systematic review with a meta-analysis; to achieve this, we only included studies in which the study flow of a diagnostic accuracy study was followed (clinical suspicion followed by performance of index test followed by the reference standard test) in order to calculate sensitivity and specificity. the initial study was designed to include only nonpigmented ak, then we broadened our inclusion criteria to both pigmented and nonpigmented ak. however, after a thorough review of the literature, 17 studies evaluated dermoscopy as a diagnostic tool for ak, and only 2 studies followed this flow. most of the studies that evaluate dermoscopic characteristics follow a different study flow: dermoscopic findings are retrieved from dermoscopic images with known histopathological diagnosis. this low number of included studies led to the impossibility of performing a quantitative analysis of data. multiple lesions on chronically photodamaged skin can lead to the clinical diagnosis of ak; a single ak, on the other hand, may present a more difficult clinical scenario in which dermoscopy plays a determining role in diagnosis. the characteristic “strawberry pattern” is most frequent in facial lesions but is not commonly found in extra-facial regions [26,27]. this characteristic pattern may also be absent in different types of ak, such as bowenoid ak, where a vascular pattern of glomerular or coiled vessels may be seen [26], or hyperkeratotic ak, where scale is the predominant feature. future studies that examine the dermoscopic pattern of ak review | dermatol pract concept 2020;10(4):e2020121 5 19. kelati a, baybay h, moscarella e, argenziano g, gallouj s, mernissi fz. dermoscopy of pigmented actinic keratosis of the face: a study of 232 cases. actas dermosifiliogr. 2017;108(9):844-851. doi: 10.1016/j. ad.2017.05.002. pmid:28705516. 20. cinotti e, labeille b, debarbieux s, et al. dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2018;32(8):1284-1291. doi: 10.1111/jdv.14791. pmid:29341263. 21. wurm e, pellacani g, longo c, et al. the value of reflectance confocal microscopy in diagnosis of flat pigmented facial lesions: a prospective study. j eur acad dermatol venereol. 2017;31(8):1349-1354. doi: 10.1111/ jdv.14171. pmid:28214381. 22. elwan nm, gheida sf, el-toukhey am, radwan ns. dermoscopic and histopathological correlation in some epidermal tumors: a preliminary study. journal of the egyptian women’s dermatologic society. 2015;12(1):2431. doi: 10.1097/01.ewx.0000452289.68228.76. 23. zalaudek i, giacomel j, schmid k, et al. dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model. j am acad dermatol. 2012;66(4):589-597. doi: 10.1016/j.jaad.2011.02.011. pmid:21839538. 24. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068-1073. doi: 10.1016/j. jaad.2010.03.039. pmid:21440329. 25. gomez-martin i, moreno s, duran x, pujol rm, segura s. diagnostic accuracy of non-melanocytic pink flat skin lesions on the legs: dermoscopic and reflectance confocal microscopy evaluation. acta derm venereol. 2019;99(1):33-40. doi: 10.2340/00015555-3029. pmid:30176037. 26. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part ii. nonmelanocytic skin tumors. j am acad dermatol. 2010;63(3):377-386; quiz 387-378. doi: 10.1016/j.jaad.2009.11.697. pmid:20708470. 27. reinehr cph, garbin gc, bakos rm. dermatoscopic patterns of nonfacial actinic keratosis: characterization of pigmented and nonpigmented lesions. dermatol s u r g . 2 0 1 7 ; 4 3 ( 1 1 ) : 1 3 8 5 1 3 9 1 . d o i : 1 0 . 1 0 9 7 / dss.0000000000001210. pmid:28538027. 28. conforti c, giuffrida r, de barros mh, resende fss, cerroni l, zalaudek i. dermoscopy of a single plaque on the face: an uncommon presentation of cutaneous sarcoidosis. dermatol pract concept. 2018;8(3):174-176. doi: 10.5826/dpc.0803a04. pmid:30116658. 29. u l r i c h m , f o r s c h n e r t, r ö w e r t h u b e r j , e t a l . differentiation between actinic keratoses and disseminated superficial actinic porokeratoses with reflectance confocal microscopy. br j dermatol. 2007; 156 suppl 3:47-52. doi: 10.1111/j.1365-2133.2007.07862.x. pmid: 17488407. 30. reinehr cph, bakos rm. actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects. anais matol. 2019;58(4):400-407. doi: 10.1111/ijd.14147. pmid:30070357. 7. micantonio t, neri l, longo c, et al. a new dermoscopic algorithm for the differential diagnosis of facial lentigo maligna and pigmented actinic keratosis. eur j dermatol. 2018;28(2):162-168. doi: 10.1684/ejd.2018.3246. pmid:29620004. 8. tschandl p, rosendahl c, kittler h. dermatoscopy of flat pigmented facial lesions. j eur acad dermatol venereol. 2015;29(1):120-127. doi: 10.1111/jdv.12483. pmid:24661420. 9. lallas a, tschandl p, kyrgidis a, et al. dermoscopic clues to differentiate facial lentigo maligna from pigmented actinic keratosis. br j dermatol. 2016;174(5):1079-1085. doi: 10.1111/bjd.14355. pmid:26784739. 10. cayirli m, kose o, demiriz m. dermatoscopy of facial non-pigmented actinic keratosis regarding to grades of the lesions. j eur acad dermatol venereol. 2013;27(9):1185-1187. doi: 10.1111/jdv.12020. pmid:23094862. 11. mcinnes mdf, moher d, thombs bd, et al. preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the prisma-dta statement. jama. 2018;319(4):388-396. doi: 10.1001/ jama.2017.19163.pmid:29362800. 12. deeks jj, bossuyt pm, gatsonis c, et al. analysing and presenting results. in: cochrane handbook for systematic reviews of diagnostic test accuracy version 1.0.0. the cochrane collaboration; 2010. available from http://srdta.cochrane.org. 13. whiting p, rutjes aw, reitsma jb, bossuyt pm, kleijnen j. the development of quadas: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. bmc med res methodol. 2003;3:25. doi: 10.1186/1471-2288-3-25. pmid:14606960 pmcid:pmc305345. 14. zalaudek i, giacomel j, argenziano g, et al. dermoscopy of facial nonpigmented actinic keratosis. br j dermatol. 2 0 0 6 ; 1 5 5 ( 5 ) : 9 5 1 9 5 6 . d o i : 1 0 . 1 1 1 1 / j . 1 3 6 5 2133.2006.07426.x. pmid:17034524. 15. huerta-brogeras m, olmos o, borbujo j, et al. validation of dermoscopy as a real-time noninvasive diagnostic imaging technique for actinic keratosis. arch dermatol. 2012;148(10):1159-1164. doi: 10.1001/archdermatol.2012.1060. pmid:23069952. 16. stoica le, voiculescu m, cirstea c. dermatoscopic and histopathological aspect of preneoplasia and skin cancers—study on 74 patients. curr health sci j. 2015;41(2):186-195. doi: 10.12865/chsj.41.02.15. pmid: 30364908. 17. lee dw, kim dy, hong jh, seo sh, kye yc, ahn hh. correlations between histopathologic and dermoscopic findings in korean actinic keratosis. microsc res tech. 2019;82(1):12-17. doi: 10.1002/jemt.23043. pmid:29676831. 18. akay bn, kocyigit p, heper ao, erdem c. dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. br j dermatol. 2010;163(6):1212-1217. doi: 10.1111/j.1365-2133.2010.10025.x. pmid:21083845. 6 review | dermatol pract concept 2020;10(4):e2020121 of the international dermoscopy society. br j dermatol. 2020;182(2):454-467. doi: 10.1111/bjd.18125. pmid:31077336. 33. k i t t l e r h , m a r g h o o b a a , a r g e n z i a n o g , e t a l . standardization of terminology in dermoscopy/dermatoscopy: results of the third consensus conference of the international society of dermoscopy. j am acad dermatol. 2016;74(6):1093-1106. doi: 10.1016/j. jaad.2015.12.038. pmid:26896294. brasileiros de dermatologia. 2019;94(6):637-657. doi: 10.1016/j.abd.2019.10.004. pmid:31789244. 31. cohen jf, korevaar da, altman dg, et al. stard 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration. bmj open. 2016;6(11):e012799. doi: 10.1136/bmjopen-2016-012799. pmid:28137831. 32. errichetti e, zalaudek i, kittler h, et al. standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (nonneoplastic dermatoses): an expert consensus on behalf supplementary table 1. excluded studies with reason for exclusion authors title reason for exclusion lee et al [1] correlations between histopathologic and dermoscopic findings in korean actinic keratosis. correlation between histopathology and dermoscopy. retrospective study of nonpigmented aks; aimed to describe histopathological findings with dermoscopic ones. description of dermoscopic features’ frequency. micantonio et al [2] a new dermoscopic algorithm for the differential diagnosis of facial lentigo maligna and pigmented actinic keratosis. aimed to distinguish between pak and lm. dermoscopic patterns to distinguish pak from lm. gómez-martín et al [3] diagnostic accuracy of non-melanocytic pink flat skin lesions on the legs: dermoscopic and reflectance confocal microscopy evaluation. ak grouped with other skin lesions. study included all pink lesions. the clinical suspicion is divided into 2 groups: malignant or benign, does not give data specifically of ak (ak grouped with inflammatory disease group). kelati et al [4] dermoscopy of pigmented actinic keratosis of the face: a study of 232 cases. does not follow diagnostic study design flow. determines frequency of dermoscopic signs. lee et al [5] correlations between dermoscopic and histopathologic findings in actinic keratosis. poster. article from this poster was published in 2019 1. li and chang [6] the investigation of dermoscopy in differential diagnosis of facial actinic keratosis. poster. lallas et al [7] dermoscopic clues to differentiate facial lentigo maligna from pigmented actinic keratosis. does not follow diagnostic study design flow. aim of the study was to determine the frequency of the dermoscopic criteria for facial pigmented lesions. elwan et al [8] dermoscopic and histopathological correlation in some epidermal tumors: a preliminary study. does not follow diagnostic study design flow. the study aimed to study epidermal tumors (bcc, sk, ak, and scc). tschandl et al [9] dermatoscopy of flat pigmented facial lesions. ak grouped with other skin lesions. considers pak and pigmented bowen’s disease as one group. rosendahl [10] diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. ak grouped with other skin lesions. adequate study design and flow, however, it groups all skin lesions into 2 groups: malignant or benign. no specific data on aks. (table s1 continues) review | dermatol pract concept 2020;10(4):e2020121 7 to differentiate facial lentigo maligna from pigmented actinic keratosis. br j dermatol. 2016;174(5):1079-1085. 8. elwan nm, gheida sf, el-toukhey am, radwan ns. dermoscopic and histopathological correlation in some epidermal tumors: a preliminary study. journal of the egyptian women’s dermatologic society. 2015;12(1):2431. 9. tschandl p, rosendahl c, kittler h. dermatoscopy of flat pigmented facial lesions. j eur acad dermatol venereol. 2015;29(1):120-127. 10. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068-1073. 11. akay bn, kocyigit p, heper ao, erdem c. dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. br j dermatol. 2010;163(6):1212-1217. 12. cinotti e, labeille b, debarbieux s, et al. dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2018;32(8):1284-1291. 13. wurm e, pellacani g, longo c, et al. the value of reflectance confocal microscopy in diagnosis of flat pigmented facial lesions: a prospective study. j eur acad dermatol venereol. 2017;31(8):1349-1354. 14. guitera p, menzies sw, argenziano g, et al. dermoscopy references 1. lee dw, kim dy, hong jh, seo sh, kye yc, ahn hh. correlations between histopathologic and dermoscopic findings in korean actinic keratosis. microsc res tech. 2019;82(1):12-17. 2. micantonio t, neri l, longo c, et al. a new dermoscopic algorithm for the differential diagnosis of facial lentigo maligna and pigmented actinic keratosis. eur j dermatol. 2018;28(2):162-168. 3. gomez-martin i, moreno s, duran x, pujol rm, segura s. diagnostic accuracy of non-melanocytic pink flat skin lesions on the legs: dermoscopic and reflectance confocal microscopy evaluation. acta derm venereol. 2019;99(1):33-40. 4. kelati a, baybay h, moscarella e, argenziano g, gallouj s, mernissi fz. dermoscopy of pigmented actinic keratosis of the face: a study of 232 cases. actas dermosifiliogr. 2017;108(9):844-851. 5. correlations between dermoscopic and histopathologic findings in actinic keratosis. j am acad dermatol. 2017;76(6):ab84. 6. li w, zhang c. the investigation of dermoscopy in differential diagnosis of facial actinic keratosis. society for investigative dermatology annual meeting; 2017; portland, oregon. 7. lallas a, tschandl p, kyrgidis a, et al. dermoscopic clues authors title reason for exclusion akay et al [11] dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pigmented actinic keratosis and lentigo maligna. aimed to distinguish between pak and lm. lesions were included only if they presented with specific patterns of lm. cinotti et al [12] dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. evaluation of different diagnostic tool. diagnostic accuracy study of dermoscopy and rcm for the diagnosis of lm. wurm et al [13] the value of reflectance confocal microscopy in diagnosis of flat pigmented facial lesions: a prospective study. evaluation of different diagnostic tool. aim of the study was to describe utility of confocal microscopy on different flat, pigmented lesions. guitera et al [14] dermoscopy and in vivo confocal microscopy are complementary techniques for diagnosis of difficult amelanotic and light-coloured skin lesions. does not follow diagnostic study design flow. study included different amelanotic and light-colored lesions. aim was for diagnosis of melanoma. stoica et al [15] dermatoscopic and histopathological aspect of preneoplasia and skin cancers study on 74 patients. correlation between histopathology and dermoscopy. aimed to correlate the dermoscopic and histopathological aspect of tumors. supplementary table 1. excluded studies with reason for exclusion (continued) ak = actinic keratosis; pak = pigmented actinic keratosis; lm = lentigo maligna, rcm = reflectance confocal microscopy 8 review | dermatol pract concept 2020;10(4):e2020121 15. stoica le, voiculescu m, cirstea c. dermatoscopic and histopatological aspect of preneoplasia and skin cancers—study on 74 patients. curr health sci j. 2015;41(2):186-195. and in vivo confocal microscopy are complementary techniques for diagnosis of difficult amelanotic a n d l i g h t c o l o u r e d s k i n l e s i o n s . b r j d e r m a t o l . 2016;175(6):1311-1319. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3): e2021021 1 large pore basal cell carcinoma: a case report ana inés lösch1, virginia mariana gonzález1, félix alberto vigovich2, margarita larralde1 1 dermatology department, hospital alemán, buenos aires, argentina. 2 histopathology department, hospital alemán, buenos aires, argentina key words: basal cell carcinoma, large pore basal cell carcinoma, dermoscopy, pore of winer, epidermal appendageal tumors citation: lösch ai, gonzález vm, vigovich fa, larralde m. large pore basal cell carcinoma: a case report. dermatol pract concept. 2021;11(3): e2021021. doi: https://doi.org/10.5826/dpc.1103a21. accepted: september 11, 2020; published: july 8, 2021 copyright: ©2021 lösch et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: lösch ana inés, md. dermatology department, hospital alemán, buenos aires, argentina. 1640 pueyrredón ave., ciudad de buenos aires, argentina. email: anaineslosch@hotmail.com case presentation a 75-year-old-male with a history of multiple basal cell carcinomas visited our clinic for aesthetic treatment of a large pore in the nasal tip that he noticed 4 months ago. following pressure application, keratinous material emerged from the center of the lesion (figure 1a). dermoscopy showed a central dilated pore surrounded by a whitish pink poorly circumscribed area with in focus branched vessels. grey pigmentation and yellowish-white scales were also seen around the central pore (figure 1b). a punch biopsy was performed and was consistent with large pore basal cell carcinoma (bcc) (figure 1, c and d). the patient underwent mohs surgery and plastic reconstruction. teaching point pore-like or large pore basal cell carcinoma is an atypical and very infrequent clinical presentation of bcc. both dilated pores and bcc, are tumors of follicular origin. some authors have postulated that the same stem cell could originate them, so they may coexist in a single cutaneous lesion. dermatologists must take this into account when making differential diagnoses of solitary enlarged pores, especially when localized on the face. dermoscopy is an excellent tool for its recognition [1, 2]. 2 image letter | dermatol pract concept. 2021;11(3): e2021021 references 1. benedetto av, benedetto ea, griffin td. basal cell carcinoma presenting as a large pore. j am acad dermatol. 2002; 47:727-32. doi: 10.1067/mjd.2002.124075. pmid: 12399765 2. carlson-sweet kl, weigand da, macfarlane df. trichoid basal cell carcinoma found in a dilated pore on the nose. dermatol surg. 2000; 26:874-6. doi: 10.1046/j.1524-4725.2000.00083.x. pmid: 10971562 figure 1. large pore in the nasal tip. (a) clinical image. (b) dermoscopy reveals a large pore surrounded by a whitish pink poorly circumscribed area (*) with superficial branched vessels (black arrow) and grey pigmentation (blue arrow). (c) histopathology (h&e, x40). dilated pilar infundibulum lined with a squamous epithelium. (d) (h&e x100) proliferation of basaloid neoplasic cells with stromal retraction sectors (white arrow) underlying the squamous epithelium and focus of calcification (black arrow). dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022050 1 dermatology practical & conceptual introduction spitz nevi of special sites, such as the vulva-, appear rare and can pose a challenge as they may display worrisome clinical-dermoscopic or histopathological features [1-4]. here we clinically, dermoscopically and histopathologically describe an extremely rare case of spitz nevus occurring on the vulva of a 47-year-old woman. case presentation a healthy 47-year-old italian woman presented with a 2-month history of a rapidly growing lesion on the outer surface of the left labium majus of the genitalia, without pain, pruritus or hemorrhage. physical examination showed an asymmetric, dark-brown papule, 9 mm in diameter, well circumscribed (figure 1a). no inguinal lymphadenopathy was revealed. dermoscopy showed an asymmetric melanocytic lesion with a basically cobblestone pattern, a diffuse blackish pigmentation with grayish shades and large brown-black globules, widely spaced and arranged asymmetrically (figure 1b). an excision biopsy was made, and histological examination revealed a compound spitz nevus, characterized by a proliferation of pigmented and epithelioid melanocytes, with no mitoses or atypical features, arranged in dermal nests and partially aligned at the dermo-epidermal junction. melanocytes showed vesicular nuclei, small nucleoli and a homogeneous cytoplasm with many melanin granules. mild perilesional lymphocytic infiltration was observed (figure 2, a_c). given the peculiar area, recent onset, rapid growth and dermoscopic features, the lesion was completely removed with clear surgical margins, and no recurrence was observed in the 6 months after the excision. discussion melanocytic lesions of the female genital area are estimated to occur in 10% to 12% of women and arise mainly in the vulva. these lesions, commonly detected during routine spitz nevus of the vulva: a very rare presentation of the genital region mario vaccaro1, marialorena coppola1, maria lentini2, francesco borgia1, elvira moscarella3, giuseppe argenziano3 1 department of clinical and experimental medicine, dermatology, university of messina, messina, italy 2 department of human pathology in adult and developmental age, university of messina, messina, italy 3 unit of dermatology, luigi vanvitelli university of campania, naples, italy key words: spitz nevus, vulva, dermoscopy, melanoma citation: vaccaro m, coppola m, lentini m, borgia f, moscarella e, argenziano g. spitz nevus of the vulva: a very rare presentation of the genital region. dermatol pract concept. 2022;12(2):e2022050. doi: https://doi.org/10.5826/dpc.1202a50 accepted: august 8, 2021; published: april 2022 copyright: ©2022 vaccaro et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: mario vaccaro, department of clinical and experimental medicine, dermatologyuniversity of messina, messina, italy. via c. valeria, gazzi. 98125 messina, italy. e-mail:vaccaro@unime.it 2 research letter | dermatol pract concept. 2022;12(2):e2022050 figure 1. spitz nevus of the vulva. (a) clinicalfeatures. (b) dermoscopicfeatures. dermatologic or gynecologic examination, include melanocytic nevi, melanosis, spitz nevi, atypical melanocytic nevi of the genital type, dysplastic nevi and melanomas [4]. spitz nevi of the vulva are very rare, with only a few cases described in the literature. . polat et al. described a case of an 11-year-old girl with a spitz nevus on the inner surface of the labium majus of the genitalia [5]. in another retrospective study about the clinical and dermoscopic characteristics of genital melanocytic nevi in children, 2more cases of spitz nevi on the labia majora have been reported [6]. in adult patients spitzoid lesions may pose diagnostic difficulties as melanoma may mimic spitz nevi from a morphological point of view. melanoma is the second most common malignancy of the vulva after squamous cell carcinoma. it generally affects postmenopausal women, with a peak incidence in the sixth and seventh decades of life, but can also affect younger women [4]. primary vulvar melanoma most frequently develops on the labia majora, followed by the labia minora and clitoral hood. roughly half of vulvar melanomas arise on glabrous (mucosal) skin, 38% at the hairy-glabrous skin junction, and 13% on hairy skin of the external genitalia [6]. conclusions in presence of new onset pigmented papules or nodules in the genital area of women, melanoma should be included in the differential diagnosis and especially in those older than 50 years, histological examination should be performed to rule out melanoma. in this report, given the peculiar area, recent onset, rapid growth and dermoscopic features, surgical excision was warranted. our case highlights the importance of assessing the genital region during routine skin cancer screening examination, with particular attention about any new or changing lesions. references 1. vaccaro m, borgia f, cannavò sp. dermoscopy of pigmented variant of acral spitz nevus. j am acad dermatol. 2015;72(1 suppl):s11-s12. doi: 10.1016/j.jaad.2014.03.036.pmid: 25500025. 2. vaccaro m, romeo u, romeo c, lentini m. spitz nevus: a rare lesion of the oralcavity.pediatrdermatol. 2016;33(2):e154-e155. doi: 10.1111/pde.12785.pmid: 27001333. figure 2. (a) pigmented melanocytic proliferation expanding superficial dermis with mild epidermal hyperplasia (h%e, scanning magnification x10). (b) proliferation of pigmented and epithelioid melanocytes arranged in dermal nests and partially aligned at the dermo-epidermal junction (h&e, scanning magnification x20). (c) melanocytes with vesicular nuclei, small nucleoli and a homogeneous cytoplasm with many melanin granules (h&e, scanning magnification x40). research letter | dermatol pract concept. 2022;12(2):e2022050 3 3. vaccaro m, marafioti i, giuffrida r, borgia f, zalaudek i.clinical and dermoscopic characterization of pediatric spitz nevi of the ear.pediatr dermatol. 2021;38(4):895-898. doi: 10.1111/ pde.14616..pmid: 34152025. 4. ferrari a, zalaudek i, argenziano g, et al. dermoscopy of pigmented lesions of the vulva: a retrospective morphological study. dermatology. 2011;222:157-166.doi: 10.1159/000323409. pmid: 21311169 5. polat m, topcuoglu ma, tahtaci y, hapa a, yilmaz f. spitz nevus of the genital mucosa. indian j dermatol venereolleprol. 2009;75(2):167-169. doi: 10.4103/0378-6323.48663. 6. murzaku ec, penn la, hale cs, pomeranz mk, polsky d. vulvar nevi, melanosis, and melanoma: an epidemiologic, clinical, and histopathologic review. j am acad dermatol. 2014;71(6):1241-1249. doi: 10.1016/j.jaad.2014.08.019. pmid: 25267379. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(3):e2021078 1 langerhans cells as morphologic mimickers of atypical melanocytes on reflectance confocal microscopy: a case report and review of the literature nadiya chuchvara1, lauren berger1, catherine reilly1, amin maghari2, babar k. rao1,3 1 center for dermatology, rutgers robert wood johnson medical school, somerset, new jersey, us 2 department of pathology and laboratory medicine, rutgers robert wood johnson medical school, new brunswick, new jersey, us 3 department of dermatology, weill cornell medicine, new york, new york, us key words: reflectance confocal microscopy, rcm, langerhans cells, dendritic cells, atypical cells citation: chuchvara n, berger l, reilly c, maghari a, rao bk. langerhans cells as morphologic mimickers of atypical melanocytes on reflectance confocal microscopy: a case report and review of the literature. dermatol pract concept. 2021;11(3):e2021078. doi: https:// doi.org/10.5826/dpc.1103a78 accepted: february 2, 2021; published: may 20, 2021 copyright: ©2021 chuchvara et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: nadiya chuchvara, ba, center for dermatology, rutgers robert wood johnson medical school, 1 worlds fair drive, somerset, nj 08873, us. email: nadiyac94@gmail.com pagetoid spread of melanocytes in the epidermis is a common indicator of melanocytic atypia, both histopathologically and with reflectance confocal microscopy (rcm). specifically on rcm, large, bright, atypical dendritic and/or roundish cells are characteristic of melanoma. however, intraepidermal langerhans cells (ilc) create the potential for diagnostic ambiguity on rcm. we describe one case of a pigmented facial lesion that was initially diagnosed as lentigo maligna (lm) due to numerous atypical perifollicular dendritic cells on rcm. additionally, we present the findings of a literature review for similar reported cases conducted by searching the following terms on pubmed: reflectance confocal microscopy, rcm, lentigo maligna, melanoma, langerhans cells, dendritic cells, and atypical cells. in our case, the lesion was determined to be a solar lentigo on histopathology. immunohistochemistry (ihc) with cd1a identified the atypical-appearing cells as ilc, as it did in 54 reported cases of benign lesions (benign melanocytic nevus, sutton/halo nevus, labial melanotic macule, and solar lentigo) misdiagnosed as malignant on rcm (melanoma, lip melanoma, lentigo maligna, and lm melanoma). according to our case and the literature, both ilc and atypical melanocytes can present with atypicalappearing dendritic and/or roundish cells under rcm. currently, there is no method to distinguish the two without ihc. therefore, the presence of pagetoid cells should continue to alert the confocalist of a potential neoplastic process, prompting biopsy, histopathologic diagnosis, and ihc differentiation. abstract 2 review | dermatol pract concept. 2021;11(3):e2021078 introduction reflectance confocal microscopy (rcm) is a technique that acquires en face images of the epidermis and papillary dermis in vivo, using a non-invasive laser device (830 nm). confocal images have a resolution comparable to traditional histopathology [1]. this enables high accuracy diagnosis without the use of biopsy, particularly for pigmented lesions, in which melanin provides strong endogenous contrast [2]. melanocytic cytologic atypia is suggested by the presence of large (>20 µm), bright, dendritic, or roundish cells [3]. pagetoid melanocytosis observed in rcm has been histopathologically correlated to melanoma [4-7]. while not specific for malignancy, the presence of pagetoid spread on rcm of a pigmented lesion carries 11 to 22 [7,8] times greater risk of melanoma, with odds ratios of 4 to 9 for dendritic cells [4,6,8] and 9.7 to 108 [4-6,8] for roundish cells. suspicion for melanoma on rcm increases when atypical cells are densely distributed (>5 cells/mm2), pleomorphic with large and unusual morphology (triangular, star-shaped), roundish, diffuse, and extend to the stratum corneum [3,5,6]. atypical dendritic or roundish pagetoid cells with folliculotropism are characteristic of lentigo maligna (lm) [9,10]. we describe a case in which a benign pigmented lesion on the cheek resembled lm on confocal images, owing to dendritic intraepidermal langerhans cells (ilc) misinterpreted as atypical melanocytes. we present a literature review of additional cases in which the presence of ilc resulted in erroneous diagnosis of melanoma on rcm. case report a 64-year-old caucasian woman presented with a 5 mm light brown papule on the left cheek that had been present for several months and was growing in size. she had a history of blistering sunburns in childhood and basal cell carcinoma of the right hand 13 years prior to presentation. family history was significant for ocular melanoma in the patient’s mother. dermoscopic examination of the lesion showed blue-gray granularity and crescent-shaped perifollicular pigmentation, which are considered indicative of melanophages in the dermis and atypical melanocytes extending down hair follicles (figure 1a) [11,12]. the patient was referred for rcm due to provider suspicion for malignancy and patient preference for a non-invasive procedure (figure 1b). rcm revealed an irregular honeycomb pattern with numerous large (>20 µm) atypical dendritic pagetoid cells, including some in a perifollicular distribution, consistent with lm (figure 2). the dermo-epidermal junction (dej) contained focal areas of small bright and large bright inflammatory cells (figure 3). a shave biopsy was performed, and tissue sections were stained with hematoxylin and eosin (h&e) (figure 4a, b). histopathologic analysis revealed solar lentigo (sl) with underlying sebaceous hyperplasia. immunohistochemistry (ihc) staining for the melanocyte-specific melan-a showed a normal distribution of benign-appearing melanocytes in the epidermis, consistent with sl (figure 4c). staining for cd1a, a membrane glycoprotein specific for langerhans figure 1. (a) dermoscopic image of the 5 mm light brown papule, showing blue-gray granularity (blue arrows) and crescent-shaped perifollicular pigmentation (red arrows). (b) corresponding rcm mosaic image at the level of the epidermis, acquired using the vivascope 1500 (caliber i.d., rochester, ny) reflectance confocal microscope. figure 2. rcm image taken at the level of the epidermis. inset demonstrates large, atypical pagetoid dendritic cells (orange arrows), with many in a perifollicular distribution (green arrows). review | dermatol pract concept. 2021;11(3):e2021078 3 figure 3. rcm image taken at the level of the dej, with focal areas of small bright and large bright inflammatory cells (blue box). figure 4. (a) sl with underlying solar elastosis and sebaceous hyperplasia (h&e, x40). (b) absence of atypical or dendritic cells with standard h&e (x200). (c) ihc with melan-a showing a normal distribution of benign-appearing melanocytes in the epidermis, consistent with sl (x200). (d) ihc with cd1a revealing numerous langerhans cells throughout the epidermis (x200) cells and immature t cells, revealed numerous langerhans cells throughout the epidermis (figure 4d). thus, the atypical dendritic cells visualized on rcm likely represented ilc, rather than atypical melanocytes. discussion rcm is an accurate tool for non-invasive differentiation between benign and malignant melanocytic lesions. for the diagnosis of lm specifically, guitera et al [10] isolated characteristic rcm features to develop an algorithmic “lm score,” resulting in a sensitivity of 85% and specificity of 76% for lesions with scores ≥2. two major features earn +2 points each (nonedged papillae and large round pagetoid cells >20 µm), three minor features earn +1 point each (three or more atyp4 review | dermatol pract concept. 2021;11(3):e2021078 ical cells at the dej in five images, follicular localization of atypical cells, and nucleated cells within the papilla), and one minor feature earns -1 point (broadened honeycomb pattern) [10]. furthermore, gomez-martin et al [13] demonstrated the utility of rcm in the diagnosis of ambiguous pigmented facial macules (91.7% sensitivity and 86.8% specificity for lm). they found two dermoscopic features (asymmetric follicular pigmentation and target like structures) and two rcm features (round, large pagetoid cells and follicular localization of atypical cells) to be associated with lm/lmm [13]. in this case, the diagnosis was compromised due to shared morphologic features of langerhans cells and atypical melanocytes on rcm [14]. both cell types tend to appear as bright cells in a pagetoid pattern on rcm, often with a dendritic morphology [5]. this explains why intraepidermal dendritic cells can be found in both lm/lentigo maligna melanoma table 1. reported cases of langerhans cells presenting as atypical melanocytes in benign lesions on rcm. rcm diagnosis reference case composition clinical features rcm cytologic findings histopathologic analysis melanoma hashemi et al.14 24 cases of bmn falsely diagnosed as melanoma pigmented lesions in various locations including shoulder, back, abdomen (others unspecified) bright cells in a pagetoid pattern: 5/24 roundish, 4/24 dendritic, 15/24 both bmn, cd1a positive, 7/24 melan-a positive, cytokeratin-20† negative yelamos et al.18 1 case of recurrent nevus falsely diagnosed as melanoma pigmented macule on right knee pleomorphic, mostly dendritic cells throughout the epidermis, dej, and in the dermal nests cmn with fibrosis suggestive of recurrent nevus; cd1a positive, sox10 normal brugues et al.19 21 cases of clinically atypical sutton (halo) nevi excised due to possibility of melanoma pigmented macules with atypical dermoscopic features such as: asymmetrical peripheral whitish halo, white/bluegray regression, peppering 13/21 atypical pagetoid cells (dendritic > roundish); atypical basal cells (roundish = dendritic); dermal atypical nucleated cells, plump cells, and bright particles sutton nevus, cd1a positive, melan-a positive (large melanocytes) in the epidermis and dej lip melanoma porto et al.20 3 cases of labial melanotic macule falsely diagnosed as lip melanoma pigmented macules on the lower lip 3/3 bright dendritic cells at the dej, around and between dermal papillae labial melanotic macule, cd1a positive, melan-a and s-100 negative (1/3) or normal (2/3) lm/lmm gomez-martin et al.13 5 cases of pigmented facial macules falsely diagnosed as lm/ lmm clinically ambiguous pigmented facial macules 5/5 abundant dendritic pagetoid cells; 4/5 round, large pagetoid cells; 3/5 atypical cells at the dej cd1a positive, 2/5 showed both basal melanocyte hyperplasia and ilc secondary to postradiotherapy pigmentation current case 1 case of sl falsely diagnosed as lm pigmented facial papule with dermoscopic features concerning for lm large, atypical dendritic pagetoid cells in a perifollicular distribution sl with underlying nodular sebaceous hyperplasia, cd1a positive, melan-a normal bmn= benign melanocytic nevus/nevi; cmn = compound melanocytic nevus; dej = dermo-epidermal junction; ilc= intraepidermal langerhans cell(s); lm = lentigo maligna; lmm – lentigo maligna melanoma; rcm = reflectance confocal microscopy; sl= solar lentigo † marker for merkel cells review | dermatol pract concept. 2021;11(3):e2021078 5 (lmm) and benign pigmented facial macules [13]. the bright appearance of langerhans cells is likely due to their birbeck granules, which have a high reflection index and thus appear light gray to white under rcm, similar to melanin [14]. langerhans cells are normally present in the epidermis and serve as antigen-presenting cells for t lymphocytes [15]. among benign lesions, they are more likely to be prominent around inflammation, such as traumatized benign melanocytic nevi (bmn), recent scars, or lichen planus-like keratosis (lplk) [16,17]. when identified on rcm in high densities, ilc are more likely to result in a false diagnosis of melanoma [14]. while dendritic cells alone are not enough to diagnose lm, as demonstrated by guitera et al [10] and gomez-martin et al [13], the follicular localization of atypical cells on rcm, correlating to asymmetric follicular pigmentation on dermoscopy, raised the level of suspicion for lm in our patient’s case. in the literature, ilc presence has been confirmed in several cases of benign lesions that were perceived to be malignant under rcm. these include suspected cases of melanoma [14,18,19], lip melanoma [20], and lm/lmm [13] (table 1). comparatively high densities of langerhans cells exist within the head, neck, trunk, and limbs [21], corresponding to the variety of locations reported. most cases described rcm findings of roundish and dendritic pagetoid cells, although some cases found atypical cells at the dej and dermis, as well. as evidenced by our case, traditional h&e stain was not sufficient in identifying ilc on histopathology and cd1a was required for further classification. in some studies, dendritic pagetoid cells were identified by rcm in lesions that were ultimately benign, but staining for langerhans cells was not pursued [10,22,23]. thus, the prevalence of ilc in pigmented lesions, and its confounding effect on rcm diagnosis, may be even greater than reported. the inability to use special stains and ihc when conducting in vivo rcm makes such morphologic mimickers indistinguishable across several lesion types. some malignant and pre-malignant lesions, particularly pigmented basal cell carcinomas [17,24], in situ or early invasive melanomas [14,25,26], pigmented actinic keratosis [27], and pigmented squamous cell carcinoma (scc) in situ [28], may also contain a high density of langerhans cells. in a study classifying melanoma into distinct types, pellacani et al [29] found that in situ and thin melanomas (<1 mm breslow thickness) were characterized by dendritic cells on rcm. while the authors did not further identify the cells immunohistochemically to rule out the possibility of ilc, this study, and others like it, highlight a possible association of dendritic cells with thin, or early, melanomas. in cases of larger suspicious pigmented lesions, rcm has the added benefit of real-time biopsy guidance, increasing the sensitivity for histopathologic detection of malignancy [10]. future studies would need to determine whether the identification of dendritic cells on rcm of a clinically ambiguous lesion would result in earlier detection of melanoma. while atypical cells have been identified as ilc rather than atypical melanocytes across benign lesions including bmn, sutton (halo) nevi, labial melanotic macules, and sl, the presence of dendritic pagetoid cells should continue to alert the confocalist of a potential neoplastic process, prompting biopsy, histopathologic diagnosis, and ihc differentiation. references 1. edwards sj, osei-assibey g, patalay r, wakefield v, karner c. diagnostic 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squamous cell carcinoma in situ. am j dermatopathol. 2018;40(3):173-179. doi: 10.1097/dad.0000000000000938. pmid: 28816741. 29. pellacani g, de pace b, reggiani c, et al. distinct melanoma types based on reflectance confocal microscopy. exp dermatol. 2014;23(6):414-418. doi: 10.1111/exd.12417. pmid: 24750486. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021082 1 the effectiveness and tolerability of preformed growth factors vehiculated through iontophoresis on patients with androgenetic alopecia and telogen effluvium: a clinical study aurora maria alessandrini, francesca bruni, bianca maria piraccini, michela starace 1 dermatology, department of experimental, diagnostic and specialty medicine, university of bologna, italy key words: iontophoresis, androgenetic alopecia, telogen effluvium, growth factors, scalp disorders, physical therapy. citation: alessandrini am, bruni f, piraccini mb, starace m. the effectiveness and tolerability of preformed growth factors vehiculated through iontophoresis on patients with androgenetic alopecia and telogen effluvium: a clinical study. dermatol pract concept. 2021;11(3):e2021082. doi: https://doi.org/10.5826/dpc.1103a82 accepted: february 19, 2021; published: may 20, 2021 copyright: ©2021 alessandrini et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. competing interests: the authors have no conflict of interest to declare. funding: none authorship: all authors contributed equally to this manuscript corresponding author: bianca maria piraccini md, phd, department of experimental, diagnostic and specialty medicine division of dermatology, university of bologna, bologna, italy, via massarenti, 1, 40138 bologna, italy. email: biancamaria.piraccini@ unibo.it background: androgenetic alopecia is characterized by a progressive miniaturization of hair follicles in a pattern distribution in genetically predisposed individuals. the efficacy of conventional therapies is variable, therefore there is a need for adjuvant and newer treatment modalities to provide faster and better outcomes. objectives: evaluation of the efficacy and tolerability of a combined therapy: preformed growth factors vehiculated through iontophoresis in patients with androgenetic alopecia and associated telogen effluvium, to obtain faster hair regrowth. materials and methods: treatment was performed between june 2018 and june 2019 on 60 patients with androgenetic alopecia and associated telogen effluvium. each patient underwent 4 sessions in total, each session was performed every 3 weeks. global photography and trichoscopy were collected at every session of therapy. all patients filed out a self-assessment questionnaire. results: results were very promising, with improvement of hair density and thickening of the hair shaft diameter in most of patients seen with both global photography and trichoscopy. all patients were satisfied of the clinical result and reported a complete reduction in hair loss. no serious adverse side effects were reported. conclusions: the use of growth factors associated with iontophoresis technique is a useful treatment for treating and preventing androgenetic alopecia. in addition, in case of associated telogen effluvium, this technique allows for an early stop of hair shedding, especially when cosmetic procedures do not provide satisfactory results in patients. abstract 2 research | dermatol pract concept. 2021;11(3):e2021082 introduction hair loss represents a problem for the patient for cosmetic and psychological reasons because hair symbolizes an important mirror of our image and a physical attractiveness to self-perception of beauty. the field of hair disorders is constantly growing. the first step to address this issue, is to collect a good historical record and perform a thorough physical examination. laboratory testing is often unnecessary, while trichoscopy is fundamental for all hair diseases. androgenetic alopecia and telogen effluvium are common causes of non-scarring alopecia. many treatments are available, and a prompt diagnosis is particularly important for the prognosis. androgenetic alopecia (aga) is the most common cause of non-cicatricial alopecia and affects up to 50% of women and 80% of men during their lifetime [1], with a frequency that increases with age after puberty. the disease is characterized by a progressive miniaturization of hair follicles in selected areas of the scalp, in genetically predisposed individuals. the effectiveness of conventional therapies with finasteride and minoxidil, in terms of the arrest of alopecia progression and induction of new hair regrowth, is variable between 40% and 60% [2], therefore over the years physical adjuvant treatments have been introduced to obtain faster and better results, especially for those patients who have not achieved satisfying results or that require further clinical improvement. this review highlights the importance of adding adjuvant physical or surgical therapies, such as prp (platelet‐rich plasma), when standard treatments do not give enough results. in addition, androgenetic alopecia can start with an episode of telogen effluvium (te) characterized by a diffuse hair loss occurring around 3 months following a triggering event and lasting for about 6 months. in te, hair loss is usually less than 50% of the scalp hair [3,4]. te occurs more frequently in adult females. preformed growth factors vehiculated through iontophoresis is one of the most innovative treatments. it is a patented technique that increases hair follicle growth through 3 combined mechanisms: application of preformed growth factors with multiple microdermal incisions of the scalp, pressure wave, and iontophoresis. the use of this technique has been investigated as a potential therapeutic option for the treatment of hair disorders due to its capacity to enhance growth factor production, facilitate hair follicle development and cycling, amplify collagen and elastin production and create microchannels that allow transdermal delivery of drugs through the stratum corneum. the technique is performed through puncturing with 0,25 mm microneedles, preventing deep injury and scar formation. the procedure is sufficient to induce skin irritation and trigger skin repair mechanisms (as measured by induction of tgf‐beta, tgf‐alpha, fgf 7, pdgf), ultimately resulting in collagen deposition by fibroblasts. the aim of this study was to evaluate the efficacy of the application of preformed growth factors with multiple microdermal incisions of the scalp vehiculated by iontophoresis in patients with aga and te, supporting its combined administration along with the existing therapeutic modalities, to obtain faster hair regrowth and patient satisfaction. materials and methods a pilot study, open‐label, not randomized, single‐group, and single‐center was performed. 30 subjects with grade ii, iii, iv, and v male androgenetic alopecia according to hamilton-norwood scale and 30 women of ludwig’s grade i, ii, iii (15 with aga and 15 with te associated) second scale were included in the study between june 2018 and june 2019. during the first enrollment visit (t0), patients underwent a dermatological examination, global photography and photomicrograph (trichoscopy and trichoscan®). the treatment procedure included 4 sessions of microdermal incision followed by iontophoresis performed every 3 weeks. during each session, a vial containing growth factors was applied on the scalp that was subsequently treated with a skin patting device followed by iontophoresis to allow absorption of the product. we performed two control visits, the first after 6 months from the first treatment and the second after one year. patients were evaluated with instrumental methods for clinical and trichoscopic evaluation and self-assessment questionnaires during each visit. no anesthesia was necessary for the procedure. the first step of this device is a controlled microdermabrasion by a sequence of micro wounds with a needle length 0,25 mm over affected areas in longitudinal, vertical, and diagonal directions, eight times in each direction or until mild erythema, which was considered as the end point to stimulate the dermis repair process resulting in increased vascularization, release of growth factors, fibroblast multiplication and increased collagen and elastin synthesis. the device also produces a radial pressure wave (mechanical action) directed to the scalp. it has 3 different effects: strengthening of the microcirculation, stimulation of cellular metabolism that increases the intake of active ingredients, stimulation of fibroblast activity with collagen and elastin production. finally, the iontophoresis induces a muscular stress enhancing the contractile capacity of the skin and inducing the dilation of the pores of the skin to facilitate the absorption of the active ingredients. at the end of the treatment, the scalp is irradiated with red led light with a bio-stimulant effect on the production of fibroblasts and elastin. each procedure lasted for about 20‐25 minutes. after the procedure, it is unnecessary to clean the scalp or apply any cream. following the procedure, no precautions research | dermatol pract concept. 2021;11(3):e2021082 3 were recommended to patients, who can continue with cosmetic or pharmacological treatments as usual. we evaluated the efficacy and tolerability of this technique before starting the treatment and after 6 and 12 months through pull test, clinical iconography, and trichoscopy; digital images were obtained at 20×, 40×, and 70× magnifications at the vertex and central hairline of the scalp and both the number and the diameter of the hairs were measured with trichoscan® software. we used a standardized grid located on the scalp at every session to correctly locate the same frontal and vertex scalp area during the treatment, using the kang’s point or “v” point as primary reference. the “v” point is calculated by the intersection of the mid‐sagittal line, and the coronal line connecting both tips of the tragus of the patient. furthermore, we questioned all patients about local adverse effects or increase in hair loss, as well as their perception of hair growth. results data was collected from a total of 60 patients, between june 2018 and june 2019. among the female patients’ group, 15 suffered from aga, and other 15 suffered from aga and associated te. all male patients (30) had aga. all patients underwent 4 sessions of preformed growth factors vehiculated through iontophoresis at an interval of 3 weeks, over a total period of 12 months. all patients were caucasian, and the mean age at the diagnosis was 39,9 (range 18-78 years). global photography and trichoscopy revealed the typical aspect of aga with the presence of diameter variability, peripilar signs and empty follicles in 75% of patients; the fifteen patients with associated te showed short hairs in regrowth at trichoscopy and a positive pull test with telogen hair roots. all enrolled patients completed the study without adverse reactions or side effects. no pain or discomfort were reported by patients during the procedure and no erosion or breakage of hair shaft was noted on the affected areas. global photography and trichoscopy showed improvement in all 60 patients with a partial or complete reduction in hair loss, confirmed by a negative pull test, associated to the perception of a hair density improvement and a hair shaft diameter thickening. the results are listed in table 1. in particular, male patients showed a 14.61% increase in the total number of hairs/cm2 in the anterior area of the scalp and a 13,62% increase in the hair diameter in the vertex area (figure 1). female patients, on the other hand, showed a 13.68% increase in the total number of hairs / cm2 at the anterior area and an increase in the hair diameter of 15,61% in the vertex area (figure 2). in all patients a reduction of vellus hair was detected in all areas of the scalp with an increase in the total number of hairs. after 1 year, the researcher’s evaluation reported an evident improvement in all patients: more in detail, a moderate improvement was reported in 6 patients and a significant improvement in 12. all patients were satisfied by the treatment; 17 referred a moderate improvement and 43 reported a significant improvement. most of them (53/60) defined the treatment as “painless and pleasant”. table 1. results of our study.   t0 t6 difference% (t0-t6) female patients anterior average hair density 163,96 186,39 13,68% vertex average hair density 161,22 188,95 17,20% anterior average vellus hair/cm2 41,43 33,71 -0,62% vertex average vellus hair/cm2 34,21 28,95 -0,51% anterior average hair diameter 0,08 0,09 14,28% vertex average hair diameter 0,08 0,10 15,61% average pull test 6,37 2,60 -59,16% male patients anterior average hair density 151,00 173,06 14,61% vertex average hair density 146,44 169,44 15,70% anterior average vellus hair/cm2 38,77 35,97 -7,23% vertex average vellus hair/cm2 38,44 34,85 -9,32% anterior average hair diameter 0,07 0,08 8,67% vertex average hair diameter 0,07 0,08 13,62% average pull test 4,60 2,47 -46,38% 4 research | dermatol pract concept. 2021;11(3):e2021082 figure 1. androgenetic alopecia in a 31‐y‐old male. clinical picture (a) and corresponding dermoscopic image (b) at baseline and clinical picture (c) and corresponding trichoscopic image (d) with increased hair density after 6 months. discussion and conclusions androgenetic alopecia (aga) is the most common cause of non-scarring alopecia, affecting up to 50% of women and 80% of men [1], with a frequency increasing with age after puberty. its prevalence is higher in caucasians than in blacks and asians [5,6]. aga is characterized by progressive hair thinning developing under the influence of a testosterone metabolite, dihydrotestosterone (dht), against a background of genetically determined susceptibility of the hair follicles, in frontal, temporal and vertex regions. clinical manifestations are different in both sexes. in males, aga determines a progressive fronto-temporal recession and a vertex loss, while in women the frontal hairline is preserved and hair loss involves more or less uniformly the frontal region, posteriorly to the hairline. female patterns might occur in males and vice versa. male aga is commonly evaluated using the hamilton-norwood scale that distinguishes 12 degrees of severity. female aga is evaluated either using the ludwig scale (3 stages), or the sinclair (5 stages) or savin scales (6 stages). pull test typically shows telogen roots, but trichoscopy is the most important tool for diagnosis. androgenetic alopecia is a slowly progressing disease that, if not treated, induces diffuse hair thinning in androgen-sensitive areas of the scalp. according to the most recent european guidelines [2], effective medical treatments, such as finasteride and minoxidil, are available with evidence level 1, but as is well known, they are chronic therapies that may lose effectiveness over time. many topical and systemic treatments are available. minoxidil still represents a milestone as a “hair growth stimulator”, even if the precise mechanism of its action is not completely understood [7]. to maintain efficacy treatment should be continuous and not suspended. over the years several types of physical treatments have assumed an important adjuvant role, especially for those patients who have not obtained satisfactory results with medical therapies or that research | dermatol pract concept. 2021;11(3):e2021082 5 desire further improvements. other treatment options include the platelet-rich plasma (prp) treatment [8,9], low-level laser (light) therapy [10], and surgery [11,12]. in addition, one of the first symptoms reported by patient is an initial hair shedding or telogen effluvium. the term telogen effluvium (te) defines a diffuse hair loss that occurs around 3 months following a triggering event, lasting for about 6 months. te results from noxious events that precipitate the entry of a large number of follicles into the telogen phase. possible causes include systemic diseases, drugs, fever, stress, weight loss, delivery, iron deficiency, and inflammatory scalp disorders. hair loss is usually less than 50% of the scalp hair [3,4]. te is more frequent in adult females and can be the consequence of an interruption of the follicular cycle with a sudden shift from the growth (anagen) phase to the rest (telogen) phase [13]. in fact, an episode of telogen effluvium can show a consequent androgenetic alopecia in predisposed subjects. we performed a study to evaluate the efficacy and tolerability of preformed growth factors applied through with iontophoresis for the treatment of androgenetic alopecia in 60 patients, 30 male and 30 females, for a period of 12 months. the evaluation was both subjective, based on an efficacy and tolerability questionnaire filled out by both the clinician and the patient, and objective, through the comparison of global photographs and serial photomicrographs (trichoscopy at 20x, 40x, 70x and trichoscan® magnifications (fotofinderdermoscope, teachscreen software, bad birnbach, germany). our study illustrated the efficacy and non-invasiveness of a treatment procedure with preformed growth factors through iontophoresis. this technique works by increasing the blood flow to hair follicles, stimulating stem cells and inducing the activation of growth factors by neovascularization and neocollagenesis. as reported in the literature, numerous growth factors can stimulate the hair growth cycle [14-17]. vegf, essential for angiogenesis and vascular permeability, is responsible for maintaining the correct vascularization of the hair follicle in the anagen phase. igf-i promotes growth by regulating cell proliferation and migration during the development of hair follicles. b-fgf promotes the anagen phase in hair follicles and is considered a potential promoter of hair growth. kgf figure 2. androgenetic alopecia in a 29‐y‐old female. clinical picture (a) and corresponding dermoscopic image (b) at baseline and clinical picture (c) and corresponding trichoscopic image (d) with increased hair density after 12 months. 6 research | dermatol pract concept. 2021;11(3):e2021082 is essential for regenerating hair follicles by stimulating more resistant stem growth. finally, egf has a direct action on fibroblasts enhancing their action on collagen and elastin production. treatment to arrest alopecia progression and induce new hair regrowth in androgenetic alopecia patients include finasteride and minoxidil. oral intake of nutritional supplements containing iron, vitamins, and aminoacids, and topical application of cosmetic lotions formulated to block acute hair shedding and promote hair growth [18] include insulin-like growth factor 1 (igf-1), fibroblast growth factor (fgf), and vascular endothelia growth factor (vegf). adjuvant and recent treatments include physical therapies such as prp or microneedling [19] where there is an improvement in hair growth through the stimulation of dermal papilla and stem cells and an increase in hair follicles blood supply with growth factors recruitment. however, these techniques are often reported as painful by the patients, and in some cases the pain is hard to bear. our study confirms the fundamental role of the association between the use of growth factors conveyed associated with the iontophoresis technique in increasing hair regrowth and hair diameter avoiding pain or discomfort symptoms. this technique represents a safe and useful option to treat androgenetic alopecia, especially when associated with telogen effluvium, through mechanisms that include stimulation and elongation of hair follicle anagen phase, increased blood microcirculation, activation of fibroblasts with collagen, and elastin production. furthermore, this procedure is simple to perform and extremely pleasant for the patient. future large controlled clinical trials exploring the utility of preformed growth factors through iontophoresis are imperative to prove its validation as an evidence‐based therapeutic option for patients with a variety of hair disorders, thus confirming its role as more than a cosmeceutical treatment. references 1. piraccini bm, alessandrini a. androgenetic alopecia. g ital dermatol venereol. 2014 feb;149(1):15-24. 2. kanti v, messenger a, dobos g, reygagne p, finner a, blumeyer a, trakatelli m, tosti a, del marmol v, piraccini bm, nast a, blume-peytavi u. evidence-based (s3) guideline for the treatment of androgenetic alopecia in women and in men short version. j eur acad dermatol venereol. 2018; 32(1): 11-22. doi: 10.1111/ jdv.14624. pmid: 29178529 3. kligman am. pathologic dynamics of human hair loss. telogen effluvium. arch dermatol. 1961; 83: 175. doi: 10.1001/archderm.1961.01580080005001. pmid: 13756813 4. trueb rm. diffuse hair loss. in: blume-peytavi u, tosti a, whiting da, trueb r, editors. hair growth and disorders, 1st edn. berlin: springer; 2008: 259272. doi: 10.1007/978-3-540-46911-7_13 5. sinclair r. male pattern androgenetic alopecia. br mj. 1998;317:865-869. doi: 10.1136/bmj.317.7162.865. pmid: 9748188 6. whiting da. male pattern hair loss: current understanding. int j dermatol. 1998; 37: 561-566. doi: 10.1046/j.13654362.1998.00542.x pmid: 9731996 7. barbareschi m. the use of minoxidil in the treatment of male and female androgenetic alopecia: a story of more than 30 years. g ital dermatol venereol. 2018 feb;153(1):102-106. 8. alves r, grimalt r. platelet-rich plasma in combination with 5% minoxidil topical solution and 1 mg oral finasteride for the treatment of androgenetic alopecia: a randomized placebo-controlled, double-blind, half-head study. dermatol surg. 2018 jan;44(1):126-130. doi: 10.1097/ dss.0000000000001198 pmid: 28562433 9. starace m, alessandrini a, d’acunto c, melandri d, bruni f, patrizi a, piraccini bm. platelet-rich plasma on female androgenetic alopecia: tested on 10 patients. j cosmet dermatol. 2019 feb;18(1):59-64. doi: 10.1111/jocd.12550 pmid: 29707872 10. kim h, choi jw, kim jy, shin jw, lee sj, huh ch. low-level light therapy for androgenetic alopecia: a 24-week, randomized, double-blind, sham device-controlled multicenter trial. dermatol surg. 2013 aug;39(8):1177-83. doi: 10.1111/dsu.12200 pmid: 23551662 11. avram mr, finney r, rogers n. hair transplantation controversies. dermatol urg. 2017 nov;43 suppl 2: s158-s162. doi: 10.1097/dss.0000000000001316 pmid: 29064980 12. rose pt. advances in hair restoration. dermatol clin. 2018 jan;36(1):57-62. doi: 10.1016/j.det.2017.09.008 pmid: 29108547 13. rebora a. telogen effluvium: a comprehensive review. clin cosmet investig dermatol. 2019 aug 21; 12: 583-590. doi: 10.2147/ ccid.s200471 pmid: 31686886 14. philpott mp, sanders da, kealey t. effects of insulin & insulin like growth factors on cultured human hair follicles: igf-i at physiologic concentrations is an important regulator of hair follicle growth in vitro. j invest dermatol. 1994; 102:857–61. doi: 10.1111/1523-1747.ep12382494 pmid: 8006448 15. ebling fg, hale pa, randall va. hormones & hair growth. in: goldsmith la, editor. biochemistry & physiology of the skin. oxford: 2nd ed. clarendon press; 1991:660–90. 16. parsley wm, perez-meza d. review of factors affecting the growth & survival of follicular grafts. j cutan aesthet surg. 2010; 3:69–75. 17. kapoor r, shome d. intradermal injections of a hair growth factor formulation for enhancement of human hair re growth-safety and efficacy evaluation in a first-in-man pilot clinical study. j cosmet laser ther. 2018 oct;20(6):369-379. doi: 10.1080/14764172.2018.1439965 pmid: 29482481 18. paus r. frontiers in the (neuro-)endocrine controls of hair growth. j investig dermatol symp proc. 2007 dec;12(2):20-2. doi: 10.1038/sj.jidsymp.5650050 pmid: 18004292 19. starace m, alessandrini a, brandi n, piraccini bm. preliminary results of the use of scalp microneedling in different types of alopecia. j cosmet dermatol. 2020 mar;19(3):646-650. doi: 10.1111/ jocd.13061 pmid: 31254437 dermatology practical & conceptual www.derm101.com letters | dermatol pract concept 2012;2(3):12 65 report some aspects of gonorrhea (gn) treatment in the former soviet union are discussed in this letter in the example of three typical cases from the 1980s. the facts follow: case 1. a lawyer, about 30 years old, who spent much time on study and work, was infected with gn. in compliance with the law at the time, he went to a dermatovenereological dispensary (prevention and treatment center), where he was registered and treated according to the instructions issued by the health care authorities [1,2]. the patient said that the treatment had been lengthy and unpleasant and subsequently would never return to the dispensary. case 2. a bachelor, about 35 years old, awarded himself a next highest military rank whenever he contracted gn; in this way he became a generalissimo (which demonstrates widespread irresponsibility: the patient was, in fact, proud of his “career”). he never visited the dermatovenereological dispensary and treated himself with intramuscular injections of bicillin (benzathine benzylpenicillin). high-risk groups were informed about methods applied in the dispensaries and avoided them. they also had general knowledge about how to treat gn with antibiotics; more responsible individuals administered themselves regular courses of bicillin injections, but others treated themselves incompletely and continued spreading infection. these cases show that the society de facto permitted many infected people, including those from higher classes, to spread sexually transmitted infections (sti). case 3. a female student was infected with gn in a students’ dormitory. initially, no symptoms were noticed. shortly thereafter, she met her future husband and a week later was admitted to a gynecology department with a diagnosis of “adnexitis”; while the fiancée developed an acute urethritis with a massive discharge of creamy pus. an acquainted physician gave them several tablets of an overseas antibiotic (unavailable in russian hospitals at that time), which ended their disease; there were no relapses. bacteriology laboratories in hospitals were sometimes unreliable, which allowed the couple to avoid some of the procedures described below. following are several citations from official manuals legally in force at that time [1,2] and from standard publications such as the medical encyclopedia [3] and the manual of dermatovenereology [4]: “if inflammation persists 5-7 days after a course of antibiotic therapy, even if gonococci have disappeared from the urethral smears, topical therapy is recommended.” [3] in the introductory part of the latest manual available [1], it is stated that topical therapy was indicated only in case of intolerance of antibiotics, but further in the text it recommended them for torpid and chronic gn, and sexual contacts were to be treated in the same way as the patients with chronic gn, even if no gonococci had been found in the smears [1]. some earlier handbooks recommended topical treatment for all patients with gn [5]. among other things, topical therapy included the following: in case of a “soft” infiltration, 0.25-1 % silver nitrate solution were instilled into the ureabout the treatment of gonorrhea in the former soviet union sergei v. jargin, m.d.1 1 peoples’ friendship university of russia, moscow, russia citation: jargin sv. about the treatment of gonorrhea in the former soviet union [letter]. dermatol pract conc. 2012;2(3):12. http:// dx.doi.org/10.5826/dpc.0203a12. copyright: ©2012 jargin. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: sergei v. jargin, m.d., clementovski per 6-82, 115184 moscow, russia. email: sjargin@mail.ru. 66 letters | dermatol pract concept 2012;2(3):12 thra; focal lesions were treated with an additional 10-20% silver nitrate solution via urethroscope. for “desquamative” urethritis, instillations of zinc or lead sulphate were recommended. for urethral adenitis: swabbing of the urethra up to the external sphincter with argentum proteinicum and glycerol was recommended. bouginage and swabbing were recommended both for a “soft” and “firm” infiltration [3]. repeated tests of cure, administered to all patients, included methods of provocation. the rationale behind the provocation was as follows: “gonococci are difficult to detect bacterioscopically, (while mechanical and chemical) irritation of tissues can help to reveal the infection in hidden places.” [2] chemical provocations in men included instillations into the urethra of 0.5 % silver nitrate solution and in women, treatment of the urethra with 1-2%, and of the cervical canal with 2-5% silver nitrate solution or lugol’s iodine solution with glycerol. mechanical provocation included bouginage or urethroscopy with urethral massage: “in protracted cases, it is advisable to induce irritation of the urethral mucosa by a massage on a bougie or urethroscope.” [2] if symptoms reappeared after the provocation, the treatment was repeated. a combined provocation was performed 7-10 days after the last treatment. urethral discharge was examined 24, 48 and 72 hours after the provocation and if there was no discharge, secretions from the prostate and seminal vesicles were examined. if no gonococci were found after the first provocation, a combined provocation including urethroscopy was repeated one month later. the urethroscopy (with a dry urethroscope, both for men and women) was stressed as necessary because pathological changes of the mucosa and urethral glands could persist in the absence of symptoms: “urethroscopy enables the determination of the character of inflammatory changes after the disappearance of gonococci and of acute clinical manifestations, which is of importance for the topical treatment.” [2] the following measures, among others, were recommended for gn in women: instillations into the urethra of 1% silver nitrate solution; urethral massage for chronic urethritis, electrocoagulation or cauterization of inflamed periurethral glands by a silver nitrate crystal fixed on a urethroscope. a “follicular” erosion of the ectocervix would be repeatedly coagulated by potassium permanganate crystals. it should be commented that coagulation or cryotherapy have been usual treatment modaliies for “pseudo-erosion” (i.e., endocervical ectopia or ectropion) independently of the presence of epithelial dysplasia [6]. for longstanding cervical erosions , electrocoagulation with subsequent insertion into the vagina for 24 hours of a swab with glycerol and ichthammol (sulfonated bitumen from shale oil) was recommended. if no gonococci were found bacterioscopically in the smears taken during the patient’s first visit, a provocation was recommended by means of an instillation of silver nitrate solution into the urethra and the cervical canal [7]. the test of cure included urethroscopy [1]. as a test of cure for women, a combined provocation 7-10 days after the treatment was applied with a repeat treatment during the next menstrual period, and then again after 2-3 periods. if clinical symptoms were persisting, but no gonococci were found, the same treatment as for chronic gn was recommended [7]. as a consequence of this approach, non-gonococcal inflammatory conditions were sometimes treated by the topical procedures (among them must have been cases of chlamydia infection because of its relatively high incidence) [8]. if no clinical symptoms were present, and no gonococci were found at two months after the last treatment, a registration with the dispensary is cancelled. the methods of topical therapy and provocations, inherited from the pre-antibiotic era, were mentioned neither in foreign handbooks of that time [9,10] nor in review articles [11-14]; while bouginage was recommended only for strictures [10]. nevertheless, topical therapy and repeated tests of cure were probably useful in some cases because of the limited availability of modern antibiotics in the former soviet union. for a pathologist, it is not entirely clear which morphological substrate corresponds to the “firm infiltration,” where bouginage was strongly recommended [1,3]; but it is obvious that inflamed and edematous mucosa can be traumatized, which might contribute to scarring and formation of strictures. at the same time, diagnostic tests for non-gonococcal urethritis, such as direct immunofluorescence for chlamydia infection, were unavailable to the public until the late 1980s or the 1990s. the outdated approach has persisted partly due to the limited access to foreign professional literature [15]. the treatment of venereal diseases, including gonorrhea, was under strict official control in the ussr. challenging the guidelines, that had remained unchanged for a long time, was equivalent to challenging legal instructions and was difficult. some sti experts understood that the instructions were obsolete. others witness that the guidelines were not always strictly adhered to; in other words, some personal judgment was involved. apparently, a psychological mechanism, including conscious or subconscious ideation of punishment, on the part of medical personnel possibly fueled in some cases by personal frustrations, obesity etc., played a role in it. some patients witnessed that abortions and gynecological manipulations, especially in women considered to be socially unprotected or “immoral,” had been quite unpleasant. there are no reliable statistics, but the abortion rate in the former soviet union was reported to be the highest in the world, which was caused not only by insufficient availability of modern contraception [16] but also by irresponsibility of some men (the author of this letter not excluded, which he today sincerely regrets). alcohol letters | dermatol pract concept 2012;2(3):12 67 misuse was a contributing factor [17]. of oral contraceptives, mainly infecundin and bisecurin (both produced in hungary), were known in the 1980s; these pills required a prescription and were used infrequently. condoms were of poor quality then: imported ones were scarce, while the soviet-made condoms were notoriously thick and at the same time tore easily. there may have been a policy in place aimed at an increase of the birth rate [18]. furthermore, as mentioned above, cervical “pseudo-erosions” (endocervical ectopia, ectropion), independent of the presence of epithelial dysplasia, have been treated with electrocoagulation. this practice is at variance with scientific evidence that does not support the hypothesis that coagulation of an ectopy provides protection against cervical cancer [19]. today, however, the attitude is changing. the instructions [1] are still valid, but at least in central dermato-venereology dispensaries in moscow mechanical provocations are no longer in use and instillations are performed only occasionally. tests for chlamydia and other pathogens are available today. some private institutions offer modern diagnostics and treatment. in the recently edited russian-language manuals, antibiotic therapy of gn is broadly discussed, while the provocations and topical treatment are not mentioned at all [20,21]. the future is therefore optimistic: the growing russian economy today enables access to modern equipment and new methods of treatment, and broadening international cooperation has attracted foreign expertise into the country. summary the treatment of gonorrhea in the former soviet union is discussed in this report with the examples of three typical cases from the 1980s. some outdated methods of topical treatment and provocation, not used in other countries at that time, are listed. being aware of lengthy and unpleasant treatment methods, high-risk groups avoided the government-run dermato-venereological dispensaries (prevention and treatment centers) and often practiced self-treatment, which, in some cases, contributed to the spread of sti. the future is therefore optimistic: the growing russian economy today enables access to modern equipment and new methods of treatment, and broadening international cooperation has attracted foreign expertise into the country. references 1. ministry of health of the ussr. [instruction for treatment and prevention of gonorrhea]. moscow, 1988. 2. ministry of health of the russian federation. [treatment and prevention of gonorrhea. methodical recommendations]. moscow, 1993. 3. porudominsky im, ilyin ii, ovchinnikov nm, et al. gonorrhea. in: [large medical encyclopaedia. 3rd ed.] moscow: soviet encyclopaedia, vol. 6]. 1977;324-36. 4. rodionov ai. [manual on the skin and sexually transmitted diseases]. moscow: piter, 2005. 5. mavrov ii. [treatment and prevention of gonococcal infection]. kiev: zdorov’ia, 1984. 6. bodiazhina vi. cervical erosion. in: [large medical encyclopaedia, vol 28. 3rd ed.]. moscow: soviet encyclopaedia, 1986;343-4. 7. batkaev ea. [gonorrhoea in women]. moscow: central order of lenin advanced training medical institute, 1986. 8. white c. sexually transmitted diseases continue to rise. bmj. 2004;329:249. 9. berger re. sexually transmitted diseases: the classic diseases. in: walsh pc, retik ab, vaughan ed, wein aj, eds. campbell’s urology. 7th ed. philadelphia: saunders, 1998:663-683. 10. tanagho ea, mcaninch jw. smiths urologie. berlin: springer, 1988. 11. willcox rr. a survey of problems in the antibiotic treatment of gonorrhoea. with special reference to south-east asia. br j vener dis. 1970;46(3):217-42. 12. welch rd, fletcher dj, nelson jh, blackwell m, fergerson j. current treatment 160 approaches for gonorrhea in men: two for the price of one. mil med. 1984;149(7):404-7. 13. bowie wr. approach to men with urethritis and urologic complications of sexually transmitted diseases. med clin north am. 1990; 74:1543-57. 14. carne ca. epidemiological treatment and tests of cure in gonococcal infection: evidence for value. genitourin med. 1997;73(1):12-5. 15. jargin sv. the state of medical libraries in the former soviet union. health info libr j. 2010;27(3):244-8. 16. popov aa, visser ap, ketting e. contraceptive knowledge, attitudes, and practice in russia during the 1980s. stud fam plann. 1993;24(4):227-35. 17. jargin sv. on the causes of alcoholism in the former soviet union. alcohol alcohol. 2010;45(1):104-5. 18. jargin sv. where have all the flowers gone? s afr med j. 2011;101(8):494. 19. machado junior lc, dalmaso as, carvalho hb. evidence for benefits from treating cervical ectopy: literature review. sao paulo med j. 2008;126(2):132-9. 20. sokolovsky ev, savichev am, kisina vi, et al. [gonococcal infection. treatment. recommendations for physicians]. saintpetersburg: foliant, 2008. 21. molochkov va, gushchin ae. [gonorrhea and associated infections. a manual for physicians]. moscow: geotar-med, 2006. dermatology: practical and conceptual editorial | dermatol pract concept 2020;10(3):e2020068 1 dermatology practical & conceptual introduction in the context of this editorial on congenital melanocytic nevi (cmn), the following points will be discussed: 1. medium and large cmn are hamartomas present at birth, but many small cmn can appear later, within the first decade of life. 2. most cmn of any size will persist throughout a lifetime, but some, especially those located on special areas, including nails and acral sites, might disappear as a result of spontaneous involution. 3. if there is any precursor lesion of melanoma, then cmn is entitled to be the most important one. the cmn family traditionally, cmn are classified into 2 groups, namely, cmn blue type and cmn non-blue type [1]. of the first group, blue nevi are the most frequent ones (figure 1, a and b); other dermal melanocytoses belonging to this group of cmn include mongolian spot, nevus of ota, and nevus of ito (figure 1, c and d). cmn of the non-blue family are also defined as superficial cmn to point out the main difference from blue-type cmn, which are typified by a more deeply situated proliferation of dendritic melanocytes. superficial cmn are traditionally subdivided into the following 3 groups based on the diameter they are expected to attain in adulthood: small cmn, <2 cm; medium cmn, 2-20 cm; and large cmn, >20 cm. this subdivision is arbitrary, but it is based on the fact that the risk for melanoma increases with the increasing size of cmn. medium and large cmn are hamartomas typified by a benign proliferation of melanocytes and keratinocytes [2,3]. they are always present at birth, whereas small cmn can frequently appear later, usually before puberty [3]. these nevi are commonly classified as early acquired melanocytic nevi (amn), but in our estimation they essentially belong to the family of cmn. this is mainly based on their similarity to “true congenital” melanocytic nevi in terms of morphological features and evolutional behavior (figure 2). reassessing the biological significance of congenital melanocytic nevi giuseppe argenziano,1 stefano caccavale,1 gabriella brancaccio,1 elvira moscarella,1 vincenzo piccolo,1 aimilios lallas2 1 dermatology unit, university of campania, naples, italy 2 first department of dermatology, aristotle university, thessaloniki, greece key words: citation: argenziano g, caccavale s, brancaccio g, moscarella e, piccolo v, lallas a. reassessing the biological significance of congenital melanocytic nevi. dermatol pract concept. 2020;10(3):e2020068. doi: https://doi.org/10.5826/dpc.1003a68 accepted: june 29, 2020; published: july 9, 2020 copyright: ©2020 argenziano et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: giuseppe argenziano, md, dermatology unit, university of campania, nuovo policlinico ed 9c, via pansini 5, 80131 naples, italy. email: editor@dpcj.org https://doi.org/10.5826/dpc.1003a68 mailto:editor@dpcj.org 2 editorial | dermatol pract concept 2020;10(3):e2020068 which tends to become stable as soon as the globules disappear [3-5]. over a variable period of time, usually years, small cmn become more elevated and acquire a papillomatous (usually on the trunk) (figure 4) or smooth (usually on the face) surface. dermoscopically, brown globules at the periphery disappear, while a cobblestone pattern becomes visible throughout the lesion. in medium and large cmn, the keratinocytic proliferation is usually seen as a verrucous surface intermingled with terminal hairs. dermoscopically, medium and large cmn may exhibit a globular pattern, a reticular pattern, or a combination of both (figure 5). most large cmn are confined to the skin, but in rare cases they may involve the central nervous system configuring the so-called neurocutaneous melanosis. this is a potentially life-threatening condition that usually occurs when a large cmn is accompanied by multiple moscopically typified by a globular pattern (figure 3). the presence of brown globules at the periphery is the hallmark of the growing phase of the lesion, morphologically, most small cmn (either present at birth or appearing in early childhood) are clinically flat or slightly raised pigmented lesions derfigure 1. (a,b) clinical and dermoscopic images of a blue nevus. (c,d) nevus of ito on the shoulder of a young boy. figure 2. a 10-year-old girl with multiple nevi. based on the history, the only “true” congenital melanocytic nevus (cmn) is the one depicted in (b), whereas the other nevi shown (c-i) appeared within the first 2-3 years of life. however, based on morphology, all of them show a globular pattern; thus the hypothesis is that all these nevi belong to the same spectrum of lesions, namely, cmn. editorial | dermatol pract concept 2020;10(3):e2020068 3 assessing this risk included medium and large cmn [17-21]. in one of the largest studies of more than 6,500 patients with medium and large cmn, 0.7% of patients developed melanoma at a median age of 7 years [22]. however, the risk of developing melanoma was by far highest in cmn 40 cm or more cmn and melanoma risk the dogmatic knowledge about the risk of melanoma in cmn states that the larger the nevus, the higher the chance of melanoma development within a preexisting cmn. most of the studies smaller cmn (satellitosis) and mostly in bathing trunk nevi (figure 6) [6]. in this clinical context a brain nuclear magnetic resonance is usually indicated within the first year of life [7]. the life cycle of cmn as mentioned above, small cmn usually tend to persist over time. especially when located on the head-neck, trunk, and limbs, small cmn undergo progressive maturation within the dermis, thus evolving into intradermal nevi. in our estimation, the great majority of dermal melanocytic nevi in adulthood belong to the group of small cmn. this is because most of amn do not show a tendency to maturation. they appear usually after puberty as a superficial, junctional, or compound proliferation of melanocytes, growing for a variable period of time and finally going through spontaneous involution [8,9]. although most small cmn tend to persist over time, there are instances in which cmn are prone to disappear. this is particularly the case in special areas including nails (figure 7) and acral sites where cmn may undergo spontaneous involution after a variable period of time, usually years [10-14]. it is unknown why some cmn undergo maturation and some disappear. a possible explanation might be related to the depth level of the skin in which the nevus is mainly proliferating. cmn of the head-neck region, trunk, and limbs are usually compound nevi histopathologically, whereas cmn of the nails and acral sites are more of the junctional type [15]. it is possible that dermal melanocytes may tend to undergo maturation while epidermal melanocytes are more prone to disappear after a variable period of time, similarly to amn. the latter are also typified by a junctional proliferation of melanocytes and they also usually undergo spontaneous involution over time [10-16]. figure 3. small congenital melanocytic nevi dermoscopically typified by a globular pattern. figure 4. (a,b) clinical and dermoscopic images of a dermal congenital melanocytic nevus on the trunk with its papillomatous surface. figure 5. (a) intermediate size congenital melanocytic nevus (cmn) with its verrucous surface intermingled with terminal hairs. dermoscopically, medium and large cmn may exhibit (b) a globular pattern, (c) a reticular pattern, or (d) a combination of both. 4 editorial | dermatol pract concept 2020;10(3):e2020068 in diameter. in the latter group, the risk may reach 10% [22]. if we compare these percentages to the risk of melanoma within an amn (recently calculated as approximately 1 out of 200,000 amn) [23], we can conclude that cmn is by far the most important melanoma precursor. melanoma risk in small cmn has not yet been calculated, perhaps because of the limitations in discriminating between small cmn and amn. in a recent study by our group, however, we reported that at our institution most of the melanomas arising within a cmn (78%) were developing in the context of a small cmn (unpublished data). this seems paradoxical, but it can be easily explained by the respective numbers of small, medium, and large cmn seen in routine practice. assuming that the risk of melanoma in a large cmn is 10%, we have to screen 10 large cmn to find 1 melanoma. in our institution, we screen a mean of 2 new patients with large cmn per year; thus we need 5 years to find 1 melanoma. assuming that the risk of melanoma in a small cmn is much lower than 10%, still the chance of finding one is much higher figure 6. a boy with a giant congenital melanocytic nevus (cmn) associated with multiple smaller cmn (satellitosis). figure 7. (a,b) clinical and dermoscopic images of a congenital melanocytic nevus of the nail matrix, undergoing spontaneous involution after 2 years (c,d). editorial | dermatol pract concept 2020;10(3):e2020068 5 benignity: a case series. pediatr dermatol. 2019;36(2):227-231. https://doi. org/10.1111/pde.13745 5. odorici g, longhitano s, kaleci s, et al. morphology of congenital nevi in dermoscopy and reflectance confocal microscopy according to age: a pilot study. j eur acad dermatol venereol. published online ahead of print, 2020 apr 10. https://doi.org/10.1111/jdv.16448 6. alikhan a, ibrahimi oa, eisen db. congenital melanocytic nevi: where are we now? part i: clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis. j am acad dermatol. 2012;67(4):495.e1-514; quiz 512514. https://doi.org/10.1016/j.jaad.2 012.06.023 7. kinsler va, aylett se, coley sc, chong wk, atherton dj. central nervous system imaging and congenital melanocytic naevi. arch dis child. 2001;84(2):152-155. https://doi.org/10.1136/adc.84.2.152 8. vezzoni r, conforti c, vichi s, et al. is there more than one road to nevus-associated melanoma? dermatol pract concept. 2020;10(2):e2020028. https://doi. org/10.5826/dpc.1002a28 9. pizzichetta ma, massone c, grandi g, pelizzo g, soyer hp. morphologic changes of acquired melanocytic nevi with eccentric foci of hyperpigmentation (“bolognia sign”) assessed by dermoscopy. arch dermatol. 2006;142(4):479483. https://doi.org/10.1001/archderm. 142.4.479 10. haenssle ha, blum a, hofmann-wellenhof r, et al. when all you have is a dermatoscope—start looking at the nails. dermatol pract concept. 2014;4(4):1120. https://doi.org/10.5826/dpc.0404a02 11. marghoob aa. congenital melanocytic nevi: evaluation and management. dermatol clin. 2002;20(4):607-616. https://doi. org/10.1016/s0733-8635(02)00030-x 12. strauss rm, newton bishop ja. spontaneous involution of congenital melanocytic nevi of the scalp. j am acad dermatol. 2008;58(3):508-511. https://doi. org/10.1016/j.jaad.2006.05.076 13. lee nr, chung hc, hong h, lee jw, ahn sk. spontaneous involution of congenital melanocytic nevus with halo phenomenon. am j dermatopathol. 2015;37(12):e137-e139. https://doi. org/10.1097/dad.0000000000000311 14. nath ak, thappa dm, rajesh ng. spontaneous regression of a congenital melanocytic nevus. indian j dermatol venemore common than usually reported because early amn might also belong to the group of cmn. they can persist or disappear based on their localization on different body areas and, much more frequently than amn, they can be found in association with melanoma, in both children and adults. small cmn, although traditionally considered as not requiring special attention, might be the most frequent melanoma precursor in terms of absolute numbers. this does not mean that the risk of melanoma on small cmn is high, but that the majority of nevi on which melanoma develops belong to the category of small cmn [25]. references 1. moscarella e, piccolo v, argenziano g, et al. problematic lesions in children. dermatol clin. 2013;31(4):535547, vii. https://doi.org/10.1016/j.det. 2013.06.003 2. schaffer jv. update on melanocytic nevi in children. clin dermatol. 2015;33(3):368-386. https://doi.org/ 10.1016/j.clindermatol.2014.12.015 3. errichetti e, patriarca mm, stinco g. dermoscopy of congenital melanocytic nevi: a ten-year follow-up study and comparative analysis with acquired melanocytic nevi arising in prepubertal age. eur j dermatol. 2017;27(5):505-510. https://doi.org/10.1684/ejd.2017.3088 4. cotton ch, goldberg gn. evolution of congenital melanocytic nevi toward because of the much higher incidence of small cmn in the clinical routine. pediatric melanoma is, in general, an extremely rare disease. in a recent systematic review, we found 2 important issues to mention (unpublished data). first, the majority (about 55%) of pediatric melanomas (defined as melanoma occurring in patients aged 18 years or less) develop as cmn-associated melanoma (figure 8). this is in contrast to what is happening in adults, in whom at least 70% of melanomas arise de novo. the second is related to the mortality for pediatric melanoma, which is higher for nevus-associated melanoma than for de novo melanoma, especially for children within the first decade of life. this difference was not attributed to breslow thickness, which was similar in both groups. thus, the only possible explanation is that at least a certain percentage of lesions that were reported as de novo melanoma were instead benign melanocytic tumors. this underlines once more the problem of morphologically difficult lesions in children, as already reported by leman et al [24]. if this is true, then the percentage of pediatric melanomas that develop on cmn is even higher than 55%. conclusions cmn are much more relevant lesions than previously considered. they are figure 8. clinical and dermoscopic images of a melanoma 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https://doi.org/10.1684/ejd.2017.3088 6 editorial | dermatol pract concept 2020;10(3):e2020068 22. krengel s, hauschild a, schäfer t. melanoma risk in congenital melanocytic naevi: a systematic review. br j dermatol. 2006;155(1):1-8. https://doi. org/10.1111/j.1365-2133.2006.07218.x 23. tsao h, bevona c, goggins w, quinn t. the transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population-based estimate. arch dermatol. 2003;139(3):282-288. https://doi. org/10.1001/archderm.139.3.282 24. leman ja, evans a, mooi w, mackie rm. outcomes and pathological review of a cohort of children with melanoma. br j dermatol. 2005;152(6):1321‐1323. https://doi.org/10.1111/j.1365-2133. 2005.06609.x 25. caccavale s, calabrese g, mattiello e, et al. cutaneous melanoma arising in congenital melanocytic nevus: a retrospective observational study. dermatology. in press. 1982;100(2):219-224. https://doi.org/10. 1016/s0022-3476(82)80638-0 19. rhodes ar, sober aj, day cl, et al. the malignant potential of small congenital nevocellular nevi: an estimate of association based on a histologic study of 234 primary cutaneous melanomas. j am acad dermatol. 1982;6(2):230-241. https://doi.org/10.1016/s0190-9622 (82)70016-7 20. berg p, lindelöf b. congenital melanocytic naevi and cutaneous melanoma. melanoma res. 2003;13(5):441-445. https:// doi.org/10.1097/00008390-20031000000002 21. tannous zs, mihm mc jr, sober aj, duncan lm. congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management. j am acad dermatol. 2005;52(2):197-203. https://doi. org/10.1016/j.jaad.2004.07.020 reol leprol. 2011;77(4):507-510. https:// doi.org/10.4103/0378-6323.82418 15. zalaudek i, longo c, ricci c, albertini g, argenziano g. classifying melanocytic nevi. in: marghoob aa, ed. nevogenesis. berlin, heidelberg: springer-verlag; 2012:25-41. https://doi. org/10.1007/978-3-642-28397-0_2 16. kinsler va, o’hare p, bulstrode n, et al. melanoma in congenital melanocytic naevi. br j dermatol. 2017;176(5):11311143. https://doi.org/10.1111/bjd.15301 17. illig l, weidner f, hundeiker m, et al. congenital nevi less than or equal to 10 cm as precursors to melanoma: 52 cases, a review, and a new conception. arch dermatol. 1985;121(10):12741281. https://doi.org/10.1001/archderm. 1985.01660100054014 18. rhodes ar, melski jw. small congenital nevocellular nevi and the risk of cutaneous melanoma. j pediatr. https://doi.org/10.1111/j.1365-2133.2006.07218.x https://doi.org/10.1111/j.1365-2133.2006.07218.x https://doi.org/10.1001/archderm.139.3.282 https://doi.org/10.1001/archderm.139.3.282 https://doi.org/10.1111/j.1365-2133.2005.06609.x https://doi.org/10.1111/j.1365-2133.2005.06609.x https://doi.org/10.1016/s0022-3476(82)80638-0 https://doi.org/10.1016/s0022-3476(82)80638-0 https://doi.org/10.1016/s0190-9622(82)70016-7 https://doi.org/10.1016/s0190-9622(82)70016-7 https://doi.org/10.1097/00008390-200310000-00002 https://doi.org/10.1097/00008390-200310000-00002 https://doi.org/10.1097/00008390-200310000-00002 https://doi.org/10.1016/j.jaad.2004.07.020 https://doi.org/10.1016/j.jaad.2004.07.020 https://doi.org/10.4103/0378-6323.82418 https://doi.org/10.4103/0378-6323.82418 https://doi.org/10.1007/978-3-642-28397-0_2 https://doi.org/10.1007/978-3-642-28397-0_2 https://doi.org/10.1111/bjd.15301 https://doi.org/10.1001/archderm.1985.01660100054014 https://doi.org/10.1001/archderm.1985.01660100054014 dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022026 1 trichofolliculoma mimicking squamous cell carcinoma ahmed abdelbary1, hadir shakshouk1 1 department of dermatology, andrology and venerology, alexandria university, egypt key words: trichofolliculoma, adnexal tumors, hamartoma, dermoscopy, case report citation: abdelbary a, shakshouk h. trichofolliculoma mimicking squamous cell carcinoma. dermatol pract concept. 2022;12(1):e2022026. doi: https://doi.org/10.5826/dpc.1201a26 accepted: june 6, 2021; published: january 2022 copyright: ©2022 abdelbary and shakshouk. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: hadir shakshouk, mbbs, msc, department of dermatology, andrology and venerology, alexandria university, egypt. e-mail: drhadir58@gmail.com introduction trichofolliculoma, a rare follicular hamartoma, manifests itself as a solitary papule or nodule in adults involving the head and neck region. it is characterized by a single primary cystic structure from which radiates numerous secondary hair follicles. while dermoscopy has been widely used as a diagnostic tool, dermoscopic features of adnexal lesions are poorly described owing to their rarity and inadequate reporting. case presentation we describe a 75-year-old male patient who presented with asymptomatic solitary nodule on the forehead of 2-years duration. upon examination, a single nodule of 1 cm diameter with central crust and raised border was noted on his forehead (figure 1a). dermoscopic evaluation revealed a nodule with central crusting, multiple fine linear vessels, and whitish circles mainly on the margin (figure 1b). these features were highly suggestive of squamous cell carcinoma. however, histopathological examination demonstrated multiple cystically dilated follicular infundibula lined by stratified squamous epithelium with numerous vellus hair follicles originating from them. multiple lobules of follicles of varying maturity were observed radiating from these dilated follicular infundibula. some showed sebaceous glands. a fibrocellular stroma surrounding the tumor was noted (figure 1c). thus, a diagnosis of trichofolliculoma was made. written informed consent for publication of clinical details and clinical images was obtained from the patient. conclusions trichofolliculoma is considered to be a rare follicular hamartoma that classically manifests as a papule or nodule with a central dilated pore and tufted hairs. this presentation corresponds histopathologically to a central primary follicle with many radiating secondary vellus hair follicles. 2 research letter | dermatol pract concept. 2022;12(1):e2022026 while thought to be diagnostic for trichofolliculoma, few cases demonstrate central hair tufting. the lack of a central hair plug, as in our case, renders the clinical diagnosis challenging. dermoscopy of trichofolliculoma is not well described in literature. panasiti et al reported a patient with single nodule suspicious for basal cell carcinoma [1]. however, dermoscopic examination revealed a central brown zone with radial brown projections without pigment network, which was described by the authors as a “firework” pattern. these projections correlated histopathologically with the nests of cells radiating from a follicular epithelium [1]. garcia-garcia and colleagues described different dermoscopic features that included a well-defined bluish nodule with a whitepink central area, shiny white structures, dotted vessels, and a central scale in one patient [2]. histopathologically, the early stages demonstrated few secondary vellus hair follicles originating from a primary follicle, whereas mature lesions showed increased number of vellus hair follicles. in later stages, thickened primary follicle with fewer secondary follicles could be seen [2]. trichofolliculoma classically presents with a hair plug emanating from the center of a nodule; however, hair plug may be absent in many cases, making the diagnosis challenging. in these cases, other serious diagnoses should be ruled out. dermoscopy of trichofolliculoma is poorly described in the literature. we introduce the possibility of new dermoscopic findings of trichofolliculoma. references 1. panasiti v, roberti v, lieto p, visconti b, calvieri s, perrella e. the “firework” pattern in dermoscopy. int j dermatol. 2013;52(9):11581159. doi: 10.1111/j.1365-4632.2011.05122.x. pmid: 22591242. 2. garcia-garcia sc, villarreal-martinez a, guerrero-gonzalez ga, miranda-maldonado i, ocampo-candiani j. dermoscopy of trichofolliculoma: a rare hair follicle hamartoma. j eur acad dermatology venereol. 2017;31(2):e123-e124. doi: 10.1111/ jdv.13870. pmid: 27504964. figure 1. (a) clinical examination showed a well-defined nodule with central crust on the forehead. (b) dermoscopic evaluation showed a nodule with central crusting, multiple fine linear vessels, and whitish circles mainly on the margin. (c) histopathologic examination showed dilated primary follicular infundibula with numerous secondary hair follicles, and a few showed sebaceous glands. a fibrocellular stroma surrounding the tumor was noted (h&e, original magnification ×20). dermatology: practical and conceptual image letter | dermatol pract concept 2021;11(1):e2021134 1 dermatology practical & conceptual golden lady andrina neff1, alexandra valeska matter1, isabel kolm1 1 department of dermatology, university hospital of zurich, switzerland key words: plane xanthoma, monoclonal gammopathy, lymphoproliferative disease, hyperlipidemia citation: neff a, matter av, kolm i. golden lady. dermatol pract concept. 2021;11(1):e2021134. doi: https://doi.org/10.5826/ dpc.1101a134 accepted: august 2, 2020; published: january 29, 2021 copyright: ©2021 neff et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: isabel kolm-djamei, md, department of dermatology, university hospital of zurich, gloriastrasse 31, 8091 zurich, switzerland. email: isabel.kolm-djamei@usz.ch case presentation a 93-year-old woman presented with confluent yellow plaques with an intense golden glow symmetrically on the neck and lateral face (figure 1, a and b) mimicking a golden camouflage. the histopathology showed cd68-positive foamy macrophages in the papillary dermis (figure 1, c and d), leading to the diagnosis of plane xanthoma. our patient showed mild dyslipidemia (total cholesterol 6.4 mmol/l [<5.0 mmol/l]). clinical stigmata for familial hyperlipidemia were not presfigure 1. (a, b) remarkable presentation of plane xanthoma on the neck and lateral face with a golden hue in a 93-year-old woman. (c, d) histopathology of plane xanthoma with cd68-positive foamy macrophages in the papillary dermis. 2 image letter | dermatol pract concept 2021;11(1):e2021134 precede such disorders by several years; therefore, a regular follow-up is recommended. references 1. cohen yk, elpern dj. diffuse normolipemic plane xanthoma associated with monoclonal gammopathy. dermatol pract concept. 2015;5(4):65-67. doi: 10.5826/dpc.0504a16. pmid:26693095. 2. morsink lm, nijhof is. diffuse plane normolipaemic xanthomatosis as a manifestation of monoclonal gammopathy. br j haematol. 2019187(4):411. doi: 10.1111/bjh.16141. pmid:31407310. ent. due to the distribution pattern, underlying hematological disorders were ruled out. teaching point the location of plane xanthomas can serve as a clue to a particular underlying disease. plane xanthomas in a normolipemic patient with favored distribution on the neck, upper trunk, and flexural folds should prompt a search of underlying hematological disorders such as monoclonal gammopathy or lymphoproliferative disease [1,2]. plane xanthomas can dermatology: practical and conceptual research | dermatol pract concept 2021;11(1):e2021145 1 dermatology practical & conceptual skin cancer and dermoscopy training for primary care physicians: a pilot study valeria de bedout1, natalie m. williams1, ana m. muñoz2, ana m. londoño2, manuela munera2, natalí naranjo2, lina m. rodriguez2, alejandra m. toro2, feng miao3, tulay koru-sengul3,4, natalia jaimes1,4 1 dr. phillip frost department of dermatology and cutaneous surgery, university of miami miller school of medicine, miami, florida, usa 2 department of dermatology, universidad pontificia bolivariana, medellin, colombia 3 department of public health sciences, university of miami miller school of medicine, miami, florida, usa 4 sylvester comprehensive cancer center, miami, florida, usa key words: skin cancer, dermoscopy, dermoscopy training, diagnostic accuracy citation: de bedout v, williams nm, muñoz am, londoño am, munera m, naranjo n, rodriguez lm, toro am, miao f, korusengul t, jaimes n. skin cancer and dermoscopy training for primary care physicians: a pilot study. dermatol pract concept. 2021;11(1):e2021145. doi: https://doi.org/10.5826/dpc.1101a145 accepted: september 22, 2020; published: january 29, 2021 copyright: ©2021 de bedout et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: this study was funded by the sylvester comprehensive cancer center global oncology innovation grant. research reported in this publication was supported by the national cancer institute of the national institutes of health under award number p30ca240139. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health.. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: natalia jaimes, md, dr. phillip frost department of dermatology and cutaneous surgery, university of miami miller school of medicine, dermatology research clinic , 1600 nw 10th ave, rsmb 2023a. miami, florida, 33136, usa. email: njaimes@med.miami.edu introduction: the primary objective of this study was to determine the diagnostic accuracy and effect of an educational training on skin cancer course and dermoscopy use among primary care physicians in rural areas of colombia. the secondary objective was to assess the diagnostic accuracy of skin cancer diagnosis and detection rate after 3 months of the initial training. methods: twenty-one primary care physicians from 6 rural areas of colombia participated in a 2-day skin cancer and dermoscopy training, followed by a day-long hands-on session on dermoscopy at a free skin cancer screening event. preand post-tests were performed using clinical and dermoscopic images to evaluate the user’s ability to diagnose and differentiate benign and malignant neoplasms. in addition, participants’ levels of confidence were assessed. results: after the training, the sensitivity and specificity of characterizing skin lesions as benign or malignant or providing a specific diagnosis (ie, angioma, seborrheic keratosis, basal cell carcinoma, etc.) increased by 23.6% (62.9% to 86.5%; p < 0.0001) and 21% (54.7% to 75.7%; p < 0.0017), respectively. in addition, levels of confidence when diagnosing skin lesions changed from extremely low or low, to high or extremely high by 20.7% (38.3% to 59%) using dermoscopic images (odds abstract 2 research | dermatol pract concept 2021;11(1):e2021145 introduction primary care physicians (pcps) play a critical role in the health system of many latin american countries. pcps are usually the first physicians to encounter the patient and are responsible for the decision-making as to whether or not a patient needs further evaluation. among dermatologic conditions, skin cancer continues to be a public health burden worldwide and most cases can be cured if detected early. thus, early detection is paramount in improving patient prognosis and quality of life, while reducing healthcare costs. various strategies, both in primary and secondary prevention, have been suggested and implemented including education for medical and non-medical communities. in fact, different educational interventions for pcps have been developed within the field of skin cancer, but few have been carried out in latin america [1] . dermoscopy is a noninvasive, in-vivo imaging technique that allows the visualization of subsurface structures of the skin that are otherwise not visible to the naked eye [2,3]. traditionally, dermoscopy has been used by, and taught to, dermatologists. however, during the last decade its use has been explored and extended to pcps [4-6]. although dermoscopy increases the diagnostic accuracy of skin cancer diagnosis, this improvement is contingent on acquiring dermoscopy training. without training, the use of dermoscopy may result in poorer performance compared to clinical examination [7-9]. it has been shown that pcps who are trained in dermoscopy not only improve their sensitivity for the diagnosis of skin cancer, but also reduce the number of unnecessary biopsies and referrals [4-6]. oftentimes, there is a lack of specialized medicine (eg, dermatology) in underserved populations including rural areas of countries such as colombia. in these populations the pcp may represent the first, and sometimes the only, healthcare provider. thus, having pcps trained in diagnosing and differentiating skin cancer using dermoscopy would be an efficient strategy to improve the early detection of skin cancer and consequently reduce morbidity and associated healthcare costs. the present pilot study developed a skin cancer and dermoscopy training intervention for pcps in the eastern rural region of the department of antioquia in the country of colombia. the department of antioquia is the second most populated department of colombia among its 32 departments, with an estimated population of 6.4 million. antioquia is located in the central northwestern part of colombia with most of its territory being part of the andes mountain range. the racial background of this region is largely mestizo and white. these individuals are more prone to developing skin cancer because of their skin phenotype, increased ultraviolet radiation (uvr) exposure due to their frequent outdoor activities (eg, agriculture), and the geographic location of their municipalities at high altitudes with high uvr indexes yearround [10]. the primary objective of this study was to determine the diagnostic accuracy and effect of an educational training on skin cancer and dermoscopy use among pcps in this rural region of colombia. the secondary objective was to assess the diagnostic accuracy of skin cancer diagnosis and detection rate after 3 months of the initial training. methods study design and population pcps from hospitals of 6 municipalities in the rural area of the eastern region of antioquia, colombia (ie, alejandría, el peñol, guatapé, marinilla, san carlos, and san rafael) were invited to participate in the study in november of 2018. this area was selected given its geographic location combined with its low healthcare access, offering level 1 or 2 medical services without specialized medicine. the total population for these 6 municipalities is 111,175. the study was irb-approved at the universidad pontificia bolivariana in medellín, colombia. intervention: training in skin cancer and dermoscopy inclusion criteria consisted of healthcare professionals working in primary care settings who were willing to voluntarily participate in the study. individuals who did not complete both preand post-tests or did not attend at least 50% of the course were excluded. pcps participating in the study received a 2-day course on the theoretical and practical aspects of diagnosing and differentiating skin cancer clinically and with dermoscopy. training was provided by ratio (or) 3.22; 95% confidence interval (ci): 2.67-3.86; p < 0.0001). the secondary objective was not achieved due to loss of follow-up of the majority of participants. conclusion: providers serving populations with limited healthcare access may benefit from education in diagnosing and differentiating skin cancer with the use of dermoscopy, which may ultimately improve patient care and reduce healthcare costs. research | dermatol pract concept 2021;11(1):e2021145 3 5 dermatology residents and 2 dermatologists with expertise in dermoscopy. a quasi-experimental study with a pre-test/ post-test design was performed. a total of 50 cases were presented on a large screen using powerpoint before and after training. first, the clinical images of all 50 cases (24 benign, 26 malignant) were presented. for each case, 3 questions were asked: 1) is the lesion benign or malignant? 2) what is the possible diagnosis (seborrheic keratosis [sk], nevus, squamous cell carcinoma [scc], melanoma, or other)? and 3) what is the level of confidence (on a scale from 1 to 5, with 1 being not confident and 5 being extremely confident)? examiners recorded their responses by writing their answer choice on a paper-based test. after completion of the presentation of clinical images, the cases were presented again with the addition of a dermoscopic image as demonstrated in figure 1, and the same 3 questions were answered. after the 2-day course, the same 50 cases were presented using the same format and questions (post-test). each trainee was given 1 minute to respond to each case in both the preand post-examinations. additionally, participants were instructed not to discuss the cases after the pre-test. a few of the test images were included by way of illustration or discussion in the teaching activities. subsequently, participants joined a 1-day hands-on session with one-on-one training during a free skin cancer screening event offered to local communities. each participating institution was provided with a dermoscope to use after training. statistical analysis descriptive statistics were used to describe the demographic information and other characteristics of the study participants including gender, type of practice (private vs public), years of practice, average of cases of dermatologic conditions seen per months, and knowledge about dermoscopy, self-skin examination, and full body skin examination. to evaluate the training intervention, pre-test and post-test results were measured. measures of validity included the sensitivity and specificity of diagnostic accuracy, and kappa statistics for agreement and overall percent agreement. dichotomous outcome measurements were created using the data provided by the participants. variables included: 1) benign vs malignant and 2) possible diagnosis. the values of these variables were used to create cross-classifications of benign and malignant lesions and to calculate overall sensitivity, specificity, overall agreement and kappa statistics with 95% confidence intervals (ci) for both pre-test and post-test. to evaluate the improvement after the 2-day course, we used mcnemar’s test to compare sensitivities, specificities, and overall agreement between pre-test and post-test. the association between diagnosis confidence and training were estimated by odds ratio (or) with corresponding 95% ci and p value. data management all of the statistical analyses were carried out using sas v9.4 (sas institute inc., cary, nc, usa). three-month follow-up to evaluate the longer-term effects of the intervention, a 3-month follow-up of the pcps was planned to learn whether the training was serving the target population. for this phase of the study, an online rehearsal course in dermoscopy was offered to the participating pcps. in addition, pcps and hospitals were asked to provide a de-identified list of patients with skin cancer diagnoses that were seen by the participating figure 1. test images. clinical and dermoscopic images of various skin lesions were presented separately during the pre-test and posttest. for each case, a clinical image (left) was presented followed by the clinical and dermoscopy (right) image: (a) melanoma, (b) basal cell carcinoma (c) seborrheic keratosis, and (d) acral nevus. a b c d 4 research | dermatol pract concept 2021;11(1):e2021145 pcps 3 months prior to and 3 months after the training course. for this list, the international statistical classification of diseases and related health problems 10th revision codes (icd-10) were used. results a total of 21 pcps from 6 hospitals of 6 municipalities participated in the course. two physicians were present for less than half of the course; therefore, 19 pcps were included in the final analysis. demographics of the pcps are listed in table 1, and information on their current understanding and clinical practice with respect to skin cancer is listed in table 2. two-day skin cancer and dermoscopy training 1. benign vs malignant the pcps ability to differentiate malignant lesions (ie, melanoma, bcc, and scc) from benign lesions (ie, nevus, dermatofibroma, angioma, and sk) was tested and analyzed using preand post-test evaluations. of the test cases, 48% of lesions were benign. preand post-test results are demonstrated in table 3. the sensitivity for skin cancer diagnosis using clinical images alone was 57.8%, improving to 71.8% (p < 0.0001) using clinical images alone, and 83.9% (p < 0.0001) using clinical and dermoscopy images. the specificity also increased from 58.5% to 66.1% (clinical images alone, p = 0.0107) and 78% (clinical and dermoscopy images, table 1. characteristics of the healthcare professionals in the study participant characteristics n % all 21 100.0 gender female 11 52.4 male 10 47.6 job type of the healthcare professional md 18 85.7 nurse 1 4.8 other 2 9.5 where do you work? unanswered 3 14.3 community hospital 11 52.4 private hospital 1 4.8 private practice 6 28.6 years of practice unanswered 2 9.5 <5 15 71.4 >5 4 19.0 table 2. skin cancer knowledge and practices of healthcare professionals in the study participant skin cancer knowledge and practices n % all 21 100.0 number of dermatology conditions seen per week unanswered 9 42.9 1 3 14.3 2 2 9.5 3 2 9.5 4 1 4.8 5 3 14.3 20 1 4.8 number of dermatology conditions seen per month unanswered 11 52.4 1 1 4.8 2 1 4.8 3 2 9.5 5 2 9.5 6 1 4.8 10 1 4.8 20 2 9.5 cases of skin cancer seen per month unanswered 7 33.3 0 5 23.8 1 5 23.8 2 3 14.3 3 1 4.8 do you know what a dermatoscope is? no 0 0.0 yes 21 100.0 have you used a dermatoscope? no 14 66.7 yes 7 33.3 have you heard of self-skin exams? no 8 38.1 yes 13 61.9 do you discuss self-skin examinations with patients? unanswered 9 42.9 no 6 28.6 yes 6 28.6 how often should self-exams be performed? unanswered 15 71.4 monthly 2 9.5 once a year 2 9.5 other 1 4.8 weekly 1 4.8 (table 2 continues) research | dermatol pract concept 2021;11(1):e2021145 5 table 3. participant responses on preand post-tests pre-test clinical pre-test dermoscopic post-test clinical post-test dermoscopic n % n % n % n % all images 1,000 100.0 1,050 100.0 952 100.0 952 100.0 accuracy (benign vs malignant) correct 282 28.2 305 29.0 324 34.0 429 45.1 incorrect 702 70.2 743 70.8 561 58.9 462 48.5 unanswered 16 1.6 2 0.2 67 7.0 61 6.4 nature of lesion benign 487 48.7 519 49.4 409 43.0 409 43.0 malignant 502 50.2 528 50.3 478 50.2 482 50.6 unanswered 11 1.1 3 0.3 65 6.8 61 6.4 diagnosis melanoma 282 28.2 285 27.1 288 30.3 241 25.3 bcc 115 11.5 137 13.0 107 11.2 137 14.4 scc 98 9.8 106 10.1 81 8.5 111 11.7 nevus 207 20.7 228 21.7 174 18.3 184 19.3 sk 79 7.9 65 6.2 71 7.5 69 7.2 dermatofibroma 35 3.5 60 5.7 39 4.1 52 5.5 angioma 95 9.5 98 9.3 65 6.8 41 4.3 other benign 73 7.3 69 6.6 60 6.3 56 5.9 unanswered 16 1.6 2 0.2 67 7.0 61 6.4 *in this table, each of the 50 images were reviewed by up to 21 participants (maximum of 1,050 images) bcc = basal cell carcinoma; scc = squamous cell carcinoma; sk = seborrheic keratosis. p < 0.0001) (figure 2). overall, after the educational intervention, the pcps’ ability to accurately identify lesions as benign or malignant significantly improved. 2. specific diagnosis the pcps ability to specifically diagnose benign (ie, angioma, nevus, dermatofibroma, sk) or malignant lesions (ie, bcc, scc, melanoma) was tested and analyzed using preand post-test evaluations. of the test cases, 22% were melanoma, 20% bcc, 10% scc, 18% nevi, 10% sk, 8% solar lentigo, 4% dermatofibroma and hematoma, and 2% angioma and angiokeratoma. the sensitivity for any skin cancer using clinical images alone was 60.1%, improving to 72.4% (clinical images alone, p < 0.0001) and 85.4% (clinical and dermoscopy images, p < 0.0001). the specificity increased from 59.4% to 66.8% (clinical images alone, p = 0.012) and 77.3% (clinical and dermoscopy images, p < 0.0001) (figure 3). 3. confidence after the educational intervention, the number of participants who labeled their level of confidence when diagnosing skin participant skin cancer knowledge and practices n % do you know the abcds of melanoma? no 4 19.0 yes 17 81.0 do you discuss sun protection measures with patients? unanswered 2 9.5 yes 19 90.5 how often do you perform full body skin exam on your patients? unanswered 6 28.6 never 3 14.3 every visit 2 9.5 once a year 2 9.5 twice a year 1 4.8 other 7 33.3 table 2. skin cancer knowledge and practices of healthcare professionals in the study (continued) 6 research | dermatol pract concept 2021;11(1):e2021145 diagnostic accuracy of benign vs. malignant sensitivity specificity agreement kappa 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 pre-test clinical post-test clinical post-test dermoscopicpre-test dermoscopic figure 2. diagnostic accuracy of benign vs malignant. an increase in sensitivity and specificity in differentiating skin lesions as benign vs malignant was observed after the two-day skin cancer and dermoscopy training. diagnostic accuracy of specific lesions sensitivity specificity agreement kappa 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 pre-test clinical post-test clinical post-test dermoscopicpre-test dermoscopic figure 3. diagnostic accuracy of specific lesions. an increase in sensitivity and specificity in diagnosing specific skin lesions was observed after the two-day skin cancer and dermoscopy training. lesions as “high” or “extremely high” increased by 19% (30.9% to 49.8%; or: 2.22; 95% ci: 1.84-2.67; p < 0.0001) for clinical images, and 28% (30.9% to 59%; or: 3.22; 95% ci: 2.67-3.86; p < .0001) for dermoscopic images (figure 4). furthermore, confidence was correlated with diagnostic accuracy. considering confidence as a continuous measurement from 1 (“extremely low”) to 5 (“extremely high”), the correct diagnosis rate increased by 34.4% for every 1-point increase in confidence (overall or: 1.34; 95% ci: 1.27-1.43). during the skin cancer screening, the majority of participants continued to report high levels of confidence (53.2% for clinical images, 73.7% for dermoscopic). three-month follow-up to evaluate the effects of the intervention on the participants’ clinical practices, a 3-month follow-up of the pcps was planned to learn whether the training was serving the target population. however, most of the participating pcps were research | dermatol pract concept 2021;11(1):e2021145 7 lost to follow-up, and the lists with icd-10 codes were only provided by 2 of the participating physicians. discussion timely and accurate skin cancer diagnosis continues to be a clinical challenge, especially in underserved populations, rural areas, and developing countries where resources and geographic locations limit access to specialized healthcare. the use of dermoscopy increases the diagnostic accuracy of skin cancer by revealing structures and features otherwise invisible to the naked eye [11]. in the primary care setting, dermoscopy has been shown to improve the diagnostic accuracy for skin cancer and enhance the capacity of pcps to appropriately triage skin lesions [3,12-15]. a randomized clinical trial found that the probability of correctly diagnosing skin lesions was 1.25 times higher in pcps using dermoscopes compared to pcps using only naked-eye examination [16]. training pcps in dermoscopy not only advances physician knowledge and diagnostic skills, but can also benefit their community, where he or she may be the only healthcare provider. in our study, the 6 hospitals served about 111,175 persons, all of whom resided in municipalities where pcps were the only healthcare providers. studies have revealed that mastery-learning courses in dermoscopy led by dermatologists improve diagnostic accuracy, increase physician confidence, and decrease referrals of benign lesions [17-21]. similarly, our study demonstrated that pcps increased their sensitivity and specificity for detecting skin cancer after participating in the 2-day course on skin cancer and dermoscopy. this highlights the already known utility of dermoscopy in the detection of skin cancer by pcps and emphasizes the impact that an educational training program may have, even when it is as short as a few days. on the other hand, confidence, which is defined as the degree of certainty in the correctness of a diagnosis, is usually influenced by a variety of factors, including experience, level of training, and self-assurance [22]. the addition of dermoscopy to the clinical examination has been shown to reduce doubt and increase confidence, especially when evaluating skin lesions that are clinically challenging, but clearly benign or malignant under dermoscopy [22]. our results demonstrate that confidence improved among the majority of participating pcps after being trained in skin cancer and dermoscopy, and was correlated with increased diagnostic accuracy. this also suggests that confidence and knowledge can be further consolidated and maintained over time when additional rehearsals or trainings occur. conventionally, skin cancer diagnosis and dermoscopy has been taught through traditional lectures and problem-based learning using images of skin lesions. in this study we used a combined approach incorporating passive (ie, traditional lectures) and active (ie, problem-based) learning strategies, followed by experiential learning with live patient encounters (lpe) during a skin cancer screening event. although there are several forms of active learning, we included problem-based learning and experiential learning with lpe in a one-on-one training as an approach to meet the 4 key requirements of active learning: 1) activating prior knowledge; 2) involving the majority of students; 3) promotconfidence levels pre-test clinical post-test clinical pre-test dermoscopic post-test dermoscopic p er c en ta g e (% ) 100 80 60 40 20 0 extremely low low moderate high extremely high figure 4. confidence levels among participants. an increase in physician confidence in diagnosing skin lesions was observed after the two-day skin cancer and dermoscopy training. 8 research | dermatol pract concept 2021;11(1):e2021145 ing metacognition to increase awareness of strengths and weaknesses as learners; and 4) providing participants with feedback about their learning [23]. lpe is an active learning strategy rated by students as better than problem-based learning, which can result in increased performance and learning [24]. this one-on-one training ensured that the providers felt comfortable handling and using a dermoscope in a real clinical setting before incorporating it in their clinical practice. our study has several limitations. first, we acknowledge that this was a pilot study, the number of participants was small, and the sample was a non-probability-based convenience population, selected based on the geographic location of the 6 municipalities. thus, our sample may not represent the target population. second, the secondary objective of the study was to follow up with the pcps after 3 months for reevaluation and to record the number of skin cancer diagnoses made since the initial training. however, this objective proved to be challenging since the majority of participants were lost to follow-up. possible reasons for this include a lack of interest and the temporality of some of the providers, as many work for less than a year during their social service. therefore, we suggest that educational initiatives abroad should involve local academic or governmental entities that can implement and maintain such programs in a more rigorous form. another alternative would be to provide the educational initiative as part of the curriculum in medical schools during the last year of training (eg, internship). furthermore, in the demographic survey related to skin cancer practices and knowledge, a large proportion of questions went unanswered by pcps, limiting the results of this questionnaire. conclusions pcps play a key role in healthcare across the globe, especially those of developing countries and rural areas, including latin america. we conclude that appropriate training in skin cancer diagnosis and dermoscopy with active learning strategies can increase physician knowledge and confidence. this may ultimately decrease healthcare costs by reducing the number of unnecessary referrals, while improving the early detection of skin cancer in underserved areas lacking healthcare specialists. references 1. goulart jm, quigley ea, dusza s, et al; informed group. skin cancer education for primary care physicians: a systematic review of published evaluated interventions. j gen intern med. 2011;26(9):1027-1035. doi: 10.1007/s11606-011-1692-y. pmid: 21472502. 2. menzies sw, ingvar c, mccarthy wh. a sensitivity and specificity analysis of the surface microscopy features of invasive melanoma. melanoma res. 1996;6(1):55-62. doi: 10.1097/00008390199602000-00008. pmid: 8640071 3. argenziano g, soyer hp. dermoscopy of pigmented skin lesions--a valuable tool for early diagnosis of melanoma. lancet oncol. 2001;2(7):443-449. doi: 10.1016/s1470-2045(00)00422-8. 4. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877-1882. doi: 10.1200/jco.2005.05.0864. pmid: 16622262. 5. westerhoff k, mccarthy wh, menzies sw. increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy. br j dermatol. 2000;143(5):1016-1020. doi: 10.1046/j.1365-2133.2000.03836.x. pmid: 11069512. 6. menzies sw, emery j, staples m, et al. impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. br j dermatol. 2009;161(6):1270-1277. doi: 10.1111/j.1365-2133.2009.09374.x. pmid: 19747359. 7. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. doi: 10.1016/s1470-2045(02)00679-4. pmid: 11902502. 8. bafounta ml, beauchet a, aegerter p, saiag p. is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. arch dermatol. 2001;137(10):13431350. doi: 10.1001/archderm.137.10.1343pmid: 11594860. 9. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. doi: 10.1111/j.1365-2133.2008.08713.x. pmid: 18616769. 10. sanclemente mesa g, hernández garzón ge. altos índices de radiación ultravioleta en medellín y en una localidad del oriente antioqueño (colombia). 2010. 11. kittler h ph, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. doi: 10.1016/ s1470-2045(02)00679-4. 12. lallas a, zalaudek i, argenziano g,, et al. dermoscopy in general dermatology. dermatol clin. 2013;31(4):679-94, x. doi: 10.1016/j.det.2013.06.008. pmid: 24075553. 13. argenziano g, soyer hp, chimenti s, argenziano g, ruocco v. impact of dermoscopy on the clinical management of pigmented skin lesions. clin dermatol. 2002;20(3):200-202. doi: 10.1016/ s0738-081x(02)00234-1. 14. argenziano g. the impact of dermoscopy on the management of pigmented skin lesions: the role of follow-up. j am acad dermatol. 2005;52(1):178; author reply 9-80. doi: 10.1016/j. jaad.2004.06.032. pmid: 15627115. 15. braun rp, rabinovitz hs, oliviero m, kopf aw, saurat jh. dermoscopy of pigmented skin lesions. j am acad dermatol. 2005;52(1):109-121. doi: 10.1016/j.jaad.2001.11.001. pmid: 15627088 16. koelink cj, vermeulen km, kollen bj, et al. diagnostic accuracy and cost-effectiveness of dermoscopy in primary care: a cluster randomized clinical trial. j eur acad dermatol venereol. 2014;28(11):1442-1449. doi: 10.1111/jdv.12306. pmid: 25493316. research | dermatol pract concept 2021;11(1):e2021145 9 17. argenziano g, puig s, zalaudek i, et al. dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. j clin oncol. 2006;24(12):1877-1882. doi: 10.1200/jco.2005.05.0864. pmid: 16622262. 18. menzies s, emery j, staples m, davies s, mcavoy b, fletcher j, et al. impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. br j dermatol. 2009;161(6):1270-1277. doi: 10.1111/j.13652133.2009.09374.x. pmid: 19747359. 19. robinson jk, jain n, marghoob aa, et al. a randomized trial on the efficacy of mastery learning for primary care provider melanoma opportunistic screening skills and practice. j gen intern med. 2018;33(6):855-862. doi: 10.1007/s11606-018-4311-3. pmid: 29404948. 20. robinson jk, maclean m, reavy r, turrisi r, mallett k, martin gj. dermoscopy of concerning pigmented lesions and primary care providers’ referrals at intervals after randomized trial of mastery learning. j gen intern med. 2018;33(6):799-800. doi: 10.1007/s11606-018-4419-5. pmid: 29637481. 21. secker lj, buis pa, bergman w, kukutsch na. effect of a dermoscopy training course on the accuracy of primary care physicians in diagnosing pigmented lesions. acta derm venereol. 2017;97(2):263-5. doi: 10.2340/00015555-2526. pmid: 27572816. 22. benvenuto-andrade c, dusza sw,, hay jl,,et al. level of confidence in diagnosis: clinical examination versus dermoscopy examination. dermatol surg. 2006;32(5):738-744. doi: 10.1097/00042728-200605000-00034. pmid: 16706773. 23. medina ms. making students’ thinking visible during active learning. am j pharm educ. 2017;81(3):41. doi: 10.5688/ ajpe81341. pmid: 28496261. 24. rohlfsen cj, sayles h, moore gf, et al. innovation in early medical education, no bells or whistles required. bmc med educ. 2020;20(1):39. doi: 10.1186/s12909-020-1947-6. pmid: 32033553. 25. landis jr, koch gg. the measurement of observer agreement for categorical data. biometrics. 1977;33(1):159-74. doi: 10.2307/2529310. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022127 1 pilar leiomyomas. dermoscopy pattern of a rare entity meryem soughi1, fatimazahra mernissi1 1 dermatology derpartment, hassan ii university hospital fes morroco citation: soughi m. pilar leiomyomas. dermoscopy pattern of a rare entity. dermatol pract concept. 2022;12(3):e2022127. doi: https://doi.org/10.5826/dpc.1203a127 accepted: october 22, 2021; published: july 2022 copyright: ©2022 soughi. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. meryem soughi, dermatology department, taounat peripheral hospital. address: ouad oum rabie 13, narjis c; fez 30070, morroco mail: msoughi@gmail.com phone: 00212611936739 case presentation a 60-year-old woman, with a personal history of a uterine fibroma, was seen for evaluation of multiple flesh-colored, erythematous papules and nodules localized on laterocervical regions. dermoscopic examination of all lesions revealed multiple shiny and whitish areas distributed homogeneously within a fine network in a single nodule (figure1, a and b). the histological investigation confirmed a pilar leiomyoma. teaching point the dermoscopic features of pilar leiomyoma tumor are not well defined, because of its rarity. it is similar to dermatofibroma with central hypopigmented area and peripheral network [1]. in our case the lesions presented widespread bright white areas, with a more regular shape respect to the “white like-cloud areas” reported by diluvio et al [2]. figure 1. a. multiple flesh-colored, erythematous papules and nodules localized on latero-cervical regions. b. multiples shiny whitish areas are distributed homogeneously over all lesions within a fine network. 2 image letter | dermatol pract concept. 2022;12(3):e2022127 references 1. paschoal fm, rezze gg. dermoscopic findings in a patient with multiple piloleiomyomas. dermatol pract concept. 2012;2(4):204a06. doi: 10.5826/dpc.0204a06. pmid: 23785620. pmcid: pmc3663367. 2. diluvio l, torti c, terrinoni a, et al. dermoscopy as an adjuvant tool for detecting skin leiomyomas in patient with uterine fibroids and cerebral cavernomas. bmc dermatol. 2014; 16;14:7. doi: 10.1186/1471-5945-14-7. pmid: 24739762. pmcid: pmc4005830. dermatology: practical and conceptual correction | dermatol pract concept 2020;10(3):e2020099 1 dermatology practical & conceptual dermatol pract concept. 2019;10(3):e2020099. june 29, 2020. doi: do10.5826/dpc.1003a99 is there more than one road to nevus-associated melanoma? in the review article titled “is there more than one road to nevus-associated melanoma?” by vezzoni et al [1] (https:// dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp1002a28), published on april 3, 2020, the institutional affiliation of one of the authors was incorrect. dr. pizzichetta’s affiliations are dermatology clinic, hospital maggiore, university of trieste and division of oncology b, cro aviano national cancer institute, aviano, italy. this article was corrected online on june 29, 2020. the editors regret the error. reference 1.  vezzoni r, conforti c, vichi s, giuffrida r, retrosi c, magaton-rizzi g, di meo n, pizzichetta ma, zalaudek i. is there more than one road to nevus-associated melanoma? dermatol pract concept. 2020;10(2):e2020028. doi: https://doi.org/10.5826/ dpc.1002a28. correction https://doi.org/10.5826/dpc _goback dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022107 1 inflammatory vitiligo hua-ching chang1,2, chun-yu lai1, yin-shuo chang1 1 department of dermatology, taipei medical university hospital, taipei, taiwan 2 department of dermatology, school of medicine, college of medicine, taipei medical university, taipei, taiwan citation: chang hc, lai cy, chang ys. inflammatory vitiligo. dermatol pract concept. 2022;12(3):e2022107. doi: https://doi.org/10.5826/dpc.1203a107 accepted: october 29, 2021; published: july 2022 copyright: ©2022 chang et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: yin-shuo chang, md, department of dermatology, taipei medical university hospital, address: no. 252, wuxing st, xinyi district, taipei city, 110, taiwan tel: 886-2-27372181 ext 8285 e-mail: ckshuo@gmail.com case presentation a 65-year-old man presented with multiple asymptomatic depigmented patches of varying sizes with an erythematous annular border over the upper back and shoulders for one week (figure 1a). histopathology from the border of one lesion revealed vacuolar interface changes and moderate perivascular lymphocytes with pigment incontinence in the superficial dermis. sox10 staining revealed a reduction in epidermal melanocytes (figure 1b). these findings were consistent with inflammatory vitiligo. after 2 weeks of 40 mg/day of oral prednisolone with a tapering dosage, the erythematous border had almost disappeared. teaching point the patterns of active and progressive vitiligo include inflammatory vitiligo, koebner phenomenon, trichrome lesions, and confetti-like depigmentation. inflammatory vitiligo is rare and characterized by erythema, scales, and pruritus at the border. although the inflammatory phase is usually transient, it can cause rapid depigmentation [1]. oral steroids are frequently used to stabilize rapidly progressive vitiligo, and ultraviolet phototherapy is another suitable treatment [2]. 2 image letter | dermatol pract concept. 2022;12(3):e2022107 references 1. rodrigues m, ezzedine k, hamzavi i, pandya ag, harris je. new discoveries in the pathogenesis and classification of vitiligo. j am acad dermatol. 2017;77(1):1-13. doi: 10.1016 /j.jaad.2016.10.048. pmid: 28619550. 2. rodrigues m, ezzedine k, hamzavi i, pandya ag, harris je. current and emerging treatments for vitiligo. j am acad dermatol. 2017;77(1):17-29. doi: 10.1016/j.jaad.2016.11.010. pmid: 28619557. figure 1. (a) multiple asymptomatic depigmented patches with erythematous annular border over the upper back and bilateral shoulders. (b) pathology with immunohistochemistry with sox10 (100x): the right half of the figure from the erythematous border of the skin lesion shows the relatively normal distribution of epidermal melanocytes compared with reduced epidermal melanocytes in the left half of the figure from the depigmented area of the skin lesion. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021048 1 dermoscopic features of mycosis fungoides and its variants in patients with skin of color: a retrospective analysis mio nakamura1, tomas huerta1, kendrick williams2 alexandra c. hristov1,3, trilokraj tejasvi1,4 1 department of dermatology, university of michigan, ann arbor, michigan, usa 2 university of michigan medical school, ann arbor, michigan, usa 3 department of pathology, university of michigan, ann arbor, michigan, usa 4 ann arbor veterans health center, ann arbor, michigan, usa key words: cutaneous t-cell lymphoma, mycosis fungoides, dermoscopy, skin of color citation: nakamura m, huerta t, williams k, hristov ac, tejasvi t. dermoscopic features of mycosis fungoides and its variants in patients with skin of color: a retrospective analysis. dermatol pract concept. 2021;11(3):e2021048. doi: https://doi.org/10.5826/dpc.1103a48 accepted: december 2, 2020; published: may 20, 2021 copyright: ©2021 nakamura et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: trilokraj tejasvi, md, department of dermatology, university of michigan, 1910 taubman center, 1500 e. medical center dr., ann arbor, mi 48109, usa. email: ttejasvi@med.umich.edu background: mycosis fungoides (mf) is a cutaneous t-cell lymphoma that disproportionately affects people with skin of color and is difficult to diagnose. objective: this study characterized the dermoscopic features of mf and its subtypes in patients with skin of color. methods: dermoscopic images of patients with skin of color seen at the cutaneous t-cell lymphoma clinic at michigan medicine dermatology between 2018 and 2019 were reviewed. specific dermoscopic features were identified and summarized for each subtype of mf. results: a total of 33 dermoscopic images from 11 patients with skin of color were reviewed. four patients had classic mf (18 dermoscopic images), 4 had hypopigmented mf (9 dermoscopic images), 1 had folliculotropic mf (4 dermoscopic images), and 2 had verrucous mf (2 dermoscopic images). classic mf was characterized by striking pigmentary change, thick black lines, white rosettes, and geometric white lines. hypopigmented mf was characterized by the loss of the patient’s natural pigment network. in folliculotropic mf, follicular plugging and hyperpigmented to violaceous perifollicular halos were observed. in verrucous mf, large, yellow-gray amorphous structures with yellow-gray ridges and comedo-like openings were observed within hyperkeratotic areas. overall, vessel morphology was difficult to discern on dermoscopy. conclusions: dermoscopic features of mf in patients with skin of color are predominantly characabstract 2 research | dermatol pract concept. 2021;11(3):e2021048 introduction mycosis fungoides (mf) is the most prevalent type of cutaneous t-cell lymphoma (ctcl) [1]. it disproportionately affects people with skin of color (soc), who have worse outcomes [2-4]. the hallmark of classic mf in soc patients is the presence of polychromatic patches and plaques, with hypoand hyperpigmentation and erythema. there are several subtypes of mf, including hypopigmented, folliculotropic, and verrucous mf [5]. early stage mf can clinically resemble dermatoses such as psoriasis and atopic dermatitis, which may lead to a delay in diagnosis. dermoscopy can be used to distinguish mf from such entities. studies have described dermoscopic features of early stage mf, including fine, short, linear vessels and orange-yellow patchy areas [6-8]. a limited number of studies have described dermoscopy findings of folliculotropic mf, including “perifollicular erythema surrounding comedo-like lesions, white structureless areas replacing lost hair follicles, and fine short linear, glomerular, and dotted vessels” [9,10]. dermoscopic features of the other subtypes of mf are not well described. furthermore, no studies to date have described dermoscopic features of mf specifically in soc patients. in this study, we characterized the dermoscopic features of mf and its subtypes in soc patients. we hypothesized that the dermoscopic features of mf in soc patients are unique due to the greater presence of the chromophore melanin. in soc, melanosomes are larger, more abundant throughout the epidermis, and singly dispersed from melanocytes to keratinocytes. the keratinocyte layers are also thicker in soc than in lighter skin. these differences pose a challenge to appreciating vessel patterns in skin lesions of soc patients. methods this was a single-center, retrospective review of dermoscopic images obtained from patients presenting to the ctcl clinic at michigan medicine dermatology between 2018 and 2019. images of all patients with soc (fitzpatrick skin type iv-vi) who gave verbal consent to have dermoscopic images obtained were included. each dermoscopic image was retrospectively and independently reviewed by four of the authors (mn, th, kw, and tt), and specific dermoscopic features were identified. any discrepancies were resolved by discussion. skin biopsy slides for histopathologic correlation were reviewed for selected cases. this study was deemed exempt from the need to obtain the patients’ informed consent by the university of michigan institutional review board (hum00155110). results the study included a total of 33 dermoscopic images from 11 soc patients. four patients had classic mf (18 dermoscopic images), 4 had hypopigmented mf (9 dermoscopic images), 1 had folliculotropic mf (4 dermoscopic images), and 2 had verrucous mf (2 dermoscopic images). classic mf (figure 1a) was characterized dermoscopically by striking pigmentary changes, including the formation of pseudonetworks made up of dark brown to gray or black clods and dots. there were thick black lines overlying erythematous to whitish pink, structureless zones, interrupted by prominent eccrine duct openings and white rosettes (figure 1b). geometric white lines (figure 1b) were also seen. histopathologically, an atypical, epidermotropic t-cell infiltrate with a band-like distribution in the superficial dermis and pigment incontinence were observed (figure 1c). hypopigmented mf (figure 2a) was characterized by patchy, amorphous, white-pink areas with reduction or loss of the patient’s natural pigment network (figure 2b). analysis of biopsy specimens demonstrated an atypical lymphoid infiltrate tagging the dermal-epidermal junction, showing some upward migration in the epidermis, and forming a band-like infiltrate in the dermis. these atypical lymphoid cells expressed cd8 (figure 2c). in folliculotropic mf, dermoscopy showed follicular plugging, perifollicular scale, and hyperpigmented to violaceous perifollicular halos (figure 3a). on histopathological analysis, a band-like lymphoid infiltrate in the superficial dermis and intrafollicular atypical t-cells were observed (figure 3b). in verrucous mf, large, multicolored amorphous structures with yellow-gray ridges and comedo-like openings mimicking seborrheic keratosis were observed within hyperkeratotic areas (figure 4a). histological analysis showed marked epidermal hyperplasia and hyperkeratosis with an associated epidermotropic, atypical t-cell infiltrate and pautrier microabscesses (figure 4b). vessel morphology was difficult to discern on dermoscopy, and the pigmentary alterations described above predominated. histopathologically, vessels in the upper dermis were obscured by the heavy, atypical lymphocytic infiltrate and pigment incontinence. terized by striking pigmentary alteration. vessel morphology is not a reliable diagnostic feature. as patients with mf and skin of color have a worse prognosis than light-skinned individuals, a better understanding of dermoscopic features may aid in early diagnosis and improve outcomes in this group. research | dermatol pract concept. 2021;11(3):e2021048 3 figure 1. (a) classic mf was characterized by (b) striking pigmentary change, including a pseudonetwork of brown-gray clods and dots, as well as thick black lines and geometric white lines (yellow arrows) surrounding structureless zones interrupted by prominent eccrine duct openings and white rosettes (yellow circles). (c) histological analysis revealed an atypical, epidermotropic t-cell infiltrate with a band-like distribution in the superficial dermis and pigment incontinence (h&e, ×200). figure 3. folliculotropic mf was characterized by (a) follicular plugging (yellow arrows), perifollicular scale, and hyperpigmented to violaceous perifollicular halos (red circles). (b) histological analysis demonstrated a band-like lymphoid infiltrate in the superficial dermis and intrafollicular atypical t-cells (h&e, ×100). figure 2. (a) hypopigmented mf was characterized by (b) patchy, amorphous white-pink areas and loss of the patient’s natural pigment network (outlined by red arrows). (c) histological analysis demonstrated an atypical lymphoid infiltrate that tagged the dermal-epidermal junction, showed some upward migration in the epidermis, and formed a band-like infiltrate in the dermis. these atypical lymphoid cells expressed cd8 (×400). 4 research | dermatol pract concept. 2021;11(3):e2021048 discussion mf, especially early stage mf, can be difficult to diagnose; the median time from symptom onset to diagnosis is 4-6 years [11-13]. although the overall prognosis of early stage mf is favorable, with a median survival of more than 20 years, african-american patients with mf have poorer survival than white patients, even after accounting for disease characteristics, socioeconomic factors, and types of treatment; this finding suggests that there are underlying differences in the biology of the disease between patients with soc and light skin [14]. although only a few, small-scale studies have tested dermoscopy in the diagnosis of mf, it seems that dermoscopy can improve the diagnostic accuracy of classic mf [15]. vessel morphology such as spermatozoa-like, fine, short linear vessels were found more often in mf than in inflammatory dermatoses such as psoriasis and dermatitis, which commonly display dotted vessels [6]. however, previous studies have only described dermoscopic features in light skin. in soc, vessel morphology is difficult to distinguish due to the greater number of melanosomes and other properties that prevent the dermoscope’s light from penetrating past the basal epidermal layer. this study characterized dermoscopic features of mf in soc patients, and confirmed that vessel morphology is often unable to be appreciated. this was reflected by the histopathologic findings of vessels obscured by the heavy lymphoid infiltrate along with notable pigment incontinence in the upper dermis. instead, mf in soc is characterized by striking pigmentary alteration. in classic mf, a pigment pseudonetwork consisting of brown-gray clods and dots was present. thick black lines surrounding structureless areas with rosettes and geometric white lines were also prominent. superposition of these changes resulted in foci reminiscent of the blue-white veil often described in dermoscopy of melanoma. these features should help one differentiate mf from other papulosquamous disorders. psoriasis in soc exhibits dotted vessels under dermoscopy, perhaps due to a thinning of the suprapapillary plates [7]. irregularly distributed vessels with brown-gray clods are seen in acute eczema [6]. hypopigmented mf is characterized by loss of the patient’s natural pigment network. although the cause of hypopigmentation is not known, it is thought to be due to the infiltration of cd8+ cytotoxic t-cells, which damage the melanocytes; this phenomenon has also been described in inflammatory vitiligo [16]. the hypopigmentation in vitiligo under dermoscopy demonstrates a well-defined border, satellite areas, micro-koebner phenomena and leucotrichia [17]. clinically, the differential diagnosis includes nevus depigmentosus and idiopathic guttate hypomelanosis. in the former, the dermoscopy features include retention of the pigment network within the hypopigmented area, while in the latter, a well-defined hypopigmented clod with an accentuated pigment network in the periphery can be appreciated. these features may help discern these benign conditions from hypopigmented mf. folliculotropic mf was characterized by follicular plugging along with perifollicular hyperpigmentation; the latter feature has not been described in light-skinned individuals. this study figure 4. verrucous mf was characterized by (a) large, multicolored amorphous structures with yellow-gray ridges (red arrows) and comedo-like openings (yellow arrows). (b) histological analysis showed marked epidermal hyperplasia and hyperkeratosis with an associated epidermotropic, atypical t-cell infiltrate and pautrier microbascesses (h&e, ×40). research | dermatol pract concept. 2021;11(3):e2021048 5 also highlights the first dermoscopic description of verrucous mf in soc: multicolored amorphous structures with yellow-gray ridges and comedo-like openings mimicking seborrheic keratoses were observed within hyperkeratotic areas. this study is limited by its single-center, retrospective nature and small sample size. larger studies are needed to better delineate dermoscopic features of mf in soc patients. however, this is the first report to date to describe dermoscopic features of mf and its variants in soc. conclusions mf in soc patients is distinct from mf in patients with light skin, and it is characterized by striking pigmentary changes. dermoscopic features such as rosettes and geometric white lines are unique to mf in soc patients, while vessel morphology is not a reliable diagnostic feature. given that soc patients with mf have worse prognosis than lightskinned individuals, a better understanding of the dermoscopic features may aid in early diagnosis and potentially improve outcomes in this group. references 1. bradford pt, devesa ss, anderson wf, toro jr. cutaneous lymphoma incidence patterns in the united states: a population-based study of 3884 cases. blood. 2009;113(21):5064-5073. doi: 10.1182/blood-2008-10-184168. pmid: 19279331. 2. weinstock ma, gardstein b. twenty-year trends in the reported incidence of mycosis fungoides and associated mortality. am j public health. 1999;89(8):1240-1244. doi: 10.2105/ ajph.89.8.1240. pmid: 10432915. 3. nath sk, james by, wilson ld. poorer prognosis of african-american patients with mycosis fungoides: an analysis of the seer dataset, 1988 to 2008. clin lymphoma myeloma leuk. 2014;14(5):419-423. doi: 10.1016/j.clml.2013.12.018. pmid: 24508350. 4. hinds ga, heald p. cutaneous t-cell lymphoma in skin of color. j am acad dermatol. 2009;60(3):359-375; quiz 376-8. doi: 10.1016/j.jaad.2008.10.031. doi: 10.1016/j.jaad.2008.10.031. pmid: 19231637. 5. lambroza e, cohen sr, phelps r, et al. hypopigmented variant of mycosis fungoides: demography, histopathology, and treatment of seven cases. j am acad dermatol. 1995;32:987-993. doi: 10.1016/0190-9622(95)91337-8. pmid: 7751470. 6. lallas a, apalla z, lefaki i, et al. dermoscopy of early stage mycosis fungoides. j eur acad dermatol venereol. 2013;27:617-621. doi: 10.1111/j.1468-3083.2012.04499.x. pmid: 22404051. 7. ozturk mk, zindancı i, zemheri e. dermoscopy of stage iia mycosis fungoides. north clin istanb. 2019;7(2):174-179. doi: 10.14744/nci.2019.02439. pmid: 32259040. 8. piccolo v, russo t, agozzino m, et al. dermoscopy of cutaneous lymphoproliferative disorders: where are we now? dermatology. 2018;234(3-4):131-136. doi: 10.1159/000490412. pmid: 30032152. 9. caccavale s, vitiello p, franco r, et al. dermoscopic characterization of folliculotropic mycosis fungoides selectively localized on trunk and limbs. int j dermatol. 2019;58(10):e187-e189. doi: 10.1111/ijd.14490. pmid: 31135956. 10. toncic rj, drvar dl, bradamante m, et al. early dermoscopic sign of folliculotropism in patients with mycosis fungoides. dermatol pract concept. 2018;8(4):328-329. doi: 10.5826/ dpc.0804a17. pmid: 30479867. 11. van doorn r, van haselen cw, van voorst vader pc, et al. mycosis fungoides: disease evolution and prognosis of 309 dutch patients. arch dermatol. 2000;136:504-510. doi: 10.1001/ archderm.136.4.504. pmid: 10768649. 12. skov ag, gniadecki r. delay in the histopathological diagnosis of mycosis fungoides. acta derm venereol. 2015;95(4):472-475. doi: 10.2340/00015555-1971. pmid: 25228392 13. eklund y, aronsson a, schmidtchen a, relander t. mycosis fungoides: a retrospective study of 44 swedish cases. acta derm venereol. 2016;96(5):669-673. doi: 10.2340/00015555-2337. pmid: 26778803. 14. su c, nguyen ka, bai hx, et al. racial disparity in mycosis fungoides: an analysis of 4495 cases from the us national cancer database. j am acad dermatol. 2017;77(3):497-502.e2. doi: 10.1016/j.jaad.2017.04.1137. pmid: 28645647. 15. bombonato c, pampena r, lallas a, giovanni p, longo c. dermoscopy of lymphomas and pseudolymphomas. dermatol clin. 2018;36(4):377-388. doi: 10.1016/j.det.2018.05.005. pmid: 30201147. 16. furlan fc, sanches ja. hypopigmented mycosis fungoides: a review of its clinical features and pathophysiology. an bras dermatol. 2013;88(6):954-960. doi: 10.1590/abd18064841.20132336. pmid: 24474105. 17. chatterjee m, neema s. dermoscopy of pigmentary disorders in brown skin. dermatol clin. 2018;36(4):473-485. doi: 10.1016/j. det.2018.05.014. pmid: 30201156. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):4 19 dermatology practical & conceptual www.derm101.com introduction pityriasis rubra pilaris (prp) is a chronic disorder of keratinization of unclear pathogenesis [1]. it typically manifests as erythematous and scaly cutaneous plaques with islands of spared skin associated with follicular scaly papules and orange palmar and plantar keratoderma. although prp is usually idiopathic, certain trigger events have occasionally been reported, mainly traumatic, infectious (infections of streptococcus, cytomegalovirus and rubella) or after vaccination [2]. however, prp-like eruptions induced by drugs have been described, albeit rarely [3-5]. we report a case of prp-like eruption that occurred during the initiation of insulin therapy. to our knowledge, no previous similar cases have been reported. case report a 29-year-old man was referred to our department because of a generalized erythematosquamous and non-pruritic derpityriasis rubra pilaris-like eruption following insulin therapy initiation talel badri1, anissa zaouak1, ghozlane lakhoua2, wafaa koubaa3, sami fennich1, ahmed zaiem2 1 department of dermatology, habib thameur hospital, faculty of medicine, university of tunis el manar, tunisia 2 national center of pharmacovigilance, faculty of medicine, university of tunis el manar, tunisia 3 laboratory of pathology, habib thameur hospital, faculty of medicine, university of tunis el manar, tunisia key words: pityriasis rubra pilaris, insulin, drug-induced, cutaneous rash, skin citation: badri t, zaouak a, lakhoua g, koubaa w, fennich s, zaiem a. pityriasis rubra pilaris-like eruption following insulin therapy initiation. dermatol pract concept 2016;6(4):4. doi: 10.5826/dpc.0604a04 received: may 31, 2016; accepted: july 30, 2016; published: october 31, 2016 copyright: ©2016 badri et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: talel badri, md, department of dermatology, habib thameur hospital, 8 rue ali ben ayed, 1008 tunis, tunisia. tel. +216.98.829.300. email: talel_badri@yahoo.fr pityriasis rubra pilaris (prp) is a chronic disorder of keratinization of unclear pathogenesis. prp-like eruptions induced by drugs have rarely been described. a previously healthy 29-year-old man presented with a generalized, rapidly spreading, erythematosquamous dermatosis, that started three days after initiation of subcutaneous insulin therapy for diabetes mellitus type 1. clinical and histopathological features were consistent with a prp-like eruption, possibly due to insulin therapy. the patient was switched to insulin analogue therapy and a complete healing of all lesions was achieved after two months. no recurrence was seen after one year of follow-up. other possible etiologies of prp were excluded. the mechanism leading to the occurrence of drug-induced prp-like eruptions are not clear. since prp may occur in the context of immunological anomalies, it is possible that diabetes mellitus type 1 may have been a predisposing condition for the development of prp in this case. abstract mailto:talel_badri@yahoo.fr 20 observation | dermatol pract concept 2016;6(4):4 histopathology a skin biopsy was performed, and histopathological examination revealed irregular hyperkeratosis with orthokeratosis and parakeratosis in addition to dilated hair follicles and keratinous plugs (figure 3). diagnosis and outcome a diagnosis of a prp-like eruption, possibly induced by insulin therapy, was suspected. insulatard® and actrapid® were discontinued and the patient was switched to insulin analogue therapy: glargine (lantus®) and glulisine (apidra®). skin lesions were treated with betamethasone ointment (30 g daily) and petrolatum. a progressive resolution of the rash was obtained and complete healing of all cutaneous lesions was achieved after two months. skin tests (patch test and intradermal test) with insulin and its additives were considered but the patient refused them. no recurrence of skin lesions was seen after one year of follow-up. discussion the acute onset of the dermatosis after insulin therapy initiation, the rapid favorable outcome after human insulin withdrawal, as well as the absence of recurrence after one year of follow-up, were suggestive of a possible responsibility of insulin therapy for the genesis of the prp-like eruption in our patient. although possible, a fortuitous association “insulin therapy—idiopathic prp” seems unlikely in our case because of the rapid resolution of the rash, as opposed to the classical chronic course of idiopathic prp, even with the use of systemic treatments, such as retinoids [1]. drug-induced prp-like eruptions are rare, and the mechanisms leading to their occurrence have not been clearly elumatosis that had rapidly spread during the previous week. it had started three days after initiation of insulatard® ([neutral protamine hagedorn insulin]: 12 iu in the morning; 8 iu in the evening) and actrapid® ([soluble regular insulin]: 4 iu b.i.d.) for a recently diagnosed diabetes mellitus type 1. the patient’s past medical history showed neither personal nor familial previous episodes of papulosquamous disorders. no other medical condition or concomitant medication intake were noticed. the patient had not received any vaccination during the previous five years and he denied any trauma. cutaneous examination revealed large areas of erythematous orange scaly plaques with small islands of uninvolved skin, as well as follicular keratotic papules. these lesions were located on the trunk (figure 1) and limbs. the patient also had an orange-red waxy keratoderma on his palms and soles with some fissures (figure. 2). no nail changes and no mucous membrane involvement were observed. there was no other organ or systemic involvement. figure 1. erythematous scaly papules coalescent into large plaques on the trunk. [copyright: ©2016 badri et al.] figure 2. bilateral orange-red waxy keratoderma. [copyright: ©2016 badri et al.] figure 3. irregular hyperkeratosis with alternating orthokeratosis and parakeratosis and corneal plugs characteristic of pityriasis rubra pilaris (hematoxylin-eosin x100). [copyright: ©2016 badri et al.] observation | dermatol pract concept 2016;6(4):4 21 references 1. gemmeke a, schönlebe j, koch a, wollina u. pityriasis rubra pilaris—a retrospective single center analysis over eight years. j dtsch dermatol ges 2010;8(6):439-44. pmid: 15982236. 2. naciri bennani b, cheikh rouhou h, waton j, et al. pityriasis rubra pilaire après vaccination. ann dermatol venereol 2011;138(11):753-6. pmid: 22078037. doi: 10.1016/j. annder.2011.01.049. 3. paz c, querfeld c, sbea cr. sorafenib-induced eruption resembling pityriasis rubra pilaris. j am acad dermatol 2011;65(2):4523. pmid: 21763585. doi: 10.1016/j.jaad.2010.03.015. 4. plana a, carrascosa jm, villavella m, ferrandiz c. pityriasis rubra pilaris-like reaction induced by imatinib. clin exp dermatol 2013;38(5):520-2. pmid: 23777493. doi: 10.1111/ced.12081. 5. schmutz jl, trechot p. telaprevir-induced pityriasis rubra pilarislike drug eruption. arch dermatol 2012; 148(10):1215-7. pmid: 23069976. doi: 10.1001/archdermatol.2012.2039. 6. feinglos mn, jegasothy bv. “insulin” allergy due to zinc. lancet 1979;1(8108):122-4. pmid: 84149. 7. raap u, liekenbrocker t, kapp a, wedi b. delayed-type hypersensitivity to protamine as a complication of insulin therapy. contact dermatitis 2005;53(1):57-8. pmid: 15982236. cidated [2-5]. the pathogenesis in our patient is also unclear. although insulin therapy is largely used worldwide, its association with prp-like eruptions has never been reported. however, since prp may occur in certain cases with underlying immunological anomalies [2], it is possible that diabetes mellitus type 1 might have contributed to the development of the dermatosis in our patient, after insulin therapy initiation. insulin preparations containing zinc or protamine (such as insulatard®) may also cause a delayed-type hypersensitivity [6,7]. however, in the absence of skin tests, the role of such additives in the genesis of the dermatosis in our patient could not be determined. conclusion although a fortuitous association could not totally be ruled out, a cutaneous reaction induced by insulin therapy in a context of underlying immunological anomalies might be the cause of the dermatosis in our patient. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022016 1 large congenital melanocytic nevus with halo phenomenon filiz cebeci1, hasan aksoy1, zeynep arslan1, bengü çobanoğlu şimşek2 1 department of dermatology, istanbul medeniyet university, goztepe suleyman yalcin city hospital, istanbul, turkey 2 department of pathology, istanbul medeniyet university, goztepe suleyman yalcin city hospital, istanbul, turkey key words: congenital melanocytic nevus, halo phenomenon citation: cebeci f, aksoy h, arslan z, şimşek bc. large congenital melanocytic nevus with halo phenomenon. dermatol pract concept. 2022;12(1):e2022016. doi: https://doi.org/10.5826/dpc.1201a16 accepted: may 8, 2021; published: january 2022 copyright: ©2022 cebeci et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: filiz cebeci assoc. prof, department of dermatology, istanbul medeniyet university, goztepe suleyman yalcin city hospital, istanbul, turkey. email: e-mail:cebecifiliz@yahoo.com introduction congenital melanocytic nevus (cmn) is a pigmented lesion present at birth or appearing in the first few weeks of life, with an incidence of 0.6%-1.6% among newborns. it develops from neural crest-derived melanocytes and usually enlarges throughout childhood. a cmn  may  remain unchanged or present a  dynamic course [1,2]. halo nevus or leukoderma acquisitum centrifugum can be defined by the presence of circular depigmentation around an acquired or congenital nevus; a halo can also develop around a melanoma. herein, we report a male adolescent with halo phenomenon around a large cmn, an uncommon finding. case presentation a 14-year-old boy was admitted to our department due to complaint of enlargement and color change of a nevus on his right shin. the lesion had been present since birth and has grown over the years; during the past year, whitening of the skin was noted to develop around it. on physical examination, there was a 12 cm × 5.5 cm ellipsoid pigmented patch containing irregularly mottled hypopigmentation and few depigmented terminal hairs, surrounded by a 0.5-cm wide depigmented halo-like patch (figure 1a). dermoscopy showed regular network and globules, suggesting that the pigmented patch was melanocytic in origin (figure 1b). the lesion was biopsied and histopathology revealed hypermelanosis at the basal cell layer, nests of nevomelanocytes in the dermis and periadnexial lymphocytic infiltration; in the areas corresponding to the depigmented part of the lesion, epidermal melanin and dermal nevus cells were notably absent (figure 2, a-d). based on the clinical and histopathological findings, the diagnosis was a large cmn with a halo phenomenon. conclusions a halo phenomenon around a nevus has been suggested to be due to immunologic responses against melanocytes mediated 2 research letter | dermatol pract concept. 2022;12(1):e2022016 figure 1. (a) melanocytic patch with irregularly mottled hypopigmentation, depigmented terminal hairs, and a depigmented halo. (b) regular network, a few pigmented globules, and depigmented areas on dermoscopy. figure 2. histopathology of the lesion. (a) intradermal nevoid nests consistent with congenital melanocytic nevus. (b) hypermelanosis in the epidermal basal cell layer corresponding to the hyperpigmented area. (c) loss of epidermal melanin and dermal nevomelanocytes corresponding to the depigmented part of the lesion (h&e, ×200). (d) loss of melanin in the basal cell layer (masson-fontana, ×400). research letter | dermatol pract concept. 2022;12(1):e2022016 3 by cytotoxic t-cells or immunoglobulin m autoantibodies [2]. unlike acquired nevi, the development of halo around a large congenital nevus is less common. halo around cmn may also be accompanied by vitiligo. a cmn with a halo may eventuate in partial or complete regression of the pigmented lesion with progressive depigmentation, remain stable, or undergo repigmentation. spontaneous involution of a cmn  is  uncommon [1,2]. halo phenomenon around a cmn usually causes anxiety and may result in unnecessary surgical procedures. however, it is usually a benign condition and cmn patients with halo phenomenon should be followed up periodically, just as those with cmn without a halo phenomenon. it is suggested that a conservative approach and dermoscopic follow-up are safe for children with a cmn. development of depigmentation around or within the cmn may be confused with pigmentary regression and conversion to malignant melanoma, and thus it is important to be aware of this phenomenon to avoid premature surgery, especially in children. informed consent: informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. karvonen sl, vaajalahti p, marenk m, janas m, kuokkanen k. birthmarks in 4346 finnish newborns. acta derm venereol. 1992;72(1):55-57. pmid: 1350148. 2. lee nr, chung hc, hong h, lee jw, ahn sk. spontaneous involution of congenital melanocytic nevus with halo phenomenon. am j dermatopathol. 2015;37(12):e137-e139. doi: 10.1097/dad.0000000000000311. pmid: 26588343. pmcid: pmc4894811. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022124 1 dermatology practical & conceptual evaluation of diagnostic accuracy and therapeutic approach of dermatologists and plastic surgeons to non-melanocytic skin lesions by using telemedicine burcu tugrul1, basak yalici-armagan2, hatice gamze demirdag3, ozge gunduz4 1. ankara city hospital, department of dermatology, ankara, turkey. 2. hacettepe univercity, faculty of medicine, department of dermatology, ankara, turkey. 3. private practice, hatice gamze demirdag dermatology clinic, ankara, turkey. 4. midnorth coast dermatology, 31 wyandra crescent port macquarie 2444 nsw, australia. key words: telemedicine, teledermatology, teledermoscopy, non-melanocytic skin lesion, diagnostic accuracy citation: tugrul b, yalici-armagan b, demirdag hg, gunduz o. evaluation of diagnostic accuracy and therapeutic approach of dermatologists and plastic surgeons to non-melanocytic skin lesions by using telemedicine. dermatol pract concept. 2022;12(3):e2022124. doi: https://doi.org/10.5826/dpc.1203a124 accepted: november 1, 2021; published: july 2022 copyright: ©2022 tugrul et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: burcu tugrul, md, ankara city hospital, department of dermatology, bilkent, çankaya, 06800, ankara, turkey, e-mail address: burcutugrul@yahoo.com introduction: in the new circumstances of coronavirus disease 2019 pandemic, tele-dermatology and tele-dermoscopy have become more important in daily practice for departments for which visuality is at the forefront as dermatology and plastic and reconstructive surgery. objectives: this study was aimed to determine diagnostic accuracy and treatment approaches of non-melanocytic skin lesions between 2 clinics by store and forward tele-dermatology method and to evaluate the contribution of tele-dermoscopy to the diagnostic accuracy for dermatologists. methods: a total of 26 patients with non-melanocytic skin lesions were included in the study. clinical images of the lesions were sent by email to 3 plastic surgeons and 3 dermatologists. the accuracy of the diagnoses was evaluated by comparing tele-dermatology with histopathology. diagnosis and treatment approaches were recorded for both clinics. dermatologists also defined their diagnosis with tele-dermoscopic images. results: the mean percentage of diagnostic accuracy among dermatologists was 74.3% and among plastic surgeons was 61.5%. there was no significant difference in diagnostic accuracy between departments (p = 0.625). there was a statistically significant difference between the departments for diagnostic and treatment approaches (p values respectively p = 0.002, p < 0.001). plastic surgeons preferred to confirm their pre-diagnosis histopathologically more than dermatologists. plastic surgeons recommended abstract 2 original article | dermatol pract concept. 2022;12(3):e2022124 introduction telemedicine (tm), defined as practicing medicine at a distance, has grown in popularity over the past ten years [1]. as social distancing becoming the new standard in the era of coronavirus disease 2019 (covid-19) pandemic, tm emerges as a key tool in medicine. it can be performed with live interaction technology via videoconferencing equipment or with store-and-forward methods via transmitting digital images or photographs of the lesions with patient clinical history [2,3]. tm has a particular value in specialties which have a strong visual aspect, such as dermatology and plastic and reconstructive surgery (prs) [4]. tm applications among plastic surgeons was observed particularly in the management of various conditions such as acute trauma, burns, and postoperative monitoring [5-8]. tele-dermatology (td) has been used since 1995 as an example of tm [9]. td is a useful alternative where specialized dermatological assistance is not available and has been used successfully to support health professionals worldwide, in either an asynchronous store-andforward format or a real-time video conferencing format [10]. the majority of td studies were related to skin cancers in the literature [11-14]. dermoscopy is a non-invasive tool for originally developed for diagnosing and detecting skin cancer. it has been shown that dermoscopy can be used in the diagnosis of pigmented and non-pigmented skin lesions over time. tele-dermoscopy (tds) is a currently defined method that aims to increase diagnostic accuracy by adding dermoscopic images to td [15]. most of the research with tds focuses on melanocytic skin lesions including melanoma and melanocytic nevus. there have been only a few reports with td and tds to diagnose non-melanocytic skin lesions (nmsls) [2,11,15]. face to face (ftf) comparisons of diagnostic accuracy and therapeutic approaches between dermatologists and plastic surgeons have controversial results [16-18]. to the best of our knowledge there is no study in english-language literature comparing the diagnostic accuracy and differences in treatment approach for nmsls between dermatology and prs departments by using td. objectives the aim of this study was to evaluate diagnostic accuracy rates and treatment approaches of dermatologists and plastic surgeons in nmsls by using tm and the contribution of the tds method to the diagnostic accuracy of dermatologists. methods patients who applied to the dermatology unit of a tertiary oncology hospital in turkey and were performed a diagnostic skin biopsy between april 2018 and march 2019 were included in the study. patients who were under 18 years old, pregnant and not volunteers were not involved. informed consent was taken from each patient and the protocol was approved by a local research and ethics review committee. lesions of the patients were examined and recorded by the same dermatologist (bt) who took clinical and dermoscopic pictures of the lesions by using her same mobile phone (iphone 7s, apple inc) and dermoscopy device with connection kit (dermlite dl3n, 3gen inc). lesions with clinical and dermatoscopic photographs which required histopathologic examination for differential diagnosis were included in the study. histopathologic examination was accepted as gold standard for diagnostic accuracy in the present study. age, gender, duration and localization of the lesions, clinical and histopathological diagnoses, clinical and dermoscopic images were recorded. the evaluation was performed using td with saf method. clinical images and a brief clinical history were sent by email to 6 physicians, namely 3 plastic surgeons and 3 dermatologists. each physician was 8 to 15 years experienced within his/her specialty. all dermatologists had completed a dermoscopy course before the study. physicians were asked to record their clinical diagnosis, which was then compared with the histopathological diagnosis. it was also questioned whether they need to confirm the diagnosis with histopathology and which treatment approaches such as excision, cryotherapy, electrotherapy or laser therapy would prefer. excision was classified as a surgical procedure while other procedure were non-surgical ones. plastic surgeons were asked if they request a dermatology consultation before treatment decision. accuracy was defined as the ability of a test to determine disease correctly by comparison with a reference/gold standard [11]. the accuracy of td for diagnosis was established by comparison with histopathological examination. physicians were asked to record their clinical diagnoses after the evaluation of the pictures and clinical information, and then clinical diagnoses were compared with the histological surgical procedures for 25 lesions (96.2%) while dermatologists for 14 (53.8%) ones. tele-dermoscopy increased the rate of diagnostic accuracy of dermatologists from 74.3% to 82.0% (p = 0.02). conclusions: tele-dermatology is an effective method for non-melanocytic skin lesions with high diagnostic accuracy. adding dermoscopy to tele-dermatology increases diagnostic accuracy of dermatologists on non-melanocytic skin lesions. original article | dermatol pract concept. 2022;12(3):e2022124 3 diagnoses. td diagnoses were accepted as correct if they were same with the histopathological diagnoses. the percentage of correct diagnosis was defined as the accuracy of td. in order to determine the diagnostic accuracy between departments, at least two out of three physicians from the same department were required to make the correct diagnosis. dermatologists were asked if they requested to evaluate dermoscopic images of the lesions to confirm their clinical diagnosis made by td. regardless of the answer, to determine the effect of tds on the diagnosis, dermatologists evaluated tele-dermoscopic images of all lesions after clinical images and were asked to make a diagnosis, too. statistical analyses were performed with the ibm spss for windows version 23.0. numerical variables were summarized as mean ± standard deviation or median (minimum-maximum). categorical variables were given as frequencies and percentages. categorical variables were compared by chi square or fisher exact test. diagnostic accuracy of the physicians were compared by mcnemar or cochran q test as appropriate. a p value less than 0.05 was considered as significant. results the clinical characteristics of patients and duration, localization, and the histopathological diagnoses of lesions are summarized in table 1. according to the diagnostic accuracy, there was no statistically significant difference within the physicians of the same department. the p value for dermatologists was 0.41 and for plastic surgeons was 0.07. the percentages of physicians diagnostic accuracy in the same department were demonstrated on figure 1. the average percentage of diagnostic accuracy among dermatologists was 74.3% and among plastic surgeons was 61.5%. there was not statistically difference in diagnostic accuracy between departments (p = 0.625). table 1. clinical characteristics of patients, features and histopathologic diagnoses of lesions clinical characteristics n (%) age, years median (min-max) 47 (18-83) gender, n (%) male female 13 (50) 13 (50) duration of lesions since childhood 3 (11.5) <1 month 3 (11.5) <1 year 5 (19) 1-5 years 6 (23) >5 years 9 (35) localization of lesions scalp 13 (50) face 1 (3.8) upper extremity 4 (15.4) lower extremity 1 (3.8) torso 7 (27) the histopathologic diagnoses seborrheic keratosis 3 verruca vulgaris 2 epidermal cyst 2 dermatofibroma 3 fibroma 3 sebaceous adenoma 1 bowen disease 1 bcc 3 scc 3 min = minimum; max = maximum; bcc = basal cell carcinoma; scc = squamous cell carcinoma 4 original article | dermatol pract concept. 2022;12(3):e2022124 dermatologists preferred surgical procedures for 14 (53.8%) lesions and nonsurgical procedures for 12 (46.2%) lesions. plastic surgeons preferred nonsurgical procedures for one lesion (3.8%) whereas surgical procedures for 25 lesions (96.2%). there was a statistically significant difference between the departments for treatment approaches (p < 0.001) (figure 2). the need of dermoscopic images in addition to clinical pictures was an average of 80.7% of the lesions for dermatologists. diagnostic accuracy of tds was 82% for all lesions which were confirmed by histopathologically. tds increased the rate of mean diagnostic accuracy of td from 74,3% to 82% among dermatologists (p = 0.02) (table 2). among plastic surgeons, the average percentage of requesting a dermatology consultation before treatment decision was 28.2% (table 2). conclusions in the current digital and locked-down world related to covid-19 pandemic, tm helps physicians for diagnosis and management of the patients. the diagnostic accuracy and therapeutic approach to nmsls by using td was evaluated between dermatology and prs departments in the current study. while there was no difference between the 2 departments in diagnostic accuracy, a significant difference was found in treatment approach in favor of the surgical approach among plastic surgeons. diagnostic reliability and accuracy of tm among dermatologists was found to vary from 47.7% to 88.0% in the literature [2,11,15,19,20]. fabbrocini et al reported a correct diagnosis rate of 52.0% for dermatologists using tds for difficult pink lesions [2]. similarly, in another study, the diagnostic rate of td was found 59.0% for non-pigmented neoplasms [11]. şenel et al reported that diagnostic accuracy of non-melanocytic skin tumors by td was 85.0% and 88.0% for 2 different dermatologists [15]. diagnostic agreement rates were reported to be between 47.7% to 87.3% for non-pigmented lesions by warshaw et al [11], giavina-bianchi et al also studied diagnostic accuracy of td for both pigmented and non-pigmented skin lesions. they reported accuracy rates of 75.0%, 71.0%, 64.0% and 50.0% for basal cell carcinoma, squamous cell carcinoma, cysts, and warts/seborrheic keratosis or lipomas, respectively [20]. although there are studies which were performed with plastic surgeons about efficacy of tm in various conditions such as wound and burn management, trauma, free flap care, cleft lip/palate repair, there is not any report about diagnostic accuracy of nmsls diagnosis with tm method [1]. ftf studies demonstrated that the overall diagnostic accuracy of skin lesions for plastic surgeons was around 60.0% to 89.0% [17,21-23]. clinical diagnosis matched with the pathological diagnosis was considered as a correct diagnosis in these studies. sönmez et al [17] reported correct diagnosis rate for prs clinic as 61.4% and matteucci et al [22] reported an overall diagnostic accuracy of malignant lesions of 83.0%. basal cell carcinomas were diagnosed with the highest degree of accuracy with 89.0%, whereas squamous cell carcinomas were with a lower level of diagnostic accuracy with 33.0% [22]. the correct diagnostic rate for basal cell carcinoma was 68.0% in the study by stone et al [21]. in hallockstudy, overall diagnostic accuracy was 65% in 2000 excised skin tumors [23]. our diagnostic accuracy rates for dermatologists and plastic surgeons in the diagnosis of nmsls were compatible with previous studies. 80.8% 53.8% 73.1% 76.9% 69.2% 53.8% 00% 10% 20% 30% 40% 50% 60% 70% 80% 90% d ia g n o st ic a c c u r a c y (% ) 1 2 3 figure 1. the frequencies of each dermatologist (the left columns) and plastic surgeon’s (the right columns) diagnostic accuracy. original article | dermatol pract concept. 2022;12(3):e2022124 5 figure 2. the frequencies of the treatment approaches of dermatologists and plastic surgeons (p <0.001) 46.2% 96.2% 53.8% 3.8% 00% 20% 40% 60% 80% 100% tr ea tm en t a p p r o a c h (% ) surgical procedures dermatologist plastic surgeon non-surgical procedures table 2. the response rates of dermatologists and plastic surgeons d1 n/n (%) d2 n/n (%) d3 n/n (%) average % in how many lesions did dermatologists request dermoscopic images to confirm their diagnosis? 24/26 (92.3) 26/26 (100) 13/26 (50) 80.7 in how many lesions was teledermoscopic pre-diagnosis histopathologically compatible? (diagnostic accuracy of tds) 23/26 (88.5) 21/26 (80.8) 20/26 (76.9) 82.0 n/nd (%) n/nd (%) n/nd (%) % for how many lesions that required dermoscopic confirmation were also requested histopathological confirmation? 10/24 (41.7) 17/26 (65.4) 8/13 (61.5) 563 p1 n (%) p2 n (%) p3 n (%) average % requesting dermatology consultation 2 (7.7) 11 (42.3) 9 (34.6) 28.2 d1 = dermatologist-1; d2 = dermatologist-2; d3 = dermatologist-3; p1 = plastic surgeon-1; p2 = plastic surgeon-2; p3 = plastic surgeon-3; n = total number of lesions; nd = total number of lesions that required dermoscopic image; tds = tele-dermoscopy although there is no data comparing diagnostic accuracy for various skin lesions between dermatologists and plastic surgeons by using tm in the scientific literature, there are some reports with ftf methods [16-18,21]. sellheyer and bergfeld reported that dermatologists accurately diagnosed neoplastic and cystic skin lesions nearly 2 times more (75%) than non-dermatologist physicians (40%) or plastic surgeons (45%) [18]. similarly, stone et al reported higher positive predictive value for basal cell carcinoma (as one of malignant nmsls) diagnosis of dermatologists (85%) than plastic surgeons (68%) [21]. in another study, similar diagnostic rates for basal cell carcinoma were reported among dermatologists and plastic surgeons which were higher than other physicians [16]. in a retrospective study by sönmez et al, which compared the diagnoses rates for various skin lesions for dermatology and prs departments, overall correct diagnosis rate of biopsied skin lesions was 64.0% for the dermatology clinic and 61.4% for the prs clinic and did not differ significantly between the 2 clinics [17]. similar to the sönmez et al study, the diagnostic accuracy rate did not differ between the 2 departments in the current study. our findings suggest that the tm method has similar results to ftf in terms of comparing diagnostic accuracy for dermatology and prs departments. with the use of dermoscopy, correct clinical diagnosis especially for the pigmented lesions and benign neoplastic lesions increased in recent years [17]. the efficacy of contribution of dermoscopy to td has been investigating recently. 6 original article | dermatol pract concept. 2022;12(3):e2022124 a study evaluating 1000 lesions suggested that td and tds might be valid and reliable tools for the diagnosis of actinic keratosis [24]. additionally, tds was reported to be superior to ftf dermoscopy and to td only for detecting early actinic keratoses [24]. braun et al reported that diagnostic accuracy of nmsls with tds was higher than traditional dermoscopic approach with the exception of kaposi sarcoma [25]. senel et al reported that td was a reliable technique for the diagnosis of nonmelanocytic skin tumors and tds increased the reliability and the accuracy of td. the accuracy of the diagnoses was significantly increased by the addition of dermoscopic images from 85% to 94% and from 88% to 95% for 2 different tele-dermatologists [15]. on the other hand, it is also reported that tds had an advantage for only biopsied pigmented lesions [19]. fabbrocini et al evaluated difficult pink lesions and reported lower correct diagnosis rate for tds than ftf examination and they discussed that this result might be cause of the absence of typical criteria of pink lesions [2]. in the present study, dermatologists had agreed that tds was helpful to confirm their clinical diagnoses in 80.7% of the images and tds increased the mean diagnostic accuracy rate from 74.3% to 82.0% for dermatologists. tds is known to improve diagnostic accuracy and to decrease the rate of unnecessary consultations in dermatology compared with td alone. in a study about specialists-to-experts store-and-forward tds, tds improved diagnostic accuracy of pigmented skin lesions compared with solitary non-expert assessment [26]. our findings suggest that dermoscopic examination is a frequently used method by dermatologists which increases their diagnostic accuracy on nmsls diagnosis. it is in the nature of the profession that surgeons are more prone to surgical approach for diagnosis or management of skin lesions [21,22]. however, some benign skin lesions could be managed non-surgically. thus, treatment approach between departments was significantly different from each other in the present study, with surgeons more prone to surgical approaches. all these differences of treatment approaches can be related to differences in postgraduate specialization training, indeed. with increasing technologic advancements, tm holds great potential to augment the dermatologist and plastic surgeon daily practice. previous studies asserted that the clinical diagnostic accuracy had important outcomes for treatment selection and the prioritization of treatment [22]. ferrandiz et al reported that teleconsultation before surgery could make an advantage for surgeon to plan the treatment procedure and surgical technique with high diagnostic accuracy rates [27]. bilgili et al found that diagnostic accuracy was affected positively by a preoperative evaluation by a dermatologist [28]. travato et al reported that e-consultation for selected plastic surgery patients was an accurate, cost-saving, time-saving technique in the evaluation and management [19]. matteucci et al emphasized the importance of specializing, especially in lesions with predicted as low malignancy risk [22]. our results support the idea that e-consultation of the skin lesions to a dermatologist via tm may be an effective method to prevent unnecessary surgery for a plastic surgeon. our study had some limitations. there were no predetermined categories for clinical diagnosis of nmsls and number of lesions was small. with higher number of physicians and different kinds of lesions, requirements of td between clinics can be determined. in conclusion, tm is an easy method for nmsls diagnosis with up to 75% of diagnostic accuracy. adding tds to td increases diagnostic accuracy for dermatologists on nmsls diagnosis. the difference in treatment approach between departments can be reduced through the effective use of td and tds via e-consultation. references 1. vyas ks, hambrick hr, shakir a, et al. a systematic review of the use of telemedicine in plastic and reconstructive surgery and dermatology. ann plast surg. 2017;78(6):736-768. doi: 10.1097/sap.0000000000001044. pmid: 28328635. 2. fabbrocini g, balato a, rescigno o, mariano m, scalvenzi m, brunetti b.. telediagnosis and face-to-face diagnosis reliability for melanocytic and non-melanocytic ‘pink’ lesions. j eur acad dermatol venereol. 2008;22(2):229-234.. doi: 10.1111/j.14683083.2007.02400.x pmid: 18211418 3. trettel a, eissing l and augustin m. telemedicine in dermatology: findings and experiences worldwide a systematic literature review. j eur acad dermatol venereol. 2018;32(2):215-224. doi: 10.1111/jdv.14341. pmid: 28516492. 4. gardiner s and hartzell tl. telemedicine and plastic surgery: a review of its applications, limitations and legal pitfalls. j plast reconstr aesthet surg. 2012;65(3) e47-e53. doi: 10.1016/j. bjps.2011.11.048. pmid: 22178033. 5. fonseca as, goldenberg dc, stocchero gf, luiz av, gemperli r. validation of videoconference with smartphones in telemedicine facial trauma care: analysis of concordance to on-site evaluation. ann plast surg. 2016;77(4):433-437. doi: 10.1097/ sap.0000000000000623. pmid: 26418788. 6. holt b, faraklas i, theurer l, cochran a, saffle jr.. telemedicine use among burn centers in the united states: a survey. j burn care res. 2012;33(1):157-162. doi: 10.1097/ bcr.0b013e31823d0b68. pmid: 22105096. 7. syed-abdul s, scholl j, chen cc, santos md, jian ws, liou dm, li yc. telemedicine utilization to support the management of the burns treatment involving patient pathways in both developed and developing countries: a case study. j burn care res. 2012;33(4):e207-e212. doi: 10.1097/bcr.0b013e318241b6b7. 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10775852. 26. marchetti a, dalle s, maucort-boulch d, et al. diagnostic concordance in tertiary (dermatologists-to-experts) teledermoscopy: a final diagnosis-based study on 290 cases. dermatol pract concept. 2020;10(3):e2020071. doi: 10.5826/dpc.1003a71. pmid: 32642316. 27. ferrandiz l, moreno-ramirez d, nieto-garcia, et al. teledermatology-based presurgical management for nonmelanoma skin cancer: a pilot study. dermatol surg. 2007;33(9):1092-1098. doi: 10.1111/j.1524-4725.2007.33223.x. pmid: 17760600. 28. bilgili me, yildiz h, cengiz bp, saydam im. effect of preoperative evaluation by a dermatologist on diagnostic accuracy. dermatol surg. 2014;40(12):1402-1408. doi: 10.1097/ dss.0000000000000168. pmid: 25350124. dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;3(2):7 53 report of a case a 45-year-old man presented with a slightly tender rash on his face of about three months’ duration. past medical history was non-contributory. physical examination revealed a solitary 1 cm erythematous nodule in the right submental area. dermatoscopy showed a structureless pattern with a gray-blue, thick, curved line and adjacent red lines (figure 1), which appeared to be a subcuticular suture, although the patient had no prior surgeries. a #22-gauge needle was used to unroof the nodule, revealing five black, coiled, beard hairs nestled deep into the dermis (figure 2), the longest measuring 6 cm in diameter (figure 3). these findings were most consistent with a diagnosis of pseudofolliculitis barbae accompanied by a characteristic foreign-body-like reaction to the retained hairs. discussion pseudofolliculitis barbae (also known colloquially as “ingrown hairs” or “razor bumps”) is a common chronic inflammatory disorder occurring most often in regions of thick hair growth after shaving. pathogenesis involves creating a sharp tip by shaving the distal end of the hair that enables intrafollicular and transfollicular penetration of pseudofolliculitis barbae: a dermatoscopic correlate barry ladizinski, m.d.,1 marigdalia ramirez-fort, m.d.,2 yoon k. cohen, d.o.,3 cliff rosendahl mbbs, ph.d.,4 david j. elpern, m.d.5 1 department of dermatology, duke university medical center, durham, north carolina, usa 2 center for clinical studies, houston, texas, usa 3 alta dermatology, phoenix, arizona, usa 4 school of medicine, university of queensland, brisbane, queensland, australia 5 the skin clinic, williamstown, massachusetts, usa key words: pseudofolliculitis barbae, pseudofolliculitis, ingrown hair, foreign body reaction, dermatoscopy, dermoscopy citation: ladizinski b, ramirez-fort m, cohen yk, rosendahl c, elpern dj. pseudofolliculitis barbae: a dermatoscopic correlate. dermatol pract conc. 2013;3(2):7. http://dx.doi.org/10.5826/dpc.0302a07. received: november 8, 2012; accepted: january 15, 2013; published: april 30, 2013 copyright: ©2013 ladizinski et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: barry ladizinski, m.d., duke university medical center, box 2822, durham nc 27710, usa. email: barryladizinski@gmail.com. conflicts of interest: the authors have no relevant conflicts of interest to disclose. figure 1. dermatoscopy showing a structureless pattern with a grayblue, thick, curved line and adjacent red lines. [copyright: ©2013 ladizinski et al.] 54 observation | dermatol pract concept 2012;3(2):7 thick hairs into the dermis [1]. as the hairs grow, they coil back into the dermis, causing an inflammatory reaction. pseudofolliculitis barbae is characterized clinically by multiple painful, pruritic erythematous papules and, less commonly, pustules, nodules, or abscesses hyperpigmentation, hypertrophic scars and keloids can also occur [2]. our patient presented with a solitary inflammatory nodule with no previous history of pseudofolliculitis. clinical examination was inconclusive. herein we present a unique dermatoscopic image of pseudofolliculitis barbae, which revealed a solitary grayblue, thick curved line and adjacent red lines set upon a structureless pattern. these findings do not clearly correlate with known neoplastic entities. based on the clinical appearance of an inflammatory nodule, basal cell carcinoma could be considered, however, branching vessels would be expected instead of the random cluster of straight red lines. thick curved lines are typically seen in seborrheic keratosis. the gray and blue colors are consistent with melanin contained within the pigmented hair shaft in the dermis. according to current understanding, collagen fibrils that are present in the dermis scatter light superficial to the deeper melanin pigment, and as blue light is scattered more than red light, the structure is seen by the dermatoscopist as gray or blue according to whether it is in the superficial or deep dermis, respectively. this is known as the tyndall effect [3] given the associated structureless pattern, lichenoid keratosis should also be considered, however, this would not typically present as a nodule. in our case, the solitary gray-blue, thick curved line corresponds to the edge of the tightly coiled cluster of ingrown hairs in the dermis. the red lines most likely represent aberrant vessels secondary to a foreign body inflammatory reaction. references 1. bolognia jl, jorizzo jl, schaffer jv. dermatology. 3rd ed. new york: saunders, 2012. 2. perry pk, cook-bolden fe, rahman z, jones e, taylor sc. defining pseudofolloculitis barbae in 2001: a review of the literature and current trends. j am acad dermatol. 2002;46:s113-9. 3. weismann k, lorentzen hf. dermoscopic color perspective. arch dermatol. 2006;142(9):1250. figure 2. following unroofing of the lesion with a 22-gauge needle, five black, coiled, beard hairs can be seen nestled deep into the dermis. [copyright: ©2013 ladizinski et al.] figure 3. the longest of the coiled hairs measured 6 cm in diameter. [copyright: ©2013 ladizinski et al.] dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):8 35 dermatology practical & conceptual www.derm101.com case report the patient presented to our coastal regional australian skin cancer clinic for an opinion on a new skin lesion on the lateral dorsum of his hand, first noticed two weeks prior. it was asymptomatic, without tenderness, bleeding, scale or itch. there was no history of trauma to the site or insect bite. there were no other similar lesions and no previous history of the lesions or history of previous skin cancers. at initial consultation the lesion was 8 x 6 mm in diameter, violaceous, plaque-like, with a slightly raised thin border and a mildly rough surface, without scale (figures 1a and 1b). dermatoscopy of the lesion showed a homogenous, nonpigmented violaceous lesion, without obvious vasculature at standard magnification. there were no keratin features or ulceration (figure 2a). the most striking dermatoscopic feature was the conspicuous shiny white structures throughout the lesion (figure 2b). because of the homogenous appearance of the lesion, its asymptomatic nature and the absence of classically worrying dermatoscopic features (such as pigmented clues, keratin features, polymorphic vessels, or ulceration), it was felt that the lesion was a benign dermal process, such as an inflamed lesion of granuloma annulare, and the patient was reassured and advised to return if the lesion was persisting or enlarging after a period of one month. the patient returned at three months, as the lesion had persisted and enlarged to 11 x 9 mm in diameter. clinical and dermatoscopic features were unchanged and it was still asymptomatic, but the patient was concerned about its growth. clinical and dermatoscopic photographs were taken with the patient’s consent, using a canon powershot g16 first description of the dermatoscopic features of acquired elastotic hemangioma—a case report tristan hicks 1, ian katz2 1 sun doctors ballina & northern rivers skin cancer clinic, ballina, australia 2 southern sun pathology, sydney, australia & department of medicine, university of queensland, brisbane, australia key words: acquired elastotic haemangioma, dermatoscopy, shiny white structures citation: hicks t, katz i. first description of the dermatoscopic features of acquired elastotic hemangioma—a case report. dermatol pract concept 2016;6(4):8. doi: 10.5826/dpc.0604a08 received: june 5, 2016; accepted: august 1, 2016; published: october 31, 2016 copyright: ©2016 hicks et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. tristan hicks, bmed, bbiomedsci, fracgp. email: trismiester@hotmail.com we present a case of acquired elastotic hemangioma (aeh), a rare, benign vascular tumor. a caucasian male in his 60s presented with an asymptomatic, solitary, non-pigmented and violaceous lesion of short duration on the dorsum of his hand. the lesion had unique clinical, dermatoscopic and pathological features. dermatoscopic images of the lesion are presented for characterization and histopathological correlation that have not previously been published or described. abstract mailto:trismiester@hotmail.com 36 observation | dermatol pract concept 2016;6(4):8 many of which are arranged parallel to the epidermis, separated by bands of collagen. the endothelial cells display digital camera (canon, tokyo, japan) coupled to a dermlite dl3n dermatoscope (3gen llc, san juan capistrano, ca, usa), (figures 1 and 2). a 4 mm punch biopsy was performed to rule out malignancy. histopathological examination of the biopsy specimen was interpreted as showing hyperkeratosis and solar damage with a prominent fairly banal capillary proliferation in the dermis. this correlated poorly with the clinical picture and formal excision was suggested. the patient was recalled and the lesion was excised. histopathological examination of the excisional specimen was interpreted as an acquired elastotic hemangioma based on the constellation of findings, including hyperkeratosis and flattened rete ridges, marked solar elastosis, and a superficial dermal horizontal band-like proliferation of capillaries (figures 3a and 3b). there was no recurrence of the lesion at follow-up at three months. discussion acquired elastotic hemangiomas are rare, benign, usually solitary lesions occurring on sun-damaged skin of exposed areas in older adults, classically the dorsum of forearms, with a slight female predilection. initiation of progesterone therapy has been potentially implicated in the unusual scenario of multiple acquired elastotic hemangiomas in perimenopausal women [1]. aeh was first described by requena et al in 2002 with a series of six cases [2]. martorell-calatayud et al in 2009 published a series of 14 cases that had been recorded over an 18-year period, all with similar clinical and histopathologic features. most commonly, these lesions are mistaken clinically for basal cell carcinomas (bcc) [3]. aeh has a slow growth rate and is typically asymptomatic, but clinically quite striking due to its violaceous appearance. histopathologically, it exhibits a superficial dermal band-like proliferation of capillaries, a “hobnail” pattern without cellular atypia or mitoses. there is invariably a narrow band of uninvolved papillary figure 1. clinical (a) and macroscopic (b) views of aeh. solitary, violaceous macular lesion on dorsum of hand (chronically sun-exposed region). raised border without evidence of scale, crust or ulceration. [copyright: ©2016 hicks et al.] figure 2. non-polarizing (npd) (a) and polarizing (pd) (b) dermatoscopy of aeh. scale 1 mm intervals. violaceous homogenous lesion without vessels but marked widespread shiny white structures visualized with polarized dermatoscopy. [copyright: ©2016 hicks et al.] figure 3. photomicrographs of the lesion, h&e stain. 40x (a) and 100x (b) magnification. superficial dermal horizontal band-like proliferation of capillaries, with marked solar elastosis, some hyperkeratosis and flattening of rete ridges. the epidermis is otherwise normal. [copyright: ©2016 hicks et al.] observation | dermatol pract concept 2016;6(4):8 37 broma, the random shiny white lines and shiny white areas seen in bccs, and the typical wickham’s striae seen lichen planus [7,8]. kaposi’s sarcoma has been described to commonly have a specific dermatoscopic polarising artefact, named “rainbow pattern,” where there are multi-colored shiny structures. it is postulated that this is due to the tightly packed capillary proliferation without intervening collagen [9]. in our example of aeh, there were no such coloration artefacts. we suggest that the specific polarization artefact of shiny white areas may be due to the horizontal band-like proliferation of capillaries in the superficial dermis with intervening collagen bundles. this specific feature, combined with the striking violaceous background and otherwise homogenous appearance of the lesion, may aid in the clinical recognition of this rare entity. conclusion in summary, we present the first description of the dermatoscopic features of acquired elastotic hemangioma. our case revealed a violaceous plaque on chronically sun-damaged skin without vessels, but revealing prominent and widespread shiny white structures. references 1. tillman n, plumb sj, cleaver d, cleaver l. acquired elastotic hemangioma: a case report of multiple lesions following progesterone therapy. http://c.ymcdn. com/sites/www.aocd.org/resource/resmgr/ meeting_resources/2015fallmeeting/ syllabus/posters/tillman15.pdf. 2015. accessed 9/5/16. dermis and a significant degree of solar elastosis. there is a normal appearing or atrophic epidermis and occasional hyperkeratosis [4]. immunohistochemical tests are not routinely required for diagnosis, although cd31 and cd34 immunostains will highlight the endothelial cells [5]. most will also express d2-40, with a minority also being smooth muscle actin positive [3]. it has been suggested that aeh may have a lymphatic origin, but this hypothesis has been questioned by tong and beer [6]. in the literature, the clinical differential diagnosis of acquired elastotic hemangioma includes bcc, granuloma annulare, patch-stage kaposi’s sarcoma, acquired tufted angioma, targetoid hemosiderotic hemangioma, low-grade angiosarcoma and capillary hemangioma [1,3,5]. whilst there is an increasing appreciation of the clinical and histopathological basis of aeh, dermatoscopy has never been described in these lesions. the dermatoscopy of this particular case showed a uniform, violaceous plaque without obvious vasculature or pigment that could aid in the diagnosis of a lesion prior to biopsy (figure 2a). however, there were prominent and widespread shiny white structures distributed evenly throughout the lesion (figure 2b). such shiny white structures are not encountered in other common lesions without other clues and are different from both the short white perpendicular/orthogonal polarizing lines (also called shiny white streaks and chrysalis or crystalline structures) seen in lesions such as melanoma, spitz naevi, lichenoid keratosis (lplk) and dermatofi2. requena l, kutzner h, mentzel t. acquired elastotic hemangioma: a clinicopathologic variant of hemangioma. j am acad dermatol 2002;47:371. pmid: 12196746. 3. m a r t o r e l l c a l a t a y u d a , b a l m e r n , sanmartín o, díaz-recuero jl, sangueza op. definition of the features of acquired elastotic hemangioma reporting the clinical and histopathological characteristics of 14 patients. j cutan pathol 2010;37(4):460-4. pmid: 19615005 doi: 10.1111/j.1600-0560.2009.01361.x. 4. weedon d. vascular tumours. in: weedon’s skin pathology, 3rd ed. london: churchill livingstone, 2010:904. 5. emanuel p, acquired elastotic haemangioma pathology. dermnetnz. http:// www.dermnetnz.org/pathology/elastotichaemangioma-path.html created 2013. updated 2015. accessed 9/5/16. 6. tong pl, beer tw. acquired elastotic hemangioma: ten cases with immunohistochemistry refuting a lymphatic origin in most lesions. j cutan pathol 2010;37(12):1259-60. pmid: 20950363. doi: 10.1111/j.1600-0560.2010.01610.x. 7. balagula y, braun rp, rabinovitz hs, et al. the significance of crystalline/ chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions. j am acad dermatol 2012;67(2):194. e1-8. pmid: 22030020. doi: 10.1016/j. jaad.2011.04.039. 8. liebman tn, rabinovitz hs, dusza sw, marghoob aa. white shiny structures: dermoscopic features revealed under polarized light. j eur acad dermatol venereol 2012;26(12):1493-7. pmid: 22035217. doi: 10.1111/j.14683083.2011.04317.x. 9. cheng st, ke cl, lee ch, wu cs, chen gs, hu sc. rainbow pattern in kaposi’s sarcoma under polarized dermoscopy: a dermoscopic pathological study. br j dermatol 2009 apr;160(4):801-9. pmid: 19067686 doi: 10.1111/j.13652133.2008.08940.x. https://www.ncbi.nlm.nih.gov/pubmed/19615005 https://dx.doi.org/10.1111/j.1600-0560.2009.01361.x http://www.dermnetnz.org/pathology/elastotic-haemangioma-path.html http://www.dermnetnz.org/pathology/elastotic-haemangioma-path.html http://www.dermnetnz.org/pathology/elastotic-haemangioma-path.html https://dx.doi.org/10.1111/j.1600-0560.2010.01610.x https://dx.doi.org/10.1016/j.jaad.2011.04.039 https://dx.doi.org/10.1016/j.jaad.2011.04.039 https://dx.doi.org/10.1111/j.1468-3083.2011.04317.x https://dx.doi.org/10.1111/j.1468-3083.2011.04317.x https://dx.doi.org/10.1111/j.1365-2133.2008.08940.x https://dx.doi.org/10.1111/j.1365-2133.2008.08940.x dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3): e2021058 1 the bork-baykal phenomenon in congenital melanocytic nevus tugba kevser uzuncakmak, defne özkoca, server serdaroğlu istanbul university-cerrahpasa, cerrahpasa medical faculty department of dermatology key words: baykal phenomenon, congenital nevus, melanocytic nevus citation: uzuncakmak tk, özkoca d, serdaroğlu s. the bork-baykal phenomenon in congenital melanocytic nevus. dermatol pract concept. 2021;11(3): e2021058. doi: https://doi.org/10.5826/dpc.1103a58 accepted: december 12, 2020; published: july 8, 2021 copyright: ©2021 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr tugba kevser uzuncakmak, md, istanbul university cerrahpasa, medical faculty,department of dermatology, istanbul, turkey. email: drtugbakevser@gmail.com case presentation a 6-month-old girl was admitted to our outpatient clinic for dermoscopic examination of a large congenital melanocytic nevus on chest (cmn). dermatological examination revealed 15x15 cm sized, light-dark brown, multicomponent cmn with 2 excision scars over the left breast. nipple and areola were not involved (figure 1a). dermoscopic examination revealed a whitish homogenous area surrounded by a brown homogenous area and dark brown, symmetrical reticular lines (figure 1b). figure 1. (a) 15x15 cm sized, light-dark brown, multicomponent cmn with two excision scars over the left breast without the involvement of the nipple and areola. (b) whitish homogeneous area surrounded by brown homogeneous area and dark brown, symmetrical reticular lines. 2 image letter | dermatol pract concept. 2021;11(3): e2021058 teaching point sparing of the nipple-areola complex (the bork–baykal phenomenon) was first reported by baykal et al in 8 cases of large congenital melanocytic nevus (cmn) sparing the areola [1]. 2 years later, happle referred to this entity as “the borkbaykal phenomenon: a new and rarely seen entity referring to the nipple-sparing nevus of the breast”. medium and large cmns are a subtype of hamartomas that present at birth. their peculiar appearance was linked to the different histopathological features and embryologic developmental periods of the affected tissues and the nipple-areola complex [2]. references 1. baykal c, solakoğlu s, polat ekinci a, yazganoğlu kd. large congenital melanocytic nevus on the breast sparing the nipple and areola. pediatr dermatol. 2015; 32: 514-517. doi: 10.1111/ pde.12610. pmid: 25940669 2. argenziano g, caccavale s, brancaccio g, moscarella e, piccolo v, lallas a. reassessing the biological significance of congenital melanocytic nevi. dermatol pract concept. 2020;10(3):e2020068. doi: 10.5826/dpc.1003a68. pmid: 32676216 dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):13 63 dermatology practical & conceptual www.derm101.com case report a 50-year-old woman presented to a dermatology clinic with a pigmented stripe on her right thumb. she reported that the stripe had appeared three years previously and that it had progressively widened. examination revealed heavily pigmented longitudinal melanonychia (figure 1a). dermatoscopy revealed melanonychia, color blue, mainly comprised of structureless blue but with lines parallel on one side. taking this variability into account, there were lines parallel varying in width but not varying in interval or color (figure 1b). there was no pigmentation of the proximal nail fold (hutchinson’s sign) or cuticle (micro-hutchinson’s sign), although pigment was visible on the nail plate through the translucent cuticle (pseudo-hutchinson’s sign). nail matrix biopsy was performed involving avulsion of the nail plate and longitudinal excision of the entire pigmented portion of the matrix, which was submitted for histological nail apparatus melanoma initially diagnosed as nail matrix blue nevus: a case report with dermatoscopy and dermatopathology bengu nisa akay1, aylin okcu heper2, luc thomas3, brigitte balme3, simon clark4,5, cliff rosendahl5,6 1 department of dermatology, ankara university faculty of medicine, ankara, turkey 2 department of pathology, ankara university faculty of medicine, ankara, turkey 3 dermatology and dermatopathology centre, hospitalier lyon sud, pierre bénite, france 4 dhm pathology, macquarie park, nsw, australia 5 tehran university of medical sciences, tehran, iran 6 school of medicine, the university of queensland, australia key words: nail, melanoma, blue nevus, dermatoscopy citation: akay bn, heper ao, thomas l, balme b, clark s, rosendahl c. nail apparatus melanoma initially diagnosed as nail matrix blue nevus: a case report with dermatoscopy and dermatopathology. dermatol pract concept. 2017;7(1):13. doi: https://doi.org/10.5826/ dpc.0701a13 received: june 27, 2016; accepted: october 22, 2016; published: january 31, 2017 copyright: ©2017 akay et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: bengu nisa akay, md, ankara universitesi tip fakultesi, ibni sina hastanesi, dermatoloji anabilim dali, 06100, altindag, ankara, turkey. email: nisaakay15@yahoo.com we present a case of nail apparatus melanoma in a 50-year-old woman presenting as new and changing longitudinal melanonychia of the right thumb. very heavy melanin pigmentation involving both the epidermis and dermis interfered with dermatopathological assessment, which initially leads to a diagnosis of nail matrix blue nevus. after consultation with a specialist multidisciplinary clinic the diagnosis was revised to invasive melanoma, a diagnosis consistent with the clinical and dermatoscopic assessment. abstract mailto:nisaakay15@yahoo.com 64 observation | dermatol pract concept 2017;7(1):13 anin staining throughout the epidermis and into the reticular dermis to such a degree that assessment of the archiexamination by a dermatopathologist. hematoxylin and eosin (h&e) stained material (figure 2a) revealed heavy meltecture and cytology of the lesion were compromised. bleached sections were examined (figure 2b), and although these did reveal an apparent melanocytic proliferation in the epidermis it was considered that this could in fact be artifactual due to the bleaching. an apparent absence of atypia in the dermal spindle cells was considered to be consistent with blue nevus, and in that context the epidermal changes were interpreted as being due to keratinocytes modified by the bleaching process. sections stained with melan a (figure 2c), ki-67 (figure 2d) and hmb45 showed staining throughout the epidermis and papillary dermis, but the presence of heavy pigmentation substantially obscured dab chromogen, making the interpretation difficult and unreliable. the diagnosis of blue nevus was questioned by the treating dermatologist because the history of a new and continuously growing nail matrix melanocytic lesion at mature age was inconsistent with a benign diagnosis and because abundant epidermal melanin is not expected in a blue nevus. clinical, dermatoscopic and dermatopathologic images were reviewed by a multidisciplinary tumor board (including dermatologists and dermatopathologists), and dermatopathology slides were also reviewed by a member of that board (author bb). they rendered a unanimous opinion that this lesion represented an invasive melanoma based on the history of recent onset and progression at mature age, the nature of the dermatoscopic melanonychia striata and the dermatopathological architecture and cytology. they commented that although it was unusual to have such a thick tumor with such a narrow band of melanonychia, this was not inconsistent with the diagnosis. following this the dermatopathological diagnosis was revised by the reporting pathologist to that of invasive nail apparatus melanoma, clark level 2, breslow thickness 0.38 mm with focal epidermal erosion and with no figure 1. clinical (a) image of the right thumbnail of a 50-year-old woman. the pigmented stripe has appeared and progressed over three years. dermatoscopy (b) displays melanonychia striata with lines parallel varying in width, but not interval or color. [copyright: ©2017 akay et al.] a b figure 2. h&e staining (a) of the matrix biopsy specimen from the lesion in figure 1 displays heavy pigmentation over both the epidermis and dermis which compromised assessment of architecture and cytology. a bleached section (b) revealed an apparent epidermal melanocytic proliferation, but this was initially interpreted as keratinocytes modified by bleaching. interpretation of sections stained with melan a (c) and ki-67 (d) was compromised by heavy melanin pigmentation substantially obscuring dab chromagen. [copyright: ©2017 akay et al.] a b c d observation | dermatol pract concept 2017;7(1):13 65 in this case the abundance of melanin in the epidermis was evidence contrary to a diagnosis of nail matrix blue nevus. clinical and dermatoscopic information can be critical to the correct interpretation of difficult dermatopathological material. the appearance at mature age, and progressive widening of longitudinal melanonychia in the form of lines in the color of melanin, is compelling evidence for melanoma and any alternative report should only be accepted if the dermatopathology is unequivocal. in the presented case, heavy pigmentation complicated dermatopathological assessment, but despite this, the final revised signed-out diagnosis, facilitated by consultation with a tertiary multidisciplinary clinic, conformed to the clinical and dermatoscopic assessment. references 1. banfield cc, redburn jc, dawber rp. the incidence and prognosis of nail apparatus melanoma. a retrospective study of 105 patients in four english regions. br j dermatol. 1998;139:276–279. 2. phan a, touzet s, dalle s, ronger-savlé s, balme b, thomas l. acral lentiginous melanoma: a clinicoprognostic study of 126 cases. br j dermatol. 2006;155:561–569. 3. phan a, dalle s, touzet s, ronger-savlé s, balme b, thomas l. dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population. br j dermatol. 2010;162:765–771. 4. phan a, touzet s, dalle s, ronger-savlé s, balme b, thomas l. acral lentiginous melanoma: histopathological prognostic features of 121 cases. br j dermatol. 2007;157:311–318. 5. weedon d, van deurse m, rosendahl c. ‘occult” melanocytes in nail matrix melanoma. am j dermatopathol. 2012;34:855. 6. thomas l, dalle s. dermoscopy provides useful information for the management of mlanonychia striata. dermatol ther. 2007;20:3–10. pmid: 17403255 doi: 10.1111/j.15298019.2007.00106.x 7. suvarna ks, layton c, bancroft jd, eds. bancroft’s theory and practice of histological techniques. 7th ed. london: churchill livingstone; 2012:251. 8. cabral es, chen fw, egbert bm, swetter sm. acquired blue nevi in older individuals: retrospective case series from a veterans affairs population, 1991 to 2013. jama dermatol. 2014;150:873– 876. 9. causeret as, skowron f, viallard am, balme b, thomas l. subungual blue nevus. j am acad dermatol. 2003;49: 310–312 10. dalle s, ronger-savle d, cicale l, balme b, thomas l. a bluegray subungual discoloration. arch dermatol. 2007;143:937–942 11. kim hs, kim yj, kim jw, yu ds. subungual blue nevus. j eur acad dermatol venereol. 2006;21:271–272. 12. moulonguet-michau i, abimelec p. nail unit blue melanocyte nevi: 2 case reports. [french]. ann dermatol venereol. 2004;131:984–986. 13. salasche sj, garland ld. tumors of the nail. dermatol clin. 1985;3:501–519. 14. smith df, morgan mb, bettencourt ms, haley ja. longitudinal melanonychia. arch dermatol. 2003;139:1209–1014. 15. vidal s, sanz a, hernández b, yus es, requena l, baranr. subungual blue nevus. br j dermatol. 1997;137:1023–1025. mitoses or lymphovascular or peri-neural invasion observed. the patient agreed to definitive treatment by distal phalanx amputation. conclusions nail apparatus melanoma is uncommon but has a relatively high mortality [1]. there is a reported female preponderance with location on the thumb having the highest prevalence (41%) [2]. the proportion of nail apparatus melanoma which are pigmented has been reported as 71.7% [3] with the median breslow thickness of nail apparatus melanoma being reported as 0.8 mm with up to 18% having spindle shaped cells [4]. all reported nail apparatus melanomas have apparently arisen de novo, there being no reports of any pre-existing associated nevus [4]. the diagnosis can be challenging both clinically and dermatopathologically [5], although this is not expected in a mature invasive melanoma. a history of new and changing longitudinal melanonychia at mature age is a clue to malignancy as is the specific dermatoscopic clue to nail apparatus melanoma of longitudinal melanonychia (brown, black, grey or blue) with lines parallel varying in width, interval and color [6]. in the present case, there was one broad band of blue color and two narrow bands of the same color. lines varying in width, but not interval and color, raised the possibility of a benign etiology, but this appearance could also be explained by the very heavy density of pigmentation. in the present case, the index of suspicion of the treating dermatologist was high and the patient was referred promptly for nail matrix biopsy. subsequent dermatopathological assessment, including h&e, melan a and ki-67 staining, was hindered by dense melanin deposition. bleaching of histological sections was employed in response to this, but it is known that this process can damage the tissue, compromising interpretation [7]. as a result of the dense melanin deposition and equivocal dermal melanocyte cytology, an initial dermatopathological diagnosis of blue nevus was rendered. blue nevi are expected to appear on the skin at mature age, but by the time they are observed they are generally stable [8]. blue nevus has rarely been reported in the nail apparatus [9-18], and although two reported cases presented with longitudinal melanonychia [16,17], the others all presented with structureless subungual pigmentation (one had associated periungal pigmentation [18]), as might be expected in a dermal pigmented melanocytic proliferation. this diagnosis of blue nevus was questioned primarily because of a history of progressive evolution clinically and also because, with only two exceptions in the literature, nail apparatus blue nevus does not exhibit epidermal pigmentation or longitudinal melanonychia. a pigmented melanocytic proliferation restricted to the dermis of the nail matrix is not expected to transfer pigment to the developing nail plate, and 66 observation | dermatol pract concept 2017;7(1):13 jellinek nj. subungual blue nevus with combined phenotypic features. j am acad dermatol. 2008;58:1021–1024. 18. gershtenson pc, krunic a, chen h, konanahalli m, worobec s. subungual and periungual congenital blue nevus. australas j dermatol. 2009;50:144–147. 16. soyer hp, kerl h. european society of pediatric dermatology clinical case reports 1984. in: baran r, dawber rpr, berker dar, haneke e, tosti a (eds). diseases of the nails and their management. 3rd ed. oxford: blackwell science ltd; 2001:616–618. 17. naylor emt, ruben bs, robeinson-bostom l, telang gh, dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(3):e 2021064 1 the role of dermoscopy in diagnosis: a case presentation of pseudoxanthoma elasticum initially misdiagnosed as pigmented contact dermatitis ömer faruk elmas1, abdullah demirbaş2, raşit kılıç3, asuman kilitçi4 1 department of dermatology, kırıkkale university, kırıkkale, turkey 2 department of dermatology, evliya çelebi training and research hospital, kütahya health sciences university, kütahya, turkey 3 department of ophthalmology, tokat gaziosmanpaşa unıversity, tokat, turkey 4 department of pathology, kırşehir ahi evran university, kırşehir, turkey key words: pseudoxanthoma elasticum, pigmented contact dermatitis, dermoscopy citation: elmas öf, demirbaş a, kılıç r, kilitçi a. the role of dermoscopy in diagnosis: a case presentation of pseudoxanthoma elasticum initially misdiagnosed as pigmented contact dermatitis. dermatol pract concept. 2021;11(3):e 2021064. doi: https://doi.org/10.5826/dpc.1103a64 accepted: november 20, 2020; published: july 8, 2021 copyright: ©2021 elmas et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: ömer faruk elmas, associate professor, department of dermatology, kırıkkale university, kırıkkale , turkey. email: omerfarukmd@gmail.com case presentation a 45-year-old female with a three-year history of bilateral ocular angioid streaks was referred to our dermatology department kırşehir ahi evran university for the evaluation of persistent cutaneous lesions, present since childhood (figure 1, a-d). the patient was previously diagnosed with pigmented contact dermatitis 5 years ago, in a different dermatology outpatient clinic. dermatological examination in our dermatology department showed confluent yellowish papules on both sides of the neck (figure 2a). dermoscopic examination revealed reticulated yellow-to-white clods on a light red background, along with defocused linear irregular vessels (figure 2b). histopathological examination showed mild epidermal atrophy, accumulation of swollen clumped fibers, mild inflammatory cell infiltration, and dilated dermal vessels (figure 2c). elastic van gieson staining showed fragmented elastic fibers. based on the clinical, dermoscopic and histopathological features, a diagnosis of pseudoxanthoma elasticum was made. detailed imaging studies showed no systemic involvement except for ocular lesions. teaching point pseudoxanthoma elasticum has a peculiar dermoscopic pattern composed of coalescing and reticulated yellow clods on a light red background [1,2]. a thorough dermoscopic 2 letter | dermatol pract concept. 2021;11(3):e 2021064 figure 1. color fundus photographs. (a, b) angioid streaks in both eyes (white arrows). (c, d) angioid streaks in fundus autofluorescence and red free images of the left eye (white arrows). figure 2. dermatologic, dermoscopic, and histopathologic examination. (a) dermatological examination showed confluent yellowish papules on the neck. (b) dermoscopic examination revealed reticulated yellow-to-white clods on a light red background, along with disfocused linear irregular vessels. (c) histopathological examination showing dermal accumulation of swollen clumped fibers. letter | dermatol pract concept. 2021;11(3):e 2021064 3 examination may prevent misdiagnosis especially in those cases characterized by subtle cutaneous manifestations. references 1. kawashima s, togawa y, miyachi h, matsue h. dermoscopic features of pseudoxanthoma elasticum. clin exp dermatol. 2018;43(2):175–179. doi: 10.1111/ced.13308. pmid: 29271496 2. persechino f, giordano d, marini cd, franceschini c, ardigò m, persechino s. dermoscopy, optical coherence tomography, and histological correlation of pseudoxanthoma elasticum. dermatol pract concep. 2019;9(3):209–210. doi: 10.5826/ dpc.0903a07. pmid: 31384495 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022061 1 sanitizing hand gels: a potential source of burn in the covid-era francesco bruzziches1, davide cosetti1, linda tognetti1, pietro rubegni1 1 dermatology unit, department of medical, surgical and neurosciences, university of siena, siena, italy key words: burn, hand sanitizing gel, sars-cov-2, skin allografts. citation: bruzziches f, cosetti d, tognetti l, rubegni p. sanitizing hand gels: a potential source of burn in the covid-era. dermatol pract concept. 2022;12(2):e2022061. doi: https://doi.org/10.5826/dpc.1202a61 accepted: may 6, 2021; published: april 2022 copyright: ©2022 bruzziches et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: francesco bruzziches, md, department of medical, surgical and neurological science dermatology section, university of siena. s. maria alle scotte hospital, viale bracci 16, 53100 siena, italy. e-mail: francescobruzziches@hotmail.it introduction the sars-cov-2 pandemic has brought new challenges to the world. to limit virus spread, effective hand hygiene is crucial. who’s recently recommended healthcare workers to perform hand hygiene at 5 crucial moments (before touching a patient, before aseptic procedures, after body fluid exposure, after touching a patient or surroundings), and generally before putting on/after removal of positive protective equipment, before food preparation and eating and after using the toilet. case presentation an otherwise healthy 43-year-old woman came to our dermatological emergency room with a burn injury in both hands, first treated with topical antibiotics dressing for 48 hours. clinical examination (figure 1) revealed second and first degree burns involving both palms, volar surface of the wrists and the back of her right hand (ie 2% of tbsa). clinically, the injury was mid-dermal in depth. the incident occurred when the patient lightened a cigarette just after having performed hand hygiene with a commercially available hand sanitizing gel. the patient noticed a blue flame over the site of gel application and was able to extinguish it by rapidly immerging both hands into cold water. the burn was managed orally with amoxicillin-clavulanate for 1 week and oral analgesics. patches of cryopreserved skin allografts were applied on the thenar eminence grade 2 burned areas for 7 days, followed by hyaluronic acid gauzes for 7 days, and hyaluronic acid cream for further 7 days. complete healing with moderate post-inflammatory dyspigmentation was observed after 21 days (figure 2). the sanitizing hand gel was composed of: denatured alcohol, triethanolamine, benzyl salicylate glycerin, carbomer, o-phenylphenol, parfum, aqua. discussion some concerns have been previously raised about the flammability characteristics of hand sanitizers gels [1]. indeed, alcohol-based hand sanitizers should contain between 60% and 80% of alcohol (usually ethanol or methanol) to be 2 research letter | dermatol pract concept. 2022;12(2):e2022061 effective: these alcohols can easily ignite and tend to burn relatively coldly. moreover, the vapor produced on the hands after gel application is flammable [2]. from march 2020, everyone has started using hand sanitizing gel in daily life, either for the recommendations and for their large availability at the entrances not only in hospitals, healthcare institutions and pharmacies, but also in every public shop and working place. this widespread use has caused an increase in irritant/allergic contact dermatitis cases, either relapsed or newly developed, and generally a worsening of atopic eczema and dryness. conclusions in the covid era, the danger related to the flammable nature of hand sanitizing gels has yet not been stressed, and the occurrence of burns after cigarette lightening following sanitizing gel application never reported. nevertheless, healthcare workers, non-healthcare workers and the general public are usually not aware, or not used to wait until the product as completely dried on the skin surface in daily life. people should now be informed on the flammability danger and should be aware of the necessity to wait few minutes to respect adequate time before getting close to ignition sources (eg cooking) or touching metal surfaces. references 1. tognetti l, de piano e, perotti r, et al.. clinical applications of skin bank bioproducts. in technology in practical dermatology. 2020:443-449. springer, cham. doi: 10.1007/978-3-030-45351-0_42 2. cristaudo a, pigliacelli f, pacifico a, damiani g, iacovelli p, morrone a. teledermatology and hygiene practices during the covid-19 pandemic. contact dermatitis. 2020;83(6):536. doi: 10.1111/cod.13683. pmid: 32754901. pmcid: pmc7436540. figure 1. clinical appearance of the patient at presentation time, 48 hours after flame burn injury due to cigarette ignition after application of hand sanitizing gel. (a) second degree burns on both palms and volar surface of the fingers and wrists. (b) first degree burn of the dorsum of the right hand and dorsal surface of the fingers of the left hand. (c) hand sanitizing gel. figure 2. (a) treatment cryopreserved skin graft for 7 days followed by hyaluron gauze for 7 days. (b) clinical appearance after 21 days at volar hand surfaces. (c) clinical appearance after 21 days at dorsal hand surfaces. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021079 1 can dermoscopy be used to predict if a melanoma is in situ or invasive? sam polesie1,2, edvin jergéus1, martin gillstedt1,2, hannah ceder1,2, johan dahlén gyllencreutz1, julia fougelberg1,2, eva johansson backman1,2, jenna pakka1,2, oscar zaar1,2, john paoli1,2 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden key words: breslow thickness, dermoscopy, inter observer variability, melanoma, projections and predictions. citation: polesie s, jergéus e, gillstedt m, ceder h, dahlén gyllencreutz j, fougelberg j, johansson backman e, pakka j, zaar o, paoli j. can dermoscopy be used to predict if a melanoma is in situ or invasive? dermatol pract concept. 2021;11(3):e2021079. doi: https://doi.org/10.5826/dpc.1103a79 accepted: february 4, 2021; published: may 20, 2021 copyright: ©2021 polesie et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: the study was financed by grants from the swedish state under the agreement between the swedish government and the county councils, the alf-agreement (alfgbg-728261). competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: sam polesie, md, phd, department of dermatology and venereology, sahlgrenska university hospital, gröna stråket 16, se-413 45 gothenburg, sweden (sam.polesie@vgregion.se) background: the preoperative prediction of whether melanomas are invasive or in situ can influence initial management. objectives: this study evaluated the accuracy rate, interobserver concordance, sensitivity and specificity in determining if a melanoma is invasive or in situ, as well as the ability to predict invasive melanoma thickness based on clinical and dermoscopic images. methods: in this retrospective, single-center investigation, 7 dermatologists independently reviewed clinical and dermoscopic images of melanomas to predict if they were invasive or in situ and, if invasive, their breslow thickness. fleiss’ and cohen’s kappa (κ) were used for interobserver concordance and agreement with histopathological diagnosis. results: we included 184 melanomas (110 invasive and 74 in situ). diagnostic accuracy ranged from 67.4% to 76.1%. accuracy rates for in situ and invasive melanomas were 57.5% (95% confidence interval [ci], 53.1%-61.8%) and 81.7% (95% ci, 78.8%-84.4%), respectively. interobserver concordance was moderate (κ = 0.47; 95% ci, 0.44-0.51). sensitivity for predicting invasiveness ranged from 63.6% to 91.8% for 7 observers, while specificity was 32.4%-82.4%. for all correctly predicted invasive melanomas, agreement between predictions and correct thickness over or under 1.0 mm was moderate (κ = 0.52; 95% ci, 0.45-0.58). all invasive melanomas incorrectly predicted by any observer as in situ had a thickness <1.0 mm. all 32 melanomas >1.0 mm were correctly predicted to be invasive by all observers. abstract 2 research | dermatol pract concept. 2021;11(3):e2021079 introduction the clinical diagnosis of melanoma is most often straightforward, as suggested by the fact that the majority are detected by the patient and not the dermatologist [1]. nonetheless, predicting preoperatively whether a melanoma is in situ or invasive is often challenging, since dermoscopic features for in situ melanomas are similar to those of thin invasive melanomas [2,3]. such a preoperative prediction is important since it helps select optimal clinical surgical margins for the diagnostic excision. international guidelines recommend a 1to 3-mm margin when invasive melanoma is suspected, to facilitate an expected subsequent wide local excision and, potentially, a sentinel lymph node biopsy [4,5]. however, if in situ melanoma is the primary clinical suspicion, the lesion may be excised directly with the recommended 5-mm surgical margin [6], conveniently avoiding an unnecessary second surgical procedure. for well-demarcated lesions not located in chronic sun-damaged skin, this pragmatic approach to optimizing the choice of surgical margins during the diagnostic excision is nowadays common practice in many swedish centers. in a recent investigation, lallas et al [3] analyzed dermoscopic features of 1,285 lesions including 325 in situ melanomas and 102 invasive melanomas with a breslow thickness <0.75 mm. in multivariable analyses including in situ melanomas, nevi, seborrheic keratosis, basal cell carcinoma, bowens disease and reed nevi the study identified atypical network, regression, irregular hyperpigmented areas, prominent skin markings and angulated lines as positive dermoscopic markers for in situ melanomas. when findings for invasive and in situ melanomas were compared, a multicomponent global pattern and blue-white veil were indicative of invasive melanomas, whereas extensive regression was the only indicator of in situ melanoma [3]. in an earlier study, silva et al [7] concluded that thin melanomas (breslow thickness <1.0 mm) tend to have asymmetry in 2 axes, ≥3 colors, atypical dots or globules, atypical network or streaks, while in situ melanomas tend to have ≤2 colors. blue-white veil and milky red areas were both associated with invasive disease [7]. while the abovementioned results are important in a research setting, their usefulness in a real-life clinical setting is more uncertain. the primary objective of this investigation was to explore dermatologists’ accuracy in discriminating in situ melanomas from invasive melanomas. methods we performed a retrospective, single-center investigation, including primary melanomas with available clinical and dermoscopic images obtained from our department. the study was approved by the regional ethics review board in gothenburg (approval number, d283-18). all dermoscopic images included in the study (supplementary file) had been acquired using a polarized light setting. melanomas that were previously biopsied or with images of suboptimal quality were excluded. all tumors were histopathologically confirmed by the hospital’s dermatopathology team. to avoid recall bias by the observers, the study only included cases that were diagnosed during 2016 (ie, >3 years prior to study initiation). the images were independently reviewed by 2 residents and 5 board-certified dermatologists. all observers had received training in dermoscopy (ie, had attended at least one dermoscopy course) apart from their daily use of dermoscopy in routine clinical practice. setting the dermatologists’ primary objective was to determine whether melanomas were invasive or in situ. if considered invasive, they estimated the breslow thickness by selecting one of the following intervals: 0-1.0; 1.01-2.0; 2.01-4.0 and >4.0 mm. outcomes the primary outcome measure was the accuracy rate in predicting in situ vs invasive melanoma, compared to the pathology report. the secondary outcomes were: (i) accuracy rate of the majority response (ie, decision of ≥4 observers), (ii) interobserver concordance, (iii) sensitivity and specificity with respect to invasive melanoma, and (iv) ability to classify invasive melanoma thickness greater or less than 1.0 mm. statistical analysis all data were analyzed using r version 3.5.3 (https:// www.r-project.org/). to measure interobserver concordance between the 7 observers and agreement compared to the pathology report, fleiss’ and cohen’s kappa (κ) were used [8,9]. the interobserver agreement was interpreted as poor (≤0), slight (>0 to 0.20), fair (>0.2 to 0.4), moderate (>0.4 to 0.6), substantial (>0.6 to 0.8) or almost perfect (>0.8). conclusions: accuracy rates for predicting thick melanomas were excellent, melanomas inaccurately predicted as in situ were all thin, and interobserver concordance for predicting in situ or invasive melanomas was moderate. preoperative dermoscopy of suspected melanomas is recommended for choosing appropriate surgical margins. research | dermatol pract concept. 2021;11(3):e2021079 3 results overall, 184 melanomas (110 invasive and 74 in situ melanomas) from 177 patients were included. the patients’ median age was 67 years (interquartile range, 57-77 years) and 83 (47%) were female. melanomas located on the trunk as well as the upper and lower extremities constituted 88% of all lesions (n = 162). overall diagnostic accuracy rates for all observers are presented in table 1. the individual accuracy rates (ie, proportion of predictions that agreed with the pathology report) ranged from 67.4% to 76.1%. when the majority decision for each lesion was considered separately, the accuracy rate was 75.0%. among the 7 dermatologists, the interobserver concordance was moderate [κ = 0.47, 95% confidence interval (ci), 0.44-0.51]. for 69 and 17 lesions, there was complete consensus among the observers that the lesions were invasive and in situ, respectively. for the invasive melanomas, the consensus response was true for 63 cases (91.3%). the corresponding number among in situ melanomas was 13 (76.5%). four melanomas were incorrectly predicted by all observers as in situ, but all had a breslow thickness ≤0.5 mm (figure 1). furthermore, all invasive melanomas that were predicted by any observer as in situ melanomas were <1.0 mm thick. the thickest melanoma classified as in situ by any observer had a breslow thickness of 0.9 mm. none of the lesions erroneously classified as in situ by any observer was ulcerated. conversely, all melanomas >1.0 mm in thickness (n = 32) were correctly classified as invasive melanomas by all observers. the sensitivity for predicting invasive melanoma ranged from 63.6% to 91.8% for the 7 observers (figure 2). the specificity ranged from 32.4% to 82.4% for the 7 observers. the breslow thickness predictions were further analyzed for all invasive melanomas that were correctly classified (629 of 770 predictions, 81.7%). for these assessments, the agreement (κ) between the observers and the pathology report for a breslow thickness over or under 1.0 mm was 0.52 (95% ci, 0.45-0.58). for the invasive melanomas where all observers agreed on the correct diagnosis (n = 63), the interobserver concordance for predicting a breslow thickness over or under 1.0 mm was also moderate (κ = 0.54; 95% ci, 0.49-0.59). discussion we report an accuracy rate ranging from 67.4% to 76.1% for predicting whether a melanoma was invasive or in situ based on clinical and dermoscopic images. for invasive lesions specifically, concordance for classification of breslow thickness over or under 1.0 mm was moderate compared to the pathology report. on the other hand, invasive melanomas >1.0 mm in thickness were all correctly classified as invasive by all observers; all invasive melanomas predicted incorrectly as in situ had a breslow thickness ≤0.9 mm, and none of these erroneously classified lesions were ulcerated. it is important and reassuring that all melanomas predicted to be in situ were histopathologically confirmed as either in situ or thin melanomas with a good prognosis. a strength of this investigation is that we included more observers and melanomas than previous investigations performed in similar settings [10-12]. while other investigations primarily focused on describing specific dermoscopic findings in invasive and in situ melanomas, our aim was to assess their usefulness in making precise diagnostic predictions. moreover, the dermoscopic images evaluated in this study are all shared in an online resource (supplementary file), which is exceedingly rare. polarized light setting was used for all cases in this study, but different dermatoscopes and camera setups were used when acquiring the images. specific meta-data, including age, skin type and relevant medical history were intentionally omitted, as the primary aim was to address the diagnostic accuracy based on images themselves. inclusion of these details could potentially have improved the accuracy rates [12]. table 1. diagnostic accuracy, by lesion characteristic1 characteristic lesions, n (%) accuracy, % (95% ci) in situ melanoma 74 (40) 57.5 (53.1-61.8) invasive melanoma 110 (60) 81.7 (78.8-84.4) breslow thickness2 (mm) <0.50 38 (21) 60.2 (54.0-66.1) 0.51 0.80 27 (15) 84.1 (78.1-89.0) 0.81 1.00 13 (7) 94.5 (87.6-98.2) 1.01 2.00 18 (10) 100 (97.1-100) 2.01 4.00 9 (5) 100 (94.3-100) >4.00 5 (3) 100 (90.0-100) ci = confidence interval. 1 values are aggregated responses for all 7 observers. 2 for 110 invasive melanomas. 4 research | dermatol pract concept. 2021;11(3):e2021079 figure 1. dermoscopic images of the 4 invasive melanomas that were predicted as in situ by all observers. all 4 lesions had a breslow thickness ≤0.5 mm. lesions (a) and (b) were located on the upper extremities, and lesions (c) and (d) were located on the scalp and arm, respectively. figure 2. sensitivity and specificity for the classification of invasive melanomas, for 7 dermatologists and for the majority decision (ie, decision of ≥4 observers). 100% 90% 361 5 7 4 2 80% 70% 60% 50% 40% 30% 20% 10% 100%90%80%70%60%50%40%30%20%10% 0% 0% se n si ti v it y specificity majority research | dermatol pract concept. 2021;11(3):e2021079 5 for the diagnosis of primary melanomas, dermoscopic evaluation outperforms evaluation with the naked eye [13]. nevertheless, the technique is more accurate when interpreted with the patient present, rather than analyzing dermoscopy images alone [14,15]. we also acknowledge the artificial setup in this investigation. making predictions such as these in real-life may have given different results. although the observers were not blinded to the fact that all lesions were either invasive or in situ melanomas, the study setting mimicked the very common scenario faced by physicians once a decision has been made to excise a melanocytic lesion in order to rule out melanoma. it is also important to underline that this investigation only included observers affiliated with a single academic center. as such, the evaluations could be expected to be more uniform since the same reference for learning has often been applied. lastly, the experience of the dermoscopist carrying out this type of evaluation is crucial, and the validity of our findings should be further assessed in multicenter studies at an international level. the incidence of melanoma has been rising drastically in europe during the past decades, and this incidence increase has especially been driven by more cases of thin invasive melanoma and in situ melanoma [16]. in fact, nowadays, more than half of all melanomas in sweden are diagnosed in their in situ growth phase [17]. rises in melanoma incidence and our quest to diagnose melanomas as early as possible will inevitably result in large numbers of excisions worldwide. although experts in dermoscopy excise substantially fewer suspicious skin lesions to find a single melanoma, a recent meta-analysis including 29 studies and almost 400,000 excisions showed that the overall number of pigmented lesions that need to be excised to find a melanoma is 9.7 [18]. with increased knowledge about the early diagnosis of melanoma, we have to find pragmatic solutions to minimize the number of unnecessary excisions of benign lesions. furthermore, studies have shown that 2-mm surgical margins, as internationally recommended for lesions suspected to be melanoma, result in incomplete excision rates of up to 24% [19,20]. it therefore seems reasonable to use a slightly larger surgical margin when in situ melanoma is suspected, to minimize the risk of incomplete diagnostic excisions, while also reducing the number of unnecessary wide local excisions afterwards. we therefore suggest that a 5-mm surgical margin is used when experienced dermoscopy users have a strong preoperative suspicion of in situ melanoma and no suspicion of invasiveness. we understand that this suggestion might be controversial for some, since this could lead to a slightly larger scar than necessary in cases when the excised lesion turned out to be a nevus. however, for atypical melanocytic lesions on surgically less-challenging body parts with a high dermoscopic suspicion of in situ melanoma, this treatment strategy could potentially lower the incomplete excision rates, minimize the number of unnecessary subsequent wide local excisions, lessen the morbidity for the patient and increase cost-effectiveness. moreover, it would not limit the ability of performing a wide local excision with a 1-cm margin in the eventual case of a thin invasive melanoma (<1 mm breslow thickness) being confirmed, nor are there any studies showing that a 5-mm margin would affect the possibility of performing a sentinel lymph node biopsy in the rare case of a thicker invasive melanoma being confirmed. although dermoscopy cannot perfectly predict if a melanoma is invasive or in situ, preoperative dermoscopic assessment of suspected melanomas should be recommended to choose the most appropriate surgical margins. supplementary materials the dermoscopic images evaluated in this study are available at: https://doi.org/10.6084/m9.figshare.12250028. references 1. mcguire st, secrest am, andrulonis r , ferris lk. surveillance of patients for early detection of melanoma: patterns in dermatologist vs patient discovery. arch dermatol. 2011;147(6):673-678. doi: 10.1001/archdermatol.2011.135. pmid: 21690529. 2. pizzichetta ma, argenziano g, talamini r, et al. dermoscopic criteria for melanoma in situ are similar to those for early invasive melanoma. cancer. 2001;91(5):992-997. pmid: 11251951. 3. lallas a, longo c, manfredini m, et al. accuracy of dermoscopic criteria for the diagnosis of melanoma in situ. jama dermatol. 2018;154:414-419. 10.1001/jamadermatol.2017.6447. pmid: 29466542. 4. swedish guidelines for malignant melanoma [article in swedish]. last updated april 29, 2019. accessed: november 17, 2020. https://kunskapsbanken.cancercentrum.se/globalassets/cancerdiagnoser/hud/vardprogram/nationellt-vardprogram-malignt-melanom.pdf 5. garbe c, amaral t, peris k, et al; european dermatology form (edf); european association of dermato-oncology (eado); european organization for research and treatment of cancer (eortc). european consensus-based interdisciplinary guideline for melanoma. part 2: treatment update 2019. eur j cancer. 2020;126:159-177. doi: 10.1016/j.ejca.2019.11.015. pmid: 31866016. 6. swetter sm, tsao h, bichakjian ck, et al. guidelines of care for the management of primary cutaneous melanoma. j am acad dermatol. 2019;80(1):208-250. doi: 10.1016/j.jaad.2018.08.055. pmid: 30392755. 7. silva vp, ikino jk, sens mm, nunes dh , di giunta g. dermoscopic features of thin melanomas: a comparative study of melanoma in situ and invasive melanomas smaller than or equal to 1mm. an bras dermatol. 2013;88(5):712-717. doi: 10.1590/ abd1806-4841.20132017. pmid: 24173175. 8. fleiss jl. measuring nominal scale agreement among many raters. psychological bulletin. 1971;76(5):378. doi: 10.1037/ h0031619. 6 research | dermatol pract concept. 2021;11(3):e2021079 9. cohen j. a coefficient of agreement for nominal scales. educational and psychological measurement. 1960;20(1):37-46. doi: 10.1177/001316446002000104. 10. carli p, de giorgi v, palli d, giannotti v , giannotti b. preoperative assessment of melanoma thickness by abcd score of dermatoscopy. j am acad dermatol. 2000;43(3):459-466. doi: 10.1067/mjd.2000.106518. pmid: 10954657. 11. tan e, oakley a, soyer hp, et al. interobserver variability of teledermoscopy: an international study. br j dermatol. 2010;163(6):1276-1281. doi: 10.1111/j.13652133.2010.10010.x. pmid: 20795998. 12. argenziano g, fabbrocini g, carli p, de giorgi v , delfino m. clinical and dermatoscopic criteria for the preoperative evaluation of cutaneous melanoma thickness. j am acad dermatol. 1999;40(1):61-68. doi: 10.1016/s0190-9622(99)70528-1. pmid: 9922013. 13. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. doi: 10.1111/j.1365-2133.2008.08713.x. pmid: 18616769. 14. dinnes j, deeks jj, chuchu n, et al; cochrane skin cancer diagnostic test accuracy group. dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. cochrane database syst rev. 2018;12(12):cd011902. doi: 10.1002/14651858. cd011902.pub2. pmid: 30521682. 15. carli p, de giorgi v, argenziano g, palli d, giannotti b. pre-operative diagnosis of pigmented skin lesions: in vivo dermoscopy performs better than dermoscopy on photographic images. j eur acad dermatol venereol. 2002;16(4):339-346. doi: 10.1046/j.1468-3083.2002.00470.x. pmid: 12224689. 16. sacchetto l, zanetti r, comber h, et al. trends in incidence of thick, thin and in situ melanoma in europe. eur j cancer. 2018;92:108-118. 10.1016/j.ejca.2017.12.024. pmid: 29395684. 17. the national board of health and welfare: statistics on cancer incidence 2018 [article in swedish]. accessed: november 17, 2020. https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2018-6-10.pdf 18. petty aj, ackerson b, garza r, et al. meta-analysis of number needed to treat for diagnosis of melanoma by clinical setting. j am acad dermatol. 2020;82(5):1158-1165. doi: 10.1016/j. jaad.2019.12.063. pmid: 31931085. 19. bakhai m, hopster d , wakeel r. a retrospective study comparing the accuracy of prehistology diagnosis and surgical excision of malignant melanomas by general practitioners and hospital specialists. clin exp dermatol. 2010;35(1):63-67. doi: 10.1111/j.1365-2230.2009.03507.x. pmid: 19778304. 20. murchie p, sinclair e , lee aj. primary excision of cutaneous melanoma: does the location of excision matter. br j general practice. 2011;61(583):131-134. doi: 10.3399/bjgp11x556272. pmid: 21276340. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022054 1 reactive pigmentation of skin graft mimicking a lentigo maligna recurrence: a case report matías gárate1, valentina vera1, nadia vega1, jonathan stevens2, verónica sanhueza3 1 department of dermatology, faculty of medicine, universidad de chile, santiago, chile 2 dermatology section, oncology institute, fundación arturo lópez pérez (falp), santiago, chile 3 pathology section, oncology institute, fundación arturo lópez pérez (falp), santiago, chile key words: dermoscopy, neoplasm recurrence, skin pigmentation, scar citation: gárate m, vera v, vega n, stevens j, sanhueza v. reactive pigmentation of skin graft mimicking a lentigo maligna recurrence: a case report. dermatol pract concept. 2022;12(2):e2022054. doi: https://doi.org/10.5826/dpc.1202a54 accepted: august 30, 2021; published: april 2022 copyright: ©2022 gárate et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: valentina vera giglio, servicio de dermatología, hospital clínico universidad de chile, santos dumont 999, independencia, santiago, chile. postal code: 8380456. e-mail: draveragiglio@gmail.com introduction there is limited information on dermoscopy of recurrent hyperpigmentation in skin grafts following lentigo maligna (lm) excision, especially in facial locations. we present a case with highly suspicious dermoscopic features of local recurrence of lm within the skin graft. case presentation a 49-year-old woman consulted with a 3-year history of hyperpigmented lesion on the left cheek, with gradual growth and darkening in the last 11 months. physical examination revealed phototype iv and an 15-mm diameter brown macule. dermoscopic evaluation (3gen – dermlite dl4®) showed a pseudo-network with asymmetric pigmented follicular openings (figure 1, a and b). incisional biopsy was performed and confirmed the diagnosis of lm. wide local excision with 5-mm margin was performed, followed by immediate reconstruction with a retro-auricular split-thickness skin graft. histopathologic examination confirmed the diagnosis of lm, without ulceration, mitosis, nor lympho-vascular invasion, and with clear surgical margins. at a 3-month follow-up, the patient reported recurrent pigmentation within the scar. physical examination revealed an erythematous scar with a brown pigmented border, 13  x  10 mm in diameter (figure 1c). dermoscopic evaluation showed brown pigmented areas extending slightly beyond the edge of the graft, with a pseudo-network pattern, asymmetric pigmented follicular openings and circles within circles, predominantly in the upper lateral area (figure 1d). recurrent lm versus reactive graft pigmentation were the proposed diagnosis. a new biopsy was performed, with complete excision of the scar, and histopathologic study ruled out malignant melanocytic neoplasia, with findings of dermal scarring, foreign body-type granulomas and dermal melanosis. sox-10 staining showed normotypic melanocytes, adequate in number and size (figure 2, ac). patient remains without signs of recurrence or pigmentation at the 6-months follow-up. 2 research letter | dermatol pract concept. 2022;12(2):e2022054 conclusions the most frequently described dermoscopic features of reactive pigmentations includes: a homogeneous radial band-like and continuous brownish lines that extends perpendicularly to the scar [1]. this case report describes unusual dermoscopic characteristics of reactive pigmentation within a skin graft, resembling a recurrence of lm. circle within circle sign is associated with lm with an odds ratio of 6.32 [2]. in addition, hyperpigmentation exceeding the edge of the scar is considered one of the most important criteria to suspect recurrent melanoma. in our case, the pattern of double circles associated with hyperpigmentation that exceeds the edge of the graft scar was observed, leading to suspect a recurrence of lm, which was histologically ruled out. we suggest that in grafts of the facial area in patients with darker skin phototypes, the underlying inflammation related to scarring would lead to reactive melanosis with a double circle pattern on dermoscopy as seen in lm recurrence in a scar. as reported by navarrete-dechent et al. in patients with scar tissue from previous treatment of lm, dermoscopy of melanoma-specific features has limitations [3], therefore, histopathological confirmation is essential for the differential diagnosis. figure 1. (a) clinical appearance pretreatment. hyperpigmented macula, 15 x 11 mm in diameter, on the left cheek. (b) dermoscopy pretreatment. brown macula, with pseudo-network structure. loss of follicular openings is observed isolated in the periphery (arrows). arboriform telangiectasias at the bottom of the lesion. (c) clinical appearance after surgery. erythematous plaque with a scar-like aspect and a brown pigmented border measuring 13 x 10 mm in diameter, on the left cheek. (d) dermoscopy after surgery. in the center of the lesion: follicular openings can be seen forming whitish circles. in the periphery: brown pigmentation which exceed the edge of the scar with the appearance of a pseudo-network. in superior lateral region: structures in a double concentric circle (arrow). a b research letter | dermatol pract concept. 2022;12(2):e2022054 3 keratosis and solar lentigines. acta dermatovenerol croat. 2019:27(3):146–152. pmid: 31542057 3. navarrete-dechent c, cordova m, liopyris k, et al. reflectance confocal microscopy and dermoscopy aid in evaluating repigmentation within or adjacent to lentigo maligna melanoma surgical scars. j eur acad dermatol venereol. 2020;34(1):74–81. doi: 10.1111/jdv.15819. pmid: 31325402. pmcid: pmc7592341. references 1. moscarella e, argenziano g, lallas a, longo c, al jalbout s, zalaudek i. pigmentation in a scar: use of dermoscopy in the management decision. j am acad dermatol. 2013;69(3):e115–e116. doi: 10.1016/j.jaad.2013.03.008. pmid: 23957988. 2. ozbagcivan o, akarsu s, ikiz n, semiz f, fetil e. dermoscopic differentiation of facial lentigo maligna from pigmented actinic figure 2. (a) histopathology examination (h&e, 4x) shows a slightly atrophic epidermis with basal hypermelanosis. proliferation of fibroblasts in the dermis associated with a perivascular lymphohistiocytic inflammatory infiltrate and the formation of granulomas with multinucleated giant cells. (b) higher magnification (h&e, 20x) shows basal hypermelanosis without proliferation of melanocytes. (c) sox-10 staining shows melanocytes of adequate number and size, equidistant and normotypic. c dermatology: practical and conceptual research | dermatol pract concept 2016;6(4):3 13 dermatology practical & conceptual www.derm101.com introduction benign lichenoid keratosis (blk), or lichen planus-like keratosis (lplk), is one of the most common diagnoses rendered in dermatopathology. formerly thought to represent a distinct entity, blk is now interpreted as the result of an inflammatory reaction directed against a benign epithelial neoplasm, usually a solar lentigo or variants thereof, namely, large-cell acanthoma and reticulated seborrheic keratosis [1,2]. the term “lichen planus-like keratosis” reflects the histopathologic resemblance to lichen planus by virtue of epidermal hyperplasia, a sawtooth pattern of rete ridges, wedgeregressing basal-cell carcinoma masquerading as benign lichenoid keratosis aleksandra kulberg1, wolfgang weyers2 1 department of dermatology, venerology, and allergology, klinikum hildesheim, germany 2 center for dermatopathology, freiburg, germany key words: basal-cell carcinoma, benign lichenoid keratosis, lichen planus-like keratosis. citation: kulberg a, weyers w. regressing basal-cell carcinoma masquerading as benign lichenoid keratosis. dermatol pract concept 2016;6(4):3. doi: 10.5826/dpc.0604a03 received: may 25, 2016; accepted: june 21, 2016; published: october 31, 2016 copyright: ©2016 kulberg et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: wolfgang weyers, md, center for dermatopathology, engelbergerstr. 19, 79098 freiburg, germany. tel. 01149761-31696; fax. 01149-761-39772. email: ww@zdpf.de background: benign lichenoid keratosis (blk, lplk) is often misdiagnosed clinically as superficial basal-cell carcinoma (bcc), especially when occurring on the trunk. however, bccs undergoing regression may be associated with a lichenoid interface dermatitis that may be misinterpreted as blk in histopathologic sections. methods: in order to assess the frequency of remnants of bcc in lesions interpreted as blk, we performed step sections on 100 lesions from the trunk of male patients that had been diagnosed as blk. results: deeper sections revealed remnants of superficial bcc in five and remnants of a melanocytic nevus in two specimens. in the original sections of cases in which a bcc showed up, crusts tended to be more common, whereas vacuolar changes at the dermo-epidermal junction and melanophages in the papillary dermis tended to be less common and less pronounced. conclusions: lesions from the trunk submitted as bcc and presenting histopathologically as a lichenoid interface dermatitis are not always blks. although no confident recommendations can be given on the basis of this limited study, deeper sections may be warranted if lesions are crusted and/ or associated with only minimal vacuolar changes at the dermo-epidermal junction and no or few melanophages in the papillary dermis. abstract 14 research | dermatol pract concept 2016;6(4):3 seen in one of many sections. having been surprised repeatedly by remnants of bcc in what was considered, at first blush, to be a blk, we re-examined in many step sections 100 lesions diagnosed as blk from the trunk of patients that had been submitted under the clinical diagnosis of bcc. the purpose of this study was (1) to assess the frequency of remnants of bcc in lesions interpreted as blk and (2) to look for histopathologic clues that may indicate a hidden bcc and may prompt deeper sections to be performed. materials and methods we re-evaluated 100 consecutive biopsy specimens from our files submitted under the clinical diagnosis of bcc and diagnosed histopathologically as blk. in order to reproduce the description of the stereotypical presentation of benign lichenoid keratosis by ackerman et al., only lesions from the trunk were included. in all cases, the original slide was reviewed and deeper sections were obtained. all sections were stained with hematoxylin and eosin. the following parameters were examined: solar elastosis, density of the infiltrate of inflammatory cells, necrotic keratocytes, colloid bodies in the papillary dermis, vacuolar degeneration of the basal cell layer, melanophages, mucin in the papillary dermis, hyperpigmentation of the basal layer, basket-woven orthokeratosis, compact orthokeratosis, mounts of parakeratosis, acanthosis, elongated rete ridges, sawtooth pattern of rete ridges and presence of a crust. each of those criteria was assessed in four grades, from absent (0), to weak (+), moderate (++), and marked (+++). results upon review of the original slides, no aggregations of bcc could be detected in any case. in deeper sections, superficial aggregations of bcc appeared in five specimens (5%, figures 1 and 2). in two lesions, step sections revealed remnants of a melanocytic nevus. the latter cases were excluded from the study. hence, histopathologic criteria were assessed for five lesions of superficial bcc with a lichenoid infiltrate and 93 lesions of blk. when the original slides of those lesions were compared, the features most indicative of bcc were crusts (40% bcc vs. 3% blk), mounts of parakeratosis (0% bcc vs. 27% blk), and vacuolar changes at the dermoepidermal junction (60% bcc vs. 94% blk). vacuolar changes were not only more common but also more pronounced in blk. likewise, melanophages tended to be more common in blks (67%), being present in a moderate or marked degree in about onethird of the cases. they were absent three of the five cases of bcc and pronounced in only one of them. weak basal hyperpigmentation was seen in two cases of bcc. it was slightly more common in lesions of blks but was classified as moderate in only 5% of those cases. as a clue to a preshaped zones of hyperkeratosis, orthokeratosis, vacuolar changes at the dermo-epidermal junction, individual necrotic keratocytes, and a superficial lichenoid infiltrate of lymphocytes often accompanied by melanophages. clinically, lichen planus is not a consideration in patients with a solitary lesion. among histopathologic features that may distinguish blk from lichen planus, but that are often missing, are foci of parakeratosis, areas with a diminished granular zone, marked solar elastosis, occasional plasma cells and eosinophils in the infiltrate, and remnants of solar lentigo or reticulated seborrheic keratosis at the edge of the lesion [3]. although the histopathologic features of blk are well established, the degree of those changes varies substantially between early and late stages, and minimal histopathologic criteria required for diagnosis of blk have never been specified. as a consequence, that diagnosis is often rendered in solar lentigines and seborrheic keratoses with only subtle lichenoid changes at the junction and a sparse infiltrate of lymphocytes. this being the case, and considering the nonspecific nature of blk, it is not surprising that data concerning the clinical presentation vary. lesions are said to be mostly solitary, but sometimes multiple; the areas of predilection are said to be arms and upper trunk, but also the face; and both, men and women, have been said to be affected more commonly [1-4]. the individual lesion has been described as a “sharply demarcated, erythematous, violaceous, tan or brown papule or plaque” measuring between 0.3 and 2 mm in diameter [4]. although “the surface is often scaly” [4], lesions are often misdiagnosed clinically as basal-cell carcinoma (bcc). according to ackerman et al., “lichen planus-like keratosis usually presents itself as a small papule on the chest or upper part of an arm of a middle-aged person, usually a man. often it is misinterpreted clinically as a basal-cell carcinoma.” [1] because that constellation of findings is very common, the diagnosis of blk is often rendered in knee-jerk fashion when confronted with a superficial lichenoid dermatitis from the trunk submitted as bcc. however, lichenoid dermatitis is a non-specific tissue reaction that may be encountered in a wide range of lesions, from disorders of immunity to infectious diseases and from melanocytic nevi and melanomas to benign and malignant epithelial neoplasms, the purpose presumably being to wipe out an antigenic stimulus. because that purpose is at least partially fulfilled, it is not surprising that the triggering stimulus may no longer be detectable in a biopsy specimen. in solitary lesions from the “chest or upper part of an arm of a middle-aged person” interpreted clinically as a basal-cell carcinoma and presenting as a lichenoid dermatitis, the triggering stimulus is usually a seborrheic keratosis, but may also be a bcc. in other words, clinicians are not always wrong. sometimes a tiny islet of bcc is left in a lesion that, in all other respects, is typical of blk, and sometimes that islet is only research | dermatol pract concept 2016;6(4):3 15 dently by lumpkin and helwig and by shapiro and ackerman in 1966. both pairs of authors were puzzled by noting, in a solitary lesion, histopathologic findings typical of lichen planus and raised the question whether those lesions represented a solitary variant of lichen planus or a previously undescribed separate entity. lumpkin and helwig referred to them as “solitary lichen planus,” whereas shapiro and ackerman chose the term “solitary lichen planus-like keratosis.” [5,6] although shapiro and ackerman had emphasized absence of findings suggestive of solar keratosis, such as sparing of adnexal structures, loss of the granular layer and of the “orderly stratified arrangement” of cells, variation of epithelial cells in size and shape, and pronounced cellular atypia [6], subsequent authors interpreted blk as a variant of actinic keratosis [7,8]. in order to distinguish lesions clearly from existing pigmented seborrheic keratosis, a more pronounced basal hyperpigmentation may militate against bcc. the same is true for basket-woven orthokeratosis that may indicate a pre-existing seborrheic keratosis and was observed more commonly in blk. mucin in the papillary dermis was noted in one case of superficial bcc with lichenoid inflammation. it was somewhat less common in blk (2 of 93 cases), but in those two cases was even more pronounced than in the case of bcc. none of the other criteria provided any clue to the presence of remnants of bcc in step sections. the criteria and the percentage of expression are listed in the table. discussion benign lichenoid keratosis (blk) was first described indepenfigure 1a. lesion originally diagnosed as blk. there is a dense lichenoid infiltrate in the upper dermis associated with fibrosis, epithelial hyperplasia, hypergranulosis, and compact orthokeratosis. step sections revealed remnants of a superficial bcc at the edge of the specimen. [copyright: ©2016 kulberg et al.] figure 1b. epithelial hyperplasia with a “sawtooth” pattern of rete ridges, hypergranulosis, and orthokeratosis. there are only minimal vacuolar changes at the dermo-epidermal junction and but a few necrotic keratocytes. numerous lymphocytes are present at the junction and in the lower half of the spinous zone. [copyright: ©2016 kulberg et al.] figure 2a. lesion originally diagnosed as blk. step sections revealed remnants of a bcc surrounded and interspersed with lymphocytes in the process of regression. at this slightly later stage, the lichenoid interface dermatitis is less pronounced. [copyright: ©2016 kulberg et al.] figure 2b. the epidermis is atrophic and infiltrated by only few lymphocytes. there are no vacuolar changes at the junction. remnants of necrotic keratocytes present themselves as “colloid bodies” beneath the basement membrane. the superficial dermis is fibrotic and harbors a few melanophages. [copyright: ©2016 kulberg et al.] 16 research | dermatol pract concept 2016;6(4):3 of solar lentigo to the violaceous plaque of blk, followed by complete disappearance of the lesion, have been documented in several studies [15-17]. in molecular studies, many blks have been found to harbor mutations commonly found in solar lentigines and seborrheic keratoses [18]. in brief, there is ample evidence that most solitary lesions displaying histopathologic features reminiscent of lichen planus are solar lentigines/reticulated seborrheic keratoses affected by a lichenoid tissue reaction. if the term blk is to maintain any specific meaning, it should be reserved to those lesions. if used in broader, non-specific fashion, i.e., for various types of regressing neoplasms affected by a lichenoid tissue reaction, it necessarily includes not only viral warts but also some solar keratoses, squamous-cell carcinomas, melanocytic nevi, and melanomas. in fact, it has been proposed to classify lichenoid keratoses into lesions “(1) associated with epithelial changes (lichenoid: seborrheic/actinic keratosis, squamous cell carcinoma, basal cell carcinoma, verruca, solar lentigo); (2) associated with melanocytic changes (lichenoid: melanocytic nevus, lentigo maligna, melanoma); and (3) miscellaneous (lichen planus, drug eruption, lupus erythematosus, cutaneous t-cell lymphoma).” [19] evidently, any usefulness of the term “lichenoid keratosis” is sacrificed by that approach. in general, blk is considered to represent an inflamed, regressing variant of solar lentigo/seborrheic keratosis. other types of lesions affected by a lichenoid tissue reaction are regarded as differential diagnoses of blk. the difficulty of differential diagnosis has been emphasized in various articles. especially, distinction from melanocytic lesions undergoing regression may be both challenging and important. in our actinic keratoses with a lichenoid infiltrate, the term “lichenoid benign keratosis” was introduced in 1976 by scott and johnson, who alluded not only to the lack of cellular atypia in blk but also to the absence of solar elastosis in many cases and to the occurrence of many lesions on the trunk [9]. in 1975, mehregan noted that, “the periphery of the lesions invariably showed areas of downward budding of pigmented basaloid cells characteristic of lentigo senilis. toward the center, these epithelial buds were obliterated by the development of an inflammatory cell infiltrate.” the latter was “not always bandlike as that of typical lichen planus, but was occasionally spotty and perivascular.” despite those deviations from previous descriptions, lesions were essentially the same as those reported as lichen planus-like keratosis: their center resembled lichen planus by virtue of “liquefaction degeneration of basal cells with incontinence of pigment” and “epidermal thickening with hypergranulosis and hyperkeratosis.” mehregan considered blk to be “an inflammatory variant of lentigo senilis.” [10] other authors confirmed mehregan’s observations. although remnants of a solar lentigo or reticulated seborrheic keratosis are not always detectable, they are found often and may serve as a clue to the diagnosis [11]. absence of such remnants has prompted some authors, to this date, to interpret blk as a distinct entity unrelated to solar lentigines and seborrheic keratoses [12,13]. however, in a lesion undergoing regression, failure to detect remnants of it must be expected. in clinical studies, blk has been found to show “a rather consistent association with senile lentigines.” [14] moreover, stages in the evolution of the pigmented macule table 1. criteria examined with degree of positivity in bcc and blk. [copyright: ©2016 kulberg et al. criteria bcc (%) n = 5 blk (%) n = 93 any degree 0 + ++ +++ any degree 0 + ++ +++ crusts 40 60 20 20 0 3 97 2 1 0 mounts of parakeratosis 0 100 0 0 0 27 73 17 10 0 vacuolar alteration 60 40 20 40 0 94 6 23 42 29 melanophages 40 60 20 0 20 67 33 38 27 -2 basal hyperpigmentation 40 60 40 0 0 47 53 42 5 0 basket-woven orthokeratosis 20 80 0 20 0 64 36 57 7 0 mucin in papillary dermis 20 8020 0 0 2 98 0 2 0 colloid bodies in papillary dermis 40 60 0 20 20 47 53 17 20 10 necrotic keratocytes 80 20 40 2020 85 15 37 30 18 hypergranulosis 40 60 0 40 0 64 36 45 18 1 “sawtooth” pattern of rete ridges 20 80 20 0 0 22 78 13 9 0 elongated rete ridges 40 60 0 0 40 61 39 33 24 4 compact orthokeratosis 40 60 40 0 0 53 47 37 16 0 inflammatory cell infiltrate 100 0 0 40 60 99 1 9 29 61 solar elastosis 100 0 40 60 40 99 1 27 59 13 research | dermatol pract concept 2016;6(4):3 17 interpretation of those cases as bcc undergoing regression. the same applies to remnants of other neoplasms, such as nests of a melanocytic nevus that turned up in two additional cases. there was no evidence of solar keratosis in any of our cases, probably because only lesions from the trunk of patients have been included. in brief, bcc was the neoplasm overlooked most commonly in lesions from the trunk. given the tendency of superficial bcc to regress that may be even more pronounced in lesions already showing definite signs of regression, the relatively low number of overlooked bccs may have little impact. nonetheless, foci of regression in a bcc do not imply regression of the entire lesion. portions of a bcc may continue to expand while others regress. the morphologic pattern of “multicentric” bcc has been attributed to “successive phases of growth and regression of the neoplasm.” [26] in any event, the diagnosis of blk was a misdiagnosis in five cases included in our study and, even more embarrassing, a histopathologic misdiagnosis overruled a correct clinical diagnosis. even with step sections, that mistake cannot be avoided entirely. nonetheless, deeper sections enhance the chance of finding remnants of the original lesion. considering effort and costs, clues as to whether deeper sections should be ordered are desirable. because of the limited number of lesions examined, no confident recommendation can be given on the basis of this study. nonetheless, the presence of crusts in concert with only minimal vacuolar alteration at the dermo-epidermal junction and no or few melanophages in the papillary dermis may justify deeper sections, whereas basket-woven orthokeratosis with mounts of parakeratosis and hyperpigmentation of the basal layer may reassure of the diagnosis of blk. aleksandra kulberg conducted this study during a fellowship at the center for dermatopathology in freiburg. references 1. ackerman ab, white w, guo y, umbert i. differential diagnosis in dermatopathology iv. philadelphia: lea & febiger, 1994:122-5. 2. weedon d. strutton g, rubin ai. weedon’s skin pathology. 3rd ed. london: churchill livingston, elsevier, 2010:47-8. 3. ackerman ab, niven j, grant-kels jm. differential diagnosis in dermatopathology. philadelphia: lea & febiger, 1982:10-13. 4. calonje e, brenn t, lazar a, mckee ph. mckee’s pathology of the skin, 4th ed. amsterdam: elsevier, 2012:231-2. 5. lumpkin lr, helwig eb. solitary lichen planus. arch dermatol 1966;93:54-5. 6. shapiro l, ackerman ab. solitary lichen planus-like keratosis. dermatologica 1966;132:386-92. pmid: 5922272. 7. hirsch p, marmelzat wl. lichenoid actinic keratosis. dermatologia int 1967;6:101-3. pmid: 5585742. 8. p i n k u s h . l i c h e n o i d t i s s u e r e a c t i o n s . a r c h d e r m a t o l 1973;107:840-6. pmid: 4575946. study, 2 of 100 lesions diagnosed originally as blk revealed remnants of a melanocytic nevus in deeper sections. this is consonant with data from the literature. in a study of 336 blks in which deeper sections were obtained, two lesions proved to be regressing melanocytic nevi [20]. in an even larger study comprising more than 1000 cases originally diagnosed as blk, 14 melanocytic nevi and 6 melanomas were identified [21]. in the original sections, the melanocytic proliferation may be masked by the dense lichenoid infiltrate at the dermo-epidermal junction. vice versa, blk may simulate a melanocytic nevus by the combined presence of lymphocytes and pigmented keratocytes with vacuolar alteration at the dermo-epidermal junction, sometimes leading to “pseudomelanocytic nests.” in cases of doubt, immunohistochemical confirmation of a melanocytic proliferation, or absence of it, is essential, and even then caution is advisable because markers of melanocytes, such as melan-a, may be falsely positive [22]. particularly challenging are cases in which the original lesion has regressed completely, leaving behind a superficial scar with coarse bundles of collagen in a thickened papillary dermis, telangiectases oriented mostly perpendicular to the skin surface, and melanophages. although some findings favor a regressed melanoma, such as large diameter and a dense horizontal band of melanophages, and others a regressed blk, such as foci of wedge-shaped hypergranulosis and clusters of necrotic keratocytes in the papillary dermis, a definite distinction between both conditions may be impossible [23]. although large series of cases diagnosed as blk have been reviewed in several studies in which deeper sections have been cut in search for other types of lesions, regressing bcc masquerading as blk has never been emphasized. this is surprising considering the clinical diagnosis of bcc in many cases of blk, especially those from the trunk, and the well-known tendency of bcc to regress. it has been estimated that 50% of bccs show histopathologic evidence of partial regression [24]. in superficial bccs, that proportion is even higher: foci devoid of neoplastic epithelial cells and characterized by a thickened papillary dermis with many fibroblasts and dilated, tortuous blood vessels are the rule, rather than the exception, contributing to the phenomenon of a seemingly “multicentric” lesion. because regression of both, superficial bcc and blk, is mediated by a dense superficial infiltrate of lymphocytes [25], confusion of both events is likely to occur in the absence of remnants of bcc or solar lentigo/seborrheic keratosis, respectively. in our review of 100 lesions diagnosed histopathologically as blk, the clinical diagnosis of bcc could be confirmed by cutting deeper sections in five lesions. the small size of aggregations of bcc, the dense lichenoid infiltrate of lymphocytes surrounding or infiltrating them, and the non-specificity of that inflammatory reaction militate against the possibility of a collision of two independent phenomena and strongly suggest 18 research | dermatol pract concept 2016;6(4):3 19. glaun rs, dutta b, helm kf. a proposed new classification system for lichenoid keratosis. j am acad dermatol 1996;35:772-4. pmid: 8912577. 20. dalton sr, fillman ep, altman ce, et al. atypical junctional melanocytic proliferations in benign lichenoid keratosis. hum pathol 2003;34:706-9. pmid: 12874767. 21. morgan mb, stevens gl, switlyk s. benign lichenoid keratosis. a clinical and pathologic reappraisal of 1040 cases. am j dermatopathol 2005;27:387-92. pmid: 16148406. 22. beltraminelli h, el shabrawi-caelen l, kerl h, cerroni l. melana-positive “pseudomelanocytic nests”: a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin. am j dermatopathol 2009;31:305-8. pmid: 19384076. doi: 10.1097/dad.0b013e31819d3769. 23. ackerman ab, white w, guo y, umbert i. differential diagnosis in dermatopathology iv. philadelphia: lea & febiger, 1994:126-9. 24. barnetson rs, halliday gm. regression in skin tumours: a common phenomenon. australas j dermatol 1997;38:s30-3. pmid: 10994476. 25. hunt mj, halliday gm, weedon d, cooke be, bernetson rs. regression in basal cell carcinoma: an immunohistochemical analysis. br j dermatol 1994;130:1-8. pmid: 7905746. 26. franchimont c, piérard ge, van cauwenberge d, damseaux m, lapiére ch. episodic progression and regression of basal cell carcinomas. br j dermatol 1982;106:305-10. pmid: 7066190. 9. scott ma, johnson wc. lichenoid benign keratosis. j cutan pathol 1976;3:217-21. pmid: 1018061. 10. mehregan ah. lentigo senilis and its evolutions. j invest dermatol 1975;65:429-33. pmid: 127813. 11. ackerman ab, guo y, vitale p. clues to diagnosis in dermatopathology ii. chicago: ascp press, 1992:265-8. 12. jang ka, kim sh, choi je, sung kj, moon kc, koh jk. lichenoid keratosis: a clinicopathologic study of 17 patients. j am acad dermatol 2000;43:511-6. pmid: 10954665. doi: 10.1067/ mjd.2000.107236. 13. kim hs, park ej, kwon ich, kim kh, kim kj. clinical and histopathologic study of benign lichenoid keratosis on the face. am j dermatopathol 2013;35:738-41. pmid: 23860115. doi: 10.1097/dad.0b013e318281cd37. 14. laur we, posey re, waller jd. lichen planus-like keratosis. j am acad dermatol 1981;4:329-36. pmid: 7217401. 15. berman a, herszenson s, winkelmann rk. the involuting lichenoid plaque. arch dermatol 1982;118:93-6. pmid: 7059225. 16. barranco vp. multiple benign lichenoid keratoses simulating photodermatoses: evolution from senile lentigines and their spontaneous regression. j am acad dermatol 1985;13:201-6. pmid: 4044948. 17. morgan mb, stevens gl, switlyk s. benign lichenoid keratosis. a clinical and pathologic reappraisal of 1040 cases. am j dermatopathol 2005;27:387-92. pmid: 16148406. 18. groesser l, herschberger e, landthaler m, hafner c. fgfr3, pik3ca and ras mutations on benign lichenoid keratosis. br j dermatol 2012;166:784-8. pmid: 22188534. doi: 10.1111/j.1365-2133.2011.10788.x. dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(1):e2022034 1 significance of primary melanoma regression on local infiltrate and outcome awatef kelati1,2, brigitte balme3, brigitte chouvet3, alexandra traverse-glehen3, juliette tantot3, olivier harou3, gérard duru4, sebastien debarbieux1, stephane dalle1,5,6, luc thomas1,5,6 1 dermatology department, hôpital universitaire lyon sud, hospices civils de lyon. pierre-bénite, france 2 dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco 3 anatomo-pathology department, hôpital universitaire lyon sud, hospices civils de lyon. pierre-bénite, france 4 research director in the claude bernard university, lyon, france 5 lyon 1 university lyon france 6 lyon cancer research center, centre léon bérard lyon france key words: primary melanoma, local infiltrate, outcome, histopathology, dermoscopy citation: kelati a, balme b, chouvet b et al. significance of primary melanoma regression on local infiltrate and outcome. dermatol pract concept. 2022;12(1):e2022034. doi: https://doi.org/10.5826/dpc.1201a34 accepted: september 1, 2021; published: january 2022 copyright: ©2022 kelati et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this work is supported in part by grants from université claude bernard lyon 1 (to lt and sd), from the hospices civils de lyon (to lt and sd), from the association vaincre le mélanome (to lt), from melarnaud (to sd), from lyrican (to sd), from the fondation arc (to sd). competing interests: none. authorship: all authors declare that they have sufficiently participated in the submitted work; all have had access to clinical material and have revised the manuscript before submission. study concept and design: ak, bb, sd, and lt; data acquisition, data analysis and interpretation, critical revision of the manuscript, and intellectual input: all authors; drafting of manuscript: ak, bb, oh, sd, and lt; statistical analysis: gd. corresponding author: awatef kelati, md, dermatology department, cheikh khalifa international university hospital, mohammed vi university of health sciences (um6ss), casablanca, morocco. e-mail: awatkelati@gmail.com introduction: the characteristics and the prognostic value of regression in primary melanomas are controversial. objectives: to further characterize “hot” and “cold” tumor’s stromas and to investigate the association between dermoscopy, pathology, and the prognostic implications of regression. methods: a 14-year-collection-based retrospective analysis was carried out on 40 patients with confirmed regressive melanomas. results: the extent of regression in dermoscopy was associated with the stage of the regression (p = 0.05) and with the melana patterns in histology (p = 0.02). blue-gray and gray-brown color of the peppering (p = 0.01), and the eccentric, multifocal character of the dermoscopic regression (p = 0.05) were associated with “hot” stromas (cd8+, granzym b+). focal histologic regression (regressing melanomas) was associated with a good outcome (p < 0.001), while a complete regression (regressed melanomas) was associated with melanoma-related death (p < 0.001). “hot” stromas (cd8+ were abstract 2 original article | dermatol pract concept. 2022;12(1):e2022034 significantly associated with survival at 10 years (p = 0.044), while “hot” stromas (granzyme b+) were associated with the locoregional extension (p = 0.016), and the initial distant metastasis (p = 0.016). conclusions: dermoscopic features of regression in primary melanomas were associated with the stage of regression, its extent, and the “hot” or “cold” nature of the tumor stroma, with prognostic implications. introduction histopathological features of regression, encountered in 10%-35% of primary cutaneous melanomas [1,2], classically appear on dermoscopy as white (or blue-white) scarlike areas (wsa) [3,4], variably admixed with blue-gray granularity (bgg) or “peppering”. both wsa and bgg are unspecific features of regression, and are often regularly distributed on more than 50% of the surface benign lesions, while they are smaller and irregularly distributed in melanomas [3–6]. recently, reticulated regression has been described in in situ or slow-growing invasive melanomas as a new dermoscopic feature of regression, and appears as a coarse blue-gray net, with thick gray-blue lines with large pink-colored holes [2,7]. although classic histopathological features of primary melanoma regression have been described over the past decades, their clinical implications and prognostic value remain unclear and controversial [2,8–16]. new interest in the evaluation of the nature of the host response, and the subsequent regression features in malignant tumors, especially melanomas, came after the development of immunotherapy. tumor stromas have been sub-classified into “hotly” and “coldly” infiltrated by immune cells [17], with the pathogenic hypothesis that “hot” tumors may respond better to immunotherapy, which stimulates the already present immune cells, whereas “cold” tumors should (or could) be initially stimulated by specific neo-adjuvant agents before the initiation of immunotherapy. objectives the primary aim of the present study was to further characterize “hot” and “cold” stromas in regressive melanomas based on dermoscopic and histopathologic criteria, and to preoperatively analyze dermoscopic features at different stages of regression. the secondary aim was to investigate the association between dermoscopy, pathology, and the prognostic implications of regression, with the ultimate goal of helping in the pre-therapeutic definition of “hot” tumors, which may benefit from postoperative adjuvant immunotherapy, and “cold” tumors, which could be included in potential neo-adjuvant clinical trials in priority before the excision of the primary tumor. methods the present study was approved by the hospices civils de lyon ethics committee, project n°20-15 (2019). it is a collection-based retrospective study of a consecutive series of patients having cutaneous melanomas with both confirmed dermoscopic and histopathological changes of regression, over a period of 14 years (2006-2019), for whom a complete set of clinical dermoscopic photographs was available. all patients gave their written informed consent for the use of their clinical records, clinical and dermoscopic images, pathological specimen at the time of the primary excision of the tumor, and subsequent inclusion in the centre de ressources biologiques (institutional biobank) of the hospices civils de lyon for research purposes. this study has not been registered in a public trial registry because it does not prospectively assigns human subjects to intervention or comparison groups to evaluate the cause and effect relationship between a medical intervention and a health outcome. this study does not fall into the scope of the french jardé law, of 16th november 2016 because it uses a preexisting cohort of patients and preexisting clinical records. the exclusion criteria were the absence or the poor quality of the dermoscopic images and the non-confirmation of the presence of histopathological features of regression upon reevaluation of the original histopathological slides. clinical history, clinical and dermoscopic images, histopathological reports, standard immunochemistry data (melana), and, when applicable, genotyping of braf mutations were directly collected from patient electronic records. dermoscopic images were analyzed by 3 independent experienced dermoscopists. regression-associated features were recorded as well (wsa and bgg), and were specifically evaluated for their presence, their disposition (central, eccentric, unifocal, multifocal), and their surface extension (on less than 25%, between 25% and 50%, or on more than 50% of the lesion). the presence or absence of reticular regression was also recorded. histopathological and melana slides were evaluated independently by 4 dermatopathologists with no knowledge of the original histopathology report; the regression was sub-classified into 3 stages as reported in the literature [2]. stage 1, or “inflammatory phase”, is characterized by a still recognizable tumor, with dense lymphocytic infiltrates admixed with nests of malignant melanocytes. stage 2 or “regressing phase” is characterized by still recognizable original article | dermatol pract concept. 2022;12(1):e2022034 3 melanoma cells, with tumor reduction or disappearance in the overlying epidermis, while in the papillary dermis the malignant tissue is replaced by lymphocytes and fibrosis. an increased vascularity is also observed because of angiogenesis, and heavily pigmented macrophages can be observed. stage 3 or “regressed melanoma” is characterized by the complete disappearance of the tumor that is replaced by a dense fibrotic tissue with vessels and melanophages in varying numbers, with few or no lymphocytes underneath a thinned epidermis. the extent of regression was also examined, and classified as focal if it involved a portion of the dermal component of the tumor, partial if it involved the entire dermal component, and complete if it involved the entire tumor [2]. additional immunophenotypic studies (cd8, langerin, granzyme b, and pdl-1) and an orcein stain were performed on formalin-fixed paraffin-embedded original pathological specimens. the proportion (%) of cells positive for cd8, granzyme b, langerin, and pdl-1 was evaluated in the area of the regression and in the tumor stroma, and categorized as covering < 5%, ⩾5 and <10%, ⩾10and <25%, ⩾25and < 50%, ⩾50 and >75%, or >75% of the whole inflammatory infiltrate. after discussion between the authors and a review of all the slides, tumors were considered as “hot” if their stroma was cd8+ on more than 25%, granzyme b+ on more than 10% of the inflammatory infiltrate, pdl-1+ on more than 5%, or langerin+ on more than 5%. otherwise, they were considered as “cold”. following our clinical practice, braf mutation was tested only for primary tumors thicker than 1.00 mm. statistical analysis analyses were performed using the statistical package for the social studies software version 20. quantitative variables were expressed as mean (± standard deviation, sd) and qualitative variables as count (percentage). progression-free survival was defined as the number of months from the diagnosis to the identification of locally recurrent or metastatic disease in the lymph nodes or distant organs. death was considered as melanoma-related in patients for whom the melanoma had progressed. a univariate analysis was performed to investigate the association between histological regression characteristics, inflammatory infiltrate status, and prognosis, using a chisquared 2 test. a p value ⩽0.05 was considered as significant. results among the 98 patients from the collection database, only 40 were included (30 were excluded because of incomplete dermoscopy record, 28 were excluded because of the absence of clear-cut histopathological features of regression). the mean (sd) age of included patients was 63.6 (15.7) years, and 82.5% of them presented with melanomas in the local stage (i and ii of the ajcc 2018 melanoma staging; table 1). within the regression area of the tumor, wsa were observed in 55% of lesions, blue-wsa in 45%, bgg in 97.5% (figures 1-3). reticular regression was observed in 75% of cases, and was associated with the polychromatic character of the lesion (p = 0.047) and the stage 2 of the regression in histology (p = 0.049). table 1. descriptive analysis of patients included in the present study total population n = 40 n (%) mean age, years (sd) 63.6 (15,7) sex, male 24 (60) lymph node metastasis 6 (15) metastatic melanoma 6 (15) dermoscopic regression variables blue-white areas blue-white white 18 (45) 22 (55) blue –white areas characteristics central eccentric 2 (5) 37 (92,5) coverage of the lesion less than 25% 25-50% more than 50% 14 (35) 10 (25) 16 (40) peppering 39 (97,5) focal total 37 (92,5) 2 (5) table 1 continues 4 original article | dermatol pract concept. 2022;12(1):e2022034 total population n = 40 n (%) color of the lesion brown-gray grey-blue grey-blue and brown-gray 13 (32.5) 14 (35) 12 (30) reticular regression in less palpable area 30 (75) grey-blue lines brown-gray lines 20 (50) 10 (25) vascularization polymorphic vessels linear irregular 25 (62.5) 2 (5) histopathology and immunochemistry melanoma histological subtype ssm regressive unclassifiable lm alm 25 (62.5) 7 (17.5) 6 (15) 2 (5) stage of the regression 1 2 3 3 (7.5) 24 (60) 13 (32.5) extent of regression complete focal partial 1 (2.5) 27 (67.5) 12 (30) melana normal (stage 1 of regression) reduced in the dermis, reduced in the epidermis absent in the dermis, reduced in the epidermis 1 (2.5) 26 (65) 13 (32.5) orcein in the regression area repressed, condensed, horizontal repressed, not condensed, horizontal 35 (87.5) 5 (12.5) immunochemistry (hot stromas) cd8+ granzyme b+ langerin + pdl1+ 37 (92.5) 22 (55) 21 (52.5) 14 (35) mutation braf v600 e 5 (12.5) melanoma staging ajcc 2018 i and ii (local) iii (loco-regional) iv (metastatic) 33 (82.5) 2 (5) 5 (12.5) evolution after 2 years of treatment death stable without clinical or radiologic evolution complete remission after more than 2 years 2 (5) 6 (15) 30 (75) ssm=superficial spreading melanoma lm: lentigo maligna alm=acral lentiginous melanoma ajcc =american joint committee on cancer table 1. descriptive analysis of patients included in the present study (continued) original article | dermatol pract concept. 2022;12(1):e2022034 5 figure 2. clinical and dermoscopic images of a regressed melanoma. white–blue scar-like areas (blue arrow), and extensive peppering (brown arrow) covering more than 75% of the lesion, with reticular regression (black circles). figure 1. clinical and dermoscopic images of a regressing melanoma. multicomponent pattern with multiple peripheral eccentric white scar-like areas (blue arrow) covering less than 50% of the lesion, with reticular regression (black circle). focal peppering (brown arrow). peppering was associated with thin melanomas (< 1mm, p = 0.012) and positive braf mutations (p = 0.028). wsa were associated with follicular migration in histology (p = 0.014). the extent of regression in dermoscopy was associated with the stage of regression (p = 0.05) and to melana patterns in histology (p = 0.023). chaotic lesions were associated with stage 1 and 2 of regression (p = 0.035), irregular thick reticular lines (p = 0.049) and blue white veil (p = 0.014) were associated with stage 2 of regression. annular granular pattern was associated with stage 2 and 3 of regression (p = 0.009). skin fissures exaggeration in dermoscopy (p < 0.001), the presence of eccentric globules (p = 0.027), blue-white area 6 original article | dermatol pract concept. 2022;12(1):e2022034 veil (p = 0.038), and perifollicular circles (p = 0.045) were associated with focal regression in histology. the loss of normal elastic fiber architecture in orcein stain was associated with the wsa with peppering (p = 0.001; table 2). on the other hand, red milky areas (p = 0.033), irregular thick reticular lines (p = 0.044), polygones (p = 0.044), and blue-gray and gray-brown color of the peppering granules (p = 0.011) were associated with “hot” granzyme b+ tumors, while “hot” cd8+ stromas were associated with skin fissures exaggeration (p = 0.043) and with the eccentric and multifocal character of regression in dermoscopy (p = 0.05). “cold” pdl1+ stromas were associated with inversed network in dermoscopy (p = 0.05) and eccentric globules (p = 0.044), while “cold” langerin+ stromas were associated with the multicomponent pattern (p = 0.032), peripheral structureless area (p = 0.026), and the rhomboidal pattern (p = 0.049) (table 2). table 2. univariate analysis variables p value immunodepression stage 3 of regression 0,000 elevated lesion (plaque ou nodular) hot stroma granzyme b+ 0,038 lesion color (polychromatic or achromic) braf mutation 0,035 regression extent 0,041 reticular regression in an area les palpable than the other areas 0,014 loco-regional metastasis dermoscopic regression (blue-white areas (scar like)) 0,041 focal regression in histology 0,004 hot stroma granzym b + 0,016 peppering focal regression (focal peppering) 0,000 low risk of recurrence after complete remission after surgery 0.029 extent of regression in dermoscopy melana expression 0,023 regression stages in histology 0,05 eccentric character of regression in dermoscopy stage 2 and 3 0,012 hot stroma cd8 + 0,05 granules color hot stroma granzym b + 0,011 reticular type of regression regression stage 2 0,049 annular granular pattern stage 2 and 3 of regression 0,009 good outcome with complete remission, and no evolution after treatment 0.001 irregular thick reticular lines stage 2 of regression 0,049 hot stroma granzyme b + 0,044 skin fissures exaggeration focal regression in histology 0,000 hot stroma cd8 + 0,043 good outcome with complete remission, and no evolution after treatment 0.002 good response to immunotherapy 0.003 table 2 continues figure 3. hot stroma in a regressive melanoma. stage 2 of histologic regression with the corresponding melana pattern as reduced in the dermis and reduced in the epidermis, and cd8+ immunochemistry on more than 50% of the inflammatory infiltrate (magnification x10). original article | dermatol pract concept. 2022;12(1):e2022034 7 variables p value blue-white area (veil) melana pattern: reduced in the dermis, reduced or normal in the epidermis 0,010 stage 2 of regression 0,014 focal regression in histology 0,038 pseudopods good outcome with complete remission, and no evolution after treatment 0.033 peripheral focal irregular network good outcome with a complete remission, and no evolution after treatment 0.05 polygones hot stroma granzym b+ 0,044 melanoma stage (ajcc 2018) the extent of regression 0.01 hot stroma cd8+ 0.038 regression stage stage 2 local extension 0.030 stage 3 melanoma specific death (at 2 years, 5 years of initial treatment) p=0.048/ p=0.020 immunotherapy response hot stroma cd8 + 0.032 progression free survival regression extent 0.005 hot stroma cd8+ 0.044 melanoma specific death regression extent 0.000 focal regression was associated with good outcome (p < 0.001) and the immunotherapy response (p < 0.001), while complete and partial regression of histology were associated with melanoma-related death (p < 0.001), regression stage 3 of histology was associated with melanoma-related death at both 2 years (p = 0.048) and 5 years (p = 0.020) since initial treatment. “hot” cd8+ stromas were associated with a good response to immunotherapy (p = 0.032), and with the survival at 10 years (p = 0.044). also, “hot” granzyme b+ stromas were associated with locoregionnal extension (p = 0.016), and initial distant metastasis (p=0.016) (table 2). the local extension (in transit metastasis) of these regressive melanomas was associated with the stage 2 of regression (p = 0.030), while locoregional extension and initially distant metastasis were associated with wsa in dermoscopy (p = 0.041) and with focal regression in histology (p = 0.008; table 2). conclusions in the present study we were able to further characterize “hot” and “cold” stromas in the context of melanoma regression based on dermoscopic criterias and the inflammatory infiltrate status. indeed, we found an association of many and specific dermoscopic features with “hot” granzyme b+ and “hot” cd8+ stromas, or “cold” pdl1+ and “cold” langerin+ stromas. this further characterization of the previous sub-classification of “hot” and “cold” stromas in melanomas [17] based on the immunopathology nature of the inflammatory infiltrate had interesting prognostic implications, as cd8+ stromas were significantly associated with a good response to immunotherapy, and to the disease free survival at 10 years, which confirms a study that has previously reported an association between cd8 t-cell infiltration and better prognosis [14]. also, “hot” granzyme b+ stromas were associated with locoregional extension and the initial distant metastasis, while no prognostic implication of langerin or pdl-1 expression around the tumor and in the regression were found in the present study. the prognostic value of pdl-1 is controversial, as some authors have failed to observe a correlation between pdl-1 expression in sentinel lymph node metastases and the outcome (which is consistent with our results), while others have reported pdl-1 as an independent negative prognostic marker in conventional melanoma, and, in contrast, others have reported pdl-1 expression in mucosal melanomas as correlated with longer recurrence-free survival [18]. a preoperatively comparison of various dermoscopic features of regressive melanoma at different stages of regression was made, and the association between dermoscopy, pathology, and the prognostic implications of regression was investigated. peppering was found as significantly associated with thin melanomas in histology, this refines knowledge about peppering that has been described as an expression of melanophages in the dermis [2], and has been significantly associated with braf mutation [2], confirming that regression may be a hallmark of brafv600 melanomas. in addition, in primary melanomas, mutated braf has been table 2. univariate analysis (continued) 8 original article | dermatol pract concept. 2022;12(1):e2022034 described as an adverse prognostic factor [20]. in the present study, even though braf mutation status was not found in many patient records because most had thin melanomas, it was significantly associated to rapidly growing melanomas, which were polychromatic, chaotic, or with a multicomponent pattern in dermoscopy, or with signs of horizontal growth and local extension. as a result, braf mutation may be a prognostic factor in regressive melanomas. also, the dermoscopic extent of regression (wsa with peppering) was significantly associated with regression stages in histology and enabled us to evaluate the aggressiveness of the tumor, since the results presented herein demonstrated an association between advanced stages of regressive melanomas and the extent of regression, and between stage iii melanoma and melanoma-related death. in addition, the presence of dermoscopic signs associated with hot stromas cd8+ or granzyme b + ( rred milky areas, irregular thick reticular lines, polygones, the peppering granules’ color, and the eccentric, multifocal character of regression), supports the idea that further dermoscopic investigations of the regression in primary melanomas would be of great help in the pre-excision therapeutic evaluation and predictable therapeutic response. reticular regression in a clinically less palpable area, which has been recently reported [7,19], was frequent in patients who had stage 2 of regression in thin melanomas. this type of regression may be correlated with the remaining junctional component and the heterogeneous dermal regression in stage 2 before the complete disappearance of the dermal tumor. remarkably, melana red immunostaining could be a good tool to confirm, characterize, and probably classify the histologic regression, especially when histologic regression is not so obvious. despite contradictions in the literature, patients with thin melanomas who show partial regression cannot be included in the “low-risk” group if the extent of regression is more than 50% [16,21,22]. completely regressive lesions represent a factor of delay in diagnosis, and of development of locoregional and distant metastasis, as it has been reported in some case reports and studies [21,23]. this was also confirmed with the results herein as melanoma-related death was associated with regressed melanomas (stage 3 and complete regression). the data herein suggest that the prognostic role of regression depends on the stage of melanoma, the stage of regression and its extent (regressing or regressed melanomas), and the “hot” or “cold” nature of the cd8+ and granzyme b+ tumor stroma, which may explain the controversies found in the literature concerning regression [2] as it has not been precisely sub-classified previously. due to the retrospective nature of this study, many important data were missing from the patient records: for example, the braf status that was not determined for all patients, especially because most melanomas were thin, it was therefore not possible to draw conclusions about the prognostic value of braf mutation in regressive melanomas. however, even though this aspect would have been interesting to determine, and for future studies, it was not among our main objectives. also, the small number of patients was due to the retrospective collection of the records and to the dermoscopic images themselves that were often not found or of poor quality, leading to the exclusion of some patient. additionally, some patients were excluded after review by experienced pathologists because regression was not objectively observed. the present study provides a better characterization of regression in primary melanomas, and a better comprehension of the “hot” or “cold” character of the stroma. an important outcome of the study is that regressing melanoma (early stages of regression) is associated with favorable outcome whereas regressed melanoma (complete regression stage 3) is associated with a worse outcome. further studies with a prospective design could help in confirming and investigating these results, especially the importance of dermoscopy in predicting the 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21748024; pmcid: pmc3118612. 20. spathis a, katoulis ac, damaskou v, et al. braf mutation status in primary, recurrent, and metastatic malignant melanoma and its relation to histopathological parameters. dermatol pract concept. 2019;9(1):54-62. doi: 10.5826/dpc.0901a13. pmid: 30775150. pmcid: pmc6368075. 21. maurichi a, miceli r, camerini t, et al. prediction of survival in patients with thin melanoma: results from a multi-institution study. j clin oncol. 2014;32(23):2479-2485. doi: 10.1200/ jco.2013.54.2340. pmid: 25002727. 22. ronan sg, eng am, briele ha, shioura nn, gupta tkd. thin malignant melanomas with regression and metastases. arch dermatol. 1987;123(10):1326-1330. pmid: 3662564. 23. t chernev g, temelkova i. primary regressive, but metastasizing melanoma!? open access maced j med sci. 2019;7(5):893-895. doi: 10.3889/oamjms.2019.048. pmid: 30962857. pmcid: pmc6447344. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(3):13 63 dermatology practical & conceptual www.derm101.com introduction pityriasis amiantacea (pa) is a scalp disorder presenting with thick, silvery/yellowish, asbestos-like scales wrapping around and binding down tufts of hair [1]. it is typically considered to be a reactive condition to several inflammatory diseases, which may affect the scalp, mainly including psoriasis, atopic dermatitis and seborrheic dermatitis [1]. however, although rarely, pa may be the presenting clinical pattern of dermatophyte infection (pa-like tinea capitis), thus emphasizing the importance of ruling out/confirming the possibility of tinea capitis when dealing with a case of pa [1,2] we here describe for the first time the usefulness of dermoscopy as a supportive diagnostic tool in an instance of pa-like tinea capitis. case report a 9-year-old girl presented with a five-week history of a progressively worsening, asymptomatic, scaling patch on the scalp. her past medical history was unremarkable and there was no personal or family history of atopic diathesis and skin diseases. physical examination showed thick, adherent, whitish, asbestos-like scales on the right parietal region of the scalp, surrounding and binding the hair (figure 1a); no other significant skin, nail or mucosal finding was evident. dermoscopic examination (performed with dermlite dl3 x10; 3gen, san juan capistrano, ca, usa) revealed diffuse white scales and compact white keratotic material adhering to tufts of hair (asbestos-like scaling) without erythema dermoscopy as a useful supportive tool for the diagnosis of pityriasis amiantacea-like tinea capitis enzo errichetti1, giuseppe stinco1 1 department of experimental and clinical medicine, institute of dermatology, university of udine, italy key words: dermoscopy, differential diagnosis pityriasis amiantacea, pityriasis amiantacea-like tinea capitis; tinea capitis. citation: errichetti e, stinco g. dermoscopy as a useful supportive tool for the diagnosis of pityriasis amiantacea-like tinea capitis. dermatol pract concept 2016;6(3):13. doi: 10.5826/dpc.0603a13 received: may 3, 2016; accepted: may 27, 2016; published: july 31, 2016 copyright: ©2016 errichetti et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: enzo errichetti, md, institute of dermatology, “santa maria della misericordia” university hospital, piazzale santa maria della misericordia, 15—33100 udine, italy. tel. (+39) 0432559820. email: enzoerri@yahoo.it clinical distinction between pityriasis amiantacea-like tinea capitis and pityriasis amiantacea due to noninfectious inflammatory diseases is a troublesome task, with a significant likelihood of diagnostic errors/delays and prescription of inappropriate therapies. we report a case of pityriasis amiantacealike tinea capitis with its dermoscopic findings in order to highlight the usefulness of dermoscopy in improving the recognition of such a condition. abstract 64 observation | dermatol pract concept 2016;6(3):13 copy turned out to be very helpful in suspecting tinea infection by showing the aforementioned “zigzag” and “question mark” hairs. in fact, although such features (or similar findings) may be rarely found in other hair disorders (e.g., “zigzag” hairs in trichorrhexis nodosa, alopecia areata and monilethrix, and “question mark” hairs in alopecia areata) [3-7], they are typically not visible in classic pa [10]. in conclusion, even though the final diagnosis relies on mycological testing, dermoscopy might come in very handy for raising the suspicion of tinea capitis presenting with a pa-like appearance by showing peculiar dermoscopic findings (e.g., as shown in this case, “zigzag” and “question mark” hairs), which are typically not detectable in instances of pa due to inflammatory diseases. obviously, further studies on larger groups of patients are needed to confirm our observations. references 1. abdel-hamid ia, agha sa, moustafa ym, el-labban am. pityriasis amiantacea: a clinical and etiopathologic study of 85 patients. int j dermatol 2003;42(4):260-4. pmid: 12694489. pmid: 10.1046/j.1365-4362.2003.01755.x. 2. ginarte m, pereiro m jr, fernández-redondo v, toribio j. pityriasis amiantacea as manifestation of tinea capitis due to microsporum canis. mycoses 2000;43(12):93-6. pmid: 10838857. doi: 10.1046/j.1439-0507.2000.00543.x. 3. rudnicka l, szepietowski jc, slowinska m, et al. tinea capitis. in: rudnicka l, olszewska m, rakowska a (eds). atlas of trichoscopy. 1st ed. london: springer-verlag, 2012;361-9. 4. arrazola-guerrero j, isa-isa r, torres-guerrero e, arenas r. tinea capitis. dermoscopic findings in 37 patients. rev iberoam micol 2015;32(4):242-6. pmid: 25728878. doi: 10.1016/j. riam.2014.09.002. (figure 1b); interestingly, several hairs displayed a “question mark” or “zigzag” (hair shaft bent at more than one point) appearance (figure 1b). as such dermoscopic findings may be found in tinea capitis [3-7], we decided to carry out a direct microscopic examination of 10% koh preparation of the scales scraped from the scalp, which showed septate branching hyphae. specimens were also cultured on conventional sabouraud’s dextrose agar medium, with evidence of microsporum canis growth after three weeks, thus confirming the diagnosis of tinea capitis. the patient was treated with oral griseofulvin (15 mg/kg once daily) with complete resolution of the clinical picture after eight weeks of therapy. discussion clinical distinction between pa due to inflammatory noninfectious diseases and pa-like tinea capitis is a challenging task, with a significant likelihood of diagnostic errors/delays and prescription of inappropriate therapies [1,2]. over the last few years, dermoscopy has been showed to be a useful auxiliary instrument for the recognition of several hair disorders [8-9], particularly dermatophyte infections [3-7]. indeed, beside nonspecific findings (broken and dystrophic hairs, black dots, scaling, erythema, etc.), tinea capitis may display peculiar dermoscopic features such as “comma” hairs, “corkscrew” hairs, “zigzag” hairs, interrupted (morse code-like) hairs, “elbowshaped” hairs and “question mark” hairs [3-7]. regarding the present instance, even though we observed dermoscopic findings that may be commonly seen in pa, i.e., diffuse white scaling and the characteristic compact white keratotic material adhering to a tuft of hair (asbestos-like scales) [10], dermosfigure 1. physical examination shows thick, whitish, asbestos-like scales surrounding and binding the hair on the right parietal region of the scalp (better visible in the box) (a). polarized light dermoscopic examination displays white scales and compact white keratotic material adhering to tufts of hair (asbestos-like scaling) without erythema; “question mark” (black arrow in the box) and “zigzag” (hair shaft bent at more than one point—black arrowhead in the box) hairs are also visible (b). [copyright: ©2016 errichetti et al.] observation | dermatol pract concept 2016;6(3):13 65 2015;72(1 suppl):s41-2. pmid: 25500038. doi: 10.1016/j. jaad.2014.05.063. 8. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol 2015;150(5):53346. pmid: 26086412. 9. rudnicka l, olszewska m, rakowska a, slowinska m. trichoscopy update 2011. j dermatol case rep 2011;5(4):82-8. pmid: 22408709. doi: 10.3315/jdcr.2011.1083. 10. verardino gc, azulay-abulafia l, macedo pm, jeunon t. pityriasis amiantacea: clinical-dermatoscopic features and microscopy of hair tufts. an bras dermatol 2012;87(1):142-5. pmid: 22481666. 5. schechtman rc, silva ndv, quaresma mv, et al. dermatoscopic findings as a complementary tool on the differential diagnosis of the etiological agent of tinea capitis. an bras dermatol 2015;90(3 suppl 1):s13-5. pmid: 26312662. doi: 10.1590/abd18064841.20153787. 6. lacarrubba f, verzì ae, micali g. newly described features resulting from high-magnification dermoscopy of tinea capitis. jama dermatol 2015;151(3):308-10. pmid: 25471133. doi: 10.1001/ jamadermatol.2014.3313. 7. wang hh, lin yt. bar code-like hair: dermoscopic marker of tinea capitis and tinea of the eyebrow. j am acad dermatol dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(2):e2021033 1 acceptance of teledermoscopy by general practitioners and dermatologists in denmark tine vestergaard1, merethe k. andersen2, anette bygum3 1 department of dermatology and allergy centre & odense patient data explorative network, odense university hospital, odense, denmark 2 audit project odense, research unit of general practice, university of southern denmark, odense, denmark 3 department of dermatology and allergy centre, odense university hospital, odense, denmark key words: provider satisfaction, teledermoscopy, teledermatology, skin cancer, malignant melanoma, general practitioner citation: vestergaard t, andersen mk, bygum a. acceptance of teledermoscopy by general practitioners and dermatologists in denmark. dermatol pract concept. 2021;11(2):e2021033. doi: https://doi.org/10.5826/dpc.1102a33 accepted: october 30, 2020; published: april 12, 2021 copyright: ©2021 vestergaard et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: tine vestergaard, md, odense university hospital, kløvervænget 15, 5000 odense c, denmark. email: tine.vestergaard@rsyd.dk background: teledermoscopy can be used to triage referrals of suspected skin cancers, thereby reducing waiting time and number of face-to-face consultations with a dermatologist. however, the success of the implementation of this technology in part relies on the acceptance of the providers. objectives: this study assessed the attitudes towards teledermoscopy of referring general practitioners and consultant dermatologists. methods: general practitioners from 48 practices and 3 dermatologists in the region of southern denmark, who had previous experience with teledermoscopy, were invited to answer questionnaires on their acceptance of the technology. results: general practitioners from 23 practices responded. all domains of the questionnaire received high scores, indicating a high degree of acceptance of teledermoscopy among respondents. all 3 dermatologists agreed that teledermoscopy was useful for triaging referrals, but they were less confident in their diagnoses and management plans proposed by teledermoscopy than in traditional face-to-face evaluations of patients. two of the 3 dermatologists were satisfied with using teledermoscopy as a consult method. conclusions: this study reports high levels of provider acceptance of teledermoscopy. however, a low response rate among general practitioners may limit its generalizability. abstract 2 research | dermatol pract concept. 2021;11(2):e2021033 introduction the rising incidence of skin cancer affects the lives of many and poses a burden to health care systems across the globe [1,2]. in denmark, persons who suspect they might have skin cancer usually consult their general practitioner (gp), who acts as a gatekeeper in triaging these lesions for further evaluation by a dermatologist or plastic surgeon. however, early signs of skin cancer may be subtle, and a sensitivity of 50%-55% for the detection of malignant melanoma has been reported for gps [3]. telemedicine is useful in dermatology, a medical specialty that relies on visual inspection and pattern recognition [4]. however, telemedicine is currently not recommended in denmark for the evaluation of possible skin cancers. in the examination of skin tumors, dermatologists use dermoscopy, which has been shown to increase the diagnostic sensitivity and specificity [5]. given the right equipment, gps can take dermoscopic images and forward them for evaluation by a dermatologist. this has been reported to be useful as a triage tool and can reduce waiting times [6]. we previously studied the diagnostic accuracy of teledermatology, including teledermoscopy, in the region of southern denmark in 2018 [7]. in the current study, we assessed the acceptance of this new technology among participating gps. in addition, we collected the views of the participating dermatologists. satisfaction of both patient and provider is believed to be an important factor in the successful implementation of novel technologies [8,9]. we previously reported that almost 90% of patients were satisfied with, or neutral towards, the use of teledermoscopy [10]. materials and methods prior diagnostic accuracy study gps from 50 practices in the region of southern denmark had been included in the diagnostic accuracy study [7]. background information on age, sex, years working as a gp, interest in dermatology and dermoscopy, and distance to the nearest dermatologist was gathered in january 2018. during the study, 2 general practices dropped out and 1 general practice did not include any patients. a total of 519 patients with 600 possible skin cancers were included. on average, each practice photographed 12.5 lesions (range, 0-41) with an iphone and handyscope, which were sent for evaluation by a dermatologist using the fotofinder hub [11]. the study was initialized with a teaching session on dermoscopy by the primary investigator in january 2018 and was completed with an evaluation and feedback session in december 2018 as proposed by the apo method [12]. gps from 29 general practices attended this meeting. in february 2019, we e-mailed an electronic questionnaire on provider acceptance of teledermoscopy to all 48 participating general practices, with a reminder 2 weeks later. questionnaire for gps the questionnaire used to assess the gps’ acceptance of teledermoscopy was the modified technology acceptance model (teletam) developed by orruño et al [13]. teletam was developed based on existing theories on adaptation and acceptance of new technologies, and was faceand content-validated by experts. it consists of 33 questions exploring 8 domains believed to influence the acceptance of teledermatology by physicians (table 1). the providers’ future intention to use teledermatology (int) is the main outcome. the other 7 domains consist of items related to the individual context (compatibility, attitude), the technological context (perceived usefulness, perceived ease of use, habits), and the organizational context (facilitators, subjective norm). at the end of the questionnaire, gps had the option to comment in free writing. we translated the english version of the questionnaire into danish after a forward translation and back-translation process. the word “teledermatology” in the original questionnaire was replaced by “teledermoscopy” in this study. answers to the questionnaire were given on a 7-point likert scale ranging from strongly disagree to strongly agree. questionnaires were created, sent and stored in redcap (research electronic data capture) hosted at open (open patient data explorative network), odense university hospital [14,15]. we speculated that a gp’s intention to use teledermoscopy might be influenced by having a dermoscope or a special interest in dermatology before the study, or by the distance to the nearest dermatologist. questionnaire for dermatologists three dermatologists who had participated in the diagnostic accuracy study on teledermoscopy were asked about their views on this novel procedure via a short questionnaire. they had 1, 4 and 9 years of experience post-specialization, and had reviewed 25.8%, 24.8% and 26.2% of the cases referred for teledermoscopy, respectively. a fourth dermatologist, who was an investigator in this study and hence not surveyed, had evaluated the remaining photos. to evaluate the dermatologists’ perceptions of teledermoscopy, the 5 questions previously applied by whited and colleagues were used [16]. these questions were considered to have face validity as they treated issues pivotal to the future implementation of teledermoscopy. a paper form with the original english wording and a danish translation was used. since the dermatologists evaluated both clinical and dermoscopic images of each skin lesion, the word “teledermatology” was maintained. research | dermatol pract concept. 2021;11(2):e2021033 3 statistical analysis stata version 16.0 was used for all statistical methods. p values <.05 were considered statistically significant. in concordance with the study by orruño et al [13], a score was calculated for each domain as the mean of the scores of the questions related to that domain. for the logistic regression analysis, the dependent variable (int) was dichotomized into 0 = low/moderate and 1 = high intention to use teledermoscopy. as in the study by orruño et al [13], we chose the median as the cut-off point between the groups; a score ≥6 was rated as high intention. because only 29 observations were available, the number of explanatory variables needed to be reduced for the regression analyses. based on previous studies, 3 domains, namely perceived usefulness (pu), perceived ease of use (peu) and facilitators (fac), were considered most important [13,17]. orruño et al [13] only found fac to be a significant predictor of int. pu and peu were dimensions in the original technology acceptance model proposed by davis [18], and both domains had high correlations with int. we found collinearity between the variables pu and peu and decided to reduce our statistical model further by excluding peu. cronbach alpha and inter-item correlation were calculated to elucidate the reliability and validity of the teletam questionnaire. results general practitioners’ responses twenty-nine gps from 23 different practices completed the teletam questionnaire. gps from another two practices reporting on technical problems did not respond, for a total of 68 non-respondents. background information on respondents and non-respondents, collected during the diagnostic accuracy study, is shown in table 2. respondents were significantly older than non-respondents and there was a trend towards respondents being more interested in dermatology. scores on the teletam questionnaire, for the 8 domains, and cronbach alpha and inter-item correlation are shown in table 3. all domains received high scores, indicating a high degree of acceptance of teledermoscopy among respondents. cronbach alpha was acceptably high for all variables except fac and com. correlation with int was moderate to high for all domains except hab. logistic regression with a very reduced model due to the low number of observations did not reveal pu or fac as significant predictors of int. having a special interest in dermatology and the distance to the nearest dermatologist did not significantly predict high int. interestingly, gps who did not own a dermoscope were 10-times more likely to report high int (95% ci, 1.3-78.1, p = .03). a few comments in free writing were received. two gps stressed the lack of reimbursement as a disadvantage, and one mentioned the cost of the equipment as a barrier. one gp commented that he still lacked routine in dermoscopy. one gp commented on the questionnaire and wanted the option to answer “not relevant.” one gp commented that he had invested in a handyscope. dermatologists’ responses the results of the questionnaire for dermatologists are shown in figure 1. all 3 dermatologists agreed that teledermoscopy was useful for triaging referrals, but they were less confident in their teledermoscopy diagnoses and management plans than in the traditional face-to-face evaluations of patients. two of the 3 dermatologists were satisfied with teledermoscopy as a consult method. discussion nowadays, in the era of social distancing, the interest in teledermoscopy is definitely increasing, not only among dermatologists but also among gps. together, these healthcare providers proved to easily use a common web platform for teledermoscopy and research purposes [19,20]. in this table 1. the 8 domains of the teletam questionnaire domain example questiona pu: perceived usefulness teledermoscopy could help me to diagnose my patients more rapidly. peu: perceived ease of use i think that teledermoscopy is a flexible technology to interact with. fac: facilitators i would use teledermoscopy if i receive adequate training. com: compatibility the use of teledermoscopy is compatible with my work habits. sn: subjective norm most of my colleagues will welcome the fact that i use teledermoscopy. hab: habits i feel comfortable with information and communication technologies. att: attitude the use of teledermoscopy is beneficial for the diagnosis of my patients. int: intention to use i have the intention to use teledermoscopy routinely with my patients. a the questionnaire comprises 33 questions overall. one example question is shown for each domain. 4 research | dermatol pract concept. 2021;11(2):e2021033 table 2. background information on participating gps, according to whether or not they responded to the teletam questionnairea characteristic respondents (n=29) non-respondents (n=68) pbno.a value no.a value male sex, n (%) 28 18 (64) 68 31 (46) .10 age, mean (sd), y 24 50.7 (8.6) 68 46.2 (10.6) .04 years working as gp, mean (sd) 22 13.7 (9.4) 63 9.7 (9.3) .10 special interest in dermatology 22 14(63.6) 61 25 (41.0) .07 have a dermoscope 23 11(47.8) 62 28 (45.2) .83 distance to nearest dermatologist, mean (sd), km 23 9.8 (11.2) 64 9.3 (11.2) .85 a number of persons who provided the requested information; b p values calculated by two-sample t test with unequal variance. gp = general practitioner; sd = standard deviation. table 3. gps’ scores on the teletam questionnaire, and crohnbach alpha and correlation with intention to use teledermoscopy variable observations, n score, mean (sd) minimum scorea cronbach alpha correlation with int pu 28 6.10 (0.65) 4.83 0.91 0.80 peu 29 5.75 (0.80) 4.50 0.89 0.65 fac 29 6.03 (0.57) 4.67 0.35 0.67 com 29 5.15 (0.63) 3.75 0.52 0.53 sn 28 5.71 (0.84) 4.00 0.84 0.63 hab 29 5.84 (0.96) 4.00 0.71 0.38 att 29 6.15 (0.57) 5.00 0.80 0.71 int 28 6.07 (0.77) 4.33 0.90 1.00 a the maximum score for every variable was 7.00. figure 1. dermatologists’ views on teledermoscopy (n = 3). *one dermatologist answered both neutral and disagree. i am less confident in my diagnoses and management plans using teledermatology than seeing patients in clinic. teledermatology is a more efficient use of the time that i spend as a consultant. teledermatology consults take longer to perform than do clinic visits. teledermatology makes it easier to triage patients to clinic appointments compared to traditional referrals. overall, i am satisfied with using teledermatology as a consult method. 100% 0% 0% 0% 0% 0% 20% 40% 60% 80% 100% 17%* 17%* 0% 0% 0% 33% 67% 67% 100% 100% agree neutral disagree research | dermatol pract concept. 2021;11(2):e2021033 5 questionnaire study, danish gps were asked about their attitudes towards the use of teledermoscopy. overall, there was a very positive attitude towards this new technology, with mean scores for all domains above what has previously been reported on the teletam questionnaire [13,17]. while high levels of satisfaction with teledermatology have been reported for both primary care physicians and dermatologists, only a few studies specifically evaluated teledermoscopy [21]. kenney et al found high levels of satisfaction with teledermoscopy in a survey of 5 primary care physicians in a hospital setting, where a trained nurse photographer took the photos [22]. in a study of mixed quantitative and qualitative measures of provider satisfaction with teledermoscopy, janda et al concluded that most participants were receptive to the use of mobile teledermoscopy in their practice [23]. both gps and dermatologists were surveyed. the study elucidated advantages and disadvantages of teledermoscopy and touched on themes such as lesion monitoring, time consumption and record keeping, which we recognize from the comments in the teletam questionnaire and feedback obtained at the evaluation session. orruño et al found fac to be the only significant predictor of int [13]. we could not replicate this result, possibly due to the low number of observations. however, we found the lowest cronbach alpha for fac, indicating that the reliability of this domain may be low in different health care settings. we also found low reliability for com, as did stratton and loescher [17]. furthermore, stratton and loescher reported low reliability for hab. in our study, the cronbach alpha for this domain was acceptably high. the validity of the teletam questionnaire seems good. we found the lowest correlation with int for hab; this corresponds to the findings of both orruño et al [13] and stratton and loescher [17]. we found that gps without a dermoscope were more likely to have high intentions to use teledermoscopy. this may be because gps already using dermoscopy have higher confidence in their diagnoses and have less need for specialist assistance through teledermoscopy or a standard referral, as shown by chappuis et al [24]. another study reported that 82% of gps using dermoscopy were confident or very confident in its use [25]. the distance to the nearest dermatologist did not influence int. however, distances to dermatologist are relatively short in all of denmark compared to australia and some nordic countries, where teledermoscopy may be even more warranted than in denmark. a major limitation to this study is the low number of observations. gps have limited time and an increasing workload; we speculate that this may be an explanation for the low participation rate. other studies reported response rates of 2%, 62% and 100% in different set-ups, with the highest response rate reported in a study of 5 primary care physicians in a hospital setting [13,22,26]. furthermore, respondents and non-respondents in our study differed in several ways. firstly, respondents were older than non-respondents. the background information was collected at the beginning of the diagnostic accuracy study in january 2018. more than 90% of the general practices employed gps in training (data not shown). in denmark, this type of employment lasts 6 or 12 months. therefore, many of these young doctors, who had potentially participated in the diagnostic accuracy study, were no longer employed at the participating practices at the time of this questionnaire study and hence could not answer the teletam questionnaire. this may also in part explain the low number of respondents. in addition, more respondents had a special interest in dermatology, which may bias their attitude towards teledermoscopy. therefore, our results may not be generalizable, and danish gps as a whole may not be as positively minded towards this new technology. however, as some of the barriers towards the use of teledermoscopy may be lacking remunerations, this could be an incentive worth taking into account in future collective bargaining. finally, our results may not be directly transferable to primary care settings in other parts of the world. in conclusion, this study found a high acceptance of teledermoscopy among gps and dermatologists. more studies investigating provider acceptance and satisfaction with teledermoscopy are warranted. references 1. gordon lg, rowell d. health system costs of skin cancer and cost-effectiveness of skin cancer prevention and screening: a systematic review. eur j cancer prev. 2015;24(2):141-149. 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[the apo method--a popular form of quality development in general practice]. ugeskrift for laeger. 2002;164(46):5390-5393. 13. orruno e, gagnon mp, asua j, ben abdeljelil a. evaluation of teledermatology adoption by health-care professionals using a modified technology acceptance model. j telemed telecare. 2011;17(6):303-307. doi: 10.1258/jtt.2011.101101. pmid: 21844171. 14. harris pa, taylor r, minor bl, et al. the redcap consortium: building an international community of software platform partners. j biomed inform. 2019;95:103208. doi: 10.1016/j. jbi.2019.103208. pmid: 31078660. 15. harris pa, taylor r, thielke r, payne j, gonzalez n, conde jg. research electronic data capture (redcap)—a metadata-driven methodology and workflow process for providing translational research informatics support. j biomed inform. 2009;42(2):377381. doi: 10.1016/j.jbi.2008.08.010. pmid: 18929686. 16. whited jd, hall rp, foy me, et al. patient and clinician satisfaction with a store-and-forward teledermatology consult system. telemed j e health. 2004;10(4):422-431. doi: 10.1089/ tmj.2004.10.422 pmid: 15689645. 17. stratton d, loescher lj. the acceptance of mobile teledermoscopy by primary care nurse practitioners in the state of arizona. j am assoc nurse practitioners. 2016;28(6):287-293. 18. davis fd. perceived usefulness, perceived ease of use, and user acceptance of information technology. mis quarterly. 1989;13(3):319-340. 19. tognetti l, cevenini g, moscarella e, et al. an integrated clinical-dermoscopic risk scoring system for the differentiation between early melanoma and atypical nevi: the idscore. journal of the european academy of dermatology and venereology : jeadv. 2018;32(12):2162-2170. doi: 10.1111/jdv.15106. pmid: 29888421. 20. tognetti l, cevenini g, moscarella e, et al. validation of an integrated dermoscopic scoring method in an european teledermoscopy web platform: the idscore project for early detection of melanoma. j eur acad dermatol venereol. 2020;34(3):640-647. doi: 10.1111/jdv.15923. pmid: 31465600. 21. mounessa js, chapman s, braunberger t, et al. a systematic review of satisfaction with teledermatology. j telemed telecare. 2018;24(4):263-270. doi: 10.1177/1357633x17696587. pmid: 28350281. 22. kenney as, yiannias ja, raghu ts, david ps, chang yh, greig he. measures of satisfaction for providers and patients using same day teledermoscopy consultation. int j dermatol. 2016;55(7):781-785. doi: 10.1111/ijd.12892. pmid: 26276548. 23. janda m, horsham c, koh u, et al. evaluating healthcare practitioners’ views on store-and-forward teledermoscopy services for the diagnosis of skin cancer. digit health. 2019;5:2055207619828225. doi: 10.1177/2055207619828225. pmid: 30792879. 24. chappuis p, duru g, marchal o, girier p, dalle s, thomas l. dermoscopy, a useful tool for general practitioners in melanoma screening: a nationwide survey. br j dermatol. 2016;175(4):744750. doi: 10.1111/bjd.14495. pmid: 26914613. 25. jones ot, jurascheck lc, utukuri m, pannebakker mm, emery j, walter fm. dermoscopy use in uk primary care: a survey of gps with a special interest in dermatology. j eur acad dermatol venereol.. 2019;33(9):1706-1712. doi: 10.1111/jdv.15614. 26. lim d, oakley am, rademaker m. better, sooner, more convenient: a successful teledermoscopy service. australas j dermatol. 2012;53(1):22-25. doi: 10.1111/j.1440-0960.2011.00836.x. pmid: 22309326. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):12 59 dermatology practical & conceptual www.derm101.com introduction anaplastic large cell lymphoma (alcl) is a rare and indolent type of mature t cell lymphoma, which is composed of large atypical lymphocytes with pleomorphic, anaplastic, or immunoblastic cytomorphology [1]. clinical manifestations include primary cutaneous type and secondary cutaneous involvement from the systemic type of alcl [1]. the primary cutaneous form is characterized by cutaneous lesions without systemic involvement and usually presents with asymptomatic, solitary, grouped, multicentric, or generalized tumors that may ulcerate and spontaneously regress [1,2]. the diagnosis of these tumoral lesions is usually made by clinical findings, histologic and immunophenotypic examiprimary cutaneous cd 30 (+) alk (-) anaplastic large cell lymphoma with dermoscopic findings: a case report tugba k. uzuncakmak1, necmettin akdeniz1, ayse s. karadag1, secil taskin1, ebru i. zemheri2, giuseppe argenziano3 1 department of dermatology, istanbul medeniyet university, istanbul, turkey 2 department of pathology, istanbul medeniyet university, pathology, istanbul, turkey 3 second university of naples, department of dermatology, naples, italy key words: anaplastic large cell lymphoma, dermoscopy, radiotherapy citation: uzuncakmak tk, akdeniz n, karadag as, taskin s, zemheri ei, argenziano g. primary cutaneous cd 30 (+) alk (-) anaplastic large cell lymphoma with dermoscopic findings: a case report. dermatol pract concept. 2017;7(1):12. doi: https://doi.org/10.5826/ dpc.0701a12 received: july 11, 2016; accepted: october 24, 2016; published: january 31, 2017 copyright: ©2017 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: tugba kevser uzuncakmak, md, istanbul medeniyet university, goztepe research and training hospital, dermatology, istanbul, turkey. tel. +90(530) 6640226. email: drtugbakevser@gmail.com primary cutaneous cd 30 (+) anaplastic large cell lymphoma (pcalcl) is a rare and indolent type of cutaneous t cell lymphoma, which usually presents as an asymptomatic solitary firm nodule that rapidly grows and often ulcerates without any systemic involvement. a 64-year-old female presented to our outpatient clinic with a one-year history of multiple pink nodular lesions on the chest, back and gluteal regions. dermoscopic examination of the nodular lesions revealed pink-to-yellow structureless areas and arborizing-to-polymorphous vessels. histopathologic examination was consistent with cd30 (+) anaplastic large cell lymphoma. systemic involvement was not detected. local radiotherapy for large nodules and surgical excision for small nodules were performed. the large nodules had totally regressed after 10 sessions of radiotherapy. abstract mailto:drtugbakevser@gmail.com 60 observation | dermatol pract concept 2017;7(1):12 less areas and polymorphous vessels (figure 2). the largest nodular lesion on the right scapular region was totally excised for diagnosis. total excision of the nodular lesion on the back revealed diffuse dermal cellular infiltration histologically (hematoxylin & eosin staining [h&e]). (figure 3a) the infiltration consisted of large atypical cells with cd3, cd4 and cd30 positivity (figure 3b and c) on immunohistochemical examination, as well as negativity for anaplastic lymphoma kinase and cd20 staining (figure 3d). she was diagnosed as cd30 (+) alk (-) anaplastic large cell lymphoma. systemic scanning for metastasis, including complete blood count, routine biochemistry, flow cytometry and body scanning with tomography were totally normal. local radiotherapy for large nodules and surgical excision for small nodules were performed. almost all of the nodular lesions had totally regressed after 10 sessions of radiotherapy. she has been under follow up without any recurrence for one year. discussion primary cutaneous anaplastic large cell lymphoma (pcalcl) is a rare type of cd 30 (+) cutaneous lymphomas, which represents 10% of all cases [3]. for the correct diagnosis, the following criteria are important: no evidence or history of lymphomatoid papulosis, mycosis fungoides or other lymphoma, no extracutaneous lesion at presentation, and predominance (>75%) of large clusters of cd30+ blast cells in the skin biopsy [3]. although there are pediatric case reports in the literature, it is more common in adults aged between 45 and 60 years. the clinical presentation includes rashes, plaques, nodules and tumors with central ulceration on the trunk and extremities that may spontaneously regress [1,3-5]. recurrence is common, but systemic involvement is rare, with secondary regional lymphadenopathy seen in only a quarter of cases [3]. imaging tests, such as computerized tomography of the neck, chest and abdomen, are required for staging and in order to differentiate the primary from the systemic form involving the skin. bone marrow biopsy and skin biopsy are also mandatory for staging. in our patient these tests were negative for systemic involvement. histologic and immunophenotypic examinations are mannations. we present a case of primary cutaneous cd 30 (+) anaplastic large cell lymphoma assessed by dermoscopy that responded very well to local radiotherapy. case report a 64-year-old female was admitted to our outpatient clinic with a one-year history of multiple pink nodular lesions of a few millimeters and centimeters in diameter on the chest, back and gluteal regions (figure 1). dermoscopic examination of the nodular lesions revealed pink-to-yellow structurefigure 1. multiple pink nodular lesions of a few millimeters and centimeters in diameter on chest and back. [copyright: ©2017 uzuncakmak et al.] figure 2. pink-to-yellow structureless areas and arborizing-to-polymorphous vessels with non-polarized dermoscopy. [copyright: ©2017 uzuncakmak et al.] observation | dermatol pract concept 2017;7(1):12 61 of the nodular lesions. we think this yellow/salmon colored background may be helpful in the differential diagnosis of cutaneous lymphomas from amelanotic melanoma. surgical excision and local radiotherapy are the primary treatment options for localized pcalcl [2,8-10] surgery is a highly effective treatment option, but relapse is also very common [2,3]. chemotherapy is used mainly for patients with multifocal, generalized lesions or relapsed disease [3]. in our patient we performed surgical excision of the small nodules and local radiotherapy for the larger lesions, which almost totally regressed after 10 sessions of radiotherapy. in conclusion, our case of anaplastic large cell lymphoma is a good example in underlining the importance of dermoscopy for the differential diagnosis of pink nodules. in the presence of the pink-yellow color and polymorphous vessels, the possibility of lymphoma should be taken into consideration. datory for the diagnosis of pcalcl. histologically pcalcl is characterized by diffuse, pleomorphic, anaplastic, or immunoblastic, non-epidermotropic lymphoid infiltrates with cohesive sheets of large cd30+ tumor cells, oval or irregularly shaped nuclei, prominent eosinophilic nucleoli and abundant cytoplasm with a high mitotic index. immunohistochemistry is essential for the determination of the ctcl subtype and in the differentiation between primary and secondary disease [3,4]. dermoscopic findings of cutaneous lymphomas are not very well known and usually focused on mycosis fungoides [6]. mascolo et al recently reported the dermoscopic findings of a series of cutaneous b cell lymphomas. in their series, the most common dermoscopic features were white circles, yellow-to-salmoncolored background/areas, scales and/ or arborizing vessels [7]. similarly, in our patient we observed pink-to-yellow structureless areas and polymorphous vessels especially visible at the periphery references 1. asha lk, thomas d, binitha mp, nandakumar g. primary cutaneous multifocal cd30+ anaplastic large cell lymphoma. indian j dermatol venereol. leprol 2006;72:376-378. 2. huang bs, chen wy, wang cw, et al. relapse pattern and treatment outcome of curative radiotherapy for primary cutaneous cd30 + anaplastic large-cell lymphoma: a retrospective cohort study. acta derm venereol. 2016;96:394-395. 3. rao sd, ravi r, govindarajan m. primary cutaneous cd 30+ anaplastic large cell lymphoma. indian j surg. 2010;72:283285. 4. daar g, küpeli s, yalçin b, et al. primary  cutaneous  anaplastic large cell lymphoma. pediatr hematol oncol. 2010;27:558-563. 5. cao c, zeng k, wang m, et al. primary cutaneous anaplastic large-cell lymphoma: a case report. dermatol ther. 2016; 29(4):224-227. 6. lallas a, apalla z, lefaki i, et al. dermoscopy  of early stage mycosis fungoides. j eur acad dermatol venereol. 2013;27(5):617-21. 7. mascolo m, piccolo v, argenziano g, et al. dermoscopy pattern, histopathology and immunophenotype of primary cutaneous b-cell lymphoma presenting as a solitary skin nodule. dermatology. 2016; 232:203-207. 8. turrión-merino l, perez-gala s, hermosa-zarza e, et al. primary cutaneous cd30+ anaplastic large cell lymphoma treated with radiotherapy and methotrexate with development of xanthomas at the sites of prior disease. j cutan pathol. 2016;43:400-405. 9. yokoi i, ishikawa e, koura a, et al. successful treatment of primary cutaneous anaplastic large cell lymphoma with intralesional methotrexate therapy. acta derm venereol. 2014;94:319-320. 10. patsinakidis n, kreuter a, moritz rk, et al. complete remission of refractory, ulcerated, primary cutaneous cd30+ anaplastic large cell lymphoma following brentuximab vedotin therapy. acta derm venereol. 2015;95:233-234. figure 3. total excision specimen of the nodular lesion on back revealed diffuse dermal cellular infiltration (h&e) (a). the infiltration consisted of large atypical cells with cd3, cd4 and cd30 positivity (b, c) immunohistochemically, as well as negativity for anaplastic lymphoma kinase and cd20 staining (d). [copyright: ©2017 uzuncakmak et al.] a b c d dermatology: practical and conceptual quiz | dermatol pract concept 2017;7(2):15 67 dermatology practical & conceptual www.derm101.com the patient a 57-year-old man presented with a one-month history of photosensitivity (figures 1, 2). on physical examination erythematous patches affected all parts of his face and dorsum of both hands. interestingly the erythematous rash affected the dorsum of hands between the joints but the joints were spared. all laboratory tests were within normal range. a skin biopsy was performed, and histopathologic examination illustrated cutaneous lupus erythematosus. acute onset of a severe rash on the face and dorsal hands amir feily1 1 skin and stem cell research center, tehran university of medical sciences, tehran, iran. citation: feily a. acute onset of a severe rash on the face and dorsal hands. dermatol pract concept. 2017;7(2):15. doi: https://doi. org/10.5826/dpc0702a15 copyright: ©2017 feily. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: amir feily, md, dr feily clinic of dermatology and hair transplant, moalem blvd, jahrom, fars, iran. tel. 00989177204638. email: dr.feily@yahoo.com figure 1. a 57-year-old man presented with a one-month history of photosensitivity. [copyright: ©2017 feily.] figure 2. photosensitive rash affected the interphalangeal spaces; the joints were spared. [copyright: ©2017 feily.] discussion systemic lupus erythematosus (sle) is a chronic disease that can affect any organ system. its clinical manifestations are highly variable, ranging from chronic to fulminant. cutane68 quiz | dermatol pract concept 2017;7(2):15 livedo reticularis, periungual erythema, telangiectasias, and raynaud phenomenon. photosensitive sle rashes basically occur on the face or upper extremities. it is necessary to differentiate photosensitive lupus rash from a dermatomyositis rash. in lupus erythematosus the interphalangeal spaces are affected, but in dermatomyositis the erythematous rashes named gottron’s papules are found over the joints and the interphalangeal areas are spared. our patient was treated successfully with prednisolone and hydroxychloroquine without recurrence after 6-month follow-up. ous lupus erythematosus (cle) is the second most common finding of sle. in a majority of cases, cle is the main and sometimes the only feature of the disease independent of systemic involvement. dermatologic manifestations of lupus include malar rash, a fixed erythema that typically spares the nasolabial folds; photosensitive rash, which is often macular or diffusely erythematous on sun-exposed regions of the face and upper extremities and generally persists for more than one day; and a discoid rash which occurs in 20% of patients with sle and can result in persistent scars. other less specific cutaneous findings include alopecia, vascular lesions such as dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022070 1 dermatology practical & conceptual introduction early melanoma diagnosis is a major prognostic factor for improved patient survival. since its introduction in the dermatological practice, total body photography has proven to be a powerful tool for uncovering new or changing pigmented lesions that are either too small or unremarkable during a routine clinical skin exam in high-risk individuals [1]. thanks to this technique, the number of reported melanomas measuring less than 2 mm in diameter, defined as micro-melanomas, is increasing. consequently, the relevance of the 6 mm size criterion of the classic abcde rule is currently under question [2]. case presentation a 29-year-old man with a personal history of melanoma consulted our clinic for his annual skin exam and total-body-photography. the comparative photography revealed a new, tiny, pigmented lesion on his right lateral trunk, measuring 1.0 mm x 1.5 mm, and appearing darker than the rest of his naevi (figure 1, a and b). the digital dermoscopy exam revealed an atypical melanocytic lesion, characterized by asymmetry, and irregular network composed of non-uniform streaks of uneven width and borders. there was expansion in an asymmetrical starburst pattern with melanocytic projections of variable sizes and bulging ends with no connection to the lesion, predominating in one extremity of the lesion, and corresponding to pseudopods (figure 1c). the lesion was excised and the histopathological analysis revealed an asymmetrical junctional melanocytic proliferation with nests of various sizes composed of large epithelioid melanocytes with cytologic atypia; pleomorphic nuclei, dusky and heavily pigmented cytoplasm, and mitotic figures. there was focal lentiginous proliferation in connection with a peripheral nest, compatible with the horizontal expansion seen in the dermoscopic image of irregular streaks, as well as isolated melanocytes in a pagetoid scatter (figure 2). two dermatopathologists reviewed the specimen. given the lentiginous spread extending over 3 papilla in the periphery of the lesion, and the pagetoid ascension, which was limited over the nests in the center of the lesion, the diagnosis of melanoma in situ, acral lentiginous subtype, was retained. a re-excision of the scar with 5 mm lateral margins and up to the muscle fascia was performed. we are currently following the patient alternating clinical exam and total body photography every 6 months according to the swiss melanoma guidelines. birth of a melanoma sofia bogiatzi1, alessandra pagnoni1, daniel hohl1, olivier gaide1 1 department of dermatology and venereology, lausanne university hospital (chuv), lausanne, switzerland key words: dermoscopy, melanoma, total body photography, dermatopathology citation: bogiatzi s, pagnoni a, hohl d, gaide o. birth of a melanoma. dermatol pract concept. 2022;12(2):e2022070. doi: https://doi.org/10.5826/dpc.1202a70 accepted: september 2, 2021; published: april 2022 copyright: ©2022 bogiatzi et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: sofia bogiatzi, md-phd, department of dermatology and venereology, lausanne university hospital (chuv), avenue beaumont 29 lausanne, ch-1011 vd, switzerland. e-mail: sofia.bogiatzi@chuv.ch 2 research letter | dermatol pract concept. 2022;12(2):e2022070 figure 2. histopathology correlate revealing features of melanoma in situ. (a-d) 10x magnification sections in different levels of the lesion depicting the asymmetrical melanocytic growth with junctional nests of various sizes, distributed unevenly. (e) 40x magnification of the b section showing the lentiginous spread in contact with a peripheral nest, corresponding to the pseudopods seen in dermoscopy. the melanocytes exhibit large nuclei compared to the neighboring keratinocytes with abundant cytoplasm, and heavy pigmentation in some of the cells. no pagetoid scatter was observed in the periphery of the lesion, compatible with an acral lentiginous subtype melanoma. (f) 40x magnification of a central nest with a mitotic figure (red asterisk). (g) 40x magnification of the d section showing interconnected nests in the center of the lesion with scattered melanocytes in the suprabasal layers of the epidermis (green asterisks), compatible with pagetoid ascension. conclusions although rare, acral lentiginous melanomas have been reported in non-acral sites and their dermoscopic features are similar to the ones observed in our patient. this case illustrates the success of time-lapse total body photography in the identification of melanomas, akin to witnessing the birth of a star, but also the fine correlation of dermoscopy and pathology. furthermore, the systematic documentation of micro-melanomas with digital dermoscopy combined with digital pathology and the molecular and genetic profiling of the excised lesions constitute a great opportunity to study these very early events of malignant melanocytic expansion. references 1. drugge ed, volpicelli er, sarac rm, strang sr, elston dm, drugge rj. micromelanomas identified with time-lapse total body photography and dermoscopy. j am acad dermatol. 2018;78(1):182-183. doi: 10.1016/j.jaad.2017.07.049. pmid: 29241777. 2. hornung a, steeb t, wessely a et al. the value of total body photography for the early detection of melanoma: a systematic review. int j environ res public health. 2021;18(4):1726. doi: 10.3390/ ijerph18041726. pmid: 33578996. pmcid: pmc7916771. figure 1. total body photography exam: a new lesion is identified during time-lapse comparison of photos. (a) total-body-photography at visit 1. (b) total-body-photography at visit 2, one year later revealing the presence of a new melanocytic lesion. inset: high power of the new lesion showing a darker pigmentation than the rest of the nevi. (c) digital dermoscopy of the new lesion showing an atypical melanocytic network with irregular streaks and pseudopods in an asymmetrical starburst pattern dominating one extremity of the lesion. dermatology: practical and conceptual observation | dermatol pract concept 2017;7(1):5 27 dermatology practical & conceptual www.derm101.com pityriasis lichenoides et varioliformis acuta in skin of color: new observations by dermoscopy balachandra s. ankad1, savitha l. beergouder1 1 department of dermatology, s. nijalingappa medical college, bagalkot, karnataka, india key words: dermoscopy, pityriasis lichenoides et varioliformis acuta, diagnosis, pattern citation: ankad bs, beergouder sl. pityriasis lichenoides et varioliformis acuta in skin of color: new observations by dermoscopy. dermatol pract concept. 2017;7(1):5. doi: http://dx.doi.org/10.5826/dpc.0701a05 received: june 19, 2016; accepted: october 28, 2016; published: january 31, 2017 copyright: ©2017 ankad et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: dr. balachandra s. ankad, professor, department of dermatology, s. nijalingappa medical college, near apmc, navanagar, bagalkot-587103, karnataka, india. tel. 91 9980410056; fax: 08354 235360. e-mail: drbsankad@gmail.com background: pityriasis lichenoides is an uncommon skin disease that presents in three different forms: pityriasis lichenoides et varioliformis acuta (pleva), pityriasis lichenoides chronica (plc) and febrile ulceronecrotic-mucha-habermann disease. these represent a spectrum of a disease. pleva presents as skin eruption of multiple, small, red papules that develop into polymorphic lesions with periods of varying remissions, as well as possible sequels of hyper/hypopigmentation and varicella-like scars. diagnosis of this condition is mainly clinical, and sometimes clinical differentiation from other conditions may be a difficult task that often requires histological analysis. in this study, pleva lesions were examined by dermoscopy, and the significance of specific dermoscopic findings was investigated in order to facilitate their differentiation from other inflammatory conditions. objectives: to evaluate dermoscopic patterns in pleva and to correlate these patterns with histopathology. materials and methods: the study was conducted at s. nijalingappa medical college, bagalkot. it was an observational case series study and patients were selected randomly. ethical clearance and informed consent were obtained. pleva lesions in early and late phases were evaluated. a manual dermlite 3 (3gen, san juan capistrano, ca) dermoscope attached to a sony (cyber shot dsc-w800, sony electronics inc., san diego, california, usa, digital, 14 mega pixels) camera was employed. histopathology was done to confirm the diagnosis. data was collected and analyzed. results were statistically described in terms of frequencies and types of dermoscopic patterns. results: there was a total of 14 patients; 8 males and 6 females. mean age of patients was 19 years. mean duration of disease was 7 months. dermoscopy in early-phase lesions revealed amorphous brownish areas around the hair follicles, dotted vessels, and scaling. dermoscopy in late-phase lesions showed whitish-structureless areas and central white crust within whitish-structureless rim with scale, focal bluish-grayish areas or centrifugal strands irregularly distributed along the periphery and yellow structures. red dots and hemorrhage were seen at the center and glomerular vessels at the periphery. conclusion: pleva demonstrates specific dermoscopic patterns that correlate well with histologic changes. new dermoscopic findings are described. thus, dermoscopy is a good diagnostic tool in the clinical diagnosis of pleva. abstract mailto:drbsankad@gmail.com 28 observation | dermatol pract concept 2017;7(1):5 ultrasound gel was applied either on the faceplate of the dermoscope or on the skin lesion and then lesions were observed through the eyepiece of the dermoscope. however, only the polarized light version was used in our study to appreciate color patterns in the dermis. although polarized dermoscopy was employed, ultrasound gel was applied for clarity of images and to lessen distortions associated with light [4]. care was taken in holding the dermoscope a little above the surface of skin lesions to visualize the vascular structures [5]. inclusion criteria: 1. patients with signs and symptoms of pleva [6], 2. patients with pleva lesions in both early and late phases were included. 3. patients who had not received or stopped treatment for pleva one month prior to the study. exclusion criteria: 1. patients with secondary infection superseding pleva. 2. patients who were receiving treatment one month prior to the study. results there were 14 patients (8 male, 6 female) in the study. the patients with pleva with mean duration of disease of 7 months [minimum 2 months and maximum 12 months] and mean age of 19 years presented with acute onset of erythematous papules with hemorrhagic crusting. two (14.28%) and 12 (85.71%) patients had early (figure 1) and late (figure 2) lesions of pleva respectively. dermoscopy of early phase lesions: it showed amorphous brownish area around the hair follicles and rim of scale in the center and dotted vessels at periphery (figure 3). dermoscopy of late phase lesions: it demonstrated whitishstructureless areas arranged in a haphazard pattern with vague introduction pityriasis lichenoides (pl), also called mucha-habermann disease, is characterized by multiple crusted and scaly papules. it includes three variants, namely, pityriasis lichenoides et varioliformis acuta (pleva), pityriasis lichenoides chronica (plc) and febrile ulceronecrotic pleva. pleva can mimic various skin conditions such as chicken pox, lymphomatoid papulosis, guttate psoriasis, lichen planus and pityriasis rosea [1,2]. dermoscopy is a non-invasive technique that allows a rapid and magnified in vivo observation of the skin surface. dermoscopy is mainly utilized for the evaluation of pigmented skin lesions and has increasing applications in dermatology [3]. here, authors evaluated dermoscopic patterns in pleva in brown skin, and these patterns may assist the clinical diagnosis. objectives to evaluate dermoscopic patterns in pleva and to correlate these patterns with histopathology. materials and methods patients this study was carried out on 14 patients attending the department of dermatology in a tertiary hospital attached to s. nijalingappa medical college at bagalkot, southern india between march 2015 and december 2015. it was an observational case series study and patients were selected randomly. a complete history and dermatological examination were performed on patients with clinical features suggestive of pleva in early and late phases. the ethical clearance was obtained by the institutional ethical committee. the patients gave written informed consent. demographic data, such as age, gender, and clinical variables in terms of site of lesions and disease duration were documented. lesions with less than 2 months’ and more than 2 months’ duration were arbitrarily termed as early and late lesions. these were referred to as target lesions and were selected for dermoscopic examination. skin biopsies were taken from target lesions to confirm the diagnosis. same dermatologist evaluated dermoscopic patterns and was unaware of clinical diagnosis. the pathologist was also unaware of the diagnosis and same pathologist evaluated histopathological changes. data was collected and analyzed. the results were statistically described as types of dermoscopic patterns. dermoscopic examination a dermlite 3 dermoscope (10x magnification) with both polarized and non-polarized lights was employed in the study. a sony camera was attached to save the images. initially, figure 1. clinical image of pityriasis lichenoides et varioliformis acuta with excoriated papules with crust. [copyright: ©2017 ankad et al.] observation | dermatol pract concept 2017;7(1):5 29 bluish-grayish areas or centrifugal strands irregularly distributed along the periphery, and yellow structures and red dots and hemorrhage within the central crust-plug (figures 5, 6). histopathological examination showed hyperkeratosis, epidermal ulceration with basophilic infiltration, vacuolar alteration of basal layer, necrotic keratinocytes, and pronounced lymphocytic infiltrate in the papillary dermis in wedge-shaped pattern along with perivascular infiltration in early phase (figure 7). in late lesions, hyperkeratosis, acanthosis, erosion in the epidermis, basal cell degeneration and lymphocytic infiltrate around capillaries were seen (figure 8) [7]. dilatation of dermal capillaries was observed in both phases. frequencies of various dermoscopic patterns are presented in table 1, and corresponding histopathological changes are depicted in table 2. glomerular and dotted vessels in the periphery (figure 4), central white crust and whitish-structureless rim with scale, focal figure 2. clinical image of pityriasis lichenoides et varioliformis acuta with erythematous papules and pustules with crust. [copyright: ©2017 ankad et al.] figure 3. dermoscopy pityriasis lichenoides et varioliformis acuta showing amorphous brownish area (yellow arrow) around the hair follicles and dotted vessels (black circle) and rim of scale. [copyright: ©2017 ankad et al.] figure 4. dermoscopy showed whitish structureless areas (black star) arranged in a haphazard pattern with vague glomerular (black circle) and dotted (yellow circle) vessels in the periphery. [copyright: ©2017 ankad et al.] figure 5. dermoscopy of pityriasis lichenoides et varioliformis acuta showing whitish-yellow structureless rim white scale (black circle), whitish crust in the centre (yellow arrow), focal bluish-grayish areas (black stars). red dots and hemorrhage within the central crust-plug (black arrows). [copyright: ©2017 ankad et al.] 30 observation | dermatol pract concept 2017;7(1):5 challenge to differentiate it from common conditions like chicken pox, guttate psoriasis, gianotti-crosti syndrome, lichen planus and pityriasis rosea, and in such situations histopathology helps to confirm the diagnosis [1]. dermoscopy is a novel diagnostic technique; beside its traditional use in melanoma detection, it is being used more and more in the assessment of other general dermatologic conditions, namely scalp and hair disorders (trichoscopy), nails abnormalities (onychoscopy), skin infections and infestations (entomodermoscopy), and cutaneous inflammatory diseases (inflammoscopy) [3]. in this study, authors evaluated dermoscopic patterns in pleva. in this study, dermoscopy of early pleva lesions i.e., lesions aged less than 2 months revealed an amorphous brownish area around the hair follicles within a rim of white scale and dotted vessels at the periphery. in a study of dermoscopy of pleva by lacarrubba et al, the authors observed an amorphous brownish structure and a ring of pinpoint and linear vessels in a “targetoid” pattern surrounding whitish-structureless areas [8]. similar findings were observed in this study. however, the targetoid pattern of vessels was not observed. vessels were in dotted pattern at the periphery. these correspond to microhemorrhages and extravasations of red blood cells in the papillary dermis. this disparity may be the result of the early stage of lesions and the dermoscopic technique followed in this study. interestingly, an amorphous brownish structure was noted around the hair follicle. this finding was not mentioned in the previous study. discussion pleva presents with a skin eruption of multiple, small, red papules that develop into polymorphic lesions and vacillates with periods of varying remissions as well as possible sequels of hyper/hypopigmentation and varicella-like scars. pleva is mainly diagnosed clinically, but sometimes it poses a great figure 6. dermoscopy of pityriasis lichenoides et varioliformis acuta showing whitish-yellow structureless areas (black circle), focal bluish-grayish areas (yellow stars), hemorrhage (black arrow) and scale. figure 7. histopathology in early phase shows hyperkeratosis, epidermal ulceration with basophilic infiltration, vacuolar alteration of basal layer, necrotic keratinocytes and pronounced lymphocytic infiltrate in the papillary dermis in wedge shaped pattern along with perivascular infiltration and dilatation of dermal capillaries is seen (h&e, 10 x). [copyright: ©2017 ankad et al.] figure 8. histopathology in late phase shows hyperkeratosis, acanthosis, erosion in the epidermis, basal cell degeneration and lymphocytic infiltrate around capillaries with dilatation of blood vessels (h&e, 10 x). [copyright: ©2017 ankad et al.] observation | dermatol pract concept 2017;7(1):5 31 supportive clue to the clinical diagnosis. in dermatofibroma, it takes on the “starburst” pattern [12], and in eccrine spiradenoma, it is arranged as structureless areas surrounding serpentine vessels [13]. histopathological correlation of white structures under dermoscopy depends on the condition. for example, it suggests hyperkeratosis, acanthosis and dermal fibrosis in hypertrophic lichen planus and prurigo nodularis; in morphea, eccrine spiradenoma and dermatofibroma it indicates increased collagen in the dermis. in pleva, it represents hyperkeratosis.thus pattern of whitish-structureless areas gives a clue to the clinical diagnosis. focal bluish-grayish areas or strands distributed peripherally were observed in late lesions. this finding is not reported in the previous study. the authors believe that this finding is due to scratching and skin of color. the configurations and patterns of focal bluish-grayish areas are specific for each condition. they are discrete, ovoid nests pattern in pigmented and superficial types of basal cell carcinoma [14]. in hyperan amorphous brownish structure corresponds to a central crust consisting of basophilic material in the epidermis and wedge-shaped lymphocytic infiltrate in the dermis. late-phase lesions demonstrated whitish-structureless areas and a central crust-plug surrounded by whitish rim with scale. this is in correlation with previous observation [8]. red dots and hemorrahges were observed in the center, within the whitish rim. whitish-structureless areas are seen in inflammatory conditions such as prurigo nodularis, hypertrophic lichen planus, and morphea and in some of the non-melanocytic skin tumors [9-13]. in hypertrophic lichen planus and prurigo nodularis it is referred to as pearly white structure spread over the entire lesion and seen characteristically in a “starburst” pattern in prurigo nodularis; and in hypertrophic lichen planus it is distributed diffusely in the centre [9, 10]. in morphea, it appears as whitish strands with dilated blood vessels [11]. in non-melanocytic tumors, white structures are arranged in a specific pattern, which give a table 1. dermoscopic patterns and their frequency. [copyright: ©2017 ankad et al.] sl. no. dermoscopic patterns frequency (n=14), n (%) 01 white structures • whitish-structureless areas in haphazard pattern • whitish-structureless rim with central crust-plug 2 (14.28) 10 (85.71) 02 red structures • dotted vessels • hemorrhages • vague glomerular 8 (57.14) 4 (28.57) 2 (14.28) 03 focal bluish-grayish areas 10 (71.42) 04 yellow globules or structures 10 (71.42) 05 amorphous brownish areas 2 (14.28) 06 scaling 8 (57.14) table 2. dermoscopic patterns and corresponding histopathological changes. [copyright: ©2017 ankad et al.] sl no. dermoscopic patterns corresponding histopathologic changes 01 whitish-structureless areas hyperkeratosis and acanthosis 02 whitish-structureless rim with central crust-plug hyperkeratosis and epidermal erosion 03 red dots and hemorrhage microhemorrhages and extravasations of red blood cells in the papillary dermis and dilatation of blood vessels 04 vague glomerular vessels dilatation of blood vessels 05 focal bluish-grayish areas melanin pigment in the dermis 06 yellow globules or structures spongiosis and basal cell degeneration 07 amorphous brownish areas crust-plug with basophilic material in epidermis and lymphocytic infiltrate in the dermis 08 scaling hyperkeratosis 32 observation | dermatol pract concept 2017;7(1):5 yellow structures were arranged diffusely within focal bluish-grayish areas and whitish structureless areas. these were not described in pleva. however, orange-yellowish structureless areas were observed in dermoscopic examination of pityriasis lichenoides chronica by errichetti et al. orange-yellowish trophic lichen planus, they are distributed centrifugally within pearly white areas [10]. in pleva, too, focal bluish-grayish areas were seen interspersed within whitish-structureless areas. thus, arrangement of focal bluish-grayish areas is useful clue to support the clinical diagnosis. figure 9. image depicting correlation of dermoscopic patterns with histopathological changes in early phase of pityriasis lichenoides et varioliformis acuta. [copyright: ©2017 ankad et al.] figure 10. image depicting correlation of dermoscopic patterns with histopathological changes in late phase of pityriasis lichenoides et varioliformis acuta. [copyright: ©2017 ankad et al.] observation | dermatol pract concept 2017;7(1):5 33 hence require skin biopsy. dermoscopy is a simple diagnostic tool that helps in the diagnosis of pleva with specific and characteristic patterns that correlate well with histopathological changes. new dermoscopic findings of pleva are described here. however, this study was performed on a limited number of patients, and hence, further studies are warranted to elucidate these findings. acknowledgements: the authors wish to acknowledge the help of dr. vijay domble for his assistance with histopathology. references 1. perrin bs, yan ac, treat jr. febrile ulceronecrotic muchahabermann disease in a 34-month-old boy: a case report and review of the literature. paediatric dermatol. 2012;29(1):53–58. 2. khachemoune a, blyumin ml. pityriasis lichenoides: pathophysiology, classification, and treatment. am j clin dermatol. 2007;8(1):29-36. 3. errichetti e, stinco g. the practical usefulness of dermoscopy in general dermatology. g ital dermatol venereol. 2015;150(5):533546. 4. bowling j. introduction to dermoscopy. in: bowling j, ed. diagnostic dermoscopy: the illustrated guide. 1st ed. west sussex: wiley-blackwell; 2012:2-14. 5. kreusch j. how to perform dermoscopy of non-pigmented skin lesions. in: zalaudek i, argenziano g, giacomel j, eds. dermatoscopy of non-pigmented skin tumors: pink – think blink. new york: crc press; 2016:17-18. 6. james wd, elston dm, neahaus im, eds. cutaneous lymphoid hyperplasia, cutaneous t-cell lymphoma, other malignant and other allied disorders. in: andrew’s diseases of the skin—clinical dermatology. 12th ed. philadelphia: elsevier; 2016:726-746. 7. mobini n, caire st, hu s, kamino h. noninfectious erythematous, papular, and squamous diseases. in: elder de, elenitsas, rosenbach m, murphy gf, rubin ai, xu x, eds. lever’s histopathology of the skin. 11th ed. philadelphia: wolters kluwer; 2015:192-239. 8. lacarrubba f, micali g. dermoscopy of pityriasis lichenoides et varioliformis acuta. arch dermatol. 2010;146(11):1322. 9. errichetti e, piccirillo a, stinco g. dermoscopy of prurigo nodularis. j dermatol. 2015;42:632–634. 10. ankad bs, beergouder sl. hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective. dermatol pract concept. 2016;6(2):9-15. 11. shim wh, jwa sw, song m, et al. diagnostic usefulness of dermatoscopy in differentiating lichen sclerosus et atrophicus from morphea. j am acad dermatol. 2012;66:690-691. 12. johr rh, stolz w. dermoscopy from a to z. in: johr rh, stolz w, eds. dermoscopy—an illustrated self-assessment guide. new york: mcgraw hill; 2010:1-26. 13. ankad bs, beergouder sl, domble v, sujana l. a serpentine inside eccrine spiradenoma: a new trichoscopic sign. int j trichol. 2015;7:38-40. pmid: 25878450 14. scalvenzi, m, lembo s, francia mg, balato a. dermoscopic patterns of superficial basal cell carcinoma. int j dermatol. 2008;47:1015–1018. 15. doshi b, khopkar u. histopathology of lichen planus and its variants. in: khopkar u, valia a, eds. lichen planus. new delhi: jaypee brothers medical publisher (p) ltd; 2013:123-147. structureless areas correspond to hemosiderin deposition in the dermis [16]. in this study, the orange hue was absent and only the yellowish color was appreciated. hence, the authors propose that yellow structures in pleva are produced as a result of the increased duration of lesions and that they represent spongiosis and basal cell degeneration on histology. yellow structures noted in hypertrophic lichen planus correspond to spongiosis and basal cell degeneration [10, 15]. in hypertrophic lichen planus, yellow structures are arranged in a “lacy network” pattern [10] and in dermatitis, they are in a diffuse pattern, giving rise to the “yellow clod” sign [17]. red dots and hemorrhages represent focal hemorrhage and dilated vessels in the papillary dermis. the types of vessels and their arrangement form an important factor in the clinical diagnosis by dermoscopy. in this study, red dots and hemorrhage were situated in the center and vague glomerular and dotted vessels at the periphery. in the previous study of dermoscopy of pleva, the authors observed a ring of pinpoint and linear vessels in a “targetoid” pattern surrounding whitish-structureless areas [8]. in inflammatory conditions, vessels are distributed and arranged in a specific pattern, which aids in an accurate diagnosis. in psoriasis, red dots are diffuse in a regularly arranged pattern on an erythematous background. in pityriasis rosea, they are distributed in an irregular or patchy manner at the periphery on a yellowish base. the cluster pattern of vessels is characteristic in all types of dermatitis [17]. in seborrheic keratosis and clear cell carcinoma, vessels are in “hair-pin” and “string of pearls” patterns respectively [18]. in pityriasis lichenoides chronica, milky red areas/globules, linear irregular and branching vessels are seen [16]. hence, the pattern of blood vessels is of diagnostic importance in the dermoscopic studies. in the present study, the authors noted focal bluishgrayish areas and yellow structures, which are not described in literature. the authors believe that the duration of lesions, scratching, and skin of color attribute to focal bluish-grayish areas and yellow structures. pleva lesions in the early phase showed an amorphous brownish area that correlated with basophilic material and wedge-shaped lymphocytic infiltrate on histology (figure 9), whereas late-phase lesions demonstrated whitish structureless areas, focal bluish-grayish areas, and yellow structures corresponding to epidermal erosion, hyperkeratosis, spongiosis, basal cell degeneration in infiltrate on histology (figure 10). however, limitations in this method do exist, and they include usage of ultrasound gel in polarized version of dermoscopy, the small study sample, and in that the same dermatologist performed dermoscopic evaluation all pleva lesions. conclusion pleva is a rare disorder that can be challenging to differentiate clinically from a number of common dermatoses, and file:///c:\pubmed\%3fterm=khachemoune%20a%5bauthor%5d&cauthor=true&cauthor_uid=17298104 file:///c:\pubmed\%3fterm=blyumin%20ml%5bauthor%5d&cauthor=true&cauthor_uid=17298104 file:///c:\l http://www.ncbi.nlm.nih.gov/pubmed/?term=errichetti%20e%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed/?term=errichetti%20e%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed/?term=stinco%20g%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed/?term=stinco%20g%5bauthor%5d&cauthor=true&cauthor_uid=26086412 http://www.ncbi.nlm.nih.gov/pubmed?term=shim%20wh%5bauthor%5d&cauthor=true&cauthor_uid=22421117 http://www.ncbi.nlm.nih.gov/pubmed?term=jwa%20sw%5bauthor%5d&cauthor=true&cauthor_uid=22421117 http://www.ncbi.nlm.nih.gov/pubmed?term=song%20m%5bauthor%5d&cauthor=true&cauthor_uid=22421117 https://www.ncbi.nlm.nih.gov/pubmed/25878450 34 observation | dermatol pract concept 2017;7(1):5 planus and pityriasis rosea. br j dermatol. 2012;166:1198-1205. 18. bowling j. non-melanocytic lesions. in: bowling j, ed. diagnostic dermoscopy: the illustrated guide. 1st ed. west sussex: wileyblackwell; 2012:59-91. 16. errichetti e, lacarrubba f, micali g, piccirillo a, stincol g. differentiation of pityriasis lichenoides chronica from guttate psoriasis by dermoscopy. clin exp dermatol. 2015;40:804–806. 17. lallas a, kyrgidis a, tzellos tg, apalla z, et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(4):e2021121 1 penile angiokeratomas (peakers): an exceedingly rare clinical variant jaime piquero-casals1, daniel morgado-carrasco2, juan francisco mir-bonafé3, eduardo rozas-muñoz4 1 department of dermatology, dermik multidisciplinary dermatological clinic, barcelona, spain 2 department of dermatology, barcelona hospital clínic, barcelona university, spain 3 department of dermatology, son llàtzer hospital, palma de mallorca, españa 4 department of dermatology, san pablo hospital de, coquimbo, chile. citation: piquero-casals j, morgado-carrasco d, mir-bonafé jf, rozas-muñoz e. penile angiokeratomas (peakers): an exceedingly rare clinical variant. dermatol pract concept. 2021;11(4):e2021121. doi: https://doi.org/10.5826/dpc.1104a121 accepted: march 14, 2021; published: october 2021 copyright: ©2021 piquero-casals et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: jaime piquero-casals, md phd, department of dermatology dermik multidisciplinary dermatological clinic. barcelona, spain. email: j.piquero@dermik.es case presentation an otherwise healthy 29-year-old man presented with multiple 1 to 3 mm purple papules present in the last 5 years on his glans and scrotum (figure 1a). he had no history of sexually transmitted diseases, nor he experienced trauma to the area. dermoscopy revealed dark blue and red lacunae, together with erythema. dermoscopic analysis confirmed angiokeratoma diagnosis (figure 1b). after explaining the benign nature of the lesions, the patient refused to receive any treatment and the papules remained stable in number at a 6-month follow-up visit. teaching point genital angiokeratomas are benign vascular lesions occurring most commonly on the scrotum or vulva. the differential diagnosis of angiokeratomas includes common nevus, blue nevus, primary melanoma, or cutaneous metastasis, angiomas, as well as others lesions with vascular patterns, such as basal cell carcinomas, and pyogenic granulomas. when angiokeratomas are diffusely present, evaluation for a lysosomal storage disease (lsds) (for instance, fabry disease) and possible referral to a clinical geneticist should be considered [1]. penile angiokeratomas (peakers) are an uncommon subtype of genital angiokeratomas [2]. these benign vascular tumors typically presenting as multiple lesions on the corona glans penis. treatment includes cryotherapy and lasers, among others. dermoscopy should be included as a part of the clinical inspection to avoid unnecessary invasive investigation [2]. informed consent: the patient gave written consent for publication of photographs related to the case. 2 image letter | dermatol pract concept. 2021;11(4):e2021121 references 1. chan b, adam dn. a review of fabry disease. skin therapy lett. 2018;23(2):4–6. pmid: 29562089 2. cohen pr, celano nj. penile angiokeratomas (peakers) revisited: a comprehensive review. dermatol ther (heidelb). 2020;10(4):551-567. doi: 10.1007/s13555-020-00399-3. pmid: 32506249. figure 1. (a) multiple 1-3 mm purple papule on glans and scrotum of 5 years’ duration. (b) dermoscopy of angiokeratoma revealing multiple dark blue and red lacunae, together with erythema. melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. thanks to dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s1): e2021162s 1 melanoma: staging and follow-up chryssoula papageorgiou1, zoe apalla1, sofia-magdalini manoli2, konstantinos lallas2, efstratios vakirlis2, aimilios lallas2 1. second dermatology department, medical school, faculty of health sciences, aristotle university of thessaloniki, greece 2. first dermatology department, medical school, faculty of health sciences, aristotle university of thessaloniki, greece key words: melanoma; staging; follow-up citation: papageorgiou c, apalla z, manoli sm, lallas k, vakirlis e, lallas a. melanoma: staging and follow-up. dermatol pract concept. 2021; 11(s1): e2021162s. doi: https://doi.org/10.5826/dpc.11s1a162s accepted: may 17, 2021; published: july 2021 copyright: ©2021 papageorgiou et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflict of interest to disclose. authorship: all authors have contributed significantly to this publication corresponding author: aimilios lallas, associate professor of dermatology, first department of dermatology, medical school, faculty of health sciences, aristotle university of thessaloniki, greece. email: alallas@auth.gr. cancer staging is the process determining to which extent a cancer has spread and where it is located in the body. a thorough staging is of utmost importance, not only because it provides the most accurate prognostic estimation, but also because several crucial decisions, such as the treatment choice and the follow-up strategy, vary according to the tumor’s stage. the current staging system for melanoma is based on the 8th edition of tnm classification issued by the american joint committee on cancer (ajcc) in 2017. it includes a clinical and a pathological staging, both consisting of 5 stages (0-iv). the stage of a melanoma is determined by several factors, among which the breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the presence and the number of tumor-involved regional lymph nodes, the presence or absence of in-transit, satellite and/or microsatellite metastases, and the presence of distant metastases. following melanoma diagnosis, an accurate medical workup, in line with the stage and the physical examination, should be performed. abstract this article is part of the dpc journal special issue melanoma today guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. 2 review | dermatol pract concept. 2021; 11(s1): e2021162s introduction staging is a process determining the extent to which a cancer has spread in a person’s body and where it is located. cancer stage is categorized from 0 to iv, with stage iv cancer corresponding to a cancer that has metastasized at distant locations. the most used system to stage solid tumors, including melanoma, is the universally accepted tnm (tumor, node, metastasis) staging system. cancer staging can be divided into clinical and pathological staging. clinical and pathological stages are defined by different criteria and may differ but are generally considered as complementary to each other. in general, clinical staging is based on all the available information obtained before surgical excision of the tumor (eg by physical examination, blood tests, and imaging), while pathological staging is performed by a pathologist and relies on the information provided by microscopic examination of the tumor following surgical resection. the clinical stage of a melanoma can be determined only following a complete excision of the primary tumor, a clinical examination of the skin and lymph nodes, and a radiologic assessment for regional and distant metastases’ detection. pathological staging of a melanoma takes into account not only the microstaging of the primary tumor and the wide excision but also considers the information on regional lymph nodes after partial or complete lymphadenectomy, when performed. a proper staging is extremely important, because it provides the most accurate prognostic estimation and allows to take several crucial decisions, such as the treatment choice and the follow-up strategy, that are based on clinical tumor stage. a continuous patient monitoring is fundamental to detect a potential relapse or a second primary melanoma and should be lifelong. however, there is still no universally adopted follow-up strategy program and different follow-up schemes have been suggested. future prospective studies are needed to evaluate different follow-up protocols according to the adopted therapy, as novel recent therapies (targeted and immunotherapies) are being increasingly used. key messages • proper staging is of utmost importance because it provides accurate prognostic estimation. several crucial decisions, such as the treatment choice and the follow up strategy, are based on the tumor stage. • physical examination during staging procedure and follow-up visits are important to avoid unnecessary imaging and laboratory tests that could increase the patients’ anxiety. a personalized approach taking into consideration the patient’s risk factors, is strongly recommended. • melanoma patients should be kept under surveillance lifelong due to an increased risk of developing a second primary melanoma and the risk of recurrence. higher intensity follow-up strategies during the first 5 years are recommended due to higher rates of regional or distant relapse. table 1. clinical staging according to ajcc 8th edition [1]. t n m stage 0 tis n0 m0 stage ia t1a n0 m0 stage ib t1b n0 m0 t2a n0 m0 stage iia t2b n0 m0 t3a n0 m0 stge iib t3b n0 m0 t4a n0 m0 stage iic t4b n0 m0 stage iii any t, tis ≥ n1 m0 stage iv any t any n m1 melanoma staging system the current staging system is based on the 8th edition of tnm classification for staging of melanoma issued by the ajcc in 2017 and is summarized in tables 1-5 [1]. this relatively new system has been broadly accepted after its publication and is considered the cornerstone for classifying melanomas [2,3]. there is both a clinical and a pathological staging, both consisting of 5 stages as follows: clinical staging: • 0: in situ disease • i and ii: localized disease stage i is further divided into substage ia and ib, while stage ii includes substages iia, iib and iic. the determining review | dermatol pract concept. 2021; 11(s1): e2021162s 3 factors for staging and substaging are the breslow thickness and the presence or absence of ulceration after the pathological assessment of the primary tumor (tables 1 and 2). of note, mitotic rate and clark’s level of invasion, previously used for sub-classification, no longer influence melanoma staging. table 2. pathological staging according to ajcc 8th edition [1]. t n m stage 0 tis n0 m0 stage ia t1a n0 m0 t1b n0 m0 stage ib t2a n0 m0 stage iia t2b n0 m0 t3a n0 m0 stage iib t3b n0 m0 t4a n0 m0 stage iic t4b n0 m0 stage iiia t1a/b, t2a n1a, n2a m0 stage iiib t0 n1b, n1c m0 t1a/b, t2a n1b/c, n2b m0 t2b, t3a n1a/b/c, n2a/b m0 stage iiic t0 n2b/c, n3b/c m0 t1a/b, t2a/b, t3a n2c, n3a/b/c m0 t3b, t4a any n ≥ n1 m0 t4b n1a/b/c, n2a/b/c m0 stage iiid t4b n3a/b/c m0 stage iv any t, tis any n m1 table 3. definition of t according to ajcc 8th edition [1]. category thickness ulceration tx: primary tumor cannot be assessed n/a n/a t0: no evidence of primary tumor n/a n/a tis (in situ) n/a n/a t1 t1a t1b ≤1 mm <0.8 mm without ulceration <0.8 0.81.0 mm with ulceration with or without ulceration t2 t2a t2b >1.02.0 mm >1.02.0 mm without ulceration >1.02.0 mm with ulceration t3 t3a t3b >2.04.0 mm >2.04.0 mm without ulceration >2.04.0 mm with ulceration t4 t4a t4b >4.0 mm >4.0 mm without ulceration >4.0 mm with ulceration • iii: regional disease regional disease is defined by the presence of metastases in regional lymph nodes and/or “in transit metastases”, “satellite metastases”, and microsatellite metastases. satellite metastases are defined as cutaneous or subcutaneous metastatic lesions up to 2 cm from the margin of the primary tumor. in-transit metastases are defined as cutaneous or subcutaneous lesions located between 2 cm from the primary tumor and the regional nodal basin. microsatellite metastases are defined as tumor nests larger than 0.05 mm in diameter in the reticular dermis, subcutis, or vessels beneath the primary invasive tumor, but separated from it by at least 0.3 mm of normal tissue on the section in which the breslow measurement was taken. regional lymph nodes metastases are defined as metastases in the lymph node basin that drains lymph from the region around the tumor. involvement of regional lymph nodes is confirmed by their pathological examination after sentinel lymph node (sln) biopsy (for clinically occult lymph node metastases) or therapeutic lymph node dissection when performed (for clinically evident regional lymph node disease). involvement of regional lymph nodes may be also detected by clinical, radiologic examination and/or diagnostic biopsies (clinical staging). therefore, there is only 1 stage group for clinical stage iii. in contrast, pathological stage iii is divided into a, b, c, and d stage groups depending on breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the number of tumor-involved regional lymph nodes, and the presence or absence of in-transit, satellite and/ or microsatellite metastases (table 4). 4 review | dermatol pract concept. 2021; 11(s1): e2021162s table 4. definition of n according to ajcc 8th edition [1]. category number of tumor-involved regional lymph node presence of in-transit, satellite, and/or microsatellite metastases nx: patients in whom the regional nodes cannot be assessed n/a no n0: no regional metastases detected n/a no n1 1 tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved node n1a 1 clinically occult (ie, detected by sln biopsy) no n1b 1 clinically detected no n1c no regional lymph node disease yes n2 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node n2a 2 or 3 clinically occult (ie, detected by sln biopsy) no n2b 2 or 3, at least 1 of which was clinically detected no n2c 1 clinically occult or clinically detected yes n3 4 or more tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 2 or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases n3a 4 or more clinically occult (ie, detected by sln biopsy) no n3b 4 or more, at least one of which was clinically detected, or presence of any number of matted nodes no n3c 2 or more clinically occult or clinically detected and/or presence of any number of matted nodes yes • iv: distant metastatic disease this stage includes distant metastases to lung, central nervous system (cns) or other organs as well as to skin, soft tissue and nonregional lymph nodes. although there is no further division to substages, a sub-classification according to the number of organs involved, which organs are involved, and serum levels of lactate dehydrogenase (ldh) is essential for prognostic reasons (table 5). staging workup histopathologic examination when a suspicious lesion is detected, a biopsy should be performed. a narrow-margin (1-3 mm) excisional biopsy is strongly preferred. in case of primary melanoma, the histopathological features along with clinical examination are determining factors for staging and further management. therefore, the pathology report should include the breslow thickness, the ulceration status, the dermal mitotic rate, the margin status, the presence, or absence of microsatellitosis, and the presence or not of pure desmoplasia. physical examination special attention should be paid to the physical examination of the entire skin surface to look for satellites or in-transit metastases but also for a second primary melanoma. physical examination of the regional lymph node basin should be included. sentinel lymph node biopsy and imaging patients with a melanoma in situ and a clinical stage ia melanoma with normal physical examination and no other symptoms need no further imaging or laboratory tests. they also are not candidates for sln biopsy at baseline. the staging procedure is completed with the performance of wide excision [1]. patients with clinical stage ib melanoma with normal physical examination and no other symptoms need no further imaging or laboratory tests at baseline. concerning sln biopsy, this should be considered in patients with t1b melanoma. the decision depends on several factors, such as comorbidities, age, mitotic rate or lymphovascular invasion [1]. patients with a t2a melanoma, should undergo sln biopsy. review | dermatol pract concept. 2021; 11(s1): e2021162s 5 patients with clinical stage ii melanoma with normal physical examination and no other symptoms need no further imaging or lab tests at baseline, but a sln biopsy should be offered [1,4,5]. in melanoma patients of any stage, if an equivocal regional lymph node is detected during clinical examination, an ultrasound (us) should be considered prior to sln biopsy. however, a negative nodal basin us is not a substitute for biopsy of clinically suspicious lymph nodes and histopathology should be warranted. moreover, abnormalities or suspicious lesions on nodal basin us should be histopathologically confirmed. the presence of lymph node metastasis can be confirmed either with core biopsy or fine-needle aspiration (fna) [6-8]. similarly, if clinical or microscopic satellite/in-transit metastases are suspected, a biopsy is mandatory. if a sln biopsy is indicated, it should be performed at the same time with the wide excision of the primary melanoma. noteworthy, sln biopsy was shown to have only prognostic (and not therapeutic) significance [9-13]. a positive sln biopsy would directly upstage a patient to stage iii, which highlights its significance as a staging procedure, especially after the introduction of adjuvant systemic therapy for stage iii. a complete lymph node dissection is not anymore recommended in case of positive sln biopsy, since it does not offer any therapeutic benefit, it has little prognostic value, and is associated with surgical morbidity [14-17]. it is, however, indicated for the treatment of lymph node metastases diagnosed clinically or by imaging, in the absence of distant metastases. imaging for baseline staging should be considered in patients with pathological stage iiia melanoma and should be performed in all patients with stage iiib/c/d [1]. imaging modalities include chest/abdominal/pelvic ct with intravenous (iv) contrast or whole-body pet/ct, with or without brain mri with iv contrast. moreover, if clinically indicated, neck region should be also checked with ct with iv contrast. finally, stage iv melanoma patients need careful total body medical imaging (ct or pet/ct, brain mri). moreover, plasma ldh should also be assessed [1]. follow-up after melanoma diagnosis, the role of ongoing surveillance of disease-free patients is of paramount importance. the main goals of the follow-up are the following: 1. early identification of relapse (local, distant) and subsequent guidance for adjuvant treatment, where appropriate. 2. early detection of a second primary melanoma and/or non-melanoma skin cancer. 3. recognition and management of side-effects, in case of adjuvant systemic treatment. early detection of relapse is associated with a higher survival rate, highlighting the importance of an adequate follow-up. the likelihood of recurrence varies according to melanoma stage at first presentation. patients with melanoma in situ, are very unlikely to recur following wide excision. there are a few exceptions though, such as lentigo maligna type [18-20]. in general, patients with earlier stage melanoma at first presentation are less likely to recur compared to table 5. definition of m according to ajcc 8th edition [1]. category anatomic site ldh level m0: no evidence of distant metastasis n/a n/a m1 evidence of distant metastases see below m1a distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node not recorded or unspecified m1a(0) not elevated m1a(1) elevated m1b distant metastasis to lung with or without m1a sites of disease not recorded or unspecified m1b(0) not elevated m1b(1) elevated m1c distant metastasis to non-cns visceral sites with or without m1a or m1b sites of disease not recorded or unspecified m1c(0) not elevated m1c(1) elevated m1d distant metastasis to cns with or without m1a, m1b, or m1c sites of disease not recorded or unspecified m1d(0) normal m1d(1) elevated 6 review | dermatol pract concept. 2021; 11(s1): e2021162s those with more advanced stages. accordingly, the timing of relapse varies according to the stage. patients with advanced melanoma tend to recur more quickly compared to those with earlier stage [21-23]. nonetheless, the vast majority of relapses are recorded in the first 5 years and most of them within 23 years following surgery. moreover, the risk of recurrence tends to decrease over time for melanoma stages, but late recurrence (more than 10 years after the initial diagnosis) cannot be excluded [21,22,24-26] patients with a personal history of melanoma are at high risk of developing a second primary melanoma. concerning the risk of developing a second primary melanoma, data reported in the literature is very heterogenous. the reported percentage of melanoma patients developing a second primary melanoma ranges between 2% and 20% [23, 27-30]. in a cohort of prospectively monitored melanoma patients, the cumulative 5-year risk of second primary melanoma was 8% [30]. interestingly, the risk appears to be higher within the first year after the diagnosis of the first melanoma, but it remains considerable for at least 5 years and very possibly even more [23, 27-30]. therefore, individuals with melanoma history should rather be considered at a life-long increased risk of developing a new primary melanoma. although the need for a follow-up in patients with melanoma is not a matter of debate, surveillance recommendations vary widely in terms of methods and frequency of visits, and examinations. as there is currently lack of evidence regarding the efficacy of follow-up strategies, different follow-up schemes have been proposed and are mainly based on expert opinions. the suggested follow-up schemes consider the melanoma stage and the presence or not of additional risk factors. as mentioned above, the first 5 years following the excision of the primary tumor are the most crucial due to high rates of relapse. this is why current guidelines suggest adopting higher intensity follow up strategies during this period. still, because of the lifetime increased risk of a second primary melanoma or a non-melanoma skin cancer, as well as the risk for late recurrence, monitoring programs for melanoma patients should go beyond 5 years, including at least 1 strongly recommended annual skin exam lifelong [31]. the modalities used to monitor melanoma patients include whole body skin examination, physical examination of the regional lymph nodes, blood tests, and imaging exams, such as chest x-ray, ultrasound, ct, pet/ct, and mri. more analytically, a clinical evaluation performed by a dermatologist is mandatory at any stage and includes a total body skin examination (with or without a total body clinical and dermoscopic digital documentation) to identify local recurrences (scar, satellite/in-transit recurrence) and subsequent primary melanoma or other skin cancers. clinical evaluation should also include the examination of the regional lymph nodes and the evaluation of patients’ symptoms and/or signs that would direct appropriate imaging if needed. ultrasound of the lymph nodes is the most accurate method to detect nodal disease and is generally recommended in patients with equivocal lymph node during physical examination, in patients with ajcc t1b stage and above, in patients who were offered sln biopsy but it was not performed or in patients with positive sln biopsy who did not undergo complete lymph node dissection [32]. other imaging modalities (ct, pet/ct, mri, chest x-ray) should be considered for monitoring asymptomatic patients in more advanced stages or when signs and symptoms may suggest distant metastasis [33]. in any clinical scenario, if there is a recurrence suspect, this should be confirmed by histopathologic analysis whenever possible. finally, routine blood testing (ldh, s100 protein) to detect recurrence is generally not recommended as low positive predictive values have been demonstrated. ongoing research focuses on liquid biopsies, namely the detection of molecular alterations in plasma and serum of melanoma patients by characterization of circulating tumor cells and cell-free circulating tumor dna [34,35]. this may provide table 6. example of follow up schedule examinations based on melanoma stage proposed by european consensus-based interdisciplinary guidelines [2]. stage clinicaldermatological examination lymph node sonography laboratory examination: ldh, s-100 ct neck, thorax, abdominal, pelvic or pet/ ct mri head year 1 to 3 4 to 10 >10 1 to 3 4 to 10 1 to 3 4 to 10 1 to 3 4 to 10 ia 6 m 12 m 12 m ib-iib 3-6 m 6 m 12 m 6 m iic-iiic 3 m 6 m 12 m 3-6 m 3-6 m 6 m iiid 3 m 6 m 12 m 3-6 m 3-6 m 3-6 m iv ned (resected, cr under therapy) 3 m 6 m 12 m 3-6 m 3-6 m 3 m iv (m1am1d) (distant metastasis) individualized; otherwise staging every 12 weeks * ned= no evidence disease, cr= complete response review | dermatol pract concept. 2021; 11(s1): e2021162s 7 valuable information on prognostic outcomes and assessment of treatment response or resistance in the future. the national comprehensive cancer network (nccn), an alliance of 31 cancer centers in the united states, has released follow up recommendations per melanoma stage [1]. according to them, no routine imaging is recommended for stage 0 (in situ) melanoma. for patients with stage ia to iia with no evidence of disease, routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended. clinical visits should be scheduled every 6 to 12 months for 5 years and annually thereafter, as clinically indicated. clinical examination in these visits should emphasize on the regional nodes and skin. for patients with stage iib to iv (with no evidence of disease), scheduled visits should be conducted every 3 to 6 months for the first 2 years, every 3 to 12 months for the next 3 years and annually thereafter, as clinically indicated again emphasizing on the regional nodes and skin. moreover, in these stages, imaging (chest x-ray, ct and/or pet/ct) every 3 to 12 months could be considered to screen for asymptomatic recurrence. regarding central nervous system (cns), a periodic brain mri should be performed for up to 3 years to screen for asymptomatic brain metastases in high-risk patients with stage iiic or higher melanoma, while more frequent surveillance is recommended for patients with prior brain metastases. however, routine imaging is not recommended after 3 to 5 years. nonetheless, in any case and at any time of follow-up period, when clinically indicated, an appropriate imaging should be offered to evaluate specific signs or symptoms. finally, if relapse occurs, imaging is recommended to assess the extent of the disease. in addition, when complete surgical resection of relapse is not feasible and active non-surgical treatment is initiated, clinical examination and/or imaging may be appropriate throughout treatment to assess treatment response. in europe, follow up schemes vary among countries, ranging in frequency from 2 to 4 times per year for 5-10 years, again with higher-intensity strategies in more advanced stages and during the first years. current european consensus-based interdisciplinary guidelines for melanoma have proposed an example of follow-up schedule examinations based on stage and is shown in table 6 [2]. irrespectively of the selected follow-up scheme, an individualized approach taking into consideration patient’s risk factors, such as risk for recurrence, prior primary melanoma, family history of melanoma and atypical mole syndrome, is optimal. moreover, patients’ education must be an integral part of the surveillance strategy and should include: a. communication on what to expect from follow-up examinations and why it is important to be compliant with the regular follow-ups. b. awareness that family members often have an increased melanoma risk. c. guidance on how to perform regular self-examination of the skin and peripheral lymph nodes. d. information regarding correct sun exposure 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(2017). completion dissection or observation for sentinel-node metastasis in melanoma. n eng j med. 2017; 376(23): 2211–2222. 16. kyrgidis a, tzellos t, mocellin s, apalla z, lallas a, pilati p, stratigos a. sentinel lymph node biopsy followed by lymph node dissection for localised primary cutaneous melanoma. cochrane database syst rev. 2015; 16(5): cd010307. doi 10.1002/14651858.cd010307.pub2. pmid: 25978975. 17. verver d, rekkas a, garbe c, van klaveren d, van akkooi acj, rutkowski p, et al. the eortc-decog nomogram adequately predicts outcomes of patients with sentinel node-positive melanoma without the need for completion lymph node dissection. eur j cancer. 2020; 134: 9–18. doi: 10.1016/j.ejca.2020.04.022. pmid: 32454396. 18. joyce km, joyce cw, jones dm, donnellan p, hussey aj, regan pj, et al. an assessment of histological margins and recurrence of melanoma in situ. plast reconstr surg glob open. 2015;3(2):e301. doi:10.1097/gox.0000000000000272. pmid: 25750840. 19. duffy kl, truong a, bowen gm, andtbacka rh, hyngstrom j, bowles t, et al. adequacy of 5-mm surgical excision margins for non-lentiginous melanoma in situ. j am acad dermatol. 2014;71(4):835-838. doi: 10.1016/j.jaad.2014.06.044. pmid: 25219711. 20. de vries k, greveling k, prens lm, munte k, koljenović s, van doorn mb, et al. recurrence rate of lentigo maligna after micrographically controlled staged surgical excision. br j dermatol. 2016;174(3):588-593. doi: 10.1111/bjd.14325. pmid: 26616840. 21. romano e, scordo m, dusza sw, coit dg, chapman pb. site and timing of first relapse in stage iii melanoma patients: implications for follow-up guidelines. j clin oncol. 2010;28(18):3042-3047. doi: 10.1200/jco.2009.26.2063. pmid: 20479405. 22. salama ak, de rosa n, scheri rp, pruitt sk, herndon je 2nd, marcello j, et al. hazard-rate analysis and patterns of recurrence in early stage melanoma: moving towards a rationally designed surveillance strategy. plos one. 2013;8(3):e57665. doi: 10.1371/journal.pone.0057665. pmid: 23516415. 23. gassenmaier m, stec t, keim u, leiter u, eigentler tk, metzler g, garbe c. incidence and characteristics of thick second primary melanomas: a study of the german central malignant melanoma registry. j eur acad dermatol venereol. 2019 jan;33(1):63-70. doi: 10.1111/jdv.15194. pmid: 30051517. 24. hofmann u, szedlak m, rittgen w, jung eg, schadendorf d. primary staging and follow-up in melanoma patients--monocenter evaluation of methods, costs and patient survival. br j cancer. 2002;87(2):151-157. doi: 10.1038/sj.bjc.6600428. pmid: 12107834. 25. osella-abate s, ribero s, sanlorenzo m, maule mm, richiardi l, merletti f, et al. risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years. int j cancer. 2015;136(10):2453-2457. doi: 10.1002/ijc.29281. pmid: 25331444. 26. crowley nj, seigler hf. late recurrence of malignant melanoma. analysis of 168 patients. ann surg. 1990;212(2):173-177. doi: 10.1097/00000658-199008000-00010. pmid: 2375648. 27. jones ms, torisu-itakura h, flaherty dc, et al. second primary melanoma: risk factors, histopathologic features, survival, and implications for follow-up. am surg 2016;82:1009-1013. doi: 10.1177/000313481608201034. pmid: 27779995. 28. schuurman ms, de waal ac, thijs ejm, van rossum mm, kiemeney lalm, aben kkh. risk factors for second primary melanoma among dutch patients with melanoma. br j dermatol. 2017;176:971-978. doi: 10.1111/bjd.15024. pmid: 27596937. 29. youlden dr, youl ph, soyer hp, aitken jf, baade pd. distribution of subsequent primary invasive melanomas following a first primary invasive or in situ melanoma queensland, australia, 1982-2010. jama dermatol. 2014;150(5):526-534. doi: 10.1001/jamadermatol.2013.9852. pmid: 25093216. 30. lallas a, apalla z, kyrgidis a, papageorgiou c, boukovinas i, bobos m, et al. second primary melanomas in a cohort of 977 melanoma patients within the first 5 years of monitoring. j am acad dermatol. 2020;82(2):398-406. doi: 10.1016/j. jaad.2019.08.074. pmid: 31499156. 31. youlden dr, baade pd, soyer hp, youl ph, kimlin mg, aitken jf, green ac, khosrotehrani k. ten-year survival after multiple invasive melanomas is worse than after a single melanoma: a population-based study. j invest dermatol. 2016 nov;136(11):22702276. doi: 10.1016/j.jid.2016.03.014. pmid: 27019458. 32. xing y, bronstein y, ross mi, askew rl, lee je, gershenwald je, et al. contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. j natl cancer inst. 2011;103(2):129-142. doi: 10.1093/jnci/ djq455. pmid: 21081714. 33. riquelme-mc loughlin c, podlipnik s, bosch-amate x, riera-monroig j, barreiro a, espinosa n, et al. diagnostic accuracy of imaging studies for initial staging of t2b-t4b melanoma patients. a cross-sectional study. j am acad dermatol. 2019;81(6):1330-1338. doi: 10.1016/j.jaad.2019.05.076. pmid: 31163236. review | dermatol pract concept. 2021; 11(s1): e2021162s 9 34. marczynski gt, laus ac, dos reis mb, reis rm, vazquez vl. circulating tumor dna (ctdna) detection is associated with shorter progression-free survival in advanced melanoma patients. sci rep. 2020;10(1):18682. doi: 10.1038/s41598-020-75792-1. pmid: 33122747. 35. huynh k, hoon ds. liquid biopsies for assessing metastatic melanoma progression. crit rev oncog. 2016;21(1-2):141-154. doi: 10.1615/critrevoncog.2016016075. pmid: 27481010. 1-indice 4-1795 dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11 (3): e2021039 1 an unusual case of meyerson phenomenon around infantile hemangioma giulia veronesi, miriam leuzzi, annalucia virdi, carlotta gurioli, iria neri dermatology department of experimental, diagnostic, and specialty medicine, university of bologna, bologna, italy key words: meyerson phenomenon, hemangioma, eczema, dermoscopy citation: veronesi g, leuzzi m, virdi a, gurioli c, neri i. an unusual case of meyerson phenomenon around infantile hemangioma. dermatol pract concept. 2021; 11 (3): e2021039. doi: https://doi.org/10.5826/dpc.1103a39 accepted: november 16, 2020; published: july 8, 2021 copyright: ©2021 veronesi et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: giulia veronesi, dermatology department of experimental, diagnostic, and specialty medicine, university of bologna, bologna, italy. email: giulia.veronesi.md@gmail.com introduction meyerson phenomenon (mp) is characterized by an eczematous halo around a pre-existing skin lesion. this phenomenon has frequently been described around melanocytic lesions or non-melanocytic skin neoplasms. only few cases related to vascular lesions have been reported in the literature. case presentation a 10-month-old caucasian boy was referred to us for a worsening infantile hemangioma with fast clinical changes and itch onset. on physical evaluation, a purple-red plaque surrounded by yellowish crusts and an erythematous scaly halo of 3.5 x 2.5 cm in diameter was observed on the back (figure 1a). parents reported that the current eczematous halo had abruptly developed around the vascular lesion 2 months before without no specific trigger. no family and personal history of atopic dermatitis, psoriasis, or allergy were reported. a second superficial infantile hemangioma, with no eczematous modifications, was detected on the patient’s left arm. dermoscopy revealed yellow sero-crusts (figure 2a). after their dissolution, a central polymorphous vascular pattern with red glomerular vessels, circle vessels, comma-like vessels, and hairpin vessels surrounded by whitish lobular septa was disclosed (figure 2b). a rim of erythema with dotted vessels and white-yellow scales characterized the vascular lesion periphery (figure 2c). the patient was diagnosed with infantile hemangioma (ih) with mp and was prescribed local treatment with fluticasone propionate once a day, with total resolution after 2 weeks (figure 1b). discussion in 1971, meyerson first described an eczematous halo dermatitis surrounding a preexisting melanocytic nevus [1]. the pathogenesis of mp is still unknown. some authors have suggested an autoimmune reaction against skin melanocytes [1]. cd4 t lymphocytes and intercellular cell adhesion molecule 1 (icam-1) were the main suspects in this immune mediated phenomenon [1]. other authors have reported that ultraviolet radiations can trigger the inflammatory process [1]. however, the mp is not limited to melanocytic nevi and it can be present in numerous other conditions. only few reports on mp in vas2 letter | dermatol pract concept. 2021; 11 (3): e2021039 cular lesions have been reported, regarding solitary angiokeratoma or nevus flammeus [2]. to the best of our knowledge, this is the first case related to an infantile hemangioma. in our case, dermoscopy supported the diagnostic process. it showed red lacunae with polymorphous vascular patterns surrounded by whitish septa in the center of the lesion, dotted vessels, and white-yellow scales at the periphery. over the last years, dermoscopy has increasingly been used in dermatological clinical practice. morphology of vascular structure and vascular pattern have been described in literature helping the correct recognition of skin tumors, infection, or inflammatory disease [3]. reddish and oval lacunae surrounded by whitish septa are the typical dermoscopic finding in ih [3]. the perilesional halo of eczema with dotted vessels and white-yellow scales oriented the mp diagnosis. the pathogenesis in vascular cases of mp is again not clear [2]. one hypothesis is that eczematous lesions on nevus flammeus can be the result of a collision with some dermatoses such as atopic dermatitis. however, figure 1. physical evaluation of infantile hemangioma with meyerson phenomenon. (a) purple-red plaque of 3.5 x 2.5 cm in diameter, surrounded by yellowish crusts and an erythematous scaly halo on the back. (b). total resolution after 2 weeks with topical steroid therapy figure 2. dermoscopic evaluation of infantile hemangioma with meyerson phenomenon. (a) yellow sero-crusts on the lesion. (b) polymorphous vascular patterns, after crusts dissolution, with red glomerular vessels, circle vessels, comma‐ like vessels and hairpin vessels (circles) surrounded by whitish septa (*). (c) a rim of erythema with dotted vessels and white-yellow scales on periphery (arrow) letter | dermatol pract concept. 2021; 11 (3): e2021039 3 atopic dermatitis on vascular lesions has a different clinical presentation compared to mp. another theory suggests that vascular malformation, together with vasodilatation, ectatic capillary vessels or altered endothelial cells, might play a role in the inflammatory process [2]. this occurs with an abnormal production of proinflammatory cytokines and the development of eczema [2]. a similar hypothesis may be supposed also in our case. however, the patient presented 2 superficial ihs and mp was observed only in the back region. this leads us to think that some local triggering events, not studied yet, may have played an important role in the pathogenetic mechanism, and will be evaluated in the future. references 1. loh j, kenny p. meyerson phenomenon. j cutan med surg. 2010;14(1):30-2. doi: 10.2310/7750.2009.08065. pmid: 20128988 2. simon v, hartschuh w, flux k. meyerson-phenomenon hides a nevus flammeus. j dtsch dermatol ges. 2011;9(4):305-7. doi: 10.1111/j.1610-0387.2010.07502.x. pmid: 20718900 3. piccolo v, russo t, moscarella e, brancaccio g, alfano r, argenziano g. dermatoscopy of vascular lesions. dermatol clin. 2018;36(4):389-395. doi: 10.1016/j.det.2018.05.006. pmid: 30201148 dermatology: practical and conceptual dermatology practical & conceptual introduction primary cutaneous b-cell lymphoma (pcbcl) is a lymphoproliferative b-cell disorder involving only the skin at the time of diagnosis. pcbcls comprise a group of rare disease that account for 20%-25% of all cutaneous lymphomas, and they are classified into 3 main types: (i) follicle center lymphoma (the most common and usually indolent), (ii) marginal zone lymphoma, and (iii) diffuse large b-cell lymphoma (the most aggressive) [1]. case presentation we present the case of a 63-year-old otherwise healthy caucasian woman who sought consultation at our skin cancer department for a cluster of lesions localized on the right cheek, presenting as pinkish-erythematous, slow-growing, firm nodules, irregularly oval in shape, with well-defined borders, that had been enlarging over the past 8 years. the largest nodule was 30 mm in diameter (figure 1a). the patient denied correlation with traumas or arthropods bites and felt no local pain or itch. no other cutaneous lesions were found at total-body checkup. systemic involvement was ruled out with laboratory tests, ultrasound examination of lymph node stations, and computed axial tomography of chest and abdomen. dermoscopic evaluation (×20; dermlite, 3gen) showed the presence of an erythematous background with salmon-colored areas, arborizing vessels, and peculiar yellow plugs surrounded by well-defined white circles (figure 1b). the integration of the clinical history and information provided by dermoscopy led to the hypothesis of b-cell lymphoma. a 5-mm punch biopsy was performed, and the histopathological report confirmed the clinical diagnosis of cutaneous b-cell lymphoma, follicle center subtype. research letter | dermatol pract concept. 2022;12(1):e2022006 1 yellow plugs: an additional dermoscopic criterion in the diagnosis of primary cutaneous b-cell lymphoma claudio conforti1, roberta giuffrida2, arianna dri1, iris zalaudek1, nicola di meo1 1 dermatology clinic, maggiore hospital, university of trieste, trieste, italy 2 department of clinical and experimental medicine, dermatology, university of messina, italy key words: cutaneous lymphoma, dermoscopy, lymphomas, diagnosis citation: conforti c, giuffrida r, dri a, zalaudek i, di meo n. yellow plugs: an additional dermoscopic criterion in the diagnosis of primary cutaneous b-cell lymphoma. dermatol pract concept. 2022;12(1):e2022006. doi: https://doi.org/10.5826/dpc.1201a06 accepted: april 25, 2021; published: january 2022 copyright: ©2022 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: roberta giuffrida, md, department of clinical and experimental medicine, dermatology, university of messina, messina, italy. email: roberta_giuffrida@hotmail.it 2 research letter | dermatol pract concept. 2022;12(1):e2022006 figure 1. (a) clinical image of the follicle center of pcbcl: pinkish-erythematous firm nodules, irregularly oval in shape, with well-defined borders, located on the cheek. (b) dermoscopy of the follicle center of pcbcl: erythematous background, salmon-colored areas, arborizing vessels, and yellow plugs surrounded by well-defined white circles. figure 2. (a) tissue fragment of pcbcl obtained by punch biopsy (standard h&e, magnification ×10). (b) histopathological picture of the lymphoma: nodular lymphoid infiltrates arranged in a follicular pattern in the dermis (standard h&e, magnification ×20). conclusions overall, pcbcls may clinically appear as papules, plaques, or nodules of different shapes, number, colors, and body locations. differential diagnosis includes a wide spectrum of pathologies, such as basal cell carcinoma, amelanotic melanoma, arthropod bite scar, or keloid, and for this reason a skin biopsy is always needed to arrive at the correct diagnosis, even if dermoscopy can help rule out other skin disorders [2]. currently available literature states that white circles and salmon-colored areas are the main common dermoscopic features of pcbcls. regarding vascularization, arborizing or serpentine vessels could be found, sometimes simultaneously, resulting in a polymorphous vascular pattern. scales are a further criterion highlighted in a retrospective study [3-5]. research letter | dermatol pract concept. 2022;12(1):e2022006 3 the presence of yellow plugs dermoscopic examination of pcbcls have yet to be reported. in our patient, yellow plugs were detectable throughout the entire lesion, and particularly evident in the central area. the term “yellow plugs” refers to yellow structures surrounded by white circles combined with an erythematous background with salmon-colored areas and arborizing vessels. the histopathological examination described nodular lymphoid infiltrates arranged in a follicular pattern in the dermis. the follicles were atypical because of the absence of polarization and mantle and showed a reduction in the number of macrophages (figure 2, a and b). the cell immunophenotypic patterns were cd20+, bcl-6+, cd10+ and partial bcl-2+. there was no evidence of adnexal involvement, so it can be assumed that the accentuated follicular plugging was the result of the upward displacement of the epidermis by the underlying conspicuous dermal infiltrate. although dermoscopy cannot replace the histopathological examination, the combination of an erythematous background, salmon-colored areas, white circles, arborizing vessels and/or scales, as previously reported by other authors, as well as peculiar yellow plugs, may be helpful in considering pcbcls in the differential diagnosis of cutaneous pink nodules. the peculiar features listed can help in promptly suspecting a possible lymphoma and in identifying the correct site for biopsy. moreover, dermoscopy can be used to monitor recurrences. since pcbcls comprise a group of rare diseases, further investigations are needed to deepen the knowledge on the subject. informed consent: written informed consent for publication of her clinical details and clinical images was obtained from the patient. references 1. willemze r, cerroni l, kempf w, et al. the 2018 update of the who-eortc classification for primary cutaneous lymphomas. blood. 2019;133(16):1703-1714. doi: 10.1182/ b l o o d 2 0 1 8 1 1 8 8 1 2 6 8 . p m i d : 3 0 6 3 5 2 8 7 . p m c i d : pmc6473500. 2. conforti c, giuffrida r, vezzoni r, resende fss, di meo n, zalaudek i. dermoscopy and the experienced clinicians. int j dermatol. 2019 jun 20. doi: 10.1111/ijd.14512. pmid: 31222814. 3. mascolo m, piccolo v, argenziano g, et al. dermoscopy pattern, histopathology and immunophenotype of primary cutaneous b-cell lymphoma presenting as a solitary skin nodule. dermatology. 2016;232(2):203-207. doi: 10.1159/000442251. pmid: 26694025. 4. geller s, marghoob aa, scope a, braun rp, myskowski pl. dermoscopy and the diagnosis of primary cutaneous b-cell lymphoma. j eur acad dermatol venereol. 2018;32(1):53-56. d o i : 1 0 . 1 1 1 1 / j d v. 1 4 5 4 9 . p m i d : 2 8 8 4 6 1 7 1 ; p m c i d : pmc5773353. 5. bombonato c, pampena r, lallas a, giovanni p, longo c. dermoscopy of lymphomas and pseudolymphomas. dermatol clin. 2018;36(4):377-388. doi: 10.1016/j.det.2018.05.005. pmid: 30201147. dermatology: practical and conceptual review | dermatol pract concept 2021;11(1):e2021132 1 dermatology practical & conceptual diet and skin barrier: the role of dietary interventions on skin barrier function milbrey a. parke1, ariadna perez-sanchez2, dina h. zamil1, rajani katta3 1 baylor college of medicine, houston, tx, usa 2 internal medicine, university of texas health science center at san antonio, tx, usa 3 department of dermatology, mcgovern medical school at uthealth, houston tx, usa key words: skin barrier, supplements, atopic dermatitis, diet citation: parke ma, perez-sanchez a, zamil dh, katta r. diet and skin barrier: the role of dietary interventions on skin barrier function. dermatol pract concept. 2021;11(1):e2021132. doi: https://doi.org/10.5826/dpc.1101a132 accepted: august 16, 2020; published: january 29, 2021 copyright: ©2021 parke et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: rajani katta, md, serves on an advisory board for vichy laboratories and is the author of a book on diet and dermatology for the general public. the other authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta, md, 6750 west loop south suite 695 bellaire, tx 77401, usa. email: info@kattamd.com multiple research studies have examined the role of specific dietary interventions and their effects on skin barrier function. the skin barrier is one of the body’s first lines of protection against environmental insults, and disruption of this natural line of defense can result in xerosis, irritation, chronic dermatitis, and other cutaneous effects. multiple laboratory, animal, and human studies have demonstrated that certain dietary interventions have the potential to impact skin barrier function. measurements of skin barrier function include stratum corneum hydration and transepidermal water loss. in this review, we examine this research and provide an overview of the effects of prebiotics, probiotics, fatty acids, and emerging research on other substances. abstract introduction the skin barrier is one of the body’s first lines of protection against environmental insults, including allergens, chemical irritants, microbial insults, and uv radiation. disruption of this natural line of defense can result in xerosis, irritation, chronic dermatitis, and other cutaneous effects [1]. given the skin barrier’s major role in providing protection from multiple threats, there has been much interest in strategies to improve and “strengthen” the skin barrier. a number of research studies have now examined the role of specific dietary interventions in enhancing skin barrier function. we review this research and provide an overview of the effects of prebiotics, probiotics, fatty acids, and emerging research on other substances. 2 review | dermatol pract concept 2021;11(1):e2021132 or signals sent by bacteria. if a threat is sensed, they can activate to repel microbes [2]. skin barrier damage also triggers cytokine secretion, which then acts to regenerate the skin barrier by facilitating the growth and differentiation of keratinocytes [11,12]. measurement of the skin barrier many methods of measuring skin barrier function exist. despite the many methods available, the optimal method of measurement is not well characterized, and conflicting results have been noted when evaluating the utility and accuracy of some methods. these uncertainties must be considered when evaluating the results of any dietary interventions on skin barrier function. the most commonly used methods measure the physical layer of the skin barrier. the parameters targeted most often are stratum corneum hydration (sch) and transepidermal water loss (tewl). sch measures the static water-holding capacity of the skin, while tewl measures dynamic water losses [13]. research indicates that both of these measures may be necessary to fully characterize the functioning of the skin barrier, and they are often used together. sch is the amount of water contained in the stratum corneum. a few different methods are used to measure this parameter. these include electrical measurements such as capacitance, electrical impedance, and conductance [14]. capacitance in particular measures surface hydration, but does not give information about the actual water content or thickness of the skin [5]. a newer method is raman spectroscopy paired with multiphoton microscopy, which can measure full-thickness hydration of the stratum corneum [5,15]. studies on evaluation of sch reveal limitations of these measurement methods. another measure of skin barrier function is that of transepidermal water loss (tewl), which measures the insensible water loss through the skin and provides information on the lipid properties of the skin [14]. this method has been validated for in vivo study of skin permeability [16] although the utility of this method for in vitro testing is questionable. synbiotics: prebiotics with probiotics synbiotics are a combination of probiotics and prebiotics, and their benefits are theorized to be due to effects on the gut microbiome. among other effects, beneficial gut microbes produce short chain fatty acids, which help improve epithelial barrier function and modulate the inflammatory response [17,18]. phenols, in contrast, are considered markers of a disturbed gut microbiome and have been demonstrated to disrupt keratinocyte differentiation in mice [19]. probiotics are live microorganisms that are thought to have health benefits [20]. lactobacillus, bifidobacterium, and the skin barrier background while the skin barrier has traditionally been described in anatomic terms, it can also be described in terms of its components. anatomically, the skin barrier can be divided into 2 layers, the dermis and epidermis. functionally, strugar et al. have described 4 main components: the physical layer, the microbiome, the immune layer, and the chemical layer. these components are all highly dependent on each other, and proper functioning of each component of the skin barrier is crucial for its protective role [2]. disruption may lead to or exacerbate such conditions as irritant dermatitis, atopic dermatitis (ad), acne, and others [3,4]. the physical layer of the skin is composed of the stratum corneum, which is the outermost layer of the skin. its main purposes include protection against water loss and against the penetration of irritants [5]. this layer can be further subdivided into cells (corneocytes) and a lipid matrix. the corneocytes secrete both the lipid precursors and the enzymes to modify these precursors into ceramides, essential and nonessential fatty acids, and cholesterol [6]. these lipids fill the extracellular space by forming lamellar bilayers, thus giving the skin its water-impermeable quality [6,7]. for the physical component of the barrier to function properly, it is believed that these lipids should be in a proportion of 50% ceramides, 25% cholesterol, and 10%-20% free fatty acids [8]. in addition, the omega-3/ omega-6 fatty acid ratio is important for barrier function, with a higher ratio of omega-3 being more favorable [9]. it is also believed that a decrease in stratum corneum thickness and differentiation is part of the pathogenesis of sensitive skin [10]. the chemical layer, distributed throughout the physical layer, contains natural moisturizing factors, defense chemicals, and components that contribute to the acidic ph of the skin. the ph of healthy skin is between 4-6, and is important for the function of the many microbes that live on the skin [2]. at an alkaline ph, which may result from the use of some moisturizers, the microbes and enzymes of the skin do not function properly. an alkaline ph also activates th2-producing endogenous serine proteases, which further disrupt the barrier [6]. crucial to all of this is the protein filaggrin, which helps strengthen the corneocyte cell envelope, form lamellar bodies, and maintain the acidic ph [6]. the microbiome layer is composed of living organisms. flora such as staphylococcus epidermidis and corynebacterium commonly predominate. however, disruption of the normally acidic chemical environment facilitates colonization by staphylococcus aureus and staphylococcus pyogenes, which may play a role in the pathogenesis of diseases such as atopic dermatitis [2,7]. the cells that make up the immune “layer” are always alert for danger signals, such as breaks in the skin barrier review | dermatol pract concept 2021;11(1):e2021132 3 saccaromyces species are among the most common microbes found in probiotics, and many but not all are found in human flora [21,22]. prebiotics such as galactooligosaccharides (gos) are substances which, when ingested, preferentially improve the growth of beneficial gut microbes. clinical studies of synbiotics in the treatment of ad have been promising, but little information is available on their skin barrier effects. in a meta-analysis of 6 studies, synbiotics with mixed bacterial strains were helpful for the treatment of ad in adults and children over the age of 1 year [23]. in a separate study, skin barrier function was measured. in this randomized controlled trial (rct), consumption of the prebiotic gos along with a probiotic milk for 4 weeks led to improved skin hydration. serum phenol levels were also restored [24]. probiotics the use of probiotics in treating inflammatory and infectious diseases of various organ systems has been of increasing interest, including in dermatology [25]. a potential role in the treatment of acne [26] and ad has been explored [27,28]. their role in treatment may be in part due to their effect on the skin barrier. the effect of probiotics on the skin barrier may be linked to their effects on immune regulation and the expression of skin barrier proteins. studies in mice and skin models have shown decreases in pro-inflammatory cytokines, as well as improvement in skin hydration, tewl, and the production of skin barrier proteins. in an ex vivo skin model, the topical application of both the lysate and whole preparations of a lactobacillus species (l. reuteri dsm 17937) decreased production of il-1 and il-8 [25]. this also upregulated the gene for aquaporin 3, an important skin barrier protein that transports water and glycerol [25]. in a human epidermis model, the topically applied lysate of the probiotic lactobacillus rhamnosus improved the expression of loricrin and filaggrin, both integral proteins of the skin barrier. this same strain decreased the destruction of desmosomes after treatment with the irritant sodium lauryl sulfate [29]. despite these promising results, direct research on the effect of probiotics alone on the skin barrier function in humans is relatively lacking. in one rct, skin hydration was increased and tewl was decreased after 12 weeks of oral lactobacillus plantarum hy7714[30]. another rct evaluated the effects of 2 months of oral lactobacillus paracasei ncc2461, and found improved skin barrier function recovery, as indicated by tewl after tape stripping [31]. another rct compared the effects of lactococcus lacti h61 consumption in milk compared to a conventional probiotic yogurt for 4 weeks. both groups had an increase in skin hydration, and the probiotic milk group also had a significant increase in sebum content [32]. prebiotics limited studies are available specifically examining the role of prebiotics. in one rct, healthy adults consuming gos for 12 weeks had greater improvement in tewl and skin hydration compared to the placebo group [33]. in mice with allergen-induced dermatitis, treatment with gos improved both clinical severity and tewl [34]. overall, more human studies are needed to establish a clear association between probiotic and prebiotic consumption and skin barrier function. human studies to date are small. however, given promising results, further research is warranted. omega-3 fatty acids omega-3 fatty acids include alpha-linolenic acid (ala), eicosapentaenoic acid (epa), and docosahexaenoic acid (dha). derivatives of omega-3 fatty acids are thought to influence the skin barrier by acting as transcription factors and decreasing inflammation as immune modulators [35]. studies in skin models and cultured human keratinocytes suggest that dha can increase filaggrin expression, attenuate inflammation, and improve epidermal keratinocyte differentiation [36-38]. an animal study demonstrated decreased tewl, increased skin hydration, and decreased skin barrier alteration by acetone [39]. epa and the ester of epa have been shown in animal studies to influence ceramides in skin [40,41]. however, studies have utilized different methodologies and have shown varying improvement [36-38]. several small human trials have examined the effects of oils rich in fatty acids. flaxseed oil, high in ala, was shown to improve tewl, skin hydration, skin scaling, and roughness in female study subjects after 12 weeks of daily consumption [42]. in another study, improvements in tewl, skin hydration, and skin sensitivity were noted [9]. in both studies, the proportion of plasma ala in those consuming flaxseed oil increased. another rct evaluated hempseed oil ingestion in those with ad. hempseed oil contains both omega-6 and omega-3 fatty acids, in a ratio of about 2:1. subjects reported improved skin dryness and less use of dermal medications with the hempseed oil. although there was a trend to improved tewl, this was not significant [43]. limited human trials have studied the effects of fish oils specifically on tewl. one rct found that use of dha for 8 weeks led to significant improvement in clinical findings of ad and an increase in plasma levels, but did not evaluate tewl [44]. another rct found that a 4-month supplementation with fish oils led to an overall 30% improvement in clinical ad scores, although this was similar to a comparison group given corn oil. of note, both groups had a baseline of 4 review | dermatol pract concept 2021;11(1):e2021132 significantly lower levels of serum fatty acids compared to patients with psoriasis [45]. while these studies are small, they suggest that consumption of oils rich in omega-3 fatty acids have the potential to improve skin barrier function, possibly in those with lower serum levels at baseline. larger studies in humans are needed to assess the magnitude of effect of these treatments. evening primrose and borage oils evening primrose oil (epo) and borage oil (bo) have been studied for the treatment of ad, with overall disappointing results [46]. however, while many ad studies have focused on measures of clinical disease severity, few have investigated their effects on skin barrier function directly. of these, some have reported promising results. gamma-linolenic acid (gla) is an omega-6 fatty acid that has exhibited beneficial properties. epo contains 8%-10% gla and bo contains up to 25% gla. [47,48]. one study described a negative correlation between tewl and serum levels of gla in children with ad. the study also noted a correlation between barrier dysfunction severity and deficiencies in essential omega-6 fatty acids such as gla [49,50]. human skin lacks the enzyme delta 6-desaturase, which converts linoleic acid (la) to gla [51-53]. as such, the skin depends on gla created in the liver [53]. oral supplementation of epo and bo supplies gla directly [47,48]. it is believed that the benefits of epo and bo may be due to the influence of gla and its metabolites on regulatory mechanisms of barrier function [53]. metabolites of gla exhibit anti-inflammatory properties and are linked to increased ceramide synthesis and improved skin barrier function [47,49,54,55]. they also inhibit the formation of leukotriene (lt)b 4 [49,56-58]. clinical studies of epo and bo have varied widely, with differing populations and doses. however, multiple studies have demonstrated significant beneficial effects on tewl [42,53,55,59]. stratum corneum hydration, overall, has not shown significant increases [53,55,60]. negative results have been reported as well, as 2 placebocontrolled trials found no differences in skin barrier function after gla supplementation [49,60]. one of these, however, did find significant improvement in tewl in a subgroup. these patients at baseline had low serum levels of a gla metabolite, suggesting the importance of baseline status in determining who might benefit from supplementation [49]. overall, while epo and bo supplementation has not shown benefit for the treatment of ad, they have shown some promise in enhancing skin barrier function. further research should examine baseline levels of gla that may benefit from supplementation, as well as comparing dosing regimens. emerging interventions l-histidine limited research has been performed on l-histidine supplementation, but results from 1 trial are promising and further research is warranted. l-histidine is an amino acid that is rapidly incorporated into filaggrin. the pathogenesis of ad has been linked to deficiencies in filaggrin, with loss of function mutations in filaggrin genes showing a strong association with ad [61]. in one small rct with 24 adult ad patients, once-daily oral l-histidine for 4 weeks significantly increased both filaggrin formation and skin barrier function. ad severity as measured by scorad improved as well, with no improvement in the placebo group [62]. combination products while some combination products have shown a reduction in tewl, the limited available research, small sample sizes, and use of multi-ingredient products limit our conclusions. this includes studies on a combination turmeric and herbal product [63], a combination borage oil, fermented milk, and vitamin product [54], and a proprietary fish oil blend with vitamin d, antioxidant mixture, and other oils [64]. conclusions several dietary interventions have been studied for their potential impact on the skin barrier, primarily in the form of dietary supplements. laboratory and animal studies have described potential mechanisms of action. while some benefits have been seen in clinical studies, a number of questions remain. clinical trials to date have utilized small sample sizes, and many have used varying dosing regimens. some studies have evaluated multiple active ingredients, making it difficult to isolate the effects of a single ingredient. in addition, several interventions have been studied in disease states, and therefore may not be applicable to those without skin disease. some studies have found that a baseline status of nutrients impacts clinical outcomes and is an important variable that should be studied further in future clinical trials. it is notable that few studies have investigated the role of dietary patterns on skin barrier function. this is an important area for future study. research studies have indicated, for example, that changes in diet can impact the gut microbiome within 1 day [65], with potential implications for the skin barrier. current research has been focused on interventions with dietary supplements and a few foods, but further research on the effects of foods and dietary patterns on the skin barrier is warranted.  although questions remain about dosing, duration, and which populations may benefit, results to date for some interventions have been promising and further research is appropriate. review | dermatol pract concept 2021;11(1):e2021132 5 references 1. kim be, leung dym. significance of skin barrier dysfunction in atopic dermatitis. allergy asthma immunol res. 2018;10(3):207215. doi: 10.4168/aair.2018.10.3.207. pmid: 29676067. 2. strugar tl, kuo a, seité s, lin m, lio p. connecting the dots: from skin barrier dysfunction to allergic sensitization, and the role of moisturizers in repairing the skin barrier. j drugs dermatol. 2019;18(6):581. pmid: 31251552. 3. lyons jj, milner jd, stone kd. atopic 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of dietary supplementation with turmeric or herbal combination tablets on skin barrier function in healthy subjects. j med food. 2018;21(12):1260-1265. doi: 10.1089/ jmf.2018.0015. pmid: 30457892. 64. segger d, matthies a, saldeen t. supplementation with eskimo skin care improves skin elasticity in women. a pilot study. j dermatol treat. 2008;19(5):279-283. doi: 10.1080/09546630801958238. pmid: 19160533. 65. wu gd, chen j, hoffmann c, et al. linking long-term dietary patterns with gut microbial enterotypes. science. 2011;334(6052):105-108. doi: 10.1126/science.1208344. dermatology practical & conceptual www.derm101.com book review | dermatol pract concept 2012;2(3):13 69 review by sarah n. walsh, m.d. inflammatory dermatopathology. a pathologist’s survival guide by steven d. billings, m.d. and jenny cotton, m.d. is a 253-page hard cover text. the contents of the book consist of a preface, an introduction, and 12 separate chapters. the chapters are organized according to basic cutaneous reaction patterns that include both epidermal and dermal patterns. chapters 2-9 (chapter 1 is the introduction) are arranged from superficial to deep cutaneous processes, and include spongiotic dermatitis, psoriasiform dermatitis, interface dermatitis, perivascular dermatitis, vasculitis and thrombotic billings sd, cotton j. inflammatory dermatopathology. a pathologist’s survival guide. new york: springer science + business media llc, 2011 citation: book review: billings sd, cotton j. inflammatory dermatopathology. a pathologist’s survival guide. new york: springer science + business media llc, 2011. dermatol pract conc. 2012;2(3):13. http://dx.doi.org/10.5826/dpc.0203a13. copyright: ©2012 hurt et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: mark a. hurt, m.d., 2326 millpark dr, maryland heights, mo 63043, usa. tel. 314.991.4470. email: markhurt@aol.com. billings sd, cotton j. inflammatory dermatopathology. a pathologist’s survival guide. new york: springer science + business media llc, 2011. 253 pp with index, $189.00. disorders, nodular and diffuse dermatitis, palisading granulomatous dermatitis, and sclerosing dermatitis. chapter 10 covers bullous dermatoses, while chapter 11 discusses panniculitis. infections are the topic for chapter 12. in chapter 13, miscellaneous dermatoses are reviewed, including invisible dermatoses and inflammatory processes that clinically mimic tumors. a table of contents is present at the beginning of the book, as well as an index at the end. the book has a mixture of both text, which predominates, and color histological photographs. each chapter is organized in a similar format, which begins with keywords that include the entities to be discussed, followed by a short paragraph describing or defining the reaction pattern to be detailed. this is followed by a schematic representation figure of the reaction pattern, which is a cartoon drawing showing the epidermis, dermis, and subcutis with the location of the pertinent changes of that pattern. specific entities under this general reaction pattern are then outlined as separate topics. each of these entities has separate sections that cover clinical features, microscopic features, and differential diagnosis. in addition, each of the entities includes at least one, if not more, color microscopic photographs, as well as two separate charts, one for the key microscopic features of the entity and the other with practical tips for the entity. some of the photomicrographs for the separate entities are of h&e stained sections, and some are of, or also include, pictures of special or immunohistochemical stains. in addition, there are some photomicrographs of entities discussed only in the differential diagnosis section. each chapter concludes with a section of sample reports for 70 book review | dermatol pract concept 2012;2(3):13 most, if not all, of the separate entities discussed, followed by a list of selected references. while the introduction chapter of many books is often low-yield, this introduction was worth reading and provided practical information, most notably regarding tips about putting together a pathology report. the section on each separate entity is brief and condensed, covering only the most pertinent features and details with only one, and less often more, accompanying histology photographs. while a more elaborate discussion and photographic depiction of each entity is lacking, that is not the intention or format of this book. the discussion of each entity is true to the authors’ purpose of this being a “survival guide.” the two tables that accompany each entity described are effective. these provide a short summary of the pertinent microscopic features and practical high-yield tips that assist in making the diagnosis or in excluding similar entities in the differential diagnosis. clinical clues that aid in making the diagnosis are also included in the “practical tips” table. another table in chapter 5 (“perivascular dermatitis” chapter) that lists both the superficial and superficial and deep patterns by the type of inflammatory cell that predominates then lists the differential diagnoses under each was also extremely handy. the microscopic photographs are of good quality, and there is an appropriate mixture of low, medium, and high power views. there were many small details for certain entities that were included, which are useful in everyday practice, including when to request additional, control, or deeper biopsies and general guidelines for normal ratios (cd4 to cd8, mast cells, and melanocytes to keratinocytes). the one thing that truly sets this book apart from other books on inflammatory dermatoses, is the section on “sample reports.” for those who do not practice dermatopathology daily, or for those who do but are in the phase of developing a style, this is an excellent reference. it covers cases in which a definitive diagnosis can be made, but more importantly includes examples of when the diagnosis is less clear-cut, and how to handle these more common and more difficult cases. while the report format may not be the style preferred by the reader, it provides good ideas to help communicate differential diagnoses or important histological features. there were only a few points that may be confusing or need clarification for the reader: 1. under the differential diagnosis of prurigo nodularis with squamous cell carcinoma (page 32), it states that prurigo nodularis can show “reactive atypia but lacks pleomorphism.” many in the pathology world incorrectly equate “atypia” to pleomorphism, and because atypia is not well defined or the meaning not agreed upon, this sentence becomes very confusing. 2. in the sample report on page 142, caution should be advised in using “interstitial granulomatous dermatitis” on the diagnosis line because this term is synonymous with a specific entity that is often associated with rheumatic disorders. 3. cutaneous mastocytosis should probably not be covered as a separate section in a book on inflammatory dermatoses, as this is an abnormal growth and accumulation of a clone of mast cells, and therefore, is best categorized as a neoplastic, and not inflammatory, disorder. the same holds true for the section on anaplastic large cell lymphoma. in addition, lipodermatosclerosis is considered by some to be a fibrosing condition, and not a true panniculitis. inflammatory dermatopathology. a pathologist’s survival guide is an easy to navigate, easy to read text that covers the most common inflammatory entities encountered in daily dermatopathology practice. the summary tables and sample reports are exceedingly useful and give this book the edge over similar texts. it is not only a practical resource for surgical pathologists and residents in their approach to inflammatory diseases, but also contains valuable tips for the more seasoned dermatopathologist. dr. walsh is a dermatopathologist at cutaneous pathology, wcp laboratories, in maryland heights, mo. contact her at sarahnwalsh@aol.com. review by almut böer-auer, m.d., ph.d. in the preface, the aims of this book are mentioned to be to “demystify inflammatory dermatopathology,” to be “a practical resource,” and to “provide examples on how we approach signing out our cases.”. the intended readership is defined as “surgical pathologists and residents.” i have to admit at the outset of this review, that i am neither a surgical pathologist nor a resident but a dermatologist/dermatopathologist and a coauthor of another textbook on the same subject, which probably gives me a slightly different perspective on the book compared to those of its intended readership.* the book at hand is thin, less than 250 pages of text, and can easily be read within a week. i am very fond of the idea of presenting a difficult subject in a brief format. i think this must be very appealing to beginners who are often frightened by the heavy tomes typical of dermatopathology. considering the brevity, the book includes quite a high number of figures, which are well taken, in focus, and of good color. all images are accompanied by meaningful legends. the schemas of patterns formed by infiltrates are nicely done and help especially those who are beginners in the field. i applaud the organization of the content according to patterns and the emphasis that the authors put on a patternbook review | dermatol pract concept 2012;2(3):13 71 based approach to diagnosis of skin biopsies. however, i do not particularly like the term “basic reaction pattern.” in my opinion, the term “basic pattern” suffices, and addition of the word “reaction” to it confuses the concept of pattern diagnosis. patterns can be induced by reactive, as well as by neoplastic processes. actually, the beauty of pattern diagnosis is that it can be applied to both. the best example for that is, of course, mycosis fungoides, which can mimic psoriasiform and lichenoid dermatitis, but there are others, like patch stage kaposi’s disease, metastatic breast cancer, mastocytosis, b-cell lymphoma, etc., which can mimic interstitial or perivascular dermatitis respectively. i have another conceptual difficulty with one of the “basic reaction patterns” defined by the authors, to wit, “palisading granulomatous dermatitis.” to me, a well-formed palisading granuloma is a nodule by pattern and falls in the category of a nodular dermatitis. if the palisading granulomas are large or arranged densely, they can present as a diffuse dermatitis. when the periphery of a palisading granuloma is biopsied, it can present as an interstitial dermatitis. i think a separate basic pattern of palisading granuloma is not necessary. every chapter on a “basic reaction pattern” includes a number of subchapters on individual diseases that commonly present with the pattern under discussion. the broad range of manifestations of some diseases (e.g., lupus erythematosus) is addressed by giving several examples. the difficulty of forcing a categorization of disease into a pattern-based approach to diagnosis becomes apparent, however, when lupus erythematosus is addressed in the chapter on “interface dermatitis with perivascular infiltrate,” even though lupus erythematosus can present itself also as a lichenoid dermatitis or as a perivascular dermatitis without epidermal change. in chapters on those patterns, however, lupus erythematosus is not found with a separate paragraph. interestingly, bullous lupus erythematosus is addressed separately in the chapter on “subepidermal vesicular dermatitis,” and lupus panniculitis is addressed separately in the chapter on “panniculitis.” this lack of logic in the organization of the content may cause some confusion in the mind of a beginner. the paragraphs on individual inflammatory skin diseases cover “clinical features,” “microscopic features,” and “differential diagnosis”—and tables accompany them on “key microscopic features” and “practical tips. . the texts are brief and include the most essential clinical aspects of the condition and a more detailed description of histopathologic findings and differential diagnoses. while the tables on “key microscopic features” are largely redundant with the text, those on “practical tips” are interesting and must be helpful especially for beginners in the field. readers here find some information on how to weigh diagnostic criteria in a certain clinical context. i was surprised to see infectious diseases addressed in a chapter on their own. this separation based on etiology has nothing to do with a pattern-based approach to the diagnosis of skin specimens. the justification given by the authors that “many of the entities do not neatly fall into a reaction pattern” is not compelling to me. when you start looking at a biopsy, you don’t know whether it is an infection, and pattern diagnosis helps you to categorize the changes and to proceed stepwise to a point where you will also consider infectious processes that induce such changes. moreover, as already mentioned, some non-infectious diseases do not neatly fall into one pattern but may form various patterns over time (e.g., lupus erythematosus). i was even more surprised to find subchapters on molluscum contagiosum and human papillomavirus infections in this book on inflammatory diseases of the skin. in my opinion, both are virusinduced hyperplasias and not infiltrates of inflammatory cells (in the classic definition of virchowian pathology). i also cannot believe that any pathologist or resident would have serious difficulties with diagnosing those two common conditions (no need to demystify). no separate chapter is devoted to alopecias. lichen planopilaris is missing from the chapter on lichen planus; alopecia of lupus erythematosus is mentioned only in the clinical description in the chapter on lupus erythematosus; and folliculitis decalvans is not addressed. admittedly, diagnosis of alopecias is a particularly difficult part of dermatopathology, but that is why i would have expected at least a paragraph discussing those difficulties instead of just neglecting it (need to demystify!) neoplastic simulators of inflammatory infiltrates are given short shrift in this text. mycosis fungoides is addressed only as a differential diagnosis of “eczematous dermatitis” in the chapter on spongiotic dermatitis; but, practically, mycosis fungoides is also a common problem in differential diagnosis of psoriasiform and psoriasiform-lichenoid patterns. even though the authors mention that, “a detailed discussion of mycosis fungoides is beyond the scope of this text,” the most frequent patterns formed by this common neoplastic simulator should have been mentioned. strangely, the neoplastic conditions mastocytosis, lymphomatoid papulosis, and anaplastic large cell lymphoma are included in the chapter on “perivascular dermatitis,” scattered between true inflammatory diseases like urticaria, perniosis, and arthropod bite reaction, and the authors do not comment on this somewhat bizarre organization of diseases. if those neoplasms deserved a paragraph of their own, why not include mycosis fungoides, which is a much more common diagnosis and differential diagnosis in the routine of dermatopathology? steven d. billings confesses in the preface that early in his career he found dermatopathology “all too confusing” especially because “terminology was impenetrable.” a simi72 book review | dermatol pract concept 2012;2(3):13 lar statement is found in the introduction, where the authors write, “inflammatory dermatopathology is especially vexing. . . . the terminology can border on the impenetrable.” that, of course, is true, and i was very curious to see in what way the authors would try to clarify terminology. there is, however, no glossary of terms relevant to the histopathology of inflammatory skin diseases, there is no reference to textbooks attempting to clarify terminology, and, for the most part, the authors employ conventional (and confusing) terminology of dermatopathology in this book without any critical comment. as an example, i wonder what a pathology resident does with one of the introductory sentences of chapter 2 on “spongiotic dermatitis”: “this chapter will focus on the group of entities encompassing the eczematous family of dermatitis . . .” even after many years of practicing dermatology/dermatopathology i have no lucid definition of “eczema” nor of an “eczematous family of dermatitis.” only four pages later, do the authors provide their definition of “eczematous dermatitis,, which is actually not a definition but a list of skin diseases that they deem to be “essentially histologically identical”: “atopic dermatitis, nummular dermatitis, contact dermatitis (both allergic and irritant contact dermatitis), dyshidrotic dermatitis (pompholyx), id reaction, and eczematous drug eruptions.” apart from the fact that terms should always be defined before they are used, why should one continue using a term that is essentially meaningless? i agree with the authors that phrasing a dermatopathology report is an art addressed almost never in dermatopathology textbooks, and i read with interest the sample reports provided by them. i think those may be helpful to colleagues who never had the chance to sign out specimens with more experienced dermatopathologists, but i also see some problematical aspects: first, i think, a sample report does not make sense without reference to an actual sample. the reports provided by the authors would be much more instructive if they had been accompanied by illustrations. second, the high number of descriptive reports among those samples gives the wrong impression that specific diagnosis cannot be reached in many cases. in my opinion, a so-called “descriptive diagnosis” is not a diagnosis—it is just a description—and descriptive reports should be the exception, rather than the rule. a dermatopathologist should make every effort to decide on a diagnosis. that includes, of course, integration with clinical information and requires firm knowledge of the clinical spectrum of skin diseases. in this context, the authors are right to stress the importance of good communication with the clinician at various places in the book. in sum, reading this book will surely help a pathologist/ resident with little or no knowledge in dermatopathology to overcome their natural resistance towards inflammatory diseases of the skin. it will assist them to avoid bad mistakes and to provide reports that are more helpful. indeed, it can help the pathologist “survive.” in the long term, however, this is obviously not enough! if you really want to perform dermatopathology at a high level, you need to know more about the broad spectrum of manifestations, both clinically and histopathologically, of inflammatory skin diseases and their neoplastic simulators. moreover, you will need to make up your own mind about a completely logical and systematic approach to the diagnosis of skin specimens, as well as about categorization and classification of inflammatory skin diseases. *as an aside i would like to mention that even though i am coauthor of a competitive text (ackerman ab, böer a, benin b, gottlieb gj. histologic diagnosis of inflammatory skin diseases. an algorithmic method based on pattern analysis. 3rd ed. new york city: ardor scribendi, ltd., 2005. isbn 1-893357-25-2), i do not have a commercial bias, because i never received any payments from the publisher, ardor scribendi, ltd., for any work related to this book and internet publication, nor did i or do i receive royalties from book sales. dr. böer-auer is a dermatologist/dermatopathologist and director of academics at dermatologikum hamburg, germany. contact dr. böer-auer at albomed@aol.com. drs. billings and cotton respond to the reviews we are grateful for the comments provided by the reviewers of our textbook on inflammatory diseases of the skin. with regards to the specific comments, we appreciate the reviewers’ more constructive comments. dr. böer-auer does highlight the problems with any classification system of biologic processes. there is always overlap and specific examples that do not neatly fit into defined categories. our organization reflects an approach that has been an effective way for us to teach dermatopathology. it is by no means the only organization scheme that may be effective. we also agree that, whenever possible, a specific diagnosis should be rendered when dealing with inflammatory diseases, and we emphasize that viewpoint in the text. it has been our experience, however, as practicing dermatopathologists, that a descriptive diagnosis must sometimes be employed and that such reports can still be useful to our clinicians. some of dr. böer-auer’s comments seem to miss the spirit of our book. the book is primarily intended for the general surgical pathologist. for this reason, we did not include a chapter on alopecias, as surgical pathologists do not commonly encounter this group of disorders. we clearly state that this book is in no way a comprehensive treatise on the subject of inflammatory dermatopathology. when one is stranded in the wilderness, however, a survival guide may still come in handy. for those who wish book review | dermatol pract concept 2012;2(3):13 73 a more detailed discussion on the subject, dr. böer-auer has graciously advertised the title and isbn number of the book she co-authored for those who may want to purchase this publication. steven d. billings, md, cleveland clinic, cleveland, oh, usa. contact dr. billings at billins@ccf.org. jenny cotton, md, phd, st. joseph mercy hospital, ann arbor, mi, usa. contact dr. cotton at cottonje@trinity-health.org. comments by mark a. hurt, m.d., book review editor i thank drs. walsh and böer-auer for providing reviews for this book, and i thank drs. billings & cotton for responding to the reviews. it is often difficult to accept criticism of one’s work, but it is also useful to consider criticism, as to fear it is to think that the worst is true. this is a small book addressing an approach to the diagnosis of inflammatory diseases of the skin. as the authors indicate in their preface, their intention was to “demystify inflammatory dermatopathology” by providing a “survival guide” for surgical pathologists and residents (presumably residents training in anatomical pathology, but it is not stated explicitly). one of the principal purposes of the book is to provide examples of how to write a report for an inflammatory disease of the skin, as “writing the report is an art never discussed.” in the 13 chapters that follow, the authors proceed to address inflammatory diseases of the skin from the epidermis, generally, to the subcutis. chapter 10, “bullous dermatitis,” seems to be out of place, in my opinion; i would have expected to see it inserted after interface dermatitis and before perivascular dermatitis. the last two chapters break with the algorithmic approach and address specific problems of infections (chapter 12) and invisible dermatoses and inflammatory mimics of neoplastic diseases (chapter 13). the chapters follow the format of introducing the pattern, followed by a number of specific conditions. the specific conditions contain bullet points of “practical tips,” which address the essentials of the condition being discussed; i liken them to “pearls.” additionally, each chapter begins with a schematic, or cartoon, of the pattern addressed. although the photographs are small, they are quality photographs—clear and crisp. the conditions addressed in each chapter are archetypes; there is no intention here for a comprehensive treatment of every disease; the reader will not encounter the entire conceptual spectrum of these conditions, and it is an unrealistic expectation. this is a benefit, oddly enough, given the focus of the text. there are other comprehensive texts; this text offers a basic conceptual framework, and its purpose is to convey that approach—not to inundate the reader with too many concretes. this is a practical consideration, because it requires some years to encounter the entire spectrum of inflammatory diseases or the spectrum of presentations of even a single inflammatory disease (mucha-habermann disease comes to mind immediately); one must begin with archetypes if there is to be any chance of engaging the reader to delve further. i do think that lymphomatoid papulosis and anaplastic large t-cell lymphoma belong in the “mimics” section instead of having a place in perivascular dermatitis, as these are neoplastic conditions, not inflammatory diseases. it is appropriate to lists these neoplasms in the differential diagnosis of inflammatory diseases, which is a common problem in the differential diagnosis. these criticisms aside, i very much enjoyed reading this book and thinking about the authors’ approach to the problems encountered by inflammatory diseases of the skin. the book also lends itself to a framework that its students can write notes in the pages and discover for themselves the variations of pattern, introduced by the authors, of the basic diseases involved here. when confronted with a task, say, putting a lecture together on a complex topic, it always helps to have a basic framework from which to begin thinking about the entire spectrum of problems. this book provides some of that framework. i believe it is a necessary read for every pathology (and dermatology) resident. i agree also with the authors that surgical pathologists will benefit from reading this book and using it at the bench. as the authors state in their preface, it can be read in a weekend (and that is no joke!) i wish i had something comparable to this book when i was a resident in pathology, some 30 years ago! it would have been enormously helpful to me then. finally, i appreciate the authors’ efforts to include examples from pathology reports. i agree with them that this is a neglected aspect of the practice of dermatopathology. when i first began practicing pathology in the 1980’s, comments were the bastard child of a report. “be definitive” was the command of my teachers; after all, everything is something specific. while this is true, one’s knowledge is not always specific, and the “comments” section of a report offers the opportunity to explain why a diagnosis is not certain in every case—in fact, no diagnosis is possible in every case. my comments sections used to look similar to those of the authors; however, in recent years, i have moved away from providing histopathological descriptions in the comments sections. as a rule, i restrict all histopathological findings to the “microscopic” section of the report, the diagnosis is located on the top line, and the comment is just below the 74 book review | dermatol pract concept 2012;2(3):13 diagnosis line. in my comments, i offer interpretations, often a differential diagnosis, as well as why the differential is, in fact, the differential. there is also another crucial aspect to the comments section; it offers an opportunity to address the clinical differential diagnosis and accept or refute each one by one. in short, and in sum, i think this is an important work because of its brevity and focus, and i recommend it to anyone with an interest in inflammatory diseases of the skin. dr. hurt practices dermatopathology privately in maryland heights, missouri. contact him at markhurt@aol.com. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(1):e2022036 1 isotretinoin treatment practices and outcomes in acne patients during the covid-19 pandemic: a single center, retrospective, comparative study mehmet fatih atak1,2, banu ismail mendi2, incilay kalay yildizhan2, hatice sanli2, banu farabi3 1 dermatology department, tokat state hospital, tokat, turkey 2 dermatology department, ankara university, ankara, turkey 3 department of internal medicine, saint peter’s university hospital, new brunswick, nj, usa key words: isotretinoin, treatment, acne, covid-19, pandemic citation: atak mf, ismail mendi b, kalay yildizhan i, sanli h, farabi b. isotretinoin treatment practices and outcomes in acne patients during the covid-19 pandemic: a single center, retrospective, comparative study. dermatol pract concept. 2022;12(1):e2022036. doi: https://doi.org/10.5826/dpc.1201a36 accepted: august 30, 2021; published: january 2022 copyright: ©2022 atak et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. mfa: conceptualization, data curation, formal analysis, methodology, resources, validation, writing-original draft, writing review & editing; bf: methodology, resources, supervision, validation, writing-original draft, writing review & editing; bi: data curation, resources; iky: writing-review & editing; hs: revision of the content corresponding author: banu farabi, department of internal medicine, saint peter’s university hospital, new brunswick, nj, usa. e-mail: banufarabi91@gmail.com introduction: the covid-19 pandemic drastically changed the priorities in healthcare services; outpatient management of acne has changed during this period. objectives: we aimed to investigate treatment practices, outcomes and identify modified follow-up schedules applied during the pandemic. methods: the patients who were admitted to dermatology outpatient clinic between march 13 and july 13, 2020, were included. patients who were admitted between march 13 and july 13, 2019, were served as controls for the study. for each patient, age, gender, treatment protocols, treatment intervals, compliance with the treatment, treatment modifications, and adverse events were recorded. results: the total number of acne patients admitted to dermatology outpatient clinics during the pandemic period was 278 and consisted of 12.3% (278) of all admissions. isotretinoin treatment was started in only 16 (5.8%) of the patients. the proportion of patients who were under follow-up was significantly higher during the pandemic period (p < 0.005). there was no difference between the pandemic period and the non-pandemic period in terms of starting isotretinoin treatment (p > 0.05). during pandemic period, 79% of the patients who used isotretinoin were followed-up every two or more months. extended follow-up intervals showed no difference for detecting side effects (p > 0.05). abstract 2 original article | dermatol pract concept. 2022;12(1):e2022036 introduction covid-19 pandemic affected the healthcare practices all over the world in 2020. it drastically changed the priorities in healthcare services, thus outpatient management of elective diseases such as acne have also been shaped during this period [1]. restrictions and the fear of infection altered outpatient clinic patient profile in dermatology clinics and resulted implementation of teledermatology visits [2]. the effects of pandemic on dermatological practices have been investigated especially in chronic diseases treating with immunosuppressive or immunomodulatory drugs, but there are not enough studies focusing on the effects of acne and its management during the pandemic. acne patients consist of an important part of the routine dermatology outpatient clinics, thus further studies are required to establish the management of acne [3]. objectives we aimed to investigate the treatment practices, treatment outcomes, adherence of acne patients and to identify modified follow-up schedules during the pandemic period. methods the irb approval for the study was obtained from the ankara university ethics committee on april 2021. the patients visited the dermatology clinic between march 13 and july 13, 2020, when first restrictions were imposed by the turkish government due to pandemic, have been retrospectively reviewed for the clinical diagnosis of acne vulgaris through electronic medical record system. a total number of 278 acne patients seen in our clinic for 4 months period during the pandemic was included in the study. for each patient age, gender, treatment protocols, treatment intervals, compliance with the treatment, adverse events were recorded. patients were stratified according to age as follow: younger than 18 years of age, and 18 years or older. treatment protocols were assessed in three categories as follows: topical treatment, systemic antibiotic treatment with topical treatments, and oral isotretinoin treatment. treatment intervals were determined in two different categories as follows: monthly or in every two months or longer. adverse events were recorded. the patients admitted in the outpatient clinic between march 13 and july 13, 2019, served as controls for the study. statistical analysis was performed using the spss 22.0 program. mean, standard deviation and percentage were used for descriptive statistics. chi-square test was performed to examine differences between categorical variables in same groups and the p value of less than 0.05 was accepted as statistically significant. results the total number of patients admitted to outpatient clinic during pandemic period was 2265. acne patients consisted of 12.3% (278) of all admissions. on the other hand, the total number of patients admitted to dermatology outpatient clinic during non-pandemic period was 7604 and 7.5% (577) were acne patients. the distribution of the patients according to the gender and age is shown in table 1, and there was no significant difference between two periods according to gender and age (p > 0.05). table 1. demographic characteristics of patients before and after the pandemic period demographic characteristics of the acne patients pandemic period (n = 278) non-pandemic period (n = 577) p values sex male 179 (64.4%) 383 (66.4%) 0.57 female 99 (35.6%) 194 (33.6%) age, years (mean) 22.80 (sd ± 7.12) 22.16 (sd ± 6.98) 0.22 < 18 64 (23%) 122 (21.1%) 0.53 > 18 214 (87%) 455 (88.9%) sd: standard deviation. conclusions: acne patients constitute an important part of dermatology outpatient clinics. during the pandemic period, majority of acne patients came for follow-up. extended follow-up periods were adopted by physicians and were found safe and effective in the current study. thus, isotretinoin treatment seems efficacious and safe during pandemic period. original article | dermatol pract concept. 2022;12(1):e2022036 3 table 2 summarizes the treatment modalities of the patients with the first admission and under follow-up in both pandemic and non-pandemic periods. among the patients who applied to dermatology outpatient clinic during pandemic period, 124 (44.6%) had first admission and 150 (54%) were under follow-up for different acne treatments, and 4 of them were consultation patients. one hundred and sixteen (93.5%) patients with first admission did not receive treatment for acne previously, whereas 8 of them were under systemic treatments (oral isotretinoin n = 2, doxycycline n = 6). of the 116 treatment naïve patients, topical treatment was given to 77 (n = 27.7%), oral isotretinoin treatment to 16 (5.8%) and systemic antibiotic treatment with topicals to 23 (8.3%) patients. of the 8 patients taking systemic treatment at first admission, doxycycline treatment was switched to oral isotretinoin for 3 patients and to azithromycin for one patient, and the others continued their current systemic treatment (oral isotretinoin n = , doxycycline n = 2). during the pandemic, 26 (9.4%) of the follow-up patients were under only topical treatments, 10 patients (3.6%) were under systemic antibiotic treatment with topical treatment, and 114 patients (41%) were under oral isotretinoin treatment. during this period, for 3 patients topical treatments were switched to oral isotretinoin because of the severity of acne and 1 of the patients under doxycycline treatment was switched to isotretinoin due to lack of efficacy. the rate of total acne patients treated with isotretinoin during the pandemic period was 50% (139 patients). of these patients, 114 (41%) were follow-up ones, 16 (5.8%) of them were started isotretinoin treatment in their first visits. the number of patients with first admission was statistically higher in non-pandemic period and the number of follow-up patients was statistically higher in pandemic period (p < 0.05). there was no statistically significant difference in the two periods according to the number of treatment naïve patients, the first admission patients previously treated with any systemic agent, and patients to whom was given systemic treatment in first admission (p > 0.05). the rate of acne patients treated with isotretinoin during the pandemic period and non-pandemic period were 50% and %39.3, respectively. isotretinoin use was found significantly higher in the pandemic period (p = 0.003). there was no statistically significant difference between the pandemic period and the non-pandemic period in terms of starting isotretinoin treatment in patients with first admission (p > 0.05). there was no significant difference for using isotretinoin treatment in patients who were under follow-up in the two groups (p = 0.17). follow-up intervals, drop-out rates and reported adverse events in patients treated with isotretinoin during pandemic and non-pandemic period are given in table 3. the rate of patients who used isotretinoin and dropped out from follow-up during the pandemic period was significantly higher than the control group (p <0.001). during the pandemic period, the rate of patients using isotretinoin, which was followed in every two or more-months, was significantly higher than the control group (p < 0.001). side effects in pandemic and non-pandemic period were seen in 10.1% and 19.8% of the patients, respectively. the rate of patients using isotretinoin who developed side effects was found significantly higher in the non-pandemic period compared to the pandemic period (p = 0.01). in the 4-month pandemic period (march-july 2020), only two patients were diagnosed with sars-cov-2 infection. one of the patients (aged 27 years) was using isotretinoin and she only showed mild upper respiratory tract infection symptoms. other patient (aged 39 years) was using topical treatments. neither of them was hospitalized. table 2. treatment status of patients admitted during the pandemic and non-pandemic period pandemic period (n = 278) non-pandemic period (n = 577) p values patients with first admission 124 (44.6%) 336 (58.2%) < 0.005 treatment naïve 116 (93.5%) 318 (94.6%) 0.652 treated with any systemic agent (antibiotics and oral isotretinoin) 8 (6.5%) 18 (5.4%) treatment naive patients started systemic isotretinoin 39 (31.4%) 129 (38.3%) 0.34 follow-up patients 150 (54%) 239 (41.4%) < 0.005 isotretinoin treatment 114 (76%) 173 (72.4%) 0.17 systemic antibiotic treatment and topical treatments 10 (6.7%) 8 (3.3%) 0.06 only topical treatments 26 (17.3%) 58 (24.3%) 0.06 treatment status in all patients isotretinoin treatment 139 (50%) 227 (39.3%) 0.003 systemic antibiotic and topicals 36 (12.9%) 103 (17.9%) 0.43 only topical treatment 103 (37.1%) 247 (42.8%) 0.43 4 original article | dermatol pract concept. 2022;12(1):e2022036 table 3. changes in follow-up intervals, patient drop-out rates, and reported adverse events in isotretinoin patients number of isotretinoin patients pandemic period (n = 139) non-pandemic period (n = 227) p values followed-up for extended intervals 79 (56.8%) 65 (28.6%) < 0.001 lost to follow-up 30 (21.6%) 6 (2.6%) < 0.001 reported adverse events 14 (10.1%) 45 (19.8%) 0.01 liver enzyme abnormality 5 (3.6%) 10 (4.4%) hypertriglyceridemia 2 (1.4%) 6 (2.6%) back pain 2 (1.4%) 9 (4%) nasal bleeding 2 (1.4%) 3 (1.3%) psychiatric symptoms 1 (0.8%) 3 (1.3%) headache 1 (0.8%) 1 (0.4%) severe xerosis-eczematous dermatitis 1 (0.8%) 4 (1.8%) dry eye syndrome 7 (3.1%) photosensitivity 1 (0.4%) anal fissure 1 (0.4%) conclusions novel coronavirus pandemic has caused significant changes in dermatology practices [3]. as depicted in our study, the accessibility to outpatient clinics and patient compliance with systemic treatments were affected by the pandemic. according to recent literature, acne patients consisted of the majority of the patients who are admitted to dermatology outpatient clinics [1], and treatment compliance was the highest in this group [3]. this might be due to that acne is relatively common condition in younger individuals and younger patients seek more care because of the psychosocial effect of the disease [4]. additionally, the knowledge of the mild disease course of covid-19 infection might cause young patients to reach hospital clinics without fear compared to elderly population ]. another reason for increased percentage of acne patients can be intense use of masks, thus causing increased prevalence of ‘mask acne’, likely result of increased usage of personal protective equipment with the current pandemic ]. the percentage of acne patients admitted to dermatology outpatient clinic during the pandemic period was found significantly increased compared to non-pandemic period in the current study. starting from march 2020, social distancing measures and restrictions were imposed to prevent the spread of the virus by turkish authorities, however, hospital admissions were exempted. these restrictions were thought to not affect the admissions of acne patients. while the rate of acne patients admitted for their first visit was significantly low in pandemic period, the rate of patients who were admitted for follow-up visits was significantly higher. this is probably as a result of avoidance of hospital visits due to non-emergent conditions during the pandemic period and high treatment compliance rate of our patient population. theoretically, isotretinoin treatment may cause disruption of the basement membrane of the mucosal surfaces by causing mucosal dryness and thinning. this, hypothetically, can increase the risk of covid-19 transmission [9]. there is no established guideline regarding the use of isotretinoin during the pandemic period. in the beginning of the pandemic british association of dermatologists recommended starting or continuing oral isotretinoin treatment where the risks are outweighed by the benefits with monthly follow-up [10]. according to this statement, if there is no risk of pregnancy, the prescriptions for several months could be given taking into account the need to monitor blood test and side effects with remote consultations. in situations where it is not possible to perform monthly pregnancy tests, home pregnancy tests are recommended as a suitable alternative [11]. with the rapid growth of teledermatology, these recommendations have been practiced and the patients were able get their prescriptions instead of in-person visits [2]. a recent study by ruggiero et al reported high degree of satisfaction and well-being after teledermatology visits [12]. between the pandemic and non-pandemic periods, there was no significant difference in the rate of starting systemic treatment for acne patients who were admitted for their first visit. additionally, the percentage of patients using isotretinoin during pandemic period was significantly higher compared to non-pandemic period. this was due to a relative increase of the number of patients who were followed-up with their current isotretinoin treatment. in our clinic, isotretinoin therapy was not avoided during the pandemic period. isotretinoin treatment needs to be monitored in terms of both teratogenesis and bone marrow and metabolic side effects (leukopenia, hypertriglyceridemia, liver enzyme abnormalities) [14,15]). although there are many studies that original article | dermatol pract concept. 2022;12(1):e2022036 5 do not support monthly laboratory testing for isotretinoin [15], there are many centers that apply monthly laboratory follow-up in clinical practice, especially in terms of teratogenicity [16]. monthly laboratory monitoring is also a common practice among physicians in our clinic. when we compared the monthly follow-up to in every two or more-month follow-up rate between the 2 groups, in every 2 or more-month follow-up the rate was higher during the pandemic period. our retrospective analysis showed that extended follow-up intervals showed no significant difference for detecting side effects of isotretinoin. additionally, the reported side effect rate was significantly lower during the pandemic period. this might be due to the lock-down and increased use of skin care products due to easy accessibility to emollients and other protective measures. in the 4-month follow-up, only one patient under isotretinoin treatment had a positive sars-cov-2 pcr result and she showed only mild upper respiratory tract infection symptoms. thus, isotretinoin treatment seems efficacious and safe during pandemic. we recommend extended intermittent laboratory follow-up to reduce the risk of sars-cov-2 transmission, however further large cohort studies are required to elaborate the risks. acne patients constitutes an important part of dermatology outpatient clinics. the proportion of acne patients was observed as significantly higher during the pandemic period. this most likely reflects young individuals seek for more care due to psychosocial effects of the disease and less fear of infection by sars-cov-2. another reason for increased percentage of acne patients is intense use of masks, causing increased prevalence of ‘mask acne’, likely result of increased usage of personal protective equipment with the current pandemic. during pandemic period, the majority of acne patients was admitted for follow-up and physicians did not avoid using isotretinoin treatment in the follow-up patients. extended follow-up periods were adopted by physicians and were found safe and effective in the current study. thus, isotretinoin treatment seems efficacious and safe during pandemic. references 1. kutlu ö, güneş r, coerdt k, metin a, khachemoune a. the effect of the “stay-at-home” policy on requests for dermatology outpatient clinic visits after the covid-19 outbreak. dermatol ther. 2020;33(4):e13581. doi: 10.1111/dth.13581. pmid: 32401401. pmcid: pmc7272831. 2. sharma a, jindal v, singla p, goldust m, mhatre m. will teledermatology be the silver lining during and after covid-19? dermatol ther. 2020;33(4):e13643. doi: 10.1111/dth.13643. pmid: 32441373. pmcid: pmc7267127. 3. alshiyab dm, al-qarqaz fa, muhaidat jm. impact of covid-19 pandemic on the continuity of care for dermatologic patients on systemic therapy during the period of strict lockdown. ann med surg (lond). 2020;60:571-4. doi: 10.1016/j.amsu.2020.11.056. pmid: 33251007. pmcid: pmc7686756. 4. aslan kayiran m, karadag as, jafferany m. psychodermatology of acne: dermatologist’s guide to inner side of acne and management approach. dermatol ther. 2020;33(6):e14150. doi: 10.1111/dth.14150. pmid: 32770727. 5. pasion r, paiva to, fernandes c, barbosa f. the age effect on protective behaviors during the covid-19 outbreak: sociodemographic, perceptions and psychological accounts. front psychol. 2020; 11:561785. doi: 10.3389/fpsyg.2020.561785. pmid: 33178069. pmcid: pmc7595956. 6. searle t, ali fr, al-niaimi f. identifying and addressing “maskne” in clinical practice. dermatol ther. 2021;34(1):e14589. doi: 10.1111/dth.14589. pmid: 33244836. 7. han c, shi j, chen y, zhang z. increased flare of acne caused by long-time mask wearing during covid-19 pandemic among general population. dermatol ther. 2020;33(4):e13704. doi: 10.1111/dth.13704. pmid: 32472634. pmcid: pmc7300566.8. 8. damiani g, gironi lc, grada a, et al. covid-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): multi-center, real-life, telemedical, observational prospective study. dermatol ther. 2021:e14848. doi: 10.1111/dth.14848. pmid: 33533563. pmcid: pmc7995182. 9. a b d e l m a k s o u d a , ve s t i t a m , e l a m a w y h s , e t a l . isotretinoin therapy in the era of covid-19. dermatol ther. 2020;33(4):e13482. doi: 10.1111/dth.13482. pmid: 32358858. pmcid: pmc7261989. 10. british association of dermatologists. guidance for managing patients on isotretinoin during the coronavirus pandemic 2020. available from: https://www.bad.org.uk/shared/get-file. ashx?itemtype=document&id=6661. 11. pathoulas jt, farah rs, fiessinger l, mansh m. an opportunity for improvement: ipledge policy changes during the coronavirus pandemic. dermatol ther. 2020;33(6):e14411. doi: 10.1111/ dth.14411. pmid: 33052629. pmcid: pmc7646038. 12. ruggiero a, megna m, annunziata mc, et al. teledermatology for acne during covid-19: high patients’ satisfaction in spite of the emergency. j eur acad dermatol venereol. 2020;34(11):e662-e663. doi: 10.1111/jdv.16746. pmid: 32534472. pmcid: pmc7323158. 13. kim jk, crimmins em. how does age affect personal and social reactions to covid-19: results from the national understanding america study. plos one. 2020;15(11):e0241950. doi: 10.1371/journal.pone.0241950. pmid: 33170903. pmcid: pmc7654776. 14. dessinioti c, zouboulis cc, bettoli v, rigopoulos d. comparison of guidelines and consensus articles on the management of patients with acne with oral isotretinoin. j eur acad dermatol venereol. 2020;34(10):2229-2240. doi: 10.1111/jdv.16430. pmid: 32277497. 15. lee yh, scharnitz tp, muscat j, chen a, gupta-elera g, kirby js. laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. jama dermatol. 2016;152(1):35-44. doi: 10.1001/jamadermatol.2015.3091. epmid: 26630323. 16. choi js, koren g, nulman i. pregnancy and isotretinoin therapy. cmaj. 2013;185(5):411-413. doi: 10.1503/cmaj.120729. pmid: 23296582. pmcid: pmc3602257. dermatology: practical and conceptual review | dermatol pract concept 2020;10(4):e2020089 1 dermatology practical & conceptual introduction skin, hair, and nail supplements have become a large and growing industry in the united states and worldwide. sometimes referred to as “beauty supplements” or “ingestible skin care,” these dietary supplements continue to increase in popularity. they are frequently promoted on social media and by celebrities, sometimes as “natural” alternatives to cosmetic procedures. these products are sold online and in stores (figure 1). dietary supplements in general are widely used, with reports indicating that approximately half of us adults report using dietary supplements [1-4]. the global beauty supplement market was valued at $3.5 billion in 2016 and is projected to grow to $6.8 billion by the end of 2024, according to a report by goldstein research [5]. as more patients, such as those with androgenetic alopecia or risks of skin, hair, and nail supplements emily k. burns1, ariadna perez-sanchez2, rajani katta3 1 baylor college of medicine, houston, tx, usa 2 department of internal medicine, university of texas health science center, san antonio, tx, usa 3 department of dermatology, mcgovern medical school at ut health, houston, tx, usa key words: dietary supplements, nutrition, diet, toxicity, adverse effects citation: burns ek, perez-sanchez a, katta r. risks of skin, hair, and nail supplements. dermatol pract concept. 2020;10(4):e2020089. doi: https://doi.org/10.5826/dpc.1004a89 accepted: may 28, 2020; published: october 26, 2020 copyright: ©2020 burns et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited funding: none. competing interests: rajani katta, md serves on the advisory board for vichy laboratories and is the author of a book for the general public on dermatology. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta, md, 6800 west loop south suite 180, bellaire, tx 77401, usa. email: info@kattamd.com skin, hair, and nail supplements, sometimes referred to as “beauty supplements” or “ingestible skin care,” are a large and growing industry. these products may contain vitamins and minerals, sometimes in very high doses. they may also contain herbs, hormones, microbes, or animal derivatives such as fish oils and collagen powders. dietary supplements are regulated as foods, not as drugs, by the us food and drug administration (fda). therefore, manufacturers do not need to provide any proof of safety, efficacy, or quality prior to sale. this is of serious concern, as many adverse effects due to supplement components have been reported. the potential risks cover multiple categories. these include acute toxicities, such as choking, as well as chronic toxicities, such as increased risk of diabetes. teratogenicity and interactions with drugs and laboratory testing have been documented in research studies. other risks include potentially increased risk of cancer with long-term use, allergic reactions, and others. it is vital that physicians educate their patients on these risks. as no post-marketing surveillance programs are required for supplements, our understanding of supplement risks is incomplete. physicians should be wary of these risks and encourage further research and regulation. abstract 2 review | dermatol pract concept 2020;10(4):e2020089 the category of skin, hair, and nail supplements includes many different ingredients, and educating patients on the potential risks of these ingredients is especially important. vitamins are frequent ingredients, such as vitamins a, c, and multiple b vitamins, as well as minerals such as zinc and brittle nails (figures 2 and 3), express an interest in these supplements, it is imperative that dermatologists be able to answer their questions and provide guidance based on the medical literature. an overview of the potential risks is especially vital. figure 1. multiple skin, hair, and nail supplements available for sale at a local retailer. figure 2. patients with androgenetic alopecia, seen here with a widened part, may inquire about the use of skin, hair, and nail supplements. figure 3. patients with brittle nails may inquire about the use of nail supplements. review | dermatol pract concept 2020;10(4):e2020089 3 required warning label indicating risk of teratogenicity, even when demonstrated in research studies. the same applies to interactions with medications and laboratory tests, even when documented by research. in this review, we describe several categories of potential risks posed by skin, hair, and nail supplements. in discussing these risks, physicians must emphasize to their patients the importance of multiple variables that impact how an individual may react to a particular supplement. these variables include age, the use of other medications, underlying medical conditions, differences in metabolism, and others. we emphasize that there are a number of other risks not discussed here. of special concern are those risks that may be severe but infrequent. such risks may only be discovered in post-marketing surveillance programs. the supplement manufacturer is solely responsible and lacks supervision for ensuring pre-marketing safety and efficacy. research and documentation of these parameters is completely optional. similarly, post-marketing surveillance by the manufacturer is not required. instead, it relies on reports from consumers, health care professionals, and industry members. in other words, the fda does not actively monitor new dietary supplements, leading to a large gap in our knowledge of supplement safety. selenium. some of these nutrients are included in supplements at very high doses (figures 4 and 5). herbal ingredients such as saw palmetto are common as well. food components are included in this category, such as collagen powders and fish oils. even hormones and microbes are marketed as having beneficial skin effects, including melatonin and probiotics [5]. the dietary supplement industry has minimal oversight from the us fda. supplements are regulated as foods, not as drugs, which has multiple implications in terms of safety and oversight [6,7]. by law, manufacturers of dietary supplements do not require approval by the fda before launching a new product [8]. in essence, any company can bring to market a dietary supplement without having to first provide any evidence of efficacy or safety. multiple vitamins, minerals, herbs, and other substances may be combined without having to first test for compatibility or interactions. in addition, fda requirements on warning labels are minimal [6]. supplements with iron must warn about overdosing and poisoning in children [9]. if a manufacturer includes a structure/function claim on a supplement label, then they must also include a statement or “disclaimer.” this disclaimer indicates that the structure/function claim has not been evaluated by the fda and that “this product is not intended to diagnose, treat, cure, or prevent any disease” [8]. other warning requirements are lacking. there is no figure 4. example of a skin hair, and nail supplement, seen here with a health claim and a disclaimer. figure 5. example of the supplement facts label for a skin, hair, and nail supplement. 4 review | dermatol pract concept 2020;10(4):e2020089 gastrointestinal upset, reduced zinc uptake, and iron overload in hemochromatosis [19]. long-term selenium use is also concerning. although the upper tolerable intake is 400 μg per day, concerns have been raised at 200 μg per day, a dose found in some hair loss supplements [20]. one randomized controlled trial (rct) examined the effects of different doses of selenium as compared to a placebo in a country with moderately low selenium status at baseline. researchers found that a 300 μg per day dose of selenium ingested daily for 5 years increased all-cause mortality as assessed 10 years later [21]. epidemiological studies have raised concern as well. multiple studies have noted that high plasma selenium levels may be associated with increased prevalence of type 2 diabetes, hyperglycemia, and dyslipidemia [22-24]. selenium may also increase the incidence of type 2 diabetes. one rct found that 200 μg per day in non-diabetic patients (average age of 63 years and average follow-up of 7.7 years) significantly increased risk for development of type 2 diabetes as compared to placebo [25]. importantly, an exposure-response gradient was found across subgroups of plasma selenium levels [25]. in patients with preexisting type 2 diabetes, administration of selenium for 3 months resulted in statistically significant elevations in serum glycosylated hemoglobin a1c (hba1c) levels, as well as fasting plasma glucose [26]. risk of nutrient overconsumption from supplements with dietary sources another challenge with the use of dietary supplements is the parallel consumption of food (table 2). nutrients are derived from both supplements and foods, and this is a concern for certain nutrients. the us food and nutrition board has published upper tolerable limits for 24 nutrients acute toxicities a number of acute toxicities have been reported (table 1). reports indicate over 23,000 emergency department visits annually in the u.s. for supplement adverse events [10]. among adults ≥65, pill-induced dysphagia or choking was associated with 37.6% of all emergency department visits for supplement adverse events, with micronutrients implicated in over 80% of cases [10]. the fda recommends a pharmaceutical tablet size of less than 22 mm and requires reporting of tablet size on all new drug applications. by contrast, supplements do not have reporting requirements or size recommendations. many products available in stores exceed 22 mm [10,11]. melatonin, a hormone sometimes marketed for “beauty” sleep, carries a risk of sedation and may increase fall risk. in one trial, a single 3-mg dose resulted in impaired postural control in older adults [12]. in terms of physiologic effects, high doses of vitamin c have been associated with the formation of calcium oxalate kidney stones, particularly in patients with impaired renal function [13,14]. high doses have also been associated with acute hemolysis in those with g6pd deficiency [15]. high doses of b6 and b12 have been associated with the development of rosacea fulminans [16]. chronic toxicities hair loss supplements may contain a number of different ingredients, including the minerals iron and selenium. although supplemental iron has not shown benefit for hair loss in those with normal levels, iron is frequently found in dietary supplements advertised for hair loss [17]. the long-term use of iron in those who are not deficient, even at low doses, has resulted in symptoms of iron overload [18]. common adverse effects of iron overdose are constipation, table 1. acute and chronic toxicities due to skin, hair, and nail supplements (selected examples) acute toxicity ingredient dysphagia or choking, particularly among adults ≥65 [10] tablet size >22 mm sedation and falling risk [12] melatonin calcium oxalate kidney stones [13,14] acute hemolysis in patients with g6pd deficiency [15] high-dose vitamin c rosacea fulminans [16] high-dose vitamin b6 high-dose vitamin b12 chronic toxicity constipation, gastrointestinal upset, reduced zinc uptake [18,19] high-dose iron increased all-cause mortality [21] increased incidence of type 2 diabetes, dyslipidemia, and hyperglycemia [22–25] high-dose selenium review | dermatol pract concept 2020;10(4):e2020089 5 in fact, despite a long history of biotin use in skin, hair, and nail supplements (figures 4 and 5), it was only in 2017 that the fda issued a warning about its potential for interactions with laboratory testing [31]. impacted tests included those testing for thyroid and cardiac function. in a clinical trial, subjects were tested with specific biotinylated immunoassays before and after taking biotin 10 mg daily for 7 days. biotin ingestion interfered with 9 out of 23 biotinylated immunoassays. researchers found falsely decreased thyroid-stimulating hormone concentrations, raising the concern of misdiagnosing hyperthyroidism in a healthy individual, as well as falsely decreased nt-probnp, a test used to help diagnose congestive heart failure [32]. troponin levels, used to diagnose myocardial infarction, were also falsely decreased. another study evaluated the accuracy of urine pregnancy tests in women consuming biotin. in nonpregnant women who ingested biotin 10 mg daily for 7 days, urine samples were tested with a qualitative b-hcg urine pregnancy test. after day 3, 3 out of 4 tests revealed the absence of a control line. in other words, certain urine pregnancy tests may not function in women consuming biotin [33]. reports in cardiology journals caution against the use of saw palmetto in patients taking warfarin due to the potential impacts on bleeding time. case reports have described [27]. these nutrients should be maintained within an optimal level of intake: not too low, but also not too high. in the case of specific nutrients, certain foods may contain high levels already. adding a supplement in these cases may quickly lead to consumption above the upper tolerable limits and result in multiple adverse effects [28]. for example, the recommended daily value (dv) for selenium in a healthy adult is 200 μg, and the upper tolerable intake level (ul) is 400 μg [27]. a single brazil nut can contain up to 90 μg of selenium [29]. these values demonstrate the risk of a supplement containing the recommended dv in conjunction with just 3 brazil nuts (270 μg). this combination exceeds the established ul, increasing the risk of adverse events. iron overload may occur even at low doses [18], raising concern about the risks of iron supplementation in conjunction with ingestion from high-iron foods. drug interactions supplements may interact with many prescription medications and laboratory tests. one literature review documented over 1,400 unique interactions with over 200 herbs and supplements [30]. since no formal surveillance programs are required for supplements, it is imperative that physicians be alert for new reports. table 2. adverse effects due to skin, hair, and nail supplements (selected examples) adverse effect ingredient interaction lab testing: thyroid-stimulating hormone, troponin, b-hcg and nt-probnp tests [30–33] biotin (vitamin b7) warfarin (leading to risk of increased bleeding) [34–36] saw palmetto teratogenicity ambiguous genitalia in male offspring [38] saw palmetto (5-alpha-reductase inhibitor) birth malformations [41–43] high-dose vitamin a allergic reactions anaphylaxis [52] hydrolyzed fish collagen drug reaction with eosinophilia and systemic symptoms [48] diindolylmethane (dim) urticarial reactions, fixed drug reactions, generalized dermatitis, anaphylaxis [50,51] dyes and preservatives used in supplements increased cancer risk skin cancer in women [57] antioxidant supplement (vitamin c, vitamin e, betacarotene, selenium, zinc) melanoma [58] high-dose selenium lung cancer in smokers [60] beta-carotene lung cancer in smokers [61] high-dose vitamins b6 and b12 6 review | dermatol pract concept 2020;10(4):e2020089 effects on reproductive organs, leading to concerns regarding its long-term use in a pediatric population [46]. allergies due to the lack of federal regulation, little is known about hypersensitivity reactions to supplements. multiple supplement ingredients have been associated with both stevens-johnson syndrome and toxic epidermal necrolysis, including ascorbic acid and chinese herbal supplements [47]. diindolylmethane, sometimes used in acne supplements, has been associated with the severe systemic allergic reaction dress (drug reaction with eosinophilia and systemic symptoms) [48]. cutaneous drug reactions and urticaria have been described in herbs used to treat skin conditions [49,50]. additives used in many supplements, including dyes and preservatives, are well-known triggers of allergic reactions. such reactions include urticarial reactions, fixed drug reactions, generalized dermatitis, and even anaphylaxis [50,51]. while the allergenicity of collagen powders derived from sources such as seafood is unknown, hydrolyzed fish collagen has been associated with anaphylaxis [52]. potential cancer risk the role of micronutrients in chemoprevention and carcinogenesis is not completely understood. animal research suggested that antioxidants, including beta-carotene, vitamin e, vitamin c and others, could have a chemoprotective effect. observational studies found that individuals who consumed diets high in fruits and vegetables containing antioxidants were at lower risk of multiple cancers [53,54]. these promising results have not been observed when supplemental doses of antioxidants (as opposed to dietary doses) have been evaluated in large, population-based rcts. in fact, in some cases supplementation may increase cancer risk. many supplements marketed as skin, hair, and nail supplements contain high levels of micronutrients. some contain high levels of vitamins a, b6, b12, e, and selenium, all of which have been associated with higher cancer risk in various groups. uv radiation enhances the formation of cutaneous free radicals, which play a pivotal role in the development of skin cancer (sc). dietary antioxidants (aos) are important in neutralizing free radicals, but dose (dietary as opposed to supplemental) and timing is critical [55]. research on small animal models suggested that ao supplementation could prevent the development of sc [56]. however, in excessive intraoperative bleeding during a craniotomy [34], intraoperative floppy iris syndrome during a cataract procedure [35], and hematuria and coagulopathy in one patient [36]. the risk factors, frequency, and extent of this effect is not known, as one study in 10 volunteers found that saw palmetto ingestion did not affect platelet function tests in this small group [37]. teratogenicity and effects on the reproductive system as current labeling laws in the united states do not require pregnancy category warnings on any supplements, physicians must counsel their patients of any potential teratogenicity risks. saw palmetto (serenoa repens) is one concerning supplement. this plant has a long history of use in asia and among native americans, especially as a treatment for benign prostatic hypertrophy (bph), and is frequently found in supplements advertised for that condition [38]. it inhibits 5-alpha-reductase, which prevents the conversion of testosterone to dihydrotestosterone [39,40]. because of this ability, saw palmetto is also featured in a number of hair loss supplements advertised for hair loss in both men and women [20]. saw palmetto, as a 5-alpha-reductase inhibitor, presents a severe teratogenicity risk. the administration of 5-alphareductase inhibitors to pregnant animals is associated with male offspring with abnormal male genitalia. therefore, these drugs are labeled pregnancy category x, the category of greatest concern for pregnant women, by pharmaceutical companies [38]. due to a lack of labeling regulations, no such warning is required for supplements, despite a similarly demonstrated mechanism of action. high doses of vitamin a are also teratogenic, with risk particularly high before the seventh week of pregnancy, at a time when some women may not be aware of their pregnancy. among pregnant women who averaged more than 10,000 iu per day of vitamin a orally (in the form of retinoid compounds), approximately 1 in 57 had a malformation owing to the supplement [42]. similarly high doses may be found in some dietary supplements advertised for skin benefits, as in certain acne supplements [44]. for many nutrients, the risks related to ingestion of high doses are not known and have not been studied systemically. zinc is often used in acne supplements and is one such nutrient that warrants further study. in one study, elevated levels of zinc in umbilical cord blood were associated with adverse neonatal neurobehavioral development [45]. melatonin is another concerning supplement. although sold as a dietary supplement, melatonin is actually a hormone that has important effects on circadian rhythms. animal studies have indicated that melatonin has profound review | dermatol pract concept 2020;10(4):e2020089 7 have described microbial contamination with bacteria [66] as well as with fungi [66,67]. multiple studies have also reported adulteration with heavy metals, such as ayurvedic medicines contaminated with lead, mercury, and arsenic [68], and collagen powders contaminated with cadmium [69]. adulteration with prescription medications has also been described for multiple supplements [70]. in addition, labeling and manufacturing errors have led to serious side effects. a manufacturing error resulted in selenium supplements containing 200 times the labeled concentration, resulting in multiple cases of acute selenium toxicity [71], while a mislabeled and improperly formulated vitamin d supplement led to a patient consuming more than 1,000 times the recommended dosage [72]. conclusions in accordance with fda regulation, all prescription drugs must include a package insert detailing black box warnings, potential risks, and pregnancy category warnings. supplements lack all of these warnings. in addition, no post-marketing surveillance programs are required. the results of these programs with prescription medications demonstrate their importance in detecting infrequent but severe side effects. such programs have led to recalls of multiple promising prescription medications, such as the antihistamine terfenadine, linked to serious cardiac arrhythmias from drug interactions [73] and the anti-obesity drugs fenfluramine and dexfenfluramine, recalled due to reports of heart valve damage [74]. in discussing the risks of dietary supplements, we emphasize that our understanding of their safety and risk profiles is incomplete. physicians should be wary of the ever-growing supplement industry and encourage further research and regulation. references 1. bailey rl, gahche jj, miller pe, thomas pr, dwyer jt. why us adults use dietary supplements. jama intern med. 2013;173(5):355-361. doi: 10.1001/ jamainternmed.2013.2299. pmid: 23381623. 2. chen f, du m, blumberg jb, et al. association among dietary supplement use, nutrient intake, and mortality among u.s. adults: a cohort study. ann intern med. 2019;170(9):604-613. pmid: 30959527. 3. kantor ed, rehm cd, du m, white e, giovannucci el. trends in dietary supplement use among us adults from 1999-2012. jama. 2016;316(14):1464-1474. doi: 10.1001/ jama.2016.14403. pmid: 27727382. 4. bailey rl, gahche jj, lentino cv, et al. dietary supplement use in the united states, 2003-2006. j nutr. 2011;141(2):261-266. doi: 10.3945/jn.110.133025. pmid: 21178089. 5. katta r, huang s. skin, hair and nail supplements: an much of this research, ao supplementation occurred before exposure to uv radiation. in human studies, by contrast, ao supplementation often occurs after years of exposure to uv light [57]. in fact, supplementation with high doses of aos may prove detrimental. in one study, researchers evaluated the effects of a combination supplement that contained promising micronutrients in the hope that it would reduce the risk of sc in women aged 35-60. this supplement contained vitamin c, vitamin e, beta-carotene, selenium, and zinc. unfortunately, the incidence rate of sc in women consuming this supplement was significantly higher than those who took a placebo [57]. another study examined the effects of selenium exposure. in this epidemiological study, the incidence of melanoma was 4 times higher in individuals exposed to high selenium levels from the environment than unexposed individuals [58]. this association between high-dose micronutrient supplementation and increased risk of cancer has been noted for other cancers as well, including lung cancer. male smokers who took beta-carotene, a precursor to vitamin a, were at increased risk for lung cancer and cardiovascular disease in comparison to a placebo group. in fact, the trial was stopped early because the mortality rate was 17% higher in the treatment group [59,60]. another study examined the effects of vitamins b6 and b12 supplementation and found a 30%40% increased risk of lung cancer among male smokers [61]. in terms of other cancers, alpha-tocopherol (vitamin e) supplementation in healthy men increased the risk of prostate cancer by 17% [62]. folic acid supplementation in healthy men also increased the risk of prostate cancer [63]. other risks a wide variety of other risks has been described from skin, hair, and nail supplements. some include well-known risks, such as sedation from melatonin. less well-known risks include hair loss that may result from high levels of selenium, vitamin a, and vitamin e [17]. ironically, these are often found in supplements marketed for use in hair loss [64]. other reported reactions are due, not to side effects from the active ingredients, but rather to the quality of the formulation. quality concerns are a major concern with supplements, as the fda does not require any proof of quality prior to sale. while manufacturers are required to follow current fda good manufacturing practices, the fda is only able to inspect a small fraction of facilities every year. for the fiscal year 2019, 51% of dietary supplement manufacturing facilities in the us and abroad were cited for noncompliance with these practices [65]. quality concerns are a serious issue, as multiple reports 8 review | dermatol pract concept 2020;10(4):e2020089 vitamin and mineral supplements. cmaj. 2003;169(1):47-48. pmid: 12847042. 20. nutrafol core for women | nutrafol. accessed march 20, 2020. https://nutrafol.com/nutrafol-core-for-women 21. rayman mp, winther kh, pastor-barriuso r, et al. effect of long-term selenium supplementation on mortality: results from a multiple-dose, randomised controlled trial. free radic biol med. 2018;127:46-54. doi: 10.1016/j. freeradbiomed.2018.02.015. pmid: 29454039. 22. bleys j, navas-acien a, guallar e. 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https://www.cdc.gov/fungal/outbreaks/rhizopusinvestigation.html 68. saper rb, phillips rs, sehgal a, et al. lead, mercury, and arsenic in usand indian-manufactured ayurvedic medicines dermatology: practical and conceptual dermatology practical & conceptual www.derm101.com quiz | dermatol pract concept 2012;3(2):12 73 the patient a 64-year-old man presented with a non-pigmented lesion on the leg (figure 1). what is your diagnosis based on the clinical and dermatoscopic presentation (figure 2)? please send your answer to dpc@derm101.com. the first correct answer will receive a complimentary copy of the book, dermatoscopy: an algorithmic method based on pattern analysis [facultas verlag, 2011]. the case and the answer to the question will be presented in the next issue of dermatology practical and conceptual. answer to january 2013 quiz the correct answer to the dermatoscopy quiz in the january 2013 issue is basal cell carcinoma (http://dx.doi.org/10.5826/ dpc.0301a11). congratulations to dr. jan lapins who was the first to send us the correct answer to this quiz! dermatoscopy: what is your diagnosis? philipp tschandl, m.d.1 1 department of dermatology, division of general dermatology, medical university of vienna, austria citation: tschandl p. dermatoscopy: what is your diagnosis? dermatol pract conc. 2013;3(2):12. http://dx.doi.org/10.5826/dpc.0302a12. copyright: ©2013 tschandl. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: philipp tschandl, m.d., department of dermatology, division of general dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria. tel. 43 1 40400 7700; fax. 43 1 408 19 28. email: philipp.tschandl@meduniwien.ac.at. figure 1. clinical image of a non-pigmented lesion on the leg. figure 2. dermatoscopic presentation of the lesion. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3):e2021062 1 acquired cutaneous lymphangiectasia: dermoscopic evidence from white-yellowish lacunae nicolás silvestre-torner1, adrián imbernón-moya1, marta martínez-garcía1, fernando burgoslázaro2 1 department of dermatology. hospital universitario severo ochoa. avenida de orellana, leganés, madrid, spain. 2 department of pathology. hospital universitario severo ochoa. avenida de orellana, leganés, madrid, spain. key words: lymphangiectasia, dermoscopy, lymphedema, breast cancer citation: silvestre-torner n, imbernón-moya a, martínez-garcía m, burgos-lázaro f. acquired cutaneous lymphangiectasia: dermoscopic evidence from white-yellowish lacunae. dermatol pract concept. 2021;11(3):e2021062. doi: https://doi.org/10.5826/dpc.1103a62 accepted: december 10, 2020; published: july 8, 2021 copyright: ©2021 silvestre -torner et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: nicolás silvestre torner, department of dermatology, hospital universitario severo ochoa, avenida de orellana, leganés, madrid, spain, plaza general vara de rey 11, 4g. email: nicolassilvestretorner@gmail.com  case presentation a 71-year-old woman, with a personal history of a left radical mastectomy and locoregional radiation therapy for breast cancer 20 years ago, was referred for assessment. she presented secondary chronic upper limb lymphedema and asymptomatic flesh-colored papulovesicles on the left axillary area (figure 1) that appeared 6 months ago. on dermoscopy, lesions presented well-demarcated red-orange lacunae surrounded by white lines (figure 2). histopathology showed multiple ectatic lymphatic vessels in the papillary dermis (figure 3). thus, a diagnosis of acquired cutaneous lymphangiectasia was made. teaching point acquired cutaneous lymphangiectasia (acl) are dilatations of surface lymphatic vessels, following lymphatic damage after surgery or radiotherapy, specially related with breast cancer [1]. often described as “frog spawn”, acl presents as multiple asymptomatic translucent vesicular lesions, resembling a lymphangioma circumscriptum. dermoscopy shows a vascular pattern with yellow-orange lacunae surrounded by white septa [2]. although acl are considered benign disorders, histopathological diagnosis is needed to rule out different disorders, including cutaneous metastases from previous cancers. 2 image letter | dermatol pract concept. 2021;11(3):e2021062 figure 1. multiple thin-walled papulovesicles on the left axillary area. figure 2. dermoscopy revealing a vascular pattern with well-circumscribed yellowish lacunae surrounded by pale septa. figure 3. histopathology revealing ectatic vessels in papillary dermis lined by a single layer of endothelial cells. references 1. valdés f, peteiro c, toribio j. acquired lymphangiectases and breast cancer. actas dermo-sifiliográficas (english edition). 2007;98(5):347-350. doi:10.1016/s1578-2190(07)70459-6 2. verzì ae, lacarrubba f, tedeschi a, micali g. localized acquired lymphangiectasias after breast surgery: enhanced non-invasive diagnosis using dermoscopy and reflectance confocal microscopy. skin res technol. 2020;26(2):205-208. doi:10.1111/srt.12780. pmid: 31549745 dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021053. 1 unilateral linear capillaritis dermoscopic examination: a distinct clinico-histopathological correlation jayanti singh1, priyadarshini sahu1, surabhi dayal1, sant prakash kataria2 1 department of dermatology, venereology and leprology, pt b d sharma university of health sciences, rohtak, haryana, india 2 department of pathology, pt b d sharma university of health sciences, rohtak, haryana, india running title: unilateral linear capillaritis dermoscopy key words: unilateral linear capillaritis, dermoscopy, pigmented purpuric dermatosis citation: singh j, sahu p, dayal s, kataria sp. dermoscopy of unilateral linear capillaritis: a distinct clinico-histopathological correlation. dermatol pract concept. 2021; 11(3): e2021053. doi: https://doi.org/10.5826/dpc.1103a53 accepted: december 7, 2020; published: july 8, 2021 copyright: ©2021 singh et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none authorship: all authors have contributed significantly to this publication corresponding author: surabhi dayal, senior professor and head of the department (m.d), department of dermatology, venereology and leprology, pt b d sharma university of health sciences, rohtak, haryana, india. email: surabhidayal7@gmail.com introduction unilateral linear capillaritis (ulc) is a rare variant of pigmented purpuric dermatosis (ppd). it is characterized by unilateral, progressive, linear eruption of purpuric patches or macules. it is a benign condition and often resolves spontaneously. to the best of our knowledge, ulc dermoscopic features have only been described in 1 case report. herein, we attempted to compare the dermoscopic features of ulc with ppd and differentiate it from linear pityriasis rosea (pr). in the present case, we also found a few more dermoscopic features characterizing ulc, which have not been reported yet in the literature. to establish ulc dermoscopic features and differentiate it from other linear dermatoses, there is the need to present additional findings to enrich the current documentation. case report a 32-year-old male presented with mildly itchy erythematous rash covering the left side of the chest, arm and forearm. the rash was ongoing in the last 3-4 months. on cutaneous examination, there were multiple erythematous, slightly scaly round-to-oval patches, varying from 0.5-5 cm in size, associated with coppery tinge, seen on the anterior part of left chest (not crossing the midline), flexor aspect of left upper limb and left palm (figure 1). other cutaneous and systemic examinations were normal. routine investigations were within normal 2 letter | dermatol pract concept. 2021; 11(3): e2021053. ranges. differential diagnosis of ulc and linear pr were considered. dermoscopy was performed using dermlite iv at 10x magnification, and revealed coppery-red background, linear white and red lines, red globules, red and brown dots, and scaling (figure 2). on histopathological examination, the epifigure 1. multiple linear erythematous, slightly scaly, patches seen on the anterior side of the left chest, flexor aspect of left upper limb and palm. figure 2. dermoscopy showing red globules (black arrow), red (red arrow) and brown dots (blue circle), scaling (blue arrow), linear white (green arrow) and red lines (blue circle) with coppery-red background (dermlite dl4, ×10, polarized light). dermis appeared mildly atrophic with loss of dermal papillae and the basal layer showed focal vacuolization (figure 3). dermis revealed edema, dense perivascular lymphocytic infiltrate, and extravasation of red blood cells (rbc). based on these findings, diagnosis of ulc was made. the patient was treated conservatively, and he recovered within 2 weeks. discussion dermoscopy can be used for differentiating ulc from linear pr. on dermoscopy of ppd, coppery-red background due to lymphohistiocytic dermal infiltration, extravasated rbcs, and hemosiderin deposition is observed. red dots and globules represent extravasated rbcs and dilated blood vessels. brown dots represent melanocytes in basal layer of epidermis and dermal melanophages in upper dermis. scaling observed in our patient, might be due to the chronicity of the lesions. in pr, peripheral white scales and few red dots are seen in yellowish background [1]. based on the clinical and dermoscopic findings we concluded that dermoscopic features of ulc are similar to the ones reported in ppd. in our case, scaling was an additional finding. recently, a case report described dermoscopy of ulc. the authors observed dermoscopic features such as linear vessels, brown reticular lines, red dots, and clods with a brown-pigmented network [2]. in addition to these features, we also observed brown dots and linear white lines along dermatoglyphics secondary to scaling. to best of the authors’ knowledge, the dermoscopic features such as brown dots and scaling in ulc have not been reported in the literature yet. thus, our findings could further help dermatologists in the diagnosis of ulc and differentiating it from linear pr, which letter | dermatol pract concept. 2021; 11(3): e2021053. 3 might preclude the need for invasive procedures such as skin biopsy for a benign and self-resolving condition. references: 1. lallas, a. kyrgidis, tg tzellos et al. accuracy of dermoscopic criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol. 2012;166(6):1198-205. doi: 10.1111/j.1365-2133.2012.10868.x. pmid: 22296226. 2. kumar p, desai c, das a. unilateral linear capillaritis. indian dermatol online j [epub ahead of print] [cited 2020 oct 29]. available from: https://www.idoj.in/preprintarticle.asp?id=295477. doi. 10.4103/idoj.idoj_649_19. figure 3. histopathological analysis showed mildly atrophic epidermis with basal layer displaying focal vacuolization and dense perivascular lymphocytic infiltrate in the dermis. dermatology: practical and conceptual research | dermatol pract concept 2021;11(1):e2021118 1 dermatology practical & conceptual general practice registrars’ management of and specialist referral patterns for atopic dermatitis anneliese willems1,2, amanda tapley3,4, alison fielding3,4, vivian tng5, elizabeth g. holliday3, mieke l. van driel6, jean i. ball7, andrew r. davey3,4, kristen fitzgerald8, 9, neil a. spike1, 2, parker j. magin3,4 1 eastern victoria gp training, general practice training organisation, melbourne, vic, australia 2 the university of melbourne, department of general practice, melbourne, vic, australia 3 the university of newcastle, school of public health and medicine, callaghan, nsw, australia 4 gp synergy, regional training organisation, nsw & act research and evaluation unit, newcastle, nsw, australia 5 department of dermatology, john hunter hospital, newcastle, nsw, australia 6 the university of queensland faculty of medicine, primary care clinical unit, brisbane, qld, australia 7 hunter medical research institute, clinical research design, it and statistical support unit (creditss), new lambton, nsw, australia 8 university of tasmania, school of medicine, hobart, tas, australia 9 general practice training tasmania (gptt), regional training organisation, hobart, tas, australia key words: atopic dermatitis, eczema, referral and consultation, general practice, dermatologist citation: willems a, tapley a, fielding a, tng v, holliday eg. van driel ml, ball ji, davey ar, fitzgerald k, spike na, magin pj. general practice registrars’ management of and specialist referral patterns for atopic dermatitis. dermatol pract concept. 2021;11(1):e2021118. doi: https://doi.org/10.5826/dpc.1101a118 accepted: july 26, 2020; published: january 29, 2021 copyright: ©2021 willems et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: the recent project was funded from 2010 to 2015 by the participating educational organisations: general practice training valley to coast, the victorian metropolitan alliance, general practice training tasmania, adelaide to outback gp training program, and tropical medical training, all of which were funded by the australian department of health. from 2016-2019, recent was funded by an australian department of health commissioned research grant and supported by gp synergy regional training organisation. gp synergy is funded by the australian department of health. this project has ethics approval through university of newcastle’s human research ethics committee: h-2009-0323. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: parker j. magin, mbbs, phd, school of medicine and public health, the university of newcastle, university drive, callaghan, nsw, 2308, australia. email: parker.magin@newcastle.edu.au background: atopic dermatitis (ad) is a common presentation in the general practice (gp) setting. implementation of appropriate referral pathways is instrumental for best patient care and is an essential skill for australian gp registrars .  objectives: we aimed to explore the prevalence and associations of gp registrar referrals to specialists for ad management. methods: a cross-sectional analysis utilizing data from the registrar clinical encounters in training (recent) project, an ongoing cohort study that documents in-consultation clinical and educational abstract 2 research | dermatol pract concept 2021;11(1):e2021118 introduction atopic dermatitis (ad) is associated with psychological, social, and quality-of-life effects in patients and their families [1,2]. ad has a 12-month prevalence of 16%-17% in childhood and is characterized by chronic inflammation and pruritus [ 3]. while ad is predominantly a childhood illness [4], an estimated 50% of those affected by ad in their early years go on to have symptoms into their teenage years and adulthood [5]. given its prevalence, ad represents a common presentation in the primary care setting. the majority of ad is mild and may be managed in primary care, rather than in specialty practice [6]. skin presentations represent 11% of all problems encountered by gp registrars. of these, 12% are “dermatitis,” including ad [7]. ad is generally a straightforward clinical diagnosis [8,9], and the treating clinician must first exclude other conditions [6]. patient education underpins treatment and all cases should be treated with emollients [8]. topical corticosteroids and, when appropriate, antimicrobial and antiseptic measures, comprise the next level of therapy [8]. this management can be appropriately delivered in primary care. in moderate-severe disease, referral may be necessary for access to additional therapies such as narrowband uvb phototherapy or oral immunosuppressive therapies [10]. additionally, a specialist’s opinion may occasionally be needed for clarification of diagnosis or for exploration of exacerbating factors, such as allergy [6]. with a breadth of management options available according to severity of ad disease, it is important for clinicians to have confidence in diagnosis and early stages of management [9]. similarly, clinicians should be competent in recognizing disease severity and have a good understanding of the indications for referral [6]. this may be problematic in primary care. some studies have suggested that gps may lack confidence in diagnosis [11,12] and management of skin disease [11,13,14]. gps and vocational trainees in specialist general practice (gp registrars) have limited formal training in managing skin disease [7,13,15]. there is relatively little teaching of dermatology during medical school [16,17]. dermatology placements are infrequent in junior doctor rotations and, as such, the bulk of dermatology learning takes place in-practice during postgraduate terms [16]. consequently, skin disease remains a learning-need for gp registrars, and gp registrars find skin consultations problematic compared to non-skin consultations [7]. there is also a lack of evidence regarding appropriate circumstances for a gp referral of skin diseases [18,19]. given the historical challenges of gp registrar management of skin disease, the frequency of ad in australia, and the challenges in providing appropriate referrals, we sought to address an evidence gap. in this study we sought to explore the nature, frequency, and associations of gp registrar specialist referrals for ad. materials and methods we performed a cross-sectional analysis of data within the registrar clinical encounters in training (recent) project. recent documents the in-consultation educational and clinical experiences of gp registrars. gp vocational training gp training in australia operates under an apprenticeship-like model wherein registrars are supervised by senior accredited gps within an accredited practice environment. training experience of australian gp registrars. registrar, patient, and consultation factors associated with referrals for ad were established using logistic regression. results: a total of 2,783 registrars (96% response rate) provided data from 381,180 consultations from 2010 to 2019. a total of 3,285 (0.55%) of 595,412 diagnoses managed were ad, of which 222 (6.8%) resulted in referral. of these referrals, 70% were to dermatologists, 17% to allergists/immunologists, and 10% to pediatricians. associations of referral included registrar female gender, patient age, longer consultation duration; an established (rather than new) ad diagnosis; supervisor advice being sought; and learning goals being generated.  conclusions:  both registrar and patient factors influence ad referral patterns. registrars referred established rather than newly diagnosed ad, suggesting a level of comfort in initial management. referral was associated with longer consultations, seeking supervisor advice, and generation of learning goals—suggesting these are more complex presentations and, possibly, registrar learning opportunities. a significant proportion of referrals were to non-dermatologist specialists. the implication of this for optimal patient care is a subject for further study.   research | dermatol pract concept 2021;11(1):e2021118 3 entails at least 3 6-month, full-time-equivalent, community -based general practice terms. recent registrars complete 3 cycles of recent data collection during training, once each term. details of 60 consecutive consultations are collected on paper-based case report forms. from these consultations, problems managed and referrals made are coded according to the international classification of primary care (second edition) classification system (icpc-2 plus) [20]. registrar and practice variables are also collected every 6 months. recent was conducted in up to 5 regional training providers (rtp), across 5 states, during 2010-2015, and in 3 regional training organisations (rto), across 3 states and 1 territory, from 2016, following a major restructuring of australian gp vocational training. this study data from 2010-2019 is included in the current study. for this study, our analyses were confined to consultations coded as “dermatitis, atopic,” “eczema,” and “eczema, infantile.” see supplementary table 1 for a complete list of inclusion and exclusion icpc-2 plus codes. outcome factor the outcome was “specialist referral made.” independent variables independent variables included in these models included registrar, practice, patient, consultation and educational factors. patient factors were: patient age group, patient gender, aboriginal or torres strait islander status, and non-english speaking background status. registrar factors were: registrar age and gender, full-time or part-time employment status, the term of gp training, whether the registrars had worked at their current practice previously, and whether they had qualified as a doctor in australia. practice factors were: the size of the practice, whether the practice was fully bulk-billing (that is, no fee charged to the patient), the rurality of the practice, the rtp or rto the registrar was enrolled with (hereafter “region”), and the socio-economic index for areas,-index of table 1. demographics of participating gp registrars and their practices registrar variables (n=2783) n (%) registrar gender male 1,055 (37.9) female 1,728 (62.1) qualified as doctor in australia yes 547 (19.8) no 2,223 (80.3) pathway registrar enrolled in general 1,930 (70.0) rural 826 (30.0) registrar round/practice variables (n=6414) registrar age (years) mean ± sd 32.6 (6.3) registrar works full-time or part-time full-time 4,770 (77.1) part-time 1,420 (22.9) registrar training term term 1 2,640 (41.2) term 2 2,091 (32.6) term 3 1,683 (26.2) practice rurality major city 3,983 (62.7) inner regional 1,633 (25.7) outer regional remote 732 (11.5) practice seifa-irsd mean ± sd 5.5 (2.8) practice routinely bulk bills yes 1,784 (28.1) no 4,566 (71.9) registrar worked at practice previously yes 1,343 (21.2) no 4,988 (78.8) practice size small (1-5 gps) 2,371 (38.4) large (6-10+ gps) 3,811 (61.6) gp = general practice; sd = standard deviation; seifa-irsd = socio-economic index for area – index of relative socioeconomic disadvantage. 4 research | dermatol pract concept 2021;11(1):e2021118 relative socioeconomic disadvantage (seifa-irsd) in which the practice was located. consultation factors were: the duration of consultation, number of problems managed within the consultation, whether ad was a new problem, whether the registrar sought assistance for diagnosis or management of the problems managed, whether pathology was ordered, whether follow-up was ordered, whether learning goals were generated, and which medications, if any, were prescribed. statistical analyses statistical analysis was at the level of problem/diagnosis. the proportion of problems/diagnoses that were atopic dermatitis and, of those, the proportion that were referred were calculated with 95% confidence intervals (ci) and were adjusted for repeated measures within registrars. descriptive statistics included frequencies for categorical variables and mean with standard deviation for continuous variables. the frequencies of categorical variables were compared between outcome categories using chi-square tests for all variables, except when fisher’s exact test was used (due to an expected count less than 5 in 25% or more cells). for continuous variables, means were compared using a t test. logistic regression has been used within the generalized estimating equations (gee) framework to account for repeated measures within registrars. an exchangeable working correlation structure was assumed. univariate analyses were conducted on each covariate with the outcome. covariates with a univariate p value < 0.20 were considered for inclusion in the multiple regression model. once the model with all significant covariates was fitted, model reduction was assessed. covariates that were no longer significant (at p < 0.2) in the multivariable model were tested for removal from the model. if the covariate’s removal did not substantively change the resulting model, the covariate was removed from the final model. a substantive change to the model was defined as any covariate in the model having a change in the effect size (odds ratio) of greater than 10%. diagnostic tests were conducted to assess goodness of fit, using the hosmer-lemeshow test for logistic models. predictors were considered statistically significant if the p value was < 0.05. statistical analyses used stata 14.1 (statacorp, college station, tx, usa) and sas v9.4 (sas institute inc., cary, nc, usa). this project has ethics approval through an appropriate human research ethics committee. results in total, 2,783 registrars (96.1% response rate) provided data from 381,180 consultations from 2010-2019, including 595,412 problems managed. table 1 shows the demographics of participating registrars. of all problems, 3,285 (0.55% [95% ci: 0.53, 0.57]) were ad. of all ad problems, 222 (6.8% [95% ci: 6.0, 7.7]) were referred. of these referrals, 70% were to dermatologists (table 2), 17% to allergists/immunologists, 10% to pediatricians, and 3% to a clinic without specifying the specialist. the characteristics associated with specialist referral are presented in table 3. as well as the associations with referral, overall findings of note are that for 9.7% of ad problems, supervisor advice or assistance was sought and for 18% of ad problems learning goals were generated. the results of univariate and multivariable logistic regression are presented in table 4. statistically significant multivariable associations of an ad problem being referred to a specialist included registrar female gender (or 1.49 [95% ci: 1.05, 2.12]) and being australian-trained (or 2.02 [1.18, 3.48]); patient age (patients aged 0-1 year less likely to be referred [or 0.58 [0.34, 0.98] compared to patients aged 2-12 years); ad being an existing problem (or 0.28 [0.18, 0.43] for a new problem); pathology being ordered (or 2.48 [1.08, 5.69]); and learning goals being generated (or 2.57 [1.69 3.90]). also significant in multivariable analyses, less non-ad problems, on average, were addressed in consultations resulting in referral (or 0.57 [95% ci: 0.43, 0.75]), and these consultations were longer (or 1.05 [95% ci: 1.02, 1.07] for each additional minute of consultation duration). in univariate analysis (table 3), referral was associated with an estimated average increase of 3 minutes in ad consultation duration. in ad consultations resulting in referral, supervisors were more likely to provide the registrar with advice or assistance (20% versus 9%), which was significant on multivariable analysis (or 1.73 [95% ci: 1.06, 1.83]). discussion the associations of gp and gp registrar referrals for ad have not been well investigated. to our knowledge this is the first analysis exploring australian gp registrars’ (or gp trainees in other countries) referrals for ad. this study table 2. referrals for atopic dermatitis (n=222) specialist frequency percentage dermatologist referral 153 70 allergist/immunologist referral 38 17 pediatrician referral 21 9.6 referral to clinic/center 4 3.2 other 3 1.4 total 219 100 note: three referrals were excluded, as they did not specify the referral type and hence have been removed from analysis. research | dermatol pract concept 2021;11(1):e2021118 5 table 3. characteristics by referral status in atopic dermatitis consultations (n = 381,180)   referral for atopic dermatitis factor group variable class no yes p value patient factors                           patient age group 0-1 years 655 (22%) 32 (15%) 0.12   2-12 years 834 (28%) 67 (31%)     13-24 years 542 (18%) 49 (23%)     25-44 years 541 (18%) 38 (18%)     45+ years 441 (15%) 30 (14%)   patient gender male 1,318 (44%) 93 (43%) 0.89   female 1,677 (56%) 121 (57%)   nesb no 2,589 (90%) 187 (88%) 0.40   yes 290 (10%) 25 (12%)   patient/practice status existing patient 1,009 (34%) 88 (40%) 0.12   new to registrar 1,722 (57%) 111 (51%)     new to practice 272 (9%) 20 (9%)   aboriginal or torres strait islander no 2,826 (99%) 210 (99.5%) 0.52   yes 38 (1%) 1 (0.5%)   registrar factors                       registrar gender male 1,131 (37%) 69 (31%) 0.078   female 1,932 (63%) 153 (69%)   registrar full-time or part-time part-time 733 (25%) 57 (27%) 0.48   full-time 2,249 (75%) 156 (73%)   term term 1 1,194 (39%) 94 (42%) 0.39   term 2 1,122 (37%) 71 (32%)     term 3 747 (24%) 57 (26%)   worked at practice previously no 2,383 (79%) 180 (82%) 0.33   yes 631 (21%) 40 (18%)   qualified as doctor in australia no 503 (16%) 29 (13%) 0.18   yes 2,547 (84%) 192 (87%)   registrar age mean (sd) 32 (6) 32 (6) 0.74 practice factors                           practice size small 1,069 (36%) 76 (36%) 0.90   large 1,906 (64%) 138 (64%)   practice routinely bulk bills no 2,132 (71%) 151 (69%) 0.49   yes 879 (29%) 69 (31%)   rurality major city 2,075 (69%) 164 (76%) 0.090   inner regional 685 (23%) 41 (19%)     outer regional remote 262 (9%) 12 (6%)   region region 1 518 (17%) 28 (13%) 0.37   region 2 139 (5%) 14 (6%)     region 3 374 (12%) 22 (10%)     region 4 1,300 (42%) 97 (44%)     region 5 28 (0.9%) 3 (1%)     region 6 506 (17%) 44 (20%)     region 7 198 (6%) 14 (6%)     seifa-irsd mean (sd) 6 (3) 6 (3) 0.098 (table 3 continues) 6 research | dermatol pract concept 2021;11(1):e2021118   referral for atopic dermatitis factor group variable class no yes p value consultation factors                         new problem seen no 1,791 (65%) 166 (85%) <0.001   yes 959 (35%) 30 (15%)   sought help any source none 2,367 (77%) 138 (62%) <0.001   supervisor 274 (9%) 45 (20%)     other sources 422 (14%) 39 (18%)   pathology ordered no 3,004 (98%) 211 (95%) 0.004   yes 59 (2%) 11 (5%)   follow-up ordered no 1,963 (64%) 131 (59%) 0.13   yes 1,100 (36%) 91 (41%)   learning goals generated no 2,339 (82%) 128 (61%) <0.001   yes 523 (18%) 81 (39%)   consultation duration mean (sd) 17 (8) 20 (9) <0.001 number of problems mean (sd) 2 (1) 2 (1) <0.001 nesb = non-english speaking background; seifa-irsd = socio-economic index for areas – index of relative socioeconomic disadvantage; sd = standard deviation. table 4. characteristics associated with a referral being made for atopic dermatitis    univariate adjusted factor group variable class or [95% ci] p value or [95% ci] p value patient factors       patient age group comparator 2-12 years   0-1 years 0.61 (0.39, 0.95) 0.027 0.58 (0.34, 0.98) 0.0417 13-24 years 1.13 (0.76, 1.67) 0.55 1.02 (0.63, 1.63) 0.9444 25-44 years 0.87 (0.58, 1.32) 0.52 0.91 (0.55, 1.50) 0.6988 45+ years 0.85 (0.54, 1.32) 0.47 1.23 (0.73, 2.05) 0.4358 registrar factors   registrar gender female 1.30 (0.97, 1.74) 0.078 1.49 (1.05, 2.12) 0.0269 qualified as doctor in australia yes 1.31 (0.88, 1.93) 0.18 2.02 (1.18, 3.48) 0.0110 practice factors seifa-irsd   1.04 (0.99, 1.10) 0.098 1.03 (0.98, 1.10) 0.2550 consultation factors               new problem seen yes 0.34 (0.23, 0.50) <.001 0.28 (0.18, 0.43) <.001 sought help any source other sources 1.57 (1.09, 2.27) 0.016 1.19 (0.73, 1.97) 0.48  comparator: none supervisor 2.82 (1.97, 4.03) <.001 1.73 (1.06, 2.83) 0.030 pathology ordered yes 2.65 (1.36, 5.17) 0.004 2.48 (1.08, 5.69) 0.031 follow-up ordered yes 1.24 (0.94, 1.64) 0.13 0.75 (0.52, 1.09) 0.13 learning goals generated yes 2.83 (2.10, 3.82) <.001 2.57 (1.69, 3.90) <.001 consultation duration   1.03 (1.02, 1.05) <.001 1.05 (1.02, 1.07) <.001 number of problems   0.69 (0.58, 0.83) <.001 0.57 (0.43, 0.75) <.001 seifa-irsd = socio-economic index for areas – index of relative socioeconomic disadvantage table 3. characteristics by referral status in atopic dermatitis consultations (n = 381,180) (continued) research | dermatol pract concept 2021;11(1):e2021118 7 provides several significant findings pertaining to registrar engagement and confidence with ad, frequency of referral, and specialist choice. summary of main findings registrars referred 6.8% of ad cases. the dermatologist was the preferred specialist to manage ad, with 70% of cases referred to this specialty, but a relatively high percentage of cases (17%) were referred to allergists/immunologists. prominent associations of referrals included longer consultations, a preexisting ad diagnosis, and consultations in which fewer issues were managed. there was increased supervisor involvement for consultations in which ad was referred and considerably increased learning-goal generation for these consultations. interpretation of findings and comparison with previous literature the context for our finding of referral of 6.8% of ad problems is that gps have previously been shown to refer 10.3% of all problems managed [21]. in an earlier analysis of this australian registrar population, we found a referral rate for skin problems of 8.0%. this earlier analysis also found that registrars were 38% (odds ratio [or] 0.62) less likely to refer skin problems compared with non-skin problems. our results, though, suggest ad remains a significant learning-need for gp registrars. compared to all problems seen (in previous analyses from recent), when presented with a diagnosis of ad, a gp registrar is more likely to seek supervisor advice or assistance (9.7% compared to 6.9% for all problems [22]), and generate learning-goals (18.4% compared to 16.6% for all problems [23]). this is consistent with previous evidence that diagnosing skin diseases (including ad) is an area that receives less attention throughout undergraduate, postgraduate, and specialist training for gp trainees [7,16,17,24]. qualified gps are also reported to have some difficulty with ad management [13]. the relative frequency of referrals of an existing rather than a new ad problem/diagnosis suggests that, while registrars may need considerable training to manage ad, they may nevertheless be comfortable with ad diagnosis and initial management. despite presenting some challenges for the early-career gp, ad is most often a straightforward diagnosis, is mostly of mild or moderate severity, and can be managed appropriately by the gp using first-line modalities. it is then likely that the advice and assistance of their supervisor may support registrars’ management of ad in the context of them having considerable learning-needs in the area. it was also apparent that referral for ad may be associated with a more complex or problematic ad presentation: longer consultation duration, greater learning-goal generation, more supervisor assistance sought, more pathology ordered, and fewer non-ad problems addressed in the index consultation. another notable finding of this study was that while the dermatologist is the specialist of choice for ad, a relatively large proportion of patients are referred to allergists/immunologists. the roles of each of these specialists as a part of the multidisciplinary team have previously been recognized in the care of moderate-severe ad [25]. significantly, the choice of specialist has been shown to influence management practices [26, 27]. allergists and dermatologists diverge in their recommendations for systemic treatments, adjunctive therapies, and preventative measures [25]. given the natural emphasis of their training, allergists/immunologists are more likely to focus on preventative strategies and potential allergic triggers [27]. our results suggest registrars are quite frequently prioritizing allergy pathways in ad management. the 17% referred to allergists/immunologists may reflect the rise in primary care recognition of the association of eczema with food allergy. a review of studies by werfel et al. in 2007 found a prevalence of food allergy in 33%-63% of cases [28]. the exact relationship between food allergy and ad remains controversial. food allergy as an aggravating factor of ad in infants and young children is well accepted [29], but there is a lack of consensus regarding food allergy as an exacerbating factor versus a cause [25, 30]. it has previously been suggested that primary care providers overemphasize the role of food allergy in ad [30]. our results also suggest a registrar emphasis on a possible allergic component to ad. overemphasis on allergies versus the overarching etiology of ad can lead to miscommunication, which results in a parent erroneously believing that a food allergy is causing their child’s ad [30]. this can then lead to restrictive diets, risking possible nutritional deficiencies, and diversion from the basics of optimizing ad management such as education, skin care, and optimal use of topical corticosteroids [30]. referral rates for ad in this study are reflective of the existing literature, as is our finding of ad as a persistent learning-need for gp registrars. as yet, there is limited literature to compare our findings of registrar ad referral pathways, and the implications of specialist choice on clinical outcomes. supplementary table 1. included diagnostic codes excluded diagnostic codes dermatitis, atopic eczema eczema, infantile rash; atopic dermatitis; flexural dermatitis; allergic dermatitis 8 research | dermatol pract concept 2021;11(1):e2021118 strengths and limitations this study has a number of strengths, in particular, its high response rate (96.1%) and broad data set (595,412 data points) and geographic distribution throughout areas classified as urban, rural, and remote across multiple australian states. as such, findings are generalizable across australia and, potentially, internationally. a limitation of the analysis was the limited clinical context provided within the consultation data. we did not have contextual information on severity of ad, of ad past history, of medicine regimens, of concurrent conditions and, thus, were unable to ascertain if individual referrals were appropriate for care escalation. implications for practice and future research our findings suggest that registrars are engaging with diagnosis and management of ad, but that ad (as with skin disease generally), remains a priority learning-need for registrars. continued reevaluation of postgraduate dermatology curricula would best focus on management components and understanding of appropriate indications for referral. clarification, such as through referral pathways, for specific specialist involvement would help to guide appropriate specialist referral according to patient presentation. furthering awareness of and access to multidisciplinary clinics, wherein a variety of specialists are available, may also help to optimize gp registrars’ contribution to ad management. conclusions our findings show that gp registrars are engaging with ad, yet it is apparent this is still a learning-need for many registrars. registrar education could include appropriate referral pathways and further clarification regarding the role of allergy in ad. references 1. drucker am, wang ar, li wq, sevetson e, block jk, qureshi aa. the burden of atopic dermatitis: summary of a report for the national eczema association. j invest dermatol. 2017;137(1):2630. doi: 10.1016/j.jid.2016.07.012. pmid: 27616422. 2. beattie pe, lewis-jones ms. a comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. br j dermatol. 2006;155(1):145-151. doi: 10.1111/j.1365-2133.2006.07185.x. pmid: 16792766. 3. asher mi, montefort s, bjorksten b, et al. worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: isaac phases one and three repeat multicountry cross-sectional surveys. lancet. 2006;368(9537):733743. doi: 10.1016/s0140-6736(06)69283-0. 4. kay j, gawkrodger dj, mortimer mj, jaron ag. the prevalence of childhood atopic eczema in a general population. j am acad dermatol. 1994;30(1):35-39. doi: 10.1016/s01909622(94)70004-4 5. mortz cg, andersen ke, dellgren c, barington t, bindslev jensen c. atopic dermatitis from adolescence to adulthood in the toacs cohort: prevalence, persistence and comorbidities. allergy. 2015;70(7):836-845. doi: 10.1111/all.12619. pmid: 25832131. 6. eichenfield lf, boguniewicz m, simpson el, russell jj, block jk, feldman sr, et al. translating atopic dermatitis management guidelines into practice for primary care providers. pediatrics. 2015;136(3):554-565. doi: 10.1542/peds.2014-3678. pmid: 26240216. 7. whiting g, magin p, morgan s, et al. general practice trainees’ clinical experience of dermatology indicates a need for improved education: a cross-sectional analysis from the registrar clinical encounters in training study. australas j dermatol. 2017;58(4):e199-e206. doi: 10.1111/ajd.12493. pmid: 27301794. 8. harris vr, cooper aj. atopic dermatitis: the new frontier. med j aust. 2017;207(8):351-356. doi: 10.5694/mja17.00463. pmid: 29020907. 9. we i d i n g e r s , n o v a k n . a t o p i c d e r m a t i t i s . l a n c e t . 2016;387(10023):1109-1122. doi: 10.1016/s0140-6736(15) 00149-x. 10. atopic dermatitis. etg complete; [updated 2019 jun]. accessed january 30, 2020. https://tgldcdp.tg.org.au/viewtopic?topicfile=dermatitis&guidelinename=dermatology#toc_d1e129. 11. rubsam ml, esch m, baum e, bosner s. diagnosing skin disease in primary care: a qualitative study of gps’ approaches. fam pract. 2015;32(5):591-595. doi: 10.1093/fampra/cmv056. pmid: 26160890. 12. moreno g, tran h, chia al, lim a, shumack s. prospective study to assess general practitioners’ dermatological diagnostic skills in a referral setting. australas j dermatol. 2007;48(2):7782. doi: 10.1111/j.1440-0960.2007.00340.x. pmid: 17535192. 13. le roux e, powell k, banks jp, ridd mj. gps’ experiences of diagnosing and managing childhood eczema: a qualitative study in primary care. br j gen pract. 2018;68(667):e73-e80. doi: 10.3399/bjgp18x694529. pmid: 29335327. 14. smith sd, harris v, lee a, blaszczynski a, fischer g. general practitioners knowledge about use of topical corticosteroids in paediatric atopic dermatitis in australia. aust fam physician. 2017;46(5):335-340. 15. whitaker-worth dl, susser ws, grant-kels jm. clinical dermatologic education and the diagnostic acumen of medical students and primary care residents. int j dermatol. 1998;37(11):855-859. doi: 10.1046/j.1365-4362.1998.00537.x. pmid: 9865874. 16. singh dg, boudville n, corderoy r, ralston s, tait cp. impact on the dermatology educational experience of medical students with the introduction of online teaching support modules to help address the reduction in clinical teaching. australas j dermatol. 2011;52(4):264-269. doi: 10.1111/j.1440-0960.2011.00804.x. pmid: 22070700. 17. gupta a, chong ah, scarff ce, huilgol sc. dermatology teaching in australian medical schools. australas j dermatol. 2017;58(3):e73-e78. doi: 10.1111/ajd.12486. pmid: 27145418. 18. sladden mj, graham-brown ra. how many gp referrals to dermatology outpatients are really necessary? j r soc med. 1989;82(6):347-348. doi: 10.1177/014107688908200611. pmid: 2810314 research | dermatol pract concept 2021;11(1):e2021118 9 19. van rijsingen mc, hanssen sc, groenewoud jm, van der wilt gj, gerritsen mj. referrals by general practitioners for suspicious skin lesions: the urgency of training. acta derm venereol. 2014;94(2):138-41. doi: 10.2340/00015555-1752. pmid: 24352366. 20. britt h. a new coding tool for computerised clinical systems in primary care--icpc plus. aust fam physician. 1997;26 suppl 2:s79-82. 21. britt h, miller gc, henderson j, et al. general practice activity in australia 2015-16. sydney university press; 2016. 22. magin p, morgan s, wearne s, et al. gp trainees’ in-consultation information-seeking: associations with human, paper and electronic sources. fam pract. 2015;32(5):525-532. doi: 10.1093/ fampra/cmv047. pmid: 26089297. 23. magin p, tapley a, davey a, et al. general practitioner trainees’ in-consultation generation of clinical questions for later answering: prevalence and associations. fam pract. 2017;34(5):599-605. doi: 10.1093/fampra/cmx021. pmid: 28369454. 24. tng etv, tapley a, davey a, et al. general practice registrars’ clinical exposure to dermatological procedures during general practice training: a cross-sectional analysis. educ prim care. 2018;29(6):357-366. doi: 10.1080/14739879.2018.1520612. pmid: 30311852. 25. eichenfield lf, ahluwalia j, waldman a, borok j, udkoff j, boguniewicz m. current guidelines for the evaluation and management of atopic dermatitis: a comparison of the joint task force practice parameter and american academy of dermatology guidelines. j allergy clin immunol. 2017;139(4s):s49-s57. doi: 10.1016/j.jaci.2017.01.009. pmid: 28390477 26. saavedra jm, boguniewicz m, chamlin s, lake a, nedorost s, czerkies la, et al. patterns of clinical management of atopic dermatitis in infants and toddlers: a survey of three physician specialties in the united states. j pediatr. 2013;163(6):1747-1753. doi: 10.1016/j.jpeds.2013.06.073. pmid: 23953725. 27. mohan gc, lio pa. comparison of dermatology and allergy guidelines for atopic dermatitis management. jama dermatol. 2015;151(9):1009-13.10.1001/jamadermatol.2015.0250. pmid: 25853940. 28. werfel t, ballmer-weber b, eigenmann pa, et al. eczematous reactions to food in atopic eczema: position paper of the eaaci and ga2len. allergy. 2007;62(7):723-728. doi: 10.1111/j.13989995.2007.01429.x. pmid: 17573718. 29. wuthrich b. food-induced cutaneous adverse reactions. allergy. 1998;53(46 suppl):131-135. doi: 10.1111/j.1398-9995.1998. tb04983.x. pmid: 9826020. 30. thompson mm, tofte sj, simpson el, hanifin jm. patterns of care and referral in children with atopic dermatitis and concern for food allergy. dermatol ther. 2006;19(2):91-96. doi: 10.1111/j.1529-8019.2006.00062.x. pmid: 16669991. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021088 1 dermoscopy of bacillary angiomatosis: utility in diagnosis and therapeutic control maria leonor enei1, francisco macedo paschoal2, rodrigo valdes3 1 brazilian society of dermatology. private practice, iquique, chile. 2 dermatology department, faculdade de medicina do abc, santo andré, brazil 3 institute of histopathology, histonor, antofagasta, chile key words: dermoscopy, dermatoscopy, bacillary angiomatosis, hiv, kaposi sarcoma. citation: enei ml, paschoal fm, valdes r. dermoscopy of bacillary angiomatosis: utility in diagnosis and therapeutic control. dermatol pract concept. 2021;11(4):e2021088. doi: https://doi.org/10.5826/dpc.1104a88 accepted: february 21, 2021; published: october, 2021 copyright: ©2021 enei et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: maria leonor enei, md, brazilian society of dermatology. private practice, santiago polanco street, 2030, iquique, chile. email: leonorenei@vtr.net introduction bacillary angiomatosis (ba) is an infectious vascular proliferation caused by bartonella henselae and bartonella quintana gram-negative bacteria. its association with hiv was described by stoler et al in 1983. the skin lesions begin as small superficial erythematous papules that grow to form friable plaques or nodules surrounded by a flaking collarette. it can compromise internal organs such as the liver or spleen and is considered potentially fatal in immunosuppressed patients, although early treatment leads to complete resolution of the lesions. in patients with hiv, the main differential diagnosis is kaposi sarcoma (ks), the most prevalent cancer in untreated individuals. dermoscopy, a non-invasive diagnostic technique that is useful for the diagnosis of both pigmented and cutaneous vascular lesions, has been used to describe ks lesions not for ba lesions yet. here we present the dermoscopic description of a case of ba in a patient with no previous hiv diagnosis. clinical presentation a 29-year-old male patient consulted the dermatology clinic in january 2020. the patient presented a lesion at the level of the nasal dorsum and covering the beard area. the lesion had a 4-week evolution. clinical examination revealed papules and grouped and well delimited red-purple nodules (figure 1a). there were no palpable adenopathies or alterations of the oral mucosa. general condition and weight were preserved. dermoscopic examination (polarized light, dermlite 4) showed oval shapes with bright red areas, and globular structures, with grayish background. arborizing telangiectasia was seen in the periphery (figure1b). upon direct questioning, the patient reported having close contact with house cats. we therefore performed a histopathological study to discriminate between the diagnostic hypothesis of ba versus ks. elisa test was positive for hiv, with a viral load of 382 iu/ml, cd-4 273/mm3 (4241509), and lymphocyte count 6,000/ul (4,000 to 10,000). 2 letter | dermatol pract concept. 2021;11(4):e2021088 figure 1. (a) exam revealed papules and red-purple nodules, grouped and well delimited on the left side of the nose. (b) dermoscopy showing oval bright red areas and globular structures, with grayish background. arborizing telangiectasias are present in the periphery. (c) exam after 3 months of treatment evidenced normal aspect of the skin. (d) dermoscopy after treatment showed complete disappearance of vascular structures. only discrete pseudo-red pigment and some arborizing telangiectasias remains. figure 2. histopathology. (a) slight acanthosis and hyperkeratosis in the epidermis. (b) the reticular dermis presents vascular, multifocal, and nodular proliferation composed of small capillary vessels, some with prominent endothelium, extravasation of erythrocytes, infiltration of lymphocytes, and neutrophil polymorphonuclear cells. (c) immunohistochemical staining (cat scratch disease, ag b henselae) revealed isolated bacilliform forms. letter | dermatol pract concept. 2021;11(4):e2021088 3 the patient started anti-retroviral treatment (genvoya®) 30 days after. based on the histopathological and immunohistochemical report (figure 2), consistent with ba, doxycycline treatment, 200 mg daily, was started. clinical improvement was evident after 3 months (figure 1c) as confirmed by control dermoscopy (figure 1d). conclusions here we present the dermoscopic findings of a case of ba in which the vascular component predominated. upon dermoscopic-histopathological correlation of the clinical presentations, the globular structures, bright red areas, and grayish areas in the background, correspond to the intense proliferation of capillary blood vessels along with the extravasation of red blood cells in the reticular dermis, and a slight acanthosis and hyperkeratosis in the epidermis, respectively. on the other hand, dermoscopic findings described in ks, namely, the presence of a homogeneous pattern of colours ranging from reddish (46.6%) to blue, pink, whitish (13.3%), or purple [1], is highly suggestive of the diagnosis [2]. the so-called polychromatic structure pattern or “rainbow pattern” has also been highlighted; it is present in all the papular nodular forms of ks and would be expected in our patient [2]. considering the site of the lesion and telangiectasias in our case, another differential diagnosis that should be considered is that of granuloma faciale. according to larger studies describing granuloma faciale, dermoscopic features should include a marked follicular, and perifollicular white halo, in addition to linear branching vessels [2]. the absence of the above mentioned dermoscopic findings, together with the presence of a marked vascular pattern, directed us to diagnose ba, a disease that is often underdiagnosed. the complete resolution documented with dermoscopy once again shows the usefulness of this technique for monitoring response to treatments. references 1. piccolo v, russo t, moscarella e, brancaccio g, alfano r, argenziano g. dermatoscopy of vascular lesions. dermatol clin. 2018;36(4):389-395. doi: 10.1016/j.det.2018.05.006. pmid: 30201148. 2. lallas a, sidiropoulos t, lefaki i, tzellos t, sotiriou e, apalla z. photoletter to the editor: dermoscopy of granuloma faciale. j dermatol case rep. 2012;6:59-60. doi: 10.3315/jdcr.2012.1101. pmid: 22826723. pmcid: pmc3399680. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(4):e2022137 1 benefits and pitfalls of using in vivo reflectance confocal microscopy in lentigo maligna diagnostics: case reports ieva povilaite1, giuseppe argenziano2, graziella babino2, claudio conforti4, elvira moscarella2, francesca pagliuca3, andrea ronchi3, iris zalaudek4, marina agozzino4 1 department of skin and venereal diseases, lithuanian university of health sciences, kaunas, lithuania 2 dermatology unit, university of campania, naples, italy 3 department of advanced biomedical sciences, pathology section, university of naples federico ii, naples, italy 4 dermatology and venereology department, maggiore hospital, university of trieste, trieste, italy key words: lentigo maligna, in vivo reflectance confocal microscopy, pigmented facial lesion, diagnostic accuracy citation: povilaite i, argenziano g, babino g, et al. benefits and pitfalls of using in vivo reflectance confocal microscopy in lentigo maligna diagnostics: case reports. dermatol pract concept. 2022;12(4):e2022137. doi: https://doi.org/10.5826/dpc.1204a137 accepted: january 13, 2022; published: october 2022 copyright: ©2022 povilaite et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ieva povilaite, md, department of skin and venereal diseases, eiveniu st.2, kaunas, lithuania; lt-50161. email: ievapovilaite@gmail.com introduction the differential diagnosis between lentigo maligna (lm) and pigmented facial lesions (pfl) might be challenging clinically and dermoscopically, especially in its early phases, because early melanoma may exhibit only subtle malignancy clues and may have overlapping features with pfl [1,2]. therefore, new diagnostic tools such as reflectance confocal microscopy (rcm) to improve early detection of lm in its initial growth phases are crucial. herein reported two cases of lm and two different approaches of using rcm. case presentation a 47-year-old man presented at our department for laser treatment of some facial brownish macules. during routine examination using a dermatoscope a macule on the tip of the nose was noted (figure 1a). dermoscopically a structureless brownish color pigmentation and irregular grayish pigmentation around some follicles were present (figure 1b). due to the doubtful appearance in dermoscopy rcm examination was performed revealing the presence of several atypical melanocytes located mainly around hair follicles (figure 1c). based on confocal features, a total surgical excision was performed and a final diagnosis of lm was confirmed (figure  1d). the patient refused the re-excision, and adjuvant therapy with imiquimod 5% cream once daily for 6 weeks was started. after 2 years of follow up, no melanoma recurrence signs were noted. a 61-year-old woman presented at our clinic for evaluation of a pigmented macule on the left cheek (figure 2a). the patient had no previous history of melanoma. both dpc_1843.indd 1dpc_1843.indd 1 14/10/22 5:29 pm14/10/22 5:29 pm 2 research letter | dermatol pract concept. 2022;12(4):e2022137 clinically and dermoscopically (figure 2b) the lesion looked suspicious. under rcm examination atypical dendritic cells were visible at the level of the epidermis, they were not located around follicles nor infiltrating them. melanocytic nests forming cords were visible at the level of the dermal-epidermal junction, with no obvious melanoma features (figure 2c). however, due to the suspicious dermoscopic aspect, the lesion was excised and a final diagnosis of lm was confirmed by histology (figure 2d). the patient is recurrence free after 2 years follow up. conclusions in the first case presented, the lesion did not show any specific features for melanoma. on dermoscopy the only subtle suspicious clue was the presence of greyish color around some follicles. this clue shows high sensitivity to malignancy (85, 1%), but quite low specificity (39, 7%) [1]. rcm helped us reveal characteristics suggestive of the melanocytic nature of the lesion. in the second case the lesion both clinically and dermoscopically looked suspicious, however rcm findings were subtle. indeed, on rcm, the lesion had regular epidermal architecture, which is noteworthy and in the early radial growth phase of melanoma, follicles were well defined without folliculotropism and widespread dendrites. in this case the confidence level of the dermatologist in making diagnosis of lm was higher with the dermatoscope. therefore, this second case supported that clinical and dermoscopic criteria are extremely important for lm diagnosis. in conclusion, lm diagnosis still remains challenging. a combined clinical/dermoscopic/confocal approach should be used for the management of pfl in order to provide a more conclusive pre-histological diagnosis leading clinicians to a correct management. figure 1. (a) clinical appearance of a small brownish macule measuring 5 mm in diameter on the distal part of the nose (red arrow). (b) dermoscopy showing light grey color around few hair follicles (red arrow). (c) rcm mosaic at level of the epidermis, showing infiltration of atypical melanocytes around adnexal structures (red square); pagetoid/dendritic melanocytes located mainly around hair follicles (red arrows). (d) histopathology: a lentiginous intraepidermal melanocytic proliferation in the context a skin with severe actinic damage. a junctional nest is shown on the left (red arrow) (h&e, ×200). dpc_1843.indd 2dpc_1843.indd 2 14/10/22 5:29 pm14/10/22 5:29 pm research letter | dermatol pract concept. 2022;12(4):e2022137 3 figure 2. (a) pigmented macule located on the left cheek (5 × 7 mm) with irregular borders and variegated color (red arrow). (b)  dermoscopy showing an asymmetric pigmented macule with atypical infiltration of interspaces and adnexal structures (red stars). (c) rcm mosaic (1.5 × 2.5 mm) at the level of the dej showing junctional nesting (red arrows) without colonization of atypical cells around hair follicles. (d) histopathology: the sublesional dermis shows marked solar elastosis and increased melanophages (black arrow: melanocytic nest; red arrows: melanophages; black stars: solar elastosis) (h&e, ×200). dpc_1843.indd 3dpc_1843.indd 3 14/10/22 5:29 pm14/10/22 5:29 pm dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022055 1 dermoscopy of viral folliculitis of the beard: report of two cases biswanath behera1, rashmi kumari2, debasis gochhait3, pavithra ayyanar4 1 department of dermatology, and venereology, aiims, bhubaneswar, india 2 department of dermatology, venereology and leprology, jipmer, puducherry, india 3 department of pathology, jipmer, puducherry, india 4 department of pathology, aiims, bhubaneswar, india key words: dermoscopy, folliculitis, molluscum contagiosum, papilloma citation: behera b, kumari r, gochhait d, ayyanar p. dermoscopy of viral folliculitis of the beard: report of two cases. dermatol pract concept. 2022;12(2):e2022055. doi: https://doi.org/10.5826/dpc.1202a55 accepted: september 1, 2021; published: april 2022 copyright: ©2022 behera et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: rashmi kumari, m.d., associate professor, dept. of dermatology, venereology and leprology, jipmer, puducherry, india pin-605006. e-mail: rashmi.sreerag@gmail.com introduction differentiating human papillomavirus (hpv) folliculitis from molluscum contagiosum (mc) folliculitis over the beard area can be clinically challenging. both can present as asymptomatic follicle-based papules, and the verrucous morphology of hpv infection and punctum of mc may not be appreciable in all cases. case presentation the first case is a 26-year-old male who presented with a history of multiple asymptomatic lesions on the beard for 4 months.. cutaneous examination showed multiple follicle-based skin-colored to pearly-white papules (figure 1a). dermoscopic examination under nonpolarized mode showed perifollicular pearly white clods (figure 1b). histology of a papule showed lobular epidermal acanthosis with prominent intracytoplasmic henderson-patterson bodies, consistent with a diagnosis of mc folliculitis (figure 1c). the second case is a 33-year-old male who had multiple asymptomatic skin lesions over the beard for the last 6 months. he denied any history of recent cosmetic procedures. cutaneous examination revealed multiple follicle-based skin colored flat-topped (2 mm x 3 mm) papules (figure 2a). dermoscopy showed a perifollicular mosaic pattern comprising a variable-shaped white knob-like area with or without central dotted and hairpin vessels (figure 2b). histology of a papule showed basket weave hyperkeratosis, hypergranulosis, moderate acanthosis, and koilocytes in upper stratum spinosum and granulosum, consistent with the diagnosis of verruca plana/hpv folliculitis (figure 2c). in both the patients, all the investigations, including hiv 1 and 2 serology, to rule out immunosuppression were negative. 2 research letter | dermatol pract concept. 2022;12(2):e2022055 conclusions mc folliculitis is rare and usually occurs in patients with either acquired or iatrogenic immunosuppression. the presence of flesh-colored to erythematous papules with or without central umbilication is the common presentation. hpv can spread from infected materials during cosmetic procedures, resulting in cosmetic warts. it can also spread along the line of the trauma due to pseudo-koebnerization of preexisting warts [2]. the case in the discussion was unique. each of the flat-topped papules over the beard area was follicle-based compared to the clustered or linear arrangement described for cosmetic warts or pseudo-koebnerization, respectively. under dermoscope, mc characteristically demonstrates a variable-shaped white clod and crown vessels with or without a central punctum. other features described are rosette, dotted and radial vessels [1,2]. verruca vulgaris demonstrates grouped papillae with dotted and hairpin vessels surrounded by a whitish halo. in contrast, the verruca plana can have dotted vessels on a yellowish background [1]. we observed a mosaic pattern comprising a white knob-like area with or without a central hairpin or dotted vessel in the hpv folliculitis. the dermoscopic features described for other infectious folliculitis are the following: dotted vessels in malassezia folliculitis; broken hairs, corkscrew hairs, black dots, zigzag hairs, and morse code hairs in dermatophytic folliculitis; central round pustule with peripheral sparse dotted vessels in staphylococcal folliculitis; and demodex tails, and demodex follicular openings in demodex folliculitis. another common mimicker, pseudo-olliculitis, demonstrates a u-shaped in-growing hair under a dermoscope [1,2]. in conclusion, we report dermoscopic features of 2 rare cases of viral folliculitis on the beard. the dermoscopic examination can help differentiate between mc folliculitis figure 1. (a) multiple follicle-based skin-colored to pearly-white (arrow) papules. (b) dermoscopic examination (heine delta20®, 10x magnification) showing perifollicular pearly white clods. (c) histology shows endophytic epithelial hyperplasia containing molluscum bodies (h & e, x50). figure 2. (a) multiple follicle-based skin-colored verrucous flat-topped papules. (b) dermoscopy (heine delta20®, 10x magnification) shows a perifollicular mosaic pattern comprising of a variable-shaped white knob-like area with or without central dotted and hairpin vessels. (c) histology shows basket weave hyperkeratosis, hypergranulosis, moderate acanthosis, and koilocytes in upper stratum spinosum and granulosum (h & e, x50). inset showing koilocytes (h & e, x400). research letter | dermatol pract concept. 2022;12(2):e2022055 3 from hpv folliculitis, with the former characterized by white clod and the latter by a mosaic pattern. references 1. piccolo v. update on dermoscopy and infectious skin diseases. dermatol pract concept. 2019;10(1):e2020003. doi: 10.5826/ dpc.1001a03. pmid: 31921490. pmcid: pmc6936624. 2. durdu m, errichetti e, eskiocak ah, ilkit m. high accuracy of recognition of common forms of folliculitis by dermoscopy: an observational study. j am acad dermatol. 2019;81(2):463-471. doi: 10.1016/j.jaad.2019.03.054. pmid: 30914342. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(3):14 67 dermatology practical & conceptual www.derm101.com case presentation a 73-year-old man with a history of non-melanoma skin cancers presented with a brown-tan 5 mm flat papule on the left arm (figure 1). dermoscopic evaluation revealed a pink pseudonetwork with focal gray-brown dots (figure 2). the differential in vivo reflectance confocal microscopy features of a large cell acanthoma: report of a case neda shahriari1, jane m. grant-kels1, harold s. rabinovitz2, margaret oliviero2, alon scope3 1 department of dermatology, university of connecticut health center, farmington, ct, usa 2 department of dermatology, university of miami miller school of medicine, miami, fl, usa 3 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel key words: rcm, large cell acanthoma, reflectance confocal microscopy citation: shahriari n, grant-kels jm, rabinovitz hs, oliviero m, scope a. in vivo reflectance confocal microscopy features of a large cell acanthoma: report of a case. dermatol pract concept 2016;6(3):14. doi: 10.5826/dpc.0603a14 received: june 13, 2016; accepted: june 18, 2016; published: july 31, 2016 copyright: ©2016 shahriari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: jane m. grant-kels, md, uconn, dermatology department, 21 south rd, farmington, ct 06032, usa. email: grant@uchc.edu reflectance confocal microscopy (rcm) is an fda approved noninvasive optical imaging technique that acquires cellular level-resolution skin images in vivo. herein, we report a case of histopathologically proven large cell acanthoma (lca) whose rcm features simulate those of squamous cell carcinoma in situ. abstract figure 1a. brown-tan 5 mm flat papule on the left arm. [copyright: ©2016 shahriari et al.] figure 1b. close up clinical image of lesion. [copyright: ©2016 shahriari et al.] mailto:grant@uchc.edu 68 observation | dermatol pract concept 2016;6(3):14 acanthotic epidermis with enlarged keratinocytes, consistent with the diagnosis of large cell acanthoma (lca) (figure 5). conclusion lca clinically presents as a discrete scaly 3-10 mm papule, or rarely as a plaque, on sun-exposed body areas, most commonly on the head and extremities [1]. hermann pinkus was the first to histopathologically characterize lca as being composed of keratinocytes with nuclei and cytoplasm twice the size of average adjacent keratinocytes and demonstrating acanthosis, hyperkeratosis, and polyploidy [2]. it was also noted that lca is usually devoid of any signs of cytologic or mitotic atypia. later, analysis of lca dna distribution established the presence of peaks of diploidy, aneuploidy and tetraploidy [2,3]. currently, the origin of this lesion has not been unequivocally established. there is debate within the literature as to whether lca is a distinct neoplastic entity or simply a derivative of seborrheic keratosis or solar lentigo, bowen’s disease, or actinic keratosis with cells displaying large nuclei. pinkus initially theorized that lca was a variant or a derivative of solar lentigo due to shared features, including both lesions occurring on sun-exposed skin regions and presenting as a scaly brown-tan lesion [4]. he argued that lca is unlikely related to an actinic keratosis, however, due to its lack of predilection for development into an scc [4]; and indeed, to the best of our knowledge, no case of lca diagnosis based on dermoscopy included irritated seborrheic keratosis, pigmented squamous cell carcinoma (scc), and traumatized nevus. reflectance confocal microscopy (rcm) of the lesion showed an uneven surface contour with both raised and depressed areas. the granular and spinous layers of the epidermis demonstrated an irregular honeycomb pattern with large keratinocytes showing some variability of size and shape (figure 3). at the dermo-epidermal junction (dej), there were bright, small, closely set edged papillae (figure 4). the rcm findings were suggestive of a pigmented scc in situ and the lesion was biopsied. histopathologic analysis revealed a sharply circumscribed lesion composed of an figure 2. dermoscopic (contact non-polarized) image of lesion revealing a pink pseudonetwork with focal gray-brown dots. [copyright: ©2016 shahriari et al.] figure 3. rcm at the granular and spinous layers of the epidermis demonstrated an irregular honeycomb pattern with large keratinocytes showing some variability of size and shape. [copyright: ©2016 shahriari et al.] observation | dermatol pract concept 2016;6(3):14 69 in contrast, sánchez yus et al. posit that lca may be a cytologic variant of bowen’s disease. their assessment was “based on the frequent disordered arrangement of the malpighian cells, its nuclear variability and occasional finding of dyskeratosis and suprabasal mitoses, as well as the involvement of skin appendages.” [6] dna studies showing polyploidy, unlike solar lentigines, have given some credence to this point of view. however, most dermatopathologists and dermatologists classify lca as one type of solar lentigo [7,8]. reflectance confocal microscopy (rcm) is an fda approved noninvasive optical imaging technique that acquires cellular level-resolution skin images in vivo. a review of the rcm patterns of the aforementioned pathological entities may be informative. rcm of solar lentigo reveals variable bright particles (probably due to melanin-containing granules in the stratum corneum) and a regular cobblestone or honeycomb pattern with distinct refractile keratinoyctes with central dark nuclei in the stratum granulosum and spinosum layers [9]. at the level of the dej, there are different sized dermal papillae with bright rings (termed “edged papillae”) and bulbous projections of epithelium [9]. the rcm features of seborrheic keratosis include bright horn pseudocysts (milia), a cobblestone pattern or broadened honeycomb pattern in the stratum spinosum, bulbous projections of epidermal rete ridges, and distorted papillary rings at the dej [10]. evolving into a scc has been reported in the literature. in line with pinkus’ theory, mehregan et al. demonstrated that solar lentigines and lca have a slight increased number of melanocytes by hmb-45 staining likely due to both lesions occurring on sun-damaged skin of adults [5]. analysis of proliferating cell nuclear antigen (pcna) showed an increased epidermal proliferation rate in actinic keratoses compared with lca and solar lentigines. figure 4. rcm at the dermo-epidermal junction demonstrated bright, small, closely set edged papillae. [copyright: ©2016 shahriari et al.] figure 5. histopathology revealed a lesion composed of an acanthotic epidermis with enlarged keratinocytes, consistent with the diagnosis of large cell acanthoma. [copyright: ©2016 shahriari et al.] 70 observation | dermatol pract concept 2016;6(3):14 cytometry and immunohistochemistry. am j dermatopathol 1994;16:140. pmid: 8030765. 4. rahbari h, pinkus h. large cell acanthoma: one of the actinic keratoses. arch dermatol. 1978;114(1):49-52. pmid: 619783. 5. mehregan dr, hamzavi, f, brown k, large cell acanthoma. int j dermatol 2003;42(1):36-9. pmid: 12581141. doi: 10.1046/j.1365-4362.2003.01587.x. 6. sánchez yus e, de diego v, urrutia s. large cell acanthoma: a cytologic variant of bowen’s disease? am j dermatopathol 1988;10:197-208. pmid: 3232750. 7. patsatsi a, lazaridou e, fotiadou c, kyriakou a, sotiriadis d. large cell acanthoma: a debate throughout the decades. dermatol pract concept 2014;4:43-5. pmid: 24520512. doi: 10.5826/ dpc.0401a05. 8. roewert hj, ackerman ab. large-cell acanthoma is a solar lentigo. am j dermatopathol 1992;14:122–32. pmid: 1533104. 9. sanchez vp, gill m, gonzalez s. lentigo. in: gonzalez s, ahlgrimm-seiss (eds.). reflectance confocal microscopy in dermatology: fundamentals and clinical applications. aula médica. 2012:31-4. 10. sanchez vp, gill m, gonzalez s. seborrheic keratosis. in: gonzalez s, ahlgrimm-seiss v (eds.). reflectance confocal microscopy in dermatology: fundamentals and clinical applications. aulamedica; 2012: 57-59. 11. ulrich m, kanitakis j, gonzalez s, et al. evaluation of bowen disease by in vivo reflectance confocal microscopy. br j dermatol 2012;166:451-3. pmid: 21824125. doi: 10.1111/j.13652133.2011.10563.x. in contrast to solar lentigines and seborrheic keratoses, the histopathologically established lca in our case with rcm was a close simulator of scc in situ demonstrating an irregular honeycomb pattern in the granular and spinous layers as previously described for bowen’s disease [11] the associated small and closely set edged papillae at the dej is also a feature frequently seen in cases of pigmented bowen’s disease. thus, unfortunately rcm did not allow us to forego a biopsy, as we needed to exclude scc in situ. to be able to distinguish lca from scc, as is readily done by dermatopathologists nowadays, more cases of lca imaged with rcm are needed. identifying the distinctive rcm features of lca will allow more precise bedside diagnosis to reduce unnecessary biopsies of this benign entity. references 1. sánchez yus e, del rio e, requena l. large cell acanthoma is a distinctive condition. am j dermatopathol. 1992;14:140-7. pmid: 1566974. 2. pinkus h. epidermal mosaic in benign and precancerous neoplasia (with special reference to large cell acanthomas). acta dermatol (kyoto). 1970;65:75-81. pmid: 5533827 3. argenyi zb, huston bm, argenyi ee, maillet mw, hurt ma. large-cell acanthoma of the skin: a study by image analysisdermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022071 1 dermatology practical & conceptual unusual presentation of kaposi sarcoma during adalimumab therapy: a case report gulsun-hazan tabak1, basak yalici-armagan1, burkay-adem sahin1, ozay gokoz2, sedat kiraz3 1 hacettepe university, school of medicine, department of dermatology and venereology, ankara, turkey 2 hacettepe university, school of medicine, department of pathology, ankara, turkey 3 hacettepe university, school of medicine, department of rheumatology, ankara, turkey key words: psoriasis, biologics, kaposi sarcoma, tnf antagonist citation: tabak gh, yalici-armagan b, sahin ba, gokoz o, kiraz s. unusual presentation of kaposi’s sarcoma during adalimumab therapy: a case report. dermatol pract concept. 2022;12(3):e2022071. doi: https://doi.org/10.5826/dpc.1203a71 accepted: october 11, 2021; published: july 2022 copyright: ©2022 tabak et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/ which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: basak yalici-armagan, md, hacettepe university, school of medicine, department of dermatology and venereology, 06100, ankara, turkey, telephone: 00903123051704, fax: 0 3123114340, e-mail: basakarmagan@gmail.com introduction kaposi sarcoma (ks) is a rare angioproliferative malignancy associated with human herpesvirus-8 (hhv-8) that involves skin and visceral organs. it typically manifests with magenta-colored macules, papules, and nodules on the skin. herein, we present a patient who developed pyogenic granuloma (pg)-like ks during adalimumab therapy for psoriatic arthritis. case presentation a 48-year-old male applied to our dermatology outpatient clinic for a bleeding lesion on the right forth toe. the lesion occurred seven-months before and grew rapidly in last onemonth. he has been diagnosed with psoriatic arthritis 4 years ago and treated with adalimumab, a tumor necrosis factor-α inhibitor (tnfi), for the last one year. dermatological examination revealed a 1cm x1 cm diameter of reddish, ulcerated, protruding hemorrhagic nodule partially covered with hyperkeratotic crust and fibrin just under the fourth toe nail (figure 1, a and b). excisional biopsy was performed with provisional diagnoses of amelanotic malignant melanoma, pg and cutaneous squamous cell carcinoma. histopathological examination showed nodular lesion in the dermis made up of atypical spindle shaped cells showing whorled structures and slit like spaces filled with erythrocytes. immunohistochemical examination indicated hhv-8 positivity and confirmed the diagnosis of ks (figure 1e). in detailed dermatological examination, purple-colored patches on the lateral aspects of both feet were noticed (figure 1, c and d). hiv serology was negative. adalimumab treatment was ceased immediately and the patient was addressed to oncology department for remaining lesions. conclusions the potential of tnfis to increase the risk of malignancy including melanoma and non-melanoma skin cancer is still controversial. although iatrogenic ks has been described in 2 research letter | dermatol pract concept. 2022;12(3):e2022071 figure 1. (a, b) reddish-purplish, firm, easy-bleeding nodule covered with hyperkeratotic crust and fibrine just under the right forth toe nail. (c, d) purple-colored patches on the lateral sides of both feet. (e) spindle cells, slit like spaces and erythrocytes, hhv8 positivity (inlet) are shown in histopathologic examination (h&e x200). research letter | dermatol pract concept. 2022;12(3):e2022071 3 organ transplant recipients receiving immunosuppressive therapy, there are only a few reports of ks during tnfi therapy that were presenting as typically purplish-red patches and papulonodular lesions on the lower leg [1]. classic ks is typically seen in older men (64–72 years) of mediterranean, eastern european (ashkenazi) jewish, or south american origin whereas endemic ks is limited to sub-saharan africa and is typically seen in young (25–40 years), black, hiv-negative men. on the other hand, ks and psoriasis speculated to share common pathogenesis particularly related with interleukin-6 cytokine pathway or the same human leukocyte antigen alleles. although we cannot explain the exact mechanism of this association whether it is a co-existence of ks and psoriasis or it is triggered by adalimumab, hiv negativity and the early age of onset compared to classical ks suggested a relationship with adalimumab in the present case. unlike reported ks cases induced by tnfi treatment, pg-like presentation with classical purple-colored patches was a remarkable finding of the current case. pg-like ks is a rare variant of ks that is difficult to diagnose clinically [2]. we present this rare case of pg-like ks that can be easily confused with other skin tumors in a patient under biologic treatment. if characteristic purple-colored patches of ks on the lateral sides of feet were not overlooked on physical examination in the current case, it could have been possible to include ks in the clinical pre-diagnoses. detailed whole body skin examination is crucial for dermatologists to provide correct clinical diagnosis for early management. further evidence is needed to clarify the relationship between biologics and malignancy development. references 1. ursini f, naty s, mazzei v, spagnolo f, grembiale rd. kaposi’s  sarcoma  in a psoriatic arthritis patient treated with infliximab. int immunopharmacol. 2010;10(7):827-828. doi: 10.1016/j.intimp.2010.04.016. pmid: 20433950. 2. megaly m, boshra n. pyogenic  granuloma-like  kaposi’s  sarcoma. lancet. 2022;399(10335):e38. doi: 10.1016/s01406736(15)00467-5. pmid: 26498707. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021037 1 collision cutaneous neoplasms consisting of melanoma and basal cell carcinoma maryam aghighi1, david chercover2,3, maral rahvar2 1 department of pathology, rutgers robert wood johnson barnabas health, livingston, nj, usa  2 department of pathology and laboratory medicine, lions gate hospital, north vancouver, bc, canada 3 department of pathology and laboratory medicine, university of british columbia, vancouver, bc, canada key words: lentigo maligna melanoma, basal cell carcinoma, collision tumor citation: aghighi m, chercover d, rahvar m. collision cutaneous neoplasms consisting of melanoma and basal cell carcinoma. dermatol pract concept. 2021; 11(3): e2021037. doi: https://doi.org/10.5826/dpc.1103a37 accepted: october 15, 2020; published: july 8, 2021 copyright: ©2021 aghighi et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: maryam aghighi m.d. department of pathology, rutgers robert wood johnson barnabas health, livingston, nj, usa. email: maryam.aghighi@rwjbh.org introduction a collision tumor is a rare neoplastic lesion presenting 2 histologically distinct tumors sharing the same anatomical location. basal cell carcinomas (bcc) have been reported to collide with other skin lesions. bcc present more than other neoplasms in collision tumors and have a high prevalence among caucasians. collision of bcc and other benign or malignant mesenchymal, epithelial, and melanocytic tumors have been reported. similarly, collision of melanoma may take place with other cutaneous lesions such as bcc. melanocytes are generally found within the basal epidermal layer and outer follicular root sheath, thus, the entrapment of non-atypical melanocytes in growing basal cell carcinomas (bcc) is not unusual as it may provide a suitable environment for the melanocytes [1]. these melanocytes are usually isolated, without cytological atypia and proliferation markers. however, the presence of atypical melanocytes within bcc is uncommon. it has been shown that lentigo maligna and superficial spreading melanoma in situ have association with bcc. melanoma cells may unexpectedly surround or colonize within bcc and hence mimic invasive melanoma [2]. case presentation here we report a case of a 91-year-old male patient presenting a translucent plaque with brown areas of pigmentation on his left lateral canthus. his clinical history reported multiple bccs, squamous cell carcinomas, and an invasive melanoma of the right cheek. the lesion was removed with curettage following clinical diagnosis of bcc. a histologic examination showed the epidermis with a malignant melanoma in-situ overlying solid nodules of a pigmented basal cell carcinoma. atypical melanocytes heavily percolated into dermal nodules of the bcc (figure 1 a-c). further immunohistochemical evaluation with melanocytic and epithelial markers (melanin a, sox-10, p63, pan-cyto2 letter | dermatol pract concept. 2021; 11(3): e2021037 keratin) confirmed the diagnosis (figure 1, d-f). the bcc contained about 50% atypical melanocytes. an unequivocal invasive melanoma component was not detected. conclusions tumors composed of melanocytic and epithelial components are categorized into biphenotypic, combined, colonized, and collision tumors. biphenotypic tumors grow from a single precursor tumor cell that differentiates into 2 distinct tumors. combined tumors consist of 2 different, but combined, cell groups. immunohistochemistry is useful to distinguish among the 2 groups. in colonized tumors, 1 tumor type diffuses but remains within the other tumor. finally, collision tumors consists of 2 different adjacent tumor cells with clear distinguishable boundaries. different hypotheses regarding the development of these tumors have been discussed. one hypothesis suggests that figure 1. collision of lmm and bcc. skin presenting in-situ melanoma heavily infiltrating the bcc dermal nodules. (a) (h&e, x 20). (b) (h&e, x100). (c) (h&e, x200). (d) atypical melanocytes are highlighted by sox10 (h&e, x20). (e) p63 marker (h&e, x20). (f) pan-cytokeratin (h&e, x20). letter | dermatol pract concept. 2021; 11(3): e2021037 3 collision tumors arises from 2 separate tumors in vicinity. another hypothesis suggests that the environment of epithelial tumors changes thanks to the production of cytokines and growth factors that induce melanocytes colonization. there are about 30 cases reported in the literature of dual cutaneous neoplasms consisting of melanoma and bcc. challenges in the diagnosis of these dual tumors are due to a chance of misdiagnosis of melanoma as a pigmented bcc. while looking for melanocytic markers, it is better to examine the dubious/uncertain lesions by immunophenotyping. isolated melanocytes can be seen at the border of pigmented bcc. however, atypical melanocytes in clusters may reveal the presence of melanoma or its metastasis in bcc. since the prognosis of the 2 entities is independent, wider excision is indicated, to exclude the possibility of an invasive malignant melanoma. references 1. belisle a, gautier m-s, ghozali f, plantier f, wechsler j. a collision tumor involving basal cell carcinoma and lentigo maligna melanoma. the american journal of dermatopathology. 2005;27(4):319-321. doi: 10.1097/01.dad.0000164603.49026.6a. pmid: 16121053 2. busam kj, halpern a, marghoob aa. malignant melanoma metastatic to a basal cell carcinoma simulating the pattern of a basomelanocytic tumor. the american journal of surgical pathology. 2006;30(1):133-136. doi: 10.1097/01. pas.0000179118.76904.02. pmid: 16330954 dermatology: practical and conceptual research | dermatol pract concept 2021;11(2):e2021030 1 dermatology practical & conceptual distance learning and spaced review to complement dermoscopy training for primary care elizabeth v. seiverling1,2, danielle li2, kathryn stevens1, peggy cyr2,3, gregory dorr4, hadjh ahrns3 1 dermatology division, maine medical center, portland, maine, usa 2 tufts university school of medicine, boston, usa 3 maine medical partners family medicine, portland, usa 4 maine medical center quality improvement, portland, usa key words: dermoscopy, primary care, skin cancer, distance learning, resident education citation: seiverling ev, li d, stevens k, cyr p, dorr g, ahrns h. distance learning and spaced review to complement dermoscopy training for primary care. dermatol pract concept. 2021;11(2):e2021030. doi: https://doi.org/10.5826/dpc.1102a30 accepted: november 6, 2020; published: april 12, 2021 copyright: ©2021 seiverling et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: innovation in education grant from maine medical center institute for teaching excellence (mite). competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: elizabeth v. seiverling md, dermatology division director maine medical center, 265 western ave, suite 1, south portland, me 04106, usa. email: eseiverlin@mmc.org background: dermoscopy aids in skin cancer identification. for family physicians who use dermoscopy, there is higher sensitivity for melanoma detection than naked-eye examination. there is a shortage of dermoscopy training for primary care providers. the triage amalgamated dermoscopic algorithm (tada) is designed for novice dermoscopists. while tada can be taught in a short dermoscopy workshop, spaced review and blended learning strategies improve knowledge retention. objectives: this study determined the impact that the addition of a distance learning platform has on clinical dermoscopy use. moreover, it evaluated dermoscopic image identification (knowledge retention) following the addition of distance learning via extension for community health outcomes (echo) to a traditional tada dermoscopy workshop. methods: primary care providers voluntarily attended a 120-minute tada dermoscopy workshop. participants completed pre-intervention, post-tada, and post-echo tests of 30 dermoscopic images of benign and malignant skin lesions. a survey was also administered to analyze clinical dermoscopy use and prior dermoscopy training. results: twenty-seven residents, faculty, and advanced practice providers participated in this longitudinal observational cohort study. mean test scores (out of 30) for images of benign and malignant lesions improved from 20.29 pre-intervention to 24.62 post-tada and 27.63 post-echo (p < .001). on average, participants attended 4 echo sessions (out of 7 total) and there was a positive correlation (r = 0.77) between the number of echos attended and post-echo scores. dermoscope use increased from 37.0% to 96.3% (p < .001). conclusion: distance learning and spaced review complement dermoscopy workshop training for primary care. abstract 2 research | dermatol pract concept 2021;11(2):e2021030 introduction skin cancer affects 1 in 5 americans [1], with melanoma accounting for 10,000 deaths annually in the united states [2]. maine has the sixth highest incidence of melanoma in the u.s. [3]. however, when melanoma is detected early, 5-year survival rates are 98% [2]. in the u.s., there is a nationwide shortage of dermatologists, with rural states, such as maine, most profoundly affected. maine has one of the lowest ratios of dermatologists per 100,000 people [4]. due to a shortage of dermatologists, skin cancer is often detected by primary care providers (pcps). indeed, many patients seek dermatologic care from their pcps, and 12%-25% of primary care visits are due to a dermatologic concern [5,6]. thus, pcps are often the first medical providers approached when a patient has a skin growth of concern. dermoscopy is a useful and cost-effective tool for melanoma detection in primary care [7]. dermoscopes are handheld instruments that use polarized and non-polarized light to illuminate subsurface skin structures (epidermis, dermoepidermal junction, and papillary dermis). most of these structures cannot otherwise be seen with the naked eye. for family physicians who use dermoscopy, there is higher sensitivity for melanoma detection than naked-eye examination [7]. however, the majority of dermoscopy training has been geared toward dermatologists, not pcps. there is no consensus on how best to teach dermoscopy. furthermore, there is no agreement on whether or not dermoscopy training should be the same for dermatologists and pcps. previous research has identified the triage amalgamated dermoscopic algorithm (tada) as an effective option for training primary care [8,9]. tada is a simplified dermoscopy algorithm with high sensitivity and specificity for benign and malignant growths [8,9]. following training with tada, the sensitivity for dermoscopic identification of malignant skin growths increased from 62.5% to 88.1% in family physicians. the specificity for dermoscopic identification of common benign growths (seborrheic keratosis, dermatofibroma, angioma) was over 90% [8]. the durability of tada training is not known. however, spaced review and blended learning strategies are well-established teaching modalities to aid with knowledge retention [12-14]. to incorporate alternative learning strategies and spaced review into our dermoscopy training, we added a distance learning platform. distance learning, also termed distance education, is a form of education in which courses are delivered via the internet without face-to-face interaction between student and instructor [12,15]. project extension for community health outcomes (echo) is a distance learning platform used in medicine to create learning loops between specialists and pcps. project echo uses videoconferencing technology to link students, residents, and practicing providers with specialists, for real-time learning and clinical practice support. the goal is to improve knowledge at the local level, resulting in fewer unnecessary referrals and better access to care. because of the ongoing (monthly) nature of project echo, participants have an opportunity to build on initial dermoscopy training. furthermore, critical to project echo is case presentation and spaced review, which is essential to creating long-term memory [13,14]. the specific objectives of this project were to: • determine the impact the addition of a distance learning platform has on clinical dermoscopy use. • evaluate dermoscopic image identification (knowledge retention) following the addition of distance learning via project echo to a traditional tada dermoscopy workshop. methods this project was reviewed by the maine medical center [mmc] institutional review board and was deemed exempt. participants were recruited via email invitation. participation was voluntary and involved a single, in-person, 120-minute tada dermoscopy workshop without compensation. participants were granted hours towards their continuing medical education requirement. to be eligible, participants had to be: [1] a primary care provider (resident, faculty, or an advanced practice provider (app) in family medicine or internal medicine), and [2] an employee of mmc or mainehealth. a pre-intervention dermoscopy test and survey was administered prior to the tada dermoscopy workshop. the test contained 30 dermoscopic images of benign and malignant neoplasms. the survey addressed demographics and asked questions regarding dermoscopy use. immediately following the tada dermoscopy workshop, participants were asked to complete a post-tada test with a different set of 30 dermoscopic images. none of the images in the post-tada test were used during the educational workshop. the dermoscopy images were selected from mainehealth’s teaching database and had been collected by author e.v.s. at mmc. images were reviewed by e.v.s., h.t.a., and k.m.s. ninety images were deemed representative examples of benign and malignant neoplasms. these 90 images were then utilized in the pre-intervention, post-tada and post-echo tests. upon completion of a tada workshop, participants were then eligible to take part in longitudinal dermoscopy training via project echo. seven dermatology/dermoscopy echos were offered over the course of 8 months. each echo adhered to a standard 60-minute format with a 20to research | dermatol pract concept 2021;11(2):e2021030 3 30-minute didactic lecture followed by interactive cases. the topics for the didactic portion included the following: basal cell carcinoma, nevus versus melanoma, psoriasis and other scaly rashes, common skin infections, dermoscopy of benign skin tumors, skin biopsy techniques, and a dermoscopy recapitulation. at the conclusion of project echo, participants took a post-echo test consisting of 30 additional dermoscopic images of benign and malignant growths. in addition to the dermoscopic image test, survey questions addressing frequency of dermoscopy use were also administered. descriptive comparisons of scores were made using mean scores along with standard deviations and were compared using the wilcoxon signed-rank test. results this longitudinal observational cohort study conducted in the state of maine included 27 residents, faculty, and apps from mmc and mainehealth. table 1 lists the characteristics of the 27 participants included in the analysis. this sample was predominantly female (70.4%, n = 19), with md or do qualifications (96.3%, n = 26), working as a family physician (88.9%, n = 24), and with fewer than 10 years of experience evaluating skin lesions (66.7%, n = 18). only 11.1% of participants had formal training in dermoscopy prior to the study. table 2 highlights survey questions that participants answered preand post-intervention. all participants reported access to a dermoscope post-intervention. pre-tada and post-echo surveys showed that dermoscope use increased from 37.0% to 96.3% (chi-square test, p <  .001), with the majority of participants now using a dermoscope weekly. overall, mean test scores (out of 30) for images of benign and malignant neoplasms improved from 20.29 preintervention to 24.62 post-tada and 27.63 post-echo. on average, participants attended 4 echo sessions out of 7 total. figure 2 highlights the results of a linear regression that shows a positive correlation (r = 0.77) between the number of echo sessions attended and post-echo test scores. discussion while dermoscopy aids in skin cancer detection and the american academy of family physicians recommends all family medicine residents be trained in dermoscopy, there is no standard dermoscopy training for pcps [16]. to improve dermoscopy training for primary care in our health system, we added monthly dermoscopy training sessions via project echo. this dermoscopy-focused echo was the first geared toward primary care in the u.s. based on our results, distance learning platforms such as project echo might be viable options for ongoing dermoscopy training for pcps. the monthly format of project echo allows for spaced review, and in this study, led to knowledge retention. improved image identification in the classroom setting does not necessarily translate to increased dermoscopy use in the clinical setting, yet, our study shows that participants dramatically increased the use of dermoscopy in their practices. while the participants in our study reported the most beneficial way to learn dermoscopy was with the live tada workshop and in-person clinical rotations, remote session learning through project echo was also a preferred learning modality. live dermoscopy workshops and in-clinic training with a dermoscopist is not feasible at many primary care sites. however, distance learning allows for virtual consults and telementoring that can serve as a surrogate to physical time in the clinic with a dermoscopy expert [17]. telementoring allows learners at multiple sites to access dermoscopy training at the same point in time. concurrent with the implementation of the multimodal dermoscopy curriculum (which included the tada workshops, clinical dermatology rotations and echo), a dermatology electronic consultation (econsult) platform was launched within our health system. this allowed participants to apply their dermoscopy training to real cases and ask for expert opinion on their own patients. the synchronous introtable 1. characteristics of 27 study participantsa variable coding no. (%) overall 27 (100.0) sex male 8 (29.6) female 19 (70.4) age 21-30 y 13 (48.1) 31-40 y 9 (33.3) 41-50 y 3 (11.1) 51-60 y 2 (7.4) training md/do 26 (96.3) board-certified pcp 9 (33.3) resident 17 (63.0) nurse practitioner 1 (3.7) specialty family medicine 24 (88.9) internal medicine 3 (11.1) years evaluating skin lesions ≤10 18 (66.7) 10+ 3 (11.1) any formal training in dermoscopy? no 23 (85.2) yes 3 (11.1) a not all participants answered every question on the survey. pcp = primary care provider. 4 research | dermatol pract concept 2021;11(2):e2021030 table 2. prevs. post-intervention survey results for 27 participants a variable coding pre-intervention, no. (%) post-intervention, no. (%) do you have access to a dermoscope? no 7 (26.0) 0 (0) yes 20 (74.0) 27 (100) do you use a dermoscope? no 16 (59.3) 1 (3.7) yes 10 (37.0) 26 (96.3) if yes, how often? daily 0 (0.0) 1 (3.7) 2-3×/week 1 (3.7) 4 (14.8) 1×/week 1 (3.7) 9 (33.3) 2-3×/month 2 (7.4) 5 (18.5) 1×/month 3 (11.1) 5 (18.5) <1×/month 3 (11.1) 2 (7.4) a not all participants answered every question on the survey. figure 1. pre-intervention and post-echo dermoscopy use echos attended all respondents p o st -e c h o t es t sc o r e 1 2 18 20 22 24 26 28 30 3 4 5 6 7 figure 2. linear regression of participant extension for community outcomes (echo) attendance and post-echo test scores. some dots represent multiple participants with the same test score and echo attendance. research | dermatol pract concept 2021;11(2):e2021030 5 duction of econsult and project echo may have contributed to increased dermoscope use. distance learning through project echo may provide a solution to effectively facilitating dermoscopy training and virtual consults in rural settings. while this study was initiated prior to the onset of covid-19, the pandemic has emphasized the importance of adding distance learning to medical education. we hope this innovative approach to teaching dermoscopy to pcps will motivate other institutions to consider distance learning platforms and spaced review to complement dermoscopy workshops and “boot camps.” this study was limited by its sample size. due to disruption caused by covid-19, there was a poor retention rate. many of our participants were deployed to inpatient services and unable to complete the final quiz. the initial tada workshops were attended by over 100 clinicians. we have only included participants who completed all 3 tests in this report. references 1. kerr oa, tidman mj, walker jj, aldridge rd, benton ec. the profile of dermatological problems in primary care. clin exp dermatol. 2010;35(4):380-383. doi: 10.1111/j.13652230.2009.03586.x. pmid: 19874334 2. cancer facts & figures 2017. american cancer society. published 2017. accessed july 8, 2020. https://www.cancer.org/content/ dam/cancer-org/research/cancer-facts-andstatistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. 3. rate of new cancers in the united states, melanomas of the skin. center for disease control and prevention. accessed july 10, 2020. https://gis.cdc.gov/cancer/uscs/dataviz.html. 4. glazer am, farberg as, winklemann rr, rigel ds. analysis of trends in geographic distribution and density of us dermatologists. jama dermatol. 2017;153(4):322-325. doi: 10.1001/ jamadermatol.2016.5411. pmid: 28146246 5. perera e, xu c, manoharan s. real-life teledermatology cases. in: soyer hp, binder m, smith a, wurm e, eds. telemedicine in dermatology. berlin: springer science & business media; 2011:123-129. 6. verhoeven ew, kraaimaat fw, van weel c, et al. skin diseases in family medicine: prevalence and health care use. ann fam med. 2008;6(4):349-354. doi: 10.1370/afm.861./ pmid: 18626035. 7. herschorn a. dermoscopy for melanoma detection in family practice. can fam physician. 2012;58(7):740-745, e372-748. pmid: 22859635. 8. seiverling ev, ahrns ht, greene a, et al. teaching benign skin lesions as a strategy to improve the triage amalgamated dermoscopic algorithm (tada). j am board fam med. 2019;32(1):96102. doi: 10.3122/jabfm.2019.01.180049. pmid: 30610147. 9. susong jr, ahrns ht, daugherty a, marghoob aa, seiverling ev. evaluation of a virtual basic dermatology curriculum for dermoscopy by using the triage amalgamated dermoscopic algorithm for novice dermoscopists. j am acad dermatol. 2020;83(2):590-592. doi: 10.1016/j.jaad.2019.05.097. pmid: 32331797. 10. wu tp, newlove t, smith l, vuong ch, stein ja, polsky d. the importance of dedicated dermoscopy training during residency: a survey of us dermatology chief residents. j am acad dermatol. 2013;68(6):1000-1005. doi: 10.1016/j.jaad.2012.11.032. pmid: 23374231. 11. chen ya, rill j, seiverling ev. analysis of dermoscopy teaching modalities in united states dermatology residency programs. dermatol pract concept. 2017;7(3):38-43. doi: 10.5826/ dpc.0703a08. pmid: 29085718. 12. ruiz jg, mintzer mj, leipzig rm. the impact of e-learning in medical education. acad med. 2006;81(3):207-212. doi: 10.1097/00001888-200603000-00002. pmid: 16501260. 13. augustin m. how to learn effectively in medical school: test yourself, learn actively, and repeat in intervals. yale j biol med. 2014;87(2):207-212. pmid: 24910566. 14. khajah mm, lindsey rv, mozer mc. maximizing students’ retention via spaced review: practical guidance from computational models of memory. top cogn sci. 2014;6(1):157-169. doi 10.111/tops.12077. pmid: 24482341. 15. distance education. national education association. accessed august 13, 2020. http://www.nea.org/home/34765.htm. 16. family medicine residency curriculum guidelines: conditions of the skin. american academy of family physicians. accessed june 3, 2019. https://www.aafp.org/medical-school-residency/ program-directors/ curriculum.html. 17. nelson kc, gershenwald je, savory sa, et al. telementoring and smartphone-based answering systems to optimize dermatology resident dermoscopy education. j am acad dermatol. 2019;81(2):e27-e28. doi: 10.1016/j.jaad.2019.01.045. pmid: 30703459. dermatology: practical and conceptual research | dermatol pract concept 2021;11(1):e2021153 1 dermatology practical & conceptual impact of the covid-19 pandemic on dermatology practice worldwide: results of a survey promoted by the international dermoscopy society (ids) claudio conforti1, aimilios lallas2, giuseppe argenziano3, caterina dianzani4, nicola di meo1, roberta giuffrida5, harald kittler6, josep malvehy7, ashfaq a. marghoob8, h. peter soyer9,10 iris zalaudek1 1 department of dermatology and venereology, dermatology clinic, maggiore hospital, university of trieste, italy 2 first dermatology department, aristotle university of thessaloniki, greece 3 department of dermatology, university of campania, luigi vanvitelli, naples, italy 4 dermatology section, plastic and reconstructive surgery unit, campus biomedico university, rome, italy 5 department of clinical and experimental medicine, dermatology, university of messina, italy 6 department of dermatology, medical university of vienna, austria 7 dermatology department, melanoma unit, hospital clinic, university of barcelona, spain 8 dermatology service, department of medicine, memorial sloan kettering cancer center, new york, ny, usa 9 the university of queensland diamantina institute, the university of queensland, dermatology research centre, brisbane, qld, australia 10 department of dermatology, princess alexandra hospital, brisbane, qld australia key words: covid-19, teledermatology, survey, sars-cov-2, dermatology citation: conforti c, lallas a, argenziano g, dianzani c, di meo n, giuffrida r, kittler h, malvehy j, marghoob aa, soyer hp, zalaudek i. impact of the covid-19 pandemic on dermatology practice worldwide: results of a survey promoted by the international dermoscopy society. dermatol pract concept. 2021;11(1):e2021153. doi: https://doi.org/10.5826/dpc.1101a153 accepted: september 27, 2020; published: january 29, 2021 copyright: ©2021 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, university of trieste, piazza dell’ospitale 1, trieste, 34125, italy. email: claudioconforti@yahoo.com introduction: the international dermoscopy society (ids) conducted an online survey to investigate the impact of coronavirus disease 2019 (covid-19) outbreak on the daily practice of dermatologists working with skin cancer patients, to collect data regarding the frequency of skin manifestations noticed by the members, and to obtain information about the use of teledermatology during the pandemic. methods: all ids members were asked to fill in a questionnaire, sent by email. a questionnaire available in english was sent to all ids members (≈16.0000 members) by email. the questionnaire was anonymous, with a compiling time of less than 5 minutes. the survey was open for 30 days (from april 24, 2020 to may 24, 2020) and it could only be filled out once. abstract 2 research | dermatol pract concept 2021;11(1):e2021153 introduction on december 2019, a novel coronavirus, sars-cov-2, started the outbreak of coronavirus disease 2019 (covid19) that rapidly spread worldwide and caused thousands of infections and deaths. because of the enormous burden, it was officially recognized as a pandemic by the world health organization on march 11, 2020 [1,2]. to cope with this worldwide emergency, hospitals have been rapidly reorganized to increase the number of intensive or sub-intensive care units, and other departments have been closed or readapted to focus only on urgent health care services, including non-deferrable dermatological visits. moreover, telemedicine services were rapidly implemented mostly to guarantee the remote management of patients requiring continuous treatment [3,4]. an increased number of unusual dermatological manifestations were reported, initially among children and later in adults, which raised the suspicion of a possible correlation between coronavirus disease 2019 (covid-19) and dermatological eruptions [5-7]. to date, no skin manifestation appears pathognomonic of covid-19, as many of the described skin rashes can be seen during the course of other viral infections. for this reason, the international dermoscopy society (ids) conducted an online survey with 3 aims: first, to investigate the impact of the covid-19 outbreak on the daily practice of dermatologists working with skin cancer patients; second, to collect data regarding the frequency of skin manifestations noticed by its members; and third, to obtain information about the use of teledermatology during the pandemic. methods a questionnaire was sent to all ids members (16,0000 members) by email. it consisted of 24 questions, 4 regarding the respondent’s personal data, 7 on the organization of the dermatology department/clinic and on possible contact with covid-19 positive patients, 9 on cutaneous manifestations in covid-19 patients, and 4 on teledermatology and diagnosis during the pandemic. the questionnaire was anonymous, of 5-minute duration, and was approved by ids executive board members. the survey was open for 30 days (from april 24, 2020 to may 24, 2020). the answers were saved only for completed questionnaires on on the digital platform surveymonkey (surveymonkey, san mateo, ca, usa) to which only 3 members (cc, al, iz) had access to monitor the progress of the survey. results overall 678 dermatologists from 52 different countries completed the questionnaire (418/678 women, 61.65%; 260/678 men, 38.35%; mean age 47.7; range 26-76 years). worldwide distribution of participants involved all 5 continents, and the majority worked in private practice (n = 264, 38.94%) clinics or university hospitals (n = 232, 34.22%) (table 1). dermatologists, 334/678 (49.26%), stated that since the beginning of the pandemic, there has been more than 75% a reduction in daily work activity to avoid crowding and results: overall, 678 dermatologists responded to the questionnaire; 334 members stated that there has been a reduction of more than 75% in daily work activity during the pandemic, 265 dermatologists worked fewer days per week, and 118 experienced telemedicine for the first time. acrodermatitis was the most frequently observed skin manifestation (n = 80) followed by urticarial rash (n = 69), morbilliform rash (n = 53) and purpuric manifestation (n = 40). in regard to the role of teledermatology, 565 dermatologists reported an increased number of teleconsultations, and the number of melanomas diagnosed during the pandemic was practically 0 for 385 (56.78%) of respondents. conclusion: this survey highlights that the outbreak had a negative impact on most dermatology services, with a significant reduction in consultation time spent for chronic patients, and an increased risk of missed melanoma and nonmelanoma skin cancer (nmsc) diagnosis. moreover, our study confirms earlier findings of a wide range of skin manifestations associated with covid-19. table 1. characteristics of the 678 members who completed the international dermoscopy society survey sex men 260 (38.35%) woman 418 (61.65%) mean age 47.7 (range 26-76) workplace (more than 1 answer possible) university hospital 232 (27.79%) private hospital 67 (8.02%) private clinic 264 (31.62%) public clinic 127 (15.20%) outpatient clinic 145 (17.37%) research | dermatol pract concept 2021;11(1):e2021153 3 to focus on dermatological emergencies. to prevent febrile patients from entering the hospital, a dedicated triage was created in most of the centers (376/678; 55.46%) where dermatologists worked to measure body temperature and to equip patients with surgical masks (table 2). to cope with the emergency, the majority of participants 265/678 (39.08%) stated that they worked fewer days per week at the dermatology departments to ensure urgent or non-renewable visits, 9/678 n=678 % count did you reduce your daily work activity since the beginning of the pandemic? yes, about 25% 10.17% 69 yes, about 50% 18.44% 125 yes, about 75% 18.44% 125 yes, more than 75% 49.26% 334 no 3.69% 25 was there a dedicated triage for dermatological outpatients? yes, patients wear the mask and temperature was measured 35.40% 240 yes, without measuring the temperature 20.06% 136 no, but patients wear the mask 22.42% 152 none of the above 22.12% 150 did you work in covid-19 dedicated departments? yes, not as dermatologist 11.21% 76 no, i worked only using teledermatology 27.73% 188 no, i worked every day as dermatologist 21.98% 149 no, i worked few days per week in the dermatology department 39.08% 265 did you come into contact with covid-19 positive patients? yes, i got in contact with confirmed case 12.83% 87 yes, i got in contact with patient confirmed case 18.29% 124 no 68.88% 467 did you test positive for covid-19? yes 3.54% 24 not 43.81% 297 a test has not been performed 52.65% 357 did you see covid-19 patients with skin manifestations? yes 16.37% 111 no 83.63% 567 n=678 % count what was the average age of the patient(s)? (more than 1 answer possible) 1-20 31.44% 58 20-40 29.34% 54 40-60 22.82% 42 >60 16.40% 30 the number of teleconsultations you were asked to do during covid-19 pandemic was as usual 16.67% 113 increased a little bit 23.30% 158 doubled 16.96% 115 multiplied 43.07% 292 the number of melanomas you diagnosed (including by teleconsultations) during the pandemic was the same as usual 15.93% 108 a little bit lower than usual 9.89% 67 almost half of the usual 4.72% 32 less than half of the usual 12.68% 86 almost zero 56.78% 385 the number of nonmelanoma skin cancers you diagnosed (including by teleconsultations) during the pandemic was the same as usual 16.52% 112 a little bit lower than usual 10.77% 73 almost half of the usual 8.26% 56 less than half of the usual 27.11% 184 almost zero 37.31% 253 during the pandemic, what was the main reason prompting patients to seek live dermatologic consultation? (more than 1 answer possible) tumors 39.09% 265 chronic skin diseases 26.99% 183 pruritic eruptions 37.32% 253 cosmetic problems 8.55% 58 no predominant reason 24.19% 164 table 2. answers from the international dermoscopy society survey questions 4 research | dermatol pract concept 2021;11(1):e2021153 (21.98%) continued working on a daily basis, and 76/678 (11.21%) worked actively in covid-19 dedicated departments. among respondents, 188/678 dermatologists (27.73%) performed smart working performing visits through digital platforms and experienced telemedicine for the first time. overall, 214 dermatologists stated to have had contact with confirmed (87; 12.83%) or strongly suspected (124; 18.29%) covid-19 patients. of those 214 dermatologists, only 24 (3.54%) tested positive for sars-cov-2. less than half of respondents (n = 297; 43.81%) reported the availability of sufficient personal protective equipment. regarding specific questions on dermatological manifestations of the virus, 1/6 of respondents stated to have visited covid-19 positive (confirmed pcr on nasopharyngeal swab) patients with clinical manifestations (table 3). most clinical manifestations were observed in patients aged 1-20 years (n = 58, 31.44%), followed by 20to 40-year age group (n = 54, 29.34%), 40-60 years (n = 42; 22.82%), and older than 60 (n = 30; 16.40%). the most frequently noted clinical manifestations were acrodermatitis (n = 80; 21.50%), urticarial rash (n = 69; 18.54%), morbilliform skin rash (n = 53; 14.24%), purpuric manifestations (n = 49; 13.17%), followed by erythema polymorphous like rash (n = 37; 9.94%) and chickenpox like rash (n = 30; 8.06%) (table 3). the skin lesions either appeared after the onset of systemic symptoms (n = 75; 35.89%) or were the only clinical manifestation in asymptomatic patients (n = 57; 27.27%) (table 3). most dermatologists reported that skin manifestations were mostly observed in asymptomatic (n = 89; 52.67%) or paucisymptomatic patients (n = 55; 32.54%). the last part of the questionnaire (questions 21-24) focused on the implementation of telemedicine during the pandemic. respondents also noted that the number of unofficial teleconsultations (eg, by mail, sms, skype, whatsapp, messenger, etc.) that they were asked to do during the covid19 pandemic has increased by 83.33% (n = 565). remarkably, the number of melanomas diagnosed in these months was practically 0 for more than half (n = 385; 56.78%) of respondents. the reduction in diagnosis is also superimposable for nonmelanoma skin cancers (nmscs) for which 253 dermatologists stated that the diagnosis was very close to 0, and 184 reported that the nmsc diagnosis was 50% less compared to previous months. last, during the pandemic, the main reason for dermatological examinations were tumors considered by the patient to be suspicious, pruritic eruptions, followed by chronic skin diseases. discussion the ids promotes research and education of dermoscopy, a tool that is mostly implemented in early skin cancer diagtable 3. skin findings in patients positive for sars-cov-2 infection according to international dermoscopy society survey questions what kinds of skin manifestations did you see? (more than 1 answer possible) % count morbilliform skin manifestation 14.24% 53 erythema polymorphous like rash 9.94% 37 erythrodermic rash 3.24% 12 chicken-pox like rash 8.06% 30 urticarial rash 18.54% 69 purpuric manifestation 13.17% 49 acrodermatitis (chilblains) 21.50% 80 herpes zoster virus reactivation 4.60% 17 psoriatic flare 2.41% 9 atopic flare 4.30% 16 skin manifestations (more than 1 answer possible) anticipated systemic symptoms 19.14% 40 appeared after systemic symptoms 35.89% 75 were the only ongoing manifestation of illness 27.27% 57 were a tardive manifestation of illness 17.70% 37 skin manifestations were more commonly seen in (more than 1 answer possible) asymptomatic patients 52.67% 89 paucisymptomatic patients 32.54% 55 symptomatic patients 14.79% 25 research | dermatol pract concept 2021;11(1):e2021153 5 nosis. in fact, the majority of ids members work, at least to some extent, in skin cancer care. the fact that nearly 700 colleagues from 52 countries responded to the survey allows a proper view on the effective global impact of the covid-19 pandemic on the routine work in dermatological care. our data highlight a 75% reduction of the work and suggest that the covid-19 health emergency had a particularly negative impact on dermatological care and practice [8]. this can be explained by the fact that most private and public clinics started to postpone all nonurgent visits and elective surgeries and medical procedures in order to reduce the risk of nosocomial transmissions. although oncologic visits or surgery were guaranteed throughout the pandemic, our survey suggests that there was a significant decrease in daily clinical care of skin cancer patients. the survey revealed an alarming decrease of melanoma diagnosis during the pandemic. it is important to monitor whether this will induce an increase of thicker melanomas in the forthcoming months and years. this is especially relevant for fast-growing melanomas that have been estimated to invade the dermis at a rate of approximately 0.5 mm per month [9]. to overcome this challenge, it is paramount to provide timely care to patients, especially those who have a high risk of developing melanoma. moreover, it would be essential, now more than ever, to increase patient and general practice physician education on early melanoma detection [10]. in this regard, the fight against skin cancer in the covid-19 era should be largely based on 2 important tools, skin self-examination and teledermatology. while there was a worrisome decrease in melanoma or nmsc diagnosis during the months of lockdown, 111/678 participants stated to have seen skin manifestations in confirmed or suspected covid patients, obtaining real-life data quickly from all over the world about the skin manifestations of the sars-cov-2 virus. a majority of cutaneous manifestations of covid-19 have been observed in asymptomatic or symptomatic patients, which means that dermatological clues may help clinicians suspect a covid-19 infection when the symptoms cannot be associated with other causes. the urticarial and morbilliform rash were the most frequent signs followed by acrodermatitis (chilblains); the latter is not typical of the summer months and it should therefore be a warning to suspect covid-19 infection, especially in the pediatric age. other authors have also shown that this sign is more frequent in children [11]. finally, our survey highlights that teledermatology consultations strongly increased during the outbreak. data from this survey demonstrated that, since the beginning of the pandemic, worldwide outpatient activities have been reduced and online dermatological consulting has increased significantly. online consultation can easily be used for dermatological diagnosis, as an initial triage of inflammatory pathologies or suspicious lesions can be identified via a video call with the aim of establishing the need to perform a dermoscopic examination to exclude or confirm a diagnosis. during this time of unexpected and sudden changes and the need of social distancing, teledermatology has made it possible for many dermatologists to take care of patients remotely [12,13], and this tool is certain to be used increasingly in the immediate future. according to the recommendations from the european academy of dermatology and venereology task forces, this is the time to organize and implement teledermatology services [14], in order to manage and care patients with skin lesions that are suspected of malignancy, non-melanoma skin cancer candidates to medical therapy and/or acute or chronic inflammatory cutaneous disorders from the safety of their homes. however, lesions suspected to be malignant should preferentially be managed via face-to-face visit [15]. this study has several limitations to underline: first of all, although the ids community has almost 16,000 members, the response rate was 4.2% (678 responses/16,000 members) despite using a mailing list to reach as many members as possible. at first, it was decided to use 2 versions of the questionnaire, one in english and one in russian; however, in order to avoid terminological bias and to ensure homogeneity of the data collected, only the questionnaires obtained in english were considered, considering that the official language of the ids is english. another limitation was that the terms “acrodermatitis’” and ‘”chilblains” were used synonymously because in the first weeks of the outbreak, when acral manifestations were observed in the pediatric population with the viral infection, there was still no direct correlation with either one of the 2 manifestations. conclusions in conclusion, our study highlights that the outbreak had a negative impact on most dermatology services with a significant reduction in the time spent with patients with chronic disease and with a currently undefined risk of missed melanoma and nmscs. moreover, our study confirms earlier findings a wide range of skin manifestations associated with covid, whereby especially the younger population develops skin lesions. following recommendations may help to close the gap of delayed healthcare for dermatologic patients in the next months: (i) improve accessibility to dermatologic care and the public health service system; (ii) implement prevention campaigns for the early detection of skin cancers; (iii) reactivate the follow-up of patients with melanocytic and nonmelanocytic tumors through reminders (calls, emails) to facilitate diagnostic and therapeutic adherence; and (iv) acrodermatitis, urticarial rash, and morbilliform skin rashes should lead to suspicion of covid-19 infection. 6 research | dermatol pract concept 2021;11(1):e2021153 acknowledgments the authors are thankful to all clinicians who completed the questionnaire. references 1. caldaria a, conforti c, di meo n, et al. covid-19 and sars: differences and similarities. dermatol ther. 2020;33(4):e13395. doi: 10.1111/dth.13395. 2. conforti c, cannavò sp, jafferany m, et al. coronavirus disease 2019: facts and controversies. dermatol ther. 2020;33(4):e13366. doi: 10.1111/dth.13366. 3. abbott lm, miller r, janda m, et al. practice guidelines for teledermatology in australia 2020;61(3):e293-e302. australas j dermatol. doi: 10.1111/ajd.13301. pmid: 32363572. 4. villani a, annunziata mc, abategiovanni l, fabbrocini g. teledermatology for acne patients: how to reduce face-to-face visits during covid-19. j cosmet dermatol. 2020;19(8):1828. doi: 10.1111/jocd.13519. pmid: 32490578. 5. piccolo v, bassi a. acral findings during the covid-19 outbreak: chilblain-like lesions should be preferred to acro-ischemic lesions. j am acad dermatol. 2020;83(3):e231. doi: 10.1016/j. jaad.2020.05.077. pmid: 32446827. 6. recalcati s. cutaneous manifestations in covid-19: a first perspective. j eur acad dermatol venereol. 2020;34(5):e212–e213. doi: 10.1111/jdv.16387 7. conforti c, zalaudek i, giuffrida r, et al. “covid-mask”: an atypical livedoid manifestation of covid-19 observed in a northern italy hospital. dermatol ther. 2020;33(4):e13701. doi: 10.1111/dth.13701 8. gisondi p, piaserico s, conti a, naldi l. dermatologists and sars-cov-2: the impact of the pandemic on daily practice. j eur acad dermatol venereol. 2020;34(6):1196-1201. doi: 10.1111/ jdv.16515. pmid: 32320091. 9. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol. 2006;142(12):1551–1558. doi: 10.1001/ archderm.142.12.1551. 10. conforti c, giuffrida r, di meo n, zalaudek i. management of advanced melanoma in the covid-19 era. dermatol ther. 2020;33(4):e13444. doi: 10.1111/dth.13444. 11. piccolo v, neri i, filippeschi c, et al. chilblain-like lesions during covid-19 epidemic: a preliminary study on 63 patients. j eur acad dermatol venereol. 2020;34(7):e291-e293. doi: 10.1111/ jdv.16526. 12. villani a, scalvenzi m, fabbrocini g. teledermatology: a useful tool to fight covid-19. j dermatolog treat. 2020;31(4):325. doi: 10.1080/09546634.2020.1750557. pmid: 32238000. 13. perkins s, cohen jm, nelson ca, bunick cg. teledermatology in the era of covid-19: experience of an academic department of dermatology. j am acad dermatol. 2020;83(1): e43-e44. doi: 10.1016/j.jaad.2020.04.048. pmid: 32305442. 14. eadv task force recommendations. accessed january 5, 2021. available online at: https://eadv.org/covid-19/task-force 15. conforti c, giuffrida r, vezzoni r, resende fss, di meo n, zalaudek i. dermoscopy and the experienced clinicians. int j dermatol. 2020;59(1):16-22. doi: 10.1111/ijd.14512. pmid: 31222814. 16. giuffrida r, conforti c, di meo n, deinlein t, guida s, zalaudek i. use of noninvasive imaging in the management of skin cancer. curr opin oncol. 2020;32(2):98–105. doi: 10.1097/ cco.0000000000000611. pmid: 31850969. dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022014 1 penile exogenous pigmentation mimicking melanoma sabina vaccari1, michelangelo la placa1, alessia barisani1, rossella lacava1, cosimo misciali1, giulio tosti2, valeria gaspari1 1 dermatology – irccs policlinico di sant’orsola, department of experimental, diagnostic and specialty medicine (dimes) – alma mater studiorum university of bologna, italy 2 division of melanoma surgery, sarcoma and rare tumors, irccs, istituto europeo di oncologia, milan, italy key words: penis, mucosal, exogenous, pigmentation, melanoma citation: vaccari s, la placa m, barisani a, et al. penile exogenous pigmentation mimicking melanoma. dermatol pract concept. 2022;12(1):e2022014. doi: https://doi.org/10.5826/dpc.1201a14 accepted: may 6, 2021; published: january 2022 copyright: ©2022 vaccari et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: alessia barisani, md, dermatology – irccs policlinico di sant’orsola, department of experimental, diagnostic and specialty medicine (dimes) – alma mater studiorum university of bologna, italy. email: alessiabarisani@gmail.com introduction the diagnosis of mucosal pigmented lesions can be challenging, as several differential diagnoses, including benign nevi, melanosis, melanoma, as well as post-inflammatory and physiological pigmentations, should be acknowledged. we report a case of penile exogenous pigmentation clinically and dermoscopically mimicking a malignant melanoma. case presentation a 65-year-old caucasian man was referred to our attention because of an asymptomatic flat pigmented lesion of the penis. he reported that the lesion had appeared about 6 months earlier. four years before, he had been diagnosed with genital lichen sclerosus and had undergone circumcision. clinical examination revealed a brown pigmented asymmetrical flat lesion with irregular borders on the glans and the adjacent shaft (figure 1a). videodermoscopy (fotofinder dermatoscope, fotofinder systems, gmbh) showed a multicomponent pattern with an uneven pigmentation, multiple irregular brown-to-black dots, a blue-whitish veil and polymorphous vessels with some linear vessels at the periphery (figure 1, b and c). the main diagnostic suspicion was penile melanoma, due to the clinical and dermoscopic aspect and the patient’s age; therefore, a skin biopsy was performed for confirmation. histopathological examination revealed epithelium hyperplasia, sclerosis and brownish-black pigment in the superficial chorion, with no evidence of atypical melanocytic proliferation, suggestive of exogenous pigment (figure 2, a and b). immunohistochemistry was negative for s-100 and mart1, excluding a melanocytic neoplasm. on the basis of the histopathological findings, a diagnosis of penile exogenous pigmentation in association with lichen sclerosus was made. we hypothesize that the lesion was a self-induced tattoo, even though the patient, suffering from a psychiatric disorder, did not confirm this hypothesis. 2 research letter | dermatol pract concept. 2022;12(1):e2022014 figure 1. penile exogenous pigmentation in a 65-year-old caucasian man. (a) clinical presentation of the lesion reveals a brown asymmetrical flat lesion with irregular borders. (b) videodermoscopy shows a multicomponent pattern with uneven pigmentation, multiple irregular brown-to-black dots, a blue-whitish veil and polymorphous vessels, circle, original magnification ×20. (c) arrow, original magnification ×60. figure 2. penile exogenous pigmentation: histopathological findings consisting of epithelium hyperplasia, sclerosis and brownish-black pigment in the superficial chorion, with no evidence of atypical melanocytic proliferation. (a) hematoxylin and eosin stain original magnification ×17. (b) hematoxylin and eosin stain original magnification ×32. research letter | dermatol pract concept. 2022;12(1):e2022014 3 on the basis of the histopathological findings, a diagnosis of a penile exogenous pigmentation in association with lichen sclerosus was made. conclusions penile melanoma is a rare entity, and therefore, its dermoscopic features have been described rarely. it may show a multicomponent pattern, multiple colors (brown, black, white, blue, red), a blue-whitish veil, regression structures, and some peripheral streaks [1]. the blue, gray, and white colors and the presence of structureless areas are considered strongly suggestive of mucosal melanoma. although videodermoscopy is a useful tool for the early diagnosis of mucosal melanoma because different colors are more easily detectable in the mucosa than in the skin, in this case it did not prove useful for the diagnosis of a mucosal exogenous pigmentation, which may show the same dermoscopic features. the homogeneous pattern shown on dermoscopy of skin tattoos has been described rarely [2]. the peculiar dermoscopic appearance of the lesion in our patient may be due to its localization on the mucosa; and as in melanoma, dermoscopy allows a better recognition of the colors and the vascular patterns. moreover, the associated lichen sclerosus may have altered the dermoscopic features of the lesion. mucosal hyperpigmentation often requires the exclusion of malignant melanoma by performing histopathological examination, especially when, as in this case, the clinical history is not helpful and diagnosis is often not possible on the basis of the clinical and dermoscopic examination alone. informed consent: written informed consent for publication of his clinical details and clinical images was obtained from the patient. references 1. de giorgi v, grazzini m, massi d, et al. melanoma of the penis: a clinical dermoscopic case study. acta derm venereol. 2010;90(1): 87-88. doi: 10.2340/00015555-0705. pmid: 20107736. 2. anthony ep, godbolt a, tang f, mcmeniman ek. malignant melanoma disguised in a tattoo. australas j dermatol. 2015;56(3):232233. doi: 10.1111/ajd.12219. pmid: 26201372. dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022003 1 dermoscopic features of nevoid hyperkeratosis of the nipple and areola conforti claudio1, dri arianna1, giuffrida roberta2, zalaudek iris1, di meo nicola1 1 dermatology clinic, university of trieste, maggiore hospital, piazza dell’ospitale 1, trieste, italy 2 experimental dermatology section, division of dermatology, university of messina, messina, italy key words: nevoid hyperkeratosis of the nipple and areola, asymptomatic plaques, hyperpigmented plaque, hyperkeratosis citation: conforti c, dri a, giuffrida r, zalaudek i, di meo n. dermoscopic features of nevoid hyperkeratosis of the nipple and areola. dermatol pract concept. 2022;12(1):e2022003. doi: https://doi.org/10.5826/dpc.1201a03 accepted: april 11, 2021; published: january 2022 copyright: ©2022 conforti et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, university of trieste, trieste, italy. e-mail: claudioconforti@yahoo.com introduction nevoid hyperkeratosis of the nipple and areola (nhna) is a rare benign condition characterized by verrucous, pigmented, and asymptomatic plaques involving the nipples and areolas. only a few cases have been reported in literature since this entity was firstly described in 1923. the etiology is still unknown, but it is hypothesized that it occurs in correlation with hormonal changes because it is more frequent in women during childbearing age, and it worsens during pregnancy. case presentation we present the case of a 27-year-old caucasian woman referred in for consultation to our skin cancer department with a 9-month history of a lesion involving the right nipple and the areola. examination revealed a hyperpigmented plaque of about 35 mm in diameter and with well-defined borders (figure 1b). the lesion was completely asymptomatic, and the patient denied pain, pruritus or discharge. she was otherwise healthy, and breast examination and general physical examination were negative. hair, nails, and mucosal sites were normal. the patient was not on medication, and she was not pregnant. dermoscopic evaluation (×20, dermlite) showed the presence of a homogeneous brown network with some hyperkeratotic areas showing yellow-brown scales (figure 2, a and b). these dermoscopic findings are in accordance with other previous cases of nhna, and the diagnosis was later confirmed performing a biopsy. discussion and conclusions cinotti et al reported that at dermoscopic examination the nhna showed a papillomatous surface with pink homogenous areas, whitish desquamation, red dots, and erosions [1]. mazzella et al reported a peculiar case of nhna resembling a pigmented basal cell carcinoma with multiple blue-gray globules and leaf-like areas [2]. 2 research letter | dermatol pract concept. 2022;12(1):e2022003 in the past, skin biopsy was certainly the most accurate way to make a diagnosis of nhna, but it could create a scar in a delicate and intimate area. histopathological examination of nhna can show variable findings such as acanthosis, hyperkeratosis, papillomatosis, keratin plugging, perivascular infiltrates of cd41 lymphocytes, melanophages and plasma cells in the superficial dermis, and hyperpigmentation of the basal layer and dermal fibrosis [1]. although the histopathological examination remains the gold standard for the diagnosis, sometimes the patient does not accept this option. dermoscopy offers the possibility of making a correct diagnosis without resorting to incisional biopsy, even if standard dermoscopic diagnostic criteria have not been defined yet. the role of dermoscopy is certainly crucial for the differential diagnosis of areola and nipple lesions, which include seborrheic keratosis, acanthosis nigricans, darier disease, epidermal nevus, basal cell carcinoma, bowen disease, paget disease, contact allergic dermatitis, chronic eczema, dermatophytosis, mycosis fungoides, and reticulate papillomatosis. all the above pathologies can be diagnosed well with dermoscopy, and for this reason our case underlines the importance of a dermoscopic evaluation of hyperpigmented or nonpigmented lesions of the areola and nipple to reduce excision rate and increase diagnostic accuracy of special-site lesions. informed consent: written informed consent for publication of her clinical details and clinical images was obtained from the patient. references 1. cinotti e, provvidenziale l, miracco c, rubegni p. treatment of nevoid hyperkeratosis of the areola and nipple with topical tacalcitol: a case report. dermatol ther. 2018;31(4):e12602. doi: 10.1111/dth.12602. pmid: 29624812. 2. mazzella c, costa c, fabbrocini g, et al. nevoid hyperkeratosis of the nipple mimicking a pigmented basal cell carcinoma. jaad case rep. 2016;2(6):500-501. doi: 10.1016/j.jdcr.2016.09.007. pmid: 28004028; pmcid: pmc5161776. figure 1. clinical appearance of the nipples and areolas of a 27-year-old woman. (a) left nipple. (b) right nipple. on the right side a pigmented and asymptomatic plaque involving nipple and areola is showed. figure 2. dermoscopic evaluation (dermlite, 3gen) (magnification x 20). (a) homogeneous brown network with diffuse hyperkeratotic areas showing yellow-brown scales (black arrows). (b) a blue structureless area (black asterisk). dermatology: practical and conceptual commentary | dermatol pract concept 2021;11(1):e2021110 1 dermatology practical & conceptual a practical method to prevent cross-infection when performing dermoscopy mohammed i. aljasser1, 2 1 division of dermatology, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia 2 king abdulla international medical research center, riyadh, saudi arabia key words: pearl, dermoscopy, dermatoscopy, plastic wrap, rubber band, tie, wire, cross-infection, covid-19 citation: aljasser mi. a practical method to prevnt cross-infection when performing dermoscopy. dermatol pract concept. 2021;11(1):e2021110. doi: https://doi.org/10.5826/dpc.1101a110 accepted: june 22, 2020; published: january 29, 2021 copyright: ©2021 aljasser. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: mohammed i. aljasser mbbs frcpc, division of dermatology, king saud bin abdulaziz university for health sciences. p.o. box 3660, riyadh 11481, saudi arabia. email: mj_derma@hotmail.com dermoscopy is a valuable noninvasive diagnostic tool in dermatology. contact dermoscopy is commonly used. due to the potential risk of cross-infection by dermoscopy, several methods have been described to decrease this risk [1]. commercially available disposable plastic covers are excellent for this purpose. however, cost and availability are limiting factors. plastic wrap has been shown to be efficient in preventing transmission of viruses [2]. one disadvantage of this method is the limited flexibility of use. this is especially true when examining multiple body sites where the plastic sheet has to be moved to the next body site. this issue can be resolved by using a small piece of plastic wrap and a rubber band (figure 1). the plastic wrap is firmly stretched over the dermatoscope faceplate then fixed in place with the rubber band (figure 2). alternatively, a metal cable tie can be used (figure 3). after completing the examination, this customized cover can be easily removed and discarded. figure 1. a small piece of plastic wrap and rubber band is required to create a custom dermoscopy faceplate cover. 1378_dp1101a110.indd 11378_dp1101a110.indd 1 1/21/21 10:10 pm1/21/21 10:10 pm 2 commentary | dermatol pract concept 2021;11(1):e2021110 figure 2. the plastic wrap is firmly stretched over the dermatoscope faceplate then fixed in place with the rubber band. figure 3. the plastic wrap can also be fixed in place using a metal cable tie. 1378_dp1101a110.indd 21378_dp1101a110.indd 2 1/21/21 10:10 pm1/21/21 10:10 pm commentary | dermatol pract concept 2021;11(1):e2021110 3 references 1. mun jh, park sm, ko hc, kim bs, kim mb. prevention of possible cross-infection among patients by dermoscopy: a brief review of the literature and our suggestion. dermatol pract concept. 2013;3(4):33-34. doi: 10.5826/dpc.0304a07. pmid:24282661. 2. zampino mr, borghi a, caselli e, et al. virologic safety of polyvinyl chloride film in dermoscopic analysis of mucosal areas. arch dermatol. 2007;143(7):945-946. doi: 10.1001/ archderm.143.7.945. pmid:17638745. 1378_dp1101a110.indd 31378_dp1101a110.indd 3 1/21/21 10:10 pm1/21/21 10:10 pm 1378_dp1101a110.indd 41378_dp1101a110.indd 4 1/21/21 10:10 pm1/21/21 10:10 pm dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022047 1 dermatology practical & conceptual case presentation a 13-year-old female patient was referred to our department for a thoracic lesion present since birth. the physical examination reveals grouped vesicles with clear and hematic content similar to “frog roe”, with a subcutaneous component and a zosteriform distribution (figure 1a). she referred episodes of pain and increased soft tissue associated for a few months ago. the polarized light dermoscopy showed pink lacunae divided by white septa and polymorphic vessels. besides, the “hypopyon sign” was shown inside the lacunae (figure 1b). the magnetic resonance imaging study reported mixed veno-lymphatic vascular malformation. thoracic frog roes with zosteriform distribution leopoldo fernández domper, manuel ballesteros redondo, josé maría martín hernández, esmeralda silva diaz 1 dermatology department, hospital clínico universitario, valencia, spain. citation: fernández domper l, ballesteros redondo m, hernández jmm, silva diaz e. thoracic frog roes with zosteriform distribution. dermatol pract concept. 2022;12(2):e2022047. doi: https://doi.org/10.5826/dpc.1202a47 accepted: july 23, 2021; published: april 2022 copyright: ©2022 fernández domper et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: leopoldo fernández domper, dermatology department, hospital clínico universitario, valencia, spain. avenida blasco ibañez 17, 46010, valencia, spain. e-mail: lfernandezdomper@gmail.com teaching point “hypopyon sign” is referred to the 2 shades of colors inside the lacunae (corresponding to dilated, thin-walled lymphatic vessels located in the papillary dermis) due to the blood deposited at the lower side of them, due to the gravity effect, and it is a well described finding in circumscribed lymphangioma [1,2]. nevertheless, it is useful for the diagnosis of any vascular malformation with lymphatic component, as show in our case. 2 image letter | dermatol pract concept. 2022;12(2):e2022047 references 1. gencoglan g, inanir i, ermertcan at. hypopyon-like features: new dermoscopic criteria in the differential diagnosis of cutaneous lymphangioma circumscriptum and haemangiomas? j eur acad dermatology venereol. 2012;26(8):1023–1025. doi: 10.1111/j.1468-3083.2011.04136.x. pmid: 21645121. figure 1. (a) clinical presentation as grouped vesicles with clear and hematic content similar to “frog roe” with a zosteriform distribution. (b) dermoscopy (polarised, 25x) of reddish lesions showing half-and-half lacunae demonstrating hypopyon-like features. 2. zaballos p, del pozo lj, argenziano g, et al. dermoscopy of lymphangioma circumscriptum: a morphological study of 45 cases. australas j dermatol. 2018;59(3):e189–e193. doi: 10.1111/ajd.12668. pmid: 28752523. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):6 27 case report a 43-year-old female patient presented with clusters of multiple firm, painful, brownish papules and nodules covering the entire lower left limb and extending up to the left flank in a zosteriform arrangement (figure 1a, 1b). dermoscopic examination was performed in five of the papules. one papule revealed a featureless central hypopigmented area with a delicate peripheral network (figure 1c, 1e). in each of the remaining four lesions, we observed the presence of a circular and/or elongated hyperpigmented structure that lacked a well-defined dermoscopic pattern within the hypopigmented central area (figure 1d, 1f). on hematoxylin and eosin histopathologic examination of two excised lesions (figure 2a— corresponding to figures 1c, 1e; figure 2b—corresponding to figure 1d, 1f), a benign mesenchymal neoplasia was observed, consisting of interlacing bundles of smooth muscle cells intermingled with various amounts of collagen bundles in accordance with the diagnosis of cutaneous leiomyoma. furthermore, in figure 2b, the elongation of the rete ridges associated with focal compact hyperkeratosis was also noted. discussion cutaneous leiomyomas are rare benign tumors arising from smooth muscle cells [1]. cutaneous leiomyomas comprise approximately 5% of all leiomyomas. according to their site of origin they can be classified into three types, those derived dermoscopic findings in a patient with multiple piloleiomyomas francisco macedo paschoal, m.d., ph.d.1, gisele gargantini rezze, m.d., ph.d.2 1 dermatology department, abc medical school, são paulo, brazil. 2 cutaneous oncology department, hospital ac camargo, são paulo, brazil. key words: piloleiomyoma, dermascopy citation: paschoal fm, rezze gg. dermoscopic findings in a patient with multiple piloleiomyomas. dermatol pract conc. 2012;2(4):6. http://dx.doi.org/10.5826/dpc.0204a06. received: april 12, 2012; accepted: august 7, 2012; published: october 31, 2012 copyright: ©2012 paschoal et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: francisco macedo paschoal, rua cardoso de almeida, 788—cj. 103, são paulo sp cep 05013-001, brasil. tel.:+55.11.38733105; fax. +55.11.38733437. e-mail: frpasch@uol.com.br. piloleiomyoma can manifest itself as a pigmented lesion and part of the differential diagnosis with other pigmented skin lesions. however, we are not aware of previous descriptions in the literature of the dermoscopic features of piloleiomyoma. this article describes the dermoscopic findings observed in a patient with multiple piloleiomyomas. on dermoscopic evaluation, piloleiomyoma has characteristics similar to dermatofibroma with a thin peripheral pigmented network and central scar-like area. some of the piloleiomyomas analyzed in this patient also presented with hyperpigmented circular and/ or elongated structures within the central hypopigmented area. abstract 28 observation | dermatol pract concept 2012;2(4):6 grouped papules or nodules localized on the trunk and limbs [1]. these tumors are painful on exposure to cold and trauma; pain could result from local pressure by the tumor on cutaneous nerves [3]. the main differential diagnosis consists of other dermal nodular lesions like dermatofibroma, eruptive syringoma, angiolipoma, neurilemoma, endometrifrom the erector pili muscle of hair follicles (piloleiomyomas); those originating from the vascular smooth muscle (angioleiomyomas); and those arising from the smooth muscle of genital skin (dartoic leiomyomas) [1,2]. cutaneous leiomyomas typically present in the second to fourth decade of life as skin-colored or brown-reddish figure 1. (a, b) hyperpigmented papules located on the left lower limb with zosteriform distribution. (c, e) the dermoscopic pattern is similar to that described in dermatofibroma without featureless central hypopigmented area and thin peripheral pigmented network. (d, f) in addition, a hyperpigmented, elongated structure with an ill-defined dermoscopic pattern can also be seen in some of the cases. [copyright: ©2012 paschoal et al.] figure 2. (a, b) histopathology shows interlacing bundles of smooth muscle cells intermingled with various amounts of collagen bundles. (b) the black arrows emphasize elongation of the rete ridges associated with focal compact hyperkeratosis. [copyright: ©2012 paschoal et al.] observation | dermatol pract concept 2012;2(4):6 29 references 1. suzuki hs, cavalin lc, werner b, sato ms, brenner fm. caso para diagnóstico. an bras dermatol 2007;82:190-2. 2. parreira lml, sípoli jm, mercante amc, orfali rl, levites j. caso para diagnóstico. an bras dermatol. 2009;84:197-9. 3. kamoj s, kumar sharma rk, kumar a, chaudhary ss, jain vk. crusted piloleiomyoma with mental retardation: a rare association. indian j dermatol. 2009;54(1):75-6. 4. pacheco ap, ramos amo, rolim mlm, oliveira fm, lopes jg, rocha kf. piloleiomioma múltiplo: relato de caso com diagnóstico diferencial. an bras dermatol. 1995;70:43-6. 5. arpaia n, cassano n, vena ga. dermatofibroma: a case report and personal considerations. dermatol surg. 2004;30(3):421. 6. puig s, romero d, zaballos p, malvehy j. dermoscopy of dermatofibroma. arch dermatol. 2005;141(1):122. 7. arpaia n, cassano n, vena ga. dermoscopic patterns of dermatofibroma. dermatol surg. 2005;31(10):1336-9. 8. de giorgi v, massi d, stante p, carli p. false “melanocytic” parameters shown by pigmented seborrheic keratoses: a finding which is not uncommon in dermoscopy. dermatol surg. 2002;28(8):776-9. 9. yoradjian a, cymbalista nc, paschoal fm. queratose seborreica simuladora de melanoma. surg cosmet dermatol. 2011;3(2)16971. oma, leiomyosarcoma, glomus tumor, eccrine spiradenoma, lipoma and blue nevus [1,4]. although piloleiomyoma is frequently pigmented, it does not frequently enter a clinician’s differential diagnosis when evaluating cutaneous pigmented lesions. moreover, we are not aware of previous dermoscopic descriptions of piloleiomyoma in the literature. dermoscopically, piloleiomyoma presents similar features of dermatofibroma with the central featureless hypopigmented area and a delicate peripheral network 5,6,7]. in addition, we observed the presence of oval and/ or elongated hyperpigmented structures within the central area that, to the best of our knowledge, have not been previously described. we suggest that it may be explained by the presence of focal compact hyperkeratosis that generates a dermoscopic feature similar to the pseudofollicular openings and pseudostreaks seen in pigmented seborrheic keratosis [8,9]. another reason for this feature could be erosions caused by scratching or picking. further observations are necessary to determine if this feature is a characteristic finding in piloleiomyoma. in vivo confocal microscopy could help to elucidate its origin. dermatology: practical and conceptual dermatology practical & conceptual commentary | dermatol pract concept. 2021; 11(4): e2021142 1 virtual dermatological congresses: a chance for equality and diversity in continuous medical education kerasia-maria plachouri1, francesk mulita2, evangelia kalloniati1, sophia georgiou1 1 dermatology department, university general hospital of patras, greece 2 department of surgery, university general hospital of patras, greece citation: plachouri km, mulita f, kalloniati e, georgiou s. virtual dermatological congresses: a chance for equality and diversity in continuous medical education. dermatol pract concept. 2021; 11(4): e2021142. doi: https://doi.org/10.5826/dpc.1104a142 accepted: may 31, 2020; published: september 2021 copyright: ©2021 plachouri et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: kerasia-maria plachouri, university general hospital of patras, rio, greece. email: kerasia.plachouri@hotmail.com despite the unquestionable contribution of in-person dermatological congresses to knowledge sharing and networking, the associated health risk of large-scale social gatherings during the covid-19 pandemic has affected the way we attend congresses, paving the way for digital, platform-based, online conferences [1]. virtual dermatological congresses indeed offer a series of important advantages, such as flexibility in the attendance of multiple pre-recorded or live sessions, quick access to supplementary material, as well as a minimal ecological footprint since long-distance travelling or production of single-use congress material are suddenly out of the picture [2]. another equally significant argument for the realization of virtual meetings, however, is the opportunity for physicians and academics who would normally be excluded from prestigious scientific meetings due to budgetary difficulties, to participate [3]. with very few exceptions, the majority of prominent national or international dermatological conferences involve registration fees that are usually beyond the financial means of participants that reside in low-income or developing countries [4]. even in cases where registration fee waivers or scholarships are available, travel and accommodation costs can constitute a considerable obstacle to some, leading to inequality issues as far as educational opportunities are concerned [4]. online congresses have no accommodation and transportation costs, and even registration fees tend to be reduced compared to in-person events. this represents a plus for financially weaker audiences [3,5]. another important aspect is the fact that the shift of medical congresses towards virtual formats and the reduced costs, can give the chance to lower-income countries researchers or researchers with inadequate funding, to participate to these events, both as attendees and as presenters [6]. thus, together with the enrichment of their educational agenda, underprivileged scientists have the chance to raise attention to their research, potentially paving the way for future funding or international collaborations [6]. after several months of social distancing and impaired educational and scientific activities, the dermatological community is eager to return to the ‘’life as we know it’’ and the traditional in-person meetings with the obvious advantages 2 commentary | dermatol pract concept. 2021; 11(4): e2021142 that accompany them. the pandemic, however, has taught us that digitalization can also serve as a tool to promote equity and diversity among scientists and physicians. it is crucial to acknowledge this valuable lesson and to take appropriate action towards this direction even when this global challenge will be over. examples of such initiatives constitute for instance, the organization of conferences with a dual format, including a virtual platform for audiences that are unable to attend due to unavailability of financial sponsorship. references 1. goldust m, shivakumar s, kroumpouzos g, murrell df, rudnicka l, jafferany m, navarini aa. virtual conferences of dermatology during the covid-19 pandemic. dermatol ther. 2020;33:e13774. doi: 10.1111/dth.13774. 2. jordan cj, palmer aa. virtual meetings: a critical step to address climate change. sci adv. 2020;6:eabe5810. doi: 10.1126/sciadv. abe5810. pmid: 32938670. 3. gupta mp, sridhar j, wykoff cc, yonekawa y. ophthalmology conferences in the coronavirus disease 2019 era. curr opin ophthalmol. 2020;31:396-402. doi: 10.1097/ icu.0000000000000688. pmid: 32740066. 4. arend me, bruijns sr. disparity in conference registration cost for delegates from lowand middle-income backgrounds. afr j emerg med. 2019;9:156-161. doi: 10.1016/j.afjem.2019.01.016. pmid: 31528535. 5. mubin o, alnajjar f, shamail a, shahid s, simoff s. the new norm: computer science conferences respond to covid-19. scientometrics. 2021; 126:1813-1827. doi: 10.1007/s11192020-03788-9. pmid: 33281245. 6. science carrers. virtual scientific conferences open doors to researchers around the world. accessed december 28, 2020. https:// www.sciencemag.org/careers/2020/04/covid-19-forces-conferences-online-scientists-discover-upsides-virtual-format. dermatology: practical and conceptual review | dermatol pract concept. 2021;11(2):e2021040 1 dermatology practical & conceptual dermoscopic features as predictors of braf mutational status and sentinel lymph node positivity in primary cutaneous melanoma nika filipović1, mirna šitum1,2, marija buljan1,2 1 department of dermatology and venereology, university hospital centre sestre milosrdnice, zagreb, croatia 2 department of dermatovenereology, school of dental medicine, university of zagreb, croatia key words: melanoma, braf, sentinel lymph node, dermoscopy citation: filipović n, šitum m, buljan m. dermoscopic features as predictors of braf mutational status and sentinel lymph node positivity in primary cutaneous melanoma. dermatol pract concept. 2021;11(2):e2021040. doi: https://doi.org/10.5826/dpc.1102a40 accepted: november 23, 2020; published: april 12, 2021 copyright: ©2021 filipović et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: nika filipović, md, department of dermatology and venereology, university hospital centre sestre milosrdnice, vinogradska cesta, 29, 10000 zagreb, croatia. email: nikafilipovic07@gmail.com dermoscopy is a diagnostic tool widely used in clinical practice for the detection of skin tumors, especially early stages of melanoma. recent studies have shown that different dermoscopic features are associated with important prognostic parameters of melanoma, such as braf mutational status and sentinel lymph node status. more than half of all melanomas harbor a mutation in the braf oncogene. the current management of advanced-stage melanomas is greatly determined by the presence or absence of a mutation in this gene, as targeted therapy with braf kinase inhibitors is one of the first therapeutic choices for these patients. sentinel lymph node status is one of the most significant predictors of a melanoma patient’s survival. recent studies have shown that different dermoscopic patterns are also associated with sentinel lymph node status. this short article reviews studies that investigated correlations between dermoscopic features, braf mutation status and sentinel lymph node status. abstract introduction melanoma is one of the most aggressive malignant skin tumors, with a rapidly increasing incidence over the course of the past 50 years worldwide, especially in fair-skinned caucasian populations [1]. in 2018, approximately 300,000 new melanoma cases were registered globally [2]. since the identification of braf as an important oncogene in melanoma in 2002 [3], new therapeutic options have been developed and successfully implemented. the braf gene encodes a serine-threonine kinase that is a member of the mapk [mitogen-activated protein kinase] signaling pathway. approximately 50%-60% of melanomas harbor a braf gene mutation, with the most common oncogenic alteration 2 review | dermatol pract concept. 2021;11(2):e2021040 involving codon 600 [3]. a growing body of literature has demonstrated that different patterns of oncogene mutations correlate with different histological and clinical features of melanoma. in particular, there is a higher frequency of braf mutations in melanomas of younger patients, melanomas located on the trunk, lesions of the superficial spreading histological subtype, and melanomas that develop on skin without chronic actinic damage [4-9]. combined targeted therapy with small-molecule inhibitors of mutant braf and down-stream kinase mek (mapk inhibitors), as well as immunotherapy with inhibitors of pd-1 (programmed cell death receptor 1), represent today’s first therapeutical choices for the majority of patients with metastatic melanoma [10]. since this approach has significantly improved overall survival, assessment of braf mutational status in tumor tissue, with standardized molecular methods, is crucial for treatment decisions. furthermore, it has been demonstrated that melanomas harboring braf mutations share certain morphological features detectable with noninvasive diagnostic tools such as dermoscopy [11]. in the past decades, dermoscopy has become a method widely used in clinical practice for detecting skin tumors, especially early stages of melanoma. since braf-mutated melanomas show specific histomorphological features, specific dermoscopic features could be anticipated as well. however, only a few studies with heterogeneous results have been published on the relationship between dermoscopic patterns of melanoma and braf mutational status. as previously mentioned, since the current management of advanced-stage melanomas is greatly determined by the presence or absence of braf mutations, identifying specific dermoscopic features associated with braf mutational status before tumor excision could be of great importance in making further diagnostic and therapeutic decisions. sentinel lymph node (sln) biopsy is a diagnostic procedure used to detect occult regional node melanoma metastases. according to international consensus and the latest american joint committee on cancer classification from 2018 [12], sln biopsy is generally indicated in melanomas with a thickness of 0.8 mm or more, and in lesions with ulceration. so far only sporadic studies regarding the correlation between dermoscopic patterns and sln status have been conducted. therefore, identifying specific dermoscopic features associated with sln positivity could also be of great significance to clinicians in making a diagnostic-therapeutic algorithm for melanoma patients. dermoscopic features and braf mutational status a study by pozzobon et al [13] was one of the first to investigate the correlation between dermoscopic features and mapk mutational status. that study identified a significant association between dermoscopic regression, designated as “peppering”, and braf mutations (or = 1.68; 95% ci, 1.089-2.581, p = .015). in addition, after acral and facial melanomas [which may show different dermoscopic patterns [14,15] were excluded from analysis, the presence of dermoscopic ulceration was also associated with braf mutation status (or = 2.64; 95% ci, 1.032-6.754; p = .032). bombonato et al [16] reported that dermoscopic ulceration and irregular peripheral streaks are positive predictors of braf-mutated melanoma. it is well known that the dermoscopic presence of streaks is a sign of tumor growth and proliferation; in fact, streaks correspond to the presence of peripheral nests of tumor cells. however, they can also be seen in nevi (eg, spitz/reed nevi). on the other hand, the same study showed that the dermoscopic presence of dotted vessels was a negative predictor of braf-mutated melanomas. only 10% of lesions with dotted vessels in that study were braf-mutated melanomas (p = .004). in contrast to the study by pozzobon et al [13], regression in the form of dermoscopic peppering did not correlate with braf-mutated melanomas [16]. fargnoli et al [17] did not identify any significant differences between dermoscopic features of braf-mutated and wild-type melanomas. these authors suggested that the limited number of dermoscopic images was the main limitation of their study. armengot-carbó et al [18] showed a strong association between the presence of blue-white veil in dermoscopy and braf mutations (p = .003). the blue-white veil corresponds to a large nest of intensely pigmented tumor cells located under a thickened epidermis [19-21]. accordingly, histomorphological studies revealed that braf-mutated melanomas had a thicker epidermis and more pigmented cells with a greater tendency to form nests than wild-type melanomas [22,23]. unfortunately, the study by bombonato et al did not report data regarding this important dermoscopic pattern [16]. furthermore, the study by armengot-carbó et al [18] did not show correlation between dermoscopic ulceration, dotted vessels and braf mutational status, as observed before [16]. this could be explained by the fact that, in the study by bombonato et al [16], genetic testing was performed mainly when there was a clinical indication, that is, in predominantly thick melanomas. consequently, there was also a higher mean breslow thickness and higher ulceration frequency, and consequently a higher frequency of dermoscopic ulceration in their study, while in a study by armengot-carbó et al [18] there were no significant differences in breslow thickness or histological ulceration. although the presence of vascularization is in general a sign of tumor invasion and progression, dotted vessels are predominantly found in thin melanomas [24]. this review | dermatol pract concept. 2021;11(2):e2021040 3 could have affected their results due to the predominance of thicker melanomas in the braf-mutated group [16]. in addition, it should be noted that the number of melanomas with dermoscopic ulceration was higher than those with histological ulceration [13,16,25], probably due to the higher sensitivity of dermoscopy, which can detect small peripheral ulcerations not found by histopathology due to sampling techniques [18]. recently, gouillon et al [26] reported an observational study of more than 100 melanomas that were compared dermoscopically and genetically. pseudopods and radial projections were both observed more frequently in braf-mutated melanomas. since these structures can be combined into “irregular peripheral streaks,” these results are concordant with findings reported by bombonato et al [16] and armengot-carbó et al [18]. blue-gray peppering and white scar-like areas, dermoscopic features related to histological regression [27], were also more frequently found in braf-mutated melanomas than in wild-type lesions (p = .044). concordant with the results of armengot-carbó et al [18], blue-white veil was more frequently present in the braf-mutated group (p = .007). additionally, gouillon et al reported for the first time ever the parallel-ridge pattern as a negative predictor of braf mutational status in acral lentiginous melanomas, as it was more frequently found in the wild-type melanoma group (p = .022) [26]. dermoscopic features and sentinel lymph node positivity as metastases from melanoma most frequently develop in lymph nodes, sln biopsy has emerged as a key diagnostic tool for determining whether cancer has spread to the regional lymph nodes. this minimally invasive procedure has successfully replaced elective lymph node dissection in the management of melanoma patients [28,29]. according to several studies, histological features of the primary lesion and sln biopsy are the most significant predictors of a melanoma patient’s survival [30,31]. gonzález-álvarez et al [32] investigated the association between dermoscopic structures and sln status, and found that the presence of an atypical pigmented network was associated with a negative sln. a dermoscopic pigmented network represents pigmented rete ridges histologically, so thicker melanomas lose these rete ridges due to tumor progression and invasion of the dermis. consequently, it is evident that in thick melanomas, where sln biopsy is done, a dermoscopic atypical pigmented network is often not found. on the other hand, the presence of dermoscopic ulceration and blotches [area of homogeneous dark pigmentation] correlated with a positive sln. the presence of a blue-white veil, atypical vessels and regression structures was not significantly correlated to sln status. pagnanelli et al [33] failed to identify any predictive dermoscopic criteria for sln positivity in melanomas thicker than 1 mm. this outcome could be explained by the fact that only 23% of patients studied had melanomas thicker than 1 mm requiring sln biopsy. conclusions even though dermoscopy cannot replace molecular methods and histopathology in determining braf mutational status and sln status, it could be a useful additional diagnostic tool in predicting these melanoma features. different dermoscopic patterns (eg, blue-white veil, ulceration, peppering) have been identified as significant predictors of braf mutational status and sln status, and therefore could be of great significance in making diagnostic-therapeutic algorithms for melanoma patients. however, further studies are needed to investigate these findings and identify other dermoscopic criteria associated with braf mutations and sln positivity. references 1. national cancer institute. 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dermatol. 2015;72(6):10361046.e2. doi: 10.1016/j.jaad.2015.02.1113. pmid: 25819940. 6. liu w, kelly jw, trivett m, et al. distinct clinical and pathological features are associated with the braft1799a(v600e) mutation in primary melanoma. j invest dermatol. 2007;127(4):900-905. doi: 10.1038/sj.jid.5700632. pmid: 17159915. 7. thomas ne, edmiston sn, alexander a, et al. association between nras and braf mutational status and melanoma-specific survival among patients with higher-risk primary melanoma. jama oncol. 2015;1(3):359-368. doi: 10.1001/jamaoncol.2015.0493. pmid: 26146664. 8. garcía-casado z, traves v, bañuls j, et al. braf, nras and mc1r status in a prospective series of primary cutaneous melanoma. br j dermatol. 2015;172(4) 1128-1131. doi: 10.1111/ bjd.13521. pmid: 25385688. 4 review | dermatol pract concept. 2021;11(2):e2021040 9. bauer j, büttner p, murali r, et al. braf mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, 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zalaudek3, zoe apalla1, marco ardigo4, patricia chellini5, natalia cordeiro5, mariana guimaraes5, athanassios kyrgidis6, elizabeth lazaridou1, caterina longo6, elvira moscarella6, ilias papadimitriou1, giovanni pellacani7, elena sotiriou1, efstratios vakirlis1, dimitrios ioannides1 1 first department of dermatology, aristotle university, thessaloniki, greece 2 department of dermatology, second university, naples, italy 3 non-melanoma skin cancer unit, department of dermatology, medical university, graz, austria 4 clinical dermatology department, ifo-san gallicano dermatological institute, rome, italy 5 instituto de dermatologia professor rubem david azulay—santa casa da misericórdia do rio de janeiro, rio de janeiro, brazil 6 skin cancer unit, arcispedale santa maria nuova, reggio emilia, italy 7 department of dermatology, university of modena, modena, italy key words: dermoscopy, psoriasis citation: lallas a, argenziano g, zalaudek i, apalla z, ardigo m, chellini p, cordeiro n, guimaraes m, kyrgidis a, lazaridou e, longo c, moscarella e, papadimitriou i, pellacani g, sotiriou e, vakirlis e, ionnides d. dermoscopic hemorrhagic dots: an early predictor of response of psoriasis to biologic agents. dermatol pract concept 2016;6(4):2. doi: 10.5826/dpc.0604a02 received: june 30, 2016; accepted: july 18, 2016; published: october 31, 2016 copyright: ©2016 lallas et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: aimilios lallas, md, msc, phd, first department of dermatology, aristotle university, thessaloniki, greece. tel.: +302313308882; fax: +302310277979. email: emlallas@gmail.com background: biologic agents are routinely used in the treatment of severe psoriasis. the evaluation of treatment response is mainly based on the physician’s global clinical assessment. objective: to investigate whether dermoscopy might enhance the assessment of response of psoriasis to treatment with biologic agents. methods: patients with severe psoriasis scheduled to receive a biologic agent were enrolled in the study. a target lesion from each patient was clinically and dermoscopically documented at baseline and after one, two and six months. the clinical response was evaluated by the recruiting clinicians at all visits, while dermoscopic images were evaluated by two independent investigators, blinded to the clinical information. chi square test was used for cross-tabulation comparisons, while odds ratios, 95% confidence intervals and p values were calculated using univariate logistic regression. results: overall, there was a significant correlation between clinical response and vessel distribution at all time points: a regular vessel distribution correlated with no response, a clustered distribution with partial response, and the dermoscopic absence of vessels with complete response. the presence of dermoscopic hemorrhagic dots was a potent predictor of favorable clinical response at the subsequent visit at all time points. among lesions initially clinically responding and later recurring, 87.5% displayed dermoscopic dotted vessels despite the macroscopic remission. conclusion: dermoscopy might be a useful additional tool for evaluating the response of psoriatic patients to biologic agents. hemorrhagic dots represent an early predictor of clinical response, while the persistence or reappearance of dotted vessels might predict clinical persistence or recurrence, respectively. abstract 8 research | dermatol pract concept 2016;6(4):2 agent of their choice based on standard clinical procedures, with the choice of drug not being at all influenced by the present study. a target lesion located on the trunk or the extremities was selected from each patient to be documented and monitored. the target lesion could be of any size and lack significant hyperkeratosis. in case all the psoriatic lesions were highly hyperkeratotic, a keratolytic cream, without steroid, was applied one week prior to the enrollment. exclusion criteria were: the previous application of topical treatment, with the exception of the keratolytic cream mentioned above, on the selected lesion or the administration of any systemic agent within the previous three months of enrollment. a clinical and dermoscopic image was captured from the target lesion at baseline visit (t0). follow up visits were scheduled after one month (t1), two months (t2) and six months (t3). during all the follow up visits, a clinical and dermoscopic image of the target lesion was captured. all dermoscopic images were captured with polarized light using dermlite photo system (3gen, san juan capistrano, ca, usa). minimal pressure was applied in order to preserve vessel morphology and to facilitate their visualization. the clinical response of the target lesion was evaluated by the recruiting clinicians in all follow up visits (t1, t2, t3) as: not responding, partially responding or completely remitted, always as compared to the baseline visit. this means that there was the possibility for a lesion to be evaluated as completely responding at a certain time point and partially (or not at all) responding at a later point (recurrence). the dermoscopic images were evaluated by two independent investigators, blinded to clinical information. in case of disagreement, a third investigator was involved. the dermoscopic variables were selected on the basis of available literature on dermoscopy of psoriasis and our initial observation that hemorrhagic dots represent a common finding in psoriatic lesions under treatment with biologic agents [6, 10-12]. an example highlighting the difference between hemorrhagic dots and the typical red dots of psoriasis is shown in figure 1 and several additional examples of hemorrhagic dots in figure 2. during the follow-up visits, the distribution of red dot vessels was assessed as regular (i.e., equally covering all the surface of the lesion), clustered (i.e., grouped arrangement of dotted vessels in some areas of the lesion, while other areas displayed no vessels), or minimal, when only a few (<10) red dots could be seen either isolated or scattered on the lesion surface. white scales are also known as a frequent dermoscopic finding in psoriasis. however, the presence of this criterion was not assessed in our study, since the included lesions were intentionally selected to exhibit minimal scaling, allowing the best possible visualization of the underlying vessels. introduction the induction of biologic agents targeting immunologic alterations of psoriasis significantly changed the management of the disease. with gathering evidence and experience on their safety and efficacy, these agents acquired an important role in the management of psoriatic patients, and their use expanded worldwide [1]. the assessment of response to treatment with biologics is mainly based on the calculation of the pasi score, which is almost universally used in studies and clinical trials [2]. in daily practice, the application of pasi score is restricted by its complexity, and the routine evaluation of treatment is typically based on the physician’s global assessment and the patient’s perspective, which is typically quantified with the dlqi form [2,3]. dermoscopy represents an easily applicable clinical diagnostic method of well-documented value for the diagnosis of skin tumors [4]. in addition, dermoscopy has been shown to be a valuable tool for monitoring response of skin cancer to topical treatment, especially after the application of nonsurgical modalities [5]. this is because it allows the visualization of alterations occurring in sub-macroscopical structures as a result of the applied treatment. more recently, the application of dermoscopy expanded also to the field of inflammatory and infectious skin diseases [6-9]. there is mounting evidence that dermoscopy enhances the differential diagnosis between psoriasis and other inflammatory dermatoses, such as dermatitis, lichen planus and pityriasis rosea [6]. furthermore, it has been assumed that dermoscopy might also be useful for monitoring the response of psoriasis to systemic drugs by providing early signs of response to treatment and by revealing residual disease or recurrence before it becomes clinically evident [8]. undoubtedly, such beneficial results of dermoscopy would be clinically relevant, providing clinicians early information on disease activity, thereby helping them to optimize patient treatment management. however, this hypothesis has not been tested up to date. the aim of this study was to investigate whether dermoscopic criteria observed in psoriatic lesions of patients under treatment with biologics could improve the assessment of the response to the applied treatment. methods this was a prospective multicentric study conducted in three dermatology centers in greece and italy. patients with severe psoriasis scheduled to receive a biologic agent were enrolled in the study. during the time period of the study, which was between september 2013 and june 2015, the four available biologic agents were adalimumab, etanercept, infliximab and ustekinumab. involved clinicians were free to administer the research | dermatol pract concept 2016;6(4):2 9 ulation comparisons. we used spearman’s rho coefficient to flag significant correlations, which were subsequently quantified. odds ratios (or), 95% confidence intervals (ci), and p values were calculated using univariate logistic regression with categorical coding. alpha level was set at 0.05. statistical analyses were performed using the ibm spss 23.0 package (ibm spss statistics for windows, version 23.0, armonk, ny, ibm corp). statistical analysis the patients’ sex, drug administered, lesion location, clinical response (no response, patial response or complete response), vessel distribution (regular, clustered, minimal or none) and the presence of the purpuric dots were the variables used. absolute and relative frequencies for all variables were obtained. non-parametric pearson’s chi square test was used for cross-tabfigure 1. the difference between red dots and hemorrhagic dots. (a) the red dots (dotted vessels) of psoriasis before treatment. (b) hemorrhagic dots in a psoriatic plaque under treatment. (c) red dots (squares) and hemorrhagic dots (circles) in psoriatic lesion under treatment. [copyright: ©2016 lallas et al.] results overall, 92 individuals were enrolled at baseline. of them, nine patients were lost at follow-up before completing the designed study period, while in eight patients the treatment was terminated or changed because of adverse events. of 75 finally included patients, 34 were men (45.3%) and 41 women (54.7%). mean age at baseline was 48.7 years and did not differ significantly between genders. of 75 target lesions, 45 were located on the trunk (60.0%) and 30 on an extremity (40.0%). the administered drugs were adalimumab in 31 patients (41.3%), etanercept in 20 patients (26.7%), infliximab in 11 patients (14.7%) and ustekinumab in 14 patients (17.3%). no clinical response of the target lesion after one month of treatment was seen in 29 patients (38.7%), partial response in 34 (45.3%) and complete response in 12 patients (16%). after two months of treatment, the clinical response of the target lesion was assessed as absent in 16 patients (21.3%), partial in 31 patients (41.3%) and complete in 28 patients (37.3%). finally, after six months of treatment, 11 target lesions (14.7%) were assessed as not responding, 23 (30.7%) as having responded partially and 41 (54.7%) as having remitted completely. during the study, clinical recurrence was detected in 8 target lesions, meaning that these plaques were assessed as completely responding at a time point and partially or not responding at a later point. at baseline visit, all included lesions dermoscopically exhibited red dots distributed regularly and densely all over the surface of the lesion, while purpuric dots were present only in one case. the results of the dermoscopic analysis at all follow up visits are shown in table 1. results of the clinical and dermoscopic analysis at follow-up visits overall, there was a significant correlation between clinical response and vessel distribution at each time point figure 2. examples of hemorrhagic dots. their presence was strongly associated with a subsequent clinical response to treatment. [copyright: ©2016 lallas et al.] 10 research | dermatol pract concept 2016;6(4):2 dots at one time point and the clinical response at following time points of the study. in particular, we investigated the association between the presence of hemorrhagic dots at t1 and clinical response at t2 and t3, as well as the presence of hemorrhagic dots at t2 and the clinical response at t3. after multivariate regression, the presence of hemorrhagic dots at t1 posed 20-fold higher odds for partial response at t2 (or=20.125, 95%ci: 3.73-108.62, p<0.001) and 10-fold higher odds for complete response at t2 (or=20.818, 95%ci: 2.05-57.15, p=0.005). in addition, lesions displaying hemorrhagic dots at t1 had an 8-fold (figure 3). in detail, at all time points, a regular vessel distribution correlated with no response, a clustered distribution with partial response, and the dermoscopic absence of vessels with complete response (t1: spearman’s rho = -0.755, p<0.001; t2: rho=-0.677, p<0.001; t3: rho=-0.746, p<0.001). notably, 7 of 8 recurring lesions lacked a clinical-dermoscopic correlation, because at the visit when they were clinically assessed as completely responding, they displayed minimal or clustered vessels dermoscopically. several analyses were performed to investigate the possible correlation between the presence of hemorrhagic table 1. results of the clinical and dermoscopic analysis at follow-up visits. [copyright: ©2016 lallas et al.] dermoscopic criteria t1 (1 month) t2 (2 months) t3 (6 months) clinical response none partial complete 29 (38.7%) 34 (45.3%) 12 (16.0%) 16 (21.3%) 31 (41.3%) 28 (37.3%) 11 (14.7%) 23 (30.7%) 41 (54.7%) vessel distribution regular clustered minimal none 31 (41.3%) 21 (28.0%) 15 (20.0%) 8 (10.7%) 14 (18.7%) 19 (25.3%) 22 (29.3%) 20 (26.7%) 16 (21.3%) 14 (18.7%) 17 (22.7%) 28 (37.3%) purpuric dots 42 (56.0%) 31 (41.3%) 5 (6.7%) figure 3. at follow-up visits: (a) dermoscopy of lesions clinically assessed as non-responding usually revealed a regular distribution of red dots. (b) a strong association was found between partial clinical response and a clustered vessel arrangement in dermoscopy. (c) a complete clinical response was typically associated with a complete dermoscopic disappearance of vessels. [copyright: ©2016 lallas et al.] higher probability for partial response a t t 3 ( o r = 8 . 4 3 7 , 9 5 % c i : 1 . 4 6 48.85, p=0.017) and a 7-fold higher probability for complete response at t3 (or=7.031, 95%ci: 1.34-36.82, p=0.021). similarly, the presence of hemorrhagic dots at t2 was associated with a 11-fold higher probability for partial response at t3 (or=10.91, 95%ci: 1.19-99.68, p=0.034) and an 8-fold higher probability for complete response at t3 (or=8.636, 95%ci: 1.01-73.79, p=0.021). notably, due to limited sample size, we were not able to adequately quantify the latter associations within each subgroup of the four different drugs used. however, our descriptive results indicate that the predictive effect of hemorrhagic dots is not influenced by the administered drug. finally, no other parameter, including age, sex and location of the lesion, was significantly correlated with re sponse at any time. discussion our results suggest that dermoscopy is useful in assessing and predicting treatment response of psoriatic lesions to treatment with biologic agents. specifically, the appearance of dermoscopic hemorrhagic dots represents an early predictor of clinical response to treatment, while reappearance of dotted vessels correlate with disease recurrence (figures 4 and 5). undoubtedly, the assessment of disease’s response to treatment with biologic agents is based on the overall clinical examination. pasi score is the most commonly used tool for evaluating the disease severity and is almost universally used in studies and clinical trials [2]. however, pasi reduction has been shown to correlate poorly with the patient’s perception of treatment success [3]. effectively, in clinical practice, the evaluation of treatments and the decision for subsequent therapeutic plans are based on a more global assessment research | dermatol pract concept 2016;6(4):2 11 the previous failure of a biologic agent was shown to represent a negative predictor of survival of the subsequent drug [3]. considering the latter, as well as the limited range of biologic agents for severe psoriasis, developing and adopting strategies aiming to prolong the survival of these agents is considered one of the major goals for the near future. in this context, any reliable additional and early information on the disease activity and its response to treatment would be by the physicians in conjunction with the patient’s perspectives and satisfaction. the high efficacy of biologic agents significantly altered the perspectives of both clinicians and patients for therapeutic success. however, all biologic agents have been associated with treatment discontinuation in a considerable proportion of patients, with ineffectiveness and loss of efficacy being the commonest reasons [3,13-16]. furthermore, very useful for clinicians in optimizing therapeutic plans. the dermoscopic pattern of psoriasis has been adequately investigated, with regularly distributed dotted vessels known to represent the dermoscopic hallmark of the disease [6,10]. specifically, it has been demonstrated that all psoriatic plaques regularly display distributed dotted vessels, even when located on specific body sites such as the scalp, palms/soles and folds [10]. the universal presence of dotted vessels in psoriatic plaques has led to the suggestion that the absence of such a vascular pattern should exclude the diagnosis of psoriasis [9]. in addition, dermoscopy has been assessed as an accurate method to differentiate psoriasis from the erythematosquamous skin diseases, such as dermatitis, lichen planus and pityriasis rosea [6]. although the latter data suggest that dermoscopy might be useful for recognizing clinically atypical psoriasis, this might not be clinically relevant for patients with moderate-to-severe disease, where the clinical diagnosis is usually straightforward, based on the typical morphology and distribution of skin lesions. however, our findings indicate that when these patients are treated with biologic agents, dermoscopy might provide useful information on the response to treatment and the disease activity. in detail, the appearance of hemorrhagic dots was shown to represent an early predictor of subsequent clinical response at all time points of our study. this finding might help clinicians to predict a favorable response to treatment even before clinical improvement appears or to expect a further improvement of lesions partially responding. this might reduce the risk of falsely assessing the drug as inefficacious in patients where clinical response appears later than the average time period. furthermore, our findings provide an initial indication that dermoscopy might enable an early detection of disease recurrence, since all recurring lesions in our study were characterized figure 4. (a) a psoriatic lesion at baseline (t0). (b) no clinical response is observed after one month of treatment (t1). however, dermoscopy reveals numerous hemorrhagic dots. (c) one month later (t2), the lesion has clinically and dermoscopically remitted completely. figure 5. (a) a psoriatic lesion at baseline (t0). (b) after two months of treatment (t2), the lesion was clinically assessed as completely remitted. however, dermoscopy did not reveal the expected complete disappearance of vessels. (c) after four months (t3), the lesion had also recurred clinically. [copyright: ©2016 lallas et al.] 12 research | dermatol pract concept 2016;6(4):2 criteria for the diagnosis of psoriasis, dermatitis, lichen planus and pityriasis rosea. br j dermatol 2012;166(6):1198-1205. pmid: 22296226. doi: 10.1111/j.1365-2133.2012.10868.x. 7. lallas a, argenziano g. dermatoscope—the dermatologist’s stethoscope. indian j dermatol venereol leprol 2014;80(6):4934. pmid: 25382503. doi:10.4103/0378-6323.144141. 8. lallas a, zalaudek i, argenziano g, et al. dermoscopy in general dermatology. dermatol clin 2013;31(4):679-94. pmid: 24075553. doi: 10.1016/j.det.2013.06.008. 9. lallas a, giacomel j, argenziano g, et al. dermoscopy in general dermatology: practical tips for the clinician. br j dermatol 2014;170(3):514-26. pmid: 24266695. doi: 10.1111/ bjd.12685. 10. lallas a, apalla z, argenziano g, et al. dermoscopic pattern of psoriatic lesions on specific body sites. dermatology 2014;228(3):250-4. pmid: 24556706. doi: 10.1159/000357914. 11. lallas a, apalla z, tzellos t, lefaki i. dermoscopy in clinically atypical psoriasis. j dermatol case rep 2012;6(2):61-2. pmid: 22826724. doi: 10.3315/jdcr.2012.1102. 12. vazquez-lopez f, kreusch j, marghoob aa. dermoscopic semiology: further insights into vascular features by screening a large spectrum of nontumoral skin lesions. br j dermatol 2004;150(2):226-31. pmid: 14996092. doi: 10.1111/j.13652133.2004.05753.x 13. gniadecki r, kragballe k, dam tn, skov l. comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. br j dermatol 2011;164(5):1091-6. pmid: 21219290. doi: 10.1111/j.1365-2133.2011.10213.x. 14. menting sp, sitaram as, bonnerjee-van der stok hm, de rie ma, hooft l, spuls pi. drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-centre database analysis. br j dermatol 2014;171(4):875-83. pmid: 24673245. doi: 10.1111/bjd.13001. 15. esposito m, gisondi p, cassano n, et al. survival rate of antitumour necrosis factor-a treatments for psoriasis in routine dermatological practice: a multicentre observational study. br j dermatol. 2013;169(3):666-72. pmid: 23647206. doi: 10.1111/ bjd.12422. 16. van den reek jmpa, van lümig ppm, driessen rjb, et al. determinants of drug survival for etanercept in a long-term daily practice cohort of patients with psoriasis. br j dermatol 2014;170(2):415-24. pmid: 24117023. doi: 10.1111/ bjd.12648. by a lack of clinical-dermoscopic correlation. specifically, although clinically assessed as completely responding, they dermoscopically displayed dotted vessels (minimal or in clusters). indeed, at the subsequent visit they recurred also clinically. an early recognition of disease recurrence might be particularly relevant, since strategies to reinforce the drug efficacy do exist. in conclusion, our results provide an initial indication that dermoscopy might be useful for evaluating the response of psoriatic patients to biologic agents. hemorrhagic dots represent an early predictor of subsequent clinical response, while the persistence or reappearance of dotted vessels might predict a subsequent clinical recurrence. this information might improve the assessment of disease activity and serve the goal of prolonging the survival of biologic agents. references 1. rustin mha. long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. br j dermatol 2012;167 suppl 3:3-11. pmid: 23082810. doi: 10.1111/j.1365-2133.2012.11208.x. 2. pathirana d, ormerod ad, saiag p, et al. european s3-guidelines on the systemic treatment of psoriasis vulgaris. j eur acad dermatol venereol 2009;23 suppl 2:1-70. pmid: 19712190. doi: 10.1111/j.1468-3083.2009.03389.x. 3. gniadecki r, bang b, bryld le, iversen l, lasthein s, skov l. comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. br j dermatol 2015;172(1):244-52. pmid: 25132294. doi: 10.1111/bjd.13343. 4. zalaudek i, lallas a, moscarella e, longo c, soyer hp, argenziano g. the dermatologist’s stethoscope—traditional and new applications of dermoscopy. dermatol pract concept 2013;3(2). pmid: 23785649. doi: 10.5826/dpc.0302a11. 5. apalla z, lallas a, tzellos t, et al. applicability of dermoscopy for evaluation of patients’ response to nonablative therapies for the treatment of superficial basal cell carcinoma. br j dermatol 2014;170(4):809-15. pmid: 24283541. doi: 10.1111/ bjd.12749. 6. lallas a, kyrgidis a, tzellos tg, et al. accuracy of dermoscopic dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3):e2021054 1 sudden onset acral pigmented macules: an innocuous diagnosis rashmi jindal, payal chauhan, robin chugh department of dermatology, venereology & leprosy, himalayan institute of medical sciences, swami rama himalayan university, dehradun, uttarakhand key words: cydnidiae, burrowing, acral, pigmented, macules citation: jindal r, chauhan p, chugh r. sudden onset acral pigmented macules: an innocuous diagnosis. dermatol pract concept. 2021;11(3):e2021054. doi: https://doi.org/10.5826/dpc.1103a54 accepted: december 5, 2020; published: july 8, 2021 copyright: ©2021 jindal et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rashmi jindal, professor at department of dermatology, venereology & leprosy, himalayan institute of medical sciences, swami ram nagar, doiwala, dehradun, india. email: rashmijindal98@gmail.com case presentation a 60-year-old healthy man presented with sudden onset of asymptomatic, brown-black macules over his feet soles. lesions were randomly distributed with relative sparing of instep, pinpoint to a few millimeters in size, non-blanchable, and non-tender (figure 1). attempts to wipe them off with alcohol swab were unsuccessful. dermoscopy (dermlite dl200 hybrid, x10, 3gen, san juan capistrano, california) revealed streaks of orange-brown pigment with ridge enhancement (figure 2). the patient had the habit of walking barefoot in his dairy shop, surrounded by ample foliage, and had noticed low flying winged insects during this rainy season. a final diagnosis of cydnidae (burrower bug) pigmentation was established, supported by a history of sudden onset of asymptomatic lesions and dermoscopic examination. teaching point pigmented macules have been previously reported in india due to burrower bug chilocoris spp (family, cydnidae; superfigure 1. multiple non-blanchable and non-tender brown-black macules over soles. 2 image letter | dermatol pract concept. 2021;11(3):e2021054 family, pentatomoidea) [1,2]. these otherwise innocuous bugs live inside the soil, feed on the roots of underground plants, and release an orange-brown pigmented substance as a defense mechanism, that stains the skin when accidentally crushed. the pattern of streaks with ridge enhancement is due to seeping of this pigmented substance into the ridges of feet soles as replicated by application of a drop of black fountain pen ink (figure 3). to the unwary, these pigmented macules may cause concern and could appear associated with syndromic lentiginosis or a viral hemorrhagic fever manifestation, resulting in unnecessary investigations. references 1. malhotra ak, lis la, ramam m. cydnidae (burrowing bug) pigmentation: a novel arthropod dermatosis. jama dermatol 2015;151:232-3. doi: 10.1001/jamadermatol.2014.2715. pmid: 25353259 2. laad g, shah s, inamadar ac. sudden-onset reddish-brown macules on the palms and soles of two children. pediatr dermatol 2017;34:605-6. doi: 10.1111/pde.13220. pmid: 28884912 figure 2. streaks of orange-brown pigment with ridge enhancement on dermoscopy (dermlite dl2 hybrid, x 10). figure 3. replication of ridge enhancement with black fountain pen ink on dermoscopy. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022049 1 tildrakizumab: successful response in two patients with psoriatic arthritis dario buononato1, gaetano licata1, alessio gambardella1, alina de rosa1, giulia calabrese1, giuseppe argenziano1 1 dermatology unit, department of mentals and physical health and preventive medicine, university of campania luigi vanvitelli, naples, italy. key words: psoriatic arthritis, psoriasis, tildrakizumab, treatment citation: buononato d, licata g, gambardella a, de rosa a, calabrese g, argenziano g. tildrakizumab: successfull response in two patients with psoriatic arthritis. dermatol pract concept. 2022;12(2):e2022049. doi: https://doi.org/10.5826/dpc.1202a49 accepted: july 22, 2021; published: april 2022 copyright: ©2022 buononato et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dario buononato, md, department of dermatology university of campania “luigi vanvitelli” via sergio pansini, 5, 80131 napoli, italy. e-mail: dario.buononato@gmail.com introduction psoriatic arthritis (psa) is a chronic, immune-mediated, inflammatory arthropathy that develops in up to 30% of patients with psoriasis. different phenotypes are recognized according to the joints involved: distal interphalangeal predominant, asymmetric oligoarticular, symmetric polyarthritis, spondylitis and arthritis mutilans. the treatment of psa includes different therapeutic strategies: conventional disease modifying antirheumatic drugs (dmards) and biologic therapies such as tumor necrosis factor (tnf) inhibitors, interleukins-17 (il-17) inhibitors, il-12/23 inhibitor. however not all agents used for psoriasis are yet approved for psa including il-23 inhibitors: there are several cases of psa successfully treated with il-23 inhibitors. case presentation we report 2cases of patients with psa and psoriasis (table 1) who successfully responded to tildrakizumab, an anti-il-23 antibody approved only for psoriasis. in the first case a 45-year-old man came to our unit with a 10 years history of psa and psoriasis. the patient presented several episodes of dactylitis with radiologically documented damage to the distal interphalangeal joints. he had been treated with methotrexate (20 mg/week) for 9 months, suspended for a significant increase in transaminases (alt 110 u/l, ast 121 u/l). we started treatment with secukinumab (300 mg sc monthly) from october 2018 to november 2019 with a partial improvement of psa and skin disease, but the patient developed upper respiratory tract infection and the drug was stopped. thus, the patient received tildrakizumab at the same dosage regimen as in psoriasis (100 mg sc every 12 weeks) with improvement in both diseases. in the second case a 56-year-old woman came to our unit with a 15 years history of psa and psoriasis. the patient suffered from peripheral asymmetric oligoarticular arthritis associated with bilateral uveitis, treated periodically with methotrexate (15 mg/week) interrupted because of several relapses. from october 2019 to september 2020, she began therapy with adalimumab (40 mg sc every 2 weeks), then stopped for the appearance of itching and skin rash. given 2 research letter | dermatol pract concept. 2022;12(2):e2022049 the impossibility of carrying out therapy with il-17 inhibitors due to a suspected concomitant ulcerative colitis, we started therapy with tildrakizumab from december 2020, getting a control of psa. conclusions il-23/il-17 cytokines are important players in the pathogenesis of psa. in particular, il-23 stabilizes the th17 phenotype, supporting secretion of il-17 which mediate the epidermal hyperplasia and keratinocyte differentiation. moreover il-23 activates the production of ltb4, exacerbating the synovial inflammation, and induces osteoclast differentiation with bone resorption result [1]. we have demonstrated that tildrakizumab is a valid therapeutic option in patients suffering from psa, as it acts inhibiting the il-23/il-17 axis, the signaling pathway primarily dysregulated in this condition. it has never been described cases of patients with psa and concomitant psoriasis with favorable response to tildrakizumab. recent studies have been published on the approval of guselkumab in psa [2]: considering that il-23 is the same target, also tildrakizumab could be a useful therapeutic option for this affection. further studies are required to evaluate the efficacy and safety of tildrakizumab in larger cohorts of patients to consider this il-23 inhibitor as a new promising treatment option for psa. references 1. nguyen ct, bloch y, składanowska k, savvides sn, adamopoulos ie.. pathophysiology and inhibition of il-23 signaling in psoriatic arthritis: a molecular insight. clin immunol. 2019;206:15-22. doi: 10.1016/j.clim.2018.09.002. pmid: 30196070. pmcid: pmc6401348. 2. boehncke wh, brembilla nc, nissen mj. guselkumab: the first selective il-23 inhibitor for active psoriatic arthritis in adults. expert rev clin immunol. 2021;17(1):5-13. doi 10.1080/1744666x.2020.1857733. pmid: 33251833. table 1. patients clinical details with tildrakizumab treatment for psoriatic arthritis patient 1 patient 2 gender male female age, years 45 56 psoriatic arthritis phenotype distal interphalangeal joints asymmetric oligoarticular joints systemic involvement psoriasis psoriasis uveitis treatment before tildrakizumab methotrexate secukinumab methotrexate adalimumab dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4):e2021091 1 stress and skin: an overview of mind body therapies as a treatment strategy in dermatology rachel graubard1, ariadna perez-sanchez2, rajani katta1,3 1 baylor college of medicine, houston, tx, usa. 2 department of internal medicine, university of texas at san antonio, usa. 3 mcgovern medical school at the university of texas houston, usa. key words: dermatology, stress, cognitive behavioral therapy, mind body therapies, biofeedback citation: graubard r, perez-sanchez a, katta r. stress and skin: an overview of mind body therapies as a treatment strategy in dermatology. dermatol pract concept. 2021;11(4):e2021091. doi: https://doi.org/10.5826/dpc.1104a91 accepted: february 22, 2021; published: september 2021 copyright: ©2021 graubard et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rachel graubard md, baylor college of medicine, houston, tx, usa. email: info@kattamd.com stress has multiple and wide-ranging physiologic and clinical impacts on skin disease. this has led to an interest in mind body therapies as potential adjunct treatments for skin disease. the stress response results in the activation of the endocrine, neurologic, and immune systems, with a resulting cascade of impacts, that are both systemic and cutaneous. the 2 main arms of the stress response are the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. the resultant release of cortisol, catecholamines, and neuropeptides has multiple effects. clinically, these have been shown to increase skin inflammation, increase itching, impair skin barrier function, impair wound healing, and suppress immunity. mind body therapies are those that focus on the interaction between the mind and the body, with the goal to influence physical function and impact health. these have been shown to ameliorate some of the harmful physiologic changes attributed to stress or to reduce harmful behaviors. in some cases, such as with biofeedback, they may also result in beneficial physiologic changes. treatments such as meditation, biofeedback, hypnosis, guided imagery, and others have been evaluated in the treatment of skin disease and have shown some benefits. although randomized controlled trials are limited, these interventions have shown beneficial effects on itching, psychosocial outcomes, and even skin severity. these interventions have been evaluated in diseases such as atopic dermatitis, psoriasis, trichotillomania, and others. given the potential benefits, improvements in psychosocial outcomes, and a low risk profile, referral to qualified practitioners or multidisciplinary clinics should be considered for some patients. abstract 2 review | dermatol pract concept. 2021;11(4):e2021091 introduction research has documented that stress has wide-ranging physiologic and clinical impacts on skin disease [1]. this has led to an interest in mind body therapies (mbts) as potential adjunct therapies in the treatment of skin disease. stress has been defined by the national cancer institute as the body‘s response to physical, mental, or emotional pressure [2]. this stress response may include both conscious and unconscious changes. stress can also refer to an emotional response. cohen et al write that “the psychological stress response is composed of negative cognitive and emotional states and occurs when demands imposed by events exceed a person’s ability to cope”[3]. a number of potential events or circumstances may produce a stress response, these are known as stressors. stress may be either acute or chronic and is determined by an individual’s perception and response to the stressor, rather than inciting circumstances. in dermatology, stress may affect skin in a variety of ways, including physiologic changes or increases in behaviors (such as scratching) that ultimately worsen skin disease. in addition, stress may arise from a skin disorder itself, resulting in a self-perpetuating cycle. a number of mbts have been evaluated for their potential impact on stress and skin disease [4]. this review will describe the potential mechanism of action and evidence for utility in the treatment of skin disease for several mind body medicine (mbm) modalities, including biofeedback, behavioral and cognitive behavioral therapy, meditation, hypnosis, and relaxation therapies. physiologic impact of stress on the skin the skin acts not only as a physical barrier to the external environment, it may outwardly express the manifestations of internal processes. through its network of mechanical and chemical receptors, nerves, musculature, and vasculature, the skin interacts closely with the central nervous system (cns) to respond to both physical and emotional stimuli. the skin is particularly sensitive to the effects of stress, either as the primary detector or the secondary receiver of the central stress response. the stress response results in activation of the endocrine, neurologic, and immune systems, with a resulting cascade of events[5]. the 2 main arms of the stress response are the sympathetic nervous system (sns) and the hypothalamic-pituitary-adrenal (hpa) axis [6]. activation of the sns results in release of the catecholamines norepinephrine and epinephrine. this response is also known as the “fight or flight response” and impacts multiple organ systems. at the level of the hpa axis, stress triggers the hypothalamus to produce corticotropin-releasing hormone (crh), which induces the release of adrenocorticotropic hormone (acth) from the pituitary gland, culminating with the release of cortisol from the adrenal glands. the release of cortisol, catecholamines, and neuropeptides has multiple systemic and cutaneous effects. in a meta-analysis investigating the relationship between psychological stress and the immune system in human subjects, chronic stressors were associated with suppression of both cellular and humoral measures [7]. in human subjects, psychological stress was associated with an increased risk of acute respiratory illness following exposure to viruses, with the dose of stress correlated to risk of infection [3]. the release of neurohormones, neuropeptides, and neurotransmitters from both arms of the stress response impacts the skin [8]. catecholamines may directly impact glands, blood vessels, and smooth muscles, while crh and cortisol have multiple, wide-ranging effects. in addition, the skin is not only a target for mediators; it is also an active participant, specifically via a local hpa axis, peripheral nerves, and skin cells including mast cells, immune cells, and keratinocytes [9]. taken together, mediators released systemically or locally have been shown to upregulate the production of other mediators, such as histamine and serotonin, increase neurogenic inflammation, increase the activation of sensory innervation, and decrease the itch-sensing threshold in itch-specific receptors [10]. these mediators may ultimately increase skin inflammation, increase itching, impair skin barrier function, impair wound healing, and suppress immunity [5,8]. clinical impact on skin disease jafferany categorized the skin conditions affected by stress including psychophysiologic disorders, which are defined as “skin diseases that are precipitated or exacerbated by psychological stress”. these include acne, alopecia areata, atopic dermatitis, psoriasis, rosacea, chronic spontaneous urticaria, and others [11]. clinically, this has been documented in multiple human studies. 2 separate prospective cohort studies reported a significant association between increased stress levels and acne severity [12, 13]. in a review of the effects of psychological stress on wound healing, the majority of studies found that stress was associated with impaired healing or dysregulation of a biomarker associated with wound healing [14]. another category is that of psychological disorders with dermatologic symptoms, such as obsessive-compulsive disorder or anxiety resulting in acne excoriee, trichotillomania, and other disorders. in addition, dermatologic disorders may have associated psychological symptoms, such as anxiety, depression, and other mood disorders related to the presence of chronic eczema, psoriasis, vitiligo and other skin disorders [11]. review | dermatol pract concept. 2021;11(4):e2021091 3 mind body therapies mind-body therapies (mbts) have been defined as therapies that “focus on the interaction between the mind and the body, with the intent to use the mind to influence physical functions and directly affect health” [15]. these therapies may ameliorate some of the harmful physiologic changes attributed to stress. they may also help reduce harmful behaviors. in some cases, such as biofeedback, they may result in beneficial physiologic changes. mbts include meditation, mindfulness-based stress reduction (mbsr), hypnotherapy, biofeedback, guided imagery, and others [15]. these are considered low risk and relatively low cost, and provide mental and physical health benefits [16]. research in the use of these therapies can be challenging, as interventions may overlap or may be combined. although randomized controlled trials are limited, the use of mbts has shown overall benefit for those with skin disorders. in a meta-analysis of psychological interventions for adults with skin disorders, it was noted that these interventions overall had a medium-sized effect on itch/scratch (8 studies) and psychosocial outcomes (17 studies) [17]. a small to medium effect on skin severity was noted (17 studies). when analyzed further, a medium effect was noted for adults with psoriasis and atopic dermatitis as compared to controls [17]. it is important to stress that these therapies are to be considered adjuncts to, and not replacements for, standard medical therapy. as fried and hussain wrote, these are “analogous to corticosteroid-sparing therapy. incorporating these techniques into conventional treatments has demonstrated efficacy in decreasing the amount of medication and ultraviolet exposure necessary to improve symptoms in psoriasis and eczema” [18]. although these are distinct therapies, researchers have noted similarities of underlying principles, such as with hypnosis and meditation. shenefelt stated that both “use natural trance states” [19]. trance is described as a shift of brain waves that can occur naturally, such as when deeply absorbed in an activity or during repetitive strong activity. during trance states, differences are seen in regional cerebral blood flow and eeg patterns as compared with the typical waking state. similarly, relaxation therapies encompass a number of distinct techniques, which have in common the ability to reduce arousal of the sns. it is also recognized that, although discussed separately, these techniques may have overlapping features. for example, “guided imagery and clinical hypnosis have significant overlap, and many studies combine these modalities.” [15]. a number of researchers have developed or studied interventions that combine these methods. jon kabat-zinn developed the mindfulness-based stress reduction program (mbsr), which consists of an 8-week course and home practice. the core of the program centers on meditation practice, guided body scan, and yoga exercises [20]. biofeedback biofeedback involves the use of a device to measure a physiologic parameter, and then using visual, auditory, or tactile cues to make the patient aware. as a patient observes these measurements, they can practice controlling the parameter [21]. the most common types of biofeedback provide information on the ans, and may include peripheral temperature measurements (hands or fingers), heart rate variability (hvr), or galvanic skin resistance (sweat gland activity) [15]. it has been shown that even children may successfully alter these parameters. in an early study, 48 children (5-15 years old) were able to raise and lower their index finger temperature with self-hypnosis and/or biofeedback [22]. clinically, 11 of 14 adults with hyperhidrosis showed clinical improvement 6 weeks after completing biofeedback treatment [23]. in a study of patients with dyshidrotic eczema, 33 patients were trained to successfully decrease skin conductance and showed clinical improvement and decreased anxiety [24]. behavioral therapy and cognitive behavioral therapy habit reversal (hr) is one type of behavioral therapy, used to help reduce habits such as scratching [25]. hr is described as being easy to learn and “essentially a self-directed approach”, although instruction is required [26]. in hr, the main components are awareness (making the patient aware of their own behaviors) and competing response (teaching patients to practice alternate strategies in place of the target behavior). other aspects of this therapy include stimulus control, relaxation training, and recruiting social support [26]. hr has shown success in the treatment of atopic dermatitis as well as repetitive behaviors such as skin picking and hair pulling [27]. 3 randomized controlled trials of hr in atopic dermatitis noted a significant reduction in severity and scratching, although the number of subjects was small and follow-up periods were brief [28]. in a review of studies of psychological interventions, hr was associated with the greatest impact on outcomes for subjects with skin disorders [17]. in 1 trial, use of hr in conjunction with standard therapy led to clinically significant reduction in eczema severity and improved quality of life for up to 1 year [29]. in another, use of hr with potent topical steroids for 3 weeks resulted in significantly improved skin severity in atopic dermatitis as compared to controls [30]. 4 review | dermatol pract concept. 2021;11(4):e2021091 cognitive behavioral therapy (cbt) adds a focus on thought patterns and has shown success in several skin disorders. in cbt, the goal is to alter dysfunctional habits “by interrupting and altering dysfunctional thought patterns (cognitions) or actions (behaviors) that damage the skin or interfere with dermatologic therapy” [31]. both cbt and hr have shown promising results in the treatment of trichotillomania [32]. in psoriasis, patients undergoing an adjunctive cbt program exhibited greater improvement in symptoms’ clinical severity, reduced stress levels, anxiety, and depression compared to patients receiving standard pharmacological treatment alone [33]. in atopic dermatitis, adjunct treatments including cbt or education with cbt led to significantly greater improvements in skin condition and reduction in topical steroid use, as compared to standard medical therapy at 1-year follow-up [34]. meditation meditation has been defined as the practice of “intentional attention training”, and may be achieved via different approaches [15]. meditation practices have been broadly divided into concentrative meditation and mindfulness meditation [35]. in the former, patients are asked to focus their attention on an object, image, or word. in the latter, patients are asked to be mindful of the present moment, with awareness of stimuli but without judgment. in a systematic review of complementary therapies for psoriasis, meditation and guided imagery therapies showed modest efficacy in 3 single-blind randomized controlled trials [36]. kabat-zin evaluated the effects of a mbsr program in patients with moderate to severe psoriasis, in which some patients receive phototherapy alone and others participated in the program by listening to an audio tape during phototherapy for 13 weeks. those in the mbsr group had significantly faster clearing of psoriatic lesions. although promising, post intervention lasted only 1 week, and did have a high dropout rate [37]. in another study, subjects who completed an 8-week mindfulness program in conjunction with their usual therapy reported a significant improvement in both self-reported psoriasis severity and quality of life as compared to controls receiving only usual therapy [38]. hypnosis hypnosis has been defined as “the intentional induction, deepening, maintenance, and termination of the trance state for a specific purpose”[39]. hypnosis creates an altered state of consciousness that renders the mind vulnerable to the power of suggestion. it is believed that through accessing the subconscious mind, an individual’s emotions, behaviors, and physiological responses can be influenced. while it may represent a useful adjunct therapy, it requires access to trained practitioners as well as careful subject selection, as some subjects exhibit greater hypnotic susceptibility than others [40]. hypnosis has been employed in dermatology to reduce pain and pruritus from skin disorders, to reduce procedure-related anxiety, to reduce harmful behaviors, and as an aid for healing skin disease [40, 41]. a trial conducted on atopic dermatitis patients that were refractory to traditional therapies, reported statistically significant improvements in scratching, discomfort, and sleep disturbances, following hypnotherapy with direct suggestions of scratching cessation and skin comfort. in addition, corticosteroid use decreased by 60% at 16 weeks [42]. in a small randomized controlled trial, adults with psoriasis who were highly hypnotizable demonstrated significantly greater improvement in skin severity with hypnotherapy (in conjunction with conventional treatment) as compared to moderately hypnotizable subjects [43]. hypnosis has also been used to help control harmful habits, such as scratching or picking [39]. 3 pediatric patients with trichotillomania responded well, and at 16 months none showed recurrence [44]. hypnosis may also be used as adjunct therapy in the treatment of verruca vulgaris. in 1 interesting trial, 17 patients with bilateral warts were hypnotized and given the suggestion that the warts would improve on one side only. in 3 months, 53% of the experimental group showed resolution on the treated side alone, as compared to no improvement, in a control group receiving no therapy [45]. in another trial, subjects who received hypnotic suggestion showed greater remission of warts than a placebo light treatment or a control group who received no treatment [46]. relaxation therapies that reduce arousal: guided imagery, progressive muscle relaxation, and others activation of the sns at times of stress, leads to a state of physiologic arousal, with increases in heart rate, blood pressure, and other parameters. by contrast, the relaxation response is considered the “physiologic and psychologic opposite of the... stress response” [16]. the relaxation response has been described as a physiological state characterized by decreased arousal of the sns [47], evidenced by a decrease in heart rate and respiratory rate along with an increase in certain brain waves and skin resistance[47]. dr. herbert benson, a pioneer in its clinical applications, describes the relaxation response as a state rather than a specific technique, that can be elicited by multiple methods [47]. several studies have used techniques such as meditation, progressive muscle relaxation, rhythmic breathing, imagery, autogenic training, and others to elicit the response [47]. “physiologically, the techniques are effective in reducing sympathetic reactivity and enhancing parasympathetic activity” review | dermatol pract concept. 2021;11(4):e2021091 5 [18]. it is believed that breathing techniques that focus on a low respiration rate with long exhalations may be a key feature in activating the parasympathetic nervous system, possibly through stimulation of the vagus nerve [48]. one review evaluated the results of 37 studies of interventions that produced a relaxation response. overall, these may be effective in reducing hypertension, insomnia, anxiety, pain, and medication use across multiple populations [49]. a number of relaxation techniques have been studied. also known as “arousal reduction” techniques, these are frequently used in conjunction with other therapies. some of the modalities discussed earlier may also independently result in a relaxation response. ersser et al describe several specific relaxation techniques [25]. progressive muscular relaxation involves tensing different muscles in the body and then releasing the tension, enabling the individual to consciously learn how to release tension. guided imagery is the use of relaxing or calming imagery, invoking all the senses, to help induce a similar feeling in the body [15]. in autogenic training, patients focus on specific parts of their body and use autosuggestions such as “skin calm and pleasantly cool” [34]. a randomized controlled trial studied the effects of progressive muscle relaxation in atopic dermatitis, and found significant decreases in pruritus and loss of sleep as compared to controls after 1 month [50]. in another randomized controlled trial, listening to 20 minutes of guided relaxation (either before or after skin wounding) led to improved skin barrier recovery as compared with a control group [51]. in a small study, children with atopic dermatitis (ages 5-15 years) were treated with hypnotherapy or a biofeedback device based on galvanic skin resistance (as a relaxation technique), and showed significant reduction in severity of surface damage and lichenification as compared with controls [52]. conclusion mbts may be considered as adjunct therapy in the treatment of several dermatologic conditions, including atopic dermatitis, psoriasis, self-induced skin conditions, and others. other indications include during dermatologic procedures [35]. further research is needed to confirm beneficial effects, to determine patient selection, and to delineate mechanisms of action. however, many of these therapies are low risk and referral to experienced practitioners or multidisciplinary clinics should be considered [4]. references 1. colavincenzo ml, granstein rd. stress and the skin: a meeting report of the weill cornell symposium on the science of dermatology. j invest dermatol. 2006;126(12):2560-2561. doi:10.1038/sj.jid.5700565. pmid: 17108900. 2. definition of stress nci dictionary of cancer terms national cancer institute. published february 2, 2011. accessed october 14, 2020. 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patient-centered program based on the relaxation response: the relaxation response resiliency program (3rp). psychosomatics. 2013;54(2):165-174. doi:10.1016/j.psym.2012.09.001. pmid: 23352048. 48. gerritsen rjs, band gph. breath of life: the respiratory vagal stimulation model of contemplative activity. front hum review | dermatol pract concept. 2021;11(4):e2021091 7 neurosci. 2018;12. doi:10.3389/fnhum.2018.00397. pmid: 30356789. 49. mandle cl, jacobs sc, arcari pm, domar ad. the efficacy of relaxation response interventions with adult patients: a review of the literature. j cardiovasc nurs. 1996;10(3):426. doi:10.1097/00005082-199604000-00003. pmid: 8820317. 50. bae bg, oh sh, park co, et al. progressive muscle relaxation therapy for atopic dermatitis: objective assessment of efficacy. acta derm venereol. 2012;92(1):57-61. doi:10.2340/000155551189. pmid: 21879233. 51. robinson h, jarrett p, broadbent e. the effects of relaxation before or after skin damage on skin barrier recovery: a preliminary study. psychosom med. 2015;77(8):844-852. doi:10.1097/ psy.0000000000000222. pmid: 26335334. 52. sokel b, christie d, kent a, lansdown r. a comparison of hypnotherapy and biofeedback in the treatment of childhood atopic eczema. contemp hypn. 1993;10:145-154. dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(1):e2022066 1 “mole removal” on instagram hashtags: a cross-sectional analysis: nevus treatment methods on instagram semih güder1, hüsna güder2 1 department of dermatology, medical faculty, bezmialem vakif university, fatih, istanbul, turkey 2 department of dermatology, medical faculty, maltepe university, maltepe, istanbul, turkey key words: instagram, nevus treatment, plasma energy devices, cauterization, social media, non-physicians practice citation: güder s, güder h. “mole removal” on instagram hashtags: a cross-sectional analysis: nevus treatment methods on instagram. dermatol pract concept. 2022;12(1):e2022066. doi:https://doi.org/10.5826/dpc.1201a66 accepted: september 13, 2021; published: january 2022 copyright: ©2022 güder and güder. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: semih güder, department of dermatology, medical faculty, bezmialem vakif university, fatih, istanbul, turkey. e-mail: semihguder@gmail.com introduction: with the increase in the use of social media, there is a steady increase in demand for medical, surgical, and cosmetic procedures. dermatologists and other physicians are leaving their cosmetic practice to non-physician service providers to keep up with the growing demand for cosmetic procedures. objectives: to examine the gender, professions, and the method of nevi treatment of the profiles using #bensilme and #moleremoval hashtags on instagram and to investigate the extent of cosmetic procedures comparing turkey’s situation with other countries. methods: in instagram, the most frequently used hashtags about nevus treatment were scanned by two dermatologists. we recorded profession, gender, country of origin, and the treatment method of nevi of profiles sharing the related posts. results: the countries with the highest share of the #moleremoval hashtag were the united kingdom (15%), india (12%), and the united states of america (10.5%), and the proportion of physicians in these countries was 16.7%, 100%, and 71.4%, respectively. in the non-physician group, plasma pen method in our country is the most used method (turkey: 97.9%, world: 75% respectively), but the use of radiofrequency cautery (world: 12.5%, turkey: 1% respectively) and cryo pen (world: 7.5%, turkey: 0.0%) methods were significantly more abroad. conclusions: we demonstrated that non-physicians mostly perform nevus destruction procedures. physicians must use social media more actively to share educational, quality, and accurate information. we suggest that the hashtags used by physicians in their social media posts should be chosen from the words used in the folk language. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022066 introduction instagram is a free social networking service for sharing photos and videos [1]. the number of daily users reached 500 million on the platform, which reached 1 billion active users per month in the last month of 2018 [2,3]. hashtags are keywords those social media users utilize to tag their posts. they are used to organize the share content, search and collect data [4,5]. more than 40% of people in the united states use social media to get health information. many people decide to receive healthcare services based on their social media posts [5]. with the increase in social media usage, there is a steady increase in demand for medical, surgical, and cosmetic procedures. this has increased in people applying to nonphysicians for cosmetic procedures and aesthetic medical treatments. dermatologists and other physicians leave cosmetic procedures to non-physician service providers to keep pace with the growing demand for cosmetic procedures. non-physician groups (aestheticians, nurses, doctor assistants, nurse assistants, make-up experts, hairdressers, etc.) harass the specialty of medical science. this situation is directly related to patient health and safety. in addition, patients treated by non-physicians experience more burns and pigmentation problems than patients treated by physicians [6]. this situation is beyond the development of blemishes and burns. melanoma, which is evaluated and destroyed by non-physicians as a simple nevus, can shorten the patient’s life span and increase the treatment costs significantly [7]. while using instagram, we observe non-physicians also do that nevus destruction in our searches related to nevus treatment. we anticipate that such practices performed in incompetent hands may endanger patient health and safety. therefore, we aimed to evaluate the professions of the profile owners and methods by using the most two hashtags related to nevus treatment on instagram. objectives we want to examine the gender, professions, and the method of nevi treatment of the profiles using #bensilme and #moleremoval hashtags on instagram and to investigate the extent of cosmetic procedures comparing turkey’s situation with other countries. in particular, we wanted to investigate the rate of non-physician practices in this regard. methods study design on may 01, 2021, two dermatologists scanned the most frequently used hashtags for nevus treatment on instagram. the most shared hashtags related to nevus treatment. were selected in turkish and english one hundred posts using the #bensilme hashtag in turkish and 100 posts using the #moleremoval hashtag, which may have an english equivalent, were planned to be examined. the analysis was started from current posts to old-dated posts, and especially melanocytic nevus-looking posts were examined. the compatibility of the shared images with melanocytic nevus was determined by the joint decision of the two dermatologists. we ended the study when we reached 100 posts from each hashtag. information on profession, gender, country of origin were collected from the profiles that shared them. the profession information specified in the profiles that share related posts was taken as a basis for the distinction between physicians and non-physicians and for the determination of other professions. in order to determine the professions of the profile owners who did not have information of professions and gave their own website information in their profiles we reached their websites. if information of profession is specified in the “about us” section of the website, we have recorded it. the information on the nevus destruction method used by the practitioners was obtained from the related posts. in data entry, we classified dermatologists and plastic surgeons as physicians. we defined the other specialists as doctors. approval for this study was obtained from the ethics committee of maltepe university faculty of medicine (approval number: 2021/900/69). inclusion and exclusion criteria melanocytic nevi, which have photos or videos both before and after destruction, were selected from publicly accessible posts. the selected posts included gender, profession, and destruction method information in the practitioner’s profile and posts. duplicate profiles and posts missing at least one of the above information were not included in the study. statistical analysis we used the shapiro-francia test to evaluate the compatibility of univariate data to normal distribution. according to quantitative data, the mann-whitney u test was used together with monte carlo results to compare two independent groups with each other. pearson chi-square, fisher exact, and fisher-freeman-holton tests were tested with the monte carlo simulation technique to compare categorical variables. in addition, column proportions were compared and expressed according to benjamini-hochberg corrected p value results. quantitative variables were represented in the tables as mean (± standard deviation) and median (25° and 75° percentile). categorical variables were shown as n (%). variables were analyzed at a 95% confidence level, and a p value of less than 0.05 was considered significant. spss 27.0 (ibm corporation) program was used to analyze variables. original article | dermatol pract concept. 2022;12(1):e2022066 3 results there were 21,711 posts in the #bensilme hashtag and 47,085 posts in the #moleremoval hashtag. the countries with the highest share of the #moleremoval hashtag in the world were the united kingdom (15%), india (12%), and the united states of america (10.5%) (table 1). in our country, 21% of practitioners were male, and 79% were female. abroad, this rate was similar to our country (30% and 70% respectively). we compared physician and non-physician groups in terms of gender. the number of male physicians in the world was significantly higher than in our country (respectively 93.3%-19.0%, p <0.001). there was no physician among female practitioners in our country. table 1. demographic data n % gender male 51 25.5% female 149 74.5% profession esthetician 108 54.0% dermatologist 28 14.0% doctor 21 10.5% hairdresser 18 9.0% plastic surgeon 15 7.5% nurse 5 2.5% masseur 4 2.0% make-up artist 1 0.5% physician / non-physician physician 64 32.0% non-physician 136 68.0% method plasmapen 136 68.0% surgical excision 23 11.5% radiofrequency cautery 18 9.0% laser 16 8.0% electrocautery 4 2.0% cryopen 3 1.5% country turkey 100 50.0% united kingdom 30 15.0% india 24 12.0% united states of america 21 10.5% australia 7 3.5% malaysia 4 2.0% pakistan 3 1.5% indonesia 2 1.0% venezuela 1 0.5% philippines 1 0.5% canada 1 0.5% nepal 1 0.5% russia 1 0.5% spain 1 0.5% table 1 continues 4 original article | dermatol pract concept. 2022;12(1):e2022066 in the non-physician group, the proportion of men in our country was significantly higher than abroad (respectively 81.0%-6.7%, p < 0.001). in the non-physician group, the rate of women in our country was also significantly higher than abroad (100%-54.3%, respectively) (p < 0.001) (table 2). when physicians and non-physicians were compared, 96% of the practices in our country were performed by non-physicians and only 4% were performed by physicians (p < 0.001). abroad, this rate was 60% and 40%, respectively (table 2) (figure 1). the countries that have the most shares of the #moleremoval hashtag abroad were uk, india, and the usa, and the proportion of physicians in these countries was 16.7%, 100%, and 71.4%, respectively (table 3). considering the professions, the rate of estheticians and hairdressers in our country was significantly higher than abroad (81%-27% for estheticians, 14%-4% for hairdressers, respectively). abroad, rate of doctors (18%-3% respectively), dermatologists (27%-1% respectively), plastic surgeons (15%-0.0% respectively), masseurs (4%-0.0% respectively) and nurses (5%-0.0% respectively) were significantly higher than our country (p < 0.001) (table 2), (figure 2). in terms of the method of destruction, plasma pen was significantly higher in our country compared to abroad (96% 40%, respectively). abroad, rate of laser (14%-2%, respectively), surgical excisions (22%-1%, respectively), radiofrequency cauterizations (17%-1%, respectively), and electrocauterizations (4%-0%, respectively) were significantly higher than in our country (table 2), (figure 3). the methods used by the physicians were similar in our country and abroad without significant difference (p = 0.577). in the non-physician group, plasma pen usage is more frequent in our country (turkey: 97.9%, world: 75.0% respectively), but abroad radiofrequency cautery (world: 12.5%, turkey: 1% respectively) and cryo pen (world: 7.5%, turkey: 0.0% respectively) usage were significantly more (p<0.001) (table 2). discussion we wanted to examine the instagram accounts using #bensilme in turkish and #moleremoval hashtags in english regarding gender, professions, and method of destroying nevus of profile owners. we planned this study to n % albania 1 0.5% iran 1 0.5% egypt 1 0.5% turkey / world turkey 100 50.0% world 100 50.0%   mean (sd)  min q1 q2 q3 max follower 8842.03 (23025.14) 59 930 2612 ### 2e+05 sd=standard deviation; q1=percentile 25; q2=percentile 50(median); q3=percentile 75. table 1. demographic data (continued) figure 1. distribution of the professions we have identified in turkey and in the world. (numbers indicate percentages). 90 80 81 27 3 18 1 27 0 15 14 4 0 turkey world 4 0 5 1 0 70 60 50 40 30 20 10 0 esthetician doctor dermatologist plastic surgeon hairdresser masseur nurse make-up artist original article | dermatol pract concept. 2022;12(1):e2022066 5 table 2. statistical analysis   turkey (n=100) n (%) world (n=100) n (%) p gender 0.194 c male 21 (21.0) 30 (30.0)   female 79 (79.0) 70 (70.0)   physician / non-physician <0.001 c physician 4 (4.0) 60 (60.0) a   non-physician 96 (96.0) b 40 (40.0)   male <0.001 c physician 4 (19.0) 28 (93.3) a   non-physician 17 (81.0) b 2 (6.7)   female <0.001 c physician 0 (0.0) 32 (45.7) a   non-physician 79 (100.0) b 38 (54.3)   profession <0.001 ff esthetician 81 (81.0) b 27 (27.0)   doctor 3 (3.0) 18 (18.0) a   dermatologist 1 (1.0) 27 (27.0) a   plastic surgeon 0 (0.0) 15 (15.0) a   hairdresser 14 (14.0) b 4 (4.0)   masseur 0 (0.0) 4 (4.0) a   nurse 0 (0.0) 5 (5.0) a   make-up artist 1 (1.0) 0 (0.0)   methods used by physician’s 0.577 ff plasmapen 2 (50.0) 10 (16.7)   laser 1 (25.0) 13 (21.7)   surgical excision 1 (25.0) 22 (36.7)   electrocautery 0 (0.0) 3 (5.0)   radiofrequency cautery 0 (0.0) 12 (20.0)   methods used by non-physician’s <0.001 ff plasmapen 94 (97.9) b 30 (75.0)   laser 1 (1.0) 1 (2.5)   electrocautery 0 (0.0) 1 (2.5)   radiofrequency cautery 1 (1.0) 5 (12.5) a   cryopen 0 (0.0) 3 (7.5) a   summary of methods <0.001 ff plasmapen 96 (96.0) b 40 (40.0)   laser 2 (2.0) 14 (14.0) a   surgical excision 1 (1.0) 22 (22.0) a   electrocautery 0 (0.0) 4 (4.0) a   radiofrequency cautery 1 (1.0) 17 (17.0) a   cryopen 0 (0.0) 3 (3.0)   follower median (q1/q3) median (q1/q3)   3313 (1850.5 / 7021) 1372 (550 / 8197.5) 0.007 u c=pearson chi-square test (monte carlo); ff=fisher freeman halton test (monte carlo); u= mann whitney u test (monte carlo); q1=percentile 25; q3=percentile 75. a=significance in the world population compared to turkey, b=significance in the turkish population compared to world. 6 original article | dermatol pract concept. 2022;12(1):e2022066 table 3. distribution of physicians and non-physicians in the world n (%) united kingdom india united states of america other countries physician 5 (17) 24 (100) 15 (71) 16 (64) doctor 4 (13.4) 1 (4.2) 4 (19) 9 (36) dermatologist 1 (3.3) 18 (75) 4 (19) 4 (16) plastic surgeon 0 5 (20.8) 7 (33.3) 3 (12) non-physician 25 (83) 0 6 (29) 9 (36) esthetician 17 (56.6) 0 3 (14.3) 7 (28) hairdresser 4 (13.4) 0 0 0 masseur 1 (3.3) 0 2 (9.6) 1 (4) nurse 3 (10) 0 1 (4.8) 1 (4) 120 100 80 60 40 20 0 physician non-physician worldturkey figure 2. distribution of physicians and non-physicians we have identified in turkey and in the world. (numbers indicate percentages). 120 100 80 60 40 20 0 plasmapen 96 40 2 14 1 22 turkey world 0 4 1 17 0 3 laser surgical excision electrocautery radiofrequency cautery cryopen figure 3. distribution of destruction method we have identified in turkey and in the world. (numbers indicate percentages). investigate the extent of non-physician practices and to compare the situation in our country with abroad. as a result of our research, we found that high rates of non-physician practices are performed in our country and overseas to treat nevi. nevus treatment options include total surgical excision, shave excision, lasers, radiofrequency, electrocautery, and cryotherapy. however, the possibility of recurrence is high after non-specific thermal or cold damage methods, and recurrent lesions are confused with atypical melanocytic nevi original article | dermatol pract concept. 2022;12(1):e2022066 7 or melanoma. due to the cosmetic appearance, it is necessary to eliminate the risk of dysplasia and melanoma in the nevus before starting nevus treatment. thus, dermoscopy is a good tool in skilled hands, but it is still a more reliable method to biopsy in doubtful cases. in general, it is accepted that all nevi should be examined histologically as medicolegal. an average of 2.3% of melanocytic nevi considered to be clinically benign was reported as microscopic malignant [8-10]. while methods in which pathological examination cannot be performed are controversial for nevus treatment, it is unacceptable for non-physicians to treat nevus. in terms of professions, the high number of estheticians and hairdressers in our country and in the uk may be because this group uses social media more actively or may prefer #bensilme and #moleremoval hashtags than physicians. on the other hand, the low rate of physicians in our country and the uk may be because physicians in these countries do not use social media actively, or it may also be since the doctor group in these countries use hashtags containing medical words instead of the more preferred hashtags in the spoken language. we have seen that dermatologists produce a small portion of the #bensilme and #moleremoval hashtags posted on instagram. however, in india, no one except the doctor used the #moleremoval disease. this may be since estheticians use more local languages than english, or india has provided this with its laws. there were only physician shares in albania, canada, egypt, iran, nepal, and pakistan, where 1 to 3 shares were examined, but no comment could be made because the number was low. plasma pen use was common in the non-physician group, especially in our country. this may be due to the fact that plasma pen devices are easily accessible, inexpensive, and practical to implement. however, it can also be caused by such devices not being recognized as medical devices. as a result of the application made by the turkish society of dermatology association to our ministry of health, the use of these devices in our country has been legally restricted to physicians only. it is essential to get medical information on social media from reliable sources. because people mainly apply to social media to make a treatment decision. information from unqualified sources can lead to misdirection, unnecessary treatment, and potential harm. for this reason, it is crucial for dermatologists, plastic surgeons, and other physicians to share quality content [11]. some studies in recent years show that instagram is a very suitable platform for educating audiences around the world. it is even recommended that dermatologists be active on social media platforms in order to access evidence-based education resources. however, dermatology specialization programs still do not use social media actively enough [12-15]. wong et al have compiled some suggestions for physicians on how create a professional instagram account. these are as follows: must be an official account, the content must be short and precise, supported with images and videos, must be online frequently, stories and posts must be share regularly, a disclaimer must be prepared for followers with medical concerns, a good patient consent form should be prepared to share patient information [2]. conclusions we have demonstrated that non-physicians widely use nevus destruction procedures. however, wrong only disappears when the right turns out. therefore, we think physicians must use social media more actively and share quality and accurate information. we suggest that physicians in turkey use #bensilme and other related tags in their social media posts on this issue, which may fill the gap in this area. in addition, physicians must share quality information on social media for educational purposes that tissue destruction devices are medical devices and must be used by physicians. data availability statement: data sharing not applicable to this article as no datasets were generated or analyzed during the current study. transparency statement: the lead author (semih güder), affirms that this manuscript is an honest, accurate, and transparent account of the study being reported that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. references 1. braunberger t, mounessa j, rudningen k, dunnick ca, dellavalle rp. global skin diseases on instagram hashtags. dermatol online j. 2017;23(5):13030/qt7sk410j3. pmid: 28537860. 2. wong xl, liu rc, sebaratnam df. evolving role of instagram in #medicine. intern med j. 2019;49(10):1329-1332. doi: 10.1111/ imj.14448. pmid: 31602768. 3. zhou j, bercovitch l. instagram and the dermatologist: an ethical analysis. j am acad dermatol. 2018;78(6):1226-1228. doi: 10.1016/j.jaad.2017.08.036. pmid: 29754890. 4. ashique kt, jayasree p, kaliyadan f. hashtags in dermatology: can we do more? clin exp dermatol. 2020;45(6):754-755. doi: 10.1111/ced.14261. epub 2020 may 24. pmid: 32363595. 5. karimkhani c, connett j, boyers l, quest t, dellavalle rp. dermatology on instagram. dermatol online j. 2014;20(7):13030/ qt71g178w9. pmid: 25046455. 6. rossi am, wilson b, hibler bp, drake la. nonphysician practice of cosmetic dermatology: a patient and 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dellavalle rp. an assessment of social media usage by dermatology residency programs. dermatol online j. 2019;25(1):13030/qt5v62b42z. pmid: 30710898. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021; 11(4): e2021130 1 teledermatology in the control of skin neglected tropical diseases: a systematic review tejas p. joshi1, vicky ren2 1 school of medicine, baylor college of medicine 2 department of dermatology, baylor college of medicine key words: global dermatology, global health, skin neglected tropical diseases, teledermatology, telemedicine citation: joshi tp, ren v. teledermatology in the control of skin neglected tropical diseases: a systematic review. dermatol pract concept. 2021; 11(4): e2021130. doi: https://doi.org/10.5826/dpc.1104a130 accepted: april 25, 2021; published: september 2021 copyright: ©2021 joshi and ren. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: tejas p. joshi, bs, school of medicine, baylor college of medicine, one baylor plaza houston, tx, usa. e-mail: tejas.joshi@bcm.edu introduction: neglected tropical diseases (ntds) include a group of about 20 illnesses that have garnered relatively little attention, despite their ability to inflict significant suffering and disability. skin neglected tropical diseases (sntds) are a subset of ntds that present with cutaneous manifestations and are well known for their ability to generate stigma and promote poverty. teledermatology (td) represents a potential method to control sntds. objective: we sought to analyze the potential for td to ease the burden of sntds. methods: we performed a systematic literature search using the texas medical center library one search, which scans 167 databases, including embase, pubmed, and scopus. we included all original investigations published after 2011 that assessed the impact of td intervention in the control of one or more sntds. we excluded studies not written in english and studies that did not perform any outcome analyses. results: twenty studies met our search criteria, and 18 expressed positive attitudes towards td. overall, we found that td may be a sustainable, cost-effective strategy for expanding access to care for individuals afflicted with sntds. however, poor image quality, lack of access to further diagnostic tests, and ethical, legal, and cultural issues pose as barriers to td utilization. conclusion: td may be helpful in achieving control of sntds but has its limitations. an integrated approach, which employs td in conjunction with other strategies, represents a realistic path for alleviating sntds. abstract 2 review | dermatol pract concept. 2021; 11(4): e2021130 introduction neglected tropical diseases (ntds) include about 20 debilitating illnesses that affect the world’s most indigent, engendering disability, and suffering [1]. as opposed to hiv/aids, tuberculosis, and malaria, ntds have garnered relatively little attention and funding [2]. nonetheless, the burden of ntds is significant, with approximately 1 billion people afflicted, resulting in a loss of roughly 26 million disability-adjusted life-years [3]. skin neglected tropical diseases (sntds) constitute a subset of ntds that present with cutaneous manifestations. as identified by the world health organization (who), they include buruli ulcer (bu), cutaneous leishmaniasis (cl), fungal diseases, leprosy, lymphatic filariasis (lf), mycetoma, onchocerciasis, post-kala-azar dermal leishmaniasis, scabies, and yaws [4]. sntds are particularly stigmatizing and lead to marginalization of afflicted individuals, trapping them in a vicious cycle of poverty and disease progression [5]. teledermatology (td) may be a powerful tool in facilitating the eradication of sntds. in the highly visual field of dermatology, td has been touted as a cost-effective, time-efficient option for care delivery. moreover, td offers 2 flexible models of care: synchronously, over a videoconferencing platform and asynchronously, through photographs sent via online communication tools (store and forward dermatology) [6]. both synchronous and asynchronous td models have been extensively deployed during the coronavirus disease 2019 (covid-19) pandemic, and despite their deficiencies, represent promising paradigms of delivering remote care [7]. as the post-pandemic utilization of td will likely grow, it is important to consider how td can aid in the management of sntds; simultaneously, it is worth keeping in mind the limitations of td. objectives considering the potential for td in the management of sntds, we reviewed the literature for cases in which td was used to manage sntds. when possible, we extracted information regarding patient and physician satisfaction with td, time to receiving a td diagnosis, concordance between td and face-to-face (ftf) diagnoses, clinical outcomes, cost of td consultation, encryption of td platform used, and adequacy of images submitted. methods we performed a literature search using the texas medical center library one search, which scans 167 databases, including embase, pubmed, and scopus. we performed our search on february 27, 2021, using the search criteria “teledermatology” and “skin neglected tropical disease.” for thoroughness, we performed cross validation with every sntd listed by the who, inputting the search criteria “teledermatology” and “[sntd recognized by the who].” we limited our search to articles published in 2011 or later. eligible studies were original investigations in which a td intervention was implemented to diagnose and/or manage one or more sntds. we excluded commentaries, editorials, and reviews that did not present any original data. we also excluded case reports (although we discuss some anecdotally to illustrate proof of concept). articles not written in english and articles that presented td along with other interventions (such that the impact of td alone could not be isolated) were also excluded from analysis. lastly, we excluded articles that implemented td in the diagnosis of sntds but did not perform any further analyses (eg, concordance measures, clinical improvement, time to diagnosis, etc.). in preparing this systematic review, we adhered to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines. we include a prisma flow diagram that illustrates our search (figure 1). results twenty studies met our search criteria (table 1). fungal infections were the most common sntds to be targeted by td, being described in 18/20 studies analyzed. scabies (10/20), cl (5/20), and leprosy (5/20) were the next most common sntds to be diagnosed by td. we did not find any eligible studie that utilized td in diagnosing mycetoma, onchocerciasis, post-kala-azar dermal leishmaniasis, or yaws. the studies we reviewed had a wide geographical distribution: latin america (6/20), africa (7/20), the middle east (4/20), and asia (3/20). interestingly, we also found one study by hwang et al evaluating td use in the united states military in deployed settings: while the majority of td consults were requested from iraq and afghanistan, almost 50 locations utilizing td appointments were described [8]. the majority of the studies we reviewed (18/20) adopted a generally favorable outlook towards td. additionally, 5 studies assessed the concordance between ftf and td consultations, and the agreement ranged from 56% [9] to 95% [10]; the study reporting 56% agreement did not consider this degree of concordance to be sufficient to recommend the independent use of td [9]. we recognize selection bias as a potential weakness of all the studies we reviewed, as patients uncomfortable with td would not have elected to participate. only 3/20 studies documented the number of individuals who declined to participate. review | dermatol pract concept. 2021; 11(4): e2021130 3 figure 1. prisma flow diagram illustrating the methodology informing our search. td= teledermatology; tmc= texas medical center records identi�ed through tmc library one search (n = 411) sc re en in g in cl u d ed el ig ib ili ty id en ti � ca ti o n records after duplicates removed (n = 175) records screened (n = 175) records excluded (n = 122) full-text articles assessed for eligibility (n = 53) full-text articles excluded (n = 33) no outcomes analyses performed by study (n =2) td implemented with another intervention (n = 8) studies included in review (n = 20) teledermatology: advantages and promises expansion of dermatologic care to underserved regions plagued by sntds represents perhaps the most significant benefit of td. while there is no study that assesses the number of dermatologists per capita by country, data from the united states alone is concerning for sharp disparities between dermatologic care in rural and urban centers, with the difference in dermatologist density between metropolitan and rural counties exceeding 4 dermatologists per 100,000 people [28]. it is likely that such disparities are more pronounced in developing regions where sntds constitute a major burden of disease. the studies we reviewed indicate the potential for td to bridge this gap in access to care, as 12/20 were conducted in rural locations and all were conducted in resource limited settings. case reports from nepal support the potential for td to penetrate rural areas and address sntds such as cl [29] and tinea incognito [30]. formation of a global network of teledermatologists may facilitate the eradication of sntds in regions where in-person care may not be feasible. additionally, the remote aspect of td provides an opportunity to practice global health sustainably and allows for continuity of care. moreover, it may have an educational value: with the patients’ consent, medical students and residents can also participate in td consults, gaining exposure to sntds and global health without having to travel. importantly, td can also help general practitioners (gps) recognize 4 review | dermatol pract concept. 2021; 11(4): e2021130 table 1. literature assessing td intervention in sntd control reference country/ region sntd location of consulting dermatologist study size major finding(s) baze, 2011 [11] honduras fi, scabies foreign location 105 91% patient satisfaction; high dermatologist satisfaction; 4.3/5 image quality garcia-romero et al, 2011[12] mexico scabies local jurisdiction 44 75% clinical improvement following td consult tsang & kovarik, 2011 [13] sub-saharan africa leprosy, lf, fi foreign location 55 58% correlation between td and pathological analysis oseit-tutu et al, 2013 [14] ghana fi local jurisdiction 34 79% concordance between ftf and td consults montazeri et al, 2013 [15] iran cl, fi local jurisdiction 91 85% concordance between ftf and td consults smith et al, 2013 [16] kenya fi local jurisdiction 32 mean sensitivity of 73% and specificity of 83% for diagnosing tinea infections via td kaliyadan et al, 2013 [10] saudi arabia fi local jurisdiction 166 95% concordance between ftf and td consults greisman et al, 2014 [17] guatemala and uganda bu, cl, fi, lf, scabies foreign location 93 td rectified gp diagnoses in 56% of cases hwang et al, 2014 [8] u.s. military facilities bu, cl, scabies, fi foreign location 658 98% of consults answered in 24 hours; 46 evacuations avoided and 41 evacuations facilitated due to td consult lipoff et al, 2015 [18] sub-saharan africa fi foreign location 1229 60% concordance between dermatologist and clinicians submitting images patro et al, 2015 [9] india fi, scabies local jurisdiction 206 56% concordance between ftf visit conducted by gp and td nguygen et al, 2017 [19] cameroon fi, leprosy, lf foreign location 145 acceptable concordance between diagnosis as made by td and light microscopy saleh et al, 2017 [20] egypt fi local jurisdiction 600 87% concordance between ftf and td consults ismail et al, 2018 [21] afghanistan cl, fi, scabies local jurisdiction 326 images of sufficient quality to render diagnoses in 94% of consults faye et al, 2018 [22] mali fi, leprosy, scabies local jurisdiction 180 96% of patients properly managed via td; mean time to dermatologist response was 32 hours messagier et al, 2019 [23] french guiana cl, fi, leprosy, scabies local jurisdiction 254 85% satisfaction from users; 92% were able to be managed in peripheral health centers cutler et al, 2019 [24] haiti fi, scabies foreign location 101 average time from intake to case closure was 1.67 days; average diagnostic concordance between haitian providers and u.s. dermatologists was 69% malmontent et al, 2020 [25] french guiana leprosy local jurisdiction 52* td used to solve four cases of leprosy singhal et al, 2020 [26] india fi; scabies local jurisdiction 520 9% of patients could not be assessed due to poor image quality; poor patient compliance to treatment following td consult also noted lee et al, 2021 [27] taiwan fi; scabies local jurisdiction 426 subjective patient improvement >75% year-round and case closure rate >85% year-round bu=buruli ulcer; cl=cutaneous leishmaniasis; fi=fungal infections; ftf=face to face; gp=general practitioner; lf=lymphatic filariasis; sntd=skin neglected tropical diseases; td=teledermatology. while the total number of cases for this study was 639, td was used in only 52 cases. review | dermatol pract concept. 2021; 11(4): e2021130 5 lesions associated with sntds endemic to the region where they practice. such an application of td was successfully applied in the united kingdom [31]. the cost savings of td should also be considered. among the evaluated studies, 3 evaluated the financial aspect of td implementation: greisman et al reported td in guatemala and uganda to be entirely feasible from a financial standpoint [17]; cutler et al reported the cost of managing a td platform in haiti to be only us$5 per month [24]; and messagier et al reported that td mitigated healthcare expenses for more than 50% of patients in french guiana [23]. as sntds affect the world’s most indigent, cost represents a significant barrier to care. td may be a cost-effective way to expand care to individuals suffering from sntds. another advantage of td is that it can be leveraged with mobile applications and artificial intelligence (ai). although none of the studies we reviewed employed mobile applications and ai in conjunction with td, we acknowledge the potential synergy of combining these technologies. recently, carrion et al reviewed the utility of mobile applications in mitigating the burden of sntds and although they concluded that numerous barriers to widespread mobile health implementation remain, their review demonstrates that creative mobile technologies, some with a modicum of success, do exist and can help curb the morbidity associated with sntds [32]. adding ai can further potentiate the power of td. a study conducted in the philippines by velasco et al showed that a neural network was able to diagnose common skin conditions with up to 94% accuracy [33]. altogether, the combination of td, mobile technologies, and ai represents a potent technological triad that may be used to control sntds. the applications of td in managing sntds that arise in non-community settings should also be acknowledged. while 19/20 studies we reviewed apply td in the management of sntds in local community settings, the study by hwang et al shows that td can be effectively utilized to manage sntds that arise in military deployments [8]. td also has the potential to be used in the management of sntds in refugee situations, and such an application of td has been suggested in the treatment of skin disease in the refugee population in europe [34] and the rohingya in bangladesh [35]. furthermore, td has the potential to diagnose non-endemic cases of sntds. in an increasingly interconnected world affected by rising global temperatures, the potential of sntds to present in regions outside the tropics has become a valid concern. in 2018, hotez summarized how recent changes in climate, globalization, and urbanization have spurred the surge of ntds in texas [36]. under these new circumstances, td may acquire a truly global scope in the management of sntds; for example, in 2019 a woman who had recently immigrated to the united states from brazil was diagnosed with leprosy using td [37]. teledermatology and its limitations inadequate image quality represents a major concern for td. six of the 20 studies we reviewed identified poor image quality as a barrier to diagnosis. furthermore, td works mostly as a triage system, and while it has the ability to identify patients that promptly need dermatologic attention, additional diagnostic procedures, such as biopsies, potassium hydroxide (koh) preparations, dermoscopy, microscopy, and analysis under wood’s lamp must all be sacrificed in an entirely td model of care. in 10/20 studies, further diagnostic evaluation was recommended following a td consult, and 2/20 studies indicated a lack of access to further diagnostic procedures. many sntds may present ambiguously, necessitating further evaluation: microscopy for buruli ulcer, cutaneous leishmaniasis, and lymphatic filariasis; biopsy for leprosy; and koh preparations for fungal infections [38]. in developing countries where sntds are endemic and resources are scarce, further studies may not be possible. in such cases, a td consult could potentially cause more harm than good by leaving the patient in a state of anxiety and uncertainty. furthermore, only 4/20 studies mentioned any kind of patient follow-up; thus, the long-term efficacy of td remains unknown. additionally, in 7/20 studies, the consulting dermatologist was located in a foreign location. as opposed to local dermatologists, dermatologists in more remote locations may not have a nuanced understanding of local disease epidemiology and available diagnostic techniques and treatments. this lack of knowledge could lead not just to potentially incorrect diagnoses but also recommendation of unavailable treatments. the ethico-legal aspects of td implementation must also be considered. patient privacy represents a valid concern for td implementation. impressively, 14/20 studies acknowledged the issue of encryption and made an attempt at preserving patient confidentiality. the studies we reviewed utilized a myriad of platforms to perform td consults, including facebook [12], whatsapp [26], dropbox [20], and tango [10], but the encryption underlying these platforms remains unclear. in fact, whatsapp has been deemed inappropriate for telemedicine due to concerns about privacy breaches [39]. as td use has increased during the covid-19 pandemic, whatsapp has come under further scrutiny. brunasso and massone point out that whatsapp is not compliant with the european union’s general data protection regulation and that caution must be exercised in utilizing td platforms [40]. ensuring confidentiality is important, as individuals afflicted with sntds comprise a particularly vulnerable population and may be unable to advocate for themselves. legal barriers to td implementation also exist globally and are more pronounced in developing countries. cutler et al addressed these limitations in their study on td implementation in 6 review | dermatol pract concept. 2021; 11(4): e2021130 haiti, citing that the legal framework surrounding telemedicine licensure and malpractice is nascent [24]. the control of sntds through td must not come at the expense of ethical and legal transgressions. finally, cultural barriers to widespread td utilization exist. from saudi arabia, kaliyadan et al reported that 14% of patients refused to have their skin photographed, citing religious and social reasons [10]. while none of the other studies we reviewed evaluate the cultural barriers to td implementation, it is possible that the hesitancy towards td use exists in other countries afflicted by sntds, many of which embrace conservative cultures. moreover, this cultural hesitancy towards td acceptance may be amplified when the encryption of td platforms is tenuous. thus, the cultural milieu limiting td use must not be overlooked. teledermatology: one piece of the puzzle the tremendous potential for td is tempered by its limitations; alone, it is unlikely to eliminate sntds. mass drug administration [41], advocacy, policy changes, involvement of key stakeholders, and greater investment in research have all been cited as elements essential to the control of sntds [42]. the community dermatology program in guerrero, mexico serves as an example of this integrated approach to managing sntds: td is combined with education, mobilization of healthcare personnel, and involvement of local and international institutions to mitigate the burden of mycetoma [43]. therefore, a more realistic picture of sntd control is one where td occupies one piece of the puzzle of sntd eradication. review limitations as we only considered published journal articles in our literature search, we recognize publication bias is a limitation to our review. furthermore, only the sntds articulated by the who were used in our search criteria; however, other ntds also present with cutaneous manifestations that can be evaluated by dermatologists. for instance, reactivated chagas disease may present as cellulitic plaques, ulcers, necrotic eschars, and panniculitis [44]. thus, our review may not exhaustively capture the application of td in the management of all sntds. conclusion sntds represent a group of stigmatizing, poverty promoting diseases that can be effectively targeted by td. td can blunt the 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doi:10.1371/journal. pntd.0005136.pmid: 28103250. 43. roberto e, guadalupe c-l, guadalupe e-c, hay r. mycetoma and the community dermatology program, mexico. trans r soc trop med hyg. published online 2021. doi:10.1093/trstmh/ traa199. pmid: 33479763. 44. rawlings parker e, sethi. chagas disease: coming to a place near you: special topics in tropical dermatology. dermatol clin. 2011;29(1). doi: 10.1016/j.det.2010.08.011. pmid: 21095528. dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(2):e2022072 1 fractional carbon dioxide (co2) laser alone versus fractional co2 laser combined with triamcinolone acetonide or trichloroacetic acid in keloid treatment: a comparative clinical and radiological study engy abd el-hamid el-azhary1, fatma mohamed abd al-salam2, hala shawky abd el-hafiz2, hala maghraby maghraby3 1 faculty of medicine kasr al-aini faculty of medicine, cairo university, cairo, egypt 2 dermatology and venereology department, faculty of medicine for girls, alazhar university, cairo, egypt 3 radiodiagnosis department, faculty of medicine for girls, alazhar university, cairo, egypt key words: keloid, fractional laser, tac, tca, doppler. citation: el-azhary ea, abd al-salam fm, hafiz hsa, maghraby hm. fractional carbon dioxide (co2) laser alone versus fractional co2 laser combined with triamcinolone acetonide or trichloroacetic acid in keloid treatment: a comparative clinical and radiological study. dermatol pract concept. 2022;12(2):e2022072. doi: https://doi.org/10.5826/dpc.1202a72 accepted: october 11, 2021; published: april 2022 copyright: ©2022 el-azhary et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: engy abd el-hamid abd el-hamid el-azhary, mbbch, general medicine and surgery, kasr al-aini faculty of medicine,, cairo university, cairo, egypt. e-mail: gi.elazhary.89@gmail.com introduction: keloids are benign fibro-proliferative scarring extending outside the initial wound. different treatment modalities as intralesional corticosteroid injection, fractional co2 laser, and others can be used either as mono or combined therapies. objectives:  to assess the efficacy of fractional co2  laser versus fractional co2  laser accompanied with either triamcinolone acetonide or trichloroacetic acid 20% in keloid treatment clinically and radiologically. methods: the current study was conducted on 45 egyptian participants with keloid scars at different sites of the body. they were classified into 3 groups treated by fractional co2 laser only (group i), fractional co2 laser followed by triamcinolone acetonide (group ii), or trichloroacetic acid application (group iii), respectively. evaluation of the keloid was done with vancouver scar scale (vss) and color doppler ultrasound (cdu) before and after treatment. four sessions 4 weeks apart were applied for the patients. they were followed-up for 8 weeks after the last session. abstract 2 original article | dermatol pract concept. 2022;12(2):e2022072 inclusion criteria either male or female, 18 to 55 years old, duration of keloid scar of more than 6 months. exclusion criteria patients who received any previous treatment during the 6 months before enrollment for their keloids, pregnant or lactating women, patients with photosensitivity, patients on retinoids treatment, and facial keloids. treatment protocol all patients underwent complete history taking, general and dermatological examinations, photographs, clinical assessment by vancouver scar scale (vss), and radiological assessment by color doppler ultrasound (cdu) of keloids. materials used fcl, tac, and tca 20%. study design this comparative study included 45 egyptian participants with keloids, they were of both sexes (21 males and 24 females), and their ages were between 20 and 55 years. we classified the 45 cases into 3 groups of 15 cases each, the first group treated by fcl alone (as shown in figure 1), the second group treated by fcl followed immediately by tac at a dose at a dose of 0.25 ml/cm³ for keloids < 3 cm and 0.5 ml/ cm³ for keloids >3 cm (equivalent to 10 mg/cm³ of tac [40 mg/ vial]) then occluded using transparent film dressings. patients were instructed to remove the dressing 3 hours after the session by sterile saline-soaked gauze (as shown in figure 2) while the third group was treated by fcl followed immediately by tca 20% application then occluded for 3 hours as in group ii (as shown in figure 3). topical anesthesia in the form of cream (prilocaine 2.5% and lidocaine 2.5%) was applied before the laser session under occlusion for 60 minutes and wiped off with saline. laser parameters used were: power = 20-25 j, stack = 1-2, timing = 300 ms (milliseconds) and spacing = 350 mm. evaluation of keloid scars before and after treatment was done by vss and cdu. the patients received 4 sessions 4 weeks apart and followed-up for 8 weeks after the last session. introduction keloids are formed due to abnormal response of wound healing where scar tissue has grown aggressively outside the initial wound borders [1]. treatment of keloid scar is debatable and burdensome though combined treatment modalities give better results than single ones [2]. triamcinolone acetonide (tac) acts through suppression of wound inflammatory factors and fibroblast growth by decreasing transforming growth factor-beta (tgf-b) expression while stimulating the breakdown of collagen and fibroblast apoptosis, thus reducing the density of fibroblasts [3]. fractional co2 laser (fcl) creates microthermal zones (mtzs), which occur due to tissue vaporization in the form of rows surrounded by normal skin through which they stimulate wound healing [4]. fcl can be used as a delivery system for many drugs as corticosteroids known as laser-assisted drug delivery (ladd) [5,6]. trichloroacetic acid (tca) induces ultrastructural changes of epidermis and dermis. tca improves the morphologic appearance of collagen and elastin. it acts through the deposition of new collagen and normalizes elastic tissue that was destroyed due to collagen i and iii overproduction and hence can be used in keloids [7]. objectives to assess the efficacy of fcl versus fcl accompanied with either tac or tca 20% in keloid treatment. keloid treatment progress was assessed clinically and radiologically. methods this comparative study was conducted from march 2017 to october 2019 at the outpatient clinic of dermatology and venereology, where 45 egyptian patients with keloids were enrolled randomly. all participants wrote down an informed consent after demonstrating the study steps, expected results, and side effects before taking part in the study. ethical aspects of human research were fulfilled in the current study after the official approval of the local research ethics committee of faculty of medicine for girls, al-azhar university, cairo, egypt with approval code (202106865). results: after treatment, there was a high statistically significant reduction in vss among the 3 groups (p ≤ 0.001); the reduction was more in group ii than in i and iii. also, a high statistically significant reduction in keloid scar thickness assessed by cdu was recorded (p ≤0.001 in group ii and p ≤0.01 in group i and iii). conclusions:  combined therapy is favorable in the treatment of keloids. trichloroacetic acid is a promising modality in treating keloid, hence it can be tried in different combinations. cdu is a promising method of keloids pre-and post-treatment assessment. original article | dermatol pract concept. 2022;12(2):e2022072 3 figure 1. female patient, 32 years old with abdominal post-surgical keloid. (a) before treatment (vss 10). (b) after 4 sessions of fractional co2 alone (vss became 6), showing good improvement. vss = vancouver scar scale. figure 2. male patient, 23 years old with back post-traumatic keloid. (a) before treatment (vss 9). (b) after 4 sessions of fractional co2 followed by tac (vss became 2), showing excellent improvement. tac = triamcinolone acetonide ; vss = vancouver scar scale. evaluation methods photographs by sony cyber shot dsc-h10, japan camera, vss (pliability, pigmentation, vascularity and scar thickness or height) were used, the scores range from 0 to 14 where 14 indicates the worst scar while score of 0 indicates normal skin. keloid scar thickness measurement by cdu using a superficial probe (10 mhz) and patient satisfaction by patient satisfaction self-assessment (score from 0 to 4; not satisfied 0%, mildly satisfied <25%, moderately satisfied 2550%, very good satisfied 50-75% or excellent satisfied >75%) were evaluated. treatment side effects stated by physicians or patients were documented. statistical analysis collected data were revised, coded, and entered into the statistical package for social science version 23. quantitative data were presented as median, inter-quartile range when data were non-parametric. the comparison of quantitative data and non-parametric distribution between more than 2 groups was made by using kruskall wallis test. the comparison of quantitative data and non-parametric distribution between two paired groups was done by using willcoxon rank test. the confidence interval was set at 95%, and the margin of error accepted was set at 5%. p-value was considered significant as the following: p > 0.05: non significant, p < 0.05: significant, and p < 0.01: highly significant. results forty-five adult egyptian cases with keloids were enrolled. they were 20 -55 years old with a mean 33.69 (± 11.02 standard deviation). among the studied groups, 24 cases were females (53.3%), while 21 were males (46.7%). the keloids were at different sites of the body (e.g. ears, chest, and back). causes of keloid varied from trauma, surgery, spontaneous, and ear piercing. nine cases (20%) had multiple keloids, 31 cases (80%) had keloid over bony prominences, and 8 cases were treated previously (17.8%). treatment outcomes clinical assessment a high statistically significant reduction in vss after treatment was detected among patients of the 3 groups with p <0.001. the most significant vss reduction was in group ii 4 original article | dermatol pract concept. 2022;12(2):e2022072 figure 3. female patient, 26 years old with thigh post-traumatic keloid. (a) before treatment (vss 8). (b) after 4 sessions of fractional co2 followed by tca 20% (vss became 4), showing good improvement but hypopigmentation occurred as a side effect. tca= trichloroacetic acid; vss = vancouver scar scale. table 1. vss before and after treatment for each group of the studied cases group i group ii group iii test value p-valueno. = 15 no. = 15 no. = 15 vss before median (iqr) 8 (6 – 11) 10 (7 – 11) 8 (8 – 11) 1.546 0.462 (ns) range 4 – 13 6 – 13 5 – 14 vss after median (iqr) 4 (3 8) 5 (4 – 8) 8 (5 – 9) 5.551 0.062 (ns) range 1 – 9 2 – 10 3 – 12 differences mean ±sd –3.40 ± 1.18 –3.73 ± 1.58 –1.73 ± 1.33 13.789 0.001 (hs) range –5 – –2 –7 – –2 –4 – 1 willcoxon rank test –3.436 –3.437 –3.151 p 0.001 (hs) 0.001 (hs) 0.002 (hs) vss = vancouver scar scale; no = number; iqr= interquartile range; ns= non significant; s= significant; hs= highly significant; sd= standard deviation. table 2. keloid thickness by cdu before and after treatment for each group of the studied cases group i group ii group iii test value p-valueno. = 15 no. = 15 no. = 15 thickness before (cm2) median (iqr) 0.81 (0.27 – 1.35) 1.82 (0.8 – 6.32) 0.36 (0.23 – 0.73) 11.131 0.004 (hs) range 0.07 – 24.5 0.36 – 23.85 0.09 – 1.4 thickness after (cm²) median (iqr) 0.48 (0.14 – 2.07) 1.12 (0.36 – 5.11) 0.32 (0.17 – 0.59) 6.162 0.046 (s) range 0.06 – 8 0.12 – 15.6 0.01 – 1.04 difference mean ± sd –1.55 ± 5.22 –1.24 ± 2.13 –0.12 ± 0.15 11.599 0.003 (hs) range –19.6 – 1.41 –8.25 – 0 –0.41 – 0.06 willcoxon rank test –2.480 –3.296 –2.513 p 0.013 (s) 0.001 (hs) 0.012 (s) cdu= color doppler ultrasound; no = number; iqr= interquartile range; s= significant; hs= highly significant; sd= standard deviation. (-3.73 ± 1.58), then in group i (-3.40 ± 1.18), and the minor reduction was in group iii (-1.73 ± 1.33) (table 1). radiological assessment the reduction in the keloid thickness measured by cdu after treatment among the 3 groups was statistically significant, where the greatest radiological reduction was in group i (-1.55 ± 5.22), then group ii (-1.24 ± 2.13), and the minor reduction was in group iii (-0.12 ±0.15) (table 2). the correlation between clinical and radiological responses was not statistically significant. patient satisfaction patient satisfaction score grades 3 and 4 were the highest among group ii with 40% (6 patients) and 46.7% (7 patients) respectively, then in group i with 6.7% (1 patient) and 33.3% (5 patients), respectively. while grades 1 and 0 of the score were the highest among patients of group iii with 26.7% (4 patients) and 20% (3 patients) respectively. original article | dermatol pract concept. 2022;12(2):e2022072 5 behera et al reported that fcl could be used in keloids excision efficiently, in agreement with the current results [12]. also, azzam et al reported that keloids could be treated by fcl securely and efficiently upon the results of their study on 30 patients who received 4 fcl sessions six weeks apart [13]. nevertheless, they recommended that fcl could give better results when used as a combined therapy. as fcl inhibits tgfb1 release but stimulates basic fibroblast growth factor (bfgf) release and hence induces epidermal regrowth and dermis collagenesis and remodeling [12,14]. the laser gives better results when used on early scars of less than 2 years [15]. in group ii, for patients who received combined therapy of fcl followed by tac this combination resulted in a significant reduction in vss parameters after treatment compared to groups i and iii with the best satisfaction score (as shown in figures 1,2 and 3). al-janahi et al treated a 72 years old african american male suffering from aggressive keloid sited at the anterior and lateral neck, back, and upper chest that lasted for 30 years resulting in flattening of keloid and improvement of pain after 1 treatment [16]. similar to the current study, alegre-sánchez et al stated that using co2 laser in combination with tac suspension 10% gives excellent results for keloid and hypertrophic scars treatment [17]. also, they declared factors affecting the results of fcl followed by tac suspension combination as the density of fcl, depth of channels created by fcl, which depend directly on laser fluency, the vehicle used, type of preparation, and formulations. in contrast, annabathula et al reported that fcl is not recommended to treat keloids as a single therapy [18], but they recommended a combined therapy for a synergistic effect of treatment. also, waibel et al reported that using fcl followed by tac suspension application in successive three treatments caused 23 % scar reduction [19]. according to alexander et al study, they used intralesional injection instead of suspension application, giving good results [20]. alegre-sánchez et al reported that tac in the form of suspension has a greater affinity than a cream or ointment, so passes through micro-channels produced by fractional ablative lasers easier [17]. also, the improvement of texture, thickness, dyschromia, and scar functionality was reported using topical corticosteroid rather than an intralesional drug. ladd facilitates penetration and provides better results when both medical as drugs and physical as laser treatments are combined [17]. another key factor in ladd is the interval between using laser and drug application. considering mtzs closure, it lasts for 6 hours after laser application; however, the vehicle or drug absorption is most successful during the first 30 minutes, while after 24 hours, no absorption is observed, so no need for further topical applications [17]. these studies came in agreement with the current study as regard laser parameters (power = 20-25 j), the form of in the current study, the relationship between clinical response measured by vss and patient satisfaction self-assessment score was not statistically significant. side effects evaluation among the studied groups among all patients, 20 (44.4 %) had no side effects, while 25 (55.6%) patients had side effects in the form of pain, itching, ulceration, hypopigmentation, and hyperpigmentation. the main side effects were increased pain and itching just after the session and subsided within a week maximum in the current study. as regards types of side effects, the results showed statistically significant difference among the 3 groups (p <0.05) whereas patients of groups i and ii had suffered from mild side effects as pain and itching while group iii patients had suffered from severe side effects as ulceration, hypopigmentation (shown in figure 3), and hyperpigmentation beside beside pain and itching.. neither clinical nor radiological responses had a statistically significant association with sex, or skin phototype of the patients, cause, site, size, multiplicity, or previous treatment of the keloid. however, the clinical improvement was better at non-bony sites as mean vss reduction was -3.36 (± 1.39) while it was -2.77 (± 1.69) at bony sites. also, no statistically significant association was found between either clinical or radiological responses and patient self-assessment score or side effects. conclusions keloid scar occurs as a result of extracellular matrix overproduction, mainly collagen. it occurs due to cytokines and growth factors overexpression [8]. keloid formation has many theories, where the most approved one was the imbalance between collagen synthesis and degradation together with the imbalance of fibroblasts proliferation, apoptosis, and inhibition [3,9]. keloid pathogenesis is mainly due to abnormal healing of wounds either due to abnormal response to inflammation or prolonged proliferative phase [9]. increased collagen synthesis is related to keloid fibroblasts stimulation through inflammatory mediators, mainly transforming growth factors beta-1 (tgf-b1). tgf-b1 isoforms are supposed to be responsible for collagen overproduction by fibroblasts in pathological scars [10]. treatment decisions must be based on the patient’s age, location, size and depth of the lesion, and past response to treatment. hence no specific treatment is best for all keloids [11]. regarding the current study, the results showed a statistically significant reduction in vss score after treatment compared to before treatment in each group with p <0.01. however, the main improvement was in pliability. according to the current study, the group i received fcl as monotherapy. compared to combined therapy in groups ii and iii, group i had good but not the best results. 6 original article | dermatol pract concept. 2022;12(2):e2022072 in the current study, the improvement of vss parameters after treatment (pliability, vascularity, pigmentation, and height/thickness of keloid) was statistically significant; however, the main improvement was in the pliability component, then thickness/height, then vascularity, and the least component improved was pigmentation. in agreement with the current results, heppt et al and azzam et al reported more evident improvement in vss parameters, where scar pliability was markedly improved while vascularity and dyspigmentation were less pronounced [13,22]. since biopsies in keloids are contraindicated as they can produce an increase in size, cdu can support activity assessment and indicate the response to treatment (as shown in figures 4,5 and 6). elrefaie et al and lobos et al advised using high-resolution ultrasonography in scar assessment to determine the suitable treatment modality as an available, quick, and affordable method [23,24]. as vss has a high range of the thickness parameter (< 2, 2-5, and > 5mm), the scar thickness may be reduced but with no changes in vss, while ultrasound measures the whole scar thickness not only the superficial height as in vss. also, cdu can assess the presence of calcifications, fistulous tracts, or muscle involvement on different body sites as ear pinna and trunk. regarding side effects, only 25 patients had adverse events in the form of increased pain and itching just after the session and subsided within a week maximum in group i and ii, while group iii had suffered from severe side effects as ulceration, hypopigmentation (as shown in figure 3), and hyperpigmentation beside pain and itching. in agreement with the current results, alexander et al reported increased size, pain, hyperpigmentation, and depigmentation [20]. also, alegre-sánchez et al explained that adverse effects might appear due to laser high fluencies and densities applied [17]. tac we used (suspension), and the time of drug application after fcl application (drug applied immediately after laser session and removed after 3 hours using sterile saline-soaked gauze). fcl combined with tac may minimize collagen production by decreasing fibroblast activity, with a low recurrence rate of 15.4%, which is superior to each modality and is ideal for large keloids [4]. regarding the current study, group iii was treated by fcl followed by topical application of tca 20%. tca is a peeling agent used for superficial and medium-depth peel according to its concentration. tca acts through coagulative necrosis and protein precipitation of epidermal cells and collagen necrosis of papillary and reticular dermis. patients of this group had the slightest improvement of keloids with the most severe side effects as ulceration, hypopigmentation, and hyperpigmentation compared with other groups. the combination between fcl and tca in the treatment of keloids has not been evaluated before. hence, we tried to evaluate it through our third group. ghonaim conducted a comparative study of 80% tca multiple puncture techniques versus botulinum toxin type a (btx-a) in keloid treatment and denoted that tca can normalize all types of scars by dermal structure reconstruction [21]. keloid fibroblasts have a greater capacity to proliferate and overproduce type i collagen. tca-treated skin expresses cytokines as interleukin-10, which is involved in type i collagen synthesis, regulation, and degradation. on treating cultured dermal fibroblasts with tca, collagen i was downregulated, and collagenase protein was upregulated, where platelet-derived growth factor-b expression was upregulated markedly, then downregulated immediately. this transient increase of platelet-derived growth factor could be beneficent for speedy wound repair [21]. figure 4. high resolution b mode ultrasonic imaging of a cutaneous keloid with homogenous echopattern. (a) before treatment showing that keloid thickness was: 0.146 cm while the length was: 1.28 cm. (b) after 4 sessions of fractional co2 alone showing decrease in the thickness to become 0.140 cm and in the length to become 1.19 cm, showing good improvement. on cdu application the lesion was completely avascular before and after treatment. cdu = color doppler ultrasound. original article | dermatol pract concept. 2022;12(2):e2022072 7 figure 5. high resolution b mode ultrasonic imaging of a subcutaneous keloid with hypoechoic echopattern deep to the skin by 2 mm. (a) before treatment showing that keloid thickness was: 0.489 cm while the length was: 5.62 cm. (b) on cdu mode application, few peripherally located vessels are seen with arterial flow of low resistance. (c) high resolution b mode ultrasonic imaging of a keloid after 4 sessions of fractional co2 followed by tac showing decrease in the thickness to become 0.448 cm and in the length to become 2.45 cm, showing excellent improvement. (d) on cdu mode the keloid was completely avascular. cdu = color doppler ultrasound; tac = triamcinolone acetonide. in the current study, regarding the site of keloid, 31 (68.9%) patients had keloids on bony prominences as chest, forearm, arm, neck, shoulder, back, interscapular, knee, and elbow, while 14 (31.1%) patients had keloids on non-bony structures as abdomen, thigh and ear lobe. we found no statistically significant relationship between the site of keloid and the clinical or radiological response; however, the clinical improvement was more at non-bony sites as mean vss reduction was -3.36 (± 1.39) while at bony sites, it was -2.77 (± 1.69). we did not notice any recurrence among studied cases compared to behera et al, who reported a high recurrence rate during a one-year follow-up period [12]. this may be due to the short period of follow-up in our study. current study limitations were a small sample of patients as we listed the patients who had the full number of sessions and follow-up so, we didn’t mention patients who didn’t complete the whole number of sessions, limited laser sessions, and had a short follow-up period. fcl alone is a potent secured treatment modality of keloid, but combined therapy gives better results. however, combined therapy of fcl and topical tac is better than monotherapy or combination with tca in treating keloids as tca can result in some serious side effects as ulceration, hypopigmentation, and hyperpigmentation. further studies of different combinations with fcl are recommended in the treatment of keloids. also, more studies to assess the efficacy of applying tca in lower concentrations after fcl versus tca as monotherapy in the treatment of keloids are needed. tca is needed to be tried alone in treating keloid or combined with other therapies other than a fractional laser, though tca can be combined with fractional laser but not in the same session to lessen the side effects. clinical assessment of keloid scar using score scales as vss is not always accurate. it may underestimate the activity in keloid scar, so adding radiological methods in assessment 8 original article | dermatol pract concept. 2022;12(2):e2022072 8. mari w, alsabri sg, tabal n, younes s, sherif a, simman r. novel insights on understanding of keloid scar: article review. j am coll clin wound spec. 2016;7(1-3):1-7. doi:10.1016/j. jccw.2016.10.001. pmid: 28053861. pmcid: pmc5197049. 9. shaheen a. comprehensive review of keloid formation. clin res dermatol. 2017;5:1-18. doi:  http://dx.doi. org/10.15226/2378-1726/4/5/00168. 10. berman b, maderal a, raphael b. keloids and hypertrophic scars: pathophysiology, classification, and treatment. dermatol surg. 2017;43 suppl 1:s3-s18. doi:10.1097/dss.0000000000000819. pmid: 27347634. 11. maghrabi, ibrahim a, and ahmed m kabel. management of keloids and hypertrophic scars: role of nutrition, drugs, cryotherapy and phototherapy.world journal of nutrition and health 2014;2(2):28-32. doi: 10.12691/jnh-2-2-4. 12. behera b, kumari r, thappa dm, malathi m. therapeutic efficacy of intralesional steroid with carbon dioxide laser versus with cryotherapy in treatment of keloids: a randomized controlled trial.  dermatol surg. 2016;42(10):1188-1198. doi:10.1097/dss.0000000000000873. pmid: 27661432. 13. azzam oa, bassiouny da, el-hawary ms, el maadawi zm, sobhi rm, el-mesidy ms. treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: a clinical, histological, and immunohistochemical study.  lasers med sci. 2016;31(1): 9-18. doi:10.1007/s10103-015-1824-4. pmid: 26498451. 14. omi t, numano k. the role of the co2 laser and fractional co2 laser in dermatology.  laser ther. 2014;23(1):49-60. doi:10.5978/islsm.14-re-01. pmid: 24771971; pmcid: pmc3999431. 15. srivastava s, kumari h, singh a. comparison of fractional co2 laser, verapamil, and triamcinolone for the treatment of keloid. adv wound care (new rochelle). 2019;8(1):7-13. doi:10.1089/ wound.2018.0798. pmid: 30705785. pmcid: pmc6350054. 16. al janahi s, lee m, lam c, chung hj. laser-assisted drug delivery in the treatment of keloids: a case of extensive refractory keloids successfully treated with fractional carbon dioxide laser followed by topical application and intralesional injection of steroid suspension.  jaad case rep. 2019;5(10):840-843. doi:10.1016/j.jdcr.2019.07.010. pmid: 31646158. pmcid: pmc6804451. 17. alegre-sánchez a, jiménez-gómez n, boixeda p. laser assisted drug delivery. vehiculización de fármacos asistida por láser.  actas dermosifiliogr (engl ed). 2018;109(10):858-867. doi:10.1016/j.ad.2018.07.008. pmid: 30266385. 18. annabathula a, sekar cs, srinivas cr. fractional carbon dioxide, long pulse nd:yag and pulsed dye laser in the management of keloids.  j cutan aesthet surg. 2017;10(2):76-80. doi:10.4103/jcas.jcas_136_16. pmid: 28852292. pmcid: pmc5561714. 19. waibel js, wulkan aj, shumaker pr. treatment of hypertrophic scars using laser and laser assisted corticosteroid delivery.  lasers surg med. 2013;45(3):135-140. doi:10.1002/lsm.22120. pmid: 23460557. 20. alexander s, girisha bs, sripathi h, noronha tm, alva ac. efficacy of fractional co2 laser with intralesional steroid compared with intralesional steroid alone in the treatment of keloids and hypertrophic scars. j cosmet dermatol. 2019;18(6):1648-1656. doi:10.1111/jocd.12887. pmid: 30770627. 21. ghonaim n. comparative study of the 80% trichloroacetic acid multiple puncture technique versus botulinum toxin type a in as cdu is of great importance to help physicians in the choice of the most appropriate modality of treatment based on each scar assessed criteria. references 1. limandjaja gc, niessen fb, scheper rj, gibbs s. the keloid disorder: heterogeneity, histopathology, mechanisms and models.  front cell dev biol. 2020;8:360. doi:10.3389/ fcell.2020.00360. pmid: 32528951. pmcid: pmc7264387. 2. andrews jp, marttala j, macarak e, rosenbloom j, uitto j. keloids: the paradigm of skin fibrosis pathomechanisms and treatment.  matrix biol. 2016;51:37-46. doi:10.1016/j.matbio.2016.01.013. pmid: 26844756. pmcid: pmc4842154. 3. betarbet u, blalock tw. keloids: a review of etiology, prevention, and treatment. j clin aesthet dermatol. 2020;13(2):33-43. pmid: 32308783. pmcid: pmc7158916. 4. thornton nj, garcia ba, hoyer p, wilkerson mg. keloid scars: an updated review of combination therapies.  cureus. 2021;13(1):e12999. doi: 10.7759/cureus.12999. pmid: 33542883. pmcid: pmc7847784 5. .cavalié m, sillard l, montaudié h, bahadoran p, lacour jp, passeron t. treatment of keloids with laser-assisted topical steroid delivery: a retrospective study of 23 cases. dermatol ther. 2015;28(2):74-78. doi:10.1111/dth.12187. pmid: 25471297. 6. bloom bs, brauer ja, geronemus rg. ablative fractional resurfacing in topical drug delivery: an update and outlook. dermatol surg. 2013;39(6):839-848. doi:10.1111/dsu.12111. pmid: 23294061. 7. yildirim s, gurel ms, gungor s, tekeli o, canat d. comparison of efficacy of chemical peeling with 25% trichloroacetic acid and 0.1% retinoic acid for facial rejuvenation. postepy dermatol alergol. 2016;33(3):199-205. doi:10.5114/ada.2016.60612. pmid: 27512355. pmcid: pmc4969415. figure 6. high resolution b mode ultrasonic imaging of a subcutaneous keloid with homogenous to hypoechoic echopattern. (a) before treatment showing that keloid thickness was: 0.175 cm while the length was: 1.10 cm. (b) after 4 sessions of fractional co2 followed by tca 20% showing decrease in the thickness to become 0.144 cm and in the length to become 0.666 cm, with moderate improvement. on cdu application the lesion was completely avascular before and after treatment. cdu = color doppler ultrasound; tca= trichloroacetic acid original article | dermatol pract concept. 2022;12(2):e2022072 9 the treatment of keloid scars. egypt j dermatol venerol 2013;33: 22-27.doi: 10.7123/01.ejdv.0000431207.04926.59. 22. heppt mv, breuninger h, reinholz m, feller-heppt g, ruzicka t, gauglitz gg. current strategies in the treatment of scars and keloids.  facial plast surg. 2015;31(4):386-395. doi:10.1055/s-0035-1563694. pmid: 26372714. 23. elrefaie am, salem rm, faheem mh. high-resolution ultrasound for keloids and hypertrophic scar assessment. lasers med sci. 2020;35(2):379-385. doi:10.1007/s10103-019-02830-4. pmid: 31240510. 24. lobos n, wortsman x, valenzuela f, alonso f. color doppler ultrasound assessment of activity in keloids. dermatol surg. 2017;43(6):817-825. doi:10.1097/dss.0000000000001052. pmid: 28195846. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022022 1 syphilitic balanitis of follmann: can dermoscopy be useful tool in the differential diagnosis? roberta vezzoni1, claudia colli2, giacomo rebez3, carlo trombetta3, andrea boltar3, iris zalaudek1, claudio conforti1 1 dermatology clinic, university of trieste, ospedale maggiore di trieste, italy 2 mst centre, asugi, trieste, italy 3 department of urology, university of trieste, asugi, trieste, italy key words: syphilitic balanitis of follmann, dermoscopy, dermatology, urology, sexually transmitted diseases citation: vezzoni r, colli c, conforti c, et al. syphilitic balanitis of follmann: can dermoscopy be useful tool in the differential diagnosis? dermatol pract concept. 2022;12(1):e2022022. doi: https://doi.org/10.5826/dpc.1201a22 accepted: june 2, 2021; published: january 2022 copyright: ©2022 vezzoni et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: claudio conforti, md, dermatology clinic, maggiore hospital of trieste, trieste, italy. e-mail: claudioconforti@yahoo.com introduction syphilis is a sexually transmitted infection caused by the spirochete treponema pallidum that has different clinical presentations. among them, there is follmann balanitis, that was first described by eugene follmann in 1948. it is a rare manifestation of primary syphilis that presents as erosive balanitis [1]. herein we report the dermoscopic description of a follmann balanitis and discuss how to differentiate it from other sexually transmitted or genital diseases. case presentation a previously healthy 28-year-old man was admitted to the urology department for the presence of painless erosions on the glans and erythema. he was initially treated with topic antibiotics and steroids but without benefit. physical examination revealed painless crusted erosions of the glans and foreskin associated with edema and ulceration of the coronal sulcus (figure 1a). dermoscopy revealed the presence of homogeneously distributed glomerular vessels and focused linear curved vessels on an erythematous background with hyperpigmented postinflammatory areas (figure 1b). b ilateral inguinal lymphadenopathy was also observed. the patient reported a high-risk sexual contact 2 months earlier. a polymerase chain reaction test performed for common sexually transmitted diseases was negative. serological tests for syphilis were positive: vdrl 1:32 and tpha 1:1280. based on these results, a diagnosis of follmann syphilitic balanitis was made. the first choice of treatment for primary syphilis is a single intramuscular injection of 2.4 million units of benzathine-penicillin, but due to allergy reported by the patient, treatment with doxycycline 100 mg twice daily for 14 days was started. at the one-month follow-up visit, complete healing of the glans was observed. 2 research letter | dermatol pract concept. 2022;12(1):e2022022 conclusions the clinical features of syphilitic balanitis or balanoposthitis are variable, as they can manifest as an edematous balanitis with erosions and crusted lesions or as a papular form with smooth white/pink coalescent papules and plaques on the surface of the glans. common clinical manifestations are the hardening of the glans penis and bilateral inguinal lymphadenopathy [1]. the differential diagnosis requires the exclusion of infectious such as candida albicans, groups b and d streptococci and herpes simplex virus, and noninfectious diseases such as lichen sclerosus et atrophicus, zoon balanitis, psoriasis, eczema, fixed drug rash and erythroplasia of queyrat (eq). even if dermoscopy is not the gold standard test for the diagnosis, it is a useful tool in the differential diagnosis. candidal balanitis is characterized by cottage cheeselike structures and blurry linear vessels, psoriasis is defined by a quite monomorphic pattern with diffusely distributed dotted vessels. on the other hand, glomerular vessels are a constant finding in eq while focused linear curved vessels and orange structureless areas are dermoscopic findings of zoon balanitis [2]. in our case, the presence of glomerular and hairpin vessels on an erythematous background without other typical signs of other pathologies helped us to exclude the differential hypotheses reported above. follmann erosive balanitis may be the only clinical expression of primary syphilis, so it is essential to include this rare clinical manifestation in the differential diagnosis of balanitis and balanoposthitis [1]. dermoscopy could be an extremely useful tool that can direct the experienced clinician towards the correct diagnosis and allow proper treatment. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. follmann e. le problème de la balanite syphilitique. ann dermatol syph. 1948;8:470–483. 2. conforti c, giuffrida r, di meo n, et al. benign dermatoses of the male genital areas: a review of the literature. dermatol ther. 2020;33(3):e13355. doi: 10.1111/dth.13355. pmid: 32239734. figure 1. (a) detail of the penis, glans, and foreskin. importantly, note the erosive erythema with adherent crusts and the presence of a hardened ulceration compatible with a chancre in the coronal sulcus. (b) dermoscopic evaluation of the coronal sulcus showing the presence of homogeneously distributed glomerular vessels and focused linear curved vessels on an erythematous background with hyperpigmented post-inflammatory areas. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021019 1 dermatology practical & conceptual dermoscopy of anserine folliculosis shekhar neema1, shivam goyal2 1 department of dermatology, armed forces medical college, pune, india 2 department of dermatology, kasturba medical college, mahe, manipal, india key words: lichen nitidus, anserine folliculosis, keratosis pilaris, dermoscopy citation: neema s, goyal s. dermoscopy of anserine folliculosis. dermatol pract concept. 2021;11(2):e2021019. doi: https://doi. org/10.5826/dpc.1102a19 accepted: september 10, 2020; published: march 8, 2021 copyright: ©2021 neema and goyal. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: both authors have contributed significantly to this publication. corresponding author: shivam goyal, mbbs, kasturba medical college, mahe, manipal, karnataka 576104, india. email: shivam. goyal3@learner.manipal.edu introduction anserine folliculosis is a rare dermatological entity presenting with multiple closely grouped follicular-oriented papules on the chin, neck, and jaw. it is difficult to clinically differentiate it from other folliculocentric keratotic disorders like keratosis pilaris, lichen nitidus, follicular mucinosis, and folliculotropic mycosis fungoides (fmf). dermoscopy can provide an essential clue in the diagnosis of anserine folliculosis and differentiate it from other known entities. case presentation here, we present 3 cases with rough lesions on the chin or jaw of varying duration (table 1). history of repeated friction in the area while studying was present. cutaneous examination revealed multiple, closely-set, grouped, skincolored, follicular-oriented papules on the chin, which felt like sandpaper on palpation (figure 1, a-c). general and systemic examination revealed no abnormality. a diagnosis of anserine folliculosis was made based on presentation. dermoscopy revealed white scales, yellow dots, and patulous follicular openings (figure 1, d-f). lichen nitidus, keratosis pilaris, follicular mucinosis, and fmf are other differential diagnoses of this presentation. dermoscopy was compared with features of other conditions (figures 2b and 3b). histopathological confirmation could not be done because the patients refused. all 3 patients were treated with topical tretinoin 0.025% cream and advised to restrict friction. anserine folliculosis mostly presents in a younger age group with follicular papules on the chin, neck, or jaw and has a sandpaper or goose skin-like feeling on touch. the patients usually give a history of friction or trauma, which has been considered a possible etiologic factor. however, it is table 1. case demographics and clinical features cases age sex clinical feature duration case 1 18 female grouped follicular papule, left jawline 2 months case 2 16 female grouped follicular papule, left jawline 2½ months case 3 21 female grouped follicular papules on chin 3 months 2 letter | dermatol pract concept 2021;11(2):e2021019 figure 1. clinical images show: (a) grouped follicular, skin-colored papules on the left jawline; (b) grouped follicular papules on left jawline; and (c) grouped follicular papules on chin and jawline. dermoscopy of anserine folliculosis shows: (d) white scales (blue arrow), patulous follicles and yellow dots (blue circle) (dermlite dl4, polarized, ×10); (e) white scales (blue arrow), patulous follicles and yellow dots (blue circle) (dermlite dl4, polarized, ×10) and (f) white scales (blue arrow), patulous follicles and yellow dots (blue circle) (dermlite dl4, polarized, ×10). not found in all cases. the presence of atopy has been linked to the incidence of anserine folliculosis. dermoscopic signs have not been elucidated to date. histopathological features include epidermis with hyperkeratosis, hypergranulosis, the focal presence or increase of the stratum lucidum, rudimentary follicles, and dilatation of follicular openings with retention of keratotic material [1]. hyperkeratosis corresponds to white scales on dermoscopy and dilatation of follicular openings with retention of keratotic material corresponding to patulous follicles and yellow dots. this condition can be compared to its close differentials, lichen nitidus, and keratosis pilaris. the absence of histopathological analysis is a limitation in our case series. lichen nitidus presents as multiple, tiny, discrete, shiny papules in clusters over the flexor aspect of upper extremities, genitalia, and anterior trunk (figure 2a). dermoscopy shows multiple white, well-circumscribed, circular areas with a smooth surface, and a brownish shadow inside the circle [2] (figure 2b). keratosis pilaris presents as keratotic follicular plugs with or without perifollicular erythema over the extensor aspect of forearms, thighs, trunk, buttocks, and face (figure 3a). dermoscopic features are twisted or coiled vellus surrounded by peripilar cast or scaling with or without perifollicular erythema and pigmentation (figure 3b). letter | dermatol pract concept 2021;11(2):e2021019 3 primary follicular mucinosis presents as one or several pink plaques, often composed of grouped follicular papules. dermoscopy features are dilated follicular ostia with follicular plugs of amorphous material. fmf presents as follicle-based patches, plaques, infiltrated plaques, tumors, and prurigo nodularis-like lesions, as well as keratosis pilaris-like lesions and acneiform lesions mostly on the head and neck region. dermoscopy shows dilation of follicular openings with partial destruction of hair follicles, orange-pink perifollicular clods, yellowish background, white/pigmented halos, white clods/structureless areas or short fine vessels, or a combination of these. these features were not seen in our cases. conclusion keratotic papules on the chin are a diagnostic challenge. anserine folliculosis is a rare entity that presents with similarities to follicular-oriented conditions. dermoscopy can aid in the diagnosis of this condition. references 1. rambhia kd, wankhade v, mukhi j, singh rp. traumatic anserine folliculosis. indian dermatol online j. 2017;8(1):59-61. doi:10.4103/2229-5178.198773. pmid: 28217481. 2. malakar s, save s, mehta p. brown shadow in lichen nitidus: a dermoscopic marker! indian dermatol online j. 2018;9(6):479480. doi: 10.4103/idoj.idoj_338_17. pmid: 30505802. figure 2. (a) clinical image shows grouped shiny white papules on the left elbow. (b) dermoscopy of lichen nitidus shows a white structureless area with a central brown area (blue circle). these structures interrupt underlying skin markings (dermlite dl4, polarized, ×10). figure 3. (a) clinical image shows skin-colored to hyperpigmented follicular papules with background hyperpigmentation over the left arm. (b) dermoscopy of keratosis pilaris shows twisted hair and peripilar cast (blue circle). erythema is present surrounding the follicle (blue arrow) (dermlite dl4, polarized, ×10) dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4): e2021106 1 body mass index and melanoma prognosis nicoletta cassano1,2, stefano caccavale3, gino a. vena1,2, giuseppe argenziano3 1 dermatology and venereology private practice, bari, italy 2 dermatology and venereology private practice, barletta, italy 3 dermatology unit, university of campania luigi vanvitelli, naples, italy key words: cutaneous melanoma, body mass index, breslow thickness, obesity citation: cassano n, caccavale s, vena ga, argenziano g. body mass index and melanoma prognosis. dermatol pract concept. 2021;11(4): e2021106. doi: https://doi.org/10.5826/dpc.1104a106 accepted: march 5, 2021; published: september 2021 copyright: ©2021 cassano et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: stefano caccavale, md, dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, via sergio pansini, 5, 80131 naples, italy. email: stefano85med@gmail.com introduction: obesity has been suggested as a risk factor in the progression of malignancies, including melanoma. most studies defined obesity using body mass index (bmi), although the index is considered an imperfect measure of body composition. objective: the aim of this article is to examine whether bmi can impact on the prognosis of cutaneous melanoma, regardless of anti-tumor therapy. the relationship between bmi and specific prognostic factors in melanoma patients has been reviewed. methods: literature search was conducted on pubmed using the terms “melanoma” and “body mass index” or “obesity”. we selected articles, published up to 30 november 2020, examining the prognostic aspects of melanoma. articles evaluating the risk and incidence of melanoma were excluded as well as studies regarding morbidity and complications following surgical procedures, or those performed in metastatic melanoma patients treated with anti-tumor therapies. results: mixed results have emerged from studies assessing the clinical outcomes in melanoma patients in relation to bmi. more consistent data seem to support the relationship between bmi and breslow thickness. conclusions: studies that focus specifically on the link between obesity and melanoma prognosis are limited; further research is needed to deepen our knowledge on this link. abstract 2 review | dermatol pract concept. 2021;11(4): e2021106 introduction there is a growing interest in exploring the relationship between cancer and anthropometric measures, including body mass index (bmi). excess body weight, accounting for both overweight (bmi within the range of 25-29.9 kg/m2) and obesity (bmi≥30 kg/m2), has notably increased worldwide over the last decades and has been associated with a higher risk for cancer of several anatomic sites [1]. obese status is characterized by the occurrence of systemic and tissue processes that might influence malignancies, such as release of cytokines and hormones from adipose tissues, chronic low-grade inflammation, increased estrogen levels, insulin resistance and hyperinsulinemia [2-4]. obesity has also been suggested to contribute to the risk and progression of cutaneous melanoma, whose major environmental risk factor is ultraviolet radiation (uv), especially as intermittent intense exposures. however, the analysis of the association between obesity and risk of melanoma has provided conflicting data so far [4,5]. recent studies have shown that increased bmi might improve outcomes in melanoma patients treated with targeted therapy and immunotherapy, providing further hints on the phenomenon known as the “obesity paradox”, although a lack of consistency has emerged from the currently available results and the issue is still under debate [6-9]. the aim of this article is to examine whether bmi can impact on the prognosis of cutaneous melanoma, regardless of anti-tumor therapy. for this purpose, the relationship between bmi and specific prognostic factors in melanoma patients has been reviewed. methods articles in english published up to 30 november 2020 were obtained from the pubmed database. a literature search was conducted using the terms “melanoma” and “body mass index” or “obesity”. we collected full article copies that were considered potentially eligible, including review articles as appropriate. the reference lists of retrieved manuscripts were also checked to find other eligible papers. we selected articles focused on prognostic aspects of melanoma (e.g., mortality/survival, relapse, metastases, progression, and histologic prognostic factors). articles investigating the risk and incidence of melanoma were excluded, as well as those on morbidity and complications after surgical procedures. studies regarding patients with metastatic melanoma treated with anti-tumor therapies have also been excluded from our review process, as this topic was beyond the purposes of this manuscript and would deserve a separate wide discussion. results melanoma outcomes only a limited number of studies have evaluated the survival rate and/or the risk of recurrence or progression in relation to bmi among melanoma patients. as previously specified, our analysis did not include studies assessing outcomes in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. no significant variations in the overall risk of mortality for melanoma according to bmi were detected in a prospective cohort study involving nearly 1.2 million uk women aged 50-64 years who were recruited into the million women study during the period 1996-2001 and followed up, on average, for 5.4 years [10]. similarly, a study on more than 900,000 adults in the usa showed no increased mortality rates from melanoma for higher categories of bmi in males or females [11]. in a total of 340 italian melanoma patients (mean breslow thickness=0.4 mm), prognosis was found to be similar in normal weight patients and in overweight/obese patients [12]. a recent analysis of the leeds melanoma cohort, with a median follow-up length of 6.7 years, showed that bmi was not associated with overall and melanoma-specific survival [13]. the comparison of 131 relapsed melanoma patients with 147 non-relapsers reported no effect of bmi on the risk of relapse [14]. in a small study that found a correlation between serum levels of leptin and sentinel lymph node metastases in melanoma patients, the mean bmi was identical for the sentinel node-positive and sentinel node-negative groups, ruling out obesity as an explanation for higher leptin values in patients with positive sentinel nodes [15]. instead, other findings seemed to indicate a variable influence of bmi on melanoma outcomes. a study of the leeds melanoma cohort, comprising 2,182 melanoma patients enrolled in the period 2001–2013, has revealed that bmi was not significantly associated with survival when it was treated as a continuous variable [hazard ratio (hr) 1.04 per 5 units, 95% confidence interval (ci) 0.91–1.18; p = 0.6)] [16]. instead, overweight individuals had better survival than subjects with normal weight after adjustment for age and sex, and after further adjustment for site and breslow thickness. the protective effect was not observed in obese patients. an analysis of data from participants in the same cohort previously showed that bmi was predictive of relapse even when corrected for breslow thickness [17]. increased bmi has been associated with worse survival in an usa investigation of 1,186 patients with surgically resected melanoma, 75% of whom had stage i or ii disease [18]. overweight patients showed a trend towards elevated review | dermatol pract concept. 2021;11(4): e2021106 3 risks of disease recurrence and death; such risks were significantly increased in obese patients (p < 0.05). however, outcome associations were weakened or lost their significance following adjustment for c-reactive protein (crp). in a retrospective analysis of 261 korean patients with primary cutaneous melanoma, overweight and obesity (bmi>23 kg/m2) were significantly associated with the development of metastases [odds ratio (or)=2.10, 95% ci 1.2–3.6] and with shorter overall survival (p = 0.033) [19]. it should be highlighted that the cut-off values for the definition of overweight and obesity are lower for asian populations as recommended by the world health organization (who), and in the korean study overweight status was defined as a bmi of 23 to 24.9 kg/ m2, while a bmi≥25 kg/m2 defined the obesity status [19,20]. breslow thickness and other histological prognostic factors some studies have investigated the relationship between bmi and breslow thickness. the characteristics of the largest and most important studies are summarized in table 1. de giorgi et al reported no association between overweight status (bmi≥25 kg/m2) and the risk of thick melanoma (breslow thickness more than 1 mm) in the total sample or men, whereas a trend towards association between bmi≥25 kg/m2 and the risk of thick melanoma was shown among women (or=1.64, 95% ci 0.82–3.28), and especially postmenopausal women (or=2.50, 95% ci 1.06–5.88) [21]. in the report by gandini et al [22], bmi was independently identified as significantly associated with breslow thickness. in the multivariate random effects model, median breslow thickness was 1.2 for bmi≥25 kg/m2 versus 0.8 for bmi<25 kg/m2 (p = 0.0008), and the multivariate logistic model disclosed a significant association of higher bmi with thick melanoma [the comparison of bmi≥25 kg/m2 vs. bmi<25 kg/ m2 produced an or of 1.34 (95% ci 1.12–1.59; p = 0.001)]. skowron et al reported that bmi≥30 kg/m2 was associated with the risk of higher breslow thickness (or=2.78, 95% ci 1.55–4.94; p = 0.001) [23]. in the multivariate analysis of significant clinical and histological criteria, these authors found that obesity had an increased risk of higher tumor thickness (or=1.86, 95% ci 0.91–3.77), but without any statistical significance (p = 0.086). when considering only clinical features in the model, obesity was significantly associated with a risk of higher breslow thickness (or=2.33, 95% ci 1.21–4.49; p = 0.011). the clinical characteristics of melanoma, its topography and visibility were not associated table 1. principal studies exploring the relationship between bmi and breslow thickness: general aspects and characteristics of melanoma cases authors de giorgi et al [21] gandini et al [22] skowron et al [23] stenehjem et al [24] study type retrospective caseseries study (single center, florence, italy) hospital-based multicenter study (italy) cross-sectional study in a prospective cohort (single center, valence, france) prospective populationbased cohort study; linkage to national cancer registry (norway) study period jan 1998-jan 2009 dec 2010-dec 2013 may 2007-may 2010 1972-2014 cases of primary melanoma examined 605 86.4% thin melanomas (including in situ melanomas) 2738 50% thin melanomas; 29% very thick melanomas; 25% ulcerated melanomas; 1% with distant metastases; 13% with lymph node involvement 427 65% thin melanomas; 17.6% very thick melanomas 2570 53.4% thin melanomas; 23.7% very thick melanomas; 4% with regional metastases, 1% with distant metastases; 16% unspecified excluded cases patients < 40 yrs of age (when stratifying by age, because of their low number) alm, mucosal, in situ and retrospective melanomas in situ, recurrent, ocular, mucosal and metastatic melanomas not histologically verified or retrospective melanomas gender 55% women; 45% men 49% women; 51% men 50% women; 50% men 44.6% women; 55.4% men age, yrs mean 53.06 (sd 16.02) median 55 mean 57.74 (sd 16.1) mean age at diagnosis 60 height and weight at the first visit, measured by a physician collected through a self-administered questionnaire measured (information not further specified) measured by trained staff mean bmi (sd), kg/m2 24.78 (4.09) not reported 25.38 (4.61) 24.7 (3.3) table 1 continues 4 review | dermatol pract concept. 2021;11(4): e2021106 with the distribution of bmi categories. instead, melanoma subtypes were differently distributed according to bmi categories (p = 0.007), with superficial spreading, lentigo maligna, and unclassified melanomas mostly found in patients with normal bmi, acral lentiginous melanoma in preobese patients and nodular melanoma in the obese patients [23]. following these publications, the study of stenehjem et al was the first to model breslow thickness as a continuous outcome in relation to anthropometric measures which were obtained prediagnostically [24]. breslow thickness was found to be significantly increased with increasing values of bmi (p trend = 0.009). a bmi>30 kg/m2 was associated with significantly higher tumor thickness as compared to normal weight patients (geometric mean ratio 1.16, 95% ci 1.04–1.30). when melanomas were stratified by anatomical site and histological variants, significant positive trends were seen for continuous variables of bmi in trunk and lower limb melanomas and in superficial spreading melanomas, respectively, but not in melanomas localized in other sites or in other histological subtypes. the shape of the expoauthors de giorgi et al [21] gandini et al [22] skowron et al [23] stenehjem et al [24] bmi categories, kg/ m2 (%) <25 (58%); ≥25 (42%) <25 (47%); ≥25 (53%) <25 (49%); 25-29.9 (38%); ≥30 (13%) < 18.5; 18.5-22.9; 23-24.9; 25-27.4; 27.5-29.9; ≥30 (% not reported) main statistical and methodological information effect of bmi on the risk of thick melanoma estimated in terms of or using a logistic regression analysis. stratification for sex and age classes, with adjustment for age (linear) within each age class and histological subtype. breslow thickness stratified into two groups: thick and thin multivariate analyses with breslow thickness as the response variable. multivariate random effects models, with center as a random factor; multivariate logistic models, taking into account possible confounding factors (including age, gender, educational and professional level, phenotype, residence, season of diagnosis, speciality of diagnosing doctor). breslow thickness stratified into two groups: thin and thick, considering also very thick melanoma and additionally evaluating breslow thickness as a continuous measure univariate and multivariate analyses, accounting for significant clinical and histopathological features. breslow thickness stratified in four groups following the ajccms, 7th ed. linear regression with log e -transformed breslow thickness (relationship with breslow thickness as a continuous outcome). adjustment for age at diagnosis, sex, ambient uv radiation of residence, average intensity of sunburns, occupational uv exposure, physical activity, education, smoking status, height. use of adjusted mean values of breslow thickness (in mm) by restricted cubic splines in generalized linear regression models (shape of the associations with breslow thickness). site of melanoma, % not reported not reported trunk 48%; head and neck 15%; upper limbs 13%; lower limbs 24% trunk 51%; head and neck 11%; upper limbs 12.5%; lower limbs 24%; not specified 1.5% histopathological subtype of melanoma ssm 89.8%; um 1.15%; lmm 3.3%; nm 2.65%; alm 1.8%; rm 1.3% not reported ssm 62%; um 17%; lmm 13.5%; nm 4%; alm 3.5% ssm 63%; nm 19%; other 4%; not specified 14% breslow thickness (mm) mean 0.87 (sd 1.07) not reported mean 1.36 mm (sd 2.47) median 1.0 (iqr 0.6-2) thin melanoma = breslow thickness ≤1 mm; thick melanoma = breslow thickness > 1 mm; very thick melanoma = breslow thickness > 2 mm ajccms= american joint committee on cancer melanoma staging; alm= acral lentiginous melanoma; bmi= body mass index; iqr= interquartile range; lmm= lentigo maligna melanoma; nm= nodular melanoma; or= odds ratio; rm= rare melanoma; sd= standard deviation; ssm= superficial spreading melanoma; um= unclassifiable/unclassified melanoma; uv= ultraviolet table 1. principal studies exploring the relationship between bmi and breslow thickness: general aspects and characteristics of melanoma cases (continued) review | dermatol pract concept. 2021;11(4): e2021106 5 sure–response curves indicated that mean breslow thickness increased until a bmi of 29 kg/m2, then plateaued at a mean of approximately 2.5 mm before declining for the highest values. in addition, when breslow thickness was examined as a dichotomous outcome according to bmi in overweight and postmenopausal women, as previously done by de giorgi et al [21], stenehjem et al did not confirm a significant association; however they did not stratify by menopausal status owing to the low number of postmenopausal participants at baseline [24]. the relationship between bmi and breslow thickness has been examined in other investigations. fang et al enrolled 1,804 patients with melanoma from 1998 to 2008, and bmi information was available for 1,186 patients. they found that increased bmi was weakly associated with increased tumor thickness, and also with older age and increased log [crp] [18]. in a retrospective study of 261 patients diagnosed with primary cutaneous melanoma in 7 korean centers between 1997 and 2017, overweight and obesity statuses (bmi>23 kg/m2) were significantly associated with increased breslow thickness [19]. a multivariate cox’s proportional hazards analysis gave a hr value of 25.62 (95% ci 5.44–120.65; p < 0.001) for the association between breslow thickness and bmi categories more than 25 kg/m2. in 100 melanoma patients enrolled within days of their melanoma diagnosis in brisbane, australia, there was a positive association between bmi and breslow thickness (or 1.12, 95% ci 1.01-1.26; p = 0.04 per unit increase in bmi) [25]. in a total of 340 italian patients with melanoma (mean breslow thickness of 0.4 mm), a significant correlation between bmi and breslow thickness (p < 0.01) was noted [12]. a recent analysis of the leeds melanoma cohort has evidenced that bmi was independently associated with thicker melanomas [13]. there are few data regarding the association of bmi with other histological features that have a prognostic value. skowron et al, in their study focusing on breslow thickness, observed that ulceration was more frequent in obese patients, although the trend was not significant [23]. similarly, von schuckmann et al noted that overweight/obese status was positively associated with ulcerated melanoma, but, again, not significantly [26]. the evaluation of the leeds melanoma cohort showed that higher bmi was associated with ulceration, in the univariable analysis, but this association did not persist in the multivariable analysis. ulceration was also associated with lower vitamin d levels [16]. in an italian cohort, a significant correlation between bmi and mitotic rate (p = 0.02) was seen [12]. in another italian study, absence of tumor infiltrating lymphocytes, a finding that appears to predispose to metastatic melanoma, was detected more frequently in obese than in non-obese melanoma patients (or=3.92, 95% ci 1.31–11.7; p = 0.010) [27]. discussion the relationship between obesity and melanoma appears to be complex. there are conflicting findings regarding the association between obesity and risk of cutaneous melanoma [4,5]. some cohort and case-control studies showed a variable positive correlation between obesity and melanoma risk, at least in men, while other studies found no convincing proofs of any association [5,10,28-32]. caution should be used for the interpretation of such data. first, evidence for an association does not necessarily support a causal relationship. moreover, methodological aspects differ between studies and could explain such divergences. it has been suggested to consider the possible effect of residual confounding by environmental and lifestyle risk factors, such as sunlight exposure, among obese and overweight subjects, as well as the variation of both bmi and other factors over time [29]. the assessment of the association between bmi and different clinical outcomes in melanoma patients (mortality/survival, risk for recurrence, sentinel node positivity, and metastases) yielded mixed results, with absence of any apparent influence according to some studies [10-16], better prognosis for overweight subjects but not for obese patients shown in one study [16], and worse outcomes for increased bmi values found by other authors [17-19]. the unfavourable outcome associations observed by fang et al were weakened or lost their significance after adjustment for crp, suggesting that elevated bmi can affect melanoma progression through mechanisms related to metabolic syndrome and/or chronic systemic inflammation, as indicated by crp concentration [18]. various reports have highlighted the link between bmi and breslow thickness [12,13,18,19,21-25], a well-established prognostic factor of cutaneous melanoma [33]. a great part of the literature exploring the obesity-melanoma connection is based on studies that adopted bmi levels to define obesity. nevertheless, bmi is thought to be an imperfect measure of body composition that is not able to differentiate between muscle and adipose tissues or to provide information on the distribution of adipose tissues, whether central, peripheral or in the context or proximity of target organs [2,34]. it is increasingly accepted that other parameters (eg, hip circumference, waist circumference, waist-to-height ratio and waist-to-hip ratio) may more accurately reflect body fat distribution. furthermore, bmi can be a less accurate marker of adiposity among older people, due to the natural trends toward reduction in height, loss of muscle and increase of adipose tissue in ageing, especially in 6 review | dermatol pract concept. 2021;11(4): e2021106 post-menopausal women [2]. regardless of the above-mentioned limitations and the need of further studies specifically designed to overcome such limitations, bmi may be interpreted as a marker reflecting, at least partially, the effect of genetic and biological mechanisms, as well as lifestyle and environmental factors. the biological mechanisms underlying the obesity-cancer link seem to be intricate and are still unclear. ever-growing evidence supports the involvement of adipose tissue in tumor development and progression via endocrine and/or paracrine pathways, secreting a variety of molecules that alter systemic and local microenvironments [1]. the obesity-related dysfunctional adipose tissue and the active cross talk between adipocytes and melanoma cells can contribute to melanoma aggressiveness and progression through the release of pro-inflammatory, pro-angiogenic and lymphangiogenic factors, as well as extracellular matrix remodelling molecules, fatty acids, and probably other substances contained into the adipocyte exosomes [4,35-40]. the obesity-related changes include a chronic state of low-grade inflammation, adipokine imbalances, elevated levels of growth factors, and hormones, such as insulin, insulin-like growth factor (igf)-1, and estrogens [1,3]. the cytokine profile of adipose tissue includes specific adipokines that may interfere with cellular processes by acting on signaling pathways, such as pi3k/akt, mapk, and jak/stat [41]. in obesity, adipocytes produce less adiponectin, that has anti-inflammatory and anti-neoplastic effects, but more leptin, that can contribute to melanoma growth and metastases [4,5,15]. experimental findings suggest the association between obesity and aggressive tumor biology with a “meta-inflammatory” state, increased immune aging and t cell dysfunction [7]. a direct role of obesity on melanoma growth and progression has been documented by investigations in animal models. diet-induced obesity has been demonstrated to increase melanoma progression in mice [42], while controlling obesity has proved to reverse the effect on melanoma progression [43]. the association between obesity and melanoma might be conditioned by many other factors, such as genetic mechanisms and insulin resistance, as well as the increased body surface, gut microbiota dysbiosis, and decreased levels of vitamin d [5,29,44,45]. several data were suggestive of an inverse association between vitamin d serum levels and melanoma thickness at diagnosis [17,25,45,46]. a recent study reported that bmi and low vitamin d levels were independently associated with thicker tumors [13]. moreover, moreno-arrones et al, while registering decreased vitamin d serum levels at melanoma diagnosis, described a significant association of this finding with both tumor mitotic rate and ulceration and a borderline association with breslow thickness and bmi [47]. genetic mechanisms have also been implicated, although the available data are still inconclusive. a genetic link between obesity and pigmentation has been proposed, as well as the role of obesity susceptibility loci in determining the risk and aggressiveness of melanoma, involving, for instance, certain vitamin d receptor polymorphisms and genetic variations in igf-1 or estrogen receptor pathways [5,45,48,49]. a strong association between breslow index and the igf-1(ca)19 repeat frequency was found (p < 0.001) in one study [50]. fang et al investigated some bmi-associated single-nucleotide polymorphisms (snps) in relation with melanoma risk or outcome. in particular, the c allele in the rs17782313 snp (within the melanocortin-4 receptor) was associated with increased bmi and poorer overall and melanoma-specific survival among patients with stage i/ii melanoma, showing a trend towards the association with elevated crp [18]. beyond biological mechanisms underlying the relationship between bmi and melanoma thickness, stenehjem et al tried to explain their results also based on behavioural mechanisms [24]. in particular, obesity and body dissatisfaction have been associated with reduced skin self-examination and consequently with the risk of delayed detection of lesions, whereas the decline in adjusted mean breslow thickness for the highest anthropometric values observed by those authors in their study might reflect a less sun-seeking attitude. moreover, according to skowron et al [23], obese people could be at higher risk of hidden melanomas because of their larger skin 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practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021; 11(4):e2021094 1 variability in the histopathological diagnosis of non-melanocytic lesions excised to exclude melanoma ian katz1, tony azzi2, alister lilleyman2, blake o’brien3, brian schapiro4, curtis thompson4,5, tarl prow6,7 1 southern sun pathology, thornleigh, nsw, & school of medicine, university of queensland, qld, australia 2 newcastle skin check, charlestown, nsw, & school of medicine, university of queensland, qld, australia 3 sullivan nicolaides pathology, bowen hills, & school of medicine, university of queensland, qld, australia 4 cta pathology, oregon, usa 5 oregon health and sciences university, oregon, usa 6 future industries institute, university of south australia, sa, australia 7 skin research centre, york biomedical research institute, hull york medical school, university of york, york, united kingdom key words: melanoma, diagnosis, seborrheic keratosis, artificial intelligence, ai, large cell acanthoma citation: katz i, azzi t, lilleyman a, o’brien b, thompson c, prow t. variability in the histopathological diagnosis of non-melanocytic lesions excised to exclude melanoma. dermatol pract concept. 2021; 11(4):e2021094. doi: https://doi.org/10.5826/dpc.1104a94 accepted: february 23, 2021; published: october 2021 copyright: ©2021 katz et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: ik and tp acknowledge the skin cancer college of australasia, brisbane, qld, australia. tp acknowledges the rattigan family foundation for their melanoma research support. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ian katz md, southern sun pathology, school of medicine, university of queensland, australia. email: driankatz@gmail.com introduction: the differential diagnosis of lesions excised to exclude melanoma include a variety of benign and malignant melanocytic and non-melanocytic lesions. objectives: we examined the variability between pathologists in diagnosing non-melanocytic lesions. methods. as part of a larger study prospectively examining the diagnosis of lesions excised to exclude melanoma in 198 patients at a primary care skin cancer clinic in newcastle, australia, we compared diagnosis made by 5 experienced dermatopathologists, of 44 non-melanocytic lesions in 44 patients aged 22-90. results: forty-four lesions (out of 217 in total) were non-melanocytic. among the 5 pathologists who examined each case there was marked variability in the terminology used to diagnose each case. the most common variability was found between seborrheic keratosis, large cell acanthoma, solar lentigo, and lichenoid keratosis. the diagnosis made by the majority of the pathologists was deemed to be the reference diagnosis. versus majority diagnosis, 4% of benign lesions were considered malignant, and 7% of malignant diagnoses were considered as benign. conclusions: the different terminology adopted and lack of consensus in the diagnosis of these non-melanocytic lesions in this setting suggests that training ai systems using gold standards may be abstract 2 research | dermatol pract concept. 2021; 11(4):e2021094 introduction clinically concerning skin lesions are commonly excised to rule out melanoma [1, 2]. common clinical mimics of melanoma, excluding the various forms of naevi, include benign and malignant entities such as seborrheic keratosis (sk), solar lentigo (sl), hemangioma, pigmented actinic keratosis, large cell acanthoma (lca), lichen planus-like keratosis/lichenoid keratosis (lplk), pigmented intraepithelial squamous cell carcinoma (iscc), or even pigmented basal cell carcinoma (bcc) [3]. cysts [4] and dermatofibromata [3] may also be occasionally excised to exclude melanoma.  these lesions are generally easily managed. the consequence of misdiagnosis is less serious than for melanoma. however, these lesions represent a significant workload in dermatopathology. the difficulty in diagnosing melanocytic lesions, especially borderline lesions, among pathologists, and how using a management-based response such as the melanocytic pathology assessment tool and hierarchy for diagnosis (mpath-dx) can improve the classification of such lesions has been reported [5]. there is significant overlap in the understanding of many of the benign lesions excised to exclude melanoma, particularly in sun-damaged skin, with many clinicians and pathologists struggling to define and distinguish lesions such as sk, lca, sl and lplk [6-10]. similarly, with regard to malignant lesions that can be included in the clinical differential diagnosis of melanoma, a 2008 report from ramos-ceballos et al described only moderate pathologists’ agreement (0.575 concordance) in a curated series of actinic keratosis and squamous cell carcinoma in situ cases [11]. this supports the hypothesis that there is a considerable difficulty when diagnosing both benign and malignant non-melanocytic lesions that are in the differential diagnosis of melanoma. with the recent advances made in whole slide imaging technology it may soon be possible to use artificial intelligence (ai) to support the diagnosis. ai will however require a gold standard diagnosis [12]. in this report, we present the first prospective study evaluating the agreement between dermatopathologists on the diagnosis of non-melanocytic lesions to exclude melanoma. forty-four non-melanocytic lesions out of 217 total lesions, including melanocytic lesions, were biopsied to exclude melanoma. biopsies were collected in a prospective manner to exclude case-selection bias. thus, this case set represents a collection of non-melanocytic clinical mimics of melanoma. five pathologists diagnosed each case, results show a significant variation in the diagnostic terminology, which aligns with prior reports on melanocytic lesion diagnostic terminology [5]. variability was highest with sk, lca, and sl diagnoses. we used a consensus diagnosis for comparison. a total of 4% of benign lesions were over-diagnosed and 7% of malignant lesions were underdiagnosed. the highest levels of agreement were found when diagnosing bcc, cysts, df, and angioma. the remaining 37 cases had varying terminology regarding actual diagnosis. these results support the need to develop a classification schema that clarifies diagnoses by eliminating the natural language currently in use for diagnosis. this will help to bridge the gap between human pattern recognition and automated diagnosis. methods human ethics and volunteers cases in this report were collected as part of a larger prospective study on the preclinical, clinical, and histological diagnosis of lesions excised to exclude melanoma, with ethics approval by bellberry human research ethics committee, australia (protocol id 2018-08-613-a-3). patients were recruited prospectively from april to december 2019 in a primary care skin cancer clinic in newcastle, nsw, australia. patients with a suspicious lesion that required shave or formal excision to exclude melanoma were asked to participate in the study. all non-melanocytic lesions including a single case thought by only one pathologist to be melanocytic in origin, and lentigo simplex (ls) were included in this report. pathologist diagnoses the first author of this article (ik) reviewed each case and chose one or more representative sections including relevant immunohistochemistry stains. five experienced dermatopathologists from australia and the usa reviewed each case. each pathologist had more than 8 years’ experience and each examined, on average, more than 15,000 skin samples/ year. the australian pathologists reviewed the glass slides while the 2 usa pathologists reviewed digital slides. there were no significant differences between glass slide and digital diagnoses. pathologists were informed about the patients’ age, sex, and basic clinical details, present on the pathology request form. they were then asked to (1) provide a one-line problematic. we propose a new management classification scheme called molem (management of lesions excised to exclude melanoma) which expands the previously described mpath-dx to include non-melanocytic lesions. research | dermatol pract concept. 2021; 11(4):e2021094 3 diagnosis, and (2) assign a risk class according to what we term molem (management of lesions to exclude melanoma) (table 1). the molem schema was adapted from the mpath-dx classification [5]. the slides presented for each case were taken as representative of the lesion including the assumption that the lesion went to the margins of the excision. the lesion diagnoses fell within molem classes i (benign) and v (malignant). the majority molem class diagnosis was taken as reference standard in terms of benign versus malignant. if there was a tie in the majority molem diagnostic class, the malignant class was assumed to be the gold standard. slide scanning and raw data slide scanning with a leica at-2 scanner (magnification x 40) and digital slides were uploaded to pathpresenter digital slide presentation platform for those pathologists who were assigned to review the digital slides. statistical analysis statistical analysis was conducted using microsoft excel 2016 and graphpad prism v7.03. results a total of 217 lesions from 198 patients were biopsied to exclude melanoma. within that biopsy pool 44 lesions from 44 patients were non-melanocytic. the average age of the patients was 67 years, there were 20 male and 24 female patients. one case was thought, by just one pathologist, to be melanocytic in origin and was included in this study. we included ls in the non-melanocytic lesions. details concerning the site of the lesion, patients’ age, and the final diagnosis made by the 5 pathologists for all examined lesions, are listed in table 2. diagnoses included sk or a variant of sk, ak, pigmented ak, iscc, lca, sl, ls, and lplk. cysts, bcc, a dermatofibroma, and an angioma were also included. there was marked variation in the diagnostic terminology used by the pathologists. discrepant diagnoses (benign versus malignant) are highlighted in red (table 2). pathologists gave 219 interpretations in total (44 lesions x 5 pathologists). one pathologist did not report one case. the 7 cases that were bcc, cysts, df, and the angioma had no discrepant diagnoses. of the other 37 cases, 12 (32%) received essentially the same diagnosis from all pathologists but with a slightly different table 1. molem reporting schema for skin lesions’ classification into 5 classes. molem class suggested management examples i no further treatment or topical benign naevus, low grade atypia, seborrheic keratosis, lichenoid keratosis, cyst, dermatofibroma, large cell acanthoma ii narrow but complete excision <5mm moderately atypical naevus, spitz iii complete excision with > 5mm but < 10mm margins melanoma in situ, severely atypical naevus iv complete excision with > 10mm margins invasive melanoma v non-melanoma skin cancer management, possibly including complete excision basal cell carcinoma, in situ and invasive squamous cell carcinoma table 2. pathologists’ diagnoses for the 44 cases. case p1 p2 p3 p4 p5 majority class 1 sl ls sl sl sl 1 2 pak pak sl and sk lca, ak and iscc iscc epidermolytic hk 1 3 sl sl/early sk sl sl sk 1 4 pig iscc arising in sk sk, macular, heavily igmented sk, inflamed sk sk 1 5 pig iscc, ak ak with adnexal extension, pigmented pak iscc pak, focal iscc 5 6 pig flat sk/lca sl/early sk sl/early sk lca sk 1 7 pig iscc   pig iscc iscc iscc 5 table 2 continues 4 research | dermatol pract concept. 2021; 11(4):e2021094 case p1 p2 p3 p4 p5 majority class 8 sl with lichenoid regression macular sk sl/early sk, inflamed (early lplk) sl, lplk sk 1 9 sl/flat sk wth lichenoid regression sk, macular, heavily pigmented sl/early sk, inflamed ak, sl, lplk sl/sk 1 10 sl, changes of regression, possible lplk sl lk lk post inflamatory pigmentation 1 11 sl sk, macular heavily pig sl sl sl 1 12 pig sk sk sl, ak sl, pak sk 1 13 pig early iscc with erosion, lichenoid inflamation lplk lplk lplk sk 1 14 sl sl sl, inflamed sl ephelis, sl 1 15 sl sl pak sl sk 1 16 sk sk, pig sk sk sk 1 17 favour irritated flat sk ls with underlying stasis sl/early sk lca lk 1 18 iscc arising in sk sk, pigmented favour clonal sk over iscc sk sk 1 19 pak, early iscc pak pak, inflamed pak pak 1 20 pak pak pak pak ak 1 21 pak and al pak, hypertrophic pak pak ak 1 22 sk sk sl/early sk sk sk 1 23 lplk lplk sk, inflamed (early lplk) lplk, possible subtle lentig proliferation lplk 1 24 irritated sk, dermal inflamation sk inflamed atypical squamous proliferation, inflamed iscc ak 5 25 late stage lplk lichenoid dermatitis with late stage lplk lplk (end stage) lplk sl 1 26 sk and pityriasis versicolour sl and early sk sl/sk lca sl 1 27 sk sk sk sk sk 1 28 porokeratosis lplk late stage porokeratosis and sl lplk porokeratosis 1 29 sl lentigo sl lca sl 1 30 overlapping sl and pig sk sk, reticulated and pigmented sk and sk, inflamed pak, sl, lca sl/sk 1 31 sk macular sk ak, slightly inflamed sk sk 1 32 sl sl sl sl sl 1 33 sl sl sl/early sk sl sk 1 34 sk pig sk sk, pigmented sk sk 1 35 pig sk sk sk, inflamed sk sk 1 table 2. pathologists’ diagnoses for the 44 cases (continued). table 2 continues research | dermatol pract concept. 2021; 11(4):e2021094 5 table 3. pathologists’ accuracy for non-melanocytic lesion diagnosis compared to majority diagnosis (bcc, cysts, df, angioma excluded). consensus reference diagnosis pathologists’ interpretation class v total interpretation (no) % concordanceclass i class i benign 167 8 175 95% class v malignant 2 7 9 78% total 169 15 184   table 4. pathologists’ accuracy for non-melanocytic lesion diagnosis compared to majority diagnosis (all cases). consensus reference diagnosis pathologitsts’ interpretation class v total interpretation (no) % concordanceclass i class i benign 182 8 190 96% class v malignant 2 27 29 93% total 184 35 219   case p1 p2 p3 p4 p5 majority class 36 sk sk sk sk sk 1 37 sl lentigo sl jmn with atypia sl 1 38 bcc bcc pinkus type bcc bcc bcc 5 39 pig bcc, superficial type bcc, pigmented bcc bcc bcc 5 40 df df df df df 1 41 pig bcc bcc, nodular, pigmented bcc, pigmented bcc bcc 5 42 tc pilar/tc follicular cyst, isthmictype (pilar or trichilemmal) pc pc 1 43 bcc bcc superficial and nodular bcc nodular bcc bcc 5 44 favour lymphangioma over hemangioma lymphangioma benign vascular neoplasm hemangioma lymphangioma 1 p1-p5= five different pathologists; sl=solar lentigo; ls=lentigo simplex; ak=actinic keratosis; pak=pigmented ak; lca=large cell acanthoma; sk=seborrheic keratosis; iscc=intra-epidermal squamous cell carcinoma; pc=pilar cyst; tc=trichilemmal cyst; pig=pigmented; bcc=basal cell carcinoma; lentig=lentiginous; lplk=lichen planus like keratosis; jmn=junctional melanocytic naevus terminology. if we exclude the 7 cases of bcc, cysts, df, and angioma, 5% of the majority benign diagnoses were considered to be malignant by at least 1 pathologist, and 22% of the majority malignant diagnoses were considered to be benign by at least 1 pathologist (table 3). if all lesions are included, 4% of the majority benign lesion diagnoses were considered to be malignant, and 7% of the majority malignant diagnoses were considered to be benign (table 4). figures 1-3 illustrate 3 representative cases. figure 1 was taken from a 59-year-old male (table 2, case 6) with a lesion on the upper back with the clinical history “? mis”. this represents one of the cases where different diagnoses were given by the 5 pathologists. the suggested diagnoses included pigmented flat sk, lca, early sk, and sl. figure 2 was taken from a 73-year-old female presenting with a lesion on the left side of the neck, (table 2, case 32) with a clinical history of “? melanocytic lesion”. the case shown in figure 2 is the one where complete diagnostic agreement was found between pathologists. the case was diagnosed as a solar lentigo. figure 3 shows a 65-year-old woman presenting with a lesion on her 6 research | dermatol pract concept. 2021; 11(4):e2021094 figure 1. (a) clinical image showing a solitary asymmetric pigmented macule in sun-damaged skin of upper back. (b) dermoscopy shows central brown dots and grey areas, and at 6-9 o’clock possible abnormal network with rhomboidal structures, and at 1-3 o’clock features of regression. (c) stained pathology slide (h&e, x20), cropped from the pathpresenter wsi shows slightly thickened epidermis but with minimal cytologic atypia and most pigment in basal keratinocytes. this is a link to the wsi: https://pathpresenter.net/#/public/display?token=34352199. figure 2. lesion unanimously diagnosed as solar lentigo. (a) clinical and (b) dermoscopic images show broad lentiginous pigment with some asymmetry and a possible abnormal network. (c) pathology (h&e, x20), showing bulbous acanthosis of epidermis hyperkeratosis increased basal pigmentation, mainly in keratinocytes. the wsi images are found at https://pathpresenter.net/#/public/display?token=1d8609e3. research | dermatol pract concept. 2021; 11(4):e2021094 7 calf (table 2, case 13). three different diagnoses were made in this case: lplk with reactive change, early pigmented iscc, and sk. discussion this is the first prospective study comparing the diagnosis made by dermatopathologists of non-melanocytic lesions excised to exclude melanoma. anecdotally, we observed that there was marked variability in the terminology adopted by 5 experienced dermatopathologists to describe and diagnose lplk, sl, sk, and lca. this prospective study also reported some disagreement between benign versus malignant lesions’ diagnoses. benign lesions were over-diagnosed by 4% and malignant lesions were under-diagnosed by 7% compared to majority diagnosis. subjectivity in the assessment of melanocytic lesions has been well documented in the literature [5] but our study is the first to prospectively show subjectivity with non-melanocytic lesions.  our results reflect inter-observer variability in a set of otherwise common lesions. there is controversy in both the literature and clinical practice regarding the relationship between lca, sk, lplk, sl, and ak [7]. whether lca is a distinct entity, or a subtype of sk is still a matter of debate. sanchez and requena report that lca was a distinctive entity [10]. however, rowert and ackerman asserted that lca is a variant of sl, and that sl (including the large cell variant) is a stage in the evolution of reticulated sk and of lplk [9]. rhabhari and pinkus reported that lca was an ak [8]. on the other hand, fraga and amin [6] investigated whether lca is a variant of solar lentigo by comparing macroscopic, microscopic, and immunophenotypic attributes of lca with conventional solar lentigo, seborrheic keratosis, actinic keratosis, and bowen disease. they concluded that lca is best considered a variant of solar lentigo with cellular hypertrophy. all of this helps explain why there is such low agreement in the diagnoses between these entities among pathologists distinguishing a sk from iscc can occasionally be challenging, both histologically and clinically [13-15]. an accurate diagnosis differentiating benign versus malignant is important. the resulting diagnosis determines treatment options which could severely impact patients with lesions in figure 3. lesion that was either defined as lichenoid keratosis, intra-epidermal squamous cell carcinoma, or seborrheic keratosis by pathologists participating to this study. (a) clinical image shows an asymmetrical lesion with red/pink and brown within sun damaged skin. (b) dermoscopy shows a pink and brown, traumatized lesion, possible peripheral network, and central inflammation. (c) dense lichenoid chronic inflammatory infiltrate with interface change with some squamous atypia that for some pathologists was diagnostic for intra-epidermal squamous cell (h&e, x10). (d) sox-10 immunohistochemistry (magnification 10x) with no significant increase in melanocytes. the wsi image of the h&e can be found at https://pathpresenter.net/#/public/display?token=0c88e847. 8 research | dermatol pract concept. 2021; 11(4):e2021094 cosmetically sensitive areas. there are case reports of malignant transformation of sk to scc and iscc within a sk is not uncommonly seen in routine dermatopathology practice. there is debate about whether this represents true transformation, chance observation of collision between the two types of lesions, or initial misdiagnosis [13]. there are a number of studies suggesting that immunohistochemical stains could be used to distinguish sk from scc, eg ki-67 and p16 [14], or bcl-2 and imp3 [15], but this is not generally used in routine clinical practice. in the current study, there were 5 lesions (11% of lesions) for which difficulty in distinguishing sk from iscc was reported. it can be argued that distinguishing histologically benign lesions has no clinical consequences. however, we argue that making a consistent diagnosis is important for 2 main reasons. firstly, we observed that the differential diagnosis of keratotic lesions including intra-epithelial squamous cell carcinoma of acanthotic type, and their management could be quite different to the management of morphologically similar benign lesions. secondly, as ai becomes more prevalent in assisting both clinical and histopathological diagnoses of these lesions, it is vital to establish gold standard diagnoses for training ai systems. we hypothesize that the high level of difficulty in accurately diagnosing the lesions histologically to produce a gold standard diagnosis is likely to significantly reduce ai performance [16]. this can be addressed by extensive research on the subject and through the integration of molecular diagnoses. adamson and welch discussed the problems in deriving a gold standard diagnosis in pathology [12]. any inherent bias in the data used to train an ai algorithm, will reflect on the final result.  the potential for biased data to negatively influence ai-based programs was made evident in the healthcare sphere [17].  thus, in the early stages of ai in skin pathology, we will have to face the problem of how to create a dataset with minimal bias in terms of disease classification and diagnoses. to help address the issue of variation in the diagnostic terminology we developed a classification schema called molem (management of lesions excised to exclude melanoma) that groups lesions with similar management strategies. this schema extends upon the mpath-dx developed by piepkorn et al [5], which only accommodates melanocytic lesions. to create more harmony in the diagnosis of the non-melanocytic lesions excised to exclude melanoma, we suggest several approaches firstly, the features of each lesion could be better defined in a consensus type meeting, with examples depicted as has been demonstrated in the development of the mpath -dx system [5]. molecular studies may help, as well as correlation with clinical and dermoscopic images, because the clinical impression can often be more typical than the histological impression. an alternative would be to term many of the lesions all “benign keratoses” or “benign keratinocytic lesion” with a note that few potential entities fall under this umbrella, and it is impossible to accurately distinguish them. it is unclear which approach would be most beneficial when defining entities for training ai algorithms. the use of an ‘umbrella’ term may accurately reflect how lesions such as sl, sk, lplk, and lca exist on a morphologic spectrum, but over-simplifying classification systems might hinder the potential for machine-based learning algorithms to offer new, and previously unrecognized insights into disease biology. regarding the issue of distinguishing benign from malignant lesions in 4% to 7% of cases, it would be beneficial to add a note with the lesions’ diagnosis to explain the diagnostic difficulty and recommend a clinical follow-up. on a similar note, it has been suggested that dividing lesions into 3 categories: benign, malignant, and “i do not know”/ uncertain” and place a comment with the latter category, might be helpful. it has been suggested that the use of ai for the diagnosis of skin lesions will be “more consistent and replicable than those based on human interpretation, but they may not be any closer to the truth” [12]. there are a few limitations to this study. firstly, this is a small study with 5 dermatopathologists submitting a diagnosis for each case. another potential weakness of the study is that some pathologists looked at routine glass slides and other pathologists looked at digital slides. finally, because these were not routine reports, there is the risk that the slides were not examined in as much detail as normal. conclusions we show that there is significant inter-pathologist variation in the terminology and diagnosis of benign lesions excised to exclude melanoma. inter-pathologist variation in distinguishing benign lesions from malignant lesions was also observed. we have proposed a new management classification scheme called molem (management of lesions excised to exclude melanoma) which expands the previously described mpath-dx to include non-melanocytic lesions. our hypothesis is that this approach has the potential to 1) clarify communication between pathologists and clinicians for improved clinical management, and 2) provide a structured diagnostic schema for future work in ai and molecular diagnostics fields. supplementary material all pathology slides for the lesions discussed in this paper are available at: https://pathpresenter.net/#/public/presentation/display? token=d08ddedf references 1. marchetti, ma, a yu, j nanda, et al. number needed to biopsy ratio and diagnostic accuracy for melanoma detection. research | dermatol pract concept. 2021; 11(4):e2021094 9 j am acad dermatol. 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10.1016/j. jaad.2013.07.027. pmid: 24176521. pmcid:pmc3992990. 6. fraga, gr and sm amin. large cell acanthoma: a variant of solar lentigo with cellular hypertrophy. j cutan pathol. 2014; 41(9):733-9. doi: 10.1111/cup.12369.pmid: 24917472. 7. patsatsi, a, e lazaridou, c fotiadou, a kyriakou, and d sotiriadis. large cell acanthoma: a debate throughout the decades. dermatol pract concept. 2014; 4(1):43-5. doi: 10.5826/ dpc.0401a05. pmid: 24520512. pmcid: pmc3919838. 8. rahbari, h and h pinkus. large cell acanthoma. one of the actinic keratoses. arch dermatol. 1978; 114(1):49-52. doi: 10.1001/ archderm.114.1.49. pmid: 619783. 9. roewert, hj and ab ackerman. large-cell acanthoma is a solar lentigo. am j dermatopathol. 1992; 14(2):122-32. doi: 10.1097/00000372-199204000-00006. pmid: 1533104. 10. sanchez yus, e, e del rio, and l requena. large-cell acanthoma is a distinctive condition. am j dermatopathol. 1992; 14(2):1407; discussion 148. doi: 10.1097/00000372-199204000-00011. pmid: 1566974. 11. ramos-ceballos, fi, st ounpraseuth, and td horn. diagnostic concordance among dermatopathologists using a threetiered keratinocytic intraepithelial neoplasia grading scheme. j cutan pathol. 2008; 35(4):386-91. doi: 10.1111/j.16000560.2007.00827.x. pmid: 18333899. 12. adamson, as and hg welch. machine learning and the cancer-diagnosis problem no gold standard. n engl j med. 2019; 381(24):2285-2287. doi: 10.1056/nejmp1907407. pmid: 31826337. 13. cimpean, i, i theate, and o vanhooteghem. seborrheic keratosis evolution into squamous cell carcinoma: a truly modified sun-related tumor? a case report and review of the literature. dermatol reports. 2019; 11(1): 7999. doi: 10.4081/dr.2019.7999. pmc6477930. pmid:31044056 pmcid:pmc6477930 14. bahrani, e, p sitthinamsuwan, th mccalmont, and lb pincus. ki-67 and p16 immunostaining differentiates pagetoid bowen disease from “microclonal” seborrheic keratosis. am j clin pathol. 2019; 151(6):551-560. doi: 10.1093/ajcp/aqz001.pmid: 30852607. 15. richey, jd, ac deng, k dresser, p o’donnell, and km cornejo. distinguishing between irritated seborrheic keratosis and squamous cell carcinoma in situ using bcl-2 and imp3 immunohistochemistry. j cutan pathol. 2018; 45(8):603-609. doi: 10.1111/ cup.13269. pmid: 29726030. 16. brinker, tj, a hekler, ah enk, et al. deep learning outperformed 136 of 157 dermatologists in a head-to-head dermoscopic melanoma image classification task. eur j cancer. 2019; 113: 47-54. doi: 10.1016/j.ejca.2019.04.001. pmid: 30981091. 17. richens, jg, cm lee, and s johri. improving the accuracy of medical diagnosis with causal machine learning. nat commun. 2020; 11(1): 3923. doi: 10.1038/s41467-020-17419-7. pmid:32782264. pmcid:pmc7419549. dermatology: practical and conceptual quiz | dermatol pract concept 2016;6(4):12 51 dermatology practical & conceptual www.derm101.com the patient an 87-year-old woman with a history of multiple basal cell carcinomas presented to a follow-up visit referring a pigmented, slowly growing lesion on her right scapula that had been present for one year. physical examination revealed an irregular 12 x 5 mm well circumscribed pigmented lesion with an elevated keratotic surface (figure 1). the dermoscopic evaluation revealed a multicomponent pattern: many colors, superior irregular pigmented network with blue-white veil and inferior cerebriform pattern surrounded by atypical pigmented network with sharp demarcation (figure 2). the patient underwent complete exeresis of the lesion and the specimen was stained with hematoxylin-eosin. histopathological examination showed a papillomatous epidermal hyperplasia with hyperkeratosis and cell nests in the dermoepidermal junction (figure 3) and proliferation of atypical intraepidermal melanocytes with a pagetoid spread (figure 4). what is your diagnosis? an irregular pigmented lesion on the back monica gonzalez-olivares1, laura najera2, dolores arias-palomo1 1 department of dermatology, hospital universitario de fuenlabrada, madrid, spain 2 department of pathology, hospital universitario de fuenlabrada, madrid, spain citation: gonzalez-olivares m, najera l, arias-palomo d. an irregular pigmented lesion on the back. dermatol pract concept 2016;6(4):12. doi: 10.5826/dpc.0604a12 copyright: ©2016 gonzalez-olivares et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. corresponding author: monica gonzalez-olivares, md, servicio de dermatología, hospital universitario de fuenlabrada, camino del molino 2, 28942 fuenlabrada, madrid, spain. email: mgonzalezo@salud.madrid.org figure 1. close up-view of the scapular area shows an irregularly pigmented lesion with a verrucous surface. [copyright: ©2016 gonzalez-olivares et al.] figure 2. dermoscopic features. multicomponent pattern. [copyright: ©2016 gonzalez-olivares et al.] 52 quiz | dermatol pract concept 2016;6(4):12 to mutations in growth factors more than just a coincidental collision between tumors [2]. these mutations may result in an altered cell-to-cell communication between melanocytes and keratinocytes that would lead to an abnormal proliferation of melanocytes and/or keratinocytes [2]. taking into account the potential consequences of overlooking a malignant melanoma, thorough clinical and dermoscopic evaluations should be performed in all patients with seborrheic keratosis in order to provide a correct diagnosis before proceeding to any destructive treatment. references 1. cascajo cd, reichel m, sánchez jl. malignant neoplasms associated with seborrheic keratoses. an analysis of 54 cases. am j dermopathol 1996;18:278-82. pmid: 8806962. 2. defazio j, zalaudek i, busam kj, cota c, marghoob a. association between melanocytic neoplasms and seborrheic keratosis: more than a coincidental collision? dermatol pract concept 2012;2(2):9. pmid: 23785597. doi: 10.5826/dpc.0202a09. 3. salerni g, alonso c, gorosito m, fernandez-bussy r. seborrheic keratosis-like melanoma. j am acad dermatol 2015;72:s53-5. pmid: 25500043. doi: 10.1016/j.jaad.2014.07.009. 4. thomas i, kihiczak ni, rothenberg j, ahmed s, schwartz ra. melanoma within the seborrheic keratosis. dermatol surg 2004;30:55961. pmid: 15056152. doi: 10.1111/j.1524-4725.2004.30178.x. 5. repertinger s, wang j, adickes e, sarma dp. melanoma in-situ arising in seborrheic keratosis: a case report. cases j 2008;1:263-5. pmid: 18947402. doi: 10.1186/1757-1626-1-263. 6. jones-caballero m, peñas pf, buezo gf, fraga j, aragüés m. malignant melanoma appearing in a seborrheic keratosis. br j dermatol 1995;133:1016-8. pmid: 8547029. doi: 10.1111/j.13652133.1995.tb06953.x. 7. yakar jb, sagi a, mahler d, zirkin h. malignant melanoma appearing in seborrheic keratosis. j dermatol surg oncol 1984;10:382-3. pmid: 6232304. diagnosis melanoma in situ arising in a seborrheic keratosis answer and explanation although previously reported, the presence of a malignant melanoma within a seborrheic keratosis is extremely rare [1,2]. seborrheic keratoses are common non-melanocytic epidermal tumors that are usually well recognized clinically. despite this, an accurate diagnosis may be troublesome at times. dermoscopy is a non-invasive method and diagnostic aid and should be performed in all lesions [3]. in addition to melanocytic nevi, malignant neoplasms arising within or adjacent to seborrheic keratoses have been previously documented [1,2,4-7]. cascajo et al performed a retrospective analysis of 54 malignant neoplasms in conjunction with seborrheic keratoses, most of them corresponding to basal cell carcinomas, followed in number by squamous cell carcinomas and two malignant melanomas [1]. in addition to the cases reported by cascajo et al, a handful of cases of melanoma arising in seborrheic keratoses have been reported in the literature [2,4-7]. this association is believed to be more than a simple coincidental collision between tumors, and the term compound tumor is proposed as the most appropriate appellation [1,2]. a possible explanation is that neoplasms may derive from the different cells that compose seborrheic keratoses: basal cell carcinoma from the predominant basaloid cells, squamous cell carcinoma from the pale eosinophilic spinous cells and malignant melanoma from the melanocytes admixed among the keratinocytes [1]. based on previous findings, defazio et al postulated that the association of nevus and melanoma with seborrheic keratosis might be due figure 3. papillomatous epidermal hyperplasia with hyperkeratosis and cell nests in the dermoepidermal junction. hematoxylin-eosinstained section of the specimen (original magnification, 40x). [copyright: ©2016 gonzalez-olivares et al.] figure 4. proliferation of atypical intraepidermal melanocytes with a pagetoid spread. note large epithelioid cells with nuclear atypia and abundant cytoplasm. hematoxylin-eosin-stained section of the specimen (original magnification, 200x). [copyright: ©2016 gonzalez-olivares et al.] dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021115 1 prurigo pigmentosa: dermoscopic evaluation hitaishi mehta1, anuradha bishnoi1, keshavamurthy vinay1, akanksha kaushik1, muthu sendhil kumaran1, arpitha kollabathula2, debajyoti chatterjee2, uma nahar saikia2, davinder parsad1 1 department of dermatology, venereology and leprology, postgraduate institute of medical education and research, chandigarh, india 2 department of histopathology; postgraduate institute of medical education and research, chandigarh, india key words: prurigo pigmentosa, keto rash, dermatoscopy, dermoscopy citation: mehta h, bishnoi a, vinay k, kaushik a, kumaran ms, kollabathula a, chatterjee d, saikia un, parsad d. prurigo pigmentosa: dermoscopic evaluation. dermatol pract concept. 2021;11(4):e2021115. doi: https://doi.org/10.5826/dpc.1104a115 accepted: march 3, 2021; published: october, 2021 copyright: ©2021 mehta et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: anuradha bishnoi, md, department of dermatology, venereology and leprology, postgraduate institute of medical education and research, sector 12, chandigarh, india. email: dranha14@gmail.com. introduction prurigo pigmentosa, also known as nagashima’s disease or “keto rash”, is an uncommon inflammatory disorder of unknown etiology with a predilection for young asian females. while erythematous papules, papulovesicles, and pruritus predominate in the acute stage, later lesions are characterized by pigmentary changes. both stages might also present a reticulated pattern and frequently coexist. dermoscopy is a non-invasive tool that allows for in-vivo detailed visualization of cutaneous lesions. the patterns seen on dermoscopic evaluation can also be correlated with histopathologic findings. although several cases of prurigo pigmentosa have been reported in literature, data on dermatoscopy for this condition is scarce. we evaluated the dermoscopic patterns in a patient with prurigo pigmentosa. we conclude that these patterns correlate with histopathological findings. case presentation a 21-year-old woman sought dermatology consultation for a recurring rash over her trunk over the last 3 years. individual lesions started as itchy, raised, and brownish bumps, which resolved over the next few days leaving brownish pigmentation. she had received topical corticosteroids and oral antihistamines in the past with minimal improvement. on examination of anterior trunk, the patient had multiple hyperpigmented papules overlying large brownish patches predominantly distributed in the intermammary and periumbilical distribution (figure 1). on dermatoscopy (dermlite ii hybrid m dermatoscope, magnification ×10 in polarized noncontact mode equipped with apple iphone 6 plus camera), lesions in varying stages of evolution could be discerned. papules revealed whitish scales, multiple irregularly distributed brownish black to blue-gray 2 letter | dermatol pract concept. 2021;11(4):e2021115 dots and globules, and blue-white veil-like structures over an ill-defined erythema background (figure 2a). resolving lesions demonstrated brownish background reticular pigmentation, islands of multiple irregular brown-gray dots sparing the skin creases, and prominent linear blood vessels (figure 2b). histopathology revealed mild hyperkeratosis, neutrophilic exocytosis, necrotic keratinocytes, interface dermatitis and pigment incontinence suggestive of prurigo pigmentosa (figure 2, c and d). the patient was started on figure 1. clinical image of anterior trunk showing multiple papules surmounted on with macular pigmentation. minocycline 100 mg once daily and showed resolution of erythematous pruritic papules (but not the hyperpigmentation) during a follow-up period of 2 months. conclusion only one case report has described the dermoscopic findings of prurigo pigmentosa. here we reported erythematous blanchable lesions in acute stage and grey spots at later stages [1]. due to the darker skin tone of our patient, erythema was less perceivable; however, the dots and globules could be easily appreciated. whitish scales in active lesions probably represented dyskeratosis, and blue-gray dots and globules represented extensive dermal pigment incontinence. the pattern of blood vessels could be seen in the resolving lesions in our patient and was linear rather than dotted. clinical differentials in our case included lichen planus, confluent and reticulated papillomatosis, primary cutaneous amyloidosis, darier disease, dowling-degos disease, and frictional melanosis. the dermoscopic differentials have been summarized in table 1. this case also shows resolving stages of all dermatoses characterized by interface dermatitis manifest blue gray dots and globules, albeit in different patterns and distributions; thus, making clinico-histologic and dermoscopic correlation mandatory [2]. we suggest the role of dermoscopy in providing support guiding diagnosis of prurigo pigmentosa, while acknowledging that these findings are based on the observation of a single patient. further studies with larger sample size are suggested to support the findings presented here. table 1. various differential diagnosis and their dermoscopic features differential diagnosis dermoscopic features lichen planus wickham striae in varying patterns with dotted, globular, or linear vessels at periphery of the lesion. blue-gray dots in resolving stages confluent and reticulated papillomatosis polygonal, homogenous, brownish globules separated by whitish striae creating a cobblestone pattern along with fine whitish scaling frictional melanosis brownish structureless areas arranged in a reticular fashion acquired dermal macular hypermelanosis (admh) pigment dots, globules and blotches arranged in a dotted, chinese letter, hem-like, reticular, or diffuse pattern depending upon the severity of the disease [2] darier disease/grover disease centrally located yellow-brown polygonal or star-shaped area surrounded by whitish halo, along with whitish scales and dotted or linear vessels, often with white halo [3] dowling-degos disease irregular, star-shaped brownish outlines over a red–brown background with follicular plugging and inclusion cysts [4] prurigo pigmentosa (current case) whitish scales, brown-red structureless areas, irregularly distributed blue-gray dots and globules, and blue-white veil-like structures over a background of erythema letter | dermatol pract concept. 2021;11(4):e2021115 3 figure 2. (a) dermoscopic image of a fully developed lesion showing whitish scales (arrows), brown-red structureless areas with poorly defined borders (red stars), multiple irregularly distributed brownish blue-gray dots and globules (yellow stars), and blue-white veil like structures (white ovals) over a background of erythema (dermlite ii, hybrid m, ×10, polarized).(b) resolving lesions demonstrated brownish background reticular pigmentation surmounted by volcano-like islands composed of multiple irregular brown-gray dots and prominent linear blood vessels (white arrows, dermlite ii, hybrid m, ×10, polarized). (c) histopathology revealed mild hyperkeratosis, acanthosis, and superficial dermis showing perivascular inflammation on low power view. (d) histopathology revealed basal cell vacuolization, pigment incontinence, apoptotic keratinocytes (arrow in inset), neutrophilic exocytosis, and interface dermatitis evident on high power magnification. references 1. bolewska a, słowińska m, bożek p, czuwara j, paluchowska e, owczarek w. prurigo pigmentosa: not that uncommon? first case in central and eastern europe. dermoscopy. postepy dermatol alergol. 2019;36(4):498-500. doi: 10.5114/ada.2019.87455. pmid: 31616229. pmcid: pmc6791151. 2. vinay k, bishnoi a, parsad d, saikia un, sendhil kumaran m. dermatoscopic evaluation and histopathological correlation of acquired dermal macular hyperpigmentation. int j dermatol. 2017;56(12):1395-9. doi: 10.1111/ijd.13782. pmid: 28971471. 3. errichetti e, stinco g, lacarrubba f, micali g. dermoscopy of darier’s disease. j eur acad dermatol venereol. 2016;30(8):1392-4. doi: 10.1111/jdv.13238. pmid: 26248700. 4. piccolo v, corneli p, russo t, danielsson m, zalaudek i, argenziano g. classic dowling degos disease: a rare genodermatosis. g ital dermatol venereol. 2019. doi: 10.23736/s03920488.19.06386-7. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(4):e2021099 1 recurrent aphthous stomatitis: treatment and management marco manfredini1, stefania guida1, matteo giovani1, nicola lippolis1, enrico spinas2, francesca farnetani1, annunziata dattola3, eleonora di matteo3, giovanni pellacani4, luca giannetti5 1 surgical, medical and dental department of morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, modena, italy 2 department of surgical sciences, university of cagliari, cagliari, italy 3 dermatology clinic, department of systems medicine, tor vergata university, rome, italy 4 dermatology clinic, department of clinical internal, anesthesiological and cardiovascular sciences, sapienza university of rome, rome, italy 5 surgical, medical and dental department of morphological sciences related to transplant, oncology and regenerative medicine, dental unit, university of modena and reggio emilia, modena, italy key words: oral, aphthae, recurrent, autoimmune, treatment, herpetiform, aphthosis, behçet disease citation: manfredini m, guida s, giovani m, lippolis n, spinas e, farnetani f, dattola a, di matteo e, pellacani g, giannetti l. recurrent aphthous stomatitis: treatment and management. dermatol pract concept. 2021;11(4):e2021099. doi: https://doi.org/10.5826 /dpc.1104a99 accepted: february 28, 2021; published: september , 2021 copyright: ©2021 manfredini et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: marco manfredini, md, surgical, medical and dental department of morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, via università, 4, modena, italy. email: manfredini07@gmail.com background: recurrent aphthous stomatitis consists of the presence of abrasions or ulcerations located on mucosae (oral or genital). objectives: the aim of this article is to review the current literature providing the main causes related to recurrent aphthous stomatitis and insights into treatment and management of this clinical condition methods: articles matching terms that correlated with “recurrent aphthous stomatitis” were searched on pubmed, embase, and cochrane library and selected according to their pertinence. results: several forms of aphthous stomatitis have been described, based on the extent (minor, major), morphology (herpetiform) and associations to other signs (behçet syndrome or more complex inflammatory syndromes). topical as well as systemic treatments have been described to obtain a faster remission of the aphthosis or to reduce associated symptoms such as pain. conclusions: recurrent aphthous stomatitis can have a mild-to-severe clinical appearance, being mainly localized on the oral mucosa or at the level of the genital area. different strategies have been described so far for its management and treatment. abstract 2 review | dermatol pract concept. 2021;11(4):e2021099 introduction aphtha is defined as a round abrasion or ulceration of oral (or genital) mucosa with a 2to 5-mm diameter [1]. lesions are usually covered by a fibrinous pseudomembrane, may be single or multiple, and usually resolve in 10-15 days, but generally recur. lesions are painful and are often exacerbated by food intake [1]. a specific etiologic factor has not been identified yet. there are at least 5 forms of aphthosis [1,2]: 1. recurrent aphthosis minor 2. recurrent aphthosis ulcer minor (mikulicz ulcer) 3. recurrent aphthosis ulcer major (sutton ulcer) 4. recurrent herpetiform ulcerations 5. behçet syndrome methods a search on the major medical literature databases including pubmed, embase and cochrane library was performed. the search was used the following search keys: “aphtha” and “recurrent” or “aphtha” and “treatment.” each article reporting relevant information on the pathogenesis as well as the management and treatment strategies was considered, and the main findings were included in the current review. diagnosis and treatment recurrent aphthous stomatitis (ras) [1], is a common oral disease characterized by multiple, small, round or oval mucosal ulcers with circumscribed margins, erythematous haloes, and yellow or gray floors that initially appear during childhood or adolescence. many diseases [3-10] that affect the oral cavity can have similar clinical presentations, making correct diagnosis difficult and sometimes delaying therapy. unfortunately, the etiology of ras of is still unknown. an ras diagnosis is based on history and clinical findings [2]. the lesions can range from 1 to several rounded, shallow, painful ulcers and recur in bouts from a few days to few months. there are at least 5 forms of ras, but the most common are minor (miras), major (maras), and herpetiformis ulcers (hu) [2]. minor ras is the most frequent, and it affects about 80% of patients with ras. aphthae are small, round or oval, usually with a gray-white pseudomembrane and an erythematous halo [1,2]. it usually occurs on non-keratinized surfaces, particularly the labial and buccal mucosa and the floor of the mouth, although it is uncommon on the gingiva, palate, or the back of the tongue [1,2]. aphthae usually heal within 10-14 days [2,11,12]. marasf is a severe form of ras that can be observed in about 10% of patients with ras. ulcers caused by maras can be larger than 1 cm and often develop on the lips, soft palate and fauces. they persist for figure 1. recurrent aphthous stomatitis in a patient with adamantiades-behçet disease. up to 6 weeks. maras frequently has its onset after adolescence, is chronic, and lasts for up 20 years or more [12,13]. herpetiformis ulcers affect about 1%-10% of patients with ras. up to 100 ulcers may be present at the same time, and while single lesions measure only few millimeters, they tend to coalesce to become large and irregular. hu are more frequent in women. despite its name, no association with herpesvirus has been found [12,13]. behçet disease (adamantiades-behçet disease [abd]) [14,15] is a chronic and multisystemic inflammatory disease, characterized by oral aphthae at its onset, with the successive appearance of ocular, vascular, gastrointestinal, nervous and mucocutaneous lesions (figure 1). abd mainly affects young (20to 40-year-old) males, but no age is spared [14,15]. the male: female ratio is reported to be from 3.1 to 1.1, with the same values being reported in the us and europe [14,15]. the etiology of abd is unknown but is most probably caused by an interplay of genetic and environmental factors [14-16]. multiple oral aphthae and ulcers can be observed in association with several other clinical findings in many autoimmune diseases [3,17] or be induced by medications [18], genetic disease [19,20], and other complex inflammatory syndromes, such as mouth and genital ulcers with inflamed cartilage (magic) syndrome [21], sweet syndrome [22-28], cyclic neutropenia [29-32], periodic fever with aphthae, pharyngitis and adenitis (sometimes termed pfapa syndrome) [33–35], nutritional deficiencies [36,37], gluten-sensitive enteropathy (celiac disease), inflammatory review | dermatol pract concept. 2021;11(4):e2021099 3 bowel disease, and immunodeficiencies [38,39] including hiv infection [40,41]. recurrent ulcerative lesions of the oropharyngeal mucosa can be associated with many viral or bacterial infections [40,42-44]; therefore, it is important to exclude an infectious etiology before initiating immunosuppressive or an immunomodulatory therapy. aids is a progressive viral infection caused by hiv-1/2 viruses, with ulcerative oral manifestations in 8% of the cases [45]. another cause of ulcerative lesions can be the herpes simplex virus infection (hsv-1/2) when oral and perioral ulcers are frequent symptoms. [43]. recurrent oropharyngeal ulcers have been described in several infectious diseases as such as: secondary syphilis, tuberculosis, histoplasmosis, lyme disease, covid-19, epstein-barr virus, and cytomegalovirus infection [44]. the role of helicobacter pylori as an etiology of ulcerative lesions of the oral cavity is still a matter of debate [42]. prevention and therapy several therapies, with variable degrees of supporting evidences, are available for the treatment of aphthous stomatitis [11]. treatment for recurrent aphthous ulcers is aimed at mitigating symptoms, shortening the healing time, and is used as a prophylaxis against recurrence. most of the treatments are prescribed without studies demonstrating therapeutic efficacy with respect to aphthous stomatitis. topical regimens are considered to be the standard treatment in mild cases of ras [2,11,46]. in more compromised cases, topical treatments are likewise very helpful in inducing lesion recovery, but they are often ineffective at prolonging disease-free intervals. medical care topical therapies can include the following: corticosteroids, cyclosporine, retinoids, antimicrobials, anesthetics [47]. topical corticosteroids are the first-line treatment, and they are used to reduce the local inflammation that induces ulceration. they include dexamethasone (0.5 mg/5ml), triamcinolone (.0,1% gel), fluocinonide (0.05% gel) and clobetasol (0.05% gel). clobetasol is a class 1 superpotent steroid, and is showing better results [2,46,47]. immunomodulatory agents, include cyclosporine and retinoids. cyclosporine has been prescribed as a systemic agent and a topical paste with variable reported efficacy, but it is now frequently used effectively as an oral rinse. isotretinoin (0.1% gel) and tretinoin in an adhesive base (0.1%), and retinoic acid in an oral base (.05%) have been prescribed for the management of ras [2,47,48]. also, systemic isotretinoin has been reported to be an effective therapy for recurrent aphthosis [49,50]. antimicrobials, including tetracycline, chlorhexidine gluconate, and diluted hydrogen peroxide have shown to reduce the duration and pain of oral aphthae [2,13]. anesthetics such as topical lidocaine (2% viscous solution, gel, or spray) or benzocaine have been used to reduce the pain associated to ras [13]. occlusive and bioadherent agents, such as gelclair, sucralfate, bismuth subsalicylate, and 2-octyl cyanoacrylate have been successfully used in ras management, because they can generate a protective coating that shields exposed and overstimulated nerve endings [11]. systemic agents systemic therapy includes the following drugs: colchicine, pentoxifylline, steroids, dapsone, thalidomide, pidotimod [16,51,52]. colchicine was reported to reduce the amount and duration of aphthae in up to 63% of patients with ras. treatment over 6 weeks, followed by long-term (years) therapy (1-2 mg daily) is recommended [53]. combination therapy with colchicine and pentoxifylline, benzathine penicillin, immunosuppressants, or interferon-alfa is possible [52]. systemic corticosteroids are prescribed as rescue therapy in patients with acute flares and in those who inadequately respond to therapy with colchicine and pentoxifylline. oral prednisolone or its equivalents, at 10-30 mg daily for up to 1 month can be prescribed during a ras exacerbation. intravenous pulse therapy at 100 mg daily for 3 days results in quick improvement for severe cases of ras [2]. dapsone (100 mg daily) can be prescribed for oral and genital aphthae; however, rapid relapses can occur after discontinuation of therapy. thalidomide at standard (100-300 mg daily) or low (50 mg daily) dosing levels was shown to be effective within 7-10 weeks following administration [54]. in a recent study a new therapeutic high dosage of pidotimod in children with pfapa (including ras) showed promising results. pidotimod is an immunomodulatory agent that increases antigen presentation and promotes adaptive th1-mediated immunity [55]. low laser therapy four types of lasers have been described in aphthae treatment: co2, nd:yag, diode, and ga1as [56]. the main goal of treatment is to decrease pain, healing time, number, and size of ulcers. the main advantage of laser therapy over other treatments is that it can be used for all the causes of the disease without systemic side effects. adamantiades-behçet disease systemic glucocorticoids are effective for most manifestations of abd. they are administered at doses of 50-60 mg of prednisone per day, or the equivalent, with a tapering scheme [14,15]. therefore, other therapies are often used instead of, or as an adjunct to systemic glucocorticoid therapy, such as 4 review | dermatol pract concept. 2021;11(4):e2021099 cyclosporine, colchicine, cyclophosphamide, dapsone, infliximab, interferon alfa-2a, and thalidomide [14-16,49,52]. when mucocutaneous lesions are the main concern in patients with mild-to-moderate aphthosis, the application of topical steroids may obviate the need for systemic therapy, mild aphthosis may also benefit from the applications of topical sucralfate, topical tetracycline, or a course of zinc sulfate (100 mg orally twice daily) or azithromycin (500 mg orally 3 times weekly) [51]. azathioprine also proved to be effective in a randomized clinical trial for the prevention of both oral and genital ulcers. in patients with more severe, recalcitrant mucocutaneous lesions, dapsone (100 mg daily) and thalidomide (100 mg daily) are considered particularly effective. conclusions recurrent aphthous stomatitis is a common disorder affecting the oral cavity with 3 main presentations: minor, major or herpetiformis ulcers. an ras diagnosis is often based on history and clinical findings. recurrent oral ulcerative lesions are rarely associated with several complex inflammatory syndromes and to viral or bacterial infections. therefore, it is always important to exclude the presence of a systemic or an infectious 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patients. oral surg oral med oral pathol oral radiol. 2020;130(4):398–401. doi: 10.1016/j. oooo.2020.06.009. pmid: 32622799. 55. radulescu m. the pharmacologic management of common lesions of the oral cavity. dent clin north am. 2016;60(2):407– 420. doi: 10.1016/j.cden.2015.12.003. pmid: 27040292. 56. akerzoul n, chbicheb s. low laser therapy as an effective treatment of recurrent aphtous ulcers: a clinical case reporting two locations. pan afr med j. 2018;30:205. pmid: 30574224. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022045 1 dermatology practical & conceptual introduction selective cyclin-dependent kinase 4/6 inhibitors (cdk 4/6i) – ribociclib, palbociclib and abemaciclib – are a novel therapeutic option for breast cancer [1]. cdk 4/6is are well tolerated and have shown a manageable safety profile, with mild hematological, gastrointestinal and cutaneous adverse events (ae). vitiligo-like lesions are a dermatologic ae exceptionally reported with cdk 4/6is use [2]. case presentation a 70-year-old woman presented with a 6-week history of asymptomatic facial hypopigmented spots. for the last 8 months, she was receiving treatment with letrozole and ribociclib for a hormone receptor-positive (hr-positive) and human epidermal growth factor receptor-2-negative (her2-negative) metastatic breast cancer. dermatological examination revealed unpigmented, well-defined macules distributed symmetrically in the neck and the face, with affectation of hair follicle (figure 1, a and b). the wood lamp examination showed bright white and sharply delineated lesions (figure 2). based on these findings, a diagnosis of vitiligo was made. discussion vitiligo is an acquired pigmentary autoimmune disorder consisting of the development of hypopigmented macules due to the selective loss of melanocytes. the cause of vitiligo remains unknown. vitiligo-like lesions have been reported as an ae in oncological patients treated with anti-programmed death-1/ programmed death-ligand 1 (pd-1/pd-l1) immunotherapies (pembrolizumab, nivolumab), as well as in patients treated with tyrosine-kinase inhibitors (imatinib, cabozantinib, pazopanib) [2]. it is considered an indicator of survival benefit in melanoma patients treated with anti-pd-1/pd-l1 immunotherapies. selective cdk 4/6is are currently approved by the us food and drug administration and the european medicines agency for the treatment of patients with hr-positive, her2-negative advanced or metastatic breast cancer. hematologic toxicity, gastrointestinal disturbances and fatigue are the most frequent side effects of this class of agents [1]. the most common dermatological adverse event is alopecia, which might be increased by the association of endocrine therapy. moreover, pruritus and a maculopapular rash have also been reported as cutaneous adverse reactions in patients treated with ribociclib [1,2]. ribociclib-induced vitiligo: a case report nicolás silvestre torner1, antonio aguilar martínez1, maría josé echarri gonzález2, sergio tabbara carrascosa1, jorge román sainz1, fernando gruber velasco1 1 department of dermatology, hospital universitario severo ochoa, leganés (madrid), spain. 2 department of oncology, hospital universitario severo ochoa, leganés (madrid), spain. key words: vitiligo, ribociclib, selective cyclin-dependent kinase 4/6 inhibitors, breast cancer, adverse event citation: silvestre-torner n, aguilar-martínez a, echarri-gonzález mj, tabbara-carrascosa s, román-sainz j, gruber-velasco f. ribociclib-induced vitiligo: a case report. dermatol pract concept. 2022;12(2):e2022045. doi: https://doi.org/10.5826/dpc.1202a45 accepted: july 29, 2021; published: april, 2022 copyright: ©2022 silvestre-torner et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: nicolás silvestre torner, department of dermatology. hospital universitario severo ochoa. avenida de orellana. zip code 28911. leganés (madrid). spain. e-mail: nicolassilvestretorner@gmail.com 2 research letter | dermatol pract concept. 2022;12(2):e2022045 figure 1. (a,b) clinical images. achromic sharply demarcated macules in the neck, cheeks and ears, with affectation of the hair follicle. figure 2. clinical image. bright white and sharply delineated lesions showed with wood lamp. vitiligo-like lesions have been described in patients treated with cdk 4/6is too, mostly in relation to ribociclib [2]. although the pathogenic mechanism between cdk 4/6is and vitiligo is still unclear, it has been classified as a class-related ae. the cell-cycle arrest and consequent apoptosis induced by cdk 4/6is [1], may lead to a premature death of melanocytes, that clinically manifests as achromic lesions. the prognostic meaning of vitiligo lesions in patients treated with cdk 4/6is remains still unclear. treatment of vitiligo induced by cdk 4/6i is challenging. similar therapeutic strategies followed in other vitiligo patients can be performed. however, immunosuppressants and biological therapies should be avoided in oncological patients. partial response has been achieved with topical immunosuppressants in combination with oral corticosteroids [2]. conlusions depigmentation may cause psychological distress and may decreased quality of life. therefore, oncological patients treated with cdk 4/6is should be informed about this potential ae and should be referred to a dermatologist for accurate diagnosis and treatment. references 1. rascon k, flajc g, de angelis c, liu x, trivedi mv, ekinci e. ribociclib in hr+/her2advanced or metastatic breast cancer patients. ann pharmacother. 2019;53(5):501–509. doi: 10.1177/1060028018817904. pmid: 30522347 2. sollena p, nikolaou v, soupos n, et al. vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors. breast cancer res treat. 2021;185(1):247-253. doi: 10.1007/s10549-020-05914-w. pmid: 32914354. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021108 1 a rare case of cutaneous metastasis of bladder transitional cell carcinoma tahel fachler1, diana prus2, amichay meirovitz3, yuval ramot1 1 department of dermatology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, israel 2 department of pathology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, israel 3 department of oncology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, israel key words: dermato-oncology, cutaneous metastasis, transitional cell carcinoma, bladder cancer citation: fachler t, prus d, meirovitz a, ramot y. a rare case of cutaneous metastasis of bladder transitional cell carcinoma. dermatol pract concept. 2021;11(4):e2021108. doi: https://doi.org/10.5826/dpc.1104a108 accepted: march 3, 2021; published: october, 2021 copyright: ©2021 fachler et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: yuval ramot, department of dermatology, hadassah medical center, hebrew university of jerusalem, the faculty of medicine, jerusalem, 9112001, israel. email: yramot@hadassah.org.il introduction cutaneous metastases originating from a primary solid visceral organ are an uncommon phenomenon, seen in 0.3% to 9% of patients [1]. cutaneous metastases from a urinary origin are especially rare, reported in only 1.1% of urologic malignancies [1]. although urothelial carcinoma is the third most prevalent malignancy in adults [2], cutaneous metastases from a genitourinary origin account for only 10.4% of cutaneous metastases. the current report provides a detailed description of a case with this rare condition. case presentation an 81-year-old man presented with a painful and tender lesion on his right arm, that had been growing for the last month. he had a clinical history of metastatic bladder transitional cell carcinoma (tcc), for the past 7 years, which was treated with radical cystectomy, chemotherapy, and immunotherapy. two years prior to admission he was treated with irradiation to the right humerus due to bone metastasis. at the time of presentation his disease was partially controlled with immunotherapy (pembrolizumab). he suffered from chronic lymphedema of the right arm due to radiotherapy-induced lymphatic injury, and he underwent a thrombectomy of an arterial occlusion on the same arm 1 month prior to presentation. he had no previous dermatological pathologies. clinical examination revealed a hardened plaque on the extensor aspect of the right arm, composed of coalescing erythematous-to-purple nodules, with partial ulceration in the middle of the lesion (figure 1a). the surrounding skin was edematous and swollen, with pigmentary changes consistent with radiotherapy-induced damage. a skin biopsy (figures 1, b-d and 2) revealed subcutaneous tissue infiltrated by poorly differentiated carcinoma cells with focal squamous differentiation and extensive necrosis (figure 1 b-d). immuno-histochemical analysis showed gata-3, p40 and ck20 positive staining (figure 2). based on the histological and immuno-histochemical findings, the diagnosis of metastatic urothelial carcinoma was made. 2 letter | dermatol pract concept. 2021;11(4):e2021108 conclusions cutaneous metastases have been reported more commonly in middle-aged and older men compared to women, and in most patients, they convey a grave prognosis, with patients typically surviving only a few weeks [2]. metastatic dissemination can occur by direct invasion, implantation on operative scars, and lymphatic or hematogenous spread [1]. in our patient, the latter is the most likely mode of dissemination due to focal vascular invasion that was observed in the primary tumor. cutaneous metastases in urothelial carcinoma pose a diagnostic challenge due to their infrequent occurrence, in addition to being further complicated by the long development period, usually several years after curative therapy [2]. additionally, they can have variable non-specific clinical presentations, such as urticarial, “nonspecific” macular rash [1], large erythematous indurated plaques, and other manifestations. differential diagnoses include radiation dermatitis, lymphedema, and lymphangiectasis, in addition to cutaneous drug reaction and opportunistic infections. in this report, we presented a rare case of cutaneous metastasis from tcc, at a progressive stage of a known metastatic malignancy. in this case, progressive disease was already present prior to the diagnosis of the dermal lesion. however, in 23.3% of cutaneous metastases, skin metastases are the first indication of malignancy. this report emphasizes the need for a cautious approach when assessing these lesions, in order to rule out metastasis at the different phases of malignant disease. references 1. thomas j mueller. cutaneous metastases from genitourinary malignancies. urology. 2004;63(6):1021-1026. doi: 10.1016/j. urology.2004.01.014. pmid: 15183939. 2. hasan o, houlihan m, wymer k, et al. cutaneous metastasis of bladder urothelial carcinoma. urol case rep. 2019;28:101066. doi: 10.1016/j.eucr.2019.101066. pmid: 31788428. figure 1. (a) an indurated and ulcerated plaque on the right arm of an 81-year-old man. (b-d) histopathology images of a skin biopsy taken from the lesion, showing major dermal infiltration by poorly differentiated carcinoma cells with focal squamous differentiation and extensive necrosis (h&e, (b) magnification x5, (c) magnification x20, (d) magnification x40). figure 2. immunohistochemistry of the skin biopsy taken from the right arm. (a) gata-3. (b) p40. (c) ck20 (x200). dermatology: practical and conceptual 1 intralymphatic histiocytosis emilio garcia-mouronte1, borja diaz-guimaraens1, emilio de dios berna-rico1, miguel dominguez-santas1 1 dermatology department, ramon y cajal university hospital, madrid, spain citation: garcia-mouronte e, diaz-guimaraens b, berna-rico e, dominguez-santas m. intralymphatic histiocytosis. dermatol pract concept. 2022;12(2):e2022067. doi: https://doi.org/10.5826/dpc.1202a67 accepted: september 6, 2021; published: april 2022 copyright: ©2022 iorizzo et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: emilio garcia-mouronte, md. dermatology department, ramon y cajal university hospital. carretera colmenar viejo km 9.100, 28034 madrid, spain. e-mail: emilio.garcia.mouronte@gmail.com case presentation an 87-year-old man presented to our dermatology department with a history of 1-year-long asymptomatic erythematous plaques on his left shoulder. he referred he had been previously diagnosed from severe osteoarthritis on this location. moreover, he denied taking regular medication, exposure to heat or suffering from any other medical condition. dermatological examination showed 2 mm wide serpiginous erythematous plaques with a vascular anatomic distribution on the anterior side of his left shoulder (figure 1). neither cervical nor axillary adenopathies were detected. after taking a punch-biopsy, a diagnosis of intralymphatic histiocytosis was established. teaching point intralymphatic histiocytosis is a benign proliferation of histiocytes within lymphatic vessels [1]. although its etiopathogenesis has not yet been clearly elucidated, it has been associated to several chronic inflammatory and degenerative disorders, such as osteoarthritis [2]. thus, dermatologists should take into account this entity whenever they are facing serpiginous erythematous plaques with a vascular distribution on a persistent swollen joint. image letter | dermatol pract concept. 2022;12(2):e2022067 figure 1. 2 mm wide serpiginous erythematous plaques with a vascular distribution on the left shoulder. 2 research letter | dermatol pract concept. 2022;12(2):e2022067 references 1. takiwaki h, adachi a, kohno h, ogawa y. intravascular or intralymphatic histiocytosis associated with rheumatoid arthritis: a report of 4 cases. j am acad dermatol. 2004;50(4):585–590. doi: 10.1016/j.jaad.2003.09.025. pmid: 15034508. 2. korman jb, burgin s, tahan sr. intralymphatic histiocytosis in association with severe osteoarthritis of the shoulder. j am acad dermatol. 2013;69(6):e314–e315. doi: 10.1016/j. jaad.2013.08.020. pmid: 24238195. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021056 1 calcipotriol/betamethasone dipropionate aerosol foam for plaque psoriasis: a prospective, observational, non-interventional, single-center study of patient adherence and satisfaction in daily use francisco josé navarro-triviño1, mario lozano-lozano2, ricardo ruiz-villaverde3 1 department of contact eczema and immunoallergic diseases, hospital universitario san cecilio, granada, spain 2 department of physical therapy, faculty of health sciences, and university of granada & sport and health joint university institute (imuds), granada, spain 3 department of psoriasis, dermatology, hospital universitario san cecilio, granada, spain key words: adherence, satisfaction, calcipotriol/betamethasone, aerosol foam, psoriasis citation: navarro-triviño fj, lozano-lozano m, ruiz-villaverde r. calcipotriol/betamethasone aerosol foam for plaque psoriasis: a prospective, observational, non-interventional, single-center study on patient adherence and satisfaction in daily use. dermatol pract concept. 2021;11(3):e2021056. doi: https://doi.org/10.5826/dpc.1103a56 accepted: december 29, 2020; published: may 20, 2021 copyright: ©2021 navarro-triviño et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this research was funded by leo pharma. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: francisco josé navarro-triviño, md, hospital universitario san cecilio, avenida de la investigación s/n, 18016 granada, spain. email: fntmed@gmail.com background: psoriasis is a chronic inflammatory disease that has a negative impact on patients’ quality of life. patients with mild–moderate psoriasis can be treated with topical medications, such as the combination drug calcipotriol/betamethasone dipropionate (cal/bd). objectives: this study investigated the adherence of psoriasis patients to therapy with cal/bd aerosol foam, as well as their satisfaction with the treatment’s efficacy, safety, and effect on their quality of life. methods: patients with mild–moderate plaque psoriasis were eligible to participate in this open-label, non-placebo controlled, prospective single-center study. adherence to treatment was assessed using the morisky-green scale 4 and 12 weeks after the start of treatment. satisfaction with the treatment was assessed using the abbreviated treatment satisfaction questionnaire for medication (tsqm-9). the severity of psoriasis was assessed on the miga and pga scales, and the impact on quality of life was assessed using the pdi and dlqi scales. results: a total of 65 patients entered the study. adherence to treatment was good, with 73.8% of patients showing high adherence at 12 weeks. satisfaction was also good, with 46 patients (70.8%) being completely satisfied. abstract 2 research | dermatol pract concept. 2021;11(3):e2021056 introduction psoriasis is a chronic inflammatory disease that affects 2%–4% of the western population [1]. it is characterized by the formation of well-defined erythematous-squamous plaques and a complex immune mechanism [2]. psoriasis is recognized by the world health organization as a debilitating, painful disease [3]. the association of comorbidities such as psoriatic arthropathy and the risk of cardiovascular disease make psoriasis a systemic disease. the disease has a psychological impact on patients, who have a greater risk of depression, anxiety, and even social stigmatization [4]. all of these have a significant negative impact on the patients’ quality of life. the development in recent years of biological drugs has revolutionized the treatment of psoriasis. however, topical medications are considered the cornerstone of therapy for many patients [5]. patients with a score less than 10 on a psoriasis severity index (eg, pasi, bsa, or dlqi) can be treated with topical monotherapy. patients with moderate plaque psoriasis who were treated with calcipotriol/betamethasone dipropionate (cal/bd) aerosol foam for 4 weeks achieved a psoriasis area and severity index (pasi) score of 75, which was higher than that achieved with 12-week methotrexate and acitretin therapy but similar to that with fumaric acid esters [6]. this finding reaffirms the indication for topical treatment in patients with mild–moderate plaque psoriasis. current guidelines recommend the topical use of a vitamin d analog (eg, calcipotriol) and a corticosteroid (eg, betamethasone dipropionate) as the first-line treatment for plaque psoriasis. the latest cochrane review on treatments for psoriasis [7] reported that the combined use of these drugs from different pharmacological groups is superior in efficacy and safety to their use separately. the combination of 0.005% calcipotriol and 0.064% betamethasone dipropionate has a lower rate of side effects than observed with topical corticosteroids (mainly skin atrophy) and vitamin d analogs (skin irritation and hypercalcemia) used separately. a new aerosol foam formulation of cal/bd (enstilar) for the treatment of plaque psoriasis was introduced in 2017. in an in vitro model of skin penetration of cal/bd aerosol foam, greater diffusion of both drugs and more stable skin concentrations were demonstrated [8]. the anti-psoriatic effect of cal/bd aerosol foam was superior to that observed with galenic ointment [9]. regarding safety, the muse study [10] demonstrated a good safety profile, and the pso-fast study [11] demonstrated efficacy and tolerability in patients with psoriasis of any severity level. adherence to topical treatment depends on multiple factors regarding the product itself and the patient. cosmetics and speed of action are essential for the patient to correctly comply with the drug dosage. however, other social and even occupational factors can significantly influence adherence. the main objective of this study was to determine the adherence to treatment with cal/bd aerosol foam in patients with mild–moderate plaque psoriasis 4 weeks after starting treatment. the secondary objectives were to evaluate the: (a) degree of patient satisfaction during and after treatment termination, and (b) treatment’ efficacy, safety, and impact on the patients’ quality of life. methods patients from november 2017 to november 2019, we recruited patients from the dermatology department at san cecilio university hospital. patients were eligible for the study if they were older than 18 years of age and had a clinical diagnosis of plaque psoriasis on the trunk and extremities for at least 6 months, with an affected body surface area (bsa) <10%, a pasi <10, and a dermatology life quality index (dlqi) score <10. other inclusion criteria were the ability to apply the treatment or, failing that, to be assisted by personnel who could apply it. moreover, their scores on the physician global assessment (pga), modified investigator’s global assessment (miga), and modified pasi (excluding the head) had to show at least a slight effect of improvement. exclusion criteria were psoriasis in areas other than the trunk and extremities (eg, scalp, face, genitals, and skin folds), a history of allergy to vitamin d analogs or topical corticosteroids, and concurrent or previous treatment with systemic corticosteroids, retinoids (eg, acitretin) or immunosuppressants (eg, methotrexate, cyclosporine, fumaric acid esters) in the past 4 weeks, etanercept (past 4 weeks), adalimumab or infliximab (past 8 weeks), ustekinumab (past 16 weeks), other biologics (past 4 weeks or 5 half-lives), psoralen (past 4 weeks), or uva or uvb phototherapy (past 2 weeks). other exclusion criteria were: a likelihood of excessive sun exposure during the study, disorders of calcium metabolism associated with hypercalcemia, skin infections, severe liver or kidney disorders, and a recent diagnosis of other psoriasis types (eg, guttate, erythrodermic, pustular, or exfoliative psoriasis). conclusions: over a 4-week period, patients treated with cal/bd aerosol foam had significant improvement in disease severity that was directly related to treatment adherence. research | dermatol pract concept. 2021;11(3):e2021056 3 study design this was an open-label, non-placebo controlled, prospective single-center study. the study protocol was approved by the ethics committee of our hospital on 19 oct 2019, with the code derm_003_2019. the study was carried out in compliance with the principles of the declaration of helsinki and good clinical practice. all patients gave written informed consent. patients who had previously used antipsoriatic or other relevant treatments underwent a pharmacological “washout period” of at least 4 weeks before starting the study. all patients were educated on how to apply cal/bd aerosol foam, with the first application directly observed by an investigator. the medication was applied only to the psoriasis plaques of the trunk and extremities, avoiding its use in areas such as the scalp, face, genitals, and skin folds. cal/bd aerosol foam was applied once a day according to the technical datasheet. complete resolution of the lesions was considered a reason for discontinuation of the treatment, while the reappearance of lesions allowed the resumption of treatment. continuous, uninterrupted use of cal/bd (once per day) was permitted for a maximum period of 4 weeks. evaluations were performed at baseline (visit 0) and at each study visit (week 4 and week 12). adherence to treatment was assessed using the morisky-green-levine scale, 4 weeks and 12 weeks after the start of treatment. the number of cans used by each patient was quantified. the degree of patient satisfaction with the treatment was assessed using the abbreviated treatment satisfaction questionnaire for medication (tsqm-9) scale at 4 weeks, and at 12 weeks in those patients who restarted treatment due to regrowth of lesions. the severity of psoriasis was assessed using the miga and pga scales, and the impact on quality of life was assessed using the psoriasis disability index (pdi) and the dlqi. the extent and severity of clinical signs of psoriasis lesions were evaluated using the mpasi. the extent of psoriasis involvement was recorded as a function of the affected body surface area (bsa). safety and tolerability were evaluated after 4 weeks of treatment with cal/bd aerosol foam, and again at 12 weeks in patients who restarted topical treatment due to the regrowth of psoriasis plaques. serious adverse events and adverse drug reactions were recorded. statistical analysis all analyses were performed using the stata statistical program version 16.0 for macos (statacorp) and the level of significance was set at p < 0.05. graphics were made using graphpad prism version 8.0.0 for macos (graphpad software).  results the study enrolled 65 patients with plaque psoriasis, including 33 men and 32 women, with a mean age of 39.7 years (range, 18–70 years). regarding the duration of psoriasis, for 36 patients it was less than 5 years, for 9 patients it was between 5 and 10 years, and for 20 patients it was greater than 10 years. no patient had previously undergone treatment with acitretin, 22 patients (33.8%) had used methotrexate, 12 had used cyclosporine, and only 1 patient had undergone biological treatment with etanercept (suspended in 2016 by personal decision). regarding previous treatments for psoriasis, 40 patients (61.5%) had previously used topical corticosteroids and 39 patients (60%) had previously used cal/bd gel. treatment adherence and satisfaction at 4 weeks (visit 1), adherence to treatment with cal/bd aerosol foam was high on the morisky-green-levine scale in 100% of the participants. at 12 weeks (visit 2), 48 patients (73.8%) showed high adherence, 14 patients (21.5%) had moderate adherence, 2 patients had poor adherence, and 1 patient was not adhering to the treatment (figure 1). patient-reported satisfaction was evaluated using the validated tsqm-9 scale at 4 weeks (visit 1): 46 patients (70.8%) were completely satisfied with the treatment, 8 patients (12.3%) were moderately satisfied, and 11 patients (16.9%) were mildly satisfied. the 12-week score (visit 2) on the tsqm-9 scale showed that 55 patients (84.6%) were completely satisfied with the treatment, 1 patient was moderately satisfied, and 9 patients (13,9%) were mildly satisfied. patients were divided into 3 groups on the basis of their treatment adherence, and the mean tsqm-9 score was calculated for each group (figure 2). there was a significant difference in tsqm-9 scores between patients who had high adherence to treatment and those who had low or no adherence (t = 32,573; p = 0.007). a kruskal-wallis test was performed to check for significant intergroup differences. a significant relationship between adherence and efficacy was evident, and there were also significant intergroup differences in favor of high adherence in all comparisons. the results are reported in table 2. efficacy the evolution of psoriasis severity (assessed with pasi, bsa) is shown in figure 3. the evolution of psoriasis severity (assessed with bsa) according to treatment adherence is shown in figure 4. the mean iga score was 1.954 (sd = 0.891) at the baseline visit, 0.94 (sd = 0.982) at visit 1, and 0.62 (sd = 1.128) at visit 2. the mean pga score was 2.8 (sd = 0.905) at the baseline visit, 1.19 (sd = 1.211) at visit 1, and 0.77 (sd = 1.1487) at visit 2. patients with psoriasis of less than 5 years’ duration had a good response to topical treatment with cal/bd aerosol foam, with a mean pasi score at week 4 of 0.49 (sd = 0.70) and at week 12 of 0.13 (sd 0.30) (p <0.01). patients with psoriasis 4 research | dermatol pract concept. 2021;11(3):e2021056 table 1. characteristics of the 65 patients with plaque psoriasis, at inclusion characteristic value age, years, mean (sd) 39.7 (12.9) sex, n male 33 female 32 marital status, n (%) single 21(32.3) married 43 (66.2) widowed 1 (1.5) education, n (%) secondary school 20 (30.8) high school certificate 28 (43.1) tertiary 17(26.2) occupational status, n (%) working or studying 13 (20.0) unemployed or disabled 42 (64.6) retired 10 (15.4) duration of psoriasis, years mean (sd) 9.5 (9.5) previous therapy with topical drugs, n (%) topical corticosteroids 40 (61.5) vitamin d 3 analogs 8 (12.0) cal/bd gel (daivobet) 39 (60.0) previous therapy with systemic drugs, n (%) methotrexate 22 (33.8) cyclosporine 12 (18.5) acitretin 0 (0) fumaric acid ester 0 (0) biological drugs 1 (1.5) none (46.2) sd = standard deviation. figure 1. morisky-green scores for adherence to cal/bd treatment at 12 weeks (visit 2). high adherence was observed in 73.8%. only 4.6% was reported as a non-adherence treatment. morisky–green scale 3 month 73.8% 1.5% 3.1% 21.5% high adherence moderate adherence bad adherence no adherence of more than 10 years’ evolution had a poor response to cal/ bd aerosol foam, with no significant change in pasi scores from week 4 (mean = 2.45; sd = 1.71) to week 12 (mean = 2.15; sd = 2.41; p = 1). quality of life, safety and satisfaction the mean dlqi score was 10.67 (sd = 4.96) at the baseline visit, 2.41 (sd = 3.87) at visit 1, and 2.24 (sd = research | dermatol pract concept. 2021;11(3):e2021056 5 5.25) at visit 2. the mean pdi score was 21.37 (sd = 9.63) at the baseline visit, 5.94 (sd = 7.64) at visit 1, and 4.41 (sd = 9.92) at visit 2. no patient had side effects related to application of cal/ bd aerosol foam. regarding its cosmetic properties, 15.4% responded that the product’s most important attribute was that it did not leave residues or spots on the skin, 7.7% valued the absence of odor, and 76.9% rated it as without data. patients reported as the most important interest the easy application of the drug to the skin. the overall cosmetic quality of cal/bd aerosol foam was rated “good” by 90.8% of the participants. in terms of general satisfaction with cal/bd aerosol foam, 66.2% of the patients were very satisfied, 15.4% was satisfied, 10.8% was not very satisfied, and 7.7% was not at all satisfied. the patients reporting little or no satisfaction corresponded to those in whom psoriasis did not improve with the treatment. discussion stein et al [12], among others, reported that the high efficacy of cal/bd aerosol foam is an important characteristic in the treatment of mild-moderate plaque psoriasis. its speed of action, in patients with mild or moderate psoriasis, deserves to be reviewed [13]. this study evaluated the adherence and satisfaction of patients with plaque psoriasis on the trunk and extremities treated with cal/bd aerosol foam. over a 4-week period, patients treated with cal/bd aerosol foam had a significant improvement in disease severity that was directly related to treatment adherence. non-compliance with topical therapy continues to be a challenge in clinical practice for patients with psoriasis, and constitutes a key limiting factor in its effectiveness [14]. according to the results obtained using the morisky-greenlevine scale, at 12 weeks only 73.8% of the participants were fully compliant with the treatment. this lack of adherence was due to the lack of response to treatment, coinciding in those patients with psoriasis duration of more than 10 years. these patients, who previously had systemic treatment, received treatment with systemic or biological therapy after the study ended. the reason why therapeutic compliance extends up to 12 weeks is directly related to the effectiveness of cal/bd aerosol foam beyond the 4 weeks indicated in the datasheet, as demonstrated by paul et al. [15]. the most frequent difficulties associated with non-compliance are the patients’ perception of the effectiveness of the product and the discomfort of the administration regimen. as observed in our study, both difficulties have been overcome with this new formulation. the quick and effective response to treatment has a direct impact on treatment compliance. patient expectations are directly linked to therapeutic adherence [16], and treatment failure plays the main role in abandoning therapy, especially in topical treatments. the secondary objective of the study was to assess patient satisfaction after cal/bd aerosol foam treatment. the results show how patient satisfaction after treatment was maintained over time. low satisfaction or dissatisfaction with the treatment, recorded in 9 patients, was justified by their having a partial or no response to the treatment. however, the cosmetic evaluation of the product by these patients was positive. as previously reported, low adherence to treatment may be justified by the acceptability of the vehicle and its cosmetics [17]. the cal/bd aerosol foam formula was developed to provide patients with comfortable and easy topical application. this allows for greater adherence to treatment compared with other topical formulations for the treatment of psoriasis. treatment adherence—an essential objective in chronic skin diseases such as psoriasis—and patient satisfaction are strongly linked, as we have observed in our study. high adherence 100 80 60 40 20 0 0 4 12 weeks ts q m 9 sc o r e moderate adherence low or no adherence figure 2. patient satisfaction with cal/bd treatment, scored on the tsqm-9 scale, according to treatment adherence. values are mean and sd 6 research | dermatol pract concept. 2021;11(3):e2021056 another variable recorded during the study was the number of packages used during treatment and follow-up at 12 weeks. of the participants, 87.6% consumed only 2 cans of cal/bd aerosol foam. with these data we corroborate what was published by balak et al. [18] and duvetorp et al. [19], who considered this medication a cost-effective treatment for plaque psoriasis. our results regarding treatment adherence, effectiveness, and tolerability of cal/bd aerosol foam support the conclusions of a recent review of studies on the use of cal/ bd aerosol foam in clinical practice [20]. the safety of cal/bd aerosol foam further strengthens its indication as the first line of therapy in patients with mild–moderate plaque psoriasis [21]. in a study, 60% of participants who had previously used cal/bd gel were asked to compare the two formulations, and 95% said that the new formulation was better, mainly due to its efficacy and cosmetics (non-greasy feel and absence of residue); the remaining 5% considered the gel and foam formulations to be similar in efficacy and cosmetics. the effectiveness of cal/bd aerosol foam is essential for adherence to treatment. this drug combination inhibits the production of one of the most important interleukins in psoriasis, il-17, and decreases its blood level [22]. however, the vasoconstrictive power of the corticosteroid in the new aerosol foam formulation is not superior to that in the gel formulation [23]. this study has limitations due to the small number of enrolled patients. a multicenter study with the participation of specialized psoriasis units could increase the number of patients studied. high adherence weeks 1240 15 12 9 6 3 0 moderate adherence low or no adherence b sa 8 6 4 2 sc o r e pasi weeks bsi 0 0 4 12 figure 3. evolution of psoriasis severity during cal/bd treatment. values are mean and sd . pasi = psoriasis area and severity index; bsa = body surface area figure 4. evolution of psoriasis severity (bsa) according to treatment adherence. values are mean and sd. bsa = body surface area research | dermatol pract concept. 2021;11(3):e2021056 7 ta b le 2 . e ffi ca cy o f tr ea tm en t ac co rd in g to a d h er en ce 8 research | dermatol pract concept. 2021;11(3):e2021056 conclusions this 12-week study in patients with plaque psoriasis on the trunk and extremities showed that cal/bd aerosol foam provides a significant improvement in its treatment, with very good adherence and a favorable safety profile. the high level of adherence, the rapid action of the drug, and the adequate cosmetics of the vehicle make cal/bd in aerosol foam a firstline topical treatment in patients with plaque psoriasis. cal/ bd aerosol foam can be considered a cost-effective drug for the treatment of plaque psoriasis. acknowledgments this research was funded by leo pharma. the sponsor did not influence the study design or planning, but has contributed on the statistical analysis support. references 1. parisi r, symmons dp, griffiths ce, ashcroft dm.; identification and management of psoriasis and associated comorbidity (impact) project team. global epidemiology of psoriasis: a systematic review of incidence and prevalence. j invest dermatol. 2013;133(2):377-385. doi: 10.1038/jid.2012.339. pmid: 23014338. 2. 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2019;33(6):1116-1123. doi: 10.1111/jdv.15398. pmid: 30916417. 14. reich k, daudén e. treatment adherence: a hurdle for real-life effectiveness in psoriasis? j eur acad dermatol venereol. 2014;28 suppl 2:1-3. doi: 10.1111/jdv.12442. pmid: 24684737. 15. paul c, stein gold l, cambazard f, et al. calcipotriol plus betamethasone dipropionate aerosol foam provides superior efficacy vs. gel in patients with psoriasis vulgaris: randomized, controlled pso-able study. j eur acad dermatol venereol. 2017;31(1):119-126. doi: 10.1111/jdv.13859. pmid: 27531752. 16. brown kk, rehmus we, kimball ab. determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. j am acad dermatol. 2006;55(4):607-613. doi: 10.1016/j.jaad.2005.12.021. pmid: 17010739. 17. bewley a, page b. maximizing patient adherence for optimal outcomes in psoriasis. j eur acad dermatol venereol. 2011;25 suppl 4:9-14. doi: 10.1111/j.1468-3083.2011.04060.x. pmid: 21507078. 18. balak dmw, carrascosa jm, gregoriou s, et al. cost per pasi-75 responder of calcipotriol plus betamethasone dipropionate cutaneous foam versus nonbiologic systemic therapies for the treatment of plaque psoriasis in seven european countries. j dermatolog treat. 2020 mar 6;1-8. doi: 10.1080/09546634.2019.1707754. pmid: 31940225. 19. duvetorp a, levin lå, engerstedt mattsson e, ryttig l. a cost-utility analysis of calcipotriol/betamethasone dipropionate aerosol foam versus ointment for the topical treatment of psoriasis vulgaris in sweden. acta derm venereol. 2019;99(4):393-399. doi: 10.2340/00015555-3112. pmid: 30628631. 20. gerdes s, velasco m, wu jj, hubo m, veverka ka. calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: a review of real-world evidence (rwe). j dermatolog treat. 2020;jan 28;1-11. doi: 10.1080/09546634.2020.1717417. pmid: 31986945. 21. amat-samaranch v, puig l. safety of calcipotriene and betamethasone dipropionate foam for the treatment of psoriresearch | dermatol pract concept. 2021;11(3):e2021056 9 asis.  expert opin drug saf. 2020;19(4):423-432. doi: 10.1080/14740338.2020.1749594. pmid: 32243212. 22. røpke m, bulai livideanu c, kaldate r, snel a, paul c. changes in interleukin-17a, macrophage-derived chemokine and adiponectin following treatment of psoriasis with calcipotriol plus betamethasone dipropionate aerosol foam: results from the psoable study. br j dermatol. 2018;178(1):e33-e34. doi: 10.1111/ bjd.15814. pmid: 28722136. 23. queille-roussel c, nielsen j, lacour jp. vasoconstrictor potency of fixed-dose combination calcipotriol (50 μg/g) and betamethasone dipropionate (0.5 mg/g) cutaneous foam versus other topical corticosteroids used to treat psoriasis vulgaris. j dermatolog treat. 2019;30(6):529-533. doi: 10.1080/09546634.2018.1529385. pmid: 30582717. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021; 11(4): e2021090 1 difference in sun exposure habits between individuals with high and low risk of skin cancer oskar karlsson1, oskar hagberg2, kari nielsen1,3, john paoli4,5, åsa ingvar1,3 1 department of dermatology, skåne university hospital, lund, sweden 2 institution of translational medicine, lund university, malmö, sweden, 3 department of clinical sciences, lund, division of dermatology, lund university, sweden 4 department of dermatology and venereology, institute of clinical science, sahlgrenska academy, university of gothenburg, gothenburg, sweden 5 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden key words: skin cancer, melanoma, risk factors, sun habits citation: karlsson o, hagberg o, nielsen k, paoli j, ingvar å. difference in sun exposure habits between individuals with high and low risk of skin cancer. dermatol pract concept. 2021; 11(4): e2021090. doi: https://doi.org/10.5826/dpc.1104a90 accepted: february 11, 2021; published: september 2021 copyright: ©2021 karlsson et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: the project was funded by lund university as master of science thesis during medical training for oskar karlsson. competing interests: the euromelanoma campaign is funded by sponsorship and part of the funding is used for data input and statistical analyses. oskar karlsson and oskar hagberg were engaged by the campaign to perform these tasks. the sponsors had no impact on the preparation, results, or publication of the study. authorship: all authors have contributed significantly to this publication. corresponding author: oskar karlsson, md, department of dermatology, skåne university hospital, lund, sweden. email: oskar.karlsson@skane.se background: skin cancer incidence is rapidly increasing. the main risk factor, sun exposure, can be modified. informational campaigns can be effective in raising skin cancer awareness and target the high-risk population. still, sun exposure habits in people at high risk of skin cancer are not wellknown. objective: to investigate if and how sun exposure habits differ between low-risk and high-risk individuals. methods: during the swedish euromelanoma campaign of 2018, questionnaires were collected containing information regarding sun exposure habits and risk factors for skin cancer. data on 4,141 participants was used to investigate the association between risk factors and sun exposure habits. results: a fair skin type and a previous history of skin cancer were significantly associated with enhanced sun protective behavior. family history of skin cancer, childhood sunburns and the presence of large/atypical nevi had no effect on sun exposure habits. going on sunny holidays were particularly unaffected by being at high risk of skin cancer. abstract 2 research | dermatol pract concept. 2021; 11(4): e2021090 introduction skin cancer is the most common cancer worldwide, predominantly affecting countries with mainly fair-skinned individuals such as australia, new zealand, north america, and europe [1]. compared to overall cancer incidence, which has decreased globally in recent years [2], skin cancer incidence is rapidly increasing [3, 4]. this trend has also been observed in sweden where the incidence of the 3 main subtypes of skin cancer (malignant melanoma, mm; squamous cell carcinoma, scc, and basal cell carcinoma, bcc) are increasing at a fast pace, of approximately 5-6% per year [5]. mm is the most aggressive form of skin cancer, accounting for 90% of all skin cancer mortality [1, 6]. the most important risk factor for mm is ultraviolet (uv) radiation which can be attributed to 65-90% of all mm cases [7, 8]. other important risk factors for mm are fair skin types (i-ii according to fitzpatrick), many common nevi, multiple large/ atypical nevi, childhood sunburns, family history of mm, and personal history of skin cancer. scc and bcc derive from keratinocytes and are often referred to as types of keratinocyte cancer (kc). kcs are very common and may cause significant morbidity but rarely metastasize [9, 10]. due to the modifiability of the main risk factor for skin cancer, uv radiation, interest to influence people to adopt healthier sun exposure habits has been raised. this can be accomplished through skin cancer awareness campaigns [11-15]. to optimize these campaigns, it is important to have knowledge of sun exposure behavior within the population. nevertheless, there is scarce evidence on differences in sun exposure habits between individuals with high risk and low risk of skin cancer. 2 studies have shown that fair-skinned individuals have safer sun exposure habits than dark-skinned individuals [16, 17], but one italian study found the opposite relationship [18]. a swedish cross-sectional study suggested that a personal history of skin cancer induced sun protective habits [19], but a systematic review from 2015 on individuals with a history of kc found that their sun protective behavior continued to be suboptimal [20]. using data from the 2018 swedish euromelanoma week campaign for skin cancer awareness, we aimed to investigate sun exposure habits in people at different risk of skin cancer. methods the regional ethical review board in gothenburg, sweden waived the need for ethical approval (registration number 608-08) since the data was anonymised. data collection every year since 1999, a european-wide skin cancer campaign, named euromelanoma, is carried out in over 30 european countries [21]. during the campaign, individuals are screened for skin cancer. the studied euromelanoma week, was held during may 14-18, 2018. dermatology clinicians from all over sweden were invited to participate. every patient participating in the euromelanoma week filled in a 2-page questionnaire (supplementary material 1). the first page of the questionnaire was completed by the patient and contained questions on sun habits, sun sensitivity, severe childhood sunburns, outdoor occupation, sunny holidays, and current use of sunbeds. the second page, completed by the dermatologist, included information regarding family history of skin cancer, patient history of skin cancer, number of common and large/atypical nevi (defined as asymmetric with ill-defined border, irregular pigmentation/color and a diameter >6mm), presence of actinic keratoses, lentigines, and clinically suspected skin cancers. statistical analysis firstly, univariate associations between risk factors for skin cancer and sun exposure behavior were tested. secondly, we constructed a multinomial regression model to test the odds of choosing one sun exposure behavior over another in the different risk categories. lastly, to compare people with varied combinations of risk factors for mm, we designed a score for different levels of risk for mm. risk factors that were used in the score were: skin type, number of common nevi, number of large/atypical nevi, family history of mm, personal history of skin cancer, and severe childhood sunburns. to correctly weigh risk factors, we used risk estimates from published meta-analyses. these were found by a literature search on pubmed using the keywords “malignant melanoma and risk factor” and “skin cancer and risk factor”. we included studies in english and published between 1998-2018, which conclusion: individuals at high risk of developing skin cancer showed suboptimal sun exposure habits and harmful traveling behaviors. we suggest that future skin cancer campaigns inform on accurate sun protection behavior during sunny holidays and associated risk factors. risk factors such as childhood sunburns, numerous common and large/atypical nevi, as well as family history of skin cancer seem to be less recognized by the population. research | dermatol pract concept. 2021; 11(4): e2021090 3 yielded 6 meta-analyses (supplementary material 2) [22-27]. since relative risks are multiplicative, the logarithms of the risk estimates from the meta-analyses were summed to create a score on the linear scale. this yielded a score ranging from 0-7. cut-offs (≤0.5, >0.5-2, >2) were chosen to clearly separate out people with a high-risk score and a low-risk score from the majority in the normal distribution of the risk-score. randomized non-parametric chi-χ2-tests were used to test significance, set to p<0.05 [28, 29]. results 43 dermatology clinics enrolled for participation and offered 5,521 appointments all over sweden. a total of 4,489 questionnaires were received. after exclusions due to incomplete information on date of birth (n=21), no written consent (n=136), or no information entered on one of the two pages (n=191), 4,141 questionnaires (figure 1) were left for analyses. overall, each question had a high answer rate of over 95%. most participants were women (66%), and 58% had a university degree. self-assessment of skin type was as follows: 3% skin type i, 18% skin type ii, 57% skin type iii and 22% skin type iv. the vast majority (96%) reported not using sunbeds and 12% not to sunbathe. most participants (59%) stated always using sunscreen when sunbathing and 87% reported going on sunny holidays every year. 9% of patients had a family history of mm. a personal history of skin cancer was found in 11% of patients (8% kc and 3% mm). for detailed descriptive statistics, see (supplementary material 3). risk behavior in relation to sex and age men were 40% more likely to not sunbathe compared to women and at the same time 50% more likely to never apply sunscreen while sunbathing. there was no difference in travelling habits between men and women. with increasing age, the participants reported less sunbathing, sunscreen use and less sunny holidays (table 1). figure 1. flow-chart for inclusion of questionnaires from the swedish euromelanoma week 2018. total questionnaires during euromelanoma week 2018 in sweden n= 4489 questionnaires received by the swedish national coordinator n= 4380 total included questionnaires in this study n=4141 excluded questionnaires: no consent n=136 no birth date n=21 not filled in properly n= 82 exluded due to arrival after deadline n=109 4 research | dermatol pract concept. 2021; 11(4): e2021090 table 1. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing and going on sunny holidays) with regard to age and sex, using female as reference category and for every 10-year increase in age. female male age (odds ratio for every 10-year increase) i never sunbathe false true reference category reference behavior 1.4 (1.2-1.8) reference behaviour 1.3 (1.2-1.4) use of sunscreen when sunbathing never sometimes always reference category 1.5 (1.0-2.3) reference behavior 0.5 (0.4-0.5) 1.3 (1.2-1.5) reference behavior 0.9 (0.8-0.9) number of weeks at sunny holidays/year 0 ≤2 weeks/year >2 weeks/year reference category reference behavior 0.9 (0.7-1.1) 0.9 (0.7-1.1) reference behavior 0.8 (0.7-0.8) 0.8 (0.7-0.9) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (female sex). the estimates for age reflect the difference in choice of a behavior for every 10-year increase in age. estimates adjusted for skin type, childhood sunburn, family history of melanoma, personal history of skin cancer, number of nevi. significance level set to p < 0.05. risk behavior in relation to skin type skin type was associated with all measured sun behaviors. multivariate analysis showed that people with skin type ii and skin types iii-iv, respectively, were 70 and 90% more likely to sunbathe compared to people with skin type i. likewise, people with skin types ii-iv were only half as likely to always, rather than sometimes, use sunscreen when sunbathing compared to people with skin type i. going on sunny holidays for ≤ 2 weeks/year (compared to no sunny holidays) was 2.3 times more common in people with skin type ii and 3.5 times more common in people with skin types iii-iv. this effect was even more pronounced when looking at the odds of going on sunny holidays for > 2 weeks/year (table 2). risk behavior in relation to childhood sunburn and family history of melanoma a higher proportion of people who remembered having had a childhood sunburn reported not to sunbathe and to always use sunscreen when sunbathing, compared to people who did not remember such an event. however, this effect disappeared in the multivariate analyses. no other sun exposure behaviors were associated with childhood sunburns. a positive family history of mm was only associated with sunscreen use when sunbathing (p=0.03) in the univariate analyses, but even this association disappeared in the adjusted analyses (table 3). risk behavior in relation to history of skin cancer having had mm or kc increased the odds of choosing not to sunbathe by 2.5 and 1.5 times, respectively, compared to an individual with no skin cancer history. the odds of always, rather than sometimes, applying sunscreen when sunbathing increased by 2.2 times in people with a history of mm and 1.5 times in people with a history of kc, compared to people with no history of skin cancer. travelling behavior was almost unaffected by having had a skin cancer (table 4). risk behavior in relation to nevi not sunbathing was only significantly associated with having 25-50 common nevi (but not to >50 nevi) compared to <25 nevi. to always use sunscreen when sunbathing was more clearly associated with the number of common nevi, with 20%, 30% and 40% odds increases in people with 25-50, 50-100 and >100 common nevi, respectively. going on sunny holidays was not associated with the number of common nevi (table 5). the presence of large/atypical nevi did not affect sun exposure habits (data not shown). risk behavior in relation to risk score the melanoma risk score yielded 416 individuals with a lowrisk score, 2886 with a medium-risk score, and 839 with a high-risk score. there was a higher proportion of women research | dermatol pract concept. 2021; 11(4): e2021090 5 table 2. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing, and going on sunny holidays) with regard to skin type, using skin type i as reference category skin type i skin type ii skin type iii skin type iv i never sunbathe false true reference category reference behavior 0.3 (0.2-0.5) reference behavior 0.1 (0.1-0.2) reference behavior 0.1 (0.1-0.2) use of sunscreen when sunbathing never sometimes always reference category 0.5 (0.3-0.9) reference behavior 0.5 (0.3-0.8) 0.9 (0.5-1.5) reference behavior 0.4 (0.2-0.6) 1.1 (0.6-1.9) reference behavior 0.4 (0.2-0.6) number of weeks at sunny holidays/ year 0 ≤2 weeks/ year >2 weeks/ year reference category reference behavior 2.3 (1.4-3.9) 2.4 (1.4-4.3) reference behavior 3.5 (2.2-5.8) 5.0 (2.9-8.6) reference behavior 3.4 (2.0-5.8) 6.0 (3.4-10.8) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (skin type i). estimates adjusted for age, sex, childhood sunburn, family history of melanoma, personal history of skin cancer, number of nevi. significance level set to p < 0.05. table 3. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing and going on sunny holidays) with regard to family history of melanoma, using no family history of melanoma as reference category. no family history of melanoma one first-degree relative with history of melanoma two or more first-degree relatives with history of melanoma i never sunbathe false true reference category reference behavior 1.2 (0.9-1.8) reference behavior 0.9 (0.4-2.0) use of sunscreen when sunbathing never sometimes always reference category 0.9 (0.4-2.0) reference behavior 1.0 (0.7-1.3) 1.0 (0.1-7.3) reference behavior 1.3 (0.7-2.3) number of weeks at sunny holidays/ year 0 ≤2 weeks/ year >2 weeks/ year reference category reference behavior 1.0 (0.7-1.5) 1.3 (0.9-2.0) reference behavior 1.1 (0.4-2.7) 1.8 (0.7-4.4) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (no family history of melanoma). estimates adjusted for age, sex, skin type, childhood sunburn, personal history of skin cancer, number of nevi. significance level set to p < 0.05. (68% vs 61%), a lower mean age (53 vs 63 years), and a higher educational level (61% vs 42% with a university degree) in the high-risk compared to the low-risk score group. people with a high-risk score were almost 2 times as likely not to sunbathe and more than 2 times as likely to use sunscreen when sunbathing compared to people with a low6 research | dermatol pract concept. 2021; 11(4): e2021090 table 4. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing and going on sunny holidays) with regard to personal history of skin cancer (malignant melanoma (mm) or keratinocyte cancer (kc)), using no history of skin cancer as reference category. no history of skin cancer history of mm history of kc i never sunbathe false true reference category reference behavior 2.5 (1.5-4.1) reference behavior 1.47 (1.1-2.1) use of sunscreen when sunbathing never sometimes always reference category 1.9 (0.6-5.8) reference behavior 2.2 (1.2-3.8) 1.0 (0.5-2.0) reference behavior 1.6 (1.2-2.1) number of weeks at sunny holidays/ year 0 ≤2 weeks/ year >2 weeks/ year reference category reference behavior 0.7 (0.4-1.3) 0.4 (0.2-0.7) reference behavior 0.8 (0.6-1.2) 0.9 (0.6-1.3) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (no history of skin cancer). estimates adjusted for age, sex, skin type, childhood sunburn, family history of melanoma, number of nevi. significance level set to p < 0.05. table 5. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing, and going on sunny holidays) with regard to number of common nevi, using <25 common nevi as reference category. <25 common nevi 25-50 common nevi 50-100 common nevi >100 common nevi i never sunbathe false true reference category reference behavior 0.7 (0.6-0.9) reference behavior 0.8 (0.5-1.1) reference behavior 0.6 (0.3-1.2) use of sunscreen when sunbathing never sometimes always reference category 0.8 (0.5-1.3) reference behavior 1.2 (1.0-1.5) 0.9 (0.4-1.8) reference behavior 1.3 (1.0-1.7) 1.0 (0.3-3.3) reference behavior 1.4 (1.0-2.2) number of weeks at sunny holidays/ year 0 ≤2 weeks/ year >2 weeks/ year reference category reference behavior 1.2 (1.0-1.6) 1.0 (0.8-1.3) reference behavior 1.1 (0.8-1.5) 1.1 (0.8-1.54) reference behavior 1.2 (0.7-2.2) 0.8 (0.4-1.4) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (<25 common nevi). estimates adjusted for age, sex, skin type, childhood sunburn, family history of melanoma, personal history of skin cancer. significance level set to p < 0.05. risk score. going on sunny holidays was not affected by risk score group (table 6). discussion based on data from questionnaires obtained during the swedish euromelanoma week campaign of 2018, sun exposure habits in individuals with different risk factors for developing skin cancer were compared. skin type affected sun exposure habits the most. age, sex, and having had a previous skin cancer was also somewhat associated with sun exposure behavior. a family history of skin cancer, the presence of large/atypical nevi, and childhood sunburns had no effects on sun exposure habits. frequency of going on research | dermatol pract concept. 2021; 11(4): e2021090 7 table 6. multivariate odds ratios (or) of choosing a risk behavior (use of sunscreen when sunbathing, sunbathing, and going on sunny holidays) with regard to risk score, using low-risk score as reference category. low-risk score medium-risk score high-risk score i never sunbathe false true reference category reference behavior 1.1 (0.8-1.5) reference behavior 1.8 (1.2-2.5) use of sunscreen when sunbathing never sometimes always reference category 0.7 (0.5-1.1) reference behavior 1.6 (1.2-2.0) 0.56 (0.3-1.1) reference behavior 2.3 (1.8-3.0) number of weeks at sunny holidays/ year 0 ≤2 weeks/ year >2 weeks/ year reference category reference behavior 1.2 (0.9-1.7) 0.9 (0.7-1.3) reference behavior 1.0 (0.7-1.5) 0.7 (0.5-1.0) or= odds of choosing a behavior over the reference behavior, compared to the same choice of behavior in the reference category (low-risk score). estimates adjusted for age and sex. significance level set to p < 0.05. sunny holidays was only affected by having a fair skin type and, modestly, by age. in agreement with earlier studies, women reported to sunbathe and to use sunscreen while sunbathing more frequently, compared to men [30, 31]. this “sunscreen paradox” in which sunscreen use opens up for prolonged sun exposure has been described before [32]. such an incorrect use of sunscreens, may result in an increased risk of skin cancer [32]. skin cancer campaigns can help to raise awareness of this potential snare and induce healthier sun exposure habits [11, 12]. as in prior health care interventions and campaigns, most of the participants in our study were women [33, 34]. considering that men in general have less healthy sun habits [16, 31] and a poorer prognosis of mm [35], it is important to design future campaigns to better capture their attention. high age (>70 years) has previously been associated with lower awareness of mm risk factors [36]. this is supported by our finding that participants reported less use of sunscreen with increasing age. however, this might partly be secondary to the decreased sunbathing and travelling on sunny holidays with older age. patient-estimated skin type was a strong predictor of sun protective behavior in our study as well as others [16, 17, 31]. this might be explained by the instant negative feedback, in form of sunburns, that individuals of skin types i and ii experience when sunbathing. nonetheless, 40% of individuals with skin type i and 80% of individuals with skin type ii answered that they sunbathe, and the majority stated that they went on sunny holidays every year (70 and 80%, respectively). these results also indicate that information about adjusting sun exposure level to the individual presupposition should be emphasized in future skin cancer campaigns. severe childhood sunburns did not significantly affect any sun protective behavior. this may indicate a low awareness in the general population of the heightened skin cancer risk that severe childhood sunburns convey [23]. however, since almost 30 % answered that they “do not remember” if they experienced a severe sunburn before 18 years of age, the results might be afflicted by recall bias, or at least non-differential information bias, making it hard to draw any solid conclusions from them. a low awareness of childhood sunburns in sweden, denmark, norway and northern england has also been found in a prior study [36]. having a first-degree relative with a previous mm had no impact on the measured sun exposure behaviors. this study therefore adds weight to the findings of previous studies that sun protective behavior is still suboptimal in family members to persons afflicted by mm [37-40]. a possible explanation is that individuals with a family history of mm might have “inherited” a risk behavior in childhood that is difficult to change later in life [38, 41]. the sun exposure behavior was, however, safer in people who themselves had had skin cancer in this study. nevertheless, it should be noted that 20% and 27% of people with a history of mm and kc, respectively, still sunbathe and that travelling behavior was nearly unaffected by having had a skin cancer. the suboptimal sun exposure behaviors in people with a history of skin cancer has also been documented previously [19, 20, 42]. a danish 8 research | dermatol pract concept. 2021; 11(4): e2021090 prospective case–control study indicated that people diagnosed with mm did improve their sun protective behavior, but only temporarily [42]. having many common nevi was associated with safer sun exposure behavior, mainly characterized by sunscreen use while sunbathing. however, the presence of large/atypical nevi had no effect on sun exposure behavior. we know from previous studies that the number of nevi is associated with the degree of sun exposure in childhood [43, 44] and also to risk of mm [22]. our results indicate that these associations are either not well-known or neglected in the general population. as the presence of many common nevi as well as the presence of large nevi are objective factors, easily observed by patients themselves, these might represent important risk factors that should be highlighted in future skin cancer awareness campaigns. our constructed risk score reflects an individual’s combined risk for skin cancer by weighing in all measured risk factors in 1 variable. indeed, we found lower odds of sunbathing and higher odds of using sunscreen while sunbathing in the group with the highest risk score for skin cancer, but we found no association with going on sunny holidays. however, differences in the risk score groups were not impressive and a high proportion of people with a high-risk score still had suboptimal sun exposure behavior. the observed unhealthy sun exposure habits in people at risk for skin cancer can have several explanations. a swedish study examining attitudes and subjective norms predicting sun protective behavior found an association between positive attitudes to getting a tan or being in the sun with uv exposure behaviors such as intentional tanning, sunbed use and the frequency of sunny holidays. the study also showed that group pressure affected sun exposure behavior [45]. a systematic review of 23 studies showed similar results and key motivators for sun exposure behaviors identified were perception of appearance and health and influence of parents, peers and media [41]. the ideal “tanned look” that prevails in modern society and bolstered by media might be another explanation [45]. furthermore, studies have shown that “uv-seekers” meet diagnostic criteria for substance-related disorders, with regards to uv exposure [46, 47]. another study performed in rodents, showed that ß-endorphins (endogenous opioid neuropeptides and peptide hormones that block pain signaling and produce a feeling of euphoria/pleasure) are synthesized at the level of the skin and elevated in plasma following low-dose uv exposure [48]. hence, there might be elements of physiological addiction to sun exposure which can both explain observed habits and obstruct a change of sun exposure behavior. skin cancer incidence is increasing rapidly but can be prevented by changing sun exposure behavior in the general population. from the results in this study, we suggest that skin cancer awareness campaigns should contain additional information on less known or ignored risk factors, such as having a first-degree relative with skin cancer, numerous nevi, multiple large/atypical nevi, or having suffered childhood sunburns. although the euromelanoma campaigns have been ongoing since 2000 [49], information about all risk factors and unhealthy sun exposure behaviors must be repeated and especially approached from a different angle, since our study results shed light on a general suboptimal sun exposure behavior in many participants. furthermore, the risk behavior least affected by being at risk of skin cancer in this study (going on sunny holidays) must be addressed. this finding is supported by 2 previous studies in which a high frequency of sunburns and inadequate sun protection was found in danes travelling to sunny destinations [50, 51]. therefore, efforts should be made to emphasize the importance of a sun protective behavior at a uv index ≥ 3 , both at home and when travelling [52]. smartphone applications (e.g. “min soltid”/“my sun time” launched by the swedish meteorological and hydrological institute in cooperation with the swedish radiation safety authority) that calculate a safe sun exposure time based on uv index and skin type might be an interesting focus of future skin cancer prevention campaigns [53]. the strengths of this study are the large size and the contemporary data from 2018. the information was collected from the entire country on people of both genders, a wide age range, and all levels of education. however, our study has also several weaknesses. firstly, all information regarding sun exposure was self-reported and might be affected by self-assessment bias (eg skin type). we could, however, not detect a difference in self-assessed skin type with sex or level of education. secondly, some of the questions from the questionnaire were phrased inadequately, such as question 11.1 “number of weeks per year at sunny holidays” which did not include a definition of what was meant by a sunny holiday. consequently, this question could have been interpreted differently by participants, possibly introducing non-differential information bias. lastly, the distribution of levels of education and gender of the participants is not representative of the entire swedish population. this might affect the ability to generalize our results but does not affect the internal validity. in summary, raising awareness of the risk factors that had no impact on sun exposure behavior (family history of mm, presence of large/atypical nevi and childhood sunburn) in this study, could be an important part of future skin cancer awareness campaigns. also, sun exposure habits during sunny holidays should be specifically addressed. finally, the underlying psychological reasons for continuing a suboptimal sun exposure behavior should be exposed and, if possible, influenced. research | dermatol pract concept. 2021; 11(4): e2021090 9 supplementary material supplementary material 1. euromelanoma questionnaire (figure s1). supplementary material 2. meta-analyses of known risk factors for malignant melanoma and estimated risk score. the sum of the log of the relative risk was used to create the score values for each individual, stating their combined risk increase for malignant melanoma (table s2). supplementary material 3. association between specific risk factors and sun exposure habits. statistical significance was tested with chi-square tests (table s3). acknowledgements we are grateful to the sponsors of the swedish euromelanoma week campaign 2018, ie beiersdorf, bristol meyer-squibb, desitin, galderma, la roche-posay, mylan/ meda who together, but without influence, supported the media campaign, the questionnaire distribution costs, and the time used for data input and statistical analyses. references 1. karimkhani c, green ac, nijsten t, weinstock ma, dellavalle rp, naghavi m, et al. the global burden of melanoma: results from the global burden of disease study 2015. the british journal of dermatology. 2017;177(1):134-40. doi: 10.1111/bjd.15510. 2. torre la, siegel rl, ward em, jemal a. global cancer incidence and mortality rates and trends--an update. cancer epidemiology, biomarkers & 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screening campaign in sweden 2008. journal of the european academy of dermatology and venereology : jeadv. 2009;23(11):1304-10. doi: 10.1111/j.1468-3083.2009.03316.x. 50. koster b, thorgaard c, philip a, clemmensen ih. vacations to sunny destinations, sunburn, and intention to tan: a cross-sectional study in denmark, 2007-2009. scandinavian journal of public health. 2011;39(1):64-9. doi: 10.1177/1403494810391526. 51. petersen b, thieden e, philipsen pa, heydenreich j, young ar, wulf hc. a sun holiday is a sunburn holiday. photodermatology, photoimmunology & photomedicine. 2013;29(4):221-4. doi: 10.1111/phpp.12048. research | dermatol pract concept. 2021; 11(4): e2021090 11 52. world health organization wmo, united nations environment programme, international commission on non-ionizing radiation protection. global solar uv index: a practical guide geneva, switzerland2002. accessed may 4, 2020. available from: http:// www.unep.org/pdf/solar_index_guide.pdf. 53. swedish radiation safety authority. [calculate “my sun exposure time”] 2020. accessed may 4, 2020. available from: https:// www.stralsakerhetsmyndigheten.se/omraden/sol-och-solarier/ rad-och-rekommendationer/berakna-min-soltid/. dermatology: practical and conceptual research | dermatol pract concept 2021;11(2):e2021140 1 dermatology practical & conceptual nd:yag laser in the treatment of nail psoriasis: clinical and dermoscopic assessment yasmin hesham ali elwan1, amira abdel azim2, michela starace3, hala shawky abd elhafiz2 1 faculty of medicine, cairo university, egypt 2 department of dermatology and venerology, al azhar university for girls in cairo, egypt 3 department of experimental, diagnostic and specialty medicine-division of dermatology, university of bologna, italy key words: nd:yag laser, nail psoriasis, napsi, dermoscopy citation: hesham ali elwan y, abdel azim a, starace m, shawky abd elhafiz h. nd:yag laser in the treatment of nail psoriasis: clinical and dermoscopic assessment. dermatol pract concept. 2021;11(2):e2021140. doi: https://doi.org/10.5826/dpc.1102a140 accepted: september 2, 2020; published: march 8, 2021 copyright: ©2021 hesham ali elwan et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: yasmin hesham ali elwan, mbbch, general medicine and surgery, faculty of medicine, cairo university, maadi, cairo, egypt. email: koki2january@gmail.com background: the nd:yag laser has emerged as a promising modality for the management of nail psoriasis owing to its ability for deep penetration of the skin surface, which has the advantage of destroying deep vessels. objective: to assess the efficacy and safety of nd:yag laser in treating nail psoriasis. methods: the present study was a randomized controlled study, conducted on 20 patients of both sexes (age older than 12 years) with mild to moderate psoriasis with nail involvement. we utilized facial telangiectasia parameters of nd:yag laser and beam diameter of 2.5 mm. laser energy started with 110 j/cm2 in the first session and 130 j/cm2 in the rest of the sessions. sessions were performed once monthly for up to 6 sessions. results: we found no statistically significant difference in total nail psoriasis severity index (napsi) and nail bed scores before and after treatment among the treated group. however, there was statistically significant improvement in nail matrix score after treatment. on the other hand, the control group did not show any statistically significant changes for all scores throughout the study, except for the nail matrix score mean difference (0.35 ± 1.23 vs -1.00 ± 1.86 in the treated group). the degree of dermoscopic improvement was evident in the treated group (45% vs 25% in the control group). however, it was not statistically significant because of small sample size. the patients’ satisfaction and the external investigator’s assessment showed statistically significant negative correlation with total napsi mean difference in the treated group. conclusion: the role of nd:yag laser in nail psoriasis is still controversial. abstract 2 research | dermatol pract concept 2021;11(2):e2021140 patients with severe psoriatic arthritis needing systemic treatment, patients with onychomycosis, and patients who received systemic anti-psoriatic treatment 2 months prior to study’s enrollment. sampling and randomization we utilized a probability, simple, random sampling technique for patient recruitment. in each eligible patient, a coin toss was used to treat a randomly allocated finger or toenail of one side, while the other side was left untreated. study intervention the eligible patients were treated with laser sessions by synchro ft nd: yag laser (deka laser). we used the facial telangiectasia parameters of nd: yag laser of a beam diameter of 2.5 mm and started laser energy with 110 j/cm2 in the first session and 130 j/cm2 in the rest of the sessions, single pulse frequency and shallow depth. all patients were advised before every session to apply topical anesthetic cream (containing lidocaine and prilocaine) to avoid pain during laser sessions. sessions were performed once monthly for up to 6 sessions. evaluation and follow-up a full history was taken of all eligible patients along with, dermatological examination for psoriatic lesions, photography of the nails (galaxy a30 phone camera; dual m16 mp, f/1.7, 27 mm [wide], pdaf; 5 mp, f/2.2, 12 mm, [ultra wide], and a clinical assessment by the nail psoriasis severity index (napsi). the evaluation was done at baseline and was repeated 1 month after the end of treatment. the subjective evaluation involved both patients and investigators. every patient was asked about his/her self satisfaction of the results of the treatment after the last session using a visual analog scale (vas); a rating of 0 for no satisfaction and a rating of 10 for the best satisfaction. the external investigator expressed the degree of improvement in percentages. using percentile and quartile ranges, patients were evaluated for degree of improvement as follows: mild improvement ≤ 25%, moderate improvement, 26-50%, marked improvement, 51-75%, excellent improvement, 76-100%. in addition, a clinical assessment by the napsi score was done for each patient. the napsi is a numerical score for scaling the severity of psoriatic lesions of the nail. the score assesses the involved areas within each nail covering the nail bed (score range 0-4) and nail matrix (score range 0-4) lesions. a composite score for each nail is then calculated (range 0-8). the final score is the sum of all nails score that ranges 0-160 [8]. the dermoscopic evaluation was done using a dermlite hud dermatoscope (polarized light, magnifying lens ×10, connected to the mobile phone camera magnifying up to introduction nail psoriasis poses a therapeutic challenge to treating dermatologists; the severity and extension of nail involvement usually drives the treatment decision [1]. laser therapy has shown to be effective and safe for nail psoriasis with high patient satisfaction. it could be used alone or combined with different therapeutic modalities [2]. the use of pulsed dye laser (pdl) to treat nail psoriasis has been explored. the best response was observed in onycholysis and subungual hyperkeratosis [3]. pdl in combination with topical tazarotene showed significantly better improvement compared to tazarotene monotherapy [4]. excimer laser has been approved for the treatment of psoriasis since 2000. however, so far in the available literature, excimer laser has not been found to be effective in a limited number of patients of nail psoriasis . this could be because of the poor penetration of uvb in the human nail plate. results of excimer laser treatment of nail psoriasis are poor and time-consuming compared to pdl [5]. recent reports demonstrated that the nd:yag laser exhibited promising effectiveness and a well-tolerated safety profile in the management of nail psoriasis [6]. in the setting of nail psoriasis, dermoscopy was reported to be an effective tool for early assessment of nail lesions, as well as in differentiating the psoriatic lesions from other disorders [7]. moreover, dermoscopy can be used for evaluation of response to treatment for nail psoriasis. thus, we conducted the present randomized controlled study to assess the efficacy and safety of nd:yag laser in treating nail psoriasis, based on clinical and dermoscopic assessment. patients and methods the initiation and patient enrollment of the study preceded the official approval of the local ethics committee of the participating institution. study design and patients the present study was a randomized, within-patient, controlled study that was conducted on 20 patients who were recruited from the dermatology and venereology outpatient clinic of al-zahraa university hospital during the period between january 2019 and march 2020. both sexes were included if they were older than 12 years old and had mild to moderate psoriasis associated with nail involvement. the diagnosis was based upon clinical characteristics of psoriasis (erythematous papules and plaques covered by silvery white scales with psoriatic nail changes). patients were instructed to stop any systemic or topical treatments for the nails 2 months before the study. we excluded patients who refused to sign the informed consent, patients who were eligible for systemic therapy, patients with pustular or erythrodermic psoriasis, research | dermatol pract concept 2021;11(2):e2021140 3 ×4x). the examination was done by a visual expert opinion method (by dr. michela starace). the expert looked at the typical dermoscopic signs of nail psoriasis. these signs were checked if they were present or not in the treated and in the control nails 1 month after the last session. statistical analysis the data were processed and analyzed using a statistical package for social sciences (spss, version 20.0 chicago, illinois, usa). the mean (± sd [standard deviation]) or median (range) were used to present the continuous data. the percentages were used to quantify the qualitative data. the association analysis was done by paired t test and chi-square test for quantitative and qualitative data. spearman correlation test was used to examine the correlation between quantitate variables. a p value < 0.05 was significant. results a total of 20 patients were included in the present study. the mean age of the included patients was 40.90 ± 17.02 and 65% of them were females. regarding the duration of psoriasis (in years) among the studied groups, the median was 9 and half of the group were between 6-13.5; and the median duration of nail psoriasis (in years) among the studied groups was 3 and half of the group were between 2-9. one-fourth of the patients were diabetic and 10.0% were hypertensive. in each patient the number of affected nails in the treated hand or foot was 5 (table 1). in the nd:yag-treated side, there were no statistically significant changes in total napsi and nail bed score after the end of the study (p > 0.05). on the other hand, there was a significant decrease in nail matrix score after treatment (19.55 ± 1.15 versus 18.55 ± 2.78; p = 0.027). in the control group, there were no statistically significant changes in any of total napsi scores after the end of the study (p > 0.05). the treated group had a significantly higher reduction in the nail matrix score than the control group at the end of treatment (1.00 ± 1.86 versus 0.35 ± 1.23, respectively; p = 0.01; table 2) (figure 1). regarding the dermoscopic assessment in the treated group, 9 cases (45.0%) showed improvement, 7 cases (35%) showed stable disease, and 4 cases (20.0%) showed worsening of disease. in the control group 5 cases (25.0%) improved, 11 cases (55.0%) remained stable, and 4 cases (20.0%) worsened with no statistically significant difference between both groups (figure 2). the number of dermoscopically improved cases was higher in the treated group [6 (30%), 2 (10%), 1 (5.0%), 3 (15.0%), and 2 (10.0%)] than the control group [4 (20.0%), 0 (0.0%), 0 (0.0%), 1 (5.0%) and 1 (5.0%)] in onycholysis with erythematous border, pitting, salmon patches, table 1. demographic and clinical characteristics of the included patients total no. = 20 age mean ± sd 40.90 ± 17.02 range 17-64 sex female male 13 (65.0%) 7 (35.0%) occupation student housewife farmer painter employee ex-employee worker 4 (20.0%) 7 (35.0%) 3 (15.0%) 2 (10.0%) 2 (10.0%) 1 (5.0%) 1 (5.0%) skin phototype ii iii iv v 1 (5.0%) 7 (35.0%) 11 (55.0%) 1 (5.0%) duration of psoriasis (years) median (iqr) 9 (6-13.5) range 2-22 duration of nail psoriasis (years) median (iqr) 3 (2-9) range 1-14 associated diseases none diabetic hypertensive 13 (65.0%) 5 (25.0%) 2 (10.0%) treated hand or foot hand foot 10 (50.0%) 10 (50.0%) number of affected nails 5 20 (100.0%) iqr = interquartile range. subungual hyperkeratosis, and trachyonychia, respectively. there were no cases of improvement in crumbling in both groups. no statistically significant differences between both groups were detected in any of the above lesions (table 2). regarding the degree of improvement as described by the patients, the median was 5, with half the patients statistically improved from 2 to 8. regarding the degree of improvement ,as described by the external investigator, the median (by percentage) was 27.5%, with half the patients statistically improved from 12.5% to 55% (p < 0.05; table 3). the only side effect encountered in our study was mild pain in (30.0%) of the patients. the rest of the patients (70.0%) did not have any side effects. discussion the results of the present study demonstrated that the nd;yag laser only improved the nail matrix lesions in our patients, with no significant improvement in the nail bed 4 research | dermatol pract concept 2021;11(2):e2021140 table 2. napsi scores and dermoscopic assessment among the treated group before start vs after end of study before nd:yag group control group p valueafter p value before after p value total napsi mean ± sd 33.90 ± 2.67 32.60 ± 4.45 0.113 32.15 ± 4.22 32.55 ± 4.43 0.46 0.082 range 30-40 23-40 17-36 19-37 nail bed score mean ± sd 14.35 ± 2.70 14.05 ± 3.30 0.632 13.40 ± 2.44 13.45 ± 3.03 0.92 0.66 range 10-20 10-20 10-17 7-17 nail matrix score mean ± sd 19.55 ± 1.15 18.55 ± 2.78 0.027 18.75 ± 4.44 19.10 ± 3.34 0.21 0.01 range 15-20 9-20 0-20 5-20 improvement by dermoscopy i 9 (45.0%) 5 (25.0%) 0.32s 7 (35.0%) 11 (55.0%) w 4 (20.0%) 4 (20.0%) onycholysis with erythematous border i 6 (30.0%) 4 (20.0%) 0.753 s 11 (55.0%) 13 (65.0%) w 3 (15.0%) 3 (15.0%) pitting i 2 (10.0%) 0 (0.0%) 0.146 s 18 (90.0%) 20(100.0%) w 0 (0.0%) 0 (0.0%) crumbling i 0 (0.0%) 0 (0.0%) 0.311 s 19 (95.0%) 20(100.0%) w 1 (5.0%) 0 (0.0%) salmon patches i 1 (5.0%) 0 (0.0%) 0.598 s 18 (90.0%) 19 (95.0%) w 1 (5.0%) 1 (5.0%) subungual hyperkeratosis i 3 (15.0%) 1 (5.0%) 0.505 s 16 (80.0%) 17 (85.0%) w 1 (5.0%) 2 (10.0%) trachyonychia i 2 (10.0%) 1 (5.0%) 0.513 s 18 (90.0%) 18 (90.0%) w 0 (0.0%) 1 (5.0%) i = improved; napsi = nail psoriasis severity index; s = stable; sd = standard deviation; w = worsened. mean difference of nail matrix score 0.35 0.6 0.4 0.2 0.0 –0.2 –0.4 –0.6 –0.8 –1.0 –1.2 –1.00 treated hand or footcontrol hand or foot figure 1. mean difference of nail matrix score between the control and the treated groups. research | dermatol pract concept 2021;11(2):e2021140 5 lesions or total clinical score. dermoscopically, the nd;yag laser led to notable improvement in the nail lesions; however, this improvement did not reach the level of statistical significance. the patient satisfaction and investigator’s opinion were significantly favorable after the end of treatment. the development of an objective tool for clinical response to treatment is one of the main challenges during the management of nail psoriasis [9]. since its validation by rich and scher in 2003 [8], the napsi has shown to be a valid tool for clinical evaluation of the degree of nail involvement in psoriasis, as well as the nail response to treatment. in the present study we found that the nd:yag laser led to statistically insignificant decrease in total napsi and nail bed scores after the end of treatment. on the other hand, there was a significant decrease in nail matrix score after treatment. such findings were contrary to the study by khashaba et al. [10] and another study by kartal et al. [6] that found significant reduction in napsi among nail psoriasis patients after nd: yag laser treatment. the exact causes of heterogeneity between our findings and the above-mentioned studies are unclear; however, such heterogeneity can be explained by many factors. first, the difference in the site of the treated nails between our study and the above-mentioned reports might have contributed to this heterogeneity. moreover, in the above studies, they treated fingernails only, while we treated finger and toenails; toenails may be more resistant to treatment than fingernails. second, different parameters of laser applications can represent another explanation for this heterogeneity in clinical response to nd:yag. in our study, we used the facial telangiectasia parameters of nd: yag laser by a beam diameter of 2.5 mm. laser energy started with 110 j/cm2 in the first session and 130 j/cm2 in the rest of the sessions, single pulse frequency, and shallow depth for up to 6 sessions. khashaba and colleagues [10] utilized a 5 mm spot size and 40 j/cm² fluence, in partially overlapping mode in each session for 4 sessions. kartal and colleagues [6] utilized a beam diameter 6 mm, laser energy was 10 j/cm2 with 1.5 hz repetition rate for 3 sessions third, the limitations of the napsi score itself table 3. degree of improvement by the patient (patient satisfaction) and the external investigator total n = 20 degree of improvement by patient (patient satisfaction) (%) median (iqr) 5 (2-8) range 0-9 degree of improvement by the external investigator (%) median (iqr) 27.5 (12.5-55) range 0-80 iqr = interquartile range. 45.0% 25.0% 35.0% 55.0% 20.0% 20.0% i s w improvement 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% treated dermoscope control dermoscope figure 2. the degree of dermoscopic improvement in the treated and control groups. 6 research | dermatol pract concept 2021;11(2):e2021140 may represent another factor. previous reports demonstrated that napsi has poor correlation with the clinical severity of nail psoriasis [11]. in addition, the method of lesion assessment by napsi is a limitation as well; the assessment depends solely on the presence of a lesion (bed or matrix) within each quadrant, regardless of the presence of other lesions or the severity of this lesion. last, our small sample size may represent another factor explaining the insignificant findings. the speculation of the impact of small sample size in our study is supported by the significant improvement in patient satisfaction and investigator’s opinion. thus, we can hypothesize that the improvement in nail features was notable; however, it did not reach the level of statistical significance because of small sample size (figures 3 and 4). conclusions nail psoriasis may be present with an extremely wide spectrum of symptoms, which vary in severity and type. dermoscopy demonstrates high efficacy in common, as well as rare, features of nail involvement [12]. in the present study, we assessed the effect of nd:yag laser on the improvement of dermoscopic features of the nails. our results demonstrated no statistically significant difference between the control and the treated groups regarding the percentage of improved lesions. this finding was consistent regardless of the type of lesion. these results contradict the previous findings by khashaba et al [10]. this may be because the dermoscopic assessment in the present study relied on the visual expert figure 3. clinical picture of a 62-year-old male patient with (a) fingernail psoriasis showing salmon patches before treatment and (b) improvement after 6 treatment sessions. figure 4. clinical picture of a 27-year-old female patient with toenail psoriasis showing (a) onycholysis and subungual hyperkeratosis before treatment that (b) improved after 6 treatment sessions. research | dermatol pract concept 2021;11(2):e2021140 7 opinion method, which is a subjective method with a high chance of low inter-rater reliability. the small sample size may represent another factor explaining the insignificant findings of our results. the degree of improvement was evident in the treated group (45% versus 25% in the control group). however, the small sample size might have hindered the effect size from reaching the margin of statistical significance (figures 5 and 6). side effects of nd:yag laser treatment are usually minor and may include pain during treatment, redness, swelling and itching immediately after the procedure that may last for few days [13]. in the present study, 6 patients (30.0%) suffered from mild pain and 14 patients (70.0%) had no side effects during laser sessions. the present study is one of the few reports that assess the efficacy and safety of nd:yag laser in treating nail psoriasis both clinically and dermoscopically. the advantages of our study include random allocation of the patients, ensuring low selection bias; the presence of a control group ensuring low performance bias; and the use of both clinical score and dermoscopic features. however, we acknowledge that the present study has some limitations. the study was a single-center experience and therefore the results cannot be generalized to the general population. the sample size of the present study was relatively small and might have hindered the outcome from reaching the margin of statistical significance. the use of a subjective method for dermoscopic assessment is another limitation. in conclusion, nd:yag laser significantly improves the satisfaction of the patients with nail psoriasis, with minimal side effects. however, its role on clinical severity score and dermoscopic features is still controversial. figure 6. dermoscopic picture of 19-year-old female patient with fingernail psoriasis showing (a) trachyonychia before treatmentthat (b) improved after 6 treatment sessions. figure 5. dermoscopic picture of a 60-year-old male patient with fingernail psoriasis showing (a) onycholysis before treatment that (b) improved after 6 treatment sessions. 8 research | dermatol pract concept 2021;11(2):e2021140 references 1. bardazzi f, starace m, bruni f, magnano m, piraccini bm, alessandrini a. nail psoriasis: an updated review and expert opinion on available treatments, including biologics. acta derm venereol. 2019;99(6):516-523. doi: 10.2340/00015555-3098. pmid: 30521057. 2. arango-duque lc, roncero-riesco m, bárcena tu, álvarez ip, lópez ef. treatment of nail psoriasis with pulse dye laser plus calcipotriol betametasona gel vs. nd:yag plus calcipotriol betamethasone gel: an intrapatient left-to-right controlled study. actas dermosifiliogr. 2017;108(2):140-144. doi: 10.1016/j. ad.2016.09.009. pmid: 28118926. 3. yin n, choudhary s, nouri k. pulsed dye laser for the treatment of nail psoriasis. cutis. 2013;92(3):129-135. pmid: 24153141. 4. huang yc, chou cl, chiang yy. efficacy of pulsed dye laser plus topical tazarotene versus topical tazarotene alone in psoriatic nail disease: a single–blind, intrapatient left–to–right controlled study. laser surg med. 2013;45(2):102-107. doi: 10.1002/lsm.22122. pmid: 23423871. 5. al-mutairi n, noor t, al-haddad a. single blinded left-to-right comparison study of excimer laser versus pulsed dye laser for the treatment of nail psoriasis. dermatol ther. 2014;4(2):197-205. doi: 10.1007/s13555-014-0057-y. pmid: 24990703. 6. kartal sp, canpolat f, gonul m, ergin c, gencturk z. longpulsed nd:yag laser treatment for nail psoriasis. dermatol surg. 2018;44(2):227–233. doi:10.1097/dss.0000000000001294. pmid: 29016537. 7. yadav ta, khopkar us. dermoscopy to detect signs of subclinical nail involvement in chronic plaque psoriasis: a study of 68 patients. indian j dermatol. 2015;60(3):272–275. doi: 10.4103/0019-5154.156377. pmid: 26120154. 8. rich p, scher rk. nail psoriasis severity index: a useful tool for evaluation of nail psoriasis. j am acad dermatol. 2003;49:206– 212. doi: 10.1067/s0190-9622(03)00910-1. pmid: 12894066. 9. zalaudek i, argenziano g, di stefani a, et al. dermoscopy in general dermatology. dermatol. 2006;212:7–18. doi: 10.1159/000089015. pmid: 16319467. 10. khashaba sa, gamil h, salah r, salah e. efficacy of long-pulsed nd-yag laser in the treatment of nail psoriasis: a clinical and dermoscopic evaluation. j dermatol treat. 2019:1-7. doi: 10.1080/09546634.2019.1668908. pmid: 31524008. 11. klaassen kmg, van de kerkhof pcm, bastiaens mt, plusjé lgjm, baran rl, pasch mc. scoring nail psoriasis. j am acad dermatol. 2014;70:1061–1066. doi: 10.1016/j. jaad.2014.02.010. pmid: 24698704. 12. yadav ta, khopkar us, dermoscopy to detect signs of subclinical nail involvement in chronic plaque psoriasis: a study of 68 patients. indian j dermatol. 2015;60(3):272-275. doi: 10.4103/0019-5154.156377. pmid: 26120154. 13. shen jh, chang cc, chen yt, hsih cj, huang h, lin bs. using a low fluence q-switched 532/1064-nm nd:yag laser for facial skin depigmentation in asian patients: outcome and complication profile analysis. ann plast surg. 2016;77:s32–s35. doi: 10.1097/ sap.0000000000000844. pmid: 27404474. melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. thanks to dermatology practical & conceptual review | dermatol pract concept. 2021; 11(s1): e2021163s 1 evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler department of dermatology, medical university of vienna, vienna, austria key words: melanoma, dermoscopy, dermatoscopy, pathology citation: kittler h. evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma. dermatol pract concept. 2021; 11(s1): e2021163s. doi: https://doi.org/10.5826/dpc.11s1a163s accepted: april 26, 2021; published: july 2021 copyright: ©2021 kittler. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none competing interests: the author has no conflict of interest to disclose corresponding author: harald kittler, md. department of dermatology, medical university of vienna, währinger guertel 18-20, 1090 vienna, austria. e-mail: harald.kittler@meduniwien.ac.at the conventional narrative states that the steadily rising incidence of melanoma among fair-skinned caucasian populations during the last decades is caused by excessive uv-exposure. there is, however, no doubt that other factors had a significant impact on the rising incidence of melanoma. pre-1980s the clinical diagnosis of melanoma was based on gross criteria such as ulceration or bleeding. melanomas were often diagnosed in advanced stages when the prognosis was grim. in the mid-1980s education campaigns such as the propagation of the abcd criteria, which addressed health care professionals and the public alike, shifted the focus towards early recognition. dermatoscopy, which became increasingly popular in the mid-1990s, improved the accuracy for the diagnosis of melanoma in comparison to inspection with the unaided eye, especially for flat and small lesions lacking abcd criteria. at the same time, pathologists began to lower their thresholds, particularly for the diagnosis of melanoma in situ. the melanoma epidemic that followed was mainly driven by an increase in the number of in situ or microinvasive melanomas. in a few decades, the landscape shifted from an unabstract this article is part of the dpc journal special issue melanoma today guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. 2 review | dermatol pract concept. 2021; 11(s1): e2021163s introduction a conventional introduction of an article on melanoma diagnosis usually includes statements on the rising incidence and mortality of melanoma in general, and that melanoma is the most lethal type of skin cancer. while the latter is not true (the lethality of merkel cell carcinoma is higher), the incidence and mortality rates of melanoma seem to have peaked recently[1]. furthermore, a conventional introduction will also include a statement that the steadily rising incidence of melanoma among fair-skinned caucasian populations is caused by excessive intermitted uv-exposure[2-4], but will not mention that increased public awareness, early recognition campaigns, technical innovations, and lower thresholds of pathologists had a significant impact on the rising incidence of melanoma. a pubmed literature search using “melanoma” and “diagnosis” keywords yields 68102 articles if unrestricted and 9621 articles if the search is limited to the past 3 years. it is obvious that even the most ambitious review cannot cover all aspects of melanoma diagnosis. like any type of scientific research, a review should not only collect data but also create a narrative with explanatory power. the aim of this review is not to be exhaustive but to focus on the evolution of the criteria and concepts for melanoma diagnosis. while melanoma was exceedingly rare pre-1980, we observed a dramatic increase in the incidence in some parts of the world [5,6]. this statement deserves an explanation. it is the major underlying hypothesis of this review that this epidemic can in most parts be explained by changing diagnostic concepts and progress in the field of in-vivo examination techniques. this interpretation is increasingly shared by others, although with different conclusions [7]. advocates of early recognition, dermatologists and general practitioners alike, are faced with increasing criticism [8,9]. according to the opinions of critics, the increased incidence of melanoma is due to overdiagnosis, that goes hand in hand with an increase in the number of unnecessary biopsies and excisions driven by in vivo examination techniques such as dermatoscopy. in this scenario overdiagnosis and unnecessary surgery lead, according to critics, to increased morbidity and anxiety, while at the same time there is no evidence supporting improved survival following early recognition. as a solution, welch et al recently suggested not to biopsy pigmented lesions with a diameter smaller than 6 mm [7]. while welch et al rightly addressed many problematic issues in the field of melanoma diagnosis, this suggestion indicates a lack of knowledge of and a lack of confidence in current diagnostic techniques. clinical diagnosis by clinical diagnosis we refer to the diagnosis of melanoma with the unaided eye, which was state-of-the art before the introduction of the dermatoscope. the natural starting point for a review on the clinical diagnosis of melanoma are the abcd criteria. these were popularized in the mid-1980s, mainly in the us [10]. before the 1980s the diagnosis of melanoma was based on gross features such as ulceration or bleeding. the abcd criteria mark the first attempt to summarize melanoma criteria in a simple mnemonic that is easy to remember. it includes asymmetry (a), border irregularity (b), color variegation (c), and diameter larger than 6mm (d) criteria. the abcd criteria were developed following the increasing need to educate physicians and the public to recognize melanoma at earlier stages. in the words of darrel rigel, who was part of the team that popularized the abcd criteria in the 1980s, it was “intended to be a simple tool that could be implemented in daily life, a mnemonic as easy as abc to alert both laypersons and healthcare professionals to the clinical features of early melanoma” [11]. along the same line, rona mckie propagated a 7-point checklist to support non-dermatologists in recognizing possible melanomas[12,13]. the checklist was known as the glasgow 7-point checklist and was quite popular in the uk. the clinical abcd criteria and the glasgow 7-point checklist became blueprints for other simple mnemonics, such as the abcd rule [14] or the 7-point checklist for dermatoscopy [15], which even in terms of their naming, directly refer to their historic models. interestingly, neither the abcd criteria dercalling to an overcalling of melanomas, a development that is now met with increased criticism. the gold standard of melanoma diagnosis is still conventional pathology, which is faced with low to moderate interobserver agreement. new insights in the molecular landscape of melanoma did not translate into techniques for the reliable diagnosis of gray zone lesions including small lesions. the aim of this review is to put our current view of melanoma diagnosis in historical context and to provide a narrative synthesis of its evolution. based on this narrative i will provide suggestions on how to rebuild the trust in melanoma diagnosis accuracy and in the benefit of early recognition. review | dermatol pract concept. 2021; 11(s1): e2021163s 3 nor the glasgow 7-point checklist were derived from statistical evidence but rather from the best judgements of expert clinicians. at the same time in 1985, a bernard ackerman, who was an influential figure in the field of dermatology and dermatopathology, wrote a lively plea for early recognition of melanoma entitled “no one should die of malignant melanoma” [16]. in a series of articles and book chapters, ackerman and his coworkers set forth and refined criteria for the clinical and histopathologic diagnosis of melanoma in situ. pre 1980s, the recognition of melanoma in situ was not widely accepted and it was rather viewed as a precursor but not as authentic melanoma. the combined effect of increased public awareness and education of healthcare professionals to recognize the early stages of melanoma had a major impact on the diagnosis of melanoma. the incidence of melanoma increased, and the epidemic of melanoma started. from an early recognition point of view, the most critical parameter in the abcd criteria was the diameter. a size threshold puts a limit to how early melanomas can be diagnosed. the abcd rule gives credit to the fact that small melanomas are difficult to diagnose because melanomas smaller than 6 mm are usually not asymmetric and multicolored, at least when viewed with the unaided eye. size limits were also part of other algorithms. the glasgow 7-point checklist established a size limit of 7 mm. a popular algorithm for the diagnosis of acral melanoma developed by saida et al determined a size limit of 7 mm for the diagnosis of acral melanoma [17]. the diagnosis of melanoma of the nail matrix is discouraged if the pigmentation covers less than 1/3 of the nail plate [18]. size limits have the problem that, at least in theory, all melanomas start smaller than 6 mm. a reevaluation of the abcd criteria in 2004, however, concluded that the size limit of 6 mm should not be lowered[19]. in light of the fact that melanomas smaller than 6 mm were increasingly recognized, the authors suggested that “the abcd should be expanded to abcde (e standing for enlargement or evolution) to emphasize the significance of evolving pigmented lesions for the diagnosis of melanoma”. the disadvantage of the newly added e criterion relies on the fact that it depends on information collected over time. although the self-reported history of patients or information provided by a spouse or partner can at times be a valuable source for this type of information, it is not perfectly reliable[20, 21]. total body photography (tbp) on the other hand, helps to detect new and changing lesions independent from the attention of the patient and thereby facilitates the detection of small and inconspicuous melanomas [22–24]. it also reduces the number of unnecessary excisions of benign lesions [25]. in a recent meta-analysis, ji-xu calculated that total body photography of high-risk individuals significantly reduced the number of biopsies needed to detect one melanoma from 14.8 to 8.6 [26]. most melanomas detected by tbp were in situ, highlighting the impact of tbp for early recognition. tbp is especially useful for individuals with multiple nevi, in whom melanomas are more difficult to detect because of the abundance of nevi [27]. the “ugly duckling” approach addresses this difficulty in attempting to find the one outlier among multiple similar looking lesions. the first attempts to popularize the “ugly duckling” approach can be attributed to the french dermatologist jj grob, who co-authored an article on this topic in 1998 [28]. unlike the abcd criteria, the “ugly duckling” method is a comparative approach that takes into account the landscape of nevi in a particular patient. it tacitly assumes that individuals have a nevus archetype and that deviations from this archetype may indicate malignancy. it is an informal method as there is no rigorous definition regarding the kind of deviation that is significant. all kinds of deviation have been used to identify the outlier lesion, such as a pink lesion among pigmented lesions, a large lesion among small lesions, and a chaotic lesion among symmetric lesions. this approach can also be used to increase specificity in patients with multiple “atypical” nevi. if all nevi look atypical and none is standing out the significance of “atypia” decreases. this inverse interpretation of the “ugly duckling” approach has been more formally investigated in the field of dermatoscopy by argenziano and coworkers [29]. in 2021, soenksen et al. successfully used the “ugly duckling” approach to automatically detect outlier lesions from photographic overviews with artificial intelligence (ai) [30]. dermatoscopy the seminal paper of pehamberger on pigmented skin lesions pattern analysis, published in 1987 [31] paved the way for future developments of the dermatoscopic diagnosis of melanoma. it described patterns of benign and malignant pigmented skin lesions and introduced and defined dermoscopic criteria that are still used today. a closer look at this classical article, however, reveals that the melanomas shown in the figures are large and could have been diagnosed without dermatoscopy. the method of dermatoscopy was still evolving and the world of dermatology was not ready to accept that melanomas can be small (smaller than 6 mm) and inconspicuous (figure 1). soon thereafter other groups followed and presented their own interpretation of pattern analysis. old concepts such as the abcd criteria and the glasgow 7-point checklist were reused for dermoscopy. stolz et al invented the abcd rule of dermoscopy and argenziano et al the 7-point checklist[14,15]. both methods aimed to differentiate melanomas from nevi. other noteworthy algorithmic approaches include menzies rule [32], the cash algorithm [33], and the chaos and clues method, which appeared later [34]. over the years 3 meta-analysis showed how dermatoscopy improved diagnostic accuracy for melanoma, compared to an unaided 4 review | dermatol pract concept. 2021; 11(s1): e2021163s eye inspection [35–37]. another milestone was the second consensus conference of dermoscopy, which was virtually held [38]. this was a turning point for the evolution of dermatoscopy because it marks the beginning of a fruitful international collaboration among different groups that tried to establish a consensus for criteria and terminology. prior to this milestone event, the study of dermatoscopy was fragmented into different small research groups that often antagonized each other. in the following years dermatoscopy differentiated into a complex science and criteria for melanoma were refined. special criteria were described for acral melanoma [39–41], facial melanoma [42–44], amelanotic and hypomelanotic melanomas [45,46], nodular melanomas [47,48], mucosal melanoma[49], nail matrix melanoma [50–53], and melanomas on chronic sun damaged skin [54]. smaller and smaller lesions were identified as melanomas thanks to dermatoscopy pushing the diagnostic boundaries, also in dermatopathology [54–58]. furthermore, argenziano et al demonstrated that when applied by experienced users, dermatoscopy reduces the number of biopsies or excisions needed to detect 1 melanoma[59]. despite these advancements, it became clear that dermatoscopy had its limitations [59–63]. it was reported that some small and flat melanomas lack melanoma clues at the beginning and can only be diagnosed by observing changes over time with sequential digital dermatoscopy [64–68]. the finding was immediately criticized as just another way to inflate the melanoma epidemic [69]. the introduction of sequential dermatoscopy to recognize changes over time, mirrors the letter e (for evolving) addition to the abcd criteria. finally, dermatoscopic images are increasingly used for training of machine learning algorithms [70–75]. computer algorithms based on deep learning outperformed dermatologists in some studies and increased the expectations that ai will replace human expertise, at least for some applications such as teledermatoscopy. the expectations are likely exaggerated because ai-based algorithms still lack the kind of adaptive general knowledge that is necessary to act independently from humans. it is likely, though, that ai will transform images-based diagnostic medicine in many ways. as recently demonstrated by tschandl et al, collaboration between humans and computers is more promising than competition [72]. histopathologic diagnosis while it is easy to pin down the beginning of the clinical and dermatoscopic diagnosis of melanoma evolution, the same does not apply to histopathology. a possible choice is the work of lv ackerman in the late 1940s. it was one of the first to systematically describe the pathology of “melanocarcinoma”, as defined then [76]. all clinical photos and microfigure 1. (a) clinical, (b) dermatoscopic, (c) histopathologic view of a tiny melanoma (<3 mm). review | dermatol pract concept. 2021; 11(s1): e2021163s 5 graphs in his original publication of a series of 75 cases show advanced cases of melanoma. of 40 patients who underwent dissection of the local lymph nodes, 37 already had lymph node metastasis at the time of diagnosis. the article is mostly interesting for its summary of beliefs about melanoma prevalent in those days. according to lv ackerman melanoma usually starts in a mole and “it is most unusual to find the changes of malignant melanoma entirely within the epidermis with no change in the dermis.” interestingly, among the suggested treatments mentioned in this article there was also castration, because it was believed that hormones have an impact on the course of the disease. in 1953, a allen and s spitz co-authored an article, in which they set forth their belief that all melanomas start in a preexisting mole, especially in a so called “active junctional nevus” [77]. the micrograph of the “activated junctional nevus immediately preceding the development of infiltrating melanocarcinoma” shown in figure 9 in their 1953 article shows a melanoma in situ. from the current point of view, most of what has been published on the pathology of melanoma pre-1970s is only of historical interest. the articles, however, witness the different concepts of ackerman, allen, spitz, and other pioneers of melanoma pathology, compared to our current view, particularly regarding melanoma in situ. what has been defined a precursor by allen and spitz, would be called a melanoma today. in the early 1970s wh clark and coworkers propagated a “histogenetic” classification of melanoma, which continues to be relevant until today [78,79]. in its original form the classification included 3 subtypes: nodular melanoma, superficial spreading melanoma, and lentigo maligna melanoma. nodular melanoma was typified by pure vertical growth, while superficial spreading melanoma expands along the epidermis (radial or horizontal growth phase). the fourth subtype, acral lentiginous melanoma, was added later. around the same time in the early 1970s, a breslow introduced the invasion thickness as prognostic marker for primary skin melanoma [80,81], and in the mid-1970s, ab ackerman and coworkers set forth histopathologic criteria for the diagnosis of melanoma that are still widely used by dermatopathologists (table 1) [82]. ackerman also popularized the concept of melanoma in situ, clinically and pathologically, and denied the concept of precursor lesions such as “allen’s active junctional nevus”, “hutchinson’s melanotic freckle”, “kossard’s lentiginous dysplastic nevus of the elderly”, and “precancerous melanosis of dubreuilh”. according to his opinion, these were evasions from the correct diagnosis of melanoma in situ. in 1992 the national institutes of health (nih) held a consensus conference to discuss the clinical and histological characteristics of early melanoma [83]. the panel of the consensus conference agreed that melanoma in situ is a distinct entity. with this official acceptance of “melanoma in situ” as authentic melanoma, the stage was finally set for early recognition to lift off. the increased public awareness, the availability of a new, accurate, and affordable in vivo examination technique, and the lower hesitancy of pathologists to diagnose melanoma in situ acted in accordance: the incidence for melanoma skyrocketed and increased more than for any other type of cancer. conventional pathology is still the gold standard for melanoma diagnosis but it is far from perfect. there is a large discrepancy of opinions and concepts among pathologists who tend to disagree on classification, terminology, the significance of subtypes, and on the model of tumor progression, but most importantly, they tend to disagree on the diagnosis [84–87]. for certain types of lesions there is large interand intra-observer variability among community-based pathologist whether a given lesion is benign or malignant. the most common issues of this sort concern the diagnosis of small or flat lesions and lesions with a spitzoid morphology. for these lesion categories, the community suggested terms with uncertain prognosis such as atypical spitz tumor (ast) [88] and superficial atypical melanocytic proliferation of uncertain malignant significance (sampus) [89]. there is certainly a need for such categories in practice but there are different table 1. significant histopathologic features of superficial spreading melanoma according to price, rywlin, and ackermann 1976 poor circumscription of the intraepidermal melanocytic component of the lesion with lateral extension of individual melanocytes increased number of melanocytes, solitary and in nests, within and above the epidermal basal-cell layer and within adnexal epithelium (pagetoid appearance) marked variation in size and shape of the melanocytic nests confluence of melanocytic nests rather than discrete nests. absence of maturation of melanocytes with descent into the dermis. melanocytes with nuclear atypia melanocytes in mitosis necrosis or degeneration of melanocytes 6 review | dermatol pract concept. 2021; 11(s1): e2021163s views about the best way to express this ambiguity. one school of thought will blame the lesion (“the lesion does not know what it is”), the other the ignorance of the reporting pathologist (“the pathologist does not know what it is”). in the early 2000s the molecular revolution in medicine gained momentum and new observations challenged our concepts of melanoma biology. the first turning point was the discovery of the significance of braf mutations in melanoma and in nevi [90]. this was soon followed by the detection of other tumorigenic mutations in other oncogenes [91] and climaxed in the description of the genomic landscape of melanoma [92]. while some of these discoveries translated into the identification of “druggable” biologic targets [93], the new insights into the genetic landscape of melanoma did not translate into reliable diagnostic methods for borderline lesions. although molecular techniques such as fluorescence in situ hybridization (fish) [94] or comparative genomic hybridization (cgh) [95] have been used to better classify borderline lesions such as spitz tumors, they remain auxiliary techniques, requiring an integration with clinical and dermoscopic observations as well as with conventional pathology[96]. the recent hype associated with ai and deep learning in image based diagnostic medicine did not leave dermatopathology untouched [97]. using random crops of digitized whole slide scans, hekler et al showed that an algorithm trained by deep learning was capable off differentiating melanoma from nevi as accurate as pathologists [98]. it is, however, currently unknown how such algorithms will perform in the everyday practice. summary and interpretation there can be no doubt that the clinical, dermatoscopic, and histopathologic criteria for the diagnosis of melanoma changed significantly over time. new inventions such as dermoscopy, tbp, and new developments in the field of ai and molecular medicine continuously modify the way we diagnose melanocytic proliferations. these developments in conjunction with increased public awareness shifted the landscape of melanoma diagnosis towards an increased detection of borderline lesions, especially with early melanomas. in a few decades we passed from an era of significant underdiagnosis to overdiagnosis. by overdiagnosis we refer to the inflation of the diagnosis of in situ or microinvasive melanomas with unknown prognostic significance. the undesired consequences of overdiagnosis should not be taken lightly. apart from putting a significant financial burden on health care systems, overdiagnosis is associated with increased anxiety and morbidity of affected individuals. however, the recent suggestion of welch and coworkers, that we should stop performing biopsies for lesions smaller than 6 mm, indicates lack of knowledge of current diagnostic techniques such as dermatoscopy. some, albeit not all melanomas, can be diagnosed with confidence by dermatoscopy even when they are smaller than 6 mm (figure 1). if early recognition of melanoma translates into improved survival is still a matter of debate. this question is not easy to answer. it would demand a randomized controlled trial with 2 arms. in 1 arm all lesions smaller than 6 mm that can be identified as melanomas by dermoscopy would be excised, in the other arm these lesions would be left alone until they reach the size of 6 mm. since such a trial has not been performed and will not be completed in the near future, we have to rely on indirect evidence such as invasion thickness. it is also true that early recognition has become a business. feeding the business demands that the melanoma epidemic is constantly rising. however, to attribute the recent decline of melanoma mortality solely to the invention of new therapies is a slap in the face of all clinicians who dedicated their work to early recognition. dermatologists or primary care clinicians, who work on the forefront of early diagnosis, are not greedy businessmen who stir up and exploit anxiety only for their own profit, in the same way as basic researchers and the pharmaceutical industry, who invent and develop new treatments against cancer, are not altruistic cure-alls. instead of turning back the wheel of time and ignoring the innovations of the last 30 years the inflated melanoma epidemic is best tackled otherwise. first, like any other diagnostic technique dermatoscopy needs training and expertise and it can have undesired side effects if used by inexperienced users. better training will produce better dermatoscopists, who know the limitations of the technique and will make better decisions. if used appropriately by sufficiently trained and experienced clinicians, dermatoscopy will reduce and not inflate the number of excisions and biopsies. second, pathologists who sign out melanocytic lesions need specific training in clinical dermatology. they need to be aware that borderline lesions are best diagnosed with an integrated approach taking into account clinical, dermatoscopic and, in some cases, also molecular findings. third, clinicians and pathologist should not be paranoid of missing a melanoma. overdiagnosis should be as undesirable as underdiagnosis. in some parts of the world vulnerability to malpractice lawsuits leads to over anxiousness, which leads to excessively low thresholds and overdiagnosis. forth, we need a shift of policy with regards to incentives. reimbursements for monitoring techniques such as tbp or digital dermatoscopy should be in the range of excisions. reimbursement of clinicians, who need a disproportionally large number of biopsies to detect one melanoma, should be capped. fifth, slides of 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melanocytic skin neoplasms. plos one. 2009;4. doi:10.1371/journal.pone.0005375. 97. brinker tj, schmitt m, krieghoff-henning ei, barnhill r, beltraminelli h, braun sa, et al. diagnostic performance of artificial intelligence for histologic melanoma recognition compared to 18 international expert pathologists. j am acad dermatol. 2021. doi:10.1016/j.jaad.2021.02.009. 98. hekler a, utikal js, enk ah, solass w, schmitt m, klode j, et al. deep learning outperformed 11 pathologists in the classification of histopathological melanoma images. eur j cancer. 2019;118: 91–96. doi: 10.1016/j.ejca.2019.06.012. 1-indice 3-1797 dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021071 1 loose anagen hair syndrome in a saudi girl mahdi al dhafiri1, muneerah alhumaidy2 1 dermatology department, college of medicine, king faisal university, alahsa, saudi arabia 2 college of medicine, king faisal university, alahsa, saudi arabia key words: loose anagen hair syndrome, black, hair, saudi, children citation: al dhafiri m, alhumaidy m. loose anagen hair syndrome in a saudi girl. dermatol pract concept. 2021;11(4):e2021071. doi: https://doi.org/10.5826/dpc.1104a071 accepted: january 29, 2021; published: october, 2021 copyright: ©2021 al dhafiri et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: mahdi al dhafiri, assistant professor, department of dermatology, college of medicine, king faisal university, alahsa, saudi arabia. email: maldhafiri@kfu.edu.sa introduction loose anagen hair syndrome (lahs) is an uncommon, self-limited condition mainly affecting young children with a fair phototype and light hair. it has a female predominance, the average age of onset is three years old. it is characterized by slowly growing hair and sparse scalp hair that is easily and painlessly pulled out. lahs is related to the premature keratinization of the inner root sheath [1]. herein, we present a case of a black-haired young girl of saudi origins with lahs.   case presentation a 3-year-old saudi girl presented to our clinic complaining, since early childhood, of slowly growing unruly scalp hair. the patient has black-colored hair that can be easily and painlessly pulled out with minor traction or combing. her mother described that the patient always had short hair and never required a haircut. there is however no consanguinity between the parents and no similar family condition, including her 3 older brothers, who have easily combable diffuse hair that requires a regular haircut. upon clinical examination, there were no signs of systemic associations with no abnormal nails, teeth, or skin findings. there were no complete alopecic areas localized on rubbing or traction zones, however, the hair pull test was positive, and the light microscopic examination of the plucked hairs revealed misshapen anagen bulbs and ruffled appearance of the cuticles (figures 1 and 2). based on this finding, a diagnosis of lahs has been made.   conclusions lahs usually affects the hair of the scalp and rarely the body hair. it clinically manifests as fine, sparse, or unmanageably unruly hair texture that is poorly growing and rarely requires haircutting. additionally, a 3 phenotypic presentation of lahs was observed, including slowly growing sparse hair, diffuse or patchy unruly hair, and excessive shedding in normally appearing hair [1, 2].  lahs has an autosomal dominant inheritance, and a mutation in k6hf and k6irs genes encoding for keratin was found in some families. however, sporadic cases of lahs were also described [1, 2]. the diagnosis of lahs is based on the clinical and light microscopic examination of the hair that shows misshapen bulbs and ruffled cuticles. however, there is no associated 2 letter | dermatol pract concept. 2021;11(4):e2021071 figure 1. light microscopy examination showing the hair’s characteristic feature in loose anagen hair syndrome with misshapen bulbs and ruffled cuticles. abnormal laboratory finding in most patients [1, 2].  lahs has an isolated presentation in most cases. nevertheless, an association with other disorders is reported, including noonan syndrome, uncombable hair syndrome, hypohidrotic ectodermal dysplasia, and nail-patella syndrome [1, 2]. lahs has a good prognosis with spontaneous improvement during adolescence or adulthood, and topical minoxidil can be used as first-line therapy [2]. there are limited black-haired children reported with lahs in egypt, india, an african american girl, and a southasian boy [1, 2]. to our knowledge, this is the first case of lahs of a child with black-colored hair from saudi arabia and the gulf area.  lahs in black-haired patients was seldomly described; however, similar cases could be underdiagnosed. physicians figure 2. light microscopy examination showing the hair’s misshapen bulbs and ruffled cuticles. probably rule this condition out since it is frequently connected to light-skin-colored children. references 1. dey v, thawani m. loose anagen hair syndrome in blacked-haired indian children. pediatr dermatol. 2013;30(5):579-83. doi: 10.1111/pde.12208. pmid: 23937400. 2. leerunyakul k, suchonwanit p. a case of loose anagen hair sy n d ro m e i n a s o u t h e a s t a s i a n b oy. ca s e re p d e r m a to l . 2019;11(2):204-208. doi: 10.1159/000501443. pmid: 31341463. pmcid:pmc6639585. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(3):e2022120 1 dermatology practical & conceptual calcinosis cutis in association with long-term stasis after electrical burn injury: a case report belkız uyar1, ömer faruk elmas2, emine müge acar3, sümeyra has4 1 düzce university, faculty of medicine, department of dermatology, düzce, turkey 2 kırıkkale university, faculty of medicine, department of dermatology, kırıkkale, turkey 3 kırşehir training and research hospital, department of dermatology, kırşehir, turkey 4 kırşehir training and research hospital, department of pathology, kırşehir, turkey keywords: calcinosis cutis, dermoscopy, dystrophic calcification, leg ulcer citation: uyar b, elmas öf, acar em, has s. calcinosis cutis in association with long-term stasis after electrical burn injury: a case report. dermatol pract concept. 2022;12(3):e2022120. doi: https://doi.org/10.5826/dpc.1203a120 accepted: october 31, 2021; published: july 2022 copyright: ©2022 uyar et al. this is an open-access article distributed under the terms of the creative commons attribution license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: belkız uyar, merkez, yörükler mah konuralp yerleşkesi, 81620 düzce merkez/düzce, telephone: 90 380 543 13 90-6324 gsm: 05057408812, e-mail address: belkisuyar@gmail.com introduction calcinosis cutis is an uncommon disorder caused by an abnormal deposit of calcium phosphate in the skin [1]. case presentation a 55-year-old male patient with a long-lasting wound on the left ankle presented with complaints of swelling and itching on his left ankle. according to his medical history, he had an electric shock to the left leg 33 years before and the wound was closed with grafting. ulceration developed at the same site 2 years before he presented at our clinic. on physical examination, he had an erythematous, ulcerated, sclerotic, 20 cm x 15 cm in size wound over the left lateral malleolus. on this wound, there were three fluctuating masses with overlying intact skin which were 1 x 1.5, 1 x 2 and 3x3 cm in size, respectively (figure 1a). dermoscopic examination showed blue to gray structureless areas, numerous coiled vessels with patchy distribution and scales (figure 2a). a thick, profuse, white, chalky material was discharged from the hole created via a punch biopsy (figure 1b). histopathological examination revealed hyperkeratosis, acanthosis, superficial dermal vascular proliferation along with dermal and subcutaneous calcification foci. x-ray examination showed irregular-defined calcified foci over the posterior aspect of the distal end of the fibula extending in a linear fashion (figure 2b). arterial and venous doppler ultrasound examinations revealed normal findings. biochemical parameters including liver and renal function tests, alkaline phosphatase, serum calcium, phosphorus, sodium, potassium, vitamin d levels, parathyroid hormone levels, cea, afp, ca-15-3, ca-19-9, total psa were within normal limits. the patient was diagnosed with a stasis ulcer with dystrophic calcification and was managed with extremity elevation, wound dressing and oral diltiazem. the patient, who has been under our control for 18 months, has not had a recurrence of the fluctuating mass (figure 1c). 2 research letter | dermatol pract concept. 2022;12(3):e2022120 figure 1. (a) an erythematous, ulcerated, sclerotic wound over the left lateral malleolus and three fluctuant masses. (b) a thick, profuse, white, chalky material discharged from the hole created via a punch biopsy. (c) 18 months after the treatment, it is seen that the fluctuant masses still do not recur. figure 2. (a) dermoscopic appearance: blue to gray structureless areas, numerous coiled vessels with patchy distribution and scale. (b) x-ray of the left lower leg showing irregular-defined calcified foci over the posterior aspect of the distal end of the fibula extending in a linear fashion. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. conclusions cutaneous calcification has been divided into five major types according to etiology: dystrophic calcinosis is the most common type of calcinosis that is associated with infection, inflammatory processes, cutaneous neoplasm, or connective tissue diseases. other types of calcinosis cutis are metastatic calcification, idiopathic calcinosis cutis, iatrogenic, and mixed calcinosis [1,2]. in the literature there a few studies on dystrophic calcification due to stasis developed as a result of chronic venous insufficiency [1]. arterial and venous doppler results of our patient were normal. however, the stasis might have been caused by worsened lymphatic drainage due to previous operations and tissue damage experienced by the patient. dystrophic calcification is reported to be a rare cause of non-healing leg ulceration [2]. it should be kept in mind that dystrophic calcification of the skin may also be associated with persistent ulceration in the setting of stasis. the treatment of calcinosis cutis is not well-established. apremilast, diltiazem, bisphosphonates, probenecid, aluminum hydroxide, aimed at altering the serum calcium-phosphorus research letter | dermatol pract concept. 2022;12(3):e2022120 3 levels, have been tried. long-term treatment with diltiazem was reported to decrease the size of calcium deposits. surgical excision or curettage is appropriate in selected patients [2]. references 1. enoch s, kupitz s, miller dr, harding kg. dystrophic calcification as a cause for non-healing leg ulcers.  int wound j. 2005;2(2):142-147. doi: 10.1111/j.1742-4801.2005.00096.x. pmid: 16722863. pmcid: pmc7951336. 2. uyar b, elmas of, acar em, has s. calcinosis cutis in association with long-term stasis after electrical burn injury: a case report. [op-025] in 5th indercos congress, 12-15 march 2020 in i̇stanbul-turkey. available from: https://indercos.org/2020/docs/ full_abstracts.pdf?a=9999 dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):7 31 case presentation an 11-year-old japanese girl presented to our department with a pigmented lesion on her right leg (figure 1). it was a blue-gray papule approximately 4 mm in diameter with a 4-year history. we suspected that it was a blue nevus or a pigmented reed/spitz nevus. on dermoscopic observation, the lesion showed homogeneous black-bluish pigmentation, suggesting a substantial amount of melanin in the dermis. this dermoscopic feature was suggestive of a blue nevus. however, near-circumferential streaks and a global feature of a “starburst pattern” were also observed, as is often found in a reed/spitz nevus (figure 2). the lesion was excised under the diagnosis of a blue nevus. histological examination revealed spindle cells with melanin pigments diffusely present in the upper dermis and around hair follicles in the mid-dermis, but not in the epidermis. the melanocytic cells were arranged in a symmetrical wedge-shaped configurablue nevus with a starburst pattern on dermoscopy takeo shiga, m.d.1, kimiko nakajima, m.d.1, masahito tarutani, m.d.1, miki izumi, m.d.2, masaru tanaka, m.d.3, shigetoshi sano, m.d.1 1 department of dermatology, kochi medical school, kochi university, kochi, japan 2 department of dermatology, tokyo women’s medical university medical center east, tokyo, japan 3 department of medical education, tokyo medical university, tokyo, japan key words: blue nevus, dermoscopy, starburst pattern, spitz nevus, histopathology citation: shiga t, nakajima k, tarutani m, izumi m, tanaka m, sano s. blue nevus with a starburst pattern on dermoscopy. dermatol pract conc. 2012;2(4):7. http://dx.doi.org/10.5826/dpc.0204a07. received: april 27, 2012; accepted: august 14, 2012; published: october 31, 2012 copyright: ©2012 shiga et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: takeo shiga, m.d., department of dermatology, kochi medical school, kochi university, kohasu, oko-cho, nankoku, kochi 783-8505, japan. tel. 81.88.880.2363; fax. 81.88.880.2364. e-mail: shigat@kochi-u.ac.jp. an 11-year-old girl presented to our department with a blue-gray papule approximately 4 mm in diameter. we suspected that it was a blue nevus or a pigmented reed/spitz nevus. on dermoscopic observation, the lesion showed homogeneous black-bluish pigmentation. this dermoscopic feature was suggestive of a blue nevus. however, near-circumferential streaks and a global feature of a “starburst pattern” were also observed, as is often found in a reed/spitz nevus. the lesion was excised and histological examination revealed spindle cells with melanin pigments diffusely present in the upper dermis and around hair follicles in the mid-dermis, but not in the epidermis. the melanocytic cells were arranged in a symmetrical wedge-shaped configuration. in addition, there was a diffuse fibrosis. finally, we made a diagnosis of a blue nevus based on these findings. abstract 32 observation | dermatol pract concept 2012;2(4):7 spitz nevus is a rapidly growing pink-red or reddish-brown dome-shaped papule or nodule, because of the scarcity of melanin. less often, the lesions are brown or even black-colored [5]. melanocytic cells in a spitz nevus are often large, and the overall distribution of cells in the dermis is wedgeshaped, with narrowing of the wedge toward the subcutaneous fat [2]. on dermoscopy, most of the spitz nevus has a typical starburst pattern with symmetrical, brown or black pigmentation. some spitz nevi show globular or atypical patterns [5]. the present case showed the characteristic histological features of a blue nevus, such as the intradermal proliferation of spindle cells with melanin pigments, the presence of abundant fibrous tissue and the absence of epidermal change. however, this case also showed the unique wedge-shaped distribution of melanocytic cells often observed in a spitz nevus. in addition, dermoscopic observation revealed two typical features with a combination of “homogeneous steel-blue pigmentation” and “starburst pattern” that suggest a diagnosis tion. in addition, there was a diffuse fibrosis (figures 3 and 4). finally, we made a diagnosis of a blue nevus based on these findings. conclusion blue nevi present as dark blue or blue-black, small macules or dome-shaped papules about 1-5 mm in diameter [1]. the histological characteristics of blue nevi are dermal melanocytes that appear as melanin-containing fibroblast-like cells grouped in irregular bundles admixed with melanin-containing macrophages, associated with excessive fibrous tissue in the middle or upper reticular dermis [2]. on dermoscopy, a blue nevus is characterized by a homogeneous, structureless pigmentation, which is often described as steel-blue coloration [3]. blue globules and dots, and pigment network-like structures are also observed in some cases of blue nevus [4]. on the other hand, spitz nevi usually present as solitary lesions on the lower extremities or the face. clinically, a figure 1. a blue-gray papule on the right leg. [copyright: ©2012 shiga et al.] figure 3. melanocytic cells showed a wedge-shaped distribution in the dermis with diffuse fibrosis (h&e, x20). [copyright: ©2012 shiga et al.] figure 2. the lesion showed homogeneous blue pigmentation with many streaks, demonstrating a starburst pattern on dermoscopic observation. [copyright: ©2012 shiga et al.] figure 4. spindle cells with melanin pigments proliferated between collagen bundles at the periphery of the lesion (h&e, x100). [copyright: ©2012 shiga et al.] observation | dermatol pract concept 2012;2(4):7 33 bution of nevus cells in the upper dermis, resulting in the rare configuration of a starburst pattern. references 1. zembowicz a, phadke pa. blue nevi and variants: an update. arch pathol lab med. 2011;135(3):327-36. 2. wolff k, goldsmith la, katz si, et al (eds). fitzpatrick’s dermatology in general medicine. 7th ed. mcgraw-hill, 2007:1099121. 3. braun rp, rabinovitz hs, oliviero m, kopf aw, saurat jh. dermoscopy of pigmented skin lesions. j am acad dermatol. 2005;52(1):109-21. 4. tsunemi y, saeki h, tamaki k. blue naevus with pigment network-like structure on dermoscopy. acta derm venereol. 2008;88(4):412-3. 5. ferrara g, argenziano g, soyer hp, et al. the spectrum of spitz nevi: a clinicopathologic study of 83 cases. arch dermatol. 2005;141(11):1381-7. 6. di cesare a, sera f, gulia a, et al. the spectrum of dermatoscopic patterns in blue nevi. j am acad dermatol. 2012;67(2):199-205. of blue nevus or spitz nevus, respectively. when there are numbers of dermoscopic findings that indicate distinct diseases, the predominant feature is given priority. in this case, the homogeneous steel-blue pigmentation was the most decisive feature to make the diagnosis of a blue nevus. thus, this case was diagnosed as a blue nevus with a starburst pattern based upon histological and dermoscopic findings. di cesare et al analyzed global and local features in 95 dermoscopic images of blue nevi, and reported that streaks were found in 4.2% of blue nevi and regularly distributed streaks at the peripheries of the lesions could not be distinguished from those observed in spitz/reed nevi [6]. in our case, it seemed that dermal melanocytic cells grew between the proliferative collagen bundles and formed streaks in the lesion. furthermore, the wedge-shaped distribution of dermal melanocytic cells, which is often observed in a spitz nevus, may be associated with the starburst pattern in a blue nevus. we consider that our case of the blue nevus is due to the coexisting dermal fibrosis, which may confine the distridermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022048 1 dermoscopic and reflectance confocal microscopy features of superficial morphea on preexisting atrophoderma of pasini and pierini chun-xiao song1, yu-ting zhang1, cheng tan1 1 department of dermatology, affiliated hospital of nanjing university of chinese medicine, nanjing, china key words: morphea, atrophoderma, hyperpigmentation, hypopigmentation, dermatology citation: song cx, zhang yt, tan c. dermoscopic and reflectance confocal microscopy features of superficial morphea on preexisting atrophoderma of pasini and pierini. dermatol pract concept. 2022;12(2):e2022048. doi: https://doi.org/10.5826/dpc.1202a48 accepted: july 28, 2021; published: april, 2022 copyright: ©2022 song et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: cheng tan, md, department of dermatology, affiliated hospital of nanjing university of chinese medicine, 155 hanzhong road, nanjing, china, 210029. e-mail: tancheng@yeah.net introduction superficial morphea (sm) is a distinct new variant of localized scleroderma with the collagen proliferated and deposited in the papillary and upper reticular dermis [1]. we present a case of sm developed on a primary lesion of atrophoderma of pasini and pierini (app), and describe related dermoscopic and reflectance confocal microscopy (rcm) features. case presentation a 26-year-old chinese woman presented with a seven-year-history of large hyperpigmented patches on the right leg. on examination, larger hyperpigmented patches were distributed in a zosteriform pattern. it spread from the right groin area, down the medial portions of the thigh, and finally to the popliteal fossa region. furthermore, multiple 2 to 3  mm depigmented macules were disseminated within these hyperpigmented patches (figure 1). dermoscopic examination of the white spots showed whitish fibrotic beams figure 1. large hyperpigmented patches were distributed in a zosteriform pattern on the right groin area, and the thigh. lesions were atrophic and slightly depressed without induration. multiple 2 to 3 mm depigmented macules speckled within the hyperpigmented patch are shown. 2 research letter | dermatol pract concept. 2022;12(2):e2022048 figure 2. dermoscopic examination of the white spots showed whitish fibrotic beams and linear arborizing vessels (green arrows). (a,b) the pigment network is irregularly distributed with a storiform pattern (red oval circles) in some speckled hypopigmented macule (blue oval circles). (c) rcm mosaic shows marked hyperreflective areas with decreased appendageal structures. histological examination of this hypopigmented macule displayed decreased epidermal thickness with flattened rete pegs. (d) mild superficial perivascular lymphocytic infiltrate and pronounce dense clumping and homogenization of collagen bundles, compared to the neighboring area’s unaltered collagen. (e,f) discrete, highly reflective clouds in the “coffee-bean” pattern under rcm, which might be corresponding to the clumps of collagen under the microscope. and linear arborizing vessels. the pigment network was irregularly distributed with a storiform pattern in some speckled hypopigmented macules. histological examination of a hypopigmented macule displayed decreased epidermal thickness with flattened rete pegs. there were mild superficial perivascular lymphocytic infiltrate and pronounce dense clumping and homogenization of collagen bundles, compared to the neighboring area’s unaltered collagen. discrete, highly-reflective clouds were in the “coffee-bean” pattern under rcm, which might be corresponding to the clumps of collagen in histopathology (figure 2). these findings were consistent with the diagnosis of sm (over app), and the application of 1% pimecrolimus ointment for 4 months showed no improvement. discussion sm is typically presented with symmetric hypopigmented to hyperpigmented patches at intertriginous sites. histologically, there are flattened rete ridges. the collagen fibers in the upper reticular dermis become thickened or homogenized, with the deeper dermis’s invariable sparing. perivascular lymphocytic infiltration is present in the superficial dermis with occasional plasma cells [2]. dermoscopic examination of the white spots in our patient showed whitish fibrotic beams and linear arborizing vessels. the pigment network is irregularly distributed with a storiform pattern in some speckled hypopigmented macules. rcm mosaic shows marked hyperreflective areas with decreased appendageal structures. divergent opinions about the relationship between sm and app are present in literature. some authors believe that sm is not identical to app considering the clinical depression of “cliff sign” and older age of onset in app. sm differs itself from app with thickened collagen in upper reticular dermis. others believe sm and app belong to the same entity mainly considering both share a chronic benign course and a favorable prognosis that usually needs no treatment [3,4]. besides, app and sm may coexist as separate entities in the same patient or association with classical morphea or systemic scleroderma, and therefore app can be considered an abortive type of scleroderma without sclerosis [4]. research letter | dermatol pract concept. 2022;12(2):e2022048 3 phenomenon. am j dermatopathol. 1999;21(4):315–3199. doi: 10.1097/00000372-199908000-00001. pmid: 10446770. 2. mosbeh as, aboeldahab s, el-khalawany m. superficial morphea: clinicopathological characteristics and a novel therapeutic outcome to excimer light therapy. dermatol res pract. 2019;2019:1967674. doi: 10.1155/2019/1967674. pmid: 31641348. pmcid: pmc6770326. 3. ling x, shi x. idiopathic atrophoderma of pasini-pierini associated with morphea: the same disease spectrum? g ital dermatol venereol. 2016;151(1):127–128. pmid: 26373865. 4. amano h, nagai y, ishikawa o. multiple morphea coexistent with atrophoderma of pasini-pierini (app): app could be abortive morphea. j eur acad dermatol venereol. 2007;21(9):1254– 1256. doi: 10.1111/j.1468-3083.2006.02131.x. pmid: 17894716. conclusions the presence of discrete hypopigmented macules of sm within the primary lesion of app adds another evidence that sm and app are part of the same spectrum of disease. the marked hyperreflective areas with discrete, highly reflective clumped as white coffee beans. dermoscopy and rcm can be applied as an ancillary diagnostic technique in sm. references 1. mcniff jm, glusac ej, lazova rz, carroll cb. morphea limited to the superficial reticular dermis: an underrecognized histologic dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021:11(4); e2021112 1 polypoid melanoma: towards a dermoscopic approach camilo rojas-erazo1, fernando valenzuela2, laura carreño3, francisco gonzález-coloma2 1 puerto montt hospital, reloncavi health service, puerto montt, chile 2 department of dermatology, faculty of medicine, university of chile, santiago, chile 3 pathology service, clinical hospital of the university of chile, santiago, chile citation: rojas-erazo c, valenzuela f, carreño l, gonzález-coloma f. polypoid melanoma: towards a dermoscopic approach. dermatol pract concept. 2021:11(4); e2021112. doi: https://doi.org/10.5826/dpc.1104a112 accepted: march 8, 2021; published: october 2021 copyright: ©2021 rojas-erazo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: francisco gonzález-coloma, department of dermatology, faculty of medicine, university of chile, santiago, chile. email: fgonzalezcoloma@gmail.com case presentation a 75-year-old man presented with a 2-inch exophytic lesion on the right gluteus with 1 year of progressive growth (figure 1, a and b). dermoscopy showed an irregular serohematic crusty surface that impaired the observation of atypical polymorphic vessels and a peduncle with multicolored pattern: diffuse red and white background with irregular yellow, brown, and black areas (figure 1c). erythematous papules of the ipsilateral coxal region had a central reddish homogeneous pattern with a peripheral pigmented rim at dermoscopy (figure 1d). histopathology revealed a polypoid melanoma, clark v level, breslow thickness of 14 mm, 12 mitoses/mm2, extensive ulceration, and perineural invasion. coxal papules were satellite metastasis. the dissemination study was negative, yet limited, because of the patient’s death, 1 month later. teaching point this rare and aggressive variant of nodular melanoma can be dermoscopically distinguished from clinically similar tumors by the recognition of irregular crusted-fibrinous surfaces, atypical polymorphic vessels, blue-white veils in the exophytic portion, a multicolored pattern, and blue-gray nests at the base [1, 2]. 2 image letter | dermatol pract concept. 2021:11(4); e2021112 references 1. cabrera r, recule f. unusual clinical presentations of malignant melanoma: a review of clinical and histologic features with special emphasis on dermatoscopic findings. am j clin dermatol. 2018;19(s1):15-23. doi:10.1007/s40257-018-0373-6. pmid: 30374898. 2. di altobrando a, patrizi a, dika e, savoia f. cauliflower-like exophytic mass on the skin: polypoid melanoma. clinical, dermoscopic, and histologic features. an bras dermatol. 2020;95(6):748750. doi:10.1016/j.abd.2020.04.010. pmid: 33041156. figure 1. (a) tumoral lesion on the right gluteus and erythematous papules on the ipsilateral coxal region. (b) crusty and pigmented surface of the tumor. (c) polarized dermoscopy (dermlite dl4w, magnification x10) reveals a multicolored pattern in the peduncle of the tumor and (d) homogeneous reddish center with pigmented periphery of satellite metastasis. dermatology: practical and conceptual letter | dermatol pract concept 2021;11(2):e2021027 1 dermatology practical & conceptual dermoscopy of a lentigo maligna less than 1.5 mm in diameter karim saleh1 1 division of dermatology and venereology, department of clinical sciences, lund university, skåne university hospital, lund, sweden key words: lentigo maligna, angulated lines, micromelanoma, dermoscopy citation: saleh k. dermoscopy of a lentigo maligna less than 1.5 mm in diameter. dermatol pract concept. 2021;11(2):e2021027. doi: https://doi.org/10.5826/dpc.1102a27 accepted: september 29, 2020; published: march 8, 2021 copyright: ©2021 saleh. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the author has no conflicts of interest to disclose. authorship: the author takes responsibility for this publication. corresponding author: karim saleh, md, phd, division of dermatology, department of clinical sciences, biomedical center b14, lund university, tornavägen 10, se-221 84 lund, sweden.  email: karim.saleh@med.lu.se introduction we report the smallest lentigo maligna (lm) detected by physical examination and dermoscopy (1.4 mm in diameter dermoscopically and 1.3 mm histologically) in a 74-year-old woman who presented to our clinic. case presentation the patient had a history of melanoma on her left arm in 2018. she visited for a regular check-up. she had not been monitored with total body photography. during physical examination a tiny lesion next to telangiectasias on her left cheek was noted. she was not aware of this lesion due to its tiny size. dermoscopy revealed sun-damaged skin with telangiectasias surrounding a 1.4-mm pattern of light brown dots forming angulated lines (figure 1). lentigo maligna was suspected and the lesion excised. histopathology confirmed the diagnosis of a lentigo maligna (figure 2). conclusions angulated lines in facial lesions are early features that can indicate lentigo maligna [1]. these lines have previously been referred to as the zigzag pattern or rhomboidal structures. akay et al. [2] documented the smallest melanoma ever published that measured 0.9 mm. however, that lesion was detected using a total-body imaging system. the lesion here is the smallest lesion detected by physical examination without the aid of an imaging system, and to the best of the author’s knowledge, the smallest lentigo maligna lesion ever published. 2 letter | dermatol pract concept 2021;11(2):e2021027 references 1. schiffner r, schiffner-rohe j, vogt t, et al. improvement of early recognition of lentigo maligna using dermatoscopy. j am acad dermatol. 2000;42(1 pt 1):25-32. doi: 10.1016/s01909622(00)90005-7. pmid: 10607316. 2. akay bn, okcu heper a, clark s, erdem c, rosendahl co, kittler h. dermatoscopy of a melanoma less than one millimeter in diameter. int j dermatol. 2017;56(12):1498-1499. doi: 10.1111/ ijd.13728. pmid: 28857145. figure 1. (a) clinical photograph of the left cheek. (b) polarized contact dermoscopy of the lesion. figure 2. (a) microscopic sections with h&e stain show an asymmetrical proliferation of melanocytes organized in nests that vary in size and distribution (×10) with a subepithelial actinic elastosis and telangiectatic vessels. lesion size was 1.3 mm. (b) the same section at ×25. (c) sox-10 stain illustrating periadnexal extension. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021133 1 dermoscopy as a useful tool in differentiation of genital lesions: lichen sclerosus ružica jurakić tončić 1, tatjana matijević 2, marija milković periša3, daška štulhofer buzina1, romana čeović 1 1 department of dermatology and venereology, school of medicine, university of zagreb, university hospital centre zagreb, zagreb, croatia 2 department of dermatology and venereology, university hospital centre osijek, osijek, croatia 3 department of pathology, school of medicine, university of zagreb and department of pathology and cytology, university hospital centre zagreb, zagreb, croatia key words: genital lesion dermoscopy, lichen sclerosus, venerology citation: tončić rj, matijević t, periša mm, buzina dš, čeović r. dermoscopy as a useful tool in differentiation of genital lesions: lichen sclerosus. dermatol pract concept. 2021;11(4):e2021133. doi: https://doi.org/10.5826/dpc.1104a133 accepted: january 21, 2021; published: october, 2021 copyright: ©2021 tončić et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ruzica jurakić tončić, md, phd. department of dermatology and venereology, university hospital centre zagreb, school of medicine, university of zagreb, zagreb, croatia. email: rjtoncic@gmail.com introduction lichen sclerosus (ls) is a chronic inflammatory disease of unknown etiology that most commonly affects the anogenital area, with a higher prevalence in women. it is characterized by ivory-white sclerotic plaques with thin wrinkled skin surface and frequently seen erosions and fissures [1]. pruritus is the most common symptom of genital lichen sclerosus (gls), significantly impairing the quality of life and can be accompanied by dyspareunia in women. scarring can lead to loss of normal anatomical architecture along with disease progression [1]. early diagnosis and proper treatment are of particular importance. although in most cases of advanced disease diagnosis is usually straightforward, early diagnosis can sometimes be challenging and present some diagnostic uncertainties. case presentation a 59-year-old, otherwise healthy woman, presented with a dark macule on her vulva which appeared spontaneously a few weeks before her visit. the patient had a fair phototype, multiple solar lentigines, and other signs of sun-damaged skin. clinical examination revealed a notably dark asymmetrical pigmented lesion with indistinct borders on the clitoral hood (figure 1 a). dermoscopy showed multiple red and white structureless areas with a blue-white zone on the left part of the lesion (figure 1, b and c). the observed dermoscopic features with a chaotic arrangement was alerting, biopsy was recommended also considering the fact that this was a newly-onset lesion. due to its hemorrhagic component, the lesion was first suspected to be a vascular tumor, and the main clinical concern was to exclude malignancy, especially melanoma. 2 letter | dermatol pract concept. 2021;11(4):e2021133 however, the biopsy was not performed immediately due to coronavirus pandemic and health system reorganization. a month after the first visit and before she underwent the biopsy, the patient came again to our clinic to report the change of the lesion. another clinical examination of the suspected lesion showed that hemorrhagic component completely disappeared and now only a delicate area of leukoplakia was noticed. in addition, a similar finding was also detected on the right labium minus. control dermoscopy was performed. multiple patchy structureless white and milky-pinkish areas on a whitish background with a small erosion area were observed (figure 2). the patient also complained about pruritus affectfigure 1. clinical and dermoscopic presentation of the lesion at the first visit. (a) clinical presentation. (b, c) dermoscopic presentation of the lesion showing multiple red and white structureless areas (arrow) with a blue-white zone on the left part of the lesion (asterisk). figure 2. dermoscopic presentation of the lesion at the second visit: multiple patchy structureless white and milky-pinkish areas on a whitish background (asterisk) with a small erosion area (arrow). ing the genital area. biopsy was recommended again, this time not because of a suspected malignant lesion, but because of ls suspicion. full-thickness skin biopsy was performed, and the histological examination showed hyalinization of the dermis with moderate inflammatory infiltrate, indicating ls. after ruling out malignancy and the confirming ls diagnosis, a potent local corticosteroid was prescribed with a good control of the disease and the regression of all clinical signs and symptoms. conclusion genital ls can present a diagnostic challenge in its early stages. it is known that ls plaques can commonly show signs of hemorrhage due dermal capillaries’ fragility and chronic scratching, but dermal hemorrhage is quite rare as a first sign of the disease [2]. also, it is notable from our case that purpura in set of genital ls lesion can give bizarre dermoscopic appearance, mimicking a potentially malignant lesion. dermoscopic patterns of large case series of genital ls were observed in few studies to date, and the features that we observed on the second visit were mentioned as one of the most consistent findings [2]. however, even though dermoscopy can help establishing a diagnosis of ls, its role is still limited. to confirm diagnosis histopathological examination can sometimes be required in cases of diagnostic uncertainty, especially when the disease is in its early stages, and to rule out malignant diagnoses affecting the genital region. we believe that genital ls can be considered as a possible differential diagnosis of melanoma in the genital region. letter | dermatol pract concept. 2021;11(4):e2021133 3 references: 1. lee a, fischer g. diagnosis and treatment of vulvar lichen sclerosus: an update for dermatologists. am j clin dermatol. 2018;19(5):695-706. doi: 10.1007/s40257-018-0364-7. pmid: 29987650. 2. borghi a, corazza m, minghetti s, bianchini e, virgili a. dermoscopic features of vulvar lichen sclerosus in the setting of a prospective cohort of patients: new observations. dermatology. 2016;232(1):71-7. doi: 10.1159/000439198. pmid :26574744 dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022005 1 diffuse juvenile bullous pemphigoid managed successfully with a short course of cyclophosphamide seema rani1, diksha aggarwal1, kabir sardana1, savitha bathula1, purnima malhotra2 1 department of dermatology, atal bihari vajpayee institute of medical sciences (abvims) and dr. ram manohar lohia hospital, new delhi, india 2 department of pathology, atal bihari vajpayee institute of medical sciences (abvims) and dr. ram manohar lohia hospital, new delhi, india key words: immunobullous, bullous pemphigoid, cyclophosphamide, juvenile bullous pemphigoid citation: rani s, aggarwal d, sardana k, savitha b, malhotra p. diffuse juvenile bullous pemphigoid managed successfully with a short course of cyclophosphamide. dermatol pract concept. 2022;12(1):e2022005. doi: https://doi.org/10.5826/dpc.1201a05 accepted: april 18, 2021; published: january 2022 copyright: ©2022 rani et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: seema rani, associate professor, department of dermatology, atal bihari vajpayee institute of medical sciences (abvims) and dr. ram manohar lohia hospital, new delhi, india. e-mail: drseemashekhar@gmail.com introduction adolescent bullous pemphigoid (bp) is a very rare entity— with generalized (erythrodermic) variant being even rarer— and management of such difficult bp cases can be challenging. case presentation a 17-year-old girl presented with a 1-month history of intense pruritus that was followed by the development of multiple fluid-filled lesions. these lesions ruptured spontaneously in 3 to 4 days and left behind painful erosions. there was no history of drug intake, trauma, recent vaccination, fever,or photosensitivity. notably, she had an intellectual disability; however, the psychiatric consultation was normal. cutaneous examination revealed multiple tensevesicles, both clear and hemorrhagic, and bullae over an erythematous base that involved 90% of the body surface areaalong with involvement of head and neck areas (figure1a). nails and mucosa were unaffected. bulla spread sign was positive and nikolsky sign was negative. tzanck smear showed eosinophils and neutrophils. the total leukocyte count was 20,000 per mm3 with 77% eosinophils in differential leukocyte count and an absolute eosinophil count of 15,400 per mm3. the serum immunoglobulin (ig) e level was normal. histopathology revealed focal clefting at the dermoepidermal junction and perivascular mononuclear inflammatory infiltrate with numerous eosinophils in the superficial dermis (figure 1b). direct immunofluorescence revealed linear deposits of igg and c3 along the basement membrane zone. based on clinical presentation and histopathological and immunological findings, a diagnosis of diffuse adolescent bp was made. the bp disease area index score was 145. 2 research letter | dermatol pract concept. 2022;12(1):e2022005 oral prednisolone 70 mg along with broad-spectrum antibiotic cover and antihistamines were started. doxycycline 100 mg and nicotinamide tablets 500 mg were added as steroid-sparing agents, but there was a progressive increase in the severity of the eruption. as a consequence, doxycycline was replaced by azathioprine 50 mg twice daily. in spite of 4 weeks of azathioprine, there were 40-50 new blisters per day, and in view of the recalcitrance, azathioprine was discontinued and cyclophosphamide 100 mg was added. after 2 weeks, the number of new lesions gradually decreased and old lesions started to heal. the patient was discharged on prednisolone 50 mg and cyclophosphamide 100 mg. two weeks later the dose of cyclophosphamide and prednisolone was tapered to 50 mg and 40 mg, respectively. during treatment patient routine hematological investigations and urineanalysis were normal. over the next 4 weeks, cyclophosphamide was stopped. azathioprine was restarted at a dose of 25 mg and gradually increased. currently the patient is undergoing oral prednisolone 15 mg and azathioprine 50 mg with a good control of her disease without any side-effects. the patient is on regular follow-up at a 4to 6-week intervals with no relapse of bullous lesions but with residual pigmentary changes (figure 2). informed consent has been taken from patient guardian (patient is minor) for the nature and side-effects of drug (cyclophosphamide). conclusions bp is the commonest immunobullous disorder worldwide, but it is rare in childhood (100 cases) and extremely uncommon in adolescence (14 cases) [1]. childhood bp is diagnosed according to the criteria of nemeth, and our case satisfied these criteria. bp is generally more responsive to treatment than pemphigus vulgaris, but there are refractory cases in figure 1. (a) multiple tense vesicles and bullae over an erythematous base. (b)subepidermal blister containing fibrin and eosinophils peri adnexal infiltrate of eosinophils in the dermis (hematoxylin and eosin stain, ×40). figure 2. healed lesions with residual pigmentary changes. which treatment resistance occurs. childhood bp usually has a good prognosis, although, in some cases the course is less benign [2]. our case had generalized bp, poor response to high doses of steroid, anti-inflammatory, antibiotics and azathioprine. non-availability of biologics at our center and economic constraints resulted in the use of cyclophosphamide that was administered as a “rescue therapy” in view of its side effect profile. our case exemplified the role of cyclophosphamide as a short-term bridge therapy, after which the patient was adequately controlled on azathioprine. in a severe and recalcitrant case, such as this one, cyclophosphamide can be used to bring the disease under control. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. patsatsi a, kyriakou a, werth vp. bullous pemphigoid in adolescence. pediatr dermatol. 2019;36(2):184-188. doi: 10.1111/ pde.13717. pmid: 30569520. 2. nemeth aj, klein ad, gould ew, schachner la. childhood bullous pemphigoid: clinical and immunologic features, treatment, and prognosis.  arch dermatol.  1991;127(3):378–386. doi:10.1001/archderm.1991.01680030098014. pmid: 1998369. dermatology: practical and conceptual research | dermatol pract concept 2017;7(1):2 11 dermatology practical & conceptual www.derm101.com introduction most non-skin cancers have shown decreased mortality over the past several decades, but the incidence and mortality of melanoma has continued to grow [1]. while early recognition and complete excision of a melanoma is curative, advanced stages remain associated with high mortality rate, despite the progress in treatment modalities. the challenge is to make “twin lesions”: which one is the bad one? improvement of clinical diagnosis with reflectance confocal microscopy secil saral1,2, daniela hartmann1,3, valerie letulè1,3, thomas ruzicka1, cristel ruini1,3, tanja von braunmühl1,3 1 department of dermatology and allergology, ludwig-maximilian university, munich, germany 2 department of dermatology and venereology, ankara university, ankara, turkey 3 städtisches klinikum münchen, fachklinik für dermatologie und allergologie, munich, germany key words: reflectance confocal microscopy, skin imaging, clinical diagnosis, dermatoscopy, nevus, melanoma citation: saral s, hartmann d, lutelè v, ruzicka t. ruini c, von braunnmühl t. “twin lesions”: which one is the bad one? improvement of clinical diagnosis with reflectance confocal microscopy. dermatol pract concept. 2017;7(1):2. doi: https://doi.org/10.5826/ dpc.0701a02 received: may 12, 2016; accepted: october 22, 2016; published: january 31, 2017 copyright: ©2017 saral et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. dr. cristel ruini and dr. tanja von braunmühl are senior authors. corresponding author: secil saral, autf ibni sina hastanesi dermatoloji ad 10. kat b blok samanpazari, ankara, turkey, 06100. tel. 00905054324682; fax. 00903123123872. email: secilsaral@gmail.com background: in vivo reflectance confocal microscopy (rcm) is a novel non-invasive diagnostic tool, which is used to differentiate skin lesions. even in lesions with similar dermatoscopic images, rcm may improve diagnostic accuracy. methods: three sets of false ‘’twin lesions’’ with similar macroscopic and dermatoscopic images are matched. all lesions are evaluated with rcm and lesions are excised for further evaluation. corresponding features in confocal images, dermatoscopy and histopathology are discussed. results: in all matched pairs, one of the lesions was diagnosed as melanoma with the observation of melanoma findings such as: epidermal disarray, pagetoid cells in epidermis and cellular atypia at the junction. benign lesions were differentiated easily with rcm imaging. conclusion: examining dermatoscopically difficult and/or similar lesions with rcm facilitates diagnostic and therapeutic decision making. using rcm in daily practice may contribute to a decrease in unnecessary excisions. abstract 12 research | dermatol pract concept 2017;7(1):2 which the patient herself had noticed enlargement and darkening in color during the past month. bleeding was not reported. the lesion was a 1.8 x 1.5 cm large macule with a central nodular component and was located on the dorsal surface of her left lower leg (figure 1a). a mild thickened crusty appearance was present. dermatoscopically, it exhibited more than one color (light and dark brown, white and pink). an atypical, reticular pattern was predominant with an inverse network. asymmetrically distributed dots and globules were observed (figure 1b). the dermatosurgeons were hesitant to perform a complete excision on the lower leg for a possibly benign lesion. patient 2 was a 76-year-old female with a recently growing lesion on the anteromedial side of her right lower leg. she could not provide details on the lesion’s history, having noticed it recently. macroscopically, it was a brown and slightly elevated 1.9 cm large macule (figure 1e), with a mildly thick surface. the differential diagnosis was a pigmented bowen’s disease, seborrheic keratosis and lentigomaligna-melanoma. under dermoscopy, the lesion revealed multiple colors (light and dark brown, white, pink). it was composed of a brown structureless background with white lines. a network was not clearly recognizable. brown globules were distributed unevenly on the lesion. some milia like cysts were also present (figure 1f). these clinically and dermatoscopically similar lesions were further investigated with rcm. lesion 1 showed epidermal disarray with pagetoid infiltration. pagetoid cells are large, with bright cytoplasm and dark nuclei, and represent one of the most common findings in melanoma [10] (figure 1c). an atypical honeycombed pattern was dominant in the epidermis, while the dermal-epidermal junction (dej) showed a non-specific pattern. vascular structures were identified. the lesion was then excised with a pre-diagnosis of melanoma. histopathologic examination confirmed rcm findings and the patient was diagnosed with superficial spreading melanoma, clark-level iii with a thickness of 0.85 mm and 0 mitoses per/mm2 (figure 1d). rcm of patient 2 showed the innocent picture of elongated cords and bulbous projections (figure 1f). corneal plugs and keratin filled invaginations were conspicuous. cells around the pseudofollicular openings were monomorphic in structure. these features were consistent with seborrheic keratosis so that a shave excision was performed. histopathological examination confirmed the diagnosis of a seborrheic keratosis (figure 1g). cases 3 & 4 patient 3 was a 76-year-old male who was referred to the dermatology department with a lesion located on his left preauricular area. the lesion was asymptomatic for 10 years, however, the patient had recognized an increase in size recently. an accurate diagnosis and to identify all of the malignant lesions while avoiding unnecessary surgical procedures in benign lesions. dermatoscopy is a widely used, reproducible method, which facilitates the differentiation of benign and malignant melanocytic and non-melanocytic lesions, especially in the hands of dermatologists [2-4]. the accuracy of melanoma detection thanks to dermoscopy has been widely investigated. characteristic dermoscopic features for melanoma are: atypical network, blue-white veil, atypical vascular pattern, irregular dots and globules, irregular streaks, irregular blotches, and regression structures [2,5,6]. pattern analysis, the abcd method, and the 7-point checklist scoring system of dermatoscopic characteristic features and clues significantly increase the diagnostic accuracy, however, they leave a not so small number of difficult lesions for excision [3,7,8]. in a systematic review over 10 years, it is reported that in skin cancer centers where dermoscopy is routinely used in practice, 76,783 nevi have been excised and among them 9,910 melanomas were detected [7]. in the case of clinically and dermatoscopically challenging lesions, in vivo reflectance confocal laser microscopy (rcm) may offer the possibility of non-invasive investigation of a lesion and improving the specificity of melanoma diagnosis [9]. rcm allows optical imaging with resolution similar to histology and good contrast, which makes imaging of the cellular architecture of epidermis and the superficial dermis (up to 250 µm) possible [10]. herein, we describe and discuss three sets of dermatoscopically “twin” lesions, where clinical and dermoscopic images overlap and might confound the real diagnosis. all of these similar lesions were excised and the diagnosis was histologically confirmed. in every twin pair, one of the lesions was a melanoma. rcm improved diagnostic accuracy and helped decisively in setting the correct diagnosis in all of the lesions examined. lesion imaging was performed using high quality digital polarized dermatoscopic photos (dermlite foto system [3gen inc, san juan capistrano, ca] and fotofinder medicam [fotofinder systems gmbh, bad birnbach, germany]) and a commercially available rcm device (vivascope® 1500, mavig gmbh, munich, germany). vivascope 1500 provides basic images with a 500 × 500 mm horizontal field of view with an imaging depth of approximately 200–250 µm, usually correlating to the upper dermis [10]. image acquisition requires a few minutes and is completely harmless for the patient. cases 1 & 2 patient 1 was a 54-year-old female who was referred to the dermatology department because of a congenital nevus in research | dermatol pract concept 2017;7(1):2 13 figure 1. hyperpigmented macular lesion on dorsal surface of leg (1a). atypical dermoscopic view with more than one color and thick reticular lines in the periphery (1b), epidermal disarray with pagetoid infiltration (arrows) in confocal image (1c). histologic examaination (h&e 100x): superficial spreading melanoma presenting atypical melanocytes, pagetoid spreading and horizontal confluence of the rete ridges in the dermis, few single-cell proliferates of atypical melanocytes, dense inflammatory infiltrate and solar elastosis (1d). brown macular lesion on dorsal surface of leg (1e). dermatoscopically, more than one colored lesion with brown globules and milia-like cysts (1f), pseudofollicular openings and elongated cords in confocal image (1g), papillomatous seborrheic keratosis (h&e 40x): massive hyperkeratosis and papillomatosis and horn cysts (1h). [copyright: ©2017 saral et al.] a b c d e f g h 14 research | dermatol pract concept 2017;7(1):2 macroscopically, the lesion consisted of a central black colored 0.4 cm papule with central ulceration and numerous small satellite lesions around the central papule (figure 2a). dermatoscopically, it exhibited more than one color (black, blue, white, gray). red-bluish-black homogeneous areas were prevalent at the center, with a central hemorrhagic plug; at the periphery, shiny white structureless areas were present (figure 2b). serpentine and linear vessels constituted the vascular component. the patient was presented to the imaging outpatient clinic for further diagnostics with the differential diagnosis of pigmented basal cell carcinoma, metastasizing blue nevus and hemangioma. patient 4 was a 75-year-old male with a lesion on the postauricular area of the scalp. he had noticed the lesion was pruritic recently. macroscopically, the lesion consisted of numerous black colored papules and brown-colored macules (figure 2f). dermatoscopic pattern consisted of brown to blue to black blotches, with asymmetrically distributed dots and globules of various sizes and colors (figure 2g). vascular structure was indistinguishable. before proceeding with surgical procedures, both lesions were examined with rcm. in vivo reflectance confocal imaging of patient 3 showed vascular, large, dark spaces separated by thin, bright septa. in real-time imaging, vascular flow with moving small round bright blood cells were clearly seen (figure 2c, 2d). atypical cells were not present. rcm imaging favored the diagnosis of an angioma. histopathologic examination with hematoxylin-eosin staining (h&e) showed a cavernous arteriovenous hemangioma (figure 2e); staining with alpha-smooth muscle and actin showed wide, dilated, lagoon-like vessels presenting a continuous rim of alpha-smooth muscle actin-positive pericytes, which confirmed previous evaluations. lesion 4 showed a disarray of the normal architecture of the epidermal superficial layers, characterized by unevenly distributed bright granular particles and cells, irregular in shape and size (figure 2i). a honeycombed or cobblestone pattern was figure 2. blue central papule and numerous satellite papules (2a). blue papule with a central hemorrhagic crust and on a shiny white structureless blue, black macule, serpentine and linear vessels (2b). vivablock® (2d, 5x5 mm) and viva image (2c) showing large spaces separated with thin septa. histologic examination revealed, cavernous, arteriovenous, hemangioma (h&e 100x): a dermal lesion composed of large dilated and both thick and rather thin-walled vessels with a lumen composed of lobulated aggregates of poorly canalized blood vessels filled with erythrocytes (2e). postauricular hyperpigmented lesion on macroscopic view (2f). multiple blue-black blotches and asymmetrically distributed dots (2g), sheets of atypical cells forming sheet-like structures, the junction substituted with an unspecific pattern (2h). dense and sparse nests with atypical cells (2i). histologic examination revealed a superficial spreading malignant melanoma (h&e 100x): the epidermis presents atypical melanocytes in a pagetoid spread. in the dermis, besides the normal melanocytes gathered in nests that show signs of maturation, nests of atypical melanocytes and single-cell proliferates of atypical melanocytes are present. solar elastosis and melanophages are in the upper dermis (2j). [copyright: ©2017 saral et al.] a b c d e f g h i j research | dermatol pract concept 2017;7(1):2 15 not recognizable. large bright cells with outlined border and dark nuclei, some of them with dendrites, were identified as round and dendritic pagetoid cells. the entire epidermis was replete with sheets of atypical cells (figure 2h). the structure of the dej demonstrated evidences of remaining meshwork pattern, but it was mostly replaced by a non-specific pattern in which atypical pleomorphic melanocytes were distributed in sheet-like structures. some irregular nests, variable in size and reflectivity, constituted dense and sparse nests. based on these findings, strikingly suggestive for malignancy, the entire lesion was excised. the patient was diagnosed with superficial spreading melanoma, clark-level iv with a tumor thickness of 3 mm, mitosis rate 3 per/mm2 and signs of regression (figure 2j). cases 5 & 6 case 5 was a 52-year-old man, referred to the hospital with a history of superficial spreading melanoma and a nevus with a change of color noticed during the previous month (figure 3a). the lesion, located on the right side of his back, was asymmetrical in color and 1 cm in diameter. dermatoscopic examination revealed a prominent globular patterned lesion with inverse network on the inferior side (figure 3b). on the superior portion, peripherally located asymmetrical thick reticular lines were areas of concern. atypical vessels were also noticed. case 6 was a 62-year-old male patient referred to the dermatology department because of a newly arisen pigmented lesion (figure 3f). macroscopically, a brown asymmetrical 0.8 cm large macule was observed on the lateral side of his left lower leg. dermatoscopically, a pseudo-reticular pattern was predominant, with asymmetrically located dark brown structureless areas at the bottom of lesion and thin reticular lines on the left side (figure 3g). because of history and dermatoscopic features, both lesions were further imaged with rcm. case 5 exhibited an atypical cobblestone pattern in the epidermis with some pagetoid cells and a disrupted ringed and meshwork pattern at the junction; dense and sparse nests were visible as dermal clusters of aggregated, pleomorphic cells. an increased vascular pattern was noticed in the superficial dermis (figure 2c, 3d). case 6, on the contrary, showed elongated cords and bulbous projections, with branching tubular structures at the periphery, consistent with a seborrheic keratosis and solar lentigo (figure 2h, 3i). both lesions were excised because of the history of growth and histopathologic examination confirmed case 5 as a superficial spreading melanoma in situ (figure 3e) in association with a compound congenital nevus and case 6 as a seborrheic keratosis (figure 3j). figure 3. hyperpigmented macule on back (3a), asymmetrical globular lesion with more than one color, and inverse network (3b). atypical cobblestone pattern in the epidermis with some pagetoid cells and dense and sparse nests were visible as dermal clusters of aggregated, pleomorphic cells (3c, 3d). malignant melanoma (h&e 200x): superficial spreading melanoma with atypical melanocytes in a pagetoid spread as well as gathered in asymmetrical nests. in the dermis, inflammatory infiltrates with melanophages are present (3e). hyperpigmented macule on lateral aspect of leg (3f). dermatoscopically pseudo-reticular pattern with asymmetrically located dark brown structureless areas and thin reticular lines on left side (3g). confocal view exhibiting elongated cords and bulbous projections, with branching tubular structures at the periphery, consistent with seborrheic keratosis and solar lentigo (3h, 3i), histologic examination revealed seborrheic keratosis (h&e 200x) with acanthosis and papillomatosis of the epidermis and hyperpigmented keratinocytes presented in a pigmented seborrheic keratosis. in addition to that, remnants of the horn cysts are shown (3j). [copyright: ©2017 saral et al.] a b c d e f g h i j 16 research | dermatol pract concept 2017;7(1):2 moving erythrocytes in between vascular dark spaces separated with thin septa. dark spaces and thin septa correlate with dermal vascular proliferations with vascular spaces on histopathology. imaging with rcm is especially beneficial in distinguishing amelanotic melanoma and other clinically featureless melanomas with indistinct dermatoscopy [17-20]. equivocal lesions with similar dermatoscopic findings are important challenges for dermatologists. reflectance confocal microscopy is reported to be beneficial in discrimination of similar lesions such as: facial lentigo maligna vs. pigmented nonmelanocytic macules and spitz nevus vs. melanoma and other equivocal lesions [21-23]. langley et al, when comparing diagnostic accuracy of rcm and dermatoscopy in a prospective examination, found sensitivity of 97% and specificity of 83% for rcm. when the two techniques were combined, none of the melanomas were missed [24]. current literature highlights high sensitivity of rcm for recognizing melanoma [23-25]. nevertheless, studies on rcm are mostly designed together with dermatoscopy and recommend integration of the two methods in the diagnostic process [23-26]. several studies on the impact of addition of rcm showed increased cost effectivity and reduced nnt [25,27,28]. in a study by pellacani et al, nnt was decreased to 4.3 from 14.6 and rcm analysis reduced the number of lesions for excision to less than half of the benign lesions (46.5%) without missing a melanoma [28]. alarcon et al reported this decrease in a study with a different design from 3.73 to 2.87 [25]. in our case series, the integration of rcm in the diagnostic process was instrumental in determining the correct diagnosis where clinical and dermatoscopic patterns were overlapping and when it was difficult to discriminate between benign and malignant lesions. in particular, similar and difficult to interpret dermoscopic patterns were quickly guided to a correct diagnosis by rcm, in a time-sparing and efficient way for both clinician and patient. references 1. hall hi, miller dr, rogers jd, bewerse b. update on the incidence and mortality from melanoma in the united states. j am acad dermatol. 1999;40(1):35-42. 2. argenziano g, catricalà c, ardigo m, et al. seven-point checklist of dermoscopy revisited. br j dermatol. 2011;164(4):785-790. 3. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-165. 4. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol. 2008;159(3):669-676. 5. kittler h, rosendahl c, cameron a. dermatoscopy: an algorithmic method based on pattern analysis. vienna: facultas; 2011. http://site.ebrary.com/lib/yale/doc?id=10772349 discussion the most important aspect of melanoma diagnosis is to recognize lesions at an early stage. early melanoma lesions sometimes have non-specific features and are hard to determine with naked-eye examination. introduction of handheld dermatoscopes and widespread use of dermatoscopy in skin cancer examination has improved specificity and sensitivity of melanoma diagnosis. however, dermatoscopic features of a melanoma are highly variable, and most of the time physicians have to excise many benign lesions in order to avoid a missed melanoma. number needed to treat (nnt) is an effective value to measure melanoma detection accuracy. the abbreviation stands for number of pigmented lesions excised to detect one melanoma [11]. carli et al reported decrease of nnt from 18 to 4.3 with dermatoscopic examination [12]. rolfe calculated nnt in a dermatology clinic (with available dermatoscopes) as 11.9 by calculating the number of seborrheic keratoses, nevi and melanoma excised to detect one melanoma. the ratio to identify non-melanoma skin cancer was significantly lower (1.97), which means about one in every two excisions with a pre-diagnosis of non-melanoma skin cancer was accurate [13]. reflectance confocal microscopic imaging is a promising non-invasive technique that facilitates the diagnosis of cutaneous melanoma and the discrimination of benign melanocytic lesions. rcm features and diagnostic criteria used in melanoma, melanocytic lesion, seborrheic keratosis and angioma diagnosis has been described [10,14-16]. epidermal disarray, pagetoid cells in epidermis, non-edged papilla, cellular atypia at the dej, atypical nests and bright nucleated cells in the upper dermis are important findings in superficial spreading melanoma imaging. two of the melanomas in our case series predominantly exhibited atypical pigment network on dermoscopy which corresponded to non-homogenous dermal papillae distribution and presence of irregular aggregates of cells in the interpapillary spaces with the rcm. the other melanoma had irregular globules and dots as the predominant pattern; the atypical globules correlate with dense and sparse nests of atypical melanocytes on rcm. black dots in dermoscopy correlate with atypical cells in the epidermis. non-edged papilla on rcm corresponds to dermal papillae without demarcated contours and bright, nucleated cells are roundish pagetoid cells on histopathologic examination. on the other hand, rcm of seborrheic keratosis is visualized as corneal plugs, corneal cysts, surface holes and crypts. elongated cords, which correspond to elongated rete ridges in histology, and bulbous projections and keratin-filled invaginations are observed. cells are monomorphic in structure without architectural atypia. in our case series, case 3 was a cavernous arteriovenous hemangioma lesion. real-time imaging is important in angiomatous structures to observe http://site.ebrary.com/lib/yale/doc?id=10772349 research | dermatol pract concept 2017;7(1):2 17 impact for accurate diagnosis. j eur acad dermatol venereol. 2015;29(6):1135-1140. 18. guitera p, pellacani g, longo c, seidenari s, avramidis m, menzies sw. in vivo reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. j invest dermatol. 2009;129(1):131-138. 19. pellacani g, longo c, malvehy j, et al. in vivo confocal microscopic and histopathologic correlations of dermoscopic features in 202 melanocytic lesions. archiv dermatol. 2008;144(12):15971608. 20. maier t, sattler ec, braun-falco m, korting hc, ruzicka t, berking c. reflectance confocal microscopy in the diagnosis of partially and completely amelanotic melanoma: report on seven cases. j eur acad dermatol venereol. 2013;27(1):e42-52. 21. de carvalho n, farnetani f, ciardo s, et al. reflectance confocal microscopy correlates of dermoscopic patterns of facial lesions help to discriminate lentigo maligna from pigmented nonmelanocytic macules. br j dermatol. 2015;173(1):128-133. 22. guida s, pellacani g, cesinaro am, et al. spitz naevi and melanomas with similar dermoscopic pattern: can confocal microscopy differentiate? br j dermatol. 2016;174(3):610-616. 23. lovatto l, carrera c, salerni g, alos l, malvehy j, puig s. in vivo reflectance confocal microscopy of equivocal melanocytic lesions detected by digital dermoscopy follow-up. j eur acad dermatol venereol. 2015;29(10):1918-1925. 24. langley rg, walsh n, sutherland ae, et al. the diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of benign and malignant melanocytic lesions: a prospective study. dermatology. 2007;215(4):365-372. 25. alarcon i, carrera c, palou j, alos l, malvehy j, puig s. impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions. br j dermatol. 2014;170(4):802-808. 26. gerger a, hofmann-wellenhof r, samonigg h, smolle j. in vivo confocal laser scanning microscopy in the diagnosis of melanocytic skin tumours. br j dermatol. 2009;160(3):475-481. 27. pellacani g, witkowski a, cesinaro am, et al. cost-benefit of reflectance confocal microscopy in the diagnostic performance of melanoma. j eur acad dermatol venereol. 2016;30(3):413-9. 28. pellacani g, pepe p, casari a, longo c. reflectance confocal microscopy as a second-level examination in skin oncology improves diagnostic accuracy and saves unnecessary excisions: a longitudinal prospective study. br j dermatol. 2014;171(5):1044-1051. 6. argenziano g, fabbrocini g, carli p, de giorgi v, sammarco e, delfino m. epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. comparison of the abcd rule of dermatoscopy and a new 7-point checklist based on pattern analysis. archiv dermatol. 1998;134(12):1563-1570. 7. argenziano g, cerroni l, zalaudek i, et al. accuracy in melanoma detection: a 10-year multicenter survey. j am acad dermatol. 2012;67(1):54-59. 8. nachbar f, stolz w, merkle t, et al. the abcd rule of dermatoscopy. high prospective value in the diagnosis of doubtful melanocytic skin lesions. j am acad dermatol. 1994;30(4):551-559. 9. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy of pigmented skin lesions—improvement in melanoma diagnostic specificity. j am acad dermatol. 2005;53(6):979985. 10. hofmann-wellenhof r, pellacani g, malvehy j, soyer hp. reflectance confocal microscopy for skin diseases. berlin: springer; 2012. springerlink (online service). http://link.springer.com/bo ok/10.1007%2f978-3-642-21997-9 11. baade pd, youl ph, janda m, whiteman dc, del mar cb, aitken jf. factors associated with the number of lesions excised for each skin cancer: a study of primary care physicians in queensland, australia. archiv dermatol. 2008;144(11):1468-1476. 12. carli p, de giorgi v, crocetti e, et al. improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. br j dermatol. 2004;150(4):687-692. 13. rolfe hm. accuracy in skin cancer diagnosis: a retrospective study of an australian public hospital dermatology department. australas j dermatol. 2012;53(2):112-117. 14. pellacani g, guitera p, longo c, avramidis m, seidenari s, menzies s. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759-2765. 15. pellacani g, cesinaro am, seidenari s. reflectance-mode confocal microscopy for the in vivo characterization of pagetoid melanocytosis in melanomas and nevi. j invest dermatol. 2005;125(3):532537. 16. pellacani g, de pace b, reggiani c, et al. distinct melanoma types based on reflectance confocal microscopy. exp dermatol. 2014;23(6):414-418. 17. ferrari b, pupelli g, farnetani f, et al. dermoscopic difficult lesions: an objective evaluation of reflectance confocal microscopy http://link.springer.com/book/10.1007%2f978-3-642-21997-9 http://link.springer.com/book/10.1007%2f978-3-642-21997-9 dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(1):e2022011 1 prevalence of atherosclerosis in psoriatic patients detected with epiaortic color doppler ultrasound and computed tomography angiography annunziata dattola1, guglielmo manenti2, donatella ferrari2, laura vollono1, salvatore marsico2, feliciana lamacchia2, maria esposito1, mattia marchesano1, arianna zangrilli1, roberto floris2, alessandro giunta1, luca bianchi1 1 dermatology department, university of rome “tor vergata”, rome, italy 2 biomedicine and prevention department, uoc of diagnostic imaging, university of rome “tor vergata”, rome, italy key words: psoriasis, color-doppler ultrasound, angio-ct, imt, risk-factor citation: dattola a, manenti g, ferrari d, et al. prevalence of atherosclerosis in psoriatic patients detected with epiaortic color doppler ultrasound and computed tomograpgy angiography. dermatol pract concept. 2022;12(1):e2022011. doi: https://doi.org/10.5826/dpc.1201a11 accepted: may 6, 2021; published: january 2022 copyright: ©2022 dattola et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: ad and gm have equally contributed to this article. corresponding author: annunziata dattola, md, phd. dermatology department, university of rome “tor vergata”, rome, italy. e-mail: nancydattola@gmail.com introduction: psoriasis (pso), a chronic inflammatory, multisystemic, and multifactorial disease can cause endothelial dysfunction, artery calcification, and atherosclerotic disease. a higher incidence of vascular occlusive events has been observed in psoriatic patients compared to healthy controls, and multiple studies confirm the association between moderate-severe pso and atherosclerosis, coronary artery calcification, and higher cardiovascular risk. objective: we sought to analyze atherosclerotic disease prevalence in epiaortic vessels of psoriatic and non-psoriatic patients to understand if pso could represent an independent risk factor predisposing to atherosclerotic disease. methods: we evaluated 47 psoriatic patients without cardiovascular risk factors with color doppler ultrasound (cdus). if atheromatous plaques were detected, a computed tomography angiography (cta) was performed. we evaluated 47 non-psoriatic patients without cardiovascular risk factors with cdus. atherosclerosis prevalence in both groups were statistically analyzed. cdus performance was compared to cta. results: in the psoriatic group (mean age 50.9 years), 6 had atheromatous plaques and 12 had an intima-media thickness (imt) > 1 mm (overall prevalence of atherosclerotic disease: 38.2%). all plaques detected with cdus were confirmed at cta.  in the control group (mean age 51.3 years), abstract 2 original article | dermatol pract concept. 2022;12(1):e2022011 introduction psoriasis (pso) is a chronic inflammatory, multisystemic, and multifactorial disease that affects about 3% of the world population [1]. the chronic systemic inflammatory process, that primarily affects the skin, also causes endothelial dysfunction, artery calcification, and atherosclerotic disease [2]. a higher incidence of vascular occlusive events has been observed in psoriatic patients compared to healthy controls, and multiple studies confirm the association between moderate-severe pso and atherosclerosis, coronary artery calcification, and higher cardiovascular risk [3-8]. young adults affected by severe pso are 3 times more likely to face myocardial infarction than controls [9], and the risk of fatal myocardial infarction or stroke is even higher in patients hospitalized with pso [10]. moreover, a higher frequency of ischemic heart disease and cerebral and peripheral vascular disease has been observed in patients affected by moderate-severe disease compared with controls [11]. thus, current opinion holds that pso is an independent risk factor for cardiovascular disease [2,12,13]. color doppler ultrasonography (cdus) of the carotid arteries is a first-level imaging technique performed in the diagnosis of carotid atherosclerotic disease. ultrasonography (us) is the modality of choice for screening, diagnosis, and monitoring atheromatous disease because it is a fast, non-invasive, low-cost technique that evaluates the macroscopic appearance of atheromatous plaques as well as flow characteristics in the carotid artery. although us is considered a useful tool in the assessment of the cardiovascular risk, there are few studies so far conducted regarding its use in patients affected by psoriasis vulgaris and psoriatic arthritis. computerized tomography angiography (cta) is a very accurate technique for evaluating carotid stenosis, outperforming cdus [14], but not as accurate in describing carotid plaques and assessing their vulnerability. objectives the aim of this study is to evaluate the prevalence of atherosclerotic disease in epiaortic vessels of psoriatic patients without conventional cardiovascular risk factors, using cdus and cta, and to analyze the presence of any difference in prevalence with non-psoriatic patients, in order to understand if pso could be considered as an independent risk factor for atherosclerotic disease. methods this study was conduct in collaboration between the departments of dermatology and diagnostic imaging at the university of rome tor vergata. the study was conducted from january 2017 to july 2017 at the department of dermatology. we enrolled 280 consecutive patients (males and females) with psoriasis vulgaris or arthropathic psoriasis. the patients underwent clinical and laboratory exams, including abdominal circumference measurements and arterial pressure. we determined if the patients were cigarette smokers and if had hypercholesterolemia, hypertriglyceridemia, and glycemia. the inclusion criteria of the study were: male and female patients aged 35-85 years, with an abdominal circumference < 102 cm for males and < 88 cm for females, cholesterol plasmatic level < 200 mg/dl, plasma glucose level < 126 mg/dl on 2 separate analyses, systolic pressure < 140 mmhg and diastolic pressure < 90 mmhg, and non-smoker or < 5 cigarettes/day smoker. the exclusion criteria were: contraindications to iodinated contrast agent administration, pregnancy, regular use of alcohol (> 2 drinks/day), oncological history, family history of vascular disease, transient ischemic attack or stroke in the previous 5 years, and current or past use of intravenous drugs. the final study group was composed of 47 psoriatic patients (patient group: 26 males and 21 females, aged 35-70 years), without conventional cardiovascular risk factors, and an equal number of non-psoriatic subjects, who had undergone epiaortic vessel cdus at the department of diagnostic imaging, recruited retrospectively between january 2017 and july 2017, (control group: 27 males and 20 females, aged 35-70 years). they underwent cdus as a general exam, and from the medical interview carried out before the us examination it was determined they were in good health with no noteworthy diseases or underlying conditions, and without conventional cardiovascular risk factors. among the psoriatic patients, 37 were affected by psoriasis vulgaris and 10 by severe psoriatic arthritis, and all of cdus revealed atheromatous plaques in 4 patients and imt > 1 mm in 4 ones (overall prevalence of 17%). the difference of atherosclerotic disease prevalence between the groups was statistically significant (p < 0.05). conclusion: our results highlight that pso could be considered a predisposing factor for atherosclerotic disease development in epiaortic vessels, as it causes an increased imt, that is also considered an independent cardiovascular risk factor.  original article | dermatol pract concept. 2022;12(1):e2022011 3 them were being treated with systemic drugs including cyclosporine and/or methotrexate and anti-tumor necrosis factor α (tnf-α) biologic drugs. all the subjects gave informed consent prior to their inclusion in the study. all the subjects underwent epiaortic vessels cdus. these evaluations were executed with a high-resolution us equipment (philips iu22 ultrasound system,), using a high-frequency linear probe (9-3 mhz) and a carotid preset. the neck vessels studied were common carotid arteries, internal carotid arteries and external carotid arteries, and we evaluated both side regions of the neck for each subject for a total of 94 common carotid arteries, 94 internal carotid arteries, and 94 external carotid arteries in the psoriatic patients and an equal number of vessels in the non-psoriatic subjects. the vertebral arteries were examined in all participants, but the results obtained were not included in the study. the us examinations were carried out by a radiologist with 5 years of experience, and the images were evaluated in consensus with a radiologist with 25 years of experience. the us exams were performed at first in b-mode with axial and longitudinal scans in order to identify arterial wall intima-media thickness (imt) of common carotid arteries and the presence of common and internal carotid plaques. the imt measurement was performed automatically with dedicated software. the mean value between left and right sides was taken into consideration and an imt <1 mm was considered normal. the presence of a plaque was considered when a focal imt was greater than 50% of the surrounding area [15]. subsequently cdus, and pulsed doppler spectral analysis were performed: peak systolic velocity (psv cm/s) and end diastolic velocity (edv cm/s) values were analyzed to determine the percentage of stenosis and plaque hemodynamics. when at least 1 carotid plaque or an increased imt of the common carotid on a side was detected with us examination, the patient was considered positive for atherosclerotic disease. if both carotids had an imt >1 mm, the average thickness of the 2 was taken into consideration. in the psoriatic patient group, if cdus examination detected atherosclerotic plaque, the patient had to go simultaneous cta of the extracranial vessels in order to confirm its presence, better define plaque features, determine the percentage of stenosis, and search for the presence of additional plaques in other locations. psoriatic patients who at cdus presented an imt >1 mm were asked to follow-up after 12 months with another cdus to check for vascular disease. the psoriatic patients who did not present any atherosclerotic pathology at cdus were asked to follow-up with regular dermatological visits. subjects of the control group underwent epiaortic vessel cdus. if a plaque revealed severe stenosis (> 70%) or if signs of surface ulceration were detected, they underwent a cta to ensure adequate therapeutic diagnostic planning of the incidental finding, according to the current clinical practice. the cta was performed using a lightspeed vct 64-slice scanner (general electric), with a pre-contrast phase and an arterial phase with bolus tracking, with a non-ionic iodinated contrast agent injection (350 mg/ml) with a flow rate of 3.5 ml/s, followed by a bolus of 20 ml of saline flush at the same speed. the images were also analyzed in 3d, with multiplanar reconstruction and volume rendering and interpreted in consensus with the same two radiologists. when a plaque was detected, the carotid stenosis was quantified by the nascet method: (distal diameter of the internal carotid − residual diameter / distal diameter of the internal carotid) ×100 [16]. the radiological features of the detected plaques analyzed with cdus and cta were the percentage of stenosis, structure, and surface. continuous variables, normally distributed (patient age, imt thickness) were presented as the mean ± standard deviation (sd) and categorical variables were presented as counts (percentage). fisher exact test was used to compare differences in atherosclerotic disease prevalence between psoriatic patients and healthy subjects. any p value < 0.05 was considered statistically significant. results the mean (sd) age of the psoriatic group was 50.9 ± 8 years (range 35-70 years), and of the control group 51.3 ± 8 years (range 35-70 years). in the psoriatic patients an imt > 1 mm without carotid plaques (figure 1) was found in 12 patients (25.5%), with a mean value of 1.4 mm (range 1.1-1.8 mm). atheromatous plaques were found in 6 patients, mean age 57.5 ± 4.6 years (range 50-64 years), with a prevalence of 12.7%. in 4 patients, an increase of imt coexisted, thus the figure 1. longitudinal us of the right common carotid artery of a 51-year-old female psoriatic patient with an imt > 1 mm without plaque. imt = intima-media thickness; us = ultrasonography. 4 original article | dermatol pract concept. 2022;12(1):e2022011 increase of imt was detected in a total of 16 patients with a prevalence of 34%. a total number of 18 patients showed carotid atherosclerotic disease with an overall prevalence of 38.2%. plaques were found in 6 patients and were localized in carotid arteries bilaterally in each patient, with a total number of 12 plaques. among these, us revealed 2 plaques located in internal carotid artery (ica), 4 plaques located in carotid bifurcations, and 6 plaques located in carotid bifurcations extended to the ipsilateral ica. moreover, the structure of the plaques was hypoechoic in 4 cases (33%) and fibrocalcific in 8 cases (67%). the plaque surface was smooth (83.4%) or irregular (16.6%), no ulceration signs were detected at us examination. in these 12 cases the plaques revealed mild stenosis, with a percentage of stenosis variable at 10-30%. pulsed doppler spectral analysis consistently showed a psv < 125 cm/s with an edv < 40 cm/s in the ica, demonstrating that the stenosis was not hemodynamically significant (figure 2). all plaques detected with cdus analysis were confirmed with cta examination (figure 3). at the final cta, 4 plaques were in a left bifurcation and ica (33.3%), 3 plaques were in a right bifurcation and ica (25%), 2 plaques were in a figure 2. (a) longitudinal ultrasonography of a hypoechoic plaque in the right internal carotid artery of a 50-year-old male psoriatic patient with a smooth surface that produced stenosis of about 25%. (b) axial ultrasonography of the same plaque. (c) longitudinal color doppler ultrasonography and pulsed doppler spectral analysis of this plaque showing a peak systolic velocity of 40 cm/s, not hemodynamically significant. original article | dermatol pract concept. 2022;12(1):e2022011 5 right bifurcation (16.6%), 1 in a left bifurcation (8.3%), 1 in a right ica (8.3%) and 1 in a left ica (8.3%); 8 plaques were fibrocalcific (67%), 2 hypoechoic plaques which were previously documented at us showed a wide fibrous cap (16.5%), and 2 were lipid-rich plaques (16.5%) (table 1). all of them produced a stenosis < 30% and none of them showed features of vulnerable plaques following both cdus and cta examinations. our results showed good agreement between the two imaging techniques, with a concordance rate of 92% between cdus and cta regarding plaque localization, 83% regarding plaque structure, and 100% regarding both percentage of stenosis and plaque surface morphology. figure 3. (a) axial ultrasound of a fibrocalcific plaque in left internal carotid artery of a 58-year-old male psoriatic patient, with a smooth surface that produced stenosis of about 20%. (b) oblique reconstruction of computed tomography angiography of the plaque that produced a stenosis of about 20%. table 1. epidemiological characteristics of psoriatic patients with plaques (n = 6) and features of these plaques (n = 12) with cdus and cta examinations* psoriatic patient technique location stenosis structure surface male, 60 years cdus right bifurcation + ica 30% fibrocalcific irregular cta right bifurcation + ica 30% fibrocalcific irregular cdus left bifurcation + ica 30% fibrocalcific irregular cta left bifurcation + ica 30% fibrocalcific irregular male, 50 years cdus right ica 25% lipid-rich smooth cta right ica 25% lipid-rich smooth cdus left bifurcation + ica 20% fibrocalcific smooth cta left bifurcation + ica 20% fibrocalcific smooth male, 58 years cdus right bifurcation 15% fibrocalcific smooth cta right bifurcation 15% fibrocalcific smooth cdus left ica 20% fibrocalcific smooth cta left ica 20% fibrocalcific smooth female, 64 years cdus right bifurcation + ica 30% fibrocalcific smooth cta right bifurcation + ica 30% fibrocalcific smooth cdus left bifurcation 20% lipid-rich smooth cta left bifurcation + ica 20% lipid-rich smooth female, 57 years cdus right bifurcation 20% lipid-rich irregular cta right bifurcation 20% fibrous + lipid core irregular cdus left bifurcation + ica 10% fibrocalcific smooth cta left bifurcation + ica 10% fibrocalcific smooth female, 56 years cdus right bifurcation + ica 15% fibrocalcific smooth cta right bifurcation + ica 15% fibrocalcific smooth cdus left bifurcation 20% lipid-rich smooth cta left bifurcation 20% fibrous + lipid core smooth *cdus errors compared to cta are highlighted in gray. cdus = color doppler ultrasonography; cta = computed tomography angiography; ica = internal carotid artery. 6 original article | dermatol pract concept. 2022;12(1):e2022011 moreover, cta did not reveal the presence of additional plaques along the carotid axes or along vertebral arteries. regarding subjects of the control group, us examination revealed imt > 1 mm without carotid atheromatous plaques in 4 people (8.5%) bilateral or unilateral, with a mean value of 1.2 mm (range 1.1-1.5). atheromatous plaques were detected in 4 subjects, mean age 62.5 ± 2.6 years (range 59-64), with a prevalence of 8.5%. plaques were unilateral in 2 cases and bilateral in 2 cases, with a total number of 6 plaques. the structure of these plaques was hypoechoic in 2 cases (33.3%), and fibrocalcific in 4 cases (66.7%), with a variable percentage of stenosis at 10-20%, and none of them were hemodynamically significant at color doppler analysis. other plaque features of the control group subjects are explained in table 2. in 2 cases an increased imt coexisted, thus an increased imt was detected in a total of 6 subjects with a prevalence of 12.7%. a total number of 8 cases showed carotid atherosclerotic disease with an overall prevalence of 17%. the fisher exact test statistic value was 0.0368, and this result highlights the presence of a statistically significant difference (p < 0.05) between the prevalence of carotid atherosclerotic disease (increase of imt and/or atheromatous plaques) in patients without cardiovascular risk factors affected by pso and those without cardiovascular risk factors and without pso. conclusions pso is a chronic systemic inflammatory disease. with the term “psoriasis march,” boehncke et al described the process that starts from genetic and environmental predisposing factors and leads to a dysregulation of the immune system that gives rise to a chronic systemic inflammatory state that also causes endothelial dysfunction, atherosclerosis, and coronary events. innate and adaptive immune systems are likewise considered responsible for pathological changes in both epidermis and vascular walls [2]. a recent meta-analysis of 4 genome-wide association studies selected a broad number of single nucleotide polymorphisms (snps) that showed a significant association with cardiovascular disease, hypertension, body mass index, hyperlipidemia, or type ii diabetes. they then investigated which one of these polymorphisms was also associated with pso [17] and identified 8 main snps codifying for a key protein in the process of lymphocyte differentiation, thrombogenesis, and in the induction of vcam1 and e-selectin on the surface of endothelial cells under the stimulation of tnf-α. this might explain its dual role in establishing a susceptibility to multiple immune-mediated and cardiovascular diseases. subcutaneous tissue is able to produce proinflammatory cytokines and c-reactive protein under the influence of mediators such as tnf-α [18]. modifications in the adipocyte metabolic profile, including alterations of adiponectin, leptin and resistin, are considered responsible in starting or maintaining the inflammatory process [19]. in particular, high blood levels of resistin seem to be related to a proinflammatory systemic state, insulin-resistance, and atherosclerosis [2]. metabolic syndrome is more frequent in psoriatic patients than in the general population [12], and its prevalence directly correlates to pso duration and severity [20]. of note, the abovementioned effects are particularly relevant when dealing with central or visceral obesity [21]. a direct correlation between severity of pso, central obesity and vascular inflammation has been reported, with concurrent reduction of these parameters after 12 months of systemic or biologic therapy [22]. table 2. epidemiological characteristics of non-psoriatic patients (n = 8) with atheromatous pathology (imt >1 mm and/or plaques) and features of the plaques (n°=6) detected with cdus non-psoriatic subjects location pathology stenosis structure morphology male, 64 years right bifurcation left bifurcation plaque plaque 15% 20% lipid-rich fibrocalcific smooth smooth bilateral imt 1.2 male, 65 years right bifurcation + ica plaque 20% fibrocalcific smooth male, 59 years left bifurcation + ica plaque 10% lipid-rich smooth female, 62 years left bifurcation right bifurcation + ica plaque plaque 15% 15% fibrocalcific fibrocalcific smooth smooth bilateral imt 1.2 female, 61 years right imt 1.2 male, 68 years bilateral imt 1.3 male, 61 years left imt 1.1 female, 62 years bilateral imt 1.1 cdus = color doppler ultrasonography; ica = internal carotid artery; imt = intima-media thickness. original article | dermatol pract concept. 2022;12(1):e2022011 7 recently, sonoelastography has been proposed as a tool in monitoring the response to treatment in psoriatic patients, as it evaluates hypodermal adipose tissue inflammation underneath lesioned plaques at baseline and during systemic treatment [23]. twenty-five years ago, mcdonald and calabresi performed the first study showing that patients with pso had more vascular occlusive events than patients without pso [3]. subsequently, multiple studies confirmed the association between moderate-severe pso and atherosclerosis, coronary artery calcification, higher cardiovascular risk, myocardial infarction, stroke and peripheral vascular disease [4-11]. it is hypothesized that this association might be due to an overrepresentation in the psoriatic population with a framingham risk score (age, hypertension, obesity, smoking, diabetes, hypercholesterolemia, hyperlipidemia, and familial history) [12]. in addition, many traditional systemic therapies for pso seem to affect cardiovascular risk, increasing cardiovascular risk factors such as hyperlipidemia, hypertension, and hyperhomocysteinemia. nevertheless, recent studies identified pso as an independent risk factor for cardiovascular disease [9,10,11,12,13,20]. an increased prevalence and severity of coronary artery calcification and atherosclerosis (measured by cardiac computed tomography, cta, or coronary angiography) has been reported in psoriatic patients compared to healthy controls [24-30]. a lower coronary flow reserve has been observed in young subjects, otherwise healthy patients with severe pso compared to controls, suggesting that early impairment of coronary microvascular function is independent of conventional cardiovascular risk factors. our study reveals abnormalities in the vessel walls of carotid arteries in a great percentage of psoriatic patients who did not have any cardiovascular risk factors. in particular, we highlighted a higher prevalence of carotid atherosclerotic disease (increased imt and/or atheromatous plaques) in patients affected by pso than in healthy subjects regardless of cardiovascular risk factors. it was detected in an increased imt, which represents a predisposing risk factor for stroke events [31]. analysis of the data also showed a higher mean age in the control group affected by atheromatous plaques than that of psoriatic patients affected by atheromatous plaques. in fact, in the control group plaques were identified only in subjects with advanced age (subjects older than 55 years, the average age of the group); on the contrary, in psoriatic group, plaques were also identified in younger patients. this also led us to the conclusion that pso can be considered an independent risk factor in the development of atheromatous pathology. our results highlighted a good agreement between cdus and cta in atheromatous plaque detection and plaque analysis, showing a 92% concordance rate between cdus and cta regarding plaque localization, 83% regarding plaque structure, and 100% regarding both percentage of stenosis and plaque surface morphology. ultrasound errors were made only in determining the plaque composition in 2 cases (2 hypoechoic plaques previously documented at us showed a wide fibrous cap at cta), and in determining the complete plaque extension along the vessel in 1 case (a plaque that at us examination seemed localized only in the carotid bifurcation and at cta appeared extended to the ipsilateral ica). in spite of being a fast, noninvasive, well tolerated, and low-cost imaging method, us is an operator-dependent examination that requires a good understanding of doppler physics and hemodynamic physiology. a more precise evaluation of the percentage of stenosis, of the composition and of the morphology of the plaque is made with cta, but it uses ionizing radiation and potentially allergenic and nephrotoxic contrast agents. in fact, cta has been proved to be an accurate modality for detection of severe carotid artery disease and, especially, for detection of occlusions [32]. this means that cdus should not be replaced as the first-line investigation for epiaortic vessels. although our results are based on a small cohort of patients, we concluded that pso could be considered a risk factor for the development of atheromatous pathology in epiaortic vessels, because primarily it causes a thickening of the imt. therefore, this study contributes to support the hypothesis that pso should be considered as an independent cardiovascular risk factor. the american society of echocardiography more recently recommended the cut-off value for imt at ≥ 1.5 mm, but set imt above 1 mm [15]. the main limitation of this study is the small cohort of subjects included and, in this regard, further studies with larger cohorts, carried on in close cooperation with different medical specialists, finalized to a correct selection of patients, are necessary to confirm and improve our results. this could be relevant in order to aid in the clinical management of psoriatic patients and offer them better diagnostic/therapeutic pathways to prevent cardiovascular disease. we propose that epiaortic cdus as the most suitable method in assessing cardiovascular risk and in the early identification of minor changes and atheromatous plaques of epiaortic vessels of psoriatic patients. references 1. dattola a, cannizzaro mv, mazzeo m, bianchi l. certolizumab pegol in the treatment of psoriasis and psoriatic arthritis: preliminary real-life data. dermatol ther (heidelb). 2017;7(4):485492. 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11(4):e2021131 1 diabetes detection and prevention in dermatology alexandra ngo1, luise froessl2, john wesley mcwhorter3, william brett perkison4, rajani katta 2,5 1 department of psychiatry, baylor college of medicine. 2 baylor college of medicine. 3 culinary nutrition of the nourish program, at the michael & susan dell center for healthy living at the university of texas school of public health. 4 department of epidemiology, human genetics, and environmental science at the at the university of texas school of public health in houston. 5 mcgovern medical school at the university of texas health science center at houston. key words: diabetes prevention, diabetes in dermatology, diabetes skin findings, psoriasis and diabetes, diabetes screening citation: ngo a, froessl l, mcworther jw, perkinson wb, katta r. diabetes detection and prevention in dermatology. dermatol pract concept. 2021; 11(4):e2021131. doi: https://doi.org/10.5826/dpc.1104a131 accepted: april 23, 2021; published: september 2021 copyright: ©2021 ngo et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: rajani katta md is the author of a book on dermatology for the general public and is on an advisory board of vichy laboratories. dr ngo, md, dr froessl, md, dr mc worther, phd, and dr perkinson, md, report no conflicts of interest. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta, md, mcgovern medical school at the university of texas health science center at houston; baylor college of medicine. 6750 west loop south, suite 695, bellaire, tx 77401. email: info@kattamd.com we are currently in the midst of an international epidemic of diabetes mellitus (dm) and prediabetes. the prevalence of dm in the united states is estimated at 9.4% of the population across all ages, while an estimated 1 in 3 americans (33.9%) has prediabetes. according to the who, about 60 million people suffer from diabetes in the european region. dermatologists may play an important role in tackling this epidemic via efforts to improve early detection of both diabetes and prediabetes. dermatologists often treat patients with, or at risk of, diabetes. this includes patients who present with cutaneous manifestations such as acanthosis nigricans, as well as patient populations at increased risk, including those with psoriasis, hidradenitis suppurativa, and polycystic ovarian syndrome. simple screening guidelines can be used to identify patients at risk, and screening can be performed via a single nonfasting blood test. the diagnosis of prediabetes is a key feature in diabetes prevention, as interventions in this group can markedly reduce progression towards diabetes. in addition to referral to a primary care physician, dermatologists may refer these patients directly to structured behavioral lifestyle intervention programs known as diabetes prevention programs. a significant portion of the population lacks routine care by a primary care physician, and current data indicates need for improvement in diabetes screening and prevention among patient groups such as those with psoriasis. these factors highlight the importance of the dermatologist’s role in the detection and prevention of diabetes. abstract 2 review | dermatol pract concept. 2021; 11(4):e2021131 introduction we are currently facing an international epidemic of diabetes mellitus and prediabetes. the prevalence of dm in the united states is estimated at 9.4% of the population across all ages, while an estimated 1 in 3 americans (33.9%) has prediabetes [1]. according to the world health organization, about 60 million people suffer from diabetes in the european region [2]. dermatologists may play an important role in fighting against this epidemic. efforts to identify and screen patients at risk can improve early detection of dm, and help identify those with prediabetes. the identification and treatment of patients with prediabetes is considered a key aspect in diabetes prevention. there are 3 main factors making the dermatologist’s potential impact on dm epidemic further possible and more important than ever. first, dermatologists often treat patients with, or at risk of, dm. this includes patients who present with cutaneous manifestations of dm, such as acanthosis nigricans, as well as patient populations at increased risk for dm, including those with psoriasis, hidradenitis suppurativa, and polycystic ovarian syndrome [3-6]. second, dermatologists can use simple screening guidelines to identify patients at risk for dm [7]. patients at risk may then be screened via a single non-fasting blood test. third, diagnosing prediabetes is a key feature in dm prevention, as interventions have been shown to markedly reduce progression to dm. in addition to referral to a primary care physician (pcp), dermatologists may refer patients with prediabetes to diabetes prevention programs, behavioral lifestyle intervention programs that are cost-effective and effective [8]. although dm screening and prevention might be typically performed by the pcp, data indicates that a significant portion of the population lacks routine care by a pcp. according to a recent study, only 75% of american adults reported a source of primary care in 2015 [9]. some subgroups saw an even more marked decline in coverage, specifically younger patients, less medically complex patients, and those belonging to minorities. in parallel, the prevalence of type 2 dm has been steadily increasing, particularly among adolescents and young adults. age of onset before 40 years has been associated with more severe long-term outcomes [10], emphasizing the importance of early diagnosis and continuous management. a significant percentage of dermatology patients at increased risk for comorbidities lack care by a pcp. this draws attention to the potential role that can be played by dermatologists in diabetes detection. a recent study found that among patients suffering from psoriasis, 21.6% of men and 16.9% of women received no primary care visits within a year from their dermatologist visit. in hidradenitis suppurativa, 28.1% of male patients and 22% of female patients were not visited further [11]. furthermore, current data indicates that there is space for improvement in dm screening and prevention. although multiple large-scale studies have found that patients with psoriasis are at higher risk for dm and other systemic comorbidities [4, 12], data indicates that healthcare providers are not adequately screening psoriasis patients for metabolic risk factors [13]. dermatologists rarely screen their patients for risk factors such as glucose levels (1.2%), bmi (9.7%), or blood pressure (2.6%) [13]. even among pcps and cardiologists, survey studies reveal that many do not routinely screen patients with psoriasis for cardiovascular risk factors [14]. the importance of early detection dermatologists may interact with patients with dm at all stages of the disease, including those who are not yet diagnosed. despite the availability of simple screening measures, dm often goes undiagnosed for years. much of this is because patients may be asymptomatic for years. these years, however, are critical. while patients are at high risk for the development of microand macrovascular complications, these have not yet become irreversible. early detection of dm and institution of early treatment may profoundly impact the course of the disease [15]. dm impacts multiple organ systems, including the brain, heart, kidneys, and skin, with significant impacts on morbidity and mortality. the national diabetes statistics report found dm to be the 7th leading cause of death in the united states in 2015 [1]. skin findings strongly associated with insulin resistance and dm approximately 85 million americans (1 in 4 individuals) were evaluated by a physician for a skin disease in 2013 [16]. certain cutaneous findings should trigger a high level of suspicion and screening for dm. in a prospective observational study conducted in a diabetes clinic, cutaneous lesions were seen in over 98% of those with type 2 dm and 34% of those with type 1 dm [17]. while there was a higher prevalence (98%) of skin manifestations in patients with dm for more than 5 years, cutaneous manifestations were still present in 80% of patients with dm for less than 5 years [17]. acanthosis nigricans (an) is a classic cutaneous manifestation of dm that is associated with hyperinsulinemia. studies indicate that elevated levels of insulin and insulin-like growth factor may act to increase epidermal keratinocyte and dermal fibroblast proliferation, resulting in hyperpigmented, thickened, and velvety areas of skin [18]. cutaneous infections are particularly prevalent in those with dm. in a prospective study of 750 patients, 79% had skin manifestations, with the most common (in 47.5% of patients) being cutaneous infections, including bacterial, viral and fungal [19]. review | dermatol pract concept. 2021; 11(4):e2021131 3 diabetic dermopathy (dd) warrants prompt evaluation for dm. the atrophic, hyperpigmented macules of dd are classically seen on the shins, and are considered a common cutaneous manifestation of dm [20]. notably, the condition is also significantly associated with microangiopathic complications of dm such as retinopathy [20] and cardiovascular disease. necrobiosis lipoidica is overall rare; although estimates vary, it is believed to impact about 1% or less of patients with dm [21]. its presence should however lead to consideration of dm, as underlying dm has been seen in anywhere from 11% [22] to 65% [23]. it may be seen prior to the development of dm as well, and reviews estimate that up to 14% of patients may later develop dm [21]. nonspecific dermatologic findings with higher prevalence in patients with dm it is important to note that some dermatologic conditions that are commonly seen in the general population have an even higher prevalence among those with dm. cutaneous xerosis is a common skin complaint overall. multiple studies examining the frequency of skin manifestations in dm have showed a high prevalence of xerosis in both type 1 and type 2 dm [24]. as xerosis often appears on the lower extremities, it is also an important element in the prevention of foot complications. one study indicated that xerosis of the feet in those with dm was associated with 3 times the number of superficial fissures [25]. similarly, acrochordons have a prevalence of about 25% in the adult population [3] and a correlation with abnormalities in carbohydrate metabolism has been established [26]. skin diseases associated with an increased risk of dm in addition to the dermatologic manifestations of dm, physicians must also be familiar with dermatologic diseases that are associated with a higher risk of dm. these include psoriasis, hidradenitis suppurativa, and polycystic ovarian syndrome. research indicates a significantly increased risk for dm and other metabolic abnormalities in patients with psoriasis.  a meta-analysis of 27 observational studies found that psoriasis is associated with both an increased prevalence and incidence of dm [4]. a 13-year study of over 52,000 patients with psoriasis in a nationwide danish cohort, reported a significantly increased risk of new-onset dm [12]. importantly, this risk was significantly higher for those with severe skin disease as compared to those with mild disease. this increased risk is attributed to a combination of the systemic inflammation seen in those with psoriasis and the higher prevalence of obesity [12, 27]. a relationship between pro-inflammatory cytokines in psoriasis and systemic effects has been revealed, suggesting their contribution to insulin resistance, weight gain, and cardiovascular events [27]. in addition, the psychosocial impact of psoriasis may contribute to behavioral risk factors for the development of obesity and dm [28]. recent research indicates a higher risk of dm in patients with hidradenitis suppurativa (hs) as well. a systematic review and meta-analysis conducted by phan et al [29] identified a small but statistically significant association of dm with hs. a recent cross-sectional study by ahmad et al [30] suggests benefits of screening for dm, as even subgroups of hs patients without traditional risk factors for dm (including age and high bmi) were found to have a high incidence of abnormal screening results. although additional research is needed, dermatologists should be aware of this association. it is important for dermatologists to diagnose polycystic ovarian syndrome (pcos), given that these patients have a higher risk of dm and often present to the dermatologist with commonly associated dermatologic manifestations, such as hirsutism, acne, acanthosis nigricans, alopecia or seborrhea [31]. a 2020 longitudinal study of pcos patients assessed the metabolic changes in patients with pcos and found a high prevalence of adverse changes in glucose metabolism, with deterioration of beta-cell function. the authors emphasize the importance of early detection and intervention in this group [32]. one prospective cohort study found a dm prevalence of close to 40% in patients with pcos, as compared to 6% in the general population of a similar age [6]. patients who are normal weight are at higher risk as well: one long-term longitudinal study found a 3-fold increase in risk of developing dm in normal-weight pcos patients compared with normal-weight women without pcos [33]. the dermatologist’s role in dm screening and prevention dermatologists can expect to see patients with prediabetes and dm, some of them undiagnosed. in fact, of the approximately 1/3 of the us population with prediabetes, 90% are unaware of their status [1]. risk increases with age, and dm screening is recommended for all patients over the age of 45. dermatologists may take a more active role in dm screening and prevention via three main routes. first, by identifying patients at risk for dm. second, by ordering screening labs. and finally, by referring to pcps and diabetes prevention programs when indicated. identifying patients at risk for dm identifying patients at risk for dm is the first step in diabetes prevention and represents an important opportunity for dermatologists. many dermatology patients, especially those 4 review | dermatol pract concept. 2021; 11(4):e2021131 who are younger, may not have a primary care physician [34]. for some, a dermatologist may be their only regular contact with the healthcare system, as with patients who are seen for annual skin cancer screening exams or those who are treated for acne. recommendations for dm screening differ based on risk factor profile. table 1 summarizes screening recommendations by the american diabetes association. in terms of patients with skin disease, guidelines are not yet defined, and this area needs further research and consensus. certainly, many patients diagnosed with acanthosis nigricans, or recurrent cutaneous fungal infections would benefit from screening. psoriasis patients who are overweight or obese should also be considered for screening. even in the absence of a high bmi, however, those with severe psoriasis may require screening. studies have demonstrated increased risk of dm even in the absence of traditional risk factors, and severity of skin disease has been linked to a higher risk for metabolic comorbidities [12, 36]. patients with skin disease severe enough to warrant biologic therapy should therefore also be screened for dm. screening laboratory tests screening may be accomplished by several methods, including via measurement of hemoglobin a1c level. this is a single non-fasting blood test, and can be used to diagnose prediabetes or dm. diabetes mellitus (dm) is classified into two main categories: type i and type ii. in the last 50 years type ii dm has steadily increased in prevalence and now accounts for 90-95% of cases in the us [35]. according to the american diabetes association (ada), diagnostic criteria for type ii diabetes includes a hemoglobin a1c level of 6.5% or above, a fasting blood glucose test of 126 mg/dl or above, an impaired glucose tolerance test, and/or a random blood glucose test of 200 mg/dl or above [7]. prediabetes diagnosis while early detection of dm remains a high priority, an increased focus has been paid to prediabetes as well. identifying these individuals is a key aspect of diabetes prevention, as evidence-based interventions have shown a relative risk reduction of 40-70% in adults with prediabetes [37]. the ada defines prediabetes as a hemoglobin a1c value of 5.7% to 6.4% or a fasting plasma glucose of 100-125 mg/dl [7], while the who defines prediabetes as a fasting plasma glucose of 110 – 125 mg/dl or an impaired glucose tolerance test. prediabetes is considered an intermediate state of hyperglycemia that has not quite surpassed the dm threshold. it has been shown that conversion from prediabetes to dm occurs at a rate of up to 19% annually, with the likelihood of progression increasing with time [37,38]. importantly, prediabetes may also revert to normoglycemia. in a cochrane systematic review, 47 of 103 prospective cohort studies indicated that regression back to normoglycemia was as high as 59% within 5 years and 42% within 6-11 years [38]. treatment of prediabetes is crucial because individuals have a window of time where lifestyle changes or medication may be successful in preventing the development of dm. the role of lifestyle change in particular has received much attention. although the number of drugs available for dm treatment has quadrupled since 1995, there has only been an estimated 8% improvement in glycemic control nationwide. this has led to a renewed emphasis on the importance of table1. summary of screening recommendations by the american diabetes association (ada) [35]. all patients 45 and over should be screened every 3 years asymptomatic patients under the age of 45 with any of the following 8 risk factors and a bmi ≥ 25 kg/m2 should undergo screening (if asian american, then bmi ≥ 23 kg/m2) demographics • high-risk race/ethnicity (black, hispanic/latino, american indian, asian american, or pacific islander) family and social history • physical inactivity • first-degree relative with diabetes medical history • hypertensive (≥ 140/ 90 mmhg or on therapy for hypertension) • other clinical conditions associated with insulin resistance such as severe obesity, acanthosis nigricans • history of cardiovascular disease • polycystic ovary syndrome (pcos) laboratory values • hdl – c < 35 mg/dl and/or triglycerides >250 mg/dl follow-up recommendations: • if results are normal, repeated screening should occur at least every 3 years • women who were diagnosed with gestational diabetes should undergo screening every 3 years • patients with prediabetes should undergo screening annually review | dermatol pract concept. 2021; 11(4):e2021131 5 lifestyle interventions, which can significantly reduce the risk of dm complications [39]. interventions for patients diagnosed with prediabetes or dm, referral to primary care is required. in addition, dermatologists may directly refer patients with prediabetes to structured lifestyle intervention programs known as certified diabetes prevention programs (dpps). these programs significantly reduce the risk of progression to dm. they also empower patients, an underappreciated yet significant benefit [40]. a randomized placebo-controlled trial documented that an individualized, structured lifestyle intervention program was able to reduce progression to dm by 58% [41]. this data led to the development of diabetes prevention programs. in the united states, the cdc has designed a diabetes prevention program based on this evidence that has been reformatted for small group sessions. similarly, in europe, the image project (development and implementation of a european guideline and training standards for diabetes prevention) has defined standards for quality of diabetes prevention programs in the eu [42]. dpps last 1 year, and focus on patient education and techniques that encourage behavioral change. patients learn techniques to help encourage healthy eating, incorporate physical activity, and use healthy coping strategies. to help build and maintain the morale, trained lifestyle coaches are scheduled to meet with patients in group settings a total of 22-24 times throughout the program [8]. the cdc maintains a database of certified programs, which are administered through a variety of healthcare providers, national and local non-profits, and telehealth programs. the cdc provides an online search tool to check for availability of programs in the local area. in the us, coverage is provided for medicare patients who meet the medical qualifications. some commercial insurance plans and employers may also provide coverage for the program cost. for those without such coverage, program costs will vary; according to the american medical association, costs to the patient for the entire 1-year program in the us were estimated at $400–$500 total [43]. in the eu, dpps are adapted and implemented at a national level, such as, for example, in germany, one of the leading countries in diabetes prevention [44]. a europe-wide multi-center study showed a significant increase in health-related quality of life indicators in patients across europe, with both diabetes and prediabetes, who participated in dpps [39]. the benefits of diabetes prevention it is well-known that dm results in serious health impacts, including increased morbidity, cardiovascular complications, and increased healthcare costs [35]. for an individual patient, reducing the risk of this chronic disease may be life changing. for those who enroll in a dpp, weight loss is another benefit. to achieve certification, a dpp must demonstrate weight loss of at least 5% in a certain percentage of participants [43]. in patients with psoriasis, weight loss is an important benefit. the medical board of the national psoriasis foundation in 2018 published their dietary recommendations for those with psoriasis. the authors “strongly recommend” weight reduction in those who are overweight or obese [45]. weight loss may be considered adjunct therapy in psoriasis [46-48] as it may result in improvement of skin disease, with studies demonstrating an improvement in pasi scores. weight loss may also improve response to systemic psoriasis therapies [49]. conclusion dermatologists may play an important role in combating the current dm epidemic. early detection of dm and treatment initiation may significantly improve patient outcomes and reduce the risk of serious complications. using demographic factors and simple screening tools in the office, patients at risk for dm may be easily identified. patients at risk may be screened via a single non-fasting blood test or referred to their pcp for further evaluation. efforts to identify those with prediabetes is a key aspect of diabetes prevention, as lifestyle intervention programs are now accessible for many and demonstrate impressive results in reducing the risk of progression to dm. these programs also set weight loss goals, which may have additional skin disease benefits. for patients with skin diseases such as psoriasis, these measures will improve both overall health and skin health. references 1. national diabetes statistics report, 2017. :20. 2. data and statistics. accessed february 21, 2021. https://www. euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-and-statistics 3. duff m, demidova o, blackburn s, 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[prevention of type 2 diabetes in germany. ideas, evidence, implementation]. med klin (munich). 2006;101(9):730-736. doi:10.1007/s00063006-1100-2. 45. ford ar, siegel m, bagel j, et al. dietary recommendations for adults with psoriasis or psoriatic arthritis from the medical board of the national psoriasis foundation: a systematic review. jama dermatol. 2018;154(8):934-950. doi:10.1001/jamadermatol.2018.1412. 46. debbaneh m, millsop jw, bhatia bk, koo j, liao w. diet and psoriasis: part i. impact of weight loss interventions. j am acad dermatol. 2014;71(1):133-140. doi:10.1016/j.jaad.2014.02.012. 47. jensen p, zachariae c, christensen r, et al. effect of weight loss on the severity of psoriasis: a randomized clinical study. jama dermatol. 2013;149(7):795-801. doi:10.1001/jamadermatol.2013.722. 48. aune d, snekvik i, schlesinger s, norat t, riboli e, vatten lj. body mass index, abdominal fatness, weight gain and the risk of psoriasis: a systematic review and dose–response meta-analysis of prospective studies. eur j epidemiol. 2018;33(12):1163-1178. doi:10.1007/s10654-018-0366-z. 49. gisondi p, del giglio m, di francesco v, zamboni m, girolomoni g. weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial. am j clin nutr. 2008;88(5):1242-1247. doi:10.3945/ ajcn.2008.26427. dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(3):e2022122 1 dermatology practical & conceptual retiform hemagioendothelioma: dermoscopic-pathological correlation saurabh mittal1, naimah aljassem2 1 department of dermatology, nmc royal hospital 2 department of pathology, nmc royal hospital citation: mittal s, aljassem n. retiform hemagioendothelioma: dermoscopic-pathological correlation. dermatol pract concept. 2022;12(3):e2022122. doi: https://doi.org/10.5826/dpc.1203a122 accepted: october 29, 2021; published: july 2022 copyright: ©2022 mittal et al. this is an open-access article distributed under the terms of the creative commons attribution-non commercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication corresponding author: dr. saurabh mittal, md, department of dermatology, nmc royal hospital, abu dhabi, uae. e-mail: drsaurabh0811@gmail.com case presentation a-31-year-old female presented with a single, asymptomatic, slowly growing, soft, cystic, dark-red nodule (with bluish periphery) of size 2 cm x1 on the medial aspect of left upper thigh, of 4-5 years duration (figure 1a). dermoscopy revealed multiple deep red-colored globules of variable sizes separated by grayish white septae (figure 1b). histology showed a tumor composed of infiltrating vascular channels, which was poorly circumscribed and was composed of partially compressed, anastomosing vessels lined by hobnail endothelial cells. the vessels were separated by attenuated fibrous walls. immunohistochemistry was positive for cd34 highlighting the florid vascular proliferation. based on the above features, a diagnosis of retiform hemangioendothelioma was made. teaching point retiform hemangioendothelioma is a rarely infiltrative neoplasm, that mostly presents as an isolated growth, commonly involving the lower limbs [1,2]. surgical excision has been used most commonly, although recurrences have been reported [2]. the unique feature observed was the grayish white septae separating the globules. histologically, these septae conformed to the attenuated fibrous walls. to our knowledge, this is the first case describing the dermoscopic features for this entity. 2 image letter | dermatol pract concept. 2022;12(3):e2022122 figure 1. (a) clinical picture showing dark-red nodule. (b) dermoscopy (dermlite 10x) revealing multiple deep red-colored globules of variable sizes separated by grayish white septae. references 1. requena l, kutzner h. hemangioendothelioma. semin diagn pathol. 2013;30(1):29-44. doi: 10.1053/j.semdp.2012.01.003. pmid: 23327728. 2. nobeyama y, ishiuji y, nakagawa h. retiform hemangioendothelioma treated with conservative therapy: report of a case and review of the literature. int j dermatol. 2016;55(2):238-243. doi: 10.1111/ijd.12908. pmid: 26267121. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(2):e2021050 1 dermoscopy as a tool in differentiating cutaneous squamous cell carcinoma from its variants dimitrios sgouros1, melpomeni theofili2, vasileia damaskou3, sofia theotokoglou2, konstantinos theodoropoulos2, alexander stratigos1, panagiotis theofilis4, ioannis panayiotides3, dimitrios rigopoulos1, alexander katoulis2 1 first department of dermatology & venereology, andreas sygros hospital, national and kapodistrian university of athens, school of medicine, athens, greece 2 second department of dermatology & venereology, attikon general university hospital, national and kapodistrian university of athens, school of medicine, athens, greece 3 second department of pathology, attikon general university hospital, national and kapodistrian university of athens, school of medicine, athens, greece 4 department of internal medicine, general hospital of nikaia agios panteleimon, piraeus, greece key words: skin tumors, bowen disease, keratoacanthoma, invasive squamous cell carcinoma, dermoscopy citation: sgouros d, theofili m, damaskou v, theotokoglou s, theodoropoulos k, stratigos a, theofilis p, panayiotides i, rigopoulos d, katoulis a. dermoscopy as a tool in differentiating cutaneous squamous cell carcinoma from its variants. dermatol pract concept. 2021;11(2):e2021050. doi: https://doi.org/10.5826/dpc.1102a50 accepted: january 4, 2020; published: april 12, 2021 copyright: ©2021 sgouros et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: d.s. and m.t. contributed equally to this manuscript. all other authors have contributed significantly to this publication. corresponding author: dimitrios sgouros, md, first department of dermatology & venereology, andreas sygros hospital, 5 i. dragoumistr, 16 121, athens, greece. email:disgo79@gmail.com background: dermoscopic features of cutaneous squamous cell carcinoma (cscc) have been widely studied, but their accuracy should be further investigated. objectives: this study assessed the diagnostic accuracy of a set of predetermined dermoscopic structures for 3 variants of cscc, namely bowen disease, keratoacanthoma and invasive cscc. methods: dermoscopic images of 56 histopathologically confirmed cscc lesions (9 bowen disease lesions, 7 keratoacanthomas, and 40 invasive csccs) were examined, and the diagnostic accuracy of dermoscopic structures was assessed. discriminative ability of statistically significant positive predictors was determined using receiver operating characteristic (roc) curves, and defined as an area under the roc curve >0.700. results: dermoscopic structures with statistical significance and discriminative ability were: for bowen disease, clustered glomerular vessels and erosions; for keratoacanthoma, a central keratin plug; and abstract 2 research | dermatol pract concept. 2021;11(2):e2021050 introduction cutaneous squamous cell carcinoma (cscc) is the second most prevalent skin cancer [1]. common risk factors for the development of cscc are cumulative sun exposure, ionizing radiation, immunosuppression, chronic skin inflammation and a family history of cscc [2]. the 3 main clinical subtypes of cscc are bowen disease (bd), keratoacanthoma and invasive cscc. dermoscopy is a noninvasive clinical tool that allows the identification of morphological characteristics of an examined lesion, not seen by the naked eye or with a magnifying lens. use of dermoscopy facilitates early diagnosis and the good clinical management of skin lesions [3]. in addition, dermoscopy contributes to the treatment of skin tumors by enabling the preoperative determination of tumor surface boundaries, assessment of the effects of local therapies, and postoperative follow-up of patients [4]. prespecified dermoscopic features of bd include pink or pigmented background, clustered glomerular vessels (coiled vessels, mimicking the glomerular apparatus of the kidney), dotted vessels (like small red dots), opaque yellow-white scales, and erosions [4-9]. dermoscopic criteria for keratoacanthoma are a white background, central keratin plug (amorphous, yellow-white to light brown), white circles around follicular openings, and vascular loops that are hairpin-like or made of linear irregular vessels [6,10]. dermoscopic features of invasive cscc depend on the state of differentiation: highly differentiated invasive cscc has a background that is white, mixed (white to pink, red to white, pink to red) or pigmented, and demonstrates hairpin-like or linear irregular vessels, keratin clods (amorphous masses of keratin, yellow-white to light-brown), white circles around follicular openings, and ulcerations (red or red to brown structureless areas) [4,6,11,12]. poorly differentiated invasive cscc exhibits a red or mixed (red to white, pink to red) background, a polymorphous vascular pattern with more than one vessel type dominating (consisting of linear irregular, hairpin-like, glomerular and, rarely, dotted types), and ulcerations [4,6,11,12]. considering the ability of invasive cscc to metastasize if left untreated, the early differential diagnosis of cscc variants is very important [1,13]. despite the importance of dermoscopy in the initial clinical evaluation, data concerning the diagnostic accuracy of dermoscopic criteria of cscc variants are limited. methods study population we enrolled 53 patients with 56 csccs (9 bd, 7 keratoacanthomas, 40 invasive csccs) from the dermato-oncology unit of the second department of dermatology-venerology of attikon university hospital in athens, greece. inclusion criteria were: (i) a histopathologic diagnosis of bd, keratoacanthoma or invasive cscc (basosquamous or metatypical basal cell carcinoma were excluded from the study) following complete surgical excision of the tumor; and (ii) a high quality dermoscopic image. all individuals gave written informed consent after being informed about the purposes of the study. the study was approved by the ethics committee of attikon university hospital. clinical and anthropometric measurements initially and without knowledge of the histopathologic diagnosis, we recorded the demographic characteristics and the history of the patients. specifically, the patients were questioned about the presence of risk factors associated with the development of non-melanoma skin cancers, such as sun exposure habits, sunburns, sunscreen usage and a history of basal cell carcinoma or cscc, as well as a full medical history. next, a thorough dermatologic examination was performed by the dermatologist. dermoscopic examination dermoscopic images were obtained using contact dermoscopy with a dermlite ii pro hybrid dermatoscope (×10) coupled to a nikon j1 camera. image evaluation was performed by 2 independent examiners (d.s., a.k.) blinded to for invasive cscc, a mixed color of the background. clustered and glomerular vessels had, for bowen disease, perfect diagnostic accuracy, with: sensitivity of 88.9% for both features; specificity of 97.9% and 93.6%, respectively; positive predictive value (ppv) of 88.9% and 72.7%, respectively; and negative predictive value (npv) of 97.8% for both. erosions had, for bd, high specificity (87.2%) and npv (91.1%), but low sensitivity (55.6%) and ppv (45.5%). a central keratin plug had, for keratoacanthoma, high specificity (87.8%) and npv (93.5%), but low sensitivity (57.1%) and ppv (40%). a mixed background color had, for invasive cscc, high specificity (81.3%) and ppv (89.7%), but low sensitivity (65%) and npv (48.2%). conclusion: dermoscopy accurately differentiates bd, through clustered glomerular vessels, from keratoacanthoma and invasive cscc. dermoscopic structures of keratoacanthoma and invasive cscc overlap, and only histopathologic analysis differentiates them precisely. research | dermatol pract concept. 2021;11(2):e2021050 3 the histopathologic diagnosis and considering predetermined dermoscopic criteria of csccs. in brief, vascular structures were scored according to their morphology (dotted, glomerular, hairpin-like, linear irregular, polymorphous) and arrangement (diffuse, clustered, peripheral). moreover, the examiners assessed the presence of keratinized structures (scales, keratin clods, central keratin plug, white circles around follicular openings), erosions, and ulcerations, and recorded the color of the lesion background (pink, red, white, pigmented, or mixed). statistical analysis continuous variables were checked for normality of distribution by visual inspection of p-p plots and are presented as mean ± sd. categorical variables are displayed as percentages. one-way analysis of variance (anova) was used for comparisons between continuous and categorical variables. differences between categorical variables were tested by forming contingency tables and performing χ2 tests. statistically significant results were considered when p < 0.05. then, the discriminative ability (accuracy) of the statistically significant positive predictors was assessed through the analysis of roc (receiver operating characteristics) curves. the accuracy of dermoscopic criteria was estimated by calculating the area under the roc curve (auroc score). in addition, sensitivity, specificity, and positive and negative predictive values (ppv and npv) of significant dermoscopic criteria with auroc score >0.700 were calculated according to standard formulas [14]. all statistical calculations were performed using spss software (version 25.0; spss inc., chicago, illinois, usa). results patients’ demographics the study considered 56 csccs from 53 patients (table 1). specifically, there were 9 bd lesions, 7 keratoacanthomas, and 40 invasive csccs (in 38 patients); 1 patient had both bd + invasive cscc. invasive cscc lesions tended to be found in older patients who were more likely to have had unintentional sun exposure (invasive cscc, 27 of 40 lesions (67.5%); bd, 4/9 (44.4%); keratoacanthoma, 2/7 (28.6%), p = .10). they also were more likely found in patients who reported a lack of sunscreen use (invasive cscc, 38/40 (95.0%); bd, 7/9 (77.8%); keratoacanthoma, 5/7 (71.4%), p = .08). no significant differences were noticed regarding the frequency of sunburns before the age of 18, intentional sun exposure, or a smoking habit. clinical features of cscc concerning patients with bd and keratoacanthoma, the most common site of occurrence of the lesions was the upper limb; these lesions were often hyperkeratotic (table 2). a nodular surface was a characteristic finding in all keratoacanthomas, while bd lesions were mainly flat-like plaque. solar lentigo in sun-exposed parts of the body and actinic keratosis also tended to be present upon inspection of both lesion types (table 2). the invasive cscc lesions were mostly located on the head and neck. they were mainly nodular and ulcerated. moreover, actinic keratosis and solar lentigo in sun-exposed body parts were frequently noted (table 2). bowen disease (n = 9) keratoacanthoma (n = 7) invasive cscc (n = 40) p age, mean ± sd, y 72.2 ± 10.2 73.3 ± 12.4 79.1 ± 9.7 .14 male sex, n (%) 6 (66.7) 3 (42.9) 28 (70.0) .38 sunburn before age 18, n (%) 3 (33.3) 1 (14.3) 10 (25.0) .68 intentional sun exposure, n (%) 9 (100) 7 (100) 36 (90.0) .42 unintentional sun exposure, n (%) 4 (44.4) 2 (28.6) 27 (67.5) .10 lack of sunscreen, n (%) 7 (77.8) 5 (71.4) 38 (95.0) .08 smoking, n (%) 6 (66.7) 3 (42.9) 13 (32.5) .16 immunosuppression, n (%) 3 (33.3) 1 (14.3) 16 (40.0) .42 cscc history, n (%) 3 (33.3) 0 (0) 10 (25.0) .26 bcc history, n (%) 0 (0) 1 (14.3) 4 (10.0) .55 bcc = basal cell carcinoma; bd = bowen disease; cscc = cutaneous squamous cell carcinoma. table 1. demographic characteristics for 56 cutaneous squamous cell carcinomas from 53 patients 4 research | dermatol pract concept. 2021;11(2):e2021050 characteristica bd (n = 9) keratoacanthoma (n = 7) invasive cscc (n = 40) p actinic keratosis 7 (77.8) 5 (71.4) 38 (95.0) .03 sl (se body parts) 7 (77.8) 5 (71.4) 36 (90.0) .06 sl (nse body parts) 0 (0) 2 (28.6) 12 (30.0) .42 fitzpatrick phototype ii 4 (44.4) 1 (14.3) 13 (32.5) .26iii 5 (55.6) 6 (85.7) 20 (50.0) iv 0 (0) 0 (0) 7 (17.5) lesion location head and neck 1 (11.1) 1 (14.3) 34 (85.0) <.001 trunk 3 (33.3) 1 (14.3) 3 (7.5) upper limb 4 (44.4) 4 (57.1) 3 (7.5) lower limb 1 (11.1) 1 (14.3) 0 (0) lesion morphology flat-like plaque 6 (75.0) 0 (0) 7 (17.5) .001 raised nodule 2 (25.0) 7 (100) 33 (82.5) no erosion-ulceration 3 (33.3) 4 (57.1) 5 (12.5) .03erosion 2 (22.2) 0 (0) 3 (7.5) ulceration 4 (44.4) 3 (42.9) 32 (80.0) hyperkeratosis 6 (66.7) 5 (71.4) 22 (55.0) .46 table 2. clinical characteristics and macroscopic features of 56 lesions a values are n (%). bd = bowen disease; cscc = cutaneous squamous cell carcinoma; nse = not sun-exposed; se = sun-exposed; sl = solar lentigo. dermoscopic features of cscc the dermoscopic features of cscc are presented in table 3. with regards to vascular structures, clustered glomerular vessels (found in 8 of 9 bd lesions (88.9%), 1 of 7 keratoacanthomas (14.3%), 3 of 40 invasive cscc (7.5%), p < .001) were present in the vast majority of bd lesions (figure 1). linear irregular vessels were observed mostly in keratoacanthoma and invasive cscc (bd, 1/9 (11.1%); keratoacanthoma, 4/7 (57.1%); invasive cscc, 24/40 (60.0%), p = .03). polymorphous vessels were detected in some keratoacanthomas and invasive cscc (bd, 0/9; keratoacanthoma, 1/7 (14.3%); invasive cscc, 10/40 (25%), p = .14). dotted and hairpin-like vessels were uncommon in our sample. a peripheral vascular distribution was identified in keratoacanthomas and invasive csccs, but it was more frequent in keratoacanthomas (bd, 0/9; keratoacanthoma, 5/7 (71.4%); invasive cscc, 23/40 (57.5%), p = .004). a diffuse vascular arrangement was more often seen in invasive cscc without, however, reaching significance (bd, 1/9 (11.1%); keratoacanthoma, 1/7 (14.3%); invasive cscc, 16/40 (40%), p = .14). concerning features of keratinization, the presence of a central keratin plug was documented in the majority of keratoacanthomas and in a small proportion of invasive cscc (bd, 0/9; keratoacanthoma, 5/7 (57.1%); invasive cscc, 5/40 (12.5%), p = .004) (figure 2, a and b). scales, white circles around follicular openings, and keratin clods were found with similar frequencies in all the examined lesion types. the presence of erosions was significantly associated with bd, while only a minor portion of invasive cscc had this finding (bd, 5/9 (55.6%); keratoacanthoma, 2/7 (28.6%); invasive cscc, 4/40 (10%), p = .007). on the contrary, ulcerations were mostly seen in invasive csccs (bd, 4/9 (44.4%); keratoacanthoma, 3/7 (42.9%); invasive cscc, 32/40 (80%), p = .03). consequently, examination of the background color revealed a significant correlation of white with keratoacanthomas (bd, 1/9 (11.1%); keratoacanthoma, 2/7 (28.6%); invasive cscc, 1/40 (2.5%), p = .04) and a predominance of a mixed color in invasive csccs (bd, 0/9; keratoacanthoma, 3/7 (42.9%); invasive cscc, 26/40 (65%), p = .002). importantly, those colors were rarely seen in bd lesions. pink predominated in bd without, however, reaching statistical significance (bd, 5/9 (55.6%); keratoacanthoma, 1/7 (14.3%); invasive cscc, 8/40 (20%), p = .07). pigmented lesions were not identified among keratoacanthomas. research | dermatol pract concept. 2021;11(2):e2021050 5 table 3. dermoscopic features of 56 cscc by histopathologic diagnosis characteristic a bd (n = 9) keratoacanthoma (n = 7) invasive cscc (n = 40) p vascular structures dotted 0 (0) 0 (0) 1 (2.5) .82 hairpin-like 0 (0) 1 (14.3) 2 (5.0) .45 glomerular 8 (88.9) 1 (14.3) 3 (7.5) <.001 linear irregular 1 (11.1) 4 (57.1) 24 (60.0) .03 polymorphous 0 (0) 1 (14.3) 10 (25.0) .22 vascular arrangement diffuse 1 (11.1) 1 (14.3) 16 (40.0) .14 clustered 8 (88.9) 1 (14.3) 0 (0) <.001 peripheral 0 (0) 5 (71.4) 23 (57.5) .004 features of keratinization scales 7 (77.8) 4 (57.1) 23 (57.5) .52 keratin clods 6 (66.7) 3 (42.9) 23 (57.5) .63 white circles 5 (55.6) 6 (85.7) 28 (70.0) .43 central keratin plug 0 (0) 4 (57.1) 5 (12.5) .004 erosions and ulcerations none 0 (0) 2 (28.6) 4 (10.0) .18 erosions 5 (55.6) 2 (28.6) 4 (10.0) .007 ulcerations 4 (44.4) 3 (42.9) 32 (80.0) .03 background color white 1 (11.1) 2 (28.6) 1 (2.5) .04 pink 5 (55.6) 1 (14.3) 8 (20) .07 red 2 (22.2) 1 (14.3) 4 (10) .60 pigmented 1 (11.1) 0 (0) 1 (2.5) .39 mixed 0 (0) 3 (42.9) 26 (65) .002 a values are n (%). bd = bowen disease; cscc = cutaneous squamous cell carcinoma. figure 1. clustered glomerular vessels (white circle) over an evenly colored pink background with slight scaling are the most striking findings in bowen disease. diagnostic significance of dermoscopic structures the auroc scores of dermoscopic structures for the examined variants of cscc are presented in table 5. regarding bd, clustered and glomerular vascular structures had excellent scores (>0.900) and hence excellent discriminative abilities, while erosions had a good score (>0.700) and discriminative ability. pink background and scales had weak scores and therefore a poor discriminative ability for bd lesions. the discriminative capacity of the central keratin plug of keratoacanthomas was good, while those of a peripheral vascular arrangement and white background were poor. for invasive cscc, a diffuse vascular arrangement and ulcerations had weak discriminative ability, while a mixed color of the background had a good discriminative potential. for dermoscopic criteria with auroc >0.700, the sensitivity, specificity, ppv and npv were calculated (table 6). among dermoscopic findings of bd, glomerular vessels, clustered vessels and erosions had high specificity (93.6%, 97.9%, 87.2%, respectively) and npv (97.8%, 97.9% table 4 presents the dermoscopic features of highly, intermediately, and poorly differentiated invasive csccs ( figures 3 and 4). white perifollicular openings were significantly associated with highly differentiated cscc. 6 research | dermatol pract concept. 2021;11(2):e2021050 figure 2. well-differentiated (a) squamous cell carcinoma and (b) keratoacanthoma sharing common clinical and dermoscopic features. pinkish white background along with linear irregular vessels and a central keratin plug are typical of both clinical entities. table 4. dermoscopic features of 40 invasive cscc by histopathologic degree of differentiation characteristica high (n = 21) intermediate (n = 12) low (n = 7) p vascular structures dotted 1 (4.8) 0 (0) 0 (0) .63 hairpin-like 1 (4.8) 1 (8.3) 0 (0) .72 glomerular 3 (14.3) 0 (0) 0 (0) .23 linear irregular 12 (57.1) 7 (58.3) 5 (71.4) .79 polymorphous 4 (19.0) 4 (33.3) 2 (28.6) .64 vascular arrangement diffuse 9 (42.9) 7 (58.3) 0 (0) .04 clustered 0 (0) 0 (0) 0 (0) peripheral 11 (52.4) 5 (41.7) 7 (100) .04 features of keratinization scales 15 (71.4) 6 (50.0) 2 (28.6) .11 keratin clods 13 (61.9) 7 (58.3) 3 (42.9) .68 white circles 18 (85.7) 8 (66.7) 2 (28.6) .02 central keratin plug 4 (19.0) 1 (8.3) 0 (0) .37 erosions and ulcerations none 3 (14.3) 1 (8.3) 0 (0) .54 erosions 3 (14.3) 1 (8.3) 0 (0) .54 ulcerations 15 (71.4) 10 (83.3) 7 (100) .25 background color white 1 (4.8) 0 (0) 0 (0) .63 ρink 4 (19.0) 3 (25.0) 1 (14.3) .84 red 2 (9.5) 2 (16.7) 0 (0) .50 pigmented 1 (4.8) 0 (0) 0 (0) .63 mixed 13 (61.9) 7 (58.3) 6 (85.7) .44 a values are n (%). research | dermatol pract concept. 2021;11(2):e2021050 7 figure 3. the dermoscopic progression of invasive squamous cell carcinoma. (a) keratin clods surrounded by white circles, linear irregular vessels heading to the center of the tumor, and pinkish white background are typical characteristics of a highly differentiated squamous cell carcinoma. (b) pronounced ulceration with diffusely arranged polymorphous vessels and prevalent red coloration are dermoscopic criteria for a poorly differentiated squamous cell carcinoma. figure 4. intermediate differentiation of invasive squamous cell carcinoma. admixed features of high differentiation such as white circles, keratin clods, and centrifugal linear vessels (white circle), and signs of low differentiation such as erosions and ulcerations (white star). 91.1%, respectively). the glomerular and clustered vessels had high sensitivity (88.9% for both), while erosions had low sensitivity (55.6%). ppv was high for clustered vessels (88.9%), moderate for glomerular vessels (72.7%), and poor for erosions (45.5%). a central keratin plug for keratoacanthoma had high specificity and npv (87.8% and 93.5%, respectively), but its sensitivity was low (57.1%) and its ppv was weak (40%). finally, a mixed color of the background for invasive csccs displayed high specificity (81.3%) and ppv (89.7%), but low sensitivity and npv (65% and 48.2%, respectively). discussion this study evaluated the accuracy of various predetermined dermoscopic criteria for the early diagnostic assessment of csccs. interesting results were obtained concerning the vascular patterns of the lesions. clustered glomerular vessels were a potent predictor of bd and peripheral vessels were weakly correlated to keratoacanthoma, as were linear irregular vessels to invasive csccs. analytically, glomerular vessels were significantly associated with bd, as they were much more frequent in bd than in keratoacanthoma or invasive cscc, in agreement with previous studies [3, 5-9, 15-19]. they had diagnostic accuracy for bd when the differential diagnosis was bd versus keratoacanthoma and invasive cscc, with high sensitivity, specificity and npv, in addition to moderate ppv. moreover, a clustered vascular arrangement was the most valuable dermoscopic clue for bd, consistent with other reports [3,20]. it revealed high sensitivity, specificity, ppv and npv for bd. it is notable that only one bd lesion had a diffuse, linear irregular vascular pattern instead of a clustered glomerular pattern, but the histopathologic diagnosis was bd progressing to invasive cscc. regarding keratoacanthoma and invasive cscc, the vascular pattern could not accurately differentiate them [12]. invasive csccs, highly and poorly differentiated, commonly displayed linear irregular vessels, but with weak discriminative ability. indeed they were detected at a similar frequency in keratoacanthoma (57.1% vs. 60% in invasive cscc). dotted, hairpin-like and polymorphous vessels were not significant features. dotted and hairpin-like vessels were scarcely observed in keratoacanthoma and invasive cscc, while polymorphous vessels were seen in some invasive csccs of intermediate and low differentiation, in accordance with previous research [12]. a peripheral vascular distribution was more 8 research | dermatol pract concept. 2021;11(2):e2021050 table 5. auroc scores of dermoscopic structures bd (n = 9) keratoacanthoma (n = 7) invasive cscc (n = 40) vascular structures dotted 0.489 0.490 0.513 hairpin-like 0.468 0.551 0.494 glomerular 0.902 0.459 0.256 linear irregular 0.258 0.531 0.644 polymorphous 0.383 0.469 0.594 vascular arrangement diffuse 0.375 0.398 0.638 clustered 0.934 0.490 0.219 peripheral 0.202 0.631 0.622 features of keratinization scales 0.602 0.480 0.444 keratin clods 0.557 0.418 0.506 white circles 0.416 0.592 0.506 central keratin plug 0.404 0.735 0.438 erosions and ulcerations none 0.436 0.602 0.488 erosions 0.714 0.551 0.331 ulcerations 0.350 0.347 0.681 background color white 0.524 0.622 0.419 ρink 0.682 0.439 0.413 red 0.558 0.510 0.456 pigmented 0.545 0.480 0.481 mixed 0.191 0.449 0.731 auroc = area under the receiver operating characteristic curve; bd = bowen disease; cscc = cutaneous squamous cell carcinoma. table 6. diagnostic accuracy of dermoscopic criteria for cscc dermoscopic criterion sensitivity specificity ppv npv bd glomerular vascular structures 88.9% 93.6% 72.7% 97.8% clustered vascular structures 88.9% 97.9% 88.9% 97.9% erosions 55.6% 87.2% 45.5% 91.1% keratoacanthoma central keratin plug 57.1% 87.8% 40% 93.5% invasive cscc mixed background 65% 81.3% 89.7% 48.2% bd = bowen disease; cscc = cutaneous squamous cell carcinoma; npv = negative predictive value; ppv = positive predictive value. research | dermatol pract concept. 2021;11(2):e2021050 9 prominent in keratoacanthoma than in invasive cscc (71.4% and 57.5%, respectively) [12]. however, the latter had a poor diagnostic accuracy, as specificity for keratoacanthoma was low. on the other hand, a diffuse vascular distribution did not reach statistical significance. concerning keratinized structures, the presence of a central keratin plug should be interpreted carefully. it should be considered suggestive of keratoacanthoma since it was encountered approximately in half of these lesions, but it was completely absent from bd and was also observed in a small proportion of highly differentiated invasive csccs. it had high specificity for keratoacanthoma but low sensitivity. therefore, a diagnosis of keratoacanthoma cannot be made with certainty upon its detection. this result is in line with previous dermoscopic studies [12,21]. furthermore, scales, keratin clods, and white perifollicular circles failed to meet statistical significance. scales and keratin clods were frequent in bd (77.8% and 66.7%, respectively), but they were also present in approximately half of keratoacanthomas and invasive csccs. white circles were more common in keratoacanthoma and invasive cscc (85.7% and 70%, respectively), but were also found in approximately half of bd lesions. the later was an unexpected finding according to existing literature, and suggests that white circles are a strong indicator of keratoacanthoma and invasive cscc. this finding is probably because white circles correspond to changes induced by orthokeratosis and parakeratosis or to an optical effect produced by the interaction of keratin-filled follicular openings with the polarized light of the dermoscope [12, 22]. moreover, white circles were significantly associated with highly differentiated invasive csccs, in synchrony with earlier data [11]. erosions and ulcerations were significant dermoscopic features, but with weak diagnostic accuracy. erosions were more commonly observed in bd than in keratoacanthoma (approximately 2-fold higher) and in invasive cscc (approximately 5-fold higher) [5-9]. they had, for bd, good discriminative ability, high specificity, and npv, but low sensitivity and ppv. ulcerations were found in the majority of invasive csccs compared to bd and keratoacanthomas (approximately 2-fold higher for both) [4, 6]. they had a poor discriminative ability for invasive cscc. furthermore, it is important to note that ulcerations observed with the unaided eye and dermoscopically in keratoacanthomas and invasive csccs were equally frequent. finally, analysis of the background color of the lesions revealed further significant features: white color for keratoacanthoma, and mixed color for invasive cscc [20]. the white color displayed a weak discriminative potential for keratoacanthoma since it was quite frequent in keratoacanthomas and rare in bd and invasive cscc (28.6% vs. 11.1% and 2.5% respectively). moreover, a mixed background color exhibited a good discriminative capacity for invasive cscc. it was present in 65% of invasive csccs and 42.9% of keratoacanthomas, but was completely absent in bd. this finding is possibly due to neo-vascularization of the malignant neoplasm in addition to the degree of differentiation, given that keratoacanthoma is considered by some dermatopathologists to be a highly differentiated invasive cscc [23]. it has high specificity and ppv for invasive cscc and low sensitivity and npv. the pink background color observed in approximately half of bd exhibited a trend toward significance (p = .07). the pigmented background was absent from keratoacanthoma, in line with a previous study [12]. therefore, the background of the lesion offers supplementary clinical evidence, but it could not aid the efficient dermoscopic differential diagnosis of cscc variants. the primary limitation of our study consists of the relatively small number of examined lesions, a fact that could impact the strength of our results. second, the suggested accuracy of dermoscopic criteria cannot be generalized, but refers only to the differential diagnosis between the 3 variants of cscc. furthermore, adequately powered studies ought to be performed to confirm our findings and improve the knowledge surrounding the overall importance of dermoscopy. conclusions the presence of clustered glomerular vessels is a highly accurate dermoscopic criterion in differentiating, rapidly and efficiently, bd from keratoacanthoma and invasive cscc, and may enhance the clinical 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10.1111/j.14683083.2009.03529.x. pmid: 20015173. 19. payapvipapong k, tanaka m. dermoscopic classification of bowen’s disease. australas j dermatol. 2015;56(1): 32-35. doi: 10.1111/ajd.12200. pmid: 25330999. 20. russo t, piccolo v, lallas a, et al. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. doi: 10.1159/000472253. pmid: 28486238. 21. adya ka, inamadar ac, palit a. dermoscopy of keratoacanthoma centrifugum marginatum. indian dermatol online j. 2019;10(3):360362. doi: 10.4103/idoj.idoj_134_18. pmid: 31149601. 22. peralta r, salerni g, cohen sabban e, marin mb, cabo h. dermoscopy of a squamous cell carcinoma of the lower lip showing multiple rosettes. dermatol pract concept. 2020;10(1):e2020022. doi: 10.5826/dpc.1001a22. pmid: 31921509. 23. weedon d, malo j, brooks d, williamson r. keratoacanthoma: is it really a variant of squamous cell carcinoma? anz j surg. 2010;80(3):129-130. doi: 10.1111/j.1445-2197.2010.05219.x. pmid: 20575911. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022051 1 dermatology practical & conceptual introduction rhinofacial entomophthoromycosis or zygomycosis is a rare infection, caused by conidiobolus corononatus involving the nasal cavity, paranasal sinuses, and soft tissues of the face. it initially starts as a painless swelling of the rhinofacial region which is locally invasive and can lead to facial disfigurement over time [1]. the disease tends to involve immunocompetent males, usually involved in agriculture between the age of 20-50 years. the diagnosis is established through histopathological and mycological examination. special stains like periodic acid schiff and silver methanamine can help in the visualization of fungal hyphae and confirmation of diagnosis. herein, we present a case of rhinofacial entomophthoromycosis and describe the dermoscopic findings seen in the patient. case presentation a 19-year-old male, a farmer by occupation from the himalayan region of north india, presented with diffuse facial swelling which initially started as nasal mass, gradually progressing to involve the upper half of the face including nose, cheeks, and forehead with significant facial disfigurement for 8 months. there were no other symptoms associated with the swelling. the patient had taken multiple short courses of antibiotics and antifungals without improvement. general physical and systemic examination of the patient was normal. upon mucocutaneous examination, diffuse skin-colored to erythematous, slight scaly, woody hard, lobulated subcutaneous swelling was present over the nose extending to involve the center of forehead, upper part of both the cheeks, inner canthus of the eye, and infraorbital area restricting the patient’ vision (figure 1a). laboratory examination including blood count and blood chemistry were within normal limits. elisa assays for detection of human immunodeficiency virus and hepatitis b surface antigen were negative. computed tomography scan revealed heterogeneously enhancing soft tissue mass in the left nasal cavity arising from inferior turbinate extending into the soft tissue of nasal septum. dermoscopic examination (x10, polarized non-contact mode) was done which revealed focal yellowish-orange structureless area, dotted and linear vessels over a background of diffuse erythema dermoscopy of rhinofacial entomophthoromycosis in skin of color: first report payal chauhan1, rashmi jindal2, nadia shirazi3 1 department of dermatology, all india institute of medical sciences (aiims), himachal pradesh, india 2 department of dermatology, himalayan institute of medical sciences, dehradun, uttarakhand 3 department of pathology, himalayan institute of medical sciences, dehradun, uttarakhand key words: dermoscopy, subcutaneous mycoses, deep mycosis, rhinofacial entomophthoromycosis citation: chauhan p, jindal r, shirazi n. dermoscopy of rhinofacial entomophthoromycosis in skin of colour: first report. dermatol pract concept. 2022;12(2):e2022051. doi: https://doi.org/10.5826/dpc.1202a51 accepted: august 11, 2021; published: april 2022 copyright: ©2022 chauhan et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: payal chauhan, assistant professor, department of dermatology, all india institute of medical sciences (aiims), himachal pradesh, india e-mail: chauhanpayal89@gmail.com 2 research letter | dermatol pract concept. 2022;12(2):e2022051 (figure 1, b and c). few white areas, scaling, and yellow follicular plugs seen as yellow dots were also appreciated. histopathological examination was done from the skin and underlying nasal mass. skin biopsy revealed epidermal acanthosis, follicular plugs, and multiple epithelioid granulomas in the dermis with eosinophilic infiltrate (figure 2, a and b). the nasal biopsy displayed amorphous eosinophilic material around fungal hyphae along with acute inflammatory infiltrate (figure 2c). gomori methanamine silver stain performed on the nasal biopsy sample demonstrated broad, aseptate fungal hyphae, a few branching at the right angle (figure 2, d and e). no organism could be grown on tissue culture. a final diagnosis of rhinofacial entomophthoromycosis was made. the patient was started on itraconazole 200 mg twice a day and potassium iodide five drops 3 times a day. discussion the clinical appearance of rhinofacial entomorphthoromycosis can mimic neoplasms like subcutaneous malignant, lymphatic oedema, tuberculosis. dermoscopy-based differential diagnosis of the present case include cutaneous tuberculosis, other deep mycosis like cutaneous sporotrichosis, though clinical appearance can help distinguish rhinofacial entomophthoromycosis from the latter. timely diagnosis of this rare disorder is important to initiate early intervention and thus reduce patient morbidity. application of dermoscopy has lately expanded to the diagnosis of deep fungal infections, though available literature is still limited [2]. to the best of our knowledge, dermoscopy of rhinofacial entomorphthoromycosis has not been previously described. generalized erythema, yellowish structureless area, presence of vessels, and white scar-like areas have been seen to be common dermoscopic features of deep mycosis [2]. the yellow follicular plugs appreciated in the dermoscopy of the present case are akin to yellow tears described in cutaneous leishmaniasis and cutaneous sporotrichosis the presence of yellowish-orange areas on dermoscopy reflect the underlying granulomas, yellow dots correspond to dilated infundibulum present on histopathology, whereas white areas represent dermal fibrosis, with generalized erythema and vessels secondary to the dermal inflammation and neoangiogenesis. figure 1. (a) diffuse skin colored to erythematous, slight scaly, subcutaneous swelling involving nose, forehead, inner canthus of eye, upper part of both cheeks. (b) dermoscopy of the swelling over infraorbital area (represented by blue star in clinical image) displays focal yellowish-orange structureless area (black star), multiple dotted vessels (black circle) over a background of diffuse erythema. yellow dots (blue circle) and scattered yellow-brown scales also appreciated. (c) focal yellowish-orange structureless area (black star), white areas (blue star), linear (black arrow) and dotted vessels seen from dermoscopy of the swelling over nose (represented by black star in clinical image). research letter | dermatol pract concept. 2022;12(2):e2022051 3 conclusions dermoscopic findings of rhinofacial entomophthoromycosi include yellowish-ornage structureless areas, erythematous background, white areas, follicular plus, scaling, linear and dotted vessels. dermoscopy can act as a useful tool in the diagnosis of this rare disfiguring deep mycosis and further work is needed in this field to corroborate findings seen in the present case. references 1. bhalla s, srivastava vk, gupta rk. rhinofacial entomophthoramycosis: a rare fungal infection in an adolescent boy. indian j pathol microbiol. 2015;58(3):402-403. doi: 10.4103/03774929.162933. pmid: 26275280.  2. dabas g, kaur h, vinay k, et al. dermoscopy in disseminated sporotrichosis. j eur acad dermatol venereol. 2019;33(1):e33-e35. doi: 10.1111/jdv.15152. epub 2018 jul 18. pmid: 29953691. figure 2. (a) histopathology of the skin over infraorbital area showing follicular plugs, epidermal acanthosis, multiple granulomas in the dermis (h&e, original magnification x4). (b) dermal granuloma formed of epithelioid cells, lymphocytes, plasma, and acute inflammatory infiltrate (h&e, original magnification x40). (c) histopathology of nasal mass demonstrating amorphous eosinophilic infiltrate surrounding fungal hyphae with dense acute inflammatory infiltrate (h&e, original magnification x20). (d) gomori methanamine silver stain showing multiple scattered broad, aseptate fungal hyphae (original magnification x 200). (e) another section showing broad, aseptate fungal hyphae with branching at right angle seen in silver methanamine stain (original magnification x 400). dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022129 1 introduction: improving remote triage is crucial given expansions in tele-dermatology and with limited in-person care during covid-19. in addition to clinical pictures, dermoscopic images may provide utility for triage. objectives: to determine if dermoscopic images enhance confidence, triage accuracy, and triage prioritization for tele-dermatology. methods: in this preliminary parallel convergent mixed-methods study, a cohort of dermatologists and residents assessed skin lesions using clinical and dermoscopic images. for each case, participants viewed a clinical image and determined diagnostic category, management, urgency, and decision making confidence. they subsequently viewed the associated dermoscopy and answered the same questions. a moderated focus group discussion followed to explore perceptions on the role of dermoscopy in tele-dermatology. results: dermoscopy improved recognition of malignancies by 23% and significantly reduced triage urgency measures for non-malignant lesions. participants endorsed specific utilities of tele-dermoscopy, such as for evaluating pigmented lesions, with limitations including poor image quality. conclusions: dermoscopic images may be useful when remotely triaging skin lesions. standardized imaging protocols are needed. dermoscopic images impact confidence and management of remotely triaged skin lesions: a preliminary study tova rogers1*, myles randolph mccrary1*, howa yeung1,2, loren krueger1, suephy c chen2,3# 1 department of dermatology, emory university school of medicine, atlanta, georgia, usa 2 regional telehealth service, visn 7, duluth, georgia, usa 3 department of dermatology, duke university, durham, north carolina, usa *these authors contributed equally to this work. #all work performed while at emory university, atlanta, georgia, usa key words: telemedicine, tele-dermatology, dermoscopy, melanoma, skin cancer citation: rogers t, mccrary mr, yeung h, krueger l, chen sc. dermoscopic images impact confidence and management of remotely triaged skin lesions: a preliminary study. dermatol pract concept. 2022;12(3):e2022129. doi: https://doi.org/10.5826/dpc.1203a129 accepted: december 8, 2021; published: july 2022 copyright: ©2022 rogers et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: suephy c. chen, md, ms, department of dermatology, duke university school of medicine, 40 duke medicine circle, clinic 3k, durham, nc 27710, tel: (919) 684 3110; fax: (919) 684 3002 e-mail: suephy.chen@duke.edu abstract dermatology practical & conceptual 2 original article | dermatol pract concept. 2022;12(3):e2022129 introduction tele-dermatology plays an important role in triage of potentially malignant skin lesions. tele-dermatology has comparable diagnostic accuracy to in-person evaluations, though, study results vary for malignant lesions [1]. the use of dermoscopic images, in addition to clinical images, can improve accuracy, especially for pigmented skin cancers [2-5]. images are imperative for the remote management of skin lesions. prior to the covid-19 pandemic, many primary providers would arrange to have patient images taken by trained in-office personnel, which are then used for store-and-forward tele-dermatology. there is also an increasing demand for patients to submit photographs of their skin problems without needing to go to the primary care office at all. covid-19 realized the difficulty of patients to have their skin lesions imaged in person. dermatologists are then faced with using patient-provided images taken with smartphones or computers [6,7]. the quality of these images is variable. dermoscopic images have become almost universally unavailable. while the social restrictions resulting from the covid-19 pandemic are loosening, remote patient care has become a possible parallel care paradigm. thus, to adequately triage patients and maintain high standards of care, innovative means are required to ensure access to high quality images, including assessing the added value of dermoscopy [1,6,8,9]. objectives our preliminary study aims to assess the impact of dermoscopic images on providers abilities to classify and triage skin lesions, and on their confidence in their decision making. we implemented a parallel convergent mixed method design to quantify the utility of dermoscopy for remotely triaging skin lesions and to assess provider’ perceptions of dermoscopy as a triage tool in tele-dermatology. methods study design and data collection a convergent parallel mixed-methods design was used to collect, analyze, and interpret quantitative and qualitative data. the study was approved by the institutional review board at emory university and the atlanta veterans affairs medical center research and development committee. the veteran integrated service network (visn) 7 teledermatology service serves as a reading hub for the community-based outpatient clinics (cbocs) in atlanta as well as for other visn 7 medical centers imagers are trained by the tele-dermatology service to take photographs per standard protocol established by the va national teledermatology service: a forest view, and close-up, and a dermoscopic view are taken for every lesion and rash. there is not mandated specific magnification or lighting. images are uploaded via vista imaging, an fda-listed image management system employed by department of veterans affairs healthcare facilities nationwide. to maintain our imaging quality standards, feedback for image quality is given for each consult (fully satisfactory, satisfactory with suggestions, and unsatisfactory). for the present study, images from tele-dermatology consults received between 12/1-31/2018 were reviewed. twenty sets of clinical and dermoscopic images were selected as representative of common benign and malignant skin lesions seen in the tele-dermatology clinic. diagnoses for malignant lesions were confirmed with biopsy. benign lesions were classified by consensus among tele-dermatology providers. clinical and dermoscopic images were de-identified and compiled into a digital slide show using microsoft powerpoint version 16.55. high image quality was maintained at 300 dots per inch. this preliminary study was conducted over a two-day period using zoom, a video communication platform with a built-in polling function. participants filled out a demographic survey, including a series of questions relating to their use of dermoscopy in their clinical practices, prior dermoscopic training, and overall confidence in their dermoscopic abilities. they were shown a clinical image of a skin lesion or multiple skin lesions and asked to determine diagnostic category, management decision (reassure versus further in-person management), perceived level of urgency with which further action is required (not urgent, urgent, emergent), and self-rated confidence level in their decision making (range from 0% to 100% confidence in intervals of 10 percentage points) (supplemental material, survey). diagnostic categories included non-neoplastic (folliculitis, epidermal inclusion cyst, verruca; 3/20 cases), benign neoplastic (actinic keratosis, seborrheic keratosis, blue nevus, sebaceous hyperplasia, dermatofibroma, melanocytic nevus, angioma; 11/20 cases), and malignant neoplastic (melanoma, basal cell carcinoma, squamous cell carcinoma; 6/20 cases). these images are supplied in supplemental table 1. participants were then shown the accompanying dermoscopic image and asked the same questions. this process was repeated for all twenty study sets. on study day two, a moderated group discussion took place in which participants were asked questions pertaining to their perception of the utility of dermoscopic images for triaging skin lesions and if the covid-19 pandemic has changed these perceptions (supplemental material, debriefing prompts). the discussion was recorded and transcribed verbatim. data analysis graphpad prism 6 (graphpad software) was used for statistical analysis and graphic presentation of survey results. paired t-tests were used to compare differences in confidence original article | dermatol pract concept. 2022;12(3):e2022129 3 and correct diagnosis before and after revealing dermoscopic images. survey data were expressed as means with 95% confidence interval. for urgency and management, mcnemar’s test was used to determine statistical significance in differences between the ratings before and after exposure to dermoscopic images. to test whether confidence was correlated with correct diagnoses, we used a regression analysis over the average self-rated confidence and average percentage of correct diagnoses per provider. results were considered significant if p resulted < 0.05. for qualitative analysis of the participant comments, 2 study investigators (tr, mrm) independently reviewed and coded the entire transcript from the group discussion. themes were developed inductively and defined as having at least three study participants having similar responses to the study questions. investigators consolidated these comments into a list of key themes designed to characterize perceived benefits, potential applications, and shortcomings of dermoscopic images for remotely triaging skin lesions. discrepancies were resolved by consensus. results demographics twenty-six physicians participated in this preliminary study, including 16 dermatology attendings and 10 residents (table 1). attending physicians had a wide spread of years in practice. half of survey participants reported using dermoscopy in ≥50% of their clinical practice. over half (55%) reported having attended at least one formal dermoscopy course. when asked about their confidence in their dermoscopic abilities, 59% of study participants indicated that they were “somewhat confident” using dermoscopy. none of the study participants were “confident” in their dermoscopic abilities. survey results using clinical images alone, 45% of physicians (12/26) correctly diagnosed the study cases. (this increased to 53% (14/26) after viewing the associated dermoscopic images (p = 0.02, paired t-test) (figure 1). the greatest increase was for malignant neoplasms (31% [8/26] versus 54% [14/26], p = 0.0007). after showing clinical images, 54% (14/26) rated non-neoplastic lesions (ie, inflammatory and infectious) as “non-urgent”, which significantly increased to 81% (21/26) after viewing the associated dermoscopic images (p < 0.0001, mcnemar test) (figure 2). there was a trend to reduce urgency for benign neoplastic lesions (from 69% to 78% non-urgent) and increase urgency for malignant neoplastic lesions (from 44% to 58% urgent/emergent) following dermoscopic images. with regards to management decisions, significantly more providers opted to provide reassurance (14/26) rather than interventions (0/26) for non-neoplastic lesions following the addition of dermoscopic images (p < 0.0001). the addition of dermoscopy did not lead to significant changes in management for benign or malignant neoplastic lesions. we found a 7.6% increase in providers' confidence in their management decisions with dermoscopy (p < 0.0001) (figure 3). there was also a weak but statistically significant (r2 = 0.246 p = 0.024) correlation between providers level of confidence and correct diagnoses. theme results we conducted a thematic analysis of the moderated discussion on the role of dermoscopy for triage during covid-19 (table 2). the first theme involved the specific utilities of dermoscopy. participants endorsed that dermoscopy was useful for suspected malignancy, pigmented lesions, lesions with well-known dermoscopic features, and in conjunction with patient history, and less useful for generalized exanthems. the second theme was image quality. many voiced that image quality for both clinical and dermoscopic images was critical and often a major limitation. thirdly, participants commented on accessibility to dermoscopy during the coronavirus pandemic, and also with technological advances and expansions in telehealth. notably, providers felt that table 1. demographics characteristics, n (%) completed survey 22/26 (84.6%) status resident 10/26 (38.5%) attending 16/26 (61.5%) years in practice (attendings) 1-5 4/13 (31%) 6-10 4/13 (31%) 11-15 1/13 (8%) > 15 4/13 (31%) % clinical practice using dermoscopy < 50% 13/26 (50%) >/= 50% 13/26 (50%) # formal dermoscopy courses 0 10/22 (45.5%) 1-2 9/22 (40.9%) 3-4 3/22 (13.6%) level of confidence in dermoscopy skills not confident 9/22 (40.9%) somewhat confident 13/22 (59.1%) confident 0 4 original article | dermatol pract concept. 2022;12(3):e2022129 100 % r es p o n d en ts t r ia g in g to ‘n o n -u r g en t ’ clinical image dermoscopy 50 0 in fe ct io us / in fl am m at or y be ni gn ne op la st ic m al ig na nt ne op la st ic figure 2. dermoscopy reduces perceived triage urgency for non neoplastic lesions. the proportion of respondents that rated non-neoplastic, benign neoplastic, and malignant neoplastic lesions as non-urgent before and after addition of dermoscopy is shown above. bar graphs illustrate the means. * indicates p < 0.05 at mcnemar test. 100 80 60 40 20 0 clinical image % c o r r ec t dermoscopy to ta l in fe ct io us / in fl am m at or y be ni gn ne op la st ic m al ig na nt ne op la st ic figure 1. dermoscopy increases % correct diagnoses for malignant lesions. the percentage of correct diagnoses for all cases, non-neoplastic, benign neoplastic, and malignant neoplastic with clinical images only and following dermoscopic images is shown above. bar graphs illustrate the means with error bars representing 95% confidence intervals. * indicates p < 0.05 at paired t-test. 100 80 60 c o n fi d en c e (% ) 40 20 0 to ta l in fe ct io us / in fl am m at or y be ni gn ne op la st ic m al ig na nt ne op la st ic clinical image dermoscopy figure 3. dermoscopy increases confidence in management decisions. the percentage of confidence for all cases, non-neoplastic, benign neoplastic, and malignant neoplastic with clinical images only and following dermoscopic images is shown above. bar graphs illustrate the means with error bars representing 95% confidence intervals. * indicates p < 0.05 at paired t-test. [1-5,10-13]. our results indicate that dermoscopy may have additional utilities. specifically, we found that dermoscopy reduced provider perception of urgency for benign lesions such as verruca (figure 2). consequently, a greater proportion of dermatologists in our study opted against prioritizing these patients for in-person evaluation. this is important in the setting of the covid-19 pandemic, as the risk of viral exposure must be balanced with the benefits of office visits. additionally, tele-dermoscopy may allow for better resource utilization [14]. the ability to reduce the number of in-person visits allows for the care of a greater volume of patients and prevents unnecessary travel. thematic analysis of the moderated discussion revealed that providers feel dermoscopic images are most useful for triaging malignant lesions and pigmented lesions, specifically those with the most common morphological features. interestingly, despite improving providers’ abilities to correctly classify malignant neoplastic lesions (figure 1), the addition of dermoscopy did not significantly affect urgency scores or management decisions. this may reflect the lack of consensus amongst providers on the perceived urgency for treating slow growing malignancies such as basal cell carcinoma [15]. while training may be a limiting factor for the usefulness of dermoscopic images, study participants also voiced concerns about the impact of image quality. the success of the visn 7 tele-dermatology program is in part due to imaging protocols that ensure consistently high image quality. this involves staff training, imaging equipment, and additional time—investments that are required for the success of future tele-dermatology efforts [16]. our moderated discussion also revealed that participants do not find dermoscopy useful for triaging widespread skin reduced access to dermoscopy during covid-19 hampered tele-dermatology efforts. however, there was hesitancy towards direct-to-consumer dermoscopy. conclusions our preliminary findings demonstrate that dermoscopy can be a useful adjunct when remotely triaging skin lesions. this finding corroborates previous studies that suggest dermoscopic images improve recognition of neoplastic lesions, particularly for pigmented lesions such as melanoma original article | dermatol pract concept. 2022;12(3):e2022129 5 table 2. perceptions of dermoscopy for triage in tele-dermatology described by study participants, presented by theme and subtheme with exemplary quotes. theme and subtheme exemplary quotes utility of dermoscopy useful for suspected malignancy and pigmented lesions “dermoscopy can be very useful for lesions suspicious for malignancy.” “(dermoscopy) has a lot to add for pigmented lesions and neoplasms.” useful for lesions with common dermoscopic morphologies “clear features can increase confidence; more obscure structures are less helpful.” “there are certain things that i can trust dermoscopy for, like single lesions with specific findings.” less useful for rashes (of note, there were no rashes included in the survey) “dermoscopy for limited portions of an exanthem, especially without history, can be misleading.” “clinical images are more reassuring and less confusing than dermoscopy for rashes.” patient history complements dermoscopic images “i want to know the patient’s problem list and how acute this is relative to other comorbidities.” “for example, if i see that this patient is immunosuppressed on the primary care note, that will change things.” importance of image quality “if you have protocols for taking photos outlined, then that is more helpful. for the most part it’s going to be patients and nurses taking photos, so we need good protocols and feedback mechanisms in place, so protocols are followed.” “the lack of utility is based on both photo quality (such as extreme close ups, blurriness, lighting), as well as not knowing what to take photos of.” increased accessibility to dermoscopy covid19 limited availability to dermoscopic images “i felt handicapped [during covid19] for neoplastic lesions, dermoscopy is crucial for those.” “[the transition to telemedicine during covid19] has made me realize the limitations of webcam and poor-quality images, which makes imaging protocols more important.” hesitancy for consumer dermoscopy “i also worry that people might think they can interpret [dermoscopic images], which might be a problem. even medical students don’t get formal training in dermoscopy.” “i’m skeptical about this technology in the hands of patients, but there might be utility for our high risk pigmented lesion patients.” eruptions. they feel that it would save time and resources to have primary providers submit dermoscopic images only for appropriate cases. however, having primary providers or patients determine which cases require dermoscopic images is asking them to decipher skin eruptions from discrete skin lesions. in the present study, we included two cases in which field actinic keratoses and field sebaceous hyperplasia were misidentified by the referring primary provider as generalized exanthems (supplemental table 1). it has been shown that primary care providers have difficulty diagnosing field actinic keratoses [17]. accordingly, the tele-dermatology imaging protocol at the visn 7 teledermatology service requires clinical and dermoscopic images for every consult. while this requires more time and resources, it eliminates the possibility for this type of error. the ideal imaging protocol is likely dependent on resources available at specific institutions. a previous study of digital imaging for tele-dermatology suggests that standardization should involve a panoramic photo, a close-up with measurements, and a dermoscopic image [18]. our study participants had a wide and varied range of dermoscopy training and utilization in clinical practice (table 1). while most (55%) of participants in our survey had training with at least 1 formal dermoscopy course, few dermatology residency programs provide formalized dermoscopy training [19]. in the present study, participants had low self-reported confidence in their dermoscopic abilities, despite some with extensive use in their clinical practice. this may be attributed to the varying utilities of dermoscopy in different contexts, for example, where participants felt dermoscopy was less useful for rashes (table 2). the addition of dermoscopy, nonetheless, proved useful for correctly triaging benign and malignant skin lesions. these results and others suggest the benefits of dermoscopy could justify a standardized curriculum to be used across residency programs. this educational gap must be addressed so that rising dermatologists are able to confidently use dermoscopy to its full potential [20-23]. our discussion revealed that providers are hesitant about consumer dermoscopy. there is concern that patients might start interpreting their own images, placing them at risk for mismanagement. this concern has been voiced by others as well [24]. however, studies have indicated that 6 original article | dermatol pract concept. 2022;12(3):e2022129 2009;61(5):753-765. doi: 10.1016/j.jaad.2009.04.032. pmid: 19679375. 4. warshaw em, gravely aa, nelson db. accuracy of teledermatology/teledermoscopy and clinic-based dermatology for specific categories of skin neoplasms. j am acad dermatol. 2010;63(2):348-352. doi: 10.1016/j.jaad.2009.10.037. pmid: 20633809. 5. ferrándiz l, ojeda-vila t, corrales a, et al. internet-based skin cancer screening using clinical images alone or in conjunction with dermoscopic images: a randomized teledermoscopy trial. j am acad dermatol. 2017;76(4):676-682. doi: 10.1016/j. jaad.2016.10.041. pmid: 28089728. 6. su my, das s. expansion of asynchronous teledermatology during the covid-19 pandemic. j am acad dermatol. 2020;83(6):e471-e472. doi: 10.1016/j.jaad.2020.08.054. pmid: 32822793. pmcid: pmc7434450. 7. blum a, menzies m. home dermoscopy during the covid-19 pandemic. dermatol pract concept. 2020;10(4):e2020091. doi: 10.5826/dpc.1004a91. pmid: 33150032. pmcid: pmc7588159. 8. lee kj, finnane a, soyer hp. recent trends in teledermatology and teledermoscopy. dermatol pract concept. 2018;8(3):214-223. doi: 10.5826/dpc.0803a13. pmid: 30116667. pmcid: pmc6092076. 9. du moulin mf, bullens-goessens yi, henquet cj, et al. the reliability of diagnosis using store-and-forward teledermatology. j telemed telecare. 2003;9(5):249-52. doi: 10.1258/135763303769211247. pmid: 14599326. 10. warshaw em, gravely aa, nelson db. reliability of store and forward teledermatology for skin neoplasms. j am acad dermatol. 2015;72(3):426-435. doi: 10.1016/j.jaad.2014.11.001. pmid: 25599624. 11. moreno-ramirez d, ferrandiz l, galdeano r, camacho fm. teledermatoscopy as a triage system for pigmented lesions: a pilot study. clin exp dermatol. 2006;31(1):13-18. doi: 10.1111/j.1365-2230.2005.02000.x. pmid: 16309470. 12. jones ot, jurascheck lc, van melle ma, et al. dermoscopy for melanoma detection and triage in primary care: a systematic review. bmj open. 2019;9(8):e027529. doi: 10.1136/bmjopen-2018-027529. pmid: 31434767. pmcid: pmc6707687. 13. ferrándiz l, ojeda-vila t, corrales a, et al. impact of dermoscopy on an internet-based skin cancer triage system: interim results of a randomized study. j am acad dermatol. 2017 feb;76(2):342-343. doi: 10.1016/j.jaad.2016.02.1165. pmid: 28088994. 14. lowe a, atwan a, mills c. teledermoscopy as a community based diagnostic test in the era of covid-19? clin exp dermatol. 2021;46(1):173-174. doi: 10.1111/ced.14399. pmid: 33405282. 15. coldiron bm, mellette jr jr, hruza gj, helm tn, garcia ca. addressing overdiagnosis and overtreatment in cancer. lancet oncol. 2014;15(8):e307. doi: 10.1016/s1470-2045(14)702955. pmid: 24988934. 16. winkelmann rr, farberg as, glazer am, et al. integrating skin cancer-related technologies into clinical practice. dermatol clin. 2017;35(4):565-576. doi: 10.1016/j.det.2017.06.018.. pmid: 28886814. 17. sola-ortigosa j, muñoz-santos c, masat-ticó t, isidro-ortega j, guilabert a; grup d'estudi de teledermatologia del vallès oriental. the role of teledermatology and teledermoscopy patient-performed tele-dermoscopy are both desirable for patients and effective [25-27]. for direct-to-patient tele-dermatology to become a viable paradigm, taking dermoscopic images needs to be foolproof and economical. efforts are underway to address these criteria with user-friendly, affordable dermatoscopes and smart phone attachments [7, 28]. care must be taken to ensure adequate instruction. an additional consideration is the rapid and effective classification of dermoscopic images using artificial intelligence (ai). recent reviews have highlighted dermoscopic image processing for the detection of skin lesions, most notably melanoma [29-33]. the potential for ai-assisted triage using tele-dermoscopy is profound and may allow for decreased costs and improved access to dermatologic care. however, some have noted concerns that the images used to develop or test algorithms is often not reported, and when present, may lack a diversity in patient population [33]. further research is needed to clarify these issues before ai is integrated into the clinic. there are several limitations to the present study. the number of survey and discussion participants was small, and composed of providers with various levels of dermoscopic training who were recruited from a single academic institution. additionally, the number of lesions included was small, and selection bias of representative images may limit interpretation of the results. the study also utilized images from the visn 7 tele-dermatology program, which serves a large number of fair skinned individuals. skin lesions in skin of color were underrepresented and could pose a potential pitfall for providers. future studies should explicitly test the utility of dermoscopy for triaging patients with darker skin. this dataset was also limited to dermatologists and dermatology residents, while primary care providers are increasingly engaged in the interpretation of dermoscopic images [34]. nonetheless, our pilot data suggests that dermoscopy images should be considered in future tele-dermatology care models, even after the pandemic is over. we encourage future studies to investigate the utility of dermoscopy for tele-dermatology in other populations including those with larger proportions skin of color patients. references 1. warshaw em, hillman yj, greer nl, et al. teledermatology for diagnosis and management of skin conditions: a systematic review. j am acad dermatol. 2011;64(4):759-772. doi: 10.1016/j.jaad.2010.08.026. pmid: 21036419. 2. warshaw em, lederle fa, grill jp, et al. accuracy of teledermatology for nonpigmented neoplasms. j am acad dermatol. 2009;60(4):579-588. doi: 10.1016/j.jaad.2008.11.892. pmid: 19217689. 3. warshaw em, lederle fa, grill jp, et al. accuracy of 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31106913. 30. young at, xiong m, pfau j, keiser mj, wei ml. artificial intelligence in dermatology: a primer. j invest dermatol. 2020;140(8):1504-1512. doi: 10.1016/j.jid.2020.02.026. pmid: 32229141. 31. goyal m, knackstedt t, yan s, hassanpour s. artificial intelligence-based image classification methods for diagnosis of skin cancer: challenges and opportunities. comput biol med. 2020;127:104065. doi: 10.1016/j.compbiomed.2020.104065. pmid: 33246265. pmcid: pmc8290363. 32. cui x, wei r, gong l, et al. assessing the effectiveness of artificial intelligence methods for melanoma: a retrospective review. j am acad dermatol. 2019;81(5):1176-1180. doi: 10.1016/j. jaad.2019.06.042. pmid: 31255749. 33. daneshjou r, smith mp, sun md, rotemberg v, zou j. lack of transparency and potential bias in artificial intelligence data sets and algorithms: a scoping review. jama dermatol. 2021;157(11):1362-1369. doi: 10.1001/jamadermatol.2021.3129. pmid: 34550305. 34. fee ja, mcgrady fp, rosendahl c, hart nd. training primary care physicians in dermoscopy for skin cancer detection: a scoping review. j cancer educ. 2020;35(4):643-650. doi: 10.1007/s13187-019-01647-7. pmid: 31792723. pmcid: pmc7363668. in the diagnosis of actinic keratosis and field cancerization. j invest dermatol. 2020;140(10):1976-1984.e4. doi: 10.1016/j. jid.2020.02.013. pmid: 32142799. 18. piccoli mf, amorim bd, wagner hm, nunes dh. teledermatology protocol for screening of skin cancer. an bras dermatol. 2015;90(2):202-10. doi: 10.1590/abd1806-4841.20153163. pmid: 25830990. pmcid: pmc4371669. 19. chen ya, rill j, seiverling ev. analysis of dermoscopy teaching modalities in united states dermatology residency programs. dermatol pract concept. 2017;7(3):38-43. doi: 10.5826/ dpc.070308. pmid: 29085718: pmcid: pmc5661161. 20. wang dm, petitt ce, goel ns, ash mm, mervak je. confidence and competency in the use of dermoscopy among new first-year dermatology residents: a repeated-pairs pre-/postassessment study of an online learning module. j am acad dermatol. 2021;85(6):1585-1587. doi: 10.1016/j.jaad.2020.11.028. pmid: 33248068. 21. patel p, khanna s, mclellan b, krishnamurthy k. the need for improved dermoscopy training in residency: a survey of us dermatology residents and program directors. dermatol pract concept. 2017;7(2):17-22. doi: 10.5826/dpc.0702a03. pmid: 28515987. pmcid: pmc5424656. 22. chevolet i, hoorens i, janssens a, et al. a short dermoscopy training increases diagnostic performance in both inexperienced and experienced dermatologists. australas j dermatol. 2015;56(1):52-55. doi: 10.1111/ajd.12203. pmid: 25302740. 23. oldenburg r, marsch a. optimizing teledermatology visits for dermatology resident education during the covid-19 pandemic. j am acad dermatol. 2020;82(6):e229. doi: 10.1016/j. jaad.2020.03.097. pmid: 32283238. pmcid: pmc7146655. 24. horsham c, snoswell c, vagenas d, et al. is teledermoscopy ready to replace face-to-face examinations for the early detection of skin cancer? consumer views, technology acceptance, and satisfaction with care. dermatology. 2020;236(2):90-96. doi: 10.1159/000506154. pmid: 32114570. 25. kong f, horsham c, rayner j, et al. consumer preferences for skin cancer screening using mobile teledermoscopy: a qualitative study. dermatology. 2020;236(2):97-104. doi: 10.1159/000505620. pmid: 32126557. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(3):e2021074 1 acquired white oral lesions with specific patterns: oral lichen planus and lupus erythematosus marco manfredini1, gioia pedroni1, laura bigi1, roberto apponi2, alberto murri dello diago2, annunziata dattola3, francesca farnetani1, giovanni pellacani4 1 dermatology unit, department of surgical, medical, dental & morphological sciences with interest in transplant, oncological & regenerative medicine, university of modena & reggio emilia, modena, italy 2 dental unit, department of surgical, medical, dental & morphological sciences with interest in transplant, oncological & regenerative medicine, university of modena & reggio emilia, modena, italy 3 dermatology clinic, department of systems medicine, tor vergata university, rome, italy 4 dermatology clinic, department of clinical, internal, anesthesiological and cardiovascular sciences, sapienza university of rome, rome, italy key words: oral white lesions, lichen planus, lupus erythematosus, mucoscopy citation: manfredini m, pedroni g, bigi l, apponi r, murri dello diago a, dattola a, farnetani f, pellacani g. acquired white oral lesions with specific patterns: oral lichen planus and lupus erythematosus. dermatol pract concept. 2021;11(3):e2021074. doi: https://doi. org/10.5826/dpc.1103a74 accepted: february 8, 2021 published: may 20, 2021 copyright: ©2021 manfredini et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. competing interests: the authors have no conflict of interest to declare. funding: none corresponding author: marco manfredini, md, department of surgical, medical, dental & morphological sciences with interest in transplant, oncological & regenerative medicine, dermatology unit, university of modena & reggio emilia, 41124 modena, italy. email: marco.manfredini@unimore.it background: diagnosis of oral white lesions might be challenging. these lesions represent a wide spectrum of diseases with different etiology and prognosis. oral white lesions can be categorized into two major groups, congenital and acquired, according to their development, and in four subgroups: lesions which can be scraped off or not and lesions with special pattern or not. objectives: the aim of this manuscript is to review, from diagnosis to treatment, the current knowledge on oral white lesions with specific pattern. methods: a review on oral white lesions with specific pattern was conducted on pubmed and scopus from inception to january 2021. results: among acquired lesions with specific pattern two clinical entities are mostly represented: oral lichenoid reactions and lupus erythematosus. the etiology of both diseases is still not known but their pathogenesis is mainly immunological. at present the mucoscopic features of those disease have been described only in few case reports or case series. immunomodulatory therapies are often the agents of choice for their treatment. conclusions: the collaboration of dermatologists and dentists as a team is important for early diagnoses and effective treatments. mucoscopy is a promising technique which may reveal important features for the differentiation of olp and le oral white lesions. abstract 2 review | dermatol pract concept. 2021;11(3):e2021074 introduction the diagnosis of white oral lesions can be challenging. these lesions represent a wide spectrum of diseases that vary in etiology and prognosis [1]. the diagnosis is complex because many lesions of the oral mucosa are autoimmune in nature or are the result of immunologically mediated diseases such as lichen planus (lp), bullous diseases, pemphigus vulgaris, mucous membrane pemphigoid, recurrent aphthous stomatitis, and erythema multiforme [2–5]. numerous familial tumor syndromes also have distinctive oral mucosal findings that may facilitate an early diagnosis [6]. often, the dermatologist and dentist work as a team to make early diagnoses and provide effective treatments. indeed, many of these pathologies are of concern to multiple medical disciplines [7,8]. according to a recent paper, white oral lesions can be categorized according to their nature of development into two major groups, namely congenital and acquired, and four subgroups: lesions which can be scraped off or not, and lesions with special patterns or not [1]. clinical features of white lesions, such as papular, anular, reticular or erosive-ulcerative patterns, or a combination of them can be used to differentiate white patterned lesions from non-patterned ones [1]. there are 2 types of acquired lesions with specific patterns: oral lichenoid reactions and lupus erythematosus (le). the first group includes: oral lp; oral lp-associated with underlying diseases (eg, thyroid disease, dyslipidemia, diabetes mellitus, hepatitis c virus infection); lichenoid contact reaction (lcr); drug-induced lichenoid reactions (dilr); and graft-versus-host reaction (gvhd). this article reviews current knowledge on white oral lesions with specific patterns, from diagnosis to treatment. methods bibliographic research for articles on the clinical features and treatment strategies of oral lesions of oral lp and le was conducted on pubmed and scopus databases from their inception to january 2021. we also searched for the mucoscopic pattern of oral lp and le using these search strings: (“dermoscopy” and “oral” and “white”), (“dermoscopy” and “mucosal”), (“mucoscopy” and “lichen”), (“mucoscopy” and “lupus”), (“mucoscopy” and “white”). articles reporting studies on pigmented lesions or lesions of the genital area were excluded. oral lp oral lp is the most frequent disease of the white oral lesion group [9]. it affects 1%-2% of the population. it is associated with skin lesions in 60%-70% of cases, and is the only manifestation in 15%-25% of patients. a typical manifestation of olp are multiple, symmetrical lesions that appear in kerfigure 1. oral lichen planus affecting the tongue. the lesion is characterized by the presence of evident white reticular lines (wickham striae). atotic/papular, erythematous/erosive or vesicle-bullous form [9]. generally, the lesions are predominant within the lips, in the buccal mucosa and on the dorsal tongue [9,10]. the leukokeratosis form, showing a distinctive network of white lines (wickham striae), is the most frequent, while the bullous form is rare (figure 1). the erosive form is characterized by areas, more or less extensive, of ulcerative mucosa. although the exact pathogenesis of olp is still unknown, immunological mechanisms are likely to have an important role. olp is considered a t cell mediated immune (autoimmune) disease in which cd8+t-cells trigger apoptosis of basal epithelial cells [9,11,12]. it is still debated if oral lp is associated with other systemic comorbidities such as diabetes mellitus (dm), thyroid disease and chronic liver disease, especially hcv infection. these associations have been observed in several studies, with an incidence ranging from 0.5% to 35% in oral lp patients [13–15]. olp lesions often have a persistent course and propensity for malignant transformation over time [16]. oral squamous cell carcinoma (oscc) is often characterized by an insidious onset, difficult diagnosis, fast evolution with frequent metastasis and disfiguring surgical treatments. a histopathologic analysis of the lesion obtained through scalpel or punch biopsy should be performed without delay if oscc is suspected [17–19]. to our best knowledge, only 5 case reports have been published on the mucoscopic appearance of oral lp. these reports have described oral lp as being characterized by white reticular lines over an erythematous-violaceous background with curved vessels. superficial crusting or scaling blunted papillae, tiny erosions, interspersed clods and a polymorphic vascular pattern have been reported [20,21]. review | dermatol pract concept. 2021;11(3):e2021074 3 oral lp treatment both topical and systemic corticosteroids are used to treat oral lp. fluocinonide embedded in an adhesive gel has been used with good results for both the leukokeratotic and erosive forms. the therapy lasts about 9 weeks without side effects. other topical corticosteroids used include: 0.1% triamcinolone acetonide, 0.1% fluocinolone acetonide, 0.05% fluocinolone acetonide, and 0.05% clobetasol propionate [1]. betamethasone has also been used with good results. in the most severe forms, systemic corticosteroids may be used, usually at the same dosage employed in cutaneous lp. although different dose regimens have been proposed, the minimal effective daily dose of prednisone is usually 15–20 mg for 2–6 weeks [1]. when both topical and systemic corticosteroids are not sufficient, immunomodulatory agents, such as calcineurin inhibitors (ci) may be used. cyclosporin has been prescribed both in adhesive bases and as a mouthwash, even though it is not always effective [22]. topical tacrolimus is a more potent ci which can be safely used as a valid treatment alternativo of recalcitrant and erosive olp. pimecrolimus topic cream has been also successfully prescribed for the treatment of erosive olp lesions. treatment with efalizumab, a recombinant humanized monoclonal immunoglobulin g antibody, led to the improvement of oral lesions present on buccal mucosa and tongue with an initial dose of 0.7 mg/kg, followed by a dosage of 1.0 mg/kg per week [23]. efalizumab inhibits the binding of leukocyte function antigen-1 (lfa1) to the intercellular adhesion molecules-1 (icam-1), thereby inhibiting the adhesion of leukocytes to other cell types lead to the improvement of olp via decreased activation and trafficking of t lymphocytes, which play a vital role in its pathologic development of olp. mycophenolate mofetil showed to be effective long term in severe cases of olp [24]. good results, both in erosive and in atrophic olp, are obtained with topical tretinoin 0.1%, though relapses are frequent. the same frequency of relapse occurs with isotretinoin gel; this, however, reduces the clinical manifestation and symptoms in 80% of patients. retinoids are generally less effective compared with topical corticosteroids [25]. several other drugs have been used for treatment of mucosal lp: griseofulvin, dapsone, hydroxichloroquine, thalidomide, levamisole. long-term (3 to 6 months) administration of griseofulvin was shown to result in complete improvement in 86% of patients with lp. in particular oral erosive lesions have responded favorably to this drug. a complete response of disease, including oral lesions was observed in patients treated with metronidazole, 500 mg twice daily for 20 to 60 days [26]. thalidomide in dose range of 50-150 mg daily produced a regression of olp. daily or prolonged treatment periods at higher doses (300 mg) may be required to prevent recurrences [12]. treatment with levamisole plus vit b12 resulted in clinical in oral signs and symptoms of olp. moreover, the treatment reduced high serum anti-gastric parietal cell autoantibody (gpca) level (a potential marker of olp) to undetectable level [27]. oral apremilast has been used for severe erosive olp at dosage of 30 mg twice a day; following completion of 12 weeks treatment, marked improvement was observed in buccal and gingival lesions, with a significant reduction in pain and discomfort [28]. recently, a high expression of human beta-defensin 2 (hbd-2), a potent antimicrobial peptide, has been reported in olp lesions. suggesting that it may be harnessed for therapeutic interventions in olp [29]. photodynamic therapy (pdt) has been successfully used in severe refractory cases of erosive olp [10,11]. however, a systematic review on the efficacy of photodynamic therapy (pdt) in the management of symptomatic olp reported inconsistent results. on the other hand, a randomized clinical trial indicated a better efficacy of pdt therapy compared to corticosteroids. generally, pdt treatment was able to reduce pain and burning sensation and to decrease the size of the lesions in symptomatic olp patients. several studies reported the effects of laser therapy on the erosive olp, including the use of 980-nm diode laser, carbon dioxide laser evaporation, bio stimulation with a pulse diode laser using 904-nm infrared rays, and low dose excimer 308-nm laser with ultraviolet (uv) b rays. although promising results were reported by some studies, the effectiveness of laser therapy in olp is yet to be proven [30]. among non-pharmacological strategies, the use of ozone (o3) as a complementary medical approach has increased progressively. ozone is a highly unstable atmospheric gas that rapidly decays into normal oxygen(o2). although not being a radical molecule, o3 is a very strong oxidant and, due to this highly toxic property, it has been widely used as a disinfectant and germicidal agent, also for medical purposes. in addition, ozone administration as a mixture of o2-o3 gases has proven to improve metabolic activity and to exert therapeutic effects in numerous diseases. the use of ozonized water in association with conventional topical corticosteroids application in olp resulted in a significant improvement of sign and pain [31]. lupus erythematosus lupus erythematosus (le) is an autoimmune disease that can be classified into three distinct forms: systemic lupus erythematosus (sle), subacute cutaneous lupus erythematosus (scle) and chronic cutaneous lupus erythematosus (ccle) [32,33]. skin lesions (85%) include the characteristic 4 review | dermatol pract concept. 2021;11(3):e2021074 butterfly rash (40%–50%), alopecia, photosensitivity, raynaud’s phenomenon, livedo reticularis, urticaria, erythema, telangiectasias, and cutaneous vasculitis [33–36]. sunlight often aggravates the malar rash [34,35]. the etiology remains unknown, however increased autoantibody generation with the imbalanced function of t lymphocytes have been reported. there is an extensive range of clinical symptoms for sle, characterized by a remarkable clinical heterogeneity due to synchronous and non-synchronous involvement of several organs with variable severity [34,35]. oral manifestations of le (9%–45% in sle, 3%–20% in ccle) include ulcerations, erythematous lesions, hyperkeratosis, honeycomb plaques, and discoid lesions. lesions generally affect the palate, buccal mucosa, and gingivae. sometimes, the vermilion zone of the lower lip (lupus cheilitis) is also affected [37]. ulcers are often aphthous-like with a white to yellow coating and a peripheral red rim especially in the hard palate [38]. a honeycomb plaque is a rare condition, revealed as a chronic, well-defined plaque along with white lacy hyperkeratosis and buccal erythema [38]. lesions generally affect both lining and masticatory mucosa, however they are less hyperkeratotic on the lining mucosa (eg, soft palate). discoid oral lesions appear as whitish striae generally radiating from the central erythematous area (“brush border” pattern), which makes it difficult to distinguish them from oral candidiasis or olp if there are no systemic or cutaneous findings. lupus cheilitis is an inflammatory condition of the lips presenting as a small or diffuse, erythematous and edematous lesion that might develop into crusty painful ulcers. this condition usually affects the vermilion zone of the lower lip [37–39]. oral manifestations of ccle are similar to erosive olp with an ulcerated or atrophic, erythematous central area and peripheral white, fine, radiating striae. occasionally the central region shows a fine stippling of white dots along with erythema. however, the oral features are generally accompanied with skin lesions. when ulcerative and atrophic oral lesions come in contact with acidic or salty foods, a pain similar to erosive olp, might be experienced. oral features of scle are the same as those of ccle [38]. diagnosis of sle can be difficult in the early stages because of its polymorphic clinical course usually characterized by remission and flares. american rheumatism association has defined several clinical and laboratory criteria for the diagnosis of sle [38]. occasionally, oral lesions characterized by the presence of radiating white striae resembling wickham’s striae, has been reported, therefore, biopsy is required for definite diagnosis [32,38]. to our knowledge, only 3 case series on the mucoscopic appearance of oral and lips le lesions have been reported, characterized by white halos and network-like white lines with long linear and dotted vessels over a diffuse erythematous background [20,40,41]. treatment at present, therapy is based on combinations of antimalarials (mainly hydroxichloroquine or quinacrine), considered as the backbone of le treatment, glucocorticoids, and immunosuppressive drugs [33]. effective protection from ultraviolet exposure with broad-spectrum sunscreens and smoking cessation are highly recommended. in addition, vitamin d supplementation is suggested in all patients with low vitamin d levels [35]. topical anti-inflammatory agents are the treatment of choice for oral ulcers (eg, 0.1% triamcinolone oral paste) shortening the course and severity of the oral lesions [42]. the duration of corticosteroid usage depends on the severity of the symptoms. if the oral lesions are refractory to the treatment, then more potent (eg, betamethasone or clobetasol in oral preparation) or systemic drugs may be needed. steroid-sparing agents, such as calcineurin inhibitors (eg, 0.03% or 0.1% tacrolimus) are also applicable when the side effects of corticosteroids pose some concern [42]. the alternative route of corticosteroid administration, intra-lesional injection, is rarely used due to pain. mild le cases can be successfully managed by means of nsaids along with anti-malarial agents. systemic corticosteroids in combination with other immunosuppressive agents and immunomodulators are frequently used for more severe conditions [33,38]. despite limited randomized evidence, immunosuppressive agents such as methotrexate, azathioprine, and cyclosporine are considered in sle patients who respond inadequately to antimalarials and glucocorticoids. other agents include retinoids, dapsone, mycophenolate mofetil or ec-mycophenolic acid and thalidomide [38]. among biological therapies, b-cell-targeted therapy showed the most promising results. several b cells targeting therapies including targeting of bcr signaling and b cell depletion are reported up to date [38,43]. belimumab and rituximab have shown efficacy in mucocutaneous manifestations of sle. according to the eular recommendations for the management of systemic lupus erythematosus belimumab should be considered in extrarenal disease with inadequate control to first-line treatments, and inability to taper glucocorticoid daily dose to acceptable levels [38]. rituximab (rtx) is currently only used off-label, in patients with severe renal or extrarenal (mainly haematological and neuropsychiatric) disease refractory to other immunosuppressive agents and/or belimumab, or in patients with contraindications to these drugs. other therapies involving the targeting of t cells and cytokines are still under investigation [44]. several molecules for sle treatment are currently at advanced stages of research trial (phase iii and iv studies) and may provide novel therapeutic strategies for sle: tabalumab and blisibimod that review | dermatol pract concept. 2021;11(3):e2021074 5 are binding b-cell activating factor (baff), dapirolizumab pegol, an anti-cd40l fab’ fragment, anifrolumab, a human monoclonal antibody to type i interferon receptor subunit [45], and the dual-target biological agents telitacicept, which is a novel recombinant taci-fc fusion protein able to inhibit baff and a proliferation inducing ligand (april) cytokines at the same time [43,44]. conclusions a team collaboration between dermatologists and dentists is important to allow early diagnoses and effective treatments of mucosal lesions of the oral cavity. olp and le oral lesions have been recently defined as “acquired oral white lesions with specific pattern” because they present as whitish lesions of the oral cavity, characterized by similar mucoscopic features such as the presence of white structures, network-like white lines and erosion/ulceration. both diseases can affect the lips and the buccal mucosa. olp have been frequently reported on the dorsal tongue, while le was more frequently reported on the palate. further studies are needed to better characterize and differentiate olp and le oral white lesions. references 1. mortazavi h, safi y, baharvand m, jafari s, anbari f, rahmani s. oral white lesions: an updated clinical diagnostic decision tree. dent j (basel) 2019;7(1):15. doi: 10.3390/dj7010015. pmid: 30736423. 2. giannetti l, generali l, bertoldi c. oral pemphigus. g ital dermatol venereol 2018;153:383–8. doi: 10.23736/s03920488.18.05887-xpmid: 29512980. 3. giannetti l, murri dello diago a, lo muzio l. behçet’s disease: minireview with emphasis on oral aspects. minerva stomatol 2018;67:246–9. doi: 10.23736/s0026-4970.18.04135-3. pmid: 29915169 4. ferreli c, giannetti l, robustelli test e, atzori l, rongioletti f. linear white lesion in the oral mucosa. jaad case rep 2019;5:694–6. doi: 10.1016/j.jdcr.2019.05.009. pmid: 31440559 5. giannetti l, 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10.1007/s40257-0170286-9. pmid: 28477309 43. yung s, yap dy, chan tm. a review of advances in the understanding of lupus nephritis pathogenesis as a basis for emerging therapies. f1000res 2020;9. doi: 10.12688/f1000research.22438.1. pmid: 32789005 44. yang b, zhao m, wu h, lu q. a comprehensive review of biological agents for lupus: beyond single target. front immunol 2020;11. doi: 10.3389/fimmu.2020.539797. pmid: 33123125 45. morand ef, furie r, tanaka y, bruce in, askanase ad, richez c, et al. trial of anifrolumab in active systemic lupus erythematosus. n engl j med 2020;382:211–21. doi: 10.1056/nejmoa1912196. pmid: 31851795 dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021072 1 an atypical presentation of extragenital lichen sclerosus et atrophicus sabina vaccari1, alessia barisani1, francesca pepe1, carlotta baraldi1, bianca maria piraccini1, valeria gaspari1 1 dermatology, irccs policlinico di sant’orsola, department of experimental, diagnostic and specialty medicine, alma mater studiorum università di bologna, italy key words: extragenital lichen sclerosus et atrophicus, morphea, dermoscopy, histopathology citation: vaccari s, barisani a, pepe f, baraldi c, piraccini bm, gaspari v. an atypical presentation of extragenital lichen sclerosus et atrophicus. dermatol pract concept. 2021;11(4):e2021072. doi: https://doi.org/10.5826/dpc.1104a72 accepted: january 29, 2021; published: october, 2021 copyright: ©2021 vaccari et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: francesca pepe, md, dermatology, department of experimental, diagnostic and specialty medicine, university of bologna. email: francesca1pepe@gmail.com introduction lichen sclerosus et atrophicus (lsa) is a chronic inflammatory, invalidating disorder mainly involving the anogenital skin. extragenital lesions are uncommon, occurring as multiple, oval, porcelain-white macules, or papules. when present, they are mostly observed on the superior trunk, axillae, buttocks, and extremities, following blaschko lines [1]. in the literature, there is a high prevalence of coexistence of lsa and morphea [2]. case presentation we report the case of a 70-year-old woman who presented bilateral symmetrical itchy lesions affecting the inner thighs, appearing as wrinkled, porcelain-white color plaques with cigarette-paper-like texture and measuring 4 cm × 4 cm (figure 1a). the lesions had been present for about 1 year. moreover, an involvement of the vulvar mucosa, with loss of clitoris and fusion between the labia majora and minora, was observed, as it happens in genital lichen sclerosus et atrophicus (lsa) (figure 2a). dermoscopy of cutaneous lesions revealed widespread whitish patches, comedo-like openings, and peppering patterns (figure 1b). on dermoscopy, the vulvar lesions showed patchy structureless milky-pinkish areas with scales and red purpuric blotches. the differential diagnosis of the skin patches included morphea and extragenital lsa, due to their clinical morphology and distribution and to the association with anogenital lesions [3]. a punch biopsy of cutaneous lesions showed a thick hyperkeratotic scale and an atrophic epidermis with flattening of the rete ridges. the basal layer cells showed hydropic degeneration. beneath the epidermis there was a broad area of pronounced lymphedema. within this zone, the collagenous fibers were swollen and homogenous and contained only a few nuclei. dermal melanophages, rare lymphocytes, and plasma cells were observed (figure 1c). based 2 letter | dermatol pract concept. 2021;11(4):e2021072 figure 1.(a) extragenital lichen sclerosus et atrophicus with porcelain-white color plaques. (b) dermoscopic patterns: abundant peppering over white-yellowish structureless areas (magnification x 20). (c) histological examination: thick hyperkerator scale an atrophic epidermis and a pale superficial dermal stroma with rare lymphocytes and plasma cells; melanophages displaced in upper dermis. figure 2. (a) genital lichen sclerosus et atrophicus with patches of sclerosis and purpuric lesions. (b) dermoscopic patterns: red purpuric blotches corresponding to ecchymosis in an intensely white background . letter | dermatol pract concept. 2021;11(4):e2021072 3 on the clinical and histological findings, a final diagnosis of extragenital lsa was made. a vulvar biopsy was also performed, confirming the diagnosis of genital lsa (figure 2b). conclusions extragenital lsa affects about 15-20% of patients with genital lsa. it is generally asymptomatic and usually affects neck, shoulders, and upper trunk, presenting as flat, white papules or slight atrophic white plaques. the diagnosis is mainly clinical and is confirmed by histopathology. clinically, our patient showed a specific skin lesions that made us hypothesize an inflammatory disease, such as morphea or extragenital lsa, but due to symmetrical distribution and the peculiar size, the lesions were not pathognomonic for any disease. the uncertainty in diagnosing extragenital lsa was due to the uncommon sites of the lesions, very close to anogenital lsa, rather than on the trunk or sites of pressure. on the contrary, dermoscopy added features suggesting the hypothesis of extragenital lsa, showing well-demarcated, whitish structureless areas, and comedo-like openings [4]. dermoscopy also allowed the differential diagnosis with morphea since the latter usually shows fibrotic beams and linear branching vessels on dermoscopy (5). a peculiar dermoscopic feature in our case was the peppered arrangement, which is usually observed only in vulvar lsa [6]: it is thought to be related to melanophages displaced in both the upper dermis and perifollicular site. thus, peppering may represent an additional dermoscopic clue in the differential diagnosis between morphea and extragenital lsa. further cases of extragenital lsa need to be reported and collected, to deepen the understanding of this rare disease’s dermoscopic features, confirming the presence of peppering as clue for differential diagnosis. references 1. lacarrubba f, pellacani g, verzì ae et al. extragenital lichen sclerosus: clinical, dermoscopic, confocal microscopy and histologic correlations. j am acad dermatol. 2015;72(1) supplement 1: 50-52. doi:10.1016/j.jaad.2014.07.008. pmid: 25500042. 2. kreuter a, wischnewski j, terras s et al. coexistence of lichen sclerosus and morphea: a retrospective analysis of 472 patients with localized scleroderma from a german tertiary referral center. j am acad dermatol. 2012;67(6):1157-1162. doi: 10.1016/j. jaad.2012.04.003. pmid: 22533994. 3. shim wh, jwa sw, song m et al. diagnostic usefulness of dermatoscopy in differentiating lichen sclerous et atrophicus from morphea. j am acad dermatol. 2012;66(4):690-1. doi: 10.1016/j. jaad.2011.06.042. pmid: 22421117. 4. garrido-ríos aa, álvarez-garrido h, sanz-muñoz c et al. a. dermoscopy of extragenital lichen sclerosus. arch dermatol. 2009;145(12):1468. doi: 10.1001/archdermatol.2009.261. pmid:20026867. 5. errichetti e, stinco g. dermoscopy in general dermatology: a practical overview. dermatol ther. 2016;6(4):471-507. doi: 10.1007/s13555-016-0141-6. pmid: 27613297. pmcid: pmc5120630. 6. borghi a, corazza m, minghetti s et al. dermoscopic features of vulvar lichen sclerosus in the setting of a prospective cohort of patients: new observations. dermatol. 2016;232:71-77. doi: 10.1159/000439198. pmid: 26574744. dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022017 1 dermoscopy of lupus miliaris disseminatus faciei lesions in different stages of evolution pankhuri dudani1, nikhil mehta1 1 department of dermatology and venereology, all india institute of medical sciences, delhi, india key words: dermatoscopy, lupus miliaris disseminatus faciei, telangiectasia, in-focus vessels, varioliform scar citation: dudani p, mehta n. dermoscopy of lupus miliaris disseminatus faciei lesions in different stages of evolution. dermatol pract concept. 2022;12(1):e2022017. doi: https://doi.org/10.5826/dpc.1201a17 accepted: may 26, 2021; published: january 2022 copyright: ©2022 dudani and mehta. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: nikhil mehta, md, department of dermatology and venereology. all india institute of medical sciences, delhi, india. e-mail: nikhilmehtadermatology@gmail.com introduction lupus miliaris disseminatus faciei (lmdf) is an uncommon chronic granulomatous disease of the head and neck region. its dermoscopic features have recently been described, mainly in fitzpatrick skin-types 2 and 3. its etiology is unknown, and adults between the second and fourth decades of life are affected most. case presentation a 35-year-old man, fitzpatrick skin-type 4, presented with asymptomatic yellowish-to-red-colored papules over the forehead, eyelids, nose, and ear helices; and elongated plaques over the neck, for 5 months. many lesions had healed with depressed varioliform and boxcar-like scars. dermoscopy of dome-shaped active papules showed structureless yellow-red areas, follicular plugs, and in-focus telangiectasias (figure 1, a and d). the latter were most prominent peripherally but were also seen centrally. few lesions showed a central white stellate region. early depressed scars showed in-focus marginal telangiectasias (figure 1, b and e). elongated plaques over neck showed similar features of yellow-red structureless areas and white areas suggestive of early scarring in a linear pattern, along with short linear and branching vessels arranged radially (figure 1, c and f). histopathology showed multiple perifollicular necrotizing epithelioid cell granulomas in the dermis consistent with lmdf (figure 2, a and b). conclusions lmdf presents as multiple skin-colored to erythematous fleshy papules and plaques over cheeks, periocular and perioral regions, especially over eyelids and earlobes. at neck, they present as elongated plaques. lesions resolve spontaneously in 1-2 years or faster with treatment, leaving depressed, atrophic, varioliform scars.  2 research letter | dermatol pract concept. 2022;12(1):e2022017 figure 1. (a) erythematous to skin-colored papules over upper and lower eyelid, with middle papule showing central depression. (b) multiple depressed erythematous scars over the right cheek. (c) linear erythematous elevated plaques over the right side of neck with background erythema. (d) dermoscopy of lesions circled in a, showing follicular plug (blue arrow), peripheral in-focus telangiectasias extending to the central region (dotted arrow); white central follicular scar is also seen. (e) telangiectasias are seen in all lesions corresponding to depressed scars in b, with a central white follicular scar. it is classically stellate, seen in lesion marked as an asterisk. (f) linear yellowish region (asterisk) and multiple in-focus short linear and linear branching vessels along the lesion (black arrows). research letter | dermatol pract concept. 2022;12(1):e2022017 3 histopathologically, lmdf is characterized by follicular plugs and a superficial dermal perifollicular granulomatous infiltrate with or without caseation. late lesions show extensive perifollicular fibrosis. dermoscopic features include follicular plugs, some resembling a target surrounding the center, with short linear and linear-branching vessels on an orange-yellow/ erythematous background. different stages of lesions have different dermoscopic features. with chronicity, there is an increase in follicular plugs and perifollicular scaling. the yellow perifollicular background is replaced by white structures in late lesions, corresponding to fibrosis replacing the granulomas [1]. dermoscopic findings of lmdf differ from other papular granulomatous facial disorders, such as papular sarcoidosis, granulomatous rosacea, lupus vulgaris, and figure 2. histopathological examination of facial papule showing features of lupus miliaris disseminates faciei. (a) irregular acanthosis of the epidermis and dermal perifollicular dense infiltrate with epithelioid cell granulomas (arrowhead) (h&e, ×100). (b) higher magnification; the infiltrate is composed of lymphocytes, epithelioid cells, and langhans giant cells (arrow) (h&e, ×400). post-kala-azar dermal leishmaniasis (table 1). papular sarcoidosis shows orange-yellow structureless areas and does not show follicular plugs and stellate scars. granulomatous rosacea shows vascular polygons not seen in lmdf. our case showed structureless yellow-orange regions, follicular plugs, and white structures as previously described [2]. in addition to documenting these features in elongated plaques, we were able to see in-focus telangiectasias, both in inflammatory lesions as well as in lesions evolving into depressed scars. some of these vessels were reaching the center of the lesions. earlier reports have noted unfocussed arborizing, comma-shaped and linear vessels. yellow areas and vascular changes were readily seen in our patient despite a darker skin phenotype. however, these observations are from one case and may be extrapolated if noted in more patients. table 1. dermoscopy of various papular granulomatous disorders on the face disorder dermoscopic findings sarcoidosis orange-yellow structureless areas with well-focused linear and branching vessels; white scar-like depigmented areas granulomatous rosacea linear reddish-violaceous vessels arranged in polygonal network with diffuse or localized orange areas lupus vulgaris yellowish-white globules, milia-like cysts, white structureless areas pinkish red background, with telangiectasias (linear, branching) white scales, shiny white streaks, white rosettes a bluish hue may be seen post-kala-azar dermal leishmaniasis multiple yellow tears and erythema granuloma faciale translucent white-gray background with whitish streaks and linear telangiectasia 4 research letter | dermatol pract concept. 2022;12(1):e2022017 dermoscopic features of lmdf lesions vary with time and can include in-focus telangiectasias in all stages of evolution, including early scars. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. litaiem n, chamli a, bacha t, et al. dermoscopic features of lupus miliaris disseminates faciei: distinct aspects depending on disease stage. clin case rep. 2020;8(9):1793–1796. doi: 10.1002/ ccr3.2979. pmid: 32983497. pmcid: pmc7495779. 2. chauhan p, jindal r, shirazi n. dermoscopy of lupus miliaris disseminatus faciei: a step closer to diagnosis. dermatol pract concept. 2020;10(3):e2020055. doi: 10.5826/dpc.1003a55. pmid: 32685274; pmcid: pmc7346596. dermatology: practical and conceptual dermatology practical & conceptual commentary | dermatol pract concept. 2021;11(4): e2021125 1 ring pressure sign: when long lasting dermoscopic observation leads the decision vincenzo piccolo, teresa russo, giuseppe argenziano dermatology unit, university of campania “luigi vanvitelli”, naples, italy. key words: ring pressure sign, dermoscopy, dermatoscopy, melanoma, mole check citation: piccolo v, russo t, argenziano g. ring pressure sign: when long lasting dermoscopic observation leads the decision. dermatol pract concept. 2021;11(4): e2021125. doi: https://doi.org/10.5826/dpc.1104a125 accepted: may 8, 2021; published: september 2021 copyright: ©2021 piccolo et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: vincenzo piccolo, md, dermatology unit, university of campania “luigi vanvitelli”, naples, italy. email: piccolo. vincenzo@gmail.com dermoscopy is an indispensable tool for early detection of skin cancer. beyond that, its widespread use can be attributed to the fact that dermoscopy is not time consuming. indeed, experienced dermoscopists take less than 1 second to analyze each of their patients’ lesions through a handheld dermoscope. this is possible due to prompt (‘gestalt’) cerebral recognition of the overall appearance of the lesion, as benign or suspicious, which does not require a detailed pattern analysis. the so-called “blink” approach allows for a rapid check of most lesions, although some cases require more time to be diagnosed and a “think” approach is necessary to take a decision [1,2]. indeed, there are cases in which the dermoscopist occasionally stops and takes time to examine a single lesion, sometimes requiring up to one minute of examination. in cases that require longer observation times, when using a contact dermoscope, a ring might appear around the observed lesion. this is due to the dermoscope pressure exerted on the patient’s skin (figures 1 and 2). while clear-cut benign or malignant lesions do not require long time to be detected, doubtful lesions are responsible for the appearance of the so-called “ring pressure sign”, which in most cases leads to excision. this sign is probably due to our inability to promptly categorize the lesion as benign or malignant; while not an absolute sign, it may be considered a good indicator for the dermoscopist’s suspicion. 2 commentary | dermatol pract concept. 2021;11(4): e2021125 references 1. blum a, argenziano g. metaphoric and descriptive terminology in dermoscopy: combine “blink” with “think”. dermatol pract concept. 2015;5(3):23. doi: 10.5826/dpc.0503a05. 2. russo t, piccolo v, lallas a, giacomel j, moscarella e, alfano r, argenziano g. dermoscopy of malignant skin tumours: what’s new? dermatology. 2017;233(1):64-73. doi: 10.1159/000472253.  figure 1. (a) a ring caused by pressure due to the long observation through contact dermoscopy is seen in this young female with this not clear cut malignant lesion. histology showed melanoma in situ. (b) dermoscopy showed in the context of light brown background a delicate irregular network. figure 2. (a) “ring pressure sign” determined by prolonged pressure of contact dermoscope in a 23-year-old woman, whose lesion was excised and melanoma in situ was diagnosed at histology. (b) pigmented network with sharp demarcation at periphery, that showed irregularity concerning thickness at dermoscopy. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(3): e2021029 1 serum sickness-like reaction: drug-induced cutaneous disease in a child ana carolina galvão dos santos de araujo1, liana moura de almeida1, ana paula moura de almeida1, elisa fontenelle de oliveira2, mayra carrijo rochael3, rodrigo aires de morais4, hudson dutra rezende1 1 álvaro alvim school hospital. department of dermatology. campos dos goytacazes, rio de janeiro, brazil. 2 fernandes figueira institute/fiocruz. department of pediatric dermatology. rio de janeiro, rio de janeiro, brazil. 3 fluminense federal university. department of pathology. niterói, rio de janeiro, brazil. 4 campos dos goytacazes, rio de janeiro, brazil. key words: serum sickness, drug hypersensitivity, allergic reaction, anti-bacterial agents, clavulanic acid. citation: galvão dos santos de araujo ac, moura de almeida l, moura de almeida ap, fontenelle de oliveira e, carrijo rochael m, aires de morais r, rezende hd. serum sickness-like reaction: drug-induced cutaneous disease in a child. dermatol pract concept. 2021; 11(3): e2021029. doi: https://doi.org/10.5826/dpc.1103a29 accepted: october 22, 2020; published: july 8, 2021 copyright: ©2021 galvão dos santos de araujo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication corresponding author: ana carolina galvão dos santos de araujo, álvaro alvim school hospital. dermatology department. campos dos goytacazes, rio de janeiro, brazil. email: anacarolinagsa@yahoo.com.br introduction serum sickness is defined as a type iii hypersensitivity reaction, which leads to complement activation and hypocomplementemia, small vessel vasculitis, and nephropathy. from a clinical perspective it resembles serum sickness-like reaction (sslr), presenting clinical similar findings. these are both rare diseases that can manifest with urticarial rash, fever, and arthralgia, mainly differing by their etiopathology and laboratory findings [1,2]. sslr pathogenesis remains unclear but is probably related to an inflammatory response to drug metabolites, more commonly, following beta-lactams use. it is not mediated by immunocomplexes and does not manifest hypocomplementemia [1,2] . case report an 18-month-old girl, presented with spread, non-pruritic, erythematous-edematous plaques (some violaceous) characterized by irregular borders (figure 1a). 2 days after, a violaceous inner halo appeared on the plaques and the patient developed systemic symptoms, including joint edema, arthralgia, limited mobility, irritability, hyporexia, and fever (figure 1b and 2). the patient had previously received oral amoxicillin/clavulanate and dipyrone treatment 5 days before the skin lesions appeared, due to cough and fever. oral prednisone 0,5mg/kg and hydroxyzine did not help fade the lesions and following further clinical deterioration the situation worsened until she was admitted at the intensive care unit (icu). 2 letter | dermatol pract concept. 2021; 11(3): e2021029 figure 1. (a)diffuse erythematous and violaceous, edematous plaques on trunk, axillary region, and face. (b) after 2 days, appearance internal violaceous halo. figure 2. diffuse arcuate and annular pink edematous plaques with central purple annular patches surrounding a yellowish center. on the first day of hospitalization leukocytosis was at 24.730/mm³, after 2 days it raised to 31.800/mm³; c reactive protein analysis increased from 29,9mg/dl on the first day, to 90,2 mg/dl. liver enzymes and renal function were normal. transthoracic echocardiogram did not demonstrate any abnormality. a skin biopsy was performed, and the histopathology showed normal epidermis, perivascular, periadnexal, and interstitial inflammatory infiltrate, consisting of lymphocytes, neutrophils and numerous eosinophils, in addition to edema, without vasculitis (figure 3). antibiotic treatment was suspended, antipyretic and oral corticosteroids (0,5 mg/kg/day) were maintained, in addition to venous hydration. after 3 days of hospitalization, she was discharged with significant improvement. conclusions diagnosis of sslr is clinical and can be made when annular, erythematous edematous plaques, similar to an urticarial reaction, usually turning violet, giving the lesion an ecchymotic aspect, appear combined with systemic symptoms, such as arthralgia/arthritis, lymphadenopathy, malaise, and fever, following 8 to 14 days of drug exposure. sslr diagnosis, needs however to be distinguished from other, potentially more serious conditions such as lyme disease, endocarditis, erythema figure 3. (h&e, x100) (magnification x400) normal epidermis, and perivascular, periadnexal and interstitial cell infiltrate inflammatory infiltrate, consisting of lymphocytes, neutrophils and eosinophils, in addition to edema without vasculitis. letter | dermatol pract concept. 2021; 11(3): e2021029 3 multiforme, kawasaki’s disease, and in some rare situations to neoplastic diseases. in this case, one of the first hypotheses considered before the dermatology evaluation, was meningococcemia, and the patient almost underwent a lumbar puncture. the treatment involves the discontinuation of the culprit drug and, if necessary, the use of corticosteroids, anti-inflammatory, antihistamines, or sometimes, intravenous gamma globulin administration [1,2]. early recognition of this condition leads to less family anxiety and a non-iatrogenic management, avoiding unnecessary and potentially harmful prescriptions [1,2]. references 1. barreira p, gomes e. serum sickness -like reaction associated with drugs intake in pediatric age. rev port imunoalergologia. 2013;21(4):267–74. 2. yorulmaz a, akın f, sert a, ağır ma, yılmaz r, arslan ş. demographic and clinical characteristics of patients with serum sickness-like reaction. clinical rheumatology. 2018;37(5):1389– 94. doi: 10.1007/s10067-017-3777-4. pmid: 28795234 dermatology: practical and conceptual dermatology practical & conceptual introduction nevus lipomatosus cutaneous superficialis (nlcs) is a hamartomatous condition characterized by the presence of mature lipocytes in the dermal tissue [1]. very few case reports had been published on the dermoscopic appearance of nlcs. we, herein, describe the dermoscopic appearance of nlcs in the skin of an indian man. case presentation a 32-year-old man with skin type iv presented with a 1-year history of a slowly growing painless swelling, which consisted of papules grouped into a papillomatous plaque over the left side of his lower back (figure 1). dermoscopic examination was done using a dermlite dl4 dermatoscope (×10) with polarized mode and pigment-enhancing mode. it showed a cerebriform pattern with sulci and gyri, multiple yellow-colored structureless areas, white structureless areas, meshwork-like pigmented lines, where a few lines were seen as 2 parallel lines, keratotic plugs in the sulci, and a rim research letter | dermatol pract concept. 2022;12(1):e2022001 1 dermoscopy of nevus lipomatosus cutaneous superficialis in a patient with skin type iv boina kinnera1, sreeramu suggu1, venkatachalam konakanchi1 1 department of dvl, andhra medical college, visakhapatnam, andhra pradesh, india key words: dermoscopy, nlcs, cerebriform appearance, indian skin citation: kinnera b, suggu s, konakanchi v. dermoscopy of nevus lipomatosus cutaneous superficialis in a patient with skin type iv. dermatol pract concept. 2022;12(1):e2022001. doi: https://doi.org/10.5826/dpc.1201a01 accepted: april 8, 2021; published: january, 2022 copyright: ©2022 kinnera et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr. konakanchi venkatachalam, department of dvl, andhra medical college, visakhapatnam, andhra pradesh, india. email: drkvchelam99@gmail.com figure 1. skin-colored papules forming a plaque over the left lumbar area. of white homogenous area at the periphery (figure 2a). the prominence of yellowish structures around hair follicles was not noted in this case, as has been described in literature on similar phototype. the pigment-enhancing mode on dermoscopy 2 research letter | dermatol pract concept. 2022;12(1):e2022001 figure 2. (a) dermoscopy showing yellow structureless areas (orange circle), keratotic plugs in the sulci (red square), white structureless areas (blue circle), parallel line pattern (green circle), and a peripheral white homogenous area (black arrow). (b) enhancement of structureless yellow areas on pigment-enhancing mode. showed enhancement of the yellow structureless areas (dermal lipocytes) and white structureless areas (dermal collagen) which further favors the diagnosis of nlcs (figure 2b). the cerebriform surface seen on dermoscopy represents the uneven surface formed by sulci and gyri, the yellow structureless areas represent dermal adipocytes, the presence of a regular pigment indicates the relative histological preservation of the normal rete ridges [2], and the white structureless areas represent the perifollicular fibrosis and thickened collagen in the dermis. our findings are consistent with the dermoscopic features described previously by vinay et al who described 5 features of nlcs: cerebriform appearance, web-like regular pigment network, rim showing a white veil, yellowish structureless areas, and comedo-like openings [2]. the differentials include lymphangioma circumscriptum, nevus sebaceous and neurofibromatosis. conclusions dermoscopy serves as a non-invasive tool in the diagnosis of nlcs and helps to differentiate it from other cutaneous conditions like lymphangioma circumscriptum, nevus sebaceous and neurofibromatosis. references 1. bhushan p, thatte ss, singh a. nevus lipomatosus cutaneous superficialis: a report of two cases. indian j dermatol. 2016;61(1):123. doi: 10.4103/0019-5154.174153. pmid: 26955147; pmcid: pmc4763661. 2. vinay k, sawatkar gu, saikia un, kumaran ms. dermatoscopic evaluation of three cases of nevus lipomatosus cutaneous superficialis. j dermatol venereol leprol. 2017;83(3):383-386. doi: 10.4103/ijdvl.ijdvl_677_16. pmid: 28366918. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(3):15 71 dermatology practical & conceptual www.derm101.com introduction molluscum contagiosum is a double-stranded dna virus, which is the cause of benign, infectious disease of the skin that is characterized by dome-shaped papules with a central dell or depression clinically [1]. in patients with altered or impaired immunity such as atopic dermatitis, after long term corticosteroid and immunosuppressive therapy use, sarcoidosis, leukemias, wiskott-aldrich syndrome and especially with acquired immune deficiency syndrome, atypical lesions of molluscum contagiosum may occur, often reaching a large size on an unusual site that can also mimic a wide spectrum of other conditions [2]. the presence of giant molluscum contagiosum in immunocompetent patients is rare, and in some reviews it was reported to be a clue for hiv infection in both the pediatric patient group and adult patients [3]. this rare infection must be kept in mind in patients who have solitary pink nodular lesions for a short time, especially on face and anogenital region. case report a 27-year-old male was admitted to our outpatient clinic with a 4-month history of a 1.5 cm in diameter, asymptomatic, pink nodular lesion on left temporal region (figure 1). he had no systemic disease or drug use history. in dermatoisolated giant molluscum contagiosum mimicking epidermoid cyst tugba k. uzuncakmak1, burce c. kuru1, ebru i. zemheri2, ilkin zindanci1, zafer turkoglu1, mukaddes kavala1 1 department of dermatology, istanbul medeniyet university school of medicine, goztepe research and training hospital, instanbul, turkey 2 department of pathology, istanbul medeniyet university school of medicine, goztepe research and training hospital, istanbul, turkey key words: dermoscopy, epidermoid cyst, molluscum contagiosum citation: uzuncakmak tk, kuru bc, zemheri ei, zindanci i, turkoglu z, kavala m. isolated giant molluscum contagiosum mimicking epidermoid cyst. dermatol pract concept 2016;6(3):15. doi: 10.5826/dpc.0603a15 received: june 15, 2016; accepted: june 18, 2016; published: july 31, 2016 copyright: ©2016 uzuncakmak et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: tugba kevser uzuncakmak, md, istanbul medeniyet university, goztepe research and training hospital, dermatology, istanbul, turkey. tel. 0 +90(530) 6640226. email: drtugbakevser@gmail.com molluscum contagiosum is a benign cutaneous viral infection which is caused by doublestranded dna poxvirus. it affects mainly children and young adults and usually presents with single or multiple umblicated papules or nodules on face, arms, legs and anogenital regions. it may present in atypical size and clinical appearance in patients with altered or impaired immunity and rarely in immuncompetent patients. herein we present an immuncompetent young adult patient with isolated giant molluscum contagiosum, which was mimicking epidermoid cyst clinically. abstract mailto:drtugbakevser@gmail.com 72 observation | dermatol pract concept 2016;6(3):15 a disease of childhood, rarely it can be seen in adults. due to the characteristic appearance of the lesions, diagnosis is generally made without laboratory testing. specific treatments or therapies are usually not administered for molluscum contagiosum infection in immunocompetent individuals, as lesions will resolve within time. dermoscopic examination may be helpful in atypical cases. dermoscopy of mc reveals a central pore or umbilication in association with polylobular white to yellowish amorphous structures, which are surrounded by linear, fine, corona-like telangiectasias [5,6] this apperance may change in atypical cases, especially in atypical localizations. histopathologic examination is mandatory in these cases. giant mc is a rare nodular variant of molluscum contagiosum, which is 0.5-1 cm or more in diameter. this clinical presentation may mimic basal cell carcinoma, furuncle, intradermal nevus, amelanotic melanoma, kerathoacanthoma and viral warts [2,3]. these lesions are rare in healthy children or adults and may accompany altered immunity, such as atopic dermatitis, corticosteroid and immunosuppressive therapy, sarcoidosis, leukemias, wiskott-aldrich syndrome and acquired immune deficiency syndrome. atypical lesions of molluscum contagiosum may occur often and reach large size with extensive distribution on unusual body parts [3,4,7]. in our patient there was no systemic disease, drug usage, immundeficiency or atopic dermatitis history. there are only a few case reports of giant molluscum contagiosum occurring in immunocompetent patients in the literature [2,7]. most of these patients are children without immunodeficiency. there are also only a few case reports of molluscum contagiosum on the scalp in immunocompetent patients—one newborn and one elderly patient. our patient was a young immunocompetent adult patient. cryotherapy, 10% koh application, trichloroacetic acid, imiqumod, systemic cimetidin, intralesional 5-fu and bleomlogical examination a white material output was detected. dermoscopic examination revealed white-yellow structureless area in the center of the of lesion and increased linear vascularity on the periphery (figure 2). excisional biopsy was offered with preliminary diagnosis of epidermoid cyst and isolated giant molluscum. histopathologically epidermal hyperkeratosis, acanthosis, widespread viral cytopathic effect and intracytoplasmic inclusion bodies were seen (figure 3). he was diagnosed with isolated giant molluscum with his clinical and histopathological findings. his laboratory tests for immunsuppresssion, including complete blood counting, immunoglobulins and hiv serology were totally normal. no recurrence was detected on the 6-month control visit. discussion molluscum contagiosum (mc) is a common infectious disease of the skin characterized by pearly dome-shaped papules with a central dell or depression located on the face, arms, legs and anogenital region, caused by the molluscum contagiosum virus [1]. the virus replicates in the epidermis and enters the skin from a small skin defect leading to impaired skin barrier function or from contaminated items, such as towels or clothes. specific lesions of mc are usually smaller than 5 mm and less than 20 in number [1-4]. although it is known to be figure 1. a 1.5 cm diameter, asymptomatic, pink tumoral lesion on left temporal region. [copyright: ©2016 uzuncakmak et al.] figure 2. white-yellow structureless area in the center of the lesion and increased linear vascularity on the periphery. [copyright: ©2016 uzuncakmak et al.] figure 3. epidermal hyperkeratosis, acanthosis, widespread viral cytopathic appearance and intracytoplasmic inclusion bodies. [copyright: ©2016 uzuncakmak et al.] observation | dermatol pract concept 2016;6(3):15 73 3. leung akc, davies hd. molluscum contagiosum—an overview. current pediatric reviews 2012;8:346-49. doi: 10.2174/ 157339612803307732 4. zalaudek i, giacomel j, cabo h, et al. entodermoscopy: a new tool for diagnosing skin infections and infestations. dermatology. 2008;216(1):14-23. pmid: 18032894. doi: 10.1159/000109353. 5. mun jh, ko hc, kim bs, kim mb. dermoscopy of giant molluscum contagiosum. j am acad dermatol. 2013 dec;69(6):e287-8. pmid: 24238183. doi: 10.1016/j.jaad.2013.04.065. 6. basu s, kumar a. giant molluscum contagiosum—a clue to the diagnosis of human immunodeficiency virus infection. j epidemiol glob health 2013;3:289–91. pmid: 24206800. doi: 10.1016/j. jegh.2013.06.002. 7. matsuda, ld bloch m. arnone m. vasconcelos dde m, nico mm. giant molluscum contagiosum: does it affect truly immunocompetent individuals? acta derm venereol 2005;85(1):88–9. pmid: 15849008. doi: 10.1080/00015550410023536. ycin and total excision are the main treatment options [1,2]. we chose total excision surgery in our patient to exclude epidermoid cyst histologically. we present this case to present giant molluscum in differential diagnosis of soft, slowly growing tumoral lesions with atypical presentation. references 1. pérez-díaz ce, botero-garcía ca, rodríguez mc, et al. giant molluscum contagiosum in an hiv positive patient. int j infect dis 2015 sep;38:153-5. pmid: 26255893. doi: 10.1016/j. ijid.2015.07.021. 2. karadag as, karadag r, bilgili sg, calka o, demircans yt. giant molluscum contagiosum in an immunocompetent child. j pak med assoc 2013;63:778-9. pmid: 23901686. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021; 11(4): e2021116 1 potential utility of oral mucosal capillaroscopy as an indicator of microvascular damage in behçet disease: a preliminary study abdullah demirbaş1, ömer faruk elmas2, gözde ulutaş demirbaş3, mustafa atasoy4, ümit türsen5, torello lotti6 1 department of dermatology, kütahya health sciences university 2 department of dermatology, kırıkkale university kırıkkale, turkey 3 department of dermatology, evliya çelebi training and research hospital, kütahya, turkey 4 health science university, kayseri city hospital, department of dermatology, kayseri, turkey 5 mersin university, department of dermatology, mersin, turkey 6 department of dermatology,guglielmo marconi university, rome, italy key words: behçet disease, capillary, handheld dermoscopy, mucoscopy, microvascular damage, oral labial mucosa citation: demirbaş a, elmas öf, demirbaş gu, atasoy m, türsen ü, lotti t. potential utility of oral mucosal capillaroscopy as an indicator of microvascular damage in beçhet disease: a preliminary study. dermatol pract concept. 2021; 11(4): e2021116. doi: https://doi.org/10.5826/dpc.1104a116 accepted: march 28, 2020; published: september 2021 copyright: ©2021 demirbaş et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: ad: literature searching, designing and writing the manuscript; ad, öfe, gud: substantial contributions to conception and design, interpretation of data; ad, öfe, ma, üt, tl: editing, revising and final approval of the manuscript. corresponding author: ömer faruk elmas, associate professor, department of dermatology, kırıkkale university kırıkkale, turkey. email: omerfarukmd@gmail.com introduction: behçet disease (bd) is an auto-inflammatory condition characterized by multisystemic vasculitis. oral mucosal capillaroscopy is an easy-to-use, repeatable, non-invasive method for evaluating mucosal microvasculature, contributing to the differential diagnosis and prognosis of various acute and chronic inflammatory diseases. objectives: this study aims to characterize and describe the oral labial mucosal capillary findings in patients with bd using handheld dermatoscopy and to investigate the relationship between the capillary findings and the severity of the disease. methods: this cross-sectional study included patients with bd and healthy subjects. capillaroscopic examination of the oral labial mucosa in each subject was performed by a handheld dermatoscope using polarized light. the clinical severity of bd was evaluated using krause’s clinical severity scoring for bd. results: sixty patients with bd and 60 healthy subjects were enrolled in the study. the frequencies of irregular capillaries, microhemorrhages, glomerular vessels, megacapillaries, and tortuous vessels abstract 2 research | dermatol pract concept. 2021; 11(4): e2021116 introduction capillaroscopy is a non-invasive diagnostic technique used to image the peripheral circulation in autoimmune diseases and acute and chronic inflammatory diseases. capillaroscopic examinations aim to investigate microvascular damage, which is directly related to many clinical findings both during diagnosis and follow-up [1-3]. oral mucosa capillaroscopy is an easyto-use, repeatable, non-invasive, and well-tolerated method that evaluates the mucosal microvasculature and contributes to the differential diagnosis and prognosis of various autoimmune disorders. the visualization and evaluation of the microvascular bed are simpler to perform at the level of the oral mucosa than on cutaneous surfaces, because of the absence of stratum corneum in some parts of the oral mucosa [4-8]. behçet disease (bd) is a systemic auto-inflammatory disease characterized by 4 main features; recurrent oral aphthous ulcers, genital ulcers, ocular involvement, and skin lesions. the underlying etiopathogenesis of the disease has not been fully elucidated yet. it is believed that the disease may be triggered by some external factors in individuals with a genetic predisposition and thus, it may cause an autoimmune response by activating the immune system. this results in multisystemic vasculitis, which is considered the key pathogenetic factor in bd. bd may involve any kind and size of arterial and venous vessels, therefore it may present with various clinical pictures. for instance, larger vascular involvements are considered as a a poor prognostic indicator. therefore, early diagnosis of microvascular damage is important to prevent these silent and potentially fatal vascular complications and to prepare an appropriate treatment plan [9-16]. this study aims to describe the oral labial mucosal capillary findings in patients with bd, using dermoscopy, and to investigate the relationship of capillary findings with the duration and severity of the disease. materials and methods subjects this research was designed as a single center, cross-sectional study. the study included patients with behcet disease and age-gender matched healthy volunteers. sixty bd patients and 60 control patients admitted to our outpatient clinic between june 1, 2020, and september 1, 2020, were included in the study (all subjects were caucasian). the parameters considered for each patient included disease duration (years), history of medication, oral ulcers, genital ulcers, erythema nodosum, superficial thrombophlebitis, acneiform eruption, arthralgia, arthritis, deep vein thrombosis, arterial involvement, ocular involvement, neurological involvement, gastrointestinal involvement, genitourinary involvement, large vessel involvement, pathergy positivity, clinical severity score, and hla-b51 status. disease severity assessment the severity of the disease was evaluated using krause’s clinical severity scoring for bd (the total score is obtained by giving one point for each mild symptoms such as oral aphthae, genital ulcer, arthralgia, erythema nodosum, papulopustular lesions, folliculitis; two points for the moderate symptoms such as arthritis, deep-vein thrombosis, anterior uveitis; and 3 points for each severe symptom such as posterior uveitis/panuveitis, retinal vasculitis, arterial thrombosis, neuro-behcet, and bowel perforation). based on the total score, the patients were sub-classified into 3 groups as mild (<4), moderate (4-6), and severe (≥7) [17]. inclusion and exclusion criteria all patients with bd met the criteria of the international behçet disease study group [18]. during the examination process, all subjects had intact oral mucosa. exclusion criteria were as follows; oral mucosal pathologies (candidiasis, lichen planus, glossitis, periodontitis, etc.), patients under 18 years of age, smoking, the use of medications that may disrupt the microvascular structure (antidiabetics, antihypertensives, antilipidemics and thyroid medicines), pregnancy, breastfeeding, and systemic disorders such as systemic vasculitis, scleroderma, sle, dermatomyositis, sjögren syndrome, antiphospholipid syndrome, mixed connective tissue disease, diabetes mellitus, hyperthyroidism, hypothyroidism, hypertension, and cardiovascular diseases. were statistically significantly higher in the patient group when compared to the healthy individuals. in addition, a correlation was detected between the oral mucosal capillaroscopic findings and disease duration, severity, and vascular complications. conclusions: our study is the first to explore the potential role of oral mucosal capillaroscopic examination in patients with bd. data obtained from this study indicated that oral mucosal capillaroscopy may be a useful tool to demonstrate microvascular damage in patients with bd. research | dermatol pract concept. 2021; 11(4): e2021116 3 oral mucosa capillaroscopy labial mucosal capillaroscopic examination was performed by 10-times hand-held dermatoscope using polarized light (dermlite dl4, 3gen inc, ca, usa). capillaroscopic images were acquired using a high-resolution cell phone attached with a 2 × optical zoom (iphone 11, apple inc, ca, usa). a total of 20 times magnification was achieved. contact dermoscopic examination without fluid was performed with the same light source, at the same room temperature (24 ° c), by the same operator in the morning. to standardize measurements and avoid artifacts, each subject was seated while examination was ongoing and each area was examined twice. the examined area was the lower lip mucosa for each patient. the capillary morphology was defined using internationally accepted dermoscopic terminology [19]. the images obtained were evaluated by a capillaroscopic examination specialist. statistical analysis descriptive statistics of the obtained data were calculated as mean ± standard deviation (sd), quartiles (25th, median, and 75th), number and percentage frequencies depending on the type of features. compliance of numerical properties to normal distribution was examined by the kolmogorov-smirnov test. independent samples t test was used to compare the patient and control groups in terms of age, and the pearson chi-square test was used in terms of oral capillaroscopic findings. also, the relationships between patient characteristics and oral capillaroscopic findings were evaluated using pearson’s chi-square test. statistical significance level was accepted as p <0.05 and spss (ver. 23, spss inc, chicago, il, usa) program was used in calculations. ethics approval all the procedures followed the helsinki declaration, and the study was approved by an institutional review board (decision date and number:2020/025). written informed consent was obtained from all participants. results demographic and clinical features a total of 60 patients with bd (27 females, 33 males) and 60 (28 females, 32 males) age and gender-matched healthy controls were included in the study. the mean age of patients and controls was 34.97±9.02 and 34.75±6.41, respectively (p = 0.880). the mean disease duration was 8.608 ± 7.5504 years. the mean clinical severity score was 5.73 ± 2.577. according to the clinical scores, 9 (15%) patients were considered to have mild disease, 33 (55%) moderate disease, and 18 (30%) severe disease. all patients were on at least 1 systemic treatment for bd. the most common treatment used was colchicine monotherapy (n=37,61.7%) followed by azathioprine monotherapy (n=9, 15%). the most common combined regimen was composed of colchicine and azathioprine (n=7, 11.67%). combinations of colchicine and corticosteroid (n=5, 8.3%), and azathioprine and corticosteroid (n=2, 3.33%) were the other regimens used (table 1). the most common clinical manifestation of bd was recurrent oral aphthae (n=60,100%), followed by recurrent genital table 1. demographic, clinical, and treatment characteristics of behçet disease group and control group behçet patients (n=60) controls (n=60) p-value gender, n (%) male female 33 (%55) 27 (%45) 32 (%53.3) 28 (%46.7) 0.855 age, mean±sd 34.97±9.02 34.75 ±6.41 0.880 disease duration (years), mean±sd 8.608 ± 7.5504 clinical severity score, mean±sd 5.73 ± 2.577 disease activity, n (%) mild moderate severe 9 (%15) 33 (%55) 18 (%30) medications, n (%) azathioprine azathioprine + corticosteroid colchicine colchicine + azathioprine colchicine + corticosteroid 9 (%15) 2 (%3.33) 37 (%61.7) 7 (%11.67) 5 (%8.33) sd= standard deviation 4 research | dermatol pract concept. 2021; 11(4): e2021116 ulcer in (n=48, 80%), erythema nodosum (n=23, 8.3%), superficial thrombophlebitis (n=5, 8.3%), acneiform eruption (n=48, 80%), ocular involvement (n=22, 36.7%), arthralgia (n=46, 76.7%), arthritis (n=16, 26.7%), pathergy positivity (n=21, 35%), deep vein thrombosis (n=6, 10%), large vessel involvement (n=5, 8.3%), genitourinary involvement (n=3, 5%), arterial involvement (n=2, 3.3%), neurological involvement (n=1, 1.7%), and gastrointestinal involvement (n=1, 1.7%). eleven patients (18.3%) showed hla b51 positivity (table 2). capillaroscopic features the frequency of irregular capillaries (figure 1, a and b), microhemorrhage (figure 2a), glomerular vessels (figure 2b), megacapillaries (figure 3a), and tortuous vessels (figure 3b) were statistically significantly higher in patients with bd when compared to the healthy subjects (p < 0.001, p = 0.049, p < 0.001, p <0.001, p< 0.001 respectively). there was no statistically significant difference between the two groups in terms of dotted vessels (figure 4a), purple area (figure 4b), white dots (figure 4c) and hyperkeratosis (figure 4d) (p = 0.584, p= 0.465, p = 0.609, p = 0.591, respectively) (table 3). statistically significant correlations were found between erythema nodosum, superficial thrombophlebitis, hlab51 and microhemorrhage, glomerular vessels, and megacapillaries (p < 0.05). there were also statistically significant correlations between irregular capillaries and erythema nodosum and acneiform rash (p < 0.05). the presence of irregular capillaries, microhemorrhages, glomerular vessels, megacapillaries, deep vein thrombosis and major vascular involvement showed statistically significant correlations (p < 0.05). no statistically significant correlation was detected between dotted vessels, purple area, white dots, hyperkeratosis, and mucocutaneous, systemic and vascular manifestations of bd (p < 0.05) (tables 4 and 5). the clinical severity score and disease duration were found to be significantly higher in patients with irregular capillaries, microhemorrhage, glomerular vessels, megacapillaries, and tortuous vessels (p < 0.05) (table 6). discussion and conclusions this preliminary study highlights the potential utility of oral capillaroscopy in detecting microvascular findings in patients with bd. bd is a chronic, systemic vasculitis that may involve any kind and size of vessels, and is characterized by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and ocular inflammation. although the underlying etiopathogenetic mechanisms of the disease have not been fully elucidated, it is suggested that an abnormal immune response occurs in individuals with genetic predisposition due to the antigenic effect of environmental factors, particularly infectious agents. this abnormal immune response causes endothelial dysfunction and vascular damage, which is thought to be associated table 2. clinical symptoms of behçet disease group symptoms n (%) mouth ulceration genital ulceration erythema nodosum acneiform rash superficial thrombophlebitis deep-vein thrombosis arthralgia arthritis eye involvement neurological involvement gastrointestinal involvement genitourinary system major vessel involvement arterial involvement positive pathergy test positivity of hla b51 60 (%100) 48 (%80) 23 (%38.3) 48 (%80) 5 (%8.3) 6 (%10) 46 (%76.7) 16 (%26.7) 22 (%36.7) 1 (%1.7) 1 (%1.7) 3 (%5) 5(%8.3) 2 (%3.3) 21 (%35) 11 (%18.3) figure 1. (a) regular capillaries. (b) irregular capillaries. research | dermatol pract concept. 2021; 11(4): e2021116 5 figure 2. (a) microhemorrhage (black arrows). (b) glomerular vessel (black arrow). figure 3. (a) megacapillar (black arrow). (b) tortuous vessels (circled area). figure 4. (a) dotted vessels (circled area). (b) purple areas (black arrow). (c) white dots (black arrows). (d) hyperkeratosis (black arrows). 6 research | dermatol pract concept. 2021; 11(4): e2021116 table 3. distribution of the oral mucosa capillaroscopy findings of behçet disease group and control group capillaroscopic findings behçet patients (n=60) n (%) control group (n=60) n (%) p-value capillary regularity regular irregular 36 (%60) 24 (%40) 60 (%100) 0 (%0) <0.001 dot vessels 32 (%53.3) 29 (%48.3) 0.584 microhemorrhage 14 (%23.3) 6 (%10) 0.049 glomerular vessels 22 (%36.7) 0 (%0) <0.001 megacapillary 23 (% 38.3) 4 (%6.7) <0.001 tortuous vessels 54 (%90) 4 (%6.7) <0.001 purple areas 28 (%46.7) 32 (%53.3) 0.465 white dots 10 (%16.7) 8 (%13.3) 0.609 hyperkeratosis 7 (%11.7) 9 (%15) 0.591 p < 0.05 is defined statistically significant and shown in bold. table 4. comparison of the relationship between mucocutaneous symptoms and oral mucosa capillaroscopic findings in behçet patients symptoms capillary regularity microhemorrhage glomerular vessels megacapillary tortuous vessels irregular capillary (n=24) regular capillary (n=36) + (n=14) (n=46) + (n=22) (n=38) + (n=23) (n=37) + (n=54) (n=6) genital ulceration + p 20 28 4 8 (p=0.598) 12 36 2 10 (p=0.542) 19 29 3 9 (p=0.348) 19 29 4 8 (p=0.690) 44 4 10 2 (p=0.389) erythema nodosum + p 16 7 8 29 (p< 0.001) 10 13 4 33 (p=0.004) 13 10 9 28 (p=0.012) 16 7 7 30 (p=0.001) 22 1 32 5 (p=0.250) acneiform rash + p 23 25 1 11 (p=0.012) 13 35 1 11 (p=0.170) 21 27 1 11 (p=0.023) 22 26 1 11 (p=0.017) 44 4 10 2 (p=0.389) superficial + thrombophlebitis p 3 2 21 34 (p=0.340) 3 2 11 44 (p=0.043) 4 1 18 37 (p=0.036) 4 1 19 36 (p=0.045) 5 0 49 6 (p=0.436) pathergy test + p 11 10 13 26 (p=0.151) 7 14 7 32 (p=0.179) 9 12 13 26 (p=0.465) 10 11 13 26 (p=0.278) 21 0 33 6 (p=0.050) hla b51 + p 7 4 17 32 (p=0.077) 5 6 9 40 (p=0.050) 6 5 16 33 (p=0.173) 7 4 16 33 (p=0.050) 10 1 44 5 (p=0.911) + = present, = absent p < 0.05 is defined statistically signifcant and shown in bold. with potentially life-threatening complications for bd. in this context, early diagnosis of microangiopathic damage becomes important to prevent such vascular complications and to set an appropriate treatment plan [9-16]. capillaroscopy is a non-invasive diagnostic technique that allows the imaging of the peripheral vascular structures and is used to determine microangiopathic damage at the early stages. devices such as video-capillaroscopy and dermoscopy are used for capillaroscopic examination. the video-capillaroscope is the most sophisticated device and provides a detailed examination. however, since it is an expensive device, it is not available in many centers. today, there are studies conducted using hand-held dermatoscopes or computed dermatoscopes. these studies reported positive results, further supporting the importance of capillaroscopy examination via dermatoscopy. studies comparing video-capillaroscope and dermoscopy, show that dermoscopy is as effective as video-capillaroscope [20-23]. research | dermatol pract concept. 2021; 11(4): e2021116 7 table 5. comparison of the relationship between systemic and vascular clinical findings and oral mucosa capillaroscopic findings in behçet patients symptoms capillary regularity microhemorrhage glomerular vessels megacapillary tortuous vessels irregular capillary (n=24) regular capillary (n=36) + (n=14) (n=46) + (n=22) (n=38) + (n=23) (n=37) + (n=54) (n=6) deep-vein + thrombosis p 6 0 18 36 (p=0.002) 5 1 9 45 (p=0.001) 6 0 16 38 (p=0.001) 6 0 17 37 (p=0.001) 6 0 48 6 (p=0.389) arthralgia + p 22 24 2 12 (p=0.025) 12 34 2 12 (p=0.361) 19 27 3 11 (p=0.177) 21 25 2 12 (p=0.035) 44 2 10 4 (p=0.008) arthritis + p 9 7 15 29 (p=0.121) 7 9 7 37 (p=0.024) 9 7 13 31 (p=0.050) 10 6 13 31 (p=0.020) 16 0 38 6 (p=0.119) eye involvement + p 10 12 14 24 (p=0.512) 8 14 6 32 (p=0.069) 12 10 10 28 (p=0.029) 10 12 13 25 (p=0.388) 22 0 32 6 (p=0.049) neurological + involvement p 1 0 23 36 (p=0.217) 1 0 13 46 (p=0.068) 1 0 21 38 (p=0.185) 1 0 22 37 (p=0.201) 1 0 53 6 (p=0.737) gastrointestinal + involvement p 1 0 23 36 (p=0.217) 1 0 13 46 (p=0.578) 1 0 21 38 (p=0.185) 1 0 22 37 (p=0.201) 1 0 53 6 (p=0.737) genitourinary + system p 2 1 22 35 (p=0.333) 3 0 11 46 (p=0.001) 3 0 19 38 (p=0.020) 3 0 20 37 (p=0.024) 3 0 51 6 (p=0.554) major vessel + involvement p 5 0 19 36 (p=0.004) 4 1 10 45 (p=0.002) 5 1 17 37 (p=0.002) 5 1 18 36 (p=0.003) 5 0 49 6 (p=0.436) arterial + involvement p 2 0 22 36 (p=0.078) 2 0 12 46 (p=0.009) 2 0 20 38 (p=0.050) 2 0 21 37 (p=0.068) 2 0 52 6 (p=0.632) + = present, = absent p < 0.05 is defined statistically signifcant and shown in bold, standard deviation for a long time, proximal nail fold was the preferred location for capillaroscopic examination [1,2,24,25]. however, recent studies demonstrate that capillaroscopy of oral microcirculation is well-tolerated, easy, fast, and provides excellent visibility of microcirculation. the absence of stratum corneum in some parts of oral mucosa allows more clear visualization of the microvascular bed. therefore, oral mucosa capillaroscopy has been the subject of many studies investigating acute and chronic systemic inflammatory diseases. in these studies, vascular visibility in the labial mucosa was suggested to be the best location of the oral region [4-8]. examination of the microvasculature with proximal nailfold capillaroscopy has been shown to be effective in determining early morphological markers of microvascular damage that are useful in the early diagnosis of systemic rheumatic diseases [26,27]. the formation mechanism of capillary morphological changes, which are common in connective tissue diseases, has been defined in conducted studies. megacapillaries develop as an abnormal angiogenic response to peripheral ischemia and are accepted as the first sign of microvascular damage. besides, capillary microhemorrhage indicating ischemia-reperfusion injury has been described. tortuous vessels have been reported to occur secondary to hypoxic status in patients with advanced vascular damage [26-28]. some studies suggested that proximal nailfold capillaroscopy is also effective in determining the degree of vascular damage in bd [29-31]. in bd, the most important factor causing changes in capillary morphology is shown to be endothelial dysfunction. it was stated that patients with longer disease duration and higher severity should have more severe damage to the capillaries. however, in the proximal nailfold capillaroscopy study, correlations between disease duration and microhemorrhage and megacapillary features were found to be weak. besides, no significant relationship between capillary morphological changes and disease activity and severity was shown [32]. 8 research | dermatol pract concept. 2021; 11(4): e2021116 table 6. comparison of the relationship between disease duration and clinical severity score and oral mucosa capillaroscopic findings in patients with behçet disease capillaroscopic findings (n) disease duration mean±sd clinical severity score mean±sd capillary regularity regular (36) irregular (24) p 7.4 ± 6.7 10.4 ± 8.5 (p=0.104) 5±1 8 ± 3 (p=0.001) dot vessels + (32) (28) p 10.1 ± 8.5 6.9 ± 6 (p=0.174) 7± 3 5±1 (p=0.005) microhemorrhage + (14) (46) p 14.4 ± 9.1 6.9 ± 6.1 (p=0.001) 9±3 5± 1 (p=0.001) glomerular vessels + (22) (38) p 12.6 ± 8.2 6.3 ± 6.1 (p=0.001) 8± 3 4±1 (p=0.001) megacapillary + (23) (37) p 11.7 ± 8.5 6.7 ± 6.3 (p=0.007) 8±3 4± 1 (p=0.001) tortuous vessels + (54) (6) p 9.1 ± 7.7 4 ± 4 (p=0.048) 6± 3 3±0 (p=0.001) purple areas + (28) (32) p 8.3 ± 7.6 8.9 ± 7.6 (p=0.651) 6±2 5±3 (p=0.003) white dots + (10) (50) p 8.6 ± 7.6 8.6 ± 7.6 (p=0.874) 6 ± 3 6± 2 (p=0.521) hyperkeratosis + (7) (53) p 9.1 ± 8.6 8.5 ± 7.5 (p=0.822) 6± 4 6 ± 2 (p=0.752) +=present, = absent, p < 0.05 is defined statistically signifcant and shown in bold. sd= standard deviation. in our study, we detected significant relationships between disease duration, severity, and oral mucosa capillaroscopic findings such as irregular capillaries, microhemorrhage, glomerular vessels, megacapillary, and tortuous vessels. in 2 different oral mucosa capillaroscopy studies conducted by scardina et al, they found that patients with rheumatoid arthritis had less calibered and elongated vessels compared to the healthy controls and that microvascular changes were correlated with disease activity [33,34]. another study showed that patients with systemic sclerosis had fewer, large-diameter, and curled capillaries compared to controls and that microvascular changes were correlated with disease activity. based on these findings, it has been suggested that capillary changes due to systemic sclerosis are not only limited to the nailfold but also occur in the oral mucosal microcirculation [35]. in a study conducted on patients with diabetic foot, a reduction in capillary density and length; and an enhancement in capillary curling were observed. the authors emphasized that oral mucosa capillaroscopy has an important diagnostic role in the early detection of microangiopathic damage [36]. scardina et al, showed that patients with burning mouth syndrome had increased capillary diameter compared to the healthy controls. the etiopathogenesis of burning mouth syndrome is not clear but vascular involvement is thought to play a role [37]. in a study conducted on 25 patients with head and neck tumors to evaluate the effect of cytotoxic chemotherapy on oral mucosal microvascularity; a significant change in the labial capillary vessels was reported [38]. in a study investigating the long-term effects of smoking on oral mucosa capillaries; capillary changes have been shown to persist for a long time even if the individual quits smoking [39]. another study showed that microvascular disorders including hemorrhagic dots, matchstick hairpin vessels, and microaneurysm are more frequent in smokers compared to non-smokers [40]. our study is not devoid of limitations. the small sample size of patients and controls at a single clinic may not reflect research | dermatol pract concept. 2021; 11(4): e2021116 9 the general population. the cross-sectional design of the study does not allow to know whether oral mucosa capillary findings are associated with the long-term complications. therefore, long-term prospective studies with larger sample size are needed. in addition, it is hard to be sure that the findings we observed are not directly associated with the drugs used by the examined patients, as all enrolled patients were undergoing at least 1 systemic medication. another limitation of our study is the lack of a group of patients with the conditions to cause capillary morphological findings, such as diabetes, hypertension, and smoking habits. hence, it is not possible to determine how specific our findings were for bd in real terms. finally, morphometric measurements of the detected capillary structures could not be made due to the use of handheld dermoscopy. to sum up, our study is the first to explore the potential role of oral mucosal capillaroscopic examination in patients with bd. we found a statistically significant difference in the presence of irregular capillaries, microhemorrhages, glomerular vessels, megacapillaries, and tortuous vessels in patients with bd compared to healthy subjects. we also observed a significant relationship between these capillaroscopic findings and vascular complications, disease duration, and clinical severity score. larger and prospective studies are needed to determine whether oral mucosal microvascular changes can be used as an early predictor of serious bd complications. references 1. smith v, herrick al, ingegnoli f, et al. eular study group on microcirculation in rheumatic diseases and the scleroderma clinical trials consortium group on capillaroscopy. standardization of nailfold capillaroscopy for the assessment of patients with raynaud’s phenomenon and systemic sclerosis. autoimmun reviews. 2020;19(3):102458. doi: 10.1016/j.autrev.2020.102458. 2. ocampo-garza ss, villarreal-alarcón ma, villarreal-treviño av, ocampo-candiani j. capillaroscopy: a valuable diagnostic tool. actas dermosifiliográficas. 2019;110(5):347-352. english, spanish. doi: 10.1016/j.ad.2018.10.018. 3. elmas öf, okçu m, demirbaş a, akdeniz n. handheld dermatoscopy as an easy-to-use capillaroscopic instrument in rheumatoid arthritis: a cross-sectional study. turkish journal of medical sciences. 2020;50(6):1540-1545. doi: 10.3906/sag-2006-6. 4. scardina ga, ruggieri a, messina p. oral microcirculation observed in vivo by videocapillaroscopy: a review. journal of oral science. 2009;51(1):1-10. doi: 10.2334/josnusd.51.1. 5. scardina ga, messina p. study of the microcirculation of oral mucosa in healthy subjects. italian journal of anatomy and embryolog. 2003;108(1):39-48. pmid: 12737514. 6. scardina ga, cacioppo a, messina p. anatomical evaluation of oral microcirculation: capillary characteristics associated with sex or age group. annals of anatomy. 2009;191(4):371-8. doi: 10.1016/j.aanat.2009.04.004. 7. bellavia f, cacioppo a, lupaşcu ca, et al. a non-parametric segmentation methodology for oral videocapillaroscopic images. computer methods and programs in biomedicine. 2014;114(3):240-6. doi: 10.1016/j.cmpb.2014.02.009. 8. scardina ga, carini f, messina p. l’esame capillaroscopico orale: nuova metodica diagnostica [oral capillaroscopy: a new diagnostic method]. reumatismo. 2005;57(4):295-304. italian. doi: 10.4081/reumatismo.2005.295. 9. alpsoy e. behçet’s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. the journal of dermatology. 2016;43(6):620-32. doi: 10.1111/1346-8138.13381. 10. greco a, de virgilio a, ralli m, et al. behçet’s disease: new insights into pathophysiology, clinical features and treatment options. autoimmun reviews. 2018;17(6):567-575. doi: 10.1016/j. autrev.2017.12.006. 11. demirbaş a, kaya i̇slamoğlu zg. can decreased monocyte to hdl-cholesterol ratio be a marker indicating the anti-inflammatory effect of the colchicine in behçet’s disease? a preliminary study. dermatol therapy. 2020;33(6):e14013. doi: 10.1111/ dth.14013. 12. türsen u. pathophysiology of the behçet’s disease. patholo gy r e s e a r ch i n t e r n a t i o n a l . 2 0 1 2 ; 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21:1093-1108. doi: 10.1016/j.berh.2007.10.001 28. hasegawa m. dermoscopy findings of nail fold capillaries in connective tissue diseases. the journal of dermatology. 2011 jan;38(1):66-70. doi: 10.1111/j.1346-8138.2010.01092.x. 29. pasqui al, pastorelli m, puccetti l, et al. microvascular assessment in behçet disease: videocapillaroscopic study. international journal of tissue reactions. 2003;25(3):105-15. doi: 10.1002/ bapi.200300570. pmid: 14756192. 30. wechsler b, le th, mouthon jm, cabane j, godeau p. periungual capillaroscopic aspects in behçet’s disease. apropos of 30 cases. annales de dermatologie et de vénéréologie. 1984;111(6-7):54350. french. pmid: 6497248. 31. movasat a, shahram f, carreira pe, et al. nailfold capillaroscopy in behçet’s disease, analysis of 128 patients. clinical rheumatology. 2009;28(5):603-5. doi: 10.1007/s10067-009-1106-2. 32. tabanlioglu onan d, i̇ncel uysal p, hayran y, et al. dermatoscopic assessment of nailfold capillary abnormalities in behçet’s disease and correlation of the findings with disease activity and severity. dermatologica sinica. 2019; 37:40-45. doi: 10.4103/ ds.ds_10_18. 33. scardina ga, messina p. microvascular periodontal alterations: a possible relationship between periodontitis and rheumatoid arthritis. clin hemorheol microcirc. 2007;37(3):229-35. pmid: 17726252. 34. scardina ga, messina p. microvascular abnormalities in patients with rheumatoid arthritis. annals of anatomy. 2006;188(5):4259. doi: 10.1016/j.aanat.2006.04.004. 35. scardina ga, pizzigatti me, messina p. periodontal microcirculatory abnormalities in patients with systemic sclerosis. journal of periodontology. 2005;76(11):1991-5. doi: 10.1902/ jop.2005.76.11.1991. 36. scardina ga, guercio g, valenti cf, tegolo d, messina p . videocapillaroscopy of the oral mucosa in patients with diabetic foot: possible diagnostic role of microangiopathic damage? journal of clinical medicine. 2020;9(11):3641. doi: 10.3390/ jcm9113641. 37. scardina ga, pisano t, carini f, valenza v, messina p. burning mouth syndrome: an evaluation of in vivo microcirculation. journal of the american dental association. 2008;139(7):940-6. doi: 10.14219/jada.archive.2008.0281. 38. scardina ga, cacioppo a, messina p. changes of oral microcirculation in chemotherapy patients: a possible correlation with mucositis? clinical anatomy. 2014;27(3):417-22. doi: 10.1002/ ca.22300. 39. scardina ga, messina m, melilli d, et al. permanence of modifications in oral microcirculation in ex-smokers. medical science monitor. 2019;25:866-871. doi: 10.12659/msm.912279. 40. ayhan e, an i̇, öztürk m, araç e. the effect of smoking on oral labial mucosa: a controlled dermoscopic study. turkish journal of dermatology. 2020; 14:14-17. doi: 10.4103/tjd.tjd_41_19. dermatology practical & conceptual www.derm101.com observation | dermatol pract concept 2012;2(4):8 35 from the lives of lesions “the idea evolved that lesions have lives, just as human beings have; that lesions look very different at different times in their lives just as human beings do; and that stages in the lives of lesions can be described and depicted roughly as early, fully developed, and late, just as human beings can be described and depicted as infantile, mature, and old.” a. bernard ackerman, m.d. from the lives of lesions, page vi (ardor scribendi, ltd, 1983) introduction a dermatopathologist can only make a specific diagnosis based on the presence of defined histologic criteria. most cases encountered in routine practice show enough criteria on standard examination to reach an unequivocal diagnosis. sometimes further steps must be taken, such as cutting deeper levels or using special stains, to clarify uncertainties. occasionally the final histologic diagnosis must remain uncertain or borderline. this most frequently occurs in the assessment of melanocytic lesions. there is no single diagnostic criterion for the histologic diagnosis of melanoma. “criteria are evaluated differently by different observers. they are derived from typical, not difficult cases, and are seldom tested. in sum, none of the criteria useful for the diagnosis of melanoma are specific and diagnostic . . .” [1]. a series of architectural and cytological criteria are listed (table 1) [2] and these criteria would apply to the majority of melanomas encountered in routine dermatopathology practice, but the quantity or quality required to make a diagnosis are not defined. it is accepted that melanomas, as with all malignant tumours, evolve over time and the rate of growth has been measured in one study [3]. currently, few very small melanomas are diagnosed [4,5]. the increased use of dermatoscopy and digital monitoring should lead to embryology of a melanoma? a case report with speculation based on dermatoscopic and histologic evidence cliff rosendahl mbbs1, alan cameron mbbs1, agata bulinska m.d.1, david harding-smith mbbs2, david weedon, m.d.3 1 school of medicine, the university of queensland, brisbane, australia 2 central medical bundaberg, bundaberg, australia 3 sullivan nicolaides pathology, brisbane, australia key words: melanoma, nevus, small melanoma, histologic criteria, dermatoscopy citation: rosendahl c, cameron a, bulinska a, harding-smith d, weedon d. embryology of a melanoma? a case report with speculation based on dermatoscopic and histologic evidence. dermatol pract conc. 2012;2(4):08. http://dx.doi.org/10.5826/dpc.0204a08. received: may 9, 2012; accepted: july 31, 2012; published: october 31, 2012 copyright: ©2012 rosendahl et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: cliff rosendahl, po box 734, capalaba, queensland, australia 4157. tel. +61.7.3245.3011; fax. +61.7.3245.3022. email: cliffrosendahl@bigpond.com. 36 observation | dermatol pract concept 2012;2(4):8 more small melanomas being encountered [6]. what is not known is how commonly these very small melanomas, at the ‘infantile’ stage of ackerman’s analogy, lack sufficient criteria to make the diagnosis of melanoma. it seems reasonable to speculate that such lesions exist. this leads us to pose the question, “can melanomas be diagnosed earlier by adding information from history and dermatoscopy to the findings at histopathology?” and we present the case that led us to consider these matters. case report a 51-year-old man with a history of five previously treated melanomas was referred for a skin examination. two lesions were identified as clinically and dermatoscopically suspicious for melanoma and were excised. they were both subsequently signed out as melanomas, one (on the back) invasive and one (on the calf) in-situ. as he was rising from the operating table the patient indicated a 2 mm pigmented lesion on his face (figure 1). he stated that he had been thinking about the doctor’s earlier question about whether he had noticed any new or changing skin lesions and he stated that he had only been aware of this lesion for two weeks. he was quite certain about this and stated that this was because of his heightened awareness of his risk for melanoma based on his past history. dermatoscopic assessment (figure 2) revealed a brown structureless lesion with several discrete gray circles, some complete and some incomplete (asymmetrically pigmented). gray structures, and more specifically gray circles, have been described as a clue to melanoma [7,8] correlating with extension of melanin-containing melanoma cells down hair follicles, and asymmetrically pigmented follicular openings are described as a clue to lentigo maligna [9]. furthermore it has been recommended that the presence of any dermatoscopic gray structures on the face should lead to a biopsy [6]. table 1. histologic criteria for the diagnosis of malignant melanoma (after ackerman) (table 32.4, weedon’s skin pathology [2].) architectural criteria asymmetry poor circumscription consumption of the epidermis epidermal nests of melanocytes showing: • confluence • variability in size and shape • haphazard interval and array solitary epidermal melanocytes showing: • predominance over nests • pagetoid spread • haphazard arrangement dermal nests showing: • variability in size and shape • confluence • lack of maturation in depth • variability in melanin distribution melanocytes within lymphovascular spaces cytological criteria nuclear pleomorphism nucleolar variability mitosis: • even deep • sometimes atypical apoptosis increased figure 1. clinical and close-up image of a (reportedly new) 2 mm pigmented skin lesion on the face of a 51-year-old man. [copyright: ©2012 rosendahl et al.] a b observation | dermatol pract concept 2012;2(4):8 37 dermatoscopic clues that support the diagnosis of melanoma should be communicated to the reporting pathologist, prompting a more careful evaluation of histologic features in very small melanocytic lesions. furthermore, using the analogy of ackerman, we suggest that in order not to misdiagnose ‘infantile’ melanomas, the diagnosis of melanoma should be entertained at a lower threshold in very small lesions, when borderline criteria are supported by clinical and dermatoscopic clues. an excision biopsy was performed and histologic examination (figures 3-5) revealed a melanocytic proliferation including areas with a lentiginous array of single melanocytes as well as some nesting at the tips of rete ridges, with some melanocytes, although small, exhibiting pleomorphic and hyperchromatic nuclei. there was a very focally confluent proliferation of single melanocytes extending down two follicles. the reporting pathologist (author dw) was unable to make a diagnosis of melanoma based on currently accepted criteria. this was not based on the absence of any criteria for melanoma but rather on an insufficient degree of cytological and architectural atypia. the pathologist did agree that there were certain apparent inconsistencies with the alternative diagnosis of nevus: a new (macular) junctional nevus is uncommon on the central part of the face at mature age. (personal observation by author dw.) although it is seen occasionally, extension down a follicle is uncommon in a non-congenital-type nevus. (personal observation by author dw.) however a diagnosis of “atypical nevus” was issued and this was confirmed by another senior pathologist at the same institution. conclusion we believe that the diagnosis of melanoma at an early stage is desirable. with this in mind we argue that clinical and figure 2. a dermatoscopic image reveals the presence of gray circles (three of which are indicated by arrows). [copyright: ©2012 rosendahl et al.] figure 3. low power view of the pigmented skin lesion illustrated above showing a melanocytic proliferation with some lentiginous array of single melanocytes as well as nesting. on the left a lentiginous array of single melanocytes extending down a hair follicle is clearly seen. [copyright: ©2012 rosendahl et al.] figure 4. higher power view showing nesting of (small) melanocytes with pleomorphic hyperchromatic nuclei and apparent partial thickness pagetoid spread. [copyright: ©2012 rosendahl et al.] figure 5. higher power view of focally confluent lentiginous single melanocytes extending into the superficial part of a follicle. [copyright: ©2012 rosendahl et al.] 38 observation | dermatol pract concept 2012;2(4):8 6. rosendahl c, cameron a, bulinska a, williamson r, kittler h. dermatoscopy of a minute melanoma. australas j dermatol. 2011;52(1):76–8. 7. rosendahl c, tschandl p, cameron a, kittler h. diagnostic accuracy of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. j am acad dermatol. 2011;64(6):1068–73. 8. rosendahl c, cameron a, tschandl p, williamson r, kittler h. the cause of dermatoscopic grey circles in non-invasive melanomas: an hypothesis supported by histopathological correlation. poster presented at the 2nd congress of the international dermoscopy society, 2009, november 12th -14th, barcelona, spain. www.greycircles.blogspot.com accessed 28/9/2010 at 12:00 gmt. 9.  schiffner r, schiffner-rohe j, vogt t, et al. improvement of early  recognition of lentigo maligna using dermatoscopy. j am acad dermatol. 2000;42(1 pt 1):25-32. references 1. massi g, leboit pe. histological diagnosis of nevi and melanoma. darmstadt, germany: steinkopff verlag, 2004. 2. weedon d. weedon’s skin pathology. 3rd ed. london, england: churchill livingstone elsevier, 2010. 3. beer j, xu l, tschandl p, kittler h. growth rate of melanoma in vivo and correlation with dermatoscopic and dermatopathologic findings. dermatol pract conc. 2011;1(1):13. http://dx.doi. org/10.5826/dpc.0101a13. 4. abbasi nr, shaw hm, rigel ds, et al. early diagnosis of cutaneous melanoma: revisiting the abcd criteria. jama. 2004;292(22):2771-6. 5. teng pp, hofmann-wellenhof r, campbell tm, soyer hp. dermoscopic presentation of a 2-mm melanoma in situ. australas j dermatol. 2010;51(2):152-3. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022027 1 bullous erythema nodosum leprosum through the dermoscope deepak vashisht1, shekhar neema1, durga madhab tripathy1, prashant sengupta2 1 department of dermatology, armed forces medical college, pune, india 2 department of pathology, armed forces medical college, pune, india key words: bullous enl, dermoscopy citation: vashsisht d, neema s, tripathy dm, sengupta p. bullous erythema nodosum leprosum through the dermoscope. dermatol pract concept. 2022;12(1):e2022027. doi: https://doi.org/10.5826/dpc.1201a27 accepted: june 29, 2021; published: january 2022 copyright: ©2022 vashisht d et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: durga madhab tripathy, senior resident, department of dermatology, armed forces medical college, pune, india. e-mail: dmt5861@gmail.com introduction erythema nodosum leprosum (enl) forms a part of type 2 leprosy reaction characterized by crops of tender evanescent erythematous nodules that appear on extensors accompanied by systemic symptoms like fever and arthritis. bullous enl is a rare variant of the type 2 reaction characterized by multiple vesicles and flaccid bullae at sites of classic enl with severe systemic symptoms. other atypical variants include necrotic, hemorrhagic, purpuric, sweet syndrome-like and erythema multiforme-like enl. nowadays, dermoscopy is routinely employed in the diagnosis of leprosy, and it shows features akin to granulomatous dermatoses, explicitly, yellow-orange background reminiscent of underlying granulomas and few specific features. specific features in the tuberculoid pole include loss of appendages and in the lepromatous pole xerosis, scaling, and hypopigmentation. leprosy reactions are characterized by vascular changes in the form of arborizing blood vessels in enl and diffuse erythema in type 1 reaction [1]. we report dermoscopic findings of bullous enl lesions in a patient, findings that revealed both typical and atypical features. case presentation a 37-year-old male, with a known case of hansen disease (borderline lepromatous leprosy) and on multidrug therapy consisting of rifampicin 600 mg monthly, dapsone 100 mg and clofazimine 50 mg daily for 1 year, presented with multiple red raised, painful, erythematous nodules distributed symmetrically over the face, back, and upper limbs. vesicles and bullae containing clear fluid were superimposed on most lesions (figure 1, a and b). there was associated redness of the eyes, a high-grade fever, and joint pains. mucosal surfaces, palms and soles were not involved, and nikolsky sign was negative. tzanck smear showed neutrophils, and acantholytic cells were absent. a slit-skin smear test for acid-fast bacilli (mycobacterium leprae) from 8 different sites, including 2 research letter | dermatol pract concept. 2022;12(1):e2022027 lesions, showed an average bacteriological index of 4+. histopathology of the involved skin showed an intraepidermal separation, spongiosis, and neutrophilic infiltrate. multiple ill-formed granulomas comprising of epithelioid cells, lymphocytes, and foamy histiocytes were noted surrounding the dermal nerves and appendages (figure 2, a and b). dermoscopy was performed using handheld dermlite dl4 dermatoscope, and images were captured with a samsung phone. it showed a homogeneous white-pink area with an irregular border and surrounding erythema, similar to findings mentioned in the literature [2]. a closer view showed a few atypical and novel features in the form of a crumpled fabric appearance of white-pink areas and brown-gray dots and globules at the periphery (figure 3, a and b). the patient was managed as a type 2 leprosy reaction (bullous enl) with prednisolone 40 mg/day and thalidomide 100 mg 4 times a day. he responded to treatment and is currently on tapering doses of steroids and thalidomide conclusions leprosy has always eluded dermatologists with its varied presentations, and bullous enl is an excellent example. with the growing popularity of dermoscopy in the diagnosis of figure 1. (a) two ruptured bullae containing clear fluid located on both the forearms. (b) solitary larger ruptured bullae over the right pinna. figure 2. histopathologic examination. (a) an intraepidermal split with spongiosis and neutrophils (×40) (black arrow). (b) multiple ill-formed granulomas comprised of epithelioid cells and lymphocytes, and foamy histiocytes were noted surrounding the dermal nerves and appendages. research letter | dermatol pract concept. 2022;12(1):e2022027 3 figure 3. dermoscopy. (a) a homogeneous white-pink area with irregular borders (blue arrow) and surrounding erythema (black arrow). (b) a closer view showed a few atypical and novel features in the form of a crumpled fabric appearance of white-pink areas (blue arrow) and brown-gray dots and globules at the periphery (black arrow and circles). leprosy, we tried to analyze dermoscopic findings of bullous enl lesions. the novelty of this case lies in intriguing clinical aspects and newer perspectives through the dermoscope. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. vinay k, kamat d, chatterjee d, narang t, dogra s. dermatoscopy in leprosy and its correlation with clinical spectrum and histopathology: a prospective observational study. j eur acad dermatol venereol. 2019;33(10):1947-1951. doi: 10.1111/ jdv.15635. pmid: 31004456. 2. chopra a, mitra d, agarwal r, saraswat n, talukdar k, solanki a. correlation of dermoscopic and histopathologic patterns in leprosy a pilot study. indian dermatol online j. 2019;10(6):663-668. doi: 10.4103/idoj.idoj_297_18. pmid: 31807445. pmcid: pmc6859759. melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. thanks to dermatology practical & conceptual review | dermatol pract concept. 2021: 11(s1): e2021161s 1 epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek dermatology clinic of trieste, maggiore hospital, piazza ospitale 1, trieste, italy key words: melanoma, epidemiology, risk factors, nevi citation: conforti c, zalaudek i. epidemiology and risk factors of melanoma: a review. dermatol pract concept. 2021: 11(s1): e2021161s. doi: https://doi.org/10.5826/dpc.11s1a161s accepted: april 28, 2021; published: july 2021 copyright: ©2021 conforti and zalaudek. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflict of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: iris zalaudek. dermatology clinic of trieste, maggiore hospital, piazza ospitale 1, trieste, italy. email: iris.zalaudek@gmail.com we are currently witnessing a worldwide increase in the incidence of melanoma. incidence in europe is about 25 cases per 100,000 population, while in australia it reaches a rate of 60 new cases per 100,000. while the epidemiological curves of the 1980’s and 1990’s suggested an increase in the incidence of melanoma across all age groups, the last 10 years’ data indicates a 5% reduction in the incidence of thin melanoma in young individuals aged between 15 and 24. this suggests a positive impact of primary prevention campaigns [1-2]. the risk factors associated with melanoma are different and multifactorial: on one hand there is a genetic predisposition, as evidenced by the increased risk in patients with dysplastic nevus syndrome, with familial melanoma or familial melanoma syndromes; on the other hand, the unprotected interaction between uv rays and phototypes i-ii increases the risk of developing melanoma, especially in case of sunburns in pediatric age. this review aims to summarize melanoma epidemiology and risk factors. abstract this article is part of the dpc journal special issue melanoma today guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. 2 review | dermatol pract concept. 2021: 11(s1): e2021161s introduction melanoma incidence is increasing in white skin populations, especially where fair-skinned individuals are subject to excessive sun exposure, as attested by incidence and prevalence data of skin cancers in australia [3]. in europe, the incidence rate is about <25 new cases of melanoma per 100,000 population; in the united states (us), 30 per 100,000; and in australia, where the incidence rate is extremely high, it reaches 60 cases per 100,000. in recent years, there has been a dramatic increase in incidence in people over 60 years of age and in general in all age groups. incidence curves suggest that the incidence will continue to increase in the coming years [4]. the most common phenotypic risk factor is sunburn-prone skin, whereas melanocortin-1 receptor (mc1r) gene variants are the most important underlying genetic determinants studied in the last decade. individuals with a high number of common nevi and those with large congenital, multiple, and/ or atypical nevi are at higher risk, and this phenotype is also genetically determined [5]. melanoma is more likely to be diagnosed in these groups of patients, which is why they need thorough follow-up and clinical monitoring. the genetic component is part of the increased risk although it is not the main factor. the most important exogenous factor of melanoma is uv exposure, particularly intermittent sun exposure [6]. epidemiology and risk factors of melanoma incidence trends cutaneous melanoma (cm) is by far the most common subtype of melanoma, accounting for more than 90% of melanoma cases [3]. since the second world war, the incidence of cm has increased while australian and north american data showed a stabilization of cm rates [7]. in these countries, primary and secondary prevention campaigns have increased allowing to limit the damage mediated by uv rays. this has been obtained by increasing information diffusion on the importance of sun protection, by implementing diagnostic systems, such as dermoscopy, allowing for early suspicious diagnosis. queensland (australia) epidemiological trends during the last 10 years, show a 5% decrease of thin melanoma incidence in young individuals between 15 and 24 years, suggesting that primary prevention efforts are being carried out successfully [7-8]. on the other hand, a significant reduction in mortality in all age groups has not yet been observed [8]. melanoma is reported as the 19th most common cancer worldwide, with estimated age-adjusted incidence rates of 2.8-3.1 per 100,000 [9]. the analysis of cm trends in europe between 1995 and 2012, shows an incidence rate ranging from 5.6/100,000 inhabitants in spain to 24/100,000 in switzerland where there is the highest number of diagnosed in situ melanomas [7]. the median age at diagnosis is 61 years for men, 56 for women. in situ melanomas constituted 25% of diagnosed melanomas, while superficial spreading melanoma (ssm) was the most frequent variant constituting 46% of diagnoses. as regards lesions’ distribution, this varied between men and women: in men the most frequent site was the trunk (43%), in women the legs (57%) [7]. otherwise, australia and the us have higher incidence rates compared to europe. the reason for this marked incidence variation is unclear and could be associated with cultural and wealth differences influencing the sun exposure time. another reason could be due to the fact that many european countries do not have a cancer registry, or this is not rigorously updated [6]. the incidence of melanoma is increasing at a greater rate than other types of cancer. the mean age at diagnosis is 57 years with higher incidence in women in the younger age groups while the ratio reverses in old age with higher incidence in men. estimates from the us report a lifetime risk of melanoma of 1 in 56 for women and 1 in 37 for men. in general, mortality rates are higher among men than women [5,6], possibly due to the later presentation of the disease. risk factors: photo-type, nevus count, ultraviolet rays several risk factors thought to be significant in the development of cutaneous melanoma have been identified by epidemiologic studies. these can be divided into environmental factors and genetic factors, but there is clearly an interaction between genetics and environment. pigmentation has an indisputable and significant influence on skin susceptibility to malignant change. melanocortin 1 receptor (mc1r) is a cell surface receptor in melanocytes that induces pigment production. there are many polymorphisms of mc1r gene, which determine the different skin phenotypes; variants such as red hair and fair skin phenotype express low pigmentation, resulting in increased sensitivity to ultraviolet (uv) light and an increased risk of associated melanoma. in addition to characterizing the phototype, melanin, is involved in defending melanocytes and keratinocytes from uv light; this explains why phototypes i and ii are at higher risk of developing melanocytic and keratinocytic cancers, being more susceptible to uv damage. a high number of acquired melanocytic nevi, the red hair phenotype and mc1r r alleles all independently increase melanoma risk. this is supported by a study carried out in queensland, australia, reporting that individuals with ≥ 20 nevi (≥ 5 mm diameter) and mc1r r/r genotype have a 25-fold increased review | dermatol pract concept. 2021: 11(s1): e2021161s 3 melanoma risk, compared to people with 0 to 4 nevi and the mc1r wt/wt genotype; while individuals with ≥ 20 nevi and the mc1r r/r genotype have an absolute melanoma risk to age 75 of 23,3% for men and 19, 3% for women [10]. several studies have shown that the main factors associated with the development of melanoma are the number of melanocytic nevi, family history of melanoma, and genetic susceptibility. melanoma in most cases arises on healthy skin, although 25% of melanomas are associated with a preexisting nevus and this justifies the double incidence of nevus associated melanoma in young adults and elderly. in addition, the number of moles is associated with the risk of developing melanoma especially in cases of more than 100 moles or moles with dysplastic appearance [11]. most cutaneous melanomas arise on skin sporadically (rather than chronically) exposed to the sun, in sites and individuals who are more prone to sunburn. the highest rates are seen in individuals with repeated intense sun exposure. this theory is further strengthened by the observation that patients with melanoma who actively reduce their sun exposure after initial diagnosis are consequently at reduced risk of developing a second primary melanoma [8]. in contrast, individuals with dark skin, or skin that darkens easily in response to sunlight but does not burn, have demonstrably lower rates of melanoma [12-13]. however, sun exposure is not directly related to melanoma development, as evidenced by the fact that melanoma can also occur in sites that are not chronically exposed to the sun. the age at which sun exposure and/or sunburn occurs also appears to be important. a systematic review [14] strongly associated intermittent sun exposure in childhood or adolescence with an increased risk of melanoma. specifically, individuals who experienced more than 5 episodes of severe sunburn had a 2-fold increased risk of melanoma [15]. one of the most important modifiable risk factors in the etiopathogenesis of melanoma is certainly uv-b exposure [16]. personal history of sunburn in childhood is associated with a higher risk, intermittent exposure is associated with melanoma, and chronic exposure is associated with actinic keratosis and keratinocyte cancers. although the melanoma-effects of uv-b exposure are well evidenced, uv-a exposure does not come without risks [17]. artificial uv exposure may play a role in the development of melanoma; in fact, the amount of uv-a exposure in a typical tanning bed session is significantly higher than exposure during normal outdoor activities or even during sunbathing sunbeds emit uv-a radiation and a meta-analysis of studies [18] that explored the incidence of melanoma following sunbed use reported a 75% increased risk in individuals under 35 years of age with a history of sunbed use. because of the increased risk of melanoma in tanning bed users, their use has been banned in many states [19]. instead, smoking, a common carcinogen, has not been independently associated with melanoma [20]. finally, there is an interesting association between melanoma and comorbidities. for instance, immunosuppressed individuals, who underwent organ transplantation, are at demonstrable risk for melanoma, including recurrence in individuals with primary melanomas resected before transplantation, although the greatest risk for these patients is to develop keratinocyte cancers. in fact, the pooled relative risk (prr) for melanoma, among liver and heart transplant patients was 5.27 (95% ci 4.50-6.62), higher than the prr in kidney transplant patients 2.54 (95% ci 2.18-2.96). according to recent data, transplant recipients are at more than double the risk of developing melanoma overall when compared to the general population [21]. in addition, patients who present other skin malignancies (basal cell or squamous cell carcinomas or mycosis fungoides) are at higher risk of developing melanoma and subsequent death from the disease [22,23]. genetic factors a family history of melanoma is a strong risk factor for the disease. considering that familial clustering of a disease is an indicator of possible heritable causes, there has been an explosion of research in the past 2 decades directed at elucidating the genetic basis of melanoma [24]. this explains why it is important to also consider the individual genetics when determining personal risk. genetic factors such as skin phenotype, clearly influence risk, as well as familiarity that counts for 5-10% of melanomas origin [25]. some of these occur in specific syndromes-such as atypical familial multiple moles and melanoma syndrome (fammm) or dysplastic nevus syndrome (dns)-where individuals have multiple, phenotypically variable moles at high risk for malignant transformation, thus presenting an almost guaranteed lifetime risk of melanoma. many individuals do not meet the diagnostic criteria for these syndromes, but still have numerous nevi, often due to cumulative sun exposure [25]. observational studies suggest a strong association between a high number of nevi and melanoma [26]. a personal history of cutaneous melanoma is also a known risk factor for additional primary melanomas [27]. all of these criteria are of great clinical value because patients with so many nevi, with familiarity for melanoma, and with dysplastic nevus syndrome are monitored nowadays with digital videodermatoscopy by performing quarterly or semiannual total body dermatoscopic examination. to assess individual risk and to carry out successfully prevention interventions risk prediction models have been developed in recent years. clinicians and patients have now 4 review | dermatol pract concept. 2021: 11(s1): e2021161s access to a series of online calculators assisting in prevention stages, early detection, and optimum treatment of melanoma, ultimately saving lives [28]. there are several variables considered in these scores, the most common being the presence of moles, freckle density, history of sunburns, and hair color [29]. mucosal melanoma mucosal melanoma is the least common of the 3 melanoma subtypes, accounting for less than 1.5% of all melanomas [30]. the incidence of mucosal melanoma varies with both gender and age [30], the median age at diagnosis is 70, except for oral cavity melanomas which tend to occur in younger patients. incidence increases with age, over 65% of cases are in fact diagnosed in patients over 60. the incidence in women is almost twice as high as in men, possibly because of the higher rates of genital tract melanomas [31] amongst women. the absolute incidence of mucosal melanoma in white populations is higher (2:1) than in non-whites [30-33]. mucosal melanomas occur most often in the head and neck region, the female genital tract, and the anorectal region [30]. no clear risk factors for mucosal melanoma are known. because mucous membranes are not exposed to the sun, uv radiation is not considered an important etiologic factor. the role of viruses-such as human papillomavirus (hpv) or human herpes virus (hhv) implicated in other malignancies of the oral cavity-has not been demonstrated [32] while smoking has been reported to be associated with a higher prevalence of oral pigmented lesions [34]. conclusion worldwide data indicates an increase in the incidence of melanoma, although primary and secondary prevention campaigns have led to a 5% reduction in the incidence of thin melanoma in individuals between 15-24 years of age, suggesting the effectiveness of preventive measures [1-2]. while it is possible to intervene with early diagnosis, there are non-modifiable risk factors that must be evaluated for each patient. among these, photo type, number of nevi, familiarity for melanoma are independent variables associated to melanoma. it is therefore necessary to intervene on the removal of known risk factors such as avoiding sunburn, avoiding the use of tanning lamps, and exposing to the sun without using sunscreen. a recent study showed that broad-spectrum sunscreens that prevent erythema are unlikely to compromise vitamin d status in healthy populations. this explains the futility of avoiding sunscreen to produce vitamin d, a theory often expressed by patients who fear the side effects of sunscreen. based on these data, a daily broad-spectrum sunscreen with high uv-a protection does not compromise vitamin d status in healthy people and should always be used, regardless of the season [35]. on the other hand, it is necessary to implement screening campaigns even in younger age groups and carry out informative campaigns to stress the importance of an annual dermatological checkup. moreover, to improve secondary prevention it is essential to disclose easy rules, such as the abcde rule (asymmetry, irregular borders, uneven color, size greater than 6 mm, and history of evolution) or the ugly duckling (a mole different from the others) that are still effective today for the early diagnosis of melanoma. the development of new technologies, such as dermoscopy, videodermoscopy and confocal microscopy, have also increased the diagnostic capacity in small melanocytic lesions [36, 37]. this fact allows earlier diagnoses, but it increases the diagnostic capacity and therefore the incidence of the disease. from 1975 to 2015, the incidence of melanoma increased approximately 6-fold in the us. the cause of this increase, according to some authors, is not due to uv-induced sun damage or to personal risk factors but to an increased clinical and histological ability to diagnose melanoma [38,39]. in fact, according to some studies, although the incidence of melanoma has increased in most continents, mortality has remained stable. a recent work points out that the cause of the increase in diagnosis and therefore incidence of melanoma is due to a medical-legal problem, ie, more dermatologists perform biopsy analysis on suspicious lesions and more pathologists tend to diagnose melanoma, even when they are faced with ‘’gray spaces’’ as in the case of dysplastic nevi [38]. according to the authors, this cycle of overdiagnosis is intensified by the use of the dermatoscope by dermatologists, which increases the number of lesions excised. the authors’ suggested solution to limit overdiagnosis would be to stop mass dermatological screening. the data reported in our review confirms an increase in the incidence of melanoma, although mortality remains stable. however, primary and secondary prevention campaigns have had a positive impact in reducing the diagnosis of melanoma, particularly in younger populations, as previously reported and discussed. moreover, dermoscopy, has not only increased the number of removed melanomas, it has also allowed to avoid benign lesions’ removal. on this point we disagree with the authors who claim that screening campaigns should be suspended because an annual examination allows the early detection of melanomas and the identification of high-risk patients (eg patients with more than 100 nevi or with dysplastic nevus syndrome) who need a closer monitoring. future studies are needed to identify the effectiveness of primary and secondary prevention, to assess its impact on worldwide incidence, and to solve current controversies. review | dermatol pract 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an independent external validation of melanoma risk prediction models using the australian melanoma family study. br j dermatol. 2020. doi: 10.1111/bjd.19706. epub ahead of print. pmid: 33270216. 6 review | dermatol pract concept. 2021: 11(s1): e2021161s 30. mclaughlin cc, wu xc, jemal a, martin hj, roche lm, chen vw. incidence of noncutaneous melanomas in the us. cancer. 2005;103:1000–1007. doi: 10.1002/cncr.20866. pmid: 15651058. 31. pandey m, mathew a, iype em. primary malignant mucosal melanoma of the head and neck region: pooled analysis of 60 published cases from india and review of literature. eur j cancer prev. 2002;11:3–10. doi: 10.1097/00008469-20020200000002. pmid: 11917203. 32. dahlgren l, schedvins k, kanter-lewensohn l, dalianis t, ragnarsson-olding bk. human papilloma virus (hpv) is rarely detected in malignant melanomas of sun sheltered mucosal membranes.  acta oncol.  2005;44:694–699. doi: 10.1080/02841860500247461. pmid: 16227159. 33. newell f, kong y, wilmott js, et 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giuffrida r, retrosi c, di meo n, zalaudek i. two controversies confronting dermoscopy or dermatoscopy: nomenclature and results. clin dermatol. doi: 10.1016/j.clindermatol.2019.07.001. pmid: 31896413. 39. welch hg, mazer bl, adamson as. the rapid rise in cutaneous melanoma diagnoses. n engl j med. 2021;384(1):72-79. doi: 10.1056/nejmsb2019760. pmid: 33406334. 1-indice 2-1789 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022064 1 cutaneous involvement of mantle cell lymphoma: report of two cases with dermatoscopic features bengü nisa akay1, banu farabi2, mehmet fatih atak1, isinsu kuzu3, aylin okcu heper3 1 department of dermatology, ankara university, ankara, turkey 2 department of internal medicine, saint peter’s university hospital, new brunswick, new jersey, usa 3 department of pathology, ankara university, ankara, turkey key words: mantle cell lymphoma, dermatoscopy, dermoscopy, prognosis, serpentine vessels citation: akay bn, farabi b, atak mf, kuzu i, heper ao. cutaneous involvement of mantle cell lymphoma: report of two cases with dermatoscopic features. dermatol pract concept. 2022;12(2):e2022064. doi: https://doi.org/10.5826/dpc.1202a64 accepted: september 6, 2021; published: april 2022 copyright: ©2022 akay et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: banu farabi, md, pgy-1, department of medicine, saint peter’s university hospital-rutgers robert wood johnson medical school, 4th floor cares, 240 easton avenue, new brunswick, nj 08901. e-mail: banufarabi91@gmail.com introduction mantle cell lymphoma (mcl) is a rare aggressive b-cell lymphoma and represents 6% of all non-hodgkin lymphomas. cutaneous involvement (ci) of systemic mcl is rarely reported and is related to poor prognosis. skin involvement in systemic lymphomas (sls) can be challenging. dermatoscopy may serve as a useful tool to diagnose and ameliorate the prognosis by leading early diagnosis. in this context, we present two cases of mcl with secondary ci, who presented with widespread plaques and nodules and describe their dermatoscopic features. case presentations the first patient was a 73-year-old male diagnosed with mcl in 2014. he referred to dermatology department for asymptomatic pink-red colored generalized skin lesions in august 2018 (figure 1a). dermatoscopic examination showed pink white structureless lesions with unfocused thick serpentine vessels (figure 1b). second patient was a 66-year-old female diagnosed with mcl in 2017, admitted for multiple nodular lesions developed on the trunk and extremities in january 2019 (figure 1c). dermatoscopic examination showed thick serpentine-branched and reticular vessels on whitish-pink violaceous background (figure 1d). both lesions were biopsied and showed similar features including diffuse infiltration of the mid and deeper dermis with medium-sized lymphocytes with irregular nuclei. the tumor cells were positive for cd5, cd20, cd79a, cyclin d1, and negative for cd10 (figure 2). both patients were diagnosed with ci of mcl. they have been treated with combined chemotherapy regimens including rituximab, unfortunately both patients were deceased due to disease dissemination (14 months and 18 months after ci, respectively). 2 research letter | dermatol pract concept. 2022;12(2):e2022064 discussion mcl originates from primarily lymph nodes and extra-nodal organs (bone marrow, spleen, gastrointestinal tract). skin involvement portends a poor prognosis and is seen in 2% of the cases. previously, 24 cases of secondary ci of mcl have been reported. the value of dermatoscopic examination in cutaneous lymphomas (cl) have been proposed in previously published studies. a recent systematic review regarding dermatoscopic findings in primary cls showed that dermatoscopy assisted skin biopsies ensure early diagnosis based on the findings such as salmon-colored background, fine short/linear irregular serpentine vessels, scale, and white areas/circles [1]. regarding the dermatoscopic features of secondary ci of sls, only 1 case of mcl has been reported and showed multiple chaotically distributed short linear vessels with multiple red dots within hair follicles on a whitish background. as the lesion progressed, wider telangiectatic vessels on a reddish background were observed, and the lesions regressed under treatment [2]. we observed pink and white structureless lesions with unfocused thick short serpentine vessels in flat lesions, as lesions became nodular as in our second patient, the vessel calibers increased, branched and reticular vessels were observed on purple-pink, white background which is hypothetically due to increased tumor volume and expansion of the dermis by malignant infiltrate. conclusions skin involvement in mcl suggests poor prognosis. though, dermatoscopic features are not specific to ci of sls, they can raise suspicion to biopsy these lesions in earliest stages. figure 1. (a,b) clinical and dermatoscopic pictures of case 1. (a) multiple erythematous indurated papules and plaques on the forehead. (b) the dermatoscopic image shows pink and white structureless lesions with unfocused thick short serpentine vessels. (c,d) clinical and dermatoscopic photos of case 2. (c) multiple, purple-colored nodular lesions on the right anterior leg. (d) the dermatoscopic image shows thick vessels, branched, and reticular vessels on purple, pink and white background. research letter | dermatol pract concept. 2022;12(2):e2022064 3 references 1. sławińska m, sokołowska-wojdyło m, olszewska b, nowicki rj, sobjanek m, zalaudek i. dermoscopic and trichoscopic features of primary cutaneous lymphomas systematic review. j eur acad dermatol venereol. 2021;35(7):1470-1484. doi: 10.1111/jdv.17219. pmid: 33710688. 2. swoboda r, kaminska-winciorek g, jaworska m, giebel s. dermoscopic follow-up of therapeutic response in mantle cell lymphoma with secondary involvement of the scalp. j cosmet dermatol. 2018 dec 5. doi: 10.1111/jocd.12826. epub ahead of print. pmid: 30520227. figure 2. histological and immunohistochemical findings of the papules from case 2. (a) diffuse proliferation of small atypical lymphoid cells with fine chromatin (h&ex10). the subcutaneous atypical lymphoid cells were expressing strong cd20 (b) and cd5 (c) , pale igd(d). (e,f) the cells were specifically negative for cd3 (e) and positive for cyclin d (f). dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021075 1 risk of birth defects from vitamin a “acne supplements” sold online dina h. zamil1, emily k. burns1, ariadna perez-sanchez2, milbrey a. parke1, rajani katta3 1 baylor college of medicine, houston, texas, usa 2 department of internal medicine, university of texas health science center at san antonio, san antonio, texas, usa 3 mcgovern medical school at university of texas health science center at houston, houston, texas, usa key words: vitamin a, acne supplements, teratogenicity, pregnancy, labeling citation: zamil dh, burns ek, perez-sanchez a, parke ma, katta r. risk of birth defects from vitamin a “acne supplements” sold online. dermatol pract concept. 2021;11(3):e2021075. doi: https://doi.org/10.5826/dpc.1103a75 accepted: february 7, 2021; published: may 20, 2021 copyright: ©2021 zamil et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests statement: rajani katta, md, serves on an advisory board for vichy laboratories and is the author of a book on diet and dermatology for the general public. the other authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta md, 6800 west loop south suite 180, bellaire, tx 77401, usa. email: info@kattamd.com background: dietary supplements are popular among us consumers and claim to address a variety of conditions, including acne. acne supplements containing vitamin a are of particular interest, due to the potentially teratogenic effects of vitamin a doses over 10,000 iu. objective: this study examined dosage, pregnancy risks, and labeling of vitamin a-containing acne supplements available online. methods: an internet search of acne supplements sold online was conducted between march and may 2020. supplement labels and websites were analyzed for vitamin a content and pregnancy warnings, and then divided into categories based on dosage and teratogenic risk. results: a total of 49 acne supplements was found, and of these 26 (53%) contain vitamin a. three supplements are likely teratogenic, 4 contain vitamin a doses exceeding the daily level of intake that meets the nutritional needs of most people, and 15 have an unknown teratogenic risk. among the 6 supplements with over 10,000 iu vitamin a, 2 have no pregnancy warning at all, including the supplement with the highest vitamin a dose found in this study. conclusions: dietary supplements are not subject to the same stringent regulations as drugs, and as such, consumers may be unaware of pregnancy risks. furthermore, fda requirements on labeling of vitamin a supplements may lead to consumer confusion regarding dosage. as such, we encourage stricter labeling requirements for vitamin a-containing supplements, including pregnancy warnings for high-dose supplements and clearer dosage labeling. abstract 2 research | dermatol pract concept. 2021;11(3):e2021075 introduction in the united states, over half of adults and one-third of children use dietary supplements [1,2]. although dietary supplements are not evaluated with the same rigor as medications by the us food and drug administration (fda), they remain popular [3,4]. in fact, one survey of national public opinion found that many users believed supplements to be so effective that even if clinical data suggested inefficacy, they would continue to consume them [3]. as such, the dietary supplement market is booming, with over 90,000 supplements on the market in the us in 2014 [5]. indeed, dietary supplements claiming to address a variety of diseases can be purchased easily, in retail stores or online [6]. many dietary supplements found online claim to target acne. in a survey among acne patients visiting a dermatology clinic, many respondents believed that supplements could help with acne, particularly vitamin a supplements [7]. dietary supplements containing vitamin a commonly report their dosages in either international units (ius) or retinol activity equivalents (rae). over-the-counter (otc) acne supplements that contain high-dose vitamin a could be unsafe, especially during pregnancy. supplemental doses of vitamin a greater than 10,000 iu (3,000 mcg rae) have been found to be particularly dangerous during the first trimester of pregnancy: approximately 1 in 57 babies born to women consuming more than 10,000 iu of supplemental preformed vitamin a daily had attributable birth defects [8]. the objective of this study was to investigate vitamin a-containing acne supplements currently available online and to identify supplements with potentially teratogenic doses. this study also sought to examine issues with labeling and regulation of vitamin a supplements. methods an online search of acne supplements sold online was conducted between march 2020 and may 2020. supplements including the terms “whitehead,” “blackhead,” and “acne” were independently searched on amazon, google, instagram, and twitter. the products found on google, instagram, and twitter were linked to their manufacturer websites. nutrition label information for each supplement was analyzed using descriptions and photos of product labels on manufacturer and third-party websites. all products that included the terms “whitehead,” “blackhead,” or “acne” in the photograph of the product label or in the online description were included in the study. supplements were examined for vitamin a content, including daily dose and forms of vitamin a. these details were used to categorize acne supplements according to dose size. the teratogenic risk of each product was calculated by converting dosages to ius or rae, when possible. thresholds for dose categorization included tolerable upper intake levels (uls) and recommended daily allowances (rdas) as well as the estimated teratogenic threshold for vitamin a [8,9]. the threshold for teratogenicity was set at 10,000 iu preformed vitamin a or 3,000 mcg rae equivalent, based on a study of vitamin a intake and birth defects among babies born to over 22,000 pregnant women [8]. supplements exceeding this dose are considered high risk. supplements with high doses were divided by vitamin a form (preformed or precursor). supplements with unknown risk were classified into 5 subcategories: (a) information in ius provided, but teratogenicity risk unknown because the form of vitamin a was not specified; (b) information in ius provided, but not enough information available to calculate mcg rae; (c) confusing labeling (difficult to understand the relative proportions of vitamin a forms or amount of vitamin a in dose); (d) labeling with discrepancies; and (e) unspecified dose. labels and websites for supplements with suspected teratogenic risk were thoroughly searched for pregnancy warnings. products with confusing labels, discrepancies in nutrition information, unspecified vitamin a form or dose, or too little information to determine teratogenicity were also identified. results a total of 49 unique acne supplements were identified, and 26 (53.1%) included some form of vitamin a. the forms of vitamin a contained in the acne supplements included vitamin a acetate, retinol acetate, retinyl acetate, beta-carotene, vitamin a palmitate, retinol palmitate, retinyl palmitate, and natural mixed carotenoids. the dose of vitamin a provided by these supplements ranged from 120 mcg rae to 21,000 mcg rae. the vitamin a-containing acne supplements were divided into 4 main categories, based on their potential teratogenicity (table 1). overall, 3 supplements exceeded the threshold for teratogenicity (category 1), and 4 supplements with high doses of vitamin a precursors, not known if teratogenic but of concern given the lack of research, were placed in category 2. the study found 11 supplements with unknown risk and 12 supplements with low doses of vitamin a that are unlikely to be teratogenic and pose low risk. among the 6 supplements with over 10,000 iu vitamin a (3 in category 1 and 3 in category 3), 2 have no pregnancy warning at all, including the supplement with the highest vitamin a dose in this study. another 2 of these supplements contain warnings on both the product bottle and website. however, these merely urge users to consult a physician prior research | dermatol pract concept. 2021;11(3):e2021075 3 to consumption if pregnant. for one of these supplements, a third-party website (but not the product bottle or product website) displays a california proposition 65 warning, disclosing that the product contains chemicals known to cause reproductive harm or birth defects. proposition 65 requires businesses to warn californian consumers about teratogenic products [10]. finally, 2 supplements have warnings advising consumers not to take the supplement if pregnant, one on both the bottle and website, the other only in website material. discussion this study found 10 acne supplements sold online that contain relatively high doses of vitamin a, 3 of which are likely teratogenic. physicians need to educate patients that purchasing “acne supplements” online may pose risks. dietary supplements do not require fda approval before going to market [11]. in fact, a manufacturer may market a supplement without providing any proof of safety or efficacy [12]. additionally, while prescription medications are required to carry pregnancy warning categories, no such requirement is in place for supplements, even for those that carry a risk of teratogenicity. finally, current fda supplement labeling regulations for vitamin a are confusing, making it difficult for consumers to evaluate teratogenic risk. risks of teratogenicity vitamin a may be found in the form of either preformed vitamin a or vitamin a precursors [9]. preformed vitamin a includes retinol and retinyl esters. vitamin a precursors include provitamin a carotenoids, such as beta-carotene [9]. given the lack of deficiency of vitamin a within the united states, the world health organization does not recommend routine vitamin a supplementation in general [13]. guidance suggests that vitamin a supplementation should be limited to a dose under 5,000 iu per day, given the risks of excess vitamin a supplementation [14]. current knowledge of teratogenicity risk posed by excess vitamin a is based on studies evaluating consumption of only preformed vitamin a, measured in ius [8]. the safety of high-dose beta-carotene, a vitamin a precursor, is not known. regarding the teratogenicity of beta-carotene, according to an expert consensus [15], the toxic effects typically associated with high-dose vitamin a are not associated with high-dose beta-carotene; nonetheless, the public is advised to remain cautious of potential adverse effects of beta-carotene. in fact, the us food and nutrition board urges against beta-carotene supplementation as its uls have not been established [9]. the fda has concluded that beta-carotene found in supplements has equivalent retinol activity to preformed retinol. one major concern, therefore, regarding supplemental table 1. classification of 26 vitamin a-containing acne supplements sold online dosage criteria no. of supplementsb 1. high doses of preformed vitamin a.a ≥3,000 mcg rae or more, which is the ul for preformed vitamin a in adults ≥19 years as well as a potentially teratogenic dose [1,2] 3 2. high doses of vitamin a precursors. a >900 mcg rae, the rda of vitamin a (both preformed and precursors) for males ≥14 years [2] 4 3. unknown risk information in mcg rae provided, but not enough information available to calculate ius 2 information in ius provided or can be calculated, but teratogenicity risk unknown because form of vitamin a or relative proportions of vitamin a forms not specified. >10,000 iu vitamin a 3 information in ius provided, but not enough information to convert to mcg rae 3 confusing labeling 4 labeling with discrepancies 3 dosage not specified 1 4. low doses of vitamin a for females. <700 mcg rae (both preformed and precursors), which is the rda for females ≥14 years [2] 6 for males. <900 mcg rae (both preformed and precursors), which is the rda for males ≥14 years [2] 9 ius = international units; rae = retinol activity equivalents; rda = recommended daily allowance; ul = tolerable upper intake level. a measured by mcg rae or ius. bsome supplements were placed into more than one category 4 research | dermatol pract concept. 2021;11(3):e2021075 beta-carotene is whether its teratogenicity risk is also similar to retinol. this concern has not been resolved, as human studies performed to date have only evaluated retinol, not supplemental beta-carotene [8,9,16]. however, of note, one recent animal study of embryonic development indeed found that nano-encapsulated beta-carotene induced craniofacial and eye birth defects, and beta-carotene in bulk formulation resulted in developmental delays [17]. drugs exhibiting evidence of teratogenicity are labeled pregnancy category d or x. category x is reserved for drugs with pregnancy risks that outweigh its benefits [18]. historically, several vitamin a derivative medications were placed in category x, including etretinate and isotretinoin. etretinate was even removed from the us market for safety reasons [14, 19]. in marked contrast, teratogenic supplements, such as the 3 identified in this study, do not have to display pregnancy category warnings to comply with labeling legislation [8,20]. while some potentially dangerous acne supplements sold online were found to have some form of warning, these were often inadequate, simply recommending consultation with a physician before use. it is quite easy for consumers to overlook these warnings in the “fine print,” especially if the warning is not on the product bottle. for supplements with an extremely high vitamin a dose, a category x warning on websites, bottles, and capsules would be more appropriate and easier for consumers to find. concerns about current labeling labeling discrepancies several supplements have issues with labeling. for instance, one supplement has no dosage of vitamin a listed. others have labeling discrepancies. two products provide conflicting versions of the supplement facts label. for one of these supplements, one version of the label displays a correct percent of the daily value (% dv), and the other displays an incorrect % dv [21, 22]. another product listed on 2 different websites has different supplement facts labels on each website. one of these supplement labels provides a dose of retinyl palmitate on a third-party website that is less than half of the dose provided on the manufacturer’s website. fda regulations on the labeling of vitamin a supplements may lead to confusion previously, vitamin a levels were reported in ius [9]. to facilitate comparison of the biological activity of different forms of vitamin a, the food and nutrition board created a new measure called rae [9]. this measure replaced ius as of january 2020 for companies with $10 million or more in annual sales [9]. to convert ius to mcg rae, knowledge of the vitamin a source is necessary [9]. converting from ius to mcg rae and vice versa is important because the estimated threshold for teratogenicity is reported in ius [8]. in this study, 2 supplements provided vitamin a dosage in mcg rae, but did not provide enough information to convert to ius, making it difficult to evaluate the teratogenic risk. three other supplements provided doses in ius, but not enough details to convert to mcg rae. we did not rely on % dv when calculating vitamin a doses. while % dv should refer to mcg rae for vitamin a, assuming the manufacturer is in compliance with regulations, the word “rae” is not required on the label [21, 22]. these regulations complicate labels and may lead to confusion on the part of consumers and healthcare professionals attempting to determine the amount of vitamin a in a supplement. we identified 4 supplements available for sale online with confusing labeling with regards to vitamin a. incorrect labeling three supplements with incorrect labeling were identified. one supplement indicates the amount of retinyl acetate in addition to the vitamin a dose in mcg rae. however, by our calculations, the amount of retinyl acetate indicated on the label does not equal the calculated vitamin a dose in mcg rae. another supplement label provides a vitamin a dose in mcg rae that is consistent with its displayed % dv [21, 22]. the vitamin a dose provided in ius on the label, however, is not equivalent to the dose provided in mcg rae [9]. finally, one supplement indicates the amount of beta-carotene it contains in ius, but it also lists vitamin a as a separate ingredient, without specifying its amount or form. conclusions the nutrition labels of acne supplements sold online can have discrepancies, may be confusing, or may be incorrect with regards to vitamin a content. given the known teratogenic effects of high-dose vitamin a, consumers of child-bearing potential should remain cautious about the consumption of acne supplements containing vitamin a. some otc acne supplements containing teratogenic doses of vitamin a fail to display adequate warnings. the fda labeling regulations for vitamin a supplements should require more stringent requirements for pregnancy warnings as well as clearer dosage labeling. after all, public opinion surveys have shown support for increased fda surveillance and regulation of dietary supplements [3]. references 1. kantor ed, rehm cd, du m, white e, giovannucci el. trends in dietary supplement use among us adults from 1999-2012. jama. 2016;316(14):1464-1474. doi: 10.1001/jama.2016.14403. pmid: 27727382. research | dermatol pract concept. 2021;11(3):e2021075 5 2. bailey rl, gahche jj, thomas pr, dwyer jt. why us children use dietary supplements. pediatr res. 2013;74(6):737-741. doi: 10.1038/pr.2013.160. pmid: 24002333. 3. blendon rj, desroches cm, benson jm, brodie m, altman de. americans’ views on the use and regulation of dietary supplements. arch intern med. 2001;161(6):805. doi: 10.1001/ archinte.161.6.805. pmid: 11268222. 4. m a t h e w s n m . p r o h i b i t e d c o n t a m i n a n t s i n d i e t a r y s u p p l e m e n t s . s p o r t s h e a l t h . 2 0 1 7 ; 1 0 ( 1 ) : 1 9 3 0 . doi: 10.1177/1941738117727736. pmid: 28850291. 5. starr rr. too little, too late: ineffective regulation of dietary supplements in the united states. am j public health. 2015;105(3):478-485. doi: 10.2105/ajph.2014.302348. pmid: 25602879. 6. morris ca, avorn j. internet marketing of herbal products. jama. 2003;290(11):1505-1509. doi: 10.1001/jama.290.11.1505. pmid: 13129992. 7. nguyen q-g, markus r, katta r. diet and acne: an exploratory survey study of patient beliefs. dermatol pract concept. 2016;6(2):21-27. doi: 10.5826/dpc.0602a05. pmid: 27222768. 8. rothman kj, moore ll, singer mr, et al. teratogenicity of high vitamin a intake. n engl j med. 1995;333(21):1369-1373. doi: 10.1056/nejm199511233332101. pmid: 7477116. 9. vitamin a fact sheet for health professionals. national institutes of health office of dietary supplements. accessed march 19, 2020. https://ods.od.nih.gov/factsheets/vitamina-healthprofessional/. 10. about proposition 65. california office of environmental health hazard assessment. 2015. accessed november 14, 2020. https:// oehha.ca.gov/proposition-65/about-proposition-65. 11. what you need to know about dietary supplements. us food & drug administration. november 29, 2017. accessed june 29, 2020. https://www.fda.gov/food/buy-store-serve-safe-food/whatyou-need-know-about-dietary-supplements. 12. katta r, huang s. skin, hair and nail supplements: an evidence-based approach. skin therapy lett. 2019;24(5):7-13. pmid: 31584785. 13. mcguire s. who guideline: vitamin a supplementation in pregnant women. geneva: who, 2011; who guideline: vitamin a supplementation in postpartum women. geneva: who, 2011. adv nutr. 2012;3(2):215–6. doi: 10.3945/an.111.001701. pmid: 22516730. 14. monga m. vitamin a and its congeners. semin perinatol. 1997;21(2):135-142. pmid: 9201819. doi: 10.1016/s01460005(97)80056-0. 15. grune t, lietz g, palou a, et al. beta-carotene is an important vitamin a source for humans. j nutr. 2010;140(12):2268s-2285s. doi: 10.3945/jn.109.119024. pmid: 20980645. 16. woutersen ra, wolterbeek ap, appel mj, et al. safety evaluation of synthetic beta-carotene. crit rev toxicol. 1999;29(6):515-542. doi: 10.1080/10408449991349267. 17. battistoni m, bacchetta r, di renzo f, metruccio f, menegola e. effect of nano-encapsulation of β-carotene on xenopus laevis embryos development (fetax). toxicol rep. 2020;7:510-519. pmid: 32346517. doi: 10.1016/j.toxrep.2020.04.004. pmid: 10628775. 18. fda pregnancy categories. chemical hazards emergency medical management. accessed july 21, 2020. https://chemm. nlm.nih.gov/pregnancycategories.htm. 19. cfr code of federal regulations title 21. 21cfr216.24. us food & drug administration. april 1, 2020. accessed july 21, 2020. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ cfrsearch.cfm?fr=216.24. 20. institute of medicine and national research council. dietary supplements: a framework for evaluating safety. washington dc: national academies press; 2005. 21. cfr code of federal regulations title 21. 21cfr101.9. us food & drug administration. april 1, 2019. accessed march 27, 2020. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ cfrsearch.cfm?fr=101.9. 22. dietary supplement labeling guide: chapter iv. nutrition labeling. us food & drug administration. march 21, 2018. accessed march 27, 2020. http://www.fda.gov/food/dietary-supplements-guidance-documents-regulatory-information/dietary-supplement-labeling-guide-chapter-iv-nutrition-labeling. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021; 11(4):e2021095 1 clonal seborrheic keratosis: a diagnostic dilemma satish udare1, priyanka patil1 1 sparkle skin & aesthetic clinic, vashi, navi mumbai, india key words: seborrheic keratosis, clonal, dermoscopy citation: udare s, patil p. clonal seborrheic keratosis: a diagnostic dilemma. dermatol pract concept. 2021; 11(4):e2021095. doi: https://doi.org/10.5826/dpc.1104a95 accepted: february 24, 2021; published: october, 2021 copyright: ©2021 udare and patil. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: authors have equally contributed to this publication. corresponding author: dr. priyanka patil, mbbs, ddv. sparkle skin & aesthetic clinic, vashi, navi mumbai, india. email: drpriyankapatil219@gmail.com. introduction clonal seborrheic keratosis (sk) is an uncommon histological subtype of seborrheic keratosis which may resemble other benign or malignant lesions [1]. herein, we highlight the clinical and histopathological features of this lesion and review the dermoscopic differential diagnoses. case presentation a 65-year-old female presented with an asymptomatic dark colored lesion, that has been gradually increasing in size for the last 30 years on the left side of the lower back. no history of bleeding. no history of any medical illness or family history of skin malignancy. on examination single, well circumscribed, irregularly shaped, hyperpigmented keratotic plaque measuring 3 cm in maximum diameter (figure 1). no palpable lymph nodes were detected. dermoscopy showed the presence of bluish black to brown globules of varying size, irregularly distributed, well demarcated borders, and milia-like cysts (figure 2). the tumor was biopsied. histopathological examination showed epidermal hyperplasia with lamellated and basket weave orthohyperkeratosis with mild papillomatosis dermoscopically corresponding to fissures and ridges. within the neoplasm two distinct subpopulations of basaloid cells (clones) were detected; one of them presented as a nest within the other (figure 3). the nests dermoscopically corresponded to the globules. occasional mitotic figures were seen within these clones. abundant melanin was present within the nested subpopulation of keratinocytes. sparse superficial perivascular lymphohistiocytic infiltrate is present. there was no interface change or lichenoid pattern to the infiltrate suggestive of clonal seborrheic keratosis. immunostaining was not performed. electrocautery of the lesion was performed with no relapse after 1 year of follow-up. conclusion in the dermoscopic differential diagnosis of clonal sk, we must consider hidroacanthoma simplex (hs) and its malignant variant, epidermal nevus, pagetoid pigmented bowen disease, in situ melanoma, and superficial basal cell carcinoma (bcc). clonal sk, is characterized by variously sized, blue-gray globular-like structures that are aggregated to form short lines or irregularly distributed within the lesion [2]. it can reveal other features suggestive of sk, including 2 letter | dermatol pract concept. 2021; 11(4):e2021095 demarcated borders, milia-like cysts, comedo-like openings, and the jelly sign. also, polymorphic vascular component is reported [2]. hs shows white globular structures surrounded by homogenous pigmented lines which are not seen in clonal sk.. dermoscopy of a pigmented malignant hidracanthoma simplex arising from a hs reveals vessels in a conspicuous and irregular shape whereas in clonal sk glomerular, hairpin and dotted vessels are seen [3]. epidermal nevus reveals large brown circles. in pagetoid pigmented bowen disease, glomerular vessels, scaly surface, small brown globules regularly packed in a patchy distribution, and a grey homogenous pigmentation are seen. bcc has other characteristics such as arborizing vessels and maple leaf areas while coiled vessels are characteristic of melanoma. the distinction between clonal sk and other benign or malignant lesions is challenging on dermoscopy. histopathological examination will lead to accurate diagnosis in doubtful cases. references 1. bouhamed m, bacha d, abdelmoula f, slama sb, lahmar a, bouraoui s, sabeh mr. clonal seborrheic keratosis: a rare skin tumor. pan afr med j. 2019;34:54. doi: 10.11604/ p a m j . 2 0 1 9 . 3 4 . 5 4 . 1 3 4 1 5 . p m i d : 3 1 7 6 2 9 2 0 ; p m c i d : pmc6859035. 2. longo c, zalaudek i, moscarella e, lallas a, piana s, pellacani g, et al. clonal seborrheic keratosis: dermoscopic and confocal microscopy characterization. j eur acad dermatol venereol. 2014;28(10):1397–400. doi: 10.1111/jdv.12261. pmid: 24033484. 3. ramyead s, diaz-cano sj, pozo-garcia l. dermoscopy of clonal seborrheic keratosis. j am acad dermatol. 2015;73(2):e47-9. doi: 10.1016/j.jaad.2015.04.013. pmid: 26183995. figure 1. (a) clinical presentation of clonal seborrheic keratosis. (b) dermoscopy reveals the presence of globular-like structures and sharply demarcated borders. figure 2. well defined islands of basaloid cell nests within an acanthotic epidermis (h&e, x40). dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022044 1 neck rejuvenation with a new infrared emission olga mastrangelo1, luigi bennardo2, irene fusco3, mario sannino1, giovanni cannarozzo1, steven paul nisticò2 1 university of rome tor vergata, rome, italy 2 department of health sciences, unit of dermatology, magna graecia university, catanzaro, italy 3 university of florence, florence, italy key words: ipl, facial aging, infrared emission, wrinkles citation: mastrangelo o, bennardo l, fusco i, sannino m, cannarozzo g, nisticò sp. neck rejuvenation with a new infrared emission. dermatol pract concept. 2022;12(2):e2022044. doi: https://doi.org/10.5826/dpc.1202a44 accepted: august 2, 2021; published: april, 2022 copyright: ©2022 mastrangelo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: luigi bennardo, department of health sciences, magna graecia university viale europa snc 88100 catanzaro italy. e-mail: luigibennardo10@gmail.com introduction human skin aging includes histological and biochemical changes. the therapeutic technology of non-invasive skin rejuvenation of intense pulsed light (ipl) is called photorejuvenation, and the technique has been used widely in cosmetic dermatology to improve facial photoaging. ipl sources are multiwavelength lights that typically emit light in the 500 to 1200 nm range. at this level, the thermal impulse causes denaturation of collagen fibers with consequent formation of new ones [1]. papers that elucidate how systems emitting light near-infrared (800–1200 nm) could produce, on human skin fibroblasts cell cultures, dermal changes in gene expression and extracellular matrix and contribute to photo rejuvenation are already present in literature [2]. case presentation we present our preliminary experience with a 63-year-old female patient treated with a new pulsed infrared emission in the range 800–1200 nm (luxea, deka mela srl). four sessions spaced 2 weeks apart were performed. the patient was recruited at magna graecia university of catanzaro and signed informed consent. local ethical committee approved the treatment protocol. the patient was photographed at the beginning and 3 months after the last treatment session (figure 1). the system is based on the pulsed emission of a wavelength range of 800–1200 nm over a 6.2 cm2 spot. the protocol used the following settings: power 30 w, handpiece moving in a linear slow motion creating an area about 5 × 5 cm. the handpiece is kept in a vertical position and in contact with the skin by applying light pressure and transparent water gel so that the entire surface of the irradiation area is always in contact with the skin. the protocol provides a progressive skin temperature rise of the epidermis up to 40-42 °c, persisting, as long as conditions allow, for a few minutes on the treatment area. the patient achieved an improvement in skin texture. a better skin tone and wrinkle reduction were observed in the neck area. 2 research letter | dermatol pract concept. 2022;12(2):e2022044 patient in the immediate post-treatment experienced an improvement in brightness and porosity of the skin. the immediate effects are visibly enhanced 2 months after the first treatment session. the response of the dermal tissue is noticeable within 5 minutes. the endpoint was considered light erythema associated with the sensation of heat reported by the patient that disappeared in 30 minutes. conclusions light devices emitting near-infrared are highly effective for skin rejuvenation. these treatments are associated with minimal patient discomfort and are well tolerated. in this context, patients require increasingly effective treatments associated with minimal pain and with the lowest possible risk of side effects. the new pulsed infrared emission in the range 800–1200 nm could be an excellent non-invasive system. furthermore, this emission mode is convenient in the neck area where the alternatives are few and still invasive. the strength of this treatment is the absence of downtime and side effects. these results promise a rapid spread of this technology and are the starting point for combined treatments to treat more complex diseases that require integrated approaches. references 1. nistico sp, silvestri m, zingoni t, tamburi f, bennardo l, cannarozzo g. combination of fractional co2 laser and rhodamine-intense pulsed light in facial rejuvenation: a randomized controlled trial. photobiomodul photomed laser surg. 2021;39(2):113-117. doi: 10.1089/photob.2020.4876. pmid: 33449867. 2. cuerda-galindo e, díaz-gil g, palomar-gallego ma, linares-garcíavaldecasas r. increased fibroblast proliferation and activity after applying intense pulsed light 800-1200 nm. ann anat. 2015;198:66-72. doi: 10.1016/j.aanat.2014.11.005. pmid: 25547460. figure 1. (a) frontal view before treatment. (b) frontal view after treatment dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(4):e2021092 1 patients with hidradenitis suppurativa negatively perceive both medical and euphemistic appellations of their disease: a study from turkey gulsen akoglu¹, pelin esme¹, irem yildiz² 1 university of health sciences, gulhane training and research hospital, department of dermatology and venereology, ankara, turkey 2 hacettepe university faculty of medicine, department of psychiatry, ankara, turkey key words: hidradenitis suppurativa, euphemism, folk name, medical appellation, psychodermatology citation: akoglu g, esme p, yildiz i. patients with hidradenitis suppurativa negatively perceive both medical and euphemistic appellations of their disease: a study from turkey. dermatol pract concept. 2021;11(4): e2021092. doi: https://doi.org/10.5826/dpc.1104a92 accepted: february 14, 2021; published: september 2021 copyright: ©2021 akoglu et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interest: none. authorship: all authors have contributed significantly to this publication. corresponding author: gulsen akoglu, md, professor, university of health sciences, gulhane training and research hospital, department of dermatology and venereology, gen. dr. tevfik saglam street, ankara, turkey. email: drakoglug@gmail.com background: the use of medical terms and folk names (euphemisms) affect a patient’s understanding of diseases and perceptions of severity. objectives: we determine the psychological effects on patients with hidradenitis suppurativa of medical and folk names of their disease. methods: this was a cross-sectional and exploratory study conducted at a tertiary referral university hospital in turkey. a questionnaire on the medical and folk names of hidradenitis suppurativa was administered to 31 males and 25 females. results: the patients expressed that they found the medical term hidradenitis suppurativa to be incomprehensible because it is a foreign term. when hearing it for the first time, it evoked negative responses such as confusion and worry about their health. half of the patients preferred their doctors to use a more understandable and pronounceable name. more than 80% of patients expressed feeling depressed and stigmatized by the folk name of their disease. they preferred the terms boils, abscesses, or hidradenitis when referring to their disease. conclusion: both medical and folk names for hidradenitis suppurativa have negative effects on patients, and most patients feel stigmatized by either term. abstract 2 research | dermatol pract concept. 2021;11(4):e2021092 introduction during medical consultations, effective communication also requires taking a patient’s social and cultural background into account, as language may influence perception and beliefs in relation to an illness. the use of medical terms and folk names (euphemisms) affect understanding the nature of diseases and perceptions of their severity and importance [1, 2]. for example, the medical term hidradenitis suppurativa (hs), which has ancient greek roots [3], may sound foreign to a patient whose language does not have similar origins or pronunciations. additional time may be required to describe the disease in detail. euphemisms are substitutions for words or phrases that are used for names or topics that are considered distasteful [4]. people tend to use euphemistic words for upsetting concepts, such as names of diseases and death. for instance, people prefer to use “relentless illness” for cancer or “pass away” for death, and this is because of long-held taboos and taboo-based fears [5]. in ancient turkey, people believed that a boil or abscess (ciban in turkish) spreads when its name is mentioned. to address this fear, more than 80 euphemistic terms for skin abscesses located in various body regions have evolved [6]. among these euphemistic words, it is common to use parts of animals’ appellatives resembling the disease features to represent different kinds of boil diseases. for example, due to the resemblance of hs axillary regions to the nipples of the dog, “dog nipple disease” has been used to name hs abscesses located at the level of the armpits [7]. in other countries, people use different names for hs according to their culture or social life. in spanish-speaking countries, people use golondrino meaning “swallow” due to the resemblance of axillary lesions of hs to the nests of swallows. other commonly used euphemistic expressions, that define hs and related abscesses in familiar and popular contexts, include “cow’s milk-filled nipples” in russia, “recurrent ingrown hair, recurrent boils, verneuil’s disease” in france, “rotten armpit” in afghanistan, and “boils/boil disease” in canada, united states of america, azerbaijan, slovenia, brussels, and other european countries. psychological effects due to the use of medical and/or folk names (euphemisms) for hs are unknown in patients. in daily practice, we observe that patients diagnosed with hs react or comment differently when talking about hs or its corresponding folk expression (euphemism). objectives in this study, we aimed to determine the psychological effects on hs patients, generated by the choice of medical or folk names to define their disease. methods this cross-sectional and exploratory study was conducted in the department of dermatovenereology in gulhane training and research hospital, university of health sciences in ankara, turkey. all consecutive patients with hs, who were diagnosed and followed up in the hs outpatient clinic of our center were invited for the study from july 1 to september 30, 2020. two illiterate and cognitively impaired patients, unable to read and understand the scales used in the study, together with a patient who was unwilling to participate, were excluded from the study. a total of 56 patients over 18 years were recruited. patients were examined by the same investigator and their sociodemographic and clinical history and characteristics were recorded. the hurley staging system was used to evaluate the clinical severity of the disease. stages range from 1 to 3 as follows: stage 1 (mild), stage 2 (moderate), or stage 3 (severe) [8]. informed consent patients who participated in this study gave written informed consent for the publication of their case details. ethics approval the local ethics committee provided ethical clearance and approval for this study (approval id: 2020-349). interviews and quality of life measurements patients were interviewed in a silent and restful room in the same center and were required to fill in a questionnaire including questions regarding the medical and folk names (euphemisms) used to define hs in public contexts. each interview was recorded by the same investigator and was completed in approximately 20 minutes, after which each patient filled in the scales. interviews on medical and folk expression of hidradenitis suppurativa a questionnaire with 11 and 10 questions concerning the medical and folk (euphemistic word) expressions of hs, respectively, was administered to evaluate thoughts, beliefs, emotions, attitudes, and behaviors of patients toward the names of their disease. some questions were open-ended, whereas others were close-ended (polar). a pilot test was previously conducted on 10 patients to evaluate and confirm understanding of the questionnaire. statistical analysis statistical analyses were performed using the statistics package for the social sciences (spss) for windows version 25.0 (ibm, armonk, ny, usa). patients’ characteristics are presented as means and standard deviations for continuous variables and as frequencies and proportions for categorical research | dermatol pract concept. 2021;11(4):e2021092 3 variables. comparisons between 2 categorical variables were performed using the chi-square analysis. a p value of <0.05 was considered statistically significant. results thirty-one males and 25 females (age range: 18-66 years; mean age: 33.5±11.3 years) were enrolled in the study (table 1). most of the patients were in clinically severe stages. almost all patients first heard hidradenitis suppurativa as the medical term of their disease from their consultant doctor (table 2). patients reported finding hs incomprehensible, because it is a foreign term and evokes negative feelings when heard. only 1 patient with a biology background understood and described the term as an inflammation affecting sweat glands. although half of the patients preferred hearing the medical expression from their doctor, only 9 patients preferred the name “hidradenitis” for daily life communication. three patients used the abbreviation “hs” for easy pronuntable 1. sociodemographic and clinical features of patients characteristics n (%) male/female 31 (55.4) / 25 (44.6) range, mean ±sd (years) 18-66; 33.5±11.3 1840 years 41 (73.2) 4160 years 15 (26.8) clinical severity hurley stage 1 14 (25) hurley stage 2 14 (25) hurley stage 3 28 (50) age at disease onset(years) 13.0-64.5 (25.6±10.0) age at the diagnosis of hs (years) 13.0-64.0 (29.2±10.0) disease duration(years) 0.0-25.0 (7.9±6.6) involved body regions axilla 42 (75.0) inguinal 43 (76.8) inframammary 7 (12.5) gluteal/perianal/ intergluteal 22 (39.3) other sites/atypical sites 31 (55.4) current treatments none 9 (16.1) topical antibiotics 8 (14.3) systemic antibiotics 12 (21.4) oral isotretinoin 2 (3.6) biologics 25 (44.6) sd = standard deviation. ciation. conversely, 1 patient avoided the use of “hs” as this abbreviation was similar to “ms” (multiple sclerosis), a profoundly serious neurological disease. almost 70% of patients were aware of the folk expression “dog nipple disease” mostly learned from a doctor (table 3). more than 80% of patients expressed negative, depressive, and stigmatizing feelings toward this euphemistic expression. they rather preferred to use boils/abscesses or hidradenitis when talking about their disease in daily life (table 4). both genders expressed discomfort for the use of the expression “dog nipple disease” during discussions with their doctors, close relatives, or other people (all p >0.05). female patients felt more uncomfortable using this term with their relatives (p <0.05), when compared to male patients in the same context. details of the answers to the questionnaire are listed in tables 2-4. discussion hidradenitis suppurativa is a challenging disease and patients are mostly depressed and feel stigmatized [9, 10]. signs and symptoms of hs reduce the quality of life, affect social lives, and it has a difficult course [11]. the present study shows the different effect produced by the disease different naming. results show that both medical and euphemistic expressions have negative effects on disease perception and affect patients’ psychosocial life. doctors should establish effective communication with their patients during consultation. physicians might choose medical expressions when communicating, to emphasize the importance and treatment of the disease, especially when the disease is chronic, disabling, or life-threatening and requires that patients and/or their families comply with recommendations and treatments [12]. medical expressions of diseases may facilitate the contribution of the patient to the problem, decision-making process, and treatment compliance [13], although this is not always the case. for instance, the medical term heart failure has been reported to cause anxiety and fear in patients [1, 2]. similarly, our data indicate that “hs” evoked confusion and concern in patients because the term sounds weird and difficult to pronounce. as a result, most patients perceived the condition described by the term as serious. nonetheless, half of the patients preferred adopting the definition provided by their doctors. this is probably due to the confidence patients had in their doctor’s knowledge of the disease and familiarity with the medical expression. conversely, the other half of the patients preferred referring to a more understandable and pronounceable name during medical consultation. this finding suggests that the medical term “hs”, confounds patients when they first hear the expression during consultation. patients usually avoid to publicly share 4 research | dermatol pract concept. 2021;11(4):e2021092 table 2. answers to questions about the medical term hidradenitis suppurativa questions and answers n (%) do you know the medical name of your disease? (n=56) no, i do not know the medical name of my disease 5 (8.9) yes, the name is hs 51 (91.1) from whom/where did you first hear about hs as the name of your disease? (n=51) from the doctor who examined me 50 (98.1) from an internet search of my lesions 1(1.9) do you think that the name “hs” is understandable? (n=56) yes 1 (1.8) no, because it is a foreign name, not in turkish 55 (98.2) additional issues mentioned specifically about the term “hs” (n=56) the term is hard to pronounce 13 (23.2) it is a weird name 3 (5.4) it is a complicated term 5 (8.9) i cannot keep in mind and remember 5 (8.9) the term is not informative 2 (3.6) other people think it is a bad disease 2 (3.6) other people think it is a weird name 1 (1.8) other people laugh at me when they hear the term 1 (1.8) i had to search the meaning of the term 1 (1.8) it makes no sense to me 1 (1.8) how did you feel when you heard the name “hs”? (n=56) puzzled about the name 20 (35.7) feared/worried about his/her health 18 (32.1) had to search what kind of disease it is on internet 7 (12.5) thought it was a bad disease 6 (10.7) demoralized 3 (5.4) thought i had cancer 2 (3.6) relieved to have a diagnosis after 11 years 1 (1.8) embarrassed that she could not say the name 1 (1.8) nothing, i trust my doctor 7 (12.5) do you prefer your doctor uses another name for your disease instead of using hs? (n=56) yes, i prefer to hear a more understandable and pronounceable disease name 28 (50.0) no, i do not 28 (50.0) i have got used to hearing the medical term; do not want any change 15 (26.8) i prefer to hear a medical term from the doctor 11 (19.6) hs = hidradenitis suppurativa. the medical term because of the fear of stigmatization, preferring to use alternative definitions. although it has progressively become consensual in medical literature, there is a long-lasting controversy regarding the medical naming of hs; some authors claim hs to be a misnomer and suggest using acne inversa as a more proper definition describing the lesions’ histology and intertriginous localizations [14]. on the contrary, although a misnomer, some authors suggest unaltering hs naming, since the disease has several characteristics other than the ones defined by histology [15]. in addition, our findings show that patients also have some problems with hs’ current medical expression. various societies and physicians usually tend to use folk names (euphemistic words) to protect patients from the negative effect of bad news and from the loss of hope and perseverance during the disease process [16]. in this study, when patients were asked about the euphemistic expressions of the disease, a significant portion indicated that they were aware of the “dog nipple disease” naming and almost 80% of them heard this folk expression from a clinician (during research | dermatol pract concept. 2021;11(4):e2021092 5 table 3. answers to questions about the folk expression “dog nipple disease” questions and answers n(%) do you know any folk name used in public for your disease? (n=56) yes, “dog nipple disease” 39 (69.6) no 17 (30.4) from whom/where did you first hear the folk term “dog nipple disease”? (n=39) from a doctor 34 (87.2) from an internet search of hs/my lesions 19 (48.7) from the doctor who examined me 14 (35.9) from a doctor on television 1 (2.6) from a relative/other person 5 (12.8) how did you feel when you learned about the name “dog nipple disease” used for your disease? (n=39) it is disgusting/repulsive/inappropriate/ugly name 8 (20.5) it is an astonishing term 6 (15.4) felt bad when i heard the name 5 (12.8) it makes sense to use “dog nipple disease,” since it resembles the lesions 4 (10.3) felt weird/shame when first heard, then got used to it 3 (7.7) it is a shameful term 2 (5.1) the disease does not resemble dog nipples 2 (5.1) i did not mind 2 (5.1) it is an insulting name 1 (2.6) i thought i had a more serious disease than i considered 1 (2.6) do not use the name because people make fun of me 1 (2.6) mentioning the nipple with disease makes me feel uncomfortable 1 (2.6) felt uncomfortable to hear an animal and nipple name in the disease 1 (2.6) feared to imagine many nipple-like lesions will spread to every part of the body when the disease progresses 1 (2.6) the term sounds like an animal disease 1 (2.6) felt uncomfortable to think that people imagine dog nipples 1 (2.6) does it annoy you that your doctor calls the name of the disease as “dog nipple disease”? (n=39) yes 22 (56.4) no 17 (43.6) when talking to your relatives, do you feel uncomfortable saying the name of your disease as dog nipple disease? (n=39) yes 23 (59.0) no 16 (41.0) when talking to other people, do you feel uncomfortable saying the name of your disease as dog nipple disease? yes 33 (84.9) no 6 (15.4) hs = hidradenitis suppurativa. consultation, on a medical website, or on tv). although this study was not conducted to investigate the need for clinicians to use euphemisms during conversations on hs, we may speculate on some issues. euphemisms can help a physician to explain the diagnosis or condition of the disease to the patient by facilitating the understanding of the disease and reducing patient’s stress levels [12]. for example, the use of medical terms, such as obesity, may be perceived as stigmatizing and blamed by the patient [1, 17]. for this reason, clinicians may prefer using euphemisms (your weight may be affecting your health, etc.) to avoid upsetting patients. the tendency to use euphemisms in a medical conversation with hs patients might be totally different and might depend on how patients’ deal with the hs’ difficult definition. physicians may consider 6 research | dermatol pract concept. 2021;11(4):e2021092 conclusions the medical and euphemistic expressions for hs have negative effects on patients, and most patients feel stigmatized by their diagnosis when named with either term. studies on stigmatization and psychological burden of hs should also include analyses on the effects of names attributed to hs, in relation to the population’ social and cultural background. acknowledgements we specially thank dr. philippe guillem for his unique and kind support. we also thank the members of the european hidradenitis suppurativa foundation and colleagues for providing information on the different euphemistic terms used for hs in their countries. references 1. ogden j, branson r, bryett a, et al. what’s in a name? an experimental study of patients’ views of the impact and function of a diagnosis. fam pract. 2003;20(3):248-253. doi:10.1093/ fampra/cmg304 2. tayler m, ogden j. doctors’ use of euphemisms and their impact on patients’ beliefs about health: an experimental study of heart failure. patient educcouns. 2005;57(3):321-326. doi:10.1016/j. pec.2004.09.001 3. hidradenitis. accessed december 2020. https://en.wiktionary.org/ wiki/hidradenitis. 4. slovenko r. euphemisms. journal psychiatry & law. 2005; 33: 533–48. doi: 10.1177/009318530503300411. 5. gungor a. tabu-örtmece (euphemism) sözler üzerine (turkish). journal of turkish research institute. 2006; 29:69-93. doi:10.14222/turkiyat732. 6. 41 soruda tabu-ortmece sozler-1 by prof dr ahmet gungor. accessed december 2020. http://gungorname.com/2021/04/24/41soruda-tabu-ortmece-sozler-i. 7. turk dil kurumu sozlukleri. accessed december 2020. https:// sozluk.gov.tr 8. hurley h. axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach. in: roenigk rk, roenigk hk jr, eds. dermatologic surgery. new york: marcel dekker; 1989:729-739. 9. matusiak l, bieniek a, szepietowski jc. psychophysical aspects of hidradenitis suppurativa. acta derm venereol. 2010;90(3):264-8. doi: 10.2340/00015555-0866. pmid: 20526543. 10. koumaki d, efthymiou o, bozi e, katoulis ac. perspectives on perceived stigma and self-stigma in patients with hidradenitis suppurativa. clin cosmet investig dermatol. 2019;12:785-790. doi: 10.2147/ccid.s180036. pmid: 31802927; pmcid: pmc6801565. 11. patel kr, lee hh, rastogi s, vakharia pp, hua t, chhiba k, singam v, silverberg ji. association between hidradenitis suppurativa, depression, anxiety, and suicidality: a systematic review and meta-analysis. j am acad dermatol. 2020;83(3):737-744. doi: 10.1016/j.jaad.2019.11.068. pmid: 31862404. table 4. preferred expressions patients use to define their lesions/disease (n=56) expressions n (%) boils/abscess 12 (21.4) hidradenitis 9 (16.1) pus 8 (14.3) acne 5 (8.9) hair root pus 4 (7.1) hs (abbreviation) 3 (5.4) dog nipple disease 3 (5.4) wound 2 (3.6) ingrown hair 1 (1.8) fungal disease 1 (1.8) not defined 8 (14.3) adopting euphemistic terms to describe hs, adapting to the patients’ level of understanding during consultation. communicating with folk names (euphemisms) supposedly helps patients to figure the disease and effectively engages them in medical conversation. although the sample size was not large, the study results showed that using folk names for hs, causes many psychosocial problems. these expressions have significant negative effects on patients, many of whom feel annoyed when they hear them from their doctors. moreover, they feel uncomfortable using folk names when mentioning the disease with other people or with family members; female patients reported more discomfort than males. these consequences might be due to the sexual connotation perceived from the word “nipple” , which might generate some sense of shame. the stigma seems to have a debilitating effect on patients leading them to choose the disease definition they feel more comfortable with. patients seem to tolerate the inconvenience caused by the folk expression “dog nipple disease” when adopted by their doctor. this is due to the respect patients have towards physicians’ expertise, authority, and knowledge. this indicates that the euphemistic expression “dog nipple disease” to define hs, is inappropriate in both consultations and public conversations. the term might have been useful and needed during ancient times, however, it is not positively accepted nowadays, as the perception derived from euphemisms’ use has changed. the original word “crippled” well illustrates this kind of change. it evolved from “handicapped” to “disabled,” and then to “people with disabilities” in time, showing how new euphemisms replace previous ones [16]. similarly, this study indicates that there is a taboo linked to the euphemism “dog nipple disease”. we suggest the use of the medical term “hs” until suitable euphemistic expressions are created. research | dermatol pract concept. 2021;11(4):e2021092 7 12. herbert a. the role of euphemisms in healthcare communication. j healthc commun. 2016, 1:2. doi: 10.4172/24721654.100014 13. tailor a, ogden j. avoiding the term ‘obesity’: an experimental study of the impact of doctors’ language on patients’ beliefs. patient educcouns. 2009;76(2):260-264. doi:10.1016/j. pec.2008.12.016 14. sellheyer k, krahl d. “hidradenitis suppurativa” is acne inversa! an appeal to (finally) abandon a misnomer. int j dermatol. 2005;44(7):535-40. doi: 10.1111/j.1365-4632.2004.02536.x. pmid: 15985019. 15. scheinfeld n. hidradenitis should not be renamed acne inversa. dermatol online j. 2006;12(7):6. doi: 10.5070/d35g21t4mq. pmid: 17459292. 16. puhl r, brownell kd. bias, discrimination, and obesity. obes res. 2001;9(12):788-805. doi:10.1038/oby.2001.108 17. koc a. hastalik isimlerinde ortmece (turkish). turk dunyasi arastirmalari 2010;188:77-94. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021; 11(4):e2021119 1 unilateral nevoid telangiectasia after pregnancy astrid herzum1, claudia micalizzi1, aurora parodi1 1 department of dermatology, di.s.sal., university of genoa, san martino polyclinic hospital irccs, genoa, italy citation: herzum a, micalizzi c, parodi a. unilateral nevoid telangiectasia after pregnancy. dermatol pract concept. 2021; 11(4):e2021119. doi: https://doi.org/10.5826/dpc.1104a119 accepted: march 14, 2021; published: october, 2021 copyright: ©2021 herzum et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: astrid herzum, md, department of dermatology, di.s.sal., university of genoa, san martino polyclinic hospital irccs, largo rosanna benzi 10, 16132 genoa, italy. email: astridherzum@yahoo.it case presentation a 40-year-old woman presented to the dermatology clinic after pregnancy for new-onset of asymptomatic patches of superficial telangiectasia, partially blanchable, mostly arranged unilaterally on the right side of her upper body, including neck, shoulder, and arm. lesions also involved bilaterally the cervical dermatomes on the chest (figure 1a). dermoscopy showed ectatic, tortuous, and thin capillaries (figure 1b). diagnosis of unilateral nevoid telangiectasia (unt) was made upon clinical and dermoscopic findings. teaching point unt is a rare, nevertheless underdiagnosed, and underreported capillary malformation, associated with increased estrogen levels [1]. it may have a striking appearance, but patients should be reassured about the benignity of the condition [2]. figure 1.(a) patches of superficial telangiectasia involving the chest bilaterally. (b) dermoscopic image of ectatic, tortuous, and thin capillaries. 2 image letter | dermatol pract concept. 2021; 11(4):e2021119 references 1. claudia m, astrid h, cozzani e, et al. unilateral nevoid telangiectasia: a rare and underdiagnosed skin disease. eur j dermatol. 2020;30(5):601-602. doi: 10.1684/ejd.2020.3867. pmid: 33185531. 2. tanglertsampan c, chanthothai j, phichawong t. unilateral nevoid telangiectasia: case report and proposal for new classification system. int j dermatol. 2015; 52:608-10. doi: 10.1111/j.13654632.2011.05279.x. pmid: 23590376 dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022023 1 umbilical endometriosis: a new dermoscopic pattern jorge juan vega-castillo1, soledad saenz-guirado1, maria luisa vega-castillo2, ricardo ruiz-villaverde1 1 dermatology department, hospital universitario san cecilio, granada, spain 2 ophtalmology department, hospital de alta resolución de écija, spain key words: endometriosis, pattern, dermoscopy citation: vega-castillo jj, saenz-guirado s, vega-castillo m, ruiz-villaverde r. umbilical endometriosis: a new dermoscopic pattern. dermatol pract concept. 2022;12(1):e2022023. doi: https://doi.org/10.5826/dpc.1201a23 accepted: june 10, 2021; published: january 2022 copyright: ©2022 vega-castillo et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ricardo ruiz-villaverde, unidad de dermatología. hospital universitario san cecilio, granada, spain. e-mail: ismenios2005@gmail.com introduction endometriosis is defined as the growth of ectopic endometrial tissue outside the uterine cavity. extra pelvic endometriosis occurs in 12% of women, and umbilical endometriosis, a rare presentation of extra pelvic endometriosis, occurs in 0.5%-1% of reported cases. umbilical endometriosis is also known as villar nodule as villar first described the condition in 1886. cutaneous endometriosis tends to settle on scars from surgical procedures (abdominal or pelvic surgery) such as hysterectomy, caesarean section, laparoscopy, or episiotomy. from a clinical point of view, it is necessary to establish a differential diagnosis with amelanotic melanoma, basal cell carcinoma, sister mary joseph nodule, or pyogenic granuloma. case presentation a 45-year-old woman attended our dermatologic outpatient clinic complaining of a 4-months history of a solitary painless umbilical nodule. the bluish-green colored lesion had not appeared on a previous scar. any recent bleeding episode was ruled out. a complete medical history revealed longterm dysmenorrhea as the only relevant clinical finding. on dermoscopy, a central white reticular pattern on a violet background was observed (figure 1a). no vascular structures, points, globules, or structures suggestive of a melanocytic lesion were observed. histopathological examination was consistent with cutaneous endometriosis (figure 1b). complementary tests, including abdominal-pelvic ct and determination of cancer antigen 125 offered results within normal ranges. conclusions there are few dermoscopic descriptions in the literature of cutaneous endometriosis [1,2]. the main dermoscopic findings and histopathological correlation are reflected in table 1. there appears to be a difference in patterns depending on the phase of the hormonal cycle, as well as the depth of the lesion, histological subtype and phototype of the patient. 2 research letter | dermatol pract concept. 2022;12(1):e2022023 table 1. dermoscopic descriptions of umbilical endometriosis authors dermatoscope model dermoscopic features interpretation polarized mode de giorgi, 2003 [3] heine-10 homogeneous reddish pigmentation, regularly distributed, gradually fading to the periphery small red globular structures (red atolls) multiple irregular glands with erythrocytes in a myxoid vascular stroma non-polarized jerez-jaime, 2013 [4] dermlite ii pro hr homogeneous reddish localized pigmentation, with no differentiated structures amorphous brown area with normal skin network myxoid vascular stroma polarized light dermoscopy costa, 2014 [5] dermlite dl3, polypoid projections of erythematous violaceous color, area with dark brown globules and area of active bleeding (mid follicular phase) increased in both characteristics (luteal phase) endometrial atrophy hemoglobin degradation after bleeding period, corresponding to hemosiderin deposits polarized light dermoscopy bonné, 2020 [2] dermlite dl4 umbilical endometriosis (polypoid structure) with drainage openings multiple irregular glands with erythrocytes and drainage openings polarized light dermoscopy sandoval, 2021 [6] unknown pink homogeneous lesion with a focal bluish blotch/clod hemosiderin deposits polarized light dermoscopy white reticular pattern (negative pigment network) is due to elongated rete ridges and is characteristic of melanoma. nevertheless, it has also been observed in spitz/reed nevi. the diffuse area of bluish color is likely related to hemosiderin deposits, unlike the referred deposits observed in other cases reported as small focused globules. histopathological examination remains the diagnostic gold standard for endometriosis. it is considered mandatory in ruling out a neoplastic condition, as more than 60% of umbilical tumors are malignant. the description of new dermoscopic patterns and their histological correlations can be helpful in the diagnosis of this entity. informed consent: informed consent for publication of clinical details and clinical images was obtained from the patient. references 1. boesgaard-kjer d, boesgaard-kjer d, kjer jj. primary umbilical endometriosis (pue). eur j obstet gynecol reprod biol. 2017;209:44–45. 44-45. doi: 10.1016/j.ejogrb.2016.05.030. pmid: 27374811. 2. bonné e, daxhelet m, simon p, del marmol v, suppa m. the peculiar dermoscopic features of primary umbilical endometriosis. j eur acad dermatol venereol. 2020;34(10):e589-e591. doi: 10.1111/jdv.16455. pmid: 32277548. figure 1. (a) polarized dermoscopy shows central white reticular pattern (blue arrow) on a violet background (blue star) (dermlite dl4, ×10). (b) histopathology shows positivity for progesterone-receptor markers in endometrial glands and stroma (immunohistochemistry: anti-progesterone receptor antibodies; original magnification, ×100). research letter | dermatol pract concept. 2022;12(1):e2022023 3 3. de giorgi v, massi d, mannone f, stante m, carli p. cutaneous endometriosis: non-invasive analysis by epiluminescence microscopy. clin exp dermatol. 2003;28(3):315-7. doi: 10.1046/j.1365-2230.2003.01194.x. pmid: 12780722. 4. jaime tj, jaime tj, ormiga p, leal f, nogueira om, rodrigues n. umbilical endometriosis: report of a case and its dermoscopic features. an bras dermatol. 2013;88(1):121-4. doi: 10.1590/ s0365-05962013000100019. pmid: 23539017; pmcid: pmc3699952. 5. costa im, gomes cm, morais oo, costa mc, abraham ls, argenziano g. cutaneous endometriosis: dermoscopic findings related to phases of the female hormonal cycle. int j dermatol. 2014;53:e130-2. doi: 10.1111/j.1365-4632.2012.05854.x. pmid: 23621541 6. sandoval m, meza-romero r, peñailillo a, villaseca má, navarrete-dechent c. dermoscopy findings of umbilical endometriosis. australas j dermatol. 2021;62(1):e139-e141. doi: 10.1111/ajd.13437. pmid: 32909620. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022015 1 dermatofibrosarcoma protuberans in the palm of a 3-year-old child omer faruk kumbuloglu1, fatih barishan2, fevziye kabukcuoglu3, haci mustafa ozdemir2 1 department of orthopaedics and traumatology, hand surgery division, sisli hamidiye etfal training and research hospital, istanbul, turkey 2 department of orthopaedics and traumatology, sisli hamidiye etfal training and research hospital, istanbul, turkey 3 department of pathology, istanbul sisli hamidiye etfal application and research center, university of health sciences, istanbul, turkey key words: pediatric dermatofibrosarcoma protuberans, handpalm masses, mohs micorgraphic surgery, imatinib citation: kumbuloglu of, barishan f, kabukcuoglu f, ozdemir hm. dermatofibrosarcoma protuberans in the palm of a 3-year-old child. dermatol pract concept. 2022;12(1):e2022015. doi: https://doi.org/10.5826/dpc.1201a15 accepted: may 5, 2021; published: january 2022 copyright: ©2022 kumbuloglu et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: fatih barishan, md, department of orthopaedics and traumatology, sisli hamidiye etfal training and research hospital, istanbul, turkey. e-mail: drbarishan@hotmail.com introduction dermatofibrosarcoma protuberans (dfsp) is a low-grade, locally invasive tumor that originates from cutaneous tissues. dfsp is the second most frequent skin sarcoma and is generally diagnosed between the ages of 30 and 50. it is mostly localized in the trunk, proximal extremities, or in the head and neck region [1]. there are a few reports showing dfsp in the dorsum of the hand of pediatric cases [2]. in this study, a case is presented of a 3-year-old boy that underwent 3 operations for dfsp in the palm of the hand. case presentation a 3-year-old male child presented to our clinic with a mass lesion at the level of the second metacarpophalangeal joint in the palm of the right hand. two months before, the patient underwent surgical excision on the palm of his right hand at another clinic. the histological diagnosis was reported as lipofibromatosis at that time. physical examination revealed a 1.5 cm × 2 cm mass in the same region (figure 1a). in the second surgical excision of the patient, the mass lesion was excised together with the overlying skin. the defective area that occurred at the excision site was closed with a full-thickness skin graft obtained from the right inguinal area. the histological examination showed a spindle cell lesion that started just below the epidermis and reaching the dermis and subcutaneous fat tissue, with short bundles crossing each other and continued beyond the surgical border. marked atypia or mitotic activity was not observed. immunohistochemical studies revealed widespread cd34 staining. the focal staining properties were observed using caldesmon and alpha smooth muscle actin stains. desmin stain, hmb45, pancytokeratin, cd31, and calponin were all negative. the 2 research letter | dermatol pract concept. 2022;12(1):e2022015 ki67 proliferation index was approximately 2-5% and the lesion was diagnosed as dfsp (figure 1, b and c). the patient was reevaluated following the histological diagnosis of dfsp and a subsequent chest x-ray did not show metastasis. physical examination did not show any sign of lymphadenopathy. the third surgical excision was planned for the patient. in the third surgical excision mohs micrographic surgery was used. the surgical excision site was mapped with the tumor in the middle (figure 2, a and b). the whole epidermal tissue, dermal tissue, first lumbrical muscle, and common palmar digital nerve were excised together with a tissue margin of 1 cm (figure 2c). since intraoperative frozen examination was reported as negative for the surgical border, a 4 cm × 3 cm wound site was left open and covered with surgical dressing, and a plaster was applied. the wound healed with a secondary closure in 6 weeks. there was no need for radiotherapy or imatinib treatment. there was no sign of recurrence at the end of the first postoperative year (figure 2, d-f). conclusions a diagnosis of dfsp is made upon clinical examination and histological evaluation of the patient and is often difficult due the frequently asymptomatic and slow progression. histological diagnosis cannot be made with routine staining. clinicians should consider dfsp in the differential diagnosis for pediatric palmar cutaneous masses; otherwise, a delay in diagnosis may cause a loss of hand function. informed consent: written informed consent for publication of clinical details and clinical images was obtained from the patient. figure 1. (a) nodular lesion at the volar side of the right hand before the second surgical excision. (b) tissue specimen evaluation after the second surgical excision: spindle cells arranged in a storiform pattern (h&e, ×400) and (c) diffuse cd34 immunostaining (×400). research letter | dermatol pract concept. 2022;12(1):e2022015 3 figure 2. (a) appearance of the hand before mohs micrographic surgery. (b) tumor mapping, placing the lesion in the center. (c) after mohs micrographic surgery. (d) wound healing process following mohs micrographic surgery 4 weeks postoperatively. (e, f) appearance of the hand following mohs micrographic surgery 1 year postoperatively with good function and no contracture development. 4 research letter | dermatol pract concept. 2022;12(1):e2022015 references 1. shah kk, mchugh jb, folpe al, patel rm. dermatofibrosarcoma protuberans of distal extremities and acral sites: a clinicopathologic analysis of 27 cases. am j surg pathol. 2018;42(3):413-419. doi: 10.1097/pas.0000000000000998. pmid: 29240584. 2. tsai yj, lin py, chew ky, chiang yc. dermatofibrosarcoma protuberans in children and adolescents: clinical presentation, histology, treatment, and review of the literature. j plast reconstr aesthet surg. 2014;67(9):1222-1229. doi: 10.1016/j. bjps.2014.05.031. pmid: 24973861. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022056 1 introduction metastatic crohn disease (mcd) is a rare skin manifestation of crohn disease (cd). mcd can develop on any cutaneous surface, but has a predilection for the genital region, especially in children [1]. herein, we present an adult case of mcd with groin localization, so as to highlight the fact that this localization can easily be overlooked if patients do not present with any gastrointestinal symptoms. case presentation a 58-year-old male presented with a painful ulcer that had appeared on his right groin 10 days earlier. he did not report having any systemic diseases or systemic symptoms involving the gastrointestinal system. upon dermatological examination there was a linear, 1.3 cm × 5 cm tender ulcer on his right groin. the ulcer was rather deep and extended to the subcutaneous tissue, forming a fistulous tract. a swab culture of the discharge showed enterococcus faecalis, enterococcus faecium, escherichia coli, and klebsiella pneumoniae growth; therefore, parenteral sulbactam-ampicillin therapy was initiated. despite the lack of high-risk sexual behavior, doxycycline was empirically added to the patient antibiotic regimen for lymphogranuloma venereum infection, but the ulcer did not improve. a skin punch biopsy sample was obtained from the edge of the ulcer and histopathological analysis showed suppurative granulomatous inflammation. histological stains were negative for bacterial and fungal microorganisms. following histopathological examination, cutaneous tuberculosis, deep fungal infection, tularemia, and syphilis, which can lead to granuloma formation, were ruled out via additional detailed tests, including skin culture, pcr, and serological tests. to assess the connection of the ulcer, fistulography was performed, which showed distribution of the radiocontrast agent in several tracts between soft tissues. abdominal computed tomography scan showed terminal ileitis and a fistula extending to the skin, although the patient did not report any gastrointestinal symptoms relating to the diagnosis of cd. colonoscopy and colonoscopic biopsy were performed, and the findings were consistent with active colitis. based on the clinical, radiological, colonoscopic, and histopathologic findings, the patient was diagnosed with mcd. after metastatic crohn disease with groin localization in an adult patient duygu gulseren1, sibel ersoy-evans1 1 hacettepe university, school of medicine, department of dermatology, ankara, turkey key words: metastatic crohn disease, groin, adult, genital ulcers, granuloma citation: gulseren d, ersoy-evans s. metastatic crohn’s disease with groin localization in an adult patient. dermatol pract concept. 2022;12(2):e2022056. doi: https://doi.org/10.5826/dpc.1202a56 accepted: august 30, 2021; published: april 2022 copyright: ©2022 gulseren et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: duygu gülseren, hacettepe university, school of medicine, department of dermatology, sihhiye/ankara, ankara, tr 06100. e-mail: duygu_gulsrn@hotmail.com 2 research letter | dermatol pract concept. 2022;12(2):e2022056 starting oral mesalazine, azathioprine, and prednisolone, the fistulous discharge decreased, but the ulcer did not heal completely (figure 1); consequently, fistulectomy and right hemicolectomy were performed. discussion mcd is the least common dermatologic manifestation of cd. in 70% of adult patients mcd lesions appear after the initial diagnosis of cd; therefore, its diagnosis can be challenging in adults without active gastrointestinal symptoms at presentation [2]. the presented patient did not have any figure 1. ulcer with incompletely healed fistula opening. gastrointestinal symptoms, which delayed the diagnosis of mcd. another challenging aspect of diagnosis is ulcer localization. although the most common presentation of mcd in children is the genital region, the most common presentation in adults is the extremities. genital localization is of particular importance in sexually active adult patients, as it can mimic sexually transmitted diseases. conclusions mcd is a rare cause of genital ulcers in adult patients and can present without gastrointestinal symptoms. genital ulcers with granuloma formation in adults should suggest mcd, even in patients that do not report any gastrointestinal symptoms. references 1. schneider sl, foster k, patel d, shwayder t. cutaneous manifestations of metastatic crohn’s disease. pediatr dermatol. 2018;35(5):566-574. doi: 10.1111/pde.13565. pmid: 29952016. 2. palamaras i, el-jabbour j, pietropaolo n, et al. metastatic crohn’s disease: a review. j eur acad dermatol venereol. 2008;22(9):10331043. doi: 10.1111/j.1468-3083.2008.02741.x. pmid: 18573158. dermatology: practical and conceptual dermatology practical & conceptual original article | dermatol pract concept. 2022;12(1):e2022031 1 comparison of actinic keratosis and severity index with physician global assessment and total lesion count and the ability to predict skin cancer ayda acar1, isil karaarslan1 1 ege university, medical faculty, department of dermatology and venereology, izmir, turkey key words: actinic keratosis, akasi, physician global assessment, skin cancer, total lesion count citation: acar a, karaarslan i. comparison of actinic keratosis and severity index with physician global assessment and total lesion count and the ability to predict skin cancer. dermatol pract concept. 2022;12(1):e2022031. doi: https://doi.org/10.5826/dpc.1201a31 accepted: august 14, 2021; published: january 2022 copyright: ©2022 acar and karaarslan. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ayda acar, md, department of dermatology, ege university faculty of medicine, university street bornova, izmir, turkey. e-mail: aydaerbas@yahoo.com introduction: actinic keratosis (ak) is a known indicator for sun damage, and subsequent squamous cell cancer may develop. the actinic keratosis and severity index (akasi) is a recently developed tool that can evaluate both field cancerization and ak severity. objectives: we sought to evaluate if akasi was a good predictor of cancer in ak patients and to compare akasi with both the physician global assessment (pga) and total lesion count (tlc). methods: ninety patients with ak were included in the study. each patient was examined, and aks were scored with akasi, pga and tlc by 2 dermatologists. the akasi, pga and tlc values were compared between patients with skin cancer and patients without skin cancer. results: mean akasi, pga, and tlc scores were 4.9, 1.7 and 9 respectively. the patients with skin cancer had higher scores of akasi, pga and tlc compared to the patients without skin cancer (p = 0.022, p = 0.014, p = 0.005, respectively). akasi, pga and tlc were very strongly correlated with each other (p < 0.001). the akasi threshold value for non-melanoma skin cancer was determined to be 5.1. conclusions: akasi, pga and tlc may be used in the assessment of the severity of ak in daily practice or studies and may be considered as valuable tools in determining high-risk patients and to choose treatment option. akasi seems to have an advantage to give a numeric threshold value for skin cancer. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022031 introduction actinic keratoses (ak) are hyperkeratotic lesions on sun-damaged skin characterized by atypical epidermal proliferation of keratinocytes that have a potential for malignant transformation to squamous cell carcinoma (scc). they are generally asymptomatic, erythematous, or pigmented papules or plaques with scales, located on sun-exposed areas like the face, scalp, ear helices, and dorsum of the hand [1]. excessive exposure to ultraviolet (uv) radiation is the major cause of ak. fairer skin types, older age, chronic use of systemic immunosuppressive drugs, and exposure to arsenic have also been described as risk factors [2-4]. in addition to immunosuppressive drugs, other drugs, such as voriconazole, calcium channel blockers, braf inhibitors, hedgehog inhibitors, hydroxyurea, and psoralen plus uva therapy have been linked to a higher risk for ak and sccs [5-8]. on the other hand, oral retinoids and nicotinamide have been linked to a reduction in the risk of ak and scc [9]. the estimated risk for an individual ak to transform into scc has been reported to be 0.075%-0.096% annually [2]. although most of aks regress spontaneously or persist without a malignant transformation, the major concern is the difficulty in estimating which lesion might have a higher potential for malignancy. the thickness or hyperkeratosis of an individual ak lesion does not have equal scc progression risk [10]; thus, treatment is highly recommended for each ak lesion. in recent years, the term field cancerization (fc), which describes an area of severe sun damage with multiple aks, telangiectasia, wrinkles, dyschromia and elastosis, has been proposed [11] and fc treatment has been recommended for a better management of the patients [3]. the identification of patients with a higher risk for malignant transformation is another important issue to consider when deciding which patients should be included in a closer follow-up program. there have been some efforts to grade the risk of patients with malignant potential. the physician global assessment (pga) scale is a subjective assessment tool that allows the physician to evaluate the overall situation of the patient [12]. pga grades aks in five categories (0: clear, 1: almost clear, 2: mild, 3: moderate, 4: severe) [12]. the total lesion count (tlc), in which physician counts the clinically evident ak lesions, is another suggested way to evaluate a patient both before and after the therapy [13]. recently, the actinic keratosis and severity index (akasi) has been suggested [12]. the akasi supplies a numerical score on an index and evaluates both the severity of ak and fc (table 1) [12]. akasi has also been reported to be useful in monitoring treatment outcomes [10]. in akasi score, the head is divided into 4 regions: scalp, forehead, left face (cheek, ear, chin, and nose), and right face. the scalp constitutes 40% of the head region, and each of the other areas constitutes 20%. for each of the 4 areas, the percentage of actinic damage is scored 0 to 6. the most prominent ak distribution, erythema, and thickness are assessed from 0-4. the maximum akasi value is 18. the pivotal study proposed an akasi score of 2.9 as mild, 5.3 as moderate, 8.3 as severe, 8.7 as very severe [12]. objectives in the literature, the data on the association between non-melanoma skin cancer and akasi, pga, and tlc is limited [14]. in this study, we sought to evaluate this association and discuss the ability of these methods to predict skin malignancy. methods the study was approved by the local ethics committee (no: 70198063-050.06.04). patients with ak, who were referred to our dermato-oncology unit within a 6-month period and who signed the informed consent form, were involved in the study. patients with a history of photosensitivity, nonmelanoma skin cancer (nmsc)-prone genodermatoses, and melanoma were excluded. a detailed anamnesis on accompanying diseases, drug usage, previous history of nmsc, duration of the present lesions, and the fitzpatrick skin type were recorded. a total-body skin and dermoscopic examination were performed for each patient. the patients were examined by 2 dermatologists at the same time in order to avoid any interobserver variability. the akasi, pga and tlc values were noted. descriptive statistics of the data were given as mean, standard deviation, median, minimum, maximum, frequency and percentage values. normality assumption of quantitative data was checked by shapiro-wilk test. independent sample t-test was used for variables with normal distribution, while mann-whitney u test and kruskal-wallis test (dunn test for paired comparisons) were used for variables that did not provide the assumption of normality. the correlation of quantitative data with each other was evaluated with spearman rho correlation coefficient. relationships between categorical variables were examined using the pearson chi-square test. a receiver operating characteristic (roc) analysis was used to determine a cutoff point for diagnostic methods. statistical analysis was performed using ibm spss statistics 25.0 (ibm spss statistics for windows, version 25.0, ibm) package program. the significance level was set at 0.05 in all analyses. original article | dermatol pract concept. 2022;12(1):e2022031 3 table 1. definition of components of actinic keratosis area and severity index (akasi) and how to calculate akasi score* evaluation of akasi [12] akasi components definitions solar damage (sd) head is divided to 4 areas: scalp (s), forehead (f), right half of the face (r), left half of the face (l). skin with solar damage for each of the 4 areas is estimated and scored 0-6. 0 (0%), 1(1-9%), 2(10-29%), 3(30-49%), 4(50-69%), 5 (70-89%), 6 (90-100%). distribution of ak (d) 0 no ak 1 isolated or scattered ak 2 clustered (small clusters up to 25 cm2) 3 clustered and confluent (aks are coalescing in a cluster of <25 cm2) 4 confluent (aks are coalescing and cannot be easily distinguish) erythema of ak (e) 0 no erythema 1 slight red 2 moderate red 3 intense red 4 very intense red thickness of ak (t) 0 no palpable or visible ak 1 just palpable ak 2 clearly palpable 3 thickened 4 very thickened total akasi score (0-18) 0.4 x (d+e+t+sd of scalp) + 0.2 x (d+e+t+sd of forehead) + 0.2 x (d+e+t+sd of right face) + 0.2 x (d+e+t+sd of left face) *adapted from the report of dirschka et al [12]. ak = actinic keratosis; akasi = actinic keratosis area and severity index. results a total of 90 patients were involved in the study. fifty-four patients (60%) were males. the age range was 48-87 years (mean age was 69 years and median age was 71). the accompanying diseases were hypertension (43%), diabetes mellitus (27%), coronary arterial disease (cad) (14%), solid organ malignancy (13%), inflammatory or autoimmune skin diseases (13%), solid organ transplantation (6%) and others (asthma, vertigo, parkinson disease, migraine, gut, essential thrombocytosis, familial mediterranean fever, hepatitis b) (10%). fourteen patients (16%) were receiving calcium channel blockers, 9 patients (10%) were receiving immunosuppressive drugs, and 1 patient was receiving hydroxyurea. the distribution of fitzpatrick skin type was as follows: 73 patients (81%) had fitzpatrick skin type ii and 17 patients (19%) had type iii. the duration of the present ak lesions ranged from 2 months to 30 years. the mean duration was 7 years. mean akasi was 4.9, mean pga was 1.7 and mean tlc was 9.3. mean akasi was 6 in male patients and 3 in female patients. the difference between male and female patients was statistically significant (p < 0.001). mean pga was 2 in male and 1 in female patients. mean tlc was 11 in male and 7 in female patients. the difference between male and female patients of pga and tlc was statistically significant (p < 0.001, p = 0.002). 4 original article | dermatol pract concept. 2022;12(1):e2022031 fifty-one patients (57%) did not have any current skin cancer or skin cancer history. a total of 39 patients (43%) had a current skin cancer and/or past history of skin cancer. among them, 28 patients (31.1%) had only previous skin cancer history, 8 patients (8.8%) had only concurrent skin cancer, and 3 patients (3.3%) had both concurrent skin cancer and previous skin cancer history. nineteen patients (21.1%) had only basal cell carcinoma (bcc) and bcc count was 26. thirteen patients (14.4%) had only scc and scc count was 21. seven patients (7.7%) had both scc and bcc, tumor count was 29 (11 for scc and 18 for bcc). one patient who had both bcc and scc also had 2 basosquamous cell carcinomas. total tumor count was 78 (44 for bcc, 32 for scc, and 2 for basosquamous cell carcinoma). in all but 7 patients all the tumors were located on the face or scalp. in 7 patients, 14 tumors (8 bccs and 6 sccs) were located on an extremity or trunk. none of the patients had skin cancer metastasis. all items were compared between the group with previous or present skin cancer (group a, n = 39) and the group with no history of skin cancer (group b, n = 51) (table 2). the mean age in group a was 70 years (median 73 years), and the mean age in group b was 69 years (median 70 years). the mean age of the patients was higher in the group with skin cancer, but it was not statistically significant (p = 0.261). mean and median ak duration was longer in the group a (mean 9, median 9) compared to the group b (mean 6, median 5). having longer ak duration in the group a was statistically significant (p = 0.009). the distribution of demographic features and scores of akasi, pga and tlc in the two groups are shown in table 2. there was no statistically significant relationship between having skin cancer and gender (p = 0.794), or accompanying diseases. however statistically significant relationship was found with not having cad (p = 0.028). ak duration was significantly related with akasi, pga and tlc scores (p = 0.038, p = 0.010, p = 0.016). mean and median akasi, pga score and tlc were higher in group a (mean 6, median 6; mean 2, median 2; and mean 11, and median 11, respectively) compared to group b (mean 4, median 4; mean 2, median 1 and mean: 8, and median 7, respectively) (table 2). the higher scores of akasi, pga and tlc in group a were statistically significant (p = 0.022, p = 0.014, p = 0.005). nineteen patients with high risk drugs or diseases for skin cancer had higher akasi scores and it was statistically significant (p = 0.033). these patients had also higher mean pga and tlc values, which were not statistically significant (p = 0.077, p = 0.221). patients were also grouped as no skin cancer (group i, n = 51 patients), patients with only bcc (group ii, n = 19 patients), patients with only scc (group iii, n = 13 patients), and patients with both bcc and scc (group iv, n = 7 patients). mean akasi score, pga, and tlc were highest in group iv. the ranking of mean values of scores was: group iii, ii, and i respectively. the increase in the mean values of akasi, pga, and tlc from group i to group iv was statistically significant (p = 0.026, p = 0.026, p = 0.038). the total number of skin cancer counts (previous and present) were not related with akasi, pga, and tlc (p = 0.064, p = 0.075, p = 0,149). akasi, pga, and tlc were correlated with each other (p < 0.001). correlation between akasi and pga, between akasi and tlc, and between pga and tlc were very strong (r = 0.881, r = 0.893, r = 0.849). as a result of roc analysis, the akasi threshold value for total nmsc was determined to be 5.1 (p = 0.022, area = 0.642). the akasi thresholds for scc and bcc according to roc analysis were 5.5 (p = 0.056, area = 0.682) and 6.9 (p = 0.926, area = 0.509), respectively. total nmsc threshold value was statistically significant. however, threshold values for only bcc or only scc groups were not statistically significant. table 2. comparison between the group with previous or present skin cancer (group a) and the group with no history of skin cancer (group b). group a group b male percent 62% 59% mean and median age 70, 73 69, 70 mean and median ak duration (years) 9, 9 6, 5 mean and median akasi 6, 6 4, 4 mean and median pga 2, 2 2, 1 mean and median tlc 11, 11 8, 7 ak = actinic keratosis; akasi = actinic keratosis area and severity index; pga = physician global assessment; tlc = total lesion count. original article | dermatol pract concept. 2022;12(1):e2022031 5 conclusions in order to determine the malignant transformation risk in ak, there is a need for scoring the disease extent and overall severity rather than evaluating the individual lesion. pga and tlc have been used for determining the severity of ak. recently, in 2017, akasi was proposed by dirschka et al [12]. in 2018, pellacani et al compared akasi with tlc [13] and found akasi a reproducible method that can be used in clinical trials as an alternative to tlc. although no significant difference was found between akasi and tlc in the interobserver variability, akasi had a slightly higher intra-class correlation coefficient compared to tlc. they stated that either of the 2 methods could be used [13]. in 2018, schmitz et al investigated the association between akasi and keratinocytic tumors [14]. they concluded patients with scc had a higher akasi score compared to patients with bcc, bowen disease or ak solely [14]. schmitz et al suggested that the akasi score of 3 is consistent with mild, 5.5 moderate, 8.5 severe, and > 11 very severe ak. their estimated akasi score for invasive scc development was found to be 7, median akasi scores of 4.8, and 7.1 and pga 2 and 2.5 in patients with bcc and scc respectively [14]. additionally, akasi was used in studies evaluating ak treatment outcomes [10, 15-18]. in 2017, dréno et al [19] recommended the actinic keratosis field assessment scale (ak-fas) to evaluate the severity of ak and sun damage, as ak-fas evaluates ak area percentage, hyperkeratosis and sun damage. the ak area is graded as i-iv (< 10%, 10%-25%, > 25%-50%, and > 50%) according to percentage of ak covering the face or scalp. hyperkeratosis and sun damage are assessed as absent or present [19]. in 2019, akfas together with akasi was used in a study of both dermoscopic and reflectance confocal microscopic evaluation of ak before and after imiquimod therapy [15]. we preferred to use akasi over ak-fas because ak-fas does not provide a numerical value as akasi does. in the present study, the median akasi, pga, and tlc values were found to be significantly higher in patients with nmsc compared with patients without nmsc. these values were highest in the patients who had both bcc and scc and in the patients who had scc alone. additionally, akasi, pga, and tlc were well correlated. the akasi threshold value for nmsc was determined to be 5.1; male patients had significantly higher akasi, pga, and tlc scores compared to female patients. the patients with current skin cancer or skin cancer history had significantly longer ak duration, higher akasi, pga, and tlc scores compared to patients without skin cancer or history of skin cancer. patients who had an immunosuppressive condition (drugs, solid organ transplantation, and systemic malignancy) had significantly higher akasi scores compared to patients without an immunosuppressive condition. our study employed akasi, pga and tlc to assess the severity of ak and to evaluate the relationship with malignancy risk. we conclude that akasi, pga, and tlc may be used in the assessment of the severity of ak in daily practice or studies. although a longer period is needed for calculation of akasi, it seems advantageous to have a numerical threshold value for skin cancer. this is the second study that evaluates this threshold value in the literature. to establish a common value, more studies are needed. references 1. siegel ja, korgavkar k, weinstock ma. current perspective on actinic keratosis: a review. br j dermatol. 2017;177(2):350-358. doi: 10.1111/bjd.14852. pmid: 27500794. 2. soyer ph, rigel ds, mcmeniman e. actinic keratosis, basal cell carcinoma and squamous cell carcinoma. in: bolognia jl, schaffer jv, cerroni l, eds. dermatology. fourth edition. elsevier, 2018:1872-1893. 3. de berker d, mcgregor jm, mohd mustapa mf, exton ls, hughes br. british association of dermatologists’ guidelines for the care of patients with actinic keratosis 2017. br j dermatol. 2017;176(1):20-43. doi: 10.1111/bjd.15107. pmid: 28098380. 4. dirschka t, gupta g, micali g, et al. real-world approach to actinic keratosis management: practical treatment algorithm for office-based dermatology. j dermatolog treat. 2017;28(5):431442. doi: 10.1080/09546634.2016.1254328. pmid: 27796187. 5. corchado-cobos r, garcía-sancha n, gonzález-sarmiento r, pérez-losada j, cañueto j. cutaneous squamous cell carcinoma: from biology to therapy. int j mol sci. 2020,22;21(8):2956. doi: 10.3390/ijms21082956. pmid: 32331425. pmcid: pmc7216042. 6. richard ma, amici jm, basset-seguin n, claudel jp, cribier b, dreno b. management of actinic keratosis at specific body sites in patients at high risk of carcinoma lesions: expert consensus from the akteam™ of expert clinicians. j eur acad dermatol venereol. 2018;32(3):339-346. doi: 10.1111/jdv.14753. pmid: 29235161. 7. williams vl, cohen pr, stewart dj. sorafenib-induced premalignant and malignant skin lesions. int j dermatol. 201;50(4):396402. doi: 10.1111/j.1365-4632.2010.04822.x. pmid: 21413947. 8. gandini s, palli d, spadola g, et al. anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis. crit rev oncol hematol. 2018;122:1-9. doi: 10.1016/j.critrevonc.2017.12.003. epub 2017 dec 13. pmid: 29458778. 9. national comprehensive cancer center. nccn clinical practice guidelines in oncology; squamous cell carcinoma (v1.2020). available from www.nccn.org. accessed november 25, 2020. 10. schmitz l, von dobbeler c, gupta g, et al. photodynamic therapy leads to significant improvement of actinic keratosis area and severity index (akasi). photodiagnosis photodyn ther. 2018; 21:66-70. doi: 10.1016/j.pdpdt.2017.10.007. pmid: 29051122. 11. heppt mv, leiter u, steeb t, et al. s3 guideline for actinic keratosis and cutaneous squamous cell carcinoma short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators. j dtsch dermatol ges. 2020;18(3):275294. doi: 10.1111/ddg.14048. pmid: 32130773. 6 original article | dermatol pract concept. 2022;12(1):e2022031 12. dirschka t, pellacani g, micali g, et al. athens ak study group. a proposed scoring system for assessing the severity of actinic keratosis on the head: actinic keratosis area and severity index. j eur acad dermatol venereol. 2017;31(8):1295-1302. doi: 10.1111/jdv.14267. pmid: 28401585. 13. pellacani g, gupta g, micali g, et al. actinic keratosis area severity index (akasi): reproducibility study and comparison with total lesion count. br j dermatol. 2018;179(3):763-764. doi: 10.1111/bjd.16559. pmid: 29572818. 14. schmitz l, gambichler t, gupta g, stücker m, dirschka t. actinic keratosis area and severity index (akasi) is associated with the incidence of squamous cell carcinoma. j eur acad dermatol venereol. 2018;32(5):752-756. doi: 10.1111/jdv.14682. pmid: 29117441. 15. benati e, longhitano s, pampena r, et al. digital follow-up by means of dermatoscopy and reflectance confocal microscopy of actinic keratosis treated with imiquimod 3.75% cream. j eur acad dermatol venereol. 2020;34(7):1471-1477. doi: 10.1111/ jdv.16143.. pmid: 31838781. 16. schmitz l, gupta g, segert mh, et al. diclofenac sodium 3% in hyaluronic acid 2.5% gel significantly diminishes the actinic keratosis area and severity index. skin pharmacol physiol. 2018;31(4):206-211. doi: 10.1159/000488248. pmid: 29791916. 17. jordan m, ghoreschi k, eberle fc. daylight photodynamic therapy for severe facial and scalp actinic keratosis: a prospective non-sponsored single-centre study employing the actinic keratosis area and severity index (akasi). eur j dermatol. 2019;29(1):6774. doi: 10.1684/ejd.2018.3492. pmid: 30827943. 18. von dobbeler c, schmitz l, dicke k, szeimies rm, dirschka t. pdt with ppix absorption peaks adjusted wavelengths: safety and efficacy of a new irradiation procedure for actinic keratoses on the head. photodiagnosis photodyn ther. 2019;27:198-202. doi: 10.1016/j.pdpdt.2019.05.015. pmid: 31176762. 19. dréno b, cerio r, dirschka t, et al. a novel actinic keratosis field assessment scale for grading actinic keratosis disease severity. acta derm venereol. 2017;97(9):1108-1113. doi: 10.2340/00015555-2710. pmid: 28536731. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):6 27 dermatology practical & conceptual www.derm101.com case presentation a 51-year-old woman presented with a 7 mm black papule on the left submandibular region (figure 1a). the papule was irregularly shaped, sharply demarcated and with a verrucous surface (figure 1b). the patient had noted the lesion only five weeks earlier and reported it had been growing rapidly. dermoscopic evaluation revealed blue-white and black clods and scale (figure 2). the differential diagnosis at this point included nodular melanoma that would have required an excisional biopsy; however, a pigmented seborrheic keratosis, which could be sampled with a shave biopsy, was considered due to the stuck-on, verrucous appearance of the lesion [1]. therefore, reflectance confocal microscopy (rcm) of the lesion was undertaken. the overall architecture was that of ridges and surface depressions filled with keratotic debris, echoing the clinically observed verrucous surface (figure 3). within the hyperplastic epidermis, including the suprabasal layers, there were numerous tangled dendritic cells (figure 4), suggestive of melanocytes in a pagetoid distribution throughout the epidermis. based on rcm examination, a melanoma was suspected and the lesion was therefore excised. histopathological analysis revealed an exophytic, well-circumscribed silhouette, the reticulated, hyperplastic epidermis showed compact hyperkeratosis, acanthosis and horn pseudocysts, intermingled with the keratinocytes throughout the lesion were numerous large, dendritic, melanin-rich melanocytes (figures 5 a, b, c) confirmed with mart-1 staining in vivo reflectance confocal microscopy features of a melanoacanthoma neda shahriari1, jane m. grant-kels1, harold s. rabinovitz2, margaret oliviero2, alon scope3 1 department of dermatology, university of connecticut health center, farmington, ct, usa 2 department of dermatology, university of miami miller school of medicine, miami fl, usa 3 department of dermatology, sheba medical center and sackler faculty of medicine, tel aviv university, tel aviv, israel key words: melanoacanthoma, rcm, microscopy, seborrheic keratosis citation: shahriari n, grant-kels jm, rabinovitz hs, oliviero m, scope a. in vivo reflectance confocal microscopy features of a melanoacanthoma. dermatol pract concept 2016;6(4):6. doi: 10.5826/dpc.0604a06 received: july 21, 2016; accepted: august 27, 2016; published: october 31, 2016 copyright: ©2016 shahriari et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: jane m. grant-kels, md, uconn dermatology dept, 21 south rd, farmington, ct 06032, usa. email: grant@ uchc.edu efforts have been expended to evaluate the reflectance confocal microscopy (rcm) features of different clinical entities in order to more thoroughly delineate benign versus malignant features. in this way, rcm can help clinicians to be more selective in regard to undertaking appropriate skin biopsies and improving their benign to malignant ratio. herein, we report a case of a histopathologically proven melanoacanthoma, a variant of seborrheic keratosis. there are scarce reports describing the rcm features of melanoacanthoma. our case demonstrated rcm features that were suspicious for melanoma. more rcm images of this benign entity are needed to establish definitive diagnostic criteria. abstract mailto:grant@uchc.edu mailto:grant@uchc.edu 28 observation | dermatol pract concept 2016;6(4):6 and consistent with the diagnosis of seborrheic keratosis, melanoacanthoma variant. discussion seborrheic keratosis (sk) is a benign epidermal proliferation commonly found in individuals in the fifth decade of life and older [2]. classically, sk is readily identified as a papule or plaque with a greasy “stuck-on” appearance, sharply demarcated borders and brown-tan color. sks may appear on the head, trunk and extremities, but always spare the figure 2. dermoscopic image shows a verrucous contour with irregular blue-white and black clods. [copyright: ©2016 shahriari et al.] figure 1. clinical photographs. (a) pigmented papule on the left submandibular region (b) the irregular, 7 mm black papule displays a verrucous surface. [copyright: ©2016 shahriari et al.] figure 3. rcm image of the lesion at the stratum corneum layer demonstrates a wellcircumscribed lesion with overall architecture of ridges and surface depressions filled with keratotic debris. [copyright: ©2016 shahriari et al.] figure 4. rcm image of lesion (500 x 500 um2) at the spinous granular layers of the epidermis show numerous tangled bright dendritic cells. [copyright: ©2016 shahriari et al.] observation | dermatol pract concept 2016;6(4):6 29 [13,14]; therefore, the “efg” rule, which assesses “elevation,” “firmness” on palpation, and continuous “growth” over one month, was established to more critically assess lesions of this subtype [15]. more recently, the use of the “blue-black rule” was prompted as an important clue for the diagnosis of pigmented nodular melanoma [16,17]. as such, the benign lesion described herein would raise suspicions for melanoma. to this end, we utilized rcm imaging to identify distinguishing features between melanoacanthoma and pigmented nodular melanoma in hopes of sparing unnecessary excisional biopsy of a benign lesion. we could not identify previous publications reporting the rcm features of melanoacanthoma. in the present case, we observed by rcm the ridges and surface depression that reflect the verrucous surface but could not observe other rcm criteria for sk, such as widening and interweaving of the rete ridges (“polycylic papillary contours”) and horn pseudocysts [18]. it is likely that the thickened keratotic surface epidermis hindered imaging of the dej. we did observe numerous, tangled dendritic cells, at the basal and supra-basal layers of the epidermis, which we interpreted as suspicious for a melanoma. of note, we did not identify any other rcm criteria of nodular melanoma—including a thinned epidermis with flattening of the dermo-epidermal junction (dej), disarranged epidermis, pleomorphic cells with bright cytoplasm at the basal layer and in pagetoid distribution, and “cerebriform” nests in the papillary dermis [19,20]. in hindsight, the dense, almost uniform proliferation of dendritic melanocytes at both the basal and suprabasal layers of the epidermis may be a clue to melanoacanthoma; however, this potential clue may be difficult to evaluate in cases where the basal layer is not explorable. on the other hand, previous reports of the presence of dendritic cells in rcm of melanomas were typically observed in flat lesions [21,22]. therefore, another possible diagnostic clue for the rcm of melanoacanthoma may be the presence of dendritic cells in the context of a thickened epidermis with rcm characteristics consistent with seborrheic keratosis, including fissures and horn pseudocysts. palmo-plantar surfaces. in addition to this classic appearance, sk can present many morphological “faces”; in fact, some sks may be quite difficult to clinically distinguish from other diagnostic entities, such as squamous cell carcinoma, melanocytic nevi, or even malignant melanomas [3,4]. on histopathology, sk can be divided into six principle variants: acanthotic, hyperkeratotic, adenoid, irritated, clonal and melanoacanthoma [5]. melanoacanthoma, a term coined by mishima and pinkus [6], is an infrequent variant of sk that is clinically notable for its dark pigmentation, making this entity difficult to distinguish from melanoma at the bedside [7]. histopathologically, melanoacanthoma shows an epidermis usually marked by hyperkeratosis, acanthosis and horn pseudocysts, as well as islands of small basaloid cells intermingled with large dendritic melanocytes. the melanocytes are large, dendritic, contain abundant melanin, and are not restricted to the basal cell layer [8,9]. melanoacanthoma has been scarcely characterized with dermoscopy or with rcm. one case of histopathologically confirmed melanoacanthoma demonstrated under dermoscopy the starburst pattern, which is usually seen in pigmented spitz/reed nevi [10]. another report of melanoacanthoma identified a cribriform pattern of ridges [11]. a more recent case series reported on the dermoscopic features of eight histopathologically proven melanoacanthomas. all eight lesions had at least one dermoscopic feature associated with sk, including comedo-like openings, sharp demarcation, more than two milia-like cysts, ridges and fissures, moth-eaten borders, or hairpin vessels [12]. however, six of these lesions also showed dermoscopic features worrisome for melanoma, which would have likely prompted a biopsy. dermoscopic evaluation of the lesion reported herein did not show any clear-cut features of sk or a starburst pattern. in fact, the clinically and dermoscopically observed blueblack pigmentation prompted us to consider the diagnosis of a pigmented nodular melanoma [13,14]. nodular melanomas may lack the classic abcd criteria for melanoma diagnosis figure 5. histopathology of the lesion shows an exophytic, well-circumscribed, reticulated epidermal proliferation confined to a markedly widened papillary dermis. the hyperplastic epidermis shows compact hyperkeratosis, acanthosis and horn pseudocysts, findings diagnostic for seborrheic keratosis. intermingled with the keratinocytes throughout the epidermis are numerous large, dendritic, melanin-rich melanocytes confirmed with mart-1 staining. [copyright: ©2016 shahriari et al.] a b c 30 observation | dermatol pract concept 2016;6(4):6 11. shankar v, nandi j, ghosh k, ghosh s. giant melanoacanthoma mimicking malignant melanoma. indian j dermatol 2011;56(1):79-81. pmid: 26083708. doi: 10.1001/jamadermatol.2015.1453. 12. chung e, marghoob aa, carrera c, marchetti ma. clinical and dermoscopic features of cutaneous melanoacanthoma. jama dermatol 2015;151(10):1129-30. 13. liu w, dowling jp, murray wk, et al. rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. arch dermatol 2006;142:1551–8. pmid: 17178980. doi: 10.1001/archderm.142.12.1551. 14. clark wh jr, from l, bernardino ea, mihm mc. the histogenesis and biologic behaviour of primary human malignant melanomas of the skin. cancer res 1969;29:705–27. pmid: 5773814. 15. kalkhoran s, milne o, zalaudek i, et al. historical, clinical, and dermoscopic characteristics of thin nodular melanoma. arch dermatol 2010;146:311–18. pmid: 20231503. doi: 10.1001/ archdermatol.2009.369. 16. argenziano g, longo c, cameron a, et al. blue‐black rule: a simple dermoscopic clue to recognize pigmented nodular melanoma. br j dermatol 2011;165(6):1251-5. pmid: 21916885. doi: 10.1111/j.1365-2133.2011.10621.x. 17. pizzichetta ma, kittler h, stanganelli i, et al. pigmented nodular melanoma: the predictive value of dermoscopic features using multivariate analysis. br j dermatol 2015;173(1):106-14. pmid: 25916655. doi: 10.1111/bjd.13861. 18. ahlgrimm-siess v, cao t, oliviero m, et al. seborrheic keratosis: reflectance confocal microscopy features and correlation with dermoscopy. j am acad dermatol 2013;69:120-6. pmid: 23415460. doi: 10.1016/j.jaad.2012.12.969. 19. segura s, pellacani g, puig s, et al. in vivo microscopic features of nodular melanomas: dermoscopy, confocal microscopy, and histopathologic correlates. arch dermatol 2008; 144:1322-20. pmid: 18936395. doi: 10.1001/archderm.144.10.1311. 20. pupelli g, ferrari b, farnetani f, et al. melanoma. in: gonzalez s (ed.). reflectance confocal microscopy in dermatology: fundamentals and clinical applications. aulamedica, 2012:47-51. 21. pellacani g, de pace b, reggiani c, et al. distinct melanoma types based on reflectance confocal microscopy. exp dermatol 2014;23:414-8. pmid: 24750486. doi: 10.1111/exd.12417. 22. braga jc, macedo mp, pinto c, et al. learning reflectance confocal microscopy of melanocytic skin lesions through histopathologic transversal sections. plos one 2013;8:e81205. pmid: 24339910. doi: 10.1371/journal.pone.0081205. in summary, in the melanoacanthoma variant of sk presented herein, ruling out melanoma proved difficult on clinical and dermoscopic examination, as well as by rcm imaging. more cases of melanoacanthomas imaged by rcm will be needed to try and establish specific rcm criteria for the diagnosis of this benign entity. references 1. longo c, farnetani f, ciardo s, et al. is confocal microscopy a valuable tool in diagnosing nodular lesions? a study of 140 cases. br j dermatol 2013;169:58-67. pmid: 23374159. doi: 10.1111/bjd.12259. 2. gill d, dorevitch a, marks r. the prevalence of seborrheic keratoses in people aged 15 to 30 years: is the term senile keratosis redundant? arch dermatol 2000;136(6):759-62. pmid: 10871940. 3. marks r, jolley d, mccormack c, dorevitch ap. who removes pigmented skin lesions? j am acad dermatol 1997;36:721-6. pmid: 9146533. doi: 10.1016/s0190-9622(97)80324-6. 4. longo c, moscarella e, piana s, et al. not all lesions with a verrucous surface are seborrheic keratoses. j am acad dermatol 2014;70:e121-3. pmid: 24831328. doi: 10.1016/j. jaad.2013.10.042. 5. roh nk, hahn hj, lee yw, choe yb, ahn kj. clinical and histopathological investigation of seborrheic keratosis. ann dermatol 2016;28(2):152-8. pmid: 27081260. doi: 10.5021/ ad.2016.28.2.152. 6. mishima y, pinkus h. benign mixed tumor of melanocytes and malpighian cells. melanoacanthoma: its relationship to bloch’s benign non-nevoid melanoepithelioma. arch dermatol 1960;81:539-50. pmid: 14422903. 7. bolognia jl, jorizzo jl, rapini rp, eds. dermatology. philadelphia, pa: mosby elsevier, 2008:1661-4. 8. schlappner ol, rowden g, phillips tm, rahim z. melanoacanthoma. ultrastructural and immunological studies. j cutan pathol 1978;5:127-41. pmid: 210197. doi: 10.1111/j.16000560.1978.tb00949.x. 9. kirkham n. tumors and cysts of the epidermis. in: elder de (ed.). lever’s histopathology of the skin. 10th ed. new delhi: lippincott, 2009:791–849. 10. rossiello l, zalaudek i, ferrara g, et al. melanoacanthoma simulating pigmented spitz nevus: an unusual dermoscopy pitfall. dermatol surg 2006;32(5):735-7. pmid: 16706772. doi: 10.1111/j.1524-4725.2006.32148.x. https://dx.doi.org/10.1001/jamadermatol.2015.1453 https://dx.doi.org/10.1001/jamadermatol.2015.1453 https://dx.doi.org/10.1001/archderm.142.12.1551 https://dx.doi.org/10.1001/archdermatol.2009.369 https://dx.doi.org/10.1001/archdermatol.2009.369 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biological therapy, visceral adipose tissue, treatment, severity. citation: ruiz-villaverde r, ruiz-carrascosa jc. study of the visceral adipose tissue in a cohort of patients with moderate-severe psoriasis treated with biological therapy. dermatol pract concept. 2022;12(1):e2022032. doi: https://doi.org/10.5826/dpc.1201a32 accepted: august 21, 2021; published: january 2022 copyright: ©2022 ruiz-villaverde and ruiz-carrascosa. this is an open-access article distributed under the terms of the  creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: ricardo ruiz-villaverde. servicio de dermatología. hospital universitario san cecilio, granada, spain. e-mail: ismenios2005@gmail.com introduction: visceral adipose tissue (vat) has a greater relationship with the genesis of the metabolic syndrome and the pathology associated with obesity. methods: a cross-sectional study of patients with moderate-severe psoriasis in the psoriasis unit of the san cecilio university hospital in granada in the period july 1, 2020 december 31, 2020, was performed. all the patients (n = 110) were receiving biological therapy to control the disease. the variables measured included age, sex, time since diagnosis, weight, height, body mass index (bmi), visceral and total fat, and severity parameters. the visceral fat index was evaluated using a bioimpedance scale, considering a cut-off point for a healthy level < 12. results: our sample consisted of 110 patients with a mean age of 47.47 years, with a clear predominance of males (61.7% of patients). after testing for normality using the kolmogorov-smirnov test, the mann-whitney u test for nonparametric data for independent samples was used, which revealed significant differences between the number of previous treatments and visceral fat (u = -2.235, p = 0.025). no statistically significant differences were found when correlating total fat or visceral fat with bmi. conclusions: the results presented lead us to consider if the levels of vat could be a factor that contributes to some extent to therapeutic refractoriness. the determination of vat using bioimpedance scales in patients with moderate-severe psoriasis is a valuable method to measure vat. abstract 2 original article | dermatol pract concept. 2022;12(1):e2022032 introduction adipose tissue generally considered a useful annex to provide protection, heat, and energy, has surpassed these activities, and as its study progresses it has positioned itself as an organ with neuroimmune-endocrine functions. through the production of molecules such as hormones, antimicrobials, cytokines, and adipokines, it participates in the function of various cells and organs, which allows it to intervene in the defense and homeostasis of the body. fat deposits are different from each other, even between those of the same type of adipose tissue. each one is complex, made up of different cells, with different functions and variations both in gene expression and in their response to hormones (the subcutaneous of the thighs responds to sex hormones, the neck, upper back and abdomen to corticosteroids) [1]. visceral adipose tissue (vat) is divided into omental or epiploic and mesenteric. it occupies the spaces between the abdominal organs and keeps them in place. it has lymph nodes and a greater number of blood vessels and adrenergic receptors than the rest of the white adipose tissue. adipocytes in visceral tissue also express a greater number of receptors for corticosteroids, and in obesity, the enzyme 11 beta-hydroxysteroid dehydrogenase is overexpressed, which generates active substances from inactive glucocorticoids, stimulating adipogenesis and increase visceral fat. therefore, visceral adipose tissue has a greater relationship with the genesis of the metabolic syndrome and the pathology associated with obesity [2, 3]. the most accurate way to measure visceral fat level is with a computerized tomography (ct) or magnetic resonance imaging (mri) scan. but without doubt, the most practical and simple way that will allow us to also measure many other parameters with greater or lesser precision depending on their quality is through a bioimpedance scale. our body is normally made up of 50% to 70% water. fat tissue barely has 10% so it is a worse conductor, generating resistance to the passage of electricity. this fact is used by bioimpedance scales to measure the time it takes for the electricity to pass through our body. considering our weight, age and race, the percentage of body fat, visceral and bone density may be calculated. objectives • to know the total and average visceral fat composition in a cohort of patients with moderate-severe psoriasis treated with biological therapy in a tertiary hospital using a biompedance scale. • establish the correlation of visceral adipose tissue with the body mass index (bmi) of the patients that make up this cohort. • establish if there is a relationship with the number of treatments and, therefore, refractoriness to them in patients with moderate-severe psoriasis. methods a cross-sectional study of patients with moderate-severe psoriasis in the psoriasis unit of the san cecilio university hospital in granada in the period july 1, 2020 december 31, 2020 was performed. patients were obtained by consecutive sampling. all patients signed an informed consent that they could revoke at any time during the study. the study is approved by the ethics committee of our hospital with code husc-der-005. the diagnosis of moderate-severe psoriasis was established when the patient met the following requirements (psoriasis area severity index [pasi] > 10, body surface area [bsa] > 10 and / or dermatology life quality index [dlqi] > 10). all the patients were receiving biological therapy to control the disease. the variables measured included age, sex, time since diagnosis, weight, height, bmi, visceral and total fat, and severity parameters (pasi, bsa, dlqi). all previous treatments that the patient had received, including systemic treatments and biological treatments, were considered. treatment with biologically effective uvb phototherapy was excluded as a treatment to consider. only the overall number of treatments was considered in those patients where the cause of switching was a primary or secondary failure, excluding safety reasons. the visceral fat index was evaluated using a bioimpedance scale (kanthor®), considering a cutoff point for a healthy level < 12 [4, 5]. the statistical software imb spss version 25 in its macos version was used for all analyses. the kolmogorov smirnov test was used to test the normality of the data. measures of central tendency and dispersion were used depending on the nature of the data. outcome variables were selected according to clinical criteria. the visceral fat variable was categorized according to the healthy cutoff point < 12 in a binomial variable for the analyses. spearman correlation test for non-parametric samples as well as the mann-whitney u test for independent samples were used to study the association and relationship between the variables collected. a statistical significance level of p < 0.05 was set. results our sample consisted of 110 patients with a mean age of 47.47 years, with a clear predominance of males (61.7% of patients). the whole sample was placed to the right of the cutoff point considered as pathological in relation to the determination of visceral fat. the rest of the characteristics evaluated are reported in table 1. after testing for normality using the kolmogorov-smirnov test, the mann-whitney u test for nonparametric data for independent samples was used, which revealed significant original article | dermatol pract concept. 2022;12(1):e2022032 3 table 1. clinical and anthropometric characteristics of the participants. outcome values age 47.47 ± 13.47 yearss gender   male 74 (61.7) female 46 (38.3) time since diagnosis (years) 22.84 ± 12.81 years weight (kg) 82.79 ± 21.00 height (m) 1.70 ± 0.1 bmi 28.49 ± 6.10 visceral fat 11.97 ± 7.30 total fat 29.02 ± 11.36 pasi 12.93 ± 5.23 bsa 15.18 ±7.42 dlqi 11.72 ± 4.66 data are presented as mean ± standard deviation or n (%), as appropriate. events, which have characteristically been associated with elevated bmi [4]. although bmi is a clinical marker of obesity, this obesity is an heterogeneous condition with varying cv and metabolic manifestations [6]. obesity causes increased levels of proinflammatory cytokines (tnfα and il6). high levels of tnfα would produce a reduction in adiponectin levels, which would lower hdl cholesterol levels, increase triglycerides and insulin resistance. this leads to an increase in vat and il6 levels that perpetuate the inflammatory process [5]. in our study, it is shown in a cohort of 110 patients treated with biological therapy that the mean is right at the cutoff point considered pathological for visceral fat levels (11.97 +/7.30; vat > 12) and we reported a statistical correlation with the number of previous treatments the patient had received. this makes us wonder if these levels could be a factor that contributes to some extent to therapeutic refractoriness. we were unable to find statistically significant differences when trying to establish a correlation between bmi levels and visceral fat levels. interestingly, the mean bmi of the presented cohort does not exceed 30 points that mark the limit of obesity, but there is a clear overweight, as well as the levels of visceral fat that have not reached the limit considered as pathological. different techniques (mainly imaging) have been postulated to determine vat. coronary ct angiography is a non-invasive imaging technique, of great prognostic utility and a predictor of cv events. sajja et al have shown in a one-year study that the reduction in vat volume measured by this technique is associated with an improvement in the coronary artery burden [7]. other techniques include ultrasonography (usg), which is regarded as a radiation technique with a lower cost than the one of ct [8]. usg measures the maximal thickness of preperitoneal mass at the anterior surface of the liver and the minimal thickness of subcutaneous fat in the upper median abdomen. gönul et al performed the first study using this technique, in which they concluded a higher prevalence of table 2. bivariate correlations between number of previously treatments and anthropometric variables.   age gender bmi total fat categorised visceral fat number of previously treatments age   0,015 0.411** 0.180* 0.087 -0.023 gender 0,015   -0.231* -0.392** -0.433** 0.119 bmi 0.411** -0.231*   0.691** 0.629** -0.059 total fat 0.180* -0.392** -691**   0.733** -0.158 categorised visceral fat 0,087 -0.433** 0-629** 0.733**   -0.205* number of previously treatments -0,023 0.119 -0.059 -0.158 -0.205*   spearman correlation coefficient. *correlation is significant at the 0.05 level; **correlation is significant at the 0.01 level. differences between the number of pre-treatments and visceral fat: u = -2.235; p = 0.025). these results showed a positive correlation between high levels of visceral fat with a greater number of previous treatments. no statistically significant differences were found when correlating total fat or visceral fat with bmi (table 2). conclusions psoriasis is a chronic inflammatory disease that is associated with a high degree of systemic and vascular inflammation. it is known to cause an increase in cardiovascular (cv) risk factors, coronary artery disease and myocardial infarction. vat is associated with this vascular inflammation and cv 4 original article | dermatol pract concept. 2022;12(1):e2022032 metabolic syndrome in patients with psoriasis but with an abdominal fat index similar to the control group [9]. as in our study, in this case with an imaging technique, the authors were unable to establish a relationship between visceral fat levels and other markers related to metabolic syndrome. finally, studies have also been conducted using 18f-fluorodeoxyglucose positron-emission tomography to measure vat volume and its relationship with vascular inflammation in patients with psoriasis. it shows how new treatments for moderate-severe psoriasis lower the volume of vat and vascular inflammation, which is why vat is an important cv biomarker [10]. our study has some limitations. it is a cross-sectional study, which has measured the visceral fat of our patients at a specific and determined moment. although there is indeed a statistically significant correlation between the number of previous biological treatments (used due to refractoriness to treatment) and the levels of visceral fat, we have not been able to detect an association with other characteristics that have been used as biomarkers and prognoses factors in metabolic syndrome such as bmi. furthermore, we have not been able to establish a correlation with imaging techniques already used in other studies due to the lack of availability of these techniques in our centre. as a conclusion to our study, we want to value the determination of vat using bioimpedance scales in patients with moderate-severe psoriasis. further studies are required to determine its correlation with other characteristics of the disease and its positioning in relation to its determination using other imaging techniques already discussed. references 1. vega-robledo gb, rico-rosillo mg. adipose tissue: immune function and alterations caused by obesity. rev alerg mex. 2019;66(3):340-353. spanish. doi: 10.29262/ram.v66i3.589. pmid: 31606018. 2. rehrer cw, karimpour-fard a, hernandez tl, et al. regional differences in subcutaneous adipose tissue gene expression. obesity (silver spring). 2012;20(11):2168-2173. doi: 10.1038/ oby.2012.117. pmid: 22627919; pmcid: pmc3434286. 3. vohl mc, sladek r, robitaille j, et al. a survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. obes res. 2004;12(8):1217-1222. doi: 10.1038/ oby.2004.153. pmid: 15340102. 4. toussirot e, aubin f, desmarets m, et al. visceral adiposity in patients with psoriatic arthritis and psoriasis alone and its relationship with metabolic and cardiovascular risk. rheumatology (oxford). 2021;60(6):2816-2825. doi: 10.1093/rheumatology/ keaa720. pmid: 33232483. 5. goolam mahyoodeen n, crowther nj, pillay l, et al. relationship of visceral fat and adipokines with cardiometabolic diseases in psoriasis. acta derm venereol. 2019; 99:1218–1223. doi: 10.2340/00015555-3327. pmid: 31580467. 6. budu-aggrey a, brumpton b, tyrrell j, et al. evidence of a causal relationship between body mass index and psoriasis: a mendelian randomization study. plos med. 2019;16(1):e1002739. doi:10.1371/journal.pmed.1002739. pmid: 30703100; pmcid: pmc6354959. 7. sajja a, abdelrahman km, reddy as, et al. chronic inflammation in psoriasis promotes visceral adiposity associated with noncalcified coronary burden over time. jci insight. 2020;5(22):e142534. doi: 10.1172/jci.insight.142534. pmid: 33104056; pmcid: pmc7710282. 8. balci a, balci dd, yonden z, et al. increased amount of visceral fat in patients with psoriasis contributes to metabolic syndrome. dermatology. 2010;220(1):32-37. doi: 10.1159/000254482. pmid: 19887761. 9. gönül m, tatar i̇, canpolat f, işıl kurmus g, ergin c, hekimoğlu b. evaluation of abdominal fat index by ultrasonography and its relationship with psoriasis and metabolic syndrome. postepy dermatol alergol. 2017;34(5):453-456. doi: 10.5114/ ada.2017.71111. pmid: 29507560. pmcid: pmc5831280.. 10. rivers jp, powell-wiley tm, dey ak, et al. visceral adiposity in psoriasis is associated with vascular inflammation by 18f-fluorodeoxyglucose positron-emission tomography/computed tomography beyond cardiometabolic disease risk factors in an observational cohort study. jacc cardiovasc imaging. 2018;11(2 pt 2):349-357. doi: 10.1016/j.jcmg.2017.08.014. pmid: 29055628. pmcid: pmc5803350. dermatology: practical and conceptual dermatology practical & conceptual review | dermatol pract concept. 2021;11(3):e 2021068 1 reflectance confocal microscopy of aging skin and skin cancer stefania guida1, giovanni pellacani1,3, silvana ciardo1, caterina longo1,2 1 dermatology unit, department of surgical, medical, dental and morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, modena, italy 2 centro oncologico ad alta tecnologia diagnostica, azienda unità sanitaria locale-istituto di ricovero e cura a carattere scientifico di reggio emilia, reggio emilia, italy 3 dermatologic unit, department of clinical internal, anesthesiological and cardiovascular sciences, sapienza university of rome, rome, italy. key words: skin aging, skin cancer, collagen, blood vessels, reflectance confocal microscopy citation: guida s, ciardo s, pellacani g, longo c. skin aging and skin cancer: reflectance confocal microscopy of skin aging and skin cancer. dermatol pract concept. 2021;11(3):e 2021068. doi: https://doi.org/10.5826/dpc.1103a68 accepted: february 3, 2021; published: may 20, 2021 copyright: ©2021 guida et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: stefania guida, md, phd, dermatology unit, department of surgical, medical, dental and morphological sciences related to transplant, oncology and regenerative medicine, university of modena and reggio emilia, via del pozzo, 71, modena 411125, italy. email: drstefaniaguida@gmail.com skin aging is a complex process that causes morphologic variations. some of these variations have been hypothesized to be involved in skin cancer development. this paper reviews current knowledge of the features of aged skin as seen with reflectance confocal microscopy (rcm). basic principles of the technique are described, and the rcm features of healthy skin and skin cancer are briefly discussed. moreover, the rcm features at different layers of young and elderly skin are described, as are the variations that occur with passing years and in relation to sun exposure that contribute to photoaging and the development of skin cancer. rcm enables the noninvasive evaluation, at quasi-histologic resolution, of aging-related skin changes, some of which are shared with skin cancer; this ability helps avoid skin biopsy. further research is needed to understand the relation between skin aging and skin cancer development. abstract introduction skin aging is a complex biological process leading to skin senescence. attention to skin aging reflects an increasing consumer demand for products and treatments that can prevent or reverse skin aging signs [1,2]. importantly, aging is strongly associated with skin cancer development. skin aging is influenced by both intrinsic factors, such as chronological age and genetic background, and extrinsic factors, mainly sun exposure, that contribute to “photoaging” [3]. interestingly, different types of skin photoaging have been identified: atrophic and hypertrophic. atrophic photoaging is typified by actinic keratosis, seborrheic keratosis, telangiectasia, and a prior diagnosis of skin cancer, while hypertrophic 2 review | dermatol pract concept. 2021;11(3):e 2021068 photoaging is characterized by high scores on photoaging severity scales, coarse wrinkles, thickness, and sallowness [4]. uv irradiation, both natural and artificial, is considered the main etiologic factor in photoaging and skin cancer. uv irradiation induces dna damage (through the formation of cyclobutane pyrimidine dimers), gene mutation, oxidative stress, immunosuppression, and inflammatory responses [5,6]. in fact, painful sunburns have been associated with the development of both melanoma and non-melanoma skin cancers (nmscs), namely squamous cell carcinoma (scc) and basal cell carcinoma (bcc) [5,7], while chronic sun exposure is considered the most important causative factor for actinic keratosis and lentigo maligna/lentigo maligna melanoma (lm/lmm) [5,8]. in the past few years, reflectance confocal microscopy (rcm) has been employed as a noninvasive technique to visualize the skin at quasi-histological resolution; it has also been used as an add-on tool in the diagnosis of skin cancer, as a second level of examination after dermoscopy, to improve diagnostic accuracy [9-12]. additionally, due to the fact that rcm avoids skin biopsy, it has also been applied to the investigation of skin aging signs [13]. this article reviews current knowledge about the use of rcm to study skin aging. in particular, basic principles of the technique are reviewed and the rcm features of different skin cancers are briefly described. basic principles of rcm technology rcm enables the analysis of healthy skin compartments by providing an in vivo optical biopsy in a totally noninvasive manner. furthermore, rcm can be repeated in the same area at different times, enabling the assessment of skin variations, such as during treatment monitoring. a reflectance confocal microscope comprises a point source of light, objective lenses, a condenser, and a point detector. the pinhole collects light from the “in focus” plane. bright contrast in rcm is related to backscattering. confocal images are in grayscale, with bright (white) structures having a higher refractive index than their surroundings [14]. melanin, keratin and collagen are examples of structures that appear bright (white). technically, rcm has an axial resolution of 3-5 μm and a lateral resolution of 1 μm, and it reaches a depth of 250 μm, corresponding to the upper dermis. two reflectance confocal microscopes are commercially available: a wide-probe microscope (vivascope 1500, mavig, germany) and a handheld model (vivascope 3000, mavig, germany). the wide-probe rcm instrument has a probe that explores the skin through a disposable plastic window adherent to a metal ring attached to the skin. the result is a sequence of full-resolution, 0.5×0.5 μm images at a defined depth, acquired and combined to create a mosaic ranging in size from 2×2 mm to 8×8 mm. when inflammatory or physiologic skin conditions are explored, a 3×3 mm vivacube, composed of 4 mosaics with a 25-μm step, is collected and analyzed. in addition to horizontal mosaics, a vertical vivastack can be acquired, creating an optical biopsy consisting of a series of 0.5×0.5 high-resolution images at different depths. the number of stacks between the first appearance of a honeycomb pattern and the first appearance of collagen, with a given depth, is used to assess epidermal thickness [13]. the handheld rcm model is a smaller, flexible device that permits the exploration of difficult-to-access areas, such as ears and skin folds. however, the handheld tool does not allow visualization of a large field of view. only single 0.5×0.5 mm images and vivastacks can be acquired. the view of larger fields is impaired [1,13]. skin morphology over the years skin aging involves variations at both the epidermal and dermal levels. these changes can be noninvasively detected with rcm. to detect skin variations that occur with passing time, it is important to understand the morphology of healthy skin as it progressively changes from young skin to elderly skin [1,13,15-23]. healthy young skin rcm can be used to evaluate the epidermis, the dermo-epidermal junction (dej) and the upper dermis (table 1). when analyzing the epidermis, the microscopist first sees the stratum corneum at the top surface. this skin layer is characterized by the presence of large, bright, anucleated cells (corneocytes) that are polygonal, 10–30 mm in size, and have the tendency to form ‘‘islands’’ surrounded by dark areas, corresponding to skin furrows [24]. going deeper to the granulosum-spinosum layer, keratinocytes are characterized by dark nuclei and bright cytoplasm. in particular, a grainy appearance is typically observed in cells of the granulosum layer, due to the presence of organelles. the organization of keratinocytes is similar to a honeycomb. therefore, the typically observed pattern at the epidermal level in people with light skin is called honeycomb pattern (figure 1a) [24]. in light-skinned people, the keratinocyte contour is brighter than the cytoplasm. conversely, people with dark skin show a different pattern, called cobblestone pattern, that is the negative of a honeycomb pattern, with pigmented (bright) keratinocytes separated by a dark contour [16]. going to the basal layer of the epidermis, basal cells appear as cells of the same size (7–12 mm) and shape although they are smaller than the keratinocytes of the upper layers and have high refractivity due to their melanin content [14]. review | dermatol pract concept. 2021;11(3):e 2021068 3 the epidermal thickness can be estimated from the number of stacks from the visualization of the honeycomb pattern to the observation of collagen [13]. interestingly, melanocytes are not recognized in healthy skin because they share features with keratinocytes in terms of size and amount of melanin [14]. at the dej level, basal cells tend to form oval or round bright rings centered by dark dermal papillae, defining the so-called ring pattern [14]. intuitively, melanin content and skin phototype influence the brightness of keratinocytes: the darker the skin phototype, the brighter the basal cells and rings appear. however, on the face, rings cannot be visualized [16]. in young subjects, the dermis is mainly composed of thin, hyper-reflective reticulated fibers, with a weblike organization (figure 1b) [16]. other structures that are visualized are the sebaceous glands, corresponding to hair shafts within hair follicles, and sweat ducts located in the dermis. the face is characterized by several hair follicles creating dark round areas centered by a hair shaft [16]. table 1. features of skin seen with reflectance confocal microscopy feature description epidermis regular honeycomb pattern polygonal keratinocytes of uniform size and shape, with well-defined borders irregular honeycomb pattern keratinocytes of variable size and shape and ill-defined borders mottled pigmentation cluster of bright keratinocytes within a honeycomb pattern epidermal thickness estimated from the number of stacks (starting from the first visualization of the honeycomb pattern to the presence of collagen) furrow aspects dark folds between groups of keratinocytes, usually described as rhomboidal in healthy skin, tending to linearity in aged skin dermo-epidermal junction polycyclic papillary contours bulbous projections that can show a variable convoluted arrangement sebaceous glands annular structures with round or oval shape, centered by hair follicles dermis thin reticular collagen bright, thin, fibrillar structures creating a weblike appearance coarse collagen coarse filamentous, thick structures with a tendency to be packed huddle collagen large blotches of amorphous material with hyporefractivity curled fibers short, thick, undulated fibers with high refractivity figure 1. reflectance confocal micrographs showing morphologic aspects of young skin. (a) regular honeycomb pattern. (b) reticular collagen. scale bars = 100 µm. 4 review | dermatol pract concept. 2021;11(3):e 2021068 skin aging signs and their correlation with skin cancer worldwide, the incidence of skin cancer is progressively increasing, and two main hypotheses have been formulated to explain this fact: increasing sun exposure and population aging [25,26]. therefore, both chronological aging and photoaging contribute to skin cancer development. it has been shown that they also contribute to skin cancer progression. epidermal changes with aging, the skin shows progressive changes that can involve all its layers. at the epidermal level, both quantitative and qualitative variations may occur. accordingly, the skin shows a progressive reduction in epidermal thickness. however, some middle-aged subjects may develop hyperplasia with evidence of polycyclic papillary contours (figure 2a), histopathologically corresponding to solar lentigo. therefore, it has been hypothesized that the skin might develop a hyperplastic response to solar damage and then show severe atrophy with progressive thinning [16]. additionally, there is a change of the overall epidermal surface, showing a prevalent linear furrow pattern with the progressive enlargement of a rhomboidal pattern and then a linear trend without intersecting lines [18,19]. the regular honeycomb pattern, typical of young age, is substituted by an irregular honeycomb pattern during the aging process [13]. the irregular honeycomb pattern shows polygonal keratinocytes with ill-defined cell borders (figure 2b) and variable size and shape due to varying degrees of keratinocyte atypia, with focal disarray in lesions such as actinic keratosis [9]. furthermore, melanocytes can be identified in benign melanocytic lesions (eg, melasma, nevus) and malignant melanocytic lesions (eg, melanoma) [16]. in addition, the presence of dyspigmentation at the epidermal level corresponds to the visualization with rcm of bright keratinocytes assembled in the context of a honeycomb pattern, called mottled pigmentation (figure 2c) [13]. mottled pigmentation, together with atypical honeycomb pattern, has been shown to be significantly more represented in older adults (aged older than 54 years) [27]. dej and dermal changes the exploration with rcm at the dej and superficial dermis level enables the visualization of dermal papillae, blood figure 2. reflectance confocal microscopy appearance of aged skin. (a) polycyclic papillary contours (green circles). (b) atypical honeycomb pattern (pink stars). (c) mottled pigmentation (white arrows). scale bars = 100 µm. figure 3. reflectance confocal micrographs at dermal level. (a) reticular collagen, typical of young subjects. (b) coarse collagen. (b) huddle collagen. (c) curled fibers in a subject with solar elastosis (red arrows). scale bars = 100 µm. review | dermatol pract concept. 2021;11(3):e 2021068 5 vessels within each dermal papilla, and collagen (table 1). in a study of 52 japanese subjects, reductions in the number and size of dermal papillae were observed in subjects older than 50 years of age compared to a group of 18to 20-year-old healthy individuals [28]. collagen fibers have specific features according to age and photodamage. in aged skin, morphologic variations of collagen include coarse collagen, huddles of collagen, and curled fibers. coarse collagen is described as a coarse network of large hyporeflecting collagen, huddle collagen appears as large blotches of amorphous material with hyporeflectivity, and curled fibers are visualized as undulated bright structures corresponding to solar elastosis (figure 3) [13]. different collagen types have been observed throughout aging in a group of 63 italian women, with reticular collagen being less evident in subjects older than 35 years and coarse and huddled collagen and curled fibers becoming increasingly represented [13]. similar results were observed in a group of 44 brazilian women [29]. skin aging quantification in photo-exposed and nonphoto-exposed skin different scores have been developed to quantify skin aging. an epidermal disarray score, which ranges from 0 to 9, is calculated from an irregular honeycomb pattern, the epidermal thickness, and a furrow pattern. an epidermal hyperplasia score, which also ranges from 0 to 9, includes the evaluation of mottled pigmentation, polycyclic papillary contours, and epidermal thickness. a collagen alteration score, which ranges from 0 to 12, is estimated from the extent of each collagen type (scored from 0 to 4) multiplied by its coefficient; the coefficient is 3 for curled fibers, 2 for huddles of collagen, 1 for coarse collagen structures, and 0 for thin reticulated collagen [17]. a study evaluated the distribution of these scores, employing rcm images of the face in correspondence of the left malar eminence, in a population of 50 women between 24 and 88 years old [17]. according to the study, the epidermal disarray score was stable until age 65 years and then increased, while the epidermal hyperplasia and collagen scores showed proportional increases with age. skin aging scores have also been explored in a larger cohort of 209 french subjects between 74 and 81 years of age [19]. the study analyzed differences between non-photo-exposed (volar arm), chronically photo-exposed (face) and intermittently photo-exposed (dorsal forearm) areas. photo-exposed areas had significant higher epidermal disarray figure 4. clinical photograph (a) and dermoscopic image (b) of a pigmented actinic keratosis of the left cheek in a 70-year-old woman. (c) reflectance confocal micrograph of the area marked by a pink square in b, showing an atypical honeycomb pattern (white squares). (d) clinical photograph and (e) dermoscopic image of a lentigo maligna on the left cheek of a 64-year-old woman. (f) reflectance confocal micrograph of the area marked by a green square in e, showing atypical cells (both rounded and dendritic) infiltrating the hair follicle (green arrows). scale bars = 100 µm. 6 review | dermatol pract concept. 2021;11(3):e 2021068 and epidermal hyperplasia scores than non-photo-exposed areas, while the collagen score was higher in the intermittently photo-exposed skin than the non-photo-exposed skin [19]. other studies have compared rcm features between non-photo-exposed and photo-exposed skin. these studies identified epidermal, dej and dermal changes that were related to chronological aging and that were more evident in photo-exposed areas. these changes included the appearance of linear furrows, mottled pigmentation, atypical honeycomb pattern, irregular ringed pattern, and huddle collagen [19-21]. from skin aging to skin cancer skin variations occurring with passing years have been related to skin cancer development and progression [4,30,31]. interestingly, rcm enables the visualization of features shared by aged skin and skin cancer at both the epidermal level, such as atypical cells or atypical honeycomb pattern, and the dermal level, such as dilated vessels or collagen variations. at the epidermal level, a focal, atypical honeycomb pattern related to chronic sun exposure is typically observed in actinic keratosis (figure 4, a and b), while a disarranged epidermal pattern and ulceration are commonly observed in scc [9,32]. additionally, since melanocytes are not visible in healthy skin, the identification of atypical cells or nests (referred to melanocytes) with rcm contributes to the differential diagnosis of lm/lmm (figure 4, c and d) with other pigmented macules of the face [33]. at the dermal level, dilated vessels may be observed in nmsc, where they are typically horizontal and branching, surrounding the tumor island in bcc and more irregular in scc [34,35]. some other morphologic variations at the dermal level include bundles of lace-like collagen in actinic keratosis and scc [36] and collagen bundles surrounding dark silhouette in hypopigmented bcc [37,38]. interestingly, fewer curled fibers, corresponding to solar elastosis, were observed in subjects with atrophic photoaging (more prone to skin cancer) than in patients with hypertrophic photoaging [4,13,23]. therefore, the lack of solar elastosis in subjects with atrophic photoaging seems to contribute to increased collagen fragmentation, which modifies the dermal microenvironment [4]. additionally, a lack of solar elastosis has been described in the adjacent skin of melanomas harboring braf mutations, which are a common finding in melanoma [39]. the correlation between specific epidermal and dermal characteristics and skin photoaging confirms that uv irradiation contributes to cellular atypia; moreover, it seems to support the notion that the dermal microenvironment is an active participant in the formation of skin cancer [4]. accordingly, increased vascularization has been implicated in skin cancer development because it provides an enriched microenvironment for tumor growth [4,30,31]. the lack of solar elastosis, observed in subjects with atrophic photoaging and in the surrounding skin of melanomas, has been hypothesized as a risk factor for the growth and expansion of skin tumors [4]. other mechanochemical interactions between aged skin and tumor, which may affect metastasis, have also been described [40]. interestingly, a different collagen morphology and increased vascularization have been observed in subjects with atrophic photoaging, who are more likely to have skin cancer and to carry melanocortin-1 receptor gene (mc1r) polymorphisms [4,22,23]. mc1r polymorphisms have been associated with the red hair phenotype, characterized by red hair, freckles, light skin and poor tanning. however, a different mc1r genotype might express different phenotypes, sharing the poor tanning ability and tendency to have freckles and light skin [41]. despite this phenotype, carrying specific mc1r polymorphisms increases the risk of melanoma and nmsc [42,43]. this finding seems to provide new insights into the relation between skin photoaging type and the susceptibility to skin cancer, but further studies are needed to explain the complex phenomena leading from skin aging to tumor development and progression. conclusions rcm facilitates the identification of in vivo features of healthy skin and the recognition of skin aging variations at different skin layers, with histopathologic resolution. skin aging changes have been shown to correlate with skin cancer development and progression. interestingly, rcm enables the visualization of features shared by aged skin and skin cancer, at both the epidermal level (eg, atypical cells or atypical honeycomb pattern) and the dermal level (eg, dilated vessels or collagen variations). however, the mechanism that links morphological variations in aging skin to skin cancer needs further 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epidermal and dermal changes by means of confocal microscopy. j am acad dermatol. 2013;68:e7382. doi: 10.1016/j.jaad.2011.08.021. pmid: 22000768. 14. rajadhyaksha m, grossman m, esterowitz d, webb rh, anderson rr. in vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. j invest dermatol. 1995;104:946-52. doi: 10.1111/1523-1747.ep12606215. pmid: 7769264. 15. sauermann k, clemann s, jaspers s, et al. age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo. skin res technol. 2002;8:5256. doi: 10.1046/j.0909-752x.2001.10297.x. pmid: 12005120. 16. longo c. well-aging: early detection of skin aging signs. dermatol clin. 2016; 34:513-518. doi: 10.1016/j.det.2016.05.014. pmid: 27692457. 17. longo c, casari a, de pace b, et al. proposal for an in vivo histopathologic scoring system for skin aging by means of confocal microscopy. skin res technol. 2013;19:e167-73. doi: 10.1111/j.1600-0846.2012.00623.x. pmid: 22672873. 18. longo c, zalaudek i, argenziano g, pellacani g. new directions in dermatopathology: in vivo confocal microscopy in clinical practice. dermatol clin. 2012;30:799-814. doi: 10.1016/j. det.2012.06.012. pmid: 23021059. 19. cinotti e, bovi c, tonini g, et al. structural skin changes in elderly people investigated by reflectance confocal microscopy. j eur acad dermatol venereol. 2020; 34(11):2652-2658. doi: 10.1111/jdv.16466 pmid: 32294278. 20. wurm em, longo c, curchin c, et al. in vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy. br j dermatol. 2012; 167:270-279 doi: 10.1111/j.1365-2133.2012.10943.x. pmid: 22428802. 21. haytoglu ns, gurel ms, erdemir a, et al. assessment of skin photoaging with reflectance confocal microscopy. skin res technol. 2014;20:363-372. doi: 10.1111/srt.12127. pmid: 24506234. 22. guida s, ciardo s, de pace b, et al. the influence of mc1r on dermal morphological features of photo-exposed skin in women revealed by reflectance confocal microscopy and optical coherence tomography. exp dermatol. 2019;28:1321-1327. doi: 10.1111/exd.14037. pmid: 31520496. 23. guida s, ciardo s, de pace b, et al. atrophic and hypertrophic skin photoaging and melanocortin-1 receptor (mc1r): the missing link. j am acad dermatol. 2021;84:187-190. doi: 10.1016/j. jaad.2020.04.075. pmid: 32335180. 24. rajadhyaksha m, gonzález s, zavislan jm, anderson rr, webb rh. in vivo confocal scanning laser microscopy of human skin ii: advances in instrumentation and comparison with histology. j invest dermatol. 1999;113:293-303. doi: 10.1046/j.15231747.1999.00690.x. pmid: 10469324. 25. arisi m, zane c, caravello s, et al. sun exposure and melanoma, certainties and weaknesses of the present knowledge. front med (lausanne). 2018; 5:235. doi: 10.3389/fmed.2018.00235. pmid: 30214901. 26. suárez b, lópez-abente g, martínez c, et al. occupation and skin cancer: the results of the helios-i multicenter case-control study. bmc public health. 2007;7:180. doi: 10.1186/1471-2458-7180. pmid: 17655745. 27. ciardo s, pezzini c, guida s, et al. a plea for standardization of confocal microscopy and optical coherence tomography parameters to evaluate physiological and para-physiological skin conditions in cosmetic science. exp dermatol. 2021. doi: 10.1111/ exd.14359. pmid: 33884663. epub ahead of print. 28. kawasaki k, yamanishi k, yamada h. age-related morphometric changes of inner structures of the skin assessed by in vivo reflectance confocal microscopy. int j dermatol. 2015;54:295-301. doi: 10.1111/ijd.12220. pmid: 25267556. 29. fossa shirata mm, alves gad, maia campos pmbg. photoageing-related skin changes in different age groups: a clinical evaluation by biophysical and imaging techniques. int j cosmet sci. 2019;41:265-273. doi: 10.1111/ics.12531. pmid: 30982995. 30. bonnans c, chou j, werb z. remodelling the extracellular matrix in development and disease. nat 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nonmelanocytic skin lesions: a systematic review. j am acad dermatol. 2019;80:1414-1427.e3. doi: 10.1016/j.jaad.2018.12.007. pmid: 30529706. 35. lupu m, caruntu c, popa mi, voiculescu vm, zurac s, boda d. vascular patterns in basal cell carcinoma: dermoscopic, confocal and histopathological perspectives. oncol lett. 2019;17:41124125. doi: 10.3892/ol.2019.10070. pmid: 30944604. 36. rishpon a, kim n, scope a, et al. reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. arch dermatol. 2009;145:766-772. doi: 10.1001/archdermatol.2009.134. pmid: 19620557. 37. segura s, puig s, carrera c, palou j, malvehy j. dendritic cells in pigmented basal cell carcinoma: a relevant finding by reflectance-mode confocal microscopy. arch dermatol. 2007;143:883886. doi: 10.1001/archderm.143.7.883. pmid: 17638732. 38. agero al, busam kj, benvenuto-andrade c, et al. reflectance confocal microscopy of pigmented basal cell carcinoma. j am acad dermatol. 2006;54:638-643. doi: 10.1016/j. jaad.2005.11.1096. pmid: 16546585. 39. spathis a, katoulis ac, damaskou v, et al. braf mutation status in primary, recurrent, and metastatic malignant melanoma and its relation to histopathological parameters. dermatol pract concept. 2019;9:54-62. doi: 10.5826/dpc.0901a13. pmid: 30775150. 40. kaur a, ecker bl, douglass sm, et al. remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. cancer discov. 2019;9:64-81. doi: 10.1158/2159-8290.cd-18-0193.pmid: 30279173. 41. tagliabue e, gandini s, garcía-borrón jc, et al. association of melanocortin-1 receptor variants with pigmentary traits in humans: a pooled analysis from the m-skip project. j invest dermatol. 2016;136:1914-1917. doi: 10.1016/j.jid.2016.05.099. pmid: 27251790. 42. tagliabue e, gandini s, bellocco r, et al. mc1r variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the m-skip project. cancer manag res. 2018;10:1143-1154. doi: 10.2147/cmar.s155283. pmid: 29795986. 43. tagliabue e, fargnoli mc, gandini s, et al. mc1r gene variants and non-melanoma skin cancer: a pooled-analysis from the m-skip project. br j cancer. 2015;113:354-363. doi: 10.1038/ bjc.2015.231. pmid: 26103569. dermatology: practical and conceptual dermatology practical & conceptual commentary | dermatol pract concept. 2021; 11(4): e 2021120 1 toxicity of infiltrative lidocaine in dermatologic surgery: are current limits valid? allison wang1, solomiya grushchak1, subuhi kaul1, patrick k lee2, jerry feldman1 1 division of dermatology, cook county health, chicago, il, usa 2 department of dermatology, university of california, irvine, california, usa key words: lidocaine, anesthesia, tumescent, drug reaction, lidocaine-associated systemic toxicity, mohs surgery citation: wang a, grushchak s, kaul s, lee pk, feldman j. toxicity of infiltrative lidocaine in dermatologic surgery: are current limits valid? dermatol pract concept. 2021; 11(4): e 2021120. doi: https://doi.org/10.5826/dpc.1104a120 accepted: march 23, 2021; published: september 2021 copyright: ©2021 wang et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: subuhi kaul, md, division of dermatology, cook county health, professional building, 6th floor, 1950 w. polk st, chicago, il, usa. email: subuhi.kaul@cookcountyhhs.org local infiltrative lidocaine is the most common anesthetic method used in dermatologic surgery. according to the food and drug administration, the maximum dose of infiltrative lidocaine with and without epinephrine is 7mg/kg and 4.5mg/ kg in adults, respectively [1]. data analyzing the validity of the proposed dosages is lacking, yet these recommendations are widely accepted. we aim to review the origin and steadfastness of the maximum doses of lidocaine for infiltrative anesthesia in cutaneous surgery. the maximum lidocaine doses are manufacturer recommendations based on early studies and there are no randomized trials available to validate this regulation [1]. moreover, these recommendations do not consider the route of administration. lidocaine was synthesized in 1943, it demonstrated a lethal dose of 1g/kg with subcutaneous infiltration of 0.5% in rodents [2]. in 1949, a human trial performed on over 800 patients showed 500 mg and 1000 mg of lidocaine (with and without epinephrine, respectively) to be safe. 2 cases of systemic toxicity occurred after deliberate overdose with 1.35 g and 3 g of lidocaine in thoracic surgeries. both patients experienced stupor and convulsions, which improved with intravenous barbiturate [2]. comparable serum lidocaine levels were confirmed via different routes and doses: 500 mg by epidural administration, 600 mg in brachial plexus blocks, and 1,000 mg in subcutaneous infiltration in legs [1]. the maximum dose limits tend to err on the side of caution and are often inadequate for brachial plexus or epidural blocks and are discussed in anesthesia literature [1,3]. lidocaine is eliminated via the hepatic cytochrome p450 3a4 pathway [1]. serum lidocaine concentration depends on several factors including patient and injection method. severe liver dysfunction or medications that inhibit cytochrome p450 3a4, such as, itraconazole, erythromycin, amiodarone, cimetidine, valproate, may theoretically result in toxicity at lower doses [1, 4]. a study on intravenous administration of lidocaine showed a lower clearance in patients with child c cirrhosis and concluded that a 50% reduction in dosage was necessary in these patients [5]. further studies showed that dose reduction is only indicated with repeated blocks administered less than 5 half-lives apart or with continuous infusion, 2 commentary | dermatol pract concept. 2021; 11(4): e 2021120 as lidocaine accumulates in cirrhotic patients [1]. notably, plasma levels attained after subcutaneous injection are lower than that by intravenous injection, thus adjustment of dose may not be necessary after subcutaneous injection, especially if only a single dose is required [1]. infiltration with epinephrine (potent vasoconstrictor) or as a diluted solution, as in tumescent anesthesia (increased local hydrostatic pressure), slows lidocaine uptake with resulting increased half-life and lower peak plasma levels, that permit a higher maximum dose to be administered [1,4,6]. lidocaine is lipophilic and slower absorption allows a depot-like effect [4]. ramon et al studied the combination of epinephrine and dilute lidocaine (0.33%) in patients undergoing facelift surgery. the half-life of lidocaine was found to be increased to 6 hours (compared with 2 hours for intravenous lidocaine) when used together with epinephrine [6]. in addition, researchers were able to safely use 3 times the threshold limit of maximum recommended lidocaine doses (17 to 26 mg/kg of lidocaine). despite the much higher doses used, the maximum lidocaine plasma concentration remained well below the toxic range (1.14 to 2.2 µg/ml) and no adverse effects were noted [6]. similarly, doses up to 55mg/kg have been administered safely with tumescent anesthesia [7]. the clinical features of lidocaine overdose depend on serum concentration and different sources cite varying serum concentrations at which toxicity is first observed [3,4,6,8]. mild symptoms are reported to occur above 5µg/ml. these include dizziness, lightheadedness, and circumoral paresthesias for which observation is recommended. neurologic and cardiopulmonary complications such as seizures, cardiac and respiratory arrest may occur between doses of 9 to 20µg/ ml – in these cases, there is the need for an emergency management with oxygen supplementation and administration of benzodiazepines (with or without intravenous lipid emulsion) [3,4,6,8,9]. in dermatologic surgery, lidocaine associated systemic toxicity (last) events are infrequent. in a review of last data from 2010 to 2014, only 2 of 67 cases were dermatologist performed procedures, both after topical lidocaine/prilocaine application [10]. based on a mandatory adverse-event data of office-based surgery in florida and alabama, only 4 dermatologist associated complications were reported over 10 years and 1 complication over 6 years, respectively [11]. 3 of these 5 were associated with lidocaine infiltration: the first was transient atrial fibrillation 2 hours after an excision performed with minimal local lidocaine, another was a wrong surgical site during a mohs procedure, and lastly, a post-excision infection with staphylococcus [10]. additionally, alam et al sought to determine if lidocaine injection in the head and neck led to higher absorption. despite using 48 mls of 1% lidocaine with 1:100,000 epinephrine, the highest recorded serum level in this study was 0.3 µg/ml [3]. a blanket cap on maximum lidocaine dose in dermatologic surgery is not scientifically valid. although simple procedures rarely require these high doses, procedures such as mohs surgery often require stacking of local anesthesia given the multiple layers and the larger areas requiring anesthesia for closure. in addition, various patient factors such as height, weight, race, medical problems should be considered in future studies. when preparing for dermatologic surgery, it would be beneficial to emphasize appropriate anesthetic technique to ensure prevention of intra-arterial injection and confirm the absence of liver disease and/or drugs that may complicate lidocaine elimination when screening patients for procedures. references 1. rosenberg ph, veering bt, urmey wf. maximum recommended doses of local anesthetics: a multifactorial concept. reg anesth pain med. 2004;29(6):564-575. doi: 10.1016/j. rapm.2004.08.003. pmid: 15635516. pmid: 18101361. 2. gordh t. xylocain, a new local analgesic. anaesthesia. 1949;4(1):4-9. doi: 10.1111/j.1365-2044.1949.tb05802.x. pmid: 18101361 3. alam m, ricci d, havey j, rademaker a, witherspoon j, west dp. safety of peak serum lidocaine concentration after mohs micrographic surgery: a prospective cohort study. j am acad dermatol. 2010;63(1):87-92. doi: 10.1016/j.jaad.2009.08.046. pmid: 20462662 4. lozinski a, huq ns. tumescent liposuction. clin plast surg. 2013;40(4):593-613. doi: 10.1016/j.cps.2013.07.006. pmid: 24093655. 5. orlando r, piccoli p, de martin s, padrini r, palatini p. effect of the cyp3a4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function. br j clin pharmacol. 2003;55(1):86-93. doi: 10.1046/j.1365-2125.2003.01718.x. pmid: 125346446. 6. ramon y, barak y, ullmann y, hoffer e, yarhi d, bentur y. pharmacokinetics of high-dose diluted lidocaine in local anesthesia for facelift procedures. ther drug monit. 2007;29(5):644-7. doi: 10.1097/ftd.0b013e3180eaa10a. pmid: 17898657. 7. ostad a, kageyama n, moy rl. tumescent anesthesia with a lidocaine dose of 55 mg/kg is safe for liposuction. dermatol surg. 1996;22(11):921-7. doi: 10.1111/j.1524-4725.1996.tb00634.x. pmid: 9063507. 8. minkis k, whittington a, alam m. dermatologic surgery emergencies: complications caused by systemic reactions, high-energy systems, and trauma. j am acad dermatol. 2016;75(2):265-84. doi: 10.1016/j.jaad.2015.11.054. pmid: 27444069. 9. park kk, sharon vr. a review of local anesthetics: minimizing risk and side effects in cutaneous surgery. dermatol surg. 2017;43(2):173-187. doi: 10.1097/dss.0000000000000887. pmid: 27608208. commentary | dermatol pract concept. 2021; 11(4): e 2021120 3 10. vasques f, behr au, weinberg g, ori c, di gregorio g. a review of local anesthetic systemic toxicity cases since publication of the american society of regional anesthesia recommendations: to whom it may concern. reg anesth pain med. 2015;40(6):698-705. doi: 10.1097/aap.0000000000000320. pmid: 26469367. 11. starling j 3rd, thosani mk, coldiron bm. determining the safety of office-based surgery: what 10 years of florida data and 6 years of alabama data reveal. dermatol surg. 2012;38(2):171-177. doi: 10.1111/j.1524-4725.2011.02206.x. pmid: 22093178. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021; 11(4):e2021093 1 dermoscopy of green nail syndrome: the “green aurora sign” miguel dominguez-santas1, borja diaz-guimaraens1, juan jimenez-cauhe1, ana suarez-valle1. 1 dermatology department, ramon y cajal university hospital, madrid, spain citation: dominguez-santas m, diaz-guimaraens b, jimenez-cauhe j, suarez-valle a. dermoscopy of green nail syndrome: the “green aurora sign”. dermatol pract concept. 2021; 11(4):e2021093. doi: https://doi.org/10.5826/dpc.1104a93 accepted: march 2, 2021; published: october, 2021 copyright: ©2021 dominguez-santas et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: miguel dominguez-santas, md. dermatology department, ramon y cajal university hospital. carretera colmenar viejo km 9.100, 28034 madrid, spain. email: miguelds92@hotmail.com case presentation a 49-year-old woman presented to our dermatology department with a 1-year-long history of asymptomatic nail discoloration affecting the thumb of her right hand. she referred that she was treated with oral fluconazole by her general practitioner with no clinical improvement. dermatological examination showed dark green discoloration of the nail plate (figure 1a). dermoscopy of the nail plate showed a brighter green discoloration with bluish hues (figure 1b). dermoscopy of the free edge showed distal onycholysis and the presence of the pigment in the ventral side of the plate (figure 1c). the patient in this manuscript provided written informed consent to the publication of her case details. teaching point green nail syndrome is caused by the accumulation of pyocyanin that is produced by pseudomonas aeruginosa bacterium [1]. although it may be confused with onychomycosis, the absence of nail bed hyperkeratosis should guide the clinician towards the correct diagnosis. onychomycosis can present the aurora borealis sign if dermoscopy is used [2], we therefore suggest using the term “green aurora sign” to differentiate green nail syndrome dermoscopy from the one seen in onychomycosis. 2 image letter | dermatol pract concept. 2021; 11(4):e2021093 references 1. maes m, richert b, de la brassinne m. green nail syndrome or chloronychia. rev med liege. 2002; 57: 233–235. 2. piraccini bm, balestri r, starace m, rech g: nail digital dermoscopy (onychoscopy) in the diagnosis of onychomycosis. j eur acad dermatol venereol. 2013; 27: 509–513. doi: 10.1111/j.1468-3083.2011.04323.x.pmid:22040510. figure 1. (a) dark green discoloration of the nail plate. (b) dermoscopy of the nail plate showed a brighter green discoloration with bluish hues. (c) dermoscopy of the free edge showed distal onycholysis and the presence of the pigment in the ventral side of the plate. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022024 1 ablative fractional erbium:yag laser resurfacing: a treatment option for acne stefania guida1, nicola lippolis1, matteo giovani1, gioia pedroni1, giacomo giovanni urtis2, giovanni pellacani1,3, francesca farnetani1, marco manfredini1 1 dermatology unit, department of surgical, medical, dental and morphological science with interest transplant, oncological and regenerative medicine, university of modena and reggio emilia, modena, italy 2 cliniche diventa, milano-roma-como, italy 3 dermatology clinic, department of clinical internal, anesthesiological and cardiovascular sciences, sapienza university of rome, rome, italy key words: acne, laser, erbium:yag, active acne citation: guida s, lippolis n, giovani m, et al. ablative fractional erbium:yag laser resurfacing: a treatment option for acne. dermatol pract concept. 2022;12(1):e2022024. doi: https://doi.org/10.5826/dpc.1201a24 accepted: may 26, 2021; published: january 2022 copyright: ©2022 guida et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: dr nicola lippolis, dermatology unit, department of surgical, medical, dental and morphological science with interest transplant, oncological and regenerative medicine, university of modena and reggio emilia, modena, italy. e-mail: lippolisnicola@yahoo.it introduction acne vulgaris is a disease of the pilosebaceous unit, characterized by a hyper keratinization process, comedo formation, and inflammatory reactions [1]. the use of lasers for the treatment of acne has been described, but the role of resurfacing lasers for active acne has not been clarified yet. case presentation we present the cases of 3 women with noninflammatory and inflammatory acne lesions. they received laser therapy because they refused prolonged topical treatments or other systemic acne therapies. no treatment was given to the patients in the previous 6 months prior to laser treatment. the patients gave informed consent to mild laser rejuvenation therapy with ablative fractionated erbium:yag laser, (xlase plus; biotec italia srl, dueville, vi). these patients were treated using the standard protocol for mild resurfacing and rejuvenation. employed parameters were 1.5 ms, 3.5 mj/cm2, 5 hz on the cheeks and the chin, and the rest of the face was treated with 1.0 ms, 2.8 mj/cm2, 6 hz. one laser session per month for 3 months was performed for each patient. overlapping pulses were performed over inflammatory lesions. after the laser sessions, the patients were instructed to apply sunscreen spf 50+ and a hydrating cream for 30 days. all 3 patients tolerated the treatment without any reported side effects. they showed a visible improvement of the skin texture and a reduction of active acne. dermatology practical & conceptual 2 research letter | dermatol pract concept. 2022;12(1):e2022024 the average value for the investigator global assessment scale (iga) was indicative of a mild-moderate acne at baseline (iga 1-2) and decreased consistently to the almost-clear stage (iga 0-1) at the last follow-up visit 3 months after the last laser session (figures 1 and 2). one paper describes the application of multiple sessions of erbium:yag laser treatment for active acne on 2 patients with inflamed cystic acne [2]. singh et al hypothesized that the mechanism of action of this laser source might be related to the photothermal effect acting on follicular hyperkeratosis and contributing to skin microbe modulation. the short follow-up period of our patients represents a limitation of this case report. further studies are needed to investigate the anti-acne effect of erbium: yag laser and its mechanism of action with respect to comedogenesis and inflammation. conclusions acne is one of the most common skin diseases. many therapeutic approaches are currently available for active acne, including laser treatments. however, the role of resurfacing figure 1. clinical pictures of a 34-year-old woman. (a) before the last erbium:yag laser session. (b) 3 months after the last erbium:yag laser session, showing the reduction of active acne lesions. figure 2. clinical pictures of a 25-year-old woman. (a) before the last erbium:yag laser session. (b) 3 months after the last erbium:yag laser session, highlighting a consistent reduction of both inflammatory and noninflammatory acne skin lesions. research letter | dermatol pract concept. 2022;12(1):e2022024 3 with erbium:yag laser has not been clarified yet. results from clinical practice, such as in the cases presented herein, highlight the importance of further investigations in this field. informed consent: written informed consent for publication of their clinical details and clinical images was obtained from all patients. references 1. manfredini m, greco m, farnetani f, et al. in vivo monitoring of topical therapy for acne with reflectance confocal microscopy. skin res technol. 2017;23:36–40. doi: 10.1111/srt.12298. pmid: 27273850. 2. singh mz, singh si, basra ps. erbium:yag laser resurfacing in patients with inflamed cystic acne. j cosmet laser ther. 2006;8(4):163-166. doi: 10.1080/14764170601034711. pmid: 19839167. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(3):e2021051 1 kidney and urinary tract involvement in epidermolysis bullosa: is routine follow-up necessary? neslihan cicek1, nurdan yildiz1, ruslan asadov2, ayse deniz yucelten3, halil tugtepe4, harika alpay1 1 department of pediatric nephrology, marmara university school of medicine, istanbul, turkey 2 department of radiology, marmara university school of medicine, istanbul, turkey 3 department of dermatology, marmara university school of medicine, istanbul, turkey 4 department of pediatric urology, marmara university school of medicine, istanbul, turkey keywords: end stage renal disease, epidermolysis bullosa, peritoneal dialysis, urinary tract involvement citation: cicek n, yildiz n, asadov r, yucelten ad, tugtepe h, alpay h. kidney and urinary tract involvement in epidermolysis bullosa: is routine follow-up necessary? dermatol pract concept. 2021;11(3):e2021051. doi: https://doi.org/10.5826/dpc.1103a51 accepted: january 3, 2021; published: may 20, 2021 copyright: ©2021 cicek et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: neslihan cicek, md. fevzi cakmak mah, muhsin yazıcıoglu cad no: 10, kaynarca-pendik, istanbul, turkey. email: drneslihancicek@yahoo.com background: several renal and urinary tract complications have been reported in patients with epidermolysis bullosa. objective: this study investigated kidney and urinary tract involvement in patients with epidermolysis bullosa. patients and methods: patients with epidermolysis bullosa in treatment at the dermatology unit were included in the study. glomerular and tubular functions were investigated. results: the study included 16 patients (4 females, 12 males) of mean 11.1 years (sd = 8.1 years). estimated gfr was normal in all patients except one with end-stage renal disease. excluding this patient, the urinary albumin/creatinine ratio and the fractional excretion of sodium were normal. the mean beta-2 microglobulin/creatinine ratio was 278.8 µg/g, and it was abnormally high in 2 patients. the mean tubular phosphorus reabsorption was 92.6%; it was abnormally low in 1 patient. severe kidney or urinary tract involvement was present in 2 patients with recessive dystrophic eb-generalized severe (rdeb-gs): one patient had obstructive bullous lesions in the urethra; the other had end-stage renal disease secondary to focal segmental glomerulosclerosis and was on peritoneal dialysis for 3 years. conclusions: assessment for renal and urinary tract involvement should become a routine part of the evaluation of patients with any type of eb, but especially of patients with rdeb-gs. patients with mild tubular dysfunction need long-term follow-up to detect early deterioration of renal function. abstract 2 research | dermatol pract concept. 2021;11(3):e2021051 introduction epidermolysis bullosa (eb) is a rare inherited disorder characterized by fragility to minor trauma, resulting in bullous skin lesions that may be associated with variable systemic involvement. currently, eb is classified into simplex, junctional, dystrophic types and kindler syndrome (mixed cleavage plane) according to the ultrastructural cleavage plane in skin and location of the target protein [1,2]. currently, immunofluorescence antigen mapping, transmission electron microscopy and genetic analysis are recommended to confirm the diagnosis as well as to classify the type and subtype of eb [2,3]. these techniques are largely inaccessible in developing countries. therefore, yenamandra et al [4] developed a clinical diagnostic matrix that indicates the presence or absence of different features for the diagnosis of 9 eb subtypes [4]. in patients with eb, respiratory, genitourinary and gastrointestinal system involvement has been described in isolated case reports and small case series. several renal complications, including iga nephropathy, amyloidosis, post-infectious glomerulonephritis, hereditary nephritis, and upper and lower urinary tract obstructions, have been reported [5-10]. these complications may lead to chronic kidney disease with high morbidity and mortality [6-8]. although renal and urinary tract involvement is usually seen in patients with the most severe subtypes (eg junctional and recessive dystrophic disease), these complications may arise in any subtype of inherited eb, including the milder forms [7,11]. patients with eb mostly refer to dermatology and pediatric outpatient clinics and are mainly concerned with skin and related complications. therefore, awareness of pediatricians about nephro-urological involvement of eb is important for the early diagnosis and treatment of complications. in this study, we investigated renal and urinary tract involvement in a series of patients with eb. materials and methods sixteen patients with eb, followed at the dermatology unit, were involved in the study. two patients were referred to the pediatric nephrology unit, and the other 14 patients had no history of kidney or urinary tract involvement. the study was approved by the ethics committee of marmara university school of medicine (09.2016.242) and was done in accordance with the declaration of helsinki. after a full explanation of the study was given to parents and children, informed consent was obtained from the parents for children and from patients for adults. demographic data were recorded from the medical files of the patients. as electron microscopy, immunologic studies and genetic analyses were not available due to technical and financial difficulties, the clinical diagnostic matrix of yenamandra et al [4] was used to diagnose the eb subtype. distribution of lesions, excessive granulation tissue, scarring, milia, nail involvement, mucosal involvement, poor dental enamel, keratoderma, chronic wounds, syndactyly, alopecia, poikiloderma, relative growth failure, survival after 2 years and affected parents were evaluated in this clinical diagnostic matrix. in all patients, fasting morning blood samples and spot urine samples were obtained. serum creatinine, cystatin c, sodium, phosphorus, 24-hour urinary sodium, phosphorus, creatinine, albumin and beta-2 microglobulin (b2m) were measured. glomerular functions were evaluated from serum creatinine, cystatin c, estimated glomerular filtration rate (egfr) and urinary albumin/creatinine ratio. egfr (normal, ≥ 90 ml/min 1.73 m2) was calculated from height and plasma creatinine using a modified schwartz formula (0.413 × height (cm) / plasma creatinine (mg/dl) [12]. renal tubular functions were assessed by determination of fractional excretion of sodium (fena), tubular phosphorus reabsorption (trp) and the urinary b2m/creatinine ratio. fena (normal, <1 %) was calculated with the formula (urinary sodium (mmol/l) × plasma creatinine (mg/dl)) / (plasma sodium (mmol/l) × urinary creatinine (mg/dl)). trp (normal, ≥85 %) was calculated with the formula 1 (urinary phosphorus (mg/dl) × plasma creatinine (mg/dl)) / (plasma phosphorus (mg/dl) × urinary creatinine (mg/dl)). the urinary b2m/ creatinine ratio was considered normal when <300 µg/g, and the urinary albumin/creatinine ratio was normal when <30 mg/g. urinary system ultrasonography was performed in all patients by the same radiologist. results the study evaluated 16 eb patients (12 males and 4 females) of mean age 11.1 years (sd = 8.1 years; range, 1.6-28.7 years). the most common types of eb were recessive dystrophic eb–generalized severe (rdeb-gs, 7 cases), junctional eb–generalized severe (jeb-gs, 3 cases) and eb simplex– localized (ebs-l, 2 cases) (table 1). kidney or urinary tract involvement was observed in 4 patients, including 1 case (#11) with focal segmental glomerulosclerosis and end-stage renal disease (esrd), 1 case (#1) with urethral obstruction and hydroureteronephrosis, and 2 patients (#5 and #12) with mild renal tubular dysfunction. the patient with esrd (#11) was excluded from further analysis. for the remaining 15 cases, the mean values of serum creatinine, cystatin c and egfr were 0.38 mg/dl (sd = 0.15), 0.7 mg/dl (sd = 0.09) and 182 ml/min 1.73 m2 (sd = 52.4), respectively, and were considered normal. the mean albumin/ creatinine ratio was 15.3 mg/g (sd = 17.2), and was normal in the 15 patients. the mean urinary b2m/creatinine ratio, an indicator of renal tubular function, was 278.8 µg/g (sd = research | dermatol pract concept. 2021;11(3):e2021051 3 577); it was high in 1 patient with eb simplex–generalized severe (ebs-gs, #5) and 1 patient with rdeb-gs (#12). fena was less than 1% and normal in all patients (excluding patient #11). the mean trp was 92.6% (sd = 3.8%); it was slightly low in a patient with rdeb-gs (#2). overall, 13 patients had normal ultrasonography findings. the patient who had urinary tract involvement was a 17.7 year-old boy with rdeb-gs (#1). he was admitted to hospital with dysuria and a poor urinary stream. ultrasonography revealed bilateral grade 1 hydroureteronephrosis. the skin lesions were present since birth and he had no previous urinary tract infection. urine cultures were sterile, and glomerular and tubular function tests were normal (table 1). uroflowmetry revealed a serious obstructive pattern, with a maximum flow rate of 4 ml/s, a voided volume of 75 ml and a voiding time of 471 s. cystoscopy was performed, and several bullous lesions in the bulbar and prostatic urethra, causing partial obstruction, were resected. after the procedure, his symptoms persisted and he was unable to empty his bladder completely. therefore, clean intermittent catheterization was suggested due to a high post-voiding residual urine volume. he couldn’t tolerate urethral catheterization, so underwent a monti procedure (creation of a conduit between the bladder and skin using part of the gastrointestinal tract). he is still on clean intermittent catheterization by monti procedure. the patient with rdeb-gs (#11) and renal involvement was a 20-year-old female with digital fusion, lower limb contractures and impaired mobility. she was referred to our pediatric nephrology clinic because of high serum creatinine (1.4 mg/dl) and proteinuria (14.3 mg/m2 h) at the age of 16 years. renal ultrasound demonstrated kidneys with increased echogenicity. she underwent renal biopsy without complications, and histopathological examination revealed focal segmental glomerulosclerosis with 30% global sclerosis. amyloidosis and immunofluorescence microscopy were negative. her renal functions deteriorated progressively and esrd developed (serum blood urea nitrogen, 70 mg/dl; serum creatinine, 6.97 mg/dl; and egfr = 10.2 ml/min 1.73 m2). peritoneal dialysis was preferred to avoid recurrent vein punctures. a double cuffed swanneck tenckhoff catheter was inserted into the peritoneal space and continuous ambulatory peritoneal dialysis was started. although she had recurrent blistering of most parts of her body, the exit site was clean (figure 1). she had only one attack of peritonitis with sterile culture during follow-up. she was not able to perform dialysis herself because of severe syndactyly, and therefore her mother performed the dialysis exchanges. table 1. clinical characteristics of 16 patients with epidermolysis bullosa case sex diagnosis1 age (years) egfr2 urinary albumin/ creatinine ratio urinary b2m/ creatinine ratio trp (%) fena (%) 1 m rdeb-gs 17.7 135 7.7 77 92 0.88 2 m rdeb-gs 11 101 11.2 40 82 0.3 3 m ebs-l 4.7 189 11.1 50 97 0.25 4 m rdeb-gi 14.5 286 7.1 83 93 0.04 5 m ebs-gs 20.2 136 16.5 390 93 0.63 6 f ebs-l 28.7 172 6.78 49.2 90 0.04 7 m rdeb-gs 14.2 191 9.6 98 91 0.43 8 m ebs-gi 4.5 205 75 102 95 0.26 9 m jeb-gs 4.5 250 11 302 90 0.07 10 m rdeb-gs 6 180 8.2 250 92 0.02 113 f rdeb-gs 20.7 3.7 1 5000 32 25.6 12 f rdeb-gs 22 265 9.1 2332 92.5 0.75 13 m jeb-gs 1.6 198 25.3 65.8 98 0.17 14 m jeb-gs 7 150 10.9 41 95 0.33 15 f rdeb-gs 2.5 148 15.3 150 93 0.56 16 m kindler syndrome 7.2 141 5.46 153 96 0.61 eb = epidermolysis bullosa; ebs-gi = eb simplex-generalized intermediate; ebs-gs = eb simplex-generalized severe; ebs-l = eb simplex-localized; egfr = estimated glomerular filtration rate; f = female; fena = fractional excretion of sodium; jeb-gs = junctional eb-generalized severe; m = male; rdeb-gi = recessive dystrophic eb-generalized intermediate; rdeb-gs = recessive dystrophic eb-generalized severe; trp = tubular phosphorus reabsorption. 1 based on clinical findings and the clinical diagnostic matrix [11]. 2 expressed in units of ml/min 1.73 m2. normal values are ≥90. 3 this patient had end-stage renal disease. 4 research | dermatol pract concept. 2021;11(3):e2021051 table 2. reported cases of renal involvement in patients with epidermolysis bullosa sex age (years) eb type renal involvement dialysis outcome ref. m 14 rdeb-hs iga nephropathy hemodialysis on follow-up [5] m 14.5 rdeb mpgn peritoneal exitus [10] f 11 rdeb iga nephropathy hemodialysis and peritoneal exitus [10] m 20 rdeb iga nephropathy no exitus [15] f 29 rdeb iga nephropathy peritoneal on follow-up [25] m 19 rdeb amyloidosis na na [26] m 22 rdeb amyloidosis na na [26] f 27 rdeb amyloidosis na na [26] f 30 rdeb amyloidosis na na [26] f 17 deb iga nephropathy no on follow-up [27] m 10 deb pign no on follow-up [28] f 17 deb amyloidosis exitus [28] f 15 rdeb nephrotic syndrome, amyloidosis no on follow-up [29] m 38 rdeb amyloidosis hemodialysis na [30] m 4 na iga nephropathy no on follow-up [31] m 33 jeb iga nephropathy hemodialysis transplantation [32] m 27 rdeb iga nephropathy no transplantation [33] m 6 rdeb nephrotic syndrome, amyloidosis no on follow-up [34] m 39 deb mpgn no on follow-up [35] deb = dystrophic epidermolysis bullosa; eb = epidermolysis bullosa; f = female; hs = hallopeau-siemens; jeb = junctional epidermolysis bullosa; m = male; mpgn = membranoproliferative glomerulonephritis; na = not available; pign = post-infectious glomerulonephritis; rdeb = recessive dystrophic epidermolysis bullosa. figure 1. peritoneal catheter exit site in patient #11, (a) on day 10 and (b) after 2 months the patient with kindler syndrome (#16) was a 7-year-old boy. ultrasonography revealed a small left kidney. radionuclide scanning with dimercaptosuccinic acid demonstrated a split function of 18% on the left kidney without scar tissue. he was diagnosed as having a hypoplastic left kidney. discussion eb is a heterogeneous, hereditary skin disorder with severe cutaneous and extracutaneous involvement. mucosal lesions can be observed in the mouth, larynx, esophagus, bronchia, research | dermatol pract concept. 2021;11(3):e2021051 5 large bowel, urogenital tract, vagina and anus [1,2]. there are only a few case reports and small case series regarding kidney and urinary tract involvement in eb. kidney and urinary tract involvement has been described in all eb types, particularly in dystrophic eb and junctional eb [13]. in our study, we evaluated renal functions and urinary tract involvement of 16 patients with eb. nephropathy is a serious complication of the major types of eb, particularly severe rdeb. the kidneys may be injured either by obstruction due to mucosal lesions or by glomerular disease [8,10]. in our series, one patient with rdeb-gs had bullous lesions within the bulbar and prostatic urethra, causing partial obstruction of outflow. it is reported that genitourinary involvement may vary from meatal stenosis leading to upper tract dilatation to severe stenosis due to bullous lesions and scarring at the ureterovesical junction requiring permanent urinary diversion [14,15]. the mechanisms may include chronic blister formation within the lining epithelia of the urinary tract, and chronic systemic inflammation [16]. the most common type in these cases is either junctional or dystrophic eb, which have serious multisystem involvement. fine et al reported that urinary retention and hydronephrosis occurred in 9.3 % and 7 % of cases, respectively, of junctional eb [7]. obstructive lesions may lead to chronic renal injury if left untreated. surgery for urethral lesions in eb patients has not been clearly described. chan et al reported a patient with obstructive uropathy and described surgical treatments in detail [10]. in our study, obstructive bullous lesions within the bulbar and prostatic urethra were resected from one young male patient. however, his symptoms did not regress, and catheterization was suggested due to the high post-voiding residual urine volume. it is important to note that the use of instruments in the urinary tract might cause serious lesions, including stenosis, and may worsen the clinical course, so should be avoided as much as possible [9]. the clinical course of this patient worsened; because he could not tolerate urethral catheterization, he underwent a monti procedure (creation of a conduit between the bladder and skin). with a significant increase in survival of eb patients, renal complications are seen more frequently. there are a few publications, mostly case reports, on kidney involvement in eb (table 2). chronic kidney disease has most commonly been reported in patients with rdeb and junctional eb. fine et al reported the mortality of patients with junctional eb and rdeb due to esrd as 0.52 % and 1.4 8%, respectively [8]. chronic post-infectious glomerulonephritis attributed to recurrent superinfections of bullous skin lesions, mesangioproliferative glomerulonephritis, iga nephropathy, and nephrotic syndrome secondary to amyloidosis leading to esrd have all been reported in eb patients [5,10,15,16,17,18]. although we have a limited number of cases, one of our patients (patient #11 with rdeb-gs) had esrd secondary to focal segmental glomerulosclerosis. even though invasive procedures should be avoided in these patients, renal biopsy may be performed successfully if necessary. focal segmental glomerulosclerosis is rare in patients with eb [19]. the mechanism of glomerular involvement is still not fully understood. compositional changes of various proteins involved in the development, structure, and function of both skin and kidney (eg integrins, laminin, collagen xvii, cd151) alter glomerular cell-matrix interactions and may result in increased glomerular capillary wall permeability through abnormal podocyte adhesion to the glomerular basement membrane or alteration in the structure of the filtration slit diaphragms [13,16,20,21]. mutations in the gene for integrin α3 (itga3), the main integrin linking podocyte foot processes to the glomerular basement membrane, cause junctional eb with interstitial lung disease and renal anomalies (ilneb, omim#614748) including congenital nephrotic syndrome, focal segmental glomerulosclerosis, bilateral renal cysts, and a spectrum of congenital anomalies of the kidney and urinary tract (cakut) [13,21]. focal segmental glomerulosclerosis and cakut were described in junctional eb with itgb6 and itgb4 mutations leading to abnormal integrin β6 and β4 subunits [19,21]. mutations in genes encoding type xvii collagen (col17a1) and laminin 332 (lama3, lamb3 and lamc2), which are expressed in renal glomerular podocytes and bind to integrins, were reported in patients with junctional eb and renal involvement [20-22]. type vii collagen interacts with laminins and integrins in the kidney. chronic renal failure, post-streptococcal glomerulonephritis, iga mesangial disease and renal amyloidosis have been reported in patients with the recessive forms of dystrophic eb, with col7a1 mutations resulting in markedly reduced or abnormal type vii collagen [13,16]. cd151, a ligand of integrins expressed in glomerular podocytes, contributes to cell adhesion and maintenance of the glomerular basement membrane. homozygous mutations in cd151 gene encoding tetraspanin cd151 were reported in patients with eb simplex and nephropathy [20,21,23]. it is believed that chronic inflammation causes glomerulonephritis due to immune complex formation or extensive immunoglobulin synthesis [24]. in our patients (excluding case #11), the mean egfr was high (182 ml/min 1.73 m2). this finding seems to be due to hyperfiltration. to our knowledge, renal tubular functions in eb have not been fully evaluated. the etiopathogenesis of tubular dysfunction may include frequent nephrotoxic antibiotic therapies to treat skin infections and chronic inflammation. hata et al [22] reported high urinary albumin, n-acetylglucosaminidase and b2m excretion, indicating glomerular and renal tubular involvement, in a patient with herlitz junctional eb and a 6 research | dermatol pract concept. 2021;11(3):e2021051 lamb3 gene mutation. they showed the absence of the α3 subunit of laminin-5 in tubular basal membranes, and suggested that the lack of laminin-5 in the renal tubular basement membrane was responsible for renal tubular involvement [22]. we found mild tubular dysfunction in 2 patients with normal egfr. although our study group was small, these data emphasize the importance of monitoring tubular functions by testing for low molecular weight proteinuria and by calculating fena and trp, to detect early deterioration of kidney functions and prevent end-organ damage, even though the majority of urinary tract involvement in eb patients may be asymptomatic before renal dysfunction develops. however, our results need to be expanded upon in large multicenter studies. the choice of hemodialysis or peritoneal dialysis for eb patients with esrd should be decided on an individual basis, taking into consideration patient and familial performance status and available facilities. peritonitis, intraperitoneal adhesions, exit site complications and sepsis limit the use of peritoneal dialysis in many patients. in this study, one patient (#11) was treated with peritoneal dialysis for 3 years without serious complications. chan et al [10] reported 2 rdeb patients treated with peritoneal dialysis: in the first case, peritoneal dialysis had to be changed to hemodialysis due to peritoneal infections and adhesions; the second patient died from sepsis 4 months after catheterization. ahmadi and antaya [25] reported a successful 14-month period of peritoneal dialysis without peritonitis or exit site complication in a 29-year-old woman with rdeb-gs and iga nephropathy. we preferred peritoneal dialysis in our patient to avoid recurrent vein punctures because of her skin lesions. at the beginning, we were concerned about her catheter exit site; however, she tolerated dialysis well, the exit site improved, and no exit site complications such as infection, blisters or bleeding were observed (figure 1). in this study, we observed 2 important complications in patients with rdeb-gs. although our study has a limited number of patients, we suggest that patients with any type of eb may have renal and urological complications that may lead to chronic renal injury. a major limitation of our study is that diagnoses of the patients were not confirmed by immunofluorescence, electron microscopic and genetic studies due to technical and financial difficulties and health care system limitations. instead, we used a clinical diagnostic matrix [4]. on the other hand, kidney involvement and urinary tract complications may arise in any subtype of eb, including milder forms [7,11,13]. therefore, the clinical diagnosis does not change the message that we emphasize in this paper. we aim to draw attention to kidney and urological problems with this study, since eb patients are mostly followed-up in dermatology and pediatric outpatient clinics and are mainly concerned with skin involvement. conclusions considering the significant increase in survival and longevity of eb patients, we strongly recommend that evaluation of glomerular and tubular functions and assessment of possible kidney-urinary tract involvement become a routine part of the diagnostic work-up of eb patients. milder complications may arise in any subtype of inherited eb. children with mild tubular dysfunction need long-term follow-up to detect early deterioration of kidney functions and to prevent organ damage later in life. references 1. morelli j.g. mechanobullous disorders. in: kliegman rm, stanton bf, st. geme jw, schor nf, behrman re, eds. nelson textbook of pediatrics. 19th ed. philadelphia, pa: elsevier saunders, 2011:2244-2246. 2. fine jd, bruckner-tuderman l, eady ra, uitto j, woodley d, zambruno g. inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. j am acad dermatol. 2014;70(6):1103–1126. doi: 10.1016/j.jaad.2014.01.903. pmid: 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epidermolysis bullosa. nat rev dis primers. 2020;6(1):78. doi: 10.1038/ s41572-020-0210-0. pmid: 32973163. 22. hata d, miyazaki m, seto s, et al. nephrotic syndrome and aberrant expression of laminin isoforms in glomerular basement membranes for an infant with herlitz junctional epidermolysis bullosa. pediatrics. 2005;116(4):601-607. doi: 10.1542/peds.2005-0160. pmid: 16147969. 23. baleato rm, guthrie pl, gubler m-c, ashman lk, roselli s. deletion of cd151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. am j pathol. 2008;173(4):927–937. doi: 10.2353/ ajpath.2008.071149. pmid: 18787104. 24. małecki m, domański m, ciechanowski k. end-stage kidney disease in patient with epidermolysis bullosa what are the treatment options? – case report. bmc nephrology. 2017;18(1):193-196. doi: 10.1186/s12882-017-0606-6. pmid: 28615054. 25. ahmadi j, antaya r. successful peritoneal dialysis in a patient with recessive dystrophic epidermolysis bullosa. pediatr dermatol. 2007;24(5):589-590 doi: 10.1111/j.1525-1470.2007.00541.x. pmid: 17958832. 26. kaneko k, someya t, ohtaki r, shimojima t, yamashiro y, ohtomo y. colchicine therapy in amyloid nephropathy due to recessive dystrophic epidermolysis bullosa. pediatr nephrol. 2003;18(12):1311-1312. doi: 10.1007/s00467-003-1310-2. pmid: 14586686. 27. kawasaki y, isome m, takano k, et al. iga nephropathy in a patient with dominant dystrophic epidermolysis bullosa. tohoku j exp med. 2008;214(4):297-301. doi: 10.1620/tjem.214.297. pmid: 18441504. 28. mann jf, zeier m, zilow e, et al. the spectrum of renal involvement in epidermolysis bullosa dystrophica hereditaria: report of two cases. am j kidney dis. 1988;11(5):437-441. doi: 10.1016/ s0272-6386(88)80059-3. pmid: 3369444. 29. gündüz k, vatansever s, türel a, sen s. recessive dystrophic epidermolysis bullosa complicated with nephrotic syndrome due to secondary amyloidosis. int j dermatol. 2000;39(2):151-153. doi: 10.1046/j.1365-4362.2000.00904.x. pmid: 10692067. 30. iida h, hasegawa t, okuma k, io h, tomino y, ikeda s. successfully maintained hemodialysis for the treatment of chronic renal failure in a patient with hallopeau-siemens type recessive dystrophic epidermolysis bullosa. j dermatol. 2012;39(2):1088-1089. doi: 10.1111/j.1346-8138.2012.01617.x. pmid: 22725264. 31. harikrishnan kn, krishnamurthy s, rajesh ng, mahadevan s. renal involvement in epidermolysis bullosa simplex: an unusual presentation. indian j pediatr. 2014;81(1):102-103. doi: 10.1007/s12098-012-0907-5. pmid: 23229918. 32. ungureanu s, adni t, brown t, inston n, heagerty a. successful renal transplant in a patient with non-herlitz junctional epidermolysis bullosa. clin exp dermatol. 2014;39(3):330-332. doi: 10.1111/ced.12300. pmid: 24635072. 33. ceuppens she, kimenai hjan, roodnat ji, et al. living donor kidney transplantation in a patient with epidermolysis bullosa: a case report. transplant proc. 2019;51(9):3074-3076. doi: 10.1016/j.transproceed.2019.04.049. pmid: 31331719. 34. pınarbaşı as, dursun i, daldaban b, et al. epidermolysis bullosa complicated with nephrotic syndrome due to aa amyloidosis: a case report and brief review of literature. saudi j kidney dis transpl. 2019;30(6):1450-1456. doi: 10.4103/13192442.275492. pmid: 31929295. 35. soliman km, fülöp t, ploth dw, herberth j. diffuse membranoproliferative glomerulonephritis with focal sclerosis and renal amyloidosis in an adult male with autosomal dominant dystrophic epidermolysis bullosa: a case report. ren fail. 2019;41(1):850854. doi: 10.1080/0886022x.2019.1614056. pmid: 31498016. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022062 1 secret of the “white belly button” during pregnancy demystified farah el hadadi1, line mezni1, laila benzekri1, mariame meziane1, karima senouci1 1 department of dermatology-venereology, ibn sina university hospital, mohammed v university, rabat, morocco key words: hypopigmentation, pregnancy, depigmentation, belly citation: el hadadi f, mezni l, benzekri l, meziane m, senouci k. secret of the “white belly button” during pregnancy demystified. dermatol pract concept. 2022;12(2):e2022062. doi: https://doi.org/10.5826/dpc.1202a62 accepted: september 2, 2021; published: april 2022 copyright: ©2022 kenani et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: farah el hadadi, department of dermatology-venereology, ibn sina university hospital, mohammed v university, rabat, morocco. e-mail: farahealhadadi1234@gmail.com introduction during pregnancy, several physiological, hormonal, immunological, metabolic and vascular changes occur [1]. the skin is one of the first organs that maybe affected. we report a case of a sudden whitish macular eruption on the belly that occurred at 30 weeks of pregnancy. case presentation a 33-year-old female patient with no particular medical history at 36 weeks of pregnancy developed a white macule with irregular borders on the belly with a downward extension which has occurred 6 weeks before (figure 1) (figure2). the patient didn’t complain about itch or pain, and no sclerosis or scales were present on physical examination. conclusions pregnancy dermatoses are classified into: structural skin changes, specific dermatoses of pregnancy and preexisting figure1. white macule of the belly with a downward extension and irregular borders in a 36 week pregnant women. 2 research letter | dermatol pract concept. 2022;12(2):e2022062 figure 2. disappearance of the lesion after childbirth. dermatosis of pregnancy [2]. a rare condition characterized by the presence of a whitish macular eruption of the belly is often a cause of concern in pregnant women. the “white belly button” is a benign physiological phenomenon; it appears as a sudden demarcation of “white areas” or a “skin pallor” that affects the skin due to a vascular abnormality resulting from an excessive stretching of the skin. the abrupt onset of this macule has never been described or reported in any scientific journal and the physio-pathological mechanism remains unknown but can be explained by the presence of a tissue hypoxia as a result of vasoconstriction of small dermal vessels. it is therefore important to differentiate this physiological pigmentation from other skin conditions such as post inflammatory hypopigmentation, vitiligo, nevus depigmentosus pityriasis versicolor and white spot disease to avoid unnecessary treatment and to reassure pregnant women about the benignity of this condition. references 1. motosko cc, bieber ak, pomeranz mk, stein ja, martires kj. physiologic changes of pregnancy: a review of the literature. int j womens dermatol. 2017;3(4):219–224. doi: 10.1016/j .ijwd.2017.09.003. pmid: 29234716. pmcid: pmc5715231. 2. sachdeva s. the dermatoses of pregnancy.  indian j dermatol. 2008;53(3):103–105. doi: 10.4103/0019-5154.43203. pmid: 19882004. pmcid: pmc2763729. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021; 11(4): e2021127 1 melanocytic or not? dermoscopy and reflectance confocal microscopy for lesions difficult to diagnose: a cross-sectional diagnostic accuracy study camila scharf1, giuseppe argenziano1, gabriella brancaccio1, gaetano licata1, andrea ronchi2, elvira moscarella1 1 dematology unit, university of campania l.vanvitelli, naples, italy 2 pathology unit, university of campania l.vanvitelli, naples, italy key words: reflectance confocal microscopy, dermoscopy, skin cancer, melanocytic, diagnosis citation: scharf c, argenziano g, brancaccio g, licata g, ronchi a, moscarella e. melanocytic or not? dermoscopy and reflectance confocal microscopy for lesions difficult to diagnose: a cross-sectional diagnostic accuracy study. dermatol pract concept. 2021; 11(4): e2021127. doi: https://doi.org/10.5826/dpc.1104a127 accepted: march 9, 2021; published: september 2021 copyright: ©2021 scharf et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: elvira moscarella, md, dermatology unit, university of campania l.vanvitelli, naples, italy. email: elvira.moscarella@gmail.com background: different techniques for non-invasive skin examination and early diagnosis of skin lesions are available nowadays, being dermoscopy and reflectance confocal microscopy (rcm) the most diffused ones. several studies supported the complementary use of dermoscopy and rcm that improves diagnostic accuracy when dealing with melanocytic lesions. objectives: to analyze rcm diagnostic accuracy in the differential diagnosis between melanocytic and non-melanocytic lesions. methods: this is a cohort selected cross-sectional study conducted at the dermatology unit of the university of campania l. vanvitelli, naples, italy, from 2012 to 2020. we searched the image database for all excised lesions for which the clinical and dermatoscopic differential diagnosis was between melanocytic and non-melanocytic and for which an rcm examination was performed. sensitivity, specificity, and diagnostic accuracy values were estimated. results: the study included 53 cases that were found to have disagreement between clinical, histological and rcm diagnosis, of which, in 31 cases the differential diagnosis was melanocytic vs non-melanocytic lesion. the rcm reached a specificity of 87% (95% ci: 0.73-1) and a sensitivity of 62.5% (95% ci: 0.29-0.96) in the present sample. diagnostic accuracy was 80.6% (95% ci: 0.67-0.94). conclusion: rcm has a high specificity in differentiating between difficult-to-diagnose melanocytic and non-melanocytic lesions. abstract 2 research | dermatol pract concept. 2021; 11(4): e2021127 introduction differentiating between melanocytic and non-melanocytic lesions may be of outmost importance, especially nowadays, when several non-invasive treatment modalities are available for basal cell carcinoma (bcc), solar lentigo (sl) and seborrheic keratosis (sk). basal cell carcinomas can resemble scars, intradermal nevi, lichenoid keratosis, seborrheic keratosis, and benign adnexal neoplasms [1]. squamous cell carcinomas can be difficult to differentiate from hyperplastic actinic keratosis or irritated seborrheic keratosis. although some melanomas are frequently diagnosed by clinic and dermoscopy, the diagnosis of many melanocytic lesions is undetermined without an analytical approach involving patient assessment, history, pattern analysis, comparison with other patient lesions, and assessment of subtle changes over time. rcm opened a new era of optical biopsies, with an evident application in the diagnosis of skin cancer due to the high reflective index of melanin and keratin. the mosaic formed during rcm imaging allows a direct correlation between dermoscopy and cytological patterns in the diagnosis of melanoma and non-melanoma skin cancer (nmsc) [2-4]. recently, studies testing the usefulness of combining rcm with digital dermoscopy monitoring have shown a reduction in the number of lesions excised to diagnose skin cancer, reflecting a 2-fold reduction in unnecessary biopsies [4]. most of the studies available in the literature discuss the accuracy of rcm in making a diagnosis that corresponds to the histology and/or compare the criteria observed in dermoscopy and/or histology with those observed under rcm examination. however, few studies directly compare the differentiation accuracy between melanocytic and non-melanocytic lesions, the majority focusing on facial lesions [5]. evaluating lesions on the face was indicated as one of the “best indications” for rcm in a recent study [6]. in this study we aimed to assess rcm diagnostic accuracy in differentiating between melanocytic and non-melanocytic lesions, when compared to dermoscopy and histological examination, the latter being the gold standard for the definitive diagnosis. objectives to calculate rcm sensitivity and specificity in the differential diagnosis between melanocytic and non-melanocytic lesions. materials and methods the study was based on a descriptive data set of consecutive cases for which rcm imaging was integrated in the diagnosis of patients who visited the dermatology unit of the university of campania luigi vanvitelli, naples, italy, from 2012 to 2020. patients who attended at the dermatology service between the specified years and had complete data in relation to clinical diagnosis, dermoscopy, confocal microscopy, and histology were included. the database of the dermatology unit includes all images of the excised lesions. images, rcm identification numbers, preoperative clinico-dermoscopic diagnosis, rcm diagnosis, and the final histologic diagnosis were recorded. rcm images were obtained using the vivascope 1500 reflectant confocal imaging system (caliberid, ny, usa). a minimum of 3 mosaics of 0.5x3x0.5 mm were performed and reconstructed in larger sizes. composite images were obtained in the granular, spinosum, dermoepidermal junction (dej) and papillary dermis layers. rcm examination usually preceedes the sugical excision of about 2 weeks. the definitive diagnoses accepted were histopathologically determined and, in cases where no biopsy was performed, the case was excluded from this study. data was recorded in an excel™ table (version 14.0.6023.1000, microsoft office professional plus 2010, © 2010 microsoft corporation, santa rosa, ca) and submitted to statistical analysis. sensitivity, specificity, and accuracy values were estimated considering the histological examination result as the gold standard. in this study sensitivity indicated the probability to diagnose a lesion through rcm, as melanocytic, in accordance with the histology result classifying the lesion as melanocytic. specificity indicated the probability to diagnose a lesion as non-melanocytic with rcm, with histology results reporting the lesion as non-melanocytic. accuracy was defined as the rcm success rate in classifying the lesion using the histologic diagnosis result as a gold standard reference. all estimates were calculated on the basis of the studied target population, that is, for cases with a discrepancy between clinical, histological, and rcm diagnosis. therefore, results cannot be extrapolated and considered valid for all cases in general. the confidence intervals presented for the evaluated parameters are 95%. were also calculated the likelihood ratio for positive results and the likelihood ratio for negative results. data was analyzed with stata/se v.14.1. statacorplp, usa, computer program. results search of the database identified 53 cases that presented a discrepancy between the clinical-dermoscopic, histological, and rcm diagnosis. among these 53 cases, 31 presented diagnostic disagreement between rcm and dermoscopy with respect to the classification as melanocytic or non-melanocytic lesions. cases of solar lentigo (sl), lichenoid keratosis (lplk), basal cell carcinoma (bcc), actinic keratosis research | dermatol pract concept. 2021; 11(4): e2021127 3 (ak), seborrheic keratosis (sk), nevi, and melanomas were included. patients had a minimum age of 9 years and a maximum age of 87 years (mean age: 66 years), being 13 women and 18 men. regarding the anatomical region, (13) 41% of the cases were in the head/neck region, (9) 25% on the limbs, (6) 22% on the back and (3) 12% other site. the longest time interval between rcm and surgical excision was of 30 days, an acceptable time interval between an index and a reference test. over these 31 cases, 23 lesions were defined by histology as non-melanocytic and 8 as melanocytic, and in 86.9% rcm was able to predict the non-melanocytic origin of the lesion, previously classified by the dermoscopy assessment as melanocytic. among the 8 melanocytic cases, in 5 of them the rcm could indicate the melanocytic origin of the lesion. sensitivity, specificity, and accuracy are shown in table 1. in the following table (table 2), the results of the study are summarized. discussion rcm revealed a high specificity in defining the melanocytic or non-melanocytic nature of a series of difficult-to-diagnose lesions. on a study sample of 31 lesions (23 non-melanocytic and 8 melanocytic), rcm was able to correctly predict the origin of the lesion in 25 cases (80,6%). in previous studies comparing dermoscopy and rcm, we see variable results. langley et al [7] found no significant difference between the sensitivities (89.2% dermoscopy and 97.3% rcm) or specificities (84.1% dermoscopy, 83% rcm) of the 2 methods. guitera et al [8] found that rcm had a higher specificity (68%) for the diagnosis of melanoma compared to dermoscopy (68% rcm, 32% dermoscopy), although there was no difference in sensitivity (91% rcm, 88% dermoscopy). however, the differences between specificities were statistically significant, favouring the combination of dermoscopy and rcm over isolated dermoscopy. finally, cinotti et al [9] compared dermoscopy table 1. statistical analysis of the rcm when used to differentiate between difficult-to-diagnose melanocytic and non-melanocytic lesions in the examined sample. results ci 95% sensitivity 62,5% 29,0% 96,0% specificity 87,0% 73,2% 100% accuracy lr+ lr80,6% +7,81 -0,26% 66,7% 94,6% (lr+)= likelihood ratio for positive results; (lr-)= likelihood ratio for negative results table 2. results histology rcm dermoscopy 8 melanocytic 6 melanoma 1 spitz nevi 1 nevus 1 melanoma 1 spitz nevi 1 sk 1 sebaceous hyperplasia 1 unm 3 um 2 sl 2 bcc 2 lplk 2 dermatofibroma non melanocytic 3 sl 2 lplk 5 ak 4 bcc 2 dermatofibroma 4 sk 2 vascular lesion 1 pinkus fibroepitelioma 3 sl 2 lplk 2 ak 5 bcc 1 dermatofibroma 1 melanoma 1 nevus 1 pinkus fibroepitelioma 6 unm 1 um 1 melanoma 1 spitz nevi 21 atypical melanocytic lesion sl= solar lentigo ;bcc= basal cell carcinoma; sk=seborrheic keratosis; ak=actinic keratosis; unm= undetermined non-melanocytic; um=undetermined melanocytic; lplk=lichen planus like keratosis. 4 research | dermatol pract concept. 2021; 11(4): e2021127 and rcm for the diagnosis of lentigo maligna. unlike previous studies, rcm showed greater sensitivity (80% vs. 61%) and less specificity (81% vs. 92%) when compared to dermoscopy. thus, the combination of dermoscopy and rcm seems to be the most promising for the diagnosis of melanoma in situ [10]. in our study, 2 cases of lesions clinically identified as solar lentigo and 2 as lplk were later diagnosed as melanoma in histology and in 3 of these cases, the rcm was able to predict the melanocytic origin of the lesion. (figures 1,2) given that conservative treatments are also on the rise, the demand for a reliable approach to non-invasive diagnosis, with a view to a more accurate indication of treatment, is increasing. however, we must consider that the diagnosis of rcm alone, without clinical and dermoscopic information, can lead to overdiagnosis of actinic keratosis and lentigo maligna [11]. in our study, we found 23 cases of lesions diagnosed as melanocytic by dermoscopy, in which rcm was able to predict the diagnosis as being a non melanocytic lesion (solar lentigo and pigmented bccs in most cases) [11, 12]. figure 1. melanoma in situ on the back of a 75-year old woman. (a) a pigmented macule on a background of intense solar damage. (b) dermoscopy showing atypical network and regression. figure 2. rcm imaging of case 1. mosaic at the level of the dermal epidermal junction (1.5x2.5 mm), showing meshwork pattern (square). roundish and dendritic pagetoid cells (arrows). in turn, when discussing the diagnosis of basal cell carcinoma (bcc), a previous study conducted by guitera et al [13] analysed 710 consecutive clinically equivocal cases and confirmed that the diagnosis of bcc is relatively accurate with rcm, almost similar to histopathological evaluation (figures 3-5). in our study, 2 lesions clinically diagnosed as bcc, later proved to be a melanoma and a melanocytic nevus by both rcm and histology, while out of the 23 lesions clinically thought to be melanocytic, 4 were bccs, all correctly diagnosed in rcm. a study by alarcon et al [14] showed that the use of rcm can decrease the number needed to treat (nnt), when calculating the proportion of equivocal lesions excised for every melanoma. the authors included a set of lesions showing dermoscopic patterns suggestive of melanoma. the analysis of the lesions with dermoscopy alone resulted in an nnt of 3.73, the combination of dermoscopy and rcm resulted in a lower nnt of 2.87, and rcm alone reduced nnt even further to 1.12. there was no significant difference between the specificities of dermoscopy and rcm versus rcm alone. another prospective intervention study on a cohort of approximately 1000 patients showed that the number of unnecessary excisions of benign nevi can be reduced by more than 50% using rcm. this reduces the nne from a potential 14.6 without rcm to a real nne of 6.8 with the systematic use of rcm in ambiguous lesions [11,15]. the main limitations of our study regard the low precision of the estimated sensitivity and ppv, due to the limited sample size. however, as the rcm is an emerging tecnique availabe only in referral centers, more cases of doubtful melanocytic or not lesions examined by rcm will be available in future. research | dermatol pract concept. 2021; 11(4): e2021127 5 figure 3. case 2: basal cell carcinoma on the tip of the nose in a 60 year-old man. (a) clinical image: a pigmented macule of 1 cm diameter. (b) in dermoscopy multiple brown concentric structures and peripheral leaf like areas. (c) rcm image showing bright tumor islands. figure 4. case 3: basal cell carcinoma in differential diagnosis with solar lentigo and melanoma. (a) flat facial lesion on the face of a 40 year-old woman with undefined borders (b) dermoscopic analysis revealing brown pseudonetwork and grey globules. figure 5. rcm of case 3. rcm mosaic (2.5 x 1.5 mm) at the level of the upper dermis featuring tumoral islands, typical of bcc. conclusions rcm showed high accuracy in differentiating between melanocytic and non-melanocytic lesions, especially when associated with dermoscopy. although rcm is considered a complementary tool to dermoscopy, it is not clear whether rcm’s diagnostic accuracy depends on the correlation with clinical and dermoscopic information or whether rcm, such as histopathology, functions as an independent procedure. like most of the studies we analysed, we must consider that diagnosing skin cancer is a very complex process and, whenever possible, we should 6 research | dermatol pract concept. 2021; 11(4): e2021127 associate all tools we have at hand, including clinical, dermoscopy, and rcm investigations. references 1. tschandl p, rosendahl c, kittler h. dermatoscopy of flat pigmented facial lesions. j eur acad dermatol venereol. 2015; 29: 120–127. doi: 10.1111/jdv.12483. 2. pellacani g, longo c, malvehy j, et al. in vivo confocal microscopic and histopathologic correlations of dermoscopic features in 202 melanocytic lesions. arch dermatol. 2008;144:1597-1608. doi: 10.1001/archderm.144.12.1597. 3. scope a, benvenuto-andrade c, agero al, et al. correlation of dermoscopic structures of melanocytic lesions to reflectance confocal microscopy. arch dermatol. 2007;143: 176-185. doi. 10.1001/archderm.143.2.176. 4. braga jc, macedo mp, pinto c, et al. learning reflectance confocal microscopy of melanocytic skin lesions through histopathologic transversal sections. plos one. 2013;8: e81205. doi: 10.1371/ journal.pone.0081205. 5. stevenson d, mickan s, mallet s, et al. systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. dermatol pract concept. 2013;3(04): 19-27. doi: doi.org/10.5826/ dpc.0304a05. 6. langley rgb, walsh n, sutherland ae, et al. the diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of benign and malignant melanocytic lesions: a prospective study. dermatology. 2007;215: 365–72. doi: 10.1159/000109087. 7. borsari s, pampena r, benati e, et al. in vivo dermoscopic and confocal microscopy multistep algorithm to detect in situ melanomas. br j dermatol. 2018; 179: 163–72. doi: 10.1111/ bjd.16364. 8. guitera p, pellacani g, longo c, et al. in vivo reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. j invest dermatol. 2009;120: 131–8. doi: 10.1038/jid.2008.193. 9. cinotti e, labeille b, debarbieux s, et al. dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna. j eur acad dermatol venereol. 2018;32(8): 1284-1921. 10. pellacani g, guitera p, longo c, et al. the impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. j invest dermatol. 2007;127(12):2759–65. doi: 10.1038/sj.jid.5700993. 11. pellacani g, pepe p, casari a, et al. reflectance confocal microscopy as a second-level examination in skin oncology improves diagnostic accuracy and saves unnecessary excisions: a longitudinal prospective study. br j dermatol. 2014;171: 1044-1051. doi: 10.1111/bjd.13148. 12. menge td, hibler bp, cordova ma, et al.concordance of handheld reflectance confocal microscopy (rcm) with histopathology in the diagnosis of lentigo maligna (lm): a prospective study. j am acad dermatol. 2016;74: 1114–1120. doi: 10.1016/j. jaad.2015.12.045. 13. guitera p, menzies sw, longo c, et al. in vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. j invest dermatol.2012;132(10): 2386-2394.doi: 10.1038/jid.2012.172. 14. alarcon i, carrera c, palou j, et al.impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions. br j dermatol. 2014;170: 802–8. doi: 10.1111/ bjd.12678. 15. witkowski am, qudzik j, arginelli f, et al. improving diagnostic sensitivity of combined dermoscopy and reflectance confocal microscopy imaging through double reader concordance evaluation in telemedicine settings: a retrospective study of 1000 equivocal cases. plos one. 2017;12: 0187748. doi: 10.1371/journal. pone.0187748. dermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(2):e2022046 1 dermatology practical & conceptual introduction the deep penetrating nevus (dpn) is a benign, acquired, melanocytic lesion that shows intense pigmentation and infiltration into the reticular dermis or subcutaneous tissue [1,2]. it affects young individuals before the third decade of life, primarily in the head and neck region. dpn usually presents as an asymptomatic, well-defined, symmetric, solitary, blue, brown, or black, papule or nodule. due to its clinical and histopathological similarities, dpn is often confused with malignant melanoma, blue nevus, and spitz nevus. since dermoscopic images of dpn are scarce, its features are not well established. here, we present a case of dpn in a patient with fitzpatrick type v skin that showed the rainbow pattern under polarized immersion dermoscopy. case presentation a 13-year-old male with fitzpatrick type v skin presented with a 1-year history of an enlarging lesion on the scalp. on examination, there was an 8 x 5 x 5 mm, well-defined, black, hyperkeratotic nodule with a central erosion (figure 1a). polarized dermoscopy with ultrasound gel immersion showed a pigmented center surrounded by rainbow patterns and bluish-white structureless areas (figure 1b). an excisional biopsy with a 3-mm margin was performed. on histopathology, a benign-appearing, symmetric tumor composed of epithelioid and spindle-shaped melanocytes extending to the hypodermis was observed (figure 2), compatible with dpn. at the 24-month follow-up there was no recurrence. conclusions there are less than 5 dermoscopic descriptions of dpn, including a globular blue-brown pattern and a polychromatic appearance [1,2]. polarized immersion dermoscopy is a suitable technique to evaluate nodular, melanocytic lesions, especially when hyperkeratosis, fissures, and ridges are present. the rainbow pattern and the clinical appearance of dpn in high fitzpatrick skin types are rare findings among the dermoscopic rainbow pattern in deep penetrating nevus arturo robles-tenorio1, miriam sarahí preciado-aguiar2, ricardo quiñones-venegas2, francisco javier salazar-torres2 1 escuela de medicina y ciencias de la salud, tecnológico de monterrey, i. morones prieto 3000, monterrey, méxico 2 instituto dermatológico de jalisco “dr. josé barba rubio”, federalismo 3102, zapopan, méxico key words: nevus, dermoscopy, dermis, pigmentation, rainbow citation: robles-tenorio a, preciado-aguiar ms, quiñones-venegas r, salazar-torres fj. dermoscopic rainbow pattern in deep penetrating nevus. dermatol pract concept. 2022;12(2):e2022046. doi: https://doi.org/10.5826/dpc.1202a46 accepted: july 27, 2021; published: april, 2022 copyright: ©2022 robles-tenorio et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: arturo robles-tenorio, 1escuela de medicina y ciencias de la salud, tecnológico de monterrey. e-mail: arturo.rt@tec.mx 2 research letter | dermatol pract concept. 2022;12(2):e2022046 figure 2. histopathology of deep penetrating nevus. a symmetric tumor composed of spindle-shaped melanocytes extending to the deep dermis was observed (h&e x 40). available images from the literature. increasing awareness of this condition in skin of color, as well as selecting an adequate dermoscopy technique can help to refine the characterization of dpn in underrepresented populations. references 1. strazzula l, senna mm, yasuda m, belazarian l. the deep penetrating nevus. j am acad dermatol. 2014;71(6):1234-1240. doi: 10.1016/j.jaad.2014.07.026. pmid: 25175710.2 2. cosgarea i, griewank kg, ungureanu l, tamayo a, siepmann t. deep penetrating nevus and borderline-deep penetrating nevus: a literature review. front oncol. 2020;10:837. doi: 10.3389/ fonc.2020.00837. pmid: 32509588. pmcid: pmc7251176.. figure 1. deep penetrating nevus. (a) clinical appearance. (b) polarized immersion dermoscopy revealed a pigmented center, rainbow patterns (red ovals), and bluish-white structureless areas. melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. thanks to dermatology practical & conceptual review | dermatol pract concept. 2021;11(s1): e2021164s 1 treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro dermatologic clinic, university of turin medical school, turin, italy key words: metastatic melanoma treatment, anti-pd1, target therapy, metastatic melanoma survival, response rate citation: quaglino p, fava p, tonella l, rubatto m, ribero s, fierro mt. treatment of advanced metastatic melanoma. dermatol pract concept. 2021;11(s1): e2021164s. doi: https://doi.org/10.5826/dpc.11s1a164s accepted: july 10, 2021; published: july 2021 copyright: ©2021 quaglino et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: this work was partially funded with the teseo project medicina di precisione nelle neoplasie mediante omica e big data, progetto strategico di eccellenza dipartimentale, department of medical sciences, university of turin. competing interests: the authors have no conflicts of interest to disclose. authorship: p.q. and p.f. have contributed equally to the article. s.r and m.t.f have equal seniorship. corresponding author: pietro quaglino md, dermatologic clinic, via cherasco 23, 10126, torino. email: pietro.quaglino@unito.it the introduction in clinical practice of new drug compounds both targeted therapies anti-braf and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. this has led to a significant improvement in terms of response rates and particularly in the overall survival (os). the long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median os rates around 24 months, with 5-year survival rates around 35-40%. as to the drugs currently available and reimbursed by the italian national health system, 3 combinations of anti-braf/anti-mek inhibitors are available (dabrafenib/trametinib, vemurafenib/ cobimetinib and the most recently introduced encorafenib/binimetinib). as for checkpoint inhibitors, first line immunotherapy is represented by anti-pd1 blockers ( nivolumab and pembrolizumab), whilst the anti-ctla-4 ipilimumab can be used as second line immunotherapy. abstract this article is part of the dpc journal special issue melanoma today guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. 2 review | dermatol pract concept. 2021;11(s1): e2021164s introduction the presence of distant metastases with soft tissues or internal organs’ involvement is classified as stage iv metastatic melanoma. according to the 8th edition american joint committee on cancer (ajcc) 2018, m1 is defined by both the anatomic site of distant metastatic disease (“a” for soft tissue, “b” for lung, “c” for other sites, and the new “d” designation added to include distant metastasis to the central nervous system), and serum lactate dehydrogenase (ldh) values (designated as “0” for not elevated and “1” for elevated [1]. only a minority of melanoma patients develop distant metastases during the course of their disease, thanks to early diagnosis. even if the prognosis for stage iv patients is still severe, the introduction of the new drug compounds, both targeted therapies anti-braf and checkpoint inhibitors, have largely improved our potential to manage these patients inducing a significant improvement in terms of response rates (rr) and particularly overall survival (os). the unsatisfactory results obtained by (bio)-chemotherapy were clearly summarized in a review study by korn et al [2], which analyzed clinical data obtained from more than 2,000 patients enrolled since 1975 in 42 phase ii trials. an overall 1-year survival rate of 25.5% and a median os of 6.2 months were achieved, with no significant improvement during the last 30 years. the long-term results of the trials with follow-up data of patients treated with targeted or immunotherapies reported median os rates around 24 months, with 5-year survival rates around 35-40% [3]. currently, the main criterion adopted to decide the best therapeutic option for an advanced patient is the presence or absence of the braf gene mutation. the braf mutation is harbored by approximately 50% of melanomas. more frequently, those arising without chronic sun-induced damage, induce the hyperactivation of the map-kinase molecular cascade, leading to an uncontrolled proliferation of cancer cells [4]. in the presence of braf mutation, both anti-braf targeted therapies and checkpoint inhibitors can be used, whilst in the presence of a braf wild pattern, only immunotherapy can be prescribed [5]. as to the drugs currently available and reimbursed by the italian national health system, 3 combinations of anti-braf/anti-mek inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). as to checkpoint inhibitors, first line immunotherapy is represented by anti-pd1 blockers (nivolumab and pembrolizumab), whilst the anti-ctla-4 ipilimumab can be used as second line. the decision-making factors defining the best treatment option in a stage iv metastatic melanoma patient are represented by: mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. this review will analyze the therapeutic tools available for the treatment of patients with metastatic melanoma and will focus on an update of results obtained by the new treatments (check point inhibitors and targeted therapies) which can be used in the clinical daily practice. anti-braf and anti-mek inhibitors the pharmacological inhibition of the mitogen-activated protein kinases (mapk) pathway by targeting the mutant v-raf murine sarcoma viral oncogene homolog b1 (braf) is a milestone in the management of metastatic melanoma. 2 randomized phase iii studies highlighted the efficacy of the dabrafenib-trametinib combination as first-line treatment in metastatic melanoma: combi-d (n=423, comparing the combination of dabrafenib/trametinib versus dabrafenib) and combi-v (n=704, which compared the combination versus vemurafenib). the primary endpoint was progression-free survival for the combi-d trial and overall survival for combi-v. in the combi-d study, the rr was 69% for the dabrafenib-trametinib combination and 53% for dabrafenib alone (p=0.0014). the median pfs was 11 months for the dabrafenib-trametinib combination and 8.8 months for dabrafenib monotherapy (p=0.0004); the median os was 25.1 months and 18.7 months, respectively (p=0.01) [6]. furthermore, the dabrafenib-trametinib combination had a better safety profile and improved health-related quality of life as well as reducing pain [6, 7]. as for the combi-v, the objective rr was 64% in the dabrafenib-trametinib combination arm and 51% in the vemurafenib arm (p<0.001) [8]. the dabrafenib-trametinib combination significantly improved os compared to vemurafenib monotherapy (26.1 compared the decision-making factors that define the best treatment approach in stage iv patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. this review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. it will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice. review | dermatol pract concept. 2021;11(s1): e2021164s 3 to 17.8 months). median pfs in dabrafenib–trametinib arm was 12.1 months and 7.3 months in the vemurafenib arm [8]. in agreement with combi-d, the side effects’ analysis and quality of life in the combi-v trial favored the combination over the monotherapy [8,9]. the results of the pooled analysis of the 2 trials were evaluated after a 22 month-follow-up period, on 563 patients in total, with 5-year pfs of 19% and 5-year os of 34%. complete responses occurred in 19% of patients and were associated with an improved long-term outcome, with an os rate of 71% at 5 years. in multivariate analysis, several baseline factors (eg performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase levels) were significantly associated with both progression-free survival (pfs) and os [10]. in particular, in a 3-year landmark pooled analysis, baseline ldh level and number of organ sites were confirmed to be significantly associated with pfs and os. in addition, baseline sum of lesion diameters (sld) was identified as a predictor for progression. in the most favorable prognostic group (normal ldh, sld <66 mm, <3 organ sites), 3-year pfs was 42% [11]. despite significant improvements with the combination therapy, braf/mek inhibition is still frequently complicated by acquired resistance, most often via upregulation of mapk signaling. in the clinical management, one possible therapeutic strategy is represented by the treatment beyond progression. this is defined as the continuation of targeted therapy in responding patients who showed an isolated disease progression that can be treated by a loco-regional approach. retrospective data suggest that treatment with braf inhibitors beyond progression is associated with improved survival, even if prospective data are still needed [12,13]. besides clinical trials, compassionate-use programs provided a relevant opportunity to retrospectively evaluate the treatment patterns and clinical outcomes in a real-world setting and to validate the results derived from controlled randomized clinical trials. in particular, describe iii was a large international multicenter study, which enrolled 509 patients. patients were categorized into 3 groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and <12 months), and short-term (on therapy <6 months) duration of benefit. in agreement with the results of the pooled analysis of combi-d and combi-v, normal ldh level and <3 metastatic sites at baseline, were associated with a longer duration of treatment benefit in a real-world setting [14]. also, the combination of vemurafenib and cobimetinib had a better outcome than vemurafenib alone in a phase 3 randomized clinical trial performed on 495 patients with previously untreated, unresectable, locally advanced, or metastatic braf v600 mutation-positive melanoma (cobrim). the combination showed a significantly higher clinical activity in terms of rr (68% vs 45%), pfs (median: 9.9 vs 6.2 months), and survival (9 months os 81% vs 73%) [15]. at a median 14.2-month follow-up, the median pfs was 12.3 months for the combination versus 7.2 months for placebo and vemurafenib (p<0.0001). median os was 22.3 months for cobimetinib and vemurafenib versus 17.4 months (for placebo and vemurafenib; p=0.005). the safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-ups [16]. the clinical activity of a third combination schedule of anti-braf/anti-mek was investigated in the clinical trial columbus. columbus was a 2-part, randomised, open-label, phase iii study. during part 1, patients were randomly assigned (1:1:1) to receive oral encorafenib 450 mg once daily, plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). part 2 of the study compared encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. at 3-year analysis, median os was 33.6 months with encorafenib plus binimetinib and 16.9 months with vemurafenib [17, 18]. median pfs was 14.9 months in the encorafenib plus binimetinib group and 7.3 months in the vemurafenib group. a confirmed overall response by blinded independent central review occurred in 63% of patients in the encorafenib plus binimetinib group compared with 51% in the encorafenib group, and 40% in the vemurafenib group. the median time to response was 1.8 months for the encorafenib plus binimetinib group. the most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%). anti-ctla4 ipilimumab is a fully humanized monoclonal antibody that binds to ctla-4, a receptor expressed on the t-cell surface that interacts with cd80 (b7-1) and cd86 (b7-2) on the antigen-presenting-cells (apcs) and downregulates t-cell response. ctla-4 blockade allows cd28 to bind to b7-1 receptors, leading to immune activation, il-2 secretion, cytotoxic t-cells expansion, and proliferation [19]. the interaction between ctla-4 and b7-1/2 takes place in an early phase of the immune response, involving “naive” t lymphocytes and the apcs. this mechanism of action explains the characteristics of the clinical activity as well as the common side effects of this drug, consisting of immune-mediated reactions (iraes) developing more frequently in the skin, gastro-intestinal tract (mainly diarrhea), liver and endocrinal glands). the trial that led to registration of ipilimumab in melanoma was a phase iii 4 review | dermatol pract concept. 2021;11(s1): e2021164s trial in which ipilimumab ± glycoprotein 100 peptide (gp100) vaccine was compared with gp100 vaccine monotherapy in patients with unresectable stage iii or stage iv melanoma. ipilimumab monotherapy significantly improved median os compared with gp100 vaccine monotherapy (10.1 months vs. 6.4 months) [20]. in another important randomized phase iii trial, the combination of ipilimumab (10 mg/kg) and dacarbazine (850 mg/sqm) resulted in significantly superior os compared to dacarbazine (850 mg/sqm) plus placebo (11.2 months vs. 9.1 months) [21]. ipilimumab produced a plateau in the survival curves: a recent pooled analysis of os data for 1.861 patients enrolled in 10 prospective and 2 retrospective trials, with up to 10-year follow-up, showed that the survival curve began to plateau around 3 years after treatment. 3-year os rates were 22%, 26%, and 20% for all, treatment-naive, and previously treated patients, respectively [22]. moreover, the results of the ipilimumab expanded access programme (eap) in italy resulted consistent with these data, confirming the activity of the drug also in specific patient’s subsets such as the elderly, the mucosal or uveal primaries, and in the presence of brain metastases [23]. anti-pd1 pd-1 represents a co-inhibitory receptor involved in the negative regulation of t-cell activation [24]. the expression of pd-1 ligand (pd-l1) on tumor cells induces the development of an immunosuppressing environment through the ligand with the pd-1 expressed on t lymphocytes, thus leading to t-cell inhibition and cancer immune system escape. two anti-pd-1 monoclonal antibodies are available in the clinical practice and can be used for the treatment of metastatic melanoma patients, ie nivolumab and pembrolizumab. the checkmate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated braf wild-type advanced melanoma. in this multicenter, double-blind, phase iii study, 418 patients with previously untreated, unresectable, stage iii/iv, wild-type braf melanoma were randomly assigned 1:1 to receive nivolumab or dacarbazine, with os as primary endpoint. the results demonstrated superior overall rr (40% vs. 13.9%, respectively) and increased 1-year os (72.9% vs. 42.1%, respectively). moreover, nivolumab treatment-related adverse events occurred in 11.7% of the patients receiving nivolumab and 17.6% of the patients receiving dacarbazine, respectively [25]. at 5-year analysis [26], orr was 42% with nivolumab and 14% with dacarbazine. fiveyear os rates were 39% with nivolumab and 17% with dacarbazine; pfs rates were 28% and 3%, respectively. among patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. in checkmate 037 phase iii trial, patients were randomly assigned 2:1 to receive nivolumab 3 mg/kg every 2 weeks or investigators’ choice chemotherapy (icc) in ipilimumab-refractory patients with advanced melanoma [27]. primary endpoints were the proportion of patients who had an objective response and os. at first interim analysis on 120 and 47 randomized patients, confirmed objective responses were reported in 31.7% of patients in the nivolumab group vs. 10.6% of patients in the icc group; no treatment-related deaths occurred. in the final 2018 report [28], the overall rr (27% v 10%) and median duration of response (32 versus 13 months) were significantly higher for nivolumab versus icc. fewer grade 3 and 4 treatment-related adverse events were observed in patients on nivolumab (14% v 34%). median os was 16 months for nivolumab versus 14 months for icc; this data should however be interpreted with caution as patients enrolled in the icc group could thereafter be treated by anti-pd1 or anti-braf targeted therapies. as to pembrolizumab, keynote-006 was an open-label, multicenter, randomized, controlled, phase 3 study in which 834 patients with advanced melanoma were randomized to receive pembrolizumab at a dose of 10 mg/kg every 2 or every 3 weeks, or with 4 doses of ipilimumab (3 mg/kg every 3 weeks). the estimated 6-months pfs rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab, respectively. estimated 1-year os rates were 74.1%, 68.4%, and 58.2%, respectively. the rr was improved when pembrolizumab was administered either every 2 or 3 weeks, as compared with ipilimumab. treatment-related adverse events of grade 3–5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) [29]. at the final 5-year follow-up data, median overall survival was 32.7 months in the combined pembrolizumab groups and 15.9 months in the ipilimumab group (p=0·00049). median pfs was 8.4 months and 3.4 months, respectively [30]. a relevant analysis from this study was done in patients who stopped pembrolizumab after 24 months as per protocol. after a median follow-up of 34·2 months from completion of pembrolizumab, the estimated 24-month pfs from treatment interruption for all 103 patients was 78.4% and 36-month os was 93.8%. estimated 24-month pfs was 85.4% for patients with complete response, 82.3% for patients with partial response, and only 39.9% for patients with stable disease. these data pave the way for the possibility of interruption of anti-pd1 treatment in responding patients after 2 years of therapy. keynote-002 study was a randomized phase ii multicenter trial in which advanced melanoma patients with progression after ipilimumab and/or braf/mek inhibitors were randomized to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. crossreview | dermatol pract concept. 2021;11(s1): e2021164s 5 over to pembrolizumab was allowed following progression on chemotherapy. a total of 180 patients were randomized to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. 6-month pfs was 34% in the pembrolizumab 2 mg/kg group, 38% in the 10 mg/kg group, and 16% in the chemotherapy group [31]. at the final post-hoc 5-year analysis, the orr was 22% and 28% in patients receiving pembrolizumab, versus 4% in patients receiving chemotherapy (p<0.0001 for both pembrolizumab doses versus chemotherapy) [32]. anti-ctla-4/anti-pd-1 combo regimens preclinical models have shown that double inhibition of ctla-4 and pd-1, when compared with single-molecule inhibition alone, synergistically increases anticancer responses 173. in the double-blind phase ii checkmate 069 study, patients were randomized to treatment with ipilimumab + nivolumab or with ipilimumab + placebo. at a median follow-up time of 24.5 months, the two-year survival was 63.8% for patients treated with nivolumab and ipilimumab in combination and 53.6% for patients treated with ipilimumab alone. in patients with wild type braf melanoma, the rr was 61% in the group of patients who received combination therapy compared to 11% of patients who received ipilimumab + placebo (p <0.001), with complete responses. reported in 22% of patients in the first group and none in patients treated with ipilimumab alone [33]. the phase iii checkmate 067 [34,35] study assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for 4 doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. the 2 primary end points were pfs and os in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. 945 patients with advanced melanoma not treated with previous therapies were recruited. combination therapy showed significantly higher pfs (11.5 months, 95% ci 8.9-16.7) than nivolumab monotherapy (6.9 months, 95% ci 4.3-9.5), or ipilimumab (2.9 months, 95% ci 2.8-3.4). the risk of death or tumor progression was reduced by 58% compared with ipilimumab monotherapy (hr 0.42; 99.5% ci 0.31-0.57). the orr was 57.6% (95% ci, 52.0-63.2) in the combination cohort versus 43.7% in nivolumab (95% ci, 38.1-49.3) and 19% (95% ci, 14.9-23.8) in the ipilimumab monotherapy group. patients treated with the combination therapy showed a complete response in 11.5% (compared with 8.9% with nivolumab and 2.2% with ipilimumab monotherapy). most interestingly, when patients were stratified for pd-l1 negativity or immunohistochemical staining positivity (less or more than 5% of pd-l1 stained tumor cells in a section of at least 100 tumor cells), the median pfs was 14.0 months for patients with pd-l1 positive tumors in both the nivolumab-plus-ipilimumab group, and the nivolumab group. in contrast, in patients with pd-l1-negative tumors, pfs was longer with combination therapy than with nivolumab alone (11.2 months [95% ci, 8.0 a not achieved] vs. 5.3 months [95% ci, 2.8 to 7.1]). in this study, nivolumab combination therapy was superior to nivolumab monotherapy or ipilimumab alone in patients with pd-l1 negative tumors, whereas in patients with pd-l1 positive tumors there was no significant difference between nivolumab monotherapy and combined therapy. overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. no sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone [36]. grade 3 or 4 treatment-related adverse events occurred in 59%, 23%, and 28% of the patients in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively. this combination therapy was approved in europe by the ema on may 2016, regardless of patients’ pd-l1 status. ckit inhibitors mutations and amplification of the kit oncogene are more frequent in melanomas arising in the skin with chronic sun damage, acral sites, or mucosal melanomas. a number of evidences from laboratory analysis and preclinical studies showed that hot-spot mutations, most frequently constituted by substitutions at exons 11 and 13, induce a pathological activation of the kit, thus an upregulation of the downstream signal transduction pathways, which are not only the mapkinase, but also the pi3k/akt, and jak/stat pathways. kit gene expression has been correlated with activating mutations, which indicates the role of kit in tumorigenesis in melanoma. therefore, kit has been suggested to be a potential therapeutic target for malignant melanoma. several trials have been conducted using kit-targeted tyrosine kinase inhibitors in melanoma in both selected and unselected patient populations. trials with imatinib showed responses if kit was mutated but not if it was wild-type and amplified [37-39]. other kit inhibitors such as dasatinib, sunitinib, and nilotininb have also exhibited responses in kit-mutant melanomas. however, taken together, these studies showed a percentage of responses around 20% and 30%, mostly of short duration without a significant impact on survival. moreover, all these studies were performed on a relatively small number of patients and there is no available 6 review | dermatol pract concept. 2021;11(s1): e2021164s randomized trial. in a recent retrospective analysis of 78 patients with metastatic melanoma harboring c-kit mutations or amplifications treated with imatinib, orr and dcr were 21.8% and 60.3%, respectively. the median os and pfs of all patients were 13.1 [40]. the limited clinical activity of targeting ckit imply that ckit mutant patients should be treated as first line with immune check point inhibitors and only after the failure of these regimens, consider the potential of ckit inhibitors. nras mutant patients nras mutations (codons 12, 13, and 61) can be detected in 15-20 % of all melanomas. these alterations have been associated with aggressive clinical behavior and a poor prognosis; however, a recent retrospective multicenter italian study did not confirm the unfavorable prognostic significance of nras mutation. a cohort of 331 patients treated with immunotherapy as first-line were retrospectively recruited: 162 nras-mutant/braf wild-type (mut/wt) and 169 wt/ wt. regarding the outcomes, no significant differences were reported in overall rr, pfs or os. irrespectively of the mutational status, a longer os was significantly associated with normal ldh, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (n/l) ratio [41]. some studies have been reported analyzing the clinical activity of anti-mek inhibitors in these patients. based on these data, a randomized phase iii trial was designed, comparing binimetinib with dacarbazine. the study enrolled 269 patients in the binimetinib arm and 133 in the dacarbazine arm. binimetinib significantly prolonged pfs and improved rr with respect to the control arm even if the clinical benefit is slow, with median pfs of 2.8 months compared to 1.5. furthermore, no differences in os were achieved. an interesting point was that the benefit in terms of pfs appear to be higher in patients with a prior immunotherapy (median 5.5 months) even if this is a retrospective analysis and thus caution should be taken [42]. patients with brain metastases the presence of brain metastases is now classified as stage iv m1d and it is associated with a poor prognosis (median survival 4 months) [43, 44] patients with active brain metastases are in fact in most cases excluded from phase iii clinical trials, particularly those involving immunotherapies [45,46] as to targeted therapies, the combi-mb was a multicenter, multicohort, open-label, phase 2 study evaluating the combination of dabrafenib/trametinib in 4 patient cohorts with melanoma brain metastases (based on the presence of symptoms, ecog, and previous radiotherapy). percentages of intracranial responses ranged from 44% to 59% with pfs lower than that found in patients with no brain metastases (19% pfs at 12 months). dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with brafv600-mutant melanoma without brain metastases, but the median duration of response was relatively short [47]. in phase ii studies that involved the use of nivolumab or pembrolizumab alone in patients with brain metastases, the percentage of responses varied from 16% to 25%, that is clearly lower than the standard immunotherapy rr of around 40% -50%. the duration of the responses was also significantly shorter [45]. the results of 3 studies carried out in patients with active brain metastases have instead highlighted the clinical activity of the combination of anti-pd1 nivolumab with ipilimumab in these patients with rr ranging from 46% to 55%. in particular, the abc study is a phase 2 study that randomized patients with asymptomatic brain metastases to receive the combination nivolumab + ipilimumab, versus nivolumab alone. a third arm involved the inclusion of patients with symptomatic brain metastases to receive exclusively nivolumab. intracranial rr were 51% in patients treated with the combination, 20% in asymptomatic patients treated with nivolumab, and 6% in symptomatic patients treated with nivolumab. the rate of intracranial responses increased to 59% with the combination in naive, non-pretreated patients, compared to 21% with monotherapy. pfs was also significantly different, 43% at 3 years with the combination versus 15% and 6% with monotherapy, respectively. the safety profile did not report significant differences with respect to that highlighted in previous studies of immune combo with a percentage of adverse events grade ¾ higher than monotherapy but still manageable from a clinical point of view in a patient setting with such a severe prognosis as those included in the study [48]. a second study reporting the results of the ipi nivo combination in patients with brain metastases is the phase ii checkmate 204 study, which enrolled 75 patients, with 55% intracranial and 53% global rr, 2.8 months’ time to response and median duration of responses not yet achieved [49]. the third nibit-m2 study is a randomized phase 3 study that included patients with brain metastases randomizing them into three arms (fotemustine, fotemnustine + ipilimumab, and nivolumab + ipilimumab). the arm treated with the immune combo obtained 44% intracranial response with pfs 36% at 4 years and 41% os at 4 years [50]. new scenarios: combining targeted and immunotherapies a novel approach which is emerging for braf-mutant patients is represented by the combination of targeted therapies and immune-checkpoint inhibitors [51], commonly review | dermatol pract concept. 2021;11(s1): e2021164s 7 referred as “triplets”. the rationale for this association is 2-fold. from the clinical point of view, it could couple the principal benefits of the 2 regimens, thus the high response rate of the targeted therapies and the remission duration of immunotherapies in an attempt to overcome the development of acquired resistance. from the biological point of view, antibraf targeted therapies have been recognized to positively modulate the immune regulation, by promoting t-cell infiltration with reduction of regulatory t-cells, inducing melanoma antigen-expression, and restoring the impaired mhc-i surface expression, thus reducing the immunosuppression and immune escape associated with the braf mutated oncogenic pathway [52]. the keynote-022 trial [53], the first phase ii trial investigating a triplet in melanoma, randomized 120 patients to receive dabrafenib/trametinib plus pembrolizumab or placebo, with pfs as primary endpoint. the study did not show a statistically significant difference in pfs, even if a non-statistically longer pfs was found in patients treated with the triplet (16.9 vs 10.7 months at 36 months follow-up); moreover, median duration of response was 25.1 months in the triplet cohort and 12.1 months in the control group. patients treated with the triplet experienced however higher toxicity rates, with 58.3% developing grade 3-5 treatment-related adverse event versus 26.7%. the imspire150 trial was a randomized phase 3 study comparing the triplet atezolizumab, vemurafenib, and cobimetinib versus vemurafenib, cobimetinib and placebo, with the primary endpoint of pfs. a total of 514 patients were enrolled. at a median 18.9 month follow-up, investigator– assessed pfs was significantly longer in the triplet group versus control (15.1 vs 10.6 months; p=0.025). the triplet figure 1. clinical activity of the 3 main combinations of targeted therapy. orr= overall response rate; pfs= progression-free-survival; os= overall survival endpoint orr, % median pfs, months median os, months (hr; 95% cl) 69 11 25.1 69.6 12.3 22.3 65.8 12.6 25.6 64-76 14,9 33.6 combi-d dbarafenib+ trametinib vs. dabrafenib cobrim4 cobimetinib + vemurafenib vs. vemurafenib combi-v5 dabrafenib + trametinib‡ vs. vemurafenib colombus encorafenib + binimetinib vs encorafenib vs vemurafenib figure 2. (a, b) development of response in a representative patient with braf mutant metastatic melanoma with lung and skin metastases: response achieved as clinically evident at the 7th week from the beginning of treatment. (c-f) ct scan performed 3 months after the beginning showing the complete clearance of lung metastases 8 review | dermatol pract concept. 2021;11(s1): e2021164s was approved by fda; however, even if the study met its primary endpoint, the values of the median pfs reached is similar to that of the keynote-022. the frequency of grade 3-4 adverse events was similar (79% versus 73%); no major adverse events were found in the triplet group and the percentage of patients who stopped all treatment due to adverse events was similar (13% in the triplet versus 16%) [54]. more recently, the results of the part 3 of the combi-i trial were presented [55]. this phase iii randomized clinical trial enrolled 532 patients to compare the combination of dabrafenib and trametinib plus spartalizumab or placebo. the pfs was longer in the triplet group even if the difference did not meet a statistical significance (16.2 versus 12 months). the objective response rate was 69% versus 64%. the percentage of patients showing grade 3 or more treatment related side effects was 55% in the triplet group versus 33% in the control arm. the results of the large randomized trials comparing the triplets versus the standard targeted regimens did not completely confirm thus until now the promising preliminary data, also showing a less favorable toxicity profile for this associations. however, all the studies identified a longer pfs of the triplet versus the control arm (with a statistical significance only in the imspire trial but with similar values across the different studies), thus it is justified to wait for a longer follow-up time to better characterize the role of the combination of targeted and immunotherapies, and to identify which could be the patients that could benefit more from this treatment. figure 3. clinical activity of immune check point inhibitors. rr= response rate; cr= complete response inclusion drug % rr 40%nivolumab nivolumab pembrolizumab pembrolizumab nivolumab+ ipilimumab untreated untreated ipi refractory ipi progressed untreatedcheckmate 066 checkmate 037 keynote 002 keynote 006 checkmate 067 31,3% % cr 7,6% 3,3% 2-3% 12-13% 21,3%58,3% 36-37% 29-31% figure 4. (a) pattern of response following immune therapy in a patient with multiple in-transit skin metastasis localised in the lower limb. (b-d) response developed during 1 year of treatment with induction of inflammation. (e) immune activation around the skin metastases, towards complete clearance confirmed at histology with development of peri-lesional vitiligo. review | dermatol pract concept. 2021;11(s1): e2021164s 9 conclusions the comparison between os rates before the development of new drugs (1-year survival 25%, median survival 6 months) [2] and those achieved with both targeted therapies and immune check point inhibitors (5-year survival 35%, median survival 24 months) clearly highlights the relevant impact that these new treatment approaches are having in the disease course of advanced metastatic melanoma and this is well recognized by the main italian national, european and american guidelines [5,56,57]. however, when considering the curves from the other side, it is evident that at 5 years, 65% of patients die due to disease progression, supporting the need of more active treatment strategies or combinations. the results from the trials analyzing the clinical activity of the so-called triplets (combo-target plus anti-pd1) gave conflicting results and it is reasonable to think that more follow-up is needed. in the daily clinical practice, the challenges are represented by the management of patients with aggressive disease and/or multiple visceral sites, as well as those with brain metastases or mucosal/coroidal primaries. the availability of adjuvant treatments is improving the disease course in stage iii patients disease-free after surgery but the management of the progressions occurring during adjuvant treatment, particularly in braf wild-type patients, still represents another clinical challenge. the availability of data coming from real life experiences together with the results of ongoing clinical trials will provide relevant informations to improve the management of these patients, as well as the identification of both prognostic and predictive factors associated with the disease course and response to treatment. references 1. gershenwald je, scolyer ra, hess 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doi:10.1016/j. annonc.2020.08.2273. 56. aiom (associazione italiana di oncologia medica) melanoma guidelines. www.aiom.it 57. seth r, messersmith h, kaur v, et al. systemic therapy for melanoma: asco guideline. j clin oncol. 2020; 38(33):3947-3970. doi: 10.1200/jco.20.00198. pmid: 32228358. 1-indice 6-1881 dermatology: practical and conceptual commentary | dermatol pract concept 2021;11(2):e2021069 1 dermatology practical & conceptual dermoscopy in the covid-19 era: magnifying the gap for clinicians khawar hussain1, ashfaq a. marghoob2, neil p. patel1 1 department of dermatology, charing cross hospital, imperial college healthcare nhs trust, london, uk 2 department of dermatology, memorial sloan kettering cancer center, new york, usa key words: dermoscopy, covid-19, medical education, skin cancer, teledermatology citation: hussain k, marghoob aa, patel np. dermoscopy in the covid-19 era: magnifying the gap for clinicians. dermatol pract concept. 2021;11(2):e2021069. doi: https://doi.org/10.5826/dpc.1102a69 accepted: february 1, 2021; published: march 8, 2021 copyright: ©2021 hussain et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: dr. khawar hussain, charing cross hospital, imperial college healthcare nhs trust, fulham palace road london w6 8rf, uk. email: khawar.hussain1@nhs.net dermoscopy is an invaluable tool that has improved the diagnostic ability of clinicians to differentiate between benign and malignant skin lesions by up to 25% [1]. it is practiced using a handheld device and interpretation is operator-dependent, such that expertise in this technique requires many hours of training. its greatest use is in the diagnosis of pigmented lesions, but dermoscopy also has an important role in the diagnosis of nonmelanoma skin cancers, benign lesions, inflammatory disorders, and even parasitic infections. the advent of teledermatology, hastened by the ongoing covid-19 pandemic, has changed the dynamic of the doctor-patient consultation and has led to extensive replacement of face-to-face consultations with virtual consultations. for teledermatological assessment of patients with suspected skin cancer, the historic practice of performing a face-to-face full skin examination has been supplanted by macroscopic and dermoscopic photographs of a specific skin lesion. traditionally, clinicians have been able to intuitively gather important diagnostic clues from a dynamic dermoscopic examination of skin lesions and have taken this method of examination for granted. as teledermatology generates static dermoscopic images and omits these dynamic dermoscopic clues, we are only now beginning to realize what has been lost. such clues and techniques include the wobble sign for intradermal nevi [2], ink test for seborrheic keratosis [3] and porokeratosis [4], furrow ink test for pigmented acral lesions [5], oblique view dermoscopy for fibrillar-pattern pigmented lesions on the sole [6], and tape stripping of hypermelanotic nevi [7]. these dynamic dermoscopic tricks augment the established dynamic clinical tests practiced for various skin lesions during face-to-face consultations, including the pinch test for dermatofibroma, the scratch test for subcorneal hematoma [8], and lifting of crusts to examine hyperkeratotic lesions. as the field of teledermoscopy evolves, it is important that dermatologists maximize the full potential of this technique, which would include embedding dynamic dermoscopic clues into standard teledermoscopy practice. in the virtual era, this could be achieved by training medical photographers to elicit these clues; for example, the furrow ink test and accompanying 2 commentary | dermatol pract concept 2021;11(2):e2021069 dermoscopic photographs could be recommended as standard practice when photographing any pigmented lesion on the palm or sole. potential drawbacks include the additional resource required for photographer training and the extra time needed per patient. additionally, where a supplementary dynamic clinical test of a skin lesion is deemed essential by the teledermatologist, such as the scratch test for a subcorneal hematoma, we should not be discouraged from asking patients to return to a conventional face-to-face dermatological consultation in this virtual era, as the stakes of a missed skin cancer diagnosis, as ever, are high. furthermore, despite the continuing shift towards virtual work, it is essential that we continue to provide dermatology trainees with teaching in techniques that can only be performed face-to-face, such as handheld dermoscopy, dynamic assessment of skin lesions, and full skin examinations. neglecting these skills would regrettably lead to a new generation of dermatologists ill-equipped to conduct a thorough face-to-face examination of skin lesions. references 1. wolner zj, yelamos o, liopyris k, et al. enhancing skin cancer diagnosis with dermoscopy. dermatol clin. 2017;35:417-437. doi: 10.1016/j.det.2017.06.003. pmid: 28886798. 2. braun rp, krischer j, saurat jh. the “wobble sign” in epiluminescence microscopy as a novel clue to the differential diagnosis of pigmented skin lesions. arch dermatol. 2000;136(7):940–942. doi: 10.1001/archderm.136.7.940-a. pmid: 10891009. 3. yagerman s, marghoob aa. the ink test: identifying 3-dimensional features of seborrheic keratoses under dermoscopy. jama dermatol. 2013;149(4):497-498. doi: 10.1001/jamadermatol.2013.2233. pmid: 23715284. 4. navarrete-dechent c, uribe p, marghoob a. ink-enhanced dermoscopy is a useful tool to differentiate acquired solitary plaque porokeratosis from other scaly lesions. j am acad dermatol. 2019;80(6):e137-e138. doi: 10.1016/j.jaad.2017.11.052. pmid: 29221722. 5. braun rp, thomas l, kolm i, french le, marghoob aa. the furrow ink test: a clue for the dermoscopic diagnosis of acral melanoma vs nevus. arch dermatol. 2008;144(12):1618-1620. doi: 10.1001/archderm.144.12.1618. pmid: 19075144. 6. maumi y, kimoto m, kobayashi k, ito n, saida t, tanaka m. oblique view dermoscopy changes regular fibrillar pattern into parallel furrow pattern. dermatology. 2009;218(4):385-386. doi: 10.1159/000202986. pmid: 19218789. 7. babino g, specchio f, lallas a, longo c, moscarella e, argenziano g. tape stripping: a very short-term follow-up procedure for suspicious black lesions. j am acad dermatol. 2015;72(6):e151-e152. doi: 10.1016/j.jaad.2015.02.1098. pmid: 25981018. 8. zalaudek i, argenziano g, soyer hp, saurat jh, braun rp. dermoscopy of subcorneal hematoma. dermatol surg. 2004;30(9):12291232. doi: 10.1111/j.1524-4725.2004.30381.x. pmid: 15355366. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(4): e2021128 1 prevalence and associations of general practice registrars’ management of atopic dermatitis: a cross-sectional analysis from the registrar clinical encounters in training study anneliese willems1,2, amanda tapley3,4, alison fielding3,4, er tsing vivian tng5, elizabeth g holliday3, mieke l van driel6, jean i ball7, andrew r davey3,4, irena patsan3,4, kristen fitzgerald8, 9, neil a spike1,2, parker j magin3,4 1 eastern victoria general practice training, regional training organisation, hawthorn, victoria, australia 2 university of melbourne, department of general practice and primary health care, berkeley street, carlton, victoria, australia 3 university of newcastle, school of medicine and public health, university drive, callaghan, newcastle, nsw, australia 4 gp synergy, regional training organisation, nsw & act research and evaluation unit, 20 mclntosh drive, mayfield west, nsw, australia 5 department of dermatology, john hunter hospital, newcastle, new lambton heights, nsw, australia 6 the university of queensland faculty of medicine, primary care clinical unit, faculty of medicine, level 8 health sciences building, royal brisbane & women’s hospital, brisbane, qld, australia 7 hunter medical research institute, clinical research design, it and statistical support unit (creditss), new lambton, nsw, australia 8 university of tasmania tasmanian school of medicine, hobart, tas, australia 9 general practice training tasmania, regional training organisation, hobart, tas, australia key words: atopic dermatitis, eczema, general practice, dermatologists, family practice citation: willems a, tapley a, fielding a, tng etv, holliday eg, van driel ml, ball ji, davey ar, patsan i, fitzgerald k, spike na, magin pj. prevalence and associations of general practice registrars’ management of atopic dermatitis: a cross-sectional analysis from the registrar clinical encounters in training study. dermatol pract concept. 2021;11(4): e2021128. doi: https://doi.org/10.5826/dpc.1104a128 accepted: march 12, 2021; published: september 2021 copyright: ©2021 willems et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: the recent project was funded from 2010 to 2015 by the participating educational organisations: general practice training valley to coast, the victorian metropolitan alliance, general practice training tasmania, adelaide to outback gp training program, and tropical medical training, all of which were funded by the australian department of health. from 2016-2019, recent was funded by an australian department of health commissioned research grant and supported by gp synergy regional training organisation. from 2019 recent is funded by gp synergy. gp synergy is funded by the australian department of health. competing interests: the authors report no conflict of interest. ethics approval: this project has ethics approval through university of newcastle’s human research ethics committee: h-2009-0323. authorship: all authors have contributed significantly to this publication. corresponding author: parker j magin, mbbs(hons), phd, mfm (clin), mgpp, gdipclinepi, dpd, fracgp, university of newcastle, school of medicine and public health, university drive, callaghan, newcastle, australia; gp synergy, regional training organisation, nsw & act research and evaluation unit, 20 mclntosh drive, mayfield west, nsw, australia. email: parker.magin@newcastle.edu.au 2 research | dermatol pract concept. 2021;11(4): e2021128 introduction atopic dermatitis (ad) is a chronic inflammatory skin condition[1] caused by the interaction of numerous environmental, genetic, and immune factors.[2] ad presents largely in childhood [3], with an estimated 12-month prevalence of 16-17% in childhood [4]. ad persists in teenagers and adults in approximately 50% of pediatric patients [5]. it is characterized by chronic inflammation and pruritis [6], and sufferers encounter a relapsing and remitting disease course [7]. carrying the heaviest global burden of skin disease [8], ad is associated with significant physical and mental health sequelae, including effects on mood, sleep, and quality of life [7, 9, 10]. childhood ad also profoundly impacts the financial, social, and psychological wellbeing of their families [11, 12]. a clinical diagnosis in most cases [1, 6], ad management depends on disease severity [13]. the majority of ad is mild [14, 15] and may be managed initially by patient education, emollients and, where appropriate, topical corticosteroids (tcs)[6]. for more severe disease, additional therapies including narrowband ultraviolet b phototherapy and oral immunosuppressive therapies may be considered through specialist consultation [16]. as a common primary health presentation [7, 17] general practice (gp) registrars may encounter ad throughout their training. in australia, general practice training operates through an in-practice apprenticeship model [18-20]. competency in the diagnosis and management of dermatological presentations, including ad, comprises an essential component of this training. historically registrars have found dermatological presentations a challenging area [21]. while training seeks to provide a typical diagnostic cross-section of what their more senior counterparts see, variations in patients and problem exposure have been reported [19, 22, 23]. in particular, registrars see younger patients and have less exposure to chronic disease [19, 22, 24-26]. how this might translate to the registrar’s clinical exposure to ad has not been established yet. the aims of this study were to explore the prevalence and associations of gp registrars managing patients with ad. methods general practice training in australia involves a minimum of three 6-month full-time-equivalent community-based general practice training terms. the registrar clinical encounters in training (recent) project records australian gp registrar’s clinical and educational experience over these training terms. data is collected once in each term, totaling 3 cycles of data collection. registrars (vocational trainees in specialist general practice) complete a paper-based case report form for each of 60 consecutive consultations. data recorded within these consultations includes patient demographics, diagnosis/problems, management, and referral choice. problems/diagnoses are coded according to the international classification of primary care (2nd edition) classification system (icpc-2 plus) [27]. in addition, on a 6-monthly basis, registrar and practice variables are also collected via questionnaire. from 2010-2015, recent was conducted in up to 5 regional training providers (rtps; across 5 states), prior to a major restructuring of australian gp vocational training. from 2016, recent has been conducted in three regional introduction: atopic dermatitis (ad) is a chronic inflammatory condition which imposes substantial burden upon patients and their families. as a frequent primary care presentation, general practice (gp) trainees must develop adequate skills in ad diagnosis and management. objectives: we aimed to explore the prevalence and associations of gp registrars’ management of patients with ad. methods: this study used data from the registrar clinical encounters in training (recent) project, an ongoing cohort study of the clinical and educational experience of australian gp registrars. registrar, patient, and consultation factors were independent variables in multivariable logistic regression with outcome factor ‘diagnosis/problem being ad’. results: from 2010-2019, 2,783 registrars (96% response rate) provided data from 381,180 consultations. ad was encountered in 0.6% of consults. ad was more likely to be seen in patients aged 0-1 years and patients from a non-english speaking background. ad was less likely to be seen in aboriginal or torres strait islander patients. learning goals were more likely to be generated for ad and these consultations were associated with registrars seeking information or assistance. ad was strongly associated with a medication being prescribed, of which the most prescribed medications were mild or moderate potency topical corticosteroids. conclusions: our findings suggest that, similar to other dermatological presentations, registrars find ad challenging to manage. there may be some gaps in ad management knowledge and application. abstract research | dermatol pract concept. 2021;11(4): e2021128 3 training organisations (rtos), training 44% of australia’s gp registrars,[28] across 3 states and a territory. for the analyses presented in this report, data from 20102019 was included. outcome measure the outcome variable was a problem/diagnosis of ad. problems/diagnoses coded as ‘dermatitis, atopic’, ‘eczema’ and ‘eczema, infantile’ were included within this outcome factor. independent variables independent variables considered in analyses encompassed registrar, patient, consultation, and practice factors (described below). registrar factors were registrar gender and age, the term of gp training, whether the registrars had worked at their current practice previously, country of primary medical degree (australian versus international), and full-time or part-time employment status. practice factors were the rurality of the practice (using the australian statistical geographical classification remoteness area (asgc-ra) classification) [29], the size of the practice, whether the practice was fully bulk-billing (wherein no fee is charged to the patient), socio-economic position of the practice locality (based on australian socio-economic indexes for areas-index of relative socio-economic disadvantage (seifa-irsd)) [30], and the region in which the registrar was working. patient factors were patient gender, age group, non-english speaking background status, aboriginal or torres strait island status, and whether the patient was new to the practice, new to the registrar, or an existing patient. consultation factors were the length of the consultation, whether ad was a new problem, the number of problems managed within the consultation, whether pathology was ordered, medications prescribed, and whether follow-up was arranged. educational consultation factors were whether sources of information (supervisor, electronic or hardcopy) were sought for the problem/diagnosis and whether learning goals were generated. medications prescribed we also examined prescribing in more detail. prescribed medications were tabulated for frequency of prescribing and, where possible for topical corticosteroids (tcs), the potency of the prescribed medication. tcs potency was inferred according to potency rankings[31] noting, where applicable, if that drug was available in different potency formulations. statistical analyses the proportion of problems/diagnosis that were atopic dermatitis was calculated with 95% confidence intervals. descriptive statistics included frequencies with percent for categorical variables and mean with standard deviation (sd) for continuous variables. the frequencies of categorical variables were compared between outcome categories using chi-squared tests or fisher’s exact test when there was an expected count less than 5 in 25% or more cells). for continuous variables, means were compared using a t-test. univariable (simple) and multivariable (adjusted) logistic regression was used within the generalized estimating equations (gee) framework to account for repeated measures within registrars. an exchangeable working correlation structure was assumed. univariable analyses estimated the relationship of each covariate with the outcome. covariates with a univariate p value <0.20 were considered for inclusion in the multivariable model. once the model with all significant covariates was fitted, model reduction was assessed. covariates which were no longer significant (at p <0.2) in the multivariable model were tested for removal from the model. if the covariate’s removal did not substantively change the resulting model (defined as a change in the effect size (odds ratio) of less than 10%), the covariate was removed from the final model. to address our aim of establishing associations of a problem/diagnosis being ad, three multivariable models were built, each with ‘ad’ as the outcome. in the first model, patient, practice, and registrar independent variables, plus whether the problem/diagnosis was a new one, were included in the model to assess variables associated with a registrar encountering ad problems/diagnoses (compared to other problems/diagnoses). in the second model, these patient/practice/registrar variables were modelled along with additional ‘consultation ’variables: consultation duration and number of problems/diagnoses dealt with in the consultation, and the registrar seeking information/assistance (from their supervisor or from another source). in the third model, all variables in the previous two models were included with further ‘consultation’ variables: pathology ordered, follow-up ordered, learning goals generated, referral ordered, and medication prescribed. the rationale for conducting the successive regression models was that patient, registrar, and practice factors could plausibly influence whether a patient presents to the registrar with ad. evaluation of these influences may be compromised by inclusion in the model of factors operating once the consultation is progressing. similarly, evaluation of the content of the consultation may be compromised by the inclusion of actions arising from the consultation. analysis was performed at the level of problem/diagnosis. the regressions modelled the log-odds that a problem/diagnosis was classified as atopic dermatitis. results are presented as odds ratios with 95% ci. statistical analyses were conducted using stata 14.1 (statacorp, college station, tx, usa) and sas v9.4 (sas institute inc., cary, nc, usa). this project 4 research | dermatol pract concept. 2021;11(4): e2021128 has been approved by the university of newcastle human research ethics committee. results from 2010-2019, 2,783 registrars (96.1% response rate) provided data from 381,180 consultations, within which 595,412 problems were managed. the demographics of participating registrars are shown below (table 1). of all problems managed 3,285 (0.6% [95% ci: 0.53 0.57]) were ad. among ad problems/diagnoses, 34% were for a new diagnosis. characteristics associated with a problem/diagnosis being ad are presented here. (table 2). results of univariate and multivariable logistic regression with the outcome of problem/diagnosis being ad are presented in (table 3). statistically significant multivariable associations of an ad problem being seen were age 0-1 years (or 1.80 [95% ci table 1. registrar and practice variables for atopic dermatitis problems being seen registrar variables (n=2783) n (%) registrar gender female 1728 (62.1) qualified as doctor (primary medical degree) in australia yes 547 (19.8) pathway registrar enrolled in general 1930 (70.0) registrar round/practice variables (n=6414) registrar age (years) mean ± sd 32.6 (6.3) registrar works pt yes 1420 (22.9) registrar training term term 1 2640 (41.2) term 2 2091 (32.6) term 3 1683 (26.2) practice rurality major city 3983 (62.7) inner regional 1633 (25.7) outer regional 653 (10.3) remote 64 (1.0) very remote 16 (0.3) practice seifa index mean ± sd 5.5 (2.8) practice routinely bulk bills yes 1784 (28.1) registrar worked at practice previously yes 1343 (21.2) practice size small (1-5 gps) 2371 (38.4) large (6-10+ gps) 3811 (61.6) table 2. characteristics associated with seeing a patient with atopic dermatitis atopic dermatitis factor group variable class no yes p patient factors patient age group 0-1 years 24215 (4%) 687 (21%) <0.001 2-12years 48591 (8%) 901 (28%) 13-24 years 77871 (13%) 591 (18%) 25-44 years 160401 (28%) 579 (18%) 45+ years 271596 (47%) 471 (15%) patient gender male 221923 (38%) 1411 (44%) <0.001 female 356223 (62%) 1798 (56%) aboriginal and torres strait islander no 540148 (98%) 3036 (99%) 0.038 yes 10055 (2%) 39 (1%) nesb* no 505865 (91%) 2776 (90%) 0.014 yes 48101 (9%) 315 (10%) patient/practice status existing patient 242797 (42%) 1097 (34%) <0.001new to registrar 291926 (51%) 1833 (57%) new to practice 43213 (7%) 292 (9%) table 2 continues research | dermatol pract concept. 2021;11(4): e2021128 5 atopic dermatitis factor group variable class no yes p registrar factors registrar gender male 216382 (37%) 1200 (37%) 0.999 female 375745 (63%) 2085 (63%) registrar ft or pt** part-time 133911 (23%) 790 (25%) 0.17 full-time 438268 (77%) 2405 (75%) term term 1 248656 (42%) 1288 (39%) <0.001term 2 190762 (32%) 1193 (36%) term 3 152709 (26%) 804 (24%) worked at practice previously no 458411 (78%) 2563 (79%) 0.63 yes 126188 (22%) 671 (21%) qualified as doctor in australia no 108879 (18%) 532 (16%) 0.006 yes 480721 (82%) 2739 (84%) registrar age mean (sd) 33 (6) 32 (6) 0.010 practice factors practice size small 221940 (39%) 1145 (36%) 0.007 large 349327 (61%) 2044 (64%) practice routinely bulk bills no 423524 (72%) 2283 (71%) 0.10 yes 163125 (28%) 948 (29%) rurality major city 364641 (62%) 2239 (69%) <0.001inner regional 150534 (26%) 726 (22%) outer regional remote 70686 (12%) 274 (8%) region region 1 135287 (23%) 546 (17%) <0.001 region 2 36043 (6%) 153 (5%) region 3 62968 (11%) 396 (12%) region 4 198987 (34%) 1397 (43%) region 5 10381 (2%) 31 (0.9%) region 6 97271 (16%) 550 (17%) region 7 51190 (9%) 212 (6%) seifa index*** mean (sd) 5 (3) 6 (3) <0.001 consultation factors new problem seen no 238042 (44%) 1957 (66%) <0.001 yes 302743 (56%) 989 (34%) sought help any source none 487113 (82%) 2505 (76%) <0.001supervisor 43925 (7%) 319 (10%) other sources 61089 (10%) 461 (14%) pathology ordered no 490393 (83%) 3215 (98%) <0.001 yes 101734 (17%) 70 (2%) follow-up ordered none 333581 (56%) 2094 (64%) <0.001gp appt or phone 225508 (38%) 1128 (34%) with someone else 33037 (6%) 63 (2%) learning goals generated no 452325 (82%) 2467 (80%) 0.032 yes 100596 (18%) 604 (20%) referral ordered no 518160 (88%) 3063 (93%) <0.001 yes 73967 (12%) 222 (7%) medication prescribed no 337749 (57%) 646 (20%) <0.001 yes 254378 (43%) 2639 (80%) consultation duration mean (sd) 19 (10) 17 (8) <0.001 number of problems mean (sd) 2 (1) 2 (1) <0.001 nesb = non-english-speaking background; (pt)=part time, (ft)= full time, seifa = socio-economic indexes for areas table 2. characteristics associated with seeing a patient with atopic dermatitis (continued) 6 research | dermatol pract concept. 2021;11(4): e2021128 table 3. simple and adjusted logistic regression with outcome: problem/diagnosis is atopic dermatitis univariable multivariable factor group variable class or [95% ci] p or [95% ci] p patient factors patient age group 0-1 years 1.53 (1.38, 1.70) <.001 1.80 (1.60, 2.02) <.001 referent: 2-12 years 13-24 years 0.41 (0.37, 0.45) <.001 0.34 (0.30, 0.38) <.001 25-44 years 0.19 (0.17, 0.22) <.001 0.15 (0.13, 0.17) <.001 45+ years 0.09 (0.08, 0.11) <.001 0.06 (0.05, 0.07) <.001 aboriginal and torres strait islander yes 0.72 (0.53, 0.98) 0.038 0.66 (0.47, 0.93) 0.016 nesb yes 1.17 (1.03, 1.33) 0.014 1.17 (1.02, 1.34) 0.022 patient/practice status new to registrar 1.38 (1.27, 1.49) <.001 1.52 (1.39, 1.66) <.001 referent: existing patient new to practice 1.49 (1.31, 1.69) <.001 1.70 (1.46, 1.98) <.001 registrar factors term term 2 1.21 (1.11, 1.32) <.001 1.20 (1.09, 1.32) <.001 referent: term 1 term 3 1.01 (0.92, 1.11) 0.81 1.05 (0.94, 1.16) 0.40 practice factors rurality inner regional 0.78 (0.71, 0.86) <.001 0.88 (0.77, 1.00) 0.053 referent: major city outer regional or remote 0.63 (0.55, 0.72) <.001 0.79 (0.66, 0.96) 0.015 region referent: region 1 region 2 1.05 (0.86, 1.29) 0.62 1.03 (0.83, 1.28) 0.78 region 3 1.55 (1.33, 1.81) <.001 1.78 (1.48, 2.13) <.001 region 4 1.74 (1.55, 1.95) <.001 1.46 (1.28, 1.66) <.001 region 5 0.74 (0.52, 1.07) 0.11 0.83 (0.54, 1.27) 0.39 region 6 1.39 (1.22, 1.60) <.001 1.13 (0.96, 1.33) 0.14 region 7 1.02 (0.86, 1.21) 0.83 1.06 (0.87, 1.29) 0.54 consultation factors new problem seen yes 0.39 (0.36, 0.42) <.001 0.20 (0.18, 0.22) <.001 sought help any source other sources 1.50 (1.35, 1.66) <.001 1.54 (1.37, 1.73) <.001 referent: none supervisor 1.41 (1.25, 1.60) <.001 1.59 (1.38, 1.84) <.001 consultation duration 0.98 (0.97, 0.98) <.001 0.98 (0.97, 0.98) <.001 number of problems 0.89 (0.86, 0.92) <.001 1.29 (1.23, 1.35) <.001 pathology ordered yes 0.11 (0.08, 0.13) <.001 0.18 (0.14, 0.25) <.001 follow-up ordered gp appt or phone 0.79 (0.73, 0.86) <.001 0.94 (0.85, 1.03) 0.19 referent: none with someone else 0.30 (0.24, 0.39) <.001 0.30 (0.22, 0.40) <.001 learning goals generated yes 1.11 (1.01, 1.22) 0.032 1.14 (1.01, 1.28) 0.037 referral ordered yes 0.51 (0.45, 0.58) <.001 0.65 (0.55, 0.77) <.001 medication prescribed yes 5.48 (5.00, 6.01) <.001 5.64 (5.07, 6.27) <.001 1.60 2.02] compared to age 1 to 12 years) and patients being of non-english speaking background (or 1.17 [95% ci: 1.02 1.34]). ad was less likely to be seen in aboriginal or torres strait islander patients (or 0.66 [95% ci 0.47 0.93]). patients presenting with ad were more likely to be new to the practice (or 1.70 [95% ci 1.46 1.98]) or new to the registrar (or 1.52 [95% ci 1.39 1.66]). ad was less likely to be seen by registrars working in outer regional, remote, or very remote areas (or 0.79 [95%ci 0.66, 0.96] compared to major city locations). ad was less likely to be a new problem for the patient (or 0.20 [95% ci 0.18 0.22] compared with an existing problem) and was associated with more issues being dealt with in these consultations (or 1.29 [ 95% ci 1.23 1.35]). pathology was less likely to be ordered (or 0.18 [95% ci 0.14 0.25]) and there was a strong association with medication being prescribed (or 5.64 [95% ci 5.07 6.27]). learning goals were more likely to be generated for ad than other problems/diagnoses (or 1.14 [95% ci 1.01 research | dermatol pract concept. 2021;11(4): e2021128 7 1.28]). ad problems/diagnoses were associated with seeking information or assistance, both from registrars’ supervisors (or 1.59 [95% ci 1.38 1.84]) or from other sources (or 1.54 [95% ci 1.37 1.73). there were 3,185 prescriptions written for ad. table 4 outlines the most prescribed medications and, where possible, the potency of the prescribed medication. topical corticosteroids (tcs) were the most prescribed medicines. of these, the most prescribed were hydrocortisone (mild/moderate potency), mometasone (potent), betamethasone (moderate/ potent), methylprednisolone aceponate (moderate), and triamcinolone (moderate). antibiotics were prescribed in 6.5% of ad problems/diagnoses. cephalexin, an oral antibiotic, was the most prescribed. discussion factors associated with gp registrar exposure to management of ad have not been well-investigated. specialist vocational training is an essential time for registrars to build exposure to, and confidence in managing, common primary care presentations. given community prevalence and disease burden, ad exposure comprises an essential part of this experience. registrar experience of patient presentations with ad atopic dermatitis accounted for 0.6% of problems seen by australian gp registrars. this is quite low when compared with the limited existing literature on gps’ consultations with ad. in a study of uk gps, 14% of consultations contained one or more dermatology problems/diagnoses (icpc-2 defined) and 12% of these problems (the joint-highest of any particular skin condition) were ad [17]. ad is most common in early childhood and infancy [3]. registrars in our study were more likely to see ad in patients aged 0-1 years compared to other age-groups, consistent with established peak periods of diagnosis [32]. registrars in our study also see a younger patient demographic than established gps [25], including in the peak 0-1 year age-group for ad [33]. thus, the finding of low frequency of seeing patients with ad compared to established gps is of particular interest. despite its greater prevalence in a younger population, ad is a chronic disease. concerns have been previously raised regarding registrar exposure to chronic disease [19, 22, 24, 26]. our findings suggest that the pattern of presentations for ad is consistent with other chronic diseases and that patients (and parents) may be more likely to choose to attend an established gp for management of this condition. registrar confidence managing ad our findings suggest that the registrars’ modest levels of experience with ad in gp vocational training, in addition to deficits in undergraduate and hospital-based pre-vocational training [34-37], may limit confidence in its management. registrars were more likely to generate learning goals within these consultations in addition to seeking information and assistance from both supervisors and other sources. consistent with previous studies [21, 38], our findings again suggest that skin conditions remain challenging for registrars to manage. ad being the problem seen is strongly associated with medication prescription. our registrars prescribed a topical corticosteroid (tcs) in 82% of consultations. tcs comprise a first line treatment for ad [6, 39]. there are 4 classes of tcs according to potency [31], grouped from mild to very potent. chidwick et al found that gps were most likely to table 4. medications prescribed for atopic dermatitis presentations medication type number of prescriptions (n = 3185) topical corticosteroids hydrocortisone aceponate (mild) mometasone (potent) methylprednisolone aceponate (moderate) betamethasone (moderate/potent) triamcinolone (moderate) clobetasol (very potent) unspecified antibiotics topical antifungal topical calcineurin inhibitor immunosuppressants and immunomodulators prednisolone azothioprine antihistamine emollients and antimicrobial measures other 2676 781 614 572 571 125 4 9 215 77 67 49 46 3 39 31 31 8 research | dermatol pract concept. 2021;11(4): e2021128 prescribe potent tcs [7]. in contrast, we found that registrars were most likely to prescribe tcs of mild or moderate potency. mild to moderate potency tcs were prescribed in 54% of ad presentations. in particular, tcs containing hydrocortisone was most likely to be prescribed. this greater prescribing of lower potency tcs suggests that registrars may have some discomfort in prescribing potent steroids. this may be in part due to the young ages of the population seen with ad. however, this is also of significance given corticosteroid phobia has been named as a significant barrier for optimizing treatment in ad [31, 39, 40]. in addition, registrars prescribed antibiotics for ad in 6.5% of presentations. bacterial colonization and superinfection may occur in ad, due to a compromised cutaneous barrier [6]. however, as shown by a recent randomized control trial, children with mildly infected ad do not require oral or topical antibiotic therapy [41]. optimized management in these scenarios is through prophylactic measures such as the increased use of emollients and tcs [31, 41]. demographics of ad presentations we also found that location and specific patient demographics impacted upon registrar exposure to ad. our findings have demonstrated a reduction in presentation of ad in outer regional and remote areas. this contrasts with previous findings of no significant differences between urban and rural areas in the prevalence of ad [42]. barriers to access healthcare in regional and remote areas may account for this finding. availability of appointments, and geographic distances involved, may lead to other health concerns being prioritized above ad for management. the context of this finding is a tendency for the impact of skin problems compared to other health conditions to be underestimated by gps (and, sometimes, for this perspective to be understood by patients themselves)[43]. we identified an increase in ad presenting in patients from nesb backgrounds. ad rates have been shown to vary between different ethnic groups [44, 45], and is notably more predominant in high income countries [45]. in australia, ad has been shown to be increased in children of chinese migrants [44, 46] however there are varied reported rates for ad in children of other ethnic migrant descent [46, 47]. whether children are firstor second-generation migrants has also been suggested to impact upon atopic disease prevalence [48]. other factors including the timing and age of migration and duration of residence may also impact ad risk [48]. our results also showed a reduction of ad presentation in aboriginal and torres strait islander patients. this finding was statistically significant and noteworthy particularly in the context of limited evidence around the prevalence of ad in aboriginal and torres strait islander patients [49]. interpretation of our findings of demographic associations must be cautious, however. further research is required to establish the relative influences of ad prevalence, relative access to health care, and other factors in associations of rurality, socioeconomic status, identification as aboriginal or torres strait islander, and non-english-speaking background with ad presentations to registrars. strengths and limitations strengths of this study include a large data set (595,412 data points) and its high response rate (96.1% particularly high for a study of gps[50]). findings are generalizable across australia, and potentially internationally, given the broad coverage of australian regions distributed across urban, rural, remote, and very remote classifications. a limitation of this study is that we were unable to comprehensively assess tcs prescriptions concentration as this information is not available in the data. another limitation was not being able to assess severity of ad seen by registrars. this would have provided valuable information in interpreting steroid and management choice. there is some difficulty in interpreting tcs choice further given that potency depends on concentration and formulation. for example, tcs containing betamethasone was prescribed in 22% of tcs prescriptions. this medication may be formulated to be moderate, potent, or very potent, and within this study we were unable to establish potency of how this medication was prescribed. implications for registrar education our findings show that gp registrars may be exposed to managing ad less frequently than their more senior gp counterparts. as such, there may be some areas in which registrars may lack confidence in management. an example is tcs choice and optimal use of antibiotics. limited exposure could also limit experience in developing the nuanced clinical skills in shared decision-making and patient self-management required in ad.[17, 51] these areas could be addressed in registrars’ education programs. our findings also show that geographic and population factors may impact registrar exposure to clinical experience with ad. rto-wide education programs should take this variability into account. conclusion our findings show that gp registrars encounter ad less often than their more senior counterparts and this experience may be variable depending on rurality and region of practice. we have identified evidence that registrars may find ad challenging to manage and that there may be some gaps in management knowledge and 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in prevalence of eczema symptoms in children from isaac phase three. j allergy clin immunol. 2009;124(6):1251-8 e23. 46. mar a, tam m, jolley d, marks r. the cumulative incidence of atopic dermatitis in the first 12 months among chinese, vietnamese, and caucasian infants born in melbourne, australia. j am acad dermatol. 1999;40(4):597-602. doi: 10.1016/s01909622(99)70443-3. 47. ponsonby al, glasgow n, pezic a, dwyer t, ciszek k, kljakovic m. a temporal decline in asthma but not eczema prevalence from 2000 to 2005 at school entry in the australian capital territory with further consideration of country of birth. int j epidemiol. 2008;37(3):559-69. doi: 10.1093/ije/dyn029. 48. tham eh, loo exl, zhu y, shek lp. effects of migration on allergic diseases. int arch allergy immunol. 2019;178(2):12840. doi. 10.1159/000494129. 49. heyes c, tait c, toholka r, gebauer k. non-infectious skin disease in indigenous australians. australas j dermatol. 2014;55(3):176-84. doi: 10.1111/ajd.12106. 50. bonevski b, magin p, horton g, foster m, girgis a. response rates in gp surveys trialling two recruitment strategies. aust fam physician. 2011;40(6):427-30. 51. ridd mj, king ajl, le roux e, waldecker a, huntley al. systematic review of self-management interventions for people with eczema. br j dermatol. 2017;177(3):719-34. doi: 10.1111/ bjd.15601. dermatology: practical and conceptual dermatology practical & conceptual introduction the desire to look more attractive has always been an undeniable demand in every society. with the effect of social media and the continuous use of filtered selfies, the longing for perfection has reached its climax. nowadays, increasingly more patients apply to dermatology clinics to eliminate skin imperfections, including nevi. we recommend removal of skin lesions performed in the classical and safe approach, and to perform histopathological examination on removed tissue. conventional elliptic surgical removal may however heal with linear scarring, which is sometimes perceived as unsatisfactory by patients. in recent years, alternative methods such as ablative lasers have been introduced as a treatment option to destroy nevus cells near the skin surface to optimize cosmetic outcome with reduced scarring risk. although laser removal is a feasible and charming option, the technique’s crucial pitfalls should not be disregarded. the main risk in destroying a nevus with ablative methods is the possibility of removing a melanoma. while early recognition and complete excision of melanoma is curative, advanced stages are associated with a high mortality rate, despite the progress in treatment modalities. misinterpretation of melanoma for a nevus may lead to delayed diagnosis of an advanced/metastatic melanoma. another potential risk of nevi laser removal is the malignant transformation of the remaining nevus cells into a melanoma. unfortunately, these theoretical scenarios exist more often than we may think and have tragic consequences. case 1 an 18-year-old female patient was referred to an experienced dermatologist because of an enlarged mass on the neck. the lesion had a history of 10 years. 2 years ago, ablative laser was performed for cosmetic reasons. the lesion enlarged in several months. this time the lesion was identified as a hypertrophic scar by the physician. he applied intralesional steroid therapy twice. the lesion enlarged continuously (figure 1, a and b) and the patient sought professional medical advice. the lesion was excised, and the pathology confirmed nodular melanoma commentary | dermatol pract concept. 2021; 11(4): e2021117 1 accelerated use of non-surgical techniques for nevi removal: primum non-nocere seçil vural1, bengü nisa akay 2, arda yaycıoğlu1, seher bostancı 2 1 koç university, school of medicine, department of dermatology and venereology 2 ankara university, faculty of medicine, department of dermatology and venereology key words: melanoma, nevus, skin neoplasms, cosmetic dermatology citation: vural s, akay bn, yaycıoğlu a, bostancı s. accelerated use of non-surgical techniques for nevi removal: primum non-nocere. dermatol pract concept. 2021; 11(4): e2021117. doi: https://doi.org/10.5826/dpc.1104a117 accepted: march 25, 2021; published: september 2021 copyright: ©2021 vural et al. this is an open-access article distributed under the terms of the creative commons attribution license bync-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: seçil vural, md, associate professor, koç university school of medicine, department of dermatology and venereology. koç üniversitesi hastanesi, davutpaşa cad, no:4 topkapı, i̇stanbul, turkey. email: sevural@ku.edu.tr 2 commentary | dermatol pract concept. 2021; 11(4): e2021117 figure 1. case reports. (a) case 1: 18-year-old woman diagnosed with pathology confirmed nodular melanoma with a breslow thickness of 7.8 mm 6 months after ablative laser, and intralesional steroid injections. (b) case 1: dermoscopy showing a nodular mass with central hemorrhagic ulcer, serpentine-branched vessels on a pink structureless area, and remnants of brown pigmentation. (c) case 3: clinical image of a superficial spreading melanoma with a breslow thickness of 0.75mm on the leg of a 33-year-old female. the lesion was first treated with chemical peels and reappeared after 3 months expanding continuously. (d) case 3: dermoscopic image showing a well demarcated lesion with chaos of border abruptness, eccentric gray-black structureless area, and white lines. (e) case 4: magnetic resonance imaging showing a melanoma metastasis in the brain causing severe edema and midline shift. the patient recalled non-surgical removal of a pigmented nevus from his leg with a breslow thickness of 7.8 mm, clark level v. sentinel lymph node biopsy showed extra capsular involvement case 2 a 30-year-old male patient was referred to our department with the diagnosis of metastatic melanoma of unknown origin to examine the primary focus. the medical history revealed that a general surgeon removed a lesion on his neck for cosmetic reasons without sending the specimen to histopathological examination. the surgeon claimed the lesion as benign. after 2 years, the patient felt the enlargement of regional lymph nodes on the neck, and histopathology revealed a metastatic melanoma. positron emission tomography showed metastasis in the lungs. after 1 year of treatment with braf and mek inhibitors, the patient passed away. commentary | dermatol pract concept. 2021; 11(4): e2021117 3 case 3 a 33-year-old woman female requested therapeutic advice from a pharmacist for pigmented nevi on her left arm. the pharmacist recommended an acidic peeling to remove or destroy the pigmented area. after the application, the patient had a severe burn affecting the area, and the lesion was partially destroyed. however, after 3 months, the lesion started to evolve and expand (figure 1, c and d). histopathological analysis confirmed the diagnosis of superficial spreading melanoma with a breslow thickness of 0.75mm and clark level of iii. case 4 a 41-year-old male dentist had a history of increasing severity of headaches, vomiting and blurred vision for the last month. cranial magnetic imaging revealed 3 masses in the brain. the most prominent lesion caused severe edema and midline shift (figure 1 e). positron emission tomography showed multiple masses, including masses at the level of the heart atrium, pancreas, lung, and subcutaneous tissue of the left leg. histopathology of the mass from the subcutaneous mass in the leg was consistent with melanoma metastasis. the patient was referred to a dermatologist to examine the skin for the primary lesion. he mentioned a previous dermatology visit when he complained from a nevus on his leg 3 years ago. at the time, the physician removed the nevus with an ablative method. the patient is currently using braf+mek inhibitors, and the large mass on the brain is treated with gamma knife radiosurgery. discussion the most common method used by non-dermatologist physicians to evaluate the malignancy potential is the abcde method (a-asymmetry, b-border, c-color, d-diameter, e-evolution). however, naked-eye assessment of a skin lesion using this method is inadequate. clinical detection of a melanoma in early stages can be very challenging, even with dermoscopy. the examination of tumoral proliferations on the skin has improved significantly with the introduction of various dermoscopic algorithms [1-3] . still, an initial melanoma can be evaluated as a nevus even by an experienced dermatoscopist and detected by digital dermoscopy follow-ups [4]. besides, many clinically similar non-melanocytic lesions exist such as dermal nevi and nodular basal cell carcinomas [5]. a histopathological evaluation of the nevi is therefore always necessary before aesthetic treatment. the risk of malpractice accusations in dermatology is comparatively low. however, malignant neoplasms of the skin require special considerations. between 2006 and 2015 malignant neoplasms of the skin and melanoma together, ranked first in dermatology liability claims and resulted in the most extensive recovery in the us, probably reflecting the worldwide situation [6, 7]. the time lap between the destruction of the primary lesion and subsequent recurrence of a melanoma ranges between 2-10 years. this makes the accurate interpretation of the harm caused by this new wave, tricky [8]. the belief that one can easily differentiate a benign nevus from a malignant one possesses a significant risk with the frequent use of ablative modalities to treat skin lesions. we recommend professional organizations to determine a new policy that incorporates skin cancer education and use of dermoscopy in certifying treating physicians. besides, a strict filing of the procedures and long-term follow-ups are needed to obtain the data allowing to measure the accuracy and safety of these techniques. even with proper education and policies, a histopathologic evaluation of the lesion is crucial prior to conducting an aesthetic removal. we are extremely concerned by the widespread use of ablative techniques to remove skin lesions, as this may increase late melanomas. as physicians, our first rule when approaching a patient should always be as stated in the famous latin phrase: ‘’first, do no harm’’. informed consent: the patients in this manuscript or their first-degree relatives provided written informed consent for the publication of their case details. references 1. argenziano g, soyer hp, chimenti s, talamini r, corona r, sera f, et al. dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet. j am acad dermatol. 2003;48(5):679-93.doi: 10.1067/mjd.2003.281. 2. carrera c, marchetti ma, dusza sw, argenziano g, braun rp, halpern ac, et al. validity and reliability of dermoscopic criteria used to differentiate nevi from melanoma: a webbased international dermoscopy society study. jama dermatol. 2016;152(7):798-806. doi: 10.1001/jamadermatol.2016.0624. 3. kittler h, pehamberger h, wolff k, binder m. diagnostic accuracy of dermoscopy. lancet oncol. 2002;3(3):159-65. doi: 10.1016/s1470-2045(02)00679-4. 4. menzies sw, emery j, staples m, davies s, mcavoy b, fletcher j, et al. impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial. br j dermatol. 2009;161(6):1270-7.doi: 10.1111/j.1365-2133.2009.09374.x. 5. hoogedoorn l, peppelman m, blokx wam, van erp pej, gerritsen mp. prospective differentiation of clinically difficult to distinguish nodular basal cell carcinomas and intradermal nevi by non-invasive reflectance confocal microscopy: a case series study. j eur acad dermatol venereol. 2015;29(2):330-6.doi: 10.1111/jdv.12548. 6. kornmehl h, singh s, adler bl, wolf ae, bochner da, armstrong aw. characteristics of medical liability claims against dermatologists from 1991 through 2015. jama dermatol. 2018;154(2):160-6.doi: 10.1001/jamadermatol.2017.3713. 4 commentary | dermatol pract concept. 2021; 11(4): e2021117 7. arimany manso j, martin fumadó c, mascaró ballester jm. medical malpractice issues in dermatology: clinical safety and the dermatologist. actas dermo-sifiliográficas (english edition). 2019;110(1):20-7.doi: 10.1016/j.adengl.2018.11.007. 8. crowson an. medicolegal aspects of neoplastic dermatology. mod pathol. 2006;19 suppl 2:s148-54. doi: 10.1038/modpathol.3800518. dermatology: practical and conceptual original article | dermatol pract concept. 2022; 12(1): e2022029 1 acne supplements sold online emily burns1, milbrey parke1, ariadna perez-sanchez2, dina zamil1, rajani katta3 1 baylor college of medicine, houston, tx, usa 2 department of internal medicine, university of texas health science center at san antonio, san antonio, tx, usa 3 department of dermatology, mcgovern medical school at university of texas health science center at houston, houston, tx, usa key words: acne supplement, dietary supplement, diet, nutrition, safety citation: burns e, parke m, perez-sanchez a, zamil d, rajani k. acne supplements sold online. dermatol pract concept. 2022; 12(1): e2022029. doi: https://doi.org/10.5826/dpc.1201a29 accepted: august 2, 2021; published: january 2022 copyright: ©2022 burns et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: rajani katta, md, department of dermatology, mcgovern medical school at university of texas health science center at houston, houston, tx, usa. e-mail: info@kattamd.com introduction: as no centralized database of acne supplements is available, we aimed to provide an overview of these products, with a focus on safety. objectives: the objectives of this study were to document the number, formulation, contents, and marketing strategies utilized by acne supplements sold online. methods: an online search was conducted between march and may 2020. products were included in the study if they used the terms: “whitehead”, “blackhead”, or “acne”. data were extracted from the website, box, and supplement facts label. results: 49 products were identified, which contained 146 unique ingredients. these included vitamins, minerals, food extracts, botanical extracts, amino acids, animal products, and distinct microbial strains. few (4.1%) products were tested by third parties. conclusions: this survey of acne supplements available online raised concerns regarding lack of warning labels, teratogenicity, exceedingly large levels of vitamins and minerals, and lack of third party testing. given the limited regulation and oversight of dietary supplements, it is imperative that physicians educate patients on the potential risks of these products. abstract 2 original article | dermatol pract concept. 2022; 12(1): e2022029 introduction dietary supplements in the us dietary supplements are becoming increasingly popular in the u.s. studies estimate that approximately 50% of the us population consumes some form of dietary supplement [1]. the number of american people who consume acne supplements is unknown. the role of dietary supplements in acne acne affects up to 50 million american residents each year, and its prevalence has been reported to be as high as 85% among people aged 12-24 years [2,3]. the role of diet and dietary supplements in the development and treatment of acne is an evolving field of study. a recent systematic review including 53 articles revealed that acne-promoting factors include high glycemic index food, dairy, fatty food, and chocolate. acne-protective factors include fruits and vegetables. the possible varying degrees of acne-promotion of specific subtypes of these foods (eg full-fat milk vs. low-fat milk) is unknown [4]. high doses of oral zinc have been shown to reduce severe and inflammatory acne in double-blind randomized control trials (rcts) [5,6]. successful trials have used different dosages and forms of zinc as well as zinc in combination with other ingredients [7]. therefore, future research is needed to elucidate the best zinc dose and form associated with improved acne outcomes. other vitamins and minerals have been studied, but double-blind rcts are lacking [5,8]. low selenium levels have been documented in patients with acne; however, the clinical significance of low selenium and acne development is unknown [5,9]. a cross-sectional study comparing blood levels of vitamins a and e in 100 patients with acne and 100 patients without acne showed that subjects with acne had significantly lower plasma concentrations of these vitamins compared to the control subjects [5,10]. other naturally occurring compounds have been evaluated in animal and in vitro studies but human studies are lacking. these compounds have exhibited antioxidant and antibacterial properties, such as (--) epigallocatechin-3-gallate from green tea and nobiletin from citrus depressa (a green citrus fruit native from taiwan and japan) [5,11,12]. in hamsters, these compounds have been shown to reduce sebum production and inhibit cell proliferation of sebaceous glands respectively. the flavonoids kaempferon and quercetin from the inpatiens balsamina flower as well as resveratrol found in several other plants have been shown to possess antibacterial properties against propionibacterium acnes in vitro [5,13,14]. figure 1. example of product image of an acne supplement sold online objectives the objective of this study was to document the number, formulation, contents, and marketing strategies utilized by acne supplements sold online. methods we conducted a search of acne supplements sold online between march 2020 and may 2020 using google, amazon, twitter, and instagram. acne supplements were defined as those featuring the words “whitehead”, “blackhead”, and/or “acne” (figure 1). data were extracted from the supplement facts label, manufacturer website, and/or third-party seller website for each product. third-party sellers include amazon and online supplement retailers. results ingredients forty-nine products were identified, which in total contained 146 unique ingredients including vitamins, minerals, food extracts, botanical extracts, amino acids, animal products, and distinct microbial strains (table 1). products contained an average of 3.18 vitamins, and the most common vitamins included in descending order were vitamins a, e, b3, b5, and b6 (table 2). products contained an average of 2.6 minerals, and the most common minerals included were zinc and selenium (table 3). many products contained supraphysiologic doses of vitamins and minerals (table 4), (figure 2). original article | dermatol pract concept. 2022; 12(1): e2022029 3 many products contained botanical and food extracts. the most common extracts included were methylsulfonylmethane (msm, 20%), coenzyme q10 (coq10,13%), horsetail powder (10%), pepper extract (10%), grape seed extract (8%), turmeric (8%), diindolylmethane (dim, 7%), and licorice root extract (6%). formulation capsules were the most common formulation, followed by tablets and gummies. table 4. high doses of vitamins and minerals from selected acne supplements nutrient labeled dose % of daily values vitamin a 21,000 mcg rae 2,333% vitamin b2 (riboflavin) 25 mg 1,923% vitamin b3 (niacin) 500 mg 2,500% vitamin b5 (pantothenic acid) 350 mg 3,500% vitamin b6 50 mg 2,500% vitamin b7 (biotin) 7500 mcg 2,500% vitamin b12 500 mcg 20,833% vitamin c 280 mg 467% chromium 250 mcg 714% zinc 50 mg 333% table 1. list of selected ingredients methylsulfonylmethane (msm) coenzyme q10 (coq10) horsetail powder pepper extract grape seed extract turmeric diindolylmethane (dim) licorice root extract bovine adrenal powder bacteriophages bovine colostrum table 2. vitamins included in acne supplements sold online vitamin % of products a 53.1 b3 (niacin) 34.7 b5 (pantothenic acid) 34.7 b6 (pyridoxine) 34.7 e (tocopherol) 34.7 no vitamins 32.7 c 30.6 b7 (biotin) 24.5 b2 (riboflavin) 16.3 b12 (cobalamin) 14.3 d 14.3 b1 (thiamine) 12.2 b9 (folate) 10.2 k 4 table 3. mineral content (%) of acne supplements sold online mineral % of products zinc 65.3 selenium 40.8 chromium 32.7 copper 28.6 magnesium 28.6 no minerals 26.5 calcium 14.3 manganese 12.2 sodium 8.2 potassium 8.2 iron 6.1 sulfur 6.1 iodine 4.1 phosphorus 4.1 figure 2. example of supplement facts label image from an acne supplement sold online 4 original article | dermatol pract concept. 2022; 12(1): e2022029 dosing 47.9% of products did not provide clear labeling for total daily dose. for example, the supplement facts box included the dose for one capsule, but the recommended dose is two capsules. pricing pricing varied from $10-204 per month supply. the median price per month was $31. third-party seals of approval approximately 4% of products displayed seals of approval from third-party testing centers recognized by the us office of dietary supplements. marketing and claims the most common marketing claims included gluten free (67%), vegan or vegetarian (45%), made in the usa (43%), natural (43%), hormonal balance or regulates hormones (43%), detoxify (41%), inflammation (39%), antioxidant (37%), proprietary blend (26%), and cruelty free (20%). most (55.1%) products used the terms “research” or “clinical study” in the marketing materials. some (8.2%) products cited a clinical study. most (55.0%) of products had an auto-delivery or subscription option available upon checkout. most (55.1%) of products had a coupon available upon checkout. other marketing techniques included before-andafter photographs (51.1%) and video testimonials (12.2%). most (83.7%) supplements were reviewed on amazon. labeling some (20.8%) products had different information provided by multiple sources. in these instances, labels provided by amazon sellers conflicted with third party sellers and/or manufacturers. for the purposes of the data collection of this study, the label from the manufacturer website was used. supplement manufacturers are required by law to include the phrase “this statement has not been evaluated by the fda. this product is not intended to diagnose, treat, cure, or prevent any disease” on the bottle if a structure/function claim is made. 12.2% of products did not have this phrase clearly visible online. a 53.1% of products did not list a phrase containing or similar to “consult your doctor or health care practitioner before use” and 30.6% of products failed to include any type of pregnancy warning. conclusions acne supplement manufacturers use a wide variety of ingredients and health claims. there is little consensus among these products regarding the number or dosing of vitamins, minerals, extracts, and other ingredients. they are sold on manufacturer websites and third-party websites. this study raises concerns about lack of us food and drug administration (fda) oversight, lack of third-party testing, teratogenicity potential, marketing practices, untested ingredient profile, supraphysiologic vitamin dosing, vulnerable patient population, and consumer confusion. the us fda regulates supplements as foods, not drugs [15]. there is no requirement to prove safety or efficacy prior to sale, and there is no limit on dosages of vitamins or minerals, even for those with defined tolerable upper limits. there is also no requirement to test or document interactions between ingredients and/or other medications [16]. although the us fda requires that supplements sold in stores display the supplement facts label, this requirement does not apply to supplements sold online. on some websites, including amazon and other third-party sellers, this label was not visible. the fda has issued good manufacturing practices (gmps), which are a set of guidelines for safe manufacturing of dietary supplements. the fda expects manufacturers to comply with gmps but does not regularly investigate for compliance with these rules [15]. in terms of quality testing, only 4.1% of products in our sample were tested by third-party companies recognized by the office of dietary supplements, including the us pharmacopeia, national sanitation foundation, and consumer lab. without us fda testing or third-party testing, consumers must rely only on the companies themselves to ensure the safety, purity, and lack of contamination of these products. to date, there is little data about the quality and safety of acne supplements sold online. ayurvedic medicines sold online have been documented to contain heavy metals including lead, mercury, and arsenic [17]. in 2015, the new york state attorney general’s office accused four national retailers of selling dietary supplements containing unadvertised, potentially allergenic ingredients. many products did not contain the advertised herbal ingredients, and some contained allergenic components, such as wheat, while advertising that the product was “gluten-free” [18]. with regards to teratogenicity, prescription medications require a package insert with pregnancy warning categories, which indicate risk to the developing fetus. no such notification is required for supplements, even for compounds that pose a known teratogenic risk. consumers of child-bearing potential should exercise caution when consuming acne supplements, as some of these products may pose a risk to the developing fetus. high dietary doses of preformed vitamin a (> 10,000 iu) during early pregnancy are associated with neural crest defects such as cleft lip, ventricular septal defect, transposition of the great vessels, hydrocephalus, and craniosynostosis [19]. original article | dermatol pract concept. 2022; 12(1): e2022029 5 in our sample, 6.1% of acne supplements sold online included potentially teratogenic levels of vitamin a. the teratogenic potential of another 8% of products containing vitamin a could not be determined because the products did not specify the form of vitamin a [20]. in terms of marketing strategies, most products (55.1%) included the terms “research” or “clinical study” on the labeling, and some products cited the research used to support the claim. two studies cited by a product were evaluating magnesium, b6, and a plant extract (vitex agnes cactus) for use in premenstrual syndrome [21,22]. these studies did not evaluate use of these components for acne. one website referenced three articles that were not found online and could not be substantiated. during the editing process, these articles were removed from the product’s website. another article did not appear in a pubmed-indexed journal [23]. our survey documented a wide variety of ingredients contained in these products, including many ingredients that have not been tested in human acne studies. the most included ingredients outside of vitamins and minerals were msm, coq10, horsetail powder, pepper extract, grape seed extract, turmeric, dim, and licorice root extract. the topical application of grape seed extract is associated with decreased sebum content in human skin [24]; however, we were unable to locate research on oral grapeseed extract intake or the other listed compounds in acne. interestingly, the few plant compounds (kaempferon, querceptin, green tea extract and nobiletin) that have been studied in hamsters and in vitro were not the most commonly used extracts. some unique and unexpected ingredients included bovine adrenal powder, a proprietary enzyme blend including digestive enzymes, bacteriophages intended to affect gut bacteria, and bovine colostrum, intended to improve natural defenses. high-dose vitamins and minerals were used in multiple products and represent another area of concern. vitamins a, b2, b3, b5, b6, b7, b12, c as well as chromium and zinc were included in very high doses. as zinc has been shown to reduce acne, it was unsurprising that zinc was the most commonly used mineral (65%) [6]. supraphysiologic doses of vitamins and minerals included in dietary supplements have been linked to multiple side effects [25]. for example, vitamins b6 and b12 have been associated with a worsening of acne in some reports [26]. surprisingly, products in our sample included both of these ingredients at high doses: vitamin b6 at 2,500% of recommended dietary allowance (rda) and vitamin b12 at 20,833% of rda. as this analysis focused on products sold online, it highlights dangers posed to a vulnerable pediatric population. many patients suffering from acne are minors. anyone, including children, can order acne supplements online. parents and pediatricians should be wary of these products, as they are readily available online. finally, of significant concern is that approximately 1 in 5 (20.8%) supplements sold in multiple outlets (manufacturer, third-party, amazon) displayed varying doses of ingredients. it is unclear which label consumers should use to evaluate the dose and ingredients included in the supplement. limitations as our study was designed only to investigate products sold online, this represents a limited sample of acne supplements. further research should evaluate products sold in stores. in addition, the authors could not find any pubmed indexed studies evaluating the components of these products using laboratory testing. dietary supplements marketed for acne include supraphysiologic levels of vitamins and minerals as well as food extracts, botanical extracts, amino acids, animal products, and microbes. these products do not require us fda approval and thus do not undergo the same rigorous safety and efficacy testing as pharmaceuticals; however, most products include the term “research” or “clinical study” on their label. few products undergo testing by third parties, although they can be pharmacologically active and can be linked to adverse effects. many of the ingredients included in acne supplements have not undergone rcts to evaluate their efficacy, and high doses of vitamin a may be associated with birth defects in pregnant patients. as the us fda does not routinely monitor supplements sold in stores or online, consumers and physicians reporting is vital for monitoring adverse events. the us fda has an online safety reporting portal, which streamlines the process of reporting product safety issues. the portal may be found here: https://www.safetyreporting.hhs.gov/srp2/en/home. aspx?sid=0506bbbe-42e5-40f9-a58b-742b04d74295 references 1. chen f, du m, blumberg jb, et al. association between dietary supplement use, nutrient intake, and mortality among us adults: a cohort study. ann intern med. 2019;170(9):604613. doi: 10.7326/m18-2478. pmid: 30959527; pmcid: pmc6736694. 2. bickers dr, lim hw, margolis d, et al. the burden of skin diseases: 2004. j am acad dermatol. 2006;55:490–500. doi: 10.1016/j.jaad.2006.05.048. pmid: 16908356. 3. white gm. recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. j am acad dermatol. 1998;39:s34–37. doi: 10.1016/s0190-9622(98)70442-6. pmid: 9703121. 4. dall’oglio f, nasca mr, fiorentini f, micali g. diet and acne: review of the evidence 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26(8):13030/qt9rp7t2p2. pmid: 32941710. dermatology: practical and conceptual dermatology practical & conceptual letter | dermatol pract concept. 2021;11(4):e2021123 1 annular atrophic lichen planus: a case report ruzica jurakic toncic1, davorin lončarić1, stefano caccavale2, joan garces reñe1, jaka radoš1 1 university hospital centre zagreb, department of dermatology and venereology, school of medicine university of zagreb, kispaticeva 12, zagreb, croatia 2 dermatology unit, department of mental and physical health and preventive medicine, university of campania luigi vanvitelli, naples, italy  key words: annular atrophic lichen planus, dermoscopy, lichen planus, morphea citation: toncic rj, lončarić d, caccavale s, reñe jg, radoš j. annular atrophic lichen planus: a case report. dermatol pract concept. 2021;11(4):e2021123. doi: https://doi.org/10.5826/dpc.1104a123 accepted: march 21, 2021; published: october, 2021 copyright: ©2021 toncic et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: ruzica jurakic toncic, md, university department of dermatology and venereology, university hospital center, zagreb and university of zagreb school of medicine, zagreb, croatia. email: rjtoncic@gmail.com introduction annular lichen planus (alp) is considered one of the rarest clinical variants of lichen planus (lp). it is characterised by a few annular lesions commonly seen on penis and scrotum or in intertriginous areas, and it is usually very resistant to therapy. annular atrophic lichen planus (aalp) is considered as a distinctive subtype of alp with histologically extensive elastolysis caused by lymphatic cells [1-2]. classical dermoscopic criteria for lp diagnosis are missing, diagnosis is therefore challenging, and histological evaluation is needed [1]. case presentation a 20-year-old female, denying use of any medication or any medical history, sought dermatological examination because of the appearance of 2 asymptomatic lesions under her breast and in her groin fold. both lesions were annular macules, sharply demarcated, violaceous, or brownish in colour with a shiny surface, measured 20 to 25 mm in long axis (figure 1). upon dermoscopic analysis, a pigmented pattern was seen with diffuse fine peppering or perifollicular pigmentation (figure 2). a more reddish sub-mammillary lesion was biopsied and the histology revealed hyperkeratosis, atrophy of epidermis, hydropic degeneration of basal keratinocytes, and lichenoid dermal infiltrate with melanophages. elastic fibers were diminished in upper dermis and the final diagnosis of aalp was reached (figure 3). laboratory examination showed negative results for both hepatitis b and c infection. after 1 month of application of high-potency topical steroids, brownish pigmentation and scarring persisted. conclusions in this variant of lp, characteristic dermoscopic criteria such as wickham striae and vascular pattern were absent. of substantial help was the discovery of a pigmented pattern due to pigment incontinence through which differential diagnoses such as morphea or granuloma annulare could be excluded.  2 letter | dermatol pract concept. 2021;11(4):e2021123 figure 1. (a) clinical presentation of both lesions on the trunk, presenting as annular red to livid lesions. (b) clinical presentation of the first lesion, close up view. (c) close up view of the second lesion on the trunk. figure 2. (a) dermoscopy of the first lesion, presenting with diffuse fine peppering or perifollicular pigmentation. lesion seems pigmented, with reddish and brownish background. pigmented pattern corresponds with pigment incontinence. (b) dermoscopy of the second lesion, which clinically presented as more livid, brownish lesion. peppering is more pronounced and background appears more gray, yellowish, and pink. lesion is not sharply delineated at the periphery. letter | dermatol pract concept. 2021;11(4):e2021123 3 references 1. güngör ş, topal io, göncü ek. dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. dermatol pract concept. 2015;5(2):45-53. doi:10.5826/dpc.0502a06. pmid: 26114051. pmcid: pmc4462898 figure 3. (a) histology of the lesion (h&e, x20). (b) histology of the lesion, details revealing hyperkeratosis, atrophy of epidermis, hydropic degeneration of basal keratinocytes and lichenoid dermal infiltrate with melanophages (h&e, x40). (c) histology, orcein stain, showing reduced elastic fibers, finding consistent with aalp. 2. jose s, kurien g. diagnostic dermoscopic features and the correlation between dermoscopic and histopathologic features in lichen planus. international journal of research in dermatology. 2020;6(5):637. doi:10.18203/issn.2455-4529.intjresdermatol20203747 dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(2):e2022068 1 an intention-to-treat-analysis of the efficacy of immunotherapy using mycobacterium w vaccine and purified protein derivative of tuberculin for warts with assessment of improvement in quality of life alpana mohta1, manoj kumar sharma2, pramila kumari3, bhikam chand ghiya1, rajesh dutt mehta1 1 department of dermatology, venereology and leprosy, sardar patel medical college, bikaner, rajasthan, india 2 department of dermatology, venereology and leprosy, jhalawar medical college, jhalawar, rajasthan, india 3 department of dermatology, venereology and leprosy, era’s medical college, lucknow, uttar pradesh, india key words: warts, hpv, ppd tuberculin, immuvac vaccine, mw vaccine, intralesional immunogens. citation: mohta a, sharma mk, kumari p, ghiya bc, mehta rd. an intention-to-treat-analysis of the efficacy of immunotherapy using mycobacterium w vaccine and purified protein derivative of tuberculin for warts with assessment of improvement in quality of life. dermatol pract concept. 2022;12(2):e2022068. doi: https://doi.org/10.5826/dpc.1202a68 accepted: september 29, 2021; published: april 2022 copyright: ©2022 mohta et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: alpana mohta, mbbs, md, senior resident, department of dermatology, venereology and leprosy, sardar patel medical college, bikaner, rajasthan. email: dralpanamohta10@gmail.com introduction: lately, immunotherapy has evolved as a safe and reliable management option for treatment of warts. various immunogens among others in use include vaccines and antigens like purified protein derivative of tuberculin (ppd) and mycobacterium w (mw) or mycobacterium indicum prani vaccines. objectives: the study was aimed to assess the effectiveness and safety profile of intralesional mw vaccine against intralesional ppd for the management of multiple warts with assessment of the improvement in quality of life (qol) using the dermatology life quality index questionnaire. methods: patients aged above 12 years with ≥2 warts were recruited for the study. these individuals were randomized into groups a and b, namely mw vaccine (group a) and ppd tuberculin (group b). at each visit, 0.1-0.2 ml of active antigen was infiltrated intralesionally into the largest/mother wart. the injections were repeated after every 4 weeks, for the next 12 weeks. qol improvement was measured. results: this intention to treat analysis was completed by 102 patients, of which 55 were in group a and 47 in group b. the rate of complete clearance was comparable in group a (76.3%) with the one in group b (65.9%, p = 0.064). prior to treatment initiation, the most severely impacted domain of life abstract 2 original article | dermatol pract concept. 2022;12(2):e2022068 by asking them to choose a number from a simple random number table. however, since this study was done in an open-label setting, both the patients and the investigators were aware of the treatment being received. the study was approved by our institutional ethical board (ethical approval number: f/spmc/ierb/2158). additionally, all the study participants gave their written informed consent to be recruited in the study. inclusion criteria individuals aged 12 years or above with 2 or more warts were included in our study. only patients with either previously untreated warts, or those who had not received treatment in the last 1 month were included. exclusion criteria immunocompromised and systemically ill patients, pregnant or lactating women, and subjects with a history of any allergy or hypersensitivity reaction to any of the components of bcg, ppd or mw in the past were excluded from the trial. treatment protocol the study participants were administered either of the 2 regimens depending upon their group. additionally, the patients were advised against taking other alternative treatments during the study period until the end of the last follow-up visit. individuals in group a were given with 0.1-0.2 ml of intralesional mw vaccine (immuvac 0.6 ml inj., cadila pharmaceuticals limited) using a 26 g needle into the base of the largest wart. correspondingly, in group b, 0.1-0.2 ml ppd tuberculin (tubersol® s1ml inj. sanofi, containing five (5) tuberculin units per test dose of 0.1 ml) was injected into the largest mother wart. the therapy was repeated every four weeks either until there was complete clearance in all the warts, or until 12 weeks (total 4 sessions), whichever happened first. follow-up and treatment response after the last session (at week 12), monthly follow-up was done for the next 3 months. the treatment response was labeled as follows: complete clearance (cc) with 100% clearance of all the warty tissue and reappearance of normal skin markings, moderate clearance (mc) with 99%-25% reduction in size or number of warts, and no clearance (nc), introduction warts or verruca are benign tumors cause by the infection of keratinocytes with the human papilloma virus (hpv) [1]. the prevalence rates of warts range from 3%-20%, with a gradual increase in incidence rate from childhood to adolescence, followed by a rapid decline after the late 20s [2]. even though in most of the cases these warts resolve on their own, the patients often resort to various treatment options due to their unsightly appearance, symptomatology and potentially contagious nature. traditionally, used destructive therapies for warts include surgical excision, cryotherapy, radiofrequency ablation, electrical and chemical cauterization, etc. bleomycin, salicylic acid, trichloroacetic acid, podophyllin, 5-fluorouracil, imiquimod, are a few of the conventional pharmacological agents in use. over the last few decades, even lasers and photodynamic therapy have been employed to treat warts. nevertheless, the usefulness of all these therapies is limited due to their absence of antiviral properties, high recurrence rates, and the need to treat ever wart individually [2]. various intralesional antigens that have been utilized for warts, namely, bacillus calmette and guerin (bcg) vaccine, measles, mumps, and rubella (mmr) vaccine, mycobacterium w (mw) vaccine, skin test antigens like purified protein derivative of tuberculin (ppd), mumps, trichophyton, and candida with good success rates [3,4]. objectives this prospective, randomized open label study was aimed to assess the effectiveness and safety profile of intralesional mw vaccine against intralesional ppd for the management of multiple warts and improvement in patients’ quality of life (qol). methods study design and randomization this was a prospective, parallel-group study conducted at the dermatology out-patient department of our tertiary care hospital. patients with 2 or more extragenital warts were evaluated and recruited for our study into two arms, namely group a (mw vaccine) and group b (ppd tuberculin). demographic data and baseline parameters including number and site of warts were noted. the patients were randomized by warts was ‘symptoms and feelings’. there was a statistically significant improvement in qol at the end of the treatment ( p <0.01). conclusion: mw vaccine holds leverage over ppd with a marginally higher rate of clearance and less adverse events for managing warts. original article | dermatol pract concept. 2022;12(2):e2022068 3 a little 1; a lot 2; very much 3. total score interpretation was done as follows: 0-1 = no effect at all on patient’s life, 2-5 = small effect, 6-10 = moderate effect, 11-20 = very large effect, and 21-30 = exceedingly large effect. the dlqi questionnaire was supplied to all the participants at week 0 and week 24 and the improvement in qol was noted by comparing the scores. these questions (q) were further divided into 6 domains in accordance with the framework of salah, ie symptoms and feelings accompanying the disease (q1-q2), impairment of daily activities (q3-q4), effects on leisure time (q5-q6), effect on work/school (q7), interpersonal relations (q8-q9), and impact of treatment on qol (q10) [5].  statistical tools statistical analysis was done using the statistical package for the social sciences version 20. paired and unpaired t-tests, chi-square test and z scores were calculate wherever necessary. categorical and continuous variables were presented as absolute numbers, percentages, mean, and standard deviation (sd). a p value of ≤0.05 was considered to be statistically significant. results this intention to treat analysis included 120 subjects randomized into 2 groups with 60 patients per group. the demographic and clinical data of both groups were comparable. while 45 patients were treatment naïve, 75 had received 1 or more treatments in the past with treatment failure or relapse. the mean duration of warts in both groups was comparable (table 1). the study was completed by 102  patients (55 in group a and 47 in group b) (figure 1). the overall number with < 25% reduction in size/number. immediate or delayed adverse events were also noted at each visit. an additionally supplementary assessment to note any signs of recurrence and delayed response was also done at 6 months after the last dose. the primary endpoint was cc of all warts at week 8 and week 12, which also included the warts that might have developed appeared or developed recurrence during the treatment period. secondary endpoints included cc at week 24, recurrence of warts at week 12 in the patients who had clearance at week 4, and recurrence of warts at week 24 in the patients who had clearance at week 12, and the side effect profile. the analysis of both primary and secondary endpoints was done according to an intention-to-treat (itt) model. randomized patients who had received at least one treatment session and returned back for at last 1 follow-up visit were included. in cases any therapy-session/follow-up visit was missed, the analysis took the status of the last-observation-carried-forward (locf) in order to estimate any subsequent observation points. this itt model presumed that if a patient with warts cc was lost to follow-up, then he did not develop any new warts or experience any recurrence. similarly, those patients who had partial or no clearance at the last visit, did not experience clearance in warts once lost to follow-up. dermatology life quality index (dlqi) questionnaire along with the clinical response, the treatment outcome was also measured by comparing the change in the score of the hindi validated version of the dlqi questionnaire at first session (week 0), and at the end of the last follow-up visit (week 24). the questionnaire had 10 questions, each having a maximum score of 3 (total score 30). every question had the following possible scores: not at all or not relevant or unanswered0; table 1. baseline demographic data of patients group a (mw vaccine) n=55 group b (ppd tuberculin) n=47 p value age distribution in years range 12-55 yrs 12-60 yrs 0.09 mean ± sd 23.5 ± 8.4 yrs 26.9 ± 11.7 yrs gender distribution male 38 33 0.91 female 17 14 male:female 2.2:1 2.3:1 duration of warts (in months) mean ± sd 7.12 ± 4.01 8.71 ± 5.13 0.08 mean number of warts ± sd 12.01 ± 6.19 10.77 ± 7.32 0.35 inference: both the groups had comparable for baseline demographics ppd = purified protein derivative of tuberculin ; mw = mycobacterium w vaccine; sd = standard deviation 4 original article | dermatol pract concept. 2022;12(2):e2022068 assessment for eligibility (n=120) treatment naϊve (n=45) previously treated (n=75) 1. refused to participate (n=11) excluded from analysis (n=18) attrition after 2nd dose (n=7) attrition after 2nd dose (n=8) mw vaccine (n=55) group a group b analysed (n=102) ppd tuberculin (n=47) attrition after 3rd dose (n=9) attrition after 3rd (n=6) 2. drop outs after 1st dose (n=7) figure 1. patient selection, follow-up and attrition in an intention-to-treat analysis. ppd = purified protein derivative of tuberculin ; mw = mycobacterium w vaccine figure 2. cumulative response rate between the 2 groups. 45 40 35 n u m b er o f pa tien ts cumulative rate of complete clearance 30 group a (mw vaccine) group b (ppd tuberculin) 25 20 15 10 5 0 0 0 baseline after 1st dose after 2nd dose after 3rd dose after 4th dose 8 11 24 18 36 31 42 3 of patients with cc in all warts (according to itt) was 42 and 31, in group a and b respectively during the final assessment done on at week 24 (figure 3,4,5,6) (table 2). between the 2 groups, the difference in the clearance rate of all warts at week at 1st, 2nd, 3rd and 4th dose was not statistically significant (figure 2). similarly, while comparing the response in only injected warts, the rate of cc was 85.45% (n = 47) and 76.59% ( n = 36), respectively. the mean number of injections required for cc in group a were 2.38, while in group b this value was 2.56. none of the patients experienced recurrence during the ensuing follow-up period. during the analysis of the impact of other factors on treatment response, we discovered that the mean number of warts had a significant influence on the rate of clearance (p <0.01). patients with cc from both groups combined had 9.13 mean number of warts. meanwhile, those with moderate to no clearance (mc and nc) had 17.26 warts. there was also a significant difference in the mean duration of warts between patients who responded and those who didn’t respond to the therapy. the combined mean duration of warts in patients from both groups with cc was 7.21 months, and that of patients with mc/nc was 9.47 months (p = 0.02). assessment of secondary outcomes revealed a comparable adverse reactions profile in both groups. the side effect event profile of our patients was excellent with transient injection site pain and erythema being the most common adverse events. other rare side effects included transient fever, injection site nodule formation and transient urticaria. while analyzing the dlqi questionnaire, the most severely affected domains were symptoms and feelings accompanying the disease (q1 and q2), and the inconvenience experienced by patients while seeking treatment (q10). the original article | dermatol pract concept. 2022;12(2):e2022068 5 figure 3. (a) multiple interdigital warts at baseline. (b) complete resolution after 4 doses of mw vaccine. figure 4. (a) multiple myrmecia wart at baseline. (b) complete resolution after 4 doses of mw vaccine. figure 5. (a) multiple interdigital warts at baseline (b) complete resolution after 2 doses of ppd tuberculin. 6 original article | dermatol pract concept. 2022;12(2):e2022068 figure 6. (a) plantar warts at baseline. (b) complete resolution after 4 doses of ppd tuberculin mean dlqi score of patients in group a and b at week 0 was 8.03 ± 1.03 sd and 7.96 ± 1.53 sd, respectively, which improved to 2.14 ± 0.77 sd and 2.71 ± 1.02 sd at week 24, respectively (p <0.01). discussion the mw vaccine is based on a cultivable non-pathogenic mycobacterium known as the mycobacterium inducus pranii, which was developed at the all india institute of medical sciences in the 1970s. after more than 36 years of being tested rigorously, the vaccine was approved for the prevention of leprosy in 2019 [6]. ppd, on the other hand, is a skin antigen used for determining an immune response to tuberculosis [7]. these immunotherapeutic agents work on the principle of eliciting a th1 mediated immune response with the production of high levels of of il-2, il-5, and ifn-γ. the role of mw for management of warts was noted for the first time by gupta et al in genital warts with an impressive success rate of 89% [8]. later meena et al observed its favorable response in multiple cutaneous warts with 83% cc rates [9]. various authors in the past have reported the effectiveness of mw in warts to range from 55% to 93% [10-12]. while ppd was first used by kus et al for management of warts with a success rate of only 29% [13]. other studies have demonstrated 46% to 96% clearance rate [14-16]. we found minimal recurrence rate in our study during the ensuing 6 months follow-up period. the rate of reduction in warts was also significant and statistically comparable between the 2 groups, however, there was a higher clearance rate in patients treated with mw vaccine. the side effect profile was also better with mw. serious side effects like injection site granuloma, atypical mycobacterial infection and generalized urticarial rash were seen only in ppd group. also, the mw group responded faster to the given treatment than ppd group. interestingly, there was only a marginal difference in the response rate between injected and distant warts, reinforcing our hypothesis that both mw vaccine and ppd tuberculin could be effective even if injected intramuscularly. one thought-provoking observation in our study was the delayed and sustained response in warts. at least 3 patients in group a and 4 in group b who only had partial clearance after the last injection, developed cc in all their warts at the end of the follow up period. it can, therefore, table 2. rate of clinical response in an intention to treat analysis clearance rate in warts group a (mw) n=55 group b (ppd) n=47 x2 value p value complete clearance 42 (76.3%) 31 (65.9%) 5.47 0.064partial clearance 9 (16.4%) 5 (10.6%) minimal / no clearance 4 (7.3%) 11 (23.4%) ppd = purified protein derivative of tuberculin; mw = mycobacterium w vaccine original article | dermatol pract concept. 2022;12(2):e2022068 7 comparative study. j cutan med surg. 2016;20(2):123-129. doi: 10.1177/1203475415616962. pmid: 26553733. 5. salah e. impact of multiple extragenital warts on quality of life in immune-competent egyptian adults: a comparative cross-sectional study. clin cosmet investig dermatol. 2018;11:289-295. doi: 10.2147/ccid.s165908. pmid: 29928139. pmcid: pmc6001836. 6. talwar gp, gupta jc, mustafa as, et al. development of a potent invigorator of immune responses endowed with both preventive and therapeutic properties. biologics. 2017;11:5563. doi: 10.2147/btt.s128308. pmid: 28496303. pmcid: pmc5422320. 7. amirnia m, khodaeiani e, fouladi df, masoudnia s. intralesional immunotherapy with tuberculin purified protein derivative (ppd) in recalcitrant wart: a randomized, placebo-controlled, double-blind clinical trial including an extra group of candidates for cryotherapy. j dermatolog treat. 2016;27(2):173-178. doi: 10.3109/09546634.2015.1078871. pmid: 26295565. 8. gupta s, malhotra ak, verma kk, sharma vk. intralesional immunotherapy with killed mycobacterium w vaccine for the treatment of ano-genital warts: an open label pilot study.  j eur acad dermatol venereol. 2008;22(9):1089-1093.  doi: 10.1111/j.1468-3083.2008.02719.x. pmid: 18484970. 9. meena jk, malhotra ak, mathur dk, mathur dc. intralesional immunotherapy with mycobacterium w vaccine in patients with multiple cutaneous warts: uncontrolled open study. jama dermatol. 2013;149(2):237-239. doi: 10.1001/jamadermatol.2013.866. pmid: 23426493. 10. chandra s, sil a, datta a, pal s, das nk. a double-blind, randomized controlled trial to compare the effectiveness and safety of purified protein derivative of tuberculin antigen with mycobacterium w vaccine in the treatment of multiple viral warts. indian j dermatol venereol leprol. 2019;85:355-66. doi: 10.4103/ijdvl.ijdvl_549_18. pmid: 31172979. 11. singh s, chouhan k, gupta s. intralesional immunotherapy with killed mycobacterium indicus pranii vaccine for the treatment of extensive cutaneous warts. indian j dermatol venereol leprol. 2014;80(6):509-514. doi: 10.4103/0378-6323.144145. pmid: 25382507. 12. garg s, baveja s. intralesional immunotherapy for difficult to treat warts with mycobacterium w vaccine. j cutan aesthet surg. 2014;7(4):203-208. doi: 10.4103/0974-2077.150740. pmid: 25722598. pmcid: pmc4338463. 13. kus s, ergun t, gun d, akin o. intralesional tuberculin for treatment of refractory warts. j eur acad dermatol venereol. 2005;19:515-516. doi: 10.1111/j.1468-3083.2004.01176.x. pmid: 15987315. 14. nimbalkar a, pande s, sharma r, borkar m. tuberculin purified protein derivative immunotherapy in the treatment of viral warts. indian j drugs dermatol. 2016;2:19-23. doi: 10.4103/2455-3972.184103 15. saoji v, lade nr, gadegone r, bhat a. immunotherapy using purified protein derivative in the treatment of warts: an open uncontrolled trial. indian j dermatol venereol leprol. 2016;82:4246. doi: 10.4103/0378-6323.171650. pmid: 26728809. 16. wananukul s, chatproedprai s, kittiratsacha p. intralesional immunotherapy using tuberculin ppd in the treatment of palmoplantar and periungual warts. asian biomed. 2009;3:739–743. doi: 10.5372/abm.v3i6.279. be concluded that in some cases both immunogens might impart a slowly developing but long-term immunity. so, the dermatologists must counsel their patients that they must wait for at least 3 months to let the immunotherapy work. it was our observation that there was a dramatic improvement in patients’ qol following the completion of treatment. fifty-three (96.3%) subjects in group a and 44 (93.6%) in group b were satisfied with their treatment. the most significant improvement was seen in the domain of ‘symptoms and feelings’. a majority of patients also reported a noteworthy improvement in their interpersonal relationships. limitations of our study included a short follow-up period, small sample size, no analysis of genital warts, absence of a control group, and no analysis of immunological parameters. another major limitation included the fact that we couldn’t perform any hpv tests, and therefore, we couldn’t evaluate the response according to hpv subtypes. the extrapolated results of the patients lost at follow-up in our itt model also posed a significant limitation. conclusion we found ppd and mw to be effective in the management of extragenital warts. both immunogens have a good safety profile and lead to a significant improvement in patients’ qol. informed consent: the authors certify that they have obtained all appropriate patient consent forms. in the form the patient(s) has/have given his/her/their consent for his/ her/their images and other clinical information to be reported in the journal. the patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. references 1. forman d, de martel c, lacey cj, et al. global burden of human papillomavirus and related diseases. vaccine. 2012;30 suppl 5:f12-f23. doi: 10.1016/j.vaccine.2012.07.055. pmid: 23199955. 2. sterling jc, handfield-jones s, hudson pm; british association of dermatologists. guidelines for the management of cutaneous warts. br j dermatol. 2001;144(1):4-11. doi: 10.1046/j.13652133.2001.04066.x. pmid: 11167676. 3. salman s, ahmed ms, ibrahim am, et al. intralesional immunotherapy for the treatment of warts: a network meta-analysis. j am acad dermatol. 2019;80 (4):922-930.e4. doi: 10.1016/j. jaad.2018.07.003. pmid: 30003983. 4. dhakar ak, dogra s, vinay k, sarangal r, kanwar aj, singh mp. intralesional mycobacterium w vaccine versus cryotherapy in treatment of refractory extragenital warts: a randomized, open-label, dermatology: practical and conceptual original article | dermatol pract concept. 2022;12(3):e2022126 1 dermatology practical & conceptual comparison of convolutional neural network architectures for robustness against common artefacts in dermatoscopic images florian katsch1, christoph rinner1, philipp tschandl2 1 center for medical statistics, informatics and intelligent systems, medical university of vienna, vienna, austria 2 department of dermatology, medical university of vienna, vienna, austria key words: image classification, object detection, instance segmentation, artefacts, dermatoscopy, citation: katsch f, rinner c, tschandl p. comparison of convolutional neural network architectures for robustness against common artefacts in dermatoscopic images. dermatol pract concept. 2022;12(3):e2022126. doi: https://doi.org/10.5826/dpc.1203a126 accepted: december 7, 2021; published: july 2022 copyright: ©2022 katsch et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: pt reports consulting fees from silverchair, honoraria from fotofinder, novartis and lilly, and grants from metaoptima technology and lilly, outside the submitted work. all other authors declare no conflict of interest. authorship: all authors have contributed significantly to this publication. corresponding author: philipp tschandl, phd, department of dermatology, medical university of vienna, währinger gürtel 18-20, 1090 vienna, austria, e-mail: philipp.tschandl@meduniwien.ac.at introduction: classification of dermatoscopic images via neural networks shows comparable performance to clinicians in experimental conditions but can be affected by artefacts like skin markings or rulers. it is unknown whether specialized neural networks are more robust to artefacts. objectives: analyze robustness of 3 neural network architectures, namely resnet-34, faster r-cnn and mask r-cnn. methods: we identified common artefacts in the ham10000, ph2 and the 7-point criteria evaluation datasets, and established a template-based method to superimpose artefacts on dermatoscopic images. the ham10000-dataset with and without superimposed artefacts was used to train the networks, followed by analyzing their robustness against artefacts in test images. performance was assessed via area under the precision recall curve and classification results. results: resnet-34 and faster r-cnn models trained on regular images perform worse than mask r-cnn on images with superimposed artefacts. artefacts added to all tested images led to a decrease in area under the precision-recall curve values of 0.030 for resnet-34 and 0.045 for faster r-cnn in comparison to only 0.011 for mask r-cnn. however, changes in model performance only became significant with 40% or more of the images having superimposed artefacts. a loss in performance occurred when the training was biased by selectively superimposing artefacts on images belonging to a certain class. conclusions: as mask r-cnn showed the least decrease in performance when confronted with artefacts, instance segmentation architectures may be helpful to counter the effects of artefacts, warranting further research on related architectures. our artefact insertion mechanism could be useful for future research. abstract 2 original article | dermatol pract concept. 2022;12(3):e2022126 introduction epidemiological studies show an increasing trend in the incidence rates of melanoma and non-melanoma skin cancer worldwide over the last 30 years [1]. according to the american joint committee on cancer melanoma staging system, stage i malignant skin alterations with a five-year survival rate of more than 90% contrasts with a survival rate of less than 15% for stage iv patients. this indicates a clear need for early, reliable and consistent diagnosis and treatment [2]. the desire for automatic lesion analysis is further intensified by a high dependency between the diagnostic quality and the examiners experience in dermoscopy, as well as a high degree of interand intra-variability of diagnoses [3,4]. methods of automatic skin lesion analysis have been the focus of research for decades, and have gained interest in recent years [5,6]. these methods are intended to support tele-dermatologic settings, improve management decisions or aid in difficult clinical scenarios, but often suffer, among other things, from the presence of artefacts in dermatoscopic images [7-12]. a common neural network used for classification is resnet, two well-known neural network architectures in computer vision are faster r-cnn and mask r-cnn (figure 1) [13,14]. the first is performing “object detection”, a process where one or multiple objects in an image can be detected and located with a rectangular “bounding box”. the latter is performing “instance segmentation” where one or more objects in an image can be found and their respective area (i.e. pixels) in the image outlined (“segmented”), and can be regarded as a cnn-based multi-instance generalisation of computer-vision based techniques of lesion segmentation [15,16]. object detection has been used in the field of automated skin cancer detection on clinical images [17], but training of instance segmentation neural networks in dermatoscopy has not yet been reported on successfully, most probably because of missing ground-truth data. objectives our hypothesis is that in contrast to resnet, the other network architectures intrinsically have to “concentrate” on regions of the classified object in an image and hence may offer robustness against artefacts surrounding the lesions. robustness in this case describes the consistency of the obtained diagnoses under the influence of artefacts in the input image data. these networks could potentially be used as off-theshelf methods with little customization-effort needed and could enable us to focus less on tedious image pre-processing such as removal of bubbles or hairs [18]. methods image datasets the primary source of dermatoscopic images was the ham10000 dataset [19]. this dataset also includes publicly available lesion segmentation masks for every image, as described previously, which are necessary for training the faster r-cnn and mask r-cnn architectures [8]. it contains 10,015 images, each with 600x450 pixels and 3-8 bit color channels. each image is assigned one of seven diagnostic classes: actinic keratosis / intraepithelial carcinoma classi�cation object detection instance segmentation mask r-cnnfaster r-cnnresnet-34 nevus nevus nevus o u tp u t a r c h it ec tu r e in p u t a p p r o a c h figure 1. a visual representation of the outputs of the three approaches. image classification (ie resnet-34) classifies the image as a whole, object detection (ie faster r-cnn) finds objects and their approximate position in the image and instance segmentation (ie mask r-cnn) finds objects and their exact spatial delimitation. original article | dermatol pract concept. 2022;12(3):e2022126 3 (akiec), basal cell carcinoma (bcc), benign keratotic lesion (bkl), dermatofibroma (df), nevus (nv), melanoma (mel), or vascular lesion (vasc). also, the ph2 and the 7-point criteria evaluation dataset were reviewed and several images were utilized to extract artefacts from [20,21]. images from those datasets were not used for other purposes within this study. we used the isic2018 test-set as the test-set to keep variation as low as possible, as it sources from the same origin as the ham10000 dataset and includes the same classes. artefact generation as with every real-world picture, dermatoscopic images can contain content considered as “artefacts”. examples are hairs, dark corners, vignettes, medical devices, different sorts of rulers, ink markings in different shapes, styles and colors, air bubbles or reflections. this work focuses on three of them: “bubbles” that originate from trapped air in the liquid between skin and the dermatoscope, “rulers” used to show the spatial dimension of a lesion, and ink “markings” on the patient’s skin used to highlight the lesion for excision or review. in order to generate artefact-modified cases, we selected 60 images from the ham10000, ph2 and 7-point criteria dataset which contain either a bubble, a ruler or a marking artefact. from those images we extracted the artefacts by manually repairing the images areas with adobe® photoshop’s® (version cc 2018 (19.1.9), adobe inc.) content aware image repair mechanism and using the difference, per rgb channel, to the untouched image as a template (figure 2). the insertion of those templates was done in a way that the position of artefacts varies according to observed patterns, using the provided segmentation mask of the target image. in figure 3, a dermatoscopic image with automatically superimposed artefacts is shown. the source code will be made available upon publication of this work at https://github.com/thisismexp/artefact_insertion. using the artefact insertion mechanism, several dataset mutations of the original ham10000 dataset were created, where artefacts were superimposed on either none or all of the images and on every image belonging to a certain diagnosis. the test portion of the ham10000 dataset, corresponding to the isic2018 challenge task 3 test-set with 1,511 images, was altered in the same way. additionally, artefacts were inserted in a certain percentage of images in 20% step increments. neural network training as representatives for image classification, object detection and instance segmentation we trained a resnet-34, a faster input: original image output: artefact template 1.) content-aware image repair 3.) rgb channel-wise di�erence 2.) extraction of repaired regions figure 2. workflow for extracting artefact templates. manually selected original images (input) were repaired manually (1), and corresponding image areas extracted (2). the channel-wise difference (3) was stored as a template for the corresponding artefact type. 4 original article | dermatol pract concept. 2022;12(3):e2022126 r-cnn (with resnet-34 backbone) and a mask r-cnn (also with a resnet-34 backbone) model as provided by the torchvision package of the open source machine learning framework pytorch [22]. all models were trained on all of the 9 generated datasets in a 5-fold cross validation fashion. transfer-learning and data augmentation including random crops, resize, rotations, mirroring operations as well as color jitter operations were used. statistics to evaluate diagnostic accuracy, all trained network models are tested against the 13 test datasets and performance was reported in terms of area under the precision recall curve (pr-auc), precision, recall, false positive (fpr) and false negative rates (fnr) and differences thereof (calculated using scikit-learn version 0.24.1) [23]. to visualize spatial activations, gradient based class activation map (grad-cam) visualizations were used. a two-sided p-value of 0.05 was regarded as statistically significant, and all calculations were performed using statsmodels version 0.12.2 [24]. results baseline performance in terms of pr-auc of our models trained and tested with no additional artefacts was 0.8 for resnet-34 and 0.72 for faster r-cnn as well as mask r-cnn. introduction of artefacts in only the test dataset led to a reduction in performance for all three architectures (figure 4) increasing with the proportion of artefacts present in the test dataset, and more severe for the resnet-34 and faster r-cnn model. with a maximum relative reduction of 0.05 pr-auc the faster r-cnn model was affected the most, resnet-34 (-0.03) the second most, and mask r-cnn was the most robust (-0.01). for resnet-34 and faster r-cnn, changes in predictive performance compared to baseline was significant at and above 40% of introduced artefacts in the test set (p < 0.01; tested using mcnemar test with edwards correction on binarized predictions). for mask r-cnn we did not detect a significant difference in predictions in all used test sets (all p values > 0.17). introducing artefacts in the training data led to biased results in all three examined architectures. artefacts introduced figure 3. example of automatically superimposed artefacts on a dermatoscopic image. (a) in the top left the original image without artefact is shown. the other 3 images show the lesion with the superimposed artefacts bubbles (b), ink markings (c) and a ruler (d). original article | dermatol pract concept. 2022;12(3):e2022126 5 into all images of the melanocytic nevi class during training decreased recall values on average by 0.218 for resnet-34, 0.129 for faster r-cnn and by 0.155 for mask r-cnn in comparison to the respective unbiased models. reduction in recall values indicate that those are indeed biased by artefacts for specific classes. this effect was more apparent the bigger the proportion of biased samples in the dataset is. considering the fpr and fnr for specific classes, a selective bias towards classes that were corrupted by artefacts during training could be observed for all three architectures. the increase in fpr for the class with inserted artefacts during training, and a simultaneous increase in fnr for all others, in fact showed a shift in classifications towards the biased class. this effect could not be observed if artefacts were inserted into none or all of the images. when inspecting heat map representations of the gradcam we observed that training with artefacts shifted the attention of the object detection and instance segmentation network away from the artefact itself towards areas of the lesion trained without inserted artefacts trained with inserted artefacts input a b c d hgfe lkji resnet-34 faster r-cnn mask r-cnn input resnet-34 faster r-cnn mask r-cnn o pnm figure 5. grad-cam for used network architectures. the first column shows the input image for the corresponding row, in its original form (top) and with bubble artefacts inserted (bottom). grad-cam heatmaps show the resnet-34 increases attention towards the bubble-area after training with artefacts (n), where the faster r-cnn network loses its initial attention towards the artefact (g) afterwards (o). the mask r-cnn architecture seems to ignore the artefact throughout (h and p). black boxes denote positions of inserted bubble artefacts. 0.00 –0.02 –0.04 mask r-cnn resnet-34 faster r-cnn 0.0 0.2 0.4 0.6 0.8 1.0 proportion of artefacts in the test set c h an g e in p r a u c –0.06 figure 4. neural networks show different robustness to inserted artefacts on the test set. precision recall curve (pr-auc) as achieved by training without additional artefacts in the train and test set was used as the baseline (0%). with increasing proportion of inserted artefacts, pr-auc decreases for resnet-34 (blue) and faster r-cnn (green), but almost not for mask r-cnn (purple). shaded areas denote 95%-confidence intervals. (figure 5). these mappings indicate an increase in robustness against these very artefacts for faster and mask r-cnn models, if trained with inserted artefacts in the dataset. 6 original article | dermatol pract concept. 2022;12(3):e2022126 conclusions we compared representatives of three neural network architectures to classify lesions in dermatoscopic images in regard to their robustness against artefacts. although as a limitation the baseline performance of the examined models were not the same, we found differences in their vulnerability to performance changes under the influence of artefacts. mask r-cnn tends to be the most robust. the influence on classification results by artefacts in test images can be reduced by augmenting training data with artificially superimposed artefacts for all three architectures. this is in line with findings by maron et al, who reduced but not eliminated brittleness of their system through data augmentation [25]. we anticipate that automated superimposition of artefacts as presented here as a further evolution of data augmentation, that together with integrating more diverse variants, will enhance robustness of automated classifiers and decision support systems further [26,27]. the initial data, in our view, warrants more in-depth follow up research on this topic, to understand which approaches are the most effective and efficient. however, this work failed to find evidence for a clinically relevant robustness against artefacts of instance segmentation for several reasons. on the one hand we used a shallow backbone network architecture for our experiments, even though current research and commercial products commonly use deeper models, and an increase in robustness against image distortions has been demonstrated by others with increased backbone capacity [28]. we also used a new template-based approach to superimpose artefacts on images. this approach leaves room for improvement with regard to the number of images the artefacts are extracted from, and a detailed analysis on how different artefact types affect the classification performance. alternatively, lesions with existing artefacts could be used after manual or automated annotations. references 1. apalla z, lallas a, sotiriou e, lazaridou e, ioannides d. epidemiological trends in skin cancer. dermatol pract concept. 2017;7(2):1-6. doi: 10.5826/dpc.0702a01. pmid: 28515985. pmcid: pmc5424654. 2. balch cm, soong s-j, atkins mb, et al. an evidence-based staging system for cutaneous melanoma. ca cancer j clin. 2004;54(3):131-149; 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2010:61. available from: https:// conference.scipy.org/proceedings/scipy2010/pdfs/seabold.pdf 25. maron rc, haggenmüller s, von kalle c, et al. robustness of convolutional neural networks in recognition of pigmented skin lesions. eur j cancer. 2021;145:81-91. doi: 10.1016/j. ejca.2020.11.020. pmid: 33423009. 26. aggarwal slp. data augmentation in dermatology image recognition using machine learning. skin res technol. 2019;25(6):815820. doi: 10.1111/srt.12726. pmid: 31140653. 27. winkler jk, sies k, fink c, et al. association between different scale bars in dermoscopic images and diagnostic performance of a market-approved deep learning convolutional neural network for melanoma recognition. eur j cancer. 2021;145:146-154. doi: 10.1016/j.ejca.2020.12.010. pmid: 33465706. 28. michaelis c, mitzkus b, geirhos r, et al. benchmarking robustness in object detection: autonomous driving when winter is coming. arxiv [cscv]. published online july 17, 2019. available from: http://arxiv.org/abs/1907.07484 dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):11 47 dermatology practical & conceptual www.derm101.com case report a 77-year-old woman with a prior renal transplantation presented with a four-month history of a progressively enlarging brownish macule on her left leg (figure 1a). she was treated with mycophenolate mofetil and tacrolimus. her past medical history included several non-melanoma skin cancers. dermoscopic examination showed atypical brownish blurry streaks regularly distributed at periphery of the lesion, simulating a “starburst” pattern; adherent white scales were present but no vessels or pigmented dots were evident (figure 1b). a complete excision of the lesion was performed. histological examination revealed parakeratotic hyperkeratosis with disorganization of the epidermal architecture and increased mitotic figures; keratinocytes with giant nuclei were associated to dyskeratotic and pigmented cells. the dermis showed a lymphohistiocytic infiltrate with absence of tumor invasion (figure 2). such findings were consistent with a diagnosis of pbd. several studies/case reports have shown that pbd may present unusual/confusing dermoscopic findings [1-2], including peripheral streaks, which have been reported in four instances [1-5]. however, differently from our patient, the streak-like projections observed in the previous cases did not represent the main dermoscopic clue, as they were associpigmented bowen’s disease presenting with a “starburst” pattern vincenzo maione1, enzo errichetti3, sara laurent roussel2, celeste lebbé1 1 department of dermatology, hôpital saint-louis, université paris 7 diderot, paris, france. 2 department of pathology, hôpital saint-louis, université paris 7 diderot, paris, france 3 department of dermatology, university of udine, italy key words: dermoscopy, bowen citation: maione v, errichetti e, roussel sara l, lebbé c. pigmented bowen’s disease presenting with a “starburst” pattern. dermatol pract concept 2016;6(4):11. doi: 10.5826/dpc.0604a11 received: july 15, 2016; accepted: july 18, 2016; published: october 31, 2016 copyright: ©2016 maione et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: vincenzo maione, md, department of dermatology, hôpital saint-louis, 1 avenue claude vellefaux, 75010 paris, france. tel. +33 0142499961; fax +33 0142494620. email: maionevincenzo@gmail.com pigmented bowen’s disease (pbd) is an uncommon in situ squamous cell carcinoma of the skin usually presenting as a dark scaly plaque involving chronically exposed sites, which is not uncommonly mistaken for other similar pigmented lesions, such as melanoma, pigmented basal cell carcinoma or seborrheic keratosis [1,2]. dermoscopy has been proven to improve its diagnosis by showing several findings, i.e., gray/brownish dots in linear arrangement, scales, coiled vessels, focal/multifocal amorphous hypopigmentation and bluish structureless areas [1,2]. however, pbd may sometimes display dermoscopic features which are typical of other pigmented lesions, thus making its recognition quite troublesome despite the use of dermoscopy [1,2]. we report a case of pbd with a “starburst” pattern, discussing its dermoscopic differential diagnosis. abstract 48 observation | dermatol pract concept 2016;6(4):11 the presence of pigmented sharply focused streaks radially distributed at the periphery of a lesion, which correspond to confluent junctional melanocytic nests and histological radial growth. the detection of the “starburst” pattern in pbd might be due to the fusion of regularly distributed peripheral dots into streak-like projections, which therefore represent melanin pigment in the epidermis or horny layer [1-2]. importantly, different from the aforementioned melanocytic lesions, the brownish streaks visible in pbd are less defined and appear out of focus and are associated with other features typical of bowen’s disease [1-5], such as white scales, as seen in our patient. in conclusion, our case underlines that pbd may present with a “starburst” pattern, thereby mimicking a spitz/reed nevus or a melanoma. even though the definitive distinction from these melanocytic lesions relies on histological examination, we believe that an attentive analysis of the radial streaks and the search of other criteria of pbd could be useful for assisting the differential diagnosis. further reports and studies are obviously needed to support such assumptions. references 1. zalaudek i, argenziano g, leinweber b, et al. dermoscopy of bowen’s disease. br j dermatol 2004;150:1112-6. pmid: 15214896. doi: 10.1111/j.1365-2133.2004.05924.x. 2. cameron a, rosendahl c, tschandl p, riedl e, kittler h. dermoscopy of pigmented bowen’s disease. j am acad dermatol 2010; 62:597-604. pmid: 20079953. doi: 10.1016/j.jaad.2009.06.008. ated with other relevant findings (e.g., pigmented network, polychromatic areas, blue veil and/or brown dots in a regular arrangement), and were not regularly distributed at the periphery to configure a “starburst” appearance [1-7]. conclusions the “starburst” pattern is classically considered the dermoscopic hallmark of spitz/reed nevus. it is characterized by figure 1. (a) clinical aspect of pigmented bowen’s disease. brownish lesion of the left leg in a patient treated with immunosuppressive drugs for her renal transplantation. (b) pigmented bowen’s disease. the dermoscopic examination showed atypical “out of focus” radial streaks (black arrow) with adherent scales (white arrow). no other dermoscopic features were present. [copyright: ©2016 maione et al.] figure 2. histologic images of bowen’s disease showed parakeratosis, epidermal disorganization with individual cell dyskeratosis, increased mitotic figures and keratinocytes demonstrating greatly enlarged nuclei. (hematoxylin-eosin stain; original magnification: 20x.). [copyright: ©2016 maione et al.] observation | dermatol pract concept 2016;6(4):11 49 mented bowen’s disease. an bras dermatol 2014;89:825-7. pmid: 25184929. 6. chung e, marchetti ma, pulitzer mp, marghoob aa. streaks in pigmented squamous cell carcinoma in situ. j am acad dermatol. 2015;72(1 suppl): s64-5. pmid: 25500048. doi: 10.1016/j. jaad.2014.08.044. 7. de giorgi v1, alfaioli b, papi f, et al. dermoscopy in pigmented squamous cell carcinoma. j cutan med surg 2009;13(6):326-9. pmid: 19919812. 3. hayashi y, tanaka m, suzaki r, mori n, konohana i. dermoscopy of pigmented bowen’s disease mimicking early superficial spreading melanoma. case rep dermatol 2009; 1:11-15. pmid: 20652107. doi: 10.1159/000227284. 4. inoue t, kobayashi k, sawada m, et al. dermoscopic features of pigmented bowen’s disease in a japanese female mimicking malignant melanoma. dermatol res pract 2010; 2010:543091. pmid: 20811602. doi: 10.1155/2010/543091. 5. mota an, piñeiro-maceira j, alves mde f, tarazona mjm. pigdermatology: practical and conceptual research letter | dermatol pract concept. 2022;12(1):e2022015 1 dermoscopy of dermatomyositis in dark skin shekhar neema1, rohit kothari1, ahmed waheed kashif1, deepak vashisht1, biju vasudevan1 1 armed forces medical college, pune, india key words: dermatomyositis, dermoscopy, dermatoscopy citation: neema s, kothari r, kashif aw, vashisht d, vasudevan b. dermoscopy of dermatomyositis in dark skin. dermatol pract concept. 2022;12(1):e2022013. doi: https://doi.org/10.5826/dpc.1201a13 accepted: may 8, 2021; published: january 2022 copyright: ©2022 neema et al. this is an open-access article distributed under the terms of the creative commons attribution-noncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication. corresponding author: shekhar neema md, febdv, associate professor, armed forces medical college, pune, india. e-mail: shekharadvait@gmail.com introduction dermatomyositis is an idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous features such as heliotrope rash, gottron papule, confluent macular erythema, poikiloderma, mechanic’s hand, ragged cuticle and periungal telangiectasia [1]. the characteristic cutaneous manifestations are difficult to appreciate in individuals with darker skin types thus making the diagnosis challenging. case presentation a 59-year-old woman presented with complaints of pruritic dark lesions over her entire body and progressive muscle weakness of 2 months’ duration. examination revealed hyperpigmentation involving the face, periocular region (heliotrope rash), upper back (shawl sign), and v area of neck (v sign), hyperpigmented papules over the knuckles ( gottron papule), hyperpigmented macules on the hand (gottron sign), hyperpigmented papules over the lateral aspect of the index finger and medial aspect of thumb ( mechanic’s hand), and ragged cuticles (figure 1, a-d). dermoscopy of the peri-ocular area revealed a brown reticular pigment network, gray dots and globules and linear out-of-focus vessels (figure 1e). dermoscopy of the gottron papule shows white-to-pink structureless areas and a reticular pigment network (figure 1f). histopathology revealed atrophic epidermis, basal cell vacuolation, melanophages in the papillary dermis, and presence of focal mucin (figure 1g). creatinine phosphokinase was 573 iu/ml, antinuclear antibody was 3+ (speckled pattern). magnetic resonance imaging of the thigh showed myositis, and high-resolution computed tomography of chest were suggestive of interstitial lung disease. a diagnosis of dermatomyositis was made based on clinical, histopathological, serological, and imaging findings. the patient was treated with methylprednisolone pulse of 1 g per day for 3 days, hydroxychloroquine 200 mg once a day and a tapering dose of oral steroids. in a second case, a 45-year-old woman presented with similar complaints of photosensitivity, pruritic dark lesions over photo-exposed areas of the face, trunk, and extremities, swelling around the eyes, and proximal muscle weakness. dermatological examination showed hyperpigmented macules over the forehead and lateral sides of cheeks and 2 research letter | dermatol pract concept. 2022;12(1):e2022015 figure 1. (a) diffuse hyperpigmentation of face including peri-ocular (heliotrope rash), zygomatic, and nasolabial folds. (b) hyperpigmented plaque over upper back (shawl sign). (c) hyperpigmented papules and macules over the knuckles (gottron papule and gottron sign). (d) hyperpigmented papules over radial aspect of index finger (mechanic’s hand). (e) dermoscopy of heliotrope rash shows brown reticular network, gray dots and globules (blue arrows) and linear out-of-focus vessels (blue stars) (dermlite dl4, polarized, ×10). (f) dermoscopy of gottron papule shows white-to-pink structureless areas (blue arrows) and a reticular pigment network (blue star) (dermlite dl4, polarized, ×10). (g) histopathological examination shows an atrophic epidermis, basal cell vacuolation, melanophages, perivascular lymphocytic infiltrate and the presence of focal mucin (hematoxylin and eosin, ×200). pas stain shows the presence of mucin (inset). research letter | dermatol pract concept. 2022;12(1):e2022015 3 erythema and edema involving the malar area (figure 2, a and b). dermoscopy showed a reticular pigment network, brownto-gray dots and globules, and linear vessels (figure 2d). the imaging, biochemical investigations, histopathology, and serology was consistent with diagnosis of dermatomyositis. conclusion cutaneous features are essential and characteristic in the diagnosis of dermatomyositis. dermoscopy of gottron papule has been described as a lump of surface scales and dotted vessels [2]. individuals with darker skin present with predominant hyperpigmentation, that poses a diagnostic difficulty. pigment incontinence that is seen in histopathology is due to basal cell damage and is seen as dots and globules on dermoscopy. linear out-of-focus vessels are due to epidermal atrophy, and focal mucin deposition is seen as structureless white areas on dermoscopy. a reticular pattern on dermoscopy occurs due to melanization of the basal layer. dermoscopy may be helpful in the diagnosis of cutaneous features of dermatomyositis in darker skin. we also tried to correlate dermoscopic findings with histopathology. this is the first report on dermoscopy of dermatomyositis in darker skin to the best of our knowledge. informed consent: written informed consent for publication of her clinical details and clinical images was obtained from the patient. references 1. findlay ar, goyal na, mozaffar t. an overview of polymyositis and dermatomyositis. muscle nerve. 2015;51(5):638-656. doi:10.1002/mus.24566. pmid: 25641317. 2. namiki t, hashimoto t, hanafusa t, miura k, yokozeki h. case of dermatomyositis with gottron papules and mechanic’s hand: dermoscopic features. j dermatol. 2018;45(1):e19-e20. doi: 10.1111/1346-8138.14072. pmid: 28971518. figure 2. (a) hyperpigmented macules over the forehead and erythema and edema over the malar area. (b) hyperpigmented macules over the lateral aspect of the cheek. (c) dermoscopy shows brown reticular network (orange arrow), gray dots and globules (blue arrow), and out-of-focus linear vessels (blue star) (dermlite dl4, polarized, ×10). dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept. 2021;11(2):e2021046 1 surgery for bowen disease: clinicopathological factors associated with incomplete excision julia fougelberg1,2, hampus ek1, magdalena claeson1,2,3,4, john paoli1,2 1 department of dermatology and venereology, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gothenburg, sweden 2 region västra götaland, sahlgrenska university hospital, department of dermatology and venereology, gothenburg, sweden 3 department of population health, qimr berghofer medical research institute, brisbane, australia 4 dermatology research centre, the university of queensland diamantina institute, the university of queensland, brisbane, australia key words: bowen disease, dermatological surgery, surgical margins, nonmelanoma skin cancer citation: fougelberg j, ek h, claeson m, paoli j. surgery for bowen disease: clinicopathological factors associated with incomplete excision. dermatol pract concept. 2021;11(2):e2021046. doi: https://doi.org/10.5826/dpc.1102a46 accepted: december 4, 2020; published: april 12, 2021 copyright: ©2021 fougelberg et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: julia fougelberg, md, department of dermatology and venereology, sahlgrenska university hospital, institute of clinical sciences, sahlgrenska academy, university of gothenburg, gröna stråket 16, 413 45, gothenburg, sweden. email: julia.fougelberg@vgregion.se background: one common treatment for bowen disease (bd) is surgical excision, but there is no international consensus on the appropriate surgical margins. objectives: this study examined what factors affect the rate of incomplete excision of bd. methods: clinicopathological data potentially linked to surgical outcome (complete or incomplete excision) were retrospectively collected from medical and histopathological records on all surgically excised bd lesions diagnosed at sahlgrenska university hospital in gothenburg, sweden during 20142015. data were analyzed with two definitions of incomplete excision: less strict (ie, bd present at the surgical margin) and strict (ie, dysplasia present at the surgical margin). results: in total, 463 bd lesions among 408 patients were included. with the less strict definition, 3 factors were associated with significantly higher rates of incomplete excision: surgical margins <3 mm, a less experienced surgeon, and use of punch biopsy excision. the same factors plus a tumor location on the head and neck area or upper extremities were associated with significantly higher rates of incomplete excision using the strict definition. after adjustment for confounders, less experience was independently associated with incomplete excision using the less strict definition, whereas less experience and location on the head and neck area or upper extremities were independently associated with incomplete excision using the strict definition. surgeon specialty was not associated with incomplete excision regardless of the definition. conclusions: when removing bd surgically, an elliptical excision with surgical margins ≥3 mm carried out by an experienced surgeon should be recommended. surgical margins may need to be adjusted depending on body site. abstract 2 research | dermatol pract concept. 2021;11(2):e2021046 introduction bowen disease (bd), or squamous cell carcinoma (scc) in situ, is a lesion with keratinocytic dysplasia restricted to the epidermis. the observed number of cases of bd has increased markedly in sweden over the past few decades. in 2019, 13,782 cases of bd were reported to the swedish national board of health and welfare, as compared to 3,816 cases reported in 1999 [1]. the risk for bd to develop into invasive scc has been estimated to be 3%–5% [2,3]. treatment options for bd include photodynamic therapy, cryotherapy, curettage, 5% 5-fluorouracil cream, 5% imiquimod cream, ablative laser therapy, radiotherapy, and, of course, surgical excision [4,5]. no single treatment has been shown to be superior to any other and there is a lack of studies on treatment effects, especially regarding surgery [6,7]. along with the rapid increase of skin cancer cases comes increased health costs and morbidity for the patients [8]. one way to decrease the rising costs is to reduce the number of incomplete excisions of keratinocyte cancer. surgical excision of bd and skin cancers in general is carried out by surgeons of several specialties, including dermatologists, general practitioners (gps), plastic surgeons, general surgeons, and otorhinolaryngologists. when surgery is considered to be the best treatment alternative, we must provide the surgeon with the right conditions, such as knowledge of optimal safety margins and information about potential risk factors for incomplete excision. such factors could include lesion size, body site and excisional method [9-11]. there is no international consensus on the most appropriate surgical margins for bd. in fact, surgical margins are not mentioned in the european or swedish clinical practice guidelines [12,13]. american guidelines advise using a 4-6 mm margin for low-risk scc including bd [14], while french guidelines recommend surgical excision for bd with a “minimal margin”, but do not specify what this margin should be [5, 15]. multiple studies compared incomplete excision rates of scc in different settings, with rates ranging from 3.9% to 17.6% [15-18]. a study on wide local excisions of histopathologically proven sccs included a subgroup of 514 bd lesions with an incomplete excision rate of 5.2% [19]. however, to our knowledge, only one previous study specifically analyzed risk factors for the incomplete excision of bd [10]. this dutch study included 86 bd lesions excised with varying surgical margins, resulting in a 17.7% incomplete excision rate. the authors concluded that smaller excision margins seemed to be the most crucial risk factor. furthermore, the study showed that incomplete excision rates were lower for dermatologists than for gps and other specialists in secondary care. the aim of this study was to further evaluate the clinicopathological risk factors for incomplete excision of bd in a larger series of patients. materials and methods in this retrospective, observational study, we reviewed medical records and histopathological reports from all consecutive cases of excised and histopathologically confirmed bd lesions diagnosed at the department of pathology at sahlgrenska university hospital in gothenburg, sweden between january 1, 2014 and december 31, 2015. data collection was approved by the regional ethical review board in gothenburg. the study included only histopathologically verified cases of bd managed by excisional biopsy. no clinical follow-up of the study participants was performed. the study participants were residents of the hospital catchment area in western sweden, meaning that most would have been caucasians with fair to medium skin types, although skin type was not consistently reported in the medical records [20]. the exclusion criteria were: bd treated with other methods, misclassified lesions (eg, bd in combination with microinvasive or invasive scc, or bd found within or connected to other types of skin cancer), inadequate clinicopathological data, lack of data concerning clear margins, and bd located in the genital area or on mucous membranes. the latter type of bd is often hpv-induced and thus more difficult to treat [21] . a number of variables potentially linked to surgical outcome were obtained from medical records and histopathological reports. the clinicopathological parameters analyzed included patient age and sex, immunosuppression, tumor size and location, medical specialty and experience of the physician carrying out the surgery (specialist vs. resident), suspected diagnosis before excision, whether a preoperative biopsy was performed, the excisional biopsy method, the surgical margin (mm) as measured by the physician carrying out the excision, and whether clear margins were achieved. data regarding complete removal were only collected from existing histopathology reports; the histopathology slides were not reviewed again. when analyzing the data, we set up a number of criteria to ensure that the evaluations were made as objectively as possible. if re-excisions were carried out on the same lesion, only data from the first excision were included concerning the surgical margin and whether or not the margins were clear. if different tumor sizes were described in the medical records, the size of the tumor mentioned on the day of surgery was used. excisions were interpreted as complete even if the distance to the resection margin was very limited. since bd lesions can sometimes be isolated and are sometimes located within areas of chronically sun-damaged skin, two different definitions of an incomplete excision were applied in separate analyses. incomplete excision according to the less strict definition implied the presence of bd or severe keratinocytic dysplasia at the border, while the strict definition of an incomplete excision was the presence of any degree of keratinocytic dysplasia at the specimen border. research | dermatol pract concept. 2021;11(2):e2021046 3 statistical analyses data were analyzed using version 3.0.3 of r (the r foundation for statistical computing, vienna, austria). fisher’s exact test was used to compare proportions, wilcoxon’s rank sum test was used for two-sample tests, and the kruskal-wallis test was used to compare three or more groups. a multiple logistic regression analysis adjusted for possible confounders was performed to identify risk factors that were independently associated with incomplete excision. outcome variables according to the strict and less strict definitions of incomplete excision were set separately, adjusting the logistic regression model for all risk factors significant on univariate analysis. p values of <0.05 were considered significant. results in total, 788 cases of surgically treated bd in 708 patients were found in the pathology register during the study period. after manual review of medical records and histopathological reports, 463 lesions in 408 patients matched the study inclusion criteria. lesions were excluded due to treatment with topical drugs or other methods (n = 230), misclassification (n = 45), location on mucous membranes (n = 34), inadequate clinicopathological data (n = 10), and lack of data concerning clear margins (n = 6). slightly more than half of the patients were women (56.0%). the patients were generally elderly, with a median age of 77.6 years (range, 40–98 years). among patients with known immune status (n = 270), 14.1% were immunosuppressed, and this group mainly consisted of organ transplant recipients. the median lesion diameter was 10.0 mm (range, 1–55 mm). a preoperative biopsy was taken in 191 cases (41.3%). clinicopathological features of excised lesions that may have influenced the incomplete excision rate are analyzed in table 1. lesions were most commonly excised by dermatologists (43.6%), followed by otorhinolaryngologists (16.8%), plastic surgeons (15.1%), general surgeons (13.0%), gps (8.0%), and others (3.5%). the experience of the surgeon who performed the excision was unknown for 49 tumors, while for the remaining 414 tumors excision was done by a specialist in 87.0% or by a resident in 13.0% of the cases. the surgical margin was only reported in 215 cases (46.4%). the most common tumor location was the head and neck area (52.8%), followed by the trunk (21.6%). an elliptic excision was used to excise 417 (95.0%) of the 439 lesions with a known excisional biopsy technique. there was a significant variation in the median diameter of excised tumors between the various medical specialties (p <0.001). gps excised smaller lesions (median diameter, 6 mm), while plastic surgeons excised larger lesions (median diameter, 13 mm). the suspected diagnosis was specified in the medical records and/or histopathological reports in 416 cases (89.8%). the diagnostic accuracy was low (21.6%) when only the main diagnosis was considered and increased slightly when differential diagnoses were also included (32.2%). after bd, the most commonly suspected main diagnosis was another keratinocytic tumor: basal cell carcinoma (bcc, 31.8%), followed by scc (19.7%) and actinic keratosis (10.5%). to understand which clinicopathological factors lead to incomplete excision, these variables were assessed using two definitions of incomplete excision, as discussed below and in table 1. less strict definition of incomplete excision the less strict definition of incomplete excision produced a lower overall rate of incomplete excision (12.8%) than did the strict definition (see below). there were no significant differences in incomplete excision rates between surgeons with different specialties (p = .16), but specialists had a significantly lower incomplete excision rate than residents (10.8% vs. 25.9%, p = .004). a significant difference in incomplete excision rates was seen regarding surgical margins, with a lower rate for a surgical margin of 3–5 mm than for <3 mm (8.7% vs. 31.6%, p = .009). no significant difference in incomplete excision rates was seen between cases with and without data on surgical margins (p = 0.26). lesions on the trunk were incompletely excised in 7.0% of cases, while lesions in the head and neck area were most frequently incompletely excised (15.2%). nevertheless, there were no significant differences in these rates. the median tumor diameter was 10.0 mm for incompletely excised bd and 8.0 mm for completely excised lesions, but the difference was not significant (p = .86). there was also no significant difference in incomplete excision rates between tumors with diameter >10 mm and those with diameter ≤10 mm (p = .57). a significant difference in incomplete excision rates was again seen when comparing excisional biopsy methods. incomplete elliptic excisions were less common than incomplete punch biopsy excisions (10.0% vs. 36.0%, p = .002). a preoperative biopsy did not affect the incomplete excision rates. incomplete excision occurred in 9.9% and 14.7% of the cases with and without a preoperative biopsy, respectively (p = 0.16). according to an adjusted logistic regression analysis using the less strict definition, only a less experienced surgeon (resident vs. specialist) remained a risk factor for incomplete excision, with an odds ratio (or) of 4.30 (95% ci, 1.5411.97; p = .005). in the adjusted analysis, we included the other significant variables from our univariate analysis (surgical margins and excisional biopsy method) as confounders. 4 research | dermatol pract concept. 2021;11(2):e2021046 table 1. clinicopathological factors associated with incomplete excision for 463 bowen disease lesions clinicopathological factor tumors, n (%) incomplete excision less strict strict n (%) p n (%) p specialty .16 .21 dermatologist 202 (43.6) 24 (11.9) 44 (21.8) otorhinolaryngologist 78 (16.8) 8 (10.3) 19 (24.4) plastic surgeon 70 (15.1) 6 (8.6) 12 (17.1) general surgeon 60 (13.0) 9 (15.0) 17(28.3) general practitioner 37 (8.0) 10 (27.0) 11 (29.7) others 16 (3.5) 2 (12.5) 7 (43.7) missing 0 experience .004 .003 specialist 360 (87.0) 39 (10.8) 76 (21.1) resident 54 (13.0) 14 (25.9) 22 (40.7) missing 49 surgical margins .009 .018 <3 mm 19 (8.8) 6 (31.6) 9 (47.4) 3-5 mm 196 (91.2) 17 (8.7) 40 (20.4) missing 248 body site .22 < .001 head & neck 244 (52.8) 37 (15.2) 71 (29.1) trunk 100 (21.6) 7 (7.0) 10 (10.0) upper extremities 60 (13.0) 8 (13.3) 20 (33.3) lower extremities 58 (12.6) 7 (12.1) 9 (15.6) missing 1 tumor diameter .57 .24 ≤10 mm 229 (71.3) 26 (11.4) 47 (20.5) >10 mm 92 (28.7) 13 (14.1) 25 (27.2) missing 142 excisional biopsy method .002 .016 elliptic 417 (95.0) 43 (10.0) 89 (21.0) punch 22 (5.0) 8 (36.0) 10 (45.0) missing 24 strict definition of incomplete excision according to the strict definition of incomplete excision, 23.8% of all lesions were incompletely excised. there were no significant differences with regard to the surgeon’s specialty (p = .21) (table 1). however, physician experience had a significant effect on the incomplete excision rate, with specialists outperforming residents (21.1% vs. 40.7%, p = .003). tumors excised with surgical margins <3 mm were incompletely removed in 47.4% of the cases, as compared to 20.4% when surgical margins of 3–5 mm were applied; this was a statistically significant difference (p = .018). there was no significant difference in incomplete excision rate between cases with and without data on surgical margins (p = .66). body site also significantly affected the surgical outcome (p < .001). in individual comparisons between body sites, excisions in the head and neck area were more frequently incomplete than excisions on the trunk (p < .001) and lower extremities (p = .046). lesions on the upper extremities were also more frequently incompletely excised than lesions on the trunk (p < .001) and lower extremities (p = .032). there was no significant difference between the median tumor diameter of incompletely and completely excised bd lesions, which was 10.0 mm in both groups (p = .46). there was also no significant difference in the incomplete excision rate between tumors >10 mm and those ≤10 mm in diameter (p = .24). research | dermatol pract concept. 2021;11(2):e2021046 5 although a punch biopsy excision was only used in 22 cases, this method had a significantly higher incomplete excision rate (45.0%) than did elliptic excision (21.0%, p = .016). as with the less strict definition, having undergone a preoperative biopsy did not affect the incomplete excision rate. incomplete excisions were observed in 21.4% of cases with a preoperative biopsy and 26.1% of cases without one (p = .18). according to the strict definition of incomplete excision, the adjusted logistic regression analysis yielded two independent risk factors for incomplete excision. one risk factor was a less experienced surgeon (resident vs. specialist), with an or of 2.76 (95% ci, 1.25-6.10; p = .012). the other risk factor was a lesion location in the head and neck area or on the upper extremities (or =3.15; 95% ci, 1.26-7.84; p = .014). in the adjusted analysis, all the significant variables from our univariate analysis were included, ie, surgical margins, excisional biopsy method, less experienced surgeon and body site. discussion we performed a large, retrospective study of surgery for bd. using the less strict definition of incomplete excision, we found 3 parameters that were significantly associated with incomplete excision: surgical margins <3 mm, less experienced surgeon, and use of a punch biopsy excision. in addition to these parameters, a tumor location in the head and neck area or on the upper extremities was also a significant risk factor for incomplete excision according to the strict definition. for both definitions, a less experienced surgeon was independently associated with incomplete excision according to logistic regression, while a tumor location in the head and neck area or on the upper extremities was also independently associated with incomplete excision using the strict definition. although bd is often found on severely sun-damaged skin, it can also appear on otherwise healthy skin without sun damage. we therefore chose to analyze our data according to two separate definitions of incomplete excision. with the less strict definition, only 11.9% of the lesions were incompletely excised, which was slightly lower than the 17.7% rate reported by westers-attema et al (10). however, according to the strict definition, the overall incomplete excision rate was higher in our study (23.8%). unfortunately, the article by westers-attema et al did not include a clear definition of what was considered an incomplete excision [10]. our study did not show any significant difference in incomplete excision rates between surgeons from different medical specialties. this result differs from the study by westers-attema et al, in which dermatologists had an incomplete excision rate of only 8.8% while other specialties showed significantly higher rates (eg, 33.3% for gps and 54.5% for plastic surgeons). however, this difference did not remain significant in the multivariate analysis [10]. other studies on the successful management of keratinocyte cancers, especially those focusing on bcc, showed similar trends [9, 22-24]. in our study, the surgeons’ experience seemed to be of greater importance than their medical specialty. however, surgical experience was not measured in years or number of surgeries performed, but only if surgery was performed by residents or specialists. it is also worth noting that plastic surgeons performed surgery more often on lesions located in the head and neck area, ie, an area where surgery is considered more difficult to perform. choosing adequate surgical margins for skin tumors is a balancing act. the surgeon needs to ensure clear margins in the excised tissue, but also wants to avoid the increased risk of hemorrhage and postoperative infection and the disfiguring scar of a larger excision. as bd is a noninvasive tumor with a relatively low risk of progressing into invasive scc, it is desirable to minimize the surgical margin. westers-attema et al recommended a 5-mm margin to achieve complete excision and to avoid re-excision or additional noninvasive treatment [10]. according to our data, an elliptical excision with margins of at least 3 mm should be recommended. this could be adjusted depending on body site. tumors located in the head and neck area or on the upper extremities were more often incompletely excised according to the strict definition. the fact that dysplasia was more often found at the specimen border in these cases may be explained by the fact that these areas, to a greater extent, contain chronically sun-damaged skin. the present study is one of the largest on this topic to date, with 463 included cases. however, the retrospective design is a clear limitation, since not all data were available in the medical records and histopathology reports. for example, there was a great lack of data on immunosuppression. we were also not able to elucidate why surgery was chosen instead of treatment with other medical or destructive alternatives. however, the most common differential diagnoses were other keratinocyte cancers such as bcc and invasive scc, which might explain why surgery was chosen. furthermore, the diagnostic accuracy among excised bd lesions was low, with the correct diagnosis among the differential diagnoses only specified in less than a third of the cases. this could indicate that cases selected to be surgically excised differed from the most characteristic bd cases, where other non-surgical treatment is often chosen. importantly, our strict definition of incomplete excision may not be relevant for body sites with extensive actinic damage since even subclinical dysplasia can be present in widespread areas. in such locations, dysplasia at the surgical border may either represent coincidental field cancerization or a true incomplete excision of the bd lesion. however, we had no means to differentiate between these two in our study. european guidelines recommend performing surgical excision (or at least a preoperative biopsy followed by histopathology) when there is uncertainty about invasiveness, ie, to 6 research | dermatol pract concept. 2021;11(2):e2021046 differ between an in situ tumor and early invasive scc [12]. in our study, surgery was used in 41.3% of the cases in which a preoperative biopsy had already confirmed the diagnosis of bd. these findings may also indicate that the clinical and dermoscopic characteristics of bd treated by excision may not be representative of all bd lesions. swedish guidelines state that excision of facial bd may be preferred to confirm complete removal [13]. in fact, more than half of the cases in this study were bd located in the head and neck area. conclusions when surgery was considered the best treatment method for bd, greater physician experience and the use of an elliptical excision with surgical margins of at least 3 mm were associated with lower incomplete excision rates. when a strict definition of incomplete excision was used, a tumor location on the trunk or lower extremities was also associated with lower incomplete excision rates. based on these results, our recommendation is to use elliptic excision with at least a 3-mm excision margin when choosing surgery for treating bd. for lesions on chronically sun-damaged skin, the consequences of leaving certain degrees of dysplasia at the specimen border should be weighed against the consequences of re-excision. references 1. the swedish cancer registry of the national board of health and welfare (cancer incidence in sweden 2019) 2020. accessed march 3, 2021. http://www.socialstyrelsen.se 2. peterka es, lynch fw, goltz rw. an association between bowen’s disease and internal cancer. arch dermatol. 1961;84:623-629. doi: 10.1001/archderm.1961.01580160087015. 3. kao gf. carcinoma arising in bowen’s disease. arch dermatol. 1986;122(10):1124-1126. pmid: 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(sdko guidelines for management of squamous cell carcinoma and basal cell carcinoma). 2016. accessed october 26, 2020. https://ssdv.se/images/pdf/sdkos_riktlinjer_for_scc__ bcc_2016.pdf. 14. national comprehensive cancer network. clinical practice guidelines in oncology. basal cell and squamous cell skin cancers. 2020. accessed october 26, 2020. http://www.nccn.org/ professionals. 15. bonerandi jj, beauvillain c, caquant l, et al. guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. j eur acad dermatol venereol. 2011;25 suppl 5:1-51. doi: 10.1111/j.1468-3083.2011.04296.x. 16. bogdanov-berezovsky a, cohen ad, glesinger r, cagnano e, rosenberg l. risk factors for incomplete excision of squamous cell carcinomas. j dermatolog treat. 2005;16(5-6):341-344. doi: 10.1080/09546630500424649. 17. mirshams m, razzaghi m, noormohammadpour p, naraghi z, kamyab k, sabouri rad s. incidence of incomplete excision in surgically treated cutaneous squamous cell carcinoma and identification of the related risk factors. acta med iran. 2011;49(12):806-809. pmid: 22174169. 18. pua vs, huilgol s, hill d. evaluation of the treatment of non-melanoma skin cancers by surgical excision. australas j dermatol. 2009;50(3):171-175. doi: 10.1111/j.1440-0960.2009.00531.x. 19. stewart tj, saunders a. risk factors for positive margins after wide local excision of cutaneous squamous cell carcinoma. j dermatolog treat. 2018;29(7):706-708. doi: 10.1080/09546634.2018.1441493. 20. trakatelli m, bylaite-bucinskiene m, correia o, et al. clinical assessment of skin phototypes: watch your words! eur j dermatol. 2017;27(6):615-619. doi: 10.1684/ejd.2017.3129. 21. paoli j, ternesten bratel a, lowhagen gb, stenquist b, forslund o, wennberg am. penile intraepithelial neoplasia: results of photodynamic therapy. acta derm venereol. 2006;86(5):418-421. doi: 10.2340/00015555-0130. 22. goulding jm, levine s, blizard ra, deroide f, swale vj. dermatological surgery: a comparison of activity and outcomes in primary and secondary care. br j dermatol. 2009;161(1):110-114. doi: 10.1111/j.1365-2133.2009.09228.x. 23. murchie p, delaney ek, thompson wd, lee aj. excising basal cell carcinomas: comparing the performance of general practitioners, hospital skin specialists and other hospital specialists. clin exp dermatol. 2008;33(5):565-571. doi: 10.1111/j.13652230.2008.02710.x. 24. salmon p, mortimer n, rademaker m, adams l, stanway a, hill s. surgical excision of skin cancer: the importance of training. br j dermatol. 2010;162(1):117-122. doi: 10.1111/j.13652133.2009.09548.x. dermatology: practical and conceptual dermatology practical & conceptual research letter | dermatol pract concept. 2022;12(1):e2022014 1 rosette-like structure: a main dermoscopic feature in a small trichilemmal cyst giulia bazzacco1, enrico zelin1, carlo alberto maronese2, vittorio ramella3, diego signoretto4, iris zalaudek1, nicola di meo1 1 dermatology clinic, maggiore hospital, university of trieste, trieste, italy 2 dermatology unit, fondazione irccs cà granda ospedale maggiore policlinico, milan, italy 3 plastic surgery department, cattinara hospital, asugi, trieste, italy 4 pathological anatomy and histology department, cattinara hospital, university of trieste, trieste, italy. key words: trichilemmal cyst, rosette, dermoscopy citation: bazzacco g, zelin e, maronese ca, et al. rosette-like structure: a main dermoscopic feature in a small trichilemmal cyst. dermatol pract concept. 2022;12(1):e2022021. doi: https://doi.org/10.5826/dpc.1201a21 accepted: may 26, 2021; published: january 2022 copyright: ©2022 bazzacco et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication and approved the final version of the submitted paper. ndm and iz defined the design and intellectual content of the paper. gb searched for literature, wrote the draft, edited the manuscript and the tables, preparing them for submission. ez, cam, and vr reviewed the article with consistent integrations. ds analyzed the histology samples and contributed to image collection. corresponding author: enrico zelin, md, dermatology clinic, hospital maggiore, trieste, italy. e-mail address: enrico.zelin@gmail.com introduction trichilemmal cysts (tcs), also called pilar cysts, represent the second most common type of cutaneous cysts, after epidermal ones [1]. tcs most commonly occur in middle-aged women and have a predilection for the scalp but can occasionally show different locations. they appear as solitary or multiple intradermal palpable papules/nodules, occurring as sporadic lesions or in hereditary/familial settings with autosomal dominant transmission [1]. from a histological point of view, tcs have an undulating epithelial wall with no granular layer and a compact keratinization and reveal an isthmic origin [1]. case presentation a 36-year-old woman was referred to our clinic with an asymptomatic papule of 1 mm in diameter above her right eyebrow that relapsed after treatment with cryotherapy, in absence of other skin lesions (figure 1a). on dermoscopy, shiny white areas arranged as a four-leaf clover (rosette-like structure) with a minimal erythematous background was seen (figure 1b). the lesion was excised, and histopathological examination indicated a multilayer cystic neoformation with eosinophilic cells positive for high molecular weight cytokeratin (ck34be12+) and absence of the granular layer, consistent with the diagnosis of tc (figure 2, a-c). on clinical examination, tcs appear as smooth, mobile, firm, dermal or subcutaneous papules or nodules with a typical diameter of 10-20 mm. they do not characteristically present visible pores [1]. dermoscopy usually shows a pinkish-yellow or homogeneous yellowish-white area with a peripheral erythematous halo and sometimes, due to the tyndall effect, the keratin material appears blueish [1]. in the present case, the tc was very small (1 mm papule) and 2 research letter | dermatol pract concept. 2022;12(1):e2022014 showed a white shiny rosette-like structure on dermoscopic evaluation. in the literature, the precise morphological correlate of rosettes is not known, since they are not specific and can be seen in various cutaneous lesions, mainly in actinic keratoses, basal cell carcinomas and squamous cell carcinomas, and rarely in cysts. this rosette-like pattern can be probably caused by horny material in the adnexal opening or by concentric perifollicular fibrosis [2]. conclusions differential diagnosis of tcs can include various entities, such as other cystic lesions but also basal cell carcinoma, squamous cell carcinoma, sebaceous hyperplasia and syringoma (table 1) [2]. moreover, these cysts can be subject to inflammation, infection, and enlargement, but rarely grow more extensively, forming proliferating tcs (adnexal tumors figure 1. clinical and dermoscopic appearance of the trichilemmal cyst. (a) a small 1-mm papule above the eyebrow of the patient. (b) dermoscopy shows shiny white areas arranged as a four-leaf clover (rosette-like structure) with a minimal erythematous background. figure 2. histopathological features of the trichilemmal cyst. (a) global appearance of the multilayer cystic neoformation, h&e, ×10. (b) eosinophilic cells and absence of granular layer, h&e, ×40. (c) cells showing positive immunohistochemistry stain for high molecular weight cytokeratin ck34be12+, ×40. research letter | dermatol pract concept. 2022;12(1):e2022014 3 table 1. dermoscopic clues that differentiate trichilemmal cyst from its main differential diagnoses lesion classic dermoscopic criteria trichilemmal cyst pinkish-yellow or homogeneous yellowish-white background peripheral erythematous halo absence of pore sign blue pigmentation (tyndall effect of keratin) epidermal cyst yellowish-white papule pore sign: keratin-filled, circular orifice, whitish, yellow, brown or black in color wobble sign (movement of the lesion with respect to the surrounding tissues, except for the pore, which represents the site of anchorage of the cyst) basal cell carcinoma arborizing vessels, sort fine telangiectasias ulceration, erosions maple-leaf like, spoke-wheel and concentric structures blue-gray globules, blue-ovoid nests squamous cell carcinoma presence of keratin, especially in conjunction with blood spots coiled vessels white structureless zones, white circles (highly differentiated sccs) predominantly red color, bleeding and ulcerations (poorly differentiated sccs) syringoma yellowish-brownish structures structureless background reticular vessels sebaceous hyperplasia central umbilication surrounded by aggregated polylobular white-yellowish structures (cumulus sign); this global appearance is known as bonbon toffee sign surrounding crown of vessels at the periphery scc = squamous cell carcinoma. usually with a benign behavior) or may even undergo malignant transformation. therefore, when there is suspicion of tc, it is appropriate to proceed to radical surgical excision with histological examination in order to exclude malignant tumors and prevent complications. in conclusion, dermoscopy represents a noninvasive tool that allows the identification of specific morphological features in different skin tumors. it significantly improves the early diagnosis of cutaneous lesions and helps in choosing the best treatment options for each case based on the suspected diagnosis. in this article, we described a very characteristic dermoscopic pattern associated with a small tc. the prompt surgical treatment and subsequent histopathological examination aided in a diagnosis of certainty and in prevented the growth of this lesion that was localized to an aesthetic area. informed consent: written informed consent for publication of her clinical details and clinical images was obtained from the patient. references 1. gencoglan g, karaarslan ik, akalin t, ozdemir f. trichilemmal cyst with homogeneous blue pigmentation on dermoscopy. australas j dermatol. 2009;50(4):301–302. doi: 10.1111/j.14400960.2009.00566.x. pmid: 19916979. 2. haspeslagh m, noë m, de wispelaere i, et al. rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation. j eur acad dermatology venereol. 2016;30(2):311–313. doi: 10.1111/jdv.13080. pmid: 25786770. dermatology: practical and conceptual observation | dermatol pract concept 2016;6(4):5 23 dermatology practical & conceptual www.derm101.com case report a female in her seventies, skin phototype ii, presented to her gynecologist with a two-month history of a lesion on the inside of her right labia minora. her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. her gynecologist prescribed, based on the suspicion of a herpes simplex infection, acyclovir 5% cream and, after some days, a hydrocortisone 1% / clotrimazole 1% cream for two weeks. because no change was visible at the followup examination, a biopsy was taken of a part of the nodule. based on the histopathological diagnosis of an amelanotic melanoma (breslow thickness of 1.3 mm), the patient was dermoscopic appearance of an amelanotic mucosal melanoma andreas blum1, ulrike beck-zoul2, laura held3, sylvie haase1 1 public, private and teaching practice of dermatology, augustinerplatz 7, 78462 konstanz, germany 2 public and private practice of gynecology, rosgartenstrasse 27, 78462 konstanz, germany 3 dermatopathology, siemensstraße 6/1, 88048 friedrichshafen, germany key words: melanoma, mucosal melanoma, dermoscopy citation: blum a, beck-zoul u, held l, haase s. dermoscopic appearance of an amelanotic mucosal melanoma. dermatol pract concept 2016;6(4):5 .doi: 10.5826/dpc.0604a05 received: august 24, 2016; accepted: august 31, 2016; published: october 31, 2016 copyright: ©2016 blum et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. all authors have contributed significantly to this publication. corresponding author: andreas blum, md, msc, public, private and teaching practice of dermatology, augustinerplatz 7, 78462 konstanz, germany. tel. +49 7531 643 11; fax. +49 7531 600 54. email: a.blum@derma.de background: hypomelanotic or amelanotic melanomas are challenging to identify, especially at mucosal sites. the dermoscopic clues to the diagnosis of mucosal melanomas have been reported to be structureless zones with the presence of blue, gray, or white colors. case: a female in her seventies noted a new lesion on the inside of her right labia that first appeared two months prior. her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. after no response to two weeks of local treatment for suspected herpes simplex infection, her gynecologist performed a skin biopsy. based on the histopathological diagnosis of an amelanotic melanoma (breslow thickness of 1.3 mm) the patient was referred to dermatology for further assessment. polarized dermoscopy revealed a distinct asymmetric, sharply demarcated homogenous white papule (4 x 5 mm) as well as polymorphous vessels. conclusion: dermoscopy may aid in the diagnosis of amelanotic mucosal melanomas. our case revealed a structureless white area and polymorphous vessels. additional clues to the diagnosis were the advanced age of the patient and the clinical presentation of a new lesion. abstract 24 observation | dermatol pract concept 2016;6(4):5 the correct diagnosis is often delayed, leading to a poor prognosis of malignant tumors, especially mucosal melanomas [6]. possible differential diagnoses of our case include herpes infection, condylomata acuminata, condyloma lata of syphilis, inflamed cysts or glands, and squamous cell carcinoma. referred to dermatology for closer examination. clinically a whitish papule on the inside of her right labia minora was visible (figure 1). under polarized dermoscopy a distinct asymmetric, sharp demarcated homogenous white papule (4 x 5 mm) with polymorphous vessels was present (figure 2). histologic examination revealed malignant melanoma mucosal type with densely packed atypical spindly-shaped melanocytes with hyperchromatic nuclei, confirmed by positivity of anti-mela antibody (figure 3). conclusion this case suggests that amelanotic mucosal melanoma may reveal diagnostic clues upon dermoscopic examination. a multicenter study that examined the dermoscopic appearance of mucosal lesions revealed that the combination of structureless zones with blue, gray or white color(s) is useful for the diagnosis of malignant lesions [1]. the highest diagnostic sensitivity was achieved when considering only the presence of blue, gray, or white color [1-3]. furthermore, polymorphous vessels is also a hint for malignancy, particularly melanoma [4,5]. additional clues to the diagnosis of our case included the age of the patient and the presentation of a new lesion [1]. pigmented and non-pigmented lesions at the mucosa are difficult to examine clinically and dermoscopically. therefore, figure 1. clinical appearance of a non-pigmented lesion of the right labia. [copyright: ©2016 blum et al.] figure 2. polarized dermoscopy showing a distinct asymmetric, sharp demarcated homogenous white papule (4 x 5 mm) with polymorphous vessels (e.g., linear, curved, hairpin-like with different diameter) (handyscope, fotofinder, bad birnbach, germany; iphone 5, apple inc., cupertino, usa). [copyright: ©2016 blum et al.] figure 3. histologic appearance: histology revealed mucosal melanoma on hematoxylin and eosin: densely packed atypical spindlyshaped melanocytes with hyperchromatic nuclei, confirmed by positivity with anti-mela antibody (top right inset). [copyright: ©2016 blum et al.] observation | dermatol pract concept 2016;6(4):5 25 3. lin j, koga h, takata m, saida t. dermoscopy of pigmented lesions on mucocutaneous junction and mucous membrane. br j dermatol 2009;161(6):1255-61. pmid:19673880. doi: 10.1111/j.1365-2133.2009.09251.x. 4. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. arch dermatol 2008;144:1120-7. pmid:18794455. doi: 10.1001/archderm.144. 9.1120. 5. menzies sw, moloney fj, byth k, et al. dermoscopic evaluation of nodular melanoma. jama dermatol 2013;149:699-709. pmid:23553375. doi:10.1001/jamadermatol.2013.2466. 6. mehra t, grözinger g, mann s, et al. primary localization and tumor thickness as prognostic factors of survival in patients with mucosal melanoma. plos one 2014;10;9(11):e112535. pmid: 25383553. doi:10.1371/journal.pone.0112535. this observation encourages the use of the dermoscope at the mucosa even in non-pigmented lesions to diagnose a malignant process as soon as possible. all suspicious lesions should undergo prompt biopsy for definitive diagnosis. references 1. blum a, simionescu o, argenziano g, et al. dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the international dermoscopy society (ids). arch dermatol 2011;147(10):1181-7. pmid:21680757. doi: 10.1001/archdermatol.2011.155. 2. de giorgi v, massi d, salvini c, et al. thin melanoma of the vulva: a clinical, dermoscopic-pathologic case study. arch dermatol 2005;141(8):1046-7. pmid:16103344. doi: 10.1001/ archderm.141.8.1046. http://www.ncbi.nlm.nih.gov/pubmed/19673880 http://dx.doi.org/10.1111/j.1365-2133.2009.09251.x http://www.ncbi.nlm.nih.gov/pubmed/18794455 http://dx.doi.org/10.1001/archderm.144.9.1120 http://dx.doi.org/10.1001/archderm.144.9.1120 http://www.ncbi.nlm.nih.gov/pubmed/23553375 http://dx.doi.org/10.1001/jamadermatol.2013.2466 http://www.ncbi.nlm.nih.gov/pubmed/25383553 http://dx.doi.org/10.1371/journal.pone.0112535 http://dx.doi.org/10.1001/archderm.141.8.1046 http://dx.doi.org/10.1001/archderm.141.8.1046 dermatology: practical and conceptual research | dermatol pract concept 2016;6(4):1 1 dermatology practical & conceptual www.derm101.com evaluation of electrical impedance spectroscopy as an adjunct to dermoscopy in short-term monitoring of atypical melanocytic lesions hannah ceder1, alexandra sjöholm hylén1, ann-marie wennberg larkö1, john paoli1 1 department of dermatology and venereology, sahlgrenska university hospital and institute of clinical sciences at the sahlgrenska academy, university of gothenburg, gothenburg, sweden key words: dermoscopy, atypical melanocytic lesion, melanoma, short-term monitoring, electrical impedance spectroscopy citation: ceder h, sjöholm hylén alexandra. wennberg larkö, a-m, paoli j. evaluation of electrical impedance spectroscopy as an adjunct to dermoscopy in short-term monitoring of atypical melanocytic lesions. dermatol pract concept 2016;6(4):1. doi: 10.5826/ dpc.0604a01 received: june 29, 2016; accepted: july 22, 2016; published: october 31, 2016 copyright: ©2016 ceder et al. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. funding: none. competing interests: none to declare. scibase ab, stockholm, sweden loaned the nevisense® equipment and electrodes needed for the study to the department of dermatology at sahlgrenska university hospital, but the company had no influence on the study design nor data analysis. all authors have contributed significantly to this publication. corresponding author: john paoli, md, associate professor, department of dermatology, sahlgrenska university hospital, 413 45 gothenburg, sweden. t. +46730404044. email: john.paoli@vgregion.se background: early detection of melanoma is vital for treatment outcome and survival. short-term sequential digital dermoscopic monitoring (st-sddm) involves the capture and assessment of dermoscopic images of one or more atypical melanocytic lesions (amls), at baseline and after four months, in order to detect early morphologic changes. electrical impedance spectroscopy (eis) is a diagnostic tool with high sensitivity for the detection of malignant melanocytic lesions. objectives: the aim of this study was to assess whether eis, in addition to st-sddm, could improve the selection of amls requiring surgery. methods: in this retrospective descriptive study, 22 amls in 19 patients were monitored with both st-sddm and eis. a modified eis decision-making algorithm was established. amls were excised if any dermoscopic changes were seen and/or if the eis score had increased significantly at follow-up. statistical analyses were made including sensitivity, specificity, ppv and npv. results: a total of seven lesions (32%) were excised. four lesions (57%) were excised solely because of dermoscopic changes including a 0.4 mm-thick melanoma and three benign nevi. three benign lesions (43%) were excised because of increased eis scores without any dermoscopic changes. the eis scores at follow-up showed high variability as compared to the initial scores. conclusion: the addition of eis to st-sddm did not identify additional malignant lesions. there was no correlation between dermoscopic changes seen with st-sddm and increased eis scores. three histopathologically benign lesions were needlessly excised. moreover, the low reproducibility and the possible interoperator variability of the method raised concerns. abstract 2 research | dermatol pract concept 2016;6(4):1 values (ppvs) as shown in table 1 [6,7]. eis is approved for clinical use, but how the eis score should be interpreted and used in clinical practice is still unclear. at the department of dermatology, sahlgrenska university hospital, the combination of clinical examination and st-sddm after four months has been used in the assessment of amls requiring follow-up to determine whether they should be surgically removed or not. objectives the objective of this study was to assess whether eis in addition to conventional practice (st-sddm) could improve the selection of patients with amls needing surgery. the secondary objective was to determine the correlation between dermoscopic changes and eis scores during short-term monitoring of amls. methods in february 2015, eis was introduced into clinical practice in combination with st-sddm at the department of dermatology, sahlgrenska university hospital. in this retrospective descriptive study, the clinical outcome of all patients with amls that were followed with st-sddm combined with eis measurements during the period from february 1 to june 30, 2015, were analyzed. the regional ethical review board assessed the study as a retrospective appraisal of quality of care and therefore had no objections to the study. all patients over the age of 18 years diagnosed with an aml and monitored with st-sddm and eis during the study period were considered eligible. patients lost to follow-up, not meeting eis measurement criteria (see below), having insufficient patient notes or with dermoscopic images of poor quality were excluded. certain criteria must be met for eis measurements to be valid. the lesion must have a background the concept of an atypical melanocytic lesion (aml) can be applied to any pigmented lesion in which the clinical and dermoscopic criteria are sufficient to classify it as melanocytic, but are insufficient to determine whether the lesion is a benign nevus or an early stage of melanoma. when patients present with one or more amls, excision for histopathological diagnosis may be necessary, but more advanced non-invasive diagnostic methods might be preferred. dermoscopy is a technique that uses a handheld magnifying device combined with either the application of immersion fluid between the transparent plate of the device and the skin or the use of cross-polarized light. this technique allows for visualization of diagnostic features of skin lesions not visible to the naked eye. it is a tool that helps the clinician to assess and differentiate between melanocytic and non-melanocytic lesions and determine whether they are benign or malignant. several diagnostic algorithms can be used (e.g., pattern analysis, 7-point checklist, abcd, menzies’ scoring method) [1,2]. although dermoscopy is a very good complement to clinical evaluation, there will always be some lesions that lead to diagnostic uncertainty. to be able to identify and monitor these lesions without unnecessary excision, the use of shortterm sequential digital dermoscopic monitoring (st-sddm) is valuable [3]. sequential digital dermoscopic monitoring (sddm) involves the capture and assessment of successive dermoscopic images of one or more amls separated by a specific time interval. sddm is performed in two settings: longterm monitoring (lt-sddm), where multiple amls are followed during regular surveillance periods (usually every 6-12 months) [4], and short-term monitoring (st-sddm), where one or a few amls are re-examined only once after a shorter surveillance period (3-4.5 months) [3]. clinicians may choose to perform st-sddm of an aml based on slightly suspicious morphologic features observed during dermoscopy during a first visit or based on a worrisome patient history although the dermoscopic features of the aml appear to be benign. nevisense® (scibase ab, stockholm, sweden) is a diagnostic tool based on electrical impedance spectroscopy (eis) [5-7]. it measures tissue resistance by administering alternating electrical currents at various frequencies to the skin. normal and abnormal tissue differ with regard to cell size, shape, density and structure of cell membranes. these different properties influence the ability of the tissue to conduct and store electricity and can influence the results of an eis measurement [5]. previous studies have resulted in an algorithm in which eis scores in the range of 0-3 in the nevisense® system represent a negative predictive value (npv, i.e., the probability that the lesion is not a melanoma) of 98%, and scores of 4-10 represent steadily increasing positive predictive table 1. negative and positive predictive values for eis measurements according to previous study [14]. eis predictive value 0-3 98% (npv*) 4 9% (ppv*) 5 13% (ppv*) 6 18% (ppv*) 7 22% (ppv*) 8 39% (ppv*) 9 51% (ppv*) 10 64% (ppv*) * npv, negative predictive value; ppv, positive predictive value. research | dermatol pract concept 2016;6(4):1 3 how eis measurements are performed have been published earlier [6,7]. since the specificity and the positive predictive value of eis measurements from previous studies were considered too low to be clinically applicable, the authors suggested a novel algorithm for the clinical management based on the eis score. a greater emphasis was placed on the clinical and dermoscopic evaluation of lesions than on the eis scores. the patients returned after four months for a follow-up visit during which new clinical and dermoscopic images were taken and nevisense® measurements were performed. the presence or absence of dermoscopic changes were visualized by comparing the two dermoscopic images on a digital monitor. the management algorithm is presented in figure 1. if the eis score at visit 1 was 9 or 10, the lesion was excised regardless of the dermoscopic assessment. otherwise, the aml(s) were followed up after four months. at follow-up, the dermoscopic images from both visits were compared. if dermoscopic changes were observed (e.g., growing or thickened network, new or bigger globules, new or growing negative network), the lesion was excised regardless of the eis score at visit 2. figures 2-3 show examples of amls with absence and presence of dermoscopic changes, respectively. if no dermoscopic changes were observed after four months, the eis score determined the management decision. if the eis score at visit 1 was 0-6 and had not increased by more than 1 point at follow-up or if the eis score at visit 1 was 7-8 and had not increased at all after four months, the aml was determined to be a benign nevus. larger increases in the eis score were interpreted as a possible sign of evolving malignancy and prompted excision. statistical analyses were made to determine the sensitivity, specificity, ppv and npv of the method. results a total of 19 patients (12 women and 7 men) with 22 amls were examined with both st-sddm and eis during the study period (table 2). the short-term interval between visits ranged from 3.5-4 months. the median age of the patients was 53 years (range 23 to 69 years). diameter of 2-20 mm, the skin must be intact (i.e., lesions are not ulcerated or bleeding), and the lesion should be free of scars or fibrosis and located in skin areas free from eczema, psoriasis, acute sunburn or terminal hair. furthermore, the lesion should not be located in specific anatomical areas, such as acral skin, genitals, eyes or mucous membranes. after a full-body skin examination, the physician decided which suspected aml(s) should be followed using st-sddm and eis. first, a clinical and a dermoscopic image were taken with a canon digital camera powershot g12, g15 or g16 (canon, tokyo, japan) and the dermoscopy device dermlite foto® (3gen; dermlite®, san juan capistrano, ca, usa) attached to the camera. a 70% solution of isopropyl alcohol in water was used as immersion fluid when acquiring the dermoscopic images. all images were stored in the patient’s electronic journal. subsequently, an eis measurement was carried out by one of two certified users (hc and ash) with the nevisense® instrument, which is equipped with a probe and a disposable five-bar electrode with an area of 5 x 5 mm. the system measures bio-impedance of the skin at 35 different frequencies, logarithmically distributed from 1.0 khz to 2.5 mhz, at four different depths utilizing 10 permutations. more exact details on figure 1. management algorithm. [copyright: ©2016 ceder et al.] figure 2. atypical melanocytic lesion without dermoscopic changes after st-sddm. the eis score was 8 at day 0 (left) and 6 at the follow-up visit (right). [copyright: ©2016 ceder et al.] 4 research | dermatol pract concept 2016;6(4):1 in 10 cases (45%), the difference in eis scores was ≥2 points and differences up to ± 4 points were observed. if the algorithm provided by the manufacturer had been followed, 19 amls would have been considered suspicious and excised. of these, only one was malignant. thus, in this very limited sample, and assuming that the nonexcised lesions were correctly diagnosed using st-sddm, the positive predictive value (ppv) of eis alone was 5.3% and the specificity was 14.3%. the sensitivity and negative predictive value (npv) were both 100%. conclusions melanoma affects more than 3700 people in sweden each year. after nonmelanoma skin cancer, malignant melanoma is the cancer type whose incidence a total of seven lesions (32%) were excised. upon histopathological examination, four were dysplastic nevi, two were compound nevi and one was a thin superficial spreading melanoma with a breslow thickness of 0.4 mm without ulceration (figure 3). four of the seven excised lesions (57%) were excised solely because of dermoscopic changes. in these cases, the eis score was reduced by 2 points at follow-up in two lesions and unchanged in the other two. three of the seven excised lesions (43%) were excised because of changes in the eis score without any dermoscopic changes. these were all histopathologically benign. none of the seven excised lesions showed both dermoscopic changes and a significantly increased eis score at follow-up. the eis scores at day 0 and at follow-up showed a rather high variability. figure 3. atypical melanocytic lesion with dermoscopic changes between the baseline visit (a and c) and follow-up (b and d). the eis score was 7 at baseline and 5 at follow-up four months later. the lesion diameter had increased (a➝ b) and several brown globules within a negative network had increased in size (circled areas in c and d). histopathologically, this atypical melanocytic lesion was confirmed as a superficial spreading melanoma. [copyright: ©2016 ceder et al.] is increasing most in sweden [8]. melanoma detection often poses a challenge in equivocal lesions or in patients with many amls. as early detection of melanoma is vital for treatment outcome and survival [9,10], additional objective information that could assist the clinician in obtaining a correct diagnosis and in deciding whether to excise the aml or not is desirable. the attempt in this study to use the eis score algorithm to complement st-sddm did not seem to provide any additional help. firstly, the evaluated algorithm did not identify additional malignant lesions. furthermore, three histopathologically benign lesions were needlessly excised because of changes in the eis score without any dermoscopic changes. these lesions would have been acquitted using only st-sddm. moreover, the discrepancies between eis scores over time were considerable in several cases, which raised concerns about the reproducibility and the possible interoperator variability of the method. changes in eis scores alone did not appear to correlate with malignancy. for example, a considerable increase of 2-4 eis points between measurements did not correlate with histopathological malignancy, and it is difficult to interpret the meaning of a decrease of the eis score by 4 points in a dermoscopically unchanged lesion. lastly, none of the lesions showing dermoscopic change had an increased eis score at follow-up, which further undermines the confidence in the measurement reliability. according to the company that produces the nevisense® instrument, the discrepancies between the eis scores could depend on the use of different operators that may result in different reference measurement quality at the first visit and at follow-up. another explanation may be the size of the lesion. the bigger the lesion is, the more measurements are required for each lesion, which may lead to errors. there are several limitations to this study. the study was retrospectively research | dermatol pract concept 2016;6(4):1 5 additional techniques could perhaps increase the specificity when analyzing amls. for example, a study on the combination of eis with near-infrared (nir) spectroscopy for analyzing melanocytic lesions provided a specificity of 95%, albeit with a lower sensitivity of 83% [11]. regarding the term aml that we use in this study, we propose that this term should replace the incorrectly used term of a clinically suspected “dysplastic nevus” which is unfortunately used by too many dermatologists today. a “dysplastic” nevus is a variant of a benign melanocytic nevus, which can only be diagnosed histopathologically with typical architectural disorder and varying degrees of nuclear atypia in intraepidermal melanocytes [12,13]. between 2-18% of the population in sweden have melanocytic lesions with a clinical suspicion of dysplastic nevus [14]. nevertheless, the exact prevalence of dysplastic nevi is unknown since the clinicopathological correlation between clinical atypia and designed and the sample size was small. the evaluation concerned eis in conjunction with st-sddm, but st-sddm was at the same time used as the gold standard for diagnosis in non-excised lesions. a histopathological diagnosis of all the lesions would perhaps have allowed for a more certain evaluation, but was not considered ethical to carry out. this is the first independent study, to our knowledge, in which eis measurements have been carried out on the same melanocytic lesion at two different points in time to test reproducibility. further studies on the reproducibility and interoperator reliability of eis are needed before conclusions can be made. eis measurements on amls showed lower specificity compared with previous studies on eis [5-7]. this may be due to the fact that the inclusion criteria in this study were different and that the sample size was smaller. consequently, the studies cannot be directly compared. eis combined with table 2. demographic data of all patients and clinical/histopathological characteristics of all atypical melanocytic lesions. [copyright: ©2016 ceder et al.] lesion sex* age location size? (mm) eisscore day 0 eisscore followup eis score difference dermoscopic change treatment histopathology 1 m 64 back 7x7 5 7 +2 no excision dysplastic nevus, moderate dysplasia 2 f 26 abdomen 6x4 6 7 +1 no none 3 m 37 back 8x4 8 6 -2 no none 4 m 41 stomach 6x5 4 3 -1 no none 5 f 24 thorax 6x5 5 6 +1 no none 6 f 60 abdomen 14x12 7 5 -2 yes excision ssm, 0.4 mm 7 f 51 gluteus 7x6 4 5 +1 no none 8 f 66 arm 2x3 5 3 -2 yes excision compound nevus, inflamed 9 f 66 back 7x5 8 5 -3 no none 10 f 27 back 10x11 3 7 +4 no excision dysplastic nevus, moderate dysplasia 11 m 66 back 9x6 5 5 0 yes excision dysplastic nevus, mild dysplasia 12 m 66 abdomen 8x6 5 9 +4 no excision dysplastic nevus, mild dysplasia 13 f 69 back 8x7 5 3 -2 no none 14 f 28 leg 6x7 7 7 0 no none 15 f 56 pubis 9x7 6 6 0 no none 16 m 67 leg 3x4 2 2 0 no none 17 m 67 leg 7x4 4 4 0 no none 18 f 23 head 3x3 4 1 -3 no none 19 f 53 leg 6x4 6 2 -4 no none 20 f 36 back 6x5 6 6 0 yes excision compound nevus, strongly pigmented 21 m 24 back 7x4 2 3 +1 no none 22 m 53 back 10x11 5 6 +1 no none * m, male; f, female; * size, maximum x minimum diameter in mm. 6 research | dermatol pract concept 2016;6(4):1 melanoma. exp dermatol 2011;20(8):648-52. pmid: 21539620. doi: 10.1111/j.1600-0625.2011.01285.x. 6. malvehy j, hauschild a, curiel-lewandrowski c, et al. clinical performance of the nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety. br j dermatol 2014;171(5):1099-107. pmid: 24841846. doi: 10.1111/ bjd.13121. 7. mohr p, birgersson u, berking c, et al. electrical impedance spectroscopy as a potential adjunct diagnostic tool for cutaneous melanoma. skin res technol 2013;19(2):75-83. pmid: 23350668. doi: 10.1111/srt.12008. 8. the swedish national board of health and welfare. swedish cancer registry. [cancer incidence in sweden 2014]. url: www. socialstyrelsen.se. 2015. accessed 6.29.16. 9. balch cm, gershenwald je, soong sj, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol 2009;27(36):6199-206. pmid: 19917835. doi: 10.1200/ jco.2009.23.4799. 10. tsao h, atkins mb, sober aj. management of cutaneous melanoma. n engl j med. 2004;351(10):998-1012. pmid: 15342808. doi: 10.1056/nejmra041245. 11. boden i, nystrom j, lundskog b, et al. non-invasive identification of melanoma with near-infrared and skin impedance spectroscopy. skin res technol 2013;19(1):e473-8. pmid: 22958059. doi: 10.1111/j.1600-0846.2012.00668.x. 12. duncan lm, berwick m, bruijn ja, et al. histopathologic recognition and grading of dysplastic melanocytic nevi: an interobserver agreement study. j invest dermatol 1993;100(3):318s-21s. pmid: 8440913. 13. shors ar, kim s, white e, et al. dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma. br j dermatol 2006;155(5):988-93. pmid: 17034530. doi: 10.1111/j.1365-2133.2006.07466.x. 14. augustsson a, stierner u, suurkula m, rosdahl i. prevalence of common and dysplastic naevi in a swedish population. br j dermatol 1991;124(2):152-6. pmid: 2003997. 15. annessi g, cattaruzza ms, abeni d, et al. correlation between clinical atypia and histologic dysplasia in acquired melanocytic nevi. j am acad dermatol 2001;45(1):77-85. pmid: 11423839. doi: 10.1067/mjd.2001.114580. 16. klein lj, barr rj. histologic atypia in clinically benign nevi. a prospective study. j am acad deramtol 1990;22(2 pt 1):275-82. pmid: 2312807. 17. roush gc, dubin n, barnhill rl. prediction of histologic melanocytic dysplasia from clinical observation. j am acad dermatol 1993;29(4):555-62. pmid: 8408790. 18. kittler h, tschandl p. dysplastic nevus: why this term should be abandoned in dermatoscopy. dermatol clin 2013;31(4):579-88, viii. pmid: 24075546. doi: 10.1016/j.det.2013.06.009. histopathological dysplasia in melanocytic nevi is very poor [14-17]. hence, the term “dysplastic nevus” is not a clinical diagnosis and should be abandoned [18]. if the clinical diagnosis of a melanocytic lesion is uncertain, the lesion should therefore be called an aml until the diagnosis is confirmed clinically with st-sddm or histopathologically after a complete excision of the lesion. in this pilot study, the addition of eis to st-sddm using a modified eis algorithm did not identify additional pathological lesions. instead, some histopathologically benign lesions were needlessly excised. in addition, there was no correlation between dermoscopic changes seen with st-sddm and significantly increased eis scores. also, the reproducibility of the eis measurements was lower than expected, which is an issue that needs to be studied further before continuing to use this method in routine care. for now, we can therefore not recommend eis in the standard management of monitoring amls. acknowledgements we would like to thank scibase ab, stockholm, sweden for loaning us the nevisense® equipment and electrodes needed to carry out this study. references 1. argenziano g, ferrara g, francione s, di nola k, martino a, zalaudek i. dermoscopy—the ultimate tool for melanoma diagnosis. semin cutan med surg 2009;28(3):142-8. pmid: 19782937. doi: 10.1016/j.sder.2009.06.001. 2. vestergaard me, macaskill p, holt pe, menzies sw. dermoscopy compared with naked eye examination for the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting. br j dermatol 2008;159(3):669-76. pmid: 18616769. doi: 10.1111/j.1365-2133.2008.08713.x. 3. altamura d, avramidis m, menzies sw. assessment of the optimal interval for and sensitivity of short-term sequential digital dermoscopy monitoring for the diagnosis of melanoma. arch dermatol 2008;144(4):502-6. pmid: 18427044. doi: 10.1001/ archderm.144.4.502. 4. salerni g, carrera c, lovatto l, et al. benefits of total body photography and digital dermatoscopy (“two-step method of digital follow-up”) in the early diagnosis of melanoma in patients at high risk for melanoma. j am acad dermatol 2012;67(1):e17-27. pmid: 21683472. doi: 10.1016/j.jaad.2011.04.008. 5. aberg p, birgersson u, elsner p, mohr p, ollmar s. electrical impedance spectroscopy and the diagnostic accuracy for malignant dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022065 1 supine dermoscopy for improved visualisation of lower limb lesions kelvin truong1,2, melissa peera1,2, raquel ruiz araujo1,2, pablo fernandez-penas1,2 1 department of dermatology, westmead hospital, sydney, new south wales, australia 2 faculty of medicine and health, university of sydney, sydney, new south wales, australia citation: truong k, peera m, ruiz araujo r, fernandez-penas p. supine dermoscopy for improved visualisation of lower limb lesions. dermatol pract concept. 2022;12(2):e2022065. doi: https://doi.org/10.5826/dpc.1202a65 accepted: august 19, 2021; published: april 2022 copyright: ©2022 truong et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: all authors have contributed significantly to this publication corresponding author: kelvin truong, department of dermatology, d5a, westmead hospital, po box 533, westmead nsw 2145, australia. e-mail: kelvin.truong@sydney.edu.au case presentation dermoscopic evaluation of suspicious lesions in the context of venous insufficiency, such as varicose veins, venous stasis, and lipodermatosclerosis, remains a diagnostic challenge. the background erythema created by non-lesional vasculature often obscures the assessment of true lesional structures. teaching point dermoscopy helps assess for atypical vascular morphology such as predominantly central vessels, polymorphous vessels, and milky red-pink areas, which is critical in differentiating malignant from benign pigmented skin lesions, especially in the context of amelanotic and hypomelanotic melanoma [1,2]. to better delineate skin lesion vasculature from background vascular noise, consider laying patients supine to reduce venous congestion (figure 1). this is particularly important in gravity-dependent areas such as the lower limbs. furthermore, use non-contact polarized dermatoscopes or immersion fluids of a high viscosity with contact dermatoscopes, to minimize blanching of vessels and thereby maximizing visualization of vascular architecture in cutaneous lesions [1]. references 1. zalaudek i, kreusch j, giacomel j, ferrara g, catricalà c, argenziano g. how to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part i. melanocytic skin tumors. j am acad dermatol. 2010;63(3):361–374; quiz 375-366. doi: 10.1016/j.jaad.2009.11.698. pmid: 20708469. 2. menzies sw, kreusch j, byth k, et al. dermoscopic evaluation of amelanotic and hypomelanotic melanoma. archives of dermatology. 2008;144(9):1120–1127. doi: 10.1001/ archderm.144.9.1120. pmid: 18794455. 2 image letter | dermatol pract concept. 2022;12(2):e2022065 figure 1. (a,c,e) dermoscopy of cutaneous lesions of the lower leg with patients standing up. minimal pressure was applied. note the prominent background blood vessels which may obscure proper examination of the skin lesion of interest. (b,d,f) dermoscopy of the same lower leg skin lesions with patients laying supine. minimal pressure was applied. reduced background blood vessels allow for clearer visualization of the lesion. dermoscopic pictures taken with medicam 1000, fotofinder systems. dermatology: practical and conceptual dermatology practical & conceptual image letter | dermatol pract concept. 2021;11(3): e 2021052 1 an unexpected shade of yellow ângela roda1, andré oliveira2 1 department of dermatology, hospital de santa maria, centro hospitalar universitário lisboa norte, lisboa, portugal 2 dermatology center, hospital cuf descobertas, lisboa, portugal key words: basal cell carcinoma, skin cancer, cholesterol, dermoscopy, histopathology citation: roda a, oliveira a. an unexpected shade of yellow. dermatol pract concept. 2021;11(3): e 2021052. doi: https://doi.org/10.5826/dpc.1103a52 accepted: december 10, 2020; published: july 8, 2021 copyright: ©2021 roda and oliveira. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited funding: none competing interests: none authorship: both authors have contributed significantly to this publication corresponding author: ângela roda, md. hospital de santa maria. av. prof. egas moniz, 1649-035 lisboa, portugal. email: angela.neto. roda@gmail.com case presentation a 45-year-old woman presented with a history of a slowly growing asymptomatic solitary yellowish-red papule on the face. dermoscopy revealed yellow globules over a yellow structureless area at the level of the upper portion of the lesion, in addition to arborizing vessels (av). the lower half of the lesion presented a large blue ovoid nest and red-purple areas suggesting traumatic hemorrhage (figure 1). histopathological examination of the skin lesion revealed a basal cell carcinoma (bcc) with cholesterol crystal deposition. teaching point when evaluating skin tumors, color is one of the most important clues for diagnosis. in dermoscopy, the yellow color has been associated with the content of keratin, calcium, and lipids. yellowish structures, including milia-like cysts and yellow lobular-like structures, have already been described in bccs figure 1. basal cell carcinoma with cholesterol crystal deposition, dermoscopy. yellow globules over a yellow structureless area and thin arborizing vessels are observed mainly in the upper half of the lesion. the lower portion of the lesion presents a large blue ovoid nest on the left side and a red-purple background, suggesting traumatic hemorrhage. 2 image letter | dermatol pract concept. 2021;11(3): e 2021052 [1]. of particular interest, in our case, dermoscopic yellow structures corresponded histologically to cholesterol clefts. cholesterol clefts have rarely been reported in cutaneous tumors other than lipid-rich tumors. however, cholesterol clefts may occur in bcc and have been associated with long-lasting disease or microtrauma [2]. references 1. 1. bellucci c, arginelli f, bassoli s, et al. dermoscopic yellow structures in basal cell carcinoma. j eur acad dermatol venereol. 2014;28(5):651-4. doi: 10.1111/jdv.12092. pmid: 23332004 2. 2. kim hj, park sh, lee sk, et al. cholesterol clefts in basal cell carcinoma: an under-recognized association. am j dermatopathol. 2018;40(8):594-596. doi: 10.1097/ dad.0000000000001147. pmid: 29570130 melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro mattioli 1885 www.mattioli1885.com chief editor prof. giuseppe argenziano, md dermatology unit, university of campania luigi vanvitelli, naples guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo grazie al contributo di melanoma today dpc journal special issue table of contents epidemiology and risk factors of melanoma: a review claudio conforti, iris zalaudek the evolution of the clinical, dermoscopic and pathologic diagnosis of melanoma harald kittler melanoma: staging and follow-up chryssoula papageorgiou, zoe apalla, sofia-magdalini manoli, konstantinos lallas, efstratios vakirlis, aimilios lallas current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco, stefania napolitano, luigi pio guerrera, teresa troiani treatment of advanced metastatic melanoma pietro quaglino, paolo fava, luca tonella, marco rubatto, simone ribero, maria teresa fierro guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. thanks to dermatology practical & conceptual review | dermatol pract concept. 2021;11(s1): e2021165s 1 current landscape and open questions on adjuvant therapies in melanoma vincenzo de falco1, stefania napolitano1, luigi pio guerrera1, teresa troiani1 medical oncology, department of precision medicine, università degli studi della campania “luigi vanvitelli”, napoli, italy key words: locoregional melanoma, stage iii melanoma, adjuvant therapy citation: de falco v, napolitano s, guerrera lp, troiani t. current landscape and open questions on adjuvant therapies in melanoma. dermatol pract concept. 2021;11(s1): e2021165s. doi: https://doi.org/10.5826/dpc.11s1a165s accepted: july 14, 2021; published: july 2021 copyright: ©2021 de falco et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: teresa troiani, md, phd, department of precision medicine, università della campania “luigi vanvitelli”, via s. pansini 5, 80131, napoli, italy. email: teresa.troiani@unicampania.it phone: 00390815666728 melanoma is a form of skin cancer that is frequently diagnosed at early stages. in most cases, surgical resection is curative. in case of thicker melanomas (> pt1b) without clinical or instrumental evidence of metastasis, a sentinel lymph node biopsy is recommended for staging purposes. if the lymph nodes are the only site of disease (macroscopic or microscopic> 1mm), configuring stage iii, the international guidelines recommend the use of adjuvant therapy with checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapies (dabrafenib plus trametinib). these drugs have shown a significant increase in recurrence-free survival, although some doubts and open questions remain. specifically, none of the available treatments has shown a clear benefit in the overall survival rates, the advantages they give in stage iiia are not well known, and finally there are still no prospective clinical studies abstract this article is part of the dpc journal special issue melanoma today guest editors prof. h. peter soyer, md, facd, fahms chair in dermatology. director, dermatology research centre, the university of queensland diamantina institute; director, dermatology department, princess alexandra hospital prof. paola queirolo, md director of the “divisione di oncologia medica del melanoma, sarcoma e tumori rari” istituto europeo di oncologia, ieo. 2 review | dermatol pract concept. 2021;11(s1): e2021165s introduction melanoma is the deadliest of skin cancers and occurs primarily the elderly, still, it is one of the most common cancers diagnosed in young adults, particularly in women [1]. about 50% of patients with cutaneous melanoma harbor a mutation in exon 15 (codon 600) of braf proto-oncogene, conferring a worse prognosis [2]. according to the new 8th edition of the american joint committee on cancer (ajcc) staging, patients with early-stage (i-ii) have an overall favorable prognosis, whereas patients with stage iii melanoma have a rather heterogeneous prognosis [3]. the discovery of immune checkpoint inhibitors and targeted therapies (tt) revolutionized the treatment scenario of metastatic melanoma and with the latest evidence these drugs were also added in adjuvant setting. in this work, we will review the state of art and the unresolved questions of adjuvant therapy. finally, we will examine future directions for stage iii cutaneous melanoma. immunotherapy (it) until few years ago, only interferon-α (ifn-α) showed a survival benefit in this setting, although it had a very modest efficacy and was limited to ulcerated melanoma [4]. anti-programmed cell death-1 (anti-pd-1) antibodies such as nivolumab and pembrolizumab and anticytotoxic t lymphocyte-associated antigen 4 (anti-ctla-4) antibodies such as ipilimumab clearly exhibited a benefit in terms of progression free survival (pfs) and overall survival (os) in patients with metastatic melanoma [5]. for this reason, several trials have evaluated the efficacy of these drugs in reducing the risk of relapse in stage iii radically resected melanomas. in 2015, eortc 18071 trial evaluated ipilimumab at a dose of 10mg/kg versus placebo for up to 3 years in patients who had undergone complete resection of stage iii melanoma [6]. both recurrence-free survival (rfs) and os were significantly superior in the ipilimumab group compared to placebo group at the cost of very high percentage of serious adverse events (5 patients died for immune-related toxicities). ipilimumab was therefore considered too toxic and was not approved by the european medicines agency (ema) in patient populations who are potentially cured with surgery alone. on the other hand, checkmate-238 trial tested nivolumab 3mg/kg vs ipilimumab 10mg/kg for up to 1 year in stage iiib-c (81.3% of study population) and stage iv radically resected melanomas [7]. the 4-year rfs was 52.4% for the nivolumab group vs 24.1% for the ipilimumab group, with a hazard ratio (hr) of 0.71 (p=.0003) [8]. most frequent adverse events were fatigue, diarrhea, pruritus, and rash but only in 14.4% of cases, these were grade 3-5. nonetheless, the keynote-054 trial compared pembrolizumab 200mg versus placebo in stage iiia-b-c radically resected melanoma: 3.5-year rfs was 59.8% versus 41.4%, respectively (hr 0.59, p<.001). adverse events were similar to those reported with other anti-pd1 inhibitors [9]. very recently, the last update of the s1404 trial was presented, in which pembrolizumab was compared with 1 year of high dose interferon or up to 3 years of ipilimumab in radically resected stage iii or iv melanoma: hr for rfs was 0.74 (p<0.001) [10]. after these strong evidences, nivolumab and pembrolizumab were approved by ema as adjuvant therapy for all stage iii melanomas (nivolumab also for radically resected stage iv). finally, also the combination of nivolumab and ipilimumab has been tested in adjuvant settings in immuned trial and checkmate-915 trial with conflicting results. in the first case, a german phase ii trial, patients with radically resected stage iv melanoma were randomly assigned to nivolumab+ipilimumab or nivolumab alone, or placebo. hr for recurrence for the doublet group vs placebo was 0.23 and median rfs was not reached after median follow-up of 28.4 months [11]. on the contrary, phase iii checkmate-915 examined adjuvant nivolumab vs combination of nivolumab and ipilimumab in resected stage iiib-d or iv melanomas, but it did not meet its endpoint [12]. these results might be due to the different study population and to the different dose/frequency of ipilimumab, nonetheless further studies are needed. targeted therapy (tt) as immunotherapies, braf and mek inhibitors represented a turning point for the treatment of braf mutant metastatic melanomas with very high response rates and a significant benefit in terms of pfs and os. regarding the efficacy in the adjuvant setting, combi-ad trial tried to show the efficacy of these drugs also in the adjuvant setting. it compared dabrafenib (braf inhibitor) 150 mg twice daily plus trametinib (mek inhibitor) at a dose of 2 mg once daily, versus placebo in stage iiia-b-c melanoma. in the last update, 3-years rfs was 58% in the experimental arm and 39% in the placebo arm (hr 0.47 p<0.001) [13]. adverse events were repreidentifying the best approach to continue the therapeutic process in case of relapse. furthermore, there are new opportunities opening up with the upcoming results of the neoadjuvant trials that could revolutionize the treatment of clinically evident stage iii melanoma. review | dermatol pract concept. 2021;11(s1): e2021165s 3 sented by pyrexia, fatigue, nausea, headache, chills, diarrhea, arthralgia, and rash. these were of grade 3 to 5 in 41% of cases. however, also dabrafenib plus trametinib became a valid option as adjuvant therapy. open questions on adjuvant therapy and how to manage recurrences despite the undoubted effectiveness of these therapies, a number of open questions still remain open. these concern for instance the timing of their use and the risk/benefit ratio in some subgroups of patients. first of all, there is still no evidence regarding the benefit in survival rates: although ipilimumab had already demonstrated an os advantage vs placebo, in the checkmate-238, following a 48 months follow-up there are no differences in os between nivolumab and ipilimumab (78% vs 77%, hr 0.87 p=0.315)[8]. however, fewer events than expected occurred in the trials, so it is underpowered. also, for pembrolizumab in s1404 no benefit in os was observed [10]. moreover, in the combi-ad trial the statistical significance did not reach the prespecified target of p=0.000019 (3-years os: 86% vs 77%, hr 0.57 p=0.0006) [13]. definitive data of these 2 studies and of keynote-054, the only study in which a cross-over between treatments was allowed, will clarify if starting the therapy at the time of relapse affects survival rates. a second important aspect is that all these studies started before the definitive data of multicentre selective lympadenectomy trial ii [14] and the german dermatologic cooperative oncology group-selective lymphadenectomy trial [15], that did not report an improvement in melanoma specific survival (mss) for complete lymph node dissection versus periodic ultrasonographic surveillance in patients with positive sentinel lymph node. this suggests that the study population does not correspond to patients treated in current clinical practice. moreover, the new edition of ajcc staging was approved and the main changes concerned stage iii: stage iiid was added, and the subgroups were re-distributed. more in detail, stage iiia now includes t1a-b n1-2a and t2a n1-2a [16]. in the adjuvant trials, only patients categorized as stage iiia with nodal metastases >1mm (checkmate-238 did not include them), were included. furthermore, patients enrolled in these trials with positive sln have had lymphadenectomy, indicating that some of the stage iiia may be up-staged. on the other hand, in clinical practice, several patients without nodal dissection could be downgraded to iiia (for example if they have metastatic non-sentinel lymph nodes). however, taking into account the high melanoma specific survival in this stage (80%-93%) [17], and the risks of durable and serious adverse events, adjuvant therapy should be carefully discussed with these patients [18]. finally, an unmet need that originated from adjuvant trials is the management of relapses during and after treatment. there is in fact a lack of prospective randomized studies investigating this question, as only retrospective experiences are reported. what we know is that the majority of recurrences are with distant metastases (including locoregional+distant metastases) and they are mostly on-treatment during anti-pd-1 therapy [19] and after treatment with targeted therapies [20, 21]. this observation led to support the idea that treatment with brafand mek-inhibitors should be prolonged to more than a year (2-3 years?) to improve its efficacy. however, when the relapse occurs during adjuvant therapy (or within few months from its conclusion), it is good practice to switch to another treatment, particularly in braf mutant patients (ittt and ttit). on the contrary, a rechallenge approach, adopting the same drugs, when the relapse occurs off treatment, could be a good option because of good response rates, especially for tt. nevertheless, data from pembrolizumab rechallenge in the keynote-054 study, performed on patients who recurred after 6 months from the completion of adjuvant therapy, were very disappointing [22]. furthermore, radical surgery followed or not by systemic adjuvant therapy, should be done when recurrence is locoregional and when radical surgery is achievable. a step forward there are several ongoing trials trying to solve the open questions for the management of locoregional melanoma. one of these issues concerns adjuvant therapy for melanomas without involvement of lymph nodes: paradoxically, 5-year survival of stage iib (87%) and iic (82%) is worse than stage iiia (93%). keynote-716 and checkmate-76k will compare the efficacy of pembrolizumab and nivolumab, respectively, versus placebo in these patients. results are expected for 2023-24. a closer change in clinical practice will probably come from neoadjuvant studies for clinical stage iii melanoma. up to now, the relapse rate for radically resected melanoma with nodal macro metastases was 40% at 2 years with immunotherapies and 40% at 3 years with targeted therapies (without considering 15-20% of patients in the trials recurred during the screening period before the start of adjuvant therapy) [23]. neoadjuvant therapy could improve outcome from surgery, could personalize adjuvant treatment based on treatment response, and could safely provide tissue for analysis of resistance mechanisms from those who do not have a pathological response. for this reason, in the last years several trials have evaluated this strategy and a recent pooled analysis summarized the results of 6 of them (2 with targeted therapy, 4 with immunotherapy) [19]. in particular, pathological complete response (pcr) was found to be a good surrogate of rfs and os. pcr rate was 39.7% in the whole cohort: worst 4 review | dermatol pract concept. 2021;11(s1): e2021165s results were found for single agent nivolumab (pcr 20%), while similar outcomes were found for dabrafenib+trametinib (47%) and for nivolumab+ipilimumab (42.7%). the rfs was similar between combination immunotherapies and targeted therapies after 1 year (84% vs 75%) while a significant difference was seen at 2 years (80% vs 47%). furthermore, with nivolumab+ipilimumab, impressive os were achieved in patients who obtained a pcr, or a near pcr, or a partial response (about 2/3 of patients) reaching 99% after 2 years. despite this very promising result, larger studies are needed to confirm these findings and to clarify other open questions such as understanding the mechanisms underlying the relapse in 21% of patients with pcr to targeted therapy. conclusion the efficacy of immunotherapy and targeted therapy as adjuvant treatment in stage iii melanoma is unquestionable. something could change soon when the overall survival results will be consolidated and when data on neoadjuvant therapy will be more consistent. to date, there is no evidence that one type of treatment among those approved is more effective than another. for this reason, personalized treatment must be based on the clinical-pathological characteristics of the disease, on patient compliance, and on comorbidities, taking into account the side effects of each drug. references 1. paulson kg, gupta d, kim ts, et al. age-specific incidence of melanoma in the united states. jama dermatol. 2020;156(1):5764. doi:10.1001/jamadermatol.2019.3353. pmid:31721989. 2. giunta ef, de falco v, napolitano s, et al. optimal treatment strategy for metastatic melanoma patients harboring braf-v600 mutations. ther adv med oncol. 2020;12. doi:10.1177/1758835920925219. pmid: 32612709. 3. balch cm, gershenwald je, soong s-j, et al. final version of 2009 ajcc melanoma staging and classification. j clin oncol. 2009;27(36):6199-6206. doi:10.1200/jco.2009.23.4799. pmid: 19917835. 4. ives nj, suciu s, eggermont amm, et al. adjuvant interferon-α for the treatment of high-risk melanoma: an individual patient data meta-analysis. eur j cancer. 2017;82:171-183. doi:10.1016/j.ejca.2017.06.006. pmid: 28692949. 5. michielin o, van akkooi acj, ascierto pa, dummer r, keilholz u, esmo guidelines committee. electronic address: clinicalguidelines@esmo.org. cutaneous melanoma: esmo clinical practice guidelines for diagnosis, treatment and follow-up†. ann oncol. 2019;30(12):1884-1901. doi:10.1093/annonc/mdz411. pmid: 31566661. 6. eggermont amm, chiarion-sileni v, grob j-j, et al. prolonged survival in stage iii melanoma with ipilimumab adjuvant therapy. new england journal of medicine. 2016;375(19):1845-1855. doi:10.1056/nejmoa1611299. pmid: 27717298. 7. weber j, mandala m, del vecchio m, et al. adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma. new england journal of medicine. 2017;377(19):1824-1835. doi:10.1056/nejmoa1709030. pmid: 28891423. 8. ascierto pa, del vecchio m, mandalá m, et al. adjuvant nivolumab versus ipilimumab in resected stage iiib-c and stage iv melanoma (checkmate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. lancet oncol. 2020;21(11):1465-1477. doi:10.1016/s1470-2045(20)30494-0. 9. eggermont amm, blank cu, mandala m, et al. adjuvant pembrolizumab versus placebo in resected stage iii melanoma. new england journal of medicine. 2018;378(19):1789-1801. doi:10.1056/nejmoa1802357. pmid: 29658430. 10. grossmann kf, othus m, patel sp, et al. final analysis of overall survival (os) and relapse-free-survival (rfs) in the intergroup s1404 phase iii randomized trial comparing either high-dose interferon (hdi) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma. jco. 2021;39(15_suppl):9501-9501. doi:10.1200/jco.2021.39.15_suppl.9501. 11. zimmer l, livingstone e, hassel jc, et al. adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage iv melanoma with no evidence of disease (immuned): a randomised, double-blind, placebo-controlled, phase 2 trial. lancet. 2020;395(10236):1558-1568. doi:10.1016/s0140-6736(20)30417-7. 12. long gv, schadendorf d, vecchio md, et al. abstract ct004: adjuvant therapy with nivolumab (nivo) combined with ipilimumab (ipi) vs nivo alone in patients (pts) with resected stage iiib-d/iv melanoma (checkmate 915). cancer res. 2021;81(13 supplement):ct004-ct004. doi:10.1158/1538-7445.am2021ct004. 13. long gv, hauschild a, santinami m, et al. adjuvant dabrafenib plus trametinib in stage iii braf-mutated melanoma. new england journal of medicine. 2017;377(19):1813-1823. doi:10.1056/nejmoa1708539. pmid:28891408. 14. faries mb, thompson jf, cochran aj, et al. completion dissection or observation for sentinel-node metastasis in melanoma. n engl j med. 2017;376(23):2211-2222. doi:10.1056/nejmoa1613210. pmid: 28591523. 15. leiter u, stadler r, mauch c, et al. final analysis of decog-slt trial: no survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node. j clin oncol. 2019;37(32):3000-3008. doi:10.1200/jco.18.02306. pmid: 31557067. 16. gershenwald je, scolyer ra, hess kr, et al. melanoma staging: evidence-based changes in the american joint committee on cancer eighth edition cancer staging manual. ca: a cancer journal for clinicians. 2017;67(6):472-492. doi:10.3322/caac.21409. pmid: 29028110. 17. garbe c, keim u, suciu s, et al. prognosis of patients with stage iii melanoma according to american joint committee on cancer version 8: a reassessment on the basis of 3 independent stage iii melanoma cohorts. j clin oncol. 2020;38(22):2543-2551. doi:10.1200/jco.19.03034. pmid: 32530760. 18. michielin o, van akkooi a, lorigan p, et al. esmo consensus conference recommendations on the management of locoregional melanoma: under the auspices of the esmo guidelines committee. ann oncol. 2020;31(11):1449-1461. doi:10.1016/j. annonc.2020.07.005. pmid: 32763452. review | dermatol pract concept. 2021;11(s1): e2021165s 5 19. owen cn, shoushtari an, chauhan d, et al. management of early melanoma recurrence despite adjuvant anti-pd-1 antibody therapy. ann oncol. 2020;31(8):1075-1082. doi:10.1016/j. annonc.2020.04.471. pmid: 32387454. 20. bhave p, pallan l, atkinson v, et al. melanoma recurrence after adjuvant targeted therapy: a multicenter analysis. jco. 2020;38(15_suppl):10016-10016. doi:10.1200/ jco.2020.38.15_suppl.10016. 21. bhave p, pallan l, long gv, et al. melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis. british journal of cancer. 2021;124(3):574-580. doi:10.1038/s41416-020-01121-y. pmid: 33087895. 22. crossover and rechallenge with pembrolizumab in recurrent patients from the eortc 1325-mg/keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage iii melanoma. journal of clinical oncology. accessed july 13, 2021. https://ascopubs.org/doi/abs/10.1200/ jco.2021.39.15_suppl.9500 23. menzies am, amaria rn, rozeman ea, et al. pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the international neoadjuvant melanoma consortium (inmc). nature medicine. 2021;27(2):301-309. doi:10.1038/s41591-020-01188-3. pmid: 33558722. 1-indice 5-1882 dermatology: practical and conceptual image letter | dermatol pract concept. 2022;12(2):e2022059 1 dermatology practical & conceptual case presentation in short, anagen hair syndrome (sas), the hairs are short, fine, and sparse since birth even if the typical patient presents to a medical consultation around the age of 5-6 years. parents often complain the hair doesn’t grow long and that they have never been cut. the presence of short hair shafts is due to a short duration of the anagen phase. hair shafts have also been described as thinner and in telogen phase. the clinician should rule out congenital hypotrichosis, loose anagen hair syndrome, telogen effluvium. teaching point we propose the card test as a quick and inexpensive method to help in the diagnosis of sas. tufts of hairs are placed on a card (figure 1a) and observed with a dermoscope at 20x magnification: thin hair shafts with pointed tips are proof the hairs have never been cut (figure 1b). this test can be done even without pulling the hair out of the scalp. card test as a simple method to diagnose short anagen syndrome matilde iorizzo1, michela starace2,3 1 private dermatology practice, bellinzona/lugano, switzerland 2 dermatology, irccs, azienda ospedaliero-universitaria di bologna, bologna, italy 3 department of experimental, diagnostic and specialty medicine, university of bologna, bologna, italy. citation: iorizzo m, starace m. card test as a simple method to diagnose short anagen syndrome. dermatol pract concept. 2022;12(2):e2022059. doi: https://doi.org/10.5826/dpc.1202a59 accepted: august 19, 2021; published: april 2022 copyright: ©2022 iorizzo et al. this is an open-access article distributed under the terms of the creative commons attributionnoncommercial license (by-nc-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: none. competing interests: none. authorship: both authors have contributed significantly to this publication. corresponding author: matilde iorizzo, md phd, private dermatology practice, viale stazione 16, 6500 bellinzona (switzerland). e-mail: matildeiorizzo@gmail.com figure 1. (a) the card test showing how a tuft of short hairs should be placed on a card before observing them with a dermatoscope. (b) multiple and exclusively pointed tips, showing the short shafts have never been cut, and after cut, are easily seen with a 20x magnification. dermatology: practical and conceptual dermatology practical & conceptual research | dermatol pract concept 2021;11(3):e2021055 1 management of a chronic skin disease in primary care: an analysis of early-career general practitioners’ consultations involving psoriasis sameerah nawaz1, amanda tapley 2, 3, andrew r. davey 2, 3 mieke l. van driel4, alison fielding 2,3, elizabeth g. holliday2, jean ball5, irena patsan2,3, alyse berrigan3, simon morgan1, neil a. spike6,7, kristen fitzgerald8,9, parker magin2,3 1 gp synergy, regional training organisation, liverpool, nsw, australia 2 the university of newcastle, school of medicine and public health, callaghan, nsw, australia 3 gp synergy, regional training organisation, nsw & act research and evaluation unit, mayfield west, nsw, australia 4 the university of queensland faculty of medicine, primary care clinical unit, brisbane, qld, australia 5 hunter medical research institute, clinical research design, it and statistical support unit (creditss), new lambton, nsw, australia 6 eastern victoria gp training, general practice training organisation, melbourne, australia 7 the university of melbourne, department of general practice, melbourne, vic, australia 8 university of tasmania, school of medicine, hobart, tas, australia 9 general practice training tasmania (gptt), regional training organisation, hobart, tas, australia key words: general practice, family practice, psoriasis, continuity of patient care, medical and graduate education, chronic disease citation: nawaz s, tapley a, davey ar, van driel ml, fielding a, holliday eg, ball j, patsan i, berrigan a, morgan s, spike na, fitzgerald k, magin p. management of a chronic skin disease in primary care: an analysis of early-career general practitioners’ consultations involving psoriasis dermatol pract concept. 2021;11(3):e2021055. doi: https://doi.org/10.5826/dpc.1103a55 accepted: december 14, 2020; published: may 20, 2021 copyright: ©2021 nawaz et al. this is an open-access article distributed under the terms of the creative commons attribution license by-nc-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. funding: the recent project was funded from 2010 to 2015 by the participating educational organisations: general practice training valley to coast, the victorian metropolitan alliance, general practice training tasmania, adelaide to outback gp training program, and tropical medical training, all of which were funded by the australian government department of health. from 2016-2019, recent is funded by an australian government department of health commissioned research grant and supported by gp synergy regional training organisation. gp synergy is funded by the australian government department of health. competing interests: the authors have no conflicts of interest to disclose. authorship: all authors have contributed significantly to this publication. corresponding author: parker magin, phd, fracgp, 20 mcintosh dr, mayfield west, 2304 nsw, australia. email: parker.magin@newcastle.edu.au background: the management of psoriasis by general practitioners (gps) is vital, given its prevalence, chronicity, and associated physical and psychosocial co-morbidities. however, there is little information on how gps (including early-career gps) manage psoriasis. objectives: this study assessed the frequency with which australian specialist gp vocational trainees (‘registrars’) provide psoriasis care and the associations of that clinical experience. methods: a cross-sectional analysis was done of data from the recent study, an ongoing multiabstract 2 research | dermatol pract concept 2021;11(3):e2021055 introduction psoriasis is an autoimmune and autoinflammatory condition resulting in chronic inflammation of the skin and, typically, a prolonged clinical course. there are different phenotypes associated with varied genetics, immune pathophysiology and symptoms [1]. the most common type, chronic plaque psoriasis, comprises 90% of cases [2]. other types of psoriasis include guttate psoriasis, generalised pustular psoriasis, palmoplantar psoriasis and erythrodermic psoriasis [3]. psoriasis can also be classified into two types according to age at onset. type i psoriasis is the more common type, comprising 75% of all cases, and is associated with early onset (before age 40) and more severe disease (hla-cw*0602 positive.) type ii psoriasis is hla-cw*0602 negative, and occurs later in life [4]. there is a wide variation in the prevalence of psoriasis among different populations. variations in prevalence may be attributable to study design (eg population-based versus hospital based, or self-reported versus clinician-diagnosed) or to geographic and environmental factors [5]. it is clear that australia has a particularly high prevalence of psoriasis [6]. psoriasis in australian aboriginal people, however, is rare or absent [7]. the burden of psoriasis on individuals can include significant physical, social and psychological impacts [8,9]. psoriasis is associated with lifestyle factors including obesity, smoking and alcohol use [10]. independent of these risk factors, psoriasis is associated with multiple medical comorbidities including psoriatic arthritis (30%), inflammatory bowel disease, metabolic syndrome, non-alcoholic fatty liver disease, cardiovascular disease, myocardial infarction, diabetes, chronic renal disease and stroke [11-14]. psychiatric and psychosocial comorbidities and impairment of quality of life are common and problematic [9,15,16]. additionally, treatments for psoriasis can have adverse effects involving multiple systems [8]. thus, given the prevalence, chronicity, and physical and psychosocial comorbidities of psoriasis, it is vital that general practitioners (gps) are continually engaged in – and have expertise in – the management of psoriasis. australian gps (family physicians) encounter psoriasis with a frequency of approximately 0.2 in every 100 patient visits [17]. patients’ experiences of gp consultations for psoriasis may often be negative, with many finding that gps have limited knowledge and, more importantly, limited appreciation of its impact on patients’ lives [18]. registrars are early-career gps practising within a national specialist general practice training program. they are establishing what may be long-lasting practice patterns in a clinical context of having been underprepared for managing skin disease by their undergraduate and junior doctor experiences [19-21]. an understanding of consultation and management patterns, as with skin disease in general, can lead to a better understanding and improvement of psoriasis management in the community setting [22]. in this study, we aimed to establish the frequency and associations of psoriasis consultations in registrars’ clinical experience. in view of the chronicity of psoriasis, we were particularly interested in the associations of factors related to the continuity of care. materials and methods this was a cross-sectional analysis of data from the registrar clinical encounters in training (recent) study. recent recent is an ongoing multi-site cohort study of australian gp registrars. participants are registrars in the 3 compulsory general-practice-based training terms of australian gp vocational training. registrars practice within an apprenticeship-like training model [23], but with considerable site cohort study of australian gp registrars’ experiences during vocational training. in recent, 60 consecutive consultations are recorded 3 times (6-monthly) during each registrar’s training. the outcome factor for this analysis was a problem/diagnosis being psoriasis, and independent variables were related to registrar, patient, practice and consultation factors. this study analysed 17 rounds of data collection (2010-2017) using univariate and multivariable regression. results: data from 1,741 registrars regarding 241,888 consultations and 377,980 problems/diagnoses were analysed. psoriasis comprised 0.15% (n=550) of all problems/diagnoses (95% ci, 0.13-0.16). significant patient multivariable associations of a problem/diagnosis being psoriasis included age, gender, being new to a practice or a registrar, and psoriasis being an existing problem rather than a new diagnosis. significant registrar associations included seeking in-consultation information/assistance, not scheduling a follow-up appointment, prescribing medication, and generating learning goals. conclusions: australian registrars have modest training exposure to psoriasis and may find psoriasis management challenging. furthermore, continuity of care (essential for optimal chronic disease management) was modest. the findings have implications for gps’ approaches to the management of psoriasis more widely as well for general practice education and training policies. research | dermatol pract concept 2021;11(3):e2021055 3 clinical autonomy (whereby they can request assistance from their experienced gp supervisor, if required). from 2010 to 2015, 5 of australia’s 17 regional training providers (rtps) participated and, since 2016, 3 of australia’s 9 regional training organisations (rtos) have participated (in 2016 there was a major restructuring of australian gp training). rtos and rtps are geographically defined, not-for-profit educational organisations. hereafter, rtos, rtps and rto subregions are referred to as ‘regions’. at the time of this analysis, individual regions had contributed from 3 to 17 rounds of data collection. the methodology has been described elsewhere [24]. briefly, registrars undertake data collection once per 6-month training term as an integral component of their educational program [25]. the data are used to compose detailed written feedback reports for registrar reflection on their clinical practice and educational and training needs. registrars may provide written informed consent for their de-identified data to also be used for research purposes. initial data collection involves registrar demographic, educational, and work experience, plus characteristics of the practice in which they are currently working. approximately mid-way through the training term, registrars record the details of 60 consecutive patient consultations on a paper-based case report form. as data collection is designed to reflect a ‘normal’ week of general practice, consultations in a specialised clinic, eg vaccination clinic, are excluded. only office-based consultations (not home visits or nursing home visits) are recorded. outcome factor the outcome factor in this study was a problem/diagnosis being ‘psoriasis’. ‘psoriasis’ was defined as the icpc-2 code s91 001 (psoriasis). in recent, problems/diagnoses are coded according to the international classification of primary care, second edition classification system (icpc-2 plus) [26]. independent variables independent variables listed in table 2 related to registrar, patient, practice, and consultation (including in-consultation educational factors). each practice’s postal code was used to define the degree of rurality, according to the australian standard geographical classification-remoteness area (asgc-ra) classification [27] and the location’s socioeconomic index for area (seifa) relative index of disadvantage [28]. statistical analysis analysis was performed on 17 rounds of data collected from 2010 to 2017. analysis was at the level of individual problem/diagnosis. the proportions of registrars’ problems/ diagnoses that were psoriasis and of consultations involving a psoriasis problem/diagnosis were calculated, with 95% confidence intervals, adjusted for clustering within registrars. to test associations of a problem/diagnosis being psoriasis, simple and multiple logistic regression were used within the generalised estimating equations (gee) framework to account for clustering of patients within registrars. (this is the lowest level of clustering in the study design: previous analyses of the recent data set have demonstrated that also adjusting for clustering at practice level is non-contributory.) all variables with a p value less than .20 in the univariate analysis were included in the multiple regression model. covariates with p >.2 in the resulting multivariable model were tested for removal. if the covariate’s removal did not substantively change the model, the covariate was removed from the final model. the outcome proportion for psoriasis was very low (0.15%), which can cause problems of complete or quasi-complete separation of data. this means that the outcome variable separates a predictor variable or a combination of predictor variables completely. to check for the impact of data separation, logistic regression coefficients were estimated using firth’s penalised likelihood in a sensitivity analysis. coefficients differed negligibly in the sensitivity analysis, and thus results from standard logistic regression were reported. results from the logistic regression were reported as odds ratios (or) with 95% confidence intervals. in order to examine 3 separate issues within our overall research question, 3 models were built, each with ‘psoriasis being the problem/diagnosis’ as the dependent variable: a) to examine the question of associations of a problem/ diagnosis being psoriasis, patient, practice, and registrar independent variables were entered in an initial regression model. b) to examine the question of in-consultation differences of a psoriasis problem/diagnosis problem compared with other problems/diagnoses, the above variables were entered in a model along with the following additional variables: consultation duration, information/assistance accessed by the registrar, number of problems/diagnoses dealt with in the consultation, and consultation duration. c) to examine the question of whether actions arising from managing psoriasis differ from those arising from other problems/diagnoses, all variables entered in the previous 2 models were entered in a new model along with the following additional variables: learning goals generated by the registrar, follow-up organised, specialist referrals made, and pathology tests and imaging exams ordered. the rationale for the building of the 3 models was that whether a patient presents with psoriasis (our first question) will plausibly be influenced by patient, registrar, and practice factors, but evaluation of this question may be biased by inclusion in the model of factors operating once the consultation is progressing. similarly, evaluation of the content of the consultation (our second question), may be 4 research | dermatol pract concept 2021;11(3):e2021055 biased by the inclusion in the model of actions arising from the consultation. the frequencies with which medicines were prescribed for psoriasis, and with which referrals were made, were calculated. the frequency with which sources of in-consultation information or assistance were sought was also calculated. statistical analyses were programmed using stata 14.0 and sas v9.4. p values <.05 were considered statistically significant. ethics approval the recent project has approval from the university of newcastle human research ethics committee (reference h-2009-0323). results the study analysed data from a total of 1,741 registrars (response rate, 96.0%). the demographics of participating registrars are presented in table 1. the registrars provided data on 241,888 consultations and 377,980 problems/diagnoses. of all problems/diagnoses, 550 (0.15% [95% ci, 0.13-0.16]) were a psoriasis problem/diagnosis. this equates to 0.22% of all consultations (95% ci, 0.20-0.24). associations of psoriasis problems/diagnoses managed by registrars table 2 presents the characteristics associated with a problem/diagnosis being psoriasis in the 1,741 registrars’ practices. table 3 presents the results of simple and multiple logistic regression analyses. significant patient associations on multivariable analysis of the problem/diagnosis being psoriasis were age group 15-34 (compared to younger or older patients), male gender (or = 0.7 for female gender), the patient being new to the practice (or = 2.6 compared to an existing patient of the practice), the patient being new to the registrar (or = 2.1 compared to an existing patient of the practice), and the problem being an existing one (or = 0.1 for a new problem). the significant registrar association was training term 3 (or = 1.3 compared to term 1). the significant multivariable consultation association of the problem/ diagnosis being psoriasis was seeking in-consultation information or assistance (or = 2.4). table 1. participating trainee, trainee-term and practice characteristics variable class n (%) or mean (sd) registrar variables (n=1741) registrar gender female 1,116 (64.1) pathway registrar enrolled in (general or rural) rural 446 (25.8) international medical graduate or qualified as a doctor in australia international graduate 302 (17.5) registrar-term or practice-term variables (n=4072) registrar training term term 1 1,613 (39.6) term 2 1,471 (36.1) term 3 988 (24.3) registrar age (years) mean (sd) 32.4 (6.1) registrar works full time yes 3079 (77.7) registrar worked at the current practice previously yes 996 (24.8) does the practice routinely bulk bill1 all patients yes 898 (22.4) number of gps working at the practice 1-5 1,430 (36.2) 6-9 2,526 (63.9) rurality of practice major city 2,443 (60.2) inner regional 1,021 (25.2) outer regional, remote or very remote 594 (14.6) seifa2 index of practice mean (sd) 5.5 (2.8) 1 bulk bill, to charge the entire costs of an episode of patient care to the australian national health care system. 2 seifa = socioeconomic index for area relative index of disadvantage. research | dermatol pract concept 2021;11(3):e2021055 5 table 2. characteristics associated with a problem/diagnosis in registrars’ practice being psoriasis variable class problem/diagnosis, n (%)1 p other psoriasis total 377,430 (100) 550 (100) patient variables age group (years) 0-14 52,353 (14) 19 (4) <.001 15-34 98,406 (26) 149 (28) 35-64 147,691 (40) 278 (51) ≥65 73,227 (20) 95 (18) gender male 138,926 (38) 251 (47) <.001 female 229,392 (62) 288 (53) aboriginal torres strait islander status no 348,082 (98) 501 (98) .32 yes 5,657 (2) 11 (2) non-english-speaking background no 328,363 (92) 480 (94) .23 yes 28,129 (8) 33 (6) patient/practice status existing patient 158,290 (43) 180 (34) <.001 new to registrar 184,591 (50) 312 (58) new to practice 25,953 (7) 43 (8) registrar variables gender male 131,335 (35) 199 (36) .54 female 246,095 (65) 351 (64) works full time no 84,158 (23) 117 (22) .53 yes 283,552 (77) 422 (78) term term 1 152,328 (40) 223 (41) .14 term 2 134,357 (36) 177 (32) term 3 90,745 (24) 150 (27) worked at practice previously no 279,145 (75) 416 (76) .42 yes 93,406 (25) 128 (24) qualified as doctor in australia no 63,796 (17) 75 (14) .058 yes 311,330 (83) 470 (86) age (years) mean (sd) 32 (6) 32 (6) .76 practice variables practice size small 134,317 (37) 192 (35) .58 large 232,596 (63) 349 (65) routine bulk billing2 no 289,580 (78) 418 (77) .68 yes 83,118 (22) 125 (23) rurality major city 225,666 (60) 337 (62) .48 inner regions 94,719 (25) 125 (23) outer regions or remote 55,786 (15) 85 (16) sub-region 1 100,799 (27) 146 (27) .89 2 36,149 (10) 46 (8) 3 49,566 (13) 74 (13) 4 151,255 (40) 227 (41) 5 10,400 (3) 12 (2) 6 29,261 (8) 45 (8) seifa (decile) mean (sd) 5 (3) 6 (3) .28 table 2. continues 6 research | dermatol pract concept 2021;11(3):e2021055 significant multivariable associations with factors arising from the registrar’s management of the problem/diagnosis included follow-up being less likely (or = 0.7 for organising follow-up), medication being prescribed (or = 3.8),and learning goals being generated (or = 2.8). medication was prescribed for 435 (79%) of psoriasis problems/diagnoses. the most common medicines prescribed for psoriasis were betamethasone (31% of all prescriptions for psoriasis), mometasone (21%) and calcipotriol and combinations (20.0%). see table 4 for the list of most commonly prescribed medications. only 180 patients with psoriasis problems/diagnoses (34%) had seen the registrar previously (for any reason), and for only 199 psoriasis problems/diagnoses (36%) was follow-up organised. in 89% of instances, this was with the registrar personally. when seen for psoriasis, 13% of patients were referred to a dermatologist, with 9% of new diagnoses being referred and 15% of previously diagnosed patients being referred. in-consultation information or assistance was accessed for 29% of psoriasis problems/diagnoses. the sources of in-consultation assistance or information used were electronic sources (64%), the registrar’s supervisor (33% of instances), hard-copy sources (6%), and specialists (4%). discussion frequency of psoriasis problems/diagnoses encountered we found that 0.22% of registrar consultations involved a psoriasis diagnosis/problem. while this is comparable to the frequency with which established gps encounter psoriasis [17], this equates to approximately once every 8 weeks, or approximately 10 times during registrars’ 3 core general practice training terms. this relative low frequency of registrars managing psoriasis (together with a lack of undergraduate and hospital doctor experience of skin disease) [19] suggests these early-career gps may have unmet learning needs related to psoriasis. this is consistent with the association we found with high levels of seeking in-consultation information or assistance and generation of learning goals in relation to psoriasis compared to other problems. variable class problem/diagnosis, n (%)1 p other psoriasis consultation variables new problem seen no 152,857 (44) 417 (84) <.001 yes 192,886 (56) 80 (16) sought help from any source no 315,534 (84) 391 (71) <.001 yes 61,896 (16) 159 (29) consultation duration (minutes) mean (sd) 19 (10) 19 (10) .47 number of problems dealt with in the consultation mean (sd) 2 (1) 2 (1) .002 consultation outcome variables imaging exam ordered no 348,644 (92) 546 (99.3) <.001 yes 28,786 (8) 4 (0.7) pathology exam ordered no 308,712 (82) 506 (92) <.001 yes 68,718 (18) 44 (8) learning goals generated no 298,600 (83) 338 (65) <.001 yes 61,465 (17) 179 (35) follow-up ordered no 211,640 (56) 351 (64) <.001 yes 165,790 (44) 199 (36) referral ordered no 331,078 (88) 470 (85) .11 yes 46,352 (12) 80 (15) medication prescribed no 211,612 (56) 115 (21) <.001 yes 165,818 (44) 435 (79) seifa = socioeconomic index for area relative index of disadvantage. 1 values are n (%) unless otherwise indicated. percentages are out of the total number of problems/diagnoses. 2 bulk bill, to charge the entire costs of an episode of patient care to the australian national health care system. table2. characteristics associated with a problem/diagnosis in registrars’ practice being psoriasis (continued) research | dermatol pract concept 2021;11(3):e2021055 7 table 3. associations of a problem/diagnosis in the registrars’ practice being psoriasis: univariate and multivariable models variable class univariate adjusted or (95% ci) p or (95% ci) p patient, registrar and practice variables patient age group (referent: 15-34 years) 0-14 0.2 (0.2, 0.4) <.001 0.3 (0.2, 0.5) <.001 35-64 1.2 (1.0, 1.5) .041 1.0 (0.8, 1.3) .82 ≥65 0.9 (0.7, 1.1) .24 0.7 (0.5, 0.9) .004 patient gender female 0.7 (0.6, 0.8) <.001 0.7 (0.6, 0.8) <.001 patient/practice status (referent: existing patient) new to practice 1.5 (1.1, 2.0) .023 2.6 (1.8, 3.7) <.001 new to registrar 1.5 (1.2, 1.8) <.001 2.1 (1.7, 2.5) <.001 term (referent: term 1) term 2 0.9 (0.7, 1.1) .31 1.0 (0.8, 1.2) .75 term 3 1.1 (0.9, 1.4) .27 1.3 (1.0, 1.6) .045 new problem seen yes 0.2 (0.1, 0.2) <.001 0.1 (0.1, 0.2) <.001 consultation variables (adjusted for above variables) sought help from any source yes 2.1 (1.7, 2.5) <.0001 2.4 (2.0, 3.0) <.001 consultation outcome variables (adjusted for above variables) imaging ordered yes 0.1 (0.0, 0.2) <.001 0.1 (0.0, 0.4) <.001 follow-up ordered yes 0.7 (0.6, 0.9) <.001 0.7 (0.6, 0.8) <.001 learning goals generated yes 2.6 (2.2, 3.1) <.001 2.8 (2.1, 3.5) <.001 pathology ordered yes 0.4 (0.3, 0.5) <.001 0.4 (0.3, 0.6) <.001 medication prescribed yes 4.8 (3.9, 6.0) <.001 3.8 (3.0, 4.8) <.001 table 4. most commonly prescribed medicines for psoriasis medication prescriptions, n (%) prescriptions for psoriasis, n (%) new prescriptions, n (%) betamethasone 193 31.4 35.8 mometasone 129 21.0 35.7 calcipotriol and combinations 123 20.0 33.3 methylprednisolone aceponate 35 5.7 80.0 hydrocortisone 27 4.4 48.1 methotrexate 13 2.1 7.7 salicylic acid 13 2.1 69.2 triamcinolone 12 2.0 41.7 methylprednisolone 11 1.8 63.6 clobetasol 6 1.0 33.3 prednisolone 6 1.0 50.0 dithranol and combinations 5 0.8 80.0 patient demographics associated with psoriasis our study showed that a patient being between the ages of 15 and 64 years was significantly associated with the problem/diagnosis being psoriasis (compared to younger or older patients). this is consistent with a previous study that found low rates of psoriasis in the paediatric population, with a peak starting at age 20 and declining after 60 [29]. although previous studies have not found any consistent difference in prevalence by gender [6], our study showed a lower likelihood of registrars seeing psoriasis in females. a possible explanation is that psoriasis has been found to be more severe in males than in females, and our finding may reflect healthcare-seeking behaviours rather than community prevalence [30]. 8 research | dermatol pract concept 2021;11(3):e2021055 associations of a psoriasis problem/diagnosis the registrar being in term 3 (vs. term 1) of their training was significantly associated with a psoriasis problem/diagnosis. this, again, may reflect the paucity of dermatological experience and expertise of registrars entering general practice and increasing confidence and comfort in addressing psoriasis with more experience. a large number of medications was prescribed by registrars for psoriasis. most were (appropriately) topical steroids and vitamin d analogues. this (together with the strong association of psoriasis problems/diagnoses with in-consultation assistance-seeking) suggests that, despite their lack of experience in this area, consultation with information sources and the gp registrars’ supervisor may facilitate appropriate treatment. implications for the management of psoriasis as a chronic disease this study found a strong association of consultations for psoriasis being for existing psoriasis. however, there were also strong associations of the patient being new to the practice, new to the registrar, and less follow-up appointments being organised. this suggests that these patients may have inconsistent provision of primary care for this problem. that is, there is low continuity of care (to some extent informational and management continuity but, especially, low interpersonal continuity) [31, 32]. this is contrary to findings of patients with chronic disease in general within this study population, where chronic disease is associated with greater continuity of care [33]. this is of considerable importance as psoriasis is a chronic disease with much associated morbidity (both psychosocial co-morbidity and high levels of co-morbid non-dermatological physical disease) [8, 9, 11, 15, 16]. one explanation for our finding is that psoriasis is being managed primarily by specialist dermatologists. even if this were the case, shared care with a generalist is essential given the physical and psychosocial co-morbidities of psoriasis. optimal generalist care, as for all chronic conditions, should include continuity of care. another interpretation is that the patients lack continuity of care with any clinician and that they do not receive coordinated care appropriate to their condition. this may be influenced by patients often not valuing gps’ expertise in skin disease (including psoriasis). a feeling that gps do not appreciate patients’ experience of skin disease has been reported [18]. further associations in our study may support this interpretation. we found a strong association with the prescription of medicines and specialist referral. an interpretation may be that many patients receive episodic care, often prompted by the need to renew psoriasis prescriptions and referrals,. they may be seeking a convenient prescriber performing a routine, discrete administrative task rather than a gp involved in ongoing, considered management of their chronic disease. possible sequelae of such a situation are different providers delivering uncoordinated medicine regimens that do not facilitate a logical progression of treatment based on response to past medications [34-36]. furthermore, holistic care of patients is likely to be compromised with a lack of addressing physical and psychosocial morbidities. lack of continuity of care will also compromise shared decision-making which has been advocated in the management of skin conditions in general [22] and in psoriasis management [37] in particular. in this context, our finding that when registrars do organise a follow-up appointment for psoriasis, it is usually with themselves (rather than another gp in the practice) should be noted. it may suggest that they appreciate the importance of, and are attempting to facilitate, interpersonal continuity of care for psoriasis. implications for education and training as we found evidence suggesting that registrars see little psoriasis in practice over the course of gp vocational training, targeted education and training in this area may be required. this could be addressed through structural changes within practice, appointment scheduling and policy regarding follow-up, along with concurrent patient education regarding the needs for continuity of care for management of their psoriasis, including shared decision-making and self-management [22]. conclusions we have identified educational and organisational aspects of registrar psoriasis management that could be optimised with changes at a registrar, practice and patient level. registrars see relatively little psoriasis in practice during vocational training, and evidence was found to suggest that registrars are finding psoriasis care challenging. this suggests opportunity for more education and training in this area. we also found evidence that psoriasis (a chronic disease with frequent comorbidity), despite registrars’ attempts, did not show the same pattern of continuity of care that is usually seen in optimal chronic disease management. references 1. liang y, sarkar mk, tsoi lc, gudjonsson je. psoriasis: a mixed autoimmune and autoinflammatory disease. curr opin immunol. 2017;49:1-8. doi: 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